Preparations containing tryptamine derivatives and their use

Abstract

Pharmaceutical compositions containing therapeutically effective amounts of psychoactive agents may be used to treat, manage, or prevent neurological disorders, mental illnesses and disorders, and other diseases and disorders. Through the delivery of these compounds, it may be possible to safely and effectively enable the subject to address undesirable symptoms of these diseases and disorders, and / or the diseases and disorders themselves. This invention relates to pharmaceutical compositions comprising compounds that are tryptamine derivatives.

Description

[Technical Field]

[0001] (Cross-reference of related applications)

[0002] This patent application claims the benefit as of the filing date of U.S. Provisional Patent Application No. 63 / 504,034, filed on 24 May 2023 (the entire disclosure thereof is invoked by reference).

[0003] (Field of Invention)

[0004] This invention relates to formulations of tryptamine derivatives and the use of such formulations. [Background technology]

[0005] (Background of the invention)

[0006] Hallucinogenic compounds are a group of compounds that affect one or more biological activities (e.g., perception, mood, and cognitive processes). While there is great diversity in the structure and chemical activity of hallucinogenic compounds, they are known as a class that induces broad-spectrum neurological activity with rapid onset and sustained duration of action. Examples of well-known hallucinogenic compounds include psilocybin, N,N-dimethyltryptamine (DMT), 5-MeO-DMT, 4-AcO-DMT, lysergic acid diethylamide (LSD), and ibogaine, which mimic serotonin (5-HT) and target central nervous system (CNS) receptors.

[0007] Many hallucinogenic compounds are found in serotonin receptor 2A (5-HT). 2A It has a hallucinogenic effect due to agonism. However, agonism alone (including partial agonism) does not induce hallucinations, and 5-HT 2A The unique relationship between and metabotropic glutamate receptor 2 (mGlu2) deserves further investigation, especially since it is associated with addictive and compulsive behaviors. For example, signaling (e.g., G qIt has been shown that (or β-arrestin aggregation) is important for the downstream contribution to hallucinogenic effects. Furthermore, as those skilled in the art know, hallucinogenic compounds (e.g., those identified in the preceding paragraph) target various 5-HT receptors (of which 14 subtypes exist) along with other CNS receptors (adrenergic receptors, dopamine receptors, histamine receptors, muscarinic receptors, opioid receptors, sigma receptors, etc.). Thus, these compounds, among others, belong to the group known as psychedelics, but their mechanisms for eliciting activity in the body are diverse and complex. Furthermore, while the hallucinogenic compounds mentioned above have been well-known for many years, there has recently been a movement to develop novel compounds in this class. For example, many new compounds are described in WO 2021 / 226416 A1 (Novel Compositions of Matter and Pharmaceutical Compositions), published on November 11, 2021. The search for novel compounds, as well as desirable formulations of known compounds, is driven by the objective of better treating, preventing, and managing a wide variety of human conditions and disorders. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2021 / 226416 [Overview of the Initiative] [Means for solving the problem]

[0009] (Summary of the invention)

[0010] This invention relates to pharmaceutical compositions comprising compounds that are tryptamine derivatives. These tryptamine derivatives are present in therapeutically effective amounts and possess desirable biological activity and clinical safety.

[0011] In some embodiments, the present invention has a structure (1): [ka] A pharmaceutical composition (which may also be called a formulation) comprising, essentially, or consisting of a therapeutically effective amount of a compound defined by, or a pharmaceutically acceptable salt, solvate, metabolite, or prodrug thereof, In the formula, R1 is selected from the group consisting of Br, F, Cl, I, CF3, and H; R2 is either H or CH3; R3 and R4 are each independently selected from the group consisting of CH3, C2H5,(H3C)2CH, H2C=CH-CH2, and H; R5 is selected from the group consisting of OCOCH3, OH, OCH3, O-phosphate, O-polyethylene glycol (PEG), O-(CH2)2(COOH)2 (succinate), O-(CH2)2(COOH) (hemisuccinate), O-sulfate, fumarate, tartrate, maleate, sugar, amino acid, and CH2SO2NHCH3 (sulfonamide); Here, if R1 is H, then R5 is CH2SO2NHCH3, CH2NHSO2CH3, or CH2NHCON(CH2CH3)2.

[0012] In some embodiments, the compound derived from structure (1) is selected from the group consisting of: 2-(2-bromo-1H-indole-3-yl)-N,N-dimethylethane-1-amine, 2-(2-chloro-1H-indole-3-yl)-N,N-dimethylethane-1-amine, 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indole-4-yl acetate, N-(2-(2-bromo-1H-indole-3-yl)ethyl)-N-isopropylpropan-2-amine, N-(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)methanesulfonamide, and N-(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)acetamide.

[0013] In some embodiments, the formulation is a pharmaceutical composition designed for oral delivery into the human body's circulation, having a rapid onset of action and duration of action.

[0014] In some embodiments, the formulation is a pharmaceutical composition designed for extended release into the human circulation by oral delivery, preferably providing a once-daily dose for, for example, at least 5 or at least 10 days. In some embodiments, the formulation is a pharmaceutical composition designed for extended release into the human circulation by oral delivery, preferably providing a twice-daily dose for, for example, at least 5 or at least 10 or at least 14 days. In some embodiments, the oral pharmaceutical compositions described herein are designed for a modified time release of a pharmacoactive ingredient (e.g., one or more compounds in structure (1)) into the human circulation.

[0015] In some embodiments, the pharmaceutical composition may include, for example, a solid, semi-solid, liquid, or flexible delivery system and may be delivered by sublingual administration, buccal administration, or oral administration. Further, the pharmaceutical active ingredient may be provided, for example, in tablets, capsules, soft gels, strips, sublingual strips, wafers, solutions, or suspensions.

[0016] In some embodiments, the pharmaceutical composition is designed for intermittent administration, for example, every other day, once a week, once a month, once a year, or as needed.

[0017] In some embodiments, the pharmaceutical composition is designed for injectable administration by an intracranial (i.p.) drug delivery device, an intravenous (i.v.) drug delivery device, an intramuscular (i.m.) drug delivery device, a subcutaneous (s.c.) drug delivery device, or an implantable drug delivery device.

[0018] In some embodiments, the pharmaceutical composition is designed for topical or transdermal administration by a patch, cream, ointment, gel, or lotion.

[0019] In some embodiments, the pharmaceutical composition is designed for intranasal delivery by a solution (liquid), gel, powder, nebulizer, spray, pneumatic delivery device, or pressurized delivery device.

[0020] In some embodiments, the compound in the pharmaceutical composition is a 5-HT 2A partial agonist.

[0021] In some embodiments, the compound in the pharmaceutical composition is a 5-HT 2A antagonist.

[0022] In some embodiments, the compound in the pharmaceutical composition is a 5-HT 2C agonist.

[0023] In some embodiments, the compound in the pharmaceutical composition is 5-HT 2B agonist.

[0024] In some embodiments, the compound in the pharmaceutical composition is 5-HT 5A inhibitor.

[0025] In some embodiments, the compound in the pharmaceutical composition is a 5-HT6 agonist.

[0026] In some embodiments, the compound in the pharmaceutical composition is 5-HT 7A agonist.

[0027] In some embodiments, the compound in the pharmaceutical composition is 5-HT 7A inverse agonist.

[0028] In some embodiments, the compound in the pharmaceutical composition modulates the sigma receptor.

[0029] In some embodiments, the compound in the pharmaceutical composition is non-hallucinogenic.

[0030] In some embodiments, the compound in the pharmaceutical composition is an antidepressant.

[0031] In some embodiments, the present invention provides a pharmaceutical composition effective for use in the treatment, management, or prevention of one or more neurological disorders, mood disorders, or impulse control disorders (including substance abuse disorders). In some embodiments, the disorder may include: depressive disorders, anxiety disorders, central nervous system inflammation associated with inflammatory disorders, Lyme disease, prion diseases, amoebic diseases, schizophrenia, schizoaffective disorder, psychotic depressive disorder, bipolar depressive disorder, treatment-resistant depressive disorder, Parkinson's disease, impulse control disorders with addictive and habitual components (including, but not limited to, alcohol abuse disorder, nicotine addiction, opioid abuse disorder, stimulant abuse disorder, hypnotic and tranquilizer addiction, gambling addiction, sex addiction, and gaming technology disorder), attention deficit disorder, intermittent rage disorder, headaches, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, eating disorders (e.g., anorexia or bulimia), acute and / or chronic pain, amyotrophic lateral sclerosis, vascular dementia or Lewy body dementia. (origin), frontotemporal dementia, Alzheimer's disease, and organic cognitive impairment and organic memory impairment.

[0032] In some embodiments, the present invention provides methods for treating, managing, or preventing one or more of the following: neurological disorders, mood disorders, or impulse control disorders (including, but not limited to, one or more of, the above disorders).

[0033] In some embodiments, the present invention provides a pharmaceutical product comprising a therapeutically effective amount of the compound of structure (1). The pharmaceutical product may be used, for example, to treat, prevent, or manage one of the above-mentioned disorders.

[0034] In some embodiments, the present invention provides the use of a pharmaceutical composition comprising a therapeutically effective amount of the compound of structure (1) for the prevention, treatment, or management of one or more of the above-mentioned disorders.

[0035] In some embodiments, the pharmaceutical composition can deliver an active ingredient compound, or a pharmaceutically acceptable salt or prodrug thereof. For example, the pharmaceutical composition may contain an HBr salt of structure (1) (e.g., an HBr salt of 4-AcO-2-Br-DMT). In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of an HBr salt of structure (1) (e.g., an HBr salt of 4-AcO-2-Br-DMT). The therapeutically effective amount may be, for example, between about 0.01 mg / kg and about 35 mg / kg, or between 0.01 mg / kg and 25 mg / kg, or between 0.01 mg / kg and 20 mg / kg, or between about 0.4 mg / kg and about 4 mg / kg, or between about 0.4 mg / kg and about 2 mg / kg. This composition may be a pharmaceutical useful for the treatment of, for example, frontotemporal degeneration or frontotemporal dementia, or other disorders or conditions described herein. In some embodiments, the composition contains or is converted to a therapeutically effective amount of an active metabolite (e.g., 2-Br-4-OH-DMT, which is the active metabolite of 2-Br-4-AcO-DMT), where 2-Br-4-AcO-DMT itself may be present in the administered pharmaceutical composition, or a salt thereof (e.g., an HBr salt) may be present in the administered pharmaceutical composition.

[0036] Compounds may possess biological activity, which may be defined as necessary by satisfactory evaluation from in vitro receptor screening and / or in vivo behavioral assessments to test for one or more of the following: hallucinogenic effects, antidepressant effects, anxiolytic effects, cognitive enhancement effects, learning, memory, post-traumatic stress disorder (PTSD), and alcohol use disorder. However, formulations included within the scope of the present invention may additionally or alternatively exhibit other neurological activities. Furthermore, in some embodiments, the pharmaceutical compositions of the present invention may have therapeutic effects that include and / or are detectable by certain biomarkers. For example, they may have or may influence neuroplastic properties related to the biomarker brain-derived neurotrophic factor (BDNF). Other biomarkers of interest that may play a role in the mechanism of action of certain pharmaceutical compositions of the present invention include, but are not limited to, the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) (these are often elevated in patients with inflammatory diseases). Reducing these biomarkers in an inflammatory environment may reduce inflammation (particularly neuroinflammation).

[0037] Through various embodiments of the present invention, one or more of the following can be demonstrated: improved in vitro receptor activity, improved functionality, improved dosage form, and improved in vivo biological activity. Due to these advantages, various embodiments of the present invention may be desirable for therapeutic use in humans to treat neurological and / or CNS disorders, as well as other disorders and conditions. [Brief explanation of the drawing]

[0038] (Brief explanation of the drawing)

[0039] [Figure 1A-1D] Figures 1A, 1B, 1C, and 1D are graphs that provide rat pharmacokinetic data.

[0040] [Figure 2A-2B]Figures 2A and 2B are also graphs that provide rat pharmacodynamic data.

[0041] [Figure 3A-3B] Figures 3A1 and 3A2 are graphs measuring the biomarker IL-6. Figures 3B1 and 3B2 are graphs measuring the biomarker BDNF. Figures 3C1 and 3C2 are graphs measuring TNFα expression. [Figure 3C] Figures 3A1 and 3A2 are graphs measuring the biomarker IL-6. Figures 3B1 and 3B2 are graphs measuring the biomarker BDNF. Figures 3C1 and 3C2 are graphs measuring TNFα expression.

[0042] [Figure 4A-4C] Figures 4A and 4B are graphs measuring mGlu2 expression. Figure 4C is a bar graph showing a control for mGlu2 expression.

[0043] [Figure 5] Figure 5 shows the crystal structure of the HBr salt form of 2-Br-4-AcO-DMT.

[0044] [Figure 6] Figure 6 is a graph showing the concentration of 2-Br-4-OH-DMT measured over time. [Modes for carrying out the invention]

[0045] (Detailed explanation)

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they would be generally understood by those skilled in the art.

[0047] As used herein and in the appended claims, the indefinite articles “a” and “an,” and the definite article “the,” include plural and singular referents unless the context explicitly states otherwise.

[0048] The terms “about” or “approximately” mean an acceptable error for a particular value as determined by those skilled in the art, the acceptable error depending in part on how the value is measured or determined. In some embodiments, the terms “about” or “approximately” mean within one standard deviation, within two standard deviations, within three standard deviations, or within four standard deviations. In some embodiments, the terms “about” or “approximately” mean 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

[0049] As used herein, unless otherwise specified, the term “abuse disorder” means a disorder or condition that affects a person’s brain and behavior, resulting in an inability to control the use of legal or illegal drugs or medicines. Prescription drugs, over-the-counter drugs, and unapproved drugs can all be abuse drugs. Drugs and medicines may also include substances such as amphetamines, opioids, cocaine, barbiturates, alcohol, marijuana, and nicotine.

[0050] As used herein, unless otherwise specified, the term “active pharmaceutical ingredient (API)” means any substance or mixture of substances intended to be used in the manufacture of a drug product (medicinal product), which, if used in the production of a drug, becomes the active ingredient of that drug product. Such substances are intended to affect the diagnosis, cure, alleviation, treatment, or prevention of a disease, or to affect the structure or function of a body.

[0051] The terms “co-administration,” “in combination,” and “in combination” include the administration of two or more therapeutic agents simultaneously, concurrently, together, or sequentially, without specific time constraints. In some embodiments, the agents are present simultaneously in cells or in the body of the subject, or exert their biological or therapeutic effects simultaneously. In some embodiments, the therapeutic agents are present in the same composition or unit dosage form. In other embodiments, the therapeutic agents are present in separate compositions or unit dosage forms. Examples of co-administered agents include, but are not limited to, antidepressants, anxiolytics, psychotropic agents, antipsychotics, anti-inflammatory agents, cognitive enhancers, β-amyloid reduction therapies or tau modulation therapies, and / or enzyme inhibitors.

[0052] As used herein, the terms “composition,” “formulation,” and “dosage form” are intended to include compositions comprising a specific component(s) (in a specific amount, where indicated) and any products(s) resulting directly or indirectly from a specific combination of a specific component(s) in a specific amount(s). “Pharmaceutical” or “pharmaceutically acceptable” means that any diluents(s), excipients(s), absorption enhancers(s), or carriers(s) in a composition, formulation, or dosage form are also compatible with the other components(s) and are not harmful to its recipient. Unless otherwise indicated, the terms “composition,” “formulation,” and “dosage form” are interchangeable herein.

[0053] As used herein, the term “transdermal” refers to a pharmaceutical product in a form for absorption into the bloodstream through the skin, or the supply of such a pharmaceutical product.

[0054] As used herein, the terms “intranasal” or “nasal, nasal cavity” refer to a pharmaceutical product in a form for absorption through the nasal mucosa, or the delivery of such a pharmaceutical product. Intranasal and nasal delivery can be carried out through a wide range of dosage forms, including, but not limited to, liquids, gels, suspensions, emulsions, liposomes, and particulates.

[0055] As used herein, “immediate-release” is defined as a formulation of the active ingredient(s) of a drug that is taken orally, intranasally, by injection (IP, IV, or SC), or transdermally, resulting in rapid absorption of the drug into the bloodstream after administration. Immediate-release may be measured in vitro using FDA industry guidance on solubility and / or permeability testing, or in vivo using plasma levels.

[0056] As used herein, unless otherwise specified, the terms “to manage,” “to control,” and “to control” mean preventing or slowing the progression, spread, or worsening of a disease or disorder, or one or more of its symptoms. Often, the beneficial effects that a subject may receive from prophylactic and / or therapeutic agents do not result in a cure for the disease or disorder. In this regard, the term “to manage” includes treating a control affected by a particular disease in an attempt to prevent or minimize the recurrence of that disease.

[0057] As used herein, improvement of symptoms of a particular disorder by administration of a particular pharmaceutical composition means any reduction (whether permanent or temporary, continuous or transient) that may be caused by or related to the administration of that composition.

[0058] As used herein, the term “metabolite” refers to the active form of a drug administered to a subject in an inactive form. For example, a drug may be administered as a prodrug in an inactive form, and after administration, the subject’s body converts the drug into an active form capable of producing the desired effect.

[0059] As used herein, “modified release” or “sustained release” is defined as a formulation of an active ingredient(s) administered orally, intranasally, by injection, or transdermally, which releases the active ingredient over several hours to several days in order to maintain a relatively constant plasma concentration of the drug. Such modifications may serve several purposes, for example: to maintain therapeutic activity over a longer period; to reduce toxic effects; to protect the active ingredient from degradation due to low pH; to direct the active ingredient to a predetermined segment of the gastrointestinal tract for topical treatment; or to direct the release of the active ingredient at a specific time. Modified release is measured according to the appropriate FDA industry guidelines for modified release formulations.

[0060] As used herein, unless otherwise specified, the term “mood disorder” refers to a group of conditions characterized by mood disturbances. Mood disorders may include mania (elevated mood disorder) or hypomania (depression). Their classification is found in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD).

[0061] As used herein, unless otherwise specified, the term “neurological disorder” refers to disorders of the central and peripheral nervous systems (e.g., the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junctions, and muscles). These disorders include: epilepsy, Alzheimer’s disease, frontotemporal dementia and other dementias, as well as cerebrovascular diseases (including, but not limited to, stroke, migraine, cluster headache and other headache disorders), multiple sclerosis, Parkinson’s disease, viral and bacterial neuroinfections, post-acute sequelae of COVID, brain tumors, traumatic disorders of the nervous system resulting from head trauma, and traumatic disorders resulting from traumatic or frightening experiences (including, but not limited to, PTSD), as well as neurological disorders resulting from malnutrition and substance abuse. Substances abused may include several addictive substances (including, but not limited to, alcohol, other drugs, and combinations thereof). Other embodiments include therapeutic and prophylactic compositions for central nervous system disorders associated with pathogenic bacterial species (including, but not limited to, Mycobacterial tuberculosis, Neisseria meningitides, Prevotella species, and Lyme disease-causing spirochete species). Further embodiments include therapeutic and prophylactic compositions for central nervous system disorders associated with viruses (including, but not limited to, human herpesviruses (e.g., Epstein-Barr virus, herpes simplex virus), RNA viruses (e.g., COVID-19, and enteroviruses), and lentiviruses (e.g., human immunodeficiency virus (HIV)), as well as disorders associated with flaviviruses (such as West Nile virus and Zika virus).

[0062] As used herein, “oral” refers to a form of pharmaceutical product intended for absorption through the oral mucosa, sublingual, buccal, esophageal, gastric, or intestinal membranes. The term “capsule” refers to an oral composition in which the API and inert components are contained as solid, liquid, or semi-solid within an outer shell composed of gelatin, polymerized cellulose, or other suitable material. Capsules are intended to be swallowed, and their composition dissolves, releasing its API for systemic absorption through the lining of the esophagus, stomach, or intestines.

[0063] The term “strip” or “oral strip” refers to an oral composition in the form of a square, rectangular, triangular, rounded, circular, or oblong shape, comprising an API and an inactive component, and optionally a salivary stimulant, forming a flexible matrix. Once in the mouth (typically placed under the tongue), the composition dissolves and releases its API for systemic absorption through the buccal, sublingual, esophageal, gastric, or intestinal lining. Examples of formulations designed for oral delivery include, but are not limited to, formulations in the form of tablets, capsules, softgels, strips, sublingual strips, wafers, liquids, or suspensions.

[0064] As used herein, unless otherwise specified, the terms “prevent,” “prevention,” and “prevention” refer to the prevention of the onset, recurrence, or spread of a disease or disorder, or one or more symptoms thereof. In certain embodiments, these terms refer to treatment or administration of the formulations provided herein, with or without one or more additional active agents, to a subject at risk of the disease or disorder presented herein, prior to the onset of symptoms. These terms encompass the inhibition or reduction of symptoms of a particular disease. Subjects with a family history of the disease, in particular, are candidates for a preventive regimen in certain embodiments. Furthermore, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term “prevention” may be used interchangeably with the term “preventive treatment.”

[0065] As used herein, unless otherwise specified, the “prophylactically effective amount” of a compound means a sufficient amount to prevent a disease or disorder, or to prevent its recurrence. The prophylactically effective amount of a compound means the amount of a therapeutic agent, either alone or in combination with one or more other agents, that provides a prophylactic benefit in preventing a disease. The term “prophylactically effective amount” may include an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0066] Further embodiments include therapeutic and prophylactic compositions for central nervous system disorders associated with fungal infections (e.g., Cryptococcus and Aspergillus). Other further embodiments include, but are not limited to, therapeutic and prophylactic compositions for central nervous system disorders associated with parasites: parasites that cause toxoplasmosis, parasites that cause malaria, parasites that cause Chagas disease, and parasites that cause amoebic infections (which may affect the nervous system). Neurological symptoms may arise from the infection itself or from an immune response to the pathogen or cytokines induced by the pathogen.

[0067] The term “subject” is defined herein as including animals (e.g., mammals (including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.)). In certain embodiments, the subject is humans.

[0068] The terms “tablet” and “wafer formulation” refer to oral compositions in spherical, rounded, oval, triangular, rhomboid, bullet-shaped, or transversely elongated shapes, comprising an API and an inactive component, and optionally a salivary stimulant. Tablets and wafer formulations may be formed by direct compression of a powder formulation. Upon ingestion, the composition dissolves, releasing its API for systemic absorption through the buccal, sublingual, esophageal, gastric, or intestinal lining.

[0069] As used herein, unless otherwise specified, the terms “therapeutic dose,” “therapeutic load,” and “effective dose” of a compound mean a sufficient amount to provide therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with that disease or disorder. “Therapeutic dose,” “therapeutic load,” and “effective dose” of a compound mean the amount of a therapeutic agent, either alone or in combination with one or more other agents, that provides therapeutic benefit in the treatment or management of a disease or disorder. The terms “therapeutic dose,” “therapeutic load,” and “effective dose” may include amounts that improve overall treatment, reduce or avoid symptoms or causes of a disease or disorder, or enhance the therapeutic effect of another therapeutic agent.

[0070] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” mean the eradication or improvement of a disease or disorder, or one or more symptoms associated with such disease or disorder. In some embodiments, these terms mean minimizing the spread or exacerbation of such disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject having the disease or disorder. In some embodiments, these terms mean administering, with or without, one or more additional active agents, a compound, formulation, or dosage form provided herein after the onset of symptoms of a particular disease.

[0071] In some embodiments, the pharmaceutical compositions of the present invention are used to treat neurological disorders, mood disorders, and abuse disorders. These compositions comprise one or more compositions within structure (1) and may be prepared for oral, transdermal, topical, intranasal, or injectable administration. In certain embodiments, the pharmaceutical composition comprises, essentially consists of, or comprises pharmaceutically acceptable salts, solvates, or prodrugs of structure (1), and combinations thereof.

[0072] In some embodiments, the active pharmaceutical ingredient is delivered in an oral pharmaceutical formulation composition, including capsules or tablets, which deliver its API into the bloodstream through the membranes of the esophagus, stomach, and / or intestines. In a non-limiting example, the oral composition may be designed to be swallowed, and its active pharmaceutical ingredient is delivered into the bloodstream through the membranes of the esophagus, stomach, and / or intestines. In some embodiments, the oral composition is in the form of tablets, capsules, wafers, or strips, which deliver its active pharmaceutical ingredient into the bloodstream sublingually, buccally, or through other oral mucosa.

[0073] In some embodiments, the oral composition includes an oral patch or oral film that delivers the active pharmaceutical ingredient into the bloodstream through the sublingual, buccal, or other oral mucosa.

[0074] In some embodiments, the oral composition includes a powder, liquid, or suspension that delivers the active pharmaceutical ingredient into the bloodstream via the sublingual, buccal, or other oral mucosa.

[0075] In some embodiments, the pharmaceutical composition of the present invention is an immediate-release formulation that releases its pharmaceutically active ingredient into the plasma upon oral administration. In some embodiments, the formulation comprises, essentially consists of, or comprises one or more pharmaceutically active ingredients of structure (1) (or their prodrugs or pharmaceutically acceptable salts or solvates) in a therapeutic or prophylactic dose, and optionally one or more excipients.

[0076] In some embodiments, the pharmaceutical composition of the present invention is an extended-release or controlled-release formulation that, upon oral administration, results in the controlled or sustained release of the pharmacokinetic active ingredient into the plasma. In some embodiments, the formulation comprises, essentially consists of, or comprises one or more pharmacokinetic active ingredients of structure (1) (or their prodrugs or pharmaceutically acceptable salts or solvates) in a therapeutic or prophylactic dose, and optionally one or more excipients.

[0077] In some embodiments, the pharmaceutical composition is designed for oral delivery and contains inert components that enhance drug delivery properties and stabilize the active ingredient. For example, one or more fillers may be included as inert components. The fillers may act as a matrix that affects the dissolution time or as binders to improve stability. Examples of fillers include, but are not limited to, starch, citric acid, tartaric acid, bicarbonate, phosphate, polyvinylpyrrolidone, cellulose (natural cellulose and modified cellulose), croscarmellose, glycolate, acrylate, acetate, gelatin, gum, alginate, pectin, chitosan, chitin, salt, polysaccharide, mucilage, sugar, sucrose, lactose, and dextrose.

[0078] Additionally or alternatively, one or more lubricants may be included as inert components. These lubricants serve to improve the flowability of the powder or reduce friction between the manufacturing parts. Examples of lubricants include, but are not limited to, magnesium stearate, talc, stearic acid, and silicon dioxide.

[0079] Additional or alternative flavorings may be included as inactive components. These flavorings may mask the taste of bitter substances or improve the taste of the oral composition. Examples of flavorings include, but are not limited to, sugars, dextrose, sucrose, sucralose, stevia, essential oils, citric acid, and natural or artificial flavorings. If necessary, colorants may be included in the powders or powders to improve the visual characteristics or to differentiate the offered products; these colorants may be, for example, natural or artificial dyes, pigments, chelates, or metals.

[0080] Additionally or alternatively, one or more surfactants may be included in the above composition. These surfactants may be, for example, emulsifiers and stabilizers that can encapsulate drugs for better stability, taste, permeability, and drug release properties. Examples of surfactants include, but are not limited to, vegetable oils, triglycerides, esters, polysorbates (Tween®), sorbitan (Span®), phospholipids (e.g., lecithin), lauryl sulfate, betaine, propionate, fatty acids, fatty alcohols, saponins and alkanolamides, amine oxides, cyclodextrins, myristates and azons.

[0081] Additionally or alternatively, in some embodiments, the pharmaceutical composition is an oral formulation comprising a co-solvent to improve the solubility, dissolution, and permeability of the drug. Examples of co-solvents include, but are not limited to, alcohols such as ethanol, isopropanol, glycerin, propylene glycol, dipropylene glycol, polyethylene glycol, diethylene monoethyl ether, cremofol, siloxane, polyethylene, and water.

[0082] Additionally or alternatively, in some embodiments, the pharmaceutical composition is an oral formulation comprising a thickener to reduce dissolution and provide a matrix suitable for delivery. Examples of thickeners include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenan, polysaccharides, and high-melting-point waxes and oils (e.g., beeswax, coconut oil, palm oil, soybean oil), stearic acid, rapeseed oil, cocoa butter, shea butter, gum, rosin, resin, paraffin, and petrolatum.

[0083] Additionally or alternatively, in some embodiments, the pharmaceutical composition is an oral formulation containing preservatives to improve formulation stability and delay microbial growth. Examples of preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chlorides, phenols, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts, and alcohols.

[0084] Additionally or alternatively, in some embodiments, the pharmaceutical composition is an oral formulation comprising an enteric coating agent to modify and extend release in the gastrointestinal tract. Examples of enteric coating agents include, but are not limited to, high-melting-point waxes, fatty acids, sugars, fibers, and polymers.

[0085] Additionally or alternatively, in some embodiments, the pharmaceutical composition is an oral formulation comprising an inert component that alters the physical properties of the drug delivery system (e.g., pH, solubility, dissolution, hydrophobicity, and stability). Many such compounds are known to those skilled in the art.

[0086] Additionally or alternatively, in some embodiments, the pharmaceutical composition is an oral formulation comprising a membrane penetration enhancer to increase systemic delivery. Examples of suitable penetration enhancers for use in the oral composition include, but are not limited to: 2~4Alcohols (e.g., ethanol and isopropanol), polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyllauramide, sorbitan (Span®), polysorbate (e.g., Tween®, polysorbate 20), fatty acids, fatty acid esters having about 10 to about 20 carbon atoms, fatty acid monoglycerides or mixtures of fatty acid monoglycerides having at least 51% total monoester content (where the monoester has 10 to 20 carbon atoms), and mixtures of fatty acid monoglycerides, fatty acid diglycerides, and fatty acid triglycerides. Suitable fatty acids include: e.g., lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid. Monoglyceride penetration enhancers include: e.g., glycerol monooleate, glycerol monolaurate, and glycerol monolinoleate. Terpenes and terpenoids originate from the biosynthesis of natural isoprene and can also be used to disrupt the skin film and increase API permeability. Examples of terpenes include, but are not limited to, menthol, menthone, camphor, nerolidol, limonene, myrcene, anethole, eugenol, 1,8-cineole, terpinolene, pinene, and humulene.

[0087] In some embodiments, the active pharmaceutical composition includes at least one matrix on which its API resides. In some embodiments, the active pharmaceutical composition includes at least two matrices on which its API resides. In some embodiments, the active pharmaceutical composition includes at least three matrices on which its API resides. In some embodiments, the active pharmaceutical composition includes at least four matrices on which its API resides. In some embodiments, the active pharmaceutical composition includes at least five matrices on which its API resides.

[0088] In some embodiments, the pharmaceutical composition is designed to be delivered orally and is in the form of a patch, powder, suspension, or liquid.

[0089] In some embodiments, the pharmaceutical compositions have a single active ingredient. These may be delivered in the absence of other compositions having an active ingredient, or may be co-administered with other compounds that are active ingredients which may or may not be present in structure (1). Where co-administration exists, in some embodiments, the first agent (which may or may not be the pharmaceutical composition of the present invention) may be administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, or 4 weeks before) the administration of the second therapeutic agent (which may or may not be the pharmaceutical composition of the present invention), simultaneously with its administration, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapeutic agent (which may or may not be the pharmaceutical composition of the present invention).

[0090] In some embodiments, the pharmaceutical composition is designed to be administered orally and contains at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, and at least 9 mg. Contains 0 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 750 mg, at least 1,000 mg, at least 1,250 mg, at least 1,500 mg, at least 1,750 mg, at least 2,000 mg, or 2,000 mg or more of the active pharmaceutical ingredient of structure (1).

[0091] In some embodiments, the pharmaceutical composition is designed to be administered orally and contains a pharmacoactive ingredient of structure (1) in a therapeutic or prophylactic dose of at least 0.001 mg / kg, at least 0.01 mg / kg, at least 0.1 mg / kg, at least 1 mg / kg, at least 5 mg / kg, at least 10 mg / kg, at least 25 mg / kg, at least 50 mg / kg, at least 100 mg / kg, at least 150 mg / kg, at least 200 mg / kg, and / or 200 mg / kg or more.

[0092] In some embodiments, systemic drug release of the oral composition containing the above-mentioned active pharmaceutical ingredient occurs with a therapeutically active onset occurring within 1 minute or less, 3 minutes or less, 5 minutes or less, 7 minutes or less, 9 minutes or less, 11 minutes or less, 13 minutes or less, 15 minutes or less, 17 minutes or less, 19 minutes or less, 21 minutes or less, 23 minutes or less, 25 minutes or less, 27 minutes or less, 30 minutes or less, 45 minutes or less, 60 minutes or less, 90 minutes or less, 120 minutes or less, 150 minutes or less, or 180 minutes or less.

[0093] In some embodiments, the duration of action of the oral composition containing the above-mentioned active pharmaceutical ingredient is at least 5 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 18 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, 1 week or more, 1 month or more, 3 months or more, 6 months or more, 1 year or more, or at least once in a lifetime.

[0094] In some embodiments, the pharmaceutical composition is in the form of a liquid formulation delivered by ip, intravenous (iv), intramuscular (im), subcutaneous (sc), or other implantable injection. The pharmaceutical active ingredient may be injected together with an inert component that solubilizes and stabilizes the pharmaceutical active ingredient for appropriate therapeutic delivery. The formulation may also include, but is not limited to, solvents such as: physiological saline, water, methanol, ethanol, PEG, isopropyl alcohol, propylene glycol, dipropylene glycol, dimethyl sulfoxide (DMSO), or functional derivatives thereof, and combinations thereof.

[0095] In some embodiments, injectable or implantable formulations use oils or surfactants to solubilize the active pharmaceutical ingredient, stabilize the active pharmaceutical ingredient, or enhance the delivery of the active pharmaceutical ingredient. Examples of such oils may include, but are not limited to, fatty acids and oils: castor oil, coconut oil, medium-chain triglycerides (MCTs), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, shea butter, or other esters, triglycerides or functional derivatives thereof, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, fatty acid monoglycerides or mixtures of fatty acid monoglycerides having a total monoester content of at least 51% (where the monoester has 10 to 20 carbon atoms), and mixtures of fatty acid monoglycerides, fatty acid diglycerides, and fatty acid triglycerides. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid. Monoglyceride penetration enhancers include, for example, glycerol monooleate, glycerol monolaurate, and glycerol monolinoleate. Examples of surfactants include, but are not limited to, polysorbates (e.g., Tween®, Polysorbate (20)), sorbitan (Span®), phospholipids (lecithin), lauryl sulfate, betaine, propionate, fatty alcohols and alkanolamides, fatty acid esters, amine oxides, myristates, and azons.

[0096] In some embodiments, the injectable or implantable formulations use stabilizers to protect the formulation or the active pharmaceutical ingredient. Examples of these stabilizers include, but are not limited to, antibacterial, antifungal, antiviral agents, or similar drugs known to those skilled in the art to inhibit microbial growth. Common preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chlorides, phenols, chlorhexidine, citrate, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts, and alcohols. Furthermore, pH adjusters may be used to improve shelf life and stabilize the active pharmaceutical ingredient within the pH range of 0–2, 2–4, 4–6, 6–8, 8–10, 10–12, or 12–14. In addition, ionic charged agents known to those skilled in the art may be used to stabilize emulsified formulations of the active pharmaceutical ingredient.

[0097] In some embodiments, the injectable or implantable formulations may be sterilized before or after packaging. Common examples of sterilization include, but are not limited to, gamma irradiation, ultraviolet light, ethylene oxide, hydrogen peroxide, peracetic acid, or filtration. The final formulation may be sufficiently sterile of pathogens before injection into the target (e.g., a patient, person, or animal requiring it).

[0098] In some embodiments, the injectable or implantable formulation contains at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 750 mg, at least 1,000 mg, at least 1,250 mg, at least 1,500 mg, at least 1,750 mg, at least 2,000 mg, or 2,000 mg or more of the active pharmaceutical ingredient.

[0099] In some embodiments, the injectable or implantable formulation contains a therapeutic or prophylactic dose of the active pharmaceutical ingredient in an amount of at least 0.001 mg / kg, at least 0.01 mg / kg, at least 0.1 mg / kg, at least 1 mg / kg, at least 5 mg / kg, at least 10 mg / kg, at least 25 mg / kg, at least 50 mg / kg, at least 100 mg / kg, at least 150 mg / kg, at least 200 mg / kg, and / or 200 mg / kg or more.

[0100] In some embodiments, the systemic drug release of the injectable or implantable formulation contains the active pharmaceutical ingredient, and the systemic drug release of the injectable or implantable formulation is designed so that therapeutically effective onset occurs within 1 minute or less, 3 minutes or less, 5 minutes or less, 7 minutes or less, 9 minutes or less, 11 minutes or less, 13 minutes or less, 15 minutes or less, 17 minutes or less, 19 minutes or less, 21 minutes or less, 23 minutes or less, 25 minutes or less, 27 minutes or less, 30 minutes or less, 45 minutes or less, 60 minutes or less, 90 minutes or less, 120 minutes or less, 150 minutes or less, and 180 minutes or less.

[0101] In some embodiments, the duration of the therapeutic or prophylactic effect of the injectable or implantable formulation is at least 5 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 18 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, 1 week or more, 1 month or more, 3 months or more, 6 months or more, 1 year or more, or at least once in a lifetime.

[0102] In some embodiments, topical or transdermal pharmaceutical compositions are in the form of sprayable liquids, gels, creams, lotions, ointments, and transdermal patches, in which the pharmacokinetic active ingredient is injected together with an inert component that enhances the delivery properties of the composition and stabilizes the pharmacokinetic active ingredient. In one embodiment, the penetration enhancer may be an inert component. Possible but not limited to the following are fatty acids and oils: castor oil, coconut oil, medium-chain triglycerides (MCTs), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, shea butter, or other esters, triglycerides, or functional derivatives thereof.

[0103] In some embodiments, surfactants may be used as emulsifiers in topical or transdermal delivery systems, and stabilizers may be used to encapsulate the drug for better stability and penetration properties. Examples of surfactants include, but are not limited to, polysorbates (e.g., Tween®, Polysorbate (20)), sorbitan (Span®), phospholipids (lecithin), lauryl sulfate, betaine, propionate, fatty alcohols and alkanolamides, fatty acid esters, amine oxides, myristates, and azons.

[0104] In some embodiments, cosolvents may be used in topical or transdermal formulations to improve the solubility and permeability of the drug, while also acting as a humectant for a better skin feel. Common cosolvents include, but are not limited to, alcohols such as ethanol, isopropanol, glycerin, propylene glycol, dipropylene glycol, polyethylene glycol, diethylene monoethyl ether, cremofol, siloxane, polyethylene, and water.

[0105] In some embodiments, thickeners can be used in topical or transdermal formulations to reduce separation and provide a suitable matrix for modified delivery. Common thickeners include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenan, gums, resins, polysaccharides, and high-melting-point waxes and oils (e.g., beeswax, coconut oil, palm oil, soybean oil), stearic acid, rapeseed, cocoa butter, shea butter, gums, rosin, resins, paraffin, and petrolatum.

[0106] In some embodiments, tackifiers can be used to increase adhesion in transdermal formulations for long-term wearability. Common tackifiers include, but are not limited to, gums, resins (natural or modified resins), carbomers, or other natural or synthetic polymers.

[0107] In some embodiments, preservatives may be used in topical or transdermal formulations to improve formulation stability and delay microbial growth. Common preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chlorides, phenols, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts, and alcohols. Additionally or alternatively, the formulation may be emulsified with a hydrophilic component (e.g., water or Aloe barbadensis juice).

[0108] In some embodiments, the transdermal dosage form is a transdermal delivery device. Any device conventional in the art for transdermal delivery of therapeutic agents to a target may be used as a transdermal delivery device for transdermal delivery of the composition of the present invention. For example, the transdermal delivery device may be a reservoir-type transdermal delivery device, a polymer-matrix-type transdermal delivery device, a drug-containing adhesive-type transdermal delivery device, or a multilaminate-type transdermal delivery device. The transdermal delivery device may be designed so that the pharmacopoeia active ingredient of the present invention is delivered in a therapeutically effective amount when in contact with the target skin.

[0109] In some embodiments, the transdermal delivery device is a drug-containing adhesive device containing a medicinal active ingredient directly dispersed in a pressure-sensitive adhesive matrix. The adhesive matrix may be supported on its top by an impermeable backing film and on its skin-facing side by an impermeable release liner. To administer the medicinal active ingredient, the release liner is removed, exposing the adhesive matrix and bringing the device into contact with the skin. The adhesive matrix functions to adhere the device to the skin, typically controlling the delivery rate of the medicinal active ingredient. Similar to polymer-matrix designs, the design of this drug-containing adhesive allows the medicinal active ingredient to diffuse out of the adhesive matrix, come into contact with the target skin, and penetrate the skin. The delivery rate of the medicinal active ingredient is typically determined by the rate of diffusion of the medicinal active ingredient(s) from the adhesive matrix. Multiple drug-containing adhesive layers may be laminated together between rate-controlling films for longer-duration delivery. The delivery rate is such that an effective amount of the medicinal active ingredient is delivered to the target (e.g., a patient) that requires it.

[0110] In some embodiments, a reservoir-type transdermal delivery device includes a reservoir (typically liquid or semi-solid) located between an impermeable backing film and a rate-controlling membrane covered with a pressure-sensitive adhesive skin-contact layer. The reservoir (which may be a solution or suspension) contains the composition of the present invention. The transdermal delivery device may be supported by an impermeable backing film, and the surface of its adhesive is protected by a release liner. To administer the active pharmaceutical ingredient of the present invention, the release liner is removed to expose the pressure-sensitive adhesive, which is then brought into contact with the skin. The active pharmaceutical ingredient of the present invention is permeable to the rate-controlling membrane, penetrates through the membrane, the adhesive comes into contact with the skin, and then penetrates into the skin. The delivery rate of the active pharmaceutical invention is typically determined by the rate at which the active pharmaceutical ingredient penetrates the rate-controlling membrane.

[0111] In some embodiments, the transdermal delivery device is of a polymer-matrix design. In this polymer-matrix design, the API can be dispersed in a polymer matrix that controls the delivery rate. Preferably, the polymer-matrix reservoir is supported on an impermeable backing layer. An adhesive layer is attached to the surface of the polymer matrix. To administer the active pharmaceutical ingredient, the release liner is removed, exposing the polymer matrix and the ring of pressure-sensitive adhesive, and the device is brought into contact with the skin. The adhesive holds the device against the skin so that the polymer matrix is ​​in direct contact with the skin. Once the polymer matrix is ​​in contact with the skin, the active pharmaceutical ingredient(s) diffuse out of the polymer matrix, come into contact with the patient's skin, and penetrate the skin. The delivery rate of the active pharmaceutical ingredient is typically determined by the diffusion rate of the active pharmaceutical ingredient out of the polymer matrix.

[0112] Adhesives may contain crosslinkable monomer units or crosslinkable sites that can be incorporated into adhesive polymers. For example, a crosslinkable monomer may be incorporated into a polyacrylate polymer. The crosslinkable monomer may, for example, provide sites for crosslinking the polymer matrix after its API has been dispersed in the polymer. Known adhesives include crosslinkable monomers for polyacrylate polymers, and known adhesives include, for example: polymethacrylates of polyols (e.g., butylene diacrylate, butylene dimethacrylate, and trimethylolpropane trimethacrylate), polyisobutylene-type adhesives, and silicones. Other monomers that provide crosslinking sites include: allyl acrylate, allyl methacrylate, diallyl maleate, silyl ethers, and silanes. The monomers are then polymerized using methods known to those skilled in the art to form a polyacrylate (acrylic) adhesive matrix, a polysiloxane (silicone) adhesive matrix, or a polyisobutylene (or other rubber) adhesive matrix containing a crosslinking agent, a functional group, or vinyl acetate for suspending, stabilizing, and releasing the above-mentioned pharmaceutical active ingredient.

[0113] In some embodiments of the present invention, the transdermal delivery device may optionally contain one or more penetration enhancers, which increase the rate at which the medicinal active ingredient penetrates the target skin. Preferably, the penetration enhancer penetrates a rate control membrane or diffuses outward from a polymer matrix or adhesive matrix, and as a result, the penetration enhancer can come into contact with the target skin and improve the penetration of the medicinal active ingredient as defined herein through the target skin.

[0114] Suitable penetration enhancers for use in the transdermal delivery devices and compositions of the present invention include: for example, C 2~4Alcohols (e.g., ethanol and isopropanol), polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyllauramide, polysorbate, sorbitan, fatty acids, esters of fatty acids having about 10 to about 20 carbon atoms, monoglycerides of fatty acids or mixtures of monoglycerides of fatty acids having at least 51% total monoester content (the monoester having 10 to 20 carbon atoms), and mixtures of monoglycerides of fatty acids, diglycerides of fatty acids, and triglycerides of fatty acids. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid. Examples of monoglyceride penetration enhancers include, for example, glycerol monooleate, glycerol monolaurate, and glycerol monolinoleate.

[0115] Additionally or alternatively, terpenes and terpenoids derived from natural isoprene biosynthesis may be used. These may be utilized to disrupt the skin film and increase API penetration. Examples of terpenes include, but are not limited to, menthol, menthone, camphor, nerolidol, limonene, myrcene, anethole, eugenol, 1,8-cineole, terpinolene, pinene, and humulene. In certain embodiments, the transdermal patches described herein are used in co-administration with a penetration enhancer. In certain embodiments, the penetration enhancer may include, but are not limited to, oils such as: castor oil, coconut oil, medium-chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, and shea butter. Other penetration enhancers for use in transdermal patches include, for example, C 2~4Alcohols (e.g., ethanol and isopropanol), polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyllauramide, polysorbate (Tween®), sorbitan (Span®), fatty acids, esters of fatty acids having about 10 to about 20 carbon atoms, monoglycerides of fatty acids or mixtures of monoglycerides of fatty acids having at least 51% total monoester content (the monoesters having 10 to 20 carbon atoms), and mixtures of monoglycerides of fatty acids, diglycerides of fatty acids, and triglycerides of fatty acids. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid. Examples of monoglyceride penetration enhancers include glycerol monooleate, glycerol monolaurate, and glycerol monolinoleate.

[0116] In some embodiments, the active pharmaceutical ingredient may be delivered by a daily topical application or transdermal patch. In some embodiments, the API may be delivered in less than 6 hours. In some embodiments, the API may be delivered between 6 and 12 hours. In some embodiments, the API may be delivered over a period of 12 to 24 hours. In some embodiments, the API may be delivered over a period of 24 to 48 hours. In some embodiments, the transdermal patch may be applied every 2 days; every 3 days; every 4 days; every 5 days; every 6 days; or every 7 days. The choice of transdermal patch delivery rate facilitates drug compliance with the target patient while simultaneously delivering a safe and effective systemic drug concentration at a steady state.

[0117] In some embodiments, the transdermal composition or topical composition contains at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 750 mg, at least 1,000 mg, at least 1,250 mg, at least 1,500 mg, at least 1,750 mg, at least 2,000 mg, or 2,000 mg or more of a pharmaceutical active ingredient.

[0118] In some embodiments, the transdermal composition or topical composition contains a therapeutic or prophylactic dose of a medicinal active ingredient in an amount of at least 0.001 mg / kg, at least 0.01 mg / kg, at least 0.1 mg / kg, at least 1 mg / kg, at least 5 mg / kg, at least 10 mg / kg, at least 25 mg / kg, at least 50 mg / kg, at least 100 mg / kg, at least 150 mg / kg, at least 200 mg / kg, and / or 200 mg / kg or more.

[0119] In some embodiments, the pharmaceutical composition is in the form of a liquid or gel, delivered transmucosally by delivery through the nose, mouth, lungs, buccal, sublingual, rectum, or another suitable membrane. The active pharmaceutical ingredient is injected together with an inert component that solubilizes and stabilizes the active pharmaceutical ingredient for appropriate therapeutic delivery. The formulation may contain a solvent. Examples of solvents include, but are not limited to, saline, water, methanol, ethanol, PEG, isopropyl alcohol, propylene glycol, dipropylene glycol, dimethyl sulfoxide (DMSO), or functional derivatives thereof.

[0120] In some embodiments, transmucosal formulations use oils or surfactants to solubilize the active pharmaceutical ingredient, stabilize the active pharmaceutical ingredient, or enhance the delivery of the active pharmaceutical ingredient. Examples of such oils may include, but are not limited to, fatty acids and oils: castor oil, coconut oil, medium-chain triglycerides (MCTs), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, shea butter, or other esters, triglycerides, or functional derivatives thereof, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, fatty acid monoglycerides or mixtures of fatty acid monoglycerides having a total monoester content of at least 51% (where the monoester has 10 to 20 carbon atoms), and mixtures of fatty acid monoglycerides, fatty acid diglycerides, and fatty acid triglycerides. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid. Monoglyceride penetration enhancers include, for example, glycerol monooleate, glycerol monolaurate, and glycerol monolinoleate. Examples of surfactants include, but are not limited to, polysorbates (e.g., Tween®, Polysorbate (20)), sorbitan (Span®), phospholipids (lecithin), lauryl sulfate, betaine, propionate, fatty alcohols and alkanolamides, fatty acid esters, amine oxides, myristates, and azons.

[0121] In some embodiments, the transmucosal formulations use stabilizers to protect the formulation or the active pharmaceutical ingredient. Examples of stabilizers include, but are not limited to, antibacterial agents, antifungal agents, antiviral agents, or similar drugs known to those skilled in the art to inhibit microbial growth. Additionally or alternatively, preservatives may be included. Common preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chlorides, phenols, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts, and alcohols. Furthermore, pH adjusters may be used to improve shelf life and stabilize the active pharmaceutical ingredient within the pH range of 0–2, 2–4, 4–6, 6–8, 8–10, 10–12, or 12–14. Additionally or alternatively, ionic chargers known to those skilled in the art may be used to stabilize emulsified formulations of the active pharmaceutical ingredient.

[0122] In some embodiments, the transmucosal formulations use thickeners to reduce formulation separation and provide a matrix for targeted drug delivery. Examples of thickeners include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenan, polysaccharides, and high-melting-point waxes and oils (e.g., beeswax, coconut oil, palm oil, soybean oil), stearic acid, rapeseed, cocoa butter, shea butter, gum, rosin, resins, paraffin, and petrolatum.

[0123] In some embodiments, the transmucosal formulation may be sterilized before or after packaging. Common examples of sterilization include, but are not limited to, gamma irradiation, ultraviolet light, ethylene oxide, hydrogen peroxide, peracetic acid, or filtration. The final formulation may be sufficiently sterile of pathogens before injection into the target (e.g., a patient, person, or animal requiring the formulation).

[0124] In some embodiments, the transmucosal formulation may be paired with a device to facilitate delivery to the nose, mouth, lungs, buccal, sublingual, rectal, or through another suitable membrane. Examples of formulations and devices include, but are not limited to, sprays, liquids, gels, nebulizers, pneumatic delivery devices, or pressurized delivery devices.

[0125] In some embodiments, the transmucosal preparation contains at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 750 mg, at least 1,000 mg, at least 1,250 mg, at least 1,500 mg, at least 1,750 mg, at least 2,000 mg, or 2,000 mg or more of the active pharmaceutical ingredient.

[0126] In some embodiments, the transmucosal preparation contains a therapeutic or prophylactic dose of the active pharmaceutical ingredient in an amount of at least 0.001 mg / kg, at least 0.01 mg / kg, at least 0.1 mg / kg, at least 1 mg / kg, at least 5 mg / kg, at least 10 mg / kg, at least 25 mg / kg, at least 50 mg / kg, at least 100 mg / kg, at least 150 mg / kg, at least 200 mg / kg, and / or 200 mg / kg or more.

[0127] In some embodiments, systemic drug release of the transmucosal preparation occurs within 1 minute or less, 3 minutes or less, 5 minutes or less, 7 minutes or less, 9 minutes or less, 11 minutes or less, 13 minutes or less, 15 minutes or less, 17 minutes or less, 19 minutes or less, 21 minutes or less, 23 minutes or less, 25 minutes or less, 27 minutes or less, 30 minutes or less, 45 minutes or less, 60 minutes or less, 90 minutes or less, 120 minutes or less, 150 minutes or less, or 180 minutes or less, resulting in a therapeutically effective manifestation.

[0128] In some embodiments, the duration of the therapeutic or preventive effect of the transmucosal preparation is at least 5 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 18 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, 1 week or more, 1 month or more, 3 months or more, 6 months or more, 1 year or more, or at least once in a lifetime.

[0129] As described herein, certain formulations are useful in enabling methods related to various dosages and / or durations of administration; providing alternative pharmacokinetic, pharmacodynamic, and / or safety profiles; enabling long-term maintenance therapy; and providing trials for novel indications for psychotropic agents.

[0130] Provided herein are methods for preventing, managing, and treating neurological disorders, mood disorders, or addiction disorders (including, but not limited to, depression, anxiety, central nervous system inflammation, Lyme disease, prion diseases, amoebic diseases, schizophrenia, Parkinson's disease, addiction (alcohol, tobacco, opioids, nicotine, tobacco, stimulants, sedatives, gambling, sex, and / or technology), headaches, PTSD, obsessive-compulsive disorder, eating disorders, pain (acute or chronic), amyotrophic lateral sclerosis, frontotemporal dementia and other dementias, Alzheimer's disease (AD), or cognitive impairment and memory impairment).

[0131] In some embodiments, the above-mentioned active pharmaceutical ingredient is co-administered with one or more therapeutic agents. These co-administered agents may include, for example, compounds of the following types: antipsychotics, antidepressants, anxiolytics, stimulants, reuptake inhibitors (SSRIs or SSNRIs), monoamine oxidase inhibitors (MAOIs), cognitive enhancers, tricyclic antidepressants, mood stabilizers, NMDA antagonists, and 5-HT agonists or 5-HT antagonists.

[0132] In yet another embodiment, the compound of structure (1) is co-administered alone or in a mixture with one or more therapeutic agents to reduce substance abuse. For the treatment of opioid addiction, other co-administered compounds may include: methadone, buprenorphine, naloxone, naltrexone, etc. For the treatment of alcohol dependence, other co-administered compounds may include: ethyl alcohol, disulfiram, naltrexone, acamprosate, benzodiazepines, etc. For the treatment of nicotine addiction, other co-administered compounds may include: low-dose nicotine, bupropion, varenicline, etc.

[0133] As a non-limiting example, the above compounds include the compounds in structure (1), or their pharmaceutically acceptable salts, solvates, or prodrugs (e.g., 2-(2-bromo-1H-indole-3-yl)-N,N-dimethylethane-1-amine; 2-(2-chloro-1H-indole-3-yl)-N,N-dimethylethane-1-amine; 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl acetate; 2-bromo2-(dimethylamino)ethyl)-1H-indole-4-yl acetate; 2-bromo-indole-3-yl)-N,N-dimethylethane-1-amine; 3-(dimethylamino)ethyl)-1H-indole-4-yl acetate; 2-bromo-indole-3-yl)-N,N-dimethylethane-1-amine; 2-(dimethylamino)ethyl)-N,N-dimethylamino)ethyl) These may be rom-3-(2-(dimethylamino)ethyl)-1H-indole-4-yl acetate; N-(2-(2-bromo-1H-indole-3-yl)ethyl)-N-isopropylpropan-2-amine; N-(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)methanesulfonamide; and N-(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)acetamide). Examples of salts of these compounds include, but are not limited to, HBr salts. In some embodiments, the above pharmaceutical compositions may be designed as immediate-release or sustained-release formulations, in the form of tablets or capsules.

[0134] In some embodiments, the pharmaceutical composition is designed such that its therapeutically effective dose is 5 mg / kg to 25 mg / kg in mice, or 0.01 mg / kg to 35 mg / kg in humans, or 0.01 mg / kg to 25 mg / kg in humans, or 0.01 mg / kg to 20 mg / kg in humans, or 0.1 mg / kg to 10 mg / kg in humans, or 0.4 mg / kg to 4 mg / kg in humans, or 0.4 mg / kg to 2 mg / kg in humans, or 1 mg / kg to 1.5 mg / kg in humans. As those skilled in the art will recognize, human formulations may be designed based on the effective dose in animals (e.g., mice). For example, see Nair, Anroop B. and Jacob, Sherry, A Simple Practice Guide for Dose Conversion Between Animals and Human, Journal of Basic and Clinical Pharmacy, pp. 27-31 (2016) (this is incorporated by reference). As a non-limiting example, the pharmaceutical composition may contain 2-(2-bromo-1H-indole-3-yl)-N,N-dimethylethane-1-amine, which may be administered as a single dose or daily or twice daily over a period of at least 5, at least 7, at least 10, or at least 14 days.

[0135] Table 9 provides examples of tablet formulations within the scope of the present invention.

[0136] [Table 9]

[0137] Table 10 provides examples of specific tablet formulations.

[0138] [Table 10]

[0139] Table 11 provides examples of specific tablet formulations.

[0140] [Table 11]

[0141] Table 12 provides examples of capsule formulations within the scope of the present invention.

[0142] [Table 12]

[0143] Table 13 provides examples of specific capsule formulations.

[0144] [Table 13]

[0145] Table 14 provides examples of specific capsule formulations.

[0146] [Table 14]

[0147] Table 15 provides examples of specific capsule formulations.

[0148] [Table 15] [Examples]

[0149] (Examples)

[0150] (Example 1 - Assay)

[0151] In vitro radioligand binding assays for various serotonergic receptors and sigma receptors are shown in Tables 1A and 1B.

[0152] [Table 1A-1] [Table 1A-2] [Table 1A-3]

[0153] [Table 1B-1] [Table 1B-2] [Table 1B-3]

[0154] In vitro receptor pharmacology reveals a wide range of serotonergic receptor and sigma receptor activity associated with various mental health disorders and neurodegenerative disorders.

[0155] (Example 2 - In vitro functional activity)

[0156] Table 2 below shows the functional activity of specific compounds. This functional activity is examined in comparison to agonism and antagonistism. In vitro pharmacology of specific serotonergic receptors shows agonism at 5-HT2A, 5-HT2C, and 5-HT6, but inverse agonism at 5-HT7A. Each of these receptors influences mental health, learning, and memory, and more specifically, 5-HT6 is involved in predictive effects as well as neuronal connectivity, neuronal growth, and neuronal migration.

[0157] [Table 2-1] [Table 2-2]

[0158] (Example 3 - Formulation used in in vivo animal experiments)

[0159] Formulations for the compounds identified in Example 2 were prepared. These formulations were used in mice for intravenous injection and in rats as oral formulations via po for PK / BBB, within limits that showed minimal side effects or minimal excipient incompatibility. The final concentration of each compound was approximately 5 mg / mL. For each compound, a typical formulation within the weight percentage range shown in Table 3 was used.

[0160] [Table 3]

[0161] (Example 4 - Mouse head-shaking response in vivo)

[0162] The head-shaking response is a preclinical assay that tests the hallucinogenic effect in mice by counting the number of times they shake their heads compared to a negative control (vehicle) or a positive control (4-AcO-DMT (a psilocybin-like psilocybin prodrug)), which is a hallucinogenic substance. The head-shaking response data for each compound (provided in Table 4 below) did not show statistically significant head shaking compared to the formulation vehicle. This indicates that each tryptamine derivative is unlikely to induce hallucinations induced by the 5-HT2A receptor in humans.

[0163] [Table 4-1] [Table 4-2]

[0164] (Example 5 - In vivo forced swimming test in mice)

[0165] The two-day Porsolt forced swim test is a preclinical assay to test the antidepressant effects in mice. Behavior on day 1 is generally presumed to be related to resilience, and longer swim times show similar antidepressant effects to the positive control (4-AcO-DMT). Behavior on day 2 is more likely to assess learning and memory, and shorter swim times indicate learning to be saved. The minimum effective dose for each active compound is presented in Table 5, which shows that each of the compounds shown has longer swim times on day 1 compared to the vehicle and shorter swim times on day 2 compared to the vehicle, indicating potential antidepressant effects as well as benefits for learning and memory.

[0166] [Table 5-1] [Table 5-2]

[0167] (Example 6 - In vivo mouse elevated cross maze)

[0168] The elevated cusp maze is a preclinical assay to test the anxiolytic effects in mice. Longer time spent in the open-arm sections or entry into the open-arm sections indicates similar anxiolytic effects to the positive control (4-AcO-DMT). As shown in Table 6, the results of this elevated cusp maze indicate that each compound has a potential anxiolytic effect that surpasses the anxiolytic effect shown by the placebo vehicle alone within the indicated dose range. Each compound showed greater entry into the arm sections and longer time spent in the open-arm sections compared to the vehicle.

[0169] [Table 6-1] [Table 6-2]

[0170] (Example 7 - In vivo fear extinction and conditioning in mice)

[0171] The fear extinction and conditioning model is a preclinical assay that involves performing a stimulus and testing the reaction time and recognition of that stimulus. This bridging model can relate anxiety, PTSD, memory, and predictive effects to a positive control (4-AcO-DMT). As shown in Table 7, each compound was shown to have a reduction in fear responses in the behavior of mice in this fear extinction and conditioning within the indicated dose range, suggesting potential in anxiety disorders, PTSD, learning disabilities, and memory impairments.

[0172] [Table 7]

[0173] (Example 8 - Reduction in alcohol consumption in mice in vivo)

[0174] To test the ability to suppress alcohol consumption, mice were given free access to 8%–20% alcohol for two weeks. Alcohol consumption was monitored for two weeks after daily administration of the test compound, relative to a positive control (4-AcO-DMT). Further studies extended this experiment to 60 days for three different doses, administering the test compound every three days to the mice. Alcohol consumption decreased similarly to near zero at 25 mg / kg and 35 mg / kg over the 60-day period, without any signs of tolerance development or negative effects. As shown in Table 8, the compound halted alcohol consumption in addicted mice within the indicated dose range, suggesting potential applications in human addiction (e.g., alcohol use disorder).

[0175] [Table 8]

[0176] (Example 9 - Comparison of oral and intravenous pharmacokinetics)

[0177] Using the formulation from Example 3, which contains 2-(2-bromo-1H-indole-3-yl)-N,N-dimethylethane-1-amine hydrobromide (also known as 2-Br-4-AcO-DMT*HBr), pharmacokinetic (PK) and metabolite profiles were established.

[0178] The pharmacokinetics (PK) of rats (Figure 6) were evaluated at an oral dose of 10 mg / kg and intravenously at 1 mg / kg. 2-Br-4-AcO-DMT*HBr was rapidly metabolized to its active metabolite, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indole-4-ol) (also called 2-Br-4-OH-DMT), by deacetylation within minutes of oral or intravenous (IV) administration. Its PK and brain concentration were evaluated by comparing plasma and brain concentrations in a cohort of three mice for each dose group. Table 16 below shows a summary of the PK parameters for the 10 mg / kg oral dose. 66% bioavailability was achieved by the conversion of 2-Br-4-AcO-DMT*HBr to 2-Br-4-OH-DMT via oral administration.

[0179] [Table 16]

[0180] Table 17 shows an overview of the PK parameters for intravenous (IV) administration at a dose of 1 mg / kg.

[0181] [Table 17]

[0182] Table 18 lists the comparisons between brain and plasma concentrations of 2-Br-4-AcO-DMT*HBr, derived from oral and intravenous (IV) administration, based on the detection of active 2-Br-4-OH-DMT.

[0183]

[0184] [Table 18]

[0185] (Example 10 - Nasal preparation)

[0186] The following formulations were prepared for intranasal delivery: 0.9% physiological saline and 0.1% DMT fumarate.

[0187] The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of rats were collected. Comparisons of the rat PK (Figures 1A, 1B, 1C, and 1D) and PD (Figures 2A and 2B) included a comparison of intranasal and subcutaneous (sc) formulations of DMT fumarate at three different doses. The detected concentrations of both DMT and its metabolite, DMT-N-oxide (DMT-NO), were determined using a modified method similar to that of Eckernas et al. (Journal of Pharmaceutical and Biomedical Analysis 2022). Each dose group contained six rats, which were restrained before administration to allow for complete intranasal administration. The intranasal (in) dose of 3 mg / kg of DMT in rats was similar to the intravenous (iv) dose in humans. max (60 ng / mL) is produced (Figure 1A- to Figure 1D). A similar maximum effect (t) is observed in human intravenous (iv) doses. max The onset time (10 minutes) and duration (<60 minutes) were observed for intranasal (in) doses. Intranasal (in) administration of DMT also resulted in dose-dependent hypothermia, as observed in similar studies on psychotropic agents (Figures 2A-2B). See Glatfelter, GC et al., ACS Pharmacology and Translational Science 2022, 5, 1181-1196, DOI:10.1021 / acsptsci.2c00177. The data show that these formulations provide desirable results when administered intranasally.

[0188] Intranasal (in) delivery of N,N-dimethyltryptamine (DMT) eliminates the need for currently available invasive delivery routes in FDA clinical trials and avoids issues associated with DMT instability that could render some oral formulations (e.g., capsules or tablets) unfeasible as a delivery option. Furthermore, using intranasal delivery can overcome the bioavailability challenges reported with DMT formulations while still providing rapid onset of action, duration of action, and required plasma levels for effective administration.

[0189] (Example 11. Evaluation of CNS biomarkers of 2-Br-4-AcO-DMT (HBr salt))

[0190] To evaluate the effects on neuroplasticity and inflammatory biomarkers, in vitro assays were performed using the mouse immortalized hippocampal neuron cell line HT22, cloned from HT4 cells. Ketamine and psilacetin were used as control compounds, and the cells were exposed to 2-Br-4-AcO-DMT HBr salt for 24 hours. Brain-derived neurotrophic factor (BDNF; Figures 3B1 and 3B2) was quantified for neuroplasticity, and the cytokines interleukin-6 (IL-6; Figures 3A1 and 3A2) and TNFα (Figures 3C1 and 3C2) were quantified for inflammation, with or without pro-inflammatory treatment with lipopolysaccharide (LPS). LPS-induced inflammation is a model for neuroinflammation similar to that observed in patients with neurodegenerative disorders. Our data show that 2-Br-4-AcO-DMT reduces IL-6 and TNFα in stressed LPS cells (Figures 3A1, 3A2, 3C1, and 3C2) and increases BDNF, a neuroplasticity marker, in control cells (Figures 3B1 and 3B2). IL-6 levels are elevated in patients with frontotemporal dementia and other neurodegenerative disorders, particularly in patients in a disinhibited state.

[0191] (Example 12. Brain tissue protein expression in mice after treatment with 2-Br-4-AcO-DMT (HBr salt))

[0192] Metabotropic glutamate receptor 2 (mGlu2) expression in the prefrontal cortex was quantified after in vivo mouse studies. Modulation of metabotropic glutamate receptor 2 (mGlu2) levels in alcohol-seeking rats may reduce relapse behavior. Tissue was collected from multiple brain regions of male C57BL / 6J mice after 18 days of daily treatment with vehicle, silacetin, or 25 mg / kg of 2-Br-4-AcO-DMT (shown as 25 mg / kg in Figures 4A-4C) under either stress-free conditions or 2 hours of tube restraint daily. Mice treated with 2-Br-4-AcO-DMT showed reduced mGluR2 expression in both stress-free and stress-stressed mice (Figures 4A and 4B, two representative samples from each condition), outperforming the effect of silacetin (n=5-6; data calculated relative to actin and then normalized to vehicle) (Figure 4C). The data in Figure 4C are expressed as mean ± standard error of the mean (SEM).

[0193] (Example 13. Crystal structure of 2-Br-4-AcO-DMT bromide salt)

[0194] To produce the HBr salt form of 2-Br-4-AcO-DMT, 4-AcO-DMT was placed in a heated and dried round-bottom flask under argon. Anhydrous dichloromethane (DCM) was added to the flask. In a separate round-bottom flask, trimethylphenylammonium tribromide (PTT) was dissolved in anhydrous DCM under argon. The PTT solution was added dropwise to the reaction mixture. The reaction mixture was stirred for 20 minutes and then concentrated under reduced pressure. The crude product was loaded onto silica and purified by column chromatography using 0%-6% isopropyl alcohol in DCM. The pure product was subjected to isopropyl ether under reduced pressure to produce an azeotropic mixture and remove excess iPrOH. The product was finally subjected to freeze-dryer conditions to remove trace amounts of water.

[0195] The product was isolated as a grayish solid, a bromide salt. Figure 5 shows its crystal structure, which is monoclinic, P21 / c, and centrosymmetric (non-chiral). Within this structure, molecules form chains through NH…Br hydrogen bonds. The structure is further assembled through combinations of weak interactions (including CH…O, CH…π, CH…Br, and van der Waals). The structure contains four small voids (each approximately 10 A³) within the unit cell, and there is no electron density.

Claims

1. Structure (1): 【Chemistry 2】 A pharmaceutical composition comprising a compound defined by, or a pharmaceutically acceptable salt, solvate, metabolite, or prodrug thereof, in a therapeutically effective amount thereof R １ , Br, F, Cl, I, CF ３ Selected from the group consisting of and H; R ２ is H or CH ３ And; R ３ and R ４ each independently selected from the group consisting of CH ３ C ２ H ５ , (H ３ C) ２ CH, H ２ C=CH-CH ２ and H; R ５ OCOCH ３ OH, OCH ３ , O-phosphate, O-polyethylene glycol (PEG), O-(CH ２ ) ２ (COOH) ２ (succinate), O-(CH ２ ) ２ (COOH) (hemisuccinate), O-sulfate, fumarate, tartrate, maleate, sugar, amino acid, and CH ２ SO ２ NHCH ３ Selected from the group consisting of (sulfonamides); R １ If H, then R ５ CH ２ SO ２ NHCH ３ ,CH ２ NHSO ２ CH ３ , or CH ２ NHCON (CH ２ CH ３ ) ２ That is, Pharmaceutical composition.

2. R １ However, Br, F, Cl, I, and CF ３ A pharmaceutical composition according to claim 1, selected from the group consisting of the following.

3. R １ The pharmaceutical composition according to claim 2, wherein is Br.

4. The pharmaceutical composition according to claim 2, wherein the compound is the HBr salt of 4-AcO-2-Br-DMT.

5. R １ The pharmaceutical composition according to claim 2, wherein F is present.

6. R ５ ga OCOCH ３ The pharmaceutical composition according to claim 1.

7. R ５ ga OCOCH ３ The pharmaceutical composition according to claim 2.

8. R ５ ga OCOCH ３ The pharmaceutical composition according to claim 4.

9. R ５ ga OCOCH ３ The pharmaceutical composition according to claim 5.

10. R ２ The pharmaceutical composition according to claim 1, wherein is H.

11. R ２ The pharmaceutical composition according to claim 2, wherein is H.

12. R ２ The pharmaceutical composition according to claim 4, wherein is H.

13. R ２ The pharmaceutical composition according to claim 5, wherein is H.

14. R ２ The pharmaceutical composition according to claim 6, wherein is H.

15. R ２ The pharmaceutical composition according to claim 7, wherein is H.

16. R ２ The pharmaceutical composition according to claim 8, wherein is H.

17. R ２ The pharmaceutical composition according to claim 9, wherein is H.

18. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 1.

19. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 2.

20. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 4.

21. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 5.

22. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 6.

23. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 7.

24. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 8.

25. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 9.

26. R ３ is CH ３ and R ４ is CH ３ The pharmaceutical composition according to claim 10, wherein

27. R ３ ga CH ３ And R ４ ga CH ３ The pharmaceutical composition according to claim 11.

28. R ３ is CH ３ and R ４ is CH ３ The pharmaceutical composition according to claim 12, wherein.

29. R ３ CH ３ And R ４ CH ３ The pharmaceutical composition according to claim 13.

30. R ３ CH ３ And R ４ CH ３ The pharmaceutical composition according to claim 14.

31. R ３ CH ３ And R ４ CH ３ The pharmaceutical composition according to claim 15.

32. R ３ CH ３ And R ４ CH ３ The pharmaceutical composition according to claim 16.

33. R ３ CH ３ And R ４ CH ３ The pharmaceutical composition according to claim 17.

34. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 1.

35. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 2.

36. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 4.

37. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 5.

38. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 6.

39. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 7.

40. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 8.

41. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 9.

42. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 10.

43. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 11.

44. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 12.

45. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 13.

46. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 14.

47. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 15.

48. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 16.

49. R ３ is CH(CH ３ ) ２ And R ４ is CH(CH ３ ) ２ The pharmaceutical composition according to claim 17.

50. R ５ The pharmaceutical composition according to claim 1, wherein is OH.

51. R ５ The pharmaceutical composition according to claim 2, wherein is OH.

52. R ５ The pharmaceutical composition according to claim 10, wherein is OH.

53. R ５ The pharmaceutical composition according to claim 11, wherein is OH.

54. R ５ The pharmaceutical composition according to claim 18, wherein is OH.

55. R ５ The pharmaceutical composition according to claim 19, wherein is OH.

56. R ５ The pharmaceutical composition according to claim 27, wherein is OH.

57. R ５ The pharmaceutical composition according to claim 34, wherein is OH.

58. R ５ The pharmaceutical composition according to claim 35, wherein is OH.

59. R ５ The pharmaceutical composition according to claim 43, wherein is OH.

60. The pharmaceutical composition according to claim 1, wherein the compound is 2-(2-bromo-1H-indole-3-yl)-N,N-dimethylethane-1-amine.

61. The pharmaceutical composition according to claim 1, wherein the compound is 2-(2-chloro-1H-indole-3-yl)-N,N-dimethylethane-1-amine.

62. The pharmaceutical composition according to claim 1, wherein the compound is 3-(2-(dimethylamino)ethyl)-1H-indole-4-ylacetate.

63. The pharmaceutical composition according to claim 1, wherein the compound is 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indole-4-ylacetate.

64. The pharmaceutical composition according to claim 1, wherein the compound is N-(2-(2-bromo-1H-indole-3-yl)ethyl)-N-isopropylpropan-2-amine.

65. The pharmaceutical composition according to claim 1, wherein the compound is N-(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)methanesulfonamide.

66. The pharmaceutical composition according to claim 1, wherein the compound is N-(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)acetamide.

67. A pharmaceutical composition according to any one of claims 1 to 66, which is an orally delivered formulation.

68. A pharmaceutical composition according to any one of claims 1 to 66, which is an injectable delivery formulation.

69. A pharmaceutical composition according to any one of claims 1 to 66, which is an intranasal delivery preparation.

70. A pharmaceutical composition according to any one of claims 1 to 66, which is a transdermal administration preparation.

71. A pharmaceutical product comprising the pharmaceutical composition described in any one of claims 1 to 66.

72. Use of the pharmaceutical composition according to any one of claims 1 to 66 for the treatment, management, or prevention of one or more of the following: neurological disorders, mood disorders, or impulse control disorders.

73. A method for treating, managing, or preventing one or more disorders selected from the group consisting of neurological disorders, mood disorders, or impulse control disorders, comprising administering a pharmaceutical composition according to any one of claims 1 to 70 to a subject.

74. A method for treating, managing, or preventing a substance abuse disorder, comprising administering a pharmaceutical composition according to any one of claims 1 to 70 to a subject.

75. A method for treating, managing, or preventing a disorder selected from the group consisting of depressive disorders, anxiety disorders, central nervous system inflammation associated with inflammatory disorders, Lyme disease, prion diseases, amoebic diseases, schizophrenia, schizoaffective disorder, psychotic depressive disorder, bipolar depressive disorder, treatment-resistant depressive disorder, and Parkinson's disease, comprising administering a pharmaceutical composition according to any one of claims 1 to 70 to a subject.

76. A method for treating, managing, or preventing impulse control disorders involving addictive and habitual components, comprising administering a pharmaceutical composition according to any one of claims 1 to 70 to a subject.

77. The method according to claim 76, wherein the impulse control disorder is selected from the group consisting of alcohol abuse disorder, nicotine addiction, opioid abuse disorder, stimulant abuse disorder, hypnotic and tranquilizer addiction, gambling addiction, sex addiction, gaming technology disorder, attention deficit disorder, intermittent rage disorder, headache, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, and eating disorders.

78. A method for treating, managing, or preventing a condition selected from the group consisting of acute pain and / or chronic pain, amyotrophic lateral sclerosis, frontotemporal dementia / frontotemporal dementia, vascular dementia or Lewy body dementia, Alzheimer's disease, and organic cognitive impairment and organic memory impairment, comprising administering a pharmaceutical composition according to any one of claims 1 to 70 to a subject.

79. The method according to claim 78, wherein the therapeutically effective dose is between 0.01 mg / kg and 35 mg / kg.

80. The method according to claim 79, wherein the therapeutically effective dose is between 0.4 mg / kg and 4 mg / kg.

81. The method according to claim 80, wherein the effective therapeutic dose is between 0.4 mg / kg and 2 mg / kg.

82. The method according to claim 81, wherein the effective therapeutic dose is between 1 mg and 1.5 kg.

83. The method according to claim 82, wherein the disorder is alcohol abuse disorder.

84. The method according to claim 83, wherein the compound is 2-(2-bromo-1H-indole-3-yl)-N,N-dimethylethane-1-amine.

85. The method according to claim 84, wherein the administration is performed daily for at least five days.

86. The method according to claim 85, wherein the administration is performed daily for at least 14 days.

87. The method according to claim 86, wherein the administration is twice daily for at least five days.

88. The method according to claim 87, wherein the administration is twice daily for at least 14 days.

89. A method for treating, managing, or preventing a condition selected from the group consisting of acute pain and / or chronic pain, amyotrophic lateral sclerosis, frontotemporal dementia or frontotemporal dementia, vascular dementia or Lewy body dementia, Alzheimer's disease, and organic cognitive impairment and organic memory impairment, comprising administering the pharmaceutical composition according to claim 3 to a subject.

90. The method according to claim 89, wherein the therapeutically effective dose is between 0.01 mg / kg and 35 mg / kg.

91. The method according to claim 90, wherein the therapeutically effective dose is between 0.4 mg / kg and 4 mg / kg.

92. The method according to claim 91, wherein the therapeutically effective dose is between 0.4 mg / kg and 2 mg / kg.

93. The method according to claim 92, wherein the condition is frontotemporal lobar degeneration or frontotemporal dementia.

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