Tryptamine prodrugs

Abstract

The invention provides a tryptamine prodrug compound. A compound represented by structural formula (I) wherein each symbol is as described in the specification, or a salt or zwitterion thereof, converted into an active agent having 5HT2A receptor agonist activity, and useful as an agent for the treatment of depression

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: June 30, 2021; priority date: June 30, 2020; application number: 202180046999.1 (international application number: PCT / CA2021 / 050907); invention name: tryptamine prodrug).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application Serial No. 63 / 045,901, filed on June 30, 2020, entitled “TRYPTAMINE PRODRUGS”, and U.S. Provisional Application Serial No. 63 / 109,095, filed on November 3, 2020, entitled “TRYPTAMINE PRODRUGS”. The entire contents of U.S. Provisional Application Serial No. 63 / 045,901 and U.S. Provisional Application Serial No. 63 / 109,095 are incorporated herein by reference where permitted. Technical Field

[0004] The present invention relates to novel tryptamine compounds, methods of making and using such compounds, compositions comprising such compounds, and uses thereof. Background Art

[0005] Tryptamines are a class of 3-aminoethyl-indoles that bind to and activate serotonin receptors (also known as 5HT receptors). Psychedelic states can be achieved by activating the 2A form of serotonin receptors by 5HT2A receptor agonist compounds. The endogenous substance of this receptor is 5-hydroxytryptamine (serotonin). Tryptamine 3-(2-aminoethyl)-indole is also an endogenous neurotransmitter.

[0006] The serotonin receptor system is associated with depression and depressive states, which are often treated with 5HT1A antagonists (Affective Disorders: Depression in Neuropsychopharmacology and Therapeutics, Chapter 6, 1st edition, Ivor S. Ebenezer, 2015). Recently, 5HT2A agonists have shown potential as depression drugs (Carhart Harris 2018 Psychopharmacology).

[0007] Tryptamine molecules that produce psychedelic states and have been used in traditional medicine may have the potential to treat mood disorders, anxiety, depression, and other conditions. For example, ayahuasca is a natural form of dimethyltryptamine (DMT) that, when combined with a monoamine oxidase inhibitor, can be ingested and produce a variable but prolonged psychedelic state that can last from 6 to 15 hours. DMT is also found naturally in the brain in small amounts and can act as a neurotransmitter.

[0008] Lysine diethylamide (LSD) is a diethylamide derivative of a naturally occurring substance from a fungus found in rye grain that also produces a psychedelic state lasting up to 8 to 12 hours.

[0009] Psilocybin is a naturally occurring plant-based tryptamine found in Psilocybe mushrooms and produces a prolonged psychedelic state of about 6 to 8 hours. Psilocybin was first synthesized in 1958 and is currently being studied as a treatment for depression. Psilocybin is a prodrug in which sirocin is the active species in vivo. Psilocybin contains a phosphate bound to the 4-hydroxyl group of sirocin, which is cleaved in the intestine when Psilocybe mushrooms or drugs are taken orally.

[0010] Simple monofunctional organic esters of sirocin have been reported. Lower alkoxy-modified sirocins have also been described. Sulfate-bound sirocins have been produced, and other monobasic and dibasic mineral acid-modified sirocins have been described. Sirocin acetate is known and has been used in underground psychedelic subcultures.

[0011] Psychedelic substances have been shown to be effective in treating depression and are more effective when combined with psychotherapy (Watts 2020 J Contextual Behavior Science). A limited number of synthetic tryptamine substances have been prepared since the earliest documented work of Albert Hoffman. Structure activity relationships for various tryptamine substances have been described (Claire 1988).

[0012] Succinate and other diacid functionalities have been explored as components of prodrug delivery systems for water-soluble, injectable forms of hydrophobic or poorly water-soluble drug substances such as testosterone, haloperidol, chloramphenicol or estradiol (Silverman and Holladay, Chapter 9.2: Prodrugs and Drug Delivery Systems in Drug Design and the Organic Chemistry of Drug Action (3rd ed.), 2014). The tetrahydrocannabinol ester of succinic acid has been patented for the treatment of glaucoma. However, cleavage of the ester is not always rapid, is unpredictable, and can depend on the structure of the moiety attached to the drug linker and must therefore be studied (Anderson 1984 J Pharma Sci). Esterases are responsible for the active cleavage of the prodrug ester group in vivo, and species differences in the number and specificity of esterases in various tissues complicate studies and optimization (Bahar 2012 J Pharm Sci).

[0013] This background information is believed to be relevant to a basic understanding of the present invention. It is not admitted that any of the foregoing is prior art with respect to any aspect of the claimed invention. Summary of the invention

[0014] The present invention relates to novel tryptamine compounds which, when administered, are converted to an active form in vivo and act as 5HT2A agonists. The compounds described herein can be used to treat psychiatric disorders such as depression, including unipolar and bipolar depressions, such as but not limited to depression, depression caused by generalized anxiety, major depressive disorder, treatment-resistant depression, and postpartum depression.

[0015] In one aspect, the present invention relates to a tryptamine or isotryptamine compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or zwitterion thereof:

[0016]

[0017] in:

[0018] (1) R1, R2 and R6 are each independently selected from hydrogen, linear or branched alkyl (preferably C 1-5 alkyl) or aralkyl;

[0019] (2) R4 is

[0020] 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 by an alkyl or CO2H; or

[0021] b. (R9)(R10)N-, wherein R9 is X-CO2H, wherein X is as defined above, and R10 is hydrogen, linear or branched alkyl (preferably C 1-5 alkyl) or aralkyl;

[0022] (3) R5 is hydrogen, linear or branched alkyl (preferably C 1-5 alkyl), aralkyl or O-R5', wherein R5' is hydrogen, linear or branched C 1-5 Alkyl; and

[0023] (4) R7 and R8:

[0024] a. Each independently selected from hydrogen, linear or branched alkyl (preferably C 1-5 alkyl)

[0025] or aralkyl; or

[0026] b. together form a non-aromatic N-containing heterocyclic ring optionally substituted with an alkyl group, preferably wherein the entire heterocyclic ring structure does not contain more than 12 atoms.

[0027] In another aspect, the present invention includes dibasic acid esters of serotonin (such as 4-hydroxy and 5-hydroxytryptamine and 6-hydroxy and 7-hydroxyisotryptamine) and other structural or functional analogs of tryptamine.

[0028] In some embodiments, R7 and R8 are the same or different and are linear or branched C 1-4 Alkyl; either the same or different and are methyl or isopropyl; such as 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.

[0029] In some embodiments, X is a linear C1-C3 chain, optionally substituted with OH or -CO2H, such as X is an unsubstituted linear C3 chain.

[0030] In another aspect, the invention relates to a composition comprising a compound described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises an oral dosage formulation or an injectable formulation.

[0031] In another aspect, the present invention includes a method of treating a psychiatric disorder, comprising the step of administering an effective amount of a compound described herein. In some embodiments, the psychiatric disorder is depression, including unipolar and bipolar depression, such as but not limited to depression, depression caused by generalized anxiety, major depressive disorder, treatment-resistant depression, and postpartum depression.

[0032] In another aspect, the invention relates to the use of a compound as described herein for treating a psychotic disorder, or in the manufacture of a medicament for treating a psychotic disorder, such as depression.

[0033] In another aspect, the present invention relates to a method for preparing a compound described herein, comprising reacting a tryptamine including serotonin or hydroxyisotryptamine with a cyclic anhydride in a suitable anhydrous solvent. In some embodiments, the solvent comprises a base having a pKa greater than 4 but less than about 9, and the resulting compound is separated into zwitterions. In some embodiments, the tryptamine comprises 4-hydroxytryptamine or 5-hydroxytryptamine or 6-hydroxyisotryptamine or 7-hydroxyisotryptamine. In some embodiments, the solvent is pyridine. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is a graph showing the plasma concentration (ng / ml) of 4-HO-DiPT versus time following subcutaneous administration of N,N-diisopropyltryptamine-4-glutaric acid at a rate of 2 mg / kg.

[0035] Figure 2 is a graph showing the plasma concentration (ng / ml) of 4-HO-DiPT following subcutaneous administration of N,N-diisopropyltryptamine-4-glutaric acid at a rate of 1.4 mg / kg. DETAILED DESCRIPTION

[0036] Embodiments of the present invention include novel synthetic tryptamine prodrugs. Prodrugs can be used to treat mental disorders (such as depression), including but not limited to major depressive disorder, refractory depression and postpartum depression. As used herein, the term "mental disorder" includes those disorders that can be diagnosed as psychological disorders or mental disorders by mental health professionals, including those disorders that can be diagnosed by reference to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0037] As used herein, the terms "treating," "treat," or "treatment" encompass both prophylactic (ie, preventing a disease) and palliative (ie, alleviating, relieving or slowing the progression of a disease, disorder or condition in a patient) treatment.

[0038] As used herein, a "psychedelic state" is an altered state of consciousness experienced by a person that may include heightened sensory perception, sensory distortions or hallucinations, and / or feelings of euphoria or despair. Psychedelic states have been described as being induced by psychiatric drugs such as DMT (dimethyltryptamine), LSD, mescaline, or psilocybin. Other known psychedelic drugs include N-methyl-N-isopropyltryptamine (MiPT) and the 4-hydroxy analog of N,N-diisopropyltryptamine (DiPT).

[0039] The present invention includes prodrugs of hydroxy-indole 5HT2A agonists that induce a psychedelic state or provide a beneficial therapeutic effect without being associated with a psychedelic state. The prodrugs can be used in combination with other treatments known to be effective for treating mental disorders (such as psychotherapy, electroconvulsive therapy and / or other drug compounds), for example, with tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MOAIs) or other antidepressants. In a preferred embodiment, the treatment can produce a lasting effect, for example, more than 1 month after a single treatment, preferably more than 3 months, and more preferably more than 6 months. In some embodiments, additional treatment may not be required.

[0040] Compound

[0041] When used herein, "compound" includes any pharmaceutically acceptable derivative or variant, including conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereoisomer 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 drug precursor compound that, after administration, releases the drug (or "activity") in vivo by certain chemical or physiological processes (e.g., hydrolysis, enzymolysis or hydrolysis, or metabolic conversion to the desired drug form). The present invention includes within its scope pharmaceutically acceptable salts of the compounds of the present invention. Therefore, the phrase "or a pharmaceutically acceptable salt thereof" is implicit in the description of all compounds described herein, unless explicitly stated to the contrary.

[0042] In some embodiments, the compounds of the present invention include prodrug compounds that are easy to purify, formulate and stabilize, and preferably can be used to provide highly soluble drug substances with rapid onset and elimination for ease of use in clinical settings. In some embodiments, the compounds can be generated as zwitterions that can be converted into pharmaceutically acceptable salts.

[0043] In some embodiments, the compounds of the present invention preferably allow rapid cleavage of the prodrug moiety in vivo to give an active pharmacophore, for example, 90% conversion can occur in less than 4 hours, preferably in less than 2 hours, and more preferably in less than 1 hour. The prodrug itself may have less, little or no pharmacological activity, but when administered to a patient, can be converted to an active compound by hydrolytic cleavage.

[0044] Diacid half esters of tryptamines, such as siroxin or other serotonins or isotryptamines, have not been described previously. Prodrug strategies implemented by combining diacids and 4-hydroxy-tryptamine or 5-hydroxy-tryptamine may not yet be proposed because prodrug strategies are usually not necessary when the drug is already soluble. Therefore, the multiple aspects of this diacid half ester prodrug strategy as described herein are considered to be novel and creative.

[0045] In one aspect, the present invention comprises a tryptamine or isotryptamine compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or zwitterion thereof:

[0046] in:

[0047] (1) R1, R2 and R6 are each independently selected from hydrogen, a linear or branched alkyl group (preferably a C1-5 alkyl group) or an aralkyl group;

[0048] (2) R4 is

[0049] 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 by an alkyl or CO2H; or

[0050] b. Wherein, R9 is X-CO2H, wherein X is as above (2)

[0051] (a) as defined above, and R10 is hydrogen, a linear or branched alkyl group (preferably C 1-5 alkyl) or aralkyl;

[0052] (3) R5 is hydrogen, linear or branched alkyl (preferably C 1-5 alkyl), aralkyl or O-R5', wherein R5' is hydrogen, linear or branched C 1-5 Alkyl; and

[0053] (4) R7 and R8:

[0054] a. Each independently selected from hydrogen, linear or branched alkyl (preferably C1-5 alkyl)

[0055] or aralkyl; or

[0056] b. together to form a non-aromatic N-containing heterocyclic ring optionally substituted by an alkyl group, preferably wherein the entire heterocyclic structure does not contain more than 12 atoms, such as pyrrolidine (NC4 ring), piperidine (NC5 ring), or morpholine (NC4O ring). "Alkyl" itself or as part of another substituent refers to a saturated branched, linear or cyclic monovalent hydrocarbon group derived by removing a 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 propane-1-yl, propane-2-yl (isopropyl), cyclopropane-1-yl, etc.; butyls, such as, butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (tert-butyl), cyclobutan-1-yl, etc.; and so on. In some embodiments, the alkyl group contains 1 to 20 carbon atoms (C 1 -C 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C 1 -C 10 In yet other embodiments, the alkyl group contains 1 to 6 carbon atoms (C 1 -C 6 Alkyl) or 1 to 4 carbon atoms (C 1 -C 4 ). C 1 -C 6 Alkyl groups are also called "lower alkyl groups".

[0057] The term "aralkyl" is a term of art and as used herein refers to an alkyl group (e.g., C 1-6 An example of an aralkyl group is a benzyl group, i.e., a phenyl-methyl group.

[0058] When used to modify a specified group or free radical, "substituted" means that one or more hydrogen atoms of the specified group or free radical are each independently replaced by one or more substituents that are the same or different. The term "substituted" specifically contemplates and allows for one or more substitutions that are common in the art. However, it is generally understood by those skilled in the art that substituents should be selected so as not to adversely affect the useful properties of the compound or adversely interfere with its function.

[0059] The term "optionally substituted" means the presence or absence of a substituent. That is, it means "substituted or unsubstituted". For example, an optionally substituted alkyl group includes an unsubstituted alkyl group and a substituted alkyl group. The substituent group used to replace the specified group may be further substituted, typically with one or more of the same or different groups selected from the various groups specified above.

[0060] Following hydrolysis or metabolism of the ester functional group R4-CO-, these prodrug structures are converted into active hydroxy-indole 5HT2A agonists.

[0061] In some non-limiting examples, the compound includes a dibasic acid ester of a tryptamine structure, such as 4-hydroxy-N, N-dimethyltryptamine (Siroxin 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 compound includes 4- and 5-substituted hemisuccinates, hemiglutarates, and citrates of 4-hydroxy derivatives of N, N-dimethyltryptamine (Siroxin), N, N-diisopropyltryptamine (4-HO-DiPT), or N-methyl-N-isopropyl-tryptamine (4-HO-MiPT).

[0062] In some embodiments, the compound includes a compound of formula I, II, III or IV, wherein R1, R2, R5, R6 are each hydrogen; X is a linear C1-4 chain. 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, thereby forming 4- or 5-hemisuccinate of siroxin.

[0063] In some embodiments, the compound includes a compound of formula I, II, III or IV, wherein 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, X is a C2 alkyl, thereby forming a hemisuccinate of 4- or 5-hydroxy-diisopropyltryptamine. In some embodiments, the compound is a compound of formula I or II, X is a C2 olefin, thereby forming a hemifumarate 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, thereby forming a hemiglutarate of 4- or 5-hydroxy-diisopropyltryptamine.

[0064] In some embodiments, R7 and R8 are each selected based on retaining or enhancing the ability of the compound to induce a psychedelic state. 4 , the psychedelic activity of tryptamine will be reduced. However, if such compounds are still 5HT2A agonists, which can produce beneficial therapeutic effects without the psychedelic state, they are still within the scope of the present invention.

[0065] In some embodiments, the compound of the present invention is a diacid zwitterion. Therefore, where X is a linear saturated alkyl, the diacid may include a common linear alkyl-diacid, including but not limited to oxalic acid, malonic acid, succinic acid, glutaric acid (gum acid), adipic acid (fatty acid), pimelic acid (menthol acid) and suberic acid (soft wood acid). In some embodiments, where X is a linear olefin, the diacid may include an acid, such as maleic acid, fumaric acid, or glutaconic acid. In other embodiments, the diacid may include a branched acid, such as citraconic acid, mesaconic acid, 2,2-dimethylsuccinic acid; substituted acid, such as tartrate, 2-(2-hydroxyethyl)-malonic acid, α-hydroxyglutaric acid; citric acid; or aromatic diacids, such as phthalic acid, isophthalic acid and p-phthalic acid, optionally with organic substituents on the aromatic ring.

[0066] In some embodiments, the compound can be one of the following:

[0067] (1)Siroxin-4-succinate

[0068]

[0069] (2) N,N-diisopropyltryptamine-4-succinate

[0070] (3) N,N-diisopropyltryptamine-4-fumarate

[0071] (4) Serosin-4-methyl-5-succinate

[0072] (5) Iso-N,N-dimethyltryptamine-6-succinate

[0073]

[0074] (6) N,N-diisopropyltryptamine-4-glutarate

[0075]

[0076] (7) N-methyl-N-isopropyltryptamine-4-glutarate

[0077] (8) Siloxin-4-glutaric acid ester

[0078] (9) N,N-diethyltryptamine-4-glutarate

[0079]

[0080] (10) N,N-diethyltryptamine-4-succinate

[0081]

[0082] (11) N,N-diisopropyltryptamine-4-(3,3-dimethylglutarate)

[0083]

[0084] In some embodiments, diacid-modified tryptamine or isotryptamine show product stability (oxidation and hydrolysis), and can be easily synthesized and purified.Diacid-modified tryptamine or isotryptamine preferably show the solubility exceeding the medicine that does not have diacid modification in biological matrix, so that they become excellent drug candidates.Similarly, diacid-modified tryptamine preferably shows relatively fast hydrolysis rate in vivo, thereby prodrug is quickly converted into the active form of medicine.This can improve the ideal pharmacokinetic properties of prodrug, including the pharmacokinetic curve with more reproducibility.These characteristics can depend on the property of indole, the different substituents attached to indole and the property of diacid ester.Stability and hydrolysis rate can be experimentally determined.

[0085] In some embodiments, the compound may include a carbamate of a tryptamine, wherein R4 is (R9)(R10)N-, wherein R9 and R10 define a carbamate residue and are as defined above. In some embodiments, the carbamate functional group includes a zwitterionic amino-functional mono- or dicarboxylic acid linked via a carbamate, including but not limited to zwitterionic compounds such as:

[0086] Natural and unnatural neutral or anionic amino acids, such as glycine, alanine, leucine, isoleucine, serine, theanine, glutamic acid, aspartic acid;

[0087] ω linear alkyl C1-6-amino acids, such as 3-aminopropionic acid, 4-amino-butyric acid;

[0088] • Other branched-chain amino acids and aromatic amino acids, such as 4-amino-benzoic acid.

[0089] In some embodiments, the present invention may include zwitterionic compounds wherein R4 comprises one or more non-ester carboxyl functional groups, such as a citric acid derivative of 4-hydroxytryptamine (V) or a glutamic acid carbamate of 4-hydroxytryptamine (VI):

[0090]

[0091]

[0092] In some embodiments, zwitterionic compounds are preferably stable at neutral or slightly acidic pH. Acylation of the hydroxyl functional group of indole can specifically prevent oxidation reactions of typical substituted phenolic compounds and indole (Manevski 2010, Drug Metabolism and Disposition and Napolitano, 1989, Tetrahedron), while also allowing dissolution. In some embodiments, zwitterions have sufficient solubility (>30 mg / ml) in a neutral and pharmaceutically acceptable pH range (3-8) to achieve the desired efficacy / efficacy. Traditionally, non-prodrug pharmacophore tryptamines must be placed and maintained in acidic media to achieve good solubility and stability. Acidic media can prevent use as injectable preparations and may cause irritation.

[0093] 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.

[0094] The diacid part is metabolically cleaved in vivo, providing an active ingredient with a dosage and kinetics sufficient to achieve a psychedelic state, which is considered necessary for the treatment of depression, such as psychedelic-assisted psychotherapy. This is particularly advantageous when designing a convenient drug that produces a psychedelic experience lasting 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 the onset of psychoactive properties can be reduced when compared to injection of free drugs (without acylation of hydroxyl functional groups). In some cases, a slightly slower onset may be preferred in order to avoid sudden attacks that may cause anxiety, especially in patients with early psychedelic onset. Therefore, in a preferred embodiment, the onset can be controlled by the metabolic rate, which can be a function of the ester and target enzyme required for hydrolysis.

[0095] In some embodiments, certain prodrug diacid moieties (e.g., succinate) can reduce the potential for abuse by inhalation or snorting. As a zwitterion, it is unlikely to be rapidly absorbed through tissues that do not have esterase activity. In addition, the zwitterion may not be absorbed directly into the brain by passive mechanisms. The cleavage rate in the digestive tract may be slower than the non-acylated form and absorption is slower, thus delaying the peak rate and the "rush" feeling that people who intend to abuse may seek.

[0096] Preparation method

[0097] The compounds described herein can be synthesized using the methods described below, or similar methods, together with synthetic methods known in the field of synthetic organic chemistry, or as understood by those of ordinary skill in the art by variations thereon. Preferred methods may include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used, and is suitable for the transformations affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the proposed transformations. This sometimes requires judgment within the skill of those skilled in the art to modify the order of the synthesis steps or to select a specific process scheme rather than another to obtain the desired compounds of the present invention.

[0098] Protection and deprotection in the following methods can be carried out by methods generally known in the art (see, for example, Greene, TW et al., Protecting Groups in Organic Synthesis, 3rd edition, Wiley (1999)). General methods for organic synthesis and functional group transformations are 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.

[0099] 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), and in U.S. Pat. No. 3075992 and Chen (JOC 1994, 3738).

[0100] For example, the succinate prodrug compounds described herein can be prepared starting from the corresponding hydroxy-indole and dianhydride using the synthetic scheme outlined in Scheme 1. The choice of reaction conditions (such as temperature, time, solvent) and work-up procedures are selected and they can be adapted to the experimental conditions recognized by those skilled in the art. Restrictions on substituents that are compatible with the reaction conditions will be apparent to those skilled in the art, and alternative or analogous methods must then be used.

[0101]

[0102] Other diacid prodrugs can be prepared using other dianhydrides, as can be readily envisioned by one skilled in the art.

[0103] Glutaric acid prodrug compounds can be prepared using the following Scheme 2 using glutaric anhydride:

[0104] Those skilled in the art can easily select appropriate conditions and solvents. The reaction with the dianhydride can occur in dichloromethane and triethylamine or pyridine. In some embodiments, the solvent comprises a base with a pKa greater than 4 but less than 9. If pyridine is used, the product is directly precipitated from the reaction mixture in the form of pure zwitterions.

[0105] The solid zwitterion can be converted to a suitable salt (eg, the hydrochloride salt) by addition of anhydrous HCl (g) in a suitable solvent or by trituration in anhydrous ethereal HCl or dioxane HCl.

[0106] The synthesis of diacid half ester prodrugs can also be produced 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 dual activated forms of diacids, such as dichloro, di-N-hydroxysuccinimide (using dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide and DMAP), diimidohydrazide (using carbonyldiimidazole), or other activated forms of diacids with hydroxyl forms of active heterocyclic species. When using dual activated forms, it is preferred to use 2 to 25 times excess of dual activated diacids to avoid covalently binding 2 tryptamines to the diacid.

[0107] Similarly, one skilled in the art can apply these methods to 6- or 7-hydroxyisochromene.

[0108] Formulations and compositions The present invention also provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more compounds described herein formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one or more additional therapeutic agents. Although the compounds described herein can be administered alone, it is preferred to administer the compounds as a pharmaceutical composition.

[0109] The term "pharmaceutical composition" refers to a composition comprising a combination of a compound of the present invention and at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a bioactive agent to an animal (particularly a mammal), including (i.e.) adjuvants, excipients or carriers, such as diluents, osmotic supplements, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, 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 of being compatible with the other ingredients of the preparation and harmless to the patient.

[0110] As used herein, "oral" administration includes swallowing in the stomach or intestine, and also includes lingual, sublingual, buccal and oropharyngeal administration. The compounds of the present invention can be administered by any suitable means for any use or method described herein, for example, oral, such as tablets, capsules (each of which can include sustained release or timed release formulations), pills, powders, granules, elixirs, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingual (e.g., as a film, effervescent tablet or a tablet that spontaneously dissolves under the tongue); parenteral, such as by subcutaneous, intravenous, intramuscular injection or infusion technology (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasal, including administration to the nasal membrane, such as by inhalation spray; or rectal, such as suppository form.

[0111] Of course, the dosage regimen of the compounds described herein will vary according to known factors, such as the pharmacokinetic and pharmacodynamic characteristics of the specific 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; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function; and the desired effect. The selected dosage level may also depend on additional factors, including the activity of the specific compounds and pharmaceutical compositions described herein, whether esters, salts or amide substituents of the compounds are used, the time of administration, the excretion or metabolic rate of the specific compound employed, 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 specific compound used, and similar factors well known in the medical field.

[0112] Typically, when used for the indicated effects, the dosage of the prodrug used in the treatment phase will be from about 0.001 to about 500 mg per dose, preferably from about 0.01 to about 200 mg per dose, most preferably from 0.1 to about 50 mg per dose, for example 10, 20, 30, 40, 50, 100 or 200 mg. Intravenously, during a constant rate infusion, the most preferred dosage range is from about 0.01 to about 10 mg / kg / minute.

[0113] The compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in multiple divided doses, such as twice, three times or four times a day. Alternatively, the dose can be provided weekly, biweekly or monthly. In a preferred embodiment, only one or two doses are required for the antidepressant effect, which can be extended by 1, 2, 3 or 6 months or longer. For tablet dosage forms, depending on the dose, the drug can account for 1wt% to 80wt% of the dosage form, more typically 5wt% to 60wt% of the dosage form. In addition to the drug, the tablet generally also contains a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, crospovidone, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, low alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. In general, the disintegrant will include 1wt% to 25wt%, preferably 5wt% to 20wt% of the dosage form.

[0114] Binders are generally used to impart viscosity to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also include diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dihydrated calcium phosphate.

[0115] Tablets may also optionally include surfactants (such as sodium lauryl sulfate and polysorbate 80), and glidants (e.g., silicon dioxide and talc). When present, the amount of surfactant is typically 0.2 wt% to 5 wt% of the tablet, and the amount of glidant is typically 0.2 wt% to 1 wt% of the tablet.

[0116] Tablets also typically include lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants are typically present in an amount of 0.25wt% to 10wt%, preferably 0.5wt% to 3wt% of the tablet.

[0117] Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents. Exemplary tablets contain up to about 80 wt % of drug, about 10 wt % to about 90 wt % of binder, about 0 wt % to about 85 wt % of diluent, about 2 wt % to about 10 wt % of disintegrant, and about 0.25 wt % to about 10 wt % of lubricant.

[0118] Tablet blends may be compressed directly or by rollers to form tablets. Alternatively, the tablet blend or a portion of the blend may be wet, dried, or melt granulated, melt congealed, or extruded prior to tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

[0119] The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1," by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 08247 6918X), the disclosure of which is incorporated herein by reference in its entirety.

[0120] A typical capsule for oral administration comprises at least one compound of the invention (eg 25 mg), lactose (eg 75 mg) and magnesium stearate (eg 15 mg).The mixture is passed through a 60 mesh screen and filled into a size 1 gelatin capsule.

[0121] Liquid preparations include suspensions, solutions, syrups and elixirs. Such preparations can be used as fillers in soft capsules or hard capsules and typically include carriers, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by, for example, reconstructing solids from a pouch. The compounds of the present invention can also be directly administered to bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous. Suitable equipment for parenteral administration includes needle (including microneedle) syringe, needleless syringe and infusion technology.

[0122] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and pH adjusters or buffers (preferably to a pH of 3.0 to 7.0, preferably 4.0 to 6.0, and more preferably 4.5 to 5.5), but for some applications they may be more appropriately formulated as sterile non-aqueous solutions or dry forms for use in combination with suitable carriers (such as sterile, pyrogen-free water or preformed, mixed aqueous buffers). Osmotic agents may be included to control tonicity.

[0123] Preparation of parenteral kits for reconstitution at the point of care under sterile conditions (e.g., by lyophilization) can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art. Typical injectable formulations are produced by aseptically placing at least one compound of the present invention (e.g., 25 mg) as a sterile filtered solution in a vial, aseptically freeze-drying, and sealing. For use, the contents of the vial are mixed with, for example, 2 mL of normal saline for injection, optionally mixed with an appropriate amount of an osmotic supplement and a pH adjuster to achieve a slightly acidic to neutral pH (e.g., pH 4-7), to produce an injectable formulation with low irritation but retaining the solubility and / or stability of the prodrug.

[0124] The compounds of the 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 aforementioned administrations.

[0125] For example, it is found that drug cyclodextrin complexes are commonly used in most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct compounding with a drug, cyclodextrins can be used as auxiliary additives, i.e., as carriers, diluents, or solubilizers. The most commonly used for these purposes are alpha, beta, and gamma cyclodextrins, examples of which can be found in PCT Publication Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148, the disclosures of which are incorporated herein by reference in their entirety.

[0126] No matter how the selected route of administration is, the compound of the present invention and / or the pharmaceutical composition of the present invention that can be used in a suitable hydrated form can be formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art. The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed in order to obtain the amount of the active ingredient that effectively realizes the desired therapeutic response for a specific patient, composition, and mode of administration.

[0127] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0128] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.

[0129] As used herein, "therapeutically effective amount" refers to the amount of one or more of the symptoms of the disorder treated that will be alleviated to a certain extent by the compound administered. Regarding the treatment of depression, a therapeutically effective amount refers to the amount of the effect of reducing the severity of depression. Depression severity can be assessed using a well-known structured assessment tool, such as a structured clinical interview for DSM-5 (SCID-5) and the GRID-Hamilton Depression Rating Scale (GRID-HAMD). The therapeutically effective amount can be less than the amount required for mental state.

[0130] The effective dose can be given with one or more administrations. For purposes of the present invention, the effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly complete a preventive or therapeutic treatment. As understood in a clinical context, the effective dose of a drug, compound, or pharmaceutical composition may be combined with another therapy, drug, compound, or pharmaceutical composition or may not be combined with another therapy, drug, compound, or pharmaceutical composition.

[0131] Treatments and uses

[0132] Treatment with the novel prodrugs of the present invention can significantly alleviate clinical or subclinical depression and avoid relapses, especially if used in conjunction with psychotherapy to treat depression. Administration of effective doses of psilocybin is known to rapidly and substantially reduce depressive symptoms, and many subjects achieve remission by four weeks of follow-up (Davis et al.). Without being limited by theory, it is believed that the psychedelic state is associated with the beneficial effects, however, some compounds (which are 5HT2A agonists) can provide the desired therapeutic effects without the psychedelic state. One aspect of the present invention includes prodrugs of those 5HT2A agonists that do provide a beneficial therapeutic state.

[0133] In general, the present invention includes the use of the compounds of the present invention herein for treating any disease or disorder that can be alleviated by a 5HT2A agonist, or the use of the compounds of the present 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.

[0134] In some embodiments, the present invention may include the use of the compounds of the present invention to treat mental 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 anxiety in advanced illnesses such as cancer and generalized anxiety disorder; depression, including major depressive disorder, postpartum depression, cluster headaches, obsessive-compulsive disorder; personality disorders, including behavioral disorders; drug disorders, including alcohol dependence, nicotine dependence, opioid dependence, cocaine dependence; and other addictions, including gambling disorder, eating disorders and body dysmorphic disorder, chronic pain or chronic fatigue.

[0135] In some embodiments, the present invention may include a method of treating a mental 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 of 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 a major depressive disorder.

[0136] For example, patients diagnosed with depression can be screened before treatment, and then prepared for the dosing process by a trained psychotherapist. During the dosing period, the compound of the present invention can be administered by injecting the patient with a sterile solution at a rate of 0.01-0.3 mg / kg. The patient is preferably seated during treatment while blindfolded. For safety reasons, trained medical staff can monitor the patient throughout the dosing phase, which may last for 12 hours. In some cases, music can be played for the patient. When the healthcare professional can determine that the drug substance has been cleared, the psychotherapist can help the patient resolve any issues related to the psychedelic experience, and the patient can then be discharged.

[0137] To further alleviate any anxiety that may occur in connection with treatment, doctors prefer to divide the treatment dose and therefore reduce the initial onset of psychological activity before administering the entire supplement at a dose to achieve the full effect.

[0138] In some embodiments, the treatment with the compounds of the present invention can be combined with the collocation treatment with another antidepressant simultaneously or continuously. In a preferred embodiment, the treatment with the compounds of the present invention is combined with psychotherapy, which can be applied before or after treatment. If before treatment, the patient can be focused on the treatment intention at this stage. If after treatment, psychotherapy is preferably performed within 48 hours of the administration phase to help the patient integrate any feelings, emotions, visions or thoughts that may occur during this phase, and to allow the psychotherapist to provide advice on how to best change thinking or behavior patterns in order to improve the antidepressant effect. After the administration phase, psychotherapy can be continued as needed, for example, up to another 3 months, to help the patient integrate any experience or learning that occurred during the administration phase.

[0139] Example

[0140] 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 their zwitterionic form can be easily visualized by those skilled in the art in their neutral form, and vice versa.

[0141] When a compound is referred to as glutaryl or succinyl, or hemiglutarate or hemisuccinate, it is understood to be the same as succinate or glutarate. For example, 4-hemiglutarate of sirocin is the same as sirocin-4-glutarate or N,N-dimethyltryptamine-4-glutarate. Similarly, 4-hemiglutarate of 4-OH-DiPT is the same as N,N-diisopropyltryptamine-4-glutarate.

[0142] Example 1. 4-hemisuccinate of siroxin

[0143] 4-Hydroxyindole is prepared using methods described in the literature (e.g., in Kargbo 2020ACS Omega) or modestly adapted methods. Thus, 4-acetoxyindole is reacted with oxalyl chloride in methyl-tert-butyl ether (MTBE) and the resulting intermediate is quenched with dimethylamine. Indole-oxalyl-dimethylamide is reduced with lithium aluminum hydride (LAH) in tetrahydrofuran (THF) to give 4-acetoxy-3-(N,N-dimethylaminoethyl)indole, which is deprotected with aqueous base to give 4-hydroxy-dimethyltryptamine (Siroxin).

[0144] 4-hydroxytryptamine reacts with excess succinic anhydride in dichloromethane (DCM) containing triethylamine and catalyzed by N,N-dimethylaminopyridine to give siroxin-4-succinate. A precipitate is formed, which is recovered after decanting and grinding with DCM. The solid is acidified in aqueous HCl, purified by chromatography and recovered after evaporation of the solvent. The structure is confirmed by NMR. Purity is determined by HPLC.

[0145] Example 2. 4-Hydroxy-diisopropyltryptamine 4-hemisuccinate (4-OH-DiPT) 4-acetoxy indole is reacted with oxalyl chloride in MTBE, and the obtained intermediate is quenched with diisopropylamine. The obtained oxamide is reduced with lithium aluminum hydride (LAH) in THF to obtain 4-acetoxy-3-(N, N-diisopropylaminoethyl) indole, and then deprotected with aqueous alkali solution to obtain 4-hydroxy-3-3-(N, N-diisopropylaminoethyl) indole. 4-OH-DiPT (5.8g, 22.3mmol, 1 equivalent) dissolved in dichloromethane (28mL, 5xV) is added to the 250mL round-bottomed flask containing a stirring bar and stirred at room temperature. Then succinic anhydride (1.3 equivalents) is slowly added to the stirred solution, and the obtained suspension is stirred at room temperature overnight. The precipitate formed in the reaction is recovered by decantation and grinding with DCM. The solid is acidified in aqueous HCl, purified by chromatography and recovered after evaporating the solvent. The structure is confirmed by NMR. Purity is determined by HPLC.

[0146] Example 3. 4-OH-DiPT 4-hemifumarate

[0147] 4-Benzyloxyindole reacts with oxalyl chloride in diethyl ether in the presence of a Friedel-Kraft catalyst, and the resulting intermediate is quenched with diisopropylamine. The resulting oxamide is reduced with lithium aluminum hydride (LAH) in THF to give 4-benzyloxy-3-(N,N-diisopropylaminoethyl)indole, which is then treated with H 2 Deprotection with Pd / C affords 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. This material is reacted with an excess of diactivated fumaric acid (N-hydroxysuccinimide) in dichloromethane, followed by quenching of any unreacted N-hydroxysuccinimide ester with aqueous acid, leaving 4-fumaryl-3-(N,N-diisopropylaminoethyl)indole.

[0148] Example 4. 5-Hydroxy-4-methyl-dimethyltryptamine 5-hemisuccinate

[0149] 4-Methyl-5-hydroxyindole (1) was reacted with benzyl chloride in K 2 CO 3In the presence of , in ACN to give 5-benzyloxy-4-methyl-indole, which is then reacted with oxalyl chloride in diethyl ether in the presence of a Friedel-Kraft catalyst and the resulting intermediate is quenched with dimethylamine. The resulting oxalyl-amide is reduced with lithium aluminum hydride (LAH) in THF to give 4-methyl-5-benzyloxy-3-(N,N-dimethylaminoethyl)indole and then deprotected with H2 and Pd / C to give 4-methyl-5-hydroxy-3-(N,N-dimethylaminoethyl)indole. This material is reacted with succinic anhydride in dichloromethane, catalyzed by N,N-dimethylamino-pyridine, to give 4-methyl-5-succinyl-3-(N,N-dimethylaminoethyl)indole.

[0150] Example 5. N,N-dimethylisochromene-6-succinate

[0151] 6-O-Benzyl-dimethylisochromen was prepared by N-alkylation of 5-BzO-indole using NaH following the procedure outlined by Glennon (J Med Chem 1984). 2 Catalytic hydrogenation of 2-(4-(2-hydroxy-4-yl)-2-nitropropene removes the benzyl group to afford the HO-functionality which is succinylated in a subsequent step using succinic anhydride to yield the indicated species.

[0152] Example 6. N,N-diisopropylamine-4-pentanedioate 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 eq) and the suspension was stirred under Ar. A solution of 4-OH-DiPT (0.26 g, 1 mmol, 1 eq) in 1.5 mL of anhydrous DCM was added, followed by 4-dimethylaminopyridine (DMAP) (37 mg, 0.3 mmol, 0.3 eq) and trimethylamine (0.18 mL, 1.3 eq) and the resulting suspension was stirred at room temperature under Ar overnight.

[0153] The mixture was decanted and the solid was ground with anhydrous DCM (3 mL) and a few drops of anhydrous MeCN. The suspension was acidified with 1M HCl (about 1.1 equivalents) and concentrated to dryness. The crude product was purified by C18 reverse phase column chromatography (40 g, A: in H 2 Purification was performed using 2% HCl in O, B: 0.05% HCl in MeCN).

[0154] The structure was confirmed by NMR. The 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 can be dissolved in water up to 50 mg / ml and lyophilized to form a white "filter cake".

[0155] Example 7. Half ester of 3,3-dimethylglutaric acid and 4-hydroxydiisopropyltryptamine 4-Hydroxy-3-(N,N-diisopropylaminoethyl)indole was reacted with 3,3-dimethylglutaric anhydride in pyridine to give 4-succinyl-3-(N,N-diisopropylaminoethyl)indole with the stoichiometry and parameters mentioned in Example 6. 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.

[0156] Example 8. Serosin-4-glutarate

[0157] 4-Hydroxydimethyltryptamine (Sirox) is reacted with excess glutaric anhydride in dichloromethane (DCM) containing triethylamine to obtain Sirox-4-pentanedioate. In another embodiment, the reaction occurs in pyridine. In either case, a precipitate is formed, which is recovered after decantation and grinding with THF. The solid is washed with DCM and then dried. The structure is confirmed by NMR.

[0158] The reaction product was suspended in 1 M HCl-ether to obtain the corresponding HCl salt form of the product, which was recovered in high yield and purity by filtration.

[0159] Example 9. HCl salt of N,N-diisopropyltryptamine-4-glutaric acid Under argon, 4-OH-DiPT (31.8 g, 0.122 mol, 1 eq.) dissolved in 160 mL of anhydrous pyridine (160 mL) was added to a 3-neck 1 L round-bottom flask. After stirring for 15 min, glutaric anhydride (18.1 g, 0.158 mol, 1.3 eq.) was added portionwise. The resulting suspension was stirred at room temperature overnight.

[0160] Anhydrous DCM (160 mL) was added to the suspension and cooled to 0 ° C for 2 h. The solid was filtered and washed with 60 mL of cold anhydrous DCM and dried overnight. At 0 ° C, the dried solid was ground with 160 mL of anhydrous DCM, followed by 160 mL of anhydrous THF, and then 160 mL of anhydrous DCM. After drying, 33.0 g was obtained by HPLC with a yield of 72% and a purity of 98.1%. By 1H-NMR (DMSO-d6) and MS [M+H] + = 375.2 confirms the zwitterion structure.

[0161] In a 100 mL round bottom flask, 18 mL of anhydrous ether HCl solution (4 M in dioxane, 2.4 mL, 9.6 mmol, 1.2 eq) 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 hours. The solid was filtered off and washed with 6 mL of Et 2 The solid was dried to give 3.16 g of the corresponding half-ester tryptamine HCl salt (96% yield, 99.0% purity by HPLC, [M+H] + =375.1).

[0162] Example 10. Siloxin Hemiglutarate

[0163] Siloxin was reacted with 1.2 equivalents of glutaric anhydride in warm THF to give Siloxin-4-glutaric acid ester, which was precipitated from the reaction mixture according to the above method. The precipitate was recovered by filtration, washed with cold 1:1 DCM / THF and dried.

[0164] Example 11. 4-OH-DiPT 4-hemimalonate

[0165] 4-OH-DiPT was dissolved in pyridine and coupled with excess malonic acid and 1.2 equivalents of DCC for 18 h at room temperature. The reaction mixture was passed through a flash tower (5 parts of diatomaceous earth) and the first fraction containing the prodrug compound was separated by precipitation and washing. The yield was about 50%. Purity>95% by HPLC.

[0166] Example 12. Comparative Rates of Prodrug Hydrolysis in Serum

[0167] Human plasma (2 ml), mouse plasma, rat plasma and dog plasma of mixed sex were balanced at 37 ° C. The compound of Example 9 was added to reach a concentration of 1.0 μg / mL. An aliquot (50 μL) of the mixture was taken out at time intervals (0, 0.004, 0.5, 1, 2 and 4 hours) and quenched with 200 μL of methanol / acetonitrile (1: 1). The sample was vortexed and stored at -80 ° C until analysis. The assay was performed in triplicate. Control samples were carried out 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 test sample. Table 1 provides the average concentration of the remaining prodrug at different time points of the experiment. The experiment shows that the rapid enzymatic degradation of the prodrug in plasma is compared with the slow non-enzymatic degradation in the relevant biological medium.

[0168] Table 1. Percentage of remaining prodrug, N,N-diisopropyltryptamine-4-glutaric acid

[0169]

[0170] Example 13. Pharmacokinetics in rats

[0171] The compound of Example 9 was administered to rats with a rate injection (intravenous and subcutaneous) of a sterile solution (2 mg / ml) at 1.4-2 mg / kg. Blood samples were collected at 15, 30, 45, 60, 120, 240 min and 360 min and analyzed for drugs and prodrugs by LCMS. The PK curves of prodrugs and active substances were obtained, and relative bioavailability was determined for each route of administration.

[0172] Generate PK-PD type curves to demonstrate drug activity ( Figure 1 and Figure 2 ). In rodents, no prodrug was observed because it was rapidly converted to the active form. The relevant PK parameters of 4-HO-DiPT after intravenous and subcutaneous injection were determined, as shown in Table 2: Table 2. PK parameters of 4-HO-DiPT after subcutaneous administration of N,N-diisopropylamine-4-glutaric acid (2 mg / kg) (coefficient of variation % in brackets).

[0173]

[0174] In some cases, head twitch reactions (HTR) or wet dog shakes (WDS) are recorded by visual observation and counting of associated muscle twitches. Generally, the intensity of the HTR is proportional to the plasma concentration of 4-HO-DIMP, with the highest intensity of head twitches occurring at Tmax of the PK curve.

[0175] Figure 1 Shown is the relationship between the plasma concentration (ng / ml) of 4-HO-DiPT and time after subcutaneous administration of N,N-diisopropyltryptamine-4-glutaric acid at a rate of 2 mg / kg.

[0176] The pharmacokinetics of 1.34 mg / ml 4-HO-DiPT HCl administered by intravenous or subcutaneous injection was performed in parallel under the same conditions as above. Figure 2 The relationship between the plasma concentration (ng / ml) of 4-HO-DiPT and time at different dosing times is shown. The variability of the active species increased significantly when administered subcutaneously and intravenously. The PK parameters are shown in Table 3. Table 3. PK parameters of 4-HO-DiPT after subcutaneous administration of N,N-diisopropylamine-4-pentanedioic acid (2 mg / kg) (coefficient of variation % in brackets).

[0177]

[0178] Example 17. Pharmacokinetics in Human Volunteers

[0179] The compound from Example 6 (N, N-diisopropyltryptamine-4-pentanedioate) was administered to human volunteers at a dosage of 0.1-0.6 mg / kg by subcutaneous injection of a sterile solution (1 mg / ml). Blood samples were collected at 5, 15, 30, 45, 60, 120, 240 and 480 min and 24 h. The drug and prodrug of the sample were analyzed by LCMS. Subjective effects were measured using standardized questionnaires. The PK analysis showed the maximum plasma concentration (CMax) at about 45 min after injection. The subjective effect showed the intensity of the psychological activity associated with the blood level.

[0180] The compound from Example 2 (4-hemisuccinate of 4-OH-DiPT) was administered to human volunteers by oral ingestion of a tablet containing 50 mg of the prodrug. Blood samples were collected at 5, 15, 30, 45, 60, 120, 240 and 480 min and 24 h. The samples were analyzed for drug and prodrug by LCMS. Subjective effects were measured using standardized questionnaires. PK analysis showed a CMax of about 90 min for injection. Subjective effects show the intensity of psychological activity related to blood levels.

[0181] Example 18. Use in therapy

[0182] The compound of Example 6 (N,N-diisopropylpropylamine-4-pentanedioate) is administered by intravenous or subcutaneous injection (about 25 mg; 0.4-0.5 mg / kg) or by oral administration (about 50-200 mg; 0.8-3.2 mg / kg) with tablets to human patients suffering from depression. In another use example, the compound of Example 6 (4-hemipentanedioate of 4-OH-DiPT) is similarly administered. Prior to administration, the patient is eligible for experience by measuring depression scores, screening for exclusion conditions (such as psychiatric history, adverse cardiac conditions, pregnancy), and finally encouraging the patient to develop a dosing plan. Administration is performed in a quiet clinic environment, and the patient rests comfortably 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 reported no longer feeling the effects of the drug and was asked to sit under supervision. When feeling normal, the patient is allowed to stand (under supervision) and allowed to walk under control. After 1 hour, the patient is discharged. After 24 hours, the patient returned to the clinic and met with the psychotherapist to discuss the treatment process. The patient recorded depression scores via a questionnaire and was discharged again. The patient was regularly counseled about the recurrence of depressive symptoms.

[0183] Example 19. Injectable Preparation Kit

[0184] Prepare a vial with 25 mg of the compound of Example 6 as the hydrochloride salt (sterile powder or lyophilisate). Place 1 ml of a 70 mM Na 2 HPO4 The final pH of the solution is 4.0-5.0. These 2 components constitute a kit for reconstitution of a drug product for subcutaneous injection at the point of care.

[0185] References

[0186] All publications, patents, patent applications, etc. mentioned in the above specification are fully incorporated herein by reference, including the following:

[0187] 1.American Psychiatric Association.(2013).Diagnostic and statisticalmanual of mental disorders(5th Ed.).https: / / doi.org / 10.1176 / appi.books.9780890425596

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[0192] 6.Carhart-Harris,R.L.,Roseman,L.,Haijen,E.,Erritzoe,D.,Watts,R.,Branchi,I.,&Kaelen,M.(2018).Psychedelics and the essential importance ofcontext.Journal of Psychopharmacology,32(7),725-731.https: / / doi.org / 10.1177 / 0269881118754710

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[0211] Definitions and Interpretation

[0212] The description of the present invention has been presented for the purpose of illustration and description, but it is not intended to be exhaustive or limited to the present invention in disclosed form. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the present invention. The embodiments are selected and described in order to best explain the principles and practical applications of the present invention, and to enable other persons of ordinary skill in the art to understand the various embodiments of the present invention and the various modifications suitable for the intended specific use. Insofar as the following description is a specific embodiment or specific use of the present invention, it is intended to be illustrative only and does not limit the claimed invention.

[0213] All devices or steps in the claims attached to this specification plus the corresponding structures, materials, actions and equivalents of the functional elements are intended to include any structure, material or action for performing functions in combination with other claimed elements as specifically claimed. References to "an embodiment", "embodiment" and the like in the specification indicate that the described embodiment may include specific aspects, features, structures or characteristics, but not every embodiment must include the aspect, feature, structure or characteristic. In addition, such phrases may but do not necessarily refer to the same embodiment mentioned in other parts of this specification. Further, when describing a specific aspect, feature, structure or characteristic in conjunction with an embodiment, it is within the knowledge of those skilled in the art to combine, affect or connect this aspect, feature, structure or characteristic with other embodiments, regardless of whether this connection or combination is explicitly described. In other words, in different embodiments, any element or feature may be combined with any other element or feature unless there is an obvious or inherent incompatibility between the two, or it is explicitly excluded.

[0214] It should be further noted that the claims may be written to exclude any optional elements. Thus, this statement is intended to serve as a precondition for the use of exclusive terms (such as "alone", "only", etc.) associated with the statement of claim elements or "negative" limitations. The terms "preferably", "preferred", "preferably", "optionally", "may", and similar terms are used to indicate that the elements, items, conditions, or steps mentioned are optional (unnecessary) features of the present invention.

[0215] Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. The term "and / or" refers to any one, any combination of items, or all of the items associated with the term.

[0216] As will be appreciated by those skilled in the art, for any and all purposes, particularly with regard to providing a written description, all scopes listed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, and the individual values, particularly integer values, constituting the scope. Enumerated scopes (e.g., weight percent or carbon group) include each specific value, integer, decimal or unit within the scope. Any listed scope can be easily identified as fully describing and enabling identical scopes to be decomposed into at least equal half, one-third, one-quarter, one-fifth or one-tenth. As a non-limiting example, each scope discussed herein can be easily decomposed into lower one-third, middle one-third and upper one-third etc.

[0217] As will also be understood by one skilled in the art, all ranges described herein and all language such as "between," "up to," "at least," "greater than," "less than," "greater than," "or more," etc. include the listed numbers and such terms refer to ranges that can subsequently be broken down into sub-ranges as discussed above.

Claims

1. A compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or zwitterion thereof: in: (1) R1, R2 and R6 are each independently selected from hydrogen, a linear or branched alkyl group, or an aralkyl group; (2) R4 is a. -X-CO2H, wherein X is a linear, cyclic or branched, saturated or unsaturated carbon chain optionally substituted with -OH or -CO2H; or an aromatic ring optionally substituted with an alkyl group or CO2H; or b. wherein R9 is X-CO2H, wherein X is as defined above in (2)(a), and R10 is hydrogen, a linear or branched alkyl group optionally substituted with -OH or -CO2H, or an aralkyl group; (3) R5 is hydrogen, linear or branched alkyl, aralkyl or O-R5', wherein R5' is hydrogen, linear or branched alkyl; and (4) R7 and R8: a. each independently selected from hydrogen, a linear or branched alkyl or aralkyl group; or b. together form a non-aromatic N-containing heterocyclic ring optionally substituted by an alkyl group.

2. The compound according to claim 1, selected from the group consisting of: (1)Siroxin-4-succinate (2) N,N-diisopropyltryptamine-4-succinate (3) N,N-diisopropyltryptamine-4-fumarate (4) Serosin-4-methyl-5-succinate (5) Iso-N,N-dimethyltryptamine-6-succinate (6) N,N-diisopropyltryptamine-4-glutarate (7) N-methyl-N-isopropyltryptamine-4-glutarate (8) Siloxin-4-glutaric acid ester (9) N,N-diethyltryptamine-4-glutarate (10) N,N-diethyltryptamine-4-succinate as well as (11) N,N-diisopropyltryptamine-4-(3,3-dimethylglutarate) 3. The compound according to claim 1, wherein: (1) R1, R2 and R6 are each independently selected from H or a linear C 1-5 alkyl; (2) R4 is -X-CO2H, wherein X is a linear or branched C optionally substituted by OH or CO2H 1-5 Carbon chain; (3) R5 is hydrogen, linear or branched C 1-5 Alkyl, aralkyl or O-R5', wherein R5' is hydrogen, linear or branched C 1-5 Alkyl; and / or (4) R7 and R8 are each independently selected from H, or a linear or branched C 1-5 alkyl.

4. The compound according to claim 3, wherein R7 and R8 are the same or different and are linear or branched C 1-4 alkyl.

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

6. The compound according to claim 3, wherein X is a linear C1-C3 chain optionally substituted by OH or CO2H.

7. The compound according to claim 5, wherein X is a linear C3 chain.

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

9. A composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable excipient.

10. The composition according to claim 9, comprising an oral dosage formulation or an injectable formulation. The composition according to claim 10 , which is a solution for injection.

12. The composition according to claim 11, 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.

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

14. The method according to claim 13, wherein: The psychiatric disorder is depression.

15. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of a psychotic disorder, such as depression.

16. A compound according to any one of claims 1 to 8 for use in the treatment of a psychiatric disorder, such as depression.

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

18. The method according to claim 17, wherein: The solvent comprises a base having a pKa greater than 4 and less than about 9, and the resulting compound is isolated as a zwitterion.

19. The method according to claim 18, wherein: The solvent is pyridine.

20. The method according to any one of claims 17 to 19, wherein: The compound is the compound according to claim 2.

21. The method according to any one of claims 17 to 20, wherein: The tryptamine is 4-hydroxy-isopropyltryptamine or sirocin, and the cyclic anhydride is succinic anhydride or glutaric anhydride.

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