Tryptamines specific to the treatment of mood disorders

Abstract

There remains a need for safe and effective tryptamine compounds that can be reliably used in the treatment of mood disorders.SOLUTION: Methods of treating mood disorders with the compounds disclosed herein. Also provided are pharmaceutical compositions comprising these compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the benefits and priority of U.S. Provisional Patent Application No. 62 / 978,075, filed on 18 February 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Depression is a common psychological problem characterized by a depressed mood and aversion to activities. Various symptoms associated with depression include persistent anxiety or sadness, feelings of helplessness, despair, pessimism, and / or worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in enjoyable activities or hobbies, hypersomnia, hypereating, loss of appetite, insomnia, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of these symptoms vary from case to case.

[0003] Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission of their symptoms even after multiple treatments with several known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) (Rush et al., 2006). This high prevalence of treatment-resistant depression (TRD) highlights the need for novel and more effective pharmacotherapies for depression targeting new mechanisms and / or patient populations.

[0004] Tryptamine is a monoamine alkaloid containing an indole ring and is structurally similar to the amino acid tryptophan, from which its name is derived.

[0005] A significant number of tryptamine compounds exist, including naturally occurring compounds and chemical derivatives with similar structures that may consist of an unsubstituted ring or a substituted ring. Many tryptamines are 5HT. 2AReceptor agonists and / or modulators of other serotonin receptors are known to be psychoactive and, in many cases, cause prolonged hallucinations. The most well-known tryptamines are psychedelic compounds, including entheogenic fungal compounds (psilocybin and psilocine), N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), bufotenine, and ibogaine. These compounds are known to have significant effects on thought, perception, and behavior. However, these compounds are currently classified as Schedule I drugs under the Controlled Substances Act due to their high potential for abuse, lack of approved medical use, and unestablished safety. Furthermore, tryptamines are metabolized through several pathways, including monoamine oxidase, which in some cases limits the oral bioavailability of certain compounds and makes their effects very short-lived. Conversely, other tryptamines have a very long duration of action, making them difficult to use in induction therapy settings. The prolonged monitoring required during this period is costly for patients and inconvenient for healthcare providers. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] Therefore, there remains a need for safe and effective tryptamine compounds that can be reliably used to treat mood disorders. [Means for solving the problem]

[0007] This disclosure relates to compound 2: [ka] or a pharmaceutically acceptable salt thereof.

[0008] In addition, this disclosure includes pharmaceutical compositions of compound 2 and methods for using the same.

[0009] In addition, this disclosure relates to a method for treating mood disorders in patients in need thereof, comprising an effective amount of compound 2 or compound 4: [ka] The method includes administering a pharmaceutically acceptable salt thereof.

[0010] For example, provided herein are methods and compositions for treating mood disorders by administering to a patient in need a pharmaceutical composition containing an effective amount of compound 2 or compound 4 or a pharmaceutically acceptable salt thereof. In embodiments, the methods and compositions may treat mood disorders, including depressive disorders, bipolar disorders and related disorders, substance-related disorders, and / or anxiety disorders.

[0011] In embodiments, the methods and compositions can treat mood disorders, including obsessive-compulsive disorder and related disorders. In embodiments, the methods and compositions can treat mood disorders, including trauma-related disorders and stressor-related disorders. In embodiments, the methods and compositions can treat mood disorders, including eating disorders and nutritional disorders. In embodiments, the methods and compositions can treat mood disorders, including cognitive disorders. In embodiments, the methods and compositions can treat mood disorders, including neurodevelopmental disorders. In embodiments, the methods and compositions can treat mood disorders, including personality disorders. In embodiments, the methods and compositions can treat mood disorders, including sexual dysfunction. In embodiments, the methods and compositions can treat mood disorders, including gender dysphoria. [Brief explanation of the drawing]

[0012] [Figure 1]The data shows immobility time during fast-start time (FST). One-way ANOVA revealed a significant primary effect of the treatment on total immobility time during FST (F(9,99)=12.42, P<0.0001). Dunnett's multiple comparison test was used to test when there was a significant difference between the group and the vehicle. Significant differences were observed between the group and the vehicle for all treatments except compound 2 at 0.1 mg / kg. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. vehicle. [Figure 2] This shows swimming time in FST. One-way ANOVA revealed a significant primary effect of the treatment on total swimming time in FST (F(9,99)=2.653, P=0.0090). Dunnett's multiple comparison test was used to test when there was a significant difference between the group and the vehicle. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. vehicle. [Modes for carrying out the invention]

[0013] This disclosure is based on formula I: [ka] (In the formula, R1 is an arbitrarily substituted C1-C4 aliphatic; R2 is an arbitrarily substituted C1-C4 aliphatic; R 26 (Selected from the group consisting of hydrogen, halogen, -CN, -OH, C1-C3 alkoxy, C1-C3 haloalkyl, OAc, -OPO(OH)2, and NH2) It contains compounds or pharmaceutically acceptable salts thereof.

[0014] In some embodiments, R1 is selected from the group consisting of Me, Et, nPr, iPr, cyclopropyl, allyl, isobutyl, and cyclopropylmethyl. In some embodiments, R2 is selected from the group consisting of Me, Et, nPr, iPr, cyclopropyl, allyl, isobutyl, and cyclopropylmethyl.

[0015] In some embodiments, R 26 is selected from the group consisting of hydrogen, F, Cl, Br, I, CF3, Me, CN, OMe, OH, OAc, and NH2. In some embodiments, R 26 is selected from the group consisting of F, Cl, Br, I, CF3, Me, CN, OMe, OH, OAc, and NH2. In some embodiments, R 26 is halogen. In some embodiments, R 26 is fluoro. In some embodiments, R 26 is chloro. In some embodiments, R 26 is bromo. In some embodiments, R 26 is iodo.

[0016] In an embodiment, the present disclosure provides

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[0017] In an embodiment, the present disclosure provides

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[0018] In an embodiment, the present disclosure provides

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[0019] This specification describes methods and compositions for treating mood disorders by administering the compounds disclosed herein to patients in need thereof. Also provided are pharmaceutical compositions comprising the compounds disclosed herein.

[0020] In embodiments, the methods and compositions can be used to treat mood disorders, including depressive disorders such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation, substance / drug-induced depressive disorder, and depressive disorders due to other medical conditions.

[0021] In some embodiments, the depressive state includes major depressive disorder and dysthymic disorder. In some embodiments, the depressive state is characterized by the occurrence of specific conditions, including, but are not limited to, psychotic depression, postpartum depression, seasonal affective disorder (SAD), mood disorders, depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, post-traumatic stress disorder, and bipolar disorder (or manic-depressive disorder). In some embodiments, depressive states expected to be treated by these embodiments of the Disclosure include, but are not limited to, major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, premenstrual syndrome, premenstrual anxiety disorder, seasonal affective disorder (SAD), anxiety disorders, mood disorders, depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, post-traumatic stress disorder, and bipolar disorder (or manic-depressive disorder).

[0022] Also provided herein are methods for treating patients suffering from treatment-resistant depression, for example, depressive disorders that do not respond to and / or do not respond to a suitable course of treatment with at least one or at least two other antidepressant compounds or therapies. For example, provided herein are methods for treating depression in a treatment-resistant patient, comprising a) optionally, identifying the patient as treatment-resistant, and b) administering an effective dose of a compound of the Disclosure. As used herein, “depressive disorder” encompasses treatment-resistant depression. In some embodiments, treatment-resistant depression occurs in patients suffering from depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple reuptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments such as psychotherapy, electroconvulsive therapy, vagal stimulation and / or transcranial magnetic stimulation. In some embodiments, a treatment-resistant patient may be identified as a patient who, despite receiving one or more standard pharmacological or non-pharmacological treatments, does not experience relief from one or more symptoms of depression (e.g., persistent anxiety or sadness, helplessness, despair, or pessimism). In certain embodiments, a treatment-resistant patient is a patient who, despite receiving treatment with two different antidepressants, does not experience relief from one or more symptoms of depression. In other embodiments, a treatment-resistant patient is a patient who, despite receiving treatment with four different antidepressants, does not experience relief from one or more symptoms of depression. In some embodiments, a treatment-resistant patient may also be identified as a patient who is undesirable or unable to develop tolerance to the side effects of one or more standard pharmacological or non-pharmacological treatments.

[0023] In some embodiments, symptoms associated with depression include, but are not limited to, persistent feelings of anxiety or sadness, helplessness, despair, pessimism and / or worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in enjoyable activities or hobbies, hypersomnia, hypereating, loss of appetite, insomnia, suicidal thoughts, or suicide attempts. In some embodiments, various symptoms associated with anxiety include, among others, fear, panic, heart palpitations, shortness of breath, fatigue, nausea, and headaches. In addition, patients suffering from any form of depression often experience anxiety. The methods of this condition are expected to be usable to treat anxiety or any of its symptoms. In some embodiments, the presence, severity, frequency, and duration of depressive symptoms vary from case to case.

[0024] In embodiments, the methods and compositions can be used to treat mood disorders, including bipolar disorder and related disorders, such as bipolar disorder type I, bipolar disorder type II, cyclothymic disorders, substance / drug-induced bipolar disorder and related disorders, as well as bipolar disorder and related disorders due to other medical conditions.

[0025] In embodiments, methods and compositions can be used to treat mood disorders, including substance-related disorders, by, for example, preventing substance use cravings, reducing substance use cravings, and / or promoting the interruption or withdrawal of substance use. Substance use disorders include the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, “substance” refers to psychoactive compounds that can be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, methods and compositions can be used to promote smoking cessation or the interruption of opioid use.

[0026] In embodiments, the methods and compositions can be used to treat mood disorders, including anxiety disorders, such as separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorders, and anxiety disorders due to other medical conditions.

[0027] In embodiments, methods and compositions can be used to treat mood disorders, including obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, excoriation disorder, skin-picking disorder, substance / drug-induced obsessive-compulsive disorder and related disorders, as well as obsessive-compulsive disorder and related disorders caused by other medical conditions.

[0028] In embodiments, the methods and compositions can be used to treat mood disorders, including trauma-related disorders and stressor-related disorders, such as reactive attachment disorder, disinhibited social interaction disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

[0029] In embodiments, the methods and compositions can be used to treat mood disorders, including eating disorders and nutritional disorders, such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidance / restriction food intake disorder.

[0030] In embodiments, the methods and compositions can be used to treat mood disorders, including cognitive impairment, such as delirium, severe dementia, mild dementia, severe or mild dementia due to Alzheimer's disease, severe or mild frontotemporal dementia, severe or mild dementia with Lewy bodies, severe or mild vascular dementia, severe or mild dementia due to traumatic brain injury, substance / drug-induced severe or mild dementia, severe or mild dementia due to HIV infection, severe or mild dementia due to prion disease, severe or mild dementia due to Parkinson's disease, severe or mild dementia due to Huntington's disease, severe or mild dementia due to other medical conditions, and severe or mild dementia due to numerous etiologies.

[0031] In embodiments, methods and compositions can be used to treat mood disorders, including neurodevelopmental disorders, such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotyped movement disorder, tic disorder, Tourette's disease, persistent (chronic) motor or vocal tic disorder, and provisional tic disorder. In some embodiments, various other neurological conditions are expected to be treated according to the methods of the present disclosure. In some embodiments, neurological conditions include, but are not limited to, learning disabilities, autism spectrum disorder, attention deficit hyperactivity disorder, Tourette's syndrome, phobias, post-traumatic stress disorder, dementia, AIDS dementia, Alzheimer's disease, Parkinson's disease, spasticity, myoclonus, muscle spasms, bipolar disorder, substance abuse disorder, urinary incontinence, and schizophrenia.

[0032] In embodiments, the methods and compositions can be used to treat mood disorders, including personality disorders, such as borderline personality disorder.

[0033] In embodiments, methods and compositions can be used to treat mood disorders, including sexual dysfunction, such as delayed ejaculation, erectile dysfunction, female orgasm disorder, female sexual interest / sexual arousal disorder, genital pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation (early ejaculation), and substance / drug-induced sexual dysfunction.

[0034] In embodiments, the methods and compositions can be used to treat mood disorders, including gender dysphoria.

[0035] In embodiments, the provided method and composition are for treating mood disorders by administering an effective amount of ethylpropyltryptamine (EPT; compound 1) or a pharmaceutically acceptable salt thereof to a subject in need thereof. [ka]

[0036] In other embodiments, the provided method and composition for treating mood disorders by administering an effective amount of methylethyltryptamine (MET; compound 2) or a pharmaceutically acceptable salt thereof to a subject in need thereof. [ka]

[0037] In other embodiments, the following structure is provided for the object requiring it: [ka] A method and composition for treating mood disorders by administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof selected from among the compounds disclosed herein.

[0038] In other embodiments, the following structure is provided for the object requiring it: [ka] [ka] A method and composition for treating mood disorders by administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof selected from among the compounds disclosed herein.

[0039] In other embodiments, the following structure is provided for the object requiring it: [ka] [ka] A method and composition for treating mood disorders by administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof selected from the above. In other embodiments, a method and composition for treating migraines or cluster headaches by administering a compound of the Disclosure to a patient in need thereof.

[0040] In other embodiments, provided herein are methods and compositions for treating inflammation by administering the compounds of the Disclosure to subjects requiring such treatment.

[0041] In an embodiment, the method includes treating a mood disorder, such as a depressive disorder, by administering to a patient in need a pharmaceutical composition containing about 0.01 mg to about 400 mg of a compound disclosed herein. In an embodiment, the dose is, for example, about 0.01 to 400 mg, 0.01 to 300 mg, 0.01 to 250 mg, 0.01 to 200 mg, 0.01 to 150 mg, 0.01 to 100 mg, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 25 mg, 0.01 to 20 mg, 0.01 to 15 mg, 0.01 to 10 mg, 0.01 to 5 mg, 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0 .1mg, 0.1~300mg, 0.1~250mg, 0.1~200mg, 0.1~150mg, 0.1~100mg, 0.1~75mg, 0.1~50mg, 0.1~25mg, 0.1~20m g, 0.1~15mg, 0.1~10mg, 0.1~5mg, 0.1~1mg, 10~300mg, 10~250mg, 10~200mg, 10~150mg, 10~100mg, 10~50mg, 1 The range can be 0-25mg, 10-15mg, 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-100mg, 20-50mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-100mg, 100-300mg, 100-250mg, 100-200mg, for example, approximately 0.25mg, 0.5mg, 0.75mg, 1mg. Examples of dosages include 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, and 400 mg.

[0042] In specific embodiments, the dosage may include amounts of the compounds disclosed herein in the range of approximately 1 mg to 200 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, as well as 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.5 mg. Examples of specific dosages include g, 1.75mg, 2mg, 2.5mg, 2.75mg, 3mg, 3.5mg, 3.75mg, 4mg, 4.5mg, 4.75mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, and 200mg.

[0043] Typically, the dosages of the compounds disclosed herein are administered to patients who require them once, twice, three or four times a day, every other day, every three days, once a week, twice a month, once a month, or three to four times a year. In embodiments, the dosage is, for example, about 1 to 400 mg / day, or 1 to 300 mg / day, or 1 to 250 mg / day, or 1 to 200 mg / day, for example, 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, 75 mg / day, 50 mg / day, 40 mg / day, 30 mg / day, 25 mg / day, 20 mg / day, 15 mg / day, 10 mg / day, 5 mg / day, or 1 mg / day.

[0044] In embodiments, pharmaceutical compositions for parenteral administration or inhalation, such as spraying or misting, of the compounds disclosed herein contain concentrations ranging from about 0.005 mg / mL to about 500 mg / mL. In embodiments, compositions contain the compounds disclosed herein in concentrations ranging from about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 100 mg / mL, about 0.005 mg / mL to about 500 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, or about 0.05 mg / mL to about 1 mg / mL.

[0045] In embodiments, the composition contains the compounds disclosed herein at concentrations of, for example, about 0.05 mg / mL to about 15 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.25 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 7 mg / mL, about 1 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 15 mg / mL, about 5 mg / mL to 25 mg / mL, about 5 mg / mL to 50 mg / mL, or about 10 mg / mL to 100 mg / mL. In embodiments, the pharmaceutical composition is formulated in total volumes of, for example, about 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0046] Typically, the dosage may be administered to the subject once, twice, three or four times a day, every other day, every three days, once a week, twice a month, once a month, or three to four times a year. In embodiments, the compounds disclosed herein are administered to the subject once in the morning or once in the evening. In embodiments, the compounds disclosed herein are administered to the subject once in the morning and once in the evening. In embodiments, the compounds disclosed herein are administered to the subject three times a day (e.g., breakfast, lunch, and dinner) at a dose of, for example, 50 mg / dose (e.g., 150 mg / day).

[0047] In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 12.5 mg / day. In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 25 mg / day. In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 35 mg / day. In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 50 mg / day. In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 75 mg / day. In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 100 mg / day. In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 150 mg / day. In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 200 mg / day. In embodiments, the compounds disclosed herein are administered to subjects in one or more doses at a dose of 250 mg / day.

[0048] In embodiments, the dosage of the compounds disclosed herein is 0.0005-5 mg / kg, 0.001-1 mg / kg, 0.01-1 mg / kg, or 0.1-5 mg / kg once, twice, three, or four times a day. For example, in embodiments, the dosage is 0.0005 mg / kg, 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.025 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 2.5 mg / kg, or 5 mg / kg once, two, three, or four times a day. In the embodiments, subjects are administered a total daily dose of the compounds disclosed herein, ranging from 0.01 mg to 500 mg, once, twice, three times, or four times per day. In an embodiment, the total amount administered to the subject over a 24-hour period is, for example, 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In the embodiment, the subject can be started with a low dose and the dosage is increased in stages. In the embodiment, the subject can be started with a high dose and the dosage is decreased.

[0049] In embodiments, the compounds disclosed herein may be administered at predetermined intervals, for example, by inhalation or orally. For example, during treatment, a patient may be administered the compounds disclosed herein at intervals of, for example, 1 year, 6 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours.

[0050] In embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to a patient under the supervision of a healthcare provider.

[0051] In embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to a patient under the supervision of a healthcare provider in a clinic dedicated to the administration of psychoactive treatment.

[0052] In embodiments, the compounds of the Disclosure are administered to a patient under the supervision of a healthcare provider in high doses intended to induce a psychedelic experience in the subject, such as 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, or 150 mg.

[0053] In some embodiments, high-dose administration to a patient under the supervision of a healthcare provider is performed regularly, for example, every three days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year, to maintain the therapeutic effect in the patient.

[0054] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered by the patient to the patient themselves, away from the supervision of a healthcare provider or at home.

[0055] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered by the patient to the patient themselves at home or away from the supervision of a healthcare provider in low doses, for example, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, or 10 mg, intended to produce a subsensory psychoactive effect or induce a threshold psychoactive effect.

[0056] In some embodiments, low-dose patient-administration is performed regularly in the patient to maintain the therapeutic effect, for example, daily, every other day, every three days, twice a week, once a week, twice a month, or once a month.

[0057] Suitable dosage forms for the compounds disclosed herein include, but are not limited to, oral forms such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions, syrups or suspensions, lozenges, as well as sublingual, buccal, tracheal, intraocular, or intranasal forms, forms for inhalation, topical forms, transdermal forms, or parenteral forms such as forms for intravenous, intraarteriole, intraperitoneal, intrasacral, intracardiac, intramuscular, or subcutaneous administration. In embodiments, such parenteral administration may be in the form of a sterile aqueous solution that may contain other substances, such as sufficient salt or glucose, to create a solution isotonic with blood. The aqueous solution should be preferably buffered (preferably to a pH of 3-9) if necessary. Preparation of suitable parenteral formulations under sterile conditions is readily achieved by standard pharmaceutical techniques well known to those skilled in the art.

[0058] The pharmaceutical compositions herein may be provided with immediate-release, delayed-release, sustained-release, or controlled-release profiles. In embodiments, pharmaceutical compositions having different drug release profiles may be combined to create a two-phase or three-phase release profile. For example, a pharmaceutical composition may be provided with immediate-release and sustained-release profiles. In embodiments, a pharmaceutical composition may be provided with sustained-release and delayed-release profiles. Such compositions may be provided as pulse formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc. The compositions may be prepared using a pharmaceutically acceptable “carrier” composed of materials considered safe and effective. The “carrier” includes all components present in the pharmaceutical formulation other than one or more active ingredients. The term “carrier” includes, but is not limited to, excipients, binders, lubricants, flow enhancers, disintegrants, fillers, and coating compositions.

[0059] The pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including percutaneous, buccal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration, or administration via implant. The compositions may be prepared by any method known in the field of pharmacy.

[0060] Such methods include the step of mixing the compounds or combinations thereof used in the Disclosure with an auxiliary agent. The auxiliary agent, also named auxiliary component, includes conventional ones in the art, such as carriers, fillers, binders, excipients, disintegrants, lubricants, colorants, flavorings, antioxidants, and wetting agents. Such auxiliary agents are preferably selected in accordance with conventional pharmaceutical practice for the intended form and route of administration.

[0061] Pharmaceutical compositions suitable for oral administration may be provided in separate dosage forms such as pills, tablets, sugar-coated or capsules, or powders or granules, or as liquids or suspensions. The active ingredient may also be provided as a bolus or paste. The composition can be further processed into suppositories or enemas for rectal administration.

[0062] Tablets may contain an active ingredient compound, as well as suitable binders, lubricants, disintegrants, colorants, flavorings, flow inducers, and solubilizers. Gelatin capsules may contain an active ingredient compound and a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, or stearic acid. Similar excipients can be used to make compressed tablets. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant tastes and protect the tablets from the air, or enterically coated to selectively disintegrate in the gastrointestinal tract. For example, for oral administration in tablet or capsule form, the active drug component may be combined with an orally administered, non-toxic, and pharmaceutically acceptable inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, or sorbitol. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic rubbers such as acacia and tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants, though not limited to these, include starch, methylcellulose, agar, bentonite, and xanthan gum.

[0063] For oral administration in liquid dosage forms, the oral drug component is combined with any orally administered, non-toxic, pharmaceutically acceptable, inert carrier such as ethanol, glycerol, or water. Examples of suitable liquid dosage forms, but not limited to, include liquids or suspensions in water, pharmaceutically acceptable fats and oils, alcohols and other organic solvents (including esters), emulsions, syrups or elixirs, suspensions, liquids and / or suspensions reconstituted from non-foaming granules, and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, excipients, sweeteners, thickeners, and solubilizers. Liquid dosage forms for oral administration may contain colorants and flavorings to enhance patient tolerance.

[0064] Suitable compositions for parenteral administration include aqueous and non-aqueous sterile solutions. Generally, water, suitable oils, physiological saline, aqueous dextrose (glucose) and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Parenteral solutions preferably contain a water-soluble salt of the active ingredient, a suitable stabilizer, and, if necessary, a buffer. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid are suitable stabilizers, either alone or in combination. Citric acid and its salts, as well as sodium EDTA, are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propylparaben, and chlorobutanol. The compositions can be provided in unit or multiple dose containers, such as sealed vials and ampoules, and can be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water, before use. For transdermal administration, for example, gels, patches, or sprays may be considered. For example, compositions or formulations suitable for intrapulmonary administration by nasal inhalation include fine powders or mists that can be produced by metered and pressurized aerosols, nebulizers, or injectors. Parenteral and intravenous forms also include minerals and other materials suitable for the chosen type of injection or delivery system.

[0065] The compounds used in the methods of this disclosure may also be administered in the form of liposome delivery systems such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. The liposomes may be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine. The compounds may be administered as components of tissue-targeted emulsions.

[0066] The compounds used in the methods of this disclosure may also be bound to soluble polymers as targetable drug carriers or prodrugs. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be bound to a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0067] The pharmaceutical compositions herein may be provided with immediate-release, delayed-release, sustained-release, or regulated-release profiles. In some embodiments, pharmaceutical compositions having different drug release profiles can be combined to create a two-phase or three-phase release profile. For example, a pharmaceutical composition may be provided with immediate-release and sustained-release profiles. In some embodiments, a pharmaceutical composition may be provided with sustained-release and delayed-release profiles. Such compositions may be provided as pulse formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

[0068] The pharmaceutical compositions described herein may be provided with abuse-preventive properties by, for example, by producing tablets that are difficult to crush or difficult to dissolve in water, using techniques known in the art.

[0069] This disclosure further includes a pharmaceutical composition, including instructions for use of the composition for use described below, in combination with packaging materials, as described below.

[0070] The precise dosage and regimen for administering the composition will inevitably depend on the type and magnitude of the therapeutic or nutritional effect to be achieved, and may vary depending on factors such as the specific compound, formulation, route of administration, age, and the condition of the individual subject to whom the composition is administered.

[0071] The compounds used in the methods of this disclosure can be administered in various forms, including those detailed herein. Treatment with the compounds may be a component of combination therapy or adjunct therapy; that is, a subject or patient requiring a drug is treated with another drug for a disease or administered with one or more of the compounds. This combination therapy may be a sequential therapy in which the patient is treated first with one drug, then with another drug, or two drugs are administered simultaneously. These may be administered independently via the same route of administration or by two or more different routes, depending on the dosage form used.

[0072] In some embodiments, the compounds disclosed herein may be administered in combination with one or more other antidepressant treatments, such as tricyclic antidepressants, MAOIs, SSRIs, and double and triple reuptake inhibitors and / or anxiolytics, for the manufacture of pharmaceuticals for treating depression, anxiety, and / or other related disorders and for preventing relapse of depression or anxiety, including alleviating depression or anxiety. In some embodiments, therapeutic agents that may be used in combination with the compounds disclosed herein include, but are not limited to, Anafranil, Adapine, Aventil, Elavir, Norpramine, Pamerol, Pertofuran, Synequan, Sulmontil, Tofranil, Vivactil, Parnate, Nadir, Marplan, Celexa, Lexapro, Luvox, Paxil, Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel (Trazodone), and Ludiomil.

[0073] definition In the context of this disclosure, the term “5-HT2a receptor agonist” is intended to mean any compound or substance that activates the 5-HT2a receptor. An agonist may be a partial agonist or a complete agonist.

[0074] The terms “aliphatic” or “aliphatic group,” as used herein, mean a fully saturated or linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain containing one or more unsaturated units, or a fully saturated or monocyclic or bicyclic hydrocarbon containing one or more unsaturated units having a single bond to the rest of the molecule (also referred to herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”). Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or has a single bond to the rest of the molecule, contains one or more unsaturated but non-aromatic units. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0075] The term "alkyl" refers to a linear or branched alkyl group. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0076] The term "haloalkyl" refers to a linear or branched alkyl group that is substituted with one or more halogen atoms.

[0077] The term "halogen" refers to F, Cl, Br, or I.

[0078] As used herein, the term “pharmaceutically acceptable” means “generally considered safe,” for example, a molecular entity or composition that is physiologically tolerable and does not typically cause an allergic reaction or similar adverse reaction when administered to humans. In embodiments, the term means a molecular entity or composition approved by a federal or state regulatory authority, the United States Pharmacopeia, or another generally recognized pharmacopoeia as a GRAS list or similar list under Sections 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, subject to premarket review and approval by the FDA for use in animals, more specifically in humans.

[0079] Where used herein, the compounds of the present invention may contain “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of a given moiety are replaced by a suitable substituent, whether preceded by the term “optionally.” Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each of its substitutable positions, and where two or more positions in any given structure can be replaced by two or more substituents selected from a particular group, the substituents may be the same or different at each position. The substituent combinations envisioned in the present invention preferably result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, means a compound that remains substantially unchanged when placed under conditions that enable their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more purposes disclosed herein.

[0080] A suitable monovalent substituent for the substitutable carbon atom of the "optionally substituted" group is, independently, a halogen; -(CH2) 0~4 R ○ ; -(CH2) 0~4 Ure ○; -(CH2) 0~4 R ○ -O-(CH2) 0~4 C(O)OR ○ ; -(CH2) 0~4 CH(OR ○ )2; -(CH2) 0~4 SR ○ ; -(CH2) 0~4 Ph(R ○ It can be replaced by (CH2) 0~4 O(CH2) 0~1 Ph(R ○ It can be substituted by (-CH=CHPh(R ○ It can be replaced by (CH2) 0~4 O(CH2) 0~1 - Pyridyl (R ○ (Can be replaced by) -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R ○ )2; -(CH2) 0~4 N(R ○ )C(O)R ○ -N(R ○ )C(S)R ○ ; -(CH2) 0~4 N(R ○ )C(O)NR ○ 2; -N(R ○ )C(S)NR ○ 2; -(CH2) 0~4 N(R ○ )C(O)OR ○ -N(R ○ )N(R ○ )C(O)R ○ -N(R ○ )N(R ○ )C(O)NR ○ 2; -N(R ○ )N(R ○ )C(O)OR ○ ; -(CH2) 0~4 C(O)R ○ -C(S)R ○ ; -(CH2) 0~4 C(O)OR ○ ; -(CH2) 0~4 C(O)SR ○ ; -(CH2) 0~4C(O)OSiR ○ 3; -(CH2) 0~4 OC(O)R ○ ; -OC(O)(CH2) 0~4 SR ○ , SC(S)SR ○ ; -(CH2) 0~4 SC(O)R ○ ; -(CH2) 0~4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -SC(S)SR ○ , -(CH2) 0~4 OC(O)NR ○ 2; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH2C(O)R ○ ; -C(NOR ○ )R ○ ; -(CH2) 0~4 SSR ○ ; -(CH2) 0~4 S(O)2R ○ ; -(CH2) 0~4 S(O)2OR ○ ; -(CH2) 0~4 OS(O)2R ○ ; -S(O)2NR ○ 2; -(CH2) 0~4 S(O)R ○ ; -N(R ○ )S(O)2NR ○ 2; -N(R ○ )S(O)2R ○ ; -N(OR ○ )R ○ ; -C(NH)NR ○ 2; -P(O)2R ○ ; -P(O)R ○ 2; -OP(O)R ○ 2; -OP(O)(OR ○ )2; SiR ○ 3; -(C 1~4 straight or branched alkylene)O-N(R ○ )2; or -(C 1~4(Linear or branched alkylene)C(O)ON(R ○ )2, and each R ○ These can be substituted as defined below, independently of hydrogen and C. 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially saturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, R ○ The two distinct entities, together with their intervening atoms, form a monocyclic or bicyclic aryl ring with 3 to 12 members, saturated, partially saturated, or having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0081] R ○ A preferred monovalent substituent (or R ○ The ring formed by taking the two distinct entities together with their intervening atoms is independently a halogen, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2; -O(HaroR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● ,-(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● ,-(C1~4 (Straight-chain or branched-chain alkylene) C(O)OR ● , or -SSR ● And each R ● It is unsubstituted, or the "halo" is preceded and substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 The pH is selected from a saturated, partially saturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, with 5 to 6 members. ○ Suitable divalent substituents for the saturated carbon atom include =O and =S.

[0082] The following are preferred divalent substituents for the saturated carbon atoms of the "arbitrarily substituted" groups: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2)) 2~3 O-, or -S(C(R*2)) 2~3 S- is an example, and each distinct presence of R* can be substituted for hydrogen, as defined below. 1~6 Selected from aliphatic or unsubstituted 5-6 member saturated, partially saturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A preferred divalent substituent bonded to an adjacent substituted carbon of the "optionally substituted" group is: -O(CR*2) 2~3 O- is an example, and each distinct presence of R* can be substituted for hydrogen, as defined below. 1~6 The material is selected from aliphatic or unsubstituted 5-6 member saturated, partially saturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0083] Suitable substituents for the aliphatic group R* include halogens and -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ●-NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● It is unsubstituted, or the "halo" is preceded and substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 The pH is, or an aryl ring having 5-6 members, saturated, partially saturated, or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0084] As a suitable substituent for the substituted nitrogen of the "arbitrarily substituted" group, -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † These include, and each R† can be independently substituted with hydrogen, or C as defined below. 1~6 An aliphatic, unsubstituted -OPh, or unsubstituted 5-6 member saturated, partially saturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, R † The two distinct entities, together with their intervening atoms, form a monocyclic or bicyclic aryl ring with 3 to 12 members, saturated, partially saturated, or 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0085] R † Suitable substituents for the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ●), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● It is unsubstituted, or the "halo" is preceded and substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 The pH is, or an aryl ring having 5-6 members, saturated, partially saturated, or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0086] As used herein, the term “pharmaceutically acceptable salt” includes both acid addition salts and base addition salts, wherein a compound is modified by preparing a salt of its acid or base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. Examples of such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, and oxalic acid. Pharmaceutically acceptable salts of the compounds disclosed herein can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods.

[0087] The terms “about” or “approximately,” as used herein, mean a range of error permissible for a particular value as determined by those skilled in the art, and which depends in part on how the value is measured or determined, i.e., on the limits of the measuring system. For example, “about” may mean within three or more standard deviations, as is customary in the art. Alternatively, “about” may mean a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Or, particularly in the context of biological systems or methods, the term may mean within about one order of magnitude of the value, e.g., within five times or up to two times. “About” and “approximately” are used interchangeably herein.

[0088] In embodiments, the term “effective dose” or “therapeutic effective dose” means an amount of compound, material, composition, pharmaceutical or other material that is effective in achieving a specific pharmacological and / or physiological effect, including but not limited to reducing the frequency or severity of grief or lethargy, depressed mood, anxiety or sadness, decreased interest in all or nearly all activities, significant changes in appetite resulting in weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, inability to concentrate, and recurrent thoughts of death or suicide; or, for example, by reducing, inhibiting or reversing one or more underlying pathophysiological mechanisms of neurological dysfunction, by modulating dopamine levels or signaling, serotonin levels or signaling, norepinephrine levels or signaling, glutamate or GABA levels or signaling, synaptic connections or neurogenesis in a particular brain region, or a combination thereof, to produce a desired pharmacological and / or physiological effect. The precise dosage varies depending on various factors, including subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.), the disease or disorder being treated, and the route of administration and the pharmacokinetics of the administered drug.

[0089] In embodiments, the deuterium-enriched compounds and their uses disclosed herein are intended to be within the scope of the methods and compositions described herein. Deuterium can be synthesized and incorporated into any position of hydrogen (protium) according to synthetic procedures known in the art. For example, deuterium can be incorporated via proton-deuterium equilibrium exchange into various positions having exchangeable protons, such as amine NH. Thus, deuterium can be incorporated selectively or non-selectively through methods known in the art.

[0090] In some embodiments, the level of deuterium at each -H site where deuterium is concentrated in the compound ranges from 0.02% to 100%.

[0091] In some embodiments, the deuterium levels at each -H site where deuterium is concentrated in the compound are 50%-100%, 70%-100%, 90%-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, or 99%-100%.

[0092] Examples of deuterium-enriched compounds disclosed herein include: [ka]

[0093] The compounds disclosed herein may be racemic isomers and / or optically active isomers. In this regard, some compounds have an asymmetric carbon atom and therefore may exist as either a racemic mixture or individual optical isomers (enantiomers). Compounds described herein that contain a chiral center include all possible stereoisomers of the compound, including compositions containing a racemic mixture of two enantiomers, and compositions containing each enantiomer individually, substantially free of other enantiomers. Thus, for example, what is intended herein is a composition containing the S enantiomer of a compound substantially free of the R enantiomer, or the R enantiomer of a compound substantially free of the S enantiomer. Where a named compound contains two or more chiral centers, the scope of this disclosure also includes compositions containing mixtures of various proportions between diastereomers, and compositions containing one or more diastereomers substantially free of one or more other diastereomers. "Substantially contained" means that the composition contains small amounts of enantiomers or diastereomers, less than 25%, 15%, 10%, 8%, 5%, 3%, or less than 1%.

[0094] Embodiment Example Methods for synthesizing, isolating, preparing, and administering various stereoisomers are known in the art. Separation of diastereomers or cis and trans isomers can be achieved by conventional techniques, for example, by fractional crystallization, chromatography, or high-performance liquid chromatography (HPLC) of stereoisomer mixtures of a drug or a suitable salt or derivative thereof. Individual enantiomers of the compounds disclosed herein can also be prepared, as appropriate, from the corresponding optically pure intermediate, or by decomposition of the corresponding racemate by HPLC using a suitable chiral support, or by fractional crystallization of diastereomer salts formed by reacting the corresponding racemate with a suitable optically active acid or base.

[0095] The compounds used in the methods disclosed herein can be prepared by techniques well known in organic synthesis and familiar to experts in the art. For example, the compounds can be prepared by synthetic transformations shown in the following general procedure and further described in the following specific examples.

[0096] Abbreviation ACN: Acetonitrile DCM: Dichloromethane DIPEA: Diisopropylethylamine DMAc: Dimethylacetamide DMSO: Dimethyl sulfoxide DMT: N,N-dimethyltryptamine HLM: Human liver microsomes HPLC: High-Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry MAO: Monoamine oxidase 5-MeO-DMT: 5-methoxy-N,N-dimethyltryptamine MLM: Mouse liver microsomes NADPH: Nicotinamide adenine dinucleotide hydrogen phosphate NMR: nuclear magnetic resonance PBS: Phosphate-buffered saline Pd / C: Palladium-supported carbon RLM: Rat liver microsomes RT: Room temperature (ambient temperature) THF: Tetrahydrofuran

[0097] General procedure [ka] [ka]

[0098] However, these may not be the only methods for synthesizing or obtaining the desired compound.

[0099] This disclosure provides pharmaceutical compositions comprising the compounds of this disclosure and pharmaceutically acceptable carriers.

[0100] The disclosed subject matter is also intended to include all isomers of atoms present in the compounds disclosed herein. Isomers include atoms that have the same atomic number but different mass numbers. As a general example, not limited to these, isomers of hydrogen include tritium and deuterium. Isomers of carbon include, 13 C and 14 Includes C.

[0101] Throughout this application, any notation of carbon in the structure, if used without further notation, 12 C, 13 C, or 14 It should be noted that this is intended to represent all isomers of carbon, such as C. Furthermore, 13 C or 14 Any compound containing C may particularly have any of the structures of the compounds disclosed herein.

[0102] Throughout this application, any notation for hydrogen in the structure, if used without further notation, 1 H, 2 H, or 3 It should also be noted that this is intended to represent all isomers of hydrogen, such as H. 2 H or 3 Any compound containing H may particularly have any of the structures of the compounds disclosed herein.

[0103] Isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, using a suitable isotope-labeling reagent instead of the unlabeled reagent used.

[0104] It should be understood that the examples and embodiments provided herein are illustrative. Those skilled in the art will envision various modifications of the examples and embodiments that are consistent with the scope of the disclosure herein. Such modifications are intended to be covered within the claims. [Examples]

[0105] (Example 1) Preparation of compound 3·HCl [ka]

[0106] Step 1: Preparation of 2-(5-fluoro-1H-indole-3-yl)-2-oxoacetyl chloride. To a mixture of 5-fluoro-1H-indole (3 g, 22.20 mmol, 1 equivalent) in THF (30 mL), oxalyl dichloride (4.23 g, 33.30 mmol, 2.91 mL, 1.5 equivalents) was added all at once under N2 at 0°C. The mixture was stirred at 15°C for 2 hours. Upon completion, the reaction mixture was concentrated to obtain 2-(5-fluoro-1H-indole-3-yl)-2-oxoacetyl chloride as a yellow solid (5.01 g, 22.21 mmol, 100% yield).

[0107] Step 2: Preparation of N-ethyl-2-(5-fluoro-1H-indole-3-yl)-2-oxo-N-propylacetamide. To a solution of N-ethylpropan-1-amine (2.90 g, 33.32 mmol, 4.63 mL, 1.5 equivalents) in DCM (20 mL), N,N-diisopropylethylamine (5.74 g, 44.42 mmol, 7.74 mL, 2 equivalents) was added. Then, 2-(5-fluoro-1H-indole-3-yl)-2-oxoacetyl chloride (5.01 g, 22.21 mmol, 1 equivalent) in THF (30 mL) was added at 0°C. The mixture was then stirred at 15°C for 2 hours. Upon completion, aqueous NH4Cl (30 mL) was added and the mixture was stirred for 5 minutes. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain N-ethyl-2-(5-fluoro-1H-indole-3-yl)-2-oxo-N-propylacetamide as a white solid (5.28 g, 19.11 mmol, 86% yield). 1 ¹H NMR (400 MHz, CDCl3) (Incomplete integral values ​​due to conformational isomerism) δ 10.80 (br s, 1H), 7.94 (dd, J = 2.0, 9.3 Hz, 1H), 7.53 (d, J = 3.2 Hz, 1H), 7.17 (ddd, J = 1.2, 4.3, 8.9 Hz, 1H), 6.93 (dt, J = 2.4, 9.0 Hz, 1H), 3.58 - 3.49 (m, 1H), 3.48 - 3.39 (m, 1H), 3.35 (q, J = 7.2 Hz, 1H), 3.29 - 3.20 (m, 1H), 1.76 - 1.53 (m, 2H), 1.25 (t, J = 7.2 Hz, 1.5H), 1.17 (t, J = 7.2 Hz, 1.5H), 1.00 (t, J = 7.6 Hz, 1.5H), 0.80 (t, J = 7.2 Hz, 1.5H).

[0108] Step 3: Preparation of N-ethyl-N-(2-(5-fluoro-1H-indole-3-yl)ethyl)propan-1-amine hydrochloride (3·HCl). To a solution of N-ethyl-2-(5-fluoro-1H-indole-3-yl)-2-oxo-N-propylacetamide (2 g, 7.24 mmol, 1 equivalent) in THF (30 mL), lithium aluminum hydride (824.18 mg, 21.72 mmol, 3 equivalents) was added at 0°C. The mixture was then stirred at 60°C for 5 hours. Upon completion, the mixture was cooled to 0°C. Water (0.83 mL) was added, and the reaction mixture was stirred for 5 minutes. Then, 0.83 mL of 30% NaOH aqueous solution was added. The mixture was filtered, and the filtrate was concentrated under vacuum. Separation of residue - HPLC column (Phenomenex Luna C18 (250 × 70 mm, 15 μm); mobile phase = water (0.05% HCl) - ACN, B% = 10% ~ 34%; R T Purified by (22 mins), N-ethyl-N-[2-(5-fluoro-1H-indole-3-yl)ethyl]propan-1-amine hydrochloride (3) was obtained as a white solid (845.6 mg, 2.97 mmol, 41% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (br s, 1H), 10.53 (br s, 1H), 7.48 - 7.30 (m, 3H), 6.94 (dt, J = 2.4, 9.2 Hz, 1H), 3.33 - 2.94 (m, 8H), 1.85 - 1.57 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13 ¹³C NMR (101 MHz, DMSO-d6) (extra peaks due to CF coupling) δ 158.40, 156.10, 133.35, 127.51, 127.41, 126.00, 113.04, 112.94, 110.07, 110.03, 109.96, 109.70, 103.69, 103.46, 52.87, 52.06, 46.94, 19.87, 17.01, 11.45, 8.86; LCMS (R T = 1.709 min, MS calculated: 248.17, [M+H]+ = 249.1).

[0109] (Example 2) Preparation of compound 4·HCl. A solution of N-ethyl-2-(5-fluoro-1H-indole-3-yl)-N-methyl-2-oxoacetamide (1.73 g, 6.97 mmol, 1 equivalent) in THF (30 mL) was mixed with lithium aluminum hydride (795.46 mg, 20.96 mmol, 3 equivalents) at 0°C. The mixture was then stirred at 60°C for 5 hours. After completion, the mixture was cooled to 0°C. Water (0.8 mL) was added, and the mixture was stirred for 5 minutes. Then, 0.8 mL of 30% NaOH aqueous solution was added. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was separated and analyzed on a preparative HPLC column (Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase = water (0.04% HCl)-ACN, B% = 10%~30%; R T Purified by (20 mins), N-ethyl-2-(5-fluoro-1H-indole-3-yl)-N-methylethane-1-amine hydrochloride (4) was obtained as a white solid (670 mg, 2.61 mmol, 37% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 10.46 (br s, 1H), 7.48 - 7.30 (m, 3H), 6.93 (dt, J = 2.4, 9.2 Hz, 1H), 3.36 - 3.00 (m, 6H), 2.79 (d, J = 5.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13 ¹³C NMR (101 MHz, DMSO-d6) (extra peaks due to CF coupling) δ 158.39, 156.09, 133.38, 127.49, 127.39, 125.96, 113.04, 112.94, 109.98, 109.94, 109.90, 109.72, 103.74, 103.51, 54.87, 50.38, 38.60, 20.20, 9.32; LCMS (R T = 1.581 min, MS calculated: 220.14, [M+H]+ = 221.1).

[0110] (Example 3) Metabolic stability of human liver microsomes The compounds disclosed herein were tested for the stability of human liver microsomes (HLMs), and the results are summarized in Table 1. Compound 2 exhibited greater metabolic stability in this model than Compound 1, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and psilocine.

[0111] HLM stability. Pooled HLM (Corning 452117) derived from adult male and female donors was used. Microsome incubation was performed in multi-well plates. The incubation medium for liver microsomes consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM) containing 0.50 mg of liver microsomes per mL. Control incubation was performed by replacing the NADPH cofactor system with PBS. The test compound (1 μM, final solvent concentration 1.0%) was incubated with microsomes at 37°C with constant shaking. 60 μL aliquots of the reaction mixture were taken at 6 time points over 60 minutes and analyzed. The reaction aliquots were stopped by adding 180 μL of cold (4°C) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 minutes, and then centrifugation at 4000 rpm for 20 minutes at 4°C to precipitate the protein. The supernatant sample (80 μL) was diluted with water (240 μL), and the residual parent compound was analyzed using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0112] Data analysis. Emission constant (k el ), half-life (t 1 / 2 ), and inherent clearance (CL int This was determined using linear regression analysis, plotted as ln(AUC) versus time.

[0113] [Table 1]

[0114] (Example 4) Metabolic stability of mouse liver microsomes The compounds disclosed herein were tested for the stability of mouse liver microsomes (MLMs), and the results are summarized in Table 2. Compound 2 exhibited greater metabolic stability than Compound 1 in this model.

[0115] MLM stability. Pooled MLMs (BIOIVT M00501) derived from CD-1 mice were used. Microsome incubation was performed in multi-well plates. The incubation medium for liver microsomes consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM) containing 0.50 mg of liver microsomes per mL. Control incubation was performed by replacing the NADPH cofactor system with PBS. The test compound (1 μM, final solvent concentration 1.0%) was incubated with microsomes at 37°C with constant shaking. 60 μL aliquots of the reaction mixture were taken at 6 time points over 60 minutes and analyzed. The reaction aliquots were stopped by adding 180 μL of cold (4°C) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 minutes, and then centrifugation at 4000 rpm for 20 minutes at 4°C to precipitate the protein. The supernatant sample (80 μL) was diluted with water (240 μL), and the residual parent compound was analyzed using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0116] Data analysis. Emission constant (k el ), half-life (t 1 / 2 ), and inherent clearance (CL int This was determined using linear regression analysis, plotted as ln(AUC) versus time.

[0117] [Table 2]

[0118] (Example 5) Metabolic stability of rat liver microsomes The compounds disclosed herein were tested for stability in rat liver microsomes (RLMs), and the results are summarized in Table 3. Both compounds exhibited low stability in this model.

[0119] RLM stability. Pooled RLM (Xenotech R1000) derived from adult male and female donors was used. Microsome incubation was performed in multi-well plates. The incubation medium for liver microsomes consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM) containing 0.50 mg of liver microsomes per mL. Control incubation was performed by replacing the NADPH cofactor system with PBS. The test compound (1 μM, final solvent concentration 1.0%) was incubated with microsomes at 37°C with constant shaking. 60 μL aliquots of the reaction mixture were taken at 6 time points over 60 minutes and analyzed. The reaction aliquots were stopped by adding 180 μL of cold (4°C) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 minutes, and then centrifugation at 4000 rpm for 20 minutes at 4°C to precipitate the protein. The supernatant sample (80 μL) was diluted with water (240 μL), and the residual parent compound was analyzed using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0120] Data analysis. Emission constant (k el ), half-life (t 1 / 2 ), and inherent clearance (CL int This was determined using linear regression analysis, plotted as ln(AUC) versus time.

[0121] [Table 3]

[0122] (Example 6) Pharmacokinetics in mice The pharmacokinetics of the compounds disclosed herein were examined in mouse plasma (Table 4) and brain (Table 5) after intravenous (iv) and oral (po) administration. Compound 2 showed improved absolute oral bioavailability (F) compared to Compound 1, consistent with its greater stability in mouse liver microsomes (see Example 4 above). Despite this improved oral exposure, the half-life of Compound 2 in plasma was similar to that of Compound 1. Overall, the findings indicate that Compound 2 can serve as an orally active and rapid-acting therapeutic agent.

[0123] Animals. Male C57BL / 6 mice aged 8–12 weeks were used in this study. Four mice were housed in each cage. Temperature and humidity were maintained at 22±3°C and 30–70%, respectively, and lighting was controlled to a 12-hour light-12-hour dark cycle. Temperature and humidity were recorded using an automated data logger system. All animals were fed laboratory rodent feed. Reverse osmosis water treated with ultraviolet light was given as needed. Animals were randomly assigned to treatment groups.

[0124] Drug. The test compound was used as a hydrogen fumarate and dissolved in a vehicle consisting of physiological saline. These were then administered intravenously (IV) via the tail vein or orally (PO) via gastric tube feeding at a dose of 10 mg / kg (calculated based on free base) and a volume of 5 mL / kg of body weight.

[0125] Sample collection and in vivo analysis. Blood samples (approximately 60 μL) were collected from the posterior orbital plexus at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (four animals at each time point) under low-concentration isoflurane anesthesia (Surgivet®). Immediately after blood collection, plasma was recovered by centrifugation at 4000 rpm for 10 minutes at 4°C, and the samples were stored at -70±10°C until in vivo analysis. Following blood collection, the animals were immediately euthanized, the abdominal vena cava was incised, and whole blood was perfused from the heart with 10 mL of saline to collect brain samples from all animals. After separation, the brain samples were rinsed three times with ice-cold saline (approximately 5-10 mL of saline in a disposable Petri dish for 5-10 seconds per rinse) and dried on blotting paper. Brain samples were homogenized using ice-cold phosphate-buffered saline (pH 7.4). The total volume of homogenates was three times the tissue mass. All homogenates were stored at -70±10°C until bioanalysis. For bioanalysis, 25 μL aliquots of plasma / brain test samples or spiked plasma / brain calibration standards were added to individually pre-labeled microcentrifuge tubes, followed by 100 μL of internal standard solution (glipizide, 500 ng / mL in acetonitrile), except for a blank containing 100 μL of acetonitrile. Samples were vortexed for 5 minutes and then centrifuged at 4000 rpm for 10 minutes at 4°C. Following centrifugation, 100 μL of each clear supernatant was transferred to a 96-well plate and analyzed by appropriate LC-MS / MS along with reference samples of each analyte used for calibration and identification.

[0126] Data analysis. Pharmacokinetic parameters were estimated using the non-compartmental analysis tool of Phoenix® WinNonlin software (Ver 8.0).

[0127] [Table 4]

[0128] [Table 5]

[0129] (Example 7) CYP inhibition of human liver microsomes The inhibition of five major cytochrome P450 (CYP) enzymes (1A2, 2C9, 2C19, 2D6, and 3A4) by the compounds disclosed herein was determined in human liver microsomes (HLM) using LC-MS / MS to monitor the metabolic transformation of a cocktail of reference CYP bases in the presence and absence of the test compounds (Table 6). At a test concentration of 10 μM, the test compounds showed limited inhibition of CYP overall. Compound 1 showed the least inhibition of most of the CYPs tested.

[0130] HLM incubation. Pooled HLM (Corning 452117) derived from adult male and female donors was used. Microsome incubation was performed in multi-well plates. Liver microsome incubation was performed using: 1) PBS (100 mM, pH 7.4), MgCl2 (3.3 mM), and NADPН (1 mM); 2) Liver microsomal protein (0.2 mg / mL); 3) Reference CYP bases: phenacetin for CYP1A2 (10 μM), diclofenac for CYP2C9 (5 μM), (S)-mephenytoin for CYP2C19 (30 μM), dextromethorphan for CYP2D6 (5 μM), and midazolam for CYP3A4 (2 μM); 4) The test compound (10 μM), a control inhibitor (3 μM α-naphthoflavone for CYP1A2, 3 μM sulfafenazole for CYP2C9, 1 μM (+)-N-3-benzylnylvanol for CYP2D6, or 3 μM ketoconazole for CYP3A4), or a solvent (for the uninhibited state) were also included. Incubation was performed at 37°C for 10 minutes with constant shaking. The reaction aliquots were stopped by adding 400 μL of cold (4°C) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), and the proteins were subsequently precipitated by centrifugation at 4000 rpm for 20 minutes at 4°C.

[0131] Sample analysis. The supernatant sample (200 μL) was diluted with water (100 μL), and the reference metabolites of each reference CYP base were quantified using appropriate liquid chromatography-tandem mass spectrometry (LC-MS / MS) methods. The inhibition percentage by the test compound or control inhibitor was calculated by comparing the formation of metabolites in the presence of the inhibitor with the formation of metabolites in the absence of the inhibitor.

[0132] [Table 6]

[0133] (Example 8) Stability in the presence of monoamine oxidase The compounds disclosed herein were tested for stability in human liver mitochondrial preparations in the presence of monoamine oxidases A and B (MAO-A and MAO-B), and the results are summarized in Table 7. In this model, the compounds disclosed herein exhibited greater MAO stability than DMT.

[0134] Liver mitochondria incubation. Human liver mitochondria (Xenotech H0610.M) were used. Mitochondrial incubation was performed in a multi-well plate. The liver mitochondria incubation medium consisted of PBS (100 mM, pH 7.4) containing 0.30 mg of liver mitochondrial protein per mL. The test compound (1 μM, final solvent concentration 1.0%) was incubated with liver mitochondrial protein at 37°C with constant shaking (total reaction volume of 100 μL per well). Analysis was performed at 6 time points over 60 minutes. At each time point, the reaction was stopped by adding 300 μL of cold (4°C) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS), followed by shaking for 10 minutes, and then the protein was precipitated by centrifugation at 4000 rpm for 20 minutes at 4°C. The supernatant sample (100 μL) was diluted with 5% trichloroacetic acid in water (300 μL), and the residual parent compound was analyzed using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0135] Data analysis. Emission constant (k el ), half-life (t 1 / 2 ), and inherent clearance (CL int This was determined using linear regression analysis, plotted as ln(AUC) versus time.

[0136] [Table 7]

[0137] (Example 9) Functional activity at serotonin receptors The compounds disclosed herein are Ca 2+ Using a functional assay of flux, agonist activity was tested against several serotonin receptor subtypes (5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A), and the results are summarized in Table 8. All compounds exhibited potent agonist activity at 5-HT2A, suggesting potential hallucinogenic activity and potential therapeutic effects. However, the efficacy of signaling at 5-HT2A and the selectivity for this target over other serotonin receptors varied dramatically even with small changes in chemical structure. For example, compound 1 showed little selectivity for 5-HT2A compared to 5-HT2B, while compound 2 showed higher selectivity for 5-HT2A compared to 5-HT2B. At the same time, compound 1 was a very effective agonist at 5-HT2A (E max =85.2%) On the other hand, compound 2 is a less potent partial agonist (E max The figure was 36.2%. Fluorination at position 5 of the indole ring also had unpredictable effects. For example, compounds 3 and 4 were significantly more potent at the 5-HT1A receptor than their non-fluorinated analogs, compounds 1 and 2, respectively. In the case of compound 3, fluorination also increased potency at 5-HT2A compared to compound 1. In the case of compound 4, fluorination had little effect on potency at 5-HT2A, but dramatically increased maximum potency compared to compound 2, resulting in higher potency than the partial agonist.

[0138] Functional assays of 5-HT2A, 5-HT2B, and 5-HT1A. Agonist activity at the receptors of 5-HT2A, 5-HT2B, and 5-HT1A was evaluated according to the standard protocol at WuXi AppTec (Hong Kong) using FLIPR Ca. 2+The determination was made using a flux assay. Briefly, stable transfected cells expressing the target receptor (HEK293 for 5-HT2A and 5-HT2B; CHO cells for 5-HT1A) were grown, plated in a 384-well plate, and incubated overnight at 37°C in 5% CO2. A fresh solution of 250 mM probenecid was prepared in 1 mL of FLIPR assay buffer. This was combined with a fluorescent dye (Fluo-4 Direct®) to a final assay concentration of 2.5 mM. The compound was diluted 1:3.16 for 10 points, and 750 nL was added to the 384-well compound using ECHO with 30 μL of assay buffer. The fluorescent dye was then added to the assay plate with assay buffer to a final volume of 40 μL. The cell plate was incubated at 37°C in 5% CO2 for 50 minutes and placed on a FLIPR Tetra together with the compound plate. Next, 10 μL of the reference and compound were transferred from the compound plate to the cell plate, and the fluorescence signal was read.

[0139] Functional assay of 5-HT2C. Agonist activity of 5-HT2C was evaluated according to its standard protocol at Eurofins DiscoverX (Fremont, CA) using FLIPR Ca. 2+The determination was made using a flux assay. Briefly, stable, transfected cells expressing the human 5-HT2C receptor were grown, plated in 384-well plates, and incubated overnight at 37°C in 5% CO2. The assay was performed using a 1× dye loading buffer consisting of 1× dye, 1× additive A, and 2.5 mM probenecid in HBSS / 20 mM Hepes. Probenecid was freshly prepared. Cells were loaded with dye before testing and incubated at 37°C for 30–60 minutes. After dye loading, cells were removed from the incubator and 10 μL of HBSS / 20 mM Hepes was added. A 3× vehicle was added to the assay buffer. Cells were incubated in a dark room at room temperature for 30 minutes to equilibrium the plate temperature. Intermediate dilutions of the sample material were performed to produce 4× samples in the assay buffer. Compound agonist activity was measured by FLIPR Tetra (MDS). Calcium recruitment was monitored for 2 minutes, and 10 μL of 4× sample in HBSS / 20 mM Hepes was added to the cells for 5 seconds during the assay.

[0140] [Table 8]

[0141] (Example 10) The effect of the head twist response (HTR) in mice. The compounds of this disclosure were tested for their ability to induce a cerebral spasm response (HTR) in mice, and the results are summarized in Table 9. Consistent with their agonist activity at the 5-HT2A receptor, both compound 1 and compound 2 induced HTR. However, the maximum effect of the compounds of this disclosure was smaller than that of the prototype 5-HT2A agonist, 4-iodo-2,5-dimethoxyamphetamine (DOI) (35.6 cerebral spasms / 20 min). The maximum effect of compound 2 in this assay (6.00 cerebral spasms / 20 min) was also smaller than that of compound 1 (14.7 cerebral spasms / 20 min), which is consistent with the smaller efficacy of compound 2 as a 5-HT2A agonist in vitro (see Example 9 above).

[0142] Animals. Eight-week-old adult male C57BL / 6 mice (body weight 20-25g) were used in this experiment. The animals were housed under controlled temperature and a 12-hour light / dark cycle (light from 7:00 to 19:00), with food and water provided as needed. The protocol was approved by the Eurofins Advinus Institutional Animal Care and Use Committee. This study was conducted strictly in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Every effort was made to minimize suffering.

[0143] Drugs and drug administration. The test compounds were used as hydrogen fumarate salts, and the DOI was used as an HCl salt. The drugs were dissolved in a vehicle consisting of physiological saline and administered subcutaneously (sc) at a volume of 10 mL / kg. The test compounds were administered to N=6 animals / groups at 5 doses each (1-100 mg / kg, calculated based on free base). The control compound DOI was administered to N=12 animals at 1 dose (3.16 mg / kg, calculated based on the HCl salt).

[0144] Procedure: Mice were administered a single dose of the test drug (or vehicle) via sc administration and immediately placed in a small open field for behavioral observation. The animals were observed continuously for 20 minutes, and the number of HTRs was counted by an observer blinded to the treatment conditions.

[0145] Statistical analysis. The data points shown in Table 9 represent the mean ± standard error (SEM) of the mean. The analysis was performed using GraphPad Prism 9.

[0146] [Table 9]

[0147] (Example 11) Forced swimming test in rats The compounds disclosed herein induced antidepressant-like effects in a forced swimming test (FST) in rats with a 23.5-hour pre-treatment time (Figure 1). Specifically, the compounds reduced immobility time and exhibited antidepressant-like effects compared to the vehicle control. These effects on immobility were observed 23.5 hours after a single dose of the compound, by which time most or all of the drug had been eliminated from the systemic circulation, suggesting that the compounds possess both rapidly acting and long-lasting antidepressant-like effects. In addition, the compounds induced a significant increase in swimming behavior during the test (Figure 2). These effects on swimming were stronger than those induced by the control antidepressant desipramine.

[0148] Animals. Male Sprague Dawley rats aged 8-10 weeks were used in this experiment. The animals were housed in two groups under controlled temperature (22±3°C) and relative humidity (30-70%) conditions, with a 12-hour light / dark cycle, and provided with food and water as needed. This experiment was conducted strictly in accordance with the requirements of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) in India. Every effort was made to minimize suffering.

[0149] Drugs and drug administration. The test compound, physiological saline vehicle, and positive control desipramine were administered subcutaneously (sc) at doses calculated based on free bases. Physiological saline was used as the vehicle. All compounds were administered in a volume of 5 mL / kg. The test compound and vehicle were administered 0.5 hours after the start of swimming training (Swim 1) and 23.5 hours before the test swim (Swim 2). Desipramine was administered three times at a dose of 20 mg / kg at 23.5 hours, 5 hours, and 1 hour before the test swim (Swim 2).

[0150] Forced swimming test (FST). Animals were randomized based on body weight to ensure minimal variability between groups, not exceeding ±20% of the mean body weight between groups. Group size was N=10 per treatment, except for the vehicle and desipramine groups, which were N=20. Rats were treated for approximately 2 minutes per day for 5 days prior to the start of the experimental procedure. On the first day of the experiment (i.e., Day 1), after randomization, the training swimming period (Swimming 1) was performed for all animals between 12:00 and 18:00 by placing each rat individually in a glass cylinder (46 cm high x 20 cm in diameter) containing 30 cm of water at 23-25°C for 15 minutes. At the end of Swimming 1, the animals were wiped dry with paper towels, placed in a heated drying cage for 15 minutes, and then returned to their respective containment cages. The animals were then administered the appropriate drug or vehicle treatment as described above. To clarify, the time of compound administration 23.5 hours prior to swim 2 means 0.5 hours after the start of swim 1 and 0.25 hours after the completion of swim 1 (i.e., immediately after returning to the containment cage). On day 1 (i.e., 24 hours after the start of swim 1), the animals underwent a 5-minute test swim (swim 2), but otherwise were under the same conditions as swim 1. The water was changed for each animal throughout all swimming periods.

[0151] Behavioral scoring was performed by observers blinded to the treatment group. Animals were continuously observed during swimming 2, and the total time spent performing the following behaviors was recorded: immobility, swimming, and climbing. A rat was judged immobility if it remained floating in the water without struggling and only made the movements necessary to keep its head above the water surface. A rat was judged swimming if it performed active swimming behavior beyond the movements necessary to keep its head above the water surface (e.g., moving around the cylinder). A rat was judged climbing if it made active movements of its forelegs, usually towards the wall, moving in and out of the water.

[0152] Statistical analysis. The data points shown in Figures 1 and 2 represent the mean ± standard error of the mean (SEM). The analysis was performed using GraphPad Prism 9. Comparisons between groups were performed using one-way analysis of variance (ANOVA) followed by Dunnett's test for comparison with the vehicle.

[0153] (Example 12) Stability of mouse plasma and brain homogenates The compounds of this disclosure were tested for stability in mouse plasma (Table 10) and mouse brain homogenates (Table 11) by LC-MS / MS. The compounds were stable under the experimental conditions, suggesting that they were substantially not subjected to plasma or brain metabolism.

[0154] Plasma stability. Positive control and test compounds (final concentration in incubation medium = 1 μM, 0.5% DMSO) were incubated in 400 μL of DBA2 mouse plasma (n=3) in a CO2 incubator at 37°C. 50 μL aliquots were removed from each incubation at 0, 5, 15, 30, 60, and 90 minutes, immediately quenched with 500 μL of ice-cold acetonitrile containing an internal standard, and then stored at -80°C. At the time of bioanalysis, all samples were thawed to room temperature. Samples were vortexed for 5 minutes, followed by centrifugation at 4,000 RPM for 15 minutes at 4°C. 100 μL aliquots of each sample were transferred to 96-well deep plates and analyzed for residual parent compounds by appropriate LC-MS / MS.

[0155] Stability of brain homogenates. Homogenate samples of brain tissue were prepared by diluting one volume of whole brain tissue from C57BL / 6 mice with three volumes of dialysis buffer (phosphate-buffered saline, pH 7.4, 0.1 M sodium phosphate and 0.15 M sodium chloride) to obtain 4-fold diluted homogenates. Positive controls and test compounds (final concentration in incubation medium = 1 μM, 0.5% DMSO) were incubated in 400 μL of the diluted mouse brain homogenates (n=3) described above in a CO2 incubator at 37°C. 50 μL aliquots were removed from each incubation at 0, 5, 15, 30, 60, and 90 minutes, immediately quenched with 500 μL of ice-cold acetonitrile containing an internal standard, and then stored at -80°C. All samples were thawed to room temperature at the time of in vivo analysis. The samples were vortexed for 5 minutes, followed by centrifugation at 4,000 RPM for 15 minutes at 4°C. 100 μL aliquots of each sample were transferred to a 96-well deep plate and analyzed for the residual parent compound using a suitable LC-MS / MS method.

[0156] [Table 10]

[0157] [Table 11]

[0158] (Example 13) Microsomal Stability of Additional Compounds Additional compounds of the present disclosure, including Compounds 3 and 4, are tested for stability in human, mouse, or rat liver microsomes as described in Examples 3 to 5. Compound 4 exhibits moderate to high stability in human and mouse microsomes, and is more stable than DMT in such preparations.

[0159] (Example 14) Pharmacokinetics of Additional Compounds in Mice Additional compounds of the present disclosure, including Compounds 3 and 4, are tested to determine their pharmacokinetic properties and oral bioavailability in mice as described in Example 6. Compound 4 exhibits moderate to high oral bioavailability.

[0160] (Example 15) Stability of Additional Compounds in the Presence of Monoamine Oxidase Additional compounds of the present disclosure, including Compounds 3 and 4, are tested to determine their stability in the presence of monoamine oxidase using liver mitochondrial preparations as described in Example 8. Compounds 3 and 4 exhibit moderate to high stability in such preparations.

[0161] (Example 16) Effects of Additional Compounds in the HTR Assay Additional compounds of the present disclosure, including Compounds 3 and 4, are tested to determine their ability to induce the head twitch response (HTR) in mice as described in Example 10. Compounds 3 and 4 induce the head twitch response in mice in a dose-dependent manner, which is consistent with their agonist activity at the 5-HT2A receptor in vitro.

[0162] (Example 17) Effects of additional compounds in forced swimming tests in rats The additional compounds of this disclosure, including compounds 3 and 4, are tested in a forced swimming test (FST) in rats, as described in Example 11. Compounds 3 and 4 reduce akinesia in this test in a dose-dependent manner, consistent with an antidepressant-like effect.

[0163] (Example 18) Synthesis of additional compounds Additional compounds of this disclosure can be prepared by standard methods known to those skilled in the art of organic synthesis, for example, those shown in Examples 1-2 and described elsewhere herein.

Claims

【Request Item 1】 【Chemistry 1】 A pharmaceutical composition for use in a method for treating mood disorders, comprising a pharmaceutically acceptable hydrochloride salt of a compound having a structure represented by , wherein the method comprises the step of administering a therapeutically effective amount of the pharmaceutically acceptable hydrochloride salt in the pharmaceutical composition to a subject in need thereof.

2. The pharmaceutical composition according to claim 1, wherein the mood disorder is selected from the group consisting of depressive disorder and bipolar disorder.

3. The pharmaceutical composition according to claim 1, wherein the mood disorder is a depressive disorder.

4. The pharmaceutical composition according to claim 1, wherein the mood disorder is treatment-resistant depressive disorder.

5. The pharmaceutical composition according to claim 1, wherein the mood disorder is selected from the group consisting of major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation, substance / drug-induced depressive disorder, and depressive disorder due to another medical condition.

6. The pharmaceutical composition according to claim 1, wherein the mood disorder is a substance-related disorder or a substance use disorder.

7. The pharmaceutical composition according to claim 1, wherein the mood disorder is selected from the group consisting of obsessive-compulsive disorder and related disorders, trauma-related disorders and stressor-related disorders, eating disorders and nutritional disorders, borderline personality disorder, attention deficit / hyperactivity disorder, and autism spectrum disorder.

8. The pharmaceutical composition according to claim 1, wherein the method comprises the step of administering 0.5 mg to 150 mg of the pharmaceutically acceptable hydrochloride salt in the pharmaceutical composition.

9. The method provides relief from grief or lethargy or fatigue, depressed mood, loss of sensation, anxious and worried feelings, fear, tension, feelings of restlessness, decreased interest in all or nearly all activities, difficulty initiating activities, significant changes in appetite resulting in weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness or decreased self-esteem, strongly held negative beliefs or pessimistic thoughts about oneself, others or the world, helplessness, inability to concentrate or distractibility, recurring thoughts of death or suicide, guilt, memory complaints, difficulty experiencing positive emotions, separation from others or The pharmaceutical composition according to claim 1, which results in improvement of at least one symptom selected from the group consisting of: feeling isolated from others, excessive vigilance, risk-taking behavior, avoidance of thoughts about stressful or traumatic events, pain and pain, rumination and obsession, compulsive behavior, talking to strangers or people one doesn't know well, wanting to be the center of attention, disruption of intrusive thoughts, inability to get through a week without using a drug, guilty of drug use, problems with friends or family due to drug use, and withdrawal symptoms from drug use.

10. The pharmaceutical composition according to claim 1, wherein the compound is administered 1 to 4 times a day in the method described above.

11. The pharmaceutical composition according to claim 1, wherein the mood disorder is an anxiety disorder.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutically acceptable hydrochloride salt is a purified solid.

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