Classifications

• • 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
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

• This disclosure relates in some aspects to compounds that are prodrugs of phenylalkylamines (e.g., psychedelic phenethylamines).
• the disclosure also relates to methods of making the compounds and pharmaceutical compositions thereof, and methods of using disclosed compounds and compositions for treating medical conditions, such as mental, behavioral, and neurodevelopmental disorders
• X is H or PO 3 H 2 ;
• R a is H or CrC 6 alkyl
• R p is H, OH, or CpCg alkoxy
• R 2 , R 3 , R 4 , and R 5 are each independently H, Br, F, Cl, I, CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrC 6 alkylthio, CrC 6 haloalkyl, CrC 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrC 6 alkylthio, CrC 6 haloalkyl, CrC 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy
• R 6 is H; or any of R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R 2 , R 3 , R 4 , R 5 , and R 6 as defined above; provided that at least two of R 2 , R 3 , R 4 , R 5 , and R 6 are not H.
• X is H or PO 3 H 2 ;
• R a is H or C r C 6 alkyl
• R p is H, OH, or C ⁇ Ce alkoxy
• R 2 , R 3 , R 4 , and R 5 are each independently H, Br, F, Cl, I, C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r Cg alkoxy, C r Cg alkylthio, C r Cg haloalkyl, C r Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ -Cg alkoxy, C ⁇ -Cg alkylthio, C ⁇ -Cg haloalkyl, C ⁇ -Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membere
• the compound has the structure of Formula (I A), (IA-1), (IA-2), (IA-3), (IA-4), (IA-5), (IA-6), (IA-7), (IB), (IC), (ID), (IE), or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:
• the compound has the structure of Formula (AA), (AA-1), (AA-2), (AA-3), (AA-4), (AA-5), (AA-6), (AA-7), (AB), (AC), (AD), (AE), or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R p , and X are as defined for Formula (I)
• R 4 is Br. In some embodiments, R 4 is C r Cg alkyl. In some embodiments, R 4 is — CH 3 . In some embodiments, R 4 is C r Cg alkylthio. In some embodiments, R 4 is — SCH 2 CH 2 CH 3 .
• R 2A is C r Cg alkyl. In some embodiments, R 2A is — CH 3 .
• R 3A is C r Cg alkyl. In some embodiments, R 3A is — CH 3 .
• R 4A is C ⁇ Cg alkyl. In some embodiments, R 4A is — CH 3 . In some embodiments, R 4A is — CH 2 CH 3 .
• R 5A is C ⁇ Cg alkyl. In some embodiments, R 5A is — CH 3 .
• R a is H. In embodiments, R a is C ⁇ Cg alkyl. In embodiments, R a is — CH 3 .
• R p is H.
• X is H. In some embodiments, X is PO 3 H 2 . [18] In some embodiments, the compound is selected from Table IA, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. In some embodiments, the compound is selected from Table
• the compound is: or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof. or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof is a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof is a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound is pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof is a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof is a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof is a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof is a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof is a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof is a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• compositions comprising a therapeutically effective amount of the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
• the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.
• the composition is provided in unit dosage form.
• the composition comprises the compound in a total amount of between 1 and 200 mg, or between 5 and 100 mg.
• the composition comprises the compound in a total amount of between 10 and 75 mg, or between 15 and 50 mg.
• the unit dosage form is an immediate release, controlled release, sustained release, extended release, or modified release formulation.
• the composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the additional active compound is selected from the group consisting of: amino acids, antioxidants, anti-inflammatory agents, analgesics, anti neuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serot
• the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, or alter pharmacokinetics or pharmacodynamics.
• the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, anti neuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.
• the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission.
• the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission.
• the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of serotonergic, dopaminergic, or noradrenergic neurotransmission.
• the medical condition is a mental health disorder.
• the mental health disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, alcohol or drug abuse or dependence disorders, a substance use disorder, substance-induced mood disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, and dissociative disorders.
• PTSD post-traumatic stress disorder
• OCD obsessive compulsive disorder
• ADHD attention deficit hyperactivity disorder
• depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).
• anxiety is generalized anxiety disorder (GAD).
• the mental health disorder is PTSD.
• the substance use disorder is alcohol use disorder (AUD), nicotine dependence or tobacco use disorder, opioid use disorder (OLID), stimulant use disorder, or sedative, hypnotic, or anxiolytic use disorder.
• the medical condition is a neurodegenerative disorder, pain or a pain disorder, or inflammation or an inflammatory disorder.
• the compound is administered together with one or more sessions of psychotherapy or psychological support.
• modulating neurotransmission comprises activating a monoamine neurotransmitter receptor and/or modulating the uptake activity of a monoamine transporter.
• the monoamine neurotransmitter receptor is any of a serotonin receptor (HTR), a dopamine receptor, and a norepinephrine receptor.
• the monoamine transporter is any of a serotonin transporter (SERT), a dopamine transporter (DAT), or a norepinephrine transporter (NET).
• the HTR is any of HTR 1A , HTR 1B , HTR 2A , HTR 2B , HTR 2C , and HTR 6 .
• modulating neurotransmission comprises agonizing HTR ⁇ .
• an active agent includes reference to a combination of two or more active agents
• an excipient includes reference to a combination of two or more excipients. While the term “one or more” may be used, its absence (or its replacement by the singular) does not signify the singular only, but simply underscores the possibility of multiple agents or ingredients in particular embodiments.
• the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
• Alkyl will be understood to include straight or branched radicals having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” can also be used.
• an alkyl group comprises from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, and most preferably from 1 to 3 carbon atoms.
• the alkyl may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, — OP(O)(OH) 2 , — OC(O)H, — OSO 2 OH, -OC(O)NH 2 , or — SONH 2 .
• Alkanyl refers to saturated branched, straight-chain, or cyclic alkyl radicals derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
• Typical alkanyl groups include methanyl; ethanyl; propanyls such as propan-1 -yl, propan-2-yl (isopropyl), and cyclopropan-1-yl; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1 -yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), and cyclobutan-1-yl; etc.
• Alkenyl refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
• the group may be in either the cis or trans conformation about the double bond(s).
• Typical alkenyl groups include ethenyl; propenyls such as prop-1 -en-1-yl, prop-1 -en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1 -en-1-yl, and cycloprop-2-en-1-yl; butenyls such as but-1 -en-1-yl, but-1 -en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2yl, buta-1 ,3-dien-1-yl, buta-1 ,3-dien-2-yl, cyclobut-1 -en-1 -yl, cyclobut-1-en-3-yl, and cyclobuta-1 ,3-dien-1 -yl; and the like.
• propenyls such as prop-1 -en-1-yl, prop-1 -
• Alkynyl refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
• Typical alkynyl groups include ethynyl; propynyls such as prop-1 -yn-1-yl, and prop-2-yn-1 -yl; butynyls such as but-1 -yn-1 -yl, but-1 -yn-3-yl, and but-3-yn-1 -yl; and the like.
• Aryl refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen (H) atom from a single carbon atom of a parent aromatic ring system.
• Typical aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyr
• amino refers to — NR 2 , wherein each R is independently H, OH, or C ⁇ Cg alkyl, wherein the C ⁇ Cg alkyl is optionally substituted.
• An amino group can be a primary amino group (— NH 2 ) a secondary amino group (— NHR), a tertiary amino group (— NR 2 ), or a quaternary amino group (— NR 3 + ), wherein R is independently H or C ⁇ Cg alkyl, wherein the C ⁇ Cg alkyl is optionally substituted.
• Cycloalkyl refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon
• Monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
• Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds.
• Bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decahydronaphthalene and adamantane.
• exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• exemplary groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.
• Cycloalkenyl refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring. However, if there is more than one double bond, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion.
• Cycloalkenyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atom
• cycloalkenyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1 ,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1 ,3-, 1 ,4- and 1 ,5-isomers), norbornene, and norbornadiene.
• a cycloalkenyl group may be unsubstituted or substituted.
• Halogen refers to fluorine, chlorine, bromine, and iodine.
• Heterocycloalkyl and “heterocyclyl” both refer to a cycloalkyl as defined above, having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S.
• Heterocycloalkyl and heterocyclyl include bicyclic compounds which include a heteroatom.
• Bicyclic compounds includes spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds
• the heteroatoms can also be oxidized, such as, but not limited to, — S(O)— and — S(O) 2 — .
• Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 , or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1 , 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
• the heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1 ,2-, 1 ,3- and 1 ,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.
• groups such as aziridine, azetidine, pyrrolidine, pipe
• heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.
• Heterocycloalkyl groups can be unsubstituted or substituted.
• Heterocycloalkenyl refers to cycloalkenyl as defined above, having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, 0 and S.
• the heteroatoms can also be oxidized, such as, but not limited to, — S(0)— and — S(0) 2 — .
• Heterocycloalkenyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 , or 3 to 12 ring members.
• heterocycloalkenyl groups any suitable number of heteroatoms can be included in the heterocycloalkenyl groups, such as 1 , 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
• exemplary heterocycloalkenyl groups include dihydrofuran, dihydropyran, dihydropyridine, tetrahydropyridine, dihydrothiazole, and dihydrothiophene.
• Heteroaryl refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, 0 or S.
• Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1 , 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5.
• Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
• the heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1 ,2,3-, 1 ,2,4- and 1 ,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
• groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1 ,2,3-, 1 ,2,4- and 1 ,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
• heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran.
• Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.
• Alkoxy refers to the formula —OR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy.
• An alkoxy may be substituted or unsubstituted.
• Acyl refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, connected via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.
• Deuterium 2 H or D
• Deuterium also called “heavy hydrogen”
• Deuterium thus accounts for approximately 0.0154% (alternately, on a mass basis, 0.0308%) of all naturally occurring hydrogen in the oceans.
• “Mon-substituted,” “non-deuterated,” and “undeuterated” may refer to compounds having no greater than the amount of deuterium expected as a percentage of naturally occurring hydrogen in a compound.
• Deuteroalkyl will be understood to include any alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a deuterium (i.e., 2 H, or D). Where an alkyl radical is substituted by more than one deuterium, it may be referred to using a prefix corresponding to the number of deuterium substitutions. For example, trideuteroalkyl refers to an alkyl in which three hydrogens have been replaced by deuteriums. A deuteroalkyl can be fully deuterated (i.e., all of the hydrogens have been replaced by deuteriums) or partially deuterated (i.e., only some of the hydrogens have been replaced by deuteriums).
• a deuteromethyl (i.e., a C! deuteroalkyl) group refers to — CH 2 D, — CHD 2 , or — CD 3 .
• a deuteroethyl (i.e., a C 2 deuteroalkyl) group refers to — CH 2 CH 2 D, — CHDCH 2 D, — CD 2 CH 2 D, — CH 2 CHD 2 , — CHDCHD 2 , — CD 2 CHD 2 , — CH 2 CD 3 , — CHDCD 3 , or — CD 2 CD 3 .
• a deuteropropyl group i.e., a C 3 deuteroalkyl refers to any partially or fully substituted n-propyl or isopropyl group.
• Haloalkyl will be understood to include any alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen (e.g., a fluorine, a chlorine, a bromine, or an iodine). Where an alkyl radical is substituted by more than one halogen, it may be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkyl refers to an alkyl substituted by two halo groups, which may be, but are not necessarily, the same halogen.
• a halogen e.g., a fluorine, a chlorine, a bromine, or an iodine
• haloalkyl groups include difluoromethyl (— CHF 2 ), bromofluoromethyl (— CHBrF), trifluoromethyl (— CF 3 ), and 2-fluoroethyl (— CH 2 CH 2 F). Additional examples of haloalkyl groups include — CHF 2 , — CH 2 F, — CH 2 CF 3 , — CH 2 CHF 2 , -CH 2 CH 2 F, -CH(CH 3 )(CF 3 ), -CH(CH 3 )(CHF 2 ), and -CH(CH 3 )(CH 2 F).
• Hydroalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
• exemplary hydroxyalkyl groups include, for example, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl.
• a hydroxyalkyl may be substituted or unsubstituted.
• Haloalkoxy refers to an — O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy).
• the halogens may be the same or different in each instance.
• Such groups include chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy.
• a haloalkoxy may be substituted or unsubstituted.
• Alkylthio refers to the formula —SR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• a non-limiting list of alkylthio are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio.
• An alkylthio may be substituted or unsubstituted.
• “Sulfenyl” refers to an —SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A sulfenyl may be substituted or unsubstituted.
• “Sulfonyl” refers to an — SO 2 R group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
• R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• An O-carboxy may be substituted or unsubstituted.
• a thiocarbonyl may be substituted or unsubstituted.
• Trihalomethanesulfonyl refers to an X 3 CSO 2 — group wherein each X is a halogen.
• Trihalomethanesulfonamido refers to an X 3 CS(O) 2 N(R A )— group wherein each X is a halogen, and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• S-sulfonamido refers to a — SO 2 N(R A R B ) group in which R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• An S-sulfonamido may be substituted or unsubstituted.
• N-sulfonamido refers to a RSO 2 N(R A )— group in which R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• An N-sulfonamido may be substituted or unsubstituted.
• An O-carbamyl may be substituted or unsubstituted.
• An N-carbamyl may be substituted or unsubstituted.
• An O-thiocarbamyl may be substituted or unsubstituted.
• R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• An N-thiocarbamyl may be substituted or unsubstituted.
• a C-amido may be substituted or unsubstituted.
• R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
• An N-amido may be substituted or unsubstituted.
• Optionally substituted unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents.
• substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl (alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, oxo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, is
• prodrugs of psychedelic phenethylamines.
• a prodrug is an inactive derivative of a pharmacologically active drug that is designed to undergo chemical or enzymatic activation in vivo, for example by the action of a metabolic process, an enzymatic process or a degradative process that removes the prodrug moiety (i.e., the “promoiety”) to form the drug.
• prodrugs can be engineered to modulate how a drug is absorbed, distributed, metabolized, and excreted by the body.
• prodrugs can also enhance pharmacokinetic properties of a drug by targeting specific tissues or cells, increasing the solubility across biological barriers, and prolonging drug release. Moreover, prodrugs can improve therapeutic efficacy by minimizing side effects, increasing drug potency, and reducing the required dosage (Jana et al. Current Medicinal Chemistry. 2010. 17(32), 3874-3908). These advantages make prodrugs a promising strategy in drug development, especially for drugs with poor bioavailability, low solubility, and high toxicity.
• WO 2022/235587 describes the use of lipid structures in prodrugs of psychedelic tryptamines and phenethylamines.
• Prodrugs containing fat-soluble lipid moieties can be useful in drug design by increasing the ability of hydrophilic drugs to cross cell lipid bilayers (Markovic et al. Med Res Rev. 2019. 39, 579-607).
• lipid-based prodrugs may not be capable of crossing tight cellular barriers such as the blood-brain barrier.
• Prodrug strategies that employ a promoiety that can bind to specific transporters on cellular barriers can be more likely to reach the active compound target within the tissue (Jornada et al. Molecules. 2016. 21 (1):42).
• this drug requires a higher dose for pharmacological activation, which may lead to unnecessary accumulation of mescaline metabolites in other tissues and can increase the chance/severity of non-target effects (Dinis Oliviera et al. Curr Mol Pharmacol. 2019. 12(3), 184-194).
• a prodrugging strategy that increases bioavailability of mescaline and other phenylalkylamines to the brain would allow for a lower dose, among other advantages associated with improved pharmacokinetics and higher central nervous system (CNS) penetration.
• vitamin B6 has six chemically distinct forms, including pyridoxine, pyridoxal, pyridoxamine, and their respective phosphorylated derivatives:
• Pyridoxal 5’-phosphate has the highest biological activity, but other forms of vitamin B6 can be converted to pyridoxal 5’-phosphate in vivo (Bachmann, et al. Molecules 2018, 23(9), 2117). Humans cannot synthesize any of the forms of vitamin B6, and must therefore obtain it by dietary means (Calderon-Ospina, et al. CNS Neurosci. Ther. 2020, 26(1), 5-13). As vitamin B6 plays an essential role in neurotransmitter production, it must be transported into the CNS (Id.).
• Transporters such as SLC19A2 and SLC19A3, also known as thiamine transporters (THTR) 1 and 2, have been shown to transport pyridoxine (Yamashiro et al., J Biol Chem. 2020, 295(50), 16998-17008).
• THTR thiamine transporters
• Various vitamin B6 conjugates have been synthesized and evaluated for their ability to act as prodrugs by enabling the transport of a therapeutically active component across cellular membranes (see, e.g., Araujo de Oliveira, et al. ACS Omega 2022, 7(14), 11678-11687; Day, et al. Mol Pharm. 2011 , 8(1), 297-301 ; Wu, et al. FASEB J.
• Applicant is unaware of the specific compounds and compositions disclosed herein having been synthesized, formulated, and/or used in the compositions and methods of the invention.
• Applicant’s disclosed compounds are particularly advantageous. For example, by improving the ability of certain drugs to cross cellular membranes and reach their receptor targets, compounds disclosed herein may produce fewer species or lower concentrations of metabolites responsible for adverse effects, resulting in improved side-effect profiles, and may provide other advantages compared to the corresponding drug compounds alone.
• X is H or PO 3 H 2 ;
• R a is H or C r C 6 alkyl
• R p is H, OH, or C ⁇ Cg alkoxy
• R 2 , R 3 , R 4 , and R 5 are each independently H, Br, F, Cl, I, C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrCg alkoxy, C ⁇ Cg alkylthio, C ⁇ Cg haloalkyl, C ⁇ Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ Cg alkoxy, C ⁇ Cg alkylthio, C ⁇ Cg haloalkyl, C ⁇ Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl
• R 6 is H; or any of R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R 2 , R 3 , R 4 , R 5 , and R 6 as defined above.
• X is H or PO 3 H 2 . In some embodiments, X is H. In some embodiments, X is PO 3 H 2 .
• R a is H or C ⁇ Cg alkyl. In some embodiments, R a is H. In some embodiments, R a is C ⁇ Cg alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). In some embodiments, R a is methyl (— CH 3 ). In some embodiments, R a is ethyl (— CH 2 CH 3 ).
• R 2 , R 3 , R 4 , and R 5 are each independently H, Br, F, Cl, I, C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ Cg alkoxy, C ⁇ Cg alkylthio, C ⁇ Cg haloalkyl, C ⁇ Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C r Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r Cg alkoxy, C r Cg alkylthio, C r Cg haloalkyl, C r Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substitute
• R 2 is H, Br, F, Cl, I, C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ Cg alkoxy, CrCg alkylthio, C ⁇ Cg haloalkyl, C ⁇ Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ Cg alkoxy, CrCg alkylthio, C ⁇ Cg haloalkyl, C ⁇ Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy
• R 2 is H. In some embodiments, R 2 is halogen (i.e., F, Cl, Br, I). In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I. In some embodiments, R 2 is C r Cg alkyl. In some embodiments, R 2 is methyl (— CH 3 ). In some embodiments, R 2 is ethyl (— CH 2 CH 3 ). In some embodiments, R 2 is C 2 -C 8 alkenyl. In some embodiments, R 2 is C 2 -C 8 alkynyl. In some embodiments, R 2 is C r Cg alkoxy.
• R 2 is methoxy. In some embodiments, R 2 is ethoxy. In some embodiments, R 2 is propoxy. In some embodiments, R 2 is isopropoxy. In some embodiments, R 2 is C r Cg alkylthio. In some embodiments, R 2 is — SCH 3 . In some embodiments, R 2 is — SCH 2 CH 3 . In some embodiments, R 2 is — SCH 2 CH 2 CH 3 . In some embodiments, R 2 is C ⁇ Cg haloalkyl. In some embodiments, R 2 is C ⁇ Cg haloalkoxy. In some embodiments, R 2 is 3- to 6-membered cycloalkyl.
• R 2 is 4- to 6-membered heterocycloalkyl. In some embodiments, R 2 is cyano. In some embodiments, R 2 is nitro. In embodiments, R 2 is amino (i.e., -NR 2 , wherein each R is independently H, OH, or C ⁇ Cs alkyl, wherein the C r C 6 alkyl is optionally substituted according to embodiments described below).
• R 2 is C ⁇ Cs alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ Cs alkoxy, C ⁇ Cs alkylthio, C ⁇ Cs haloalkyl, C ⁇ Cs haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each C ⁇ Cs alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r C 6 alkoxy, C r C 6 alkylthio, C ⁇ Cs haloalkyl, C ⁇ Cs haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, or amino is independently optionally substituted by de
• R 2 is unsubstituted CrC 6 alkyl, unsubstituted C 2 -C 8 alkenyl, unsubstituted C 2 -C 8 alkynyl, unsubstituted CrC 6 alkoxy, unsubstituted CrC 6 alkylthio, unsubstituted CrC 6 haloalkyl, unsubstituted CrC 6 haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH 2 ).
• R 2 is substituted CrC 6 alkyl, substituted C 2 -C 8 alkenyl, substituted C 2 -C 8 alkynyl, substituted CrC 6 alkoxy, substituted CrC 6 alkylthio, substituted CrC 6 haloalkyl, substituted C r C 6 haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR 2 , wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoy
• R 3 is H, Br, F, Cl, I, C r C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r C 6 alkoxy, C r C 6 alkylthio, C r C 6 haloalkyl, C r C 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C r C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r C 6 alkoxy, C r C 6 alkylthio, C r C 6 haloalkyl, C r C 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen,
• R 3 is H. In some embodiments, R 3 is halogen (i.e., F, Cl, Br, I). In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 is I. In some embodiments, R 3 is CrC 6 alkyl. In some embodiments, R 3 is methyl (— CH 3 ). In some embodiments, R 3 is ethyl (— CH 2 CH 3 ). In some embodiments, R 3 is C 2 -C 8 alkenyl. In some embodiments, R 3 is C 2 -C 8 alkynyl. In some embodiments, R 3 is CrC 6 alkoxy.
• R 3 is methoxy. In some embodiments, R 3 is ethoxy. In some embodiments, R 3 is propoxy. In some embodiments, R 3 is isopropoxy. In some embodiments, R 3 is C r C 6 alkylthio. In some embodiments, R 3 is — SCH 3 . In some embodiments, R 3 is — SCH 2 CH 3 . In some embodiments, R 3 is — SCH 2 CH 2 CH 3 . In some embodiments, R 3 is CrC 6 haloalkyl. In some embodiments, R 3 is CrC 6 haloalkoxy. In some embodiments, R 3 is 3- to 6-membered cycloalkyl.
• R 3 is 4- to 6-membered heterocycloalkyl. In some embodiments, R 3 is cyano. In some embodiments, R 3 is nitro. In embodiments, R 3 is amino (i.e., -NR 2 , wherein each R is independently H, OH, or CrC 6 alkyl, wherein the CrC 6 alkyl is optionally substituted according to embodiments described below).
• R 3 is CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrC 6 alkylthio, CrC 6 haloalkyl, CrC 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrC 6 alkylthio, CrC 6 haloalkyl, CrC 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl
• R 3 is unsubstituted C r Cg alkyl, unsubstituted C 2 -C 8 alkenyl, unsubstituted C 2 -C 8 alkynyl, unsubstituted C r Cg alkoxy, unsubstituted C r Cg alkylthio, unsubstituted C r Cg haloalkyl, unsubstituted C r Cg haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH 2 ).
• R 3 is substituted CrC 6 alkyl, substituted C 2 -C 8 alkenyl, substituted C 2 -C 8 alkynyl, substituted CrC 6 alkoxy, substituted CrC 6 alkylthio, substituted CrC 6 haloalkyl, substituted CrC 6 haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR 2 , wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl,
• R 4 is H, Br, F, Cl, I, C Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrC 6 alkylthio, CrC 6 haloalkyl, CrC 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrCg alkylthio, C r Cg haloalkyl, C r Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy
• R 4 is H. In some embodiments, R 4 is halogen (i.e., F, Cl, Br, I). In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is I. In some embodiments, R 4 is C r Cg alkyl. In some embodiments, R 4 is methyl (— CH 3 ). In some embodiments, R 4 is ethyl (— CH 2 CH 3 ). In some embodiments, R 4 is C 2 -C 8 alkenyl. In some embodiments, R 4 is C 2 -C 8 alkynyl. In some embodiments, R 4 is CrC 6 alkoxy.
• R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is propoxy. In some embodiments, R 4 is isopropoxy. In some embodiments, R 4 is CrC 6 alkylthio. In some embodiments, R 4 is — SCH 3 . In some embodiments, R 4 is — SCH 2 CH 3 . In some embodiments, R 4 is — SCH 2 CH 2 CH 3 . In some embodiments, R 4 is CrC 6 haloalkyl. In some embodiments, R 4 is CrC 6 haloalkoxy. In some embodiments, R 4 is 3- to 6-membered cycloalkyl.
• R4 is 4- to 6-membered heterocycloalkyl. In some embodiments, R 4 is cyano. In some embodiments, R 4 is nitro. In embodiments, R 4 is amino (i.e., -NR 2 , wherein each R is independently H, OH, or CrC 6 alkyl, wherein the CrC 6 alkyl is optionally substituted according to embodiments described below).
• R 4 is CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrC 6 alkylthio, C r Cg haloalkyl, C r Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each C r Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r Cg alkoxy, C r Cg alkylthio, C r Cg haloalkyl, C r Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl
• R 4 is unsubstituted C r Cg alkyl, unsubstituted C 2 -C 8 alkenyl, unsubstituted C 2 -C 8 alkynyl, unsubstituted CrC 6 alkoxy, unsubstituted CrC 6 alkylthio, unsubstituted CrC 6 haloalkyl, unsubstituted CrC 6 haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH 2 ).
• R 4 is substituted CrC 6 alkyl, substituted C 2 -C 8 alkenyl, substituted C 2 -C 8 alkynyl, substituted CrC 6 alkoxy, substituted CrC 6 alkylthio, substituted CrC 6 haloalkyl, substituted CrC 6 haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR 2 , wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl,
• R 5 is H, Br, F, Cl, I, CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, C Cg alkylthio, C r Cg haloalkyl, C r Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, nitro, or amino; wherein each C r Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r Cg alkoxy, CrCg alkylthio, C r Cg haloalkyl, C r Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl este
• R 5 is H. In some embodiments, R 5 is halogen (i.e., F, Cl, Br, I). In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I. In some embodiments, R 5 is CrC 6 alkyl. In some embodiments, R 5 is methyl (— CH 3 ). In some embodiments, R 5 is ethyl (— CH 2 CH 3 ). In some embodiments, R 5 is C 2 -C 8 alkenyl. In some embodiments, R 5 is C 2 -C 8 alkynyl. In some embodiments, R 5 is C r C 6 alkoxy.
• R 5 is methoxy. In some embodiments, R 5 is ethoxy. In some embodiments, R 5 is propoxy. In some embodiments, R 5 is isopropoxy. In some embodiments, R 5 is C r C 6 alkylthio. In some embodiments, R 5 is — SCH 3 . In some embodiments, R 5 is — SCH 2 CH 3 . In some embodiments, R 5 is — SCH 2 CH 2 CH 3 . In some embodiments, R 5 is C r C 6 haloalkyl. In some embodiments, R 5 is C r C 6 haloalkoxy. In some embodiments, R5 is 3- to 6-membered cycloalkyl.
• R 5 is 4- to 6-membered heterocycloalkyl. In some embodiments, R 5 is cyano. In some embodiments, R 5 is nitro. In embodiments, R 5 is amino (i.e., -NR 2 , wherein each R is independently H, OH, or C ⁇ Cs alkyl, wherein the C r C 6 alkyl is optionally substituted according to embodiments described below).
• R 5 is CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrC 6 alkylthio, CrC 6 haloalkyl, CrC 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino, each CrC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CrC 6 alkoxy, CrC 6 alkylthio, CrC 6 haloalkyl, CrC 6 haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or amino is independently optionally substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl
• R 5 is unsubstituted C r C 6 alkyl, unsubstituted C 2 -C 8 alkenyl, unsubstituted C 2 -C 8 alkynyl, unsubstituted C r C 6 alkoxy, unsubstituted C r C 6 alkylthio, unsubstituted C r C 6 haloalkyl, unsubstituted C r C 6 haloalkoxy, unsubstituted 3- to 6-membered cycloalkyl, unsubstituted 4- to 6-membered heterocycloalkyl, or unsubstituted amino (i.e., — NH 2 ).
• R 5 is substituted C r C 6 alkyl, substituted C 2 -C 8 alkenyl, substituted C 2 -C 8 alkynyl, substituted C r C 6 alkoxy, substituted C r C 6 alkylthio, substituted C r C 6 haloalkyl, substituted C r C 6 haloalkoxy, substituted 3- to 6-membered cycloalkyl, substituted 4- to 6-membered heterocycloalkyl, or substituted amino (i.e., — NR 2 , wherein each R is independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl,
• R 6 is H.
• any of R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, with the remaining of R 2 , R 3 , R 4 , R 5 , and R 6 as defined above.
• R 2 and R 3 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, and R 4 , R 5 , and R 6 are as defined above.
• R 2 and R 3 are taken together to form a 3- to 6-membered cycloalkyl (e.g., a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl).
• R 2 and R 3 are taken together to form a 3- to 6-membered cycloalkenyl (e.g., a cyclobutenyl, cyclopentenyl, or cyclohexenyl).
• R 2 and R 3 are taken together to form a 4- to 6-membered heterocycloalkyl.
• R 2 and R 3 are taken together to form a dihydrofuran ring.
• R 2 and R 3 are taken together to form a dihydropyran ring.
• R 2 and R 3 are taken together to form a 4- to 6-membered heterocycloalkenyl.
• R 2 and R 3 are taken together to form a furanyl.
• R 3 and R 4 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, and R 2 , R 5 , and R 6 are as defined above.
• R 3 and R 4 are taken together to form a 3- to 6-membered cycloalkyl.
• R 3 and R 4 are taken together to form a 3- to 6-membered cycloalkenyl.
• R 3 and R 4 are taken together to form a 4- to 6-membered heterocycloalkyl.
• R 3 and R 4 are taken together to form a dihydrofuran ring. In other embodiments, R 3 and R 4 are taken together to form a dihydropyran ring. In some embodiments, R 3 and R 4 are taken together to form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R 3 and R 4 are taken together to form a furanyl. In some embodiments, R 3 and R 4 are taken together to form a 3,4-methylenedioxy ring.
• R 4 and R 5 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, and R 2 , R 3 , and R 6 are as defined above.
• R 4 and R 5 are taken together to form a 3- to 6-membered cycloalkyl.
• R 4 and R 5 are taken together to form a 3- to 6-membered cycloalkenyl.
• R 4 and R 5 are taken together to form a 4- to 6-membered heterocycloalkyl.
• R 4 and R 5 are taken together to form a dihydrofuran ring. In other embodiments, R 4 and R 5 are taken together to form a dihydropyran ring. In some embodiments, R 4 and R 5 are taken together to form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R 4 and R 5 are taken together to form a furanyl.
• R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl, and R 2 , R 3 , and R 4 are as defined above.
• R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl.
• R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkenyl.
• R 5 and R 6 are taken together to form a 4- to 6-membered heterocycloalkyl.
• R 5 and R 6 are taken together to form a dihydrofuran ring. In other embodiments, R 5 and R 6 are taken together to form a dihydropyran ring. In some embodiments, R 5 and R 6 are taken together to form a 4- to 6-membered heterocycloalkenyl. For example, in some embodiments, R 5 and R 6 are taken together to form a furanyl.
• R 2 and R 3 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl;
• R 5 and R 6 are taken together to form a 3- to 6-membered cycloalkyl, 4- to 6-membered cycloalkenyl, or 4- to 6-membered heterocycloalkyl, or 4- to 6-membered heterocycloalkenyl; and
• R 4 is H, Br, F, Cl, I, C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ Cg alkoxy, C ⁇ Cg alkylthio, C ⁇ Cg haloalkyl, C ⁇ Cg haloalkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl
• At least one of R 2 , R 3 , R 4 , R 5 , and R 6 is not H. In some embodiments, at least two of R 2 , R 3 , R 4 , R 5 , and R 6 are not H. In embodiments, at least three of R 2 , R 3 , R 4 , R 5 , and R 6 are not H.
• the compound has the structure of Formula (IA): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 24 and R 5A are each independently CrC 6 alkyl, CrC 6 haloalkyl, or CrC 6 deuteroalkyl; and R 4 , R a , R p , and X are as defined above for Formula (I).
• R 2A is CrC 6 alkyl. In some embodiments, R 24 is methyl. In some embodiments, R 2A is C r Cg haloalkyl. In some embodiments, R 2A is trifluoromethyl (i.e., — CF 3 ). In some embodiments, R 24 is trideuteromethyl (i.e., — CD 3 ).
• R 5A is C r Cg alkyl. In some embodiments, R 5A is methyl. In some embodiments, R 5A is C r Cg haloalkyl. In some embodiments, R 5A is trifluoromethyl (i.e., — CF 3 ). In some embodiments, R 5A is trideuteromethyl (i.e., — CD 3 ).
• the compound has the structure of Formula (IA-1): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (IA-2): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (IA-3): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (IA-4): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (IA-5): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (IA-6): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (IA-7): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (IB): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein: R 3A , R 4A , and R 5A are each independently C r C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C r C 6 haloalkyl, wherein the C r C 6 alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl, and wherein R a , R p , and X are as defined above for Formula (I).
• R 3A , R 4A , and R 5A are each independently C r C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C r C 6 haloalkyl, wherein the C r C 6 alkyl is optionally substituted by 3- to 6-membered cyclo
• R 3A is C r C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C r C 6 haloalkyl, wherein the C r C 6 alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl.
• R 3A is C r C 6 alkyl.
• R 3A is C r C 6 alkyl, C 2 -C 8 alkenyl.
• R 3A is C 2 -C 8 alkynyl.
• R 3A is r C 6 haloalkyl.
• R 3A is unsubstituted.
• R 3A is C r C 6 alkyl, wherein the C r C 6 alkyl is substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl.
• R 3A is C ⁇ Cg alkyl, wherein the C r Cg alkyl is substituted by 3- to 6-membered cycloalkyl (e.g., cyclopropyl).
• R 3A is C r Cg alkyl, wherein the C ⁇ Cg alkyl is substituted by 6- to 10-membered aryl (e.g., phenyl).
• R 4A is C ⁇ Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C ⁇ Cg haloalkyl, wherein the CrCg alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl. In some embodiments, R 4A is C ⁇ Cg alkyl. In some embodiments, R 4A is C ⁇ Cg alkyl, C 2 -C 8 alkenyl. In some embodiments, R 4A is C 2 -C 8 alkynyl. In some embodiments, R 4A is r C 6 haloalkyl.
• R 4A is unsubstituted.
• R 4A is C ⁇ Cg alkyl, wherein the C ⁇ Cg alkyl is substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl.
• R 3A is C r Cg alkyl, wherein the CpCg alkyl is substituted by 3- to 6-membered cycloalkyl (e.g., cyclopropyl).
• R 4A is CpCg alkyl, wherein the C r Cg alkyl is substituted by 6- to 10-membered aryl (e.g., phenyl).
• R 5A is C r Cg alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C r Cg haloalkyl, wherein the CrCg alkyl is optionally substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl.
• R 5A is C r Cg alkyl.
• R 5A is C r Cg alkyl, C 2 -C 8 alkenyl.
• R 5A is C 2 -C 8 alkynyl.
• R 5A is r C 6 haloalkyl.
• R 5A is unsubstituted.
• R 5A is C r Cg alkyl, wherein the C r Cg alkyl is substituted by 3- to 6-membered cycloalkyl or 6- to 10-membered aryl.
• R 5A is CrC 6 alkyl, wherein the C C 6 alkyl is substituted by 3- to 6-membered cycloalkyl (e.g., cyclopropyl).
• R 5A is C C 6 alkyl, wherein the C r Cg alkyl is substituted by 6- to 10-membered aryl (e.g., phenyl).
• the compound has the structure of Formula (IC): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein n is independently at each occurrence 1 or 2; and R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (ID): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R 4 , R a , R p , and X are as defined above for Formula (I).
• the compound has the structure of Formula (IE): or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof, wherein R’ and R” are independently H, D, or F, and wherein R a , R p , and X are as defined above for Formula (I).
• R’ and R are both H.
• R’ and R are both D.
• R’ and R are both F.
• R’ is H and R” is D.
• R’ is H and R” is F.
• a disclosed compound comprises a compound of Applicant’s Int’l Application Nos. PCT/US2022/041279 (Pub. No. W02023/028091A1), PCT/US2022/041283 (Pub. No. W02023/028092A2), and PCT/US2022/044771 (Pub. No. W02023/049480A1), each of which is fully incorporated herein by reference, bound to a vitamin B6 promoiety according to various embodiments described herein.
• a disclosed compound comprises any suitable phenylalkylamine, phenethylamine, or tryptamine drug (e.g., a phenylalkylamine, phenethylamine, or tryptamine drug that comprises a primary amine moiety) bound to a vitamin B6 promoiety according to various embodiments described herein.
• Such compounds include, for example, 2C-x, DOx, Ariadne-type, cathinone, and amphetamine compounds.
• the drug is a compound disclosed in PiHKAL (Shulgin & Shulgin. 1992. PiHKAL. A chemical love story, Transform Press, Berkeley, CA).
• the drug is a compound disclosed in TiHKAL (Shulgin & Shulgin. 1997. TiHKAL: The Continuation, Transform Press, Berkeley, CA).
• R a , R p , and R 4 are selected from Table I, and R 2 , R 3 , R 5 , and R 6 are as defined in Formula (I) or any subformula thereof.
• the compound is a compound of Formula (IA) selected from Table IA, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:
• the compound is a compound of Formula (IB) selected from Table IB, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:
• the compound is a compound of Formula (IE) selected from Table IE, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof: Table IE.
• Representative compounds of Formula (IE) are a compound of Formula (IE) selected from Table IE, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof: Table IE.
• the compound is selected from the group consisting of or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound is selected from the group consisting of or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound is selected from the group consisting of or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound is selected from the group consisting of or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound is selected from the group consisting of or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound is selected from the group consisting of or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• the compound is selected from the group consisting of
• the compound is selected from the group consisting of
• the compound is selected from the group consisting of
• the compound is selected from the group consisting of
• the compound is selected from the group consisting of or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof
• the compound is selected from the group consisting of or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof.
• a single compound of will mean that the specified compound (e.g., by structural formula or description) is the only disclosed compound in the embodiment, i.e., that a compound, composition, or method consists of, consists essentially of, or comprises no further disclosed compound(s) (i.e., compound(s) having a different structural formula or description). It does not mean the embodiment has only a single molecule or single instance of the specified compound.
• embodiments “consisting of a single compound of Formula (I)” will include embodiments of “a compound of Formula (I),” or the use of “a compound of Formula (I),” and such embodiments, as well as embodiments of a composition “consisting essentially of a single compound of Formula (I),” each may comprise for example 5 mg, 10 mg, 50 mg, 100 mg, and other disclosed or known mass amounts or molar amounts of the compound of Formula (I).
• one or more compounds may be excluded from a claim to a group of compounds, such as a Markush group of compounds, such as “a compound of Formula (I).”
• one or more compounds also may be excluded from a claim to a composition consisting essentially of a group of compounds.
• one or more compounds also may be excluded from a claim to a composition comprising a group of compounds.
• one or more compounds also may be excluded from a claim to a use of a group of compounds.
• one or more compounds also may be excluded from a claim to a use of a composition consisting essentially of a group of compounds.
• one or more compounds also may be excluded from a claim to a use of a composition comprising a group of compounds.
• one or more compounds may be excluded from all claims to a group of compounds.
• one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, but are not excluded from a claim to a use of a group of compounds or compositions thereof. In some embodiments, one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition comprising a group of compounds, but are not excluded from a claim to a use of a group of compounds or compositions thereof.
• one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, but are not excluded from a composition comprising the one or more compounds together with one or more additional disclosed compounds and/or additional active compounds.
• one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, and also may be excluded from a claim to a use of a group of compounds or compositions consisting essentially thereof, but are not excluded from a composition comprising the one or more compounds together with one or more additional disclosed compounds and/or additional active compounds, or a use of a composition comprising the one or more compounds together with one or more additional disclosed compounds and/or additional active compounds.
• one or more compounds may be excluded from a claim to a group of compounds, and also may be excluded from a claim to a composition consisting essentially of a group of compounds, and also may be excluded from a claim to a use of a group of compounds or compositions consisting essentially thereof, and further may be excluded from a composition comprising the one or more compounds together with one or more additional disclosed compounds and/or additional active compounds, but are not excluded from a claim to a use of a composition comprising the one or more compounds together with one or more additional disclosed compounds and/or additional active compounds.
• compositions will be understood to also encompass pharmaceutically acceptable salts of such compounds.
• pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, and which may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
• Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecy
• the disclosed compounds are administered as part of a pharmaceutical composition or formulation, but will be prepared for inclusion in such composition or formulations as isolated or purified compounds.
• isolated purified
• substantially pure refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced.
• An “isolated,” “purified,” or “substantially pure” preparation of a compound is accordingly defined as a preparation having a chromatographic purity (of the desired compound) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method.
• the substantially pure compound used in the invention is substantially free of any other active compounds which are not intended to be administered to a subject.
• substantially free can be taken to mean that no active compound(s) other than the active compound intended to be administered to a subject are detectable by HPLC or other similar detection method, or are below a desired threshold of detection such as defined above.
• any reference to a disclosed compound or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof will include all amorphous and polymorphic forms.
• the compounds used in the disclosed compositions and methods may exist in different forms.
• the compounds may exist in stable and metastable crystalline forms, isotropic and amorphous forms, milled forms and nano-particulate forms, all of which are intended to be within the scope of the invention.
• disclosed compounds may include crystalline forms, known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
• Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
• a disclosed compound having deuterium substitution (e.g., a deuteroalkyl group), has a deuterium isotopic purity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%.
• the compound has an isotopic purity of at least 50%.
• the compound has an isotopic purity of at least 55%.
• the compound has an isotopic purity of at least 60%.
• the compound has an isotopic purity of at least 65%. In another embodiment, the compound has an isotopic purity of at least 70%. In another embodiment, the compound has an isotopic purity of at least 75%. In another embodiment, the compound has an isotopic purity of at least 80%. In another embodiment, the compound has an isotopic purity of at least 85%. In another embodiment, the compound has an isotopic purity of at least 90%. In another embodiment, the compound has an isotopic purity of at least 91 %. In another embodiment, the compound has an isotopic purity of at least 92%. In another embodiment, the compound has an isotopic purity of at least 93%. In another embodiment, the compound has an isotopic purity of at least 94%.
• the compound has an isotopic purity of at least 95%. In another embodiment, the compound has an isotopic purity of at least 96%. In another embodiment, the compound has an isotopic purity of at least 97%. In another embodiment, the compound has an isotopic purity of at least 98%. In another embodiment, the compound has an isotopic purity of at least 99%. In another embodiment, the compound has an isotopic purity of at least 99.5%. In another embodiment, the compound has an isotopic purity of at least 99.6%. In another embodiment, the compound has an isotopic purity of at least 99.7%. In another embodiment, the compound has an isotopic purity of at least 99.8%. In another embodiment, the compound has an isotopic purity of at least 99.9%.
• isotopic enrichment may be described as a percentage indicating the percent of isotopic atoms at a particular site on the molecule. The percentage can be referred to as the “isotopic purity” of the isotopically-labeled compound.
• a disclosed compound having deuterium substitution is a mixture of the deuterated compound and a corresponding non-deuterated compound (i.e., the corresponding compound wherein none of the hydrogens are substituted by a deuterium, e.g., at no position of the compound will the presence of deuterium be higher than the natural abundance of deuterium isotope).
• At least 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100% are deuterium-substituted compounds (wherein the other compounds in such mixtures are the corresponding non-substituted compounds).
• at least 1 % of the compounds are deuterium-substituted.
• at least 2% of the compounds are deuterium-substituted.
• At least 3% of the compounds are deuterium-substituted. In an embodiment, at least 4% of the compounds are deuterium-substituted. In an embodiment, at least 5% of the compounds are deuterium-substituted. In an embodiment, at least 10% of the compounds are deuterium-substituted. In an embodiment, at least 20% of the compounds are deuterium-substituted. In an embodiment, at least 30% of the compounds are deuterium-substituted. In an embodiment, at least 40% of the compounds are deuterium- and/or fluorine- substituted. In an embodiment, at least 50% of the compounds are deuterium-substituted.
• At least 60% of the compounds are deuterium-substituted. In an embodiment, at least 70% of the compounds are deuterium-substituted. In an embodiment, at least 80% of the compounds are deuterium-substituted. In an embodiment, at least 90% of the compounds are deuterium-substituted. In an embodiment, at least 95% of the compounds are deuterium-substituted. In an embodiment, at least 96% of the compounds are deuterium-substituted. In an embodiment, at least 97% of the compounds are deuterium-substituted. In an embodiment, at least 98% of the compounds are deuterium-substituted.
• At least 99% of the compounds are deuterium- and/or fluorinesubstituted. In an embodiment, at least 99.5% of the compounds are deuterium-substituted. In an embodiment, at least 99.8% of the compounds are deuterium-substituted. In an embodiment, at least 99.9% of the compounds are deuterium-substituted.
• a disclosed composition comprises a mixture of one or more deuterium-substituted compounds and corresponding non-substituted compounds in a fixed ratio, and will contain a ratio of deuterium-substituted to non-substituted compounds (as mole ratio or mass ratio), including a pharmaceutically acceptable salt, hydrate, or solvate thereof, of 1 :1 , at least 1 :1, at least 1.1 :1 , at least 1.2:1, at least 1.3:1 , at least 1.4:1 , at least 1.5:1 , at least 1.6:1 , at least 1.7:1 , at least 1.8:1 , at least 1.9:1 , at least 2.0:1 , at least 2.5:1 , at least 3.0:1 , at least 4.0:1, at least 5.0:1 , at least 6.0:1 , at least 7.0:1, at least 8.0:1, at least 9.0:1, and at least 10:1 , at least 11
• a disclosed composition comprises a disclosed compound having fluorine substitution (e.g., a fluoroalkyl group) and corresponding non-substituted compounds in a fixed ratio, and contains a ratio of fluorine-substituted to non-substituted compounds (as mole ratio or mass ratio) of 1 :1 , at least 1 :1, at least 1 .1:1, at least 1.2:1, at least 1.3:1 , at least 1 .4:1, at least 1.5:1 , at least 1.6:1 , at least 1 .7:1, at least 1.8:1 , at least 1.9:1 , at least 2.0:1 , at least 2.5:1 , at least 3.0:1 , at least 4.0:1, at least 5.0:1 , at least 6.0:1 , at least 7.0:1 , at least 8.0:1 , at least 9.0:1 , and at least 10:1, at least 11 :1 , at
• a disclosed compound may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms.
• Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
• the invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms.
• Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
• Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard tests described herein and other similar tests which are well known in the art. Examples of methods that can be used to obtain optical isomers of the compounds according to the present disclosure include the following: i) physical separation of crystals whereby macroscopic crystals of the individual enantiomers are manually separated.
• This technique may particularly be used if crystals of the separate enantiomers exist (i.e., the material is a conglomerate), and the crystals are visually distinct; ii) simultaneous crystallization whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis, a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral aux
• the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
• the desired enantiomer is then released from the diastereomers; viii) kinetic resolutions comprising partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
• the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; and xiii) transport across chiral membranes whereby a racemate is placed in contact with a thin membrane barrier.
• the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.
• a disclosed compound may be provided in a composition that is not enantiomerically enriched (i.e., a composition comprising the disclosed compound(s) as a racemic mixture).
• a disclosed compound may be provided in a composition that is enantiomerically enriched, such as a mixture of enantiomers in which one enantiomer is present in excess, in particular to the extent of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%, and up to (and including) 100%.
• a disclosed compound in a composition enantiomerically enriched with the R-isomer, comprising the R-isomer in enantiomeric excess of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.
• a disclosed compound in a composition enantiomerically enriched with the S-isomer, comprising the S-isomer in enantiomeric excess of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.
• a disclosed compound is provided in a composition comprising the R-isomer and the S-isomer in a R:S ratio of about 20:1 to about 1 :20. In some embodiments, the R:S ratio is greater than about 20:1 , or about 20:1 , 15:1 , 12:1 , 10:1 , 9:1, 8:1 , 7:1 , 6:1, 5:1 , 4:1 , 3:1 , or 2:1. In some embodiments, a disclosed compound is provided as the R-isomer in an enantiomerically pure composition.
• the R:S ratio is about 1 :1 , 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :12, 1 :15, 1 :20, or greater than about 1 :20.
• a disclosed compound is provided as the S-isomer in an enantiomerically pure composition.
• disclosed compounds are synthesized according to a reaction sequence that produces an compound of Formula (A), also referred to herein as a “pyridoxal-imine,” wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R p , and X are as defined for Formula (I).
• pyridoxal-imine compounds of Formula (A) are also useful as prodrugs for phenethylamine psychedelics.
• pyridoxal-imine compounds of Formula (A) are used in place of a compound of Formula (I) in any embodiment described herein, such as an embodiment describing a pharmaceutical composition, method of treatment, or use of a compound of Formula (I).
• the compound of Formula (A) is a compound of Formula (AA), (AA-1), (AA-2), (AA-3), (AA-4), (AA-5), (AA-6), (AA-7), (AB), (AC), (AD), (AE), or a pharmaceutically acceptable salt,
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R p , and X are as defined for Formula (I).
• a disclosed compound is provided in a composition comprising a pyridoxal-imine of Formula (A) and a pyridoxal-amine compound of Formula (I) in an (A):(l) ratio of about 20:1 to about 1 :20.
• the (A):(l) ratio is greater than about 20:1 , or about 20:1 , 15:1 , 12:1 , 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1, 3:1, or 2:1.
• a disclosed compound is provided as the compound of Formula (A) in a pure composition.
• the (A):(l) ratio is about 1 :1 , 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :12, 1 :15, 1 :20, or greater than about 1 :20.
• a disclosed compound is provided as the compound of Formula (I) in a pure composition.
• features of disclosed compounds provide various advantages. Such advantages may be related to modulation of neurotransmission, pharmacokinetics, such as properties related to absorption, distribution, metabolism, and excretion of a disclosed compound, and subjective effects, such as upon administration to a subject. In some embodiments, such advantages are determined relative to a comparator. In some embodiments, the comparator for a disclosed compound is the corresponding component drug that is not bound to a pyridoxal promoiety.
• the permeability, such as apparent permeability, of a compound describes how effectively it can pass through a membrane.
• a medium permeability compound may have an in vitro apparent permeability of 50-150 nm/s, wherein the range is inclusive.
• a high permeability compound may have an in vitro apparent permeability in excess of 150 nm/s, wherein the range is inclusive.
• Measures of permeability, such as in vitro methods are available to one of skill in the art and include, e.g., a Madin-Darby canine kidney cell line (MDCK) permeability assay and a parallel artificial membrane permeation assay (PAMPA).
• MDCK Madin-Darby canine kidney cell line
• PAMPA parallel artificial membrane permeation assay
• PAMPA is an in vitro model of passive diffusion, which has shown a high degree of correlation with permeation across a variety of barriers, including Caco-2 cultures, the gastrointestinal tract, blood-brain barrier, and skin. See, e.g., Chavda & Shah, Chapter 25 - Self-emulsifying delivery systems: one step ahead in improving solubility of poorly soluble drugs, In Micro and Nano Technologies, Nanostructures for Cancer Therapy, Elsevier, 2017, pages 653-718.
• a disclosed compound has medium permeability. In some embodiments, a disclosed compound has high permeability. In some embodiments, a disclosed compound has increased permeability relative to its corresponding component drug compound. In some embodiments, a disclosed compound has increased permeability relative to a comparator. In embodiments, permeability of a disclosed compound is increased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200% relative to a comparator.
• a disclosed compound is actively transported across a barrier (such as a mucosal barrier, e.g., a gastrointestinal (Gl) barrier; or the blood-brain barrier (BBB)).
• a disclosed compound is actively transported across the Gl barrier.
• a disclosed compound is actively transported across the BBB.
• the bioavailability of a disclosed compound may higher than a comparator compound, or higher than a phenylalkylamine drug lacking a vitamin B6-derived promoiety as disclosed in embodiments herein, because the disclosed compound may be actively transported across a barrier, whereas the phenylalkylamine drug may only diffuse passively across the same barrier.
• a disclosed compound is actively transported by epithelial cells, such as intestinal enterocytes or renal proximal tubular cells.
• a disclosed compound is actively transported across a barrier by a transporter (e.g., carrier) protein.
• a disclosed compound is actively transported across a barrier by a transporter protein for which vitamin B6 is a substrate.
• vitamin B6 transporters in humans are still not fully characterized, but may include human solute carriers SLC19A2 and SLC19A3, also known as thiamine transporters (THTR) 1 and 2, and ABC transporters; and may be similar in structure and/or function to transporters that have been characterized for yeasts and plants, which include Tpnlp, Bsu1 , members of the plant purine permease (PUP) family, and Mtmlp (Parra et al. Cells. 2018;7(7):84).
• THTR thiamine transporters
• a disclosed compound has reduced clearance relative to a comparator.
• clearance refers to intrinsic clearance.
• pharmacokinetic parameters including intrinsic clearance and half-life, are determined using an in vitro metabolic stability study comprising human liver microsomes. Methods for assessing metabolic stability, such as in vitro clearance and half-life, are described in, e.g., Gajula et al., Drug Metab Rev. 2021 ;53(3):459-477 and Knights et al., Curr Protoc Pharmacol. 2016;74:7.8.1 -7.8.24.
• Pharmacokinetic parameters may also be determined in vivo, such as in a human, e.g., according to the paradigm described by Brown et al., Clin Pharmacokinet. 2017;56(12):1543-1554. Additionally, identification of metabolites and interactions with CYP enzymes may be performed as described in, e.g., Caspar et al., Drug Test Anal. 2018; 10(1): 184-195.
• the half-life of a disclosed compound is increased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200% relative to the comparator.
• disclosed compounds are not substrates for monoamine oxidase enzymes. In some embodiments, disclosed compounds do not inhibit the activity of monoamine oxidase enzymes. In some embodiments, disclosed compounds do not irreversibly inhibit the activity of monoamine oxidase enzymes. In some embodiments, disclosed compounds do not reversibly inhibit the activity of monoamine oxidase enzymes. Monoamine oxidase enzymes include isoenzymes MAO-A and MAO-B. In some embodiments, disclosed compounds are not substrates for monoamine oxidase A (MAO-A). In some embodiments, disclosed compounds do not inhibit the activity of MAO-A. In some embodiments, disclosed compounds do not irreversibly inhibit the activity of MAO-A.
• disclosed compounds do not reversibly inhibit the activity of MAO-A. In some embodiments, disclosed compounds are not reversible inhibitors of MAO-A (RIMAs). In some embodiments, the IC 50 of disclosed compounds at MAO-A is greater than 10 pM. Herein, a threshold of greater than or equal to 10 pM (EC 50 or IC 50 ) may be used to determine an absence of activity. In some embodiments, the MAO enzymes are of mammalian origin. In some embodiments, the MAO enzymes are of human origin.
• disclosed compounds are orally bioavailable.
• disclosed compounds have an oral bioavailability (%F) of about or at least 50%, 60%, 70%, 80%, or 90%.
• %F oral bioavailability
• a disclosed compound has reduced adverse events relative to a comparator.
• adverse events include those related to neurotoxicity, cardiotoxicity, and renal toxicity, among others.
• the reduction for at least one adverse event is at least a 5% reduction, at least a 10% reduction, at least a 15% reduction, at least a 25% reduction, at least a 50% reduction, at least a 75% reduction, at least a 90% reduction, at least a 95% reduction, at least a 99% reduction, or a reduction beyond the threshold of measurement, whether determined within-patient or across patients or patient groups, or in a rodent or other suitable animal model, or determined in vitro, in silico, or otherwise measured using a standard such as one known to those of ordinary skill for the determination or quantification of the adverse event(s) in question, such as relating to anxiety, cardiovascular effects such as blood pressure and heart rate, hyperthermia, hyperhidrosis, jaw tightness and bruxism, muscle tightness, psychostimulation, appetite, nausea, concentration
• administration of a disclosed compound or composition thereof does not cause a neurotoxic effect, such as in an in vitro assay or upon administration to a subject.
• a disclosed compound or composition thereof causes a reduced neurotoxic effect, such as in an in vitro assay or upon administration to a subject.
• the reduction of a neurotoxic effect is at least a 5% reduction, at least a 10% reduction, at least a 15% reduction, at least a 25% reduction, at least a 50% reduction, at least a 75% reduction, at least a 90% reduction, or at least a 95% reduction, or at least a 99% reduction, relative to a comparator.
• the comparator is the disclosed compound’s corresponding component drug compound.
• a neurotoxic effect is determined by measuring one or more of: a) oxidative stress and dopamine-based quinones; b) mitochondrial dysfunction; and c) activation of glial cells.
• neurotoxicity or a reduction thereof is determined by evaluating mitochondrial dysfunction.
• Mitochondrial dysfunction may be evaluated by measuring one or more of mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the mitochondrial cytochrome c release, and ADP/ATP ratio. See, e.g., Taghizadeh et al., Free Radic Biol Med. 2016;99: 11-19, in which markers of mitochondrial dysfunction include a significant increase in ROS formation, collapse of MMP, mitochondrial swelling, outer membrane damage, cytochrome c release from the mitochondria, and increased ADP/ATP ratio.
• MMP mitochondrial membrane potential
• neurotoxicity or a reduction thereof is determined by assessing the activation of glial cells. Activation of quiescent glial cells has been described, e.g., by Herndon et al., Toxicological Sciences. 2014; 138(1): 130-138. Reactive astrogliosis can be measured with glial fibrillary acidic protein (GFAP) staining, and microglia reactivity can be visualized by immunostaining complement type 3 receptor (CD11 b). See, e.g., Frau et al., J Neurochem. 2013; 124(1 ):69-78 and Frau et al., Neurotoxicol. 2016;56:127-138. In embodiments, neurotoxicity or a reduction thereof is determined in vitro. In embodiments, neurotoxicity or a reduction thereof is determined in vivo.
• GFAP glial fibrillary acidic protein
• a subject administered a disclosed compound does not experience serotonin syndrome.
• a subject administered a disclosed compound experiences reduced incidence and/or severity of serotonin syndrome, e.g., relative to administration of a comparator compound.
• Co-administration of agents that increase serotonin levels, such as SERT inhibitors and MAOIs have been shown to potentiate serotonin neuromodulation, a potential complication of which is serotonin syndrome. See, e.g., Izumi et al., Eur J Pharmacol. 2006;532(3):258-64, Nakagawasai et al., Neurotoxicol.
• Serotonin syndrome ranges in severity from mild to fatal, and clinical presentations include autonomic dysfunction, neuromuscular excitation, and altered mental status, as described in, e.g., Boyer & Shannon, N Engl J Med. 2005;352(11 ):1112-20 and Wang et al., Cleve Clin J Med. 2016 Nov;83(11):810-817.
• a subject administered a disclosed compound does not experience delirium.
• a subject administered a disclosed compound experiences reduced incidence and/or severity of delirium, e.g., relative to administration of a comparator compound.
• Signs of delirium such as drug-induced delirium, include disturbances of consciousness, attention, cognition, and perception.
• the severity of delirium may be assessed using available tools, e.g., the Memorial Delirium Assessment Scale (MDAS) subitems and Karnofsky Performance Status scale (KPS). See, e.g., Boettger et al., J Geriatrics. 2014:247042; Carter et al. Drug Saf.
• MDAS Memorial Delirium Assessment Scale
• KPS Karnofsky Performance Status scale
• a disclosed compound does not cause cardiotoxicity following administration to a subject.
• reduced severity and/or incidence of cardiotoxicity is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator compound.
• disclosed compounds do not cause irregular heartbeat, e.g., tachycardia.
• disclosed compounds show reduced inhibition of a cardiac ion channel, such as by at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200% relative to a comparator.
• disclosed compounds do not inhibit the function of, such as block, cardiac ion channels.
• disclosed compounds do not block calcium channel CAV1.2.
• disclosed compounds do not block potassium channel hERG. In embodiments, disclosed compounds do not block sodium channel NAV1.5. In embodiments, a disclosed compound has an IC 50 of greater than 10 pM for any one or more of CAV1.2, hERG, and NAV1.5. In embodiments, CAV1.2, hERG, and NAV1.5 are of human origin.
• a disclosed compound does not cause rhabdomyolysis following administration to a subject.
• reduced severity and/or incidence of rhabdomyolysis is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator compound.
• disclosed compounds do not cause kidney injury, such as acute kidney injury, following administration to a subject.
• reduced severity and/or incidence of kidney injury is observed following administration of a disclosed compound to a subject, e.g., relative to administration of a comparator compound.
• disclosed compounds do not elevate serum levels of rhabdomyolysis markers and/or kidney injury markers, e.g., muscular enzymes and creatinine phosphokinase.
• administration of a disclosed compound results in reduced markers of rhabdomyolysis and/or kidney injury, such as reductions by at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200%, relative to a comparator.
• administration of disclosed compounds to a subject does not result in a reduction of any one or more of renal vasoconstriction, intraluminal cast formation, and direct myoglobin toxicity.
• administering a disclosed compound to a subject causes a psychoactive effect in the subject.
• psychoactive effects are assessed using one or more of a Peak Experience Scale (PES), e.g., as described in Reckweg et al., Front Pharmacol. 2021 ;12:760671 , the Mystical Experience Questionnaire (MEQ), the Ego Dissolution Inventory (EDI), the Challenging Experience Questionnaire (CEQ), and the 5-Dimensional Altered States of Consciousness Questionnaire (5D-ASC).
• PES Peak Experience Scale
• MEQ Mystical Experience Questionnaire
• EDI Ego Dissolution Inventory
• CEQ Challenging Experience Questionnaire
• 5D-ASC 5-Dimensional Altered States of Consciousness Questionnaire
• onset and duration of psychoactive effects may be determined by observing and/or interviewing the subject, such as by using a self-report symptom questionnaire, or by asking the subject to document subjective psychoactive effects, i.e., the subject’s experience.
• the self-report symptom questionnaire is the Subjective Drug Effects Questionnaire (SDEQ), a 272-item questionnaire measuring perceptual, mood, and somatic changes caused by psychedelics (Katz et al. J Abnorm Psych, 1968;73:1-14).
• the self-report symptom questionnaire is the List of Complaints (LC), a 66-item questionnaire that reliably measures physical and general discomfort (see, e.g., Holze et al. 2022. Psychopharmacol, 239:1893-1905). Psychoactive effects and onset and duration of such effects may additionally be determined according to methods known to one of skill in the art.
• LC List of Complaints
• compounds of Formula (I) are prepared according to the following general reaction sequence. Briefly, in a first reaction step, a phenethylamine precursor is reacted with a pyridoxal precursor. A condensation reaction between the phenethylamine primary amine (— NH 2 ) and the pyridoxal aldehyde (— COH) reversibly forms the imine compound of Formula (A), along with water (H 2 O) as a reaction byproduct.
• the imine compound of Formula (A) may be isolated from the reaction mixture.
• the compound of Formula (A) can be isolated, purified, and used as a pyridoxal-imine prodrug as described in various embodiments herein.
• the compound of Formula (A) can be used as a synthetic intermediate (with or without being isolated from the reaction mixture) in the synthesis of compounds of Formula (I).
• the compound of Formula (A) is reduced with a suitable reducing agent (e.g., NaBH 4 ) to irreversibly form a pyridoxal-amine prodrug of Formula (I):
• pyridoxal is depicted generically with X being H or PO 3 H 2 .
• X being H or PO 3 H 2 .
• pyridoxal (wherein X is H) or pyridoxal 5'-phosphate (wherein X is PO 3 H 2 ) can both be used to produce compounds of Formula (A) and Formula (I) according to disclosed methods of synthesis.
• reaction schemes above depict exemplary synthetic routes useful for the synthesis of compounds of Formula (I), they may also be used to synthesize compounds of Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IA-3), Formula (IA-4), Formula (IA-5), Formula (IA-6), Formula (IA-7), Formula (IB), Formula (IC), or Formula (ID).
• compositions such as pharmaceutical compositions, comprising a disclosed compound, such as a compound of any disclosed Formulae or subformula thereof.
• “Pharmaceutical compositions” are compositions comprising disclosed compound(s) together in an amount (for example, in a unit dosage form) with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments will not have a single carrier, diluent, or excipient alone, but will include multiple carriers, diluents, and/or excipients.
• compositions can be prepared by standard pharmaceutical formulation techniques as disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th ed., Academic Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, N.J.; Pharm. Principles of Solid Dosage Forms (1993), Technomic Pub. Co., Inc., Lancaster, Pa.; and Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; & Poznansky et al. Drug Delivery Systems (1980), R.L. Juliano, ed., Oxford, N.Y., pp. 253-315).
• “Pharmaceutically acceptable” used in connection with an excipient, carrier, diluent, or other ingredient means the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with cells of humans and animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk/benefit ratio.
• compositions comprising a disclosed compound can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal.
• the compounds employed in the methods of this disclosure are effective as oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal compositions.
• Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. (See, e.g., Remington, 2020.)
• compositions are preferably formulated in a unit dosage form, each dosage containing a therapeutically effective amount of the active ingredients, for example in the dosage amounts disclosed below.
• unit dosage form refers to a physically discrete unit suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect(s), in association with a suitable pharmaceutical carrier, diluent, or excipient.
• Unit dosage forms are often used for ease of administration and uniformity of dosage.
• Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof (e.g., one half a “full” dose for a “booster” dose as described below), of the pharmaceutical composition administered.
• Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo.
• Unit dosage forms also include ampules and vials with liquid compositions disposed therein.
• Unit dosage forms further include compounds for transdermal administration, such as “patches” that contact the epidermis (including the mucosa) of a subject for an extended or brief period of time.
• the disclosed compositions are formulated in a pharmaceutically acceptable oral dosage form.
• Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like) and oral solid dosage forms.
• the disclosed pharmaceutical compositions also may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• a disclosed composition is formulated as an oral solid dosage form.
• Oral solid dosage forms may include but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and/or any combinations thereof.
• Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations.
• the disclosed oral solid dosage forms may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
• a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet
• a pill including a sterile packaged powder
• the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-melt tablet. Additionally, pharmaceutical formulations may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.
• Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
• pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
• Oral solid dosage forms also can comprise one or more pharmaceutically acceptable additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).
• a compatible carrier complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).
• Supplementary active compounds include preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents.
• Preservatives can be used to inhibit microbial growth or increase stability of the active ingredient thereby prolonging the shelf life of the formulation.
• Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate.
• Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as alpha lipoic acid.
• a disclosed composition is formulated as an oral liquid dosage form.
• Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like.
• These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients.
• Solvents may be, for example, water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.
• Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
• Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
• Liquid formulations also may be prepared as single dose or multi-dose beverages.
• Suspensions may include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil.
• Suitable oils also include carrier oils such as MCT and long chain triglyceride (LCT) oils.
• Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides.
• Suspension formulations may include alcohols, (such as ethanol, isopropyl alcohol, hexadecyl alcohol), glycerol, and propylene glycol.
• Ethers, such as polyethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations.
• Suspension can thus include an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion, or a water-in-oil emulsion.
• formulations comprising the disclosed compositions and at least one dispersing agent or suspending agent for oral administration to a subject.
• the formulation may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
• the aqueous dispersion can comprise amorphous and non-amorphous particles consisting of multiple effective particle sizes such that a drug is absorbed in a controlled manner over time.
• Dosage forms for oral administration can be aqueous suspensions selected from the group including pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, e.g., Singh et al., Encyclopedia of Pharm. Tech., 2nd Ed., 754-757 (2002).
• the liquid dosage forms may comprise additives, such as one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, or (g) flavoring agents.
• compositions also may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• Topical dosage forms include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams.
• penetrants and carriers can be included in the pharmaceutical composition.
• Penetrants are known in the art, and include, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
• carriers which may be used include Vaseline®, lanolin, PEG, alcohols, transdermal enhancers, and combinations thereof. D. Pharmaceutical Combinations
• compositions are not limited to combinations of a single compound, or (when formulated as a pharmaceutical composition) limited to a single carrier, diluent, and/or excipient alone, but may also include combinations of multiple compounds (including additional active compounds), and/or multiple carriers, diluents, and excipients.
• Pharmaceutical compositions of this disclosure thus may comprise a disclosed compound together with one or more other active agents (or their derivatives and analogs) in combination, together with one or more pharmaceutically-acceptable carriers, diluents, and/or excipients, and additionally with one or more other active compounds.
• a formulation of the disclosure will be prepared so as to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects.
• “Therapeutic effects” that may be increased or added in embodiments of the disclosure include, but are not limited to, antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, and stimulant effects.
• “Synergistic effects” should be understood to include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect, that are greater than the additive contributions of the components acting alone. Numerous methods known to those of skill in the art exist to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby producing “1 +1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol. 2019; 10:1222), or the equation of Loewe additivity (Loewe & Muischnek, Arch Exp Pathol Pharmacol.
• a synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, Clin Pharmacokinet. 1981 ;6: 429-453) and the median-effect equation (Chou & Talalay, Adv Enzyme Regul. 1984;22:27-55).
• the corresponding graphs associated with the equations referred to above are the concentration-effect curve and combination index curve, respectively. Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
• a disclosed pharmaceutical composition comprises an additional active compound.
• the additional active compound is selected from the group consisting of: amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents (e.g., psychoplastogens), monoamine oxidase inhibitors, tryptamines, terpenes, phenylalkylamines, sedatives, stimulants, serotonergic agents, and vitamins.
• the additional active compound is selected from the group consist
• the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, increase plasticity (e.g., neural plasticity), or alter pharmacokinetics or pharmacodynamics.
• the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.
• an additional active compound is a tryptamine.
• tryptamines are compounds having the general structure below, wherein R N1 , R N2 , R a , R p , R 2 , R 4 , R 5 , R 6 , and R 7 are as defined herein and as generally understood in the art:
• R N1 , R N2 , R a , R p , R 2 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, deuterium, halogen (F, Cl, Br, or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
• any two of R N1 , R N2 , R a , R p , R 2 , R 4 , R 5 , R 6 , and R 7 and the intervening atoms can be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
• the tryptamine is a quaternary salt, in which an additional R N3 is connected to the nitrogen to which R N1 and R N2 are bound; wherein R N3 is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
• the additional active compound is a tryptamine selected from the group consisting of O-Phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 6-allyl-N,N-diethyl- norlysergamide (AL-LAD), N,N-dibutyltryptamine (DBT), N,N-diethyltryptamine (DET), N,N-diisopropyl- tryptamine (DiPT), 5-methoxy-a-methyltryptamine (a,O-DMS), N,N-dimethyl-tryptamine (DMT), 2,a-dimethyltryptamine (2,a-DMT), a,N-dimethyltryptamine (a,N-DMT), N,N-dipropyltryptamine (DPT), N-ethyl-N-isopropyltryptamine (EiPT), a-ethyl
• 5-methoxytryptamine (5-MeO-DET), N,N-diisopropyl-5-methoxy-tryptamine (5-MeO-DiPT), N,N,diallyl- 5-methoxytryptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-isopropyl-
• 4-methoxy-N-methyltryptamine (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyltryptamine (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyltryptamine (5,6-MeO-MiPT), 5-methoxy-N-methyl-tryptamine (5-MeO-NMT), 5-methoxy-N,N-tetramethylenetryptamine (5-MeO-pyr-T), 6-methoxy-1 -methyl-1 ,2,3,4-tetra- hydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl-tryptamine (5-MeO-TMT), N,N-dimethyl-
• 5-methylthiotryptamine (5-MeS-DMT), N-isopropyl-N-methyltryptamine (MiPT), a-methyltryptamine (a-MT), N-ethyltryptamine (NET), N-methyltryptamine (NMT), 6-propylnorlysergamide (PRO-LAD), N,N-tetra- methylenetryptamine (pyr-T), tryptamine (T), 7-methoxy-1 -methyl-1, 2, 3, 4-tetrahydrocarboline (THH), or a,N-dimethyl-5-methoxytryptamine (a,N,O-TMS), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.
• an additional tryptamine will be a “complex tryptamine” or other indolamine and including such examples as iboga alkaloids such as ibogaine, and their analogs, metabolites, and derivatives, and beta-carbolines.
• the additional active compound is a phenylalkylamine.
• a phenylalkylamine may be a phenylalkylamine having the structure of Formula (A), wherein R N1 , R N2 , R a , R p , and each of R 2 -R 6 are as defined herein and as generally understood in the art.
• the additional active compound is a phenylalkylamine selected from the group consisting of a-ethyl-3,4,5-trimethoxy-phenethylamine (AEM), 4-allyloxy-3,5-dimethoxy- phenethylamine (AL), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH), 2,5-dimethoxy-4-ethylthio- amphetamine (ALEPH-2), 2,5-dimethoxy-4-isopropylthioamphetamine (ALEPH-4), 2,5-dimethoxy-4-phenyl- thioamphetamine (ALEPH-6), 2,5-dimethoxy-4-propylthioamphetamine (ALEPH-7), 2,5-dimethoxy- a-ethyl-4-methylphenethylamine (ARIADNE), 3,4-diethoxy-5-methoxy-phenethylamine (ASB), 4-butoxy-3,5-ethyl-3,4,5
• MDEA 3.4-methylenedioxy-N-ethylamphetamine
• C-B 4-bromo-2,5-dimethoxyphenethylamine
• C-BZ 4-benzyloxy-3,5-dimethoxy- amphetamine
• C-C 4-chloro-2,5-dimethoxyphenethylamine
• DME 2,5-dimethoxy-3,4- methylenedioxyamphetamine
• DMDA 2,3-dimethoxy-4,5-methylenedioxyamphetamine
• DPEA 3,4-dimethoxyphenethylamine
• DOAM 4-amyl-2,5-dimethoxyamphetamine
• DOB 4-bromo-2,5-dimethoxyamphetamine
• DOBU 4-butyl-2,5-dimethoxyamphetamine
• DOC 4-chloro-2,5-dimethoxyamphetamine
• DOEF 2,5-dimethoxy-4- (2-fluoroethyl)amphetamine
• DOET 2,5-dimethoxy-4-ethylamphetamine
• DOI 2,5-dimethoxy-4-methylamphetamine
• MCM 2.5-dimethoxy-4-ethoxyamphetamine
• MEPEA 4-ethoxy-3-methoxyphenethylamine
• MMDA 3-methoxy-4,5-methylenedioxyamphetamine
• MMDA-2 2-methoxy- 4,5-methylenedioxyamphetamine
• MMDA-3a 2-methoxy-3,4-methylenedioxyamphetamine
• MME 2,4-dimethoxy-5-ethoxyamphetamine
• MP 2,5-dimethoxy-4-(n)-propoxyamphetamine
• MPM 2,5-dimethoxy-2-propoxyamphetamine
• ORTHO-DOT 3,5-dimethoxy-4-propoxyphenethylamine
• P 3,5-dimethoxy-4- phenethyloxyphenethylamine
• PEA phenethylamine
• the additional active compound is an ergoline. In embodiments, the additional active compound is an ergot alkaloid. In embodiments, the additional active compound is a lysergamide.
• lysergamides are compounds having the general structure below, wherein R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are as defined herein and as generally understood in the art:
• R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are each independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
• any two of R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 and the intervening atoms can be taken together to form an optionally substituted optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
• the lysergamide is a quaternary salt, in which an additional R 6A is connected to the nitrogen to which R 6 is bound; wherein R 6A is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
• the additional active compound is a lysergamide selected from the group consisting of lysergic acid diethylamide (i.e., LSD, LSD-25, LAD, Delysid), 6-ethyl-6-nor-lysergic acid diethylamide (ETH-LAD), 6-propynyl-6-nor-lysergic acid diethylamide (PARGY-LAD), 6-allyl-6-nor-lysergic acid diethylamide (AL-LAD), 6-propyl-6-nor-lysergic acid diethylamide (PRO-LAD), 6-isopropyl-6-nor-lysergic acid diethylamide (IP-LAD), 6-cylopropyl-6-nor-lysergic acid diethylamide (CIP-LAD), 6-butyl-6-nor-lysergic acid diethylamide (BU-LAD), 6-(2-fluoroethylamide, LSD, L
• compositions comprise a therapeutically effective amount or an effective amount of a disclosed compound, such as for administration to a subject.
• Administration of pharmaceutical compositions in a “therapeutically effective amount,” or an “effective amount” to a subject means administration of an amount of composition sufficient to achieve the desired effect.
• an “effective amount” means an amount effective in treating the stated disorder or symptoms in a subject
• “therapeutic effect” would be understood to mean the responses(s) in a subject after treatment that are judged to be desirable and beneficial.
• a pharmaceutical composition includes a disclosed compound
• it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg/kg or less (including a dose of 0.10 mg/kg or less, 0.05 mg/kg or less, 0.01 mg/kg or less, and 0.005 mg/kg or less), at least 0.50 mg/kg, at least 0.55 mg/kg, at least 0.60 mg/kg, at least 0.65 mg/kg, at least 0.70 mg/kg, at least 0.75 mg/kg, at least 0.80 mg/kg, at least 0.85 mg/kg, at least 0.90 mg/kg, at least 0.95 mg/kg, at least 1.0 mg/kg, at least 1.1 mg/kg, at least 1.2 mg/kg, at least 1.3 mg/kg, or at least 1.4 mg/kg, at least 1.5 mg/kg, at least 1.6 mg/kg, at least 1.7 mg/kg, at least 1.8
• a pharmaceutical composition includes a disclosed compound
• it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient) between about 0.01 mg/kg and 0.1 mg/kg, such as about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg about 0.08 mg/kg about 0.09 mg/kg, and about 0.1 mg/kg, as well as ranges between these values.
• a single dose is between about 0.1 mg/kg and 1.0 mg/kg, such as about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg about 0.8 mg/kg about 0.9 mg/kg, and about 1 .0 mg/kg, as well as ranges between these values.
• a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg,
• a pharmaceutical composition includes a disclosed compound
• it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) between about 0.1 mg and 1.0 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, and about 1.0 mg, as well as ranges between these values.
• a single dose is between about 1 mg and 10 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg, as well as ranges between these values.
• a single dose is between about 10 mg and 100 mg.
• a pharmaceutical composition includes a disclosed compound
• it may be present in an amount so that a single dose is (in a microgram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 pg/kg or less (including a dose of 0.10 pg/kg or less, 0.05 pg/kg or less, and 0.01 pg/kg or less), at least 0.50 pg/kg, at least 0.55 pg/kg, at least 0.60 pg/kg, at least 0.65 pg/kg, at least 0.70 pg/kg, at least 0.75 pg/kg, at least 0.80 pg/kg, at least 0.85 pg/kg, at least 0.90 pg/kg, at least 0.95 pg/kg, at least 1.0 pg/kg, at least 1.1 pg/kg, at least 1.2 pg/kg, at least 1.3 pg/kg, at least 1.4 pg/kg, at
• a pharmaceutical composition includes a disclosed compound
• it may be present in an amount so that a single dose is (in a microgram dosage amount calculated based on the kilogram weight of the patient) between about 0.01 pg/kg and 0.1 pg/kg, such as about 0.01 pg/kg, about 0.02 pg/kg, about 0.03 pg/kg, about 0.04 pg/kg, about 0.05 pg/kg, about 0.06 pg/kg, about 0.07 pg/kg about 0.08 pg/kg about 0.09 pg/kg, and about 0.1 pg/kg, as well as ranges between these values.
• a single dose is between about 0.1 pg/kg and 3.0 pg/kg, such as about 0.1 pg/kg, about 0.2 pg/kg, about 0.3 pg/kg, about 0.4 pg/kg, about 0.5 pg/kg, about 0.6 pg/kg, about 0.7 pg/kg about 0.8 pg/kg about 0.9 pg/kg, about 1.0 pg/kg, about 1.2 pg/kg, about 1.4 pg/kg, about 1.6 pg/kg, about 1.8 pg/kg, about 2.0 pg/kg, about 2.2 pg/kg, about 2.4 pg/kg, about 2.6 pg/kg, about 2.8 pg/kg, about 3.0 pg/kg, as well as ranges between these values.
• a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 pg or less (including a dose of 10 pg or less, 5 pg or less, and 1 pg or less), from about 25 to 1000 pg, 50 to 1000 pg, 100 to 1000 pg, 200 to 1000 pg, 300 to 1000 pg, 400 to 1000 pg, 500 to 1000 pg, or greater than 1000 pg.
• a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenylalkylamine or tryptamine, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg/kg or less (including a dose of 0.10 mg/kg or less, 0.05 mg/kg or less, 0.01 mg/kg or less, and 0.005 mg/kg or less), at least 0.50 mg/kg, at least 0.55 mg/kg, at least 0.60 mg/kg, at least 0.65 mg/kg, at least 0.70 mg/kg, at least 0.75 mg/kg, at least 0.80 mg/kg, at least 0.85 mg/kg, at least 0.90 mg/kg, at least 0.95 mg/kg, at least 1.0 mg/kg, at least 1.1 mg/kg, at least 1.2 mg/kg, at least 1.3 mg/kg, or at least 1.4 mg/kg, at least 1.5 mg
• a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenylalkylamine or a tryptamine, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at
• a dose of a disclosed compound is in the range of about 1 mg to about 100 mg.
• the dose may be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.
• a dose of a disclosed compound is between about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 30 mg.
• a dose of a disclosed compound is about 1 mg, about 10 mg, or about 25 mg.
• a dose of a disclosed compound is in the range of about 0.001 mg to about 1 g.ln some embodiments, a dose of a disclosed compound is in the range of about 100 mg to about 250 mg. In some embodiments, a dose of a disclosed compound is about 25 mg.
• a disclosed compound is administered daily. In embodiments, a disclosed compound is administered twice a day. In embodiments, a disclosed compound is administered three times a day. In embodiments, a disclosed compound is administered every other day. In embodiments, a disclosed compound is administered every third day. In embodiments, a disclosed compound is administered every fourth day. In embodiments, a disclosed compound is administered every fifth day. In embodiments, a disclosed compound is administered weekly. In embodiments, a disclosed compound is administered every other week. In embodiments, a disclosed compound is administered every third week. In embodiments, a disclosed compound is administered monthly.
• about 50 mg of a disclosed compound is administered daily. In some embodiments, about 50 mg of a disclosed compound is administered twice a day. In some embodiments, about 50 mg of a disclosed compound is administered three times a day. In some embodiments, about 50 mg of a disclosed compound is administered every other day. In some embodiments, about 50 mg of a disclosed compound is administered every third day. In some embodiments, about 50 mg of a disclosed compound is administered every fourth day. In some embodiments, about 50 mg of a disclosed compound is administered every fifth day. In some embodiments, about 50 mg of a disclosed compound is administered weekly. In some embodiments, about 50 mg of a disclosed compound is administered every other week. In some embodiments, about 50 mg of a disclosed compound is administered every third week. In some embodiments, about 50 mg of a disclosed compound is administered monthly.
• about 100 mg of a disclosed compound is administered daily. In some embodiments, about 100 mg of a disclosed compound is administered twice a day. In some embodiments, about 100 mg of a disclosed compound is administered three times a day. In some embodiments, about 100 mg of a disclosed compound is administered every other day. In some embodiments, about 100 mg of a disclosed compound is administered every third day. In some embodiments, about 100 mg of a disclosed compound is administered every fourth day. In some embodiments, about 100 mg of a disclosed compound is administered every fifth day. In some embodiments, about 100 mg of a disclosed compound is administered weekly. In some embodiments, about 100 mg of a disclosed compound is administered every other week. In some embodiments, about 100 mg of a disclosed compound is administered every third week. In some embodiments, about 100 mg of a disclosed compound is administered monthly.
• about 150 mg of a disclosed compound is administered daily. In some embodiments, about 150 mg of a disclosed compound is administered twice a day. In some embodiments, about 150 mg of a disclosed compound is administered three times a day. In some embodiments, about 150 mg of a disclosed compound is administered every other day. In some embodiments, about 150 mg of a disclosed compound is administered every third day. In some embodiments, about 150 mg of a disclosed compound is administered every fourth day. In some embodiments, about 150 mg of a disclosed compound is administered every fifth day. In some embodiments, about 150 mg of a disclosed compound is administered weekly. In some embodiments, about 150 mg of a disclosed compound is administered every other week. In some embodiments, about 150 mg of a disclosed compound is administered every third week. In some embodiments, about 150 mg of a disclosed compound is administered monthly.
• about 200 mg of a disclosed compound is administered daily. In some embodiments, about 200 mg of a disclosed compound is administered twice a day. In some embodiments, about 200 mg of a disclosed compound is administered three times a day. In some embodiments, about 200 mg of a disclosed compound is administered every other day. In some embodiments, about 200 mg of a disclosed compound is administered every third day. In some embodiments, about 200 mg of a disclosed compound is administered every fourth day. In some embodiments, about 200 mg of a disclosed compound is administered every fifth day. In some embodiments, about 200 mg of a disclosed compound is administered weekly. In some embodiments, about 200 mg of a disclosed compound is administered every other week. In some embodiments, about 200 mg of a disclosed compound is administered every third week. In some embodiments, about 200 mg of a disclosed compound is administered monthly.
• about 250 mg of a disclosed compound is administered daily. In some embodiments, about 250 mg of a disclosed compound is administered twice a day. In some embodiments, about 250 mg of a disclosed compound is administered three times a day. In some embodiments, about 250 mg of a disclosed compound is administered every other day. In some embodiments, about 250 mg of a disclosed compound is administered every third day. In some embodiments, about 250 mg of a disclosed compound is administered every fourth day. In some embodiments, about 250 mg of a disclosed compound is administered every fifth day. In some embodiments, about 250 mg of a disclosed compound is administered daily. In some embodiments, about 250 mg of a disclosed compound is administered weekly. In some embodiments, about 250 mg of a disclosed compound is administered every other week. In some embodiments, about 250 mg of a disclosed compound is administered every third week. In some embodiments, about 250 mg of a disclosed compound is administered monthly.
• an initial dose of a disclosed compound is administered, which is then boosted 30 minutes-4 hours later by administering a second dose of the disclosed compound.
• the boosted dose is administered about 30 min after the initial dose.
• the boosted dose is administered about 60 min after the initial dose.
• the boosted dose is administered about 90 min after the initial dose.
• the boosted dose is administered about 120 min after the initial dose.
• the boosted dose is administered about 150 min after the initial dose.
• the boosted dose is administered about 180 min after the initial dose.
• the boosted dose is administered about 210 min after the initial dose.
• the boosted dose is administered about 240 min after the initial dose.
• the boosted dose is from about 10% to 100% of the amount of the initial dose. In some embodiments, the boosted dose is the same amount as the initial dose. In some embodiments, the boosted dose is about half of the amount of the initial dose. In some embodiments, this dosing schedule is performed daily. In some embodiments, this dosing schedule is performed twice a day. In some embodiments, this dosing schedule is performed three times a day. In some embodiments, this dosing schedule is performed every other day. In some embodiments, this dosing schedule is performed every third day. In some embodiments, this dosing schedule is performed every fourth day. In some embodiments this dosing schedule is performed every fifth day. In some embodiments, this dosing schedule is performed weekly. In some embodiments, this dosing schedule is performed every other week. In some embodiments, this dosing schedule is performed every third week. In some embodiments, this dosing schedule is performed monthly.
• a dose of a disclosed compound may be in the range of about 1 mg/kg to about 100 mg/kg.
• the dose may be about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg.
• the dose of a disclosed compound is between about 0.1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 50 mg/kg, or about 5 mg/kg to about 30 mg/kg. In some embodiments, the dose of a disclosed compound is about 1 mg/kg, about 10 mg/kg, or about 25 mg/kg. In some embodiments, the dose of a disclosed compound is in the range of about 0.001 mg/kg to about 1 g/kg. In some embodiments, the dose of a disclosed compound is in the range of about 100 mg/kg to about 250 mg/kg. In some embodiments, the dose of a disclosed compound is about 25 mg/kg.
• a disclosed compound is administered, e.g., as a single dose or one or more times per week (up to twice daily or even three times a days). In some embodiments, a disclosed compound is administered according to a dosing schedule provided herein. In some embodiments, a disclosed compound is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
• dosages may vary depending upon whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by the skilled artisan (e.g., medical or familial history).
• Dose amount, frequency or duration may be increased or reduced, as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications.
• the skilled artisan with the teaching of this disclosure in hand will appreciate the factors that may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.
• the dose actually administered will be determined by a physician, in light of the relevant circumstances, including the disorder to be treated, the chosen route of administration, the actual composition or formulation administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms, and therefore any dosage ranges disclosed herein are not intended to limit the scope of the disclosure.
• dosage levels below the lower limit of a disclosed range may be more than adequate, while in other cases doses above a range may be employed without causing any harmful side effects, provided for instance that such larger doses also may be divided into several smaller doses for administration, either taken together or separately.
• suggested dosage amounts may be known by reference to the format of the preparation itself.
• suggested dosage amounts may be known by reference to the means of administration or by reference to the packaging and labeling, package insert(s), marketing materials, training materials, or other information and knowledge available to one of skill or the public.
• kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefore, and a suitable container.
• Individual unit dosage forms can be included in multi-dose kits or containers, pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.
• kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefore, and a suitable container.
• Individual unit dosage forms can be included in multi-dose kits or containers, pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.
• Kits generally comprise suitable packaging.
• the kits may comprise one or more containers comprising any compound described herein.
• Each component if there is more than one component
• the kits may be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.
• the kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub- unit doses.
• kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
• Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
• kits of the disclosure can further contain package inserts and other printed instructions (e.g., on exterior packaging) for administering the disclosed compositions and for their appropriate therapeutic use.
• disclosed compounds are used to modulate neurotransmission.
• disclosed compounds are used to treat a condition, such as a disease or a disorder.
• disclosed compounds are used in the manufacture of a medicament for the therapeutic and/or the prophylactic treatment of a condition, such as a disease or a disorder.
• disclosed compounds are administered as part of psychedelic-assisted therapy.
• disclosed compounds are administered in a therapeutically effective amount to a subject having a condition, such as a disease or a disorder.
• the condition is a mental health disorder.
• the condition is a neurodegenerative disorder.
• the condition is an inflammatory disorder.
• the condition is pain and/or inflammation.
• disclosed compounds are administered to a subject that is healthy.
• the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to any mammal, including murines, simians, mammalian farm animals, mammalian sport animals, and mammalian pets, such as canines and felines, although preferably humans. Such terms will be understood to include one who has an indication for which a compound, composition, or method described herein may be efficacious, or who otherwise may benefit by the invention. In general, all of the compounds, compositions, and disclosed methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood. The disclosed methods of treatment also can be modified to treat multiple patients at once, including couples or families. Hence, these terms will be understood to also mean two or more individuals.
• disclosed compounds or compositions thereof are orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation or transdermally administered to a subject.
• the disclosed compounds and the disclosed compositions and formulations comprising them are useful in methods for treating a patient in need of such treatment.
• administering a disclosed compound modulates neurotransmission in a subject, such as following administration of a pharmacologically effective amount to said subject.
• modulating neurotransmission comprises regulating levels of monoamines in, for example, the CNS and peripheral tissues.
• modulating neurotransmission comprises increasing levels of monoamines in, for example, the CNS and peripheral tissues of a subject to whom a disclosed compound has been administered.
• modulating neurotransmission comprises decreasing levels of monoamines in, for example, the CNS and peripheral tissues of a subject to whom a disclosed compound has been administered.
• modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.
• administration of a disclosed compound or composition thereof results in inhibiting the reuptake of one or more neurotransmitters. In some embodiments, administration of a disclosed compound or composition thereof results in increasing the extracellular concentration of one or more neurotransmitters, including the amount of extracellular serotonin, dopamine, or norepinephrine.
• the disclosed compounds are used to modulate neurotransmission, such as neurotransmission in a subject.
• the disclosed compositions when administered in a pharmacologically effective amount, thus affect monoaminergic neurotransmission, including serotonergic, dopaminergic, and noradrenergic neurotransmission.
• the disclosed compositions when administered in a pharmacologically effective amount, are used to treat a medical condition linked to dysregulation or inadequate functioning of neurotransmission, and in specific embodiments, are used to treat a medical condition linked to monoaminergic neurotransmission.
• administration of a disclosed compound or composition thereof results in modulation of one or more monoamine receptors, such as a serotonin receptor, a dopamine receptor, or a norepinephrine receptor.
• administration of a disclosed compound or composition thereof results in agonism or partial agonism of a monoamine receptor, including any one or more of a serotonin receptor, a dopamine receptor, and a norepinephrine receptor.
• administration of a disclosed compound or composition thereof results in activation of a serotonin receptor.
• administration of a disclosed compound or composition thereof results in agonism and/or antagonism of a serotonin receptor (HTR).
• administration of a disclosed compound or composition thereof results in agonism or partial agonism of an HTR, such as any one or more of an HTR b such as HTR 1A and HTR 1B , an HTR 2 , such as HTR 2A , HTR 2B , and HTR 2C , and HTR 6 .
• a drug comprised in a disclosed compound has an in vitro EC 50 (agonist mode) for any one or more of HTR 1A , HTR 1B , HTR 2A HTR 2B , and HTR 6 that is less than 10 pM, less than 5 pM, less than 1 M, less than 0.5 pM, or less than 0.1 pM.
• a drug comprised in a disclosed compound has an in vitro EC 50 (agonist mode) for HTR ⁇ that is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM.
• administration of a disclosed compound or composition thereof results in increased agonism of HTR 2A relative to other HTRs.
• administration of a disclosed compound or composition thereof results in increased agonism of HTR 2A relative to any one or more of an HTR!, such as HTR 1A and HTR 1B , another HTR 2 , such as HTR 2B and HTR 2C , an HTR 5 , e.g., HTR 5A , HTR 6 , and an HTR 7 , e.g., HTR 7D .
• a drug comprised in a disclosed compound modulates the activity of a dopamine receptor (DR), such as any one or more of DRD1 , DRD2, DRD3, DRD4, and DRD5.
• a drug comprised in a disclosed compound agonizes or partially agonizes a dopamine receptor.
• a drug comprised in a disclosed compound agonizes or partially agonizes DRD2.
• a drug comprised in a disclosed compound agonizes or partially agonizes the DRD2 short isoform (DRD2S).
• a drug comprised in a disclosed compound has an in vitro EC50 for DRD2S that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM.
• Determining agonism and antagonism, and measuring EC 50 and IC 50 , respectively, may be determined according to methods available to one of skill in the art.
• measuring Gq-mediated calcium flux is a known method for assessing modulation, e.g., activation, of HTR 2A , a widely recognized target of psychedelic compounds. See, e.g., Klein et al., ACS Pharmacol Transl Sci. 2020 14;4(2):533-542; Flanagan et al., ACS Pharmacol Transl Sci. 2020;4(2):488-502; Toro-Sazo et al., PLoS One.
• disclosed compounds or compositions thereof when administered in a pharmacologically effective amount, result in modulation of one or more membrane monoamine transporters, including any one or more of a serotonin membrane transporter (SERT), a dopamine membrane transporter (DAT), a norepinephrine membrane transporter (NET), and a vesicular monoamine transporter.
• a drug comprised in a disclosed compound blocks the uptake activity of monoamine transporters.
• a drug comprised in a disclosed compound blocks the uptake activity of one or more of a serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).
• a drug comprised in a disclosed compound inhibits the uptake activity of any one or more of SERT, DAT, and NET. In some embodiments, a drug comprised in a disclosed compound inhibits the uptake activity of SERT, DAT, and NET. In embodiments, a drug comprised in a disclosed compound has an in vitro IC 50 of less than 10 pM for any one or more of SERT, DAT, and NET. In embodiments, a drug comprised in a disclosed compound does not inhibit the uptake activity of SERT. In embodiments, a drug comprised in a disclosed compound has an in vitro IC 50 of less than 10 pM for SERT. In embodiments, a drug comprised in a disclosed compound selectively inhibits the uptake activity of SERT. In embodiments, a drug comprised in a disclosed compound shows greater potency for inhibiting the uptake activity of SERT relative to DAT and NET.
• Determining whether a disclosed compound results in inhibition of the uptake activity of a monoamine transporter, or whether such activity is lacking, may be determined according to available methods, which may include live-cell fluorescent assays or radioactive assays.
• inhibition of monoamine uptake may be determined in rat synaptosomes or human platelets. See, e.g., Segonzac et al., J Neurochem. 1985;44(2):349-56; Cozzi et al., J Neural Transm (Vienna). 2009; 116(12):1591 -9.
• inhibitory activity may be compared to uptake inhibitors having low nM potency, e.g., DAT inhibitor GBR 12909, NET inhibitor desipramine, and SERT inhibitor clomipramine.
• administration of a disclosed compound or composition according to the methods herein results in an improved pharmacological profile, such as a relative increase in agonism of serotonin receptors compared to dopamine and/or norepinephrine receptors, compared to a corresponding composition, which may be an increase of 5% or more, 10% or more, 25% or more, or 50% or more, and including amounts in between.
• a relative increase in agonism of serotonin receptors compared to dopamine and/or norepinephrine receptors compared to a corresponding composition, which may be an increase of 5% or more, 10% or more, 25% or more, or 50% or more, and including amounts in between.
• Measurements of agonism of a receptor will be as understood by those in the art or by reference to the general knowledge in the art.
• an improved pharmacological profile of a disclosed compound or composition will be a relative increase in extracellular concentration of serotonin compared to dopamine and/or norepinephrine, compared to a corresponding non-substituted composition, which may be an increase of 5% or more, 10% or more, 25% or more, or 50% or more, and including amounts in between.
• Measurements of extracellular concentration of a neurotransmitter will be as understood by those in the art or by reference to the general knowledge in the art.
• Detecting a change in monoamine levels in a subject can be achieved according to methods known to one of skill, for example, brain microdialysis ( chefser et al., Curr Protoc Neurosci. 2009; Chapter: Unit 7.1 ; Darvesh et al., Expert Opin Drug Discov. 2011 ;6(2):109-127) and brain imaging, for example, positron emission tomography (PET) and single photon emission computed tomography (SPECT) (see e.g., Wong & Gjedde, Encyclopedia Neurosci, 2009; 939-952 and Takano, Front Psychiatry. 2018; 9:228).
• PET positron emission tomography
• SPECT single photon emission computed tomography
• a disclosed compound is used to increase neuroplasticity.
• Neuroplasticity also known as neural plasticity or brain plasticity, refers to the brain's ability to change and adapt in response to experiences, learning, and environmental factors. Neuroplasticity occurs through several mechanisms, including synaptic plasticity, which involves the strengthening or weakening of connections (synapses) between neurons. Synaptic plasticity is often associated with learning and memory processes. Another form of plasticity is called structural plasticity, which involves changes in the physical structure of neurons, such as the growth of new dendritic branches or the formation of new synapses.
• increasing neuroplasticity contributes to the therapeutic effects of a disclosed compound in a subject.
• increasing neuroplasticity by administering a disclosed compound to a subject treats a disease or disorder in the subject.
• Neuroplasticity can be defined in terms of neuritogenesis, spinogenesis, and synaptogenesis in neurons.
• Neuritogenesis refers to the process by which neurons generate and extend their neurites (i.e., to form axons and dendrites). Neuritogenesis is a critical step in neural development and the formation of neuronal circuits.
• Spinogenesis refers to the formation of dendritic spines, which are small protrusions on the dendrites of neurons. Dendritic spines are crucial for synaptic connections and play a vital role in synaptic transmission and plasticity.
• Synaptogenesis refers to the formation of synapses, which is crucial for the establishment and refinement of neural circuits, and is a fundamental process underlying learning, memory, and information processing in the brain.
• administering increases neuritogenesis.
• Neuritogenesis can be measured in terms of total neurite length, maximum neurite length, number of neurite nodes, and/or number of neurite extremities.
• administration of a disclosed compound or composition thereof increases total neurite length.
• administration of a disclosed compound or composition thereof increases maximum neurite length.
• administration of a disclosed compound or composition thereof increases the number of neurite nodes.
• administration of a disclosed compound or composition thereof increases the number of neurite extremities.
• administration of a disclosed compound or composition thereof to a subject results in an increase in the number of dendritic branches, the number of dendritic crossings, the density of dendritic spines, the density of synapses (i.e., number of synapses per neuron), or total dendritic length.
• these factors can be measured using a Sholl analysis and other techniques known to those of skill in the art (Ly et al. ACS Pharmacol Transl Sci. 2020;4(2):452-460).
• a disclosed compound is used to treat a medical condition, such as a disease or disorder.
• a disclosed compound is used in the manufacture of a medicament to treat a condition, such as a disease or disorder.
• a disclosed compound or pharmaceutical composition comprising the disclosed compounds are administered to a subject by one or more routes of administration, including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes.
• routes of administration including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes.
• treating and/or preventing a condition in a subject comprising administering to the mammal a therapeutically effective amount of a disclosed compound or pharmaceutical composition.
• “treating” or “treatment” refers to treating a disease or disorder in a subject, and preferably in a human, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e.
• treatment includes prevention. In other embodiments, treatment does not include prevention. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood to one of skill in view of the teachings herein and the knowledge in the art.
• a disclosed compound is used to treat a central nervous system (CNS) disorder.
• CNS disorders include diseases of the nervous system (e.g., movement disorders, neurodegenerative disorders) as well as mental, behavioral, and neurodevelopmental disorders, such as those in the DSM-5, Merck Manual, ICD-11 , or other such diagnostic resources known to one of skill. i. Mental, Behavioral, or Neurodevelopmental Disorders
• a disclosed compound is used to treat a mental, behavioral, or neurodevelopmental disorder.
• disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental, behavioral, or neurodevelopmental disorder, thereby treating said mental, behavioral, or neurodevelopmental disorder.
• a disclosed composition when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a mental, behavioral, or neurodevelopmental disorder.
• the ICD-11 which is incorporated by reference herein in its entirety, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant disturbance in an individual's cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning.
• Such disorders include, but are not limited to, neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.
• a mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11.
• the term mental disorder (or “mental health disorder”) generally refers to a disease condition that involves negative changes in emotion, mood, thinking, and/or behavior.
• mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotion, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of suffering.
• mental disorder and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11 , or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11 , ICD-10, DSM-5, or DSM-IV (each of which is incorporated by reference herein in its entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.
• a disclosed compound is used to treat a mental health disorder.
• disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating said mental health disorder.
• a disclosed composition when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a mental health disorder.
• a compound or composition of the disclosure is used to reduce the symptoms of a mental health disorder. The symptoms of the mental health disorder to be treated shall be able to be determined by one of skill in the art, by reference to the general understanding of the art regarding that disorder.
• measures of therapeutic efficacy include reports by a subject or an observer.
• measures of therapeutic efficacy include responses to a questionnaire.
• measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject- or observer-reported measures.
• GID-7 Generalized Anxiety Disorder Scale-7
• MADRS Montgomery-Asberg Depression Rating Scale
• GAF Global Assessment of Functioning Scale
• CGI Clinical Global Impression
• a disclosed compound is used to treat a neurodevelopmental disorder.
• a “neurodevelopmental disorder” is a neurological and/or cognitive disorder that arises during the developmental period that involves significant difficulties in the acquisition and execution of specific neurological functions (e.g., intellectual, motor, language, or social functions).
• the neurodevelopmental disorder is a disorder of intellectual development, a developmental speech or language disorder, autism spectrum disorder, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.
• a disclosed compound is used to treat schizophrenia or another primary psychotic disorder.
• these disorders are characterized by significant impairments in reality and alterations in behavior manifest in positive symptoms like persistent delusions, persistent hallucinations, disorganized thinking and speech, grossly disorganized behavior, as well as experience of negative symptoms such as blunted or flat affect and avolition and psychomotor disturbances.
• a disclosed compound is used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder.
• a disclosed compound is used to treat catatonia.
• catatonia refers to a category of syndromes characterized by the co-occurrence of several symptoms of decreased, increased, or abnormal psychomotor activity.
• the catatonia is associated with another mental disorder.
• the catatonia is induced by substances or medications.
• a disclosed compound is used to treat a mood disorder.
• mood disorders are categorized according to the specific type(s) of mood episodes, and their pattern over time. The primary types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes.
• the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder), a depressive disorder, or a substance-induced mood disorder.
• the mood disorder is a depressive disorder.
• the depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder (formally known as dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, seasonal affective disorder, mixed depressive and anxiety disorder, or an unspecified depressive disorder.
• depression is assessed through the Patient Health Questionnaire-9 (PHQ-9) screening tool, Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale, Beck Depression Inventory (BDI-II), Zung Self-Rating Depression Scales (SDS), Major Depression Inventory (MDI), Center for Epidemiologic Studies Depression Scale (CED-D), Rome Depression Inventory (RDI), Hamilton Rating Scale for Depression (HRSD), and Carroll Rating Scale (CRS).
• PHQ-9 Patient Health Questionnaire-9
• MADRS Montgomery-Asberg Depression Rating Scale
• BDI-II Beck Depression Inventory
• SDS Zung Self-Rating Depression Scales
• MDI Major Depression Inventory
• CED-D Center for Epidemiologic Studies Depression Scale
• RDI Rome Depression Inventory
• Hamilton Rating Scale for Depression HRSD
• CRS Consumer Rating Scale
• a disclosed compound is used to treat an anxiety or fear-related disorder.
• An “anxiety disorder” refers to a class of mental disorders that induce excessive or abnormal fear, dread, or worry.
• the anxiety disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or a substance-induced anxiety disorder.
• a disclosed compound is used to treat an obsessive-compulsive or related disorder.
• these disorders are characterized by repetitive thoughts and behaviors, such as cognitive phenomena (obsessions, intrusive thoughts and preoccupations).
• the disorder is characterized by a compulsive need to accumulate possessions and distress related to discarding them (i.e., hoarding disorder).
• the disorder is body-focused and can be characterized by recurrent and habitual actions (hair-pulling, skin-picking).
• the disorder is obsessive-compulsive disorder, body dysmorphic disorder, olfactory reference disorder, hypochondriasis, hoarding disorder, a body-focused repetitive behavior disorder, or a substance-induced obsessive-compulsive disorder.
• a disclosed compound is used to treat a disorder associated with stress.
• the disorder associated with stress has an identifiable stressor that is a causal factor, like exposure to a stressful or traumatic event, or a series of such events or adverse experiences. Stressors may be within the normal range of life experiences (e.g., divorce, socioeconomic problems), or from a threatening or traumatizing experience. In general, the nature and duration of the symptoms that arise in response to the stressor can distinguish the disorder from everyday stress.
• a disclosed compound is used to treat post-traumatic stress disorder, complex post-traumatic stress disorder, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder.
• a disclosed compound is used to treat a dissociative disorder.
• Dissociative disorders can be characterized by involuntary disruption or discontinuity in the normal integration of one or more of the following: identity, sensations, perceptions, affects, thoughts, memories, control over body movements, or behavior.
• dissociative disorder symptoms can be severe, and may result in impairment in personal, social, educational, occupational or other areas of functioning.
• a disclosed compound is used to treat dissociative neurological symptom disorder, dissociative amnesia (including amnesia with dissociative fugue and without dissociative fugue), trance disorder, possession trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization- derealization disorder.
• a disclosed compound is used to treat a feeding or eating disorder.
• Feeding or eating disorders generally involve abnormal eating or feeding behaviors that are not explained by another health condition, and are not developmentally appropriate or culturally sanctioned. These disorders can involve preoccupation with food as well as body weight and shape concerns.
• a disclosed compound is used to treat anorexia nervosa (including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.
• a disclosed compound is used to treat an elimination disorder.
• Elimination disorders include, for example, the repeated voiding of urine into clothes or bed, and the repeated passage of feces in inappropriate places once the individual has reached a developmental age when continence is ordinarily expected.
• a disclosed compound is used to treat enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or encopresis (including both with encopresis constipation or overflow incontinence, and encopresis without constipation or overflow incontinence).
• a disclosed compound is used to treat a disorder of bodily distress or bodily experience.
• Disorders of bodily stress typically involve bodily symptoms that the subject finds distressing and to which the subject devotes excessive attention.
• Bodily integrity dysphoria typically involves a disturbance in the person’s experience of the body manifested by persistent discomfort or intense feelings of body configuration.
• a disclosed compound is used to treat a bodily distress disorder (including mild, moderate, and severe bodily distress disorder) or body integrity dysphoria.
• a disclosed compound is used to treat a disorder due to substance use or addictive behaviors.
• Disorders due to substance use or addictive behaviors are mental and/or behavioral disorders that develop predominantly as a result of the use of psychoactive substances (including medications and illegal or illicit substances), or specific repetitive rewarding and reinforcing behaviors.
• a disclosed compound is used to treat disorders due to substance use (i.e., a substance use disorder, or SUD).
• the substance use disorder is associated with alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics or anxiolytics, cocaine, stimulants (e.g., amphetamines, methamphetamines, methcathinone, synthetic cathinones, caffeine), hallucinogens, nicotine, volatile inhalants, MDMA or MDA, dissociative drugs like ketamine and phencyclidine, or another substance (including medications and non-psychoactive substances).
• stimulants e.g., amphetamines, methamphetamines, methcathinone, synthetic cathinones, caffeine
• hallucinogens e.g., nicotine, volatile inhalants, MDMA or MDA
• dissociative drugs e.g., ketamine and phencyclidine
• another substance including medications and non-psychoactive substances.
• the substance use disorder is selected from alcohol use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalants use disorder, opioids use disorder, sedatives use disorder, hypnotics use disorder, anxiolytics use disorder, stimulants use disorder, and tobacco use disorder.
• the substance use disorder is alcohol use disorder.
• the substance use disorder is cannabis use disorder.
• the substance use disorder is caffeine use disorder.
• the substance use disorder is phencyclidine use disorder.
• the substance use disorder is inhalant use disorder.
• the substance use disorder is opioids use disorder.
• the substance use disorder is sedatives use disorder.
• the substance use disorder is hypnotics use disorder. In some embodiments, the substance use disorder is anxiolytics use disorder. In some embodiments, the substance use disorder is stimulants use disorder. In some embodiments, the substance use disorder is tobacco use disorder. In some embodiments, the substance use disorder is alcohol use disorder, wherein said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism. In some embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder).
• another addictive behavior e.g., gambling disorders, gaming disorder.
• a substance use disorder can be screened using a Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), the Opioid Risk Tool - OLID (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).
• S2BI Screening to Brief Intervention
• ASSIST Alcohol, Smoking, and Substance Involvement Screening Test
• BTAD Brief Screener for Alcohol, Tobacco, and other Drugs
• TAPS Tobacco, Alcohol, Prescription medication, and other Substance use
• ORT-OUD Opioid Risk Tool - OLID Chart
• DAST-10 Drug Abuse Screen Test
• TAPS Tobacco, Alcohol, Prescription medication, and other Substance use
• a disclosed compound is used to treat an impulse control disorder.
• impulse control disorders are characterized by the repeated failure to resist an impulse, drive, or urge to perform an act that is rewarding to the subject despite negative long-term consequences, such as harm to the subject or a significant impairment in important areas of the subject’s functioning.
• impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts.
• a disclosed compound is used to treat pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.
• a disclosed compound is used to treat a disruptive behavior disorder or a dissocial disorder.
• Such disorders may be broadly characterized by persistent behavior problems that range from persistently defiant, disobedient, provocative or spiteful behaviors to behaviors that violate the rights of others or norms, rules, or laws.
• a disclosed compound is used to treat oppositional defiant disorder (including oppositional defiant disorder with chronic irritability-anger and oppositional defiant disorder without chronic irritability-anger) or conduct-dissocial disorder (including childhood-onset conduct-dissocial disorder and adolescent-onset conduct-dissocial disorder).
• a disclosed compound is used to treat a personality disorder.
• Personality disorders may be generally characterized by problems in perceiving one’s identity, self-worth, accuracy of self-view, and self-discretion that is manifest in patterns of cognition, emotional experience, emotional expression, and maladaptive behavior.
• a disclosed compound is used to treat a mild, moderate, or severe personality disorders.
• a disclosed compound is used to treat a prominent personality trait or patterns (e.g., negative affectivity, detachment, dissociality, disinhibition, anankastia, borderline pattern).
• the personality disorder is antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, masochistic or sadistic behavior, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, psychopathy, sociopathy, schizoid personality disorder, or schizotypal personality disorder.
• a disclosed compound is used to treat a paraphilic disorder.
• Paraphilic disorders can be characterized by persistent and intense patterns of atypical sexual arousal, the focus of which involves others whose age or status renders them unwilling or unable to consent.
• a disclosed compound is used to treat exhibitionistic disorder, voyeuristic disorder, pedophilic disorder, coercive sexual sadism disorder, frotteuristic disorder, other paraphilic disorders involving non-consenting individuals, or paraphilic disorders involving solitary behavior or consenting individuals.
• a disclosed compound is used to treat a factitious disorder.
• factitious disorders may be characterized by intentionally feigning, falsifying, inducing or aggravating medical, psychological, or behavior signs and symptoms or injury to oneself or another person.
• Subjects with factitious disorders may seek treatment or otherwise present themselves or another person as ill, injured, or impaired.
• a disclosed compound is used to treat factitious disorder imposed on self or a factitious disorder imposed on another.
• a disclosed compound is used to treat a neurocognitive disorder.
• Neurocognitive disorders may be characterized by primary clinical defects in cognitive functioning that are acquired (rather than developmental), and therefore the subject experiences a decline from a previously attained level of functioning.
• a disclosed compound is used to treat delirium.
• the delirium is associated with another disease or disorder.
• the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances).
• a disclosed compound is used to treat mild neurocognitive disorder.
• a disclosed compound is used to treat an amnestic disorder.
• the amnestic disorder is associated with another disease or disorder.
• the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances).
• a disclosed compound is used to treat dementia.
• the dementia is associated with Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, Lewy body disease, a psychoactive substance (including medications and illicit or illegal substances).
• a disclosed compound is used to treat a behavioral or psychological disturbance associated with dementia.
• dementia is assessed using a Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).
• FAQ Functional Activities Questionnaire
• AD8 Ascertain Dementia 8
• MMSE Mini-Cog
• MMSE Mini-Cog
• MSE Mini-Mental State Exam
• MoCA Montreal Cognitive Assessment
• NPI-Q Neuropsychiatric Inventory Questionnaire
• a disclosed compound is used to treat a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium.
• the syndrome associated with pregnancy or the puerperium involves significant mental and behavioral features, including a depressive symptom.
• the disorder includes psychotic symptoms.
• a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, with psychotic symptoms.
• a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, without psychotic symptoms.
• a disclosed compound is used to treat a sleep-wake disorder.
• sleepwake disorders are associated with difficulty initiating or maintaining sleep (e.g., insomnia), excessive sleepiness (e.g., hypersomnolence disorders), respiratory disturbance during sleep (e.g., sleep-related breathing disorders (SRBDs), such as obstructive sleep apnea (OSA), central sleep apnea (CSA), sleep- related hypoventilation disorders, sleep-related hypoxemia disorder, snoring, catathrenia, Cheyne-Stokes breathing, and sleep-disordered breathing), disorders of the sleep-wake schedule (e.g., circadian rhythm sleep-wake disorders), abnormal movements during sleep, or problematic behavioral or psychological events that occur while falling asleep, during sleep, or upon arousal from sleep (e.g., parasomnia disorders).
• a disclosed compound is used to treat an insomnia disorder, a hypersomnolence disorder, a sleep
• a disclosed compound is used to treat sexual dysfunction.
• sexual dysfunctions can be defined as syndromes wherein a subject may have difficulty experiencing personally satisfying, non-coercive sexual activities.
• a disclosed compound is used to treat hypoactive sexual desire dysfunction, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse.
• a disclosed compound or composition is administered together with psychotherapy, such as psychosocial or behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry. 1999;56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav. 2009;23(1):168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav. 2009;23(1):168-174; in J Consul Clin Psychol. 2005;73(2):354-59; or in Case Reports in Psychiatry. Vol.
• psychotherapy such as psychosocial or behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry. 1999;56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav. 2009;23(1):168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav. 2009;23(1)
• a disclosed compound or composition may be administered in conjunction with or as an adjunct to psychotherapy.
• psychotherapy is neither necessitated nor desired, or no specific type of psychotherapy is necessitated or desired, however any of the disclosed methods can be used in combination with one or more psychotherapy sessions.
• the flexibility to participate in specific therapies, as well as to choose between any such therapies (or to decide to forgo any specific therapy), while still receiving clinically significant therapeutic effects, is among the advantages of the invention.
• a patient can participate in numerous other therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.
• “psychotherapy” is specifically “psychedelic-assisted psychotherapy.”
• Psychedelic-assisted psychotherapy broadly, includes a range of related approaches that involve at least one session where the patient ingests a psychedelic and is monitored, supported, or otherwise engaged by one or more trained mental health professionals while under the effects of the psychedelic (see, e.g., Schenberg 2018). Protocols have been developed for the standardization of procedures which emphasize a high degree of care (see, e.g., Johnson 2008), such as the therapeutic approach used by MAPS to treat patients with PTSD using MDMA (e.g., as described in Mithoefer 2017).
• the psychotherapy conducted with a disclosed compound is conducted in widely spaced sessions. These sessions can be as frequently as weekly but are more often approximately monthly or less frequently. In most cases, a small number of sessions, on the order of one to three, is needed for a patient to experience significant clinical progress, as indicated, for example, by a reduction in the symptoms of the mental health disorder being treated.
• psychotherapy comprises multiple sessions, during some of which a disclosed compound is administered (“drug-assisted psychotherapy”); in others, the patient participates in psychosocial or behavioral therapy without concomitant administration of a drug, or without administration of a disclosed compound.
• a disclosed compound or composition is administered together with standardized psychological treatment or support, which refers to any accepted modality of standard psychotherapy or counseling sessions, whether once a week, twice a week, or as needed; whether in person or virtual (e.g., over telemedicine or by means of a web program or mobile app); and whether with a human therapist or a virtual or Al “therapist.”
• therapist refers to a person who treats a patient using the disclosed compositions and methods, whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, although it will be understood that certain requirements will be appropriate to certain aspects of the drug-assisted therapy (e.g., prescribing, dispensing, or administering a drug, offering psychotherapeutic support).
• a “person” may also include an Al.
• a patient will participate in a treatment protocol or a disclosed method, or be administered a disclosed composition as part of such a method, if the patient meets certain specified inclusion criteria, does not meet certain specified exclusion criteria, does not meet any specified withdrawal criteria during the course of treatment, and otherwise satisfies the requirements of the embodiment of the disclosure as claimed.
• such administration occurs without or with reduced risk of side effects that would require physician supervision, and therefore allow for treatment at home or otherwise outside of a clinic and without the need for such supervision, and/or additionally without the requirement of adjunctive psychotherapy (although it also may be provided in certain embodiments herein).
• a disclosed compound or composition may be administered in conjunction with or as an adjunct to psychotherapy.
• psychotherapy is neither necessitated nor desired, or no specific type of psychotherapy is necessitated or desired, however any of the disclosed methods can be used in combination with one or more psychotherapy sessions.
• the flexibility to participate in specific therapies, as well as to choose between any such therapies (or to decide to forgo any specific therapy), while still receiving clinically significant therapeutic effects, is among the advantages of the invention.
• a patient can participate in numerous other therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.
• certain personalized approaches i.e., “personalized” or “precision” medicine
• individual characteristics including drug metabolism (e.g., CYP2D6 or CYP3A4) or individual genetic variation.
• drug metabolism e.g., CYP2D6 or CYP3A4
• genetic variation refers to a change in a gene sequence relative to a reference sequence (e.g., a commonly-found and/or wild-type sequence). Genetic variation may be recombination events or mutations such as substitution/deletion/insertion events like point and splice site mutations.
• the genetic variation is a genetic variation in one or more cytochrome P450 (CYP or CYP450) enzymes that affects drug metabolism, including metabolism of a disclosed composition, and including CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5.
• cytochrome P450 CYP or CYP450
• CYP enzymes include CYP1A1 , CYP1 B1 , CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1 , CYP2G1 , CYP2J2, CYP2R1 , CYP2S1, CYP3A5P1 , CYP3A5P2, CYP3A7, CYP4A11 , CYP4B1 , CYP4F2, CYP4F3, CYP4F8, CYP4F11 , CYP4F12, CYP4X1 , CYP4Z1, CYP5A1 , CYP7A1 , CYP7B1, CYP8A1 , CYP8B1, CYP11A1 , CYP11 B1 , CYP11 B2, CYP17, CYP19
• a disclosed compound or composition is taken together with a compound that is metabolized by the same CYP enzyme(s) as the disclosed compound, so as to permit a lower dose to be taken, increase the effective bioavailability of one or both, or otherwise affect drug metabolism or pharmacokinetics.
• the dose of a disclosed composition is adjusted, such as reduced, when administered to a subject known to be a poor metabolizer of an active compound in the composition (e.g., having a genetic variation in CYP2D6 and/or CYP3A4), or increased when administered to a subject known to be a rapid metabolizer.
• a patient is tested using ordinary means known to those of skill to determine if the patient is a poor or rapid metabolizer for one or more such CYP enzymes.
• the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which has been implicated in mood and anxiety symptoms in humans.
• the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs.
• SNPs single nucleotide polymorphisms
• the FKBP5 gene has been implicated in responses to stress and trauma, and such SNPs are correlated with susceptibility to certain depression, PTSD, and anxiety disorders.
• a genetic variation is an inclusion criteria for the administration of a disclosed compound.
• a genetic variation is an exclusion criteria for the administration of a disclosed compound.
• the mammal being treated has altered epigenetic regulation of a gene, the expression of which is associated with a mental health condition or susceptibility to a mental health treatment, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.
• a mental health condition such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.
• a disclosed compound is used to treat a neurodegenerative disorder.
• disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a neurodegenerative disorder.
• a disclosed composition when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a neurodegenerative disorder.
• neurodegenerative disorder refers to a class of progressive, chronic, and debilitating conditions characterized by the gradual loss of structure and function of neurons within the central nervous system (CNS) or peripheral nervous system (PNS). These disorders involve the degeneration, impairment, or death of neuronal cells, leading to a decline in cognitive, motor, and/or sensory abilities.
• CNS central nervous system
• PNS peripheral nervous system
• Neurodegenerative disorders can be classified according to primary clinical features, e.g., dementia, parkinsonism, or motor neuron disease, anatomic distribution of neurodegeneration, e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations, or principal molecular abnormality (Dugger B, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology. 2017:9(7);a028035). These disorders may involve various etiologies, including but not limited to, presence of pathogenic proteins, age, environmental stressors, and genetic predisposition (Armstrong R. Folia Neuropathologica. 2020:58(2);93-112).
• the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis or Charcot’s disease, chronic traumatic encephalopathy, corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease or Parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury.
• Alzheimer’s disease amyotrophic lateral sclerosis or Charcot’s disease
• chronic traumatic encephalopathy corticobasal degeneration
• dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease or Parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury.
• a disclosed compound is used to treat pain and/or inflammation, such as a pain disorder and/or an inflammatory disorder.
• a disclosed compound is administered, such as in a pharmacologically effective amount, to a subject having pain and/or inflammation, thereby treating said pain and/or inflammation.
• a disclosed composition when administered in a pharmacologically effective amount, provides beneficial therapeutic effects for the treatment of pain and/or inflammation.
• a disclosed compound is used to treat a pain disorder.
• the pain disorder is any of arthritis, allodynia, atypical trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesia, hyperalgesia, neuralgia, neuritis, neurogenic pain, phantom limb pain, analgesia, anesthesia dolorosa, causalgia, sciatic nerve pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorders, headache disorders, migraine headaches, chronic cluster headaches, concussion headache, short-lasting unilateral neuralgiform headache attacks, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, or pain associated with cancer.
• a disclosed compound is used to treat an inflammatory disorder.
• the inflammatory disorder is characterized by inflammation of an organ or tissue.
• the inflammatory disorder comprises any one or more of skin inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreatic inflammation, kidney inflammation, bladder inflammation, gastric inflammation, intestinal inflammation, neuroinflammation, and brain inflammation.
• the inflammatory disorder is a disorder that causes acute inflammation, or that exhibits chronic inflammation as a symptom.
• the inflammatory disorder comprises chronic inflammation.
• a disclosed compound is used to reduce inflammation.
• a disclosed compound is used in the manufacture of a medicament to reduce inflammation.
• a disclosed compound e.g., in a therapeutically effective amount, is administered to a subject to reduce inflammation.
• Pain such as chronic pain, and improvements thereof, such as a reduction of symptoms, may be measured according to known methods, e.g., by subject reporting, pain diaries, pain scales, applicable questionnaires (assessments of chronic pain and its impact on physical, emotional and social functions), ecological momentary assessments and computerized versions thereof. See, e.g., Salaffi et al., Best Practice & Research Clinic Rheumatol, 2015;29(1): 164-186 and Hawker et al., Arthritis Care Res (Hoboken). 2011 ;63 Suppl 11 :S240-52.
• Exemplary questionnaires include the Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP), Migraine Diagnosis Questionnaire, the Migraine-Screen Questionnaire (MS-Q), the Fibromyalgia Survey Questionnaire (FSQ).
• a reduction in inflammation may be measured according to various methods available to one of skill.
• Inflammatory biomarkers may be detected from biological specimens, for example, a subject’s blood, such as plasma or serum, or saliva.
• inflammation may be detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell count from a blood test.
• CRP may also be detected in a saliva sample.
• Salivary CRP is not synthesized locally in the mouth and may reflect more systemic levels of inflammation compared to other inflammatory biomarkers, such as cytokines (Szabo & Slavish, Psychoneuroendocrinology. 202; 124: 105069).
• clinical pathology data e.g., hematology data on erythrocyte parameters, platelet count, total number of leukocytes, and leukocyte differentials and morphology, coagulation data on clotting times and fibrinogen, and clinical chemistry data on total protein, albumin and globulin, liver enzymes, renal parameters, electrolytes, and bilirubin can provide an initial indication of the presence and potentially the location of inflammation, in the absence of specific data on immune tissues. See, e.g., Germolec et al., Methods Mol Biol. 2018; 1803:57-79 and Luo et al., Clin Lab. 2019 1 ; 65(3) .
• Example 1 Synthesis of 4-(((4-bromo-2,5-dimethoxyphenethyl)amino)methyl)-5-(hydroxy methyl)-2-methylpyridi n-3-ol HCI (Compound 1 A-1 ) i: pyridoxal HCI, MeOH, 4 A molecular sieves; ii: NaBH 4 , MeOH; ill: MeOH, 1 M HCI in Et 2 O
• Metabolic stability assays measure the intrinsic clearance (CL int ) of a compound, providing critical data needed to calculate other key pharmacokinetic parameters, e.g., bioavailability and half-life (t 1/2 ).
• Phase I and/or Phase II metabolites are identified using mass spectrometry (MS). The % compound remaining and half-life of the disclosed compound (parent compound) are determined. MS data, such as extracted ion chromatograms, show parent and major metabolites. Metabolic transformation for each observed metabolite is elucidated, and metabolite masses, peak areas, and retention times are determined. Metabolic profiling may also be conducted according to the methods described in Muller & Rentsch, Anal Bioanal Chem. 2012;402:2141-2151 and Pedersen et al., Drug Metab Dispos. 2013;41 :1247-1255.
• the disclosed compound is incubated in different concentrations in a mix containing buffer, enzymes, and substrate. Then, fluorescence is measured using a plate reader and percentage inhibition may be extrapolated out from the readings. Alternatively, the inhibitory effects of the disclosed compound on CYP enzymes may be assessed using high-performance liquid chromatography. Inhibition is evaluated using the Michaelis-Menten method. CYP enzyme inhibition may be conducted according to the methods described in Lin et al., J Pharm Sci. 2007;96(9):2485-95 and Wojcikowski et al., Pharmacol Rep. 2020;72(3):612-621.
• Metabolizing enzymes in the liver such as CYP450 enzymes, are responsible for the majority of drug metabolism that occurs in the body.
• Six CYP450 class enzymes metabolize 90 percent of drugs, and two of the most significant metabolizers are CYP3A4 and CYP2D6 (Lynch & Price, Am Fam Physician. 2007;76(3):391 -6).
• Compounds can interact with such enzymes by inhibiting their enzymatic activity (CYP inhibition) or by inducing their gene expression (CYP induction).
• Example 5 In vitro evaluation of membrane permeability and interactions with P-glycoprotein (P-gp) in MDCKII MDR1 cells
• a bidirectional permeability study (apical to basolateral [AB] and basolateral to apical [BA]) is conducted to evaluate the apparent permeability of the disclosed compound. Additionally, the compound is evaluated to determine if it acts as a P-gp substrate in MDCKII-MDR1 and mock MDCKII cell lines.
• the disclosed compound and reference compounds are evaluated in two directions in the absence and presence of a P-gp inhibitor.
• the MDCKII and MDCKII-MDR1 cells are incubated in a transport buffer on both apical [A] and basolateral [B] sides. Then, the disclosed compound is added to each side of the cells and incubated. The rate of transport of the disclosed compound is determined in the absence or presence of a P-gp inhibitor.
• the permeability of the cells is measured using a LC MS/MS system. The efflux ratio of the disclosed compound is calculated to determine if it is a P-gp substrate.
• CD(t) is the measured concentration in the donor well at time t (expressed as IS ratio)
• CR(t) is the measured concentration in the receiver well at time t (expressed as IS ratio)
• C o is the initial concentration in the donor solution (expressed as IS ratio).
• %l ntegrity 100 x [1 -RFUbasolateral/RFUapical]
• LY RFU values are normalized by background mean values.
• a test item is considered to be a P-gp substrate when the efflux ratio in the absence of the inhibitor is >2 and if the ratio is significantly reduced in the presence of a P-gp inhibitor.
• TAAR1 may be a promising target for the treatment of neuropsychiatric disorders.
• the effects of TAAR1 activation on dopaminergic neurotransmission may provide therapeutic benefit for addiction, such as substance use disorders (Liu & Li, Front Pharmacol. 2018;9:279).
• Example 8 Prodrug Absorption and Hydrolysis in an In Vitro Model of Human Intestinal Mucosa
• Caco-2 cells are derived from the human colon adenocarcinoma cell line, and are a valuable in vitro model for studying drug absorption in intestinal cells.
• Caco-2 cells are cultured on transwell inserts with a semi-porous polycarbonate membrane, forming a continuous monolayer that closely mimics the morphology and function of human small intestinal epithelial cells, and compartments on either side to mimic the intestinal lumen and bloodstream.
• marker enzyme expression, uptake, transport, and permeability characteristics akin to those of small intestinal epithelial cells, Caco-2 cells offer a robust model for understanding drug absorption processes.
• a Caco-2 permeability assay is performed using the CacoReadyTM model (Readycell, Barcelona, Spain) consisting of Caco-2 cells seeded on polycarbonate filters (0.4 pm pore size, 6.5 mm diameter), in the apical chamber of 24-well high throughput screening plates (Corning Incorporated, NY, USA). Cells are seeded at a density of 1 x 10 5 cells per mL in an appropriate medium and buffer solution. Cell culturing proceeds at 37 °C for 21 days, with culture medium changes every second day to allow the formation of a confluent monolayer. The apical chamber represents the intestinal lumen, and the basal chamber represents the bloodstream.
• TEER transepithelial electrical epithelial resistance
• P app apparent permeability coefficient
• Results can show that certain disclosed compounds having a drug bound to a vitamin B6 (e.g. pyridoxal) promoiety are likely to be absorbed and hydrolyzed by human intestinal mucosa cells. The absorption and hydrolysis rate is also evaluated and compared amongst compounds. Results can be represented as a concentration (pg/mL) per incubation time. Differences between the in vitro absorption and hydrolysis of disclosed compounds and suitable comparator compounds are also determined according to the described methods.
• a vitamin B6 e.g. pyridoxal
• the mouse head-twitch response is a behavioral test that reflects S-HT ⁇ receptor activation and can be predictive of psychedelic effects in humans (Halberstadt et al., J Psychopharmacol. 2011 ;25(11): 1548— 1561 ).
• the HTR is widely used as a behavioral surrogate for human psychedelic effects for its ability to reliably distinguish psychedelic from non-psychedelic 5-HT 2A receptor agonists (Halberstadt & Geyer, Psychopharmacol (Berl). 2013;227(4):727-3).
• mice Male C57BL/6 J mice (6-8 weeks old) are obtained and housed in a vivarium that meets all requirements for care and treatment of laboratory animals. Mice are housed up to four per cage in a climate-controlled room on a reverse-light cycle (lights on at 1900 h, off at 0700 h) and are provided with ad libitum access to food and water, except during behavioral testing. Testing is conducted between 1000 and 1800 h. All animal experiments are conducted in accordance with applicable guidelines and are approved by an appropriate animal care committee.
• mice are anesthetized and a small neodymium magnet is attached to the dorsal surface of the cranium using dental cement. Following a two-week recovery period, HTR experiments are carried out in a well-lit room with at least 7 days between sessions to avoid carryover effects.
• Test compounds are dissolved in a suitable solvent, e.g., water containing 5% Tween 80, and administered IP at a volume of 5 or 10 mL/kg body weight immediately prior to testing. Different doses are tested to produce a dose-response curve. Mice are injected with drug or vehicle, and HTR activity is recorded in a glass cylinder surrounded by a magnetometer coil for 30 min. Coil voltage is low-pass filtered (2e10 kHz cutoff frequency), amplified, and digitized (20 kHz sampling rate) using a Powerlab/8SP with LabChart v 7.3.2 (ADInstruments, Colorado Springs, CO, USA), then filtered off-line (40e200 Hz band-pass).
• a suitable solvent e.g., water containing 5% Tween 80
• Head twitches are identified manually based on the following criteria: 1) sinusoidal wavelets; 2) evidence of at least two sequential head movements (usually exhibited as bipolar peaks) with frequency 40 Hz; 3) amplitude exceeding the level of background noise; 4) duration ⁇ 0.15 s; and 5) stable coil voltage immediately preceding and succeeding each response.
• Head twitch counts are analyzed using one-way analyses of variance (ANOVA). Post hoc pairwise comparisons between selected groups are performed using Tukey’s studentized range method. The entire recordings are examined for head twitches. In some cases a shorter block of time is analyzed to accommodate compounds with a brief duration-of-action, as potency calculations can be confounded by extended periods of inactivity. ED 50 values and 95% confidence limits are calculated using nonlinear regression. Relationships between HTR potency and binding affinities are assessed using linear regression and ordinary least-squares regression. For all analyses, significance is demonstrated by surpassing an a-level of 0.05.
• ANOVA analyses of variance
• Results can show that certain disclosed compounds having a psychedelic drug bound to a vitamin B6 (e.g. pyridoxal) promoiety are likely to produce psychedelic effects in humans. The magnitude of such effects is also evaluated and compared amongst compounds. Results can be represented as ED 50 (mg/kg). Differences between the mouse HTR of disclosed compounds and suitable comparator compounds are also determined according to the described methods.
• a vitamin B6 e.g. pyridoxal

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