Tryptamine Prodrugs

Abstract

The present invention provides a tryptamine prodrug compound. The compound represented by formula (I) [wherein each symbol is as described in the specification] or its salt or zwitterion is converted into an active substance having 5HT2A receptor agonist activity, and is useful as a drug for treating depression. [Formula 1] TIFF2024546138000041.tif36100

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of Provisional Patent Application No. 63 / 289,501 (filed December 14, 2021), the contents of which are incorporated herein by reference. [Background technology]

[0002] 2. Background of the Invention FIELD OF THEINVENTION The present invention relates to novel tryptamine compounds, methods of making and using such compounds, compositions containing such compounds, and uses thereof.

[0003] Description of the Prior Art Tryptamines are a class of 3-aminoethyl-indoles that bind to and activate serotonin receptors, also called 5HT receptors. A hallucinogenic state can be achieved by activation of the 2A form of the serotonin receptor with 5HT2A receptor agonist compounds. The endogenous substance of this receptor is 5-hydroxy-tryptamine (serotonin). Tryptamine 3-(2-aminoethyl)-indoles are also endogenous neurotransmitters.

[0004] The serotonin receptor system is involved in depression and depressive states, which are generally treated with 5HT1A antagonists (Non-Patent Document 1). More recently, 5HT2A agonists have shown efficacy as drugs for depression (Non-Patent Document 2).

[0005] Tryptamine molecules that produce hallucinogenic states that have been used in traditional medicine may have therapeutic potential for the treatment of mood disorders, distress, depression, etc. For example, ayahuasca is a natural form of dimethyltryptamine (DMT) which, when combined with monoamine oxidase inhibitors, can be ingested and produce a prolonged hallucinogenic state that can variably last from 6 to 15 hours. DMT is also found naturally in small amounts in the brain and can act as a neurotransmitter.

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

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

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

[0009] Hallucinogens have been shown to be effective for treating depression, and are even more effective in treating depression when accompanied by psychotherapy (Non-Patent Document 3).

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

[0011] Succinate and other diacid functionalities have been explored as components of prodrug delivery systems aimed at water-soluble injectable forms of hydrophobic or poorly water-soluble drug substances such as testosterone, haloperidol, chloramphenicol or estradiol (Non-Patent Document 4). Tetrahydrocannabinol esters of succinic acid have been patented for the treatment of glaucoma. However, ester cleavage may not be rapid, predictable, and dependent on the structure of the moiety attached to the drug, and therefore must be explored (Non-Patent Document 5). Esterase enzymes are 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 exploration and optimization (Non-Patent Document 6).

[0012] This background information is believed to be relevant to a basic understanding of the present invention. It is not an admission that any of the preceding is prior art to any aspect of the claimed invention. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Affective Disorders: Depression in Neuropsychopharmacology and Therapeutics, Chapter 6, 1st Edition. Ivor S. Ebenezer, 2015 [Non-Patent Document 2] Carhart-Harris 2018 Psychopharmacology [Non-Patent Document 3] Watts 2020 J Contextual Behavioral Science [Non-Patent Document 4] Silverman and Holladay, Chapter 9.2: Prodrugs and Drug Delivery Systems in The Organic Chemistry of Drug Design and Drug Action (3rd ed.), 2014 [Non-Patent Document 5] Anderson 1984 JPharmaSci [Non-Patent Document 6] Bahar 2012 JPharmSci Summary of the Invention [Problem to be solved by the invention]

[0014] Summary of the Invention It is an object of the present invention to obviate or mitigate at least one of the above mentioned disadvantages of the prior art.

[0015] It is another object of the present invention to provide novel N-methoxybenzyl-tryptamine compounds. [Means for solving the problem]

[0016] The present invention relates to novel tryptamine compounds, which when administered, are converted to active forms in vivo and act as 5HT2A agonists.The compounds described herein can be useful for treating psychiatric disorders such as depressive states, including unipolar and bipolar depressive states, such as, but not limited to, depression, depression from generalized anxiety disorder, major depression, treatment-resistant depression and postpartum depression.

[0017] In one aspect, the present invention provides a compound according to formula (I), (II), (III) or (IV): [ka] [ka] or a pharma- ceutically acceptable salt or zwitterion thereof, During the ceremony: (1) R1, R2, and R6 are each independently hydrogen, linear or branched alkyl, preferably C 1-5 alkyl, or arylalkyl; (2) R4: a. -X-CO2H, [wherein X is a linear, cyclic or branched, saturated or unsaturated carbon chain (preferably C 1-5 alkyl), or an aromatic ring optionally substituted with alkyl or COH; or b. (R9)(R10)N-, [wherein R9 is X-CO2H, where X is defined above, and R10 is a straight or branched alkyl (preferably C 1-5 alkyl) or arylalkyl] and; (3) R5 is hydrogen, linear or branched alkyl (preferably C 1-5 alkyl), arylalkyl, or O-R5', where R5' is hydrogen, linear or branched alkyl (preferably C 1-5 alkyl); and (4) R7 and R8 are: a. each independently is hydrogen, straight 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 where the entire heterocyclic structure does not contain more than 12 atoms.

[0018] In another embodiment, the invention includes diacid esters of hydroxytryptamines, such as 4-hydroxy and 5-hydroxytryptamines and 6-hydroxy and 7-hydroxyisotryptamines, as well as other structural or functional analogs of the hallucinogenic tryptamines.

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

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

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

[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, but not limited to, unipolar and bipolar depressive conditions, such as depression, depression from generalized anxiety disorder, major depression, treatment-resistant depression, and postpartum depression.

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

[0024] In another aspect, the present invention relates to a method for making 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 contains a base with a pKa greater than 4 but less than 9, and the resulting compound is isolated as a zwitterion. In some embodiments, the tryptamine includes 4-hydroxy or 5-hydroxytryptamine or 6-hydroxy or 7-hydroxyisotryptamine. In some embodiments, the solvent is pyridine. [Brief description of the drawings]

[0025] [Figure 1] FIG. 1 is a graph showing the plasma concentration of 4-HO-DiPT (ng / ml) versus time following subcutaneous administration of N,N-diisopropyltryptamine-4-glutarate at a rate of 2 mg / kg. [Diagram 2] FIG. 2 is a graph showing the plasma concentration (ng / ml) of 4-HO-DiPT following subcutaneous administration of N,N-diisopropyltryptamine-4-glutarate at a rate of 1.4 mg / kg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments of the present invention include novel synthetic tryptamine prodrugs. These prodrugs may be useful for the treatment of mental disorders such as depression, including, but not limited to, major depression, treatment-resistant depression, and postpartum depression. As used herein, the term "mental disorder" includes disorders that can be diagnosed by a mental health professional as a psychological or psychiatric disorder, including those that can be diagnosed by reference to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

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

[0028] As used herein, a "hallucinatory state" is an altered state of consciousness experienced by a person, which may include enhanced perception, altered perception or hallucinations, and / or feelings of euphoria or despair.Hallucinatory states have been described as resulting from hallucinogens such as DMT (dimethyltryptamine), LSD, mescaline, or psilocybin.Other known hallucinogens include the 4-hydroxy analogs of N-methyl-N-isopropyltryptamine (MiPT) and N,N-diisopropyltryptamine (DiPT).

[0029] The present invention includes prodrugs of hydroxy-indole 5HT2A agonists that induce hallucinatory states or still provide beneficial therapeutic effects without hallucinatory states. The prodrugs may be used in combination with other treatments known to be effective for treating psychiatric disorders, such as psychotherapy, electroconvulsive therapy, and / or other pharmaceutical compounds, for example, 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, further treatment may not be necessary.

[0030] compound As used herein, "compound" includes any pharma- ceutically acceptable derivatives or modifications, including conformers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The expression "prodrug" refers to a compound that is a drug precursor that, upon administration, releases a drug (or "active agent") through some chemical or physiological process in vivo (e.g., hydrolysis, enzymatic cleavage or hydrolysis, or metabolism is converted to the desired drug form). The present invention includes within its scope pharma-ceutically acceptable salts of the compounds of the present invention. Thus, the phrase "or a pharma-ceutically acceptable salt thereof" 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 include prodrug compounds that can be used to provide highly soluble drug substances that are easily purified, formulated, and stable, and preferably with fast onset and elimination for convenient use in clinical settings. In some embodiments, the compounds can be prepared as zwitterions that can be converted to pharma- ceutically acceptable salts.

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

[0033] Diacid hemiesters of tryptamines, such as psilocin or other hydroxytryptamines or isotryptamines, have been described previously. Prodrug strategies implemented by combining diacids with 4-hydroxy-tryptamine or 5-hydroxy-tryptamine have not been proposed, as prodrug strategies are typically not necessary when the drug is already soluble. Therefore, this aspect of the diacid hemiester prodrug strategy as described herein is believed to be novel and original.

[0034] In one aspect, the present invention provides a compound according to formula (I), (II), (III) or (IV): [ka] [ka] or a pharma- ceutically acceptable salt or zwitterion thereof, During the ceremony: (5) R1, R2, and R6 are each independently hydrogen, linear or branched alkyl, preferably C 1-5 alkyl, or arylalkyl; (6) R4: a. -X-CO2H, [wherein X is a linear, cyclic or branched, saturated or unsaturated carbon chain (preferably C 1-5 alkyl), or an aromatic ring optionally substituted with alkyl or COH; or b. (R9)(R10)N-, [wherein R9 is X-CO2H, where X is defined above, and R10 is a straight or branched alkyl (preferably C 1-5 alkyl) or arylalkyl] and; (7) R5 is hydrogen, linear or branched alkyl (preferably C 1-5alkyl), arylalkyl, or O-R5', where R5' is hydrogen, linear or branched alkyl (preferably C 1-5 alkyl); and (8) R7 and R8 are: a. each independently is hydrogen, straight or branched alkyl (preferably C 1-5 alkyl), or arylalkyl; or b. Forming together non-aromatic N-containing heterocycles optionally substituted with alkyl, preferably where the entire heterocyclic structure does not contain more than 12 atoms, preferably where the entire heterocyclic structure does not contain more than 12 atoms, for example, pyrrolidine (NC4 ring), piperidine (NC5 ring), or morpholine (NC4O ring).

[0035] Unless otherwise stated, a structure depicted herein is also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, a structure depicted herein is intended to include compounds that differ only in the presence of one or more isotopically enriched atoms; for example, hydrogen, carbon, nitrogen, oxygen, chlorine, or fluorine, respectively. 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 17 O. 18 O. 36 Cl or 18Compounds having the present structures including F substitutions are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention. Additionally, deuterium ( 2 The incorporation of heavier isotopes such as H) offers certain therapeutic advantages resulting from higher metabolic stability, e.g. In vivo It may provide increased half-life or reduced dosage requirements.

[0036] Unless otherwise stated, diastereomeric excess is expressed as %de, i.e., for diastereomers X and Y, diastereomeric excess of X=((xy) / (x+y))*100, where x and y are the proportions of X and Y, respectively.

[0037] Unless otherwise stated, enantiomeric excess is given as % ee, i.e., for enantiomers X and Y, the enantiomeric excess of X=((xy) / (x+y))*100, where x and y are the proportions of X and Y, respectively.

[0038] "Alkyl" by itself or as part of another substituent refers to a saturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by removal of one hydrogen atom from a single carbon atom of a parent alkane. The term "alkyl" includes cycloalkyl. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl, such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, and the like; butanyl, such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, and the like; and the like. In some embodiments, an alkyl group contains 1 to 20 carbon atoms (C1-C 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C1-C 10In 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 as used herein refers to an alkyl group substituted with an aryl group, such as C 1-6 It refers to an alkyl group, where the residue is linked to the main molecule via the alkyl group. An example of an arylalkyl is the benzyl group, i.e., the phenyl-methyl group.

[0040] "Substituted" when used to modify a particular group or radical means that one or more hydrogen atoms of the particular group or radical are replaced, each independently of the other, with the same or different substituents. The term "substituted" specifically envisions and takes into account one or more substituents that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as not to adversely affect the useful characteristics of the compound or adversely interfere with its function.

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

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

[0043] In some non-limiting examples, the compounds include diacid esters of tryptamine structures, such as 4-hydroxy-N,N-dimethyltryptamine (psilocin or 4-HO-DMT), 4-hydroxy-N,N-diethyltryptamine (4-HO-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-dimethyl)tryptamine, and 4-hydroxy-5-methyl-N,N-dialkyltryptamine. In some embodiments, the compounds include 4- and 5-substituted hemisuccinate, hemiglutarate, and citrate esters of the 4-hydroxy derivative of N,N-dimethyltryptamine (psilocin), N,N-diisopropyltryptamine (4-HO-DiPT), or N-methyl-N-isopropyl-tryptamine (4-HO-MiPT).

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

[0045] In some embodiments, the compound comprises a compound of formula I, II, III, or IV, where R1, R2, R5, 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 of formula I or II, where X is a C2 alkyl, thus forming a hemisuccinate ester of 4- or 5-hydroxy-diisopropyltryptamine. In some embodiments, the compound is a compound of formula I or II, where X is a C2 alkene, thus forming a hemifumarate ester of 4- or 5-hydroxy-diisopropyltryptamine. In some embodiments, the compound is a compound of formula I or II, where X is a C3 alkyl chain, thus forming a hemiglutarate ester of 4- or 5-hydroxy-diisopropyltryptamine.

[0046] In some embodiments, R7 and R8 are selected based on whether they maintain or enhance the compound's ability to induce hallucinogenic state.It is known that when R7 or R8 is larger than C4, the hallucinogenic activity of tryptamine is reduced.However, such compounds are still within the scope of the present invention if they are still 5HT2A agonists that can produce beneficial therapeutic effects without hallucinogenic state.

[0047] In some embodiments, the compounds of the present invention are diacid zwitterions. Thus, when X is a straight chain saturated alkyl, the diacids can include common straight chain alkyl α,ω-diacids, including, without limitation, 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 straight chain alkene, the diacids can include acids such as maleic acid, fumaric acid, or glutaconic acid. In other embodiments, the diacids can include branched acids such as citraconic acid, mesaconic acid, 2,2-dimethylsuccinic acid; substituted acids such as tartronic acid, 2-(2-hydroxyethyl)-malonic acid, a-hydroxyglutaric acid; citric acid; or aryl diacids such as phthalic acid, isophthalic acid, and p-phthalic acid, optionally with organic substituents on the aromatic ring.

[0048] In some embodiments, the compound may be one of the following:

[0049] (1) Psilocin-4-succinate [ka]

[0050] (2) N,N-diisopropyltryptamine-4-succinate [ka]

[0051] (3) N,N-diisopropyltryptamine-4-fumarate [ka]

[0052] (4) Psilocin-4-methyl-5-succinate [ka]

[0053] (5) Iso-N,N-dimethyltryptamine-6-succinate [ka]

[0054] (6) N,N-Diisopropyltryptamine-4-glutarate [ka]

[0055] (7) N-methyl N-isopropyltryptamine-4-glutarate [ka]

[0056] (8) Psilocin-4-glutarate [ka]

[0057] (9) N,N-Diethyltryptamine-4-glutarate [ka]

[0058] (10) N,N-Diethyltryptamine-4-succinate [ka]

[0059] (11) N,N-diisopropyltryptamine-4-(3,3-dimethylglutarate) [ka]

[0060] In some embodiments, the diacid modified tryptamines or isotryptamines exhibit product stability (oxidation and hydrolysis) and can be easily synthesized and purified. The diacid modified tryptamines or isotryptamines preferably exhibit superior solubility in biological matrices over drugs without the diacid modification, making them excellent drug candidates. Moreover, the diacid modified tryptamines preferably exhibit a relatively fast rate of hydrolysis in vivo so as to rapidly convert the prodrug to the active form of the drug. This can result in improved desirable pharmacokinetic properties for the prodrug, including a more reproducible pharmacokinetic profile. These properties can depend on the nature of the indole, the various substituents attached to the indole, and the nature of the diacid ester. The stability and hydrolysis rate can be determined experimentally.

[0061] In some embodiments, the compounds may include carbamate esters of tryptamine, where R4 is (R9)(R10)N-, where R9 and R10 define a carbamate residue and are as defined above. In some embodiments, the carbamate functionality includes zwitterionic amino-functional mono- or dicarboxylic acids linked via a carbamate, including, but not limited to: 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, e.g. 3-aminoproprionic acid, 4-amino-butyric acid; Other branched and aromatic amino acids, such as 4-amino-benzoic acid Examples of zwitterionic compounds include:

[0062] In some embodiments, the present invention provides 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 of 4-hydroxytryptamine (VI): [ka] [ka] may include.

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

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

[0065] The diacid moiety is metabolically cleaved in vivo to produce the active ingredient at a dose and kinetics sufficient to achieve the hallucinogenic state considered necessary for use in the treatment of depressive states, such as psychedelic-assisted psychotherapy. This is particularly advantageous in designing a convenient drug therapy that produces a hallucinogenic experience for a period of less than 8 hours, preferably less than 6 hours, and more preferably less than 4 hours. In this sense, the requirement for hydrolysis is an additional step and therefore may reduce the rate of onset of psychotropic properties when compared to injection of the free drug (without acylation of the hydroxyl function). A slightly slower onset rate may be preferred in some cases, especially in hallucinogenic untreated patients, to avoid abrupt onset that may cause anxiety. Thus, in a preferred embodiment, the onset rate 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 succinates, may reduce the potential for misuse by inhalation or snorting. As zwitterions, they are unlikely to be rapidly absorbed through tissues that lack esterase activity. Furthermore, zwitterions are unlikely to be directly absorbed into the brain by passive mechanisms. Compared to non-acylated forms, they may be cleaved slower in the intestine and absorbed slower, thus delaying the peak rate and the "high" feeling that a person with intent to abuse may seek.

[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 modifications thereto that will be understood by those skilled in the art. Preferred methods can include, but are not limited to, those described below. The reactions are carried out in a solvent or solvent mixture that is suitable for the reagents and materials used and that is suitable for the transformations effected. It will be understood by those skilled in the art of organic synthesis that the functional groups present on the molecule should be consistent with the proposed transformations. This may require judgment well within the skill of the artisan to change the order of synthetic steps or to select one particular processing scheme over another to obtain the desired compound of the present invention.

[0068] Protection and deprotection in the following processes can 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 transformations can be found in: Trost, BM et al., eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, 1st Edition, Pergamon Press, New York, NY (1991); March, J., Advanced Organic Chemistry.

[0069] 4- and 5-hydroxy-tryptamines 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 can be prepared starting from the corresponding hydroxy-indoles and diacid anhydrides using the synthetic scheme outlined in Scheme 1. Reaction conditions such as temperature, time, solvent selection, and work-up procedures are selected as appropriate for the experimental conditions as recognized by those skilled in the art. Restrictions on the substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and as a result, alternative or similar methods should be used. [ka]

[0071] As can be readily envisioned by one of ordinary skill in the art, other diacid prodrugs can be prepared using other diacid anhydrides.

[0072] Glutarate prodrug compounds can be prepared using glutaric anhydride using Scheme 2 below: [ka]

[0073] One 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 greater than 4 but less than 9. When pyridine is used, the product precipitates directly from the reaction mixture in pure form as a zwitterion.

[0074] The solid zwitterion can be converted to a suitable salt, e.g., the hydrochloride salt, by addition of anhydrous HCl (g) in a suitable solvent or by trituration in anhydrous ethereal HCl or dioxane HCl.

[0075] Synthesis of diacid hemiester prodrugs can also be prepared using a variety of 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 doubly activated forms of the diacids, such as dichlorides, di-N-hydroxysuccinimide (using dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide and DMAP), di-imizadolides (using carbonyldimidizole), or other activated forms of the diacids using the hydroxy form of an active heterocyclic species. When using doubly activated forms, it is preferred to use a 2-25 fold excess of the doubly activated diacid to avoid covalent attachment of the two tryptamines to the diacid.

[0076] Similarly, one skilled in the art can apply these methods to 6- or 7-hydroxyisotryptamines.

[0077] Formulations and Compositions The present invention also provides pharma- ceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described herein, formulated together with one or more pharma- ceutically acceptable carriers (additives) 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 preferred to administer the compounds as a pharmaceutical composition.

[0078] The term "pharmaceutical composition" refers to a composition that contains the compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, and includes adjuvants, excipients, or vehicles, such as diluents, osmolality enhancers, preservatives, bulking agents, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants, polymers, solubilizers, stabilizers, antioxidants, and dispersants, depending on the nature of the mode of administration and dosage form. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the patient.

[0079] As used herein, "oral" administration includes swallowing for ingestion in the stomach or intestine, and further includes lingual, sublingual, buccal and oropharyngeal administration. The compounds of the present invention can be administered for any of the uses or methods described herein by any suitable means, for example, orally, such as tablets, capsules (each of which may include sustained or extended release formulations), pills, powders, granules, elixirs, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually (e.g., thin films, effervescent tablets, or tablets that dissolve naturally under the tongue); parenterally, such as by subcutaneous, intravenous, intramuscular injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, such as by inhalation spray, including administration to the nasal mucosa; or rectally, such as in the form of a suppository.

[0080] Dosage regimens for the compounds described herein will of course vary depending on known factors such as the pharmacokinetic and pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of symptoms; type of concurrent treatment; frequency of treatment; route of administration, renal and hepatic function of the patient; and the desired effect. The selected dosage level may also depend on additional factors including the activity of the particular compounds and pharmaceutical compositions described herein, whether an ester, salt, or amide substituent of the compound is used, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, duration of treatment, other drugs that may be administered to the patient, compounds and / or materials used in combination with the particular compound used, and similar factors are well known in the medical arts.

[0081] Generally, when used for the indicated effects, dosages of prodrugs for a treatment session range from between about 0.001 to about 500 mg per dose, such as 10, 20, 30, 40, 50, 100 or 200 mg, preferably between about 0.01 to about 200 mg per dose, and most preferably between about 1 to about 50 mg per dose. Intravenously, the most preferred doses range from about 0.01 to about 10 mg / kg / min during a constant rate infusion.

[0082] The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in multiple divided doses, such as two, three, or four times a day. Alternatively, doses may be provided weekly, biweekly, or monthly. In preferred embodiments, only one or two doses are required for antidepressant effect, which may extend for one, two, three, or six months, or longer.

[0083] For tablet dosage forms, depending on the dose, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant comprises 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0084] Binders are generally used to impart cohesion to tablet formulations.Suitable binders include microcrystalline 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, microcrystalline cellulose, starch and calcium hydrogen phosphate dihydrate.

[0085] Tablets may optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, surfactants are typically in an amount of 0.2% to 5% by weight of the tablet, and glidants are typically in an amount of 0.2% to 1% by weight of the tablet.

[0086] Tablets also generally contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are generally present in an amount of 0.25% to 10%, preferably 0.5% to 3%, by weight of the tablet.

[0087] Other conventional ingredients include antioxidants, colouring agents, flavouring agents, preservatives and taste masking agents.

[0088] Exemplary tablets contain up to about 80% by weight of drug, about 10% to about 90% by weight of binder, about 0% to about 85% by weight of diluent, about 2% to about 10% by weight of disintegrant, and about 0.25% to about 10% by weight of lubricant.

[0089] 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 extrusion granulated before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; or may be encapsulated.

[0090] Tablet formulation 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 of which is incorporated herein by reference in its entirety.

[0091] 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 packed into a No. 1 gelatin capsule.

[0092] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can 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 emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid, for example from a sachet.

[0093] The compound of the present invention may be directly administered into bloodstream, into muscle, or into internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous.Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors and infusion techniques.

[0094] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and pH adjusting or buffering agents (preferably to a pH of 3.0-7.0, preferably 4.0-6.0, and more preferably 4.5-5.5), although for some applications they may be more suitably formulated as sterile non-aqueous solutions or as a dry form for use in conjunction with a suitable vehicle such as sterile, pyrogen-free water or a preformed, premixed aqueous buffer. Osmotic agents may be included to control osmotic pressure.

[0095] The preparation of parenteral kits for reconstitution at the point-of-care under sterile conditions, eg, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0096] A typical injectable formulation is produced by aseptically placing at least one compound of the invention (e.g., 25 mg) into a vial as a sterile-filtered solution, aseptically lyophilizing, and sealing. For use, the contents of the vial are mixed with, e.g., 2 mL of injectable saline, optionally with appropriate amounts of osmolality supplements and pH adjusters to achieve a slightly acidic to neutral pH (e.g., pH 4-7), to produce an injectable formulation that is mild but retains the solubility and / or stability of the prodrug.

[0097] The compounds of the present invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the above-mentioned modes of administration.

[0098] 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 can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, i.e., as carriers, diluents, or solubilizers. Alpha, beta, and gamma cyclodextrins are most commonly used for these purposes, and examples of these can be found in PCT International Publication Nos. WO91 / 11172, WO94 / 02518, and WO98 / 55148, the disclosures of which are incorporated herein by reference in their entirety.

[0099] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those skilled in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0100] 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 may start dosing of the compounds of the invention used in the pharmaceutical composition at levels lower than required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0101] In general, a suitable daily dose of a compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0102] As used herein, "therapeutically effective amount" refers to the amount of compound administered that relieves to some extent one or more of the symptoms of the disorder being treated.For the treatment of depression, a therapeutically effective amount refers to an 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).A therapeutically effective amount can be an amount less than that required for hallucinatory state.

[0103] An effective dosage may 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 achieve prophylactic or therapeutic treatment, directly or indirectly. As understood in the clinical context, an effective dosage of a drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another treatment, drug, compound or pharmaceutical composition.

[0104] Treatment Methods and Uses Treatment with the novel prodrugs of the present invention can substantially alleviate clinical or subclinical depression and avoid relapse, especially when used in combination with psychotherapy for the treatment of depression.It is known that the administration of an effective dose of psilocybin can rapidly and significantly reduce depressive symptoms, and many subjects achieve remission through a four-week follow-up (Davis et al.).Without being limited by theory, it is believed that the hallucinogenic state is associated with beneficial effects, but some compounds that are 5HT2A agonists can produce desirable therapeutic effects without hallucinogenic states.One embodiment of the present invention includes prodrugs of 5HT2A agonists that provide beneficial therapeutic states.

[0105] In general, the invention includes the use of the compounds of the invention herein for treating any disease or disorder that can be alleviated by a 5HT2A agonist, or the use of the compounds of the invention herein for the manufacture of a medicament for treating any disease or disorder that can be alleviated by a 5HT2A agonist, or a method of treating any disease or disorder that can be alleviated by a 5HT2A agonist.

[0106] In some embodiments, the present invention may include the use of the compounds of the present invention to treat psychiatric disorders.In some embodiments, the present invention may include the use of the compounds of the present invention to treat depression, and in particular drug-resistant depression.Other conditions that may be treated include: anxiety disorders, including generalized anxiety disorder, depression, including postpartum depression, cluster headaches, obsessive-compulsive disorder, personality disorders, including conduct disorder, drug disorders, including alcoholism, nicotineism, opioidism, cocaineism, and other addictions, including gambling disorders, eating disorders, and body dysmorphic disorder, chronic pain, or chronic fatigue.

[0107] In some embodiments, the present invention may include a method for treating a psychiatric disorder, comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof. In one embodiment, a method for treating depression is provided, comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof. The depression may be drug-resistant depression or depression.

[0108] For example, a patient diagnosed with depression may be screened prior to treatment and then prepared for a dosing session by a trained psychotherapist. Within the dosing session, the compound of the present invention may be administered to the patient at a rate of 0.01-0.3 mg / kg by injection of a sterile solution. The patient is preferably blindfolded and seated for the duration of the session. For safety, a trained health care professional may monitor the patient during the dosing session, which may last up to 12 hours. In some cases, music may be played for the patient. When the health care professional is able to determine that the drug substance has been removed, the psychotherapist assists the patient with any questions related to the hallucinatory experience, after which the patient may be discharged.

[0109] To further alleviate any anxiety that may arise related to treatment, a physician may choose to divide the therapeutic dose, thereby reducing the initial onset of psychoactivity, before applying the full complement of dosages to achieve the full effect.

[0110] In some embodiments, treatment with the compound of the present invention can be combined with concomitant treatment with another antidepressant, either simultaneously or consecutively.In a preferred embodiment, treatment with the compound of the present invention is combined with psychotherapy, which can be applied before or after treatment. In the former case, the session can focus the patient on the intention of treatment. In the latter case, psychotherapy is preferably performed within 48 hours of the medication session to help the patient integrate any feelings, emotions, perspectives or thoughts that may have occurred during the session, and also to allow the psychotherapist to provide advice on how best to change thinking or behavior patterns to improve antidepressant outcome.Psychotherapy can be continued as necessary after the medication session, for example up to another 3 months, to help the patient integrate any experiences or learning that have occurred to the patient during the medication session. EXAMPLES

[0111] Working Example The present invention may be described with reference to the following examples, which are provided for illustrative purposes only. All terms, names, abbreviations or acronyms are those commonly understood by those of ordinary skill in the art. Compounds shown in their zwitterionic form may be readily envisioned in their neutral form by those of ordinary skill in the art, and vice versa.

[0112] 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 of psilocin is the same as psilocin-4-glutarate or N,N dimethyltryptamine-4-glutarate.Similarly, the 4-hemiglutarate of 4-OH-DiPT is the same as N,N diisopropyltryptamine-4-glutarate.

[0113] Example 1. 4-hemisuccinate ester of psilocin 4-Hydroxyindoles were prepared using methods described in the literature such as Kargbo 2020 ACS Omega) or methods somewhat adapted from those described in the literature: 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 give 4-acetoxy-3-(N,N-dimethylaminoethyl)indole, which was deprotected using aqueous base to give 4-hydroxy-dimethyltryptamine (psilocin).

[0114] 4-Hydroxytryptamine was reacted with excess succinic anhydride catalyzed by N,N-dimethylaminopyridine in dichloromethane (DCM) containing triethylamine to give psilocin-4-succinate. A precipitate formed, which was recovered after decantation and trituration with DCM. The solid was acidified in aqueous HCl, purified by chromatography, and recovered after evaporation of the solvent. The structure was confirmed by NMR. The purity was determined by HPLC.

[0115] Example 2. 4-Hydroxy-diisopropyltryptamine (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 eq.) was added to a 250 mL round bottom flask containing a stir bar, dissolved in dichloromethane (28 mL, 5 volumes) and stirred at room temperature. Succinic anhydride (1.3 eq.) was then added slowly to the stirred solution and the resulting suspension was stirred overnight at room temperature. The precipitate formed in the reaction mixture was collected by decantation and trituration with DCM. The solid was acidified with aqueous HCl, purified by chromatography, and collected after evaporation of the solvent. The structure was confirmed by NMR and the purity was determined by HPLC.

[0116] Example 3. 4-Hemi-Fumarate Ester of 4-OH-DiPT 4-Benzyloxyindole was reacted with oxalyl chloride in the presence of a Friedel-Crafts catalyst in diethyl ether, and the resulting intermediate was quenched with di-isopropylamine. The resulting oxalyl-amide was reduced with lithium aluminum hydride (LAH) in THF to give 4-benzyloxy-3-(N,N-diisopropylaminoethyl)indole, which was then deprotected using H2 and Pd / C to give 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. This material was reacted with an excess of inactivated fumaric acid (N-hydroxysuccinimide) in dichloromethane, followed by quenching of the unreacted N-hydroxysuccinimide ester with aqueous acid to liberate 4-fumaroyl-3-(N,N-diisopropylaminoethyl)indole.

[0117] Example 4. 5-Hydroxy-4-methyl-dimethyltryptamine 5-hemisuccinate 4-Methyl-5-hydroxyindole (1) was reacted with benzyl chloride in the presence of K2CO3 in ACN to give 5-benzyloxy-4-methyl-indole, which was then reacted in the presence of Friedel-Crafts catalyst in diethyl ether, and the resulting intermediate was quenched with di-methylamine. The resulting oxalyl-amide was reduced with lithium aluminum hydride (LAH) in THF to give 4-methyl-5-benzyloxy-3-(N,N-dimethylaminoethyl)indole, which was then deprotected using H2 and Pd / C to give 4-methyl-5-hydroxy-3-(N,N-dimethylaminoethyl)indole. This material was reacted with succinic anhydride in dichloromethane catalyzed by N,N-dimethylamino-pyridine to give 4-methyl-5-succinoyl-3-(N,N-dimethylaminoethyl)indole.

[0118] Example 5. N,N-Dimethylisotryptamine-6-succinate Following the method outlined in Glennon (J Med Chem 1984), 6-O-benzyl-dimethylisotryptamine was prepared by N-alkylation of 5-BzO-indole using NaH. The benzyl group was removed by catalytic hydrogenation using Pd / C / H2 to give the HO-functional group, which was succinylated in the next step using succinic anhydride to give the named species.

[0119] Example 6. N,N-Diisopropyltryptamine-4-glutarate To an oven-dried 50 mL round-bottom flask containing 1.2 mL of anhydrous DCM was added glutaric anhydride (0.205 g, 1.8 mmol, 1.8 equiv) and the suspension was stirred under Ar. A solution of 4-OH-DiPT (0.26 g, 1 mmol, 1 equiv) in 1.5 mL of 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) and the resulting suspension was stirred overnight at room temperature under Ar.

[0120] The mixture was decanted and the solid was triturated with anhydrous DCM (3 mL) containing a few drops of anhydrous MeCN. The suspension was acidified with 1 M HCl (ca. 1.1 eq.) 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).

[0121] 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, which was filtered, washed with ether, and dried. Yield (>95%, purity >95%; DSC endotherm 174C). The solid could be dissolved in water to 50mg / ml and lyophilized to form a white "cake".

[0122] Example 7. Hemiester of 3,3-dimethylglutaric acid and 4-hydroxydiisopropyltryptamine 4-Hydroxy-3-(N,N-diisopropylaminoethyl)indole was reacted with 3,3-dimethylglutaric anhydride in pyridine using the stoichiometry and parameters described in Example 6 to give 4-succinoyl-3-(N,N-diisopropylaminoethyl)indole. The precipitate 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.

[0123] Example 8. Psilocin-4-glutarate 4-Hydroxydimethyltryptamine (psilocin) was reacted with excess glutaric anhydride in dichloromethane (DCM) containing triethylamine to give psilocin-4-glutarate. In another example, the reaction took place in pyridine. In both cases, a precipitate formed, which was recovered after decantation and trituration with THF. The solid was washed with DCM and then dried. The structure was confirmed by NMR.

[0124] The reaction product was suspended in 1M HCl-ether to give the corresponding HCl salt form of the product, which was recovered by filtration in high yield and purity.

[0125] Example 9. HCl salt of N,N-diisopropyltryptamine-4-glutarate In a three-necked 1 L round bottom flask under argon was added 4-OH-DiPT (31.8 g, 0.122 mol, 1 equiv) (160 mL) 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 portions. The resulting suspension was stirred at room temperature overnight.

[0126] Anhydrous DCM (160 mL) was added to the suspension, which was cooled for 2 h to 0° C. The solid was filtered and washed with 60 mL of cold anhydrous DCM and dried overnight.

[0127] The dried solid was triturated with 160 mL of anhydrous DCM, followed by 160 mL of anhydrous THF, then 160 mL of anhydrous DCM at 0° C. After drying, 33.0 g was obtained in 72% yield and 98.1% purity by HPLC. The structure of the zwitterion was confirmed by 1H-NMR (DMSO-d6) and MS [M+H]. + =375.2.

[0128] To 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 above 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 Et2O. The solid was dried to give 3.16 g of the corresponding hemiester tryptamine HCl salt (96% yield, 99.0% purity by HPLC, [M+H] + =375.1).

[0129] Example 10. Hemiglutarate ester of psilocin Following the procedure described above, psilocin was reacted with 1.2 equivalents of glutaric anhydride in hot THF to give psilocin-4-glutarate which precipitated from the reaction mixture. The precipitate was collected by filtration, washed with cold 1:1 DCM / THF, and dried.

[0130] 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 approx. 50%. Purity >95% by HPLC.

[0131] Example 12. Comparative rates of prodrug hydrolysis in serum Pooled gender-mixed human plasma (2 ml), mouse plasma, rat plasma and dog plasma were equilibrated at 37°C. Compound of Example 9 was added to achieve a concentration of 1.0 ug / mL. Aliquots (50 uL) of this mixture were withdrawn at designated time intervals (0, 0.004, 0.5, 1, 2 and 4 hours) and quenched with 200 uL of methanol / acetonitrile (1:1). Samples were vortexed and stored at -80°C until analysis. Assays were performed in triplicate. Control samples were performed in phosphate buffered saline (PBS, pH 7.4) and simulated gastric fluid (SGF, pH 2). Samples were analyzed by HPLC-MS to determine the amount of prodrug and drug in each sample tested. Table 1 shows the average concentration of prodrug remaining at different time points of the experiment. This experiment demonstrates the rapid enzymatic cleavage of the prodrug in plasma versus the slow non-enzymatic hydrolysis in relevant biological media.

[0132] [Table 1]

[0133] Example 13. Pharmacokinetics in rats The compound from Example 9 was administered to rats by injection (intravenous and subcutaneous) using sterile solutions (2 mg / ml) at rates of 1.4 to 2 mg / kg. Blood samples were taken at 15, 30, 45, 60, 120, 240 and 360 minutes and analyzed by LCMS for drug and prodrug. PK profiles of the prodrug and active species were obtained and the relative bioavailability was determined for each route of administration.

[0134] To demonstrate the activity of the drug, PK-PD type curves were generated (Figures 1 and 2). In rodents, the prodrug was not observed as it was rapidly converted to the active form. The relevant PK parameters for intravenous (iv) and subcutaneous (sc) administration of 4-HO-DiPT were determined and are shown in Table 2:

[0135] [Table 2]

[0136] In some cases, Head Twitch Responses (HTR) or Wet Dog Shakes (WDS) were recorded by visual observation and the associated muscle twitches were counted. In general, the intensity of the HTR was proportional to the plasma concentration of 4-HO-DIPT, and the highest intensity of the head twitch occurred at the Tmax of the PK profile.

[0137] FIG. 1 shows the plasma concentration of 4-HO-DiPT (ng / ml) versus time following subcutaneous administration of N,N-diisopropyltryptamine-4-glutarate at a rate of 2 mg / kg.

[0138] The pharmacokinetics of 1.34 mg / ml 4-HO-DiPT HCl administered by intravenous or subcutaneous injection was performed in parallel under identical conditions as described above. Figure 2 shows the plasma concentration of 4-HO-DiPT (ng / ml) versus time for the different doses. Increased variability of the active species is readily apparent when administered subcutaneously and intravenously. PK parameters are shown in Table 3.

[0139] [Table 3]

[0140] Example 17. Pharmacokinetics in human volunteers The compound from Example 6 (N,N-diisopropyltryptamine-4-glutarate) was administered to human volunteers by subcutaneous injection of a sterile solution (1 mg / ml) at a dosage of 0.1-0.6 mg / kg. Blood samples were taken at 5, 15, 30, 45, 60, 120, 240 and 480 minutes and 24 hours. Samples were analyzed by LCMS for drug and prodrug. Subjective effects were measured using a standardized questionnaire. PK analysis showed maximum plasma concentrations (CMax) approximately 45 minutes after injection. Subjective effects indicate the intensity of psychoactivity, which correlates with blood levels.

[0141] The compound from Example 2 (4-hemisuccinate ester of 4-OH-DiPT) was administered to human volunteers by oral ingestion of a tablet containing 50 mg of prodrug. Blood samples were taken at 5, 15, 30, 45, 60, 120, 240 and 480 minutes and 24 hours. Samples were analyzed for drug and prodrug by LCMS. Subjective effects were measured using a standardized questionnaire. PK analysis showed a CMax of approximately 90 minutes after injection. Subjective effects indicate the intensity of psychoactivity, which correlates with blood levels.

[0142] Example 18. Use in treatment The compound of Example 6 (N,N-diisopropyltryptamine-4-glutarate) was administered to human patients suffering from depression by intramuscular (im) or subcutaneous injection (approximately 25 mg; 0.4-0.5 mg / kg) or orally using tablets (approximately 50-200 mg; 0.8-3.2 mg / kg). In another example of use, the compound of Example 6 (4-hemiglutarate ester of 4-OH-DiPT) was administered similarly. Prior to the dosing session, patients are qualified for experience by measurement of depression scores, screened for exclusions (e.g., history of psychiatric illness, adverse cardiac conditions, pregnancy), and finally, the patient is encouraged to clearly state the intention of the dosing session. Dosing is performed in a quiet clinic setting, with the patient comfortably resting in a tilted but unrestrained position to avoid falling. The patient's eyes are covered and music is played. The drug is administered. After 4 hours, the patient reports that they no longer feel the effects of the drug and are asked to get up and sit down under supervision. If they feel normal, they are allowed to stand (supervised), and if they feel under control, they are allowed to move around. After 1 hour, the patient is released. By 24 hours, the patient returns to the clinic and sees the psychotherapist to discuss the session in detail. The patient records a depression score by questionnaire and is released again. Periodically, the patient is asked about the recurrence of depressive symptoms.

[0143] Example 19. Injectable formulation kit A vial was prepared with 25 mg of the compound in Example 6 as the hydrochloride salt (sterile powder or lyophilisate). In another vial was placed 1 ml of a sterile filtered solution containing 70 mM Na2HPO4. The final pH of the solution was 4.0-5.0. These two components constitute the kit for the reconstitution of the formulation for subcutaneous injection at the point of care.

[0144] Example 20. Deuterated analog of N,N-diisopropyltryptamine-4-glutarate (FT-104) HCl The following multi-step synthesis was carried out to prepare a deuterated analog of N,N-diisopropyltryptamine-4-glutarate.

[0145] (a) Reduction with LiAlD4 [ka]

[0146] A three-neck 250 ml round bottom flask (labeled Flask 1) was placed on a magnetic stirrer equipped with a condenser, dropping funnel and a gas inlet adapter.

[0147] Flask 1 was flushed with argon for 30 minutes. 70 mL of anhydrous THF was added to the flask and stirring was started.

[0148] LiAlD4 (2.56 g, 4 eq.) was added slowly in portions over 15 min. After the addition of LiAlD4, stirring was continued at room temperature for an additional hour.

[0149] 4.4 g of 2-(4-hydroxy-1H-indol-3-yl)-N,N-diisopropyl-2-oxoacetamide was taken in a 250 ml flask (labeled as flask 2) containing 70 ml of anhydrous THF and mixed well. The suspension in flask 2 was transferred to a dropping funnel and slowly added to the LiAlD4 suspension in flask 1 in 45 minutes. During the addition, the temperature rose. The dropping rate of the starting material in the dropping funnel was adjusted so that the reaction temperature was below 40°C.

[0150] After the addition, the reaction mixture was slowly started to heat up to 75° C. using an oil bath, increasing the temperature in 10° C. intervals each time, waiting until the desired temperature was reached.

[0151] The reaction mixture was refluxed for 5 h and the reaction was monitored by LCMS.

[0152] The heat was removed, the mixture was cooled to 50° C., and the oil bath was replaced with an ice bath.

[0153] 4.5 ml of THF:H2O (1:1) was slowly added, followed by 2.3 ml of 15% NaOH and 5 ml of H2O. The reaction mixture was stirred for 30 min.

[0154] The reaction mixture was filtered through a silica gel pad and washed with 5x5ml THF. It was concentrated using a rotary evaporator and dried under high vacuum. Weight of solid 4-HO-DiPT-D4(L) SPS-04-205-1: 2.99 g (yield: 85%).

[0155] The structure of DiPT-D4 is: [M+H] + = 265.07 and was consistent with 1H-NMR.

[0156] (b) Coupling with glutaric anhydride [ka]

[0157] A three-neck 250 ml round bottom flask was placed on a magnetic stirrer equipped with a gas inlet adapter.

[0158] The flask was flushed with argon for 15 minutes. 15 ml of anhydrous pyridine was added along with 2.99 g of 4-HO-DiPT-D4. Stirring gave a brown solution.

[0159] Glutaric anhydride, 1.65 g (1.3 eq.) was charged in two portions and stirring continued under argon. The reaction mixture became cloudy indicating product formation. The reaction mixture was left stirring under argon overnight.

[0160] The reaction was monitored by LCMS the next morning (approximately 95% conversion) and the reaction mixture was cooled using an ice / water bath.

[0161] 15 ml of anhydrous DCM was added and stirring was continued for a further 2 h.

[0162] The solid was filtered and freeze-dried. Weight of solid: 3.8 g.

[0163] This solid was triturated multiple times with 5 volumes of anhydrous DCM followed by 5 volumes of anhydrous THF at 0° C. to remove pyridine from the product, monitored by LCMS.

[0164] Weight of solid N,N-diisopropyltryptamine-4-glutarate-D4(L) AAT-12-157-2: 1.45 g (yield: 34%) The structure of N,N-diisopropyltryptamine-4-glutarate-D4 is: [M+H] + =379.13 and 1 H-NMR was consistent.

[0165] HCl salt formation [ka]

[0166] A three-neck 50 ml round bottom flask was placed on a magnetic stirrer equipped with a gas inlet adapter.

[0167] Charged with 3.4 ml EtO and 3.4 ml 2M HCl in EtO (1.8 eq.). Cooled to 0° C. using an ice / water bath.

[0168] 1.43 g of FT-104-D4 was crushed with a spatula and slowly added to the stirred solution. Stirring was continued for an additional 2 hours at 0°C.

[0169] Filtered and washed with Et2O 3x1 ml and transferred to a 20 ml vail.

[0170] Dried under high vacuum. Weight of white solid (L) AAT-12-163: 1.418 g (90% yield).

[0171] The structure of N,N-diisopropyltryptamine-4-glutarate-D4 (FT-104-D4) HCl is: Mass: [M+H] + =379.20;[2M+H] + =756.80 and 1 H-NMR was consistent.

[0172] References All publications, patents, patent applications, etc. mentioned in the above specification are hereby incorporated by reference in their entirety, including: 1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th edition). https: / / doi.org / 10.1176 / appi.books.9780890425596 2. Anderson, W.K., and 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., and 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., and 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., and 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., and 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., and Reider, P.J. (1994). Improved Fischer Indole Reaction for the Preparation of N,N-Dimethyltriptamines: 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., and 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., and 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., and Nelson, D. (1984).Synthesis and Evaluation of a Novel Series of N,N-Dimethyltriptamines.Chemischer Informationsdienst, 15(24).https: / / doi.org / 10.1002 / chin.198424187 13. Hofmann A, Troxler F. Esters of indoles. U.S. Pat. No. 3,075,992 and Process for the production of new esters of the indole series Swiss Patent No. 386,422. 14. International Society for CNS Drug Development.(2003).GRID-HAMD-17 Structured Interview Guide.ISCDD. 15. Kargbo, R.B., Sherwood, A., Walker, A., Cozzi, N.V., Dagger, RE, Sable, J., O'Hern, K., Kaylo, K., Patterson, T., Tarpley, G., and Meisenheimer, P. (2020). Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin.ACS Omega, 5(27), 16959-16966. https: / / doi.org / 10.1021 / acsomega.0c02387 16. Lieberman, H.A., & Lachman, L. (1980). Pharmaceutical dosage forms--tablets, vol.1. Marcel Dekker. 17. Luethi, D., & Liechti, M.E. (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., and 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., and Shulgin, A. (2017). Tihkal: the continuation. Transform Press. 22. Silverman, RB, and Holladay, MW (2014).Prodrugs and Drug Delivery Systems.The organic chemistry of drug design and drug action.Elsevier Academic Press. 23. Watts, R., and Luoma, JB (2020). The use of the psychological flexibility model to support psychedelic assisted therapy. Journal of Contextual Behavioral Science, 15, 92-102. 24. Patents GB942548, GB912714 and US9630941.

[0173] Definitions and Interpretation The description of the present invention has been presented for purposes of illustration and description, but it is not intended to be exhaustive or limited to the invention in the disclosed form. 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 selected 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 appropriate for the particular use contemplated. To the extent that the following description is of specific embodiments or particular uses of the invention, it is intended to be illustrative only and not limiting of the invention as claimed.

[0174] The corresponding structures, materials, acts, and equivalents of all means or steps and functional elements in the claims appended hereto are intended to include any structures, materials, or acts for performing a function in combination with other claimed elements as specifically claimed.

[0175] References in the specification to "one embodiment," "an embodiment," or the like indicate that the embodiment being described may include a particular aspect, feature, structure, or characteristic, but not necessarily all embodiments include that aspect, feature, structure, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment that is referenced in other parts of the specification. Moreover, when a particular aspect, feature, structure, or characteristic is described in connection with an embodiment, it is within the knowledge of one of ordinary skill in the art to combine, affect, or associate such aspect, feature, structure, or characteristic with other embodiments, regardless of whether such association or combination is explicitly described. In other words, an element or feature may be combined with any other element or feature in different embodiments unless there is an obvious or inherent incompatibility between the two or unless it is specifically excluded.

[0176] It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a predicate for the use of exclusive terminology such as "solely," "only," and the like, or the use of a "negative" limitation in connection with the recitation of claim elements. The terms "preferably," "preferred," "preferred," "optionally," "may," and similar terms are used to indicate that the recited element, item, condition, or step is an optional (but not essential) feature of the invention.

[0177] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated.

[0178] It will be understood by those skilled in the art that for any and all purposes, especially with respect to providing a written description, all ranges described herein also encompass any and all possible subranges and combinations of subranges, as well as the individual values, particularly integer values, that make up the range. A described range (e.g., mass percent or carbon group) includes each specific value, integer, decimal, or unit within the range. Any recited range can be easily recognized as specifically describing and allowing the same range to be broken down into at least 2, 3, 4, 5, or 10 equal parts. As a non-limiting example, each range discussed herein can be easily broken down into a lower third, a middle third, and an upper third, etc.

[0179] It will also be appreciated by those of ordinary skill in the art that all ranges recited herein, and all language such as "between," "up to," "at least," "greater than," "less than," "more than," "or more," and the like, are inclusive of the recited numbers and that such terms refer to ranges that may then be broken down into sub-ranges, as discussed above.

Claims

1. Formula (I), (II), (III) or (IV) 【Chemistry 1-1】 【Chemistry 1-2】 or a pharma- ceutically acceptable salt or zwitterion thereof, comprising the formula: During the ceremony: (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), or an aromatic ring optionally substituted with alkyl or COH; or b. (R9)(R10)N-, [wherein R9 is X-CO2H, where X is defined as above, and R10 is a straight or branched alkyl (preferably C １－５ alkyl) or arylalkyl] and (3) R5 is hydrogen, linear or branched alkyl (preferably C １－５ alkyl), arylalkyl, or O-R5', where R5' is hydrogen, linear or branched alkyl (preferably C １－５ alkyl); and (4) R7 and R8 are: a. each independently represents hydrogen, straight 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 where the entire heterocyclic structure does not contain more than 12 atoms; The above compound.

2. （１） Psilocin-4-succinate 【Chemistry 2】 (2) N,N-diisopropyltryptamine-4-succinate, 【Chemistry 3】 (3) N,N-diisopropyltryptamine-4-fumarate 【Chemistry 4】 (4) Psilocin-4-methyl-5-succinate 【Chemistry 5】 (5) Iso-N,N-dimethyltryptamine-6-succinate 【Chemistry 6】 (6) N,N-diisopropyltryptamine-4-glutarate 【Chemistry 7】 (7) N-methyl-N-isopropyltryptamine-4-glutarate 【Chemistry 8】 (8) Psilocin-4-glutarate 【Chemistry 9】 (9) N,N-diethyltryptamine-4-glutarate 【Chemistry 10】 (10) N,N-diethyltryptamine-4-succinate 【Chemistry 11】 (11) N,N-diisopropyltryptamine-4-(3,3-dimethylglutarate) 【Chemistry 12】 2. The compound of claim 1 selected from the group consisting of:

3. During the ceremony: (1) R1, R2, and R6 are each independently H or a linear C １－５ alkyl; (2) R4 is -X-CO2H, where X is a straight or branched C alkyl group optionally substituted with OH or CO2H. １－５ is a carbon chain; (3) R5 is hydrogen, straight or branched C １－５ alkyl, arylalkyl, or O-R5', where R5' is hydrogen, straight or branched C １－５ is alkyl; and / or (4) R7 and R8 are each independently H or a straight or branched C １－５ selected from alkyl, The compound of claim 1.

4. R7 and R8 are the same or different and are linear or branched C １－４ The compound of claim 3, wherein the aryl group is an alkyl group.

5. The compound according to claim 4, wherein R7 and R8 are each methyl or isopropyl.

6. 4. The compound of claim 3, wherein X is a linear C1-C3 chain optionally substituted with OH or CO2H.

7. 6. The compound of claim 5, wherein X is a linear C3 chain.

8. 8. The compound of claim 7, wherein R7 and R8 are both methyl, or R7 and R8 are both isopropyl, or one of R7 and R8 is methyl and the other is isopropyl.

9. At least one or more of hydrogen, carbon, nitrogen, oxygen, chlorine, or fluorine, respectively ２ H. ３ H. １１ C. １３ C. １４ C. １３ N. １５ N. １７ O. １８ O. ３６ Cl or １８ The compound according to any one of claims 1 to 8, wherein F is substituted.

10. A composition comprising a compound according to any one of claims 1 to 9 and a pharma- ceutically acceptable excipient.

11. The composition of claim 10 comprising an oral dosage formulation or an injectable formulation.

12. The composition of claim 11, which is an injectable solution.

13. The composition of claim 12, wherein the solution has a pH between about 3.0 and 7.0, preferably 4.0 to 6.0, and more preferably 4.5 to 5.

5.

14. A method for treating a psychiatric disorder comprising administering an effective amount of a compound according to any one of claims 1 to 9.

15. 15. The method of claim 14, wherein the psychiatric disorder is depression.

16. A compound according to any one of claims 1 to 9 for use in the treatment of a psychiatric disorder such as depression.

17. 13. A method for making a compound of claim 1 comprising reacting a tryptamine, including hydroxytryptamine or hydroxyisotryptamine, with a cyclic anhydride in a suitable anhydrous solvent.

18. 20. The method of claim 17, wherein the solvent contains a base having a pKa greater than 4 and less than about 9, and the resulting compound is isolated as a zwitterion.

19. 20. The method of claim 18, wherein the solvent is pyridine.

20. 20. The method of claim 19, wherein the compound is a compound according to claim 2.

21. 18. The method of claim 17, wherein the tryptamine is 4-OH diisopropyltryptamine or syrosine and the cyclic anhydride is succinic anhydride or glutaric anhydride.

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