Preparation of phenylethylamine and cathinone as well as stereoisomers and precursors of phenylethylamine and cathinone

Abstract

In one aspect, the invention provides a synthetic method of methyl ketone hydrochloride, and 3, 4-methylenedioxypropiophenone (MDP) is used as a starting material. In another aspect, the disclosure provides stereoisomers of methyl ketones. In another aspect, the present disclosure provides phenylethylamine or cathinone covalently bound to a chemical moiety in the form of a prodrug. The prodrug forms described herein allow for slow / sustained / controlled delivery of the parent phenylethylamine or cathinone into the blood system in a manner that increases the duration of therapeutic efficacy.

Description

Technical Field

[0001] The disclosed subject matter generally relates to phenethylamines and cathinones. The disclosed subject matter relates to methods for preparing the cathinone methylone and its stereoisomers, as well as compositions and uses thereof. The disclosed subject matter also relates to phenethylamines or cathinones covalently bound to a chemical moiety in prodrug form. The technology described in the present invention allows for the slow / continuous / controlled delivery of the parent phenethylamine or cathinone into the bloodstream when administered, particularly orally, in a manner that increases the duration of the therapeutic effect, ease of administration, patient compliance, and / or combinations of these characteristics. In addition, the technology allows for the gradual release of the parent phenethylamine or cathinone over an extended period of time, thereby eliminating sharp rises in drug levels and reducing cardiovascular stress, likelihood of addiction / abuse, and / or other common stimulant side effects associated with psychoactive compounds. Background Art

[0002] Methylone (3,4-methylenedioxy-N-methylcathinone) belongs to a group of psychoactive synthetic cathinones known as β-ketophenylamines. It is a synthetic MDMA analogue, differing in that there is a ketone at the benzyl position. Methylone was first synthesized in 1996 and is an illicit street drug. It induces psycho-stimulant and empathogenic effects similar to MDMA, and its mechanism of action involves the monoaminergic system.

[0003] MDMA (3,4-methylenedioxymethamphetamine), commonly known as ecstasy, is a psychoactive drug primarily used for recreational purposes. MDMA acts mainly by increasing the activity of the neurotransmitters serotonin, dopamine, and norepinephrine in a part of the brain. In 2017, the US Food and Drug Administration (FDA) approved a limited study of MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), and some preliminary evidence suggests that MDMA may enhance the effectiveness of psychotherapy.

[0004] Although structurally very similar to MDMA, methylone has different pharmacological and functional properties. In a clinical case series of 21 individuals, methylone showed improvement of PTSD symptoms in 81% of patients. Currently, the only treatments approved for PTSD are the serotonergic antidepressants sertraline and paroxetine, so drugs showing antidepressant-like activity should improve PTSD symptoms. Methylone may have the strongest effect in preclinical screening for classical antidepressant activity (forced swim test). Methylone also showed benefits in a mouse model of PTSD, improving fear extinction recall after conditioned fear, which is consistent with treatment response in this test. Together with the clinical case series results, these data strongly support the possibility of a clinically effective treatment for PTSD.

[0005] Users of methylone reported a rapid onset of 15 - 30 minutes and a short duration of 2 - 3.5 hours. In a prospective naturalistic observational study comparing self - administration of methylone and MDMA in healthy volunteers (Lourdes et al. (2021) Biology 10:788), a significant increase in both systolic and diastolic blood pressure was observed for both drugs, while only methylone was associated with an increase in heart rate. Subjects reported stimulant - like effects starting 1 hour after dosing, and most of these effects had almost disappeared 4 hours later.

[0006] Analysis of the parent and metabolites in human and rat urine samples showed that the metabolic pathways of methylone and MDMA are similar. They both undergo extensive biotransformation via cytochrome p450 isoform 2D6, which is consistent with their rapid kinetics and short duration of action. In a rat PK / PD study, methylone showed rapid kinetics, with a T Max of 15 minutes and a t 1 / 2 of 1 hour (Elmore et al. (2017) Neuropsychopharmacology 42:649). In the same study, it appeared that the methylone plasma concentration was associated with locomotor activation.

[0007] As an alternative to sustained - release formulations, prodrugs have been used to extend the duration of action and reduce the toxicity and / or side effects associated with an initial sharp rise in drug levels. Examples of such prodrugs can be found in US 7,105,486 and WO 2022 / 053696, in which the amino functional groups of d - amphetamine and MDMA are covalently linked to amino acids to form amide bonds. In the case of d - amphetamine, the resulting L - lysine - conjugated prodrug, known as lisdexamfetamine, showed a longer duration of action of 10 - 12 hours, compared to 3 - 6 hours for the unconjugated form of d - amphetamine. It was reported that the toxicity / tolerance of lisdexamfetamine was more favorable compared to the unconjugated form of d - amphetamine, which can be attributed to, but is not limited to, a significant reduction in the pharmacological activity of the prodrug due to structural modification, a natural gating mechanism at the hydrolysis site limiting the release of active amphetamine from the prodrug, and a lack of brain permeability of the prodrug.

[0008] Amino groups, such as those present in methylone or MDMA, can be derivatized into different conjugated prodrugs, characterized by the newly formed functional groups and their specific processes of converting to release the active drug. Examples of conjugated amine prodrugs, such as amide prodrugs, peptide or polypeptide prodrugs, carbamate prodrugs, acyloxyalkoxycarbonyl prodrugs, acyloxymethyl prodrugs, phosphoramide prodrugs, and phosphonyloxyalkyl prodrugs, can be found in Rautio et al. (2018) Nat.Rev.Drug Discov.17:559.

[0009] Accordingly, an object of the present invention is to provide a psychoactive agent that exhibits favorable pharmacokinetic and / or pharmacodynamic characteristics for the treatment of CNS disorders such as PTSD.

[0010] Another object of the present invention is to provide a psychoactive agent that exhibits favorable toxicity and / or tolerance characteristics for CNS disorders such as PTSD.

[0011] Another object of the present invention is to provide a phenethylamine prodrug (such as MDMA) or a cathinone prodrug (such as methylone) that can be hydrolyzed after absorption and directly converted into the parent compound in a therapeutically active form.

[0012] Another object of the present invention is to provide an improved method for synthesizing a psychoactive agent such as methylone.

[0013] Another object of the present invention is to provide stereoisomers of a psychoactive agent such as methylone.

[0014] Another object of the present invention is to provide a pharmaceutical composition of a psychoactive agent such as methylone. SUMMARY OF THE INVENTION

[0015] In one aspect, the present disclosure provides a method for synthesizing methylone HCl, comprising the steps of: (i) reacting 3,4-methylenedioxyphenylacetone (MDP) with copper(II) bromide and potassium bromide in toluene, and after completion of the reaction, removing the insoluble copper salts and soluble copper salts to obtain 2-bromo-3',4'-(methylenedioxy)phenylacetone (MDPBP); (ii) obtaining a solution of MDPBP in methyl isobutyl ketone (MIBK), and adding a 40% aqueous solution of methylamine to the MDPBP solution; and (iii) obtaining the organic layer from (ii), and adding HCl in isopropanol to the organic layer to obtain methylone HCl. In one embodiment, the method further comprises the steps of: obtaining a solution of methylone HCl in methanol, and adding isopropanol to the methylone HCl solution to obtain purified methylone HCl.

[0016] In another aspect, the present disclosure relates to pharmaceutical compositions comprising stereoisomers of the compounds described herein, such as stereoisomers of methyl ketones. In one embodiment, the pharmaceutical composition comprises substantially pure (R)-methyl ketone and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprises substantially pure (S)-methyl ketone and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition comprises (R)-methyl ketone in enantiomeric excess relative to the (S)-methyl ketone enantiomer and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprises (S)-methyl ketone in enantiomeric excess relative to the (R)-methyl ketone enantiomer and a pharmaceutically acceptable carrier. The present disclosure also provides a method of treating, for example, post-traumatic stress disorder (PTSD), anxiety disorders, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, acute stress disorder (ASD), cluster headache, conditions associated with cancer, hypokinesia, burn-out, bore-out, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea or vomiting in a mammal by administering an effective amount of a methyl ketone stereoisomer. The present disclosure also provides a method of treating, for example, mood disorders, anxiety disorders, personality disorders, fibromyalgia, suicidal ideation, substance use disorder (SUD), eating disorders, borderline personality disorder (BPD) and other personality disorders, obsessive-compulsive disorder (OCD), palliative care / hospice anxiety, existential distress, chronic pain syndromes, body dysmorphia, phobias, social anxiety in autistic adults and sleep regulation in a mammal by administering an effective amount of a methyl ketone stereoisomer.

[0017] In another aspect, the present disclosure relates to pharmaceutical compositions of the compounds described herein, such as methyl ketones, including pharmaceutically acceptable salts of methyl ketones and / or stereoisomers of methyl ketones, and / or isotopologues and isotopomers of methyl ketones, as well as polymorphs and other solid forms of any of the foregoing. In one embodiment, the methyl ketone pharmaceutical composition is a high-purity methyl ketone pharmaceutical composition. In one embodiment, the methyl ketone pharmaceutical composition is a methyl ketone composition that is stable at room temperature. In one embodiment, the methyl ketone pharmaceutical composition is non-mutagenic and free of mutagenic impurities. In one embodiment, the methyl ketone pharmaceutical composition is suitable for humans. In one embodiment, the methyl ketone pharmaceutical composition is a methyl ketone pharmaceutical composition on a commercial scale. The present disclosure also provides a method of treating, for example, post-traumatic stress disorder (PTSD), anxiety disorders, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, acute stress disorder (ASD), cluster headache, conditions associated with cancer, hypokinesia, burnout, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea or vomiting in a mammal by administering an effective amount of the methyl ketone pharmaceutical composition. The present disclosure also provides a method of treating, for example, mood disorders, anxiety disorders, personality disorders, fibromyalgia, suicidal ideation, substance use disorder (SUD), eating disorders, borderline personality disorder (BPD) and other personality disorders, obsessive-compulsive disorder (OCD), palliative / hospice anxiety, existential distress, chronic pain syndromes, body dysmorphia, phobias, social anxiety in autistic adults, and sleep regulation in a mammal by administering an effective amount of the methyl ketone pharmaceutical composition.

[0018] In another aspect, the present disclosure relates to compounds of phenethylamine or cathinone precursors in prodrug form. The present disclosure also provides a pharmaceutical composition comprising an effective amount of a phenethylamine or cathinone precursor and a pharmaceutically acceptable carrier. The present disclosure also provides a method of treating, in a mammal, for example, post-traumatic stress disorder (PTSD), anxiety disorders, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, acute stress disorder (ASD), cluster headache, conditions associated with cancer, hypomotility, burnout, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea or vomiting by administering an effective amount of a phenethylamine or cathinone precursor. The present disclosure also provides a method of treating, in a mammal, for example, mood disorders, anxiety disorders, personality disorders, fibromyalgia, suicidal ideation, substance use disorder (SUD), eating disorders, borderline personality disorder (BPD) and other personality disorders, obsessive-compulsive disorder (OCD), palliative care / hospice anxiety, existential distress, chronic pain syndromes, body dysmorphia, phobias, social anxiety in adults with autism and sleep regulation by administering an effective amount of a phenethylamine or cathinone precursor.

[0019] As shown in the drawings, the features and advantages of the subject matter of the present invention will become more apparent from the following detailed description of the selected embodiments. It should be recognized that the disclosed and claimed subject matter is capable of modification in various aspects, all of which do not depart from the scope of the claims. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive, and the full scope of the subject matter is set forth in the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The following drawings form a part of this specification and are included to further illustrate certain aspects of the present disclosure. The subject matter of the present invention can be better understood by reference to one or more of these drawings in conjunction with the detailed description of the specific embodiments presented herein.

[0021] Figures 1A - 1D : Methyl ketone improves fear extinction recall in a PTSD mouse model. ( Figure 1A ) Schematic of the experimental design. A single CS-US (tone-shock) pairing was performed on Day 1, followed by 6 CS presentations in a novel context (Context B). Thirty minutes before extinction training on Day 2, methyl ketone or saline vehicle was injected. On Day 3, the freezing time to the CS was quantified. ( Figure 1B ) Methyl ketone significantly reduced the freezing time during the first cue (extinction recall) on Day 3 compared to saline (t (26) = 2.350, p < 0.05). ( Figure 1C)Shows the immobility time relative to the period before each of the 6 cues on Day 3 (to control for motor effects). There was a significant cue x drug interaction (F (5,130) = 2.409, p < 0.05). ([[]]END]] Figure 1D )No motor changes were observed on Day 3 (t (26) = 1.073, p > 0.05). Methyl ketone group, N = 12 (30 mg / kg, IP, orange diamonds), and saline control group, N = 16 (black squares). *p < 0.05

[0022] Figure 2 : One methyl ketone enantiomer ((S)-methyl ketone) mimics the rapid and robust antidepressant-like activity of racemic methyl ketone in the forced swim test (FST) in rats. Thirty minutes before testing in the FST, a single dose of (R)-methyl ketone, (S)-methyl ketone, racemic methyl ketone (all 10 mg / kg, IP), or vehicle was administered. The immobility time during the test duration (5 min) is shown as the percentage of immobility time (e.g., 60% of 5 min = 3 min). ****p < 0.0001 compared to vehicle, N = 8 - 9 per group.

[0023] Figure 3 : Dynamic vapor sorption (DVS) results for TCL20422 (lot number 213220, a mixture of type B + type A), % weight change relative to % RH (upper figure) and weight relative to time (lower figure), showing that this material does not absorb or desorb water. Detailed Description

[0024] In one aspect, the present disclosure provides a method for synthesizing methylone hydrochloride, which comprises the following steps: (i) reacting 3,4-methylenedioxyphenylpropanone (MDP) with copper(II) bromide and potassium bromide in toluene, and after completion of the reaction, removing insoluble copper salts and soluble copper salts to obtain 2-bromo-3',4'-(methylenedioxy)phenylpropanone (MDPBP); (ii) obtaining a solution of MDPBP in methyl isobutyl ketone (MIBK), and adding 40% aqueous methylamine solution to the MDPBP solution; and (iii) obtaining an organic layer from (ii), and adding an isopropanol solution of HCl to the organic layer to obtain methylone hydrochloride. In one embodiment, the reaction in step (i) is carried out at 85 - 95 °C. In one embodiment, the insoluble copper salts are removed by filtration through diatomaceous earth. In one embodiment, the soluble copper salts are removed by washing with ammonium hydroxide. In one embodiment, in step (ii), the solution containing MDPBP and methylamine is mixed at 30 °C. In one embodiment, in step (iii), the isopropanol solution containing HCl is added to the organic layer at a temperature below 10 °C, such as at a temperature of 0 - 10 °C.

[0025] In one embodiment, the method further comprises the following steps: obtaining a methanol solution of methylone hydrochloride, and adding isopropanol to the methylone hydrochloride solution to obtain purified methylone hydrochloride. In one embodiment, the solution containing methylone hydrochloride and isopropanol is heated to reflux at 65 °C. In one embodiment, the solution containing methylone hydrochloride and isopropanol is maintained at 0 - 10 °C after being heated to reflux at 65 °C. In one embodiment, the purified methylone hydrochloride is obtained by drying under reduced pressure at 60 °C.

[0026] In another aspect, the present disclosure relates to a pharmaceutical composition comprising stereoisomers of the compounds described herein (such as stereoisomers of methylone). In one embodiment, the pharmaceutical composition comprises substantially pure (R)-methylone and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprises substantially pure (S)-methylone and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition comprises (R)-methylone in enantiomeric excess relative to the (S)-methylone enantiomer and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprises (S)-methylone in enantiomeric excess relative to the (R)-methylone enantiomer and a pharmaceutically acceptable carrier.

[0027] In other aspects, the present disclosure provides phenethylamine or cathinone prodrugs that exhibit favorable pharmacokinetic properties and beneficial side effect profiles, making the compounds provided herein particularly suitable for therapeutic use.

[0028] In one embodiment, provided herein is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0029]

[0030] Wherein:

[0031] Y is -C(O)- or -CH2-;

[0032] X is independently selected from the group consisting of:

[0033] (a) an amino acid or a peptide,

[0034] (b) -C(O)R 3 ,

[0035] (c) -C(O)OR 3 ,

[0036] (d) -C(O)OCH(R 4 )OR 5 ,

[0037] (e) -CH2OC(O)R 3 ,

[0038] (f) -P(O)(OH)2,

[0039] (g) -CH2OP(O)(OH)2,

[0040] (h) -C(O)(CH2) n Z a R 5 ,

[0041] (i)

[0042] (j)

[0043] (k) And

[0044] (l)

[0045] Wherein:

[0046] n is 3 or 4;

[0047] R 1 and R 2 are each independently -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0048] R 3 is selected from the group consisting of: -C 1-6alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0049] R 4 、R 7 、R 8 、R 9 and R 10 are each independently H, -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0050] R 5 is selected from the group consisting of: -C(O)R 3 、-C(O)OR 3 、-P(O)OR 11 (OR 12 )、amino acids, and peptides;

[0051] Z a and Z b are each independently O or NR 4 ;

[0052] Z c is selected from: OC(O)R 3 or OP(O)(OR 4 )2;

[0053] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH, and CF3;

[0054] R 11 and R 12 are each independently H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, or heteroaryl.

[0055] In some embodiments of the foregoing compounds, R 1and R 2 are each independently methyl or ethyl. In some embodiments, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12 are each independently H or methyl. In some embodiments, R 10 is methyl. In some embodiments, when Y is -CH2-, X is not an amino acid, a peptide or a -P(O)(OH)2 group.

[0056] According to another embodiment, the compound of formula (I) is a compound having the structure of formula (III) or a pharmaceutically acceptable salt thereof:

[0057]

[0058] wherein:

[0059] X is independently selected from the group consisting of:

[0060] (a) an amino acid or a peptide,

[0061] (b) -C(O)R 3 ,

[0062] (c) -C(O)OR 3 ,

[0063] (d) -C(O)OCH(R 4 )OR 5 ,

[0064] (e) -CH2OC(O)R 3 ,

[0065] (f) -P(O)(OH)2,

[0066] (g) -CH2OP(O)(OH)2,

[0067] (h) -C(O)(CH2) n Z a R 5 ,

[0068] (i)

[0069] (j)

[0070] (k) and

[0071] (l)

[0072] wherein:

[0073] n is 3 or 4;

[0074] R 1 and R 2 are each independently -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0075] R 3 is selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0076] R 4 , R 7 , R 8 , R 9 and R 10 are each independently H, -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0077] R 5 is selected from the group consisting of: -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 )2, amino acids and peptides;

[0078] Z a and Z b are each independently O or NR 4 ;

[0079] Z c is selected from: OC(O)R 3 or OP(O)(OR 4 )2;

[0080] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF3;

[0081] R 11 and R 12 are each independently H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

[0082] In some embodiments of the foregoing compounds, R 1 and R 2 are each independently methyl or ethyl. In some embodiments, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12 are each independently H or methyl. In some embodiments, R 10 is methyl. In some embodiments, X is an amino acid. In some embodiments, the compound is selected from the group consisting of Compounds 1 - 402 of Tables 1, 2 and 3 below.

[0083] According to some embodiments, the compound of formula (I) is a compound having the structure of formula (IV) or a pharmaceutically acceptable salt thereof:

[0084]

[0085] Wherein:

[0086] X is independently selected from the group consisting of:

[0087] (a) -C(O)R3 ,

[0088] (b) -C(O)OR 3 ,

[0089] (c) -C(O)OCH(R 4 )OR 5 ,

[0090] (d) -CH2OC(O)R 3 ,

[0091] (e) -CH2OP(O)(OH)2,

[0092] (f) -C(O)(CH2) n Z a R 5 ,

[0093] (g)

[0094] (h)

[0095] (i) and

[0096] (j)

[0097] wherein:

[0098] n is 3 or 4;

[0099] R 1 and R 2 are each independently -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0100] R 3 is selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0101] R 4 、R 7 、R 8 、R 9 and R 10 are each independently H, -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0102] R 5 is selected from the group consisting of: -C(O)R 3 、-C(O)OR 3, -P(O)OR 11 (OR 12 ), amino acids and peptides;

[0103] Z a and Z b are each independently O or NR 4 ;

[0104] Z c is selected from: OC(O)R 3 or OP(O)(OR 4 )2;

[0105] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF3;

[0106] R 11 and R 12 are each independently H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted by one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl.

[0107] In some embodiments of the foregoing compounds, R 1 and R 2 are each independently methyl or ethyl. In some embodiments, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11and R 12 Each independently is H or methyl. In some embodiments, R 10 is methyl.

[0108] According to some embodiments, the compound of formula (I) is a compound having the structure of formula (V) or a pharmaceutically acceptable salt thereof:

[0109]

[0110] Wherein:

[0111] X is independently selected from the group consisting of:

[0112] (a) an amino acid or a peptide,

[0113] (b) -C(O)R 3 ,

[0114] (c) -C(O)OR 3 ,

[0115] (d) -C(O)OCH(R 4 )OR 5 ,

[0116] (e) -CH2OC(O)R 3 ,

[0117] (f) -P(O)(OH)2,

[0118] (g) -CH2OP(O)(OH)2,

[0119] (h) -C(O)(CH2) n Z a R 5 ,

[0120] (i)

[0121] (j)

[0122] (k) and

[0123] (l)

[0124] Wherein:

[0125] n is 3 or 4;

[0126] R 3 is selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0127] R 4 , R 7 , R 8 , R 9 and R 10 Each independently is H, -C 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0128] R 5 Selected from the group consisting of: -C(O)R 3 、-C(O)OR 3 、-P(O)OR 11 (OR 12 ), amino acids and peptides;

[0129] Z a and Z b Each independently is O or NR 4 ;

[0130] Z c Selected from: OC(O)R 3 OR OP(O)(OR 4 )2;

[0131] R 6 Selected from the group consisting of: H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF3;

[0132] R 11 and R 12 Each independently is H, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 A haloalkyl, aryl or heteroaryl group, wherein -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 A haloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 3-6 Cycloalkyl, -C 1-6 Substituted with haloalkyl, aryl or heteroaryl.

[0133] In some embodiments of the aforementioned compounds, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Zb is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro, or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12 are each independently H or methyl. In some embodiments, R 10 is methyl. In some embodiments, X is an amino acid.

[0134] According to some embodiments, the compound of formula (I) is a compound having the structure of formula (VI) or a pharmaceutically acceptable salt thereof:

[0135]

[0136] Wherein:

[0137] X is independently selected from the group consisting of:

[0138] (a) -C(O)R 3 ,

[0139] (b) -C(O)OR 3 ,

[0140] (c) -C(O)OCH(R 4 )OR 5 ,

[0141] (d) -CH2OC(O)R 3 ,

[0142] (e) -CH2OP(O)(OH)2,

[0143] (f) -C(O)(CH2) n Z a R 5 ,

[0144] (g)

[0145] (h)

[0146] (i) and

[0147] (j)

[0148] Wherein:

[0149] n is 3 or 4;

[0150] R 3 is selected from the group consisting of: -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl, heteroaryl,

[0151] R 4 , R 7 , R 8 , R 9 and R 10 are each independently H, -C 1-6 alkyl or -C 3-6 cycloalkyl;

[0152] R 5 is selected from the group consisting of: -C(O)R 3 , -C(O)OR 3 , -P(O)OR 11 (OR 12 ), amino acids and peptides;

[0153] Z a and Z b are each independently O or NR 4 ;

[0154] Z c is selected from: OC(O)R 3 or OP(O)(OR 4 )2;

[0155] R 6 is selected from the group consisting of: H, -C 1-6 alkyl, -C 3-6 cycloalkyl, alkoxy, amino, nitro, halo, cyano, -OH and CF3;

[0156] R 11 and R 12 are each independently H, -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl, wherein -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6 cycloalkyl, -C 1-6 haloalkyl, aryl or heteroaryl is unsubstituted or substituted with one or more -C 1-6 alkyl, -C 1-6 heteroalkyl, -C 3-6Cycloalkyl, -C 1-6 substituted with haloalkyl, aryl or heteroaryl.

[0157] In some embodiments, R 4 is H or methyl. In some embodiments, Z a is NH. In some embodiments, Z b is O or NH. In some embodiments, Z b R 5 together are NO2 or N3. In some embodiments, R 6 is H, methyl, methoxy, nitro or chloro. In some embodiments, R 7 is methyl. In some embodiments, R 8 , R 9 , R 10 , R 11 and R 12 are each independently H or methyl. In some embodiments, R 10 is methyl. In some embodiments, the compound is selected from the group consisting of Compounds 403 - 511 of Table 4 below.

[0158] For some embodiments of the foregoing compounds, the amino acid, dipeptide, tripeptide or polypeptide may comprise one or more of the naturally occurring (L-) amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, phenylalanine, serine, tryptophan, threonine, tyrosine and valine.

[0159] Without being bound by theory, prodrugs of cathinone (such as methyl ketones) or prodrugs of phenethylamine (such as MDMA) are thought to act as a system for the controlled systemic release of the main active ingredient of the parent molecule through in vivo bioactivation. This bioactivation can be achieved by enzymatic or chemical cleavage of a covalently bound promoiety, or by a combination of enzymatic and chemical cleavage of a covalently bound promoiety.

[0160] As used herein, "alkyl" and other groups having the prefix "alk" (such as alkoxy, alkanoyl, alkenyl, alkynyl, etc.) refer to a carbon chain which may be straight-chain, branched-chain or a combination thereof. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, etc. "Alkenyl", "alkynyl" and other similar terms include carbon chains containing at least one unsaturated C-C bond.

[0161] The term "haloalkyl" refers to an alkyl group to which 1 to 9 halo groups are attached. Examples include -CH2F, -CHF2, -CF3, -CH2CH2F, -CHFCH2F, -CF2CH2F, -CF2CHF2, and -CF2CF3.

[0162] The term "cycloalkyl" means a carbocyclic ring that does not contain a heteroatom and includes monocyclic, bicyclic, and tricyclic saturated carbocyclic rings, as well as fused ring systems. Such fused ring systems can include a ring that is partially or fully unsaturated (such as a benzene ring) to form a fused ring system (such as a benzo-fused carbocyclic ring). Cycloalkyl includes fused ring systems such as spiro-fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl, adamantyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthyl, and the like. Similarly, "cycloalkenyl" means a carbocyclic ring that does not contain a heteroatom and contains at least one non-aromatic C-C double bond, and includes monocyclic, bicyclic, and tricyclic partially saturated carbocyclic rings, as well as benzo-fused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

[0163] Unless otherwise specifically stated, the term "cycloalkoxy" includes a cycloalkyl group attached to an oxygen-bonded atom.

[0164] Unless otherwise specifically stated, the term "alkoxy" includes an alkyl group attached to an oxygen-bonded atom.

[0165] Unless otherwise specifically stated, the term "aryl" includes polycyclic systems as well as monocyclic systems such as phenyl or naphthyl.

[0166] Unless otherwise specifically stated, the term "aryloxy" includes polycyclic systems as well as monocyclic systems such as phenyl or naphthyl attached to a linkage site through an oxygen-bonded atom.

[0167] The term "C0-C6 alkyl" includes alkyl groups containing 6, 5, 4, 3, 2, 1 carbon atoms or no carbon atoms. When the alkyl is a terminal moiety, the alkyl with no carbon atoms is a hydrogen atom substituent. When the alkyl is a bridging moiety, the alkyl with no carbon atoms is a direct bond.

[0168] Unless otherwise specifically stated, the term "hetero" includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems containing one or more O, S, or N atoms (including mixtures of these atoms) in the ring. The heteroatoms replace ring carbon atoms. Thus, for example, C5 heterocycloalkyl is a five-membered ring containing from 5 carbon atoms to no carbon atoms. Examples of heteroaryl include pyridyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

[0169] Unless otherwise specifically stated, the term "heteroaryloxy" describes a heteroaryl group attached to a point of attachment through an oxygen atom linker. Examples of heteroaryl(C 1-6 )alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazoylethyl, isoxazolylmethyl, thiazolylmethyl, thiazoylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazoylethyl, thiadiazolylmethyl, thiadiazoylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazoylethyl, pyridylmethyl, pyridylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl, and quinoxalinylmethyl. C 3-7 Examples of heterocycloalkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl, tetrahydrofuryl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

[0170] The term "N-heterocyclo C 4-7 alkyl" describes a non-aromatic heterocyclic compound having 3 - 6 carbon atoms and one ring-forming nitrogen atom. Examples include azetidinyl, pyrrolidinyl, piperidinyl, and perhydroazepinyl. Examples of aryl(C 1-6 )alkyl include, for example, phenyl(C 1-6 )alkyl and naphthyl(C 1-6 )alkyl. C 3-6 Examples of heterocycloalkylcarbonyl(C 1-6 )alkyl include, for example, azetidinylcarbonyl(C 1-6 )alkyl, pyrrolidinylcarbonyl(C 1-6 )alkyl, piperidinylcarbonyl(C 1-6 )alkyl, piperazinylcarbonyl(C 1-6 )alkyl, morpholinylcarbonyl(C 1-6 )alkyl, and thiomorpholinylcarbonyl(C 1-6 )alkyl.

[0171] Unless otherwise specifically stated, "amine" includes primary, secondary, and tertiary amines.

[0172] Unless otherwise stated, the term "carbamoyl" includes -ΝHC(O)OC1-C4 alkyl and -OC(O)NHC1-C4 alkyl.

[0173] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms.

[0174] The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl can represent pentafluorophenyl or phenyl ring. Additionally, substitution can occur at any group. For example, substituted aryl(C 1-6 )alkyl includes substitution on the aryl as well as substitution on the alkyl.

[0175] The "oxide" of the term heteroaryl is used in the well-known chemical sense and includes, for example, N-oxides of nitrogen atoms.

[0176] The term "polymorph" refers to different crystalline forms of the same compound, drug substance, or active ingredient; these can include solvates or hydrates (also known as pseudopolymorphs) and amorphous forms.

[0177] The compounds described herein contain one or more double bonds and can therefore give rise to cis / trans isomers as well as other conformational isomers. The present invention includes all such possible isomers and mixtures of such isomers.

[0178] The compounds described herein can contain one or more asymmetric centers and can therefore give rise to diastereoisomers and optical isomers. The present invention includes all such possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. The above formula (I) is shown with no defined stereochemistry at certain positions. The present invention includes all stereoisomers of formula (I) and their pharmaceutically acceptable salts. Additionally, mixtures of stereoisomers and isolated specific stereoisomers are also included.

[0179] During the synthetic processes used to prepare such compounds, or in racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be mixtures of stereoisomers.

[0180] In one aspect, the present invention provides a concise route for preparing methyl ketone enantiomers. The method of the present invention can obtain substantially pure methyl ketone enantiomers. For the (S)-methyl ketone, "substantially pure" means that the compound (S)-methyl ketone is at least substantially separated from the environment in which it is formed or detected. Substantial purity can include a composition containing at least about 80.0%, or at least about 85.0%, or at least about 90.0%, or at least about 95.0%, or at least about 97.0%, or at least about 98.0%, or at least about 99.0%, or at least about 99.2%, or at least about 99.4%, or at least about 99.6%, or at least about 99.8%, or at least about 99.9% or even about 100% of the compound. For the (R)-methyl ketone, "substantially pure" means that the compound (R)-methyl ketone is at least substantially separated from the environment in which it is formed or detected. Substantial purity can include a composition containing at least about 80.0%, or at least about 85.0%, or at least about 90.0%, or at least about 95.0%, or at least about 97.0%, or at least about 98.0%, or at least about 99.0%, or at least about 99.2%, or at least about 99.4%, or at least about 99.6%, or at least about 99.8%, or at least about 99.9% or even about 100% of the compound.

[0181] Embodiments of the present invention also include compositions containing the (S)-methyl ketone. Preferably, these compositions are pharmaceutical compositions comprising the (S)-methyl ketone and at least one pharmaceutically acceptable excipient. In some embodiments, the compositions and pharmaceutical compositions can be prepared with substantially pure (S)-methyl ketone. In some embodiments, the enantiomeric excess (ee) of the compositions and pharmaceutical compositions is at least 90% ee, preferably at least 95% ee, more preferably at least 98% ee, and even more preferably at least 99% ee, and most preferably about 100% ee. The compositions and pharmaceutical compositions can also be prepared as mixtures of the enantiomeric forms of the compound (e.g., a racemic mixture, or a mixture in which the ratio of (S)-methyl ketone to (R)-methyl ketone is 60:40, 70:30, 80:20, or 90:10).

[0182] Embodiments of the invention also include compositions containing (R)-methyl ketone. Preferably, these compositions are pharmaceutical compositions comprising (R)-methyl ketone and at least one pharmaceutically acceptable excipient. In some embodiments, the compositions and pharmaceutical compositions can be prepared with substantially pure (R)-methyl ketone. In some embodiments, the enantiomeric excess (EE) of the compositions and pharmaceutical compositions is at least 90% EE, preferably at least 95% EE, more preferably at least 98% EE, and even more preferably at least 99% EE, and most preferably about 100% EE. The compositions and pharmaceutical compositions can also be prepared as mixtures of the enantiomeric forms of the compound (e.g., a racemic mixture, or a mixture in which the ratio of (R)-methyl ketone to (S)-methyl ketone is 60:40, 70:30, 80:20, or 90:10).

[0183] In another aspect, the present invention provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof described herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a salt of the compound described herein.

[0184] A "pharmaceutical composition" is a formulation containing a compound in a form suitable for administration to a subject. As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0185] A "pharmaceutically acceptable excipient" means an excipient that can be used in the preparation of a pharmaceutical composition, which is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary as well as human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes one and more than one such excipient.

[0186] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids or co-crystal formers. The crystalline forms can exist as salts, solvates, hydrates or inclusion compounds. When the compounds of the present invention are acidic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases (including inorganic and organic bases). Salts derived from such inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts (cupric and cuprous salts), iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts (manganic and manganous salts), potassium salts, sodium salts, zinc salts, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines (such as naturally occurring and synthetically substituted amines). Other pharmaceutically acceptable organic non-toxic bases or co-crystal formers that can form salts or co-crystals include ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosaminoglycan, histidine, hydrabamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0187] When the compounds of the present invention are basic, their corresponding salts or co-crystals can be conveniently prepared from pharmaceutically acceptable non-toxic acids (including inorganic and organic acids). Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Particularly preferred are benzenesulfonic acid, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

[0188] According to some embodiments, a pharmaceutical composition can be prepared comprising a compound represented by formula (I) (or a pharmaceutically acceptable salt or co-crystal thereof) as an active ingredient and a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.

[0189] According to another embodiment, the pharmaceutical composition of the present invention can comprise a pharmaceutically acceptable carrier / excipient, a compound of formula (I) or a pharmaceutically acceptable salt / co-crystal, and the corresponding parent psychoactive agent of the compound of formula (I).

[0190] Dose levels of from about 0.0001 mg to about 100 mg per kilogram of body weight per day may be useful in treating the following conditions, such as: post-traumatic stress disorder (PTSD), anxiety disorders, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, acute stress disorder (ASD), cluster headache, conditions associated with cancer, hypomotility, fatigue, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea or vomiting. By administering an effective amount of a phenethylamine or cathinone precursor, dose levels of from about 0.0001 mg to about 100 mg per kilogram of body weight per day may be useful in treating the following conditions, such as: mood disorders, anxiety disorders, personality disorders, fibromyalgia, suicidal ideation, substance use disorder (SUD), eating disorders, borderline personality disorder (BPD) and other personality disorders, obsessive-compulsive disorder (OCD), palliative / hospice anxiety, existential distress, chronic pain syndromes, body dysmorphia, phobias, social anxiety in adults with autism and sleep regulation.

[0191] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the target being treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, formulated with a suitable and acceptable amount of "GRAS" material, which may vary from about 5% to about 95% of the total composition. Unit dosage forms will generally contain an active ingredient between about 0.001 mg and about 5000 mg, typically 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 5.0 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 3000 mg, 5000 mg or any dose in between.

[0192] Suitable pharmaceutical compositions as described herein include those containing an effective amount of an active ingredient to achieve its intended purpose. Determination of the effective amount is entirely within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the present disclosure are effective over a wide range of doses. However, it is understood that the specific dose level for any particular patient will depend on a variety of factors, including age, weight, general health, gender, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease being treated.

[0193] The composition, shape, and type of the dosage forms provided herein will generally vary according to their use. For example, a dosage form used in the acute treatment of a disease may contain a greater amount of one or more active ingredients including those of formula (I) than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain a lesser amount of one or more active ingredients including those of formula (I) than an oral dosage form used to treat the same disease. These and other ways in which the specific dosage forms provided herein differ from one another will be readily understood by those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing, Easton, Pa (2000). In practice, the compounds represented by formula (I) or their pharmaceutically acceptable salts / cocrystal combinations of the present disclosure can be combined with drug excipients, carriers, or diluents as the active ingredient in an essential mixture according to conventional pharmaceutical compounding techniques. The carrier can take various forms depending on the form of the preparation required for administration, such as oral, mucosal (e.g., nasal, sublingual, vaginal, inhalation, cystic, rectal, ophthalmic, buccal, or otic), parenteral (including intravenous, intradermal, subcutaneous, bolus, intramuscular, or intraarterial), or topical (e.g., transdermal, percutaneous, eye drops, or other ophthalmic preparations). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration, such as capsules (with or without polymer coatings, sustained release or enteric coated or modified for targeted delivery), sachets, or tablets (coated or uncoated or bilayer or sustained release or delayed release, including microencapsulated) or tablets containing spray-dried intermediates, each containing a predetermined amount of the active ingredient. In addition, the compositions can be presented as powders, granules, coated sustained release granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, water-in-oil emulsions, or oil-in-water liquid emulsions, liposomes, nano-suspensions. In addition to the above common dosage forms, the compounds represented by formula (I) or their pharmaceutically acceptable salts or cocrystals can also be administered by controlled release or modified release formulations and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Generally speaking, such methods include the step of combining the active ingredient with excipients or carriers that constitute one or more essential ingredients. Generally, the compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier / excipient or a subdivided solid carrier / excipient or both. The product can then be conveniently shaped into the desired appearance.

[0194] In some embodiments, the amount or dose of the active ingredient provided herein ranges from 5 - 250 mg. In some embodiments, the amount or dose of the active ingredient provided herein is less than 50 mg. In some embodiments, the amount or dose of the active ingredient provided herein ranges from 5 - 50 mg. In some embodiments, the amount or dose of the active ingredient provided herein is less than 25 mg. In some embodiments, the amount or dose of the active ingredient provided herein ranges from 5 - 25 mg. In some embodiments, the amount or dose of the active ingredient provided herein ranges from 50 - 350 mg. In some embodiments, the amount or dose of the active ingredient provided herein ranges from 50 - 500 mg. In some embodiments, the amount or dose of the active ingredient provided herein ranges from 5 - 1,000 mg.

[0195] In some embodiments, the amount or dose of the active ingredient provided herein can range from about 1 mg to about 100 mg. For example, the amount or dose of the active ingredient administered can be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some embodiments, the amount or dose of the active ingredient provided herein is between about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 30 mg. In some embodiments, the amount or dose of the active ingredient provided herein is about 1 mg, about 10 mg, or about 25 mg. In some embodiments, the amount or dose of the active ingredient provided herein ranges from about 0.001 mg to about 1 g. In some embodiments, the amount or dose of the active ingredient provided herein ranges from about 100 mg to about 250 mg. In some embodiments, the amount or dose of the active ingredient provided herein is about 25 mg.

[0196] In some embodiments, the active ingredient provided herein is administered daily. In some embodiments, the active ingredient is administered twice a day. In some embodiments, the active ingredient is administered three times a day. In some embodiments, the active ingredient is administered every other day. In some embodiments, the active ingredient is administered every three days. In some embodiments, the active ingredient is administered every four days. In some embodiments, the active ingredient is administered every five days. In some embodiments, the active ingredient is administered weekly. In some embodiments, the active ingredient is administered every other week. In some embodiments, the active ingredient is administered every three weeks. In some embodiments, the active ingredient is administered monthly.

[0197] Accordingly, the pharmaceutical compositions of the present disclosure may comprise a pharmaceutically acceptable carrier / excipient and a compound of formula (I) or a pharmaceutically acceptable salt / cocrystal. The compound of formula (I) or a pharmaceutically acceptable salt / cocrystal thereof may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0198] The pharmaceutical carriers employed may, for example, form oral solid dosage forms such as powders, capsules, and tablets, including fillers such as talc, calcium carbonate, microcrystalline cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, and mixtures thereof. Binders such as Kollidon. Disintegrants such as sodium carboxymethylcellulose crosslinked, crospovidone, sodium starch glycolate, pregelatinized starch, gums, and other starches and mixtures thereof. Lubricants such as calcium stearate, magnesium stearate, syloid silica gel, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (such as peanut oil, sesame oil, corn oil, or soybean oil), ethyl oleate agar, or other lipid formulated lubricants and mixtures thereof. Tablets and capsules are preferred oral dosage units employing solid pharmaceutical carriers due to ease of administration. Each solid oral dosage unit may further be coated with a specialized polymer so as to effect delayed release or sustained release of the contents of the dosage unit. The compound of formula (I) may be administered by delayed release or sustained release means or by delivery devices well known to those of ordinary skill in the art. Non-limiting examples of delayed release or sustained release include those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 5,059,595. Such dosage forms may be used to effect slow release or controlled release of one or more ingredients, for example, using polymers such as hydroxypropylmethylcellulose, which are typically in matrix form such as gels, osmotic membranes, microemulsions, osmotic systems, liposomes, microspheres, or combinations thereof. Controlled release formulations may be used to protect the dosage unit from exposure to the gastric environment; delay the release of the active ingredient to the lower gastrointestinal tract (such as the colon); or slow the release of the active ingredient such that the blood level of the drug may be reduced and the occurrence of side effects may be affected.

[0199] Examples of gaseous carriers include carbon dioxide and nitrogen.

[0200] In preparing oral liquid compositions for oral dosage forms, any convenient pharmaceutical medium may be employed. For example, water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. may be used to form oral liquid dosage forms such as suspensions, elixirs, and solutions.

[0201] Tablets containing the compositions of the present disclosure may be prepared by compressing or molding them, optionally with one or more accessory ingredients or adjuvants.

[0202] Compressed tablets can be prepared by compressing an active ingredient in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. Each tablet preferably contains from about 0.001 mg to about 5000 mg of active ingredient, and each cachet or capsule preferably contains from about 0.001 mg to about 5000 mg of active ingredient.

[0203] The pharmaceutical compositions of the present disclosure suitable for parenteral administration (including intravenous, intramuscular, subcutaneous, ophthalmic and intra-arterial) can be prepared as solutions or suspensions of the active compound in injectable ingredients. Parenteral dosage forms are preferably sterile or capable of being sterilized before administration to a patient. Non-limiting examples of suitable vehicles include Water for Injection USP, Dextrose Injection, Sodium Chloride Injection and Lactated Ringer's Injection. Suitable surfactants, such as polysorbate 80, can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, ethanol, propylene glycol and mixtures thereof in non-aqueous vehicles such as oils (e.g., corn oil, sesame oil, isopropyl myristate). Antioxidants, such as ascorbic acid or ascorbyl palmitate, which help to stabilize the formulation. In addition, preservatives can be included to prevent the deleterious growth of microorganisms.

[0204] In addition, the composition can be in the form of a sterile powder for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile, non-irritating, isotonic, and must be an effective fluid suitable for easy injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; thus, preservatives are preferably included to prevent the contaminating action of microorganisms such as bacteria and fungi, for example, benzalkonium chloride, chlorobutanol, methylparaben, propylparaben, disodium edetate, sorbic acid, or other agents known to those skilled in the art. The pharmaceutical compositions of the present disclosure can be in forms suitable for topical application to the skin and its appendages or various mucous membranes, such as aerosols, patches, creams, ointments, emulsions, dusting powders, lotions, etc. Routes that can be used include nasal, sublingual, vaginal, rectal, ophthalmic, buccal, or otic. In addition, the composition can be in a form suitable for transdermal or intradermal microneedle devices. These formulations can be prepared using conventional processing methods with the compounds of formula (I) or their pharmaceutically acceptable salts of the present disclosure. For example, creams, emulsions, or ointments are prepared by mixing hydrophilic materials and water with about 5 wt% to about 30 wt% of the compound to produce a cream, emulsion, or ointment having the desired consistency. Examples of typical excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, isopropyl myristate, mineral oil, and mixtures thereof. If desired, humectants (such as occlusives, moisturizers, emollients) can also be added to the pharmaceutical composition and dosage form. The pH of the pharmaceutical composition or dosage form can also be adjusted to improve the delivery of formula (I). Dosage forms suitable for treating oral mucosal tissue can be formulated as mouthwashes or oral gels.

[0205] The pharmaceutical compositions of the present disclosure can be in forms suitable for rectal administration, wherein the carrier is solid or liquid or a spray. Preferably, the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with the softened or melted carrier, then cooling and molding in a mold.

[0206] In addition to the aforementioned carrier components, the pharmaceutical formulations described above may, where appropriate, include one or more other carrier components such as diluents, buffers, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or a liquid concentrate. The addition of preservatives such as preservatives is widely accepted in the pharmaceutical field as a means of simulating long-term storage to determine characteristics such as shelf life or the stability of the formulation over time (see, for example, Jens T. Carstensen, Drug stability: Principles & Practice. 2nd Edition, Marcel Dekker, NY, NY. 1995, pages 379-80).

[0207] All diseases, conditions, and disorders listed herein are defined as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization (WHO).

[0208] The term "ICH Q3A" refers to the guidelines and standards described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (2006) Impurities in new drug substances: Q3A(R2), which can be obtained at www.ema.europa.eu / en / ich-q3a-r2-impurities-new-drug-substances-scientific-guideline. The term "ICH Q3B" refers to the guidelines and standards described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (2006) Impurities in new drug products: Q3B(R2), which can be obtained at www.ema.europa.eu / en / ich-q3b-r2-impurities-new-drug-products-scientific-guideline. The term "ICH Q3C" refers to the guidelines and standards described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (2021) Impurities: guideline for residual solvents: ICH Q3C(R8). The term "ICH Q3D" refers to the guidelines and standards described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (2019) Guideline for elemental impurities: ICH Q3D(R1).

[0209] As used herein, the terms "reduce", "lower", "mitigate" and similar terms mean a reduction of at least about 10%, about 15%, about 20%, about 25%, about 35%, about 50%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97% or more.

[0210] As used herein, the terms "improve", "increase", "enhance" and similar terms indicate an increase of at least about 10%, about 15%, about 20%, about 25%, about 50%, about 75%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500% or more.

[0211] In one embodiment, a variety of other therapeutic agents can be used for administration in combination with the compositions and methods provided herein.

[0212] On the other hand, the present disclosure provides methods for treating and / or preventing a disease or condition (such as a neuropsychiatric disorder) and / or improving the symptoms of a subject in need thereof, which comprise administering to the subject an effective amount of a compound provided herein. In some embodiments, the disease or condition is selected from post-traumatic stress disorder (PTSD), anxiety disorder, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, acute stress disorder (ASD), cluster headache, conditions associated with cancer, hypokinesia, burnout, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorder, nausea or vomiting. In some embodiments, by administering an effective amount of a phenethylamine or cathinone precursor, the disease or condition is selected from mood disorder, anxiety disorder, personality disorder, fibromyalgia, suicidal ideation, substance use disorder (SUD), eating disorder, borderline personality disorder (BPD) and other personality disorders, obsessive-compulsive disorder (OCD), palliative care / hospice anxiety, existential distress, chronic pain syndrome, body dysmorphia, phobia, social anxiety in adults with autism and sleep regulation. In some embodiments, the disease or condition is PTSD. In some embodiments, the disease or condition is anxiety disorder. In some embodiments, the disease or condition is depression. In some embodiments, the neuropsychiatric disorder is major depressive disorder. In some embodiments, major depressive disorder is selected from the group consisting of disruptive mood dysregulation disorder, single and recurrent episodes of major depressive disorder, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / drug-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, and combinations thereof. In some embodiments, the neuropsychiatric disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neuropsychiatric disorder is acute stress disorder. In some embodiments, the neuropsychiatric disorder is fibromyalgia. In some embodiments, the neuropsychiatric disorder is mood disorder. In some embodiments, the neuropsychiatric disorder is anxiety disorder.In some embodiments, the anxiety disorder is selected from the group consisting of: generalized anxiety disorder, panic disorder, panic attack, phobic anxiety disorder, illness anxiety disorder, dissociative, stress-related, other non-psychotic mental disorders of a somatic form, acute stress reaction, brief adjustment reaction, neurasthenia, psychophysiological disorder, obsessive-compulsive disorder, reaction to severe stress and adjustment disorder, separation anxiety disorder, episodic paroxysmal anxiety, selective mutism, specific phobia, social anxiety disorder (social phobia), agoraphobia, substance / medication-induced anxiety disorder, anxiety disorder due to another medical condition, anxiety during pregnancy and childbirth, antenatal anxiety during pregnancy (before childbirth), postpartum anxiety, animal type phobia (fear of spiders, other animal type phobias), natural environment type phobia (fear of thunderstorms), blood phobia, injection and infusion phobia, other medical care phobia, injury phobia, situation type phobia (claustrophobia, fear of heights), other unspecified anxiety disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation disorder (skin picking disorder), and combinations thereof. In some embodiments, the neuropsychiatric disorder is an eating disorder. In some embodiments, the neuropsychiatric disorder is a personality disorder (PD). In some embodiments, the personality disorder is selected from the group consisting of: borderline personality disorder (BPD), avoidant personality disorder (AvPD), antisocial personality disorder (AsPD), schizotypal personality disorder, other disorders that produce anxiety and fear, specific personality disorders, impulse disorders, gender identity disorder, paraphilia, other sexual dysfunctions, other adult personality and behavior disorders, unspecified adult personality and behavior disorders, personality and behavior disorders due to known physiological conditions. In some embodiments, the PD subject also has depression. In some embodiments, the neuropsychiatric disorder is a somatic symptom disorder. In some embodiments, the somatic symptom disorder is selected from the group consisting of: illness anxiety disorder, conversion disorder (functional neurological symptom disorder), psychological factors affecting other medical conditions, factitious disorder, other specified somatic symptoms and related disorders, unspecified somatic symptoms and related disorders, and combinations thereof. In some embodiments, the subject has suicidal tendencies. In some embodiments, the neuropsychiatric disorder is treatment-resistant.

[0213] The compounds provided herein can be used for various therapeutic purposes. In one embodiment, a compound is administered to a subject to treat a neuropsychiatric disorder. For the purposes of the compositions and methods provided herein, "subject" includes humans and other animals, preferably mammals and most preferably humans. Thus, the compounds provided herein are suitable for human therapy and veterinary applications. In another embodiment, the subject is a mammal, and in another embodiment, the subject is a human. As used herein, "condition", "disease", or "disorder" refers to a condition that can be ameliorated by administration of the compounds provided herein and their pharmaceutical compositions.

[0214] The methods and compositions described herein can be used for the prevention as well as for the amelioration of the signs and / or symptoms of a condition such as a neuropsychiatric disorder. The term "treatment" as used to refer to treating a condition of a subject includes: preventing, inhibiting, or ameliorating the condition of the subject, as well as reducing or ameliorating the signs or symptoms of the condition. Treatment goals can include endpoints such as improvement in the DSM-5 severity scale, measurement of increased resilience and quality of life, engagement of the positive cognitive valence system, and corresponding reduction of negative valence.

[0215] Those skilled in the art will understand that methods of treatment and / or prevention, including administration of the compounds provided herein for the treatment and / or prevention of one or more indications as described herein, also include: using the compounds provided herein in the manufacture of a medicament for the treatment and / or prevention of one or more indications as described herein; and using the compounds provided herein for the treatment and / or prevention of one or more indications as described herein.

[0216] Pharmaceutical compositions for the compounds and methods provided herein are contemplated. The compositions and methods provided herein are formulated for storage in the form of lyophilized formulations or aqueous solutions by mixing the compounds having the desired purity with optional pharmaceutically acceptable carriers, excipients, or stabilizers. Acceptable carriers, excipients, or stabilizers are non-toxic to the recipients at the dosages and concentrations employed and include buffers, such as phosphates, citrates, acetates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol, or benzyl alcohol; alkyl parabens, such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; sweetening agents and other flavoring agents; fillers, such as microcrystalline cellulose, lactose, corn, and other starches; binders; additives; coloring agents; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants or polyethylene glycol (PEG). In another embodiment, the pharmaceutical compositions provided herein are in water-soluble form, such as present as pharmaceutically acceptable salts, which means including acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness of the free base and are not biologically or otherwise undesirable, which are formed with inorganic acids and organic acids, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. "Pharmaceutically acceptable base addition salts" include those salts derived from the following inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Formulations for in vivo administration are preferably sterile. This can be readily achieved by filtration through sterile filtration membranes or other methods.

[0217] Pharmaceutically acceptable excipients for the formulations of the compounds provided herein include, but are not limited to: diluents such as microcrystalline cellulose, starch, mannitol, anhydrous calcium hydrogen phosphate or silica, calcium carbonate, co-blends of microcrystalline cellulose and talc; disintegrants such as sodium starch glycolate or croscarmellose sodium; binders such as povidone, copovidone or hydroxypropyl cellulose; lubricants such as magnesium stearate or sodium stearyl fumarate; glidants such as colloidal silica; and film coatings such as white Opadry II or PVA-based brown Opadry II.

[0218] The compounds provided herein may be purified. The compounds herein may be at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure or at least 99.9% pure.

[0219] The term "impurity" refers to any component in a drug product that is not an active pharmaceutical ingredient or an excipient or carrier in the drug product. "Impurity profile" is a description of the identified and unidentified impurities in a drug product. "Identified impurity" is an impurity for which structural characterization has been achieved, while "unidentified impurity" is an impurity for which structural characterization has not been achieved and is defined only by qualitative analytical characteristics (e.g., chromatographic retention time). "Potential impurity" is an impurity that may theoretically arise during manufacture or storage; it may or may not actually be present in the active pharmaceutical ingredient or active ingredient.

[0220] The term "degradation product" refers to an impurity caused by a chemical change in the active pharmaceutical ingredient or active ingredient brought about by, for example, the effects of light, temperature, pH, water or reaction with an excipient and / or carrier and / or the immediate container-closure system during the manufacture and / or storage of a drug product or active ingredient. "Degradation profile" is a description of the degradation products observed in an active pharmaceutical ingredient, drug product or active ingredient. "Identified degradation product" is a degradation product for which structural characterization has been achieved, while "unidentified degradation product" is a degradation product for which structural characterization has not been achieved and is defined only by qualitative analytical characteristics (e.g., chromatographic retention time).

[0221] In some embodiments, the purity of the compound of formula (I) or a pharmaceutically acceptable salt thereof, as determined by high performance liquid chromatography (HPLC), is at least 99%, such as at least 99.5% as determined by HPLC. In some embodiments, the purity of the compound of formula I or a pharmaceutically acceptable salt thereof, as determined by HPLC, is at least 99.9%, such as at least 99.95% as determined by HPLC.

[0222] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof gives rise to two or fewer impurity peaks as determined by HPLC. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof does not give rise to an impurity peak greater than 0.2% as determined by HPLC. In some embodiments, there is no impurity peak greater than 0.15% as determined by HPLC. In some embodiments, there is no impurity peak greater than 0.1% as determined by HPLC.

[0223] In another aspect, the present disclosure relates to pharmaceutical compositions of the compounds described herein, such as methyl ketones, including pharmaceutically acceptable salts of methyl ketones, and / or stereoisomers of methyl ketones, and / or isotopically configured forms and isotopomers of methyl ketones, and polymorphs and other solid forms of any of the foregoing. In one embodiment, the methyl ketone pharmaceutical composition is a high-purity methyl ketone pharmaceutical composition. In one embodiment, the methyl ketone pharmaceutical composition is a room-temperature stable methyl ketone pharmaceutical composition. In one embodiment, the methyl ketone pharmaceutical composition is non-mutagenic and free of mutagenic impurities. In one embodiment, the methyl ketone pharmaceutical composition is suitable for humans. In one embodiment, the methyl ketone pharmaceutical composition is a commercial-scale methyl ketone pharmaceutical composition.

[0224] In some embodiments, the methyl ketone pharmaceutical compositions described herein comply with the guidelines and standards described in The United States Pharmacopeia 43 - National Formulary 38. Rockville, MD: United States Pharmacopeial Convention; 2020, USP. General Chapter <1111> Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use and / or European Pharmacopoeia Commission. General Chapter 5.1.4. Microbiological Quality of Pharmaceutical Preparations. European Pharmacopoeia, 10th Edition, 2020.

[0225] The present disclosure provides high - purity pharmaceutical compositions comprising a methyl ketone, which comprise a pharmaceutically acceptable salt of the methyl ketone (e.g., methyl ketone hydrochloride), and / or a stereoisomer of the methyl ketone (e.g., (S) - methyl ketone), and / or an isotopic configurational isomer and isotopic isomer of the methyl ketone, and polymorphs and other solid forms of any of the foregoing; and a pharmaceutically acceptable carrier. In some embodiments, the high - purity methyl ketone pharmaceutical composition is stable at room temperature. In some embodiments, the high - purity methyl ketone pharmaceutical composition is non - mutagenic and free of mutagenic impurities. In some embodiments, the high - purity methyl ketone pharmaceutical composition is suitable for humans. In some embodiments, the high - purity methyl ketone pharmaceutical composition is a methyl ketone pharmaceutical composition on a commercial scale. In some embodiments, the high - purity methyl ketone pharmaceutical composition meets the acceptance thresholds listed in ICH Q3A and ICH Q3B guidelines. In some embodiments, the residual solvent levels of the high - purity methyl ketone pharmaceutical composition meet the standards listed in ICH Q3C guidelines. In some embodiments, the elemental impurity levels of the high - purity methyl ketone pharmaceutical composition meet the standards listed in ICH Q3D guidelines.

[0226] In some embodiments, the high-purity pharmaceutical composition comprising a methyl ketone or a stereoisomer thereof (e.g., (S)-methyl ketone) or a pharmaceutically acceptable salt thereof (e.g., methyl ketone hydrochloride) has a purity of at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, at least 99.9% pure, at least 99.91% pure, at least 99.92% pure, at least 99.93% pure, at least 99.94% pure, at least 99.95% pure, at least 99.96% pure, at least 99.97% pure, at least 99.98% pure, at least 99.99% pure or greater than 99.99% pure.

[0227] In some embodiments, the high-purity pharmaceutical composition comprises racemic methyl ketone that is at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, at least 99.9% pure, at least 99.91% pure, at least 99.92% pure, at least 99.93% pure, at least 99.94% pure, at least 99.95% pure, at least 99.96% pure, at least 99.97% pure, at least 99.98% pure, at least 99.99% pure or greater than 99.99% pure. In some embodiments, the high-purity pharmaceutical composition comprises (S)-methyl ketone that is at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, at least 99.9% pure, at least 99.91% pure, at least 99.92% pure, at least 99.93% pure, at least 99.94% pure, at least 99.95% pure, at least 99.96% pure, at least 99.97% pure, at least 99.98% pure, at least 99.99% pure or greater than 99.99% pure. In some embodiments, the high-purity pharmaceutical composition comprises (R)-methyl ketone that is at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, at least 99.9% pure, at least 99.91% pure, at least 99.92% pure, at least 99.93% pure, at least 99.94% pure, at least 99.95% pure, at least 99.96% pure, at least 99.97% pure, at least 99.98% pure, at least 99.99% pure or greater than 99.99% pure. In some embodiments, the high-purity pharmaceutical composition comprises methyl ketone hydrochloride that is at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, at least 99.9% pure, at least 99.91% pure, at least 99.92% pure, at least 99.93% pure, at least 99.94% pure, at least 99.95% pure, at least 99.96% pure, at least 99.97% pure, at least 99.98% pure, at least 99.99% pure or greater than 99.99% pure.

[0228] In some embodiments, a high-purity pharmaceutical composition comprising a methyl ketone or a stereoisomer thereof (e.g., (S)-methyl ketone) or a pharmaceutically acceptable salt thereof (e.g., methyl ketone hydrochloride) has two or fewer impurity peaks as determined by HPLC. In some embodiments, a high-purity pharmaceutical composition comprising a methyl ketone or a stereoisomer thereof (e.g., (S)-methyl ketone) or a pharmaceutically acceptable salt thereof (e.g., methyl ketone hydrochloride) has one impurity peak as determined by HPLC. In some embodiments, a high-purity pharmaceutical composition comprising a methyl ketone or a stereoisomer thereof (e.g., (S)-methyl ketone) or a pharmaceutically acceptable salt thereof (e.g., methyl ketone hydrochloride) does not have an impurity peak greater than 0.04%, greater than 0.03%, greater than 0.02%, greater than 0.01%, or greater than 0.005% as determined by HPLC. In some embodiments, a high-purity pharmaceutical composition comprising a methyl ketone or a stereoisomer thereof (e.g., (S)-methyl ketone) or a pharmaceutically acceptable salt thereof (e.g., methyl ketone hydrochloride) does not have impurities detectable by HPLC.

[0229] In some embodiments, the high-purity pharmaceutical composition has one or more impurities detectable by HPLC, selected from 2,3-Methylone, 2-bromo-3',4'-(methylenedioxy)propiophenone (MDPBP), and 3,4-methylenedioxypropiophenone (MDP). In some embodiments, the high-purity pharmaceutical composition does not have 2,3-Methylone detectable by HPLC. In some embodiments, the high-purity pharmaceutical composition does not have 2-bromo-3',4'-(methylenedioxy)propiophenone (MDPBP) detectable by HPLC. In some embodiments, the high-purity pharmaceutical composition does not have 3,4-methylenedioxypropiophenone (MDP) detectable by HPLC. In some embodiments, the high-purity pharmaceutical composition does not have 2,3-Methylone detectable by HPLC.

[0230] On the other hand, the present disclosure provides a drug composition that is stable at room temperature and contains methyl ketone, which comprises a pharmaceutically acceptable salt of methyl ketone (e.g., methyl ketone hydrochloride), and / or a stereoisomer of methyl ketone (e.g., (S)-methyl ketone), and / or an isotopically-configured form and isotopomer of methyl ketone, as well as polymorphs and other solid forms of any of the foregoing; and a pharmaceutically acceptable carrier. In some embodiments, the room temperature-stable drug composition is a high-purity drug composition. In some embodiments, the room temperature-stable drug composition is formulated into an oral dosage form, such as a tablet or a capsule. In some embodiments, the room temperature-stable methyl ketone drug composition is non-mutagenic and free of mutagenic impurities. In some embodiments, the room temperature-stable methyl ketone drug composition is suitable for humans. In some embodiments, the room temperature-stable methyl ketone drug composition is a methyl ketone drug composition on a commercial scale. In some embodiments, the room temperature-stable methyl ketone drug composition meets the acceptance thresholds listed in the ICH Q3A and ICH Q3B guidelines. In some embodiments, the residual solvent level of the room temperature-stable methyl ketone drug composition meets the standards listed in the ICH Q3C guidelines. In some embodiments, the elemental impurity level of the room temperature-stable methyl ketone drug composition meets the standards listed in the ICH Q3D guidelines.

[0231] A room temperature-stable methyl ketone drug composition means that after a specified time interval (e.g., one month, three months, six months, nine months, twelve months, eighteen months, twenty-four months, or thirty-six months), when the drug composition is assayed by HPLC, the amount of methyl ketone is 90 - 110% of the initial amount of methyl ketone, preferably between 97 - 103%, and the impurities meet the acceptance thresholds listed in the ICH Q3A and ICH Q3B guidelines, and the total impurities are no more than 5%. In some embodiments, the total impurities are no more than 4.5%, no more than 4%, no more than 3.5%, no more than 3%, no more than 2.5%, no more than 2%, no more than 1.5%, no more than 1%, or no more than 0.5%.

[0232] In some embodiments, the room temperature-stable pharmaceutical composition comprises a racemic methyl ketone that is stable at room temperature for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years. In some embodiments, the room temperature-stable pharmaceutical composition comprises an (S)-methyl ketone that is stable at room temperature for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years. In some embodiments, the room temperature-stable pharmaceutical composition comprises an (R)-methyl ketone that is stable at room temperature for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years. In some embodiments, the room temperature-stable pharmaceutical composition comprises methyl ketone hydrochloride that is stable at room temperature for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years.

[0233] In some embodiments, a room temperature-stable pharmaceutical composition is stable for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years when stored or preserved at a temperature between 15°C and 30°C. In some embodiments, a room temperature-stable pharmaceutical composition is stable for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years when stored or preserved at a temperature between 25°C and 30°C. In some embodiments, a room temperature-stable pharmaceutical composition is stable for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years when stored or preserved at a temperature of 20 ± 2°C. In some embodiments, a room temperature-stable pharmaceutical composition is stable for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years when stored or preserved at a temperature of 22 ± 2°C. In some embodiments, a room temperature-stable pharmaceutical composition is stable for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years when stored or preserved at a temperature of 24 ± 2°C. In some embodiments, a room temperature-stable pharmaceutical composition is stable for at least one month, at least three months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years when stored or preserved at a temperature of 25 ± 2°C.

[0234] In some embodiments, a room temperature stable pharmaceutical composition is stable for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years when stored or preserved at a relative humidity (RH) of at least 60%. In some embodiments, a room temperature stable pharmaceutical composition is stable for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least one year, at least fifteen months, at least eighteen months, at least twenty-one months, at least two years, or at least three years when stored or preserved at a relative humidity of at least 75%.

[0235] In some embodiments, a room temperature stable pharmaceutical composition is stable for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months when stored or preserved at a temperature of 40 °C and a relative humidity (RH) of 75%.

[0236] Provided herein are non-mutagenic pharmaceutical compositions comprising methyl ketone, which comprise a pharmaceutically acceptable salt of methyl ketone (e.g., methyl ketone hydrochloride), and / or a stereoisomer of methyl ketone (e.g., (S)-methyl ketone), and / or an isotopic configurational isomer and isotopic isomer of methyl ketone, and polymorphs and other solid forms of any of the foregoing; and a pharmaceutically acceptable carrier. In some embodiments, the non-mutagenic methyl ketone pharmaceutical composition is stable at room temperature. In some embodiments, the non-mutagenic methyl ketone pharmaceutical composition is a high purity methyl ketone pharmaceutical composition. In some embodiments, the non-mutagenic methyl ketone pharmaceutical composition is suitable for humans. In some embodiments, the non-mutagenic methyl ketone pharmaceutical composition is a methyl ketone pharmaceutical composition on a commercial scale. In some embodiments, using an in vitro Ames test, it is determined that the methyl ketone pharmaceutical composition is non-mutagenic. In some embodiments, the non-mutagenic methyl ketone pharmaceutical composition meets the acceptance thresholds listed in the ICH Q3A and ICH Q3B guidelines. In some embodiments, the residual solvent levels of the non-mutagenic methyl ketone pharmaceutical composition meet the standards listed in the ICH Q3C guidelines. In some embodiments, the elemental impurity levels of the non-mutagenic methyl ketone pharmaceutical composition meet the standards listed in the ICH Q3D guidelines.

[0237] In some embodiments, the methyl ketone pharmaceutical composition meets at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the specifications listed in Table 1. In some embodiments, the methyl ketone pharmaceutical composition meets all of the specifications listed in Table 1.

[0238] Table 1:

[0239]

[0240]

[0241] NMT = not more than

[0242] In some embodiments, the methyl ketone pharmaceutical composition is formulated as a capsule in an oral dosage form and meets at least one, at least two, at least three, at least four, or at least five of the specifications listed in Table 2. In some embodiments, the methyl ketone pharmaceutical composition meets all of the specifications listed in Table 2.

[0243] Table 2.

[0244]

[0245]

[0246] In some embodiments, the methyl ketone pharmaceutical composition is formulated as a capsule in an oral dosage form, which meets at least one, at least two, at least three, at least four, or at least five of the specifications listed in Table 3 after a specified time interval (e.g., one month, three months, six months, nine months, twelve months, eighteen months, twenty-four months, or thirty-six months). In some embodiments, the methyl ketone pharmaceutical composition meets all of the specifications listed in Table 3.

[0247] Table 3.

[0248]

[0249]

[0250] The compounds provided herein can also be encapsulated in microcapsules prepared by methods including but not limited to coacervation techniques, interfacial polymerization (e.g., using hydroxymethylcellulose or gelatin microcapsules, or poly(methyl methacrylate) microcapsules), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), and coarse emulsions. Sustained-release formulations can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers, which are in the form of shaped articles (e.g., membranes) or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (which are injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprorelin acetate), and poly-D-(-)-3-hydroxybutyric acid), which is a microsphere-based delivery system composed of the desired bioactive molecule incorporated into a poly-DL-lactide-co-glycolide (PLG) matrix).

[0251] Administration of a pharmaceutical composition comprising a compound provided herein (e.g., in the form of a sterile aqueous solution) can be carried out in a variety of ways, including but not limited to oral, subcutaneous, intravenous, intranasal, intraauricular, transdermal, topical (e.g., gels, ointments, emulsions, creams, etc.), intraperitoneal, intramuscular, intrapulmonary, transvaginal, parenteral, rectal, or intraocular. As is known in the art, the pharmaceutical composition can be formulated correspondingly according to the mode of introduction.

[0252] In some embodiments, the pharmaceutical formulation is an oral dosage form. In some embodiments, the pharmaceutical formulation is a parenteral dosage form. In some embodiments, the pharmaceutical composition comprises tablets. In some embodiments, the pharmaceutical composition comprises capsules. In some embodiments, the pharmaceutical composition comprises a dry powder. In some embodiments, the pharmaceutical composition comprises a solution. In some embodiments, more than one dosage form is administered to the subject substantially simultaneously. In some embodiments, the entire therapeutic dose can be administered to the subject in the form of one tablet or capsule. In some embodiments, the therapeutic dose can be divided into multiple tablets or capsules.

[0253] Unless the context clearly dictates otherwise, as used herein, the singular forms "a" and "the" include plural referents. For example, the term "molecule" can also include multiple molecules.

[0254] The terms "about" or "approximately" are used interchangeably herein and mean that a particular value as determined by a person of ordinary skill in the art is within an acceptable error range, which will depend in part on how the value is measured or determined, i.e., the limitations of the measuring system. For example, in accordance with the practice in the art, "about" can mean within 1 or more standard deviations. In addition, as used herein, the term "about" when referring to a measurable value (such as a dose, time, temperature, etc.) means to cover variations of ±20%, ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of the specified amount.

[0255] Unless the context clearly indicates otherwise, a reference to a particular numerical value includes at least that particular value. When expressing a range of values, another embodiment includes from one specific value and / or to another specific value. In addition, a reference to a value stated within a range includes each value within that range. All ranges include the end values and are combinable.

[0256] As used herein, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., elements that coexist in some cases and do not coexist in other cases. Multiple elements listed with "and / or" should be interpreted in the same way, i.e., "one or more" of the elements so combined. Other elements different from those specifically identified may optionally be presented, whether or not related to those elements specifically identified by the "and / or" clause. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising", a reference to "A and / or B" in one embodiment may refer to only A (optionally including elements other than B); in another embodiment, it may refer to only B (optionally including elements other than A); in yet another embodiment, it may refer to A and B (optionally including other elements); and so on.

[0257] As used herein, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted inclusively, i.e., including at least one of the multiple elements or the list of elements, and including more than one of them, and optionally, additional unlisted items. Only terms that clearly indicate the contrary, such as "only one of..." or "exactly one of...", or when used in an embodiment, "consisting of..." will refer to exactly one element of some or a list of elements. Generally, the term "or" as used herein when preceded by exclusive terms such as "any one", "one of...", "only one of...", or "only one of..." should be interpreted to indicate only an exclusive alternative form (i.e., "one or the other, but not both").

[0258] As used herein, the phrase "at least one" in reference to a list of one or more elements shall be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each element specifically listed in the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified within the list of elements referred to by the phrase "at least one", whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently, "at least one of A and / or B") can, in one embodiment, mean at least one, optionally including more than one, of A, where B is absent (and optionally including elements other than B); in another embodiment, it can mean at least one, optionally including more than one, of B, where A is absent (and optionally including elements other than A); in yet another embodiment, it can mean at least one, optionally including more than one, of A and at least one, optionally including more than one, of B (and optionally including other elements); and so on.

[0259] Unless the context otherwise indicates, it is expressly intended that the various features described herein can be used in any combination.

[0260] Any patent, patent application publication, or scientific publication cited herein is hereby incorporated by reference in its entirety.

[0261] The following examples are provided to more fully illustrate the preferred embodiments. However, they should in no way be construed as limiting the broad scope of the invention.

[0262] Examples

[0263] Example 1

[0264] Synthesis method

[0265] The compounds of formula (I) of the present invention can be prepared starting from the parent molecule II according to the proposed synthetic routes outlined in Schemes 1-17 below. Methyl ketone IIa (Y = CO, R 1 = CH3, R 2 = CH3), ethyl ketone IIb (Y = CO, R 1 = CH3, R 2 = CH2CH3), butyl ketone IIc (Y = CO, R 1 = CH2CH3, R 2 = CH3) and MDMA IId (Y = CH2, R 1= CH3, R 2 = CH3) can be prepared using procedures such as those described in WO9639133A1 (IIa); Heather E. et al. Drug Test. Analysis, 2017, 9, 426 (IIa); Maheux C.R. et al. Drug Test. Analysis, 2016, 8, 847 (IIb); Maheux C.R. et al. Drug Test. Analysis, 2012, 4, 17 (IIc); and Milhazes N. et al. Anal. Chem. Act. 2007, 596, 231 (IId).

[0266] The amino acid-derived prodrugs of formula Ib and Id can be prepared by coupling the required amine II with a suitable amino acid, as presented in Scheme 1 below, where R 11 and R 12 are each independently selected from the side chain residues of naturally occurring amino acids. To couple the amino acid with II, it is preferred to protect one amino group with a protecting group (Pg) prior to the reaction of the amino acid with II. Reagents and methods for protecting the amino group in the reactants are known in the art. Examples of protecting groups that can be used to protect the amino group include, but are not limited to, fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), trifluoroacetate (TFA), acetate (Ac), and benzyloxycarbonyl (CBZ). Preferably, the carboxylic acid group in the N-protected amino acid is activated by an acid activator (sometimes also referred to as a coupling reagent) to facilitate the reaction of the N-protected amino acid with II. Examples of acid activators (coupling reagents) well known in the art include, but are not limited to, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (HBTU), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU). The use of a suitable acyl halide or acid anhydride as the activated acylating group in the N-protected amino acid is also contemplated. After coupling by any standard coupling procedure to obtain the intermediate protected prodrug Ia, deprotection can be carried out using standard reagents known in the art to obtain the desired prodrug Ib. After deprotecting the newly added Ic amino group, this amino acid prodrug can be further derivatized to a dipeptide by repeating the coupling procedure to obtain prodrug Id.

[0267] Scheme 1

[0268]

[0269] Alternatively, the peptide-derived prodrug of formula Id can be prepared by coupling the required amine II with a suitable dipeptide, as presented in Scheme 2 below. This conjugation can be accomplished under the conditions described previously for intermediate Ia (Scheme 1). The required dipeptide is provided by coupling two amino acids, each independently selected from the naturally occurring L-amino acids, using standard peptide coupling protocols known in the art.

[0270] Scheme 2

[0271]

[0272] The amide prodrug of formula Ie can be prepared by coupling the required amine II with a suitable acylating agent, as shown in Scheme 3 below. Acylation of the amino group of II can be achieved by reacting with an acyl chloride (Z = Cl) or acid anhydride (Z = -OC(O)R 3 or -OC(O)tert-butyl) in a suitable solvent (such as dichloromethane, THF, DMF, acetonitrile or toluene) in the presence of a base (such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO3, K2CO3 or 2,6-dimethylpyridine). The coupling reaction can also be carried out with a carboxylic acid (Z = OH) in the presence of a coupling reagent such as N,N'-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (HBTU) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other similar reagents well known to those skilled in the art.

[0273] Scheme 3

[0274]

[0275] The carbamate prodrug of formula If can be prepared by coupling the required amine II with a suitable chloroformate, as shown in Scheme 4 below. The coupling reaction is carried out in the presence of a base (such as diisopropylethylamine (DIPEA), triethylamine, NaOH, NaHCO3, K2CO3 or pyridine) in a suitable solvent (such as dichloromethane, THF, ethyl acetate, acetonitrile, 1,4-dioxane) or in water. Alternatively, the carbamate If can be prepared by sequentially adding triphosgene to amine II in a solvent (such as dichloromethane) in the presence of a base (such as diisopropylethylamine (DIPEA)), followed by addition of an alkoxide (such as NaOR 3 ).

[0276] Scheme 4

[0277]

[0278] The acyloxyalkoxycarbonyl prodrugs of formula Ig (Scheme 5) can be prepared by sequentially coupling the desired amine II with chloroformate 1-chloroethyl ester in a solvent (such as dichloromethane) in the presence of a base (such as triethylamine or diisopropylethylamine), and then adding the selected carboxylic acid ester. This carboxylic acid ester can be generated by reacting the corresponding carboxylic acid R 3 CO2H with a base (such as triethylamine or cesium carbonate) in a solvent (such as DMF or acetonitrile). Alternatively, the acyloxyalkoxycarbonyl prodrugs of formula Ig can be obtained directly by coupling the desired amine II with an electrophilic acylating agent (such as carboxylic acid 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl ester) in a solvent (such as dichloromethane) in the presence of a base (such as triethylamine or diisopropylethylamine).

[0279] Scheme 5

[0280]

[0281] The acyloxymethyl prodrugs of formula Ih can be prepared by coupling the requisite amine II with an appropriate chloromethyl ester in a solvent (such as acetonitrile) in the presence of a basic agent (such as triethylamine) (Scheme 6). The chloromethyl ester R 3 C(O)OCH2Cl can be prepared according to the procedures described in US20150274670A1 and US20070155729A1, in which the acyl chloride of formula R 3 COCl is reacted with paraformaldehyde.

[0282] Scheme 6

[0283]

[0284] The phosphoramidate prodrugs of formula Ii can be prepared according to the procedures described in WO 2020 / 008064. As shown in Scheme 7 below, PCl5 is added to the desired amine II in the presence of a basic agent (such as pyridine) and in a solvent (such as dichloromethane). Then a mixture of water / DMSO is added to hydrolyze the dichlorophosphoramidate solution to obtain the phosphoramidate prodrugs of formula Ii.

[0285] Scheme 7

[0286]

[0287] The phosphonyloxymethyl of formula Ik can be prepared from the desired amine II in a two-step sequence as presented in Scheme 8 below. Following the procedure found in WO 2020 / 008064, a solution of amine II in a solvent such as acetonitrile can be treated with a base agent such as K2CO3, NaI, and di-tert-butyl chloromethylphosphonate at a controlled temperature of 50 °C to obtain the protected phosphonate Ij. This intermediate is hydrolyzed under aqueous acidic conditions to give the phosphonyloxymethyl prodrug Ik.

[0288] Scheme 8

[0289]

[0290] The phosphonyloxyalkoxycarbonyl prodrug of formula Im (Scheme 9) can be prepared according to the procedure described by Safadi M. et al. in Pharm Res, 1993, 10(9), 1350 by sequentially coupling the required amine II with a chloroalkyl chloroformate in a solvent such as dichloromethane in the presence of a base such as triethylamine or diisopropylethylamine, and then adding a suitably protected phosphate ester such as dibenzyl phosphate (R 11 and R 12 = benzyl). This phosphate ester can be generated by reacting the corresponding phosphonic acid with a base such as silver carbonate in a solvent such as DMF or acetonitrile. When R 11 and R 12 are benzyl, the phosphate ester intermediate IL can be deprotected in a solvent such as ethyl acetate under a H2 atmosphere using a catalytic amount of Pd / C to obtain the dihydrogen phosphate Im.

[0291] Scheme 9

[0292]

[0293] The amide prodrug of formula Ip can be prepared by coupling the desired amine II with the carboxylic acid Io as presented in Scheme 10 below. When Z a is O, NH, or NCH3, those carboxylic acids are commercially available, where a variety of R 3 groups such as alkyl, cycloalkyl, aryl, heteroaryl, and amino acids can be found. The coupling reaction can be carried out in the presence of a coupling reagent such as N,N-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (HBTU), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other similar reagents well-known to those skilled in the art. If the carboxylic acid is not commercially available, it can be prepared by reacting the amino group of In (Z a=NR 4 ) or acylation by reaction of a hydroxy group (Za = O) with a carboxylic acid (Z = OH) to prepare Io. Alternatively, in the presence of a base (such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO3, K2CO3 or 2,6-dimethylpyridine), in a suitable solvent (such as dichloromethane, THF, DMF, acetonitrile or toluene), the amine In can be reacted with an acyl chloride (Z = Cl) or an acid anhydride (Z = -OC(O)R 3 or -OC(O)tert-butyl).

[0294] Scheme 10

[0295]

[0296] The carbamate prodrug of formula It can be prepared by coupling the desired amine II with benzyl alcohol Is, as presented in Scheme 11 below. When Z b is O, NH or NCH3, the benzyl alcohol is commercially available, where a variety of R 3 groups can be found, such as alkyl, cycloalkyl, aryl, heteroaryl and amino acids. The coupling reaction can be carried out as described in US2017 / 0145044A1, by sequentially reacting the benzyl alcohol with a reagent (such as carbonyldiimidazole) in a solvent (such as dichloromethane), and then adding amine II. If the benzyl alcohol is not commercially available, Is can be prepared in a two-step sequence, where the desired commercially available phenol (Z b = O) or aniline (Z b = NR 4 ) Iq is acylated in a similar manner as described above for the preparation of Io (Scheme 10), and then the benzaldehyde Ir is reduced with a reagent (such as sodium borohydride) in a solvent (such as dichloromethane) in the presence of an alcohol (such as isopropanol).

[0297] Scheme 11

[0298]

[0299] The carbamate prodrug of formula Ix can be prepared by coupling the desired amine II with benzyl alcohol Iw, as presented in Scheme 12 below, and following a similar assembly sequence as described in Scheme 11 above. When Z b is O, NH or NCH3, the benzyl alcohol is commercially available, where a variety of R 3 groups can be found, such as alkyl, cycloalkyl, aryl, heteroaryl and amino acids. The coupling reaction can be carried out by sequentially reacting the benzyl alcohol with a reagent (such as carbonyldiimidazole) in a solvent (such as dichloromethane), and then adding amine II. If the benzyl alcohol is not commercially available, Iw can be prepared in a two-step sequence, where the desired commercially available phenol (Zb =O) or aniline (Z b =NR 4 ) Iu is acylated in a manner similar to that described above for the preparation of Io (Scheme 10), and then reduced with a reagent (such as sodium borohydride) in a solvent (such as dichloromethane) in the presence of an alcohol (such as isopropanol) to give benzaldehyde Iv.

[0300] Scheme 12

[0301]

[0302] The phosphonate prodrug of formula Iaa can be prepared by coupling the desired amine II with benzyl alcohol Iz, as presented in Scheme 13 below, and following a similar assembly sequence as described previously in Scheme 11. The protected phosphate ester Iy can be obtained by reacting a commercially available phenol Iq-1 with a protected phosphate ester reagent (such as di-tert-butyl chlorophosphate or dibenzyl chlorophosphate) in a solvent (such as THF or dichloromethane) in the presence of a base (such as triethylamine, i-Pr2NEt or DBU) and in the presence of a catalyst (such as DMAP). Benzyl alcohol Iz is obtained by treating benzaldehyde Iy with a reagent (such as sodium borohydride) in a solvent (such as dichloromethane) in the presence of an alcohol (such as isopropanol). The formation of the carbamate linkage can be carried out by reacting benzyl alcohol with a reagent (such as carbonyldiimidazole) and then adding amine II. The phosphate ester can be deprotected under acidic conditions (Pg = tert-butyl) using a reagent (such as TFA or HCl aq. ) in a solvent (such as dichloromethane or THF) to give Iaa. Unless R 6 is incompatible with the reduction conditions, such as R 6 =NO2, CN or Br, the deprotection can also be carried out under hydrogenolysis conditions (Pg = benzyl) using Pd / C as a catalyst in a solvent (such as methanol) under a H2 atmosphere.

[0303] Scheme 13

[0304]

[0305] Phosphonate prodrugs of formula Idd can be prepared by coupling the desired amine II with benzyl alcohol Icc as presented in Scheme 14 below and following a similar assembly sequence as previously described in Scheme 11. Protected phosphate Ibb can be obtained by reacting commercially available phenol Iu-1 with a protected phosphate reagent (such as di-tert-butyl chlorophosphate or dibenzyl chlorophosphate) in the presence of a base (such as triethylamine, i-Pr2NEt or DBU) in a solvent (such as THF or dichloromethane) in the presence of a catalyst (such as DMAP). Benzyl alcohol Icc is obtained by treating benzaldehyde Ibb with a reagent (such as sodium borohydride) in a solvent (such as dichloromethane) in the presence of an alcohol (such as isopropanol). Carbamate bond formation can be carried out by reacting the benzyl alcohol with a reagent (such as carbonyldiimidazole) and then adding amine II. The phosphate can be deprotected under acidic conditions (Pg = tert-butyl) using a reagent (such as TFA or HCl aq. ) in a solvent (such as dichloromethane or THF) to give Iaa. Unless R 6 is incompatible with reducing conditions, such as R 6 = NO2, CN or Br, the deprotection can also be carried out under reducing conditions (Pg = benzyl) using Pd / C as a catalyst in a solvent (such as methanol) under a H2 atmosphere.

[0306] Scheme 14

[0307]

[0308] Amide prodrugs of formula Ihh can be prepared by coupling the desired amine II with carboxylic acid Igg as presented in Scheme 15 below. This carboxylic acid can be generated in a 3-step sequence starting from phenol Iee, which can be prepared according to the synthesis reported by Nicolaou M.G. et al. (J. Org. Chem, 1996, 61, 8636). Acylation of Iee can be carried out by reacting the phenol with a carboxylic acid (Z = OH) in the presence of a coupling reagent such as N,N-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (HBTU) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other similar reagents well known to those skilled in the art. Alternatively, the phenol Iee can also be reacted with an acyl chloride (Z = Cl) or acid anhydride (Z = -OC(O)R in the presence of a base (such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO3, K2CO3 or 2,6-dimethylpyridine) in a suitable solvent (such as dichloromethane, THF, DMF, acetonitrile or toluene).3 Or -OC(O)tert -butyl) reaction. The deprotection of Iff can be carried out under weakly acidic conditions (Pg = TBS), using a reagent (such as PPTS), in a solvent (such as methanol) (Crouch, R.D. Tetrahedron, 2013, 69, 2383), or under reducing conditions (Pg = benzyl), using Pd / C as a catalyst in a solvent (such as methanol), under a H2 atmosphere. The corresponding primary alcohol can be oxidized using a reagent (such as Jones reagent) in a solvent (such as acetone) to obtain carboxylic acid Igg, which can then be coupled with amine II in the presence of a coupling reagent as described above.

[0309] Scheme 15

[0310]

[0311] The phosphonate prodrug of formula Ijj can be prepared by coupling the required amine II with carboxylic acid Iii, as presented in Scheme 16 below. This carboxylic acid can be obtained according to the synthesis reported by Nicolaou M.G. et al. (J. Org. Chem, 1996, 61, 8636). The formation of the amide bond can be carried out by the reaction of the required amine II with carboxylic acid Iii in the presence of a coupling reagent such as N,N - dicyclohexylcarbodiimide (DCC), N - ethyl - N'-(3 - dimethylaminopropyl)-carbodiimide (EDC), 1,1 - carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazol - 1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (HBTU), and O - (7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other similar reagents well - known to those skilled in the art. The phosphonate prodrug Ijj can be obtained by deprotecting the corresponding dibenzyl phosphate under reducing conditions, using Pd / C as a catalyst, in a solvent (such as methanol), under a H2 atmosphere.

[0312] Scheme 16

[0313]

[0314] The amide prodrugs of formula Inn can be prepared by coupling the desired amine II with carboxylic acid Imm as presented in Scheme 17 below. This carboxylic acid can be generated in a 4-step sequence starting from phenol Ikk, which can be prepared according to the synthesis reported by Liao Y. and Wang B. (Bioorg. Med. Chem. Lett., 1999, 9, 1795). The acylation of Ikk can be carried out by the reaction of the phenol with carboxylic acid (Z = OH) in the presence of a coupling reagent such as N,N-dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (HBTU), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other similar reagents well-known to those skilled in the art. Alternatively, the phenol Ikk can also be reacted with acyl chloride (Z = Cl) or acid anhydride (Z = -OC(O)R 3 or -OC(O)tert-butyl) in the presence of a base such as diisopropylethylamine (DIPEA), triethylamine, 4-methylmorpholine, NaHCO3, K2CO3 or 2,6-dimethylpyridine in a suitable solvent such as dichloromethane, THF, DMF, acetonitrile or toluene. The deprotection of ILL can be carried out using a reagent such as AcOH in a solvent mixture such as THF / H2O under weakly acidic conditions (Pg = TBS). The corresponding primary alcohol can be oxidized to carboxylic acid Imm in a 2-step sequence, where first the alcohol is oxidized to aldehyde using a reagent such as MnO2 in a solvent such as dichloromethane, and then a Kraus-type reaction is carried out using a reagent well-known to those skilled in the art. Finally, the carboxylic acid Imm can be coupled with amine II in the presence of a coupling reagent as described above to obtain the prodrug Inn.

[0315] Scheme 17

[0316]

[0317] Examples of the compounds of formula (I) according to the present invention include any one of Compounds 1 - 402 in Tables 4, 5 and 6 below and Compounds 403 - 511 in Table 7 (and pharmaceutically acceptable salts of any one of these compounds):

[0318] Table 4

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] Table 5

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] Table 6

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343] Table 7

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351] Compound 1: (2S)-2,6-diamino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylhexanamide

[0352]

[0353] Compound 1 was prepared by the following procedure: Step 1: Di-tert-butyl ((5S)-6-((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)amino)-6-oxohexane-1,5-diyl) dicarbamate. At room temperature, diisopropylethylamine (3.6 mL), HOBT (0.87 g), di-Boc-lysine (1.7 g), EDC (0.9 mL), and DMAP (0.1 g) were added to a solution of methyl ketone hydrochloride (1.03 g) in 100 mL of CH2Cl2. The reaction mixture was stirred overnight at room temperature and then 100 mL of CH2Cl2 was added. The resulting solution was washed with 200 mL of 1 M HCl, 200 mL of saturated aqueous NaHCO3, and 200 mL of saturated aqueous NaCl. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using 30 - 50% EtOAc in hexane. The pure fractions were then combined and concentrated to give the desired Boc-protected intermediate as an off-white solid.

[0354] Step 2: (2S)-2,6-diamino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylhexanamide. To a solution of di-tert-butyl ((5S)-6-((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)amino)-6-oxohexane-1,5-diyl) dicarbamate from Step 1 in CH2Cl2 (10 mL) was added 10 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 hours, diluted with 10 mL of CH2Cl2, and adjusted to pH 1 with 20 mL of 1 M HCl. The layers were separated and 20% NaOH was added to the aqueous layer aq. to give pH > 10. This resulting basic aqueous layer was extracted twice with 20 mL of CH2Cl2. The combined organic layers were concentrated under reduced pressure to give Compound 1 as a solid.

[0355] Compound 2: 2-Amino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylethanamide.

[0356]

[0357] Compound 2 was prepared through the following procedure: Step 1: tert-Butyl (2-((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)amino)-2-oxoethyl)carbamate. At room temperature, diisopropylethylamine (1.8 mL), Boc-glycine (0.47 g), EDC (0.5 mL), DMAP (0.1 g), and HOBT (0.42 g) were added to a solution of methyl ketone hydrochloride (0.5 g) in 50 mL of CH2Cl2. The reactants were stirred overnight at room temperature, and then 50 mL of CH2Cl2 was added. The resulting solution was washed with 100 mL of 1M HCl, 100 mL of saturated aqueous NaHCO3, and 100 mL of saturated aqueous NaCl. The organic layer was concentrated under reduced pressure to give an off-white solid. This crude product was carried on to the next step without purification.

[0358] Step 2: 2-Amino-N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylethanamide. To a solution of tert-Butyl (2-((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)amino)-2-oxoethyl)carbamate from Step 1 in CH2Cl2 (10 mL) was added 10 mL of trifluoroacetic acid. The reactants were stirred at room temperature for 4 hours, diluted with 30 mL of CH2Cl2, and adjusted to pH 1 with 20 mL of 1M HCl. The layers were separated and 20% NaOH was added to the aqueous layer aq. to give pH > 10. This resulting basic aqueous layer was extracted twice with 20 mL of CH2Cl2. The combined organic layers were concentrated under reduced pressure to give Compound 2 as a solid.

[0359] Compound 25: N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-N-methylethanamide.

[0360]

[0361] Compound 25 was prepared by the following procedure: Diisopropylethylamine (0.9 mL) was added to a solution of methyl ketone hydrochloride (0.5 g) in 50 mL of CH2Cl2. The solution was stirred at room temperature for 15 minutes, cooled to 0 °C and acetyl chloride (0.3 mL) was added. After 30 minutes at 0 °C, the reaction mixture was warmed to room temperature and stirred overnight. The volatiles were then removed under reduced pressure to give a yellow solid, which was dissolved in 150 mL of CH2Cl2. The resulting solution was washed twice with 100 mL of saturated aqueous NaHCO3 and 100 mL of saturated aqueous NaCl. The organic layer was concentrated under reduced pressure to give Compound 25 as a solid.

[0362] Compound 45: N-(1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)-2,2,2-trifluoro-N-methylethanamide.

[0363]

[0364] Compound 45 was prepared by the following procedure: Under nitrogen, methyl ketone hydrochloride (500 mg, 2.05 mmol, 1.0 equiv) and DCM (4 mL, 8 vol) and DIPEA (1.09 mL, 6.25 mmol, 3 equiv) were added to a 25 mL round bottom flask. A light brown solution was formed after stirring for 10 min. The solution was cooled to 0 °C and trifluoroacetic anhydride (483 mg, 2.3 mmol, 1.12 equiv) in DCM (1 mL, 2 vol) was added dropwise, with off gassing and a minor exotherm from 4 °C to 10 °C observed. After stirring for 30 min at 0 °C to 10 °C, HPLC monitoring indicated 66% product and 33% starting material. Additional DIPEA (0.44 mL, 1.23 mmol equiv) and trifluoroacetic anhydride (237 mg, 0.55 equiv) were added and the reaction mixture was stirred overnight at ambient temperature. HPLC analysis the next day showed 95% product and no detectable starting material. The reaction mixture was washed with water (5 mL x 2), the DCM layer was dried (MgSO4) and concentrated to give an orange solid. The solid was purified by column chromatography (10 g silica gel, 100% DCM) to give 372 mg of Compound 45 as a solid.

[0365] Compound 50: 1-(((1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamoyl)oxy)ethyl 2-methylpropanoate.

[0366]

[0367] Compound 50 was prepared by the following procedure: Triethylamine (1.19 g in 2 mL of CH2Cl2) was added to a suspension of methyl ketone hydrochloride (1.35 g) in CH2Cl2 (10 mL) at 0 °C. The resulting beige solution was stirred at 0 °C for 10 minutes, and then isobutyric acid 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl ester (2.0 g in 4 mL of CH2Cl2) was added dropwise over 5 minutes. The reaction mixture was stirred between -5 and 5 °C for 1 h, then warmed to RT (15 - 20 °C) and stirred over the weekend (about 66 h), and an orange solution was obtained. Then, at below 25 °C, 1 M aqueous acetic acid solution (7 mL) was added dropwise over 5 minutes and stirred for 5 minutes. The phases were separated and the organic layer was washed with 1 M aqueous K2CO3 solution (3 × 7 mL), then with 20% brine (7 mL). The material was concentrated in vacuo at 30 °C and then redissolved in ethyl acetate (10 mL). The organic matter was washed with 1 M aqueous K2CO3 solution (2 × 7 mL), then with 20% brine (7 mL), and then concentrated in vacuo at 40 °C. The crude material was purified by silica gel column chromatography and eluted with 1 - 10% ethyl acetate in heptane. The clear fractions were concentrated in vacuo at 40 °C and then stripped from TBME (3 × 20 mL) to give Compound 50.

[0368] Compound 71: Methyl (1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamate.

[0369]

[0370] Compound 71 was prepared by the following procedure: Under nitrogen, methyl ketone hydrochloride (500 mg, 2.05 mmol, 1.0 equiv) and DCM (4 mL, 8 vol) and DIPEA (1.09, 6.25 mmol, 3 equiv) were added to a 25 mL round-bottom flask. The reactants were cooled to 0 °C, and methyl chloroformate (257 mg, 2.7 mmol, 1.3 equiv) in DCM (1 mL, 2 vol) was added dropwise over 5 minutes, forming a light brown solution with an exotherm observed from 6 °C to 12 °C. HPLC analysis showed that the starting material had been consumed. The reaction was worked up by washing with water (5 mL × 2) using a phase separator. The DCM was concentrated to give a clear oil. The oil was purified by column chromatography (10 g silica gel, 100% DCM) to give 197 mg of Compound 71 as a clear oil.

[0371] Compound 77: Pentyl (1-(benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)(methyl)carbamate.

[0372]

[0373] Compound 77 was prepared by the following procedure: Diisopropylethylamine (0.9 mL) and triethylamine (0.46 mL) were added to a solution of methyl ketone hydrochloride (0.5 g) in 50 mL of CH2Cl2. The solution was stirred at room temperature for 15 minutes, cooled to 0 °C and amyl chloroformate (0.5 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 90 minutes. Volatiles were removed under reduced pressure to give an off-white solid, which was then dissolved in 100 mL of CH2Cl2. The resulting solution was washed twice with 100 mL of saturated aqueous NaHCO3 and 100 mL of saturated aqueous NaCl. The organic layer was concentrated under reduced pressure to give Compound 77 as a solid.

[0374] Example 2

[0375] Evaluate the effects of prodrugs and stereoisomers on the pharmacokinetic properties and efficacy of methyl ketones

[0376] The pharmacokinetic properties of methyl ketone after single intravenous (IV), intraperitoneal (IP) or oral gavage (PO) administration in male Sprague Dawley rats were determined using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method that had been established and validated in rats for methyl ketone. Rats (n = 3 per group) received a single dose of methyl ketone: 5 mg / kg IV, 15 mg / kg IP or 15 mg / kg PO. Plasma was sampled at time points between 0.083 - 24 hours to determine methyl ketone levels, and key parameters (e.g., C max 、T max 、T 1 / 2 and AUC) were determined from the data analysis. The results are shown in Table 8.

[0377] Table 8: Selected pharmacokinetic parameters of methyl ketone after single IV, PO and IP administration to male Sprague-Dawley rats

[0378]

[0379]

[0380] To investigate whether the prodrug prolongs the half-life or alters other fundamental pharmacokinetic properties of methyl ketone (e.g., C max or T max) Rats were treated with each prodrug IV, IP, or PO. For each compound, three groups of rats were treated as follows: For Group 1, a single dose of methyl ketone was administered to 3 male Sprague-Dawley rats by an IV bolus at 5 mg / kg. For Group 2, a single dose of methyl ketone was administered to 3 male Sprague-Dawley rats by oral gavage (PO) at 15 mg / kg. For Group 3, a single dose of methyl ketone was administered to 3 male Sprague-Dawley rats by IP at 15 mg / kg. For all groups, blood samples were collected from each animal at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose to determine plasma concentration. Plasma concentration was quantified by liquid chromatography tandem mass spectrometry (LC-MS / MS). A bioanalytical method was established and validated, yielding a lower limit of quantification (LLOQ) of 1 ng / mL and an upper limit of quantification (ULOQ) of 3000 ng / mL for methyl ketone. Phoenix WinNonlin (version 8.3) was used to analyze plasma concentration-time data to characterize the PK properties of the analyte. A non-compartmental analysis model and linear / log trapezoidal method were applied to calculate PK parameters.

[0381] Metabolic stability

[0382] Stability in whole blood

[0383] The test compound (prodrug, concentration 2 μM) was added to pre-warmed fresh rat or human whole blood (EDTA K3) and incubated at 37 °C for up to 2 hours, with each experiment repeated twice. The disappearance of the test compound and the accumulation of methyl ketone were monitored at 0, 10, 30, 60, and 120 minutes.

[0384] Stability in buffer or simulated gastric fluid (SGF)

[0385] The test compound (prodrug, concentration 2 μM) was added to buffer (citrate pH 4.5, citrate or phosphate pH 6.8) or SGF and incubated at 37 °C for 2 hours, with each experiment repeated twice. The disappearance of the test compound and the accumulation of methyl ketone were monitored at 0, 10, 30, 60, and 120 minutes.

[0386] Hepatocyte stability

[0387] Incubate the test compound (prodrug, concentration 0.1 - 20 mg / mL) with human or rat hepatocytes at 37 °C. Terminate the reaction by adding cold acetonitrile containing an internal standard (IS) at appropriate time points (including time points: 0, 10, 30, 60, 90, and 120 minutes). After centrifugation, analyze the supernatant by LC-MS / MS. Monitor the disappearance of the test compound and the accumulation of methyl ketone over a period of time.

[0388] Prepare a stock solution in dimethyl sulfoxide (DMSO) and store it in a freezer at -20 °C. On the day of the experiment, prepare additional dilutions in an appropriate solvent. Prepare the positive control solution in the same manner. On the day of the experiment, prepare additional dilutions. The organic content in the final incubation should be ≤1.0%.

[0389] Prepare a quenching solution with acetonitrile containing tolbutamide / labetalol (internal standard) for incubating samples. Record the detailed concentrations. The quenching solution is stored at room temperature and kept on ice before use.

[0390] Thaw and isolate cryopreserved hepatocytes using a cryopreserved hepatocyte thawing medium. Determine the viability of hepatocytes using the trypan blue exclusion method, and viable cells should be ≥70%. Prepare the cell suspension to an appropriate concentration using Williams' E medium.

[0391] Perform the incubation in a 96-well plate. Incubate the test article with the hepatocyte suspension (in triplicate) at a cell density of 0.5×10 6 cells / mL. Then, incubate the sample plate in an incubator at 37 °C, 5% CO2, and 95% relative humidity, while shaking on a plate shaker at 150 rpm. At each designated time point, terminate the incubation by adding 3 volumes of cold quenching solution.

[0392] Positive control, incubate 7-ethoxycoumarin and 7-hydroxycoumarin in parallel at 3 μM. Include medium control samples in the absence of cells. Determine that the total organic concentration in the mixture is ≤1%.

[0393] Place all sample plates on a plate shaker at 500 rpm for 15 minutes and centrifuge at 3,220×g for 20 minutes. If necessary, dilute the supernatant with a water / organic mixture at an appropriate ratio for LC / MS / MS analysis.

[0394] Analyze the concentrations of the test compound and the control compound in the samples by using liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS / MS) method. Perform chromatogram plotting and peak area integration.

[0395] Using a semi - quantitative method, i.e., using the peak area ratio of the analyte to the internal standard, the concentrations of the test article, methyl ketone, and control compound in the sample were determined. No calibration curve and QC were applied, and the analyte / internal standard peak area ratio was used as the concentration in the sample.

[0396] The in vitro elimination constant k of the compound e Calculated from the log - linear plot of concentration or analyte / internal standard peak area ratio against time, and the half - life (t 1 / 2 ) was determined using the following equation:

[0397] t 1 / 2 (min)=0.693 / k e

[0398] The estimated value of the in vitro intrinsic hepatic clearance (CL int ) was calculated from the rate of substrate disappearance in hepatocyte incubation as follows:

[0399] CL int(肝细胞) =0.693 / half - life / million cells

[0400] CL int(肝) =CL int(肝细胞) ×number of stem cells×hepatic scaling factor

[0401] The parameters used in the equations are summarized in Table 9 below.

[0402] Table 9

[0403]

[0404] Behavioral pharmacological studies to evaluate the efficacy of prodrugs and enantiomers

[0405] Antidepressant efficacy in the forced swim test (FST)

[0406] The forced swim test (FST) is a classical model for evaluating the antidepressant-like activity of compounds and has been used for over 40 years (Porsolt et al. (1977) Nature 266:730 - 732; Detke et al. (1995) Psychopharmacology 121:66 - 72). All classes of antidepressants, including selective serotonin reuptake inhibitors, noradrenergic reuptake inhibitors, tricyclic antidepressants, and more recently, rapid-acting antidepressants such as ketamine, psilocybin, or MDMA, have been shown to reduce the immobility state in the FST. Methylone has robust, dose-dependent antidepressant-like effects in the rat forced swim test (FST). Compared to vehicle-treated control groups, a single dose of 5 mg / kg methylone reduced immobility by approximately 50%, while a 15 mg / kg dose reduced immobility by nearly 100%. The accompanying changes in climbing and / or swimming behaviors respectively reflect the noradrenergic and serotonergic activities of methylone.

[0407] All FST studies were conducted and scored by experimenters blinded to the treatment groups and according to a standard protocol. Briefly, rats were placed in a round plexiglass container filled with water. For each animal, the water temperature was maintained at 22 - 25 °C and varied. Day 1 (training) consisted of a 15-min acclimation trial, and Day 2 (testing, 24 h later) consisted of a 5-min test. Using a time sampling procedure, animals were observed every 5 s during the test session (60 times or 5 min) and scored for immobility (defined as failure to struggle), swimming (defined as circular motion around the circumference of the tank), or climbing (defined as upward escape behavior). Data were expressed as a percentage of the test session (e.g., the number of immobility counts divided by 60). After typical statistical analyses (e.g., unpaired t-tests or ANOVA), p-values less than 0.05 indicated statistical significance.

[0408] To determine whether prodrugs and / or enantiomers have antidepressant-like effects and to compare them to methylone, rats were treated with each compound 30 min prior to testing. Additional tests were performed 24, 72, 168 h or longer after dosing.

[0409] Effect on fear extinction in a post-traumatic stress disorder (PTSD) model

[0410] Methyl ketone (30 mg / kg, IP) significantly improved fear extinction recall in a PTSD mouse model (Figure 1). Fear extinction memory deficits are characteristic of PTSD in patients (Wicking et al. (2016) Neurobiology of Learning and Memory 136:116). SSRI antidepressants, similar to two drugs already approved for treating PTSD (i.e., paroxetine and sertraline), prevent fear memory generalization and enhance extinction (Pedraza et al. (2019) Transl Psychiatry 9:53). Enhanced fear extinction may also underlie the beneficial effects of MDMA as a treatment for PTSD (Feduccia and Mithoefer (2018) Progress in Neuro-Psychopharmacology & Biological Psychiatry 84(Part A), 221-228).

[0411] Effective PTSD treatment facilitates the dissociation between traumatic memories and the patient's fear response, such that cues of the traumatic memory less readily elicit a fear response. This is modeled by a mouse fear extinction paradigm lasting 3 days. On Day 1 (conditioned fear), mice are trained to acquire a "traumatic memory" by associating a conditioned stimulus (CS, tone) with an unconditioned stimulus (US, foot shock). On Day 2 (extinction training), they are trained to forget the traumatic memory association by presenting the CS 6 times (without the US) in a novel environment. On Day 3 (extinction recall), the mice are "asked" whether the tone (CS) still elicits a fear response, as measured by the time spent freezing upon hearing the tone. The shorter the freezing time, the better the memory extinction. Drugs that improve extinction recall reduce the freezing time on Day 3 and thus show potential as a treatment for PTSD.

[0412] Work using MDMA has shown that administration of MDMA (7.5 mg / kg) 30 minutes before extinction training following conditioned fear enhanced extinction recall, measured as a 35% reduction in freezing compared to a control group injected with saline (Young et al. (2015) Transl Psychiatry 5:e634). Using a similar experimental design, recent results have shown that methyl ketone (30 mg / kg) significantly enhanced fear extinction recall (Figure 1), approaching 60%, compared to a saline control ( Figure 1B ). Using these methods, prodrugs and / or enantiomers are administered to mice and their efficacy is tested in a fear extinction model to evaluate their efficacy in treating PTSD and other memory disorders.

[0413] Anxiolytic effects in other behavioral anxiety models

[0414] The anxiolytic effects of methylone and its prodrugs in mice or rats were evaluated using additional behavioral tests including haptotaxis in the elevated plus maze (EPM) and the open field test (OFT). Methylone (5, 10, 20 mg / kg, SC) has been shown to reduce haptotaxis (time spent in close proximity to the perimeter of an open field) in rats ( et al. (2017) Front Psychiatry 8:232), consistent with an anxiolytic effect. These models are described in more detail below. Prodrugs were screened in these behaviors to determine the anxiolytic efficacy of each compound.

[0415] Methylone reduces the time spent in the center of the OFT relative to the periphery, which is consistent with an anxiolytic-like response. Methylone is also a stimulant that increases locomotor activity in this test. The compounds were screened for their effects on two parameters. Briefly, rodents were assessed over a 30-minute OFT using an automated activity monitoring system. Rodents were acclimated to the room 30 minutes prior to the start of the test. The following parameters were captured: horizontal distance traveled, total ambulation time, and number of ambulations. Vertical activity (time and counts), center versus periphery time data, and total time reports were reported in 5-minute bins.

[0416] EPM is a classic anxiety model that also takes advantage of rodents' dislike for open spaces. The effects of prodrug compounds and methyl ketones were tested in this model. In brief, rodents were adapted to the lounge at least 30 minutes before the start of the experiment. The test was conducted under dim light (40lux). The elevated plus maze consists of two open arms and two closed arms (arm length: 30cm; width: 5cm). The open arms have a small edge of 1cm, while the closed arms are bordered by 15cm walls. At the beginning of the task, the rodents were placed in the center of the elevated plus maze, facing the open arms, and video-tracked while exploring the maze for 5 minutes. The time spent in the open arms and closed arms was measured and analyzed. The time spent in the open arms is longer than in the closed arms, which is consistent with the anxiolytic effect.

[0417] Example 3

[0418] Synthesis of methyl ketones

[0419] Starting from 3,4-methylenedioxypropiophenone (MDP), methyl ketone hydrochloride was prepared in three stages as shown in Scheme 18 below.

[0420] Scheme 18

[0421]

[0422] The chemical formula of methyl ketone hydrochloride is C 11 H 13NO3·HCl; molecular weight 243.7 g / mol (HCl), 207.2 g / mol (free base). The chemical structure of methyl ketone hydrochloride is

[0423]

[0424] Stage 1 : 3,4-methylenedioxyphenylpropanone (MDP) to 2-bromo-3',4'-(methylenedioxy)propiophenone (MDPBP)

[0425]

[0426] React 3,4-methylenedioxyphenylpropanone (MDP) with copper(II) bromide (CuBr2) and potassium bromide (KBr) in toluene. Heat the resulting suspension of reactants to 85 - 95 °C for 24 hours. After completion, cool the reactants to 22 - 24 °C and filter through diatomaceous earth to remove insoluble copper salts. Wash the filtrate up to 5 times with 2.8% ammonium hydroxide to remove soluble copper salts. Distill the organic layer under reduced pressure to remove toluene,

[0427] leaving a brown solid.

[0428] Stage 2 : 2-bromo-3',4'-(methylenedioxy)propiophenone (MDPBP) to methyl ketone hydrochloride

[0429]

[0430] At 22 ± 2 °C, within 45 ± 15 minutes, add 40% aqueous methylamine solution to a solution of 2-bromo-3',4'-(methylenedioxy)propiophenone (MDPBP) in MIBK. Stir the reaction mixture at 30 °C for 4 hours. After completion, quench the reaction with 20% aqueous sodium hydroxide (NaOH) while maintaining the temperature at 22 ± 2 °C. Separate the layers and wash the organic layer three times with water. Cool the organic layer to 0 - 10 °C and slowly add isopropanol (IPA) containing 0.5 - 0.6 N HCl, maintaining the temperature below 10 °C. Stir the resulting solution at 0 - 10 °C for at least 2 hours and then filter. Wash the solid with IPA and then sample and analyze its purity by HPLC (IPC2). If the sample purity > 98% and there are no impurities > 0.5% and the appearance is white to off-white, dry the material. If the process specifications are not met, perform stage 3 purification.

[0431] Stage 3 : Purification of methyl ketone hydrochloride

[0432]

[0433] If methyl ketone hydrochloride does not meet the process specifications, additional purification steps are required. Heat the mixture of methyl ketone hydrochloride in methanol and isopropyl alcohol to reflux (65 °C). Stir the resulting solution at reflux for 1 hour. Cool the slurry to 0 - 10 °C and hold at this temperature for 2 hours. Filter the solid and wash with isopropyl alcohol, then dry under reduced pressure at 60 °C. Sample the resulting solid and analyze its purity by HPLC and its moisture content by loss on drying (LOD).

[0434] In - process control (IPC) checks are performed at various stages of the reaction, including verification of hold times, pH adjustment, etc. IPC purity tests are used at each major step (stage) of the synthesis to ensure that the quality of the intermediate product is adequate before proceeding to the next synthesis step. Table 10 presents the results of two batches prepared according to this example, as well as the results of three (“reference”) batches prepared according to the standard method. Relative to the reference batches, the purity of the batches prepared according to this example is improved and the yield is increased by more than 8 - fold.

[0435] Table 10: Bulk analysis of API batches

[0436]

[0437] NMT = Not more than; ND = Not detected.

[0438] Potential sources of impurities in the synthesized methyl ketone may include residual starting materials, potential process impurities, and degradation products. These may include:

[0439]

[0440] The following is a description of the HPLC method used for determining assay and related substances.

[0441] Table 11: Chromatographic conditions

[0442] Column Waters Symmetry C18 4.6×150mm, 5μ Flow rate 1.0 mL / min Mode Gradient Injection volume 10 μL Column temperature 25℃±2℃ Detector 254 nm Run time 32 min

[0443] Table 12: Gradient

[0444]

[0445]

[0446] Solution preparation :

[0447] Mobile phase A - (MPA)

[0448] Add 1000 mL of water to an HPLC vial. Add 200 μL of TEA (triethylamine) and mix well.

[0449] Mobile phase B - (MPB)

[0450] Add 1000 mL of ACN to an HPLC vial. Add 200 μL of TEA (triethylamine) and mix well.

[0451] Diluent

[0452] Methanol

[0453] Table 13: Desired retention times:

[0454] Compound Retention time (minutes) Relative retention time (RRT) Methyl ketone 7.9 1.00 2,3 - Methyl ketone 8.5 1.08 MDP 13.4 1.70 MDPB 16.8 2.13

[0455] The data in Table 14 compared the methyl ketones synthesized as described in this example with a "reference" material commercially available from Cayman chemicals. The methyl ketones synthesized as described in this example had fewer impurities and lower impurity levels compared to the reference material, where the unspecified impurities of the reference material were greater than the impurity acceptance thresholds according to the ICH Q3A and ICH Q3B guidelines.

[0456] Table 14:

[0457]

[0458]

[0459] Since MDPBP is electrophilic and thus mutagenic, an in vitro Ames test was performed as described in Table 8. 2,3 - methyl ketone and MDP are not electrophilic and thus only computer - based quantitative / qualitative structure - activity relationship (QSAR) was performed (Cayley et al. (2023) Regulatory Toxicology and Pharmacology 144:105490), and the results were negative. Thus, one aspect of the present invention is to produce methyl ketones that are not mutagenic and do not have mutagenic impurities.

[0460] Example 4

[0461] Alternative synthesis of methoxy ketones

[0462] As described below, using an alternative synthesis, starting from 3,4 - methylenedioxypropiophenone (MDP), methyl ketone hydrochloride was prepared.

[0463] Phase 1:

[0464]

[0465] React 15 mL / g of toluene containing 3,4 - methylenedioxyphenyl - 2 - propanone (MDP) with copper(II) bromide (CuBr₂) (2.9 g / g, 2.3 equivalents) and potassium bromide (KBr) (0.13 g / g, 0.2 equivalents) by heating to 85 - 95 °C and stirring for at least 24 hours. After completion, cool the reaction mixture to 15 - 25 °C and filter through Celite 545 (0.79 g / g). Wash the filtrate twice with toluene and add it to a clean container. Then add 9 mL / g of water containing ammonia (1 mL / g) to the container and stir for at least 5 minutes. Allow the phases to separate and remove the bottom aqueous layer. Solids are observed at the interface of the two layers and these are retained in the organic layer. Add 9 mL / g of water containing ammonia (1 mL / g) two more times and stir for at least 5 minutes to allow the phases to separate and remove the bottom aqueous layer. Solids are observed at the interface of the two layers and these are retained in the organic layer. Pool the aqueous layers and add them back to the container. Add toluene and stir for at least 5 minutes and separate the layers. Combine the organic layers from this step and the previous step into the container. Add 300 mL of THF to the organic layer on a 55 g scale to aid in dissolving the solids. Add saturated brine (10 mL / g) and stir for at least 5 minutes to allow the phases to separate and remove the bottom aqueous layer. Dry the organic phase over MgSO₄, then filter and wash with toluene (3 mL / g). Evaporate the filtrate to dryness (maximum temperature 50 °C).

[0466] Stage 2:

[0467]

[0468] The product of the previous stage was dissolved in tetrahydrofuran (26 mL / g) and added dropwise to water (1.67 mL / g, 5 equivalents) containing 40% by weight of methylamine in stirring at 15-25° C. over 1 hour, and then stirred for 3 hours. Then saturated brine (5 mL / g) at 15-25° C. and sodium hydroxide (0.15 g / g, 1 equivalent) at 15-25° C. were added and stirred for at least five minutes. The layers were separated and the bottom aqueous layer was removed from the container. Water (2.5 mL / g) at 15-25° C. was added. Concentrated sulfuric acid (1 mL / g) at 15-25° C. was added dropwise over about one hour while stirring until a pH of 1 was reached. n-heptane (5 mL / g) was added and stirred for at least 5 minutes, and then the layers were separated. Tert-butyl methyl ether (TBME; 5 mL / g) was added and then stirred for at least 5 minutes. The layers were separated and the bottom aqueous layer was added back to the container. This step was repeated twice more. Add tert-butyl methyl ether (10mL / g), and under stirring, drip an aqueous solution (10mL / g) of sodium hydroxide (1.6g / g) at 15-25°C in about one hour until a pH of 12 is reached. Then add saturated brine (5mL / g) at 15-25°C and stir for at least five minutes. Separate the layers and add the bottom aqueous layer back to the container. Then add tert-butyl methyl ether (5mL / g) and stir for at least 5 minutes. Separate the layers and add the bottom aqueous layer back to the container. Then add tert-butyl methyl ether (5mL / g) and stir for at least 5 minutes, then separate the layers. The organic layers of the previous steps are collected and added to a clean container, then cooled to 0-10°C. A 2-propanol solution (1mL / g) of hydrochloric acid (5-6M) at 0-10°C is dripped in about 15 minutes. The resulting solution is stirred at 0-10°C for at least one hour, then filtered. The filtrate was washed with tert-butyl methyl ether (5 mL / g) and dried under vacuum at 45 °C.

[0469] Purification of the final product

[0470] The final product was obtained by slurrying methyl ketone hydrochloride in isopropanol at 60°C, cooling to 5-10°C, then filtering and drying. The final purity was 99.1%.

[0471] Example 5

[0472] Purification and separation of methyl ketone enantiomers

[0473] The solid of the mixture of methyl ketone enantiomers was dissolved in 60% hexane / 40% EtOH / 0.1% diethylamine (DEA) to a concentration of 2 mg / mL. 4.2 mg (2.1 mL of the starting material solution) was injected and loaded into CHIRALPAK On a (10×250 mm, 5 μm) HPLC preparative column, 70% hexane / 30% EtOH / 0.1% DEA was used as the eluent at a flow rate of 6.0 mL / min and monitored at 228 nm. A certain volume (about 221 μL / injection = about 2-fold molar equivalents of the expected DEA in each fraction) of 2.0 N HCl was pre-added to each fraction container. The first fraction (F1) was collected starting from the inflection point of the UV reading (about 7 min) and 4.4 mL was collected, then switched to the second fraction (F2). F2 was collected until the local UV minimum, then switched to the third fraction (F3). F3 was collected and 7.5 mL was collected, then switched to the fourth fraction (F4). F4 was collected until 1 minute after the UV reached the baseline. Immediately after the last injection, the fraction containers were transferred to a rotary evaporator (rotation speed: 20 - 120 rpm; bath temperature: 35 °C), and the eluent was removed by vacuum distillation until the material was under full vacuum. The resulting material was a white solid powder and it was reconstituted in 100% EtOH and filtered through a 0.45 μm filter into a 40 mL vial via a syringe. At this point, most of the material was the DEA-HCl salt.

[0474] To remove the DEA-HCl salt, the material was dissolved in 20% MeOH / 80% H2O / 0.05% trifluoroacetic acid (TFA) to a concentration of up to 20 mg / mL. TFA was chosen as the acidic modifier due to its relatively low boiling point (72.4 °C), which is close to the boiling point of the mobile phase solvent ethanol (78.4 °C). Up to 500 mg (limited by the size of the injection loop) was injected and loaded onto a Phenomenex Luna 10 μm PREP C18(3), 250×50 mm HPLC preparative column, using 20% MeOH / 80% H2O / 0.05% TFA as the eluent at a flow rate of 100.0 mL / min and monitored at 228 nm. A single fraction of the entire peak eluting at about 11 minutes was collected. Immediately after the last injection, the single fraction container was transferred to a rotary evaporator (rotation speed: 20 - 120 rpm; bath temperature: 60 °C), and the eluent was removed by vacuum distillation until the material was under full vacuum. The resulting material was an amber oil and it was reconstituted in the minimum amount of 100% EtOH and filtered directly into the finished product container through a 0.45 μm filter via a syringe.

[0475] The container (via appropriate fittings) is adapted to a rotary evaporator, which is set under an inert atmosphere for processing. There is a vacuum trap in the Dewar flask, which is cooled by a dry ice / acetone bath on the vacuum tube. The solvent is carefully removed via vacuum distillation until the material is in a complete vacuum state. The container is removed from the vacuum, sampled, and capped under an inert atmosphere. The final mass is recorded after sampling. The removal of DEA is confirmed via refractive index analysis.

[0476] The typical purity of the earlier eluting (R)-methyl ketone enantiomer is about 99% ee, and there is little loss of its enantiomeric purity (about 98% ee) during post-purification handling. The typical purity of the later eluting (S)-methyl ketone enantiomer is about 99% ee, and there is little loss of its enantiomeric purity (about 98% ee) during post-purification handling.

[0477] Example 6

[0478] Competitive radioligand binding studies of methyl ketone enantiomers indicate that (S)-methyl ketone has antidepressant and anxiolytic benefits where it has less cardiovascular side effects

[0479] Methyl ketones act on three monoamine transporters, the serotonin transporter (SERT), the dopamine transporter (DAT), and the norepinephrine transporter (NET). Racemic methyl ketone binds to SERT, DAT, and NET, and through these transporters, it inhibits the reuptake of the neurotransmitters serotonin (5HT), dopamine (DA), and norepinephrine (NE), and promotes their release. The antidepressant-like and anxiolytic effects of racemic methyl ketone may be related to its action on SERT, while the cardiovascular side effects may be related to its action on NET. Therefore, this study aimed to examine whether either of the two methyl ketone enantiomers showed preferential binding to SERT and / or weaker binding to NET, in order to identify a compound that has the antidepressant-like and anxiolytic effects of racemic methyl ketone and fewer cardiovascular side effects.

[0480] Methods

[0481] Rat brain (Sprague Dawley, 200 - 250 g) synaptosomes were isolated from the midbrain and hindbrain for serotonin transporter assays, from the striatum for dopamine transporter assays, and from the hippocampus and overlying occipital cortex for norepinephrine transporter (NET) assays. The radioligands used were: 3 [³H] Citalopram 81.4 Ci / mmol (PerkinElmer NET1039250UC; lot number 2960876). 3H]WIN3542882.8 Ci / mmol (PerkinElmer NET1033250UC; lot number 2891473). 3 H]Nisoxetine 79.2 Ci / mmol (PerkinElmer NET1084250UC; lot number 2970324). The non-specific compounds used were: Citalopram (Tocris Bioscience 1427). JHW007 (Tocris Bioscience 4351). Nisoxetine (Abcam ab146004). The test compounds studied were: racemic methyl ketone hydrochloride; (R)-methyl ketone hydrochloride; (S)-methyl ketone hydrochloride.

[0482] For the membrane preparation, the rat brain was dissected, and the tissue was added to ice-cold lysis buffer (50 mM Tris HCl; 5 mM MgCl2; 5 mM EDTA; protease inhibitor mixture) and homogenized. The homogenate was centrifuged at 100×g for 2 minutes, and the supernatant was aliquoted into polypropylene Eppendorf tubes. The supernatant was centrifuged at 17,000×g for 10 minutes at 4°C to reprecipitate the cell lysate. The pellet was resuspended in fresh wash buffer (50 mM Tris-HCl; 5 mM MgCl2; 5 mM EDTA) and centrifuged at 17,000×g for a third time for 10 minutes at 4°C. The pellet was resuspended in wash buffer containing 10% sucrose as a cryoprotectant, aliquoted (0.3 mL) and stored at -80°C. Using BCA assay to analyze the protein content of the homogenate samples. On the day of the assay, the membrane preparation was thawed, and the pellet was resuspended in the final assay buffer.

[0483] The competitive binding assay was performed in 96-well polypropylene plates with a final volume of 250 μL per well. To each well was added 150 μL of membrane, 50 μL of test compound, non-specific compound or buffer, and 50 μL of buffer containing the radioligand solution. The plates were incubated at 30°C for 90 minutes with gentle agitation. Using a 96-well FILTERMATE TM Harvester, the incubation was stopped by vacuum filtration onto pre-soaked (with wash buffer containing PEI) GF / C filters, and then washed 5 times with ice-cold wash buffer. The filters were then dried under a warm air stream, sealed in polyethylene, scintillation mixture was added, and counted for radioactivity in a TriLux 1450 MicroBeta counter. For each drug concentration, non-specific binding was subtracted from total binding to obtain specific binding. Using (Graphpad Software Inc)'s non-linear curve fitting routine fits the data to determine the IC 50 . Subsequently, the ChengPrusoff equation is used to calculate K i .

[0484] Results:

[0485] Table 15 shows the summary of the IC 50 and inhibitor constant values (K i ) of racemic methyl ketone, (R)-methyl ketone, and (S)-methyl ketone at SERT, DAT, and NET. Overall, the results indicate that (S)-methyl ketone is a more potent SERT inhibitor than racemic methyl ketone, its effect is comparable at DAT, and its potency is almost twice lower than that of racemic methyl ketone at NET. In contrast, (R)-methyl ketone is approximately three times less potent than racemic methyl ketone at SERT and DAT, but has comparable potency at NET. This suggests that (S)-methyl ketone exhibits potentially favorable binding characteristics, which achieve (1) stronger affinity for SERT, which site is considered the basis for the efficacy of methyl ketone, (2) comparable affinity for DAT, and (3) lower affinity for NET, which site may be the basis for the cardiovascular effects of methyl ketone. Generally speaking, based on its effects at the monoamine transporters SERT, DAT, and NET, the (S)-methyl ketone stereoisomer has the potential to exhibit the beneficial activities of racemic methyl ketone at lower doses and may therefore have fewer cardiovascular side effects.

[0486] Table 15: Summary of competitive ligand binding studies

[0487]

[0488] Example 7

[0489] Methyl ketone enantiomers: Effects on the reuptake inhibition of serotonin, dopamine, and norepinephrine

[0490] To expand the results of the binding studies and determine whether the different effects of methyl ketone enantiomers on binding to SERT, NET, and DAT have a functional impact on neurotransmitter reuptake inhibition, it was investigated whether the degree of reuptake inhibition of serotonin (5HT), norepinephrine (NE), and / or dopamine (DA) by the methyl ketone enantiomers (R)-methyl ketone or (S)-methyl ketone is the same as that of racemic methyl ketone.

[0491] Methods:

[0492] The materials used were: neurotransmitter 3 H]5-HT (PerkinElmer, NET498001MC), 3H]Dopamine (PerkinElmer, NET673250UC), 3 H]Norepinephrine (PerkinElmer, NET377250UC); test compound racemic methyl ketone hydrochloride (Merck, M-140); (R)-methyl ketone hydrochloride (Pisgah Labs); (S)-methyl ketone hydrochloride (Pisgah Labs); reference compounds citalopram (Tocris Bioscience 1427), JHW007 (Tocris Bioscience 4351), nisoxetine (Abcam ab146004).

[0493] Using standard protocols, synaptosomes were prepared from Sprague Dawley (200 - 250 g) rat brain regions (hippocampus for NE, striatum for DA, and midbrain for 5-HT). The tissues were dissected, sucrose buffer (0.32 M) was added, homogenized with a Dounce homogenizer, and centrifuged at 100×g to remove cells and debris. The supernatant was collected and centrifuged at 17,000×g for 10 minutes at 4 °C to pellet the synaptosomes. The pellet was resuspended in fresh assay buffer.

[0494] Uptake assays were performed in 96-well plates with a final volume of 250 μL per well. 150 μL of synaptosomes, 50 μL of test, non-specific compound, or buffer alone were added to each well. The plates were incubated at 30 °C for 30 minutes with gentle agitation. Then 50 μL of buffer containing radiolabeled neurotransmitter was added to each well to initiate uptake. The plates were incubated at 30 °C for an additional 5 minutes with gentle agitation. Using a 96-well FilterMate TM Harvester, incubation was stopped by vacuum filtration onto pre-soaked GF / C filters, which were then washed 3 times with ice-cold wash buffer. The filters were then dried under a warm air stream, sealed in polyethylene, scintillation mixture was added, and radioactivity was counted in a TriLux 1450 MicroBeta counter.

[0495] For each drug concentration, non-specific uptake was subtracted from total uptake to obtain specific uptake. Data were fitted using a non-linear curve fitting routine in (Graphpad Software Inc) to determine the IC 50 .

[0496] Results:

[0497] Table 16 shows the uptake inhibition IC of racemic methyl ketone, (R)-methyl ketone, and (S)-methyl ketone for each of 5HT, DA, and NE50 Value and release of EC 50 Summary of values. Overall, the results are consistent with those observed in competitive binding studies. Specifically, compared to racemic methyl ketone and (R)-methyl ketone, (S)-methyl ketone is a more potent inhibitor of serotonin (5HT) and dopamine (DA) reuptake and is a more potent serotonin releaser. The effects of the three compounds on norepinephrine (NE) are consistent. Combining the results of the competitive binding studies, these results further support that the (S)-methyl ketone stereoisomer provides greater efficacy via its effect on serotonin and smaller cardiovascular side effects via norepinephrine.

[0498] Table 16: Summary of uptake inhibition and release studies using (R)-methyl ketone, (S)-methyl ketone, and racemic methyl ketone

[0499]

[0500]

[0501] Example 8

[0502] In in vitro cardiovascular safety screening tests, neither methyl ketone nor its stereoisomers bind to cardiac channel nodes Combination.

[0503] In vitro cardiovascular safety screening tests were conducted to investigate the effects of racemic methyl ketone and two methyl ketone stereoisomers ((R)-methyl ketone and (S)-methyl ketone) on selected ion channels that are important in cardiovascular function and activity. Antagonism of any ion channel in this screening significantly increases the risk of cardiovascular effects.

[0504] Method:

[0505] Electrophysiological assays were performed using the Qube electrophysiology platform to dissect the activities of three compounds ((R)-methyl ketone, (S)-methyl ketone, or racemic methyl ketone) on the ion channel targets specified below. In the cases presented, IC 50 values were determined by nonlinear least squares regression analysis. Reference standards were tested as part of each assay to ensure the validity of the results obtained. Results showing inhibition greater than 50% were considered to represent a significant effect of the test compound and are listed in the following tables, which have separate calculated results or calculable IC 50 .

[0506] Using the automated whole-cell patch clamp (Qube 384) technique, depolarizing currents of hNav1.5 and hCav1.2 and outward potassium current of hERG were recorded in the multi-well mode. Recombinant HEK-293 cells stably transfected with human Nav1.5 cDNA, a recombinant HEK293 cell line expressing human Cav1.2 (L-type voltage-gated calcium channel, hCav1.2α1C / β2a / α2δ1), and recombinant CHO-K1 cells stably transfected with human hERG cDNA were used separately in each assay.

[0507] Reference compounds: Tetracaine, nifedipine, and verapamil were tested against hNav1.5, hCav1.2, and hERG at multiple concentrations simultaneously to obtain IC50 values.

[0508] The ion channels tested were Eurofins kit component number: CPROFullQB2DR, voltage-gated sodium channels: HEK-Nav1.5 (peak), HEK-Nav1.5 (late, antagonist); voltage-gated potassium channels: HEK-Kv4.3 / KChIP2, CHO-hERG, CHO-KCNQ1 / minK; voltage-gated calcium channels: HEK-Cav1.2, inward rectifier potassium channels: HEK-Kir2.1.

[0509] The methods used in this study were developed and validated by Eurofins and are reliable and reproducible. The assays were performed under the following conditions.

[0510] hNav1.5 sodium channel assay - Qube APC Using the pulse mode to measure the onset and steady-state block of peak Nav1.5 current, repeated every 5 seconds. The pulse mode consisted of: a hyperpolarizing pulse to -120 mV for 200 ms duration; depolarization to -15 mV amplitude for 40 ms duration; then a step to 40 mV for 200 ms; and finally a 100 ms ramp (1.2 V / s) to the holding potential of -80 mV. The peak current was measured during the step to -15 mV.

[0511] hKv4.3 / hKChIP2 potassium channel assay - Qube APC After achieving the whole-cell configuration, the cells were held at -80 mV. The onset and steady-state block of hKv4.3 current were measured using the pulse mode, with an amplitude ranging from -80 mV to 40 mV for 110 ms duration, and finally a 100 ms ramp (1.2 V / s) down to -80 mV. This protocol was delivered every 5 s to monitor the current amplitude.

[0512] hCav1.2 (L-type) Calcium Channel Assay - After achieving whole-cell configuration with Qube APC, the cell was held at -90 mV. Cav1.2 current was elicited by: a 50-ms pulse to -100 mV, followed by a 200-ms pulse to +20 mV, and then returned to the holding potential of -90 mV. This protocol was delivered three times every 60 s to monitor the current amplitude.

[0513] hNav1.5 Late Current Sodium Channel Assay - Qube APC measured the onset and steady-state block of late Nav1.5 current using a pulse protocol that was repeated every 5 s and consisted of: a hyperpolarizing pulse to -120 mV for 200 ms duration; depolarization to -15 mV amplitude for 40 ms duration; followed by a step to 40 mV for 200 ms; and finally a 100-ms ramp (1.2 V / s) to the holding potential of -80 mV. The late current was measured as the capacitive current evoked by 50 nM ATXII during the slow ramp.

[0514] hERG Potassium Channel Assay - After achieving whole-cell configuration with Qube APC, the cell was held at -80 mV. The cell was held at this voltage for 50 ms to measure the leak current, which was subtracted online from the tail current. The cell was depolarized to +40 mV for 500 ms and then ramped to -80 mV over 100 ms to evoke the hERG tail current. This protocol was delivered once every 8 s to monitor the current amplitude.

[0515] hKCNQ1 / hminK Potassium Channel Assay - After achieving whole-cell configuration with Qube APC, the cell was held at -80 mV. KCNQ1 / minK current was elicited by: a pulse from -80 mV to 60 mV for 1000 ms, followed by a ramp from 60 mV to -80 mV over 115 ms, during which the outward peak current was measured upon cell membrane depolarization. This protocol was delivered once every 15 s to monitor the current amplitude.

[0516] hKir2.1 Potassium Channel Assay - After achieving whole-cell configuration with Qube APC, the cell was held at -30 mV. Kir2.1 current was elicited by: a single 500-ms pulse to -120 mV, and then returned to the holding potential of -30 mV. This protocol was delivered once every 20 s to monitor the current amplitude.

[0517] Results:

[0518] As shown in Table 17, the results of this study indicate that the stereoisomers ((R)-methyl ketone or (S)-methyl ketone) and the racemic methyl ketone have no effect on the cardiac ion channels tested. All control (reference) compounds elicited the expected effects, validating this assay. In summary, this suggests that methyl ketone and its enantiomers do not directly inhibit the activity of cardiac channels.

[0519] Table 17: Summary of the estimated IC 50 of compounds

[0520]

[0521]

[0522] *N / C indicates that the observed mean inhibition < 25%

[0523] Example 9

[0524] Use the rat forced swim test (FST) to evaluate the antidepressant properties of methyl ketone stereoisomers

[0525] Racemic methyl ketone (10 mg / kg, IP) had the maximum antidepressant-like effect in the forced swim test (FST) in rats, with a nearly 100% reduction in the immobility state compared to vehicle-treated controls. To determine whether one enantiomer of methyl ketone could mimic the potent antidepressant-like effect of racemic methyl ketone, rats were treated with a single dose of racemic methyl ketone, (R)-methyl ketone, (S)-methyl ketone (all at 10 mg / kg, IP) or vehicle 30 min before the FST test. The (S)-methyl ketone enantiomer mimicked the rapid and potent antidepressant-like effect of racemic methyl ketone, while (R)-methyl ketone had no effect compared to vehicle-treated animals ( Figure 2 ). Thus, all of the activity of methyl ketone appears to be driven by the activity of one enantiomer ((S)-methyl ketone).

[0526] Example 10

[0527] X-ray powder diffraction (XRPD) analysis of synthesized methyl ketone hydrochloride

[0528] Two GMP batches 213220 and 22720 of methyl ketone hydrochloride were evaluated and analyzed by X-ray powder diffraction (XRPD), NMR, and thermogravimetric analysis (TGA).

[0529] Based on the overlay of the X-ray powder diffraction (XRPD) patterns of methyl ketone hydrochloride batches 213220 and 227220, it was readily apparent by eye that the two XRPD patterns did not completely overlap. Thus, the two batches had significantly different crystalline phases. Additionally, the XPRD could not be indexed, indicating that the two batches had a mixture of crystalline forms rather than just one form.

[0530] In addition, neither batch of the TGA showed a melting point (apparently or otherwise), indicating the absence of solvates. The NMR data for the two batches of methyl ketone were also in complete agreement, indicating (like the TGA results) the absence of solvates. Elemental analysis was also performed on the two batches; neither class 1 nor class 2a was present in either of them.

[0531] The two batches 213220 and 22720 were recrystallized, and the raw materials and the recrystallized materials were examined and compared as described above. The XRPD spectra of the recrystallized batch of 213220 did not match those of the original batch. However, the two recrystallized GMP batches were nearly identical to each other, indicating that they were the same crystalline material. In addition, indexing of the two recrystallized batches of 213220 and 227200 indicated that each of them had a monoclinic structure. Furthermore, the matching of the XRPD peaks observed for the recrystallized batch 227220 indicated that the sample consisted mainly of a single crystal form that was comparable to the calculated pattern (Nycz et al. (2011) Journal of Molecular Structure 1002:10 - 18) of the methyl ketone hydrochloride structure (deposit number 819333) obtained from the CCDC. The TGA of the recrystallized batch of 213220 also did not show the presence of any water.

[0532] Table 18 - 21 provides the results of the stability studies for the methyl ketone hydrochloride batches 213220 and 227220 and for the capsules containing the methyl ketone hydrochloride batch 227220.

[0533] Table 18

[0534]

[0535]

[0536] BDL = Below detection limit; BRT = Below reporting threshold (<0.05%); GMP = Good Manufacturing Practice; HPLC = High - Performance Liquid Chromatography; KF = Karl Fischer; MDP = 3,4 - Methylenedioxyphenyl - 2 - propanone; MDPBP = 2 - Bromo - 3',4' - (methylenedioxy)propiophenone; N / A = Not applicable; ND = Not detected; NMT = Not more than; R&D = Research and Development; RH = Relative humidity; USP = United States Pharmacopeia.

[0537] 1 Sample preparation error. The preparation was modified before the 6 - month time point

[0538] Table 19

[0539]

[0540]

[0541] BDL = Below Detection Limit; BRT = Below Reporting Threshold (<0.05%); GMP = Good Manufacturing Practice; HPLC = High Performance Liquid Chromatography; KF = Karl Fischer; MDP = 3,4-Methylenedioxyphenylpropanone; MDPBP = 2-Bromo-3',4'-(methylenedioxy)propiophenone; N / A = Not Applicable; ND = Not Detected; NMT = Not More Than; R&D = Research and Development; RH = Relative Humidity; RRT = Relative Retention Time; USP = United States Pharmacopeia.

[0542] 1 Sample preparation error. Preparation was modified prior to the 6-month time point

[0543] Table 20: Stability test results for capsules of GMP batch 227220 of methylone hydrochloride: 40°C / 75% RH

[0544]

[0545] GMP = Good Manufacturing Practice; HPLC = High Performance Liquid Chromatography; KF = Karl Fischer; ND = Not Detected; NMT = Not More Than; RH = Relative Humidity; RRT = Relative Retention Time; USP = United States Pharmacopeia.

[0546] Table 21: Stability test results for capsules of GMP batch 227220 of methylone hydrochloride: Batch: 25°C / 60% RH

[0547]

[0548] GMP = Good Manufacturing Practice; HPLC = High Performance Liquid Chromatography; KF = Karl Fischer; ND = Not Detected; NMT = Not More Than; RH = Relative Humidity; USP = United States Pharmacopeia.

[0549] Example 11

[0550] Evaluate methyl ketone hydrochloride samples using X-ray powder diffraction (XRPD) and dynamic vapor sorption (DVS)

[0551] Two batches of methylone hydrochloride samples were submitted to evaluate the stability of the solid form under different humidity conditions. Dynamic vapor sorption (DVS) analysis was performed to evaluate the kinetic hygroscopicity and to assess the need for variable humidity XRPD, as well as to determine the appropriate humidity conditions for such XRPD analysis. Samples before and after DVS were analyzed by conventional XRPD for solid form confirmation or any possible form changes.

[0552] Results and Discussion

[0553] The following table summarizes the sample information and their corresponding XRPD and DVS data files:

[0554]

[0555] XRPD analysis of the original sample

[0556] The XRPD pattern of batch 213220 is consistent with the previously obtained XRPD pattern of this batch. As described in the previous example, it is a mixture of Form A and Form B in patent application WO2023 / 081403A1, where Form B is the main form. Batch KRR-R&D-2022-II-58 was recrystallized from batch 213220 and mainly exhibited a single crystal Form A phase, consistent with the data of this batch obtained previously.

[0557] DVS

[0558] The DVS results of the two samples are summarized in the following table. For batch 213220, the curves depicting the percentage change in sample weight against the percentage relative humidity (%RH) and weight against time are shown in Figure 3 . Both samples exhibited relatively low hygroscopicity, with a water absorption rate of less than 0.3 wt% between 5% and 95% RH. After desorption, the sample of batch 213220 showed little hysteresis and almost lost all the water adsorbed, while the sample of batch KRR-R&D-2022-II-58 showed a slight hysteresis and retained approximately 0.06% of the adsorbed water.

[0559]

[0560] XRPD analysis of the samples after DVS

[0561] The XRPD patterns of the samples before and after DVS of batches 213220 and KRR-R&D-2022-II-58 were compared respectively. For the samples after DVS of both batches, no form change was observed.

[0562] Conclusion

[0563] The crystal form stability and kinetic hygroscopicity of two batches (213220 and KRR-R&D-2022-II-58) of methyl ketone hydrochloride were evaluated via XRPD and DVS. The XRPD analysis of the samples before DVS confirmed that batch 213220 was a mixture of Form A and Form B, where Form B was the main form, while batch KRR-R&D-2022-II-58 mainly exhibited a single Form A crystal phase.

[0564] DVS analysis showed that both samples exhibited low hygroscopicity and that the materials did not absorb or desorb water within 5% to 95% RH, and XRPD analysis of the samples after DVS showed no change in their physical form. Therefore, there is no need to conduct variable humidity XRPD studies.

[0565] Experiment

[0566] X-ray powder diffraction (XRPD)

[0567] Each sample was prepared in a silicon low-background holder using slight manual pressure to keep the sample surface flat and flush with the reference surface of the sample holder. The single-crystal Si low-background holder has circular grooves (10 mm in diameter and approximately 0.2 mm in depth) for holding the sample. The Rigaku Smart-Lab diffractometer used was configured for Bragg-Brentano reflection geometry using a line-source X-ray beam. The Bragg-Brentano geometry is controlled by passive divergence and receiving slits, and the sample itself acts as the focusing component of the optical device. The data collection parameters are shown below:

[0568]

[0569] Dynamic vapor sorption (DVS)

[0570] DVS analysis was performed using a TA Instruments Q5000 dynamic vapor sorption analyzer. This instrument was calibrated using a standard weight and a sodium bromide humidity standard. Approximately 12 - 13 mg of each powder sample was loaded onto a quartz pan with a metal coating for analysis. The samples were analyzed from 5 to 95% RH (adsorption cycle) and from 95 to 5% RH (desorption cycle) in 10% RH steps. After meeting the equilibrium criterion of a 0.01% weight change within 5 minutes, or after 90 minutes if the equilibrium criterion was not met, the step was moved to the next one. The percentage weight change values were calculated using Microsoft 2016.

[0571] Those skilled in the art will understand that the above-described embodiments can be changed without departing from the broad inventive concept of the present invention. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.

Claims

1. A method for synthesizing methyl ketone hydrochloride, the method comprising (i) reacting 3,4-methylenedioxypropiophenone (MDP) with copper(II) bromide and potassium bromide in toluene, and after the reaction is completed, removing insoluble copper salts and soluble copper salts to obtain 2-bromo-3',4'-(methylenedioxy)propiophenone (MDPBP); (ii) obtaining a solution of MDPBP in methyl isobutyl ketone (MIBK), and adding 40% aqueous methylamine solution to the MDPBP solution; and (iii) obtaining an organic layer from (ii), and adding HCl in isopropanol to the organic layer to obtain methyl ketone hydrochloride.

2. The method according to claim 1, wherein the reaction in step (i) is carried out at 85°C - 95°C.

3. The method according to claim 1, wherein the insoluble copper salts are removed by filtration through diatomaceous earth.

4. The method according to claim 1, wherein the soluble copper salts are removed by washing with ammonium hydroxide.

5. The method according to claim 1, wherein the solution containing MDPBP and methylamine is mixed at 30°C.

6. The method according to claim 1, wherein the HCl in isopropanol is added to the organic layer at a temperature below 10°C.

7. The method according to claim 6, wherein the temperature is 0 - 10°C.

8. The method according to claim 1, wherein the method further comprises the following steps: Obtaining a solution of methyl ketone hydrochloride in methanol, and adding isopropanol to the methyl ketone hydrochloride solution to obtain purified methyl ketone hydrochloride.

9. The method according to claim 8, wherein the solution containing methyl ketone hydrochloride and isopropanol is heated to reflux at 65°C.

10. The method according to claim 9, wherein the solution is maintained at 0 - 10°C after being heated to reflux at 65°C.

11. The method according to claim 8, wherein the purified methyl ketone hydrochloride is obtained by drying under reduced pressure at 60°C.

12. A pharmaceutical composition, the pharmaceutical composition comprising methyl ketone hydrochloride synthesized or obtainable according to any one of claims 1 - 11; and a pharmaceutically acceptable carrier.

13. A method of treatment, the method comprising administering to a subject in need of such treatment an effective amount of methyl ketone hydrochloride synthesized or obtainable according to any one of claims 1 - 11.

14. The method according to claim 13, wherein the treatment is for post-traumatic stress disorder (PTSD), anxiety disorder, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), fibromyalgia, depression, acute stress disorder (ASD), cluster headache, conditions associated with cancer, hypomotility, burnout, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorder, nausea or vomiting.

15. The method according to claim 13, wherein the treatment is for post-traumatic stress disorder (PTSD).

16. The method according to claim 13, wherein the treatment is for anxiety disorder.

17. The method according to claim 13, wherein the treatment is for depression.

18. The method according to claim 13, wherein the treatment is for a personality disorder.

19. A pharmaceutical composition comprising substantially pure (S)-methyl ketone and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising (S)-methyl ketone in an enantiomeric excess relative to the (R)-methyl ketone enantiomer; and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising methyl ketone having a purity greater than 99.7% as determined by HPLC.

22. The pharmaceutical composition according to claim 21, wherein the composition is a pharmaceutically acceptable salt of methyl ketone or a substantially pure stereoisomer of methyl ketone.

23. The pharmaceutical composition according to claim 22, wherein the pharmaceutically acceptable salt of methyl ketone is methyl ketone hydrochloride.

24. The pharmaceutical composition according to claim 22, wherein the substantially pure stereoisomer of methyl ketone is (S)-methyl ketone.

25. The pharmaceutical composition according to claim 21, having a purity of at least about 99.96% as determined by HPLC.

26. The pharmaceutical composition according to claim 21, wherein there is no impurity peak greater than 0.02% as determined by HPLC.

27. The pharmaceutical composition according to claim 21, wherein the composition does not have mutagenic impurities detectable by HPLC.

28. The pharmaceutical composition according to claim 21, wherein one or more impurities selected from 2,3-methyl ketone, 2-bromo-3',4'-(methylenedioxy)propiophenone (MDPBP), and 3,4-methylenedioxypropiophenone (MDP) cannot be detected by HPLC.

29. The pharmaceutical composition according to claim 21, having between 5 mg and 1,000 mg of the methyl ketone or its stereoisomer or its pharmaceutically acceptable salt.

30. The pharmaceutical composition according to claim 21, wherein the composition is a composition stable at room temperature.

31. The pharmaceutical composition according to claim 21, wherein the composition is suitable for humans.

32. The pharmaceutical composition according to claim 21, wherein the composition meets the acceptance thresholds listed in the ICH Q3A and ICH Q3B guidelines.

33. A pharmaceutical composition comprising methyl ketone that is stable at room temperature.

34. The pharmaceutical composition according to claim 33, wherein the composition is a pharmaceutically acceptable salt of methyl ketone or a substantially pure stereoisomer of methyl ketone.

35. The pharmaceutical composition according to claim 34, wherein the pharmaceutically acceptable salt of methyl ketone is methyl ketone hydrochloride.

36. The pharmaceutical composition according to claim 34, wherein the substantially pure stereoisomer of methyl ketone is (S)-methyl ketone.

37. The pharmaceutical composition according to claim 33, having between 5 mg and 1,000 mg of the methyl ketone or its stereoisomer or its pharmaceutically acceptable salt.

38. The pharmaceutical composition according to claim 37, wherein the composition is an oral dosage form.

39. The pharmaceutical composition according to claim 38, wherein the oral dosage form is a capsule or a tablet.

40. The pharmaceutical composition according to claim 33, wherein the composition is stable for at least six months at room temperature.

41. The pharmaceutical composition according to claim 33, wherein the composition is stable for at least six months at a temperature between 15 °C and 30 °C.

42. The pharmaceutical composition according to claim 33, wherein the composition is stable for at least six months at a temperature of at least 25 °C.

43. The pharmaceutical composition according to claim 33, wherein the composition is stable for at least six months at a relative humidity of at least 60%.

44. The pharmaceutical composition according to claim 33, wherein the composition is stable for at least six months at a temperature of about 25 °C and a relative humidity of at least 60%.

45. The pharmaceutical composition according to claim 33, wherein the composition meets the acceptance thresholds listed in the ICH Q3A and ICH Q3B guidelines.

46. A method of treatment, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to any one of claims 19 - 45.

47. The method according to claim 46, wherein the treatment is directed to post - traumatic stress disorder (PTSD), anxiety disorder, attention - deficit / hyperactivity disorder (ADHD), obsessive - compulsive disorder (OCD), fibromyalgia, depression, acute stress disorder (ASD), cluster headache, conditions associated with cancer, hypomotility, burnout, boredom, migraine, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorder, nausea or vomiting.

48. The method according to claim 46, wherein the treatment is for post - traumatic stress disorder (PTSD).

49. The method according to claim 46, wherein the treatment is for acute stress disorder (ASD).

50. The method according to claim 46, wherein the treatment is for anxiety disorder.

51. The method according to claim 46, wherein the treatment is for depression.

52. The method according to claim 46, wherein the treatment is for personality disorder.

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