WO2025019403A2 - Amino-phénylméthylène-imidazolones substituées - Google Patents

Amino-phénylméthylène-imidazolones substituées Download PDF

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WO2025019403A2
WO2025019403A2 PCT/US2024/037994 US2024037994W WO2025019403A2 WO 2025019403 A2 WO2025019403 A2 WO 2025019403A2 US 2024037994 W US2024037994 W US 2024037994W WO 2025019403 A2 WO2025019403 A2 WO 2025019403A2
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compound
disorder
alkyl
pharmaceutically acceptable
tautomer
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WO2025019403A3 (fr
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Gregory DWULET
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • 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

Definitions

  • This disclosure relates in some aspects to novel compounds containing an amino-phenylmethylene-imidazolone (i.e., amino-phenylmethylidene-imidazolone) core structure.
  • the disclosure further relates to methods of synthesizing the compounds, compositions containing the compounds, and methods of using such compounds, including their administration to subjects.
  • features of the compounds include neuromodulatory activity, for example, antagonism of serotonin receptors.
  • the compounds are useful as therapeutic agents, e.g., antipsychotic agents.
  • compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof wherein: R a , R b , and R c are each independently H, C ⁇ Cg alkyl, or C ⁇ Cg haloalkyl; R 2 and R 5 are each independently H or C ⁇ Cg alkyl; R 4 is halogen or H; and is a single or double bond.
  • the compound has the structure of Formula (II),
  • the compound has the structure of Formula (III),
  • the compound has the structure of Formula (VII),
  • R a is H. In some embodiments, R a is C r Cg alkyl. In some embodiments, R a is methyl.
  • R b is H. In some embodiments, R b is C r Cg alkyl. In some embodiments, R b is methyl. In some embodiments, R b is ethyl. In some embodiments, R b is C ⁇ Cg haloalkyl.
  • R c is H. In some embodiments, R c is C ⁇ Cg alkyl. In some embodiments, R c is methyl.
  • R 2 is C ⁇ Cg alkyl. In some embodiments, R 2 is methyl.
  • R 5 is C ⁇ Cg alkyl. In some embodiments, R 5 is methyl.
  • R 4 is halo. In some embodiments, R 4 is bromo. In some embodiments, R 4 is chloro. In some embodiments, R 4 is iodo. In some embodiments, R 4 is H.
  • the compound has E geometry.
  • the compound has the structure of: or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof.
  • the compound has the structure of: or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof.
  • the compound has the structure of:
  • a compound having the structure a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof.
  • a compound having the structure a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof.
  • a compound having the structure pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof is provided.
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of any disclosed embodiment, or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method of modulating neurotransmission in a subject comprising administering to the subject the compound or pharmaceutical composition of any disclosed embodiment.
  • modulating neurotransmission comprises antagonizing the 5-HT 2A receptor.
  • a compound or pharmaceutical composition of any disclosed embodiment for use in the treatment of a medical condition.
  • 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 or pharmaceutical composition of any disclosed embodiment.
  • 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 neurodegenerative disorder, a pain disorder, or a movement disorder.
  • the medical condition is schizophrenia or a primary psychotic disorder.
  • the medical condition is schizophrenia, schizoaffective disorder, schizophreniform disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, paraphrenia, postpartum psychosis, major depressive disorder with psychotic features, a substance-induced psychotic disorder, or a psychotic disorder due to another condition.
  • FIG. 1 shows dose-response curves for 2a and 2c in the IP-One assay in antagonist mode with methiothepin (mesylate salt) as the positive control.
  • the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • alkyl includes straight or branched radicals having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds.
  • Alkyl includes all possible structural isomers.
  • the term “butyl” encompasses n-butyl, sec-butyl, isobutyl, and ferf-butyl. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” can also be used.
  • an alkyl group comprises from 1 to 10 carbon atoms, from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms.
  • the alkyl may be optionally substituted at one or more positions.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • an “effective amount” or “a therapeutically effective amount” refers to an amount of an active agent that is sufficient to provide the desired therapeutic effect at a reasonable benefit/risk ratio.
  • the effective amount can vary depending upon the subject and the disease condition being treated or health benefit sought, the weight and age of the subject, the severity of the disease condition or degree of health benefit sought, the manner of administration, and the like, all of which can readily be determined by one of ordinary skill in the art.
  • “Therapeutic effect” or “therapeutic efficacy” means the responses(s) in a mammal, and preferably a human, after treatment that are judged to be desirable and beneficial. Depending on the disorder to be treated, or improvement in mental health or functioning sought, and depending on the particular constituent(s) in the disclosed compositions under consideration, those responses may therefore differ, but would be readily understood by those of ordinary skill.
  • Measures of therapeutic effect includes any outcome measure, endpoint, effect measure, or measure of effect within clinical or medical practice or research which is used to assess the effect, both positive and negative, of an intervention or treatment, whether patient-reported (e.g., questionnaires), based on other patient data (e.g., patient monitoring), gathered through laboratory tests such as blood work, urine samples, etc., through medical examination by a doctor or other medical professional, or by digital tools or means, e.g., electronic tools such as online tools, smartphones, wireless devices, biosensors, or health apps.
  • patient-reported e.g., questionnaires
  • other patient data e.g., patient monitoring
  • laboratory tests such as blood work, urine samples, etc.
  • digital tools or means e.g., electronic tools such as online tools, smartphones, wireless devices, biosensors, or health apps.
  • 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 serotonin 2A (5-HT2A) receptor is the primary excitatory G-protein-coupled receptor in the serotonin (5-HT) receptor family, and is integral in modulating various physiological and psychological functions (Nichols DE & Nichols CD. Chem. Rev. 2008; 108(5): 1614-1641; Zhang et al. Front. Pharmacol. 2015;6:225; Carhart-Harris et al. J. Psychopharmacol. (Oxf.) 2017;31 (9): 1091— 1120).
  • the 5-HT2A receptor is highly expressed in the mammalian brain, particularly in the cortex, where it is the most abundant 5-HT receptor (Andrade R. Neuropharmacology 2011 ;61 (3):382— 386).
  • the 5-HT 2A receptor is a significant target for pharmacological intervention (Sriram K & PlayStation PA. Mol. Pharmacol. 2018;93(4):251— 258).
  • Activation of the 5-HT 2A receptor mediates the hallucinogenic effects of psychedelic compounds, such as lysergic acid diethylamide (LSD) and psilocin.
  • Psychedelic 5-HT 2A receptor agonists are under investigation for their potential to treat various medical conditions, including mental health disorders (Vollenweider FX & Preller KH. Nat. Rev. Neurosci. 2020;21 (11):611— 624).
  • some 5-HT 2A receptor agonists e.g., (R)-2,5-dimethoxy-4-iodoamphetamine
  • exert robust anti-inflammatory effects in mouse models of vascular and pulmonary inflammation Neuropharmacology.
  • 5-HT 2A receptor agonists can also increase neuroplasticity and metaplasticity, making them promising as potential therapeutics for treating neurodegenerative conditions and traumatic brain injuries, among other conditions (see, e.g., Olson DE. Biochemistry. 2022;61 (3):127— 136; Nardou et al. Nature. 2023;618(7966):790— 798; Kozlowska et al. J Neurochem. 2022;162(1 ):89— 108; Khan et al. Front. Neurol. 2021 ;12:685085.).
  • 5-HT 2A receptor antagonists are useful therapeutics and research tools.
  • 5-HT 2A receptor antagonism is a defining characteristic of many atypical antipsychotic medications used to treat schizophrenia, bipolar disorder, and depressive disorders (Casey et al. Biochem Pharmacol. 2022;200:115028).
  • 5-HT 2A receptor antagonists particularly those with high selectivity for the 5-HT 2A receptor, such as ketanserin— can be used to study psychedelic 5-HT 2A receptor agonists by mitigating or blocking their hallucinogenic effects (Vollenweider et al. NeuroReport. 1998;9(17):3897).
  • Radiolabeled ketanserin has been used in neuroimaging studies to visualize and quantify the distribution of 5-HT 2A receptors in the brain, and [ 3 H]ketanserin is an invaluable tool for radioligand binding assays used to identify new drugs that target the 5-HT 2A receptor (Paterson et al. Med Res Rev. 2013;33(1):54— 111).
  • novel compounds having an amino-phenylmethylene-imidazolone (APMI) core structure.
  • APMI amino-phenylmethylene-imidazolone
  • the compound has the structure of Formula (I), or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof, wherein:
  • R a , R b , and R c are each independently H, C r Cg alkyl, or C r Cg haloalkyl;
  • R 2 and R 5 are each independently H or C r Cg alkyl
  • R 4 is H or halogen; and single or double bond.
  • R a , R b , and R c are each independently H, C r Cg alkyl, or CrC 6 haloalkyl.
  • R a is H.
  • R a is C r Cg alkyl.
  • R a is methyl.
  • R a is ethyl.
  • R a is propyl (i.e., n-propyl or isopropyl).
  • R a is C r Cg haloalkyl.
  • R a is C r Cg fluoroalkyl.
  • R a is fluoromethyl (e.g., -CH 2 F, -CHF 2 , -CF 3 ). In some embodiments, R a is fluoroethyl. In some embodiments, R a is -CH 2 CF 3 .
  • R b is H. In some embodiments, R b is C ⁇ Cg alkyl. In some embodiments, R b is methyl. In some embodiments, R b is ethyl. In some embodiments, R b is propyl. In some embodiments, R b is C ⁇ Cg haloalkyl. In some embodiments, R b is C ⁇ Cg fluoroalkyl. In some embodiments, R b is fluoromethyl. In some embodiments, R b is fluoroethyl. In some embodiments, R b is -CH 2 CF 3 .
  • R c is H. In some embodiments, R c is C ⁇ Cg alkyl. In some embodiments, R c is methyl. In some embodiments, R c is ethyl. In some embodiments, R c is propyl (i.e., n-propyl or isopropyl). In some embodiments, R c is C ⁇ Cg haloalkyl. In some embodiments, R c is C ⁇ Cg fluoroalkyl. In some embodiments, R c is fluoromethyl. In some embodiments, R c is fluoroethyl. In some embodiments, R c is -CH 2 CF 3 .
  • R 2 is H or C ⁇ -Cg alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is C ⁇ Cg alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl.
  • R 4 is H or halo. In some embodiments of Formula (I), R 4 is H. In some embodiments, R 4 is halo. In some embodiments, R 4 is F, Cl, Br or I. In some embodiments, R 4 is F. In some embodiments, R 4 is Br. In some embodiments, R 4 is Cl. In some embodiments, R 4 is I.
  • R 5 is H or C ⁇ Cg alkyl. In some embodiments, R 5 is H. In some embodiments, R 5 is C ⁇ Cg alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is propyl.
  • tautomeric compounds may be possible for a disclosed compound, depending, e.g., on the substitution pattern of the imidazolone ring.
  • the tautomeric forms may include include:
  • a disclosed compound exists predominantly in tautomeric form A. In some embodiments, a disclosed compound exists predominantly in tautomeric form B. In some embodiments, a disclosed compound exists predominantly in tautomeric form C. In some embodiments, a disclosed compound exists in multiple tautomeric forms. In some embodiments, multiple tautomeric forms may be in equilibrium with each other.
  • Disclosed compounds may exhibit geometric isomerism around the carbon-carbon double bond that connects the imidazolinone and phenyl rings, as shown below.
  • the disclosure includes both E and Z geometric isomers.
  • the synthesis of a disclosed compound results in the selective formation of one isomer.
  • the particular synthesis used for a disclosed compound results in the formation of a mixture of E and Z isomers
  • the isomers can be separated and obtained in pure form if desired, using standard techniques in the art. Such techniques include, for example, chromatography (e.g., column chromatography, high-performance liquid chromatography, preparative thin-layer chromatography), selective crystallization, and selective derivatization.
  • Both E and Z isomers are encompassed by the present disclosure, as are mixtures of E and Z isomers, regardless of which isomer is depicted in any particular chemical structure or scheme herein.
  • a disclosed compound has E geometry.
  • a disclosed compound has Z geometry.
  • a compound of Formula (I) has E geometry.
  • a compound of Formula (I) has Z geometry.
  • a disclosed composition comprising a disclosed compound comprises the compound in a mixture of E and Z isomers.
  • the composition comprises less than about 1 % of the E isomer, or about 1 %, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or greater than about 99% of the E isomer.
  • the composition comprises less than about 1 % of the Z isomer, or about 1 %, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or greater than about 99% of the Z isomer.
  • the composition comprises the E and Z isomers in an EIZ ratio of between about 1 :100 and 100:1.
  • the compound has the structure of Formula (II), wherein R 2 , R 4 , and R 5 are as defined for Formula (I).
  • R 2 is H or CrC 6 alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is C ⁇ Cg alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl (i.e., n-propyl or isopropyl).
  • R 4 is H or halo. In some embodiments, R 4 is H. In some embodiments, R 4 is halo. In some embodiments, R 4 is F, Cl, Br or I. In some embodiments, R 4 is F. In some embodiments, R 4 is Br. In some embodiments, R 4 is Cl. In some embodiments, R 4 is I.
  • R 5 is H or C ⁇ Cg alkyl. In some embodiments, R 5 is H. In some embodiments, R 5 is C ⁇ Cg alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is propyl.
  • a compound of Formula (II) has E geometry. In some embodiments, a compound of Formula (II) has Z geometry.
  • the compound has the structure of Formula (III), wherein R 4 is as defined for Formula (I).
  • R 4 is H or halo. In some embodiments, R 4 is H. In some embodiments, R 4 is halo. In some embodiments, R 4 is F, Cl, Br or I. In some embodiments, R 4 is F. In some embodiments, R 4 is Br. In some embodiments, R 4 is Cl. In some embodiments, R 4 is I.
  • a compound of Formula (III) has E geometry. In some embodiments, a compound of Formula (III) has Z geometry.
  • the compound has the structure of Formula (IV) or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof, wherein R a , R b , and R c are each independently H, C ⁇ Cg alkyl, or C ⁇ Cg haloalkyl; and X is H or halo.
  • R a , R b , and R c are each independently H, C ⁇ Cg alkyl, or CrCg haloalkyl.
  • R a is H.
  • R a is C ⁇ Cg alkyl.
  • R a is methyl.
  • R a is ethyl.
  • R a is propyl (i.e., n-propyl or isopropyl).
  • R a is C ⁇ Cg haloalkyl.
  • R a is C ⁇ Cg fluoroalkyl.
  • R a is fluoromethyl (e.g., -CH 2 F, -CHF 2 , -CF 3 ). In some embodiments, R a is fluoroethyl. In some embodiments, R a is -CH 2 CF 3 .
  • R b is H. In some embodiments, R b is C ⁇ Cg alkyl. In some embodiments, R b is methyl. In some embodiments, R b is ethyl. In some embodiments, R b is propyl (i.e., n-propyl or isopropyl). In some embodiments, R b is C ⁇ Cg haloalkyl.
  • R b is C ⁇ Cg fluoroalkyl. In some embodiments, R b is fluoromethyl. In some embodiments, R b is fluoroethyl. In some embodiments, R b is -CH 2 CF 3 .
  • R c is H. In some embodiments, R c is C ⁇ Cg alkyl. In some embodiments, R c is methyl. In some embodiments, R c is ethyl. In some embodiments, R c is propyl (i.e., n-propyl or isopropyl). In some embodiments, R c is C ⁇ Cg haloalkyl. In some embodiments, R c is C ⁇ Cg fluoroalkyl. In some embodiments, R c is fluoromethyl. In some embodiments, R c is fluoroethyl. In some embodiments, R c is -CH 2 CF 3 .
  • X is H. In some embodiments, X is halo. In some embodiments, X is F, Cl, Br or I. In some embodiments, X is F. In some embodiments, X is Br. In some embodiments, X is Cl. In some embodiments, X is I.
  • a compound of Formula (IV) has E geometry. In some embodiments, a compound of Formula (IV) has Z geometry.
  • R a , R b , and R c are each independently H, C ⁇ Cg alkyl, or C ⁇ Cg haloalkyl;
  • R 3 , R 4 , and R 5 ’ are each independently H or C ⁇ Cg alkyl; and single or double bond.
  • R a , R b , and R c are each independently H, C ⁇ Cg alkyl, or C ⁇ Cg haloalkyl.
  • R a is H.
  • R a is C ⁇ Cg alkyl.
  • R a is methyl.
  • R a is ethyl.
  • R a is propyl (i.e., n-propyl or isopropyl).
  • R a is C ⁇ Cg haloalkyl.
  • R a is C ⁇ Cg fluoroalkyl.
  • R a is fluoromethyl (e.g., -CH 2 F, -CHF 2 , -CF 3 ). In some embodiments, R a is fluoroethyl. In some embodiments, R a is -CH 2 CF 3 .
  • R b is H. In some embodiments, R b is C ⁇ Cg alkyl. In some embodiments, R b is methyl. In some embodiments, R b is ethyl. In some embodiments, R b is propyl (i.e., n-propyl or isopropyl). In some embodiments, R b is C ⁇ Cg haloalkyl. In some embodiments, R b is C ⁇ Cg fluoroalkyl. In some embodiments, R b is fluoromethyl. In some embodiments, R b is fluoroethyl. In some embodiments, R b is -CH 2 CF 3 .
  • R c is H. In some embodiments, R c is C ⁇ Cg alkyl. In some embodiments, R c is methyl. In some embodiments, R c is ethyl. In some embodiments, R c is propyl (i.e., n-propyl or isopropyl). In some embodiments, R c is C ⁇ Cg haloalkyl. In some embodiments, R c is C ⁇ Cg fluoroalkyl. In some embodiments, R c is fluoromethyl. In some embodiments, R c is fluoroethyl. In some embodiments, R c is -CH 2 CF 3 .
  • R 3 ' is H or C ⁇ Cg alkyl. In some embodiments, R 3 ' is H. In some embodiments, R 3 ' is C r Cg alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 3 ' is ethyl. In some embodiments, R 3 ' is propyl.
  • R 4 ' is H or C r Cg alkyl. In some embodiments, R 4 ' is H. In some embodiments, R 4 ' is C r Cg alkyl. In some embodiments, R 4 ' is methyl. In some embodiments, R 4 ' is ethyl. In some embodiments, R 4 ' is propyl.
  • R 5 ' is H or C r Cg alkyl. In some embodiments, R 5 ' is H. In some embodiments, R 5 ' is C r Cg alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 ' is ethyl. In some embodiments, R 5 ' is propyl.
  • a compound of Formula (V) has E geometry. In some embodiments, a compound of Formula (V) has Z geometry.
  • the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof, wherein R a , R b , and R c are each independently H, C ⁇ Cg alkyl, or C ⁇ Cg haloalkyl.
  • R a , R b , and R c are each independently H, C ⁇ Cg alkyl, or C ⁇ Cg haloalkyl.
  • R a is H.
  • R a is C ⁇ Cg alkyl.
  • R a is methyl.
  • R a is ethyl.
  • R a is propyl (i.e., n-propyl or isopropyl).
  • R a is C ⁇ Cg haloalkyl.
  • R a is C ⁇ Cg fluoroalkyl.
  • R a is fluoromethyl (e.g., -CH 2 F, -CHF 2 , -CF 3 ). In some embodiments, R a is fluoroethyl. In some embodiments, R a is -CH 2 CF 3 .
  • R b is H. In some embodiments, R b is C r Cg alkyl. In some embodiments, R b is methyl. In some embodiments, R b is ethyl. In some embodiments, R b is propyl (i.e., n-propyl or isopropyl). In some embodiments, R b is C ⁇ Cg haloalkyl. In some embodiments, R b is C ⁇ Cg fluoroalkyl. In some embodiments, R b is fluoromethyl. In some embodiments, R b is fluoroethyl. In some embodiments, R b is -CH 2 CF 3 .
  • R c is H. In some embodiments, R c is C ⁇ Cg alkyl. In some embodiments, R c is methyl. In some embodiments, R c is ethyl. In some embodiments, R c is propyl (i.e., n-propyl or isopropyl). In some embodiments, R c is C ⁇ Cg haloalkyl. In some embodiments, R c is C ⁇ Cg fluoroalkyl. In some embodiments, R c is fluoromethyl. In some embodiments, R c is fluoroethyl. In some embodiments, R c is -CH 2 CF 3 .
  • a compound of Formula (VI) has E geometry. In some embodiments, a compound of Formula (VI) has Z geometry.
  • the compound has the structure of Formula (VII), or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof, wherein R 4 is halogen or H.
  • R 4 is H.
  • R 4 is halo.
  • R 4 is F, Cl, Br or I.
  • R 4 is F.
  • R 4 is Br.
  • R 4 is Cl.
  • R 4 is I.
  • the compound is selected from Table 1.
  • the compound has the structure of: or a pharmaceutically acceptable salt, tautomer, isotopic derivative, hydrate, or solvate thereof.
  • Disclosed compounds can be chemically synthesized according to standard techniques known to one of skill, including the following general procedures.
  • a disclosed compound can be synthesized by condensation of suitable benzaldehyde and imidazolinone precursors:
  • Suitable reaction conditions for such a condensation may include thermal conditions (e.g., heating the aryl aldehyde and imidazolinone in the absence of solvent, such as to a temperature of greater than about 150 °C), and acid- or base-catalyzed Knoevenagel condensation conditions.
  • a disclosed compound is synthesized by Knoevenagel condensation of an aryl aldehyde and an imidazolinone in glacial acetic acid.
  • a disclosed compound is synthesized by Knoevenagel condensation of an aryl aldehyde and an imidazolinone in glacial acetic acid heated above reflux temperatures (e.g., in a pressure reactor).
  • Suitable catalysts for the Knoevenagel condensation include, e.g., ammonium acetate, piperidine.
  • Chlorinated, brominated, and iodinated compounds of Formula (I) can be produced by halogenation of the corresponding 4-unsubstituted compound (i.e., wherein R 4 is H), according to standard techniques.
  • a compound wherein R 4 is Cl may be synthesized by reacting the corresponding compound in which R 4 is H with a chlorinating agent (e.g., NCS, Cl 2 ) in a suitable solvent (e.g., CH 2 CI 2 ).
  • a compound wherein R 4 is Br may be synthesized by reacting the corresponding compound in which R 4 is H with a brominating agent (e.g., NBS, Br 2 ) in a suitable solvent (e.g., CH 2 CI 2 , glacial acetic acid).
  • a compound wherein R 4 is Br may be synthesized by reacting the corresponding compound in which R 4 is H with an iodinating agent (e.g., l 2 /Ag 2 SO 4 , ICI) in a suitable solvent (e.g., EtOH, glacial acetic acid).
  • an iodinating agent e.g., l 2 /Ag 2 SO 4 , ICI
  • EtOH e.g., EtOH, glacial acetic acid
  • a fluorinated compounds of Formula (I) (i.e., wherein R 4 is F) can be synthesized by: (1) converting 2,5-dimethoxyaniline to an aryldiazonium intermediate with fluoroboric acid, followed by pyrolysis to yield 2,5-dimethoxyfluorobenzene; (2) converting 2,5-dimethoxyfluorobenzene to 4-fluoro-2,5-dimethoxybenzaldehyde using a Vilsmeier-Haack reaction; and (3) condensation with a suitable imidazolinone precursor.
  • a compound wherein R 4 is halogen can be synthesized using a halogenated benzaldehyde precursor.
  • benzaldehyde precursors are commercially available, including 4-bromo-2,5-dimethoxybenzaldehyde. If such a precursor is not commercially available, it can be readily synthesized according to standard techniques known to one of skill. For example, 4-bromo-2,5-dimethoxybenzaldehyde can be synthesized by bromination of 2,5-dimethoxybenzaldehyde (see, e.g., Example 1).
  • Subsequent alkylation of one or more of the amines can be conducted according to methods known to those of skill in the art (e.g., to install a C ⁇ Cg alkyl or C ⁇ Cg haloalkyl).
  • reaction schemes depict exemplary reaction conditions, including exemplary reagents and/or solvents, suitable alternatives are also embraced by the present disclosure.
  • HCI is depicted as an exemplary acid in the synthesis of glycocyamidine
  • other acids e.g., mineral acids, organic acids
  • adaptation of this exemplary procedure for the synthesis of disclosed compounds with different structural features by modifying precursor compounds and/or reaction conditions is within the capabilities of the person of skill.
  • compositions will be understood to also encompass pharmaceutically acceptable salts of such compounds.
  • pharmaceutically acceptable salt refers to a salt 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 the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
  • One of ordinary skill in the art can select from among a wide variety of available counterions those that are pharmaceutically acceptable.
  • exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lac
  • Certain compounds disclosed herein may contain one or more ionizable groups, such as an amine that can be quaternized (e.g., to form an ammonium). All possible ionic forms of such molecules and salts thereof are included in the present disclosure.
  • a compound described herein 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.
  • 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)-.
  • 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).
  • 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., an isotopically enriched compound (or “isotopolog”).
  • isotopes that can be incorporated into such 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, for example 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
  • substitution with heavier isotopes such as deuterium ( 2 H) can in embodiments afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopologs of a disclosed compound can generally be prepared by carrying out the procedures disclosed in the schemes or in the Examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the invention 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 of a disclosed compound comprises a biologically labile group on a functional moiety (e.g., an amine) of the compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • Suitable functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides. These functional groups can be attached to the drug molecule via a linker that is designed to be cleaved under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage. The choice of functional group depends on factors such as stability, ease of synthesis, enzymatic activity, and desired rate of prodrug conversion.
  • An individual compound of the disclosure may be administered as part of a pharmaceutical composition or formulation, but will be prepared for inclusion in such composition or formulations as isolated or purified compounds.
  • isolated purified
  • substantially pure refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced.
  • An “isolated,” “purified,” or “substantially pure” preparation of a compound is accordingly defined as a preparation having a chromatographic purity (of the desired compound) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method.
  • compositions such as pharmaceutical compositions, comprising a disclosed compound.
  • “Pharmaceutical compositions” are compositions that comprise a disclosed compound together in an amount (for example, in a unit dosage form) with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments include multiple carriers, diluents, and/or excipients.
  • Compositions can be prepared by standard pharmaceutical formulation techniques such as disclosed in, e.g., Adejare A. Remington: The Science and Practice of Pharmacy. 23rd ed. Cambridge, MA: Academic Press; 2020.; Budavari S, O’Neil M, Smith A. The Merck Index. 12th ed.
  • “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.
  • a pharmaceutical composition 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.
  • a disclosed compound employed in the methods of this invention is effective as an 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.
  • a disclosed composition may be formulated in a unit dosage form, each dosage containing a therapeutically effective amount of a disclosed compound, for example in the dosage amounts disclosed below.
  • unit dosage form refers to a physically discrete unit suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect(s), in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • Unit dosage forms are often used for ease of administration and uniformity of dosage.
  • Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof (e.g., one half a “full” dose for a “booster” dose as described below), of the pharmaceutical composition administered.
  • Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo.
  • Unit dosage forms also include ampules and vials with liquid compositions disposed therein.
  • Unit dosage forms further include compounds for transdermal administration, such as “patches” that contact the epidermis (including the mucosa) of a subject for an extended or brief period of time.
  • the disclosed compositions are formulated in a pharmaceutically acceptable oral dosage form.
  • Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like) and oral solid dosage forms.
  • the disclosed pharmaceutical compositions also may be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, comprising physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • a disclosed composition is formulated as an oral solid dosage form.
  • Oral solid dosage forms may include but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and/or any combinations thereof.
  • Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations.
  • the disclosed oral solid dosage forms may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-melt tablet. Additionally, pharmaceutical formulations may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.
  • An oral solid dosage form 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.
  • An oral solid dosage form also can comprise one or more pharmaceutically acceptable additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).
  • a compatible carrier complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).
  • Supplementary active compounds include preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents.
  • Preservatives can be used to inhibit microbial growth or increase stability of the active ingredient thereby prolonging the shelf life of the formulation.
  • Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate.
  • Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as alpha lipoic acid.
  • a disclosed composition is formulated as an oral liquid dosage form.
  • Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like.
  • These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients.
  • Solvents may be, for example, water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.
  • a liquid dosage form for oral administration may be in the form of a pharmaceutically acceptable emulsion, syrup, elixir, suspension, or solution, which may comprise 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 a disclosed composition 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 compound 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. (Swarbrick J, Boylan JC. Encyclopedia of Pharmaceutical Technology. 2nd ed. CRC Press; 2002:754-757).
  • the liquid dosage forms may comprise additives, such as one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, or (g) flavoring agents.
  • a disclosed composition may also 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 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 invention thus may comprise a disclosed compound together with one or more other active agents 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 invention is 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 invention 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 et al. Front Pharmacol.. 2019;10:1222), or the equation of Loewe additivity (Loewe S & Muischnek H. Archiv fur experimentelle Pathologie und Pharmakologie.
  • a synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford NHG & Sheiner LB. Clin Pharmacokinet. 1981 ;6:429-453) and the median-effect equation (Chou TC & Talalay P. Adv Enzyme Regul. 1984;22:27-55).
  • Sigmoid-Emax equation Holford NHG & Sheiner LB. Clin Pharmacokinet. 1981 ;6:429-453
  • the median-effect equation Chou TC & Talalay P. Adv Enzyme Regul. 1984;22:27-55.
  • a disclosed pharmaceutical composition comprises an additional active compound.
  • the additional active compound is selected from the group consisting of: amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents (e.g., psychoplastogens), monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, NMDA modulators,
  • the additional active compound is selected from the
  • 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.
  • the additional active agent compound is a 5-HT 2A receptor agonist.
  • the additional active agent compound is a tryptamine, phenethylamine, or lysergamide, such compounds being generally known in the art (Shulgin A, Shulgin A. PiHKAL: A Chemical Love Story. Berkeley, CA: Transform Press; 1991 ; Shulgin A, Shulgin A. TiHKAL: The Continuation. Berkeley, CA: Transform Press; 1997; Grob CS, Grigsby J. Handbook of Medical Hallucinogens. New York, NY: Guilford Press; 2021; Nichols DE. Psychedelics. Pharmacological Reviews. 2016;68(2):264-355; Glennon RA. Arylalkylamine Drugs of Abuse: An Overview of Drug Discrimination Studies. Pharmacology Biochemistry and Behavior. 1999;64:251-256; each of which is incorporated by reference as if fully set forth herein).
  • a pharmaceutical composition comprises 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 a 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) between about 0.01 mg/kg and 0.1 mg/kg, such as about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg about 0.08 mg/kg about 0.09 mg/kg, and about 0.1 mg/kg, as well as ranges between these values.
  • a single dose is between about 0.1 mg/kg and 1.0 mg/kg, such as about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg about 0.8 mg/kg about 0.9 mg/kg, and about 1.0 mg/kg, as well as ranges between these values.
  • a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is less than about 0.01 mg/kg, such as between about 0.001 and 0.01 mg/kg.
  • a pharmaceutical composition includes a disclosed compound, it may be present in an amount so that a single dose is greater than about 1.0 mg/kg, such as between about 1 and 10 mg/kg.
  • a pharmaceutical composition includes a disclosed compound
  • it may be present in an amount so that a single dose is between about 0.1 mg and 1.0 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, and about 1.0 mg, as well as ranges between these values.
  • a single dose is between about 1 mg and 10 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg, as well as ranges between these values.
  • a single dose is between about 10 mg and 100 mg, such as about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg, 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 greater than about 100 mg.
  • dosages may vary depending upon whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by the skilled artisan (e.g., medical or familial history).
  • Dose amount, frequency or duration may be increased or reduced, as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications.
  • the skilled artisan with the teaching of this disclosure in hand will appreciate the factors that may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.
  • the dose actually administered will be determined by a physician, in light of the relevant circumstances, including the disorder to be treated, the chosen route of administration, the actual composition or formulation administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms, and therefore any dosage ranges disclosed herein are not intended to limit the scope of the 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.
  • kits containing a pharmaceutical composition or formulation of the invention, suggested administration guidelines or prescribing information therefore, and a suitable container.
  • Individual unit dosage forms can be included in multi-dose kits or containers, pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • the kits may be 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 invention 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.
  • a disclosed compound is used to modulate neurotransmission.
  • a disclosed compound is used to treat a medical condition, such as a disease or a disorder.
  • a disclosed compound is used in the manufacture of a medicament for the therapeutic and/or the prophylactic treatment of a condition, such for the treatment of a disease or a disorder.
  • a disclosed compound is 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.
  • the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to any mammal, preferably a human. Such terms will be understood to include one who has an indication for which a compound, composition, or method described herein may be efficacious.
  • a disclosed compound or composition is orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation or transdermally administered to a subject.
  • the compound or composition when administered through one or more such routes, is useful in methods for treating a subject in need of such treatment.
  • a disclosed compound modulates 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.
  • a disclosed compound modulates monoaminergic neurotransmission by binding to and agonizing, partially agonizing, or antagonizing a monoamine receptor (e.g., any of a serotonin, dopamine, and/or norepinephrine receptor).
  • a disclosed compound modulates monoaminergic neurotransmission by binding to and agonizing, partially agonizing, or antagonizing a monoamine transporter (e.g., any of a serotonin, dopamine, and/or norepinephrine transporter).
  • a disclosed compound modulates monoaminergic neurotransmission. In some embodiments, a disclosed compound modulates serotonergic neurotransmission. In some embodiments, a disclosed compound modulates dopaminergic neurotransmission. In some embodiments, a disclosed compound modulates norepinephrine neurotransmission. In some embodiments, a disclosed compound modulates monoaminergic neurotransmission by binding to and agonizing, partially agonizing, or antagonizing a monoamine transporter (e.g., any of SERT, DAT, and/or NET).
  • a monoamine transporter e.g., any of SERT, DAT, and/or NET
  • a disclosed compound antagonizes serotonin receptors, such as serotonin-2 (5-HT 2 ) receptors.
  • the 5-HT 2 receptor family consists of the three distinct receptor subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C .
  • 5-HT ⁇ and 5-HT 2C receptors are more highly expressed in the brain than the 5-HT 2B subtype.
  • Antagonism of the 5-HT ⁇ receptor may provide therapeutic value through a variety of mechanisms, and is a common feature of many antipsychotic (e.g., atypical antipsychotic) drugs.
  • “treating” or “treatment” refers to treating a disease or disorder in a subject, 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.
  • a disclosed compound is used to treat a central nervous system (CNS) disorder.
  • CNS disorders include diseases of the nervous system (e.g., movement disorders, inflammatory disorders, neurodegenerative disorders) as well as mental, behavioral, and neurodevelopmental disorders, such as those characterized by the DSM-5, Merck Manual, ICD-11 , or other such diagnostic resources known to those of skill. i. Mental, Behavioral, or Neurodevelopmental Disorders
  • a disclosed compound or composition is used to treat a mental, behavioral, or neurodevelopmental disorder.
  • a disclosed compound or composition is administered, such as in a therapeutically effective amount, to a subject having a mental, behavioral, or neurodevelopmental disorder, thereby treating said mental, behavioral, or neurodevelopmental disorder.
  • a disclosed compound or composition when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a mental, behavioral, or neurodevelopmental disorder.
  • the ICD-11 which is incorporated by reference herein in its entirety, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant disturbance in an individual's cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning.
  • Such disorders include, but are not limited to, neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.
  • a mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11.
  • the term mental disorder (or “mental health disorder”) generally refers to a disease condition that involves negative changes in emotion, mood, thinking, and/or behavior.
  • mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotion, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of suffering.
  • mental disorder and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11, or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11 , ICD-10, DSM-5, or DSM-IV (each of which is incorporated by reference herein in its entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.
  • a disclosed compound or composition is used to treat a mental health disorder.
  • a disclosed compound or composition is administered, such as in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating said mental health disorder.
  • a disclosed compound or composition when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a mental health disorder.
  • the compounds and compositions of the invention 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 in a subject.
  • a subject has a neurodevelopmental disorder.
  • a subject is at risk of a neurodevelopmental disorder.
  • the diagnosis of a neurodevelopmental disorder and determining that a subject is at risk of a neurodevelopmental disorder will be known to those in the art.
  • Examples of a neurodevelopmental disorder, treatable using the disclosed compounds include a disorder of intellectual development, a developmental speech or language disorder, autism spectrum disorder, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder.
  • a disclosed compound is used to treat schizophrenia or another primary psychotic disorder.
  • a subject has schizophrenia or another primary psychotic disorder.
  • a subject is at risk of schizophrenia or another primary psychotic disorder.
  • the diagnosis of schizophrenia or another primary psychotic disorder and determining that a subject is at risk of schizophrenia or another primary psychotic disorder will be known to those in the art, and may include a diagnostic and/or assessment tool such as the Mini International Neuropsychiatric Interview, Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Brief Psychiatric Rating Scale, Clinical Global Impressions Scale, .
  • Examples of a psychotic disorder include schizophrenia, schizoaffective disorder, schizophreniform disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, paraphrenia, postpartum psychosis, major depressive disorder with psychotic features, a substance-induced psychotic disorder, or a psychotic disorder due to another condition.
  • the schizophrenia is paranoid schizophrenia, disorganized (i.e., hebephrenic) schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, or residual schizophrenia.
  • a disclosed compound is used to treat a mood disorder.
  • a subject has a mood disorder.
  • a subject is at risk of a mood disorder.
  • the diagnosis of a mood disorder and determining that a subject is at risk of a mood disorder will be known to those in the art.
  • Examples of a mood disorder, treatable using the disclosed compounds include 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.
  • a subject has an anxiety or fear-related disorder.
  • a subject is at risk of an anxiety or fear-related disorder.
  • the diagnosis of an anxiety or fear-related disorder and determining that a subject is at risk of an anxiety or fear-related disorder will be known to those in the art.
  • Examples of an anxiety or fear-related disorder, treatable using the disclosed compounds include 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.
  • a subject has an obsessive-compulsive or related disorder.
  • a subject is at risk of an obsessive-compulsive or related disorder. The diagnosis of an obsessive-compulsive or related disorder and determining that a subject is at risk of obsessive-compulsive or related disorder will be known to those in the art.
  • Examples of an obsessive-compulsive or related disorder, treatable using the disclosed compounds, include an 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.
  • a subject has a disorder associated with stress.
  • a subject is at risk of a disorder associated with stress.
  • the diagnosis of a disorder associated with stress and determining that a subject is at risk of a disorder associated with stress will be known to those in the art.
  • Examples of a disorder associated with stress, treatable using the disclosed compounds include 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.
  • a subject has a dissociative disorder.
  • a subject is at risk of a dissociative disorder.
  • the diagnosis of a dissociative disorder and determining that a subject is at risk of a dissociative disorder will be known to those in the art.
  • Examples of a dissociative disorder, treatable using the disclosed compounds include 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.
  • a subject has a feeding or eating disorder.
  • a subject is at risk of a feeding or eating disorder. The diagnosis of a feeding or eating disorder and determining that a subject is at risk of a feeding or eating disorder will be known to those in the art.
  • Examples of a feeding or eating disorder, treatable using the disclosed compounds, include anorexia nervosa (including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.
  • anorexia nervosa including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight
  • bulimia nervosa including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight
  • bulimia nervosa including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight
  • bulimia nervosa including anorexia with significantly low body weight
  • a disclosed compound is used to treat a disorder due to substance use or addictive behaviors.
  • a subject has a disorder due to substance use or addictive behaviors.
  • a subject is at risk of a disorder due to substance use or addictive behaviors.
  • the diagnosis of a disorder due to substance use or addictive behaviors and determining that a subject is at risk of a disorder due to substance use or addictive behaviors will be known to those in the art, and may include a diagnostic and/or assessment tool such as 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 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
  • 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).
  • Examples of a substance use disorder, treatable using the disclosed compounds include 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, wherein said alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism.
  • a disclosed compound is used to treat an impulse control disorder.
  • a subject has an impulse control disorder.
  • a subject is at risk of an impulse control disorder.
  • impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts.
  • Examples of an impulse control disorder, treatable using the disclosed compounds include 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.
  • a subject has a disruptive behavior disorder or a dissocial disorder.
  • a subject is at risk of a disruptive behavior disorder or a dissocial disorder. The diagnosis of a disruptive behavior disorder or a dissocial disorder and determining that a subject is at risk of a disruptive behavior disorder or a dissocial disorder will be known to those in the art.
  • Examples of a disruptive behavior disorder or a dissocial disorder, treatable using the disclosed compounds include 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).
  • oppositional defiant disorder including oppositional defiant disorder with chronic irritability-anger and oppositional defiant disorder without chronic irritability-anger
  • 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.
  • a subject has a personality disorder.
  • a subject is at risk of a personality disorder. The diagnosis of a personality disorder and determining that a subject is at risk of a personality disorder will be known to those in the art.
  • 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).
  • Examples of a personality disorder include 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 neurocognitive disorder.
  • a subject has a neurocognitive disorder.
  • a subject is at risk of a neurocognitive disorder.
  • the diagnosis of a neurocognitive disorder and determining that a subject is at risk of a neurocognitive disorder will be known to those in the art.
  • Examples of a neurocognitive disorder, treatable using the disclosed compounds include delirium, amnestic disorder, dementia, Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, or Lewy body disease.
  • a neurocognitive disorder, treatable using the disclosed compounds is associated with a psychoactive substance (including medications and illicit or illegal substances).
  • 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 dementia.
  • the dementia is associated with Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, Lewy body disease, a psychoactive substance (including medications and illicit or illegal substances).
  • a disclosed compound is used to treat a behavioral or psychological disturbance associated with dementia.
  • dementia is assessed using a Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).
  • FQ Functional Activities Questionnaire
  • AD8 Ascertain Dementia 8
  • MMSE Mini-Cog
  • MMSE Mini-Mental State Exam
  • MoCA Montreal Cognitive Assessment
  • NPI-Q Neuropsychiatric Inventory Questionnaire
  • a disclosed compound is used to treat a sleep-wake disorder.
  • a subject has a sleep-wake disorder.
  • a subject is at risk of a sleep-wake disorder.
  • the diagnosis of a sleep-wake disorder and determining that a subject is at risk of a sleep-wake disorder will be known to those in the art.
  • Examples of a sleep-wake disorder, treatable using the disclosed compounds include an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder.
  • a disclosed compound or composition is used to treat a neurodegenerative disorder.
  • a disclosed compound or composition is administered, such as in a therapeutically effective amount, to a subject having a neurodegenerative disorder, thereby treating said neurodegenerative disorder.
  • a disclosed compound or composition when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a neurodegenerative disorder.
  • 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).
  • the diagnosis of a neurodegenerative disorder and determining that a subject is at risk of a neurodegenerative disorder will be known to those in the art.
  • Examples of a neurodegenerative disorder, treatable using the disclosed compounds, include 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, cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease or parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury.
  • Alzheimer’s disease amyotrophic lateral sclerosis or Charcot’s disease, chronic traumatic encephalopathy, corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease or parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury.
  • a disclosed compound or composition is used to treat a pain disorder.
  • a disclosed compound or composition is administered, such as in a therapeutically effective amount, to a subject having a pain disorder, thereby treating said pain disorder.
  • a disclosed compound or composition when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a pain disorder.
  • a “pain disorder” refers to a class of medical conditions characterized by the experience of persistent or recurrent physical or psychological pain, either localized or widespread, that significantly impairs an individual's daily functioning and quality of life. These disorders may involve various etiologies, including but not limited to nociceptive, neuropathic, psychogenic, idiopathic or radicular origins.
  • a compound is used to treat neuropathic pain.
  • a compound is used to treat psychogenic pain.
  • a compound is used to treat idiopathic pain.
  • a compound is used to treat radicular pain.
  • a neurodegenerative disorder examples include both acute or chronic pain.
  • a disclosed compound is used to treat pain associated with chemotherapy (e.g., chemotherapy associated neuropathy).
  • a disclosed compound is used to treat arthritis, back pain, central pain, chronic fatigue syndrome, cluster headaches, migraine headaches, phantom limb pain, complex regional pain syndrome, neuropathic pain, compression mononeuropathy, inflammatory pain, diabetic neuropathy, fibromyalgia, focal neuropathy, herniated disc pain, or sciatica. H. Examples
  • High-performance liquid chromatography was conducted using an Agilent 1260 HPLC system with a HALO® C18 reverse phase column (2.1 x 50 mm, 2.7 pm); the column temperature was 40 °C, flow rate 1 mL/min, injection volume 0.5 pL, solvent system gradient of 90:10 to 5:95 A:B (A: 0.05% trifluoroacetic acid in water; B: 0.05% trifluoracetic acid in acetonitrile). All compounds were >95% pure by HPLC.
  • NOESY 2D Nuclear Overhauser Effect Spectroscopy
  • Disclosed compounds were evaluated in a [ 3 H]ketanserin competitive binding assay with cloned 5-HT 2A receptors stably expressed in HEK293 cells. The compounds were evaluated at concentrations from 0.4 nM to 10 M in duplicate, and dose-response curves were constructed to determine their binding constants (K).
  • the reaction mixture was filtered through GF/B plates using Perkin Elmer Filtermate Harvester, and then each plate was washed 4 times with 250 pL cold wash buffer.
  • the filter plates were dried for 1 h at 50 °C. After drying, the bottom of the filter plate wells was sealed using Perkin Elmer Unifilter-96 backing seal tape. 50 pL of Perkin Elmer Microscint 20 cocktail was added. The top of filter plates was sealed with Perkin Elmer TopSeal-A sealing film. 3 H trapped on the filter was counted using a Perkin Elmer MicroBeta2 Reader. Data were analyzed with GraphPad Prism 5.0 (GraphPad software).
  • the canonical 5-HT 2A receptor signaling pathway involves activation of G aq proteins that subsequently activate phospholipase C (PLC) (Nichols DE. Pharmacol. Ther. 2004; 101 (2): 131 -181).
  • PLC phospholipase C
  • the hydrolysis of phosphatidylinositol membrane lipids by PLC triggers a metabolic signaling cascade that ultimately results in the generation of inositol-1 ,4,5-triphosphate (IP3), inositol diphosphate (IP2), and inositol monophosphate (IP1) (Kadamur et al. Annu. Rev. Physiol.
  • the standard curve was prepared according to the manufacturer’s instructions, starting at 7,700 nM IP1 in stimulation buffer and diluted 4-fold to create 9 points in duplicate. Each point of the standard curve was added to an empty assay plate in a volume of 14pL. 14 pL of stimulation buffer was added as a negative control.
  • PAMPA membrane permeability assay
  • BBB blood-brain barrier
  • the PAMPA assay is a high-throughput screening technique that simulates the passive diffusion of compounds across the blood-brain barrier to provide early-stage predictive data on the ability of a compound to reach the CNS through passive diffusion alone (Di, L.; Kerns, E. H.; Fan, K.; McConnell, 0. J.; Carter, G. T. High Throughput Artificial Membrane Permeability Assay for Blood-Brain Barrier. Eur. J. Med. Chem. 2003, 38 (3), 223-232).
  • the plate lid was installed and the plate was incubated at 25 °C for 16 h. After incubation, 50 pL aliquots from each well of the acceptor and donor plates were transferred into a 96-well plate. 200 pL of methanol (containingWO nM alprazolam, 200nM caffeine, and 200 nM diclofenac as internal standards) was added into each well. The plate lid was reinstalled and the plate was vortexed at 750 rpm for 100 s. Each sample was then centrifuged at 3,220 g for 20 min.

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Abstract

La présente divulgation concerne, selon certains aspects, de nouveaux composés contenant une structure centrale d'amino-phénylméthylène-imidazolone (c'est-à-dire, amino-phénylméthylidène-imidazolone). Selon certains aspects, la divulgation concerne en outre des procédés de synthèse des composés, des compositions contenant les composés, et des procédés d'utilisation de tels composés, y compris leur administration à des sujets. Dans certains aspects, des caractéristiques des composés comprennent une activité neuromodulatrice, par exemple, un antagonisme de récepteurs de la sérotonine. Dans certains aspects, les composés sont utiles en tant qu'agents thérapeutiques, par exemple, en tant qu'agents antipsychotiques.
PCT/US2024/037994 2023-07-15 2024-07-15 Amino-phénylméthylène-imidazolones substituées Ceased WO2025019403A2 (fr)

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