Injectable pharmaceutical preparations

Abstract

This specification provides injectable pharmaceutical formulations, methods for manufacturing them, kits, and their use in the treatment of diseases or disorders. The injectable pharmaceutical formulations comprise a psychotropic agent, a release regulator, and an aqueous vehicle. The pharmaceutical formulations enable time-limited, controlled release of the psychotropic agent when administered by injection, such as subcutaneous injection. Diseases or disorders treatable with the pharmaceutical formulations include, for example, neuropsychiatric disorders or disorders, or inflammatory diseases or disorders, such as central nervous system (CNS) disorders and / or psychological disorders, including those related to the 5-HT2 receptor.

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Application No. 63 / 464,265 filed on 5 May 2023, U.S. Provisional Application No. 63 / 507,062 filed on 8 June 2023, and U.S. Provisional Application No. 63 / 599,483 filed on 15 November 2023, each of which is incorporated herein by reference in its entirety.

[0002] This disclosure generally relates to injectable pharmaceutical formulations, including psychotropic agents, and their use in the treatment of neuropsychiatric disorders or inflammatory disorders, such as central nervous system (CNS) disorders and / or psychological disorders, including those related to the 5-HT2 receptor. [Background technology]

[0003] Currently available drug treatments for mood disorders, anxiety disorders, trauma-related disorders, and substance use disorders are characterized by (partial) ineffectiveness. Despite treatment with therapeutic doses and various augmentants, a significant proportion of patients fail to recover, and those who achieve symptom relief often experience burdensome adverse effects and are at high risk of suicidal behavior or completed suicide.

[0004] Over the past 30 years, there has been a resurgence of interest in the study of hallucinogens, dissociative agents, and enterogens. Various such drugs, when combined with psychotherapy, have shown early but robust efficacy after a limited number of doses (typically 1 to 3 drug-assisted psychotherapy sessions). For example, the enterogen methylenedioxymethamphetamine (MDMA) passed the first phase III trial in patients with PTSD [Mitchell JM, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27:1025-1033]. Diethyl lysine (LSD) has shown clinical promise in the treatment of alcohol use disorder [Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J Neurol Sci. 2020, 411:116715; Fuentes JJ, et al. Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials. Front Psychiatry. 2020; 10:1-14]. In the tryptamine class of serotonergic hallucinogens, psilocybin (the active ingredient in "magic mushrooms") has been shown to reduce weekend anxiety (MDD) [Griffiths RR, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30:1181-1197], as well as smoking cessation [Garcia-Romeu A, Griffiths RR, Johnson MW.Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction.Curr Drug Abuse Rev.2014;7:157-164, de Veen BTH,et al.Psilocybin for treating substance use disorders? Expert Rev Neurother.2017;17:203-212, Johnson MW,et al.Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction.J Psychopharmacol.2014;28:983-992, and Johnson MW, Garcia-Romeu A, Griffiths RR.Long-term follow-up of psilocybin-facilitated smoking cessation.Am J Drug Alcohol [Abuse.2017;43:55-60] showed promise in a Phase II trial, and N,N-dimethyltryptamine (DMT, also known as 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine) (usually as the active ingredient in ayahuasca) is associated with mood [Vollenweider FX, Preller KH. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci.2020;21:611-624, Barker SA. N,N-dimethyltryptamine (DMT), an endogenous hallucinogen: Past, present, and future research to determine its role and function. Front Neurosci.2018;12:1-17, and Strassman RJ, et al.Dose-response study of N,N-Dimethyltryptamine in humans II: Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry. 1994;51:98-108], as well as potential addiction [Thomas G, et al. Ayahuasca-assisted therapy for addiction: Results from a preliminary observational study in Canada. Curr Drug Abuse Rev. 2013; Oliveira-Lima AJ, et al. Effects of ayahuasca on the development of ethanol-induced behavioral sensitization and on a post-sensitization treatment in mice. Physiol Behav. 2015;142:28-36, Nolli LM, et al. Effects of the hallucinogenic beverage ayahuasca on voluntary ethanol intake by rats and on cFos expression in brain areas relevant to drug addiction. Alcohol. 2019, Fabregas JM, et al. Assessment of addiction severity among ritual users of ayahuasca. Drug Alcohol Depend. 2010;111:257-261, Argento E, et al. Exploring ayahuasca-assisted therapy for addiction: A qualitative analysis of preliminary findings among an Indigenous community in Canada. Drug Alcohol Rev. 2019;38:781-789, and Noorani T, et al.[Psychedelic therapy for smoking cessation: Qualitative analysis of participant accounts. J Psychopharmacol. 2018;32:756-769] shows promising effects.

[0005] The binding profile of DMT is well characterized. DMT acts on numerous ion channel receptors and metabotropic receptors. This includes 5-hydroxytryptamine-(5-HT) from the 5-HT / serotonin family. 1A , 5-HT 2A , 5-HT 2C It binds to serotonin transporter (SERT) receptors due to its affinity for them [Cameron LP, Olson DE. Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT). ACS Chem Neurosci. 2018;9:2344-2357]. DMT is 5-HT 2A It is a potent agonist at the receptor, and through it (like other serotonergic hallucinogens), it exerts many subjective effects, visual effects, and potentially therapeutic effects [Cameron LP, Olson DE. Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT). ACS Chem Neurosci. 2018;9:2344-2357, Carbonaro TM, Gatch MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull. 2016;126:74-88]. 5-HT 2AActivation has also been linked to increased synaptic plasticity [Ly C, et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018;23:3170-3182, Ly C, et al. Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth. ACS Pharmacol Transl Sci. 2020, and Inserra A, De Gregorio D, Gobbi G. Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms. Pharmacol Rev. 2021;73:202-277]. Furthermore, DMT binds to other receptors, including trace amine-associated receptors (TAARs) and sigma-1 receptors, potentially contributing to enhanced neuroprotective plasticity [Carbonaro TM, Gatch MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull. 2016;126:74-88; Barker SA. N,N-dimethyltryptamine (DMT), an endogenous hallucinogen: Past, present, and future research to determine its role and function. Front Neurosci. 2018;12:1-17].

[0006] Despite their high potency in serotonin 5-HT2R, the therapeutic value of certain tryptamine hallucinogens is hindered by accelerated metabolism in the liver and gastrointestinal tract, particularly by monoamine oxidase (MAO) enzymes. For example, DMT is not orally active and is converted to inactive metabolites before sufficient brain penetration can occur. For this reason, DMT is typically administered with monoamine oxidase inhibitors (as in the case of ayahuasca) to extend its duration of action. Similarly, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) lacks oral bioavailability and is instead usually vaporized and inhaled to produce hallucinogenic effects. Such MAO-mediated metabolism is also thought to contribute to the high variability of the pharmacokinetic (PK) profiles of various tryptamines in humans, including significant interpatient pharmacokinetic variability after oral psilocybin administration and intravenous (IV) administration of DMT.

[0007] Furthermore, compared to the long-lasting subjective effects of other serotonergic hallucinogens such as LSD (8-20 hour duration of action) and psilocybin (6-8 hour duration of action), the duration of action of short-acting tryptamine hallucinogens such as DMT and 5-MeO-DMT, administered to humans as a bolus via inhalation or intravenous or intramuscular injection, is remarkably short, limiting their use in effective therapy. In the case of DMT, the onset of subjective effects on perception and consciousness (also referred to as hallucinatory states) is rapid and overwhelming, with a marked and strong visual peak experience observed within 2 minutes of administration. The hallucinogenic state resolves rapidly, and subjective effects return to baseline approximately 20-30 minutes (or just before) after administration [Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R. Dose-response study of N,N-Dimethyltryptamine in humans II: Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry. 1994;51:98-108]. On the other hand, the short duration spent in the hallucinogenic state is considered therapeutically limited, making a highly granular assessment of the pharmacodynamic (PD) effect and safety profile inherently difficult. On the other hand, short-acting tryptamine hallucinogens are potentially more controllable and clinically scalable compared to long-acting hallucinogenic compounds such as LSD and psilocybin, which often requires clinical observation of patients under surveillance for 7-8 hours or more before discharge.

[0008] Continuous controlled intravenous infusions have been studied to improve the therapeutic profile of DMT by avoiding excessive drug levels associated with bolus IV injections or inhalations, and to provide a more scalable duration of effect (e.g., a peak effect of approximately 30–120 minutes) [Gallimore AR, Strassman RJ. A model for the application of target-controlled intravenous infusion for a prolonged immersive DMT psychedelic experience. Front Pharmacol. 2016;7:1-11]. DMT infusions administered over approximately 90 minutes allowed for escalation of exposure in a time-controlled manner while maximizing the drug's effect. However, infusion protocols (e.g., when patients receive the drug over extended periods, such as more than one hour) are generally not clinically practical due to the significant clinical resources and personnel required, which present considerable challenges in scaling up treatment for larger patient populations.

[0009] As a result, there is a need for new formulation and delivery approaches that provide alternatives that retain the pharmacokinetic and pharmacological benefits of intravenous administration (i.e., resulting in a targeted duration of peak effect lasting approximately 30–120 minutes), but are nevertheless clinically practical, convenient for patients, and economical for sponsors and service providers. [Overview of the project]

[0010] Therefore, this disclosure is at least in part based on the identification of novel injectable pharmaceutical formulations, kits, and therapeutic methods that enable time-limited, temporally controlled release of psychotropic drugs. In the case of short-acting tryptamine hallucinogens such as DMT, 5-MeO-DMT, and their analogues (e.g., deuterated analogues), this controlled release would result in a peak effect duration of approximately 30–120 minutes to maximize therapeutic benefits and reduce side effects. In doing so, the injectable pharmaceutical formulation extends the time a patient spends in a hallucinatory state compared to a bolus IV injection of the same tryptamine hallucinogen, without excessively extending the release and the resulting peak effect duration beyond approximately 120 minutes, thus avoiding the long-term clinical observation requirements imposed by longer-acting psychotropic drugs such as LSD and psilocybin.

[0011] These and other objectives, which will become apparent in the detailed description below, have been achieved by the inventors' discovery of novel injectable pharmaceutical formulations containing psychotropic agents in combination with specific release regulators, which can be administered as bolus injections, including subcutaneous bolus injections, exhibiting a controllable and linear release of the psychotropic agent. In the case of tryptamine hallucinogens such as DMT, 5-MeO-DMT, and their analogues (e.g., deuterated analogues), the desired controlled release can be achieved to mimic the clinically advantageous 30-120 minute peak effect profile achieved only by IV infusion of such psychotropic agents.

[0012] In other words, this disclosure provides the following: (1) A pharmaceutical preparation for injection, Psychotropic drugs and, Hyaluronic acid and, Aqueous vehicle and, A psychotropic drug is a pharmaceutically acceptable salt of the compound of formula (I), or a stereoisomer, solvate, or prodrug thereof. [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium. R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R4 and R5 are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy. R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R8 and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. Alternatively, an injectable pharmaceutical formulation in which R8 and R9 optionally join together with the nitrogen atoms to which they are bonded to form an unsubstituted or substituted heterocycloalkyl group. (2) The compound has the structure of formula (II), or a stereoisomer, solvate, or prodrug thereof, [ka] During the ceremony, X1 and X2 are independently hydrogen or deuterium. Y1 and Y2 are independently hydrogen or deuterium. Each Z1 is independently hydrogen or deuterium. Each Z2 is independently hydrogen or deuterium. The injectable pharmaceutical preparation according to (1), wherein R2, R4, R5, R6, and R7 are independently hydrogen or deuterium. (3) Psychotropic drugs, [ka] [ka] The injectable pharmaceutical preparation according to (1) or (2), which is a pharmaceutically acceptable salt of at least one compound selected from the group consisting of, or a stereoisomer, solvate, or prodrug thereof. (4) An injectable pharmaceutical preparation according to any one of (1) to (3), wherein the psychotropic agent is a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8). (5) An injectable pharmaceutical preparation according to any one of (1) to (3), wherein the psychotropic agent is a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6). (6) An injectable pharmaceutical preparation according to any one of (1) to (3), wherein the psychotropic agent is a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-2). (7) An injectable pharmaceutical preparation according to any one of (1) to (3), wherein the psychotropic drug is an active salt mixture comprising (i) a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8) and (ii) one or more pharmaceutically acceptable salts of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11). (8) The injectable pharmaceutical preparation according to (7), wherein the active salt mixture comprises (i) 60% to 99% by weight of a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8) based on the total weight of the active salt mixture, and (ii) 1% to 40% by weight in total of a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11) based on the total weight of the active salt mixture. (9) A compound having the structure of formula (III), or its stereoisomer, solvate, or prodrug, [ka] During the ceremony, X1 and X2 are independently hydrogen or deuterium. Y1 and Y2 are independently hydrogen or deuterium. Each Z1 is independently hydrogen or deuterium. Each Z2 is independently hydrogen or deuterium. Each Z3 is independently hydrogen or deuterium. The injectable pharmaceutical preparation according to (1), wherein R2, R4, R6, and R7 are independently hydrogen or deuterium. (10) Psychotropic drugs, [ka] [ka] [ka] A pharmaceutical preparation for injection according to (1) or (9), which is a pharmaceutically acceptable salt of at least one compound selected from the group consisting of, or a stereoisomer, solvate, or prodrug thereof. (11) An injectable pharmaceutical preparation according to any one of (1), (9), or (10), wherein the psychotropic agent is a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-20). (12) An injectable pharmaceutical preparation according to (1) or any one of (9) to (11), wherein the psychotropic agent is an active salt mixture comprising (i) a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-20) and (ii) one or more pharmaceutically acceptable salts of 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-22) and / or 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-23). (13) An injectable pharmaceutical preparation according to any one of (1) to (12), wherein the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate. (14) An injectable pharmaceutical preparation according to any one of (1) to (13), wherein the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, or succinate. (15) An injectable pharmaceutical preparation according to any one of (1) to (14), wherein the concentration of the psychotropic drug by weight per total volume of the pharmaceutical preparation (in terms of free base equivalent) is approximately 1 mg / mL to approximately 100 mg / mL. (16) An injectable pharmaceutical preparation according to any one of (1) to (15), wherein the concentration of the psychotropic drug by weight per total volume of the pharmaceutical preparation (in terms of free base equivalent) is approximately 10 mg / mL to approximately 50 mg / mL. (17) An injectable pharmaceutical preparation according to any one of (1) to (16), wherein the hyaluronic acid salt is sodium hyaluronate. (18) An injectable pharmaceutical preparation according to any one of (1) to (17), wherein the hyaluronic acid has a weight-average molecular weight of approximately 500 kDa to approximately 2,000 kDa. (19) An injectable pharmaceutical preparation according to any one of (1) to (18), wherein the hyaluronic acid has a weight-average molecular weight of approximately 1,000 kDa to approximately 1,800 kDa. (20) An injectable pharmaceutical preparation according to any one of (1) to (19), wherein the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 0.1% to approximately 2% (w / v). (21) An injectable pharmaceutical preparation according to any one of (1) to (20), wherein the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 0.1% to approximately 1% (w / v). (22) An injectable pharmaceutical preparation according to any one of (1) to (21), wherein the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 0.1% to approximately 0.75% (w / v). (23) An injectable pharmaceutical preparation according to any one of (1) to (22), wherein the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 0.1% to approximately 0.5% (w / v). (24) An injectable pharmaceutical preparation according to any one of (1) to (23), wherein the aqueous vehicle contains water and sodium chloride. (25) The injectable pharmaceutical preparation according to (24), wherein the pharmaceutical preparation contains sodium chloride at a concentration of approximately 0.1% to approximately 0.8% (w / v) in terms of weight per unit volume of the pharmaceutical preparation. (26) An injectable pharmaceutical preparation having a pH of approximately 3 to approximately 7, as described in any one of (1) to (25). (27) An injectable pharmaceutical preparation according to any one of (1) to (26), having an osmolality of approximately 150 mOsm / kg to approximately 600 mOsm / kg. (28) An injectable pharmaceutical preparation according to any one of (1) to (27), having a viscosity of less than approximately 3,000 cP. (29) A pharmaceutical preparation for injection according to any one of (1) to (28), which is suitable for subcutaneous injection. (30) An injectable pharmaceutical preparation according to any one of (1) to (29), which is suitable for bolus subcutaneous injection. (31) An injectable pharmaceutical preparation according to any one of (1) to (30), wherein the injectable pharmaceutical preparation provides a peak effect duration of approximately 30 minutes to approximately 120 minutes after administration to a human subject via bolus subcutaneous injection. (32) A kit suitable for preparing an injectable pharmaceutical preparation described in any one of (1) to (31), wherein the kit is (a1) A first solution containing a psychotropic drug and an aqueous vehicle, (b1) A kit comprising a second solution containing hyaluronic acid and an aqueous vehicle. (33) A method for treating central nervous system (CNS) disorders and / or psychological disorders in a subject requiring treatment, comprising administering a therapeutically effective amount of any one of the injectable pharmaceutical preparations described in (1) to (31) to the subject. (34) The method according to (33), wherein the CNS disorder and / or psychological disorder is a substance use disorder. (35) The method according to (34), wherein the substance use disorder is alcohol use disorder. (36) The method according to (33), wherein the CNS disorder and / or psychological disorder is an anxiety disorder. (37) The method of (36) wherein the anxiety disorder is generalized anxiety disorder (GAD). (38) Generalized anxiety disorder is accompanied by depression, as described in (37). (39) The method of determining whether an anxiety disorder is social anxiety disorder as described in (36). (40) The method according to (33), wherein the CNS disorder and / or psychological disorder is a depressive disorder. (41) The method according to (40), wherein the depressive disorder is major depressive disorder (MDD) or treatment-resistant depression (TRD). (42) CNS disorders and / or psychological disorders include post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinatory crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder. The method according to (33), wherein at least one is selected from the group consisting of Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia nervosa, bulimia nervosa, pedophilia, exhibitionism, voyeurism, fetishism, sexual masochism or sadism, cross-dressing disorder, sexual dysfunction, and obesity. (43) The method according to any one of (33) to (42), wherein the injectable pharmaceutical preparation is administered by injection. (44) The method according to any one of (33) to (43), wherein the injectable pharmaceutical preparation is administered by subcutaneous injection. (45) The method according to any one of (33) to (44), wherein the injectable pharmaceutical preparation is administered by bolus subcutaneous injection. (46) The method of (45), wherein a bolus subcutaneous injection provides a duration of peak effect of approximately 30 minutes to approximately 120 minutes after administration. (47) A pharmaceutical preparation for injection, Psychotropic drugs and, Carboxymethylcellulose salt, Aqueous vehicle and, A psychotropic drug is a pharmaceutically acceptable salt of the compound of formula (I), or a stereoisomer, solvate, or prodrug thereof. [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium. R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R4 and R5 are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy. R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R8 and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. Alternatively, an injectable pharmaceutical formulation in which R8 and R9 optionally join together with the nitrogen atoms to which they are bonded to form an unsubstituted or substituted heterocycloalkyl group. (48) The injectable pharmaceutical preparation according to (47), wherein the carboxymethylcellulose salt is carboxymethylcellulose sodium. (49) The injectable pharmaceutical preparation according to (47) or (48), wherein the carboxymethylcellulose salt has a weight-average molecular weight of about 50 kDa to about 450 kDa. (50) An injectable pharmaceutical preparation according to any one of (47) to (49), wherein the concentration of carboxymethylcellulose salt by weight per total volume of the pharmaceutical preparation is approximately 0.55% to approximately 1% (w / v). A kit suitable for preparing an injectable pharmaceutical preparation described in any one of (51), (47), to (50), wherein the kit is (a1) A first solution containing a psychotropic drug and an aqueous vehicle, (b1) A kit comprising a second solution containing a carboxymethylcellulose salt and an aqueous vehicle. (52) A method for treating central nervous system (CNS) disorders and / or psychological disorders in a subject requiring treatment, comprising administering a therapeutically effective dose of any one of the injectable pharmaceutical preparations described in (47) to (50). (53) The method of (52), wherein the CNS disorder and / or psychological disorder is a substance use disorder. (54) The method of (53) wherein the substance use disorder is alcohol use disorder. (55) The method of (52) wherein the CNS disorder and / or psychological disorder is an anxiety disorder. (56) The method of (55) relating to the anxiety disorder being generalized anxiety disorder (GAD). (57) Generalized anxiety disorder is accompanied by depression, as described in (56). (58) The method of determining whether an anxiety disorder is social anxiety disorder as described in (55). (59) The method of (52), wherein the CNS disorder and / or psychological disorder is a depressive disorder. (60) The method according to (59), wherein the depressive disorder is major depressive disorder (MDD) or treatment-resistant depression (TRD). (61) CNS disorders and / or psychological disorders including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinatory crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder. The method according to (52), wherein at least one is selected from the group consisting of Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia nervosa, bulimia nervosa, pedophilia, exhibitionism, voyeurism, fetishism, sexual masochism or sadism, cross-dressing disorder, sexual dysfunction, and obesity. (62) The method according to any one of (52) to (61), wherein the injectable pharmaceutical preparation is administered by injection. (63) The method according to any one of (52) to (62), wherein the injectable pharmaceutical preparation is administered by subcutaneous injection. (64) The method according to any one of (52) to (63), wherein the injectable pharmaceutical preparation is administered by bolus subcutaneous injection. (65) The method according to any one of (52) to (64), wherein a bolus subcutaneous injection provides a peak effect duration of approximately 30 minutes to approximately 120 minutes after administration. (66) Injectable pharmaceutical preparations, Psychotropic drugs and, Hyaluronic acid and, Aqueous vehicle and, An injectable pharmaceutical preparation in which the psychotropic agent is a pharmaceutically acceptable salt of ketamine, or a stereoisomer, solvate, or prodrug thereof. (67) The injectable pharmaceutical preparation according to (66), wherein the pharmaceutically acceptable salt is an inorganic salt. (68) The injectable pharmaceutical preparation of (66) or (67), wherein the pharmaceutically acceptable salt is the hydrochloride salt. (69) An injectable pharmaceutical preparation according to any one of (66) to (68), wherein the concentration of the psychotropic drug by weight per total volume of the pharmaceutical preparation (in terms of free base equivalent) is approximately 1 mg / mL to approximately 100 mg / mL. (70) An injectable pharmaceutical preparation according to any one of (66) to (69), wherein the concentration of the psychotropic drug by weight per total volume of the pharmaceutical preparation (in terms of free base equivalent) is approximately 10 mg / mL to approximately 50 mg / mL. (71) An injectable pharmaceutical preparation according to any one of (66) to (70), wherein the hyaluronic acid salt is sodium hyaluronate. (72) An injectable pharmaceutical preparation according to any one of (66) to (71), wherein the hyaluronic acid salt has a weight-average molecular weight of approximately 500 kDa to approximately 2,000 kDa. (73) An injectable pharmaceutical preparation according to any one of (66) to (72), wherein the hyaluronic acid has a weight-average molecular weight of approximately 1,000 kDa to approximately 1,800 kDa. (74) An injectable pharmaceutical preparation according to any one of (66) to (73), wherein the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 0.1% to approximately 2% (w / v). (75) An injectable pharmaceutical preparation according to any one of (66) to (74), wherein the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 0.1% to approximately 1% (w / v). (76) An injectable pharmaceutical preparation according to any one of (66) to (75), wherein the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 0.1% to approximately 0.75% (w / v). (77) An injectable pharmaceutical preparation according to any one of (66) to (76), wherein the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 0.1% to approximately 0.5% (w / v). (78) An injectable pharmaceutical preparation according to any one of (66) to (77), wherein the aqueous vehicle comprises water and sodium chloride. (79) The injectable pharmaceutical preparation according to (78), wherein the pharmaceutical preparation contains sodium chloride at a concentration of approximately 0.1% to approximately 0.8% (w / v) in terms of weight per unit volume of the pharmaceutical preparation. (80) An injectable pharmaceutical preparation having a pH of approximately 3 to approximately 7, as described in any one of (66) to (79). (81) An injectable pharmaceutical preparation according to any one of (66) to (80), having an osmolality of approximately 150 mOsm / kg to approximately 600 mOsm / kg. (82) An injectable pharmaceutical preparation according to any one of (66) to (81), having a viscosity of less than approximately 3,000 cP. (83) A pharmaceutical preparation for injection according to any one of (66) to (82), which is suitable for subcutaneous injection. (84) An injectable pharmaceutical preparation according to any one of (66) to (83), which is suitable for bolus subcutaneous injection. (85) An injectable pharmaceutical preparation according to any one of (66) to (84), wherein the injectable pharmaceutical preparation provides a duration of peak effect of approximately 30 minutes to approximately 120 minutes after administration to a human subject via bolus subcutaneous injection. A kit suitable for preparing an injectable pharmaceutical preparation described in any one of (86)(66)~(85), wherein the kit is (a1) A first solution containing a psychotropic drug and an aqueous vehicle, (b1) A kit comprising a second solution containing hyaluronic acid and an aqueous vehicle. (87) A method for treating central nervous system (CNS) disorders and / or psychological disorders in a subject requiring treatment, comprising administering a therapeutically effective dose of any one of (66) to (85) of an injectable pharmaceutical preparation. (88) Use of any one of the injectable pharmaceutical preparations described in (1) to (31) for the treatment of patients with central nervous system (CNS) disorders and / or psychological disorders. (89) An injectable pharmaceutical preparation described in any one of (1) to (31) for use in therapeutic purposes. (90) Use of any one of the injectable pharmaceutical preparations described in (47) to (50) for the treatment of patients with central nervous system (CNS) disorders and / or psychological disorders. (91) An injectable pharmaceutical preparation described in any one of (47) to (50) for use in therapeutic purposes. (92) Use of any one of the injectable pharmaceutical preparations described in (66) to (85) for the treatment of patients with central nervous system (CNS) disorders and / or psychological disorders. (93) An injectable pharmaceutical preparation described in any one of (66) to (85) for use in therapeutic purposes. [Brief explanation of the drawing]

[0013] The preceding paragraphs are provided as a general introduction and are not intended to limit the scope of the following claims. The embodiments described, along with their further advantages, will be best understood by referring to the following detailed description, when considered in conjunction with the accompanying drawings.

[0014] [Figure 1] A general synthetic route for preparing compounds of formula (I), such as compounds I-2 and I-6, is shown. [Figure 2] A general synthetic route for preparing compounds of formula (I), such as compounds I-1, I-4, I-5, and I-8, is shown. [Figure 3] The drug release percentage versus time profiles of formulations 1-6 compared to a control during a dialysis-drug release study are shown. [Figure 4] The drug release percentage versus time profile of formulation 7 compared to the control when subjected to a dialysis-drug release study is shown. [Figure 5] The drug release percentage versus time profile of formulation 8 compared to the control when subjected to a dialysis-drug release study is shown. [Figure 6] The drug release percentage versus time profile of formulation 9 compared to the control when subjected to a dialysis-drug release study is shown. [Figure 7A] The drug release percentage versus time profiles (Figure 7A) and corresponding primary release rate plots (Figure 7B) for formulations 10–12, compared to a control when subjected to a dialysis-drug release study, are shown. [Figure 7B] Same as above. [Figure 8A]The drug release percentage versus time profiles (Figure 8A) and corresponding primary release rate plots (Figure 8B) for formulations 13–15, compared to a control when subjected to a dialysis-drug release study, are shown. [Figure 8B] Same as above. [Figure 9A] The drug release percentage versus time profiles (Figure 9A) and corresponding primary release rate plots (Figure 9B) for formulations 16–18, compared to the control when subjected to dialysis-drug release studies, are shown. [Figure 9B] Same as above. [Figure 10A] The drug release percentage versus time profiles (Figure 10A) and corresponding primary release rate plots (Figure 10B) for formulations 19–21, compared to a control when subjected to a dialysis-drug release study, are shown. [Figure 10B] Same as above. [Figure 11] The drug release percentage versus time profiles of formulations 22-27 compared to a control when subjected to a dialysis-drug release study are shown. [Figure 12A] The individual DMT-d10 plasma concentration-time curves in male beagle dogs (animal IDs: 068M, 069M, 070M) after subcutaneous administration of 0.1 mg / kg of DMT-d10 from the control (Figure 12A) and formulation 28 (Figure 12B) are shown. [Figure 12B] Same as above. [Figure 13A] The mean DMT-d10 plasma concentration-time curves in male beagle dogs after subcutaneous administration of DMT-d10 at concentrations of 0.1, 0.5, and 1 mg / kg from formulations 28-30, respectively, are shown on a linear scale (Figure 13A) and a logarithmic scale (Figure 13B). [Figure 13B] Same as above. [Figure 14] The dose-proportionality of Cmax and AUCinf from the mean DMT-d10 plasma concentration-time curves in male beagle dogs after subcutaneous administration of DMT-d10 at 0.1, 0.5, and 1 mg / kg from formulations 28-30, respectively, is shown. [Figure 15]This shows the effect of sodium hyaluronate concentration on the mean concentration-time profile of DMT-d10 after SC administration of DMT-d10 at a dose of 1 mg / kg from formulations 30-33. *Formulation 31, which was administered with 0.5 mg / kg of free base, was dose-adjusted to 1 mg / kg. [Figure 16] This shows the effect of sodium hyaluronate concentration on the mean residence time (MRTinf) of DMT-d10 after SC administration of DMT-d10 at a dose of 1 mg / kg from formulations 30-33. *Formulation 31, which was administered with 0.5 mg / kg of free base, was dose-adjusted to 1 mg / kg. [Figure 17] This shows the effect of sodium hyaluronate concentration on the plasma half-life (t1 / 2) of DMT-d10 after SC administration of DMT-d10 at a dose of 1 mg / kg from formulations 30-33. *Formulation 31, which was administered with 0.5 mg / kg of free base, was dose-adjusted to 1 mg / kg. [Figure 18] This shows the effect of sodium hyaluronate concentration on the maximum plasma concentration (Cmax) of DMT-d10 after SC administration of DMT-d10 at a dose of 1 mg / kg from formulations 30-33. *Formulation 31, which was administered with 0.5 mg / kg of free base, was dose-adjusted to 1 mg / kg. [Figure 19] This shows the effect of sodium hyaluronate concentration on total DMT-d10 exposure (AUCinf) after SC administration of DMT-d10 at a dose of 1 mg / kg from formulations 30-33. *Formulation 31, which was administered with 0.5 mg / kg of free base, was dose-adjusted to 1 mg / kg. [Figure 20A] The mean DMT-d10 plasma concentration-time curves in male beagle dogs after subcutaneous administration of 1 mg / kg free base from formulation 34 (nominal dose solution concentration of 20 mg / mL delivered in a 0.05 mL / kg dosing volume) compared to the control (nominal dose solution concentration of 4 mg / mL delivered in a 0.25 mL / kg dosing volume) are shown on a linear scale (Figure 20A) and a logarithmic scale (Figure 20B). [Figure 20B] Same as above. [Figure 21A]The mean plasma concentration-time curves of DMT and DMT-d10 in male beagle dogs after subcutaneous co-administration of 0.5 mg / kg / analyte free base from formulation 35, on a linear scale (Figure 21A) and a logarithmic scale (Figure 21B), are shown. [Figure 21B] Same as above. [Figure 22] The drug release percentage (ketamine) versus time profiles of formulations 36-38 compared to a control during a dialysis-drug release study are shown. [Modes for carrying out the invention]

[0015] The following detailed description of embodiments of the Disclosure includes numerous specific details to provide a complete understanding of the embodiments of the Disclosure. However, it will be apparent to those skilled in the art that embodiments of the Disclosure can be carried out without these specific details. In other examples, well-known methods, procedures, components, and circuits are not described in detail so as not to unnecessarily obscure aspects of the embodiments of the Disclosure.

[0016] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0017] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms. This term includes linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl (t-Bu) ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0018] The term "substituted alkyl" refers to an alkyl group as defined herein, where one or more carbon atoms in the alkyl chain are optionally substituted with heteroatoms such as -O-, -N-, -S-, -S(O) n -(n is 0 to 2), -NR- (R is hydrogen or alkyl), etc., and are also substituted with deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO 2- heteroaryl, and -NR ’ R ’’ wherein, R ’ and R ’’ may be the same or different and are each selected from the group consisting of 1 to 10 substituents selected from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic groups.

[0019] "Alkylene" is -O-, -NR 10 -, -NR 10 C(O), -C(O)NR 10This term refers to a divalent aliphatic hydrocarbyl group having 1 to 6 carbon atoms, including 1 to 3 carbon atoms in either a linear or branched chain, which may be optionally interrupted by one or more groups selected from the following. Examples of this term include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), etc.

[0020] A "substituted alkylene" refers to an alkylene group having 1 to 3 hydrogen atoms substituted by substituents, as described for carbon in the definition of "substitution" below.

[0021] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0022] The terms "alkylaminoalkyl", "alkylaminoalkenyl", and "alkylaminoalkynyl" are R ’ NHR ’’ - Refers to the base, R ’ R is an alkyl group as defined herein, ’’ is an alkylene, alkenylene, or alkynylene group as defined herein.

[0023] The term "alkalyl" or "aralkyl" refers to an alkylene-aryl group and a substituted alkylene-aryl group, and alkylene, substituted alkylene, and aryl are defined herein.

[0024] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term "alkoxy" also refers to an alkenyl-O-group, a cycloalkyl-O-group, a cycloalkenyl-O-group, and an alkynyl-O-group, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0025] The term "substituted alkoxy" refers to a substituted alkyl-O-group, a substituted alkenyl-O-group, a substituted cycloalkyl-O-group, a substituted cycloalkenyl-O-group, and a substituted alkynyl-O-group, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0026] The term "alkoxyamino" refers to an -NH-alkoxy group, where alkoxy is as defined herein.

[0027] The term "haloalkoxy" refers to an alkyl-O-group in which one or more hydrogen atoms on the alkyl group are substituted with a halo group, and includes groups such as trifluoromethoxy.

[0028] The term "haloalkyl" refers to an alkyl group substituted as described above, where one or more hydrogen atoms on the alkyl group are substituted with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

[0029] The term "alkylalkoxy" refers to an -alkylene-O-alkyl group, an alkylene-O-substituted alkyl group, a substituted alkylene-O-alkyl group, and a substituted alkylene-O-substituted alkyl group, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0030] The term "alkylthioalkoxy" refers to an -alkylene-S-alkyl group, an alkylene-S-substituted alkyl group, a substituted alkylene-S-alkyl group, and a substituted alkylene-S-substituted alkyl group, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0031] "Alkenyl" refers to a straight-chain or branched hydrocarbyl group having 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, and having at least 1, such as 1 to 2, double bond unsaturated sites. This term includes, by way of example, vinyl, allyl, and but-3-en-1-yl. This term includes cis and trans isomers, or mixtures of these isomers.

[0032] The term "substituted alkenyl" refers to an alkenyl group as defined herein having 1 to 5 substituents, or 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thiocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0033] "Alkynyl" refers to a straight-chain or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, such as 2 to 3 carbon atoms, and having at least 1, such as 1 to 2, triple bond unsaturated sites. Examples of such alkynyl groups include ethynyl (-C≡CH), and propargyl (-CH2C≡CH).

[0034] The term "substituted alkynyl" refers to an alkynyl group as defined herein having 1 to 5 substituents or 1 to 3 substituents selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0035] "Alkynyloxy" refers to an -O-alkynyl group, where alkynyl is as defined herein. Examples of alkynyloxy include ethynyloxy and propynyloxy.

[0036] "Acyl" includes HC(O)- group, alkyl-C(O)- group, substituted alkyl-C(O)- group, alkenyl-C(O)- group, substituted alkenyl-C(O)- group, alkynyl-C(O)- group, substituted alkynyl-C(O)- group, cycloalkyl-C(O)- group, substituted cycloalkyl-C(O)- group, cycloalkenyl-C(O)- group, substituted cycloalkenyl-C(O)- group, aryl-C(O)- group, substituted aryl-C(O)- group, heteroaryl-C (O)-groups, substituted heteroaryl-C(O)-groups, heterocyclyl-C(O)-groups, and substituted heterocyclyl-C(O)-groups refer to alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl contains the "acetyl" group CH3C(O).

[0037] "Acylamino" is -NR 20 C(O) alkyl group, -NR 20 C(O) substituted alkyl group, NR 20 C(O) cycloalkyl group, -NR 20 C(O)-substituted cycloalkyl groups, -NR 20 C(O)cycloalkenyl group, -NR 20 C(O)-substituted cycloalkenyl group, -NR 20 C(O) alkenyl group, -NR 20 C(O) substituted alkenyl group, -NR 20 C(O) alkynyl group, -NR 20 C(O) substituted alkynyl group, -NR 20 C(O)aryl group, -NR 20 C(O) substituted aryl group, -NR 20 C(O) heteroaryl group, -NR 20 C(O)-substituted heteroaryl group, -NR 20 C(O) heterocyclic group, and -NR 20 This refers to a C(O) substituted heterocyclic group, R 20is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0038] "Aminocarbonyl" or the term "aminoacyl" is -C(O)NR 21 R 22 It refers to the base, R 21 and R 22 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. 21 and R 22 These groups may optionally join with the nitrogen atoms to which they are bonded to form heterocyclic or substituted heterocyclic groups, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein.

[0039] "Aminocarbonylamino" is -NR 21 C(O)NR 22 R 23 It refers to the base, R 21 , R 22 , and R 23 These are independently selected from hydrogen, alkyl, aryl, or cycloalkyl, or two R groups are joined to form a heterocycline group.

[0040] The term "alkoxycarbonylamino" refers to the -NRC(O)OR group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, and alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0041] The term "acyloxy" refers to alkyl-C(O)O-groups, substituted alkyl-C(O)O-groups, cycloalkyl-C(O)O-groups, substituted cycloalkyl-C(O)O-groups, aryl-C(O)O-groups, heteroaryl-C(O)O-groups, and heterocyclyl-C(O)O-groups, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0042] "Aminosulfonyl" is -SO2NR 21 R 22 It refers to the base, R 21 and R 22 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. 21 and R 22 These groups can optionally join with the nitrogen atoms to which they are bonded to form heterocyclic or substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein.

[0043] "Sulfonylamino" is -NR 21 SO2R 22 It refers to the base, R 21 and R 22R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic. 21 and R 22 These atoms may optionally join with the atoms to which they are bonded to form heterocyclic or substituted heterocyclic groups, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein.

[0044] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (such as one present in a phenyl group) or a ring system having multiple fused rings, which may or may not be aromatic, as long as the bonding site is through an atom of an aromatic ring (examples of such aromatic ring systems include naphthyl, anthuryl, and indanyl). Examples of this term include phenyl and naphthyl. If not restricted by the definition of aryl substituents, such aryl groups may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamide, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl.

[0045] "Aryloxy" refers to an -O-aryl group, where aryl includes, as defined herein, for example, phenoxy, naphthoxy, and optionally substituted aryl groups, as also defined herein.

[0046] "Amino" refers to the -NH2 group.

[0047] The term "substituted amino" refers to a -NRR group, where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl, provided that at least one R is not hydrogen.

[0048] The term "azid" refers to the -N3 group.

[0049] "Carboxyl," "carboxy," or "carboxylate" refers to -CO2H or its salts.

[0050] "Carboxyl-ester" or "carboxy-ester," or the term "carboxyalkyl" or "carboxylalkyl" refers to -C(O)O-alkyl group, -C(O)O-substituted alkyl group, -C(O)O-alkenyl group, -C(O)O-substituted alkenyl group, -C(O)O-alkynyl group, -C(O)O-substituted alkynyl group, -C(O)O-aryl group, -C(O)O-substituted aryl group, -C(O)O-cycloalkyl group, -C(O)O-substituted cycloalkyl group, -C(O)O-cycloalkenyl The terms refer to -C(O)O-substituted cycloalkenyl groups, -C(O)O-heteroaryl groups, -C(O)O-substituted heteroaryl groups, -C(O)O-heterocyclic groups, and -C(O)O-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0051] "(Carboxyl-ester)oxy" or "carbonate" refers to an -O-C(O)O-alkyl group, -O-C(O)O-substituted alkyl group, -O-C(O)O-alkenyl group, -O-C(O)O-substituted alkenyl group, -O-C(O)O-alkynyl group, -O-C(O)O-substituted alkynyl group, -O-C(O)O-aryl group, -O-C(O)O-substituted aryl group, -O-C(O)O-cycloalkyl group, -O-C(O)O-substituted cycloalkyl group, -O-C(O)O-cycloalkenyl group, -O-C(O)O-substituted cycloalkenyl group, -O-C(O)O-heteroaryl group, -O-C(O)O-substituted heteroaryl group, -O-C(O)O-heterocyclic group, and -O-C(O)O-substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0052] "Cyano" or "nitrile" refers to a -CN group.

[0053] "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms with one or more cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, or multiple ring structures such as adamantanyl.

[0054] The term "substituted cycloalkyl" includes deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- This refers to a cycloalkyl group having 1 to 5 substituents selected from alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl groups, or 1 to 3 substituents.

[0055] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group with 3 to 10 carbon atoms, having one or more rings and at least one double bond, for example, one to two double bonds.

[0056] The term "substituted cycloalkenyl" includes deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2-This refers to a cycloalkenyl group having 1 to 5 substituents selected from substituted alkyl, -SO2-aryl, and -SO2-heteroaryl groups, or 1 to 3 substituents.

[0057] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group consisting of 5 to 10 carbon atoms, having a single ring or multiple rings and at least one triple bond.

[0058] "Cycloalkoxy" refers to -O-cycloalkyl.

[0059] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0060] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine.

[0061] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0062] A "heteroaryl" refers to an aromatic group comprising 1 to 10 heteroatoms selected from the group consisting of 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, and oxygen, nitrogen, and sulfur in the ring. Such a heteroaryl group may have a single ring in its ring system (e.g., pyridinyl, imidazolyl, or furyl) or multiple fused rings (e.g., in groups such as indolidinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), and at least one ring in the ring system is aromatic if the bonding site is through an atom of the aromatic ring. In some embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Examples of this term include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless restricted by the definition of heteroaryl substituents, such heteroaryl groups include acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamide, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It may be optionally substituted with 1 to 5 substituents selected from substituted alkyls, -SO2-aryls, -SO2-heteroaryls, and trihalomethyls, or with 1 to 3 substituents.

[0063] The term "heteroaralkyl" refers to an alkylene-heteroaryl group, where alkylene and heteroaryl are defined herein. Examples of this term include pyridylmethyl, pyridylethyl, and indolylmethyl.

[0064] "Heteroaryloxy" refers to -O-heteroaryl.

[0065] "Heterocyclic," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including fusion bridges and spiro-ring systems, and having 3 to 20 ring atoms containing 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, and in fusion ring systems, one or more of the rings may be cycloalkyl, aryl, or heteroaryl, if the bonding site is via a non-aromatic ring. In some embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0066] Examples of heterocyclic and heteroaryl compounds include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, dihydroindole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthidine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, and phenoxadi. These include phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinil, thiomorpholinil (also called thiamorpholinil), 1,1-dioxothiomorpholinil, piperidinil, pyrrolidine, tetrahydrofuranil, benzo[d][1,3]oxathiol, benzo[d][1,3]dioxol, etc.

[0067] Unless restricted by the definition of heterocyclic substituents, such heterocyclic groups include deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It may be optionally substituted with 1 to 5 substituents selected from substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fusion heterocycles, or with 1 to 3 substituents.

[0068] "Heterocyclyloxy" refers to the -O-heterocyclyl group.

[0069] The term "heterocyclilthio" refers to a heterocyclic -S- group.

[0070] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0071] The term "hydroxyamino" refers to the -NHOH group.

[0072] "Nitro" refers to the -NO2 group.

[0073] "Oxo" refers to an oxygen (O) atom.

[0074] "Sulfonyl" refers to SO2-alkyl groups, SO2-substituted alkyl groups, SO2-alkenyl groups, SO2-substituted alkenyl groups, SO2-cycloalkyl groups, SO2-substituted cycloalkyl groups, SO2-cycloalkenyl groups, SO2-substituted cycloalkenyl groups, SO2-aryl groups, SO2-substituted aryl groups, SO2-heteroaryl groups, SO2-substituted heteroaryl groups, SO2-heterocyclic groups, and SO2-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Examples of sulfonyls include methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0075] "Sulfonyloxy" refers to -OSO2-alkyl groups, OSO2-substituted alkyl groups, OSO2-alkenyl groups, OSO2-substituted alkenyl groups, OSO2-cycloalkyl groups, OSO2-substituted cycloalkyl groups, OSO2-cycloalkenyl groups, OSO2-substituted cycloalkenyl groups, OSO2-aryl groups, OSO2-substituted aryl groups, OSO2-heteroaryl groups, OSO2-substituted heteroaryl groups, OSO2-heterocyclic groups, and OSO2-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0076] The term "aminocarbonyloxy" refers to the -OC(O)NRR group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, and alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

[0077] "Thiol" refers to the -SH group.

[0078] The term "thioxo" or "thioketo" refers to a (=S) atom.

[0079] "Alkylthio" or the term "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. The sulfoxide may exist as one or more stereoisomers.

[0080] The term "substituted thioalkoxy" refers to an -S-substituted alkyl group.

[0081] The term "thioaryloxy" refers to an aryl-S-group, where the aryl group is as defined herein and includes optionally substituted aryl groups as also defined herein.

[0082] The term "thioheteroaryloxy" refers to a heteroaryl-S-group, where the heteroaryl group is as defined herein and includes optionally substituted aryl groups as also defined herein.

[0083] The term "thioheterocyclooxy" refers to a heterocyclyl-S-group, where the heterocyclyl group is as defined herein and includes any optionally substituted heterocyclyl groups as also defined herein.

[0084] In addition to the disclosures herein, when used to modify a particular group or radical, the term “substitution” may also mean that one or more hydrogen atoms of a particular group or radical are each independently of one another substituted with the same or different substituents as defined below.

[0085] In addition to the groups disclosed with respect to individual terms herein, substituents for substituting one or more hydrogens on a saturated carbon atom in a specified group or radical (any two hydrogens on a single carbon are =O, =NR) 70 、=N-OR 70 (Can be replaced with =N2 or =S) Unless otherwise specified, deuterium, -R 60 , halo, =O, -OR 70 , -SR 70 , -NR 80 R 80 , trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R 70 , -SO2O - M + , -SO2OR 70 , -OSO2R 70 , -OSO2O - M + , -OSO2OR 70 ,-P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R70 、 -C(S)R 70 、 -C(NR 70 )R 70 、 -C(O)O - M + 、 -C(O)OR 70 、 -C(S)OR 70 、 -C(O)NR 80 R 80 、 -C(NR 70 )NR 80 R 80 、 -OC(O)R 70 、 -OC(S)R 70 、 -OC(O)O-M + 、 -OC(O)OR 70 、 -OC(S)OR 70 、 -NR 70 C(O)R 70 、 -NR 70 C(S)R 70 、 -NR 70 CO2 - M + 、 -NR 70 CO2R 70 、 -NR 70 C(S)OR 70 、 -NR 70 C(O)NR 80 R 80 、 -NR 70 C(NR 70 )R 70 、及び -NR 70 C(NR 70 )NR 80 R 80 であり、R 60 は、任意選択的に置換されたアルキル、シクロアルキル、ヘテロアルキル、ヘテロシクロアルキルアルキル、シクロアルキルアルキル、アリール、アリールアルキル、ヘテロアリール、及びヘテロアリールアルキルからなる群から選択され、各R 70 は独立して、水素又はR 60 であり、各R 80 は独立して、R 70 又は代替的に、それらが結合する窒素原子と一緒に取られた2つのR 80’The compounds form a 5, 6, or 7-membered heterocycloalkyl group, which optionally contains 1 to 4 additional heteroatoms of the same or different type selected from the group consisting of O, N, and S, where N may have a -H or C1-C3 alkyl substitution, and each M + Each M is a counterion with a single net positive charge. + Independently, for example, K + na + Li + Alkaline ions such as + N(R 60 ) Ammonium ions such as 4, or [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 These may include alkaline earth ions such as (the subscript 0.5 means that one of the counterions of such a divalent alkaline earth ion is the ionized form of the compound of this disclosure and the other is a typical counterion such as a chloride, or that two ionized compounds disclosed herein can play the role of counterions of such a divalent alkaline earth ion, or that a biionized compound disclosed herein can play the role of counterions of such a divalent alkaline earth ion). A specific example is -NR 80 R 80 It is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methylpiperazin-1-yl, and N-morpholinyl.

[0086] In addition to the disclosures herein, the substituents of hydrogen on unsaturated carbon atoms in “substituted” alkenes, alkynes, aryl and heteroaryl groups are, unless otherwise specified, deuterium, -R 60 Hello, -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70 、 -SO3 - M + 、 -SO3R 70 、 -OSO2R 70 、 -OSO3 - M + 、 -OSO3R 70 、 -PO3 -2 (M + )2, -P(O)(OR 70 )O - M + 、 -P(O)(OR 70 )2, -C(O)R 70 、 -C(S)R 70 、 -C(NR 70 )R 70 、 -CO2 - M + 、 -CO2R 70 、 -C(S)OR 70 、 -C(O)NR 80 R 80 、 -C(NR 70 )NR 80 R 80 、 -OC(O)R 70 、 -OC(S)R 70 、 -OCO2 - M + 、 -OCO2R 70 、 -OC(S)OR 70 、 -NR 70 C(O)R 70 、 -NR 70 C(S)R 70 、 -NR 70 CO2 - M + 、 -NR 70 CO2R 70 、 -NR 70 C(S)OR 70 、 -NR 70 C(O)NR 80 R 80 、 -NR 70 C(NR 70 )R 70 、及び -NR 70 C(NR 70 )NR 80 R 80 であり、R 60 、R 70 、R 80 、及びM+ This is as previously defined, except in the case of substituted alkenes or alkynes, where the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + This is conditional on the fact that it is not the case.

[0087] In addition to the groups disclosed with respect to individual terms herein, substituents on hydrogen atoms on nitrogen in "substituted" heteroalkyl and cycloheteralkyl groups are, unless otherwise specified, -R 60 ,-OM + , -OR 70 , -SR 70 , -SM + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 -S(O)2O-M + -S(O)2OR 70 -OS(O)2R 70 -OS(O)2O-M + -OS(O)2OR 70 ,-P(O)(O-)2(M + )2, -P(O)(OR 70 )OM + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 ,-C(S)R 70 -C(NR 70 )R 70 , -C(O)OR 70 , -C(S)OR 70 -C(O)NR 80 R 80 -C(NR 70 )NR 80 R 80 ,-OC(O)R 70 ,-OC(S)R 70 -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 And R 60 , R 70 , R 80 , and M + This is as previously defined.

[0088] In addition to the disclosures herein, in some embodiments, the substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0089] Unless otherwise specified, polymers achieved by defining substituents having further substituents on themselves (for example, a substituted aryl having a substituted aryl group as a substituent itself substituted with a substituted aryl group, which is then further substituted with a substituted aryl group) are not intended to be included herein. In such cases, the maximum number of such substitutions is 3. For example, the sequential substitutions of substituted aryl groups specifically intended herein are limited to substituted aryl-(substituted aryl)-substituted aryl. However, substituents defined as polyethers, for example, do not have more than 3 sequential substitutions, such as -O-(CH2CH2O) n -H may be present, and in the formula, n may be 1, 2, 3, or more.

[0090] Unless otherwise indicated, the naming of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group, followed by the adjacent functional groups toward the bonding site. For example, the substituent "arylalkyloxycarbonyl" refers to the (aryl)-(alkyl)-OC(O)- group.

[0091] It is understood that, with respect to any of the groups disclosed herein that contain one or more substituents, such groups do not include any substitutions or substitution patterns that are sterically unrealizable and / or synthetically unfeasible. Furthermore, the compounds in question include all stereochemical isomers resulting from the substitutions of these compounds.

[0092] When a substituent or group is described as "comprise(s) deuterium" or "comprising deuterium," it should be understood that the substituent or group itself may be deuterium, or the substituent or group may contain at least one deuterium substitution in its chemical structure. For example, when a substituent "-R" is defined as deuterium-containing, it should be understood that -R may be a group such as -D (-deuterium), or -CD3, which is consistent with other requirements given for -R.

[0093] As used herein, the term “fat” refers to a compound having a long-chain (linear) hydrophobic moiety consisting of hydrogen and 4 to 26 carbon atoms, which may be fully saturated or partially unsaturated.

[0094] The terms "pharmaceutically acceptable," "physiologically acceptable," etc., are used herein to refer to compounds, materials, compositions, and / or drug formulations that are within the bounds of sound medical judgment, suitable for use in contact with human tissue without excessive toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit-risk ratio. When referring to salts, the terms "pharmaceutically acceptable salt," etc., mean a salt that is acceptable for administration to patients such as mammals (a salt having a counterion that has acceptable mammalian safety for a given dosage regimen). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases, such as sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts; from addition salts with inorganic acids, such as hydrochlorides, hydrobroms, sulfates, sulfamates, phosphates, nitrates, and perchlorates, if the molecule contains a basic functional group; and from addition salts with organic acids, such as formates, tartrates, besilates, mesilates, acetates, maleates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemioxalates, hemifumarates, propions, stearates, lactates, citrates, ascorbicates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, and isethionates. When in solid form, a salt designated as a "hemi-" salt indicates that the stoichiometry of the target compound with respect to the counterion is approximately 2:1, whereas a solid salt form without the "hemi-" descriptor has a stoichiometry of approximately 1:1 with respect to the counterion. For example, DMT hemi-fumarate indicates that the ratio of DMT to fumarate is 2:1, while DMT fumarate indicates that the ratio of DMT to fumarate is 1:1.

[0095] "Solvate" means the physical association of a compound or salt of the Disclosure with one or more solvent molecules, which are organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain examples, for example, a solvate can be isolated if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate may exist in regular and / or irregular arrangements. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both the solution phase and the isolateable solvate. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Thus, exemplary solvates include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.

[0096] A "stereoisomer" refers to a compound that has the same atomic bonding but different atomic arrangements in space. Stereoiomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms of compounds, such as racemic compounds and optically pure stereoisomers, are contemplated herein. Chemical formulas and compounds that have at least one stereocenter but are drawn without reference to stereochemistry are contemplated to include both racemic compounds and distinct stereoisomers, such as R- and / or S-stereoisomers, and each diastereomer substitution to the extent that their diastereomers are geometrically feasible.

[0097] A "crystalline" solid is a type of solid whose basic three-dimensional structure contains a highly regular pattern of atoms or molecules that form a crystal lattice with long-range order, and therefore exhibits a sharp, characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern. In some cases, crystalline solids may exist in different crystalline forms known as "polymorphs," having the same chemical composition but differing in the packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have various solid-state physical properties that affect the safety and efficacy of pharmaceuticals based on the compound, as well as, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, fluidity, and compressibility of the compound. Further purification may also be achieved in terms of overall physical or optical purity during the process of preparing polymorphs. As used herein, the term "amorphous" refers to a solid material that does not substantially have long-range order in the position of its molecules, where the molecules are randomly arranged in a clearly defined arrangement, e.g., there is no effective molecular packing and no long-range order. Amorphous solids are generally isotropic, meaning they exhibit similar properties in all directions and do not have a distinct melting point. For example, an amorphous material is a solid material that, in its X-ray power diffraction (XRPD) pattern, does not substantially have sharp, characteristic crystalline peaks (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids. Therefore, the subject compound / material of “amorphous” is a compound / material characterized as substantially lacking crystallinity, meaning it has less than 10% crystallinity, less than 8% crystallinity, less than 6% crystallinity, less than 4% crystallinity, less than 2% crystallinity, less than 1% crystallinity, or 0% crystallinity, i.e., at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphousness, as determined, for example, by XRPD. For example, in some embodiments, the degree of crystallinity % may be determined by measuring the intensity of one or more peaks in the XRPD diffractogram compared to a reference peak that may be a known standard or internal standard.For example, other characterization techniques such as differential scanning calorimetry (DSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, including quantitative methods that provide the aforementioned percentages in terms of weight percentage, may be used to determine the percentage of the compound / substance in question that is amorphous or crystalline.

[0098] When referring to the X-ray powder diffraction (XRPD) patterns of the materials of this disclosure, the expression "characterized by an X-ray powder diffraction pattern having at least three characteristic peaks at a diffraction angle (2θ ± 0.2°) selected from..." should be understood to include those materials characterized by having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more (including all of them) listed characteristic XRPD diffraction peaks. Furthermore, this expression is intended to be open to the inclusion of other XRPD diffraction peaks that are not listed.

[0099] The compounds described herein may exist in different salt, solvate, stereoisomer, and crystalline / amorphous (including polymorphic) forms, and it will be understood that this disclosure is intended to include all such substitutions, for example, solvates of pharmaceutically acceptable salts of the stereoisomers of the compounds in question.

[0100] The term "tamper-resistant" is recognized in the art to describe a form of drug formulation that makes it more difficult to abuse the drug portion of the formulation, for example, through extraction for intravenous use or grinding for free base use, thereby reducing the risk of drug abuse.

[0101] As used herein, the terms “stable,” “stability,” etc., include chemical stability and solid-state (physical) stability. The term “chemical stability” means that a compound can be stored under normal storage conditions in an isolated form or in the form of a formulation provided, for example, mixed with a pharmaceutically acceptable carrier, diluent, or adjuvant as described herein, with little or no chemical degradation or decomposition. “Solid-state stability” means that a compound can be stored under normal storage conditions in an isolated solid form or in the form of a solid formulation provided, for example, mixed with a pharmaceutically acceptable carrier, diluent, or adjuvant as described herein, with little or no change in the solid state (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid phase transition).

[0102] As used herein, the term “composition” is equivalent to the term “formulation.”

[0103] As used herein, the terms “to treat” or “treatment” mean treating or treating a disease or medical condition of a patient, such as a mammal (particularly a human), which includes, for example, improving the disease or medical condition, such as causing the elimination or regression of the disease or medical condition of the patient; suppressing the disease or medical condition, for example, by delaying or cessating the onset of the disease or medical condition of the patient; or alleviating one or more symptoms of the disease or medical condition of the patient. Treatment may provide therapeutic benefits, such as the elimination or improvement of one or more physiological or psychological symptoms associated with the underlying condition, disease, or disorder, so that improvement is observed in the patient, regardless of the fact that the patient may still be affected by the condition. In some embodiments, treatment may also refer to prevention, i.e., preventing the onset of the disease or medical condition or otherwise delaying the onset of the disease or medical condition of the patient.

[0104] In this specification, the terms “patient” or “subject” as used interchangeably may be any mammal, including, for example, humans. A patient or subject may have, or be prone to, a condition being treated.

[0105] Psychotropic drugs are chemical substances that can cross the blood-brain barrier, act on the nervous system, and have the ability to cause changes in perception, mood, consciousness, cognition, and / or behavior. Classification of psychotropic drugs includes anxiolytics (e.g., benzodiazepines, barbiturates, etc.), empathogens-entactogens (e.g., MDMA, MDA, AMT, etc.), stimulants (e.g., amphetamines, modafinil, etc.), depressants (e.g., sedatives, hypnotics, and opioids), and hallucinogens such as hallucinogens, dissociative agents, and delirium-inducing agents (e.g., psilocybin, LSD, DMT, mescaline, salvia divinolam, scopolamine, etc.).

[0106] As used herein and unless otherwise specified, the terms “to manage,” “to control,” and “to control” refer to the prevention or delay of the progression, spread, or worsening of a disease, disorder, or condition, or one or more of its symptoms. In many cases, the beneficial effects obtained by a subject from a preventive and / or therapeutic agent do not result in a cure for the disease, disorder, or condition. In this regard, the term “managing” includes treating a subject suffering from a particular disease, disorder, or condition in an attempt to prevent or minimize the recurrence of the disease, disorder, or condition, or one or more of its symptoms.

[0107] "Therapeutic effective dose" refers to the amount of a compound or its salt form sufficient to treat a particular disorder or disease, or one or more symptoms thereof, and / or prevent the onset of the disease or disorder (prophylactic effective dose). As used herein, unless otherwise specified, the "prophylactic effective dose" of an active agent is the amount sufficient to prevent a disease, disorder, or condition, or to prevent its recurrence. The term "prophylactic effective dose" may include an amount that improves overall prevention or enhances the prophylactic effect of another prophylactic agent.

[0108] The term "administration schedule" refers to a plan that outlines the type, amount, duration, and procedure of medications used in drug therapy in chronological order, including the dosage, method of administration, order of administration, and administration days for each drug. The dates designated for administration are determined before drug administration begins. Administration is continued by repeating a series of administration schedules, which are called "courses." A "continuous" administration schedule means administration every day without interruption during a course of treatment. If the administration schedule follows an "intermittent" administration schedule, the number of administration days may be followed by "rest days" or non-administration days during the course. A "drug-free period" indicates a time when the drug is not being administered according to a prescribed administration schedule. For example, after several courses of treatment, a subject may be prescribed a regulated drug-free period as part of the administration schedule, for example, before resuming active treatment.

[0109] As used herein, "bolus" refers to the administration of a specific amount of an active pharmaceutical ingredient (API) (e.g., a psychotropic drug) within 30 minutes or less (e.g., by injection) so that the concentration of the API in the body increases rapidly. Bolus injections are typically administered intravenously (directly into a vein), intramuscularly (inside the muscle), intradermally (under the skin), or subcutaneously (inside the fat or skin). Therefore, a bolus injection differs from an "infusion," in which a specific amount of API (e.g., a psychotropic drug) is administered by a single or multiple injection over a longer period than 30 minutes, resulting in a more stable kinetic profile of the API concentration in the body, and potentially reaching a steady state over a longer period of exposure.

[0110] The term “toxic spike” is used herein to describe a spike in the concentration of any compound described herein that may cause sedative or psychotropic side effects, such as hallucinations, dizziness, and nausea, which not only have immediate effects but also affect treatment compliance. In particular, side effects may be more pronounced at blood concentration levels above approximately 300 ng / mL (e.g., above approximately 300, 400, 500, or 600 ng / mL).

[0111] According to IUPAC, "osmolality" is the exponent of the negative natural logarithm of the rational activity of water and the molar mass of water. More simply, osmolality is the expression of the number of osmotically active particles (solute particles) in 1 kg of solution, expressed herein as the number of milliosmoles (mOsm) per 1 kg of solution. Therefore, osmolality is a function of the number of particles only and is not related to the molecular weight, size, shape, or charge of the particles (see DKFaria et al., MEMendes and NMSumita, J.Bras.Pata!.Med.Lab., 53, 1, 38-45 (2017) for a discussion on measuring serum osmolality). For example, one mole of a non-dissociating substance (e.g., glucose) dissolved in 1 kg of water has an osmolality of 1 Osm / kg (1000 mOsm / kg), while one mole of a substance that dissociates into two distinct species in a solution (e.g., sodium chloride) dissolved in 1 kg of water has an osmolality of 2 Osm / kg (2000 mOsm / kg).

[0112] When solutions are defined herein as "isotonic" with respect to each other, they have the same osmolality. For example, when a formulation is defined as isotonic with human serum, the formulation has the same osmolality as human serum. Human serum typically has an osmolality of about 275 to about 300 mOsm / kg (L. Hooper et al., BMJ Open, 2015; 5(10): e008846).

[0113] "Syringeable" or "syringeable" refers to the force required to inject a given solution at a given rate through a selected needle length and gauge, relating to whether a formulation can be administered through a syringe. The flow through a hollow needle is given by the Hagen-Poiseuille equation (1):

number

[0114] Unless otherwise specified, concentrations expressed in terms of weight per unit volume (w / v) are calculated from grams (g) per milliliter (mL). These concentrations may also be expressed as a percentage (%w / v); for example, the concentration of 1 g of solute in 100 mL of solution is 1%w / v.

[0115] As used herein, and unless otherwise specified, “neuropsychiatric disorder or condition” is defined as a behavioral or psychological problem associated with a known neurological condition, typically as a group of co-occurring symptoms. Examples of neuropsychiatric disorders include, but are not limited to, schizophrenia, cognitive deficits in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, cognitive deficit disorders, seizures, convulsions, headache disorders, addiction, eating disorders, anger, bipolar disorder and mania, depressive disorders, anxiety disorders, or any combination thereof.

[0116] As used herein, “inflammatory condition” or “inflammatory disease” broadly refers to chronic or acute inflammatory diseases. Inflammatory conditions and inflammatory diseases include, but are not limited to, rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis); spondyloarthritis (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome); crystalline arthropathy (e.g., gout, pseudogout, calcium pyrophosphate deposition disease); multiple sclerosis; Lyme disease; polymyalgia rheumatica; connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjögren's syndrome); and blood Examples include inflammatory conditions such as vascular inflammation (e.g., polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome), trauma or ischemia, sarcoidosis; vascular diseases including atherosclerosis, atherosclerosis, and occlusive diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis; ocular diseases including uveitis, corneal diseases, iritis, iridocyclitis, glaucoma, or any combination thereof.

[0117] All diseases and disorders listed herein may be defined as those described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association, or in the International Classification of Diseases (ICD) published by the World Health Organization.

[0118] As used herein, “adjunctive therapy,” “adjunctive therapy,” etc., refer to therapies given in addition to primary or initial therapy to improve or maximize efficacy. For example, a subject diagnosed with depressive disorder who is receiving one or more antidepressant therapies (e.g., SSRIs) as primary or initial therapy but has an inadequate response to antidepressant therapy or, otherwise, has not achieved the desired outcome with antidepressant therapy, may be administered the pharmaceutical formulations of the Disclosure as “adjunctive therapy” to improve or maximize therapeutic efficacy. In this example involving depressive disorder, the adjunctive therapy may improve or maximize therapeutic efficacy by reducing depressive symptoms compared to primary or initial therapy alone. Primary or initial therapy and adjunctive therapy, including the pharmaceutical formulations of the Disclosure, may, but do not have to be, prescribed and / or administered by the same person (e.g., a clinician). For example, primary or initial therapy (e.g., SSRI therapy) may be prescribed by a first clinician and self-administered by the patient, while adjunctive therapy, including the pharmaceutical formulations of the Disclosure, may be prescribed and / or administered by a second clinician. Alternatively, primary or initial therapy (e.g., SSRI therapy) may be prescribed by a first clinician and self-administered by the patient, while adjunctive therapies, including the pharmaceutical formulations of this disclosure, may be prescribed and / or administered by the same (first) clinician.

[0119] As used herein, the term “insufficient response” refers to the lack of clinically significant improvement in symptoms, as measured, for example, by one or more of the assessment scales described herein. An insufficient response to an appropriate course of treatment with antidepressant therapy may be determined retrospectively or predictively. A predictive determination of an insufficient response refers to a determination made by the prescribing clinician or therapist after the administration of part of the course of treatment. A retrospective determination refers to a determination made by the prescribing clinician or therapist after the administration of a fully sufficient course of treatment.

[0120] As used herein, "peak effect," "peak hallucinogenic effect," and "peak experience" refer to the subjective effect on strong perception and consciousness, which is the peak effect that usually correlates with a VAS score of 70 mm or higher. For short-acting tryptamine hallucinogens such as DMT, 5-MeO-DMT, and their analogues (e.g., deuterated analogues), the peak effect in humans is associated with a drug plasma concentration of 40 ng / mL or higher.

[0121] The term "effect size" refers to a statistical calculation that can be used to compare the effectiveness of different drugs by quantifying the magnitude of the difference between treatments ("between groups"). It is a dimensionless measure of the difference in outcomes under two different therapeutic interventions. Thus, effect size informs clinicians about the magnitude of the therapeutic effect. Unless otherwise stated herein, where used, effect size is calculated using Cohen's d method, from the difference between the mean change in the intragroup efficacy endpoint obtained from the treatment group (e.g., administration of pharmaceutically acceptable salts of the compounds in formulas (I)-(III)) and the mean change in the intragroup efficacy endpoint obtained from the placebo:

number

[0122] As used herein, the terms “and / or” include any and all combinations of one or more of the enumerated items relating to them. As used throughout this specification and the subsequent claims, “a,” “an,” and “the” include plural references in addition to singular ones, unless the context otherwise explicitly indicates. The term “about” relating to a number means that the value can fluctuate by 5% above or below. For example, a value of about 100 means between 95 and 105 (or any value between 95 and 105).

[0123] Pharmaceutical preparations This specification discloses an injectable pharmaceutical formulation comprising a psychotropic agent or drug, a release regulator such as a hyaluronic acid or carboxymethylcellulose salt, and an aqueous vehicle.

[0124] A pharmaceutical formulation is suitable for injection, and therefore its administration in therapy typically involves parenteral injection of the formulation through the skin or other external boundary tissue rather than the gastrointestinal tract, resulting in the active pharmaceutical ingredient contained within being delivered directly to blood vessels, organs, tissues, or lesions using gravity or force. Being suitable for injection, i.e., "for injection" or "injectable," means that the formulation is, for example, as defined in the United States Pharmacopeial (USP) Convention, General Requirements / <1> This means that the injectable preparations comply with the pharmacopoeia requirements, as described in Injections, 33. For example, the injectable preparations are prepared by methods designed to ensure that they meet the pharmacopoeia requirements for sterility, pyrogens, particulate matter, and other contaminants, and, where appropriate, contain growth inhibitors (e.g., antimicrobial preservatives) and / or antioxidants. An example of a pharmacopoeia requirement is the USP Pyrogen Test. <151> , USP Bacterial Endotoxin Test <85> , USP Antimicrobial Effectiveness Testing <51> , USP Antimicrobial Agents-Content <341> , USP Sterilization and Sterility Assurance of Compendial Articles <1211> , USP Particulate Matter in Injections <788> , and USP Stability Tests <71> These are some examples, but are not limited to them. For example, to be suitable for injection, the endotoxin limit, defined on a dose basis, is equal to K / M, where K is the threshold human fever dose of endotoxin per kg of body weight, M is equal to the maximum recommended human dose of the product per kg of body weight over a period of 1 hour, Escherichia coli should not be present in 1 g of the formulation, the total aerobic microbial count (TAMC) should be less than 1,000 colony-forming units (CFU) / g, and the total yeast and mold count (TYMC) should not exceed 100 CFU / g.

[0125] Being suitable for injection, i.e., “for injection” or “injectable,” further means that the pharmaceutical formulation is characterized as having physiological and chemical properties, such as pH, osmolality, and viscosity, that allow administration through the skin or other external boundary tissue via a needle, syringe, cannula, catheter, or other suitable injection device without causing excessive tissue necrosis, pain, or inflammation (e.g., phlebitis) at the injection site. Injectable pharmaceuticals generally have a pH of about 2–11 for IV and intramuscular injections and about 3–9 for subcutaneous injections (Usach I, et al. Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site. Adv Ther. 2019 Nov;36(11):2986-2996). pH values ​​that are too high are associated with tissue necrosis, while pH values ​​that are too low are associated with pain and inflammation at the injection site. Injectable drugs generally have an osmolality of 150–600 mOsm / kg, and an osmolality closest to that of human serum (275–approximately 300 mOsm / kg) is preferred. Hypertonic injections with osmolality above 600 mOsm / kg have been reported to cause erythrocyte serration formation and significant pain, while hypotonic solutions with osmolality below 150 mOsm / kg may cause hemolysis and pain at the injection site (Roethlisberger D. et al. If Euhydric and Isotonic Do Not Work, What Are Acceptable pH and Osmolality for Parenteral Drug Dosage Forms?, Journal of Pharmaceutical Sciences, 106(2), 2017, 446-456). Injectable medications administered using standard syringes and needle gauges generally have a viscosity of less than approximately 50 centipoise (cP). Higher viscosity sometimes requires an injection force that is too high for standard syringes and gauge needles to withstand. Some medications may not be able to be administered through a syringe (they may not be "syringeable").However, some injectable pharmaceuticals with much higher viscosities (cP less than 100 to 10,000 or more) can be administered by injection, for example, when administering non-Newtonian fluids or when using injection devices designed for high-viscosity fluids, such as auto-injectors for high-viscosity fluids. The pH, osmolality, and viscosity of the pharmaceutical formulations of this disclosure are within the range reported to be suitable for injection, and particularly suitable for subcutaneous injection.

[0126] Pharmaceutical formulations are typically in the form of solutions, but other dosage forms such as suspensions, emulsions, micelles, liposomes, microspheres, and nanosystems suitable for injection are also intended. Solid forms suitable for solutions or suspensions in liquid before injection are also disclosed. In some embodiments, pharmaceutical formulations are disclosed as ready-to-use sterile solutions. In some embodiments, pharmaceutical formulations are disclosed as reconstituted solutions prepared from sterile dried soluble products, including lyophilized powders and tablets for subcutaneous injection, which are reconstituted in an aqueous vehicle before use. In some embodiments, pharmaceutical formulations are disclosed as ready-to-use sterile suspensions. In some embodiments, pharmaceutical formulations are disclosed as reconstituted solutions prepared from sterile dried soluble products, which are reconstituted in an aqueous vehicle before use. In some embodiments, pharmaceutical formulations are disclosed as ready-to-use sterile emulsions.

[0127] In some embodiments, the injectable pharmaceutical preparation is suitable for intravenous administration (directly into a vein), i.e., it is an intravenous pharmaceutical preparation. In some embodiments, the injectable pharmaceutical preparation is suitable for intramuscular administration (inside the muscle), i.e., it is an intramuscular pharmaceutical preparation. In some embodiments, the injectable pharmaceutical preparation is suitable for intradermal administration (below the skin), i.e., it is an intradermal pharmaceutical preparation. In some embodiments, the injectable pharmaceutical preparation is suitable for subcutaneous administration (inside the fat or the skin layer immediately below the dermis and epidermis), i.e., it is a subcutaneous pharmaceutical preparation.

[0128] Subcutaneous administration is a minimally invasive mode of administration. Subcutaneous tissue has few blood vessels, and therefore, drugs injected into it are intended to have a slow, sustained absorption rate, often with some degree of depot effect. Compared to other routes of administration, this is slower than intravenous and intramuscular injection, but still faster than intradermal injection. The convenience and speed of subcutaneous delivery lead to improved patient compliance and, when necessary, faster access to the drug. Subcutaneous administration can be performed by injection or by implanting a sustained-release or sustained-release device under the surface of the skin. The injection or device site can be changed if multiple injections or devices are required. Subcutaneous formulations are usually much easier to handle for both the patient and the physician. A particular advantage of the subcutaneous delivery route in the therapeutic methods of this disclosure is that it allows the physician to administer the drug with considerably less intervention with the patient compared to intravenous infusion protocols associated with DMT-based therapies. Furthermore, patients can be trained to administer the drug themselves. Such self-administration can be particularly useful during maintenance administration, when clinical observation and / or psychotherapy may not play a very prominent role in the overall treatment. Typically, injection volumes of up to approximately 3 mL are acceptable via subcutaneous routes, particularly those administered to the patient's abdomen, while injection volumes of approximately 2 mL or less are well acceptable across various injection sites. Larger subcutaneous injection volumes exceeding approximately 3 mL are often associated with pain. For patients requiring multiple doses, several unit-dose formulations may be injected into multiple sites on the body surface. Specific pharmacopoeia requirements regarding subcutaneous injections are outlined in the USP Particulate Matter in Injections. <788> This includes, but is not limited to, meeting the standards.

[0129] The pharmaceutical formulation may be suitable for bolus injection, in which an individual amount of psychotropic drug is administered by injection within 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less. The bolus injection may involve a single injection or multiple injections performed within the above time ranges. Therefore, administering multiple bolus injections within the above time range of 30 minutes or less (for example, two injections administered within 5 minutes of each other, each lasting 30 seconds) would be considered a bolus administration as defined herein. In some embodiments, the bolus injection is accompanied by a single injection within the above time ranges. The pharmaceutical formulation may be suitable for bolus subcutaneous injection, such as a single bolus subcutaneous injection; that is, the pharmaceutical formulation is a bolus subcutaneous pharmaceutical formulation. The pharmaceutical preparation may be suitable for bolus intramuscular injection, such as a single bolus intramuscular injection; that is, the pharmaceutical preparation is a bolus intramuscular pharmaceutical preparation. The pharmaceutical preparation may be suitable for bolus intradermal injection, such as a single bolus intradermal injection; that is, the pharmaceutical preparation is a bolus intradermal pharmaceutical preparation. The pharmaceutical preparation may be suitable for bolus intravenous injection, such as a single bolus intravenous injection; that is, the pharmaceutical preparation is a bolus intravenous pharmaceutical preparation.

[0130] The pharmaceutical formulation may be suitable for infusion injection, in which individual amounts of psychotropic drugs are administered by injection over long periods of time exceeding 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, and 120 minutes. Infusion injection may involve a single long-duration injection or multiple injections (short or long durations) within the aforementioned time ranges. Therefore, administering multiple bolus injections over a long period exceeding 30 minutes would be considered infusion administration as defined herein. In some embodiments, the infusion injection involves a single injection within the aforementioned time ranges. The pharmaceutical formulation may be suitable for infusion subcutaneous injection. The pharmaceutical formulation may be suitable for infusion intramuscular injection. The pharmaceutical formulation may be suitable for infusion intravenous injection.

[0131] psychotropic drugs Injectable pharmaceutical preparations may contain psychotropic agents. Psychotropic agents may include anxiolytics (e.g., benzodiazepines, barbiturates, etc.), empathogens-entactogens (e.g., MDMA, MDA, AMT, etc.), stimulants (e.g., amphetamines, modafinil, etc.), depressants (e.g., sedatives, hypnotics, and opioids), and / or hallucinogens (e.g., tryptamine hallucinogens), dissociative agents, or delirium-inducing agents (e.g., psilocybin, LSD, DMT, mescaline, salvia divinolam, scopolamine, etc.). Psychotropic agents may also be free base compounds or pharmaceutically acceptable salts of free base compounds. Combinations of psychotropic agents may also be used.

[0132] In some embodiments, psychotropic agents are dissociative agents, dissociative hallucinogens, anesthetics, arylcyclohexylamines, 1,2-diarylethylamines, β-ketoarylcyclohexylamines, and / or compounds that modulate NMDA receptors. Examples of such psychotropic agents include, but are not limited to, ketamine, methoxetamine, deschloroketamine, N-ethyldeschloroketamine (ethicridone), 3-methoxyphencyclidine, methoxyethiccyclidine, ephenidine, ranisemin, dextromethorphan, dextrorphan, methoxyketamine, norketamine (e.g., (R)-norketamine, (S)-norketamine, or mixtures thereof), hydroxynorketamine (e.g., 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, or mixtures thereof), or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, or combinations thereof.

[0133] In some embodiments, the psychotropic agent is an opioid. Examples of opioids include, but are not limited to, racemorphan, levorphanol, racemethorphan, buprenorphine, morphine, loperamide, morphine, codeine, hydrocodone, oxymorphone, buprenorphine, fentanyl, methadone, tramadol, alpha-methylacetylfentanyl, alfentanyl, butylfentanyl, carfentanyl, 3-methylcarfentanyl, 4-fluorofentanyl, beta-hydroxyfentanyl, alpha-methylfentanyl, cis-3-methylfentanyl, beta-hydroxy-3-methylfentanyl, remifentanyl, sufentanyl, 3-methylthiofentanyl, naloxone, and naltrexone, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, or combinations thereof.

[0134] In some embodiments, the psychotropic agent is cathinone, 3,4-methylenedioxyamphetamine compounds, aminoalkyl-substituted benzofurans, substituted amphetamines, aminoindan, stimulants, diphenhydramine, hydroxazine, phenylephrine, dopamine, adrenaline, lidocaine, oxymetazoline, clemastine, chlorpheniramine, or 6-chloro-2-aminotetraline. In some embodiments, the pharmaceutical compound is cathinone, aminoalkyl-substituted benzofurans, and aminoindan, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

[0135] In some embodiments, the psychotropic agent is a lysergamid. Examples of lysergamids include, but are not limited to, methylisopropyl lysergamid, ethylisopropyl lysergamid, 6-allyl-6-nor-LSD, 6-ethyl-6-nor-lysergic acid diethylamide, 1-acetyl-LSD, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 1-propionyl-lysergic acid diethylamide, 1-cyclopropionyl-d-lysergic acid diethylamide, N1-butyryl-lysergic acid diethylamide, and 6-propyl-6-nor-lysergic acid diethylamide, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, or combinations thereof.

[0136] In some embodiments, the psychotropic agent is a phenethylamine. Examples of phenethylamines include, but are not limited to, mescaline, 2,5-dimethoxy-4-bromophenethylamine (2C-B), 2-(4-iodo-2,5-dimethoxyphenyl)ethane-1-amine (2C-I), 2-(4-chloro-2,5-dimethoxyphenyl)ethane-1-amine (2C-C), 2,5-dimethoxy-4-iodoamphetamine, 2-[2,5-dimethoxy-4-(propylsulfanyl)phenyl]ethane-1-amine, and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethaneamine, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, or combinations thereof.

[0137] In some embodiments, the psychotropic agent is a tryptamine hallucinogen. Examples of tryptamine hallucinogens include, but are not limited to, N,N-dimethyltryptamine, N,N-diethyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N-isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N-ethyltryptamine, N,N-diisopropyltryptamine, 4-hydroxy-N-methyl-N-ethyltryptamine, 5-methoxy-N,N-diisopropyltryptamine, 5-methoxy-N,N-dimethyltryptamine, O-acetylpsisine, psilocine, and the tryptamine hallucinogens listed below, or their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs, or combinations thereof.

[0138] Examples of psychotropic drugs that can be classified as hallucinogens, such as hallucinogens (e.g., tryptamine hallucinogens), dissociative agents, or delirium-inducing agents include 9,10-didehydro-6-allyl-N,N-diethylergoline-8β-carboxamide, 9,10-didehydro-6,N,N-triethylergoline-8β-carboxamide, N,N-dimethyltryptamine, N,N-diethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, N,N-dibutyltryptamine, N,N-diethyltryptamine, N, N-diisopropyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N-isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N-ethyltryptamine, 4-hydroxy-N-methyl-N-ethyltryptamine, 5-methoxy-N,N-diisopropyltryptamine, 5-methoxy-α-methyltryptamine, 2,α-dimethyltryptamine, α,N-dimethyltryptamine N,N-dipropyltryptamine, N-ethyl-N-isopropyltryptamine, α-ethyltryptamine, O-acetylpsisine, psilocine, harmanine (7-methoxy-1-methyl-p-carbolin), harmanine (7-methoxy-p-carbolin), 4-hydroxy-diethyltryptamine and phosphate esters, 4-hydroxy-diisopropyltryptamine, 4-hydroxy-methyltryptamine, 4-hydroxytryptamine, 5-hydroxytryptamine, 4-hydroxy C-dipropyltryptamine, 4-hydroxy-N-methyl-N-ethyl-tryptamine, 4-hydroxy-N-methyl-N-isopropyl-tryptamine, 4-hydroxy-NN-tetramethylene-tryptamine, d-iso-LSD, I-LSD, I-iso-LSD, N,N-diisopropyl-4,5-methylenedioxytryptamine, N,N-diisopropyl-5,6-methylenedioxytryptamine, N,N-dimethyl-4,5-methylenedioxytryptamine, N,N-dimethyl-5,6-Methylenedioxytryptamine, 2-Methyl-DMT, 5-MeO-Diethyltryptamine, 5-MeO-Diisopropyltryptamine, 4-MeO-N-Isopropyl-N-methyltryptamine, 5-MeO-N-Isopropyl-N-methyltryptamine, 5-MeO-NMT, 5-MeO-2,N,N-Trimethyltryptamine, N-Isopropyl-N-methyltryptamine, Alpha-Methyltryptamine, Alpha-Methyl-4-OH-Tryptamine, N-Methyltryptamine, 5-MeO-α,N-Dimethyltryptamine, 4-Allyloxy-3,5-dimethoxyphenethylamine, 2,5-dimethoxy-4-methylthioamphetamine, 2,5-dimethoxy-4-ethylthioamphetamine, 2,5-dimethoxy-4-i-propylthioamphetamine, 2,5-dimethoxy-4-phenylthioamphetamine, 2,5-dimethoxy-4-n-propylthioamphetamine, 2,5-dimethoxy-α-ethyl-4-methylphenethylamine, 3,4-diethoxy-5-methoxyphenethylamine, 4-n-butoxy-3,5-dimethoxyphenethylamine, 2,5- Dimethoxy-4,N-dimethylamphetamine, 4-bromo-2,5-β-trimethoxyphenethylamine, 4-methyl-2,5,β-trimethoxyphenethylamine, β-methoxy-3,4-methylenedioxyphenethylamine, 3,4,5,β-tetramethoxyphenethylamine, 3,5-dimethoxy-4-bromoamphetamine, 2-bromo-4,5-methylenedioxyamphetamine, 4-bromo-2,5,dimethoxyphenethylamine, 4-benzyloxy-3,5-dimethoxyamphetamine, 2,5-dimethoxy-4-chlorophenethylamine Luamine, 2,5-dimethoxy-4-methylphenethylamine, 2,5-dimethoxy-4-ethylphenethylamine, 3,5-dimethoxy-4-ethoxyamphetamine, 2,5-dimethoxy-4-fluorophenethylamine, 2,5-dimethoxy-3,4-dimethylphenethylamine, 2,5-dimethoxy-3,4-(trimethylene)phenethylamine, 2,5-dimethoxy-3,4-(tetramethylene)phenethylamine, 3,6-dimethoxy-4-(2-aminoethyl)benzonorborane, 1,4-dimethoxynaptyl-2-ethylamine, 2,5-Dimethoxyphenethylamine, 2,5-Dimethoxy-4-iodophenethylamine, 2,5-Dimethoxy-4-nitrophenethylamine, 2,5-Dimethoxy-4-i-propoxyphenethylamine, 2,5-Dimethoxy-4-n-propoxyphenethylamine, 4-Cyclopropyl-3,5-Dimethoxyphenethylamine, 2,5-Dimethoxy-4-methylseleneophenethylamine, 2,5-Dimethoxy-4-methylthiophenethylamine, 2,5-Dimethoxy-4-ethyl Thiophenethylamine, 2,5-dimethoxy-4-i-propylthiophenethylamine, 2,6-dimethoxy-4-i-propylthiophenethylamine, 2,5-dimethoxy-4-n-propylthiophenethylamine, 2,5-dimethoxy-4-cyclopropylmethylthiophenethylamine, 2,5-dimethoxy-4-t-butylthiophenethylamine, 2,5-dimethoxy-4-(2-methoxyrthylthio(methoxyrthylthio))phenethylamine, 2,5-dimethoxy-4-cyclopropylthiophenethylamine, 2,5 -Dimethoxy-4-s-butylthiophenethylamine, 2,5-dimethoxy-4-(2-fluorothio)phenethylamine, 2,5-dimethoxy-4-triduuteromethoxyphenethylamine, 2,4,5-trimethoxy-β,β-diduuterophenethylamine, 2,5-dimethoxy-4-methylphenethylamine, 2,4-dimethoxyamphetamine, 2,5-dimethoxyamphetamine, 2,4-dimethoxyamphetamine, 2,5-dimethoxy-3,4-methylenedioxyamphetamine, 2,5-dimethoxy-4-bromoamphetamine n, 2,5-dimethoxy-4-chloroamphetamine, 2,5-dimethoxy-4-(2-fluoroethyl)-amphetamine, 2,5-dimethoxy-4-iodoamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,6-dimethoxy-4-methylamphetamine, 2,5-dimethoxy-4-n-propylamphetamine, 3,5-dimethoxy-4-ethoxyphenethylamine, 2,4,5-triethoxyamphetamine, 2,4-diethoxy-5-methoxyamphetamine, 2,5-diethoxy-4-methoxyamphetamine, 4,5-Dimethoxy-2-ethoxyamphetamine, N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine, 2,5-dimethoxy-3,4-(trimethylene)amphetamine, 3,6-dimethoxy-4-(2-aminopropyl)benzonorborane, 2,5-dimethoxy-3,4-dimethylamphetamine, 2,5-dimethoxy-4-ethylthio-N-hydroxyphenethylamine, 2,5-dimethoxy-N-hydroxy-4-n-propylthiophenethylamine, 2,5-dimethoxy-4-s-butylthio-N-hydroxyphenethyl Amine, 3,5-dimethoxy-4-i-propoxyphenethylamine, 5-ethoxy-2-methoxy-4-methylamphetamine, 2-amino-(3,4-methylenedioxyphenyl)butane, 3-methoxy-4,5-methylenedioxyphenethylamine, 3,4,5-trimethoxyphenethylamine, 3,5-dimethoxy-4-metalloxyphenethylamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-N-ethylamphetamine, 3,4-methylenedioxy-N -Methylamphetamine, 3,4-methylenedioxy-N-hydroxyamphetamine, 3,4-methylenedioxy-5-ethoxyphenethylamine, 2,5-dimethoxy-4-ethoxyapmphetamine, 3-methoxy-4-ethoxyphenethylamine, 2-methylamino-1-(3,4-methylenedioxyphenyl)butane, 3-methoxy-4,5-methylenedioxyamphetamine, 2-methoxy-4,5-methylenedioxyamphetamine, 2-methoxy-3,4-methylenedioxyamphetamine , 4-Methoxy-2,3-methylenedioxyamphetamine, 3,5-dimethoxy-4-n-propoxyphenethylamine, 4-ethoxy-5-methoxy-3-methylthiophenethylamine, 3,5-dimethoxy-4-ethylthiophenethylamine, 3,4-dimethoxy-5-methylthiophenethylamine, 3,5-dimethoxy-5-methylthiophenethylamine, 3,4,5-trimethoxyamphetamine, 2,4,5-trimethoxyamphetamine, 2,3,5-trimethoxyamphetamine, 2,3,6-trimethoxyamphetamine, 2,4,6-Trimethoxyamphetamine, 4,5-Dimethoxy-3-ethylthiophenethylamine, 4-Ethyl-2-methoxy-5-methylthioamphetamine, 5-Methoxy-4-methyl-2-methylthioamphetamine, 2-Methoxy-4-methyl-5-methylthioamphetamine, 2-Methoxy-4-methyl-5-methylsulfinylamphetamine, 3,5-Dimethoxy-4-n-propylthiophenethylamine, Salvinolin A, Ibotenic acid, Muscimol, Dextromethorphan, Ketamine, Esketamine (S(+)-enantiomer of ketamine), No Examples include, but are not limited to, lucetamines (e.g., (R)-norketamine, (S)-norketamine, or mixtures thereof), hydroxynorketamines (e.g., 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, or mixtures thereof), phencyclidine, disosylpine (MK-801), scopolamine, hyoscyamine, aporfin, lysergic acid amides, cathine, cathinone, and boacangin, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, or combinations thereof.

[0139] Tryptamine hallucinogens In some embodiments, the psychotropic agent is a tryptamine hallucinogen. Tryptamine hallucinogens generally share a basic core structure of indole (condensed benzene and pyrrole rings) and a 2-aminoethyl group on a second carbon (a third aromatic atom, the first being a heterocyclic nitrogen), as shown below. Many tryptamine hallucinogens are 5-HT 2A They are receptor agonists, that is, they are 5-HT 2A It enhances receptor activity, and this is a subtype of the 5-HT2 receptor belonging to the serotonin receptor family, which includes both partial and full agonists. [ka]

[0140] In some embodiments, the tryptamine hallucinogen is optionally substituted on the tryptamine ring. In some embodiments, the tryptamine hallucinogen is N,N-dialkyltryptamine. In some embodiments, the tryptamine hallucinogen is N,N-dimethyltryptamine, N,N-diethyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N-isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N-ethyltryptamine, or N,N-diisopropyltryptamine, where tryptamine is optionally substituted or a combination thereof. In some embodiments, the tryptamine hallucinogen is substituted with one or more deuterium atoms. In some embodiments, the tryptamine hallucinogen is optionally substituted at the 4th or 5th position of the tryptamine ring with substituents selected from hydroxy, acetoxy, or methoxy. In some embodiments, the tryptamine is 4-hydroxy-N-methyl-N-ethyltryptamine, psilocine, 5-methoxy-N,N-diisopropyltryptamine, 5-methoxy-N,N-dimethyltryptamine, or O-acetylpsilocine (4-acetoxy-N,N-dimethyltryptamine), or a combination thereof.

[0141] A tryptamine hallucinogen may be a pharmaceutically acceptable salt of one of the compounds of the Disclosure, as defined below, for example, a pharmaceutically acceptable salt of a compound of formula (I) to (III). A tryptamine hallucinogen may be a pharmaceutically acceptable salt of a single compound of the Disclosure, or a pharmaceutically acceptable salt of a mixture of the compounds of the Disclosure. If an injectable pharmaceutical preparation contains an ion (protonated form) of one of the compounds of the Disclosure and an ion (counterion) that counteracts the charge of one of the compounds of the Disclosure in solution, then it contains a pharmaceutically acceptable salt of one of the compounds of the Disclosure (for example, a pharmaceutically acceptable salt of a compound of formula (I) to (III)) (as a tryptamine hallucinogen). Accordingly, a pharmaceutically acceptable salt of one of the compounds of the Disclosure (for example, a compound of formula (I) to (III)) may be pre-formed, for example, as a fumarate of one of the compounds of the Disclosure, and then combined with a release regulator and an aqueous vehicle to form an injectable pharmaceutical preparation. In other words, the pharmaceutical formulation for injection may be prepared from pre-formed, typically solid, and possibly crystalline solid forms, of pharmaceutically acceptable salts of the compounds of the Disclosure (e.g., compounds of formulas (I) to (III)). Alternatively, the pharmaceutically acceptable salts of the compounds of the Disclosure in the pharmaceutical formulation may be, for example, the compounds of the Disclosure (e.g., compounds of formulas (I) to (III)) as a free base, with available H₂ that can ionize / protonate the compounds of the Disclosure. + The compounds may be formed in situ by contact with an aqueous vehicle containing (aqueous) ions. The distribution of the free base and protonated species (salt form) of the compound may be present in the solution depending on the pH of the pharmaceutical formulation, but the pharmaceutical formulation generally contains at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, and at least 99% of the molar proportion of the protonated compound (salt form). In most cases, the pharmaceutical formulation contains at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, and at least 99.9% of the molar proportion of the protonated compound (salt form) relative to the most preferred water solubility.

[0142] In some embodiments, the tryptamine hallucinogen is a pharmaceutically acceptable salt of the compound of formula (I), or a stereoisomer, solvate, or prodrug thereof. [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium. R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R4 and R5 are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy. R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R8 and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. Alternatively, R8 and R9 may optionally join with the nitrogen atoms bonded to them to form unsubstituted or substituted heterocycloalkyl groups.

[0143] X1 and X2 may be the same or may be different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or deuterium, and X2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, X2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X2 is a substituted C1-C6 alkyl. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, one of X1 and X2 is deuterium and the other is hydrogen. In some embodiments, one or more of X1 and X2 are substituted or non-substituted C3-C 10 It is cycloalkyl. In some embodiments, one or more of X1 and X2 are unsubstituted C3-C 10 These are cycloalkyl compounds, and examples may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, one or more of X1 and X2 are substituted C3-C 10 It is a cycloalkyl group. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkenyls, for example, unsubstituted or substituted allyls.

[0144] Y1 and Y2 may be the same or may be different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0145] In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogen, such as fluoro, chloro, bromo, and iodine. In some embodiments, R2 is an unsubstituted C1-C6 alkyl group, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R2 is a substituted C1-C6 alkyl group. When R2 is a substituted C1-C6 group, preferred substituents include, but are not limited to, deuterium, halogens (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R2 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R2 is an unsubstituted or substituted alkynyl. In some embodiments, R2 is a substituted or unsubstituted C3-C 10 It is a cycloalkyl group. In some embodiments, R2 is an unsubstituted C3-C 10 The cycloalkyl group is a cycloalkyl group, and examples may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R2 is a substituted C3-C 10It is a cycloalkyl group. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R2 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, R2 is an unsubstituted or substituted aryl group. In some embodiments, R2 is an unsubstituted or substituted heteroaryl group.

[0146] R4 and R5 may be the same or different. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R4 is hydroxyl. In some embodiments, R4 is an unsubstituted C1-C6 alkyl group, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R4 is a substituted C1-C6 alkyl group. When R4 is a substituted C1-C6 alkyl group, preferred substituents may include, but are not limited to, polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R4 is an unsubstituted alkoxy group, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R4 is a substituted alkoxy. When R4 is a substituted alkoxy, preferred substituents include, but are not limited to, polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, or polyether substituents. The alkoxy group may contain one or more substituents. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc. In some embodiments, R4 is an unsubstituted alkylthio, and examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio.In some embodiments, R4 is a substituted alkylthio group. The alkylthio group may contain one or more substituents. In some embodiments, R4 is an alkylthio group substituted with one or more deuterium atoms. The alkylthio group may contain one or more deuterium substitutions. For example, when the alkylthio group is a C1 alkylthio group (i.e., a methyl group), the deuterium-substituted C1 alkylthio groups may be -SCDH2, -SCD2H, and -SCD3. In some embodiments, R4 is a haloalkylthio (alkylthio substituted with one or more halogen atoms), examples of which include, but are not limited to, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3, -SCH2CH2CH2F, -SCH2CH2CHF2, -SCH2CH2CF3, -SCH2CH2CH2CH2F, -SCH2CH2CH2CHF2, and -SCH2CH2CH2CF3, with particular mention of -SCH2F, -SCHF2, and -SCF3. In some embodiments, R4 is an unsubstituted or substituted acyloxy, examples of which include, but are not limited to, acetoxy (-OCOCH3), propionoxy (-OCOCH2CH3), and butyroxy (-OCOCH2CH2CH3).

[0147] In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxyl. In some embodiments, R5 is an unsubstituted C1-C6 alkyl group, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R5 is a substituted C1-C6 alkyl group. When R5 is a substituted C1-C6 alkyl group, preferred substituents may include, but are not limited to, polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R5 is an unsubstituted alkoxy group, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R5 is a substituted alkoxy. When R5 is a substituted alkoxy, preferred substituents include, but are not limited to, polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, or polyether substituents. The alkoxy group may contain one or more substituents. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc. In some embodiments, R5 is an unsubstituted alkylthio, examples of which include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio. In some embodiments, R5 is a substituted alkylthio.The alkylthio group may contain one or more substituents. In some embodiments, R5 is an alkylthio group substituted with one or more deuterium atoms. The alkylthio group may contain one or more deuterium substitutions. For example, if the alkylthio group is a C1 alkylthio group (i.e., a methyl group), the deuterium-substituted C1 alkylthio groups may be -SCDH2, -SCD2H, and -SCD3. In some embodiments, R5 is a haloalkylthio (alkylthio substituted with one or more halogen atoms), examples of which include, but are not limited to, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3, -SCH2CH2CH2F, -SCH2CH2CHF2, -SCH2CH2CF3, -SCH2CH2CH2CH2F, -SCH2CH2CH2CHF2, and -SCH2CH2CH2CF3, with particular mention of -SCH2F, -SCHF2, and -SCF3. In some embodiments, R5 is an unsubstituted or substituted acyloxy, examples of which include, but are not limited to, acetoxy (-OCOCH3), propionoxy (-OCOCH2CH3), and butyroxy (-OCOCH2CH2CH3).

[0148] R6 and R7 may be the same or may be different. In some embodiments, R6 and R7 are the same. In some embodiments, R6 and R7 are different. In some embodiments, R6 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is a halogen, e.g., fluoro, chloro, bromo, and iodine. In some embodiments, R6 is an unsubstituted or substituted alkyl (e.g., an unsubstituted or substituted C1-C6 alkyl). In some embodiments, R6 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R6 is a substituted C1-C6 alkyl. When R6 is a substituted C1-C6 alkyl, preferred substituents may include, but are not limited to, deuterium, halogens (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R6 is an unsubstituted or substituted alkenyl, for example, an unsubstituted or substituted allyl. In some embodiments, R6 is an unsubstituted or substituted alkynyl. In some embodiments, R6 is an unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R6 is an unsubstituted C3-C 10 These are cycloalkyl compounds, and examples may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R6 is a substituted C3-C 10It is a cycloalkyl group. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R6 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, R6 is an unsubstituted or substituted aryl group. In some embodiments, R6 is an unsubstituted or substituted heteroaryl group.

[0149] In some embodiments, R7 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is a halogen, such as fluoro, chloro, bromo, and iodine. In some embodiments, R7 is an unsubstituted or substituted alkyl (e.g., an unsubstituted or substituted C1-C6 alkyl). In some embodiments, R7 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R7 is a substituted C1-C6 alkyl. When R7 is a substituted C1-C6, preferred substituents include, but are not limited to, polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R7 is an unsubstituted or substituted alkenyl, for example, an unsubstituted or substituted allyl. In some embodiments, R7 is an unsubstituted or substituted alkynyl. In some embodiments, R7 is an unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R7 is an unsubstituted C3-C 10The cycloalkyl group is a cycloalkyl group, and examples may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R7 is a substituted C3-C 10 It is a cycloalkyl group. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R7 is an unsubstituted or substituted heterocycloalkyl group. In some embodiments, R7 is an unsubstituted or substituted aryl group. In some embodiments, R7 is an unsubstituted or substituted heteroaryl group.

[0150] R8 and R9 may be the same or different. In some embodiments, R8 and R9 are the same. In some embodiments, R8 and R9 are hydrogen. In some embodiments, R8 and R9 are deuterium. In some embodiments, R8 and R9 are unsubstituted or substituted alkyls, such as unsubstituted or substituted C1-C6 alkyls. In some embodiments, R8 and R9 are different. In some embodiments, R8 is hydrogen and R9 is an unsubstituted or substituted C1-C6 alkyl.

[0151] In some embodiments, R8 and / or R9 are unsubstituted C1-C6 alkyl groups, examples of which include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl, preferably methyl. In some embodiments, R8 and / or R9 are substituted C1-C6 alkyl groups. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R8 and / or R9 are alkyl groups substituted with one or more deuterium, for example, C1-C6 alkyl groups substituted with one or more deuterium. The alkyl group may contain one or more deuterium substitutions. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the deuterium-substituted C1 alkyl group may be -CDH2, -CD2H, and -CD3, with particular reference to -CD3. In some embodiments, R8 and / or R9 are haloalkyls, examples of which include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular reference to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3. In some embodiments, R8 and / or R9 are unsubstituted or substituted alkenyls, e.g., unsubstituted or substituted allyls. In some embodiments, R8 and / or R9 are unsubstituted or substituted alkynyls. In some embodiments, R8 and / or R9 are substituted or unsubstituted C3-C 10 It is cycloalkyl. In some embodiments, R8 and / or R9 are unsubstituted C3-C 10 These are cycloalkyl compounds, and examples include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R8 and / or R9 are substituted C3-C 10It is a cycloalkyl group. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R8 and / or R9 are unsubstituted or substituted heterocycloalkyl groups. In some embodiments, R8 and / or R9 are unsubstituted or substituted aryl groups. In some embodiments, R8 and / or R9 are unsubstituted or substituted heteroaryl groups.

[0152] In some embodiments, R8 and / or R9, together with the nitrogen atoms bonded to them, join to form an unsubstituted or substituted heterocycloalkyl group. The unsubstituted heterocycloalkyl group may be, for example, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered ring, and may be optionally fused to other rings. The unsubstituted heterocycloalkyl group contains at least one nitrogen ring atom (the nitrogen atoms interposed in R8 and R9) and optionally contains at least one additional heterocyclic atom, which may be one or more of nitrogen, sulfur, or oxygen atoms for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of unsubstituted heterocycloalkyl groups formed by joining R8 and R9 together with the nitrogen atoms bonded to them include: [ka] These include, but are not limited to, the following:

[0153] In some embodiments, R8 and R9, together with the nitrogen atoms bonded to them, join to form a substituted heterocycloalkyl group. The substituted heterocycloalkyl group may be, for example, a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered ring, and may be optionally fused with other rings. The substituted heterocycloalkyl group contains at least one nitrogen ring atom (the nitrogen atom interposed between R8 and R9) and may optionally contain additional heterocyclic atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 heterocyclic atoms (at least one of which is a nitrogen ring atom). Examples of substituted heterocycloalkyl groups include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which are substituted with at least one substituent. Substituents may include, but are not limited to, any enumerated herein, polar substituents such as deuterium, halogens (e.g., fluorine), hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether group), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. Substitutive heterocycloalkyls formed by joining R8 and R9 together with the nitrogen atoms bonded to them contain heterocycloalkyl groups substituted with one, two, three, four, or more substituents. The substituents may be located on the carbocyclic atom or on the heterocyclic atom.

[0154] Examples of substituted heterocycloalkyl groups formed by joining R8 and R9 together with the nitrogen atoms bonded to them include: [ka] These include, but are not limited to, the following:

[0155] In some embodiments, the tryptamine hallucinogen is a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug of a compound of formula (I), wherein one or more of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R8, and R9 optionally contain deuterium. In some embodiments, at least one of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R8, and R9 contains deuterium. In some embodiments, at least one of X1, X2, Y1, Y2, R5, R8, and R9 contains deuterium. In some embodiments, at least one of X1, X2, Y1, Y2, R8, and R9 contains deuterium. In some embodiments, X1, X2, R8, and R9 contain deuterium. In some embodiments, X1, X2, Y1, Y2, R8, and R9 contain deuterium. In some embodiments, X1, X2, and R5 contain deuterium. In some embodiments, X1, X2, Y1, Y2, R5, R8, and R9 contain deuterium.

[0156] In some embodiments, the tryptamine hallucinogen is a pharmaceutically acceptable salt of the compound of formula (II), or a stereoisomer, solvate, or prodrug thereof. [ka] During the ceremony, X1 and X2 are independently hydrogen or deuterium. Y1 and Y2 are independently hydrogen or deuterium. Each Z1 is independently either hydrogen or deuterium. Each Z2 is independently either hydrogen or deuterium. R2, R4, R5, R6, and R7 are independently hydrogen or deuterium.

[0157] X1 and X2 may be the same or may be different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is deuterium and X2 is hydrogen.

[0158] Y1 and Y2 may be the same or may be different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, Y1 is deuterium and Y2 is hydrogen.

[0159] In some embodiments, X1, X2, Y1, and Y2 are hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium.

[0160] In some embodiments, each Z1 is hydrogen. In some embodiments, each Z1 is deuterium. In some embodiments, one Z1 is hydrogen, while the other two Z1s are deuterium. In some embodiments, one Z1 is deuterium, while the other two Z1s are hydrogen. In some embodiments, each Z2 is hydrogen. In some embodiments, each Z2 is deuterium. In some embodiments, one Z2 is hydrogen, while the other two Z2s are deuterium. In some embodiments, one Z2 is deuterium, while the other two Z2s are hydrogen. In some embodiments, each Z1 and Z2 are hydrogen. In some embodiments, each Z1 and Z2 are deuterium.

[0161] In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is hydrogen. R2, R4, R5, R6, and R7 may be the same, for example, R2, R4, R5, R6, and R7 may each be hydrogen, or alternatively, R2, R4, R5, R6, and R7 may each be deuterium. In some embodiments, at least one of R2, R4, R5, R6, and R7 is deuterium, or at least two of R2, R4, R5, R6, and R7 are deuterium, or at least three of R2, R4, R5, R6, and R7 are deuterium, or at least four of R2, R4, R5, R6, and R7 are deuterium.

[0162] In some embodiments, at least one of X1, X2, Y1, Y2, Z1, Z2, R2, R4, R5, R6, and R7 is deuterium. In some embodiments, X1, X2, Z1, and Z2 are deuterium. In some embodiments, X1, X2, Y1, and Y2 are deuterium. In some embodiments, X1, X2, Y1, Y2, Z1, and Z2 are deuterium.

[0163] In some embodiments, the tryptamine hallucinogen is a pharmaceutically acceptable salt of the compound of formula (III), or a stereoisomer, solvate, or prodrug thereof. [ka] During the ceremony, X1 and X2 are independently hydrogen or deuterium. Y1 and Y2 are independently hydrogen or deuterium. Each Z1 is independently either hydrogen or deuterium. Each Z2 is independently either hydrogen or deuterium. Each Z3 is independently hydrogen or deuterium. R2, R4, R6, and R7 are independently hydrogen or deuterium.

[0164] X1 and X2 may be the same or may be different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is deuterium and X2 is hydrogen.

[0165] Y1 and Y2 may be the same or may be different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, Y1 is deuterium and Y2 is hydrogen.

[0166] In some embodiments, X1, X2, Y1, and Y2 are hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium.

[0167] In some embodiments, each Z1 is hydrogen. In some embodiments, each Z1 is deuterium. In some embodiments, one Z1 is hydrogen, while the other two Z1s are deuterium. In some embodiments, one Z1 is deuterium, while the other two Z1s are hydrogen. In some embodiments, each Z2 is hydrogen. In some embodiments, each Z2 is deuterium. In some embodiments, one Z2 is hydrogen, while the other two Z2s are deuterium. In some embodiments, one Z2 is deuterium, while the other two Z2s are hydrogen. In some embodiments, each Z1 and Z2 are hydrogen. In some embodiments, each Z1 and Z2 are deuterium.

[0168] In some embodiments, each Z3 is hydrogen. In some embodiments, each Z3 is deuterium. In some embodiments, one Z3 is hydrogen, while the other two Z3s are deuterium. In some embodiments, one Z3 is deuterium, while the other two Z3s are hydrogen. In some embodiments, each Z1, Z2, and Z3 is hydrogen. In some embodiments, each Z1 and Z2 is hydrogen, and each Z3 is deuterium. In some embodiments, each Z1, Z2, and Z3 is deuterium. In some embodiments, each Z1 and Z2 is deuterium, and each Z3 is hydrogen.

[0169] In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is hydrogen. R2, R4, R6, and R7 may be the same, for example, each of R2, R4, R6, and R7 may be hydrogen, or alternatively, each of R2, R4, R6, and R7 may be deuterium. In some embodiments, at least one of R2, R4, R6, and R7 is deuterium, or at least two of R2, R4, R6, and R7 are deuterium, or at least three of R2, R4, R6, and R7 are deuterium.

[0170] In some embodiments, at least one of X1, X2, Y1, Y2, Z1, Z2, Z3, R2, R4, R6, and R7 is deuterium. In some embodiments, X1, X2, Z1, and Z2 are deuterium, and each Z3 is hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium, and each Z3 is hydrogen. In some embodiments, X1, X2, Y1, Y2, Z1, and Z2 are deuterium, and each Z3 is hydrogen. In some embodiments, X1, X2, and Z3 are deuterium. In some embodiments, X1, X2, Y1, Y2, and Z3 are deuterium. In some embodiments, X1, X2, Y1, Y2, Z1, Z2, and Z3 are deuterium.

[0171] In some embodiments, tryptamine hallucinogens include the following exemplary compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0172] In some embodiments, the compound, for example, the compound of formula (I) or (II), is a deuterated analog of DMT, for example, [ka] [ka] Other examples include, but are not limited to, combinations thereof.

[0173] In some embodiments, the deuterated analogs of DMT are 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-2), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10), and 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10). It is one or more of the following: su(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12).

[0174] In some embodiments, the compound, for example, the compound of formula (I) or (III), is a deuterated analog of 5-MeO-DMT, for example, [ka] [ka] [ka] Other examples include, but are not limited to, combinations thereof.

[0175] In some embodiments, the deuterated analogs of 5-MeO-DMT are 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-20), 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-22), 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-23), and 2-(5-methoxy-1H-indole-3 -yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-18), 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-19), 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-24), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-34), 2-(5-( (Methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-36), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-37), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-32), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3) Ethane-1-amine-2,2-d2(I-33), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-38), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-28), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-2,2-d2(I-29), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,It is one or more of the following: N-dimethylethane-1-amine-1-d(I-26), 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-2-d(I-27), and 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine(I-25).

[0176] Any position in a compound defined herein as containing deuterium has more minimal deuterium incorporations than those found naturally occurring in hydrogen (about 0.016 atomic%). In some embodiments, any position in a compound defined herein as containing deuterium has at least 10 atomic%, at least 20 atomic%, at least 25 atomic%, at least 30 atomic%, at least 40 atomic%, at least 45 atomic%, at least 50 atomic%, at least 60 atomic%, at least 70 atomic%, at least 80 atomic%, at least 90 atomic%, at least 95 atomic%, and at least 99 atomic% minimal deuterium incorporations at the deuterated site.

[0177] The compounds described herein, for example, the compounds of formulas (I) to (III), may contain stereocenters. In such cases, formulas (I) to (III) are drawn without regard to stereochemistry, but the compounds may exist as different stereoisomers. Accordingly, this disclosure includes all possible stereoisomers, including not only racemic compounds but also individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and non-racemic mixtures thereof. If a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis known in the art, by decomposition of the final product or any convenient intermediate, or by chiral chromatography. Decomposition of the final product, intermediate, or starting material may be carried out by any suitable method known in the art.

[0178] In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (III), are nonsteric centers. In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (III), are racemates. In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (III), are enantiomerically enriched (one enantiomer present in a higher proportion), including being enantiomerically pure. In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (III), are provided as single diastereomers. In some embodiments, the compounds described herein, for example, the compounds of formulas (I) to (III), are provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixture may include equal mixtures or mixtures enriched with a particular diastereomer (one diastereomer present in a higher proportion than another).

[0179] As described herein, racemic compounds, for example, compounds of formulas (I) to (III), may contain about 50% of the R- and S-stereoisomers based on the molar ratio of one of the isomers (about 48 to about 52 mol%, or about 1:1 ratio). In some embodiments, a pharmaceutical formulation, drug, or therapeutic method may involve combining separately produced R- and S-stereoisomer compounds in approximately equal molar ratios (e.g., about 48 to 52%). In some embodiments, a drug or pharmaceutical formulation may contain mixtures of different ratios of distinct R- and S-stereoisomer compounds. In some embodiments, a pharmaceutical formulation contains an excess (more than 50%) of the R-enantiomer. Preferred molar ratios of R / S may be about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher. In some embodiments, a pharmaceutical formulation may contain an excess of the S-enantiomer by reversing the ratios provided for R / S. Other preferred amounts of R / S may also be selected. For example, the R-enantiomer may be concentrated and present in amounts of, for example, at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. In other embodiments, the S-enantiomer may be concentrated in amounts of, for example, at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. The ratios between all these exemplary embodiments, as well as larger and smaller ratios, are still within the scope of this disclosure. Pharmaceutical formulations may contain racemic mixtures and mixtures of the distinct compounds of formulas (I) to (III) in salt form.

[0180] In some embodiments, the compounds of formulas (I) to (III) are agonists of the serotonin 5-HT2 receptor. 2A It is a receptor agonist. In some embodiments, the compounds of formulas (I) to (III) are serotonin 5-HT 1A It is a receptor agonist. In some embodiments, the compounds of formulas (I) to (III) are serotonin 5-HT 2CIt is a receptor agonist.

[0181] In some embodiments, the tryptamine hallucinogen used in the preparation of the pharmaceutical formulation is chemically pure, having a purity of, for example, 90%, 92%, 94%, 96%, 97%, 98%, or 99% as measured by ULC or HPLC. In some embodiments, the tryptamine hallucinogen does not have a single impurity exceeding 1%, 0.5%, 0.4%, 0.3%, or 0.2% as measured by ULC or HPLC. In some embodiments, the tryptamine hallucinogen has a chemical purity exceeding 97 area%, 98 area%, or 99 area% as measured by ULC or HPLC. In some embodiments, the tryptamine hallucinogen does not have a single impurity exceeding 1 area%, 0.5 area%, 0.4 area%, 0.3 area%, or 0.2 area% as measured by ULC or HPLC.

[0182] The compounds disclosed herein, for example, acids that can be used to form pharmaceutically acceptable (acid addition) salts of the compounds of formulas (I) to (III) include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid) Acids (naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfate, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α -Oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, sugar acid, succinic acid, sulfuric acid, sulfamic acid, tannin Examples of acids include, but are not limited to, acids, tartaric acids (e.g., DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including mono- and di-fatty acids, e.g., adipico(hexanedi)ic acid, lauric(dodecanoic) acid, linoleic acid, myristic(tetradecanoic) acid, capric(decanoic) acid, stearic(octadecanoic) acid, oleic acid, caprylic(octanoic) acid, palmitic(hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.). Combinations of acids may be used to form mixtures of acid addition salts.

[0183] When an injectable pharmaceutical formulation is prepared from a pre-formed pharmaceutically acceptable salt of a compound disclosed herein, certain salt forms are preferred among the above list because they have physical and pharmaceutical features / properties that are well suited to pharmaceutical preparation and administration. For example, preferred salt forms of the compounds disclosed herein (e.g., compounds of formulas (I) to (III)) have one or more of the following characteristics: they tend to form salts and are easy to prepare in high yield; they are stable and have distinct physical properties such as crystallinity, lack of pleomorphism, and high fusion / fusion enthalpy; they are slightly or not hygroscopic; they flow freely, do not aggregate / adhere to surfaces, and have a regular form; they have acceptable water solubility for the intended route of administration; and / or they are physiologically acceptable, for example, they do not cause irritation when administered to mammals.

[0184] Crystallinity When pre-formed as a solid, pharmaceutically acceptable salts of the compounds of the present disclosure (e.g., compounds of formulas (I) to (III)) may be crystalline or amorphous, preferably crystalline, as determined, for example, by X-ray powder diffraction (XRPD). In some embodiments, pharmaceutically acceptable salts of the compounds of the present disclosure are amorphous, as determined, for example, by XRPD and / or DSC. Pharmaceutically acceptable salts of the compounds of the present disclosure may exist in a stable amorphous form. In some embodiments, a high-purity amorphous form of the pharmaceutically acceptable salt of the compounds of the present disclosure is provided, where at least 92% by weight, at least 94% by weight, at least 96% by weight, at least 98% by weight, at least 99% by weight, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compounds of the present disclosure is in an amorphous form, as determined, for example, by X-ray powder diffraction and / or DSC. In some embodiments, the pharmaceutically acceptable salt of the compounds of the present disclosure is crystalline. Crystalline forms offer advantages, for example, in terms of stability, and provide well-defined physical properties that are desirable for pharmaceutically appropriate preparation and administration. A pharmaceutically acceptable salt of the compound of this disclosure may be in a stable crystalline form. In some embodiments, a pharmaceutically acceptable salt of the compound of this disclosure has a crystallinity percentage of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.5%, and up to 100%, as determined by XRPD and / or DSC analysis. In some embodiments, a high-purity crystalline form of a pharmaceutically acceptable salt of the compound of this disclosure is provided, where at least 90% by weight, at least 95% by weight, at least 99% by weight, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of this disclosure is in a crystalline form, as determined, for example, by X-ray powder diffraction and / or DSC. For example, their pre-formed salt forms having a high crystallinity as determined by discrete and sharp Bragg diffraction in an X-ray diffractogram are preferred.

[0185] XRPD analysis can be performed, for example, with a Bruker D5000 X-ray powder diffractometer using CuKα radiation (wavelength = 1.54060 Å). The instrument may be equipped with a microfocus X-ray tube. The tube voltage and amperage can be set to 40 kV and 30 mA, respectively. The diverging and scattering slit widths can be set to 2 mm, and the detector slit width can be set to 0.2 mm. The diffracted radiation can be detected by a NaI scintillation detector. A theta-2 theta continuous scan of 2.0 to 40° (4 seconds / step, 0.01° step size) can be used.

[0186] From the perspective of pharmaceutical production processes, the advantageous salt form of the compound of this disclosure is one that readily yields a crystalline solid by crystallization in an acceptable yield and with a preferred volume coefficient without proceeding through oil, making it suitable for mass production.

[0187] The salt forms of the compounds of this disclosure (e.g., compounds of formulas (I) to (III)) may, in some cases, exist in different polymorphs (i.e., forms having different crystalline structures), however, the preferred salt forms of this disclosure are those that can crystallize into a single crystalline form or a single polymorph, as determined by XRPD and / or differential scanning calorimetry (DSC). Furthermore, it is generally desirable that the salt forms are fluid, do not aggregate / adhere to surfaces, and have a regular morphology.

[0188] Chemical / Solid State Stability In some embodiments, pharmaceutically acceptable salts of the compounds of the present disclosure have melting onset temperatures ranging from about 100°C, about 110°C, about 120°C, about 130°C, about 140°C, about 150°C, about 160°C, about 170°C, about 180°C, about 190°C, and up to about 250°C, up to about 225°C, up to about 210°C, and up to about 200°C, as determined by DSC.

[0189] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is approximately 90 J·g, as determined by DSC.-1 From, approximately 100 J·g -1 From, approximately 110J·g -1 From, approximately 120J·g -1 From, approximately 130 J·g -1 From, approximately 140 J·g -1 From, approximately 150 J·g -1 From, approximately 160 J·g -1 From, up to approximately 190 J·g -1 , maximum approximately 180J·g -1 , maximum approximately 170J·g -1 It has a melting enthalpy of .

[0190] Pre-formed pharmaceutically acceptable salts of the compounds of this disclosure, suitable for pharmaceutical manufacturing, may be characterized by being non-hygroscopic or slightly hygroscopic, preferably non-hygroscopic. Hygroscopicity can be measured herein by performing a moisture adsorption / desorption isotherm using a dynamic vapor adsorption (DVS) analyzer, starting with exposure at 30% relative humidity (RH), increasing the humidity to a maximum of 95% RH, decreasing the humidity to 0% RH, and finally increasing the humidity back to the starting 30% RH, and is classified as follows: Non-hygroscopic: <0.2%; Slightly hygroscopic: ≥0.2% and <2%; Hygroscopic: ≥2% and <15%; Highly hygroscopic: ≥15%; Deliquescent: Sufficient water is absorbed to form a liquid; All values ​​are measured as weight increase (w / w due to water acquisition) at >95%RH and 25°C.

[0191] In some embodiments, pharmaceutically acceptable salts of the compounds of the present disclosure, as determined by DVS, have a weight increase of less than 1% w / w, less than 0.8% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, less than 0.1% w / w, less than 0.08% w / w, less than 0.06% w / w, less than 0.05% w / w, and less than 0.02% w / w at over 95% RH.

[0192] Pre-formed pharmaceutically acceptable salts of the compounds disclosed herein can be maintained / stored in open or closed environments, such as in open or closed flasks / vials, without significant decomposition (e.g., without a significant decrease in chemical purity) or physical changes (e.g., changes in morphology, deliquescence, etc.) under ambient or stress conditions such as 25°C / 60%RH, 25°C / 90+%RH, or 40°C / 75%RH. For example, dry powder samples in salt form disclosed herein may undergo purity changes of less than 10%, less than 5%, and less than 1% when stored under ambient or stress conditions (e.g., elevated temperature, e.g., 40°C, and / or humidity).

[0193] Physiological tolerability The preferred salt forms of the compounds of this disclosure are physiologically acceptable and do not cause excessive irritation or tissue damage at the injection site. Therefore, preferred pharmaceutically acceptable salts of the compounds of this disclosure, for example, the compounds of formulas (I) to (III), are organic acids, preferably organic acids having a mild acidity, for example, 1.0 or higher, 1.5 or higher, 2.0 or higher, 2.5 or higher, 3.0 or higher, 3.5 or higher, 4.0 or higher, 4.5 or higher, for example, 3.0 to 6.5 pK in water a It is formed from organic acids that have [a certain characteristic].

[0194] solubility The aqueous solubility of pharmaceutically acceptable salts of the compounds disclosed herein can be determined by equilibrating an excess of solid with 1 mL of water at 22°C for 24 hours. A 200 μL aliquot can be centrifuged at 15,000 revolutions per minute (rpm) for 15 minutes. The supernatant can be analyzed by ULC or HPLC, and the solubility can be expressed as its free base equivalent (mg FB / mL). For example, pharmaceutically acceptable salt forms of the compounds disclosed herein can be prepared, and their solubility and the pH of the solution can be measured.

[0195] In some embodiments, pharmaceutically acceptable salts of the compounds of the Disclosure, for example, compounds of formulas (I) to (III), have a water solubility of about 5 mg / mL to about 400 mg / mL at 22°C. In some embodiments, pharmaceutically acceptable salts of the compounds of the Disclosure range from about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, and about 110 mg The compounds have water solubility ranging from approximately 120 mg / mL, approximately 130 mg / mL, approximately 140 mg / mL, approximately 150 mg / mL, and up to approximately 400 mg / mL, up to approximately 380 mg / mL, up to approximately 360 mg / mL, up to approximately 340 mg / mL, up to approximately 320 mg / mL, up to approximately 300 mg / mL, up to approximately 280 mg / mL, up to approximately 260 mg / mL, up to approximately 250 mg / mL, or any range in between. In some embodiments, pharmaceutically acceptable salts of the compounds of this disclosure have water solubility ranging from approximately 200 mg / mL to approximately 400 mg / mL. In some embodiments, pharmaceutically acceptable salts of the compounds of this disclosure have water solubility ranging from approximately 150 mg / mL to approximately 250 mg / mL. In some embodiments, pharmaceutically acceptable salts of the compounds of this disclosure have water solubility greater than about 1 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL.

[0196] In some embodiments, pharmaceutically acceptable salts of the compounds of the Disclosure, for example, the compounds of formulas (I) to (III), are fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemioxalates, or hemifumarates. From the viewpoint of providing desirable physical and pharmaceutical characteristics such as those described above, preferred pharmaceutically acceptable salts are fumarates, hemifumarates, benzoates, salicylates, and succinates of the compounds disclosed herein, for example, the compounds of formulas (I) to (III), with fumarates, benzoates, and salicylates being particularly preferred. In some embodiments, pharmaceutically acceptable salts of the compounds of the Disclosure, for example, the compounds of formulas (I) to (III), are benzenesulfonates.

[0197] In some embodiments, pharmaceutically acceptable salts are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate of N,N-dimethyltryptamine (DMT). In some embodiments, pharmaceutically acceptable salts are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate of 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT). In some embodiments, pharmaceutically acceptable salts are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). In some embodiments, the pharmaceutically acceptable salt is 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(DMT-d 10) are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate. In some embodiments, pharmaceutically acceptable salts are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(DMT-d8). In some embodiments, pharmaceutically acceptable salts are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(DMT-d2). In some embodiments, the pharmaceutically acceptable salt is 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(5-MeO-DMT-d 10 The salts are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate of 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(5-MeO-DMT-d5). In some embodiments, the salts are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate of 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(5-MeO-DMT-d 13 These are fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate.

[0198] In some embodiments, DMT or a deuterated analog of DMT (e.g., DMT-d 10 A pharmaceutically acceptable salt of ) is a crystalline solid disclosed in PCT / EP2023 / 050702, which is incorporated herein by reference in its entirety.

[0199] Table 1 provides non-limiting examples of pharmaceutically acceptable salts of the compounds of formulas (I) and (II). [Table 1]

[0200] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the fumarate of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-1a) (i.e., the fumarate of compound I-1 shown below). In some embodiments, when salt I-1a is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.7°, 22.5°, 23.9°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source. [ka]

[0201] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the benzoate of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-1b) (i.e., the benzoate of compound I-1 shown above). In some embodiments, when salt I-1b is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 11.1°, 12.6°, 13.5°, 15.8°, 16.1°, 17.1°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.7°, 23.8°, 24.6°, 26.9°, 29.2°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source.

[0202] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the salicylate of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-1c) (i.e., the salicylate of compound I-1 shown above). In some embodiments, when salt I-1c is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.7°, 21.0°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuKα radiation source.

[0203] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the succinate of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-1d) (i.e., the succinate of compound I-1 shown above). In some embodiments, when salt I-1d is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.8°, 11.7°, 14.3°, 14.7°, 17.0°, 17.4°, 19.6°, 20.6°, 22.3°, 22.6°, 22.9°, 23.1°, 23.4°, 24.9°, 25.2°, 26.3°, 26.8°, 27.3°, 27.7°, 28.8°, 29.1°, 30.9°, 31.5°, 33.8°, 34.5°, 36.5°, and 39.2°, as determined by XRPD using a CuKα radiation source.

[0204] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the oxalate of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-1e) (i.e., the oxalate of compound I-1 shown above). In some embodiments, when salt I-1e is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 11.3°, 12.3°, 15.6°, 17.7°, 19.5°, 20.0°, 20.8°, 21.4°, 22.3°, 22.7°, 24.8°, 25.7°, 26.7°, 27.9°, 28.7°, 29.5°, 31.4°, 33.0°, 35.4°, 36.5°, and 38.6°, as determined by XRPD using a CuKα radiation source.

[0205] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the glycolate of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-1f) (i.e., the glycolate of compound I-1 shown above). In some embodiments, when salt I-1f is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 8.2°, 12.2°, 12.9°, 15.8°, 16.3°, 17.8°, 19.2°, 20.1°, 21.7°, 23.6°, 24.4°, 24.6°, 24.9°, 26.0°, 26.6°, 27.8°, 29.6°, 30.2°, 32.0°, 32.3°, 33.0°, 33.9°, and 34.6°.

[0206] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the hemisodium salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-1g) (i.e., the hemisodium salt of compound I-1 shown above). In some embodiments, when salt I-1g is in crystalline solid form, it is determined by XRPD using a CuKα radiation source to be 8.7°, 11.5°, 13.6°, 14.2°, 15.2°, 17.4°, 17.6°, 18.0°, 19.3°, 19.6°, 20.1°, 20.6°, 21.9°, 22.1°, 22.9°, 23.2°, 2 It is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 3.5°, 24.5°, 25.0°, 25.5°, 26.1°, 26.4°, 27.1°, 28.4°, 28.7°, 29.8°, 30.4°, 30.7°, 31.4°, 31.8°, 33.4°, and 33.9°.

[0207] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the hemi-fumarate of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-1h) (i.e., the hemi-fumarate of compound I-1 shown above). In some embodiments, when salt I-1h is in crystalline solid form, it is determined by XRPD using a CuKα radiation source to be 8.1°, 11.3°, 12.2°, 13.3°, 14.2°, 16.2°, 17.6°, 18.3°, 18.6°, 19.5°, 19.8°, 20.0°, 20.2°, 20.9°, 21.4°, 21.9°, 2 It is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 2.3°, 22.7°, 22.9°, 23.8°, 24.5°, 25.0°, 25.2°, 26.1°, 26.4°, 26.9°, 28.4°, 28.8°, 29.5°, 29.8°, 30.9°, and 32.7°.

[0208] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the fumarate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8a) (i.e., the fumarate of compound I-8 shown below). In some embodiments, when salt I-8a is in a crystalline solid state, it is determined by XRPD using a CuKα radiation source, with values ​​of 7.8°, 10.3°, 10.9°, 12.5°, 13.6°, 14.6°, 15.2°, 15.5°, 15.8°, 16.1°, 16.6°, 17.0°, 18.4°, 19.0°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.3°, 23.8°, 24.1°, 25.1°. Characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 2θ, 26.2°, 26.8°, 27.3°, 27.9°, 28.3°, 28.9°, 29.3°, 29.6°, 29.9°, 30.6°, 31.0°, 31.3°, 32.4°, 32.9°, 33.3°, 33.6°, 34.3°, 34.9°, 35.7°, 36.1°, 37.4°, 38.0°, and 38.5°. In some embodiments, when salt I-8a is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.8°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8a is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 23.8°, 24.1°, and 25.1°, as determined by XRPD using a CuKα radiation source. [ka]

[0209] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the benzoate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8b) (i.e., the benzoate of compound I-8 shown above). In some embodiments, when salt I-8b is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.3°, 24.6°, 25.1°, 25.3°, 25.5°, 26.9°, 28.3°, 28.9°, 29.3°, 31.4°, 31.6°, 32.0°, 32.3°, 32.8°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8b is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.6°, 26.9°, 29.3°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8b is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 23.8°, 24.6°, 26.9°, 29.3°, and 35.1°, as determined by XRPD using a CuKα radiation source.

[0210] In some embodiments, the pharmaceutically acceptable salt of the compounds of this disclosure is the salicylate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8c) (i.e., the salicylate of compound I-8 shown above). In some embodiments, when salt I-8c is in crystalline solid form, it is determined by XRPD using a CuKα radiation source to be 9.6°, 10.5°, 11.4°, 12.3°, 13.4°, 14.2°, 14.9°, 15.6°, 16.1°, 17.1°, 18.1°, 18.7°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 22.2°, 22.6°, 23.7°, 24.6°. Characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 2θ, 25.2°, 25.6°, 26.1°, 26.4°, 27.4°, 27.5°, 27.8°, 28.5°, 28.8°, 29.4°, 29.7°, 30.3°, 31.0°, 31.3°, 32.1°, 32.7°, 33.1°, 33.5°, 34.4°, and 35.0°. In some embodiments, when salt I-8c is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8c is in a crystalline solid state, it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.3°, 24.6°, 25.6°, 28.5°, and 32.1°, as determined by XRPD using a CuKα radiation source.

[0211] Table 2 provides non-limiting examples of pharmaceutically acceptable salts of the compounds of formulas (I) and (III). [Table 2-1] [Table 2-2] [Table 2-3]

[0212] In some embodiments, the pharmaceutically acceptable salt is the hydrochloride of N,N-dimethyltryptamine (DMT). In some embodiments, the pharmaceutically acceptable salt is the hydrochloride of 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT). In some embodiments, the pharmaceutically acceptable salt is the hydrochloride of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). In some embodiments, the pharmaceutically acceptable salt is 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(DMT-d 10 ) is the hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is the hydrochloride salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(DMT-d8). In some embodiments, the pharmaceutically acceptable salt is the hydrochloride salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(DMT-d2). In some embodiments, the pharmaceutically acceptable salt is the hydrochloride salt of 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(5-MeO-DMT-d 10The hydrochloride salt of ) is. In some embodiments, the pharmaceutically acceptable salt is the hydrochloride salt of 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(5-MeO-DMT-d5). In some embodiments, the pharmaceutically acceptable salt is the hydrochloride salt of 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(5-MeO-DMT-d 13 It is the hydrochloride salt of ).

[0213] Various methods and procedures may be used to prepare preformed pharmaceutically acceptable salts of the compounds of this disclosure, and such methods and procedures are generally known to those skilled in the art. In some embodiments, the preformed pharmaceutically acceptable salts of the compounds of this disclosure are (a) Suspending or dissolving the free base of a compound of the Disclosure (for example, a compound of formula (I) to (III)) in a solvent or a mixture of solvents, (b) To provide a mixture by contacting an acid with a compound of the present disclosure, (c) Selectively heating the mixture, (d) Optionally cooling the mixture, (e) Prepared by isolating the salt.

[0214] A variety of solvents may be used, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent is a protic solvent. In some embodiments, the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxane (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ether solvents (e.g., t-butyl methyl ether (TBME)), hexane, heptane, and octane, and combinations thereof. In some embodiments, the solvent is ethanol.

[0215] Suitable acids for use during the contact step include those described above. The acid may be an inorganic acid (e.g., hydrochloric acid) or an organic acid, with organic acids being preferred. In some embodiments, the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, and glycolic acid. In some embodiments, the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, and succinic acid, with fumaric acid, benzoic acid, and salicylic acid being preferred. In some embodiments, a stoichiometric (or hyperstoichiometric) amount of the acid is contacted with the compound of the disclosure. In some embodiments, a quasi-stoichiometric (e.g., 0.5 molar equivalent) amount of the acid is contacted with the compound of the disclosure. For example, if the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemate, the use of a quasi-stoichiometric amount of the acid may be desirable.

[0216] In some embodiments, the mixture is heated before cooling, for example, by reflux.

[0217] In some embodiments, the mixture is cooled to allow the salt to precipitate from the solution. In some embodiments, the salt precipitates from the solution in a crystalline form. In some embodiments, the salt precipitates from the solution in an amorphous form.

[0218] The isolation of salts can be carried out by various well-known isolation techniques, such as filtration and decantation. In some embodiments, the isolation step includes filtering the mixture.

[0219] After isolation, additional crystallization and / or recrystallization steps may be optionally performed as desired, for example, to increase purity, crystallinity, etc.

[0220] Activated salt mixture A pharmaceutical formulation may contain, as a psychotropic agent, a pharmaceutically acceptable salt of a single compound of the Disclosure (e.g., a single compound of formulas (I) to (III)), or a pharmaceutically acceptable salt of a mixture of the compounds of the Disclosure (e.g., a mixture of compounds of formulas (I) to (III)). In one embodiment, the pharmaceutical formulation may contain a mixture of isotopologes of the compounds of the Disclosure in salt form as a psychotropic agent. In some embodiments, the target compounds of formulas (I) to (III) may be present in the pharmaceutical formulation at a purity of at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, or at least 99% by weight, based on the total weight of the mixture of isotopologes of the compounds of formulas (I) to (III) in salt form present in the pharmaceutical formulation. For example, as a target compound in salt form, DMT-d 10 Pharmaceutical formulations prepared using a salt (the salt form of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4) may additionally contain isotopologs of the target compound in salt form, such as DMT-d9 salt and DMT-d8 salt. In some embodiments, the pharmaceutical formulation is substantially free of other isotopologs of the target compound in salt form, for example, the pharmaceutical formulation has other isotopologs of the target compound in salt form in amounts of 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or less than 0.5 mole percent.

[0221] If an injectable pharmaceutical preparation contains, as a psychotropic agent, pharmaceutically acceptable salts of a mixture of the compounds of the present disclosure (e.g., a mixture of the compounds of formulas (I) to (III)), such mixture may be referred to herein as an “active salt mixture.” In some embodiments, the active salt mixture is a fumarate mixture, and the listed salt forms are fumarates. In some embodiments, the active salt mixture is a benzoate mixture, and the listed salt forms are benzoates. In some embodiments, the active salt mixture is a salicylate mixture, and the listed salt forms are salicylates. In some embodiments, the active salt mixture is a succinate mixture, and the listed salt forms are succinates.

[0222] In some embodiments, the pharmaceutical formulation is (i) DMT-d 10 (ii) a pharmaceutically acceptable salt of (1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), (ii) a pharmaceutically acceptable salt of DMT-d9, namely one or more of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11) The active salt mixture comprises an acceptable salt, and optionally (iii) a pharmaceutically acceptable salt of DMT-d8, namely one or more pharmaceutically acceptable salts of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12). In some embodiments, the activated salt mixture is (i) DMT-d based on the total weight of the activated salt mixture, in a range of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. 10This includes pharmaceutically acceptable salts of, namely, pharmaceutically acceptable salts of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8). In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more pharmaceutically acceptable salts of (ii) DMT-d9, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), in total, in amounts of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between. In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more pharmaceutically acceptable salts of (iii) DMT-d8, namely, 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12), in total, less than 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between. In some embodiments, the activated salt mixture is (i) DMT-d 10(ii) a pharmaceutically acceptable salt of (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), and (ii) a pharmaceutically acceptable salt of DMT-d9, namely one or more pharmaceutically acceptable salts of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), or essentially consisting of them.

[0223] In some embodiments, the pharmaceutical formulation contains (i) 90% to 99% by weight, or any range between thereof, of DMT-d based on the total weight of the active salt mixture. 10(ii) an active salt mixture comprising a pharmaceutically acceptable salt of, namely, a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), and, based on the total weight of the active salt mixture, a total of 1% to 10% by weight, or any range between thereof, a pharmaceutically acceptable salt of DMT-d9, namely, one or more pharmaceutically acceptable salts of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11).In some embodiments, the active salt mixture (and therefore the pharmaceutical formulation) is (1) a pharmaceutically acceptable salt of DMT-d8, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl) (1) A pharmaceutically acceptable salt of DMT-d7, (2) A pharmaceutically acceptable salt of DMT-d6 (a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12)), (2) A pharmaceutically acceptable salt of DMT-d7, (3) A pharmaceutically acceptable salt of DMT-d6 (a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine(I-4)), (4) A pharmaceutically acceptable salt of DMT-d5 (5) a pharmaceutically acceptable salt of DMT-d4 (salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1,2,2-d4(I-5)), (6) a pharmaceutically acceptable salt of DMT-d3, (7) a pharmaceutically acceptable salt of DMT-d2 (2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-2) and / or (1) is a salt of one or more of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-2,2-d2(I-3)), (8) a pharmaceutically acceptable salt of DMT-d1, and (9) a pharmaceutically acceptable salt of DMT (a salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine(I-1)) is not present in any detectable amount, or otherwise substantially present in any other way. For example, in some embodiments, the total weight of pharmaceutically acceptable salts of DMT isotopologs not listed in (i) or (ii), e.g., those listed in (1) to (9), is less than 1% by weight, less than 0.75% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.25% by weight, less than 0.2% by weight, less than 0.1% by weight, or 0% by weight, based on the total weight of the active salt mixture.

[0224] In some embodiments, the pharmaceutical formulation is (i) DMT-d 10(ii) One or more fumarates of the following: (ii) Fumarate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), (ii) Fumarate of DMT-d9, i.e., 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11) The mixture of active salts comprises a salt, and optionally one or more fumarates of (iii) DMT-d8, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12). In some embodiments, the activated salt mixture is (i) DMT-d based on the total weight of the activated salt mixture, in a range of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. 10It contains the fumarate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8). In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more fumarates of (ii) DMT-d9, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), in total, in amounts of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between. In some embodiments, the activated salt mixture contains, based on the total weight of the activated salt mixture, one or more fumarates of (iii) DMT-d8, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12), in total, less than 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between. 10 (ii) a fumarate of (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), and (ii) a fumarate of DMT-d9, namely one or more fumarates of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), or essentially consisting of them.

[0225] In some embodiments, the pharmaceutical formulation is (i) DMT-d 10 (ii) One or more benzoic acids from the following: (ii) the benzoate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), (ii) the benzoate of DMT-d9, i.e., 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11) The salt and the active salt mixture comprises, optionally, one or more benzoates of (iii) DMT-d8, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12). In some embodiments, the activated salt mixture is (i) DMT-d based on the total weight of the activated salt mixture, in a range of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. 10It contains the benzoate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8). In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more benzoates of (ii) DMT-d9, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), in total, in amounts of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between. In some embodiments, the activated salt mixture contains, based on the total weight of the activated salt mixture, one or more benzoates of (iii) DMT-d8, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12), in total, in amounts of 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between. 10 (ii) a benzoate of (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), and (ii) a benzoate of DMT-d9, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), consisting of or essentially comprising these.

[0226] In some embodiments, the pharmaceutical formulation is (i) DMT-d 10 (ii) Salicylates of (1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), (ii) Salicylates of DMT-d9-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), one or more of the following salicylates The mixture of active salts comprises salts, and optionally (iii) salicylates of DMT-d8, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12). In some embodiments, the activated salt mixture is (i) DMT-d based on the total weight of the activated salt mixture, in a range of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. 10It contains salicylates, namely, salicylates of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8). In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more salicylates of (ii) DMT-d9, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), in total, in amounts of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between. In some embodiments, the activated salt mixture contains, based on the total weight of the activated salt mixture, one or more salicylates of (iii) DMT-d8, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12) in total, i.e., 0 to 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between. 10(ii) a salicylate of (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), and (ii) a salicylate of DMT-d9, namely one or more salicylates of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), or essentially composed of them.

[0227] In some embodiments, the pharmaceutical formulation is (i) DMT-d 10 (ii) succinates of (1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), (ii) succinates of DMT-d9-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or succinates of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11) The salt comprises a mixture of activated salts, and optionally one or more succinates of (iii) DMT-d8 succinates, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12). In some embodiments, the activated salt mixture is (i) DMT-d based on the total weight of the activated salt mixture, in a range of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. 10It contains succinates, namely the succinate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8). In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more succinates of (ii) DMT-d9 succinates, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11) in total, in amounts of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between. In some embodiments, the activated salt mixture contains, based on the total weight of the activated salt mixture, in total, 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between (iii) succinates of DMT-d8, namely, 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-7), and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-12) succinates. In some embodiments, the activated salt mixture contains (i) DMT-d 10 (ii) a succinate of (i) the succinate of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-8), and (ii) a succinate of DMT-d9, namely 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-10) and / or 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-11), or essentially consisting of these succinates.

[0228] In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising (i) a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), (ii) a pharmaceutically acceptable salt of DMT-d7, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1-d, and optionally (iii) a pharmaceutically acceptable salt of DMT-d6, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine(I-4). In some embodiments, the activated salt mixture comprises pharmaceutically acceptable salts of (i)2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6) in amounts of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. In some embodiments, the activated salt mixture includes (ii) a pharmaceutically acceptable salt of DMT-d7, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1-d, in a range of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between, based on the total weight of the activated salt mixture. In some embodiments, the activated salt mixture contains a pharmaceutically acceptable salt of (iii) DMT-d6, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine(I-4) in an amount of 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between, based on the total weight of the activated salt mixture.In some embodiments, the active salt mixture consists of, or is essentially composed of, (i) a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-6), and (ii) a pharmaceutically acceptable salt of DMT-d7, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1-d.

[0229] In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising (i) a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-2), (ii) a pharmaceutically acceptable salt of DMT-d1, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1-d, and optionally (iii) a pharmaceutically acceptable salt of DMT, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine. In some embodiments, the activated salt mixture comprises pharmaceutically acceptable salts of (i)2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-2) in amounts of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. In some embodiments, the activated salt mixture includes (ii) a pharmaceutically acceptable salt of DMT-d1, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1-d, in a range of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between, based on the total weight of the activated salt mixture. In some embodiments, the activated salt mixture includes a pharmaceutically acceptable salt of (iii) DMT, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine, in an amount of 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between, based on the total weight of the activated salt mixture.In some embodiments, the active salt mixture consists of, or essentially consists of, (i) a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-2), and (ii) a pharmaceutically acceptable salt of DMT-d1, i.e., a pharmaceutically acceptable salt of 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1-d.

[0230] In some embodiments, the pharmaceutical formulation is (i) 5-MeO-DMT-d 10 (ii) a pharmaceutically acceptable salt of (i) 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-20), (ii) one or more pharmaceutically acceptable salts of 5-MeO-DMT-d9, i.e., 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-22) and / or 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-23) The active salt mixture comprises a pharmaceutically acceptable salt of (iii) 5-MeO-DMT-d8, namely one or more pharmaceutically acceptable salts of 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-18), 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-19), and 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-24). In some embodiments, the activated salt mixture is (i) 5-MeO-DMT-d based on the total weight of the activated salt mixture in a range of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. 10This includes pharmaceutically acceptable salts of, namely, pharmaceutically acceptable salts of 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-20). In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more pharmaceutically acceptable salts of (ii) 5-MeO-DMT-d9, namely 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-22) and / or 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-23), in total, in amounts of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between. In some embodiments, the activated salt mixture is based on the total weight of the activated salt mixture and is in total a pharmaceutically acceptable salt of (iii) 5-MeO-DMT-d8 in an amount of 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between thereof, i.e., 2-(5-methoxy-1H-indole-3-yl)-N,N-bis( It contains one or more pharmaceutically acceptable salts of methyl-d3)ethane-1-amine-1,1-d2(I-18), 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-19), and 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-24).In some embodiments, the active salt mixture (and thus the pharmaceutical formulation) does not contain, or otherwise substantially contains, one or more pharmaceutically acceptable salts of (iii) 5-MeO-DMT-d8, namely 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-18), 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-19), and 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-24). In some embodiments, the active salt mixture contains (i) 5-MeO-DMT-d. 10 (ii) a pharmaceutically acceptable salt of (ii) a pharmaceutically acceptable salt of (ii) 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-20), and (ii) a pharmaceutically acceptable salt of (ii) 5-MeO-DMT-d9, namely one or more pharmaceutically acceptable salts of 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-22) and / or 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-23), or essentially consisting of them.

[0231] In some embodiments, the pharmaceutical formulation is (i) 5-MeO-DMT-d 13 A pharmaceutically acceptable salt of, namely, a pharmaceutically acceptable salt of 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-34), (ii)5-MeO-DMT-d 12pharmaceutically acceptable salts of, namely, one or more pharmaceutically acceptable salts of 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-36) and / or 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-37), and optionally (iii)5-MeO-DMT-d 11 The active salt mixture comprises one or more pharmaceutically acceptable salts of 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2(I-32), 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-2,2-d2(I-33), and 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2-d2(I-38). In some embodiments, the activated salt mixture is (i) 5-MeO-DMT-d based on the total weight of the activated salt mixture in a range of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between. 13 pharmaceutically acceptable salts of (ii) 5-MeO-DMT-d 125-MeO-DMT-d3(I-36) and / or 2-(5-methoxyd3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-37) are pharmaceutically acceptable salts of (iii) 5-MeO-DMT-d3(I-36) and / or 2-(5-methoxyd3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-37). In some embodiments, the active salt mixture contains, based on the total weight of the active salt mixture, in total, 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between. 11 5-MeO-DMT-d 11 5-MeO-DMT-d 13pharmaceutically acceptable salts of, namely, pharmaceutically acceptable salts of 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(I-34), and (ii) 5-MeO-DMT-d 12 The material consists of, or is essentially composed of, one or more pharmaceutically acceptable salts of 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,2,2-d3(I-36) and / or 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2-d3(I-37).

[0232] In some embodiments, the pharmaceutical formulation is (i) one or more pharmaceutically acceptable salts of 5-MeO-DMT-d5, i.e., 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-28) and / or 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-2,2-d2(I-29), (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d4, i.e., 2-(5-methoxy-d3)-1 The active salt mixture comprises one or more pharmaceutically acceptable salts of H-indole-3-yl)-N,N-dimethylethane-1-amine-1-d(I-26) and / or 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-2-d(I-27), and optionally (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d3, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine(I-25). In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more pharmaceutically acceptable salts of (i) 5-MeO-DMT-d5 in total, in the ranges of 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 90% to 99% by weight, or any range in between, namely, 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-28) and / or 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-2,2-d2(I-29).In some embodiments, the activated salt mixture comprises, based on the total weight of the activated salt mixture, one or more pharmaceutically acceptable salts of (ii) 5-MeO-DMT-d4, namely 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1-d(I-26) and / or 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-2-d(I-27), in total, in amounts of 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 1% to 10% by weight, or any range in between. In some embodiments, the activated salt mixture contains, based on the total weight of the activated salt mixture, a pharmaceutically acceptable salt of (iii) 5-MeO-DMT-d3, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-25) in an amount of 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range in between. In some embodiments, the activated salt mixture (and therefore the pharmaceutical formulation) does not contain, or otherwise substantially does not contain, a detectable amount of a pharmaceutically acceptable salt of (iii) 5-MeO-DMT-d3, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine (I-25).In some embodiments, the activated salt mixture is one or more pharmaceutically acceptable salts of (i) 5-MeO-DMT-d5, i.e., 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2(I-28) and / or 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-2,2-d2(I-29) (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d4, namely, one or more pharmaceutically acceptable salts of 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1-d(I-26) and / or 2-(5-methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-2-d(I-27), or essentially consisting of them.

[0233] Psychotropic content For use in the treatment of diseases or disorders disclosed herein, namely neuropsychiatric disorders or disorders, or inflammatory diseases or disorders, including, for example, central nervous system (CNS) disorders and / or psychological disorders related to the 5-HT2 receptor, the pharmaceutical formulations contain a therapeutically effective dose of a psychotropic agent. In terms of unit dose, the pharmaceutical formulations contain a free base dose (free base equivalent when a salt form is used) of the psychotropic agent (e.g., tryptamine hallucinogens such as pharmaceutically acceptable salts of compounds of formulas (I) to (III)) typically in amounts of about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, or any range in between thereof. For example, a pharmaceutical preparation containing 40.4 mg of DMT fumarate (304.34 g / mol molar mass) would have a free base equivalent of approximately 25 mg of DMT per unit dose (188.27 g / mol molar mass). The pharmaceutical preparation may also contain other suitable therapeutic agents, if desired.

[0234] Pharmaceutical preparations are available in approximately 1 mg / mL, 2 mg / mL, 4 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, 12 mg / mL, 15 mg / mL, 18 mg / mL, 20 mg / mL, 22 mg / mL, 25 mg / mL, 28 mg / mL, 30 mg / mL, 32 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, and approximately The free base concentration of the psychotropic agent may be 70 mg / mL, approximately 75 mg / mL, approximately 80 mg / mL, approximately 85 mg / mL, approximately 90 mg / mL, approximately 95 mg / mL, approximately 100 mg / mL, or any range in between, for example, approximately 5 mg / mL to approximately 70 mg / mL, approximately 10 mg / mL to approximately 50 mg / mL, approximately 15 mg / mL to approximately 40 mg / mL, or approximately 20 mg / mL to approximately 35 mg / mL, for example, the free base concentration (free base equivalent when the salt form is used) of the compounds of formulas (I) to (III). For example, a pharmaceutical preparation prepared from 40.4 mg of DMT fumarate (molar mass of 304.34 g / mol) in the total volume of 1 mL of the pharmaceutical preparation would have a free base concentration of the psychotropic agent of approximately 25 mg / mL (in this example, free DMT base, molar mass of 188.27 g / mol). Of these concentrations, free base concentrations of psychotropic drugs below approximately 70 mg / mL yield a favorable controlled-release profile across the widest range of release regulator molecular weights and concentrations. However, difficulties in pharmaceutical formulations can be encountered at free base concentrations above approximately 70 mg / mL. Firstly, achieving a targeted controlled-release effect at these higher free base concentrations may require increasing the concentration of the release regulator accordingly. Exceeding the limit of the release regulator concentration can be problematic because the resulting higher viscosity may complicate or hinder the use of sterile filtration (which, in the case of pharmaceutical formulations containing hyaluronic acid, is effectively the only suitable sterilization technique available) and may cause increased pain at the injection site.Secondly, a decrease in the stability of pharmaceutical formulations can be experienced at higher free base concentrations of approximately 70 mg / mL or more, and precipitation may occur in accordance with the pharmacopoeia requirements for particulate matter in injectable formulations such as subcutaneous dosage forms (USP Particulate Matter in Injections). <788> This is a major concern. For example, in subcutaneous injection formulations, attempts to reduce the free base concentration by dilution (increasing the injection volume) may not be possible because higher injection volumes, especially those exceeding 3 mL, are associated with pain at the injection site. As a result, for subcutaneous pharmaceutical formulations, the free base concentration of psychotropic drugs (e.g., tryptamine hallucinogens such as compounds of formulas (I) to (III)) is typically maintained at less than approximately 70 mg / mL, less than approximately 65 mg / mL, less than approximately 60 mg / mL, and less than approximately 55 mg / mL, with 10 to 50 mg / mL being preferred.

[0235] For these reasons, from the perspective of pharmaceutical formulations containing tryptamine hallucinogens, tryptamine hallucinogens with longer half-lives, such as deuterated tryptamine hallucinogens, may offer significant advantages over their non-deuterated counterparts, particularly in subcutaneous formulations. Specifically, deuterated tryptamine hallucinogens have a favorable metabolic degradation profile that can result in higher plasma concentrations and enhanced brain penetration, and as a result, therapeutic doses may be reduced in some embodiments. For example, early human clinical studies have shown that the therapeutically relevant hallucinogenic dose of DMT (non-deuterated) may be in the range of approximately 70 mg or more (free base), while 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4(DMT-d 10 For deuterated analogs of DMT, such as DMT-d, their longer half-lives in vivo may require smaller doses (e.g., 10-50 mg, 15-50 mg, 20-40 mg, 30-50 mg, free base) to maintain the desired blood concentration. 10 The lower dosing requirements of deuterated DMT analogs, such as those mentioned above, allow for the use of lower concentrations of release regulators to achieve the desired controlled release profile and enable lower injection volumes.

[0236] Release regulator Pharmaceutical formulations include release regulators. Release regulators are components primarily involved in providing a controlled, configurable, and linear release of psychotropic drugs (e.g., tryptamine hallucinogens such as pharmaceutically acceptable salts of compounds of formulas (I) to (III)) during injection of pharmaceutical formulations, such as subcutaneous injection. Without theoretical limitations, release regulators act by thickening the pharmaceutical formulation and increasing its viscosity, while potentially also providing an electrostatic attraction with the psychotropic drug, so that during injection, the psychotropic drug is released slowly from the injection site (e.g., in the case of subcutaneous injection, inside the fat or the skin layer just below the dermis and epidermis), absorbed more slowly, and resulting in a depot-like release effect. Release regulators may be polymeric materials such as hyaluronic acid salts or carboxymethylcellulose salts, which may or may not be crosslinked. The release rate of the psychotropic drug can be controlled through the crosslinking or lack thereof of the release regulator, or the degree of crosslinking. Uncrosslinked release regulators typically result in shorter release profiles than crosslinked ones, as crosslinking can significantly prolong release, such as over a day or more. For the delivery of tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I)–(III)) where controlled release is required to result in a peak effect duration of approximately 30–120 minutes, release regulators are generally uncrosslinked to avoid excessively prolonging the release period. For clarity, release regulators are considered a separate component from psychotropic agents. Release regulators are also considered a separate component from pharmaceutically acceptable additives (such as buffers, isotonic agents, and pH adjusters) described below, even though release regulators may perform similar functions to certain additives, if such pharmaceutically acceptable additives are included in the pharmaceutical formulations of this disclosure. For example, release regulators are considered different from isotonic agents, even though release regulators contribute to the overall osmolality of the pharmaceutical formulation. In another example, release regulators are considered different from buffers or pH adjusters, even though they may affect the pH of a pharmaceutical formulation.

[0237] Hyaluronic acid In some embodiments, the release regulator is a hyaluronic acid salt (an anionic salt form of hyaluronic acid), which is a non-sulfated glycosaminoglycan and long-chain polymer of the glucuronic acid-N-acetylglucosamine disaccharide unit. Hyaluronic acid salts are biocompatible and widely distributed throughout human connective tissue, epithelial tissue, and nerve tissue. Examples of hyaluronic acid salts include, but are not limited to, sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, zinc hyaluronate, and magnesium hyaluronate, or combinations thereof. In some embodiments, the release regulator is sodium hyaluronate. Hyaluronic acid salts may be produced by microbial fermentation and purification processes, preferably in accordance with the pharmacopoeia, but are not limited thereto. From a purification standpoint, hyaluronic acid salts are known to be heat-sensitive and therefore typically cannot be sterilized by thermal sterilization methods such as steam sterilization or dry heat sterilization / depyrogenation, which can cause polymer degradation. Instead, hyaluronic acid salts are sterilized by sterile filtration, such as sterile filtration through a filter size of 0.25 μm or less. After sterile filtration, hyaluronic acid salts can optionally be sterilized by a secondary sterilization process such as ethylene oxide (ETO) gas sterilization or gamma sterilization under harsher conditions.

[0238] In some embodiments, hyaluronic acid refers to a natural hyaluronic acid that is unsubstituted, unmodified with pendant groups, unconjugated, uncrosslinked, or otherwise covalently modified. Rather, natural hyaluronic acid has an unmodified disaccharide unit of glucuronic acid-N-acetylglucosamine. Examples include, but are not limited to, sodium hyaluronate products available from Lifecore Biomedical, Inc.

[0239] In some embodiments, the hyaluronic acid is a non-natural hyaluronic acid, i.e., substituted, modified with pendant groups, conjugated, crosslinked, deacetylated, or otherwise covalently modified. The non-natural hyaluronic acid may be, in particular, acetylated, deacetylated, alkylated, esterified, amidated, hydrazidated, epoxy grafted, silylated, sulfated, and / or crosslinked hyaluronic acid. These modifications, such as crosslinking, can enable the formation of hydrogels of the hyaluronic acid. The degree of modification or substitution in the non-natural hyaluronic acid is typically about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any range in between. Examples of non-natural hyaluronic acid salts include, but are not limited to, sodium hyaluronate salts modified with pendant tyramine groups (amidal hyaluronates) by introducing tyramine onto a glucuronide unit using amide bonding chemistry (EDC chemistry), and Corgel® BioHydrogel products available from Lifecore Biomedical, Inc., in which tyramine-substituted sodium hyaluronate (TS-NaHy) derived from the above is subsequently crosslinked by forming a stable dihydroxyphenyl covalent bond through an enzyme-driven reaction, for example, involving horseradish peroxidase. While cross-linked hyaluronic acid or hyaluronic acid hydrogels may be used in some cases, for the delivery of tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)) where controlled release is required to produce a peak effect duration of approximately 30 to 120 minutes, hyaluronic acid is generally not cross-linked or in hydrogel form so as not to excessively prolong the release period and the resulting peak effect duration beyond approximately 120 minutes.

[0240] The weight-average molecular weight (Mw) of hyaluronic acid salts is approximately 500kDa, 550kDa, 600kDa, 650kDa, 700kDa, 750kDa, 800kDa, 850kDa, 900kDa, 950kDa, 1,000kDa, 1,200kDa, 1,300kDa, 1,400kDa, 1,500kDa, 1,600kDa, 1,700kDa, 1,800kDa, 1,900kDa, and 2,000kDa. , or any range in between, for example, about 500 kDa to about 2,000 kDa, about 600 kDa to about 1,500 kDa, about 750 kDa to about 1,000 kDa, about 1,000 kDa to about 2,000 kDa, about 1,000 kDa to about 1,900 kDa, about 1,000 kDa to about 1,800 kDa, about 1,200 kDa to about 1,800 kDa, about 1,500 kDa to about 1,700 kDa, or about 1,600 kDa to about 1,800 kDa. A weight-average molecular weight of hyaluronic acid exceeding the aforementioned upper limits results in a pharmaceutical formulation that is too viscous, thereby complicating the sterilization filtration process and potentially causing painful injections, especially in the case of subcutaneous injection. Furthermore, hyaluronic acid salts with a weight-average molecular weight exceeding the aforementioned upper limit may result in a release profile that is too slow to achieve the desired peak effect duration of approximately 30–120 minutes for some tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I)–(III)). On the other hand, hyaluronic acid salts with a weight-average molecular weight below the aforementioned lower limit may not produce a significant controlled release effect, and the pharmaceutical formulation may even behave similarly to one formulated without a release regulator. In some embodiments, the hyaluronic acid has a molecular weight range of approximately 500 kDa, approximately 600 kDa, approximately 700 kDa, approximately 800 kDa, approximately 900 kDa, approximately 1,000 kDa, approximately 1,100 kDa, approximately 1,200 kDa, approximately 1,300 kDa, approximately 1,400 kDa, approximately 1,500 kDa, approximately 1,600 kDa, approximately 1,700 kDa, approximately 1,800 kDa, approximately 1,900 kDa, and approximately 2,000 kDa, or any intermediate range between any of these values. In some embodiments, the hyaluronic acid has a molecular weight range of approximately 500 kDa to approximately 2,000 kDa.In some embodiments, the hyaluronic acid has a molecular weight range of approximately 500 kDa to approximately 750 kDa. In some embodiments, the hyaluronic acid has a molecular weight range of approximately 750 kDa to approximately 1,000 kDa. In some embodiments, the hyaluronic acid has a molecular weight range of approximately 750 kDa to approximately 1,500 kDa. In some embodiments, the hyaluronic acid has a molecular weight range of approximately 1,000 kDa to approximately 1,800 kDa. In some embodiments, the hyaluronic acid has a molecular weight range of approximately 900 kDa to approximately 1,400 kDa. The weight-average molecular weight of the hyaluronic acid will then fall somewhere within this molecular weight range.

[0241] Suitable hyaluronic acid salts include, but are not limited to, the sodium hyaluronate products HA700K (molecular weight range of 500 to less than 750 kDa), HA1M (molecular weight range of 750 to 1,000 kDa), and HA15M (molecular weight range of over 1,000 to 1,800 kDa) available from Lifecore Biomedical, Inc., and Hyatrue® HA-EP1.8 (molecular weight range of 900 to 1,400 kDa) available from Bloomage Freda Biopharm Co. Ltd.

[0242] The concentrations of hyaluronic acid by weight per total volume of the pharmaceutical preparation, expressed as a percentage (%w / v), are approximately 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.08%, 0.09%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, and 0.8%. The hyaluronic acid concentration may be 5%, approximately 0.9%, approximately 0.95%, approximately 1%, approximately 1.1%, approximately 1.2%, approximately 1.3%, approximately 1.4%, approximately 1.5%, approximately 1.6%, approximately 1.7%, approximately 1.8%, approximately 1.9%, approximately 2%, or any range in between, for example, approximately 0.1% to approximately 2%, approximately 0.1% to approximately 1.5%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 0.75%, approximately 0.1% to approximately 0.5%, approximately 0.15% to approximately 1%, approximately 0.2% to approximately 0.75%, or approximately 0.25% to approximately 0.5%. As the concentration of hyaluronic acid increases, the viscosity of the pharmaceutical formulation also increases. Exceeding viscosity standards is problematic for sterile filtration (and hyaluronic acid is sensitive to heat sterilization techniques) and can cause increased pain at the injection site. Furthermore, in the case of tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)) for which a release is required that results in a peak effect duration of approximately 30 to 120 minutes, excessively high concentrations of hyaluronic acid may prolong the release profile and the resulting peak effect duration beyond approximately 120 minutes, requiring prolonged clinical observation under monitoring, which is clinically undesirable. For these reasons, in such embodiments, the concentration of hyaluronic acid is preferably not greater than approximately 1%, approximately 0.95%, approximately 0.9%, approximately 0.85%, approximately 0.8%, approximately 0.75%, approximately 0.7%, approximately 0.65%, approximately 0.6%, approximately 0.55%, and approximately 0.5% w / v. In preferred embodiments, the concentration of hyaluronic acid is approximately 0.1% to approximately 0.5% w / v. Attempts to reduce the concentration of hyaluronic acid by dilution (increasing the injection volume) may not be possible in subcutaneous formulations, for example, because higher injection volumes, especially those exceeding 3 mL, are associated with pain at the injection site.Conversely, hyaluronic acid concentrations below the aforementioned lower limit may not produce a significant controlled release effect, and the pharmaceutical formulation may even behave similarly to one formulated without a release regulator.

[0243] In some embodiments, the ratio of the free base concentration of the psychotropic drug (e.g., the free base concentration of the compounds of formulas (I) to (III)) in terms of weight per total volume of the pharmaceutical preparation, expressed as a percentage (%w / v), to the concentration of hyaluronic acid by weight per total volume of the pharmaceutical preparation is approximately 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, and 5 The ratios are 0:1, approximately 55:1, approximately 60:1, approximately 65:1, approximately 70:1, approximately 75:1, approximately 80:1, approximately 85:1, approximately 90:1, approximately 95:1, approximately 100:1, approximately 105:1, approximately 110:1, approximately 115:1, approximately 120:1, approximately 125:1, approximately 130:1, or any range in between, for example, approximately 10:1 to approximately 130:1, approximately 15:1 to approximately 120:1, approximately 20:1 to approximately 110:1, or approximately 25:1 to approximately 100:1. For tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)) where a release profile is required to produce a peak effect duration of approximately 30 to 120 minutes, ratios below the aforementioned lower limits may result in pharmaceutical formulations with a release profile that is too prolonged (too slow) from a clinical practical standpoint. Ratios exceeding the aforementioned upper limits tend to result in a release that is not significantly different from formulations lacking release regulators (too fast). However, if a faster release profile is desired, or if other parameters in the formulation can counteract any fast release effect resulting from the use of such higher ratios, higher ratios of the free base concentration of the psychotropic drug (mg / mL) to the hyaluronic acid concentration (%w / v), such as up to approximately 500:1, 400:1, 300:1, 200:1, or 140:1, may be used.

[0244] In some embodiments, the ratio of the weight-average molecular weight (Mw) of hyaluronic acid (in kDa) to the free base concentration of the psychotropic drug (e.g., the free base concentration of the compounds of formulas (I) to (III)) in terms of weight per total volume (mg / mL) of the pharmaceutical formulation is approximately 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, and 60 :1, approximately 65:1, approximately 70:1, approximately 75:1, approximately 80:1, approximately 85:1, approximately 90:1, approximately 95:1, approximately 100:1, or any range in between, for example, approximately 17:1 to approximately 100:1, approximately 20:1 to approximately 100:1, approximately 22:1 to approximately 80:1, approximately 24:1 to approximately 60:1, or approximately 25:1 to approximately 55:1, or approximately 26:1 to approximately 100:1, or approximately 28:1 to approximately 100:1, or approximately 30:1 to approximately 75:1. Ratios below the aforementioned lower limit may result in a pharmaceutical formulation with a release profile similar to that of a formulation without a release regulator (too fast), while ratios above the aforementioned upper limit may result in excessively prolonged release (too slow) and the resulting peak effect duration, which is undesirable for certain tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)). In some embodiments, such as when the psychotropic agent is a pharmaceutically acceptable salt of a compound of formula (III), the ratio of the weight-average molecular weight of the hyaluronic acid (at kDa) to the free base concentration of the psychotropic agent, in terms of weight per total volume (mg / mL) of the pharmaceutical formulation, is preferably about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, and about 40 :1, approximately 45:1, approximately 50:1, approximately 55:1, approximately 60:1, approximately 65:1, approximately 70:1, approximately 75:1, approximately 80:1, approximately 85:1, approximately 90:1, approximately 95:1, approximately 100:1, or any range in between, for example, approximately 35:1 to approximately 100:1, approximately 40:1 to approximately 100:1, approximately 42:1 to approximately 80:1, approximately 44:1 to approximately 60:1, or approximately 45:1 to approximately 55:1.

[0245] Carboxymethylcellulose salt In some embodiments, the release regulator is a carboxymethylcellulose salt, which is a carboxymethyl group (-CH2COO) bonded to some of the hydroxyl groups of the glucopyranose monomer constituting the cellulose backbone. - It is a cellulose derivative having ). Examples of carboxymethylcellulose salts include, but are not limited to, the sodium salt of carboxymethylcellulose (sodium carboxymethylcellulose). However, carboxymethylcellulose salts may also be produced by reacting alkali cellulose with sodium monochloroacetate, and this reaction may be carried out under strictly controlled conditions to control the degree of substitution (DS), which is the average number of hydroxyl groups of the carboxymethylated glucopyranose monomer, with a theoretical limit of 3.0 DS. For pharmacopoeia compliance, the resulting polymer is purified and dried.

[0246] In some embodiments, the carboxymethylcellulose salt is unsubstituted, unmodified with pendant groups, unconjugated, uncrosslinked, or otherwise covalently modified. Rather, the carboxymethylcellulose salt has a cellulose backbone formed from a glucopyranose monomer substituted only with carboxymethyl groups. For example, in some embodiments, the carboxymethylcellulose salt is crosslinked with glycolic acid to form a croscarmellose salt such as croscarmellose sodium.

[0247] The carboxymethylcellulose salt may have a degree of substitution (DS) of 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, 1.2, or any range in between, for example, 0.45 to less than 0.9, 0.9 to less than 1.2, or 1.2 to 1.5. In some embodiments, the carboxymethylcellulose salt has a DS of 0.85 to 1.15 or 0.9 to 1.0.

[0248] The weight-average molecular weight (Mw) of carboxymethylcellulose salts is typically less than approximately 500 kDa, for example, approximately 50 kDa, 60 kDa, 70 kDa, 80 kDa, 90 kDa, 100 kDa, 110 kDa, 120 kDa, 130 kDa, 140 kDa, 150 kDa, 160 kDa, 170 kDa, 180 kDa, and 190 kDa. These ranges are approximately 200 kDa, 210 kDa, 220 kDa, 230 kDa, 240 kDa, 250 kDa, 300 kDa, 350 kDa, 400 kDa, 450 kDa, or any range in between, for example, approximately 90 kDa to 300 kDa, 100 kDa to 300 kDa, 100 kDa to 275 kDa, and 150 kDa to 250 kDa. Weight-average molecular weights of carboxymethylcellulose salts exceeding the aforementioned upper limits generally result in pharmaceutical formulations that exceed the viscosity requirements for injection and syringeability and are not generally approved by the Food and Drug Administration (FDA) for use in injection. Therefore, a suitable carboxymethylcellulose salt is typically one having a Brookfield viscosity of about 400 cP, about 600 cP, about 800 cP, about 1,000 cP, about 1,200 cP, about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, about 2,500 cP, about 2,750 cP, about 3,000 cP, about 3,100 cP, or any range in between, for example, about 400 cP to about 3,100 cP or about 1,500 cP to about 3,100 cP, as measured as a 2% aqueous solution using spindle number 3 at 30 rpm.

[0249] Examples of carboxymethylcellulose salts include, but are not limited to, Aqualon® and Blanose® sodium carboxymethylcellulose products available from Ashland, such as Aqualon® / Blanose® grades 9M8F PH, 9M8XF, 9M31F PH, 9M31XF PH, and 7MF PH. In some embodiments, the carboxymethylcellulose salt is 7MF PH from Ashland (sodium carboxymethylcellulose; Mw=250kDa; DS=0.7; Brookfield viscosity of 400cP–800cP, measured as a 2% aqueous solution using spindle number 3 at 30 rpm).

[0250] The concentration of carboxymethylcellulose salt by weight per total volume of the pharmaceutical formulation, expressed as a percentage (%w / v), may be approximately 0.55%, approximately 0.6%, approximately 0.65%, approximately 0.7%, approximately 0.75%, approximately 0.8%, approximately 0.85%, approximately 0.9%, approximately 0.95%, approximately 1%, or any range in between, for example, approximately 0.6% to approximately 1%, approximately 0.7% to approximately 1%, approximately 0.75% to approximately 1%, approximately 0.75% to approximately 0.9%, and approximately 0.75% to approximately 0.8%. Concentrations of carboxymethylcellulose salt exceeding the aforementioned upper limits may result in a pharmaceutical formulation that is too viscous for, for example, sterile filtration, injectability, and / or syringeability, and may cause increased pain at the injection site. In contrast, carboxymethylcellulose salt concentrations below the aforementioned lower limit may not produce a significant controlled release effect, and the pharmaceutical formulation may even behave similarly to one formulated without a release regulator.

[0251] In some embodiments, the ratio of the free base concentration of the psychotropic drug (e.g., the free base concentration of the compounds of formulas (I) to (III)) in terms of weight per total volume of the pharmaceutical preparation, expressed as a percentage (%w / v), to the concentration of the carboxymethylcellulose salt by weight per total volume of the pharmaceutical preparation is approximately 10:1, approximately 15:1, approximately 20:1, and approximately 25:1. Approximately 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1, or any range in between, for example, approximately 10:1 to 100:1, 13:1 to 90:1, 15:1 to 75:1, or 20:1 to 50:1.

[0252] In some embodiments, the ratio of the weight-average molecular weight (in kDa) of the carboxymethylcellulose salt to the free base concentration of the psychotropic drug (e.g., the free base concentration of the compounds of formulas (I) to (III)) in terms of weight per total volume (mg / mL) of the pharmaceutical formulation is approximately 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 8:1, 10:1, 12:1, 14:1, 16:1, and 18: 1. Approximately 20:1, 22:1, 24:1, 26:1, 28:1, 30:1, 32:1, 34:1, 36:1, 38:1, 40:1, 42:1, 44:1, 46:1, 48:1, 50:1, or any range in between, for example, approximately 1:1 to 50:1, 5:1 to 40:1, 10:1 to 30:1, 15:1 to 20:1, or approximately 1:1 to 10:1.

[0253] Water-based vehicle The pharmaceutical formulation includes an aqueous vehicle. The term "vehicle" as used herein means diluents, adjuvants, excipients, carriers, and / or any other auxiliary or auxiliary components, together with these, the psychotropic agents and release agents of this disclosure are formulated for administration to mammals. The aqueous vehicle, and therefore the pharmaceutical formulation, includes water, such as water for injection (WFI). Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or isotonic saline, phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose, and Ringer's lactate injection.

[0254] In addition to water, aqueous vehicles, and therefore pharmaceutical formulations, may optionally contain one or more pharmaceutically acceptable additives as desired / as needed. “Pharmacochemically acceptable additives” may be diluents, adjuvants, excipients, carriers, or any other auxiliary or auxiliary components approved by federal or state regulatory agencies or listed in the United States Pharmacopeia or other generally accepted pharmacopoeias for use in mammals such as humans. Examples of pharmaceutically acceptable additives include, but are not limited to, water-miscible vehicles, non-aqueous vehicles, antimicrobial or antiseptic agents against microbial growth, stabilizers, isotonic agents, buffers, antioxidants, local anesthetics, complexing agents, chelating agents or sequential agents, pH adjusters, and absorption enhancers (including combinations thereof). It should be understood that many pharmaceutically acceptable additives may perform several functions within the same pharmaceutical formulation; for example, a buffer may also act as an isotonic agent, and vice versa.

[0255] Examples of water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide, or combinations thereof.

[0256] Examples of non-aqueous vehicles include, but are not limited to, plant-derived fixed oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, medium-chain triglycerides from coconut oil, and palm seed oil, or combinations thereof.

[0257] Examples of antimicrobial or preservative agents include, but are not limited to, phenol (e.g., phenol), cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid, thimerosal, benzalkonium chloride, benzethonium chloride, methyl-, ethyl-, and propyl-parabens, benzoic acid, sodium benzoate, and sorbic acid, or combinations thereof.

[0258] Examples of stabilizers include, but are not limited to, fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohol, glycerol, methionine, monothioglycerol, ascorbic acid, citric acid, polysorbate, arginine, and sorbitol, or combinations thereof. For example, fatty acids can act as lipid carriers. Fatty acids may have 4 to 30 carbon atoms, 6 to 28 carbon atoms, 8 to 24 carbon atoms, 10 to 20 carbon atoms, or 12 to 18 carbon atoms. Fatty acids may be mono-fatty acids or di-fatty acids. Exemplary fatty acids include, but are not limited to, adipic acid (hexanediic acid), lauric acid (dodecanoic acid), linoleic acid, myristic acid (tetradecanoic acid), capric acid (decanoic acid), stearic acid (octadecanoic acid), oleic acid, caprylic acid (octanoic acid), palmitic acid (hexadecenoic acid), sebacic acid, undecylenic acid, caproic acid, arachidic acid, behenic acid, lignoceric acid, palmitic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and combinations thereof. In some embodiments, the pharmaceutical formulation is formulated without fatty acids to prevent hydrogel formation and excessively prolonged release (see Kang NW, et al. Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin. Pharmaceutics. 2021 Jun 11;13(6):864 for an example of a hydrogel that produces release over several days).

[0259] Isotonic agents are chemical substances that, when included in a pharmaceutical formulation, adjust the osmolality of the formulation. Sometimes, the concentrations of psychotropic agents and release regulators in the pharmaceutical formulation provide the desired osmolality, and therefore, an isotonic agent is not needed / included. Alternatively, the concentrations of psychotropic agents and release regulators in the pharmaceutical formulation do not provide the osmolality standard for injection, and therefore, one or more isotonic agents may be included to reach the desired osmolality. When a pharmaceutical formulation contains an isotonic agent, the concentration of the isotonic agent is adjusted to take into account the osmolality contribution from the concentrations of psychotropic agents and release regulators in order to provide a pharmaceutical formulation having a desired osmolality range (e.g., 150-600 mOsm / kg). Examples of isotonic agents include, but are not limited to, sodium chloride; potassium chloride; calcium chloride; magnesium chloride; dextrose; glucose; mannitol; lactose; sorbitol; sucrose; alanine; ethanol; benzyl alcohol; creatinine; glycine; glycerol; histidine; polyethylene glycol; propylene glycol; sodium bicarbonate; sodium hydroxide; hydrochloric acid; phosphoric acid; phosphates such as sodium phosphate or potassium phosphate; acetic acid; acetates such as sodium acetate, potassium acetate, or ammonium acetate; citric acid; citrates such as sodium citrate or potassium citrate; arginine; ascorbic acid; ascorbates such as potassium ascorbate or sodium ascorbate; EDTA; EDTAs such as sodium edetate or calcium edetate; lactic acid; lactates such as potassium lactate or sodium lactate; tartaric acid; tartrates such as sodium tartrate or potassium tartrate, and combinations thereof. In some embodiments, the isotonic agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, magnesium chloride, dextrose, glucose, mannitol, lactose, sorbitol, sucrose, and sodium lactate. Typically, the isotonic agent is sodium chloride.In some embodiments, the pharmaceutical formulation contains sodium chloride in a concentration in terms of weight per unit volume of the pharmaceutical formulation, expressed as a percentage (%w / v) of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, or any range in between, for example, about 0.1% to about 0.6%, about 0.2% to about 0.55%, or about 0.3% to about 0.5% w / v.

[0260] A buffer is a chemical substance that, when included in a pharmaceutical formulation, contains a weak acid and its conjugate base in equilibrium, which resists pH changes when an acid or base is added to the pharmaceutical formulation. In other words, the addition of an acid or base to a pharmaceutical formulation shifts the equilibrium position in favor of the weak acid or conjugate base, respectively, and as a result, the concentration of free protons in the pharmaceutical formulation (and therefore pH) does not change significantly, or changes less than expected relative to the amount of acid or base added (until the buffer volume is reached). For clarity, the buffer is considered a component separate from the psychotropic agent (e.g., pharmaceutically acceptable salts of the compounds of this disclosure, such as pharmaceutically acceptable salts of the compounds of formulas (I) to (III)). In this sense, the buffer is not merely a counterion for the protonated forms of the compounds of this disclosure. Rather, the buffer, when included, provides a buffering effect to resist pH changes exceeding those that may be provided by the psychotropic agent. The buffer is also considered a component separate from the release regulator, which in this case also provides a buffering effect to resist pH changes exceeding those that may be provided by the release regulator. Examples of buffering agents include, but are not limited to, phosphate buffers (phosphates and phosphoric acid, pKa=2.14, 7.20, and 12.37), acetate buffers (acetates and acetic acid, pKa=4.76), citrate buffers (citric acid and citric acid, pKa=3.13, 4.76, and 6.40), ascorbic acid buffers (ascorbic acid and ascorbic acid, pKa=4.10 and 11.6), benzoate buffers (benzoates and benzoic acid, pKa=4.20), oxalate buffers (oxalates and oxalic acid, pKa=1.25 and 4.14), formate buffers (formates and formic acid, pKa=3.75), or combinations thereof. Generally, a suitable buffer is optionally selected, comprising an acid having a pKa value (or, in the case of polybasic acids, an acid having at least one pKa value) within ±1 of the desired pH of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation is not formulated using a buffer.

[0261] Examples of antioxidants include, but are not limited to, bisulfites and sodium metabisulfite, ascorbic acid, citric acid, tartaric acid, thiol derivatives, or combinations thereof. In some embodiments, the pharmaceutical formulation has an oxygen content of less than 2 ppm, such as 0.1 ppm to 2 ppm.

[0262] Examples of local anesthetics include, but are not limited to, procaine hydrochloride.

[0263] Examples of complexing agents include, but are not limited to, cyclodextrins, such as ca-cyclodextrin, β-cyclodextrin, hydroxypropyl-3-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether-7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.), or combinations thereof.

[0264] Examples of chelating or sequestering agents include, but are not limited to, EDTA.

[0265] Examples of pH adjusting agents include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid, or combinations thereof.

[0266] Absorption enhancers include, but are not limited to, hyaluronidase enzymes. In pharmaceutical formulations containing hyaluronic acid, hyaluronidase enzymes may have the additional effect of accelerating drug release by breaking down the hyaluronic acid when an increase in the release rate is desired. This additive may be added to the pharmaceutical formulation immediately before injection, or it may be injected separately as part of a multi-component injection, such as by using a dual-chamber syringe or a multi-syringe (e.g., two syringes) setting. In some embodiments, the pharmaceutical formulation does not contain hyaluronidase enzymes, nor are hyaluronidase enzymes used during or after the injection of the pharmaceutical formulation.

[0267] In some embodiments, the pharmaceutical formulation comprises a psychotropic agent (e.g., tryptamine hallucinogens such as pharmaceutically acceptable salts of compounds of formulas (I) to (III)), a release regulator, and an aqueous vehicle comprising physiological saline, optionally a buffer, optionally a pH adjuster (e.g., sodium hydroxide), and optionally an isotonic agent other than sodium chloride. In some embodiments, the pharmaceutical formulation comprises a psychotropic agent (e.g., tryptamine hallucinogens such as pharmaceutically acceptable salts of compounds of formulas (I) to (III)), a release regulator, and an aqueous vehicle comprising water for injection, optionally a buffer, and optionally a pH adjuster (e.g., sodium hydroxide), wherein the aqueous vehicle does not contain an isotonic agent such as sodium chloride. In some embodiments, the pharmaceutical formulation comprises a psychotropic agent (e.g., tryptamine hallucinogens such as pharmaceutically acceptable salts of compounds of formulas (I) to (III)), a release regulator, and an aqueous vehicle comprising water for injection or physiological saline, and optionally a pH adjuster (e.g., sodium hydroxide), and the pharmaceutical formulation is formulated without a buffer. In some embodiments, the pharmaceutical formulation comprises or essentially consists of a psychotropic agent (e.g., tryptamine hallucinogens such as pharmaceutically acceptable salts of the compounds of formulas (I) to (III)), a release regulator, and water and an optional isotonic agent (e.g., sodium chloride) as an aqueous vehicle. Essentially consisting of means that the presence of additional components in the pharmaceutical formulation is acceptable on the condition that the amount of such additional components does not substantially affect the essential characteristics of the pharmaceutical formulation, i.e., that the pharmaceutical formulation is suitable for injection and results in a time-limited, controlled release of the psychotropic agent. In some embodiments administering a tryptamine hallucinogen (e.g., pharmaceutically acceptable salts of the compounds of formulas (I) to (III)), this time-limited, controlled release results in a peak effect duration of approximately 30 to 120 minutes.

[0268] Physiochemical properties Pharmaceutical formulations may have a pH of approximately 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, 10, 10.25, 10.5, 10.75, 11, or any range in between. Generally, pH values ​​that are too high are associated with tissue necrosis, while pH values ​​that are too low are associated with pain and inflammation at the injection site. In some embodiments, the pharmaceutical formulation is suitable for intravenous injection (it is an intravenous pharmaceutical formulation) or intramuscular injection (it is an intramuscular pharmaceutical formulation) and has a pH in the range of about 2 to about 11, about 3 to about 9, about 4 to about 7, and about 4.5 to about 6. In some embodiments, the pharmaceutical formulation is suitable for subcutaneous injection (it is a subcutaneous pharmaceutical formulation) and has a pH in the range of about 3 to about 9, about 3 to about 7, about 4 to about 9, about 4 to about 7.5, about 4 to about 7, about 4.5 to about 7.5, about 4.5 to about 7, about 4.5 to about 6.5, and about 4.5 to about 6.

[0269] The pharmaceutical formulations are approximately 150 mOsm / kg, 155 mOsm / kg, 160 mOsm / kg, 165 mOsm / kg, 170 mOsm / kg, 175 mOsm / kg, 180 mOsm / kg, 185 mOsm / kg, 190 mOsm / kg, 195 mOsm / kg, 200 mOsm / kg, 225 mOsm / kg, 250 mOsm / kg, 275 mOsm / kg, 300 mOsm / kg, 325 mOsm / kg, 350 mOsm / kg, 375 mOsm / kg, 400 mOsm / kg, 425 mOsm / kg, and approximately The osmolality may be 450 mOsm / kg, approximately 475 mOsm / kg, approximately 500 mOsm / kg, approximately 525 mOsm / kg, approximately 550 mOsm / kg, approximately 575 mOsm / kg, approximately 600 mOsm / kg, or any range in between, for example, approximately 150 to approximately 600 mOsm / kg, approximately 200 to approximately 500 mOsm / kg, approximately 250 to approximately 550 mOsm / kg, approximately 275 to approximately 500 mOsm / kg, approximately 300 to approximately 450 mOsm / kg, approximately 150 mOsm / kg to approximately 200 mOsm / kg, or approximately 150 mOsm / kg to approximately 175 mOsm / kg. Osmolality outside these ranges has been reported to cause pain. In some embodiments, the pharmaceutical formulation is isotonic with human serum, i.e., has an osmolality of about 275 to about 300 mOsm / kg.

[0270] Pharmaceutical preparations are available in the following concentrations: less than approximately 10,000 cP, less than approximately 9,000 cP, less than approximately 8,000 cP, less than approximately 7,000 cP, less than approximately 6,000 cP, less than approximately 5,000 cP, less than approximately 4,000 cP, less than approximately 3,000 cP, less than approximately 2,000 cP, less than approximately 1,000 cP, less than approximately 500 cP, less than approximately 100 cP, less than approximately 50 cP, less than approximately 45 cP, and approximately Less than 40 cP, approximately less than 35 cP, approximately less than 30 cP, approximately less than 25 cP, approximately less than 20 cP, for example, approximately 1 cP, approximately 2 cP, approximately 3 cP, approximately 4 cP, approximately 5 cP, approximately 8 cP, approximately 10 cP, approximately 12 cP, approximately 15 cP, approximately 18 cP, approximately 20 cP, approximately 22 cP, approximately 25 cP, approximately 28 cP, approximately 30 cP, approximately 32 cP, approximately 35 cP, approximately 38 cP, approximately 40 cP, approximately 4 2cP, approximately 45cP, approximately 50cP, approximately 60cP, approximately 70cP, approximately 80cP, approximately 90cP, approximately 100cP, approximately 150cP, approximately 200cP, approximately 250cP, approximately 300cP, approximately 350cP, approx. 400cP, approx. 500cP, approx. 600cP, approx. 800cP, approx. 1,000cP, approx. 1,200cP, approx. 1,500cP, approx. 1,750cP, approx. 2,000c The viscosity may be approximately 2,250 cP, 2,500 cP, 2,750 cP, 3,000 cP, 3,100 cP, 3,500 cP, 4,000 cP, 4,500 cP, 5,000 cP, 6,000 cP, 7,000 cP, 8,000 cP, 9,000 cP, 10,000 cP, or any range in between. Such viscosity values ​​allow the pharmaceutical formulation to be syringe-able and injectable without causing excessive pain at the injection site, for example. In some embodiments, such as when the release regulator used is a hyaluronic acid, a suitable viscosity value also allows for the use of sterile filtration as a sterilization technique. In some embodiments, the pharmaceutical formulation is suitable for subcutaneous injection (it is a subcutaneous pharmaceutical formulation) and preferably has a viscosity of less than about 3,000 cP, less than about 2,500 cP, less than about 2,000 cP, less than about 1,500 cP, less than about 1,000 cP, less than about 500 cP, less than about 100 cP, less than about 50 cP, less than about 25 cP, less than about 20 cP, for example, about 1 cP, about 2 cP, about 3 cP, about 4 cP, about 5 cP, about 8 cP, about 10 cP, about 12 cP, about 15 cP, about 18 cP, about 20 cP, about 22 cP, or any range in between.

[0271] In some embodiments, the pharmaceutical formulation has a shelf life as an aqueous solution of at least 1, 2, 3, 4, 5, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or longer, without significant product degradation or physical changes such as precipitation. In some embodiments, the pharmaceutical formulation can be maintained / stored as an aqueous solution in an open or closed environment, such as an open or closed flask / vial, under quasi-ambient, ambient, or stress conditions (temperature rise), without significant degradation or physical changes such as precipitation. Pharmaceutical formulations with a long shelf life of at least several days or at least several weeks are advantageous because, if desired, they can be fully prepared before administration and optionally stored without substantially affecting efficacy or injectability. In some embodiments, as psychotropic agents, pharmaceutical formulations formed from the compounds of the Disclosure, e.g., pharmaceutically acceptable salts of the compounds of formulas (I) to (III), are characterized by increased stability compared to formulations prepared using the same compounds as the free base, but otherwise substantially the same. For example, pharmaceutical formulations of the Disclosure formed from the compounds of the Disclosure, e.g., pharmaceutically acceptable salts of the compounds of formulas (I) to (III), are at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, and at least 70% more stable than formulations prepared from free base counterparts but otherwise substantially the same, in terms of physical changes such as degradation or precipitation, during storage for 24 hours, 48 ​​hours, 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, or longer.

[0272] Release kinetics Pharmaceutical formulations enable the time-limited, temporally controlled release of psychotropic drugs via bolus injection into humans, particularly via bolus subcutaneous injection. When delivering tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I)-(III)), pharmaceutical formulations enable the controlled release of tryptamine hallucinogens via bolus injection into humans, particularly via bolus subcutaneous injection, which mimics a clinically favorable peak effect duration course of approximately 30-120 minutes achievable by IV infusion of such psychotropic drugs over approximately 90 minutes. In some embodiments, the duration of the peak effect after a bolus injection of the pharmaceutical formulation, preferably a bolus subcutaneous injection of the pharmaceutical formulation, is approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 65 minutes, approximately 70 minutes, approximately 75 minutes, approximately 80 minutes, approximately 85 minutes, approximately 90 minutes, approximately 95 minutes, approximately 100 minutes, approximately 105 minutes, approximately 110 minutes, approximately 115 minutes, approximately 120 minutes, or any range in between, for example, approximately 30 to approximately 120 minutes, approximately 30 to approximately 45 minutes, approximately 40 to approximately 100 minutes, approximately 45 to approximately 90 minutes, approximately 50 to approximately 75 minutes, or approximately 60 to approximately 70 minutes.

[0273] In some embodiments, controlled release of a hallucinogen (e.g., tryptamine hallucinogen) places the patient in a hallucinogenic state for approximately 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 130 minutes, 140 minutes, 150 minutes, 160 minutes, 170 minutes, 180 minutes, or any range in between, for example, approximately 35 minutes to 100 minutes, approximately 40 minutes to 80 minutes, approximately 35 minutes to 45 minutes, approximately 50 minutes to 60 minutes, approximately 40 minutes to 50 minutes, and approximately 90 minutes to 120 minutes, correlating with positive clinical outcomes.

[0274] Non-exclusive examples of PD clinical scales, diary assessments, and clinician or caregiver assessments that may be used to evaluate the duration of action, duration of hallucinogenic state, duration of peak effect, mental state, mood, and drug effect in patients after injection include the Mystical Experience Questionnaire (MEQ30), the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC), the Hallucinogen Rating Scale (HRS), the evaluation of "Any drug effect" on a visual analog scale (VAS), the 5-item Persisting Effects Questionnaire (PEQ) assessing the meaningfulness, the spirituality and psychological insights and challenges of the experience and overall drug effect, and the NeuroCart test battery. Examples of such tests include, but are not limited to, battery (e.g., saccadic eye movements, smooth tracking eye movements, adaptive tracking, body sway, pupil size ratio, Bond and Lader's Visual Analog Scales (VAS B&L) and Bowdle's Visual Analog Scale (VAS Bowdle)), pharmacological electroencephalogram (EEG), State-Trait Anxiety Inventory (STAI), Dutch Temperament and Character Inventory (TCI), Revised Dutch Personality Trait Inventory-2 (NPV-2-R), Mood State Profile (POMS), Real-Time Intensity Scale, and MINI.The time course for a patient to experience the peak effect can also be evaluated by the time the patient has a drug concentration in their blood of 40 ng / mL or higher, for example, approximately 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 ng / mL, 70 ng / mL, 75 ng / mL, 80 ng / mL, 85 ng / mL, 90 ng / mL, 95 ng / mL, 100 ng / mL, 105 ng / mL, 110 ng / mL, 115 ng / mL, 120 ng / mL, 125 ng / mL, 130 ng / mL, 135 ng / mL, 140 ng / mL, 145 ng / mL, 150 ng / mL, or any range in between. The time course a patient spends in a hallucinatory state is also the time a patient has therapeutically relevant concentrations of the drug in their blood, for example, the time a patient has concentrations ranging from approximately 20 ng / mL to approximately 150 ng / mL, for example, approximately 20 ng / mL, approximately 25 ng / mL, approximately 30 ng / mL, approximately 35 ng / mL, approximately 40 ng / mL, approximately 45 ng / mL, approximately 50 ng / mL, approximately 55 ng / mL, approximately 60 ng / mL, approximately 65 ng / mL, approximately 70 ng / mL, approximately 75 ng / mL It can be evaluated by the time at which drug concentrations of approximately L, 80 ng / mL, 85 ng / mL, 90 ng / mL, 95 ng / mL, 100 ng / mL, 105 ng / mL, 110 ng / mL, 115 ng / mL, 120 ng / mL, 125 ng / mL, 130 ng / mL, 135 ng / mL, 140 ng / mL, 145 ng / mL, 150 ng / mL, or any range in between.

[0275] The Mystical Experiences Questionnaire was initially developed during an online survey on psilocybin-containing mushrooms and validated using data from experimental studies with controlled doses of psilocybin. The revised version includes 30 items (MEQ30) on subjective drug effects and has been retrospectively completed. Effects are scored total and across four subdomains (mystical, positive mood, spatial / temporal, and ineffability) based on the percentage of the maximum possible score. A Mystical Experiences Questionnaire (MEQ30) score of over 60%, the benchmark for a complete mystical experience, has been shown to be a mediator of symptom improvement in past hallucinogenic clinical trials. In some embodiments, the methods herein provide patients with Mystical Experiences Questionnaire (MEQ30) scores of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and at least 95%. In some embodiments, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, and at least 90% of subjects treated by the methods described herein have Mystical Experiences Questionnaire (MEQ30) scores of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and at least 95%.

[0276] The 5D-ASC (5-Dimensional Altered State of Consciousness Assessment Scale) measures altered states of consciousness and includes 94 items (visual analog scale). The 5D-ASC scale measures alterations in mood, perception, self-experience to the environment, and thought disorders. The measure consists of five subscales / dimensions and eleven lower-order scales. The 5D-ASC dimension, "Oceanic Boundlessness" (27 items), measures derealization and depersonalization associated with positive emotional states ranging from elevated mood to exhilarating mental elevation. Corresponding lower-order scales include "Integrated Experience," "Spiritual Experience," "Blissful State," and "Insight." The dimension, "Anxious Ego Dissolution" (21 items), summarizes ego diffusion and loss of self-control phenomena associated with anxiety. Corresponding lower-order scales include "Departure from Body," "Cognitive Control Disorder," and "Anxiety." The dimension “Visionary Restructurization” (18 items) consists of lower-order scales “Complex Imagery,” “Simple Imagery,” “Auditory-Visual Synesthesia,” and “Changes in Perceptual Meaning.” Two further dimensions describe “Auditory Alteration” (15 items) and “Reduced Alertness” (12 items). Scoring is based on the percentage of the maximum possible score. The scale is well validated and widely used to characterize the subjective effects of various hallucinogenic drugs. In some embodiments, the 5D-ASC is used to measure changes in a subject’s subjective hallucinogenic experience. In some embodiments, the method herein provides a patient with a 5D-ASC score of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% (e.g., on the Oceanic Feeling subscale). In some embodiments, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, and at least 90% of subjects treated using the methods described herein have 5D-ASC scores (e.g., on the subscale of oceanic feeling) of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and at least 95%.

[0277] The Hallucinogenic Rating Scale (HRS) is a questionnaire containing up to 100 items, designed to assess the subjective effects of hallucinogenic substances. Participants rate their responses to most questions on a five-point intensity scale: 0=not at all, 1=slightly, 2=moderate, 3=quite, and 4=extreme. Some questions have slightly modified scales, one of which asks participants to rate the time from drug administration to feeling the effects on a scale of no effect, 0-5 minutes, 5-15 minutes, 15-30 minutes, 30-60 minutes, or more than 1 hour. Questions are grouped into factors or domains including 1) somaesthesia, 2) affect, 3) perception, 4) cognition, 5) willpower, and 6) intensity. In some embodiments, the methods herein provide patients with a Hallucinogenic Rating Scale (HRS) score of at least 1.8, at least 2.0, at least 2.2, at least 2.4, at least 2.6, at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 3.6, at least 3.8, or 4.0 (e.g., on the intensity subscale). In some embodiments, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, and at least 90% of subjects treated with the methods herein have a score on the intensity subscale of the HRS greater than >2.79, e.g., at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 3.6, at least 3.8, or 4.0.

[0278] Visual Analog Scales (VAS) are psychometric response scales that can be used in questionnaires. They are a means of measuring subjective characteristics or attitudes that cannot be measured directly. When answering VAS items, respondents identify their level of agreement with a statement by indicating their position along a continuous line between two endpoints, typically a horizontal 100mm line marked from "not at all" or "definitely not" on the left to "very much" or "definitely so" on the right. Bond and Lader's VAS involves subjects indicating how they feel on a 16-point horizontal 100mm visual analog scale (with vertical markings). From these measurements, three main factors are calculated as described by Bond and Lader: attention (from 9 scores), satisfaction (often called mood, from 5 scores), and calmness (from 2 scores). Bowdle's VAS and drug assessment VAS provide subjects with drug assessment questionnaire items, namely drug impressions, namely liking and disliking drugs. Any drug effect on the VAS is indicated by the subject on a horizontal 100 mm visual analog scale (with vertical markings) that has an item for any drug effect ("Able to feel any drug effect"). In some embodiments, the subject has a maximum VAS score of 60 mm or more or 70 mm or more after treatment (e.g., Bond and Lader VAS, Bowle VAS and Drug Evaluation VAS, and / or any drug effect on the VAS). In some embodiments, the subject has a VAS score of 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 85 mm, 90 mm, or 95 mm or more after treatment (e.g., Bond and Lader VAS, Bowle VAS and Drug Evaluation VAS, and / or any drug effect on the VAS).In some embodiments, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, and at least 90% of subjects treated by the methods described herein report a maximum VAS score of 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 85 mm, 90 mm, or 95 mm or greater after treatment (e.g., Bond and Lader VAS, Bowlle VAS and drug evaluation VAS, and / or any of the drug efficacy VAS). In some embodiments, after treatment, the subject experiences a duration of approximately 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, or any range in between, for example, a duration of approximately 30 to 120 minutes, 30 to 45 minutes, 40 to 100 minutes, 45 to 90 minutes, 50 to 75 minutes, or 60 to 70 minutes, and a VAS efficacy score of 70 mm or higher.

[0279] The five-item Persistence-Boosting Effect Questionnaire (PEQ) is a five-item questionnaire that assesses significance, psychological impact, psychological insight, and the degree to which a participant's experience during a medication session was psychologically challenging. Scores are evaluated on a scale from 0 (not at all) to 5 (extremely). Higher scores (after considering reverse scoring items) indicate a stronger and more sustained therapeutic effect. In some embodiments, patients report their experiences according to the PEQ as the most meaningful experience of their life, or the most meaningful experience among their top five experiences. In some embodiments, patients report their experiences according to the PEQ as the most psychologically insightful experience of their life, or the most psychologically insightful experience among their top five experiences.

[0280] The Mood State Profile (POMS) measures six identifiable mood or affective states: tension-anxiety, depression-disappointment, anger-hostility, energy-activity, and fatigue-helplessness. In the original POMS, these states are addressed through a 65-point 5-point adjective rating scale, with the addition of a sixth dimension (emotionally confused-confused) not found in the abbreviated POMS, which uses 32 questions to assess different time periods (usually the past two hours, sometimes the past week). The scales use a 5-point scoring system ranging from 0 (not at all) to 4 (extremely). Scores for different states are calculated using a scoring algorithm.

[0281] In the real-time intensity scale, subjects are asked to verbally assess the psychological intensity of their experience on a scale of 0 to 4 (0=not at all, 1=slightly, 2=moderate, 3=very, 4=extreme) for three levels: visual intensity, physical intensity, and emotional / metacognitive intensity. These responses are recorded during drug administration (during the experience). In some embodiments, the method herein provides patients with a real-time intensity scale score (e.g., on the emotional / metacognitive subscale) of at least 1.8, at least 2.0, at least 2.2, at least 2.4, at least 2.6, at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 3.6, at least 3.8, or 4.0. In some embodiments, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, and at least 90% of subjects treated by the methods described herein have a score on a real-time intensity scale greater than >2.79, for example, at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 3.6, at least 3.8, or 4.0.

[0282] In some embodiments, the pharmaceutical formulation results in the controlled release of psychotropic agents, such as tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)), after bolus injection, including bolus subcutaneous injection, which achieves the onset of effect within approximately 30 minutes, 25 minutes, 20 minutes, 15 minutes, and 10 minutes after administration, for example, within approximately 1 to 30 minutes, 5 to 25 minutes, 10 to 20 minutes, 15 to 30 minutes, and 5 to 10 minutes. In some embodiments, the pharmaceutical formulation results in the controlled release of psychotropic agents, such as tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)), after bolus injection, including bolus subcutaneous injection, which achieves the disappearance of effects for more than about 35 minutes to a maximum of about 180 minutes after administration, for example, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, about 125 minutes, about 130 minutes, about 135 minutes, about 140 minutes, about 145 minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, or any range in between.

[0283] In some embodiments, the pharmaceutical formulation provides controlled release of psychotropic drugs, such as tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)), after bolus injection, including bolus subcutaneous injection, at a blood drug concentration of 40 ng / mL or higher corresponding to the peak hallucinogenic effect. For example, after a bolus injection, including a bolus subcutaneous injection, the pharmaceutical formulation may result in blood drug concentrations of approximately 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 ng / mL, 70 ng / mL, 75 ng / mL, 80 ng / mL, 85 ng / mL, 90 ng / mL, 95 ng / mL, 100 ng / mL, 105 ng / mL, 110 ng / mL, 115 ng / mL, 120 ng / mL, 125 ng / mL, 130 ng / mL, 135 ng / mL, 140 ng / mL, 145 ng / mL, 150 ng / mL, or any range in between. For maximum therapeutic benefit and clinical scalability, these drug concentrations (and therefore peak effect) are preferably delivered for durations of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, or any range in between.

[0284] In some embodiments, the pharmaceutical formulation contains approximately 20 ng / mL, approximately 25 ng / mL, approximately 30 ng / mL, approximately 35 ng / mL, approximately 40 ng / mL, approximately 45 ng / mL, approximately 50 ng / mL, approximately 55 ng / mL, approximately 60 ng / mL, approximately 65 ng / mL, approximately 70 ng / mL, approximately 75 ng / mL, approximately 80 ng / mL, approximately 85 ng / mL, approximately 90 ng / mL, approximately 95 ng / mL, approximately 100 ng / mL, approximately 105 ng / mL, approximately 110 ng / mL, approximately 115 ng / mL, approximately 120 ng / mL, approximately 125 ng / mL, approximately 130 ng / mL, approximately 135 ng / mL, approximately 140 ng / mL, This involves bolus subcutaneous injection and subsequent bolus injections resulting in controlled release of psychotropic drugs such as tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)) that place the subject in a hallucinatory state at therapeutically relevant concentrations of the drug in the blood, such as approximately 145 ng / mL, approximately 150 ng / mL, or any range in between, e.g., approximately 20 to approximately 150 ng / mL, or approximately 30 to approximately 100 ng / mL, or approximately 60 to approximately 100 ng / mL, or approximately 40 to approximately 80 ng / mL, or approximately 45 to approximately 60 ng / mL, or approximately 60 to approximately 80 ng / mL, including bolus subcutaneous injection. The hallucinogenic state and therapeutically related concentrations of the drug may last for approximately 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 130 minutes, 140 minutes, 150 minutes, 160 minutes, 170 minutes, 180 minutes, or any range in between.

[0285] Furthermore, the desirable pharmaceutical formulation achieves the aforementioned duration of peak effect and / or hallucinogenic state duration, but with a maximum plasma level (C) of approximately 200 ng / mL, approximately 195 ng / mL, approximately 190 ng / mL, approximately 185 ng / mL, approximately 180 ng / mL, approximately 175 ng / mL, approximately 170 ng / mL, approximately 165 ng / mL, approximately 160 ng / mL, or approximately 155 ng / mL. maxTo avoid a burst release of tryptamine hallucinogens exceeding IV, a controlled release of tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)) is achieved, including bolus subcutaneous injection. As a result, the pharmaceutical formulations of the present disclosure, in particular the subcutaneous pharmaceutical formulations of the present disclosure, result in smoother, more controlled delivery of the psychotropic drug contained therein compared to a bolus IV injection of the same drug formulated without release modifiers, which are known to cause a high level of drug spike immediately after IV injection. In preferred embodiments, the pharmaceutical formulations result in a maximum concentration of the drug in the blood (C) of about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, 80 ng / mL, or any range in between. max For example, C of approximately 60 ng / mL to approximately 80 ng / mL max In addition, controlled release of tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)) after bolus injection, including bolus subcutaneous injection, is provided to achieve the aforementioned duration of peak effect and / or duration of hallucinogenic state.

[0286] In some embodiments, the pharmaceutical formulation results in the controlled release of psychotropic drugs, such as tryptamine hallucinogens (e.g., pharmaceutically acceptable salts of compounds of formulas (I) to (III)), after bolus injection, including bolus subcutaneous injection, which corresponds to a blood drug concentration of about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, or any range in between, for example, about 60 ng / mL to about 80 ng / mL, followed by about 20 ng / mL A steady-state exposure is achieved at a concentration of approximately 60 ng / mL, or any range in between, for example, approximately 20 ng / mL to approximately 40 ng / mL, approximately 25 ng / mL to approximately 35 ng / mL, approximately 20 ng / mL to approximately 30 ng / mL, or approximately 40 ng / mL to approximately 50 ng / mL, and the steady-state exposure lasts for at least 30 minute...

Claims

1. A pharmaceutical preparation for injection, Psychotropic drugs and, Hyaluronic acid and, Aqueous vehicle and, The psychotropic agent is a pharmaceutically acceptable salt of the compound of formula (I), or a stereoisomer, solvate, or prodrug thereof. 【Chemistry 1】 During the ceremony, X １ and X ２ These are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. Y １ and Y ２ These are independently selected from the group consisting of hydrogen and deuterium, R ２ However, selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, R ４ and R ５ These are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy. R ６ and R ７ are each independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ８ and R ９ These are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. Alternatively, R ８ and R ９ However, it is an injectable pharmaceutical preparation that optionally joins with nitrogen atoms bound to them to form unsubstituted or substituted heterocycloalkyl groups.

2. The compound has the structure of formula (II), or a stereoisomer, solvate, or prodrug thereof. 【Chemistry 2】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, Each Z １ These are independently hydrogen or deuterium, Each Z ２ These are independently hydrogen or deuterium, R ２ , R ４ , R ５ , R ６ , and R ７ The injectable pharmaceutical preparation according to claim 1, wherein is independently hydrogen or deuterium.

3. The aforementioned psychotropic drug, 【Chemistry 3-1】 【Chemistry 3-2】 The injectable pharmaceutical preparation according to claim 1, which is a pharmaceutically acceptable salt of at least one compound selected from the group consisting of, or a stereoisomer, solvate, or prodrug thereof.

4. The aforementioned psychotropic drug is 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ The injectable pharmaceutical preparation according to claim 1, which is a pharmaceutically acceptable salt of (I-8).

5. The aforementioned psychotropic drug is 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1-d ２ The injectable pharmaceutical preparation according to claim 1, which is a pharmaceutically acceptable salt of (I-6).

6. The aforementioned psychotropic drug is 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d ２ The injectable pharmaceutical preparation according to claim 1, which is a pharmaceutically acceptable salt of (I-2).

7. An anterotropic drug is (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ A pharmaceutically acceptable salt of (I-8) and (ii) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ (I-10) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2-d ３ The injectable pharmaceutical preparation according to claim 1, which is an active salt mixture comprising one or more pharmaceutically acceptable salts of (I-11).

8. (i) Based on the total weight of the activated salt mixture, 60% to 99% by weight of 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ Based on the total weight of the pharmaceutically acceptable salt of (I-8) and (ii) the active salt mixture, a total of 1% to 40% by weight of 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ (I-10) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2-d ３ The injectable pharmaceutical preparation according to claim 7, comprising one or more pharmaceutically acceptable salts of (I-11).

9. The compound has the structure of formula (III), or its stereoisomer, solvate, or prodrug, 【Chemistry 4】 During the ceremony, X １ and X ２ These are independently hydrogen or deuterium, Y １ and Y ２ These are independently hydrogen or deuterium, Each Z １ These are independently hydrogen or deuterium, Each Z ２ These are independently hydrogen or deuterium, Each Z ３ These are independently hydrogen or deuterium, R ２ , R ４ , R ６ , and R ７ The injectable pharmaceutical preparation according to claim 1, wherein is independently hydrogen or deuterium.

10. The aforementioned psychotropic drug, 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 The injectable pharmaceutical preparation according to claim 1, which is a pharmaceutically acceptable salt of at least one compound selected from the group consisting of, or a stereoisomer, solvate, or prodrug thereof.

11. The aforementioned psychotropic drug is 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ The injectable pharmaceutical preparation according to claim 1, which is a pharmaceutically acceptable salt of (I-20).

12. The aforementioned psychotropic drug is (i) 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ A pharmaceutically acceptable salt of (I-20) and (ii) 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ (I-22) and / or 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d) ３ ) Ethane-1-amine-1,1,2-d ３ The injectable pharmaceutical preparation according to claim 1, which is an active salt mixture comprising one or more pharmaceutically acceptable salts of (I-23).

13. The injectable pharmaceutical preparation according to claim 1, wherein the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate.

14. The injectable pharmaceutical preparation according to claim 1, wherein the concentration of the psychotropic agent by weight per total volume of the pharmaceutical preparation (from the viewpoint of free base equivalent) is about 1 mg / mL to about 100 mg / mL.

15. The injectable pharmaceutical preparation according to claim 1, wherein the concentration of the psychotropic agent by weight per total volume of the pharmaceutical preparation (from the viewpoint of free base equivalent) is about 10 mg / mL to about 50 mg / mL.

16. The injectable pharmaceutical preparation according to claim 1, wherein the hyaluronic acid salt is sodium hyaluronate.

17. The injectable pharmaceutical preparation according to claim 1, wherein the hyaluronic acid salt has a weight-average molecular weight of about 500 kDa to about 2,000 kDa.

18. The injectable pharmaceutical preparation according to claim 1, wherein the hyaluronic acid salt has a weight-average molecular weight of about 1,000 kDa to about 1,800 kDa.

19. The injectable pharmaceutical preparation according to claim 1, wherein the concentration of the hyaluronic acid by weight per total volume of the pharmaceutical preparation is about 0.1% to about 2% (w / v).

20. The injectable pharmaceutical preparation according to claim 1, wherein the concentration of the hyaluronic acid by weight per total volume of the pharmaceutical preparation is about 0.1% to about 1% (w / v).

21. The injectable pharmaceutical preparation according to claim 1, wherein the concentration of the hyaluronic acid by weight per total volume of the pharmaceutical preparation is about 0.1% to about 0.75% (w / v).

22. The injectable pharmaceutical preparation according to claim 1, wherein the concentration of the hyaluronic acid by weight per total volume of the pharmaceutical preparation is about 0.1% to about 0.5% (w / v).

23. An injectable pharmaceutical preparation according to claim 1, having a pH of approximately 3 to approximately 7.

24. The injectable pharmaceutical preparation according to claim 1, having an osmolality of approximately 150 mOsm / kg to approximately 600 mOsm / kg.

25. The injectable pharmaceutical preparation according to claim 1, having a viscosity of less than approximately 3,000 cP.

26. The injectable pharmaceutical preparation according to claim 1, which is suitable for subcutaneous injection.

27. The injectable pharmaceutical preparation according to claim 1, which is suitable for bolus subcutaneous injection.

28. The injectable pharmaceutical preparation according to claim 1, wherein the injectable pharmaceutical preparation provides a duration of peak effect of approximately 30 minutes to approximately 120 minutes after administration to a human subject via bolus subcutaneous injection.

29. A kit suitable for preparing the injectable pharmaceutical preparation described in claim 1, wherein the kit is (a1) A first solution comprising the psychotropic drug and the aqueous vehicle, (b1) A kit comprising a second solution containing the hyaluronic acid and the aqueous vehicle.

30. A method for treating central nervous system (CNS) disorders and / or psychological disorders in a subject requiring such treatment, comprising administering a therapeutically effective amount of the injectable pharmaceutical preparation described in claim 1 to the subject.

31. The method according to claim 30, wherein the CNS disorder and / or psychological disorder is a substance use disorder.

32. The method according to claim 31, wherein the substance use disorder is alcohol use disorder.

33. The method according to claim 30, wherein the CNS disorder and / or psychological disorder is an anxiety disorder.

34. The method according to claim 33, wherein the anxiety disorder is generalized anxiety disorder (GAD).

35. The method according to claim 34, wherein the generalized anxiety disorder is accompanied by depression.

36. The method according to claim 33, wherein the anxiety disorder is social anxiety disorder.

37. The method according to claim 30, wherein the CNS disorder and / or psychological disorder is a depressive disorder.

38. The method according to claim 37, wherein the depressive disorder is major depressive disorder (MDD) or treatment-resistant depression (TRD).

39. The aforementioned CNS disorder and / or psychological disorder may include post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinatory crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use disorder, The method according to claim 30, wherein the at least one is selected from the group consisting of Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia nervosa, bulimia nervosa, pedophilia disorder, exhibitionism disorder, voyeurism disorder, fetishism disorder, sexual masochism or sadism disorder, cross-dressing disorder, sexual dysfunction, and obesity.

40. The method according to claim 30, wherein the injectable pharmaceutical preparation is administered by injection.

41. The method according to claim 30, wherein the injectable pharmaceutical preparation is administered by subcutaneous injection.

42. The method according to claim 30, wherein the injectable pharmaceutical preparation is administered via bolus subcutaneous injection.

43. The method according to claim 42, wherein the bolus subcutaneous injection provides a duration of peak effect of approximately 30 minutes to approximately 120 minutes after administration.

44. A pharmaceutical preparation for injection, Psychotropic drugs and, Hyaluronic acid and, Aqueous vehicle and, An injectable pharmaceutical preparation wherein the psychotropic agent is a pharmaceutically acceptable salt of ketamine, or a stereoisomer, solvate, or prodrug thereof.

45. The injectable pharmaceutical preparation according to claim 44, wherein the pharmaceutically acceptable salt is an inorganic salt.

46. The injectable pharmaceutical preparation according to claim 44, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

47. A kit suitable for preparing the injectable pharmaceutical preparation described in claim 44, wherein the kit is (a1) A first solution comprising the psychotropic drug and the aqueous vehicle, (b1) A kit comprising a second solution containing the hyaluronic acid and the aqueous vehicle.

48. A method for treating a central nervous system (CNS) disorder and / or psychological disorder in a subject requiring treatment, comprising administering a therapeutically effective amount of the injectable pharmaceutical preparation described in claim 44 to the subject.

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