Novel psilocine derivatives with prodrug properties

Abstract

The present invention provides a novel group of active compounds based on the psychoactive compound psilocin. The psilocin derivatives provided herein exhibit improved pharmacokinetic properties during uptake and reduced side effects resulting from the metabolites thus formed, compared to psilocin. 2A Due to the affinity of the novel psilocin derivatives for the -receptor, these derivatives are particularly advantageous for use in therapy, for example in the treatment of depression or drug addiction.

Description

[Technical Field]

[0001] This application claims priority to German Patent Application DE10 2020 121 965.2, filed on 21 August 2020, and U.S. Provisional Application US63 / 118,842, filed on 27 November 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] In nature, psilocine is found only in its precursor form, as a phosphate ester called "psilocybin." In the precursor, the oxidation-sensitive psychoactive compound psilocine is protected by a phosphate group. When taken into the body, this protecting group is hydrolyzed and cleaved, releasing the active compound psilocine.

[0003] To date, all medical and clinical research has used naturally occurring psilocybin. It is important to note that the industrial synthesis of psilocybin is a complex and costly process that uses carcinogenic catalysts, and therefore should be critically examined, at least for GMP applications.

[0004] Research into hallucinogens has been resurging since around 1990.

[0005] In 2018, the U.S. FDA approved a study by Compass Pathways that treated patients with treatment-resistant depression with the active compound psilocybin.

[0006] Recent studies have shown promising results in treating cancer-related anxiety and in nicotine or alcohol withdrawal.

[0007] In particular, so-called "microdosing," or the application of small doses, has become a focus of research in recent years. The purpose of this dosage form is to avoid inducing hallucinations and to avoid side effects by using small doses and long dosing intervals, even within a range of several days or several weeks.

[0008] There is growing pharmaceutical interest in novel psilocine derivatives, particularly those that exhibit modified (accelerated or delayed) activity in the human body due to their structure. Only a limited range of psilocine derivatives have been documented in the literature (see, for example, US3,075,992 and CH386,442), and none of these have led to the development of successful therapeutic products. Therefore, there remains an urgent and unmet need for novel psilocine derivatives with improved therapeutic properties. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent No. 3,075,992 [Overview of the Initiative]

[0010] This invention addresses this need and provides novel and readily manufactured psilocine derivatives based on carbonate or amino acid derivatization. The novel psilocine derivatives provided herein exhibit improved properties that make them highly advantageous for therapeutic applications. [Brief explanation of the drawing]

[0011] [Figure 1] Thin-layer chromatograms of the starting material psilocine (E), the final product psilocine-4-ylethyl carbonate (CO3), and the intermediate product psilocine-4-yl-Fmoc-tryptophanate (AS) in chloroform / ethanol 10:1 (left panel) and dichloromethane / methanol 7:3 (right panel), respectively. [Figure 2] Thin-layer chromatograms of the starting material psilocin (E), the final product psilocin-4-ylethyl carbonate (CO3), and the intermediate product psilocin-4-yl-Fmoc-tryptophanate (AS) in tert-butyl methyl ether / ethanol 8:2 (left panel), hexane / ethyl acetate 7:3 (center panel), and tert-butyl methyl ether / isopropanol 8:2 (right panel), respectively. [Figure 3] HPLC-MS spectrum of psilocin-4-ylethyl carbonate from the reaction solution. [Figure 4] HPLC-MS spectrum of psilocin-4-yl-Fmoc-tryptophanate from the reaction solution. [Figure 5A] Stability of novel psilocine carbonates in HCl. Percentage of parent compound remaining after incubation in a 1% HCl solution for 24 hours. [Figure 5B] Stability of novel psilocine carbonates in HCl. Percentage of psilocine released from the test compound during incubation in 1% HCl. [Figure 5C] Stability of novel psilocine carbonates in HCl. Percentage of psilocine tert-butyl carbonate remaining after incubation in a 1% HCl solution for 24 hours. [Figure 5D] Stability of novel psilocine carbonates in HCl. Percentage of psilocine released from the test compound during incubation in 1% HCl. See Example 9. [Figure 6A] Pharmacokinetics of novel thyrosine carbonates in mice. Plasma thyrosine concentrations after intravenous administration of the test compound to mice. Data are expressed as mean ± SEM. [Figure 6B] Pharmacokinetics of novel thyrosine carbonates in mice. Plasma thyrosine concentrations after oral administration of the test compound to mice. Data are expressed as mean ± SEM. [Figure 6C]Pharmacokinetics of novel psilocybin carbonates in mice. Plasma psilocybin concentrations after intravenous administration of psilocybin or psilocybin-4-yl-ethyl carbonate to mice. Data are expressed as mean ± SEM. [Figure 6D] Pharmacokinetics of novel psilocine carbonates in mice. Plasma psilocine concentrations after oral administration of psilocybin or psilocine-4-yl-ethyl carbonate to mice. Data are expressed as mean ± SEM. [Figure 6E] Pharmacokinetics of novel psilocybin carbonates in mice. Plasma psilocybin concentrations after intravenous administration of psilocybin or psilocybin-4-yl-tert-butyl carbonate to mice. Data are expressed as mean ± SEM. [Figure 6F] Pharmacokinetics of novel psilocybin carbonates in mice. Plasma psilocybin concentrations after oral administration of psilocybin or psilocybin-4-yl-tert-butyl carbonate to mice. Data are expressed as mean ± SEM. [Figure 6G] Pharmacokinetics of novel psilocybin carbonates in mice. Plasma psilocybin concentrations after intravenous administration of psilocybin or psilocybin-4-ylbenzyl carbonate to mice. Data are expressed as mean ± SEM. [Figure 6H] Pharmacokinetics of novel thyrosine carbonates in mice. Plasma thyrosine concentrations after oral administration of psilocybin or thyrosine-4-yl-benzyl carbonate to mice. Data are expressed as mean ± SEM. See Example 12. [Modes for carrying out the invention]

[0012] Detailed explanation: Definition: For convenience, certain terms used in this specification, examples, and claims are set forth herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as those commonly understood by those skilled in the art to which the invention pertains.

[0013] As used herein, unless otherwise expressly indicated or the context contradicts it, the terms “a,” “an,” and “the” are used synonymously with “one or more” and “at least one.” Therefore, for example, a composition containing a compound of formula (I) can be interpreted as referring to a composition containing “one or more” compounds of formula (I).

[0014] As used herein, the terms “administer,” “administering,” or “administration” refer to administering to a patient a compound or a pharmaceutically acceptable salt of said compound, or a composition or preparation containing said compound or a pharmaceutically acceptable salt of said compound.

[0015] As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group (i.e., a group consisting of carbon and hydrogen atoms) which may be linear or branched. Therefore, an “alkyl” group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. 1-12 "Alkyl" refers to an alkyl group having 1 to 12 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless otherwise specified in the specification, alkyl groups may be substituted as needed.

[0016] As used herein, the term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group that may be linear or branched. 1-12"Alkylene" refers to an alkylene group having 1 to 12 carbon atoms. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2-, or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Preferred exemplary alkylene groups include methylene, ethylene, propylene, or butylene. Unless otherwise specified in the specification, the alkylene chain may be optionally substituted.

[0017] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is bonded to the remainder of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. An alkenyl group containing a maximum of 12 carbon atoms is C2-C 12 Alkenyl, and an alkenyl group containing a maximum of 10 carbon atoms is C2-C 10 Alkenyl, and an alkenyl group containing a maximum of 6 carbon atoms is C2-C6 alkenyl, and an alkenyl group containing a maximum of 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all the moieties described above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10 Alkenyl includes all the moieties described above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9, and C 10 Alkenyl. Similarly, C2-C 12 Alkenyl includes all the foregoing moieties, but also includes C 11 And C 12 Alkenyl. C2-C 12Non-limiting examples of alkenyls include ethenyl(vinyl), 1-propenyl, 2-propenyl(allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl Examples include 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless otherwise specified in the specification, alkyl groups may be substituted as needed.

[0018] "Alkenylene" or "alkenylene chain" refers to an unsaturated, linear or branched divalent hydrocarbon chain radical having one or more olefins and 2 to 12 carbon atoms. C2-C 12 Non-limiting examples of alkenylenes include etenylene, propenylene, and n-butenylene. The alkenylene chain is bonded to the rest of the molecule via single bonds and to radical groups (e.g., those described herein) via single bonds. The bonding sites of the alkenylene chain to the rest of the molecule and radical groups can be via one carbon or any two carbons within the chain. Unless otherwise specified in the specification, the alkenylene chain may be substituted as needed.

[0019] An "alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups can contain any number of carbon atoms from 2 to 12. Alkynyl groups containing up to 12 carbon atoms are C2-C 12 Alkynnyl groups, which contain up to 10 carbon atoms, are C2-C 10 Alkynyl groups containing up to six carbon atoms are C2-C6 alkynyls, and alkynyl groups containing up to five carbon atoms are C2-C5 alkynyls. C2-C5 alkynyls include C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. C2-C6 alkynyls include all the parts described above for C2-C5 alkynyls, but also include C6 alkynyls. 10 Alkynnyl includes all the parts described above for C2-C5 alkynyls and C2-C6 alkynyls, but also C7, C8, C9 and C 10 This also includes alkynyl. Similarly, C2-C 12 Alkinyl includes all of the above parts, but C 11 and C 12 Includes alkynyl. C2-C 12 Non-limiting examples of alkenyls include ethynyl, propynyl, butynyl, and pentynyl. Unless otherwise specified in the specification, alkyl groups may be substituted as needed.

[0020] "Alkynylene" or "alkynylene chain" refers to an unsaturated, linear or branched divalent hydrocarbon chain radical having one or more alkynes and 2 to 12 carbon atoms. C2-C 12Non-limiting examples of alkylylenes include ethynylene, propynylene, and n-butynylene. The alkylylene chain is bonded to the remainder of the molecule via single bonds and to radical groups (e.g., those described herein) via single bonds. The bonding sites of the alkylylene chain to the remainder of the molecule and to radical groups can be via any two carbon atoms in the chain having a suitable valency. Unless otherwise specified in the specification, the alkylylene chain may be substituted as needed.

[0021] "alkoxy" is the formula -OR a It refers to the base of, and in the formula, R a This is an alkyl, alkenyl, or alkynyl group as defined above, containing 1 to 12 carbon atoms. Unless otherwise specified in the specification, the alkoxy group may be substituted as needed.

[0022] "Aryl" refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, which is bonded to the remainder of the molecule by a single bond. For the purposes of this disclosure, aryls can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include condensed or bridging ring systems. Examples of aryls, but not limited to, include acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified in the specification, "aryl" may be substituted as needed.

[0023] As used herein, the term “comprising” (or “comprise,” “comprises,” etc.) means “containing, inter alia,” that is, “containing, among further optional elements,…” unless otherwise explicitly stated or the context contradicts this. In addition, the term also includes the narrower meanings of “consisting essentially of” and “consisting of.” For example, the term “A containing B and C” means “A containing B and C, in particular,” and A may contain further optional elements (e.g., “A containing B, C and D” is also included), but the term also includes the meanings of “A consisting of B and C” and “A consisting of B and C” (i.e., A does not contain any components other than B and C).

[0024] The terms “effective dose” and “therapeutic effective dose” are used interchangeably in this disclosure and refer to the amount of a compound or a salt thereof (or a pharmaceutical composition containing such compound or salt) that, when administered to a patient, can produce the intended result. The “effective dose” will vary depending on the active ingredient, the state, disorder, or condition being treated, and its severity, as well as the age, weight, physical condition, and responsiveness of the mammal being treated.

[0025] Where used herein, the terms “optional,” “optionally,” and “may” indicate that the indicated feature may or may not be present. Whenever the terms “optional,” “optionally,” or “may” are used, the present invention relates specifically to both the possibility of the corresponding feature being present or, alternatively, the possibility of the corresponding feature not being present. For example, where a component of a composition is indicated as “optional,” the present invention relates specifically to both the possibility of the corresponding component being present (contained in the composition) or the possibility of the corresponding component not being present in the composition.

[0026] A "heteroaryl" refers to a 5-20 membered ring system comprising a hydrogen atom, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring containing a compound having an aromatic resonance structure (e.g., 2-pyridone), which is bonded to the remainder of the molecule by single bonds. For the purposes of this disclosure, heteroaryls can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include condensed or bridging ring systems. Nitrogen, carbon, or sulfur atoms in the heteroaryl may be oxidized as needed. Nitrogen atoms may be quaternized as needed. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2a]pyridinyl, carbazolyl, cinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, Examples include, but are not limited to, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1Hpyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the specification, heteroaryl groups may be substituted as needed.

[0027] "Aralkyl" or "arylalkyl" is a compound of the formula -R b -R c This refers to the radical of the expression, where R is located in the formula. b R is an alkylene group as defined above, c This is one or more aryl radicals as defined above, such as benzyl, diphenylmethyl, etc. Unless otherwise specified in the specification, the aralkyl group may be substituted as needed.

[0028] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which the atoms forming the ring are each carbon atoms, bonded to the rest of the molecule by single bonds. A carbocyclic ring can contain 3 to 20 carbon atoms. Examples of carbocyclic rings as defined herein include aryl and cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Unless otherwise specified in the specification, the carbocyclyl group may be substituted as needed.

[0029] "Cycloalkyl" refers to a stable, non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting only of carbon and hydrogen atoms, having 3 to 20 carbon atoms (for example, 3 to 10 carbon atoms) and including condensed, crosslinked, or spirocyclic ring systems bonded to the remainder of the molecule by single bonds. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified in the specification, cycloalkyls may be substituted as needed.

[0030] "Cycloalkenyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which may include condensed or bridging ring systems, and having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, with the remainder of the molecule bonded by single bonds. Examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cycloctenyl. Examples of polycyclic cycloalkenyls include bicyclo[2.2.1]hepta-2-enyl. Unless otherwise specified in the specification, the cycloalkenyl group may be substituted as needed.

[0031] "Cycloalkynyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which may include condensed or bridging ring systems, and having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, with the remainder of the molecule bonded by single bonds. Examples of monocyclic cycloalkynyls include cycloheptynyl and cyclooctinyl. Unless otherwise specified in the specification, the cycloalkynyl group may be substituted as needed.

[0032] "Haloalkyl" refers to the alkyl group defined above, which is substituted with one or more halo radicals, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified in the specification, the haloalkyl group may be substituted as needed.

[0033] A "heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable saturated, unsaturated, or aromatic 3-20 membered ring consisting of 2-19 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, bonded to the remainder of the molecule by single bonds. Examples of heterocyclyls or heterocyclic rings include heteroaryls, heterocyclylalkyls, heterocyclylalkenyls, and heterocyclylalkynyls. Unless otherwise specifically stated herein, heterocyclyls can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including condensed, cross-linked, or spirocyclic ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocyclyl may be oxidized as necessary, the nitrogen atom may be quaternized as necessary, and the heterocyclyl may be partially or completely saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxothiomorpholinil, and 1,1-dioxothiomorpholinil. Unless otherwise specifically stated herein, heterocyclyl groups may be substituted as needed.

[0034] As used herein, the term “protective gas” refers to an inert gas, preferably argon. In other embodiments, different protective gases may also be used, such as elemental gases like nitrogen, noble gases like helium, neon, argon, krypton, and xenon, and gaseous molecular compounds like sulfur hexafluoride.

[0035] As used herein, the term “substituted” means any of the groups described herein (e.g., alkyl, alkoxy, aryl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom is substituted by bonding to a non-hydrogen atom, including but not limited to halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl groups, alkoxy groups, and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; and silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by higher-order bonds (e.g., double or triple bonds) to heteroatoms such as oxygen in oxo, carbonyl, carboxyl, and ester groups, as well as nitrogen in imines, oximes, hydrazones, and nitrile groups. For example, "substituted" means one or more hydrogen atoms are replaced by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h -OC(=O)NR g R h , -OR g , -SR g -SOR g , -SO2R g , -OSO2R g , -SO2OR g ,=NSO2R g , and -SO2NR g R hContains any of the above groups that are replaced by -C(=O)R. "Substituted" also means that one or more hydrogen atoms are replaced by -C(=O)R g , -C(=O)OR g -C(=O)NR g R h ,-CH2SO2R g -CH2SO2NR g R h It means any of the above bases that are replaced by R. g and R h These are the same or different, independently of any of the above groups, which are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. In addition, each of the aforementioned substituents may be substituted with one or more of the substituents mentioned above, as needed.

[0036] As used herein, the term “treatment” (or “to treat”), relating to a disease or disorder, refers to the management and care of a patient for the purpose of combating a disease or disorder, such as by reversing, alleviating, inhibiting, or delaying one or more symptoms of such disease or disorder. It also refers to the administration of a compound or composition for the purpose of preventing the onset of symptoms of a disease or disorder, alleviating such symptoms, or eliminating the disease or disorder. Preferably, “treatment” is curative, ameliorative, or palliative.

[0037] Whenever a numerical range is provided / disclosed herein, it should be understood that all values ​​and subranges contained within each numerical range are intended to be included within the scope of the present invention. Therefore, explicitly and individually, the present invention relates to each value that falls within the numerical ranges disclosed herein, and to each subrange contained within the numerical ranges disclosed herein.

[0038] It should be further understood that the present invention relates specifically to each and all combinations of the features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the present invention relates specifically to each combination of meanings (including general and / or preferred meanings) for the various bases and variables contained in formula (I).

[0039] Compounds of this disclosure: This invention provides a novel group of active compounds based on the psychoactive compound psilocine. The psilocine derivatives provided herein exhibit improved pharmacokinetic properties during uptake and reduced side effects resulting from the metabolites thus formed, compared to psilocine. 5-HT 2A -Due to the affinity of novel thyrosine derivatives for receptors, these derivatives are particularly advantageous for use in therapies, such as the treatment of depression or drug addiction.

[0040] In one embodiment, the present invention relates to a novel psilocine derivative according to the following general formula (I): [ka] In the formula, R 1 However, -O-(C 1-12 Selected from the group consisting of alkyl, -O-heteroaryl, -O-CH2-aryl, heterocyclyl, -CH(-NH2)-(heteroaryl), -O-(alkylene)-O-alkyl, and -CH(-NH2)-alkyl, the alkyl, alkylene, aryl, heteroaryl, and heterocyclyl groups are each substituted with one or more substituents as needed, R 2 and R 3 If R is methyl, 1 However, it is not -CH2-NH2 or -CH(-NH2)-CH3, R 2 and R 3 However, each is independently selected from hydrogen, methyl, and ethyl, provided that R 2 and R 3 Both are not hydrogen, R 4 However, hydrogen or -C(=O)-O-(C 1-6 The present invention provides alkyl compounds or pharmaceutically acceptable salts thereof.

[0041] In some embodiments, base R 1 The alkyl, alkylene, aryl, heteroaryl, and heterocyclyl groups in the compound are halogen, aryl, amino, heteroarylalkoxy, thioalkoxy, hydroxyl, thiol, amino, guanidino, and -C(=O)-NR. A R B , -C(=O)-OR A , and optionally substituted with one or more substituents selected from the group consisting of disulfanyl, R A and R B This is independently selected from the group consisting of hydrogen and alkyl.

[0042] In some embodiments of the compound of formula (I), R 1 is -O-(C 1-12alkyl), -O-CH2-phenyl, -CH2-NH2, -CH(-NH2)-CH3, -CH(-NH2)-CH(-CH3)-CH3, -CH(-NH2)-CH2-CH(-CH3)-CH3, -CH(- NH2)-CH(-CH3)-CH2CH3, -CH(-NH2)-CH2CH2-S-CH3, -CH(-NH2)-CH2-SH, -CH(-NH2)-CH2-OH, -CH(-NH2)-CH(-CH3) -OH, -CH(-NH2)-CH2-C(=O)-NH2, -CH(-NH2)-CH2CH2-C(=O)-NH2, -CH(-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazole-4-yl), -CH(- NH2)-CH2-phenyl, -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1H-indole-3-yl), -(pyrrolidine-2-yl), -(4-hydroxypyrrolidine-2-yl), -CH(-NH2)-CH2-SS-CH2-CH(-NH2)-COOH, -CH(-NH2)-CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=O )-NH2, -CH2-NH-CH3, -CH(-NH2)-CH2CH2-SH, -CH(-NH2)-CH2CH2-OH, -CH(-NH2)-CH2-(3,4-dihydroxyphenyl), -CH(-NH2)-CH2-(5-hydroxy-1H-indole-3-yl), -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH(-CH3)-CH2-NH2, -C(-NH2)=CH2, -O-(1-[R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 )-1H-indole-4-yl),-O-(C 1-12 Alkylene)-O-(1-[R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 )]-1H-indole-4-yl),-CH(-NH2)-CH2-COO-(1-[R 4-3-[(-CH2CH2-N(-R 2 )-R 3 )]-1H-indol-4-yl), -CH(-NH2)-CH2CH2-COO-(1-[R 4 -3-[(-CH2CH2-N(-R 2 )-R 3 )]-1H-indol-4-yl), -CH(-NH2)-CH2-S-S-CH2-CH(-NH2)-COO-(1-[R 4 -3-[(-CH2CH2-N(-R 2 )-R 3 )]-1H-indol-4-yl), -O-(5-(aminomethyl)isoxazol-3-yl), and -CH(-NH2)-(3-hydroxy-isoxazol-5-yl), selected from the group consisting of R 2 and R 3 are each independently selected from hydrogen, methyl and ethyl, provided that R 2 and R 3 are not both hydrogen, R 4 is hydrogen or -C(=O)-O-(C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, R 1 is selected from the group consisting of -O-(C 1-12 alkyl) and -O-CH2-phenyl. The -O-(C 1-12 alkyl) group may be, for example, an -O-(C 2-5 alkyl) group such as ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, tert-butyloxy, or neopentyloxy. However, R 1 may also be, for example, -O-(C 6-12 alkyl) (e.g., C6 alkoxy, C7 alkoxy, C8 alkoxy, C9 alkoxy, C 10 alkoxy, C 11 alkoxy, or C 12 alkoxy).

[0044] In some embodiments, R 1 -CH2-NH2, -CH(-NH2)-CH3, -CH(-NH2)-CH(-CH3)-CH3, -CH(-NH2)-CH2-CH(-CH3)-CH3, -CH(-NH2)-CH(-CH3)-CH2CH3, -CH(-NH2)-CH2CH2 -S-CH3, -CH(-NH2)-CH2-SH, -CH(-NH2)-CH2-OH, -CH(-NH2)-CH(-CH3)-OH, -CH(-NH2)-CH2-C(=O)-NH2, -CH(-NH2)-CH2CH2-C(=O)-NH2, -CH The group is selected from the following: (-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazole-4-yl), -CH(-NH2)-CH2-phenyl, -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1H-indole-3-yl), and -(pyrrolidine-2-yl).

[0045] In some embodiments, R 1-CH(-NH2)-CH(-CH3)-CH3, -CH(-NH2)-CH2-CH(-CH3)-CH3, -CH(-NH2)-CH(-CH3)-CH2CH3, -CH(-NH2)-CH2CH2-S-CH3, -CH(-NH2)- CH2-SH, -CH(-NH2)-CH2-OH, -CH(-NH2)-CH(-CH3)-OH, -CH(-NH2)-CH2-C(=O)-NH2, -CH(-NH2)-CH2CH2-C(=O)-NH2, -CH(-NH2)-CH2-C The group is selected from OOH, -CH(-NH2)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazole-4-yl), -CH(-NH2)-CH2-phenyl, -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1H-indole-3-yl), and -(pyrrolidine-2-yl).

[0046] In some embodiments, R 1 The group is selected from -(4-hydroxypyrrolidine-2-yl), -CH(-NH2)-CH2-SS-CH2-CH(-NH2)-COOH, -CH(-NH2)-CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=O)-NH2, -CH2-NH-CH3, -CH(-NH2)-CH2CH2-SH, -CH(-NH2)-CH2CH2-OH, -CH(-NH2)-CH2-(3,4-dihydroxyphenyl), -CH(-NH2)-CH2-(5-hydroxy-1H-indole-3-yl), -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH(-CH3)-CH2-NH2, and -C(-NH2)=CH2.

[0047] In some embodiments, R 2 and R 3 is methyl. In some embodiments, R 2 and R 3 is ethyl. In some embodiments, R 2 It is methyl, and R3 is hydrogen. In some embodiments, R 2 It is ethyl, and R 3 is hydrogen. Preferably, R 2 and R 3 These are methyl compounds.

[0048] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -C(=O)-O-(C 2-4 It is alkyl. Preferably, R 4 It is hydrogen.

[0049] In a preferred embodiment, the novel psilocine derivative according to formula (I) is a compound having the following formula or a pharmaceutically acceptable salt thereof, [ka] In the formula, R 1 is -O-(C 2-5 Selected from the group consisting of alkyl, -O-CH2-phenyl, -CH2-NH2, -CH(-NH2)-CH2-COOH, and -CH(-NH2)-CH2-(1H-indole-3-yl). In preferred embodiments, R 1 The group is selected from the group consisting of -O-CH2CH3, -O-CH2CH2CH3, -O-CH(-CH3)-CH3, -O-CH2CH2CH2CH3, -O-CH2-CH(-CH3)-CH3, -OC(-CH3)3, -O-CH2-C(-CH3)3, -O-CH2-phenyl (i.e., benzyloxy), -CH2-NH2, -CH(-NH2)-CH2-COOH, and -CH(-NH2)-CH2-(1H-indole-3-yl).

[0050] In some embodiments, R 2 is methyl or ethyl. Preferably, R 2 It is methyl.

[0051] In some embodiments, R 3is methyl or ethyl. Preferably, R 3 It is methyl.

[0052] R 2 and R 3 It is particularly preferable that each of them be methyl.

[0053] Preferred examples of novel psilocine derivatives according to the present invention include any one of the following compounds (and a pharmaceutically acceptable salt of any of these compounds): [ka]

[0054] In some embodiments, the present invention provides compounds having the following molecular structures: [ka]

[0055] In some embodiments, the present invention provides psilocine derivatives having the following structure: [ka]

[0056] The present invention relates to psilocine derivatives described herein in any form, for example, a non-salt form or a salt, particularly a pharmaceutically acceptable salt form.

[0057] Accordingly, the scope of the present invention encompasses all pharmaceutically acceptable salt forms of psilocine derivatives of formula (I) that can be formed, for example, by protonation of an atom carrying a lone pair of electrons that is readily protonated with an inorganic or organic acid, such as an amino group, or as a salt of an acid group (such as a carboxylic acid group) having a physiologically acceptable cation. Examples of base addition salts include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salt, meglumine salt, ethylenediamine salt, or choline salt; aralkylamine salts such as N,N-dibenzylethylenediamine salt, benzathine salt, or benetamine salt; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, or isoquinoline salt; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, or tetrabutylammonium salt; and basic amino acid salts such as arginine salt, lysine salt, or histidine salt.Exemplary acid addition salts include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate salt), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipine, gluconate, glycolate, nicotinate, benzoate, and saline. This includes organic salts such as cylates, ascorbic acid, pamoate (embonate), camphorate, glucoheptanoate, or pivalate; sulfonates such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besilate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate; glycerophosphates; and acidic amino acid salts such as aspartate or glutamate. Further pharmaceutically acceptable salts are described in the literature, e.g., Stahl PH & Wermuth CG (eds.), “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, 2002 and the references cited therein. Preferred examples of pharmaceutically acceptable salts of the psilocine derivative according to the present invention include, for example, fumarate, maleate, oxalate, malate, tartrate, or methanesulfonic acid (mesylate) salts. A particularly preferred pharmaceutically acceptable salt is fumarate. A particularly preferred pharmaceutically acceptable salt is oxalate.

[0058] The scope of the present invention also includes any physical form of psilocine derivatives provided herein, including any hydrated or solvated form, and any amorphous or crystalline form.

[0059] Furthermore, psilocine derivatives of formula (I) may exist in the form of different isomers, particularly stereoisomers (e.g., enantiomers or diastereomers). All such isomers of the compounds of formula (I) are intended as part of the present invention, either as mixtures or in pure or substantially pure forms. Any tautomers of the compounds described herein are also encompassed by the present invention. With respect to stereoisomers, the present invention encompasses isolated optical isomers of the psilocine derivatives according to the present invention, and any mixtures thereof (in particular, including racemic mixtures / racemates). Racemates can be separated by physical methods, such as fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. Individual optical isomers may also be prepared by using the corresponding optically active starting materials in their synthesis, or they may be obtained from the corresponding racemates by salt formation with optically active acids, followed by crystallization. In the case of the compounds psilon-4-yl aspartate and psilon-4-yl tryptophanate, the carbon atom supporting the -NH2 group (the C of the respective amino acid aspartate or tryptophan) α The atoms (corresponding to the atoms) may exist in the (S) configuration, the (R) configuration, or as a racemic mixture, and it is preferable that the carbon atoms exist in the (S) configuration (similar to the naturally occurring amino acids L-aspartate and L-tryptophan). 1 For any other compound of formula (I) having an amino acid residue as, the C of each amino acid residue α Atoms can similarly exist in (S) configuration, (R) configuration, or as a racemic mixture, thereby C α It is preferable that the atoms exist in a (S) configuration.

[0060] The scope of the present invention also includes psilocine derivatives of formula (I) in which one or more atoms are replaced by specific isotopes of the corresponding atoms. For example, the present invention includes derivatives in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e., 2This invention also includes compounds of formula (I) in which H (also referred to as "D") is substituted. Therefore, this invention also includes compounds of formula (I) enriched with deuterium. Natural hydrogen contains about 99.98 mol% hydrogen-1 ( 1 H) and approximately 0.0156 mol% deuterium ( 2 It is an isotopic mixture containing H or D. The deuterium content at one or more hydrogen positions in the compound of formula (I) can be increased using deuterating techniques known in the art. For example, the compound of formula (I) or the reactants or precursors used in the synthesis of the compound of formula (I) can be subjected to an H / D exchange reaction using heavy water (D2O), for example. The deuterium content can be determined using, for example, mass spectrometry or NMR spectroscopy. It is generally preferred that the psilocine derivative of formula (I) is not deuterium enriched. Therefore, naturally occurring hydrogen atoms or 1 It is preferable that hydrogen atoms are present. Therefore, in particular, the present invention is preferable that all hydrogen atoms are naturally occurring hydrogen atoms or 1 This relates to psilocine derivatives of formula (I) where H is a hydrogen atom.

[0061] Due to their molecular structures, the psilocine derivatives according to the present invention enable improved manufacturing methods and exhibit novel, beneficial pharmacological properties.

[0062] In particular, due to their specific molecular structures, the psilocybin adducts according to the present invention are pharmacologically released, taken up, and metabolized in the human body with different pharmacokinetics (compared to psilocybin).

[0063] The pharmacological "inactivation" of the active compound (psilosine) in the form of a prodrug suppresses the rapid "flooding" of the active compound, thereby reducing the potential for abuse.

[0064] The potential for psychotropic substance poisoning is associated with a rapid increase in their concentration upon ingestion. Therefore, from a pharmaceutical perspective, active compounds that result only in a gradual increase from the initial concentration are desirable.

[0065] The present invention provides compounds that have been found to be particularly suitable as rapid-acting therapeutic agents because they are hydrolyzed to psilocine in the body faster than psilocybin is hydrolyzed, thus acting more rapidly than psilocybin. Furthermore, the compounds provided herein exert their effects on organisms only after endogenous metabolism to the actual active compound psilocine, thereby providing a longer-lasting effect (depot effect). Compounds that are hydrolyzed more slowly can provide a particularly long depot effect. Therefore, the present invention particularly provides for R in formula (I). 1 By selecting a group that is more or less rapidly hydrolyzable, it becomes possible to fine-tune the release characteristics of the psilocine derivatives provided herein.

[0066] The more stable and uniform release of active compounds within living organisms further contributes to reducing side effects.

[0067] Therefore, the "depot effect" resulting from such delayed release is a particular advantage of the present invention.

[0068] In further embodiments, the selection of the amino acid derivative used can provide additional beneficial pharmacological effects of the psilocine derivative, in addition to the delaying effect.

[0069] Exemplary amino acid derivatives are those described above (e.g., R 1 However, is it -CH2-NH2 corresponding to the glycine derivative, or R 1 However, the aspartate derivative is either -CH(-NH2)-CH2-COOH or R 1 However, it is a psilocine derivative that corresponds to the tryptophan derivative -CH(-NH2)-CH2-(1H-indole-3-yl).

[0070] Therefore, for example, in the case of psilocine aspartate, the resulting betaine structure improves the uptake of psilocine aspartate. In the case of psilocine tryptophanate, the amino acid tryptophan released by the metabolism of psilocine tryptophanate reduces or mitigates the side effect of "serotonin starvation" that can occur during conventional psilocine therapy.

[0071] Further aspects of the present invention relate to methods for producing novel psilocine derivatives provided herein, as well as methods and uses of these novel compounds, particularly treatment methods and therapeutic uses.

[0072] Method for preparing the compounds of this disclosure In one embodiment, the present disclosure provides a method for producing the compounds of the present disclosure.

[0073] In some embodiments, the present disclosure provides a method for producing a psilocine derivative (as described herein), comprising the following steps: (a) Prepare a suspension of psilocine in solvent I, (b) Adding the activator under a protective gas atmosphere, (c) Adding a derivatizing agent, (d) Stirring the mixture under a protective gas atmosphere (for example, for at least 3 hours), (e) Stopping the reaction by diluting with a solvent (e.g., solvent I from step (a)), (f) Concentrating the solvent, (g) Dissolve the residue in solvent II, (h) Extract with 1M HCl, water and saturated saline solution, (i) Drying the organic phase with a desiccant at 40-60°C under vacuum (reduced pressure), (j) Obtaining the crude product, (k) Purify the crude product by recrystallization and / or column chromatography, (l) A method is provided that includes obtaining a psilocine derivative according to the present invention.

[0074] In one embodiment, step (a) involves suspending 0.21 mmol to 2.1 mmol of psilocine in 10 ml to 100 ml of solvent I, where solvent I is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, and dichloromethane.

[0075] This can be done at temperatures of -78°C to 45°C, preferably 5°C to 40°C, and more preferably at room temperature (293.15 Kelvin, 20°C).

[0076] In one embodiment, step (b) involves adding 0.5 mmol to 5 mmol of an activator, such as a nitrogen base and / or carbodiimide.

[0077] In this case, in preferred embodiments, the nitrogen base is selected from triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine. The carbodiimide that can be added is preferably selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0078] The resulting solution is aerated with a protective gas.

[0079] Deprotonating agents such as n-butyllithium (n-BuLi) and / or acid anhydrides or acid chlorides may also be used.

[0080] In one embodiment, in step (c), 0.25 mmol to 2.5 mmol of a derivatizing agent is added dropwise through a septum, and the derivatizing agent is selected from ethyl chloroformate, di-tert-butyl pyrocarbonate, N-carbobenzoxy-glycine, N-(9-fluorenylmethyloxycarbonyl)-L-tryptophan, and 4-benzyl N-carbobenzoxy-L-aspartate.

[0081] In one embodiment, in step (d), the mixture is stirred at 20-28°C for 2-10 hours under a protective gas atmosphere. In another embodiment, the mixture is stirred at 20°C for at least 3 hours and / or up to 6 hours under a protective gas atmosphere.

[0082] In further embodiments, step (e) is used to stop the reaction by adding 30 ml to 300 ml of solvent I from step (a).

[0083] In further embodiments, in step (f), the mixture is dried, preferably under vacuum, in a rotary evaporator and redissolved in 30 ml to 300 ml of solvent II, which is selected from ethyl acetate, diethyl ether, and dichloromethane.

[0084] In one embodiment, step (h) is performed by extracting with 20 ml to 200 ml of 1 mole (1 M) hydrochloric acid. In one embodiment, a subsequent extraction is performed using 20 ml to 200 ml of water. In one embodiment, a final extraction is performed using 20 ml to 200 ml of saturated saline solution.

[0085] In further embodiments, step (i) involves drying the mixture. Particularly preferred is drying at a temperature of 35°C to 60°C and under a vacuum (reduced pressure) of 30 to 60 mbar.

[0086] Preferred desiccants are anhydrous calcium chloride, anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous magnesium sulfate, or anhydrous calcium sulfate. In one embodiment, the desiccant is anhydrous MgSO4, the temperature is 45°C, and the vacuum is 40 mbar.

[0087] The crude product obtained in steps (a) to (j) contains the psilocine derivative according to the present invention.

[0088] In further embodiments, the crude product is further purified. Purification may be carried out, for example, by dissolving in isopropanol, then evaporating at 50°C and 400 mbar until crystallization occurs, and / or by column purification with 50 g of silica using an eluate mixture of dichloromethane / methanol (for example, in one embodiment in a ratio of 8:2). Other column materials and eluents known in the art can also be used.

[0089] In one embodiment, in recrystallization from isopropanol, the enhancement or strengthening of crystallization is promoted by the addition of diisopropyl ether.

[0090] This method achieves yields exceeding 65% by weight (weight measurement of the amount of final product relative to the initial material). In some embodiments, yields exceeding 70% by weight, 75% by weight, 80% by weight, and up to 85% by weight, 90% by weight, and even up to 95% by weight are achieved.

[0091] Further details of the manufacturing method are provided in the examples and will be apparent to those skilled in the art.

[0092] Therefore, the present invention provides a compound having a general molecular structure (I) that can be produced in high purity using the method according to the present invention. [ka] The base in equation (I) is defined as follows: R 1 is -O-(C 1-12alkyl), -O-CH2-phenyl, -CH2-NH2, -CH(-NH2)-CH3, -CH(-NH2)-CH(-CH3)-CH3, -CH(-NH2)-CH2-CH(-CH3)-CH3, -CH(- NH2)-CH(-CH3)-CH2CH3, -CH(-NH2)-CH2CH2-S-CH3, -CH(-NH2)-CH2-SH, -CH(-NH2)-CH2-OH, -CH(-NH2)-CH(-CH3) -OH, -CH(-NH2)-CH2-C(=O)-NH2, -CH(-NH2)-CH2CH2-C(=O)-NH2, -CH(-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazole-4-yl), -CH(- NH2)-CH2-phenyl, -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1H-indole-3-yl), -(pyrrolidine-2-yl), -(4-hydroxypyrrolidine-2-yl), -CH(-NH2)-CH2-SS-CH2-CH(-NH2)-COOH, -CH(-NH2)-CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=O )-NH2, -CH2-NH-CH3, -CH(-NH2)-CH2CH2-SH, -CH(-NH2)-CH2CH2-OH, -CH(-NH2)-CH2-(3,4-dihydroxyphenyl), -CH(-NH2)-CH2-(5-hydroxy-1H-indole-3-yl), -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH(-CH3)-CH2-NH2, -C(-NH2)=CH2, -O-(1-[R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 )-1H-indole-4-yl),-O-(C 1-12 Alkylene)-O-(1-[R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 )]-1H-indole-4-yl),-CH(-NH2)-CH2-COO-(1-[R 4]-3-[(-CH2CH2-N(-R 2 )-R 3 )]-1H-indole-4-yl),-CH(-NH2)-CH2CH2-COO-(1-[R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 )]-1H-indole-4-yl),-CH(-NH2)-CH2-SS-CH2-CH(-NH2)-COO-(1-[R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 Selected from -1H-indole-4-yl), -O-(5-(aminomethyl)isoxazole-3-yl), and -CH(-NH2)-(3-hydroxy-isoxazole-5-yl).

[0093] R 2 and R 3 Each is independently selected from hydrogen, methyl, and ethyl, however, R 2 and R 3 Neither of them is hydrogen.

[0094] R 4 However, hydrogen or -C(=O)-O-(C 1-6 It is alkyl.

[0095] In particular, the present invention provides compounds having the following general molecular structures, which can be similarly produced with high purity using the method according to the present invention. [ka] The base in this formula is defined as follows: R 1 is -O-(C 2-5 Alkyl compounds, particularly ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, tert-butyloxy, or neopentyloxy.

[0096] R 2 It is methyl (-CH3) or ethyl (-C2H5), especially methyl.

[0097] R 3 It is methyl (-CH3) or ethyl (-C2H5), especially methyl.

[0098] Pharmaceutical composition: The present invention provides a pharmaceutical / pharmacological composition comprising at least one psilocine derivative according to the present invention and optionally one or more pharmaceutically acceptable excipients. The present invention also relates to psilocine derivatives or the aforementioned pharmaceutical compositions for use in therapy (or as pharmaceuticals).

[0099] The psilocine derivatives provided herein may be administered as compounds themselves or formulated as pharmaceutical / pharmaceutical compositions or pharmaceuticals. The pharmaceutical compositions / pharmaceuticals may optionally contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, and / or antioxidants.

[0100] The pharmaceutical composition is based on techniques known to those skilled in the art, e.g., Remington: The Science and Practice of Pharmacy, Pharmaceutical Press, 22 ndPharmaceutical formulations can be manufactured using the technologies published in this edition. The pharmaceutical composition can be formulated as oral or parenteral dosage forms, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal administration. Oral dosage forms include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, liquids, emulsions, suspensions, syrups, elixirs, reconstituted powders and granules, dispersing powders and granules, medicinal gums, chewing tablets, and effervescent tablets. Parenteral dosage forms include liquids, emulsions, suspensions, dispersants, reconstituted powders and granules. Emulsions are a preferred dosage form for parenteral administration. Rectal and vaginal dosage forms include suppositories and vaginal suppositories (ovula). Nasal dosage forms can be administered, for example, by inhalation and blowing using a measuring inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches, and transdermal delivery systems.

[0101] Treatment method: The present invention further includes serotonin 5-HT 2A The present invention relates to thyrosine derivatives described herein (which may exist in non-salt form or in pharmaceutically acceptable salt form), or pharmaceutical compositions comprising at least one thyrosine derivative, for use in the treatment of receptor-related disorders / disorders. In particular, the present invention relates to thyrosine derivatives or pharmaceutical compositions described herein for use in the treatment of anxiety disorders, attention-deficit / hyperactivity disorder (ADHD), depression, cluster headaches, cancer-related conditions, diminished motivation, burn-out, bore-out, migraines, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea, or vomiting.

[0102] This invention also relates to serotonin 5-HT 2AThis document refers to the use of thyrosine derivatives described herein in the manufacture of pharmaceuticals for the treatment of receptor-related disorders, preferably anxiety disorders, attention-deficit / hyperactivity disorder (ADHD), depression, cluster headaches, cancer-related conditions, diminished motivation, burnout syndrome, boredom syndrome, migraines, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea, or vomiting.

[0103] Furthermore, the present invention relates to diseases / disorders, particularly serotonin 5-HT 2A The present invention provides a method for treating receptor-related disorders in subjects requiring such treatment, comprising administering a therapeutically effective amount of a thyrosine derivative according to the present invention to said subject. Preferably, the disorders to be treated are anxiety disorders, attention-deficit / hyperactivity disorder (ADHD), depression, cluster headaches, cancer-related conditions, diminished motivation, burnout syndrome, boredom syndrome, migraines, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea, or vomiting.

[0104] In principle, psilocine derivatives of formula (I) or the corresponding pharmaceutical compositions may be administered to subjects by any convenient route of administration. Various routes for administering pharmaceuticals are known in the art and include, in particular, oral (e.g., as tablets, capsules, vaginal suppositories, elixirs, or as ingestible liquids or suspensions), topical (e.g., percutaneous, intranasal, ocular, buccal, and sublingual), parenteral (e.g., by injection or infusion techniques, such as by implantation of depots subcutaneously or intramuscularly, including injections into the subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, or intrasternal regions), pulmonary (e.g., by inhalation or inhalation therapy using aerosols from the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or anterior chamber), rectal, or vaginal administration.

[0105] The psilocine derivatives (or corresponding pharmaceutical compositions) according to the present invention are particularly preferably administered orally, sublingually, or nasally (for example, as a nasal spray or nasal drop). Suitable dosage forms for oral administration include, for example, coated or uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, liquids, emulsions, suspensions, syrups, elixirs, reconstituted powders or granules, dispersing powders or granules, medicinal gums, chewing tablets, or effervescent tablets. In the case of oral administration, the psilocine derivatives or pharmaceutical compositions are preferably administered by oral ingestion, particularly by swallowing. Thus, the compounds or pharmaceutical compositions can be administered so as to enter the gastrointestinal tract through the mouth, which may also be referred to as “oral-gastrointestinal” administration.

[0106] The subject or patient treated according to the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male or female human) or a non-human mammal. Most preferably, the subject / patient treated according to the present invention is a human.

[0107] This specification references several documents, including patent applications / patents. While the disclosures of these documents are not considered relevant to the patentability of the present invention, they are incorporated herein by reference in their entirety. More specifically, all referenced documents are incorporated by reference to the same extent as each individual document is explicitly and individually indicated to be incorporated by reference.

[0108] Any reference in this Specification to prior publications (or information derived therefrom) should not be considered an acknowledgment, acceptance, or in any way an implication that the corresponding prior publication (or information derived therefrom) forms part of the common sense in the technical field to which this Specification relates.

[0109] The present invention will be described here with reference to the following embodiments, which are merely illustrative and should not be construed as limitations on the scope of the invention. [Examples]

[0110] Example 1: Method for producing psilocin-4-ylethyl carbonate Psilosine (2.1 mmol / 429 mg) was suspended in tetrahydrofuran (100 ml) at 25°C. Triethylamine (5.0 mmol / 0.7 ml) was added, and the mixture was aerated with argon. A clear solution was obtained. Ethyl chloroformate (2.5 mmol / 0.24 ml) was added dropwise through a septum. Upon addition, a whitish turbidity immediately formed in the solution. The mixture was stirred at 25°C under argon for 2.5 hours.

[0111] LC / MS at a wavelength of 225 nm showed that the reaction mixture sample had reacted almost completely with the starting materials. HPLC allowed for the quantification of 77% of the product.

[0112] The reaction mixture is stirred under argon at 25°C for a further 1 hour, then diluted with tetrahydrofuran (300 ml) to stop the reaction. The reaction mixture is concentrated in a rotary evaporator at 42°C and then dried to a maximum of 10 mbar.

[0113] The raw product was taken up in 300 ml of ethyl acetate and extracted with 200 ml of 1 M hydrochloric acid, 200 ml of water, and 200 ml of saturated saline solution. The organic phase was then dried with some MgSO4. Subsequently, the organic phase was gradually concentrated in a rotary evaporator, and the product was crystallized from the solution as colorless crystals.

[0114] For purification, the material was recrystallized from isopropanol at 50°C. After cooling, some diisopropyl ether was added to enhance crystal formation. After filtration, 410 mg of colorless crystals were obtained.

[0115] The preparation of psilocine-4-ylethyl carbonate can also be carried out as described above, but dichloromethane (instead of tetrahydrofuran) is used to suspend the psilocine. Furthermore, after the initial concentration and drying steps, the extraction / washing step can be skipped, and if desired, the product can be filtered instead, for example, through a small silica plug. For purification, the compound can also be stabilized as a fumarate or oxalate and recrystallized in acetone.

[0116] Example 2: Method for producing psilosine-4-ylneopentyl carbonate Psilosine (2.0 mmol / 408 mg) was suspended in dichloromethane (12 ml) at 25°C. Triethylamine (2.6 mmol / 0.36 ml) was added, and the mixture was aerated with argon. A clear solution was obtained. Neopentyl chloroformate (2.1 mmol / 0.32 ml) was added dropwise through a septum. Upon addition, a whitish turbidity immediately formed in the solution. The mixture was stirred at 25°C under argon for 2.5 hours.

[0117] The reaction was stopped by dilution with dichloromethane (40 ml). The desired crude product could be obtained by filtration through a small silica plug. For purification, the compound could be stabilized as a fumarate or oxalate and recrystallized in acetone.

[0118] 420 mg of oxalate was obtained as colorless crystals.

[0119] Example 3: Method for producing psilocin-4-ylbenzyl carbonate Psilosine (4.9 mmol / 1.0 g) was suspended in dichloromethane (25 ml) at 25°C. Triethylamine (6.4 mmol / 0.90 ml) was added, and the mixture was aerated with argon. A clear solution was obtained. Benzyl chloroformate (5.4 mmol / 0.80 ml) was added dropwise through a septum. Upon addition, a whitish turbidity immediately formed in the solution. The mixture was stirred at 25°C under argon for 2.5 hours.

[0120] The reaction was stopped by dilution with dichloromethane (60 ml). The desired crude product could be obtained by filtration through a small silica plug. For purification, the compound could be stabilized as a fumarate or oxalate and recrystallized in acetone.

[0121] 1.70 g of oxalate was obtained as colorless crystals.

[0122] Example 4: Method for producing psilocin-4-yltryptophanate Psilosine (1.5 mmol / 300 mg) was suspended in tetrahydrofuran (100 ml) at 25°C. 4-dimethylaminopyridine (1.8 mmol / 220 mg) and dicyclohexylcarbodiimide (1.8 mmol / 370 mg) were added, and the mixture was aerated with argon. The mixture was stirred at room temperature (RT) for 15 minutes. Fmoc-L-tryptophan (1.8 mmol / 770 mg) was added. After the addition, the suspension became clear and a solution was formed. The mixture was stirred at 25°C under argon for 5 hours.

[0123] In LC / MS at a wavelength of 225 nm, the reaction mixture sample showed a 23% reaction. HPLC still detected large amounts of psilocin and unreacted Fmoc-L-tryptophan.

[0124] The reaction mixture was stirred under argon at 25°C for a further 1 hour, then diluted with tetrahydrofuran (200 ml) to stop the reaction. The reaction mixture was concentrated in a rotary evaporator at 42°C and then dried to a maximum of 10 mbar.

[0125] The product was taken up in 200 ml of ethyl acetate and extracted with 150 ml of 1 M hydrochloric acid, 150 ml of water, and 150 ml of saturated saline solution. The organic phase was then dried with some MgSO4. The organic phase was then removed by distillation in a rotary evaporator, and the product was obtained as 1.2 g of yellow solid.

[0126] The bioproduct was column-treated with 50 g of silica using an eluent mixture of hexane / ethyl acetate in a 7:3 ratio. This yielded 208 mg of the intermediate product as a colorless solid.

[0127] Cutting off the protective layer: The intermediate product was dissolved in 20 ml of tetrahydrofuran at 25°C. Piperidine (0.7 mmol / 59 mg) was added dropwise, and the mixture was aerated with argon. The mixture was stirred at room temperature for 24 hours, and complete deprotection was demonstrated by thin-layer chromatography. The reaction mixture was concentrated in a rotary evaporator at 42°C and then dried at a maximum of 10 mbar. The resulting product was column-treated with 20 g silica using an eluate mixture of tert-butyl methyl ether / ethanol + 1% ammonia in a ratio of 7:3. This yielded 106 mg of a nearly colorless solid.

[0128] Example 5: Method for producing psilocyne-4-yl tert-butyl carbonate The method for producing psilon-4-yl tert-butyl carbonate is similar to the method for producing psilon-4-ylethyl carbonate (see Example 1).

[0129] This method involves the following steps: a. Prepare a suspension of psilocine in tetrahydrofuran, b. Add triethylamine and 4-dimethylaminopyridine under a protective gas atmosphere, c. Adding di-tert-butyl pyrocarbonate (dissolved in tetrahydrofuran), d. Stir the mixture under a protective gas atmosphere for at least 3 hours, e. The reaction is stopped by diluting with tetrahydrofuran, f. Remove tetrahydrofuran by distillation in a rotary evaporator, and dissolve the residue in ethyl acetate. Extraction is performed using g. 1M HCl, water, and saturated saline solution. The organic phase is dried with a desiccant at 40-60°C under vacuum. i. To obtain a biological product containing psilocin-4-yl tert-butyl carbonate, j. Recrystallization from isopropanol, etc.

[0130] Example 6: Method for producing psilocin-4-ylglycinate The method for producing psilon-4-ylglycinate is similar to the method for producing psilon-4-yltryptophanate (see Example 4).

[0131] This method involves the following steps: a. Prepare a suspension of psilocine in tetrahydrofuran, b. Adding 4-dimethylaminopyridine and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, Adding cN-carbobenzoxyglycine, d. Stir the mixture under a protective gas atmosphere for at least 5 hours, e. The reaction is stopped by diluting with tetrahydrofuran, f. Remove tetrahydrofuran by distillation in a rotary evaporator, and dissolve the residue in ethyl acetate. Extract with g. 1M HCl, water, and saturated saline solution. The organic phase is dried with a desiccant at 40-60°C under vacuum. i. To obtain a raw intermediate product containing psilocin-4-yl-Cbz glycinate, j. Purification by column chromatography using hexane / ethyl acetate, k. Cleavage of the protecting group by hydration using palladium-activated carbon in ethanol, This includes purification by column chromatography using l.tert-butylmethyl ether / ethanol 1% ammonia.

[0132] Example 7: Method for producing psilocine aspartate The method for producing psilon aspartate is similar to the method for producing psilon-4-yltryptophanate (see Example 4).

[0133] This method involves the following steps: a. Prepare a suspension of psilocine in tetrahydrofuran, b. Adding 4-dimethylaminopyridine and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, c. Adding 4-benzyl N-carbobenzoxy L-aspartate, d. Stir the mixture under a protective gas atmosphere for at least 5 hours, e. The reaction is stopped by diluting with tetrahydrofuran, f. Remove tetrahydrofuran by distillation in a rotary evaporator, and dissolve the residue in ethyl acetate. Extraction is performed using g. 1M HCl, water, and saturated saline solution. The organic phase is dried with a desiccant at 40-60°C under vacuum. i. To obtain a biological intermediate product containing psilocin-4-yl-N-Cbz benzyl aspartate, j. Purification by column chromatography using hexane / ethyl acetate, k. Cleavage of the protecting group by hydration using palladium-activated carbon in ethanol, This includes purification by column chromatography using l.tert-butylmethyl ether / ethanol 1% ammonia.

[0134] Example 8: Solubility and lipophilicity of psilocine / methocine carbonate Introduction Three novel compounds (i.e., psilocybin-4-ylethyl carbonate, psilocybin-4-yltert-butyl carbonate, and N-methyl-N-ethyltryptamine-4-ylethyl carbonate) were tested in vitro for their solubility in aqueous solution and their lipophilicity compared to psilocybin and psilocybin.

[0135] Water solubility and lipophilicity can be of significant importance in drug development. Firstly, both properties can influence the pharmacokinetics and bioavailability of a compound in vivo. Secondly, these properties can help determine the suitability of various compounds for development into different dosage forms.

[0136] method Dynamic turbidimetric solubility assay Each test compound was diluted to 10 mM in DMSO. From this solution, six further dilutions of each test compound were prepared in DMSO (0.02, 0.1, 0.2, 1, 2, and 5 mM). Each of these solutions was then further diluted to 1 / 50 in buffer (0.01 M phosphate-buffered saline (pH 7.4)), resulting in a final DMSO concentration of 2% and final test compound concentrations of 0.4, 2, 4, 20, 40, 100, and 200 μM. Visible particles were present when psilocybin was diluted to 10 mM in DMSO; therefore, seven final dilutions prepared for psilocybin were 0.2, 1, 2, 10, 20, 50, and 100 μM. A DMSO blank was also included. Three replication wells were designated for each concentration. Following dilution in buffer, the plates were incubated with shaking at room temperature for 5 minutes, and then absorbance was measured at 620 nm using a Molecular Devices SpectraMax384 UV detector. Nicardipine was tested as a control compound. Psilosine-4-ylethyl carbonate, psilocybin-4-yltert-butyl carbonate, and N-methyl-N-ethyltryptamine-4-ylethyl carbonate were in salt form (hemifumarate), while psilocybin and psilocybin were free bases.

[0137] Solubility was estimated from the concentration of the test compound normalized to the DMSO blank, resulting in an absorbance increase exceeding a threshold of 0.005 absorbance units.

[0138] Micro-shaking flask LogD A 10 mM solution of each test compound was diluted in DMSO to obtain a 400 μM solution, which was then serially diluted in 2.5% DMSO in PBS to generate calibration curves (0.014, 0.04, 0.12, 0.37, 1.11, 3.33, and 10 μM). Six replicas of each test compound were incubated at 10 μM in a 1:9 octanol:PBS (pH 7.4) ratio. After incubation at room temperature for 2 hours with shaking at 600 rpm, the incubation plate was centrifuged for 15 minutes to separate the layers, and two aliquots were taken from the PBS layer. The first was left neat, and the second was diluted 10-fold to obtain a diluted sample. Internal standards were added to both the calibration curves and the PBS incubation samples for analysis by LC MS / MS. Verapamil was tested as a control compound. Psyrosine-4-ylethyl carbonate, psirosine-4-yltert-butyl carbonate, and N-methyl-N-ethyltryptamine-4-ylethyl carbonate were in salt form (hemifumarate), while psilocybin and psirosine were free bases.

[0139] LogD was measured as the concentration in the PBS layer relative to the created calibration curve, with respect to a starting concentration of 10 μM. All six copies of the neat sample were averaged to obtain one value for each, and the same calculation was performed for the diluted samples.

[0140] result Dynamic turbidimetric solubility assay When preparing a 10 mM stock solution of psilocybin in DMSO, particles were observed. All other compounds appeared to dissolve completely at 10 mM. Therefore, psilocybin was tested only at a maximum concentration of 100 μM in the assay. In contrast, the solubility of the other compounds could be tested at a maximum concentration of 200 μM. [Table 1] Micro-immersion flask LogD [Table 2]

[0141] conclusion Solubility: While psilocybin exhibited good solubility up to 100 μM, the other novel compounds tested showed good solubility up to 200 μM. The challenges encountered while preparing a 10 mM stock solution of psilocybin support the interpretation that the novel compounds tested exhibit greater water solubility compared to psilocybin.

[0142] Lipophilicity: All novel compounds tested showed a LogD greater than that of psilocybin and greater than that of psilocybin. The relatively low LogD of psilocybin may be consistent with its limited permeability (Hartmann T and Schmitt J (2004) Lipophilicity-beyond octanol / water: a short comparison of modern technologies. Drug Discov Today 1(4):431-439). In contrast, the logD > 1 observed for the novel compounds is consistent with the range reported to be optimal for orally administered CNS drugs (Kerns EH and Di L (2008) Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization. ISBN 0123695201 Academic Press). These results indicate that the psilocybin carbonate according to the present invention can cross the blood-brain barrier (BBB) ​​faster than psilocybin, which is highly advantageous for therapeutic applications. Furthermore, the improved solubility / lipophilicity profile of the novel compound may enhance the absorption of the prodrug by passive diffusion when administered via parenteral routes, compared to psilocybin.

[0143] Example 9: Stability of novel psilocine carbonate in HCl Introduction Four novel compounds (i.e., psilocin-4-ylethyl carbonate, psilocin-4-yl tert-butyl carbonate, psilocin-4-ylneopentyl carbonate, and psilocin-4-ylbenzyl carbonate) were tested for their stability in 1% hydrochloric acid (HCl) compared to psilocybin. These conditions were selected to provide insights into the chemical stability of the compounds at pH similar to gastric conditions.

[0144] method Four milligrams of each test compound were diluted in 2 ml of distilled water to obtain a 2 mg / ml solution. Next, 2 ml of the test compound solution was added to 2 ml of 2% (v / v) HCl in distilled water to obtain a final HCl concentration of 0.32 mM (pH 0.5). The test solutions were incubated at 37°C for approximately 26 hours with continuous stirring. The concentrations of the parent compound and psilocine were analyzed at various time points using LC-MS. The concentrations of both the free parent prodrug and psilocine were expressed in comparison to the initial concentration of the parent prodrug.

[0145] result The results obtained in this experiment are shown in Figures 5A to 5D.

[0146] conclusion Considering the results described above, all psilocine carbonates tested showed greater degradation in 1% HCl than psilocybin, and it was found that each was successfully converted to psilocine under these conditions. Furthermore, psilocine tert-butyl carbonate was particularly susceptible to degradation in 1% HCl, showing rapid and complete chemical decomposition to psilocine within approximately 4 hours of testing. These findings support the interpretation that psilocine carbonates generally exhibit more rapid conversion to the active molecule psilocine under highly acidic conditions.

[0147] Example 10: Ingestion Test Chemical substances and reagents P1: Psyrosine-4-ylethyl carbonate (salt: hemifmarate) P2: Psilosine-4-yl tert-butyl carbonate (salt: hemifmarate) M1: Prodrug of 5,6-methylenedioxy-2-aminoindan (MDAI) (salt: hemioxalate) M2: 3,4-Methylenedioxyamphetamine (MDA) prodrug (salt: hemioxalate) Formic acid (Rotipuran® ≥98%, pa) and sodium fluoride (NaF, ≥99%, pa) were obtained from Carl Roth (Karlsruhe, Germany). Acetonitrile (ACN, LC-MS grade), 10M ammonium formate (99.995%), absolute ethanol, ascorbic acid (99%), and dimethyl sulfoxide (DMSO) were purchased from Sigma Aldrich (Steinheim, Germany). Deionized water was prepared using a Medica® Pro deionizer from ELGA (Celle, Germany). Calf serum was obtained from Thermo Fisher Scientific (Waltham, USA). Mobile phase A (water, 1% ACN, 0.1% HCOOH, 2mM NH4) + HCOO - ) and mobile phase B (0.1% HCOOH, 2mM NH4 in ACN) + HCOO - The following was prepared fresh before the analysis.

[0148] Intake Test Two volunteers (one male and one female) ingested approximately 1 mg each of P1 and M1 (Study 1) and P2 and M2 (Study 2) in gelatin capsules (exact amounts are shown in Tables 3 and 4). One blood sample was collected before substance ingestion and used as a zero control. After ingestion, samples were collected for approximately 8 hours, increasing the time interval between sample collections (exact protocols are shown in Tables 4 and 5). Blood was collected in EDTA Monovette (Sarstedt, Numbrecht, Germany) and immediately centrifuged after collection (15 minutes, 4,000 × g). The obtained serum was transferred to a plastic tube, and NaF (approximately 30 mg) and ascorbic acid (approximately 5 mg) were added to enhance the stability of the analyte. [Table 3] [Table 4]

[0149] Sample preparation 200 μL of serum was spiked with an internal standard solution (10 μL), and soluble proteins were precipitated by adding ACN (600 μL). After adding ammonium formate (10 M, 200 μL), the mixture was thoroughly mixed and the aqueous phase was separated from the organic phase. After centrifugation (6 min, 4,000 × g), 500 μL of the organic phase was transferred to another vial and evaporated at 40°C under a gentle nitrogen stream until dry. The sample was reconstituted in 100 μL of mobile phase (A / B, 90 / 10, v / v) and used for analysis. For quantification, a blank sample and six-point calibrations (0.5, 1.0, 2.0, 5.0, 10, 20 ng / mL) in calf serum were prepared as described above.

[0150] HPLC-MS / MS analysis The HPLC-MS system consisted of a Nexera X2 UHPLC system comprising three LC-30 AD pumps, a DGU-30A3 degasser, a SIL-30AC autosampler, a CTO-10AS column oven, and a CBM-20A controller (Shimadzu, Duisburg, Germany), coupled to a QTRAP 6500plus triple quadrupole linear ion trap mass spectrometer with a TurboIonSpray Interface (Sciex, Darmstadt, Germany). MS was operated in positive electrospray ionization mode. Data acquisition was performed using Analyst software (version 1.7) in a scheduled multiple reaction monitoring mode (detection window: 60 seconds). MS parameters (declustering potential, inlet potential, collision energy, and collision cell outlet potential) were optimized for all substances to obtain the best possible signal intensity (a summary of MRM parameters is shown in Table 5). The ion source temperature and ion source voltage were set to 550°C and +5500V, respectively. The residence time was 20 milliseconds per MRM transition. The curtain gas (N2) pressure was 35 psi, the ion source gas 1 and 2 (compressed air) pressures were 50 and 60 psi, respectively, and the collision gas (N2) pressure was set to "high". Chromatographic separation was performed using a Kinetex® biphenyl column (100 × 2.1 mm, 2.6 μm particle size, Phenomenex, Aschaffenburg, Germany) equipped with a corresponding guard column (SecurityGuard® ULTRA Cartridges UHPLC Biphenyl 2.1 mm ID column, Phenomenex, Aschaffenburg, Germany). The autosampler and column oven temperatures were set to 10°C and 40°C, respectively. The injection volume was 10 μL. Gradient elution with mobile phases A and B was applied as shown in Table 6. [Table 5] [Table 6]

[0151] The detection limit (LOD) and the quantification limit (LOQ) were determined according to German DIN 32645. The concentrations of the calibration applied were 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 ng / mL. The LOD and LOQ are shown in Table 7.

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

[0152] Conclusion P1: After oral administration of P1, only tyrosine was detected in the serum, and P1 itself (LOD 0.05 ng / mL) was not detected. The maximum concentration of tyrosine (1.1 ± 0.5 ng / mL) was observed 56 ± 13 minutes after P1 application. This is approximately 1 hour earlier than described after oral application of psilocybin by Brown et al. (Brown RT et al., Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults, Clin Pharmacokinet (2017) 56:1543 - 1554, DOI: 10.1007 / s40262 - 017 - 0540 - 6). P1 is a high - release prodrug of tyrosine in vivo.

[0153] P2: Following oral administration of P2, only psilocine was detected in the serum; P2 itself (LOD 0.07 ng / mL) was not detected. The maximum concentration of psilocine (1.13 ± 0.01 ng / mL) was observed 90 ± 56 minutes after P2 administration. This is within the same range or slightly earlier than described by Brown et al. (ibid.) for oral administration of psilocybin. P2 has a potentially shorter T2 than psilocybin. max It functions in vivo as a prodrug of psilocin.

[0154] Example 11: Further solubility and lipophilicity of psilocynth carbonate Introduction One novel compound (i.e., psilocycin-4-yl-benzyl carbonate) was tested in vitro for its solubility and lipophilicity in aqueous solution.

[0155] Water solubility and lipophilicity can be of significant importance in drug development. Firstly, both properties can influence the pharmacokinetics and bioavailability of a compound in vivo. Secondly, these properties can help determine the suitability of various compounds for development into different dosage forms.

[0156] method Dynamic solubility assay The test compound and control compound were diluted to 10 mM with DMSO, then further diluted to 1 / 50th with 50 mM PB (pH 7.4) to a target concentration of 200 μM. The samples were vortexed for at least 2 minutes, then shaken at room temperature for 24 hours (800 rpm). Concentration was measured by visual assessment before centrifugation and injection into the ULC system. Carmbamezepine and chloramaphenicol were used as control compounds. Each compound was tested in duplicate. Psilosin-4-yl-benzyl carbonate was tested as its hydrochloride salt.

[0157] Shaking Flask LogD Assay The test compound and the control compound were diluted to 10 mM in DMSO. 2 μl of each stock solution was bisected into tubes. 1-Octanol saturated phosphate buffer (PB) (pH 7.4) was prepared by adding 1-octanol to 100 mL of 100 mM PB (7.4). PB saturated 1-octanol was prepared by adding 10 mL of 100 mM PB (7.4) to 100 ml of 1-octanol. 149 μl of each solution was aliquoted into the corresponding tubes. Then, these were mixed vigorously for 2 minutes and shaken at room temperature for 1 hour (800 rpm). Before detection using LC-MS / MS, appropriate volumes of buffer and 1-octanol layer samples were aliquoted and diluted. Chlorpromazine, nadolol, and propranolol were used as control compounds. Cyrosine-4-yl-benzyl carbonate, chlorpromazine, and propranolol were tested as hydrochlorides.

[0158] LogD was calculated according to the following equation:

Number

[0159] Results Kinetic solubility assay

Table 14

Table 15

[0160] Conclusion Solubility: Cyrosine-4-yl-benzyl carbonate showed a solubility of up to >230 μM.

[0161] Lipophilicity: Psyrosine-4-ylbenzyl carbonate exhibited a LogD within the optimal range reported for orally administered CNS drugs (Kerns EH and Di L (2008) Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, ISBN 0123695201, Academic Press). The LogD of psilocybin was higher than that previously reported for psilocybin, indicating relatively high lipophilicity and therefore a high ability to cross the blood-brain barrier (BBB).

[0162] Example 12: Pharmacokinetics of a novel thyrosine carbonate in mice Introduction Three novel compounds (i.e., psilocin-4-ylethyl carbonate, psilocin-4-yltert-butyl carbonate, and psilocin-4-ylbenzyl carbonate) were tested in mice to confirm their ability to release psilocin in vivo, and their plasma psilocin pharmacokinetics were compared to those of psilocybin.

[0163] method Laboratory animals Twenty-seven male C57BL / 6J mice (Charles River UK), weighing 22-25g at purchase, were housed in groups in polypropylene cages (3s). The mice were kept on a normal 12-hour light-dark cycle (lights on from 07:00 to 19:00) with free access to standard pellet feed (Envigo 2018) and filtered tap water. The holding chamber was maintained at 21±4℃ with a relative humidity of 55±15%.

[0164] Experimental Procedure On the day of administration, the weight of the mice was measured and they were identified by tail marking using an oil-based marker pen. They were not fasted on the day of administration. Three animals were assigned to a control group that did not receive any treatment but had blood drawn to allow for the collection of a blank matrix. The remaining animals were divided into two cohorts. Animals in the first cohort received a single oral dose of one of the test compounds, and animals in the second cohort received a single intravenous dose of one of the test compounds (into the lateral tail vein). After treatment, blood was collected by phleblow from the lateral tail vein of the orally administered animals at 5, 15, 30, 45, 60, 120, and 240 minutes post-administration. Blood was collected by phleblow from the opposite lateral tail vein of the intravenously administered animals at the same time points. Psyrosine-4-ylethyl carbonate, psilocin-4-yl-tert-butyl carbonate, and psilocin-4-ylbenzyl carbonate were in salt form (hemifmarate), while psilocybin was a free base. The dose of psilocin-4-ylbenzyl carbonate, rather than psilocin-4-ylethyl carbonate or psilocin-4-yl-tert-butyl carbonate, was corrected for the salt weight. All compounds were formulated in physiological saline and administered at a volume of 5 ml / kg.

[0165] The treatment groups are summarized in the table below. [Table 16]

[0166] 25 μl of blood was collected from each animal at each time point. Blood samples were collected in K2EDTA-coated tubes (e.g., Sarstedt Microvette 300K2E tubes) and held on wet ice (10,000 RPM, 2 minutes) before centrifugation. 10 μl of plasma was withdrawn and placed in individually identified Axygen minitubes. The samples were first held on dry ice and then transferred to a freezer overnight at approximately -80°C. Blank matrix plasma samples were handled in the same manner as test samples. Psilosine levels in the samples were determined using LC-MS / MS. All pharmacokinetic parameters were calculated manually. Measurements less than LLOQ (=2.5~5 ng / ml) were included as 0 ng / ml.

[0167] result [Table 17] [Table 18] [Table 19]

[0168] The plasma thyrosine concentrations after intravenous or oral administration of the test compounds to mice are shown in Figures 6A and 6B, respectively. Individual figures for each test compound are further shown in Figures 6C to 6H. These figures concern the plasma thyrosine concentrations after intravenous administration of thyrosine-4-ylethyl carbonate (Figure 6C) or after oral administration (Figure 6D), the plasma thyrosine concentrations after intravenous administration of thyrosine-4-yltert-butyl carbonate (Figure 6E) or after oral administration (Figure 6F), and the plasma thyrosine concentrations after intravenous administration of thyrosine-4-ylbenzyl carbonate (Figure 6G) or after oral administration (Figure 6H).

[0169] conclusion An overview of IV data: Psilosine was detected after administration of all compounds, indicating that each compound was converted to psilocybin in vivo upon intravenous administration. Upon intravenous administration, all novel compounds exhibited similar or higher C2 levels than psilocybin. max This showed that, in particular, psilocybin-4-yl-benzyl carbonate has about twice the amount of C as psilocybin. max This indicates that overall exposure was greater, as shown by AUC. max The results were nearly identical across all test compounds.

[0170] An overview of PO data: Psilosine was detected after administration of all compounds, and it was shown that each compound was converted to psilocybin in vivo in mice when administered orally. When administered orally, all novel compounds were found to have a slightly lower C content than psilocybin. max This was shown. max is a delay T max With the exception of psilocin-4-yl-benzyl carbonate, which showed a time of 45 minutes, all test compounds were nearly equivalent (30 minutes).

[0171] Commentary on IV vs. oral administration of thyrosine-4-ylbenzyl carbonate: The relatively efficient conversion of thyrosine-4-yl-benzyl carbonate to thyrosine during intravenous administration is in contrast to oral administration of this compound (corresponding to a relatively low oral % bioavailability), and T max Compared to other test compounds, it showed a slight delay in reaction, and exposure was relatively low.

[0172] Example 13: Head spasm response induced by novel thyrosine / methosine carbonate Introduction Four novel compounds (i.e., psilocybin-4-ylethyl carbonate, psilocybin-4-yl tert-butyl carbonate, N-methyl-N-ethyltryptamine-4-ylethyl carbonate, and psilocybin-4-ylbenzyl carbonate) and psilocybin were used to produce serotonin 2A (5-HT). 2AWe tested in mice their ability to induce the cephalic spasm response (HTR), an involuntary, paroxysmal head rotation that occurs in rodents after the activation of the receptors.

[0173] HTR is a psychedelic and non-psychedelic 5-HT 2A Receptor agonists can be used to differentiate between them, and importantly, the potency of compounds to induce HTR in rodents correlates with their potency to induce psychedelic effects in humans (Halberstadt AL et al., Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species, Neuropharmacology (2020), doi:10.1016 / j.neuropharm.2019.107933).

[0174] method Laboratory animals Forty-eight male C57BL / 6J mice (Charles River UK), weighing 20-25g at the time of purchase, were housed in groups in polypropylene cages (3s). The mice were kept on a normal 12-hour light-dark cycle (lights on from 07:00 to 19:00) with free access to standard pellet feed (Envigo2018) and filtered tap water. The holding chamber was maintained at 21±4℃ with a relative humidity of 55±15%.

[0175] Experimental Procedure Mice were weighed and assigned to drug treatment groups based on their weight. Animals were administered by forced oral administration of either psilocybin (0.3 mg / kg), psilocybin-4-yl-ethyl carbonate hemifumarate (0.3 mg / kg), psilocybin-4-yl-tert-butyl carbonate hemifumarate (0.3 mg / kg), N-methyl-N-ethyltryptamine-4-yl-ethyl carbonate hemifumarate (0.3 mg / kg), or psilocybin-4-ylbenzyl carbonate hemifumarate (0.3 mg / kg), and placed in clean, transparent cages containing a light layer of sawdust. Then, for 60 minutes after administration, uninformed raters counted the number of head convulsions. The given doses for the salt forms of the compounds were adjusted to ensure equivalent drug doses (0.3 mg / kg) across all treatment groups. All compounds were formulated in physiological saline and administered at a volume of 5 ml / kg.

[0176] result [Table 20]

[0177] conclusion Over a 60-minute period following administration, both psilocybin-4-yl-ethyl carbonate and N-methyl-N-ethyltryptamine-4-yl-ethyl carbonate induced a similar average number of head spasms compared to psilocybin. Psyrosine-4-yl-benzyl carbonate also induced spasms of a similar magnitude to those induced by psilocybin. max The response was induced at 15–30 minutes, which was similar to that induced by N-methyl-N-ethyltryptamine-4-yl-ethyl carbonate at 0–15 minutes. These findings suggest that 5-HT is necessary for psychedelic effects in humans. 2A This supports the idea that receptor activation occurs after administration of these compounds in mice. In certain embodiments, for example, the following are provided: (Item 1) Psyrosine derivatives according to general formula (I):

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Claims

1. The compound of the following formula: 【Chemistry 12】 During the ceremony, R ２ , ２ , ２ , ２ is selected from -O-CH ２ CH ３ , -O-CH ２ CH ２ CH ３ , -O-CH(CH ３ )-CH ３ , -O-CH ２ CH ２ CH ２ CH ３ , -O-CH ２ -CH(CH ３ )-CH ３ , -O-C(CH ３ ) ３ , -O-CH ２ -C(CH ３ ) ３ , -O-CH ２ -phenyl, -CH<000002​​​​​​​​​​​ R ２ However, it is methyl or ethyl, R ３ However, it is either methyl or ethyl. or a pharmaceutically acceptable salt thereof, wherein the compound is 【Chemistry 14】 Not the compound or its pharmaceutically acceptable salt.

2. R １ However, -O-CH ２ CH ３ , -O-CH ２ CH ２ CH ３ , -O-CH(CH ３ ) - CH ３ , -O-CH ２ CH ２ CH ２ CH ３ , -O-CH ２ -CH(CH ３ ) - CH ３ , -O-C(CH ３ ) ３ , -O-CH ２ -C(CH ３ ) ３ , or -O-CH ２ - The compound according to claim 1, wherein the compound is phenyl.

3. R １ However, -CH ２ -NH ２ , -CH(-NH ２ ) - CH ２ -COOH, and -CH(-NH) ２ ) - CH ２ A compound according to claim 1, selected from -(1H-indole-3-yl).

4. R ２ and R ３ The compound according to any one of claims 1 to 3, wherein each of the compounds is methyl.

5. The aforementioned compound is the following compound: 【Chemistry 13】 The compound according to claim 1, selected from any one of the or a pharmaceutically acceptable salt thereof.

6. The compound is in the form of a pharmaceutically acceptable salt, The compound according to any one of claims 1 to 3 and 5, wherein the pharmaceutically acceptable salt is a fumarate, maleate, oxalate, malate, tartrate, or mesylate.

7. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3 and 5, and optionally one or more pharmaceutically acceptable excipients.

8. Serotonin 5-HT ２Ａ A composition comprising a compound according to any one of claims 1 to 3 and 5, for use in the treatment of receptor-related diseases / disorders.

9. A method for producing the compound according to any one of claims 1 to 3 and 5, comprising the following steps: (a) Prepare a suspension of psilocine in solvent I, (b) Adding an activator under a protective gas atmosphere, wherein the activator is a nitrogen base, a carbodiimide, or a combination thereof. (c) Adding a derivatizing agent, wherein the derivatizing agent is ethyl chloroformate, di-tert-butyl pyrocarbonate, N-(9-fluorenylmethyloxycarbonyl)-L-tryptophan, 4-benzyl N-carbobenzoxy-L-aspartate, or N-benzyloxycarbonyl-L-tryptophan. (d) Stir the mixture under a protective gas atmosphere for at least 3 hours, (e) Stopping the reaction by diluting with a solvent, (f) Concentrating the solvent, (g) Dissolve the residue in solvent II, (h) Extract with 1 M HCl, water and saturated saline solution, (i) Drying the organic phase with a desiccant at 40-60°C under vacuum, (j) Obtaining the crude product, (k) Purify the crude product by recrystallization and / or column chromatography, (l) A method comprising obtaining the compound according to any one of claims 1 to 3 and 5.

10. (i) The activator is a nitrogen base, a carbodiimide, or a combination thereof, (ii) The derivatizing agent is ethyl chloroformate, di-tert-butyl pyrocarbonate, N-carbobenzoxy-glycine, N-(9-fluorenylmethyloxycarbonyl)-L-tryptophan, 4-benzyl N-carbobenzoxy-L-aspartate, N-carbobenzoxy-L-tryptophan, or N-benzyloxycarbonyl-L-tryptophan. (iii) The solvent I is tetrahydrofuran, 2-methyltetrahydrofuran, or dioxane, and (iv) The method according to claim 9, wherein solvent II is ethyl acetate, diethyl ether, dichloromethane, or a combination thereof.

11. The method according to claim 10, wherein the yield of the compound is at least 60% by weight relative to the starting material.

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