Novel dephosphated spectromentin derivatives with

Abstract

The invention provides a group of novel active compounds based on a psychially active compound, namely dephosphorized nummulina velutipes. Derivatives of dephosphorized nummulin provided herein exhibit improved pharmacokinetic characteristics during ingestion as compared to dephosphorized nummulin, and side effects caused by metabolites formed thereby are reduced. These derivatives are particularly advantageous for use in therapy, for example in the treatment of depression or drug addiction, due to the affinity of the novel dephosphorized nummulin derivatives for the 5-HT2A receptor.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180051296.8 (Filing Date: August 23, 2021, Inventive Title: Novel psilocin derivatives with prodrug properties).

[0002] This application claims priority to German Patent Application DE 10 2020 121 965.2 filed August 21, 2020 and U.S. Provisional Application US 63 / 118,842 filed November 27, 2020, the contents of which are incorporated herein by reference. BACKGROUND

[0003] In nature, psilocin is only present in its precursor form, the phosphate ester, which is called “psilocybin”. In the precursor, the oxidation-sensitive psychoactive compound psilocin is protected by the phosphate group. After ingestion in the body, this protecting group is hydrolytically cleaved and the active compound psilocin is released.

[0004] To date, all medical and clinical studies have used natural psilocybin. It is important to note that the industrial synthesis of psilocybin is a complex and expensive process which, due to the use of carcinogenic catalysts, requires strict scrutiny at least for GMP applications.

[0005] Since around 1990, research into psychedelics has been on the rise again.

[0006] In 2018, the US health authority FDA approved a study by the company “Compass Pathways”, in which patients with treatment-resistant depression were to be treated with the active compound psilocybin.

[0007] Recent studies have shown promising results in the treatment of anxiety associated with cancer and in the withdrawal of nicotine or alcohol.

[0008] In particular, the application of so-called “microdosing”, i.e. the administration of small doses, has shifted the focus of research in recent years. The aim of this form of administration is to avoid inducing hallucinations and to avoid side effects by using small doses and long dosage intervals in the range of days or even weeks.

[0009] New psilocin derivatives, in particular those which, due to their structure, exhibit a changed (accelerated or delayed) activity in the human body, are increasingly attracting the interest of the pharmaceutical industry.

[0010] Since only a limited range of dephospho- psilocin derivatives has been described in the literature (see, e.g., US 3,075,992 and CH 386,442), none of which has been successfully developed into a therapeutic product, there is still an urgent and unmet need for new dep hospho- psilocin derivatives with improved therapeutic properties.

[0011] The present application meets this need and provides novel and easily producible dep hospho- psilocin derivatives based on carbonate or amino acid derivatization. The new dep hospho- psilocin derivatives provided herein exhibit improved properties which make them highly advantageous for therapeutic use. SUMMARY

[0012] Figure 1 Thin layer chromatogram of the starting material dep hospho- psilocin (E), the final product ethyl carbonate dep hospho- psilocin-4-yl ester (CO3) and the intermediate Fmoc-tryptophan dep hospho- psilocin-4-yl ester (AS) in chloroform / ethanol 10:1 (left panel) and dichloromethane / methanol 7:3 (right panel), respectively.

[0013] Figure 2 Thin layer chromatogram of the starting material dep hospho- psilocin (E), the final product ethyl carbonate dep hospho- psilocin-4-yl ester (CO3) and the intermediate Fmoc-tryptophan dep hospho- psilocin-4-yl ester (AS) in tert-butyl methyl ether / ethanol 8:2 (left panel), hexane / ethyl acetate 7:3 (middle panel) and tert-butyl methyl ether / isopropanol 8:2 (right panel), respectively.

[0014] Figure 3 HPLC-MS spectrum of ethyl carbonate dep hospho- psilocin-4-yl ester from the reaction solution.

[0015] Figure 4 HPLC-MS spectrum of Fmoc-tryptophan dep hospho- psilocin-4-yl ester from the reaction solution.

[0016] Figure 5 Stability of the new dep hospho- psilocin carbonates in HC1. (A) Percentage of parent compound remaining after incubation in 1% HC1 solution for more than 24 hours. (B) Percentage of dep hospho- psilocin released from the test compounds during incubation in 1% HC1. (C) Percentage of dep hospho- psilocin tert-butyl carbonate remaining after incubation in 1% HC1 solution for more than 24 hours. (D) Percentage of dep hospho- psilocin released from the test compounds during incubation in 1% HC1. See Example 9.

[0017] Figure 6: Pharmacokinetics of novel dephospho-vernamycin carbonates in mice. (A) Plasma dephospho-vernamycin concentrations following intravenous administration of test compounds to mice. Data shown as mean ± SEM. (B) Plasma dephospho-vernamycin concentrations following oral administration of test compounds to mice. Data shown as mean ± SEM. (C) Plasma dephospho-vernamycin concentrations following intravenous administration of vernamycin or ethyl carbonic acid dephospho-vernamycin-4-yl ester to mice. Data shown as mean ± SEM. (D) Plasma dephospho-vernamycin concentrations following oral administration of vernamycin or ethyl carbonic acid dephospho-vernamycin-4-yl ester to mice. Data shown as mean ± SEM. (E) Plasma dephospho-vernamycin concentrations following intravenous administration of vernamycin or t-butyl carbonic acid dephospho-vernamycin-4-yl ester to mice. Data shown as mean ± SEM. (F) Plasma dephospho-vernamycin concentrations following oral administration of vernamycin or t-butyl carbonic acid dephospho-vernamycin-4-yl ester to mice. Data shown as mean ± SEM. (G) Plasma dephospho-vernamycin concentrations following intravenous administration of vernamycin or benzyl carbonic acid dephospho-vernamycin-4-yl ester to mice. Data shown as mean ± SEM. (H) Plasma dephospho-vernamycin concentrations following oral administration of vernamycin or benzyl carbonic acid dephospho-vernamycin-4-yl ester to mice. Data shown as mean ± SEM. See Example 12. DETAILED DESCRIPTION

[0018] DEFINITIONS

[0019] For convenience, certain terms used in the specification, examples, and claims are collected here. Unless defined otherwise, all technical and scientific terms used in the present disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0020] As used herein, the terms “a,” “an,” and “the” can be used interchangeably with “one or more” or “at least one” unless otherwise indicated by the context, or unless otherwise indicated by the context, or unless contradiction is implied by the context. Thus, for example, a composition comprising “a” compound of Formula (I) can be interpreted to mean a composition comprising “one or more” compounds of Formula (I).

[0021] As used herein, the terms “administer,” “administering,” or “administration” refer to the administration of a compound or a pharmaceutically acceptable salt of a compound or a composition or formulation comprising the compound or a pharmaceutically acceptable salt of a compound to a patient.

[0022] 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) that can be straight-chained or branched. Thus, "alkyl" does not include any carbon-carbon double bonds or any carbon-carbon triple bonds. "C 1-12 alkyl" means 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 t-butyl). Unless otherwise specified herein, an alkyl group can be optionally substituted.

[0023] As used herein, the term "alkylene" refers to an alkandiyl group, i.e., a divalent saturated acyclic hydrocarbon group that can be straight-chained or branched. "C 1-12 alkylene" means 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 herein, an alkylene chain can be optionally substituted.

[0024] "Alkenyl" or "alkenyl group" refers to a straight-chained or branched hydrocarbon chain having two to twelve carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups include any number of carbon atoms from 2 to 12. Alkenyl groups having up to 12 carbon atoms are C2-C 12 alkenyl groups, alkenyl groups having up to 10 carbon atoms are C2-C 10 alkenyl groups, alkenyl groups having up to 6 carbon atoms are C2-C6 alkenyl groups, and alkenyl groups having up to 5 carbon atoms are C2-C5 alkenyl groups. C2-C5 alkenyl groups include C5 alkenyl groups, C4 alkenyl groups, C3 alkenyl groups, and C2 alkenyl groups. C2-C6 alkenyl groups include all of the above C2-C5 alkenyl groups, but also include C6 alkenyl groups. C2-C 10 alkenyl groups include all of the above C2-C5 alkenyl groups and C2-C6 alkenyl groups, but also include C7, C8, C9, and C 10 alkenyl groups. Similarly, C2-C 12 alkenyl groups include all of the foregoing, but also include C 11 and C 12 alkenyl groups. C2-C 12Non-limiting examples of alkenyl groups 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, 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, the alkyl groups can be optionally substituted.

[0025] “Alkenylene” or “alkenylene chain” refers to an unsaturated straight-chain or branched divalent hydrocarbon chain radical of one or more alkenes and two to twelve carbon atoms. C2-C 12 Non-limiting examples of alkenylene groups include ethynylene, propynylene, n-butenylene, and the like. The alkenylene chain is attached to the remainder of the molecule through a single bond, and to the group (such as those described herein) through a single bond. The points of attachment of the alkenylene chain to the remainder of the molecule, as well as to the group, can be through one carbon or any two carbons within the chain. Unless otherwise specified, the alkenylene chain can be optionally substituted.

[0026] “Alkynyl” or “alkynyl group” refers to a straight-chain or branched hydrocarbon chain having two to twelve carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the remainder of the molecule through a single bond. Alkynyl groups encompassing any number of carbon atoms from 2 to 12 are included. Alkynyl groups comprising up to 12 carbon atoms are C2-C 12 Alkynyl groups comprising up to 10 carbon atoms are C2-C 10Alkynyl. Similarly, C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C 10 Alkynyl. Similarly, C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C 10 Alkynyl. Similarly, C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C 12 Alkynyl. Similarly, C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C 11 Alkynyl. Similarly, C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C 12 Alkynyl. Similarly, C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C 12 Alkynyl. Similarly, C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C

[0027] “Alkynyl” refers to an unsaturated straight-chain or branched-chain hydrocarbon group having one or more alkyne and two to twelve carbon atoms. C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C 12 Alkynyl. Similarly, C2-C6alkynyl includes all the foregoing moieties but also includes C7, C8, C9, and Cio alkynyl groups. C2-C

[0028] “Alkoxy” refers to a group of the formula -OR a where R a is an alkyl, alkenyl, or alkynyl group as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0029] “Aryl” refers to a hydrocarbon ring system containing hydrogen, six to eighteen carbon atoms, and at least one aromatic ring, and connected to the rest of the molecule by a single bond. For purposes of the present disclosure, aryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems. Aryl includes, but is not limited to, aryl groups derived from acanthylene, acenaphthylene, ac phenanthrene, azulene, azoline, benzene, , chrysene, fluorene, indacene, indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an “aryl” group is optionally substituted.

[0030] As used herein, the term "comprising" (or "comprise", "comprises" etc.) has the meaning "including at least" unless explicitly stated otherwise or contradicted by context. In addition to this broad meaning, the term also includes the narrow meanings of "consisting essentially of and "consisting of". For example, the term "A comprises B and C" has the meaning "A includes at least B and C", wherein A can include further optional elements (e.g. can also cover "A comprises B, C and D") but the term also includes the meaning of "A consists essentially of B and C" and the meaning of "A consists of B and C" (i.e. A contains no further components than B and C).

[0031] The terms "effective amount" and "therapeutically effective amount" are used interchangeably herein in the disclosure and refer to the amount of a compound or salt thereof (or a pharmaceutical composition containing the compound or salt) which, when administered to a patient, is capable of performing an intended result. The "effective amount" will vary depending on the active ingredient, the condition, disorder or disease to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.

[0032] As used herein, the terms "optional", "optionally" and "may" mean that the indicated feature can be present but is not required to be present. Whenever the terms "optional", "optionally" or "may" are used, the present application specifically relates to both possibilities, i.e. the corresponding feature is present or the corresponding feature is not present. For example, if a component of a composition is indicated as "optional", the present application specifically relates to both possibilities, i.e. the respective component is present (included in the composition) or the respective component is not present in the composition.

[0033] "Heteroaryl" means a 5- to 20-membered ring system comprising hydrogen atoms, 1 to 19 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, at least 1 aromatic ring, including compounds having aromatic resonance structure (e.g., 2-pyridinone), and connected to the rest of the molecule by a single bond. For purposes of the present disclosure, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in heteroaryl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolanyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[6] [1,4]dioxepinyl, 1,4benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolanyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2a]pyridinyl, carbazolyl, cinnolinyl, dibenzo furanyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indoxazinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 oxazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 phenyl 1H pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically noted in the specification, heteroaryl is optionally substituted.

[0034] "Arylalkyl" or "arylalkyl" means a group of the formula -R b -R c where R b is alkyl as defined above, and R c is one or more aryl groups as defined above, e.g., benzyl, diphenylmethyl, and the like. Unless otherwise specifically noted in the specification, arylalkyl is optionally substituted.

[0035] "Carbocyclyl," "carbocyclic ring," or "carbocyclic" means a ring structure in which the atoms forming the ring are each carbon and connected to the rest of the molecule by a single bond. A carbocyclic ring can comprise 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryl and cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Unless otherwise specifically noted in the specification, carbocyclyl is optionally substituted.

[0036] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon group consisting only of carbon and hydrogen atoms, which can include fused, bridged, or spiro cyclo ring systems having three to twenty carbon atoms, for example having three to ten carbon atoms, and which is connected to the rest of the molecule by a single bond. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group can be optionally substituted.

[0037] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group having one or more carbon-carbon double bonds consisting only of carbon and hydrogen atoms, which can include fused or bridged ring systems having three to twenty carbon atoms, preferably having three to ten carbon atoms, and which is connected to the rest of the molecule by a single bond. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Polycyclic cycloalkenyl groups include, for example, bicyclo[2.2.1]hept-2-enyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkenyl group can be optionally substituted.

[0038] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group having one or more carbon-carbon triple bonds consisting only of carbon and hydrogen atoms, which can include fused or bridged ring systems having three to twenty carbon atoms, preferably having three to ten carbon atoms, and which is connected to the rest of the molecule by a single bond. Monocyclic cycloalkynyl groups include, for example, cycloheptinyl, cyclooctynyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0039] "Haloalkyl" refers to an alkyl group substituted with one or more halo groups, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0040] "Heterocyclyl," "heterocyclyl ring," or "heterocycle" means a stable saturated, unsaturated, or aromatic 3- to 20-membered ring which consists of 2 to 19 carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which is connected to the rest of the molecule by a single bond. Heterocyclyl or heterocyclyl ring includes heteroaryl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless otherwise specifically noted in the specification, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon, or sulfur atom in a heterocyclyl group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolizinyl, octahydroisoindolizinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, trithianyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specifically noted in the specification, a heterocyclyl group can be optionally substituted.

[0041] As used herein, the term "shielding gas" means an inert gas, preferably argon. In other embodiments, different shielding gases can also be used, for example, elemental gases such as nitrogen, inert gases such as helium, neon, argon, krypton, xenon, and gaseous molecular compounds such as sulfur hexafluoride.

[0042] The term "substituted" as used herein means any of the groups described herein (e.g., alkyl, alkoxy, aryl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, 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 a higher order bond (e.g., a double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by -NRg R h R g C(=O)R h R g C(=O)NR g R h R g C(=O)OR h R g SO2R h OC(=O)NR g R h OR g SR g SOR g SO2R g OSO2R g SO2OR g =NSO2R g SO2NR g R h R g -C(=O)R g -C(=O)OR g -C(=O)NR h -CH2SO2R g -CH2SO2NR g R h R g and R h are the same or different and independently 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 an 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 bond. Additionally, each of the above substituents can also be optionally substituted with one or more of the above substituents.

[0043] As used herein, the term "treatment" (or "treating") in relation to a disease or condition refers to the management and care of a patient for the purpose of combating the disease or condition, e.g., to reverse, alleviate, inhibit, or delay the disease or condition, or one or more symptoms thereof. It also refers to the administration of a compound or composition to prevent the onset of a symptom, to alleviate such symptoms, or to eliminate the disease or condition. Preferably, "treatment" is curative, ameliorative, or palliative.

[0044] It is to be understood that wherever a numerical range is provided herein, all values and subranges encompassed within that range are intended to be within the scope of the present application. Thus, the application contemplates each and every subrange within the ranges disclosed herein, as well as each and every value within the ranges disclosed herein.

[0045] It is also to be understood that the application specifically contemplates each and every combination of the features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the application specifically contemplates each and every combination of the meanings of the various groups and variables encompassed in Formula (I), including general and / or preferred meanings.

[0046] The compounds of the present disclosure:

[0047] The present application provides a new class of active compounds based on the psychoactive compound norpsilocin. In comparison to norpsilocin, the norpsilocin derivatives provided herein exhibit improved pharmacokinetic properties during uptake, as well as reduced side effects resulting from metabolites formed therefrom. Due to the affinity of the new norpsilocin derivatives for the 5-HT 2A receptor, these derivatives are particularly advantageous for use in therapy, e.g., for the treatment of depression or drug addiction.

[0048] In one aspect, the present application provides a new norpsilocin derivative according to the following general Formula (I):

[0049]

[0050] wherein R 1 is selected from the group consisting of -O-(C 1-12 alkyl), -O-heteroaryl, -O-CH2-aryl, heterocyclyl, -CH(-NH2)-(heteroaryl), -O-(alkylene)-O-alkyl, and -CH(-NH2)-alkyl, wherein each of the alkyl, alkylene, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents, wherein when R 2 and R 3 are methyl, R 1is not -CH2-NH2or -CH(-NH2)-CH3;

[0051] R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, and ethyl, provided that R 2 and R 3 are not both hydrogen; and

[0052] R 4 is hydrogen or -C(=0)-0-(C 1-6 alkyl) or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the alkyl, alkylene, aryl, heteroaryl, and heterocyclyl groups in the group R 1 are optionally substituted with one or more substituents selected from the group consisting of halo, aryl, amino, heteroaryl alkoxy, thioalkoxy, hydroxyl, thiol, amino, guanidinyl, -C(=0)-NR A R B , -C(=0)-OR A , and dihydrothioxy, and R A and R B are independently selected from the group consisting of hydrogen and alkyl.

[0054] In some embodiments of the compound of formula (I), R 1 is selected from the group consisting of -0-(C 1-12alkyl), -0-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(=0)-NH2, -CH(-NH2)-CH2CH2-C(=0)-NH2, -CH(-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazol-4-yl), -CH(-NH2)-CH2-phenyl, -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1H-indol-3-yl), -(pyrrolidin-2-yl), -(4-hydroxypyrrolidin-2-yl), -CH(-NH2)-CH2-S-S-CH2-CH(-NH2)-COOH, -CH(-NH2)-CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=0)-NH2, -CH2-NH-CH3, -CH(-NH2)-CH2CH2-SH, -CH(-NH2)-CH2CH2-OH, -CH(-NH2)-CH2-(3,4-dihydroxyphenyl), -CH(-NH2)-CH2-(5-hydroxy-1H-indol-3-yl), -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH(-CH3)-CH2-NH2, -C(-NH2)=CH2, -0-(1- [R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 ]-1H-indol-4-yl), -0-(C 1-12 alkylene)-0-(1- [R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 ]-1H-indol-4-yl), -CH(-NH2)-CH2-COO-(1- [R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3)-1H-indol-4-yl), -CH(-NH2)-CH2-CH2-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);

[0055] R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, and ethyl, provided that R 2 and R 3 are not both hydrogen; and

[0056] R 4 is hydrogen or -C(=O)-O-(C 1-6 alkyl) or a pharmaceutically acceptable salt thereof.

[0057] 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 can be, for example, an -O-(C 2-5 alkyl) group, such as an ethoxy group, an n-propoxy group, an iso-propoxy group, an n-butoxy group, an iso-butoxy group, a tert-butoxy group, or a neopentoxy group. However, R 1 may also be, for example, an -O-(C 6-12 alkyl) group (such as a C6alkoxy group, a C7alkoxy group, a C8alkoxy group, a C9alkoxy group, a C 10 alkoxy group, a C 11 alkoxy group, or a C 12 alkoxy group).

[0058] 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(=0)-NH2, -CH(-NH2)-CH2CH2-C(=0)-NH2, -CH(-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazol-4-yl), -CH(-NH2)-CH2-phenyl, -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1H-indol-3-yl), and -(pyrrolidin-2-yl).

[0059] 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(=0)-NH2, -CH(-NH2)-CH2CH2-C(=0)-NH2, -CH(-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazol-4-yl), -CH(-NH2)-CH2-phenyl, -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1H-indol-3-yl), and -(pyrrolidin-2-yl).

[0060] In some embodiments, R 1-CH(-NH2)-CH2-S-S-CH2-CH(-NH2)-COOH, -CH(-NH2)-CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=0)-NH2, -CH2-NH-CH3, -CH(-NH2)-CH2CH2-SH, -CH(-NH2)-CH2CH2-OH, -CH(-NH2)-CH2-(3,4-dihydroxyphenyl), -CH(-NH2)-CH2-(5-hydroxy-lH-indol-3-yl), -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH(-CH3)-CH2-NH2, and -C(-NH2)=CH2.

[0061] In some embodiments, R 2 and R 3 are methyl. In some embodiments, R 2 and R 3 are ethyl. In some embodiments, R 2 is methyl and R 3 is hydrogen. In some embodiments, R 2 is ethyl and R 3 is hydrogen. Preferably, R 2 and R 3 are each methyl.

[0062] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -C(=0)-0-(C 2-4 alkyl). Preferably, R 4 is hydrogen.

[0063] In a preferred aspect, the novel depodophyllotoxin derivatives according to formula (I) are compounds of formula:

[0064]

[0065] wherein R 1 is selected from the group consisting of -0-(C 2-5 alkyl), -0-CH2-phenyl, -CH2-NH2, -CH(-NH2)-CH2-COOH, and -CH(-NH2)-CH2-(lH-indol-3-yl). In a preferred embodiment, R 1-O-CH2CH3, -O-CH2CH2CH3, -O-CH(-CH3)-CH3, -O-CH2CH2CH2CH3, -O-CH2-CH(-CH3)-CH3, -O-C(-CH3)3, -O-CH2-C(-CH3)3, -O-CH2-phenyl (i.e. benzyloxy), -CH2-NH2, -CH(-NH2)-CH2-COOH, and -CH(-NH2)-CH2-(1 H-indol-3-yl).

[0066] In some embodiments, R 2 is methyl or ethyl. Preferably, R 2 is methyl.

[0067] In some embodiments, R 3 is methyl or ethyl. Preferably, R 3 is methyl.

[0068] In some embodiments, R 2 and R 3 are each methyl.

[0069] Preferred examples of novel dephospho-sterigmatocystin derivatives according to the present application include any one of the following compounds (as well as pharmaceutically acceptable salts of any one of these compounds):

[0070]

[0071]

[0072] In some embodiments, the present application provides a compound having the following molecular structure:

[0073]

[0074]

[0075] In some embodiments, the present application provides a dephospho-sterigmatocystin derivative having the following structure:

[0076]

[0077]

[0078] The present application relates to any form of the dephospho-sterigmatocystin derivatives described herein, such as a non-salt form or a salt form, in particular a pharmaceutically acceptable salt.

[0079] Accordingly, the scope of the present application includes all pharmaceutically acceptable salt forms of the depophosphorin derivatives of formula (I), which can be formed, for example, by protonation of an atom bearing an easily protonatable lone pair of electrons, such as an amino group, with a physiologically acceptable cation, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base-addition salts include, for example: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc salts; ammonium salts; fatty amino acid salts, such as tromethamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, meglumine, ethylenediamine, or choline salts; aralkyl amino acid salts, such as N,N-dibenzylethylenediamine, benzathine, phenethylamine salts; heterocyclic aromatic amine salts, such as pyridine, methylpyridine, quinoline, or isoquinoline salts; quaternary ammonium salts, such as tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltributylammonium, methyltrioctylammonium, or tetrabutylammonium salts; and basic amino acid salts, such as arginine, lysine, or histidine salts. Exemplary acid-addition salts include, for example: inorganic acid salts, such as hydrochlorides, hydrobromides, hydroiodides, sulfates (such as sulfate or bisulfate), nitrates, phosphates (such as phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonates, bicarbonates, perchlorates, borates, or thiocyanates; organic acid salts, such as acetates, propionates, butyrates, valerates, hexanoates, heptanoates, octanoates, cyclopentanepropionates, decanoates, undecanoates, oleates, stearates, lactates, maleates, oxalates, fumarates, tartrates, malates, citrates, succinates, adipates, gluconates, glycolates, nicotinates, benzoates, salicylates, ascorbates, pamoates (embonates), camphorates, gluheptanoates, or pivalates; sulfonic acid salts, such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-benzenesulfonate, camphorsulfonate; glycerophosphonates; and acidic amino acid salts, such as aspartates or glutamates. Other pharmaceutically acceptable salts are described in the literature, for example in Stahl PH and Wermuth CG (eds), “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, 2002, and references cited therein.Preferred examples of pharmaceutically acceptable salts of the dephospho- psilocin derivatives according to the present application include, for example, fumarates, maleates, oxalates, malates, tartrates or methanesulfonates (methanesulfonate / mesylate). A particularly preferred pharmaceutically acceptable salt is the fumarate. Another particularly preferred pharmaceutically acceptable salt is the oxalate.

[0080] The scope of the present application also includes the dep hospho- psilocin derivatives provided herein in any hydrated or solvated form and in any physical form, including any amorphous or crystalline form.

[0081] Furthermore, the dep hospho- psilocin derivatives of formula (I) can exist in different isomeric, in particular stereoisomeric (e.g. enantiomeric or diastereomeric) forms. All such isomers of the compounds of formula (I) are considered to be part of the present application, whether in mixture or pure or substantially pure form. The present application also includes any tautomers of the compounds described herein. As far as stereoisomers are concerned, the present application includes the isolated optical isomers of the dep hospho- psilocin derivatives according to the present application as well as any mixture thereof, particularly including racemic mixtures / racemates. The racemates can be resolved into their individual optical isomers by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or by chiral column chromatography. The individual optical isomers can also be prepared by using corresponding optically active starting materials in their synthesis, or they can be obtained from the corresponding racemates by salt formation with an optically active acid followed by crystallization. In the case of the compounds aspartate dep hospho- psilocin-4-yl ester and tryptophan dep hospho- psilocin-4-yl ester, the carbon atom carrying the -NH2 group (corresponding to the C α -atom of the corresponding amino acid aspartate or tryptophan) can be present in the (S)-configuration, while in the (R)-configuration, or as a racemic mixture, preferably said carbon atom is present in the (S)-configuration (as the naturally occurring amino acids L- aspartate and L-tryptophan). For any other compound of formula (I) having an amino acid residue as R 1 , the C α -atom of the corresponding amino acid residue can likewise be present in the (S)-configuration, in the (R)-configuration or as a racemic mixture, wherein preferably said C α -atom is present in the (S)-configuration.

[0082] The scope of the present application also includes dep hospho- psilocin derivatives of formula (I), wherein one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the present application includes compounds of formula (I), wherein one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e., 2H; also referred to as "D"). Thus, the present application also encompasses deuterium-enriched compounds of formula (I). Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 1 H) and about 0.0156 mol-% deuterium ( 2 H or D). The deuterium content at one or more hydrogen positions in a compound of formula (I) can be increased using deuteriation techniques known in the art. For example, a compound of formula (I) or a reactant or precursor used in the synthesis of a compound of formula (I) can be subjected to an H / D exchange reaction using, for example, heavy water (D2O). The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. It is generally preferred that the depudepsidomycins of formula (I) are not enriched in deuterium. Thus, it is preferred that the naturally occurring hydrogen atoms or 1 H hydrogen atoms are present in the compounds of formula (I). Thus, the present application particularly relates to depudepsidomycins of formula (I), wherein all hydrogen atoms are naturally occurring hydrogen atoms or 1 H hydrogen atoms.

[0083] Due to their molecular structure, the depudepsidomycins according to the present application allow for an improved production process and, in addition, exhibit new beneficial pharmacological properties.

[0084] In particular, due to their specific molecular structure, the adducts of depudepsidomycins according to the present application are pharmacologically released, taken up and metabolized in the human body with different pharmacokinetics (compared to psilocybin).

[0085] The pharmacological "inactivation" of the active compound in the form of a prodrug (depudepsidomycins) reduces the potential for abuse, since a rapid "flood" of the active compound is inhibited.

[0086] The potential for addiction to psychotropic drugs is associated with a rapid increase in their concentration after intake. Therefore, from a pharmaceutical point of view, active compounds are sought which only lead to a slow increase from the initial concentration.

[0087] The present application provides compounds which have been found to act faster than psilocybin, for example, because they are hydrolyzed in vivo to depudepsidomycins faster than psilocybin, which makes these compounds particularly suitable as fast-acting therapeutic drugs. In addition, the compounds provided herein only act on the organism after endogenous metabolism to the actually active compound depudepsidomycins, so that a more sustained effect (depot effect) is obtained. Compounds which are hydrolyzed more slowly can provide particularly long depot effects. Thus, the present application allows fine-tuning of the release properties of the depudepsidomycins derivatives provided herein, in particular by selecting groups which are more or less rapidly hydrolyzable as R 1 .

[0088] In addition, more stable and uniform release of the active compound in the organism contributes to a reduction of side effects.

[0089] Thus, the "depot effect" resulting from such delayed release is a particular advantage of the present application.

[0090] In further embodiments, by selecting the amino acid derivative to be used, beneficial additional pharmacological effects of the hypophosphorous daldiniafuviata derivative can be obtained in addition to the delaying effect.

[0091] Exemplary amino acid derivatives have been described hereinbefore (e.g. hypophosphorous daldiniafuviata derivatives, wherein R 1 is -CH2-NH2, corresponding to a glycine derivative, wherein R 1 is -CH(-NH2)-CH2-COOH, corresponding to an aspartic acid derivative, or wherein R 1 is -CH(-NH2)-CH2-(1 H-indol-3-yl), corresponding to a tryptophan derivative).

[0092] Thus, for example, in the case of aspartic acid hypophosphorous daldiniafuviata, the resulting betaine structure provides for a better uptake of the aspartic acid hypophosphorous daldiniafuviata. In the case of tryptophan hypophosphorous daldiniafuviata, the amino acid tryptophan, which is released by metabolism of tryptophan hypophosphorous daldiniafuviata, reduces or mitigates the side effect of "serotonin hunger" that can occur during conventional hypophosphorous daldiniafuviata therapy.

[0093] Further aspects of the present application relate to methods of producing the novel hypophosphorous daldiniafuviata derivatives provided herein as well as methods and uses, in particular therapeutic methods and therapeutic uses, of these novel compounds.

[0094] Methods of preparing the compounds of the present disclosure:

[0095] In one aspect, the present disclosure provides a method of preparing a compound of the present disclosure.

[0096] In some embodiments, the present disclosure provides a method for producing a hypophosphorous daldiniafuviata derivative (as described herein), the method comprising the steps of:

[0097] (a) preparing a suspension of hypophosphorous daldiniafuviata in solvent I;

[0098] (b) adding an activating agent under a protective gas atmosphere;

[0099] (c) adding a derivatizing agent;

[0100] (d) stirring the mixture under a protective gas atmosphere (e.g. for at least 3 hours);

[0101] (e) stopping the reaction by dilution with a solvent (e.g. solvent I from step (a));

[0102] (f) concentrating the solvent;

[0103] (g) dissolving the residue in solvent II;

[0104] (h) extraction with 1 M HCI, water and saturated brine solution;

[0105] (i) drying the organic phase with a drying agent under vacuum (or reduced pressure) at 40-60 °C;

[0106] (j) obtaining the crude product;

[0107] (k) purifying the crude product by recrystallization and / or column chromatography;

[0108] (l) obtaining the depodophyllotoxin derivative according to the application.

[0109] In one embodiment, in step (a), 0.21 mmol to 2.1 mmol of depodophyllotoxin is suspended in 10 ml to 100 ml of solvent I, wherein solvent I is selected from the group consisting of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran and dichloromethane.

[0110] This can be carried out at a temperature between -78 °C and 45 °C, preferably at a temperature between 5 °C and 40 °C, more preferably at room temperature (293.15 Kelvin; 20 °C).

[0111] In one embodiment, in step (b), between 0.5 mmol and 5 mmol of an activating agent, such as a nitrogen base and / or a carbodiimide, is added.

[0112] In this case, in a preferred embodiment, the nitrogen base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine. The carbodiimide that can be added is preferably selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0113] The obtained solution is purged with a protective gas.

[0114] It is also possible to use deprotonating agents, such as n-butyl lithium (n-BuLi) and / or an acid anhydride or acid chloride.

[0115] In one embodiment, in step (c), between 0.25 mmol and 2.5 mmol of derivatizing agent is added dropwise through a septum, wherein the derivatizing agent is selected from the group consisting of ethyl chloroformate, di-tert-butyl pyrocarbonate, N-benzyloxycarbonyl-glycine, N-(9-fluorenylmethoxycarbonyl)-L-tryptophan and N-benzyloxycarbonyl-L-aspartic acid 4-benzyl ester.

[0116] In one embodiment, in step (d), the mixture is stirred at 20-28 °C under a protective gas atmosphere for 2 to 10 hours. In one embodiment, it is stirred for at least 3 hours and at most 6 hours; and / or at 20 °C under a protective gas atmosphere.

[0117] In another embodiment, in step (e), the reaction is stopped by adding between 30 ml and 300 ml of solvent I from step (a).

[0118] In another embodiment, in step (f), the mixture is dried, preferably in a rotary evaporator under vacuum, and re-dissolved in between 30 ml and 300 ml of solvent II, wherein solvent II is selected from the group consisting of ethyl acetate, diethyl ether and dichloromethane.

[0119] In one embodiment, in step (h), extraction is performed with between 20 ml and 200 ml of 1 molar (1 M) hydrochloric acid. In one embodiment, extraction is subsequently performed with between 20 ml and 200 ml of water. In one embodiment, extraction is subsequently performed with between 20 ml and 200 ml of a saturated brine solution.

[0120] In another embodiment, in step (i), the mixture is dried. It is particularly preferred to dry with a drying agent at a temperature between 35 °C and 60 °C and a vacuum (reduced pressure) of 30-60 mbar.

[0121] The preferred drying agent is anhydrous calcium chloride, anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous magnesium sulfate or anhydrous calcium sulfate. In one embodiment, the drying agent is anhydrous MgS04, the temperature is 45 °C and the vacuum is 40 mbar.

[0122] The crude product obtained in steps (a) to (j) contains the dephosphorized psilocybin derivative according to the application.

[0123] In another embodiment, the crude product is further purified. Purification can be performed, for example, by dissolving in isopropanol and subsequently evaporating at 50 °C and 400 mbar until crystallization and / or column purification with 50 g of silica using a mixture of eluents dichloromethane / methanol (for example in a ratio of 8:2 in one embodiment). Other column materials and eluents known in the art can also be used.

[0124] In one embodiment, in the recrystallization from isopropanol, the crystallization is facilitated by the addition of diisopropyl ether.

[0125] Using this method, a yield of more than 65% by weight (measured by weight of the final product relative to the amount of the initial material) can be achieved. In some embodiments, a yield of more than 70% by weight, more than 75% by weight, more than 80% by weight and at most 85% by weight, at most 90% by weight and even at most 95% by weight is achieved.

[0126] Further details regarding the production process are provided in the examples and will be apparent to the skilled person.

[0127] Thus, the present application provides compounds having the general molecular structure (I) which can be produced in high purity using the process according to the present application:

[0128]

[0129]

[0130] wherein the groups in formula (I) are defined as follows:

[0131] R 1 selected from -0-(C 1-12alkyl), -0-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(=0)-NH2, -CH(-NH2)-CH2CH2-C(=0)-NH2, -CH(-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1 H-imidazol-4-yl), -CH(-NH2)-CH2-phenyl, -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1 H-indol-3-yl), -(pyrrolidin-2-yl), -(4-hydroxypyrrolidin-2-yl), -CH(-NH2)-CH2-S-S-CH2-CH(-NH2)-COOH, -CH(-NH2)-CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=0)-NH2, -CH2-NH-CH3, -CH(-NH2)-CH2CH2-SH, -CH(-NH2)-CH2CH2-OH, -CH(-NH2)-CH2-(3,4-dihydroxyphenyl), -CH(-NH2)-CH2-(5-hydroxy-1 H-indol-3-yl), -CH2CH2-NH2, -CH2CH2CH2

[0132] -NH2, -CH(-CH3)-CH2-NH2, -C(-NH2)=CH2, -0-(1 -[R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 ]-3-[(-CH2CH2-N(-R 1-12 ]-3-[(-CH2CH2-N(-R 4 ]-3-[(-CH2CH2-N(-R 2 ]-3-[(-CH2CH2-N(-R 3 ]-3-[(-CH2CH2-N(-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).

[0133] R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl and ethyl, with the proviso that R 2 and R 3 are not simultaneously hydrogen.

[0134] R 4 is hydrogen or -C(=O)-O-(C 1-6 alkyl).

[0135] In particular, the present application provides compounds having the following general molecular structure, which can likewise be produced in high purity using the method according to the application:

[0136]

[0137] wherein the radicals in this formula are defined as follows:

[0138] R 1 is -O-(C 2-5 alkyl), in particular ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or neopentoxy.

[0139] R 2 is methyl (-CH3) or ethyl (-C2H5), in particular methyl.

[0140] R 3 is methyl (-CH3) or ethyl (-C2H5), in particular methyl.

[0141] Pharmaceutical compositions:

[0142] This invention provides pharmaceutical / pharmacological compositions comprising at least one dephosphorylated psilocybin derivative according to the invention and optionally one or more pharmaceutically acceptable excipients. The invention also relates to the dephosphorylated psilocybin derivatives provided herein or the aforementioned pharmaceutical compositions for use in therapeutics (or as pharmaceutical agents).

[0143] The dephosphorylated psilocybin derivatives provided herein can be administered as compounds on their own, or formulated into pharmaceutical / pharmacological compositions or agents. Pharmaceutical compositions / agents may optionally contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, and / or antioxidants.

[0144] Pharmaceutical compositions can be formulated using techniques known to those skilled in the art, such as those published in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22nd edition. Pharmaceutical compositions can be formulated into dosage forms for oral, parenteral, intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, sugar-coated lozenges, solutions, emulsions, suspensions, syrups, elixirs, reconstitution powders and granules, dispersible powders and granules, medicated gums, chewable tablets, and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions, and reconstitution powders and granules. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovulas. Dosage forms for nasal administration can be administered via inhalation and blowing, for example, through a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, balms, patches, and transdermal delivery systems.

[0145] Treatment methods:

[0146] This invention also relates to dephosphorylated psilocybin derivatives as described herein (which may be in a non-salt form or a pharmaceutically acceptable salt form) or pharmaceutical compositions comprising at least one dephosphorylated psilocybin derivative for the treatment of serotonin 5-HT. 2A Receptor-related diseases / conditions. Specifically, this invention relates to dephosphorylated psilocybin derivatives or pharmaceutical compositions as described herein for the treatment of anxiety disorders, attention deficit hyperactivity disorder (ADHD), depression, cluster headaches, cancer-related disorders, decreased drive, fatigue, boredom, migraines, Parkinson's disease, pulmonary hypertension, schizophrenia, eating disorders, nausea, or vomiting.

[0147] The present application also relates to the use of a dephospho- verpaconine derivative as described herein for the manufacture of a medicament for the treatment of a serotonin 5-HT 2A receptor related disease / disorder, preferably for the treatment of anxiety, attention deficit hyperactivity disorder (ADHD), depression, cluster headache, cancer-related conditions, drive reduction, burnout, boredom, migraine, Parkinson's disease, pulmonary arterial hypertension, schizophrenia, eating disorders, nausea or vomiting.

[0148] Further, the present application provides a method of treating a disease / disorder, in particular a serotonin 5-HT 2A receptor related disease / disorder in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a dep hospho-verpaconine derivative according to the present application. Preferably, the disease / disorder to be treated is anxiety, attention deficit hyperactivity disorder (ADHD), depression, cluster headache, cancer-related conditions, drive reduction, burnout, boredom, migraine, Parkinson's disease, pulmonary arterial hypertension, schizophrenia, eating disorders, nausea or vomiting.

[0149] In principle, the dep hospho-verpaconine derivative of formula (I) or the corresponding pharmaceutical composition can be administered to a subject by any convenient route of administration. Various routes of administration for administering a medicament are known in the art and include inter alia oral (e.g. as tablets, capsules, ovules, elixirs or as ingestible solutions or suspensions), topical (e.g. transdermal, intranasal, ocular, buccal and sublingual), parenteral (e.g. using injection or infusion techniques, including, for example, by injection, e.g. subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intra-cardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intra-articular, subarachnoid or intrasternal, e.g. by implanting a reservoir, e.g. subcutaneous or intramuscular), pulmonary (e.g. by inhalation or insufflation of powders, using, for example, an inhaler or insufflator, e.g. by mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or intracameral), rectal or vaginal.

[0150] Particularly preferred, the dep hospho-verpaconine derivative (or the corresponding pharmaceutical composition) according to the present application is administered orally, sublingually or nasally (e.g. as a nasal spray or as a nasal drop). Suitable dosage forms for oral administration include, for example, coated or uncoated tablets, soft gelatin capsules, hard gelatin capsules, buccal tablets, sugar-coated tablets, solutions, emulsions, suspensions, syrups, elixirs, reconstitutable powders or granules, dispersible powders or granules, medicated gums, chewable tablets or effervescent tablets. For oral administration, the dep hospho-verpaconine derivative or the pharmaceutical composition is preferably administered by oral ingestion, in particular by swallowing. Thus, the compound or the pharmaceutical composition can be administered through the oral cavity into the gastrointestinal tract, which can also be referred to as "oral-gastrointestinal" administration.

[0151] The subject or patient to be treated according to the present application can 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) or a non-human mammal. Most preferably, the subject / patient to be treated according to the present application is a human.

[0152] In this specification, a number of documents including patents and patent applications are cited. The disclosure of these documents, while not specifically incorporated by reference into this patent application, are hereby incorporated by reference. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document had been incorporated by reference.

[0153] The citation of any prior publication (or information derived from it) in this specification is not, and should not be taken as an acknowledgment or admission that the prior publication (or information derived from it) is part of the common general knowledge in the field of endeavour to which this specification relates.

[0154] The application will now be described with reference to the following examples, which are by way of illustration only and should not be construed to limit the scope of the application.

[0155] Example

[0156] Example 1 : Method for the production of ethyl carbamate dephospho- psilocin-4-yl ester

[0157] Dephospho-psilocin (2.1 mmol / 429 mg) was suspended in tetrahydrofuran (100 ml) at 25 °C. Triethylamine (5.0 mmol / 0.7 ml) was added and argon was bubbled through. This resulted in a clear solution. Ethyl chloroformate (2.5 mmol / 0.24 ml) was added dropwise through a septum. Immediately after addition, a white haze formed in the solution. The solution was stirred for 2.5 hours at 25 °C under argon.

[0158] The sample of the reaction mixture showed almost complete reaction of the starting material in LC / MS at a wavelength of 225 nm. According to HPLC, 77% of the product could be quantified.

[0159] The reaction was stirred for a further hour at 25 °C under argon, after which the reaction was stopped by dilution with tetrahydrofuran (300 ml). The reaction mixture was concentrated on a rotary evaporator at 42 °C and then dried at up to 10 mbar.

[0160] The crude product was dissolved in 300 ml of ethyl acetate and extracted with 200 ml of 1 M hydrochloric acid, 200 ml of water and 200 ml of a saturated brine solution. The organic phase was then dried over some MgS04. The organic phase was then slowly concentrated on a rotary evaporator, causing the product to crystallise from the solution as colourless crystals.

[0161] For purification, the material was recrystallized from isopropanol at 50 °C. To enhance the formation of crystals, some diisopropyl ether was added after cooling. After filtration, 410 mg of colorless crystals were obtained.

[0162] The production of ethyl carbodiphosphate veracefungin-4-yl ester can also be performed as described above, but dichloromethane (instead of tetrahydrofuran) is used to suspend veracefungin. Furthermore, after the initial concentration and drying step, the extraction / washing step can also be skipped and, if necessary, the crude product can be filtered instead, for example through a small plug of silica. For purification, the compound can also be stabilized as a fumarate or oxalate salt and recrystallized from acetone.

[0163] Example 2: Method for the production of neopentyl carbodiphosphate veracefungin-4-yl ester

[0164] Veracefungin (2.0 mmol / 408 mg) was suspended in dichloromethane (12 ml) at 25 °C. Triethylamine (2.6 mmol / 0.36 ml) was added and argon was bubbled through. This resulted in a clear solution. Chloroformic acid neopentyl ester (2.1 mmol / 0.32 ml) was added dropwise through a septum. Immediately after addition, a white haze formed in the solution. Stirring was continued under argon at 25 °C for 2.5 hours.

[0165] The reaction was stopped by dilution with dichloromethane (40 ml). Filtration through a small plug of silica can yield the desired crude product. For purification, the compound can be stabilized as a fumarate or oxalate salt and recrystallized from acetone.

[0166] 420 mg of the oxalate salt were obtained as colorless crystals.

[0167] Example 3: Method for the production of benzyl carbodiphosphate veracefungin-4-yl ester

[0168] Veracefungin (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 argon was bubbled through. This resulted in a clear solution. Chloroformic acid benzyl ester (5.4 mmol / 0.80 ml) was added dropwise through a septum. Immediately after addition, a white haze formed in the solution. Stirring was continued under argon at 25 °C for 2.5 hours.

[0169] The reaction was stopped by dilution with dichloromethane (60 ml). Filtration through a small plug of silica can yield the desired crude product. For purification, the compound can be stabilized as a fumarate or oxalate salt and recrystallized from acetone.

[0170] 1.70 g of the oxalate salt were obtained as colorless crystals.

[0171] Example 4: Method for the production of tryptophan dephospho-humulin-4-yl ester

[0172] Dephospho-humulin (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 argon was bubbled through. Stirring was performed at room temperature (RT) for 15 minutes. Fmoc-L-tryptophan (1.8 mmol / 770 mg) was added. After addition, the suspension became clear and a solution was formed. Stirring was performed at 25°C under argon for 5 hours.

[0173] A sample of the reaction mixture showed a reaction rate of 23% in LC / MS at a wavelength of 225 nm. According to HPLC, a large amount of dephospho-humulin and unreacted Fmoc-L-tryptophan was still detectable.

[0174] The reaction was stirred for another hour at 25°C under argon, after which the reaction was stopped by dilution with tetrahydrofuran (200 ml). The reaction mixture was concentrated on a rotary evaporator at 42°C and subsequently dried at a maximum of 10 mbar.

[0175] The crude product was dissolved in 200 ml ethyl acetate and extracted with 150 ml 1M hydrochloric acid, 150 ml water and 150 ml saturated brine solution. Subsequently, the organic phase was dried over some MgS04. Subsequently, the organic phase was distilled off on a rotary evaporator, resulting in 1.2 g of crude product in the form of a yellow solid.

[0176] The crude product was worked up on a 50 g silica column using an eluent mixture of hexane / ethyl acetate in a ratio of 7:3. This resulted in 208 mg of this intermediate product in the form of a colourless solid.

[0177] Cleavage of the protecting group:

[0178] The intermediate product was dissolved in 20 ml tetrahydrofuran at 25°C. Piperidine (0.7 mmol / 59 mg) was added dropwise and argon was bubbled through. Stirring was performed at room temperature for 24 hours, and thin layer chromatography showed complete deprotection. The reaction mixture was concentrated on a rotary evaporator at 42°C and subsequently dried at a maximum of 10 mbar. The crude product obtained was worked up on a 20 g silica column using an eluent mixture of tert-butyl methyl ether / ethanol in a ratio of 7:3 with 1% ammonia. This resulted in 106 mg of almost colourless solid.

[0179] Example 5: Method for the production of tert-butyl carbonate dephospho-humulin-4-yl ester

[0180] The method for the production of tert-butyl carbonate dephospho-humulin-4-yl ester is similar to the method for the production of ethyl carbonate dephospho-humulin-4-yl ester (see example 1).

[0181] It comprises the following steps:

[0182] a. Preparation of a suspension of dephospho- veracein in tetrahydrofuran;

[0183] b. Addition of triethylamine and 4-dimethylaminopyridine under a protective gas atmosphere;

[0184] c. Addition of di-tert-butyl dicarbonate (dissolved in tetrahydrofuran), and

[0185] d. Stirring of the mixture under a protective gas atmosphere for at least 3 hours;

[0186] e. Stopping of the reaction by dilution with tetrahydrofuran;

[0187] f. Evaporation of the tetrahydrofuran on a rotary evaporator and dissolution of the residue in ethyl acetate;

[0188] g. Extraction with 1 M HCI, water and saturated brine solution;

[0189] h. Drying of the organic phase with a drying agent at 40-60°C and under vacuum;

[0190] i. Obtaining of a crude product containing the tert-butyl carbonic acid depohospho- veracein-4-yl ester;

[0191] j. Recrystallization from isopropanol.

[0192] Example 6: Method for the production of glycine depohospho-veracein-4-yl ester

[0193] The method for the production of glycine depohospho-veracein-4-yl ester is similar to the method for the production of tryptophan depohospho-veracein-4-yl ester (see Example 4).

[0194] It comprises the following steps:

[0195] a. Preparation of a suspension of depohospho-veracein in tetrahydrofuran;

[0196] b. Addition of 4-dimethylaminopyridine and 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide hydrochloride;

[0197] c. Addition of N-benzyloxycarbonylglycine;

[0198] d. Stirring of the mixture under a protective gas atmosphere for at least 5 hours;

[0199] e. Stopping of the reaction by dilution with tetrahydrofuran;

[0200] f. Evaporation of the tetrahydrofuran on a rotary evaporator and dissolution of the residue in ethyl acetate;

[0201] g. extraction with 1 M HCI, water and saturated brine solution;

[0202] h. drying of the organic phase with drying agent at 40-60 °C and under vacuum;

[0203] i. obtaining a crude intermediate containing dephospho-ino-4-yl-Cbz glycine ester;

[0204] j. purification by column chromatography using hexane / ethyl acetate;

[0205] k. cleavage of the protecting group by hydration using palladium on activated carbon in ethanol;

[0206] 1. purification by column chromatography using t-butyl methyl ether / ethanol 1% ammonia.

[0207] Example 7: Method for the production of depohospho-ino-4-yl-aspartic acid ester

[0208] The method for the production of depohospho-ino-4-yl-aspartic acid ester is similar to the method for the production of tryptophan depohospho-ino-4-yl ester (see example 4).

[0209] It comprises the following steps:

[0210] a. preparation of a suspension of depohospho-ino in tetrahydrofuran;

[0211] b. addition of 4-dimethylamino pyridine and 1-ethyl-3-(3'-dimethylamino propyl) carbodiimide hydrochloride;

[0212] c. addition of N-benzyloxycarbonyl L-aspartic acid 4-benzyl ester;

[0213] d. stirring of the mixture under an atmosphere of protective gas for at least 5 hours;

[0214] e. stopping of the reaction by dilution with tetrahydrofuran;

[0215] f. evaporation of tetrahydrofuran on a rotary evaporator and dissolution of the residue in ethyl acetate;

[0216] g. extraction with 1 M HCI, water and saturated brine solution;

[0217] h. drying of the organic phase with drying agent at 40-60 °C and under vacuum;

[0218] i. obtaining a crude intermediate containing depohospho-ino-4-yl-N-Cbz benzyl aspartic acid ester;

[0219] j. purification by column chromatography using hexane / ethyl acetate;

[0220] k. Cleavage of protecting group by hydration using palladium on activated carbon in ethanol;

[0221] l. Purification by column chromatography using tert-butyl methyl ether / ethanol 1% ammonia.

[0222] Example 8: Solubility and lipophilicity of dephospho- psilocin / metocin carbonates

[0223] Introduction

[0224] Three novel compounds (i.e. ethyl dephospho-psilocin-4-yl carbonate, tert-butyl dephospho-psilocin-4-yl carbonate and ethyl N-methyl-N-ethyl-tryptamine-4-yl carbonate) were tested in vitro for solubility in aqueous solution and lipophilicity compared to psilocin and dephospho-psilocin.

[0225] Solubility in water and lipophilicity can be of importance in drug development. Firstly, both properties can influence the pharmacokinetics and bioavailability of a compound in vivo. Secondly, these properties can help determine whether different compounds are suitable for development into different dosage forms.

[0226] Methods

[0227] Kinetic turbidimetric solubility analysis

[0228] 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 1:50 in buffer (0.01 M phosphate buffered saline, pH 7.4) so that the final DMSO concentration was 2% and the final test compound concentration tested was 0.4, 2, 4, 20, 40, 100 and 200 mM. As psilocin was visibly particulate when diluted to 10 mM in DMSO, seven final dilutions were prepared for psilocin instead at 0.2, 1, 2, 10, 20, 50 and 100 mM. DMSO blanks were also included. Three replicate wells were specified for each concentration. After dilution in buffer, the plates were incubated for 5 minutes at room temperature on a plate shaker and then absorbance was measured at 620 nm using a Molecular Devices SpectraMax 384 UV detector. Nicardipine was tested as a control compound. Ethyl dephospho-psilocin-4-yl carbonate, tert-butyl dephospho-psilocin-4-yl carbonate and ethyl N-methyl-N-ethyl-tryptamine-4-yl carbonate were in salt form (hemifumarate) whereas psilocin and dephospho-psilocin were in free base form.

[0229] Solubility was estimated from the concentration of test compound that produced an absorbance increase over the 0.005 absorbance unit threshold and normalized to the DMSO blank.

[0230] Microscale shake flask LogD

[0231] A 10 mM solution of each test compound was diluted in DMSO to give a 400 mM solution, which was then serially diluted into PBS containing 2.5% DMSO to generate a calibration curve (0.014, 0.04, 0.12, 0.37, 1.11, 3.33, and 10 mM). Six replicates of each test compound were incubated at 10 mM in a 1 :9 ratio of octanol:PBS (pH 7.4). After incubation at room temperature with shaking at 600 rpm for two hours, the incubation plates were centrifuged for 15 minutes to separate the layers, and then two aliquots were removed from the PBS layer. The first was left neat, and the second was diluted 10-fold to provide a diluted sample. An internal standard was added to the calibration curve and the PBS incubation samples for analysis on LC MS / MS. Verapamil was tested as a control compound. Ethyl carbamate dephospho- psilocin-4-yl ester, t-butyl carbamate dephospho-psilocin-4-yl ester, and ethyl carbamate N-methyl-N-ethyl-tryptamine-4-yl ester were in salt form (hemifumarate), while psilocin and dephospho-psilocin were in free base.

[0232] LogD was measured as the concentration in the PBS layer against the calibration curve generated relative to the starting concentration of 10 mM. The average of all six replicates of neat samples was taken, giving one value per sample, and the same calculation was done for the diluted sample values.

[0233] Results

[0234] Kinetic turbidimetric solubility analysis

[0235] When preparing the 10 mM psilocin stock solution in DMSO, particulates were seen. All other compounds appeared to be fully dissolved at 10 mM. For this reason, psilocin was only tested at a maximum concentration of 100 mM in the analysis. In contrast, solubility of the other compounds was tested up to 200 mM.

[0236] Table 1: Maximum concentration of each compound tested in the solubility analysis. The compounds were soluble at the concentrations shown. Note that psilocin was tested at a lower maximum concentration due to problems with compound solubility during preparation of the stock solution.

[0237]

[0238] Microscale shake flask LogD

[0239] Table 2: Average LogD of each compound calculated using six replicates in microshaker flask analysis.

[0240]

[0241] Conclusions

[0242] Solubility:

[0243] Psilocybin showed good solubility up to 100 mM, while the other novel compounds tested showed good solubility up to 200 mM. The challenges encountered in preparing a 10 mM stock solution of psilocybin support the interpretation that the novel compounds tested show greater aqueous solubility compared to psilocybin.

[0244] Lipophilicity:

[0245] All novel compounds tested showed a LogD greater than psilocybin and greater than or equal to dephospho-psilocybin. Psilocybin’s relatively low LogD can be consistent with 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 novel compounds’ logD > 1 is consistent with a range that has been reported as optimal for CNS drugs administered orally (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 suggest that dephospho-psilocybin carbonates according to the present application can cross the blood brain barrier (BBB) more rapidly than psilocybin, which makes them highly advantageous for therapeutic applications. Furthermore, the improved solubility / lipophilicity profile of the novel compounds compared to psilocybin can enhance the absorption of prodrugs through passive diffusion when administered through non-oral routes.

[0246] Example 9: Stability of novel dephospho-psilocybin carbonates in HC1

[0247] Brief Description

[0248] Four novel compounds (i.e. ethyl carbocyclic depolarized psilocybin-4-yl ester, tert-butyl carbocyclic depolarized psilocybin-4-yl ester, neopentyl carbocyclic depolarized psilocybin-4-yl ester and benzyl carbocyclic depolarized psilocybin-4-yl ester) were tested for their stability in 1% hydrochloric acid (HC1) compared to psilocybin. These conditions were chosen to gain insight into the chemical stability of the compounds at a pH similar to the conditions in the stomach.

[0249] Method

[0250] Each test compound was diluted in 2 ml of distilled water to obtain a 2 mg / ml solution. Subsequently, 2 ml of the test compound solution was added to 2 ml of distilled water containing 2% (v / v) HC1, resulting in a final HC1 concentration of 0.32 mM (pH 0.5). The test solutions were incubated at 37°C under continuous stirring for approximately 26 hours. The concentrations of the parent compound and depolarized psilocybin were analyzed at different time points using LC-MS. The concentrations of released parent prodrug and depolarized psilocybin were expressed relative to the starting concentration of the parent prodrug.

[0251] Results

[0252] The results obtained in this experiment are shown in Figure 5 A to 5D.

[0253] Conclusion

[0254] In view of the above results, it has been found that all tested carbocyclic depolarized psilocybin esters show greater degradation in 1% HC1 than psilocybin, each of which successfully converted to depolarized psilocybin under these conditions. In addition, depolarized psilocybin tert-butyl carbocyclic ester is particularly susceptible to degradation by 1% HC1, showing rapid and complete chemical degradation to depolarized psilocybin in approximately four hours of testing. These findings support the interpretation that carbocyclic depolarized psilocybin esters will generally convert to the active molecule depolarized psilocybin more rapidly under highly acidic conditions.

[0255] Example 10: Ingestion study

[0256] Chemicals and reagents

[0257] P1 - ethyl carbocyclic depolarized psilocybin-4-yl ester (salt: hemi-fumarate)

[0258] P2 - tert-butyl carbocyclic depolarized psilocybin-4-yl ester (salt: hemi-fumarate)

[0259] M1 - prodrug of 5,6-methylenedioxy-2-aminoindane (MDAI) (salt: hemi-oxalate)

[0260] M2 - prodrug of 3,4-methylenedioxymethamphetamine (MDA) (salt: hemi-oxalate)

[0261] Formic acid ( Sodium fluoride (NaF, ≥99%, Pa) was obtained from Carl Roth (Karlsruhe, Germany). Acetonitrile (ACN, LC-MS grade), ammonium formate 10M (99.995%), anhydrous ethanol, ascorbic acid (99%), and dimethyl sulfoxide (DMSO) were purchased from Sigma Aldrich (Steinheim, Germany). Materials from ELGA (Celle, Germany) were also used. Deionized water was prepared using a Pro deionizer. Fetal bovine serum was obtained from Thermo Fisher Scientific (Waltham, USA). Mobile phase A (1% ACN, 0.1% HCOOH, 2 mM NH4) was freshly prepared prior to analysis. + HCOO - (in water) and mobile phase B (0.1% HCOOH, 2mM NH4) + HCOO - (In ACN).

[0262] Intake study

[0263] Two volunteers (1M, 1F) ingested approximately 1 mg each of P1 and M1 (Study 1) and P2 and M2 (Study 2) from gelatin capsules (exact amounts in Tables 3 and 4). A blood sample was collected prior to ingestion of the substance as a zero control. Samples were collected approximately 8 hours after ingestion, with increasing time intervals between samplings (exact protocols in Tables 4 and 5). Blood was collected in an EDTA monoovette (Sarstedt, Nümbrecht, Germany) and centrifuged immediately after collection (15 min, 4,000 x g). The resulting serum was transferred to plastic tubes and NaF (approximately 30 mg) and ascorbic acid (approximately 5 mg) were added to increase the stability of the analyte.

[0264] Table 3: Study Design and Sample Collection Plan for Study 1

[0265]

[0266]

[0267] Table 4: Study Design and Sample Collection Plan for Study 2

[0268]

[0269] Sample preparation

[0270] Internal standard solution (10 μL) was spiked into 200 μL serum and ACN (600 μL) was added to precipitate soluble proteins. Prior to thorough mixing, ammonium formate (10 M, 200 μL) was added and the aqueous phase was separated from the organic phase. After centrifugation (6 min, 4,000 x g), 500 μL of the organic phase were transferred to another vial and evaporated to dryness at 40 °C under a gentle stream of nitrogen. The samples were reconstituted in 100 μL of mobile phase (A / B, 90 / 10, v / v) and used for analysis. For quantification, a six-point calibration in blank sample and calf serum (0.5, 1.0, 2.0, 5.0, 10, 20 ng / mL) was prepared as described above.

[0271] HPLC-MS / MS analysis

[0272] The HPLC-MS system consisted of a Nexera X2 UHPLC system (Shimadzu, Duisburg, Germany) composed of three LC-30AD pumps, one DGU-30A3 degasser, one SIL-30AC autosampler, one CTO-10AS column oven and one CBM-20A controller coupled to a QTRAP 6500 plus triple quadrupole linear ion trap mass spectrometer (Sciex, Darmstadt, Germany) equipped with a Turbo Ion Spray interface. The MS was operated in positive electrospray ionization mode. Data acquisition was performed in the predetermined multiple reaction monitoring mode (detection window: 60 seconds) using Analyst software (version 1.7). MS parameters (de-clustering potential, entrance potential, collision energy and collision cell exit potential) were optimized for all substances to obtain the best possible signal strength (a summary of MRM parameters is given in Table 5). The ion source temperature and the ion source voltage were set to 550 °C and +5500 V, respectively. The dwell time for each MRM transition was 20 ms. 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 on a biphenyl column (100 x 2.1 mm, 2.6 μm particle size, Phenomenex, Aschaffenburg, Germany) with a corresponding guard column (Security Guard 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 was performed with mobile phases A and B as indicated in Table 6. Chromatographic separation was performed on a biphenyl column (100 x 2.1 mm, 2.6 μm particle size, Phenomenex, Aschaffenburg, Germany) with a corresponding guard column (Security Guard 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 was performed with mobile phases A and B as indicated in Table 6. TM Chromatographic separation was performed on a biphenyl column (100 x 2.1 mm, 2.6 μm particle size, Phenomenex, Aschaffenburg, Germany) with a corresponding guard column (Security Guard 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 was performed with mobile phases A and B as indicated in Table 6.

[0273] Table 5: HPLC gradient

[0274]

[0275] Table 6: MRM parameters

[0276]

[0277] Limit of detection (LOD) and limit of quantification (LOQ) were determined according to German DIN 32645. The concentrations of the applied calibrants were 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40 and 0.45 ng / mL. LOD and LOQ are shown in Table 7.

[0278] Table 7: LOD and LOQ according to DIN 32645

[0279]

[0280] Table 8: Concentration of analytes detected in samples of test person A in study 1.

[0281]

[0282] Table 9: Concentration of analytes detected in samples of test person B in study 1.

[0283]

[0284]

[0285] * Concentration below calculated LOQ and extrapolated

[0286] Table 10: C of dephosphorylated Hymenophobin and MDAI after oral intake of about 1 mg P1 and M1 最大 , T 最大 , elimination half-life (t 1 / 2 ) and elimination constant (k el ).

[0287]

[0288] Table 11: Concentration of analytes detected in samples of test person A in study 2

[0289]

[0290]

[0291] * Concentration below calculated LOQ and extrapolated

[0292] Table 12: Concentrations of analytes detected in samples of test person B in study 2.

[0293]

[0294] Concentrations below calculated LOQ and extrapolated

[0295] Table 13: Cmax of psilocin and M2 after oral intake of about 1 mg of P2 and M2 最大 , T 最大 , elimination half-life (t 1 / 2 ) and elimination constant (k el ).

[0296]

[0297] Conclusion

[0298] P1 : After oral intake of P1, only psilocin was detected in serum, but not P1 itself (LOD 0.05 ng / mL). The maximum concentration of psilocin (1.1 ± 0.5 ng / mL) was observed 56 ± 13 minutes after P1 was applied. This is about one hour earlier than described 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) after oral psilocybin. P1 is a fast release prodrug of psilocin in vivo.

[0299] P2: After oral intake of P2, only psilocin was detected in serum, but not P2 itself (LOD 0.07 ng / mL). The maximum concentration of psilocin (1.13 ± 0.01 ng / mL) was observed 90 ± 56 minutes after P2 was applied. This is in the same range or slightly earlier than described by Brown et al. (in the above cited reference) after oral psilocybin. P2 acts as a prodrug of psilocin in vivo with a T 最大 that can be shorter than psilocybin.

[0300] Example 11 : Solubility and lipophilicity profile of other psilocin carbonates

[0301] A novel compound (i.e. benzyl carbonate of psilocin-4-yl ester) was tested in vitro for its solubility and lipophilicity in aqueous solution.

[0302] Water solubility and lipophilicity can be of importance in drug development. First, both properties can influence the pharmacokinetics and bioavailability of a compound in the body. Second, these properties can help determine whether different compounds are suitable for development into different dosage forms.

[0303] Method

[0304] Kinetic solubility analysis

[0305] Test and control compounds were diluted to 10 mM in DMSO and then further diluted 1 :50 to a target concentration of 200 mM in 50 mM PB (pH 7.4). Samples were vortexed for at least 2 minutes and then shaken (800 rpm) for 24 hours at room temperature. Visual appearance was assessed prior to centrifugation and injection into the UPLC system to measure concentration. Carmbamezepine and Chloramaphenicol were run as control compounds. Each compound was tested in duplicate. Bensulide was tested as the hydrochloride salt.

[0306] Shake flask LogD analysis

[0307] Test and control compounds were diluted to 10 mM in DMSO. 2 μΐ of each stock solution was aliquoted into tubes in duplicate. 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 μΐ of each solution was aliquoted into the respective tubes. These were then mixed vigorously for 2 minutes and shaken (800 rpm) for one hour at room temperature. Appropriate volumes of buffer and 1-octanol layer samples were aliquoted and diluted prior to detection using LC-MS / MS. Chlorpromazine, Nadolol, and Propranolol were run as control compounds. Bensulide, Chlorpromazine, and Propranolol were tested as the hydrochloride salt.

[0308] LogD was calculated according to the following equation:

[0309]

[0310] Results

[0311] Kinetic solubility analysis

[0312] Table 14: Concentration of each compound tested in solubility analysis. The compounds were soluble at the concentrations indicated.

[0313]

[0314] Shake flask LogD

[0315] Table 15: Average LogD calculated for each compound in shake flask analysis.

[0316]

[0317] Conclusions

[0318] Solubility:

[0319] Benzyl carbamate dephospho-hirsuticin-4-yl ester showed a solubility of up to >230 μΜ.

[0320] Lipophilicity:

[0321] Benzyl carbamate dephospho-hirsuticin-4-yl ester exhibited a LogD in the optimal range reported for oral 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 benzyl carbamate dephospho-hirsuticin-4-yl ester was greater than that reported for hirsuticin, indicating a relatively higher lipophilicity and therefore a greater ability to cross the blood brain barrier (BBB).

[0322] Example 12: Pharmacokinetics of novel dephospho-hirsuticin carbonates in mice

[0323] Brief Introduction

[0324] Three novel compounds (i.e. ethyl carbamate dephospho-hirsuticin-4-yl ester, t-butyl carbamate dephospho-hirsuticin-4-yl ester and benzyl carbamate dephospho-hirsuticin-4-yl ester) were tested in mice to confirm their ability to release dephospho-hirsuticin in vivo and to provide a comparison of their plasma dephospho-hirsuticin pharmacokinetics with hirsuticin.

[0325] Methods

[0326] Experimental animals

[0327] Twenty-seven male C57BL / 6J mice (Charles River UK) weighing 22-25 g at the time of purchase were housed in groups of three in polyprene cages. Mice were maintained on a reverse 12-hour light-dark cycle (lights on from 07:00-19:00) with ad libitum access to standard pelleted diet (Envigo 2018) and filtered tap water. The holding room was maintained at 21 ± 4 °C with a relative humidity of 55 ± 15%.

[0328] Experimental procedure

[0329] Mice were weighed and identified by tail markings using a permanent marker pen on the day of dosing. Food was not withheld on the day of dosing. Three animals were allocated to a control group which received no treatment but were bled to enable collection of blank matrices. The remaining animals were divided into two groups, animals in the first group received a single oral dose of a test compound and animals in the second group received a single intravenous dose (in the lateral tail vein) of a test compound. Following treatment, orally dosed animals were bled by incision of the lateral tail vein at 5, 15, 30, 45, 60, 120 and 240 minutes post-dose. Intravenously dosed animals were bled by incision of the contralateral tail vein at the same time points. Ethyl carbamic acid psilocybin-4-yl ester, tert-butyl carbamic acid psilocybin-4-yl ester and benzyl carbamic acid psilocybin-4-yl ester are in salt form (hemifumarate salt) whereas psilocin is in free base form. The dose of benzyl carbamic acid psilocybin-4-yl ester (but not ethyl carbamic acid psilocybin-4-yl ester or tert-butyl carbamic acid psilocybin-4-yl ester) was corrected for salt weight. All compounds were formulated in saline and dosed in a volume of 5 ml / kg.

[0330] The following table summarises the dosing groups.

[0331] Table 16: Summary of dosing groups in oral (PO) and intravenous (IV) dosing cohorts.

[0332]

[0333]

[0334] 25 μl of blood was collected from each animal at each time point. Blood samples were collected into K2EDTA-coated tubes (e.g., Sarstedt Microvette 300K2E tubes) and stored on wet ice before centrifugation (10,000 RPM for 2 minutes). 10 μL of plasma was drawn and placed into individually labeled Axygen mini-tubes. Samples were initially stored on dry ice and then transferred to a freezer at approximately -80°C overnight. Blank matrix plasma samples were processed in the same manner as test samples. The level of dephosphorylated psilocybin in the samples was determined using LC-MS / MS. All pharmacokinetic parameters were calculated manually. Measurements below LLOQ (=2.5–5 ng / ml) were included as 0 ng / ml.

[0335] result

[0336] Table 17: Key parameters calculated for each test compound when administered to mice via intravenous injection. All parameters correspond to measurements of dephosphorylated psilocybin.

[0337]

[0338]

[0339] Note: IV, intravenous. *Due to sampling difficulties, one animal was sampled at 7.5 min instead of 5 min. All animals receiving this compound showed C at the time point of the first successful sampling. 最大 .

[0340] Table 18: Key parameters calculated for each test compound when administered to mice via oral tube feeding. All parameters correspond to measurements of dephosphorylated psilocybin.

[0341]

[0342] Note: PO, for oral administration.

[0343] Table 19: Absolute oral bioavailability (F) percentage of dephosphorylated psilocybin calculated for each test compound.

[0344]

[0345] The plasma concentrations of dephosphorylated psilocybin after intravenous or oral administration of the test compound to mice were displayed as follows: Figure 6 In A and 6B. Furthermore... Figure 6 C through 6H also show separate charts for each tested compound, covering intravenous administration ( Figure 6 C) or orally ( Figure 6 D) Administer ethyl chloropsisin-4-yl ester intravenously ( Figure 6 E) or orally (Figure 6 F) Administer dephosphorylated psilocybin-4-methyl-tert-butyl carbonate and intravenous ( Figure 6 G) or orally ( Figure 6 H) Plasma concentration of dephosphorylated psilocybin after administration of benzyl carbonate dephosphorylated psilocybin-4-yl ester.

[0346] in conclusion

[0347] General comments on the IV data:

[0348] Dephosphorylated psilocybin was detected after administration of all compounds, indicating that each compound is converted to dephosphorylated psilocybin in vivo upon intravenous administration. The C60 values ​​of all novel compounds were [not specified] upon intravenous administration. 最大 Similar to or higher than psilocybin. In particular, benzyl carbonate dephosphorylated psilocybin-4-yl ester shows a C... 最大 It is approximately twice that of psilocybin, resulting in a larger overall exposure, as shown in AUC. 最大 The results were roughly equal among all the compounds tested.

[0349] General comments on PO data:

[0350] Dephosphorylated psilocybin was detected after administration of all compounds, indicating that each compound was converted to dephosphorylated psilocybin in mice upon oral administration. Upon oral administration, the C60 values ​​of all novel compounds were [missing information]. 最大 Slightly lower than psilocybin. The T values ​​among all tested compounds were... 最大 Roughly equal (30 min), except for benzyl carbonate dephosphorylated psilocybin-4-yl ester, which exhibited a delayed Tg. 最大 (45 min).

[0351] Comments on benzyl carbonate dephosphorylated psilocybin-4-yl ester IV relative to oral administration:

[0352] Benzyl carbonate dephosphorylated psilocybin-4-yl ester is relatively efficiently converted to dephosphorylated psilocybin upon intravenous administration, in contrast to oral administration of this compound (corresponding to a relatively low oral bioavailability %), where T 最大 It showed a slight delay and relatively low exposure compared to other tested compounds.

[0353] Example 13: Novel dephosphorylated psilocybin / tryptophan carbonate-induced head twitching response

[0354] Introduction

[0355] The ability of four novel compounds (i.e. ethyl carbonic acid dephospho-hHallucinogen-4-yl ester, t-butyl carbonic acid dephospho-hHallucinogen-4-yl ester, ethyl carbonic acid N-methyl-N-ethyltryptamine-4-yl ester and benzyl carbonic acid dephospho-hHallucinogen-4-yl ester) and hHallucinogen to induce the head-twitch response (HTR) in mice, which is an involuntary, phasic head rotation that occurs in rodents upon activation of the serotonin 2A (5-HT 2A ) receptor, was tested.

[0356] The HTR can be used to distinguish between hallucinogenic and non-hallucinogenic 5-HT 2A receptor agonists, and importantly, the potency of a compound to induce HTR in rodents correlates with its potency to induce hallucinogenic 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).

[0357] Methods

[0358] Experimental animals

[0359] Forty-eight male C57BL / 6J mice (Charles River UK) weighing 20-25 g at the time of purchase were housed in groups of three in polypropylene cages. Mice were maintained on a positive phase 12-hour light-dark cycle (lights on from 07:00-19:00) with ad libitum access to standard pelleted chow (Envigo 2018) and filtered tap water. The holding room was maintained at 21 ± 4 °C with a relative humidity of 55 ± 15%.

[0360] Experimental procedure

[0361] Mice were weighed and assigned to drug treatment groups according to body weight. Animals were given vehicle, psilocin (0.3 mg / kg), ethyl psilocin-4-yl carbonate hemi-fumarate (0.3 mg / kg), t-butyl psilocin-4-yl carbonate hemi-fumarate (0.3 mg / kg), N-methyl-N-ethyltryptamine-4-yl-ethyl carbonate hemi-fumarate (0.3 mg / kg), or benzyl psilocin-4-yl carbonate hemi-fumarate (0.3 mg / kg) by oral gavage and placed in clean, transparent cages containing a thin layer of wood shavings. The number of head twitches was then counted by a scorer blinded to treatment conditions within 60 minutes after drug administration. The dose of salt form compounds was adjusted to ensure equal drug dose (0.3 mg / kg) across all treatment groups. All compounds were formulated in saline and administered in a volume of 5 ml / kg.

[0362] Results

[0363] Table 20: Mean number of head twitches calculated six minutes after drug administration. N=8 for all groups.

[0364]

[0365] Note: SEM, standard error of the mean.

[0366] Conclusions

[0367] Ethyl psilocin-4-yl carbonate and N-methyl-N-ethyltryptamine-4-yl-ethyl carbonate induced similar mean number of head twitches compared to psilocin within 60 minutes after drug administration. Benzyl psilocin-4-yl carbonate also induced E 最大 reactions similar in magnitude to those induced by psilocin, and N-methyl-N-ethyltryptamine-4-yl-ethyl carbonate did so at the 0-15 min time point. These findings support the occurrence of 5-HT 2A receptor activation following administration of these compounds in mice, which is necessary for the hallucinogenic effects in humans.

Claims

1. A depodophyllotoxin derivative according to general formula (I), wherein: R 1 selected from the group consisting of ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, neopentyl, -O-CH2-phenyl, -CH2-NH2, -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)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazol-4-yl), -CH(-NH2)-CH2-(4-hydroxyphenyl), -CH(-NH2)-CH2-(1H-indol-3-yl), -(4-hydroxypyrrolidin-2-yl), -CH(-NH2)-CH2-S-S-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-indol-3-yl), -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH(-CH3)-CH2-NH2, -C(-NH2)=CH2, -O-(1-[R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 ]-3-[(-CH2CH2-N(-R 1-12 )-R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 ]-3-[(-CH2CH2-N(-R 4 )-R 2 ]-3-[(-CH2CH2-N(-R 3 )-R 4 ]-3-[(-CH2CH2-N(-R 2 )-R 3 )]-1H-indol-4-yl), -CH(-NH2)-CH2-SS-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); R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl and ethyl, provided that R 2 and R 3 are not simultaneously hydrogen; and R 4 is hydrogen or -C(=O)-O-(C 1-6 alkyl); or a pharmaceutically acceptable salt thereof.

2. The dephosphorinated pleuromutilin derivative according to claim 1, wherein R 1 is ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or neopentoxy or -O-CH2-phenyl.

3. The dephosphorized stereocaulin derivative of claim 1, wherein R 1 is selected from the group consisting of -CH2-NH2, -CH(-NH2)-CH2-SH, -CH(-NH2)-CH2-OH, -CH(-NH2)-CH(-CH3)-OH, -CH(-NH2)-CH2-C(=0)-NH2, -CH(-NH2)-CH2CH2-C(=0)-NH2, -CH(-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1H-imidazol-4-yl), -CH(-NH2)-CH2-(4-hydroxyphenyl), and -CH(-NH2)-CH2-(1H-indol-3-yl).

4. The dephosphorized stereocaulin derivative according to claim 1, wherein R 1 is selected from the group consisting of -CH(-NH2)-CH2-SH, -CH(-NH2)-CH2-OH, -CH(-NH2)-CH(-CH3)-OH, -CH(-NH2)-CH2-C(=0)-NH2, -CH(-NH2)-CH2CH2-C(=0)-NH2, -CH(-NH2)-CH2-COOH, -CH(-NH2)-CH2CH2-COOH, -CH(-NH2)-CH2CH2CH2CH2-NH2, -CH(-NH2)-CH2CH2CH2-NH-C(=NH)-NH2, -CH(-NH2)-CH2-(1 H-imidazol-4-yl), -CH(-NH2)-CH2-(4-hydroxyphenyl), and -CH(-NH2)-CH2-(1 H-indol-3-yl).

5. The dephosphorized stereocaulin derivative of claim 1, wherein R 1 is selected from the group consisting of -(4-hydroxypyrrolidin-2-yl), -CH(-NH2)-CH2-S-S-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-lH-indol-3-yl), -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH(-CH3)-CH2-NH2, and -C(-NH2)=CH2.

6. The depophosphorin derivative according to any one of claims 1 to 5, wherein R 2 and R 3 are each methyl.

7. The depophosphorin derivative according to any one of claims 1 to 5, wherein R 2 is methyl and R 3 is hydrogen.

8. The depophosphorin derivative according to any one of claims 1 to 5, wherein R 2 is methyl and R 3 is ethyl.

9. The depophosphorin derivative according to any one of claims 1 to 8, wherein R 4 is hydrogen.

10. The dep phosphorized shiitake mushroom acid derivative according to any one of claims 1 to 8, wherein R 4 is -C(=0)-0-(C 2-4 alkyl).

11. The depodophyllotoxin derivative according to claim 1, wherein the depodophyllotoxin derivative is selected from any one of the following compounds or a pharmaceutically acceptable salt thereof:

12. The depodophyllotoxin derivative according to any one of claims 1 to 11, wherein the depodophyllotoxin derivative is in the form of a pharmaceutically acceptable salt; wherein the pharmaceutically acceptable salt is preferably a fumarate, maleate, oxalate, malate, tartrate or mesylate, more preferably an oxalate or fumarate.

13. A pharmaceutical composition comprising at least one depodophyllotoxin derivative according to any one of claims 1 to 12 and optionally one or more pharmaceutically acceptable excipients.

14. The depophosphokojiabin-derived of any one of claims 1 to 12 or the pharmaceutical composition of claim 13 for use in the treatment of serotonin 5-HT 2A receptor related diseases / disorders.

15. The depodophyllotoxin derivative for use according to claim 14 or the pharmaceutical composition for use according to claim 14, wherein the depodophyllotoxin derivative or the pharmaceutical composition is for use in the treatment of anxiety, attention deficit hyperactivity disorder (ADHD), depression, cluster headache, a condition associated with cancer, reduced drive, burnout, boredom, migraine, Parkinson’s disease, pulmonary arterial hypertension, schizophrenia, an eating disorder, nausea or vomiting.

16. A method of producing a depodophyllotoxin derivative according to any one of claims 1 to 12, the method comprising the following steps: (a) preparing a suspension of depodophyllotoxin in a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane; (b) adding an activating agent under a protective gas atmosphere, wherein the activating agent is a nitrogen base, a carbodiimide or a combination thereof; preferably, wherein the activating agent is triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide or a combination thereof; (c) adding a derivatizing agent, wherein the derivatizing agent is ethyl chloroformate, di-tert-butyl pyrocarbonate, N-benzyloxycarbonyl-glycine, N-(9-fluorenylmethoxycarbonyl)-L-tryptophan, N-benzyloxycarbonyl-L-aspartic acid 4-benzyl ester, N-benzyloxycarbonyl-L-tryptophan or N-benzyloxycarbonyl-L-tryptophan; (d) stirring the mixture under a protective gas atmosphere for at least 3 hours; (e) stopping the reaction by dilution with the solvent from step (a); (f) concentrating the solvent; (g) dissolving the residue in a solvent selected from ethyl acetate, diethyl ether, dichloromethane and combinations thereof; (h) extracting with 1 M HCI, water and a saturated brine solution; (i) drying the organic phase with a drying agent under vacuum at 40-60 °C; (j) obtaining a crude product; (k) purifying the crude product by recrystallization and / or column chromatography; (l) obtaining a depodophyllotoxin derivative according to any one of claims 1 to 12.

17. The method of claim 16, wherein the yield of the dephosphorized volvarol derivative is at least 60% by weight relative to the starting material.

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