Tryptamines specific for use in treatment of mood disorders

Abstract

To provide safe and effective tryptamine compounds that can reliably be used for treatment of mood disorders.SOLUTION: The invention provides methods of treating mood disorders with compounds disclosed herein. Also provided are pharmaceutical compositions that include those compounds.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 978,075, filed February 18, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Depression is a common psychological problem, and refers to a state of low mood and aversion to activity.The various symptoms associated with depression include persistent anxiety or sadness, helplessness, despair, sadness and / or worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in pleasurable activities or hobbies, excessive sleep, excessive eating, anorexia, insomnia, suicidal thoughts, and suicide attempts.The presence, severity, frequency, and duration of the above symptoms vary from case to case.

[0003] Approximately one-third of patients with major depressive disorder (MDD) never 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 new and more effective pharmacotherapies for depression that target novel mechanisms and / or patient populations.

[0004] Tryptamine is a monoamine alkaloid that contains an indole ring and is structurally similar to the amino acid tryptophan from which it is named.

[0005] There are a significant number of tryptamine compounds, including naturally occurring compounds and chemical derivatives with similar structures that may have unsubstituted or substituted rings. Many tryptamines are 5HT 2AThey are receptor agonists and / or modulators of other serotonin receptors and are known to be psychoactive, in many cases causing long-lasting hallucinations. The best known tryptamines are psychedelic compounds, including the entheogenic fungal-derived compounds (psilocybin and psilocin), N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), bufotenin, and ibogaine. These compounds are known to have significant effects on thinking, 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 lack of established safety. Additionally, tryptamines are metabolized by several pathways, including monoamine oxidase, in some cases limiting the oral bioavailability of some compounds and resulting in a very short-lived effect. Conversely, other tryptamines have a very long duration of action, making them difficult to use in an induction therapy setting, during which extended monitored clinical sessions are costly for patients and inconvenient for healthcare providers. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, 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] The present disclosure relates to compound 2: [ka] or a pharma- ceutically acceptable salt thereof.

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

[0009] Additionally, the present disclosure provides a method of treating a mood disorder in a patient in need thereof, comprising administering to said patient an effective amount of Compound 2 or Compound 4: [ka] or a pharma- ceutically acceptable salt thereof.

[0010] For example, provided herein are methods and compositions directed to treating mood disorders by administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of Compound 2 or Compound 4, or a pharma- ceutically 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 may treat mood disorders including obsessive-compulsive disorder and related disorders. In embodiments, the methods and compositions may treat mood disorders including trauma-related disorders and stressor-related disorders. In embodiments, the methods and compositions may treat mood disorders including eating disorders and nutritional disorders. In embodiments, the methods and compositions may treat mood disorders including cognitive disorders. In embodiments, the methods and compositions may treat mood disorders including neurodevelopmental disorders. In embodiments, the methods and compositions may treat mood disorders including personality disorders. In embodiments, the methods and compositions may treat mood disorders including sexual dysfunction. In embodiments, the methods and compositions may treat mood disorders including gender dysphoria. [Brief description of the drawings]

[0012] [Figure 1]Immobility time in the FST is shown. One-way ANOVA revealed a significant main effect of treatment on total time spent immobile in the FST (F(9,99)=12.42, P<0.0001). Dunnett's multiple comparison test was used to test if groups were significantly different from vehicle. All treatments were significantly different from vehicle except Compound 2 at 0.1 mg / kg. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. vehicle. [Diagram 2] Swimming time in the FST is shown. One-way ANOVA revealed a significant main effect of treatment on total time spent swimming in the FST (F(9,99)=2.653, P=0.0090). Dunnett's multiple comparison test was used to test if groups were significantly different from vehicle. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. vehicle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure provides compounds of formula I: [ka] (In the formula, R 1 is an arbitrarily substituted C 1 ~C 4 It is aliphatic; R 2 is an arbitrarily substituted C 1 ~C 4 It is aliphatic; R 26 are hydrogen, halogens, -CN, -OH, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, OAc, -OPO(OH) 2 , and N.H. 2 (selected from the group consisting of or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, R1 is selected from the group consisting of Me, Et, nPr, iPr, cyclopropyl, allyl, isobutyl, and cyclopropylmethyl. 2 is selected from the group consisting of Me, Et, nPr, iPr, cyclopropyl, allyl, isobutyl, cyclopropylmethyl.

[0015] In some embodiments, R 26 are hydrogen, F, Cl, Br, I, and CF 3 , Me, CN, OMe, OH, OAc, and NH 2 In some embodiments, R 26 are F, Cl, Br, I, and CF 3 , Me, CN, OMe, OH, OAc, and NH 2 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 iodine.

[0016] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: [ka] or a pharma- ceutically acceptable salt thereof.

[0017] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0018] In an embodiment, the present disclosure provides a method for producing a pharmaceutical composition comprising: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0019] Described herein are methods and compositions for treating mood disorders by administering to a patient in need thereof the compounds disclosed herein. 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 dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation disorder, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

[0021] In some embodiments, depressive conditions include major depressive disorder and dysthymic disorder. In some embodiments, depressive conditions develop under unique circumstances, including but 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 conditions expected to be treated by this aspect of the disclosure include but are not limited to major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder (SAD), anxiety, 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 is a method for treating a patient suffering from treatment-refractory depression, for example, a depressive disorder that is unresponsive and / or unresponsive to at least one or at least two other antidepressant compounds or suitable courses of therapy.For example, provided herein is a method 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 present disclosure.As used herein, "depressive disorder" includes treatment-refractory depression.In some embodiments, treatment-refractory depression occurs in patients suffering from depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments, such as psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation. In some embodiments, a treatment-resistant patient may be identified as a patient who does not experience relief from one or more symptoms of depression (e.g., persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism) despite receiving one or more standard pharmacological or non-pharmacological treatments. In certain embodiments, a treatment-resistant patient is a patient who does not experience relief from one or more symptoms of depression despite receiving treatment with two different antidepressants. In other embodiments, a treatment-resistant patient is a patient who does not experience relief from one or more symptoms of depression despite receiving treatment with four different antidepressants. In some embodiments, a treatment-resistant patient may also be identified as a patient who is unwilling or unable to tolerate 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 anxiety or sadness, helplessness, despair, sadness and / or worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in enjoyable activities or hobbies, oversleeping, overeating, anorexia, 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 headache. In addition, patients suffering from any form of depression often experience anxiety. It is expected that the method of the present condition can be used to treat either anxiety or its symptoms. In some embodiments, the presence, severity, frequency, and duration of symptoms of depression 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, e.g., bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to another medical condition.

[0025] In embodiments, the methods and compositions can be used to treat mood disorders, including substance-related disorders, for example, by preventing substance use cravings, reducing substance use cravings, and / or promoting cessation or withdrawal from substance use. Substance use disorders include abuse of psychoactive compounds, such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, a "substance" refers to a psychoactive compound that can be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the methods and compositions can be used to promote smoking cessation or cessation 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 / medication-induced anxiety disorder, and anxiety disorders due to another medical condition.

[0027] In embodiments, the methods and compositions can be used to treat mood disorders including obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation disorder, skin-picking disorder, substance / medication-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder and related disorders due to another medical condition.

[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 interpersonal 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 and nutritional disorders, such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorders, and avoidant / restrictive food intake disorders.

[0030] In embodiments, the methods and compositions can be used to treat mood disorders including cognitive disorders, 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, severe or mild dementia due to 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 another medical condition, and severe or mild dementia due to multiple etiologies.

[0031] In embodiments, the methods and compositions can be used to treat mood disorders, including neurodevelopmental disorders, such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotypic 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, autistic disorders, 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 disorders, 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, the methods and compositions can be used to treat mood disorders including sexual dysfunction, such as delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genitopelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, early ejaculation, and substance / medication induced sexual dysfunction.

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

[0035] In embodiments, provided are methods and compositions for treating a mood disorder by administering to a subject in need thereof an effective amount of ethylpropyltryptamine (EPT; Compound 1) or a pharma- ceutically acceptable salt thereof. [ka]

[0036] In other embodiments, provided are methods and compositions for treating a mood disorder by administering to a subject in need thereof an effective amount of methylethyltryptamine (MET; Compound 2) or a pharma- ceutically acceptable salt thereof. [ka]

[0037] In another embodiment, provided is a method for treating a subject in need thereof comprising administering to the subject a compound having the following structure: [ka] and a medicament for treating a mood disorder comprising administering to said patient an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0038] In another embodiment, provided is a method for treating a subject in need thereof comprising administering to the subject a compound having the following structure: [ka] [ka] and a medicament for treating a mood disorder comprising administering to said patient an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0039] In another embodiment, provided is a method for treating a subject in need thereof comprising administering to the subject a compound having the following structure: [ka] [ka] and n is an integer from 0 to 10. In another embodiment, provided herein are methods and compositions for treating a mood disorder by administering an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, selected from: In another embodiment, provided herein are methods and compositions for treating a migraine or cluster headache by administering a compound disclosed herein to a patient in need thereof.

[0040] In other embodiments, provided herein are methods and compositions for treating inflammation by administering to a subject in need thereof a compound of the present disclosure.

[0041] In embodiments, the method includes treating a mood disorder, e.g., a depressive disorder, by administering to a patient in need thereof a pharmaceutical composition comprising about 0.01 mg to about 400 mg of a compound disclosed herein. In embodiments, the dose may be, for example, about 0.01-400 mg, 0.01-300 mg, 0.01-250 mg, 0.01-200 mg, 0.01-150 mg, 0.01-100 mg, 0.01-75 mg, 0.01-50 mg, 0.01-25 mg, 0.01-20 mg, 0.01-15 mg, 0.01-10 mg, 0.01-5 mg, 0.01-1 mg, 0.01-0.5 ... .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 may be 0 to 25 mg, 10 to 15 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 300 mg, 100 to 250 mg, or 100 to 200 mg, for example, about 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, Example dosages are 1.25mg, 1.5mg, 1.75mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, and 400mg.

[0042] In specific embodiments, a dosage can include an amount of a compound disclosed herein in the range of, for example, about 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, including, for example, 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, or 2.5 mg. Doses of 100 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 15 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, and 200 mg are examples of specific doses.

[0043] Typically, dosages of the compounds disclosed herein are administered to a patient in need thereof once, twice, three times, or four times a day, every other day, every third day, once a week, twice a month, once a month, or three to four times a year. In embodiments, dosages are, for example, about 1-400 mg / day, or 1-300 mg / day, or 1-250 mg / day, or 1-200 mg / day, such as 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, e.g., spray or mist, of the compounds disclosed herein include a concentration of about 0.005 mg / ml to about 500 mg / mL. In embodiments, the compositions include the compounds disclosed herein at a concentration of, for example, 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 an embodiment, the composition comprises a compound disclosed herein at a concentration 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 an embodiment, the pharmaceutical composition is formulated, for example, in a total volume of 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 a subject once, twice, three times, or four times a day, every other day, every third day, once a week, twice a month, once a month, or three to four times a year. In an embodiment, the compounds disclosed herein are administered to a subject once in the morning or once in the evening. In an embodiment, the compounds disclosed herein are administered to a subject once in the morning and once in the evening. In an embodiment, the compounds disclosed herein are administered to a subject three times a day (e.g., breakfast, lunch, and dinner), for example, at a dose of 50 mg / dose (e.g., 150 mg / day).

[0047] In an embodiment, the compound disclosed herein is administered to the subject at 12.5 mg / day in one or more doses. In an embodiment, the compound disclosed herein is administered to the subject at 25 mg / day in one or more doses. In an embodiment, the compound disclosed herein is administered to the subject at 35 mg / day in one or more doses. In an embodiment, the compound disclosed herein is administered to the subject at 50 mg / day in one or more doses. In an embodiment, the compound disclosed herein is administered to the subject at 75 mg / day in one or more doses. In an embodiment, the compound disclosed herein is administered to the subject at 100 mg / day in one or more doses. In an embodiment, the compound disclosed herein is administered to the subject at 150 mg / day in one or more doses. In an embodiment, the compound disclosed herein is administered to the subject at 200 mg / day in one or more doses. In an embodiment, the compound disclosed herein is administered to the subject at 250 mg / day in one or more doses.

[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 per 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, twice, three or four times per day. In embodiments, a subject is administered a total daily dose of a compound disclosed herein between 0.01 mg and 500 mg once, twice, three times, or four times per day. In embodiments, the total amount administered to a subject in 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 embodiments, subjects can be started on a low dose and the dosage is gradually increased, hi embodiments, subjects can be started on a high dose and the dosage is decreased.

[0049] In embodiments, the compounds disclosed herein can be administered at a predetermined interval, for example, via inhalation or oral administration.For example, during treatment, patients can 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, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is administered to a patient under the supervision of a health care provider.

[0051] In an embodiment, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is administered to a patient under the supervision of a medical provider in a clinic that specializes in administering psychoactive treatments.

[0052] In embodiments, compounds of the disclosure are administered to a patient under the supervision of a healthcare provider at high doses intended to induce a psychedelic experience in the subject, e.g., 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, administration of high doses to a patient under the supervision of a healthcare provider is performed periodically to maintain therapeutic benefit in the patient, for example, every 3 days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year.

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

[0055] In some embodiments, the compounds of the present disclosure or pharma- ceutically acceptable salts thereof are administered by the patient at home or away from the supervision of a health care provider to the patient themselves at low doses intended to result in a sub-perceptible psychoactive effect or to induce a threshold psychoactive effect, e.g., 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.

[0056] In some embodiments, administration of low doses to the patient themselves is done periodically, for example, daily, every other day, every third day, twice a week, once a week, twice a month, or once a month, to maintain therapeutic benefit in the patient.

[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, intratracheal, intraocular, or intranasal forms, forms adapted for inhalation, topical, transdermal, or parenteral forms, such as forms adapted for intravenous, intraarteriolar, intraperitoneal, intrathecal, intraventricular, intramuscular, or subcutaneous administration. In embodiments, for such parenteral administration, the solution may be in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salts or glucose, to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished 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 modified release profiles. In embodiments, pharmaceutical compositions with different drug release profiles may be combined to create biphasic or triphasic release profiles. For example, pharmaceutical compositions may be provided with immediate release and sustained release profiles. In embodiments, pharmaceutical compositions may be provided with sustained release and delayed release profiles. Such compositions may be provided as pulsatile formulations, multi-layer tablets, or capsules containing tablets, beads, granules, etc. The compositions may be prepared using pharma- ceutical acceptable "carriers" composed of materials deemed safe and effective. "Carriers" include all ingredients present in a pharmaceutical formulation other than one or more active ingredients. The term "carrier" includes, but is not limited to, excipients, binders, lubricants, glidants, disintegrants, fillers, and coating compositions.

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

[0060] Such methods include the step of mixing the compound or combination thereof used in the present disclosure with an auxiliary agent, also named auxiliary ingredient, including those conventional in the art, such as carriers, fillers, binders, excipients, disintegrants, lubricants, colorants, flavorings, antioxidants, and wetting agents. Such auxiliary agents are suitably selected for the intended form and route of administration, consistent with conventional pharmaceutical practice.

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

[0062] Tablets can contain the active ingredient compound and suitable binders, lubricants, disintegrants, coloring agents, flavoring agents, flow inducers, and solubilizers. Gelatin capsules can contain the active ingredient compound and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar excipients can be used to make compressed tablets. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated to selectively disintegrate in the digestive tract. For example, for oral administration in unit dosage form of tablet or capsule, the active drug ingredient can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers, such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0063] For oral administration in liquid dosage forms, the oral drug components are combined with any oral, non-toxic, pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Examples of suitable liquid dosage forms include, but are not limited to, solutions or suspensions in water, pharma- ceutically acceptable fats and oils, alcohols and other organic solvents (including esters), emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent 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 coloring agents and flavoring agents to enhance patient acceptance.

[0064] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile solutions. In general, water, a suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffer substances. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. The compositions may be provided in unit-dose or multi-dose containers, such as sealed vials and ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water, prior to use. For transdermal administration, for example, gels, patches, or sprays may be contemplated. Compositions or formulations suitable for pulmonary administration, for example by nasal inhalation, include fine powders or mists that can be generated by metered pressurized aerosols, nebulizers, or insufflators. Parenteral and intravenous forms also include minerals and other materials that are compatible with the type of injection or delivery system chosen.

[0065] The compound used in the method of the present disclosure can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. The compound can be administered as a component of a tissue-targeting emulsion.

[0066] The compounds used in the disclosed methods can also be conjugated to soluble polymers as targetable drug carriers or as prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds can be conjugated to classes of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsiloncaprolactone, 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 modified release profiles. In some embodiments, pharmaceutical compositions with different drug release profiles may be combined to create a biphasic or triphasic release profile. For example, the pharmaceutical compositions may be provided with immediate release and sustained release profiles. In some embodiments, the pharmaceutical compositions may be provided with sustained release and delayed release profiles. Such compositions may be provided as pulsatile formulations, multi-layer tablets, or capsules containing tablets, beads, granules, etc.

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

[0069] The present disclosure further includes pharmaceutical compositions, as described below, in combination with packaging material and instructions for use of the composition for the uses described below.

[0070] The exact dosage and regimen of administration of the compositions will necessarily depend on the type and magnitude of the therapeutic or nutritional effect to be achieved, and may vary depending on factors such as the particular compound, formulation, route of administration, or the age and condition of the individual subject to which the composition is to be administered.

[0071] The compounds used in the disclosed methods can be administered in various forms, including those detailed herein. Treatment with the compounds can be a component of combination therapy or adjunctive therapy, i.e., the subject or patient in need of the drug is treated with or administers another drug for the disease in combination with one or more of the compounds. This combination therapy can be a sequential therapy, where the patient is first treated with one drug and then with another drug, or where two drugs are administered simultaneously. These can be administered independently by the same route of administration or by two or more different routes of administration, 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 dual and triple uptake inhibitors and / or anxiolytics, to manufacture a medicament for treating depression, anxiety, and / or other related disorders, including relieving depression or anxiety, and preventing the recurrence of 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, Elavil, Norpramin, Pamelor, Pertofuran, Sinequan, Surmontil, Tofranil, Bibactil, Parnate, Nardil, Marplan, Celexa, Lexapro, Luvox, Paxil, Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel (Trazodone), and Ludiomil.

[0073] definition In the context of the present disclosure, the term "5-HT2a receptor agonist" is intended to mean any compound or substance that activates the 5-HT2a receptor. Agonists can be partial or full agonists.

[0074] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or has a single point of attachment to the rest of the molecule and contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl"). Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C ring that is fully saturated or has a single point of attachment to the rest of the molecule, contains one or more units of unsaturation, but is not aromatic. 3 ~C 6 Refers to a hydrocarbon. 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 straight or branched chain alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

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

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

[0078] As used herein, the term "pharmaceutical acceptable" refers to molecular entities and compositions that are "generally regarded as safe", e.g., physiologically tolerated and typically do not produce allergic or similar adverse reactions when administered to humans. In embodiments, the term refers to molecular entities and compositions that have been approved by federal or state government regulatory agencies, the United States Pharmacopeia, or another generally recognized pharmacopoeia, as listed on the GRAS list or similar list under Sections 204(s) and 409 of the Federal Food, Drug and Cosmetic Act for pre-market review and approval by the FDA for use in animals, and more specifically, in humans.

[0079] As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. The combinations of substituents envisioned by the present invention are preferably those that result in the production of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that are substantially unchanged when placed under conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0080] Suitable monovalent substituents at a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2 ) 0~4 R ○ ; -(CH 2 ) 0~4 OR ○ ; -(CH 2 ) 0~4 R ○ , -O-(CH 2 ) 0~4 C(O)OR ○ ; -(CH 2 ) 0~4 CH(OR ○ ) 2 ; -(CH 2 ) 0~4 S.R. ○ ; -(CH 2 ) 0~4 Ph(R ○ -(CH 2 ) 0~4 O(CH 2 ) 0~1 Ph(R ○ -CH=CHPh(R ○ -(CH 2 ) 0~4 O(CH 2 ) 0~1 -Pyridyl (R ○ -NO 2 ;-CN;-N 3 ; -(CH 2 ) 0~4 N(R ○ ) 2 ; -(CH 2 ) 0~4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH 2 ) 0~4 N(R ○ )C(O)NR ○ 2 ; -N(R ○ )C(S)NR ○ 2 ; -(CH 2 ) 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 ○ ; -(CH 2 ) 0~4 C(O)R ○ ; -C(S)R ○ ; -(CH 2 ) 0~4 C(O)OR ○ ; -(CH 2 ) 0~4 C(O)SR ○ ; -(CH 2 ) 0~4 C(O)OSiR ○ 3 ; -(CH 2 ) 0~4 OC(O)R ○ ; -OC(O)(CH 2 ) 0~4 SR ○ 、SC(S)SR ○ ; -(CH 2 ) 0~4 SC(O)R ○ ; -(CH 2 ) 0~4 C(O)NR ○ 2 ; -C(S)NR ○ 2 ; -C(S)SR ○ ; -SC(S)SR ○ 、-(CH 2 ) 0~4 OC(O)NR ○ 2 ; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH 2 C(O)R ○ ; -C(NOR ○ )R ○ ; -(CH 2 ) 0~4 SSR ○ ; -(CH 2 )0~4 S(O) 2 R ○ ; -(CH 2 ) 0~4 S(O) 2 OR ○ ; -(CH 2 ) 0~4 OS(O) 2 R ○ ;-S(O) 2 NR ○ 2 ; -(CH 2 ) 0~4 S(O)R ○ ; -N(R ○ )S(O) 2 NR ○ 2 ; -N(R ○ )S(O) 2 R ○ ; -N(OR ○ )R ○ -C(NH)NR ○ 2 ; -P(O) 2 R ○ ;-P(O)R ○ 2 ;-OP(O)R ○ 2 ; -OP(O)(OR ○ ) 2 ;SiR ○ 3 ; -(C 1~4 Linear or branched alkylene)ON(R ○ ) 2 ; or -(C 1~4 Linear or branched alkylene)C(O)ON(R ○ ) 2 And each R ○ may be substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, -CH 2-(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 ○ two separate occurrences of may be taken together with their intervening atoms to form a 3-12 membered saturated, partially saturated, or mono- or bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and may be substituted as defined below.

[0081] R ○ A suitable monovalent substituent of (or R ○ (a ring formed by taking two separate occurrences of -CH together with their intervening atoms) are independently selected from halogen, -(CH 2 ) 0~2 R ● , -(Halo R ● ), -(CH 2 ) 0~2 OH, -(CH 2 ) 0~2 OR ● , -(CH 2 ) 0~2 CH(OR ● ) 2 ; -O(HaloR ● ), -CN, -N 3 , -(CH 2 ) 0~2 C(O)R ● , -(CH 2 ) 0~2 C(O)OH, -(CH 2 ) 0~2 C(O)OR ● , -(CH 2 ) 0~2 S.R. ● , -(CH 2 ) 0~2 SH, -(CH 2 ) 0~2 NH 2 , -(CH 2 ) 0~2 NHR ● , -(CH 2 ) 0~2 NR ● 2 , -NO2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● And each R ● is unsubstituted or substituted only with one or more halogens preceded by "halo" and independently represents C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5-6 membered saturated, partially saturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0082] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR* 2 , =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O) 2 R*, =NR*, =NOR*, -O(C(R* 2 )) 2~3 O- or -S(C(R* 2 )) 2~3 S-, each separate occurrence of R* is hydrogen, C which may be substituted as defined below. 1~6 Selected from aliphatic or unsubstituted 5-6 membered saturated, partially saturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbons of the "optionally substituted" group include the following: -O(CR* 2 ) 2~3 and each individual occurrence of R* is hydrogen, C which may be substituted as defined below. 1~6It is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially saturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0083] Suitable substituents for the aliphatic group of R* include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 Each R ● is unsubstituted or substituted only with one or more halogens preceded by "halo" and independently represents C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5-6 membered saturated, partially saturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0084] Suitable substituents for a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2 , -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH 2 C(O)R † , -S(O) 2 R † , -S(O) 2 NR † 2 , -C(S)NR † 2 , -C(NH)NR † 2 , or -N(R † )S(O) 2 R †wherein each R is independently selected from hydrogen, C which may be substituted as defined below. 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 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 † two separate occurrences of together with their intervening atoms form an unsubstituted 3-12 membered saturated, partially saturated, or monocyclic or bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0085] R † Suitable substituents for the aliphatic group are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 And each R ● is unsubstituted or substituted only with one or more halogens preceded by "halo" and independently represents C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5-6 membered saturated, partially saturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0086] As used herein, the term "pharmaceutically acceptable salts" includes both acid addition salts and base addition salts, and a compound is modified by making its acid or base salt. 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. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, naphthalenesulfonic, methanesulfonic, ethanedisulfonic, and oxalic acids. The pharma- ceutically acceptable salts of the compounds disclosed herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

[0087] The term "about" or "approximately" as used herein means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more standard deviations, as is customary in the art. Alternatively, "about" can mean within a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, particularly for biological systems or methods, the term can mean within an order of magnitude of a value, for example within 5-fold or 2-fold. "About" or "approximately" are used interchangeably herein.

[0088] In embodiments, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and / or physiological effect, including, but not limited to, reducing sadness or lethargy, depressed mood, anxiety or sadness, decreased interest in all or nearly all activities, significant increase or decrease in appetite resulting in weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, inability to concentrate, and the frequency or severity of recurrent thoughts of death or suicide, or to reduce, inhibit, or reverse one or more of the underlying pathophysiological mechanisms underlying neurological dysfunction, modulating dopamine levels or signaling, modulating serotonin levels or signaling, modulating norepinephrine levels or signaling, modulating glutamate or GABA levels or signaling, modulating synaptic connections or neurogenesis in certain brain regions, or combinations thereof, to produce a desired pharmacological and / or physiological effect. The exact dosage will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.), the disease or disorder being treated, and the route of administration and pharmacokinetics of the administered agent.

[0089] In embodiments, the deuterium-enriched compounds disclosed herein and their uses are contemplated 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 into various positions that have exchangeable protons, such as amine NH, via proton-deuterium equilibrium exchange. Thus, deuterium can be selectively or non-selectively incorporated through methods known in the art.

[0090] In some embodiments, the level of deuterium at each deuterium enriched -H site of the compound is between 0.02% and 100%.

[0091] In some embodiments, the level of deuterium at each deuterium-enriched -H site of the compound is between 50% and 100%, between 70% and 100%, between 90% and 100%, between 95% and 100%, between 96% and 100%, between 97% and 100%, between 98% and 100%, or between 99% and 100%.

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

[0093] The compounds disclosed herein may be in their racemic and / or optically active isomers. In this regard, some of the compounds have asymmetric carbon atoms and therefore may exist as either racemic mixtures or individual optical isomers (enantiomers). The compounds described herein that contain chiral centers include all possible stereoisomers of the compounds, including compositions that include racemic mixtures of the two enantiomers, as well as compositions that include each enantiomer individually, substantially free of the other enantiomers. Thus, for example, contemplated herein are compositions that include the S enantiomer of the compound substantially free of the R enantiomer, or the R enantiomer of the compound substantially free of the S enantiomer. When the named compounds contain more than one chiral center, the scope of the disclosure also includes compositions that include mixtures of various ratios between the diastereomers, as well as compositions that include one or more diastereomers that are substantially free of one or more of the other diastereomers. By "substantially free" it is meant that the composition contains minor amounts of an enantiomer or diastereomer, less than 25%, 15%, 10%, 8%, 5%, 3%, or even 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 a stereoisomeric mixture of a drug or a suitable salt or derivative thereof. Individual enantiomers of the compounds disclosed herein can also be prepared, where appropriate, from corresponding optically pure intermediates, or by resolution, such as by HPLC, of ​​the corresponding racemates using suitable chiral supports, or by fractional crystallization of diastereomeric salts formed by reacting the corresponding racemates with a suitable optically active acid or base.

[0095] The compounds used in the methods of the present disclosure can be prepared by techniques well known in organic synthesis and known to those skilled in the art. For example, the compounds can be prepared by the synthetic transformations illustrated in the following general procedures and further described in the specific examples that follow.

[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 phosphate hydrogenate NMR: nuclear magnetic resonance PBS: Phosphate-buffered saline Pd / C: Palladium on 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 ways to synthesize or obtain the desired compounds.

[0099] The present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharma- ceutically acceptable carrier.

[0100] The disclosed subject matter is also intended to include all isomers of atoms present in the compounds disclosed herein. Isomers include atoms having the same atomic number but different mass numbers. As a general, non-limiting example, isomers of hydrogen include tritium and deuterium. Isomers of carbon include 13 C and 14 Contains C.

[0101] Any designation of carbon in a structure throughout this application, when used without further designation, represents 12 C. 13 C, or 14 It should be noted that all isomers of carbon such as C are intended to represent. 13 C or 14 Any compound containing C may specifically have the structure of any of the compounds disclosed herein.

[0102] Any designation of hydrogen in a structure throughout this application, when used without further designation, represents 1 H, 2 H, or3 It should also be noted that all isomers of hydrogen, such as H, are intended to represent. 2 H or 3 Any compound containing H may specifically have the structure of any of the compounds disclosed herein.

[0103] Isotopically labeled compounds can generally be prepared by conventional techniques known to those of skill in the art, substituting an appropriate isotopically labeled reagent for the non-labeled reagent utilized.

[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 consistent with the scope of the disclosure of this specification. Such modifications are intended to be encompassed by the scope of the claims. EXAMPLES

[0105] Example 1 Preparation of compound 3 HCl [ka]

[0106] Step 1: Preparation of 2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride. A mixture of 5-fluoro-1H-indole (3 g, 22.20 mmol, 1 equiv.) in THF (30 mL) was heated at 0 °C for 2 h at 4 °C for 3 h. 2 Then oxalyl dichloride (4.23 g, 33.30 mmol, 2.91 mL, 1.5 equiv) was added in one portion. The mixture was stirred at 15° C. for 2 h. Upon completion, the reaction mixture was concentrated to give 2-(5-fluoro-1H-indol-3-yl)-2-oxo-acetyl chloride as a yellow solid (5.01 g, 22.21 mmol, 100% yield).

[0107] Step 2: Preparation of N-ethyl-2-(5-fluoro-1H-indol-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 eq) in DCM (20 mL) was added N,N-diisopropylethylamine (5.74 g, 44.42 mmol, 7.74 mL, 2 eq). Then, 2-(5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (5.01 g, 22.21 mmol, 1 eq) in THF (30 mL) was added at 0° C. The mixture was then stirred at 15° C. for 2 h. Upon completion, NH 4 Aqueous Cl solution (30 mL) was added and the mixture was stirred for 5 min. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give N-ethyl-2-(5-fluoro-1H-indol-3-yl)-2-oxo-N-propylacetamide as a white solid (5.28 g, 19.11 mmol, 86% yield). 1 H NMR (400 MHz, CDCl 3 ) (fractional integrals due to conformers) 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-indol-3-yl)ethyl)propan-1-amine hydrochloride (3·HCl). To a solution of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-2-oxo-N-propylacetamide (2 g, 7.24 mmol, 1 equiv) in THF (30 mL) was added lithium aluminum hydride (824.18 mg, 21.72 mmol, 3 equiv) at 0° C. The mixture was then stirred at 60° C. for 5 h. Upon completion, the mixture was cooled to 0° C. Water (0.83 mL) was added and the reaction mixture was stirred for 5 min. Then 0.83 mL of 30% aqueous NaOH was added. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified using a preparative HPLC column (Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase = water (0.05% HCl)-ACN, B% = 10%-34%; R T = 22 min) to afford N-ethyl-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]propan-1-amine hydrochloride (3) 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 C NMR (101 MHz, DMSO-d6) (extra peaks due to C-F 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. To a solution of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide (1.73 g, 6.97 mmol, 1 equiv.) in THF (30 mL) was added lithium aluminum hydride (795.46 mg, 20.96 mmol, 3 equiv.) at 0° C. The mixture was then stirred at 60° C. for 5 h. Upon completion, the mixture was cooled to 0° C. Water (0.8 mL) was added and the mixture was stirred for 5 min. Then, 0.8 mL of 30% aqueous NaOH was added. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified using a prep-HPLC column (Phenomenex luna C18 (250×70 mm, 15 um); mobile phase=water (0.04% HCl)-ACN, B%=10%-30%; R T =20 min) to afford N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine hydrochloride (4) 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 C NMR (101 MHz, DMSO-d6) (extra peaks due to C-F 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. Compounds of the present disclosure were tested for stability in human liver microsomes (HLM) 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 psilocin.

[0111] HLM stability. Pooled HLM (Corning 452117) from adult male and female donors were used. Microsomal incubations were performed in multiwell plates. The incubation medium for liver microsomes was PBS (100 mM, pH 7.4), MgCl 2 0.50 mg liver microsomes per mL. 2 (1 mM), and NADPH (1 mM). Control incubations were performed by replacing the NADPH cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with the microsomes at 37° C. with constant shaking. At six time points over 60 min, 60 μL aliquots of the reaction mixture were taken at each time point and analyzed. 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 min and then centrifugation at 4000 rpm for 20 min at 4° C. to precipitate proteins. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography tandem mass spectrometry (LC-MS / MS) method.

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

[0113] [Table 1]

[0114] Example 4 Metabolic stability of mouse liver microsomes. Compounds of the present disclosure were tested for mouse liver microsome (MLM) stability and the results are summarized in Table 2. Compound 2 exhibited greater metabolic stability than Compound 1 in this model.

[0115] MLM stability. Pooled MLM from CD-1 mice (BIOIVT M00501) were used. Microsomal incubations were performed in multiwell plates. The incubation medium for liver microsomes was PBS (100 mM, pH 7.4), MgCl 2 0.5 mg / mL containing 0.5 mg of liver microsomes. 2 (1 mM), and NADPH (1 mM). Control incubations were performed by replacing the NADPH cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with the microsomes at 37° C. with constant shaking. At six time points over 60 min, 60 μL aliquots of the reaction mixture were taken at each time point and analyzed. 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 min and then centrifugation at 4000 rpm for 20 min at 4° C. to precipitate proteins. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography tandem mass spectrometry (LC-MS / MS) method.

[0116] Data analysis. Emission constant (k el ), half-life (t 1 / 2 ), and intrinsic clearance (CLint ) was determined on plots of ln(AUC) versus time using linear regression analysis.

[0117] [Table 2]

[0118] Example 5 Metabolic stability of rat liver microsomes. Compounds of the present disclosure were tested for rat liver microsome (RLM) stability and the results are summarized in Table 3. Both compounds exhibited poor stability in this model.

[0119] RLM stability. Pooled RLM (Xenotech R1000) from adult male and female donors were used. Microsomal incubations were performed in multiwell plates. The incubation medium for liver microsomes was PBS (100 mM, pH 7.4), MgCl 2 0.50 mg liver microsomes per mL. 2 (1 mM), and NADPH (1 mM). Control incubations were performed by replacing the NADPH cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with the microsomes at 37° C. with constant shaking. At six time points over 60 min, 60 μL aliquots of the reaction mixture were taken at each time point and analyzed. 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 min and then centrifugation at 4000 rpm for 20 min at 4° C. to precipitate proteins. Supernatant samples (80 μL) were diluted with water (240 μL) and analyzed for remaining parent compound using a purpose-built liquid chromatography tandem mass spectrometry (LC-MS / MS) method.

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

[0121] [Table 3]

[0122] Example 6 Pharmacokinetics in mice The pharmacokinetics of the compounds of the present disclosure were examined in mouse plasma (Table 4) and brain (Table 5) after intravenous (iv) and oral (po) dosing. 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, fast-acting therapeutic agent.

[0123] Animals. Male C57BL / 6 mice, 8-12 weeks of age, 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 provide a 12-h light and 12-h dark cycle. Temperature and humidity were recorded with an automated data logger system. All animals were fed a laboratory rodent diet. UV-treated reverse osmosis water was provided ad libitum. Animals were randomly assigned to treatment groups.

[0124] Drugs. Test compounds were used as hydrogen fumarate salts and dissolved in a vehicle consisting of saline. They were then administered intravenously (iv) via the tail vein or orally (po) via gavage at a dose of 10 mg / kg (calculated based on the free base) and a volume of 5 mL / kg body weight.

[0125] Sample collection and bioanalysis. Blood samples (approximately 60 μL) were collected from the retro-orbital plexus under low-concentration isoflurane anesthesia (Surgivet®) at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (four animals per time point). Immediately after blood collection, plasma was collected by centrifugation at 4000 rpm for 10 minutes at 4°C, and samples were stored at -70±10°C until bioanalysis. Following blood collection, animals were immediately sacrificed, the abdominal vena cava was incised, whole blood was perfused transcardially using 10 mL saline, and brain samples were collected from all animals. After separation, brain samples were rinsed three times with ice-cold saline (5-10 sec / rinse using approximately 5-10 mL saline in a disposable Petri dish for each rinse) and dried with blotting paper. Brain samples were homogenized using ice-cold phosphate buffered saline (pH 7.4). The total volume of homogenate 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 individual pre-labeled microcentrifuge tubes, followed by 100 μL of internal standard solution (Glipizide, 500 ng / mL in acetonitrile) except for blanks where 100 μL of acetonitrile was added. Samples were vortexed for 5 minutes and then centrifuged at 4000 rpm for 10 minutes at 4°C. Following centrifugation, 100 μL of each cleared supernatant was transferred to a 96-well plate and analyzed by a purpose-built LC-MS / MS method along with authentic samples of each analyte used for calibration and identification.

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

[0127] [Table 4]

[0128] [Table 5]

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

[0130] HLM Incubation. Pooled HLM (Corning 452117) from adult male and female donors were used. Microsomal incubations were performed in multiwell plates. Liver microsome incubations were performed in 1) PBS (100 mM, pH 7.4), MgCl 2(3.3 mM), and NADPH (1 mM); 2) liver microsomal protein (0.2 mg / mL); 3) reference CYP substrates: 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); and 4) contained test compound (10 μM), control inhibitor (α-naphthoflavone at 3 μM for CYP1A2, sulfaphenazole at 3 μM for CYP2C9, (+)-N-3-benzylnirvanol at 1 μM for 2C19, quinidine at 3 μM for CYP2D6, or ketoconazole at 3 μM for CYP3A4), or vehicle (for uninhibited conditions). Incubations were carried out at 37° C. for 10 min with constant shaking. 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), followed by centrifugation at 4000 rpm for 20 min at 4° C. to precipitate proteins.

[0131] Sample analysis. Supernatant samples (200 μL) were diluted with water (100 μL) and the reference metabolites of each reference CYP substrate were quantified using a purpose-built liquid chromatography tandem mass spectrometry (LC-MS / MS) method. Percent inhibition by test compounds or control inhibitors was calculated by comparing the formation of metabolites in the presence of inhibitors to the formation of metabolites in the absence of inhibitors.

[0132] [Table 6]

[0133] Example 8 Stability in the presence of monoamine oxidase Compounds of the present disclosure were tested for stability in the presence of monoamine oxidases A and B (MAO-A and MAO-B) in a preparation of human liver mitochondria, and the results are summarized in Table 7. Compounds of the present disclosure exhibited greater MAO stability than DMT in this model.

[0134] Incubation of liver mitochondria. Human liver mitochondria (Xenotech H0610.M) were used. Mitochondria incubation was performed in multi-well plates. The incubation medium for liver mitochondria consisted of PBS (100 mM, pH 7.4) containing 0.30 mg of liver mitochondrial protein per mL. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with liver mitochondrial protein at 37° C. with constant shaking (total reaction volume of 100 μL per well). Six time points were analyzed over 60 min. 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 min and then precipitation of proteins by centrifugation at 4000 rpm for 20 min at 4° C. Supernatant samples (100 μL) were diluted with 5% trichloroacetic acid in water (300 μL) and analyzed for remaining parent compound using a purposeful liquid chromatography tandem mass spectrometry (LC-MS / MS) method.

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

[0136] [Table 7]

[0137] Example 9 Functional activity at serotonin receptors The compounds of the present disclosure are 2+ Using a flux functional assay, compounds were tested for agonist activity at 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 as well as 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 over 5-HT2B, while compound 2 was highly selective for 5-HT2A compared to 5-HT2B. At the same time, compound 1 was a highly effective agonist at 5-HT2A (E max = 85.2%), whereas compound 2 was a low-potency partial agonist (E max = 36.2%). Fluorination at the 5-position of the indole ring also had unexpected effects. For example, compounds 3 and 4 were both 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 resulted in greater potency at the 5-HT2A receptor compared to compound 1. In the case of compound 4, fluorination had little effect on potency at the 5-HT2A receptor, but dramatically increased the maximum potency compared to compound 2, resulting in a highly potent rather than partial agonist.

[0138] Functional assays at 5-HT2A, 5-HT2B, and 5-HT1A. Agonist activity at 5-HT2A, 5-HT2B, and 5-HT1A receptors was assayed using FLIPR Ca at WuXi AppTec Co., Ltd. (Hong Kong) according to their standard protocols. 2+ The flux assay was used to determine the cellular fate of the receptors of interest. Briefly, stably transfected cells expressing the receptors of interest (HEK293 for 5-HT2A and 5-HT2B; CHO cells for 5-HT1A) were grown, plated in 384-well plates, and incubated at 37°C, 5% CO. 2The cells were incubated at 4°C overnight. A solution of 250 mM probenecid in 1 mL of FLIPR assay buffer was freshly prepared. This was combined with the fluorescent dye (Fluo-4 Direct™) to a final assay concentration of 2.5 mM. Compounds were diluted 1:3.16 for 10 points and 750 nL was added to a 384-well compound using an 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, 5% CO 2 The cells were incubated at RT for 50 min and placed in the FLIPR Tetra along with the compound plate. 10 μL of standards and compounds were then transferred from the compound plate to the cell plate and the fluorescent signal was read.

[0139] Functional assay at 5-HT2C. Agonist activity at 5-HT2C was assayed using FLIPR Ca2+ at Eurofins DiscoverX (Fremont, CA) according to their standard protocol. 2+ The flux assay was used to determine the expression of the human 5-HT2C receptor. Briefly, stably transfected cells expressing the human 5-HT2C receptor were grown, plated in 384-well plates, and incubated at 37°C, 5% CO 2 Plates were incubated overnight at 37°C for 30-60 min. The assay was performed in 1x dye loading buffer consisting of 1x dye, 1x additive A, and 2.5mM probenecid in HBSS / 20mM Hepes. Probenecid was freshly prepared. Cells were loaded with dye before testing and incubated at 37°C for 30-60 min. After dye loading, cells were removed from the incubator and 10μL of HBSS / 20mM Hepes was added. 3x vehicle was included in the assay buffer. Cells were incubated in the dark at room temperature for 30 min to equilibrate plate temperature. Intermediate dilutions of sample stock were performed to generate 4x samples in assay buffer. Compound agonist activity was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 min and 10μL of 4x samples in HBSS / 20mM Hepes were added to cells for 5 s during the assay.

[0140] [Table 8]

[0141] Example 10 Effect of Head Twitch Response (HTR) in mice The compounds of the present disclosure were tested for their ability to induce head twitch 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 maximal effect of the compounds of the present disclosure was smaller than that of the prototypic 5-HT2A agonist, 4-iodo-2,5-dimethoxyamphetamine (DOI) (35.6 head twitches / 20 min). The maximal effect of compound 2 in this assay (6.00 head twitches / 20 min) was also smaller than that of compound 1 (14.7 head twitches / 20 min), consistent with the smaller potency of compound 2 as an agonist of 5-HT2A in vitro (see Example 9 above).

[0142] Animals. Eight-week-old adult male C57BL / 6 mice (body weight 20-25 g) were used in the study. Animals were housed under controlled temperature and a 12-h light / dark cycle (lights on between 07:00 and 19:00) with food and water available ad libitum. The protocol was approved by the Eurofins Advinus Institutional Animal Care and Use Committee. The study was performed in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All efforts were made to minimize suffering.

[0143] Drugs and Drug Administration. Test compounds were used as hydrogen fumarate salts and DOI was used as the HCl salt. Drugs were dissolved in a vehicle consisting of saline and administered subcutaneously (sc) at a volume of 10 mL / kg. Test compounds were administered at 5 doses per compound (1-100 mg / kg, calculated on the basis of the free base) using N=6 animals / group. The control compound DOI was administered at 1 dose (3.16 mg / kg, calculated on the basis of the HCl salt) using N=12 animals.

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

[0145] Statistical Analysis. Data points shown in Table 9 are means ± standard error of the mean (SEM). Analysis was performed using GraphPad Prism 9.

[0146] [Table 9]

[0147] Example 11 Forced swimming test in rats The compounds of the present disclosure induced antidepressant-like effects in the forced swimming test (FST) in rats at a pretreatment time of 23.5 hours (Figure 1). Specifically, the compounds reduced immobility time compared to vehicle control, indicating antidepressant-like effects. These effects on immobility were observed 23.5 hours after a single compound administration, at which time most or all of the drug had been cleared from the systemic circulation, suggesting that the compounds have both fast-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 the study. The animals were housed in groups of two under controlled temperature (22±3°C) and relative humidity (30-70%) conditions, with a 12-h light / dark cycle and food and water available ad libitum. The study was performed in strict accordance with the requirements of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India. All efforts were made to minimize suffering.

[0149] Drugs and Drug Administration. Test compounds, saline vehicle, and the positive control desipramine were administered subcutaneously (sc) at doses calculated based on the free base. Saline was used as the vehicle. All compounds were administered in a volume of 5 mL / kg. Test compounds and vehicles 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 each time, 23.5 hours, 5 hours, and 1 hour before the test swim (Swim 2).

[0150] Forced Swim Test (FST). Animals were randomized based on body weight to ensure minimal variation between groups and did not exceed ±20% of the mean body weight between groups. Group sizes were N=10 per treatment, except for the vehicle and desipramine groups, where N=20. Rats were handled for approximately 2 min per day for 5 days prior to beginning the experimental procedure. On the first day of the experiment (i.e., day 1), after randomization, a training swim session (Swim 1) was conducted for all animals by placing the rats individually into a glass cylinder (46 cm high x 20 cm diameter) containing 23-25°C water to a depth of 30 cm for 15 min between 12:00 and 18:00. At the end of Swim 1, animals were dried with paper towels and placed in a heated dry cage for 15 min, then returned to their respective housing cages. Animals were then administered the appropriate drug or vehicle treatment as described above. For clarity, the time of compound administration 23.5 h prior to swim 2 means 0.5 h after the start of swim 1 and 0.25 h after completion of swim 1 (i.e., immediately after returning to the housing cage). On day 1 (i.e., 24 h after the start of swim 1), animals performed a 5 min test swim (swim 2) but otherwise under the same conditions as swim 1. During all swim sessions, water was changed for each animal.

[0151] Behavioral scoring was performed by an observer blinded to the treatment group. Animals were continuously observed during swim 2, and the total time spent performing the following behaviors was recorded: immobility, swimming, and climbing. Rats were scored as immobile if they remained floating in the water without struggling, making only the movements necessary to keep their head above the water surface. Rats were scored as swimming if they made active swimming behaviors (e.g., moving around the cylinder) beyond those necessary just to keep their head above the water surface. Rats were scored as climbing if they made active movements of their forepaws in and out of the water, usually toward the wall.

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

[0153] Example 12 Stability of mouse plasma and brain homogenates Compounds of the present disclosure were tested for stability in mouse plasma (Table 10) and mouse brain homogenate (Table 11) by LC-MS / MS. The compounds were stable under the conditions of the experiment, suggesting that they are not substantially subject 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 200 mL of PBS at 37 °C for 1 h. 2 The samples were incubated with 400 μL of DBA2 mouse plasma (n=3) in an incubator. 50 μL aliquots were removed from each incubation at 0, 5, 15, 30, 60, and 90 minutes and immediately quenched with 500 μL of ice-cold acetonitrile containing the internal standard, then stored at -80°C. At the time of bioanalysis, all samples were thawed to room temperature. Samples were vortexed for 5 minutes, then centrifuged 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 remaining parent compound by a purpose-built LC-MS / MS method.

[0155] Brain homogenate stability. Brain tissue homogenate samples 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 a 4-fold diluted homogenate. Positive control and test compounds (final concentration in incubation medium = 1 μM, 0.5% DMSO) were incubated in 200°C for 30 min at 37°C with CO 2The samples were incubated in an incubator with 400 μL of the diluted mouse brain homogenate (n=3) as described above. Aliquots of 50 μL were removed from each incubation at 0, 5, 15, 30, 60, and 90 minutes and immediately quenched with 500 μL of ice-cold acetonitrile containing the internal standard, then stored at -80°C. At the time of bioanalysis, all samples were thawed to room temperature. Samples were vortexed for 5 minutes, then centrifuged at 4,000 RPM for 15 minutes at 4°C. Aliquots of 100 μL of each sample were transferred to a 96-well deep plate and analyzed for remaining parent compound by a purpose-built LC-MS / MS method.

[0156] [Table 10]

[0157] [Table 11]

[0158] Example 13 Microsomal stability of additional compounds Additional compounds of the disclosure, including compounds 3 and 4, were tested for stability in human, mouse, or rat liver microsomes as described in Examples 3-5. Compound 4 exhibited moderate to high stability in human and mouse microsomes, making it more stable than DMT in such preparations.

[0159] Example 14 Pharmacokinetics of additional compounds in mice Additional compounds of the 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 Effect of additional compounds in the HTR assay Additional compounds of the disclosure, including compounds 3 and 4, were tested to determine their ability to induce a head twitch response (HTR) in mice, as described in Example 10. Compounds 3 and 4 induced a head twitch response in mice in a dose-dependent manner, consistent with their agonist activity at the 5-HT2A receptor in vitro.

[0162] (Example 17) Effects of additional compounds in the forced swimming test in rats Additional compounds of the disclosure, including compounds 3 and 4, were tested in the rat forced swim test (FST), as described in Example 11. Compounds 3 and 4 reduced immobility in this test in a dose-dependent manner, consistent with an antidepressant-like effect.

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

Claims

【Request 1】 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound according to claim 1 and a pharma- ceutically acceptable adjuvant or carrier.

3. A method for treating a mood disorder, comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 2 to a subject in need thereof.

4. 4. The method of claim 3, wherein the mood disorder is selected from the group consisting of a depressive disorder and a bipolar disorder.

5. 4. The method of claim 3, wherein the mood disorder is a depressive disorder.

6. 4. The method of claim 3, wherein the mood disorder is treatment-resistant depressive disorder.

7. 4. The method of claim 3, wherein the mood disorder is selected from the group consisting of major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation disorder, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

8. 4. The method of claim 3, wherein the mood disorder is a substance-related disorder.

9. 4. The method of claim 3, wherein the mood disorder is a substance use disorder.

10. 4. The method of claim 3, wherein the mood disorder is an anxiety disorder.

11. 4. The method of claim 3, wherein the mood disorder is selected from the group consisting of obsessive-compulsive disorder and related disorders, trauma-related and stressor-related disorders, eating and feeding disorders, borderline personality disorder, attention-deficit / hyperactivity disorder, and autism spectrum disorder.

12. 12. The method of any one of claims 3 to 11, comprising administering about 0.5 mg to 150 mg of the compound of claim 1 or the pharmaceutical composition of claim 2.

13. The method according to any one of claims 3 to 11, wherein the compound according to claim 1 or the pharmaceutical composition according to claim 2 is administered in an amount of from 10 mg to 20 mg.

14. The method according to any one of claims 3 to 11, wherein the compound according to claim 1 or the pharmaceutical composition according to claim 2 is administered in an amount of from 20 mg to 40 mg.

15. The method according to any one of claims 3 to 11, wherein the compound according to claim 1 or the pharmaceutical composition according to claim 2 is administered in an amount of from 40 mg to 80 mg.

16. The method according to any one of claims 3 to 11, wherein the compound according to claim 1 or the pharmaceutical composition according to claim 2 is administered in an amount of 80 mg to 100 mg.

17. The method according to any one of claims 3 to 11, wherein the compound according to claim 1 or the pharmaceutical composition according to claim 2 is administered in an amount of from 100 mg to 120 mg.

18. The method according to any one of claims 3 to 11, wherein the compound according to claim 1 or the pharmaceutical composition according to claim 2 is administered in an amount of from 120 mg to 150 mg.

19. Sadness or lethargy or fatigue, depressed mood, loss of sensation, anxious and anxious feelings, feelings of fear, tension, restlessness, decreased interest in all or almost all activities, difficulty initiating activities, marked increase or decrease in appetite resulting in weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness or low self-esteem, strongly held negative beliefs or pessimistic thoughts about self, others or the world, feelings of helplessness, inability to concentrate or distractibility, recurrent thoughts of death or suicide, feelings of guilt, memory complaints, difficulty experiencing positive emotions, feeling detached or detached from people 19. The method of any one of claims 3 to 18, which results in improvement of at least one symptom selected from the group consisting of: sensations, hypervigilance, risk-taking behavior, avoidance of thoughts about stressful or traumatic events, aches and pains, ruminative thoughts and obsessions, compulsive behavior, talking to unfamiliar people or strangers, being the center of attention, disturbing intrusive thoughts, inability to go a week without using drugs, guilt at drug use, problems with friends or family because of drug use, and withdrawal symptoms due to drug use.

20. 20. The method of any one of claims 3 to 19, wherein the compound of claim 1 or the pharmaceutical composition of claim 2 is administered via a route selected from the group consisting of oral, buccal, sublingual, inhalation mist, topical, intranasal, subcutaneous, intramuscular, and intravenous.

21. 21. The method according to any one of claims 3 to 20, wherein the compound according to claim 1 or the pharmaceutical composition according to claim 2 is administered 1 to 4 times daily.

22. 21. The method according to any one of claims 3 to 20, wherein the compound according to claim 1 or the pharmaceutical composition according to claim 2 is administered 1 to 10 times per month.

23. 1. A method for treating a mood disorder comprising administering to a patient in need thereof: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutical composition comprising a pharma- ceutically acceptable excipient.

24. 24. The method of claim 23, wherein the mood disorder is selected from the group consisting of a depressive disorder and a bipolar disorder.

25. 24. The method of claim 23, wherein the mood disorder is a depressive disorder.

26. 24. The method of claim 23, wherein the mood disorder is treatment-resistant depressive disorder.

27. 24. The method of claim 23, wherein the mood disorder is selected from the group consisting of major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation disorder, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

28. 24. The method of claim 23, wherein the mood disorder is a substance-related disorder.

29. 24. The method of claim 23, wherein the mood disorder is a substance use disorder.

30. 24. The method of claim 23, wherein the mood disorder is an anxiety disorder.

31. 24. The method of claim 23, wherein the mood disorder is selected from the group consisting of obsessive-compulsive disorder and related disorders, trauma-related and stressor-related disorders, eating and feeding disorders, borderline personality disorder, attention-deficit / hyperactivity disorder, and autism spectrum disorder.

32. 32. The method of any one of claims 23 to 31, comprising administering between about 0.5 mg and 150 mg of the compound.

33. 32. The method of any one of claims 23 to 31, comprising administering about 10 mg to 20 mg of the compound.

34. 32. The method of any one of claims 23 to 31, comprising administering about 20 mg to 40 mg, about 40 mg to 80 mg, about 80 mg to 100 mg, about 100 mg to 120 mg, or about 120 mg to 150 mg of the compound.

35. Sadness or lethargy or fatigue, depressed mood, loss of sensation, anxious and anxious feelings, feelings of fear, tension, restlessness, decreased interest in all or almost all activities, difficulty initiating activities, marked increase or decrease in appetite resulting in weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness or low self-esteem, strongly held negative beliefs or pessimistic thoughts about self, others or the world, feelings of helplessness, inability to concentrate or distractibility, recurrent thoughts of death or suicide, feelings of guilt, memory complaints, difficulty experiencing positive emotions, feeling detached or detached from people 35. The method of any one of claims 23 to 34, which results in improvement of at least one symptom selected from the group consisting of: sensations, hypervigilance, risk-taking behavior, avoidance of thoughts about stressful or traumatic events, aches and pains, ruminative thoughts and obsessions, compulsive behavior, talking to strangers or people you don't know, being the center of attention, disturbing intrusive thoughts, inability to go a week without using drugs, guilt at drug use, problems with friends or family because of drug use, and withdrawal symptoms due to drug use.

36. 36. The method of any one of claims 23 to 35, comprising administering the composition via a route selected from the group consisting of oral, buccal, sublingual, inhalation mist, topical, intranasal, subcutaneous, intramuscular, and intravenous.

37. 37. The method of any one of claims 23 to 36, wherein the composition is administered 1 to 4 times daily.

38. 37. The method of any one of claims 23 to 36, wherein the composition is administered 1 to 10 times per month.

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