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WO2025042885A1 - Sels et formes solides de modulateurs de récepteur de la sérotonine de benzothiophène et de benzoselenophène - Google Patents

Sels et formes solides de modulateurs de récepteur de la sérotonine de benzothiophène et de benzoselenophène Download PDF

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Publication number
WO2025042885A1
WO2025042885A1 PCT/US2024/043028 US2024043028W WO2025042885A1 WO 2025042885 A1 WO2025042885 A1 WO 2025042885A1 US 2024043028 W US2024043028 W US 2024043028W WO 2025042885 A1 WO2025042885 A1 WO 2025042885A1
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Prior art keywords
acid
compound
solid form
disorder
hci
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English (en)
Inventor
Cody DICKINSON
Jeremy Forest
David Gilles
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Kuleon LLC
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Kuleon LLC
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Publication of WO2025042885A1 publication Critical patent/WO2025042885A1/fr
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    • 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
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D345/00—Heterocyclic compounds containing rings having selenium or tellurium atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the solid form is a polymorph of the free base form of the compound.
  • the solid form is a salt, and maybe a polymorph of the salt.
  • the salt may be formed from an acid selected from hydrochloric acid, fumaric acid, galactaric (mucic) acid, naphthalene-1 ,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane-1 ,2-disulfonic acid, lactobionic acid, p- toluenesulfonic acid, D- glucoheptonic acid, thiocyanic acid, (-)-L-pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, D-gluconic acid, benzenesulfonic acid, D,L-lactic acid, oxalic acid, ole
  • the solid form may be a crystalline solid, a hydrate, or a combination thereof.
  • the crystalline solid may be substantially a single form, such as a polymorph form.
  • the polymorph may be selected to have one or more desired properties, particularly improved properties, such as physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.
  • the one or more desired properties may comprise melting point, glass transition temperature, flowability, thermal stability, mechanical stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.
  • compositions comprising a solid form of a disclosed compound, and a pharmaceutically acceptable excipient.
  • the method comprises administering to a subject an effective amount of a solid form of at least one of the foregoing solid forms, or a pharmaceutical composition thereof.
  • the subject is suffering from a neurological disease or a psychiatric disorder, or both, such as a neurodegenerative disorder.
  • the neurological disorder or psychiatric disorder, or both may comprise depression, addiction, anxiety, or a post-traumatic stress disorder, and/or the neurological disorder or psychiatric disorder, or both, may comprise treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis, obesity or other eating disorders, or a substance use disorder such as alcohol, tobacco, opioids, amphetamine, and methamphetamine.
  • the neurological disorder or psychiatric disorder, or both comprises stroke, traumatic brain injury, or a combination thereof.
  • the method may comprise further comprising administering an effective amount of an empathogenic agent and/or a 5-HT2A antagonist to the subject.
  • the 5-HT2A antagonist may be selected from MDL-11 ,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741 , SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin.
  • the method may further comprise administering a compound described herein to modulate one or more serotonin receptor subtypes in a synergistic manner.
  • the method comprises administering at least one compound selected from 4-hydroxy-3- (dimethylaminoethyl)-benzoselenophene, 4-acetoxy-3-(dimethylaminoethyl)-benzoselenophene,
  • 5-HT 2 A and/or 5-HT 2 B receptor antagonists are examples of 5-HT 2 A and/or 5-HT 2 B receptor antagonist.
  • administering the solid form of the compound comprises oral, intravenous, parenteral, or topical administration.
  • oral administration is used, but in other particular embodiments, administration is by injection, inhalation, intraocular, intravaginal, intrarectal ortransdermal route.
  • Figure 1 shows a single crystal structure drawing of Solid Form A of Compound I HCI, as described in Example 17.
  • Figure 2 shows a single crystal structure drawing of Solid Form B of Compound II HCI, as described in Example 18.
  • Figure 3 shows an XRPD pattern of Solid Form A of Compound I HCI, as described in Example 19.
  • Figure 4 shows an XRPD pattern of Solid Form A of Compound I HCI with Rietveld refinement, as described in Example 19.
  • Figure 5 shows an XPRD pattern of Solid Form B of Compound II HCI after the additional grinding, as described in Example 19.
  • Figure 6 shows a an XPRD pattern of Solid Form B of Compound II HCI after the additional grinding with Rietveld refinement, as described in Example 19.
  • administering refers to any suitable mode of administration, including, oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini- osmotic pump, to the subject.
  • a slow-release device e.g., a mini- osmotic pump
  • Compound VIII "4-hydroxy-3-(dimethylaminoethyl)-benzoselenophene” (aka SelenopsilocinTM or SelenopsilTM) refers to Compound IX having the following structure:
  • Subject refers to an animal, such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human subject.
  • “Therapeutically effective amount” or “therapeutically sufficient amount” or “effective or sufficient amount” refers to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.
  • Neuronal plasticity refers to the ability of the brain to change its structure and/or function continuously throughout a subject's life. Examples of the changes to the brain include, but are not limited to, the ability to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses.
  • Brain disorder refers to a neurological disorder which affects the brain's structure and function.
  • Brain disorders can include, but are not limited to, Alzheimer's, Parkinson's disease, psychological disorder, depression, treatment resistant depression, addiction, anxiety, post- traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis, stroke, traumatic brain injury, and substance use disorder (e.g., alcohol, tobacco, opioids, amphetamine and methamphetamine).
  • substance use disorder e.g., alcohol, tobacco, opioids, amphetamine and methamphetamine.
  • Combination therapy refers to a method of treating a disease or disorder, wherein two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents.
  • the compounds of the invention can be used in combination with other pharmaceutically active compounds.
  • the compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy.
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • Neurotrophic factors refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.
  • Modulate or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule.
  • agonists, partial agonists, antagonists, and allosteric modulators e.g., a positive allosteric modulator
  • a G protein-coupled receptor e.g., 5-HT2c
  • Agonism refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.
  • “Agonist” refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response.
  • “5-HT2C agonist” can be used to refer to a compound that exhibits an EC50 with respect to 5-HT2C activity of no more than about 1 00 mM.
  • the term “agonist” includes full agonists or partial agonists.
  • “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor.
  • Partial agonist refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.
  • “Positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.
  • Antagonist refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur.
  • Antagonist or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.
  • composition refers to a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation.
  • “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject.
  • Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.
  • binders include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.
  • Solid forms of Compounds I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms of Compounds I through XII and methods of administering the solid forms of Compounds I through XII.
  • the solid form of the compound is a crystalline form of the compounds described herein. In some embodiments, the solid form of the compound is a salt of the compound. In some embodiments, the solid form of a compound selected from Compounds I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII is a polymorph, such as a polymorph of the free base compound or a polymorph of the salt. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.
  • the solid form of a compound selected from Compounds I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII comprises a salt of said compound.
  • Suitable salts include a pharmaceutically acceptable salt at least one of those compounds.
  • the salt may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic acids such as formic
  • Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, et
  • the salt may be formed using an acid from Table 1.
  • the acid salts of the compounds disclosed herein can have any suitable stoichiometric ratio of acid to the compound.
  • the molar ratio of acid to the compound is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to the compound of from about 0.5 to about 2, such as about 0.5, about 1 or about 2.
  • any one of Compounds I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII of the present disclosure are in a solid form.
  • the solid form may be a crystalline form or an amorphous form.
  • the solid form is a crystalline form, such as a polymorph.
  • the solid form of the compound is a salt.
  • the solid form is a crystalline salt form of the compound.
  • solid forms of Compounds I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII such as crystalline forms including salt and non-salt crystalline forms of the compounds, may exist in more than one crystal form. Such different forms are referred to as polymorphs.
  • the disclosed compounds are particular polymorphs of Compounds I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII or a salt form of Compounds I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII.
  • the solid form of the compounds disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of a disclosed compound that provides one or more desired properties.
  • the crystalline form offers advantages over the amorphous form of the molecule.
  • the disclosed polymorph offers improved properties as compared to another polymorph of the target compound.
  • the compound may be a salt or free base (e.g., zwitterionic) compound.
  • the one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles; and/or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and/or half-life.
  • physical properties including but not limited to, melting point, glass transition temperature, flowability, and/or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.
  • chemical properties such as, but not limited to, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles
  • the desired polymorph may be produced by techniques known to persons of ordinary skill in the art. Such techniques include, but are not limited to, crystallization in particular solvents and/or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and/or complexing with an inert agent.
  • a precipitation agent such as a salt, glycol, alcohol, etc.
  • co-crystallization such as a salt, glycol, alcohol, etc.
  • lyophilization such as a salt, glycol, alcohol, etc.
  • spray drying such as g., freeze drying, and/or complexing with an inert agent.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the solid forms of Compounds I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII, illustrated above, and a pharmaceutically acceptable excipient.
  • Such compositions are suitable for administration to a subject, such as a human subject.
  • compositions of the present disclosure can be prepared in a wide variety of oral, parenteral and topical dosage forms.
  • Oral preparations include tablets, pills, powder, capsules, lozenges, cachets, slurries, suspensions, etc., suitable for ingestion by the patient.
  • the compositions of the present disclosure can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the compositions of the present disclosure can be administered transdermally.
  • compositions of this disclosure can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995).
  • the present disclosure also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and the solid form a compound of the present disclosure.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington's").
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 70% or 10% to 70% of the compounds of the present disclosure.
  • Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from com, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross- linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the compounds of the present disclosure are dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include suspensions, for example, water or water/propylene glycol suspensions.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty
  • the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p- hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
  • preservatives such as ethyl or n-propyl p- hydroxy benzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as sucrose, aspartame or saccharin
  • sweetening agents such as sucrose, aspartame or saccharin.
  • Formulations can be adjusted for osmolarity.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include suspensions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Oil suspensions can be formulated by suspending the compound of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these.
  • the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
  • These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
  • an injectable oil vehicle see Minto, J Pharmacol. F,xp. Ther. 281 :93-102, 1997.
  • the pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
  • compositions of the present disclosure can also be delivered as microspheres for slow release in the body.
  • microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J Biomater Sci. Polym. Ed 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J Phann. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months.
  • the pharmaceutical compositions of the present disclosure can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ.
  • parenteral administration such as intravenous (IV) administration or administration into a body cavity or lumen of an organ.
  • the formulations for administration will commonly comprise a solution or suspension of the compositions of the present disclosure dissolved or suspended in a pharmaceutically acceptable carrier.
  • acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables.
  • compositions of the present disclosure can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs.
  • the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenteral ly-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
  • the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, for example, by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
  • liposomes particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo.
  • Al-Muhammed J Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro,Am. J Hosp. Pharm. 46:1576-1587, 1989.
  • compositions of the present disclosure can be administered by any suitable means, including oral, parenteral and topical methods.
  • Transdermal administration methods by a topical route, can be formulated as applicator sticks, suspensions, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the compounds of the present invention.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the compound of the present invention can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, and the like as is known to those of ordinary skill in the art.
  • Suitable dosage ranges for the compounds disclosed herein include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg.
  • Suitable dosages for the compound of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200,300,400, 500, 600, 700, 800, 900 or 1000 mg.
  • the compounds disclosed herein can be administered at any suitable frequency, interval and duration.
  • the compounds can be administered once an hour, or two, three or more times an hour, once a day, or two, three, or more times per day, or once every 2, 3, 4, 5, 6, or 7 days, so as to provide the preferred dosage level.
  • representative intervals include 5, 10, 15, 20, 30, 45 and 60 minutes, as well as 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours.
  • the compound of the present invention can be administered once, twice, or three or more times, for an hour, for I to 6 hours, for I to 12 hours, for 1 to 24 hours, for 6 to 12 hours, for 12 to 24 hours, for a single day, for 1 to 7 days, for a single week, for 1 to 4 weeks, for a month, for 1 to 12 months, for a year or more, or even indefinitely.
  • composition can also contain other compatible therapeutic agents.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in modulating a glucocorticoid receptor, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • the compounds of the present disclosure can be co-administered with a second active agent.
  • Co-administration includes administering the compound of the present disclosure and active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other.
  • Co-administration also includes administering the compound of the present disclosure and active agent simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
  • the compound of the present disclosure and the active agent can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.
  • co-administration can be accomplished by co-formulation, such as by preparing a single pharmaceutical composition including both the compound of the present disclosure and a second active agent.
  • the compound of the present disclosure and the second active agent can be formulated separately.
  • the disclosed compounds and the second active agent can be present in the compositions of the present disclosure in any suitable weight ratio, such as from about 1:100 to about 100: 1 (w/w), or about 1 :50 to about 50: 1, or about 1 :25 to about 25: 1 , or about 1 :10 to about 10:1 , or about 1:5 to about 5:1 (w/w).
  • the compound of the present disclosure and the second active agent can be present in any suitable weight ratio, such as about 1: 100 (w/w), 1:50, 1:25, 1 :10, 1:5, 1 :4, 1 :3, 1 :2, 1:1, 2:1, 3:1 , 4:1 , 5:1, 10:1, 25:1 , 50:1 or 100:1 (w/w).
  • suitable weight ratio such as about 1: 100 (w/w), 1:50, 1:25, 1 :10, 1:5, 1 :4, 1 :3, 1 :2, 1:1, 2:1, 3:1 , 4:1 , 5:1, 10:1, 25:1 , 50:1 or 100:1 (w/w).
  • Other dosages and dosage ratios of the compound of the present disclosure and the active agent are suitable in the compositions and methods disclosed herein.
  • the solid forms of any of the compounds of the present disclosure can be used for increasing neuronal plasticity.
  • the compounds of the present disclosure can also be used to treat any brain disease.
  • the compounds of the present disclosure can also be used for increasing at least one of translation, transcription or secretion of neurotrophic factors.
  • a compound of the present disclosure is used to treat neurological diseases.
  • the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the neurological disease is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neurological disease is a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer's disease, Alzheimer’s psychosis, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).
  • the neurological disease is a migraine or cluster headache.
  • the neurological disease is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease.
  • the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post- traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.
  • addiction e.g., substance use disorder
  • the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.
  • a compound of the present disclosure is used for increasing neuronal plasticity. In some embodiments, the compounds described herein are used for treating a brain disorder. In some embodiments, the compounds described herein are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors.
  • the present disclosure provides a method of treating a disease, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure.
  • the disease is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps.
  • the present invention provides a method of treating a disease of women's reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.
  • the compounds of the present disclosure have activity as 5-HT2 C , 5-HT 2 A and/or 5-HT 2 B modulators.
  • the compounds of the present disclosure elicit a biological response by activating the 5-HT 2C receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT 2C receptor), while antagonizing the 5-HT 2A and/or 5-HT 2B receptors.
  • the compounds of the present disclosure elicit a biological response by activating the 5-HT 2 A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT 2 A receptor).
  • the compounds of the present disclosure are 5- HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity).
  • the compounds of the present disclosure are selective tyrosine kinase B (TrkB) modulators and promote neural plasticity (e.g., cortical structural plasticity).
  • TrkB selective tyrosine kinase B
  • promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof.
  • increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
  • the 5-HT 2A modulators are non- hallucinogenic.
  • non-hallucinogenic 5-HT 2A modulators e.g., 5- HT 2A agonists
  • the 5-HT 2A modulators are non- hallucinogenic.
  • non-hallucinogenic5-HT 2 A modulators e.g., 5- HT 2A antagonists
  • the 5-HT2C modulators e.g., 5-HT2C agonists
  • the 5-HT2C modulators are non- hallucinogenic.
  • non-hallucinogenic 5-HT 2 c modulators e.g., 5- HT 2 c agonists
  • the compounds described herein are 5-HT 2 c agonists (e.g., full or partial agonists) that exhibit antagonistic activity (e.g., full or partial) at 5-HT 2 A-
  • the compounds described herein are 5-HT2C agonists (e.g., full or partial agonists) that exhibit antagonistic activity (e.g., full or partial) at 5-HT2B.
  • the hallucinogenic potential of the compounds described herein is assessed in vitro.
  • the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs.
  • the compounds described herein elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.
  • serotonin receptor modulators such as modulators of serotonin receptor 2C (5-HT2C modulators, e.g., 5-HT2C agonists), are used to treat a brain disorder.
  • the presently disclosed compounds can function as 5-HT2C agonists alone, or in combination with a second therapeutic agent that also is a 5-HT 2 c modulator. In such cases the second therapeutic agent can be an agonist or an antagonist.
  • Serotonin receptor modulators useful as second therapeutic agents for combination therapy as described herein are known to those of skill in the art and include, without limitation, MDL- 11 ,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741 , SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221 , nefazodone, MDL- 100,907, pimavanserin, nelotanserin and lorcaserin.
  • the serotonin receptor modulator used as a second therapeutic is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof
  • the serotonin receptor modulator is administered prior to a compound disclosed herein, such as about three or about hours prior administration of a compound disclosed herein.
  • the serotonin receptor modulator is administered at most about one hour prior to the presently disclosed compound.
  • the second therapeutic agent is a serotonin receptor modulator.
  • the second therapeutic agent serotonin receptor modulator is provided at a dose of from about 10 mg to about 350 mg.
  • the serotonin receptor modulator is provided at a dose of from about 20 mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 10 mg to about 100 mg. In certain such embodiments, the compound of the present disclosure is provided at a dose of from about 10 mg to about 100 mg, or from about 20 mg to about 200 mg, or from about 15 mg to about 300 mg, and the serotonin receptor modulator is provided at a dose of about 10 mg to about 100 mg.
  • non-hallucinogenic 5-HT 2 c modulators e.g., 5-HT 2 c agonists
  • the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT 2C receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
  • non-hallucinogenic 5-HT 2 c modulators are used for increasing neuronal plasticity.
  • non-hallucinogenic 5-HT 2 c modulators are used for treating a brain disorder.
  • non-hallucinogenic 5-HT 2 c modulators are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors.
  • the 5- HT2C modulators increase neuronal activity and/or can be used for treating a brain disorder by modulating a TrkB receptor (e.g., TrkB agonist).
  • compounds of the present disclosure are “multifunctional” 5-HT2C agonists that also exhibit antagonistic activity at 5-HT2A, which induces a synergistic effect that can be therapeutically effective at treating certain diseases and disorders, such as psychotic disorders (e.g., schizophrenia) and addiction (e.g., cocaine and/or methamphetamine use disorder(s)).
  • the 5-HT2C agonists also exhibit antagonistic activity at 5-HT2B.
  • the presently disclosed compounds are given to patients in a low dose that is lower than would produce noticeable psychedelic effects but high enough to provide a therapeutic benefit.
  • This dose range is predicted to be between 200 pg (micrograms) and 2 mg.
  • Neuronal plasticity refers to the ability of the brain to change structure and/or function throughout a subject's life. New neurons can be produced and integrated into the central nervous system throughout the subject's life. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.
  • increasing neuronal plasticity by treating a subject with one or more of the disclosed compound can treat neurodegenerative disorder, Alzheimer's, Parkinson's disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis, stroke, traumatic brain injury, or substance use disorder.
  • the present disclosure provides methods for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of the present disclosure. In some embodiments, increasing neuronal plasticity improves a brain disorder described herein.
  • a compound of the present disclosure is used to increase neuronal plasticity.
  • the compounds used to increase neuronal plasticity have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • decreased neuronal plasticity is associated with a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neuropsychiatric disease includes, for example, migraine, cluster headache, post- traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder).
  • brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • the experiment or assay to determine increased neuronal plasticity of any compound of the present disclosure is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentrationresponse experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2A binding assay, a 5-HT2C agonist assay, a 5-HT2c antagonist assay, a TrkB agonist assay, a TrkB antagonist assay, or a 5-HT2A blocking experiment (e.g., ketanserin blocking experiments).
  • the experiment or assay to determine the hallucinogenic potential of any compound of the present invention is a mouse head- twitch response (HTR) assay.
  • HTR mouse head- twitch response
  • the present disclosure provides a method for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound disclosed herein.
  • the present disclosure provides a method of treating a disease, including administering to a subject in need thereof, a therapeutically effective amount of any of the compounds described in the present disclosure.
  • the disease is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps.
  • the present disclosure provides a method of treating a disease of women's reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.
  • the present disclosure provides a method of treating a brain disorder, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the present disclosure provides a method of treating a brain disorder with combination therapy, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure and at least one additional therapeutic agent.
  • 5-HT 2 A modulators e.g., 5-HT 2 A agonists
  • 5-HT 2C modulators e.g., 5-HT 2 C agonists
  • TrkB modulators e.g., TrkB agonists
  • the brain disorders comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT 2 A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
  • a compound of the present disclosure is used to treat brain disorders.
  • the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the brain disorder is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, panic disorder, suicidality, schizophrenia, Alzheimer’s psychosis, and addiction (e.g., substance abuse disorders such as amphetamine use and methamphetamine use).
  • brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • the present disclosure provides a method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.
  • the brain disorder is a neurodegenerative disorder, Alzheimer's, Parkinson's disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.
  • the brain disorder is a neurodegenerative disorder, Alzheimer's, or Parkinson's disease.
  • the brain disorder is a psychological disorder, depression, addiction, anxiety, or a post-traumatic stress disorder.
  • the brain disorder is depression.
  • the brain disorder is addiction.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury or substance use disorder.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.
  • the brain disorder is stroke or traumatic brain injury.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder.
  • the brain disorder is schizophrenia.
  • the brain disorder is alcohol use disorder.
  • the method further comprises administering one or more additional therapeutic agent that is lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Ability), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil),
  • additional therapeutic agent
  • a second therapeutic agent that is an empathogenic agent is administered.
  • suitable empathogenic agents for use in combination with the present solid forms include phenethylamines, such as 3,4-methylene-dioxymethamphetamine (MDMA), and analogs thereof.
  • MDMA 3,4-methylene-dioxymethamphetamine
  • Other suitable empathogenic agents for use in combination with the presently disclosed compounds include, without limitation:
  • MDAL N-Allyl-3,4-methylenedioxy-amphetamine
  • MDBU N-Butyl-3,4-methylenedioxyamphetamine
  • MDCPM N-Cyclopropylmethyl-3,4-methylenedioxyamphetamine
  • MDDM N,N-Dimethyl-3,4-methylenedioxyamphetamine
  • MDE N-Ethyl-3,4-methylenedioxyamphetamine
  • MDHOET N-(2-Hydroxyethyl)-3,4-methylenedioxy amphetamine
  • MDIP N-lsopropyl-3,4-methylenedioxyamphetamine
  • MDMC N-Methyl-3,4-ethylenedioxyamphetamine
  • MDMEO N-Methoxy-3,4-methylenedioxyamphetamine
  • MDMEOET N-(2-Methoxyethyl)-3,4-methylenedioxyamphetamine
  • MDMP 3,4- Methylenedioxy-N-methylphentermine
  • MDPEA 3,4-Methylenedioxyphenethylamine
  • MDPH 3,4-methylenedioxyphenethylamine
  • MDPL N-Propargyl-3,4-methylenedioxyamphetamine
  • MDAI Methylenedioxy-2-aminoindane
  • Methylone also known as "3,4-methylenedioxy-N-methylcathinone
  • Ethylone also known as 3,4-methylenedioxy-N-ethylcathinone
  • GHB Gamma Hydroxybutyrate or sodium oxybate
  • MDPR N-Propyl-3,4-methylenedioxyamphetamine
  • the compounds of the present disclosure are used in combination with the standard of care therapy for a neurological disease described herein.
  • the standard of care therapies may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof.
  • Nonlimiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole.
  • Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. Additional examples of standard of care therapeutics are known to those of ordinary skill in the art.
  • Neurotrophic factors refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.
  • Increasing at least one of translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain.
  • increasing at least one of translation, transcription, or secretion of neurotrophic factors can increase neuronal plasticity.
  • increasing at least one of translation, transcription, or secretion of neurotrophic factors can promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and/or increasing dendritic spine density.
  • the compound described herein are used to increase at least one of translation, transcription, or secretion of neurotrophic factors.
  • a compound of the present disclosure is used to increase at least one of translation, transcription, or secretion of neurotrophic factors.
  • increasing at least one of translation, transcription or secretion of neurotrophic factors treats a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).
  • the experiment or assay used to determine increase translation of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.
  • the experiment or assay used to determine increase transcription of neurotrophic factors includes gene expression assays, PCR, and microarrays.
  • the experiment or assay used to determine increase secretion of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.
  • the present disclosure provides a method for increasing at least one of translation, transcription or secretion of neurotrophic factors, comprising contacting a neuronal cell with a compound disclosed herein.
  • Embodiment 1 wherein the compound is a salt.
  • Embodiment 3 The solid form of Embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-1 ,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane-1,2-disulfonic acid, lactobionic acid, p- toluenesulfonic acid, D-glucoheptonic acid, thiocyanic acid, (-)-L-pyroglutamic acid, methanesulfonic acid, L-malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, D- gluconic acid, benzenesulfonic acid, D,L-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, L- aspartic acid,
  • Embodiment 4 The solid form of Embodiment 3, wherein the stoichiometric ratio of acid to the selected compound is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.
  • Embodiment 3 wherein the stoichiometric ratio of acid to the selected compound is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.
  • Embodiment 6 The solid form of Embodiment 3, wherein the stoichiometric ratio of acid to the selected compound is selected from about 0.5, 1 and 2 molar equivalents of the acid.
  • Embodiment 1 wherein the solid form is a free base form of the selected compound.
  • Embodiment 8 wherein the crystalline solid is a substantially single polymorph.
  • Solid Form A of Compound I HCI has an XRPD pattern comprising one or more peaks chosen from the peaks listed in Table 10, for example comprising two or more peaks chosen from the peaks listed in Table 10, such as comprising three or more peaks chosen from the peaks listed in Table 10, for example comprising four or more peaks chosen from the peaks listed in Table 10.
  • Embodiment 10 wherein the Solid Form A of Compound I HCI has an XRPD pattern comprising one or more peaks, comprising two or more peaks, comprising three or more peaks, or comprising four or more peaks chosen from about 26.62 °20, about 19.01 °20, about 17.27 °20, about 13.07 °20, about 9.46 °20, about 8.18 °20, and about 4.96 °20.
  • Solid Form A of Compound I HCI has an XRPD pattern comprising one or more peaks, comprising two or more peaks, comprising three or more peaks, or comprising four peaks chosen from about 19.01 °20, about 17.27 °20, about 9.46 °20, and about 4.96 °20.
  • Embodiment 17 wherein the Solid Form B of Compound II HCI has an XRPD pattern comprising one or more peaks chosen from the peaks listed in Table 12, for example comprising two or more peaks chosen from the peaks listed in Table 12, such as comprising three or more peaks chosen from the peaks listed in Table 12.
  • Embodiment 17 wherein the Solid Form B of Compound II HCI has an XRPD pattern comprising one or more peaks, comprising two or more peaks, comprising three or more peaks, or comprising four or more peaks chosen from about 25.93 °20, about 23.59 °20, about 19.70 °20, about 17.21°20, about 16.36 °20, about 15.22 °20, about 14.57 °20, and about 6.75 °20.
  • Embodiment 17 wherein the Solid Form B of Compound II HCI has an XRPD pattern comprising one or more peaks, comprising two or more peaks, comprising three or more peaks, or comprising four peaks chosen from about 25.93 °20, about 23.59 °20, about 19.70 °20, and about 17.21°20.
  • Embodiment 25 wherein the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.
  • the at least one improved property comprise melting point, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and/or organic solvents, reactivity, compatibility with excipients and/or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.
  • a pharmaceutical composition comprising a solid form of a compound according to any one of Embodiments 1 - 26, and a pharmaceutically acceptable excipient.
  • a method comprising administering to a subject an effective amount of a solid form of a compound according to any one of Embodiments 1-26, or a pharmaceutical composition according to claim 27. 29. The method of Embodiment 28, wherein the subject has a neurological disease or a psychiatric disorder, or both.
  • Embodiment 30 The method of Embodiment 29, wherein the neurological disorder is a neurodegenerative disorder.
  • Embodiment 31 The method of Embodiment 29, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder.
  • Embodiment 29 wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis or substance use disorder.
  • Embodiment 29 wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.
  • administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.
  • Embodiment 29 The method of Embodiment 29, further comprising administering to the subject an effective amount of an empathogenic agent.
  • Embodiment 39 The method of Embodiment 38, wherein the substance use disorder is amphetamine use disorder.
  • Embodiment 40 The method of Embodiment 38, wherein the substance use disorder is methamphetamine use disorder.
  • Compound I is synthesized in accordance with the synthetic schemes provided in U.S. Patent Application Publication No. 2023/0257346, published on August 17, 2023 and owned by Kuleon, LLC, including Synthetic Scheme B.
  • the resulting Compound I is isolated as a solid and is characterized to evaluate its physical properties.
  • the evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DYS), and/or solubility testing in organic solvents, water, and mixed solvent systems.
  • XRPD data is used to assess crystallinity.
  • PLM data is used to evaluate crystallinity and particle size/morphology.
  • DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion.
  • TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability.
  • DYS data is used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).
  • the information obtained is used for designing the subsequent salt screen.
  • the salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts.
  • Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and/or 2 molar equivalents of the acid.
  • Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water.
  • the techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:
  • the cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice/acetone bath), or slow cooling.
  • the solids formed will be recovered by filtration and dried (air dried or vacuum dried).
  • the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.
  • the stoichiometric ratio of acid to the selected compound is confirmed by 1 H NMR, HPLC, or both as is known to those of ordinary skill in the art.
  • the salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1 H NMR spectroscopy to ensure chemical integrity.
  • KF water titration is performed on salts that are hydrated.
  • DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present.
  • Example 1 The procedures of Example 1 are repeated separately with each of Compounds II, III, IV, V, VI, VII and VIII to isolate salt forms of those compounds.
  • the active pharmaceutical ingredient (API) of Compound I which may be a free base or a salt, is characterized to evaluate its physical properties.
  • the evaluation is performed by X- ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption/desorption (DVS), and/or solubility testing in organic solvents, water, and mixed solvent systems.
  • XRPD data is used to assess crystallinity.
  • PLM data is used to evaluate crystallinity and particle size/morphology.
  • DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion.
  • TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability.
  • DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity.
  • About 10 to 15 solvents may be selected from the list below, based on their properties
  • Solvents are used as a single solvent or as solvent mixtures, some containing water.
  • the techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening:
  • API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).
  • API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C).
  • the cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice/acetone bath), or slow cooling.
  • the solids formed will be recovered by filtration and dried (air dried or vacuum dried).
  • API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt.
  • the solids formed will be recovered by filtration and dried (air dried or vacuum dried).
  • API is added to a solvent or mixture of solvents, where the API is not fully dissolved. The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried). • API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.
  • API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.
  • API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating/cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried).
  • API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization).
  • the amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.
  • API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.
  • Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days).
  • the solvent system used can be pre-saturated with the APL.
  • the final solids will be filtered and dried (air dried or vacuum dried).
  • API is heated to a specific temperature and cooled (at ambient conditions or in a dry box).
  • the solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated/solvated, and by 1 H NMR spectroscopy to ensure chemical integrity.
  • KF water titration is performed on forms that are hydrated.
  • DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present.
  • variable temperature analyses including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.
  • DSC Differential scanning calorimetry thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 Jig). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °c at a heating rate of 10°C/min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL/min) at 25°C to 210°C with a heating rate of I 0°C/min.
  • the sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen.
  • the relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step.
  • the desorption scan is measured from 85 to 0% relative humidity with the same equilibration time.
  • the sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed.
  • the original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm.
  • the sample is heated at an average rate of 5 Kmin- 1 using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2.
  • the temperature is held constant at selected intervals for 10 min while the sample is exposed to X- rays and multiple scans were recorded.
  • a 28-range of 4.00 - 100.0° is used with a step size of 0.005° 28.
  • the DSC thermogram reveals endothermic transitions.
  • TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and/or melting of the sample.
  • these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.
  • the moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities.
  • the change in moisture content over 10.0 to 95.0 % relative humidity is small.
  • the change in moisture content over 10.0 to 95.0 % relative humidity is reversible.
  • the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.
  • Example 3 The procedures of Example 3 are repeated separately with each of Compounds II, III, IV, V, VI, VII and VIII to isolate salt forms of those compounds.
  • Example 5 Evaluation of Metabolic Stability in Human Liver Microsomes
  • Microsomal Assay Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). B-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCh), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich.
  • 7.5 mM stock preparations of test compounds of the disclosed compounds are prepared in a suitable solvent, such as DMSO.
  • the 7.5 mM stock preparations are diluted to 12.5-50 pMin acetonitrile (ACN).
  • ACN acetonitrile
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCh.
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 pL aliquot of the 12.5-50 pM test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes.
  • Reactions are initiated by addition of pre-warmed NADPH solution.
  • the final reaction volume is 0.5 mL and contains 4.0 mg/mL human liver microsomes, 0.25 pM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCb.
  • the reaction mixtures are incubated at 37 °C, and 50 pL aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 pL of ice-cold ACN (acetonitrile) with internal standard to stop the reactions.
  • ACN acetonitrile
  • the plates are stored at 4 °C for 20 minutes after which 100 pL of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.
  • Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the positive control, 7- ethoxycoumarin (1 pM). Testing is done in triplicate.
  • in vitro T1 s for test compounds are calculated from the slopes of the linear regression of% parent remaining (In) vs incubation time relationship.
  • the apparent intrinsic clearance is calculated using the following equation:
  • Compound I free base was prepared according to the same procedure as set forth in Example 8, except starting material 2 was replaced with 3-bromo-6-fluorobenzo[b]selenophene prepared in accordance with the methods set forth in Paegle, E., Belyakov, S., Arsenyan, P. Eur. J. Org. Chem. 2014, 18, 3831-3840, which is incorporated herein by reference in its entirety for all purposes.
  • the Solid Form A of Compound I HCI has an XRPD pattern comprising one or more peaks chosen from the peaks listed in Table 10. In some embodiments, the Solid Form A of Compound I HCI has an XRPD pattern comprising two or more peaks chosen from the peaks listed in Table 10. In some embodiments, the Solid Form A of Compound I HCI has an XRPD pattern comprising three or more peaks chosen from the peaks listed in Table 10. In some embodiments, the Solid Form A of Compound I HCI has an XRPD pattern substantially the same as that in Figure 3.
  • an XRPD pattern that is substantially the same as another XRPD pattern means the patterns represent the same form of the material as is well understood by one skilled in the art when taking into account, for example, variability associated among samples and instruments, and experimental conditions.
  • Example 10b The recrystallization procedure set forth in Example 10b was performed on the HCI salt of Compound I, except cooling was only performed down to room temperature (no freezer). This yielded crystalline material in the form of thin colorless needles (Solid Form B of Compound I HCI).
  • Solid Form B of Compound II HCI has an XRPD pattern comprising one or more peaks chosen from those in Table 12.
  • the Solid Form B of Compound II HCI has an XRPD pattern comprising two or more peaks chosen from those in Table 12. In some embodiments, the Solid Form B of Compound II HCI has an XRPD pattern comprising three or more peaks chosen from those in Table 12. In some embodiments, the Solid Form B of Compound II HCI has an XRPD pattern substantially the same as that in Figure 5.
  • 3-bromo-4-fluorobenzo[b]selenophene starting material was prepared according to the methods set forth in Paegle, E., Belyakov, S., Arsenyan, P. Eur. J. Org. Chem. 2014, 18, 3831- 3840, which is incorporated herein by reference in its entirety for all purposes.
  • the filtrate was concentrated in vacuo and passed through a silica plug (30% ethyl acetate/hexanes, then 100% ethyl acetate).
  • the polar components were collected separately, concentrated, and used in the next step without further purification.
  • the reaction mixture was filtered through Celite.
  • the phases were separated, and the aqueous phase extracted with ethyl acetate (x2).
  • the combined organic extracts were washed with 6M HOI (x3).
  • the combined acidic washes were cooled to 0 °C and carefully basified to pH 12 by the addition of KOH pellets.
  • the aqueous phase was extracted with DOM (x3) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • the phases were separated the and aqueous phase extracted with diethyl ether (x2).
  • the combined organic extracts were washed with water (x3) and with 6M HCI (x5) which was collected separately.
  • the combined acidic washes were cooled to 0 °C and basified to pH 12 by the careful addition of KOH pellets.
  • the aqueous phase was extracted with DCM (x3) and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford 2-(4- methoxybenzo[b]selenophen-3-yl)-/ ⁇ /,/ ⁇ /-dimethylethan-1-amine as a pale yellow oil in >95% purity (125 mg, 86% yield).
  • Example 10a The recrystallization procedure set forth in Example 10a is performed on the HCI salt of Compound IX, yielding crystalline Solid Form A of Compound IX HCI.
  • Example 10b The recrystallization procedure set forth in Example 10b is performed on the HCI salt of Compound IX, yielding crystalline Solid Form B of Compound IX HCI.
  • reaction mixture was concentrated in vacuo and the crude reaction mixture was subjected to silica gel column chromatography (100% ethyl acetate, then 5 and 8% MeOH/DCM) to provide the target intermediate (102 mg, 81% yield).
  • Step A The product of Step A was free based by washing it in a solution of with sat. aq. NaHCO 8 , resulting in a tannish solid.
  • Example 10a The recrystallization procedure set forth in Example 10a is performed on the HCI salt of Compound X, yielding crystalline Solid Form A of Compound X HCI.
  • Example 10b The recrystallization procedure set forth in Example 10b is performed on the HCI salt of Compound X, yielding crystalline Solid Form B of Compound X HCI.
  • a colorless needle shaped crystal of Solid Form A of Compound I HCI having approximate dimensions of 0.100x0.120x0.550 mm was mounted on a Mitegen micromesh mount in a random orientation.
  • Data were collected from a shock-cooled single crystal at 150(2) K on a Bruker AXS D8 Quest three circle diffractometer with a fine focus sealed tube X-ray source using a Triumph curved graphite crystal as monochromator and a Photon II charge-integrating pixel array (CPAD) detector.
  • the twin relationship was obtained using Rotax with the two components being related by a 180-degree rotation around the (-1 0 1) reciprocal axis, which was applied in Apex4 to obtain the second moiety.
  • the two components were integrated using Saint and corrected for absorption using twinabs, resulting in the following statistics: 9071 data (4805 unique) involve domain 1 only, mean l/sigma 14.08894 data (4664 unique) involve domain 2 only, mean l/sigma 6.915667 data (8931 unique) involve 2 domains, mean l/sigma 10.4491 data (489 unique) involve 3 domains, mean l/sigma 15.62 data (2 unique) involve 4 domains, mean l/sigma 20.0.
  • the exact twin matrix identified by the integration program was found to be: -0.45225, 0.00009, -1.45216, 0.00005, -1.00000, -0.00005, -0.54779, -0.00087, 0.45225.
  • the structure was solved using dual methods with only the non-overlapping and corrected reflections of component 1.
  • the structure was refined using the hklf 4 routine with the non-overlapping and corrected reflections of component 1.
  • Table 5 provides crystal data and structure refinement for Solid Form A of Compound I HCI.
  • Table 5 Figure 1 is a single crystal structure drawing of Solid Form A of Compound I HCI generated using FinalCif. See D. Kratzert, FinalCif, V139, https://dkratzert.de/finalcif.html.
  • a colorless plate shaped crystal of Solid Form B of Compound II HCI having approximate dimensions of 0.150x0.400x0.420 mm was mounted on a Mitegen micromesh mount in a random orientation.
  • Data were collected from a shock-cooled single crystal at 150(2) K on a Bruker AXS D8 Quest three circle diffractometer with a fine focus sealed tube X- ray source using a Triumph curved graphite crystal as monochromator and a Photon II chargeintegrating pixel array (CPAD) detector.
  • the structure was solved by direct methods with SHELXT and refined by full-matrix least-squares methods against P using SHELXL-2019/2. See G. M. Sheldrick, Acta Cryst. 2015, A71 , 3-8, doi:10.1107/S2053273314026370; and G. M. Sheldrick, Acta Cryst. 2015, C71 , 3-8, doi: 10.1107/S2053229614024218. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were refined with isotropic displacement parameters.
  • Table 6 provides crystal data and structure refinement for Solid Form B of Compound II HCI.
  • Figure 2 is a single crystal structure drawing of Solid Form B of Compound II HCI generated using FinalCif. See D. Kratzert, FinalCif, V139, dkratzert.de/finalcif.html.
  • Example 19 X-ray powder diffraction analysis (XRPD or PXRD) of Solid Form A of Compound I HCI and Solid Form B of Compound II HCI
  • XRPD X-ray powder diffraction
  • Solid Form B of Compound II HCI exhibited excessive preferred orientation after collection of initial data (needle shaped crystals were visible upon inspection by optical microscopy) and required additional grinding (20 minutes using an agate mortar and pestle) and recollection of diffraction data for analysis.
  • Rietveld refinements were performed against the models of the single crystal structure data sets using the HighScore software of Panalytical.
  • the “Expanded Rietveld Phase Fit” option of Highscore was used.
  • Refinement of preferred orientation was included using a spherical harmonics model.
  • split width and shape refinement was included.
  • Table 11 provides a list of observed peaks from the XRPD pattern of Solid Form B of Compound II HCI.
  • Table 12 lists the prominent peaks from the XRPD pattern of Solid Form B of Compound II HCI.
  • Example 20 Biological Examples
  • HTR Head-Twitch Response
  • Dose-response studies for compounds of Formula I are performed in four consecutive steps:
  • HTR-inducing drugs typically have biphasic bell-shaped (inverted U-shaped) dose-response functions, with ascending and descending phases.
  • doses covering the entire extent of the ascending phase should be included, as well as at least one dose that falls on the descending phase.
  • a pilot dose-finding study is performed to identify a set of doses that matches those requirements.
  • male C57BL/6J mice will be injected with a range of doses (typically 0.3-30 mg/kg) by the IP or SC route and then behavior will be recorded in a magnetometer chamber for up to 150 minutes.
  • HTR counts will be analyzed using a 1-way ANOVA followed by a post-hoc test (Dunnett’s test).
  • the median effective dose (ED50 value) for the compounds (in mg/kg or moles/kg) will calculated by nonlinear regression using a gaussian or sigmoidal model.
  • the potencies of compounds and other reference compounds can also be compared statistically using an extra- sum-of-squares F-test.
  • HTR counts can be binned (e.g., blocks of 1 , 2, 5, or 10 minutes) and analyzed using a 2-way ANOVA (drug x time) followed by a post-hoc test (Dunnett’s test or Tukey’s test).
  • a two-step pulse (applied every 10 s) from -80 mV initially to 40 mV for 2 s and then to -60 mV for 4 s, is used to elicit hERG currents.
  • solutions of the drugs are prepared fresh from 10 mM stocks in DMSO. The final DMSO concentration never exceeds 1%.
  • Functional assay screens at 5-HT and opioid receptors are performed in parallel using the same compound dilutions and 384-well-format high-throughput assay platforms. Assays are used to assess activity at all human isoforms of the receptors, except where noted for the mouse 5-HT 2 A receptor.
  • Receptor constructs in pcDNA vectors are generated from the Presto- Tango GPCR Iibrary39 with minor modifications. All tested compounds of Formula I are serially diluted in drug buffer (HBSS, 20 mM HEPES, pH 7.4 supplemented with 0.1% bovine serum albumin and 0.01% ascorbic acid) and dispensed into 384-well assay plates using a FLIPR Tetra automated dispenser head (Molecular Devices).
  • Every plate includes a positive control such as 5-HT (for all 5-HT receptors), DADLE (DOR), salvinorin A (KOR), and DAMGO (MOR).
  • 5-HT for all 5-HT receptors
  • DADLE DOR
  • KOR salvinorin A
  • MOR DAMGO
  • HEK Flp-ln 293, T-Rex stable cell lines are loaded with Fluo-4 dye for one hour, stimulated with compounds and read for baseline (0-10 s) and peak fold-over-basal fluorescence (5 min) at 25 °C on the FLIPR Tetra system.
  • - mediated cAMP accumulation is detected using the split-luciferase GloSensor assay in HEKT cells measuring luminescence on a Microbeta Trilux (Perkin Elmer) with a 15 min drug incubation at 25 °C.
  • 5-HTI D For measurement of 5-HTI D , 5-HTI E , 5-HT 4 , and 5-HT 5 A functional assays, - arrestin2 recruitment is measured by the Tango assay using HTLA cells expressing tobacco etch virus (TEV) fused- -arrestin2, as described previously with minor modifications.
  • TMV tobacco etch virus
  • Cell lines were not authenticated, but they ae purchased mycoplasma-free and tested for mycoplasma contamination. Data for all assays are plotted and nonlinear regression is performed using “log(agonist) vs. response” in GraphPad Prism to yield estimates of the efficacy (Emax and half- maximal effective concentration (ECso)).
  • mice Male and female C57/BL6J mice (12 weeks old) are administered a compound of Formula I via i.p. injection at doses of either 50 mg kg— 1 , 10 mg kg-1 or 1 mg kg-1. Mice are euthanized 15 min or 3 h after injection by cervical dislocation. Two males and two females are used per dose and time point. Brain and liver are collected, flash-frozen in liquid nitrogen, and stored at -80 °C until metabolomic processing. Whole brain and liver sections are lyophilized overnight to complete dryness, then homogenized with 3.2mm diameter stainless-steel beads using a GenoGrinder for 50 s at 1,500 rpm.
  • Ground tissue is then extracted using 225 pl cold methanol, 190 pl water, 750 pl methyl tert-butyl ether (MTBE). Seven method blanks and seven quality-control samples (pooled human serum, BiolVT) are extracted at the same time as the samples.
  • the nonpolar fraction of MTBE is dried under vacuum and reconstituted in 60 pl of 90:10 (v/v) methanol: toluene containing 1-cyclohexyldodecanoic acid urea as an internal standard. Samples are then vortexed, sonicated and centrifuged before analysis.
  • samples are randomized before injection with method blanks and quality-control samples are analyzed between every ten study samples.
  • a six-point calibration curve is analyzed after column equilibration using blank injections, and then after all study samples. Blanks are injected after the calibration curve to ensure no that none of the tested compound is retained on the column and carried over to samples.
  • Reconstituted sample (5 pl) is injected onto a Waters Acquity LIPLC OSH C18 column (100 mm x 2.1 mm, 1.7 pm particle size) with an Acquity LIPLC OSH C18 VanGuard precolumn (Waters) using a Vanquish LIHPLC coupled to a TSQ Altis triple quadrupole mass spectrometer (Thermo Fisher Scientific).
  • Mobile phase A consists of 60:40 v/v acetonitrile/ water with 10 mM ammonium formate and 0.1% formic acid.
  • Mobile phase B consists of 90:10 v/v isopropanol/acetonitrile with 10 mM ammonium formate and 0.1% formic acid.
  • HEK293T cells are maintained, passaged, and transfected in DMEM medium containing 10% FBS, 100 Units/mL penicillin, and 100pg/mL streptomycin (Gibco-ThermoFisher, Waltham, MA) in a humidified atmosphere at 37°C and 5% CO2. After transfection, cells are plated in DMEM containing 1% dialyzed FBS, 100 Units/mL penicillin, and 100pg/mL streptomycin for BRET2, calcium, and GloSensor assays.
  • Cells are plated either in six-well dishes at a density of 700,000-800,000 cells/well, or 10-cm dishes at 7-8 million cells/dish. Cells are transfected 2-4 hours later, using a 1 :1 :1 :1 DNA ratio of receptor:Ga-RLuc8:Gp:Gy-GFP2 (100 ng/construct for six-well dishes, 750 ng/construct for 10-cm dishes), except for the Gy-GFP2 screen, where an ethanol coprecipitated mixture of Gpi-4- is used at twice its normal ratio (1 : 1 :2:1).
  • Transit 2020 (Mirus Biosciences, Madison, Wl) is used to complex the DNA at a ratio of 3 pL Transit/pg DNA, in OptiMEM (Gibco-ThermoFisher, Waltham, MA) at a concentration of 10 ng DNA/pL OptiMEM.
  • OptiMEM Gabco-ThermoFisher, Waltham, MA
  • cells are harvested from the plate using Versene (0.1M PBS + 0.5 mM EDTA, pH 7.4), and plated in poly-D-lysine-coated white, clear bottom 96-well assay plates (Greiner Bio- One, Monroe, NC) at a density of 30,000-50,000 cells/well.
  • Plates are then read in an LB940 Mithras plate reader (Berthold Technologies, Oak Ridge, TN) with 395 nm (RLuc8-coelenterazine 400a) and 510 nm (GFP2) emission filters, at 1 second/well integration times. Plates are read serially six times, and measurements from the sixth read were used in all analyses. BRET2 ratios are computed as the ratio of the GFP2 emission to RLuc8 emission.
  • Cells are plated in 10-cm plates as described in the BRET2 protocol and co-transfected with receptor (1 pg) and Ga-subunit (1pg) cDNA. The next day, cells are plated at 15,000 cells/well in poly-D-lysine coated black, clear bottom 384-well plates (Greiner Bio-One, Monroe, NC). The following day, growth medium are aspirated and replaced with 20 pL assay buffer containing 1x Fluo-4 Direct Calcium Dye (ThermoFisher Scientific, Waltham, MA) and incubated for 60 minutes at 37°C (no CO2).
  • Cells are plated in 10-cm plates as previously described. Cells are transfected with plasmids encoding cDNA for the Giosensor reporter (Promega, Madison, Wl), receptor, and Ga- subunit at a ratio of 2:1:1 (2 pg: 1 pg: 1pg). The next day, cells are plated in black, clear-bottom, 384-well white plates. After aspiration of the medium on the day of the assay, cells are incubated for 60 minutes at 37°C with 20 pL of 5 mM luciferin substrate (GoldBio, St. Louis, MO) freshly prepared in assay buffer.
  • 10 pL of drugs are added using the FLIPR Tetra® liquid-handling robot and read after 15 minutes in a Spectramax luminescence plate reader (Molecular Devices, San Jose, CA) with a 0.5 second signal integration time.
  • 10 pL of drugs are added for a 15-minute incubation period.
  • 10 pL of isoproterenol final concentration of 200 nM are added and incubated for an additional 15- minute period before reading.

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Abstract

L'invention concerne des sels et des formes solides des analogues de benzosélénophène et de benzothiophène décrits ici.
PCT/US2024/043028 2023-08-21 2024-08-20 Sels et formes solides de modulateurs de récepteur de la sérotonine de benzothiophène et de benzoselenophène Pending WO2025042885A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210145851A1 (en) * 2019-11-19 2021-05-20 Paul Edward Stamets Tryptamine compositions for enhancing neurite outgrowth
WO2022269265A1 (fr) * 2021-06-23 2022-12-29 LDN Pharma Limited Compositions comprenant un agoniste du sous-type 3 du récepteur de la 5-hydroxytryptamine (5-ht)
US20230202978A1 (en) * 2022-03-04 2023-06-29 Reset Pharmaceuticals, Inc. Co-crystal or salt
US20230257346A1 (en) * 2021-08-12 2023-08-17 Kuleon, LLC Benzoselenophene and selenophenopyridine analogs and methods of modulating the serotonin 5-ht2c receptor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210145851A1 (en) * 2019-11-19 2021-05-20 Paul Edward Stamets Tryptamine compositions for enhancing neurite outgrowth
WO2022269265A1 (fr) * 2021-06-23 2022-12-29 LDN Pharma Limited Compositions comprenant un agoniste du sous-type 3 du récepteur de la 5-hydroxytryptamine (5-ht)
US20230257346A1 (en) * 2021-08-12 2023-08-17 Kuleon, LLC Benzoselenophene and selenophenopyridine analogs and methods of modulating the serotonin 5-ht2c receptor
US20230202978A1 (en) * 2022-03-04 2023-06-29 Reset Pharmaceuticals, Inc. Co-crystal or salt

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RUDIN ET AL.: "2-Aminopropyl)benzo[beta]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice", NEUROPSYCHOPHARMACOLOGY, vol. 47, 2022, pages 914 - 923, XP037703363, DOI: 10.1038/s41386-021-01221-0 *
SEKHON: "Pharmaceutical co-crystals - a review", ARS PHARM, vol. 50, no. 3, 2009, pages 99 - 117, XP055020300 *

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