Novel compositions and pharmaceutical compositions

Abstract

To provide novel compositions and pharmaceutical compositions.SOLUTION: Pharmaceutical formulations of novel indole compounds and psilocybin analogs are manufactured, provided in novel oral, transdermal and nasal pharmaceutical compositions for use to treat neurological, mood or abuse diseases and disorders. The present invention relates to: novel indole compounds, the administration of psilocybin and psilocybin chemical analogues, and novel indole chemical compounds; and pharmaceutical compositions, methods of preparing the pharmaceutical compositions, and methods of treating neurological diseases or disorders using the analogues and novel compounds.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 021,866, filed May 8, 2020; U.S. Provisional Patent Application No. 63 / 106,516, filed October 28, 2020; and U.S. Provisional Patent Application No. 63 / 134,805, filed January 7, 2021.

[0002] Field of the Disclosure The present invention relates to novel indole compounds, administration of psilocybin, psilocybin chemical analogs, and novel indole chemical compounds; and to pharmaceutical compositions, methods of preparing pharmaceutical compositions, and methods of treating neurological diseases or disorders using the above - mentioned analogs and novel compounds.

Background Art

[0003] Background of the Invention Psychoactive drugs are compounds that affect behavior, mood, thought, or perception. Psychoactive drugs include antipsychotics, anxiolytics, stimulants, reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and mood stabilizers. Some of these compounds have historically been used for off - label psychoactive activities and are currently the subject of active clinical efficacy investigations. In addition to potential therapeutic efficacy, these drugs must be investigated for all relevant pharmaceutical properties, including minimum and maximum dosing thresholds and the most effective delivery systems.

[0004] Indole compounds represent a diverse class of compounds with broad biomedical potential across many targets including cancer, cardiovascular, gastrointestinal, and a wide range of neuropathies. In in vivo biosynthesis, the amino acid tryptophan precursor of serotonin has been an optimal scaffold for many drugs containing the heterocyclic indole skeleton. Serotonin (5-HT) supports many important bodily functions including mood, sleep, appetite, intestinal motility, and sexual health. The serotonergic system consists of a class of G-protein coupled receptors, 5-HT 1 ~5-HT 7 and their subtypes (1A, 2A, 2B, etc.).

[0005] Most serotonergic targeted therapeutics are antidepressants, either as selective reuptake inhibitors (collectively: SSRIs), direct 5-HT modulators (atypical), or in combination with norepinephrine inhibitors (SNRIs). Although not fully understood, the general mechanism of action of approved therapeutics relies on increasing the concentrations of the monoamines, 5-HT and norepinephrine, in postsynaptic receptors to restore synaptic balance. However, these medications generally lack efficacy (only 20 - 30% more effective than placebo), have significant side effects, and onset is delayed by weeks to months.

[0006] The sigma-1 receptor (σ receptor) is an intracellular receptor expressed in specific regions of the brain. Modulation and agonism of sigma-1 (σ 1 ) have been shown to have positive effects on locomotor activity, mood disorders, increased brain-derived neurotrophic factor (BDNF), neuron growth, and neurogenesis. Various classes of psychotropic drugs including antipsychotics, antidepressants, selective serotonin reuptake inhibitors (SSRI) and motor neuron drugs bind to the (σ 1 ) receptor. Binding of SSRI to the σ1 receptor may mediate the serotonin-independent actions of this class of drugs. The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous σ1 receptor modulator.

[0007] Psilocybin is an indole alkaloid produced by over 200 species of mushrooms and a naturally occurring psychoactive prodrug. Psilocybin is a prodrug that is dephosphorylated in vivo by oral administration to produce the active compound, psilocin. Both psilocybin and psilocin are indole compounds and are known to be potent 5-HT agonists and can cross the blood-brain barrier. The therapeutic significance of psilocybin has been widely demonstrated by active clinical research targeting depression, anxiety, migraine, addiction, dementia, Alzheimer's disease, eating disorders, obsessive-compulsive disorder, and palliative care.

[0008] Magic mushroom is a general term for a group of over 200 naturally occurring mushrooms that contain psilocybin and active psilocybin chemical analogs and combinations thereof. Similarly, other naturally occurring psychedelic indole compounds include N,N-dimethyltryptamine (DMT), 5-methoxy-DMT (5-MeO-DMT), lysergamide (e.g., LSD), and ibogaine. Fruits and extracts containing these natural products have been orally ingested for their psychoactive effects. The exact dose-response activity has been difficult to quantify due to the variability of individual responses, the difficulty of measuring the potency of natural organisms and extracts, and the different intrinsic potencies and ratios of different analogs and combinations thereof. This is exacerbated only by serotonin receptor activity and the interaction of the sigma-1 (σ 1 ) receptor. Specifically, for neurodegenerative diseases and cognitive function, agonists of the sigma 1 receptor (e.g., DMT) have been shown to enhance brain plasticity, which is important in memory and learning.

[0009] Psilocybin and its known analogs have been synthesized and bioengineered. In the mid-20th century, Sandoz Pharmaceuticals briefly sold an oral formulation of psilocybin for use as an adjunctive therapy in psychotherapy. The product was quickly removed from the market because individual responses to the dosage form were unpredictable. As of 2020, the US Drug Enforcement Administration classifies psilocybin as a Schedule 1 drug, which has a high potential for abuse, no approved medical uses, and no recognized safety for use under medical supervision.

[0010] The administration and evaluation of the pharmaceutical efficacy of these compounds have proven to be difficult. One reason is that the plasma concentration-time curve is highly variable. Additionally, psilocybin and especially DMT undergo first-pass metabolism in oral dosage forms, thereby reducing the availability of the pharmaceutical active ingredient before it enters the systemic circulation. There are also wide individual differences in the renal excretion of the compounds. Furthermore, pH and monoamine oxidase (MAO) enzymatic cleavage of psilocybin to the pharmaceutical active ingredient psilocin after oral delivery can also be a pharmacodynamic determinant. As a result, the research on the optimal dosage for treating various neurological disorders has not been rigorously pursued.

[0011] The 2016 Johns Hopkins study reported that relatively high doses, such as a dosing regimen of 0.2 mg / kg correlated with plasma concentrations of 4 - 8 ng / mL, are required to induce psychedelic effects. The in vivo half-life of psilocin is approximately 50 minutes, resulting in a psychedelic experience that lasts 4 - 6 hours, during which trained experts monitor subjects in a clinical setting. Psychotherapy is conducted before and after the psychedelic dose to prepare the patient and integrate the experiential results into personal responses to improve depressive thoughts and behaviors, and the drug acts only as a holistic tool. However, inpatient treatment, needless to say, increases the risk of adverse events while the patient is under the influence of the psychedelic drug, is extremely costly for the patient, and time-consuming for healthcare providers.

[0012] Furthermore, positive psychological effects were seen as the dose increased, but as the dose increased, negative side effects such as anxiety, negative imagery, nausea, and headache also increased. Therefore, professional monitoring of patients is necessary before, during, and after a psychedelic session. Recently, microdosing has been used to administer psychedelic substances at very low sub-perceptual doses. Psychedelic substances that are microdosed include LSD (lysergic acid diethylamide), cannabis, and psilocybin analogs. Reports of microdosed substances such as DMT and 5-MeO-DMT are few because the lack of bioavailability and short half-life make their administration difficult. Microdosing has been reported to have beneficial therapeutic effects in improving mood, mental concentration, energy levels, and creativity without abolishing the hallucinogenic effect.

[0013] Microdosing of psychedelic substances greatly reduces the psychotropic effect, and anecdotally, the dose is usually 1 / 10 (one-tenth th ) of the psychedelic dose. Many clinical studies of psychedelics for alleviating depression and PTSD exclude participants with a history of heart disease, psychosis, and schizophrenia because these conditions can be worsened by the strong psychotropic effect, but microdosing can alleviate these problems. Treatments without psychedelic effects eliminate the need for drug administration in the clinical setting and allow for more traditional, flexible, and affordable drug regimens. Reports of microdosing have shown improvements in cognitive benefits such as productivity, creativity, and abstract thinking; a combination of evidence suggesting that psychedelics reduce neuroinflammation and increase neuroplasticity and neuronal connections may lead to effective treatments for dementia, Alzheimer's disease, and other neurocognitive disorders.

[0014] The transdermal and nasal administration of pharmaceutical active ingredients has many advantages when used for psychostimulants. In particular, thyroxine is the product of the conversion of psilocin, a prodrug that is converted to thyroxine in the digestive tract. By avoiding the gastrointestinal tract via the transdermal application of thyroxine, problems due to absorption and food interactions can be avoided. Since the therapeutic effect of orally administered DMT can only be achieved by co-administration of MAOI, the transdermal system provides a new delivery method with reduced metabolism and improved pharmacokinetic / pharmacodynamic (PK / PD) properties. Other advantages of transdermal administration include avoiding first-pass metabolism; providing treatment for several days with a single application, thereby improving patient compliance; and extending the activity of drugs with short half-lives due to the reservoir of drugs present in the delivery system and its controlled release characteristics.

[0015] Systemic delivery of pharmaceutical components by administration to the nasal mucosa can be advantageous. Nasal delivery enables avoidance of intestinal metabolism and first-pass metabolism. Furthermore, nasal delivery of systemic drugs can bypass the blood-brain barrier and enter the brain via the olfactory and trigeminal nerve pathways, which can be advantageous for pharmaceutical administration of central nervous system diseases. A further advantage of nasal administration is the rapid systemic absorption via the nasal mucosa. Combining this with a compound with a short half-life such as DMT can have significant clinical advantages over longer-acting psychedelics.

[0016] Oral delivery of drugs is often preferred over various other drug administration routes due to ease of ingestion, pain avoidance, good patient compliance, and dispensing history. However, many problems such as low solubility of drugs in an aqueous environment, taste, stability of drugs with pharmaceutical excipients, various dissolution rates, unknown gastrointestinal absorption problems, and food effects are still associated with oral delivery. Oral pharmaceutical formulations are recognized as a scientific endeavor that requires specific knowledge and innovative design in the general field.

[0017] Recent studies on psilocybin and its psilocybin analogs and combinations thereof have been reported to be effective in models of substance use disorders and small-scale clinical trials including post-treatment Lyme disease syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression and anxiety, opioid intoxication, alcohol intoxication, nicotine intoxication, cannabinoid intoxication, headache, central nervous system inflammation, dementia, and disorders of cognition and memory. These promising experimental reports using psilocybin and its analogs have determined the most advantageous dosage and dosing period; improved pharmacokinetic (PK) profile, pharmacodynamic (PD) profile, or safety profile; evaluation of the benefits of long-term or maintenance treatment; development of treatment regimens to maximize the biological effectiveness for treating the disease; and the urgent need to determine formulations that enable the use of these compounds in other potential advantageous benefits. Furthermore, there is a need for the development of novel, safe and effective exogenous serotoninergic and / or sigma-1 modulators for treating neurological, mood and substance use disorders or diseases.

Summary of the Invention

Means for Solving the Problems

[0018] Summary Provided herein are novel indole compounds having biological effectiveness and increased clinical safety.

[0019] These compounds include a compound of structure (1) or a pharmaceutically acceptable salt or solvate thereof: Structure (1)

Chemical

[0020] A further aspect of the present invention is a compound according to the above structure (1) selected from the group consisting of:

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

[0021] In another aspect of the present invention, a compound of structure (2) or a pharmaceutically acceptable salt or solvate thereof: Structure (2)

Chemical formula

[0022] Specific compounds of structure (2) are 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-bromo-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine. Other specific compounds of structure (2) that are of particular interest are 1-(2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, 1-(2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, and 1-(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide.

[0023] Another aspect of the present invention is a compound of structure (3) or a pharmaceutically acceptable salt or solvate thereof: Structure (3) [Chemical formula] wherein R 1 is selected from the group consisting of F, Cl, Br, I or CF 3 ; R 2 is CH 3 ; R 3 and R 4 are each independently, optionally, H, CH 3 C 2 H 5 (H 3 C) 2 CH, or H 2 C=CH-CH 2 and is a compound or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of.

[0024] Specific compounds of structure (3) are 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, (R)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-vinylethanamine, 2-(2-bromo-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, or N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine.

[0025] This specification provides pharmaceutical compositions designed to release the pharmaceutical active ingredients described herein into the bloodstream through transdermal application of the pharmaceutical active ingredients to the skin and nasal cavity. These pharmaceutical compositions are transdermal or transnasal pharmaceutical formulations. The pharmaceutical active ingredients can be applied by means such as sprayable liquids, gels, creams, lotions, ointments, transdermal patches, etc.

[0026] In one embodiment, the transdermal pharmaceutical composition and the transnasal composition of the pharmaceutical active ingredient can be compounds as described by structures (1), (2), (3), and compounds listed in Table (1) and any ionic or salt forms thereof.

[0027] In certain embodiments, psilocybin analogs and combinations thereof include any compounds that are structurally related to psilocybin and functionally mimic and / or antagonize the action of serotonin. In another embodiment, the pharmaceutical active ingredient includes psilocybin and active analogs and combinations thereof. The active analogs of psilocybin and combinations thereof include, but are not limited to, the compounds listed in Table (2) of psilocybin analogs.

[0028]

Table 2

[0029] The present specification provides for the manufacture of transdermal or transnasal pharmaceuticals using as pharmaceutical active ingredients the novel compounds described by structures (1), (2), and (3), the novel compounds listed in Table (1), and the psilocybin analogs of Table (2), and salts or solvates thereof, for treating neurological, mood, and abuse disorders or diseases.

[0030] The transdermal and transnasal pharmaceutical compositions of the present invention provide compositions described for use in medicaments for treating, managing, or preventing diseases.

[0031] In another embodiment, the pharmaceutical composition is designed for oral delivery to the human systemic circulation with rapid onset and duration.

[0032] In another embodiment, the pharmaceutical composition is designed to provide sustained release into the human systemic circulation via oral delivery, preferably at a once-daily dose.

[0033] The oral pharmaceutical compositions described herein can be designed for modified timed release of the pharmaceutical active ingredient into the human systemic circulation over an extended period. The composition may be composed of a solid, semi-solid, liquid, or flexible delivery system and can be administered sublingually, buccally, or orally. The pharmaceutical active ingredient can be provided in tablets, capsules, softgels, strips, sublingual strips, cachets, solutions, suspensions.

[0034] In one embodiment, the oral pharmaceutical composition contains a pharmaceutical active ingredient of the novel compounds described by structures (1), (2), (3), the novel compounds of Table (1), and the psilocybin analogs of Table (2), or salts or solvates thereof. Combinations of psilocybin analogs and / or novel indole compounds as pharmaceutical active ingredients of pharmaceutical formulations are also part of the present invention.

[0035] The present invention provides the described compositions for use in the treatment, management, or prevention of neurological disorders, mood disorders, or substance use disorders or diseases, where the disorders can be depression, central nervous system inflammation, addiction, headache, or dementia, or disorders of cognition and memory.

[0036] The present invention provides combinations of the compounds and analogs described herein for topical, nasal, or oral application in combination with a pharmaceutically active ingredient approved by a regulatory authority for the treatment, management, or prevention of neurological, mood, and substance use disorders or diseases. The approved pharmaceutically active ingredient can be delivered to a patient in need thereof by any delivery system approved by a regulatory authority. In one aspect of the invention, the approved pharmaceutically active ingredient for use in combination with the novel indole or psilocybin analogs is an MAOI. In another aspect of the invention, the approved pharmaceutically active ingredient is a 5-HT antagonist.

[0037] Also provided herein are novel synthetic routes for providing the novel indole compounds of structures (1), (2), and (3), and the novel compounds of Table (1) and psilocybin analogs of Table (2). The novel syntheses of the compounds described are as set forth in the specific examples described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0038]

Figure 1

[0039]

Figure 2

[0040] Detailed Description Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0041] 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 clearly dictates otherwise.

[0042] The terms "about" or "approximately" mean an acceptable error of a particular value as determined by one of ordinary skill in the art and depend in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means 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.

[0043] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" refer to the eradication or amelioration of a disease or disorder, or one or more symptoms associated with a disease or disorder. In certain embodiments, the term refers to minimizing the spread or worsening of a disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject having such a disease or disorder. In some embodiments, the term refers to the administration of a compound or dosage form provided herein, with or without one or more additional active agents, after the onset of symptoms of a particular disease.

[0044] As used herein, unless otherwise specified, the term "substance use disorder" is a disorder or disease that affects a person's brain and behavior and results in the inability to control the use of legal or illegal drugs or medications. Prescription drugs, over-the-counter drugs, and unapproved drugs can all be substances of abuse. Drugs and medications can also include substances such as amphetamines, opioids, cocaine, barbiturates, alcohol, marijuana, and nicotine.

[0045] As used herein, unless otherwise specified, the term "mood disorder" refers to a group of conditions characterized by underlying disturbances in a person's mood. Mood disorders can be in the group of mania (elevated mood disorder) or hypomania (depressive disorder). This classification is described in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD).

[0046] As used herein, unless otherwise specified, the term "neuropathy" refers to diseases of the central and peripheral nervous systems, such as the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junctions, and muscles. These disorders include epilepsy, Alzheimer's disease and other dementias, stroke, migraine, cluster headache and other headache disorders including cerebrovascular diseases, multiple sclerosis, Parkinson's disease, neurological infections, brain tumors, traumatic disorders of the nervous system due to head injury, as well as traumatic disorders due to trauma or terrifying experiences (post-traumatic stress disorder, such as PTSD), and neuropathies as a result of nutritional disorders and substance abuse. The substances abused can be any number of addictive substances, particularly alcohol and drugs and combinations thereof. Many bacterial infections (e.g., Mycobacterial tuberculosis, Neisseria meningitides), viral infections (e.g., human immunodeficiency virus (HIV), Lyme disease, enterovirus, West Nile virus, Zika), fungal infections (e.g., Cryptococcus, Aspergillus), and parasitic infections (e.g., malaria, Chagas) can affect the nervous system. Neurological symptoms can occur due to the infection itself or due to the immune response.

[0047] As used herein, unless otherwise specified, the terms "prevent", "preventing", and "prevention" refer to preventing the onset, recurrence, or spread of a disease or disorder or one or more symptoms thereof. In certain embodiments, the term refers to treatment or administration with a compound formulation provided herein, with or without one or more additional active agents, to a subject at risk of a disease or disorder provided herein, particularly prior to the onset of symptoms. These terms encompass inhibition or alleviation of symptoms of a particular disease. In certain embodiments, subjects having a family history of a disease in particular are candidates for a prevention regimen. Additionally, subjects having 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".

[0048] As used herein, unless otherwise specified, the terms "manage", "managing", and "management" refer to preventing or delaying the progression, spread, or worsening of a disease or disorder or one or more symptoms thereof. In many cases, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject afflicted with a particular disease in an attempt to prevent or minimize recurrence of the disease.

[0049] As used herein, improvement of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any alleviation, whether permanent or temporary, persistent or transient, that may result from or be related to the administration of the composition.

[0050] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with one or more other agents, provides a prophylactic benefit in the prevention of a disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0051] As used herein, unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound mean an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. The "therapeutically effective amount" and "effective amount" of a compound mean an amount of a therapeutic agent that, alone or in combination with one or more other agents, provides a therapeutic benefit in the treatment or management of a disease or disorder. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves the overall treatment, alleviates or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effectiveness of another therapeutic agent.

[0052] As used herein, unless otherwise specified, a "pharmaceutically active ingredient (API)" is any substance or mixture of substances that is intended to be used in the manufacture of a drug (pharmaceutical) product and that becomes an active ingredient of the drug product when used in the manufacture of the drug. Such substances are intended to affect the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure or function of the body.

[0053] As used herein, unless otherwise specified, the term "drug product" generally refers to the final dosage form, such as an oral, nasal, or transdermal formulation, that contains a pharmaceutically active ingredient but is not necessarily associated with inactive ingredients.

[0054] As used herein, the terms "composition", "formulation", and "dosage form" are intended to encompass a composition containing specific ingredient(s) (if shown, in the specified amounts), as well as any product directly or indirectly resulting from a combination of specific amounts of specific ingredient(s). "Pharmaceutical" or "pharmaceutically acceptable" means that any diluent(s), excipient(s), absorption enhancer(s) or carrier(s) in the composition, formulation or dosage form is compatible with the other ingredient(s) and is not harmful to its recipient. Unless otherwise indicated, the terms "composition", "formulation", and "dosage form" are used interchangeably herein.

[0055] As used herein, the term "transdermal" relates to a pharmaceutical in a form that is absorbed into the bloodstream through the skin or to the delivery thereof.

[0056] As used herein, the term "nasal" relates to a pharmaceutical in a form for absorption through the nasal mucosa or to the delivery thereof. Nasal delivery can be affected by a wide range of dosage forms including, but not limited to, solutions, gels, suspensions, emulsions, liposomal formulations and particulate formulations. for absorption through the nasal mucosa or to the delivery thereof. Nasal delivery can be affected by a wide range of dosage forms including, but not limited to, solutions, gels, suspensions, emulsions, liposomal formulations and particulate formulations.

[0057] As used herein, "oral" relates to a pharmaceutical in a form for absorption through the oral mucosa, sublingual membrane, buccal membrane, esophageal membrane, gastric membrane, or intestinal membrane. The term "capsule" refers to an oral composition in which the API and inactive ingredients are contained as a solid, liquid or semi-solid within an outer shell composed of gelatin, polymeric cellulose or other suitable material. Capsules are intended to be swallowed, and the composition dissolves and releases the API for systemic absorption through the esophageal, gastric or intestinal lining.

[0058] The terms "tablet" and "cachet" include oral compositions that are spherical, round, oval, triangular, diamond, small spherical, or oblong in shape and contain API, inactive ingredients, and, optionally, a saliva stimulant, which are formed by direct compression of a powder formulation. When placed in the mouth, the composition dissolves and releases the API for systemic absorption through the buccal, sublingual, esophageal, gastric, or intestinal inner layers.

[0059] The term "strip" or "oral strip" includes oral compositions that are square, rectangular, triangular, round, annular, or oblong in shape and contain API, inactive ingredients, and, optionally, a saliva stimulant, which form a flexible matrix. Generally, when placed under the tongue and in the mouth, the composition dissolves and releases the API for systemic absorption through the buccal, sublingual, esophageal, gastric, or intestinal inner layers.

[0060] As used herein, "immediate release" is defined as a formulation of a pharmaceutical active ingredient(s) that is taken orally, nasally, or transdermally and results in rapid absorption of the drug into the blood after administration. Immediate release can be measured in vitro using the FDA industry guidelines for dissolution and / or permeability testing, or in vivo using plasma levels.

[0061] As used herein, "modified release" or "extended release" is defined as a formulation of a pharmaceutical active ingredient(s) that is taken orally, nasally, or transdermally and releases the pharmaceutical active ingredient over a period of hours or days to maintain a relatively constant plasma concentration of the drug. Such modifications can have several purposes, such as maintaining therapeutic activity over a long period, reducing toxic effects, protecting the active substance from degradation by low pH, targeting the active substance to a predetermined segment of the gastrointestinal tract for local treatment, or targeting the release of the active substance at a specified time point. Modified release is measured according to the appropriate FDA industry guidelines for modified release formulations.

[0062] As used herein, the term "subject" is defined to include animals such as mammals including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0063] The terms "co-administered", "in combination with", and "in combination" include administering two or more therapeutic agents simultaneously, together or sequentially within no particular time limit. In one embodiment, the agents are present simultaneously within the cell or in the body of the subject or exert their biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, the first agent can 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), simultaneously with, 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.

[0064] As used herein, the term "psilocybin analog" is defined to include any compound that is structurally related to psilocybin and that functionally mimics and / or antagonizes the action of serotonin. Certain embodiments herein provide salts, co-crystals, solvates, isomers, hydrates, ions, zwitterions, complexes, prodrugs, precursors, metabolites, and / or other derivatives of psilocybin. Certain embodiments herein provide a mixture of two or more of the psilocybin analogs provided herein. As described herein, the psilocybin analog is selected from the group consisting of the compounds listed in Table (2) and salts and solvates thereof. Certain embodiments herein provide a mixture of two or more of the psilocybin analogs provided herein.

[0065] The psilocybin analogs described herein can be synthesized using any method known to those of ordinary skill in the art. It is known that certain compounds can be provided by applying biological processes to manufactured articles, and the compounds are bioengineered.

[0066] The psilocybin analogs described herein can be provided by alcohol or acid-base extraction of the compound from natural sources containing the psychostimulant compound. The extraction methods are well known to those of ordinary skill in the art.

[0067] In certain embodiments, the formulations of the present invention can be obtained synthetically or by bioengineering; or psilocybin and psilocybin analogs and combinations thereof, which can be extracted from naturally occurring mushrooms, are used. As described herein, some of the manufacturing processes can be novel, and others can use techniques that are well described in the art.

[0068] (a) A pharmaceutical dosage form, pharmaceutical preparation and composition containing a pharmaceutically active ingredient which is a novel indole of structure (1), structure (2), structure (3) or (b), or a psilocybin analog is provided herein. The dosage form, pharmaceutical preparation and composition release the pharmaceutically active ingredient into the bloodstream upon transdermal, nasal or oral administration. In certain embodiments, the psilocybin analog is serotonin. In certain embodiments, the psilocybin analog is 4-hydroxytryptophan. In certain embodiments, the psilocybin analog is 4-hydroxytryptofall. In certain embodiments, the psilocybin analog is 4-hydroxy-indole-3-acetaldehyde. In certain embodiments, the psilocybin analog is 4-hydroxy-indole-3-acetic acid. In certain embodiments, the psilocybin analog is norserotonin. In certain embodiments, the psilocybin analog is aeruginascin. In certain embodiments, the psilocybin analog is baeocystin. In certain embodiments, the psilocybin analog is norbaeocystin. In certain embodiments, the psilocybin analog is 4-hydroxy-N-methyl-N-ethyltryptamine (4-OH-MET). In certain embodiments, the psilocybin analog is 4-hydroxy-diethyltryptamine (4-OH-DET). In certain embodiments, the psilocybin analog is 4-hydroxy-N,N-dipropyltryptamine (4-OH-DPT). In certain embodiments, the psilocybin analog is 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT). In certain embodiments, the psilocybin analog is N,N-dimethyltryptamine (DMT). In certain embodiments, the psilocybin analog is indole-3-acetic acid. In certain embodiments, the psilocybin analog is N,N-dimethyltryptamine-N-oxide (DMT-NO). In certain embodiments, the psilocybin analog is lysergic acid diethylamide (LSD). In certain embodiments, the psilocybin analog is O-acetylserotonin (4-AcO-DMT). In certain embodiments, the psilocybin analog is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).In certain embodiments, the psilocybin analog is bufotenin (5-OH-DMT). In certain embodiments, the psilocybin analog is ibogaine.

[0069] In certain embodiments, the exemplary compound has a structure as shown in structure (1):

Chemical formula

[0070] In certain embodiments, the psilocybin analogs and combinations thereof provided herein include any compound that is structurally related to psilocybin and functionally mimics and / or antagonizes the action of serotonin.

[0071] In certain embodiments, the exemplary psilocybin analogs and combinations thereof are the compounds provided in Table (2).

[0072] In certain embodiments, a pharmaceutical formulation and composition comprising a pharmaceutically active ingredient that is any one of (a) an indole of a compound of the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, can be used in combination with other active agents.

[0073] In certain embodiments, the pharmaceutical formulation comprises a MAOI. MAOIs are drugs of the enzyme family that catalyze the oxidation of monoamines, and certain psilocybin analogs and their combinations are known to be enzymatically degraded by MAOIs. MAOIs include, but are not limited to, harmala alkaloids, harmine, harman, harmaline, hydrazine, iproniazid, isocarboxazid, nialamide, phenelzine, hydracarbazine, tranylcypromine, biferemelane, moclobemide, pirindole, tropoxone, rasagiline, selegiline, safinamide, and other reversible inhibitors of monoamine oxidase A (RIMA).

[0074] Certain embodiments herein include pharmaceutical formulations and compositions comprising a pharmaceutically active ingredient that is either (a) an indole of structure (1) or (b) a psilocybin analog and combinations thereof, and optionally, a monoamine oxidase inhibitor (also known as an MAO inhibitor or MAOI), such formulations and compositions being prepared for transdermal administration.

[0075] Certain embodiments of the present specification include pharmaceutical active ingredients that are either (a) indoles of structure (1), structure (2), or structure (3), or (b) psilocybin analogs and combinations thereof, and, optionally, monoamine oxidase inhibitors (also known as MAO inhibitors or MAOIs), and such pharmaceutical formulations and compositions are prepared for oral administration. In certain embodiments, 5-HT antagonists can be used as allosteric regulators or to improve the therapeutic benefits of psilocybin analogs. Certain 5-HT antagonists are known to be able to reduce the psychoactivity induced by psilocybin analogs, which can be beneficial for treatment or for reducing side effects. Certain 5-HT antagonists include, but are not limited to, ketanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, cyproheptadine, trazodone, mirtazapine, nefazodone, niaprazine, pizotifen, methysergide, or 2-bromo-LSD (BOL-148).

[0076] In certain embodiments, pharmaceutical formulations and compositions comprising pharmaceutical active ingredients that are either (a) indoles of structure (1), structure (2), or structure (3), or (b) psilocybin analogs, and combinations thereof are used to treat neurological, mood, and substance use disorders. These formulations and compositions can be prepared for transdermal administration.

[0077] In certain embodiments, pharmaceutical formulations and compositions comprising pharmaceutical active ingredients that are either (a) indoles of compounds belonging to the structures of structure (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof are used to treat neurological, mood, and substance use disorders. These formulations and compositions can be prepared for nasal administration.

[0078] In certain embodiments, pharmaceutical formulations and compositions comprising a pharmaceutically active ingredient of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof are used to treat neurological, mood, and substance use disorders. These formulations and compositions can be prepared for oral administration. Certain embodiments relate to the use of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, for preparing pharmaceutical formulations and compositions for treating the specific medical indications provided herein. The pharmaceutical formulations and compositions are intended for transdermal delivery of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, in a subject in need thereof. Transdermal formulations can be manufactured in the form of sprayable liquids, gels, creams, lotions, ointments, and transdermal patches and are applied topically to the desired area.

[0079] Certain embodiments relate to the use of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, for preparing pharmaceutical formulations and compositions for treating the specific medical indications provided herein. The pharmaceutical formulations and compositions are intended for oral delivery of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, in a subject in need thereof. Oral formulations can be manufactured in the form of tablets, capsules, softgels, strips, oral patches and are intended for oral delivery to a patient in need of treatment.

[0080] In certain embodiments, the pharmaceutical formulation can be formulated for immediate release of the API. In certain embodiments, the immediate release formulation is a transdermal composition or a nasal composition.

[0081] In certain embodiments, the pharmaceutical formulation can be formulated for immediate release of the API. In certain embodiments, the immediate release formulation is an oral composition.

[0082] In certain embodiments, the pharmaceutical formulation can be formulated for modified release of the API. In certain embodiments, the immediate release formulation is a transdermal composition.

[0083] In certain embodiments, the pharmaceutical formulation can be formulated for modified release of the API. In certain embodiments, the immediate release formulation is an oral composition.

[0084] In certain embodiments, the transdermal composition includes a transdermal patch or a nasal formulation that delivers the pharmaceutically active ingredient into the bloodstream across the skin or mucosa. In certain embodiments, the embodiments herein include the use of a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for preparing a pharmaceutical composition for treating neurological, mood and abuse disorders, the composition being prepared for transdermal or nasal administration.

[0085] In certain embodiments, a formulation of a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof results in immediate release of the pharmaceutically active ingredient into the plasma upon transdermal, nasal or oral administration. In certain embodiments, a formulation comprising a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof includes a therapeutically or prophylactically effective amount of the pharmaceutically active ingredient and, optionally, one or more excipients.

[0086] In certain embodiments of the transdermal, nasal, or oral formulations of the present invention, psilocybin, psilocybin analogs, and combinations thereof that can be obtained synthetically or by bioengineering; or that can be extracted from naturally occurring mushrooms, which are well described in the art, are used.

[0087] In certain embodiments of the transdermal, nasal, or oral formulations of the present invention, psilocybin, psilocybin analogs, and combinations thereof that can be obtained synthetically or by bioengineering; or that can be extracted from naturally occurring mushrooms, are used by employing the novel chemical synthesis techniques or extraction techniques described herein.

[0088] In certain embodiments, the transdermal pharmaceutical administration composition is in the form of a sprayable liquid, gel, cream, lotion, ointment, and transdermal patch, and the pharmaceutical active ingredient is incorporated with inactive ingredients that enhance the delivery characteristics of the composition and stabilize the pharmaceutical active ingredient. In one embodiment, the penetration enhancer can be an inactive ingredient. Examples of penetration enhancers can include, but are not limited to, castor oil, coconut oil, medium-chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, shea butter, or other esters, triglycerides, or fatty acids and oils that are functional derivatives thereof.

[0089] In certain embodiments, surfactants may be used in the transdermal delivery system as emulsifiers and stabilizers, and drugs can be encapsulated for good stability and permeability. Examples of surfactants include, but are not limited to, polysorbates (e.g., Tween®, polysorbate 20), sorbitans (Span®), phospholipids (lecithin), lauryl sulfate, betaine, propionate, fatty alcohols and alkanolamides, fatty acid esters, amine oxides, myristates, and azone.

[0090] In certain embodiments, cosolvents can be used in transdermal formulations to improve drug solubility and permeability while acting as wetting agents for 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, Cremophor, siloxane, polyethylene, and water.

[0091] In certain embodiments, thickening agents can be used in transdermal formulations to reduce separation and provide a matrix suitable for modified delivery. Common thickening agents include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenan, gums, resins, polysaccharides, and high melting point waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosin, resins, paraffin, and petrolatum.

[0092] In certain embodiments, tackifiers can be used in transdermal formulations to enhance adhesion for long-term wearability. Common tackifiers include, but are not limited to, gums, resins (natural or modified), carbomers, or other natural or synthetic polymers.

[0093] In certain embodiments, preservatives can be used in transdermal formulations to improve formulation stability and delay microbial growth. Common preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chlorides, phenol, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts, and alcohols. Finally, the formulation is typically emulsified with a hydrophilic component such as water or Aloe barbadensis juice.

[0094] In certain embodiments, formulations comprising a pharmaceutically active ingredient of (a) an indole of structure (1) or (b) a psilocybin analog and combinations thereof provide controlled release of the pharmaceutically active ingredient upon administration. In certain embodiments, a formulation comprising a pharmaceutically active ingredient comprises a therapeutically or prophylactically effective amount of the pharmaceutically active ingredient(s) and a drug release control component capable of controlled sustained release of the pharmaceutically active ingredient directly into the bloodstream.

[0095] In certain embodiments, the transdermal dosage form is a transdermal delivery device. Any conventional device in the art for transdermally delivering a therapeutic agent to a patient can be used for transdermal delivery of the compositions of the present invention and as a transdermal delivery device. For example, the transdermal delivery device can be a reservoir-type transdermal delivery device, a polymeric matrix-type transdermal delivery device, or a drug-in-adhesive type transdermal delivery device or a multilaminate type transdermal delivery device. The transdermal delivery device is designed such that, when in contact with the skin of the patient, the pharmaceutically active ingredient of the present invention is delivered in a therapeutically effective amount.

[0096] In certain embodiments, the transdermal delivery device is a drug-containing adhesive device that includes a pharmaceutically active ingredient directly dispersed in a pressure-sensitive adhesive matrix. The adhesive matrix is preferably supported on the top surface by an impermeable backing film and on the side facing the skin by an impermeable release liner. To administer the pharmaceutically active ingredient, the release liner is removed to expose the adhesive matrix, and the device is brought into contact with the skin. The adhesive matrix adheres the device to the skin and typically functions to control the delivery rate of the pharmaceutically active ingredient. Similar to polymer matrix design, drug-containing adhesive design allows the pharmaceutically active ingredient to diffuse from the adhesive matrix, contact the patient's skin, and permeate through the skin. The delivery rate of the pharmaceutically active ingredient is usually determined by the diffusion rate of the pharmaceutically active ingredient(s) from the adhesive matrix. For longer extended delivery, multiple drug-containing adhesive layers can be laminated together between rate-controlling membranes. The delivery rate is such that an effective amount of the pharmaceutically active ingredient is delivered to the patient in need of the pharmaceutically active ingredient.

[0097] In certain embodiments, the reservoir-type transdermal delivery device preferably includes a reservoir (usually 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 may be a solution or dispersion and contains the composition of the present invention. The transdermal delivery device is preferably supported by an impermeable backing film, and the adhesive surface is protected by a release liner. To administer the pharmaceutically active ingredient of the present invention, the release liner is peeled off to expose the pressure-sensitive adhesive, and the pressure-sensitive adhesive is brought into contact with the skin. The pharmaceutically active ingredient of the present invention can permeate through the rate-controlling membrane, permeate through the rate-controlling membrane and the adhesive, contact the skin, and permeate through the skin. The delivery rate of the active pharmaceutical invention is usually determined by the rate at which the pharmaceutically active ingredient permeates through the rate-controlling membrane.

[0098] In certain embodiments, the transdermal delivery device is a polymeric matrix design. In a polymeric matrix design, the psilocybin analogs and combinations thereof are dispersed in a polymeric matrix that controls the delivery rate of the pharmaceutical active ingredient. Preferably, the reservoir of the polymeric matrix is supported on an impermeable backing layer. An adhesive layer is attached to the surface of the polymeric matrix. To administer the pharmaceutical active ingredient, the release liner is removed to expose the polymeric 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 such that the polymeric matrix is in direct contact with the skin. When the polymeric matrix contacts the skin, the pharmaceutical active ingredient(s) diffuse from the polymeric matrix, contact the patient's skin, and permeate through the skin. The delivery rate of the pharmaceutical active ingredient is typically determined by the diffusion rate of the pharmaceutical active ingredient from the polymeric matrix.

[0099] The adhesive can include crosslinking monomer units or sites and can be incorporated into an adhesive polymer. For example, crosslinking monomers can be incorporated into polyacrylate polymers. The crosslinking monomers can provide sites, for example, for crosslinking the polymeric matrix after dispersing the psilocybin analogs and combinations thereof in the polymer. Known adhesives include crosslinking monomers for polyacrylate polymers, such as polymethacrylic acid esters of polyols such as 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 ether, and silane. The monomers are then polymerized using methods known to those skilled in the art to include a crosslinking agent, functional groups, or an adhesive matrix of polyacrylate (acrylic), polysiloxane (silicone), or polyisobutylene (or other rubber) containing vinyl acetate to suspend, stabilize, and release the pharmaceutical active ingredient.

[0100] In one embodiment of the present invention, the transdermal delivery device may optionally contain one or more penetration enhancers that increase the rate at which the pharmaceutically active ingredient permeates through the patient's skin. Preferably, the penetration enhancer permeates through the rate-controlling membrane or diffuses from the polymeric matrix or the adhesive matrix to contact the patient's skin and improve the permeation of the pharmaceutically active ingredient as defined herein through the patient's skin. Suitable penetration enhancers for use in the transdermal delivery devices and compositions of the present invention include, for example, C 2-4Alcohols, such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, polysorbate, sorbitan, fatty acids, esters of fatty acids having from about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoesters content of at least 51% (the monoesters having from 10 to 20 carbon atoms), and mixtures of mono-, di- and tri-glycerides of fatty acids are included. 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. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt the skin membrane and increase API permeability. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt the skin membrane 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. In certain embodiments, the transdermal patch described herein is used in co-administration with a permeation enhancer. In certain embodiments, permeation enhancers can include, but are not limited to, 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 permeation enhancers for use in transdermal patches include, for example, C 2-4Alcohols, such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, polysorbate (Tween®), sorbitan (Span®), fatty acids, esters of fatty acids having from about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoesters content of at least 51% (the monoesters having from 10 to 20 carbon atoms), and mixtures of mono-, di- and tri-glycerides of fatty acids are included. 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. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt the skin membrane 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.

[0101] In certain embodiments, the delivery rate of the pharmaceutically active ingredient can be delivered by once-daily transdermal patch application. In certain embodiments, the delivery rate of the API can be delivered over a period of 6 to 12 hours. In certain embodiments, the delivery rate of the API can be delivered over a period of 12 to 24 hours. In certain embodiments, the delivery rate of the API can be delivered over a period of 24 to 48 hours. In other embodiments, the transdermal patch can be applied once every 2 days; once every 3 days; once every 4 days; once every 5 days; once every 5 days; or once every 7 days. The delivery rate options for the transdermal patch promote patient compliance while delivering a steady-state systemic safe and effective drug concentration.

[0102] As described herein, certain embodiments provide methods related to different dosages and / or administration periods; provide alternative pharmacokinetic profiles, pharmacodynamic profiles, and / or safety profiles; enable long-term maintenance therapy; provide for testing of new indications for psilocybin analogs; and provide transdermal formulations of the pharmaceutical active ingredients described herein that are useful in other potential advantageous benefits. In certain embodiments, the formulations provided herein (e.g., sprayable liquids, gels, creams, lotions, ointments, or transdermal patches for dermal delivery of a pharmaceutical active ingredient) contain a pharmaceutical active ingredient ((a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2) alone or in combination) in a specific pharmaceutically active amount. In certain embodiments, the specific amount of the pharmaceutical active ingredient disclosed herein in the formulation is, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, at least about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or at least 100 mg.In certain embodiments, a specific amount of the silibinin analog in the formulation is, for example, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg, at least about 23 mg, at least about 24 mg, at least about 25 mg, at least about 26 mg, at least about 27 mg, at least about 28 mg, at least about 29 mg, at least about 30 mg, at least about 31 mg, at least about 32 mg, at least about 33 mg, at least about 34 mg, at least about 35 mg, at least about 36 mg, at least about 37 mg, at least about 38 mg, at least about 39 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg or at least 100 mg.

[0103] In more specific embodiments, a specific amount of the pharmaceutically active ingredient disclosed herein in the formulation is, for example, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg or at least 100 mg.

[0104] In more specific embodiments, a specific amount of the pharmaceutically active ingredient in the formulation is, for example, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg, at least about 23 mg, at least about 24 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg or at least 100 mg.

[0105] In certain embodiments, the pharmaceutically active ingredient in the pharmaceutical formulation is, for example, about 5 mg to 100 mg, or about 5 mg to 25 mg, or about 25 mg to 50 mg, or about 50 mg to 75 mg, or about 75 mg to 100 mg.

[0106] As described herein, certain embodiments provide a transdermal formulation of the pharmaceutically active ingredient described herein with respect to the skin application size for a transdermal delivery device. The application area is an important metric for determining drug flux, varying the dose, and providing a sufficient area for efficient transdermal delivery. In certain embodiments, the API ((a) indole of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) the compounds of Table (2) (alone or in combination) is contained within a drug delivery device (e.g., a sprayable liquid, gel, cream, lotion, ointment, or transdermal patch) and is 1 cm or less, or at least 2 cm 2 , at least 3 cm 2 , at least 4 cm 2 , at least 5 cm 2 , at least 6 cm 2, at least 7 cm 2 , at least 8 cm 2 , at least 9 cm 2 , at least 10 cm 2 , at least 15 cm 2 , at least 20 cm 2 , at least 25 cm 2 , at least 30 cm 2 , at least 35 cm 2 , at least 40 cm 2 , at least 45 cm 2 , at least 50 cm 2 , at least 60 cm 2 , at least 70 cm 2 , at least 80 cm 2 , at least 90 cm 2 , or at least 100 cm 2 , at least 150 cm 2 , at least 200 cm 2 , at least 250 cm 2 , at least 300 cm 2 , at least 350 cm 2 , at least 400 cm 2 , at least 450 cm 2 , at least 500 cm 2 , at least 600 cm 2 , at least 700 cm 2 , at least 800 cm 2 , at least 900 cm 2 , or at least 1000 cm 2 is applied to the skin of a human or mammal in an area of...

[0107] In certain embodiments, the API is included, alone or in combination, within a drug delivery device (e.g., a sprayable liquid, gel, cream, lotion, ointment, or transdermal patch), and is 1 cm or less, or at least 2 cm 2 , at least 3 cm 2 , at least 4 cm 2 , at least 5 cm 2 , at least 6 cm 2 , at least 7 cm 2, at least 8 cm 2 , at least 9 cm 2 , at least 10 cm 2 , at least 15 cm 2 , at least 20 cm 2 , at least 25 cm 2 , at least 30 cm 2 , at least 35 cm 2 , at least 40 cm 2 , at least 45 cm 2 , at least 50 cm 2 , at least 60 cm 2 , at least 70 cm 2 , at least 80 cm 2 , at least 90 cm 2 , or at least 100 cm 2 and is applied to the skin of a human or mammal in an area of

[0108] In one embodiment, the API is, alone or in combination, about 1 cm 2 to 10 cm 2 , about 10 cm 2 to 40 cm 2 , about 40 cm 2 to 100 cm 2 , or more preferably 5 cm 2 to 40 cm 2 and is applied to the skin of a human or mammal in an area of

[0109] In certain embodiments, the pharmaceutically active ingredient is delivered in an oral pharmaceutical composition comprising a capsule or tablet that delivers the API into the bloodstream through the membranes of the esophagus, stomach, and / or intestine.

[0110] In certain embodiments, the oral composition is swallowed and the pharmaceutically active ingredient is further delivered into the bloodstream through the membranes of the esophagus, stomach, and / or intestine.

[0111] In certain embodiments, the oral composition comprises tablets, cachets, or strips that deliver the pharmaceutically active ingredient into the bloodstream through the sublingual, buccal, or other oral mucosa.

[0112] In certain embodiments, the oral composition comprises an oral patch or an oral film that delivers the pharmaceutically active ingredient into the bloodstream through the sublingual, buccal, or other oral mucosa.

[0113] In certain embodiments, the oral composition is swallowed and the pharmaceutically active ingredient is further delivered into the bloodstream through the membranes of the esophagus, stomach, and / or intestine.

[0114] In certain embodiments, the oral composition comprises a powder, a solution, or a suspension that delivers the pharmaceutically active ingredient into the bloodstream through the sublingual, buccal, or other oral mucosa.

[0115] In certain embodiments, the oral composition is swallowed and the pharmaceutically active ingredient is further delivered into the bloodstream through the membranes of the esophagus, stomach, and / or intestine.

[0116] In certain embodiments, formulations of pharmaceutically active ingredients of (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, result in immediate release of the pharmaceutically active ingredient into the plasma upon oral administration. In certain embodiments, formulations comprising pharmaceutically active ingredients of (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, comprise a therapeutically or prophylactically effective amount of the pharmaceutically active ingredient and, optionally, one or more excipients.

[0117] In certain embodiments, formulations of pharmaceutically active ingredients of (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, result in modified release of the pharmaceutically active ingredient into the plasma upon oral administration. In certain embodiments, formulations comprising pharmaceutically active ingredients of (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, comprise a therapeutically or prophylactically effective amount of the pharmaceutically active ingredient and, optionally, one or more excipients.

[0118] In certain embodiments, the embodiments herein include the use of a pharmaceutical active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for preparing a pharmaceutical composition for treating neurological, mood, and substance use disorders, and the composition is prepared for oral administration.

[0119] In certain embodiments, the embodiments herein include the use of a pharmaceutical active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for preparing a pharmaceutical composition for treating neurological, mood, and substance use disorders, and the composition is prepared for oral administration.

[0120] In certain embodiments, the oral composition contains inactive ingredients that enhance drug delivery properties and stabilize the active ingredient.

[0121] In one embodiment, a filler may be included as an inactive ingredient. The filler can act as a matrix that affects dissolution time or as a binder to improve tablet stability. Fillers include, but are not limited to, starch, citric acid, tartaric acid, bicarbonate, phosphate, polyvinylpyrrolidone, cellulose (natural and modified), croscarmellose, glycolate, acrylate, acetate, gelatin, gum, alginate, pectin, chitosan, chitin, salts, polysaccharides, mucilage, sugars, sucrose, lactose, and dextrose.

[0122] In another embodiment, a lubricant may be included as an inactive ingredient. The lubricant acts to improve powder flowability or reduce friction of manufacturing parts. These can include, but are not limited to, magnesium stearate, talc, stearic acid, and silicon dioxide.

[0123] In yet another embodiment, a flavoring agent may be included as an inactive ingredient. The flavoring agent can mask the taste of the bittering agent or improve the taste of the oral composition. These include, but are not limited to, sugars, dextrose, sucrose, sucralose, stevia, essential oils, citric acid, and natural or artificial flavoring agents. Optionally, a colorant can be included in the powder to improve visual characteristics or to differentiate the product offering. These colorants can be natural or artificial dyes, pigments, chelates or metals.

[0124] In certain embodiments, the oral composition contains a surfactant which is an emulsifying agent and stabilizer capable of encapsulating the drug for better stability, taste, permeability and drug release characteristics. Surfactants include, but are not limited to, vegetable oils, triglycerides, esters, polysorbates (Tween®), sorbitans (Span®), phospholipids (such as lecithin), lauryl sulfate, betaines, propionates, fatty acids, fatty alcohols, saponins and alkanolamides, amine oxides, cyclodextrins, myristates and azones.

[0125] In certain embodiments, the oral composition contains a co-solvent to improve drug solubility, dissolution and permeability. Co-solvents include, but are not limited to, alcohols such as ethanol, isopropanol, glycerin, propylene glycol, dipropylene glycol, polyethylene glycol, diethylene monoethyl ether, cremophor, siloxane, polyethylene, and water.

[0126] In certain embodiments, the oral composition contains a thickening agent to reduce dissolution and provide a matrix suitable for delivery. Examples of thickening agents include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenan, polysaccharides, and high melting point waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosins, resins, paraffin, and petrolatum.

[0127] In certain embodiments, the oral composition contains a preservative to improve formulation stability and delay microbial growth. Examples of preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chlorides, phenol, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts, and alcohols.

[0128] In certain embodiments, the oral composition contains an enteric coating to modify and extend release within the gastrointestinal tract. Examples of enteric coatings include high melting point waxes, fatty acids, sugars, fibers, and polymers.

[0129] In another embodiment, the oral composition contains an excipient that changes physical properties of the drug delivery system such as pH, solubility, dissolution, hydrophobicity, and stability. Many such compounds are known to those skilled in the art.

[0130] In certain embodiments, the oral composition contains a membrane permeation enhancer to increase systemic delivery. Suitable permeation enhancers for use in oral compositions include, for example, C 2-4Alcohols, such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, sorbitan (Span®), polysorbate (e.g., Tween®, polysorbate 20), fatty acids, esters of fatty acids having from about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoester content of at least 51% (the monoester having from 10 to 20 carbon atoms), and mixtures of mono-, di- and tri-glycerides of fatty acids are included. 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. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt the skin membrane and increase API permeability. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt the skin membrane 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.

[0131] In certain embodiments, the pharmaceutically active ingredient of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, is included in at least one matrix of the oral composition. In another embodiment, the pharmaceutically active ingredient of ((a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, is included in at least two matrices of the oral composition. In another embodiment, the pharmaceutically active ingredient of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (1), and combinations thereof, is included in at least three matrices of the oral composition. In another embodiment, the pharmaceutically active ingredient of ((a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, is included in at least four matrices of the oral composition. In yet another embodiment, the pharmaceutically active ingredient of ((a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, is included in at least five matrices of the oral composition.

[0132] In certain embodiments, the pharmaceutical active ingredient is a single active ingredient. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in capsule form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table 1, (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in tablet form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in cachet form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in strip form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered via a transdermal patch. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in powder form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in suspension form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in solution form.

[0133] In another embodiment, the mixture of psilocybin analogs is delivered in the same oral composition as described herein. In a preferred embodiment, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is administered orally in the oral composition described herein, alone or in combination with other (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2).

[0134] In certain embodiments, the oral composition comprises a pharmaceutically effective amount of 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, and / or at least 500 mg of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof.

[0135] In certain embodiments, the systemic drug release of an oral composition containing a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, occurs with a therapeutically active onset of 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.

[0136] In certain embodiments, the duration of the therapeutic or prophylactic effect of an oral composition containing a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, lasts for 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, and at least 1 week.

[0137] As described herein, certain embodiments provide methods regarding different dosages and / or administration periods; provide alternative pharmacokinetic profiles, pharmacodynamic profiles, and / or safety profiles; enable long-term maintenance therapy; provide tests for new indications for psilocybin analogs; and provide oral compositions of the pharmaceutically active ingredients described herein that are useful in other potential advantageous benefits.

[0138] Methods for preventing, managing, and treating post-treatment Lyme disease syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression, anxiety, substance use disorders including but not limited to opioid use disorder, alcohol use disorder, nicotine use disorder, cannabinoid use disorder, headache, central nervous system inflammation, dementia, and cognition and memory by transdermal, transnasal, or oral administration of psilocybin analogs are provided herein.

[0139] In certain embodiments, the pharmaceutically active ingredient is a single pharmaceutically active ingredient. In preferred embodiments, (a) an indole of a compound belonging to the structures of formulas (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is delivered by a transdermal patch delivery system. In preferred embodiments, the pharmaceutically active ingredient is transdermally delivered by a transdermal patch delivery system.

[0140] In another embodiment, a mixture of psilocybin analogs is delivered by the same transdermal delivery system. In preferred embodiments, the psilocybin analog is transdermally delivered alone or in combination with other psilocybin analogs in a transdermal patch delivery system.

[0141] In another embodiment, the pharmaceutically active ingredient is co-administered with one or more therapeutic agents. The co-administered agent can be an MAOI. In another embodiment, a compound from another class of neurologically active agents is co-administered to provide a synergistic therapeutic effect. Other neurologically active agents include compounds classified into the following classes of compounds: antipsychotics, antidepressants, anxiolytics, stimulants, reuptake inhibitors (SSRI or SSNRI), monoamine oxidase inhibitors (MAOI), cognitive enhancers, tricyclic antidepressants, mood stabilizers, NMDA antagonists, and 5-HT antagonists.

[0142] In yet another embodiment, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2) is co-administered, either alone or as a mixture, with one or more therapeutic agents to reduce substance abuse. For the treatment of opioid addiction, other co-administered compounds can include methadone, buprenorphine, naloxone, naltrexone, and the like. For the treatment of alcohol dependence, other co-administered compounds can include ethyl alcohol, disulfiram, naltrexone, acamprosate, benzodiazepine, and the like. For the treatment of nicotine addiction, other co-administered compounds can include low-dose nicotine, bupropion, varenicline, and the like.

[0143] Methods for preventing, managing, and treating post-treatment Lyme disease syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression, anxiety, neurological, mood, or addiction disorders including addictions, opioid addiction, alcohol addiction, nicotine addiction, cannabinoid addiction, but not limited to these, headaches, central nervous system inflammation, dementia, cognition, and memory by transdermally administering a psilocybin analog are provided herein.

Example

[0144] Example 1: Purified N,N-dimethyltryptamine (DMT 1.8% w / w, wet) was dissolved in a combination of ethyl acetate (7.2% w / w, wet) and ethanol (7.2% w / w, wet), incorporated into Duro-Tak 4098 acrylate adhesive (83.8% w / w, wet), and mixed well. The mixture was formulated to a thickness of 150 μm on the silicon-treated surface of a Scotchpak 9709 release liner. The formulation was dried at 75°C and laminated onto a backing of occlusive Scotchpak 9733 polyester, after which the transdermal patch was cut to a size of 10 cm 2 and stored in a heat-sealed aluminum pouch to reduce oxidation.

[0145] Linear drug release (n = 3 transdermal patches) was observed over 72 hours, and more than 80% of DMT was released at 72 hours (Figure 1). The average DMT flux was quantified over 72 hours at 37 μg / cm 2* hr.

[0146] Example 2: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (8.0% w / w, wet) and incorporated into Duro-Tak 4098 adhesive (90.0% w / w, wet), and mixed thoroughly. The mixture was formulated to a thickness of 250 μm on a release liner. After drying the formulation and laminating it onto a closed backing, the transdermal patch was cut into 10 cm 2 sized pieces. The final transdermal patch (6.4% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 72 hours at 43 μg / cm 2* hr.

[0147] Example 3: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (8.1% w / w, wet) and incorporated into silicone adhesives Bio PSA 7-4302 (44.9% w / w, wet) and Bio PSA 7-4202 (44.9% w / w, wet), and mixed thoroughly. The mixture was formulated to a thickness of 150 μm on a release liner. After drying the formulation and laminating it onto a closed backing, the transdermal patch was cut into 10 cm 2 sized pieces. The final transdermal patch (3.9% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 48 hours at 31 μg / cm 2* hr.

[0148] Example 4: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (4.0% w / w, wet), incorporated into Duro-Tak 6908 polyisobutylene adhesive (94.0% w / w, wet), and mixed thoroughly. The mixture was formulated to a thickness of 150 μm on a release liner. After drying the formulation and laminating it onto a occlusive backing, the transdermal patch was cut into 10 cm 2 sized pieces. The final transdermal patch (5.4% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 30 hours at 7 μg / cm 2* hr.

[0149] Example 5: Purified DMT (3.8% w / w, wet) was dissolved in ethanol (15.9% w / w, wet), incorporated into Duro-Tak 4098 adhesive (80.3% w / w, wet), and mixed thoroughly. The mixture was formulated to a thickness of 200 μm on a release liner. After drying the formulation and laminating it onto a occlusive backing, the transdermal patch was cut into 10 cm 2 sized pieces. The final transdermal patch (10.9% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 48 hours at 57 μg / cm 2* hr.

[0150] Example 6 Purified DMT (4.2% w / w, wet) was dissolved in ethanol (11.2% w / w, wet), incorporated into Duro-Tak 4098 acrylate adhesive (77.5% w / w, wet), and after that, isopropyl myristate (7.1% w / w, wet) was added and mixed thoroughly. The mixture was formulated to a thickness of 200 μm on a release liner. After drying the formulation and laminating it onto a occlusive backing, the transdermal patch was cut into 10 cm 2 sized pieces. The final transdermal patch (10.3% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 48 hours at 145 μg / cm 2* hr.

[0151] Example 7: Purified 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT, 3.2% w / w, wet) was dissolved in ethanol (12.4% w / w, wet) and incorporated into Duro-Tak 4098 acrylate adhesive (84.4 w / w, wet) and mixed thoroughly. The mixture was formulated to a thickness of 200 μm on the silicone-treated surface of a release liner. The formulation was dried and laminated onto an occlusive polyester backing, after which the transdermal patch was cut into 10 cm 2 sized pieces. The final transdermal patch (9.0% w / w 4-AcO-DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average 4-AcO-DMT flux was quantified over 48 hours at 98 μg / cm 2* hr.

[0152] Example 8: A second DIA containing the excipients listed above is poured directly onto the backing and laminated onto a rate control membrane. Next, the DIA-coated liner from Example 1 is laminated onto the backing / DIA / membrane material to form a multilayer delivery system. The transdermal patch is then die-cut to the appropriate size.

[0153] The DIA poured onto the liner (and then applied directly onto the skin) does not require as high a drug load as the second DIA. The second DIA acts as a reservoir and diffuses the drug through the rate control membrane after manufacture until equilibrium between the first DIAs is achieved. When applied, the second DIA permeates the drug through the membrane to the skin at a zero-order rate until the drug reservoir is sufficiently depleted.

[0154] Example 9: The N,N-dimethyltryptamine (DMT) free base was dissolved in 25 mg / mL acetone. 7 mg / mL of fumaric acid was added dropwise to precipitate DMT fumarate. The precipitate was washed twice with fresh acetone and dried under nitrogen.

[0155] DMT fumarate (18.0% w / w) was dissolved in deionized water (82.0% w / w) to obtain a therapeutically effective aqueous gel vehicle for nasal absorption at an appropriate pH = 6. The formulation of the DMT fumarate gel can be administered via the nasal cavity in a small volume of 0.04 - 0.50 mL for a therapeutic effect. Potency analysis using tryptamine internal standard quantification revealed a DMT free base concentration of 135.5 mg / mL, and after storage for 106 days under dark conditions at room temperature, there were no other decomposition by-products.

[0156] Example 10: The Franz cell apparatus was used to determine API release and permeability through a human skin mimic (Strat - M membrane, Millipore), and the patch effectiveness of Examples 1 - 8 was compared. The receptor well (10% ethanol in water) was maintained at 32°C throughout the experiment, and 10 mL was removed at each sampling point. The drug flux was determined using the gradient of zero - order permeating API over the specified time range. In Examples 1 - 9, tryptamine (50 μg / mL) was added as an internal standard and LC - MS was used to achieve potency analysis of the API while using UV detection at 280 nm to quantify the API.

[0157] Example 11: The free base 4 - AcO - DMT (8% w / w) was dissolved in ethanol (4% w / w), and further povidone (2% w / w), butylated hydroxytoluene (1% w / w) and FD&C Blue No.1 were added. This solution was added to Ceolus KG 1000 microcrystalline cellulose (16% w / w) and mannitol (47% w / w), mixed simultaneously, and then dried to form a uniformly coated powder. Further, Prosolv HD 90 silicified microcrystalline cellulose (20% w / w), Cabosil silicon dioxide (1% w / w) and magnesium stearate (1% w / w) were added and blended until homogeneous. Using a die set and sufficient force, 250 mg tablets for the ingestion of 4 - AcO - DMT for therapeutic use were formed.

[0158] Example 12: 2-(2-Chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine A mixture of tryptamine hydrochloride (1 g, 5.1 mmol) and N-chlorosuccinimide (NCS, 0.69 g, 5.2 mmol) in acetic acid (50 mL) and formic acid (15 mL) was stirred for about 20 minutes. The product 2-chloro-tryptamine (confirmed by 2D NMR spectroscopy) was dried, purified, and 211 mg (1.09 mmol) was further reacted with sodium cyanoborohydride (139.26 mg, 2.22 mmol) in methanol (21 mL) and formaldehyde (0.222 mL, 2.75 mmol) at 0 °C under nitrogen and stirred for 2.5 hours. The reaction was quenched with 1.0 M sodium hydroxide (27 mL) and extracted three times with methyl-tert-butyl ether (MTBE). The residue was dried over sodium sulfate and concentrated as a light brown oil / solid. LC-MS, 1 H and 13 C Based on the NMR data, the final product contained mostly 2-chloro-N,N-dimethyltryptamine. The formula of the product C 12 H 15 N 2 Cl m / z 222.0924, [M+H] + 223.0997 1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 2.13 (s, 6 H) 2.34 - 2.38 (m, 2 H) 2.68 - 2.80 (m, 3 H) 6.91 - 6.99 (m, 1 H) 7.02 (t, J=7.54 Hz, 2 H) 7.20 (d, J=7.99 Hz, 2 H) 7.40 (d, J=7.81 Hz, 1 H) 11.53 (br s, 1 H)

[0159] Example 13: 2-(2-Bromo-1H-indol-3-yl)-N,N-dimethylethane-1-amine Using a previously recorded method, N,N-dimethyltryptamine (2.88 mmol) was synthesized and dissolved in anhydrous acetonitrile (36 mL, 15 mg / mL) under inert conditions. This was combined with copper(II) bromide (1.93 g, 8.65 mmol) and stirred for 2 hours. The reaction was quenched with 40 mL of water, 100 mL of EtOAc was added, and then 40 mL of saturated ammonium carbonate was added. The organic layer was washed, dried over sodium sulfate, filtered, and concentrated to a light brown oil (302.3 mg). The final major product, 2-bromo-N,N-dimethyltryptamine, was confirmed by LC-MS, 1D, and 2D NMR spectroscopy. Formula of the product: C 12 H 15 N 2 Br m / z 266.0419, [M+H] + 267.0491 1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 2.21 (s, 6 H) 2.38 - 2.47 (m, 2 H) 2.73 - 2.88 (m, 3 H) 6.93 - 7.03 (m, 1 H) 7.03 - 7.11 (m, 1 H) 7.28 (br d, J=7.99 Hz, 1 H) 7.46 - 7.51 (m, 1 H) 11.61 (br s, 1 H)

[0160] Example 14: 2-Bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate Using a previously recorded method, 4-acetoxy-N,N-dimethyltryptamine (14.9 mg, 0.06 mmol) was synthesized and dissolved in anhydrous acetonitrile (1 mL) under inert conditions. Copper(II) bromide (40.5 mg, 0.18 mmol) was added and the reaction was stirred for 2 hours. During workup, the major product, 2-bromo-4-acetoxy-N,N-dimethyltryptamine, was confirmed by LC-MS and 1D NMR spectroscopy. Formula of the product: C 14 H17 N 2 O 2 Brm / z 324.0473, [M+H] + 325.0546 1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 2.21 - 2.25 (m, 13 H) 2.32 - 2.39 (m, 12 H) 2.71 - 2.75 (m, 3 H) 6.74 (d, J=7.63 Hz, 1 H) 7.06 - 7.10 (m, 2 H) 7.18 (d, J=8.17 Hz, 2 H) 11.91 (s, 1 H)

[0161] Example 15: 2-(2-Chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine Using a previously recorded method, 4-methoxy-N,N-dimethyltryptamine (130 mg, 0.6 mmol) was synthesized and dissolved in anhydrous acetonitrile (3.6 mL). Copper(II) chloride (241 mg, 1.8 mmol) was added and stirred overnight under an inert atmosphere. Quenched with water (14 mL), extracted 3 times with EtOAc, and washed with saturated ammonium carbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give an orange semi-solid (38.2 mg, 25% yield). This was purified by HPLC to give 2-chloro-4-methoxy-N,N-dimethyltryptamine, which was confirmed by LC-MS, 1D and 2D NMR spectroscopy.

[0162] The formula of the product: C 13 H 17 N 2 OClm / z 252.1029, [M+H] + 253.1102 1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 2.27 - 2.39 (m, 14 H) 2.50 - 2.60 (m, 6 H) 2.89 - 3.05 (m, 5 H) 3.84 - 3.99 (m, 9 H) 6.54 - 6.66 (m, 2 H) 6.92 (d, J=8.17 Hz, 1 H) 7.03 - 7.19 (m, 2 H) 11.71 (s, 1 H)

[0163] Example 16: 1-(-3-(2-(Dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide The nitro group of N-methyl-3-nitrobenzenesulfonamide is reduced to aniline via palladium on carbon (H 2 / Pd / C) and aqueous HCl in ethanol solvent. This product is treated with sodium nitrite to obtain a diazonium salt, which is then reduced to hydrazine using SnCl 2 (all at 0 °C). The hydrazone is formed upon condensation with 4,4-dimethyoxy-N,N-dimethylbutylamine in aqueous hydrochloric acid. The final product is formed via a Fischer indole reaction in which the hydrazone reacts with polyphosphoric acid in refluxing chloroform to initiate cyclization.

[0164] This compound can be further halogenated at the C-2 position according to the copper(II) halide protocol of the previous example.

[0165] Example 17: Computational Analysis Six different receptor models were tested according to the crystal structures recorded in the RCSB Protein Data Bank (PDB) for various serotonin receptors and sigma-1. These receptor structures include 5-HT 2A 、5-HT 2B 、5-HT 1B 、and σ 1 (PDB IDs are also shown in the column headings).

[0166] For each static protein structure, to increase accuracy as much as possible, the PDB file of the crystal structure containing the binding ligand most chemically similar to the scaffold of tryptamine was used (e.g., LSD or ergotamine binding). The overall workflow was executed using various aspects of the Schrödinger software suite. 3D SMILES for each ligand were uploaded according to literature-recommended protonation and / or the charge of tryptophan, and various conformers were generated and minimized using Schrödinger LigPrep. The final list of compounds was screened using the Glide scores generated by Schrödinger Glide, including the structures listed in Table 3. Validation of this technique was performed by including known agonists of the 5-HT and σ 1 receptors and comparing with experimental binding assay data. The docking scores of the known agonists and experimental data were equivalent and within experimental error for activity. For example, the (+)-LSD enantiomer showed greater in vitro activity at the 5-HT 2A receptor than the (-)-LSD enantiomer, and the values rendered in our calculations showed the same trend in activity.

[0167]

Table 3-1

Table 3-2

Table 3-3

Table 3-4

[0168] This disclosure has been described in connection with specific embodiments and examples. However, unless otherwise indicated, the claimed invention should not be unduly limited to such specific embodiments and examples. In certain embodiments, for example, the following are provided: (Item 1) A compound of the following formula: Structure (2) [Chemical formula] In the formula, R 1 is selected from the group consisting of H, F, Cl, Br, I or CF 3 ; R 2 is H or CH 3 ; R 3 and R 4 are each independently, optionally, H, CH 3 , C 2 H 5 , (H 3 C) 2 CH, or H 2 C=CH-CH 2 selected from the group consisting of; R 5 is OCH 3 , OCOCH 3 , O-phosphate, O-polyethylene glycol (PEG), O-(CH 2 ) 2 (COOH) 2 (succinate), O-(CH 2 ) 2 (COOH)(hemisuccinate) and CH 2 SO 2 NHCH 3 (sulfonamide) selected from the group consisting of; when R 1 is H, R 5 is CH 2 SO 2 NHCH 3 compounds, and pharmaceutically acceptable salts or solvates thereof. (Item 2) The compound according to item 1, selected from the group consisting of 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-bromo-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 1-(2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, 1-(2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, and 1-(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide. (Item 3) A compound of the following formula: Structure (3) [Chemical formula] In the formula, R 1 is selected from the group consisting of F, Cl, Br, I or CF 3 ; R 2 is CH 3 ; R 3 and R 4 are each independently, optionally, H, CH 3 C 2 H 5 (H 3 C) 2 CH, or H 2 C=CH-CH 2 selected from the group consisting of, a compound. (Item 4) 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, (R)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-vinyl ethenamine, 2-(2-bromo-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, or N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, the compound according to item 3, selected from the group consisting of (Item 5) A pharmaceutical composition comprising a pharmaceutically active ingredient, wherein the pharmaceutically active ingredient is a compound selected from the group consisting of a compound of structure (2), a compound of structure (3), or a psilocybin analog. (Item 6) The composition according to item 5, wherein the psilocybin analog is selected from the group consisting of psilocybin, psilocin, 4-hydroxy-indole-3-acetic acid, 4-hydroxytryptophol, 4-hydroxytryptophan, norsilocin, aeruginascin, baeocystin, norbaeocystin, 4-hydroxy-N-methyl-N-ethyltryptamine (4-OH-MET), 4-hydroxy-diethyltryptamine (4-OH-DET), 4-hydroxy-N,N-dipropyltryptamine (4-OH-DPT), 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT), N,N-dimethyltryptamine (DMT), indole-3-acetic acid, N,N-dimethyltryptamine-N-oxide (DMT-NO), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), bufotenin (5-OH-DMT), 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), lysergic acid diethylamide (LSD), 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), ibogaine, and combinations thereof. (Item 7) The composition according to item 5, wherein the compound is selected from the group consisting of 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-bromo-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 1-(2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, 1-(2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, or 1-(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide. (Item 8) The composition according to item 5, wherein the compound is selected from the group consisting of 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, (R)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-vinylethanamine, 2-(2-bromo-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, or N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine. (Item 9) The pharmaceutical composition according to item 5, wherein the composition is for oral delivery, nasal delivery or transdermal delivery of the pharmaceutically active ingredient. (Item 10) The pharmaceutical composition according to item 5, wherein the transdermal composition is selected from the group consisting of a sprayable liquid, a gel, a cream, a lotion, an ointment, or a transdermal patch. (Item 11) The pharmaceutical composition according to item 5, wherein the oral composition is a tablet, a capsule, a cachet or a strip. (Item 12) The pharmaceutical composition according to item 5, wherein the nasal composition is selected from the group consisting of a gel, a sprayable liquid, an emulsion, or an ointment. (Item 13) A method for treating or preventing a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of structure (2), structure (3) or a psilocybin analog. (Item 14) The method according to item 16, wherein the disease is a neurological disorder, a mood disorder or a substance use disorder. (Item 15) The method according to item 16, wherein the disease is selected from the group consisting of depression, central nervous system inflammation, addiction, headache or dementia, or impairment of cognition and memory. (Item 16) The method according to item 7, wherein the disease is selected from the group consisting of epilepsy, headache, dementia, traumatic injury, substance abuse, multiple sclerosis or Parkinson's disease. (Item 17) A method for preparing the compound according to item 2. (Item 18) A method for preparing the compound according to item 4.

Claims

Claim 1: A compound of the following formula (Structure 1): 【Chemistry 7】 During the ceremony, X is a halogen selected from the group consisting of F, Cl, Br, and I; R 1 is an aliphatic substituent having a primary, secondary, tertiary or quaternary amine; R 2 is hydroxyl; With the proviso that the compound is not 2-bromo-3-[2-(dimethylamino)ethyl]-1H-indol-4-ol or 2-chloro-3-[2-(dimethylamino)ethyl]-1H-indol-4-ol.

2. The compound of claim 1, wherein X is Br.

3. The compound according to claim 1 or claim 2, wherein R 1 is an aliphatic substituent having a tertiary amine.

4. The compound of claim 1 or claim 2, wherein R 1 is an aliphatic substituent having a secondary amine.

5. The compound according to claim 1, wherein R 1 is (dimethylamino)ethyl.

6. The compound of claim 1, wherein the compound is 2-fluoro-3-[2-(dimethylamino)ethyl]-1H-indol-4-ol.

7. The compound of claim 1, wherein the compound is 2-iodo-3-[2-(dimethylamino)ethyl]-1H-indol-4-ol.

8. The compound of claim 1, wherein the compound is 3-[2-(dimethylamino)ethyl]-2-trifluoromethyl-1H-indol-4-ol.

9. A pharmaceutical composition comprising an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a compound described in any one of claims 1 to 8.

10. A pharmaceutical composition comprising an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is 2-bromo-3-[2-(dimethylamino)ethyl]-1H-indol-4-ol.

11. A pharmaceutical composition comprising an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is 2-chloro-3-[2-(dimethylamino)ethyl]-1H-indol-4-ol.

12. The pharmaceutical composition described in any one of claims 9 to 11, wherein the pharmaceutical composition is for oral delivery, nasal delivery or transdermal delivery of the active pharmaceutical ingredient.

13. The pharmaceutical composition of any one of claims 9 to 12, wherein the pharmaceutical composition is a transdermal composition, the transdermal composition being selected from the group consisting of a sprayable liquid, a gel, a cream, a lotion, an ointment, or a transdermal patch.

14. The pharmaceutical composition of any one of claims 9 to 12, wherein the pharmaceutical composition is an oral composition, the oral composition being a tablet, capsule, cachet or strip.

15. The pharmaceutical composition of any one of claims 9 to 12, wherein the pharmaceutical composition is a nasal composition, and the nasal composition is selected from the group consisting of a gel, a sprayable liquid, an emulsion, or an ointment.

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