Prodrugs of psilocin and related 4-hydroxytryptamines

Abstract

The present invention relates prodrugs of psilocin and related 4-hydroxytryptamines as well as their medical uses in general and in the treatment of psychiatric disorders.

Description

Prodrugs of psilocin and related 4-hydroxytryptamines The present invention relates prodrugs of psilocin and related 4-hydroxytryptamines as well as their medical uses in general and in the treatment of psychiatric disorders. Major depressive disorder (MDD) and related psychiatric disorders constitute a con- siderable disease burden. Since the approval of the first serotonin (5-HT) reuptake inhibitor in 1987, no significantly new treatment modalities have been introduced into clinical practice. A large fraction of depressive individuals does not respond to currently available therapies, and the resulting condition is denoted as treatment-resistant de- pression (TRD). Furthermore, currently available treatments often have to be adminis- tered over extended periods, may be very difficult to withdraw (e.g., Venlafaxine), and / or are associated with patient acceptance and compliance problems (e.g., electro- convulsive therapy). Therefore, a significant clinical need for novel therapeutic inter- ventions for MDD and especially TRD exists. Recently, renewed attention in the neuropsychiatric field has been directed towards 5-HT2A agonists such as lysergic acid diethylamide (LSD) and psilocin (cf. e.g., Car- hart-Harris et al. J. Psychopharmacol.2017, 31, 1091). The latter is generally admin- istered as the phosphate ester prodrug psilocybin, which is, in contrast to psilocin, sta- ble against aerobic oxidation. Upon oral administration in humans, psilocybin is ab- sorbed in the small intestine and immediately cleaved by alkaline phosphatases to yield psilocin (cf. Tylš et al. Eur. Neuropsychopharmacol.2014, 24, 342). The 5-HT2A receptor agonists psilocin / psilocybin and LSD are frequently referred to as the “classical” or serotonergic psychedelics. In addition to these, compounds with other mechanisms of action, referred to as non-classical psychedelics, are currently being studied in clinical trials and have entered clinical practice. Non-classical psychedelics with therapeutic potential include, in particular, ketamine and MDMA (cf. e.g., Heifets et al. Neuropsychopharmacology 2023, 49, 104). Both classical and non-classical psychedelics are considered and currently evaluated as therapeutic interventions for conditions beyond depression. Potential applications include post-traumatic stress disorder (PTSD) (cf. e.g., Henner et al. J. Neurol. Sci.2022, 439, 120302), depressions related to somatic disease and terminal illness (cf. e.g., Ross et al. Neuropharmacology 2022, 216, 109174), neurodegenerative disor- ders such as Alzheimer's disease (cf. Kozlowska et al. J. Neurochem.2022, 162, 89), anorexia nervosa (c.f. Majić et al. Nat Med 2023, 29, 1906), and others. Here, the synthesis and structure-property relationships of 4-hydroxytryptamine pro- drugs from two classes are described: ester and acyloxymethyl derivatives (cf. Scheme 1).Scheme 1: General structures of ester and acyloxymethyl prodrugs of 4-hydroxytryp- tamines. Referring to Scheme 2, besides the natural product psilocybin 2, synthetic prodrugs of psilocin 1 have been described. This encompasses, in particular, esters of psilocin with various acids. Several carboxylate esters 3 of psilocin have been described by Hof- mann et al. (US 3075992 A). More recently, carbonate esters 4 (cf. WO 2022 / 038299 A1), thiocarbonates (cf. e.g., US 11707447 B1), and acyloxymethyl prodrugs 5 of psilocin have been reported (cf. WO 2022 / 038299 A1 and WO 2023 / 023347 A1).Scheme 2: Psilocin prodrugs and their established syntheses: synthesis of psilocy- bin 2 (Hofmann et al. Experientia 1958, 14, 107), synthesis of carboxylate esters 3 (US 3075 992 A / Hofmann et al.1963), synthesis of carbonate esters 4 (WO 2022 / 038299 A1 / Grill 2022), and synthesis of acyloxymethyl prodrugs 5 (WO 2023 / 023347 A1 / Clark et al.2023). However, a systematic search for analogs with a suitable pharmacokinetic and physi- cochemical profile for application routes beyond peroral or intravenous administration is still lacking. In particular, such application routes are buccal, sublingual, nasal, inha- latory, and transdermal delivery. Many of these application routes can ensure a fast onset of the subjective effects dur- ing psychedelic treatment settings with lower inter-individual variability than oral psilo- cybin dosage. This is expected to eliminate undesired waiting times, increase the effi- ciency of therapist interactions, and improve the predictability of the evoked subjective experience. In contrast, the desired subjective experience may be at risk upon peroraladministration, if gastrointestinal absorption is delayed and protracted and, as a con- sequence, the required plasma concentrations of the drug are not reached. Such an unpredictable pharmacokinetic behavior can occur upon peroral administration, since gastric emptying and gastrointestinal absorption is highly dependent on multiple factors that can only partially be controlled, such as previous food intake and metabolic status of the patient (cf. Vinarov et al. Eur. J. Pharm. Sci.2021, 162, 105812). Further, a dosing with fast onset allows the adjustment of the psychedelic experience, if, for example, patient and therapist decide during the session to increase the intensity of the experience (re-dosing), or if it is desired to titrate the dosage depending on the tolerance and desire of the patient. Such a titration dosing may be preferred in cases where the therapist or the patient is uncertain about the tolerance towards the psyche- delic experience. In a psychedelic treatment setting, re-dosing and titration cannot rea- sonably be performed by intravenous or other invasive and potentially threatening forms of drug administration, since this would be incompatible with the intimate and preferentially non-clinical treatment setting. Intravenous administration can, for exam- ple, in many countries only be performed in rooms that fulfil certain legal requirements and therefore do not provide the desired sense of sociability. For the settings described above, in which fast dosing and release is desired, a prodrug with short half-life in human blood plasma in the order of minutes is required. In addition, the prodrug should be sufficiently stable in saliva and other secretions so that no degradation occurs be- fore the prodrug has been absorbed. A premature cleavage of the prodrug, i.e. drug release before entering the bloodstream, would result in the presence of a highly potent 5-HT receptor agonist in a high concentration at mucosal tissues. This can lead to disturbances of the local blood circulation, increase of thrombocyte activity, increase of peristaltic activity in the gastrointestinal tract, and other undesired and harmful ad- verse effects (cf. Mohammad-Zadeh et al. J. Vet. Pharmacol. Ther.2008; 31, 187). It is therefore undesirable to use the biologically active 5-HT receptor agonist for trans- mucosal application while an inactive prodrug releasing the active drug only after reaching the blood circulatory system is highly preferred for the administration of ser- otonergic psychedelics. In light of the current evaluation and promise of psychedelic treatments for diseases in which, for example, the swallowing capacity of patients is restricted or absent, as inAlzheimer's disease, application routes of 4-hydroxytryptamine prodrugs are required that rely neither on the patient's ability to swallow or on injection. Swallowing is fre- quently restricted in neurodegenerative diseases such as Alzheimer's disease and in- jections are a relatively drastic procedure, particularly if repeated, i.e., if regular admin- istration is desired. In this setting, a fast drug release in human plasma may not be essential and an extended release can potentially be tolerated better, or even be ad- vantageous due to a less sudden onset of action. These benefits are illustrated by the considerable success of externally applied patches for the transdermal delivery of opi- oid analgesics (cf. e.g., Kress, Eur. J. Pain 2009, 13, 219). Going beyond the therapeutic setting into the potential applications of small, repeated or continuous doses of psychedelics (micro-dosing) as neuro-enhancing drugs, the administration of suitable skin-permeating prodrugs formulated in transdermal patches appears highly attractive. For the latter application, in which a constant exposure and extended drug release is required, compounds with a slow cleavage rate in human plasma or tissue may be preferable over prodrugs with a fast release. Taken together, there is considerable potential for application routes beyond peroral or injectable formulations in the field of serotonergic psychedelic drugs, and the re- spective formulations should contain inactive prodrugs that are stable until entering the bloodstream. WO 2023 / 023347 A1 and WO 2022 / 13314 A1 describe psilocin prodrugs. WO 2023 / 173227 A1 aims to describe O-ACOM (acyloxymethyl) psilocin derivatives. How- ever, the analytical characterization of the substances described in WO 2023 / 173227 A1 was extremely superficial. In contrast, the present inventors have carried out a very extensive characterization of the substances according to the present invention. Ac- cording to the present inventors’ finding based on analytical data, the substances pro- duced in WO 2023 / 173227 A1 are not O-ACOM derivatives, but rather N-ACOM de- rivatives. For example, as evident by inspection of the experimental characterization provided in WO 2023 / 173227 and comparison with analytical data of the substances according to the present invention and those of WO 2023 / 023347 A1, the isolated compounds D(III), D(IV), and D(XIX) described in WO 2023 / 173227 A1 do not at all conform with the structures shown in WO 2023 / 173227 A1. WO 2023 / 173227 A1 doesnot provide any evidence for the existence of the indicated compounds D(V), D(VI), D(VII) and D(VIII), instead respective regioisomers are synthesized in WO 2023 / 173227 A1. Accordingly, in view of the prior art, an object underlying the present invention is to provide prodrugs derived from 4-hydroxytryptamines which can be applied in medicine, particularly in treating psychiatric disorders. It is a further objective of the present in- vention to provide the use of such prodrugs in medicine and, particularly in treating psychiatric disorders. An even further object underlying the present invention is to pro- vide a novel synthesis method for producing acyloxymethyl derivatives of hydroxytryp- tamines having a high and more reliable yield. The solution to the above technical problems is provided by the embodiments charac- terized in the claims. Accordingly, the present invention relates to a psilocin prodrug having the following formula (1) or salts thereof,(1), wherein R1and R2can be the same or different from each other and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neo- pentyl, and phenyl residues; wherein, in the salts of formula (1), the product of said formula (1) is protonated. Particularly, an anion of the salts of formula (1) is selected from the group consistingof acetate, propionate, butyrate, malonate, maleate, succinate, fumarate, levulinate, and mesylate. More particularly, the salt of the compound according to formula (1) is a mesylate or fumarate salt, even more particularly a fumarate salt. In a preferred embodiment, in the above formula (1) R1 and R2 are selected from me- thyl and ethyl residues, particularly where R1 and R2 are a methyl residue. In a further embodiment, the present invention relates to a psilocin prodrug having the following formula (2) wherein R3isobutyl, tert-butyl, neopentyl, phenyl, and 2-furyl residues; and, R1 and R2 can be the same or different from each other and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neo- pentyl, and phenyl residues. In a preferred embodiment, in the above formula (2) R1 and R2 are selected from me- thyl and ethyl residues, particularly where R1 and R2 are a methyl residue. Moreover, herein described is a prodrug for use as a medicament, the prodrug having the formula (3) or salts thereof,wherein R6 is seece rom e group conss ng o cycopropy, sopropyl, n-propyl, isobutyl, tert-butyl, neopentyl, phenyl, and 2-furyl residues; and, provided that R6 is selected from the group consisting of isopropyl and 2-furyl residues, R4 and R5 are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl residues and combinations thereof; and, provided that R6 is selected from the group consisting of n-propyl, cyclopropyl, isobutyl, tert-butyl, neopentyl, and phenyl residues, R4 and R5 are not the same and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl residues; and wherein, in the salts of formula (3), the product of said formula (3) is protonated. Particularly, an anion of the salts of formula (3) is selected from the group consisting of acetate, propionate, butyrate, malonate, maleate, succinate, fumarate, levulinate, and mesylate. More particularly, the salt of the compound according to formula (3) is a mesylate or fumarate salt, even more particularly a fumarate salt. In the present application, the term “fumarate” denotes a salt in which fumaric acid is completely deprotonated, thereby forming a salt with the compound of formula (1), (2) or (3), which is monobasic, i.e., protonated once, in a 1:2 ratio. Thus, the alternative term “hemifumarate” may be used to indicate this stoichiometry. Importantly, the “fumarate” salt form has to be distinguished from other terms such as “hydrogen fumarate” or “bifumarate” which denote other protonation states and acid:base ratios.Further, the present invention relates to a prodrug for use as a medicament, the pro- drug (i) having the formula (1) or salts thereof, (ii) the prodrug having the formula (2), or (iii) the prodrug having the formula (3) or salts thereof. Even further, the present invention relates to a prodrug for use in the treatment of psychiatric disorders, the prodrug (i) having the formula (1) or salts thereof, (ii) the prodrug having the formula (2), or (iii) the prodrug having the formula (3) or salts thereof. The present inventors have conducted extensive research to provide a solution to the above problems and found that the herein described prodrugs and structures are ex- cellently suited to be used in medicine and, particularly, in the treatment of psychiatric disorders. In this work, the term “prodrug” relates to a pharmaceutically inactive compound that can be metabolized in the body to produce a pharmaceutically active drug. Regarding the herein shown derivatives of 4-hydroxytryptamines, the prodrugs are typically cleaved at the ester bond in the patient yielding the respective 4-hydroxytryptamine as the active compound. Further, the term “psychedelic treatment” or “psychedelic therapy” relates to a treat- ment using psychedelic drugs or being assisted by psychedelic drugs, which is usually conducted under professional supervision. Moreover, several forms of administering pharmaceuticals are mentioned hereinbelow. In this context, “buccal administration” refers to administration of a drug in the buccal area, i.e., in the cheek of a patient. “Sublingual administration” refers to the application of a drug under the tongue of a patient. Further, “inhalatory administration” refers to the application of a drug into the respiratory system of a patient by applying said drug during inhalation. Similarly, “intranasal administration” relates to administration of a drug into the nose of a patient. Further, the term “transdermal administration” refers to administration of a drug by delivering said drug across the skin of a patient. Hereinafter, the prodrugs and their uses will be described in detail.Prodrugs having formula (1) or formula (2)– ester prodrugs In one aspect, the present invention relates to a prodrug having the formula (1) or a salt thereof, wherein the anion of the salts of formula (1) is preferably selected from the group consisting of acetate, propionate, butyrate, malonate, maleate, succinate, fumarate, levulinate, and mesylate, more preferably mesylate or fumarate, even more preferably fumarate.In another aspect, the present invention relates to a prodrug fumarate salt having the formula (2)wherein R3 is selected from the group consisting of ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, neopentyl, phenyl, and 2-furyl residues; and, R1 and R2 can be the same or different from each other and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neo- pentyl, and phenyl residues.In the fumarate salt of formula (2), R3 is selected from the group consisting of ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, neopentyl, phenyl, and 2-furyl residues, while in formula (1) said residue is fixed to be a cyclopropyl group. The choice of said residue majorly impacts both the passive membrane permeability of the prodrug and its toxicity. Generally, high lipophilicity and high passive membrane permeability of the prodrugs inversely correlate with cell viability. Moreover, the nature of said residue has a major impact on the cleavage rate of the herein described prodrugs in human saliva and human blood plasma. Therefore, said residue has been chosen to accommodate for both a high passive membrane permeability and a low toxicity while also achieving a low cleavage rate in human saliva and a high cleavage rate in human blood plasma. Aliphatic promoieties comprising acyl residues with three to five, preferably three or four, carbon atoms along with aromatic promoieties represent a good compromise be- tween the above-described factors and, particularly, between passive membrane per- meability and cellular tolerability. That is, in view of a good balance between high passive membrane permeability and cellular tolerability, in the fumarate salt of formula (2), R3 is preferably selected from isopropyl, tert-butyl, and 2-furyl residues. Further, R3 in formula (2) is more preferably selected from isopropyl, while in formula (1) said residue is fixed to be a cyclopropyl group. In view of a low cleavage rate in human saliva of the herein described prodrugs, the prodrug of formula (1) with the cyclopropyl residue is particularly excellent. Even further, in view of a high cleavage rate in human blood plasma of the herein described prodrugs, R3 in formula (2) is preferably selected from isopropyl, tert-butyl, and 2-furyl residues, while in formula (1) said residue is fixed to be a cyclopropyl group. In this context, if R3 in formula (2) is a tert-butyl residue, the cleavage rate in human blood plasma is low rendering the herein described prodrug in such case beneficial for applications requiring extended release in human blood plasma. In view of the balancing of the above-described factors, i.e., the passive membrane permeability, toxicity, and optimal cleavage rates in saliva and plasma for a rapid onset, R3 is selected as mentioned above, while in formula (1) said residue is fixed to be a cyclopropyl group.Obviously, in the salts of formula (1) or formula (2), the product of said formulae is protonated. That is, the counterion of the herein described protonated compound is an anion. The free bases of lipophilic tertiary amines, i.e., the prodrugs of formula (1) have a low solubility in water and usually have a liquid, viscous or resinous consistency at ambient conditions. These properties are not well compatible with the requirements of storage, purification, and pharmaceutical formulation of active pharmaceutical ingredients. Therefore, the herein described prodrugs may also be provided as salts, which im- proves water solubility significantly, rendering them more suitable for preparation pro- cedures, storage, and most administration routes. On the other hand, providing the free bases is typically more effective for administration routes which require a certain degree of lipophilicity such as transdermal administration. Preferably, an anion of the salts of formula (1) is selected from the group consisting of acetate, propionate, butyrate, malonate, maleate, succinate, levulinate, fumarate, me- sylate, tartrate, citrate, lactate, pamoate, glutarate, adipate, and edisylate. More pref- erably, an anion of the salts of formula (1) is selected from the group consisting of acetate, propionate, butyrate, malonate, maleate, succinate, levulinate, fumarate, and mesylate and, particularly, said anion is mesylate or fumarate, even more preferably fumarate. That is, fumarates are particularly favorable since they form free-flowing, readily water-soluble colorless solids, thus, being optimal considering the above re- quirements of storage, purification, and pharmaceutical formulation. The prodrugs of the present invention preferably have a high passive membrane per- meability Pe. In the context of the PAMPA model, a passive membrane permeability is considered to be high if it is above 1.5 × 10-6cm / s. Preferably, the passive membrane permeability Pe is at least 5 × 10-6cm / s, at least 6 × 10-6cm / s, more preferably at least 7 × 10-6cm / s and even more preferably at least 8 × 10-6cm / s. In particularly preferable cases, Pe may even be at least 9 × 10-6cm / s, at least 10 × 10-6cm / s, or even at least 11 × 10-6cm / s. Particularly, a high Pe ensures that the prodrugs of the present inven- tion are able to penetrate biological membranes without being dependent on active transport mechanisms. Thus, both the absorption of the prodrug in various tissues aswell as the administration to the cells of interest are significantly affected by the passive membrane permeability. In this context, comparing the 4-hydroxytryptamine parent compounds of the herein described prodrugs with the prodrugs of formula (1) or formula (2), esterification of the phenolic hydroxy group has an influence on the membrane permeability, i.e., it may increase or even decrease the membrane permeability. This may be attributed to the loss of an intramolecular hydrogen bond between said hydroxy group and the tertiary amino group. Such an intramolecular hydrogen bond can influence the polarity of the hydroxytryptamine by two mechanisms: First, by reducing the conformational flexibility of the hydroxytryptamine and thereby favoring conformations with a smaller polar sur- face area and less dipole momentum. Second, by reducing the number of possible hydrogen bonds of the involved functional groups to water molecules in the solvation shell. Thus, as mentioned above, specific residues R3 of formula (2) and the cyclopro- pyl residue of formula (1) are described here, which are sufficiently lipophilic to com- pensate for the loss of intramolecular hydrogen bonding and show a correlation with a high passive membrane permeability. Here, the passive membrane permeability of various prodrugs was determined by means of a parallel artificial membrane permeability assay (PAMPA) as is described in detail below. As has already been mentioned, a high passive membrane permeability has to be bal- anced with a low toxicity of the prodrugs, i.e., a suitable tolerance of human cells against the prodrugs. In this context, the prodrugs preferably have low toxicity towards human cells. For example, if toxicity is tested using the human hepatocyte-derived HuH-7 cell line, a percentage of cells withstanding incubation using the prodrugs according to the pre- sent invention for 2 h (cell viability for 2 h) may be 60 % or more, preferably 70 % or more, and particularly preferably 80 % or more. Similarly, a percentage of cells with- standing incubation using the prodrugs according to the present invention for 24 h (cell viability for 24 h) may be 50 % or more, preferably 60 % or more, and particularly pref- erably 70 % or more. A suitable assay for evaluating cell viability is described in detailbelow. Following absorption of the prodrugs by a patient, the temporal course of pharmaco- logical drug effects is governed by the release kinetics of the prodrug in blood and potentially other tissues. In this context, blood represents the first and main compart- ment in which the prodrug is localized and from which it is distributed to the drug target sites. Within human blood, the herein described prodrugs are thought to be cleaved by plasma esterases or other plasma-specific factors. In view of different applications of the prodrugs, both a fast or a slow cleavage of said prodrugs in human blood plasma might be beneficial. In particular, fast cleavage is preferred in cases where a fast drug effect is to be achieved. In contrast, in cases where a long-lasting drug effect is to be achieved, slow cleavage after administration is preferred. It is therefore possible, using the prodrugs described here, to adjust the surge and onset of the drug effects. In particular, a less sudden onset may be desired for a larger initial dose, whereas a faster onset may be preferred in a re-dosing setting during treatment. Further to cleavage in human blood plasma, cleavage of the prodrugs in human saliva has a significant impact on suitability of said prodrugs for specific administration routes such as buccal and sublingual administration. That is, in order to achieve transport of a high amount of prodrug to a patient’s blood and other tissues the cleavage rate of the prodrug in human saliva is preferably low. In this context, the term “low cleavage rate” relates to half-life periods of the prodrugs in human saliva of at least 15 min. In such time frames, the prodrug can readily be absorbed into the patient’s tissues in short duration applications, e.g., buccal and sublingual applications, without excessive cleavage of the prodrug in the saliva prior to absorption. In view of the above, the prodrug according to the present invention preferably exhibits a half-life period of at least 15 min in human saliva at 37 °C. Prodrugs having formula (3) – acyloxymethyl prodrugs In a further aspect of the present invention, a psilocin prodrug having the formula (3)or salts of a product of formula (3) are provided. (3),, group of cyclopropyl, isopropyl, n- propyl, isobutyl, tert-butyl, neopentyl, phenyl, and 2-furyl residues. In a case that R6 is selected from the group consisting of isopropyl and 2-furyl residues, R4 and R5 are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl residues and combinations thereof. However, in a specific embodiment, even in a case that R6 is selected from the group consisting of isopropyl and 2-furyl residues, R4 and R5 may not be the same and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl residues. Further, in a case that R6 is selected from the group consisting of n-propyl, cyclopropyl, isobutyl, tert-butyl, neopentyl, and phenyl residues, R4 and R5 are not the same and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl residues. Moreover, similar to formula (1) or (2), in the salts of formula (3), the product of said formula (3) is protonated. That is, the counterion of the herein de- scribed protonated compound is an anion. Further, regarding the salts of products of formula (3), the preferred salts described in relation to formula (1) are also applicable to said salts of the products of formula (3). Even further, the above explanations regarding the preferred passive membrane per- meability, the toxicity, the cleavage and stability in human blood plasma and saliva also apply to this aspect of the present invention.Synthesis method of acyloxymethyl derivatives of hydroxytryptaminesFurther to the above-described prodrugs, a synthesis method of acyloxymethyl deriv- atives of hydroxytryptamines is provided. In this context, in contrast to acid chlorides, which can be used to synthesize esters of the phenolic hydroxy of hydroxytryptamines such as e.g., compounds of formula (1) or (2), the softer alkyl halides required for acyloxymethylation are non-selective and react with the tertiary amino group and the indole nitrogen besides the phenolic hydroxy group. This leads to complex reaction mixtures and low yields of the desired product. Tedious and wasteful purification procedures afford the targeted acyloxymethyl pro- drugs in generally less than 10 % yield (cf. e.g., WO 2023 / 023347 A1). In general, the synthetic yields previously reported for the acyloxymethyl prodrugs (cf. WO 2023 / 023347 A1) are neither compatible with commercial production nor with an efficient exploration of the molecular diversity in this compound class. That is, synthetic yields of less than 10 % are incompatible with active pharmaceutical ingredient pro- duction, both from an economic and a pharmaceutical product quality perspective. A large extent of side reactions increases the risk of problematic contaminants in the final product, thus requiring wasteful and extensive purification procedures. Therefore, this aspect of the present invention provides a synthesis route having high and more relia- ble yield and being suitable for commercial production by addressing the described lack of chemoselectivity. The herein described synthesis method of acyloxymethyl derivatives of hydroxytrypta- mines comprises the steps of a) providing a hydroxytryptamine bearing a phenolic hydroxy group; b) protecting the nitrogen comprised in the indole ring system of said hydroxytrypta- mine using a benzyloxycarbonyl protection group (Cbz); c) reacting the N-protected hydroxytryptamine with a halogenomethyl carboxylate com- pound R’-(C=O)-OCH2-Hal, thereby forming an N-protected acyloxymethyl hydroxy- tryptamine; and d) deprotecting the nitrogen comprised in the indole ring system of the N-protectedacyloxymethyl hydroxytryptamine. In particular, the hydroxytryptamine provided in step a) comprises one phenolic hy- droxy group without further hydroxy groups. Said hydroxytryptamine, for example, may comprise said phenolic hydroxy group at position 4 of the indole ring system. That is, said hydroxytryptamine may be psilocin or 4-hydroxy-N-methyl-N-ethyltryptamine (4- OH-MET). The step b) of protecting the hydroxytryptamine can be achieved by reaction with the Heller-Sarpong reagent (formula (3), cf. Heller et al. Org. Lett.2010, 12, 4572) under thermodynamic control, which yields an N-protected hydroxytryptamine in good to ex- cellent yield. Said reaction can be conducted in anhydrous organic solvents, e.g., ac- etonitrile, using a non-nucleophilic base, e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), for instance at ambient temperature for several hours. (3)Subsequently, in step c), said N-protected hydroxytryptamine can be reacted with a halogenomethyl carboxylate compound R’-(C=O)-OCH2-Hal. Due to the protection of the nitrogen comprised in the indole ring system, said compound is able to selectively react with the unprotected phenolic hydroxy group, thereby forming an N-protected acyloxymethyl hydroxytryptamine. An exemplary synthesis procedure is as follows. First, the N-protected hydroxytryptamine is treated with NaH in anhydrous N,N-dime- thylformamide (DMF) at 0 °C until gas generation ceases. Then, the temperature is reduced to -30 to -50 °C and the halogenomethyl carboxylate compound R’-(C=O)- OCH2-Hal is added in anhydrous tetrahydrofuran (THF). Subsequently, the reaction mixture is allowed to warm to ambient temperature while the reaction is continued for several hours. In view of it being an excellent leaving group, the halogen in step c) preferably is iodine. In step d), the nitrogen comprised in the indole ring system is deprotected. Such depro- tection step may be achieved e.g. by catalytic hydrogenation of the N-protectedacyloxymethyl hydroxytryptamine using Pd / C and H2. The described synthesis procedure is able to provide acyloxymethyl hydroxytrypta- mines in high yields. That is, in the critical acyloxylmethylation step, isolated yields of e.g., 14 to 44 % are achieved, which represents a significant improvement as com- pared to the previously reported yields in the single-digit percentage range. Use of prodrugs having formula (1), (2) or (3) Further to the above, the present invention includes the use of a prodrug having for- mulae (1) or (2) or (3) as a medicament. In this context, the preferred and particular embodiments described above are fully applicable regarding the use as a medicament. In a specific use, the prodrug described herein can be used in the treatment of psychi- atric and neurological disorders. Particularly, said disorders may be depression, post- traumatic stress disorder, substance use disorder, anorexia nervosa, and neurodegen- erative diseases such as Alzheimer's disease. Further, a particular treatment in which the prodrug can be applied includes psyche- delic therapy. Moreover, in view of the above-described use for treating psychiatric disorders, it is preferable that the prodrug’s administration is buccal, sublingual, inhalatory, intranasal, and / or transdermal. Specifically, for instance, some of the above-described embodi- ments are particularly preferred in combination with specific drug administration routes, e.g., the free bases can be particularly advantageous for transdermal administration, which usually requires a certain degree of lipophilicity. That is, specific pharmaceutical formulations that realize an advantageous pharmaco- kinetic profile in combination with the prodrugs described herein are, in particular, but not restricted to the following forms: lozenges, mucoadhesive patches or films, sprays for application in the oral cavity or in the nose, tablets and other solid dosage forms for buccal and sublingual application, pellets and other granular dosage forms for applica- tion in the oral or nasal cavities, liquid formulations for application in a nebulizer orvaporizer, semisolid or liquid dosage forms that increase their viscosity upon applica- tion in the oral or nasal cavity and form an adhesive film from which the absorption can occur. For the purpose of transdermal delivery, adhesive skin patches are one pre- ferred formulation. In addition, semisolid dosage forms such as ointments or liquids and sprays which are applied to the skin can be used for transdermal application. Fur- thermore, the compounds described here may be applied in more conventional ways, such as in peroral solid, semisolid, or liquid dosage forms like tablets, hard capsules with a powdery, granular, or pellet filling, soft capsules with liquid, semisolid, or solid filling, suppositories and enemas. Preferably, the prodrugs are not administered perorally or intravenously. As has been mentioned above, avoiding peroral and intravenous administration and, preferably, providing buccal, sublingual, inhalatory, intranasal, and / or transdermal ad- ministration of the prodrugs can ensure a fast onset of the subjective effects during psychedelic treatment settings with lower inter-individual variability than oral psilocybin dosage. Thus, undesired waiting times can be eliminated, the efficiency of therapist interactions can be increased, and the predictability of the evoked subjective experi- ence can be improved. Further, a dosing with fast onset allows the adjustment of the psychedelic experience. Even further, intravenous or other invasive and potentially threatening forms of drug administration may be incompatible with the intimate and preferentially non-clinical treatment setting, particularly, if the prodrugs are applied in psychedelic therapy. Moreover, considering that some psychiatric disorders may involve restricted or absent swallowing capacity of patients, as in Alzheimer's disease, application routes of the prodrugs are required that do not rely on the patient's ability to swallow. In such cases, the administration cannot reasonably be peroral. That is, in this specific case, the most preferable administration may be transdermal. An additional advantage of bypassing the peroral and gastrointestinal administration route is that the effects of first-pass metabolism in the liver are eliminated. Thereby, itmay be possible to use lower dosages. Furthermore, metabolism in the liver has indi- vidual variability due to induction or inhibition of enzymes and other predispositions such as age and the presence or absence liver diseases. If the first-pass metabolism is avoided by non-enteral application routes, a more reliable and less variable effect of the applied drug can be expected. Examples The present invention is further described in the following with reference to examples. Materials and methods Chemicals and solvents were purchased from commercial suppliers such as Carbolu- tion, BLDpharm, Fisher Scientific, Sigma Aldrich, and TCI. Ethyl acetate was distilled prior to use. All other chemicals were used as received if not stated otherwise. Psilocin (4-OH-DMT, 1) was prepared based on literature procedures (cf. Sherwood et al. Syn- thesis 2020, 52, 688; and Shirota et al. J. Nat. Prod.2003, 66, 885). For purification and analytic characterizations, the following devices and methods were used: Amberlyst A-21 activation Commercial Amberlyst A-21 resin (Sigma-Aldrich, Germany) was activated by adding HPLC-grade methanol (1 mL per gram resin), stirring for 5 min, and filtration. This treat- ment was repeated with anhydrous THF (2x0.8 mL per gram resin) and HPLC-grade dichloromethane (DCM) (2x0.8 mL per gram resin). Volatiles were removed by rotary evaporation, and the resin was further dried under high vacuum overnight to give a free-flowing solid that was stored in an amber-colored bottle. Column Chromatography Flash column chromatography was carried out on silica gel (40 – 63 μm, 60 Å, Material Harvest) using a Biotage Isolera One system and various column sizes. The dimen- sions of the columns are provided in the detailed synthetic descriptions below. Lyophilization Freeze-drying was performed on a Christ Alpha 1-2 LDplus lyophilizer.High-performance liquid chromatography (HPLC) Analytical measurements were performed using a Jasco HPLC system equipped with an RP-18 column. Detailed information on chromatographic separation and detection is given in the description of the respective application. Preparative HPLC was performed on an ÄKTA purifier (GE Healthcare, Germany) equipped with a Reprospher 100 C18-DE guard column (5 μm, 30 x 16 mm, Dr. Maisch GmbH) and a Reprosil 100 C18 column (10 μm, 150 x 30 mm, Dr. Maisch GmbH). Mixtures of distilled water (eluent A) and acetonitrile (eluent B) buffered with 0.1 % trifluoroacetic acid (TFA) were used as mobile phase at a flow rate of 20.0 mL / min using one of the gradients listed in Table 1. The chromatographic sepa- ration was monitored by UV detection at 214, 254, and 280 nm. Table 1: Gradient settings. Gradi- settings ent I 30 % B (0.6 CV); 100 % B (4.6 CV); 100 % B (6.1 CV); 30 % B (6.2 CV); 30 % B (7.2 CV) II 10 % B (0.6 CV); 100 % B (4.6 CV); 100 % B (6.1 CV); 10 % B (6.2 CV); 10 % B (7.2 CV) Mass Spectrometry High resolution mass spectra (HR MS) were recorded on a Bruker micrOTOF-Q II mass spectrometer calibrated with sodium formate cluster ions. NMR Spectroscopy1H,13C, and19F NMR spectra as well as APT spectra were recorded at room temper- ature on 300 MHz or 500 MHz Varian instruments. In addition, COSY, HSQC and HMBC spectra were recorded but are not shown in this application for the sake of brevity. Chemical shifts (δ) are reported in parts per million (ppm) relative to the resid- ual undeuterated or partially deuterated solvent peak according to the literature (cf. Fulmer et al. Organometallics 2010, 29, 2176). Coupling constants (J) are reported in Hertz (Hz). The following abbreviations are used to indicate the signal multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sxt (sextet), spt (septet), oct(octet), n (nonet), m (multiplet), br s (broad singlet) as well as their combinations.13C signals were classified as follows: Cq (quarternary), CH (tertiary), CH2 (secondary), and CH3 (primary). All NMR spectra were integrated and processed using ACD / Spectrus Processor 2016.1. pH Measurements The pH values of aqueous solutions were measured using a pH meter 766 (Knick, Germany). Thin-layer Chromatography (TLC) TLC was performed on Macherey-Nagel Polygram® SIL G / UV254 and ALOX N / UV254 precoated sheets. Components were visualized by UV irradiation (254 nm) or by stain- ing with aqueous KMnO4 solution (1 g KMnO4, 2 g Na2CO3, 100 mL H2O) or aqueous FeCl3 solution (1 g FeCl3, 50 mL H2O, 50 mL MeOH). Passive membrane permeation assay (PAMPA) The passive membrane permeability was evaluated with a pre-coated PAMPA plate system (BD Gentest, BD Bioscience, Germany) following the guidelines of the manu- facturer and a previous literature report (cf. Kühl et al. Eur. J. Med. Chem.2022, 240, 114585). Phosphate-buffered saline (PBS) pH 7.4 (Sigma-Aldrich, Germany) was used for all experiments. Analyte concentrations were determined on a Jasco HPLC system equipped with a UV detector and an RP-18 column (Chromolith® Performance RP- 18e, 100x4.6 mm) using one of the gradients listed in Table 2. For all samples, the injection volume was 40 µl. Table 2: HPLC settings for the analysis of PAMPA samples. Eluent A Eluent B Flow Gradient water (0.1 % TFA) acetonitrile (0.1 % TFA) 1.0 mL / min 1 % B (0.2 min) 100 % B (7.0 min) 100 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min) water (0.1 % TFA) acetonitrile (0.1 % TFA) 1.0 mL / min 1 % B (0.2 min) 50 % B (7.0 min) 50 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min)UV detection was performed at 286 nm except for phenytoin (220 nm) and acetyl sali- cylic acid (228 nm). Prior to performing the assay, the PAMPA plate was warmed to room temperature for 0.5 h. In the donor plate, 300 μL of the 200 μM compound solu- tions in PBS (4 % dimethyl sulfoxide (DMSO)) were dispensed in triplicate, and in the acceptor plate, 200 μL of PBS buffer were added to all wells. The plates were com- bined, and the system was incubated at 25 °C for 5 h. Upon completion of the incuba- tion, donor and acceptor plate were separated. The wells were homogeneously mixed with a pipette, and a 100 µl sample of each donor and acceptor well was transferred to 96 well U-bottom polypropylene plates (Greiner Bio-One, Germany) for quantitative HPLC analysis. Six-point calibration curves (10, 25, 50, 100, 150, and 200 μM) were generated for all permeating compounds and references (Phenytoin, Imipramine HCl, Caffeine) with correlation coefficients (R2) being at least 0.99. For Furosemide, an eight-point calibration curve (0.1, 1, 10, 25, 50, 100, 150, and 200 μM) was generated due to the low passive membrane permeability. Permeability (Pe) and mass retention (R) were calculated as described in the literature (cf. e.g., Chen et al. Pharm. Res. 2008, 25, 1511; and Kansy et al. J. Med. Chem.1998, 41, 1007). Stability in phosphate-buffered saline Accelerated degradation studies were performed using Dulbecco’s phosphate buffered saline (PBS) pH 7.3 (Sigma-Aldrich, Germany). In a thermoblock, 1386 µL PBS and 28 µl of a 5 mM analyte stock solution in DMSO were prewarmed to 80 °C for 10 min in separate plastic vials. Then, 14 µl of the prewarmed 5 mM analyte stock solution were added to the prewarmed PBS, and the mixture was vortexed vigorously. In ap- propriate time intervals, samples of the reaction mixture (100 µl) were taken directly after vortexing. The samples were kept at -20 °C until being analyzed or analyzed di- rectly. Analyte quantifications were performed on a Jasco HPLC system equipped with a UV detector and an RP-18 column (Chromolith® Performance RP-18e, 100x4.6 mm) using one of the acetonitrile / water gradients listed in Table 2. For all samples, the in- jection volume was 40 µl and UV detection was performed at 286 nm. The data were analyzed graphically (Origin Pro 2015) assuming zero and first order kinetics. Data points with an area under the curve (AUC) of less than 100 µV∙min were not included in further analysis due to their insufficient signal-to-noise ratio. In all cases, first order kinetics were found as judged by the quality of fit (R2>0.9). Errors were esti- mated based on the uncertainty of the linear fit.Cell viability Cell viability in HuH-7 cells in the presence of compound dilutions was determined using the CellTiter-Blue reagent (Promega) according to manufacturer´s instructions (cf. CellTiter-Blue Cell Viability Assay, Promega Corporation, Madison, 2016). In order to assess cytotoxic effects of compounds in cell culture, HuH-7 cells were incubated in presence of these compounds in a 96-well plate for 2 h or 24 h. In order to generate a calibration curve for cell viability, a serial dilution (1:2 dilution series) of cells was seeded into control wells. Measurement of cell viability is based on the assay develop- ment using CellTiter-Blue reagent (Resazurin, blue color), which is reduced to resofurin (pink color) by viable cells. Prior to performing the assay, a 96-well assay plate (F-bottom, transparent, Greiner) containing HuH-7 cells (20,000 cells per well) in culture medium was prepared. Test compounds were added to obtain a final volume of 100 µL per well before the 96-well plate was incubated at 37 °C, 5 % CO2 and 95 % relative humidity (RH) for 2 h or 24 h. CellTiter-Blue reagent (1-2 mL) was diluted with cell culture medium (10 mL) in a Fal- con tube and prewarmed to 37 °C. The 96-well plate was removed from the incubator, the medium aspirated using a vacuum pump and 100 µL of diluted CellTiter-Blue rea- gent was added to each well. After incubation at 37 °C, 5 % CO2 and 95 % RH for 1- 3 h, a color change was visible and the fluorescence was measured at 560 / 590 nm (^ex / ^em). Drug release kinetics in human blood plasma The release kinetics of the prodrugs were evaluated in vitro in analogy to the precedent literature (cf. e.g., Christrup et al. Int. J. Pharm.1997, 154, 157). As ZnSO4 was found to affect the analyte’s signal intensity presumably by complexation, acetonitrile (2:1) was used as protein precipitation agent (cf. Polson et al. J. Chromatogr. B 2003, 785, 263). Pooled human blood plasma (Biowest, France) and sterile Dulbecco’s phosphate buffered saline (PBS) pH 7.3 (Sigma-Aldrich, Germany) were used for all experiments. The blood plasma was aliquoted upon receipt and stored at -20 °C. 10 % solutions were prepared by thawing a plasma aliquot at 2-8 °C, distributing it into plastic vials and diluting with the appropriate volume of sterile PBS. The 10 % and 100 % plasma aliquots were stored at -20 °C and thawed at 2-8 °C directly before the assay was performed. In a thermoblock, a plasma aliquot and 10 µl of a 5 mM prodrug solution inDMSO were prewarmed to 37 °C for 10 min in separate plastic vials. Then, 1000 µl of the prewarmed plasma sample was added to the prodrug solution, and 9x100 µl sam- ples were withdrawn at appropriate time intervals. The enzymatic reaction was quenched by immediate mixing of the samples (100 µl) with acetonitrile (200 µl). Blank samples were prepared by mixing 10 % or 100 % plasma (100 µl) with acetonitrile (200 µl), respectively. Samples of the initial reaction mixture were prepared by adding the 5 mM prodrug solution (1 µl) to a blank sample. Centrifugation (13,000 rpm, 3 min) of the quenched samples afforded clear superna- tants which were transferred to 96 well U-bottom polypropylene plates (Greiner Bio- One, Germany). Analyte quantifications were performed on a Jasco HPLC system equipped with a UV detector and an RP-18 column (Chromolith® Performance RP- 18e, 100x4.6 mm) using one of the gradients listed in Table 3. Prodrug degradation was monitored using undiluted supernatant and a 10 min chromatographic method. Simultaneous quantification of residual prodrug and released parent drug was per- formed with diluted samples (75 µl supernatant, 25 µl H2O (+0.4 % TFA)) using a 17 min method. For all samples, the injection volume was 40 µL and the flow was set to 1.0 mL / min. UV detection was performed at 286 nm except for acetyl salicylic acid (ASA, 228 nm). The data were analyzed graphically (Origin Pro 2015) assuming zero and first order kinetics. If not stated otherwise, first order kinetics were found as judged by the quality of fit (R2>0.9). Table 3: HPLC settings for quantitative analysis of plasma samples. Analyte Eluent A Eluent B Gradient 8a, 8e water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 30 % B (7.0 min) 30 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min) ASA water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 50 % B (7.0 min) 50 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min) 8b-d, 8g-i water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 10, 11 100 % B (7.0 min) 15a-d 100 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min)Analyte Eluent A Eluent B Gradient 7a, 7b water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 8b 20 % B (10.0 min) 30 % B (10.1 min) 30 % B (15 min) 1 % B (15.1 min) 1 % B (17.0 min) 8i, 15b water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 20 % B (10.0 min) 35 % B (10.1 min) 35 % B (15 min) 1 % B (15.1 min) 1 % B (17.0 min) 15d water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 20 % B (10.0 min) 40 % B (10.1 min) 40 % B (15 min) 1 % B (15.1 min) 1 % B (17.0 min) 8c water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 20 % B (10.0 min) 45 % B (10.1 min) 45 % B (15 min) 1 % B (15.1 min) 1 % B (17.0 min) Prodrug stability in human whole saliva Human whole saliva was collected from three non-smoking individuals (1 male, 2 fe- male, age 24-27 years) by expectoration into plastic vials (spitting method), which has been recommended in the literature (cf. Navazesh, Ann. N. Y. Acad. Sci.1993, 694, 72). Sampling was performed before breakfast, i.e. at least 8 h after the last food intake and tooth brushing, in order to minimize the impact of diet and dental materials on esterase activity (cf. Lindqvist et al. Eur. J. Oral Sci.1980, 88, 229). Freshly collected saliva and 5 mM stock solutions of the analytes in DMSO were pre- warmed to 37 °C for 10 min. Then, 700 µl prewarmed saliva was added to 7 µl of the prodrug stock, and the mixture was incubated at 37 °C. Samples (100 µL) were taken at selected time points (0, 10, 20, 40, 60 min; 2 h or 24 h) and immediately quenched with acetonitrile (200 µl). Blank samples were prepared by mixing saliva (100 µl) with acetonitrile (200 µl). Centrifugation (3,000 rpm, 5 min) of the quenched samples af- forded clear supernatants which were transferred to 96 well U-bottom polypropylene plates (Greiner Bio-One, Germany). Analyte quantifications were performed on aJasco HPLC system equipped with a UV detector and an RP-18 column (Chromolith® Performance RP-18e, 100x4.6 mm) using the gradients listed in Table 4. Samples that gave rise to asymmetric peaks inadequate for quantification were diluted (1:1) with H2O (+0.1 % TFA). The injection volume was 40 µl and the flow was set to 1.0 mL / min. UV detection was performed at 286 nm. The data were analyzed graphically (Origin Pro 2015) assuming zero and first order kinetics. If not stated otherwise, the reactions fol- lowed first order kinetics as judged by the quality of fit (R2>0.9). Table 4: HPLC settings for quantitative analysis of saliva samples. Analyte Eluent A Eluent B Gradient 8b, 8d, 8f, 8i water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 15a, 15b, 15d 100 % B (7.0 min) 100 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min) 7a, 7b water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 15c 50 % B (7.0 min) 50 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min) 8c water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 100 % B (12.0 min) 100 % B (13.0 min) 1 % B (13.1 min) 1 % B (15.0 min) 7c,8e water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 30 % B (7.0 min) 30 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min) 8a water (0.1 % TFA) acetonitrile (0.1 % TFA) 1 % B (0.2 min) 25 % B (7.0 min) 25 % B (8.0 min) 1 % B (8.1 min) 1 % B (10.0 min)Syntheses of precursors 3-(2-(Ethyl(methyl)amino)-2-oxoacetyl)-1H-indol-4-yl acetate (18) To an ice-cooled solution of oxalyl1.30 g, 10.3 mmol, 1.80 eq) in an- hydrous methyl tert-butyl ether (MTBE) (3.3 mL) under inert atmosphere was added 4- acetoxyindole (1.00 g, 5.71 mmol, 1.00 eq) dissolved in anhydrous MTBE (6.7 mL) dropwise over 5 min. While stirring for 4 h at 0-10°C, a bright yellow precipitate formed. Then, volatiles were removed in vacuo, and the residue was dissolved in anhydrous THF (16.5 mL). The obtained solution was cooled with an icebath, and a solution of N- ethyl-N-methylamine (1.18 mL, 812 mg, 13.7 mmol, 2.40 eq) in anhydrous THF (2.7 mL) was added dropwise. Subsequently, the reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion, volatiles were re- moved by rotary evaporation and the residue was dissolved in DCM (200 mL). The organic phase was washed with 0.1 N HCl (2x50 mL), brine (2x50 mL), dried over an- hydrous Na2SO4, and evaporated. The crude was finally recrystallized from a mixture of DCM (1.5 mL) and 2-propanol (6.0 mL), filtered over a Büchner funnel with filter paper, and washed with heptane (2.0 mL), which afforded 18 (1.15 g, 3.98 mmol, 69 %) as an off-white solid. The NMR spectra show a mixture of amide rotamers (Rotamer 1: Rotamer 2 = 1:1.3). Rotamer 1:1H NMR (500 MHz, (CD3)2SO): δ = 12.34-12.66 (m, 1H), 8.05 (d, J = 3.2 Hz, 1H), 7.40-7.49 (m, 1H), 7.29 (td, J = 7.9 Hz, J‘ = 1.4 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 3.43 (q, J = 7.1 Hz, 2H), 2.83 (s, 3H), 2.27-2.41 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H) ppm. Rotamer 2:1H NMR (500 MHz, (CD3)2SO): δ = 12.34-12.66 (m, 1H), 8.11 (d, J = 3.3 Hz, 1H), 7.40-7.49 (m, 1H), 7.29 (td, J = 7.9 Hz, J‘ = 1.4 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 3.19 (q, J = 7.0 Hz, 2H), 2.93 (s, 3H), 2.27-2.41 (m, 3H), 1.05 (t, J = 6.97 Hz, 3H) ppm.13C NMR (75 MHz, CDCl3): δ = 185.6 (Cq, 1C), 171.1 / 170.9 (Cq, 1C), 168.6 / 168.1 (Cq, 1C), 144.4 (Cq, 1C), 139.3 (Cq, 1C), 138.1 (CH, 1C), 124.8 (CH, 1C), 118.4 (Cq, 1C), 116.1 / 116.0 (CH, 1C), 113.7 / 113.6 (Cq, 1C), 110.9 (CH, 1C), 45.1 / 41.7 (CH2, 1C), 34.9 / 31.4 (CH3, 1C), 21.7 (CH3, 1C), 13.5 / 12.1 (CH3, 1C) ppm. HR MS (ESI+): m / z [2M+Na]+calcd. for [C30H32N4NaO8]+: 599.2112, found 599.2113; [M+Na]+calcd. for[C15H16N2NaO4]+: 311.1002, found 311.1010. 4-Hydroxy-N-ethyl-N-methyltryptamine (6) Under inert atmosphere, 18 (1.50 g,1.00 eq) was dissolved in anhydrous 2-Me-THF (47 mL) and cooled to 0°C by immersing the Schlenk tube into an ice bath. Then, a 2.3 M solution of LiAlH4 in 2-Me-THF (7.24 mL, 632 mg, 16.7 mmol, 3.2 eq) was added dropwise by syringe yielding a bright yellow suspension. After the addition, the ice bath was removed, a nitrogen-filled balloon was installed, and the mixture was heated to reflux. After refluxing for 4 h, the reaction mixture was cooled with an ice bath, and quenched by dropwise addition of THF / H2O (27:100, 1.73 mL). Anhydrous Na2SO4 (3.45 g) was added, followed by aminofunctionalized silica gel (1.71 g) and DCM (14.4 mL), and the mixture was stirred for 15 min before being filtered via a fritted glass piece under inert atmosphere. The filter cake was washed with a DCM / MeOH mixture (9:1, 55 mL), and the combined filtrates were concentrated by rotary evapora- tion to give a yellow solid. This was filtered through a pad of aminofunctionalized silica (m= 9.829 g) using DCM (492 mL) as eluent. Rotary evaporation finally afforded the title compound 6 (874.4 mg, 4.01 mmol, 77 %) as a colorless crystalline solid.1H NMR (500 MHz, CD3CN): δ = 12.92 (br s, 1H), 8.90 (br s, 1H), 6.91 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 6.82 (dd, J = 8.1 Hz, J‘ = 0.9 Hz, 1H), 6.32 (dd, J = 7.5 Hz, J‘ = 0.9 Hz, 1H), 2.86-2.93 (m, 2H), 2.63-2.70 (m, 2H), 2.51 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H) ppm.13C NMR (126 MHz, CD3CN): δ = 153.2 (Cq, 1C), 140.2 (Cq, 1C), 123.7 (CH, 1C), 122.4 (CH, 1C), 118.7 (Cq, 1C), 114.9 (Cq, 1C), 106.4 (CH, 1C), 103.4 (CH, 1C), 60.1 (CH2, 1C), 52.7 (CH2, 1C), 42.4 (CH3, 1C), 26.0 (CH2, 1C), 11.7 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C13H18N2NaO]+: 241.1311, found 241.1313.4-Hydroxy-N-ethyl-N-methyltryptammonium fumarate (17) The free base 6 (95.1 mg,dissolved in acetone (1.5 mL), mixed with a solution of fumaric acid (25.3 mg, 218 µmol, 0.50 eq) in acetone (4.0 mL), and allowed to stand at 5 °C for 1.5 h. Finally, the suspension was centrifuged (3,500 RCF, 5 min), the supernatant decanted, and the solids washed twice with cold acetone (5 °C, 2x1.2 mL), taken up in distilled water and lyophilized. This afforded 17 (106 mg, 383 µmol, 88 %) as a colorless solid.1H NMR (500 MHz, (CD3)2SO): δ = 11.51 (br s, 1H), 10.64 (br s, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.80 (t, J = 7.7 Hz, 1H), 6.75 (dd, J = 7.9 Hz, J’ = 1.0 Hz, 1H), 6.48 (s, 1H), 6.28 (dd, J = 7.5 Hz, J’ = 0.9 Hz, 1H), 2.97 (t, J = 7.1 Hz, 2H), 2.84 (t, J = 7.0 Hz, 2H), 2.69 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.06 ppm (t, J = 7.2 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 167.5 (Cq, 1C), 151.6 (Cq, 1C), 138.7 (Cq, 1C), 134.9 (CH, 1C), 121.9 (CH, 1C), 121.3 (CH, 1C), 116.7 (Cq, 1C), 111.6 (Cq, 1C), 103.4 (CH, 1C), 102.8 (CH, 1C), 57.7 (CH2, 1C), 50.4 (CH2, 1C), 40.5 (CH3, 1C), 23.2 (CH2, 1C), 10.6 (CH3, 1C) ppm. HR MS (ESI+): m / z [2M+C2H2]2+calcd. for [C28H38N4O2]2+: 231.1492, found 231.1486; [M+H]+calcd. for [C13H19N2O]+: 219.1492, found 219.1489. The spec- troscopic data correspond to the ones previously reported in the literature.

[0030] Synthesis of ester prodrugs having formula (1) or formula (2) General procedure (GP1): HPLC-pure material for biological assays Under inert atmosphere, the 4-hydroxytryptamine (1.00 eq) was dissolved in anhy- drous THF (0.5 M with respect to the 4-hydroxytryptamine), and the solution was cooled to 0 °C. Subsequently, the respective acid chloride was added. The resulting suspension was allowed to warm to ambient temperature and stirred until the starting material was completely consumed according to TLC. Unreacted starting material was visualized by staining with FeCl3 solution. Upon completion, volatiles were removed byrotary evaporation, and the obtained crude was purified by means of reversed-phase chromatography on a preparative HPLC instrument (gradient II). The collected product fractions were concentrated by rotary evaporation and lyophilized. The obtained residue was dissolved in DCM (75 mM with respect to the tryptamine) and stirred with activated Amberlyst A-21 (0.87 mg Amberlyst A-21 per μmol trypta- mine) for 30 min, filtered and concentrated. This procedure was carried out four times in order to ensure quantitative trifluoroacetate removal. Alternatively, the oily residue was partitioned between diethyl ether and carbonate buffer (0.1 M, pH 10.6), washed twice with carbonate buffer, dried over Na2SO4 and evaporated. The generated free base (1.00 eq) was then dissolved in acetone (at least 137 mM with respect to the tryptamine), mixed with a solution of fumaric acid (0.50 eq) in acetone (at least 46 mM with respect to fumaric acid), and allowed to stand at 5 °C for at least 1.5 h. Finally, the suspension was centrifuged (3,500 RCF, 5 min), the supernatant decanted, and the solids washed twice with cold acetone (5 °C), taken up in distilled water and lyophilized. If required, residual traces of acetone were removed by heating to 40 °C for 22 h. An exemplary procedure for the synthesis and purification on the gram scale is pro- vided in the description of compound 7c. 4-iso-Butyryloxy-N,N-dimethyltryptammonium fumarate (7a)4-Hydroxy-N,N- mg, eq) was reacted with iso-butyryl chloride (105 µl, 104 mg, 979 µmol, 1.00 eq) for 5 h, purified by HPLC and subsequently converted into 4-iso-butyryloxy-N,N-dimethyltryptamine (19a) by alkaline extraction as described in GP1.19a (200 mg, 730 µmol, 75 %) was obtained as a yel- low oil.1H NMR (500 MHz, (D3C)2CO): δ = 10.15 (br s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 2.95 (spt, J = 7.0 Hz, 1H), 2.85- 2.90 (m, 2H), 2.48-2.57 (m, 2H), 2.23 (s, 6H), 1.36 (d, J = 7.0 Hz, 6H) ppm.13C NMR (126 MHz, (D3C)2CO): δ = 176.1 (Cq, 1C), 145.6 (Cq, 1C), 140.0 (Cq, 1C), 123.8 (CH,1C), 122.0 (CH, 1C), 121.2 (Cq, 1C), 113.3 (Cq, 1C), 112.5 (CH, 1C), 109.9 (CH, 1C), 62.0 (CH2, 1C), 45.8 (CH3, 2C), 34.9 (CH, 1C), 26.0 (CH2, 1C), 19.3 (CH3, 2C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C16H22N2NaO2]+: 297.1573, found 297.1574. Reaction of 19a (200 mg, 730 µmol, 1.00 eq) with fumaric acid according to GP1 yielded 7a (240 mg, 721 µmol, 99 %) as a colorless solid.1H NMR (500 MHz, (D3C)2SO): δ = 11.09 (br s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 1.2 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.52 (s, 1H), 2.92 (spt, J = 7.1 Hz, 1H), 2.79-2.87 (m, 2H), 2.66-2.75 (m, 2H), 2.35 (s, 6H), 1.29 (d, J = 7.1 Hz, 6H) ppm.13C NMR (126 MHz, (D3C)2SO): δ = 175.4 (Cq, 1C), 167.3 (Cq, 1C), 143.8 (Cq, 1C), 138.5 (Cq, 1C), 134.7 (CH, 1C), 123.4 (CH, 1C), 121.0 (CH, 1C), 119.5 (Cq, 1C), 111.3 (CH, 1C), 110.3 (Cq, 1C), 109.3 (CH, 1C), 59.5 (CH2, 1C), 44.3 (CH3, 2C), 33.5 (CH, 1C), 23.5 (CH2, 1C), 18.8 (CH3, 2C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C16H22N2NaO2]+: 297.1573, found 297.1569; [M+H]+calcd. for [C16H23N2O2]+: 275.1754, found 275.1750. 4-(2-Furoyl)oxy-N,N-dimethyltryptammonium fumarate (7b)4-Hydroxy-N,N- mg, eq) was reacted with 2-furoyl chloride (99.9 µl, 130 mg, 993 µmol, 1.00 eq) for 3 h, purified by HPLC and subsequently converted into 4-(2-furoyl)oxy-N,N-dimethyltryptamine (19b) by alkaline extraction as described in GP1.19b (237 mg, 795 µmol, 80 %) was obtained as a col- orless solid.1H NMR (300 MHz, (D3C)2CO): δ = 10.22 (br s, 1H), 7.95 (dd, J = 1.6 Hz, J’ = 0.7 Hz, 1H), 7.57 (dd, J = 3.5 Hz, J’ = 0.7 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.77 (dd, J = 3.5 Hz, J’ = 1.8 Hz, 1H), 2.83- 2.92 (m, 2H), 2.41-2.59 (m, 2H), 2.08 (s, 6H) ppm.13C NMR (75 MHz, (D3C)2CO): δ = 157.8 (Cq, 1C), 148.6 (CH, 1C), 145.3 (Cq, 1C), 144.5 (Cq, 1C), 140.0 (Cq, 1C), 124.2 (CH, 1C), 122.0 (CH, 1C), 121.1 (Cq, 1C), 120.2 (CH, 1C), 113.3 (Cq, 1C), 113.2 (CH, 1C), 112.7 (CH, 1C), 110.4 (CH, 1C), 61.9 (CH2, 1C), 45.5 (CH3, 2C), 25.6 (CH2, 1C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C17H18N2NaO3]+: 321.1210, found321.1214; [M+H]+calcd. for [C17H19N2O3]+: 299.1390, found 299.1396. Reaction of 19b (237 mg, 795 µmol, 1.00 eq) with fumaric acid according to GP1 yielded 7b (281.2 mg, 789 µmol, 99 %) as a colorless solid.1H NMR (500 MHz, (D3C)2SO): δ = 11.17 (br s, 1H), 8.12 (d, J = 0.9 Hz, 1H), 7.65 (dd, J = 3.4 Hz, J’ = 0.6 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.78-6.88 (m, 2H), 6.51 (s, 1H), 2.76-2.86 (m, 2H), 2.60-2.68 (m, 2H), 2.18 (s, 6H) ppm.13C NMR (126 MHz, (D3C)2SO): δ = 167.4 (Cq, 1C), 156.8 (Cq, 1C), 148.6 (CH, 1C), 143.3 (Cq, 1C), 142.8 (Cq, 1C), 138.6 (Cq, 1C), 134.8 (CH, 1C), 124.0 (CH, 1C), 121.1 (CH, 1C), 120.2 (CH, 1C), 119.5 (Cq, 1C), 112.8 (CH, 1C), 111.6 (CH, 1C), 110.2 (Cq, 1C), 109.8 (CH, 1C), 59.6 (CH2, 1C), 43.9 (CH3, 2C), 23.1 (CH2, 1C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C17H18N2NaO3]+: 321.1210, found 321.1206; [M+H]+calcd. for [C17H19N2O3]+: 299.1390, found 299.1391. 4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptammonium fumarate (7c)4-Hydroxy-N,N- mg, eq) was reacted with cyclopropanecarboxylic acid chloride (89 µL, 101 mg, 970 µmol, 1.00 eq) for 3.5 h and evaporated to dryness. Due to incomplete consumption, the crude was again dissolved in anhydrous THF (2.8 mL) and reacted with cyclopropanecarboxylic acid chloride (24 µL, 25.4 mg, 243 µmol, 0.25 eq) and triethylamine (34 µL, 24.6 mg, 243 µmol, 0.25 eq) for 1.5 h at ambient temperature. The crude was purified by HPLC and sub- sequently converted into 4-(cyclopropanecarbonyloxy)-N,N-dimethyltryptamine (19c) by alkaline extraction as described in GP1.19c (232.8 mg, 855 µmol, 88 %) was ob- tained as a colorless solid with a melting point of 106–109 °C. In contrast to the free bases of the other prodrugs described in this application, the free base of compound 7c is solid at room temperature, which may be useful with respect to formulation as API in mucoadhesive patches, lozenges, sublingual tables, or other non-classical dos- age forms that circumvent the gastrointestinal passage.1H NMR (500 MHz, (CD3)2CO): δ = 10.15 (br s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.70 (dd, J = 7.7 Hz, J’ = 0.7 Hz, 1H), 2.87-2.95 (m, 2H),2.50-2.59 (m, 2H), 2.25 (s, 6H), 1.96-2.03 (m, 1H), 1.03-1.14 (m, 4H) ppm.13C NMR (126 MHz, CD3CN): δ = 175.0 (Cq, 1C), 145.2 (Cq, 1C), 139.7 (Cq, 1C), 124.2 (CH, 1C), 122.3 (CH, 1C), 121.0 (Cq, 1C), 113.2 (Cq, 1C), 112.8 (CH, 1C), 110.3 (CH, 1C), 61.6 (CH2, 1C), 45.5 (CH3, 2C), 25.2 (CH2, 1C), 13.5 (CH, 1C), 9.5 (CH2, 2C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C16H20N2NaO2]+: 295.1417, found 295.1427. Reaction of 19c (219 mg, 805 µmol, 1.00 eq) with fumaric acid according to GP1 yielded 7c (257 mg, 777 µmol, 97 %) as a colorless powder.1H NMR (500 MHz, (CD3)2SO): δ = 11.05 (br s, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 1.3 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.52 (s, 1H), 2.79- 2.87 (m, 2H), 2.63-2.73 (m, 2H), 2.34 (s, 6H), 1.94-2.02 (m, 1H), 0.96-1.10 (m, 4H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 173.4 (Cq, 1C), 166.9 (Cq, 1C), 143.6 (Cq, 1C), 138.5 (Cq, 1C), 134.5 (CH, 1C), 123.6 (CH, 1C), 121.0 (CH, 1C), 119.6 (Cq, 1C), 111.4 (CH, 1C), 110.4 (Cq, 1C), 109.4 (CH, 1C), 59.8 (CH2, 1C), 44.3 (CH3, 2C), 23.3 (CH2, 1C), 12.6 (CH, 1C), 8.9 (CH2, 2C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C16H20N2NaO2]+: 295.1417, found 295.1412; [M+H]+calcd. for [C16H21N2O2]+: 273.1598, found 273.1596. Gram-scale synthesis of 7c: 4-Hydroxy-N,N-dimethyltryptamine 1 (896 mg, 4.39 mmol, 1.00 eq) was subjected to esterification as described above for the small scale. After evaporation of volatiles, the crude was partitioned between diethyl ether (290 mL) and carbonate buffer (0.1 M, pH 10.6, 140 mL), and the organic phase was washed twice with carbonate buffer (0.1 M, pH 10.6, 2x90 mL). Drying over Na2SO4 followed by rotary evaporation af- forded 19c (1.15 g, 4.24 mmol, 97 %) as a brownish solid. This was dissolved in ace- tone (12.0 mL) and added to a solution of fumaric acid (246 mg, 2.12 mmol, 0.50 eq) in acetone (49 mL). After standing at 5 °C for 1.5 h, the colorless precipitate was iso- lated by filtration over a Buchner funnel and washing with cold acetone (2x10 mL). Drying at 40 °C afforded 7c (1.30 g, 3.93 mmol, 93 %) as a colorless, free-flowing solid.4-Acetoxy-N-ethyl-N-methyltryptammonium fumarate (8a) – Reference Example4-Acetoxy-N-ethyl-N- was a commercial supplier as a brown powder and purified via RP-HPLC. The obtained trifluoroacetate salt (80.7 mg, 216 µmol, 1.00 eq) was converted into 4-acetoxy-N-ethyl-N-methyltryptamine (20a) using Amberlyst A-21 and subsequently reacted with fumaric acid as described in GP1. This yielded 8a (33.1 mg, 104 µmol, 48 %) as a colorless solid. Free base 20a:1H NMR (300 MHz, (CD3)2CO): δ = 10.20 (br s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 2.82-2.97 (m, 2H), 2.55-2.65 (m, 2H), 2.45 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 2.26 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H) ppm. Fumarate salt 8a:1H NMR (300 MHz, (CD3)2SO): δ = 11.10 (br s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.52 (s, 1H), 2.83- 2.92 (m, 2H), 2.73-2.82 (m, 2H), 2.68 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H) ppm.13C NMR (75 MHz, (CD3)2SO): δ = 169.6 (Cq, 1C), 167.2 (Cq, 1C), 143.5 (Cq, 1C), 138.5 (Cq, 1C), 134.7 (CH, 1C), 123.8 (CH, 1C), 121.0 (CH, 1C), 119.4 (Cq, 1C), 111.5 (CH, 1C), 110.1 (Cq, 1C), 109.4 (CH, 1C), 57.3 (CH2, 1C), 50.6 (CH2, 1C), 40.2 (CH3, 1C), 22.8 (CH2, 1C), 20.9 (CH2, 1C), 10.9 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C15H21N2O2]+: 261.1598, found 261.1597. The spectroscopic data correspond to the ones previously reported in the literature.

[0030] 4-Butyryloxy-N-ethyl-N-methyltryptammonium fumarate (8b)4-Hydroxy-N-ethyl-N- mg, eq) was reacted with n-butanoyl chloride (47.6 µl, 48.8 mg, 458 µmol, 1.00 eq) for 1 h, purified by HPLC, converted into 4-butyryloxy-N-ethyl-N-methyltryptamine (20b) using Amberlyst A-21and finally reacted with fumaric acid according to GP1. This yielded the pharmaceuti- cally acceptable fumarate salt 8b (38.4 mg, 111 µmol, 24 %) as a colorless solid. Free base 20b:1H NMR (300 MHz, (CD3)2CO): δ = 10.17 (br s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 2.82-2.95 (m, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.53-2.65 (m, 2H), 2.45 (q, J = 7.1 Hz, 2H), 2.26 (s, 3H), 1.80 (sxt, J = 7.4 Hz, 2H), 1.06 (m, 6H) ppm. Fumarate salt 8b:1H NMR (500 MHz, (CD3)2SO): δ = 11.06 (br s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.65 (dd, J = 7.6 Hz, J‘ = 0.7 Hz, 1H), 6.52 (s, 1H), 2.62-2.87 (m, 6H), 2.56 (q, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.70 (sxt, J = 7.4 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H) ppm.13C NMR (126 MHz, CD3OD): δ = 174.3 (Cq, 1C), 174.2 (Cq, 1C), 145.1 (Cq, 1C), 140.6 (Cq, 1C), 137.1 (CH, 1C), 125.2 (CH, 1C), 122.9 (CH, 1C), 120.5 (Cq, 1C), 113.1 (CH, 1C), 110.6 (CH, 1C), 109.3 (Cq, 1C), 57.6 (CH2, 1C), 52.4 (CH2, 1C), 40.3 (CH3, 1C), 37.0 (CH2, 1C), 22.9 (CH2, 1C), 19.4 (CH2, 1C), 14.0 (CH3, 1C), 9.8 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C17H25N2O2]+: 289.1911, found 289.1911. 4-Hexanoyloxy-N-ethyl-N-methyltryptammonium fumarate (8c) – Reference Ex- ample4-Hydroxy-N-ethyl- mg, eq) was reacted with n-hexanoyl chloride (65.3 µl, 61.7 mg, 458 µmol, 1.00 eq) for 1.75 h, purified by HPLC, converted into 4-hexanoyloxy-N-ethyl-N-methyltryptamine (20c) using Amber- lyst A-21 and finally reacted with fumaric acid according to GP1. This yielded the phar- maceutically acceptable fumarate salt 8c (83.7 mg, 224 µmol, 49 %) as a colorless solid. Free base 20c:1H NMR (300 MHz, (CD3)2CO): δ = 10.18 (br s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 2.82-2.95 (m, 2H), 2.72 (t, J =7.5 Hz, 2H), 2.55-2.65 (m, 2H), 2.45 (q, J = 7.2 Hz, 2H), 2.26 (s, 3H), 1.78 (quin, J = 7.3 Hz, 2H), 1.33-1.53 (m, 4H), 1.05 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 6.9 Hz, 3H) ppm. Fumarate salt 8c:1H NMR (500 MHz, (CD3)2SO): δ = 11.08 (br s, 1H), 7.23 (dd, J = 8.1 Hz, J’ = 0.6 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.65 (dd, J = 7.6 Hz, J’ = 0.6 Hz, 1H), 6.51 (s, 1H), 2.81-2.89 (m, 2H), 2.71-2.77 (m, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.62 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.68 (quin, J = 7.4 Hz, 2H), 1.29-1.41 (m, 4H), 1.06 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 172.2 (Cq, 1C), 167.4 (Cq, 1C), 143.6 (Cq, 1C), 138.5 (Cq, 1C), 134.8 (CH, 1C), 123.6 (CH, 1C), 121.0 (CH, 1C), 119.5 (Cq, 1C), 111.5 (CH, 1C), 110.3 (Cq, 1C), 109.4 (CH, 1C), 57.4 (CH2, 1C), 50.6 (CH2, 1C), 40.3 (CH3, 1C), 33.4 (CH2, 1C), 30.7 (CH2, 1C), 24.0 (CH2, 1C), 23.1 (CH2, 1C), 21.8 (CH2, 1C), 13.8 (CH3, 1C), 11.1 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C19H29N2O2]+: 317.2224 , found 317.2228. 4-iso-Butyryloxy-N-ethyl-N-methyltryptammonium fumarate (8d)4-Hydroxy-N-ethyl-N- mg, 1.00 eq) was reacted with iso-butyryl chloride (48.0 µl, 48.8 mg, 458 µmol, 1.00 eq), purified by HPLC, con- verted into 4-iso-butyryloxy-N-ethyl-N-methyltryptamine (20d) using Amberlyst A-21 and finally reacted with fumaric acid according to GP1. This yielded the pharmaceuti- cally acceptable fumarate salt 8d (41.2 mg, 119 µmol, 26 %) as an off-whitesolid. Free base 20d:1H NMR (300 MHz, (CD3)2CO): δ = 10.17 (br s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 2.84-3.03 (m, 3H), 2.55-2.67 (m, 2H), 2.45 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.36 (d, J = 6.9 Hz, 6H), 1.04 (t, J = 7.1 Hz, 3H) ppm. Fumarate salt 8d:1H NMR (500 MHz, CD3OD): δ = 7.25-7.31 (m, 1H), 7.23 (s, 1H), 7.12 (t, J = 7.9 Hz, 1H), 6.71 (dd, J = 7.7 Hz, J‘ = 0.6 Hz, 1H), 6.68 (s, 1H), 3.44 (t, J = 7.3 Hz, 2H), 3.14- 3.26 (m, 4H), 2.96 (dt, J = 13.9 Hz, J‘ = 7.0 Hz, 1H), 2.84 (s, 3H), 1.38 (d, J = 7.0 Hz,6H), 1.28 (t, J = 7.3 Hz, 3H) ppm.13C NMR (126 MHz, CD3OD): δ = 177.8 (Cq, 1C), 172.1 (Cq, 1C), 145.4 (Cq, 1C), 140.7 (Cq, 1C), 136.4 (CH, 1C), 125.3 (CH, 1C), 123.1 (CH, 1C), 120.5 (Cq, 1C), 113.0 (CH, 1C), 110.6 (CH, 1C), 108.7 (Cq, 1C), 57.3 (CH2, 1C), 52.6 (CH2, 1C), 40.3 (CH3, 1C), 35.4 (CH, 1C), 22.8 (CH2, 1C), 19.5 (CH3, 2C), 9.5 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C17H25N2O2]+: 289.1911, found 289.1911. 4-(Cyclopropanecarbonyloxy)-N-ethyl-N-methyltryptammonium fumarate (8e)4-Hydroxy-N-ethyl-N- mg, 1.00 eq) was reacted with cyclopropanecarboxylic acid chloride (41.6 µl, 47.9 mg, 458 µmol, 1.00 eq), puri- fied by HPLC, converted into 4-(cyclopropanecarbonyloxy)-N-ethyl-N-methyltrypta- mine (20e) by alkaline extraction and finally reacted with fumaric acid according to GP1. This yielded the pharmaceutically acceptable fumarate salt 8e (121.4 mg, 352 µmol, 77 %) as a colorless solid. Free base 20e:1H NMR (500 MHz, (D3C)2CO): δ = 10.15 (br s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 2.88-2.98 (m, 2H), 2.59-2.70 (m, 2H), 2.46 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.96-2.03 (m, 1H), 1.06-1.15 (m, 4H), 1.04 (t, J = 7.2 Hz, 3H) ppm. Fumarate salt 8e:1H NMR (500 MHz, (D3C)2SO): δ = 11.09 (br s, 1H), 7.23 (dd, J = 8.1 Hz, J’ = 0.6 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.51 (s, 1H), 2.83-2.91 (m, 2H), 2.73-2.81 (m, 2H), 2.63 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H), 1.94- 2.06 (m, 1H), 0.99-1.10 (m, 7H) ppm.13C NMR (126 MHz, (D3C)2SO): δ = 173.4 (Cq, 1C), 167.3 (Cq, 1C), 143.6 (Cq, 1C), 138.5 (Cq, 1C), 134.8 (CH, 1C), 123.6 (CH, 1C), 121.0 (CH, 1C), 119.6 (Cq, 1C), 111.4 (CH, 1C), 110.4 (Cq, 1C), 109.4 (CH, 1C), 57.3 (CH2, 1C), 50.5 (CH2, 1C), 40.3 (CH3, 1C), 22.8 (CH2, 1C), 12.6 (CH, 1C), 11.2 (CH3, 1C), 8.9 (CH2, 2C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C17H22N2NaO2]+: 309.1573, found 309.1567; [M+H]+calcd. for [C17H23N2O2]+: 287.1754, found287.1747. 4-Pivaloyloxy-N-ethyl-N-methyltryptammonium fumarate (8f)4-Hydroxy-N-ethyl-N- mg, 1.00 eq) was reacted with pivaloyl chloride (980 µl, 959 mg, 7.96 mmol, 17.4 eq) for 1 h, purified by HPLC, converted into 4-pivaloyloxy-N-ethyl-N-methyltryptamine (20f) using Amberlyst A-21 and finally reacted with fumaric acid according to GP1. This yielded the pharmaceuti- cally acceptable fumarate salt 8f (56.1 mg, 156 µmol, 34 %) as a colorless solid. Free base 20f:1H NMR (300 MHz, (CD3)2CO): δ = 10.18 (br s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 2.85-2.98 (m, 2H), 2.57-2.70 (m, 2H), 2.44 (q, J = 7.2 Hz, 2H), 2.24 (s, 3H), 1.44 (s, 9H), 1.03 (t, J = 7.1 Hz, 3H) ppm. Fumarate salt 8f:1H NMR (500 MHz, CD3OD): δ = 7.29 (dd, J = 8.2 Hz, J’ = 0.6 Hz, 1H), 7.25 (s, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.69 (s, 1H), 6.64 (dd, J = 7.7 Hz, J’ = 0.6 Hz, 1H), 3.46-3.52 (m, 2H), 3.20 (s, 4H), 2.84 (s, 3H), 1.45 (s, 9H), 1.27 (t, J = 7.3 Hz, 3H) ppm.13C NMR (126 MHz, CD3OD): δ = 179.5 (Cq, 1C), 171.5 (Cq, 1C), 145.8 (Cq, 1C), 140.8 (Cq, 1C), 136.3 (CH, 1C), 125.0 (CH, 1C), 123.2 (CH, 1C), 120.7 (Cq, 1C), 113.0 (CH, 1C), 110.7 (CH, 1C), 108.6 (Cq, 1C), 57.0 (CH2, 1C), 52.7 (CH2, 1C), 40.4 (CH3, 1C), 40.4 (Cq, 1C), 27.7 (CH3, 3C), 22.9 (CH2, 1C), 9.5 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C18H27N2O2]+: 303.2067, found 303.2078. 4-(3-Methylbutanoyl)oxy-N-ethyl-N-methyltryptammonium fumarate (8g)4-Hydroxy-N-ethyl-N- mg, eq) was reacted with 3-methylbutanoyl chloride (55.9 µl, 55.2 mg, 458 µmol, 1.00 eq) for 1 h, purifiedby HPLC, converted into 4-(3-methylbutanoyl)oxy-N-ethyl-N-methyltryptamine (20g) using Amberlyst A-21 and finally reacted with fumaric acid according to GP1. This yielded the pharmaceutically acceptable fumarate salt 8g (33.1 mg, 91.8 µmol, 20 %) as a colorless solid. Free base 20g:1H NMR (300 MHz, (CD3)2CO): δ = 10.19 (br s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.13 (s, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 2.82-2.96 (m, 2H), 2.54-2.67 (m, 4H), 2.46 (q, J = 7.0 Hz, 2H), 2.18-2.34 (m, 4H), 0.98-1.13 (m, 9H) ppm. Fumarate salt 8g:1H NMR (500 MHz, (CD3)2SO): δ = 11.10 (br s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 2.77- 2.91 (m, 4H), 2.65-2.74 (m, 2H), 2.58 (d, J = 7.1 Hz, 2H), 2.43 (s, 3H), 2.09-2.21 (non, J = 6.8 Hz, 1H), 1.08 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.6 Hz, 6H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 171.5 (Cq, 1C), 167.0 (Cq, 1C), 143.5 (Cq, 1C), 138.5 (Cq, 1C), 134.6 (CH, 1C), 123.7 (CH, 1C), 121.1 (CH, 1C), 119.4 (Cq, 1C), 111.5 (CH, 1C), 110.0 (Cq, 1C), 109.4 (CH, 1C), 57.2 (CH2, 1C), 50.6 (CH2, 1C), 42.3 (CH2, 1C), 40.2 (CH3, 1C), 25.1 (CH, 1C), 22.9 (CH2, 1C), 22.2 (CH3, 2C), 10.9 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C18H27N2O2]+: 303.2067, found 303.2070. 4-(tert-Butylacetyl)oxy-N-ethyl-N-methyltryptammonium fumarate (8h)4-Hydroxy-N-ethyl-N- mg, eq) was reacted with tert-butylacetyl chloride (64.9 µl, 61.7 mg, 458 µmol, 1.00 eq) for 3.5 h, purified by HPLC, converted into 4-(tert-butylacetyl)oxy-N-ethyl-N-methyltryptamine (20h) using Amberlyst A-21 and finally reacted with fumaric acid according to GP1. This yielded the pharmaceutically acceptable fumarate salt 8h (111.2 mg, 297 µmol, 65 %) as a colorless solid. Free base 20h:1H NMR (300 MHz, (CD3)2CO): δ = 10.20 (br s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.13 (s, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 2.84-2.97 (m, 2H), 2.55-2.69 (m,4H), 2.47 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.18 (s, 9H), 1.07 (t, J = 7.2 Hz, 3H) ppm. Fumarate salt 8h:1H NMR (500 MHz, (CD3)2SO): δ = 11.09 (br s, 1H), 7.23 (dd, J = 8.1 Hz, J’ = 0.7 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.63 (dd, J = 7.6 Hz, J’ = 0.7 Hz, 1H), 6.51 (s, 1H), 2.82-2.89 (m, 2H), 2.70-2.79 (m, 2H), 2.63 (q, J = 7.2 Hz, 2H), 2.57 (s, 2H), 2.37 (s, 3H), 1.11 (s, 9H), 1.06 (t, J = 7.1 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 171.1 (Cq, 1C), 167.9 (Cq, 1C), 143.9 (Cq, 1C), 139.0 (Cq, 1C), 135.3 (CH, 1C), 124.1 (CH, 1C), 121.5 (CH, 1C), 120.0 (Cq, 1C), 111.9 (CH, 1C) , 110.8 (Cq, 1C), 109.8 (CH, 1C), 57.9 (CH2, 1C), 51.1 (CH2, 1C), 47.0 (CH2, 1C), 40.8 (CH3, 1C), 30.9 (Cq, 1C), 29.8 (CH3, 3C), 23.5 (CH2, 1C), 11.6 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C19H29N2O2]+: 317.2224, found 317.2225. 4-Benzoyloxy-N-ethyl-N-methyltryptammonium fumarate (8i)4-Hydroxy-N-ethyl-N- mg, 1.00 eq) was reacted with benzoyl chloride (27.7 µl, 33.8 mg, 240 µmol, 1.05 eq) for 30 min, purified by HPLC, converted into 4-benzoyloxy-N-ethyl-N-methyltryptamine (20i) using Amberlyst A-21 and finally reacted with fumaric acid according to GP1. This yielded the pharma- ceutically acceptable fumarate salt 8i (27.0 mg, 71.0 µmol, 31 %) as a colorless solid. Free base 20i:1H NMR (300 MHz, (CD3)2CO): δ = 10.29 (br s, 1H), 8.30 (d, J = 7.8 Hz, 2H), 7.69- 7.85 (m, 1H), 7.58-7.66 (m, 2H), 7.32 (dd, J = 8.1 Hz, J' = 0.7 Hz, 1H), 7.04-7.21 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 2.78-2.92 (m, 2H), 2.50-2.61 (m, 2H), 2.23 (q, J = 7.1 Hz, 2H), 2.00 (s, 3H), 0.85 (t, J = 7.1 Hz, 3H) ppm. Fumarate salt 8i:1H NMR (500 MHz, (CD3)2SO): δ = 11.13 (br s, 1H), 8.21 (dd, J = 8.1 Hz, J’ = 1.0 Hz, 2H), 7.73-7.80 (m, 1H), 7.63 (t, J = 7.8 Hz, 2H), 7.29 (dd, J = 8.2 Hz, J’ = 0.6 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 2.72-2.80 (m, 2H), 2.59-2.68 (m, 2H), 2.27-2.37 (m, J = 6.5 Hz, 2H), 2.04 (s, 3H), 0.84 ppm (t, J = 7.2 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 166.7 (Cq, 1C), 165.1(Cq, 1C), 143.6 (Cq, 1C), 138.6 (Cq, 1C), 134.4 (CH, 1C), 134.0 (CH, 1C), 129.9 (CH, 2C), 129.1 (CH, 2C), 129.0 (CH, 1C), 123.8 (CH, 1C), 121.1 (CH, 1C), 119.6 (Cq, 1C), 111.7 (CH, 1C), 110.3 (Cq, 1C), 109.7 (CH, 1C), 57.5 (CH2, 1C), 50.4 (CH2, 1C), 40.1 (CH3, 1C), 23.0 (CH2, 1C), 11.2 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C20H23N2O2]+: 323.1754, found 323.1756. 4-(2-Furoyl)oxy-N-ethyl-N-methyltryptammonium fumarate (8j)4-Hydroxy-N-ethyl-N- mg, eq) was dissolved in anhydrous THF (0.93 mL) and reacted with 2-furoyl chloride (57.3 µl, 74.7 mg, 573 µmol, 1.25 eq) and triethylamine (96.0 µl, 69.5 mg, 687 µmol, 1.50 eq) for 1 h. After removing volatiles by rotary evaporation, the crude was purified by HPLC, converted into 4-(2-furoyl)oxy-N-ethyl-N-methyltryptamine (20j) by alkaline extraction and finally reacted with fumaric acid according to GP1. This yielded 8j (27.7 mg, 74.8 µmol, 16 %) as a colorless solid. Free base 20j:1H NMR (300 MHz, (D3C)2CO): δ = 10.27 (br s, 1H), 7.94 (dd, J = 1.8 Hz, J’ = 0.7 Hz, 1H), 7.58 (dd, J = 3.5 Hz, J' = 0.7 Hz, 1H), 7.31 (dd, J = 8.2 Hz, J’ = 0.7 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.87 (dd, J = 7.7 Hz, J' = 0.7 Hz, 1H), 6.76 (dd, J = 3.5, J' = 1.8 Hz, 1H), 2.81-2.93 (m, 2H), 2.51-2.67 (m, 2H), 2.30 (q, J = 7.2 Hz, 2H), 2.08 (s, 3H), 0.92 (t, J = 7.1 Hz, 3H) ppm. Fumarate salt 8j:1H NMR (500 MHz, (D3C)2SO): δ = 11.20 (br s, 1H), 8.08-8.14 (m, 1H), 7.62-7.69 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.77- 6.86 (m, 2H), 6.50 (s, 1H), 2.80-2.91 (m, 2H), 2.70-2.79 (m, 2H), 2.43-2.50 (m, 2H), 2.19 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H) ppm.13C NMR (126 MHz, (D3C)2SO): δ = 167.6 (Cq, 1C), 156.8 (Cq, 1C), 148.6 (CH, 1C), 143.2 (Cq, 1C), 142.8 (Cq, 1C), 138.6 (Cq, 1C), 134.9 (CH, 1C), 124.1 (CH, 1C), 121.1 (CH, 1C), 120.2 (CH, 1C), 119.5 (Cq, 1C), 112.7 (CH, 1C), 111.6 (CH, 1C), 110.1 (Cq, 1C), 109.8 (CH, 1C), 57.2 (CH2, 1C), 50.2 (CH2, 1C), 39.6 (CH3, 1C), 22.5 (CH2, 1C), 10.9 (CH3, 1C) ppm. The N-methyl13Csignal is superimposed by that of DMSO-d5 as evidenced by the HSQC and HMBC spectra. HR MS (ESI+): m / z [M+H]+calcd. for [C18H21N2O3]+: 313.1547, found 313.1544. Synthesis of acyloxymethyl prodrugs having formula (2) Synthesis of N-benzyloxycarbonyl derivatives Benzyl imidazole-1-carboxylate (9) This compound was preparedprocedure (cf. Heller et al. Org. Lett. 2010, 12, 4572). To an ice-cold solution of imidazole (3.76 g, 55.0 mmol, 1.00 eq) in dry THF (50 mL) was added benzyl chloroformate (4.25 mL, 5.08 g, 28.3 mmol, 0.51 eq) dropwise. The obtained suspension was stirred at 0°C for 1 h, followed by stirring for 4 h at ambient temperature. The suspended solids were then separated by filtration, and the filter cake was washed with diethyl ether (50 mL). The filtrate was concentrated under reduced pressure. Subsequently, the colorless residue was dis- solved in diethyl ether (100 mL), washed with water (2x50 mL) and dried over MgSO4. The solvent was removed under reduced pressure, which gave 9 as a colorless oil (4.59 g, 22.7 mmol, 83 %). The isolated material was found to be stable for at least 16 weeks when stored at -20°C.1H NMR (300 MHz, CDCl3): δ = 8.15 (s, 1H), 7.34-7.49 (m, 6H), 7.01-7.12 (m, 1H), 5.42 (s, 2H) ppm.13C NMR (75 MHz, CDCl3): δ = 148.8 (Cq, 1C), 137.3 (CH, 1C), 134.1 (Cq, 1C), 130.9 (CH, 1C), 129.3 (CH, 1C), 129.0 (CH, 2C), 128.9 (CH, 2C), 117.3 (CH, 1C), 70.0 (CH2, 1C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C11H10N2NaO2]+: 225.0634, found 225.0634. The analytical data correspond to the ones previously de- scribed in the literature.

[0032] 1-Benzyloxycarbonyl-4-hydroxy-N,N-dimethyltryptamine (10) A flame-dried Schlenk flaskN,N-dimethyltryptamine 1 (1.36 g, 6.66 mmol, 1.00 eq). Benzyl 1H-imidazole-1-carboxylate 9 (1.48 g, 7.32 mmol, 1.10 eq) dissolved in anhydrous acetonitrile (20 mL) was added, followed by 1,8-di- azabicyclo[5.4.0]undec-7-ene (497 µl, 507 mg, 3.33 mmol, 0.50 eq). The resulting brown solution was stirred for 26 h at ambient temperature. Afterwards, the reaction mixture was concentrated by rotary evaporation, quenched by addition of 0.5 M aque- ous NaOH (35 mL) and the mixture was extracted with dichloromethane (3x200 mL). The pooled organic layers were dried over Na2SO4 and concentrated in vacuo. Purifi- cation by column chromatography (ethyl acetate (EtOAc) / triethylamine (TEA) 99 / 1 (v / v), SiO250 g) afforded 10 (1.35 g, 3.99 mmol, 60 %) as a yellowish oil which crystallized upon standing.1H NMR (500 MHz, CDCl3): δ = 13.45 (br s, 1H), 7.73 (br d, J = 5.1 Hz, 1H), 7.44-7.52 (m, 2H), 7.33-7.44 (m, 3H), 7.28 (s, 1H), 7.19 (t, J = 8.1 Hz, 1H), 6.74 (dd, J = 7.9 Hz, J‘ = 0.6 Hz, 1H), 5.42 (s, 2H), 2.84-2.92 (m, 2H), 2.66-2.74 (m, 2H), 2.37 (s, 6H) ppm.13C NMR (126 MHz, CDCl3): δ = 152.2 (Cq, 1C), 150.9 (Cq, 1C), 137.9 (Cq, 1C), 135.4 (Cq, 1C), 128.8 (CH, 2C), 128.7 (CH, 1C), 128.5 (CH, 2C), 126.2 (CH,1C), 121.8 (CH,1C), 120.0 (Cq, 1C), 119.7 (Cq, 1C), 111.4 (CH, 1C), 106.6 (CH, 1C), 68.5 (CH2, 1C), 61.0 (CH2, 1C), 45.4 (CH3, 2C) , 25.2 (CH2, 1C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C20H22N2NaO3]+: 361.1523, found 361.1512; [M+H]+calcd. for [C20H23N2O3]+: 339.1703, found 339.1701.1-Benzyloxycarbonyl-4-hydroxy-N-ethyl-N-methyltryptamine (11) 4-Hydroxy-N-ethyl-N-mmol, 1.00 eq) was dissolved in anhydrous acetonitrile (10.3 mL) under a nitrogen atmosphere. After adding benzyl 1H-imidazole-1-carboxylate 9 as a frozen solid (764 mg, 3.78 mmol, 1.10 eq) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (256 µL, 262 mg, 1.72 mmol, 0.50 eq), the re- sulting violet solution was stirred at ambient temperature for 18 h. The reaction mixture was then concentrated under reduced pressure, mixed with a 0.5 M aqueous NaOH solution (17 mL), and extracted with dichloromethane (3x100 mL). The organic phase was dried over Na2SO4, concentrated and purified by column chromatography (Cyclo- hexane / EtOAc 100 / 0 –0 / 100 (v / v), 1 % TEA, SiO225 g), which yielded 11 (1.08 g, 3.07 mmol, 89 %) as a colorless solid. 1H NMR (500 MHz, CDCl3): δ = 13.55 (br s, 1H), 7.70 (s, 1H), 7.46-7.51 (m, 2H), 7.34-7.44 (m, 3H), 7.28 (s, 1H), 7.18 (t, J = 8.1 Hz, 1H), 6.72 (dd, J = 8.0 Hz, J‘ = 0.5 Hz, 1H), 5.42 (s, 2H), 2.87-2.93 (m, 2H), 2.71-2.76 (m, 2H), 2.55 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H) ppm.13C NMR (126 MHz, CDCl3): δ = 152.2 (Cq, 1C), 150.9 (Cq, 1C), 137.9 (Cq, 1C), 135.4 (Cq, 1C), 128.8 (CH, 2C), 128.7 (CH, 1C), 128.6 (CH, 2C), 126.3 (CH, 1C), 121.8 (CH, 1C), 120.2 (Cq, 1C), 120.0 (Cq, 1C), 111.6 (CH, 1C), 106.7 (CH, 1C), 68.6 (CH2, 1C), 58.7 (CH2, 1C), 52.2 (CH2, 1C), 42.3 (CH3, 1C), 25.4 (CH2, 1C), 11.4 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C21H25N2O3]+: 353.1860, found 353.1861. Synthesis of iodomethyl carboxylates General procedure (GP2): iodination of chloromethyl carboxylates This protocol is based on a literature procedure (cf. Bandgar et al. J. Med. Chem.2011, 54, 1191; and Jones et al. Beilstein J. Org. Chem.2019, 15, 801). A 3.3 M solution of chloromethyl carboxylate (1.00 eq) in anhydrous acetonitrile was allowed to react with sodium iodide (1.80 eq) at 30-35 °C under a nitrogen atmosphere in a flame-driedSchlenk tube under exclusion of light. Subsequently, dichloromethane (1.4 mL per mmol of chloromethyl carboxylate) and water (1.4 mL per mmol of chloromethyl car- boxylate) were added, and the biphasic mixture was stirred for 10 min. The organic phase was separated, washed with 2 % aqueous Na2S2O3 solution (0.7 mL per mmol of chloromethyl carboxylate) and dried over Na2SO4. Evaporation in vacuo at ambient temperature afforded the target product in good to excellent yield. Iodomethyl carbox- ylates were stored at 2-8°C under exclusion of light and under inert gas. Iodomethyl pivalate (12a) Chloromethyl pivalate (957 µL, 1.001.00 eq) was subjected to the reac- tion conditions outlined in GP2 for 16 h. Aqueous workup followed by evaporation at ambient temperature afforded 12a (1.17 g, 4.83 mmol, 73 %) as a yellowish oil.1H NMR (300 MHz, CDCl3): δ =5.92 (s, 2H), 1.19 (s, 9H) ppm.13C NMR (75 MHz, CDCl3): δ = 176.5 (Cq, 1C), 39.0 (Cq, 1C), 31.5 (CH2, 1C), 26.7 (CH3, 3C) ppm. In line with the literature, the molecular ion was not detectable by ESI+MS of a solution of 12a in acetonitrile.[19a]The spectroscopic properties correspond to the ones previously reported in the literature.[18-19]Iodomethyl butyrate (12b) Chloromethyl butyrate (1.90 mL,1.00 eq) was subjected to the re- action conditions outlined in GP2 for 6 h. Aqueous workup followed by evaporation at ambient temperature yielded 12b (3.02 g, 13.2 mmol, 90 %) as a colorless to slightly yellowish oil.1H NMR (300 MHz, CDCl3): δ = 5.91 (s, 2H), 2.31 (t, J = 7.3 Hz, 2H), 1.68 (sxt, J = 7.4 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H) ppm.13C NMR (75 MHz, CDCl3): δ = 171.8 (Cq, 1C), 36.3 (CH2, 1C), 30.7 (CH2, 1C), 18.2 (CH2, 1C), 13.7 (CH3, 1C) ppm. The mo- lecular ion was not detectable by ESI+MS of a solution of 12b in acetonitrile.Synthesis of acyloxymethyl derivatives of 4-hydroxytryptamines (compounds according to formula (3)) 1-Benzyloxycarbonyl-4-pivaloyloxymethyloxy-N,N-dimethyltryptammonium tri- fluoroacetate (13a) (Reference Example)A solution of 10 (550 mg, 1.63 mmol, 1.00 eq) in anhydrous DMF (7.6 mL) was treated with NaH (60 % suspension in mineral oil, 97.5 mg, 2.44 mmol, 1.50 eq) at 0 °C. After 25 min at 0 °C, gas generation ceased and a clear brown solution was obtained. The temperature was then lowered to -30 to -40 °C. Iodomethyl pivalate 12a (413 mg, 1.71 mmol, 1.05 eq) as a solution in anhydrous THF (7.6 mL) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, and stirring was continued for 5 h. Then, the reaction mixture was poured into aq.1 N NaOH (7.7 mL) and extracted with ethyl acetate (3x60 mL). The organic layer was dried over Na2SO4, concentrated, dissolved in acetonitrile (+0.1 % TFA) and purified by means of re- versed-phase chromatography on a preparative HPLC instrument (conditions I). Evap- oration of volatiles followed by lyophilization afforded 13a (335 mg, 591 µmol, 36 %) as a yellowish oil.1H NMR (500 MHz, CD3CN): δ = 10.05 (br s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.48-7.54 (m, 2H), 7.46 (s, 1H), 7.36-7.45 (m, 3H), 7.27 (t, J = 8.3 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 5.91 (s, 2H), 5.41 (s, 2H), 3.26-3.35 (m, 2H), 3.13-3.20 (m, 2H), 2.88 (s, 3H), 2.87 (s, 3H), 1.14 (s, 9H) ppm.13C NMR (126 MHz, CD3CN): δ = 178.4 (Cq, 1C), 161.0 (Cq, q, JC-F= 35.8 Hz, 1C), 151.3 (Cq, 1C), 151.1 (Cq, 1C), 138.4 (Cq, 1C), 136.4 (Cq, 1C), 129.6 (CH, 2C), 129.6 (CH, 1C), 129.3 (CH, 2C), 126.8 (CH, 1C), 124.6 (CH, 1C), 120.3 (Cq, 1C), 117.4 (Cq, q, JC-F = 291.2 Hz, 1C), 116.1 (Cq, 1C), 110.6 (CH, 1C), 107.3 (CH, 1C), 85.6 (CH2, 1C), 69.6 (CH2, 1C), 58.8 (CH2, 1C), 43.5 (CH3, 2C), 39.5 (Cq, 1C), 27.0 (CH3, 3C), 22.7 (CH2, 1C) ppm.19F NMR (282 MHz, CD3CN): δ = -76.2 (s, 3F) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C26H33N2O5]+: 453.2384, found453.2388. 1-Benzyloxycarbonyl-4-n-butanoyloxymethyloxy-N,N-dimethyltryptammonium trifluoroacetate (13b) (Reference Example) A solution of 10 (400 mg, 1.18DMF (5.6 mL) was treated with NaH (60 % suspension in mineral oil, targeted, 70.9 mg, 1.77 mmol, 1.50 eq) at - 30 to -45 °C. After stirring for 30 min at this temperature, iodomethyl butyrate 12b (404 mg, 1.77 mmol, 1.50 eq) as a solution in anhydrous THF was slowly added. The reaction mixture was allowed to slowly warm to room temperature and stirred for further 5 h. Subsequently, the reaction mixture was poured into aq.1 N NaOH (5.4 mL) and extracted with ethyl acetate (3x20 mL). The organic layer was dried over Na2SO4, con- centrated, dissolved in acetonitrile (+0.1 % TFA) and purified by means of reversed- phase chromatography on a preparative HPLC instrument (conditions I). Evaporation of volatiles followed by lyophilization afforded 13b (96.8 mg, 171 µmol, 14 %) as a col- orless oil.1H NMR (500 MHz, CD3CN): δ = 10.74 (br s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 7.1 Hz, 2H), 7.46 (s, 1H), 7.35-7.45 (m, 3H), 7.27 (t, J = 8.3 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 5.90 (s, 2H), 5.41 (s, 2H), 3.24-3.35 (m, 2H), 3.10-3.22 (m, 2H), 2.86 (s, 6H), 2.32 (t, J = 7.3 Hz, 2H), 1.57 (sxt, J = 7.4 Hz, 2H), 0.85 (t, J = 7.5 Hz, 3H) ppm.13C NMR (126 MHz, CD3CN): δ = 173.7 (Cq, 1C), 161.2 (Cq, q, JC-F = 35.1 Hz, 1C), 151.3 (Cq, 1C), 151.2 (Cq, 1C), 138.4 (Cq, 1C), 136.5 (Cq, 1C), 129.6 (CH, 2C), 129.6 (CH, 1C), 129.3 (CH, 2C), 126.8 (CH, 1C), 124.6 (CH, 1C), 121.1, 120.4 (Cq, 1C), 117.6 (Cq, q, JC-F =292.5 Hz, 1C), 116.3 (Cq, 1C), 110.6 (CH, 1C), 107.3 (CH, 1C), 85.4 (CH2, 1C), 69.6 (CH2, 1C), 58.7 (CH2, 1C), 43.3 (CH3, 2C), 36.4 (CH2, 1C), 22.7 (CH2, 1C), 18.8 (CH2, 1C), 13.7 (CH3, 1C) ppm.19F NMR (282 MHz, CD3CN): δ = -76.1 ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C25H31N2O5]+: 439.2227, found 439.2224.1-Benzyloxycarbonyl-4-pivaloyloxymethyloxy-N-ethyl-N-methyltryptammonium trifluoroacetate (13c) (Reference Example)Under a nitrogen atmosphere, 11 (100 mg, 284 µmol, 1.00 eq) was dissolved in dry DMF (1.3 mL). After cooling to -40 to -50 °C, NaH (60 % dispersion in mineral oil, 17.0 mg, 426 µmol, 1.50 eq) was added slowly followed by a solution of iodomethyl pivalate 12a (103 mg, 426 µmol, 1.50 eq) in dry THF (1.3 mL). The reaction mixture was allowed to warm to room temperature and stirring was continued for 2 h. Subse- quently, the mixture was poured into 1 N NaOH (1.35 mL) and extracted with ethyl acetate (3x5 mL). The organic layer was dried over Na2SO4, concentrated, dissolved in acetonitrile (+0.1 % TFA) and purified by means of reversed-phase chromatography on a preparative HPLC instrument (conditions I). Evaporation of volatiles followed by lyophilization afforded 13c (73.3 mg, 126 µmol, 44 %) as a colorless oil.1H NMR (500 MHz, CD3CN): δ = 9.57 (br s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.49-7.55 (m, 3H), 7.34-7.47 (m, 3H), 7.30 (t, J = 8.3 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 5.93 (d, J = 6.7 Hz, 1H), 5.90 (d, J = 6.7 Hz, 1H), 5.43 (s, 2H), 3.34-3.40 (m, 1H), 3.09-3.30 (m, 5H), 2.83- 2.86 (m, 3H), 1.28 (t, J = 7.3 Hz, 3H), 1.14 (s, 9H) ppm.13C NMR (126 MHz, CD3CN): δ = 178.4 (Cq, 1C), 151.4 (Cq, 1C), 151.3 (Cq, 1C), 138.5 (Cq, 1C), 136.5 (Cq, 1C), 129.7 (CH, 2C), 129.6 (CH, 1C), 129.4 (CH, 2C), 126.9 (CH, 1C), 124.8 (CH, 1C), 120.4 (Cq, 1C), 116.2 (Cq, 1C), 110.6 (CH, 1C), 107.5 (CH, 1C), 85.8 (CH2, 1C), 69.7 (CH2, 1C), 56.5 (CH2, 1C), 52.1 (CH2, 1C), 39.9 (CH3, 1C), 39.5 (Cq, 1C), 27.0 (CH3, 3C), 22.5 (CH2, 1C), 9.3 (CH3, 1C) ppm. Trifluoroacetate counterion not detected due to low signal intensity caused by C-F coupling.19F NMR (282 MHz, CD3CN): δ = -76.3 (s, 3F) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C27H35N2O5]+: 467.2540, found 467.2549.1-Benzyloxycarbonyl-4-n-butanoyloxymethyloxy-N-ethyl-N-methyltryptammo- nium trifluoroacetate (13d) (Reference Example) A solution of 11 (200 mg, 567DMF (2.7 mL) was treated with NaH (60 % suspension in mineral oil, 34.1 mg, 851 µmol, 1.50 eq) at 0 °C. After 30 min at 0 °C, gas generation ceased and a clear brown solution was obtained. The temperature was then lowered to -25 °C to -30 °C, and 12b (129 mg, 567 µmol, 1.00 eq) as a solution in anhydrous THF (2.7 mL) was slowly added. After completion of the addition, the reaction mixture was allowed to slowly warm to room temperature. After stirring for 4 h, the mixture was poured into aq.1 N NaOH (2.7 mL) and extracted with ethyl acetate (3x10 mL). The organic layer was dried over Na2SO4, concentrated, dissolved in acetonitrile (+0.1 % TFA) and purified by means of reversed-phase chro- matography on an preparative HPLC instrument (conditions I). Evaporation of volatiles followed by lyophilization afforded 13d (133 mg, 234 µmol, 41 %) as an orange oil.1H NMR (300 MHz, CD3CN): δ = 10.47 (br s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.35-7.56 (m, 6H), 7.28 (t, J = 8.2 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 5.87-5.97 (m, 2H), 5.43 (s, 2H), 3.05-3.41 (m, 6H), 2.84 (d, J = 4.7 Hz, 3H), 2.33 (t, J = 7.3 Hz, 2H), 1.58 (sxt, J = 7.4 Hz, 2H), 1.29 (t, J = 7.3 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H) ppm.13C NMR (75 MHz, CD3CN): δ = 173.6 (Cq, 1C), 151.4 (Cq, 1C), 151.3 (Cq, 1C), 138.4 (Cq, 1C), 136.5 (Cq, 1C), 129.6 (CH, 2C), 129.6 (CH, 1C), 129.3 (CH, 2C), 126.8 (CH, 1C), 124.7 (CH, 1C), 120.4 (Cq, 1C), 116.4 (Cq, 1C), 110.6 (CH, 1C), 107.4 (CH, 1C), 85.6 (CH2, 1C), 69.6 (CH2, 1C), 56.4 (CH2, 1C), 51.8 (CH2, 1C), 39.7 (CH3, 1C), 36.4 (CH2, 1C), 22.4 (CH2, 1C), 18.8 (CH2, 1C), 13.6 (CH3, 1C), 9.3 (CH3, 1C) ppm. Trifluoroacetate counterion not detected due to low signal intensity caused by C-F coupling.19F NMR (282 MHz, CD3CN): δ = -76.1 (s, 3F) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C26H33N2O5]+: 453.2384, found 453.2387.4-Pivaloyloxymethyloxy-N,N-dimethyltryptammonium fumarate (15a)A 100 mL two- 67.9 µmol, 0.12 eq). After three evacuation-backfill cycles with nitrogen, the flask was filled with hydrogen gas and equipped with a hydrogen-containing balloon. Then, a solution of 13a (335 mg, 591 µmol, 1.00 eq) in EtOAc (37.5 mL) was added via syringe, and the reaction mixture was stirred at room temperature for 16 h. Subsequently, the reaction mixture was fil- tered through a pad of cotton. The filter cake was rinsed with EtOAc (3x5 mL) and concentrated by rotary evaporation. The crude was then dissolved in acetonitrile (ACN) / H2O (1:1, +0.1 % TFA) and purified by means of reversed-phase chromatog- raphy on a preparative HPLC instrument (conditions II). The product fractions were concentrated by rotary evaporation, set to pH 10-11 using 1 N NaOH (8.7 mL) and extracted with dichloromethane (3x150 mL). Drying over Na2SO4 followed by rotary evaporation afforded a colorless oil. In order to remove residual traces of TFA which had been detected by19F NMR spectroscopy, the oil was dissolved in 200 mL Et2O, and the organic phase was washed with carbonate buffer (0.1 M, pH 10.6, 3x50 mL). Drying over Na2SO4 followed by evaporation of volatiles afforded 4-pivalo- yloxymethyloxy-N,N-dimethyltryptamine 14a (110 mg, 346 µmol, 59 %) as a colorless solid.1H NMR (300 MHz, CD3CN): δ = 9.10 (br s, 1H), 7.05-7.09 (m, 1H), 6.98-7.05 (m, 1H), 6.94-6.98 (m, 1H), 6.68 (dd, J = 7.3 Hz, J‘ = 1.2 Hz, 1H), 5.87 (s, 2H), 2.86-3.00 (m, 2H), 2.46-2.55 (m, 2H), 2.23 (s, 6H), 1.16 (s, 9H) ppm.13C NMR (75 MHz, (CD3)2CO): δ = 177.4 (Cq, 1C), 152.3 (Cq, 1C), 139.7 (Cq, 1C), 122.7 (CH, 1C), 122.5 (CH, 1C), 119.0 (Cq, 1C), 114.4 (Cq, 1C), 107.2 (CH, 1C), 102.9 (CH, 1C), 86.2 (CH2, 1C), 62.4 (CH2, 1C), 45.7 (CH3, 2C), 39.4 (Cq, 1C), 27.2 (CH3, 3C), 25.7 (CH2, 1C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C18H26N2NaO3]+: 341.1836, found 341.1835; [M+H]+calcd. for [C18H27N2O3]+: 319.2016, found 319.2020. The analytical data correspond to the ones previously reported in the literature.

[0011] To a solution of fumaric acid (19.4 mg, 166 µmol, 0.48 eq) in acetone (3.0 mL), 14a(110 mg, 346 µmol, 1.00 eq) dissolved in acetone (1.9 mL) was added and the ob- tained mixture was thoroughly vortexed. After standing for 1.5 h at 5°C, the suspension was centrifuged (3,500 RCF, 5 min) and decanted. The residue was washed with cold (5 °C) acetone (2 × 0.8 mL) and lyophilized, which afforded 15a (106 mg, 282 µmol, 82 %) as a colorless solid.1H NMR (500 MHz, (CD3)2SO): δ = 10.89 (br s, 1H), 7.05 (d, J = 2.1 Hz, 1H), 7.01-7.03 (m, 1H), 6.96-7.00 (m, 1H), 6.63 (d, J = 7.5 Hz, 1H), 6.48 (s, 1H), 5.89 (s, 2H), 2.91- 2.98 (m, 2H), 2.67-2.74 (m, 2H), 2.39 (s, 6H), 1.12 ppm (s, 9H) ppm.13C NMR (75 MHz, (CD3)2SO): δ = 176.7 (Cq, 1C), 167.4 (Cq, 1C), 150.5 (Cq, 1C), 138.3 (Cq, 1C), 134.9 (CH, 1C), 122.5 (CH, 1C), 121.6 (CH, 1C), 117.3 (Cq, 1C), 111.2 (Cq, 1C), 106.5 (CH, 1C), 101.7 (CH, 1C), 85.2 (CH2, 1C), 60.1 (CH2, 1C), 44.0 (CH3, 2C), 38.4 (Cq, 1C), 26.6 (CH3, 3C), 23.4 (CH2, 1C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C18H26N2NaO3]+: 341.1836, found 341.1829; [M+H]+calcd. for [C18H27N2O3]+: 319.2016, found 319.2014. 4-n-Butanoyloxymethyloxy-N,N-dimethyltryptammonium fumarate (15b)A 50 mL two- µmol, 0.15 eq). After three evacuation-backfill cycles with nitrogen, the flask was filled with hydrogen gas and equipped with a hydrogen-containing balloon. Then, a solution of 13b (90.1 mg, 163 µmol, 1.00 eq) in EtOAc (13 mL) was added via syringe, and the reac- tion mixture was stirred at room temperature for 6 h. Subsequently, the reaction mix- ture was filtered through a pad of cotton. The filter cake was rinsed with EtOAc (3x2 mL) and concentrated by rotary evaporation. The crude was then dissolved in ACN / H2O (1:1, +0.1 % TFA) and purified by means of reversed-phase chromatography on a preparative HPLC instrument (conditions II). The product fractions were concen- trated by rotary evaporation, set to pH 10-11 using 1 N NaOH (2.9 mL) and extracted with dichloromethane (3x45 mL). Drying over Na2SO4 followed by rotary evaporation afforded 4-n-butanoyloxymethyloxy-N,N-dimethyltryptamine 14b (40.4 mg, 133 µmol,81 %) as an impure yellowish oil which was used in the next step without further puri- fication.1H NMR (500 MHz, CD3CN): δ = 9.32 (br s, 1H), 7.04-7.09 (m, 1H), 6.98-7.04 (m, 1H), 6.96 (d, J = 1.7 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 5.86 (s, 2H), 2.92-3.01 (m, 2H), 2.50- 2.59 (m, 2H), 2.32 (t, J = 7.3 Hz, 2H), 2.21-2.29 (m, 6H), 1.60 (sxt, J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H) ppm. To a solution of fumaric acid (6.65 mg, 56.7 µmol, 0.43 eq) in acetone (1.4 mL), 14b (40.4 mg, 133 µmol, 1.00 eq) dissolved in acetone (0.8 mL) was added and the ob- tained mixture was thoroughly vortexed. After standing for 6 h at 5 °C, the suspension was centrifuged (3,500 RCF, 5 min) and decanted. The residue was washed with cold (5°C) acetone (2 × 0.3 mL) and lyophilized, which afforded 15b (33.2 mg, 91.6 µmol, 69 %) as a colorless solid.1H NMR (500 MHz, (CD3)2SO): δ = 10.92 (br s, 1H), 7.07 (d, J = 1.7 Hz, 1H), 7.01-7.05 (m, 1H), 6.95-7.01 (m, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.50 (s, 1H), 5.89 (s, 2H), 2.92- 3.03 (m, 2H), 2.73-2.86 (m, 2H), 2.46 (s, 6H), 2.34 (t, J = 7.3 Hz, 2H), 1.54 (sxt, J = 7.3 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 172.1 (Cq, 1C), 167.5 (Cq, 1C), 150.4 (Cq, 1C), 138.3 (Cq, 1C), 134.9 (CH, 1C), 122.6 (CH, 1C), 121.6 (CH, 1C), 117.2 (Cq, 1C), 110.8 (Cq, 1C), 106.4 (CH, 1C), 101.6 (CH, 1C), 84.8 (CH2, 1C), 59.7 (CH2, 1C), 43.6 (CH3, 2C), 35.3 (CH2, 1C), 23.0 (CH2, 1C), 17.7 (CH2, 1C), 13.2 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+Na]+calcd. for [C17H24N2NaO3]+: 327.1679, found 327.1667; [M+H]+calcd. for [C17H25N2O3]+: 305.1860, found 305.1852. 4-Pivaloyloxymethyloxy-N-ethyl-N-methyltryptammonium fumarate (15c)A 25 mL two- µmol, 0.12 eq). After three evacuation-backfill cycles with nitrogen, the flask was filled with hydrogen gas and equipped with a hydrogen-containing balloon. Then, a solution of 13c (71.1 mg, 122 µmol, 1.00 eq) in EtOAc (7.8 mL) was added via syringe, and the reac-tion mixture was stirred at room temperature for 4.5 h. Subsequently, the reaction mix- ture was filtered through a pad of cotton. The filter cake was rinsed with EtOAc (3x1 mL) and concentrated by rotary evaporation. The crude was then dissolved in ACN / H2O (1:1, +0.1 % TFA) and purified by means of reversed-phase chromatography on a preparative HPLC instrument (conditions II). The product fractions were concen- trated by rotary evaporation, set to pH 10-11 using 1 N NaOH (1.8 mL) and extracted with dichloromethane (3x30 mL). Drying over Na2SO4 followed by rotary evaporation afforded a colorless oil. In order to remove residual traces of TFA which had been detected by19F NMR spectroscopy, the oil was dissolved in 20 mL Et2O, and the or- ganic phase was washed with carbonate buffer (0.1 M, pH 10.6, 3x10 mL). Drying over Na2SO4 followed by evaporation of volatiles afforded 4-pivaloyloxymethyloxy-N-ethyl- N-methyltryptamine 14c (28.0 mg, 84.2 µmol, 69 %) as a colorless oil.1H NMR (300 MHz, (CD3)2CO): δ = 10.08 (br s, 1H), 6.95-7.10 (m, 3H), 6.66-6.73 (m, 1H), 5.94 (s, 2H), 2.97-3.04 (m, 2H), 2.59-2.70 (m, 2H), 2.48 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.18 (s, 9H), 1.05 (t, J = 7.2 Hz, 3H) ppm. To a solution of fumaric acid (4.89 mg, 42.1 µmol, 0.50 eq) in acetone (0.6 mL), 14c (28.0 mg, 84.2 µmol, 1.00 eq) dissolved in acetone (0.9 mL) was added and the ob- tained mixture was thoroughly vortexed. After standing for 1.5 h at 5°C, the suspension was centrifuged (3,500 RCF, 5 min) and decanted. The residue was washed with cold (5°C) acetone (2 × 0.2 mL) and lyophilized, which afforded 15c (25.8 mg, 66.1 µmol, 78 %) as a colorless crystalline solid.1H NMR (500 MHz, (CD3)2SO): δ = 10.90 (br s, 1H), 7.06 (d, J = 1.8 Hz, 1H), 7.01-7.04 (m, 1H), 6.96-7.01 (m, 1H), 6.63 (d, J = 7.3 Hz, 1H), 6.47 (br s, 1H), 5.89 (s, 2H), 2.91-3.00 (m, 2H), 2.73-2.82 (m, 2H), 2.61-2.72 (m, 2H), 2.42 (s, 3H), 1.12 (s, 9H), 1.07 (t, J = 7.2 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 176.6 (Cq, 1C), 167.4 (Cq, 1C), 150.5 (Cq, 1C), 138.3 (Cq, 1C), 134.9 (CH, 1C), 122.7 (CH, 1C), 121.6 (CH, 1C), 117.2 (Cq, 1C), 110.8 (Cq, 1C), 106.5 (CH, 1C), 101.7 (CH, 1C), 85.2 (CH2, 1C), 57.3 (CH2, 1C), 50.2 (CH2, 1C), 40.1 (CH3, 1C), 38.4 (Cq, 1C), 26.6 (CH3, 3C), 22.7 (CH2, 1C), 10.7 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C19H29N2O3]+: 333.2173, found 333.2175.4-n-Butanoyloxymethyloxy-N-ethyl-N-methyltryptammonium fumarate (15d)A 50 mL two- µmol, 0.12 eq). After three evacuation-backfill cycles with nitrogen, the flask was filled with hydrogen gas and equipped with a hydrogen-containing balloon. Then, a solution of 13d (133 mg, 234 µmol, 1.00 eq) in EtOAc (14.5 mL) was added via syringe, and the reaction mixture was stirred at room temperature for 4.5 h. Subsequently, the reaction mixture was fil- tered through a pad of cotton. The filter cake was rinsed with EtOAc (3x2 mL) and concentrated by rotary evaporation. The crude was then dissolved in ACN / H2O (1:1, +0.1 % TFA) and purified by means of reversed-phase chromatography on a prepara- tive HPLC instrument (conditions II). The product fractions were concentrated by rotary evaporation, set to pH 10-11 using 1 N NaOH (3.3 mL) and extracted with dichloro- methane (3x50 mL). Drying over Na2SO4 followed by rotary evaporation afforded a colorless oil. In order to remove residual traces of TFA which had been detected by19F NMR spectroscopy, the oil was dissolved in 40 mL Et2O, and the organic phase was washed with carbonate buffer (0.1 M, pH 10.6, 3x20 mL). Drying over Na2SO4 fol- lowed by evaporation of volatiles afforded 4-n-butanoyloxymethyloxy-N-ethyl-N-me- thyltryptamine 14d (49.6 mg, 156 µmol, 68 %) as a colorless oil.1H NMR (300 MHz, (CD3)2CO): δ = 10.44 (br s, 1H), 6.93-7.11 (m, 3H), 6.66 (d, J = 7.6 Hz, 1H), 5.93 (s, 2H), 2.92-3.05 (m, 2H), 2.58-2.70 (m, 2H), 2.40-2.54 (m, 2H), 2.35 (t, J = 7.3 Hz, 2H), 2.26-2.31 (m, 3H), 1.62 (sxt, J = 7.4 Hz, 2H), 0.99-1.10 (m, 3H), 0.91 (t, J = 7.4 Hz, 3H) ppm. To a solution of fumaric acid (9.04 mg, 77.9 µmol, 0.50 eq) in acetone (1.7 mL), 14d (49.6 mg, 156 µmol, 1.00 eq) dissolved in acetone (0.9 mL) was added and the obtained mixture was thoroughly vortexed. After standing for 1.5 h at 5 °C, the suspen- sion was centrifuged (3,500 RCF, 5 min) and decanted. The residue was washed with cold (5 °C) acetone (2 × 0.4 mL) and lyophilized, which afforded 15d (39.2 mg, 104 µmol, 67 %) as a colorless solid.1H NMR (500 MHz, (CD3)2SO): δ = 10.93 (s, 1H), 7.07 (d, J = 2.2 Hz, 1H), 7.03 (dd, J = 8.1 Hz, J = 0.7 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.63 (dd, J = 7.6 Hz, J =0.6 Hz, 1H),6.47 (s, 1H), 5.89 (s, 2H), 2.91-3.02 (m, 2H), 2.77-2.85 (m, 2H), 2.71 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H), 1.54 (sxt, J = 7.3 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H), 0.84 ppm (t, J = 7.4 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 172.1 (Cq, 1C), 167.8 (Cq, 1C), 150.5 (Cq, 1C), 138.3 (Cq, 1C), 135.1 (CH, 1C), 122.6 (CH, 1C), 121.6 (CH, 1C), 117.2 (Cq, 1C), 111.1 (Cq, 1C), 106.5 (CH, 1C), 101.6 (CH, 1C), 84.8 (CH2, 1C), 57.5 (CH2, 1C), 50.1 (CH2, 1C), 40.0 (CH3, 1C), 35.3 (CH2, 1C), 22.7 (CH2, 1C), 17.7 (CH2, 1C), 13.3 (CH3, 1C), 10.8 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C18H27N2O3]+: 319.2016, found 319.2026. 4-Pivaloyloxymethyloxy-N-ethyl-N-methyltryptammonium mesylate (16) A 25 mL two-necked flaskmg, 14.1 µmol, 0.12 eq). After three evacuation-backfill cycles with nitrogen, the flask was filled with hydrogen gas and equipped with a hydrogen-containing balloon. Then, a solution of 13c (71.1 mg, 122 µmol, 1.00 eq) in EtOAc (7.8 mL) was added via syringe, and the reac- tion mixture was stirred at room temperature for 4.5 h. Subsequently, the reaction mix- ture was filtered through a pad of cotton. The filter cake was rinsed with EtOAc (3x1 mL) and concentrated by rotary evaporation. The crude was then dissolved in ACN / H2O (1:1, +0.1 % TFA) and purified by means of reversed-phase chromatography on a preparative HPLC instrument (conditions II). The product fractions were concen- trated by rotary evaporation, set to pH 10-11 using 1 N NaOH (1.8 mL) and extracted with dichloromethane (3x30 mL). Drying over Na2SO4 followed by rotary evaporation afforded a colorless oil. In order to remove residual traces of TFA which had been detected by19F NMR spectroscopy, the oil was dissolved in 20 mL Et2O, and the or- ganic phase was washed with carbonate buffer (0.1 M, pH 10.6, 3x10 mL). Drying over Na2SO4 followed by evaporation of volatiles afforded 4-pivaloyloxymethyloxy-N-ethyl- N-methyltryptamine 14c (28.0 mg, 84.2 µmol, 69 %) as a colorless oil.1H NMR (300 MHz, (CD3)2CO): δ = 10.08 (br s, 1H), 6.95-7.10 (m, 3H), 6.66-6.73 (m, 1H), 5.94 (s, 2H), 2.97-3.04 (m, 2H), 2.59-2.70 (m, 2H), 2.48 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.18 (s, 9H), 1.05 (t, J = 7.2 Hz, 3H) ppm.14c (19.7 mg, 59.3 µmol, 1.00 eq) was then dissolved in acetone (0.8 mL) and added to a solution of methanesulfonic acid (3.89 µl, 5.69 mg, 59.3 µmol, 1.00 eq) in acetone (0.2 mL), followed by cyclohexane (3.0 mL). The mixture was thoroughly vortexed, al- lowed to stand at 5 °C for 2 h, then centrifuged (3,500 RCF, 5 min) and decanted. The residue was washed with cold (5 °C) cyclohexane (2 × 0.5 mL) and lyophilized, which afforded 16 (16.4 mg, 38.3 µmol, 65 %) as a yellowish oil.1H NMR (500 MHz, (CD3)2SO): δ = 11.04 (br s, 1H), 9.03-9.24 (m, 2H), 7.18 (d, J = 2.3 Hz, 1H), 6.98-7.11 (m, 2H), 6.70 (dd, J = 7.3 Hz, J = 1.1 Hz, 1H), 5.87-5.99 (m, 2H), 3.02-3.30 (m, 6H), 2.85 (d, J = 5.0 Hz, 2H), 2.30 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.12 (s, 7H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 176.9 (Cq, 1C), 150.1 (Cq, 1C), 138.4 (Cq, 1C), 123.5 (CH, 1C), 122.0 (CH, 1C), 116.8 (Cq, 1C), 108.2 (Cq, 1C), 106.6 (CH, 1C), 101.7 (CH, 1C), 85.1 (CH2, 1C), 55.7 (CH2, 1C), 50.3 (CH2, 1C), 38.8 (CH3, 1C), 38.4 (Cq, 1C), 26.6 (CH3, 3C), 21.4 (CH2, 1C), 8.9 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C19H29N2O3]+: 333.2173, found 333.2179.Characterization of compound properties Passive membrane permeability and cell viability Table 5: Passive membrane permeability Pe, mass retention R, and viability of human hepatocyte-derived cells (HuH-7) after incubation with the respective prodrug. All val- ues are the mean of triplicates ± standard deviation unless otherwise stated. Cell Viability in HuH7 at Pe 50 µM [%] Compound - R [%] [106cm / s] 2 h Incuba- 24 h Incu- tion bation 7a n.d. n.d. 96.9 ± 1.6 81.9 ± 2.8 7b n.d. n.d. 104.3 ± 1.9 80.0 ± 4.8 7c n.d. n.d. 104.4 ± 4.5 83.8 ± 1.7 8aa5.6 ± 0.8 4 88.7 ± 3.0 85.4 ± 3.6 8b 9.2 ± 0.8 4 88.1 ± 6.0 83.7 ± 1.0 Carboxylic 8ca11.8 ± 1.0 7 30.2 ± 1.0 74.3 ± 8.0 ester 8d 9.5 ± 0.7 4 91.4 ± 3.7 82.1 ± 2.3 prodrugs8e n.d. n.d. 101.2 ± 3.1 8718..73±±29..068f 10.7 ± 0.7 -2 80.4 ± 2.1 79.4 ± 2.1 8g 10.6 ± 0.8 2 81.7 ± 8.6 79.8 ± 4.6 8h 11.2 ± 0.8 1 28.7 ± 1.1 42.3 ± 25.9 8i 9.4 ± 0.8 6 95.0 ± 3.8 80.1 ± 1.7 8j n.d. n.d. 89.6 ± 3.4 78.0 ± 2.0 15a 9.1 ± 0.5 4 61.6 ± 6.0 61.6 ±18.4 Acyloxymethyl 15b 8.1 ± 0.8b7b90.0 ± 5.2 79.3 ± 3.5 prodrugs 15c 9.7 ± 0.6 2 48.3 ± 16.1 47.1 ± 10.4 15d 8.0 ± 0.3 6 85.4 ± 2.7 80.6 ± 3.3 N-Cbz deriva- 10 n.d. n.d. 0.1 ± 0.2 -1.3 ± 0.1 tives 11 n.d. n.d. 0.1 ± 0.2 -2.1 ± 0.1 Acetylsali- n.d. n.d. 92.9 ± 3.3 83.8 ± 3.8 cylic acid Caffeine12.8 ^ 0.9c1 109.8 ± 3.3 85.4 ± 0.9 Furosemide-0.4 ^ 0.3c2 121.9 ± 13.8 90.7 ± 1.1 Imipramine References 12.4 ± 1.0c21 91.1 ± 3.7 24.4 ± 5.3 HCl Phenytoin 7.5 ^ 1.0c57 122.9 ± 1.7 84.2 ± 2.7 Psilocin 1 n.d. n.d. 93.7 ± 6.3 72.5 ± 8.3 4-OH-MET 11.0 ± 1.0 29 91.0 ± 1.7 82.9 ± 1.3 fumarate 17aReference examples.bMean of six replicates.cliterature: cf. Chen et al. Pharm. Res. 2008, 15, 1511: Pe(Caffeine) = (9.89 ^ 1.52)∙10-6cm / s, Pe(Furosemide)= (0.46 ^ 0.06)∙10-6cm / s, Pe(Imipramine HCl) = (10.11 ^ 0.30)∙10-6cm / s, Pe(Pheny- toin) = (5.73 ^ 0.53)∙10-6cm / s. Table 5 shows the passive membrane permeability and mass retention of the synthe- sized compounds in comparison to N-Cbz precursors and reference compounds. As can be seen, a high membrane permeability (> 1.5∙10-6cm / s) was found for all inves- tigated prodrugs. Regarding Pe, a value of at least 5 × 10-6cm / s can be considered to be preferable and is fulfilled by all measured prodrugs. The more preferable values of at least 8 × 10-6cm / s are achieved by compounds 8b and 8d, 8f to 8i, and 15a to 15d. Further, the highest Pe measured can be observed for compounds 8f to 8h, in which R3 of formula (1) is one of tert-butyl, isobutyl, and neopentyl, due to their lipophilicity. Regarding cell viability of HuH-7 cells, generally, incubation with prodrugs resulted in a similar cell viability as incubation with the parent drugs 1 and 17. In addition, data obtained after incubating for 2 h show the same trends as data obtained after 24 h incubation except in the case of reference compound 8c. As already mentioned above, high lipophilicity and high passive membrane permeability of the prodrugs inversely correlate with cell viability. The N-carbamates 10 and 11 were found to be extremely toxic for HuH-7 cells, likely due to the combination of a relatively high lipophilicity and a phenolic pKacloser to 6.3. Aliphatic promoieties R3comprising acyl residues with three or four carbon atoms, along with aromatic promoieties R3, represent a good com- promise between passive membrane permeability and cellular tolerability. In view of cell viability, compounds 8b, 7a / 8d, 7b, 7c / 8e and 8i, as well as 15d are most preferred, in which R3 of formula (1) is one of n-propyl, isopropyl, 2-furyl, cyclopropyl and phenyl.Stability in human saliva and human blood plasma Table 6: Prodrug cleavage in human saliva and human plasma. All values are the mean of triplicates ± standard deviation unless otherwise stated. Compound t1 / 2[min] at 37 °C and [prodrug]0= 50 µM Human 10 % Human 100 % Human SalivaaPlasma Plasma Carboxylic 7a 15-60 0.36 ± 0.02en.d. ester prodrugs 7b 15-60 n.d. < 0.1e7c > 60 n.d. n.d. 8ab15-60 0.69 ± 0.14 n.d. 8b 15-60 0.64 ± 0.04 n.d. 8cb< 15 0.66 ± 0.13 n.d. 8d 15-60 0.44 ± 0.03 n.d. Carboxylic 8e > 60 n.d. 0.84 ± 0.11cester prodrugs 8f > 60 n.d. > 60e8g n.d. > 8en.d. 8h n.d. > 8en.d. 8i 15-60 1.5 ± 0.5dn.d. 8j 15-60 n.d. 0.14 ± 0.01 Acyloxyme- 15a 15-60 n.d. > 300 mind,ethyl prodrugs 15b < 15 3.5 ± 0.8d0.48 ± 0.10 15c < 15 n.d. > 300 mine15d < 15 4.2 ± 0.1dn.d. N-Cbz 10 n.d. n.d. > 5700d,ederivatives 11 n.d. n.d. > 5700d,eReference Acetylsalicylic > 60 n.d. 146 ± 19facidaMean of three measurements performed with fresh samples of three individuals.bReference examples.cTwo measurements.dNo clear distinction between zero and first order kinetics possible.eNo replicates.f[ASS]0 = 560 µM; cf. Harthon et al. Acta Pharmacologica et Toxicologica 1971, 29, 155: (130 ± 48) min.Referring to Table 6, the behavior of the prodrugs in human blood plasma has been studied. The rate of prodrug depletion in diluted (10 %) and undiluted (100 %) human blood plasma at 37 °C was investigated by HPLC-UV analysis of aliquots that were quenched after appropriate time intervals. Starting from an initial prodrug concentration of 50 µM, prodrug depletion was detectable within seconds to minutes except for pro- drugs bearing sterically extremely hindered acyl residues (8f-h, 15a, 15c). Where ap- plicable, half-lives were determined from semi-logarithmic plots of the raw data. These half-lives are considered to reflect the cleavage activity associated with plasma ester- ases or other plasma-specific factors, because non-catalyzed hydrolysis in the PBS buffer used for plasma dilution was found to proceed significantly slower, even at 80 °C (Table 7).Table 7: Stability of the prodrugs in PBS at 80 °C. t1 / 2 [min] in PBS, 80 °C Compound [prodrug]0 = 50 µM 7a n.d. 7b n.d. 7c n.d. 8aa34.0 ± 0.7 8b 82.0 ± 1.6 8ca69.5 ± 1.2 Carboxylic ester 8d 137 ± 1 prodrugs 8e n.d. 8f 738 ± 16 8g 321 ± 4 8h 1354 ± 66 8i 58.4 ± 1.1 8j n.d. Acyloxymethyl 15a 458 ± 23 prodrugs 15b 58.6 ± 3.5 15c 534 ± 12 15d 73.3 ± 1.2 N-Cbz derivatives 10 n.d. 11 n.d. References Psilocin 1 n.d. 4-HO-MET fumarate 17 116 ± 4 Acetylsalicylic acid n.d.aReference examples. Again, referring to Table 6, while the nature of the acyl residue turned out to have a major influence on the cleavage kinetics, the substitution pattern of the aminoethyl side chain appears less relevant (cf.7a vs.8d, 7b vs.8j, 15b vs.15d). Hence, the relative cleavage kinetics which are observed for the 4-OH-MET prodrugs can be expected to be equally valid for prodrugs that bear other substituents at the sidechain nitrogen. In particular, the 4-OH-MET prodrugs can therefore be considered valid surrogates for the very closely related psilocin. The isobutyrate esters of 4-OH-MET 8d and of psilocin7a were identified as fastest-metabolized prodrug in human plasma within the studied library. The 2-furoyl and in particular the cyclopropanecarboxylic ester analogs of 4-OH-MET 8j and 8e and of psilocin (7b and 7c, respectively) were shown to have slower drug release kinetics. With respect to sublingual administration, the prodrug stability in human whole saliva freshly collected from three caucasian individuals with an initial prodrug concentration of 50 µM has further been tested (Table 6). Due to the large inter-individual differences of salivary esterase activity (cf. e.g., María et al. RSC Adv.2020, 10, 24352), the mean half-lives obtained were used as rough estimates for prodrug stability and classified into three groups (< 15 min / 15-60 min / > 60 min). As expected, acyloxymethyl pro- drugs were metabolized faster in saliva than carboxylic ester prodrugs (8b vs.15d, 8f vs.15c) while, surprisingly, the inverse trend was found in human plasma. Only few prodrugs (7c, 8e, 8f, R3 = cyclopropyl, cyclopropyl, and tert-butyl, respectively) were found to have very high stability in human whole saliva (t1 / 2 > 60 min). With respect to the short duration of the sublingual administration and the excellent permeability of the parent drugs psilocin and 4-HO-MET, prodrugs with average half-lives above 15 min can be regarded as sufficiently stable for sublingual administration. Stability of prodrugs in methanol The stability of the exemplary carboxylic ester 8b in methanol was studied by dissolving a few milligrams of the fumarate ester in CD3OD at ambient temperature and measuring1H NMR spectra in appropriate time intervals. Using the singlet originating from the fumarate anion (6.68 ppm) as an internal reference, the obtained spectra are quantitatively comparable. This analysis revealed that approximately 50 % of the initial amount of ester degraded within 18 days (Scheme 3), exemplifying the lability of carboxylic hydroxytryptamine esters in the presence of nucleophiles.8b.Equilibrium solubility of prodrugs For each reported solubility result, one shake-flask experiment was carried out unless otherwise stated. Measurements at pH 2.0 were performed in 0.01 M HCl. Measure- ments at pH 6.8 were performed in a KH2PO4 / K2HPO4 buffer with an ionic strength of 70 mM. For each experiment, the solid, HPLC-purified sample (1.7 – 25 mg) was sus- pended in 250 – 500 µL of the aqueous buffer in a glass vial. The solution containing solid excess of the sample was then capped and shaken at 220 rpm in an Infors HT Minitron incubator at a defined temperature for 6 hours. Three aliquots (3 x 70 µL) were removed with a fine pipette from each shake-flask experiment, and the saturated solu- tion in these aliquots was separated from precipitate by centrifugation (10000 rpm, 5 min) at the assay temperature. The clear supernatant (50 µL) was decanted, diluted with H2O (+0.1 % TFA) as indicated below, and the concentration of sample in each aliquot was measured by HPLC-UV using calibrations curves (6 – 8 points, R2>0.99). For this, 40 µL of the diluted aliquots were injected into the HPLC system equipped with a ReproSil-Pur 120 ODS-3 column (5 µm, 50 x 2 mm, Dr. Maisch GmbH), eluted with mixtures of ACN and H2O (+0.1 % TFA) and a suitable gradient, and detected at 286 nm (7a, 7b, 7c, 19c) or 244 nm (furosemide). The reported values are the mean of three measured concentrations. The error was estimated based on the standard deviation of the three measurements and the uncertainty of the calibration curve. Re- sults are provided in Table 8. Table 8: Equilibrium solubility of selected prodrugs along with references. Temperature Dilution Equilibrium Solubility Compound pH [°C] Factor [mM] [mg / mL] Furosemidea,b2.0 25 2 (17 ± 4)∙10-3(5.5 ± 1.2)∙10-3Furosemide 2.0 35.5 2 (22 ± 2)∙10-3(7.3 ± 0.8)∙10-37a6.835.5 1000 43.6 ± 1.4 14.5 ± 0.5 7b6.835.5 1000 17.2 ± 0.6 6.1 ± 0.2 7c6.835.5 500 13.6 ± 0.7 4.5 ± 0.2 19c6.835.5 500 32.6 ± 0.8 8.9 ± 0.2aThree independent shake flask experiments performed in parallel, reported values are the mean of 9 concentration measurements.bcf. E. Baka et al. Journal of Pharmaceutical and Biomedical Analysis 2008, 46, 335: (18.7 ± 1.2)∙10-3mg / mL.35.5°C is the mean temperature of the anterior part of the oral cavity (cf. Moore et al. European J. Orthod.1999, 21, 249). pH 6.8 was chosen in accordance with the re- ported mean oral mucosal pH of various parts of the oral cavity (pH 6.78 ± 0.04, cf. Aframian et al. Oral Dis.2006, 12, 420). The salivary pH is maintained by three buffer systems (bicarbonate, phosphate, and protein), and saliva’s ionic strength is up to 70 mM (cf. Macakova et al. Tribology International 2011, 44, 956). Hence, the condi- tions chosen for the solubility assay closely resemble the conditions present during sublingual or buccal administration. Assuming 1.1 mL as saliva volume in the oral cav- ity (cf. Llena-Puy, Med. Oral. Patol. Oral Cir. Bucal.2006, 11(5), E449), the mass of 7a that is soluble in this volume is stoichiometrically equivalent to a psilocybin dose of 13.6 mg which is in the range of clinically studied oral psilocybin doses (cf. Johnson et al., Neurotherapeutics 2017, 14, 734). Considering the treatment setting, it may also be preferable to use multiple, smaller, fast-onset formulation doses in order to titrate the total dosage according to the subjective effects on the patient.Additional experiments / data 1 A: Target compounds: TFA salts, free bases and fumarates (2:1 stoichiometry of tryptamine:fumaric acid) of the following esters with variable R3 according to below Figure 1 were obtained.Figure 3: General structure of psilocin esters with variable R3 Characterization was carried out on the fumarates. As protonation equilibria in solution are rapid, the characterization provided in the following sections 1A–E is expected to be valid for the free bases as well. A unique feature of the cyclopropanoyl ester 7c is its exceptional stability in human saliva and rapid cleavage in human plasma, which renders it a preferable prodrug entity of psilocin for use in pharmaceutical formulations that are applied into the oral cavity and are intended for buccal or sublingual drug de- livery. This stability profile is distinct from esters where R3 = alkyl, aryl. R3= Chemical name Salt form / free Compound ID (Internal) Com- base of fumarate pound ID Cyclo- O-Cyclopropanoyl- Fumarate MY14 7c propyl psilocin JS188 Ethyl O-n-Propionyl- Fumarate MY29 Not as- psilocin signed n-Propyl O-n-Butyrylpsilocin Fumarate MY32 Not as- signed t-Butyl O-Pivaloyl-psilocin Fumarate MY35 Not as- signed Isopro- O-Isobutyryl- Fumarate JS184 7a pyl psilocin 2-Furyl O-(2-Furoyl)- Fumarate JS185 7b psilocin1 B: Characterization: Stability of psilocin esters under forced degradation con- ditions Experimental details are identical to those described hereinabove, with the exception of the commercially obtained PBS buffer (Sigma-Aldrich), which in some of the present set of experiments was observed by us to have a pH of 7.2 (previous set of experi- ments: pH 7.3). In short, compounds (50 μM) were incubated at 80 °C in phosphate-buffered saline (PBS) pH 7.2, samples were cooled upon withdrawal, and stability profiles were deter- mined by a series of HPLC-UV measurements as described in the original application. Conclusion: The cyclopropanoyl ester of psilocin demonstrates higher stability under forced degradation conditions in comparison to structurally closely related esters and is therefore a preferable prodrug entity of psilocin for use in pharmaceutical formula- tions. Chemical name Compound Com- Half-life Remark ID (Internal) pound ID t1 / 2[min] O-Cyclopropanoyl- MY14 7c 178 ± 2 Compound already men- psilocin fumarate JS188 (pH 7.3) tioned above, but no forced degradation data O-Propionylpsilocin MY29 Not as- 28 fumarate signed O-n-Butyrylpsilocin MY32 Not as- 48 fumarate signed O-Pivaloylpsilocin MY35 Not as- 813 fumarate signed O-Isobutyr- JS184 7a 106 ± 1 Compound already men- ylpsilocin fumarate (pH 7.3) tioned above, but no forced degradation data O-(2-Furoyl)- JS185 7b 25.8 ± Compound already men- psilocin fumarate 0.2 (pH tioned above, but no forced 7.3) degradation data 1 C: Characterization: Stability of psilocin esters in human saliva Experimental details are either identical to those described herein above, with the ex- ception that activated instead of resting saliva was used for the comparison of the compounds described below. Activated saliva was obtained as follows. Saliva samples were taken in the morningafter fasting for 10 hours and before breakfast and tooth brushing. Salivation was stim- ulated by chewing of paraffin using a 1.5 g paraffin wax sample (15 pellets) with a melting point of about 49°C. The paraffin was moved from one side of the mouth to the other in order to activate all salivary glands (Kerr, 1961). After chewing for 1 min, whole saliva was collected in test tubes and the saliva was used directly after collection; pre- heating was limited to 1 min at 37°C. Only one sample of activated saliva was with- drawn per day since the salivary esterase activity reportedly declines in subsequent samples. Next, compounds (50 μM) were incubated with freshly obtained, activated human sa- liva of a single person at 37 °C and stability profiles were determined by a series of HPLC-UV measurements. Conclusion: The cyclopropanoyl ester of psilocin surprisingly demonstrates a consid- erably higher stability in human saliva in comparison to structurally closely related es- ters and is therefore a preferable prodrug entity of psilocin for use in pharmaceutical formulations that are applied into the oral cavity and are intended for buccal or sublin- gual drug delivery. Chemical name Compound Compound ID Half-life t1 / 2 [min] ID (Internal) (original applica- tion) O-Cyclopropanoyl- MY14 7c 259 psilocin fumarate JS188 O-Propionylpsilocin MY29 Not assigned 20.6 fumarate O-n-Butyrylpsilocin MY32 Not assigned 6.01 fumarate O-Pivaloylpsilocin MY35 Not assigned no degradation at 330 min. fumarate O-Isobutyryl-psilocin JS184 7a Non-activated saliva: 15 – 60 fumarate minutes (triplicate) Non-activated saliva (same individual as above): 24.0 min. O-(2-Furoyl)-psilocin JS185 7b Non-activated saliva: 15 – 60 fumarate minutes (triplicate) Non-activated saliva (same individual as above): 16.8 minutes1 D: Characterization: Cleavage of psilocin esters in human plasma Experimental details are identical to those described herein above. In short, compounds (50 μM) were incubated with human plasma at 37 °C and stability profiles were determined by a series of HPLC-UV measurements. The concentration of the human plasma in the degradation experiments was varied to account for the differences in stability observed for the compounds. For the pivaloyl ester prodrug (MY35), the human plasma was not diluted before addition of the com- pounds because this compound was shown to be highly stable against hydrolysis in plasma. Compound MY14 / JS188 was measured with plasma concentrations of 10 and 100%. For all other compounds, the plasma was diluted to a final concentration of 10% with phosphate-buffered saline (pH 7.3, Sigma Aldrich). Conclusion: The cyclopropanoyl, propionyl, isobutyryl and n-butyryl esters of psilocin are rapidly cleaved in human plasma to deliver the target drug psilocin. In contrast, the pivaloyl ester of psilocin demonstrates a considerably slower cleavage and is therefore not suitable for prodrug applications like psychedelic treatment sessions where a fast release of the active drug is desired. Chemical name Compound ID Com- Half-life Remarks (Internal) pound ID t1 / 2 [min] O-Cyclopropanoyl- MY14 7c 0.42 ± 100 % plasma, mean psilocin fumarate JS188 0.05 of triplicates 3.73 ± 10 % plasma, mean of 0.04 duplicates O-Propionylpsilocin MY29 Not as- 0.34 10 % plasma, no repli- fumarate signed cates O-n-Butyrylpsilocin MY32 Not as- 0.38 10 % plasma, no repli- fumarate signed cates O-Pivaloylpsilocin MY35 Not as- 111 100 % plasma, no rep- fumarate signed licates O-Isobutyrylpsilocin JS184 7a 0.36 ± 10 % plasma, mean of fumarate 0.02 triplicates (Already described above) O-(2-Furoyl)-psilocin JS185 7b < 0.1 100 % plasma, mean fumarate of triplicates (Already described above for 1 replicate)1 E: Characterization: Retention times on RP-HPLC Background: Retention times of closely related compounds on RP-HPLC can be used as relative indicators of lipophilicity. Since a certain extent of lipophilicity is a prerequi- site for passive membrane permeation, in-vitro measurements of lipophilicity can serve to classify compounds with respect to their expected absorption behavior through bio- logical barriers such as mucous membranes in the oral cavity, the nose, gut or the intestine. In general, a moderate-to-high lipophilicity favors partitioning from aqueous media into biological membranes thus enabling membrane permeation while low lipo- philicity rules out passive permeation across biological barriers. Psilocybin was used as a structurally closely related analog with zwitterionic character, high polarity and low passive membrane permeability ("negative control"). Fumaric acid was used as a highly polar, small-molecular, charged reference compound and furthermore to identify the fumaric acid peak in the experiment with the various psilocin ester fumarates. Acetylsalicylic acid was used as a phenol ester reference compound with known passive membrane permeability ("positive control"). Experimental procedure: In a solvent-resistant 96-well U-bottom polypropylene plate (Greiner Bio-One, Germany), 5 mM stock solutions in DMSO (10 µL) and 10 mM stock solutions in DMSO (5 µL) were diluted with H2O + 0.1% TFA to a final volume of 100 µL. The obtained 500 µM solutions were analyzed on a Jasco HPLC system equipped with a UV detector and a ReproSil-Pur ODS-3 column (5 µm, 50 x 2 mm, Dr. Maisch GmbH) using the following gradient: 1 % B (0.0 min), 1 % B (0.2 min), 100 % B (3.5 min), 100% B (4.5 min), 1 % B (4.6 min), 1 % B (4.9 min). H2O + 0.1% TFA (A) and ACN + 0.1% TFA (B) served as eluents. The flow rate was set to 1.0 mL / min, the wavelength to 286 nm, and the injection volume to 10 µL. Conclusion: The retention times of the highly polar compounds fumaric acid and psilo- cybin (negative control) are considerably lower than that of the positive control acetyl- salicylic acid. The retention times of the reference compounds provide a degree of calibration for the lipophilicity scale, and therefore also for the expected passive mem- brane permeability scale in this experiment. It is obvious that the psilocin esters de- scribed in this invention have a considerably higher lipophilicity, and therefore higher expected passive membrane permeability, than the negative control psilocybin.Chemical name Com- Compound Retention time comment pound ID ID [min] (Internal) (UV monitoring at 286 nm) Fumaric acid - Not as- 0.40 signed Psilocybin JS213 Not as- 0.70 Low permeabil- signed (1–50% ACN gra- ity through intes- dient, broad peak) tinal mucosa.aPsilocin JSX7 1 1.56 Acetyl salicylic acid ASA Reference 1.96 Phenol ester with high peroral bioavailability due to passive membrane per- meation, used as reference compound.bO-n-Propionylpsilocin MY29 Not as- 2.34 fumarate signed O-n-Butyrylpsilocin MY32 Not as- 2.46 fumarate signed O-Cyclopropanoyl- JS188 7c 2.49 psilocin fumarate O-Pivaloylpsilocin MY35 Not as- 2.55 fumarate signed O-Isobutyryl-psilocin JS184 7a 2.55 fumarate O-(2-Furoyl)-psilocin JS185 7b 2.55 fumarateac.f. Eivindvik, K.; Rasmussen, K. E.; Sund, R. B., Handling of Psilocybin and Psilocin by Everted Sacs of Rat Jejunum and Colon. Acta Pharm Nord 1989, 1 (5), 295-302. http: / / europepmc.org / abstract / MED / 2610906bc.f. Nagelschmitz, J.; Blunck, M.; Kraetzschmar, J.; Ludwig, M.; Wensing, G.; Hohl- feld, T., Pharmacokinetics and Pharmacodynamics of Acetylsalicylic Acid after Intra- venous and Oral Administration to Healthy Volunteers. Clinical Pharmacology: Ad- vances and Applications 2014, 6 (null), 51-59.10.2147 / CPAA.S47895 2 A: Suitability of various salt forms of psilocin esters for use as active phar- maceutical ingredients Drug molecules which are organic bases are generally formulated and applied as their salt forms, in which the counterion can be chosen from a wide variety of inorganic and organic acids. The use of salt forms is motivated by their technological and biophar- maceutical properties, such as chemical and physical stability, solubility, hygroscopic- ity, and the counterion can be chosen to modulate these properties in a desired way.In particular, it is technologically preferable to isolate drug molecules at the end of production process in a form that reliably forms suitable crystalline forms which can be separated from liquid phases. Due to the ease of separation from liquid phases, such crystalline forms frequently possess higher purity than semisolid or liquid products. In the later stages of the pharmaceutical production process, it is preferable to handle compounds in a salt form that does not liquify or aggregate into larger particles, in particular upon contact with humidity. Furthermore, the counterion or acid used in salt forms can have an impact on the stability of the active drug molecule, and this is par- ticularly relevant if the drug molecule contains a functional group that is prone to hy- drolytic degradation. In the case of the prodrugs described in this invention, the ester or acyloxymethyl moiety at the phenolic oxygen of the hydroxytryptamines represents such a labile functional group which is highly sensitive towards acid / base catalyzed hydrolytic degradation. It is therefore considered of paramount importance, particularly for the drug class described herein, to evaluate various counterions for salt forms. With a particular view on technological and stability properties, there have been eval- uated the hygroscopicity and stability of various salt forms under controlled humidity conditions as described in the European Pharmacopeia 11.8, chapter 5.11. Salt forms were obtained by reacting solutions of the free bases with the calculated amount of organic and inorganic acids in solution and subsequent evaporation of the liquid phase. Further details are provided in section 3. herein below. The salt forms were then exposed to controlled humidity as described in the Pharm. Eur. v.11. In short, 35 to 55 mg of the salt forms were weighed exactly into inert, open metal containers and exposed to 79 % relative humidity conditions (saturated ammo- nium chloride solution) at 25 °C for 43 hours. The containers were then weighed and the relative mass change was calculated. In most cases, as indicated by the standard deviation provided in the results table, experiments were performed in duplicate and demonstrated good reproducibility. Furthermore, the visual aspects of the material were recorded as indicated under "Further observations". The results (Assessment: preferential profile for pharmaceutical usage) have been cat- egorized as follows: a - highly suitable b - moderately suitablec - restricted suitability d - not suitable Conclusions: In contrast to all other evaluated salt forms, the fumarates of all assessed psilocin ester prodrugs demonstrated a very suitable pharmaceutical profile with re- spect to hygroscopicity, physical character (powder vs. oil / gum) and chemical stability. Particularly remarkable is the low stability of the salt forms of the relatively strong acids (hydrochloric, methanesulfonic) which likely involves chemical degradation by acid- catalyzed hydrolysis and subsequent discoloration by oxidative oligomerization. Chemical name Cmpd. Cmpd. ID Mass Classification Further Assessment: ID (In- change according to observa- preferential ternal) Ph.Eur. tions profile for pharmaceuti- cal usage O-Cyclopropanoyl- JS188 7c 0.17 ± not hygro- free-flow- a psilocin Fumarate 0.04% scopic ing, white MY14 to off- white O-Cyclopropanoyl-MY15Not as- 15.85 ± deliquescent Solid that c psilocin Hydrochlo- signed 1.84% turned ride into an oil, brown O-Cyclopropanoyl-MY16Not as- -2.79 ± not hygro- brown ag- b psilocin Mesylate signed 0.01% scopic gregates (solid) O-Cyclopropanoyl-MY18Not as- 2.03 ± deliquescent oily, d psilocin Hy- signed 0.43% brown drogenmaleate O-Cyclopropanoyl-MY19Not as- 8.10 ± deliquescent Solid that c psilocin monohy- signed 0.37% turned drogencitrate into an oil, brown O-Cyclopropanoyl-MY20Not as- 7.72 ± deliquescent Solid that c psilocin dihy- signed 0.12% turned drogencitrate into an oil, brown O-Cyclopropanoyl-MY21Not as- n.d. deliquescent oily, d psilocin acetate signed brown O-n-PropionylpsilocinMY29Not as- -0.09 ± not hygro- free-flow- a Fumarate signed 0.01% scopic ing, off-Chemical name Cmpd. Cmpd. ID Mass Classification Further Assessment: ID (In- change according to observa- preferential ternal) Ph.Eur. tions profile for pharmaceuti- cal usage white O-n-ButyrylpsilocinMY32Not as- -0.08 ± not hygro- free-flow- a Fumarate signed 0.02% scopic ing, off- white O-PivaloylpsilocinMY35Not as- 8.48 ± hygroscopic free-flow- b Fumarate signed 0.46% ing, off- white 3. Synthetic procedures and analytical data for the target compounds and their intermediates (TFA salts, free bases, fumarates): Experimental Section General Procedure 1 (GP1): Esterification of Psilocin Under inert atmosphere, psilocin (1.00 eq) was dissolved in anhydrous THF (0.5 M with respect to psilocin). Subsequently, the respective acid chloride was added. The resulting suspension was stirred until the starting material was completely consumed according to TLC. Unreacted starting material was visualized by staining with FeCl3 solution. Upon completion, volatiles were removed by rotary evaporation, and the ob- tained crude was purified by means of reversed-phase chromatography. The collected product fractions were concentrated by rotary evaporation and lyophilized. The obtained residue was partitioned twice between ethyl acetate and carbonate buffer (0.1 M, pH 10.6). The combined organic phases were washed with carbonate buffer three times and evaporated, which yielded the free base of the respective psilocin ester.4-n-Propionyloxy-N,N-dimethyltryptamine (MY28)Psilocin (301 mg, 1.47 mmol, 1.00 eq) was reacted with propionyl chloride (164 µl, 170 mg, 1.84 mmol, 1.25 eq) for 1 h and subsequently converted into the free base by alkaline extraction as described in GP1. MY28 (347 mg, 1.33 mmol, 90 %) was obtained as a colorless oil.1H NMR (300 MHz, (CD3)2SO): δ 10.37 – 10.25 (s, 1H), 7.26 (dd, J = 8.2 Hz, J’ = 0.9 Hz, 1H), 7.13 – 7.03 (m, 2H), 6.77 (dd, J = 7.6 Hz, J’ = 0.9 Hz, 1H), 2.98 – 2.89 (m, 2H), 2.74 (q, J = 7.5 Hz, 2H), 2.62 – 2.54 (m, 2H), 2.29 (s, 6H), 1.27 (t, J = 7.5 Hz, 3H) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C15H21N2O2]+: 261.1598, found 261.1601. 4-n-Butyryloxy-N,N-dimethyltryptamine (MY31) Psilocin (281 mg, 1.38 mmol,reacted with butyryl chloride (182 µl, 183 mg, 1.72 mmol, 1.25 eq) for 1 h, purified by RP chromatography (25 g C-18, H2O / ACN +0.1% TFA (v / v) 100 / 0 – 80 / 20) and subsequently converted into the free base by alkaline extraction. For quantitative removal of the trifluoroacetate coun- terion, the extraction procedure described in GP1 was carried out twice. MY31 (288 mg, 1.05 mmol, 76 %) was obtained as a yellow oil.1H NMR (500 MHz, (CD3)2SO): δ 10.38 (s, J = 8.6 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.13 – 7.04 (m, 2H), 6.77 (d, J = 7.7 Hz, 1H), 2.98 – 2.91 (m, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.62 – 2.57 (m, 2H), 2.30 (s, J = 2.0 Hz, 6H), 1.81 (sext, J = 7.4 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C16H23N2O2]+: 275.1754, found 275.1753.4-Pivaloyloxy-N,N-dimethyltryptamine (MY34) Psilocin (287 mg, 1.40 mmol,reacted with pivaloyl chloride (219 µl, 212 mg, 1.76 mmol, 1.25 eq) for 1 h. Then, triethylamine (195 µL, 142 mg, 1.40 mmol, 1.00 eq) and pivaloyl chloride (175 µL, 169 mg, 1.41 mmol, 1.00 eq) were added, and stirring at ambient temperature was continued for 1 h. Purification by RP chromatography (25 g C-18, H2O / ACN +0.1% TFA (v / v) 100 / 0 – 80 / 20) and subse- quent conversion into the free base by alkaline extraction as described in GP1 yielded MY34 (259 mg, 898 µmol, 51 %) as a colorless solid.1H NMR (300 MHz, (CD3)2SO): δ 10.19 (s, 1H), 7.24 (dd, J = 8.2 Hz, J’ = 0.9 Hz, 1H), 7.11 (dt, J = 2.2 Hz, J’ = 1.0 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.65 (dd, J = 7.6 Hz, J’ = 0.9 Hz, 1H), 2.98 – 2.85 (m, 2H), 2.60 – 2.50 (m, 2H), 2.25 (s, 6H), 1.45 (s, 9H) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C17H25N2O2]+: 289.1911, found 289.1912. General Procedure 2: Synthesis of Fumarates The free base psilocin ester (1.00 eq) was dissolved in acetone (at least 132 mM with respect to the tryptamine), mixed with a solution of fumaric acid (0.50 eq) in acetone (at least 46 mM with respect to fumaric acid), and allowed to stand at 5 °C for at least 1.5 h. Finally, the suspension was centrifuged (3,500 RCF, 5 min), the supernatant de- canted, and the solids washed twice with cold acetone (5 °C), taken up in distilled water and lyophilized. If required, residual traces of acetone were removed by heating to 40 °C for 22 h. 4-n-Propyloxy-N,N-dimethyltryptammonium fumarate (MY29)Reaction of MY28 (130 mg, 499 μmol, 1.00 eq) with fumaric acid (29.0 mg, 250 µmol, 0.50 eq) according to GP2 yielded MY29 (149 mg, 397 μmol, 80 %) as a colorless solid.1H NMR (500 MHz, (CD3)2SO): δ = 11.09 (s, 1H), 7.23 (dd, J = 8.2 Hz, J = 0.8 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.67 (dd, J = 7.7 Hz, J = 0.8 Hz, 1H), 6.51 (s, 1H), 2.87 – 2.81 (m, 2H), 2.74 – 2.67 (m, 4H), 2.38 (s, 6H), 1.18 (t, J = 7.5 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 172.9 (Cq, 1C), 167.5 (Cq, 1C), 143.6 (Cq, 1C), 138.5 (Cq, 1C), 134.8 (CH, 1C), 123.6 (CH, 1C), 121.0 (CH, 1C), 119.5 (Cq, 1C), 111.5 (CH, 1C), 110.2 (Cq, 1C), 109.3 (CH, 1C), 59.6 (CH2, 1C), 44.1 (CH3, 2C), 26.9 (CH2, 1C), 23.3 (CH2, 1C), 8.84 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C15H21N2O2]+: 261.1598, found 261.1600. 4-n-Butyryloxy-N,N-dimethyltryptammonium fumarate (MY32) Reaction of MY31 (130 mg,acid (27.5 mg, 237 µmol, 0.50 eq) according to GP2 yielded MY32 (139 mg, 358 μmol, 76 %) as a colorless solid.1H NMR (500 MHz, (CD3)2SO): δ = 11.10 (s, 1H), 7.24 (dd, J = 8.1 Hz, J = 0.8 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.66 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 6.51 (s, 1H), 2.88 – 2.83 (m, 2H), 2.72 (dd, J = 9.4 Hz, J = 6.5 Hz, 2H), 2.67 (t, J = 7.3 Hz, 2H), 2.38 (s, 6H), 1.70 (sext, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 172.0 (Cq, 1C), 167.6 (Cq, 1C), 143.5 (Cq, 1C), 138.5 (Cq, 1C), 134.8 (CH, 1C), 123.6 (CH, 1C), 121.0 (CH, 1C), 119.5 (Cq, 1C), 111.5 (CH, 1C), 110.2 (Cq, 1C), 109.3 (CH, 1C), 59.5 (CH2, 1C), 44.1 (CH3, 1C), 35.2 (CH2, 1C), 23.3 (CH2, 1C), 17.8 (CH2, 1C), 13.4 (CH3, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C16H23N2O2]+: 275.1754, found 275.1755.4-Pivaloyloxy-N,N-dimethyltryptammonium fumarate (MY35) Reaction of MY34 (150 mg,acid (30.2 mg, 260 µmol, 0.50 eq) according to GP2 yielded MY35 (169 mg, 420 μmol, 81 %) as a colorless solid.1H NMR (500 MHz, (CD3)2SO): δ = 11.08 (s, 1H), 7.23 (dd, J = 8.1 Hz, J = 0.8 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.57 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 6.52 (s, 1H), 2.84 (dd, J = 9.0 Hz, J = 6.6 Hz, 2H), 2.69 (dd, J = 9.1 Hz, J = 6.6 Hz, 2H), 2.32 (s, 6H), 1.37 (s, 9H) ppm.13C NMR (126 MHz, (CD3)2SO): δ = 176.9 (Cq, 1C), 167.1 (Cq, 1C), 144.2 (Cq, 1C), 138.5 (Cq, 1C), 134.6 (CH, 1C), 123.1 (CH, 1C), 121.0 (CH, 1C), 119.7 (Cq, 1C), 111.1 (CH, 1C), 110.5 (Cq, 1C), 109.2 (CH, 1C), 59.3 (CH2, 1C), 44.4 (CH3, 2C), 38.7 (Cq, 1C), 26.9 (CH3, 3C), 23.6 (CH2, 1C) ppm. HR MS (ESI+): m / z [M+H]+calcd. for [C17H25N2O2]+: 289.1911, found 289.1909. General Procedure 3 (GP3): Synthesis of Pharmaceutically Acceptable Salt Forms Derived from 4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptamine 4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptamine JS187 (1.00 eq) was dissolved in acetone (146 mM with respect to the tryptamine), added to a solution of the respec- tive acid, and allowed to stand at 5 °C overnight. In case of precipitate formation (GP3- A), the suspension was centrifuged (3,500 RCF, 5 min), the supernatant decanted, and the solids washed twice with cold acetone (5 °C), taken up in distilled water and lyophilized. Otherwise (GP3-B), volatiles were removed in vacuo and the residue ly- ophilized.4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptamine Hydrochloride (MY15)Reaction of JS187 (140 mg, 514 μmol, 1.00 eq) with 0.1 M aqueous hydrochloric acid (5.14 mL, 514 µmol, 1.00 eq) according to GP3-B yielded MY15 (120 mg, 389 μmol, 76 %) as a reddish solid.1H NMR (300 MHz, (CD3)2SO): δ 11.35 (s, J = 2.6 Hz, 1H), 11.00 (s, 1H), 7.34 – 7.20 (m, 2H), 7.06 (t, J = 7.9 Hz, 1H), 6.71 (dd, J = 7.7 Hz, J’ = 0.8 Hz, 1H), 3.35 – 3.26 (m, 2H), 3.11 (dd, J = 10.0 Hz, J’ = 6.2 Hz, 2H), 2.83 – 2.76 (m, 6H), 2.11 (ddd, J = 11.4 Hz, J’ = 5.3 Hz, J’’ = 3.2 Hz, 1H), 1.08 (ddd, J = 8.9 Hz, J’ = 4.9 Hz, J’’ = 2.3 Hz, 4H) ppm. 4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptammonium Mesylate (MY16)Reaction of JS187 (140 mg, 514 μmol, 1.00 eq) with a solution of methanesulfonic acid (33.4 µL, 49.4 mg, 514 µmol, 1.00 eq) in acetone (5.0 mL) according to GP3-B yielded MY16 (191 mg, 518 μmol, 101 %) as a yellowish solid.1H NMR (300 MHz, (CD3)2SO): δ 11.32 – 11.17 (m, 1H), 9.49 (s, 1H), 7.34 – 7.22 (m, 2H), 7.07 (t, J = 7.9 Hz, 1H), 6.72 (dd, J = 7.7 Hz, J’ = 0.8 Hz, 1H), 3.37 (dt, J = 8.9 Hz, J’ = 5.9 Hz, 2H), 3.05 (dd, J = 9.5 Hz, J’ = 6.5 Hz, 2H), 2.86 (d, J = 4.8 Hz, 6H), 2.38 (d, J = 2.5 Hz, 3H), 2.08 (tt, J = 7.6 Hz, J’ = 4.7 Hz, 1H), 1.15 – 1.02 (m, 4H) ppm.4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptammonium Hydrogenmaleate (MY18)Reaction of JS187 (140 mg, 514 μmol, 1.00 eq) with a solution of maleic acid (59.7 mg, 514 µmol, 1.00 eq) in acetone (5.0 mL) according to GP3-B yielded MY18 (195 mg, 503 μmol, 98 %) as a hygroscopic yellowish solid.1H NMR (300 MHz, (CD3)2SO): δ 11.34 – 11.20 (1, 1H), 7.34 – 7.21 (m, 2H), 7.08 (t, J = 7.9 Hz, 1H), 6.73 (dd, J = 7.6 Hz, J’ = 0.8 Hz, 1H), 6.07 (d, J = 1.4 Hz, 2H), 3.38 (dd, J = 9.3 Hz, J’ = 6.5 Hz, 2H), 3.04 (dd, J = 9.1 Hz, J’ = 6.7 Hz, 2H), 2.86 (s, 6H), 2.07 (tt, J = 7.5 Hz, J’ = 4.9 Hz, 1H), 1.16 – 0.99 (m, 4H) ppm. 4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptammonium Hydrogencitrate (MY19)Reaction of JS187 (140 mg, 514 μmol, 1.00 eq) with a solution of citric acid monohy- drate (54.0 mg, 257 µmol, 0.50 eq) in acetone (2.5 mL) according to GP3-A yielded MY19 (150 mg, 204 μmol, 79 %) as a hygroscopic yellowish solid.1H NMR (300 MHz, (CD3)2SO): δ 11.15 (s, 1H), 7.30 – 7.17 (m, 2H), 7.05 (t, J = 7.9 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 3.03 – 2.87 (m, 4H), 2.58 (s, J = 1.6 Hz, 6H), 2.55 (d, J = 1.3 Hz, 1H), 2.51 (s, 1H), 2.08 (s, 1H), 2.02 (dq, J = 7.7 Hz, J’ = 4.8 Hz, J’’ = 3.9 Hz, 1H), 1.06 (ddd, J = 8.0 Hz, J’ = 6.4 Hz, J’’ = 2.7 Hz, 4H) ppm.4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptammonium Dihydrogencitrate (MY20)Reaction of JS187 (140 mg, 514 μmol, 1.00 eq) with a solution of citric acid monohy- drate (108.0 mg, 514 µmol, 1.00 eq) in acetone (3.5 mL) according to GP3-A yielded MY20 (131.8 mg, 284 μmol, 55 %) as a hygroscopic yellowish solid.1H NMR (300 MHz, (CD3)2SO): δ 11.16 (s, 1H), 7.32 – 7.18 (m, 2H), 7.05 (t, J = 7.9 Hz, 1H), 6.69 (dd, J = 7.6 Hz, J’ = 0.9 Hz, 1H), 3.13 – 2.88 (m, 4H), 2.63 (d, J = 3.7 Hz, 6H), 2.55 (d, J = 1.3 Hz, 1H), 2.08 (s, 1H), 2.07 – 1.98 (m, 1H), 1.14 – 1.01 (m, 4H) ppm. 4-(Cyclopropanecarbonyloxy)-N,N-dimethyltryptammonium Acetate (MY21)Reaction of JS187 (140 mg, 514 μmol, 1.00 eq) with a solution of acetic acid (30.9 mg, 514 µmol, 1.00 eq) in acetone (5.0 mL) according to GP3-B yielded MY21 (168 mg, 505 μmol, 98 %) as a hygroscopic yellowish solid.1H NMR (300 MHz, (CD3)2SO): δ 11.02 (s, 1H), 7.22 (dt, J = 8.1 Hz, J’ = 0.9 Hz, 1H), 7.15 – 7.12 (m, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.64 (dd, J = 7.6 Hz, J’ = 0.9 Hz, 1H), 2.79 (dd, J = 9.2 Hz, J’ = 6.6 Hz, 2H), 2.54 – 2.46 (m, 2H), 2.22 (s, J = 0.9 Hz, 6H), 2.02 – 1.93 (m, 1H), 1.90 (s, J = 0.9 Hz, 3H), 1.12 – 1.00 (m, 4H) ppm. 4. Passive permeation under mimicked sublingual conditions (PermeaPad) Experimental Procedure: The PermeaPad plate system (PHABIOC GmbH, Ger- many) is a validated model for buccal absorption and features a barrier consisting of two cellulose layers that envelop a layer of lipids. The passive membrane permeability under buccal conditions was evaluated following the guidelines of the manufacturerand a previous literature report (Jacobsen, A.-C.; Nielsen, S.; Brandl, M.; Bauer-Brandl, A., Drug Permeability Profiling Using the Novel Permeapad® 96-Well Plate. Pharm. Res. 2020, 37 (6), 93. 10.1007 / s11095-020-02807-x). Phosphate-buffered saline (PBS) with physiological osmolality adjusted to pH 6.5 (donor wells) and pH 7.4 (ac- ceptor wells) using conc. HCl was used for all experiments (Sena, A.; Costa, A.; Bastos, F.; Pinto, A. C.; Vitorino, C.; Nunes, A.; Simões, S., Development of a Buccal in Vitro Permeation Method – Exploring Aqbd Implementation. Int. J. Pharm. 2023, 643, 123255). Analyte concentrations were determined on a Jasco HPLC system equipped with a UV detector and an RP-18 column (Chromolith® Performance RP-18e, 100x4.6 mm) using one of the gradients listed in the following table. H2O + 0.1% TFA (A) and ACN + 0.1% TFA (B) served as eluents except for the phosphate esters JS173 and JS213 where H2O + 0.14% conc. H3PO4 (A) and MeOH + 0.14% conc. H3PO4 (B) were used. For all samples, the injection volume was 40 µL. UV detection was per- formed at 286 nm except for calcein (495 nm), carbamazepin (300 nm), metoprolol tartrate (274 nm), hydrocortisone (248 nm), and acetyl salicylic acid (228 nm). Table: Routinely used gradient settings for analytical HPLC runs: Flow Gradient 1 % B (0.2 min), 100 % B (7.0 min), 100 % B (8.0 min), 1.0 mL / min 1 % B (8.1 min), 1 % B (10.0 min) 1 % B (0.2 min), 50 % B (7.0 min), 50 % B (8.0 min), 1.0 mL / min 1 % B (8.1 min), 1 % B (10.0 min) 400 μL of the 200 μM compound solutions in PBS pH 6.5 (4 % dimethyl sulfoxide (DMSO)) were dispensed in triplicate into the donor wells, and the bottom plate was covered with the screen plate. Each acceptor well was then charged with 200 μL of PBS pH 7.4, and the setup was sealed with adhesive foil and incubated at 25 °C. After 60 min of incubation, 100 µL samples for quantitative HPLC analysis were taken from the top (acceptor) wells and replaced with fresh PBS pH 7.4. Another 180 min of incu- bation later, donor and acceptor plate were separated. The wells were homogeneously mixed with a pipette, and a 100 µL sample of each donor and acceptor well was trans- ferred to 96 well U-bottom polypropylene plates (Greiner Bio-One, Germany) for quan- titative HPLC analysis.Six-point calibration curves (10, 25, 50, 100, 150, and 200 μM) were generated for all permeating compounds and references with correlation coefficients (R2) being at least 0.99. After analyte quantification, permeability (Pe) and mass retention (R) were calcu- lated as described in the literature mentioned above. The apparent permeability of a given compound was calculated as the mean ± standard deviation (SD) of the individ- ual replicate’s apparent permeability. The experiment was validated based on the ob- tained permeability ranking of the reference compounds. Conclusion: The passive membrane permeability of psilocin prodrugs is highly depend- ent on the pH value of the donor and acceptor compartments. Even at a relatively low donor pH of 6.5, which promotes protonation of the psilocin analogs and thereby im- pedes their passive permeability, the passive permeability of the novel prodrugs de- scribed herein generally surpasses that of psilocybin. JS188 / JS187 = 7c / 19c (cyclo- propanoyl-psilocin free base and fumarate) display the highest passive permeability of the prodrugs studied. At pH 7.4 in both compartments, resembling physiological con- ditions, JS187 / 19c is highly membrane-permeable as judged by comparison with the benchmark hydrocortisone. Chemical name Compound Compound Pe[10-6cm / s] R [%] ID (Inter- ID nal) see above JS184 7a 4.5 ± 0.3 2 see above JS185 7b 3.9 ± 0.2 3 see above JS188 7c 4.6 ± 0.2 5 see above JS187 19c 5.0 ± 0.2 -1 see above JS187 19c 9.1 ± 0.2 1 pH 7.4 in both com- pH 7.4 in both partments compartments see above JS057 8a 3.7 ± 0.6 5 see above JSRL088 8b 3.4 ± 0.5 12 see above JS066 8c 3.4 ± 0.4 10 see above JSRL089 8d 4.7 ± 0.4 -12 see above JS183 8e 4.4 ± 0.1 4 see above JSRL087 8f 3.3 ± 0.3 12Chemical name Compound Compound Pe [10-6cm / s] R [%] ID (Inter- ID nal) see above JSRL090 8g 3.8 ± 0.4 7 see above JS064 8h 3.8 ± 0.1 5 see above JS047 8i 4.5 ± 0.3 10 see above MY05 8j 3.4 ± 0.8 12 see above JS116 15a 3.6 ± 0.3 9 see above JS157 15b 3.3 ± 0.2 14 see above JS101 15c 2.7 ± 0.3 7 see above JS113 15d 3.3 ± 0.07 11 Calcein - Reference No permeation de- tected. Psilocybin JS213 Reference 2.7 ± 0.7 -5 4-Phosphory- JS173 Reference 2.14 ± 0.4 -6 loxy-N-ethyl-N- methyltrypta- mine Psilocin JSX7 1 4.4 ± 1.1 5 4-OH-MET JS056 17 4.1 ± 0.4 16 fumarate Hydrocortisone - Reference 7.0 ± 0.3 3 Metoprolol Tar- - Reference 4.4 ± 0.3 2 trate Caffeine - Reference 13.6 ± 0.4 6 Carbamazepin - Reference 8.7 ± 0.6 105: Stability under forced degradation conditions Experimental procedure: Already described hereinabove Chemical name Compound Compound ID Half-life t1 / 2 [min] in PBS, 80°C ID (Internal) [prodrug]0 = 50 µM O-Isobutyryl- JS184 7a 106 ± 1 psilocin fumarate O-(2-Furoyl)- JS185 7b 25.8 ± 0.2 psilocin fumarate O-Cyclopropa- JS188 7c 178 ± 2 noyl-psilocin fumarate O-Cyclopropa- JS183 8e 209 ± 1 noyl-4-Hydroxy-N- ethyl-N-methyl- tryptamine fumarate O-(2-Furoyl)-4- MY05 8j 29.0 ± 0.4 Hydroxy-N-ethyl- N-methyltrypta- mine fumarate c.f. application JS105 10 184 ± 5 c.f. application JS086 11 136 ± 4 Acetylsalicylic - Reference 27.9 ± 0.3 acid6: Stability in plasma and saliva Experimental procedure: Already described above for resting saliva; activated saliva: see above. Chemical name Cpd IDCpd IDHalf-life t1 / 2[min] at 37°C and (Internal) [prodrug]0 = 50 µM in Human 10% human 100% human saliva plasma plasma O-Cyclopropa- JS188 7c Activated 3.73 ± 0.04, 0.42 ± 0.05, noyl-psilocin saliva: mean of dupli- mean of tripli- fumarate cates cates > 60 c.f. application JSRL090 8g > 60 No new data 3.56 ± 0.04, mean of tripli- cates c.f. application JS064 8h No new No new data > 300, no data replicates 7: Additional NMR spectroscopic data Compound 15b1H NMR (CD3OD, 500 MHz): δ = 7.08 (s, 1H), 7.01-7.07 (m, 2H), 6.72 (dd, J = 6.1 Hz, J’ = 2.3 Hz, 1H), 6.68 (s, 1H), 5.95 (s, 2H), 3.33-3.39 (m, 2H), 3.19-3.26 (m, 2H), 2.93 (s, 6H), 2.36 (t, J = 7.3 Hz, 2H), 1.62 (sxt, J = 7.3 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H) ppm.13C{1H} NMR (126 MHz, CD3OD): δ = 174.7 (Cq, 1C), 173.2 (Cq, 1C), 151.5 (Cq, 1C), 140.5 (Cq, 1C), 136.7 (CH, 1C), 124.2 (CH, 1C), 123.4 (CH, 1C), 118.4 (Cq,1C), 109.8 (Cq, 1C), 107.6 (CH, 1C), 102.6 (CH, 1C), 85.5 (CH2, 1C), 60.7 (CH2, 1C), 43.7 (CH3, 2C), 36.9 (CH2, 1C), 23.7 (CH2, 1C), 19.3 (CH2, 1C), 13.8 (CH3, 1C) ppm.1H NMR (300 MHz, CD3CN): δ = 9.27 (br s, 1H), 6.98-7.12 (m, 3H), 6.69 (dd, J = 7.2 Hz, J’ = 1.3 Hz, 1H), 6.61 (s, 1H), 5.90 (s, 2H), 3.06-3.18 (m, 2H), 2.97-3.06 (m, 2H), 2.63 (s, 6H), 2.33 (t, J = 7.3 Hz, 2H), 1.59 (sxt, J = 7.4 Hz, 2H), 0.87 (t, J = 7.5 Hz, 3H) ppm.

Claims

Claims 1. Prodrug having the following formula (1) or salts thereof,(1), wherein R1 and R2 can be the same or different from each other and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neo- pentyl, and phenyl residues; wherein, in the salts of formula (1), the product of said formula (1) is protonated.

2. Prodrug according to claim 1, wherein an anion of the salts of formula (1) is se- lected from the group consisting of acetate, propionate, butyrate, malonate, maleate, succinate, fumarate, levulinate, and mesylate, particularly mesylate and fumarate, more particularly fumarate.

3. Prodrug according to claim 1 or 2, wherein R1 and R2 are selected from methyl and ethyl residues, particularly where R1 and R2 are a methyl residue.

4. Prodrug fumarate salt having the following formula (2)wherein R3s seece rom e group conss ng o e y, sopropy, n-propyl, isobutyl, tert-butyl, neopentyl, phenyl, and 2-furyl residues; and, R1 and R2 can be the same or different from each other and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neo- pentyl, and phenyl residues.

5. Prodrug according to claim 4, wherein R1 and R2 are selected from methyl and ethyl residues, particularly where R1 and R2 are a methyl residue.

6. Prodrug according to any one of claims 1 to 5, having a passive membrane per- meability Pe of at least 6 × 10-6cm / s.

7. Prodrug according to any one of claims 1 to 6, having a half-life period of at least 15 min in human saliva at 37 °C.

8. Prodrug for use in the treatment of psychiatric and / or neurological disorders, the prodrug being as defined in any one of claims 1 to 7.

9. Prodrug for use in the treatment of psychiatric and / or neurological disorders ac- cording to claim 8, wherein the psychiatric and / or neurological disorder is one of de- pression, post-traumatic stress disorder, substance use disorder, anorexia nervosa, and neurodegenerative diseases, particularly Alzheimer's disease.

10. Prodrug for use in the treatment of psychiatric and / or neurological disorders ac- cording to claim 8 or 9, wherein the prodrug administration is buccal, sublingual, inha- latory, intranasal, and / or transdermal.

11. Prodrug for use in the treatment of psychiatric and / or neurological disorders ac- cording to any one of claims 8 to 10, wherein the treatment includes psychedelic ther- apy.

12. Prodrug having the following formula (3) or salts thereof,wherein R6 is selected from the group consisting of cyclopropyl, isopropyl, n-propyl, isobutyl, tert-butyl, neopentyl, phenyl, and 2-furyl residues; and, provided that R6 is selected from the group consisting of isopropyl and 2-furyl residues, R4 and R5 are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl residues and combinations thereof; and, provided that R6 is selected from the group consisting of n-propyl, cyclopropyl, isobutyl, tert-butyl, neopentyl, and phenyl residues, R4 and R5 are not the same and are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl residues; and wherein, in the salts of formula (3), the product of said formula (3) is protonated.

13. Prodrug according to claim 12, wherein an anion of the salts of formula (1) is selected from the group consisting of acetate, propionate, butyrate, malonate, maleate, succinate, fumarate, levulinate, and mesylate, particularly mesylate and fumarate, more particularly fumarate.

14. Prodrug for use in the treatment of psychiatric and / or neurological disorders, the prodrug being as defined in claim 12 or 13.

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