Tryptamine prodrug

Abstract

The present invention provides tryptamine prodrug compounds of formula (I): [Formula 1] The compound represented by the formula: JPEG2023531311000036.jpg46170 [wherein each symbol is as defined in the specification], or a salt or zwitterion thereof, is converted to an active form having 5HT2A receptor agonist activity and is useful as a drug for treating depression.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Application No. 63 / 045,901 (filed Jun. 30, 2020, title of invention: TRYPTAMINE PRODRUGS), U.S. Provisional Application No. 63 / 109,095 (filed Nov. 3, 2020, title of invention: TRYPTAMINE PRODRUGS) and U.S. Patent Application No. 17 / 364,047 (filed Jun. 30, 2021, title of invention: TRYPTAMINE PRODRUGS). The entire contents of U.S. Provisional Application No. 63 / 045,901, No. 63 / 109,095 and U.S. Patent Application No. 17 / 364,047 are incorporated herein by reference.

[0002] Technical field The present invention relates to novel tryptamine compounds, methods for producing and using such compounds, compositions containing such compounds, and their use.

Background Art

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

[0004] The serotonin receptor system has been associated with depressive and dysthymic 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 that produce psychedelic states and have been used in traditional medicine may have therapeutic potential for treating mood disorders, distress, depression, etc. For example, ayahuasca is a natural form of dimethyltryptamine (DMT), which can be ingested when combined with monoamine oxidase inhibitors and produces a long-lasting psychedelic state that can vary but lasts for 6 to 15 hours. DMT has also been found to occur naturally in small amounts in the brain and may act as a neurotransmitter.

[0006] Lysergic acid diethylamide (LSD) is a diethylamide derivative of a natural product derived from fungi found in rye grass and also produces a psychedelic state that can last up to 8 to 12 hours.

[0007] Psilocybin is a natural plant-based tryptamine found in mushrooms of the genus Psilocybe and produces a long-lasting psychedelic state of about 6 to 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 is a phosphate ester bound to the 4-hydroxy group of psilocin, and this bond is cleaved in the intestine when mushrooms of the genus Psilocybe or the drug is orally ingested:

[0008] [Chemical formula]

[0009] Simple monofunctional organic esters of silosin have been reported. Lower alkoxy radical-modified silosin has also been described. Sulfate ester bond silosin has been produced, and other monobasic and dibasic mineral acid-modified silosins have been described. Silosin acetate is known and used in the underground psychedelic subculture.

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

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

[0012] Succinic esters and other diacid functional groups have been investigated as components of prodrug delivery systems for water-soluble injectable forms of drugs that are hydrophobic or poorly water-soluble, such as testosterone, haloperidol, chloramphenicol, or estradiol (Silverman and Holladay, Chapter 9.2: Prodrugs and Drug Delivery Systems in The Organic Chemistry of Drug Design and Drug Action (3 rdEd), 2014). Tetrahydrocannabinol esters of succinic acid are patented as therapeutic agents 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 the 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 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 into active forms in vivo 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 general 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) which may be substituted with -OH or -CO2H, or an aromatic ring which may be substituted with alkyl or CO2H); or b. (R9)(R10)N- (where R9 is X-CO2H, X is as described above, and R10 is hydrogen, -OH or a linear or branched alkyl (preferably a C 1~5 alkyl) or arylalkyl which may be substituted with -CO2H); (3) R5 is hydrogen, a linear or branched alkyl (preferably a C 1~5 alkyl), 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 arylalkyl, or b. together form an optionally alkyl-substituted non-aromatic N-containing heterocycle, preferably with the entire heterocyclic structure containing no more than 12 atoms] or a pharmaceutically acceptable salt or zwitterion thereof.

[0018] 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 1~4is alkyl; or is the same or different and is 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 is isopropyl.

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

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

[0022] In another aspect, the present invention includes a method of 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 resulting from generalized anxiety, major depression, treatment-resistant depression, and postpartum depression.

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

[0024] In another aspect, the present invention relates to a method of manufacturing a compound described herein, comprising reacting a tryptamine comprising hydroxytryptamine or hydroxyisotryptamine with a cyclic anhydride in a suitable water-insoluble solvent. In some embodiments, the solvent comprises a base having a pKa of 4-9, 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 DESCRIPTION OF THE DRAWINGS

[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.

DETAILED DESCRIPTION OF THE INVENTION

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

[0027] As used herein, the terms "treating," "treat," or "treatment" include both prophylactic, i.e., preventive treatment, and symptomatic treatment, i.e., reducing, alleviating, or delaying the progression of a patient's disease, disorder, or condition.

[0028] In this specification, a "psychedelic state" is an altered state of consciousness experienced by an individual, which may include enhanced sensory perception, perceptual distortions or hallucinations, and / or feelings of well-being or despair. A psychedelic state is described as being caused by psychedelic drugs such as DMT (dimethyltryptamine), LSD, mescaline or psilocybin. Other known psychedelic drugs include 4-hydroxy analogs of N-methyl-N-isopropyltryptamine (MiPT) and N,N-diisopropyltryptamine (DiPT).

[0029] The present invention includes prodrugs of hydroxyindole 5HT2A agonists that either induce a psychedelic state or still produce beneficial therapeutic effects without being related to a psychedelic state. The prodrugs may be used in combination with other known therapies effective for treating mental disorders, such as psychotherapy, electroconvulsive therapy, and / or other pharmaceutical compounds, such as tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), selective norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MOAI) or other antidepressants. In a preferred embodiment, the treatment may produce a lasting effect of more than one month, preferably more than three months, more preferably more than six months, for example, after a single treatment. In some embodiments, additional therapy may not be necessary.

[0030] Compound As used herein, the term "compound" includes pharmaceutically acceptable derivatives or variants thereof, including conformational isomers (e.g., cis, trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomeric mixtures and other mixtures of such isomers, as well as solvates, hydrates, polymorphs, pseudopolymorphs, tautomers, esters, salts and prodrugs. The expression "prodrug" refers to a compound that is a drug precursor and releases a drug (or "active form") in vivo through some chemical or physiological process (e.g., hydrolysis, enzymatic cleavage or hydrolysis, or metabolism converts it to the desired drug form) after administration. The present invention includes pharmaceutically acceptable salts of the compounds of the present invention within its scope. Thus, the term "pharmaceutically acceptable salt" is implicitly included in the description of all compounds described herein unless explicitly stated to the contrary.

[0031] In some embodiments, the compounds of the present invention include prodrug compounds that are readily purified, formulated, and stable, and may preferably be used to provide highly soluble drugs that act rapidly and are 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 preferably cleave the prodrug moiety rapidly in vivo to generate the active pharmacophore, for example, with 90% conversion occurring in less than 4 hours, preferably less than 2 hours, more preferably less than 1 hour. The prodrug itself may have low, little 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 hydroxytryptamines or isotryptamines 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 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 C 1~5 alkyl) optionally substituted with -OH or -CO2H, or an aromatic ring optionally substituted with alkyl or CO2H); or b. [Chemical formula]

[0037] (where R9 is X-CO2H, X is as defined in (2)a, and R10 is hydrogen, -OH or a 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' (wherein R5' is hydrogen, linear or branched alkyl (preferably C 1~5 alkyl)), and; (4) R7 and R8 are a. independently selected from hydrogen, linear or branched alkyl (preferably C 1~5 alkyl), or arylalkyl, or b. together form an optionally alkyl-substituted non-aromatic N-containing heterocycle, preferably having no more than 12 atoms in the entire heterocyclic structure, such as pyrrolidine (NC4 ring), piperidine (NC5 ring), or morpholine (NC4O ring).] or a pharmaceutically acceptable salt or zwitterion thereof.

[0038] "Alkyl", whether 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 the parent alkane. The term "alkyl" includes cycloalkyl. Representative alkyl groups include methyl; ethyl; propyls (e.g., propane-1-yl, propane-2-yl (isopropyl), cyclopropane-1-yl); butanyls (e.g., butane-1-yl, butane-2-yl (sec-butyl), 2-methylpropane-1-yl (isobutyl), 2-methylpropane-2-yl (t-butyl), cyclobutane-1-yl), etc., but are not limited thereto. In some embodiments, the alkyl group contains 1 to 20 carbon atoms (C1-C 20 alkyl). In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C1-C 10 alkyl). In yet other embodiments, the 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 in the art and, as used herein, refers to an alkyl group substituted with an aryl group, such as C1~6 Refers to an alkyl group, and the aryl group is linked to the main molecule through the alkyl group. An example of arylalkyl is the benzyl group, i.e., the phenylmethyl group.

[0040] When used in modifying a specified group or radical, "substituted" means that one or more hydrogen atoms of the specified group or radical are each independently replaced by the same or different substituents. The term "substituted" specifically contemplates and tolerates one or more substituents common in the art. However, those skilled in the art generally understand that the substituents should be selected such that they do not adversely affect the useful properties of the compound nor interfere detrimentally with its function.

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

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

[0043] In some non-limiting examples, the compounds include diesters of tryptamine structures such as 4-hydroxy-N,N-dimethyltryptamine (psilocin 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 (psilocin), N,N-diisopropyltryptamine (4-OH-DiPT), or N-methyl-N-isopropyltryptamine (4-OH-MiPT).

[0044] In some embodiments, the compounds include compounds represented by Formula I, II, III, or IV, wherein R1, R2, R5, and 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 represented by Formula I or II, and X is a C2 alkyl, thus forming a 4- or 5-hemisuccinate of psilocin.

[0045] In some embodiments, the compound comprises a compound of formula I, II, III or IV, wherein R1, R2, R5, and R6 are each hydrogen; X is a straight-chain C1-C4 alkyl chain; and R7 and R8 are each isopropyl. In some embodiments, the compound is a compound of formula I or II, and X is C2 alkyl, thus forming the hemisuccinate ester of 4- or 5-hydroxy diisopropyltryptamine. In some embodiments, the compound is a compound of formula I or II, and X is C2 alkene, thus forming the hemifumarate ester of 4- or 5-hydroxy diisopropyltryptamine. In some embodiments, the compound is a compound of formula I or II, and X is a C3 alkyl chain, thus forming the hemiglutarate ester of 4- or 5-hydroxy diisopropyltryptamine.

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

[0047] In some embodiments, the compounds of the invention are zwitterions of diacids. Thus, when X is a straight-chain saturated alkyl, the diacid may include, but is not limited to, common straight-chain alkyl α,ω-diacids such as 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 where X is a straight-chain alkene, the diacid may include acids such as maleic acid, fumaric acid, or glutaconic acid. In other embodiments, the diacid may include branched acids such as citraconic acid, mesaconic acid, 2,2-dimethylsuccinic acid; substituted acids such as tartronic acid, 2-(2-hydroxyethyl)-malonic acid, α-hydroxyglutaric acid; citric acid; or aryl diacids that may have organic substituents on an 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) Silosine-4-succinate

Chem.

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

Chem.

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

Chem.

[0051] (4) Silosine-4-methyl-5-succinate

Chem.

[0052] (5) N,N-Dimethylisotriptamine-6-succinate

Chem.

[0053] (6) N,N-Diisopropyltriptamine-4-glutarate

Chem.

[0054] (7) N-Methyl-N-isopropyltriptamine-4-glutarate

Chem.

[0055] (8) Silosine-4-glutarate

Chem.

[0056] (9) N,N-Diethyltriptamine-4-glutarate

Chem.

[0057] (10) N,N-Diethyltriptamine-4-succinate

Chem.

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

Chem.

[0059] In some embodiments, the diacid-modified tryptamine or isotryptamine is stable (to oxidation and hydrolysis), and can be readily synthesized and purified. The diacid-modified tryptamine or isotryptamine preferably exhibits greater solubility in a biological matrix than the unmodified drug, making it an excellent drug candidate. Further, the diacid-modified tryptamine preferably has a relatively high rate of hydrolysis in vivo, rapidly converting the prodrug to the active form of the drug. This can provide improved desirable pharmacokinetics for the prodrug, including a more reproducible pharmacokinetic profile. These properties may depend on the nature of the indole, the various substituents attached to the indole, and the nature of the diacid ester. Stability and rate of hydrolysis can be determined experimentally.

[0060] In some embodiments, the compound may include a carbamate of tryptamine where R4 is (R9)(R10)N- (where R9 and R10 are carbamate residues as previously defined). In some embodiments, the carbamate functional group includes a zwitterionic amino-functionalized mono- or dicarboxylic acid linked through the carbamate, including but not limited to zwitterionic compounds such as: - natural and non-natural neutral or anionic amino acids such as glycine, alanine, leucine, isoleucine, serine, threonine, glutamic acid, aspartic acid; - linear alkyl α,ω-amino acids such as 3-aminopropionic acid, 4-aminobutyric acid; - other branched and aromatic amino acids such as 4-aminobenzoic acid may be mentioned.

[0061] In some embodiments, the invention may include a zwitterionic compound where R4 includes one or more non-ester carboxy functional groups, such as the citrate ester derivative of 4-hydroxytryptamine (V) or the glutamate carbamate of 4-hydroxytryptamine (VI):

[0062] [Chem.]

[0063] In some embodiments, the zwitterionic compound is preferably stable at neutral or slightly acidic pH. Acylation of the hydroxy functional group of indole can specifically prevent typical oxidation reactions 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, the non-prodrug pharmacophore tryptamine has to be kept in an acidic medium to achieve good solubility and stability. The acidic medium may prevent its use as an injectable formulation and may cause irritation.

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

[0065] The diacid moiety is cleaved metabolically in vivo, resulting in an active ingredient with a sufficient dose and kinetics to achieve a psychedelic state that is thought to be required for the treatment of depressive states, such as in psychedelic-assisted psychotherapy. This is particularly advantageous when designing a convenient formulation that produces a psychedelic experience with a duration of less than 8 hours, preferably less than 6 hours, more preferably less than 4 hours. In this sense, the need for hydrolysis is an additional step that can slow the onset of the psychotropic properties compared to the injection of the free drug (where the hydroxy functionality is not acylated). A slightly slower onset may be preferred in some cases to avoid a sudden onset that can cause anxiety, particularly in psychedelic-naive patients. Thus, in a preferred embodiment, the rate of onset may be controlled by the rate of metabolism, which may potentially be a function of the ester and the target enzyme required for hydrolysis.

[0066] In some embodiments, certain prodrug diacid moieties, such as succinate esters, may have the potential to reduce the potential for abuse by inhalation or nasal absorption. Being zwitterionic, they are less likely to be rapidly absorbed in tissues lacking esterase activity. Additionally, zwitterions are likely to not be directly absorbed into the brain by passive mechanisms. The rate of cleavage in the intestine is slower and absorption may be slower than the non-acylated form, potentially delaying the "rush" sensation and peak rate that may be sought by those with an intent to abuse.

[0067] Manufacturing method The compounds described in this specification 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 thereof that are understood by those skilled in the art. Preferred methods may include, but are not limited to, the methods 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 reactions being affected. Those skilled in the art of organic synthesis will understand that the reactions presented are consistent with the functionality present on the molecule. This may require judgment within the skill of those skilled in the art when changing the order of the synthetic steps or selecting a different processing scheme rather than a particular one to obtain the desired compound of the present invention.

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

[0069] 4- and 5-hydroxytryptamine can be produced by adopting 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) in the art, as well as US Patent No. 3075992 and Chen (JOC 1994, 3738).

[0070] For example, the succinic acid ester prodrug compounds described in this specification may be produced using the synthetic scheme outlined in Scheme 1 starting from the corresponding hydroxyindole and diacid anhydride. Reaction conditions such as temperature, time, and solvent that may be suitable for the experimental conditions recognized by those skilled in the art are selected, and the procedure is selected. The restrictions on substituents compatible with the reaction conditions can be readily understood by those skilled in the art, and in such cases, another or similar method must be used.

Chemical formula

[0071] The following Scheme 2 may be utilized to produce a glutaric acid ester prodrug compound using glutaric anhydride:

Chemical formula

[0072] Those skilled in the art can readily select appropriate conditions and solvents. The reaction with the diacid anhydride 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 pure form as a zwitterion.

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

[0074] Also, the synthesis of the diacid hemi-ester prodrug may be carried out 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 dichlorides, di-N-hydroxysuccinimide (using dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide and DMAP), di-imidazolide (using carbonyldiimidazole), or other activated forms of the diacid such as the anhydride or double-activated forms of the diacid having the hydroxy form of the active heterocyclic species. When using the double-activated form, it is preferred to use a 2- to 25-fold excess of the double-activated diacid to avoid covalent bonding of two tryptamines to the diacid.

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

[0076] Pharmaceutical formulations and compositions The present invention also provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more of the compounds described herein formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents and optionally one or more additional therapeutic agents. Although it is possible to administer the compounds described herein alone, it is preferred 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" refers to a medium generally recognized in the art for the delivery of bioactive agents to animals, particularly mammals, and depending on the form of administration and the nature of the dosage form, i.e., adjuvants, excipients or vehicles such as diluents, osmotic agents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, polymers, solubilizers, stabilizers, antioxidants and dispersing agents. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0078] As used herein, "oral" administration includes swallowing for ingestion into the stomach or intestine, and further includes sublingual, buccal and oropharyngeal administration. The compounds of the present invention can be administered for any of the uses or methods described herein by oral administration by suitable means, such as tablets, capsules (each of which may include sustained or controlled release formulations), pills, powders, granules, elixirs, suspensions (including nano-suspensions, micro-suspensions, spray-dried dispersions), syrups and emulsions; by sublingual administration (e.g., as thin films, effervescent tablets or tablets that spontaneously dissolve sublingually); by parenteral administration such as subcutaneous, intravenous, intramuscular injection or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions, suspensions); by nasal administration including administration to the nasal mucosa by, for example, an inhalation spray; or by rectal administration such as suppositories.

[0079] The dosing schedule of the compounds described in this specification will of course vary depending on known factors such as the pharmacokinetic and pharmacological properties of a particular agent and its form and route of administration; the species, age, sex, health, medical condition and weight of the recipient; the nature and degree of the symptoms; the type of co - therapy; the frequency of treatment; the route of administration, the renal and hepatic function of the patient; and the desired effect. The dose selected will depend on the activity of the particular compounds and pharmaceutical compositions described in this specification, whether an ester, salt or amide of the compound is used, the time of administration, the rate of excretion or metabolism of the compound used, the rate and extent of absorption, the duration of treatment, other drugs that may be administered to the patient, compounds and / or materials used in combination with the compound used, and further factors including similar factors well known in the medical art.

[0080] Generally, for the administration of prodrugs for treatment, when used for their effect, the dose is about 0.001 to about 500 mg per administration, preferably about 0.01 to about 200 mg per administration, most preferably about 0.1 to about 50 mg per administration, for example 10, 20, 30, 40, 50, 100 or 200 mg. For intravenous administration, the most preferred dose is by infusion at a constant rate of about 0.01 to about 10 mg / kg / min.

[0081] The compounds of the present invention may be administered once a day, or the total daily dose may be divided and administered in multiple doses, for example, 2, 3 or 4 times a day. Alternatively, it may be administered weekly, bi - weekly or monthly. In a preferred embodiment, the administration required for the antidepressant effect is only 1 or 2 times and may last for 1, 2, 3 or 6 months, or longer.

[0082] In the case of tablets, depending on the dosage, the drug may be 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. Tablets generally contain a disintegrant in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, crystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, 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 the tablets, a binder is generally used. Suitable binders include crystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. 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] Tablets may also contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant is usually 0.2% to 5% by weight of the tablet, and the glidant is usually 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 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight.

[0086] Other conventional ingredients include antioxidants, colorants, flavorants, preservatives, and flavor corrective agents.

[0087] Typical 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.

[0088] The tablet blend may be compressed directly or by roller to form tablets. Alternatively, the tablet blend or a portion of the blend may be wet, dry, or melt granulated, melt solidified, or extruded prior to tableting. The final formulation may include one or more layers, may or may not be coated; or may be encapsulated.

[0089] The tablet formulation is discussed in detail in “Pharmaceutical Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0 8247 6918 X), the disclosure of which is incorporated herein by reference in its entirety.

[0090] Typical capsules for oral administration contain at least one (e.g., 25 mg) of the compounds of the present invention, lactose (e.g., 75 mg), and magnesium stearate (e.g., 15 mg). The mixture is passed through a 60-mesh sieve and filled into No. 1 gelatin capsules.

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

[0092] In addition, the compounds of the present invention may be administered directly into the blood, muscle or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include syringes with needles (including microneedles), needleless syringes and infusion techniques.

[0093] Parenteral formulations are usually aqueous solutions that may contain excipients such as salts, carbohydrates, and pH adjusting or buffering agents (preferably pH 3.0 to 7.0, preferably 4.0 to 6.0, more preferably 4.5 to 5.5), but in some applications, they may be more suitably formulated as sterile non-aqueous solutions or in dry form for use with a suitable vehicle (e.g., sterile pyrogen-free water or pre-prepared ready-to-mix aqueous buffer). An osmotic pressure adjuster may be incorporated to control the osmotic pressure.

[0094] The preparation of parenteral kits, for example by lyophilization, for reconstitution under sterile conditions at the point of care can be readily achieved using standard pharmaceutical techniques well known to those skilled in the art.

[0095] A typical injectable formulation is produced by aseptically placing at least one (e.g., 25 mg) of the compounds of the present invention into a vial as a sterile filtered solution, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with, for example, 2 mL of injectable saline, and optionally an appropriate amount of osmotic pressure supplement and a pH adjuster to achieve a slightly acidic to neutral pH (e.g., pH 4 to 7) to produce 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 cyclodextrin and its appropriate derivatives or polymers, polyethylene glycols containing such, so as to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability.

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

[0098] Regardless of the selected route of administration, the compounds of the present invention and / or the pharmaceutical compositions of the present invention, when used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention may vary so as to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition and form of administration.

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

[0100] Generally, a suitable daily dosage of the compounds of the present invention will be the amount of the compound that is the lowest dosage effective to produce a therapeutic effect. Such effective amount generally depends on the factors described above.

[0101] As used herein, "therapeutically effective amount" refers to the amount of a compound administered that reduces to some extent one or more symptoms of the disorder being treated. With respect to the treatment of depression, a therapeutically effective amount refers to the amount having an effect of reducing the severity of depression. The severity of depression can be evaluated 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 therapeutically effective amount may be less than the amount required for a psychedelic state.

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

[0103] Therapeutic methods and uses Treatment with the novel prodrugs of the present invention may substantially alleviate clinical or potential depression and, particularly when used in combination with psychotherapy for the treatment of depression, may avoid recurrence. It is known that administration of an effective amount of psilocybin has resulted in a rapid and substantial reduction in depressive symptoms and that many subjects achieve remission through a four-week follow-up (Davis et al.). Without being bound by theory, although a psychedelic state is thought to be associated with beneficial effects, some compounds that are 5HT2A agonists may produce the desired therapeutic effects without being accompanied by a psychedelic state. One aspect of the present invention includes prodrugs of 5HT2A agonists that produce beneficial therapeutic states.

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

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

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

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

[0108] To further alleviate any anxiety that may arise in connection with the treatment, the physician may choose to divide the dosage, thereby reducing the initial onset of the psychoactive effect before administering all of the amount required to achieve the full effect.

[0109] In some embodiments, treatment with the compound of the present invention may be combined, either concomitantly or sequentially, with treatment with another antidepressant. In a preferred embodiment, treatment with the compound of the present invention is combined with psychotherapy, which may be performed before or after the treatment. If it is before the treatment, the patient's intention to be treated may be focused on the administration of the compound of the present invention. If it is after, the psychotherapy is preferably performed within 48 hours of the administration of the compound of the present invention, to help the patient summarize any sensations, emotions, visions or thoughts that may have occurred during the administration of the compound of the present invention, and to enable the psychotherapist to advise on the best ways to change thinking or behavioral patterns to improve the antidepressant outcome. Optionally, after the administration of the compound of the present invention, for example for up to an additional three months, psychotherapy may be continued to help the patient summarize any experiences or learnings that occurred in the patient during the administration.

Example

[0110] The present invention can be described with reference to the following examples. These examples are provided for illustrative purposes only. All terms, names, abbreviations, or acronyms are those commonly understood by those skilled in the art. Compounds shown in zwitterionic form are readily envisioned by those skilled in the art in their neutral form, and vice versa.

[0111] When a compound is referred to as a glutaroyl or succinoyl, or a hemiglutaric acid ester or hemisuccinic acid ester, it is understood to be the same as the succinic acid ester or glutaric acid ester. For example, the 4-hemiglutaric acid ester of syrosingopine is the same as syrosingopine-4-glutarate or N,N-dimethyltryptamine-4-glutarate. Similarly, the 4-hemiglutaric acid ester of 4-OH-DiPT is the same as N,N-diisopropyltryptamine-4-glutarate.

[0112] Example 1 4 - hemisuccinate ester of psilocin 4-Hydroxyindole was prepared by the method described in Kargbo 2020 ACS Omega or a method adapted therefrom as appropriate. That is, 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-hydroxy dimethyltryptamine (syrosingopine).

[0113] 4-Hydroxytryptamine was reacted with an excess of succinic anhydride in dichloromethane (DCM) having triethylamine in the presence of N,N-dimethylaminopyridine as a catalyst to obtain syrosingopine-4-succinate. A precipitate was formed and, after decantation and trituration with DCM, this 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 - hemisuccinate ester of 4 - hydroxy diisopropyltryptamine (4 - OH - DiPT) 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 deprotected with an aqueous base to give 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. 4-OH-DiPT (5.8 g, 22.3 mmol, 1 equiv) was added to a 250 mL round-bottom flask containing a stir bar, dissolved in dichloromethane (28 mL, 5×V), and stirred at room temperature. Then, succinic anhydride (1.3 equiv) was slowly added to the stirred solution, and the resulting suspension was stirred at room temperature overnight. The precipitate formed in the reaction was recovered by decantation and trituration with DCM. The solid was acidified with hydrochloric acid, purified by chromatography, and recovered after evaporation of the solvent. The structure was confirmed by NMR. The purity was determined by HPLC.

[0115] Example 3 4 - hemifumarate ester of 4 - OH - DiPT 4-Benzyloxyindole was reacted with oxalyl chloride in diethyl ether in the presence of a Friedel-Crafts catalyst, and the resulting intermediate was quenched with diisopropylamine. The resulting oxalyl amide was reduced with lithium aluminum hydride (LAH) in THF to give 4-benzyloxy-3-(N,N-diisopropylaminoethyl)indole, and this was deprotected using H2 and Pd / C to give 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. This material was reacted with excess activated fumaric acid (N-hydroxysuccinimide) in dichloromethane, and then all unreacted N-hydroxysuccinimide esters were quenched with an acid solution to give 4-fumaryl-3-(N,N-diisopropylaminoethyl)indole.

[0116] Example 4 5 - hemisuccinate ester of 5 - hydroxy - 4 - methyl dimethyltryptamine 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-Crafts catalyst, and the resulting intermediate is quenched with dimethylamine. The resulting oxalyl amide is reduced with lithium aluminum hydride (LAH) in THF to obtain 4-methyl-5-benzyloxy-3-(N,N-dimethylaminoethyl)indole, which is 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 According to the method outlined by Glennon (JMedChem 1984), 6-O-benzyl dimethylisotriptamine is produced by N-alkylation of 5-BzO-indole using NaH. The benzyl group is removed by catalytic hydrogenation using Pd / C / H2 to obtain the OH functional group, which is then succinylated with succinic anhydride in the next step to obtain the title compound.

[0118] Example 6 N,N - diisopropyltryptamine - 4 - glutarate Anhydrous glutaric acid (0.205 g, 1.8 mmol, 1.8 equiv) 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. A solution of 1.5 mL of 4-OH-DiPT (0.26 g, 1 mmol, 1 equiv) in anhydrous DCM was added, followed by 4-dimethylaminopyridine (DMAP) (37 mg, 0.3 mmol, 0.3 equiv) and trimethylamine (0.18 mL, 1.3 equiv), and the resulting suspension was stirred overnight at room temperature under an Ar atmosphere.

[0119] The mixture was decanted and the solid was triturated with anhydrous DCM (3 mL) to which a few drops of anhydrous MeCN were added. The suspension was acidified with 1 M hydrochloric acid (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 H2O, B: 0.05% HCl in MeCN).

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

[0121] Example 7 Hemiester of 3,3 - dimethylglutaric acid and 4 - hydroxy diisopropyltryptamine Using the stoichiometry and parameters described in Example 6, 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole was reacted with anhydrous 3,3-dimethylglutaric acid in pyridine to give 4-succinoyl-3-(N,N-diisopropylaminoethyl)indole. The precipitate formed in the reaction 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 Psilocin - 4 - glutarate 4-Hydroxy dimethyltryptamine (serotonin) was reacted with excess anhydrous glutaric acid in dichloromethane (DCM) containing triethylamine to give serotonin-4-glutarate. In another example, the reaction was carried out in pyridine. In both cases, a precipitate was formed and this 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 give the corresponding HCl salt product, which was 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 anhydrous pyridine. After stirring for 15 minutes, anhydrous glutaric acid (18.1 g, 0.158 mol, 1.3 equivalents) was added portionwise. The resulting suspension was stirred at room temperature overnight.

[0125] Anhydrous DCM (160 mL) was added to the suspension, and this was cooled to 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 using 160 mL of anhydrous DCM, then 160 mL of anhydrous THF, and then 160 mL of anhydrous DCM. After drying, 33.0 g was obtained with a yield of 72% and an HPLC purity of 98.1%. The structure of the zwitterion was confirmed by 1H-NMR (DMSO-d6) and MS [M+H] + = 375.2.

[0127] 18 mL of anhydrous diethyl ether HCl solution (4 M 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 zwitterion (3.0 g, 8.0 mmol) was added portionwise, 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 to obtain 3.16 g of the corresponding hemiester tryptamine HCl salt (yield 96%, HPLC purity 99.0%, [M+H] + = 375.1).

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

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

[0130] Example 12 Relative rate of prodrug hydrolysis in serum Pooled male and female human plasma (2 ml), mouse plasma, rat plasma, and dog plasma were equilibrated at 37 °C. The compound of Example 9 was added to a concentration of 1.0 μg / mL. Aliquots (50 μL) of the mixture were withdrawn at the specified times (0, 0.004, 0.5, 1, 2, and 4 hours) and quenched with 200 μL of methanol / acetonitrile (1:1). The samples were vortexed and stored at -80 °C until analysis. The assay was performed 3 times. Control samples were treated in phosphate buffered saline (PBS, pH 7.4) and simulated gastric fluid (SGF, pH 2). The samples were analyzed by HPLC-MS to determine the amounts of prodrug and drug in each test sample. Table 1 shows the average concentrations of residual prodrug at various time points of the experiment. The experiment shows rapid enzymatic cleavage of the prodrug in plasma and slow non-enzymatic hydrolysis in the related biological media.

[0131]

Table 1

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

[0133] To demonstrate the activity of the drug, PK-PD curves were created (Figures 1 and 2). In rodents, the prodrug was rapidly converted to the active form, so it was not observed. The PK parameters for the i.v. and s.c. administration of 4-OH-DiPT are shown in Table 2.

[0134]

Table 2

[0135] In some cases, head twitch response (HTR) or intense shakes (WDS: Wet Dog Shakes) were recorded by visual observation and counting of related muscle contractions. Generally, the intensity of HTR was proportional to the blood concentration of 4-OH-DIPT, and the intensity of head twitches 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-glutamate.

[0137] Pharmacokinetic analysis of 1.34 mg / ml of 4-OH-DiPT HCl administered intravenously or by subcutaneous injection was carried out in parallel under the same conditions. Figure 2 shows the blood concentration (ng / ml) of 4-OH-DiPT over time for each administration. It is immediately apparent that there is a large variation due to the active species in the case of s.c. and i.v. 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) is 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 are taken at 5 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, 240 minutes, 480 minutes, and 24 hours later. The samples are analyzed for the drug and prodrug by LCMS. The subjective effects are measured using a standardized questionnaire. The PK analysis shows the maximum blood concentration (CMax) at approximately 45 minutes after injection. The subjective effects indicate the intensity of the psychoactive effects correlated with the blood levels.

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

[0141] Example 18 Use in therapy The compound of Example 6 (N,N - diisopropyltryptamine - 4 - glutarate) is administered to human patients suffering from depression by i.m. or s.c. injection (about 25 mg; 0.4 - 0.5 mg / kg), or by oral administration in tablets (about 50 - 200 mg; 0.8 - 3.2 mg / kg). In another example, the compound of Example 6 (4 - hemiglutaric acid ester of 4 - OH - DiPT) is administered similarly. Prior to dosing, patients are selected by measuring the depression score, screened for exclusions (e.g., history of psychosis, undesirable heart conditions, pregnancy), and finally, patients are encouraged to indicate their willingness to receive the medication. In a quiet examination room, the patient is made to rest in a reclined but unrestrained position to avoid falls during administration. The patient's eyes are covered and music is played. The drug is administered. Four hours later, when the patient reports no longer feeling the effect of the drug, the patient is asked to get up under supervision. The patient is permitted to stand (under supervision) if feeling normal and to move around if feeling in control. One hour later, the patient is allowed to go home. Within 24 hours thereafter, the patient returns to the examination room to meet with a psychotherapist to talk in detail about the dosing. The patient records the depression score on a questionnaire and is sent home again. The patient is examined at regular intervals for recurrence of depressive symptoms.

[0142] Example 19 Kit of injectable pharmaceutical formulations Prepare a vial using 25 mg (sterile powder or lyophilized product) of the compound in Example 6 as the hydrochloride salt. Place 1 ml of a sterile - filtered solution with 70 mM of Na2HPO4 in another vial. The final pH of the solution is 4.0 - 5.0. These two components constitute a kit for the reconstitution of a drug product for subcutaneous injection at the treatment site.

[0143] References All publications, patents, patent applications, etc., referred to in this specification, including the following, are hereby incorporated 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 13. Hofmann A, Troxler F. Esters of indoles. U.S. Patent No. 3,075,992, and Process for the production of new esters of the indole series. Swiss Patent Invention 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, R. E., Sable, J., O’Hern, K., Kaylo, K., Patterson, T., Tarpley, G., & 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., & 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. 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[0144] Definitions and interpretations The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations should be apparent to those of ordinary skill in the art without departing from the scope and spirit of the present invention. The principles and practical applications of the present invention have been best explained and various aspects with various modifications have been selected and described to enable other ordinary skill in the art to understand the present invention in terms of the best mode contemplated and suitable for a particular use. It is intended that the following description be illustrative only of specific aspects or particular uses of the claimed invention and not be construed as limiting the claimed invention.

[0145] All means or steps-plus-function elements in the claims appended hereto are intended to include any structure, material, or act for performing the functions in combination with other claimed elements as specifically claimed, for implementing the functions in combination with other claimed elements.

[0146] References to "one aspect", "aspect", etc. in the specification mean that the described aspect may include a particular aspect, feature, structure, or characteristic, but not necessarily all aspects include that aspect, feature, structure, or characteristic. Also, such phrases may refer to the same aspect mentioned in other parts of the specification, but not necessarily so. Further, when a particular aspect, feature, structure, or characteristic is described in relation to an aspect, combining, acting on, or connecting such aspect, feature, structure, or characteristic with other aspects is within the knowledge of those skilled in the art, whether or not such connection 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, provided that there is no obvious or essential incompatibility between the two, or the combination is not specifically excluded.

[0147] It should be further noted that the claims may be described to exclude optional elements. This statement itself is intended to serve as a premise for the use of exclusive terminology, such as the use of "only", "merely", etc., in relation to the enumeration of claim elements or the use of "negative" limitations. Terms such as "preferably", "preferred", "choose", "optionally", "may", and similar terms are used to mean that the element, item, condition, or step referred to is an optional (not required) feature of the present invention.

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

[0149] As will be understood by those skilled in the art, for all purposes, particularly in terms of providing a written description, all ranges described in this specification also include 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., weight percent or carbon group) includes each specific value, integer, decimal, or unit within the range. Any range recited is fully described and can be readily recognized as being divisible into at least 2, 3, 4, 5, or 10 equal parts. As a non-limiting example, each range described in this specification can be readily divided into a lower third, a middle third, and an upper third, etc.

[0150] As will also be understood by one of ordinary skill in the art, all ranges and all terms recited in this specification, such as "up to," "at least," "greater than," "less than," "over," "greater than or equal to," etc., are inclusive of the recited numbers and refer to ranges that can be subsequently divided into subranges, as explained above. The invention described in the original patent claims at the time of filing is appended below. [1] Formula (I), (II), (III) or (IV): [ka] [Wherein, (1) R1, R2 and R6 are independently selected from hydrogen, linear or branched alkyl or arylalkyl; (2) R4 is, a. -X-CO2H (where X is a linear, cyclic or branched, saturated or unsaturated carbon chain which may be substituted with -OH or -CO2H; or an aromatic ring which may be substituted with alkyl or CO2H), or b. [ka] (where R9 is X-CO2H, X is as defined in (2)a, and R10 is hydrogen, -OH or a linear or branched alkyl or arylalkyl which may be substituted with -CO2H); ( 3) R5 is hydrogen, a linear or branched alkyl, arylalkyl or O-R5’ (where R5’ is hydrogen, a linear or branched alkyl); (4) R7 and R8 a. are independently selected from hydrogen, a linear or branched alkyl, or arylalkyl, or b. together form a non-aromatic N-containing heterocycle which may be substituted with alkyl] a compound represented thereby or a pharmaceutically acceptable salt or zwitterion thereof. [2](1) Silosine-4-succinate [ka] (2) N,N-Diisopropyltryptamine-4-succinate

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[10] The composition according to [9], comprising an oral formulation or an injectable formulation.

[11] The composition according to

[10] , which is an injectable solution.

[12] The composition according to

[11] , wherein the pH of the solution is about 3.0 to 7.0, preferably 4.0 to 6.0, more preferably 4.5 to 5.5.

[13] A method for treating a mental disorder, comprising the step of administering an effective amount of the compound according to any one of [1] to [8].

[14] The method according to

[13] , wherein the mental disorder is depression.

[15] Use of the compound according to any one of [1] to [8] in the manufacture of a medicament for treating a mental disorder, such as depression.

[16] The compound according to any one of [1] to [8] for use in the treatment of a mental disorder, such as depression.

[17] A method for producing the compound according to [1], comprising reacting tryptamine containing hydroxytryptamine or hydroxyisotryptamine with a cyclic anhydride in a suitable anhydrous solvent.

[18] The method according to

[17] , wherein the solvent contains a base having a pKa of 4 to about 9, and the resulting compound is isolated as a zwitterion.

[19] The method according to

[18] , wherein the solvent is pyridine.

[20] The method according to any one of

[17] to

[19] , wherein the compound is the compound according to [2].

[21] The method according to any one of

[17] to

[20] , wherein the tryptamine is 4-hydroxy-isopropyltryptamine or serotonin, and the cyclic anhydride is succinic anhydride or glutaric anhydride.

Claims

Claim 1 N,N - Diisopropyltryptamine - 4 - glutarate 【Chemical 1】 or a pharmaceutically acceptable salt or zwitterion thereof. Claim 2 Use of the compound according to claim 1 or a pharmaceutically acceptable salt or zwitterion thereof in the manufacture of a medicament for treating mental disorders. Claim 3 Use according to claim 2, wherein the mental disorder is depression.

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