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 of related applications This application claims priority to U.S. Provisional Application No. 63 / 045,901 (filed June 30, 2020, title: TRYPTAMINE PRODRUGS), U.S. Provisional Application No. 63 / 109,095 (filed November 3, 2020, title: TRYPTAMINE PRODRUGS), and U.S. Patent Application No. 17 / 364,047 (filed June 30, 2021, title: TRYPTAMINE PRODRUGS). The entire contents of U.S. Provisional Applications No. 63 / 045,901, No. 63 / 109,095, and U.S. Patent Application No. 17 / 364,047 are incorporated into this application by reference.

[0002] Technical field This invention relates to novel tryptamine compounds, methods for producing and using the compounds, compositions containing the compounds, and the uses thereof. [Background technology]

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

[0004] The serotonin receptor system has been linked to 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 medications for depression (Carhart-Harris 2018 Psychopharmacology).

[0005] Tryptamine molecules, which induce psychedelic states and have been used in conventional medicine, may have therapeutic potential for treating mood disorders, distress, and depression. For example, ayahuasca, a natural form of dimethyltryptamine (DMT), can be taken in combination with monoamine oxidase inhibitors to induce a prolonged psychedelic state that can last for 6 to 15 hours, though the effects may fluctuate. DMT is also found to be produced in small amounts in nature in the brain and may act as a neurotransmitter.

[0006] Lysergic acid diethylamide (LSD) is a naturally occurring diethylamide derivative derived from a fungus found in the grain rye, and it also produces a psychedelic state lasting up to 8 to 12 hours.

[0007] Psilocybin is a natural plant-derived tryptamine found in mushrooms of the genus Psilocybe, which induces a prolonged psychedelic state lasting approximately 6-8 hours. First synthesized in 1958, psilocybin is currently being investigated as a treatment for depression. Psilocybin is a prodrug, with psilocin being the active species in vivo. Psilocybin consists of a phosphate ester bonded to the 4-hydroxy group of psilocin; this bond is cleaved in the intestines when Psilocybe mushrooms or the drug are ingested orally.

[0008] [ka]

[0009] Simple monofunctional organic esters of psilocine have been reported. Lower alkoxy radical-modified psilocines have also been described. Sulfate-esterified psilocines have been manufactured, and other mononucleotide and dinucleotide mineral-acid-modified psilocines have been described. Silocine acetate is known and used in underground psychedelic subcultures.

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

[0011] Since the earliest recorded work of Albert Hoffman, the number of tryptamine substances synthesized has been limited. The structure-activity relationships of various tryptamine substances have been described (Claire 1988).

[0012] Succinate esters and other diacid functional groups have been investigated as components of prodrug delivery systems for hydrophobic or poorly water-soluble drugs, such as testosterone, haloperidol, chloramphenicol, or estradiol, in water-soluble and injectable forms (Silverman and Holladay, Chapter 9.2: Prodrugs and Drug Delivery Systems in The Organic Chemistry of Drug Design and Drug Action (3 rdEd), 2014). The tetrahydrocannabinol ester of succinic acid is patented as a therapeutic agent for glaucoma. However, ester cleavage is not always rapid, predictable, and may depend on the structure of the moiety that binds to the drug, and thus must be investigated (Anderson 1984 JPharmaSci). The enzyme esterase is responsible for the active cleavage of prodrug ester groups in vivo, and species differences in the amount and specificity of esterases in various tissues complicate investigation and optimization (Bahar 2012 JPharmSci).

[0013] This background art is considered to be related to a basic understanding of the present invention. However, it is not admitted that these are prior art with respect to any aspect of the present invention claimed herein.

Summary of the Invention

[0014] The present invention relates to novel tryptamine compounds that are converted in vivo to an active form upon administration and act as 5HT2A agonists. The compounds described in this specification may be useful for the treatment of mental disorders, such as depressive states including unipolar and bipolar depressive states, such as, but not limited to, depression, depression resulting from 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]

Chemical formula

[0017] [Wherein, (1) R1, R2 and R6 are independently selected from hydrogen, linear or branched alkyl, preferably C 1~5 alkyl, or arylalkyl; (2) R4 is a. -X-CO2H (where X is a linear, cyclic or branched, saturated or unsaturated carbon chain (preferably a C 1~5 alkyl) optionally substituted with -OH or -CO2H, or an aromatic ring optionally substituted with alkyl or CO2H); or b. (R9)(R10)N- (where R9 is X-CO2H, X is as described above, and R10 is hydrogen, a linear or branched alkyl (preferably a C 1~5 alkyl) or an arylalkyl optionally substituted with -OH or -CO2H); (3) R5 is hydrogen, a linear or branched alkyl (preferably a C 1~5 alkyl), an arylalkyl or O-R5’ (where R5’ is hydrogen, a linear or branched alkyl (preferably a C 1~5 alkyl)); (4) R7 and R8 are a. independently selected from hydrogen, a linear or branched alkyl (preferably a C 1~5 alkyl), or an arylalkyl, or b. together form an optionally alkyl-substituted non-aromatic N-containing heterocycle, preferably the entire heterocyclic structure contains no more than 12 atoms] or a pharmaceutically acceptable salt or zwitterion thereof. [[ID=******]]

[0018] [[ID=******]] [[ID=******]] In another aspect, the invention includes diesters 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 1~4They are alkyl; or they are the same or different, and are methyl or isopropyl; for example, both R7 and R8 are methyl, both R7 and R8 are isopropyl, or one of R7 and R8 is methyl and the other isopropyl.

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

[0021] In another aspect, the present invention relates to compositions comprising the compounds described in this specification and pharmaceutically acceptable excipients. In some embodiments, the compositions include oral formulations or injectable formulations.

[0022] In another aspect, the present invention includes a method for treating a mental disorder, comprising the step of administering an effective amount of a compound described herein. In some embodiments, the mental disorder is a depressive state, including unipolar and bipolar depressive states, such as, but not limited to, depression, depression arising from generalized anxiety, major depressive disorder, treatment-resistant depression, and postpartum depression.

[0023] In another aspect, the present invention relates to the use of the compounds described in this specification in the manufacture of a medicament for treating a mental disorder, or for treating a mental disorder such as depression.

[0024] In another aspect, the present invention relates to a method for producing the compounds described in this specification, 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 drawing]

[0025] [Figure 1] Figure 1 is a graph showing the blood concentration (ng / ml) of 4-OH-DiPT over time after subcutaneous administration of 2 mg / kg of N,N-diisopropyltryptamine-4-glutarate. [Figure 2] Figure 2 is a graph showing the blood concentration (ng / ml) of 4-OH-DiPT after subcutaneous administration of 1.4 mg / kg of N,N-diisopropyltryptamine-4-glutarate. [Modes for carrying out the invention]

[0026] Detailed explanation Aspects of the present invention include novel synthetic tryptamine prodrugs. These prodrugs may be useful in treating depression, including, but not limited to, major depressive disorder, treatment-resistant depression, and postpartum depression. In this specification, the term “mental disorder” includes disorders that a mental health professional may diagnose as a psychological or mental disorder, including disorders diagnosed by referring to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0027] In this specification, the terms “to treat,” “to treat,” or “treatment” encompass both preventive measures, i.e., protective measures, and symptomatic measures, i.e., reducing, mitigating, or slowing the progression of a patient’s disease, disability, or condition.

[0028] In this specification, “psychedelic state” is an altered state of consciousness experienced by an individual, which may include enhanced sensory perception, perceptual distortion or hallucination, and / or euphoria or despair. Psychedelic states are described as being induced 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 comprises a prodrug of a hydroxyindole 5HT2A agonist that induces or is not associated with a psychedelic state and still provides beneficial therapeutic effects. The prodrug may be used in combination with other therapies known to be effective in treating mental disorders, such as psychotherapy and electroconvulsive therapy, and / or concurrently 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 a preferred embodiment, the treatment may produce sustained effects for, for example, 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 In this specification, “compound” includes conformational isomers (e.g., cis, 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 variants, including solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salts and prodrugs. The term “prodrug” refers to a drug precursor compound that, after administration, releases the drug (or “active form”) in vivo through several chemical or physiological processes (e.g., hydrolysis, enzymatic cleavage or hydrolysis, or metabolism that converts it to a desired drug form). The present invention includes, within its scope, pharmaceutically acceptable salts of the compounds of the present invention. Accordingly, the phrase “pharmaceutically acceptable salt” is implicitly included in the description of all compounds described in this specification unless explicitly stated otherwise.

[0031] In some embodiments, the compounds of the present invention may comprise a prodrug compound that is readily purified, formulated, and stable, and may preferably be used to provide a highly soluble drug that rapidly exerts its effects and is excreted for convenient use in clinical settings. In some embodiments, the compounds may be generated as zwitterions, which may be converted to pharmaceutically acceptable salts.

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

[0033] Tryptamine, such as serotonin or other hydroxytryptamine or isotryptamine diacid hemi-esters, have not been described heretofore. Since a prodrug strategy is usually not necessary when the drug is soluble, it is highly likely that a prodrug strategy combining a diacid with 4-hydroxytryptamine or 5-hydroxytryptamine has not been proposed. Therefore, the diacid hemi-ester prodrug strategy described in this specification is considered novel and inventive.

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

[0035] [Chemical formula]

[0036] [Wherein, (1) R¹, R² and R⁶ are each independently hydrogen, linear or branched alkyl, preferably C 1~5 alkyl, or arylalkyl; (2) R⁴ is a. -X-CO₂H (where X is a linear, cyclic or branched, saturated or unsaturated carbon chain (preferably C 1~5 alkyl) optionally substituted with -OH or -CO₂H, or an aromatic ring optionally substituted with alkyl or CO₂H); or b. [Chemical formula] <able to>

[0037] (where R⁹ is X-CO₂H, X is as defined in (2)a, and R¹⁰ is hydrogen, -OH or linear or branched alkyl (preferably C 1~5 alkyl) or arylalkyl optionally substituted with -CO₂H); (3) R⁵ is hydrogen, linear or branched alkyl (preferably C1~5 Alkyl), arylalkyl, or O-R5' (where R5' is hydrogen, linear or branched alkyl (preferably C) 1~5 Alkyl) is) is; (4) R7 and R8 are, a. Independently, hydrogen, linear or branched alkyl (preferably C 1~5 Selected from alkyl or arylalkyl, b. Together, preferably forming a non-aromatic nitrogen-containing heterocyclic ring which may be alkyl-substituted, such as pyrrolidine (NC4 ring), piperidine (NC5 ring), or morpholine (NC4O ring), where the entire heterocyclic structure does not contain more than 12 atoms. or containing a pharmaceutically acceptable salt or zwitterion thereof.

[0038] "Alkyl," either by itself or as part of another substituent, refers to a saturated, branched, linear, or cyclic monovalent hydrocarbon radical obtained by removing one hydrogen atom from a single carbon atom of a parent alkane. The term "alkyl" includes cycloalkyls. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl (e.g., propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl); butanyls (e.g., butane-1-yl, butane-2-yl(sec-butyl), 2-methylpropan-1-yl(isobutyl), 2-methylpropan-2-yl(t-butyl), cyclobutan-1-yl), etc. In some embodiments, an alkyl group consists of 1 to 20 carbon atoms (C1 to C20). 20 Alkyl) is included. In other embodiments, alkyl groups consist of 1 to 10 carbon atoms (C1 to C 10 It contains alkyl groups. In yet another embodiment, the alkyl group contains 1 to 6 carbon atoms (C1-C6 alkyl) or 1 to 4 carbon atoms (C1-C4). C1-C6 alkyl groups are also known as "lower alkyls".

[0039] The term "arylalkyl" is a term used in the art, and in this specification, it refers to an alkyl group substituted with an aryl group, for example, C1~6 This refers to an alkyl group, where the aryl group is linked to the main molecule through the alkyl group. An example of an arylalkyl group is the benzyl group, or phenylmethyl group.

[0040] When used to describe the modification of a specified group or radical, "substituted" means that one or more hydrogen atoms of the specified group or radical are independently replaced by identical or different substituents. The term "substituted" specifically assumes and permits one or more substituents common in the art. However, it is generally understood by those skilled in the art that substituents should be selected so as not to adversely affect the useful properties of the compound or to adversely interfere with its function.

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

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

[0043] In some non-limiting examples, the compounds include diacid esters of tryptamine structures such as 4-hydroxy-N,N-dimethyltryptamine (psilosine 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 hemisuccinates, hemiglutarates, and citrates of 4-hydroxy derivatives of N,N-dimethyltryptamine (psilocine), N,N-diisopropyltryptamine (4-OH-DiPT), or N-methyl-N-isopropyltryptamine (4-OH-MiPT).

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

[0045] In some embodiments, the compound comprises a compound represented by formula I, II, III, or IV, wherein 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 selected based on the criterion of 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 decreases. However, if such a compound is a 5HT2A agonist that can produce beneficial therapeutic effects without inducing a psychedelic state, then these are also within the scope of the present invention.

[0047] In some embodiments, the compounds of the present invention are zwitterions of diacids. Therefore, when X is a linear and saturated alkyl, the diacid may include, but is not limited to, common linear alkyl α,ω-diacids, including oxalic acid, malonic acid, succinic acid, glutaric acid (pentanedioic acid), adipic acid (hexanediic acid), pimelic acid (heptanedioic acid), and suberic acid (octanedioic acid). In some embodiments where X is a linear alkene, the diacid may include an acid, 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) Silosin-4-succinate [ka]

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

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

[0051] (4) Silosin-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, diacid-modified tryptamines or isotryptamines are stable (oxidation and hydrolysis) and can be easily synthesized and purified. Diacid-modified tryptamines or isotryptamines preferably exhibit greater solubility in the biological matrix than unmodified drugs, making them excellent drug candidates. Furthermore, diacid-modified tryptamines preferably exhibit a relatively high rate of hydrolysis in vivo, rapidly converting the prodrug into the active drug. This allows for improved and desirable pharmacokinetics of the prodrug, including a more reproducible pharmacokinetic profile. These properties may depend on the properties of indole, the various substituents bound to indole, and the properties of the diacid ester. Stability and hydrolysis rate can be determined experimentally.

[0060] In some embodiments, the compound may contain a carbamate of tryptamine in which R4 is (R9)(R10)N- (where R9 and R10 are carbamate residues, as defined previously). In some embodiments, the carbamate functional group contains a zwitterionic amino-functionalized mono or dicarboxylic acid linked via the carbamate, which may include, but are not limited to, zwitterionic compounds, e.g.: - Natural and unnatural neutral or anionic amino acids, such as glycine, alanine, leucine, isoleucine, serine, threonine, glutamic acid, and aspartic acid; - Linear alkyl α,ω-amino acids, e.g., 3-aminopropionic acid, 4-aminobutyric acid; - Other branched amino acids and aromatic amino acids, such as 4-aminobenzoic acid These are some examples.

[0061] In some embodiments, the present invention may include a zwitterionic compound in which R4 comprises one or more non-esterified carboxyl functional groups, for example, a citrate derivative of 4-hydroxytryptamine (V) or a glutamate carbamate of 4-hydroxytryptamine (VI):

[0062] [ka]

[0063] In some embodiments, zwitterionic compounds are preferably stable at neutral or slightly acidic pH. Acylation of the hydroxyl functional group of indole specifically prevents the oxidation reactions typical of substituted phenolic compounds and indole (Manevski 2010 Drug Metabolism and Disposition and Napolitano 1989 Tetrahedron), while maintaining solubility. In some embodiments, the zwitterion has sufficient solubility (>30 mg / ml) at neutral and pharmaceutically acceptable pH values ​​(3-8) to achieve the required potency / efficacy. Conventionally, tryptamine, a non-prodrug pharmacophore, must be kept in an acidic medium to achieve good solubility and stability. Acidic mediums may interfere with use as an injectable formulation and may cause irritation.

[0064] The zwitterionic form may also be conveniently purified and isolated by recrystallization from common pharmaceutical solvents, such as water, methanol, ethanol, propanol, isopropanol, acetone, or mixtures thereof.

[0065] The diacid portion is metabolically cleaved in vivo, yielding an active ingredient with sufficient dose and kinetics to achieve the psychedelic state considered necessary for the treatment of depressive states, such as in psychedelic psychotherapy. This is particularly advantageous when designing formulations that produce a favorable psychedelic experience lasting less than 8 hours, preferably less than 6 hours, and more preferably less than 4 hours. In this sense, the need for hydrolysis is an additional step that can delay the onset of psychoactive properties compared to the infusion of the free drug (where the hydroxyl functional group is not acylated). A slightly slower onset may be preferable in some cases, as it avoids sudden onsets that could cause anxiety, particularly in patients who have never experienced psychedelia before. Therefore, in a preferred embodiment, the rate of onset may be controlled by the rate of metabolism, which may be a function of the ester and the target enzymes 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. Being zwitterionic, they are less likely to be rapidly absorbed in tissues lacking esterase activity. Furthermore, zwitterionic ions are less likely to be directly absorbed into the brain by passive mechanisms. The rate of cleavage in the intestines may be slower, potentially leading to slower absorption than the non-acylated form, which could delay the "rush" sensation and peak rate that individuals with intent to abuse might seek.

[0067] Manufacturing method The compounds described in this specification can be synthesized by the methods described below or similar methods, in conjunction with known synthetic methods in the art of synthetic organic chemistry, or by variations thereof as understood by those skilled in the art. Preferred methods may include, but are not limited to, those described below. The reactions are carried out in a solvent or solvent mixture that is appropriate for the reagents and materials used and suitable for the reaction being affected. Those skilled in organic synthesis will understand that the presented reactions are consistent with the functionalities present on the molecules. This may require judgment within the scope of the skill of those skilled in the art when changing the order of the synthetic steps or selecting a different processing scheme than one given one, in order to obtain the desired compounds of the present 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 of organic synthesis and functional group transformation 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); found in March, J., Advanced Organic Chemistry.

[0069] 4- and 5-hydroxytryptamines can be produced in the art by employing the methods described in 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. Patent No. 3,075,992 and Chen (JOC 1994, 3738).

[0070] For example, the succinate ester prodrug compounds described in this specification may be prepared using the synthetic scheme outlined in Scheme 1, starting from the corresponding hydroxyindole and dihydrohydride. Reaction conditions, such as temperature, time, and solvent, that may be suitable for experimental conditions recognized by those skilled in the art, are selected, and the procedure is chosen. Restrictions on substituents suitable for the reaction conditions are readily apparent to those skilled in the art, and in such cases, another or similar method must be used. [ka] As will be readily apparent to those skilled in the art, other dioxide prodrugs may be prepared using other dioxide anhydrides.

[0071] Glutaric acid anhydride may be used to produce glutaric acid ester prodrug compounds using the following scheme 2: [ka]

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

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

[0074] Furthermore, the synthesis of diacid hemiester prodrugs may be carried out using various other methods and techniques well known to those skilled in the art (Rautio, Nature Rev in Drug Discovery 2018, 17, 559), for example, using anhydrides or dual-activated forms of diacids, such as dichloride, di-N-hydroxysuccinimide (using dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide and DMAP), di-imizadolide (using carbonyldimidizole), or other activated forms of diacids having the hydroxyl form of an active heterocyclic species. When using dual-activated forms, it is preferable to use a 2-25-fold excess of dual-activated diacid to avoid the covalent bonding of two tryptamines to the diacid.

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

[0076] Formulations and compositions The present invention also provides a pharmaceutically acceptable composition comprising one or more compounds described herein in a therapeutically effective amount, formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one or more further therapeutic agents. While the compounds described herein may be administered alone, it is preferable to administer the compounds as a pharmaceutical composition.

[0077] The term “pharmaceutical composition” means a composition comprising the compound of the present invention in combination with at least one pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” means a medium for which the delivery of bioactive drugs to animals, particularly mammals, is generally permitted in the art, and depending on the form of administration and the nature of the dosage form, includes adjuvants, excipients or vehicles, such as diluents, osmotic complements, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, polymers, solubilizers, stabilizers, antioxidants and dispersants. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient.

[0078] In this specification, “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 may be administered for any of the uses or methods described in this specification by appropriate means, for example, by oral administration such as tablets, capsules (each of which may include sustained-release or sustained-release formulations), pills, powders, granules, elixirs, suspensions (including nano-suspensions, micro-suspensions, spray-drying dispersants), syrups, and emulsions; by sublingual administration (e.g., as thin films, effervescent tablets, or tablets that spontaneously dissolve under the tongue); by parenteral administration such as subcutaneous, intravenous, intramuscular injection, or infusion techniques (e.g., sterile aqueous or non-aqueous solutions, suspensions); by nasal administration, including administration to the nasal mucosa by inhalation spray, for example; or by rectal administration such as suppositories.

[0079] The dosage regimens for the compounds described in this specification will naturally vary depending on known factors, such as the pharmacokinetic and pharmacological characteristics of a particular drug and its form and route of administration; the recipient's species, age, sex, health, medical condition, and weight; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function; and the desired effect. The selected dosage may also depend on further factors, including the activity of the particular compounds and pharmaceutical compositions described in this specification, whether to use esters, salts, or amides of the compounds, the time of administration, the rate of excretion or metabolism of the compounds used, the rate and degree of absorption, the duration of treatment, other drugs that may be administered to the patient, compounds and / or materials used in combination with the compounds used, and similar factors well known in the field of medicine.

[0080] Generally, the dosage of a prodrug for therapeutic purposes, when used to achieve its desired effect, is approximately 0.001 to 500 mg per dose, preferably approximately 0.01 to 200 mg per dose, and most preferably approximately 0.1 to 50 mg per dose, for example, 10, 20, 30, 40, 50, 100, or 200 mg. For intravenous administration, the most preferred dose is approximately 0.01 to 10 mg / kg / min at a constant infusion rate.

[0081] The compound of the present invention may be administered once daily, or the entire daily dose may be divided into multiple doses, for example, two, three, or four times a day. Alternatively, it may be administered weekly, bi-weekly, or monthly. In a preferred embodiment, only one or two doses are required for the antidepressant effect, which may last for one, two, three, or six months, or longer.

[0082] In the case of tablets, the drug may be 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight, depending on the dose. 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, crystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant is 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0083] To impart cohesiveness to tablets, binders are generally used. Suitable binders include crystalline cellulose, gelatin, sugars, 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, crystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0084] The tablets may also contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and fluidizers, such as silicon dioxide and talc. If present, the surfactants are usually present in an amount of 0.2% to 5% by weight of the tablet, and the fluidizers are usually present in an amount of 0.2% to 1% by weight of the tablet.

[0085] Generally, tablets also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant is generally present in an amount of 0.25% to 10% by weight, preferably 0.5% to 3% by weight, of the tablet.

[0086] Other commonly used ingredients include antioxidants, colorants, flavorings, preservatives, and taste enhancers.

[0087] Typical tablets contain up to approximately 80% by weight of the drug, approximately 10% to 90% by weight of the binder, approximately 0% to 85% by weight of the diluent, approximately 2% to 10% by weight of the disintegrant, and approximately 0.25% to 10% by weight of the lubricant.

[0088] Tablets may be formed by compressing the tablet blend directly or by rollers. Alternatively, the tablet blend or a portion of the blend may be wet, dry, or melt-granulated, melt-solidified, or extruded before tableting. The final formulation may contain one or more layers, and may be coated or uncoated; or it may be encapsulated.

[0089] The formulation of tablets is 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 thereof is incorporated herein by reference in its entirety.

[0090] A typical capsule for oral administration contains at least one of the compounds of the present 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 gelatin capsules No. 1.

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

[0092] Furthermore, the compounds of the present invention may be administered directly into the bloodstream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include syringes with needles (including microneedles), needleless syringes, and injection techniques.

[0093] Parenteral formulations are typically aqueous solutions containing excipients such as salts and carbohydrates, and pH adjusters or buffering agents (preferably pH 3.0 to 7.0, preferably 4.0 to 6.0, more preferably 4.5 to 5.5). However, for some applications, they may be more appropriately formulated as sterile non-aqueous solutions or as dry forms used with a suitable vehicle (e.g., sterile pyrogen-free water or a pre-prepared aqueous buffer for immediate mixing). Osmotic regulators may be added to control osmotic pressure.

[0094] The preparation of parenteral kits for reconstitution under sterile conditions in a clinical setting, for example by lyophilization, can be easily achieved 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 of the compounds of the present invention (e.g., 25 mg) into a vial as a sterile filtration solution, aseptically lyophilizing it, and sealing it. For use, the contents of the vial are mixed with, for example, 2 mL of injectable saline solution, and optionally an appropriate amount of osmotic complement and a pH adjuster to achieve a slightly acidic to neutral pH (e.g., pH 4-7) to prepare a low-irritation injectable formulation and maintain the solubility and / or stability of the prodrug.

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

[0097] For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complex formation with drugs, cyclodextrins may be used as auxiliary additives, i.e., as carriers, diluents, or solubilizers. The most commonly used for these purposes are α, β, and γ cyclodextrins, examples of which can be found in International Publications 91 / 11172, 94 / 02518, and 98 / 55148 (these disclosures are incorporated herein by reference in their entirety).

[0098] Regardless of the chosen route of administration, the compounds and / or pharmaceutical compositions of the present invention, which may be used in an appropriate hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. The actual dose of the active ingredient in the pharmaceutical composition of the present invention may be varied so as to obtain an amount of the active ingredient effective in achieving a desirable therapeutic response for a particular patient, composition, and form of administration.

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

[0100] Generally, the appropriate daily dose of the compound of the present invention is the minimum amount of the compound that is effective in producing a therapeutic effect. Such an effective dose generally depends on the factors mentioned above.

[0101] In this specification, “therapeutic dose” refers to the amount of compound administered that reduces, to some extent, one or more symptoms of the disorder being treated. In relation to the treatment of depression, the therapeutic dose refers to the amount that has the effect of reducing the severity of depression. The severity of depression 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). The therapeutic dose may be less than the amount required for a psychedelic state.

[0102] An effective dose can be administered in one or more doses. For the purposes of this invention, the effective dose of a drug, compound, or pharmaceutical composition is sufficient to directly or indirectly achieve a preventive or therapeutic action. As understood in clinical contexts, the effective dose 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 use Therapies using the novel prodrugs of the present invention may substantially alleviate clinical or latent depression and, in particular, may prevent relapse when used in combination with psychotherapy for the treatment of depression. Effective doses of psilocybin are 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.). While not theoretically bound, psychedelic states are thought to be associated with beneficial effects, but some compounds that are 5HT2A agonists may produce the desired therapeutic effect without inducing a psychedelic state. One aspect of the present invention involves 5HT2A agonist prodrugs that produce beneficial therapeutic states.

[0104] Generally, the present invention includes the use of the compounds of the present invention for treating diseases or disorders that may be relieved by 5HT2A agonists, the use of the compounds of the present invention for manufacturing pharmaceuticals that treat diseases or disorders that may be relieved by 5HT2A agonists, or methods for treating diseases or disorders that may be relieved by 5HT2A agonists.

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

[0106] In some embodiments, the present invention may include a method for treating a mental disorder, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need of treatment. In one embodiment, a method for treating depression is provided, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need of treatment. 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 containing 0.01–0.3 mg / kg of the compound of the present invention may be administered to the patient. The patient is seated, preferably blindfolded, for the duration of administration. For safety, a trained medical professional may monitor the entire administration, 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 has been eliminated, the psychotherapist may assist the patient with any questions regarding psychedelic experiences, after which the patient may be discharged.

[0108] To further alleviate any anxiety that may arise in connection with the treatment, the physician may choose to divide the dose, thereby reducing the initial onset of psychoactive effects before administering the full dose required 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 concurrently or sequentially. In preferred embodiments, treatment with the compounds of the present invention may be combined with psychotherapy, which may be administered before or after treatment. If administered before, the patient's therapeutic intent may be focused on the administration of the compounds of the present invention. If administered after, psychotherapy may preferably be administered within 48 hours of administration of the compounds of the present invention to help the patient organize any sensations, feelings, visions or thoughts that may have occurred during administration of the compounds of the present invention, and to allow the psychotherapist to advise on the best ways to modify thought or behavioral patterns to improve antidepressant outcomes. If necessary, psychotherapy may be continued after administration of the compounds of the present invention, for example for up to a further 3 months, to help the patient organize any experiences or learnings that occurred during administration. [Examples]

[0110] The present invention can be described with reference to the following examples, which are provided for illustrative purposes only. All terms, names, abbreviations, or acronyms are as commonly understood by those skilled in the art. Compounds shown in zwitterionic form can be readily recalled by those skilled in the art in terms of their neutral form, 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, 4-hemiglutarate of psilocine is the same as psilocine-4-glutarate or N,N-dimethyltryptamine-4-glutarate. Similarly, 4-hemiglutarate of 4-OH-DiPT is the same as N,N-diisopropyltryptamine-4-glutarate.

[0112] Example 1: 4-hemicuccinate of psilocin 4-Hydroxyindole was prepared by the method described in Kargbo 2020 ACS Omega or by a method appropriately adapted thereto. Specifically, 4-acetoxyindole was reacted with oxalyl chloride in methyl-t-butyl ether (MTBE), and the resulting intermediate was quenched with dimethylamine. Indole-oxalyl-dimethylamide was reduced with lithium aluminum hydride (LAH) in tetrahydrofuran (THF) to obtain 4-acetoxy-3-(N,N-dimethylaminoethyl)indole, which was deprotected using an aqueous base to obtain 4-hydroxydimethyltryptamine (psilocine).

[0113] 4-hydroxytryptamine was reacted with excess succinic anhydride in dichloromethane (DCM) containing triethylamine, using N,N-dimethylaminopyridine as a catalyst, to obtain silosin-4-succinate. A precipitate was formed, and after decantation and trituration using DCM, it was recovered. 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 oxalylamide was reduced with lithium aluminum hydride (LAH) in THF to obtain 4-acetoxy-3-(N,N-diisopropylaminoethyl)indole, which was deprotected with an aqueous base to obtain 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. 4-OH-DiPT (5.8 g, 22.3 mmol, 1 equivalent) was added to a 250 mL round-bottom flask containing a stirring bar, dissolved in dichloromethane (28 mL, 5 × V), and stirred at room temperature. Then, succinic anhydride (1.3 equivalents) was slowly added to the stirred solution, and the resulting suspension was stirred overnight at room temperature. The precipitate formed in the reaction product was recovered by decantation and trituration using DCM. The solid was acidified with hydrochloric acid, purified by chromatography, and recovered after evaporation of the solvent. The structure was confirmed by NMR. Purity was determined by HPLC.

[0115] Example 3: 4-hemifumarate of 4-OH-DiPT 4-Benzyloxyindole is reacted with oxalyl chloride in diethyl ether in the presence of a Friedel-Craft catalyst, and the resulting intermediate is quenched with diisopropylamine. The resulting oxalylamide is reduced with lithium aluminum hydride (LAH) in THF to obtain 4-benzyloxy-3-(N,N-diisopropylaminoethyl)indole, which is then deprotected using H2 and Pd / C to obtain 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. This substance is reacted with an excess of activated fumaric acid (N-hydroxysuccinimide) in dichloromethane, and then all unreacted N-hydroxysuccinimide ester is quenched with an acid solution to obtain 4-fumaroyl-3-(N,N-diisopropylaminoethyl)indole.

[0116] Example 4: 5-Hydroxy-4-methyldimethyltryptamine 5-hemicuccinate 4-methyl-5-hydroxyindole (1) is reacted with benzyl chloride in ACN in the presence of K2CO3 to obtain 5-benzyloxy-4-methylindole, which is then reacted with oxalyl chloride in diethyl ether in the presence of a Friedel-Craft catalyst, and the resulting intermediate is quenched with dimethylamine. The resulting oxalylamide is reduced with lithium aluminum hydride (LAH) in THF to obtain 4-methyl-5-benzyloxy-3-(N,N-dimethylaminoethyl)indole, which is then deprotected with H2 and Pd / C to obtain 4-methyl-5-hydroxy-3-(N,N-dimethylaminoethyl)indole. This substance is reacted with succinic anhydride in dichloromethane using N,N-dimethylaminopyridine as a catalyst to obtain 4-methyl-5-succinoyl-3-(N,N-dimethylaminoethyl)indole.

[0117] Example 5: N,N-dimethylisotryptamine-6-succinate Following the method outlined in Glennon (J. Med Chem 1984), 6-O-benzyldimethylisotryptamine is prepared by N-alkylation of 5-BzO-indole using NaH. The benzyl group is removed by catalytic hydrogenation using Pd / C / H2 to obtain an OH functional group, which is then succinally converted with succinic anhydride in the next step to obtain the marked compound.

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

[0119] The mixture was decanted, and the solid was triturated using anhydrous DCM (3 mL) with a few drops of anhydrous MeCN added. The suspension was acidified with 1 M hydrochloric acid (approximately 1.1 equivalents), concentrated, and dried. The crude product was purified by C18 reversed-phase column chromatography (40 g, A: 0.05% HCl in H2O, B: 0.05% HCl in MeCN).

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

[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 obtain 4-succinoyl-3-(N,N-diisopropylaminoethyl)indole. The precipitate formed in the reaction product was recovered by decantation and trituration in THF. The solid was washed with DCM and dried. The structure was confirmed by NMR.

[0122] Example 8: Silosin-4-glutarate 4-Hydroxydimethyltryptamine (psilocine) was reacted with excess glutaric anhydride in dichloromethane (DCM) containing triethylamine to obtain psilocine-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 1 M HCl-ether to obtain the corresponding HCl salt product, which was then filtered and recovered in high yield and purity.

[0124] Example 9: HCl salt of N,N-diisopropyltryptamine-4-glutarate 4-OH-DiPT (31.8 g, 0.122 mol, 1 equivalent) was added to a 1 L three-necked round-bottom flask under an argon atmosphere and dissolved in 160 mL of pyridine anhydride. After stirring for 15 minutes, glutaric acid anhydride (18.1 g, 0.158 mol, 1.3 equivalents) was added in small amounts. The resulting suspension was stirred overnight at room temperature.

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

[0126] The dried solid was triturated at 0°C with 160 mL of anhydrous DCM, followed by 160 mL of anhydrous THF, and then 160 mL of anhydrous DCM. After drying, 33.0 g was obtained in 72% yield and 98.1% HPLC purity. The zwitterion structure was confirmed by 1H-NMR (DMSO-d6) and MS [M+H] + = 375.2.

[0127] 18 mL of anhydrous diethyl ether HCl solution (4M in dioxane, 2.4 mL, 9.6 mmol, 1.2 equivalents) was slowly added to a 100 mL round-bottom flask and stirred at room temperature for 10 minutes. The above zwitterions (3.0 g, 8.0 mmol) were added in portions, and the resulting suspension was stirred for 2 hours. The solid was filtered off and washed with 6 mL of Et2O. The solid was dried and 3.16 g of the corresponding hemiester tryptamine HCl salt was added (yield 96%, HPLC purity 99.0%, [M+H]). + We obtained =375.1).

[0128] Example 10: Hemiglutarate ester of psilocin Silosine is reacted with 1.2 equivalents of glutaric anhydride in warm THF to obtain psilocine-4-glutarate, which is then precipitated from the reaction mixture according to the method described above. The precipitate is collected by filtration, washed with cold 1:1 DCM / THF, and dried.

[0129] Example 11: 4-hemimalonic acid ester of 4-OH-DiPT 4-OH-DiPT was dissolved in pyridine and coupled with excess malonic acid and 1.2 equivalents of DCC at room temperature for 18 hours. 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 rate of prodrug hydrolysis in serum Pooled mixed human plasma (2 ml), mouse plasma, rat plasma, and canine plasma were equilibrated at 37°C. The compound from Example 9 was added to a concentration of 1.0 ug / mL. Aliquots (50 uL) of the mixture were taken at specified times (0, 0.004, 0.5, 1, 2, and 4 hours) and quenched with 200 uL methanol / acetonitrile (1:1). The samples were vortexed and stored at -80°C until analysis. The assay was performed three times. Control samples were treated in phosphate-buffered saline (PBS, pH 7.4) and simulated gastric juice (SGF, pH 2). The samples were analyzed by HPLC-MS to determine the amounts of prodrugs and drugs in each test sample. Table 1 shows the mean concentrations of residual prodrugs at various time points in the experiment. The experiment demonstrates rapid enzymatic cleavage of prodrugs in plasma and slow non-enzymatic hydrolysis in the associated biological media.

[0131] [Table 1]

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

[0133] PK-PD curves were created to illustrate drug activity (Figures 1 and 2). In rodents, the prodrug was rapidly converted to the active form and therefore no activity was observed. Table 2 shows the PK parameters for IV and sc administration of 4-OH-DiPT.

[0134] [Table 2]

[0135] In several cases, a hyperspastic response (HTR) or severe tremors (WDS: Wet Dog Shakes) were recorded by visual observation and counting of associated muscle spasms. Generally, the intensity of HTR was proportional to the blood concentration of 4-OH-DIPT, and the intensity of hyperspasticity was highest at the Tmax of the PK profile.

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

[0137] Pharmacokinetic analyses of 1.34 mg / ml 4-OH-DiPT HCl administered intravenously or subcutaneously were performed in parallel under identical conditions. Figure 2 shows the blood concentration (ng / ml) of 4-OH-DiPT over time for each administration. It is immediately clear that there is significant variation depending on the active species in the case of sc administration and intravenous administration. The 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) was administered to human volunteers at a dose of 0.1–0.6 mg / kg by subcutaneous injection using a sterile solution (1 mg / ml). Blood samples were collected at 5, 15, 30, 45, 60, 120, 240, 480, and 24 hours. The samples were analyzed for the drug and prodrug by LC-MS. Subjective effects were measured using a standardized questionnaire. PK analysis showed the maximum blood concentration (CMax) approximately 45 minutes after injection. Subjective effects indicated the intensity of psychoactive effects correlated with blood levels.

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

[0141] Example 18: Use in treatment The compound of Example 6 (N,N-diisopropyltryptamine-4-glutarate) is administered to human patients with depression by im or sc infusion (approximately 25 mg; 0.4-0.5 mg / kg) or by oral administration in tablet form (approximately 50-200 mg; 0.8-3.2 mg / kg). In another example, the compound of Example 6 (4-OH-DiPT 4-hemiglutarate) is administered similarly. Prior to administration, patients are selected and screened for exclusion (e.g., history of psychosis, undesirable cardiac conditions, pregnancy), and finally, patients are encouraged to express their willingness to receive 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 played. The drug is administered. Four hours later, when the patient reports that they no longer feel the effects of the drug, they are asked to get up under supervision. The patient is allowed to stand (under supervision) when they feel normal and to move around when they feel they are under control. After one hour, the patient is sent home. Within the next 24 hours, the patient returns to the consultation room to see the psychotherapist to discuss medication in more detail. The patient completes a depression score questionnaire and is sent home again. The patient is seen at regular intervals for relapses of depressive symptoms.

[0142] Example 19: Kit for an injectable formulation Prepare a vial using 25 mg (sterile powder or lyophilized) of the compound from Example 6 as the hydrochloride salt. Place 1 ml of sterile filtered solution containing 70 mM Na2HPO4 into another vial. The final pH of the solution should be 4.0–5.0. These two components constitute a kit for reconstituting the drug product for subcutaneous injection in clinical settings.

[0143] References All publications, patents, patent applications, etc., referenced in this specification, including the following, are incorporated herein by reference in their entirety: 1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th Ed.). https: / / doi.org / 10.1176 / appi.books.9780890425596 2. Anderson, W. K., & Mulumba, B. (1984). Synthesis of Methyl 2,3-bis(hydroxymethyl)-5-phenyl-7-oxabicyclo[2.2.1]hepta-2,5-diene- 6-carboxylate bis(N-methylcarbamate) derivatives as potential antitumor agents. Journal of pharmaceutical sciences, 73(8), 1182-1183. https: / / doi.org / 10.1002 / jps.2600730844 3. Anderson, B. D., Conradi, R. A., & Lambert, W. J. (1984). Carboxyl group catalysis of acyl transfer reactions in corticosteroid 17- and 21-monoesters. Journal of pharmaceutical sciences, 73(5), 604-611. https: / / doi.org / 10.1002 / jps.2600730507 4. Bahar, F. G., Ohura, K., Ogihara, T., & Imai, T. (2012). Species Difference of Esterase Expression and Hydrolase Activity in Plasma. Journal of Pharmaceutical Sciences, 101(10), 3979-3988. https: / / doi.org / 10.1002 / jps.23258 5. Baumann, M., Baxendale, I. R., Ley, S. V., & Nikbin, N. (2011). An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals. Beilstein Journal of Organic Chemistry, 7, 442-495. https: / / doi.org / 10.3762 / bjoc.7.57 6. Carhart-Harris, R. L., Roseman, L., Haijen, E., Erritzoe, D., Watts, R., Branchi, I., & Kaelen, M. (2018). Psychedelics and the essential importance of context. Journal of Psychopharmacology, 32(7), 725-731. https: / / doi.org / 10.1177 / 0269881118754710 7. Chen, C.-yi, Senanayake, C. H., Bill, T. J., Larsen, R. D., Verhoeven, T. R., & Reider, P. J.(1994). Improved Fischer Indole Reaction for the Preparation of N,N-Dimethyltryptamines: Synthesis of L-695,894, a Potent 5-HT1D Receptor Agonist. The Journal of Organic Chemistry, 59(13), 3738-3741. https: / / doi.org / 10.1021 / jo00092a046 8. Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021; 78(5):481-489. doi:10.1001 / jamapsychiatry.2020.3285 9. Ebenezer, I. S. (2015). Affective Disorders: Depression in Neuropsychopharmacology and Therapeutics, Chapter 6 Neuropsychopharmacology and therapeutics. John Wiley & Sons Inc. 10. First, M. B., W., W. J. B., Karg, R. S., & Spitzer, R. L. (2016). Scid-5-Cv: structured clinical interview for Dsm-5 disorders, clinician version. American Psychiatric Association Publishing. 11. Fricke, J., Lenz, C., Wick, J., Blei, F., & Hoffmeister, D. (2018). Production Options for Psilocybin: Making of the Magic. Chemistry - A European Journal, 25(4), 897-903. https: / / doi.org / 10.1002 / chem.201802758 12. Glennon, R. A., Jacyno, J. M., Young, R., Mckenney, J. D., & Nelson, D. (1984). Synthesis and Evaluation of a Novel Series of N,N-Dimethylisotryptamines. Chemischer Informationsdienst, 15(24). https: / / doi.org / 10.1002 / chin.198424187 [ PubMed ] 13. Hofmann A, Troxler F. Esters of indoles.Process for the production of new esters of the indole series. Price tracking number 386422 years [ PubMed ] 14. International Society for CNS Drug Development. (2003). GRID-HAMD-17 Structured Interview Guide. ISCDD. 15. Kargbo, RB, Sherwood, A., Walker, A., Cozzi, NV, Dagger, RE, Sable, J., O'Hern, K., Kaylo, K., Patterson, T., Tarpley, G., & Meisenheimer, P. (2020). Direct Phosphorylation of Psilocybin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin. ACS Omega, 5(27), 16959-16966. https: / / doi.org / 10.1021 / acsomega.0c02387 16. Lieberman , HA , & Lachman , L. (1980). Pharmaceutical dosage forms--tablets, vol. 1. Marcel Decker. 17. Luethi, D., & Liechti, ME (2018). Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics. International Journal of Neuropsychopharmacology, 21(10), 926-931. https: / / doi.org / 10.1093 / ijnp / pyy047 18. Manevski, N., Kurkela, M., Hoeglund, C., Mauriala, T., Court, M. H., Yli-Kauhaluoma, J., & Finel, M. (2010). Glucuronidation of psilocin and 4-hydroxyindole by the human UDP-glucuronosyltransferases. Drug metabolism and disposition: the biological fate of chemicals, 38(3), 386-395. https: / / doi.org / 10.1124 / dmd.109.031138 19. Napolitano, A., d'Ischia, M., Prota, G., Schultz, T., & Wolfram, L. (1989). Oxidation of 4,6- and 7-hydroxyindoles. Tetrahedron, 45, 6749-6760. 20. Rautio, J., Meanwell, N. A., Di, L., & Hageman, M. J. (2018). The expanding role of prodrugs in contemporary drug design and development. Nature reviews. Drug discovery, 17(8), 559-587. https: / / doi.org / 10.1038 / nrd.2018.46 21. Shulgin, A. T., & Shulgin, A. (2017). Tihkal: the continuation. Transform Press. 22. Silverman, R. B., & Holladay, M. W. (2014). Prodrugs and Drug Delivery Systems. The organic chemistry of drug design and drug action. Elsevier Academic Press. 23. Watts, R., & Luoma, JB (2020). The use of the psychological flexibility model to support psychedelic assisted therapy. Journal of Contextual Behavioral Science, 15, 92-102. 24. British Patent Applications No. 942548, No. 912714 and U.S. Patent No. 9630941

[0144] Definitions and Interpretations The descriptions of the present invention are presented for illustrative and explanatory purposes, but are not intended to be entirely identical to or limited to the disclosed forms of the invention. Many variations and modifications will be apparent to those skilled in the art without departing from the scope and spirit of the invention. The descriptions are selected to best illustrate the principles and practical applications of the invention and to enable other those skilled in the art to understand the invention in various forms with various modifications to suit specific intended uses. The following descriptions are intended to be illustrative of, and not limiting, the claimed invention insofar as they relate to specific forms or specific uses of the invention.

[0145] In the claims attached herein, all means or step-plus-function elements corresponding structures, materials, actions, and equivalents are intended to include any structures, materials, or actions for performing a function in combination with other claimed elements, as specifically claimed.

[0146] References to “aspect,” “aspect,” etc., in the specification mean that the described aspect may include a particular aspect, feature, structure, or characteristic, but not all aspects are required to include that aspect, feature, structure, or characteristic. Furthermore, such phrases may, but are not required, refer to the same aspect as referred to in other parts of the specification. Moreover, if a particular aspect, feature, structure, or characteristic is described in relation to a particular aspect, it is within the knowledge of a person skilled in the art to combine, operate, or link such aspect, feature, structure, or characteristic with other aspects, whether such linkage or combination is explicitly described or not. In other words, any element or feature may be combined with any other element or feature in a different aspect, unless there is a clear or essential incompatibility between them, or the combination is specifically excluded.

[0147] It should be further noted that claims may be written in a way that excludes optional elements. This statement itself is intended to act as a prerequisite to the use of exclusive terminology, such as "only," "only," etc., in relation to the enumeration of claim elements or the use of "negative" limitations. The terms "preferably," "desirable," "choose," "optionally," "may," and similar terms are used to mean that the element, item, condition, or process mentioned is an optional (not required) feature of the invention.

[0148] The singular forms "a," "an," and "the" include plural anaphora unless otherwise clearly specified by the context. The term "and / or" means any one of the items to which it relates, any combination of items, or all of the items.

[0149] As those skilled in the art will understand, for all purposes, and especially in terms of providing written descriptions, all scopes described in this specification also include all possible sub-scopes and combinations thereof, as well as the individual values, particularly integer values, that constitute those scopes. Each scope described (e.g., weight percentage or carbon group) includes each specific value, integer, decimal, or identity element within that scope. Any scope enumerated is sufficiently described that it is readily apparent that the same scope can be divided into at least two, three, four, five, or ten parts. As a non-limiting example, each scope described in this specification can be readily divided into a lower third, a middle third, an upper third, and so on.

[0150] As those skilled in the art will understand, all scopes and all words described in this specification, such as "~", "at most", "at least", "greater than", "less than", "greater than", "greater than or equal to", etc., include the numbers described, and such terms refer to a scope that can subsequently be divided into subscopes, as explained above.

Claims

1. The following formula: 【Chemistry 1】 Hydrochloride salt of [unclear].

2. The hydrochloride salt according to claim 1 in crystalline form.

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

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is an oral preparation.

5. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is an injectable formulation.

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

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

0.

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

0.

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

0.

10. A pharmaceutical product comprising the hydrochloride salt according to claim 1 or 2, or the pharmaceutical composition according to any one of claims 3 to 9, for the treatment of mental disorders.

11. The pharmacopoeia according to claim 10, wherein the mental disorder is selected from major depressive disorder, treatment-resistant depression, postpartum depression, unipolar depressive state, bipolar depressive state, depression arising from generalized anxiety, anxiety disorder, anxiety in advanced illness, generalized anxiety disorder, drug addiction, gambling disorder, eating disorder, body dysmorphic disorder, chronic pain, and chronic fatigue.

12. The pharmacopoeia according to claim 11, wherein the mental disorder is major depressive disorder.

13. The pharmacopoeia according to claim 11, wherein the mental disorder is treatment-resistant depression.

14. The pharmacopoeia according to claim 11, wherein the mental disorder is postpartum depression.

15. The pharmacopoeia according to claim 11, wherein the mental disorder is a unipolar depressive state.

16. The pharmacopoeia according to claim 11, wherein the mental disorder is a bipolar depressive state.

17. The pharmacopoeia according to claim 11, wherein the mental disorder is depression arising from generalized anxiety.

18. The pharmacopoeia according to claim 11, wherein the mental disorder is an anxiety disorder.

19. The pharmacopoeia according to claim 11, wherein the mental disorder is anxiety in an advanced illness.

20. The pharmacopoeia according to claim 11, wherein the mental disorder is a generalized anxiety disorder.

21. The pharmaceutical product according to claim 11, wherein the mental disorder is drug dependence.

22. The pharmaceutical product according to claim 11, wherein the mental disorder is gambling disorder.

23. The pharmaceutical product according to claim 11, wherein the mental disorder is an eating disorder.

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

25. The pharmacopoeia according to claim 11, wherein the mental disorder is chronic pain.

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

27. The pharmacopoeia according to claim 11, further comprising administering 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 pharmacopoeia according to claim 27, further comprising administering the treatment to target TCA.

29. The pharmacopoeia according to claim 27, further comprising administering an SSRI as the target of treatment.

30. The pharmacopoeia according to claim 27, further comprising administering the treatment to an SNRI.

31. The pharmacopoeia according to claim 27, further comprising administering the treatment to MOAI.

32. A method for producing N,N-diisopropyltryptamine-4-glutarate hydrochloride, (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. Methods that include...

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

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

35. The method according to any one of claims 32 to 34, further comprising lyophilizing a hydrochloride salt of N,N-diisopropyltryptamine-4-glutarate.

36. A parenteral kit for reconstitution, (a) vials containing N,N-diisopropyltryptamine-4-glutarate hydrochloride as a sterile powder or lyophilized product; and (b) Vials containing sterile solution for injection A kit that includes this.

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