Tryptamine prodrugs

Abstract

To provide a compound useful for the treatment of mental disorders, such as a depressive condition including unipolar and bipolar depressive conditions, for example, but not limited to, depression, depression from generalized anxiety, major depression, treatment resistant depression, and postpartum depression.SOLUTION: The present invention provides a tryptamine prodrug compound represented by the following formula.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 045,901, filed June 30, 2020, entitled "TRYPTAMINE PRODRUGS," U.S. Provisional Application No. 63 / 109,095, filed November 3, 2020, entitled "TRYPTAMINE PRODRUGS," and U.S. Patent Application No. 17 / 364,047, filed June 30, 2021, entitled "TRYPTAMINE PRODRUGS." The entire contents of U.S. Provisional Application Nos. 63 / 045,901, 63 / 109,095, and U.S. Patent Application No. 17 / 364,047 are incorporated herein by reference.

[0002] Technical Field The present invention relates to novel tryptamine compounds, methods of making and using such compounds, compositions containing such compounds, and uses thereof. [Background technology]

[0003] Tryptamine is a 3-aminoethylindole that binds to and activates serotonin receptors, also known as 5HT receptors. A psychedelic state may be achieved through activation of the 2A form of the serotonin receptor by 5HT2A receptor agonists. The endogenous substance for this receptor is 5-hydroxytryptamine (serotonin). Tryptamine, 3-(2-aminoethyl)indole, is also an endogenous neurotransmitter.

[0004] The serotonin receptor system has been implicated 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 potential as medicines for depression (Carhart-Harris 2018 Psychopharmacology).

[0005] Tryptamine molecules, which produce psychedelic states and have been used in conventional medicine, may have therapeutic potential for treating mood disorders, distress, and depression. For example, ayahuasca is a natural form of dimethyltryptamine (DMT), which, when combined with monoamine oxidase inhibitors, produces a prolonged psychedelic state that can last anywhere from 6 to 15 hours, although this can vary. DMT is also found naturally occurring in small amounts in the brain, where it may act as a neurotransmitter.

[0006] Lysergic acid diethylamide (LSD), a diethylamide derivative of a natural product derived from a fungus found in the grain rye, also produces a psychedelic state lasting up to 8-12 hours.

[0007] Psilocybin is a naturally occurring plant tryptamine found in Psilocybe mushrooms that produces a prolonged psychedelic state, lasting approximately 6-8 hours. Psilocybin was first synthesized in 1958 and is currently being investigated as a treatment for depression. Psilocybin is a prodrug, with psilocin being the active species in vivo. Psilocybin is formed by binding a phosphate ester to the 4-hydroxyl group of psilocin. When Psilocybe mushrooms or the drug are ingested orally, this bond is broken in the intestine:

[0008] [ka]

[0009] Simple monofunctional organic esters of psirosin have been reported. Lower alkoxy radical-modified psirosin has also been described. Sulfate-linked psirosin has been prepared, and other monobasic and dibasic mineral acid-modified psirosin has been described. Acetate psirosin is known and used in underground psychedelic subcultures.

[0010] Psychedelics have been shown to be effective in treating depression, and when combined with psychotherapy, they are even more effective in treating depression (Watts 2020 J Contextual Behavioral Science).

[0011] Since perhaps the earliest documented work by Albert Hoffman, a limited number of tryptamine substances have been synthesized, and structure-activity relationships have been described for a variety of tryptamine substances (Claire 1988).

[0012] Succinate and other diacid functional groups have been explored as components of prodrug delivery systems for water-soluble, injectable forms of hydrophobic or poorly water-soluble drugs, such as testosterone, haloperidol, chloramphenicol, or estradiol (Silverman and Holladay, Chapter 9.2: Prodrugs and Drug Delivery Systems in The Organic Chemistry of Drug Design and Drug Action (3 rdEd), 2014). Tetrahydrocannabinol esters of succinic acid have been patented for the treatment of glaucoma. However, ester cleavage is not always rapid or predictable and may depend on the structure of the drug-binding moiety and therefore must be explored (Anderson 1984 JPharmaSci). Enzymes, esterases, are responsible for the active cleavage of prodrug ester groups in vivo, and species-specific variations in the abundance and specificity of esterases in various tissues complicate exploration and optimization (Bahar 2012 JPharmSci).

[0013] This background is believed to be relevant to a fundamental understanding of the present invention, but is not admitted to be prior art to any aspect of the claimed invention. Summary of the Invention

[0014] The present invention relates to novel tryptamine compounds that are converted to active forms in vivo upon administration and act as 5HT2A agonists. The compounds described herein may be useful in the treatment of psychiatric disorders, such as depressive states, including unipolar and bipolar depressive states, including, but not limited to, depression, depression due to generalized anxiety, major depression, treatment-resistant depression, and postpartum depression.

[0015] In one aspect, the present invention provides a tryptamine or isotryptamine compound represented by formula (I), (II), (III), or (IV):

[0016] [ka]

[0017] [In the formula, (1) R1, R2 and R6 are independently hydrogen, linear or branched alkyl, preferably C 1~5 alkyl, or arylalkyl; (2)R4 is a. -X-CO2H (wherein X is a linear, cyclic or branched, saturated or unsaturated carbon chain (preferably C), optionally substituted with -OH or -CO2H) 1~5 alkyl) or an aromatic ring optionally substituted with alkyl or COH; or b. (R9)(R10)N— (wherein R9 is X—CO2H, X is as previously described, and R10 is a linear or branched alkyl (preferably C) optionally substituted with hydrogen, —OH, or —CO2H) 1~5 alkyl) or arylalkyl); (3) R5 is hydrogen, linear or branched alkyl (preferably C 1~5 alkyl), arylalkyl or O-R5' (wherein R5' is hydrogen, linear or branched alkyl (preferably C 1~5 alkyl); (4) R7 and R8 are a. Independently, hydrogen, linear or branched alkyl (preferably C 1~5 alkyl), or arylalkyl; or b. together form a non-aromatic N-containing heterocycle, optionally substituted with alkyl, preferably wherein the entire heterocyclic structure does not contain more than 12 atoms. or a pharmaceutically acceptable salt or zwitterion thereof.

[0018] In another aspect, the invention includes diacid esters of hydroxytryptamines, such as 4-hydroxy and 5-hydroxytryptamine and 6-hydroxy and 7-hydroxyisotryptamine, and other structural or functional analogs of psychedelic tryptamines.

[0019] In some embodiments, R7 and R8 are the same or different and are linear or branched C 1~4alkyl; or are the same or different and are methyl or isopropyl; for example, R7 and R8 are both methyl, R7 and R8 are both isopropyl, or one of R7 and R8 is methyl and the other is isopropyl.

[0020] In some embodiments, X is a linear C1-C3 chain optionally substituted with OH or -CO2H, for example, X is an unsubstituted linear C3 chain.

[0021] In another aspect, the invention relates to compositions comprising a compound described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises an oral formulation or an injectable formulation.

[0022] 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 due to generalized anxiety, major depression, treatment-resistant depression, and postpartum depression.

[0023] In another aspect, the invention relates to the use of a compound as described herein for treating a psychiatric disorder, or in the manufacture of a medicament for treating a psychiatric disorder, such as depression.

[0024] In another aspect, the present invention relates to a method for preparing a compound described herein, comprising reacting a tryptamine, including hydroxytryptamine or hydroxyisotryptamine, with a cyclic anhydride in a suitable anhydrous solvent. In some embodiments, the solvent comprises a base having a pKa of 4 to 9, and the resulting compound is isolated as a zwitterion. In some embodiments, the tryptamine comprises 4-hydroxy or 5-hydroxytryptamine or 6-hydroxy or 7-hydroxyisotryptamine. In some embodiments, the solvent is pyridine. [Brief explanation of the drawings]

[0025] [Figure 1] FIG. 1 is a graph showing the blood concentration of 4-OH-DiPT (ng / ml) over time following subcutaneous administration of 2 mg / kg N,N-diisopropyltryptamine-4-glutarate. [Figure 2] FIG. 2 is a graph showing the blood concentration of 4-OH-DiPT (ng / ml) after subcutaneous administration of 1.4 mg / kg of N,N-diisopropyltryptamine-4-glutarate. DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description Aspects of the present invention include novel synthetic tryptamine prodrugs. The prodrugs may be useful in the treatment of psychiatric disorders, such as depression, including, but not limited to, major depression, treatment-resistant depression, and postpartum depression. As used herein, the term "psychiatric disorder" includes disorders that a mental health professional may diagnose as psychological or psychiatric disorders, including disorders diagnosed by reference to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0027] The terms "treating," "treat," or "treatment," as used herein, include both preventative, i.e., prophylactic, and palliative, treatment, i.e., mitigating, alleviating, or slowing the progression of a patient's disease, disorder, or condition.

[0028] As used herein, a "psychedelic state" is an altered state of consciousness experienced by an individual, which may include enhanced sensory perception, perceptual distortions or hallucinations, and / or feelings of euphoria or despair. Psychedelic states have been described as being produced by psychedelic drugs, such as DMT (dimethyltryptamine), LSD, mescaline, or psilocybin. Other known psychedelic drugs include 4-hydroxy analogs of N-methyl-N-isopropyltryptamine (MiPT) and N,N-diisopropyltryptamine (DiPT).

[0029] The present invention includes prodrugs of hydroxyindole 5HT2A agonists that still provide beneficial therapeutic effects without inducing or being associated with a psychedelic state. The prodrugs may be used in combination with other therapies known to be effective in treating psychiatric disorders, such as psychotherapy, electroconvulsive therapy, and / or with other pharmaceutical compounds, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MOAIs), or other antidepressants. In preferred embodiments, the treatment may produce a sustained effect, 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 therapy may not be necessary.

[0030] compound As used herein, "compound" includes conformational isomers (e.g., cis- and trans-isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers, and other mixtures of such isomers, as well as pharmaceutically acceptable derivatives or modifications, including solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salts, and prodrugs. The term "prodrug" refers to a compound that is a drug precursor, which releases a drug (or "active form") after administration through some chemical or physiological process in vivo (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 present invention. Thus, the phrase "pharmaceutically acceptable salt" is implicit in the description of all compounds described herein, unless expressly stated to the contrary.

[0031] In some embodiments, the compounds of the present invention may be used to provide highly soluble drugs, including prodrug compounds, that are easily purified, formulated, and stable, preferably with rapid onset of action and excretion for convenient use in clinical settings. In some embodiments, the compounds may be produced as zwitterions, which may be converted to pharmaceutically acceptable salts.

[0032] In some embodiments, the compounds of the present invention preferably undergo rapid cleavage of the prodrug moiety in vivo to yield the active pharmacophore, for example, 90% conversion may occur in less than 4 hours, preferably less than 2 hours, and more preferably less than 1 hour. The prodrug may itself have little, little, or no pharmacological activity, but may be converted to the active compound when administered to a patient, for example, by hydrolytic cleavage.

[0033] Diacid hemiesters of tryptamines, such as psilocin or other hydroxytryptamines or isotryptamines, have not been previously described. Because a prodrug strategy is typically not necessary when the drug is soluble, a prodrug strategy combining a diacid with 4-hydroxytryptamine or 5-hydroxytryptamine likely has not been proposed. Therefore, the diacid hemiester prodrug strategy described herein is believed to be novel and inventive.

[0034] In one aspect, the present invention provides a tryptamine or isotryptamine compound represented by formula (I), (II), (III), or (IV):

[0035] [ka]

[0036] [In the formula, (1) R1, R2 and R6 are independently hydrogen, linear or branched alkyl, preferably C 1~5 alkyl, or arylalkyl; (2)R4 is a. -X-CO2H (wherein X is a linear, cyclic or branched, saturated or unsaturated carbon chain (preferably C), optionally substituted with -OH or -CO2H) 1~5 alkyl) or an aromatic ring optionally substituted with alkyl or COH); or b. [ka]

[0037] (wherein R9 is X-CO2H, X is as defined in (2)a), and R10 is a linear or branched alkyl (preferably C 1~5 alkyl) or arylalkyl); (3) R5 is hydrogen, linear or branched alkyl (preferably C1~5 alkyl), arylalkyl, or O-R5' (wherein R5' is hydrogen, straight or branched alkyl (preferably C 1~5 alkyl); (4) R7 and R8 are a. Independently, hydrogen, linear or branched alkyl (preferably C 1~5 alkyl), or arylalkyl; or b. taken together form a non-aromatic N-containing heterocycle, optionally substituted with alkyl, preferably wherein the entire heterocyclic structure does not contain more than 12 atoms, such as pyrrolidine (NC ring), piperidine (NC ring), or morpholine (NC O ring). or a pharmaceutically acceptable salt or zwitterion thereof.

[0038] "Alkyl," by itself or as part of another substituent, refers to a saturated, branched, straight-chain, or cyclic monovalent hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent alkane. The term "alkyl" includes cycloalkyl. Representative alkyl groups include, but are not limited to, methyl; ethyl; propyls (e.g., propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl); butanyls (e.g., butan-1-yl, butan-2-yl (sec-butyl), 2-methylpropan-1-yl (isobutyl), 2-methylpropan-2-yl (t-butyl), cyclobutan-1-yl), and the like. In some embodiments, an alkyl group is a group having 1 to 20 carbon atoms (C1-C6). 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C1 to C 10 In yet other embodiments, an alkyl group contains 1 to 6 carbon atoms (C1-C6 alkyl) or 1 to 4 carbon atoms (C1-C4). C1-C6 alkyl is also known as "lower alkyl."

[0039] The term "arylalkyl" is a term of the art and is used herein to refer to an alkyl group substituted with an aryl group, e.g., C1~6 An aryl group is linked to the main molecule through an alkyl group. An example of an arylalkyl is a benzyl group, i.e., a phenylmethyl group.

[0040] "Substituted," when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each independently replaced with the same or different substituents. The term "substituted" specifically contemplates and allows for one or more substituents common in the art. However, those skilled in the art generally understand that substituents should be selected so as not to adversely affect the useful properties of the compound or adversely interfere with its function.

[0041] The term "optionally substituted" refers to the presence or absence of a substituent group. That is, it means "substituted or unsubstituted." For example, optionally substituted alkyl includes both unsubstituted and substituted alkyl. The substituents used to substitute the specified group may be further substituted, typically with one or more of the same or different groups selected from the various groups previously described.

[0042] These prodrug structures are converted to the active hydroxyindole 5HT2A agonists after hydrolysis or metabolism of the ester functionality R4-CO-.

[0043] In some non-limiting examples, the compounds include diacid esters of the tryptamine structure, such as 4-hydroxy-N,N-dimethyltryptamine (psirosin or 4-OH-DMT), 4-hydroxy-N,N-diethyltryptamine (4-OH-DET), 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT), 4-hydroxy-N-methyl-N-isopropyltryptamine (4-OH-MIPT), 5-hydroxy-N,N-dimethyltryptamine, 4-methyl-5-hydroxy-N,N-dimethyltryptamine, and 4-hydroxy-5-methyl-N,N-dialkyltryptamine. In some embodiments, the compounds include 4- and 5-substituted hemisuccinate, hemiglutarate, and citrate esters of 4-hydroxy derivatives of N,N-dimethyltryptamine (psirosin), N,N-diisopropyltryptamine (4-OH-DiPT), or N-methyl-N-isopropyltryptamine (4-OH-MiPT).

[0044] In some embodiments, the compound comprises a compound of Formula I, II, III, or IV, where R1, R2, R5, and R6 are each hydrogen; X is a linear C1-4 alkyl; and R7 and R8 are each methyl. In preferred embodiments, the compound is a compound of Formula I or II, where X is a C2 alkyl, thus forming the 4- or 5-hemisuccinate ester of psilocin.

[0045] In some embodiments, the compound includes a compound represented by Formula I, II, III, or IV, where R1, R2, R5, and R6 are each hydrogen; X is a linear C1-C4 alkyl chain; and R7 and R8 are each isopropyl. In some embodiments, the compound is a compound represented by Formula I or II, where X is a C2 alkyl, thus forming a hemisuccinate ester of 4- or 5-hydroxydiisopropyltryptamine. In some embodiments, the compound is a compound represented by Formula I or II, where X is a C2 alkene, thus forming a hemifumarate ester of 4- or 5-hydroxydiisopropyltryptamine. In some embodiments, the compound is a compound represented by Formula I or II, where X is a C3 alkyl chain, thus forming a hemiglutarate ester of 4- or 5-hydroxydiisopropyltryptamine.

[0046] In some embodiments, R7 and R8 are each selected based on maintaining or enhancing the compound's ability to induce a psychedelic state. It is known that if R7 or R8 is longer than C4, the psychedelic activity of tryptamine is reduced. However, if such compounds are 5HT2A agonists that can produce beneficial therapeutic effects without a psychedelic state, they are also within the scope of the present invention.

[0047] In some embodiments, the compounds of the present invention are diacid zwitterions. Thus, when X is a linear, saturated alkyl, the diacid may include common linear alkyl α,ω-diacids, including, but not limited to, oxalic acid, malonic acid, succinic acid, glutaric acid (pentanedioic acid), adipic acid (hexanedioic acid), pimelic acid (heptanedioic acid), and suberic acid (octanedioic acid). In some embodiments, when X is a linear alkene, the diacid may include acids such as maleic acid, fumaric acid, or glutaconic acid. In other embodiments, the diacid may include branched acids such as citraconic acid, mesaconic acid, and 2,2-dimethylsuccinic acid; substituted acids such as tartronic acid, 2-(2-hydroxyethyl)-malonic acid, and α-hydroxyglutaric acid; citric acid; or aryl diacids, which may have organic substituents on the aromatic ring, such as phthalic acid, isophthalic acid, and p-phthalic acid.

[0048] In some embodiments, the compound may be one of the following: (1) Psilocin-4-succinate [ka]

[0049] (2) N,N-Diisopropyltryptamine-4-succinate [ka]

[0050] (3) N,N-Diisopropyltryptamine-4-fumarate [ka]

[0051] (4) Psilosin-4-methyl-5-succinate [ka]

[0052] (5) N,N-dimethylisotryptamine-6-succinate [ka]

[0053] (6) N,N-Diisopropyltryptamine-4-glutarate [ka]

[0054] (7) N-methyl-N-isopropyltryptamine-4-glutarate [ka]

[0055] (8) Psilosin-4-glutarate [ka]

[0056] (9) N,N-Diethyltryptamine-4-glutarate [ka]

[0057] (10) N,N-Diethyltryptamine-4-succinate [ka]

[0058] (11) N,N-Diisopropyltryptamine-4-(3,3-dimethylglutarate) [ka]

[0059] In some embodiments, the diacid-modified tryptamine or isotryptamine is stable (oxidation and hydrolysis) and easily synthesized and purified. The diacid-modified tryptamine or isotryptamine preferably exhibits greater solubility in biological matrices than drugs without the diacid modification, making it an excellent drug candidate. Furthermore, the diacid-modified tryptamine preferably exhibits a relatively high rate of hydrolysis in vivo, allowing for rapid conversion of the prodrug to the active drug form. This can result in improved and desirable pharmacokinetics of the prodrug, including a more reproducible pharmacokinetic profile. These properties may depend on the nature of the indole, various substituents attached to the indole, and the nature of the diacid ester. Stability and hydrolysis rate can be determined experimentally.

[0060] In some embodiments, the compound may comprise a carbamate ester of tryptamine, where R4 is (R9)(R10)N-, where R9 and R10 are carbamate residues as defined above. In some embodiments, the carbamate functionality comprises zwitterionic amino-functionalized mono- or dicarboxylic acids linked via a carbamate ester, including, but not limited to, zwitterionic compounds such as: natural and unnatural neutral or anionic amino acids, such as glycine, alanine, leucine, isoleucine, serine, threonine, glutamic acid, aspartic acid; - linear alkyl α,ω-amino acids, such as 3-aminopropionic acid, 4-aminobutyric acid; - Other branched and aromatic amino acids, such as 4-aminobenzoic acid Examples include:

[0061] In some embodiments, the present invention may include zwitterionic compounds in which R4 contains more than one non-ester carboxy functional group, such as the citrate ester derivative of 4-hydroxytryptamine (V) or the glutamic acid carbamate ester of 4-hydroxytryptamine (VI):

[0062] [ka]

[0063] In some embodiments, zwitterionic compounds are preferably stable at neutral or slightly acidic pH. Acylation of the indole hydroxyl functionality specifically prevents oxidation reactions typical of substituted phenolic compounds and indoles (Manevski 2010 Drug Metabolism and Disposition and Napolitano 1989 Tetrahedron), while maintaining solubility. In some embodiments, zwitterions have sufficient solubility (>30 mg / ml) at neutral and pharmaceutically acceptable pH values ​​(3-8) to achieve the desired potency / efficacy. Traditionally, tryptamine, a non-prodrug pharmacophore, must be maintained in an acidic medium to achieve good solubility and stability. Acidic media can prevent its use as an injectable formulation and can cause irritation.

[0064] Zwitterionic embodiments may also allow for convenient purification and isolation by recrystallization from common pharmaceutical solvents such as water, methanol, ethanol, propanol, isopropanol, acetone, or mixtures thereof.

[0065] The diacid moiety is metabolically cleaved in vivo, providing the active ingredient with sufficient dosage and kinetics to achieve the psychedelic state believed necessary for the treatment of depressive conditions, e.g., for use in psychedelic-related psychotherapy. This is particularly advantageous in designing convenient formulations that produce psychedelic experiences lasting less than 8 hours, preferably less than 6 hours, and more preferably less than 4 hours. In this sense, the need for hydrolysis represents an additional step that can slow the onset of psychotropic properties compared to injection of the free drug (where the hydroxyl functionality is not acylated). A slightly slower onset may be preferable in some cases, to avoid a sudden onset that can cause anxiety, especially in psychedelic-naive patients. Thus, in preferred embodiments, the rate of onset may be controlled by the rate of metabolism, which may be a function of the ester and the target enzyme required for hydrolysis.

[0066] In some embodiments, certain prodrug diacid moieties, such as succinate esters, may reduce the potential for abuse via inhalation or nasal absorption. As zwitterions, they are unlikely to be rapidly absorbed by tissues lacking esterase activity. Furthermore, zwitterions are unlikely to be directly absorbed into the brain via passive mechanisms. The rate of cleavage in the intestine is slower, potentially resulting in slower absorption than non-acylated forms, potentially delaying the "rush" and peak velocity that may be desired by those with intent to abuse.

[0067] Manufacturing method The compounds described herein can be synthesized using the methods described below or similar methods, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereof as will be appreciated by those skilled in the art. Preferred methods may include, but are not limited to, those described below. Reactions are carried out in a solvent or solvent mixture appropriate to the reagents and materials used and suitable for the reaction being affected. Those skilled in the art of organic synthesis will understand that the proposed reaction is consistent with the functionality present on the molecule. This may require judgment within the skill of the art in altering the order of synthetic steps or selecting one processing scheme over another to obtain the desired compounds of the invention.

[0068] The protection and deprotection in the following reactions may be carried out by procedures generally known in the art (see, for example, Greene, TW et al., Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)). General methods and functional group transformations in organic synthesis are described in Trost, BM et al., eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, 1 st Edition, Pergamon Press, New York, NY (1991); March, J., Advanced Organic Chemistry.

[0069] 4- and 5-hydroxytryptamine can be prepared by adapting methods described in the art by Baumann et al. (Beilstein 2011, 7, 442), Shulgin (The Vaults of Erowid: TiHKAL: The Chemical Story, by Alexander and Ann Shulgin) and Fricke (Eur Chem J 2019, 25, 897), as well as U.S. Pat. No. 3,075,992 and Chen (JOC 1994, 3738).

[0070] For example, the succinate prodrug compounds described herein may be prepared using the synthetic scheme outlined in Scheme 1, starting with the corresponding hydroxyindole and dianhydride. Reaction conditions, e.g., temperature, time, solvent, and procedures are selected and procedures chosen that may be suitable for the experimental conditions recognized by those skilled in the art. Restrictions on substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and in such cases, alternative or similar methods must be used. [ka] As would readily occur to one skilled in the art, other diacid prodrugs may be prepared using other diacid anhydrides.

[0071] Glutaric anhydride may be used to prepare glutarate ester prodrug compounds using Scheme 2 below: [ka]

[0072] Those skilled in the art can easily select appropriate conditions and solvents. The reaction with the dianhydride can occur in dichloromethane and triethylamine, or pyridine. In some embodiments, the solvent contains a base with a pKa of 4 to 9. When pyridine is used, the product precipitates directly from the reaction mixture in pure form as a zwitterion.

[0073] The solid zwitterion may be converted to a suitable salt, such as the hydrochloride salt, by addition of anhydrous HCl (gas) in a suitable solvent or by trituration in anhydrous ethereal HCl or dioxane HCl.

[0074] The synthesis of diacid hemiester prodrugs may also be carried out using a variety of other methods and techniques known to those skilled in the art (Rautio, Nature Rev in Drug Discovery 2018, 17, 559), for example, using an anhydride or doubly activated form of the diacid, such as a dichloride, di-N-hydroxysuccinimide (using dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide, and DMAP), di-imizadolide (using carbonyl dimidizole), or other activated form of the diacid bearing the hydroxy form of the active heterocyclic species. When using a doubly activated form, it is preferable to use a 2- to 25-fold excess of the doubly activated diacid to avoid covalently linking two tryptamines to the diacid.

[0075] Similarly, one skilled in the art can apply these methods to 6- or 7-hydroxyisotryptamine.

[0076] Formulations and Compositions The present invention also provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the 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, it is preferable to administer the compounds as a pharmaceutical composition.

[0077] The term "pharmaceutical composition" refers to a composition comprising a compound of the present invention in combination with at least one pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a vehicle generally accepted in the art for the delivery of bioactive agents to animals, particularly mammals, and includes, depending on the mode of administration and the nature of the dosage form, adjuvants, excipients or vehicles, such as diluents, osmotic agents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, flavoring agents, antibacterial agents, antifungal agents, lubricants, polymers, solubilizers, stabilizers, antioxidants and dispersing agents. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.

[0078] As used herein, "oral" administration includes swallowing for ingestion into the stomach or intestines, 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, oral administration such as tablets, capsules (each of which may contain sustained-release or extended-release formulations), pills, powders, granules, elixirs, suspensions (including nanosuspensions, microsuspensions, and spray-dried dispersions), syrups, and emulsions; sublingual administration (e.g., as thin films, effervescent tablets, or tablets that spontaneously dissolve under the tongue); parenteral administration such as subcutaneous, intravenous, intramuscular injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions, suspensions); nasal administration, including administration to the nasal mucosa, for example, by inhalation spray; or rectal administration, such as a suppository.

[0079] Dosage regimens for the compounds described herein will, of course, vary depending on known factors, such as the pharmacokinetic and pharmacological properties of the particular agent and its form and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; type of concurrent treatment; frequency of treatment; route of administration, the patient's renal and hepatic function; and the desired effect. The selected dosage may depend on additional factors, including the activity of the particular compounds and pharmaceutical compositions described herein, whether an ester, salt, or amide of the compound is used, the time of administration, the rate of excretion or metabolism of the 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 compound used, and similar factors well known in the medical arts.

[0080] Generally, the dosage of a prodrug for treatment, when used for its intended effect, is about 0.001 to about 500 mg per administration, preferably about 0.01 to about 200 mg per administration, and most preferably about 0.1 to about 50 mg per administration, e.g., 10, 20, 30, 40, 50, 100, or 200 mg. For intravenous administration, the most preferred dosage is about 0.01 to about 10 mg / kg / minute at a constant rate infusion.

[0081] The compounds of the present invention may be administered once daily, or the total daily dose may be divided into multiple doses, for example, two, three, or four times daily. Alternatively, they may be administered weekly, biweekly, or monthly. In preferred embodiments, only one or two doses are required for antidepressant effect, which may last for one, two, three, or six months, or longer.

[0082] In the case of tablets, 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. Tablets generally contain a disintegrant in addition to the drug. 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.

[0083] Binders are generally used to give tablets cohesion.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 calcium hydrogen phosphate dihydrate.

[0084] Tablets may also contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surfactants typically represent 0.2% to 5% by weight of the tablet, and glidants typically represent 0.2% to 1% by weight of the tablet.

[0085] Tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricant generally comprises 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight.

[0086] Other conventional ingredients include antioxidants, colorants, flavorings, preservatives and taste-masking agents.

[0087] A typical tablet contains 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.

[0088] Tablet blends may be compressed directly or by roller to form tablets. Alternatively, tablet blends or portions of blends may be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers, and may be coated or uncoated; or may be encapsulated.

[0089] 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), the disclosure of which is incorporated herein by reference in its entirety.

[0090] A typical capsule for oral administration contains at least one 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.

[0091] Liquid preparations include suspensions, solutions, syrups and elixirs. Such preparations may be used as fillers in soft or hard capsules, and usually contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents. Liquid preparations may also be prepared by reconstituting a solid, for example, from a sachet.

[0092] The compound of the present invention can also be directly administered into blood, muscle or internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous.Suitable device for parenteral administration includes syringe with needle (including microneedle), needleless syringe and infusion technology.

[0093] Parenteral formulations are usually aqueous solutions that may contain excipients such as salts and carbohydrates, and pH adjusting or buffering agents (preferably pH 3.0 to 7.0, preferably 4.0 to 6.0, more preferably 4.5 to 5.5), but for some applications they may be more appropriately formulated as sterile non-aqueous solutions or as dry forms to be used with an appropriate vehicle (e.g., sterile pyrogen-free water or a pre-prepared aqueous buffer solution for extemporaneous mixing). To control osmolality, an osmotic agent may be added.

[0094] Preparation of parenteral kits, eg, by lyophilization, for reconstitution in sterile conditions at the point of care, is readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0095] A typical injectable formulation is prepared by aseptically placing at least one compound of the invention (e.g., 25 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 with an appropriate amount of an osmolality supplement and a pH adjuster to achieve a slightly acidic to neutral pH (e.g., pH 4-7), to produce a mild injectable formulation and maintain the solubility and / or stability of the prodrug.

[0096] For use in any of the above-mentioned dosage forms, the compounds of the present invention may be combined with soluble macromolecules such as cyclodextrins and their suitable derivatives or polyethylene glycol containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability.

[0097] 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 may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as auxiliary additives, i.e., as carriers, diluents, or solubilizers. Most commonly used for these purposes are α-, β-, and γ-cyclodextrins, examples of which can be found in WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148 (the disclosures of which are incorporated herein by reference in their entireties).

[0098] Regardless of the route of administration selected, the compounds of 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 of skill in the art. The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention may be varied so as to provide an amount of the active ingredient effective to achieve the desired therapeutic response for the particular patient, composition, and mode of administration.

[0099] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start administration of a compound of the invention in a pharmaceutical composition at a lower amount than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0100] 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 amount will generally depend upon the factors described above.

[0101] 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 is effective in reducing the severity of depression. Depression severity can be assessed using well-known structured assessment tools, such as the Structured Clinical Interview for 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.

[0102] An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of a drug, compound, or pharmaceutical composition is an amount sufficient to effect prophylactic or therapeutic treatment, directly or indirectly. As understood in a clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another therapy, drug, compound, or pharmaceutical composition.

[0103] Treatment Methods and Uses Treatment with the novel prodrugs of the present invention may substantially alleviate clinical or subclinical depression and may prevent relapse, especially when used in combination with psychotherapy for the treatment of depression. Administration of an effective amount of psilocybin has been shown to rapidly and significantly reduce depressive symptoms, with many subjects achieving remission over a 4-week follow-up period (Davis et al.). Without wishing to be bound by theory, it is believed that the psychedelic state is associated with beneficial effects, although some 5HT2A agonist compounds may produce desired therapeutic effects without the psychedelic state. One aspect of the present invention includes prodrugs of 5HT2A agonists that produce beneficial therapeutic states.

[0104] In general, the present invention includes the use of a compound of the present invention to treat a disease or disorder that may be alleviated by a 5HT2A agonist, the use of a compound of the present invention to manufacture a medicament for treating a disease or disorder that may be alleviated by a 5HT2A agonist, or a method of treating a disease or disorder that may be alleviated by a 5HT2A agonist.

[0105] In some embodiments, the present invention may involve the use of the compounds of the present invention to treat psychiatric disorders. In some embodiments, the present invention may involve the use of the compounds of the present invention to treat depression, particularly drug-resistant depression. Other conditions that can be treated include anxiety disorders, including anxiety in advanced illnesses such as cancer and generalized anxiety disorder, depression, including major depressive disorder, postpartum depression, cluster headache, obsessive-compulsive disorder, personality disorders, including conduct disorder, drug addiction, including alcohol, nicotine, opioid, and cocaine addiction, and other addictions, including gambling disorder, eating disorders and body dysmorphic disorder, chronic pain, or chronic fatigue.

[0106] In some embodiments, the present invention may include a method for treating a psychiatric disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. In one embodiment, a method for treating depression is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. The depression may be drug-resistant depression or major depressive disorder.

[0107] For example, a patient diagnosed with depression may be screened by a trained psychotherapist prior to treatment and then prepared for administration. During administration, a sterile solution of 0.01 to 0.3 mg / kg of a compound of the present invention may be injected into the patient. The patient is preferably seated and blindfolded for the duration of the administration. For safety, a trained medical professional may monitor the entire administration, which may continue for up to 12 hours. In some cases, music may be played for the patient. Once the medical professional determines that the drug has been eliminated, the psychotherapist may assist the patient with any questions regarding the psychedelic experience, after which the patient may be discharged.

[0108] To further mitigate any anxiety that may arise related to treatment, a physician may choose to divide the dose, thereby reducing the initial onset of psychoactive effects before administering the full amount to achieve the full effect.

[0109] In some embodiments, treatment with the compounds of the present invention may be combined with 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 may precede or follow treatment. If treatment precedes treatment, the patient's treatment focus may be focused on the administration of the compounds of the present invention. If treatment follows, psychotherapy is preferably administered within 48 hours of administration of the compounds of the present invention to help the patient process any sensations, emotions, visions, or thoughts that may have occurred during administration of the compounds of the present invention, and to allow the psychotherapist to advise on how best to change thought or behavior patterns to improve antidepressant outcomes. If necessary, psychotherapy may be continued after administration of the compounds of the present invention for, for example, up to another three months to help the patient process any experiences or learnings that occurred during administration. [Example]

[0110] 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.

[0111] When a compound is referred to as glutaroyl or succinoyl, or hemiglutarate or hemisuccinate, it is understood to be the same as succinate or glutarate. For example, the 4-hemiglutarate ester of psirosin is the same as psirosin-4-glutarate or N,N-dimethyltryptamine-4-glutarate. Similarly, the 4-hemiglutarate ester of 4-OH-DiPT is the same as N,N-diisopropyltryptamine-4-glutarate.

[0112] Example 1 4-hemisuccinate ester of psilocin 4-Hydroxyindole was prepared by the method described in Kargbo 2020 ACS Omega or an appropriate adaptation thereof. 4-Acetoxyindole was reacted with oxalyl chloride in methyl tert-butyl ether (MTBE), and the resulting intermediate was quenched with dimethylamine. The indole-oxalyl-dimethylamide was reduced with lithium aluminum hydride (LAH) in tetrahydrofuran (THF) to give 4-acetoxy-3-(N,N-dimethylaminoethyl)indole, which was deprotected using aqueous base to give 4-hydroxydimethyltryptamine (psilocin).

[0113] 4-Hydroxytryptamine was reacted with excess succinic anhydride in dichloromethane (DCM) with triethylamine, catalyzed by N,N-dimethylaminopyridine, to give psilocin-4-succinate. A precipitate formed and was collected after decantation and trituration with DCM. The solid was acidified with hydrochloric acid, purified by chromatography, and recovered after evaporation of the solvent. The structure was confirmed by NMR. The purity was determined by HPLC.

[0114] Example 2 4-Hydroxydiisopropyltryptamine (4-OH-DiPT) 4-Hemisuccinate 4-Acetoxyindole was reacted with oxalyl chloride in MTBE, and the resulting intermediate was quenched with diisopropylamine. The resulting oxalyl amide was reduced with lithium aluminum hydride (LAH) in THF to give 4-acetoxy-3-(N,N-diisopropylaminoethyl)indole, which was then deprotected with aqueous base to give 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. 4-OH-DiPT (5.8 g, 22.3 mmol, 1 equiv.) was dissolved in dichloromethane (28 mL, 5× V) in a 250 mL round-bottom flask equipped with a stir bar and stirred at room temperature. Succinic anhydride (1.3 equiv.) was then slowly added to the stirred solution, and the resulting suspension was stirred overnight at room temperature. The precipitate that formed in the reaction was collected by decantation and trituration with DCM. The solid was acidified with hydrochloric acid, purified by chromatography, and recovered after evaporation of the solvent. The structure was confirmed by NMR. The purity was determined by HPLC.

[0115] Example 3 4-Hemi-Fumarate Ester of 4-OH-DiPT 4-Benzyloxyindole is reacted with oxalyl chloride in diethyl ether in the presence of a Friedel-Crafts catalyst, and the resulting intermediate is quenched with diisopropylamine. The resulting oxalyl amide is reduced with lithium aluminum hydride (LAH) in THF to give 4-benzyloxy-3-(N,N-diisopropylaminoethyl)indole, which is then deprotected using H2 and Pd / C to give 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. This material is reacted with excess activated fumaric acid (N-hydroxysuccinimide) in dichloromethane, followed by quenching any unreacted N-hydroxysuccinimide ester with an acid solution to give 4-fumaroyl-3-(N,N-diisopropylaminoethyl)indole.

[0116] Example 4 5-Hydroxy-4-methyldimethyltryptamine 5-hemisuccinate 4-Methyl-5-hydroxyindole (1) is reacted with benzyl chloride in ACN in the presence of KCO to give 5-benzyloxy-4-methylindole, which is then reacted with oxalyl chloride in diethyl ether in the presence of a Friedel-Crafts catalyst, and the resulting intermediate is quenched with dimethylamine. The resulting oxalyl amide is reduced with lithium aluminum hydride (LAH) in THF to give 4-methyl-5-benzyloxy-3-(N,N-dimethylaminoethyl)indole, which is deprotected with H and Pd / C to give 4-methyl-5-hydroxy-3-(N,N-dimethylaminoethyl)indole. This material is reacted with succinic anhydride in dichloromethane using N,N-dimethylaminopyridine as a catalyst to give 4-methyl-5-succinoyl-3-(N,N-dimethylaminoethyl)indole.

[0117] Example 5 N,N-dimethylisotryptamine-6-succinate Following the method outlined by Glennon (J Med Chem 1984), 6-O-benzyl dimethylisotryptamine is prepared by N-alkylation of 5-BzO-indole using NaH. The benzyl group is removed by catalytic hydrogenation using Pd / C / H to give an OH functionality, which is succinylated in the next step with succinic anhydride to give the title compound.

[0118] Example 6 N,N-Diisopropyltryptamine-4-glutarate Glutaric anhydride (0.205 g, 1.8 mmol, 1.8 equiv) was added to an oven-dried 50 mL round-bottom flask containing 1.2 mL of anhydrous DCM, and the suspension was stirred under Ar. A solution of 1.5 mL of 4-OH-DiPT (0.26 g, 1 mmol, 1 equiv) in anhydrous DCM was added, followed by 4-dimethylaminopyridine (DMAP) (37 mg, 0.3 mmol, 0.3 equiv) and trimethylamine (0.18 mL, 1.3 equiv). The resulting suspension was stirred overnight at room temperature under Ar.

[0119] The mixture was decanted and the solid was triturated with anhydrous DCM (3 mL) with a few drops of anhydrous MeCN. The suspension was acidified with 1 M hydrochloric acid (approximately 1.1 equiv.) and concentrated to dryness. The crude product was purified by C18 reverse-phase column chromatography (40 g, A: 0.05% HCl in HO, B: 0.05% HCl in MeCN).

[0120] The structure was confirmed by NMR. Purity was determined by HPLC (>97%). The solid was resuspended in 1 M HCl-dioxane to form the HCl salt, filtered, washed with ether, and dried. Yield >95%, purity >95%, DSC endotherm 174°C. The solid could be dissolved in water up to 50 mg / ml and lyophilized to form a white "cake."

[0121] Example 7 Hemiester of 3,3-dimethylglutaric acid and 4-hydroxydiisopropyltryptamine Using the stoichiometry and parameters described in Example 6, 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole was reacted with 3,3-dimethylglutaric anhydride in pyridine to give 4-succinoyl-3-(N,N-diisopropylaminoethyl)indole. The precipitate that formed in the reaction was collected by decantation and trituration in THF. The solid was washed with DCM and dried. The structure was confirmed by NMR.

[0122] Example 8 Psilosin-4-glutarate 4-Hydroxydimethyltryptamine (psirosin) was reacted with excess glutaric anhydride in dichloromethane (DCM) containing triethylamine to give psirosin-4-glutarate. In another example, the reaction was carried out in pyridine. In both cases, a precipitate formed, which was recovered after decantation and trituration with THF. The solid was washed with DCM and dried. The structure was confirmed by NMR.

[0123] The reaction product was suspended in 1M HCl-ether to give the corresponding HCl salt product, which was recovered by filtration in high yield and purity.

[0124] Example 9 HCl salt of N,N-diisopropyltryptamine-4-glutarate In a three-necked 1 L round-bottom flask under argon, 4-OH-DiPT (31.8 g, 0.122 mol, 1 equiv.) was dissolved in 160 mL of anhydrous pyridine. After stirring for 15 min, glutaric anhydride (18.1 g, 0.158 mol, 1.3 equiv.) was added in small portions. The resulting suspension was stirred at room temperature overnight.

[0125] Anhydrous DCM (160 mL) was added to the suspension, which was cooled for 2 h at 0° C. The solid was filtered, washed with 60 mL of cold anhydrous DCM and dried overnight.

[0126] The dried solid was triturated with 160 mL of anhydrous DCM, followed by 160 mL of anhydrous THF, and then 160 mL of anhydrous DCM at 0° C. After drying, 33.0 g was obtained in 72% yield and 98.1% HPLC purity. The structure of the zwitterion was confirmed by H-NMR (DMSO-d6) and MS [M+H]. + =375.2.

[0127] In a 100 mL round-bottom flask, 18 mL of anhydrous diethyl ether HCl solution (4 M in dioxane, 2.4 mL, 9.6 mmol, 1.2 equiv.) was slowly added and stirred at room temperature for 10 min. The zwitterion (3.0 g, 8.0 mmol) was added in portions, and the resulting suspension was stirred for 2 h. The solid was filtered off and washed with 6 mL of EtO. The solid was dried to give 3.16 g of the corresponding hemiester tryptamine HCl salt (96% yield, 99.0% HPLC purity, [M+H] + =375.1).

[0128] Example 10 Hemiglutarate ester of psilocin Psilosin is reacted with 1.2 equivalents of glutaric anhydride in warm THF to give silosin-4-glutarate, which is precipitated from the reaction mixture as previously described. The precipitate is collected by filtration, washed with cold 1:1 DCM / THF, and dried.

[0129] Example 11 4-hemimalonate ester of 4-OH-DiPT 4-OH-DiPT was dissolved in pyridine and coupled with excess malonic acid and 1.2 equivalents of DCC for 18 hours at room temperature. The reaction mixture was passed through a flash column (5 parts diatomaceous earth), and the first fraction containing the prodrug compound was isolated by precipitation and washing. Yield: approximately 50%. HPLC purity: >95%.

[0130] Example 12 Relative Rates of Prodrug Hydrolysis in Serum Pooled mixed-gender human plasma (2 ml), mouse plasma, rat plasma, and dog plasma were equilibrated at 37°C. The compound of Example 9 was added to a concentration of 1.0 μg / mL. Aliquots (50 μL) of the mixture were withdrawn at the designated times (0, 0.004, 0.5, 1, 2, and 4 hours) and quenched with 200 μL of methanol / acetonitrile (1:1). Samples were vortexed and stored at -80°C until analysis. Assays were performed in triplicate. Control samples were processed in phosphate-buffered saline (PBS, pH 7.4) and simulated gastric fluid (SGF, pH 2). Sample analysis was performed by HPLC-MS to determine the amount of prodrug and drug in each test sample. Table 1 shows the average residual prodrug concentrations at various time points during the experiment. The experiment demonstrates rapid enzymatic cleavage of the prodrug in plasma and slow non-enzymatic hydrolysis in relevant biological media.

[0131] [Table 1]

[0132] Example 13 Pharmacokinetics in rats The compound obtained in Example 9 was injected (intravenously and subcutaneously) into rats at 1.4-2 mg / kg using a sterile solution (2 mg / ml). Blood samples were collected at 15, 30, 45, 60, 120, 240, and 360 minutes and analyzed for drug and prodrug by LCMS. PK profiles of the prodrug and active species were obtained, and the relative bioavailability was determined for each route of administration.

[0133] PK-PD curves were generated to demonstrate drug activity (Figures 1 and 2). In rodents, prodrug activity was not observed because it was rapidly converted to the active form. PK parameters for iv and sc administration of 4-OH-DiPT are shown in Table 2.

[0134] [Table 2]

[0135] In some cases, head twitch responses (HTR) or wet dog shakes (WDS) were recorded by visual observation and counting of associated muscle twitches. In general, the intensity of the HTR was proportional to the blood concentration of 4-OH-DIPT, with the intensity of the head twitches being greatest at the Tmax of the PK profile.

[0136] FIG. 1 shows the blood concentration of 4-OH-DiPT (ng / ml) over time after subcutaneous administration of 2 mg / kg N,N-diisopropyltryptamine-4-glutarate.

[0137] Pharmacokinetic analysis of 1.34 mg / ml 4-OH-DiPT HCl administered intravenously or subcutaneously was performed in parallel under identical conditions. Figure 2 shows the blood concentration of 4-OH-DiPT (ng / ml) versus time for each dose. The large variability due to the active species is readily apparent for both sc and intravenous administration. PK parameters are shown in Table 3.

[0138] [Table 3]

[0139] Example 17 Pharmacokinetics in Human Volunteers The compound obtained in Example 6 (N,N-diisopropyltryptamine-4-glutarate) is administered to human volunteers at doses of 0.1 to 0.6 mg / kg by subcutaneous injection using a sterile solution (1 mg / ml). Blood samples are collected at 5, 15, 30, 45, 60, 120, 240, 480 minutes, and 24 hours. Samples are analyzed for drug and prodrug by LCMS. Subjective effects are measured using a standardized questionnaire. PK analysis shows a maximum blood concentration (Cmax) approximately 45 minutes after injection. Subjective effects indicate the intensity of psychoactive effects, which correlates with blood levels.

[0140] The compound obtained in Example 2 (4-hemisuccinate ester of 4-OH-DiPT) is administered to human volunteers by oral ingestion of a tablet containing 50 mg of the prodrug. Blood is collected at 5, 15, 30, 45, 60, 120, 240, 480 minutes, and 24 hours. Samples are analyzed for drug and prodrug by LCMS. Subjective effects are measured using a standardized questionnaire. PK analysis shows a Cmax approximately 90 minutes after ingestion. Subjective effects indicate psychoactive intensity, which correlates with blood levels.

[0141] Example 18 Therapeutic Use The compound of Example 6 (N,N-diisopropyltryptamine-4-glutarate) is administered to human patients suffering from depression by intravenous or subcutaneous injection (approximately 25 mg; 0.4-0.5 mg / kg) or oral administration via tablet (approximately 50-200 mg; 0.8-3.2 mg / kg). In another example, the compound of Example 6 (4-hemiglutarate ester of 4-OH-DiPT) is administered similarly. Prior to administration, patients are selected by measuring their depression scores, screened for exclusions (e.g., history of psychiatric illness, adverse cardiac conditions, pregnancy), and finally, encouraged to express their willingness to administer the medication. The medication is administered in a quiet examination room with the patient resting in a tilted but unrestrained position to avoid falls. The patient's eyes are covered, and music is playing. The drug is administered. After 4 hours, the patient reports no longer feeling the effects of the drug and is asked to stand up under supervision. The patient is allowed to stand (with supervision) when they feel normal and to move around when they feel in control. After one hour, the patient is sent home. Within the next 24 hours, the patient returns to the office and sees the psychotherapist to discuss medication in detail. The patient completes a depression score questionnaire and is sent home again. The patient is seen at regular intervals for recurrence of depressive symptoms.

[0142] Example 19 Injectable Formulation Kit Prepare a vial with 25 mg of the compound in Example 6 as the hydrochloride salt (sterile powder or lyophilized). In a separate vial, add 1 ml of a sterile-filtered solution of 70 mM NaHPO. The final pH of the solution is 4.0-5.0. These two components constitute a kit for reconstitution of the drug product for subcutaneous injection at the point of care.

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[0144] Definitions and Interpretation The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exact or to be limited to the disclosed form of the invention. 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 others skilled in the art to understand the invention in various embodiments with various modifications as suited to the particular uses envisioned. Insofar as the following description relates to specific embodiments or particular uses of the invention, it is intended to be merely illustrative of the claimed invention, not limiting thereof.

[0145] In the claims appended hereto, corresponding structure, materials, acts, and equivalents of all means or step-plus-function elements are intended to include any structure, material, or act for performing a function in combination with other claimed elements as specifically claimed.

[0146] References in the specification to "one embodiment," "an embodiment," or "an embodiment" mean 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. Also, such phrases may, but do not necessarily, refer to the same embodiment referenced elsewhere in the specification. Furthermore, when a particular aspect, feature, structure, or characteristic is described in connection with one embodiment, it is within the knowledge of one of ordinary skill in the art to combine, interact, or link such aspect, feature, structure, or characteristic with other embodiments, whether or not such linkage 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 them or the combination is specifically excluded.

[0147] It is further noted that the claims may be drafted to exclude optional elements. This statement, as such, is intended to serve as a prerequisite for the use of exclusive terminology, such as "only," "only," etc., in connection with the recitation of claim elements or the use of a "negative" limitation. The terms "preferably," "preferably," "select," "optionally," "may," and similar terms are used to mean that the recited element, item, condition, or step is an optional (but not required) feature of the invention.

[0148] 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 to which this term relates.

[0149] As those skilled in the art will understand, for all purposes, particularly in terms of providing a written description, all ranges set forth in this specification also encompass any and all possible subranges and combinations of subranges, as well as the individual values, particularly integers, that make up the range. A recited range (e.g., weight percent or carbon groups) includes each specific value, integer, decimal, or unit within the range. Any recited range is fully descriptive, and it is readily recognizable that the same range can be divided into at least 2, 3, 4, 5, or 10 equal parts. As a non-limiting example, each range set forth in this specification can be readily divided into a lower third, a middle third, an upper third, etc.

[0150] As will also be understood by those of ordinary skill in the art, all ranges and all terms set forth herein, such as "up to," "at least," "greater than," "less than," "over," "greater than or equal to," etc., are inclusive of the recited numbers, and such terms refer to ranges that can be further divided into subranges, as explained above.

Claims

1. The following formula: 【Chemistry 1】 The hydrochloride salt of.

2. 10. The hydrochloride salt of claim 1 in crystalline form.

3. 10. A pharmaceutical composition comprising a therapeutically effective amount of the hydrochloride salt of claim 1 or 2, and one or more pharmaceutically acceptable excipients.

4. 4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is an oral formulation.

5. 4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is an injectable formulation.

6. 6. The pharmaceutical composition of claim 5, wherein the injectable formulation is a solution.

7. 7. The pharmaceutical composition according to claim 6, wherein the solution has a pH of 3.0 to 7.

0.

8. 7. The pharmaceutical composition according to claim 6, wherein the solution has a pH of 4.0 to 6.

0.

9. 7. The pharmaceutical composition according to claim 6, wherein the solution has a pH of 4.0 to 5.

0.

10. A medicament comprising the hydrochloride salt of claim 1 or 2 or the pharmaceutical composition of any one of claims 3 to 9 for treating a psychiatric disorder.

11. 11. The pharmaceutical composition of claim 10, wherein the psychiatric disorder is selected from major depression, treatment-resistant depression, postpartum depression, unipolar depressive state, bipolar depressive state, depression resulting from generalized anxiety, anxiety disorder, anxiety in advanced illness, generalized anxiety disorder, substance dependence, gambling disorder, eating disorder, body dysmorphic disorder, chronic pain, and chronic fatigue.

12. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is major depression.

13. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is treatment-resistant depression.

14. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is postpartum depression.

15. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is a unipolar depressive state.

16. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is bipolar depression.

17. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is depression caused by generalized anxiety.

18. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is an anxiety disorder.

19. The pharmaceutical composition of claim 11, wherein the psychiatric disorder is anxiety in advanced disease.

20. The method of claim 11, wherein the psychiatric disorder is generalized anxiety disorder.

21. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is drug addiction.

22. The pharmaceutical composition of claim 11, wherein the mental disorder is gambling disorder.

23. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is an eating disorder.

24. The pharmaceutical composition according to claim 11, wherein the mental disorder is body dysmorphic disorder.

25. The pharmaceutical composition according to claim 11, wherein the psychiatric disorder is chronic pain.

26. The pharmaceutical composition according to claim 11, wherein the mental disorder is chronic fatigue.

27. The pharmaceutical composition of claim 11, wherein the treatment further comprises administering to the subject a tricyclic antidepressant (TCA), a selective serotonin reuptake inhibitor (SSRI), a selective norepinephrine reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MOAI), or other antidepressant.

28. The pharmaceutical composition of claim 27, wherein the treatment further comprises administering a TCA to the subject.

29. 28. The pharmaceutical composition of claim 27, wherein the treatment further comprises administering an SSRI to the subject.

30. 28. The pharmaceutical composition of claim 27, wherein the treatment further comprises administering an SNRI to the subject.

31. The pharmaceutical composition of claim 27, wherein the treatment further comprises administering an MOAI to the subject.

32. A method for producing N,N-diisopropyltryptamine-4-glutarate hydrochloride, comprising: (a) contacting N,N-diisopropyl-4-hydroxytryptamine with glutaric anhydride in a solvent to obtain N,N-diisopropyltryptamine-4-glutarate or its zwitterion; and (b) contacting N,N-diisopropyltryptamine-4-glutarate or its zwitterion with hydrogen chloride to obtain the hydrochloride salt of N,N-diisopropyltryptamine-4-glutarate. A method comprising:

33. 33. The method of claim 32, wherein the solvent comprises a base having a pKa of 4 to 9.

34. 34. The method of claim 33, wherein the solvent is pyridine.

35. 35. The method of any one of claims 32 to 34, wherein the method further comprises lyophilizing the hydrochloride salt of N,N-diisopropyltryptamine-4-glutarate.

36. 1. A parenteral kit for reconstitution comprising: (a) a vial containing N,N-diisopropyltryptamine-4-glutarate hydrochloride as a sterile powder or lyophilizate; and (b) a vial containing a sterile solution for injection; Includes a kit.

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