WO2023044574A1 - Dérivés de mescaline phosphorylés et sulfonés et leurs procédés d'utilisation - Google Patents

Dérivés de mescaline phosphorylés et sulfonés et leurs procédés d'utilisation Download PDF

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WO2023044574A1
WO2023044574A1 PCT/CA2022/051412 CA2022051412W WO2023044574A1 WO 2023044574 A1 WO2023044574 A1 WO 2023044574A1 CA 2022051412 W CA2022051412 W CA 2022051412W WO 2023044574 A1 WO2023044574 A1 WO 2023044574A1
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group
sulfate
phosphate
compound
chemical
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Jillian M. HAGEL
Chang-Chun LING
Peter J. Facchini
Kaveh MATINKHOO
David James PRESS
Jessica Bik-jing LEE
Glynnis Elizabeth JENSEN
Ye CAI
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Enveric Biosciences Canada Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/62—Quaternary ammonium compounds
    • C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • compositions and methods disclosed herein relate to a chemical compound known as mescaline. Furthermore, the compositions and methods disclosed herein relate, in particular, to phosphorylated and sulfonated derivatives of mescaline.
  • the biochemical pathways in the cells of living organisms may be classified as being part of primary metabolism, or as being part of secondary metabolism. Pathways that are part of a cell’s primary metabolism are involved in catabolism for energy production or in anabolism for building block production for the cell. Secondary metabolites, on the other hand, are produced by the cell without having an obvious anabolic or catabolic function. It has long been recognized that secondary metabolites can be useful in many respects, including as therapeutic compounds.
  • Mescaline (chemical name 3,4,5 trimethoxyphenethylamine), for example, is a secondary metabolite that is naturally produced by certain cactus species belonging to a variety of genera within the plant family of Cactaceae.
  • Cactus species which can produce mescaline include, for example, cactus species belonging to the genus Lophophora, including Lophophora williamsii (peyote) and Lophophora diffusa and cactus species belonging to the genus Echinopsis/Trichocereus, including Echinopsis pachanoi/Trichocereus pachanoi (also known as San Pedro), Echinopsis peruviana/Trichocereus peruvianus (also known as Peruvian torch), (Echinopsis lageniformis/Tnchocereus bndgesii/ (also known as Peruvian torch), and Echinopsis lageniformis/Tnchocereus bndgesii/ (also known
  • mescaline is a psychoactive compound and is therefore used as a recreational drug.
  • Mescaline is also used in Native American religious ceremonies, and for spiritual purposes by Andean indigenous cultures.
  • mescaline has been evaluated for its potential in the treatment of addictions, notably alcohol addiction (Bogenschutz, M.P. and Johnson M. W. (2016), Prog, in Neuro- Psychopharmacol. & Biol. Psychiatry 64; 250- 258; Romeu, A.G. et al., (2017), Exp. Clin. Psychopharmacol. 2016 Aug; 24(4): 229-268).
  • mescaline Although the toxicity of mescaline is low, adverse side effects, including, for example, panic attacks, paranoia, and psychotic states, sometimes together or individually referred to as “a bad trip”, are not infrequently experienced by mescaline users. Furthermore, mescaline can induce nausea and vomiting.
  • the present disclosure relates to mescaline and derivative compounds.
  • the present disclosure relates to phosphorylated and sulfonated mescaline derivatives and methods of making and using these compounds.
  • the present disclosure provides, in at least one embodiment, in accordance with the teachings herein, a chemical compound or salt thereof having the chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H; and wherein
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring.
  • the phosphate or sulfate group can be an ionic phosphate or ionic sulfate group and forms a phosphate or sulfate salt counterbalanced by a cation.
  • the phosphate or sulfate group can be an ionic phosphate or ionic sulfate group and forms a phosphate or sulfate salt counterbalanced by a monovalent, bivalent, trivalent, or tetravalent cation.
  • the phosphate group can be an ionic phosphate group forming a salt with a monovalent cation (Z + ), the formed salt having the formula: HPO4' Z + .
  • the phosphate group can be an ionic phosphate group forming a salt with a monovalent cation (Z + ), the formed salt having the formula: (PO4 2- ) (Z + )2.
  • the sulfate group can be an ionic sulfate group forming a salt with a monovalent cation (Z + ), the formed salt having the formula: SCU- Z + .
  • the monovalent cation (Z + ) can be selected from Na + , K + , NH4 + , tetra-n-butyl ammonium ([N(C4H9)4] + ), and triethyl ammonium (EtsNH4 + ).
  • the phosphate group can be an ionic phosphate group forming a salt with a divalent cation (Z 2+ ), the formed salt having the formula: PO4 2 ' Z 2+ .
  • the phosphate group can be an ionic phosphate group forming a salt with a divalent cation (Z 2+ ), the formed salt having the formula (HPO4')2 Z 2+ , wherein the second ionic phosphate group (HPO4‘) is a phosphate substituent of a second molecule of the compound having formula (I).
  • the phosphate group can be an ionic sulfate group forming a salt with a divalent cation (Z 2+ ), the formed salt having the formula (SO4 2 Z 2+ , wherein the second ionic sulfate group (SO4‘) is a sulfate substituent of a second molecule of the compound having formula (I).
  • the divalent cation (Z 2+ ) can be selected from Mg 2+ and Ca 2+ .
  • one, two or three of X2, X3 and X4 can be a phosphate group or a sulfate group.
  • one, two or three of Xi, X3 and X4 can be a phosphate group or a sulfate group.
  • one, two or three of Xi, X2 and X3 can be a phosphate group or a sulfate group.
  • one, two or three of Xi, X3 and Xs can be a phosphate group or a sulfate group.
  • one, two or three of Xi, X2 and X4 can be a phosphate group or a sulfate group.
  • compound (I) can contain one or two sulfate groups but does not contain a phosphate group.
  • compound (I) can contain one or two phosphate groups but does not contain a sulfate group.
  • compound (I) can contain at least one sulfate group and at least one phosphate group.
  • compound (I) can contain one sulfate group and one phosphate group.
  • compound (I) can contain two sulfate groups and one phosphate group.
  • compound (I) can contain one sulfate group and two phosphate groups.
  • compound (I) can contain one sulfate group or one phosphate group.
  • compound (I) can contain one sulfate group or one phosphate group, and at least one of Xi, X2, X3, X4, and Xs is an O-alkyl group.
  • compound (I) can contain one sulfate group or one phosphate group, and at least one of Xi, X2, X3, X4, and Xs is an O-alkyl group, and Xi, X2, X3, X4, and X5 which are not a sulfate group, a phosphate group, or an O-alkyl group are a hydrogen atom.
  • compound (I) can contain one sulfate group or one phosphate group, and one of Xi, X2, X3, X4, and X5 is an O-alkyl group, and Xi , X2, X3, X4, and X5 which are not a sulfate group, a phosphate group, or an O-alkyl group, are a hydrogen atom.
  • compound (I) can contain one sulfate group or one phosphate group, two of Xi, X2, X3, X4, and X5 are an O- alkyl group, and Xi, X2, X3, X4, and X5 which are not a sulfate group, a phosphate group, or an O-alkyl group, are a hydrogen atom.
  • compound (I) can contain one sulfate group or one phosphate group, wherein one of X2, X3, and X4 are a sulfate or phosphate group, two of X2, X3, and X4 are an O-alkyl group, and Xi and X5 are a hydrogen atom.
  • compound (I) can contain one sulfate group or one phosphate group, wherein one of X2, and X3, are a sulfate or phosphate group, two of X2, X3, and X4 are an O-alkyl group, and Xi and X5 are a hydrogen atom.
  • compound (I) can contain one phosphate group, wherein one of X2, and X3, is a phosphate group, two of X2, X3, and X4 are an O-alkyl group, and Xi and X5 are a hydrogen atom.
  • compound (I) can contain one sulfate group, wherein X3 is a sulfate group, X2, and X4 are an O-alkyl group, and Xi and X5 are a hydrogen atom.
  • compound (I) can contain one phosphate group, wherein X3 is a phosphate group, X2, and X4 are an O-alkyl group, and Xi and X5 are a hydrogen atom.
  • compound (I) can contain one phosphate group, wherein X2 is a phosphate group, X3, and X4 are an O-alkyl group, and Xi and X5 are a hydrogen atom.
  • the O-alkyl group can be a (Ci-C6)-O-alkyl group.
  • the O-alkyl group can be a (Ci-C3)-O-alkyl group.
  • the O-alkyl group can be a methoxy group (-O-CH3).
  • the compound of formula (I) when W is N + (R6)(R7)(Rs), the compound of formula (I) can include a counterbalancing anion to form a salt, wherein the salt is formed by the anion and the nitrogen atom (N + ).
  • the sulfate or the phosphate group can be an ionic sulfate or ionic phosphate group, and the compound of formula (I) can be a zwitterionic compound.
  • the compound having formula (I) can be selected from the group of chemical compounds having a formula (III); (IV); or (V): wherein in chemical formula (V), Z +/2+ is a mono or divalent cation balancing the negatively charged sulfate group, forming a salt having the formula
  • Z + in compound (V), can be selected from Na + , K + , NH 4 + , tetra-n-butyl ammonium ([N(C 4 H9) 4 ] + ), and triethyl ammonium (EtsNH 4 ).
  • Z 2+ in compound (V), can be selected from Mg 2+ and Ca 2+ .
  • the chemical compound can be selected from (Vb); (V c ); (Vd); (V e ); (Vf); (V g ); and (Vh):
  • the present disclosure relates to pharmaceutical and recreational drug formulations comprising mescaline derivatives. Accordingly, in one aspect, the present disclosure provides, in at least one embodiment, a pharmaceutical or recreational drug formulation comprising an effective amount of a chemical compound or salt thereof having the chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H; and wherein
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring, together with a pharmaceutically acceptable excipient, diluent, or carrier.
  • the present disclosure relates to methods of treatment of psychiatric disorders. Accordingly, the present disclosure further provides, in one embodiment, a method for treating a psychiatric disorder, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising a chemical compound or salt thereof having the chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H; and wherein
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring, and wherein the pharmaceutical formulation is administered in an effective amount to treat the psychiatric disorder in the subject.
  • the compound having formula (I) upon administration can interact with a receptor in the subject to thereby modulate the receptor and exert a pharmacological effect.
  • the receptor can be a 5- HTIA receptor, or a 5-HT2A receptor.
  • the disorder can be a 5- HTIA receptor mediated disorder, or a 5-HT2A receptor mediated disorder.
  • the present disclosure provides, in at least one embodiment, a method for modulating for a receptor selected from 5-HTIA receptor, and a 5-HT2A receptor with a chemical compound or salt thereof having formula (I): wherein, Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi , X2, X3, X4, and X5 are a phosphate group or a sulfate group, and two of Xi , X2, X3, X4, and Xs are H; and wherein
  • W is -N(R 4 )(RS) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring, under reaction conditions sufficient to modulate the 5-HTIA receptor, or 5-HT2A receptor.
  • the reaction conditions can be in vitro reaction conditions.
  • the reaction conditions can be in vivo reaction conditions.
  • the present disclosure relates to methods of making phosphorylated and sulfonated mescaline derivatives. Accordingly, in one aspect, the present disclosure provides, in at least one embodiment, a method of making a phosphorylated or sulfonated mescaline derivative, the method comprising reacting a phosphor-oxidous compound or a sulfur-oxidous compound with a chemical compound having the formula (II): wherein, Xi, X2, X3, X4, and Xs are H, a reactive group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a reactive group, and two of Xi, X2, X3, X4, and Xs are H; and wherein
  • W is -CH2N(R 4 )(RS), or -CH 2 N + (R6)(R7)(R8), or COOH;
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Rs, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Rs, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring, to thereby form the phosphorylated or sulfonated mescaline derivative, the formed phosphorylated or sulfonated mescaline derivative having the chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H; and wherein
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring.
  • the reactive group can be a hydroxy group and the sulfur-oxidous compound can be a pyridinium sulfur trioxide or tetrabutylammonium hydrogen sulfate.
  • the reactive group can be a hydroxy group and the phosphor-oxidous compound can be tetra-O-benzyl pyrophosphate or dibenzyl chlorophosphate.
  • the method can comprise the performance of at least one of the chemical reactions depicted in FIG. 11, FIG. 12, or FIG. 13 under reaction conditions sufficient to form the chemical compound having formula (I).
  • the compound having chemical formula (I) can be a compound having the chemical formula (III): and the least one chemical synthesis reaction is selected from chemical reaction (d); (c) and (d); (b), (c), and (d); and (a), (b), (c), and (d) depicted in FIG. 11 , wherein the least one chemical synthesis reaction is conducted under reaction conditions sufficient to form the chemical compound having formula (III).
  • the compound having chemical formula (I) can be a compound having the chemical formula (IV): and the least one chemical synthesis reaction is selected from chemical reaction (d); (c) and (d); (b), (c), and (d); (a), (c), and (d); and (a), (b) (c), and (d) depicted in FIG. 12, wherein the least one chemical synthesis reaction is conducted under reaction conditions sufficient to form the chemical compound having formula (IV).
  • the compound having chemical formula (I) can be a compound having the chemical formula (Vb): and the least one chemical synthesis reaction is selected from chemical reaction (c); (b) and (c); and (a), (b), and (c) depicted in FIG. 13, wherein the least one chemical synthesis reaction is conducted under reaction conditions sufficient to form the chemical compound having formula (Vb).
  • the present disclosure provides, in at least one embodiment, a use of a chemical compound or salt thereof having chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H;
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 ); (i) R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Rs, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Rs, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring, in the manufacture of a pharmaceutical or recreational drug formulation.
  • the manufacture can comprise formulating the chemical compound with an excipient, diluent, or carrier.
  • the present disclosure provides, in at least one embodiment, a use of a chemical compound or salt thereof having chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H;
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring, together with a diluent, carrier, or excipient as a pharmaceutical or recreational drug formulation.
  • FIG. 1 depicts the chemical structure of mescaline.
  • FIG. 2 depicts a certain prototype structure of mescaline and mescaline derivative compounds.
  • Certain carbon atoms may be referred to herein by reference to their position within the prototype structure, i.e., Ci , C2, C3 etc. The pertinent atom numbering is shown.
  • certain compounds may be named in accordance with the same. Thus, for example, in 3,4,5 trimethoxyphenethylamine (mescaline) C3, C4, Cs are each bonded to a methoxy group.
  • FIGS. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I and 3J depict the chemical structures of certain example mescaline derivatives, notably 3,4,5-X2,X3,X4- mescaline derivatives (FIGS. 3A, 3B), 2,4,5-XI XS,X4 mescaline derivatives (FIGS. 3C, 3D), 2,3,4-XIX2,X 3 mescaline derivatives (FIGS. 3E, 3F), 2,4,6-XI,X3,XS mescaline derivatives (FIGS. 3G, 3H), 2,3,5- X1.X2.X4 mescaline derivatives (FIGS.
  • FIGS. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I and 3J Xi, X2, X 3 , X 4 , and X 5 are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, and 1 to 3 of Xi, X2, X3, X4, and X5 are a phosphate group or a sulfate group.
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring (FIGS. 3A, 3C, 3E, 3G, 3I), or (ii) Re, R? and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R? and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring, wherein the positively charged nitrogen atom in compound is balanced by M a negatively charged anion (FIGS. 3B, 3D, 3F, 3H, 3 J), or by a negatively charged sulfate group (FIG. 3K).
  • FIGS. 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H, 4I, 4J, 4K, 4L, 4M, 4N, 40, 4P, 4Q, 4R, 4S, 4T, 4U and 4V depict the chemical structures of certain example mescaline derivatives, notably, a 2-sulfonyl-4,6-X3,Xs mescaline derivative (FIG. 4A), a 2-phosphate-4,6-X3,Xs mescaline derivative (FIG. 4B), a 2,6-Xi,Xs-4- sulfonyl mescaline derivative (FIG.
  • Xi, X3, and X5 are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring.
  • FIGS. 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, 5K and 5L depict the chemical structures of certain example mescaline derivatives, notably, a 4- sulfonyl-2,6-dihydroxy mescaline derivative (FIG. 5A), a 4-phosphate-2,6-di- hydroxy mescaline derivative (FIG. 5B), a 2,6-di-methoxy,4-sulfonyl mescaline derivative (FIG. 5C), a 2,6-di-methoxy-4-phospho mescaline derivative (FIG.
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring.
  • FIGS. 6A, 6B, 6C, 6D, 6E, 6F, 6G and 6H depict the chemical structures of certain example mescaline derivatives, notably, a 2-ethoxy-4- sulfonyl-6-hydroxy mescaline derivative, wherein R4 and Rs, are hydrogen atoms (FIG. 6A), a 2-ethoxy-4-phosphate-6-hydroxy mescaline derivative, wherein R4 and Rs, are hydrogen atoms (FIG. 6B), a 2-ethoxy-4-sulfonyl-6-hydroxy mescaline derivative, wherein R4 and Rs, are ethyl groups (FIG.
  • FIG. 6C a 2-ethoxy-4-phospho- 6-hydroxy mescaline derivative, wherein R4 and Rs, are methyl groups
  • FIG. 6D a 2-ethoxy-4-sulfonyl-6-hydroxy mescaline derivative, wherein R4 is a hydrogen atom and Rs, is an ethyl group
  • FIG. 6E 2-ethoxy-4-phosphate-6-hydroxy mescaline derivative, wherein R4 is a hydrogen atom and Rs, is a methyl group
  • FIG. 6F 2-ethoxy-4-sulfonyl-6-hydroxy mescaline derivative, wherein R4 and Rs are joined forming a piperidine group
  • FIG. 6H a 2-ethoxy-4-phosphate- 6-hydroxy mescaline derivative, wherein R4 and Rs are joined forming a piperidine group
  • FIGS. 7A, 7B, 7C, 7D, 7E, 7F, 7G and 7H depict the chemical structures of certain example mescaline derivatives, notably, a 2-ethoxy-4- sulfonyl-6-hydroxy mescaline derivative, wherein Re, R7 and Rs are hydrogen atoms (FIG. 7A), a 2-ethoxy-4-phospho-6-hydroxy mescaline derivative, wherein Re, R7 and Rs are hydrogen (FIG. 7B), a 2-ethoxy-4-sulfonyl-6-hydroxy mescaline derivative, wherein Re and R7 are hydrogen atoms, and Rs is an ethyl group (FIG.
  • FIGS. 8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8I, 8 J, 8K, 8L, 8M, 8N, 80, 8P, 8Q, 8R, 8S and 8T depict the chemical structures of certain example mescaline derivatives, notably and a 2-ethoxy-4-sulfonyl-6-hydroxy mescaline derivative, wherein R4 and Rs are joined forming a 6 membered heterocyclic ring wherein a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by an oxygen atom to form a morpholinyl ring (FIG.
  • FIG. 8A a 2-ethoxy-4- phosphate-6-hydroxy mescaline derivative, wherein R4 and Rs are joined forming a 6 membered heterocyclic ring wherein a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by an oxygen atom to form a morpholinyl ring
  • FIG. 8B a 2-ethoxy-4-sulfonyl-6-hydroxy mescaline derivative, wherein R4 and Rs are joined forming a 6 membered heterocyclic ring wherein a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a hydrogen atom to form a piperazine ring
  • FIG. 8B a 2-ethoxy-4- phosphate-6-hydroxy mescaline derivative, wherein R4 and Rs are joined forming a 6 membered heterocyclic ring wherein a carbon atom (together with its hydrogen atoms, relative to piperidine) is
  • FIGS. 9A, 9B, 9C, 9D, 9E, 9F, and 9G depict the chemical structures of certain example mescaline derivatives, notably, a 2-hydroxy-4,6-X3,Xs mescaline derivative (FIG. 9A), a 2,6-XiXs-4-hydroxy mescaline derivative (FIG. 9B), a 2,4-Xi,X3-6-hydroxy-mescaline derivative (FIG. 9C), a 2,4-di-hydroxy-6-Xs- mescaline derivative (FIG. 9D), a 2,6-di-hydroxy-4-X3-mescaline derivative (FIG. 9E), a 2-Xi-4,6-di-hydroxy-mescaline derivative (FIG.
  • Xi, X3 and X5 which are not a hydroxy group can be an O-alkyl group, an O-acyl group, a hydrogen atom, or a glycosyloxy group.
  • R4 and Rs can be an alkyl group, an acyl group, or a hydrogen, atom, or R4 and Rs can be joined to from a heterocyclic ring.
  • FIGS. 10A, 10B and 10C depict certain example syntheses pathways of phosphorylated and sulfonated mescaline derivatives, notably an example synthesis of an example single phosphorylated mescaline derivative (FIG. 10A) and an example single sulfonated mescaline derivative (FIG. 10B).
  • FIG 10B further shows an example synthesis reaction to allow for modifications of the amine group.
  • FIG. 10C depicts an example synthesis of example mescaline derivatives containing multiple sulfate or phosphate groups.
  • FIG. 11 depicts another example synthesis pathway for an example single phosphorylated mescaline derivative according to the present disclosure.
  • FIG. 12 depicts another example synthesis pathway for another example single phosphorylated mescaline derivative according to the present disclosure.
  • FIG. 13 depicts another example synthesis pathway for an example single sulfonated mescaline derivative according to the present disclosure.
  • FIGS. 14A (I), 14A (II), 14B, 14C, 14D, 14E, 14F, 14G, 14H, 141, 14J, 14K, 14L, 14M, 14N, 140, 14P, 14Q, 14R, 14S, 14T, and 14U depict various graphs representing certain experimental results, notably, graphs obtained in the performance of experimental assays to evaluate the efficacy of an example compound having chemical formula (III), notably, a cell viability assay (FIGS. 14A(i) and 14A(ii)); a radioligand HT2A receptor binding assay using 2C-B (positive control) (FIG.
  • FIG. 14B a radioligand HT2A receptor binding assay using MDMA (positive control) (FIG. 14C); a radioligand HT2A receptor binding assay using mescaline (positive control) (FIG. 14D); a radioligand HT2A receptor binding assay using escaline (positive control) (FIG. 14E); a radioligand HT2A receptor binding assay using proscaline (positive control) (FIG. 14F); a radioligand HT2A receptor binding assay using tryptophan (negative control) (FIG. 14G); a radioligand HT2A receptor binding assay using compound (III) (FIG. 14H); a radioligand HTIA receptor binding assay using 2C-B (FIG.
  • a radioligand HTIA receptor binding assay using MDMA (FIG. 14J); a radioligand HTIA receptor binding assay using mescaline (FIG. 14K); a radioligand HTIA receptor binding assay using escaline (FIG. 14L); a radioligand HTIA receptor binding assay using proscaline (FIG. 14M); a radioligand HTIA receptor binding assay using compound (III) (FIG. 14N); a cAMP assay in the presence of varying concentrations of 2C-B in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin (FIG.
  • a cAMP assay in the presence of varying concentrations of MDMA in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin (FIG. 14P); a cAMP assay in the presence of varying concentrations of mescaline in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin (FIG. 14Q); a cAMP assay in the presence of varying concentrations of escaline in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin (FIG.
  • FIG. 14R a cAMP assay in the presence of varying concentrations of proscaline in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin
  • FIG. 14T a cAMP assay in the presence of varying concentrations of tryptophan in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin
  • FIG. 14U a cAMP assay in the presence of varying concentrations of compound (III) in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin
  • FIGS. 15A, 15B, 15C, and 15D depict various graphs representing certain experimental results, notably, graphs obtained in the performance of experimental assays to evaluate the efficacy of an example compound having chemical formula (IV), notably, a cell viability assay (FIG. 15A), a radioligand HT2A receptor binding assay using compound (IV) (FIG. 15B); a radioligand HTIA receptor binding assay using compound (IV) (FIG. 15C); and a cAMP assay in the presence of varying concentrations of compound (IV) in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin (FIG. 15D).
  • a cell viability assay FIG. 15A
  • a radioligand HT2A receptor binding assay using compound (IV) FIG. 15B
  • a radioligand HTIA receptor binding assay using compound (IV) FIG. 15C
  • a cAMP assay in the presence of varying concentrations of compound (IV
  • FIGS. 16A, 16B, 16C and 16D depict various graphs representing certain experimental results, notably, graphs obtained in the performance of experimental assays to evaluate the efficacy of an example compound having chemical formula (Vb), notably, a cell viability assay (FIG. 16A), a radioligand HT2A receptor binding assay using compound (Vb) (FIG. 16B); a radioligand HTIA receptor binding assay using compound (Vb) (FIG. 16C); and a cAMP assay in the presence of varying concentrations of compound (Vb) in +5HTIA cells and -5HTIA cells stimulated with 4 pM forskolin (FIG. 16D).
  • FIGS. 16A, 16B, 16C and 16D depict various graphs representing certain experimental results, notably, graphs obtained in the performance of experimental assays to evaluate the efficacy of an example compound having chemical formula (Vb), notably, a cell viability assay (FIG. 16A), a radioligand
  • compositions, systems or processes will be described below to provide an example of an embodiment of each claimed subject matter. No embodiment described below limits any claimed subject matter and any claimed subject matter may cover processes, compositions or systems that differ from those described below.
  • the claimed subject matter is not limited to compositions, processes or systems having all of the features of any one composition, system or process described below or to features common to multiple or all of the compositions, systems or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any claimed subject matter.
  • compositions, system or process described below may be the subject matter of another protective instrument, for example, a continuing patent application, and the applicant(s), inventor(s) orowner(s) do not intend to abandon, disclaim or dedicate to the public any such subject matter by its disclosure in this document.
  • compositions, systems or processes will be described below to provide an example of an embodiment of each claimed subject matter. No embodiment described below limits any claimed subject matter and any claimed subject matter may cover processes, compositions or systems that differ from those described below.
  • the claimed subject matter is not limited to compositions, processes or systems having all of the features of any one composition, system or process described below or to features common to multiple or all of the compositions, systems or processes described below. It is possible that a composition, system, or process described below is not an embodiment of any claimed subject matter.
  • compositions, system or process described below may be the subject matter of another protective instrument, for example, a continuing patent application, and the applicant(s), inventor(s) orowner(s) do not intend to abandon, disclaim or dedicate to the public any such subject matter by its disclosure in this document.
  • any range of values described herein is intended to specifically include the limiting values of the range, and any intermediate value or sub-range within the given range, and all such intermediate values and sub-ranges are individually and specifically disclosed (e.g., a range of 1 to 5 includes 1 , 1.5, 2, 2.75, 3, 3.90, 4, and 5).
  • other terms of degree such as “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of the modified term if this deviation would not negate the meaning of the term it modifies.
  • mescaline refers to a chemical compound having the structure set forth in FIG. 1. It is noted that mescaline is also known in the art as 3,4,5 trimethoxyphenethylamine.
  • mescaline prototype structure refers to the chemical structure shown in FIG. 2. It is noted that specific carbon atoms in the mescaline prototype structure are numbered. Reference may be made to these carbon and numbers herein, for example Ci, C2, C3, and so forth.
  • sulfate group refers to a molecule containing one atom of sulfur covalently bonded to four atoms of oxygen, and having the chemical formula SO4 2 '. One of the oxygen atoms may be chemically bonded to another atom, resulting in the sulfate group having a single negative charge.
  • Other entities bonded to the sulfate group may be referred to as sulfonated entities, e.g., a sulfonated mescaline derivative, and compounds bonded to the sulfate group may be said to carry a sulfonyl group.
  • phosphate group refers to a molecule containing one atom of phosphorus covalently bonded to four oxygen atoms (three single bonds and one double bond), and having the chemical formula PO4 3 '.
  • One of the oxygen atoms may be chemically bonded to another atom, resulting in the phosphate group having a double negative charge (-OPOs 2- ).
  • one or two of the oxygen atoms may be bonded to a hydrogen atom to form HPO4 2 ' (and having a single negative charge when so bonded) or H2PO4 (and having no charge when so bonded), respectively.
  • Other entities bonded to the phosphate group may be referred to as phosphorylated entities, e.g., a phosphorylated mescaline derivative.
  • hydroxy group refers to a molecule containing one atom of oxygen bonded to one atom of hydrogen, and having the chemical formula -OH. A hydroxy group through its oxygen atom may be chemically bonded to another entity.
  • glycosylated or glycosyl refer to a saccharide group, such as a mono-, di-, tri- oligo- or a poly-saccharide group, which can be or has been bonded from its anomeric carbon either in the pyranose or furanose form, either in the a or the p conformation.
  • the bonded saccharide group When bonded through its anomeric carbon via an oxygen atom to another entity, the bonded saccharide group, inclusive of the oxygen atom, may be referred to herein as a “glycosyloxy” group.
  • Example monosaccharide groups include, but are not limited to, a pentosyl, a hexosyl, or a heptosyl group.
  • the glycosyloxy group may also be substituted with various groups. Such substitutions may include lower alkyl, lower alkoxy, acyl, carboxy, carboxyamino, amino, acetamido, halo, thio, nitro, keto, and phosphatyl groups, wherein the substitution may be at one or more positions on the saccharide.
  • glycosyl are further stereoisomers, optical isomers, anomers, and epimers of the glycosyloxy group.
  • a hexose group for example, can be either an aldose or a ketose group, can be of D- or L- configuration, can assume either an a- or p- conformation, and can be a dextro- or levo-rotatory with respect to plane-polarized light.
  • Example glycosyloxy and glycosyl groups further include, glucosyl group, glucuronic acid group, a galactosyl group, a fucosyl group, a xylose group, an arabinose group, and a rhamnose group.
  • alkyl group refers to a hydrocarbon group arranged in a chain having the chemical formula -CnH2n+i.
  • Alkyl groups include, without limitation, methyl groups (-CH3), ethyl groups (-C2H5), propyl groups (-C3H7) and butyl groups (-C4H9).
  • O-alkyl group refers to a hydrocarbon group arranged in a chain having the chemical formula -O-CnH2n+i.
  • O-Alkyl groups include, without limitation, O-methyl groups (-O-CH3), O-ethyl groups (-O-C2H5), O-propyl groups (-O-C3H7) and O-butyl groups (-O-C4H9).
  • acyl group refers to a carbon atom double bonded to an oxygen and single bonded to an alkyl group. The carbon atom further can be bonded to another entity.
  • O-acyl group refers to an acyl group in which the carbon atom is single bonded to an additional oxygen atom.
  • the additional oxygen atom can be bonded to another entity.
  • hetero refers to a saturated or partially saturated or aromatic cyclic group, in which one or more (for example, one or two) ring atoms are a heteroatom selected from N, O, or S, the remaining ring atoms being C. Included are, for example, (C3-C20), (C3-C10), and (Cs-Ce) cyclic groups comprising one or two hetero atoms selected from O, S, or N.
  • aryl group refers to an aromatic ring compound in which at least one hydrogen compound has been removed from the aromatic ring to permit the bonding of a carbon atom in the aromatic ring to another entity.
  • the aryl groups can optionally be a substituted Ce-Cu-aryl.
  • the aryl group can further optionally be substituted Ce-C -aryl, or phenyl.
  • Further aryl groups include phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl, indanyl, or indenyl and the like.
  • O-aryl group refers to an aryl group in which the carbon atom in the aromatic ring is single bonded to an additional oxygen atom.
  • the additional oxygen atom can be bonded to another entity.
  • phosphor-oxidous compound refers to a compound including at least one phosphorus atom and a plurality of oxygen atoms, which when reacted with a reactive group, such as a hydroxy group, can form a phosphate group, and include, for example, tetra-O-benzyl pyrophosphate, phosphorus pentoxide (P2O5), and phosphorus oxychloride/trimethylphosphate.
  • sulfur-oxidous compound refers to a compound including at least one sulfur atom and a plurality of oxygen atoms, which when reacted with a reactive group, such as a hydroxy group, can form a sulfate group, and include, for example, pyridinium sulfur trioxide, and trimethylamine-sulfur trioxide.
  • receptor refers to a protein present on the surface of a cell (such as a human cell, for example, a central nervous system (CNS) cell, a hypothalamus cell, a neocortex cell), or in a cell not associated with a cellular surface (e.g., a soluble receptor) capable of mediating signaling to and/or from the cell, or within the cell and thereby affect cellular physiology.
  • a cell such as a human cell, for example, a central nervous system (CNS) cell, a hypothalamus cell, a neocortex cell
  • a cell not associated with a cellular surface e.g., a soluble receptor
  • Example receptors include, 5-HTIA receptors, 5-HTI B receptors, 5-HT2A receptors, and “5- HT2B receptors”, and so on.
  • signaling refers to a response in the form of a series of chemical reactions which can occur when a molecule, including, for example, the mescaline derivatives disclosed herein, interacts with a receptor. Signaling generally proceeds across a cellular membrane and/or within a cell, to reach a target molecule or chemical reaction, and results in a modulation in cellular physiology. Thus, signaling can be thought of as a transduction process by which a molecule interacting with a receptor can modulate cellular physiology, and, furthermore, signaling can be a process by which molecules inside a cell can be modulated by molecules outside a cell.
  • receptor binding assays for example, radioligand binding assays, such as e.g., [ 3 H]ketanserin assays may be used to evaluate receptor 5- HT 2 A receptor activity
  • competition assays for example, competition assays, and saturation binding assays, and the like.
  • 5-HTIA receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HTIA receptors can mediate a plurality of central and peripheral physiologic functions of serotonin.
  • Ligand activity at 5-HTIA is generally not associated with hallucination, although many hallucinogenic compounds are known to modulate 5-HTIA receptors to impart complex physiological responses (Inserra et al., 2020, Pharmacol. Rev 73: 202).
  • 5-HTIA receptors are implicated in various brain neurological disorders, including depression and anxiety, schizophrenia, and Parkinson’s disease (Behav. Pharm. 2015, 26:45-58).
  • 5-HTIB receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HTIB receptors can mediate a plurality of central and peripheral physiologic functions of serotonin.
  • Ligand activity at 5-HTI B is generally not associated with hallucination, although many hallucinogenic compounds are known to modulate 5-HTIA receptors to impart complex physiological responses (Inserra et al., 2020, Pharmacol. Rev. 73: 202).
  • 5-HTIB receptors are implicated in various brain neurological disorders, including depression (Curr. Pharm. Des. 2018, 24:2541-2548).
  • 5-HT2A receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HT2A receptors can mediate a plurality of central and peripheral physiologic functions of serotonin. Central nervous system effects can include mediation of hallucinogenic effects of hallucinogenic compounds.
  • 5-HT2A receptors are implicated in various brain neurological disorders (Nat. Rev. Drug Discov. 2022, 21 :463-473; Science 2022, 375:403-411 ).
  • 5-HT2B receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin.
  • 5-HT2B receptors can mediate a plurality of central and peripheral physiologic functions of serotonin. Central nervous system effects can include mediation of hallucinogenic effects of hallucinogenic compounds.
  • 5-HTbA receptors are implicated in various brain neurological disorders, including schizophrenia (Pharmacol. Then 2018, 181 :143-155) and migraine (Cephalalgia 2017, 37:365-371).
  • pharmaceutical formulation refers to a preparation in a form which allows an active ingredient, including a psychoactive ingredient, contained therein to provide effective treatment, and which does not contain any other ingredients which cause excessive toxicity, an allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • the pharmaceutical formulation may contain other pharmaceutical ingredients such as excipients, carriers, diluents, or auxiliary agents.
  • the term “recreational drug formulation”, as used herein, refers to a preparation in a form which allows a psychoactive ingredient contained therein to be effective for administration as a recreational drug, and which does not contain any other ingredients which cause excessive toxicity, an allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • the recreational drug formulation may contain other ingredients such as excipients, carriers, diluents, or auxiliary agents.
  • the term “effective for administration as a recreational drug”, as used herein, refers to a preparation in a form which allows a subject to voluntarily induce a psychoactive effect for non-medical purposes upon administration, generally in the form of self-administration.
  • the effect may include an altered state of consciousness, satisfaction, pleasure, euphoria, perceptual distortion, or hallucination.
  • the term “effective amount”, as used herein, refers to an amount of an active agent, pharmaceutical formulation, or recreational drug formulation, sufficient to induce a desired biological or therapeutic effect, including a prophylactic effect, and further including a psychoactive effect. Such effect can include an effect with respect to the signs, symptoms or causes of a disorder, or disease or any other desired alteration of a biological system.
  • the effective amount can vary depending, for example, on the health condition, injury stage, disorder stage, or disease stage, weight, or sex of a subject being treated, timing of the administration, manner of the administration, age of the subject, and the like, all of which can be determined by those of skill in the art.
  • treating and “treatment”, and the like, as used herein, are intended to mean obtaining a desirable physiological, pharmacological, or biological effect, and includes prophylactic and therapeutic treatment.
  • the effect may result in the inhibition, attenuation, amelioration, or reversal of a sign, symptom orcause of a disorder, or disease, attributable to the disorder, or disease, which includes mental and psychiatric diseases and disorders.
  • Clinical evidence of the prevention or treatment may vary with the disorder, or disease, the subject, and the selected treatment.
  • pharmaceutically acceptable refers to materials, including excipients, carriers, diluents, counterions or auxiliary agents, that are compatible with other materials in a pharmaceutical or recreational drug formulation and within the scope of reasonable medical judgement suitable for use in contact with a subject without excessive toxicity, allergic response, irritation, or other adverse response commensurate with a reasonable risk/benefit ratio.
  • substantially pure and “isolated”, as may be used interchangeably herein describe a compound, e.g., a mescaline derivative, which has been separated from components that naturally accompany it.
  • a compound is substantially pure when at least 60%, more preferably at least 75%, more preferably at least 90%, 95%, 96%, 97%, or 98%, and most preferably at least 99% of the total material (by volume, by wet or dry weight, or by mole percent or mole fraction) in a sample is the compound of interest.
  • Purity can be measured by any appropriate method, e.g., in the case of polypeptides, by chromatography, gel electrophoresis or HPLC analysis.
  • the present disclosure relates to mescaline derivatives.
  • the present disclosure provides novel phosphorylated and sulfonated mescaline derivatives.
  • the herein provided compositions exhibit functional properties which deviate from the functional properties of mescaline.
  • the phosphorylated and sulfonated mescaline derivatives can exhibit pharmacological properties which deviate from mescaline, including, for example, with respect to interaction the derivatives with receptors, such as the HT2a receptor or HTia receptor.
  • the mescaline derivatives may exhibit physico-chemical properties which differ from mescaline.
  • mescaline derivatives may exhibit superior solubility in a solvent, for example, an aqueous solvent.
  • the mescaline derivatives in this respect are useful in the formulation of pharmaceutical and recreational drug formulations.
  • the mescaline derivatives of the present disclosure can conveniently be synthetically produced. The practice of this method avoids the extraction of mescaline from cactus plants and the performance of subsequent chemical reactions to achieve mescaline derivatives. Furthermore, the growth of cactus plants can be avoided thus limiting the dependence on climate and weather, and potential legal and social challenges associated with the cultivation of cactus plants containing psychoactive compounds. The method can efficiently yield substantial quantities of the mescaline derivatives.
  • the present disclosure provides derivatives of a compound known as mescaline of which the chemical structure is shown in FIG. 1.
  • the derivatives herein provided are, in particular, sulfonated and phosphorylated derivatives.
  • the present disclosure provides, in accordance with the teachings herein, in at least one embodiment, a chemical compound having chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H;
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3- 10-membered heterocyclic ring.
  • the present disclosure provides sulfonated and phosphorylated chemical compounds which are derivatives of mescaline, notably derivatives having chemical formula (I), wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group.
  • X2, X3 and X4 can be H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group or a glycosyloxy group, wherein 1 to 3 of X2, X3 and X4, can be a phosphate group or a sulfate group, bonded to carbon atoms C3, C4 and Cs, respectively.
  • Xi and Xs can be hydrogen atoms.
  • Xi, X3 and X4 can be H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi , X3 and X4, can be a phosphate group or a sulfate group, bonded to carbon atoms C2, C4 and Cs, respectively.
  • X2 and X5 can be hydrogen atoms.
  • Xi, X2 and X3 can be H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi , X2 and X3, can be a phosphate group or a sulfate group, bonded to carbon atoms C2, C3 and C4, respectively.
  • X4 and Xs can be hydrogen atoms.
  • Xi, X3 and Xs can be H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi , X3 and Xs, can be a phosphate group or a sulfate group, bonded to carbon atoms C2, C4 and Cs, respectively.
  • X2 and X4 can be hydrogen atoms.
  • Xi, X2 and X4 can be H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi , X2 and X4, can be a phosphate group or a sulfate group, bonded to carbon atoms C2, C3 and Cs, respectively.
  • X3 and Xs can be hydrogen atoms.
  • FIGS. 3B, 3D, 3F, 3H, and 3J the positive charge on the nitrogen atom is counterbalanced with an anion (M _ ).
  • M _ an anion
  • the compounds of the present disclosure are zwitterionic, and a counterbalancing ion (M _ ) may not be required.
  • FIG. 3K shown therein is substantively the chemical compound of FIG. 3B wherein X3 has been selected to be a sulfate group.
  • the chemical compound in FIG. 3K is a zwitterionic compound.
  • Xi can be a sulfate group.
  • X3 and X5 can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi can be a phosphate group.
  • X3 and X5 can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • X3 can be a sulfate group.
  • Xi and Xs can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • X3 can be a phosphate group.
  • Xi and X5 can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • X5 can be a sulfate group.
  • Xi and X3 can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xs can be a phosphate group.
  • Xi and X3 can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi and X3 can each be a sulfate group.
  • Xs can be selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi and X3 can each be a phosphate group.
  • Xs can be selected from a hydrogen atom, an O- alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi and Xs can each be a sulfate group.
  • X3 can be selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi and Xs can each be a sulfate group.
  • X3 can be selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • X3 and Xs can each be a sulfate group.
  • Xi can be a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • X3 and Xs can each be a phosphate group.
  • X3 can be a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • X3 can be a phosphate group
  • Xs can be a sulfate group
  • Xi can be a hydrogen atom, an O- alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • X3 can be a sulfate group, and Xs can be a phosphate group.
  • Xi can be a hydrogen atom, an O- alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi can be a sulfate group
  • Xs can be a phosphate group
  • X3 can be a hydrogen atom, an O- alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi can be a phosphate group
  • Xs can be a sulfate group
  • X3 can be a hydrogen atom, an O- alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi, X3 and Xs can each be a phosphate group.
  • Xi, X3 and Xs can each be a sulfate group.
  • Xi can be a sulfate group, and X3 and Xs can each be a phosphate group.
  • Xi and X4 can be a phosphate group and X3 can each be a sulfate group.
  • Xi and X3 can be a sulfate group, and Xs can be a phosphate group.
  • Xi and X5 can be a sulfate group and Xs can each be a phosphate group.
  • the ionic phosphate and sulfate groups include positively charged cations. Whether such cations are included in the chemical compounds of the present disclosure can depend on, for example, whether the compounds possess other positively charged substituents. Thus, for example, as herein described, depending on the selection of substituents, the nitrogen atom (N) of the ethylamino chains, in some embodiments, be positively charged. Such positive charge may obviate the need for a cation to counterbalance ionic sulfate of phosphate groups.
  • a covalent bond may be formed between a negatively charged oxygen atom of a phosphate or sulfate group and another atom, thus eliminating a negative charge.
  • the phosphate group may in other embodiments be HRCU- or H2PO4, instead of PO4 2 ' , as shown in FIGS. 4B, 4D, 4F, 4H, 4J, 4L, 4P - 4Q, 4S - 4V, orthe sulfate group in other embodiments, may be HSO4, instead of SO4; as shown in FIGS. 4A, 4C, 4E, 4G, 4I, 4K, 4N - 4P, 4R - 4V.
  • the phosphate or sulfate group can be an ionic phosphate or sulfate group and can form a phosphate or sulfate salt counterbalanced by a cation.
  • the phosphate or sulfate group can be an ionic phosphate or ionic sulfate group and can form a phosphate or sulfate salt counterbalanced by a mono-valent, bi-valent, tri-valent, or tetra-valent cation.
  • the phosphate group can be an ionic phosphate group and can form a phosphate salt with a mono-valent cation (Z + ), including any pharmaceutically acceptable monovalent cation, the salt having the formula: HPCU- Z + .
  • the phosphate group can be an ionic phosphate group and can form a phosphate salt with a mono-valent cation (Z + ), the phosphate salt having the formula: (PO4 2 ')(Z + )2.
  • the sulfate group can be an ionic sulfate group and can form a sulfate salt with a monovalent cation (Z + ), including any pharmaceutically acceptable monovalent cation, the sulfate salt having the formula: SO Z + .
  • a monovalent cation can be selected from Na + , K + , NH4 + , tetra-n-butyl ammonium ([N(C4H9)4] + ), and triethyl ammonium (Et 3 NH 4 + ).
  • the phosphate group can be an ionic phosphate group and can form a phosphate salt with a divalent cation (Z 2+ ), including any pharmaceutically acceptable divalent cation, the phosphate salt having the formula: PO4 2 ' Z 2+ .
  • the phosphate group can be an ionic phosphate group and can form a phosphate salt with a divalent cation (Z 2+ ), the salt having the formula (HPO4')2 Z 2+ , wherein the second ionic phosphate group (/.e., the second of the two (HPCU-) groups) is a phosphate substituent of a second molecule of the compound having formula (I).
  • a salt can for, example, have the chemical formula the formula (IV a ):
  • the sulfate group can be an ionic sulfate group and can form a sulfate salt with a divalent cation (Z 2+ ), the salt having the formula (SO4')2 Z 2+ , wherein the second ionic sulfate group (SO4‘) (/.e., the second of the two (SO 4 -) groups) is a sulfate substituent of a second molecule of the compound having formula (I).
  • SO4‘ the second of the two (SO 4 -) groups
  • a salt can for, example, have the chemical formula the formula (V a ):
  • a bivalent cation (Z 2+ ) can be selected from Mg 2+ and Ca 2+ .
  • a trivalent cation for example, a trivalent metallic cation, such as Cr 3+ or Fe 3+ , or tetravalent cation (Z 4+ ), for example, a tetravalent metallic cation, such as Ti 4+ or Si 4+ may be used to counterbalance ionic phosphate or sulfate groups.
  • FIGS. 4A - 4V Xi, X3 and Xs are bonded to carbon atoms C2, C4 and Ce, respectively. Furthermore, X2 and X4 are hydrogen atoms.
  • the compounds shown in FIGS. 4A - 4V correspond with the compound shown in FIG. 3G. It is to be clearly understood, that, in this respect, FIGS. 4A - 4V represent example embodiments. Similarly, in further example embodiments, in accordance with the present disclosure, in each of the mescaline derivative compounds shown in FIGS.
  • any one, any two, or any three of Xi, X2, X3, X4 and X5 can be a phosphate or sulfate groups, wherein the Xi, X2, X3, X4, and X5 groups which are not a sulfate group or phosphate group, can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, and wherein two of Xi, X2, X3, X4, and X5 are a hydrogen atom.
  • Xi, X2, X3, X4 and X5 groups can be a hydrogen atom, an O-alkyl group, an O-acyl group , a hydroxy group or a glycosyloxy group.
  • O-alkyl groups include, without limitation, methoxy groups (-OCH3), ethanoxy groups (-OC2H5), propoxy groups (-OC3H7) and butanoxy groups (-OC4H9).
  • O-acyl groups include, without limitation, acetoxy groups (-OCOCH3), propoxy groups (- OCOCH2CH3) and butanoxy groups (-OCOCH2CH2CH3).
  • glycosyl groups in accordance with the present disclosure, can be any glycosyl group, including a mono-, di-, tri- oligo- or a poly-saccharide group, bonded from the anomeric carbon, either in the pyranose or furanose form, either in the a- or the p-conformation.
  • the glycosyl group may also be substituted with various groups.
  • substitutions may include lower alkyl, lower alkoxy, acyl, carboxy, carboxyamino, amino, acetamido, halo, thio, nitro, keto, and phosphatyl groups.
  • Such substitutions may be at one or more positions on the saccharide.
  • the glycosyl group is a D-glucosyl group, D- fructosyl group, D-mannosyl group, D-ribosyl group, D-talosyl groups, D-lyxosyl group, D-allosyl group, D-altrosyl group, D-gulosyl group, D-isosyl group, D- quinovosyl group, D-maltosyl group, D-cellobiosyl group, D-lactosyl group, D- maltotiosyl group, D-glucuronic acid group, D-galactosyl group, D-fucosyl group, D-xylosyl group, D-arabinosyl group, or a D-rhamnosyl group.
  • the glycosyl group is an L-glucosyl group, L- fructosyl group, L-mannosyl group, L-ribosyl group, L-talosyl groups, L-lyxosyl group, L-allosyl group, L-altrosyl group, L-gulosyl group, L-isosyl group, L- quinovosyl group, L-maltosyl group, L-cellobiosyl group, L-lactosyl group, L- maltotiosyl group, L-glucuronic acid group, L-galactosyl group, L-fucosyl group, L- xylosyl group, L-arabinosyl group, or a L-rhamnosyl group.
  • X3 is a sulfate group, and Xi and Xs are each a hydroxy group.
  • X3 is a phosphate group
  • Xi and X5 are each a hydroxy group.
  • X3 is a sulfate group, and Xi and Xs are each a methoxy group.
  • X3 is a phosphate group, and Xi and X5 are each a methoxy group.
  • X3 is a sulfate group, and Xi and Xs are each an acetoxy group.
  • X3 is a phosphate group
  • Xi and X5 are each an acetoxy group.
  • X3 is a sulfate group
  • Xi is an ethoxy group
  • Xs is a hydroxy group
  • X3 is a sulfate group
  • Xi is an ethoxy group
  • Xs is a hydroxy group
  • X3 is a sulfate group
  • Xi is a hydroxy group
  • Xs is a propoxy group
  • X3 is a phosphate group
  • Xi is a hydroxy group
  • Xs is a propoxy group
  • X3 is a sulfate group, and Xi is an acetoxy group and Xs are each a propoxy group.
  • X3 is a phosphate group, and Xi is an acetoxy group and Xs are each a propoxy group.
  • FIGS. 5A- 5L Xi, X3 and Xs are bonded to carbon atoms C2, C4 and Ce, respectively. Furthermore, X2 and X4 are hydrogen atoms.
  • the compounds shown in FIGS. 5A - 5L correspond with the compound shown in FIG. 3G.
  • X3 is a sulfonyl or a phosphate group.
  • the compounds shown in FIGS. 5A - 5L correspond with the compound shown in FIG. 4B. It is to be clearly understood, that, in this respect, FIGS.
  • any one, any two, or all three of Xi , X2, X3, X4 and X5 can be phosphate group or sulfate group, wherein Xi, X2, X3, X4 and X5 groups which are not a phosphate group or sulfate group, can be independently selected from a hydroxy group, an O-alkyl group, an O-acyl group, or a glycosyloxy group.
  • any one of Xi, X3, and X5 can be independently selected from a hydroxy group, an O-alkyl group, an O-acyl group or a glycosyloxy group.
  • W in the chemical compound having formula (I), in one embodiment, W can be -N(R4)(Rs), and R4 and Rs can be independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring.
  • R4 and Rs are each a hydrogen atom.
  • R4 and Rs are each an ethyl group or methyl group, respectively.
  • R4 is a hydrogen atom and Rs is a methyl group.
  • R4 and Rs are joined together and form a 6-member heterocyclic ring (piperidine ring).
  • W can be -N + (R6)(R7)(Rs), and Re, R7 and Rs can independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring.
  • W when W is N + (Re)(R7)(Rs), the compound of formula (I) includes a pharmaceutically acceptable anion.
  • the compounds of the present disclosure may be zwitterionic, due to the presence of a negative charge on the phosphate or sulfate group (and the positive charge on the nitrogen atom).
  • compounds, (III) and (IV) herein are zwitterionic compounds.
  • Re, R? and Rs are each a hydrogen atom.
  • Re and R? are each a hydrogen atom, and Rs, is an ethyl group.
  • Re and R? are each an ethyl group, and Rs, is a hydrogen atom group.
  • Re and R? are joined together and form a 6-member heterocyclic ring (piperidine ring), and Rs is a hydrogen atom.
  • the positively charged nitrogen atom in the phenylethylamine chain is not counterbalanced by an exogenous cation. Instead, the positively charged nitrogen atom is counterbalanced by the ionic phosphate or sulfate groups these compounds possess.
  • the negatively charged anions and positively charged cations (which may be denoted herein as M- (see: e.g., FIGS. 3H - 3J) and Z + (see: e.g., FIGS. 6G - 6H), respectively), can vary in different embodiments provided by the present disclosure.
  • the corresponding counterion (cation or anion) is a pharmaceutically acceptable ion.
  • Suitable cations include a potassium ion (K + ), sodium ion (Na + ), calcium ion (Ca 2+ ), magnesium ion (Mg 2+ ), ammonium ion (NH4 + ), tetra-n-butyl ammonium ion ([N(C4H9)4] + ), or triethyl ammonium ion (EtsNH4 + ), for example.
  • Xi, X3 and Xs are bonded to carbon atoms C2, C4 and Ce, respectively.
  • X2 and X4 are hydrogen atoms.
  • the compounds shown in FIGS. 6A - 6H and 7A - 7H correspond with the compound shown in FIG. 3G and FIG. 3H, respectively.
  • X3 is a sulfate group or a phosphate group.
  • the compounds shown in FIGS. 6A - 6H and 7A - 7H correspond with the compound shown in FIG. 4C and FIG. 4D.
  • Xi is an ethoxy group and X5 is a hydroxyl group.
  • the compounds shown in FIGS. 6A - 6H and 7A - 7H correspond with the compound shown in FIGS. 5G and 5H. It is to be clearly understood, that, in this respect, the compounds shown in FIGS. 6A - 6H and 7A - 7H represent example embodiments.
  • any one, any two, or all three of Xi , X2, X3, X4 and X5 can be phosphate or sulfate groups, wherein the Xi, X2, X3, X4 and X5 groups which are not a sulfate group, can be independently selected from a hydroxy group, an O- alkyl group, an O-acyl group or a glycosyloxy group.
  • any one of Xi, X3, and Xs can be independently selected from a hydroxy group, an O- alkyl group, an O-acyl group or a glycosyloxy group.
  • W can be -N(R4)( S), and the R4 and Rs groups are joined to form a heterocyclic ring, or W can be -N + (R6)(R7)(Rs), and two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring.
  • the R4 and Rs groups or two of Re, R7 and Rs can be joined together to form a 4-10-membered heterocyclic ring (counting the nitrogen atom), wherein one or more carbons in the ring may be substituted with O, or NRe, wherein R9 is a hydrogen atom, or an alkyl, aryl, or acyl group.
  • R4 and Rs are joined forming a 6 membered heterocyclic ring, and a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by an oxygen atom, forming a morpholinyl ring.
  • R4 and Rs are joined forming a 6 membered heterocyclic ring, and a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a hydrogen atom, forming a piperazine ring.
  • R4 and Rs are joined forming a 6 membered heterocyclic ring, and a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a methyl group, forming an N-methyl piperazine.
  • a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a methyl group, forming an N-methyl piperazine.
  • the methyl group represents an example of an alkyl group.
  • the nitrogen atom may be bonded to other alkyl groups.
  • R4 and Rs are joined forming a 6 membered heterocyclic ring, and a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to an acetyl group, forming an N-acetyl piperazine.
  • the acetyl group represents an example of an acyl group.
  • the nitrogen atom may be bonded to other acyl groups.
  • the compound further includes a negatively charged anion (M-) balancing the positively charged nitrogen atom.
  • M- negatively charged anion
  • Example embodiments in this respect are shown in FIGS. 8K - 8T.
  • the negatively charged anion can vary in different embodiments, and includes a potassium ion, a sodium ion, and an ammonium ion, for example.
  • Re and R? are joined forming a 6 membered heterocyclic ring, and a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by an oxygen atom, forming a morpholinyl ring, and Rs is a hydrogen atom.
  • Re and R? are joined forming a 6 membered heterocyclic ring a 6 membered ring, and a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a hydrogen atom forming a piperazine ring, and Rs is a hydrogen atom.
  • Re and R? are joined forming a 6 membered heterocyclic ring, and a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to a methyl group, forming an N-methyl piperazine ring, and Rs is a hydrogen atom.
  • the methyl group represents an example of an alkyl group.
  • the nitrogen atom may be bonded to other alkyl groups.
  • Re and R? are joined forming a 6 membered heterocyclic ring, and a carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom bonded to an acetyl group, forming an N-acetyl piperazine ring, and Rs is an N- acetyl piperazine ring.
  • the acetyl group represents an example of an acyl group.
  • the nitrogen atom may be bonded to other acyl groups.
  • Re and R? are joined forming a 6 membered heterocyclic ring
  • a first carbon atom (together with its hydrogen atoms, relative to piperidine) is substituted by a nitrogen atom
  • the nitrogen atom and a second carbon atom are further joined to form a 5 membered heterocyclic ring, forming an octohydropyrrolopyrazine
  • Rs is a hydrogen atom
  • the 5-membered heterocyclic group represents an example of an aryl group.
  • the nitrogen atom may be bonded to other aryl groups.
  • examples compounds in accordance with formula (I) are provided. These include compounds having the chemical formula: (III); (IV); and (V), as hereinafter depicted.
  • the present disclosure provides a compound having chemical formula (III):
  • the present disclosure provides a compound having chemical formula (IV): [00214] In a further example embodiment, the present disclosure provides a compound having chemical formula (V): wherein, Z +/2+ is a mono or divalent cation balancing the negatively charged sulfate group, forming a salt having the formula
  • the present disclosure provides a chemical compound selected from (Vb); (V c ); (Vd); (V e ); (Vf); (V g ); and (Vh):
  • the present disclosure relates to phosphorylated or sulfonated mescaline derivatives.
  • the present disclosure provides, in particular, a chemical compound or salt thereof having formula (I): wherein,
  • Xi, X2, X3, X 4 , and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H; W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 ); (i) R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring.
  • Xi, X2, X3, X4, or Xs can be an O-alkyl group, Ci-C2o)-0-alkyl group, (Ci-Cw)-O-alkyl group, (Ci-Ce)-O-alkyl group, or (Ci-Cs)-O- alkyl group (-OC3H7 (O-propyl; propoxy); -OC2H5 (O-ethyl; ethoxy); or -OCHs (O- methyl; methoxy)).
  • R4, Rs, Re, R7, or Rs can be an alkyl group, (C1- C2o)-alkyl group, (Ci-Cw)-alkyl group, (Ci-Ce)-alkyl group, or (Ci-C3)-alkyl group (- CH2CH2CH3 (propyl); -CH2CH3 (ethyl); or -CH 3 (methyl)).
  • R4 or Rs or any two of Re, R7, or Rs can be a joined together to form a 3-10 membered heterocyclic ring, a 3-9 membered heterocyclic ring, or a 3-6 membered heterocyclic ring.
  • Example compounds in accordance with example embodiments, in his respect, include each of compounds (III); (IV); (V); (Vb); (V c ); (Vd); (V e ); (Vf); (V g ); and (V h ).
  • the phosphorylated or sulfonated mescaline derivatives of the present disclosure may be used to prepare a pharmaceutical or recreational drug formulation.
  • the present disclosure further provides in another aspect, pharmaceutical and recreational drug formulations comprising sulfonated and phosphorylated mescaline derivatives.
  • the present disclosure provides in a further embodiment a pharmaceutical or recreational drug formulation comprising a chemical compound having chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H;
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring, together with a diluent, carrier, or excipient.
  • the pharmaceutical or recreational drug formulations may be prepared as liquids, tablets, capsules, microcapsules, nanocapsules, trans-dermal patches, gels, foams, oils, aerosols, nanoparticulates, powders, creams, emulsions, micellar systems, films, sprays, ovules, infusions, teas, decoctions, suppositories, etc. and include a pharmaceutically acceptable salt or solvate of the sulfonated and phosphorylated mescaline derivative compound together with an excipient.
  • excipient as used herein means any ingredient other than the chemical compound of the disclosure.
  • excipient may depend on factors such as the particular mode of administration, the effect of the excipient on solubility of the chemical compounds of the present disclosure and methods for their preparation will be readily apparent to those skilled in the art.
  • Such compositions and methods for their preparation may be found, for example, in “Remington’s Pharmaceutical Sciences”, 22 nd Edition (Pharmaceutical Press and Philadelphia College of Pharmacy at the University of the Sciences, 2012).
  • compositions comprising the sulfonated and phosphorylated mescaline derivatives of the present disclosure may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include both solid and liquid formulations.
  • Solid formulations include tablets, capsules (containing particulates, liquids, microcapsules, or powders), lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solutions, liposomal preparations, microencapsulated preparations, creams, films, ovules, suppositories, and sprays.
  • Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. [00229] Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate di hydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch and dibasic calcium phosphate di hydrate.
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80.
  • surface active agents may comprise from 0.2% (w/w) to 5% (w/w) of the tablet.
  • Tablets may further contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate.
  • Lubricants generally comprise from 0.25% (w/w) to 10% (w/w), from 0.5% (w/w) to 3% (w/w) of the tablet.
  • tablets may contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from 1 % (w/w) to 25% (w/w) or from 5% (w/w) to 20% (w/w) of the dosage form.
  • auxiliary ingredients include anti-oxidants, colourants, flavouring agents, preservatives, and taste-masking agents.
  • the chemical compound of the present disclosure may make up from 1 % (w/w) to 80 % (w/w) of the dosage form, more typically from 5% (w/w) to 60% (w/w) of the dosage form.
  • Exemplary tablets contain up to about 80% (w/w) of the chemical compound, from about 10% (w/w) to about 90% (w/w) binder, from about 0% (w/w) to about 85% (w/w) diluent, from about 2% (w/w) to about 10% (w/w) disintegrant, and from about 0.25% (w/w) to about 10% (w/w) lubricant.
  • the pharmaceutical and recreational drug formulations comprising the sulfonated and phosphorylated mescaline derivatives of the present disclosure may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • the pharmaceutical and recreational drug formulations can be administered parenterally (for example, by subcutaneous, intravenous, intraarterial, intrathecal, intraventricular, intracranial, intramuscular, or intraperitoneal injection).
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffering agents (in one embodiment, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile water.
  • Formulations comprising the sulfonated and phosphorylated mescaline derivatives of the present disclosure for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the chemical compounds of the disclosure may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
  • the pharmaceutical or recreational drug formulations of the present disclosure also may be administered topically to the skin or mucosa, i.e., dermally, or transdermally.
  • Example pharmaceutical and recreational drug formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, cosmetics, oils, eye drops, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Example carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporate (see: for example, Finnin, B. and Morgan, T.M., 1999 J. Pharm. Sci, 88 (10), 955-958).
  • Topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g., PowderjectTM, BiojectTM, etc.) injection.
  • Pharmaceutical and recreational drug formulations for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid pharmaceutical compositions can contain suitable pharmaceutically acceptable excipients.
  • the pharmaceutical compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Pharmaceutical compositions in pharmaceutically acceptable solvents can be nebulized by use of inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder pharmaceutical compositions can be administered, e.g., orally, or nasally, from devices that deliver the formulation in an appropriate manner.
  • the compounds may be included in compositions such as a food or food product, a beverage, a food seasoning, a personal care product, such as a cosmetic, perfume or bath oil, or oils (both for topical administration as massage oil, or to be burned or aerosolized).
  • the chemical compounds of the present disclosure may also be included in a “vape” product, which may also include other drugs, such as nicotine, and flavorings.
  • the compounds may be metabolized by the subject, and converted into other chemical entities.
  • the compounds may be hydrolyzed, and phosphate or sulfate groups may be removed from the compounds, for example, by an endogenously present phosphatase or sulfatase.
  • the pharmaceutical formulations comprising the chemical compounds of the present disclosure may be used to treat a subject, and in particular to treat a psychiatric disorder in a subject.
  • the present disclosure includes in a further embodiment, a method for treating a brain neurological disorder or psychiatric disorder, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising a chemical compound having chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H;
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R? and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3- 10-membered heterocyclic ring, together with a diluent, carrier, or excipient.
  • the phosphorylated and sulfonated mescaline derivative compounds may be used as a pharmaceutical or recreational drug. Accordingly, in another aspect the present disclosure provides, in at least one embodiment, a use of a chemical compound or salt thereof having a chemical formula (I): wherein,
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H; and wherein
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10- membered heterocyclic ring.
  • Brain neurological disorders include psychiatric disorders that may be treated for example, neurodevelopmental disorders such as intellectual disability, global development delay, communication disorders, autism spectrum disorder, and attention-deficit hyperactivity disorder (ADHD); bipolar and related disorders, such as mania, and depressive episodes; anxiety disorder, such as generalized anxiety disorder (GAD), agoraphobia, social anxiety disorder, specific phobias (natural events, medical, animal, situational, for example), panic disorder, and separation anxiety disorder; stress disorders, such as acute stress disorder, adjustment disorders, post-traumatic stress disorder (PTSD), and reactive attachment disorder; dissociative disorders, such as dissociative amnesia, dissociative identity disorder, and depersonalization/derealization disorder; somatoform disorders, such as somatic symptom disorders, illness anxiety disorder, conversion disorder, and factitious disorder; eating disorders, such as anorexia nervosa, bulimia nervosa, rumination disorder, pica, and binge-eating disorder; sleep disorders, such as narcolepsy
  • Brain neurological disorders further include headache disorders, including migraines, including, for example, aural migraine
  • the compounds of the present disclosure may be used to be contacted with a receptor to thereby modulate the receptor.
  • Such contacting includes bringing a compound of the present disclosure and receptor together under in vitro conditions, for example, by introducing the compounds in a sample containing a receptor, for example, a sample containing purified receptors, or a sample containing cells comprising receptors.
  • In vitro conditions further include the conditions described in Example 1 hereof.
  • Contacting further includes bringing a compound of the present disclosure and receptor together under in vivo conditions.
  • Such in vivo conditions include the administration to an animal or human subject, for example, of a pharmaceutically effective amount of the compound of the present disclosure, when the compound Is formulated together with a pharmaceutically active carrier, diluent, or excipient, as hereinbefore described, to thereby treat the subject.
  • the compound Upon having contacted the receptor, the compound may activate the receptor or inhibit the receptor.
  • receptors with which the compounds of the present disclosure may be contacted include, the HT2A or HTi A receptors.
  • the mescaline derivatives of the present disclosure may bind to a variety of receptors, 5-HT2A and 5-HTIA receptors are considered to be particularly relevant because in vitro agonism of mescaline, and certain mescaline derivatives at these receptors has been correlated with key effects of drug action(s).
  • the mescaline derivative and therapeutic agent 3,4-methylenedioxy- methamphetamine (MDMA) is a 5-HT2A receptor agonist (Simmler et al., 2013, British J. Pharmacol. 168: 458), and this effect is thought to be responsible for the MDMA-induced mesolimbic dopamine release (Dunlap et al., 2018, ACS Chem. Neurosci. 9: 2408).
  • MDMA is also a 5-HTIA receptor agonist (Simmler et al., 2013, British J. Pharmacol. 168: 458; mescaline, Rickli et al., 2016, Eur. Neuropharm. 26: 1327) and even micromolar in vitro Kivalues for MDMA at 5-HTiA appear to be physiologically relevant.
  • MDMA administration results in a postsynaptic upregulation of the 5-HTIA receptor in the cortex and hypothalamus that is noticeable 1 week after acute administration (Inserra et al., 2020, Pharmacol. Rev. 73: 202). Furthermore, MDMA is a therapeutic agent used in U.S. -based clinical trials for the treatment of post-traumatic stress disorder (PTSD), anxiety and other neuropathologies (Dunlap et al., 2018, ACS Chem. Neurosci .9: 2408).
  • PTSD post-traumatic stress disorder
  • mescaline and certain mescaline derivatives 4-Bromo-2,5-dimethoxyphenethylamine (2C-B), escaline, and proscaline.
  • Mescaline’s effects are attributed in large part to its action as a 5-HT2A serotonin receptor agonist, although mescaline binds in a similar concentration range to 5-HT IA prompting recent consideration of 5-HT IA as an additional key target (Cassels and Saez-Briones, 2018, ACS Chem. Neurosci. 9: 2448).
  • assays for determining receptor binding of a given compound include ligand competition assays with an established radiolabeled ligand, resulting in a Ki value. Additional assays may be performed wherein positive and negative controls with pre-determined Ki values are titrated to cell cultures with engineered ‘receptor response systems.’
  • condition that may be treated in accordance herewith can be any receptor mediated disorder, including, for example, an HT2A receptor-mediated disorder or HTIA receptor-mediated disorder.
  • HT2A receptor-mediated disorder or HTIA receptor-mediated disorder.
  • disorders include, anxiety, depression, schizophrenia, and PTSD, for example.
  • the compound upon having contacted a receptor, may modulate the receptor. However, at the same time other receptors may not be modulated.
  • a compound may activate or inhibit a first receptor, however the compound may at the same time not modulate a second receptor, or upon having contacted a first receptor and a second receptor, the compound may modulate the first receptor, however the compound may at the same time not modulate the second receptor.
  • the sulfonated and phosphorylated mescaline derivatives of the present disclosure may be prepared in any suitable manner, including by any organic chemical synthesis methods, biosynthetic methods, or a combination thereof.
  • One suitable method of to making the sulfonated and phosphorylated mescaline derivatives of the present disclosure initially involves selecting and obtaining or preparing a precursor compound of the phosphorylated or sulfonated mescaline derivative compound and a phosphor-oxidous or a sulfur- oxidous compound and reacting the precursor compound and the phosphor- oxidous compound or sulfur-oxidous compound to obtain the phosphorylated and sulfated mescaline derivatives of the present disclosure.
  • Suitable precursor compounds include compounds comprising the prototype structure shown in FIG. 2, including, for example, in an embodiment, a chemical compound having the formula (II): wherein,
  • Xi, X2, X3, X4, and Xs are H, a reactive group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and X5 are a reactive group, and two of Xi, X2, X3, X4, and X5 are H;
  • W is -CN(R 4 )(R 5 ) or -CN + (R 6 )(R7)(R 8 ) or COOH;
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or
  • Re, R7 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R7 and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring.
  • FIGS. 10A, 10B, 10C, 11, 12, and 13 Examples of suitable chemical reactions that may be performed in accordance herewith are depicted in FIGS. 10A, 10B, 10C, 11, 12, and 13, and are hereinafter further detailed, including in the Example section.
  • the precursor compound of the sulfonated or phosphorylated mescaline derivative may be provided in a more or less chemically pure form, for example, in the form of a hydroxy-containing mescaline derivative preparation having a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9%.
  • the precursor compound of the sulfonated or phosphorylated mescaline derivative mescaline derivative may be chemically synthesized or obtained from a fine chemical manufacturer.
  • any phosphor-oxidous compounds and sulfur-oxidous compounds may be selected, obtained, or prepared, for example, using a suitably protected phenolic derivative which is then subjected to either a phosphorylation or sulfation on the available hydroxyl group(s) on the benzene ring.
  • Suitable sulfur-oxidous compounds that may be used in this respect include, for example, pyridinium sulfur trioxide and tetrabutylammonium hydrogen sulfate, and suitable phosphorus-oxidous compounds that may be used in this respect include, for example, tetra-O-benzyl pyrophosphate, and dibenzyl chlorophosphite.
  • a precursor compound of the sulfonated or phosphorylated mescaline derivative is provided, and the precursor compound of the sulfonated or phosphorylated mescaline derivative and sulfur- oxidous or phosphor-oxidous compound are contacted to react in a chemical reaction resulting in the formation of a phosphorylated or sulfonated mescaline derivative compound.
  • the phosphor-oxidous compound or sulfur-oxidous compound may be provided in a more or less chemically pure form, for example, in the form of a phosphate or sulfate compound preparation having a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9%.
  • the phosphor-oxidous compound or sulfur-oxidous compound may be chemically synthesized or obtained from a fine chemical manufacturer.
  • one, two or three of Xi, X2, X3, X4, and X5 in compound (II) can be hydroxy groups, O-alkyl groups, or hydrogen atoms.
  • one, two or three of X2, X3 and X4 in compound (II) can be a hydroxy group, wherein when (i) one of X2, X3, and X4, is an hydroxy group, the other two of X2, X3 and X4 are independently selected from a glycosyloxy group, an O-alkyl group, an O-acyl group, and each of Xi and X5 are a hydrogen atom, (ii) when two of X2, X3, and X4, are an hydroxy group, the other one of X2, X3 and X4 is selected from a glycosyloxy group an O-alkyl group, an O- acyl group, and each of Xi, and X5 are a hydrogen atom, and (iii) when three of X2, X3, and X4, are an hydroxy group, each of Xi, and X5 are a hydrogen atom.
  • one, two or three of Xi, X3 and X4 in compound (II) can be a hydroxy group, wherein when (i) one of Xi, X3, and X4, is an hydroxy group, the other two of Xi, X3 and X4 are independently selected from a glycosyloxy group, an O-alkyl group, an O-acyl group, and each of X2 and X5 are a hydrogen atom, (ii) when two of Xi, X3, and X4, are an hydroxy group, the other one of Xi, X3 and X4 is selected from a glycosyloxy group an O-alkyl group, an O- acyl group, and each of X2, and X5 are a hydrogen atom, and (iii) when three of Xi, X3, and X4, are an hydroxy group, each of X2, and X5 are a hydrogen atom.
  • one, two or three of Xi, X2 and X3 in compound (II) can be a hydroxy group, wherein when (i) one of Xi, X2, and X3, is an hydroxy group, the other two of Xi, X2 and X3 are independently selected from a glycosyloxy group, an O-alkyl group, an O-acyl group, and each of X4 and X5 are a hydrogen atom, (ii) when two of Xi, X2, and X3, are an hydroxy group, the other one of Xi, X2 and X3 is selected from a glycosyloxy group an O-alkyl group, an O- acyl group, and each of X4, and X5 are a hydrogen atom, and (iii) when three of Xi, X2, and X3, are an hydroxy group, each of X4, and X5 are a hydrogen atom.
  • one, two or three of Xi, X3 and X5 in compound (II) can be a hydroxy group, wherein when (i) one of Xi, X3, and X5, is an hydroxy group, the other two of Xi, X3 and X5 are independently selected from a glycosyloxy group, an O-alkyl group, an O-acyl group, and each of Xi and X5 are a hydrogen atom, (ii) when two of Xi, X3, and X5, are an hydroxy group, the other one of Xi, X3 and X5 is selected from a glycosyloxy group an O-alkyl group, an O- acyl group, and each of X2, and X4 are a hydrogen atom, and (iii) when three of Xi, X3, and Xs, are an hydroxy group, each of X2, and X4 are a hydrogen atom.
  • one, two or three of Xi, X2 and X4 in compound (II) can be a hydroxy group, wherein when (i) one of Xi, X2, and X4, is an hydroxy group, the other two of Xi, X2 and X4 are independently selected from a glycosyloxy group, an O-alkyl group, an O-acyl group, and each of X3 and Xs are a hydrogen atom, (ii) when two of Xi, X2, and X4, are an hydroxy group, the other one of Xi, X2 and X4 is selected from a glycosyloxy group an O-alkyl group, an O- acyl group, and each of X3, and Xs are a hydrogen atom, and (iii) when three of Xi, X2, and X4, are an hydroxy group, each of X3, and Xs are a hydrogen atom.
  • R4 or Rs, or any two of Re, R7, or Rs groups can be joined together to form a 4-10-membered heterocyclic ring, wherein one or more carbons in the ring may be substituted with O, or NR9, wherein R9 is a hydrogen atom, or an alkyl, aryl or acyl group.
  • FIGS. 9A - 9G shown therein are example hydroxy-containing mescaline derivatives.
  • Xi can be a hydroxy group.
  • R2 and R3 can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • X3 can be a hydroxy group.
  • R1 and R3 can be independently selected from a hydrogen atom, an O-alkyl group, an acyl group, a hydroxy group, or a glycosyloxy group.
  • Xs can be a hydroxy group.
  • R1 and R2 can be independently selected from a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi and Xs can each be a hydroxy group.
  • R3 can be selected from a hydrogen atom, an O-alkyl group, an O- acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi and Xs can each be a hydroxy group.
  • R1 can be selected from a hydrogen atom, an O-alkyl group, an O- acyl group, a hydroxy group, or a glycosyloxy group.
  • X3 and Xs can each be a hydroxy group.
  • R1 can be a hydrogen atom, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group.
  • Xi, X3 and Xs can each be a hydroxy group.
  • FIGS. 9A - 9G Xi, X3 and Xs, in the chemical compound having chemical formula (II), are bonded to carbon atoms C2, C4 and Ce, respectively. Furthermore, X2 and X4 are hydrogen atoms.
  • the compounds shown in FIGS. 9A - 9G can be understood to correspond with the compound shown in FIG. 3G. It is further noted that the hydroxy-containing derivates shown in FIGS. 9A - 9G may be used to make the phosphorylated and sulfonate mescaline derivatives shown in FIGS. 4A - 4V, respectively. It is to be clearly understood, that, in this respect, FIGS.
  • mescaline derivative compounds shown in FIGS. 3A - 3F, and 3H - 3I may be selected, wherein any one, any two, or all three of Xi, X3 and X5 can be hydroxy groups, wherein the Xi, X3 and X5 groups which are not a hydroxy group, can be independently selected from a hydrogen atom, an alkyl group, or an acyl group. Any thus selected hydroxy-containing mescaline derivatives may all be used to make phosphorylated and sulfonated mescaline derivatives in accordance with the present disclosure.
  • FIG. 10A shows an example of chemical synthesis of monophosphorylated and sulfonated mescaline derivatives.
  • 1- O-tert-butyldiphenylsilyl-3,5-dimethoxyphenol (10A-1) as a starting material, a treatment with n-butyllithium can regio-selectively deprotonate the more accessible proton at C-4 to form the corresponding phenyllithium, which is subsequently quenched with DMF followed by a hydrolysis to form the corresponding aldehyde (10A-2). After another condensation with nitromethane, the corresponding 2-nitro-vinyl derivative 10A-3 is formed.
  • the conjugated alkene functionality is then reduced via sodium borohydride to provide compound 10A-4.
  • T 0 facilitate the installation of a sulfate or a phosphate
  • the O-tert-b uty Id i phe ny Isi ly I group is removed using tetra-n-butylammonium fluoride to form the corresponding phenolic derivative 10A-5.
  • the hydroxyl group of the phenol 10A-5 is reacted with pyridinium sulfur trioxide to install the 4-sulfate and the nitro functionality on the side chain is subsequently reduced by hydrogenation; after treating the obtained compound with an ion exchange resin such as the Amberlite IR-120 (Na + ), the desired mescaline derivative bearing a 4-O-sulfate 10A-6 is obtained.
  • an ion exchange resin such as the Amberlite IR-120 (Na + )
  • the phenol 10A-5 can be reacted with tetra-O-benzyl pyrophosphate to install a 4-O,O-dibenzylphosphate group (10A-7) which can be further subject to a catalytic hydrogenation to remove all the benzyl groups as well as the nitro functionality on the side chain, and the desired 4-O-phosphorylated mescaline derivative 10A-8 is obtained after a similar treatment of the obtained intermediate with Amberlite IR-120 (Na + ).
  • FIG. 10B depicts another example reaction sequence to prepare N,N-substituted mescaline derivatives that contain either a sulfate or phosphate.
  • 1-bromo-4-benzyloxy-2,6-dimethoxybenzene (10B-1) as a starting material, the bromide is first exchanged with n-buty llithium to form the corresponding phenyllithium that subsequently quenches with 1 ,2-epoxyethane for form the corresponding primary alcohol 10B-2.
  • the alcohol is then activated via a mesylation to form compound 10B-3 which subsequently undergoes a nucleophilic substitution with any substituted amines such as diethylamine to provide compound 10B-4.
  • the 4-O-benzyl is then removed by a catalytic hydrogenation to form the key phenol 10B-5.
  • the phenol 10B-5 is reacted with pyridinium sulfur trioxide to install the 4-sulfate, and after treating the obtained compound with Amberlite IR-120 (Na + ), the desired 4- O-monosulfated mescaline derivative 10B-6 is obtained.
  • the phenol 10B-5 is reacted with tetra-O-benzyl pyrophosphate to install a 4-O,O-dibenzylphosphate group (10B- 7).
  • a catalytic hydrogenation is carried out to remove all the benzyl groups and the desired 4-O-phosphorylated mescaline derivative 10B-8 is obtained after a similar treatment of the obtained intermediate with Amberlite IR-120 (Na + ).
  • FIG. 10C which further depicts a further example reaction sequence to synthesize the mescaline analogues containing multiple a 2- ethoxy group and either two phosphates or two sulfonates.
  • a 2- ethoxy group containing multiple a 2- ethoxy group and either two phosphates or two sulfonates.
  • tert-butyldiphenylsilyl chloride 2.0 equiv.
  • the remaining hydroxyl group is then alkylated with ethyl iodide to provide compound 10C-3.
  • a condensation is then carried out with nitromethane to form the corresponding 2-nitrovinyl derivative 10C-4, and the conjugated double bond is then reduced with sodium borohydride to afford compound 10C-5.
  • the two silyl protecting groups are then removed using tetra-n-butylammonium fluoride to provide the key phenol 10C-6.
  • the phenol 10C-6 is reacted with pyridinium sulfur trioxide to afford compound 10C-7.
  • the nitro functionality on the side chain is reduced by an appropriate condition, such as a catalytic hydrogenation, to provide the desired disulfate 10C-8 in the sodium form after a treatment with Amberlite IR-120 (Na + ).
  • the phenol 10C-5 is reacted with tetra-O-benzyl pyrophosphate to install two 4-O,O-dibenzylphosphate groups to provide compound 10C-9.
  • a catalytic hydrogenation is carried out to remove all the benzyl groups as well as the nitro functionality on the side chain.
  • the desired mescaline derivative 10C-10 is obtained.
  • Xi, X2, X3, X4, and Xs are H, a phosphate group, a sulfate group, an O-alkyl group, an O-acyl group, a hydroxy group, or a glycosyloxy group, wherein 1 to 3 of Xi, X2, X3, X4, and Xs are a phosphate group or a sulfate group, and two of Xi, X2, X3, X4, and Xs are H;
  • W is -N(R 4 )(R 5 ) or -N + (R6)(R7)(R 8 );
  • R4 and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or R4, and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3-10-membered heterocyclic ring; or (IV) Re, R? and Rs are independently or simultaneously H, an alkyl group, or an acyl group, or any two of Re, R? and Rs are joined together, along with the nitrogen atom to which they are attached, to form a 3- 10-membered heterocyclic ring, wherein the method involves performing at least one of the chemical synthesis reactions depicted in FIGS. 10A, 10B, 10C, 11 , 12, or 13.
  • the compound having formula (I) can be a compound having chemical formula (III): and the least one chemical synthesis reaction is selected from chemical reaction (d); (c) and (d); (b), (c), and (d); and (a), (b), (c), and (d) depicted in FIG. 11.
  • the reactions can be conducted under the conditions identified in FIG. 11 , and as described in further detail in Example 1 , however, as will be readily understood to those of skill in the art, the reaction conditions may be modified, to establish other conditions sufficient to conduct the noted reactions and obtain the desired product or intermediate product.
  • temperatures, reaction times, and other conditions may be varied, for example, by evaluating the obtained compounds under a series of different conditions (e.g., different temperatures, reaction times etc.), and selecting a preferred condition.
  • the compound having formula (I) can be a compound having chemical formula (IV): and the least one chemical synthesis reaction is selected from chemical reaction (d); (c) and (d); (b), (c), and (d); (a), (c), and (d); and (a), (b) (c), and (d) depicted in FIG. 12.
  • the reactions can be conducted under the conditions identified in FIG. 12, and as described in further detail in Example 2, however, as will be readily understood to those of skill in the art, the reaction conditions may be modified, to establish other conditions sufficient to conduct the noted reactions and obtain the desired product or intermediate product.
  • temperatures, reaction times, and other conditions may be varied, for example, by evaluating the obtained compounds under a series of different conditions (e.g., different temperatures, reaction times etc.), and selecting a preferred condition.
  • the compound having formula (I) can be a compound having chemical formula (Vb): and the least one chemical synthesis reaction is selected from chemical reaction (c); (b) and (c); and (a), (b), and (c) depicted in FIG. 13.
  • the reactions can be conducted under the conditions identified in FIG. 13, and as described in further detail in Example 3, however, as will be readily understood to those of skill in the art, the reaction conditions may be modified, to establish other conditions sufficient to conduct the noted reactions and obtain the desired product or intermediate product.
  • temperatures, reaction times, and other conditions may be varied, for example, by evaluating the obtained compounds under a series of different conditions (e.g., different temperatures, reaction times etc.), and selecting a preferred condition.
  • the reactants are reacted under reaction conditions which permit the reactants to chemically react with each other and form a product, i.e., the phosphorylated or sulfonated mescaline derivatives of the present disclosure.
  • reaction conditions may be selected, adjusted, and optimized as known by those of skill in the art.
  • the reactions may be conducted in any suitable reaction vessel (e.g., a tube, bottle).
  • suitable solvents that may be used are polar solvents such as, for example, dichloromethane, dichloroethane, toluene, and so-called participating solvents such as acetonitrile and diethyl ether.
  • Further suitable solvents that may be used are for example, water, alcohol (such as methanol, ethanol, tetrahydrofuran (THF), dichloromethane, acetone, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), or a combination of solvents.
  • Suitable temperatures may range from, for example, e.g., from about - 78 °C to about 100 °C.
  • catalysts also known as promoters, may be included in the reaction such as iodonium dicollidine perchlorate (IDCP), any silver or mercury salts, trimethylsilyl trifluoromethanesulfonate (TMS-triflate, TMSOTf), or trifluoronmethanesulfonic acid (triflic acid, TfOH), N-iodosuccinimide, methyl triflate.
  • IDCP iodonium dicollidine perchlorate
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • TfOH trifluoronmethanesulfonic acid
  • reaction times may be varied.
  • reaction conditions may be optimized, for example, by preparing several phosphate or sulfate containing compound preparations and hydroxy-containing mescaline derivative preparations and reacting these in different reaction vessels under different reaction conditions, for example, different temperatures, using different solvents etc., evaluating the obtained phosphorylated or sulfonated mescaline derivative reaction product, adjusting reaction conditions, and selecting a desired reaction condition.
  • reaction conditions for performing sulfonation and phosphorylation reactions may be found in e.g., U. Pradere, et al., Chem. Rev. 2014, 114, 9154-9218; W. Kozak, et a!., Asian J. Org. Chem. 2018, 7,314 -323.
  • PrestoBlue assays were first performed.
  • the PrestoBlue assay measures cell viable activity based on the metabolic reduction of the redox indicator resazurin and is a preferred method for routine cell viability assays (Terrasso et al., 2017, J Pharmacol. Toxicol. Methods 83: 72).
  • Results of these assays were conducted using both control ligands (e.g., 2C-B (4-bromo-2,5-dimethoxyphenethylamine), MDMA, mescaline, etc.) and novel derivatives, in part as a pre-screen for any remarkable toxic effects on cell cultures up to concentrations of 1 mM.
  • HepG2 is a human hepatoma that is most commonly used in drug metabolism and hepatotoxicity studies (Donato et al., 2015, Methods Mol Biol 1250: 77).
  • HepG2 cells were cultured using standard procedures using the manufacture’s protocols (ATCC, HB-8065). Briefly, cells were cultured in Eagle’s minimum essential medium supplemented with 10% fetal bovine serum and grown at 37°C in the presence of 5% CO2. To test the various compounds with the cell line, cells were seeded in a clear 96-well culture plate at 20,000 cells per well. After allowing cells to attach and grow for 24 hours, compounds were added at 1 mM, 10 mM, 100 mM, and 1 mM. Methanol was used as vehicle, at concentrations 0.001 , 0.01 , 0.1 , and 1 %.
  • Triton X-100 concentrations used were 0.0001 , 0.001 , 0.01 and 0.1 %.
  • Cells were incubated with compounds for 48 hours before assessing cell viability with the PrestoBlue assay following the manufacture’s protocol (ThermoFisher Scientific, P50200).
  • PrestoBlue reagent was added to cells and allowed to incubate for 1 hour before reading.
  • Absorbance readings were performed at 570 nm with the reference at 600 nm on a SpectraMax iD3 plate reader. Non-treated cells were assigned 100% viability.
  • 14A(i) - 14A(ii) shows results for phenylalkylamine compounds 2C-B(4-bromo-2,5- dimethoxyphenethylamine) (A), MDMA (B), mescaline (C), and the toxic control compound Triton X €.
  • Data acquired for the derivative having chemical formula (III) is displayed as “(III)” on the x-axis in panel D.
  • Assays for determining receptor binding of a given compound include ligand competition assays with an established radiolabeled ligand, resulting in a Ki value. Additional assays may be performed wherein positive and negative controls with pre-determined Ki values are titrated to cell cultures with engineered ‘receptor response systems.’
  • Results of these cellular assays can provide certain information regarding the overall strength of receptor activation, although negative results in these artificial systems do not necessarily correlate with in vivo impact.
  • a variety of positive controls MDMA, 2C-B, mescaline, escaline, proscaline
  • mescaline, escaline, proscaline with established receptor binding and known in vivo efficacy profiles are included in cellular assays.
  • [ 3 H]ketanserin is a well-established antagonist used routinely in competition assays to evaluate competitive activity of novel drug candidates at the 5-HT2A receptor (Maguire et a/., 2012, Methods Mol Biol 897: 31).
  • competition assays using [ 3 H]ketanserin were employed as follows. SPA beads (RPNQ0010), [ 3 H]ketanserin (NET1233025UC), membranes containing 5-HT2A (ES-313- M400UA), and isoplate-96 microplate (6005040) were all purchased from PerkinElmer.
  • Radioactive binding assays were carried out using Scintillation Proximity Assay (SPA).
  • SPA Scintillation Proximity Assay
  • mixtures of 10 ug of membrane containing 5-HT2A receptor was pre-coupled to 1 mg of SPA beads at room temperature in a tube rotator for 1 hour in binding buffer (50 mM Tris-HCI pH7.4, 4 mM CaCl2, 1 mM ascorbic acid, 10 mM pargyline HCI).
  • binding buffer 50 mM Tris-HCI pH7.4, 4 mM CaCl2, 1 mM ascorbic acid, 10 mM pargyline HCI.
  • the beads and membrane were aliquoted in an isoplate-96 microplate with increasing amounts of [ 3 H]ketanserin (0.1525 nM to 5 nM) and incubated for two hours at room temperature in the dark with shaking.
  • Tryptophan was included as a negative control as it has no activity at the 5-HT2A receptor.
  • 2C-B and MDMA were used as positive controls since they are phenylalkylamine-type molecules with relatively strong (Marcher-Rorsted et al., 2020, ACS Chem. Neurosci. 11 : 1238) or more moderate (Simmler et al., 2013, British J. Pharmacol. 168: 458) 5-HT2A receptor binding activities, respectively.
  • Mescaline was included as an additional positive control with established binding activity at the 5-HT2A receptor (Rickli et al., 2016, Eur. Neuropsychopharm. 26: 1327).
  • Escaline and proscaline were included in this study for comparative purposes, for although their 5-HT2A receptor binding mode is understudied they are established mescaline-type hallucinogens known to induce head-twitch responses in mice (Halberstadt et al., J. Psychopharm. 33: 406). Mouse head-twitch response has been correlated with 5-HT2A receptor engagement (Halberstadt, 2015, Behav. Brain Res. 277: 99). Specific binding in counts per minute (cpm) was calculated by subtracting non-specific binding from total binding. Specific binding (pmol/mg) was calculated from pmol of [ 3 H]ketanserin bound per mg of protein in the assay.
  • FIG. 14B, 14C and 14D show the competition binding curves for 2C-B, MDMA and mescaline, respectively, as positive controls (binding).
  • FIG. 14E and 14F show the competition binding curves for escaline and proscaline, respectively, for comparative purposes.
  • FIG. 14G shows the competition binding curve for tryptophan as a negative control (no binding).
  • the competition binding curve for compound with formula (III), designated “(III)” in FIG. 14H, reveals binding compared to the negative control.
  • SPA beads RPNQ0011
  • radiolabeled 8-hydroxy-DPAT [propyl-2,3- ring-1 ,2,3- 3 H] (NET929250UC)
  • isoplate-96 microplate 6005040
  • Radioactive binding assays were carried out using the Scintillation Proximity Assay (SPA).
  • mixtures of 10 jug of membrane containing HTIA receptor was pre-coupled to 1 mg of SPA beads at room temperature in a tube rotator for 1 hour in binding buffer (50 mM Tris-HCI pH 7.4, 10 mM MgSO4, 0.5 mM EDTA, 3.7% glycerol, 1 mM ascorbic acid, 10 pM pargyline HCI).
  • binding buffer 50 mM Tris-HCI pH 7.4, 10 mM MgSO4, 0.5 mM EDTA, 3.7% glycerol, 1 mM ascorbic acid, 10 pM pargyline HCI.
  • the beads and membrane were aliquoted in an isoplate-96 microplate with increasing amounts of 8-hydroxy-DPAT [propyl-2,3- ring-1 ,2,3- 3 H] (0.1525 nM to 5 nM) and incubated for two hours at room temperature in the dark with shaking.
  • Ki values were calculated from the competition displacement data using the competitive binding analysis from GraphPad PRISM software. 2C-B, MDMA and mescaline were used as positive controls since they are phenylalkylamine-type molecules with relatively strong (2C- B; Rickli et al., 2015, Neuropharmacology 99: 546) or more moderate (MDMA, Simmler et a/., 2013, British J. Pharmacol.
  • FIGS. 141, 14J and 14K show the competition binding curves for 2C-B, MDMA and mescaline, respectively, as positive controls (binding).
  • FIGS. 14L and 14M show the competition binding curves for escaline and proscaline, respectively, for comparative purposes.
  • the competition binding curve for compound with formula (III), designated “(III)” in FIG. 14N, reveals binding at higher ligand concentrations.
  • CH0-K1/Gai5 (GenScript, M00257) (-5-HTIA) and CH0-K1/5- HTiA/Gais (GenScript, M00330) (+5-HTIA) cells lines were used. Briefly, CHO- K1/Gais is a control cell line that constitutively expresses Gais which is a promiscuous G q protein. This control cell line lacks any transgene encoding 5- HTIA receptors, but still responds to forskolin; thus, cAMP response to forskolin should be the same regardless of whether or not 5-HTi A agonists are present.
  • CHO-K1/5-HTiA/Gais cells stably express 5-HTIA receptor in the CHO-K1 host background.
  • Gais is a promiscuous G protein known to induce calcium flux response, present in both control and 5-HTIA cell lines.
  • Gais may be recruited in place of Gai/o, which could theoretically dampen cAMP response (Rojas and Fiedler 2016, Front Cell Neurosci 10: 272).
  • 5-HTi A agonist 2C-B as a positive control to ensure sufficient cAMP response was observed, thereby indicating measurable recruitment of Gai/o protein to activated 5-HTi A receptors.
  • 2C-B is a relatively strong 5-HTIA receptor agonist among members of the phenylalkylamine structural class (Rickli et al., 2015, Neuropharmacology 99: 546). While MDMA and mescaline are known to bind 5-HTIA receptor in vitro (MDMA, Simmler et al., 2013, British J. Pharmacol 168: 458; mescaline, Rickli et al., 2016, Eur. Neuropharm 26: 1327), information regarding their ability to engage 5-HTIA receptor-coupled responses in living cell cultures is lacking. Therefore, these molecules were included for comparative purposes only. Similarly, escaline and proscaline were included in this study for strictly comparative purposes.
  • Cells were maintained in complete growth media as recommended by supplier (GenScript) which is constituted as follows: Ham’s F12 Nutrient mix (HAM’S F12, GIBCO #11765-047) with 10% fetal bovine serum (FBS) (Thermo Scientific #12483020), 200 mg/ml zeocin (Thermo Scientific #R25005) and/or 100 mg/ml hygromycin (Thermo Scientific #10687010). The cells were cultured in a humidified incubator with 37°C and 5% CO2. Cells maintenance was carried out as recommended by the cell supplier. Briefly, vials with cells were removed from the liquid nitrogen and thawed quickly in 37°C water bath.
  • the vial’s outside was decontaminated by 70% ethanol spray.
  • the cell suspension was then retrieved from the vial and added to warm (37°C) complete growth media and centrifuged at 1 ,000 rpm for 5 minutes. The supernatant was discarded, and the cell pellet was then resuspended in another 10 ml of complete growth media and added to the 10 cm cell culture dish (Greiner Bio-One #664160). The media was changed every third day until the cells were about 90% confluent. The -90% confluent cells were then split 10:1 for maintenance or used for experiment.
  • Both cells were seeded at the density of 30,000 cells/well in 100 ml complete growth media and cultured 24 hours in humidified incubator at 37°C and 5% CO2. On the experiment day, the media of cells was replaced with serum/antibiotic free culture media. Then the cells were treated for 20 minutes with test molecules dissolved in induction medium (serum/antibiotic free culture media containing 4 pM forskolin, 500 mM IBMX (isobutyl-1 -methylxanthine, Sigma-Aldrich, Cat. #17018) and 100 mM (RO 20- 1724, Sigma-Aldrich, Cat. #B8279)). Forskolin induced cAMP formation whereas IBMX and RO 20-1724 inhibited the degradation of cAMP.
  • induction medium serum/antibiotic free culture media containing 4 pM forskolin, 500 mM IBMX (isobutyl-1 -methylxanthine, Sigma-Aldrich, Cat. #17018) and 100 mM (RO
  • FIG. 140 illustrates reduction in cAMP levels in 5-HTIA receptor expressing cells stimulated with 4 pM forskolin as levels of 2C-B increase, indicating 5-HTIA receptor binding by 2C-B in these cells. Conversely, this trend of decreasing % cAMP levels with increasing 2C-B is not observed in cells lacking expression of 5-HTIA receptor.
  • FIG. 14P and FIG. 14Q illustrate mild or no change in cAMP levels in 5-HTIA receptor expressing cells (+5-HTIA) stimulated with 4 pM forskolin as levels of MDMA and mescaline increase, respectively. These results indicate mild or no 5-HTIA receptor engagement by MDMA and mescaline in these cells, respectively.
  • FIG. 14T illustrates no reduction in cellular cAMP levels in either cell culture (+5-HTiAand -5-HT1A) stimulated with induction medium and treated with increasing doses of tryptophan, indicating a lack of 5-HTIA activity by this molecule in +5-HTIA cells.
  • 5-HTIA receptor binding evaluation for compound with formula (III) (designated simply “(III)” along the x-axis) is shown in FIG. 14U. Comparison of data acquired in +5-HTIA cultures with those acquired in -5-HT1A cultures suggests no receptor modulation at evaluated ligand concentrations.
  • FIG. 15B shows radioligand competition assay results for compound with formula (IV), depicted on the x-axis as “(IV)”. Results demonstrate receptor modulation compared to negative control.
  • FIG. 15C shows radioligand competition assay results for compound with formula (IV), depicted on the x-axis as “(IV)”. Results demonstrate receptor modulation with increasing ligand concentrations.
  • tetrabutylammonium hydrogen sulfate (234 mg, 674 pmol) was added to the aqueous phase and the resulting mixture was stirred for 1 hour before DCM was added. The layers were separated, and the organic phase was washed with water (5 x 10 mL) and then brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford compound 4 (20 mg).
  • LC-HESI-MS calculated: 331 .11 m/z [M ( suifate)+H] + ; observed 332.16 m/z.
  • FIG. 16B shows radioligand competition assay results for compound with formula (Vb), depicted on the x-axis as “Vb”. Results demonstrate receptor modulation compared to negative control.
  • FIG. 16C shows radioligand competition assay results for compound with formula (IV), depicted on the x-axis as “IV”. Results demonstrate receptor modulation with increasing ligand concentrations.

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Abstract

L'invention concerne de nouveaux composés dérivés de mescaline phosphorylés et sulfonés et des formulations pharmaceutiques et médicamenteuses à usage récréatif les contenant. Les composés peuvent être produits par réaction d'un dérivé de mescaline précurseur avec un composé phosphoré-oxydé ou soufré-oxydé.
PCT/CA2022/051412 2021-09-24 2022-09-23 Dérivés de mescaline phosphorylés et sulfonés et leurs procédés d'utilisation WO2023044574A1 (fr)

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WO2024026568A1 (fr) * 2022-08-05 2024-02-08 Enveric Biosciences Canada Inc. Dérivés hétérocycliques condensés de la mescaline

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US20070269902A1 (en) * 2001-10-12 2007-11-22 Joseph Beechem Antibody complexes and methods for immunolabeling

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US20070269902A1 (en) * 2001-10-12 2007-11-22 Joseph Beechem Antibody complexes and methods for immunolabeling

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SPICER CHRISTOPHER D., PUJARI-PALMER MICHAEL, AUTEFAGE HÉLÈNE, INSLEY GERARD, PROCTER PHILIP, ENGQVIST HÅKAN, STEVENS MOLLY M.: "Synthesis of Phospho-Amino Acid Analogues as Tissue Adhesive Cement Additives", ACS CENTRAL SCIENCE, vol. 6, no. 2, 26 February 2020 (2020-02-26), pages 226 - 231, XP093055919, ISSN: 2374-7943, DOI: 10.1021/acscentsci.9b01149 *

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WO2024026568A1 (fr) * 2022-08-05 2024-02-08 Enveric Biosciences Canada Inc. Dérivés hétérocycliques condensés de la mescaline

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