C4-Carbonothioate Substituted Tryptamine Derivatives and Methods of Use Related Applications

Abstract

Disclosed are novel C4-carbonothioate substituted tryptamine derivative compounds, as well as pharmaceutical and recreational drug formulations containing the same. The pharmaceutical formulations can be used to treat cranial nerve disorders.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 321,440, filed March 18, 2022, and U.S. Provisional Patent Application No. 63 / 347,835, filed June 1, 2022. The entire disclosures of U.S. Provisional Patent Application Nos. 63 / 321,440 and 63 / 347,835 are incorporated herein by reference.

[0002] The compositions and methods disclosed herein relate to a class of compounds known as tryptamines. Additionally, the compositions and methods disclosed herein relate to C4-substituted tryptamine derivatives, and in particular, C4-carbonothioate substituted tryptamine derivatives. [Background technology]

[0003] The following paragraphs are provided to explain the background of the present disclosure, but are not an admission that any of the matter discussed therein is prior art or part of the knowledge of those skilled in the art.

[0004] Tryptamines are a class of compounds that share a common chemical structure (specifically, a fused benzene and pyrrole ring, both known as indole, linked to the pyrrole ring at its third carbon atom, a 2-aminoethyl group) and can be formulated as therapeutic drug compounds. For example, psilocybin is being evaluated for its clinical potential as a drug in the treatment of mental health conditions (Daniel, J. et al., Mental Health Clin., 2017;7(1):24-28), including treating anxiety in terminal cancer patients (Grob, C. et al., Arch. Gen. Psychiatry, 2011, 68(1)71-78) and alleviating symptoms of treatment-resistant depression (Cathart-Harris, RL et al., Lancet Psychiatry, 2016, 3:619-627). Other known pharmaceutical compounds within the tryptamine class of compounds include, for example, melatonin, serotonin, bufotenin, dimethyltryptamine (DMT), and psilocin.

[0005] It is generally understood that tryptamine-based drugs can exert their in vivo therapeutic effects by molecular interaction with macromolecules present in human cells, known as receptors. In this regard, it can be considered, broadly speaking, that specific receptors are localized in relatively fixed anatomical spaces (e.g., specific brain tissues). After drug administration, the drug travels through the body to the receptor, interacts with it, and then exits the body. When a tryptamine-based drug is administered, it is generally desirable that the drug be specifically active in a desired anatomical location within the patient's body (e.g., specific brain tissues and / or specific receptors, such as 5-hydroxytryptamine (5-HT) receptors). Furthermore, it is generally desirable that the specific molecular interaction between the drug and the receptor (such as 5-HT receptor) is such that the drug-receptor molecular interaction results in the appropriate modulation of the target receptor.

[0006] In many cases, the observed pharmacological effects of tryptamine-based drugs are less than optimal, i.e., administration of the drug does not achieve the desired therapeutic effect (e.g., successful treatment of a psychotic disorder) and / or undesirable side effects may be observed.

[0007] The root causes of these shortcomings observed in pharmacological effects may be diverse. For example, the administered drug may also interact with other receptors than its target receptor; and / or the specific molecular interaction between the drug and the target may not cause the desired receptor modulation; and / or the drug concentration at the receptor may be lower than optimal. In this respect, it can be said that known tryptamine-based drugs often exhibit less than optimal pharmacodynamic (PD) properties, i.e., properties that are less than optimal with respect to the pharmacological effect that the drug has on the body. Thus, for example, the efficacy of the drug, the drug concentration at the receptor location, and the molecular interaction between the drug and the receptor may not be as desired.

[0008] Furthermore, as with many pharmaceutical compounds, tryptamine compounds can penetrate various tissues by diffusion when administered, resulting in a wide distribution of the drug compound in the body (Bodor, N. et al., 2001, J. Pharmacy and Pharmacology, 53:889-894). Thus, often a large portion of the administered drug does not reach the desired target receptor. This in turn may require more frequent drug administration. Such frequent administration is less convenient for patients and may negatively affect patient compliance with prescribed drug therapy. Furthermore, toxicity generally associated with drug formulations tends to be more problematic as a result of the wide distribution of the drug throughout the patient's body, because undesirable side effects may develop as a result of the drug's interaction with healthy organs.

[0009] Furthermore, it is generally desirable for a drug compound to exert its pharmacological effect for an adequate period of time. However, tryptamine-based drugs can exhibit high blood plasma clearance (typically on the order of minutes) when administered systemically to a patient (Vitale, A. et al., 2011, J. of Nucl.Med, 52(6), 970-977). Thus, rapid drug clearance can require frequent administration of tryptamine-based drug formulations. In this regard, it can be said that known tryptamine-containing drugs often exhibit less than optimal pharmacokinetic (PK) properties, i.e., less than optimal properties with respect to the movement of the drug in the body to and from the desired anatomical site (e.g., including less than optimal drug absorption, distribution, metabolism, and excretion).

[0010] Thus, there is a need in the art for improved tryptamine compounds. Summary of the Invention

[0011] The following paragraphs are intended to provide the reader with a more detailed explanation, but are not intended to define or limit the claimed subject matter of the present disclosure.

[0012] In one aspect, the present disclosure relates to tryptamines and derivative compounds thereof.

[0013] In another aspect, the present disclosure relates to C4-substituted tryptamine derivative compounds.

[0014] In another aspect, the present disclosure relates to C4-carbonothioate substituted tryptamine derivative compounds.

[0015] Thus, in one aspect, the present disclosure provides, in at least one embodiment, a compound according to the present disclosure, comprising a compound of formula (I): [ka] providing a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and Here, R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0016] In at least one embodiment, in one aspect, the carbonothioate moiety or derivative thereof has the formula (III): [ka] may have; Here, R 4b is an alkyl group, a cycloalkyl group, or an aryl group, each of which is optionally substituted.

[0017] In at least one embodiment, in one aspect, the carbonothioate moiety or derivative thereof has the formula (IV): [ka] may have; Here, R 4c is an alkyl group, a cycloalkyl group, or an aryl group, each of which is optionally substituted.

[0018] In at least one embodiment, in one aspect, R 4b can be a C1-C6 alkyl optionally substituted with a halogen atom, an alkyl group, a cycloalkyl group, or an aryl group.

[0019] In at least one embodiment, in one aspect, R 4b can be a C1-C3 alkyl optionally substituted with a halogen atom, an alkyl group, a cycloalkyl group, or an aryl group.

[0020] In at least one embodiment, in one aspect, the aryl group can be a phenyl group.

[0021] In at least one embodiment, in one aspect, R 4b can be methyl, ethyl, isopropyl, butyl, -CH2-cyclopropyl, -CH(CH3)-cyclopropyl, -C(CH3)2-cyclopropyl or -CH2-phenyl.

[0022] In at least one embodiment, in one aspect, R 4b can be an aryl group.

[0023] In at least one embodiment, in one aspect, the aryl group can be a phenyl group.

[0024] In at least one embodiment, in one aspect, R 4b can be a C1-C6 alkyl optionally substituted with a halogen atom, an alkyl group, a cycloalkyl group, or an aryl group; and wherein one or more of the carbon atoms in the C1-C6 alkyl group are optionally substituted with an oxygen (O) atom.

[0025] In at least one embodiment, in one aspect, R 4c can be a C1-C6 alkyl optionally substituted with a halogen atom, an alkyl group, a cycloalkyl group, or an aryl group.

[0026] In at least one embodiment, in one aspect, the aryl group can be a phenyl group.

[0027] In at least one embodiment, in one aspect, R 4c can be methyl, ethyl, isopropyl, butyl, -CH2-cyclopropyl, -CH(CH3)-cyclopropyl, -C(CH3)2-cyclopropyl or -CH2-phenyl.

[0028] In at least one embodiment, in one aspect, R 4c can be an aryl group.

[0029] In at least one embodiment, in one aspect, the aryl group can be a phenyl group.

[0030] In at least one embodiment, in one aspect, R 4c can be a C1-C6 alkyl optionally substituted with a halogen atom, an alkyl group, a cycloalkyl group, or an aryl group; and wherein one or more of the carbon atoms in the C1-C6 alkyl group are optionally substituted with an oxygen (O) atom.

[0031] In at least one embodiment, in one aspect, the compounds are selected from the group consisting of E(I), E(II), E(III), E(IV), E(V), E(VI), E(VII), E(VIII), E(IX), E(X), E(XI), E(XII), E(XIII), E(XIV), E(XV), E(XVI), E(XVII), E(XVIII), E(XIX), and E(XX): [ka] TIFF2025510666000006.tif226159.

[0032] In another aspect, the present disclosure relates to pharmaceutical and recreational drug formulations comprising a C4-carbonothioate substituted tryptamine derivative compound. Thus, in one aspect, the present disclosure relates to at least one embodiment of a compound of formula (I): [ka] providing a pharmaceutical or recreational drug formulation comprising an effective amount of a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; And here R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0033] In at least one embodiment, in one aspect, the pharmaceutical formulation can be a prodrug pharmaceutical formulation, where a compound having formula (I) is hydrolyzed in vivo to produce a compound having formula (VI): [ka] forming a compound having the formula: Here, R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0034] In another aspect, the present disclosure relates to a method for treating cranial nerve disorders. Thus, in one embodiment, the present disclosure further provides a method for treating cranial nerve disorders, the method comprising administering to a patient a compound of formula (I): [ka] administering to a subject in need thereof a pharmaceutical formulation comprising a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; And here R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group, wherein the pharmaceutical preparation is administered in an amount effective to treat a cranial nerve disorder in a subject.

[0035] In at least one embodiment, in one aspect, a compound having Formula (I) upon administration can interact with a receptor in a subject, thereby modulating the receptor and exerting a pharmacological effect.

[0036] In at least one embodiment, in one aspect, the receptor is 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 1B Receptor, 5-HT 2B Receptor, 5-HT 3AThe receptor may be an ADRA1A receptor, an ADRA2A receptor, a CHRM1 receptor, a CHRM2 receptor, a CNR1 receptor, a DRD1 receptor, a DRD2S receptor, an OPRD1 receptor, a GABAA receptor, or an NMDAR receptor.

[0037] In at least one embodiment, in one aspect, a compound having formula (I) upon administration can interact with a transmembrane transport protein in a subject, thereby modulating the transmembrane transport protein and exerting a pharmacological effect.

[0038] In at least one embodiment, in one aspect, the transmembrane transport protein can be a dopamine activated transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein.

[0039] In at least one embodiment, in one aspect, upon administration, a compound having formula (I) hydrolyzes in vivo to form a compound of formula (VI): [ka] forming a compound having the formula: Here, R 3a and R 3b each independently represents a hydrogen atom, an alkyl group, or an aryl group; and wherein the compound having formula (VI) interacts with the receptor, thereby modulating the receptor in a subject and exerting a pharmacological effect.

[0040] In at least one embodiment, in one aspect, the receptor is: 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 1B Receptor, 5-HT 2B Receptor, 5-HT 3A The receptor may be an ADRA1A receptor, an ADRA2A receptor, a CHRM1 receptor, a CHRM2 receptor, a CNR1 receptor, a DRD1 receptor, a DRD2S receptor, an OPRD1 receptor, a GABAA receptor, or an NMDAR receptor.

[0041] In at least one embodiment, in one aspect, the disorder is: 5-HT 1A Receptor-Mediated Disorders, 5-HT 2A Receptor-Mediated Disorders, 5-HT 1B Receptor-Mediated Disorders, 5-HT 2B Receptor-Mediated Disorders, 5-HT 3A The disorder may be a receptor-mediated disorder, an ADRA1A receptor-mediated disorder, an ADRA2A receptor-mediated disorder, a CHRM1 receptor-mediated disorder, a CHRM2 receptor-mediated disorder, a CNR1 receptor-mediated disorder, a DRD1 receptor-mediated disorder, a DRD2S receptor-mediated disorder, an OPRD1 receptor-mediated disorder, a GABAA receptor-mediated disorder, or an NMDAR receptor-mediated disorder.

[0042] In at least one embodiment, in one aspect, a dose can be administered from about 0.001 mg to about 5,000 mg.

[0043] In another aspect, the present disclosure provides, in at least one embodiment, (i) a 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 1B Receptor, 5-HT 2B Receptor, 5-HT 3A The present invention provides a method for modulating a receptor selected from a 5-HT agonist, an ADRA1A receptor, an ADRA2A receptor, a CHRM1 receptor, a CHRM2 receptor, a CNR1 receptor, a DRD1 receptor, a DRD2S receptor, an OPRD1 receptor, a GABAA receptor, or an NMDAR receptor; or (ii) a transmembrane transport protein selected from a dopamine activated transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein; the method comprises modulating (i) a 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 1B Receptor, 5-HT 2B Receptor, 5-HT 3Aa receptor, an ADRA1A receptor, an ADRA2A receptor, a CHRM1 receptor, a CHRM2 receptor, a CNR1 receptor, a DRD1 receptor, a DRD2S receptor, an OPRD1 receptor, a GABAA receptor, or an NMDAR receptor; or (ii) a dopamine activated transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transporter protein having the chemical formula (I): [ka] A compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b each independently represents a hydrogen atom, an alkyl group, or an aryl group; and (i) 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 1B Receptor, 5-HT 2B Receptor, 5-HT 3A receptor, ADRA1A receptor, ADRA2A receptor, CHRM1 receptor, CHRM2 receptor, CNR1 receptor, DRD1 receptor, DRD2S receptor, OPRD1 receptor, GABAA receptor, or NMDAR receptor, or (ii) under reaction conditions sufficient to modulate a dopamine-activated transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein.

[0044] In at least one embodiment, in one aspect, the reaction conditions can be in vitro reaction conditions.

[0045] In at least one embodiment, in one aspect, the reaction conditions can be in vivo reaction conditions.

[0046] In another aspect, the present disclosure relates to a method of making a C4-carbonothioate substituted tryptamine derivative compound. Thus, disclosed herein, in one aspect, is a compound having the formula (VI): [ka] A method for making a compound having the formula: wherein the method comprises reacting (h) and (l) under reaction conditions sufficient to convert compound 8 or compound 15 to form E(VI): [ka] The method includes carrying out one of the chemical reactions selected from the group consisting of:

[0047] In at least one embodiment, in one aspect, the method includes performing chemical reaction (h), and prior to performing chemical reaction h, (i) Chemical reactions (g); (ii) sequentially, chemical reactions (f) and (g), respectively; (iii) sequentially, chemical reactions (e), (f), and (g), respectively; (iv) sequentially, chemical reactions (d), (e), (f), and (g), respectively; (v) each of chemical reactions (c), (d), (e), (f), and (g) in sequence; (vi) each of chemical reactions (b), (c), (d), (e), (f), and (g) in sequence; or (vii) Sequentially, each of chemical reactions (a), (b), (c), (d), (e), (f), and (g), may include one implementation of; where chemical reactions (a), (b), (c), (d), (e), (f), and (g) are the chemical reactions identified as (a), (b), (c), (d), (e), (f), and (g) in Figures 3A(i) and 3A(ii), respectively; and wherein each of the chemical reactions is carried out under conditions sufficient to form E(VI).

[0048] In at least one embodiment, in one aspect, the method includes performing chemical reaction (l) and prior to performing chemical reaction (l): (i) Chemical reaction (k); (ii) each of chemical reactions (j) and (k) in sequence; or (iii) each of chemical reactions (i), (j), and (k) in sequence; One of the following will be implemented; and Optionally, prior to carrying out chemical reaction (l), (iv) Chemical reactions (m) may include one implementation of; where chemical reactions (i), (j), (k), and (m) are the chemical reactions identified as (i), (j), (k), and (m) in Figure 3A(iii), respectively; and wherein each of the chemical reactions is carried out under conditions sufficient to form E(VI).

[0049] In another aspect, the present disclosure relates to the use of a C4-carbonothioate substituted tryptamine derivative compound. That is, the present disclosure further relates, in at least one embodiment, to the use of a compound of formula (I): [ka] Use of a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0050] In at least one embodiment, manufacturing can include formulating the compound with a pharma- ceutically acceptable excipient, diluent, or carrier.

[0051] In another aspect, the present disclosure provides, in at least one embodiment, a pharmaceutical or recreational drug formulation comprising a compound of formula (I): [ka] Use of a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0052] In at least one embodiment, in one aspect, the pharmaceutical agent is an agent for treating a cranial nerve disorder.

[0053] Other features and advantages will become apparent from the following detailed description, but it should be understood that the detailed description is intended only to illustrate preferred embodiments of the present disclosure by way of example, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from the detailed description.

[0054] The present disclosure will now be described, by way of example only, in the following paragraphs of this specification in conjunction with the accompanying drawings, in which: The drawings provided herein are provided for a better understanding of the exemplary embodiments and to more clearly show how various embodiments may be implemented; The drawings are not intended to limit the present disclosure. [Brief description of the drawings]

[0055] [Figure 1] The chemical structure of tryptamine is shown. [Diagram 2] Specific prototype structures of tryptamine and tryptamine derivative compounds, i.e., indoles, are shown. Specific carbon and nitrogen atoms may be referred to herein with reference to their locations within the indole structure, i.e., N1, C2, C3, etc. Appropriate atom numbering is shown. [Diagram 3]FIGS. 3A(i), 3A(ii), 3A(iii), 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, 3L, 3M(i), 3M(ii), 3M(iii), 3N(i), 3N(ii), 3O(i), 3O(ii), 3P, 3Q, 3R, 3S(i) and 3S(ii) depict exemplary chemical reactions for making exemplary compounds provided by the present disclosure, i.e., compounds having formula E(VI) (FIGS. 3A(i) and 3A(ii) together depict exemplary synthetic route A, and FIG. 3A(iii) depicts exemplary synthetic route B); and certain experimental results. Shown are various graphs (Figures 3B-3S(ii)), in particular graphs obtained in carrying out experimental assays to evaluate the efficacy of an exemplary compound having formula E(VI): in particular a cell viability assay (Figures 3B, 3C), a saturation binding assay of [3H]ketanserin at the 5-HT2A receptor (Figure 3D); a competition assay with psilocin as a positive control (binding) (Figure 3E); a competition assay with tryptophan as a negative control (non-binding) (Figure 3F); a competition assay with a compound having formula E(VI) designated as "E-VI" (Figure 3G); cAMP assay in the presence of various concentrations of a compound having the formula E(VI), denoted as "E-VI", in +5HT1A and -5HT1A cells (Fig. 3H); cAMP assay in the presence of 4 μM forskolin and various concentrations of tryptophan in +5HT1A and -5HT1A cells (Fig. 3I); cAMP assay in the presence of various concentrations of psilocin in +5HT1A and -5HT1A cells stimulated with 4 μM forskolin (Fig. 3J); cAMP assay in the presence of various concentrations of psilocin in +5HT1A and -5HT1A cells stimulated with 4 μM forskolin (Fig. 3K); cAMP assay in the presence of various concentrations of serotonin in T1A cells (Figure 3K); cAMP assay in the presence of various concentrations of a compound having the chemical formula E(VI), denoted as "E-VI", in +5HT1A and -5HT1A cells in the presence of 4 μM forskolin (Figure 3L); psilocybin metabolic conversion assay (Figures 3M(i)-3M(iii)); assay controls for psilocin metabolic release assay (Figures 3N(i)-3N(ii)); metabolic stability assay for a compound having the chemical formula E(VI) (Figures 3O(i)-3O(ii));and a drug-induced head-shake response (HTR) assay using a compound having the chemical formula E(VI) denoted as "E-VI" (Figure 3P); a mouse PK study analyzing plasma psilocybin levels after 1 mg / kg intravenous administration of psilocybin (Figure 3Q); a mouse PK study analyzing plasma psilocin levels after oral administration of various levels of psilocybin (Figure 3R); and a mouse PK study using a compound having the chemical formula E(VI) (Figures 3S(i) and 3S(ii)). [Figure 4] 4A, 4B, 4C, 4D(i), 4D(ii), 4E, and 4F depict an exemplary chemical reaction to make an exemplary compound provided by the present disclosure, i.e., a compound having formula E(VI) in FIG. 4A (Panel A, FIG. 4A); for comparison purposes, another chemical reaction and a compound having formula B(II) (Panel B, FIG. 4A); and a compound related to the exemplary chemical reaction ((Panel C, FIG. 4A)), and various graphs (FIGS. 4BX-3F) depicting certain experimental results, in particular graphs obtained from conducting experimental assays to evaluate the efficacy of an exemplary compound having formula B(II), in particular a competitive assay for a compound having formula B(II) designated "B-II." (Figure 4B), cAMP assay in the presence of 4 μM forskolin and various concentrations of compound having chemical formula B(II) denoted as "B-II" in +5HT1A and -5HT1A cells (Figure 4C); metabolic stability assay for compound having chemical formula B(II) (Figures 3D(i) and 3D(ii)); control comparative metabolic stability assay for compounds having chemical formula E(VI) and B(II) denoted as "E(VI)" and "B(II)", respectively (Figure 3E); and control comparative drug-induced head-shaking response (HTR) assay using compounds having chemical formula E(VI) and B(II) denoted as "E(VI)" and "B(II)", respectively (Figure 4F).

[0056] These drawings together with the following detailed description will make apparent to those skilled in the art how the present disclosure may be practically practiced. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] Various compositions, systems, or processes are described below to provide examples of embodiments of each claimed subject matter. The embodiments described below are not intended to limit any claimed subject matter, and any claimed subject matter may include processes, compositions, or systems other than those described below. Claimed subject matter is not limited to compositions, processes, or systems having all of the features of any one of the compositions, systems, or processes described below, or to features common to more than one or all of the compositions, systems, or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any claimed subject matter. Any subject matter disclosed in the compositions, systems, or processes described below that are not claimed herein may be the subject matter of another protective legal document, such as a pending patent application; and the applicant, inventor, or owner does not intend to relinquish, relinquish, or make available to the public any such subject matter by its disclosure herein.

[0058] As used herein and in the claims, singular forms such as "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise. Throughout this specification, unless otherwise indicated, "comprise," "comprises," and "comprising" are used inclusively rather than exclusively, whereby a referenced integer or group of integers may include one or more other integers or groups of integers not specifically stated.

[0059] Various compositions, systems, or processes are described below to provide examples of embodiments of each of the claimed subject matter. The embodiments described below do not limit any of the claimed subject matter, and any claimed subject matter may include processes, compositions, or systems different from those described below. The claimed subject matter is not limited to compositions, processes, or systems having all of the features of any one of the compositions, systems, or processes described below, or to features common to more than one or all of the compositions, systems, or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any of the claimed subject matter. Any subject matter disclosed in the compositions, systems, or processes described below that are not claimed herein may be the subject matter of another protective legal document, such as a pending patent application; and the applicant, inventor, or owner does not intend to relinquish, relinquish, or make public any such subject matter by its disclosure herein.

[0060] When ranges are used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formulas), all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Except in the experimental examples, or unless otherwise specified, all numerical values ​​expressing amounts of ingredients or reaction conditions used herein are understood to be modified in any case by the term "about". The term "about" when referring to a range of numbers or values ​​means that the number or numerical range referred to is an approximation within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary from 1% to 15% of the range of the number or numerical value referred to, as easily recognized by the context. Moreover, any range of values ​​described herein is specifically intended to include the limits of the range and any intermediate values ​​and subranges within the stated range; all such intermediate values ​​and subranges are individually and specifically disclosed (e.g., the range of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). Similarly, other terms of degree, such as "substantially" and "approximately," used herein, refer to deviations from the modified term by a reasonable amount such that the end result is not significantly altered. These terms of degree should be considered to include deviations from the modified term if such deviations do not negate the meaning of the term they modify.

[0061] Unless otherwise defined, scientific and technical terms used in connection with the formulations described herein have the meanings commonly understood by those of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined solely by the claims.

[0062] All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Terms and Definitions

[0063] The term "tryptamine" refers to a compound having the structure shown in FIG.

[0064] The term "indole archetype structure" refers to the chemical structure shown in Figure 2. Note that certain carbon and nitrogen atoms in the indole archetype structure are numbered. These carbon and nitrogen numbers, e.g., C2, C4, N1, etc., may be referenced herein. Additionally, chemical groups attached to the indole archetype structure that follow the same numbering may be referenced (e.g., the reference chemical groups R4 and R6 attached to the C4 and C6 atoms, respectively). Additionally, R 3a and R 3b is in this respect the reference chemical group extending from the ethylamino group extending from the C3 atom of the prototype indole structure.

[0065] As used herein, the term "tryptamine derivative" refers to a compound that can be derived from tryptamine; such compounds have the chemical formula (VII): [ka] containing an indole archetype structure having a C3 ethylamine or ethylamine derivative group; where R4 is a substituent (any atom or group other than a hydrogen atom) that contains a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group. Thus, tryptamine derivative compounds include compounds that contain a substituent at the C4 position, as defined. Additional other atoms (such as N1) may also be substituted. Furthermore, in this regard, for example, a tryptamine derivative that contains a substituted atom or group at C4 may be referred to as a C4-substituted tryptamine derivative. In formula (VII), R4 may be, for example, a carbonothioate moiety or a derivative thereof, and the tryptamine derivative may be referred to as a C4-carbonothioate substituted tryptamine derivative.

[0066] As used herein, a "carbonothioate moiety or derivative thereof" refers to a compound having the formula (XII): a or (XII) b : [ka] refers to derivatives containing a group having the formula: where R4' is a hydrocarbon group, such as an alkyl group, a cycloalkyl group, or an aryl group. a and (XII) b It should be noted that the partially bonded oxygen atom of a group having the formula: may be bonded to another entity, including, for example, to the C4 atom of tryptamine. 4a , 4b , 4c , 4d For example, R 4a , R 4b , R 4c , or R 4d It is further noted that when such numbers are included, they represent the chemical entities extending from the carboxyl group extending from the so-numbered C atom of the prototypical indole structure. Thus, for example, R 4c is a chemical entity extending from a carbonothioate group attached to the C4 atom of an indole ring structure.

[0067] As used herein, the terms "halogen," "halogenated," and "halo-" refer to a class of chemical elements consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Thus, a halogenated compound may be referred to as a "fluorinated," "chlorinated," "brominated," or "iodinated" compound.

[0068] The terms "hydroxy group" and "hydroxy" as used herein refer to a molecule that contains one atom of oxygen bonded to one atom of hydrogen and has the chemical formula -OH. The hydroxy group may be chemically bonded to another entity through the oxygen atom.

[0069] The term "alkyl group" as used herein refers to straight and / or branched saturated alkyl radicals containing from 1 to "p" carbon atoms ("C1-Cp-alkyl"; e.g., p can be an integer between 2 and 20, e.g., 3, 6, 10, or 20), including methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl, etc., depending on the numerical value of "p," where the variable p is an integer indicating the maximum number of carbon atoms in the alkyl radical. Alkyl groups further include hydrocarbon groups arranged in a chain having the chemical formula -CH2n+1; including, without limitation, methyl (-CH3), ethyl (-CH5), propyl (-CH7), and butyl (-CH9).

[0070] The term "alkylene" refers to a divalent group derived from an alkane by removal of two hydrogen atoms from the same carbon atom. Non-limiting examples of alkylenes include ethylene (-C2H4)-), propylene (-C3H6)-, and butylene (-C4H8)-). For purposes of this application, alkylene is further understood to be methylene (-CH2-).

[0071] The term "cycloalkyl" refers to a cycloalkyl group (C3-C 20 ), (C3~C 10 ), and (C3-C6) cycloalkyl groups; and includes saturated and partially saturated cycloalkyl groups, further including cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, and cyclohexane.

[0072] As used herein, the term "O-alkyl group" refers to a group having the formula -OC n H 2n+1Non-limiting examples of O-alkyl groups include O-methyl groups (-O-CH3), O-ethyl groups (-O-C2H5), O-propyl groups (-O-C3H7), and O-butyl groups (-O-C4H9).

[0073] As used herein, the term "aryl group" refers to a hydrocarbon group arranged in an aromatic ring, e.g., C6-C 14 -Aryl, C6-C 10 Further examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, tolyl, xylyl, or indenyl groups, and the like.

[0074] As used herein, the term “alcohol group” or “hydroxyl alkyl” refers to a group having the chemical formula C n H n+1 Refers to hydrocarbon groups arranged in a chain with OH. Depending on the carbon chain, the chain-length specific alcohol group may be called methanol group (n=1) or hydroxymethyl, ethanol group (n=2) or hydroxyethyl, propanol group (n=3) or hydroxypropyl, butanol group (n=4) or hydroxybutyl, etc.

[0075] As used herein, the term "receptor" refers to a protein present on the cell surface or in a cell that is not in communication with the cell surface (e.g., a soluble receptor) that can mediate a signal to and / or from or within a cell, thereby affecting cellular physiology. Exemplary receptors include 5-HT 1A Receptor, 5-HT 1B Receptor, 5-HT 2A Receptors, and "5-HT 2BIn this regard, "signal transduction" refers to a response in the form of a series of chemical reactions that can occur when a molecule, including, for example, a C4-substituted tryptamine derivative disclosed herein, interacts with a receptor. Signal transduction generally permeates across the cell membrane and / or proceeds within the cell to reach a target molecule or chemical reaction, resulting in the regulation of cell physiology. Thus, signal transduction can be considered a transduction process by which a molecule interacting with a receptor can regulate cell physiology, and further, signal transduction can be a process by which a molecule inside the cell can be regulated by a molecule outside the cell. Signal transduction and the interaction between a molecule and a receptor (including, for example, affinity, binding efficiency, and kinetics) can be evaluated by various assays, such as receptor binding assays (radioligin binding assays (e.g., receptor 5-HT 2A For example, the receptor activity of 3 These assays include those known in the art, such as [H]ketanserin assays, competitive assays, and saturation binding assays.

[0076] As used herein, the term "5-HT 1A "Receptor" refers to a subclass of the family of receptors for the neurotransmitter and peripheral signal mediator serotonin. 1A The 5-HT receptor can mediate multiple central and peripheral physiological functions of serotonin. 1A Although ligand activity in 5-HT is not generally associated with hallucinogenic symptoms, many hallucinogenic compounds have been shown to inhibit 5-HT 1A It is known to modulate 5-HT receptors to produce complex physiological responses (Inserra et al., 2020, Pharmacol. Rev 73:202). 1A The receptor has been implicated in a variety of neurological disorders, including depression and anxiety, schizophrenia, and Parkinson's disease (Behav. Pharm. 2015, 26:45-58).

[0077] As used herein, the term "5-HT 1B"Receptor" refers to a subclass of the receptor family for the neurotransmitter and peripheral signal mediator serotonin. 1B The 5-HT receptor can mediate multiple central and peripheral physiological functions of serotonin. 1B Although ligand activity in 5-HT is not generally associated with hallucinogenic symptoms, many hallucinogenic compounds have been shown to inhibit 5-HT 1A It is known to modulate 5-HT receptors to produce complex physiological responses (Inserra et al., 2020, Pharmacol. Rev. 73:202). 1B The receptor is involved in a variety of neurological disorders, including depression (Curr. Pharm. Des. 2018, 24:2541-2548).

[0078] As used herein, the term "5-HT 2A "Receptor" refers to a subclass of the receptor family for the neurotransmitter and peripheral signal mediator serotonin. 2A The 5-HT receptor can mediate several central and peripheral physiological functions of serotonin. Central nervous system effects can include mediating the hallucinogenic effects of hallucinogenic compounds. 2A The receptor is involved in various neurological disorders (Nat.Rev.Drug Discov. 2022, 21:463-473; Science 2022, 375:403-411).

[0079] As used herein, the term "5-HT 2B "Receptor" refers to a subclass of the receptor family for the neurotransmitter and peripheral signal mediator serotonin. 2B The 5-HT receptor can mediate several central and peripheral physiological functions of serotonin. Central nervous system effects can include mediating the hallucinogenic effects of hallucinogenic compounds. bA The receptor is involved in various neurological disorders, including schizophrenia (Pharmacol. Ther. 2018, 181:143-155) and migraine (Cephalalgia 2017, 37:365-371).

[0080] As used herein, the term "5-HT 3A "Receptor" refers to a subclass of the receptor family for the neurotransmitter and peripheral signal mediator serotonin. 3A The 5-HT receptor can mediate multiple central and peripheral physiological functions of serotonin. 3A The receptor is involved in a variety of neurological disorders, including depression (Expert Rev. Neurother. 2016, 16:483-95).

[0081] The term "ADRA1A receptor" as used herein refers to a subclass of a receptor family also known as α1-adrenergic receptors, which can be modulated by selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) (Int. J. Mol Sci. 2021, 22: 4817; Brain Res. 1285 2009, 148-157). ADRA1A receptors are involved in various brain neurological disorders, including depression.

[0082] The term "ADRA2A receptor" as used herein refers to a subclass of receptor family also known as α2-adrenergic receptor.ADRA2A receptor is involved in various brain neurological disorders, including attention deficit hyperactivity disorder (ADHD) (J.Am.Acad.Child.Adolesc.Psychiatry 2014,53:153-73), mania, bipolar disorder and schizophrenia.

[0083] The term "CHRM1 receptor" as used herein refers to a subclass of receptors also known as "muscarinic cholinergic receptor 1", which can be modulated by selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine) and tricyclic antidepressants (TCAs). The CHRM receptor class is involved in a variety of brain neurological disorders, including depression, major depressive disorder (MDD), and bipolar disorder (Mol. Psychiatry 2019, 24:694-709).

[0084] The term "CHRM2 receptor" as used herein refers to a subclass of receptors also known as "muscarinic cholinergic receptor 2" that can be modulated by tricyclic antidepressants (TCAs). The CHRM receptor class is involved in a variety of brain neurological disorders, including depression, major depressive disorder (MDD), and bipolar disorder (Mol. Psychiatry 2019, 24:694-709).

[0085] As used herein, the term "CNR1 receptor" refers to a subclass of receptors also known as "cannabinoid receptors CB1" that can be modulated by cannabinoid compounds. CNR receptors are involved in a variety of brain neurological disorders, including depression and schizophrenia (Pharmacol.Res.2021, 170:105729).

[0086] As used herein, the term "DRD1 receptor" refers to a subclass of receptors that can be regulated by dopamine, also known as "dopamine receptor D1". Dopamine receptors are involved in various brain neurological disorders, including schizophrenia, psychosis, and depression (Neurosci.Lett. 2019, 691:26-34).

[0087] As used herein, the term "DRD2S receptor" refers to a subclass of receptors that can be regulated by dopamine, also known as "dopamine receptor D2S". Dopamine receptors are involved in various brain neurological disorders, including schizophrenia, psychosis, and depression (Neurosci.Lett. 2019, 691:26-34).

[0088] The term "OPRD1 receptor" as used herein refers to a subclass of receptors also known as "opioid receptor D1" that can be modulated by opioid compounds.OPRD1 receptors are involved in various brain neurological disorders, including psychopathy and substance use disorders (Mol.Psychiatry 2020, 25:3432-3441).

[0089] The term "GABAA receptor" as used herein refers to a subclass of receptors that can be regulated by γ-aminobutyric acid, also known as "γ-aminobutyric acid (GABA) receptor A". GABAA receptors are involved in a variety of brain neurological disorders, including anxiety, major depressive disorder, and postpartum depression (Trends Pharmacol.Sci.2018, 39:710-732).

[0090] As used herein, the term "NMDAR receptor" refers to a subclass of receptors also known as "N-methyl-D-aspartate receptors". NMDAR receptors are glutamatergic receptors that are involved in a variety of brain neurological disorders, including epilepsy, autism spectrum disorder, and schizophrenia (Transl. Psychiatry 2022, 12:243).

[0091] The term "DAT" as used herein refers to a transmembrane transport protein, also known as "dopamine-activated transporter", which is involved in dopamine transport to the cytoplasm. DAT is involved in various brain neurological disorders, particularly dopamine-related disorders, such as attention-deficit hyperactivity disorder (ADHD), bipolar disorder, and clinical depression, anxiety, etc. (Am. J. Med. Genet. B Neuropsychiatr. Genet. 2018, 177: 211-231).

[0092] As used herein, the term "NET" refers to the Na of extracellular norepinephrine or extracellular noradrenaline. + / Cl - It refers to a transmembrane transport protein involved in the dependent reuptake, also known as the "norepinephrine transporter" or "noradrenaline transporter" or "NAT". NETs are involved in various brain neurological disorders, including attention deficit hyperactivity disorder (ADHD) and clinical depression (Neurosci. Biobehav. Rev, 2013, 37:1786-800).

[0093] The term "SERT" as used herein refers to a transmembrane transport protein, also known as "serotonin transporter", which is involved in transporting serotonin, particularly from the synaptic cleft back to the presynaptic neuron, thereby terminating the action of serotonin. SERT is involved in various brain neurological disorders, including anxiety and depression (Pharmacol.Rep.2018, 70:37-46).

[0094] The term "modulate a receptor" as used herein refers to the ability of a compound disclosed herein to alter the function of a receptor. A receptor modulator may activate or inhibit the activity of a receptor depending on the concentration of a compound exposed to the receptor. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and / or may only be exerted in a specific cell type. The term "modulate a receptor" also refers to altering the function of a receptor by increasing or decreasing the probability that a complex will form between the receptor and a natural binding partner to form a multimer. A receptor modulator may increase the probability that such a complex will form between the receptor and a natural binding partner, may increase or decrease the probability that a complex will form between the receptor and a natural binding partner depending on the concentration of a compound exposed to the receptor, and / or may decrease the probability that a complex will form between the receptor and a natural binding partner. It is further noted that the C4-carbonothioate substituted tryptamine derivatives of the present disclosure may alter the function of a receptor by acting as an agonist or antagonist of the receptor, and that the C4-carbonothioate substituted tryptamine derivatives according to the present disclosure may alter the function of a receptor by directly interacting with or binding to it, or by indirectly interacting with it through one or more other molecular entities. In general, the receptor may be any receptor, including any of the receptors set forth herein (e.g., 5-HT 1A Receptor, 5-HT 1B Receptor, 5-HT 2A Receptors, and 5-HT 2BTherefore, to refer to modulating a specific receptor, we use the term "5-HT 1A "Modulates the 5-HT receptor" 1B "Modulates the 5-HT receptor" 2A "Modulates the 5-HT receptor" 2B It will be apparent that terms such as "modulating a receptor" may be used herein.

[0095] The term "receptor-mediated disorder" as used herein refers to a disorder characterized by abnormal receptor activity. Receptor-mediated disorders may be fully or partially mediated by modulating the receptor. In particular, receptor-mediated disorders are those in which modulation of the receptor has some effect on the underlying disease, e.g., administration of a receptor modulator results in some improvement in at least some of the subjects treated. In general, the receptor may be any receptor, including any of the receptors set forth herein (e.g., 5-HT 1A Receptor 、 5-HT 1B Receptor 、 5-HT 2A Receptors, and 5-HT 2B Therefore, to refer to a specific receptor-mediated disorder, we use the term "5-HT 1A Receptor-Mediated Disorders," "5-HT 1B Receptor-Mediated Disorders, 5-HT 2A Receptor-Mediated Disorders," "5-HT 2B It will be apparent that terms such as "receptor-mediated disorder" may be used.

[0096] The term "pharmaceutical formulation" as used herein refers to a preparation in which the active ingredients contained therein (including psychoactive ingredients) are in a form that allows them to provide effective treatment, and does not contain any other ingredients that cause excessive toxicity, allergic response, irritation, or other adverse response that is commensurate with a reasonable risk / benefit ratio. Pharmaceutical formulations may contain other pharmaceutical ingredients, such as additives, carriers, diluents, or adjuvants.

[0097] The term "recreational drug formulation" as used herein refers to a preparation in a form that allows the psychoactive ingredient contained therein to be effective for recreational administration and does not contain any other ingredients that cause excessive toxicity, allergic response, irritation, or other adverse response that is commensurate with a reasonable risk / benefit ratio. Recreational drug formulations may contain other ingredients such as additives, carriers, diluents, or auxiliary agents.

[0098] As used herein, the term "effective for administration as a recreational drug" refers to a preparation, generally in a form for self-administration, that allows a subject to spontaneously induce a psychoactive effect upon administration for non-medical purposes. The effect may include a different state of consciousness, a feeling of satisfaction, a feeling of euphoria, a feeling of euphoria, an altered perception, or hallucinations.

[0099] The term "effective amount" as used herein refers to an amount of an active substance, pharmaceutical preparation, or recreational drug preparation sufficient to induce a desired biological or therapeutic effect, including preventive effects, and further including psychoactive effects. Such effects may include effects on the symptoms, symptoms, or causes of disorders or diseases, or other desired changes in biological systems. Effective amounts may vary, for example, depending on the health condition, injury stage, injury stage, or disease stage, weight, or sex of the subject being treated, the timing of administration, the method of administration, the age of the subject, etc. (all of which can be determined by those skilled in the art).

[0100] As used herein, the terms "treating" and "treatment" and the like are intended to mean obtaining a desired physiological, pharmacological, or biological effect, and include preventative and therapeutic treatments. The effect may result in the inhibition, attenuation, amelioration, or reversal of the symptoms, symptoms, or pathogenesis of a disorder or disease, including mental and psychiatric disorders and disorders. Clinical evidence of prevention or treatment may vary depending on the disorder or disease, the subject, and the treatment selected.

[0101] As used herein, the term "pharmaceutical acceptable" refers to a material, including an excipient, carrier, diluent, or adjuvant, that is compatible with other materials in a pharmaceutical or recreational drug formulation and that, within the bounds of sound medical judgment, is suitable for use in contact with a subject without undue toxicity, allergic reaction, irritation, or other adverse response commensurate with a reasonable risk / benefit ratio.

[0102] The terms "substantially pure" and "isolated", used synonymously herein, refer to a compound, such as a C4-carbonothioate substituted tryptamine derivative, that is separated from components that naturally or synthetically accompany it. Typically, a compound is substantially pure when at least 60% (by volume, wet or dry weight, or by mole percent (%) or mole fraction) of the total material in a sample is the compound of interest, more preferably at least 75%, more preferably at least 90%, 95%, 96%, 97%, or 98%, and most preferably at least 99%. Purity can be measured by any suitable method, such as by chromatography, gel electrophoresis, or HPLC analysis.

[0103] General Practice As described hereinabove, the present disclosure relates to tryptamine derivatives. In particular, the present disclosure provides novel C4-substituted tryptamine derivatives, and in particular C4-carbonothioate substituted tryptamine derivatives. In general, the compositions provided herein exhibit functional properties that deviate from tryptamine. Thus, for example, C4-carbonothioate substituted tryptamine derivatives may exhibit pharmacological properties that deviate from tryptamine. Furthermore, C4-carbonothioate substituted tryptamine derivatives may exhibit physicochemical properties that are different from tryptamine. Thus, for example, C4-carbonothioate substituted tryptamine derivatives may exhibit superior solubility in a solvent, for example, an aqueous solvent. Furthermore, C4-carbonothioate substituted tryptamine derivatives may exhibit pharmacokinetics or pharmacodynamics that are different from the unsubstituted compound. In this respect, C4-carbonothioate substituted tryptamine derivatives are useful in the formulation of pharmaceutical and recreational drug formulations.

[0104] In the following, selected embodiments are described with reference to the drawings.

[0105] Thus, in one aspect, the present disclosure provides derivatives of the compound known as tryptamine, the chemical structure of which is shown in Figure 1. The derivatives provided herein are, in particular, C4-substituted tryptamine derivatives, i.e., derivatives in which the C4 atom is bonded to a substituent, in particular a carbonothioate moiety or derivative thereof.

[0106] Thus, in one aspect, the present disclosure provides, in at least one embodiment, a compound of formula (I): [ka] providing a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0107] Thus, with reference to compounds having formula (i), in this aspect, R4 may be a carbonothioate moiety or derivative thereof, i.e., a carbonothioate moiety or derivative attached to the C4 atom of the tryptamine compound via its oxygen atom.

[0108] In some embodiments, in one aspect, the carbonothioate moiety or derivative thereof has the formula (III): [ka] may have; Here, R 4b is an alkyl group, a cycloalkyl group, or an aryl group, each of which is optionally substituted.

[0109] In some embodiments, the carbonothioate moiety or derivative thereof has formula (IV): [ka] may have; Here, R 4c is an alkyl group, a cycloalkyl group, or an aryl group, each of which is optionally substituted.

[0110] In some embodiments, in the compound having formula (III), R 4b is optionally a halogen atom (chloro, fluoro, bromoiodo), an alkyl group (e.g., C1-C 10 alkyl or C1-C6 alkyl or C1-C3 alkyl), cycloalkyl groups (e.g., C3-C 10 cycloalkyl or C3-C6 cycloalkyl), or an aryl group, for example a C1-C6 alkyl substituted with a phenyl group.

[0111] In some embodiments, in the compound having formula (III), R 4b may be a C1-C3 alkyl (i.e., C1-C3 alkylene (e.g., methylene, ethylene, propylene) optionally substituted with a halogen atom (chloro, fluoro, bromo, iodo), an alkyl group, a cycloalkyl group, or an aryl group, such as a phenyl group.

[0112] In some embodiments, in the compound having formula (III), R 4b can be methyl, ethyl, isopropyl, butyl, -CH2-cyclopropyl, -CH(CH3)-cyclopropyl, -C(CH3)2-cyclopropyl, or -CH2-phenyl.

[0113] In some embodiments, R 4b can be an aryl group, for example a phenyl group.

[0114] In some embodiments, in the compound having formula (III), R4b can be a C1-C6 alkyl optionally substituted with a halogen atom (chloro, fluoro, bromo, iodo), an alkyl group, a cycloalkyl group, or an aryl group, where one or more of the carbon atoms in the C1-C6 alkyl group is replaced with an oxygen (O) atom.

[0115] In some embodiments, in the compound having formula (IV), R 4c is optionally a halogen atom (chloro, fluoro, bromo, iodo), an alkyl group (e.g., C1-C 10 alkyl or C1-C6 alkyl or C1-C3 alkyl), cycloalkyl groups (e.g., C3-C 10 cycloalkyl or C3-C6 cycloalkyl), or an aryl group, for example a C1-C6 alkyl substituted with a phenyl group.

[0116] In some embodiments, in the compound having formula (IV), R 4c can be methyl, ethyl, isopropyl, butyl, -CH2-cyclopropyl, -CH(CH3)-cyclopropyl, -C(CH3)2-cyclopropyl or -CH2-phenyl.

[0117] In some embodiments, in the compound having formula (IV), R 4c can be an aryl group, for example a phenyl group.

[0118] In some embodiments, in the compound having formula (IV), R 4c can be a C1-C6 alkyl optionally substituted with a halogen atom (chloro, fluoro, bromo, iodo), an alkyl group, a cycloalkyl group, or an aryl group, wherein one or more of the carbon atoms in the C1-C6 alkyl group are substituted with an oxygen (O) atom.

[0119] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(I): [ka] has.

[0120] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(II): [ka] has.

[0121] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(III): [ka] has.

[0122] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(IV): [ka] has.

[0123] In one aspect, the disclosure provides a compound represented by formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(V): [ka] has.

[0124] In some embodiments, in one aspect, in the compound having formula (I), R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(VI): [ka] has.

[0125] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(VII): [ka] has.

[0126] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(VIII): [ka] has.

[0127] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(IX): [ka] has.

[0128] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(X): [ka] has.

[0129] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XI): [ka] has.

[0130] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XII): [ka] has.

[0131] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XIII): [ka] has.

[0132] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XIV): [ka] has.

[0133] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XV): [ka] has.

[0134] In some embodiments, in one aspect, in the compound having formula (I), R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XVI): [ka] has.

[0135] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XVII): [ka] has.

[0136] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XVIII): [ka] has.

[0137] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XIX): [ka] has.

[0138] In one aspect, the disclosure provides a compound having formula (I), where R4 is a carbonothioate moiety or a derivative thereof, and the compound has formula E(XX): [ka] has.

[0139] With further reference to the compounds having formula (I), R 3a and R 3b are independently a hydrogen atom or (C 20 )-alkyl or aryl groups, for example, phenyl groups. 3a and R 3b are independently a hydrogen atom or (C 10 )-alkyl or aryl groups, for example, phenyl groups. 3a and R3b are independently a hydrogen atom or a (C1-C6)-alkyl group or an aryl group, for example a phenyl group. 3a and R 3b are independently a hydrogen atom, a methyl group, an ethyl group, or a propyl group, or an aryl group, such as a phenyl group.

[0140] Thus, in brief summary, the present disclosure provides C4-carbonothioate substituted tryptamine derivatives, particularly those having the formula (I): [ka] providing a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0141] The above includes a C4-carbonothioate substituted tryptamine, The carbonothioate moiety or a derivative thereof has the chemical formula (III): [ka] It may have Here, R 4b is an alkyl group, a cycloalkyl group, or an aryl group, each of which is optionally substituted; and further includes C4-carbonothioate substituted tryptamines, where the carbonothioate moiety or a derivative thereof has the chemical formula (IV): [ka] may have; Here, R 4c is an alkyl group, a cycloalkyl group, or an aryl group, each of which is optionally substituted, to provide a C4-carbonothioate substituted tryptamine.

[0142] In another embodiment, R 3a and R 3b are independently a hydrogen atom or (C 20 )-alkyl or aryl groups, for example, phenyl groups. 3a and R 3b are independently a hydrogen atom or (C 10 )-alkyl group or an aryl group (e.g., a phenyl group). 3a and R 3b are independently a hydrogen atom or a (C1-C6)-alkyl group or an aryl group, for example a phenyl group. 3a and R 3b are independently a hydrogen atom, a methyl group, an ethyl group, or a propyl group, or an aryl group, such as a phenyl group.

[0143] The C4-carbonothioate-substituted tryptamine derivatives of the present disclosure may be used to prepare pharmaceutical or recreational drug formulations.Accordingly, in one embodiment, the present disclosure further provides in another aspect pharmaceutical and recreational drug formulations comprising the C4-carbonothioate-substituted tryptamine derivatives.Accordingly, in one aspect, the present disclosure further provides in one aspect a compound of formula (i): [ka] providing a pharmaceutical or recreational drug formulation comprising a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0144] The pharmaceutical or recreational drug formulations may be prepared as liquids, tablets, capsules, microcapsules, nanocapsules, transdermal patches, gels, foams, oils, aerosols, nanoparticles, powders, creams, emulsions, micelles, films, sprays, ovoids, drops, teas, decoctions, suppositories, and the like, and include a pharma- ceutically acceptable salt or solvate of the C4-carbonothioate tryptamine derivative compound together with an excipient. The term "excipient" as used herein means any component other than the compound of the present disclosure. To prepare a pharmaceutical formulation according to the present disclosure, the C4-carbonothioate substituted tryptamine derivative compound is generally first prepared and obtained in a substantially pure form, most preferably at least 98%, 99%, or 99.9% pure, and then formulated with a pharma- ceutically acceptable excipient. As will be readily understood by those skilled in the art, the choice of excipient may depend on factors such as the particular mode of administration, the effect of the excipient on the solubility of the compound of the present disclosure, and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 22nd Edition (Pharmaceutical Press and Philadelphia College of Pharmacy at the University of the Sciences, 2012).

[0145] The dosage when using the compounds of the present disclosure may vary within wide limits, and as is usual and known to those skilled in the art, the dosage may be adjusted to the individual conditions in each individual case. The dosage depends, for example, on the nature and severity of the disease being treated, the pathology of the patient, the compound used, whether an acute or chronic disease state is being treated, or whether prophylaxis is being performed, the mode of delivery of the compound, or whether an additional active compound is administered in addition to the compound of the present disclosure. Representative dosages of the present invention include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to about 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Representative doses of the present disclosure include, but are not limited to, about 0.0001 to about 1,000 mg, about 10 to about 160 mg, about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg. Multiple doses may be administered on the same day (e.g., 2, 3, or 4 doses), especially when a relatively large amount is deemed necessary. Depending on the subject and as deemed appropriate by the patient's physician or caregiver, it may be necessary to deviate upwards or downwards from the doses described herein.

[0146] The pharmaceutical and drug formulations comprising the C4-carbonothioate-substituted tryptamine derivative compounds of the present disclosure may be administered orally.Oral administration may involve swallowing so that the compound enters the digestive tract, or oral buccal or sublingual administration may be used, whereby the compound enters the bloodstream directly from the mouth.The formulation suitable for oral administration includes both solid and liquid formulations.

[0147] Solid formulations include tablets, capsules (including particulates, liquids, microcapsules, or powders), lozenges (including liquid-filled lozenges), chews, multiparticulates and nanoparticles, gels, solid solutions, liposomal preparations, microencapsulated preparations, creams, films, ovules, suppositories, and sprays.

[0148] Liquid preparations include suspension, solution, syrup and elixir.Such preparations can be used as filler in soft or hard capsules, and typically contain carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oil, and one or more emulsifiers and / or suspending agents.Liquid preparations can also be prepared by reconstitution of solid, for example from sachet.

[0149] Binders are generally used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose.

[0150] Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.

[0151] Tablets may also optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80. If present, the surfactants may comprise from 0.2% (w / w) to 5% (w / w) of the tablet.

[0152] Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% (w / w) to 10% (w / w), preferably from 0.5% (w / w) to 3% (w / w) of the tablet.

[0153] In addition to the C4-carbonothioate-substituted tryptamine derivative compound, the tablet may contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, disintegrants make up 1% (w / w) to 25% (w / w) or 5% (w / w) to 20% (w / w) of the dosage form.

[0154] Other possible adjunct ingredients include antioxidants, colorants, flavorings, preservatives, and taste-masking agents.

[0155] For tablet dosage forms, a compound of the disclosure may comprise from 1% (w / w) to 80% (w / w) of the dosage form, more typically from 5% (w / w) to 60% (w / w) of the dosage form, depending on the desired effective amount of the compound.

[0156] Exemplary tablets contain up to about 80% (w / w) of compound, from about 10% (w / w) to about 90% (w / w) of binder, from about 0% (w / w) to about 85% (w / w) of diluent, from about 2% (w / w) to about 10% (w / w) of disintegrant, and from about 0.25% (w / w) to about 10% (w / w) of lubricant.

[0157] Tablet formulations are discussed in Pharmaceutical Dosage Forms: Tablets, Volumes 1-3, CRC Press (2008).

[0158] Pharmaceutical and recreational drug formulations comprising the C4-carbonothioate substituted tryptamine derivative compounds of the present disclosure may also be administered directly into the bloodstream, into muscle, or into internal organs. Thus, pharmaceutical and recreational drug formulations may be administered parenterally (e.g., by subcutaneous, intravenous, intraarterial, intrathecal, intraventricular, intracranial, intramuscular, or intraperitoneal injection). Parenteral formulations are typically aqueous solutions containing additives such as salts, carbohydrates, and buffers (in one embodiment, to pH 3-9), although for some applications, they may be more suitably formulated as sterile non-aqueous solutions used with a suitable vehicle such as sterile water, or as dry forms.

[0159] The formulations comprising the C4-carbonothioate-substituted tryptamine derivative compounds of the present disclosure for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compounds of the present disclosure may be formulated as solids, semi-solids, or thixotropic liquids for administration as implanted depots that provide modified release of active compounds. Examples of such formulations include drug-coated stents and poly(dl-lactic-co-glycolic acid) copolymers (PGLA) microspheres.

[0160] The pharmaceutical or recreational drug formulations of the present disclosure may also be administered topically to the skin or mucosa, i.e., on the skin or transdermally. Examples of pharmaceutical and recreational drug formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, cosmetics, oils, eye drops, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Examples of carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated (see, for example, Finnin, B. and Morgan, TM, 1999 J.Pharm.Sci, 88 (10), 955-958).

[0161] Other means of local administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection (eg Powderject®, Bioject®, etc.).

[0162] Pharmaceutical formulations and recreational drug formulations for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders.Liquid or solid pharmaceutical compositions may contain suitable pharmaceutically acceptable additives.In some embodiments, pharmaceutical compositions are administered by oral or nasal respiratory routes for local or systemic effect.Pharmaceutical compositions in pharmaceutically acceptable solvents may be nebulized by using inert gas.Nebulized solutions may be inhaled directly from nebulizing devices; alternatively, nebulizing devices may be attached to face masks tents or intermittent positive pressure breathing machines.Solution, suspension, or powder pharmaceutical compositions may be administered orally or intranasally, for example, from devices that deliver the formulation in an appropriate manner.

[0163] It should be noted that in some embodiments, the compound in the pharmaceutical formulation may act as a prodrug. Prodrugs represent modalities to regulate the bioavailability of drugs, regulate drug release timing, and / or reduce negative side effects. Similarly, formulation and delivery can be considered to obtain the above results. Thus, optimizing all three variables (prodrug moiety, formulation, delivery system) together can be an effective strategy in drug discovery. An example of a "targeting system" designed to specifically reach cells in the brain and obtained by simultaneously utilizing prodrugs, nanoparticles, and nasal administration strategies is described, for example, by Botti et al. (2021, Pharmaceutics, 13:1114).

[0164] In further embodiments in which the C4-carbonothioate substituted tryptamine derivative compounds of the present disclosure are used as recreational drugs, the compounds can be included in compositions such as food or food products, beverages, food seasonings, cosmetics, perfumes or bath additives, or personal care products such as oils (both for topical administration as massage oils, or for burning or aerosolizing).The compounds of the present disclosure can also be included in "vape" products, which can also contain nicotine and other agents such as flavorings.

[0165] Thus, it will be apparent that the C4-carbonothioate substituted tryptamine derivative compounds can be used as medicines or recreational drugs. Thus, in another aspect, the present disclosure provides, in at least one embodiment, a compound of formula (I): [ka] Use of a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group.

[0166] Pharmaceutical formulations containing the compounds of the present disclosure may be used to treat subjects and to treat cranial neuropathy in subjects. Thus, in a further embodiment, the present disclosure includes a method for treating cranial neuropathy, comprising: The method is: Chemical formula (I): [ka] administering to a subject in need thereof a pharmaceutical formulation comprising a compound having the formula: where R4 is a carbonothioate moiety or a derivative thereof; and where R 3a and R 3b are each independently a hydrogen atom, an alkyl group, or an aryl group, and wherein the pharmaceutical preparation is administered in an amount effective to treat a cranial nerve disorder.

[0167] Cranial neurological disorders include psychiatric disorders that can be treated, including, for example: Neurodevelopmental disorders (such as intellectual disability, global developmental delay, communication disorders, autism spectrum disorders, and attention-deficit hyperactivity disorder (ADHD)); bipolar disorder and related disorders (such as manic and depressive episodes); anxiety disorders (such as generalized anxiety disorder (GAD), agoraphobia, social anxiety disorder, specific phobias (e.g., natural events, medical events, animal events, situational events), panic disorder, and separation anxiety disorder); stress disorders (such as acute stress disorder, adjustment disorder, post-traumatic stress disorder (PTSD), and reactive attachment disorder); dissociative disorders (such as dissociative amnesia, dissociative identity disorder, and depersonalization / derealization disorder); somatoform disorders (such as a lack of awareness of the body's surface eating disorders (such as anorexia nervosa, bulimia nervosa, rumination, pica, and binge eating disorder); sleep disorders (such as narcolepsy, insomnia, hypersomnolence, breathing-related sleep disorder, parasomnia, and restless legs syndrome); disruptive behavior disorders (such as kleptomania, pyromania, intermittent explosive disorder, conduct disorder, and oppositional defiant disorder); depression (such as major mood dysregulation disorder, major depressive disorder (MDD), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depression, postpartum depression, and depression due to another medical condition, such as psychiatric and existential distress in the setting of a life-threatening cancer (ACS) Pharmacol.Transl.Sci.4: 553-562; J.Psychiatr.Res 137: 273-282); substance-related disorders (such as alcohol-related disorders, cannabis-related disorders, inhalant use-related disorders, stimulant use disorders, and smoking disorders); neurocognitive disorders (such as delirium); schizophrenia; obsessive-compulsive disorders (such as obsessive-compulsive disorder (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania, skin picking disorder, substance / medication-induced obsessive-compulsive disorder, and obsessive-compulsive disorder associated with another medical condition); and personality disorders (such as antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizophrenic personality disorder).Cranial nerve disorders further include headache disorders; headache disorders include migraine (e.g., aura migraine, non-aura migraine, menstrual migraine, chronic migraine, vestibular migraine, abdominal migraine, hemiplegic migraine) and other headache disorders.

[0168] In one aspect, the compounds of the present disclosure may be used to contact a receptor, thereby modulating the receptor. Such contacting includes combining the compounds of the present disclosure with the receptor under in vitro conditions, for example, by introducing the compound into a sample containing the receptor (e.g., a sample containing purified receptor, or a sample containing cells having the receptor). In vitro conditions further include the conditions described in Example 1 herein. Contacting further includes combining the compounds of the present disclosure with the receptor under in vivo conditions. Such in vivo conditions include, for example, administering a pharmacologic effective amount of the compounds of the present disclosure to an animal or human subject, where the compounds of the present disclosure are formulated with a pharmacologic active carrier, diluent, or excipient, as described herein above, thereby treating the subject. 5 When contacted with the receptor, the compounds may activate the receptor or inhibit the receptor.

[0169] In one aspect, receptors that may be contacted with the compounds of the present disclosure include, for example, 5-HT 1A Receptor, 5-HT 2A Receptor, 5-HT 1B Receptor, 5-HT 2B Receptor, 5-HT 3A receptor, ADRA1A receptor, ADRA2A receptor, CHRM1 receptor, CHRM2 receptor, CNR1 receptor, DRD1 receptor, DRD2S receptor, OPRD1 receptor, GABAA receptor, or NMDAR receptor.

[0170] Thus, in a further aspect, the condition that may be treated according to the present invention may be any receptor-mediated disorder, for example, 5-HT 1A Receptor-Mediated Disorders, 5-HT 2A Receptor-Mediated Disorders, 5-HT 1B Receptor-Mediated Disorders, 5-HT 2B Receptor-Mediated Disorders, 5-HT3A Receptor-mediated disorder, ADRA2A receptor-mediated disorder, AVPR1A receptor-mediated disorder, CHRM1 receptor-mediated disorder, CHRM2 receptor-mediated disorder, CNR1 receptor-mediated disorder, DRD1 receptor-mediated disorder, DRD2S receptor-mediated disorder, OPRD1 receptor-mediated disorder, GABAA receptor-mediated disorder, or NMDAR receptor-mediated disorder. Such disorders include, but are not limited to, schizophrenia, psychosis, attention deficit hyperactivity disorder, autism, and bipolar disorder.

[0171] In some embodiments, when the compound contacts the receptor, it can modulate the receptor. However, at the same time, the other receptor is not modulated. For example, the compound can modulate a first receptor (e.g., 5-HT 1A receptor), while the compound may simultaneously activate or inhibit a second receptor (e.g., 5-HT 2A receptors); or, the first 5-HT 2A Receptors and secondary 5-HT 1A Upon contact with the receptor, the compound binds the first 5-HT 2A Can modulate receptors, e.g., 5-HT 2A The compound activates or inhibits the second 5-HT 1A Does not modulate receptors.

[0172] In one embodiment, in one aspect, upon administration, the compounds of the present disclosure can interact with a transmembrane transport protein in a subject, thereby regulating the transmembrane transport protein and exerting a pharmacological effect. Such contacting can include combining the compound with the transmembrane protein under in vitro conditions, for example, by introducing the compounds of the present disclosure into a sample containing the transmembrane transport protein, for example, a sample containing a purified transmembrane transport protein or a sample containing a cell containing the transmembrane transport protein. Contacting can further include combining the compounds of the present disclosure with the transmembrane transport protein under in vivo conditions. Such in vivo conditions can include, for example, administration of a pharmacologic effective amount of a compound of the present disclosure to an animal or human subject, where the compound of the present disclosure is formulated with a pharmacologic active carrier, diluent, or excipient, as described herein above, thereby treating the subject.

[0173] In one embodiment, in one aspect, the transmembrane transport protein can be a dopamine activated transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transport protein.

[0174] In one embodiment, in one aspect, upon administration, a compound having formula (I) is hydrolyzed in vivo to form a compound having formula (VI): [ka] It should be noted that it is possible to form a compound having the formula: Here, R 3a and R 3b each independently represents a hydrogen atom, an alkyl group, or an aryl group; and wherein the compound having formula (VI) interacts with the receptor, thereby modulating the receptor and exerting a pharmacological effect in the subject.In this regard, the compounds of the present disclosure can be formulated as prodrug pharmaceutical formulations, i.e., the formulated compound itself does not mediate the pharmacological effect, but rather the compound obtained after in vivo hydrolysis of the formulated compound by the subject mediates the pharmacological effect.The hydrolysis occurs, for example, in the digestive tract of the subject upon oral delivery of the prodrug pharmaceutical formulation.

[0175] We now describe methods for making the disclosed C4-carbonothioate substituted tryptamine derivative compounds. It should be noted at the outset that, in general, the disclosed C4-carbonothioate substituted tryptamine derivative compounds can be prepared by any suitable method, including any organic chemical synthesis method, biosynthetic method, or a combination thereof.

[0176] Examples of suitable chemical reactions that can be performed in accordance with the present invention are shown in Figures 3A(i), 3A(ii), 3A(iii) and 4A (panel I); and are described in further detail in the Examples section hereinafter.

[0177] Generally, as known to those skilled in the art, to carry out a chemical synthesis reaction, selected reactants are reacted under suitable reaction conditions for the reactants to chemically react with each other to produce the product, i.e., the C4-carbonothioate substituted tryptamine derivative compound of the present disclosure. Such suitable reaction conditions can be selected, adjusted, and optimized as known to those skilled in the art. The reaction may be carried out in any suitable reaction vessel (e.g., tube, bottle). Suitable solvents used are, for example, polar solvents such as dichloromethane, dimethylformamide, dichloroethane, toluene, and so-called participating solvents such as acetonitrile and diethyl ether. Suitable temperatures can range, for example, from about -78°C to about 60°C. Additionally, a catalyst (also known as a promoter) may be included in the reaction (such as iodonium dicollidine perchlorate (IDCP), any silver or mercury salt, trimethylsilyl trifluoromethanesulfonate (TMS-triflate, TMSOTf) or trifluoromethanesulfonic acid (triflic acid, TfOH), N-iodosuccinimide, methyl triflate, etc.). Additionally, the reaction time may vary. As will be readily understood by those skilled in the art, the reaction conditions can be optimized, for example, by preparing multiple reaction preparations and reacting them in separate reaction vessels under different reaction conditions (e.g., at different temperatures, using different solvents, etc.), evaluating the products of the obtained C4-carboxylic acid substituted tryptamine derivative compounds, adjusting the reaction conditions, and selecting the desired reaction conditions.

[0178] Referring to Figures 3A(i) and 3A(ii), in one embodiment, the compound having formula (I) has formula E(VI): [ka] may be a compound having the formula: A method for preparing a compound having the chemical formula E(VI) comprises chemical reaction (h): [ka] may include carrying out; Here, the chemical reaction is carried out under suitable conditions to convert compound 8 to form E(VI).

[0179] Suitable and sufficient reaction conditions for carrying out chemical reaction (h) include carrying out reaction (h) in the presence of about 0.1 M to 1.5 M tetrabutylammonium fluoride (TBAF), for example in tetrahydrofuran (THF), including about 0.75, 0.9 M, 1 M, 1.1 M, or 1.25 M TBAF. Thus, TBAF can be added dropwise, for example at 0° C., and after 30 minutes, water can be added, and the aqueous layer can be separated and extracted with dichloromethane (DCM) to obtain E(VI).

[0180] With reference to FIG. 3A(ii), it can be said that chemical reaction (h) is the final reaction in chemical synthesis pathway A to synthesize compound 9 (corresponding to compound E(VI)) from compound 8. Thus, with further reference to FIG. 3A(ii), it will be clear that further chemical reactions may be carried out to make compound E(VI). For example, compound 7 may further be selected to carry out chemical reaction (g) shown in FIG. 3A(ii) to synthesize compound 8, which may in turn be used to synthesize compound 9 by carrying out chemical reaction (h). Thus, as another example, compound 6 may further be selected to carry out chemical reaction (f) shown in FIG. 3A(ii) to synthesize compound 7, which may in turn be used to synthesize compound 8 by carrying out chemical reaction (g), which may in turn be used to synthesize compound 9 by carrying out chemical reaction h. Thus, similarly, with reference to FIG. 3A(i), any one of compounds 1, 2, 3, 4, or 5 is selected and one or more suitable chemical reactions selected from the depicted reactions (a), (b), (c), (d), and (e) are carried out to obtain compound 6, which, as described above, may be used to synthesize compound 7, which may in turn be used to synthesize compound 8, which may in turn be used to synthesize compound 9.

[0181] Thus, in one exemplary embodiment, chemical reaction (g) can be carried out prior to reaction (h) (in the sequential (i.e., alphabetical) order shown).

[0182] In one exemplary embodiment, chemical reactions (f) and (g) can be carried out sequentially (in the sequential (i.e., alphabetical) order shown) prior to reaction (h).

[0183] In one exemplary embodiment, chemical reactions (e), (f), and (g) can be carried out sequentially (in the sequential (i.e., alphabetical) order shown) prior to reaction (h).

[0184] In one exemplary embodiment, chemical reactions (d), (e), (f), and (g) are carried out sequentially (in the sequential (i.e., alphabetical) order shown) prior to reaction (h).

[0185] In one exemplary embodiment, chemical reactions (c), (d), (e), (f), and (g) can be carried out sequentially (in the sequential (i.e., alphabetical) order shown) prior to reaction (h).

[0186] In one exemplary embodiment, chemical reactions (b), (c), (d), (e), (f), and (g) can be carried out sequentially (in the sequential (i.e., alphabetical) order shown) prior to reaction (h).

[0187] In an exemplary embodiment, chemical reactions (a), (b), (c), (d), (e), (f), and (g) can be carried out sequentially (in the sequential (i.e., alphabetical) order shown) prior to reaction (h).

[0188] Referring now to FIG. 3A(iii), in one embodiment, the compound having formula (I) has formula E(VI): [ka] may be a compound having the formula: A method for preparing a compound having the chemical formula E(VI) involves chemical reaction (l): [ka] may include carrying out; Here, a chemical reaction is carried out under suitable conditions to convert compound 15 to form E(VI).

[0189] Suitable and sufficient reaction conditions for carrying out chemical reaction (l) include adding a solution of benzyl chlorothioformate in DMF to a solution of compound 15 and potassium carbonate in dimethylformamide (DMF) and carrying out reaction (l) by reacting reactant 15 with benzyl chlorothioformate, for example, at room temperature, for example, for at least 6 hours, e.g., about 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, or 24 hours, to form E(VI).

[0190] Referring to FIG. 3A(iii), chemical reaction (l) is the final reaction in chemical synthesis pathway B to synthesize compound 9 (corresponding to compound E(VI)) from compound 15. It will be apparent, therefore, that further chemical reactions may be carried out to make compound E(VI). Thus, for example, further compound 14 may be selected to synthesize compound 15 by carrying out chemical reaction (k) shown in FIG. 3A(iii), which may in turn be used to synthesize compound 9 by carrying out chemical reaction (l). Thus, as another example, compound 13 may be selected to synthesize compound 14 by carrying out chemical reaction (j) shown in FIG. 3A(iii), which may in turn be used to synthesize compound 15 by carrying out chemical reaction (k), which may in turn be used to synthesize compound 9 by carrying out chemical reaction (l). Thus, similarly, with reference to Figure 3A(iii), it will be apparent that compound 12 may be selected, and one or more suitable chemical reactions may be selected and carried out by reference to Figure 3A(iii) to obtain compound 13, which may be used to synthesize compound 14, as described above, which may in turn be used to synthesize compound 15, which may in turn be used to synthesize compound 9. It is further noted that compound 11 may be used to carry out a reaction to form compound 9 from compound 15. Compound 11 may optionally be synthesized from compound 10 according to chemical reaction (m) shown in Figure 3A(iii).

[0191] Thus, in one exemplary embodiment, reaction (l) is preceded by chemical reaction (k) (in alphabetical order).

[0192] In one exemplary embodiment, chemical reactions (j) and (k) can be carried out sequentially (in the sequential (i.e., alphabetical) order shown) prior to reaction (l).

[0193] In an exemplary embodiment, chemical reactions (i), (j), and (k) can be carried out sequentially (in the sequential (i.e., alphabetical) order shown) prior to reaction (l).

[0194] In an exemplary embodiment, reaction (m) can optionally be carried out prior to chemical reaction (l).

[0195] In some embodiments, the compound referred to herein can be isolated in pure form or substantially pure form, including but not limited to the C4-carbonothioate substituted tryptamine derivative having formula E(I), E(II), E(III), E(IV), E(V), E(VI), E(VII), E(VIII), E(IX), E(X), E(XI), E(XII), E(XIII), E(XIV), E(XV), E(XVI), E(XVII), E(XVIII), E(XIX) or E(XX).Therefore, the compound referred to herein can be, for example, at least 90%, 95%, 96%, 97%, or 98%, or at least 99% pure.

[0196] It will now be apparent from the above description that novel C4-carbonothioate substituted tryptamine derivatives are disclosed herein. The C4-carbonothioate substituted tryptamine derivatives can be formulated for use as pharmaceutical agents or recreational drugs. Examples of embodiments and aspects of the present disclosure are further illustrated by the following examples.

[0197] Working Example Example 1: Synthesis and analysis of the first C4-carbonothioate substituted tryptamine derivative This Example 1 first describes an exemplary method for the synthesis of exemplary compounds disclosed herein, in particular, the synthesis of a C4-carbonothioate substituted tryptamine having formula E(VI), with reference to Figures 3A(i), 3A(ii) and 3A(iii). Figures 3A(i) and 3A(ii) together show a first exemplary synthetic pathway A, including chemical reactions (a), (b), (c), (d), (e), (f), (g) and (h). Figure 3A(iii) shows a second exemplary synthetic pathway B, including chemical reactions (i), (j), (k), (l) and (m).

[0198] Thus, referring first to FIG. 3A(i), a dry three-neck RBF was charged with 4-benzyloxyindole 1 (14.0 g, 62.7 mmol) and Et2O (327 mL) under an argon atmosphere. The mixture was cooled to 0° C. in an ice bath. An argon sparger was placed in the RBF and bubbled into the reaction mixture to drive evolved HCl gas out of the reaction. Oxalyl chloride (10.9 mL, 129 mmol) was added dropwise over 40 min while maintaining a low temperature. The mixture was stirred at 0° C. for 5 h (see reaction (a)). The argon bubble was removed and dimethylamine (157 mL, 314 mmol) (2 M in THF) was added dropwise over 1 h at 0° C. using a separatory filter. The mixture was allowed to warm to room temperature and stirred overnight (see reaction (b)). Diethyl ether (200 mL) was added and the mixture was cooled to 0° C. The resulting precipitate (crude product 3) was filtered and transferred to an Erlenmeyer flask. The solid was suspended in water (300 mL) and stirred for 30 min. It was then filtered and washed with more HO to remove residual salts. The crude solid was further dried under vacuum and used in the next step without further purification.

[0199] Lithium aluminum hydride (LiAlH4) (60.2 mL, 120 mmol) (2 M in THF) was added to a dry three-neck flask under an argon atmosphere. The flask was fitted with a reflux condenser and an additional filter. Dry 1,4-dioxane (100 mL) was added and the mixture was heated to 60° C. in an oil bath. In a separate flask, compound 3 (7.46 g, 23.1 mmol) was dissolved in a mixture of THF (60 mL) and 1,4-dioxane (120 mL). With rapid stirring, this solution was added dropwise to the reaction flask over 1 h using an additional filter. The oil bath temperature was kept at 70° C. for 4 h, then vigorously refluxed at an oil bath temperature of 95° C. overnight (16 h). The reaction was placed in an ice bath and a solution of distilled H2O (25 mL) in THF (65 mL) was added dropwise to quench the LiAlH4, resulting in a grey flocculent precipitate. Et2O (160 mL) was added to aid in dispersion of the compound and improve filtration. The slurry was stirred for 1 h and the mixture was then filtered using a Büchner funnel. The filtered precipitate was washed on the filter with hot Et2O (2x 200 mL), triturated, returned to the reaction flask and stirred vigorously with additional hot Et2O (300 mL). The slurry was filtered and the precipitate was washed on the filter with Et2O (120 mL) and hexanes (2x 120 mL). All organic filtrates were combined and dried (MgSO4). After removing the drying agent by filtration, the filtrate was concentrated under vacuum and dried under high vacuum. The crude residue was triturated with EtOAc / hexanes (1:9, 25 mL) to give the crude product (4), which was used in the next step without further purification (see reaction (C)).

[0200] To a solution of 4 (5.00 g, 17.0 mmol) in dry THF (100 mL) cooled to −78 °C under an argon atmosphere was added dropwise a 1 M solution of potassium bis(trimethylsilyl)amide (KHMDS) (18.7 mL, 18.7 mmol) in THF. After stirring at −78 °C for 1 h, a solution of triisopropylsilyl chloride (TIPSCl) (3.82 mL, 17.8 mmol) in THF (19.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 1 h, the reaction was quenched with H2O (40 mL), the THF was evaporated under reduced pressure, and the aqueous solution was further diluted with H2O (75 mL) and extracted with DCM (3x 100 mL). The organic layers were washed with combined brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (MeOH / DCM 5:95 to 10:90) to give the pure product as a light brown oil (6.99 g, 91%). The product (5) was characterized as follows: 1 H NMR (400 MHz, CDCl3) δ 7.58 - 7.51 (m, 2H), 7.44 - 7.39 (m, 2H), 7.38 - 7.33 (m, 1H), 7.12 (dd, J = 8.4, 0.8 Hz, 1H), 7.08 - 6.99 (m, 1H), 6.94 (s, 1H), 6.60 (dd, J = 7.7, 0.7 Hz, 1H), 5.20 (s, 2H), 3.12 - 3.04 (m, 2H), 2.67 - 2.58 (m, 2H), 2.16 (s, 6H), 1.69 (h, J = 7.5 Hz, 3H), 1.16 (d, J = 7.5 Hz, 18H) (see reaction (d)).

[0201] To a stirred solution of 5 (6.99 g, 15.5 mmol) dissolved in 95% EtOH (310 mL) was added 10% palladium on carbon (1.65 g, 1.55 mmol). The mixture was placed under vacuum for 5 min and then alternately purged with H2 gas until a pressurized hydrogen atmosphere was formed, then allowed to stir at room temperature for 75 min. The palladium on carbon was removed by filtration through Celite, and the filtrate, dried over anhydrous magnesium sulfate, was concentrated under reduced pressure to give 6 (4.67 g, 84%) as an off-white solid. The data confirming 6 are as follows: MS-ESI: Calculated: 361.2670; Observed: 361. 2668 m / z [M+H] + . 1 H NMR (400 MHz, MeOD) δ 6.98 (d, J = 8.6 Hz, 2H), 6.91 (dd, J = 8.4, 7.5 Hz, 1H), 6.42 (dd, J = 7.5, 0.8 Hz, 1H), 3.06 (t, J = 6.9 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.39 (s, 6H), 1.72 (p, J = 7.5 Hz, 3H), 1.16 (d, J = 7.5 Hz, 18H). In particular, the organosilyl substituent at the N1 position of compound 6 may be abbreviated as TIPS (triisopropylsilyl). Thus, compound 6 may also be referred to as TIPS-psilocin (see reaction (e)).

[0202] Referring now to FIG. 3A(ii), a solution of compound 6 (100 mg, 277 μmol) and 4-chloronitrophenylformate (58.7 mg, 291 μmol) in dichloromethane (DC (1.39 mL) was cooled to 0° C. to which was added N,N-diisopropylethylamine (96.6 μL, 555 μmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 2 h. After 2 h, TLC (MeOH / DCM 12:88) showed almost complete conversion to the desired product 7 (see reaction (f)). To the reaction mixture (crude product 7) was added a solution of benzyl mercaptan (49.3 μL, 416 μmol) and N,N-diisopropylethylamine (96.5 μL, 554 μmol) with vigorous stirring at room temperature. After 2 h, the volatiles were removed under vacuum and the crude residue 8 was used in the next step without further purification (see reaction (g)).

[0203] To a solution of crude product 8 (141 mg, 276 μmol) in dry THF (1.38 mL) was added dropwise tetrabutylammonium fluoride (TBAF) solution (1 M in tetrahydrofuran (THF), 414 μL, 414 μmol) at 0° C. After 30 min, water (2 mL) was added and the aqueous layer was separated and extracted with DCM (3× 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (MeOH / DCM 1:9) to give the pure product as a yellow waxy solid (33 mg, 34%). The following data was obtained for structure confirmation: MS-ESI, calculated: 355.1475; observed: 355.1467 m / z [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.41 - 7.26 (m, 5H), 7.21 (d, J = 8.2 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.99 - 6.94 (m, 1H), 6.88 (dd, J = 7.6, 0.8 Hz, 1H), 4.20 (s, 2H), 2.92 (dd, J = 9.0, 6.7 Hz, 2H), 2.66 - 2.58 (m, 2H), 2.30 (s, 6H). These data confirmed the structure of the compound having formula 9 (see reaction (h)). The purity of compound 9 was estimated to be 95%. It should be noted that the compound having formula 9 corresponds to E(VI).

[0204] Compound 9 (formula E(VI)) can also be synthesized using an alternative route without the production of the psilocin intermediate according to the exemplary synthetic method shown in FIG. 3A(iii). Referring now to FIG. 3A(iii), to a mixture of triphosgene 10 (0.50 g, 1.68 mmol) and triethylamine (694 μL, 4.96 mmol) in DCM (19.0 mL) at −10° C. (NaCl / water / ice bath) was added a solution of benzyl mercaptan (582 μL, 4.96 mmol) in DCM (1.5 mL). The mixture was allowed to warm to room temperature and stirred for 2 h. Two-thirds of the volatiles were removed under reduced pressure and hexane (25 mL) was added to the residue. The resulting precipitate was filtered and the filtrate was concentrated under vacuum to give crude product 11 as a yellow oil; this was used in the next step without further purification (see reaction (m)). The synthesis of psilocin (15) has been reported previously (Shirota et al., J. Nat. Prod. 2003, 66:885-887; Kargbo et al., ACS Omega 2020, 5:16959-16966) but is shown for clarity and completeness in Figure 3A(iii) (see reactions (i), (j), and (k)). To a solution of psilocin 15 (50.0 mg, 245 μmol) and potassium carbonate (33.8 mg, 245 μmol) in DMF (1.00 mL) was added a solution of 11 (137 mg, 734 μmol, 3 equiv.) in dimethylformamide (DMF) (500 μL). The resulting mixture was stirred at room temperature for 18 h. TLC analysis (MeOH / DCM 15:85, UV and KMnO4 staining) against an authentic standard of compound 9 (i.e., compound E(VI)) confirmed that compound 9 (R f :0.4) and about 40% remaining psilocin (see reaction (l)).

[0205] It should be noted that there are several ways to introduce a thiocarbonate moiety into a molecule. Such methods include: (1) generation of activated p-nitrophenyl carbonate followed by displacement of p-nitrophenol with the desired thiol (see reactions (f) and (g) in FIG. 3A(ii)); or (2) use of different thiocarbonylation reagents, i.e., alkyl chlorothioformates (e.g., compound 11 in FIG. 3A(iii)) or alkyl imidazolothioformates (16): [ka] Including the use of.

[0206] Due to the presence of competing nucleophilic sites on psilocin (4-OH and indole nitrogen), the above thiocarbonylating reagents show different reactivities towards this molecule. To obtain an optimized synthetic route for incorporating thiocarbonates, synthetic reactions (e.g., compounds 11, 16) using various reagents and reactions (e.g., reactions (f), (g), or (l)) may be performed and the different synthetic routes may be compared, e.g., for yield, ease of operation, and the preferred reagent and reaction may be selected.

[0207] The difference between the synthetic pathways shown in Figures 3A(i) and 3A(ii) on the one hand (pathway A) and 3A(iii) on the other hand (pathway B) is that in synthetic pathway A, the aromatic nitrogen requires protection to achieve the desired reactivity between the p-nitrophenylformylating reagent and psilocin, i.e., N インドール - the use of the TIPS intermediate (compound 6). However, in synthetic route B, the use of reagent 11 does not require protection of the aromatic indole nitrogen atom, resulting in a synthetic route that requires fewer overall steps to be carried out.

[0208] Assessment of cell viability upon treatment with psilocin derivatives To establish suitable ligand concentrations for competitive binding assays, the PrestoBlue assay was first performed. The PrestoBlue assay measures cell viability based on the metabolic reduction of the redox indicator resazurin and is the preferred method for routine cell viability assays (Terrasso et al., 2017, J. Pharmacol. Toxicol. Methods 83:72). The results of these assays were performed as a preliminary screen for any significant toxic effects on cell cultures, in part at concentrations up to 1 mM, using both control ligands (e.g., psilocybin, psilocin, DMT) and novel derivatives. A known cytotoxin (Triton X-100, Pyrgiotakis G. et al., 2009, Ann. Biomed. Eng. 37:1464-1473) was included as a general marker of toxicity. Drug-induced changes in cell health in simple in vitro systems such as the HepG2 cell line are typically used as a frontline screening approach in the pharmaceutical industry (Weaver et al., 2017, Expert Opin. Drug Metab. Toxicol. 13: 767). HepG2 is the most commonly used human hepatoma in drug metabolism and hepatotoxicity testing (Donato et al., 2015, Methods Mol Biol 1250:77). Herein, HepG2 cells were cultured using standard procedures according to the manufacturer's protocol (ATCC, HB-8065). Briefly, cells were cultured in Eagle's minimum essential medium supplemented with 10% fetal bovine serum and grown at 37°C in the presence of 5% CO2. To test various compounds with this cell line, cells were seeded at 20,000 cells / well in clear 96-well culture plates. After cells were allowed to attach and grow for 24 hours, compounds were added at 1 mM, 10 mM, 100 mM, and 1 mM. Methanol was used as vehicle at concentrations of 0.001, 0.01, 0.1, and 1%. Concentrations of TritonX used as a positive control for toxicity were 0.0001, 0.001, 0.01, and 0.1%.Cells were incubated with compounds for 48 hours and then cell viability was assessed by PrestoBlue assay (ThermoFisher Scientific, P50200) according to the manufacturer's protocol. PrestoBlue reagent was added to cells and incubated for 1 hour before reading. Absorbance readings were performed at 570 nm with a reference of 600 nm on a SpectraMax iD3 plate reader. Untreated cells were considered 100% viable. Bar graphs show mean ± SD (n=3). Significance was determined by two-way ANOVA followed by Dunnett's multiple comparison test and is indicated by *** (P<0.0001), ** (P<0.001), * (P<0.005). Data obtained for derivatives with formula E(VI) are labeled "E(VI)" on the x-axis in Figures 3B and 3C.

[0209] Radioligand receptor binding assay 5-HT 2A Activity at the receptor was assessed as follows: Evaluation of drug binding is an essential step in the characterization of all drug-target interactions (Fang 2012, Exp. Opin. Drug Discov. 7:969). The binding affinity of a drug to its target is traditionally considered an acceptable surrogate for its in vivo efficacy (Nunez et al. 2012, Drug Disc. Today 17:10). Competitive assays, also called displacement or regulatory binding assays, are a common approach to measure the activity of ligands at target receptors (Flanagan 2016, Methods Cell Biol 132: 191). In these assays, a standard radioligand acting as either an agonist or antagonist is considered to be associated with a specific receptor. G protein-coupled receptor 5-HT 2A in the case of,[ 3 H]ketanserin is a 5-HT 2A It is an existing antagonist that is commonly used in competitive assays to evaluate the competitive activity of new drug candidates at the receptor (Maguire et al., 2012, Methods Mol Biol 897: 31). Thus, 5-HT 2ATo evaluate the activity of novel C4-carbonothioate-substituted tryptamine derivatives at the receptor, 3 A competitive assay utilizing [H]ketanserin was used as follows: SPA beads (RPNQ0010), [ 3 H]ketanserin (NET1233025UC), 5-HT 2A Membranes containing 5-HT (ES-313-M400UA) and isoplate-96 microplates (6005040) were both purchased from PerkinElmer. Radioactive binding assays were performed using Scintillation Proximity Assay (SPA). For saturation binding assays, 5-HT 2A A mixture of receptor-containing membranes (10 μg) was pre-bound to SPA beads (1 mg) in binding buffer (50 mM Tris-HCl (pH 7.4), 4 mM CaCl2, 1 mM ascorbic acid, 10 mM pargyline HCl) for 1 h at room temperature on a tube rotator. After pre-binding, the beads and membranes were 3 Increasing amounts of [H]ketanserin (0.1525 nM to 5 nM) were dispensed into an Isoplate-96 microplate and incubated for 2 h at room temperature in the dark with shaking. After incubation, samples were read on a MicroBeta2 macroplate counter (Perkin Elmer). Nonspecific binding measurements were performed in the presence of 20 mM spiperone (S7395-250MG, Sigma). The equilibrium binding constant (K d ) was determined from saturation binding curves using the "single-site saturation binding analysis" method in GraphPad PRISM software (version 9.2.0). Competitive binding assays were performed using a fixed concentration (1 nM) of [ 3 H]ketanserin and different concentrations (3 nM-1 mM) of tryptophan, psilocin (30 pM-10 mM), or unlabeled test compounds (3 nM-1 mM) were used as in the saturation binding assay. i Values ​​were calculated from competitive displacement data using competitive binding analysis in GraphPad PRISM software. Tryptophan was included as a negative control because tryptophan inhibits 5-HT 2AOn the other hand, psilocin was used as a positive control because it has no activity at the 5-HT 2A This is because it has established binding activity to the 5-HT receptor (Kim et al., 2020, Cell 182: 1574). 2A [ 3 Panel A shows the saturation binding curves of 5-HT [H]ketanserin. 2A [ 3 The specific saturation ligand binding of [H]ketanserin (0.1525 nM to 5 nM) is shown, which was obtained after subtracting the nonspecific binding values ​​(shown in panel B). Specific binding in counts per minute (cpm) was calculated by subtracting nonspecific binding from total binding. Specific binding (pmol / mg) is expressed as pmol [H]ketanserin bound per mg protein in the assay. 3 H] ketanserin. d was calculated by fitting the data to a one-site binding model in PRISM software (version 9.2.0). Figure 3E shows the results of two independent experiments (panels A and B) generating two competitive binding curves with psilocin as a positive control (binding). Figure 3F shows competitive binding curves for psilocybin (panel A) and tryptophan (panel B). Psilocybin inhibits 5-HT in vivo. 2A The intact psilocybin molecule itself is known to release the bound metabolite psilocin, but not 5-HT 2A 3G shows very weak (McKenna and Peroutka, 1989, J. Neurosci. 9: 3482) or almost negligible (PDSP Certified Data; https: / / pdsp.unc.edu / databasess / pdsp.php) binding. Tryptophan was included as a negative control (non-binding). The competitive binding curve for the compound having formula E(VI) (denoted as "E-VI") is shown in FIG. 3G.

[0210] 5-HT 1A Cell lines and control ligands used to evaluate activity against CHO-K1 / Ga15 (GenScript, M00257)(-5-HT 1A ) and CHO-K1 / 5-HT 1A / Ga 15 (GenScript, M00330)(+5-HT 1A ) cell line was used. 15 Ga 15 A control cell line constitutively expressing 5-HT 1A lacking the transgene encoding the receptor but still responding to forskolin; thus, the cAMP response to forskolin is not related to the 5-HT 1A It should be the same regardless of the presence or absence of the agonist. 1A / Ga 15 The cells were cultured in a CHO-K1 host background to express 5-HT 1A Stably expressing the receptor. In particular, 15 induced a calcium efflux response and reduced the calcium efflux response in control cell lines and in 5-HT 1A +5-HT is a promiscuous G protein known to be present in both IL-1 and IL-2 cell lines. 1A In cells, Ga 15 But, G ai / o Instead of activated 5-HT, this could theoretically reduce the cAMP response (Rojas and Fiedler, 2016, Front Cell Neurosci. 10: 272). Therefore, it is important to ensure that a sufficient cAMP response is observed, thereby reducing the amount of activated 5-HT. 1A G to receptor ai / o As positive controls, indicating measurable mobilization of the protein, two known 5-HT 1A These included agonists, namely psilocin (Cameron and Olson, 2018, ACS Chem Neurosci. 9:2344) and serotonin (Rojas and Fiedler, 2016, Front Cell Neurosci. 10: 272). In contrast, tryptophan inhibits 5-HT 1AIt is not known to activate the receptor and was therefore used as a negative control. Cells were maintained in complete growth medium as recommended by the supplier (GenScript); complete growth medium consisted of: Ham's F12 Nutrient mix (HAM's F12, GIBCO #11765-047) containing 10% fetal bovine serum (FBS) (Thermo Scientific #12483020), 200 mg / ml Zeocin (Thermo Scientific #R25005) and / or 100 mg / ml Hygromycin (Thermo Scientific #10687010). Cells were cultured at 37°C in a humidified incubator with 5% CO2. Cells were maintained as recommended by the cell supplier. Briefly, vials containing cells were removed from liquid nitrogen and quickly thawed in a 37°C water bath. Just before the cells were completely thawed, the outside of the vial was decontaminated by spraying with 70% ethanol. The cell suspension was then removed from the vial, added to warm (37°C) complete growth medium, and centrifuged at 1,000 rpm for 5 minutes. The supernatant was discarded, and the cell pellet was resuspended in another 10 ml of complete growth medium and added to a 10 cm cell culture dish (Greiner Bio-One #664160). The medium was changed every 3 days until the cells reached approximately 90% confluence. The growing cells at approximately 90% confluence were then split 10:1 for cell maintenance or for use in experiments.

[0211] 5-HT 1A Assessment of receptor modulation 5-HT 1A Activation inhibits cAMP production, so 5-HT 1A The agonist activity of the test molecules in the endothelial cells was measured by the decrease in cAMP levels caused by the application of 4 mM forskolin. The change in intracellular cAMP levels due to the treatment of the novel molecules was measured using the cAMP-Glo ​​assay kit (Promega #V1501). Briefly, +5-HT 1A Cells were seeded into columns 1-6 of a white-walled, clear-bottom 96-well plate (Corning, #3903) and incubated with basal 5-HT 1ACells were seeded in columns 7-12. Both cells were seeded at a density of 30,000 cells / well in 100 ml of complete growth medium and cultured for 24 h in a humidified incubator at 37 °C and 5% CO2. On the day of the experiment, the medium of the cells was replaced with serum / antibiotic-free medium. The cells were then treated for 20 min with the test molecules dissolved in induction medium (serum / antibiotic-free medium containing 4 mM forskolin, 500 mM IBMX (isobutyl-1-methylxanthine, Sigma-Aldrich, Cat. No. 17018) and 100 mM (RO 20-1724, Sigma-Aldrich, Cat. No. B8279). Forskolin induced cAMP production, whereas IBMX and RO 20-1724 inhibited cAMP degradation. Luminescence levels of cells incubated in induction medium (containing 4 mM forskolin) without the molecule being tested were normalized to represent 100% cAMP in this assay. PKA was added to the lysate and mixed, followed by the addition of a PKA substrate. PKA was activated by cAMP, and the amount of ATP consumed by PKA phosphorylation directly corresponded to the cAMP level in the lysate. Reduced ATP caused reduced conversion of luciferin to oxyluciferin, resulting in reduced 5-HT 1A Activation resulted in decreased luminescence. 1A Figure 3I shows increasing levels of cAMP in cultured cells incubated with increasing concentrations of forskolin, independent of expression. 1A and 5-HT1A) did not decrease the cellular cAMP level, and +5-HT 1A This molecule causes 5-HT in cells 1A Figure 3J shows that increasing psilocin levels suppressed 4 mM forskolin-stimulated 5-HT 1A Receptor expressing cells (+5-HT 1A ) and demonstrated that psilocin-induced 5-HT in these cells 1A Conversely, this trend of decreasing %cAMP levels with increasing psilocin suggests a 5-HT1A Figure 3K shows that increased serotonin (5-HT) levels suppressed 4 mM forskolin-stimulated 5-HT 1A It was shown that cAMP levels in receptor-expressing cells are reduced, and that serotonin (5-HT)-induced 5-HT in these cells 1A Conversely, this trend of decreasing %cAMP levels with increasing serotonin (5-HT) suggests that 5-HT 1A It is not observed in cells lacking receptor expression. 1A Receptor binding assessment is shown in Figure 3L. 1A Comparison of the data obtained in cultures with those obtained in -5-HT1A cultures suggests a modest receptor modulation at higher ligand concentrations.

[0212] In vitro metabolic stability assays using intestinal fractions, liver fractions, serum fractions, alkaline phosphatase buffer, esterase buffer, and control buffer A fundamental evaluation in drug discovery is the assessment of absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME / PK) (Eddershaw et al., 2000, Drug Discovery Today 5(9):409-414). The first ADME screen for a new chemical entity is the in vitro metabolic stability screen (Ackley et al., 2004, Methods in Pharmacology and Toxicology Optimization in Drug Discovery (in vitro methods), Yan Z, Caldwell GW Eds; Humana Press Inc, New Jersey, pp.151-164). Drug stability upon exposure to human liver microsomes and liver S9 cell fractions is a common in vitro assay that estimates in vivo drug metabolism by the liver (Richardson et al., 2016 Drug Metabolism Letters 10:83-90). First-pass metabolism is also often estimated in vitro using intestinal microsomal and cellular S9 fractions (Hatley et al., 2017, Biopharmaceuticals & Drug Disposition, 38(2):155-160). Furthermore, it is well known that human serum, and in particular circulating serum esterases, can contribute to systemic drug metabolism (Williams, FM 1987, Pharmacology and Therapeutics, 34:99-109). Many pharmacological agents are classified as prodrugs because they undergo metabolic transformation in vivo upon administration to release the active drug compound in systemic compartments (Zawilska JB et al., 2013, Pharmacological Reports, 65:1-14). Psilocybin, a serotonergic hallucinogen, is a well-known prodrug that is metabolized to the psychoactive product psilocin (Dinis-Oliveira, RJ 2017, Drug Metabolism Reviews, 49(1):84-91).To evaluate the ability of the test molecules to act as prodrugs of psilocin as well, time-dependent metabolic stability assays were performed using human AB serum, human intestinal microsomes (HIM), human intestinal S9 fraction (HIS9), human liver microsomes (HLM), human liver S9 fraction (HLS9), human alkaline phosphatase, and porcine esterase. Assays in enzyme-free buffer were also performed for control purposes and general evaluation of compound stability. Liquid chromatography coupled with mass spectrometry (LC-MS) was used to follow the conversion of the test molecules to psilocin. Both intestinal and liver fractions and NADPH RapidStart reagent were purchased from Sekisui / XenoTech. Human AB serum was purchased from Sigma. For intestinal and hepatic metabolism assays, 2.5 μM of candidate compound was incubated with 400 μg / ml of each cell fraction (HLM, HLS9, HIM, or HIS9) in 50 mM potassium phosphate buffer (pH 7.4) containing 3 mM MgCl2 and 1 mM EDTA and supplemented with NADPH RapidStart at 37 °C. Samples were sampled at the start of the assay and every 20 minutes for 2 hours. Samples from each time point were precipitated with 1:1 volume of acetonitrile to stop the reaction, then centrifuged at 4000xg for 20 minutes. The supernatant was analyzed for the presence of candidate prodrugs (parent molecule) and psilocin (predicted metabolite) using Orbitrap LC-MS (Thermo Scientific) by the method described above (Menendez-Perdomo et al., 2021, J. Mass Spectrom., 56: e4683). Serum assays were performed with 10% human AB serum in 50 mM potassium phosphate buffer, pH 7.4, containing 3 mM MgCl2 and 1 mM EDTA. Bovine alkaline phosphatase assays were performed with 1 unit of purified enzyme in 50 mM potassium phosphate buffer, pH 7.4, containing 3 mM MgCl2 and 1 mM EDTA. Porcine esterase assays were performed with 1 unit of purified enzyme in 50 mM potassium phosphate buffer, pH 7.4, containing 3 mM MgCl2 and 1 mM EDTA.Assay concentrations (μM) of both the parent "prodrug" molecule and the psilocin metabolite, quantified by LC-MS using the usual standard curve procedure, were plotted as a function of assay time (min). 1 / 2 ) was determined from the metabolism curve plots using the one-phase exponential decay function of GraphPad PRISM software (version 9.2.0). The amount of parent prodrug at time zero was set to 100%.

[0213] A positive control was first tested to ensure that the assays were working properly. Psilocybin is known to be metabolized to psilocin by alkaline phosphatase in the intestine (Dinis-Oliveira, 2017 Drug Metab.Rev.49: 84-91), and therefore can be used as a positive control for the HIM, HIS9, and alkaline phosphatase assays. Procaine is known to be metabolized to 4-aminobenzoic acid by esterase in serum and liver (Henrikus and Kampffmeyer, 1992, Xenobiotica 22: 1357-1366), and therefore can be used as a positive control for the AB serum, HLM, and esterase assays. Verapamil is known to be metabolized in the liver to various metabolites (Hanada et al., 2008, Drug Metab. Dispos. 36: 2037-2042) (catabolic products are not examined in this study) and therefore can be used as an additional control for the HLS9 and HLM assays.

[0214] Figures 3M(i), 3M(ii) and 3M(iii) show the results of the "psilocin release" metabolic conversion assay using psilocybin as a parent prodrug control for the HIM (panel C), HIS9 (panel D) and alkaline phosphatase (panel E) assays. In this context, psilocybin was further subjected to the negative control buffer assay (panel A), AB serum (panel B), HLM (panel F) and HLS9 (panel G) assays. In particular, these plots show that psilocybin is stable in the liver fraction without being converted to psilocin. Furthermore, the stability of psilocybin was confirmed in the assay buffer, confirming that the conversion of this molecule is due to enzymes in the cellular fraction and not to buffer components. Finally, these results show that psilocybin is stable in serum without being converted to psilocin. Figures 3N(i) and 3N(ii) show the results of additional controls for assay validation: procaine and AB serum (panel A); procaine and HLM (panel B); verapamil and HLS9 (panel C); procaine and esterase (panel D); verapamil and HLM (panel E). Figures 3O(i) and 3O(ii) show metabolic stability curves for the compound having formula E(VI), designated as "E(VI)", in HLM (panel A), HLS9 (panel B), HIM (panel C), HIS9 (panel D), AB serum (panel E), and buffer control (panel F).

[0215] 5-HT in mice 2A In vivo assessment of receptor agonism The drug-induced head-shake response (HTR), a rapid involuntary movement of the mouse head with little or no involvement of the trunk, is a potentiation of neuronal 5-HT by established and novel hallucinogenic compounds. 2AHTR is an established in vivo behavioral model used to measure the activation of the 5-HT2AR receptor (Canal and Morgan, 2012, Drug Testing Analysis, 4:556-576). Indeed, HTR has been widely utilized as a behavioral proxy in mice and rats to predict hallucinogenic potential in humans and can reliably distinguish between hallucinogenic and non-hallucinogenic 5-HT2AR agonists (Halberstadt and Geyer, 2013, Psychopharmacology 227: 727-739; Gonzalez-Maeso et al., 2007, Neuron 53:439-452). To assess 5-HT2AR agonism in vivo, HTR was measured in mice treated with control and test compounds over a defined time frame after administration. All experiments were approved by the University of Calgary Animal Care Committee in accordance with the Canadian Council on Animal Care guidelines. Briefly, 8-week-old male and female C57BL / 6-Elite mice were obtained from Charles River. Prior to compound administration, all mice were group-housed and then single-housed on a 12:12-h light / dark schedule (lights on at 07:00) with food and water ad libitum. Prior to any behavioral screening, mice were handled and placed in the test chamber for at least 5 min each day for three consecutive days and allowed to acclimate to the experimental room for 1 h before testing. Test chambers were cleaned with 70% ethanol solution between experiments. Control and test compounds, prepared at a stock concentration of 100 mM in DMSO, were diluted in sterile saline (0.9% NaCl). Prior to drug administration, mice were video-monitored for 30 min in a plexiglass test chamber (25.5 x 12.5 x 12.5 cm [L x W x H]) to acclimate to the test environment and to examine spontaneous HTR after drug administration. Thirty minutes later, compounds were administered by intraperitoneal (ip) injection at 1 mg / kg and mice were video monitored for 30 minutes before being returned to their home cages.HTR analysis was performed by an experimenter blinded to the treatment group of interest using Behavioral Observation Research Interactive Software (BORIS, version 7, DOI:10.1111 / 2041-210X.12584). Pre-drug behavior was examined in a 15-30 min time window before drug administration. Post-drug behavior was analyzed in a 15-30 min time window after drug administration. HTR associated with intraperitoneal administration of psilocybin was included as a positive control measure. HTR associated with intraperitoneal administration of vehicle (0.9% NaCl) was included as a negative control measure. Elevated incidence of HTR within the defined monitoring time was observed in (1) mice treated with psilocybin, and (2) mice treated with compound E (VI), compared to treated control mice that received intraperitoneal injections of vehicle (0.9% NaCl). These results are shown in Figure 3P, where vehicle is represented as "veh", psilocybin is represented as "PCB", compound of formula E(VI) is represented as "E-VI", pre-drug data is represented as "pre-", and post-drug data is represented as "pro-". Each replicate mouse is represented by a black dot along the corresponding vertical bar (N=2-6 / compound).

[0216] Pharmacokinetic (PK) evaluation of drug metabolism to psilocin in mice Prodrugs are molecules that have little or no pharmacological activity themselves, but which, by chance or design, have built-in structural instability that allows for in vivo biotransformation. Psilocybin was recognized as a natural prodrug of the active substance psilocin soon after the identification and chemical synthesis of this compound in 1957 (Coppola et al., 2022 J Xenobiot. 12: 41-52).

[0217] To further explore the potential of the novel C4-carboxylic acid substituted tryptamine derivatives for use as psilocin prodrugs, a mouse PK study was performed. The purpose of this study was to evaluate the time-dependent in vivo conversion of the novel derivatives ("parent molecules") to active psilocin metabolites. Specifically, the study was performed using both PO (oral, by mouth) and IV (intravenous) administration. Briefly, the procedure is as follows: For each compound (i.e., parent molecule), N=12 male C57BI / 6 mice were administered a single intravenous dose (1 mg / kg) or a single oral dose (1, 3, or 10 mg / kg) (N=3 mice per dose group). Serial blood draws by tail nick were performed at 8 time points up to 24 hours post-dose. Samples were collected in K2EDTA tubes, plasma was separated, and all samples were frozen until bioanalysis for parent compound and psilocin metabolites. Psilocybin was also evaluated as the parent compound using this same protocol to establish a reference PK profile. LC-MS / MS methods were developed for (1) each parent compound and (2) psilocin metabolites, using unary 6-8 point calibration curves (within ±25% precision of standard 75% (±25% LLOQ)). Sample processing and analysis included 96 plasma and 4 dosing solutions per compound, with 2 calibration curves encompassing the sample batches. Nominal analyte concentrations were calculated for dosing solutions based on the amount of weighed test substance dissolved in the exact dosing solution volume. However, to account for test substance instability or other unaccountable factors, dosing solutions were sampled by LC-MS immediately prior to dosing into animals to obtain a "measured" test substance amount. A measured dose was considered the same as the nominal dose if the concentration of the formulation was within 20% of the nominal concentration. However, if the measured dose was outside this window, this new "measured" dose was used in all calculations. Each mouse was represented by its number (e.g., M01, M02...). The calculated values ​​were as follows: T max is the time when the maximum test substance concentration was observed; C max is the maximum observed concentration; Apparent t 1 / 2is the apparent terminal half-life; AUC 0-tlast is the area under the concentration versus time curve from time zero to the last measurable concentration; AUC 0-inf is the area under the "concentration versus time curve" from time zero to infinity; MRT 0-inf is the average residence time from time zero to infinity; V ss is the steady-state volume of distribution; F(%) is bioavailability = (Dose iv *AUC po ) / (Dose po *AUC iv )*100. SD indicates significant deviation at N=3 unless otherwise specified. A more detailed description of the methodology used to perform the mouse PK studies described above can be found at https: / / intervivo.com / pk-safety-studies / #pk-bridge; accessed July 19, 2022.

[0218] The PK results of psilocybin following psilocybin administration are found in Tables 1A-1B, and Figure 3Q. Notably, psilocybin was only detectable in animals dosed intravenously; conversely, it was not detectable in animals dosed orally at any dose; suggesting a degree of instability and / or rapid conversion to psilocin. The PK results of psilocybin following psilocybin administration are found in Tables 2A-2B (1 mg / kg intravenous dose), Tables 3A-3B (1 mg / kg oral dose), Tables 4A-4B (3 mg / kg oral dose), Tables 5A,B (10 mg / kg oral dose), Table 6 (psilocin exposure), and Figure 3R.

[0219] [Table 1]

[0220] [Table 2]

[0221]

Table 3

[0222]

Table 4

[0223]

Table 5

[0224]

Table 6

[0225]

Table 7

[0226]

Table 8

[0227]

Table 9

[0228]

Table 10

[0229]

Table 11

[0230] Results regarding the PK of compound E(VI) after E(VI) administration are found in Tables 7A and 7B. Notably, only plasma from animals administered E(VI) intravenously showed detectable levels of E(VI). Conversely, plasma from animals administered E(VI) orally did not produce any detectable levels of E(VI). As can be seen from Tables 7A and 7B, the mean E(VI) plasma concentrations were associated with a relatively high standard deviation (SD), likely due to problems in quantitation (see notes in Table 7A).

[0231] [Table 12]

[0232] [Table 13]

[0233] Results regarding the PK of psilocin following E(VI) administration can be found in Tables 8A-8B (1 mg / kg intravenous dose), Tables 9A-9B (1 mg / kg oral dose), Tables 10A-10B (3 mg / kg oral dose), Tables 11A-11B (10 mg / kg oral dose), Table 12 (Comparative summary of intravenous dosing data), Table 13 (Comparative summary of oral dosing data), Table 14 (psilocin exposure) and Figures 3S(i) and 3S(ii).

[0234] [Table 14]

[0235] [Table 15]

[0236] [Table 16]

[0237] [Table 17]

[0238] [Table 18]

[0239] [Table 19]

[0240] [Table 20]

[0241] [Table 21]

[0242] [Table 22]

[0243] In vitro measurement of pharmacological interaction profiles of receptors, transporters and enzymes relevant to targeted health conditions To expand the pharmacological profiling to include a broader range of targets known to be involved or associated with brain neurological disorders, compound E (VI) was evaluated for receptor interactions (https: / / www.eurofinsdiscoveryservices.com / ). Specifically, a cell-based screening assay panel known as "SAFETYscan E / IC150 ELECT" was used to evaluate the interaction of 20 proteins with different derivative molecules (12 GPCR receptors (ADRA1A, ADRA2A, AVPR1A, CHRM1, CHRM2, CNR1, DRD1, DRD2S, HTR1A (5-HT 1A ), HTR1B(5-HTR 1B ), HTR2B(5-HT 2B), OPRD1), three types of ion channels (GABAA, HTR3A (5-HT 3A ), NMDAR), one enzyme (MAO-A), and three transporters (DAT, NET, SERT).

[0244] (i) EFC-based cAMP second messenger assay Of the 12 GPCR proteins, eight were analyzed by cAMP second messenger assays: ADRA2A, CHRM2, CNR1, DRD1, DRD2S, HTR1A, HTR1B, and OPRD1. Briefly, we used a panel of cell lines stably expressing untagged GPCR proteins that endogenously signal via cAMP. These assays were performed in a homogenous, non-imaging assay format using a technique called enzyme fragment complementation (EFC). i or G s Activation of GPCRs via second messenger signaling was monitored. EFC uses β-galactosidase (β-gal) as a functional endpoint. The β-gal enzyme is split into two complementary moieties: enzyme acceptor (EA) and enzyme donor (ED). In this assay, exogenously introduced ED fused to cAMP (ED-cAMP) competes with endogenously generated cAMP for binding to an anti-cAMP specific antibody. Active β-gal is formed by complementation of exogenous EA with unbound ED-cAMP. The active enzyme then converts a chemiluminescent substrate, generating an output signal detectable in a standard microplate reader.

[0245] These eight cAMP-based assays were tested in both agonist and antagonist modes, as well as in G s Format (without forskolin) or G i Format (EC 80 In the presence of forskolin, s and G iFor agonist assays: Cell media was aspirated from GPCR-containing cultures and replaced with 15 μl of 2:1 HBSS / 1-mM HEPES:cAMP XS + Ab Reagent. i Five microliters of derivative compounds prepared as EC80 forskolin in the 300-well format were added to the cells at the final target concentration and pre-incubated for 30 minutes. The final assay vehicle concentration was 1%. After pre-incubation, the assay signal was developed by the addition of (1) 20 μL of cAMP XS+ ED / CL lysis cocktail, and (2) 20 μL of cAMP XS+ EA reagent, incubated for 1 hour and 3 hours, respectively. Antagonist assays were performed with a pre-incubation (30 minutes) entailing exposure to the test derivative, followed by EC 80 The assays were performed in the same manner as the agonist assays, except for exposure to established agonists at EC 80 Forskolin was included in the assay buffer.

[0246] In all eight cAMP assays (agonist or antagonist format), the resulting chemiluminescent signal was measured using a PerkinElmer Envision® instrument. Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). Percent activity was calculated according to standard methods. For example, G s For agonist mode assays, percent activity was calculated using the following formula: % activity = 100% x [mean RLU of test derivative - mean RLU of vehicle control] / [mean RLU of control ligand - mean RLU of vehicle control]. s For antagonist mode assays, the percentage of inhibition (%) was calculated using the following formula: % Inhibition = 100% x [1 - [mean RLU of test derivative - mean RLU of vehicle control] / [EC 80 Mean RLU of control ligand - Mean RLU of vehicle control. iFor agonist mode assays, percent activity was calculated using the following formula: % activity = 100% x [1 - [mean RLU of test derivative - mean RLU of control ligand] / [mean RLU of vehicle control - mean RLU of control ligand]]. i For antagonist or negative allosteric assays, percent inhibition was calculated using the following formula: % Inhibition = 100% x [mean RLU of test compound - EC 80 [mean RLU of control ligand] / [mean RLU of forskolin positive control - EC 80 Mean RLU of control]. For the first screen, if the calculated percent response returned a negative value or a value greater than 100, the percent response was capped at 0% or 100%, respectively. To assess assay performance and establish positive control criteria, the ligands listed in Table 13 were evaluated along with the test derivatives. The results of the EFC-based cAMP second messenger assay for GPCRs using the ligand of compound E (VI) or the positive control are shown in Table 14.

[0247] (ii) Calcium second messenger assay Of the 12 GPCR proteins, four were analyzed by calcium second messenger assay: ADRA1A, AVPR1A, CHRM1, and HTR2B. Briefly, the Calcium No WashPLUS assay monitors GPCR activity through Gq second messenger signaling in live cells in a non-imaging assay format. Eurofins DiscoverX used dedicated cell lines stably expressing Gq-coupled GPCR proteins. Calcium mobilization was monitored using calcium-sensitive dyes introduced into the cells. GPCR activation by test or control compounds resulted in calcium release from intracellular stores and an increase in dye fluorescence that was measured in real time.

[0248] Four GPCR proteins analyzed by calcium second messenger assays were examined in both agonist and antagonist modes. Cell lines were expanded from frozen stocks according to standard methods; seeded in microplates and incubated at 37°C prior to testing. Assays were performed using 1X dye loading buffer consisting of 1X dye (DiscoverX, Calcium No WashPLUS kit, Cat. No. 90-0091), 1X Additive A, and HBSS / 20mM Hepes with 2.5mM probenecid. Dye was added to cells prior to testing. Media was aspirated from cells and replaced with 25μL of dye loading buffer and incubated at 37°C for 45 minutes, then at room temperature for 20 minutes. For agonist determinations, cells were incubated with test compounds to induce responses. After dye addition, cells were removed from the incubator and 2X compound in 25μL of HBSS / 20mM Hepes was added using a FLIPR Tetra (MDS). Agonist activity of the compounds was measured on a FLIPR Tetra. Calcium mobilization was monitored for 2 min, including a 5 sec baseline measurement. For antagonist determination, cells were pre-incubated with the test compound and then EC 80Agonists were added at a concentration of 0.01 mg / mL. After dye addition, cells were removed from the incubator and 25 μL of 2× test compound was added. Cells were incubated at room temperature in the dark for 30 minutes to equilibrate plate temperature. After incubation, antagonist determination was initiated by adding 25 μL of 1× derivative compound at 3×EC80 agonist using FLIPR. Antagonist activity of compounds was measured using FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes, including a 5 second baseline measurement. In both agonist and antagonist modes, data analysis was initiated using FLIPR and area under the curve was calculated for the entire 2 minute measurement reading. Compound activity was analyzed using CBIS data analysis suite (ChemInnovation, CA). For agonist mode assays, percent activity was calculated using the following formula: % activity = 100% x [mean RFU of test compound - mean RFU of vehicle control] / [mean RFU of control ligand - mean RFU of vehicle control]. For antagonist mode assays, percent inhibition was calculated using the following formula: % inhibition = 100% x [1 - [mean RFU of test compound - mean RFU of vehicle control] / [EC 80 Mean RFU of control - Mean RFU of vehicle control]. For the first screen, if the calculated percent response returned a negative value or a value greater than 100, the percent response was capped at 0% or 100%, respectively. To assess assay performance and establish positive control criteria, the ligands listed in Table 13 were evaluated along with the test derivatives. The results of the EFC-based cAMP second messenger assay for GPCRs using the ligand of compound E (VI) or the positive control are shown in Table 14.

[0249] (iii) Ion channel assay We investigated both the "blocker activity" and "opener activity" of putative ligands against three different ion channels (GABAA, HTR3A, and NMDAR). Briefly, Eurofins DiscoverX was used with the FLIPR Membrane Potential Assay Kit (Molecular Devices); this assay kit utilizes a dedicated fluorescent indicator dye in combination with a quencher to reflect real-time membrane potential changes associated with ion channel activation and ion transporter proteins. Unlike traditional dyes such as DiBAC, the FLIPR Membrane Potential Assay detects ion flux in both directions, so both variable and control conditions can be monitored in a single experiment. Cell lines were expanded from frozen stocks according to standard methods, seeded in microplates, and incubated at 37°C. Assays were performed in 1X dye loading buffer consisting of 1X dye and 2.5 mM probenecid (if used). Dye was added to cells prior to testing and incubated at 37°C for 30-60 minutes. For agonist ("opener") assays, cells were incubated with samples (i.e., containing derivatives or control compounds; Table 13) to induce a response as follows: Dilutions of sample stocks were made to create 2-5X samples (i.e., containing derivatives or control compounds) in assay buffer. 10-25 μL of 2-5X sample was then added to the cells and incubated for 30 minutes at 37°C or room temperature. Antagonist ("blocker") assays were performed by removing cells from the incubator after dye addition and incubating at EC 80The same method was used, except that 10-25 μL of 2-5X samples (i.e., containing derivatives or control compounds) were added to the cells in the presence of agonist. Cells were incubated at room temperature in the dark for 30 minutes to equilibrate plate temperature. Compound activity was measured on a FLIPR Tetra (Molecular Devices). Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). For agonist mode assays, percent activity was calculated using the following formula: % activity = 100% x [mean RLU of test derivative - mean RLU of vehicle control] / [mean control ligand - mean RLU of vehicle control]. For antagonist mode, percent inhibition was calculated using the following formula: % inhibition = 100% x [1 - [mean RLU of test derivative - mean RLU of vehicle control] / [EC 80 Mean RLU of control - Mean RLU of vehicle control]. For the first screen, if the calculated percent response returned a negative value or a value greater than 100, the percent response was capped at 0% or 100%, respectively. To assess assay performance and establish positive control criteria, the ligands listed in Table 13 were evaluated along with the test derivatives. The results of the EFC-based cAMP second messenger assay for GPCRs using compound E (VI) ligand or positive control are shown in Table 14.

[0250] (iv) Neurotransmitter transporter uptake assay Molecular Devices Neurotransmitter Transporter Uptake Assay Kit was used to investigate the effect of test compounds on three different transporters (DAT, NET, SERT). The kit provided a homogeneous fluorescence-based assay for the detection of dopamine, norepinephrine, or serotonin transporter activity in cells expressing these transporters. The kit uses fluorescent substrates that mimic biogenic amine neurotransmitters taken up into cells by specific transporters, resulting in elevated intracellular fluorescence intensity. Cell lines were expanded from frozen stocks according to standard methods and seeded into microplates and incubated at 37°C prior to testing. Assays were performed in 1X dye loading buffer consisting of 1X dye and 2.5 mM probenecid (if used). Dye was then added to the cells and incubated at 37°C for 30-60 minutes. A "blocker" or antagonist format assay was performed in which cells were pre-incubated with the sample (i.e., containing the sample derivative or positive control compound) as follows: Dilutions of sample stocks (i.e., containing sample derivatives or positive control compounds; Table 13) were made to create 2-5X samples in assay buffer. After dye loading, cells were removed from the incubator and 10-25 μL of 2-5X samples (i.e., containing sample derivatives or positive control compounds) were added to EC 80 The cells were added in the presence of agonist. The cells were incubated at room temperature in the dark for 30 minutes to allow plate temperature equilibration. Compound activity was measured on a FLIPR Tetra (Molecular Devices) and activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). For antagonist ("blocker") mode, percent inhibition was calculated using the following formula: % Inhibition = 100% x [1 - [mean RLU of test sample - mean RLU of vehicle control] / [EC 80Mean RLU of control - Mean RLU of vehicle control]. For the first screen, if the calculated percent response returned a negative value or a value greater than 100, the percent response was capped at 0% or 100%, respectively. To assess assay performance and establish positive control criteria, the ligands listed in Table 13 were evaluated along with the test derivatives. The results of the EFC-based cAMP second messenger assay for GPCRs using the ligand of compound E (VI) or the positive control are shown in Table 14.

[0251] (v) MAO-A enzyme assay For the MAO-A assay, all chemicals and enzyme preparations were from Sigma. Briefly, the enzyme and test compounds (i.e., derivatives or control compounds; see Table 13) were pre-incubated at 37°C for 15 min before the addition of substrate. The reaction was initiated by the addition of kynuramine and incubated at 37°C for 30 min. The reaction was stopped by the addition of NaOH. The amount of 4-hydroquinone formed was determined by spectrofluorimetry with excitation wavelengths of 310 nm and emission detection at 380 nm. For each assay, the microplate was transferred to a PerkinElmer Envision® instrument for reading by standard methods. The activity of the compounds was analyzed using the CBIS data analysis suite (ChemInnovation, CA). The percentage of inhibition was calculated using the following formula: % inhibition = 100% x [1 - [mean RLU of test samples - mean RLU of vehicle control] / [mean RLU of positive control - mean RLU of vehicle control]]. For the first screen, if the calculated percent response returned a negative value or a value greater than 100, the percent response was capped at 0% or 100%, respectively. To assess assay performance and establish positive control criteria, the ligands listed in Table 13 were evaluated along with the test derivatives. The results of the EFC-based cAMP second messenger assay for GPCRs using the ligand of compound E (VI) or the positive control are shown in Table 14.

[0252] [Table 23]

[0253] [Table 24]

[0254] Example 2: Comparative evaluation of C4-carbonothioate-substituted tryptamine derivatives and C4-carbonate-substituted tryptamine derivatives With reference to FIG. 4A (including the following panels: Panel A, Panel B, and Panel C), presented herein are exemplary chemical synthesis reactions (p), (q), (see Panel A) and (r) (see Panel B), and various exemplary compounds related to the chemical synthesis reactions (p), (q), and (r), in particular, compounds 1, 2, 3, 4, and E(VI) (see Panel A); compounds 4, 5, and B(II) (see Panel B); and compounds 6 and 7 (see Panel C). Compounds having chemical formula B(II) (Panel B) and compounds having chemical formula E(VI) (Panel A) (hereinafter simply referred to as B(II) and E(VI), respectively) can be said to be C4-carbonate ester substituted tryptamine derivatives and C4-carbonothioate substituted tryptamine derivatives, respectively. It should be noted that the chemical structures of B(II) and E(VI) differ from each other by one atom. In particular, in the alkylene chain ak2 extending from the carboxyl moiety of the C4-substituent in B(II), a carbon atom is replaced with an oxygen atom (indicated by bold font in panel B), while in the alkylene chain ak1 extending from the carboxyl moiety of E(VI), a carbon atom is replaced with a sulfur atom (indicated by bold font in panel A).

[0255] It should be noted that the benzyl carbonate moiety (see panel C, compound 6) (as present in B(II)) is routinely and widely used as a protecting group for alcohols and amines in organic synthesis reactions. In contrast, however, there are no comparable reports using the benzyl thiocarbonate moiety (see panel C, compound 7) (as present in E(VI)) for the above purpose.

[0256] Furthermore, once incorporated, the benzyl carbonate (see panel C, compound 6) (when included in B(II)) can be reliably deprotected with hydrogen gas under reducing conditions to present the unprotected alcohol, whereas the benzyl thiocarbonate (see panel C, compound 7) (when included in E(VI)) can be cleaved under oxidative conditions (e.g., H2O2) or with nucleophilic fluorides (Greene's Protective Groups in Organic Synthesis, 5th Edition, 2006). th Edition), PGM Wuts, Wiley, 2014).

[0257] Furthermore, referring to Figure 4A, panel B, the reagent required for the incorporation of the benzyl carbonate moiety in the synthesis of B(II) according to synthetic reaction (r), i.e., benzyl chloroformate 5, is widely available commercially. In contrast, referring to Figure 4A, panel A, the reagent required for the introduction of the benzyl thiocarbonate moiety in the synthesis of E(VI) according to synthetic reaction (q), benzyl chlorothioformate 3, typically must first be synthesized in the laboratory from phosgene or triphosgene 1 (see reaction (p)), thus limiting its general availability as a protecting group.

[0258] Furthermore, with regard to chemical stability, the carbonothioate 7 and carbonate 6 functional groups are known to exhibit substantially different hydrolysis rates (Pharmaceutical Research, 1993, 10, 639-648).

[0259] Furthermore, the functional pharmacological properties of B(II) and E(VI) have been evaluated and are described herein below.

[0260] To further compare B(II) and E(VI), B(II) was subjected to the same pharmacological assays as E(VI). The first series of assays, namely (1) cell viability assay, (2) radioligand receptor binding assay, and (3) 5-HT 1A Evaluation of receptor modulation revealed little difference between B(II) and E(VI). Briefly, the results are as follows: First, cell viability was assessed as described in Example 1, except that B(II) was assessed instead of E(VI). Cytotoxicity was relatively comparable for the two compounds, with CD40 for B(II). 50 = 65.9 μM and E(VI) for CD 50 = 74.5 μM (Figure 3C). Second, 5-HT 2A Activity at the receptor was evaluated as described in Example 1, except that the compound of formula B (II) was evaluated instead of the compound of formula E (VI). 2A Receptor binding was similar to that of E(VI), with K of 277 nM and 130 nM, respectively. i Third, 5-HT 1A The experimental method to evaluate the modulation of 5-HT was carried out as described in Example 1, except that compound B(II) was evaluated instead of E(VII). Both molecules inhibited 5-HT with sufficient potency to calculate EC50 values. 1A (See FIG. 3H for data on E(VI)).

[0261] However, an unexpected difference between B(II) and E(VI) was observed when performing in vitro metabolic stability assays. Evaluation of the metabolic stability of the novel molecules and their ability to release psilocin under various in vitro conditions was performed as described in Example 1, except that compound B(II) was used instead of compound E(VI). Figures 4D(i), 4D(ii) show the metabolic stability curves B(II) in HLM (panel A), HLS9 (panel B), HIM (panel C), HIS9 (panel D), AB serum (panel E), and buffer control (panel F). These results demonstrated the unexpected stability of B(II), which did not readily degrade to psilocin under any conditions. In contrast, E(VI) was rapidly converted to psilocin in liver fractions and serum (Figures 3O(i), 3O(ii)). B(II) had a half-life (T) of 218 and 537 minutes in HLM and HLS9 fractions, respectively. 1 / 2 ), whereas E(VI) was metabolized much more rapidly (i.e., T of 6 and 5 min in the HLM and HLS9 fractions, respectively). 1 / 2 An even more striking difference was seen in AB serum, where B(II) could not be degraded at all, whereas E(VI) was rapidly metabolized (T 1 / 2 = 14 min). For ease of comparison, the data for B(II) and E(VI) are summarized side-by-side in Figure 4E, along with the psilocybin control data. This summary clearly shows the unique and distinct metabolic conversion profiles for psilocybin, B(II), and E(VI).

[0262] A further potentially significant difference between B(II) and E(VI) is the 5-HT 2A was observed during in vivo evaluation of receptor agonism. In vivo HTR evaluation was performed as described in Example 1, except that compound B(II) was used instead of compound E(VI). For ease of comparison, data for B(II) and E(VI) are summarized side-by-side in FIG. 4F, along with psilocybin control data. Both molecules induced head shaking, but elevated responses were observed in mice treated with E(VI) compared to B(II).

[0263] Supporting the in vitro metabolic conversion data, in vivo mouse pharmacokinetic (PK) evaluation of drug metabolism to psilocin revealed major differences between B(II) and E(VI). Pharmacokinetic (PK) evaluation was performed in the same manner as described in Example 1, except that compound B(II) was used instead of compound E(VI). Consistent with the in vitro data (Figures 4B, 4C), the in vivo PK results highlight the relative stability of B(II) compared to E(VI) in mice orally dosed at 3 mg / kg and 10 mg / kg. The data in Table 15 show that B(II) remains in the plasma for up to 4 hours after dosing (10 mg / kg), while E(VI) is not detected at any time point, suggesting that B(II) is metabolized slowly, whereas E(VI) is rapidly metabolized. Unfortunately, comparisons were not possible in mice orally dosed at 1 mg / kg, because neither B(II) nor E(VI) were detected in plasma. Furthermore, data characterized by large standard deviations (e.g., Tables 7A, 7B) precluded meaningful comparisons between intravenously dosed mice.

[0264] The PK profile of psilocin was also different in mice administered B(II) compared to E(VI). The data in Tables 16 and 17 show higher psilocin levels in B(II)-treated mice, resulting in higher overall psilocin exposure in these animals during the sampling period. A number of possible explanations could explain why B(II) exhibits greater stability than E(VI) under various in vitro and in vivo conditions, yet mice treated with B(II) appear to have higher psilocin levels. First, the instability of E(VI) in plasma (Figures 3O(i), 3O(ii), 4E) leads to rapid degradation to psilocin, which in turn increases the "peak" psilocin concentration (C max ) occurred before the first sampling (0.25 h after dosing). B(II) is relatively stable in plasma and instead depends on slow metabolism in the liver and / or intestine (Figures 4D(i), 4D(ii), 4E), and sampling between 0.25 and 24 h was similar to that of C(II). maxand may have allowed for more accurate estimation of exposure. Second, E(VI) may not be directly or exclusively converted to psilocin. Intermediates or off-pathway catabolites may occur. Supporting this view, E(VI) disappears almost completely upon in vitro exposure to AB serum, yielding much lower amounts of psilocin from the expected 1:1 molar ratio of E(VI):psilocin (Figures 3O(i), 3O(ii)). On the other hand, B(II) may be catabolized to a greater extent to psilocin, avoiding off-target pathways or intermediates.

[0265] Moreover, further differences between B(II) and E(VI) were observed in in vitro measurements of the pharmacological interaction profile. All assays were performed as described using "SAFETYscan E / IC150 ELECT" (https: / / www.eurofinsdiscoveryservices.com / ), except that compound B(II) was used instead of E(VI). For ease of comparison, Table 18 summarizes the data for both B(II) and E(VI), respectively. Multiple assays showed differences between the behavior of B(II) and E(VI). For example, B(II) failed to elicit a response in the CHRM2 (antagonist mode) and OPRD1 (agonist mode) assays (EC 50 >100 μM, or IC 50 >100 μM; Table 18), whereas E(VI) induced a response in both cases (IC 50 = 51.24 μM and EC 50 = 28.52 μM). Furthermore, E(VI) failed to elicit responses in AVPR1A (antagonist mode) and MAO-A (inhibitor mode) assays (IC 50 >100 μM; Table 18), whereas B(II) induced a response in both cases (IC 50 = 42.64 μM and IC 50 =21.86μM).

[0266] Thus, in summary, this Example 2 demonstrates substantial differences in chemical and pharmacological properties when comparing compounds E(VI) and B(II). In particular, when E(VI) and B(II) are evaluated in various pharmacological assays, the two compounds unexpectedly exhibit substantially different pharmacological properties. These differences in pharmacological properties seem particularly unexpected in light of the structural similarity between E(VI) and B(II).

[0267] [Table 25]

[0268] [Table 26]

[0269] [Table 27]

[0270] [Table 28] TIFF2025510666000081.tif150159

Claims

1. Chemical formula (I): 【Chemical 1】 A compound having the formula: R ４ is a carbonothioate moiety or a derivative thereof; R ３ａ and R ３ｂ are each independently a hydrogen atom, an alkyl group, or an aryl group; compound.

2. The carbonothioate moiety or derivative thereof has the chemical formula (III): 【Chemistry 2】 and R ４ｂ is an alkyl group, a cycloalkyl group, or an aryl group, each of which may be substituted; The compound of claim 1.

3. The carbonothioate moiety or derivative thereof has the chemical formula (IV): 【Chemistry 3】 and R ４ｃ is an alkyl group, a cycloalkyl group, or an aryl group, each of which may be substituted; The compound of claim 1.

4. R ４ｂ may be substituted with a halogen atom, an alkyl group, a cycloalkyl group or an aryl group, １ ~C ６ The compound of claim 2, wherein the compound is alkyl.

5. R ４ｂ may be substituted with a halogen atom, an alkyl group, a cycloalkyl group or an aryl group, １ ~C ３ The compound of claim 2, wherein the compound is alkyl.

6. The compound described in claim 5, wherein the aryl group is a phenyl group.

7. R ４ｂ is methyl, ethyl, isopropyl, butyl, -CH ２ -cyclopropyl, -CH(CH ３ )-cyclopropyl, —C(CH ３ ) ２ -cyclopropyl or -CH ２ The compound of claim 2, wherein the aryl group is -phenyl.

8. R ４ｂ The compound of claim 2 , wherein is an aryl group.

9. The compound of claim 8, wherein the aryl group is a phenyl group.

10. R ４ｂ may be substituted with a halogen atom, an alkyl group, a cycloalkyl group or an aryl group, １ ~C ６ alkyl, １ ~C ６ The compound of claim 2, wherein one or more of the carbon atoms in the alkyl group may be replaced with an oxygen (O) atom.

11. R ４ｃ may be substituted with a halogen atom, an alkyl group, a cycloalkyl group or an aryl group, １ ~C ６ The compound of claim 3, wherein the aryl group is alkyl.

12. The compound of claim 11, wherein the aryl group is a phenyl group.

13. R ４ｃ is methyl, ethyl, isopropyl, butyl, -CH ２ -cyclopropyl, -CH(CH ３ )-cyclopropyl, —C(CH ３ ) ２ -cyclopropyl or -CH ２ -phenyl.

14. R ４ｃ The compound of claim 3 , wherein is an aryl group.

15. The compound of claim 14, wherein the aryl group is a phenyl group.

16. R ４ｃ may be substituted with a halogen atom, an alkyl group, a cycloalkyl group or an aryl group, １ ~C ６ alkyl, １ ~C ６ The compound of claim 3 , wherein one or more of the carbon atoms in the alkyl group may be replaced with an oxygen (O) atom.

17. R ４ is a carbonothioate moiety or a derivative thereof, and is selected from the group consisting of E(I), E(II), E(III), E(IV), E(V), E(VI), E(VII), E(VIII), E(IX), E(X), E(XI), E(XII), E(XIII), E(XIV), E(XV), E(XVI), E(XVII), E(XVIII), E(XIX), and E(XX): 【Chemistry 4】 【change】 A compound selected from the group consisting of:

18. A pharmaceutical or recreational drug formulation comprising an effective amount of a compound according to any one of claims 1 to 17 together with a pharmaceutically acceptable excipient, diluent or carrier.

19. 19. The pharmaceutical formulation of claim 18, which is a prodrug pharmaceutical formulation, A compound having formula (I) is hydrolyzed in vivo to form a compound of formula (VI): 【Chemistry 5】 producing a compound having the formula R ３ａ and R ３ｂ are each independently a hydrogen atom, an alkyl group, or an aryl group; Pharmaceutical preparations.

20. A composition for treating a cranial nerve disorder in a subject, comprising a compound described in any one of claims 1 to 17.

21. Upon administration, the compound having formula (I) is hydrolyzed in vivo to form a compound of formula (VI): 【Chemistry 6】 21. The composition of claim 20, which produces a compound having the formula: R ３ａ and R ３ｂ are each independently a hydrogen atom, an alkyl group, or an aryl group; composition.

22. The disorder is 5-HT １Ａ Receptor-mediated disorders, 5-HT ２Ａ Receptor-mediated disorders, 5-HT １Ｂ Receptor-mediated disorders, 5-HT ２Ｂ Receptor-mediated disorders, 5-HT ３Ａ 21. The composition of claim 20, wherein the disorder is a CNR1 receptor-mediated disorder, an ADRA1A receptor-mediated disorder, an ADRA2A receptor-mediated disorder, a CHRM1 receptor-mediated disorder, a CHRM2 receptor-mediated disorder, a CNR1 receptor-mediated disorder, a DRD1 receptor-mediated disorder, a DRD2S receptor-mediated disorder, an OPRD1 receptor-mediated disorder, a GABAA receptor-mediated disorder, or an NMDAR receptor-mediated disorder.

23. The composition described in claim 20, wherein the composition is administered so that 0.001 mg to 5,000 mg of the compound is administered to the subject.

24. (i) 5-HT １Ａ Receptor, 5-HT ２Ａ Receptor, 5-HT １Ｂ Receptor, 5-HT ２Ｂ Receptor, 5-HT ３Ａ 1. An in vitro method for modulating a receptor selected from a dopamine activated transporter (DAT), a norephedrine transporter (NET), or a serotonin transporter (SERT) transmembrane transporter protein; comprising: The method comprises: (i) administering 5-HT １Ａ Receptor, 5-HT ２Ａ Receptor, 5-HT １Ｂ Receptor, 5-HT ２Ｂ Receptor, 5-HT ３Ａ 19. A compound according to any one of claims 1 to 17, under reaction conditions sufficient to modulate (i) 5-HT receptor, ADRA1A receptor, ADRA2A receptor, CHRM1 receptor, CHRM2 receptor, CNR1 receptor, DRD1 receptor, DRD2S receptor, OPRD1 receptor, GABAA receptor, or NMDAR receptor; or (ii) dopamine activated transporter (DAT), norephedrine transporter (NET), or serotonin transporter (SERT) transmembrane transporter proteins. １Ａ Receptor, 5-HT ２Ａ Receptor, 5-HT １Ｂ Receptor, 5-HT ２Ｂ Receptor, 5-HT ３Ａ receptor, ADRA1A receptor, ADRA2A receptor, CHRM1 receptor, CHRM2 receptor, CNR1 receptor, DRD1 receptor, DRD2S receptor, OPRD1 receptor, GABAA receptor, or NMDAR receptor; or (ii) a dopamine activated transporter (DAT), norephedrine transporter (NET), or serotonin transporter (SERT) transmembrane transporter protein; method.

25. Chemical formula (VI): 【Chemistry 7】 (h) and (l) under reaction conditions sufficient to convert compound 8 or compound 15 to form E(VI): 【Chemistry 8】 A method comprising carrying out one of the chemical reactions selected from:

26. carrying out a chemical reaction (h), and prior to carrying out the chemical reaction (h): (i) Chemical reaction (g); (ii) each of chemical reactions (f) and (g) in sequential order; (iii) each of chemical reactions (e), (f), and (g) in sequential order; (iv) each of chemical reactions (d), (e), (f), and (g) in sequential order; (v) each of chemical reactions (c), (d), (e), (f), and (g) in sequential order; (vi) each of chemical reactions (b), (c), (d), (e), (f), and (g) in sequential order; or (vii) each of chemical reactions (a), (b), (c), (d), (e), (f), and (g) in sequential order; [0033] Chemical reactions (a), (b), (c), (d), (e), (f), and (g) are the chemical reactions identified in Figures 3A(i) and 3A(ii) as (a), (b), (c), (d), (e), (f), and (g), respectively; each of said chemical reactions is carried out under conditions sufficient to form E(VI); 26. The method of claim 25.

27. The chemical reaction (l) is carried out, and prior to carrying out the chemical reaction (l), (i) Chemical reaction (k); (ii) each of chemical reactions (j) and (k) in sequential order; or (iii) each of chemical reactions (i), (j), and (k) in sequential order; and optionally prior to carrying out chemical reaction (l), (iv) chemical reaction (m); [0033] Chemical reactions (i), (j), (k), and (m) are the chemical reactions identified in Figure 3A(iii) as (i), (j), (k), and (m), respectively; Each of the chemical reactions is carried out under conditions sufficient to form E(VI); 26. The method of claim 25.

28. Use of a compound according to any one of claims 1 to 17 in the manufacture of a pharmaceutical or recreational drug formulation.

29. The use of claim 28, wherein the manufacturing comprises formulating the compound with a pharmaceutically acceptable excipient, diluent, or carrier.

30. The use of claim 28, wherein the pharmaceutical preparation is for the treatment of cranial nerve disorders.

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