WO2024178425A1 - Tryptamines hydroxyalkylées et méthoxyalkylées - Google Patents

Tryptamines hydroxyalkylées et méthoxyalkylées Download PDF

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WO2024178425A1
WO2024178425A1 PCT/US2024/017324 US2024017324W WO2024178425A1 WO 2024178425 A1 WO2024178425 A1 WO 2024178425A1 US 2024017324 W US2024017324 W US 2024017324W WO 2024178425 A1 WO2024178425 A1 WO 2024178425A1
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disorder
compound
pharmaceutically acceptable
solvate
stereoisomer
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PCT/US2024/017324
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English (en)
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David Nichols
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2A Biosciences, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the disclosure relates to methods of synthesizing the compounds, compositions containing the compounds, and methods of using such compounds, including their administration to subjects.
  • features of the compounds include neuromodulatory activity, for example, activation of serotonin receptors.
  • the compounds are useful as therapeutic agents, such as anti-inflammatory agents.
  • Psychedelics such as psilocybin and LSD, and entactogens such as MDMA, are currently being investigated for various medical uses, owing to their psychedelic, anxiolytic, and antidepressant effects.
  • psilocybin has received FDA Breakthrough Therapy designation for its efficacy in treating depression in combination with psychological support.
  • Psilocybin is a naturally occurring tryptamine alkaloid found in fungi including the Psilocybe genus. Psilocybin is currently being investigated for various medical uses, owing to its psychedelic, anxiolytic, and antidepressant effects. In vivo, psilocybin is rapidly dephosphorylated by endogenous phosphatase enzymes to produce psilocin, the active compound that agonizes serotonin 2 (5-HT 2 ) receptors in the brain and in other tissues. [04] Beyond mental health, psychedelics may be promising for treating inflammatory, neurological, and neurodegenerative diseases and disorders.
  • a compound of Formula (1) or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein: alkyl, —(CH 2 ) 2 O–C 1 -C 6 alkyl, —CH 2 O–C 1 -C 6 alkyl, —(CH 2 ) 3 OPO 3 H 2 , —(CH 2 ) 2 OPO 3 H 2 , or —CH 2 OPO 3 H 2 ; R 2 is C 1 -C 6 alkyl; and R' and R'' are both C 1 -C 6 alkyl; or R' is H, and R'' is C 1 -C 6 alkyl or —CH 2 –C 6 -C
  • R 1 is—(CH 2 ) 2 OH, —(CH 2 ) 3 OH, or —CH 2 OH. In some embodiments, R 1 is —(CH 2 ) 3 O–C 1 -C 6 alkyl, —(CH 2 ) 2 O–C 1 -C 6 alkyl, or —CH 2 O–C 1 -C 6 alkyl. In some embodiments, R 1 is —(CH 2 ) 3 OCH 3 , —(CH 2 ) 2 OCH 3 , or —CH 2 OCH 3 . In some embodiments, R 1 is —(CH 2 ) 2 OCH 3 .
  • R 1 is —(CH 2 ) 3 OPO 3 H 2 , —(CH 2 ) 2 OPO 3 H 2 , or —CH 2 OPO 3 H 2 . In some embodiments, R 1 is —(CH 2 ) 2 OPO 3 H 2 . [09] In some embodiments, R 2 is methyl. [10] In some embodiments, the compound has the structure of Formula (1A), 2024-02-26 or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof. [11] The compound of claim 1, wherein the compound has the structure of Formula (1B), or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof.
  • R' and R'' are both C 1 -C 6 alkyl. In some embodiments, R' and R'' are both methyl. In embodiments, R' and R'' are both ethyl. In some embodiments, R' and R'' are both isopropyl. [13] In some embodiments, R' is H, and R'' is C 1 -C 6 alkyl. In some embodiments, R'' is methyl. In some embodiments, R'' is ethyl. In some embodiments, R'' is isopropyl.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is unsubstituted.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is substituted by methyl. In some embodiments, R' is H, and R'' is —CH 2 –(2-methylphenyl), —CH 2 –(3-methylphenyl), or —CH 2 –(4-methylphenyl). [15] In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by C 1 -C 6 alkyl. In some embodiments, R' and R'' are taken together to form an azetidinyl optionally substituted by C 1 -C 6 alkyl.
  • the azetidinyl is unsubstituted. In some embodiments, the azetidinyl is substituted by C 1 -C 6 alkyl. In some embodiments, R' and R'' are taken together to form . [16] In some embodiments, the compound is selected from TABLE 1 , or a pharmaceutically acceptable 2024-02-26 salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof. , or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof.
  • compositions comprising a therapeutically effective amount of the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer 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 about 0.01 and 100 mg.
  • the composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • 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, 2024-02-26 empathogens, psychedelics, plasticity-inducing agents, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sed
  • modulating neurotransmission comprises agonizing the 5-HT 2A or 5-HT 2C receptor.
  • a method of increasing neuroplasticity comprising administering to the subject the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the pharmaceutical composition of any of the disclosed embodiments.
  • a method of treating a medical condition in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of the compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the pharmaceutical composition of any of the disclosed embodiments.
  • the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission.
  • the medical condition is a mental, behavioral, or neurodevelopmental disorder.
  • the medical condition is a neurodevelopmental disorder, schizophrenia or another primary psychotic disorder, catatonia, a mood disorder, an anxiety or fear-related disorders, an obsessive-compulsive or related disorder, a disorder specifically associated with stress, a dissociative disorder, a feeding or eating disorder, an elimination disorder, a disorder of bodily distress or bodily experience, a disorder due to substance use or addictive behavior, an impulse control disorder, a disruptive behavior or dissocial disorder, a personality disorder, a paraphilic disorder, a factitious disorder, a neurocognitive disorder, a mental or behavioral disorder associated with pregnancy, childbirth or the puerperium, a sleep-wake disorder, or a sexual dysfunction.
  • a compound is administered together with one or more sessions of psychotherapy.
  • the medical condition is inflammation or an inflammatory disorder.
  • inflammation is 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, ocular inflammation, or brain inflammation.
  • the inflammatory disorder is an acute inflammatory disorder.
  • the inflammatory disorder is a chronic inflammatory disorder.
  • the inflammatory disorder is a steroid-resistant disorder.
  • the inflammatory disorder is selected from the group consisting of asthma, 2024-02-26 chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, septicemia, conjunctivitis, and Alzheimer’s disease.
  • the inflammatory disorder is dermatitis.
  • dermatitis is atopic dermatitis, chronic photosensitivity dermatitis, eczema, atopic eczema, contact eczema, dryness eczema, seborrheic eczema, discoid eczema, varicose eczema, herpetic dermatitis, neurodermatitis, autosensitizing dermatitis, stasis dermatitis, purulent dermatitis, dyshidrotic eczema, follicular eczema, spongiotic dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.
  • the subject has a compromised immune system.
  • the subject has an autoimmune disorder.
  • the subject has a contraindication to a corticosteroid.
  • treating inflammation or an inflammatory disorder comprises reducing the level of an inflammatory biomarker by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.
  • the inflammatory biomarker is an inflammatory response gene product.
  • the inflammatory response gene product is mRNA.
  • the mRNA is Arg-1 , ICAM1 , VCAM1, MCP1, IL-6, IL-1 ⁇ , Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF- ⁇ mRNA.
  • the inflammatory response gene product is a protein.
  • the protein is Arg-1, ICAM1, VCAM1, MCP1, IL-6, IL-1 ⁇ , Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF- ⁇ .
  • the medical condition is an ophthalmic disorder.
  • the ophthalmic disorder is an inflammatory disorder.
  • the medical condition is a neurodegenerative disorder.
  • 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.
  • a compound of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment of a medical condition for use in the treatment of a medical condition.
  • the use of the compound of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a medicament for the treatment of a medical condition for use in the treatment of a medical condition.
  • the pharmaceutical composition of any of the disclosed embodiments for use in the treatment of a medical condition.
  • Use of the pharmaceutical composition of any of the disclosed embodiments for the manufacture of a medicament for the treatment of a medical condition use of the pharmaceutical composition of any of the disclosed embodiments for the manufacture of a medicament for the treatment of a medical condition.
  • FIG.1 shows radioligand binding affinity assay data for Compound 1 for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, as described in Example 5.
  • FIG.2 shows radioligand binding affinity assay data for Compound 2 for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, as described in Example 5.
  • FIG.3 shows radioligand binding affinity assay data for Compound 3 for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, as described in Example 5.
  • FIG.4 shows radioligand binding affinity assay data for Compound 4 for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, as described in Example 5.
  • FIG.5 shows cell-based agonist IP-One assay data for Compound 1 for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, as described in Example 6.
  • FIG.6 shows cell-based calcium flux assay data for Compound 1 for the 5-HT 2A receptor, as described in Example 6.
  • FIG.7 shows cell-based agonist IP-One assay data for Compound 2 for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, as described in Example 6.
  • FIG.8 shows cell-based calcium flux assay data for Compound 2 for the 5-HT 2A receptor, as described in Example 6.
  • FIG.9 shows cell-based agonist IP-One assay data for Compound 3 for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, as described in Example 6.
  • FIG.10 shows cell-based calcium flux assay data for Compound 3 for the 5-HT 2A receptor, as described in Example 6.
  • FIG.11 shows cell-based agonist IP-One assay data for Compound 4 for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, as described in Example 6.
  • FIG.12 shows cell-based calcium flux assay data for Compound 4 for the 5-HT 2A receptor, as described in Example 6.
  • DETAILED DESCRIPTION OF THE INVENTION [55] While various aspects and features of certain embodiments are summarized above, the following detailed description illustrates several exemplary embodiments in further detail to enable one of skill in the art to practice such embodiments, and to make and use the full scope of the invention claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications.
  • an active agent includes reference to a combination of two or more active agents
  • reference to “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 terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements).
  • the term “or” is used herein to mean, and is used interchangeably with, the term “and/or,” unless context clearly indicates otherwise.
  • 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.
  • 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, 2024-02-26 and most preferably from 1 to 3 carbon atoms.
  • the alkyl may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkenyl, alkynyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, cycloalkenyl, 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 , and —SONH 2 .
  • an alkyl group will be optionally substituted. In embodiments, an alkyl group will be substituted at one or more positions. In embodiments, an alkyl group will not be substituted at any positions.
  • 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-en-2-yl, prop-2-en-1-y
  • Alkenyl group can be substituted or unsubstituted.
  • 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 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, phenant
  • an aryl group comprises from 6 to 20 carbon atoms, more preferably, between 6 to 12 carbon atoms.
  • An aryl group can be substituted or unsubstituted.
  • 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 atoms, 5 to 2024-02-26 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
  • 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 cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl group 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.
  • Cycloalkylmethyl refers to a radical having a methylene component and a cycloalkyl component, where the methylene component links the cycloalkyl component to the point of attachment.
  • the cycloalkyl component is as defined above, and can include any number of carbons, such as 3 to 6 carbon atoms (i.e., a C 3 -C 6 cycloalkylmethyl), 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 9 carbon
  • the cycloalkylmethyl group is a cyclopropylmethyl group.
  • a cycloalkylmethyl group can be substituted or unsubstituted.
  • Halogen refers to fluorine, chlorine, bromine, and iodine.
  • Heterocycloalkyl refers 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 includes 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, azetidinyl, 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, azetidinyl, pyrrolidine,
  • 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.
  • heterocycloalkyl groups can be substituted with C1-6 alkyl or oxo ( ⁇ O), among many others.
  • Alkyl-heterocycloalkyl refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of attachment.
  • the alkyl component can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent.
  • the heterocycloalkyl component is as defined above. Alkyl-heterocycloalkyl groups can be substituted or unsubstituted.
  • 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, O 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.
  • a heteroaryl includes groups such as pyrrole, pyridine, imidazole, pyrazole, 2024-02-26 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.
  • Alkyl-heteroaryl refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of attachment.
  • the alkyl component can include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent.
  • the heteroaryl component is as defined within.
  • Alkyl-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.
  • a non-limiting list of 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.
  • Alkylthio or “thioalkyl” 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.
  • “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.
  • “Haloalkyl” refers to 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).
  • dihaloalkyl refers to an alkyl substituted by two halo groups, which may be, but are not necessarily, the same halogen.
  • haloalkyl groups include difluoromethyl (—CHF 2 ), bromofluoromethyl (—CHBrF), trifluoromethyl (—CF 3 ), and 2-fluoroethyl (—CH 2 CH 2 F).
  • 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).
  • a haloalkyl may be substituted or unsubstituted.
  • “Hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
  • hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxy- 2024-02-26 propyl, 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 but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy.
  • a haloalkoxy 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.
  • “Sulfinyl” refers to an —S( ⁇ O)—R group in which R can be the same as defined with respect to sulfenyl. A sulfinyl 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.
  • O-carboxy refers to a —RC( ⁇ O)O— group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carboxy may be substituted or unsubstituted.
  • “Ester” and “C-carboxy” refer to a —C( ⁇ O)OR group in which R can be the same as defined with respect to O-carboxy. Ester and C-carboxy groups may be substituted or unsubstituted.
  • Thiocarbonyl refers to a —C( ⁇ S)R group in which R can be the same as defined with respect to O-carboxy. 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.
  • 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.
  • 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.
  • O-carbamyl refers to a —OC( ⁇ O)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.
  • An O-carbamyl may be substituted or unsubstituted.
  • N-carbamyl refers to an ROC( ⁇ O)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-carbamyl may be substituted or unsubstituted.
  • O-thiocarbamyl refers to a —OC( ⁇ S)—N(R A R B ) group in which R A and R B can be independently 2024-02-26 hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • N-thiocarbamyl refers to an ROC( ⁇ S)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-thiocarbamyl may be substituted or unsubstituted.
  • C-amido refers to a —C( ⁇ O)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.
  • a C-amido may be substituted or unsubstituted.
  • N-amido refers to a RC( ⁇ O)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.
  • 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 some embodiments, 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.
  • an optionally substituted group has four substituents. If no 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, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyan
  • a compound of Formula (1) 2024-02-26 or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof, wherein: alkyl, or —(CH 2 ) n OPO 3 H 2 ; n is 1, 2, or 3; R 2 is C 1 -C 6 alkyl; or R' is H, and R'' is C 1 -C 6 alkyl or —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 ary
  • R 1 is —(CH 2 ) n OH, —(CH 2 ) n OCH 3 , —(CH 2 ) n O–C 1 -C 6 alkyl, or —(CH 2 ) n OPO 3 H 2 .
  • R 1 is —(CH 2 ) n OH or —(CH 2 ) n OCH 3 .
  • R 1 is —(CH 2 ) n OH.
  • R 1 is —(CH 2 ) n OCH 3 .
  • R 1 is —(CH 2 ) n O–C 1 -C 6 alkyl.
  • R 1 is —(CH 2 ) n OPO 3 H 2 .
  • n is 1, 2, or 3.
  • n is 1.
  • n is 2.
  • n is 3.
  • R 1 is —(CH 2 ) 2 OH, —(CH 2 ) 3 OH, —CH 2 OH, —(CH 2 ) 3 O–C 1 -C 6 alkyl, —(CH 2 ) 2 O–C 1 -C 6 alkyl, —CH 2 O–C 1 -C 6 alkyl, —(CH 2 ) 3 OPO 3 H 2 , —(CH 2 ) 2 OPO 3 H 2 , or —CH 2 OPO 3 H 2 .
  • R 1 is —(CH 2 ) 2 OH, —(CH 2 ) 3 OH, or —CH 2 OH.
  • R 1 is —(CH 2 ) 2 OH. In some embodiments, R 1 is —(CH 2 ) 3 OH. In some embodiments, R 1 is —CH 2 OH. [103] In some embodiments, R 1 is —(CH 2 ) 3 O–C 1 -C 6 alkyl, —(CH 2 ) 2 O–C 1 -C 6 alkyl, or —CH 2 O–C 1 -C 6 alkyl. In some embodiments, R 1 is —(CH 2 ) 3 O–C 1 -C 6 alkyl. In some embodiments, R 1 is —(CH 2 ) 3 OCH 3 .
  • R 1 is —(CH 2 ) 2 O–C 1 -C 6 alkyl. In some embodiments, R 1 is —(CH 2 ) 2 OCH 3 . In some embodiments, R 1 is —CH 2 O–C 1 -C 6 alkyl. In some embodiments, R 1 is —CH 2 OCH 3 . [104] In some embodiments, R 1 is —(CH 2 ) 3 OPO 3 H 2 , —(CH 2 ) 2 OPO 3 H 2 , or —CH 2 OPO 3 H 2 . In some embodiments, R 1 is —(CH 2 ) 3 OPO 3 H 2 . In some embodiments, R 1 is —(CH 2 ) 2 OPO 3 H 2 . In some embodiments, R 1 is —(CH 2 ) 2 OPO 3 H 2 .
  • R' is H, and R'' is C 1 -C 6 alkyl or —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' and R'' are both C 1 -C 6 alkyl.
  • R' and R'' can be the same or different.
  • R' and R'' are both C 1 -C 6 alkyl
  • R' and R'' are both methyl.
  • R' is methyl and R'' is ethyl.
  • R' is C 1 -C 6 alkyl
  • R'' is C 1 -C 6 alkyl or —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 2024-02-26 aryl, F, Cl, Br, or I.
  • R' and R'' are both methyl.
  • R' and R'' are both ethyl. In some embodiments, R' and R'' are both isopropyl. [107] In some embodiments, R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is unsubstituted. In some embodiments, R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is unsubstituted.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is substituted by methyl.
  • R' is H, and R'' is —CH 2 –(2-methylphenyl), —CH 2 –(3-methylphenyl), or —CH 2 –(4-methylphenyl). In some embodiments, R'' is —CH 2 –methylenedioxyphenyl. In some embodiments, R'' is —CH 2 –dihydrofuranylphenyl. [108] In some embodiments, R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by C 1 -C 6 alkyl.
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is unsubstituted.
  • R' and R'' are taken together to form a 4-membered heterocyclyl, such as an azetidinyl.
  • R' and R'' are taken together to form a 5-membered heterocyclyl, such as a pyrrolidine.
  • R' and R'' are taken together to form a 6-membered heterocyclyl, such as a piperidine.
  • the 4- to 6-membered heterocyclyl contains an additional heteroatom.
  • R' and R'' are taken together to form a 6-membered heterocyclyl containing an additional heteroatom, such as an oxygen (morpholine), a sulfur (thiomorpholine), or a nitrogen (a piperazine).
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by C 1 -C 6 alkyl.
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by methyl.
  • R' and R'' are taken together to form a dimethylazetidinyl.
  • R' and R'' are taken together to form a 2,4-dimethylazetidinyl.
  • R' and R'' are taken together to form or , wherein the asterisk (*) indicates the point of connection to the remainder of the compound.
  • R' and R'' are taken together to form a tetramethylazetidinyl.
  • R' is H, and R'' is C 1 -C 6 alkyl; or R' and R'' are both C 1 -C 6 alkyl. In some embodiments, R' is H and R'' is C 1 -C 6 alkyl.
  • R' is H, and R'' is C 1 -C 6 alkyl or —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' and R'' are both C 1 -C 6 alkyl.
  • R' and R'' can be the same or different.
  • R' and R'' are both C 1 -C 6 alkyl
  • R' and R'' are both methyl.
  • R' is methyl and R'' is ethyl.
  • R' is C 1 -C 6 alkyl
  • R'' is C 1 -C 6 alkyl or —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' and R'' are both methyl.
  • R' and R'' are both ethyl. In some embodiments, R' and R'' are both isopropyl. [111] In some embodiments, R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is unsubstituted. In some embodiments, R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is unsubstituted.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, 2024-02-26 and R'' is —CH 2 –phenyl, wherein the phenyl is substituted by methyl.
  • R' is H, and R'' is —CH 2 –(2-methylphenyl), —CH 2 –(3-methylphenyl), or —CH 2 –(4-methylphenyl). In some embodiments, R'' is —CH 2 –methylenedioxyphenyl. In some embodiments, R'' is —CH 2 –dihydrofuranylphenyl. [112] In some embodiments of Formula (1A), R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by C 1 -C 6 alkyl.
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is unsubstituted.
  • R' and R'' are taken together to form a 4-membered heterocyclyl, such as an azetidinyl.
  • R' and R'' are taken together to form a 5-membered heterocyclyl, such as a pyrrolidine.
  • R' and R'' are taken together to form a 6-membered heterocyclyl, such as a piperidine.
  • the 4- to 6-membered heterocyclyl contains an additional heteroatom.
  • R' and R'' are taken together to form a 6-membered heterocyclyl containing an additional heteroatom, such as an oxygen (morpholine), a sulfur (thiomorpholine), or a nitrogen (a piperazine).
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by C 1 -C 6 alkyl.
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by methyl.
  • R' and R'' are taken together to form a dimethylazetidinyl.
  • R' and R'' are taken together to form a 2,4-dimethylazetidinyl.
  • R' and R'' are taken together to form , wherein the asterisk (*) indicates the point of connection to the remainder of the compound.
  • R' and R'' are taken together to form a tetramethylazetidinyl.
  • R' is H, and R'' is C 1 -C 6 alkyl; or R' and R'' are both C 1 -C 6 2024-02-26 alkyl. In some embodiments, R' is H and R'' is C 1 -C 6 alkyl.
  • R' is H, and R'' is C 1 -C 6 alkyl or —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' and R'' are both C 1 -C 6 alkyl.
  • R' and R'' can be the same or different.
  • R' and R'' are both C 1 -C 6 alkyl
  • R' and R'' are both methyl.
  • R' is methyl and R'' is ethyl.
  • R' is C 1 -C 6 alkyl
  • R'' is C 1 -C 6 alkyl or —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I; or R' and R'' are both C 1 -C 6 alkyl In some embodiments, R' and R'' are both methyl.
  • R' and R'' are both ethyl. In some embodiments, R' and R'' are both isopropyl. [115] In some embodiments, R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is unsubstituted. In some embodiments, R' is H, and R'' is —CH 2 –C 6 -C 12 aryl, wherein the C 6 -C 12 aryl is substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is unsubstituted.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is substituted by C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl, C 6 -C 12 aryl, F, Cl, Br, or I.
  • R' is H, and R'' is —CH 2 –phenyl, wherein the phenyl is substituted by methyl.
  • R' is H, and R'' is —CH 2 –(2-methylphenyl), —CH 2 –(3-methylphenyl), or —CH 2 –(4-methylphenyl). In some embodiments, R'' is —CH 2 –methylenedioxyphenyl. In some embodiments, R'' is —CH 2 –dihydrofuranylphenyl. [116] In some embodiments of Formula (1A), R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by C 1 -C 6 alkyl.
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is unsubstituted.
  • R' and R'' are taken together to form a 4-membered heterocyclyl, such as an azetidinyl.
  • R' and R'' are taken together to form a 5-membered heterocyclyl, such as a pyrrolidine.
  • R' and R'' are taken together to form a 6-membered heterocyclyl, such as a piperidine.
  • the 4- to 6-membered heterocyclyl contains an additional heteroatom.
  • R' and R'' are taken together to form a 6-membered heterocyclyl containing an additional heteroatom, such as an oxygen (morpholine), a sulfur (thiomorpholine), or a nitrogen (a 2024-02-26 piperazine).
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by C 1 -C 6 alkyl.
  • R' and R'' are taken together to form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is substituted by methyl.
  • R' and R'' are taken together to form a dimethylazetidinyl.
  • R' and R'' are taken together to form a 2,4-dimethylazetidinyl.
  • R' and R'' are taken together to form , wherein the asterisk (*) indicates the point of connection to the remainder of the compound.
  • R' and R'' are taken together to form a tetramethylazetidinyl.
  • a compound, or a pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic derivative, hydrate, or solvate thereof selected from TABLE 1 below. TABLE 1.
  • Exemplary Compounds of Formula (1) 2024-02-26 2024-02-26 2024-02-26 2024-02-26 2024-02-26 [118]
  • the compound is selected from the group consisting of: , 2024-02-26 , or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof.
  • the compound acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof is selected from TABLE 1 below. TABLE 1.
  • the compound is selected from the group consisting of: , 2024-02-26 , or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof.
  • the pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof.
  • the compound is 2024-02-26 pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof.
  • the compound is or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof.
  • or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof thereof.
  • the compound is , or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, or solvate thereof.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, and which may be synthesized by conventional chemical methods.
  • 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.
  • nonaqueous media e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
  • salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
  • One of ordinary skill in the art can select from among a wide variety of available counterions 2024-02-26 those that are pharmaceutically acceptable. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt.
  • Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenyl- propionate, 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, dodec
  • Certain compounds disclosed herein may contain one or more ionizable groups (groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)). All possible ionic forms of such molecules and salts thereof are included in the present disclosure.
  • a disclosed compound can exist in solid or liquid form. In the solid state, the compound may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline compounds.
  • solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The subject matter described herein includes such solvates.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties.
  • Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the compounds described herein 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 disclosure includes 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 selective crystallization, enzymatic resolution, asymmetric synthesis (including asymmetric chemical synthesis and asymmetric enzymatic synthesis), kinetic resolution, and chiral chromatography (including chiral liquid chromatography, gas chromatography, and high-performance liquid chromatography).
  • asymmetric synthesis including asymmetric chemical synthesis and asymmetric enzymatic synthesis
  • kinetic resolution including chiral liquid chromatography, gas chromatography, and high-performance liquid chromatography.
  • the disclosure also includes compounds with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., isotopically enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • Examples of isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, and 36 Cl respectively.
  • isotopically labeled compounds can be used in metabolic studies (with 14 C), reaction kinetic studies (with, e.g., 2 H or 3 H), detection or imaging techniques, such as 2024-02-26 positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • An 18 F-labeled compound may be particularly desirable for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the disclosure also includes prodrugs of disclosed compounds.
  • a “prodrug” is a precursor of a biologically active pharmaceutical agent, which may undergo a chemical or a metabolic conversion to become the biologically active agent.
  • a prodrug can be converted ex vivo to the biologically active pharmaceutical agent by chemical transformative processes.
  • a prodrug is converted to the biologically active pharmaceutical agent by the action of a metabolic process, an enzymatic process or a degradative process that removes the prodrug moiety to form the biologically active pharmaceutical agent.
  • Typical examples of prodrugs include compounds with biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • Suitable functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides. These functional groups can be attached to the drug molecule via a linker that is designed to be cleaved under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage. The choice of functional group depends on factors such as stability, ease of synthesis, enzymatic activity, and desired rate of prodrug conversion. [126] Generally, the individual disclosed compounds will be administered as part of a pharmaceutical composition or formulation, and are prepared for inclusion in such composition or formulations as isolated or purified compounds.
  • isolated refers 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 disclosure is substantially free of any other active compounds which are not intended to be administered to a subject.
  • substantially free 2024-02-26 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.
  • 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 embodiments, such advantages are determined relative to a comparator.
  • the comparator is a tryptamine having a 7-alkyl substituent but lacking a 4-(2-hydroxyalkyl) or 4-(2-methoxyalkyl) substituent.
  • the comparator is a 7-alkyl (e.g., 7-methyl) analog of psilocybin, psilocin, or an N,N-dialkyltryptamine (e.g., DMT, DET, DiPT).
  • the comparator is a tryptamine having a 4-(2-hydroxyalkyl) or 4-(2-methoxyalkyl) substituent but lacking a 7-alkyl group.
  • the comparator is a 4-(2-hydroxyalkyl)- or 4-(2-methoxyalkyl)-substituted N,N-dialkyltryptamine (e.g., 4-(2-hydroxymethyl)-DMT, 4-(2-methoxymethyl)-DiPT, etc.).
  • N,N-dialkyltryptamine e.g., 4-(2-hydroxymethyl)-DMT, 4-(2-methoxymethyl)-DiPT, etc.
  • 4-(2-hydroxyalkyl)-7-alkyl tryptamine compounds such as compounds of Formula (1A)
  • 4-(2-methoxyalkyl)-7-alkyl tryptamine compounds such as compounds of Formula (1B) are prepared according to the following exemplary reaction sequences.
  • precursor (A) can be converted directly to intermediate (D), for example by Pd-catalyzed cross-coupling with potassium (2-methoxyethyl)trifluoroborate in the presence of a suitable base, such as cesium carbonate.
  • a suitable base such as cesium carbonate.
  • disclosed 4-(2-hydroxyalkyl)-7-alkyl compounds compounds of Formula (1A) can be prepared according to the exemplary reaction scheme below : [134] Additional procedures known in the art that are useful for preparing the disclosed compounds can be found in WO2023/010000. [135] The skilled artisan understands that while the reaction schemes depict exemplary reagents and/or solvents, alternatives are also embraced by the present disclosure.
  • compositions such as pharmaceutical compositions, comprising a disclosed compound.
  • “Pharmaceutical compositions” are compositions that include the 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 such as disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th ed., Acad.
  • 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.) [141]
  • the disclosed 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, 2024-02-26 such as “patches” that contact the epidermis (including the mucosa) for an extended or brief period of time.
  • a disclosed composition is 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.
  • a disclosed pharmaceutical composition may be prepared as a formulation 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.
  • disclosed pharmaceutical compositions may be formulated into a topical formulation (e.g., a topical dosage form).
  • Topical formulations include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams; and may include a pharmaceutically acceptable excipient.
  • compositions include, for example, penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, gelling agents, and other such ingredients as will be generally known to one of skill.
  • the topical formulation comprises a penetration enhancer.
  • penetration enhancers are generally characterized by their ability to increase the permeability of biological barriers, such as scalp skin.
  • including a penetration enhancer in the formulation increases the bioavailability of the active agent(s) by improving the ability of the active agent(s) to diffuse into the skin tissue.
  • Penetration enhancers include, for example, include fatty acids and oils such as castor oil, coconut oil, medium chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petroleum jelly, cocoa butter, shea butter, or other esters, triglycerides, or functional derivatives thereof.
  • the penetration enhancer is 1,2-lauryl ether, aprotinin, azone, benzalkonium chloride, benzalkonium bromide, cetylpyridinium chloride, cetyltrimethyl ammonium, cyclodextrin, dextran sulfate, glycol, lauric acid, lauric acid, propylene, lysophosphatidylcholine, menthol, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, chitosan, sodium glycocholate, sodium deoxyglycocholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, dimethyl sulfoxide, or a combination thereof.
  • the penetration enhancer is selected from a group comprising lower chain alcohol with a carbon chain length of 1 to 5, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxychoiate, sodium taurodeoxyeholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, fysophosphatidylchoiine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulphate, Polyoxyethylene-9-lauryl ether, Polyoxythylene-20-cetyiether, Benzalkonium chloride, cetylpyridinium chloride, Vitamin E TPGS, Caprylocaproyl poiyoxylglycerides, Stearoyl Macrogolglycerides, Propylene Glycol Dicaprylocaprate or mixtures thereof.
  • a topical formulation may comprise a penetration enhancer at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%
  • the topical formulation comprises a carrier.
  • Carriers can be designed to give controlled release profiles, improved circulation times and better penetration across the epithelium.
  • the carrier is a hydrophobic drug carrier.
  • Hydrophobic drug carriers can have the advantage of exhibiting slow sustained release and may adhere well to biological surfaces. Hydrophobic drug carriers can have slow (i.e., extended) release kinetics, or may also be constructed to have a rapid or immediate release profile.
  • New techniques include the development of hydrophilic coatings on hydrophobic nanoparticles to improve their transport across tissue surfaces while retaining the slow-release profiles. These include polyethylene glycol and chitosan coatings (see, e.g., de la Fuente, et al.
  • aqueous media such as water, saline, glycine, hyaluronic acid and the like
  • solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like
  • solvents dispersion media
  • coatings antibacterial and antifungal agents
  • isotonic and absorption delaying agents or any other inactive ingredient.
  • Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed.1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed.2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10th ed.2001); and Handbook of Pharmaceutical Excipients (Raymond C.
  • the topical formulation comprises an emulsifier.
  • the emulsifier may be an anionic, cationic, or neutral emulsifier.
  • the emulsifier is an anionic emulsifier selected from the group consisting of alkyl sulfate, aralkyl sulfates, alkyl ethoxy ether sulfates, alkaryl sulphonates, alkyl succinates, alkyl sulfosuccinates, N-alkoyl sarconsinates, isethionates, N-acyl taurate, sodium lauryl sulfate, sodium laureth sulfate, sodium oleyl succinate, sodium dodecylbenzenesulfonate, and sodium lauryl sarconsinate.
  • Exemplary non-ionic or neutral emulsifiers include sorbitan ester, ethoxylated sorbitan ester, 2024-02-26 ethoxylated alkyl ether, ethoxylated fatty acid ether, fatty alcohol, ethoxylated fatty alcohol, and esters of glycerin and fatty acids.
  • the emulsifiers are synthetic or natural polymers.
  • the emulsifier includes silicon.
  • the emulsifier is a silicone (e.g., dimethicone, phenyltrimethicone, PEG dimethicone, PPG dimethicone, etc.).
  • the topical formulation comprises an antioxidant.
  • the antioxidant may be amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g., urocanic acid) and derivatives thereof peptides, such as D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g., anserine), carotenoids, carotenes (e.g., ⁇ -carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, liponic acid and derivatives thereof (e.g., dihydroliponic acid), aurothioglucose, propylthiouracil and other thiols (e.g., thiorodoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl, propyl, amy
  • the topical formulation comprises a thickener.
  • the thickener may be crosslinked polyacrylic acids and derivatives thereof, polysaccharides and derivatives thereof, such as xanthan gum, agar agar, alginates or tyloses, cellulose derivatives (e.g., carboxymethylcellulose or hydroxycarboxymethylcellulose), fatty alcohols, monoglycerides and fatty acids, polyvinyl alcohol and PVP.
  • the topical formulation comprises a cosmetically and/or dermo-cosmetically active substance.
  • a cosmetically and/or dermo-cosmetically active substance may be a color-imparting active substance, skin- or hair-pigmenting composition, tinting composition, tanning composition, bleach, keratin-hardening substance, antimicrobial active substance, light filter active substance, repellent active substance, substance having hyperemic activity, substance having keratolytic or keratoplastic activity, anti- 2024-02-26 phlogistic agent, substance having keratinizing activity, antioxidant active substance or substance active as a free radical scavenger, skin-moisturizing substance or skin humectant, refatting active substance, substance having antierythematous or antiallergic activity, branched fatty acid, and any mixture thereof.
  • the topical formulation comprises a perfume oil.
  • Natural fragrances are extracts of blossoms (lily, lavender, rose, jasmine, neroli, ylang-ylang), stalks and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, caraway, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), woods (pinewood, sandalwood, guajak wood, cedar wood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax).
  • Typical synthetic fragrance compounds are products of the type consisting of the esters, ethers, aldehydes, ketones, alcohols and hydrocarbons.
  • Essential oils of low volatility which are generally used as aroma components, are also suitable as perfume oils, e.g., sage oil, chamomile oil, clove oil, balm oil, mint oil, cinnamon leaf oil, lime tree blossom oil, juniper oil, vetiver oil, oliban oil, galbanum oil, labolanum oil and lavandin oil.
  • the topical formulation comprises a solvent, and optionally a cosolvent.
  • Any solvent(s) and cosolvent(s) may be collectively referred to as a “solvent system.”
  • the solvent system chosen can affect the stability, bioavailability, and overall efficacy of the formulation.
  • the solvent system is capable of dissolving or solubilizing the active agent(s) and any included excipients at the desired concentration(s), and should be stable and compatible with the active agent(s) and any other excipients) in the formulation.
  • the solvent system comprises more than one solvent, the ratio of cosolvents is optimized, for example to increase the penetration or bioavailability of an active agent.
  • Solvents that may be included in topical formulations may include, without limitations, water, ethanol, polyhydric alcohols (e.g., glycerin), 1,3-butylene glycol, propylene glycol, hexylene glycol, propane diol, ethylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, other sugars which are liquid at room temperature, water-soluble alkoxylated nonionic polymers such as polyethylene glycol, and combinations thereof.
  • polyhydric alcohols e.g., glycerin
  • 1,3-butylene glycol propylene glycol
  • hexylene glycol propane diol
  • ethylene glycol diethylene glycol
  • dipropylene glycol dipropylene glycol
  • diglycerin diglycerin
  • sorbitol other sugars which are liquid at room temperature
  • water-soluble alkoxylated nonionic polymers such as polyethylene glycol, and combinations thereof.
  • Solvents may be present, individually or in total (if more than one solvent is included), in the formulation in an amount ranging from about 0.1 wt% to about 95 wt% (calculated as the total weight of solvents in the formulation divided by the total weight of the formulation).
  • the topical formulation comprises a viscosity modifying agent.
  • the viscosity modifying agent is a thickener.
  • Common thickeners include but are not limited to: acrylates, carbomers, cellulose matrices, silicones, carrageenans, gums, resins, polysaccharides, and high melting point waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosins, resins, paraffins, and petroleum jelly.
  • the viscosity modifying agent is a carbohydrate.
  • Exemplary carbohydrates include monosaccharides, disaccharides, oligosaccharides, and polysaccharides.
  • Exemplary polysaccharides include cellulose, methylcellulose, hydroxypropylmethylcellulose, chitin, galactoarabinan, polygalactose, and polyarabinose.
  • Exemplary glycerides includes hydroxystearic acid monoglyceride, hydroxystearic acid diglyceride, isostearic acid monoglyceride, isostearic acid diglyceride, oleic acid monoglyceride, oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride, linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acid monoglyceride, linolenic acid diglyceride, erucic acid monoglyceride, erucic acid diglyceride, tartaric acid monoglyceride, tartaric acid diglyceride, citric acid monoglyceride, citric acid diglycer
  • the viscosity modifying agent is a polymer.
  • the polymer may be a natural or synthetic polymer.
  • Natural polymers include polysaccharides, nucleic acid, and proteins.
  • Synthetic polymers include polyesters, polyureas, polycarbonates, polyvinyl alcohol, polyamides, polyethers, polyesters, polyamines, polytyrosines, polyanhydrides, polyphosphazenes, polyacrylamides, polyacrylates, polymethacrylates, polyvinylpyrrolidone (PVP), etc.
  • Exemplary thickening agents include alginate derivatives, preneutralized carbomer 430, hydrophilic silicas, polysaccharides, xanthan gum, guar guar, agar agar, carboxymethylcellulose, hydroxyethylcellulose, polyacrylates, polyacrylamides, PVP, and salts.
  • the topical formulation comprises an adhesion modifying agent.
  • the topical formulation comprises an adhesive polymer.
  • Adhesive polymers have physicochemical properties that allow prolonged binding to tissue surfaces.
  • inclusion of an adhesive polymer in the formulation increases the amount of time that an active agent is in contact with, and can diffuse across, a barrier (e.g., skin).
  • the adhesive polymer is chitosan, gelatin guar gum, lectins, sodium alginate, soluble starch, tragacanth, xanthan gum deacetylated gum, polyacrylic acid, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, a thiomer, polycarbophil, hyaluronic acid, dermatan sulfate, or a combination thereof.
  • the adhesion modifying agent is a tackifier. Common tackifiers include but are not limited to gums, resins (natural or modified), carbomers, or other natural or synthetic polymers.
  • the topical formulation comprises a preservative.
  • Preservatives can be used to inhibit microbial growth or increase stability of the formulation, 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 (e.g., sodium benzoate), vitamin A, vitamin C (ascorbic acid), citric acid, vitamin 2024-02-26 E, and tocopherol.
  • the topical formulation comprises an antioxidant. Without being bound by theory, antioxidants generally can delay or inhibit the oxidative decomposition of components of the topical formulations, which may thereby improve the stability and extend the shelf-life thereof.
  • the antioxidant is ⁇ -tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, methionine, citric acid, ascorbic acid, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, propyl gallate, cysteine, or a combination thereof.
  • the antioxidant is a cyclodextrin, D- ⁇ -tocopherol, rosmarinic acid, or a combination thereof.
  • the topical formulation comprises a solubilizing agent.
  • solubilizing agents generally form complexes with active ingredients which can have different physicochemical properties than the active ingredient alone.
  • the properties of the complexes can increase the solubility of the active agent(s) in the formulation.
  • the solubilizing agent is a water-soluble organic solvent, a non-ionic surfactant, a water insoluble lipid, an organic liquid, a cyclodextrin, or a phospholipid.
  • the solubilizing agent is a water-soluble enhancing agent.
  • the water-soluble enhancing agent is polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, xanthan gum, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, dimethylsulfoxide, or a combination thereof.
  • the solubilizing agent is propylene glycol.
  • the solubilizing agent is xanthan gum.
  • the solubilizing agent is a non-ionic surfactant.
  • the non-ionic surfactant is Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, mono- and di-fatty acid esters of PEG 300, 400, or 1750, or a combination thereof.
  • the solubilizing agent is an organic liquid.
  • the organic liquid is beeswax, d-alpha-tocopherol, oleic acid, or a medium-chain mono- or diglyceride.
  • the solubilizing agent is a cyclodextrin.
  • the solubilizing agent is a phospholipid.
  • the phospholipid is hydrogenated soy phosphatidylcholine, distearoyl- phosphatidylglycerol, L-alpha-dimyristoyl-phosphatidylcholine, or L-alpha-dimyristoyl-phosphatidylglycerol.
  • the solubilizing agent is lecithin.
  • the topical formulation comprises a colorant.
  • Suitable colorants and/or dyes and/or pigments include colors such as e.g., white, black, yellow, blue, green, pink, red, orange, violet, indigo, brown, and combinations thereof, pigments such as, e.g., Timica Extra Large Sparkles, titanium dioxide and chromium oxide greens, ultramarine blues and pinks and ferric oxides.
  • Colorants and/or dyes and/or pigments may be present, individually or in total (if more than one colorant and/or dye and/or pigment is included), in disclosed formulations in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of colorants and/or dyes and/or pigments in the formulation divided by the total weight of the 2024-02-26 formulation). Colorants may be present, individually or in total (if more than one colorant is included), in disclosed formulations in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of colorants in the formulation divided by the total weight of the formulation). [160] In embodiments, the topical formulation comprises a binder.
  • Suitable binders include, without limitations, polyvinylpyrrolidone (PVP), marine colloids, carboxyvinyl polymers, starches, cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (carmellose), hydroxypropylmethylcellulose, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, and salts thereof (e.g., carmellose sodium), natural gums such as karaya, xanthan, carrageenans, gellan gum, locust bean gum, gum arabic and tragacanth, chitosan, colloidal magnesium aluminum silicate, and colloidal silica.
  • PVP polyvinylpyrrolidone
  • marine colloids such as hydroxyethylcellulose, carboxymethylcellulose (carmellose), hydroxypropylmethylcellulose, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, and salts thereof (e.g., carmellose sodium), natural gums such as
  • Binders may be present, individually or in total (if more than one binder is included), in disclosed formulations in an amount ranging from about 0.01 wt% to about 5 wt% (calculated as the total weight of binders in the formulation divided by the total weight of the formulation).
  • the topical formulation comprises a humectant.
  • Humectants such as low molecular weight polyethylene glycol (e.g., PEG6-PEG12), may be present, individually or in total (if more than one humectant is included), in the formulation in an amount of up to about 10 wt%, up to about 5 wt%, up to about 3 wt%, up to about 1 wt%, or up to about 0.1 wt% (calculated as the total weight of humectants in the formulation divided by the total weight of the formulation).
  • the topical formulation comprises a surfactant.
  • the surfactants that can be included in the formulation may be anionic, nonionic, or amphoteric compounds.
  • anionic surfactants are one or more of higher alkyl sulfates such as potassium or sodium lauryl sulfate, higher fatty acid monoglyceride monosulfates, such as the salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, alkyl sulfonates such as sodium dodecyl benzene sulfonate, higher fatty sulfoacetates, higher fatty acid esters of 1,2 dihydroxypropane sulfonate.
  • higher alkyl sulfates such as potassium or sodium lauryl sulfate
  • higher fatty acid monoglyceride monosulfates such as the salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids
  • alkyl sulfonates such as sodium dodecyl benzene sulfonate
  • higher fatty sulfoacetates higher fatty acid esters of 1,2 dihydroxypropane
  • water soluble nonionic surfactants are condensation products of ethylene oxide with various hydrogen-containing compounds that are reactive therewith and have long hydrophobic chains (e.g., aliphatic chains of about 12 of 20 carbon atoms), which condensation products contain hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides and other fatty moieties, and with propylene oxide and polypropylene oxides, e.g., Pluronic materials such as Pluronic F127.
  • Exemplary suitable alkyl polyglycoside (APG) surfactant(s) that may be used in the formulation may comprise APG C8-C10, APG C10-C16, decyl glucoside, coco-glucoside, anionic APG carboxylate, sodium lauryl glucose carboxylate, lauryl glucoside, D-glucopyranose (oligomeric, CIO-16 glycosides, carboxymethyl ethers, sodium salts), C12-C16 fatty alcohol glycoside, and combinations thereof.
  • Exemplary APG surfactant(s) that may be used may have an industry designation of Plantaren® 2000 N UP/MB, Plantapon® LGC Sorb, Plantaren® 1200 N UP/MB, and Plantaren® 818 UP/MB.
  • Surfactants may be present, individually or in total (if more than one surfactant is included) in the formulation in an amount ranging from 2024-02-26 about 0.01 wt% to about 10 wt% (calculated as the total weight of surfactants in the formulation divided by the total weight of the formulation ).
  • the topical formulation comprises a gelling agent.
  • Exemplary gelling agent(s) used in disclosed formulations may comprise pectins, starches, and gelatin forms derived from animals or from plants (e.g., pork gelatin).
  • the pectin in the formulation may include, e.g., high methoxyl pectin, low methoxyl pectin, or a combination thereof.
  • the pectin is amidated pectin.
  • the pectin is non-amidated pectin.
  • the pectin is a combination of amidated pectin and non-amidated pectin.
  • the gelatin in the formulation may include Type A gelatin, Type B gelatin, a hide or skin gelatin (e.g., calf skin, pig skin) and/or a bone gelatin (e.g., calf bone, pig bone) used alone or in combination.
  • Gelling agent(s) may be present, individually or in total (if more than one gelling agent is included) in the formulation in an amount ranging from about 0.1 wt% to about 20 wt% (calculated as the total weight of gelling agents in the formulation divided by the total weight of the formulation).
  • 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.
  • 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).
  • 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 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.
  • 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.
  • compositions 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 poly(ethylene 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 Pharm. Tech., 2nd Ed., 754-757 (2002).
  • liquid dosage forms may comprise additives, e.g., one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting 2024-02-26 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.
  • a disclosed pharmaceutical composition may be formulated in an ophthalmic formulation.
  • Ophthalmic formulations of the disclosure include topical formulations, such as eye drops, gels, and ointments; and may comprise excipients suitable for topical formulations, e.g., penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e.g., tackifiers), preservatives, antioxidants, adhesive polymers, solubilizing agents, colorants, binders, humectants, surfactants, gelling agents, and other such ingredients described herein and as will be generally known to one of skill in the art.
  • excipients suitable for topical formulations e.g., penetration enhancers, carriers, diluents, emulsifiers, stabilizers, solvents and cosolvents, viscosity modifying agents (e.g., thickeners), adhesion modifying agents (e
  • a disclosed ophthalmic formulation may contain one or more viscosity- modifying agents and have a viscosity that feels comfortable to the eye and does not cause blurring of the vision.
  • an ophthalmic formulation may have a viscosity of 1.0 to 100,000 cP (e.g., from about 2.0 to 90,000 cP or from about 2.5 to 75,000 cP).
  • Viscosity-modifying agents are substances that have the ability to cause thickening (increase the viscosity) of ophthalmic formulations.
  • Viscosity modifying agents include xanthan gum, edetate, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene glycol, propylene glycol alginate, chitosan, and tragacanth. Hydrogels may also be used as viscosity-enhancing excipients, particularly in artificial tears. Compatible viscosity-adjusting agents can be used in all formulations mentioned herein. Concentrations of viscosity-modifying agents in ophthalmic formulations of the disclosure can range from about 0.1 percent to about 10 percent by weight (e.g., between 1 percent and 5 percent by weight). Sorbitol may be used as a combined tonicity-adjusting and viscosity-modifying excipient.
  • Sorbitol may be used in ophthalmic formulations of the disclosure in a concentration range from about 0.1 to about 10 percent (e.g., from 2 percent to 5 percent by weight).
  • the ophthalmic formulation may comprise a penetration enhancer, for example to aid penetration of the active compound(s) into and across the skin or eyelid skin.
  • Exemplary penetration enhancers for ophthalmic formulations include, e.g., any of an aliphatic alcohol, fatty acid (including salts thereof), fatty acid ester, polyalcohol alkyl ether, polyoxyethylene alkyl ether, glyceride, polyalcohol medium chain fatty acid ester, polyoxyethylene sorbitan fatty acid ester, alkyl lactate ester, terpene, and organic amine.
  • the penetration enhancer is any of ethanol, glycerol, diethylene glycol, propylene glycol, polyethylene glycol and higher aliphatic alcohols (e.g., a saturated or unsaturated higher aliphatic alcohol having 12 to 22 carbon atoms such as oleyl alcohol, lauryl alcohol and stearyl alcohol), capric acid, myristic acid, palmitic acid, lauric acid, stearic acid, isostearic acid, oleic acid, linoleic acid, and linolenic acid (including salts thereof); an ester of a fatty acid such as myristic acid, palmitic acid, lauric acid, stearic acid, 2024-02-26 isostearic acid, oleic acid, linoleic acid, linolenic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, pivalic acid, caproic acid, heptanoic acid
  • the ophthalmic formulation comprises a hydrating agent.
  • Hydrating agents may also facilitate penetration of the active compound(s) through the cell or junctions of the barriers including mucosal, mucocutaneous, and stratum corneum layers.
  • Exemplary hydrating agents include, e.g., hyaluronic acid (or a salt thereof, e.g., sodium hyaluronate), water, saline solution, and PVP, propylene glycol, glycerol, sorbitol, polyethylene glycol, dexpanthenol, panthothenic acid, ectoin, carboxyvinyl polymer, carmellose sodium, and povidone.
  • the ophthalmic formulation comprises a surfactant.
  • Surfactants may facilitate dissolution and/or absorption of formulation components, and include, e.g., any of an anionic surfactant, cationic surfactant, nonionic surfactant and amphoteric surfactant.
  • Exemplary surfactants include, e.g., any of a fatty acid salt, alkyl sulfate, polyoxyethylene alkyl sulfate, alkylsulfo carboxylate salt, alkylether carboxylate salt, amine salt, quanternary ammonium salt, polysorbate 80, poloxamer, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, alkyl betaine, dimethylalkylglycine, and lecithin.
  • the ophthalmic formulation comprises a gum and/or resin, e.g., any of a sodium polyacrylate, cellulose ether, calcium alginate, carboxyvinyl polymer, ethylene-acrylic acid copolymer, vinyl pyrrolidone polymer, vinyl alcohol-vinyl pyrrolidone copolymer, nitrogen-substituted acrylamide polymer, polyacrylamide, cationic polymer such as cationic guar gum, dimethylacrylic ammonium polymer, acrylic acid-methacrylic acid copolymer, polyoxyethylene-polypropylene copolymer, polyvinyl 2024-02-26 alcohol, pullulan, agar, gelatine, chitosan, polysaccharide from tamarindo seed, xanthan gum, carageenan, high-methoxyl pectin, low-methoxyl pectin, guar gum, acacia gum, microcrystalline cellulose, arabin
  • the ophthalmic formulation comprises a pH adjuster.
  • a pH adjuster may be used to adjust the pH of the formulation to a desired range, such as pH 4-10, pH 5-8, or any range that maximizes the penetration through the skin of the compound(s) in the composition.
  • the pH adjuster is any of hydrochloric acid, citric acid, sodium citrate, acetic acid, sodium acetate, ammonium acetate, succinic acid, tartaric acid, L-sodium tartrate, sodium hydrate, potassium hydrate, sodium carbonate, sodium hydrogencarbonate, lactic acid, calcium lactate, sodium lactate, sodium fumarate, sodium propionate, boric acid, ammonium borate, maleic acid, phosphoric acid, sodium hydrogenphosphate, malic acid, adipic acid, triethanolamine, diisopropanolamine, meglumine, monoethanolamine, sulfuric acid, and aluminum potassium sulfate.
  • the ophthalmic formulation comprises a stabilizer.
  • Exemplary stabilizers include, e.g., sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium formaldehyde sulfoxylate, L-ascorbic acid, erythorbic acid, L-cysteine, thioglycerol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbyl palmitate, alpha-tocopherol, nordihydroguaiaretic acid, disodium edetate, tetrasodium edetate dehydrate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, phosphoric acid, citric acid, ascorbic acid and/or succinic acid.
  • sodium bisulfite sodium sulfite, sodium pyrosulfite, sodium formaldehyde sulfoxylate, L-ascorbic acid, erythorbic acid, L-c
  • Additional ophthalmic formulations of the disclosure include contact lenses.
  • a disclosed compound or pharmaceutical composition is incorporated into a contact lens for ocular drug delivery.
  • the contact lens may be a hydrogel contact lens or a molecularly imprinted contact lens.
  • Another exemplary contact lens drug delivery system known to those of skill in the art is the experimental SIGHT (Sustained Innovative Glaucoma and Ocular Hypertension Treatment) treatment, which seeks to treat mild to moderate glaucoma and ocular hypertension (see Clinical Trial NCT04747808).
  • the SIGHT drug-eluting lens for glaucoma treatment incorporates the FDA-approved drug bimatoprost into contact lenses that are formulated for controlled drug release.
  • the SIGHT lens comprises drug and barrier layers on the lens surface to control the diffusion release kinetics of the drug.
  • Ophthalmic formulations of the disclosure include those of similar material design as the SIGHT lens, as well as others generally known to those of skill in the art (e.g., as described in Franco, et al., Polymers , 2021, 13, 1102).
  • a disclosed pharmaceutical composition may comprise any excipient (e.g., a surfactant, carrier, antioxidant, and the like) at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 2024-02-26 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about
  • 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 compound of Formula (1) 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, 1926, Arch. Exp. Pathol Pharmacol.
  • 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, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins.
  • amino acids e.g., anti-inflammatory agents, analgesics, antineuropathic and
  • 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.
  • R N1 , R N2 , R ⁇ , R ⁇ , R 2 , R 4 , R 5 , R 6 , and R 7 are as defined herein and as generally understood in the art: [187]
  • R N1 , R N2 , R ⁇ , R ⁇ , 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 ⁇ , R ⁇ , R 2 , R 4 , R 5 , R 6 , and R 7 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 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, 2024-02-26 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- ⁇ -methyltryptamine ( ⁇ ,O-DMS), N,N-dimethyl- tryptamine (DMT), 2, ⁇ -dimethyltryptamine (2, ⁇ -DMT), ⁇ ,N-dimethyltryptamine ( ⁇ ,N-DMT), N,N-dipropyltryptamine (DPT), N-ethyl-N-isopropyltryptamine (EiPT), ⁇ -ethyltryptamine selected from the group consisting
  • 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 phenethylamine.
  • phenethylamines are compounds having the general structure below, wherein R N1 , R N2 , R ⁇ , 2024-02-26 R ⁇ , and each of R 2 -R 6 are as taught herein and as generally understood in the art: [191]
  • R N1 , R N2 , R ⁇ , R ⁇ , and each of R 2-6 are 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.
  • R 3 and R 4 are joined together to form an optionally substituted heterocyclyl, such as a dioxole (as with MDMA), a furan, a tetrahydrofuran, a thiophene, a pyrrole, a pyridine, a pyrrolidine, an ethylene oxide, an ethylenimine, a trimethylene oxide, a pyran, a piperidine, an imidazole, a thiazole, a dioxane, a morpholine, or a pyrimidine.
  • R 3 and R 4 are joined together to form an optionally substituted aryl, such as a phenyl.
  • the phenethylamine comprises a quaternary ammonium cation wherein each of R N1 , R N2 , and an additional R N3 are independently an alkyl group or an aryl group, and with all other substituents as above .
  • the phenethylamine 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 phenethylamine selected from the group consisting of ⁇ -ethyl-3,4,5-trimethoxy-phenethylamine (AEM), 4-allyloxy-3,5- dimethoxyphenethylamine (AL), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH), 2,5-dimethoxy-4-ethylthioamphetamine (ALEPH-2), 2,5-dimethoxy-4-isopropylthioamphetamine (ALEPH-4), 2,5-dimethoxy-4-phenylthio-amphetamine (ALEPH-6), 2,5-dimethoxy-4-propylthio- amphetamine (ALEPH-7), 2,5-dimethoxy- ⁇ -ethyl-4- methylphenethylamine (ARIADNE), 3,4-diethoxy-5-methoxy-phenethylamine (ASB), 4-butoxy-3,5- dimethoxyphenethylamine (
  • the additional active compound is an ergoline. In some embodiments, the additional active compound is an ergot alkaloid. In some embodiments, the additional active compound is a lysergamide. As understood by those in the art, 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 taught herein and as generally understood in the art: [194] In some embodiments, 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 substitute
  • 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, 2024-02-26 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 mammal after treatment that are judged to be desirable and beneficial.
  • those responses shall differ, but would be readily understood by those of ordinary skill, through an understanding of the disclosure herein and the general knowledge of the art (e.g., by reference to the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for the stated disorder).
  • 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,
  • 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 0.001 mg/kg and 0.1 mg/kg, such as about 0.001 mg/kg, 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 (in a milligram dosage amount calculated based on the kilogram weight of the patient) about 20 pg/kg body weight or less (e.g., less than 20 pg/kg, less than 15 pg/kg, less than 10 pg/kg, or less than 5 pg/kg body weight, e.g., from 1 to 20 pg/kg body weight, e.g., from 1 to 5 pg/kg, from 5 to 10 pg/kg, from 10 to 15 pg/kg, or from 15 to 20 pg/kg, e.g., about 5 pg/kg, about 10 pg/kg, about 15 pg/kg, or about 20 pg/kg).
  • 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) about less than about 20 ng/mL (e.g., 0.05 to 20 ng/mL, e.g., 0.1 to 15 ng/mL, 0.5 to 10 ng/mL, or 1 to 5 ng/mL, e.g., 0.05 to 0.1 ng/mL, 0.1 to 0.2 ng/mL, 0.2 to 0.3 ng/mL, 0.3 to 0.4 ng/mL, 0.4 to 0.5 ng/mL, 0.5 to 1.0 ng/mL, 1.0 to 5 ng/mL, 5 to 10 ng/mL, 10 to 15 ng/mL, or 15 to 20 ng/mL, e.g., about 0.05 ng/mL, 0.1 ng/mL, 0.2 ng/mL
  • the circulating drug plasma level of the compound is below the limit of detection (e.g., 0.1 ng/mL or less).
  • 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), 2024-02-26 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
  • 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 an additional active compound, for instance where the additional active compound is a phenethylamine or another 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
  • a pharmaceutical composition includes an additional active compound, for instance where the additional active compound is a phenethylamine 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 202
  • 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 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 those of skill or the public.
  • kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefor, 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. 2024-02-26 G. Kits
  • Another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefor, 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.
  • kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can 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).
  • pharmacies e.g., hospital pharmacies and compounding pharmacies.
  • information pertaining to dosing and proper administration (if needed) will be printed onto a multi-dose kit directly (e.g., on a blister pack or other interior packaging holding the compositions or formulations of the disclosure); however, 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.
  • 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.
  • H. Methods of Use [214] In some aspects, provided herein are methods of using the disclosed compounds. In some embodiments, 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 therapy.
  • disclosed compounds are administered along with psychotherapy, psychological support, or patient monitoring.
  • 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 a pain disorder.
  • disclosed compounds are administered to a subject that is healthy.
  • the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and 2024-02-26 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.
  • 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.
  • a. Modulating Neurotransmission [217] In some embodiments, disclosed compounds modulate neurotransmission in a subject, such as following administration of a therapeutically effective amount to said subject.
  • modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.
  • modulating neurotransmission comprises regulating levels of monoamines in, for example, the CNS and peripheral tissues.
  • modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.
  • disclosed compounds activate serotonin receptors.
  • disclosed compounds agonize and/or antagonize serotonin receptors (5-HT receptors, such as the 5-HT 2 receptor).
  • the 5-HT 2 receptor family consists of the three distinct receptor subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C .5-HT 2A and 5-HT 2C receptors are more highly expressed in the brain than the 5-HT 2B subtype. Psilocin and other related psychoactive tryptamines exert their psychoactive effects primarily by acting as 5-HT 2A receptor agonists. However, many of these tryptamines (including psilocin) are also agonists at the 5-HT 2B and 5-HT 2C receptors, owing to high sequence homology among the three 5-HT 2 receptor subtypes (Nichols, Pharmacol. Rev., 2016, 68, 264-355).
  • Activation of all 5-HT 2 receptor subtypes may result in reduced efficacy or detrimental side effects.
  • activation of 5-HT 2C receptors has been shown to functionally oppose effects of 5-HT 2A receptor activation ( id .), while activation of 5-HT 2B receptors in cardiac muscle tissue has been linked to heart valve disease (Hutcheson, et al., Pharmacol. Ther.2011, 132(2): 146–157).
  • disclosed compounds agonize or partially agonize 5-HT receptors, such as any one or more of an 5-HT 1 receptor, such as 5-HT 1A and 5-HT 1B , an 5-HT 2 receptor, such as 5-HT 2A , 5-HT 2B , and 5-HT 2C , and 5-HT 6 .
  • a disclosed compound has an in vitro EC 50 (agonist mode) for any one or more of 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2C , and 5-HT 6 that is less than 10 ⁇ M, less than 5 ⁇ M, less than 1 ⁇ M, less than 0.5 ⁇ M, or less than 0.1 ⁇ M.
  • a disclosed compound has an in vitro EC 50 (agonist mode) for 5-HT 2A that is less than 1 ⁇ M, less than 0.5 ⁇ M, less than 0.1 ⁇ M, less than 0.05 ⁇ M, less than 0.01 ⁇ M, less than 0.005 ⁇ M, or less than 0.001 ⁇ M. In embodiments, a disclosed compound has an in vitro EC 50 (agonist mode) for 5-HT 2C that is less than 1 ⁇ M, less than 0.5 ⁇ M, less than 0.1 ⁇ M, less than 0.05 ⁇ M, less than 0.01 ⁇ M, less than 0.005 ⁇ M, or less than 0.001 ⁇ M.
  • disclosed compounds show greater potency at 5-HT 2A relative to another 5-HT receptor. In some embodiments, disclosed compounds show greater potency at 5-HT 2A relative to any one or more of an 5-HT 1 receptor, another 5-HT 2 receptor, such as 5-HT 2B and 5-HT 2C , a 5-HT 5 receptor, a 5-HT 6 receptor, and a 5-HT 7 receptor.
  • 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. In one example, measuring Gq-mediated calcium flux is a known method for assessing modulation, e.g., activation, of 5-HT 2A , a widely recognized target of psychedelic compounds.
  • a disclosed compound has increased selectivity for the 5-HT 2A receptor over another serotonin receptor (e.g., the 5-HT 2B receptor, or the 5-HT 2C receptor). In some embodiments, a disclosed compound has increased selectivity for the 5-HT 2A receptor over the 5-HT 2B receptor.
  • a disclosed compound has increased selectivity for the 5-HT 2A receptor over the 5-HT 2C receptor.
  • selectivity is defined as functional activity selectivity, calculated by the ratio of the half-maximal effective concentration (EC 50 ) of a disclosed compound for one receptor (e.g., the 5-HT 2A receptor) as compared to another receptor (e.g., a serotonin receptor, such as the 5-HT 2B receptor, or the 5-HT 2C receptor).
  • EC 50 half-maximal effective concentration
  • selectivity can be defined as affinity selectivity, defined by the ratio of binding affinity (e.g., as assessed by K i ) for one receptor (e.g., the 5-HT 2A receptor) as compared to another receptor (e.g., a serotonin receptor, such as the 5-HT 2B receptor, or the 5-HT 2C receptor).
  • affinity selectivity defined by the ratio of binding affinity (e.g., as assessed by K i ) for one receptor (e.g., the 5-HT 2A receptor) as compared to another receptor (e.g., a serotonin receptor, such as the 5-HT 2B receptor, or the 5-HT 2C receptor).
  • affinity selectivity defined by the ratio of binding affinity (e.g., as assessed by K i ) for one receptor (e.g., the 5-HT 2A receptor) as compared to another receptor (e.g., a serotonin receptor, such as the 5-HT 2B receptor, or the 5-HT 2C receptor).
  • a disclosed compound has an affinity selectivity of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold selectivity for the 5-HT 2A receptor over the 5-HT 2B receptor.
  • a disclosed compound has improved affinity selectivity for the 5-HT 2A receptor over the 5-HT 2B receptor, relative to a comparator.
  • a disclosed compound has a functional activity selectivity of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold selectivity for the 5-HT 2A receptor over the 5-HT 2B receptor.
  • a disclosed compound has improved affinity selectivity for the 5-HT 2A receptor over the 5-HT 2B receptor, relative to a comparator.
  • a disclosed compound has an affinity selectivity of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold selectivity for the 5-HT 2C receptor over the 5-HT 2B receptor.
  • a disclosed compound has improved affinity selectivity for the 5-HT 2C receptor over the 5-HT 2B receptor, relative to a comparator.
  • a disclosed compound has a functional activity selectivity of about 1.1-fold, 1.5-fold, 1.6-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, or at least 150-fold selectivity for the 5-HT 2C receptor over the 5-HT 2B receptor.
  • a disclosed compound has improved affinity selectivity for the 5-HT 2C receptor over the 5-HT 2B receptor, relative to a comparator.
  • a disclosed compound modulates neurotransmission in a subject, such as following administration of a therapeutically effective amount to said subject.
  • modulating neurotransmission contributes to the therapeutic effects of a disclosed compound in a subject.
  • modulating neurotransmission by administering a disclosed compound to a subject treats a disease or disorder in the subject.
  • Neurotransmission refers to the transfer of information between neurons. Information is emitted by a neuron when an action potential occurs, resulting in the release of neurotransmitters into a synapse. Neurotransmission can thus be quantified by measuring parameters of action potential firing in a population of neurons. In some embodiments, neurotransmission is quantified by measuring the general action potential firing activity (Obien et al. Front Neurosci .2015;8:423; Morin et al.
  • General action potential firing activity parameters include spike rate, burst rate, and/or spike contrast.
  • neurotransmission is quantified by measuring burst structure. Burst structure parameters include burst spike number, burst duration, and/or burst amplitude.
  • neurotransmission is quantified by measuring oscillatory behavior. Oscillatory behavior is measured as the 2024-02-26 standard deviation of spike rate, burst rate, and/or burst amplitude.
  • neurotransmission is quantified by measuring the synchronicity of activity of a neuron population.
  • Synchronicity is measured as the coefficient of variation in spike rate, burst rate, and/or burst duration across a neuron population. Synchronicity is also measured as synchronicity share, synchronicity distance, and/or spike simplex.
  • a disclosed compound modulates spike rate. Spike rate is the number of action potentials per second. In some embodiments, a disclosed compound modulates burst rate. Neurons may send out a series of action potentials in rapid succession, known as a burst. Burst rate is the number of bursts per second. In some embodiments, a disclosed compound modulates spike contrast.
  • Spike contrast is a measure of variability in neuronal activity, measured as the difference between the number of spikes occurring in the first half and second half of a recording duration (i.e.700 milliseconds).
  • a disclosed compound modulates burst spike number. Burst spike number is the number of spikes per burst. In some embodiments, a disclosed compound modulates burst duration. Burst duration is the mean duration of detected bursts.
  • neurotransmission is measured as the burst amplitude. To obtain burst amplitude, an integral function with a decay is calculated over the timestamps of bursts. The burst amplitude is the peak value of the integral, which increases with highly frequent and numerous spiking.
  • a disclosed compound modulates oscillatory behavior. Oscillatory behavior is a measure of variability in a parameter, measured as the standard deviation of a parameter over time within the experimental episode. In some embodiments, a disclosed compound modulates the synchronicity of activity in a neuron population. Synchronicity is a measure of the relative variability in activity across a neuron population. In some embodiments, a disclosed compound modulates synchronicity share. Synchronicity share is the average number of units involved in population bursts, higher values reflecting a higher degree of synchronicity in bursts occurring amongst populations of neurons. In some embodiments, a disclosed compound modulates synchronicity distances.
  • Synchronicity distances are defined as the average distance of burst starts within a population burst from the population burst center, lower values reflecting a stronger synchronicity of a network.
  • a disclosed compound modulates spike simplex.
  • Spike simplex is a measure of connectivity and complexity in a neuronal network, higher values reflecting higher synchronicity among neurons.
  • 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 2024-02-26 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.
  • a disclosed compound 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.
  • a disclosed compound increases total neurite length. In some embodiments, a disclosed compound increases maximum neurite length. In some embodiments, a disclosed compound increases the number of neurite nodes. In some embodiments, a disclosed compound increases the number of neurite extremities. [234] In some embodiments, administration of a disclosed compound 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.
  • disclosed compounds are used to treat a medical condition, such as a disease or disorder.
  • disclosed compounds are used in the manufacture of a medicament to treat a condition, such as a disease or disorder.
  • disclosed compounds or pharmaceutical compositions 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.
  • 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 mammal, 2024-02-26 the method 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 mammal, 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.
  • 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.
  • 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 In some embodiments, disclosed compounds are 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.
  • the disclosed compositions when administered in a therapeutically effective amount, provide 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 2024-02-26 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.
  • disclosed compounds are 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.
  • the disclosed compositions when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental health disorder.
  • the compounds and compositions of the disclosure are 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.
  • Non-limiting representative examples of applicable 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
  • SAQ Substance Abuse Questionnaire
  • MINI 5 Mini International Neuropsychiatric Interview 5
  • 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.
  • 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. In some embodiments, 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- ⁇ sberg 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- ⁇ sberg Depression Rating Scale
  • BDI-I 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
  • HRSD Hamilton Rating Scale for Depression
  • 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, d
  • 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.
  • 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.
  • 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 including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight
  • bulimia nervosa including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight
  • bulimia nervosa including anorexia with significantly low body weight, anorexia with dangerously low
  • 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).
  • enuresis including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis
  • 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
  • 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 2024-02-26 (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 - OUD (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).
  • S2BI Screening to Brief Intervention 2024-02-26
  • 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 - OUD Chart
  • DAST-10 Drug Abuse Screen Test
  • TAPS Tobacco, Alcohol, Prescription medication,
  • 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. [257]
  • 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.
  • 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.
  • sleep-wake 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, 2024-02-26 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
  • sleep-wake disorders are associated with difficulty
  • a disclosed compound is used to treat an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder.
  • 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.2012, Article ID 731638), motivational interviewing based therapy (e.g., as described in J Consul Clin Psychol 2001; 69(5): 858-62), meditation based therapy, such as transcendental meditation based therapy (e.g., as described in J Consul Clin Psychol 2000; 68(3): 515-52), or the therapeutic approach used by MAPS to treat patients with PTSD (e.g.
  • psychotherapy such as psychosocial
  • disclosed compounds and compositions 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 2024-02-26 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 AI “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 AI.
  • 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.
  • the disclosed pharmaceutical compositions are administered, 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).
  • the disclosed compositions may be administered in conjunction with or as an adjunct to psychotherapy.
  • psychotherapy is neither necessitated nor desired, or no 2024-02-26 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
  • 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. [274] In some embodiments, 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.
  • CYP or CYP450 cytochrome P450
  • CYP enzymes include CYP1A1, CYP1B1, 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, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A
  • a disclosed composition is taken together with a compound that is metabolized by the same CYP enzyme(s) as the disclosed composition, 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.
  • 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 2024-02-26 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs.
  • SNPs single nucleotide polymorphisms
  • a genetic variation is an inclusion criteria for the administration of a disclosed compound. In some embodiments, 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 or susceptibility to a mental health treatment such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.
  • the disclosed compositions when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a neurodegenerative disorder.
  • a 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.
  • 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). T hese 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.
  • iii. Pain Disorders [282] In some embodiments, disclosed compounds are used to treat a pain disorder.
  • disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a pain disorder.
  • the disclosed compositions when administered in a 2024-02-26 therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a pain disorder.
  • a “pain disorder” refers to a class of medical conditions characterized by the experience of persistent or recurrent physical or psychological pain, either localized or widespread, that significantly impairs an individual's daily functioning and quality of life. These disorders may involve various etiologies, including but not limited to nociceptive, neuropathic, psychogenic, idiopathic or radicular origins.
  • a compound is used to treat neuropathic pain.
  • a compound is used to treat psychogenic pain. In embodiments, a compound is used to treat idiopathic pain. In embodiments, a compound is used to treat radicular pain.
  • Pain disorders may manifest as acute or chronic pain, and they can affect different parts of the body, such as musculoskeletal, neurological, gastrointestinal, or visceral systems. Pain can be expressed as, but is not limited to, post-herpetic pain, trigeminal pain, occipital pain, or pudendal pain. In embodiments, a disclosed compound is used to treat pain associated with chemotherapy (e.g., chemotherapy associated neuropathy).
  • chemotherapy e.g., chemotherapy associated neuropathy
  • a disclosed compound is used to treat arthritis, back pain, central pain, chronic fatigue syndrome, cluster headaches, migraine headaches, phantom limb pain, complex regional pain syndrome, compression mononeuropathy, diabetic neuropathy, fibromyalgia, focal neuropathy, herniated disc pain, or sciatica.
  • pain is assessed using the Pain, Consumment, and General Activity Scale (PEG), the Numeric Rating Scale (NRS), the Visual Analog Scale (VAS), Behavioral Pain Scale (BPS), and the Faces Pain Scale-Revised (FPS-R).
  • PEG Pain, Consumment, and General Activity Scale
  • NRS Numeric Rating Scale
  • VAS Visual Analog Scale
  • BPS Behavioral Pain Scale
  • FPS-R Faces Pain Scale-Revised
  • Inflammation is an essential immune response to tissue insults such as microbial infection, acute injury, chemical irritants or other such dysregulation of normal tissue functioning.
  • the inflammatory process is a feature of the innate immune system, whereby molecular patterns of tissue damage are recognized and responded to by a variety of inflammatory agents such as cytokines and chemokines. These inflammatory agents act directly to remove harmful stimuli and initiate various signaling responses to return damaged tissue to a state of homeostasis. Although this response is often self-terminating, the resolution of inflammation may fail for multiple reasons, extending the inflammation response into a chronic stage (Ahmed AU. Front Biol.2011:6(4): 274–281).
  • 5-HT 2A receptors are involved in cognitive function and working memory, mediate the effects of psychedelic compounds, and have been implicated in mechanisms underlying 2024-02-26 neuropsychiatric disorders such as schizophrenia (Nichols CD. Cardiovasc Psychiatry Neurol. 2009;475108).
  • 5-HT 2A receptors are found in multiple immune related tissues such as the spleen, thymus, and circulating lymphocytes, as well as in components of both the innate and adaptive immune systems (Stefulj J, et al. Brain Behav Immun.2000 Sep;14(3):219-24; Clo ⁇ z-Tayarani I, et al. Int Immunol.2003 Feb;15(2):233-40).
  • Anti-inflammatory doses of psychedelics also can be below the threshold for producing subjective or behavioral effects, meaning they may exhibit anti-inflammatory effects without triggering a psychedelic “trip.”
  • (R)-DOI inhibits TNF- ⁇ induced expression of genes encoding intracellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), and inflammatory cytokines IL-6 and IL-1 ⁇ , and chemokines monocyte chemotactic protein-1 (MCP1).
  • ICM1 intracellular adhesion molecule-1
  • VCAM1 vascular cell adhesion molecule-1
  • MCP1 monocyte chemotactic protein-1
  • R-DOI also blocks activation and nuclear translocation of NF- ⁇ B, nitric oxide synthase activity, and downregulates asthma-associated protein arginase-1 (Nau F Jr, et al. PLoS One.2013 Oct 2;8(10):e75426; Flanagan & Nichols. Int’l Review Psych.2018.30(4), 363-375; Flanagan et al. ACS Pharmacol Transl Sci . 2024;7(2):478–492). Further, some psychedelic compounds potently suppress select key proinflammatory biomarkers, while leaving others unaffected.
  • a disclosed compound is a potent anti-inflammatory agent that acts on specific inflammation mediators, thereby returning chronically inflamed tissue to a healthy state.
  • the anti-inflammatory effect is enacted without broadly suppressing the immune system, and can therefore be beneficial to treat inflammatory disease where steroids are contraindicated, or the condition is steroid resistant.
  • a disclosed compound decreases an inflammatory response in a subject.
  • the inflammatory response is quantified by a change in the level of an inflammation response biomarker.
  • the level of an inflammation response biomarker represents the expression level of an inflammation response gene. For example, an increased level of an inflammation response biomarker in a subject can be compared to a baseline level of the same biomarker, said increase being indicative of increased expression of the inflammation response gene encoding that biomarker.
  • a disclosed compound exhibits potent anti-inflammatory properties.
  • administration of a disclosed compound suppresses several pro-inflammatory markers (e.g., mRNA encoding IL6, IL1b, GMCSF, Arg1, and IL5).
  • administration of a disclosed compound suppresses pro-inflammatory markers to baseline levels.
  • the biomarker of inflammation response gene expression is mRNA. In some embodiments, the biomarker of inflammation response gene expression is a protein.
  • the inflammation response gene is TNF ⁇ , Arg-1, IL-4, IL-5, IL-6, IL-8, IL-9, IL-1 ⁇ , Il-lA, IL-12, IL-13, IFN ⁇ , IFNb, IFNg, TGF- ⁇ , IL-15, IL-17, IL-20, IL-22, LTA, IL-23, IL-18, VCAM1, ICAM1, MCP1, MMP-9, Muc5ac, Gm-csf, CCL2, CCL5, CCL3, CCL4, CCL11, CD11a, CD3, CD4, CD8, or CRP .
  • the inflammation response gene encodes an inflammatory agent.
  • An inflammatory agent is a protein that activates an inflammatory response.
  • Inflammatory agents include, for example, the proteins IL-1 ⁇ , TNF ⁇ , IL-15, IL-17, Arg-1, and IL-18.
  • the inflammation response gene encodes an 2024-02-26 anti-inflammatory agent.
  • An anti-inflammatory agent is a protein that reduces an inflammatory response.
  • Anti-inflammatory agents include, for example, the proteins IL-1, IL-4, IL-10, IL-11, and IL-13.
  • the inflammation response gene encodes an agent that may be inflammatory or anti-inflammatory.
  • leukemia inhibitory factor, interferon-alpha, IL-6, and transforming growth factor (TGF- ⁇ ) can act as either inflammatory or anti-inflammatory cytokines under various circumstances (Zhang JM, An J.
  • the inflammation response gene is ICAM1.
  • the biomarker of inflammation response is an ICAM1 gene product.
  • the biomarker is ICAM1 mRNA.
  • the biomarker is the ICAM1 protein.
  • the inflammation response gene is VCAM1.
  • the biomarker of inflammation response is a VCAM1 gene product.
  • the biomarker is VCAM1 mRNA.
  • the biomarker is the VCAM1 protein.
  • the inflammation response gene is MCP1. In some embodiments, the biomarker of inflammation response is a MCP1 gene product.
  • the biomarker is MCP1 mRNA. In some embodiments, the biomarker is the MCP1 protein. In some embodiments, the inflammation response gene is IL-5. In some embodiments, the biomarker of inflammation response is a IL-5 gene product. In some embodiments, the biomarker is IL-5 mRNA. In some embodiments, the biomarker is the IL-5 protein. In some embodiments, the inflammation response gene is IL-6. In some embodiments, the biomarker of inflammation response is a IL-6 gene product. In some embodiments, the biomarker is IL-6 mRNA. In embodiments, the biomarker is the IL-6 protein. [296] In some embodiments, the inflammation response gene is IL-9.
  • the biomarker of inflammation response is a IL-9 gene product. In some embodiments, the biomarker is IL-9 mRNA. In some embodiments, the biomarker is the IL-9 protein. In some embodiments, the inflammation response gene is IL-15. In some embodiments, the biomarker of inflammation response is a IL-15 gene product. In some embodiments, the biomarker is IL-15 mRNA. In some embodiments, the biomarker is the IL-15 protein. In some embodiments, the inflammation response gene is IL-1 ⁇ . In some embodiments, the biomarker of inflammation response is a IL-1 ⁇ gene product. In some embodiments, the biomarker is IL-1 ⁇ mRNA.
  • the biomarker is the IL-1 ⁇ protein. In some embodiments, the inflammation response gene is Arg-1. In some embodiments, the biomarker of inflammation response is a Arg-1 gene product. In some embodiments, the biomarker is Arg-1 mRNA. In some embodiments, the biomarker is the Arg-1 protein. [297] In some embodiments, the inflammation response gene is Gm-csf . In some embodiments, the biomarker of inflammation response is a Gm-csf gene product. In some embodiments, the biomarker is Gm-csf mRNA. In some embodiments, the biomarker is the Gm-csf protein. In some embodiments, the inflammation response gene is Muc5ac .
  • the biomarker of inflammation response is a Muc5ac gene product. In some embodiments, the biomarker is Muc5ac mRNA. In some embodiments, the 2024-02-26 biomarker is the Muc5ac protein. In some embodiments, the inflammation response gene is MMP-9. In some embodiments, the biomarker of inflammation response is a MMP-9 gene product. In some embodiments, the biomarker is MMP-9 mRNA. In some embodiments, the biomarker is the MMP-9 protein. In some embodiments, the inflammation response gene is TGF- ⁇ . In some embodiments, the biomarker of inflammation response is a TGF- ⁇ gene product. In some embodiments, the biomarker is TGF- ⁇ mRNA.
  • the biomarker is the TGF- ⁇ protein.
  • the inflammation response biomarker is a cytokine. Cytokines are small signaling proteins that coordinate the interactions of different cell types involved in the amplification and regulation of the inflammatory response.
  • the cytokine biomarker is IL-2, IFN- ⁇ , TNF ⁇ , TNF ⁇ , GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17, IL-25, IL-33, or TGF- ⁇ .
  • the inflammation response biomarker is a chemokine.
  • Chemokines are small signaling proteins that induce the movement of other cell types, such as toward a tissue injury site.
  • the chemokine biomarker is CCL-1 to CCL-28, CXCL-1 to CXCL-16, IL-8, MCP1, RANTES, XCL1, XCL2, or CX 3 CL1.
  • the inflammation response biomarker is an enzyme.
  • the enzyme biomarker is Arg-1.
  • the biomarker of inflammation for a particular inflammatory disease, comorbidity, or patient demographic will be known to those of skill in the art ( See: Sreedhar R, et al. General Mechanisms of Immunity and Inflammation.
  • a disclosed compound causes the level of an inflammation response biomarker in a subject to become closer to a baseline level.
  • Base level refers to the level of a biomarker observed in healthy populations not experiencing inflammation.
  • a disclosed compound reduces the level of an inflammatory biomarker. In some embodiments, a disclosed compound does not reduce the level of an inflammatory biomarker below baseline. In some embodiments, a disclosed compound reduces the level of an inflammatory biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.
  • an inflammatory biomarker e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker
  • a disclosed compound reduces the level of an inflammatory biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) to within about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of its baseline level.
  • an inflammatory biomarker e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker
  • a disclosed compound decreases the concentration of one or more inflammatory biomarkers in a sample by about 100 pg/mL, 90 pg/mL, 80 pg/mL, 70 pg/mL, 60 pg/mL, 50 pg/mL, 40pg/mL, 30 pg/mL, 20 pg/mL, 10 pg/mL, 5 pg/mL, or 1 pg/mL.
  • the 2024-02-26 sample is a tissue sample.
  • the sample is a blood sample.
  • the same is a plasma sample.
  • a disclosed compound increases the level of an anti-inflammatory biomarker.
  • a disclosed compound does not increase the level of a pro-inflammation biomarker above baseline. In some embodiments, a disclosed compound increases the level of a pro-inflammation biomarker (e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker) by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%.
  • a pro-inflammation biomarker e.g., an mRNA biomarker, a cytokine biomarker, a chemokine biomarker
  • a disclosed compound increases the concentration of one or more anti-inflammatory biomarkers in a sample by about 100 pg/mL, 90 pg/mL, 80 pg/mL, 70 pg/mL, 60 pg/mL, 50 pg/mL, 40pg/mL, 30 pg/mL, 20 pg/mL, 10 pg/mL, 5 pg/mL, or 1 pg/mL.
  • the sample is a tissue sample.
  • the sample is a blood sample.
  • the same is a plasma sample.
  • the dosage of a disclosed compound used to elicit an anti-inflammatory effect is sub-behavioral.
  • a disclosed compound is used to elicit an anti-inflammatory effect at dosage between about 0.001 and 0.01 mg/kg, between about 0.01 and 0.05 mg/kg, between about 0.05 mg/kg and 0.1 mg/kg, between about 0.1 mg/kg and 0.2 mg/kg, between about 0.4 mg/kg and 0.3 mg/kg, between about 0.3 mg/kg and 0.4 mg/kg, or between about 0.4 mg/kg and 0.5 mg/kg.
  • a disclosed compound is used to treat an inflammatory disorder. In embodiments, a disclosed compound is used to reduce inflammation.
  • a disclosed compound is used in the manufacture of a medicament to treat an inflammatory disorder or reduce inflammation.
  • the disorder is an acute inflammatory disorder.
  • the disorder is a chronic inflammatory disorder.
  • the inflammatory disorder is asthma, chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, septicemia, conjunctivitis, Alzheimer’s disease, or another inflammatory condition described herein.
  • a disclosed compound is useful for treating an inflammatory condition in patients with autoimmune disorders or otherwise compromised immune systems.
  • a disclosed compound is useful for treating chronic inflammation in patients with type 1 diabetes, type 2 diabetes, multiple sclerosis (MS), lupus, rheumatoid arthritis, psoriatic arthritis, reactive arthritis, Addison disease, Celiac disease, autoimmune encephalitis, gout, vasculitis, mixed connective tissue disease, undifferentiated connective tissue disease, myositis, scleroderma, Sjogren’s syndrome, uveitis, inflammatory bowel disease (IBD), Guillain-Barre syndrome, psoriasis, grave’s disease, scleroderma (systemic sclerosis), dermatomyositis, Hashimoto thyroiditis, pernicious anemia, Alzheimer’s disease, heart disease, cardiovascular disease, chronic hepatic and renal disease, fibromyalgia, allergies, or chronic obstructive pulmonary disease (COPD).
  • MS multiple sclerosis
  • COPD chronic obstructive pulmonary disease
  • a disclosed compound is useful for treating chronic inflammation in an immunocompromised chemotherapy patient. 2024-02-26 [306] In some embodiments, a disclosed compound is useful for treating an inflammatory condition in patients with a steroid-resistant disease or disorder.
  • the steroid-resistant disease or disorder is steroid resistant nephrotic syndrome (SRNS), steroid-resistant inflammatory bowel syndrome (IBS), steroid-resistant asthma, steroid-resistant acute graft-versus-host disease, steroid-resistant ulcerative colitis, steroid-resistant Crohn's disease, steroid-resistant chronic obstructive pulmonary disease (COPD), steroid-resistant pulmonary fibrosis, steroid-resistant leukemias, steroid-resistant rheumatoid arthritis, or steroid-resistant idiopathic nephrosis.
  • SRNS steroid resistant nephrotic syndrome
  • IBS steroid-resistant inflammatory bowel syndrome
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • a disclosed compound is useful for treating an inflammatory condition in a patient with a contraindication to a corticosteroid.
  • Contraindications to corticosteroids can occur, for example, because of hypersensitivity to any component of a corticosteroid formulation, concurrent administration of live or live-attenuated vaccines (e.g., when using immunosuppressive doses), systemic fungal infection, osteoporosis, uncontrolled hyperglycemia, adrenal suppression, Cushing syndrome, diabetes mellitus, glaucoma, cataracts, joint infection, uncontrolled hypertension, herpes simplex keratitis, myopathy, certain psychiatric disturbances and/or disorders, and varicella infection.
  • live or live-attenuated vaccines e.g., when using immunosuppressive doses
  • systemic fungal infection e.g., when using immunosuppressive doses
  • osteoporosis uncontrolled hyperglycemia
  • adrenal suppression e.g., when using immunosuppressive
  • exemplary contraindications include peptic ulcer disease, congestive heart failure, and viral or bacterial infections not controlled by anti-infective or antibacterial agents.
  • a disclosed compound is useful for treating 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, ocular inflammation, or brain inflammation.
  • the inflammatory disorder is any of acne vulgaris, acid reflux/heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, Anemia, appendicitis, arteritis, arthritis, including osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathy such as ankylosing spondylitis, reactive arthritis (Reiter syndrome), psoriatic arthritis, enteroarthritis associated with inflammatory bowel disease, Whipple and Behcet's disease, septic arthritis, gout (also known as gouty arthritis, crystalline synovitis, metabolic arthritis), pseudogout (calcium pyrophosphate deposition disease), and Still's disease.
  • ALD age-related macular degeneration
  • allergies allergic rhinitis
  • Alzheimer's disease amyotrophic lateral sclerosis
  • Anemia appendicitis
  • arteritis
  • Arthritis can affect a single joint (monoarthritis), two to four joints (oligoarthritis), or five or more joints (polyarthritis).
  • the inflammatory disorder is any of long COVID, a food allergy, post-treatment lyme disease syndrome, and an ulcer.
  • an inflammatory disorder is any of asthma, atherosclerosis, autoimmune disorder, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, including NF- ⁇ B-induced inflammatory cancer; cardiovascular disease, including hypertension, endocarditis, myocarditis, heart valve dysfunction, congestive heart failure, myocardial infarction, diabetic heart abnormalities, vascular inflammation, including arteritis, phlebitis, and 2024-02-26 vasculitis; arterial occlusive disease, including arteriosclerosis and stenosis; inflammatory cardiac hypertrophy, peripheral arterial disease, aneurysm, embolism, incision, pseudoaneurysm, vascular malformation, vascular nevus, thrombosis, thrombophlebitis, varicose veins, stroke, cardiac arrest, and carditis; celiac disease, cellulitis, cervicit
  • the inflammatory disorder is a dermatitis disorder.
  • dermatitis refers to inflammation of the skin which can occur chronically due to skin barrier dysfunction, abnormal inflammatory response, and persistent itching (Nakahara T, et al. J Dermatol. 2021;48(2):130-139; Beck LA, et al. JID Innov.2022;2(5):100131).
  • redness et al. J Dermatol. 2021;48(2):130-139
  • Beck LA et al. JID Innov.2022;2(5):100131
  • further clinical phenotypes of dermatitis disorders are highly heterogeneous, reflecting the diversity and complexity of the underlying mechanisms leading to the disorder (Renert-Yuval Y, et al.
  • the inflammatory disorder is a dermatitis disorder, including atopic dermatitis, chronic photosensitivity dermatitis, eczema, atopic eczema, contact eczema, dryness eczema, seborrheic eczema, discoid eczema, varicose eczema, herpetic dermatitis, neurodermatitis, autosensitizing dermatitis, stasis dermatitis, purulent dermatitis, dyshidrotic eczema, follicular eczema, spongiotic dermatitis, hand dermatitis, diaper dermatitis, occupational contact dermatitis, and lichen planus-like atopic dermatitis.
  • a dermatitis disorder including atopic dermatitis, chronic photosensitivity dermatitis, eczema, atopic eczema, contact eczema, dry
  • the dermatitis disorder is atopic dermatitis. In some embodiments, the dermatitis disorder is chronic photosensitivity dermatitis. In some embodiments, the dermatitis disorder is eczema. In some embodiments, the dermatitis disorder is atopic eczema. In some embodiments, the dermatitis disorder is contact eczema. In some embodiments, the dermatitis disorder is dryness eczema. In some embodiments, the dermatitis disorder is seborrheic eczema. In some embodiments, the dermatitis disorder is discoid eczema.
  • the dermatitis disorder is varicose eczema. In some embodiments, the dermatitis disorder is herpetic dermatitis. In some embodiments, the dermatitis disorder is neurodermatitis. In some embodiments, the dermatitis disorder is herpetic dermatitis. In some embodiments, the dermatitis disorder is autosensitizing dermatitis. In some embodiments, the dermatitis disorder is stasis 2024-02-26 dermatitis. In some embodiments, the dermatitis disorder is purulent dermatitis. In some embodiments, the dermatitis disorder is dyshidrotic eczema. In some embodiments, the dermatitis disorder is follicular eczema.
  • the dermatitis disorder is spongiotic dermatitis. In some embodiments, the dermatitis disorder is hand dermatitis. In some embodiments, the dermatitis disorder is diaper dermatitis. In some embodiments, the dermatitis disorder is occupational contact dermatitis. In some embodiments, the dermatitis disorder is lichen planus-like atopic dermatitis.
  • the inflammatory disorder is any of dermatitis, including atopic dermatitis, chronic photosensitivity dermatitis, eczema, atopic eczema, contact eczema, dryness eczema, seborrheic eczema, sweating disorders, discoid eczema, venous eczema, herpetic dermatitis, neurodermatitis, and autosensitizing dermatitis, stasis dermatitis, purulent sweaty, lichen planus, psoriasis, including psoriasis vulgaris, nail psoriasis, prickly psoriasis, scalp psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis; rosacea, and sclerodermatitis, including atopic
  • 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, Psychoneuroendocrin.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.20191;65(3). v.
  • a disclosed compound is used to treat an ophthalmic disease or disorder.
  • Ophthalmic diseases and disorders often result from infection and/or inflammation of ocular tissue, and are the leading cause of corneal blindness and visual morbidity worldwide (Bourne RR, et al. Lancet Glob Health. 2013;1(6):e339-49). Repeated episodes of either infection or inflammation triggers a chronic inflammatory disease process that can result in vascularization and subsequent vision threatening scarring of the cornea (Vaidyanathan U, et al. Med Hypothesis Discov Innov Ophthalmol.2019;8(3):163-176).
  • Corticosteroids are often used to control the ophthalmic inflammatory response, however, this treatment is immunosuppressive and can result in uncontrolled pathogen replication, loss of an intact corneal epithelial barrier, increased ocular pressure and eventual deterioration of vision (Fung AT, et al. Clin Exp Ophthalmol. 2020;48(3):366-401).
  • modulation with 5-HT receptor agonists has been shown to have anti-inflammatory and anti-vascularization properties, and the ability to decrease ophthalmic pressure (Foster T, et al. Invest Ophthalmol Vis Sci.2020;61(7):429).
  • a disclosed compound can be used to reduce, or ameliorate, or prevent an ophthalmic disease or disorder, non-limiting examples of which are described herein.
  • administration of a disclosed compound reduces intraocular pressure in a subject.
  • a disclosed compound is used to treat ocular hypertension.
  • a disclosed compound is used to treat glaucoma.
  • the glaucoma is 2024-02-26 open-angle glaucoma, normal-tension glaucoma, angle-closure glaucoma, congenital glaucoma, neovascular glaucoma, pigmentary glaucoma, exfoliation glaucoma, uveitic glaucoma, or glaucoma caused by another factor (e.g., cataracts, tumors, eye injury).
  • another factor e.g., cataracts, tumors, eye injury.
  • a disclosed compound is used to treat allergic conjunctivitis, including vernal keratoconjunctivitis and atopic keratoconjunctivitis; dry eye syndrome and meibomian gland dysfunction; cataracts; keratoconus; bullous and other keratopathy; Fuch's endothelial dystrophy; ocular cicatricial pemphigoid; conditions associated with photoreactive keratotomy (PRK) healing and other corneal healing; conditions associated with tear lipid degradation or lacrimal gland dysfunction; uveitis, including anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, non-infectious uveitis, and infectious uveitis; keratitis; scleritis; crizis; cyclitis; ocular graft versus host disease (GVHD); optic neuritis; ocular Stevens Johnson Syndrome; blepharitis
  • the ophthalmic disease or disorder is an inflammatory disorder.
  • the ophthalmic disease or disorder is macular degeneration (e.g., age-related macular degeneration), keratoconjunctivitis, conjunctivitis, keratitis, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, retinitis pigmentosa, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber's disease, retinal detachment, retinal pigment epithelial detachment, rubeosis iridis, corneal neovascularization, retinal neo- vascularization, choroidal neovascularization, retinochoroidal neovascularization, or a combination thereof.
  • macular degeneration e.g., age-related macular degeneration
  • the ophthalmic disease is macular degeneration. In some embodiments, the ophthalmic disease is keratoconjunctivitis. In some embodiments, the ophthalmic disease is conjunctivitis. In some embodiments, the ophthalmic disease is keratitis. In some embodiments, the ophthalmic disease is diabetic retinopathy. In some embodiments, the ophthalmic disease is retinopathy of prematurity. In some embodiments, the ophthalmic disease is polypoidal choroidal vasculopathy. In some embodiments, the ophthalmic disease is ischemic proliferative retinopathy. In some embodiments, the ophthalmic disease is retinitis pigmentosa.
  • the ophthalmic disease is cone dystrophy. In some embodiments, the ophthalmic disease is proliferative vitreoretinopathy. In some embodiments, the ophthalmic disease is retinal artery occlusion. In some embodiments, the ophthalmic disease is retinal vein occlusion. In some embodiments, the ophthalmic disease is Leber's disease. In some embodiments, the ophthalmic disease is retinal detachment. In some embodiments, the ophthalmic disease is retinal pigment epithelial detachment. In some embodiments, the ophthalmic disease is rubeosis iridis. In some embodiments, the ophthalmic disease is corneal neovascularization.
  • the ophthalmic disease is retinal neovascularization. In some embodiments, the ophthalmic disease is choroidal neovascularization. In some embodiments, the ophthalmic disease is retinochoroidal neovascularization. 2024-02-26 I. Examples [322] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.
  • EXAMPLE 1 Synthesis of 4-(2-hydroxyethyl)-7-methyl- N,N -diethyltryptamine (Compound 2) [323] To a stirred solution of 4-bromo-2-nitrotoluene (3.00 g, 13.9 mmol) in THF (116 mL) cooled to approximately ⁇ 41 °C in an acetonitrile/dry ice bath, vinylmagnesium bromide (99.2 mL, 41.7 mmol, 0.45 M in THF) was added dropwise and the reaction was allowed to stir for 12 h eventually warming to room temperature. Once complete as determined by TLC, 100 mL of a sat.
  • EXAMPLE 2 Synthesis of 4-(2-hydroxyethyl)-7-methyl- N,N -dimethyltryptamine (Compound 1) [336] To a stirred solution of 2-(7-methyl- 1H -indol-4-yl)ethyl-2,2-dimethylpropanoate (127 mg, 0.490 mmol) in Et 2 O (1.62 mL), was added over 5 min, a solution of oxalyl chloride (0.042 mL, 0.499 mmol) in Et 2 O (1.00 mL) at 0 °C.
  • EXAMPLE 3 Synthesis of 4-(2-methoxyethyl)-7-methyl- N,N -dimethyltryptamine (Compound 3) [341] To a stirred solution of 4-(2-hydroxyethyl)-7-methyl- 1H -indole (461 mg, 2.63 mmol) dissolved in THF (17.5 mL) and triethylamine (1.10 mL, 7.89 mmol) was added methanesulfonyl chloride (0.305 mL, 3.95 mmol) dropwise at 0 °C under an atmosphere. After 0.5 h the mixture was complete by TLC and concentrated under reduced pressure.
  • EXAMPLE 4 Synthesis of 4-(2-methoxyethyl)-7-methyl- N,N -dimethyltryptamine (Compound 4) [348] To a stirred solution of 4-(2-methoxyethyl)-7-methyl- 1H -indole (148 mg, 0.782 mmol) in Et 2 O (3.18 2024-02-26 mL), was added over 5 min, a solution of oxalyl chloride (0.073 mL, 0.860 mmol) in Et 2 O (1.00 mL) at 0 °C.
  • EXAMPLE 5 In Vitro Receptor Binding Assays [353] Methods: Membrane was extracted from 5-HT 2A /HEK293, 5-HT 2B /HEK293 and 5-HT 2C /HEK293 cells. The reference compounds and screening compounds were 4-fold serially diluted in 100% DMSO for 8 points. Transferred 1 ⁇ L of serial diluted references and screening compounds to the assay plates. Then added 100 ⁇ L/well of membrane and 100 ⁇ L/well of radioligand 3 H-LSD. Incubated at room temperature for 1 hour. Filtered the reaction mixture through the GF/C plate using PerkinElmer Filtermate Harvester and wash 2024-02-26 the plates. Dried the filter plate for 1 hour at 50 °C.
  • EXAMPLE 6 In Vitro Receptor Binding Assays [357] Methods (5-HT 2A and 5-HT 2C IP-One Functional Activity Assays): Intracellular accumulation of IP-1 2024-02-26 was measured using an IP-One HTRF assay kit (Cat.# 62IPAPEJ, Cisbio) at WuXi AppTec Co. Ltd. (Hong Kong) Discovery Biology Unit according to their standard protocols. Briefly, the reference compounds and screening compounds were 3.16-fold serially diluted in 100% DMSO for 10 points using Bravo.70 nL of compounds were added to the assay plate using Echo555.
  • IP-1 d2 Reagent working solution 3 ⁇ L of IP-1 Tb Cryptate Antibody working solution to all wells.
  • the plates were incubated for 1 hour at room temperature and read on for fluorescence at 620 nm and 665 nm on an EnVision Multimode Plate Reader (PerkinElmer).
  • the ratio of the acceptor and donor emission signals (665/620) were calculated for each individual well and substituted into the standard curve to obtain the log concentration of IP level.
  • the average background control signal was subtracted from each well and values were normalized to the maximal response of 5-HT at 3 ⁇ M (100%). % MAX was calculated by taking the average normalized maximal response at the highest concentration tested.
  • media was aspirated and replaced with 100 ⁇ L HBSS supplemented with 30 mM HEPES (pH 7.4), loaded with 5 ⁇ M Fluo-2 AM HA (ION Biosciences, San Marcos, TX) and 2.5 mM water-soluble probenecid (Thermo Fisher Scientific, Waltham, MA). Plates were incubated for 1 h at 37 °C, washed once with 100 ⁇ L HBSS ⁇ HEPES, and maintained in 100 ⁇ L HBSS ⁇ HEPES supplemented with 2.5 mM water-soluble probenecid.
  • the plates of dye-loaded cells were placed into a FlexStation 3 microplate reader (Molecular Devices, Sunnyvale, CA) set at 37 °C to monitor fluorescence (excitation, 485 nm; emission, 525 nm; cutoff, 515 nm). Plates were read for 30 s (2 s interval) to establish baseline fluorescence and then administered 50 ⁇ L of the test compounds and read for an additional 120 s. After obtaining a calcium flux trace for each sample, the area under the curve (AUC) was calculated for the 150 s run time and baseline (not stimulated) subtracted.
  • AUC area under the curve
  • Dose-response curves for Compound 2 are provided in FIG.7 (IP-One) and FIG.8 (Ca flux).
  • Dose-response curves for Compound 3 are provided in FIG.9 (IP-One) and FIG.10 (Ca flux).
  • Dose-response curves for Compound 4 are provided in FIG.11 (IP-One) and FIG.12 (Ca flux).
  • OVA exposure methods are based on a previously described mouse model of acute asthma (Nau et al. Am J Physiol. Lung Cellular Mo Physiol. 2015, 308(2), L191 ⁇ 198). [368] OVA-alone treated rats are exposed to 3 times weekly exposure of 10.0 mg of OVA slowly dissolved in 10.0 mL of 0.9% sterile saline solution in a 15 L (38.00 ⁇ 19.05 ⁇ 19.7 cm) acrylic induction chamber. No more than 6 animals are exposed in the chamber per challenge.
  • OVA aerosol was generated using an ultrasonic nebulizer in conjunction with a Pari Proneb pump at a 1.0% OVA concentration for a total duration of 30 min, as described in Palmans et al. Am. J. Respir Crit Care Med.2000, 161, 627 ⁇ 635.
  • rats are exposed in groups of 3 ⁇ 4 rats/group to the appropriate concentration of drug dissolved in a total volume of 4.5 mL of sterile saline using an inExpose nose-only inhalation system 30 min prior to each OVA challenge.
  • Each 4.5 mL of sample is aerosolized using a nebulizer in conjunction with a Pari Proneb pump. Exposures last 15 min.
  • a differential pressure transducer is connected on one pole to the main chamber and on the second pole to a reference chamber.
  • the transducer measures pressure differences between both chambers as caused by the respiratory cycle, mainly inhalation and exhalation.
  • Computer software provides a breath-by-breath analysis of pressure signals and transforms pressure differences via computerized calculations to a dimensionless empirically established value, enhanced pause or PenH.
  • the chamber pressure signal is calibrated by dynamic injection of 5 mL of room air via 2024-02-26 syringe. Rats are then placed in the chamber, where baseline data is recorded for 5 min following a 10 min habituation period in the plethysmograph. After measurement of baseline PenH, either aerosolized saline (0.9% NaCl Solution) or an aqueous solution of MeCh in increasing concentrations (4, 8, 16, 32 mg/mL) is nebulized through an inlet of the plethysmography chamber for 3 min, followed by measurements of PenH values for 3 min. A vibrating-mesh nebulizer is used to generate aerosol.
  • Results may show that certain disclosed compounds possess potent anti-inflammatory properties, and more specifically that they may reduce PenH max values and suppress pulmonary inflammation.
  • EXAMPLE 8 Assessment of Ocular Inflammation Following Application of Compounds [364] Purpose: Ocular inflammation and uveitis encompass potentially sight-threatening diseases with local and systemic etiologies. Cytokines, e.g. IL-6 (Ghasemi, Ocul Immunol Inflamm.2018;26(1):37-50) and IL-8 (Ghasemi et al.
  • Ocul Immunol Inflamm.2011 Dec;19(6):401-12 can contribute to ocular inflammation.
  • Methods Ocular inflammation is assessed according to known methods with modifications. For example, ocular inflammation can be assessed in induced models of uveitis (see, e.g., WO2015074137A1, which describes an endotoxin-induced model in Example 1 and an LPS-induced model in Example 2), a chemical cauterization model of corneal inflammation (see, e.g., Example 4 of WO2015074137A1), or in human subjects at risk of experiencing or currently experiencing such inflammation.
  • induced models of uveitis see, e.g., WO2015074137A1, which describes an endotoxin-induced model in Example 1 and an LPS-induced model in Example 2
  • a chemical cauterization model of corneal inflammation see, e.g., Example 4 of WO2015074137A1
  • Results & Significance Application of a disclosed compound, such as topical application, can prevent and/or reduce ocular inflammation. Reductions in ocular inflammation may lead to improvements in symptomatology associated with ocular inflammation, including but not limited to eye redness, pain, and alterations in sight, e.g., blurred vision.
  • EXAMPLE 9 In Vivo Model for Assessing Atopic Dermatitis Following Application of Compounds [367] Purpose: Atopic dermatitis, or eczema, is characterized by chronic inflammation, and can result in inflammatory symptoms such as irritation of the skin. In some embodiments, disclosed compounds and compositions are useful for treating atopic dermatitis.
  • the purpose of this experiment is to assess the therapeutic effects (e.g., inhibiting and/or reducing the various end-points associated with atopic dermatitis) of disclosed compounds and compositions in a mouse in vivo model of atopic dermatitis.
  • the model for this study uses the flaky tail mouse strain, which carries a mutation in the gene for the epidermal protein filaggrin, which is comparable to the mutation underlying human atopic dermatitis or eczema (Fallon et al., Nat Genetics, 2009, 41: 602-608). Challenging these mice with topically applied ovalbumin results in a condition resembling atopic dermatitis.
  • mice typically exhibit eczema and increased skin levels of inflammatory biomarkers following ovalbumin application.
  • exemplary measures of efficacy include skin 2024-02-26 flakiness, skin levels of Type 2 helper T-cell (Th2) and cytokines, such as IL4, IL5 and IL10.
  • Th2 Type 2 helper T-cell
  • cytokines such as IL4, IL5 and IL10.
  • Methods The protocol for application of ovalbumin to the skin of flaky tail mice has been described in the literature ( id. ). In brief, the abdomens of 3-5 week old mice are shaved 24 hours prior to cutaneous application of ovalbumin suspensions (50 ⁇ g in 50 ⁇ L PBS), which are applied to the abdomen as described previously ( id. ).
  • mice are pretreated with a disclosed compound prior to and during the application of ovalbumin to study the effects of preventing and inhibiting the development of atopic dermatitis.
  • the mice are treated with a disclosed compound following 4-5 weeks of ovalbumin treatment (after atopic dermatitis symptoms have appeared) to study the effects of the compound in treating the symptoms.
  • the compound is administered (e.g., intravenously, intramuscularly, by oral gavage) at several doses to study dose dependent effects.
  • mice are euthanized and skin punch biopsy specimens from each abdomen are harvested, snap frozen in liquid nitrogen, and homogenized with HTAB buffer.
  • Results are expected to show that administration of a disclosed compound or composition prevents, inhibitors, and/or treats the symptoms atopic dermatitis.
  • EXAMPLE 10 In Vitro Metabolic Stability of Compounds [374] The purpose of this experiment is to assess the metabolic stability of disclosed compounds in an in vitro assay. The liver is a major site of drug metabolism in the body, and liver microsomes, hepatocytes, and liver S9 fractions can be used to determine the in vitro intrinsic clearance of a compound.
  • liver microsomal stability assay is performed according to available methods, e.g., in accordance with the methods described in US 2008/0045588 with modifications.
  • the assay is conducted at 1 mg per mL liver microsome protein with an NADPH-generating system in 2% NaHCO3 (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM MgCl2).
  • Test compounds are prepared as solutions in 20% acetonitrile-water and added to the assay mixture (final assay concentration 5 microgram per mL) and incubated at 37° C. Final concentration of acetonitrile in the assay should be ⁇ 1%. Aliquots (50 ⁇ L) are taken out at times 0, 15, 30, 45, and 60 min, and diluted with ice cold acetonitrile (200 ⁇ L) to stop the reactions.
  • Results show a measurement of the in vitro intrinsic clearance of disclosed 2024-02-26 compounds. Such data provides a prediction of the metabolic stability and clearance of the compounds.
  • EXAMPLE 11 In Vivo Assessment of Behavioral Effects of Compounds Using HTR [362] The mouse head-twitch response (HTR) is a behavioral test that reflects 5-HT 2A receptor activation and can be predictive of psychedelic effects in humans (Halberstadt et al.
  • 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).
  • Methods An HTR assay is performed in accordance with the methods described in Klein et al., Neuropharmacol, 2018;142:231-239 to assess the effects of disclosed compounds in 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. [364] A head-mounted magnet and a magnetometer detection coil is used to assess HTR, as previously described (Halberstadt & Geyer, Psychopharmacol (Berl).
  • mice are anesthetized and a small neodymium magnet is attached to the dorsal cranial surface using dental cement. Following a 2-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.
  • 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).
  • 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 2024-02-26 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 ⁇ -level of 0.05. [368] Results can be represented as ED 50 (mg/kg). Differences between the mouse HTR of disclosed compounds and suitable comparator compounds can be determined according to methods described herein. [369] The foregoing description, for purposes of explanation, uses specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that specific details are not required in order to practice the invention. Thus, the foregoing description of specific embodiments of the invention is presented for purposes of illustration and description.

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Abstract

La présente invention concerne, selon certains aspects, certains analogues de psilocine et de psilocybine, tels que des tryptamines contenant une substitution 4-(2-hydroxyalkyl)-7-alkyle ou 4-(2-méthoxyalkyl)-7-alkyle sur le cycle phényl-indole. Selon certains aspects, l'invention concerne des compositions pharmaceutiques contenant les composés, et des procédés d'utilisation de tels composés et compositions pour moduler la neurotransmission (par exemple, la neurotransmission sérotoninergique), moduler la neuroplasticité, et traiter des états médicaux, tels que des troubles et des états inflammatoires.
PCT/US2024/017324 2023-02-24 2024-02-26 Tryptamines hydroxyalkylées et méthoxyalkylées WO2024178425A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150050344A1 (en) * 2013-07-23 2015-02-19 Revalesio Corporation Compositions and methods for upregulating hippocampal plasticity and hippocampus-dependent learning and memory
WO2022082058A1 (fr) * 2020-10-16 2022-04-21 Eleusis Therapeutics Us, Inc. Méthode de traitement par alcaloïdes tryptamines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150050344A1 (en) * 2013-07-23 2015-02-19 Revalesio Corporation Compositions and methods for upregulating hippocampal plasticity and hippocampus-dependent learning and memory
WO2022082058A1 (fr) * 2020-10-16 2022-04-21 Eleusis Therapeutics Us, Inc. Méthode de traitement par alcaloïdes tryptamines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE 17 February 2021 (2021-02-17), ANONYMOUS: "CHEMBL20167", XP093207085, Database accession no. 103185918 *

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