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WO2025217471A1 - 2-hemifly phenéthylamines - Google Patents

2-hemifly phenéthylamines

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Publication number
WO2025217471A1
WO2025217471A1 PCT/US2025/024182 US2025024182W WO2025217471A1 WO 2025217471 A1 WO2025217471 A1 WO 2025217471A1 US 2025024182 W US2025024182 W US 2025024182W WO 2025217471 A1 WO2025217471 A1 WO 2025217471A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
disorder
alkyl
inflammation
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/024182
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English (en)
Inventor
David Nichols
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
2a Biosciences Inc
Original Assignee
2a Biosciences Inc
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Filing date
Publication date
Application filed by 2a Biosciences Inc filed Critical 2a Biosciences Inc
Publication of WO2025217471A1 publication Critical patent/WO2025217471A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the disclosure relates to novel compounds, such as phenethylamines with a substituted 2,3-benzo- furan (i.e., “hemiFLY”) core pharmacophore, compositions comprising them, methods of their synthesis, and methods of their use, including their administration to subjects.
  • Disclosed compounds provide neuromodulatory and/or anti-inflammatory activity, such as via activation of serotonin receptors.
  • Disclosed compounds are useful as therapeutic agents to treat medical conditions, such as psychiatric disorders and inflammatory conditions.
  • 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. Beyond mental health, psychedelics and related serotonin receptor agonists may be promising for treating inflammatory, neurological, and neurodegenerative diseases and disorders. However, there exists an ongoing need for the development of novel therapeutic compounds that can be used to treat a broad range of disease indications, especially chronic conditions that lack effective treatments.
  • R 4 is H, F, Cl, Br, I, CN, N0 2 , C r Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r Cg haloalkyl, C r Cg alkoxy, CrC 6 haloalkylthio, C r Cg alkylthio, C 3 -C 6 cycloalkylmethyl, or — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl;
  • R 5 is C r Cg alkoxy, — (CH 2 ) 0.3 OH, — (CH ⁇ -O-CrCg alkyl, — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl,
  • R and R' are each independently H or C ⁇ Cg alkyl
  • R N is H or — CH 2 -Ar; wherein Ar is 6- to 12-membered heterocyclyl or C 6 -C 12 aryl optionally substituted by F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl; and
  • R a is H or C ⁇ Cg alkyl; and R b is H; or R a and R b together with the intervening atoms form a 3- to 6-membered cycloalkyl; or R N and R b together with the intervening atoms form a 4- to 8-membered heterocyclyl, and R a is H or CrCg alkyl; or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • R N is H. In some embodiments, R N is CH 2 -Ar.
  • R a is H. In some embodiments, R a is C ⁇ Cg alkyl. In some embodiments, R a is methyl. In some embodiments, R a is ethyl.
  • R 4 is F, Cl, Br, or I. In some embodiments, R 4 is Br. In some embodiments, R 4 is I. In some embodiments, R 4 is C r Cg alkyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl. In some embodiments, R 4 is — CH 2 COOCH 3 . In some embodiments, R 4 is — CH 2 COOCH 2 CH 3 .
  • R 5 is methoxy. In some embodiments, R 5 is — (CH 2 ) 2 OH or — (CH 2 ) 2 OCH 3 . In some embodiments, R 5 is — (CH 2 ) 2 OH or — (CH 2 ) 2 OCH 3 . In some embodiments, R 5 is — CH 2 COOCH 3 . In some embodiments, R 5 is — COONH 2 or— COONHCH 3 .
  • R and R' are both H. In some embodiments, R is H and R' is C ⁇ Cg alkyl. In some embodiments, R and R' are both C ⁇ Cg alkyl.
  • the compound has the structure of Formula (2): wherein each variable is as defined for Formula (1), or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound has the structure of Formula (3): wherein:
  • X, Y, and Z are each independently H, F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl; or X and Y are taken together to form a 4- to 6-membered heterocyclyl, and Z is H, F, Cl, Br, I, OH, C r Cg alkoxy, C 3 -C 6 cycloalkyl, or phenyl; or Y and Z are taken together to form a 4- to 6-membered heterocyclyl, and X is H, F, Cl, Br, I, OH, C r Cg alkoxy, C 3 -C 6 cycloalkyl, or phenyl; and wherein each other variable is as defined for Formula (1), or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • X is OH. In some embodiments, X is methoxy. In some embodiments, X is F, Cl, Br, or I. In some embodiments, X is phenyl. In some embodiments, X is C 3 -C 6 cycloalkyl. In some embodiments, X is cyclopropyl.
  • Y and Z are H.
  • X and Y are taken together to form O— (methylenedioxy), wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.
  • X and Y are taken together to form a dihydrofuranyl.
  • X and Y are taken together to form , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.
  • X and Y are taken together to form a furanyl.
  • X and Y are taken together to form or ⁇ / 0 , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.
  • a compound selected from Table 1 or a pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.
  • a compound selected from the group of compounds defined herein as Group A or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • a compound selected from the group of compounds defined herein as Group B or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • a compound selected from the group of compounds defined herein as Group C or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • a compound selected from the group of compounds defined herein as Group D or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • composition comprising a therapeutically effective amount of any of the disclosed compounds, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutical composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.
  • pharmaceutical composition is in unit dosage form.
  • pharmaceutical composition comprises the compound in a total amount of between about 0.01 and 100 mg.
  • the pharmaceutical composition is formulated for topical administration.
  • the pharmaceutical composition is formulated as an aerosol, emulsion, spray, ointment, salve, gel, paste, lotion, liniment, oil, or cream.
  • the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients selected from the group consisting of 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, and gelling agents.
  • penetration enhancers e.g., 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
  • solubilizing agents colorants, binders, humectants, surfactants, and gelling agents.
  • the pharmaceutical composition further comprising a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the pharmaceutical composition comprises an additional active compound 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, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sed
  • modulating neurotransmission comprises agonizing the 5-HT2A or 5-HT 2C receptor.
  • modulating neurotransmission comprises agonizing other serotonin receptor subtypes, including agonizing or partially agonizing any one or more of a 5-Huze receptor, such as 5-HT 1A and 5-HT 1B , a 5-HT 2 receptor, such as 5-HT 2A and 5-HT 2C , and a 5-HT 6 receptor.
  • 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.
  • the 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, 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.
  • mRNA is Arg-1, ICAM1, VCAM1, CCL2, IL-6, IL-1 , Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-ft mRNA.
  • the inflammatory response gene product is a protein.
  • the protein is Arg-1, ICAM1, VCAM1, MCP1 , IL-6, IL-10, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-0.
  • the medical condition is an ophthalmic disorder.
  • the ophthalmic disorder is an inflammatory disorder.
  • medical condition is 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 neovascularization, choroidal neovascularization, or retinochoroidal neovascularization.
  • 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 (TBI), including mild traumatic brain injury (mTBI).
  • 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
  • a compound of any one of the disclosed embodiments, or the composition of any one of the disclosed embodiments, for use in the treatment of a medical condition is a compound of any one of the disclosed embodiments, or the composition of any one of the disclosed embodiments, for use in the treatment of a medical condition.
  • FIG. 1 shows the dose-response curve from a cell-based agonist calcium flux assay for 2-(4-isobutyl- 5-methoxy-2,3-DHB-7-yl)ethan-1 -amine hydrochloride (HCI) for 5-HT 2A and 5-HT 2B , as described in Example 6.
  • HCI 2-(4-isobutyl- 5-methoxy-2,3-DHB-7-yl)ethan-1 -amine hydrochloride
  • FIG. 2 shows the dose-response curve from a cell-based agonist calcium flux assay for 1 -(4-isobutyl- 5-methoxy-2,3-dihydrobenzofuran-7-yl) butan-2-amine for 5-HT 2A and 5-HT 2B , as described in Example 6.
  • FIG. 3 shows the dose-response curve from a cell-based agonist calcium flux assay for 2-(4-allyl-5- methoxy-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine for 5-HT 2A and 5-HT 2B , as described in Example 6.
  • FIG. 4 shows the dose-response curve from a cell-based agonist calcium flux assay for 2-(4-bromo-5- (2-methoxyethyl)-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine for 5-HT 2A and 5-HT 2B , as described in Example 6.
  • FIG. 5 shows the dose-response curve from a cell-based agonist calcium flux assay for 2-(4-isobutyl- 5-(2-methoxyethyl)-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine HCI for 5-HT 2A and 5-HT 2B , as in Example 6.
  • FIG. 6 shows a dose response curve of response of PenH, a measure of airway resistance, to increasing methacholine concentrations in naive mice, mice exposed to ovalbumin (OVA), and mice treated with 0.5 mg/kg exemplary compound (EC) 2-(4-isobutyl-5-methoxy-2,3-dihydrobenzofuran-7-yl)ethan-1-amine HCI and OVA, as described in Example 7.
  • FIG. 7A shows the HTR count (15 min fractions) of exemplary compound 2-(4-isobutyl-5-methoxy-
  • FIG. 7B shows the activity in volt-seconds (V*s) of exemplary compound 2-(4-isobutyl-5-methoxy-
  • FIG. 7C shows the cumulative number of head twitch events observed during a 30-min period (sum 30 min) of compound 2-(4-isobutyl-5-MeO-2,3-DHB-7-yl)ethan-1 -amine HCI at 0.1 , 0.3, 1 , 3, and 10 mpk.
  • FIG. 7D shows the activity in volt-seconds (V*s over 30 minutes) of exemplary compound 2-(4-isobutyl-5-methoxy-2,3-dihydrobenzofuran-7-yl)ethan-1-amine HCI at 0.1 , 0.3, 1 , 3, and 10 mpk.
  • FIG. 8A shows the HTR count (15 min fractions) of exemplary compound 2-(4-isobutyl-5-(2-methoxy- ethyl)-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine HCI at 0.1, 0.3, 1 , 3, and 10 mpk over 60 minutes.
  • FIG. 8B shows the activity in volt-seconds (V*s) of exemplary compound 2-(4-isobutyl-5-(2-methoxy- ethyl)-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine HCI at 0.1, 0.3, 1 , 3, and 10 mpk over 60 minutes.
  • FIG. 8C shows the cumulative number of head twitch events observed during a 30-minute period (sum 30 min) of exemplary compound 2-(4-isobutyl-5-(2-methoxyethyl)-2,3-DHB-7-yl)ethan-1 -amine HCI at 0.1 , 0.3, 1, 3, and 10 mpk (here and above, and solely as shorthand, “DHB” refers to dihydrobenzofuran).
  • FIG. 8D shows the activity in volt-seconds (V*s over 30 minutes) of exemplary compound 2-(4-iso-butyl-5-(2-methoxyethyl)-2,3-dihydrobenzofuran-7-yl)ethan-1-amine HCI at 0.1 , 0.3, 1 , 3, and 10 mpk.
  • FIG. 9A shows the HTR count (15 min fractions) of exemplary compound (S)-3-(4-isobutyl-5- methoxy-2,3-dihydrobenzofuran-7-yl)-3-methylpiperidine at 0.1 , 0.3, 1 , 3, and 10 mpk over 60 minutes.
  • FIG. 9B shows the activity in volt-seconds (V*s) of exemplary compound (S)-3-(4-isobutyl-5- methoxy-2,3-dihydrobenzofuran-7-yl)-3-methylpiperidine at 0.1 , 0.3, 1 , 3, and 10 mpk over 60 minutes.
  • FIG. 9C shows the cumulative number of head twitch events observed during a 30-min period (sum 30 min) of compound (S)-3-(4-isobutyl-5-MeO-2,3-DHB-7-yl)-3-methylpiperidine at 0.1 , 0.3, 1, 3, and 10 mpk.
  • FIG. 9D shows the activity in volt-seconds (V*s over 30 minutes) of exemplary compound (S)-3-(4-isobutyl-5-methoxy-2,3-dihydrobenzofuran-7-yl)-3-methylpiperidine at 0.1 , 0.3, 1 , 3, and 10 mpk.
  • FIG. 10A shows the HTR count (15 min fractions) of a vehicle control and reference compound DOI (1 mpk) over 60 minutes.
  • FIG. 10B shows the activity in volt-seconds (V*s) of a vehicle control and reference compound DOI (1 mpk) over 60 minutes.
  • FIG. 10C shows the cumulative number of head twitch events observed during a 30-minute period (sum 30 min) of a vehicle control (Veh) and reference compound DOI (1 mpk).
  • FIG. 10D shows the activity in volt-seconds (V*s over 30 minutes) of a vehicle control (Veh) and reference compound DOI (1 mpk).
  • an active agent includes a combination of two or more active agents
  • an excipient includes 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, for example, multiple agents or ingredients in some embodiments.
  • “about” includes numbers that fall within a range of ⁇ 10% of a number, in embodiments within ⁇ 5% of a number, in embodiments within ⁇ 2% of a number, in embodiments within ⁇ 1 % of a number, in embodiments within ⁇ 0.5% of a number, and in embodiments within ⁇ 0.1 % of a number, unless otherwise stated or evident from the context (such as where a number would impermissibly exceed 100% of a possible value).
  • 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.
  • an alkyl group will be optionally substituted.
  • 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.
  • An alkenyl group can be substituted or unsubstituted.
  • 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.
  • An alkynyl group can be substituted or unsubstituted.
  • 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, phenanthrene, picene, pleiadene, pyrene,
  • Cycloalkyl refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon
  • Monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds.
  • Bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decahydronaphthalene and adamantane.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • exemplary groups include 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
  • 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, 0 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,
  • 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.
  • 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, 0 or S.
  • Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 , or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5.
  • Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
  • a heteroaryl includes groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1 ,2,3-, 1 ,2,4- and 1 ,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran.
  • Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.
  • 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 CO-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.
  • R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein.
  • alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy.
  • An alkoxy group 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 group 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 group 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). Where an alkyl radical is substituted by more than one halogen, it may be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkyl refers to an alkyl substituted by two halo groups, which may be, but are not necessarily, the same halogen.
  • a halogen e.g., a fluorine, a chlorine, a bromine, or an iodine
  • haloalkyl groups include difluoromethyl (— CHF 2 ), bromofluoromethyl (— CHBrF), trifluoromethyl (— CF 3 ), and 2-fluoroethyl (— CH 2 CH 2 F). Additional examples of haloalkyl groups include -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH(CH 3 )(CF 3 ), — CH(CH 3 )(CHF 2 ), and — CH(CH 3 )(CH 2 F). A haloalkyl group may be substituted or unsubstituted.
  • Haloalkylthio refers to any alkylthio group as defined above, wherein one or more hydrogen atoms are replaced by a halogen (e.g., a fluorine, a chlorine, a bromine, or an iodine). Where an alkylthio radical is substituted by more than one halogen, it may be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkylthio refers to an alkylthio substituted by two halo groups, which may be, but are not necessarily, the same halogen.
  • a halogen e.g., a fluorine, a chlorine, a bromine, or an iodine
  • haloalkylthio groups include — SCF 3 , — 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 group may be substituted or unsubstituted.
  • Hydroalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
  • exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxy- propyl, 2-hydroxypropyl and 2,2-dihydroxyethyl.
  • a hydroxyalkyl group 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 group 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 group may be substituted or unsubstituted.
  • a sulfinyl group 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 group may be substituted or unsubstituted.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
  • An O-carboxy group may be substituted or unsubstituted.
  • a thiocarbonyl group 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 — S0 2 N(R A R B ) group in which R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
  • R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
  • An S-sulfonamido group may be substituted or unsubstituted.
  • N-sulfonamido refers to a RS0 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 group may be substituted or unsubstituted.
  • An O-carbamyl group may be substituted or unsubstituted.
  • R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
  • An N-carbamyl group may be substituted or unsubstituted.
  • An O-thiocarbamyl group may be substituted or unsubstituted.
  • R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
  • An N-thiocarbamyl group may be substituted or unsubstituted.
  • R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.
  • a C-amido group may be substituted or unsubstituted.
  • An N-amido group may be substituted or unsubstituted.
  • any group above can be substituted or unsubstituted. Accordingly, in some embodiments, each group is substituted. In other embodiments, each group is unsubstituted. In other embodiments, each group is optionally substituted.
  • 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. In another embodiment, an optionally substituted group has four substituents.
  • substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl (alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyana
  • the phenethylamine pharmacophore is one of the most well-known chemical scaffolds found in biologically active molecules, such as neurotransmitters (e.g., dopamine) and psychoactive drugs (e.g., the entactogen 3,4-methylenedioxymethamphetamine, also known as MDMA).
  • neurotransmitters e.g., dopamine
  • psychoactive drugs e.g., the entactogen 3,4-methylenedioxymethamphetamine, also known as MDMA.
  • One class of phenethylamine compounds known as the “2C” or “2C-x” compounds, are ring-substituted phenethylamines containing methoxy groups on the 2 and 5 positions of the benzene ring, and an additional (often lipophilic) substituent at the 4 position.
  • 2C compounds are potent and selective 5-HT 2A receptor agonists, and have been historically studied as pharmacophores in SAR studies of psychedelic drugs. Certain 2C compounds have effects similar to those of entactogens such as MDMA, as well as effects similar to those of “classic” psychedelics such as psilocybin.
  • the present disclosure relates to substituted 2,3-benzofuran compounds (i.e., “hemiFLY” derivatives of phenethylamines).
  • hemiFLY substituted 2,3-benzofuran compounds
  • some asymmetric dihydrofuran phenethylamine analogs have been reported (Nichols et al. J Med Chem. 1991 ;34:276-281 ; Monte et al. J Med Chem. 1996; 39(15): 2953-2961)
  • Applicant is unaware of the specific compounds and compositions disclosed herein having been synthesized, formulated, and/or used in the compositions and methods of the disclosure.
  • the structure-activity relationships, pharmacology, pharmacokinetics, and therapeutic efficacy of such compounds remains largely uncharacterized.
  • to Applicant’s knowledge no experimentally determined 5-HT 2A binding affinities or potencies for 2-hemiFLY compounds have been reported in the scientific literature.
  • the disclosure relates to compounds of Formula (1): wherein:
  • R 4 is H, F, Cl, Br, I, CN, N0 2 , CrCg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrCg haloalkyl, C ⁇ Cg alkoxy, CrCg haloalkylthio, C C 6 alkylthio, C 3 -C 6 cycloalkylmethyl, or — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl;
  • R 5 is CrCg alkoxy, — (CH 2 ) 0.3 OH, — (CH ⁇ -O-CrCg alkyl, — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl,
  • R and R' are each independently H or C ⁇ Cg alkyl
  • R N is H or — CH 2 -Ar; wherein Ar is 6- to 12-membered heterocyclyl or C 6 -C 12 aryl optionally substituted by F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl; and
  • R a is H or C ⁇ Cg alkyl; and R b is H; or R a and R b together with the intervening atoms form a 3- to 6-membered cycloalkyl; or R N and R b together with the intervening atoms form a 4- to 8-membered heterocyclyl, and R a is H or C r Cg alkyl; or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • R 4 is H, F, Cl, Br, I, CN, NO 2 , C ⁇ Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r Cg haloalkyl, C r Cg alkoxy, C r Cg haloalkylthio, C r Cg alkylthio, C 3 -C 6 cycloalkylmethyl, or — (CH 2 ) 0-3 -C(O)-O-C 1 -Cg alkyl.
  • R 4 is H.
  • R 4 is F.
  • R 4 is Cl.
  • R 4 is Br.
  • R 4 is I. In embodiments, R 4 is CN. In embodiments, R 4 is NO 2 . In embodiments, R 4 is C ⁇ Cg alkyl. In embodiments, R 4 is methyl. In embodiments, R 4 is ethyl. In embodiments, R 4 is propyl. In embodiments, R 4 is butyl. In embodiments, R 4 is isobutyl. In embodiments, R 4 is pentyl. In embodiments, R 4 is neopentyl. In embodiments, R 4 is C 2 -C 6 alkenyl. In embodiments, R 4 is vinyl. In embodiments, R 4 is allyl. In embodiments, R 4 is C 2 -C 6 alkynyl.
  • R 4 is ethynyl. In embodiments, R 4 is CrCg haloalkyl. In embodiments, R 4 is trifluoromethyl. In embodiments, R 4 is C C 6 alkoxy. In embodiments, R 4 is methoxy. In embodiments, R 4 is C C 6 haloalkylthio. In embodiments, R 4 is 2-fluoro- ethylthio. In embodiments, R 4 is C ⁇ Cg alkylthio. In embodiments, R 4 is methylthio. In embodiments, R 4 is ethylthio. In embodiments, R 4 is propylthio. In embodiments, R 4 is butylthio.
  • R 4 is isobutylthio. In embodiments, R 4 is C 3 -C 6 cycloalkylmethyl. In embodiments, R 4 is cyclopropylmethyl. In embodiments, R 4 is — (CH 2 ) 0-3 -C(O)-O-C 1 -C 6 alkyl. In embodiments, R 4 is — COO-C C 6 alkyl. In embodiments, R 4 is — CH 2 COO-C C 6 alkyl. In embodiments, R 4 is — (CH 2 ) 2 COO-C 1 -C 6 alkyl. In embodiments, R 4 is — (CH 2 ) 3 COO-C C 6 alkyl. In embodiments, R 4 is — CH 2 COOCH 3 . In embodiments, R 4 is — CH 2 COOCH 2 CH 3 .
  • R 5 is C r Cg alkoxy, — (CH 2 ) 0.3 OH, — (CH ⁇ -O-CrCg alkyl, — (CH 2 )O.3-C(0)-0-C 1 -C 6 alkyl, — (CH 2 )o. 3 -C(0)-NH 2 , or — (CH 2 ) 0.3 -C(O)-NH-C 1 -C 6 alkyl; wherein n is from 0 to 3.
  • R 5 is C r Cg alkoxy.
  • R 5 is methoxy.
  • R 5 is — (CH 2 ) 0.3 OH.
  • R 5 is — CH 2 OH, — CH 2 CH 2 OH, or — CH 2 CH 2 CH 2 OH. In embodiments, R 5 is — (CH 2 ) 0.3 -O-C 1 -Cg alkyl. In embodiments, R 5 is — CH 2 OCH 3 , — CH 2 CH 2 OCH 3 , or — CH 2 CH 2 CH 2 OCH 3 . In embodiments, R 5 is — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl.
  • R 5 is — COOCH 3 , — CH 2 COOCH 3 , — CH 2 CH 2 COOCH 3 , or — CH 2 CH 2 CH 2 COOCH 3 .
  • R 5 is — (CH 2 ) 0.3 -C(O)-NH 2 .
  • R 5 is -CONH 2 , -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , or -CH 2 CH 2 CH 2 CONH 2 .
  • R and R' are each independently H or C ⁇ Cg alkyl.
  • R is H.
  • R is C ⁇ Cg alkyl (e.g., methyl, ethyl, propyl).
  • R' is H.
  • R' is C ⁇ Cg alkyl.
  • R and R' are both H.
  • R is H and R' is C ⁇ Cg alkyl.
  • R is H and R' is methyl.
  • R and R' are both C ⁇ Cg alkyl.
  • R and R' are both methyl.
  • R a is H or C ⁇ Cg alkyl. In embodiments, R a is H. In embodiments, R a is C ⁇ Cg alkyl. In embodiments, R a is methyl. In embodiments, R a is ethyl.
  • R N is H or — CH 2 -Ar, wherein Ar is 6- to 12-membered heterocyclyl or C 6 -C 12 aryl optionally substituted by F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl.
  • R N is H.
  • R N is — CH 2 -Ar.
  • R N is — CH 2 -Ar, and Ar is 6- to 12-membered heterocyclyl optionally substituted by F, Cl, Br, I, OH, C r Cg alkoxy, or phenyl.
  • R N is — CH 2 -Ar, and Ar is unsubstituted 6- to 12-membered heterocyclyl.
  • R N is — CH 2 -Ar, and Ar is 6- to 12-membered heterocyclyl substituted by F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl.
  • R N is — CH 2 -Ar, and Ar is benzodioxolyl (e.g., 1 ,3-benzodioxolyl).
  • R N is — CH 2 -Ar, and Ar is benzofuranyl (e.g., 1 -benzofuranyl).
  • R N is — CH 2 -Ar
  • Ar is C 6 -C 12 aryl optionally substituted by F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl.
  • R N is — CH 2 -Ar
  • Ar is unsubstituted C 6 -C 12 aryl.
  • R N is — CH 2 -Ar
  • Ar is phenyl.
  • R N is — CH 2 -Ar, and Ar is naphthyl.
  • R N is — CH 2 -Ar
  • Ar is C 6 -C 12 aryl substituted by F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl.
  • R N is — CH 2 -Ar
  • Ar is phenyl substituted by F, Cl, Br, or I.
  • R N is — CH 2 -Ar
  • Ar is 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, or 2-iodophenyl.
  • R N is — CH 2 -Ar, and Ar is 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, or 3-iodophenyl.
  • R N is — CH 2 -Ar, and Ar is phenyl substituted by OH.
  • R N is — CH 2 -Ar, and Ar is 2-hydroxyphenyl.
  • R N is — CH 2 -Ar, and Ar is phenyl substituted by C ⁇ Cg alkoxy.
  • R N is — CH 2 -Ar, and Ar is 2-methoxyphenyl.
  • R N is — CH 2 -Ar, and Ar is phenyl substituted by phenyl.
  • R N is — CH 2 -Ar, and Ar is biphenyl (e.g., 2-biphenyl).
  • R N is — CH 2 -Ar, and Ar is 2-(4-hydroxyphenyl)phenyl.
  • R N is — CH 2 -Ar, and Ar is phenyl substituted by C 3 -C 6 cycloalkyl.
  • R N is — CH 2 -Ar, and Ar is phenyl substituted by cyclopropyl (e.g., 2-cyclopropylphenyl).
  • R b is H.
  • R b and R N together with the intervening atoms form a 4- to 8-membered heterocyclyl.
  • R b and R N together with the intervening atoms form an azetidinyl.
  • R b and R N together with the intervening atoms form a pyrrolidinyl.
  • R b and R N together with the intervening atoms form a piperidinyl.
  • R b and R N together with the intervening atoms form an azepanyl.
  • R a and R b together with the intervening atoms form a 3- to 6-membered cycloalkyl.
  • R a and R b together with the intervening atoms form a cyclopropyl.
  • R a and R b together with the intervening atoms form a cyclobutyl.
  • R a and R b together with the intervening atoms form a cyclopentyl.
  • R a and R b together with the intervening atoms form a cyclohexyl.
  • the compound has the structure of Formula (2), or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof, wherein R a , R 4 , and R 5 are as defined for Formula (1).
  • R a is H or C ⁇ Cg alkyl. In embodiments, R a is H. In embodiments, R a is C ⁇ Cg alkyl. In embodiments, R a is methyl. In embodiments, R a is ethyl.
  • R 4 is H, F, Cl, Br, I, CN, NO 2 , C ⁇ Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r Cg haloalkyl, C r Cg alkoxy, C r Cg haloalkylthio, C r Cg alkylthio, C 3 -C 6 cycloalkylmethyl, or — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl; wherein n is from 0 to 3.
  • R 4 is H.
  • R 4 is F.
  • R 4 is Cl.
  • R 4 is Br. In embodiments, R 4 is I. In embodiments, R 4 is CN. In embodiments, R 4 is NO 2 . In embodiments, R 4 is C r Cg alkyl. In embodiments, R 4 is methyl. In embodiments, R 4 is ethyl. In embodiments, R 4 is propyl. In embodiments, R 4 is butyl. In embodiments, R 4 is isobutyl. In embodiments, R 4 is pentyl. In embodiments, R 4 is neopentyl. In embodiments, R 4 is C 2 -C 6 alkenyl. In embodiments, R 4 is vinyl. In embodiments, R 4 is allyl.
  • R 4 is C 2 -C 6 alkynyl. In embodiments, R 4 is ethynyl. In embodiments, R 4 is C ⁇ Cg haloalkyl. In embodiments, R 4 is trifluoromethyl. In embodiments, R 4 is C ⁇ Cg alkoxy. In embodiments, R 4 is methoxy. In embodiments, R 4 is C ⁇ Cg haloalkylthio. In embodiments, R 4 is 2-fluoroethylthio. In embodiments, R 4 is C ⁇ Cg alkylthio. In embodiments, R 4 is methylthio. In embodiments, R 4 is ethylthio. In embodiments, R 4 is propylthio.
  • R 4 is butylthio. In embodiments, R 4 is isobutylthio. In embodiments, R 4 is C 3 -C 6 cycloalkylmethyl. In embodiments, R 4 is cyclopropylmethyl. In embodiments, R 4 is — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl; wherein n is from 0 to 3. In embodiments, R 4 is — COO-C r C 6 alkyl. In embodiments, R 4 is — CH 2 COO-C 1 -C 6 alkyl. In embodiments, R 4 is — (CH 2 ) 2 COO-C 1 -C 6 alkyl. In embodiments, R 4 is — (CH ⁇ COO-CpCg alkyl. In embodiments, R 4 is — CH 2 COOCH 3 . In embodiments, R 4 is — CH 2 COOCH 2 CH 3 .
  • R 5 is C r Cg alkoxy, — (CH 2 ) 0.3 OH, — (CH ⁇ -O-CpCg alkyl, — (CH 2 ) 0-3 -C(O)-O-C 1 -Cg alkyl, — (CH 2 )o. 3 -C(0)-NH 2 , or — (CH 2 ) 0.3 -C(O)-NH-C 1 -C 6 alkyl; wherein n is from 0 to 3.
  • R 5 is C ⁇ Cg alkoxy.
  • R 5 is methoxy.
  • R 5 is — (CH 2 ) 0-3 OH.
  • R 5 is — CH 2 OH, — CH 2 CH 2 OH, or — CH 2 CH 2 CH 2 OH. In embodiments, R 5 is — (CH ⁇ -O- ⁇ -Cg alkyl. In embodiments, R 5 is — CH 2 OCH 3 , — CH 2 CH 2 OCH 3 , or — CH 2 CH 2 CH 2 OCH 3 . In embodiments, R 5 is — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl. In embodiments, R 5 is — COOCH 3 , — CH 2 COOCH 3 , — CH 2 CH 2 COOCH 3 , or — CH 2 CH 2 CH 2 COOCH 3 .
  • R 5 is — (CH 2 ) 0.3 -C(O)-NH 2 . In embodiments, R 5 is -CONH 2 , -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , or -CH 2 CH 2 CH 2 CONH 2 .
  • R and R' are each independently H or C ⁇ Cg alkyl.
  • R is H.
  • R is C ⁇ Cg alkyl (e.g., methyl, ethyl, propyl).
  • R' is H.
  • R' is C ⁇ Cg alkyl.
  • R and R' are both H.
  • R is H and R' is C ⁇ Cg alkyl.
  • R is H and R' is methyl.
  • R and R' are both C ⁇ Cg alkyl.
  • R and R' are both methyl.
  • the compound has the structure of Formula (3), wherein
  • X, Y, and Z are each independently H, F, Cl, Br, I, OH, C r Cg alkoxy, C 3 -C 6 cycloalkyl, or phenyl; or
  • X and Y are taken together to form a 4- to 6-membered heterocyclyl, and Z is H, F, Cl, Br, I, OH, CrC 6 alkoxy, C 3 -C 6 cycloalkyl, or phenyl; or
  • Y and Z are taken together to form a 4- to 6-membered heterocyclyl, and X is H, F, Cl, Br, I, OH, C r C 6 alkoxy, C 3 -C 6 cycloalkyl, or phenyl; and
  • R a , R 4 , and R 5 are as defined for Formula (1); or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • X, Y, and Z are each independently H, F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl.
  • X is F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl; and Y and Z are both H.
  • Y is F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl; and X and Z are both H.
  • Z is F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl; and X and Y are both H.
  • X and Y are each independently F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl; and Z is H.
  • X and Z are each independently F, Cl, Br, I, OH, C r Cg alkoxy, or phenyl; and Y is H.
  • Y and Z are each independently F, Cl, Br, I, OH, C r Cg alkoxy, or phenyl; and X is H.
  • X is H, F, Cl, Br, I, OH, C r Cg alkoxy, or phenyl.
  • X is F, Cl, Br, or I.
  • X is H.
  • X is F.
  • X is Cl.
  • X is Br.
  • X is I.
  • X is OH.
  • X is C r Cg alkoxy.
  • X is methoxy.
  • X is phenyl.
  • X is 4-hydroxyphenyl.
  • X is C 3 -C 6 cycloalkyl.
  • X is cyclopropyl.
  • Y is H, F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl.
  • Y is F, Cl, Br, or I.
  • Y is H.
  • Y is F.
  • Y is Cl.
  • Y is Br.
  • Y is I.
  • Y is OH.
  • Y is C ⁇ Cg alkoxy.
  • Y is methoxy.
  • Y is phenyl.
  • Y is 4-hydroxyphenyl.
  • Y is C 3 -C 6 cycloalkyl.
  • Y is cyclopropyl.
  • Z is H, F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl.
  • Z is F, Cl, Br, or I.
  • Z is H.
  • Z is F.
  • Z is Cl.
  • Z is Br.
  • Z is I.
  • Z is OH.
  • Z is C ⁇ Cg alkoxy.
  • Z is methoxy.
  • Z is phenyl.
  • Z is 4-hydroxyphenyl.
  • Z is C 3 -C 6 cycloalkyl.
  • Z is cyclopropyl.
  • X and Y are taken together to form a 4- to 6-membered heterocyclyl.
  • X and Y are taken together to form ⁇ O— " 'p (methylenedioxy), wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.
  • X and Y are taken together to form a dihydrofuranyl.
  • X and Y are taken together to form , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.
  • X and Y are taken together to form a furanyl.
  • X and Y are
  • ** ** taken together to form ⁇ 0— ‘ or ⁇ i x /p , wherein * and ** indicate the points of connection between X and the rest of the compound, and between Y and the rest of the compound, respectively.
  • Y and Z are taken together to form a 4- to 6-membered heterocyclyl.
  • Y and Z are taken together to form (methylenedioxy), wherein * and ** indicate the points of connection between Y and the rest of the compound, and between Z and the rest of the compound, respectively.
  • Y and Z are taken together to form a dihydrofuranyl.
  • Y and Z are taken together to form O- 7 or i — t , wherein * and ** indicate the points of connection between Y and the rest of the compound, and between Z and the rest of the compound, respectively.
  • Y and Z are taken together to form a furanyl.
  • Y and Z are taken together to form , wherein * and ** indicate the points of connection between Y and the rest of the compound, and between Z and the rest of the compound, respectively.
  • R a is H or C ⁇ Cg alkyl. In embodiments, R a is H. In embodiments, R a is C ⁇ Cg alkyl. In embodiments, R a is methyl. In embodiments, R a is ethyl.
  • R 4 is H, F, Cl, Br, I, CN, N0 2 , C ⁇ Cg alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r Cg haloalkyl, C r Cg alkoxy, C r Cg haloalkylthio, C r Cg alkylthio, C 3 -C 6 cycloalkylmethyl, or — (CH 2 )o_ 3 -C(0)-0-C 1 -Cg alkyl; wherein n is from 0 to 3.
  • R 4 is H.
  • R 4 is F.
  • R 4 is Cl.
  • R 4 is Br. In embodiments, R 4 is I. In embodiments, R 4 is CN. In embodiments, R 4 is N0 2 . In embodiments, R 4 is C r Cg alkyl. In embodiments, R 4 is methyl. In embodiments, R 4 is ethyl. In embodiments, R 4 is propyl. In embodiments, R 4 is butyl. In embodiments, R 4 is isobutyl. In embodiments, R 4 is pentyl. In embodiments, R 4 is neopentyl. In embodiments, R 4 is C 2 -C 6 alkenyl. In embodiments, R 4 is vinyl. In embodiments, R 4 is allyl.
  • R 4 is C 2 -C 6 alkynyl. In embodiments, R 4 is ethynyl. In embodiments, R 4 is C ⁇ Cg haloalkyl. In embodiments, R 4 is trifluoromethyl. In embodiments, R 4 is C ⁇ Cg alkoxy. In embodiments, R 4 is methoxy. In embodiments, R 4 is C ⁇ Cg haloalkylthio. In embodiments, R 4 is 2-fluoroethylthio. In embodiments, R 4 is C ⁇ Cg alkylthio. In embodiments, R 4 is methylthio. In embodiments, R 4 is ethylthio. In embodiments, R 4 is propylthio.
  • R 4 is butylthio. In embodiments, R 4 is isobutylthio. In embodiments, R 4 is C 3 -C 6 cycloalkylmethyl. In embodiments, R 4 is cyclopropylmethyl. In embodiments, R 4 is — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl; wherein n is from 0 to 3. In embodiments, R 4 is — COO-CrCg alkyl. In embodiments, R 4 is — CH 2 COO-C 1 -C 6 alkyl. In embodiments, R 4 is — (CH ⁇ COO-CrCg alkyl. In embodiments, R 4 is — (CH ⁇ COO-C Cg alkyl. In embodiments, R 4 is — CH 2 COOCH 3 . In embodiments, R 4 is — CH 2 COOCH 2 CH 3 .
  • R 5 is C ⁇ Cg alkoxy, — (CH 2 ) 0.3 OH, — (CH 2 )o.3-0-C 1 -Cg alkyl, — (CH 2 ) 0-3 -C(O)-O-C 1 -Cg alkyl, — (CH 2 )o. 3 -C(0)-NH 2 , or — (CH 2 ) 0.3 -C(O)-NH-C 1 -C 6 alkyl; wherein n is from 0 to 3.
  • R 5 is C r Cg alkoxy.
  • R 5 is methoxy.
  • R 5 is — (CH 2 ) 0-3 OH.
  • R 5 is — CH 2 OH, — CH 2 CH 2 OH, or — CH 2 CH 2 CH 2 OH. In embodiments, R 5 is — (CH ⁇ o-s-O-C Cg alkyl. In embodiments, R 5 is — CH 2 OCH 3 , — CH 2 CH 2 OCH 3 , or — CH 2 CH 2 CH 2 OCH 3 . In embodiments, R 5 is — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl. In embodiments, R 5 is — COOCH 3 , — CH 2 COOCH 3 , — CH 2 CH 2 COOCH 3 , or — CH 2 CH 2 CH 2 COOCH 3 .
  • R 5 is — (CH 2 ) 0.3 -C(O)-NH 2 . In embodiments, R 5 is -CONH 2 , -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , or -CH 2 CH 2 CH 2 CONH 2 .
  • R and R' are each independently H or C ⁇ Cg alkyl.
  • R is H.
  • R is CrC 6 alkyl (e.g., methyl, ethyl, propyl).
  • R' is H.
  • R' is CrC 6 alkyl.
  • R and R' are both H.
  • R is H and R' is CrC 6 alkyl.
  • R is H and R' is methyl.
  • R and R' are both CrC 6 alkyl.
  • R and R' are both methyl.
  • R 5 when R 5 is methoxy, R a is methyl, and R N is H, R 4 is not I. In embodiments, when R 5 is methoxy, R a is methyl, and R N is H, R 4 is not halogen.
  • R 5 when R 5 is methoxy, R a is methyl, and R N is H, R 4 is CN, NO 2 , C r C 6 alkyl, C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkylthio, C r C 6 alkylthio, C 3 -C 6 cycloalkylmethyl, or — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl; wherein n is from 0 to 3.
  • R 4 when R 5 is methoxy, R a is methyl, and R N is H, R 4 is C 2 -C 6 alkyl.
  • the compound has the structure of any of Formulae (l)-(VI), wherein R, R', R 4 , R 5 , and R N are as defined for Formula (1):
  • the compound is not
  • the compound is not
  • the compound is not any of:
  • the compound is selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxy, a-hydrogen hemiFLY compound.
  • the 5-methoxy, a-hydrogen hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxy, a-ethyl hemiFLY compound.
  • the 5-methoxy, a-ethyl hemiFLY compound is selected from the group consisting of:
  • the compound is a 5-hydroxyethyl, a-hydrogen hemiFLY compound.
  • the 5-hydroxyethyl, a-hydrogen hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-hydroxyethyl, a-ethyl hemiFLY compound.
  • the 5-hydroxyethyl, a-ethyl hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxyethyl, a-hydrogen hemiFLY compound.
  • the 5-methoxyethyl, a-hydrogen hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxyethyl, a-ethyl hemiFLY compound.
  • the 5-methoxyethyl, a-ethyl hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-hydroxymethyl, a-hydrogen hemiFLY compound.
  • the 5-hydroxymethyl, a-hydrogen hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-hydroxymethyl, a-ethyl hemiFLY compound.
  • the 5-hydroxymethyl, a-ethyl hemiFLY compound is selected from the group consisting of:
  • the compound is a 5-methoxymethyl, a-hydrogen hemiFLY compound.
  • the 5-methoxymethyl, a-hydrogen hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxymethyl, a-ethyl hemiFLY compound.
  • the 5-methoxymethyl, a-ethyl hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, and isotopic derivative thereof.
  • the compound is a 5-methoxy piperidine hemiFLY compound. In embodiments, the 5-methoxy piperidine hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof. [180] In some embodiments, the compound is a 5-hydroxyethyl piperidine hemiFLY compound. In embodiments, the 5-hydroxyethyl piperidine hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxyethyl piperidine hemiFLY compound.
  • the 5-methoxyethyl piperidine hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-hydroxymethyl piperidine hemiFLY compound.
  • the 5-hydroxymethyl piperidine hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxymethyl piperidine hemiFLY compound.
  • the 5-methoxymethyl piperidine hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxy cyclopropyl hemiFLY compound.
  • the 5-methoxy cyclopropyl hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-hydroxyethyl cyclopropyl hemiFLY compound.
  • the 5-hydroxyethyl cyclopropyl hemiFLY compound is selected from the group consisting of:
  • the compound is a 5-methoxyethyl cyclopropyl hemiFLY compound.
  • the 5-methoxyethyl cyclopropyl hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-hydroxymethyl cyclopropyl hemiFLY compound.
  • the 5-hydroxymethyl cyclopropyl hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a 5-methoxymethyl cyclopropyl hemiFLY compound.
  • the 5-methoxymethyl cyclopropyl hemiFLY compound is selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • the compound is a further substituted hemiFLY compound, such as alkyl substituted, such as bearing one or two methyl substituents on the dihydrobenzofuran ring.
  • the further substituted hemiFLY compound is selected from the group of the Group D compounds as defined herein, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • additional compounds include those in which the substituent on the phenyl ring at R N is located at a different position on the ring.
  • the phenyl ring comprises a substituent (e.g., a hydroxy or methoxy group) in the para position relative to the point of substitution indicated by the asterisk, in other embodiments the substituent is located at the ortho or meta position.
  • Additional compounds include, e.g., the bromine replaced with another halogen, the cyclopropyl replaced with another cycloalkyl or alkyl, the methoxy replaced with another alkoxy, and the like.
  • salts of disclosed compounds refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, and which may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
  • nonaqueous media e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
  • 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, clavular
  • 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.
  • the compound may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • 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.
  • Hydrates 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.
  • chiral chromatography 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 CI 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 positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • 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. In vivo, 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.
  • Commonly used 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.
  • 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 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.
  • the comparator for a disclosed compound is a 2C compound (e.g., 2C-C, 2C-B,
  • the comparator for a disclosed compound is the corresponding 2C compound with an identical substitution pattern, except for the 2-hemiFLY moiety.
  • the comparator is 2C-B. In some embodiments, wherein
  • Disclosed compounds can be synthesized from a substituted benzofuran precursor (e.g., wherein R 4 or R 5 are as defined for Formula (1)):
  • the substituted benzofuran precursor comprises an alkylated dihydrofuranyl moiety (e.g., wherein the C3-position of the dihydrofuran ring is methylated or dimethylated).
  • a first step (i.) the benzofuran is halogenated with a suitable halogenating agent (e.g., Br 2 ).
  • a suitable halogenating agent e.g., Br 2
  • the halogenated intermediate is subjected to a cross-coupling reaction (e.g., using a Pd and/or Ru-based catalyst) to install an ami no-protected (e.g., Boc-protected) 2-aminoalkyl side chain.
  • the cross-coupling reaction is a palladium-catalyzed cross coupling with a boron (R-BY 3 ) reagent (e.g., an organotrifluoroborane or the like).
  • R a and R b together with the intervening atoms form a 3- to 6-membered cycloalkyl can be synthesized according to the same approach, wherein R a and R b of the boron reagent (together with the intervening atoms) form a cycle; for example, potassium ((1R,2R)-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate can be used to install a cyclopropylamine side chain.
  • deprotection of the amine yields the compound of Formula (1).
  • a suitably substituted benzofuran precursor is commercially available. If no precursor having a desired R 4 or R 5 group is commercially available, such precursors can be synthesized as described in EXAMPLE 1 (for an exemplary synthesis of a compound in which R 4 is C ⁇ Cg alkyl), or as follows.
  • the R 4 substituent corresponds to the 4-position of “classical” 2C-X and DOx phenethylamine psychedelics.
  • the 4-substituent is introduced by substitution of the corresponding 4-substituted phenethylamine (e.g., as in the halogenation of 2C-H to yield 2C-B, 2C-I, etc.), or by substitution of the aryl group a suitable precursor prior to the introduction of the ethylamino side chain (e.g., as in the case of the 2C-T series).
  • similar approaches can be used for disclosed compounds, and appropriate modifications, substitutions, changes, and variations of these known synthetic procedures can be made by those skilled in the art without undue burden.
  • certain compounds wherein R 5 is — (CH 2 )o. 3 OH, — (CH 2 ) 0.3 -O-C 1 -C 6 alkyl, — (CH 2 )O_ 3 -C(0)-0-C 1 -C 6 alkyl, — (CH 2 )o. 3 -C(0)-NH 2 , or — (CH 2 ) 0.3 -C(O)-NH-C 1 -C 6 alkyl
  • the reductive amination may be conducted according to standard techniques. For example, the starting materials may first be reacted to form an imine intermediate, which is then reduced by sodium borohydride in a second step. Alternatively, the reductive amination can be done in one step using sodium triacetoxyborohydride or sodium cyanoborohydride as the reducing agent.
  • 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.
  • “Pharmaceutically acceptable” used in connection with an excipient, carrier, diluent, or other ingredient means the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with cells of humans and animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk/benefit ratio.
  • compositions comprising a disclosed compound can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal.
  • the compounds employed in disclosed methods are effective as oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound (see, e.g., Remington, 2020).
  • compositions can be formulated in a unit dosage form, each dosage containing a therapeutically effective amount of the active ingredients, for example in the dosage amounts disclosed below.
  • unit dosage form refers to a physically discrete unit suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect(s), in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • Unit dosage forms are often used for ease of administration and uniformity of dosage.
  • Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof (e.g., one half a “full” dose for a “booster” dose as described below), of the pharmaceutical composition administered.
  • Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo.
  • Unit dosage forms also include ampules and vials with liquid compositions disposed therein.
  • Unit dosage forms further include compounds for transdermal administration, such as “patches” that contact the epidermis (including the mucosa) 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 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.
  • 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.
  • viscosity modifying agents e.g., thickeners
  • adhesion modifying agents e.g., tackifiers
  • preservatives e.g., antioxidants, adhesive polymers
  • solubilizing agents e.g., 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 glycodeoxycholate, sodium taurodeoxycholate, 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 polyoxylglycerides, 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
  • 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 & Drug Delivery Systems (Howard Ansel et al., eds., Lippincott Williams & Wilkins, 7th ed. 1999); Remington: The Science & Practice of Pharmacy (Alfonso Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel Hardman et al., eds., McGraw-Hill, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond Rowe et al., APhA, 4th ed. 2003).
  • 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, 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.
  • 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 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., p-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., thiorodox
  • the antioxidant is a-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-a-tocopherol, rosmarinic acid, or a combination thereof.
  • 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-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
  • 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, arabinogalactan/galactoarabinan, polygalactose, and polyarabinose.
  • the viscosity modifying agent is a glyceride.
  • Exemplary glycerides include 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 diglyceride, malic acid monoglyceride, malic acid monoglyceride, malic acid diglyceride, and mixture thereof.
  • 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 E, and tocopherol.
  • 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®, Gelucire® 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 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).
  • the topical formulation comprises a binder.
  • Suitable binders include, without limitation, 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
  • carboxyvinyl polymers starches
  • cellulosic polymers such as hydroxyethylcellulose, carboxymethylcellulose (carmellose), hydroxypropylmethylcellulose, hydroxyethylpropylcellulose, hydroxybut
  • Binders may be present, individually or in total (if there is more than one binder), 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).
  • PEG6-PEG12 low molecular weight polyethylene glycol
  • the topical formulation comprises a surfactant.
  • the surfactants that can be included in the formulation may be anionic, nonionic, or amphoteric compounds.
  • Suitable examples of 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 di hydroxypropane sulfonate.
  • 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 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 dosage forms, such as oral solid dosage forms, such as capsules or tablets.
  • Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
  • pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
  • Oral solid dosage forms also can comprise one or more pharmaceutically acceptable additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).
  • 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 composition is formulated as an oral liquid dosage form.
  • Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients.
  • Solvents include water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.
  • Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
  • Liquid formulations also may be prepared as single dose or multi-dose beverages.
  • Suspensions may include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil.
  • Suitable oils also include carrier oils such as MCT and long chain triglyceride (LCT) oils.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, (such as ethanol, isopropyl alcohol, hexadecyl alcohol), glycerol, and propylene glycol.
  • Ethers, such as polyethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations.
  • Suspension can thus include an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion, or a water-in-oil emulsion.
  • formulations comprising the disclosed compositions and at least one dispersing agent or suspending agent for oral administration to a subject.
  • the formulation may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
  • the aqueous dispersion can comprise amorphous and non-amorphous particles consisting of multiple effective particle sizes such that a drug is absorbed in a controlled manner over time.
  • Dosage forms for oral administration can be aqueous suspensions selected from the group including pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, e.g., Singh et al., Encyclopedia 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 agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, or (g) flavoring agents.
  • compositions may be prepared as formulations suitable for subcutaneous, IP, IM, or IV 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
  • 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, isostearic acid, oleic acid, linoleic acid, linolenic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, pivalic acid, caproic acid, heptanoic acid, malonic 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, quaternary 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 alcohol, pullulan, agar, gelatine, chitosan, polysaccharide from tamarindo seed, xanthan gum, carageenan, high-methoxyl pectin, low-methoxyl pectin, guar gum, acacia gum, microcrystalline cellulose, arabinogalactan
  • 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, triethanol amine, diisopropanolamine, meglumine, monoethanolamine, sulfuric acid, and aluminum potassium sulfate.
  • the ophthalmic formulation comprises a stabilizer.
  • 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.
  • 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 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 6
  • 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 synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981 , Clin. Pharmacokinet. 6: 429-453) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55).
  • the graphs corresponding to the equations referred to above are the concentration-effect curve and combination index curve, respectively. Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
  • a 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, neuroplastogens), monoamine oxidase inhibitors (e.g., selective MAO-A inhibitors, RIMAs), tryptamines, terpenes, phenethylamines,
  • plasticity-inducing agents
  • the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, increase plasticity (e.g., neural plasticity), or alter pharmacokinetics or pharmacodynamics.
  • the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.
  • an additional active compound is a tryptamine.
  • tryptamines are compounds having the general structure below, wherein R N1 , R N2 , R a , R p , R 2 , R 4 , R 5 , R 6 , and R 7 are as defined herein and as generally understood in the art:
  • R N1 , R N2 , R a , R p , R 2 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, deuterium, halogen (F, Cl, Br, or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
  • any two of R N1 , R N2 , R a , R p , R 2 , R 4 , R 5 , R 6 , and R 7 and the intervening atoms can be taken together to form an optionally substituted optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
  • the tryptamine is a quaternary salt, in which an additional R N3 is connected to the nitrogen to which R N1 and R N2 are bound; wherein R N3 is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
  • the additional active compound is a tryptamine selected from the group consisting of psilocybin, psilocin, psilacetin, DBT, DET, DiPT, a,O-DMS, DMT, 2,a-DMT, a,N-DMT, DPT, EiPT, AET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-TMT, 4-HO-DMT, 5-HO-DMT (i.e., bufotenine), 4-HO-DPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPT, 4-HO-pyr-T, ibogaine, MBT, 4,5-MDO-DiPT, 5,6-MDO-DiPT,
  • 5-MeO-MiPT 5,6-MeO-MiPT, 5-MeO-NMT, 5-MeO-pyr-T, 5-MeO-TMT, 5-MeS-DMT, MiPT, a-MT (i.e., AMT), NET, NMT, pyr-T, tryptamine, and a,N,O-TMS, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.
  • a-MT i.e., AMT
  • NET NET
  • NMT pyr-T
  • the systematic naming of tryptamines involves the use of prefixes and suffixes to indicate substitutions on the indole ring and/or the side chain of the tryptamine core structure.
  • EiPT stands for ethyl isopropyl tryptamine, also known as N-ethyl-N-isopropyltryptamine (i.e., N-ethyl-N-[2-(1 H-indol-3-yl)ethyl] propan-2-amine).
  • an additional tryptamine is a complex tryptamine or indolamine, including 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 a , R p , and each of R 2 -R 6 are as taught herein and as generally understood in the art:
  • R N1 , R N2 , R a , R p , 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 mescaline, a-ethylmescaline, escaline, symbescaline, metaescaline, allylescaline, methallyl- escaline, asymbescaline, cyclopropylmescaline, phenescaline, 4-desoxymescaline, isomescaline, proscaline, metaproscaline, isoproscaline, thiomescaline, thioescaline, thioproscaline, thiobuscaline, a thiomescaline analog (e.g., 3-TM, 4-TM), buscaline, a thioisomescaline (e.g., 2-TIM, 3-TIM, 4-TIM), Aleph (i.e., DOT), a thiometaescaline (e.g., 3-TME, 4-TME, 5-TME),
  • phenethylamines such as those herein, involves the use of prefixes and suffixes to indicate substitutions on the phenyl ring and/or side chain of the phenethylamine core structure.
  • MDBZ stands for methylenedioxybenzylamphetamine (i.e., 3,4-methylenedioxy-N-benzylamphetamine).
  • the additional active compound is an ergoline.
  • the additional active compound is an ergot alkaloid.
  • the additional active compound is a lysergamide.
  • lysergamides are compounds having the general structure below, wherein R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are as taught herein and as generally understood in the art:
  • R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are each independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
  • any two of R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 and the intervening atoms can be taken together to form an optionally substituted optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
  • the lysergamide is a quaternary salt, in which an additional R 6A is connected to the nitrogen to which R 6 is bound; wherein R 6A is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
  • the additional active compound is a lysergamide selected from the group consisting of LSD, ETH-LAD, PARGY-LAD, AL-LAD, PRO-LAD, IP-LAD, CIP-LAD, BU-LAD, FLUOROETH-LAD, ALD, ALD-52, N-acetyl-LSD, 1 P-LSD, 1 B-LSD, 1V-LSD, 1cP-LSD, 1 D-LSD, 1 P-AL-LAD, 1cP-AL-LAD, 1 P-ETH-LAD, LA-SS-Az, LSZ, LSD-Pip, and MIPLA, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.
  • tryptamines, phenethylamines, and lysergamides useful as additional active compounds for purposes of the disclosure and thus contemplated for inclusion therein will be as generally known in the art (see, e.g., PiHKAL; TiHKAL; Grob & Grigsby, Handbook of Medical Hallucinogens, 2021 ; Luethi & Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacol Reviews, 2016; 68(2), 264-355; Glennon, Pharmacol Biochem Behavior, 1999; 64, 251-256; each of which is incorporated by reference as if fully set forth herein).
  • 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.
  • 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/
  • 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/
  • a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg
  • a pharmaceutical composition includes a disclosed compound
  • it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) between about 0.1 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, or about 1.0 mg, as well as ranges between these values.
  • a single dose is between about 1 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, or 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 a tryptamine, it may be present in an amount so that a single dose is (in a milligram dosage amount calculated based on the kilogram weight of the patient), e.g., 0.25 mg/kg or less (including a dose of 0.10 mg/kg or less, 0.05 mg/kg or less, 0.01 mg/kg or less, and 0.005 mg/kg or less), at least 0.50 mg/kg, at least 0.55 mg/kg, at least 0.60 mg/kg, at least 0.65 mg/kg, at least 0.70 mg/kg, at least 0.75 mg/kg, at least 0.80 mg/kg, at least 0.85 mg/kg, at least 0.90 mg/kg, at least 0.95 mg/kg, at least 1.0 mg/kg, at least 1.1 mg/kg, at least 1.2 mg/kg, at least 1.3 mg/kg, or at least 1.4 mg/kg, at least
  • 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 least
  • 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.
  • dose, frequency, and timing may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.
  • the dose actually administered will be determined by a physician, in light of the relevant circumstances, including the disorder to be treated, the chosen route of administration, the actual composition or formulation administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms, and therefore any dosage ranges disclosed herein are not intended to limit the scope of the invention.
  • 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 shall 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.
  • another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the invention, 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 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.
  • the 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).
  • kits of the disclosure can further contain package inserts and other printed instructions (e.g., on exterior packaging) for administering the disclosed compositions and for their appropriate therapeutic use.
  • disclosed compounds are used to modulate neurotransmission.
  • disclosed compounds are used to treat a condition, such as a disease or a disorder.
  • disclosed compounds are used in the manufacture of a medicament for the therapeutic and/or the prophylactic treatment of a condition, such as a disease or a disorder.
  • disclosed compounds are administered as part of 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 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 methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood. The disclosed methods of treatment also can be modified to treat multiple patients at once, including couples or families. Hence, these terms will be understood to also mean two or more individuals.
  • disclosed compounds or compositions thereof are orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation or transdermally administered to a subject.
  • the disclosed compounds and the disclosed compositions and formulations comprising them are useful in methods for treating a patient in need of such treatment.
  • disclosed compounds bearing a 5-carboxyalkyl (e.g., 5-carboxymethyl) substituent can engage certain amino acid residues in a serotonin (e.g., 5-HT2A) receptor.
  • “engage” refers to non-covalent interactions between a compound and a receptor, leading to association, interaction, and/or binding between the compound and receptor.
  • the non-covalent interaction is a hydrogen-bonding, ionic, or van der Waals interaction.
  • disclosed compounds having a 5-carboxyalkyl substituent engage certain residues of transmembrane helices of serotonin receptors.
  • a disclosed compound engages certain amino acid residues in transmembrane helix 6 (TM6).
  • TM6 transmembrane helix 6
  • a disclosed compound engages an asparagine residue on TM6 (e.g., N343 of TM6).
  • engaging amino acid residues confers advantageous properties, such as increased receptor binding affinity, increased functional activity, improved selectivity for one receptor subtype (e.g., 5-HT 2A ) over another (e.g., 5-HT 2B ), and improved therapeutic efficacy (e.g., as anti-inflammatory agents).
  • a disclosed compound having a 5-carboxamido substituent may be useful as a locally active therapeutic agent.
  • Systemic administration of therapeutically active agents may directly or indirectly affect multiple organs and tissues throughout the body. Consequently, systemic administration of a compound may give rise to a greater number or extent of adverse effects (e.g., side effects) at a therapeutically active dose.
  • adverse effects e.g., side effects
  • certain psychedelics have been shown to exert potent antiinflammatory effects, but are also psychoactive or have other effects on the central nervous system (CNS) that may be undesired or unnecessary in the context of treating certain medical conditions (e.g., skin or muscle inflammation).
  • CNS central nervous system
  • a compound that exhibits minimal penetration into the CNS it may be desired to administer a compound that exhibits minimal penetration into the CNS, but has therapeutic effects (e.g., anti-inflammatory effects) in tissues and organs in which the compound is directly administered, or in tissues and organs proximal to the site of administration.
  • Such compounds may be referred to as “locally active,” because their action is localized to the area to which (or close to which) they are applied.
  • compounds having a 5-carboxamido substituent may be substrates for an enzyme (e.g., an amidase). Inactivation (e.g., hydrolysis) of such compounds (e.g., by an enzyme) may prevent systemic action or penetration into the CNS, thereby localizing their therapeutic effects to (or close to) the site of administration.
  • administration of a disclosed compound having a 5-carboxamido substituent in a disclosed topical formulation exerts therapeutic (e.g., anti-inflammatory) effects locally, without causing psychoactive or other effects associated with penetration into the CNS.
  • 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 .
  • S-HT ⁇ 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.
  • a compound especially one that may be used regularly or over a relatively long time period, to have reduced activity (e.g., agonism) of 5-HT 2B .
  • disclosed compounds agonize or partially agonize 5-HT receptors, such as any one or more of a 5-HT receptor, such as 5-HT 1A and 5-HT 1B , a 5-HT 2 receptor, such as 5-HT 2A , 5-HT 2B , and 5-HT 2C , and a 5-HT 6 receptor.
  • a disclosed compound has an in vitro EC 50 (agonist mode) for any one or more of 5-HT 1A , 5-HT 1 B , 5-HT 2A , 5-HT 2C , and 5-HT 6 that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM.
  • a disclosed compound has an in vitro EC 50 (agonist mode) for 5-HT 2A that is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM.
  • a disclosed compound has an in vitro EC 50 (agonist mode) for 5-HT 2C that is less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.05 pM, less than 0.01 pM, less than 0.005 pM, or less than 0.001 pM.
  • 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 a 5-HT 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.
  • measuring Gq-mediated calcium flux is a known method for assessing modulation, e.g., activation, of 5-HT ⁇ , a widely recognized target of psychedelic compounds. See, e.g., Klein et al., ACS Pharmacol Transl Sci. 2020 14;4(2):533-542; Flanagan et al., ACS Pharmacol Transl Sci. 2020;4(2):488-502; Toro-Sazo et al., PLoS One.
  • 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 ⁇ 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 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 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 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 ⁇ 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,
  • 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,
  • 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,
  • 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. In some embodiments, modulating neurotransmission contributes to the therapeutic effects of a disclosed compound in a subject. In some embodiments, 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. J Biosci Bioeng. 2005; 100(2): 131 -143). General action potential firing activity parameters include spike rate, burst rate, and/or spike contrast. In embodiments, 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 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.
  • 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.
  • 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.
  • a disclosed compound modulates burst duration.
  • Burst duration is the mean duration of detected bursts.
  • neurotransmission is measured as the 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.
  • administering a disclosed compound increases neuroplasticity.
  • Neuroplasticity also known as neural plasticity or brain plasticity, refers to the brain's ability to change and adapt in response to experiences, learning, and environmental factors. Neuroplasticity occurs through several mechanisms, including synaptic plasticity, which involves the strengthening or weakening of connections (synapses) between neurons. Synaptic plasticity is often associated with learning and memory processes. Another form of plasticity is called structural plasticity, which involves changes in the physical structure of neurons, such as the growth of new dendritic branches or the formation of new synapses.
  • increasing neuroplasticity contributes to the therapeutic effects of a disclosed compound in a subject.
  • increasing neuroplasticity by administering a disclosed compound to a subject treats a disease or disorder in the subject.
  • Neuroplasticity can be defined in terms of neuritogenesis, spinogenesis, and synaptogenesis in neurons.
  • Neuritogenesis refers to the process by which neurons generate and extend their neurites (i.e., to form axons and dendrites). Neuritogenesis is a critical step in neural development and the formation of neuronal circuits.
  • Spinogenesis refers to the formation of dendritic spines, which are small protrusions on the dendrites of neurons. Dendritic spines are crucial for synaptic connections and play a vital role in synaptic transmission and plasticity.
  • Synaptogenesis refers to the formation of synapses, which is crucial for the establishment and refinement of neural circuits, and is a fundamental process underlying learning, memory, and information processing in the brain.
  • 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. In embodiments, a disclosed compound increases total neurite length. In embodiments, a disclosed compound increases maximum neurite length. In embodiments, a disclosed compound increases the number of neurite nodes. In embodiments, a disclosed compound increases the number of neurite extremities.
  • 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. ACS Pharmacol Transl Sei. 2020;4(2):452-460).
  • 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 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. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood to one of skill in view of the teachings herein and the knowledge in the art.
  • 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.
  • diseases of the nervous system e.g., movement disorders, neurodegenerative disorders
  • 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.
  • 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 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 I CD-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.
  • measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject- or observer-reported measures.
  • GID-7 Generalized Anxiety Disorder Scale-7
  • MADRS Montgomery-Asberg Depression Rating Scale
  • GAF Global Assessment of Functioning Scale
  • CGI Clinical Global Impression
  • a disclosed compound is used to treat a neurodevelopmental disorder.
  • a “neurodevelopmental disorder” is a neurological and/or cognitive disorder that arises during the developmental period that involves significant difficulties in the acquisition and execution of specific neurological functions (e.g., intellectual, motor, language, or social functions).
  • the neurodevelopmental disorder is a disorder of intellectual development, a developmental speech or language disorder, autism spectrum disorder, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.
  • a disclosed compound is used to treat schizophrenia or another primary psychotic disorder.
  • these disorders are characterized by significant impairments in reality and alterations in behavior manifest in positive symptoms like persistent delusions, persistent hallucinations, disorganized thinking and speech, grossly disorganized behavior, as well as experience of negative symptoms such as blunted or flat affect and avolition and psychomotor disturbances.
  • a disclosed compound is used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder.
  • a disclosed compound is used to treat catatonia.
  • catatonia refers to a category of syndromes characterized by the co-occurrence of several symptoms of decreased, increased, or abnormal psychomotor activity.
  • the catatonia is associated with another mental disorder.
  • the catatonia is induced by substances or medications.
  • a disclosed compound is used to treat a mood disorder.
  • mood disorders are categorized according to the specific type(s) of mood episodes, and their pattern over time. The primary types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes.
  • the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder), a depressive disorder, or a substance-induced mood disorder.
  • the mood disorder is a depressive disorder.
  • the depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder (formally known as dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, seasonal affective disorder, mixed depressive and anxiety disorder, or an unspecified depressive disorder.
  • depression is assessed through the Patient Health Questionnaire-9 (PHQ-9) screening tool, Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale, Beck Depression Inventory (BDI-II), Zung Self-Rating Depression Scales (SDS), Major Depression Inventory (MDI), Center for Epidemiologic Studies Depression Scale (CED-D), Rome Depression Inventory (RDI), Hamilton Rating Scale for Depression (HRSD), and Carroll Rating Scale (CRS).
  • PHQ-9 Patient Health Questionnaire-9
  • MADRS Montgomery-Asberg Depression Rating Scale
  • BDI-II Beck Depression Inventory
  • SDS Zung Self-Rating Depression Scales
  • MDI Major Depression Inventory
  • CED-D Center for Epidemiologic Studies Depression Scale
  • RDI Rome Depression Inventory
  • Hamilton Rating Scale for Depression HRSD
  • CRS Consumer Rating Scale
  • a disclosed compound is used to treat an anxiety or fear-related disorder.
  • An “anxiety disorder” refers to a class of mental disorders that induce excessive or abnormal fear, dread, or worry.
  • the anxiety disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or a substance-induced anxiety disorder.
  • a disclosed compound is used to treat an obsessive-compulsive or related disorder.
  • these disorders are characterized by repetitive thoughts and behaviors, such as cognitive phenomena (obsessions, intrusive thoughts and preoccupations).
  • the disorder is characterized by a compulsive need to accumulate possessions and distress related to discarding them (i.e., hoarding disorder).
  • the disorder is body-focused and can be characterized by recurrent and habitual actions (hair-pulling, skin-picking).
  • the disorder is obsessive-compulsive disorder, body dysmorphic disorder, olfactory reference disorder, hypochondriasis, hoarding disorder, a body-focused repetitive behavior disorder, or a substance-induced obsessive-compulsive disorder.
  • a disclosed compound is used to treat a disorder associated with stress.
  • the disorder associated with stress has an identifiable stressor that is a causal factor, like exposure to a stressful or traumatic event, or a series of such events or adverse experiences. Stressors may be within the normal range of life experiences (e.g., divorce, socioeconomic problems), or from a threatening or traumatizing experience. In general, the nature and duration of the symptoms that arise in response to the stressor can distinguish the disorder from everyday stress.
  • a disclosed compound is used to treat post-traumatic stress disorder, complex post-traumatic stress disorder, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder.
  • a disclosed compound is used to treat a dissociative disorder.
  • Dissociative disorders can be characterized by involuntary disruption or discontinuity in the normal integration of one or more of the following: identity, sensations, perceptions, affects, thoughts, memories, control over body movements, or behavior.
  • dissociative disorder symptoms can be severe, and may result in impairment in personal, social, educational, occupational or other areas of functioning.
  • a disclosed compound is used to treat dissociative neurological symptom disorder, dissociative amnesia (including amnesia with dissociative fugue and without dissociative fugue), trance disorder, possession trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization- derealization disorder.
  • a disclosed compound is used to treat a feeding or eating disorder.
  • Feeding or eating disorders generally involve abnormal eating or feeding behaviors that are not explained by another health condition, and are not developmentally appropriate or culturally sanctioned. These disorders can involve preoccupation with food as well as body weight and shape concerns.
  • a disclosed compound is used to treat anorexia nervosa (including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.
  • a disclosed compound is used to treat an elimination disorder.
  • Elimination disorders include, for example, the repeated voiding of urine into clothes or bed, and the repeated passage of feces in inappropriate places once the individual has reached a developmental age when continence is ordinarily expected.
  • a disclosed compound is used to treat enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or encopresis (including both with encopresis constipation or overflow incontinence, and encopresis without constipation or overflow incontinence).
  • a disclosed compound is used to treat a disorder of bodily distress or bodily experience.
  • Disorders of bodily stress typically involve bodily symptoms that the subject finds distressing and to which the subject devotes excessive attention.
  • Bodily integrity dysphoria typically involves a disturbance in the person’s experience of the body manifested by persistent discomfort or intense feelings of body configuration.
  • a disclosed compound is used to treat a bodily distress disorder (including mild, moderate, and severe bodily distress disorder) or body integrity dysphoria.
  • a disclosed compound is used to treat a disorder due to substance use or addictive behaviors.
  • disorders due to substance use or addictive behaviors are mental and/or behavioral disorders that develop predominantly as a result of the use of psychoactive substances (including medications and illegal or illicit substances), or specific repetitive rewarding and reinforcing behaviors.
  • a disclosed compound is used to treat disorders due to substance use (i.e., a substance use disorder, or SUD).
  • the substance use disorder is associated with alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics or anxiolytics, cocaine, stimulants (e.g., amphetamines, methamphetamines, methcathinone, synthetic cathinones, caffeine), hallucinogens, nicotine, volatile inhalants, MDMA or MDA, dissociative drugs like ketamine and phencyclidine, or another substance (including medications and non-psychoactive substances).
  • stimulants e.g., amphetamines, methamphetamines, methcathinone, synthetic cathinones, caffeine
  • hallucinogens e.g., nicotine, volatile inhalants, MDMA or MDA
  • dissociative drugs e.g., ketamine and phencyclidine
  • another substance including medications and non-psychoactive substances.
  • the substance use disorder is selected from alcohol use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalants use disorder, opioids use disorder, sedatives use disorder, hypnotics use disorder, anxiolytics use disorder, stimulants use disorder, and tobacco use disorder.
  • the substance use disorder is alcohol use disorder.
  • the substance use disorder is cannabis use disorder.
  • the substance use disorder is caffeine use disorder.
  • the substance use disorder is phencyclidine use disorder.
  • the substance use disorder is inhalant use disorder.
  • the substance use disorder is opioids use disorder.
  • the substance use disorder is sedatives use disorder.
  • the substance use disorder is hypnotics use disorder.
  • the substance use disorder is anxiolytics use disorder. In embodiments, the substance use disorder is stimulants use disorder. In embodiments, the substance use disorder is tobacco use disorder. In embodiments, the substance use disorder is alcohol use disorder, wherein said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism. In embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder).
  • a substance use disorder can be screened using a Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), the Opioid Risk Tool - OLID (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).
  • S2BI Screening to Brief Intervention
  • ASSIST Alcohol, Smoking, and Substance Involvement Screening Test
  • BTAD Brief Screener for Alcohol, Tobacco, and other Drugs
  • TAPS Tobacco, Alcohol, Prescription medication, and other Substance use
  • ORT-OUD Opioid Risk Tool - OLID Chart
  • DAST-10 Drug Abuse Screen Test
  • TAPS Tobacco, Alcohol, Prescription medication, and other Substance use
  • a disclosed compound is used to treat an impulse control disorder.
  • impulse control disorders are characterized by the repeated failure to resist an impulse, drive, or urge to perform an act that is rewarding to the subject despite negative long-term consequences, such as harm to the subject or a significant impairment in important areas of the subject’s functioning.
  • impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts.
  • a disclosed compound is used to treat pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.
  • a disclosed compound is used to treat a disruptive behavior disorder or a dissocial disorder.
  • Such disorders may be broadly characterized by persistent behavior problems that range from persistently defiant, disobedient, provocative or spiteful behaviors to behaviors that violate the rights of others or norms, rules, or laws.
  • a disclosed compound is used to treat oppositional defiant disorder (including oppositional defiant disorder with chronic irritability-anger and oppositional defiant disorder without chronic irritability-anger) or conduct-dissocial disorder (including childhood-onset conduct-dissocial disorder and adolescent-onset conduct-dissocial disorder).
  • a disclosed compound is used to treat a personality disorder.
  • Personality disorders may be generally characterized by problems in perceiving one’s identity, self-worth, accuracy of self-view, and self-discretion that is manifest in patterns of cognition, emotional experience, emotional expression, and maladaptive behavior.
  • a disclosed compound is used to treat a mild, moderate, or severe personality disorder.
  • 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, or a psychoactive substance (including medications and illicit or illegal substances).
  • a disclosed compound is used to treat a behavioral or psychological disturbance associated with dementia.
  • dementia is assessed using a Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).
  • FAQ Functional Activities Questionnaire
  • AD8 Ascertain Dementia 8
  • MMSE Mini-Cog
  • MMSE Mini-Cog
  • MSE Mini-Mental State Exam
  • MoCA Montreal Cognitive Assessment
  • NPI-Q Neuropsychiatric Inventory Questionnaire
  • a disclosed compound is used to treat a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium.
  • the syndrome associated with pregnancy or the puerperium involves significant mental and behavioral features, including a depressive symptom.
  • the disorder includes psychotic symptoms.
  • a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, with psychotic symptoms.
  • a disclosed compound is used to treat mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, without psychotic symptoms.
  • a disclosed compound is used to treat a sleep-wake disorder.
  • 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, Cheyne-Stokes breathing, and sleep-disordered breathing), disorders of the sleep-wake schedule (e.g., circadian rhythm sleep-wake disorders), abnormal movements during sleep, or problematic behavioral or psychological events that occur while falling asleep, during sleep, or upon arousal from sleep (e.g., parasomnia disorders).
  • a disclosed compound is used to treat an insomnia disorder, a hypersomnolence disorder, a sleep
  • a disclosed compound is used to treat sexual dysfunction.
  • sexual dysfunctions can be defined as syndromes wherein a subject may have difficulty experiencing personally satisfying, non-coercive sexual activities.
  • a disclosed compound is used to treat hypoactive sexual desire dysfunction, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse.
  • a disclosed compound or composition is administered together with psychotherapy, such as psychosocial or behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174; in J Consul Clin Psychol 2005; 73(2): 354-59; or in Case Reports in Psychiatry, Vol.
  • psychotherapy such as psychosocial or behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168
  • 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 one session where the patient ingests a psychedelic and is monitored, supported, or otherwise engaged by one or more trained mental health professionals while under the effects of the psychedelic (see, e.g., Schenberg 2018). Protocols have been developed for the standardization of procedures which emphasize a high degree of care (see, e.g., Johnson 2008), such as the therapeutic approach used by MAPS to treat patients with PTSD using MDMA (e.g., as described in Mithoefer 2017).
  • the psychotherapy conducted with a disclosed compound is conducted in widely spaced sessions. These sessions can be as frequently as weekly but are more often approximately monthly or less frequently. In most cases, a small number of sessions, on the order of one to three, is needed for a patient to experience significant clinical progress, as indicated, for example, by a reduction in the symptoms of the mental health disorder being treated.
  • psychotherapy comprises multiple sessions, during some of which a disclosed compound is administered (“drug-assisted psychotherapy”); in others, the patient participates in psychosocial or behavioral therapy without concomitant administration of a drug, or without administration of a disclosed compound.
  • a disclosed compound or composition is administered together with standardized psychological treatment or support, which refers to any accepted modality of standard psychotherapy or counseling sessions, whether once a week, twice a week, or as needed; whether in person or virtual (e.g., over telemedicine or by means of a web program or mobile app); and whether with a human therapist or a virtual or Al “therapist.”
  • therapist refers to a person who treats a patient using the disclosed compositions and methods, whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, although it will be understood that certain requirements will be appropriate to certain aspects of the drug-assisted therapy (e.g., prescribing, dispensing, or administering a drug, offering psychotherapeutic support).
  • a “person” may also include an Al.
  • a patient will participate in a treatment protocol or method, or be administered a disclosed composition as part of 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.
  • 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 specific type of psychotherapy is necessitated or desired.
  • the flexibility to participate in specific therapies, 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 disclosure.
  • 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.
  • personalized approaches i.e., “personalized” or “precision” medicine
  • individual characteristics including drug metabolism (e.g., CYP2D6 or CYP3A4) or individual genetic variation.
  • drug metabolism e.g., CYP2D6 or CYP3A4
  • genetic variation refers to a change in a gene sequence relative to a reference sequence (e.g., a commonly-found and/or wild-type sequence). Genetic variation may be recombination events or mutations such as substitution/deletion/insertion events like point and splice site mutations.
  • the genetic variation may be a variation in one or more cytochrome P450 enzymes that affect drug metabolism, including metabolism of a disclosed composition, and including CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5.
  • CYP enzymes include CYP1A1 , CYP1 B1 , CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1, CYP2G1 , CYP2J2, CYP2R1 , CYP2S1 , CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1 , CYP4F2, CYP4F3, CYP4F8, CYP4F11 , CYP4F12, CYP4X1 , CYP4Z1 , CYP5A1 , CYP7A1, CYP7B1, CYP8A1 , CYP8B1 , CYP11A1, CYP11 B1 , CYP11 B2, CYP17, CYP19, CYP19
  • 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.
  • a patient is tested using ordinary means known to those of skill to determine if the patient is a poor or rapid metabolizer for one or more such CYP enzymes.
  • the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which has been implicated in mood and anxiety symptoms in humans.
  • the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs.
  • SNPs single nucleotide polymorphisms
  • the FKBP5 gene has been implicated in responses to stress and trauma, and such SNPs are correlated with susceptibility to certain depression, PTSD, and anxiety disorders.
  • a genetic variation is an inclusion criteria for the administration of a disclosed compound.
  • a genetic variation is an exclusion criteria for the administration of a disclosed compound.
  • the mammal being treated has altered epigenetic regulation of a gene, the expression of which is associated with a mental health condition or susceptibility to a mental health treatment, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.
  • a mental health condition such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.
  • disclosed compounds are used to treat a neurodegenerative disorder.
  • disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a neurodegenerative disorder.
  • the disclosed compositions when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a neurodegenerative disorder.
  • neurodegenerative disorder refers to a class of progressive, chronic, and debilitating conditions characterized by the gradual loss of structure and function of neurons within the central nervous system (CNS) or peripheral nervous system (PNS). These disorders involve the degeneration, impairment, or death of neuronal cells, leading to a decline in cognitive, motor, and/or sensory abilities.
  • CNS central nervous system
  • PNS peripheral nervous system
  • Neurodegenerative disorders can be classified according to primary clinical features, e.g., dementia, parkinsonism, or motor neuron disease, anatomic distribution of neurodegeneration, e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations, or principal molecular abnormality (Dugger B, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology. 2017:9(7);a028035). These disorders may involve various etiologies, including but not limited to, presence of pathogenic proteins, age, environmental stressors, and genetic predisposition (Armstrong R. Folia Neuropathologica. 2020:58(2);93-112).
  • the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis (Charcot’s disease), chronic traumatic encephalopathy, Lytico-Bodig disease, Huntington’s disease, corticobasal degeneration, dementias including vascular dementia, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease, Parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury (TBI) including mild traumatic brain injury (mTBI).
  • TBI traumatic brain injury
  • mTBI mild traumatic brain injury
  • 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 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 a subject’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.
  • a compound is used to treat idiopathic pain.
  • 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.
  • a disclosed compound is used to treat pain associated with chemotherapy (e.g., chemotherapy associated neuropathy).
  • a 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 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). Chronic inflammation is often associated with or underlies a variety of pathological conditions, including major cardiovascular and neuropsychiatric disorders (Nichols CD. Cardiovasc Psychiatry Neurol 2009:475108).
  • 5-HT 2A serotonin receptor subtype in mediating the termination of the inflammatory response.
  • 5-HT 2A receptors are found throughout the body, including in both the central nervous system and peripheral tissues (Flanagan & Nichols. In’l Rev of Psychiatry. 2018;30(4):363-375).
  • 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 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; Cloez-Tayarani I, et al. Int Immunol. 2003 Feb; 15(2):233-40). Research on 5-HT 2A receptors at these tissues have elucidated their role in modulating the immune response (Flanagan TW, Nichols CD. Int Rev Psychiatry. 2018 Aug;30(4):363-375).
  • the potency required to achieve anti-inflammatory effects of some psychedelic compounds is at levels in the low picomolar range, approximately 500x more potent than conventional corticosteroids at their target.
  • 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-a induced expression of genes encoding intracellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), and inflammatory cytokines IL-6 and IL-10, and chemokines monocyte chemotactic protein-1 (MCP1/CCL2).
  • ICM1 intracellular adhesion molecule-1
  • VCAM1 vascular cell adhesion molecule-1
  • MCP1/CCL2 chemokines monocyte chemotactic protein-1
  • R-DOI also blocks activation and nuclear translocation of NF-KB, 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.
  • some psychedelic compounds potently suppress select key proinflammatory biomarkers, while leaving others unaffected. For the biomarkers where suppression is evident, suppression is potent and returns levels to baseline, not suppressed below baseline levels, even at relatively high doses of drug (Nichols CD. Neuropharmacol. 2022;219: 109232). Thus, some psychedelics can reduce expression of certain key inflammatory components, while leaving the immune response largely intact. This is a unique mechanism of action among known anti-inflammatory and immunomodulatory agents, and may be advantageous as it is predicted to have fewer side effects such as opportunistic infections that are associated with broad immunosuppressants like corticosteroids (id.).
  • 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.
  • 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.
  • increased expression of an inflammation response gene can be associated with chronic inflammation.
  • decreased expression of an inflammation response gene can be associated with chronic inflammation.
  • 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.
  • disclosed compounds may exert their anti-inflammatory effects due to functional selectivity at the 5-HT 2A receptor, whereby the compound engages certain amino acid residues within receptor, stabilizing it in a conformation that triggers anti-inflammatory signal transduction pathway effectors.
  • the biomarker of inflammation response gene expression is mRNA. In embodiments, the biomarker of inflammation response gene expression is a protein. In embodiments, the inflammation response gene is, or encodes, TNFa, Arg-1, IL-4, IL-5, IL-6, IL-8, IL-9, IL-1/3, ll-IA, IL-12, IL-13, IFNa, IFNb, IFNg, TGF-/3, IL-15, IL-17, IL-20, IL-22, LTA, IL-23, IL-18, VCAM1, ICAM1, MCP1 (CCL2), MMP-9, Muc5ac, Gm-csf (CSF2), CCL2, CCL5, CCL3, CCL4, CCL11, CD11a, CD3 (CD3D, CD3E, CD3G, CD3Z), CD4, CD8 (CD8A, CD8B), 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 p, TNFa, IL-15, IL-17, Arg-1 , and IL-18.
  • the inflammation response gene encodes an 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 can act as either inflammatory or anti-inflammatory cytokines under various circumstances (Zhang JM, An J. Int Anesthesiol Clin. 2007 Spring;45(2):27-37).
  • TGF-P transforming growth factor
  • 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 CCL2.
  • the biomarker of inflammation response is a CCL2 gene product.
  • the biomarker is CCL2 mRNA.
  • the biomarker is the MCP1 protein. In embodiments, the inflammation response gene is IL-5. In embodiments, the biomarker of inflammation response is a IL-5 gene product. In embodiments, the biomarker is IL-5 mRNA. In embodiments, the biomarker is the IL-5 protein. In embodiments, the inflammation response gene is IL-6. In embodiments, the biomarker of inflammation response is a IL-6 gene product. In embodiments, the biomarker is IL-6 mRNA. In embodiments, the biomarker is the IL-6 protein. In embodiments, the inflammation response gene is IL-9. In embodiments, the biomarker of inflammation response is a IL-9 gene product. In embodiments, the biomarker is IL-9 mRNA.
  • the biomarker is the IL-9 protein. In embodiments, the inflammation response gene is IL-15. In embodiments, the biomarker of inflammation response is a IL-15 gene product. In embodiments, the biomarker is IL-15 mRNA. In embodiments, the biomarker is the IL-15 protein. In embodiments, the inflammation response gene is IL-1/3. In embodiments, the biomarker of inflammation response is a IL-1/3 gene product. In embodiments, the biomarker is IL-1/3 mRNA. In embodiments, the biomarker is the IL-1 p protein. In embodiments, the inflammation response gene is Arg-1. In embodiments, the biomarker of inflammation response is an Arg-1 gene product.
  • the biomarker is Arg-1 mRNA. In embodiments, the biomarker is the Arg-1 protein. In embodiments, the inflammation response gene is Gm-csf. In embodiments, the biomarker of inflammation response is a Gm-csf gene product. In embodiments, the biomarker is Gm-csf mRNA. In embodiments, the biomarker is the Gm-csf protein. In embodiments, the inflammation response gene is Muc5ac. In embodiments, the biomarker of inflammation response is a Muc5ac gene product. In embodiments, the biomarker is Muc5ac mRNA. In embodiments, the biomarker is the Muc5ac protein. In embodiments, the inflammation response gene is MMP-9.
  • the biomarker of inflammation response is a MMP-9 gene product. In embodiments, the biomarker is MMP-9 mRNA. In embodiments, the biomarker is the MMP-9 protein. In embodiments, the inflammation response gene is TGF-fi. In embodiments, the biomarker of inflammation response is a TGF-fi gene product. In embodiments, the biomarker is TGF-fi mRNA. In embodiments, the biomarker is the TGF-0 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-y, TNFa, TNFp, 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-p.
  • 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 CX3CLI .
  • 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. In: Watanabe K & Arumugam S. eds.
  • a disclosed compound causes the level of an inflammation response biomarker in a subject to become closer to a baseline level.
  • Baseline level refers to the level of a biomarker observed in healthy populations not experiencing inflammation. Baseline levels differ among biomarkers and will be known to those of skill, or can be measured by standard techniques (Calder PC, et al. Br J Nutr. 2013 Jan; 109 Suppl 1 :S1-34).
  • a disclosed compound reduces the level of an inflammatory biomarker. In embodiments, a disclosed compound does not reduce the level of an inflammatory biomarker below baseline. In 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 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. In embodiments, a disclosed compound does not increase the level of a pro-inflammation biomarker above baseline. In 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. In embodiments, 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 a patient with an autoimmune disorder.
  • a compound is useful for treating an inflammatory condition in a patient with a compromised immune system.
  • a compound is useful for treating chronic inflammation in a patient 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
  • a disclosed compound is useful for treating an inflammatory condition in a patient 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 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
  • asthma steroid-resistant acute graft-versus-host disease
  • steroid-resistant ulcerative colitis steroid-resistant Crohn's disease
  • steroid-resistant COPD steroid-
  • 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, or varicella infection.
  • Additional 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. Arthritis can affect a single joint (monoarthritis), two to four joints (oligoarthritis), or five or more joints (polyarthritis).
  • AMD age-related macular degeneration
  • the inflammatory disorder is any of long COVID, a food allergy, an ulcer, asthma, atherosclerosis, autoimmune disorder, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, including NF-KB-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 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; celia
  • 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
  • redness et al. J Dermatol. 2021 ;48(2):130-139
  • Beck LA et al. JID Innov. 2022;2(5):100131
  • redness redness
  • persistent itching and dry skin
  • 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.
  • the dermatitis disorder is chronic photosensitivity dermatitis.
  • the dermatitis disorder is eczema.
  • the dermatitis disorder is atopic eczema.
  • the dermatitis disorder is contact eczema.
  • the dermatitis disorder is dryness eczema.
  • the dermatitis disorder is seborrheic eczema.
  • the dermatitis disorder is discoid eczema.
  • the dermatitis disorder is varicose eczema.
  • the dermatitis disorder is herpetic dermatitis. In embodiments, the dermatitis disorder is neurodermatitis. In embodiments, the dermatitis disorder is herpetic dermatitis. In embodiments, the dermatitis disorder is autosensitizing dermatitis. In embodiments, the dermatitis disorder is stasis dermatitis. In embodiments, the dermatitis disorder is purulent dermatitis. In embodiments, the dermatitis disorder is dyshidrotic eczema. In embodiments, the dermatitis disorder is follicular eczema. In embodiments, the dermatitis disorder is spongiotic dermatitis.
  • the dermatitis disorder is hand dermatitis. In embodiments, the dermatitis disorder is diaper dermatitis. In embodiments, the dermatitis disorder is occupational contact dermatitis. In 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 (e.g., Germolec et al. Methods Mol Biol. 2018;1803:57-79; Luo et al. Clin Lab. 2019 1 ;65(3)).
  • Ophthalmic Diseases and Disorders e.g., Germolec et al. Methods Mol Biol. 2018;1803:57-79; Luo et al. Clin Lab. 2019 1 ;65(3).
  • 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, 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.
  • the range for normal intraocular pressure is generally considered to be between 10 and 21 mmHg. This pressure is primarily determined by the balance between how much aqueous humour is produced in the eye and how much is drained away. Factors such as the thickness and stiffness of the cornea also play a role in influencing this pressure. Typically, intraocular pressure averages around 15 to 16 mmHg, with potential variations of up to 6 mmHg. For instance, during nighttime, this pressure often drops due to reduced aqueous humour production. Moreover, intraocular pressure can change in response to several physiological factors, including exercise, heart rate, breathing, fluid consumption, and the use of certain systemic or topical medications.
  • Elevated intraocular pressure can lead to optic nerve damage, a condition known as glaucoma. If there's no optic nerve damage, the term ocular hypertension is used.
  • Various factors can contribute to increased intraocular pressure, including conditions like orbital swelling, traumatic hyphema, blockage in the pupil, retained surgical materials, inflammation within the eye, or the use of corticosteroids.
  • High intraocular pressure is a significant risk factor for glaucoma, and conversely, glaucoma frequently involves an increase in intraocular pressure.
  • Symptoms that may arise from elevated intraocular pressure or from a combination of glaucoma and increased pressure include optic nerve damage, bleeding of the optic disc, defects in the nerve fiber layer, notching, a vertically elongated cup, uneven or progressive enlargement of the optic cup, diminished field of vision, seeing halos, blurry vision, and eye discomfort, among others.
  • a disclosed compound is used to treat glaucoma.
  • the glaucoma is 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).
  • a compound is used to treat allergic conjunctivitis, including vernal keratoconjunctivitis; 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; ulceris; cyclitis; ocular GVHD; optic neuritis; ocular Stevens Johnson Syndrome; blepharitis; ocular rosacea
  • 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 neovascularization, choroidal neovascularization, retinochoroidal neovascularization, or a combination thereof.
  • macular degeneration e.g., age-related macular degeneration
  • the ophthalmic disease is macular degeneration. In embodiments, the ophthalmic disease is keratoconjunctivitis. In embodiments, the ophthalmic disease is conjunctivitis. In embodiments, the ophthalmic disease is keratitis. In embodiments, the ophthalmic disease is diabetic retinopathy. In embodiments, the ophthalmic disease is retinopathy of prematurity. In embodiments, the ophthalmic disease is polypoidal choroidal vasculopathy. In embodiments, the ophthalmic disease is ischemic proliferative retinopathy. In embodiments, the ophthalmic disease is retinitis pigmentosa.
  • the ophthalmic disease is cone dystrophy. In embodiments, the ophthalmic disease is proliferative vitreoretinopathy. In embodiments, the ophthalmic disease is retinal artery occlusion. In embodiments, the ophthalmic disease is retinal vein occlusion. In embodiments, the ophthalmic disease is Leber's disease. In embodiments, the ophthalmic disease is retinal detachment. In embodiments, the ophthalmic disease is retinal pigment epithelial detachment. In embodiments, the ophthalmic disease is rubeosis iridis. In embodiments, the ophthalmic disease is corneal neovascularization.
  • the ophthalmic disease is retinal neovascularization. In embodiments, the ophthalmic disease is choroidal neovascularization. In embodiments, the ophthalmic disease is retinochoroidal neovascularization.
  • Step 1 5-Methoxy-4-(2-methylprop-1 -en-1 -yl)benzofuran
  • Step 4 Tert-butyl (2-(4-isobutyl-5-methoxy-2,3-di hydrobenzofuran-7-yl) ethylcarbamate
  • Step 5 2-(4-lsobutyl-5-methoxy-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine HCI (Compound 8)
  • Step 1 5-Methoxy-4-(2-methylprop-1 -en-1 -yl) benzofuran
  • Step 4 (Z)-4-l so butyl-5-methoxy-7- (2- n itro but-1 -en-1 -yl)-2, 3-dihydrobenzofuran
  • Step 4 Tert-butyl (2-(5-methoxy-2,3-dihydrobenzofuran-7-yl)ethyl)carbamate (5)
  • Step 6 Tert-butyl (2-(4-iodo-5-methoxy-2,3-dihydrobenzofuran-7-yl)ethyl)-l2-azanecarboxylate (7)
  • Step 7 Tert-butyl (4-allyl-2,5-dimethoxyphenethyl)carbamate (8)
  • Step 8 2-(4-all yl-5-methoxy-2, 3-di hyd robenzofu ran-7-y l)eth an- 1 -amine (Compound 9)
  • Step 1 2-(5-(2-methoxyethyl)-4-(2-Me-prop-1 -en-1 -yl)-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine (2)
  • Step 3 tert-butyl (2-(4-isobutyl-5-(2-methoxyethyl)-2,3-dihydrobenzofuran-7-yl)ethyl)carbamate (4)
  • Step 4 2-(4-isobutyl-5-(2-methoxyethyl)-2,3-DHB-7-yl)ethan-1 -amine HCI (Compound 44)
  • Step 3 7-bromo-5-methoxy-2,3-dihydrobenzofuran (4) [377] To a solution of 7-bromo-2,3-dihydrobenzofuran-5-ol (9.4 g, 43.7 mmol, 1 eq) in DMF (100 mL) was added K 2 C0 3 (18.1 g, 131 mmol, 3 eq) and Mel (12.4 g, 87.4 mmol, 5.44 mL, 2 eq). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was diluted with H 2 0 (1 L) at 0 °C, and then extracted with EtOAc (200 mL x 3).
  • Step 4 4-(5-methoxy-2,3-dihydrobenzofuran-7-yl)isoxazole (5)
  • Step 7 ethyl 4-cyano-4-(5-methoxy-2,3-dihydrobenzofuran-7-yl)pentanoate (8)
  • reaction mixture was quenched by addition of sat. aq. NH 4 CI (100 mL) at 0 °C.
  • the combined organic layers were extracted with EtOAc (100 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 8 5-(5-methoxy-2,3-dihydrobenzofuran-7-yl)-5-methylpiperidin-2-one (9)
  • Step 12 (S)-5-(4-isobutyl-5-methoxy-2,3-dihydrobenzofuran-7-yl)-5-methylpiperidin-2-one (13) and
  • the aqueous phase was purified by prep-HPLC (HCI condition, column: Phenomenex Luna C18 100 x 40 mm x 5 m; mobile phase: [H 2 0 (0.04% HCI)-ACN]; gradient: 1%— 60% B over 8.0 min) to give (S)-3-(4-isobutyl-5- methoxy-2,3-dihydrobenzofuran-7-yl)-3-methylpiperidine (“(S)-2CIB-2-hemiFLY-MePip”) (154 mg, 449 pmol, 71.2% yield, 98.5% purity, HCI) as a yellow amorphous solid.
  • the aqueous phase was purified by prep-HPLC (HCI condition, column: Phenomenex Luna C18 100 x 30 mm x 5 pm; mobile phase: [H 2 0 (0.04% HCI)-ACN]; gradient: 15%— 45% B over 8.0 min) to give (R)-3-(4-isobutyl-5-MeO-2,3-DHB-7-yl)- 3-methylpiperidine (“(R)-2CIB-2-hemiFLY-MePip”) (125 mg, 364 pmol, 57.8% yield, 99.2% purity, HCI) as a pale yellow amorphous solid.
  • media was aspirated and replaced with 100 pL HBSS supplemented with 20 mM HEPES (pH 7.4), loaded with 5 pM 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 pL HBSS-HEPES, and maintained in 100 pL 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 pL of test compound and read for an additional 120 s.
  • the tested exemplary compounds included 2-(4-isobutyl-5- methoxy-2,3-DHB-7-yl)ethan-1 -amine HCI, 1-(4-iBu-5-methoxy-2,3-DHB-7-yl)butan-2-amine, 2-(4-allyl-5-MeO- 2,3-DHB-7-yl)ethan-1-amine, 2-(4-Br-5-(2-methoxyethyl)-2,3-DHB- 7-yl)ethan-1 -amine, and 2-(4-iBu-5-(2-MeO- ethyl)-2,3-DHB-7-yl)ethan-1 -amine HCI, as represented in Table 2.
  • Results Assay results are provided in Table 2, with EC50 and span values for each tested compound.
  • FIG. 1 shows the calcium response elicited by increasing levels of 2-(4-isobutyl-5-methoxy-2,3- dihydrobenzofuran-7-yl)ethan-1 -amine (“2CIB-2-hemiFLY”) at 5-HT 2A and 5-HT 2B receptors.
  • FIG. 2 shows the calcium response elicited by increasing levels of 1-(4-isobutyl-5-methoxy-2,3-dihydrobenzofuran-7-yl) butan-2-amine (“4CIB-2-hemiFLY”) at 5-HT 2A and 5-HT 2B receptors.
  • FIG. 1 shows the calcium response elicited by increasing levels of 2-(4-isobutyl-5-methoxy-2,3- dihydrobenzofuran-7-yl)ethan-1 -amine (“2CIB-2-hemiFLY”) at 5-HT 2A and 5-HT 2B receptors.
  • FIG. 2 shows the calcium response elicited by increasing levels of 1-(4-
  • FIG. 3 shows the calcium response elicited by increasing levels of 2-(4-allyl-5-methoxy-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine (“2CAL-2-hemiFLY”) at 5-HT 2A and 5-HT 2B receptors.
  • FIG. 4 shows the calcium response elicited by increasing levels of 2-(4-bromo-5-(2-methoxyethyl)-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine (“2CB-2-hemiFLY-5ME) at 5-HT 2A and 5-HT 2B receptors.
  • FIG. 5 shows the calcium response elicited by increasing levels of 2-(4-isobutyl-5-(2-methoxyethyl)-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine (“2CIB-2-hemiFLY-5ME”) at 5-HT 2A and 5-HT 2B receptors.
  • the tested exemplary compounds exhibited agonism at each serotonin receptor subtype, with many having potency (EC50), in the submicromolar range. Lower EC50 values are indicative of greater potency.
  • the observed span was comparable across 5-HT 2A and 5-HT 2B for several exemplary compounds.
  • Span refers to the difference between the baseline (minimal) and maximal calcium flux responses induced by a compound, representing the efficacy of a compound, such as how strongly it can activate the receptor to mobilize intracellular calcium.
  • a larger span corresponds to a more robust receptor activation.
  • certain compounds exhibited greater span for either 5-HT 2A relative to 5-HT 2B or 5-HT 2B relative to 5-HT 2A , indicating a difference in efficacy.
  • 1-(4-isobutyl-5-methoxy-2,3-DHB-7-yl)butan-2-amine may be acting as a full agonist at 5-HT 2A with a span of about 87 (achieving a near-maximal response) but as a partial agonist at 5-HT 2B with a span of about 55 (achieving only about half of the maximal response).
  • AHR airway hyperresponsiveness
  • OVA ovalbumin
  • mice were separated into three experimental groups: 1) Naive mice were not exposed to OVA sensitization and challenge, 2) OVA mice were sensitized and challenged with the allergen OVA to induce allergic airway inflammation and hyperresponsiveness, and 3) 0.5 mg/kg exemplary compound + OVA.
  • the exemplary compound was administered to mice via intraperitoneal injection. Respiratory parameters were measured 48 hours after the final OVA exposure. Airway responsiveness to methacholine was measured using nonlnvaslve whole-body plethysmography (WBP) in unrestrained mice.
  • WBP nonlnvaslve whole-body plethysmography
  • PenH to be a reliable, sensitive measure of bronchoconstriction and a superior measure in assessing the degree of bronchoconstriction compared to other derived parameters such as box pressure or box flow (Djuric et al., Brain, Behav. Immun. 1998, 12(4), 272-84).
  • FIG. 6 shows the relationship between maximum enhanced pause (APenH) at increasing levels of methacholine for each experimental group. Higher PenH values indicate greater airway obstruction or hyperresponsiveness. The highest PenH values were detected from the OVA group, indicating increased airway constriction in response to methacholine. In contrast, the lowest delta PenH values were measured from the naive group, indicative of relatively reduced inflammation and hyperresponsivity. Surprisingly, treatment with 0.5 mg/kg 2-(4-isobutyl-5-methoxy-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine hydrochloride mitigated the hyperresponsivity associated with OVA exposure. Mice treated with the exemplary compound exhibiting PenH values comparable to that of naive mice.
  • PenH is considered a proxy to anti-inflammatory effects due to its correlation with asthma pathophysiology, e.g., reduced eosinophil infiltration, Th2 cytokine production, and airway remodeling. Whereas exaggerated bronchoconstriction was observed in the OVA group, treatment with the exemplary compound reduced PenH values to levels representative of normal airway function, indicating potent anti-inflammatory effects of 2-(4-isobutyl-5-methoxy-2,3-dihydrobenzofuran-7-yl)ethan-1 -amine hydrochloride.
  • HTR head-twitch response
  • HTR assays were performed in accordance with the methods described in Klein et al., Neuropharmacol, 2018;142:231-239, with modifications, to assess HTRs and motor activity in male C57BL/6J mice treated with exemplary compounds of the disclosure.
  • Test compounds Exemplary compounds were dissolved in saline (0.9% NaCI) and administered in doses ranging from 0 to 30 mg/kg (mpk) intraperitoneally (i.p.) in 5 ul of vehicle per g of animal mass.
  • R-DOI ((-)-R-2,5-dimethoxy-4-iodo-amphetamine) was used as positive control in the same vehicle and route of administration.
  • Raw signals were bandpass-filtered (70-110 Hz FIR filter). Filtered signals were rectified (absolute value x2), baseline-subtracted, and smoothed with a moving average. Potential HTR events were identified as maxima in the processed signal, as described by de la Fuente et al., J Neurosci Methods. 2020 Jan 16:334:108595. For spectral validation, unfiltered data segments ( ⁇ 2x event width around peaks) underwent spectral analysis.
  • FIG. 7A and FIG. 7B show HTR count and activity over a 60 minute period, with FIG. 7C and FIG. 7D presenting cumulative HTR count and activity over a 30 minute period, for mice treated with either a vehicle control or 2-(4-isobutyl-5-methoxy-2,3-DHB-7-yl)ethan-1-amine HCI (“2CIB-2-hemiFLY”) at levels ranging from 0.1 to 10 mpk.
  • the exemplary compound produced a clear increase in HTR counts over time.
  • An inverted U-shapedose-response became apparent, with doses of 1 and 3 mpk doses reaching statistical significance.
  • the ED50 was estimated at 0.34 mpk.
  • the exemplary compound produced a sustained effect on HTR at 1 mpk for the entire duration of the recording session.
  • the 10 mpk dose produced the characteristic inverted U-shape as the result of a delay in the onset of HTR stimulation.
  • the exemplary compound did not produce any meaningful effects on motor activity at the tested concentration range.
  • FIG. 8A and FIG. 8B show HTR count and activity over a 60 min period, with FIG. 8C and FIG. 8D presenting cumulative HTR count and activity over a 30 min period, for mice treated with either a vehicle control or 2-(4-isobutyl-5-(2-MeO-ethyl)-2,3-DHB-7-yl)ethan-1 -amine (“2CIB-2-hemiFLY-5ME”) at levels ranging from 0.1 to 10 mpk.
  • the compound produced a statistically significant reduction of HTR at doses of 10 and 30 mpk.
  • the HTR counts during the entire recording period neared zero at the 30 mpk dose.
  • the ID50 was estimated at 10.0 mpk.
  • the effect on HTR was matched by an apparent reduction of motor activity that reached statistical significance at 30 mpk with an estimated ID50 of 8.7 mpk, as shown in FIG. 8D.
  • FIG. 9A and FIG. 9B show HTR count and activity over a 60 minute period, with FIG. 9C and FIG. 9D presenting cumulative HTR count and activity over a 30 minute period, for mice treated with either a vehicle control or (S)-3-(4-isobutyl-5-methoxy-2,3-DHB-7-yl)-3-methylpiperidine at levels ranging from 0.1 to 10 mpk.
  • the exemplary compound did not meaningfully change HTR counts at any of the doses tested compared to the vehicle control.
  • a mild, non-significant reduction in HTR can be observed during the first 15 min at the highest doses tested that appeared to return to baseline shortly after.
  • the exemplary compound had a marked effect on motor suppression at the highest doses tested of 10 and 30 mpk with a calculated ID50 of 5.3 mpk, as shown in FIG. 9D.
  • FIG. 10A and FIG. 10B show HTR count and activity over a 60 minute period
  • FIG. 10C and FIG. 10D present the cumulative HTR count and activity over a 30 minute period
  • R-DOI produced a characteristic peak of HTR responses during the first 30 min post administration with a gradual decrease over time.
  • the effect on HTR was matched with an increase in motor activity. Both readouts attained statistical significance in the comparison of the sum of HTR and motor activity during the first 30 min post dosing.
  • HTR refers to the discrete number of head twitch events observed within a defined period
  • activity such as motor activity
  • exemplary compounds exhibited a range of activity across HTR and motor activity, with 2-(4-isobutyl-5-(2-methoxyethyl)-2,3-DHB-7-yl) ethan-1 -amine (“2CIB-2-hemiFLY-5ME”) eliciting the most robust HTR and activity, while the remaining compounds exhibited a reduced response for each metric.
  • Membrane is extracted from 5-HT 2A /HEK293, 5-HT 2B /HEK293 and 5-HT 2C /HEK293 cells.
  • Reference compounds and screening compounds are 4-fold serially diluted in 100% DMSO for 8 points. Transfer 1 pL of serial diluted references and screening compound to the assay plates. Then add 100 pL/well of membrane and 100 pL/well of radioligand 3 H-LSD. Incubate at room temperature for 1 hour. Filter the reaction mixture through the GF/C plate using PerkinElmer Filtermate Harvester and wash the plates. Dry the filter plate for 1 hour at 50 °C.
  • IP1 d2 Reagent working solution 3 pL of IP1 Tb Cryptate Antibody working solution to all wells.
  • the plates are incubated for 1 hour at room temperature and read on for fluorescence at 620 nm and 665 nm on an EnVision Multimode Plate Reader (Perkin Elmer).
  • the ratio of the acceptor and donor emission signals (665/620) are calculated for each individual well and substituted into the standard curve to obtain the log concentration of IP level.
  • the average background control signal is subtracted from each well and values are normalized to the maximal response of 5-HT at 3 pM (100%).
  • % MAX is calculated by taking the average normalized maximal response at the highest concentration tested.
  • IP1 d2 Reagent working solution 3 pL of IP1 Tb Cryptate Antibody working solution to all wells. Plates are incubated for 1 h at room temperature and read for fluorescence at 620 nm and 665 nm on an EnVision Multimode Plate Reader (PerkinElmer).
  • Results Expected results will show that disclosed compounds bind to 5-HT 2A , 5-HT 2B , and/or 5-HT 2C receptors with varying affinities, confirming their interaction with 5-HT receptor subtypes. Results will provide insight into receptor selectivity and show compounds have therapeutic applications for CNS disorders, neuroplasticity, pain, and inflammation-related conditions.
  • 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), and neuropeptides, e.g., substance P (Bignami et al. Curr Drug Targets. 2016; 17(11): 1265-74), can contribute to ocular inflammation.
  • Ocular inflammation is assessed according to known methods with modifications.
  • ocular inflammation can be assessed in induced models of uveitis (see, e.g., WO2015/074137A1 , 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 WO2015/074137A1), or in human subjects at risk of experiencing or currently experiencing such inflammation.
  • a disclosed compound such as by 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.
  • Atopic dermatitis or eczema
  • eczema is characterized by chronic inflammation, and can result in inflammatory symptoms such as irritation of the skin.
  • 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 flakiness, skin levels of Type 2 helper T-cell (Th2) and cytokines, such as IL4, IL5 and IL10.
  • 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. Samples are centrifuged, and supernatants are subjected to cytokine profiling by ELISA for the levels of biomarkers (e.g., Th2, IL4, IL5, and IL10) using protein standards for quantification.
  • biomarkers e.g., Th2, IL4, IL5, and IL10
  • Results are expected to show that administration of a disclosed compound or composition prevents, inhibitors, and/or treats the symptoms atopic dermatitis.
  • High intraocular pressure is a significant risk factor and/or symptom of various ophthalmic diseases and disorders (e.g., glaucoma) and ocular pathologies.
  • the purpose of this protocol is to assess the effects of administering a disclosed compound on intraocular pressure in an in vivo rat model.
  • test compound will be administered directly to the ocular surface of both eyes using a calibrated positive displacement pipette. Baseline and subsequent IOP measurements will be completed using the TonoLab Rebound Tonometer. IOP measurements will be completed while the animal is fully awake. Three sets of 6 IOP measurements are recorded and averaged for each eye. Animals will receive a “loading dose” series of three administrations (10 pL of a solution of test compound per administration) over a 10-minute period, i.e., 10 pL every 2-3 minutes.
  • Results may show that administration of a disclosed compound results in a reduction of IOP, which can indicate utility in treating ophthalmic diseases and disorders associated with elevated IOP.
  • liver microsomes, hepatocytes, and liver S9 fractions can be used to determine the in vitro intrinsic clearance of a compound. See, e.g., Ackley et al., Metabolic Stability Assessed by Liver Microsomes and Hepatocytes. In Yan & Caldwell (eds) Optimization in Drug Discovery. Methods Pharmacol Toxicol. Humana Press, and Richardson et al., Drug Metab Lett. 2016;10(2):83-90).
  • liver microsomal stability assay is performed according to available methods, e.g., in accordance with the methods described in US 2008/0045588 with modifications. Briefly, the assay is conducted at 1 mg per mL liver microsome protein with an NADPH-generating system in 2% NaHCO 3 (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM MgCI 2 ). 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 pL) are taken out at times 0, 15, 30, 45, and 60 min, and diluted with ice cold acetonitrile (200 pL) to stop the reactions. Samples are centrifuged at 12,000 RPM for 10 min to precipitate proteins. Supernatants are transferred to microcentrifuge tubes and stored for LC/MS/MS analysis of the degradation half-life of the test compounds.
  • Results show a measurement of the in vitro intrinsic clearance of disclosed compounds. Such data provides a prediction of the metabolic stability and clearance of the compounds.
  • hCE1 and hCE2 are Phase I drug-metabolizing enzymes of the serine hydrolase superfamily, which may hydrolyze a variety of ester-containing compounds.
  • hCE1 and hCE2 are the most extensively studied of the human CEs. They differ in their substrate specificity and tissue distribution.
  • hCE 1 is expressed in many organs especially in the liver, with low expression in the gastrointestinal tract.
  • hCE2 protein is also expressed in many extrahepatic tissues, especially in the gastrointestinal tract and at lower levels in the liver (Fukami and Yokoi. Drug Metab Pharmacokinet. 2012;27(5):466-477; Imai T. Drug Metab Pharmacokinet. 2006;21 (3):173-185).
  • Test systems for this assay include hCE1-b, hCE1-c, hCE2 expressed enzymes, and/or human liver/intestinal microsomes incubated with and without CE inhibitor.
  • concentration of test compound is 1 pM.
  • a positive control substrate (trandolapril for hCE1 ; irinotecan for hCE2, monitoring for the formation of 7-ethyl-10-hydroxycamptothecin) is also included.
  • Test compounds are introduced as 100 pL of a 10 mM DMSO stock solution. Analysis is conducted by LC-MS/MS to determine the amount of test compound remaining at each time point for each isoform, half life, and standard error of half life.
  • Results may show that certain disclosed compounds (e.g., those having a 5-carboxyalkyl or ester substituent) are substrates for hCE1 and/or hCE2 and are susceptible to hydrolysis in vivo.
  • the cells are incubated at room temperature for 20 min before the fixative is aspirated and each well washed twice with DPBS.
  • Cells are permeabilized using 0.2% Triton X-100 in DPBS for 20 minutes at room temperature without shaking. Plates are blocked with antibody diluting buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS for 1 h at room temperature. Then, plates are incubated overnight at 4 °C with gentle shaking in ADB containing a chicken anti-MAP2 antibody (1 :10,000; EnCor, CPCA-MAP2). The next day, plates are washed three times with DPBS and once with 2% ADB in DPBS.
  • ADB antibody diluting buffer
  • BSA bovine serum albumin
  • Plates are incubated for 1 h at room temperature in ADB containing an anti-chicken IgG secondary antibody conjugated to Alexa Fluor 488 (1 : 500) and washed five times with DPBS. After the final wash, 100 p L of DPBS is added per well.
  • Regions of the infralimbic cortex are microdissected according to the Allen Brain Atlas (Lein et al. Nature. 2007;445:168-176) and processed further for electron microscopy. Samples are then stained with buffered 1 .5% reduced osmium tetroxide for 45 minutes, rinsed thoroughly, further stained with 1 % aqueous uranyl acetate overnight at 4°C, dehydrated and embedded in Eponate 12TM epoxy resin. A blockface that spans from the medical cortical surface to the corpus callosum is then trimmed and 150-250 serial ultrathin sections (55 nm) are collected onto silicon chips using diamond knives (Diatome) on an ultramicrotome. Serial sections on silicon chips are loaded into a scanning electron microscope for imaging.
  • the apical tuft region is identified, and a series of images are collected from a region of interest identified on consecutive sections. Following image alignment, the datasets for each animal constitute volumes of at least 20x20x10 pm in dimension with voxel sizes of 8x8*55 nm. Cross sections of eight random dendrites are samples for the central section of each volume. Skeletons of the dendritic centerline and dendritic spines are traced by human experts. Dendritic spine densities (spines/micron) are calculated for each volume).
  • Embryos are decapitated, skin and skull gently removed and hemispheres are separated. After removing meninges and brain stem, the hippocampi are isolated, chopped with a sterile razor blade in Chop solution (Hibernate-E without Calcium containing 2% B-27) and digested in 2 mg/mL papain dissolved in Hibernate-E without Calcium for 30 minutes ( ⁇ 5 min) at 30°C. Hippocampi are triturated 10-15 times with a fire-polished silanized Pasteur pipette in Hibernate-E without Calcium containing 2% B-27, 0.01 % DNasel, 1 mg/mL BSA, and 1 mg/mL Ovomucoid Inhibitor.
  • mice cortical neurons are seeded on poly-D-lysine pre-coated 96-well plates at a density of 2.6 x 10 4 cells per well.
  • test compounds for three different time points (4 h, 8 h and 24 h), followed by a complete medium change.
  • cells are treated with 40 ng/mL of a positive control (Fibroblast Growth Factor, FGF) or vehicle control (VC) for 48 h.
  • FGF Fibroblast Growth Factor
  • VC vehicle control
  • Treated primary neurons are fixed on day 4 by addition of equal volume 4% paraformaldehyde (PFA) to the medium at room temperature (RT) for 30 minutes.
  • Cells are rinsed two times with PBS and are permeabilized with 0.1% Triton X-100 in PBS for 30 minutes at RT.
  • cells are blocked for 90 min at RT with 20% horse serum, 0.1% Triton X-100 in PBS.
  • samples are incubated with the primary antibody against Beta Tubulin Isotype III at 4°C overnight. The next day, the cells are further incubated for another 30 min at RT.
  • Results are expected to show that administration of disclosed compounds increase dendritogenesis, spinogenesis, and/or neuroplasticity.
  • the purpose of this study is to test disclosed compounds for potential neuroprotective effects in an optic nerve crush (ONC) model in rats. Animals will receive prophylactic dosing of the compounds (and optionally, one or more comparator compounds) 3 days prior to injury induction. Animals will undergo optical coherence tomography (OCT) exams starting at baseline, and again 7, 14, and 21 days after injury.
  • OCT optical coherence tomography
  • OCT retinal nerve fiber layer
  • IPL inner plexiform layer
  • Total retinal thickness using a 9x9 spider plot.
  • Animals will also undergo pupillary light reflex testing daily for up to 5 days post procedure and prior to anesthesia for OCT.
  • whole eye samples will be collected and will undergo immunofluorescent staining using Brn3a and RBPMS to stain for retinal ganglion cells (RGCs) and counterstained with DAPI. From these, RGC loss will be calculated.
  • *IV dosing may be adjusted to IP if daily dosing is required, dependent on frequency needed and vet consult.
  • Results are expected to show that administration of disclosed compounds demonstrate protective effects, as determined by retinal ganglion cell counts, and other measures described herein.
  • R 4 is H, F, Cl, Br, I, CN, NO 2 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkylthio, C r C 6 alkylthio, C 3 -C 6 cycloalkylmethyl, or — (CH 2 ) 0.3 -C(O)-O-C 1 -C 6 alkyl;
  • R 5 is C r C 6 alkoxy, -(CH 2 ) 0.3 OH, -(CH ⁇ -O- ⁇ -Cg alkyl, -(CH 2 ) M -C(O)-O-C 1 -C 6 alkyl, -(CH 2 ) M -C(O)-NH 2 , or — (CH 2 )O_ 3 -C(0)-NH-C 1 -C 6 al
  • R N is H or — CH 2 -Ar; wherein Ar is 6- to 12-membered heterocyclyl or C 6 -C 12 aryl optionally substituted by F, Cl, Br, I, OH, CrC 6 alkoxy, or phenyl; and R a is H or C ⁇ Cg alkyl; and R b is H; or R a and R b together with the intervening atoms form a 3- to 6-membered cycloalkyl; or R N and R b together with the intervening atoms form a 4- to 8-membered heterocyclyl, and R a is H or C ⁇ Cg alkyl; or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • X, Y, and Z are each independently H, F, Cl, Br, I, OH, C ⁇ Cg alkoxy, or phenyl; or X and Y are taken together to form a 4- to 6-membered heterocyclyl, and Z is H, F, Cl, Br, I, OH, C ⁇ Cg alkoxy, C 3 -C 6 cycloalkyl, or phenyl; or Y and Z are taken together to form a 4- to 6-membered heterocyclyl, and X is H, F, Cl, Br, I, OH, CrC 6 alkoxy, C 3 -C 6 cycloalkyl, or phenyl; or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, or isotopic derivative thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of embodiments 1-43, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions of embodiment 44, wherein the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration.
  • composition 46 The pharmaceutical composition of embodiment 44 or 45, wherein the composition is in unit dosage form.
  • composition of embodiment 46 comprising the compound in a total amount of between about 0.01 and 100 mg.
  • composition of embodiment 48 formulated as an aerosol, emulsion, spray, ointment, salve, gel, paste, lotion, liniment, oil, or cream.
  • composition of embodiment 48 or 49 comprising one or more pharmaceutically acceptable excipients selected from the group consisting of 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, and gelling agents.
  • pharmaceutically acceptable excipients selected from the group consisting of 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,
  • composition of any one of embodiments 44-50 further comprising 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, empathogens, psychedelics, plasticity-inducing agents, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, NMDA modulators, NMDA antagonists, and vitamins.
  • the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents,
  • a method of modulating neurotransmission in a subject comprising administering to the subject the compound of any one of embodiments 1 -43, or the composition of any one of embodiments 44-52.
  • modulating neurotransmission comprises agonizing the 5-HT 2A or 5-HT 2C receptor.
  • a method of increasing neuroplasticity in a subject comprising administering to the subject the compound of any one of embodiments 1 -43, or the composition of any one of embodiments 44-52.
  • 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 one of embodiments 1-43, or the composition of any one of embodiments 44-52.
  • 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.
  • 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.
  • inflammatory disorder is selected from the group consisting of asthma, 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.
  • 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.
  • 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%.
  • mRNA comprises Arg-1, ICAM1, VCAM1, CCL2, IL-6, IL-1 ft, Gm-csf, IL-5, IL-9, IL-15, Muc5ac, mmp9, or TGF-ft mRNA.
  • embodiment 80 The method of embodiment 78 or 79, wherein the medical condition is 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 neovascularization, choroidal neovascularization, or retinochoroidal neovascularization.
  • the medical condition is macular degeneration, keratoconjunctivitis, conjunctivitis, keratitis, diabetic retinopathy, retinopathy of pre
  • 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.
  • 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,

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Abstract

L'invention concerne de nouveaux composés, tels que des phénéthylamines ayant un pharmacophore à noyau 2,3-benzofurane substitué (c'est-à-dire "hémiFLY"). Selon certains aspects, l'invention concerne également des compositions pharmaceutiques comprenant les composés, des procédés de synthèse des composés et des procédés d'utilisation de tels composés, y compris leur administration à des sujets. Selon certains aspects, des caractéristiques utiles des composés selon l'invention comprennent une activité neuromodulatrice et/ou anti-inflammatoire, par exemple par activation de récepteurs de la sérotonine. Dans certains autres aspects, les composés sont utiles en tant qu'agents thérapeutiques pour traiter des problèmes médicaux, tels que des troubles psychiatriques et des problèmes inflammatoires.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150025063A1 (en) * 2005-07-28 2015-01-22 Duke University Antiparkinsonian Action of Phenylisopropylamines
WO2023283386A2 (fr) * 2021-07-07 2023-01-12 Arcadia Medicine, Inc. Compositions psychoactives plus fiables
US20230150963A1 (en) * 2020-06-08 2023-05-18 Tactogen Inc. Advantageous benzofuran compositions for mental disorders or enhancement

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150025063A1 (en) * 2005-07-28 2015-01-22 Duke University Antiparkinsonian Action of Phenylisopropylamines
US20230150963A1 (en) * 2020-06-08 2023-05-18 Tactogen Inc. Advantageous benzofuran compositions for mental disorders or enhancement
WO2023283386A2 (fr) * 2021-07-07 2023-01-12 Arcadia Medicine, Inc. Compositions psychoactives plus fiables

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