Improving the pharmacokinetics of tryptamine prodrugs

Abstract

Formula (I): TIFF2026501775000046.tif59128 or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is present in a dose of about 30 mg to about 50 mg, calculated as the free base, together with a pharmaceutically acceptable carrier. Also described is a method of treating a psychiatric disorder, comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. § 119(e) of provisional patent application SN63 / 478,593, filed January 5, 2023, provisional patent application SN63 / 505,237, filed May 31, 2023, and provisional patent application SN63 / 507,600, filed June 12, 2023, the contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION In one of its aspects, the present invention relates to a method for treating a psychiatric disorder in a patient. In another of its aspects, the present invention relates to an injectable composition, preferably for a method for treating a psychiatric disorder in a patient. [Background technology]

[0003] Tryptamines are a class of 3-aminoethyl-indoles that bind to and activate serotonin receptors, also known as 5HT receptors. A psychedelic state can be achieved by activating the 2A form of the serotonin receptor with 5HT2A receptor agonist compounds. The endogenous substrate for this receptor is 5-hydroxytryptamine (serotonin). Tryptamine 3-(2-aminoethyl)-indole is also an endogenous neurotransmitter.

[0004] The serotonin receptor system is involved in depression and depressive states, which are commonly treated with 5HT1A antagonists (Affective Disorders: Depression in Neuropsychopharmacology and Therapeutics, Chapter 6, First Edition. Ivor S. Ebenezer, 2015). More recently, 5HT2A agonists have shown promise as medicines for depression (Carhart-Harris 2018 Psychopharmacology).

[0005] Tryptamine molecules, which produce psychedelic states and are used in traditional medicine, may have potential for treating mood disorders, depression, and other conditions. For example, ayahuasca, a natural form of dimethyltryptamine (DMT), can be ingested in combination with a monoamine oxidase inhibitor to produce a variable but prolonged psychedelic state that can last from 6 to 15 hours. DMT has also been found to occur naturally in trace amounts in the brain, where it may act as a neurotransmitter.

[0006] Lysergic acid diethylamide (LSD) is a diethylamide derivative of a naturally occurring substance derived from a fungus found in rye kernels, which also produces a prolonged psychedelic state of up to 8-12 hours.

[0007] Psilocybin is a naturally occurring, plant-based tryptamine found in Psilocybe mushrooms that produces a prolonged psychedelic state of approximately 6-8 hours. Psilocybin was first synthesized in 1958 and is currently being investigated as a treatment for depression. Psilocybin is a prodrug, and psilocin is the active species in vivo. Psilocybin contains a phosphate attached to the 4-hydroxy group of psilocin, which is cleaved in the intestine when Psilocybe mushrooms or the drug substance are orally ingested: [ka]

[0008] Simple monofunctional organic esters of psilocin have been reported. Lower alkoxy radical-modified psilocins have also been described. Sulfate-linked psilocin has been produced, and other monobasic and dibasic mineral acid-modified psilocins have been described. Psilocin acetate is known and is used in underground psychedelic subcultures.

[0009] Psychedelics have been shown to be effective in treating depression, and even more effective in treating depression when associated with psychotherapy (Watts 2020 Journal of Contextual Behavioral Science).

[0010] A limited number of synthetic tryptamine substances have been prepared since perhaps the earliest documented work of Albert Hoffman. Structure-activity relationships have been described for a variety of tryptamine substances (Claire 1988).

[0011] The functionality of succinic acid and other diacids has been explored as components of prodrug delivery systems for hydrophobic or poorly water-soluble drug substances, such as testosterone, haloperidol, chloramphenicol, or estradiol, in water-soluble, injectable forms (Silverman and Holladay, Chapter 9.2: Prodrugs and Drug Delivery Systems in The Organic Chemistry of Drug Design and Drug Action (3rd Ed), 2014). Tetrahydrocannabinol esters of succinic acid have been patented for the treatment of glaucoma. However, ester cleavage is not consistently rapid or predictable and may depend on the structure of the drug-linked moiety, so investigations must be performed (Anderson 1984 JPharmaSci). Esterase enzymes are responsible for the active cleavage of prodrug ester groups in vivo, and species differences in the abundance and specificity of esterases in various tissues complicate investigation and optimization (Bahar 2012 JPharmaSci).

[0012] 4-Glutaroyl-3-(2-diisopropylaminoethyl)-1H-indole hydrochloride—also referred to herein as RE104 HCl (formally FT-104)—is a prodrug of the synthetic psychedelic drug 3-(2-diisopropylaminoethyl)-1H-indol-4-ol (also referred to as 4-OH-DiPT or isoprosin), a molecule structurally related to psilocin: [ka] RE104 HCl is converted in vivo by esterases to 4-OH-DiPT and is being developed as an SC injection to ensure rapid and complete absorption and a short, reproducible psychedelic experience from the drug.

[0013] The active molecule, 4-OH-DiPT, acts as a serotonin (5-HT) agonist, particularly at the 5-HT2A and 5-HT2B subtypes, and these receptors have been suggested to contribute to 4-OH-DiPT-mediated activity. 4-OH-DiPT belongs to the tryptamine group, more specifically, the 4-substituted tryptamines, which also include the well-known psychedelic compound psilocybin. Psilocybin is a natural product produced by numerous species of Psilocybe mushrooms. The phosphate group at the 4-position of psilocybin tryptamine is enzymatically cleaved in the body to produce psilocin, an agonist of various serotonin receptors, most importantly the 5-HT2A receptor, which has been suggested to explain its psychedelic activity (Nichols, 2004). In RE104 HCl, the glutarate group at position 4 of tryptamine is hydrolyzed to form 4-OH-DiPT, which is responsible for the agonist activity at 5-HT2A.

[0014] Classical serotonergic hallucinogenic drugs, a group of compounds that bind to 5-hydroxytryptamine (5-HT) receptors, are characterized by their ability to induce changes in sensory perception, emotion, thought, and sense of self, resulting in remodeling of mental function (Vollenweider, 2001; Kometer et al., 2012; Vollenweider et al., 1998), which have been described as mystical experiences occurring during psilocybin treatment. These changes have been repeatedly observed to predict subsequent behavioral and emotional effects, including reductions in depression and anxiety (Griffiths et al., 2011; Griffiths et al., 2016; Ross et al., 2016).

[0015] Several lines of evidence suggest that serotonergic hallucinogens, such as psilocin and isoprosin (4-OH-DiPT), have clinical potential for inducing therapeutically beneficial behavioral changes in a variety of psychiatric conditions. Following psychedelic administration, sustained changes in attitude, depression, anxiety, well-being, substance abuse, and mindfulness have been documented. These long-term changes in psychological functioning have been associated with mystical experiences, connection, emotional breakthroughs, and increases in neural entropy (Aday et al., 2020). Furthermore, emerging evidence suggests that psychedelic-assisted psychotherapy may be a powerful treatment for depression and other psychological disorders (Carhart-Harris et al., 2016).

[0016] It has also been reported that cancer patients often develop chronic, clinically significant symptoms of depression and anxiety, which are associated with negative psychiatric and medical outcomes ( Swift et al., 2017 ; Griffiths et al., 2016 ; Ross et al., 2016 ).

[0017] Promising results have also been obtained in a study in patients with obsessive-compulsive disorder (OCD) (Moreno et al., 2006), in which subjects received up to four doses of psilocybin, separated by at least one week, in an ascending dosing sequence of 100 μg / kg, 200 μg / kg, and 300 μg / kg. Reductions in OCD symptom scores were observed in all subjects during at least one of the test sessions, with reductions ranging from 23 to 100%.

[0018] The efficacy of psilocybin is also being explored in alcoholism (Bogenschutz et al., 2015). A recent (2021) review manuscript evaluated the clinical efficacy of serotonergic psychedelics and their therapeutic effects on mental health conditions (Andersen et al., 2021). The literature review included 16 papers representing 10 independent psychedelic-assisted therapy trials (7 with psilocybin, 2 with ayahuasca, and 1 with LSD), involving 188 patients suffering from cancer- or illness-related anxiety and depressive disorders (including major depressive disorder, OCD, or substance use disorders). While caution is advised when assessing the efficacy of psychedelic-assisted therapy due to the small sample sizes and open-label nature of many of the studies reviewed, two larger controlled trials evaluating depressive (and anxiety) symptoms in cancer patients reported comparable efficacy despite using an inactive placebo or low-dose psilocybin as controls (Andersen et al., 2021).

[0019] Finally, anecdotal evidence on the effects of 4-OH-DiPT (isoprosin) (10–20 mg orally) has been provided by Shulgin, who suggests that the drug, when used recreationally, is broadly comparable to other serotonergic psychedelics such as psilocin, but is distinguished by the relatively short duration of its effects (Shulgin and Shulgin, 1997). Referring to oral administration of isoprosin, Shulgin (1997) stated, "There are doubts as to whether any other psychedelic drug can rival this one in speed, intensity, and shortness of action." Onset and duration of effects suggested a dose associated with only mild physical awareness within 1 hour after oral administration of 10 mg, with a more rapid onset of effects within 15 minutes at 20 mg. Recovery was noted by 3 hours after oral administration of 20 mg. However, controlled studies on the safety, tolerability, and pharmacokinetics of 4-OH-DiPT in humans are lacking, due in part to the compound's lack of stability (easily oxidized in air) and very low solubility (less than 2 mg / mL in PBS).

[0020] Conversion to the prodrug RE104 offers improved stability and solubility while providing a means for esterase-mediated cleavage to generate the active compound 4-OH-DIPT in situ (in vivo) (see U.S. Pat. No. 1,129,2765). However, what is needed is a clearer understanding of the pharmacokinetics of RE104 or a pharmaceutically acceptable salt thereof (such as HCl) in humans relative to 4-OH-DiPT and psilocybin. It is also desirable to have a clearer understanding of dosing in humans relative to RE104 or a pharmaceutically acceptable salt thereof (such as the HCl salt). Summary of the Invention

[0021] It is an object of the present invention to obviate or mitigate at least one of the above-mentioned disadvantages of the prior art.

[0022] It is an object of the present invention to provide improved delivery and pharmacokinetics following administration of RE104 or a pharmaceutically acceptable salt thereof (such as the HCl salt).

[0023] Another object of the present invention is to provide a psychedelic experience of shorter duration following administration of a prodrug of RE104 or a pharmaceutically acceptable salt thereof (such as the HCl salt) at a level that results in a complete mystical experience in the majority of subjects, defined as 60% or greater for each domain of the Mystical Experiences Questionnaire (MEQ-30). [See Ko, K et al. Front. Psychiatry 2022, 13, 917199]

[0024] Another object of the present invention is to provide a psychedelic experience of shorter duration following administration of a prodrug of RE104 or a pharmaceutically acceptable salt thereof (such as the HCl salt) at a level expected to produce a therapeutic effect compared to administration of psilocybin at an effective dosage level.

[0025] It is yet another object of the present invention to produce fewer side effects, particularly blood pressure and headaches, following administration of a prodrug of RE104 or a pharmaceutically acceptable salt thereof (such as HCl) at levels expected to produce a therapeutic effect compared to administration of psilocybin at effective dosage levels.

[0026] It is yet another object of the present invention to provide improved safety and tolerability following administration of a prodrug of RE104 or a pharmaceutically acceptable salt thereof (such as HCl) at levels expected to produce a therapeutic effect compared to administration of psilocybin at effective dosage levels.

[0027] In one aspect, the present invention relates to a composition comprising a compound described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises an oral or injectable formulation.

[0028] In another aspect, the invention includes a method of treating a psychiatric disorder, comprising administering an effective amount of a compound described herein. In some embodiments, the psychiatric disorder is a depressive condition, including unipolar and bipolar depressive conditions, such as, but not limited to, depression, depression from generalized anxiety, major depression, treatment-resistant depression, and postpartum depression.

[0029] In another aspect, the invention relates to the use of a compound described herein for treating a psychiatric disorder, or in the manufacture of a medicament for treating a psychiatric disorder, such as depression.

[0030] In another aspect, the present invention provides a method of treating a psychiatric disorder, comprising administering to a patient of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is present in a dose of about 30 mg to about 50 mg, calculated as the free base, together with a pharmaceutically acceptable carrier.

[0031] In another aspect, the present invention provides a method of treating a psychiatric disorder, comprising administering to a patient of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is present in a dose of 30 mg or about 40 mg, calculated as the free base, together with a pharmaceutically acceptable carrier.

[0032] In another aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is present in a dose of 1 mg / kg, calculated as the free base, together with a pharmaceutically acceptable carrier.

[0033] In another aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is present in a dose of about 30 mg to about 50 mg, calculated as the free base, together with a pharmaceutically acceptable carrier.

[0034] In another aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is present in a dose of about 30 mg or about 40 mg, calculated as the free base, together with a pharmaceutically acceptable carrier.

[0035] Administration of a prodrug of RE104 described herein or a pharmaceutically acceptable salt thereof (such as HCl) can be useful for treating psychiatric disorders, e.g., depression, including depressive conditions, including, but not limited to, unipolar and bipolar depressive conditions, such as depression, generalized anxiety depression, major depression, treatment-resistant depression, and postpartum depression. [Brief explanation of the drawings]

[0036] Embodiments of the present invention will now be described with reference to the accompanying drawings, in which: [Figure 1] FIG. 1 is a schematic diagram of the design of the human clinical study described in Example 2. [Figure 2] 1 shows the modified Drug Effect Questionnaire (DEQ) used in the human clinical study described in Example 2. [Figure 3] 1 shows the revised Mystical Experiences Questionnaire (MEQ) used in the human clinical study described in Example 2. [Figure 4]1 shows mean DEQ elevation scores by dose over time in the human clinical study described in Example 2. [Figure 5] 1 shows the mean MEQ scores by individual domain and total score per RE104 dose level in the human clinical study described in Example 2. [Figure 6] 1 shows mean plasma 4-OH-DiPT concentrations and DEQ high scores over time for the RE104 33 mg dose group in the human clinical study described in Example 2. [Figure 7] 1 shows the mean plasma 4-OH-DiPT concentrations versus DEQ high scores for all cohorts in the human clinical study described in Example 2. [Figure 8] 5 shows 5-HT2A binding to RE104 in the study described in Example 3. [Figure 9] 5 shows 5-HT2A binding of 4-OH-DiPT in the study described in Example 3. [Figure 10] 5 shows 5-HT2B binding to RE104 in the study described in Example 3. [Figure 11] 5 shows 5-HT2A activation of RE104 in the study described in Example 3. [Figure 12] 1 shows mouse plasma concentrations of RE104 over time in the study described in Example 3. [Figure 13] 1 shows rat plasma concentrations of RE104 over time in the study described in Example 3. [Figure 14] 1 shows dog plasma concentrations of RE104 over time in the study described in Example 3. [Figure 15] 1 shows human plasma concentrations of RE104 over time in the study described in Example 3. [Figure 16] 1 shows the mean 4-OH-DiPT plasma concentrations and mean number of head tremor responses (HTRs) counted over 10-minute intervals as a function of time following intravenous (IV) and subcutaneous (SC) administration of RE104 or 4-OH-DiPT to groups of three rats in the study described in Example 3. [Figure 17]1 shows the correlation between HTR and mean 4-OH-DiPT plasma concentrations for an intravenous dose of 2 mg / kg RE104 (lines represent curves of best fit) in the study described in Example 3. [Figure 18] 1 shows the correlation between HTR and mean 4-OH-DiPT plasma concentrations for a 2 mg / kg subcutaneous dose of RE104 (lines represent curves of best fit) in the study described in Example 3. [Figure 19] 1 shows the correlation between HTR and mean 4-OH-DiPT plasma concentrations for an intravenous dose of 1.39 mg / kg 4-OH-DiPT (line represents the curve of best fit) in the study described in Example 3. [Figure 20] 1 shows the correlation between HTR and mean 4-OH-DiPT plasma concentrations for a subcutaneous dose of 1.39 mg / kg 4-OH-DiPT (line represents the curve of best fit) in the study described in Example 3. [Figure 21] The effects of RE104 and RE109 (Silo singlet rats) on specific behaviors in the forced swim test (immobility time in Figure 21, swimming time in Figure 22, and climbing time in Figure 23), respectively, are shown (n=12 male Wistar rats per treatment group). [Error bars represent standard error of the mean. *P<0.05, **P<0.01, ***P<0.001 vs. vehicle by one-way ANOVA followed by Dunnett's multiple comparison test. ††P<0.01 vs. vehicle by unpaired t-test. ‡P<0.05, ‡‡‡P<0.001 compared to RE109]. [Figure 22] The effects of RE104 and RE109 (Silo singlet rats) on specific behaviors in the forced swim test (immobility time in Figure 21, swimming time in Figure 22, and climbing time in Figure 23), respectively, are shown (n=12 male Wistar rats per treatment group). [Error bars represent standard error of the mean. *P<0.05, **P<0.01, ***P<0.001 vs. vehicle by one-way ANOVA followed by Dunnett's multiple comparison test. ††P<0.01 vs. vehicle by unpaired t-test. ‡P<0.05, ‡‡‡P<0.001 compared to RE109]. [Figure 23]The effects of RE104 and RE109 (Silo singlet rats) on specific behaviors in the forced swim test (immobility time in Figure 21, swimming time in Figure 22, and climbing time in Figure 23), respectively, are shown (n=12 male Wistar rats per treatment group). [Error bars represent standard error of the mean. *P<0.05, **P<0.01, ***P<0.001 vs. vehicle by one-way ANOVA followed by Dunnett's multiple comparison test. ††P<0.01 vs. vehicle by unpaired t-test. ‡P<0.05, ‡‡‡P<0.001 compared to RE109]. DETAILED DESCRIPTION OF THE INVENTION

[0037] Detailed Description of the Preferred Embodiments In one of its aspects, the present invention provides a method of treating a psychiatric disorder, comprising administering to a patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is present in a dose of about 30 mg to about 50 mg, calculated as the free base (e.g., about 30 mg or about 40 mg, calculated as the free base), together with a pharmaceutically acceptable carrier.

[0038] Preferred embodiments of this method may include any one or any two or more combinations of the following features: The compound of formula (I) is used in the form of its hydrochloride salt; When used as the hydrochloride salt, the compound of formula (I) is used in a dose of about 33 mg or about 44 mg; The compound of formula (I) has a duration of action of about 2.5 hours to about 4.5 hours after administration; The compound of formula (I) has a duration of action of about 3.5 hours or 3.7 hours after administration; Compounds of formula (I) have a C in the range of about 1000 ng / mL to about 2000 ng / mL in patientsmax having; Compounds of formula (I) have a C in the range of about 1500 ng / mL to about 1800 ng / mL in patients max having; Compounds of formula (I) exhibit a T in the range of about 20 to 30 minutes in patients max having; Compounds of formula (I) have a T in the range of about 15 minutes in patients max having; The compound of formula (I) after administration has the formula (II) [ka] and the compound of formula (II) has a C in the range of about 100 ng / mL to about 300 ng / mL in patients. max having; The compound of formula (I) after administration has the formula (II) [ka] and the compound of formula (II) has a C in the range of about 120 ng / mL to about 300 ng / mL in patients. max having; The compound of formula (I) after administration has the formula (II) [ka] and the compound of formula (II) has a T in the range of about 60 minutes to about 150 minutes in the patient. max It has. The compound of formula (I) after administration has the formula (II) [ka] and the compound of formula (II) has a T in the range of about 60 minutes to about 80 minutes in the patient. max having; the method demonstrates that the mean MEQ30 score in the patient is at least 50%; and / or The method demonstrates that the mean MEQ30 score in patients is at least 60%; the pharmaceutical composition is administered to the patient by injection; and / or The pharmaceutical composition is administered to the patient by subcutaneous injection.

[0039] As used herein, the term "mental disorder" includes disorders that can be diagnosed as psychological or psychiatric disorders by a mental health professional, including disorders that can be diagnosed by reference to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0040] As used herein, the terms "treating," "treat," or "treatment" include both preventative, i.e., prophylactic, and palliative, treatment, i.e., mitigating, alleviating, or slowing the progression of the patient's disease, disorder, or condition.

[0041] As used herein, a "psychedelic state" refers to an altered state of consciousness experienced by a person, which may include enhanced perceptions, perceptual distortions or hallucinations, and / or euphoria or despair. Psychedelic states have been described as resulting from psychedelic drugs such as DMT (dimethyltryptamine), LSD, mescaline, or psilocybin. Other known psychedelic drugs include the 4-hydroxy analogs of N-methyl-N-isopropyltryptamine (MiPT) and N,N-diisopropyltryptamine (DiPT).

[0042] The present invention includes the use of prodrugs of hydroxyindole 5HT2A agonists, such as RE104, that induce a psychedelic state or still provide beneficial therapeutic effects without being associated with a psychedelic state. The prodrugs may be used in combination with other treatments known to be effective in treating psychiatric disorders, such as psychotherapy, electroconvulsive therapy, and / or other pharmaceutical compounds, for example, with a tricyclic antidepressant (TCA), selective serotonin reuptake inhibitor (SSRI), selective norepinephrine reuptake inhibitor (SNRI), monoamine oxidase inhibitor (MOAI), or other antidepressant. In preferred embodiments, treatment may provide sustained effects, for example, for more than one month, preferably more than three months, and more preferably more than six months, after a single treatment. In some embodiments, additional treatment may not be required.

[0043] compound As used herein, "compound" includes any pharmaceutically acceptable derivative or modification, including conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomeric mixtures and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The term "prodrug" refers to a compound that is a drug precursor that releases a drug (or "active agent") in vivo after administration through some chemical or physiological process (e.g., hydrolysis, enzymatic cleavage or hydrolysis, or metabolic conversion to the desired drug form). The present invention includes within its scope pharmaceutically acceptable salts of the compounds of the invention. Thus, the phrase "or a pharmaceutically acceptable salt thereof" is implicit in the description of all compounds described herein, unless expressly stated otherwise.

[0044] In some embodiments, compounds used in the compositions and treatment methods of the present invention can be easily purified, formulated, and used to provide highly soluble drug substances, including stable prodrug compounds, preferably with rapid onset and clearance for convenient use in clinical settings. In some embodiments, compounds can be produced as zwitterions, which can be converted to pharmaceutically acceptable salts.

[0045] In some embodiments, the compounds of the present invention preferably allow for rapid cleavage of the prodrug moiety in vivo to yield the active pharmacophore, for example, 90% conversion can occur in less than 4 hours, preferably less than 2 hours, and more preferably less than 1 hour. A prodrug may itself have less, little, or no pharmacological activity, but can be converted to an active compound upon administration to a patient, for example, by hydrolytic cleavage.

[0046] Formulations and Compositions The present invention also provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more compounds described herein, formulated together with one or more pharmaceutically acceptable carriers (excipients) and / or diluents, and optionally one or more additional therapeutic agents. While it is possible for the compounds described herein to be administered alone, they are preferably administered as a pharmaceutical composition.

[0047] The term "pharmaceutical composition" refers to a composition comprising a compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to a medium (i.e., adjuvants, additives or vehicles, such as diluents, osmotic complements, preservatives, excipients, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, polymers, solubilizers, stabilizers, antioxidants, and dispensing agents) generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, depending on the mode of administration and the nature of the dosage form. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.

[0048] As used herein, "oral" administration includes swallowing for gastric or intestinal uptake, and further includes lingual, sublingual, buccal and oropharyngeal administration.The compounds of the present invention can be administered for any of the uses or methods described herein by any suitable means, for example, orally, for example, by tablets, capsules (each of which may contain sustained-release or time-release formulations), pills, powders, granules, elixirs, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions, sublingually (for example, as thin films, effervescent tablets or tablets that spontaneously dissolve under the tongue); parenterally, for example, by subcutaneous, intravenous, intramuscular injection or infusion techniques (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal mucosa by inhalation spray, etc.; or rectally, for example, in the form of a suppository.

[0049] Preferred formulations allow for subcutaneous injection, and the preferred route of injection is subcutaneous.

[0050] Dosing regimens for the compounds described herein will, of course, vary depending on known factors, such as the pharmacokinetic and pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, condition, and weight of the recipient; the nature and extent of the symptoms; the type of concomitant treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function; and the desired effect. The selected dosage level may also depend on additional factors, including the activity of the particular compounds and pharmaceutical compositions described herein, whether ester, salt, or amide substituents of the compound are used, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of treatment, other drugs that may be administered to the patient, compounds and / or materials used in combination with the particular compound used, and similar factors well known in the medical arts.

[0051] Generally, the dosage of the prodrug for a treatment session, when used for the indicated effect, ranges from about 0.001 to about 500 mg / dose, preferably about 0.01 to about 200 mg / dose, preferably about 0.1 to about 50 mg / dose, e.g., 10, 20, 30, 40, 50, 100, or 200 mg. In a more preferred embodiment, the dosage of the prodrug for a treatment session, when used for the indicated effect, ranges from about 30 mg to about 50 mg per dose, e.g., 33 mg or 44 mg.

[0052] Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0053] The compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in multiple divided doses, such as two, three, or four times daily. Alternatively, doses can be provided weekly, biweekly, or monthly. In preferred embodiments, only one or two doses are required for antidepressant effect, which can extend for one, two, three, or six months or more.

[0054] In tablet dosage forms, depending on the dosage, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant comprises 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0055] Binders are generally used to impart cohesion to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

[0056] Tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surfactants are typically present in an amount of 0.2% to 5% by weight of the tablet, and glidants are typically present in an amount of 0.2% to 1% by weight of the tablet.

[0057] Tablets also generally contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are generally present in an amount of 0.25% to 10% by weight of the tablet, preferably 0.5% to 3%.

[0058] Other conventional ingredients include antioxidants, colorants, flavorants, preservatives and taste-masking agents.

[0059] Exemplary tablets contain up to about 80% by weight of drug, about 10% to about 90% by weight of binder, about 0% to about 85% by weight of diluent, about 2% to about 10% by weight of disintegrant, and about 0.25% to about 10% by weight of lubricant.

[0060] Tablet blends may be compressed directly or by roller to form tablets. Alternatively, tablet blends or portions of blends may be wet-, dried-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated, uncoated, or encapsulated.

[0061] Tablet formulations are discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1" by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0 8247 6918 X).

[0062] A typical capsule for oral administration contains at least one of a compound of the invention (e.g., 25 mg), lactose (e.g., 75 mg), and magnesium stearate (e.g., 15 mg). The mixture is passed through a 60-mesh sieve and filled into a No. 1 gelatin capsule.

[0063] Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations can be used as excipients in soft or hard capsules, and typically contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid formulations can also be prepared by reconstituting solids, for example, from sachets.

[0064] The compound used in the present invention can be directly administered into bloodstream, muscle or internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous.Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors and infusion techniques.

[0065] Parenteral formulations are typically aqueous solutions which may contain additives such as salts, carbohydrates, and pH adjusters or buffers (preferably to a pH of 3.0-7.0, preferably 4.0-6.0, more preferably 4.5-5.5), although for some applications they may be more suitably formulated as sterile nonaqueous solutions or as a dry form for use with an appropriate vehicle such as sterile pyrogen-free water or premade extemporaneous mix aqueous buffer. An osmotic agent may be included to control isotonicity.

[0066] Preparation of parenteral kits for reconstitution at the point of care under sterile conditions, eg, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0067] A typical injectable preparation is produced by aseptically placing at least one compound of the invention (e.g., 25 mg, 33 mg, or 44 mg) as a sterile-filtered solution into a vial, aseptically lyophilizing, and sealing. For use, the contents of the vial are mixed with, for example, 2 mL of injectable saline, and optionally appropriate amounts of osmolality complement and pH adjuster to achieve a slightly acidic to neutral pH (e.g., pH 4-7) to produce an injectable preparation that is mild yet retains the solubility and / or stability of the prodrug.

[0068] The compounds used in the present invention may be combined with soluble polymeric entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers to improve solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the above modes of administration.

[0069] For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. The most commonly used for these purposes are alpha, beta, and gamma cyclodextrins, examples of which can be found in WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0070] Regardless of the route of administration selected, the compounds used in the present invention and / or pharmaceutical compositions of the present invention, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. Actual dosage levels of the active ingredient in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0071] A person of ordinary skill in the art (e.g., a nurse, nurse practitioner, physician, or veterinarian) can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, such a person can start doses of the compounds of the invention used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0072] In general, a suitable daily dose of a compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0073] As used herein, a "therapeutically effective amount" refers to that amount of compound administered that will relieve to some extent one or more of the symptoms of the disorder being treated. With respect to the treatment of depression, a therapeutically effective amount refers to an amount that has the effect of reducing the severity of depression. Depression severity can be assessed using well-known structured assessment tools, such as the DSM-5 (SCID-5) and the GRID-Hamilton Depression Rating Scale (GRID-HAMD). A therapeutically effective amount may be less than the amount required for a psychedelic state.

[0074] An effective dose can be administered in one or more administrations. For purposes of this invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment, either directly or indirectly. As understood in a clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another treatment, drug, compound, or pharmaceutical composition.

[0075] Treatment Methods and Uses Treatment with the compounds of the present invention, such as RE104 described herein, can substantially alleviate clinical or subclinical depression and prevent relapse, especially when used in combination with psychotherapy for the treatment of depression. Administration of an effective dose of psilocybin is known to result in a rapid and significant reduction in depressive symptoms, with many subjects achieving remission through a 4-week follow-up (Davis et al.). Without being limited by theory, it is believed that the psychedelic state is associated with beneficial effects, but some compounds that are 5HT2A agonists can provide the desired therapeutic effect without the psychedelic state. One aspect of the present invention includes prodrugs of 5HT2A agonists that provide beneficial therapeutic states.

[0076] In general, the present invention includes the use of a compound of the present invention for treating any disease or disorder that can be alleviated by a 5HT2A agonist, or the use of a compound of the present invention for the manufacture of a medicament for treating any disease or disorder that can be alleviated by a 5HT2A agonist, or a method of treating any disease or disorder that can be alleviated by a 5HT2A agonist.

[0077] In some embodiments, the present invention may include the use of the compounds described herein to treat psychiatric disorders. In some embodiments, the present invention may include the use of the compounds of the present invention to treat depression, particularly major depressive disorder, postpartum depression, and treatment-resistant depression. Other conditions that may be treated include anxiety disorders (including anxiety in advanced illnesses (e.g., cancer)), as well as generalized anxiety disorder, cluster headache, obsessive-compulsive disorder, personality disorders including conduct disorder, drug addictions including alcoholism, nicotine addiction, opioid addiction, and cocaine addiction, and other addictions including gambling disorder, eating disorders, and body dysmorphic disorder, chronic pain, or chronic fatigue.

[0078] In some embodiments, the present invention may include a method for treating a psychiatric disorder, comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof. In one embodiment, a method for treating depression is provided, comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof. The depression may be drug-resistant depression or major depressive disorder.

[0079] For example, a patient diagnosed with depression may be screened before treatment and then prepared for the dosing session by a trained psychotherapist. During the dosing session, the compound of the present invention may be administered to the patient by injection of a sterile solution at a rate of 0.01 to 0.3 mg / kg. The patient is preferably blindfolded and seated for the duration of the session. For safety, a trained medical professional may monitor the patient throughout the entire dosing session, which may last up to 12 hours. In some cases, music may be played for the patient. Once the medical professional determines that the drug substance has been removed, the trained medical professional may assist the patient with any questions regarding the psychedelic experience, after which the patient may be discharged.

[0080] To further alleviate possible anxiety compared to treatment, physicians may prefer to split the treatment dose, thereby reducing the initial onset of psychoactive effects before applying the full complement of doses to achieve the full effect.

[0081] In some embodiments, treatment with the compounds of the present invention may be combined with concurrent treatment with another antidepressant, either simultaneously or sequentially. In a preferred embodiment, treatment with the compounds of the present invention is combined with psychotherapy, which can be applied before or after treatment. If before, the session can focus the patient on the intention of treatment. If after, psychotherapy is preferably performed within 48 hours of the medication session to help the patient integrate any feelings, emotions, visions or thoughts that may have occurred during the session, and to allow the psychotherapist to provide advice on how best to change thinking or behavior patterns to improve antidepressant outcomes. Psychotherapy can be continued as needed after the medication session, for example, for up to another 3 months, to help the patient integrate the experiences or learning that occurred during the medication session.

[0082] The present invention can be described with reference to the following examples. These examples are provided for illustrative purposes only. All terms, names, abbreviations, or acronyms are those commonly understood by those skilled in the art. Compounds shown in zwitterionic form can be readily visualized in their neutral form by those skilled in the art, and vice versa. The examples should not be used to interpret or limit the scope of the invention.

[0083] Example 1 Early Research and Nonclinical Pharmacology RE104 hydrochloride (RE104 HCl) is a prodrug of the synthetic psychedelic drug 3-(2-diisopropylaminoethyl)-1H-indol-4-ol (4-OH-DiPT or isoprosin), a molecule structurally related to psilocin. 4-OH-DiPT has been reported as a substance of abuse that produces subjective experiences in recreational settings similar to psilocybin but with shorter-lasting psychoactive properties (Shulgin and Shulgin, 1997). While no formal human studies with 4-OH-DiPT have been documented, the literature presents limited pharmacological and nonclinical studies. 4-OH-DiPT acts as a serotonin (5-hydroxytryptamine [5-HT]) agonist, specifically at the 2A and 2B subtypes. Several lines of evidence suggest that serotonergic hallucinogens, such as those following administration of psilocybin (the active substance of which is psilocin) and isoprosin, have clinical potential to induce therapeutically beneficial behavioral changes in a variety of psychiatric conditions.

[0084] For all studies, the placebo was commercially available 0.9% saline. All drug administration for the following studies was by a single subcutaneous (SC) injection in the patient's upper arm. While not limiting with regard to the route of administration, subcutaneous injection has the following advantages: (1) it ensures dose absorption, whereas oral absorption is often associated with nausea and may result in dose loss due to vomiting; (2) it ensures complete and reproducible absorption, whereas GI absorption can vary depending on several parameters, including the metabolic profile of the individual and recent food intake; (3) it ensures the fastest and most complete systemic availability by avoiding the delays associated with GI transit; and (4) these combined factors result in greater reproducibility of absorption rate and overall PK profile, which also ensures consistency in the duration and intensity of the drug's effect from one treatment to the next.

[0085] Nonclinical Pharmacology Like psilocybin and psilocin, RE104 and 4-OH-DiPT are 5-HT2A agonists. Receptor binding studies (5-HT2A and 5-HT2B agonist radioligand assays) showed that the active moiety, 4-OH-DiPT, is more potent (IC50s of 150 nM and 42 nM at 5-HT2A and 5-HT2B, respectively) than the prodrug RE104 (IC50s of 1600 nM and 740 nM at 5-HT2A and 5-HT2B, respectively). Furthermore, in vitro radioligand binding assays demonstrated that RE104 may interact with other receptors (e.g., 5-HT transporters and kappa and mu opioid receptors) like 4-OH-DiPT (5-HT transporter, kappa opioid, 5-HT1A, 5-HT1B, mu opioid, and muscarinic M2 receptors). However, engagement at the 5-HT2A and 5-HT2B receptors is predominant for both RE-104 and 4-OH-DiPT compared to all other receptors included in the screening assay.

[0086] When administered to rats, 5-HT2A agonists (e.g., psilocybin, psilocin, RE104, and 4-OH-DiPT) induce behaviors such as head twitch, wet dog shakes, tremors, hindlimb abduction, and backward walking due to exaggerated pharmacology at serotonin receptors (Halberstadt et al., 2011; Haberzettl et al., 2013; Rickli 2016 Eur Neuropharmacol; Klien 2020 ACS Pharmacol Transl Sci). Head tremors in rodents correlate with hallucinogenic responses similar to those seen in humans with psychedelic effects (Willins and Meltzer, 1997). Exaggerated pharmacology associated with acute or chronic overstimulation of serotonin receptors has been reported to result in a condition known as serotonin syndrome (SS). Serotonin syndrome is an adverse drug reaction resulting from excessive serotonergic activity observed at very high dose levels, such as those assessed in nonclinical toxicology studies described in investigator brochures, and can occur in humans with excessive acute or chronic exposure (Boyer and Shannon, 2005). Acute SS associated with serotonin agonists, such as psilocybin, develops roughly proportionally to plasma levels of the active drug and typically resolves within a relatively short period (<24 hours). Chronic SS may have more serious health consequences and should be avoided. RE104 is being developed as a single-use medication with limited repeated, intermittent use, so only mild to moderate effects of exaggerated pharmacology can be expected. See, for example, Franciscongeli 2019 Int J Mol Sci.

[0087] Safety Pharmacology In behavioral studies in rats, single SC administration of 10, 25, or 50 mg / kg RE104 HCl induced significant acute and reversible neuropharmacological effects; however, all observations were attributed to exaggerated pharmacological effects of the test article (i.e., SS) at serotonin receptors. The incidence and duration of observations were dose-related. At 10 mg / kg, effects were observed between 30 minutes (min) and 1 hour (h). At 25 mg / kg, effects were observed for up to 6 hours, and at 50 mg / kg, effects were observed for up to 6 hours after dosing but had resolved by 24 hours.

[0088] In a respiratory function study in male rats, RE104 HCl at single SC doses of 10, 25, and 50 mg / kg resulted in increases in respiratory rate (8-28%) and decreases in tidal volume (28-30%) and minute ventilation (24-31%). All of these changes were transient, returning to pre-dose values ​​by the 6-hour post-dose reading. Based on the small magnitude and transient nature of these changes, they were not considered adverse.

[0089] In cardiovascular studies, RE104 HCl given as a single SC dose of 1 mg / kg caused a small, transient increase in heart rate but no effect on blood pressure in conscious, telemetered beagle dogs. Transient increases in heart rate and blood pressure (systolic, diastolic, and mean) were observed at the 3 and 8 mg / kg doses. No significant, biologically relevant effects on cardiac rhythm, electrocardiogram (ECG) parameters, or body temperature were observed with SC doses of 1, 3, or 8 mg / kg RE104 HCl. At the highest concentration tested (30 µM as the zwitterion), RE104 HCl showed minimal effects in the human ether-a-go-go-related gene (hERG) tail current assay, with hERG current amplitude reduced by 5.9 ± 1.6%.

[0090] toxicology A non-GLP single-dose, dose-ranging study was conducted in rats and dogs with RE104 HCl to explore toxicity and establish the maximum tolerated dose (MTD) via SC injection. The rat study explored dosing using two formulations: water for injection (WFI) at pH 3-4 and phosphate-buffered saline (PBS) at final pH 4.5-5. Single doses of 20-300 mg / kg formulated in WFI produced dose-dependent, pharmacologically relevant systemic serotonergic clinical signs. Similarly, SC administration of RE104 at doses of 25-225 mg / kg formulated in PBS elicited clinical signs of SS at approximately 1 hour, which resolved by 24 hours. At 225 mg / kg, decreased food consumption, body weight, and body temperature (females) were observed.

[0091] Injection site reactions were observed at all doses (20-150 mg / kg) formulated in WFI and at 75 mg / kg formulated in PBS. Clinical signs were reversible by recovery day 13 (study day 14). Microscopic injection site lesions were observed after a single dose of 225 mg / kg. The MTD in rats for RE104 in WFI was 150 mg / kg, and the MTD in PBS was 75 mg / kg.

[0092] A GLP 14-day extended single SC dose toxicity study in rats evaluated doses of 0 (PBS), 10, 25, and 75 mg / kg. Animals were necropsied on post-dose study days 2 and 14 (also referred to as recovery day 13).

[0093] RE104 Systemic exposure to HCl and 4-OH-DiPT (C max and AUC 0-t ) there were no substantial sex differences (>2-fold). In general, greater than dose-proportional increases in systemic exposure to RE104 and 4-OH-DiPT were seen with increasing dose over the 10-75 mg / kg range, except for 4-OH-DiPT Cmax in males, which showed a non-dose-proportional increase.

[0094] Clinical signs of acute mild SS ("exaggerated pharmacology of the serotonin 2A receptor") were evident in all RE104 HCl dose groups, with reversible changes at the injection site including edema / inflammatory infiltrates in all treatment groups at 25 and 75 mg / kg RE104.

[0095] In male rats, the changes resolved in all groups by day 2 and the animals remained normal.

[0096] Preclinical Pharmacokinetics and Metabolism The pharmacokinetics (PK) of RE104 and 4-OH-DiPT were characterized after a single intravenous (IV) or SC dose of 2 mg / kg RE104 HCl in rats. RE104 was only measurable in plasma between 5 minutes and 0.25 hours after dosing after IV administration and only measurable at 5 minutes after subcutaneous SC administration; therefore, PK parameters could not be determined for RE104 in this study. Active 4-OH-DiPT exhibited a short elimination half-life (t) in plasma for all routes of administration, with t of 0.426 hours (IV) and 0.678 hours (SC). Absolute bioavailability of RE104 after SC dosing approached 100% in rats. In monkeys, RE104 was also rapidly converted to 4-OH-DiPT, with half-lives of 0.631 and 0.950 hours after IV and SC administration, respectively. In dogs, the conversion of RE104 to 4-OH-DiPT was slower; the half-life of the parent drug, RE104, after SC administration was 1.3 hours, while the half-life of 4-OH-DiPT after SC administration was 0.888 hours. The half-life of 4-OH-DiPT after IV administration was 0.863 hours. In dogs, the absolute bioavailability of RE104 after SC administration was also close to 100%.

[0097] The active species 4-OH-DiPT derived from RE104 HCl metabolism had low plasma protein binding to animal plasma proteins (approximately 30–60% bound) and showed higher binding to human plasma proteins that was concentration-dependent (approximately 80–93% bound over the range of 1–20 μM).

[0098] In hepatocytes, the in vitro intrinsic clearance (CLint) values ​​of RE104 were fastest in rats and slowest in dogs, with CLint values ​​of 6.66, 4.88, 3.45, 1.14, and 0.87 mL / hr / 106 cells for rats, rabbits, humans, monkeys, and dogs, respectively. The metabolite profiles of RE104 in human, rat, rabbit, dog, and monkey hepatocytes were qualitatively similar across these species, with only minor differences. The human hepatocyte metabolic profile of 4-OH-DiPT was also qualitatively similar to the metabolic profiles of RE104 in rat, rabbit, dog, and monkey hepatocytes, with only minor differences. In vitro assays using recombinant human enzymes (Supersomes), including multiple cytochrome P450 (CYP) enzymes, flavin-containing monooxygenase (FMO), and monoamine oxidase (MAO) enzymes, demonstrated that RE104 is not a substrate for any of the cytochrome P450, FMO, or MAO isoforms. The enzymatic conversion of RE104 to 4-OH-DiPT is likely mediated by plasma esterases such as cholinesterases.

[0099] Rationale for medication and exposure limits The no-observed-adverse-effect level (NOAEL) for local injection-site changes was determined to be 10 mg / kg in male and female rats. For systemic effects, the NOAEL was 10 mg / kg. A dose of 10 mg / kg in males was considered the low-observed-adverse-effect level (LOAEL). A dose of 10 mg / kg in rats provides a human equivalent dose [HED] (expressed as zwitterion) of approximately 97 mg, assuming a human weight of 60 kg and a standard (FDA Guidance, 2005) body surface area (BSA) conversion factor. This HED dose is approximately 19-fold higher than the proposed starting dose of 5 mg (expressed as zwitterion) in this study and 2-fold higher than the maximum proposed dose of 48 mg (expressed as zwitterion). At 10 mg / kg, the maximum plasma concentration (Cmax) of RE104 was 0.751 ng / mL, and the area under the concentration-time curve from time zero to the last time point (AUC0-t) was not determined due to rapid conversion to 4-OH-DiPT; for 4-OH-DiPT, the mean Cmax was 542 ng / mL, and AUC 0-t The mean mean serotonin concentration (MTD) was 1230 h ng / mL. A non-GLP dose-ranging study was conducted in dogs to determine the MTD. Single SC doses of 7.5, 15, and 20 mg / kg were evaluated. Clinical signs of SS were evident across the dose range, with hypersalivation, behavioral and postural changes at all doses.

[0100] A GLP 14-day extended single SC dose toxicity study in dogs was conducted at doses of 0, 3, 8, and 20 mg / kg RT-104 HCl. Systemic exposure (C) of RT-104 HCl and 4-OH-DiPT was assessed. max and AUC 0-t ) showed no gender differences. Increases in exposure were approximately dose-proportional for RE104 HCl and greater than dose-proportional for 4-OH-DiPT over the dose range of 3 to 20 mg / kg. Clinical signs were limited to serotonin syndrome.

[0101] The NOAEL was determined to be 8 mg / kg in dogs. The HED of 8 mg / kg in dogs is approximately 267 mg (expressed as zwitterion), assuming a human body weight of 60 kg and a standard BSA conversion factor. This HED provides a safety margin of approximately 53-fold over the proposed starting dose of 5 mg (expressed as zwitterion) and 5-fold over the proposed maximum dose of 48 mg (expressed as zwitterion) in this study. The 8 mg / kg dose in dogs resulted in C values ​​of 3300 ng / mL and 4540 h·ng / mL for RE104, respectively, and 360 ng / mL and 1010 h·ng / mL for 4-OH-DiPT, respectively. max and AUC 0-t was related to.

[0102] Based on a NOAEL of 10 mg / kg in rats and 8 mg / kg in dogs, the maximum recommended safe starting dose (MRSD) of RE104 HCl for the RT-104-101 study, applying a 10-fold margin of safety, is 9.7 mg (Table 1). The actual proposed starting dose for the first-in-human (FIH) study was 5 mg (RE104 free base), and therefore the margin of safety for the starting dose was higher.

[0103] Based on a comparison of the effective dose range of psilocybin / psilocin (21-30 mg orally) in various psychiatric disorders, the oral bioavailability of psilocin in humans of approximately 53%, and the affinity of psilocin for the 5-HT2A receptor, the effective dose of 4-OH-DiPT is estimated to be in the range of 10 mg-30 mg. Because subcutaneous administration of RE-104 HCl in animals was 100% bioavailable, the parent dose is expected to be in the same dose range. Therefore, 5.5 mg (RE104 HCl free base) was considered a conservative dose and was expected to allow for a safe starting dose.

[0104] Based on the NOAEL and MRSD in Table 2, proposed dose levels were proposed for some of the human cohorts 1-4 planned for the RE104-101 study reported in Example 2.

[0105] Example 2 Rationale for the study This is the first clinical study conducted with RE104 HCl. It is designed to investigate the safety, tolerability, PK, and pharmacodynamic (PD) properties of RE104 HCl after a single dose administered as an SC injection in healthy women. Data obtained in this study will provide a basis for further clinical development of RE104 HCl and will be used to support dose selection in future Phase 2 studies in the target patient population.

[0106] the purpose The safety, tolerability, PD and PK of RE104 will be characterized in a Phase 1 first-in-human (FIH) study.

[0107] design A schematic diagram of the study design is shown in Figure 1.

[0108] The study was a double-blind, randomized, placebo-controlled, phase 1, single-ascending-dose study in up to six cohorts of healthy women. Eligibility was assessed during a screening period of up to 28 days prior to enrollment. For the treatment period, subjects were admitted to the Clinical Research Unit (CRU) one day before dosing (Day -1). On Day 1, all subjects received their assigned SC dose of RE104 HCl or placebo in a fed state (after staying overnight at the CRU, consuming their scheduled dinner on Day -1, and consuming breakfast on Day 1). Subjects were allowed to select a snack from a scheduled menu starting 4 hours after dosing. Subjects were discharged from the clinic on Day 2 (approximately 24 hours after dosing) if all required study procedures were completed and they were deemed medically fit. Subjects returned to the clinic for a follow-up visit on Day 10 (±2 days).

[0109] Six cohorts were enrolled in the study. Six single doses were tested in six cohorts (Cohort 1 to Cohort 6) of eight healthy female subjects (six active and two placebo), as shown in Figure 1 and Table 3.

[0110] The starting dose was 5.5 mg of RE104 HCl. Sentinel was used in all cohorts. Within each cohort, two subjects were initially treated: one subject received RE104 HCl and one subject received placebo. If no clinically significant safety issues were observed at least 24 hours after Sentinel dosing, as determined by the principal investigator (PI), the remaining six subjects in each cohort were dosed (five active, one placebo).

[0111] This study was overseen by a Safety Review Committee (SRC). The intent of the SRC was to ensure that treatment did not pose undue risk to subjects. Safety, tolerability, and available PK data were evaluated by the SRC between each cohort before escalating to the next dose level (Table 3). After dosing of each cohort was completed, the SRC met to discuss dose escalation. Escalation to the next higher dose level was performed only after evaluation of safety and tolerability data, including up to and at least 24 hours post-dose, of all evaluable subjects in the previous dose cohort. When deemed necessary, available PK results were requested for dose escalation decisions.

[0112] Inclusion criteria The study population included healthy adult subjects who met all of the following inclusion criteria: --Signed informed consent in a language understandable by the subject prior to any study-related procedures. --Healthy female subjects aged 18 to 65 years (inclusive) at the time of screening. --Subject weighs at least 60 kg and has a BMI between 18.0 and 30.0 kg / m2 (inclusive) at screening. --Subject self-reports at least one substantial prior recreational experience with a hallucinogenic or psychedelic compound (not including cannabis products) with the most recent experience occurring more than 90 days prior to study drug administration. --Women of childbearing potential (WOCBP) must be non-lactating, have a negative pregnancy test at screening and admission, and be willing to undergo additional pregnancy tests as needed throughout the study. Women of childbearing potential (WOCBP) who are sexually active with an uncastrated male partner must agree to continuously and appropriately use a double-barrier method of contraception with high effectiveness (e.g., condoms and oral contraceptives [OCPs], long-acting hormonal implants, injectable hormonal, vaginal ring, or intrauterine device [IUD]) during the study and for at least 90 days after study drug administration, as assessed by the PI. If hormonal contraception is used, it must be initiated at least 30 days before study drug administration. Women who abstain from heterosexual intercourse as part of their normal lifestyle and are not planning to become pregnant are also eligible to participate. --Women who are not WOCBP must be either surgically sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or postmenopausal. Postmenopausal status will be confirmed by testing for follicle-stimulating hormone (FSH) levels (≥ 30 IU / mL) in screening amenorrheal women. --Female subjects must refrain from donating oocytes for screening until at least 90 days after study drug administration.

[0113] Exclusion criteria Subjects were excluded if they met any of the following criteria: --Subject has a current or history of any clinically significant disease, such as a cardiovascular, neurological, pulmonary, hepatic, renal, metabolic, gastrointestinal, urinary, immunological, endocrine, or psychiatric disease or disorder, or other abnormality that may affect safety or confound the results of the study. --Subjects have a current or history of a clinically significant psychiatric disorder as assessed at screening by the International Neuropsychiatric Interview (MINI) questionnaire and an interview by a qualified medical professional (clinical psychologist or psychiatrist). --Subjects are at risk for suicide at screening and baseline according to the Columbia-Suicide Severity Rating Scale (C-SSRS) (score of 4 or 5 for thoughts or any suicidal behavior) or according to the clinical judgment of a qualified health professional (clinical psychologist or psychiatrist); or have a history of suicidal ideation or behavior. --Close (first-degree) blood-related family members or individuals currently or previously diagnosed with a psychotic or bipolar disorder. --Clinically significant illness, medical / surgical procedure, or trauma within 4 weeks prior to screening. --Subject has a history of cancer, excluding basal cell carcinoma, that has been in remission for at least 5 years prior to screening. -- Previous major adverse reaction to hallucinogens or psychedelic drugs (not including cannabis products) as determined by a qualified / trained investigator. -- Use of any medication, including over-the-counter (OTC) medications, in the 28 days or 5 half-lives (whichever is longer) prior to study drug administration, except for the following: - Hormonal contraceptives for WOCBP. - Paracetamol up to 3000 mg per day or ibuprofen up to 1200 mg per day for up to 3 days. - Acute use of topical steroids. --Use of ayahuasca, kambo, yopo, ibogaine, psilocybin, dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), Syrian Rue, or other psychedelic agents or mixtures thereof in their synthetic or naturally occurring forms, as well as use of amphetamines, opioids, or 3,4-methylenedioxymethamphetamine (MDMA) in the 90 days prior to screening and up until EOS / ET. --Use of synthetic or naturally occurring cannabinoids beginning 28 days prior to study drug administration and agreeing to abstain until EOS / ET. --Subject is cotinine positive at screening or on day -1. --Positive alcohol breath test or urine screen for drugs of abuse at screening or on day -1. --Subject has a history of substance abuse according to the most recent Diagnostic and Satistical Manual of Mental Disorders (DSM) available at the time of study initiation, or as determined by a medically qualified investigator, or within one year prior to screening. Excessive alcohol intake within 180 days prior to screening (regular alcohol intake ≥ 14 units / week for female subjects). One unit (8 gr) is equivalent to 1 / 2 pint (280 mL) of beer, 1 shot of spirits (25 mL), or 1 small glass of wine (125 mL). Alcohol consumption from 48 hours prior to study drug administration until the last PK sample was collected. --Consumption of products containing caffeine, xanthine, or poppy seed from 48 hours prior to study drug administration until the last PK sample was collected. --Participation in another clinical trial involving the investigational treatment within 30 days or 5 half-lives, whichever is longer, prior to screening. --Reception of any vaccine within 28 days prior to study drug administration and up to EOS / ET. Use of psychoactive medications (e.g., selective serotonin reuptake inhibitors, e.g., paroxetine or citalopram), haloperidol, any medications with MAO activity (e.g., isocarboxazid, phenelzine, selegiline or tranylcypromine, linezolid, and methylene blue), or any drugs shown to be potential inducers of serotonin syndrome, from 28 days prior to study drug administration through EOS / ET. See Tables 4 and 5, section 5.3.1.1 for prohibited medications. --Positive results for serum hepatitis B surface antigen (HbsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) at screening. --Female subjects who are pregnant, lactating, or have a positive pregnancy test at screening or day -1. Resting (for at least 5 minutes) systolic blood pressure >140 or <90 mmHg, or resting diastolic blood pressure >90 or <40 mmHg; resting (for at least 5 minutes) pulse rate outside the range of <40 or >100 beats / minute at screening or any time before study drug administration. Any clinically significant abnormality in rhythm, conduction, or morphology of the resting electrocardiogram (ECG) and any clinically significant abnormality in the 12-lead ECG that the investigator believes may interfere with interpretation of the change in corrected QT interval (QTc) at screening or any time before study drug administration. For female subjects, QTc ≥ 480 ms at screening or Day -1. --Estimated glomerular filtration rate (eGFR) ≤60 mL / min / 1.73 m at screening. - Subject has any skin condition, administration site abnormality or tattoo that precludes SC administration (e.g., local or systemic infection) and / or local site reaction assessment. --Subject has inadequate peripheral venous access. - The subject is an immediate family member, an employee of the research facility, or has a subordinate relationship (e.g., spouse, parent, child, sibling) to an employee of the research facility involved in the conduct of this study, or may be compelled to consent. --A positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) within seven days of admission to the CRU. --Subjects who are not fully vaccinated against COVID-19, as defined by local, state, and national guidelines and requirements at the CRU. --Current evidence or history of COVID-19 or influenza-like illness, as defined by fever (>37.5°C) and two or more of the following symptoms within seven days prior to dosing: cough, sore throat, runny nose, sneezing, limb / joint pain, headache, vomiting / diarrhea (in the absence of a known cause other than influenza or COVID-19 infection).

[0114] Study limitations - Pharmacotherapy and health foods Table 4 shows the list of prohibited medications and health foods for the RE104-101 study. Table 5 reports the list of specific drugs that may cause serotonin syndrome and were prohibited for the study.

[0115] Study drug and matching placebo The active study product was RE104 HCl, a prodrug of the synthetic psychedelic drug 3-(2-diisopropylaminoethyl)-1H-indol-4-ol (4-OH-DiPT or isoprosin), a molecule structurally related to psilocin. 4-OH-DiPT acts as a 5-HT agonist, specifically on the 5-HT2A and 5-HT2B subtypes. RE104 HCl was used as an injectable solution. RE104 HCl was provided in two components: a lyophilized form of RE104 HCl and LYO-RE104 HCl containing the diluent RE-PBS, a phosphate-buffered saline solution used as a diluent when preparing the final injection solution. The placebo was volume-matched 0.9% sterile saline.

[0116] Formulation, storage, preparation and handling The RE104 HCl for SC injection used was a sterile lyophilized solid (LYO-RT-104 HCl) in a vial for reconstitution, which was combined with aqueous diluent according to the pharmacy's instructions. Each LYO-RE104 HCl vial contained an amount of active ingredient equivalent to the RE104 zwitterion.

[0117] For example, for Cohort 4, the vial contained 36.3 mg of lyophilized drug substance, equivalent to 33 mg of RE104 zwitterion. A diluent composed of an approximately stoichiometric amount of dibasic sodium phosphate was used to solubilize and neutralize LYO-RE104 HCl, resulting in a solution of approximately pH 5 ready for injection. Prior to injection, 1.1 mL of RE-PBS was added to the 36.3 mg vial of LYO-RE104 HCl to yield 33 mg / mL RT-104 HCl, equivalent to 30 mg / mL of RE104 zwitterion (free base). The remaining cohorts were treated in a similar manner.

[0118] LYO-RE104 HCl vials were stored at -20°C. The diluent, RE-PBS, was prepared aseptically by combining water for injection, dibasic sodium phosphate (60 mM), and sodium chloride (40 mM) in solution. The composition was selected so that dibasic sodium phosphate neutralized the carboxylic acid of RE104 HCl, thus generating the RE104 zwitterion in a pH 5 solution. RE-PBS vials were stored at room temperature (15-25°C). After mixing RE104 and RE-PBS, the solution was administered within 60 minutes.

[0119] Medication and Administration Dosing occurred at times agreed upon with the study pharmacy and acceptable to the investigator. RE104 HCl or placebo was administered as a SC injection in the upper arm. Subjects received RE104 HCl or placebo in the fed state. The time of RE104 HCl or placebo administration was recorded on the eCRF. The regimen used is outlined in Table 3.

[0120] Within each cohort, two sentinel subjects were initially treated: one subject received RE104 HCl and one subject received placebo. If no clinically significant safety issues, as determined by the PI, were observed at least 24 hours after the sentinel dose, the remaining six subjects in the cohort were dosed (five active, one placebo). All drug administration occurred under direct medical supervision. Study subjects were supervised during the potentially psychoactive study drug period by professionals trained to monitor psychedelic experiences.

[0121] Safety and Tolerability There were no serious adverse events (AEs) in any of the treated participants, and all dosing was completed (Table 6).

[0122] The most common treatment-related AEs for RE104 were nausea, sinus tachycardia (asymptomatic with a maximum recorded value of 115 beats / min), restlessness, and headache.

[0123] Two participants, one at 38 mg and one at 44 mg, experienced distress as a severe AE and received midazolam. Both AEs resolved after administration of the combination medication.

[0124] No injection site adverse reactions were reported, with one AE being mild bruising related to the administration procedure.

[0125] There were no apparent blood pressure effects or clinically significant vital sign, clinical laboratory, or electrocardiogram findings during the study.

[0126] Pharmacodynamics The Drug Effect Questionnaire (DEQ) Feel / High has been widely used in studies of acute subjective responses to various substances to assess two important aspects of subjective experience: (1) the intensity of the substance effect and (2) the desirability of the substance effect (Morean et al., 2013). The modified DEQ assesses the extent to which subjects (1) feel any substance effect(s) and (2) feel high. This version of the DEQ includes the following items: "Are you feeling a drug effect right now?" (FEEL); "Are you high right now?" (HIGH). Figure 2 shows the modified DEQ used.

[0127] The modified DEQ was used as an 11-point numerical rating scale (0–10) administered by qualified staff. After receiving the study drug, subjects were asked to respond verbally to indicate how strong the drug effect felt and how high it felt on a scale of 0–10 ( Kollltveit et al., 2020 ).

[0128] The Mystical Experiences Questionnaire (MEQ30) is a validated questionnaire assessing individual episodes of mystical experiences produced by classical hallucinogens (Barrett et al. 2015). The validated MEQ30 uses 30 questions across four experiential domains: (i) mysticism (including items related to internal unity, external unity, intuitive truth, and the divine); (ii) positive mood; (iii) transcendence of time and space; and (iv) ineffability. Subjects are asked to rate each item on the MEQ30 on a 6-point scale. Figure 3 shows the modified MEQ30 used.

[0129] The mean DEQ-high scores over time demonstrated a dose-dependent effect (see Figure 4).

[0130] For doses ≥ 33 mg, peak DEQ-High scores ranged from 7 to 10, with a mean time-to-peak score of 1.1 hours; mean duration at 33 mg was 3.7 hours, with all participants having a score ≤ 1 at 4 hours post-dose.

[0131] A dose-related increase in the frequency of MEQ responders was observed, with 66.7%, 83.3%, and 100% of participants in the 33 mg, 38 mg, and 44 mg RE104 treatment groups, respectively, having a “complete” mystical experience (defined as a MEQ total score of 60% or greater), which is predictive of clinical efficacy, based on the MEQ total score (Table 7).

[0132] The proportion of MEQ responders by domain and dose group is shown in Figure 5 .

[0133] Pharmacokinetics Concentrations of RE104 and isoprosin in plasma were determined using validated liquid chromatography tandem mass spectrometry (LC-MS / MS) assays.

[0134] The half-life of the RE104 prodrug was approximately 0.5 hours across dose levels, and RE104 was undetectable in plasma within 5 hours of administration at any dose.

[0135] The maximum plasma concentration of 4-OH-DiPT after RE104 administration was proportional to the RE104 dose.

[0136] The results of the PK studies are reported in Table 8.

[0137] The PK profile of 4-OH-DiPT matched the PD profile, with peak plasma concentrations and PD effects consistent; however, subjective drug effects declined more rapidly than 4-OH-DiPT plasma levels (example from the 33 mg dose group shown in Figure 6).

[0138] When PK-PD correlations were examined across all cohorts and dose levels, mean 4-OH-DiPT concentrations appeared to correlate with mean DEQ-high scores across the range of 40 to 100 ng / mL (Figure 7).

[0139] Below 40 ng / mL, the mean DEQ-high score did not exceed a value of 2.

[0140] RE104 Phase 1 FIH Results Summary Overall, RE104 HCl was generally well tolerated, with robust pharmacodynamic (PD) effects observed at doses of 33 mg and above that closely matched the pharmacokinetic (PK) profile of 4-OH-DiPT.

[0141] The Drug Effect Questionnaire (DEQ-High) scores and Mystical Experiences Questionnaire (MEQ) responder rates observed at RE104 doses of 33 mg and above indicate the potential for treatment efficacy in therapeutic trials, given that the intensity and quality of the subjective drug experience may predict treatment response to psilocybin therapy in depression (Griffiths et al.; Roseman et al.; and Ross et al.).

[0142] The mean duration of the subjective experience with 33 mg of RE104 HCl was 3.7 hours, representing a 50% reduction in psychoactive experience compared to previous evidence with psilocybin and a convenient duration for clinical monitoring.

[0143] The adverse effect (AE) profile of RE104 HCl is similar to that of psilocybin (Goodwin et al.; and Carbonaro et al.), with no serious AEs and no clinically significant vital sign, laboratory, or electrocardiogram findings at doses of 44 mg or less.

[0144] Two adverse experiences were observed at doses of 38 mg and above.

[0145] These data indicated dose selection of RE104 HCl at 33 mg for a planned randomized, active, dose-controlled Phase 2 trial in women with moderate to severe postpartum depression (PPD).

[0146] Subcutaneous (SC) administration of RE104 HCl at therapeutically relevant dose levels (33 mg) demonstrates an improved safety and tolerability profile compared to administration of psilocybin; SC administration of the prodrug allows for faster absorption and earlier peak activity (approximately 1 hour), as well as the shortest (optimal) duration of psychoactive activity, making it useful and convenient for patients, physicians, and payers.

[0147] Administration of a prodrug of RE104 HCl demonstrates an improved sore throat profile compared to administration of psilocybin, with dose proportionality without undue variability.

[0148] Administration of RE104 HCl demonstrated robust and broad pharmacodynamic effects at the 33 mg dose level, with a reduced duration of experience compared to psilocybin at 25 mg.

[0149] Administration of the prodrug of RE104 HCl demonstrated MEQ total and domain scores reaching 60% or greater for 33 mg, which is predictive of clinical efficacy compared to administration of psilocybin.

[0150] Example 3 This example describes the preclinical characterization of RE104, including pharmacological, pharmacokinetic (PK), pharmacodynamic, and metabolic investigations. In anticipation of further clinical development as a potential treatment for depressive disorders, this example reports the results of a 28-day, two-arm, single-dose forced swim test (FST) study in rats comparing the effects of RE104 and psilocin-4-glutarate (RE109), a psilocin prodrug that also contains a glutaric acid moiety.

[0151] Materials and Methods molecular synthesis The synthesis of prodrugs RE104 and RE109 was carried out according to the teachings of US Pat. No. 11,292,765 B2 [Bryson].

[0152] Receptor Pharmacology Receptor binding and agonist activity (Eurofins Cerep, Serres-Lévaux, France) were determined as previously described (Bryant et al.; Choi et al.; and Porter et al.). Increasing concentrations of 4-OH-DiPT or RE104 were added to HEK-293 cell cultures expressing human recombinant 5-HT2A receptors at 0.1 nM [ 125 Increasing concentrations of RE104 were incubated with 0.2 nM [I] 1-(4-iodo-2,5-dimethoxyphenyl)isopropylamine (DOI) in CHO cell cultures expressing human recombinant 5-HT2B receptors. 125 I] and incubated with DOI.

[0153] Radioligand concentrations were determined by scintillation counting; compound binding was determined by [ 125 Activation was calculated as percent inhibition of [I]DOI binding. For agonist activity assays, test concentrations of RE104 were incubated with HEK-293 cells expressing human recombinant 5-HT2A receptors; IP1 production was detected using homogeneous time-resolved fluorescence. Activation was calculated as a percentage of the response to a positive control (10 μM 5-HT). Further details are provided in the Supplementary Methods section below.

[0154] Prodrug cleavage The stability of RE104 was assessed in 2 mL of plasma from male CD-1 mice, male Sprague Dawley rats, mixed-breed beagle dogs, and mixed-breed humans by measuring the concentrations of RE104 and 4-OH-DiPT at 0, 0.5, 1, 2, and 4 hours of incubation at 37°C using liquid chromatography tandem mass spectrometry (LC-MS / MS) (InterVivo Solutions, Inc., Mississauga, Ontario, Canada). Average values ​​from three replicate assays are reported. See Supplementary Methods for further details.

[0155] Pharmacokinetics and Pharmacodynamics Plasma samples from adult male Sprague Dawley rats were analyzed to determine RE104 and 4-OH-DiPT concentrations after intravenous (IV) dosing of 2 mg / kg (InterVivoSolutions, Inc.). Plasma test compound concentrations were determined by LC-MS / MS. The RE104 dose was maintained at 2 mg / kg for subcutaneous (SC) and oral (PO) administration, while the 4-OH-DiPT dose was adjusted to 1.39 mg / kg to match the molar dose of RE104 (5.34 μmol / kg). Pharmacokinetic parameters and administration routes of each analyte were estimated from the plasma concentration versus time curves for each animal. The head tremor response (HTR), also known as wet-dog shaking, was assessed by observing rats for automatic behavior consisting of rapid alternating head rotations (Gonzalez-Maeso et al. and Halberstadt et al.); HTRs were counted manually using 10-minute intervals up to 2 hours after dosing and at 3, 3.5, and 4 hours after dosing.

[0156] Plasma PK of RE104 and 4-OH-DiPT was evaluated in male beagle dogs after three consecutive doses of RE104 administered by IV injection, SC injection, and oral gavage at dose levels of 1, 1, and 5 mg / kg, respectively (QPS Taiwan, New Taipei City, Taiwan). Two consecutive doses were administered 7 days apart. Plasma samples were analyzed using an LC-MS / MS method (lower limit of quantitation of 1.00 ng / mL for both analytes).

[0157] Two male cynomolgus monkeys were administered three treatments in a crossover study design (Calvert Laboratories, Inc., Scott Township, PA; QPS, LLC, Newark, DE, USA). In Treatment 1, RE104 was administered as an IV bolus dose of 1 mg / kg. In Treatment 2, RE104 was administered as an SC injection at 0.5 mg / kg. In Treatment 3, RE104 was administered PO at 5 mg / kg. All dosage formulations were prepared in phosphate-buffered saline. For each treatment, plasma PK of RE104 and 4-OH-DiPT was analyzed via blood samples using an LC-MS / MS method.

[0158] Blood sampling time points are described in Supplementary Methods. Pharmacokinetic parameters were calculated using Phoenix WinNonlin, version 6.3 or 8.2 (Certara, Princeton, NJ, USA).

[0159] Metabolite profiling and identification Metabolite profiling and characterization were performed using rat, dog, and non-human primate plasma samples after a single SC injection of RE104 (QPS, LLC, Newark, Delaware, USA). Groups of 12 Sprague Dawley rats (6 males and 6 females, 8-10 weeks old at the time of dosing) received SC injections of RE104 at doses of 10, 25, or 75 mg / kg. Groups of 6 beagle dogs (3 males and 3 females, 9-10 months old at the time of dosing) received SC injections of RE104 at 3, 8, or 20 mg / kg, respectively. Two male cynomolgus monkeys received a single SC injection of 0.5 mg / kg RE104.

[0160] Blood collection time points are included in the Supplementary Methods. Blood samples were centrifuged to obtain plasma. Plasma samples for rat and dog studies were pooled across time points to one sample per dose and sex; plasma samples from monkeys were pooled to generate one combined sample.

[0161] In vitro metabolite profiling was performed using pooled (10 donors) cryopreserved primary human hepatocytes (QPS, LLC, Newark, DE, USA) incubated with 1 μM 4-OH-DiPT in triplicate or 1 μM lorazepam (positive control) in duplicate for up to 24 h at 37 °C in a humidified incubator filled with 5% CO2. Metabolite formation was monitored at 0, 4, 8, and 24 h, respectively. As a negative control, 1 μM 4-OH-DiPT was incubated in duplicate without hepatocytes. The positive and negative control samples were determined at 0, 8, and 24 h, respectively. RE104 and its metabolites were identified and profiled using ultra-high-performance liquid chromatography (Supplementary Methods).

[0162] Forced swim test (FST) The FST, a common model of antidepressant-like activity in rats that measures immobility, swimming, and climbing behavior in rats after exposure to water, was adapted from a previously described psilocin protocol applying standard FST observations up to 35 days after a single dose of psychedelic drug and revalidated using RE109 as the source of active psilocin (Hibicke et al. and Slattery et al.).

[0163] Adult male Wistar rats (8-10 weeks old) were randomized in parallel to receive a single SC intraperitoneal dose of vehicle, 1 mg / kg RE104, or an equivalent dose of RE-109 (1 mg / kg) (n=12 per treatment; acclimatization to the laboratory was allowed for 2 days, and FST measurements were performed on days 7, 14, and 28). Each rat was placed into a water-filled cylinder (20 cm diameter and 45 cm height) for 15 minutes for initial exposure 24 hours before testing. On the test day, animals were individually placed into a glass cylinder containing 35 cm of water maintained at 25 ± 1°C. A camera recorded the 5-minute session.

[0164] Immobility time, swimming time, and climbing time (seconds) were measured for 5-minute sessions from videotaped data by a blinded observer using a stopwatch. Statistical analysis was performed using GraphPad Prism-5 with one-way analysis of variance followed by Dunnett's test / Tukey's post-hoc test or unpaired t-test. For trend analysis, a linear repeated measures model was used for each endpoint. The intercept (model-estimated time on the day of dosing), slope (change in swimming, climbing, and immobility time by study day), and P-value of the slope parameter were calculated.

[0165] Animal Welfare All experiments involving animals were performed in accordance with protocols approved by the research facility's Institutional Animal Care and Use Committee or equivalent organization.

[0166] result Receptor Pharmacology The chemical structure of the RE104 prodrug and active compound 4-OH-DiPT has the following chemical structure: [ka]

[0167] The binding affinities of RE104 and 4-OH-DiPT for the 5-HT2A receptor were determined using a radioligand inhibition binding assay in HEK-293 cells. The binding K of RE104 and 4-OH-DiPT at the 5-HT2A receptor was 4300 nM (Figure 8) and 120 nM (Figure 9), respectively. RE104 binding to the 5-HT2B receptor in CHO cells was also evaluated, and the results showed a K similar to that of 5-HT2A receptor binding (1800 nM; Figure 10).

[0168] To determine whether the RE104 prodrug can functionally activate the 5-HT2A receptor, a cellular agonist effect assay was performed in HEK-293 cells (FIG. 11). The EC50 of RE104 at the 5-HT2A receptor was greater than 30,000 nM, indicating extremely low potency of RE104 at the 5-HT2A receptor.

[0169] Prodrug cleavage The kinetics of conversion of the RE104 prodrug to the active 4-OH-DiPT were measured in solution and plasma. RE104 demonstrated slow conversion in aqueous solution as a function of pH, but conversion was rapid (<30 min) and complete (>95%) in plasma from mice, rats, and humans when incubated at 37 °C (Figures 12–15). Prodrug cleavage of RE104 was significantly slower in dog plasma (39% remained after 4 h of incubation). In all plasma matrices, 4-OH-DiPT was formed at a rate and amount consistent with hydrolysis of the glutarate leaving group of RE104, and 4-OH-DiPT was oxidatively unstable in culture medium, as previously reported for the structurally related compound psilocin (Brown et al. and Hasler et al.). The psilocin prodrug RE109 demonstrated similar results to RE104, with rapid cleavage to psilocin when incubated with human plasma (data not shown).

[0170] Pharmacokinetic studies were conducted in rats, dogs, and non-human primates. Mean estimated PK parameters for 4-OH-DiPT after 2 mg / kg IV, PO, and SC administration of RE104 (prodrug) in Sprague-Dawley rats are shown in Supplementary Table 1. After IV administration, RE104 was almost completely metabolized to 4-OH-DiPT within 5 minutes (96.7%) and was not measurable in plasma within 5 minutes of dosing with either administration method. The half-life of 4-OH-DiPT was similar after IV (0.60 h) and SC (0.67 h) administration of RE104. The overall mean plasma exposure (area under the curve [AUC]) of 4-OH-DiPT formed from RE104 was slightly higher after SC administration than after IV administration (AUC0-last [standard deviation]: 203 [42.8] h ng / mL vs. 146 [4.62] h ng / mL), but this may be due to the higher concentration in the SC dosing solution (2.09 mg / mL) compared with the IV dosing solution (1.68 mg / mL) or variability associated with the small number of animals per treatment group (n = 3). Overall plasma exposure of 4-OH-DiPT after PO dosing was extremely low, suggesting that RE104 is poorly absorbed from the rat gastrointestinal tract.

[0171] The PK of 4-OH-DiPT in rats was determined by direct administration of 4-OH-DiPT (1.39 mg / kg IV, PO, and SC). The mean estimated PK parameters of 4-OH-DiPT after administration to rats are summarized in Supplementary Table 2. The smaller administered dose is equimolar to 2 mg / kg RE104, accounting for the smaller molecular weight of the active drug and allowing direct comparability. When administered IV to rats, 4-OH-DiPT demonstrated a short half-life (0.74 h), a steady-state volume of distribution of 5.9 L / kg, and a total body clearance of 9.4 L / h / kg. After SC administration, plasma concentrations peaked at 0.61 h, with a mean bioavailability of 88.6%, whereas PO administration resulted in peak plasma concentrations at 0.25 h and a low mean bioavailability (0.825%).

[0172] The PK of RE104 and 4-OH-DiPT was determined after IV, SC, and PO administration in dogs. Consistent with the in vitro cleavage studies, conversion of the prodrug to the active drug was slower in dogs than in rats. RE104 was rapidly absorbed after SC (1 mg / kg) and PO (5 mg / kg) administration, and plasma concentrations showed a rapid decline after an IV bolus (Supplementary Table 3). The mean absolute bioavailability of RE104 was 121% after a single SC dose of 1 mg / kg RE104 and 0.854% after a single PO dose of 5 mg / kg RE104. The mean metabolic ratios of 4-OH-DiPT to RE104 were 0.339, 0.332, and 7.04 after single doses of 1 mg / kg IV RE104, 1 mg / kg SC RE104, and 5 mg / kg PO RE104, respectively.

[0173] Similarly, RE104 was rapidly absorbed after IV (1 mg / kg) and SC (0.5 mg / kg) administration in non-human primates, resulting in a significant increase in 4-OH-DiPT plasma concentrations. max The mean terminal half-life of 4-OH-DiPT after IV and SC administration was 0.63 and 0.95 hours, respectively. Collectively, these data confirm a half-life of less than 1 hour for the active compound, 4-OH-DiPT, after IV and SC administration of RE104 in vivo and support the SC administration of RE104.

[0174] Pharmacodynamics HTR in rodents is a pharmacodynamic measure of 5-HT2A receptor agonism, which is associated with psychedelic or hallucinogenic effects (Gonzalez-Maeso et al. and Halberstadt et al. (2013)). To clarify potential PK-pharmacodynamic relationships, we measured HTR after administration of RE104 and 4-OH-DiPT in rats. The mean number of HTRs over a 10-minute interval and the mean 4-OH-DiPT plasma concentration in rats as a function of time are plotted in Figure 16; HTRs peaked immediately after IV administration of 2 mg / kg RE104 and 1.39 mg / kg 4-OH-DiPT and declined over the 4-hour observation period. After SC administration of 2 mg / kg RE104 or 1.39 mg / kg 4-OH-DiPT, the mean number of HTRs peaked within 1 hour and declined similarly over the observation period. HTR duration reflected the PK profile of 4-OH-DiPT after IV and SC administration of 2 mg / kg RE104 and 1.39 mg / kg 4-OH-DiPT. Furthermore, mean HTR values ​​correlated with 4-OH-DiPT plasma concentrations after IV and SC administration of 2 mg / kg RE104 and 1.39 mg / kg 4-OH-DiPT (r 2 =0.7019; Figures 17-20).

[0175] metabolism The metabolic profile of RE104 was determined across rats, dogs, and non-human primates in pooled plasma samples after a single SC dose of RE104. In pooled plasma samples from rats administered 10, 25, or 75 mg / kg RE104 between 0 and 10 h, hydrolysis to 4-OH-DiPT was the major metabolic pathway identified (>67% of total metabolites in plasma across all doses). The next most abundant metabolite in rat plasma was 4-hydroxy-indole-2-acetic acid (hydrolysis and N-dealkylation), accounting for up to -18% of total metabolites in pooled plasma across all RE104 doses. Other minor metabolic pathways in rats (defined by <10% of total peak area) included hydrolysis followed by (1) oxidation, (2) dual oxidation, (3) glucuronidation, (4) oxidation and glucuronidation, or (5) dual oxidation, dehydrogenation, and glucuronidation.

[0176] The major metabolite in pooled dog plasma 0-12 hours after SC administration of 3, 8, and 20 mg / kg RE104 was 4-OH-DiPT, accounting for 3.34% to 16.5% of the total composition across all doses; a significant portion of the drug remained as RE104 (78.5% to 96.0% across all doses). Other metabolic pathways were minor, resulting in multiple unidentified products with molecular weights consistent with single and multiple oxidation, glucuronidation, and hydrogenation steps. No other metabolites from this category accounted for more than 3% of the total plasma composition across all doses.

[0177] In pooled plasma samples collected from monkeys 0–12 hours after dosing, the unchanged RE104 parent molecule represented 71.1% of the total peak area, while the active compound, 4-OH-DiPT, represented 4.42% of the total peak area. The most abundant metabolite identified represented glucuronidation of 4-OH-DiPT (24.5% of the total peak area). Because rapid conversion to the active drug was expected, 1 μM 4-OH-DiPT was incubated with pooled plated human hepatocytes; primarily the O-glucuronide and negligible amounts of other metabolites (including 4-hydroxyindole-2-acetic acid) were produced, suggesting qualitatively similar metabolism of RE104 between the tested species.

[0178] Antidepressant-like activity in the FST Antidepressant-like effects were assessed using a modified FST in rats, specifically developed to assess the sustained effects of psychedelic drugs after a single dose (Hibicke et al.). When RE104 and RE109 were administered, characteristic serotonergic behaviors (e.g., HTR, piloerection, rearing, and prostrate posture) lasting approximately 3 hours were observed on the day of dosing; these responses were not observed in vehicle-treated animals. The first FST was conducted 7 days after the single dose. Significant decreases in mean immobility time were observed for RE104 on days 7, 14, and 28, and for RE109 on days 14 and 28 (P<0.05; Figures 21-23), demonstrating sustained effects by both compounds.

[0179] The decrease in immobility was explained by an increase in swimming and climbing escape behavior (diving was not observed). Mean swimming time was significantly increased for both RE104 (P < 0.01) and RE109 (P < 0.05) compared with vehicle. Trends from days 7 to 28 showed a steadily increasing amount of swimming (P = 0.08) and a gradual decrease in climbing (P < 0.004) for RE109, whereas climbing gradually increased (P < 0.02) and swimming decreased (P < 0.001) over the 28-day period for RE104; immobility remained constant for both compounds and was different from vehicle (P < 0.05). By day 28, differences were observed between RE104 and RE109 in the amount of swimming (P<0.05) and climbing (P<0.001), with swimming and climbing accounting for 55% and 45% of RE104 escape behavior, respectively, compared with 74% and 26% of RE109 escape behavior, respectively.

[0180] Consideration The results in the Examples demonstrate that the active compound, 4-OH-DiPT, exhibits 5-HT2A receptor binding affinity comparable to that previously described for the active compound psilocybin (psilocin), supporting a similar pharmacological profile (Rickli et al.). The prodrug RE104 was rapidly metabolized to 4-OH-DiPT in preclinical models, and the half-life and PK profile of 4-OH-DiPT following RE104 administration corresponded to the duration of pharmacodynamic effect (HTR). Furthermore, a single dose of RE104 in rats induced long-term antidepressant-like activity in the FST over a 28-day period, comparable to the activity of psilocin formed in situ following administration of the psilocybin prodrug RE109. Taken together, these results confirm that RE104 administration most likely activates 5-HT2A receptors via the active compound 4-OH-DiPT, inducing behavioral effects and antidepressant-like activity comparable to psilocybin (Gonzalez-Maeso et al. and Hibicke et al.).

[0181] The in vitro pharmacology data presented here are consistent with previous observations of 4-OH-DiPT binding to 5-HT2A receptors, with K values ​​in the nanomolar range (Rickli et al.). Conversely, RE104 binding to 5-HT2A and 5-HT2B receptors was substantially reduced compared to 4-OH-DiPT, with K values ​​in the micromolar range. Functional activation of 5-HT2A receptors by 4-OH-DiPT was previously reported with EC50 values ​​of 6.82 nM and 93 nM (Rickli et al. and Gatch et al.). The EC50 of RE104 at 5-HT2A was greater than 30,000 nM, demonstrating very low potency that is likely irrelevant to in vivo pharmacology. These results are also consistent with previous observations of 4-O-acetyltryptamine, which exhibits reduced activation of 5-HT2A receptors compared to its 4-hydroxy counterpart (Klein et al.). Taken together, these results confirm that 4-OH-DiPT is likely the only active species following RE104 administration.

[0182] Plasma concentrations of 4-OH-DiPT after RE104 administration correlate with pharmacodynamic HTR responses in rats, similar to the PK-pharmacodynamic and pharmacodynamic receptor occupancy relationships seen with psilocybin in human volunteers (Madsen et al.). The half-life of 4-OH-DiPT observed after IV or SC administration of RE104 in rats was approximately one-third of the half-life reported for psilocin after oral administration of Gymnopilus spectabilis, a psilocin-containing mushroom species (the terminal half-life of 4-OH-DiPT is approximately 40 minutes, compared with the distribution and elimination half-lives of psilocin, which are 117 and 148 minutes, respectively) (Chen et al.). The observed PK and pharmacodynamic profiles are also consistent with anecdotal reports of a 2-3 hour duration of psychedelic effects of 4-OH-DiPT in humans (Shulgin), suggesting that administration of RE104 in clinical settings may reduce clinical monitoring requirements compared to psilocybin administration (6-8 hours) (von Rotz et al.; Goodwin et al.; and Carbonaro et al.).

[0183] In summary, the proposed distribution-metabolism model for RE104 involves the enzymatic conversion of the prodrug to 4-OH-DiPT. The circulating prodrug is believed to be peripherally restricted as a charged zwitterion at neutral pH and unable to readily diffuse into the brain. The active monoamine species is able to penetrate the central nervous system, causing near-immediate but short-term behavioral changes (e.g., HTR) and long-term antidepressant-like behavior. Circulating 4-OH-DiPT is metabolized to glucuronide (major metabolite) or indoleacetic acid (minor metabolite, rats), both of which are likely to be inactive species. In general, the metabolic profile of RE104 in animal models is similar to that of psilocybin and serotonin (Dinis-Oliveira), although the formation of indoleacetic acid may be reduced in higher species (particularly humans) due to the difficulty of monoamine oxidase in metabolizing the isopropyl derivative. Combined with in vitro metabolic profiling from human hepatocytes, these data support the elimination of RE104 via urine and feces primarily as a glucuronide metabolite, which also most likely reflects psilocybin (Dinis-Oliveira). The lower absolute oral bioavailability of RE104 compared to IV or SC administration supports the use of an injectable formulation of RE104.

[0184] RE104 demonstrated antidepressant-like activity similar to that of psilocin in the FST model with extended efficacy (Hibicke et al.). Both RE104 and RE109 reduced immobility time compared to vehicle, an effect maintained for 28 days after a single dose. The findings with RE109 are consistent with previous reports of sustained antidepressant-like effects observed in the FST after a single dose of psilocybin, and it is noteworthy that these results have been successfully translated into clinical practice (Goodwin et al. and Hibicke et al.). Furthermore, these data are consistent with previous reports that the antidepressant-like effects of serotonergic agonists and reuptake inhibitors are specifically reflected by reduced immobility in the FST, further suggesting that the antidepressant effects of serotonergic psychedelics are mediated by serotonergic modulation (Slattery et al. and Cryan et al.). Increased swimming and climbing accounted for the remainder of the study with RE104 and RE109 administration, with a trend toward increased climbing over 28 days for RE104 and decreased climbing for RE109, reaching significance on day 28, although complementary trends of increased swimming for RE109 and decreased swimming for RE104 were observed. Previous studies have shown that swimming and climbing behaviors are differentially responsive to selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, and therefore result from differential modulation of the serotonergic and adrenergic systems, respectively (Detke et al. and Lucki et al.). Similarly, with 5-HT1A agonists, swimming in the FST was observed to be preferable to climbing in the first long-term FST study in psilocybin-treated rats (Hibicke et al. and Lucki et al.), and in particular, psilocin is a more potent 5-HT1A agonist than 4-OH-DiPT (Rickli et al.). Furthermore, when administered in a drug-dose paradigm using the extended FST test (Masuda et al.), the opposite of immobility (indicating depression and / or despair) in rodents is climbing, not swimming.The differences in climbing and swimming observed in the FST may indicate small but persistent differences in specific receptor system interactions and the location and extent of downstream neuroplastic modifications that psychedelic molecules can induce (Rickli et al. and Detke et al.).

[0185] The results in this example confirm that rapid cleavage of the novel prodrug RE104 to the 5-HT2A-activating compound 4-OH-DiPT results in pharmacodynamic effects indicative of a short duration of psychedelic activity in preclinical models. Furthermore, the antidepressant-like activity of RE104 was confirmed in a translational proof-of-concept assay. Together, these studies demonstrate the potential therapeutic efficacy of RE104 in humans for depressive disorders with a short duration of psychoactive state, similar to that observed in recent randomized clinical trials of psilocybin.

[0186] Supplementary method Receptor Pharmacology For receptor binding assays, the concentrations of test compounds were 3 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, and 30 μM (4-OH-DiPT) and 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, and 30 μM (RE104). The half-maximal inhibitory concentration (IC50) and Hill coefficient were determined by nonlinear regression analysis of competition curves generated from average replicates (n = 2) using Hill equation curve fitting. The inhibition constant was calculated using the Cheng-Prusoff equation: Ki = IC50 / (1 + L / KD), where L = radioligand concentration, and KD = radioligand affinity for the receptor (determined by Scatchard plot). In functional activity assays, RE104 test concentrations were 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM, and 30 μM. EC50 and IC50 values ​​were determined by nonlinear regression analysis of concentration-response curves generated with average replicate values ​​using Hill equation curve fitting. For all receptor pharmacology assays, data were analyzed with software developed at Cerep (Hill Software, Celles-Revescoe, France) and verified by comparison with data generated by the commercially available software SigmaPlot® 4.0 for Windows (© 1997 by SPSS Inc.).

[0187] Prodrug cleavage Stock solutions of 0.1 mg / mL 4-OH-DiPT and RE104 were prepared in dimethyl sulfoxide and diluted 100-fold to 1 μg / mL with 2 mL of pooled mixed-race human, mixed-race Beagle dog, male CD-1 mouse, or male Sprague Dawley rat plasma (containing K2EDTA as an anticoagulant). Triplicate aliquots (50 μL) of each spiked plasma solution were immediately added to 200 μL of ice-cold methanol / acetonitrile (50:50 v / v) containing the internal standard to generate time zero samples. The spiked plasma solutions were incubated at 37°C in an orbital shaker set at 75 rpm, and 50 μL samples were taken in triplicate after 30 minutes and 1, 2, and 4 hours of incubation. The reaction was stopped by immediately adding each sample to 200 μL of ice-cold methanol / acetonitrile containing the internal standard(s). Samples were mixed by vortexing and then stored at -80°C until analysis.

[0188] Because RE104 was found to be unstable in mouse, rat, and human plasma, plasma-containing calibration standards could not be used for absolute quantification; therefore, peak area ratios of analyte to internal standard versus incubation time are reported. For 4-OH-DiPT stability samples, mouse, dog, and human plasma samples were analyzed using rat plasma calibration standards. Calibration standards were prepared in plasma for each species and analyzed in batches by LC-MS / MS. Sample batches consisted of triplicate system suitability standards (containing analyte and internal standard), blank samples without internal standard, zero samples (containing internal standard), and appropriate calibration standards in ascending order, including at least six non-zero standard samples and assay samples, followed by triplicate system suitability samples.

[0189] PK sampling method and time point For rat PK evaluation, approximately 0.25 mL of blood was collected continuously over 6 hours via a surgically placed carotid artery catheter at eight time points (5, 15, 30, and 45 minutes after dosing, and 1, 2, 4, and 6 hours after dosing) and immediately transferred to tubes containing K2EDTA on ice.For dog PK evaluation, approximately 0.5 mL of blood was collected via a superficial vein before dosing and 5 minutes (IV injection and SC injection only), 15 minutes, and 30 minutes after dosing, and 1, 2, 4, 8, 16, 24, 48, and 72 hours after dosing, into tubes containing K2EDTA with 10 mM dichlorvos as an anticoagulant and stabilizer, respectively. For non-human primate PK evaluation, blood samples (approximately 1 mL) were collected by venipuncture of the femoral vein before dosing and at 5, 15, and 30 minutes and 1, 1.5, 2, 4, 8, and 12 hours after dosing into tubes containing 10 mM dichlorvos in K2EDTA.

[0190] Metabolite Profiling and Identification: In experiments conducted in rats, blood samples were collected before dosing and at 15, 30, and 1, 2, 4, 6, and 10 hours after dosing. Blood samples from dogs were collected before dosing and at 5, 30, and 1, 2, 4, 8, 12, and 24 hours after dosing. Monkey blood samples were collected before dosing and at 5, 15, 30, and 1, 1.5, 2, 4, 8, and 12 hours after dosing. A mixture of acetonitrile:methanol:mic acid (50:50:0.1, v / v / v) was added to the pooled plasma samples at a volume three times that of plasma, vortexed for 3 minutes, and centrifuged at 3000 rpm for 10 minutes at 4°C. The supernatant was evaporated in a water bath at 25°C under a stream of nitrogen gas. The dried residue was reconstituted in acetonitrile:methanol:water:mic acid (15:15:70:0.1, v / v / v / v), centrifuged at 3000 rpm for 10 min, and then transferred to ultra-high performance liquid chromatography (UHPLC) vials.

[0191] For plated human hepatocytes, after incubation with 4-OH-DiPT, all samples were quenched with an equal volume of acetonitrile:methanol:mic acid (50:50:0.1, v / v / v). The quenched samples were mixed by pipetting, collected, and stored at or below -70°C until analysis by liquid chromatography-tandem mass spectrometry. The processing of the positive control lorazepam sample was identical to that of the 4-OH-DiPT. Plated human hepatocyte incubation samples were immediately frozen at or below -70°C and thawed to room temperature before sample processing. A 500 μL aliquot of each sample was transferred to a matrix tube (1.4 mL), followed by the addition of 500 μL of the solvent mixture acetonitrile:methanol:mic acid (50:50:0.1, v / v / v). The resulting mixture was vortex mixed for 2 minutes and centrifuged at 3000 rpm for 10 minutes. Supernatants from triplicate incubations were pooled to generate pooled samples (1.5 mL / each) for LC-MS analysis.

[0192] For all metabolite identification and profiling experiments, RE104 and its metabolites were identified and profiled by UHPLC on a Shimadzu Nexera™ UHPLC system coupled with a SCIEX 6600 Triple TOF® high-resolution mass spectrometer. Mass spectrometry was performed using an electrospray ionization source operating in positive ion mode with full-scan TOF MS and MS / MS modes. Proposed metabolite structures were based on the accurate masses of the observed molecular ions and their associated mass fragmentation patterns. The fragmentation patterns of the proposed metabolites were compared with the common fragment ions obtained from RE104 and 4-OH-DiPT reference standards. Metabolite Pilot software from Sciex was used to search for unknown metabolites. Potential metabolite molecular ions were searched based on metabolic pathways.

[0193] The percentage of RE104 and its metabolites relative to the total area of ​​compound-related substances was obtained by integrating the extracted ion chromatogram peaks on the full-scan mass chromatogram. The percentage of each component's peak area relative to the total peak area was determined using the following formula: component % peak area = (component peak area × 100%) / total integrated peak area of ​​compound-related substances.

[0194] While the present invention has been described with reference to exemplary embodiments and examples, this description is not intended to be construed in a limiting sense. Accordingly, various modifications of the exemplary embodiments, as well as other embodiments of the invention, will be apparent to those skilled in the art upon reference to this description. It is therefore intended that the appended claims cover any such modifications or embodiments.

[0195] All publications, patents, and patent applications mentioned in this specification are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

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[0197] Definitions and Interpretations The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the invention. The embodiments have been chosen and described to best explain the principles and practical applications of the invention and to enable those skilled in the art to understand the invention in various embodiments with various modifications suited to the particular uses contemplated. To the extent that the following description refers to a specific embodiment or a particular use of the invention, it is intended for purposes of illustration only and not to limit the claimed invention.

[0198] The corresponding structures, materials, acts, and equivalents of all means or steps and functional elements in the claims appended hereto are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed.

[0199] References herein to "one embodiment," "an embodiment," or the like indicate that the described embodiment may include a particular aspect, feature, structure, or characteristic, but not all embodiments necessarily include that aspect, feature, structure, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referenced elsewhere in this specification. Furthermore, when a particular aspect, feature, structure, or characteristic is described in connection with an embodiment, it is within the knowledge of one of ordinary skill in the art to combine, affect, or connect such aspect, feature, structure, or characteristic with other embodiments, regardless of whether such connection or combination is explicitly described. In other words, any element or feature may be combined with any other element or feature in different embodiments unless there is an obvious or inherent incompatibility between the two or unless specifically excluded.

[0200] It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a predicate for the use of exclusive terms such as "solely," "only," and the like in connection with the recitation of claim elements or the use of a "negative" limitation. The terms "preferably," "preferred," "preferably," "optionally," "may," and similar terms are used to indicate that the recited element, item, condition, or step is an optional (but not essential) feature of the invention.

[0201] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated.

[0202] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to providing a written description, all ranges recited herein also encompass any and all possible subranges and combinations thereof, as well as the individual values, particularly integers, that make up the ranges. A recited range (e.g., weight percent or carbon group) includes each specific value, integer, decimal, or identity within the range. Any recited range can be readily recognized as fully descriptive and allows for division of the same range into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range recited herein can be readily broken down into a lower third, middle third, upper third, etc.

[0203] Also, as will be understood by one of ordinary skill in the art, all ranges set forth herein, and all terms such as "between," "up to," "at least," "greater than," "less than," "more than," "greater than or equal to," etc., are inclusive of the recited number(s), and such terms refer to ranges that can be subsequently broken down into subranges as described above.

[0204] List of Embodiments The following is a list of non-limiting embodiments of the present invention. 1. Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is present in a dose of about 30 mg to about 50 mg, calculated as the free base, together with a pharmaceutically acceptable carrier. 2. Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is present in a dose of 30 mg or 40 mg, calculated as the free base, together with a pharmaceutically acceptable carrier. 3. The injectable composition of embodiment 1 or embodiment 2, wherein the compound of formula (I) is its hydrochloride salt. 4. The injectable composition of embodiment 2, wherein the compound of formula (I) is its hydrochloride salt present in a dose of 33 mg or 44 mg. 5. The injectable composition according to any one of embodiments 1 to 4, wherein the injectable composition is a subcutaneous injectable composition. 6. A method for treating a psychiatric disorder, comprising administering to a patient in need thereof a compound of formula (I): [ka] Administering a pharmaceutical composition comprising a compound of formula (I). 7. A method for treating a psychiatric disorder, comprising administering to a patient in need thereof a compound of formula (I): [ka] Administering a pharmaceutical composition comprising a compound of formula (I). 8. The method of embodiment 6 or embodiment 7, wherein the compound of formula (I) is its hydrochloride salt. 9. The method of embodiment 7, wherein the compound of formula (I) is its hydrochloride salt present in a dose of 33 mg or 44 mg. 10. A method for treating a psychiatric disorder, comprising administering to a patient in need thereof a compound of formula (I): [ka] Administering a pharmaceutical composition comprising a compound of formula (I). 11. The method of any one of embodiments 6 to 10, wherein the compound of formula (I) has a duration of action of about 2.5 hours to about 4.5 hours after administration. 12. The method of any one of embodiments 6-10, wherein the compound of formula (I) has a duration of action of about 3.5 hours or 3.7 hours after administration. 13. The compound of formula (I) has a C in the range of about 1000 ng / mL to about 2000 ng / mL in a patient. max 13. The method of any one of embodiments 6 to 12, comprising: 14. The compound of formula (I) has a C in the range of about 1500 ng / mL to about 1800 ng / mL in a patient. max 13. The method of any one of embodiments 6 to 12, comprising: 15. Compounds of formula (I) produce a T in the range of about 20 minutes and 30 minutes in patients max 15. The method of any one of embodiments 6 to 14, comprising: 16. A compound of formula (I) induces a T in the range of about 15 minutes in a patient max 15. The method of any one of embodiments 6 to 14, comprising: 17. The compound of formula (I) after administration is [ka] and the compound of formula (II) has a C in the range of about 100 ng / mL to about 300 ng / mL in the patient. max 17. The method of any one of embodiments 6 to 16, comprising: 18. The compound of formula (I) after administration is [ka] and the compound of formula (II) has a C in the range of about 120 ng / mL to about 300 ng / mL in the patient. max 17. The method of any one of embodiments 6 to 16, comprising: 19. The compound of formula (I) after administration is [ka] and the compound of formula (II) has a T in the range of about 60 minutes to about 150 minutes in the patient. max 19. The method of any one of embodiments 6 to 18, comprising: 20. A compound of formula (I) is administered to produce a compound of formula (II) [ka] and the compound of formula (II) is converted to a compound of formula (II) having a T in the range of about 60 minutes to about 80 minutes in the patient. max 19. The method of any one of embodiments 6 to 18, comprising: 21. The method of any one of embodiments 6 to 20, demonstrating that the mean MEQ30 score in the patients is at least 50%. 22. The method of any one of embodiments 6 to 20, demonstrating that the mean MEQ30 score in the patients is at least 60%. 23. The method according to any one of embodiments 6 to 22, wherein the pharmaceutical composition is an injectable pharmaceutical composition. 24. The method according to any one of embodiments 6 to 22, wherein the pharmaceutical composition is a pharmaceutical composition for subcutaneous injection.

[0205] [Table 1] Abbreviations: BSA = body surface area; HED = human equivalent dose; NOAEL = no observed adverse effect level; MRSD = maximum recommended safe starting dose. a.HED calculated based on animal to human BSA conversion factors as detailed in FDA Guidance, 2005. b. Based on a weight of 60 kg. c.1.62m 2 Based on BSA. d.NOAEL = 10 mg / kg in female rats e.NOAEL = 8 mg / kg in female and male dogs.

[0206] [Table 2] Doses are shown in the table as RE104 HCl. These doses are equivalent to 5, 10, 20, and 30 mg of RE104-zwitterion. b. Example calculation for Cohort 1: 97.2 mg / 5 mg = 19-fold lower than the scaled NOAEL dose.

[0207] [Table 3]

[0208] [Table 4] Abbreviations: 5-MeO-DMT = 5-methoxy-N,N-dimethyltryptamine; AE = adverse event; DMT = dimethyltryptamine; EOS = end of study; ET = early termination; LSD = lysergic acid diethylamide (LSD); OTC = over-the-counter; PK = pharmacokinetics.

[0209] [Table 5-1] [Table 5-2] Sources: https: / / www.uspharmacist.com / article / drug-induced-serotonin-syndrome and https: / / www.uptodate.com / contents / serotonin-syndrome-serotonin-toxicity#H3

[0210] [Table 6-1] AEs by preferred duration (participants with a score of -2 or greater across all dose levels)

[0211] [Table 6-2] SAE, serious adverse event

[0212] [Table 7] MEQ, Mystical Experiences Questionnaire;

[0213] [Table 8] C max , maximum plasma concentration; CV, coefficient of variation; t 1 / 2 , half-life; T max , time to maximum plasma concentration.

[0214] Supplementary table

[0215] [Table 9] 4-OH-DiPT, 4-hydroxy-N,N-diisopropyltryptamine; AUC0--, area under the curve from dose extrapolated to infinity; AUC0-last, area under the curve from dose to tlast; Cmax, maximum observed concentration after parenteral administration; fm, fraction metabolized (AUC iv [parent] プロドラッグ / AUC iv [parent] 親at equimolar doses); IV, intravenous; MRT0--, mean residence time from the time of dosing extrapolated to infinity; PO, per os (oral); NA, not applicable; SC, subcutaneous; SD, standard deviation; t1 / 2, half-life; tmax, time of maximum concentration observed after parenteral administration. a Calculated from AUC0--(IV) for 4-OH-DiPT (152 h·ng / mL) administered at an equimolar dose.

[0216] [Table 10] 4-OH-DiPT, 4-hydroxy-N,N-diisopropyltryptamine; AUC0--, area under the curve from time of dosing extrapolated to infinity; AUC0-last, area under the curve from time of dosing to time; C0, concentration extrapolated to time zero after IV dosing; CL, clearance; Cmax, maximum observed concentration after parenteral administration; F, oral bioavailability ([dose lV xAUC PO [ / [dose PO xAUC IV [x100]; IV, intravenous; MRT0--, mean residence time from the time of dosing extrapolated to infinity; PO, per os (oral); NA, not applicable; SC, subcutaneous; SD, standard deviation; t1 / 2, half-life; tmax, time to maximum observed concentration after parenteral administration; Vss, volume of distribution at steady state.

[0217] [Table 11] AUC 0-t , area under the concentration-time curve from time 0 to the last time point; AUC 0-72h , area under the concentration-time curve from time 0 to 72 h; AUC 0-∞ Area under the concentration-time curve from time 0 to infinity; CL, clearance; C max , maximum plasma exposure; F, bioavailability; IV, intravenous; MR, metabolic rate; NA, not applicable; NC, not calculated; SC, subcutaneous; SD, standard deviation, t 1 / 2, elimination half-life;t last , the last measured time; t max , maximum exposure time;V d , volume of distribution. a n-1;AUC 0-∞ and t 1 / 2 is C max A reliable determination could not be made for two men because their later measurable concentrations were below 3. b n=2;AUC 0-∞ and t 1 / 2 is C max A reliable determination could not be made for one man because the subsequent measurable concentration was less than 3. c n=0;AUC 0-∞ and t 1 / 2 is C max A reliable determination could not be made for either man because subsequent measurable concentrations were less than 3.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is present in a dose of about 30 mg to about 50 mg, calculated as the free base, together with a pharmaceutically acceptable carrier.

2. Formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is present in a dose of 30 mg or 40 mg, calculated as the free base, together with a pharmaceutically acceptable carrier.

3. 3. The injectable composition of claim 1 or claim 2, wherein the compound of formula (I) is its hydrochloride salt.

4. 3. The injectable composition of claim 2, wherein the compound of formula (I) is its hydrochloride salt present in a dose of 33 mg or 44 mg.

5. The injectable composition according to any one of claims 1 to 4, wherein the injectable composition is a subcutaneous injection composition.

6. A method for treating a psychiatric disorder, comprising administering to a patient in need of treatment a compound of formula (I): 【Transformation 3】 Administering a pharmaceutical composition comprising a compound of formula (I).

7. A method for treating a psychiatric disorder, comprising administering to a patient in need thereof a compound of formula (I): 【Chemistry 4】 Administering a pharmaceutical composition comprising a compound of formula (I).

8. 8. The method of claim 6 or claim 7, wherein the compound of formula (I) is its hydrochloride salt.

9. 8. The method of claim 7, wherein the compound of formula (I) is its hydrochloride salt present in a dose of 33 mg or 44 mg.

10. A method for treating a psychiatric disorder, comprising administering to a patient in need of treatment a compound of formula (I): 【Transformation 5】 Administering a pharmaceutical composition comprising a compound of formula (I).

11. The method of any one of claims 6 to 10, wherein said compound of formula (I) has a duration of action of about 2.5 hours to about 4.5 hours after administration.

12. 11. The method of any one of claims 6 to 10, wherein said compound of formula (I) has a duration of action of about 3.5 hours or 3.7 hours after administration.

13. The compound of formula (I) has a C in the range of about 1000 ng / mL to about 2000 ng / mL in the patient. ｍａｘ The method according to any one of claims 6 to 12, comprising:

14. The compound of formula (I) has a C in the range of about 1500 ng / mL to about 1800 ng / mL in the patient. ｍａｘ The method according to any one of claims 6 to 12, comprising:

15. The compound of formula (I) has a T in the range of about 20 minutes and 30 minutes in the patient. ｍａｘ The method according to any one of claims 6 to 14, comprising:

16. The compound of formula (I) has a T in the range of about 15 minutes in the patient. ｍａｘ The method according to any one of claims 6 to 14, comprising:

17. The compound of formula (I) after administration has the formula (II) 【Transformation 6】 wherein said compound of formula (II) has a C in the range of about 100 ng / mL to about 300 ng / mL in said patient. ｍａｘ The method according to any one of claims 6 to 16, comprising:

18. The compound of formula (I) after administration has the formula (II) 【Transformation 7】 wherein said compound of formula (II) has a C in the range of about 120 ng / mL to about 300 ng / mL in said patient. ｍａｘ The method according to any one of claims 6 to 16, comprising:

19. The compound of formula (I) after administration has the formula (II) 【Transformation 8】 wherein said compound of formula (II) has a T in said patient in the range of about 60 minutes to about 150 minutes. ｍａｘ The method according to any one of claims 6 to 18, comprising:

20. The compound of formula (I) after administration has the formula (II) 【Chemistry 9】 wherein said compound of formula (II) has a T in said patient in the range of about 60 minutes to about 80 minutes. ｍａｘ The method according to any one of claims 6 to 18, comprising:

21. 21. The method of any one of claims 6 to 20, wherein the mean MEQ30 score in said patients is demonstrated to be at least 50%.

22. 21. The method of any one of claims 6 to 20, wherein the mean MEQ30 score in said patients is demonstrated to be at least 60%.

23. The method according to any one of claims 6 to 22, wherein the pharmaceutical composition is an injectable pharmaceutical composition.

24. The method according to any one of claims 6 to 22, wherein the pharmaceutical composition is a pharmaceutical composition for subcutaneous injection.

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