Tryptamine Compositions and Methods

Abstract

Pharmaceutically acceptable salts of tryptamine compounds, uses of such salt forms in treating diseases associated with the serotonin 5-HT2 receptor, pharmaceutical compositions, including those adapted for inhaled administration, containing the salt forms, methods of delivering the pharmaceutically acceptable salt forms (e.g., via inhalation), and methods of treating diseases or disorders associated with the serotonin 5-HT2 receptor, such as central nervous system (CNS) disorders and psychiatric disorders, using the salt forms (Formula (I)). [Formula 1] JPEG2025502208000028.jpg3855

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 299,599, filed January 14, 2022, and U.S. Provisional Patent Application No. 63 / 384,704, filed November 22, 2022, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates generally to pharmaceutically acceptable salts of tryptamine compounds, which in some embodiments are serotonin 5-HT2 receptor agonists and their use in treating diseases associated with the 5-HT2 receptor. [Background technology]

[0003] Serotonin 5-HT2 receptors (5-HT2Rs) contain 5-HT 2A , 5-HT 2B , and 5-HT 2C There are three closely related subtypes of 5-HT, which are the primary targets of classical serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, and 2,5-dimethoxy-4-bromoamphetamine (DOB). They share approximately 60% transmembrane amino acid homology, which poses the challenge of designing molecules with selectivity for one subtype over the others. Each subtype is expressed in a unique pattern in mammals (both peripheral tissues and the central nervous system) and, when stimulated, produces unique biochemical, physiological, and behavioral effects. For example, 5-HT 2A Activation of Rs primarily mediates hallucinogenic effects and causes anti-inflammatory effects, whereas 5-HT 2C Activation of Rs reduces feeding behavior. However, 5-HT 2B Chronic activation of Rs is associated with valvular heart disease (VHD), a life-threatening adverse event (AE). 2A There is concern that patients who may benefit from R-pharmacotherapy may be reluctant to experience the hallucinogenic effects.

[0004] Tryptamines are a class of serotonergic hallucinogens with very high potency (in some cases, subnanomolar affinity) at serotonin 5-HT2Rs. 2B Rs and 5-HT 2C 5-HT than Rs 2A Their selectivity for Rs—in some cases 100-fold—distinguishes them from typical hallucinogens and other serotonergic hallucinogens.

[0005] AEs caused by tryptamines and other serotonergic hallucinogens are associated with relatively high doses, possibly 5-HT 2A Rs and 5-HT 2C Because of their very high potency on Rs, the active oral dose of tryptamines and other hallucinogens is extremely low. For example, (2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethan-1-amine (2C-C-NBOMe) is orally active at doses as low as 25 μg, whereas highly potent hallucinogenic doses range from 500 to 700 μg. Therefore, misuse or abuse above these doses can cause negative experiences in patients, presenting as an acute hallucinatory crisis, commonly known as a "horrific hallucination," in which patients experience visual and auditory hallucinations, agitation, aggression, psychosis, remorse, and feelings of distress. Intoxication has also been associated with toxicity (e.g., rhabdomyolysis) and death. Tryptamines, such as N,N-dimethyltryptamine (DMT) (IUPAC: 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine), can undergo extensive first-pass metabolism and become orally inactive.

[0006] As a result, the therapeutic index of many tryptamine hallucinogens is relatively narrow, and maximizing the therapeutic benefit of potential drug candidates requires fine tuning of the dose and route of administration, along with dose titration, to reduce side effects and improve safety.

[0007] Furthermore, like many free base pharmaceuticals, the free base form of tryptamine is generally not suitable for pharmaceutical processing and application. For example, DMT free base is a low melting point solid (approximately 46°C) and is known to be sensitive to oxygen, heat, and light under long-term storage.

[0008] Therefore, 5-HT 2B There is a need for tryptamines that overcome the R and adverse event problems, while also improving their bioavailability and enhancing their activity and exposure. There is a further need for efficient, more convenient, and controllable tryptamine formulations that do not result in neurologically toxic (e.g., psychotomimetic toxicity) plasma concentrations. There is also a need for stable, physiologically acceptable forms of tryptamine that are suitable for pharmaceutical preparation and administration. Summary of the Invention

[0009] The present disclosure is based, at least in part, on the identification of salt forms of compounds that modulate the serotonin 5-HT2 receptor and methods of using them to treat diseases associated with the serotonin 5-HT2 receptor. More specifically, the present disclosure provides novel salt forms of N,N-dimethyltryptamine (DMT) and derivatives thereof that have advantageous physical and pharmaceutical properties and allow for the preparation of efficient, more convenient, and controllable pharmaceutical formulations for the treatment of diseases / conditions, such as neuropsychiatric diseases or disorders, inflammatory diseases or disorders, central nervous system (CNS) disorders, autonomic nervous system (ANS) disorders, pulmonary disorders, and / or cardiovascular disorders.

[0010] These and other objects, which will become apparent during the detailed description that follows, have been achieved by the inventors' discovery of novel salt forms of compounds of formula (I) that have one or more of the following desirable physical and pharmaceutical characteristics: ease and tendency to salt formation and crystallize (e.g., high yield); stable, well-defined physical properties (e.g., crystallinity, lack of polymorphism, high melting point, and high enthalpy of fusion); stability to moisture, including high humidity (hygroscopicity); desirable appearance (e.g., free flowing, lack of aggregation / adhesion, regular morphology); acceptable water solubility; and physiological acceptability, particularly acceptability upon pulmonary administration (e.g., non-irritating).

[0011] Therefore, such suitable salt forms of the compounds described herein (e.g., compounds of Formula (I)) can be administered in a controlled manner, for example, via inhalation, by avoiding first-pass metabolism, along with the rapid absorption and rapid onset of action provided by the large surface area, abundant vasculature, and thin air-blood barrier of the alveolar region, thereby allowing the use of relatively low doses, a low incidence of systemic side effects, and a more favorable pharmacokinetic profile. In particular, pulmonary administration of suitable salt forms of the compounds described herein (e.g., compounds of Formula (I)) in combination with an N-methyl-D-aspartate (NMDA) receptor antagonist (e.g., nitrous oxide, a dissociative anesthetic that provides sedation and euphoria and controls and / or reduces the activation effect of 5-HT2R) can reduce the risk of overstimulation and thus the occurrence of psychiatric adverse effects, such as acute hallucinatory crisis.

[0012] Thus, the present disclosure provides: (1) Formula (I), [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are deuterium; R2, R4, R5, R6, and R7 are independently hydrogen or deuterium; and A pharmaceutically acceptable salt of a compound of the formula: wherein R8 and R9 are independently selected from the group consisting of -CH3, -CDH2, -CD2H, - and -CD3, or a solvate thereof. (2) A pharmaceutically acceptable salt according to (1), wherein at least one of R8 and R9 contains deuterium. (3) A pharmaceutically acceptable salt according to (1) or (2), wherein R2, R4, R5, R6, and R7 are hydrogen. (4) A pharmaceutically acceptable salt according to (1) or (2), wherein at least one of R2, R4, R5, R6, and R7 is deuterium. (5) A pharmaceutically acceptable salt according to any one of (1) to (4), wherein R8 and R9 are —CH3. (6) A pharmaceutically acceptable salt according to any one of (1) to (4), wherein R8 and R9 are independently selected from the group consisting of -CDH2, -CD2H, and -CD3. (7) A pharmaceutically acceptable salt according to any one of (1) to (4), wherein R8 and R9 are -CD3. (8) The compound of formula (I) [ka] The pharmaceutically acceptable salt according to any one of (1) to (7), selected from the group consisting of: (9) The compound of formula (I) [ka] The pharmaceutically acceptable salt according to (1), (10) The pharmaceutically acceptable salt according to any one of (1) to (9), which is crystalline as determined by X-ray powder diffraction (XRPD). (11) The pharmaceutically acceptable salt according to any one of (1) to (10), which has a water solubility of about 10 mg / mL to about 400 mg / mL. (12) The pharmaceutically acceptable salt according to any one of (1) to (11), which has an onset melting temperature of about 100°C to about 210°C as determined by differential scanning calorimetry (DSC). (13) Approximately 110 J·g as determined by differential scanning calorimetry (DSC). -1 ~Approx. 180 J·g -1 The pharmaceutically acceptable salt according to any one of (1) to (12), having a melting enthalpy of (14) The pharmaceutically acceptable salt according to any one of (1) to (13), having a weight gain of less than 1% w / w when exposed to a relative humidity (RH) of >95% RH as determined by dynamic vapor sorption (DVS). (15) The pharmaceutically acceptable salt according to any one of (1) to (14), which is an addition salt of the compound of formula (I) with an organic acid. (16) The pharmaceutically acceptable salt according to any one of (1) to (15), which is a fumarate, a benzoate, a salicylate, or a succinate of the compound of formula (I). (17) A pharmaceutically acceptable salt according to any one of (1) to (16), which is a fumarate salt of the compound of formula (I). (18) The pharmaceutically acceptable salt according to any one of (1) to (16), which is a benzoate salt of the compound of formula (I). (19) A pharmaceutically acceptable salt according to any one of (1) to (16), which is a salicylate salt of the compound of formula (I). (20) The pharmaceutically acceptable salt according to any one of (1) to (16), which is a succinate salt of the compound of formula (I). (21) A pharmaceutically acceptable salt according to any one of (1) to (16), which is a fumarate salt of 2-(1H-ind-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8a). (22) The pharmaceutically acceptable salt according to (21), which is a crystalline solid form 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. (23) A pharmaceutically acceptable salt according to any one of (1) to (16), which is a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8b). (24) The pharmaceutically acceptable salt according to (23), which is a crystalline solid form 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. (25) A pharmaceutically acceptable salt according to any one of (1) to (16), which is a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8c). (26) The pharmaceutically acceptable salt according to (25), which is a crystalline solid form 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. (27) A pharmaceutically acceptable salt according to any one of (1) to (16), which is a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8d). (28) A pharmaceutical composition comprising the pharmaceutically acceptable salt according to any one of (1) to (27) and a pharmaceutically acceptable vehicle. (29) The pharmaceutical composition according to (28), wherein any position in the compound of formula (I) bearing deuterium has a minimum deuterium incorporation of at least 50 atomic % at the site of deuteration. (30) The pharmaceutical composition according to (28) or (29), which is adapted for administration via inhalation. (31) The pharmaceutical composition according to (28) or (29), which is adapted for oral administration. (32) The pharmaceutical composition according to (28) or (29), which is adapted for intravenous administration. (33) The pharmaceutical composition according to (28) or (29), which is adapted for subcutaneous administration. (34) The pharmaceutical composition according to (28) or (29), which is adapted for intramuscular administration. (35) The pharmaceutical composition according to (28) or (29), which is adapted for nasal administration. (36) A liquid dosage form prepared by reconstituting a solid dosage form of the pharmaceutical composition according to (28) or (29) in a pharmaceutically acceptable liquid medium. (37) A method for delivering the pharmaceutically acceptable salt according to any one of (1) to (27) to a patient in need thereof, comprising: A method comprising administering to a patient via inhalation an aerosol, wherein the aerosol comprises a pharmaceutically acceptable salt of a compound of formula (I) in a carrier. (38) The method of (37), wherein the pharmaceutically acceptable salt is delivered to the patient's central nervous system via pulmonary absorption. (39) The method according to (37) or (38), wherein the carrier is air, oxygen, or a mixture of helium and oxygen. (40) The method according to (39), wherein the carrier is a mixture of helium and oxygen. (41) The method according to (40), wherein the mixture of helium and oxygen is heated to about 50°C to about 60°C. (42) The method according to (40) or (41), wherein helium is present in the mixture of helium and oxygen at about 50% to 90% by volume, and oxygen is present in the mixture of helium and oxygen at about 50% to 10% by volume. (43) The method according to any one of (37) to (42), further comprising administering a pre-treatment inhalation therapy prior to administration of an aerosol comprising a pharmaceutically acceptable salt of the compound of formula (I) and a carrier. (44) The method of (43), wherein the pretreatment inhalation therapy comprises administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C. (45) The method of (44), comprising: (i) administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C; and (ii) administering to the patient via inhalation an aerosol comprising a pharmaceutically acceptable salt of the compound of Formula (I) in a mixture of helium and oxygen heated to about 50°C to about 60°C. (46) The method according to (45), further comprising repeating steps (i) and (ii) 1 to 5 times. (47) A pharmaceutically acceptable salt of a compound of formula (I) is delivered to the central nervous system of a patient and exhibits at least a 25% improvement in drug bioavailability compared to oral delivery, and at least a 25% improvement in drug bioavailability compared to oral delivery. max At least a 25% increase in T compared to oral delivery max The method according to any one of (37) to (46), which provides at least a 50% reduction in the amount of α-tocopherol, β ... (48) The method according to any one of (37) to (47), wherein the aerosol is a mist. (49) The method according to any one of (37) to (48), wherein the aerosol is prepared by atomization of a pharmaceutically acceptable salt of the compound of formula (I). (50) The method according to (49), wherein the nebulization is carried out using a device selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a breath-actuated nebulizer, and a vibrating mesh nebulizer. (51) The method of (49) or (50), wherein the nebulization is carried out using a driving gas comprising nitrous oxide for entrainment of the nebulized form of the pharmaceutically acceptable salt of the compound of formula (I). (52) The method according to (51), wherein the nitrous oxide is present in the driving gas at a concentration of 15 to 25% by volume relative to the total volume of the driving gas. (53) The method according to any one of (37) to (52), wherein the aerosol is administered for 20 to 60 minutes. (54) A method for treating a patient with a central nervous system (CNS) disorder and / or a psychiatric disorder, comprising: A method comprising administering to a patient a therapeutically effective amount of the pharmaceutically acceptable salt according to any one of (1) to (27). (55) CNS disorders and / or psychiatric disorders include post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or 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, and nicotine use disorder. 54. The method of claim 54, wherein the neuropsychiatric disorder is at least one selected from the group consisting of neuropsychiatric disorders, cocaine use disorder, 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, binge eating disorder, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, cross-dressing disorder, sexual dysfunction, and obesity. (56) The method according to (54), wherein the CNS disorder and / or psychiatric disorder is alcohol use disorder. (57) The method according to (54), wherein the CNS disorder and / or psychiatric disorder is generalized anxiety disorder (GAD). (58) The method according to (54), wherein the CNS disorder and / or psychiatric disorder is social anxiety disorder. (59) The method according to (54), wherein the CNS disorder and / or psychiatric disease is treatment-resistant depression (TRD). (60) An active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); and (ii) one or more pharmaceutically acceptable salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and a pharmaceutically acceptable vehicle. (61) The pharmaceutical composition according to (60), wherein the active salt mixture comprises (i) 60% to 98% by weight of a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8), based on the total weight of the active salt mixture, and (ii) 2% to 40% by weight in total of one or more pharmaceutically acceptable salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11), based on the total weight of the active salt mixture. (62) The pharmaceutical composition according to (60) or (61), wherein the active salt mixture comprises (i) 90% to 98% by weight of a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8), based on the total weight of the active salt mixture, and (ii) 2% to 10% by weight in total of one or more pharmaceutically acceptable salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11), based on the total weight of the active salt mixture. (63) The pharmaceutical composition according to any one of (60) to (62), wherein the active salt mixture comprises (i) a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8a), and (ii) one or more fumarate salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10a) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11a). (64) The pharmaceutical composition according to any one of (60) to (62), wherein the active salt mixture comprises (i) a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8b), and (ii) one or more benzoates of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10b) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11b). (65) The pharmaceutical composition according to any one of (60) to (62), wherein the active salt mixture comprises (i) a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8c), and (ii) one or more salicylates of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10c) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11c). (66) The pharmaceutical composition according to any one of (60) to (62), wherein the active salt mixture comprises (i) a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8d), and (ii) one or more succinate salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10d) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11d). (67) A method for treating a patient with a central nervous system (CNS) disorder and / or a psychiatric disorder, comprising: A method comprising administering to a patient via inhalation a therapeutically effective amount of an aerosol comprising a pharmaceutically acceptable salt according to any one of (1) to (27) in a carrier. (68) The method according to (67), wherein the aerosol is a mist. (69) The method according to (67) or (68), wherein the carrier is air, oxygen, or a mixture of helium and oxygen. (70) The method of (69), wherein the carrier is a mixture of helium and oxygen, and the mixture of helium and oxygen is heated to about 50°C to about 60°C before administering the aerosol to the patient. (71) CNS disorders and / or psychiatric disorders include post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or 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 any one of (67) to (70), wherein the condition is at least one selected from the group consisting of alcohol use disorder, 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, binge eating disorder, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, cross-dressing disorder, sexual dysfunction, and obesity. (72) The method according to any one of (67) to (71), wherein the CNS disorder and / or psychiatric disorder is alcohol use disorder. (73) The method according to any one of (67) to (71), wherein the CNS disorder and / or psychiatric disorder is generalized anxiety disorder (GAD). (74) The method according to any one of (67) to (71), wherein the CNS disorder and / or psychiatric disorder is social anxiety disorder. (75) The method according to any one of (67) to (71), wherein the CNS disorder and / or psychiatric disorder is treatment-resistant depression (TRD). (76) The method according to any one of (67) to (75), wherein the aerosol is prepared by atomization of a pharmaceutically acceptable salt of the compound of formula (I). (77) The method according to (76), wherein the nebulization is carried out using a device selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a breath-actuated nebulizer, and a vibrating mesh nebulizer. (78) The method of (76) or (77), wherein the nebulization is carried out using a driving gas comprising nitrous oxide for entrainment of the nebulized form of the pharmaceutically acceptable salt of the compound of formula (I). (79) The method according to (78), wherein the nitrous oxide is present in the driving gas at a concentration of 15 to 25% by volume relative to the total volume of the driving gas. (80) The method according to any one of (67) to (79), wherein the aerosol is administered for 20 to 60 minutes. (81) A method for delivering the pharmaceutically acceptable salt according to any one of (1) to (27) to a patient in need thereof, comprising: A method comprising administering to a patient by inhalation via a dry powder inhaler, wherein the dry powder comprises a pharmaceutically acceptable salt of a compound of formula (I). (82) The method of (81), wherein the dry powder comprises a particulate carrier having a pharmaceutically acceptable salt of the compound of formula (I) on its surface. (83) The method of (82), wherein a pharmaceutically acceptable salt of the compound of formula (I) is releasably absorbed onto the surface of a particulate carrier, such that upon inhalation by a patient, the compound of formula (I) is released from the particulate carrier within the patient. (84) The method of (81), wherein the dry powder is formed from a pharmaceutically acceptable salt of the compound of formula (I) in solid particulate form. (85) The method according to any one of (81) to (84), wherein the pharmaceutically acceptable salt of the compound of formula (I) is delivered to the central nervous system of the patient via pulmonary absorption. (86) The method according to any one of (81) to (85), further comprising administering a pretreatment inhalation therapy to the patient prior to administration of the dry powder. (87) The method according to (86), wherein the pretreatment inhalation therapy comprises administering to the patient by inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C. (88) The method according to (86) or (87), wherein the pretreatment inhalation therapy and administration of the dry powder to the patient are repeated 1 to 5 times. (89) A pharmaceutically acceptable salt of a compound of formula (I) is delivered to the central nervous system of a patient and exhibits at least a 25% improvement in drug bioavailability compared to oral delivery, and at least a 25% improvement in drug bioavailability compared to oral delivery. max At least a 25% increase in T compared to oral delivery max The method according to any one of (81) to (88), which provides at least a 50% reduction in the amount of α-tocopherol, β ... (90) A pharmaceutically acceptable salt according to any one of (1) to (27), and Combination medications, including N-methyl-D-aspartate (NMDA) receptor antagonists. (91) The combination drug therapy according to (90), wherein the NMDA receptor antagonist is at least one selected from the group consisting of ketamine, nitrous oxide, memantine, and dextromethorphan. (92) The combination drug therapy according to (90) or (91), wherein the NMDA receptor antagonist is nitrous oxide. (93) The combination drug therapy according to (92), wherein the pharmaceutically acceptable salt and nitrous oxide are provided for administration as a single aerosol. (94) The combination drug therapy according to (92), wherein the pharmaceutically acceptable salt and nitrous oxide are provided for administration as separate dosage forms. (95) The combination drug therapy of (94), wherein the pharmaceutically acceptable salt is provided for administration as an aerosol and the nitrous oxide is provided for administration as a therapeutic gas mixture. (96) A method for treating a patient with a central nervous system (CNS) disorder and / or a psychiatric disorder, comprising: A method comprising administering to a patient via inhalation a therapeutically effective amount of a pharmaceutically acceptable salt of any one of (1) to (27) and an N-methyl-D-aspartate (NMDA) receptor antagonist. (97) CNS and / or psychiatric disorders include post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or 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, and nicotine use disorder. 96. The method of claim 96, wherein the neuropsychiatric disorder is at least one selected from the group consisting of neuropsychiatric disorders, cocaine use disorder, 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, binge eating disorder, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, cross-dressing disorder, sexual dysfunction, and obesity. (98) The method according to (96) or (97), wherein the CNS disorder and / or psychiatric disorder is alcohol use disorder. (99) The method according to (96) or (97), wherein the CNS disorder and / or psychiatric disorder is generalized anxiety disorder (GAD). (100) The method according to (96) or (97), wherein the CNS disorder and / or psychiatric disorder is social anxiety disorder. (101) The method according to (96) or (97), wherein the CNS disorder and / or psychiatric disorder is treatment-resistant depression (TRD). (102) The method according to any one of (96) to (101), wherein the NMDA receptor antagonist is at least one selected from the group consisting of ketamine, nitrous oxide, memantine, and dextromethorphan. (103) The method according to any one of (96) to (102), wherein the NMDA receptor antagonist is nitrous oxide. (104) The method of (103), wherein the pharmaceutically acceptable salt and nitrous oxide are administered to the patient as a single aerosol. (105) The method of (103), wherein the pharmaceutically acceptable salt and nitrous oxide are administered in separate dosage forms. (106) The method of (105), wherein the pharmaceutically acceptable salt is administered as an aerosol and the nitrous oxide is administered as a therapeutic gas mixture. (107) The method according to (105) or (106), wherein the pharmaceutically acceptable salt and nitrous oxide are administered sequentially. (108) The method according to (105) or (106), wherein the pharmaceutically acceptable salt and nitrous oxide are administered substantially sequentially. (109) An inhalation delivery device for delivering a combination of nitrous oxide and a pharmaceutically acceptable salt according to any one of (1) to (27) by inhalation to a patient in need thereof, comprising: an inhalation exit portal for administration of a combination of nitrous oxide and a pharmaceutically acceptable salt to a patient; a container configured to deliver nitrous oxide gas to the inhalation outlet portal; and a device configured to generate and deliver to an inhalation outlet portal an aerosol comprising a pharmaceutically acceptable salt. (110) The inhalation delivery device of (109), wherein the inhalation outlet portal is a mouthpiece or mask that covers the patient's nose and mouth. (111) The inhalation delivery device according to (109) or (110), wherein the device configured to generate and deliver an aerosol to the inhalation outlet portal is a nebulizer. (112) The inhalation delivery device according to (111), wherein the nebulizer is a jet nebulizer and the nitrous oxide gas acts as a driving gas for the jet nebulizer. (113) An inhalation delivery device according to any one of (109) to (112), further comprising electronics configured to provide remote actuation and operational control of the inhalation delivery device. (114) Use of a pharmaceutically acceptable salt of any one of (1) to (27) for treating a patient with a central nervous system (CNS) disorder and / or a psychiatric disorder. (115) A pharmaceutically acceptable salt of any one of (1) to (27) for use in therapy. [Brief explanation of the drawings]

[0013] The foregoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the claims that follow. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings. [Figure 1] FIG. 1 shows a general synthetic route for making compounds of formula (I), for example, compounds I-1, I-2, I-4, and I-6. [Figure 2] FIG. 2 shows a general synthetic route for making compounds of formula (I), such as compounds I-1, I-4, I-5, and I-8. [Figure 3] FIG. 3 shows the X-ray powder diffractograms of Example 6 (I-1f; glycolate salt), Example 9 (I-1i; hemifumarate salt), and Example 1 (I-1a; fumarate salt). [Figure 4] FIG. 4 shows the X-ray powder diffractograms of Example 2 (I-1b; benzoate), Example 3 (I-1c; salicylate), and Example 7 (I-1g; hemioxalate). [Figure 5] FIG. 5 shows the X-ray powder diffractograms of Example 5 (I-1e; oxalate salt), Example 4 (I-1d; succinate salt), and Example 8 (I-1h; hemifumarate salt). [Figure 6] FIG. 6 shows the X-ray powder diffractograms of Example 26 (I-8a; fumarate salt) compared to Example 1 (I-1a; fumarate salt). [Figure 7] FIG. 7 shows the X-ray powder diffractograms of Example 27 (I-8b; benzoate salt) compared to Example 2 (I-1b; benzoate salt). [Figure 8] FIG. 8 shows the X-ray powder diffractograms of Example 28 (I-8c; salicylate) compared to Example 3 (I-1c; salicylate). [Figure 9] FIG. 9 shows the DSC curve of Example 1 (I-1a; fumarate salt). [Figure 10] FIG. 10 shows the DSC curve of Example 2 (I-1b; benzoate). [Figure 11] FIG. 11 shows the DSC curve of Example 4 (I-1d; succinate salt). [Figure 12] FIG. 12 shows the DSC curve of Example 5 (I-1e; oxalate salt). [Figure 13] FIG. 13 shows the DSC curve of Example 3 (I-1c; salicylate). [Figure 14] FIG. 14 shows the DSC curve of Example 6 (I-1f; glycolate salt). [Figure 15] FIG. 15 shows the DSC curve of Example 9 (I-1i; hemifumarate salt). [Figure 16] FIG. 16 shows the DSC curve of Example 8 (I-1h; hemifumarate salt). [Figure 17] FIG. 17 shows the DVS isotherm of Example 1 (I-1a; fumarate salt). [Figure 18] FIG. 18 shows the DVS isotherm for Example 2 (I-1b; benzoate salt). [Figure 19] FIG. 19 shows the DVS isotherm of Example 4 (I-1d; succinate salt). [Figure 20] FIG. 20 shows the DVS isotherm for Example 3 (I-1c; salicylate). [Figure 21] FIG. 21 shows the DVS isotherm of Example 5 (I-1e; oxalate salt). [Figure 22] FIG. 22 shows the DVS isotherm for Example 6 (I-1f; glycolate salt). [Figure 23] FIG. 23 shows the DVS isotherm of Example 8 (I-1h; hemifumarate salt). [Figure 24] FIG. 24 shows the DVS isotherm for Example 7 (I-1g; hemi-oxalate salt). [Figure 25] FIG. 25 shows the 1H NMR spectrum of Example 1 (I-1a; fumarate salt). [Figure 26] FIG. 26 shows the 1H NMR spectrum of Example 2 (I-1b; benzoate salt). [Figure 27] FIG. 27 shows the 1H NMR spectrum of Example 3 (I-1c; salicylate salt). [Figure 28] FIG. 28 shows the 1H NMR spectrum of Example 5 (I-1e; oxalate salt). [Figure 29] FIG. 29 shows the 1H NMR spectrum of Example 8 (I-1h; hemifumarate salt). [Figure 30] FIG. 30 shows the 1H NMR spectrum of Example 6 (I-1f; glycolate salt). [Figure 31] FIG. 31 shows the 1H NMR spectrum of Example 4 (I-1d; succinate salt). [Figure 32] FIG. 32 shows the 1H NMR spectrum of Example 7 (I-1g; hemi-oxalate salt). [Figure 33A] 33A-33B show the single crystal of I-8b (benzoate) in terms of molecular structure (FIG. 33A) and asymmetric crystal unit cell (FIG. 33B). [Figure 33B] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0014] In the following detailed description of embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present disclosure. However, it will be apparent to those skilled in the art that embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0015] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0016] When a substituent or group is described as "containing deuterium" or "comprising deuterium," it is to be understood that the substituent or group itself can be deuterium, or the substituent or group can contain at least one deuterium substitution in its chemical structure. For example, if the substituent "-R" is defined as containing deuterium, it is to be understood that -R can be -D (-deuterium), or a group such as -CD consistent with the other requirements set forth for -R.

[0017] As used herein, the term "fat" refers to a compound having a long-chain (linear) hydrophobic moiety composed of hydrogen and 4 to 26 carbon atoms, and may be fully saturated or partially unsaturated.

[0018] The phrases "pharmaceutically acceptable," "physiologically acceptable," and the like are used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. When referring to salts, the phrases "pharmaceutically acceptable salt," "physiologically acceptable salt," and the like mean salts that are acceptable for administration to a patient, such as a mammal (salts having counterions that have acceptable mammalian safety for a given administration 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, and, where the molecule contains a basic functional group, from addition salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, sulfamate, phosphates, nitrates, perchlorates, and the like, as well as from addition salts with organic acids such as formates, tartrates, besylates, mesylates, acetates, maleates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemixalates, hemifumarates, propionates, stearates, lactates, citrates, ascorbates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, isethionates, and the like.

[0019] "Solvate" refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate can exist in an ordered and / or irregular arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. 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.

[0020] "Stereoisomer" and "stereoisomer" refer to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms of compounds, including racemates 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 intended to include both racemates and individual stereoisomers, such as R- and / or S-stereoisomers, and each permutation of the diastereomers, as long as the diastereomers are geometrically feasible.

[0021] A "crystalline" solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules forming a crystal lattice with long-range order, and thus exhibits sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern. In some cases, a crystalline solid may exist in different crystalline forms known as "polymorphs," which have the same chemical composition but differ 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, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility of the compound, as well as the safety and efficacy of pharmaceuticals based on the compound. In the process of preparing polymorphs, further refinement can also be achieved in terms of overall physical or optical purity. As used herein, the term "non-crystalline" refers to a solid material that does not have substantial long-range order in the position of its molecules; the molecules are arranged randomly, such that there is effectively no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., 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 does not have substantially sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in the XRPD pattern. Broad peaks are characteristic of amorphous solids. Thus, a "non-crystalline" subject compound / material is a compound / material characterized as having substantially no crystallinity, e.g., a crystallinity of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, or 0%, i.e., at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined by XRPD. For example, in some embodiments, the percent crystallinity may be determined by measuring the intensity of one or more peaks in an XRPD diffractogram compared to a reference peak, which may be a known standard or an 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 above percentages in terms of weight percent, may be used to determine the percent amorphous or crystalline of a subject compound / substance.

[0022] When referring to X-ray powder diffraction (XRPD) patterns of materials of the present disclosure, the phrase "characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from" should be understood to include those materials characterized as having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more (inclusive) of the recited characteristic XRPD diffraction peaks. Furthermore, this phrase is intended to be open to the inclusion of other XRPD diffraction peaks not recited.

[0023] It will be understood that the compounds herein may exist in different salt, solvate, stereoisomeric, crystalline / non-crystalline (including polymorphic) forms, and that the present disclosure is intended to include all permutations thereof, for example, solvates of pharmaceutically acceptable salts of stereoisomers of the subject compounds.

[0024] A "vapor" is a solid substance in the gas phase at a temperature below its critical temperature, meaning that the vapor can be condensed to a liquid by increasing the pressure on it without decreasing the temperature.

[0025] As used herein, an "aerosol" is a suspension of fine solid particles or liquid droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide, and other gases, and mixtures thereof). As used herein, a "mist" is a subset of aerosol, distinct from vapor, and is a dispersion of liquid droplets (liquid phase) suspended in a gas phase (e.g., air, oxygen, helium, and mixtures thereof). The liquid droplets of an aerosol or mist may contain a drug moiety dissolved in an aqueous liquid, an organic solvent, or a mixture thereof. The gas phase of an aerosol or mist may contain other gases, including air, oxygen, helium, or mixtures thereof. A mist does not contain solid particles. The aerosols and mists of the present disclosure can be generated by any suitable method and device, examples of which are described herein, for example, through the use of an inhaler or nebulizer.

[0026] As used herein, the term "sustained release" describes the release period of certain formulations of the present disclosure that are formulated to increase the release period, for example, to a maximum value, which, in the case of ingested oral formulations, is ultimately limited by the time the gastrointestinal tract naturally expels all of the drug with food. As used herein, the term "release period" describes the time frame during which any compound described herein is released from a vehicle (e.g., a matrix) to achieve a plasma concentration of the compound described herein. The start time of the release period is defined from the time of administration to a subject, which, when orally ingested, is considered to be approximately equivalent to entry into the stomach and initial dissolution by gastric enzymes and acids. The end time of the release period is defined as the time when the entire loaded drug has been released. In some embodiments, the release period can be greater than about 4 hours, greater than 8 hours, greater than 12 hours, greater than 16 hours, or greater than 20 hours, greater than about 24 hours, greater than 28 hours, greater than 32 hours, greater than 36 hours, or greater than 48 hours, or less than about 48 hours, less than 36 hours, 4 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less.

[0027] The term "tamper-resistant" is art-recognized as describing an aspect of a drug formulation that makes it more difficult to use the formulation to abuse the drug portion of the formulation, for example, via extraction for intravenous use or crushing for free base use, thereby reducing the risk of drug abuse.

[0028] As used herein, the terms "stable," "stability," and the like include chemical stability and solid-state (physical) stability. The term "chemical stability" means that a compound can be stored under normal storage conditions, either in an isolated form or in a formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no chemical degradation or decomposition. "Solid-state stability" means that a compound can be stored under normal storage conditions, either in an isolated solid form or in a solid formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no solid-state changes (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid-state phase transition).

[0029] As used herein, the term "composition" is equivalent to the term "formulation."

[0030] As used herein, the term " inhalation session " describes the administration event that a subject inhales a given dose of drug, regardless of the number of breaths required to inhale a given dose.For example, a subject prescribed to take 10 mg of drug twice a day will perform two inhalation sessions, and each inhalation session will provide 10 mg of drug.The duration and number of breaths of each inhalation session will depend on factors such as the inhalation device used, the amount of drug inhaled per breath, the drug concentration of the dosage form, and the breathing pattern of the subject.

[0031] As used herein, the term "treating" or "treatment" refers to treating or curing a disease or medical condition in a patient, e.g., a mammal (especially a human), including ameliorating a disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a patient; inhibiting a disease or medical condition, e.g., by slowing or arresting the onset of the disease or medical condition in a patient; or alleviating one or more symptoms of a disease or medical condition in a patient. Treatment may provide a therapeutic benefit, such as eradicating or ameliorating one or more physiological or psychological symptoms associated with an underlying condition, disease, or disorder, such that an 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 refer to prophylaxis, i.e., preventing the occurrence of a disease or medical condition or otherwise delaying the onset of a disease or medical condition in a patient.

[0032] A "patient" or "subject," as used interchangeably herein, may be any mammal, including, for example, a human. The patient or subject may have the condition to be treated or may be susceptible to the condition to be treated.

[0033] As used herein, unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. Often, the beneficial effects a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term "managing" encompasses treating a subject afflicted with a particular disease, disorder, or condition in an effort to prevent or minimize the recurrence of the disease, disorder, or condition, or one or more symptoms thereof.

[0034] A "therapeutically effective amount" refers to an amount of a compound or salt form thereof sufficient to treat a particular disorder or disease, or one or more symptoms thereof, and / or prevent the occurrence of the disease or disorder. As used herein, unless otherwise specified, a "prophylactically effective amount" of an active agent is an amount sufficient to prevent a disease, disorder, or condition, or to prevent its recurrence. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effect of another prophylactic agent.

[0035] The term "administration schedule" refers to a plan that chronologically shows the type, amount, duration, and procedure of drug treatment, including the dosage, administration method, administration order, and administration date of each drug. The designated administration date is determined before the start of drug administration. Administration is continued by repeating a series of administration schedules, each of which is considered a "course." A "continuous" administration schedule means that the drug is administered daily without interruption during the treatment course. If the administration schedule follows an "intermittent" administration schedule, the days of administration may be followed by "rest days" or non-administration days of the drug during the course. A "drug holiday" indicates that the drug is not administered according to a predetermined administration schedule. For example, after receiving several treatment courses, a subject may be prescribed a regulated drug holiday as part of the administration schedule, for example, before resuming active treatment.

[0036] The term "toxic spike" is used herein to describe a spike in the concentration of any compound described herein that would result in side effects such as sedation or psychotomimetic effects such as hallucinations, dizziness, and nausea, which not only have an immediate effect but also affect treatment compliance. In particular, side effects may be more pronounced at blood concentration levels above about 300 ng / L (e.g., about 300, 400, 500, 600, or more ng / L).

[0037] As used herein, and unless otherwise specified, a "neuropsychiatric disease or disorder" refers to a behavioral or psychological problem associated with a known neurological condition, typically defined as a group of coexisting symptoms. Examples of neuropsychiatric disorders include, but are not limited to, schizophrenia, cognitive impairment in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder and mania, depression, or any combination thereof.

[0038] As used herein, "inflammatory condition" or "inflammatory disease" broadly refers to chronic or acute inflammatory diseases. Inflammatory conditions and diseases include, but are not limited to, rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthropathies (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathies (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, Sjogren's syndrome), and others. group); vasculitis (e.g., polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome), inflammatory conditions resulting from trauma or ischemia, sarcoidosis; vascular diseases including atherosclerosis, and vascular occlusive diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis; and ophthalmic diseases, such as uveitis, corneal disease, iritis, iridocyclitis, glaucoma, and cataracts.

[0039] All diseases and disorders listed herein may be defined as set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association, or the International Classification of Diseases (ICD), published by the World Health Organization.

[0040] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. As used throughout this description and the claims that follow, the meaning of "a," "an," and "the" includes plural references as well as singular references unless the context clearly indicates otherwise. The term "about" in connection with a numerical value means that the value may vary above or below 5%. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

[0041] Compounds and Salt Forms Disclosed herein is a compound of formula (I): [ka] During the ceremony, X1 and X2 are independently hydrogen or deuterium; Y1 and Y2 are independently hydrogen or deuterium; R2, R4, R5, R6, and R7 are independently hydrogen or deuterium; and R8 and R9 are independently selected from the group consisting of -CH3, -CDH2, -CD2H, - and -CD3, or a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, or prodrug thereof.

[0042] X1 and X2 may be the same or 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 is deuterium and X2 is hydrogen.

[0043] Y1 and Y2 may be the same or 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 is deuterium and Y2 is hydrogen.

[0044] In some embodiments, X1, X2, Y1, and Y2 are hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium.

[0045] In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen.

[0046] In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen.

[0047] In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen.

[0048] In some embodiments, R6 is deuterium. In some embodiments, R6 is hydrogen.

[0049] In some embodiments, R7 is deuterium. In some embodiments, R7 is hydrogen.

[0050] 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.

[0051] 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 methyl (-CH3). In some embodiments, R8 and R9 are partially deuterated methyl groups, i.e., -CDH2 or -CD2H. In some embodiments, R8 and R9 are fully deuterated methyl groups (-CD3).

[0052] In some embodiments, at least one of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R8, and R9 comprises deuterium. In some embodiments, at least X1, X2, R8, and R9 comprise deuterium. In some embodiments, at least X1, X2, Y1, Y2, R8, and R9 comprise deuterium. In some embodiments, X1, X2, Y1, and Y2 are deuterium, and R8 and R9 are fully deuterated methyl groups (-CD3).

[0053] Without being bound by any particular theory, it is believed that compounds described herein having site-specific deuteration, as well as outer ring moieties, maintain preferential agonism of the serotonin 5-HT2 receptor, have improved exposure (e.g., preventing high drug concentrations (spikes) observed immediately after administration), and have advantageous enzymatic degradation profiles for improved bioavailability and brain penetration. Compared with compounds susceptible to MAO-mediated deamination / oxidation processes, e.g., to indole acetic acid (IAA) metabolites, compounds of formula (I) containing deuterium substitutions, for example, can advantageously delay enzymatic degradation, thereby improving bioavailability and simultaneously enhancing brain levels of the active compound, effectively reducing therapeutic doses and preventing high drug concentrations ("spikes") observed acutely after administration. As a result, such compounds may be effective in preventing the 5-HT2 receptor associated with valvular heart disease. 2B This may result in reduced side effects and toxicity, including toxicity caused by receptor activation.

[0054] The compound of formula (I) may contain a stereocenter. In such cases, although formula (I) is drawn without regard to stereochemistry, the compound may exist as different stereoisomers. Accordingly, the present disclosure encompasses all possible stereoisomers, including not only racemates but also individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and non-racemic mixtures thereof. When compounds are desired as single enantiomers, they may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods, as known in the art. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method known in the art.

[0055] In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are non-stereocentric. In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are racemic. In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are enantiomerically enriched (one enantiomer is present in a higher proportion), including enantiomerically pure. In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are provided as a single diastereomer. In some embodiments, the compounds described herein, e.g., compounds of Formula (I), are provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixture can include an equal mixture or a mixture enriched in a particular diastereomer (one diastereomer is present in a higher percentage than another).

[0056] In some embodiments, the compounds of Formula (I) are agonists of the serotonin 5-HT2 receptor.

[0057] In some embodiments, the compound of Formula (I) is a serotonin 5-HT 2A It is an agonist of the receptor.

[0058] In some embodiments, the compound of formula (I) is [ka] [ka] is selected from the group consisting of:

[0059] A list of compound numbers, IUPAC names, and substituents for the compounds identified above is provided in Table 1. [Table 1]

[0060] Acids for use in preparing the pharmaceutically acceptable (acid addition) salts disclosed herein 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-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-3-sulfonic acid, naphthalene-4-sulfonic acid, naphthalene-5-sulfonic acid, naphthalene-6-sulfonic acid, naphthalene-7-sulfonic acid, naphthalene-8-sulfonic acid, naphthalene-9-sulfonic acid, naphthalene-10 ... benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, Cholic 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, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (e.g. For example, they include, but are not limited to, DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid, thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexanedio) 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.).

[0061] Certain salts are preferred among the above list because they have physical and pharmaceutical characteristics / properties that make them suitable for pharmaceutical preparation and administration. For example, preferred salt forms of the compounds disclosed herein (e.g., compounds of Formula (I)) 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 well-defined physical properties such as crystallinity, lack of polymorphism, and high enthalpy of fusion; they are slightly or not hygroscopic; they are free-flowing, do not aggregate / adhere to surfaces, and have a regular morphology; they have acceptable water solubility for the intended route of administration; and / or they are physiologically acceptable, particularly for pulmonary administration, e.g., do not cause irritation when administered to the lungs.

[0062] Crystallinity A pharmaceutically acceptable salt of a compound of Formula (I) may be crystalline or amorphous, for example, as determined by X-ray powder diffraction (XRPD), and is preferably crystalline. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is amorphous. Amorphous forms typically have higher water solubility and dissolution rates than their crystalline counterparts and may therefore be suitable for fast-acting dosage forms adapted to rapidly release the active ingredient, such as orodispersible dosage forms and immediate release (IR) dosage forms. A pharmaceutically acceptable salt of a compound of Formula (I) may be in a stable amorphous form. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is provided in an amorphous form, for example, as determined by XRPD and / or DSC. Thus, pharmaceutical compositions may be prepared from one or more amorphous forms of a pharmaceutically acceptable salt of a compound of Formula (I) and used in the treatments described herein. In some embodiments, a highly pure amorphous form of a pharmaceutically acceptable salt of a compound of Formula (I) is provided. For example, the pharmaceutical composition may comprise a pharmaceutically acceptable salt of the compound of Formula (I), wherein at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of Formula (I) present in the pharmaceutical composition is in amorphous form as determined, for example, by X-ray powder diffraction and / or DSC.

[0063] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is crystalline. Crystalline forms provide well-defined physical properties that are advantageous, for example, in terms of stability and are desirable for pharmaceutical preparation and administration. The pharmaceutically acceptable salt of the compound of Formula (I) can be in a stable crystalline form. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) 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 highly pure crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I) is provided. For example, the pharmaceutical composition may comprise a pharmaceutically acceptable salt of the compound of Formula (I), wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of Formula (I) present in the pharmaceutical composition is in crystalline form, e.g., as determined by X-ray powder diffraction and / or DSC. Salt forms having a high degree of crystallinity, e.g., as determined by discrete, sharp Bragg diffraction in an X-ray diffractogram, are preferred.

[0064] XRPD analysis can be performed, for example, on a Bruker D5000 X-ray powder diffractometer using CuKα radiation (wavelength = 1.54060 Å). The instrument may be equipped with a fine-focus X-ray tube. The tube voltage and amperage can be set to 40 kV and 30 mA, respectively. The divergence and scattering slit widths can be set to 2 mm, and the detector slit width can be set to 0.2 mm. Diffracted radiation can be detected by a NaI scintillation detector. A theta-2-theta continuous scan from 2.0 to 40° (4 s / step, 0.01° step size) can be used.

[0065] With respect to pharmaceutical production processes, advantageous salt forms of the compound of formula (I) are those that readily crystallize to give crystalline solids in acceptable yields without oil and with favorable volume factors suitable for large scale production.

[0066] While salt forms of the compound of Formula (I) can exist in different polymorphic forms (i.e., forms with different crystalline structures), preferred salt forms of the present disclosure are those that can crystallize into a single crystalline form or a single polymorphic form as determined by XRPD and / or differential scanning calorimetry (DSC). It is also generally desirable for the salt to be free-flowing, not aggregate / adhere to surfaces, and have an ordered morphology.

[0067] Chemical / Solid State Stability In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has an onset melting temperature of from about 100°C, from about 110°C, from about 120°C, from about 130°C, from about 140°C, from about 150°C, from about 160°C, from about 170°C, from about 180°C, from about 190°C, and up to about 250°C, up to about 225°C, up to about 210°C, or up to about 200°C, as determined by DSC.

[0068] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has a molecular weight of about 90 J·g as determined by DSC. -1 From this, it is approximately 100 J·g -1 Approximately 110 J·g -1 Approximately 120 J·g -1 Approximately 130 J·g -1 Approximately 140 J·g -1 Approximately 150 J·g -1 Approximately 160 J·g -1 up to approximately 190 J·g -1 , maximum approximately 180J·g -1 , maximum approximately 170J·g -1 It has a melting enthalpy of

[0069] Pharmaceutically acceptable salts of compounds of formula (I) suitable for pharmaceutical manufacture may be characterized as non-hygroscopic or slightly hygroscopic, preferably non-hygroscopic. Hygroscopicity, as used herein, can be measured using a dynamic vapor sorption (DVS) analyzer by performing a moisture sorption / desorption isotherm in which the exposure starts at 30% relative humidity (RH), the humidity is increased up to 95% RH, the humidity is decreased to 0% RH, and finally the humidity is increased back to the starting 30% RH, and is classified according to the following: Non-hygroscopic: <0.2%; slightly hygroscopic: ≥0.2% and <2%; hygroscopic: ≥2% and <15%; very hygroscopic: ≥15%; deliquescent: sufficient water is absorbed to form a liquid; all values ​​are measured as weight gain (w / w due to water gain) at >95% RH and 25°C.

[0070] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) has a weight gain at >95% RH 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, or less than 0.02% w / w as determined by DVS.

[0071] Dry powder samples of the pharmaceutically acceptable salts of the present disclosure can be maintained / stored in an open or closed environment, such as in an open or closed flask / vial, without significant degradation (e.g., without significant loss of chemical purity) or physical change (e.g., change in morphology, deliquescence, etc.) under ambient or stress conditions, e.g., 25°C / 60% RH, 25°C / 90+% RH, 40°C / 75% RH, etc. For example, dry powder samples of the salt forms disclosed herein can have less than 10%, less than 5%, and less than 1% change in purity or morphology when stored under ambient or stress conditions (e.g., elevated temperature, e.g., 40°C, and / or humidity).

[0072] Solution-phase compositions (e.g., liquid dosage forms) of pharmaceutically acceptable salts of the present disclosure can be maintained / stored in open or closed environments, such as open or closed flasks / vials, under ambient or stress conditions, e.g., 25°C / 90+% RH, 40°C / 75% RH, etc., without significant degradation. Thus, in some embodiments, the present disclosure provides stable solution-phase compositions (e.g., liquid dosage forms) of pharmaceutically acceptable salts of a compound of Formula (I) (e.g., stable solvates of a salt form of a compound of Formula (I) in a solvated form, preferably a fully solvated form) that can be stored for extended periods of time as a solution, such as in the form of an aqueous solution, an organic solvent solution, or an aqueous / organic solvent mixture, without significant degradation or physical changes, such as oiling of the solution. The solvent that can be used to form the solution-phase composition may be any one or more of the solvents described herein, such as water, ethanol, fruit juice, etc. In some embodiments, the solution-phase composition is an aqueous solution-phase composition comprising a pharmaceutically acceptable salt of a compound of Formula (I) solvated with water (and optionally other ingredients, such as those found in fruit juice). The identification of a stable solution-phase composition is advantageous, at least in part, because such compositions do not need to be used immediately after preparation, e.g., within 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, 45 seconds, 30 seconds, 15 seconds, or 10 seconds after preparation. Instead, stable solution-phase compositions (e.g., liquid dosage forms) of a pharmaceutically acceptable salt of a compound of Formula (I) described herein can be prepared in advance, if desired, and optionally stored, and can be administered within hours, days, or even weeks after preparation without substantially affecting efficacy, e.g., without significant degradation of the dimethyltryptamine-type active agent.

[0073] In some embodiments, aqueous solutions formed from pharmaceutically acceptable salts of the compound of Formula (I) are characterized by increased stability compared to aqueous solutions prepared from the compound of Formula (I) (free base) but otherwise substantially the same. For example, the pharmaceutically acceptable salts of the compound of Formula (I) may be 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%, at least 70% or more stable in terms of chemical purity (% remaining activity) in aqueous solutions exposed to 40°C for 24 hours, 48 ​​hours, 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, or more compared to aqueous solutions prepared using the compound of Formula (I) (free base), but otherwise substantially the same. Such improved stability behavior can also be found in pharmaceutical compositions of the present disclosure.

[0074] Physiological acceptability Suitable salt forms of the compound of formula (I) are physiologically acceptable. In particular, when formulated for pulmonary administration, lung irritation can lead to coughing after inhalation, which is known to reduce the delivered dose and thus adversely affect patient compliance and therapeutic efficacy. Therefore, suitable salt forms are those that do not cause excessive irritation. For this reason, preferred addition salts of the compound of formula (I) are formed from organic acids, preferably organic acids with mild acidity, for example, pK in water of 1.0 or more, 1.5 or more, 2.0 or more, 2.5 or more, 3.0 or more, 3.5 or more, 4.0 or more, 4.5 or more, for example, 3.0 to 6.5. a Furthermore, depending, for example, on the route of administration and the optional use of taste-masking agents such as sweeteners, flavorings, etc., it may be desirable to use acid addition salts that impart a pleasant taste profile (e.g., sweet, citrusy, etc.), while unpleasant-tasting salt forms (e.g., bitter, astringent, etc.) may still be acceptable.

[0075] solubility The water solubility of the compound of formula (I) and its salts can be determined by equilibrating an excess of the solid with 1 mL of water at 22°C for 24 hours. A 200 uL aliquot can be centrifuged at 15,000 rpm for 15 minutes. The supernatant can be analyzed by HPLC, and the solubility can be expressed as its free base equivalent (mg FB / mL). For example, a pharmaceutically acceptable salt of the compound of formula (I) can be prepared, and the solubility and pH of the solution can be measured.

[0076] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has a water solubility of from about 5 mg / mL to about 400 mg / mL at 22° C. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has a water solubility of from about 1 mg / mL, from about 2 mg / mL, from about 3 mg / mL, from about 5 mg / mL, from about 10 mg / mL, from about 20 mg / mL, from about 30 mg / mL, from about 40 mg / mL, from about 50 mg / mL, from about 60 mg / mL, from about 70 mg / mL, from about 80 mg / mL, from about 90 mg / mL, from about 100 mg / mL. The salt of the compound of Formula (I) has a water solubility of about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, and up to about 400 mg / mL, up to about 380 mg / mL, up to about 360 mg / mL, up to about 340 mg / mL, up to about 320 mg / mL, up to about 300 mg / mL, up to about 280 mg / mL, up to about 260 mg / mL, or up to about 250 mg / mL. In some embodiments, the salt of the compound of Formula (I) has a water solubility of about 200 mg / mL to about 400 mg / mL. In some embodiments, the salt of the compound of Formula (I) has a water solubility of about 150 mg / mL to about 250 mg / mL. In some embodiments, the salt of the compound of Formula (I) has a water solubility of 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.

[0077] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of the compound of Formula (I). In terms of providing desirable physical and pharmaceutical characteristics such as those described above, preferred pharmaceutically acceptable salts are the fumarate, benzoate, salicylate, and succinate salts of the compounds disclosed herein, for example, compounds of Formula (I) including fumarate, benzoate, and salicylate salts.

[0078] Exemplary pharmaceutically acceptable salt forms (ie, addition salt forms) of the above-identified compounds are provided in Table 2. [Table 2]

[0079] In some embodiments, the pharmaceutically acceptable salt is the fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1a) (i.e., the fumarate salt of compound I-1 shown below). In some embodiments, salt I-1a is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in Figures 3 and 6. [ka]

[0080] In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1b) (i.e., the benzoate salt of compound I-1 shown above). In some embodiments, salt I-1b is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in Figures 4 and 7.

[0081] In some embodiments, the pharmaceutically acceptable salt is the salicylate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1c) (i.e., the salicylate salt of compound I-1 shown above). In some embodiments, salt I-1c is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in Figures 4 and 8.

[0082] In some embodiments, the pharmaceutically acceptable salt is the succinate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1d) (i.e., the succinate salt of compound I-1 shown above). In some embodiments, salt I-1d is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 5 .

[0083] In some embodiments, the pharmaceutically acceptable salt is the oxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1e) (i.e., the oxalate salt of compound I-1 shown above). In some embodiments, salt I-1e is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 5 .

[0084] In some embodiments, the pharmaceutically acceptable salt is the glycolate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1f) (i.e., the glycolate salt of compound I-1 shown above). In some embodiments, salt I-1f is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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°, as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 3 .

[0085] In some embodiments, the pharmaceutically acceptable salt is the hemioxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1g) (i.e., the hemioxalate salt of compound I-1 shown above). In some embodiments, salt I-1g has peaks of 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°, 23.5°, 24.0°, 25.0°, 26.0°, 27.0°, 28.0°, 29.0°, 30.0°, 31.0°, 32.0°, 33.0°, 34.0°, 35.0°, 36.0°, 37.0°, 38.0°, 39.0°, 40.0°, 41.0°, 42.0°, 43.0°, 44.0°, 45.0°, 46.0°, 47.0°, 48.0°, 49.0°, 50.0°, 51.0°, 52.0°, 53.0°, 54.0°, 55.0°, 56.0°, 57.0°, 58.0°, 59.0°, 60.0°, 61.0°, 62.0°, 63.0°, 64.0°, 65.0°, 66.0°, 67.0°, A crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 4.5°, 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°.

[0086] In some embodiments, the pharmaceutically acceptable salt is the hemifumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1h) (i.e., the hemifumarate salt of compound I-1 shown above). In some embodiments, salt I-1h has a peak intensity of 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°, 22.3°, 23.0°, 24.0°, 25.0°, 26.0°, 27.0°, 28.0°, 29.0°, 30.0°, 31.0°, 32.0°, 33.0°, 34.0°, 35.0°, 36.0°, 37.0°, 38.0°, 39.0°, 40.0°, 41.0°, 42.0°, 43.0°, 44.0°, 45.0°, 46.0°, 47.0°, 48.0°, 49.0°, 50.0°, 51.0°, 52.0°, 53.0°, 54.0°, 55.0°, 56.0°, 57.0°, 58.0°, 59.0°, 60.0°, 61.0°, 62.0°, 63.0°, 64.0°, 65.0°, 66.0°, A crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 2.7°, 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°.

[0087] In some embodiments, the pharmaceutically acceptable salt is the fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8a) (i.e., the fumarate salt of compound I-8 shown below). In some embodiments, salt I-8a has the following peaks: 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°, 26.2°, as determined by XRPD using a CuKα radiation source, e.g., as shown in FIG. 6 . and 38.5°. In some embodiments, salt I-8a is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 6 . In some embodiments, salt I-8a is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 6 . [ka]

[0088] In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8b) (i.e., the benzoate salt of compound I-8 shown above). In some embodiments, salt I-8b is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 7 . In some embodiments, salt I-8b is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 7 . In some embodiments, salt I-8b is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 7.

[0089] In some embodiments, the pharmaceutically acceptable salt is the salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8c) (i.e., the salicylate salt of compound I-8 shown above). In some embodiments, salt I-8c has a molar average of 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°, 25.2°, 26.2°, 27.2°, 28.2°, 29.2°, 30.2°, 31.2°, 32.2°, 33.2°, 34.2°, 35.2°, 36.2°, 37.2°, 38.2°, 39.2°, 40.2°, 41.2°, 42.2°, 43.2°, 44.2°, 45.2°, 46.2°, 47.2°, 48.2°, 49.2°, 50.2°, 51.2°, 52.2°, 53.2°, 54.2°, 55.2°, 56.2°, 57.2°, 58.2°, 59.2°, 60.2°, 61.2°, 62.2 and 35.0°. In some embodiments, salt I-8c is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 8 . In some embodiments, salt I-8c is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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, e.g., as shown in FIG. 8.

[0090] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc., with hydrates and ethanolates being preferred. Solvates can be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. In one non-limiting example, as a hydrate, the pharmaceutically acceptable salts described herein may be monohydrates, dihydrates, etc.

[0091] Also disclosed herein is a method for stabilizing a compound of formula (I), comprising preparing a pharmaceutically acceptable salt of a compound of formula (I).

[0092] Also disclosed herein are methods for preparing pharmaceutically acceptable salts of compounds of formula (I). Various methods and procedures for addition salt formation are known to those skilled in the art, any of which may be utilized in the present disclosure. In some embodiments, the method comprises: (a) suspending the free base of the compound of formula (I) in a solvent or mixture of solvents; (b) contacting an acid with a compound of formula (I) to provide a mixture; (c) optionally heating the mixture; (d) optionally cooling the mixture; and (e) isolating the salt.

[0093] The disclosed methods can use a variety of solvents, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent used in the method for preparing the salt is a protic solvent. In some embodiments, the solvent used in the method for preparing the salt 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.

[0094] Suitable acids for use in preparing pharmaceutically acceptable acid addition salts may include those previously described. The acid may be an inorganic 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.

[0095] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with the compound of Formula (I). In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with the compound of Formula (I). For example, when the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt, using a substoichiometric amount of acid may be desirable.

[0096] In some embodiments, the mixture is heated, for example, to reflux, before cooling.

[0097] In some embodiments, the mixture is cooled, causing the salt to precipitate from solution. In some embodiments, the salt precipitates from solution in a crystalline form. In some embodiments, the salt precipitates from solution in an amorphous form.

[0098] Isolation of the salt can be accomplished by a variety of well-known isolation techniques, such as filtration, decantation, etc. In some embodiments, the isolation step comprises filtering the mixture.

[0099] After isolation, additional crystallization and / or recrystallization steps may also be optionally performed, if desired, to, for example, increase purity, crystallinity, etc.

[0100] Therapeutic Uses and Methods Also disclosed is a method of treating a subject having a disease or disorder, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (I).

[0101] The dose and frequency (single or multiple doses) of the compound salt administered can vary depending on a variety of factors, including, but not limited to, the salt form / compound administered; the disease / condition being treated; the route of administration; the subject's body size, age, sex, health, weight, body mass index, and diet; the nature and extent of the symptoms of the disease being treated; the presence of other diseases or other health problems; the type of concomitant therapy; and complications from any disease or treatment regimen. Other treatment regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

[0102] Therapeutically effective amounts for use in humans can be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. A dose for humans can be adjusted by monitoring the response to treatment and adjusting the dose upward or downward.

[0103] Dosage can vary depending on the requirements of the patient and the compound or its salt form used.In the context of the pharmaceutical compositions provided herein, the dosage administered to the patient should be sufficient to bring about beneficial therapeutic responses in the patient over time.The size of the dosage will also be determined by the existence, nature and degree of adverse side effects.Generally, treatment is initiated with a smaller dosage that is less than the optimal dosage of the compound.Then, the dosage is increased by small increments until the optimal effect under the circumstances is reached.

[0104] Dosage amount and interval can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, thereby providing a treatment regimen commensurate with the severity of the individual's disease state.

[0105] Routes of administration can include oral routes (e.g., enteral / gastric delivery, buccal administration, e.g., buccal, lingual, and sublingual routes), parenteral routes (e.g., intravenous, intradermal, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration), topical routes (e.g., conjunctival, intracorneal, intraocular, ocular, auricular, transdermal, nasal (e.g., intranasal), vaginal, urethral, ​​respiratory, and rectal administration), inhalation, or others sufficient to affect a beneficial therapeutic response.

[0106] Administration may follow a continuous or intermittent dosing schedule. The dosing schedule may vary depending on the salt form and compound used, the condition being treated, the route of administration, etc. For example, administration may be performed once daily (QD), or in divided doses throughout the day, such as twice daily (BID), three times daily (TID), four times daily (QID), or more. In some embodiments, administration may be performed every night (QHS). In some embodiments, the compound / pharmaceutical composition may be administered as needed (PRN). Administration may also be performed on a weekly basis, such as once weekly, twice weekly, three times weekly, four times weekly, every other week, every two weeks, or less frequently. The dosing schedule may also specify a defined number of treatments per treatment course, such as 1, 2, 3, 4, 5, 6, 7, or 8 treatments per treatment course. Sound medical judgment may be used to determine other dosing schedules as appropriate.

[0107] Administration can be continuous (administration 7 days per week) or intermittent, depending on, for example, pharmacokinetics and clearance / accumulation of the drug in a particular subject. If intermittent, the schedule can be, for example, 4 days of administration and 3 days of rest (rest days) per week, or any other intermittent administration schedule deemed appropriate based on sound medical judgment. For example, intermittent administration can involve the administration of a single dose within a treatment course. Continuous or intermittent administration continues for a particular treatment course, typically at least a 28-day cycle (1 month), which can be repeated with or without a rest period. Longer or shorter courses, such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 ​​days, or more, or any range therebetween, can also be used. The course can be repeated without or with a rest period, depending on the subject. Other schedules are possible depending on the presence or absence of adverse events, response to treatment, patient convenience, etc.

[0108] Utilizing the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that does not cause substantial toxic or adverse side effects (e.g., caused by sedative or psychotomimetic toxic spikes in plasma concentrations of any of the compounds of Formula (I)) and is fully effective in treating the clinical symptoms exhibited by a particular patient. This design should involve careful selection of active compounds and salt forms by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.

[0109] A therapeutically effective amount of a salt form of a compound disclosed herein can vary depending on the various factors described above, but typically, a compound of formula (I) is administered in an amount ranging from about 0.00001 mg to about 10 mg per kilogram of recipient body weight per day, or any range therebetween, e.g., about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg , about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg of the compound of formula (I) (active).

[0110] Pharmaceutically acceptable salts of the compounds of the present disclosure may be administered in hallucinogenic doses. Oral or otherwise hallucinogenic doses, in some embodiments, can range from about 0.083 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, about 0.45 mg / kg, about 0.5 mg / kg, up to about 5 mg / kg, about 4 mg / kg, about 3 mg / kg, about 2 mg / kg, about 1 mg / kg, about 0.95 mg / kg, about 0.9 mg / kg, about 0.85 mg / kg, about 0.8 mg / kg, about 0.75 mg / kg, about 0.7 mg / kg, about 0.65 mg / kg, about 0.6 mg / kg, about 0.55 mg / kg of a compound of Formula (I) (based on the active form). As noted above, higher doses may be used in some embodiments. In some embodiments, the hallucinogenic dose is administered once and may be repeated at intervals of at least one week. In some cases, no more than five doses are administered in any one treatment course. The course may be repeated as needed, with or without a drug-free period. Such acute treatment regimens may involve psychotherapy before, during, and / or after administration of the hallucinogenic dose. These treatments are appropriate for the various mental health disorders disclosed herein, including, but not limited to, major depressive disorder (MDD), treatment-resistant depression (TRD), anxiety disorders, and substance use disorders (e.g., alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, tobacco use disorder, and cocaine use disorder).

[0111] Administration of subpsychoactive (but potentially still serotonergic) concentrations may be performed in some embodiments to achieve sustained therapeutic benefit with reduced toxicity and may therefore be suitable for microdosing. Oral or other hallucinogen-free doses, in some embodiments, can range from about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, or about 0.01 mg / kg to less than about 0.083 mg / kg, about 0.08 mg / kg, about 0.075 mg / kg, about 0.07 mg / kg, about 0.06 mg / kg, about 0.05 mg / kg, about 0.04 mg / kg, about 0.03 mg / kg, or about 0.02 mg / kg of a compound of Formula (I) (based on the active form). Typically, a hallucinogen-free dose is administered up to daily for a course of treatment (e.g., one month). However, there is no limit to the number of doses administered at non-hallucinogenic doses, and administration may be less frequent or more frequent if deemed appropriate. The course may be repeated as necessary, with or without a drug holiday.

[0112] Hallucinogen-free doses may be administered, for example, via modified, controlled, sustained, or extended release dosage forms, including, but not limited to, depot dosage forms, implants, patches, and pumps, which may optionally be remotely controlled, by transdermal delivery, subcutaneous administration, orally, etc., where the dose achieves blood levels similar to low oral doses, yet will not produce hallucinations.

[0113] Hallucinogenic-free doses can be used, for example, for the chronic treatment or maintenance of various diseases or disorders disclosed herein, including, but not limited to, depression (e.g., MDD), inflammation, pain, and neuroinflammation.

[0114] Pharmaceutically acceptable salts of the compounds of the present disclosure can be used in maintenance regimens. As used herein, "maintenance regimen" generally refers to the administration of a pharmaceutically acceptable salt of a compound of the present disclosure after the target dose is reached, for example, after the completion of a titration regimen, and / or after a good clinical response, such as an improvement in the patient's condition, for example, to either the same drug or a different drug. In some embodiments, a patient is administered a first drug for a treatment regimen and a second drug for a maintenance regimen, where the first and second drugs are different. For example, a patient is administered a treatment regimen in which the first drug is not a dimethyltryptamine-type compound (for example, the first drug is a serotonergic hallucinogenic drug, such as LSD, psilocybin, MDMA, or a non-hallucinogenic drug), and then in the maintenance regimen, a salt form of a compound of the present disclosure (as the second drug) is administered. In another example, a treatment regimen (first drug) uses a salt form of the present disclosure that is different from that of the maintenance regimen (second drug). In some embodiments, patients are administered the same salt form of the present disclosure for both the treatment regimen and the maintenance regimen. In either case, the maintenance dose can be used to "maintain" the therapeutic response and / or prevent relapse. When the same salt form of the present disclosure is used for both the original treatment regimen and the maintenance regimen, the maintenance dose can be sub-therapeutic. In some embodiments, the maintenance dose is a hallucinogenic dose. In some embodiments, the maintenance dose is a non-hallucinogenic dose. Generally, administration is performed daily or intermittently for the maintenance regimen, but the maintenance regimen can also be performed continuously, for example, over days, weeks, months, or years. Furthermore, the maintenance dose can be administered to patients for an extended period of time, even chronically.

[0115] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is administered intravenously to a subject as a single bolus dose within the above-described dose ranges, e.g., about 0.1 mg / kg to about 0.8 mg / kg, or about 0.2 mg / kg to about 0.5 mg / kg, or about 0.3 mg / kg. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is administered intravenously to a subject as a perfusion dose within the above-described dose ranges, e.g., about 0.1 mg / kg to about 0.8 mg / kg, or about 0.2 mg / kg to about 0.5 mg / kg, or about 0.45 mg / kg. The perfusion may be administered over a duration of, for example, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours. A pharmaceutically acceptable salt of a compound of Formula (I) may be administered via infusion at a rate of about 0.1 mg / min, 0.2 mg / min, 0.3 mg / min, 0.4 mg / min, 0.5 mg / min, 0.6 mg / min, 0.7 mg / min, 0.8 mg / min, 0.9 mg / min, 1 mg / min, 1.5 mg / min, 2 mg / min, 2.5 mg / min, 3 mg / min, 3.5 mg / min, 4 mg / min, 4.5 mg / min, 5 mg / min, or as deemed appropriate by a medical professional. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is administered intravenously to a subject as a bolus within the above-mentioned dosage range, e.g., about 0.1 mg / kg to about 0.8 mg / kg, or about 0.2 mg / kg to about 0.5 mg / kg, or about 0.3 mg / kg, followed by a perfusion within the above-mentioned dosage range, e.g., about 0.1 mg / kg to about 0.8 mg / kg, or about 0.2 mg / kg to about 0.5 mg / kg, or about 0.45 mg / kg.

[0116] The subject to be treated herein may have a disease or disorder associated with the serotonin 5-HT2 receptor.

[0117] In some embodiments, the disease or disorder is a neuropsychiatric disease or disorder, or an inflammatory disease or disorder.

[0118] In some embodiments, the disease or disorder is, for example, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders (including, but not limited to, bipolar I disorder, bipolar II disorder, and cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinatory crisis, social anxiety disorder, substance use disorder (including, but not limited to, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder). and / or central nervous system (CNS) disorders and / or psychological disorders, including, but not limited to, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, chronic fatigue syndrome, Lyme disease, gambling disorder, eating disorders (including, but not limited to, anorexia nervosa, bulimia nervosa, binge eating disorder, etc.), and paraphilic disorders (including, but not limited to, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, and cross-dressing disorder, etc.), sexual dysfunction (e.g., decreased libido), and obesity.

[0119] In some embodiments, the methods provided herein are used to treat subjects with depressive disorders. As used herein, the term "depressive disorder" or "depression" refers to a group of disorders characterized by a persistent low mood that can affect a person's thoughts, behavior, emotions, and sense of well-being over a period of time. In some embodiments, depressive disorders disrupt a person's physical and mental function. In some embodiments, depressive disorders cause physical symptoms such as weight loss, aches and pains, headaches, cramps, or indigestion. In some embodiments, depressive disorders cause mental symptoms such as persistent sadness, hopelessness and irritability, guilt, lethargy or helplessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, difficulty remembering, or difficulty making decisions. In some embodiments, the depressive disorder is major depressive disorder (MDD), atypical depression, bipolar disorder, catatonic depression, depressive disorder due to physical illness, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, or treatment-resistant depression (TRD).

[0120] In some embodiments, the disease or disorder is major depressive disorder (MDD). As used herein, the term "major depressive disorder" refers to a condition characterized by periods of depressed mood present in most situations. Major depressive disorder is often accompanied by low self-esteem, loss of interest in usually enjoyable activities, low energy, and pain without a clear cause. In some cases, the definition of major depression is characterized by depressive symptoms lasting at least two weeks. In some cases, individuals experience periods of depression several years apart. In some cases, individuals experience depressive symptoms nearly constantly. Major depressive disorder can adversely affect an individual's personal, work, or school life, as well as sleep, eating habits, and general health. Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of adults who commit suicide had major depressive disorder or another related mood disorder. Dysthymia is a subtype of major depressive disorder that consists of the same cognitive and physical problems as major depressive disorder, but the symptoms are less severe but last longer. Examples of symptoms of major depressive disorder include, but are not limited to, feelings of sadness, fear, emptiness, or hopelessness, angry outbursts, minor irritability or frustration, loss of interest or pleasure in most or all usual activities, sleep disturbances including insomnia or hypersomnia, fatigue or lack of energy, loss of appetite, weight loss or gain, anxiety, agitation or restlessness, diminished ability to think, speak, or move, feelings of lethargy or guilt, fixation on past failures or self-blame, disturbed thinking, concentration, decision-making, and memory, frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide, and unexplained physical problems such as back pain or headaches.

[0121] As used herein, the term "atypical depression" refers to a condition in which an individual exhibits a long-term pattern of signs of mood reactivity (i.e., mood brightening in response to actual or potentially positive events), significant weight gain, increased appetite, hypersomnia, a feeling of heaviness and sluggishness in the arms or legs, and / or sensitivity to interpersonal rejection that results in significant social or occupational harm. Exemplary symptoms of atypical depression include, but are not limited to, daily feelings of sadness or depression, loss of pleasure in previously enjoyable activities, significant changes (gain or loss) in weight or appetite, near-daily insomnia or hypersomnia, noticeable physical restlessness or exhaustion, daily fatigue or low energy, near-daily feelings of hopelessness, helplessness or excessive guilt, near-daily problems concentrating or making decisions, recurring thoughts of death or suicide, suicide attempts, or attempted suicide.

[0122] As used herein, the term "bipolar disorder" refers to a condition in which an individual experiences unusual changes in mood, energy, activity level, and ability to perform daily tasks. Individuals with bipolar disorder experience periods of abnormal agitation, changes in sleep patterns and activity levels, and abnormal behavior. These distinct periods are called "mood episodes." Mood episodes are significantly different from the person's typical mood and behavior. Examples of symptoms of mania and excessive behavior include, but are not limited to, abnormally cheerful, volatile, or irritable behavior; increased activity, energy, or irritability; exaggerated feelings of happiness and confidence; decreased need for sleep; abnormal talkativeness, racing thoughts, distractibility, and poor decision-making, such as continually spending money, taking sexual risks, or making foolish investments. Examples of depressive episodes or depressed mood symptoms include, but are not limited to, depressed feelings, such as sadness, emptiness, despair, or fear; a significant loss of interest in or a lack of enjoyment in all or nearly all activities; significant weight loss or weight gain, or decreased or increased appetite; insomnia or hypersomnia (excessive sleep or excessive sleepiness); restless or sluggish behavior; fatigue or low energy; feelings of helplessness or excessive or inappropriate guilt; impaired thinking ability or impaired concentration or indecisiveness; and thoughts of suicide or attempted suicide. Bipolar disorders include type I bipolar disorder, type II bipolar disorder, and cyclothymic disorder. Type I bipolar disorder is defined by a manic episode lasting at least 7 days or by severe manic symptoms requiring hospitalization. Subjects with type I bipolar disorder may also experience depressive episodes, which typically last at least 2 weeks. Depressive episodes with mixed characteristics, i.e., simultaneous depressive and manic symptoms, are also possible. Bipolar disorder type 2 is characterized by a pattern of depressive and hypomanic episodes, but not the severe manic episodes typical of bipolar disorder type 1. Cyclothymic disorder (also called cyclothymia) is characterized by periods of hypomanic symptoms (elevated mood and euphoria) and depressive symptoms lasting for at least two years.The mood swings are not sufficient in number, severity, or duration to meet full criteria for a hypomanic or depressive episode.

[0123] As used herein, the term " catatonic depression " refers to the state that individuals are silent and immobile for a long time.The example of catatonic depression symptoms includes but is not limited to: feeling sad every day, losing interest in most activities, sudden weight gain or loss, appetite change, difficulty falling asleep, difficulty getting up, restlessness, irritability, helplessness, guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and / or suicide attempt.

[0124] As used herein, the term "depressive disorder caused by physical illness" refers to the state in which an individual experiences depressive symptoms due to another illness. Examples of physical illnesses that are known to cause depressive disorders include, but are not limited to, HIV / AIDS, diabetes, arthritis, stroke, brain disorders such as Parkinson's disease, Huntington's disease, multiple sclerosis and Alzheimer's disease, metabolic diseases (for example, vitamin B12 deficiency), autoimmune diseases (for example, lupus and rheumatoid arthritis), viral or other infectious diseases (hepatitis, mononucleosis, herpes), back pain, and cancer (for example, pancreatic cancer).

[0125] As used herein, the term "postpartum depression" refers to a condition resulting from childbirth and hormonal changes, psychological adjustment to parenthood, and / or fatigue. Although postpartum depression is often associated with women, men can also suffer from postpartum depression. Examples of symptoms of postpartum depression include, but are not limited to, feelings of sadness, hopelessness, emptiness, or heaviness; crying more frequently than usual or for no apparent reason; worrying or experiencing excessive anxiety; feeling irritable, irritable, or restless; excessive sleepiness or being unable to sleep even when the baby is sleeping; difficulty concentrating, remembering details, or making decisions; experiencing anger or rages; losing interest in normally enjoyable activities; experiencing physical aches and pains, including frequent headaches, stomach problems, and muscle aches; overeating or eating too little; withdrawing from or avoiding friends and family; difficulty forming or forming emotional attachments with the baby; intermittent doubts about one's ability to care for the baby; and thoughts of harming oneself or the baby.

[0126] As used herein, the term "premenstrual dysphoric disorder" refers to a condition in which an individual experiences recurring symptoms of mood instability, irritability, depression, and anxiety during the premenstrual phase of the menstrual cycle, which subside around or shortly thereafter. Examples of symptoms of premenstrual dysphoric disorder include, but are not limited to, instability (e.g., mood swings), irritability or anger, depression, anxiety and tension, decreased interest in usual activities, difficulty concentrating, moodiness and low energy, changes in appetite (e.g., overeating or craving certain foods), excessive or insomnia, a feeling of being overwhelmed or out of control, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, abdominal bloating, and weight gain), self-deprecating thoughts, tension or tingling, decreased interest in usual activities (e.g., work, school, friends, hobbies, etc.), subjective difficulty concentrating, and easy fatigue.

[0127] As used herein, the term "seasonal affective disorder" refers to a condition in which an individual's mood changes based on the time of year. In some cases, individuals experience low mood, low energy, or other depressive symptoms during the fall and / or winter seasons. In some cases, individuals experience low mood, low energy, or other depressive symptoms during the spring and / or summer seasons. Examples of seasonal affective disorder symptoms include, but are not limited to, feeling depressed most of the day or almost every day, losing interest in previously enjoyable activities, low energy, difficulty sleeping, changes in appetite or weight, feelings of lethargy or irritability, difficulty concentrating, feelings of hopelessness, helplessness, or guilt, and frequent thoughts of death or suicide.

[0128] In some embodiments, the depressive disorder comprises a medical diagnosis based on the criteria and classification of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. In some embodiments, the depressive disorder comprises a medical diagnosis based on an independent medical evaluation.

[0129] In some embodiments, the methods described herein are provided to a subject with treatment-resistant depression. In some embodiments, the subject has been diagnosed with treatment-resistant depression (TRD). The term "treatment-resistant depression" refers to a type of depression that does not respond or is resistant to at least one or more treatment attempts of appropriate dosage and duration. In some embodiments, a subject with treatment-resistant depression has not responded to one treatment attempt, two treatment attempts, three treatment attempts, four treatment attempts, five treatment attempts, or more. In some embodiments, a subject with treatment-resistant depression has been diagnosed with major depressive disorder and has not responded to three or more treatment attempts. In some embodiments, a subject with treatment-resistant depression has been diagnosed with bipolar disorder and has not responded to one treatment attempt.

[0130] In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment.

[0131] In some embodiments, the disease or disorder is an anxiety disorder. As used herein, the term "anxiety disorder" refers to a state of worry, uncertainty, and / or fear resulting from the anticipation of an event and / or situation. Anxiety disorders cause physiological and psychological signs or symptoms. Non-limiting examples of physiological symptoms include muscle tension, palpitations, sweating, dizziness, shortness of breath, tachycardia, tremors, fatigue, apprehension, irritability, and sleep disturbances. Non-limiting examples of psychological symptoms include fear of dying, fear of embarrassment or humiliation, fear of an event occurring, etc. Anxiety disorders also impair a subject's cognition, information processing, stress level, and immune response. In some embodiments, the methods disclosed herein treat chronic anxiety disorders. As used herein, "chronic" anxiety disorders are recurrent. Examples of anxiety disorders include, but are not limited to, generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, panic attacks, phobia-related disorders (e.g., phobias related to flying, heights, certain animals such as spiders / dogs / snakes, receiving injections, blood, etc., agoraphobia), separation anxiety disorder, selective mutism, anxiety due to physical illness, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and substance-induced anxiety disorder.

[0132] In some embodiments, a subject in need thereof develops an anxiety disorder after experiencing the effects of a disease. The effects of the disease include the individual being diagnosed with the disease, the individual's loved ones being diagnosed with the disease, social isolation due to the disease, isolation from the disease, or social distancing as a result of the disease. In some embodiments, the individual is quarantined to prevent the spread of the disease. In some embodiments, the disease is COVID-19, SARS, or MERS. In some embodiments, the subject develops an anxiety disorder after losing their job, losing their home, or fearing not being able to find work.

[0133] In some embodiments, the disease or disorder is generalized anxiety disorder (GAD). Generalized anxiety disorder is characterized by excessive anxiety and worry, fatigue, restlessness, increased muscle pain or soreness, poor concentration, irritability, and / or difficulty sleeping. In some embodiments, a subject with generalized anxiety disorder does not have associated panic attacks. In some embodiments, the methods herein are provided to a subject with generalized anxiety disorder who also has symptoms of depression. In some embodiments, after treatment, symptoms are reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before treatment.

[0134] In some embodiments, the disease or disorder is social anxiety disorder. As used herein, "social anxiety disorder" refers to a significant fear or anxiety about one or more social situations in which an individual is exposed to potential scrutiny by others. Non-limiting examples of situations that induce social anxiety include social interactions (e.g., conversations, meeting unfamiliar people, etc.), being observed (e.g., eating and drinking), and performing in front of others (e.g., giving a speech). In some embodiments, the social anxiety disorder is limited to speaking or performing in public. In some embodiments, treatment according to the methods of the present disclosure reduces or improves the symptoms of social anxiety disorder. In some embodiments, after treatment, symptoms are reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before treatment.

[0135] In some embodiments, the disease or disorder is an obsessive-compulsive disorder, such as obsessive-compulsive disorder (OCD), body-focused repetitive behavior disorder, hoarding disorder, gambling disorder, compulsive shopping, compulsive internet use, compulsive video gaming, compulsive sexual behavior, bulimia, exercise addiction, body dysmorphic disorder, hoarding disorder, self-injurious dermatopathy, trichotillomania, excoriation, substance-induced obsessive-compulsive disorder and related disorders, or obsessive-compulsive disorder caused by another physical illness, or a combination thereof. In some embodiments, the disease or disorder is obsessive-compulsive disorder (OCD).

[0136] In some embodiments, at least one sign or symptom of an anxiety disorder improves after a treatment disclosed herein, hi some embodiments, the sign or symptom of an anxiety disorder is measured according to a diary assessment, a physician or caregiver assessment, or a clinical scale. In some embodiments, treatment results in a measurable improvement in one or more of the following: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scale (HADS), Generalized Anxiety Disorder questionnaire-IV (GADQ-IV), Hamilton Anxiety Rating Scale (HARS), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire 4 (PHQ-4), Social Phobia Inventory (SPIN), Brief Trauma Questionnaire (BTQ), Combat Exposure Scale (CES), Mississippi Scale for Combat-Related PTSD (M-PTSD), Posttraumatic Maladaptive Beliefs Scale(PMBS), Perceived Threat Scale(DRRI-2 Section:G), PTSD Symptom Scale-Interview for DSM-5(PSS-I-5), Structured Interview for PTSD(SI- PTSD), Davidson Trauma Scale(DTS), Impact of Event Scale-Revised(IES-R), Posttraumatic Diagnostic Scale(PDS-5), Potential Stressful Events Interview(PSEI), Stressful LifeEvents Screening Questionnaire(SLESQ)、Spielberger’s Trait and Anxiety、Generalized Anxiety Dis- order 7-Item Scale、The Psychiatric Institute Trichotillomania Scale(PITS)、ThemgH Hairpulling Scale(MGH-HPS)、The NIMH Trichotillomania Severity Scale(NIMH-TSS)、The NIMH Trichotillomania Impairment Scale(NIMH- TIS)、The Clinical Global Impression(CGI)、the Brief Social Phobia Scale(BSPS)、The Panic Attack Questionnaire(PAQ)、Panic Disorder Severity Scale、Florida Obsessive-Compulsive Inventory(FOCI)、The Leyton Obsessional Inventory Survey Form、The Vancouver Obsessional Compulsive Inventory(VOCI)、The Schedule of Compulsions,Obsessions,and Pathological Impulses(SCOPI)、Padua Inventory-Revised(PI-R)、Quality of Life(QoL)、The Clinical Global Improvement(CGI)スケール、The Yale-Brown Obsessive-Compulsive Scale(Y-BOCS)、The Yale-Brown Obsessive-Compulsive Scale Second Edition(Y-BOCS-II)、The Dimensional Yale-Brown Obsessive-Compulsive Scale(DY-BOCS)、The National Institute of Mental Health- GlobalObsessive-Compulsive Scale (NIMH-GOCS), The Yale-Brown Obsessive-Compulsive Scale Self-Report (Y-BOCS-SR), The Obsessive-Compulsive Inventory-Revised (OCI-R), and Dimensional Obsessive-Compulsive Scale (DOCS), or a combination thereof. In some embodiments, treatment in accordance with the methods of the present disclosure results in about a 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in anxiety disorder compared to before treatment according to any one of the diary assessments, physician or caregiver assessments, or clinical scales described herein or known in the art.

[0137] In some embodiments, the disease or disorder is attention deficit disorder (ADD). ADD is most commonly diagnosed in children under 16 years of age who have six or more symptoms of inattention (five or more for older teenagers) for at least six consecutive months, but who do not have signs of hyperactivity / impulsivity. Symptoms of inattention include, but are not limited to, difficulty paying attention, avoiding long intellectual tasks such as homework, difficulty staying on task, being disorganized or forgetful, not listening when spoken to, and not paying attention to details. Frequently losing things, making careless mistakes, and having trouble following instructions. In some embodiments, the disease or disorder is attention deficit hyperactivity disorder (ADHD). ADHD is characterized by a persistent pattern of inattention and / or hyperactivity-impulsivity. Hyperactive-impulsive symptoms often include, but may not be limited to, fidgeting or squirming when sitting, leaving one's seat when one is expected to be seated, running, sprinting, or climbing at inappropriate times, not being able to quietly pursue hobbies, being constantly on the move, talking excessively, answering questions before they have been fully asked, having difficulty waiting one's turn, and interrupting or interrupting others during conversations or activities.

[0138] In some embodiments, the disease or disorder is a headache disorder. As used herein, the term "headache disorder" refers to a disorder characterized by recurrent headaches. Headache disorders include migraine, tension headache, cluster headache, and chronic daily headache syndrome.

[0139] Disclosed herein in some embodiments are methods for treating cluster headache in a subject in need thereof. In some embodiments, at least one sign or symptom of cluster headache improves after treatment. In some embodiments, the sign or symptom of cluster headache is measured according to a diary assessment, a physical or mental evaluation by a clinician, or a neurological examination. Cluster headache is a primary headache disorder and belongs to the trigeminal autonomic headaches. Cluster headache is defined as a unilateral headache accompanied by at least one autonomic symptom ipsilateral to the headache. Attacks are characterized by severe unilateral pain, primarily in the first division of the trigeminal nerve to the fifth cranial nerve, whose primary function is to provide sensory and motor innervation to the face. Attacks are also associated with significant unilateral cranial autonomic symptoms, and subjects often experience agitation and restlessness during attacks. In some embodiments, subjects with cluster headache also experience nausea and / or vomiting. In some embodiments, subjects with cluster headaches experience unilateral pain, excessive tearing, facial flushing, ptosis, miosis, redness of the eye, swelling under or around one or both eyes, sensitivity to light, nausea, agitation, and restlessness.

[0140] In some embodiments, disclosed herein are methods for treating migraine in a subject in need thereof. Migraine is a moderate to severe headache that affects one or both sides of the head, feels pulsating, and lasts from 2 to 72 hours. Migraine symptoms include headache, nausea, sensitivity to light, sound, or smell, dizziness, difficulty speaking, vertigo, vomiting, seizures, distorted vision, fatigue, or loss of appetite. Some subjects also experience a pre-symptomatic phase several hours or days before the headache and / or a post-symptomatic phase after the headache has subsided. Pre-symptomatic and post-symptomatic symptoms include increased or decreased locomotor activity, depression, cravings for certain foods, repeated yawning, fatigue, and neck stiffness and / or pain. In some embodiments, the migraine is migraine without aura, migraine with aura, chronic migraine, abdominal migraine, basilar artery migraine, menstrual migraine, ophthalmoplegic migraine, ocular migraine, ophthalmic migraine, or hemiplegic migraine. In some embodiments, the migraine is migraine without aura. Migraine without aura includes migraine-like headache without headache. In some embodiments, the migraine is migraine with aura. Migraine with aura is primarily characterized by transient focal neurological symptoms that usually precede or sometimes occur simultaneously with headache. Less commonly, the aura may occur without headache or may occur with a non-migraine-like headache. In some embodiments, the migraine is hemiplegic migraine. Hemiplegic migraine is a migraine with aura and associated motor paralysis. In some embodiments, the hemiplegic migraine is familial hemiplegic migraine or sporadic hemiplegic migraine. In some embodiments, the migraine is basilar artery migraine. Subjects with basilar artery migraine have migraine-like headaches and auras accompanied by many other basilar-related symptoms, including difficulty speaking, world spinning, tinnitus, or motor paralysis. In some embodiments, the migraine is menstrual migraine. Menstrual migraine occurs just before and during menstruation. In some embodiments, the subject has abdominal migraine. Abdominal migraine is often experienced by children. Abdominal migraine is not a headache, but rather a stomachache.In some embodiments, the subject with abdominal migraine suffers from a migraine headache. In some embodiments, the subject has ophthalmic migraine, also known as "ocular migraine." A subject with ophthalmic migraine experiences brief loss of vision in one eye along with or after a migraine headache. In some embodiments, the subject has ophthalmoplegic migraine. Ophthalmoplegic migraine is a recurrent attack of migraine headache associated with paresis of one or more ophthalmic cranial nerves. In some embodiments, the subject in need of treatment experiences chronic migraine. As defined herein, a subject with chronic migraine experiences headaches on more than 15 days per month. In some embodiments, the subject in need of treatment experiences episodic migraine. As defined herein, a subject with episodic migraine experiences headaches on fewer than 15 days per month.

[0141] In some embodiments, disclosed herein are methods of treating chronic daily headache syndrome (CDHS) in a subject in need thereof. Subjects with CDHS experience headaches for more than four hours on more than 15 days per month. Some subjects experience these headaches for six months or more. CDHS affects 4% of the general population. Chronic migraine, chronic tension-type headache, new-onset persistent daily headache, and medication-overuse headache account for the majority of chronic daily headaches.

[0142] In some embodiments, after treatment according to the methods of the present disclosure, the frequency of headaches and / or related symptoms is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before said treatment.

[0143] In some embodiments, after treatment according to the methods of the present disclosure, the length of headache attacks is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before said treatment.

[0144] In some embodiments, at least one sign or symptom of a headache disorder is improved after administration of a compound disclosed herein, hi some embodiments, the sign or symptom of a headache disorder is measured according to a diary assessment, a physician or caregiver assessment, or a clinical scale. In some embodiments, treatments of the present disclosure result in measurable improvements in one or more of the following: Visual Analog Scale, Numeric Rating Scale, Short Form Health Survey, Profile of Mood States, Pittsburgh Sleep Quality Index, Major Depression Inventory, Perceived Stress Scale, 5-Level EuroQoL-5D, Headache Impact Test, ID-migraine, 3-item screener, Minnesota Multiphasic Personality Inventory, Hospital Anxiety and Depression Scale (HADS), 50 Beck Depression Inventory (BDI; both the original BD151 and the second edition BDI-1152), 9-item Patient Health Questionnaire (PHQ-9), Migraine Disability Assessment Questionnaire (MI-DAS), Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1), European Quality of Life-5 Dimensions (EQ-5D), Short-form 36 (SF-36), or a combination thereof.In some embodiments, treatment according to the methods of the present disclosure results in about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in headache disorder compared to pre-treatment according to any one of the diary assessments, physician or caregiver assessments, or clinical scales described herein or known in the art. In some embodiments, signs or symptoms of headache disorder are measured according to diary assessments, physician physical or mental evaluations, imaging tests, electroencephalograms, blood tests, neurological tests, or combinations thereof. In some embodiments, blood tests evaluate blood chemistry and / or vitamins.

[0145] In some embodiments, the disease or disorder is a substance use disorder. Substance addictions that can be treated using the methods herein include addictions to addictive substances / agents, such as recreational narcotics and addictive drugs. Examples of addictive substances / agents include, but are not limited to, alcohol, such as ethyl alcohol, gamma hydroxybutyrate (GHB), caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opiates and other morphine-like opioid agonists, such as heroin, phencyclidine and phencyclidine-like compounds, hypnotics and sedatives, such as benzodiazepines, methaqualone, mecloqualone, etaqualone, and barbiturates, and psychostimulants, such as cocaine, amphetamines and amphetamine-related drugs, such as dextroamphetamine and methylamphetamine. Examples of addictive drugs include, for example, benzodiazepines, barbiturates, and alfentanil, allylprodine, alphaprodine, anileridine benzylmorphine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyratebutyrate, dipipanone, eptazocine, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanylfentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofenitanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol phanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, (OXYCONTIN®), oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, fentanylIn some embodiments, the disease or disorder is an alcohol use disorder (AUD). In some embodiments, the disease or disorder is a nicotine use (e.g., smoking) disorder, and the therapy is used, for example, to quit smoking.

[0146] In some embodiments, the present disclosure provides for the management of sexual dysfunctions, which may include, but are not limited to, sexual desire disorders, e.g., decreased libido; sexual arousal disorders, e.g., those causing lack of desire, lack of arousal, pain during intercourse, and orgasmic disorders such as anorgasmia; and erectile dysfunction; particularly sexual dysfunction disorders resulting from psychological factors.

[0147] In some embodiments, the disease or disorder is an eating disorder. As used herein, the term "eating disorder" refers to any of a wide range of psychological disorders characterized by abnormal or disturbed eating habits. Non-limiting examples of eating disorders include pica, anorexia nervosa, bulimia nervosa, rumination disorder, avoidant / restrictive food intake disorder, binge eating disorder, other specified eating or drinking disorder, unspecified eating or drinking disorder, or a combination thereof. In some embodiments, the eating disorder is pica, anorexia nervosa, bulimia nervosa, rumination disorder, avoidant / restrictive food intake disorder, binge eating disorder, or a combination thereof. In some embodiments, the methods disclosed herein treat chronic eating disorders. As used herein, "chronic" eating disorders are recurrent. In some embodiments, at least one sign or symptom of the eating disorder improves after administration of a compound disclosed herein. In some embodiments, the sign or symptom of the eating disorder is measured according to a diary assessment, a physician's or caregiver's assessment, or a clinical scale.Non-limiting examples of clinical measures, diary assessments, and physician or caregiver assessments include the Mini International Neuropsychiatric Interview (MINI), McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), Eating Disorder Examination (EDE), Eating Disorder Questionnaire (EDE-Q), Eating Disorder Examination Questionnaire Short Form (EDE-QS), Physical Appearance State and Trait Anxiety Scale-State and Trait version (PASTAS), Spielberger State-Trait Anxiety Inventory (STAI), Eating Disorder Readiness Ruler (ED-RR), Visual Analogue Rating Scales (VAS), Montgomery-Asberg Depression Rating Scale (MADRS), Yale-Brown Cornell Eating Disorder Scale (YBC-EDS), Yale-Brown Cornell Eating Disorder Scale Self Assessment (YBC-EDS), and the Yale-Brown Cornell Eating Disorder Scale Self Assessment (YBC-EDS). Report (YBC-EDS-SRQ), Body Image State Scale (BISS), Clinical impairment assessment (CIA) questionnaire, Eating Disorder Inventory (EDI) (e.g., 3rd edition: EDI-3), Five Dimension Altered States of Consciousness Questionnaire (5D-ASC), Columbia-Suicide Severity Rating Scale (C-SSRS), Life Changes Inventory (LCI), and combinations thereof.In some embodiments, treatment in accordance with the methods of the present disclosure results in about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in eating disorder compared to before treatment according to any one of the diary assessments, physician or caregiver assessments, or clinical scales described herein or known in the art.

[0148] In some embodiments, the disease or disorder is multiple sclerosis (MS). MS is a chronic, inflammatory disease of unknown etiology involving an immune-mediated attack on the central nervous system. Myelin and the oligodendrocytes that form it appear to be the primary targets of inflammatory attacks, but axons themselves are also damaged. MS disease activity can be monitored by cranial scans, including brain magnetic resonance imaging (MRI), the accumulation of disability, and the rate and severity of relapses. A clinically definite diagnosis of MS, as determined by the Poser criteria, requires at least two neurological events suggestive of demyelination in the CNS that are separated in time and location. Various MS disease stages and / or types are described in Multiple Sclerosis Therapeutics (Duntiz, 1999). Relapsing-remitting multiple sclerosis (RRMS) is the most common form at the time of initial diagnosis. Many subjects with RRMS have an initial relapsing-remitting course for 5 to 15 years, then progress to secondary progressive MS (SPMS) disease. Relapses result from inflammation and demyelination, while recovery of nerve conduction and remission are accompanied by resolution of inflammation, redistribution of sodium channels on demyelinated axons, and remyelination. In some embodiments, the multiple sclerosis is relapsing multiple sclerosis. In some embodiments, the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis. In some embodiments, the methods herein reduce symptoms of multiple sclerosis in a subject. In some embodiments, the symptoms are multiple sclerosis disease activity monitored by MRI, relapse rate, accumulation of disability, frequency of relapses, reduction in adjustment for confirmed disease progression, reduction in time to confirmed relapse, frequency of clinical deterioration, brain atrophy, neurological dysfunction, neuronal damage, neurodegeneration, neuroapoptosis, confirmed risk of progression, deterioration of visual function, fatigue, motor impairment, cognitive impairment, brain volume loss, abnormalities observed in whole-brain MTR histograms, deterioration in overall health, functional status, quality of life, and / or severity of symptoms during work. In some embodiments, the methods herein reduce or inhibit brain volume loss. In some embodiments, brain volume is measured by percent brain volume change (PBVC). In some embodiments, the methods herein increase the time to confirmed disease progression.In some embodiments, the time to confirmed disease progression is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, e.g., at least 20-60%. In some embodiments, the methods herein reduce abnormalities observed in whole-brain MTR histograms. In some embodiments, the accumulation of disability is measured by the Kurtzke Expanded Disability Status Scale (EDSS) score. In some embodiments, the accumulation of disability is assessed by the time to confirmed disease progression as measured by the Kurtzke Expanded Disability Status Scale (EDSS) score.

[0149] In some embodiments, the disease or disorder is characterized by or associated with neuroinflammation. The treatments described herein can provide cognitive benefits to subjects suffering from neurological and neurodegenerative diseases, such as Alzheimer's disease and other dementia subtypes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and other diseases in which neuroinflammation is a hallmark of the disease pathophysiology or progression. For example, emerging hallucinogenic research / clinical evidence indicates that hallucinogens may be useful as disease-modifying treatments in subjects suffering from neurodegenerative diseases, such as Alzheimer's disease and other forms of dementia. Vann Jones, SAand O'Kelly, A. “Psychedelics as a Treatment for Alzheimer's Disease Dementia” Front. Synaptic Neurosci., 21, August 2020; Kozlowska, U., Nichols, C., Wiatr, K., and Figiel, M. (2021), “From psychiatry to neurology:Psychedelics as prospective therapeutics for neurodegenerative disorders” Journal of Neurochemistry, 00, 1-20; Garcia-Romeu, A., Darcy, S., Jackson, H., White, T., Rosenberg, P. (2021), “Psychedelics as Novel Therapeutics in Alzheimer's Disease: Rationale and Potential Mechanisms” In: Current Topics in Behavioral Neurosciences. Springer, Berlin, Heidelberg. For example, hallucinogens are believed to stimulate neurogenesis, induce neuroplastic changes, and reduce neuroinflammation. Thus, in some embodiments, the methods of the present disclosure are used to treat neurological and neurodegenerative disorders in which neuroinflammation is implicated in disease pathogenesis, such as, for example, Alzheimer's disease, dementia subtypes, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).In some embodiments, the disclosed methods are used to treat Alzheimer's disease. In some embodiments, the disclosed methods are used to treat dementia. In some embodiments, the disclosed methods are used to treat Parkinson's disease. In some embodiments, the disclosed methods are used to treat amyotrophic lateral sclerosis (ALS). As described above, such treatments may stimulate neurogenesis, induce neuroplastic changes, and / or provide neuroinflammatory benefits (e.g., reduced neuroinflammation compared to before treatment began), resulting in slowing or preventing disease progression, slowing or reversing brain atrophy, and reducing associated symptoms (e.g., memory loss in the case of Alzheimer's disease and related dementia disorders). Pharmaceutical compositions adapted for, but not limited to, oral and / or sustained-release administration (e.g., subcutaneous administration) are suitable for such treatment methods, with hallucinogen-free administration being preferred. In some embodiments, treatment according to the methods of the present disclosure results in about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in cognition in a subject afflicted with a neurological or neurodegenerative disease compared to before treatment according to any one of a diary assessment, physician or caregiver assessment, or clinical scale described herein or known in the art.

[0150] Furthermore, many of the behavioral problems associated with chronic and / or life-threatening diseases, including neurodegenerative disorders such as Alzheimer's disease, can benefit from treatment with the compounds / salt forms disclosed herein. Indeed, depression, anxiety, or stress can be common in patients with chronic and / or life-threatening diseases such as Alzheimer's disease, autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, and psoriasis), cancer, coronary heart disease, diabetes, epilepsy, HIV / AIDS, hypothyroidism, multiple sclerosis, Parkinson's disease, and stroke. For example, depression is common in Alzheimer's disease as a consequence of the disease and is a risk factor for the disease itself. Symptoms of depression, anxiety, or stress can occur after the diagnosis of the disease or illness. Patients who suffer from depression, anxiety, or stress concurrently with other medical diseases or illnesses may have more severe symptoms of both, and the illness and depression, anxiety, or stress may persist even as the patient's physical health improves. The compounds / salt forms described herein can be used to treat depression, anxiety and / or stress associated with chronic or life-threatening diseases or illnesses.

[0151] Thus, in some embodiments, the methods provided herein are used to treat symptoms associated with chronic and / or life-threatening diseases or disorders, including neurological and neurodegenerative diseases, such as depression, anxiety, and / or stress. In some embodiments, the methods provided herein reduce at least one sign or symptom of a neurological and / or neurodegenerative disease. In some embodiments, the methods provided herein reduce at least one sign or symptom of a neurological and / or neurodegenerative disease (e.g., depression, anxiety, and / or stress) by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment, e.g., according to any one of a diary assessment, a clinician or caregiver assessment, or a clinical scale assessment described herein or known in the art.

[0152] In some embodiments, the disease or disorder is Alzheimer's disease. In some embodiments, the methods herein are used to treat depression, anxiety, and / or stress associated with Alzheimer's disease. In some embodiments, the disease or disorder is Parkinson's disease. In some embodiments, the methods herein are used to treat depression, anxiety, and / or stress associated with Parkinson's disease. In some embodiments, the disease or disorder is amyotrophic lateral sclerosis (ALS). In some embodiments, the methods herein are used to treat depression, anxiety, and / or stress associated with amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder is depression and anxiety associated with cancer. As noted above, oral and / or sustained release administration is suitable for such uses, particularly when blood levels of the active ingredient (e.g., a compound of Formula (I)) are kept below the hallucination threshold.

[0153] In some embodiments, the methods disclosed herein are used to treat brain injuries, including traumatic brain injury (TBI). TBI is damage to the brain caused by an external force and can be classified based on severity, ranging from mild traumatic brain injury (mTBI / concussion) to severe traumatic brain injury. TBI can also be classified by mechanism, such as closed or penetrating head injury, or other characteristics, such as whether it occurs in a specific location or over a wide area. TBI can result in physical, cognitive, social, emotional, and behavioral symptoms that can be treated herein. Some imaging techniques used for diagnostic and recovery markers include computed tomography (CT) and magnetic resonance imaging (MRI).

[0154] In some embodiments, the disease or disorder is a neurological and developmental disorder, such as autism spectrum disorder, including Asperger's syndrome. For example, Asperger's syndrome is a subtype of autism spectrum disorder that can be treated with anxiety medication. Subjects with autism spectrum disorder may exhibit various signs and symptoms, including but not limited to, a preference for non-social stimuli, abnormal non-verbal social behavior, reduced attention to social stimuli, irritability, anxiety (e.g., particularly generalized anxiety and social anxiety), and depression. In some embodiments, autism spectrum disorder comprises a medical diagnosis based on the criteria and classification of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Current evidence supports the use of hallucinogens to improve behavioral atypicalities in autism spectrum disorders, including poor social behavior, anxiety, and depression (see Markopoulos A, Inserra A, De Gregorio D, Gobbi G. Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder. Front Pharmacol. 2022;12:749068). Signs and symptoms of autism spectrum disorders can be treated using the methods herein.

[0155] In some embodiments, the disease or disorder is a genetic condition that causes learning disabilities and cognitive impairment.An example of such a genetic condition is fragile X syndrome, which is caused by a change in the gene Fragile X Messenger Ribonucleoprotein 1 (FMR1), and this can cause mild to moderate intellectual disability in most males and about one-third of affected females.Fragile X syndrome and autism spectrum disorder are closely related because the FMR1 gene is the main genetic cause of autism spectrum disorder (see Markopoulos A, Inserra A, De Gregorio D, Gobbi G. Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder.Front Pharmacol.2022;12:749068). Subjects with fragile X syndrome may exhibit anxiety, hyperactive behavior (e.g., rigidity and obsessive-compulsive behavior), attention deficit disorder, abnormalities in moodiness and aggression, poor recognition memory, and / or characteristics of autism spectrum disorder, and these signs and symptoms may be treated using the methods herein. Clinical trials using hallucinogens for the treatment of fragile X syndrome and autism spectrum disorder are currently underway (ClinicalTrials.gov, number NCT04869930).

[0156] In some embodiments, the disease or disorder is psychological distress, for example, psychological distress in frontline healthcare workers.

[0157] In some embodiments, the compounds and compositions disclosed herein are used to treat tic disorders, including Tourette's syndrome, also known as Tourette's syndrome, Tourette's disorder, Gilles de la Tourette's syndrome (GTS), or simply Tourette's syndrome or TS. Tic disorders can also be pediatric autoimmune disorders associated with streptococcal infections (PANDAS), transient tic disorders, chronic tic disorders, or tic disorders not otherwise specified (NOS). Tic disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) or similarly by the World Health Organization (ICD-10 codes) based on type (motor or vocal) and tic duration (sudden, rapid, nonrhythmic movements). Tics are classified as simple or complex, involuntary or semivoluntary, sudden, brief, intermittent, repetitive movements (motor) or sounds (vocal). Simple tics, such as blinking or facial contortions, can be relatively easily camouflaged and may go unnoticed. Complex tics, such as body contortions, self-injurious behaviors, obscene gestures, or shouting socially inappropriate words or phrases, appear to be intentional and are particularly distressing. Transient tic disorders are typically characterized by multiple motor and / or vocal tics occurring over a period of at least four weeks but less than 12 months. Chronic tic disorders are typically characterized by single or multiple motor or vocal tics, but not both, present for more than a year. Tourette syndrome is diagnosed when both motor and vocal tics (not necessarily simultaneously) are present for more than a year. Thus, Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and vocal tics. The typical age of onset is between 5 and 7 years of age. Affected children can be the target of teasing from their peers, resulting in low self-esteem, social isolation, poor school performance, depression, and anxiety. In addition to causing social embarrassment, sudden, intense tics are painful, and severe head and neck tics have been reported to cause secondary neurological disorders such as compressive cervical myelopathy. Patients with Tourette syndrome are also at increased risk for obsessive-compulsive disorder (OCD), depression, and attention-deficit hyperactivity disorder (ADHD).Tic disorder NOS is diagnosed when tics are present but do not meet the criteria for any specific tic disorder. The methods of the present disclosure can also be used to treat tics induced as a side effect of medication, tics associated with autism, and Tourette's syndrome (the presence of Tourette's-like symptoms that are not Tourette's syndrome (e.g., as a result of another disease or condition, such as a sporadic, genetic, or neurodegenerative disorder)).

[0158] In some embodiments, the disease or disorder may involve a condition of the autonomic nervous system (ANS).

[0159] In some embodiments, the disease or disorder includes a pulmonary disorder (eg, asthma and chronic obstructive pulmonary disorder (COPD)).

[0160] In some embodiments, the disease or disorder includes a cardiovascular disorder (eg, atherosclerosis).

[0161] In some embodiments, the present disclosure provides for the management of different types of pain, including, for example, cancer pain, such as intractable cancer pain; neuropathic pain; post-operative pain; opioid-induced hyperalgesia and opioid-related tolerance; neuralgia; post-operative / post-surgery pain; complex regional pain syndrome (CRPS); shock; limb amputation; severe chemical or thermal burns; sprains, ligament tears, fractures, wounds, and other tissue injuries; dental surgery, procedures, and illnesses; labor and delivery; during physical therapy; radiation poisoning; acquired immune deficiency syndrome (AIDS); epidural (or epidural) fibrosis; orthopedic pain; back pain; failed back surgery and failed laminectomy; sciatica; Painful conditions include, but are not limited to, sickle cell crises accompanied by pain; arthritis; autoimmune diseases; intractable bladder pain, e.g., pain associated with certain viruses, such as shingles pain or herpes pain; acute nausea, e.g., pain that can cause nausea or abdominal pain often accompanied by severe nausea; migraine headaches, e.g., with aura; and other conditions, including depression (e.g., acute depression or chronic depression), depression accompanied by pain, alcoholism, acute agitation, intractable asthma, acute asthma (e.g., unrelated pain conditions can trigger asthma), epilepsy, acute brain injury and stroke, Alzheimer's disease, and other disorders. Pain may be persistent or chronic, lasting for weeks to years, in some cases despite healing or resolution of the injury or illness that caused the pain, and in some cases, despite previous medications and / or treatments. Furthermore, the present disclosure encompasses the treatment / management of any combination of these types of pain or conditions.

[0162] In some embodiments, the pain being treated / managed is acute breakthrough pain or pain associated with wind-up, which may occur in chronic pain conditions. In some embodiments of the present disclosure, the pain being treated / managed is cancer pain, such as, for example, intractable cancer pain. In some embodiments of the present disclosure, the pain being treated / managed is post-operative pain. In some embodiments of the present disclosure, the pain being treated / managed is orthopedic pain. In some embodiments of the present disclosure, the pain being treated / managed is back pain. In some embodiments of the present disclosure, the pain being treated / managed is neuropathic pain. In some embodiments of the present disclosure, the pain being treated / managed is dental pain. In some embodiments of the present disclosure, the condition being treated / managed is depression. In some embodiments of the present disclosure, the pain being treated / managed is chronic pain in opioid-tolerant patients.

[0163] In some embodiments, the disease or disorder is arthritis. Types of arthritis include osteoarthritis, rheumatoid arthritis, pediatric arthritis, fibromyalgia, gout, and lupus. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is rheumatoid arthritis. In some embodiments, the disease or disorder is pediatric arthritis. In some embodiments, the disease or disorder is gout. In some embodiments, the disease or disorder is lupus. In some embodiments, the disease or disorder is fibromyalgia. Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood problems. Fibromyalgia is thought to amplify painful sensations by affecting brain and spinal cord processes involved in pain and non-pain signaling. Symptoms often begin after an event such as physical trauma, surgery, infection, or significant psychological stress. In other cases, symptoms build up gradually over time, and there is no single triggering event. Women are more likely than men to develop fibromyalgia. Many people with fibromyalgia also have tension headaches, temporomandibular joint (TMJ) disorders, irritable bowel syndrome, anxiety, and depression.

[0164] In some embodiments, the disease or disorder is inflammatory bowel disease (IBD). IBD is a term for two conditions, Crohn's disease and ulcerative colitis, characterized by chronic inflammation of the gastrointestinal (GI) tract, and such prolonged inflammation leads to damage to the GI tract. Subjects suffering from IBD may experience persistent diarrhea, abdominal pain, rectal bleeding / bloody stool, weight loss, and fatigue. IBD may be diagnosed, and treatment may be monitored using one or more of endoscopy, colonoscopy, contrast x-ray, MRI, computed tomography (CT), stool samples, and blood tests, all of which are known to those skilled in the art.

[0165] In some embodiments, the disease or disorder is a sleep disorder such as narcolepsy, insomnia, nightmare disorder, sleep apnea, central sleep apnea, obstructive sleep apnea, hypopnea, sleep-related hypoventilation, restless legs syndrome, and jet lag. In some embodiments, the disease or disorder is narcolepsy.

[0166] In some embodiments, the present disclosure relates to a method of treating a disease or condition by modulating N-methyl-D-aspartate (NMDA) activity, the method comprising administering an effective amount of a pharmaceutically acceptable salt of a compound described herein (e.g., a compound of Formula (I)) to a subject in need thereof. In some embodiments, the disease or condition is selected from the following: levodopa-induced dyskinesia; dementia (e.g., Alzheimer's dementia), tinnitus, treatment-resistant depression (TRD), major depressive disorder, melancholic depression, atypical depression, dysthymia, neuropathic pain, agitation caused by or associated with Alzheimer's disease, pseudobulbar effect, autism, ocular function, generalized anxiety disorder, Alzheimer's disease, schizophrenia, diabetic neuropathy, acute pain, depression, bipolar depression, suicidality, neuropathic pain, or post-traumatic stress disorder (PTSD). In some embodiments, the disease or condition is a psychiatric or mental disorder (e.g., schizophrenia, mood disorder, substance-induced psychosis, major depressive disorder (MDD), bipolar disorder, bipolar depression (BDep), post-traumatic stress disorder (PTSD), suicidal ideation, anxiety, obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD)). In other embodiments, the disease or condition is a neurological disorder (e.g., Huntington's disease (HD), Alzheimer's disease (AD), or systemic lupus erythematosus (SLE)).

[0167] In some embodiments, the present disclosure relates to a method for treating ophthalmic diseases such as uveitis, corneal diseases, iritis, iridocyclitis, glaucoma, and cataracts by ophthalmically administering a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of formula (I) to a subject in need thereof. For example, the compound / salt forms herein can be administered ophthalmologically in the form of a solution, suspension, ointment, emulsion, gel-forming solution, powder for solution, gel, intraocular insert, and implant. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is administered in the form of eye drops.

[0168] The administering physician can provide a prophylactic or therapeutic treatment method by adjusting the amount and timing of any of the compound salt forms described herein based on the observation of one or more symptoms of the disorder or condition being treated.

[0169] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0170] Administration can be systemic or local.In some embodiments, administration to mammals results in the systemic release (for example, into the bloodstream) of the compound of the present disclosure.Administration methods can include, but are not limited to, for example, inhalation via nebulizer or inhaler; oral; enteral route of stomach and rectum; topical administration such as transdermal and intradermal; and parenteral administration.

[0171] The compounds of the present disclosure have an advantageous metabolic degradation profile that prevents the high drug concentrations observed immediately after administration while also enhancing brain levels of the active compound, so that in some embodiments, the therapeutic dose can be reduced. Thus, the compounds of formula (I) (in salt form) are serotonergic but can also be used to treat, for example, 5-HT associated with valvular heart disease, to achieve a sustained therapeutic effect. 2B It can be administered at sub-psychoactive concentrations with reduced toxicity, such as that associated with receptor activation (Rothman, RB, and Baumann, MH, 2009, Serotonergic drugs and valvular heart disease, Expert Opin Drug Saf 8, 317-329).As a result, the salt form of the compound of formula (I) can be suitable for microdosing.

[0172] In some embodiments, the pharmaceutically acceptable salt forms of the present disclosure may be used as an independent therapy. In some embodiments, the pharmaceutically acceptable salt forms of the present disclosure may be used as an adjunctive / combined therapy. In some embodiments, a subject with a disorder is administered a pharmaceutically acceptable salt of a compound of the present disclosure and at least one additional therapy and / or therapeutic agent. In some embodiments, the administration of the additional therapy and / or therapeutic agent occurs before the administration of a pharmaceutically acceptable salt form of the present disclosure. In some embodiments, the administration of the additional therapy and / or therapeutic agent occurs after the administration of a pharmaceutically acceptable salt form of the present disclosure. In some embodiments, the administration of the additional therapy and / or therapeutic agent occurs simultaneously with the administration of a pharmaceutically acceptable salt form of the present disclosure. In some embodiments, the additional therapy is an antidepressant, an anticonvulsant, lisdexamfetamine dimesylate, an antipsychotic, an anxiolytic, an anti-inflammatory, a benzodiazepine, an analgesic, a cardiovascular agent, an opioid antagonist, or a combination thereof.

[0173] In some embodiments, the additional therapy is a benzodiazepine. In some embodiments, the benzodiazepine is diazepam or alprazolam.

[0174] In some embodiments, the additional therapy is an N-methyl-D-aspartate (NMDA) receptor antagonist. In some embodiments, the NMDA receptor antagonist is ketamine. In some embodiments, the NMDA receptor antagonist is nitrous oxide.

[0175] In some embodiments, the additional therapy is an antidepressant. In some embodiments, the antidepressant indirectly affects neurotransmitter receptors, for example, through interactions that affect the responsiveness of other molecules at the neurotransmitter receptor. In some embodiments, the antidepressant is an agonist. In some embodiments, the antidepressant is an antagonist. In some embodiments, the antidepressant acts (directly or indirectly) on more than one type of neurotransmitter receptor. In some embodiments, the antidepressant is selected from buproprion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine.

[0176] In some embodiments, the antidepressant is a tricyclic antidepressant (TCA), a selective serotonin reuptake inhibitor (SSRI), a serotonin and nordrenaline reuptake inhibitor (SNRI), a dopamine reuptake inhibitor (DRI), a nordrenaline reuptake monoamine oxidase inhibitor (MAOI), including an inhibitor (NRU), a dopamine, serotonin and nordrenaline reuptake inhibitor (DSNRI), a reversible inhibitor of monoamine oxidase type A (RIMA), or a combination thereof. In some embodiments, the antidepressant is a TCA. In some embodiments, the TCA is imipramine or clomipramine. In some embodiments, the antidepressant is an SRI. In some embodiments, the SSRI is escitalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, or a combination thereof. In some embodiments, the SNRI is venlafaxine. In some embodiments, the additional therapy is pregabalin. In some embodiments, the pharmaceutically acceptable salt forms of the present disclosure are administered in combination with a reversible inhibitor of monoamine oxidase type A (RIMA). Such combinations may be administered in the same dosage form or may be co-administered in separate dosage forms. Such combinations may improve the bioavailability (e.g., oral bioavailability) of the compound of Formula (I) by minimizing enzymatic degradation mediated by MAO enzymes, such as deamination / oxidation processes.Examples of reversible inhibitors of monoamine oxidase type A (RIMA) include, but are not limited to, moclobemide, traxatone, brofaromine, caroxazone, eprobemide, methylene blue, metralindole, minaprine, harmaline, harmine, roscilidine, amiflamine, cimoxatone, cercloremine, CX157, befloxacinth, esprilone, tetrindole, 5-(2-aminopropyl)indole (5-IT), α-methyltryptamine (AMT), and natural sources (e.g., Syrian rue, turmeric, curcumin).

[0177] In some embodiments, the additional therapy is an anticonvulsant. In some embodiments, the anticonvulsant is gabapentin, carbamazepine, ethosuximide, lamotrigine, felbamate, topiramate, zonisamide, tiagabine, oxcarbazepine, levetiracetam, divalproex sodium, phenytoin, or fosphenytoin. In some embodiments, the anticonvulsant is topiramate.

[0178] In some embodiments, the additional therapy is an antipsychotic drug, hi some embodiments, the antipsychotic drug is a phenothiazine, a butyrophenone, a thioxanthene, a clozapine, a risperidone, an olanzapine or a sertindole, a quetiapine, an aripiprazole, a zotepine, a perospirone, a neurokinin-3 antagonist such as osanetant and talnetant, a rimonabant, or a combination thereof.

[0179] In some embodiments, the additional therapy is an anti-inflammatory agent, which is a nonsteroidal anti-inflammatory drug (NSAIDS), a steroid, acetaminophen (a COX-3 inhibitor), a 5-lipoxygenase inhibitor, a leukotriene receptor antagonist, a leukotriene A4 hydrolase inhibitor, an angiotensin-converting enzyme antagonist, a beta-blocker, an antihistamine, a histamine 2 receptor antagonist, a phosphodiesterase-4 antagonist, a cytokine antagonist, a CD44 antagonist, an anti-tumor agent, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor (a statin), an estrogen, an androgen, an antiplatelet agent, an antidepressant, a Helicobacter pylori inhibitor, a proton pump inhibitor, a thiazolidinedione, a dual-action compound, or a combination thereof.

[0180] In some embodiments, the additional therapy is an anti-anxiety agent, hi some embodiments, the anti-anxiety agent is selected from alprazolam, an alpha blocker, an antihistamine, a barbiturate, a beta blocker, bromazepam, a carbamate, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, an opioid, oxazepam, temazepam, or triazolam.

[0181] In some embodiments, the additional therapy is an opioid antagonist. Non-limiting examples of opioid antagonists include naloxone, naltrexone, nalmefene, nalorphine, nalorphine dinicotinate, dinicotinate, levallrphan, samidorphan, nalodeine, alvimopan, methylnaltrexone, naloxegol, 6-naltrexol, axelopran, bebenopran, methylsamidorphan, naldemedine, buprenorphine, decozine, butorphanol, levorphanol, nalbuphine, pentazocine, and phenazocine.

[0182] In some embodiments, the additional therapy is a cardiovascular drug. Non-limiting examples of cardiovascular drugs include digoxin or (3β,5β,12β)-3-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribohexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide, lisinopril, captopril, ramipril, trandolapril, ), benazepril, cilazapril, enalapril, moexipril, perindopril, quinapril, fludrocortisone, enalaprilate, quinapril, perindopril, apixaban, dabigatran, ed edoxaban, heparin, rivaroxaban, warfarin, aspirin, clopidogrel, dipyridamole, prasugrel, ticagrelor, azilsartan, candesartan, eprosartan, irbesartan ), losartan, olmesartan, telmisartan, valsartan caubitril, acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol,These include amlodipine, diltiazem, felodipine, nifedipine, nimodipine, nisolidipine, verapamil, statins, nicotinic acid, diuretics, vasodilators, and combinations thereof.

[0183] In some embodiments, the subject is administered at least one therapy, non-limiting examples of which include transcranial magnetic stimulation, cognitive behavioral therapy, interpersonal therapy, dialectical behavioral therapy, mindfulness techniques, or acceptance and commitment therapy, or a combination thereof.

[0184] Pharmaceutical Composition Also disclosed herein is a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula (I) and a pharmaceutically acceptable vehicle. The pharmaceutical composition may contain one or more pharmaceutically acceptable salts of a compound of formula (I).

[0185] A "pharmaceutically acceptable vehicle" can be a vehicle approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in mammals, such as humans. As used herein, the term "vehicle" refers to a diluent, adjuvant, excipient, carrier, or any auxiliary or supplementary ingredient with which a compound of the present disclosure or a salt form thereof is formulated for administration to a mammal. Such pharmaceutical vehicles can be solid or liquid, such as water and oil, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical vehicles can be water, saline, juice (e.g., fruit juice), gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Pharmaceutical vehicles can include one or more gases, for example, to act as carriers for administration via inhalation. Additionally, adjuvants, stabilizers, thickeners, lubricants, taste-masking agents, colorants, and other pharmaceutical additives may be included in the disclosed compositions, such as those specified herein below.

[0186] The pharmaceutical composition may comprise a single compound of formula (I) in salt form, or a mixture of compounds of formula (I) in either free base or salt form, i.e., the pharmaceutical composition may be formed from an isotopologue mixture of the disclosed compounds. In some embodiments, the subject compound of formula (I) may be present in the pharmaceutical composition in a purity of 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%, or at least 99% by weight, based on the total weight of the isotopologues of the compound of formula (I) present in the pharmaceutical composition. For example, a pharmaceutical composition formulated using DMT d-10 salt (salt form of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4) as the subject compound can further include an isotopologue of the subject compound, e.g., DMT d-9, DMT d-8, etc., as a free base or salt form, stereoisomer, solvate, or mixture thereof. In some embodiments, the composition is substantially free of other isotopologues of the compound in either free base or salt form, e.g., the composition has less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or 0.5 mole percent of other isotopologues of the compound.

[0187] In some embodiments, any position in a deuterium-bearing compound has a minimum deuterium bonding that is greater than the naturally occurring percentage in hydrogen (about 0.016 atomic %), hi some embodiments, any position in a deuterium-bearing compound has a minimum deuterium incorporation of 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 %, or at least 99 atomic % at the deuteration site.

[0188] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle and pharmaceutically acceptable salts of at least two compounds of Formula (I) (the pharmaceutically acceptable salts of at least two compounds of Formula (I) are referred to as an "active salt mixture"). In some embodiments, the pharmaceutical composition comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of DMT d-10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1,2,2-d (I-8), (ii) a pharmaceutically acceptable salt of DMT d-9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,2,2-d (I-10) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1,2-d (I-11), and optionally (iii) DMT Pharmaceutically acceptable salts of d-8, i.e., one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-7), and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12).

[0189] In some embodiments, the active salt mixture is a fumarate mixture and the listed salt form is fumarate. In some embodiments, the active salt mixture is a benzoate mixture and the listed salt form is benzoate. In some embodiments, the active salt mixture is a salicylate mixture and the listed salt form is salicylate. In some embodiments, the active salt mixture is a succinate mixture and the listed salt form is succinate.

[0190] In some embodiments, the pharmaceutical composition comprises an active salt mixture comprising: (i) 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92%, or any range therebetween, by weight of DMT, based on the total weight of the active salt mixture; a pharmaceutically acceptable salt of d-10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); (ii) DMT in an amount of 2 wt.% to 40 wt.%, 3 wt.% to 35 wt.%, 4 wt.% to 30 wt.%, 5 wt.% to 25 wt.%, 6 wt.% to 20 wt.%, 7 wt.% to 15 wt.%, 8 wt.% to 10 wt.%, or any range therebetween, based on the total weight of the active salt mixture. the sum by weight of one or more pharmaceutically acceptable salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11), and (iii) 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 0% by weight, or any range therebetween, of DMT, based on the total weight of the active salt mixture. The weight sum of one or more pharmaceutically acceptable salts of d-8, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-7), and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12).

[0191] For example, in some embodiments, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90% to 98% by weight, or any range therebetween, of a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8), based on the total weight of the active salt mixture; and (ii) 2% to 10% by weight, or any range therebetween, of one or more pharmaceutically acceptable salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11), based on the total weight of the active salt mixture.In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) comprises a pharmaceutically acceptable salt of DMT d-8 (a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1-d (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-2,2-d (I-7), and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,2-d (I-12)), a pharmaceutically acceptable salt of DMT d-7, DMT A pharmaceutically acceptable salt of d-6 (a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-4)), a pharmaceutically acceptable salt of DMT d-5, a pharmaceutically acceptable salt of DMT d-4 (a salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d4 (I-5)), a pharmaceutically acceptable salt of DMT d-3, a pharmaceutically acceptable salt of DMT d-2 (one or more salts of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2) and / or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-3)), DMT The composition contains an undetectable amount of, or is otherwise substantially free of, a pharmaceutically acceptable salt of d-1, and a pharmaceutically acceptable salt of DMT (salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1)).For example, in some embodiments, the weight of pharmaceutically acceptable salts of isotopologues of compounds of Formula (I) not listed in (i) or (ii), e.g., a pharmaceutically acceptable salt of DMT d-8, a pharmaceutically acceptable salt of DMT d-7, a pharmaceutically acceptable salt of DMT d-6, a pharmaceutically acceptable salt of DMT d-5, a pharmaceutically acceptable salt of DMT d-4, a pharmaceutically acceptable salt of DMT d-3, a pharmaceutically acceptable salt of DMT d-2, a pharmaceutically acceptable salt of DMT d-1, and a pharmaceutically acceptable salt of DMT, is, in total, less than 1 wt %, less than 0.75 wt %, less than 0.5 wt %, less than 0.4 wt %, less than 0.3 wt %, less than 0.25 wt %, less than 0.2 wt %, less than 0.1 wt %, or 0 wt %, based on the total weight of the active salt mixture.

[0192] In one embodiment, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90% to 98% by weight, or any range therebetween, of a fumaric acid salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8a), based on the total weight of the active salt mixture; and (ii) 2% to 10% by weight, or any range therebetween, of one or more fumaric acid salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10a) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11a), based on the total weight of the active salt mixture. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) comprises a fumarate salt of DMT d-8 (a fumarate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1-d (I-6a), 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-2,2-d (I-7a), and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,2-d (I-12a)), a fumarate salt of DMT d-7, a fumarate salt of DMT d-6 (a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine (I-4a)), DMT The composition does not contain, or is substantially free of, detectable amounts of fumarate d-5, fumarate DMT d-4 (fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d4 (I-5a)), fumarate DMT d-3, fumarate DMT d-2 (fumarate salts of one or more of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 ((I-2a) and / or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-3a)), fumarate DMT d-1, and fumarate DMT (fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1a)).For example, in some embodiments, the weight of fumarate salts of isotopologues of compounds of Formula (I) not listed in (i) or (ii), e.g., DMT d-8 benzoate, DMT d-7 fumarate, DMT d-6 fumarate, DMT d-5 fumarate, DMT d-4 fumarate, DMT d-3 fumarate, DMT d-2 fumarate, DMT d-1 fumarate, and DMT fumarate, is, in total, less than 1 wt %, less than 0.75 wt %, less than 0.5 wt %, less than 0.4 wt %, less than 0.3 wt %, less than 0.25 wt %, less than 0.2 wt %, less than 0.1 wt %, or 0 wt %, based on the total weight of the active salt mixture.

[0193] In another embodiment, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90% to 98% by weight, or any range therebetween, of a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8b), based on the total weight of the active salt mixture; and (ii) 2% to 10% by weight, or any range therebetween, of one or more benzoate salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10b) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11b), based on the total weight of the active salt mixture. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) comprises a benzoate salt of DMT d-8 (a benzoate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1-d (I-6b), 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-2,2-d (I-7b), and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,2-d (I-12b)), a benzoate salt of DMT d-7, a benzoate salt of DMT d-6 (a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine (I-4b)), DMT Benzoate salt of DMT d-5, benzoate salt of DMT d-4 (benzoate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d4 (I-5b)), benzoate salt of DMT d-3, benzoate salt of DMT d-2 (benzoate salt of one or more of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2b) and / or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-3b)), DMT It does not contain detectable amounts of, or is substantially free of, the benzoate salt of d-1, and the benzoate salt of DMT (the benzoate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1b)).For example, in some embodiments, the weight of benzoate salts of isotopologues of compounds of Formula (I) not listed in (i) or (ii), e.g., DMT d-8 benzoate, DMT d-7 benzoate, DMT d-6 benzoate, DMT d-5 benzoate, DMT d-4 benzoate, DMT d-3 benzoate, DMT d-2 benzoate, DMT d-1 benzoate, and DMT benzoate, is, in total, less than 1 wt %, less than 0.75 wt %, less than 0.5 wt %, less than 0.4 wt %, less than 0.3 wt %, less than 0.25 wt %, less than 0.2 wt %, less than 0.1 wt %, or 0 wt %, based on the total weight of the active salt mixture.

[0194] In another embodiment, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90% to 98% by weight, or any range therebetween, of the salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8c), based on the total weight of the active salt mixture; and (ii) 2% to 10% by weight, or any range therebetween, of one or more salicylates of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10c) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11c), based on the total weight of the active salt mixture. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) comprises a salicylate salt of DMT d-8 (one or more of the salicylate salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1-d (I-6c), 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-2,2-d (I-7c), and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,2-d (I-12c)), a salicylate salt of DMT d-7, a salicylate salt of DMT d-6 (the salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine (I-4c)), DMT salicylate of DMT d-5, salicylate of DMT d-4 (salicylate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d4 (I-5c)), salicylate of DMT d-3, salicylate of DMT d-2 (salicylate of one or more of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2c) and / or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-3c)), DMT The composition is free from or substantially free of detectable amounts of the salicylate salt of d-1, and the salicylate salt of DMT (the salicylate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1c)).For example, in some embodiments, the weight of salicylates of isotopologues of compounds of Formula (I) not listed in (i) or (ii), e.g., DMT d-8 salicylate, DMT d-7 salicylate, DMT d-6 salicylate, DMT d-5 salicylate, DMT d-4 salicylate, DMT d-3 salicylate, DMT d-2 salicylate, DMT d-1 salicylate, and DMT salicylate, is, in total, less than 1 wt %, less than 0.75 wt %, less than 0.5 wt %, less than 0.4 wt %, less than 0.3 wt %, less than 0.25 wt %, less than 0.2 wt %, less than 0.1 wt %, or 0 wt %, based on the total weight of the active salt mixture.

[0195] In yet another embodiment, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90% to 98% by weight, or any range therebetween, of the succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8d), based on the total weight of the active salt mixture; and (ii) 2% to 10% by weight, or any range therebetween, of one or more succinate salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10d) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11d), based on the total weight of the active salt mixture. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) comprises a succinate salt of DMT d-8 (a succinate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1-d (I-6d), 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-2,2-d (I-7d), and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,2-d (I-12d)), a succinate salt of DMT d-7, a succinate salt of DMT d-6 (a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine (I-4d)), DMT succinate of DMT d-5, succinate of DMT d-4 (succinate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d4 (I-5d)), succinate of DMT d-3, succinate of DMT d-2 (succinate of one or more of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2d) and / or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-3d)), DMT The compound is free from or substantially free from detectable amounts of the succinate salt of d-1 and the succinate salt of DMT (the succinate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1d)).For example, in some embodiments, the weight of succinate salts of isotopologues of compounds of Formula (I) not listed in (i) or (ii), e.g., DMT d-8 succinate, DMT d-7 succinate, DMT d-6 succinate, DMT d-5 succinate, DMT d-4 succinate, DMT d-3 succinate, DMT d-2 succinate, DMT d-1 succinate, and DMT succinate, is, in total, less than 1 wt %, less than 0.75 wt %, less than 0.5 wt %, less than 0.4 wt %, less than 0.3 wt %, less than 0.25 wt %, less than 0.2 wt %, less than 0.1 wt %, or 0 wt %, based on the total weight of the active salt mixture.

[0196] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is chemically pure, e.g., has a chemical purity of greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% by UPLC or HPLC. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has no single impurity of greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by UPLC or HPLC. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by UPLC or HPLC. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has no single impurity of greater than 1 area%, greater than 0.5 area%, greater than 0.4 area%, greater than 0.3 area%, or greater than 0.2 area% by UPLC or HPLC.

[0197] Pharmaceutical compositions can be formulated using enantiomerically pure compounds of the present disclosure, such as compounds of Formula (I), or racemic mixtures of compounds. As described herein, racemic compounds of Formula (I) can contain about 50% of the R- and S-stereoisomers based on a molar ratio of one of the isomers (about 48 to about 52 mole %, or about a 1:1 ratio). In some embodiments, a composition, medicament, or method of treatment can involve combining separately produced R- and S-stereoisomers of a compound in an approximately equal molar ratio (e.g., about 48 to 52%). In some embodiments, a medicament or pharmaceutical composition can include a mixture of different ratios of R- and S-stereoisomers of distinct compounds. In some embodiments, a pharmaceutical composition contains an excess (greater than 50%) of the R-enantiomer. Suitable R / S molar ratios can be about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher. In some embodiments, the pharmaceutical composition can contain an excess of the S-enantiomer, reversing the provided ratio of R / S. Other suitable amounts of R / S can also be selected. For example, the R-enantiomer can be enriched, e.g., 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 can be enriched, e.g., 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%. Ratios between all of these exemplary embodiments, as well as larger and smaller ratios, are still within the scope of the present disclosure. The composition can also contain a mixture of the racemate and a separate compound of Formula (I) in salt form.

[0198] Pharmaceutical compositions may be formulated with one or more crystalline forms of a pharmaceutically acceptable salt of the compound of Formula (I), including one or more crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a single crystalline polymorph. Pharmaceutical compositions may be formulated with one or more amorphous forms of a pharmaceutically acceptable salt of the compound of Formula (I), including one or more amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a mixture of amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a single amorphous polymorph. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline and amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a highly purified crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I). For example, the pharmaceutical composition may comprise a pharmaceutically acceptable salt of the compound of Formula (I), wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of Formula (I) present in the pharmaceutical composition is in crystalline form as determined, for example, by X-ray powder diffraction and / or DSC.

[0199] The pharmaceutical composition may be in the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, suppositories, or sustained-release formulations thereof, or any other form suitable for administration to mammals. Administration of the subject compound may be systemic or local. In some cases, the pharmaceutical composition is formulated for administration to humans according to routine procedures as a pharmaceutical composition adapted for oral, intravenous, subcutaneous, intramuscular, intradermal, transdermal, or inhalation administration, or other administration routes described herein. Examples of suitable pharmaceutical vehicles and methods for their formulation are described in Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, Chapters 86, 87, 88, 91, and 92, which are incorporated herein by reference. The choice of vehicle will be determined in part by the specific compound, salt form and the specific method used to administer the composition.Therefore, there are a wide variety of suitable formulations for the subject pharmaceutical composition.The liquid form preparation includes solution and emulsion, for example, water, water / propylene glycol solution, viscous aqueous solution / suspension or organic solvent.

[0200] When administered to mammals, the compounds and compositions of the present disclosure and pharmaceutically acceptable vehicles may be sterile. In some cases, for example, when the subject compounds are administered intravenously, intradermally, intramuscularly, transdermally, or via inhalation, aqueous media such as water, saline, viscous aqueous solutions / suspensions, and aqueous dextrose and glycerol solutions are used as vehicles.

[0201] The amount of a pharmaceutically acceptable salt of a compound of formula (I) in a unit dose preparation may, for example, be (on an active basis) 0.001 mg to 1000 mg, 0.001 mg to 500 mg, 0.001 mg to 100 mg, or 0.001 mg to 75 mg, or 0.001 mg to 50 mg, or 0.001 mg to 25 mg, or 0.001 mg to 10 mg, or 0.01 mg to 8 mg, or 0.1 mg to 5 mg, or 1 mg to 3 mg, or 0.0 The dosage may be modified or adjusted to provide 0.1 mg, 0.01 mg, 0.1 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, about 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, or any range therebetween of a compound of formula (I), or as deemed appropriate using sound medical judgment depending on the particular use, route of administration, potency of the active ingredient, etc. The composition may also include other compatible therapeutic agents, if desired.

[0202] In some embodiments, the pharmaceutical composition comprises at least 0.1%, at least 0.5%, at least 1%, 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%, and up to 99.9%, up to 99.5%, up to 99%, up to 98%, up to 97%, up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55% by weight of a pharmaceutically acceptable salt of a compound of Formula (I), based on the total weight of the pharmaceutical composition.

[0203] The pharmaceutical compositions disclosed herein can be administered at once or multiple times at intervals.It is understood that the exact dosage and duration of treatment can vary according to the age, weight and condition of the patient being treated, and can be empirically determined by using known testing protocols or by extrapolating from in vivo or in vitro testing or diagnostic data.It is understood that for any specific individual, specific dosage regimen can be adjusted over time, and in some cases should be adjusted, according to individual need and the professional judgment of the person who manages or supervises the administration of preparations.

[0204] If the patient's condition does not improve, at the physician's discretion, the compounds may be administered chronically, i.e., over an extended period throughout the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0205] If the patient's condition improves, the compound may be given continuously or temporarily discontinued for a period of time (ie, a "drug holiday"), at the physician's discretion.

[0206] Once the patient's condition has improved, a maintenance dose can be administered as needed. Thereafter, the dose or frequency of administration, or both, can be reduced depending on the symptoms, to a level at which the improved condition is maintained. However, the patient may require intermittent treatment for a long period of time if symptoms recur.

[0207] In some embodiments, the pharmaceutical composition has an onset of therapeutic action within 60, 50, 40, 30, 20, 10, or 5 minutes. In some embodiments, the pharmaceutical composition has a duration of acute effect of 480, 420, 360, 300, 240, 180, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, or 5 minutes or less. In some embodiments, the pharmaceutical composition has a drug dissolution time of 120, 90, 60, 50, 40, 30, 20, 10, or 5 seconds or less.

[0208] As described below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid, semi-solid, or liquid form, including those compatible with the following: A. Oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, films, or capsules, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue, etc.; B. Parenteral administration, such as subcutaneous, intradermal, intramuscular, intravenous, or epidural injection, as a sterile solution or suspension, or sustained release formulation, including viscous aqueous solutions / suspensions or others that produce a depot effect; C. Topical / transdermal administration, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin, or to mucosal surfaces such as orifices and / or nasal cavities, e.g., as an aqueous or non-aqueous solution, suspension, liposomal dispersion, emulsion, microemulsion, or sol-gel, e.g., intravaginally or rectally as a pessary, cream, or foam; D. Modified-release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, and programmed-release, and gastroretentive dosage forms, which can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126); and E. Inhalation administration, eg, as an aerosol, preferably as a mist.

[0209] Any pharmaceutical composition described herein can include (as an active ingredient) at least one pharmaceutically acceptable salt of a compound of Formula (I) described herein. Tamper-resistant dosage forms / packaging of any disclosed pharmaceutical composition are contemplated.

[0210] A. Oral Administration The pharmaceutical compositions disclosed herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration, including both intestinal / gastric delivery routes and oral routes such as buccal, lingual, and sublingual administration.Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.The oral dosage forms of the present disclosure can optionally be formulated with a monoamine oxidase (MAO) inhibitor, including a reversible inhibitor of monoamine oxidase type A (RIMA), to improve the oral bioavailability of the compound of Formula (I) by minimizing the enzymatic degradation mediated by MAO enzymes, such as deamination / oxidation processes. In addition to the active ingredient and optional MAO inhibitor, the pharmaceutical composition may contain one or more pharmaceutically acceptable vehicles, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, preservatives, antioxidants, lyoprotectants, stabilizers, solubilizers, complexing agents, and flavoring agents.

[0211] Binders or granulating agents impart cohesiveness to the tablet and ensure that it remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isagol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan (larch). Suitable fillers include, but are not limited to, cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, and AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions disclosed herein in an amount of, for example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 99% by weight, or any range therebetween.

[0212] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.When present in sufficient amounts, certain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol can impart the properties of some compressed tablets that can be disintegrated in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

[0213] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV, citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; alain; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions disclosed herein varies depending on the type of formulation and is readily discernible by those skilled in the art. The pharmaceutical compositions disclosed herein may contain, for example, about 0.5 to about 15% by weight, or about 1 to about 5% by weight, of disintegrant.

[0214] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as glycerol behenate and polyethylene glycol (PEG), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil, zinc stearate, ethyl oleate, ethyl laurate, agar, starch, lycopodium, silica, or silica gel, such as AEROSIL® 200 (WR Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co. of Boston, Mass.), and mixtures thereof. The pharmaceutical compositions disclosed herein may contain, for example, about 0.1 to about 5% by weight of a lubricant.

[0215] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc.

[0216] Coloring agents include any of the approved, certified, water-soluble FD&C dyes and insoluble FD&C dyes suspended on alumina hydrate, as well as color lakes and mixtures thereof. Color lakes are combinations of water-soluble dyes by adsorption onto hydrous heavy metal oxides, resulting in an insoluble form of the dye.

[0217] Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.

[0218] Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweetening agents, such as saccharin and aspartame.

[0219] Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.

[0220] Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

[0221] Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0222] Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0223] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0224] It is understood that many vehicles can serve multiple functions, even within the same formulation.

[0225] The pharmaceutical compositions disclosed herein may be formulated as compressed tablets, capsules, caplets, gel capsules, and capsule compositions, tablet crushers, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, or enteric-coated tablets, caplets, and capsules, sugar-coated tablets, caplets, and capsules, or film-coated tablets, caplets, and capsules. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be useful for masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets produced by multiple compression cycles, including layered tablets, compression-coated tablets, or dry-coated tablets. The oral pharmaceutical composition of the present disclosure may be a solid dosage form intended for oral administration, obtained, for example, by dry granulation through single or multiple compression of powder or granules. In some embodiments, the oral pharmaceutical composition may be obtained using wet granulation techniques. In some embodiments, the oral pharmaceutical composition may be obtained by molding, heating / annealing, or extrusion techniques.

[0226] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more vehicles described herein, including binders, disintegrants, release-controlling polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0227] In some embodiments, a pharmaceutical composition (e.g., a tablet composition formulated for oral administration, such as a monolayer tablet composition) comprises any of the pharmaceutically acceptable salts of a compound of Formula (I) described herein and a polymer.

[0228] In some embodiments, the tablet composition is a modified release tablet adapted for sustained release, for example, maximum sustained release. In some embodiments, in the formulations of the present disclosure, the release duration of any of the compounds described herein (e.g., compounds of formula (I)) is more than 4 hours, more than 6 hours, more than 8 hours, more than 10 hours, more than 12 hours, more than 16 hours, more than 20 hours, more than 24 hours, more than 28 hours, more than 32 hours, more than 36 hours, more than 48 hours.

[0229] In some embodiments, the tablet composition is adapted for tamper resistance. In some embodiments, the tablet composition comprises polyethylene oxide (PEO) of about 2,000 to about 7,000 KDa MW, e.g., in combination with HPMC. In some embodiments, the tablet composition may further comprise polyethylene glycol (PEG), e.g., PEG8K. In some embodiments, the tablet composition may further comprise a polymer carrying one or more negatively charged groups, e.g., polyacrylic acid. In some embodiments, the tablet composition comprising PEO is further subjected to heating / annealing, e.g., extrusion conditions.

[0230] In some embodiments, the pharmaceutical composition comprises (i) a water-insoluble, neutrally charged non-ionic matrix, (ii) a polymer bearing one or more negatively charged groups, and (iii) any of the pharmaceutically acceptable salts of a compound of Formula (I) described herein.

[0231] In some embodiments, the polymer carrying one or more negatively charged groups is selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite, hyaluronic acid, anionic gums, salts thereof, or mixtures thereof. In some embodiments, the anionic gum is selected from the group consisting of naturally occurring substances and semi-synthetic substances. In some embodiments, the naturally occurring substances are selected from the group consisting of alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, gum karaya, guar gum, and gum tragacanth. In some embodiments, the semi-synthetic substances are selected from the group consisting of carboxymethyl-chitin and cellulose gum.

[0232] Furthermore, without intending to be bound by theory, in some embodiments, the role of a polymer bearing one or more negatively charged groups, e.g., a moiety of acidic nature, such as the acidic polymers described herein, surprisingly results in significant retention of any compound described herein (e.g., a compound of Formula (I)) in the matrix. In some embodiments, this negative charge can be generated in situ, for example, based on the release of a proton due to the pKa and under certain pH conditions, or through electrostatic interaction / negative charge generation. It is further noted that the acidic polymer can be a salt of a corresponding weak acid that becomes the relevant protonated acid in the stomach. Without wishing to be bound by theory, this can neutralize the charge and reduce the interaction of any compound described herein with the matrix. Furthermore, the release matrix can be further complemented with other inert pharmaceutical ingredients, such as fillers, disintegrants, flow improvers, lubricants, colorants, taste-masking agents, etc., to aid in the preparation of a suitable solid dosage form.

[0233] In some embodiments, the water-insoluble, neutrally charged nonionic matrix is ​​selected from a cellulosic polymer such as HPMC, alone or reinforced by blending with a component selected from the group consisting of starch; wax; neutral gum; polymethacrylate; PVA; PVA / PVP blend; and mixtures thereof. In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC).

[0234] In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC). In some embodiments, the tablet composition comprises about 10-70%, 20-60%, or 30-50% by weight of hydroxypropyl methylcellulose, about 10-30%, or 15-20% by weight of starch, or any combination thereof.

[0235] The dosage form may be an immediate release (IR) dosage form, examples of which include, but are not limited to, immediate release (IR) tablets or immediate release (IR) capsules. Dosage forms adapted for immediate release may contain one or more pharmaceutically acceptable vehicles that readily disperse, dissolve, or disintegrate in the gastric environment so as not to delay or prolong the dissolution / absorption of the active ingredient. Examples of pharmaceutically acceptable vehicles for immediate release dosage forms include, but are not limited to, one or more binders / granulating agents, matrix materials, fillers, diluents, disintegrants, dispersants, solubilizers, lubricants, and / or performance modifiers. In some embodiments, the immediate release (IR) dosage form is an immediate release (IR) tablet containing one or more of microcrystalline cellulose, sodium carboxymethylcellulose, magnesium stearate, mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the immediate release (IR) dosage form contains microcrystalline cellulose, sodium carboxymethylcellulose, and magnesium stearate. In some embodiments, the immediate release (IR) dosage form comprises mannitol, crospovidone, and sodium stearyl fumarate.

[0236] The pharmaceutical compositions disclosed herein can be formulated as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two compartments, one sliding over the other to completely enclose the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methylparaben, propylparaben, and sorbic acid. The liquid, semisolid, and solid dosage forms disclosed herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsules may also be coated as known by those skilled in the art to modify or maintain dissolution of the active ingredient.

[0237] The pharmaceutical compositions disclosed herein may be in the form of an orodispersible dosage form (ODF). Such dosage forms, for example, when administered intraorally through the mucosal lining of the oral cavity, e.g., buccal, lingual, and sublingual administration, have increased bioavailability and a more rapid onset of action compared to oral administration via the gastrointestinal tract, allowing pregastric absorption of the compounds / salts herein. Orodispersible dosage forms can be prepared by various techniques, such as freeze-drying (lyophilization), molding, spray-drying, mass extrusion, or compression. Preferably, the orodispersible dosage form is prepared by lyophilization. In some embodiments, the orodispersible dosage form disintegrates in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being received in the oral cavity. In some embodiments, the orodispersible dosage form dissolves in less than about 90 seconds, less than about 60 seconds, or less than about 30 seconds after being received in the oral cavity. In some embodiments, the orodispersible dosage form disperses in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being placed in the oral cavity. In some embodiments, the pharmaceutical composition meets the United States Pharmacopeia (USP) disintegration test in less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds. <701> The disintegration time is in the form of an orodispersible dosage form such as an orally disintegrating tablet (ODT) that conforms to the United States Pharmacopeia (USP) Disintegration Test. <701> In accordance with the above, orodispersible dosage forms having longer disintegration times, e.g., 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, or any range therebetween, or longer, are also contemplated, e.g., when adapted for sustained release.

[0238] In some embodiments, the orodispersible dosage form is a sublingual dosage form that disintegrates / dissolves under the tongue, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the sublingual dosage form disintegrates / dissolves under the tongue, whereby when mixed with saliva, it is converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, which is then swallowed. In some embodiments, the orodispersible dosage form (ODx) is an oral dosage form that disintegrates / dissolves in the oral cavity, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the oral mucous membrane and enter the venous circulation there. In some embodiments, the oral dosage form disintegrates / dissolves in the oral cavity, whereby when mixed with saliva, it is converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, which is then swallowed.

[0239] In some embodiments, the pharmaceutical composition is in the form of an orodispersible dosage form, such as a fast-dissolving tablet, also known as an orodispersible tablet (ODT) or fast-dispersing tablet (FDT). Fast-dissolving tablets can be prepared by various techniques, such as freeze-drying (lyophilization), molding, spray-drying, bulk extrusion, or compression. Fast-dissolving tablets are preferably prepared by freeze-drying. In some embodiments, fast-dissolving tablets disintegrate in the oral cavity in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being placed in the oral cavity. In some embodiments, fast-dissolving tablets dissolve in less than about 90 seconds, less than about 60 seconds, or less than about 30 seconds when placed in an aqueous environment, such as the oral cavity.

[0240] In some embodiments, the pharmaceutical composition is in the form of a lyophilized FDT. In some embodiments, the lyophilized FDT is prepared by creating a porous matrix by sublimating water from a pre-frozen aqueous formulation of the drug containing a matrix-forming agent and other vehicles as described herein, such as one or more cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc. In some embodiments, the FDT comprises a two-component framework of a lyophilized matrix system that works together to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, and maltodextrin. This component maintains shape and provides mechanical strength to the tablet (binder). In some embodiments, the second component is a matrix support / disintegration promoter such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and / or starch, which acts by adhering the porous framework provided by the water-soluble polymer and accelerating the disintegration of the FDT. In some embodiments, the lyophilized FDT comprises gelatin and mannitol. In some embodiments, the lyophilized orodispersible dosage form (e.g., lyophilized FDT) comprises gelatin, mannitol, and one or more of a cryoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, etc., with particular reference to citric acid. A non-limiting example is Zydis® orally dispersible tablets (available from Catalent). In some embodiments, the formulation (e.g., Zydis® orally dispersible tablets) comprises one or more water-soluble polymers, such as gelatin, one or more matrix materials, fillers, or diluents, such as mannitol, a pharmaceutically acceptable salt of the compound of Formula (I), and optionally a cryoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, and / or a flavoring agent. In some embodiments, the formulation (e.g., Zydis® orally dispersible tablets) comprises gelatin, mannitol, a pharmaceutically acceptable salt of the compound of Formula (I), and an organic acid, non-limiting examples of which are citric acid and / or tartaric acid.

[0241] In some embodiments, the pharmaceutical composition is in the form of an orodispersible dosage form, such as a lyophilized wafer. In some embodiments, the pharmaceutical composition is in the form of a lyophilized wafer protected for long-term storage by special packaging that excludes moisture, oxygen, and light. In some embodiments, the lyophilized wafer is produced by sublimating water from a pre-frozen aqueous formulation of a drug-containing matrix-forming agent and a cryoprotectant, and other excipients such as lyoprotectants, preservatives, and flavoring agents, to produce a porous matrix. In some embodiments, the lyophilized wafer comprises a thin, water-soluble film matrix. In some embodiments, the wafer comprises a two-component framework of a lyophilized matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer, such as gelatin, dextran, alginate, and maltodextrin. This component maintains shape and provides mechanical strength to the wafer (binder). In some embodiments, the second component is a matrix support / disintegration promoter, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and / or starch, which acts by adhering the porous framework provided by the water-soluble polymer, accelerating the disintegration of the wafer. In some embodiments, the freeze-dried wafer includes gelatin and mannitol. In some embodiments, the freeze-dried wafer includes gelatin, mannitol, and one or more of a cryoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, etc., with particular reference to citric acid.

[0242] In some embodiments, the wafer can comprise a single layer, a double layer, or a triple layer. In some embodiments, a single layer wafer contains an active agent and one or more vehicles, such as those described herein. In some embodiments, a double layer wafer contains one or more vehicles, such as a solubilizing agent, in a first layer and an active agent in a second layer. This configuration allows the active agent to be stored separately from the vehicle, increasing the stability of the active agent and optionally increasing the shelf life of the composition compared to when the vehicle and active agent are contained in a single layer. For triple layer wafers, each layer can be different, or two layers, such as the top and bottom layers, can have substantially the same composition. In some embodiments, the bottom and top layers surround a core layer containing the active agent. In some embodiments, the bottom and top layers can include one or more vehicles, such as a solubilizing agent. In some embodiments, the bottom and top layers have the same composition. Alternatively, the bottom and top layers can include different vehicles or different amounts of the same vehicle. The core layer typically contains an active agent and optionally one or more vehicles.

[0243] Pharmaceutically acceptable vehicles (e.g., carriers or excipients) that may be used in orodispersible dosage forms (ODFs) include, but are not limited to, cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, cyclodextrins, bioadhesives, permeation / absorption enhancers, or other pharmaceutically acceptable vehicles listed herein.

[0244] Examples of pharmaceutically acceptable cryoprotectants include, but are not limited to, disaccharides such as sucrose and trehalose, anionic polymers such as sulfobutylether-β-cyclodextrin (SBECD) and hyaluronic acid, and hydroxylated cyclodextrins.

[0245] Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0246] Examples of pharmaceutically acceptable antioxidants that may serve to further enhance the stability of the compositions include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​or its salts (cysteine ​​hydrochloride), sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0247] Examples of pharmaceutically acceptable 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, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerin, methionine, monothioglycerin, ascorbic acid, citric acid, polysorbates, arginine, cyclodextrin, microcrystalline cellulose, modified cellulose (e.g., carboxymethylcellulose, sodium salt), sorbitol, and cellulose gels.

[0248] Examples of pharmaceutically acceptable solubilizers (or solubilizing agents) include citric acid, hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyl 40 stearate, purified shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethylethylcellulose, powdered agar, guar gum, succinic acid, copolyvidone, cellulose acetate phthalate, tartaric acid, sodium dioctyl sulfosuccinate, zein, nonfat powdered milk, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethylmethylcellulose, cellulose acetate phthal ... Examples of suitable surfactants include, but are not limited to, cellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, poly(sodium 4-styrenesulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, lauromacrogol, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyltryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate. Of these, citric acid is preferred in some embodiments, such as ODT formulations.

[0249] Flavoring agents include natural flavors extracted from plants such as fruit, and synthetic blends of compounds that produce a pleasant taste and taste-masking effect.Examples of flavoring agents include, but are not limited to, aspartame, saccharin (as sodium, potassium, or calcium saccharin), cyclamate (as sodium, potassium, or calcium salt), sucralose, acesulfame K, thaumatin, neohisperidin, dihydrochalcone, ammoniated glycyrrhizin, glucose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, wintergreen oil, peppermint oil, methyl salicylate, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, lemon, lime, and lemon lime.

[0250] Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance delivery of the compositions described herein.

[0251] Examples of suitable bioadhesives include, but are not limited to, cyclodextrins, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose, modified cellulose gums, and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately crosslinked starch, modified starch, and sodium starch glycolate; acrylic polymers such as carbomer and its derivatives (polycarbophil, Carbopol®, etc.); polyvinylpyrrolidone (PVP); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, and pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride); and croscarmellose (e.g., croscarmellose sodium). Such polymers may be crosslinked. Combinations of two or more bioadhesives may also be used.

[0252] Examples of permeation agents / absorption enhancers include, but are not limited to, sulfoxides such as dodecyl methyl sulfoxide, octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxy-undecyl methyl sulfoxide, 2-hydroxydodecyl methyl sulfoxide; menthol; surfactant-lecithin organogel (PLO) formed from an aqueous phase having one or more of poloxamer, CARBOPOL, and PEMULEN, an oily phase formed from one or more of isopropyl palmitate and PPG-2 myristyl ether propionate, and lecithin; fatty acids, esters, and alcohols such as oleic acid and oleyl alcohol; keto acids such as levulinic acid; glycols and glycol ethers, for example, diethylene glycol monoethyl ether; including mixtures thereof.

[0253] Disclosed herein is a pharmaceutical composition in a controlled release dosage form, comprising a compound disclosed herein and one or more of the release-controlling excipients or carriers described herein.Suitable controlled release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof.The pharmaceutical composition may also contain non-release-controlling excipients or carriers.

[0254] Further disclosed herein are enteric-coated pharmaceutical compositions comprising a compound disclosed herein and one or more controlled-release excipients or carriers for use in enteric-coated dosage forms. The pharmaceutical compositions may also include non-controlled-release excipients or carriers.

[0255] Further disclosed are effervescent dosage forms of pharmaceutical compositions comprising a compound disclosed herein and one or more controlled-release excipients or carriers for use in effervescent dosage forms. The pharmaceutical compositions may also include non-controlled-release excipients or carriers.

[0256] Further disclosed are pharmaceutical compositions in dosage forms having an immediate release component and at least one delayed release component, capable of discontinuously releasing the compound in at least two successive pulses separated by about 0.1 up to about 24 hours (e.g., about 0.1, 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 10, 22, or 24 hours). The pharmaceutical compositions include a compound disclosed herein and one or more controlled-release and non-controlled-release excipients or carriers, such as excipients or carriers suitable for disrupting semipermeable membranes and swellable materials.

[0257] Also disclosed herein are pharmaceutical compositions in dosage forms for oral administration to a subject, comprising a salt form of a compound disclosed herein and one or more pharmaceutically acceptable vehicles encapsulated in an intermediate reactive layer comprising a gastric juice-resistant outer layer, a gastric juice-resistant polymer layer material partially neutralized with alkali and having cation exchange capacity.

[0258] In some embodiments, the pharmaceutical composition is in the form of an immediate release capsule for oral administration and may further comprise cellulose, iron oxide, lactose, magnesium stearate, and sodium starch glycolate.

[0259] In some embodiments, the pharmaceutical composition is in the form of a delayed-release capsule for oral administration and may further comprise cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

[0260] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed-release tablet for oral administration and may further comprise carnauba wax, crospovidone, diacetylated monoglyceride, ethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0261] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed-release tablet for oral administration and may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0262] Also disclosed herein are pharmaceutical compositions in effervescent dosage forms comprising a pharmaceutically acceptable salt of a compound of Formula (I) and one or more pharmaceutically acceptable vehicles, which may be controlled-release vehicles and / or non-controlled-release vehicles. Effervescent means that the dosage form releases gas when mixed with a liquid, including water, juice, saliva, and the like. In some embodiments, the effervescent dosage forms of the present disclosure comprise an organic acid and a carbon dioxide source, referred to herein as an "effervescent couple." Such effervescent dosage forms effervescent (gas-releasing) through a chemical reaction between the organic acid and the carbon dioxide source. Effervescence occurs when exposed to an aqueous environment, such as when placed in water, juice, or other drinkable liquid, or from the aqueous environment in the oral cavity, such as saliva in the mouth. Specifically, carbon dioxide gas is produced by the reaction between the organic acid and the carbon dioxide source upon contact with an aqueous medium, such as water, juice, or saliva. While the use of a disintegrant is optional, effervescent dosage forms do not require a disintegrant because they facilitate in situ gas release and accelerate the disintegration process.

[0263] For purposes of clarity, "effervescent couple" refers to at least one organic acid and at least one carbon dioxide source, regardless of assembly. For example, the organic acid and carbon dioxide source may be mixed (as powders), layered on top of each other, agglomerated or otherwise "glued" together in the form of granules, or kept separate from each other, for example, in separate layers within a dosage form. Furthermore, the term "couple" in this context is not intended to be limited to only organic acid and carbon dioxide source, but is open to the inclusion of other materials unless otherwise specified. For example, an effervescent aggregate / granule made by combining (or gluing) an organic acid and a carbon dioxide source may include other vehicles, including a binder (adhesive), and the effervescent aggregate / granule may be referred to as an effervescent couple.

[0264] The organic acid may be a mono-, di-, tri-, tetra-, or may contain more acid groups. One organic acid or a mixture of organic acids may be used. In addition to an acid group (e.g., one or more carboxylic acid moieties), the organic acid may also contain one or more hydroxyl functional groups as part of its structure (i.e., the organic acid may be a hydroxy acid). In some embodiments, the organic acid is an alpha-hydroxy acid. In some embodiments, the organic acid is a beta-hydroxy acid. In some embodiments, the organic acid is a gamma-hydroxy acid. Examples of hydroxy acids include, but are not limited to, glycolic acid, lactic acid, citric acid, tartaric acid, and malic acid. In some embodiments, the organic acid is citric acid and / or tartaric acid. In some embodiments, the organic acid is citric acid. In some embodiments, the organic acid is tartaric acid. In some embodiments, the organic acid is an enedioic acid, examples of which include, but are not limited to, fumaric acid and maleic acid. In some embodiments, the organic acid is fumaric acid. In some embodiments, the organic acid is maleic acid. Mixtures and / or hydrates of the disclosed organic acids can also be used in the pharmaceutical compositions of the present disclosure. In some embodiments, the organic acid is not a sulfonic acid (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, the organic acid is not a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.).

[0265] Carbon dioxide sources include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, and sesquicarbonate. Carbon dioxide sources may be used alone or in combination. In some embodiments, the carbon dioxide source is sodium bicarbonate. In some embodiments, the carbon dioxide source is sodium carbonate. In some embodiments, the carbon dioxide source is potassium carbonate. In some embodiments, the carbon dioxide source is potassium bicarbonate. However, reactants that release gases other than oxygen or carbon dioxide and that are safe for human consumption are also contemplated for use in the disclosed effervescent dosage forms in addition to or in place of a carbon dioxide source. Without wishing to be bound by theory, it is believed that effervescence helps to rapidly disintegrate the dosage form and, with some routes of administration, such as the oral route, may help reduce the perception of grittiness by providing a distracting effervescent sensory experience.

[0266] In some embodiments, the effervescent dosage form is reconstituted in a drinkable fluid, such as water or juice, to form an oral liquid dosage form (e.g., a solution), which is then ingested. In some embodiments, the effervescent dosage form is placed in the oral cavity, where it comes into contact with an aqueous environment (saliva) and effervesces, causing disintegration / dissolution of the dosage form. Here, the contents of the effervescent dosage form are converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, by mixing with saliva, and then swallowed. Alternatively, the effervescent dosage form may be an intraoral dosage form, such as a buccal, lingual, or sublingual dosage form, where it is placed in the aqueous environment (saliva) of the oral cavity, effervescence causes disintegration / dissolution of the dosage form, and the contents are pregastricly absorbed through the oral mucosa. Such pregastric absorption may increase bioavailability and provide a rapid onset of action compared to oral administration via the digestive tract. In some embodiments, the effervescent dosage form is a sublingual dosage form that disintegrates / dissolves under the tongue, thereby allowing the contents (e.g., a compound of the present disclosure) to be absorbed through the mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the effervescent dosage form is an oral dosage form that disintegrates / dissolves in the oral cavity, thereby allowing the contents (e.g., a compound of the present disclosure) to be absorbed through the mucous membrane of the oral cavity and enter the venous circulation there. Because effervescent dosage forms can be reconstituted into an easy-to-swallow liquid or semi-solid dosage form or taken orally, they may be beneficial for treating pediatric / adolescent patients or patients who generally have difficulty swallowing conventional dosage forms, such as regular tablets or capsules.

[0267] When adapted for oral administration, it may be beneficial to formulate the effervescent dosage form with a bioadhesive in addition to the effervescent couple. A "bioadhesive" is a substance that promotes adhesion or attachment to a biological surface, such as a mucous membrane. For example, a bioadhesive can adhere to the biological surface when placed in contact with the surface (e.g., a mucous membrane), thereby allowing the composition of the present disclosure to adhere to the surface and promoting efficient transfer of the contents of the dosage form to the biological surface. Various polymers known in the art can be used as bioadhesives, such as polymeric substances, preferably those having an average (weight-average) molecular weight of greater than 5,000 g / mol. Preferably, such polymeric substances are capable of rapidly swelling when placed in contact with an aqueous medium, such as water or saliva, and / or are substantially insoluble in water at room temperature and atmospheric pressure. Examples of suitable bioadhesives include, but are not limited to, cyclodextrins, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose, modified cellulose gums, and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately crosslinked starch, modified starch, and sodium starch glycolate; acrylic polymers such as carbomer and its derivatives (polycarbophil, Carbopol®, etc.); polyvinylpyrrolidone (PVP); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, and pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride); and croscarmellose (e.g., croscarmellose sodium). Such polymers may be crosslinked. Combinations of two or more bioadhesives may also be used.

[0268] The effervescent couple can be coated with a pharmaceutically acceptable vehicle, such as, for example, a binder, a protective coating, e.g., a solvent protective coating, an enteric coating, an anti-caking agent, and / or a pH adjuster, to prevent premature reaction, e.g., from air, humidity, and / or other components contained in the pharmaceutical composition. Each component of the effervescent couple, e.g., an organic acid and / or a carbon dioxide source, can also be individually coated with a pharmaceutically acceptable vehicle, e.g., a binder, a protective coating, e.g., a solvent protective coating, an enteric coating, an anti-caking agent, and / or a pH adjuster, to prevent premature reaction, e.g., from air, humidity, and / or other components contained in the pharmaceutical composition. The effervescent couple can also be mixed with previously lyophilized particles, e.g., one or more pharmaceutically active ingredients coated with a solvent protective coating or an enteric coating.

[0269] Effervescent dosage forms may be made by methods known to those skilled in the art including, but not limited to, slugging, direct compression, roller compaction, dry or wet granulation, melt granulation, melt granulation, vacuum granulation, and fluidized bed spray granulation, any of which may optionally be followed by compression / tabletting.

[0270] The pharmaceutical compositions disclosed herein may be formulated as non-effervescent or effervescent granules and powders. The non-effervescent or effervescent granules and powders may be reconstituted into a liquid dosage form or alternatively compressed to form either non-effervescent or effervescent tablet dosage forms, respectively. Pharmaceutically acceptable vehicles used in non-effervescent or effervescent granules or powders include, but are not limited to, binders, granulators, fillers, diluents, sweeteners, wetting agents, stabilizers, solubilizers, anti-caking agents, pH adjusters, or any other pharmaceutical vehicle described herein. In some embodiments, the pharmaceutically acceptable vehicle comprises an organic acid, such as glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and / or maleic acid.

[0271] Pharmaceutically acceptable vehicles used in effervescent granules or powders include an effervescent couple, i.e., an organic acid and a carbon dioxide source. Effervescent powders can be produced by blending or mixing an organic acid and a carbon dioxide source (the effervescent couple) with any other desired pharmaceutically acceptable vehicle. Effervescent granules can be produced by physically adhering or "gluing" the effervescent couple (organic acid and carbon dioxide source) together using an edible or pharmaceutically acceptable binder, including, for example, polyvinylpyrrolidone, polyvinyl alcohol, L-leucine, polyethylene glycol, gum arabic, and combinations thereof. These types of granules are generally made by a process known as "wet granulation." Granulation solvents, such as ethanol and / or isopropyl alcohol, are often used to aid this type of granulation process. Because the effervescent couple is physically bound together in the granules, the gas-generating reaction is usually very vigorous, leading to rapid dissolution. Another type of "wet granulation" product specific to effervescent products is known as a "fused" granule. These granules are formed by reacting an organic acid and a carbon dioxide source in a highly controlled manner with small amounts of water (or sometimes a hydroalcoholic granulation solvent, such as various commercial grades of ethanol or isopropyl alcohol). Because the effervescent reaction produces carbon dioxide, fused granules tend to be very porous, which reduces their density and dissolution time. Therefore, effervescent granules prepared by wet granulation or fusion processes may be desirable for making orodispersible dosage forms or other dosage forms requiring rapid dissolution / disintegration performance. Effervescent tablet dosage forms prepared by tableting, e.g., compression, of effervescent granules or powders are also included in the present disclosure.

[0272] The pharmaceutical compositions disclosed herein may be formulated as liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.

[0273] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form (e.g., an effervescent dosage form) disclosed herein into a pharmaceutically acceptable liquid medium (e.g., an aqueous medium) such as, for example, water, juice, or other drinkable fluid prior to use. In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising a crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I) into a pharmaceutically acceptable aqueous medium. In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising a non-crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I) into a pharmaceutically acceptable aqueous medium.

[0274] Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and, optionally, a preservative. Aqueous alcoholic solutions may contain a pharmaceutically acceptable di(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and a water-miscible solvent containing one or more hydroxyl groups, e.g., propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. For a liquid dosage form, the solution, for example, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.

[0275] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients disclosed herein and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, and polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weights of the polyethylene glycol. These formulations may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. In some embodiments, examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0276] Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance delivery of the compositions described herein.

[0277] The pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres, or nanosystems.

[0278] The pharmaceutical compositions disclosed herein can be disclosed as non-effervescent or effervescent granules and powders that can be reconstituted into liquid dosage forms.The pharmaceutically acceptable vehicle used in the non-effervescent granules or powders can include diluents, sweeteners, and wetting agents.The pharmaceutically acceptable vehicle used in the effervescent granules or powders can include organic acids and carbon dioxide sources.

[0279] Coloring and flavoring agents may be used in all of the above dosage forms.

[0280] The pharmaceutical compositions disclosed herein may be co-formulated with other active ingredients that do not impair the desired therapeutic effect, or with substances that complement the desired effect. One example is an oral dosage form formulated with a monoamine oxidase (MAO) inhibitor, including a reversible inhibitor of monoamine oxidase type A (RIMA), to improve the oral bioavailability of the compound of Formula (I) by minimizing enzymatic degradation mediated by MAO enzymes, such as deamination / oxidation processes.

[0281] B. Parenteral Administration The pharmaceutical compositions disclosed herein can be administered parenterally by injection, infusion, perfusion, or implantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intradermal, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0282] The pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, supra).

[0283] In some embodiments, the pharmaceutical composition is in the form of an injectable (liquid) dosage form (e.g., for administration intravenously, intramuscularly, subcutaneously, etc.). In some embodiments, an injectable (liquid) dosage form (e.g., for administration intravenously, intramuscularly, subcutaneously, etc.) is prepared by reconstituting a solid dosage form disclosed herein in a pharmaceutically acceptable liquid medium, such as water, saline, a viscous aqueous solution / suspension, a water-miscible vehicle (e.g., an organic solvent such as N-methyl-2-pyrrolidone), etc., prior to use. In some embodiments, an injectable (liquid) dosage form is prepared by reconstituting a solid dosage form comprising a crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I) in a pharmaceutically acceptable liquid medium. In some embodiments, an injectable (liquid) dosage form is prepared by reconstituting a solid dosage form comprising a non-crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I) in a pharmaceutically acceptable liquid medium.

[0284] Pharmaceutical compositions intended for parenteral administration may contain one or more pharmaceutically acceptable vehicles, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizing agents, solubilizing agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, cryoprotectants, thickening or viscosity-building agents, pH-adjusting agents, and inert gases.

[0285] Suitable aqueous vehicles include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil, and medium-chain triglycerides of palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0286] Suitable antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propylparaben, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate, acetate, and citrate buffers. Suitable antioxidants include those described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including ca-cyclodextrin, β-cyclodextrin, hydroxypropyl-3-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.). Suitable thickening or viscosity-building agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose (e.g., sodium carboxymethylcellulose), hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, crosslinked versions of any of the above, and combinations of the above.

[0287] In some embodiments, the pharmaceutical composition is in an injectable (liquid) dosage form. In some embodiments, the injectable (liquid) dosage form comprises a pharmaceutically acceptable salt of the compound of Formula (I), an aqueous vehicle (e.g., isotonic saline), a buffer (e.g., citrate buffer), optionally a pH adjuster (e.g., sodium hydroxide), and optionally an isotonic agent. In some embodiments, the injectable (liquid) dosage form comprises a pharmaceutically acceptable salt of the compound of Formula (I), an aqueous vehicle (e.g., isotonic saline), and a pH adjuster (e.g., sodium hydroxide), and the injectable (liquid) dosage form is formulated without a buffer (e.g., citrate buffer). In some embodiments, the injectable (liquid) dosage form is prepared by reconstituting a solid dosage form comprising a crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I) in an aqueous vehicle such as isotonic saline. Reconstitution of the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I) can be performed immediately before use.

[0288] The pharmaceutical compositions disclosed herein can be formulated for single or multiple dose administration.Single dose preparations are packaged in ampoules, vials or syringes.Multiple dose parenteral preparations must contain antimicrobial agents at bacteriostatic or fungistatic concentrations.All parenteral preparations must be sterile, as is known and practiced in the art.

[0289] In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile solutions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry soluble products, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile suspensions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry insoluble products, which are reconstituted with a vehicle before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile emulsions.

[0290] The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot or to produce a depot-like effect.

[0291] In some embodiments, the pharmaceutical compositions disclosed herein are dispersed in a solid internal matrix surrounded by an outer polymer membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse sufficiently.Suitable internal matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate. Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene-propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate copolymer with vinyl chloride, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer.

[0292] In some embodiments, the pharmaceutical composition is in the form of an injectable viscous aqueous solution / suspension to provide slow / sustained absorption or a depot-like effect. Here, viscosity-building pharmaceutical vehicles, such as thickening or viscosity-building agents, may be used, including, but not limited to, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose (e.g., sodium carboxymethylcellulose), hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the above. In some embodiments, the pharmaceutically acceptable vehicle comprises sodium carboxymethylcellulose, hyaluronic acid and its salts, or a combination thereof. In some embodiments, the pharmaceutically acceptable vehicle comprises hyaluronic acid and its salts. Such viscous aqueous solution / suspension dosage forms may be particularly suitable for subcutaneous injection or intramuscular administration, where the active ingredient may be slowly released from the injection site and absorbed over a sustained period, creating a depot-like release effect. Additionally, crosslinked versions of any of the foregoing may be utilized. The release rate of the active ingredient can be controlled by controlling the degree of crosslinking of any of the thickening or viscosity-building agents described herein, or by controlling the rate at which any of the foregoing is crosslinked through the use, amount, or type of crosslinking agent used. For example, slow / sustained absorption or a depot-like effect can be achieved by using or forming crosslinked hyaluronic acid at the injection site. In some embodiments, administration of the viscous aqueous solution / suspension dosage form, for example, via subcutaneous or intramuscular injection, provides a release period of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, or any range therebetween, or longer.

[0293] In some embodiments, the pharmaceutical composition is formulated as a pharmaceutically acceptable salt of the compound of Formula (I) that is poorly water soluble (e.g., water solubility less than 5 mg / mL, less than 4 mg / mL, less than 3 mg / mL, less than 2 mg / mL, less than 1 mg / mL, less than 0.5 mg / mL, less than 0.1 mg / mL at 22° C.), such as a fatty acid salt of the compound of Formula (I). Examples of fatty acid salt forms include, but are not limited to, those formed by contacting the compound of Formula (I) with adipic (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, caprylic (octano) acid, palmitic (hexadecano) acid, sebacic acid, undecylenic acid, or caproic acid. Such pharmaceutical compositions may be particularly suitable for subcutaneous injection or intramuscular administration, where the active ingredient slowly dissolves, slowly releases from the injection site, and can be absorbed over a sustained period, creating a depot-like release effect. These "sustained-release" salts may optionally be formulated with thickening or viscosity-building agents, for example, in viscous aqueous solution / suspension formulations. In some embodiments, administration of a pharmaceutical composition formulated with a poorly water-soluble pharmaceutically acceptable salt of a compound of Formula (I), for example, via subcutaneous or intramuscular injection, provides a release period of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, or any range therebetween, or longer.

[0294] C. Topical Administration The pharmaceutical compositions disclosed herein can be administered topically to the skin, orifices, or mucous membranes. Topical administration as described herein includes conjunctival, intracorneal, intraocular, ophthalmic, otic, transdermal, nasal (intranasal), vaginal, urethral, ​​respiratory, and rectal administration.

[0295] The pharmaceutical compositions disclosed herein may be formulated in any dosage form suitable for topical administration for local or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, washes, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions disclosed herein may contain active ingredients mixed under sterile conditions with a pharmaceutically acceptable vehicle, and with any preservatives, buffers, absorption enhancers, and propellants that may be required. Liposomes, micelles, microspheres, nanosystems, and mixtures thereof may also be used. Dosage forms for topical (e.g., intranasal) administration may optionally be formulated with a monoamine oxidase (MAO) inhibitor, including a reversible inhibitor of monoamine oxidase type A (RIMA), to improve the bioavailability of the compound of Formula (I) by minimizing enzymatic degradation mediated by MAO enzymes, such as deamination / oxidation processes.

[0296] Pharmaceutically acceptable vehicles suitable for use in the topical formulations disclosed herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizing agents, solubilizing agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, cryoprotectants, thickening or viscosity-building agents, and inert gases.

[0297] The ointments, pastes, creams, and gels may contain, in addition to the active ingredient, vehicles such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0298] Powders and sprays can contain, in addition to the active ingredient, a vehicle such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays, such as those used for (intra)nasal administration, can additionally contain customary propellants, such as fluorohydrocarbons, chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0299] Transdermal delivery devices (for example, patches) may also be used.Such dosage forms have the additional advantage of providing controlled delivery of active ingredients to the body.That is, the pharmaceutically acceptable salt of the compound of formula (I) can be administered through transdermal patches at steady-state concentration, thereby allowing the active ingredient to be gradually administered over time, and avoiding the drug spikes and adverse events / toxicity associated with the active ingredient.

[0300] Transdermal patch dosage forms may be formulated with varying amounts of active agent (a compound of Formula (I), provided in salt form) depending on the disease / condition being treated. The amount of active agent in a unit dose preparation may be, for example, 5 mg, 10 mg, 20 mg, about 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 5 mg to 25 mg, or 10 mg to 20 mg, or 12 mg to 18 mg, or 13 mg to 16 mg, or 14 mg to 15 mg, or as deemed appropriate using sound medical judgment for a particular application. Transdermal patches formulated with the disclosed compounds may be suitable for microdosing to achieve sustained therapeutic benefit with reduced toxicity. In some embodiments, compounds of the present disclosure may be administered via a transdermal patch at subpsychoactive (yet potentially serotonergic) concentrations for extended periods, such as, for example, 8, 24, 48, 72, 84, 96, or 168 hour periods.

[0301] In addition to the active ingredient(s) and any pharmaceutically acceptable vehicle, a transdermal patch may comprise one or more of a pressure-sensitive adhesive layer, a backing, and a release liner, as known to those of ordinary skill in the art.

[0302] A transdermal patch formulation can be prepared by dissolving or dispersing the active ingredient in a suitable medium. In some embodiments, a pharmaceutically acceptable salt of the compound of formula (I) can be directly dissolved / dispersed in the polymer matrix forming the pressure-sensitive adhesive layer. Such a transdermal patch is called a drug-in-adhesive (DIA) patch. A preferred DIA patch form is one in which the active ingredient is uniformly distributed throughout the pressure-sensitive adhesive polymer matrix. In some embodiments, the active ingredient may be provided in a layer containing the active ingredient and a polymer matrix separate from the pressure-sensitive adhesive layer in addition to the active ingredient. In either case, the pharmaceutically acceptable salt of the compound of formula (I) may be optionally formulated with a suitable vehicle, such as a carrier, a permeation agent / absorption enhancer, a moisturizer / crystallization inhibitor, etc., to increase the flux across the skin.

[0303] Examples of carrier agents include C8-C12 fatty acids such as oleic acid, undecanoic acid, valeric acid, heptanoic acid, pelargonic acid, capric acid, lauric acid, and eicosapentaenoic acid. 22 Fatty acids; C8-C such as octanol, nonanol, oleyl alcohol, decyl alcohol, and lauryl alcohol 22 Fatty alcohols; C8-C such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate 22 Lower alkyl esters of fatty acids; C6-C such as diisopropyl adipate 22 Di(lower) alkyl esters of diacids; C8-C such as glyceryl monolaurate 22These may include, but are not limited to, monoglycerides of fatty acids; tetrahydrofuryl alcohol polyethylene glycol ethers; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkyl aryl ethers of polyethylene oxide; polyethylene oxide monomethyl ether; polyethylene oxide dimethyl ether; glycerol; ethyl acetate; acetoacetic esters; N-alkylpyrrolidones; cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or derivatives such as 2-hydroxypropyl-β-cyclodextrin; and terpenes / terpenoids such as limonene, linalool, myrcene, pinenes such as α-pinene, caryophyllene, citral, eucoliptol, and mixtures thereof.

[0304] Examples of permeation agents / absorption enhancers include, but are not limited to, sulfoxides such as dodecyl methyl sulfoxide, octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxy-undecyl methyl sulfoxide, 2-hydroxydodecyl methyl sulfoxide; menthol; surfactant-lecithin organogel (PLO) formed from an aqueous phase having one or more of poloxamer, CARBOPOL, and PEMULEN, an oily phase formed from one or more of isopropyl palmitate and PPG-2 myristyl ether propionate, and lecithin; fatty acids, esters, and alcohols such as oleic acid and oleyl alcohol; keto acids such as levulinic acid; glycols and glycol ethers, for example, diethylene glycol monoethyl ether; including mixtures thereof.

[0305] Examples of humectants / crystallization inhibitors include, but are not limited to, polyvinylpyrrolidone-co-vinyl acetate, HPMC, polymethacrylate, and mixtures thereof.

[0306] The pressure-sensitive adhesive layer may be formed from polymers including, but not limited to, acrylics (polyacrylates including alkyl acrylics), polyvinyl acetate, natural and synthetic rubbers (e.g., polyisobutylene), ethylene vinyl acetate copolymers, polysiloxanes, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene butadiene rubber block copolymers, and mixtures thereof. The pressure-sensitive adhesive layer used in the transdermal patches of the present disclosure may be formed from an acrylic polymer pressure-sensitive adhesive, preferably an acrylic copolymer pressure-sensitive adhesive. The acrylic copolymer pressure-sensitive adhesive may be obtained by copolymerization with one or more alkyl(meth)acrylates (e.g., 2-ethylhexyl acrylate); aryl(meth)acrylates; arylalkyl(meth)acrylates; and (meth)acrylates having functional groups, such as hydroxyalkyl(meth)acrylates (e.g., hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate, and 4-hydroxybutyl methacrylate), carboxylic acid-containing (meth)acrylates (e.g., acrylic acid), and alkoxy(meth)acrylates (e.g., methoxyethyl acrylate), optionally with one or more copolymerizable monomers (e.g., vinylpyrrolidone, vinyl acetate, etc.). Specific examples of acrylic pressure-sensitive adhesives may include, but are not limited to, DURO-TAK products (Henkel) such as DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 87-2074, DURO-TAK 87-235A, DURO-TAK 87-2510, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 87-2516, DURO-TAK 387-2052, and DURO-TAK 87-2677.

[0307] The backing used in the transdermal patch of the present disclosure may include flexible backings such as films, nonwoven fabrics, Japanese paper, woven cotton fabrics, knitted fabrics, woven fabrics, and laminated composites of nonwoven fabrics and films. Such backings are preferably made of soft materials that can closely contact the skin and conform to its movements, and that can prevent skin rashes and other discomfort after prolonged use of the patch. Examples of backing materials include, but are not limited to, polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polystyrene, nylon, cotton, rayon acetate, rayon, rayon / polyethylene terephthalate composites, polyacrylonitrile, polyvinyl alcohol, acrylic polyurethane, ester polyurethane, ether polyurethane, styrene-isoprene-styrene copolymer, styrene-butadiene-styrene copolymer, styrene-ethylene-propylene-styrene copolymer, styrene-butadiene rubber, ethylene-vinyl acetate copolymer, or cellophane. Preferred backings do not adsorb or release the active ingredient. In order to prevent the adsorption and release of the active ingredient, improve the percutaneous absorption of the active ingredient, and prevent skin rashes and other discomfort, the backing preferably comprises one or more layers made of the above-mentioned materials and having water vapor permeability.Specific examples of the backing include, but are not limited to, 3M COTRAN products such as 3M COTRAN ethylene vinyl acetate membrane film 9702, 3M COTRAN ethylene vinyl acetate membrane film 9716, 3M COTRAN polyethylene membrane film 9720, and 3M COTRAN ethylene vinyl acetate membrane film 9728.

[0308] The release liner used in the transdermal patch of the present disclosure may include, but is not limited to, polyester film with one or both sides treated with a release coating, polyethylene-laminated high-quality paper treated with a release coating, and glass paper treated with a release coating. The release coating may be a fluoropolymer, silicone, fluorosilicone, or any other release coating known to those skilled in the art. The release liner may have an uneven surface to facilitate easy removal of the transdermal patch from the package. Examples of release liners include, but are not limited to, SCOTCHPAK products from 3M Company, such as 3M SCOTCHPAK 9744, 3M SCOTCHPAK 9755, 3M SCOTCHPAK 9709, and 3M SCOTCHPAK 1022.

[0309] Other layers may also be used, such as an abuse-deterrent layer formulated with one or more irritants (eg, sodium lauryl sulfate, poloxamer, sorbitan monoester, glyceryl monooleate, spices, etc.).

[0310] The methods disclosed herein using transdermal patch dosage forms provide systemic delivery of low amounts of active ingredient, preferably over extended periods of time, such as up to 168 hours, for example, 2 to 96 hours, or 4 to 72 hours, or 8 to 24 hours, or 10 to 18 hours, or 12 to 14 hours. In particular, the compound of formula (I) can be delivered in low, stable, and consistent doses, so as to avoid harmful or undesirable side effects. In some embodiments, the compound of formula (I) is administered transdermally at subpsychoactive (yet potentially serotonergic) concentrations.

[0311] Exemplary drug-in-adhesive (DIA) patch formulations may each comprise, based on the total weight of the DIA patch formulation, 5-30% by weight of a pharmaceutically acceptable salt of a compound of Formula (I), 30-70% by weight of a pressure-sensitive adhesive (e.g., DURO-TAK 387-2052, DURO-TAK 87-2677, and DURO-TAK 87-4098), 1-10% by weight of a permeation / absorption enhancer (e.g., oleyl oleate, oleyl alcohol, levulinic acid, diethylene glycol monoethyl ether, etc.), and 5-35% by weight of a crystallization inhibitor (e.g., polyvinylpyrrolidone-co-vinyl acetate, HPMC, polymethacrylic acid, etc.), although it will be understood that many variations are possible in light of the teachings herein.

[0312] The automatic injection device provides a method of delivering the compositions disclosed herein to a patient. The compositions disclosed herein may be administered to a patient using an automatic injection device via several known devices, a non-limiting list of which includes transdermal, subcutaneous, and intramuscular delivery.

[0313] In some transdermal, subcutaneous or intramuscular applications, the compositions disclosed herein are absorbed through the skin.Passive transdermal patch devices often include an absorption layer or membrane that is placed on the outer layer of the skin.The membrane typically contains a dose of a substance that is allowed to be absorbed through the skin to deliver the composition to the patient.Typically, only substances that are easily absorbed through the outer layer of the skin can be delivered by such transdermal patch devices.

[0314] Other automatic injection devices disclosed herein are configured to provide increased skin permeability to improve delivery of the disclosed compositions. Non-limiting examples of structures used to increase permeability to improve movement of the compositions into, across, or into the muscle include the use of one or more microneedles, which in some embodiments may be coated with the compositions disclosed herein. Alternatively, hollow microneedles may be used to provide a fluid channel for delivery of the disclosed compositions below the outer layer of the skin. Other devices disclosed herein include transdermal delivery via iontophoresis, sonophoresis, reverse iontophoresis, or a combination thereof, and other techniques known in the art for increasing skin permeability to facilitate drug delivery.

[0315] Pharmaceutical compositions can also be administered locally by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection, e.g., POWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, Oreg.).

[0316] The pharmaceutical compositions disclosed herein can be in the form of ointment, cream and gel.Suitable ointment vehicles include, for example, oily or hydrocarbon vehicles, including lard, benzoated lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsifying or absorbing vehicles, such as hydrophilic petrolatum, hydroxystearic sulfate and anhydrous lanolin; water-removing vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of various molecular weights; emulsion vehicles, including cetyl alcohol, glyceryl monostearate, lanolin, stearic acid, either water-in-oil (W / O) emulsion or oil-in-water (O / W) emulsion (see Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollients, but generally require the addition of antioxidants and preservatives.

[0317] Suitable cream bases can be oil-in-water or water-in-oil. Cream vehicles are water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which generally consists of petrolatum and fatty acid alcohols such as cetyl or stearyl alcohol. The aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in cream formulations can be a nonionic, anionic, cationic, or amphoteric surfactant.

[0318] Gels are semi-solid suspensions. Single-phase gels contain organic polymers dispersed substantially uniformly throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers, such as carbomer, carboxypolyalkylene, Carbopol®; hydrophilic polymers, such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose-based polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, dispersants such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, and / or stirring.

[0319] The pharmaceutical compositions disclosed herein may be administered rectally, urethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, poultice or cataplasm, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, tampon, gel, foam, spray, or enema. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.

[0320] Rectal, urethral, ​​and vaginal suppositories are solids for insertion into bodily orifices; they are solid at normal temperatures but melt or soften at body temperature, releasing the active ingredient into the orifice. Pharmaceutically acceptable vehicles used in rectal and vaginal suppositories include bases such as stiffening agents that produce melting points near body temperature when formulated with the pharmaceutical compositions disclosed herein, and antioxidants described herein include bisulfite and sodium metabisulfite. Suitable vehicles include cocoa butter (theobroma oil), glycerinated gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid; and glycerinated gelatin. Combinations of various vehicles can be used, including, but not limited to, cocoa butter (theobroma oil), glycerinated gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid; and glycerinated gelatin. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0321] The pharmaceutical compositions disclosed herein may be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solution, gels, intraocular inserts, and implants.

[0322] The pharmaceutical compositions disclosed herein can be administered intranasally. The terms "nasal," "intranasal," and similar terms refer to a route of administration or a dosage form adapted to that route, where the pharmaceutical dosage form is ingested into or through the nose (e.g., the nasal cavity). Similarly, "nasal delivery device" or "intranasal delivery device" is intended to mean a device that administers an active ingredient to the nasal cavity. In some embodiments, the intranasal dosage form may be in the form of an aqueous or non-aqueous solution, a suspension, a liposomal dispersion, an emulsion, a microemulsion, or a sol-gel. Non-limiting examples of intranasal administration include the introduction of a solution or suspension in the form of a nasal spray or nasal drops (direct injection), or the intranasal application of a gel, emulsion, or ointment. Compared to oral dosage forms such as tablets or capsules, intranasal delivery provides rapid absorption, a more rapid onset of therapeutic action, and avoidance of first-pass metabolism. The amount of active ingredient absorbed depends on many factors. These factors include, but are not limited to, drug concentration, drug delivery vehicle, mucosal contact time, venous drainage of mucosal tissue, the degree to which the drug is ionized at the pH of the absorption site, the size of the drug molecule, and its relative lipid solubility.

[0323] The pharmaceutical composition of the present disclosure for nasal administration comprises a compound of the present disclosure, such as a pharmaceutically acceptable salt of the compound of Formula (I), and optionally a pharmaceutically acceptable vehicle, including a permeation / absorption enhancer that promotes the nasal absorption of the active ingredient after nasal administration and an agent that improves the brain penetration of the drug after nasal administration, a diluent, a binder, a lubricant, a glidant, a disintegrant, a desensitizing agent, an emulsifier, a bioadhesive, a solubilizer, a suspending and dispersing agent, a thickening or viscosity-building agent, an isotonic agent, a pH adjuster, a buffer, a carrier, a flavoring agent, a sweetener, and a mixture thereof. In some embodiments, the active ingredient is present in the pharmaceutical composition in particulate form. In some embodiments, the particle size of the active ingredient is about 60 microns or less, which can help ensure the uniformity of any blend of particles with other ingredients or provide proper dispersion in a liquid vehicle.

[0324] Transport of the active ingredient across intact mucosal surfaces (such as the nasal mucosa) can be enhanced by optionally combining it with a permeation agent / absorption enhancer, examples of which include, but are not limited to, cationic polymers, surfactants, chelating agents, mucolytic agents, cyclodextrins, polymeric hydrogels, combinations thereof, and any other similar absorption enhancers known to those skilled in the art. Representative examples of permeation agents / absorption enhancers include, but are not limited to, phospholipids such as phosphatidylglycerol, phosphatidylcholine, lysophosphatidyl derivatives such as lysophosphatidylethanolamine, lysophosphatidylcholine, lysophosphatidylglycerol, lysophosphatidylserine, lysophosphatidic acid, polyols such as glycerol, propylene glycol, fatty acid esters, etc. Gelling or viscosity-increasing excipients may also be used.

[0325] Transport of active ingredients across intact mucosal surfaces can also be enhanced by increasing the time the formulation adheres to the mucosal surface. Bioadhesives, such as hydrogel-forming agents, exhibit mucoadhesion and controlled drug release properties and can be included in the intranasal compositions described herein. Exemplary bioadhesives that can bind to the nasal mucosa include, but are not limited to, polycarbophil, polylysine, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, pectin, Carbopol 934P, polyethylene oxide 600K, one or more poloxomers such as Pluronic® F127 and / or Pluronic® F-68, polyisobutylene (PIB), polyisoprene (PIP), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), xanthan gum, guar gum, and locust bean gum. Other nasal delivery compositions are chitosan-based, which are suitable for increasing the residence time of active ingredients on mucosal surfaces, thereby increasing their bioavailability. Thiolated polymeric vehicles that form covalent bonds with cysteine-rich subdomains of the mucus membrane can also provide mucus adhesion that extends the contact time between the active ingredient and the membrane.

[0326] The intranasal compositions may also contain one or more preservatives, such as quaternary ammonium salts, such as lauralkonium chloride, benzalkonium chloride, benzododecinium chloride, cetylpyridium chloride, cetrimide, and domiphen bromide; alcohols, such as benzyl alcohol, chlorobutanol, o-cresol, and phenylethyl alcohol; organic acids or salts thereof, such as benzoic acid, sodium benzoate, potassium sorbate, and parabens; or complex formers, such as EDTA.

[0327] The intranasal dosage form may also contain an ion exchange resin, such as a microsphere, carrying a suitable anionic group, such as a carboxylic acid resid...

Claims

1. Formula (I), 【Chemistry 1】 During the ceremony, X １ and X ２ is deuterium, Y １ and Y ２ is deuterium, R ２ , R ４ , R ５ , R ６ , and R ７ are independently hydrogen or deuterium, and R ８ and R ９ are independently -CH ３ , -CDH ２ , -CD ２ H, - and -CD ３ A pharmaceutically acceptable salt of a compound of the formula: selected from the group consisting of:

2. R ８ and R ９ 2. The pharmaceutically acceptable salt of claim 1, wherein at least one of is deuterium.

3. R ８ and R ９ are independently -CDH ２ , -CD ２ H, and -CD ３ 2. The pharmaceutically acceptable salt of claim 1 selected from the group consisting of:

4. R ８ and R ９ But, -CD ３ 2. The pharmaceutically acceptable salt of claim 1, wherein:

5. The compound of formula (I) 【Chemistry 2】 2. The pharmaceutically acceptable salt of claim 1, wherein:

6. 10. The pharmaceutically acceptable salt of claim 1, which is crystalline as determined by X-ray powder diffraction (XRPD). (i) having a water solubility of about 10 mg / mL to about 400 mg / mL; (ii) has an onset melting temperature of from about 100°C to about 210°C, as determined by differential scanning calorimetry (DSC); (iii) has an enthalpy of fusion of about 110 J·g −1 to about 180 J·g −1 as determined by differential scanning calorimetry (DSC); (iv) has a weight gain of less than 1% w / w when exposed to a relative humidity (RH) of >95% RH as determined by dynamic vapor sorption (DVS); or 10. The pharmaceutically acceptable salt of claim 1 which is a combination thereof.

8. 2. The pharmaceutically acceptable salt of claim 1, which is an addition salt of the compound of formula (I) with an organic acid.

9. 2. The pharmaceutically acceptable salt of claim 1, which is a fumarate, benzoate, salicylate, or succinate salt of the compound of formula (I).

10. 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ 2. The pharmaceutically acceptable salt of claim 1, which is the fumarate salt of (I-8a).

11. 11. The pharmaceutically acceptable salt of claim 10, which is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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.

12. 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ 2. The pharmaceutically acceptable salt of claim 1, which is the benzoate salt of (I-8b).

13. 13. The pharmaceutically acceptable salt of claim 12, which is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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.

14. 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ 2. The pharmaceutically acceptable salt of claim 1, which is the salicylate salt of (I-8c).

15. 15. The pharmaceutically acceptable salt of claim 14, which is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising 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.

16. 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ 2. The pharmaceutically acceptable salt of claim 1, which is the succinate salt of (I-8d).

17. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 1 to 16 and a pharmaceutically acceptable vehicle.

18. 18. The pharmaceutical composition of claim 17, wherein any position in said compound of formula (I) bearing deuterium has a minimum deuterium incorporation of at least 50 atomic % at the site of deuteration.

19. 18. The pharmaceutical composition of claim 17, adapted for intravenous, subcutaneous, or intramuscular administration.

20. 18. The pharmaceutical composition of claim 17, adapted for nasal administration.

21. 17. A liquid dosage form prepared by reconstituting a solid dosage form comprising a pharmaceutically acceptable salt of any one of claims 1 to 16 in a pharmaceutically acceptable liquid medium.

22. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 1 to 16 for use in the treatment of a disease or disorder by inhalation.

23. For use in the treatment of central nervous system (CNS) disorders and / or psychiatric disorders A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 1 to 16.

24. The CNS disorder and / or psychiatric disorder is (i) post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or 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, 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, binge eating disorder, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, cross-dressing disorder, sexual dysfunction, and obesity; (ii) have an alcohol use disorder; (iii) generalized anxiety disorder (GAD); (iv) social anxiety disorder; (v) treatment-resistant depression (TRD); or (vi) major depressive disorder (MDD) 24. The pharmaceutical composition for use according to claim 23, wherein

25. (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ (ii) a pharmaceutically acceptable salt of (I-8), and (ii) 2-(1H-indol-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 and one or more pharmaceutically acceptable salts of (I-11), and a pharmaceutically acceptable vehicle.

26. The active salt mixture comprises: (i) 60% to 98% by weight of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ (I-8), and (ii) a total of 2% by weight to 40% by weight of 2-(1H-indol-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 pharmaceutical composition according to claim 25, comprising one or more pharmaceutically acceptable salts of (I-11).

27. The active salt mixture comprises: (i) 90% to 98% by weight of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ (I-8), and (ii) a total of 2% by weight to 10% by weight of 2-(1H-indol-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 pharmaceutical composition according to claim 25, comprising one or more pharmaceutically acceptable salts of (I-11).

28. The active salt mixture comprises: (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ (I-8a) fumarate salt, and (ii) 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,2,2-d ３ (I-10a) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2-d ３ 28. A pharmaceutical composition according to any one of claims 25 to 27, comprising one or more fumarate salts of (I-11a).

29. The active salt mixture comprises: (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2,2-d ４ (I-8b) benzoate salt, and (ii) 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,2,2-d ３ (I-10b) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) ethane-1-amine-1,1,2-d ３ One or more benzoates of (I-11b); or (i) the salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8c), and (ii) one or more salicylate salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10c) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11c); or (i) the succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8d), and (ii) one or more succinate salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10d) and / or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11d). The pharmaceutical composition according to any one of claims 25 to 27, comprising:

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