Compositions with psilocybin and baeocystin derivatives

Abstract

This invention provides compositions containing serocerabin or psilocybin derivatives, characterized by improved pharmacokinetic properties, for the treatment of metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), malabsorption syndrome (MASLD), metastatic atherosclerosis (MetALD), MASH, or sarcopenia; for the treatment of neurological disorders, including stroke and aLS; and for aging.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 589,387, filed October 11, 2023, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0003] Psilocybin produces alterations in consciousness and mood, including various hallucinogenic effects. Hallucinogenic substances are currently being investigated for the treatment of several conditions and symptoms, including depression, post-traumatic stress disorder, obsessive-compulsive disorder, and addiction. Based on clinical research to date, hallucinogenic experiences are a component of the anticipated treatments studied to date.

[0004] Significant efforts have been made to understand the mechanisms and comorbidities of metabolic disorders in order to better design treatments. Sarcopenia is commonly found in patients with metabolic disorders. Sarcopenia is a medical term describing the loss of skeletal muscle mass, which typically occurs in metabolic disorders, aging, cancer, gastrointestinal, kidney, lung, or liver diseases, or as a result of other diseases and their treatments, including obesity and metabolic disorders (including type 2 diabetes), and can impact overall health and quality of life. Sarcopenia may be triggered or exacerbated by metabolic disorders (including obesity, type 2 diabetes, MASLD), in which case it is defined as metabolically abnormal sarcopenia, and may be associated with insulin resistance / glucose intolerance. Therefore, there is a need to develop new compositions and methods for treating metabolic disorders and sarcopenia. Summary of the Invention

[0005] In an embodiment, the present invention provides an extended-release composition comprising about 0.01 mg to about 20 mg of psilocin or a psilocin derivative, wherein the composition provides as described by USP <711> The following dissolution characteristics were measured:

[0006] Approximately 15% to approximately 35% of the said serocerin or psilocybin derivatives are released within approximately 0.5 hours;

[0007] Approximately 45% to approximately 64% of the said serocerin or psilocybin derivatives are released within approximately 2 hours;

[0008] Approximately 65% ​​to approximately 85% of the said serocerin or psilocybin derivatives are released within approximately 4 hours; and

[0009] Not less than about 80% of the said serocerin or psilocybin derivatives are released within about 10 hours.

[0010] In embodiments, this disclosure provides an extended-release composition comprising about 0.01 mg to about 40 mg of a psilocybin derivative, wherein the composition provides a release from USP <711> The following dissolution curves were measured:

[0011] Approximately 15% to approximately 35% of the said psilocybin derivatives are released within approximately 0.5 hours;

[0012] Approximately 45% to approximately 64% of the said psilocybin derivatives are released within approximately 2 hours;

[0013] Approximately 65% ​​to approximately 85% of the said psilocybin derivatives are released within approximately 4 hours; and

[0014] No less than about 80% of the said naked head cinnamon derivative is released within about 10 hours.

[0015] In an embodiment, the present invention provides a composition containing 4-O-polyethylene glycolated psilocybin that is immediately released and comprises about 0.01 mg to about 40 mg of polyethylene glycolated psilocybin.

[0016] In an embodiment, the present invention provides an extended-release composition comprising about 0.01 mg to about 20 mg of serocerin or about 0.01 mg to about 40 mg of a psilocybin derivative as described herein, wherein said composition satisfies USP <905> Or the minimum content uniformity requirements provided in European Pharmacopoeia 2.9.40.

[0017] In an embodiment, this disclosure provides a method for treating metabolic disorders or sarcopenia in patients in need, the method comprising administering to the patient a therapeutically effective amount of the composition of this disclosure.

[0018] In its implementation, this disclosure provides a method for treating neuropsychiatric or neurodegenerative conditions and diseases in patients in need, including stroke and stroke-related defects, including visual impairment following occipital lobe stroke, including amyotrophic lateral sclerosis (ALS), the method comprising administering to the patient a therapeutically effective amount of the composition of this disclosure.

[0019] In the implementation plan, the composition is administered as the sole agent or in combination with other agents to patients in need to treat symptoms and diseases.

[0020] In its implementation, this disclosure provides a method for treating patients in need of prediabetes, type II diabetes, obesity, metabolic dysfunction-related fatty liver disease (MASLD and MetALD), metabolic dysfunction steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), dyslipidemia, or sarcopenia, the method comprising administering to the patient a therapeutically effective amount of the composition of this disclosure.

[0021] Other embodiments will be apparent to those skilled in the art based on this disclosure. Attached Figure Description

[0022] Figure 1 This is a graph showing the dissolution curve of composition A over time.

[0023] Figure 2 This is a graph showing simulated concentrations versus time for immediate and extended release of serocerabin, with dose as the plane. Shaded areas represent minimum and maximum values ​​from the simulation. Gray shaded areas represent immediate release, and blue shaded areas represent modified release.

[0024] Figure 3 This is a graph showing the pharmacokinetic curves and key PK parameters of PEG4, PEG6, PEG8, and PEG10-glucopyranosine.

[0025] Figure 4 This is a graph showing the number of head twitching responses after administration of 3 mg / kg serocepin or the polyethylene glycol-modified derivative of the psilocybin equivalent.

[0026] Figure 5A This graph shows the agonist activities of psilocybin and PEG4-, PEG6-, PEG8-, and PEG10-psilocybin against human 5-HT2A (green), 5-HT2B (red), and 5-HT2C (blue) receptors, as evaluated by FLIPR (fluorescence imaging plate reader) Penta assay. All PEGylated compounds retain very similar pharmacodynamic characteristics to psilocybin.

[0027] Figure 5B It is 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl isobutylcarbamate (i-buPSI). 1 H and 13 C NMR spectrum.

[0028] Figure 5C It is (((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxy)carbonyl)-L-isoleucine methyl ester (IleMePSI) 1 H and 13C NMR spectrum.

[0029] Figure 5D It is (((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxy)carbonyl)-L-isoleucine (IlePSI) 1 H and 13 C NMR spectrum.

[0030] Figure 5E It is 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2-fluoroethyl)carbamate (CFEtPSI). 1 H and 13 C NMR spectrum.

[0031] Figure 5F It is 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2,2-difluoroethyl)carbamate (CF2EtPSI). 1 H and 13 C NMR spectrum.

[0032] Figure 5G It is 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2,2,2-trifluoroethyl)carbamate (CF3EtPSI). 1 H and 13 C NMR spectrum.

[0033] Figure 5H It is 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(3,3,3-trifluoropropyl)carbamate (CF3PrPSI). 1 H and 13 C NMR spectrum.

[0034] Figure 5I The results are based on in vitro testing of the chemical hydrolytic stability of the derivative in 0.1 M HCl (pH 1) and 10 mM PBS (pH 7.4) at 37°C to simulate the physiological pH conditions encountered by the drug during oral administration.

[0035] Figure 6 This is a graph showing the pharmacokinetic curves and key PK parameters of IleMe-carbamate psilocybin and CF3-Et-carbamate psilocybin.

[0036] Figure 7 It is a graph showing the area under the curve for weight gain in the three study groups. p<0.05; p<0.0001.

[0037] Figure 8This is a graph showing blood glucose levels after an oral glucose tolerance test. Compared to the control group, p<0.05.

[0038] Figure 9 This is a set of images showing liver histology from three study groups. PEG8-naked ginseng treatment reduced hepatic steatosis.

[0039] Figure 10 This is a schematic diagram of the research plan.

[0040] Figure 11 The graph shows the results of treatment with 0.05 mg / kg cilostabrine daily for 30 days.

[0041] Figure 12 This is a diagram showing the results of behavioral studies conducted to evaluate the use of seroxibin.

[0042] Figure 13 It is a bar graph showing the size of the lesion 24 hours after photothrombotic stroke and 45 days after treatment with a mediator, a mediator plus selocillin, or selocillin.

[0043] Figure 14 It is a bar graph showing the spike density in the perilesional and distal regions of the lesion in mice that have experienced photothrombotic stroke and have been treated with a mediator, a mediator plus selocillin, or selocillin for 45 days.

[0044] Figure 15 This is a set of figures showing the results of studies on serocillin in G93A SOD1 mice.

[0045] Figure 16A These are a set of photomicrographs of WI-38 cells after the specified treatment (top bright field, bottom Hoechst33342). Scale bar = 200 μm.

[0046] Figure 16B This is a bar graph showing the quantification of SA-β-Gal positive cells. n = 4, with 2 biological replicates and 2 technical replicates from the UT, Doxo, Psib 0.1, and Psib 1 groups, and n = 2 technical replicates in Psin 0.1 and Psin 1. One-way ANOVA with Dunnett's multiple comparison test. =p<0.01, =p<0.0001.

[0047] Figure 17A This is an immunoblot of phosphorylated p38 in WI-38 fibroblasts treated with the specified compounds. For UT, Doxo, Psib 0.1, and Psib 1, n=3. For Psin 0.1 and Psin 1, n=1.

[0048] Figure 17B This is an immunoblot of histone H3 in WI-38 fibroblasts treated with the specified compounds. For UT, Doxo, Psib 0.1, and Psib 1, n=2. For Psin 0.1 and Psin 1, n=1.

[0049] Figure 18 This is a powder X-ray diffraction pattern of anhydrous thiopsisin. Detailed Implementation Plan

[0050] Xelocillin is a phosphate prodrug; its active compound, psilocybin, is rapidly released in the intestine via dephosphorylation. Psilocybin is known to be a receptor agonist that exerts its hallucinogenic effects by activating isotype 2A (5-HT2AR) of the serotonin (5-HT) receptor in the CNS. Furthermore, in addition to being a partial agonist of 5-HT2AR, psilocybin has been shown to be a partial agonist of 5-HT2CR and an antagonist of 5-HT2BR.

[0051] Although the role of 5-HT outside the CNS is only partially understood, it is well known that all of these 5-HT2Rs are also expressed outside the CNS, for example in the intestine, adipose tissue, pancreas and liver (Oh CM, Park S, Kim H. Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity. Diabetes Metab J. 2016; 40(2): 89-98), where they are involved in regulating several biological processes, including metabolic processes. For example, 5-HT has a direct effect on the liver, where it regulates hepatic blood flow, nerve innervation, and wound healing processes (Richard G. Ruddell, Derek A. Mann, Grant A. Ramm, The function of serotonin within the liver, Journal of Hepatology, Vol. 48, No. 4, 2008, pp. 666-675, https: / / doi.org / 10.1016 / j.jhep.2008.01.006), and also has a direct effect on adipose tissue, particularly by participating in key processes in the pathogenesis and regression of obesity (Oh, CM, Namkung, J., Go, Y. et al. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat Commun 6, 6794 (2015). https: / / doi.org / 10.1038 / ncomms7794). Therefore, it may be possible to treat metabolic diseases by specifically targeting peripheral 5-HTR with serotonergic compounds that cannot cross the blood-brain barrier (BBB), while avoiding unwanted central hallucinations.

[0052] Globally, the most prevalent metabolic disorders are obesity, type 2 diabetes, and metabolic dysfunction-associated fatty liver disease (MASLD), which can develop into its complication, metabolic dysfunction-associated steatohepatitis (MASH), characterized by fibrosis and inflammation, and an increased risk of developing cirrhosis and / or liver cancer. Furthermore, a new type of hepatic steatosis, called MetALD, has recently been introduced, defined as alcohol consumption of 20–50 g of alcohol daily (or 140–350 g per week) for women and 30–60 g of alcohol daily (or 210–420 g per week) for men. Within the MetALD spectrum, some individuals may primarily exhibit MASLD characteristics, while others may be more predisposed to alcoholic liver disease (ALD). In recent years, increasing data have suggested that MASLD may be related to aging (He QJ, Li YF, Zhao LT, Lin CT, Yu CY, Wang D. Recent advances in age-related metabolic dysfunction-associated steatotic liver disease. World J Gastroenterol. 2024 Feb 21; 30(7): 652-662. doi:10.3748 / wjg.v30.i7.652.PMID:38515956;PMCID:PMC10950625). In this context, age-related MASLD will become a major global health problem, and targeting aging-related processes will become a new approach to treating MASLD.

[0053] Hallucinogenic drugs such as serocillin are known for their ability to induce neuroplasticity and stimulate neurogenesis, which may contribute to their therapeutic potential in certain neurological disorders. Stroke is a leading cause of death and a major contributing factor to severe disability worldwide. Occipital lobe stroke affects the brain's visual processing center, often resulting in significant visual impairment. These strokes are typically unilateral, affecting one hemisphere of the visual cortex, leading to significant damage to visual perception and processing. This damage can greatly impact the quality of life of affected individuals. Currently, there are no treatments that can promote visual recovery, prompting the exploration of new therapies. Therefore, there is a need to develop new compositions and methods for treating this condition.

[0054] Amyotrophic lateral sclerosis (ALS), also known in the United States as motor neuron disease (MND) or Lou Gehrig's disease, is a rare, terminal neurodegenerative disease that causes the progressive loss of upper and lower motor neurons that normally control voluntary muscle contraction. ALS is the most common form of motor neuron disease. In its early stages, ALS typically presents with progressive muscle stiffness, twitching, weakness, and weight loss. Motor neuron loss usually continues until the ability to eat, speak, move, and ultimately breathe is completely lost.

[0055] definition

[0056] Throughout this disclosure, references are made to various patents, patent applications, and publications (including non-patent publications). The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes in order to fully describe the prior art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the referenced patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0057] For convenience, certain terms used in the specification, embodiments, and claims are collected herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0058] When immediately preceding a numerical value, the term “about” indicates a range (e.g., plus or minus 10% of the value). For example, “about 50” could mean 45 to 55, “about 25,000” could mean 22,500 to 27,500, etc., unless the context of this disclosure otherwise or is inconsistent with such interpretation. For example, in a list of numerical values ​​such as “about 49, about 50, about 55…”, “about 50” refers to a range extending to less than half the interval between the preceding and following values, e.g., greater than 49.5 to less than 52.5. Furthermore, the phrases “less than about” or “greater than about” should be understood according to the definition of the term “about” provided herein. Similarly, when the term “about” precedes a series of numerical values ​​or ranges of values ​​(e.g., “about 10, 20, 30” or “about 10–30”), it refers to the endpoints of all values ​​or ranges in the series, respectively.

[0059] The term “therapeuticly effective” when applied to dosage or amount refers to an amount of compound or pharmaceutical composition that is sufficient to produce the desired clinical benefit when administered to a patient or subject in need.

[0060] In the implementation scheme, the effective amount of serocerin or psilocybin derivative is the amount required to reduce at least one symptom of a metabolic disorder or sarcopenia or neuropsychiatric or neurodegenerative disease or condition as otherwise described herein. In the implementation scheme, the therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the disease condition (e.g., the subject's weight and age, the severity of the disease condition, the method of administration, etc.), which can be readily determined by those skilled in the art. The specific dosage will vary depending, for example, on the dosing regimen to be followed, the time of administration, the tissue of administration, and the physical delivery system carrying it.

[0061] In this article, the term "treatment" as used with respect to a patient refers to the improvement of at least one symptom of a patient's condition (e.g., metabolic disorder or sarcopenia or neuropsychiatric or neurodegenerative disease or condition). Treatment may be an improvement or at least a partial improvement of the condition or disease or its symptoms.

[0062] As used herein, the phrase “pharmaceutically acceptable” refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and in proportion to a reasonable benefit / risk ratio.

[0063] As used herein, the term "salt" includes pharmaceutically acceptable salts, such as alkali metal salts commonly used to form free acids and addition salts used to form free bases. Salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Base addition salts include, but are not limited to, ethylenediamine, N-methylglucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylhydroxymethylamine, dehydroabimethamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, such as lysine and arginine, dicyclohexylamine, etc. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts, etc. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compound with a suitable inorganic or organic acid using any of a variety of known methods.

[0064] This disclosure further covers compounds described herein as single isomers that are substantially free of other isomers, or as mixtures of various isomers.

[0065] When listing a range of values, the aim is to cover every value within that range and its subranges. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0066] The following terms are intended to have the meanings presented below and are used to understand the description and intended scope of this disclosure. When the description may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms (if present) shall have the following meanings unless otherwise stated. It should also be understood that any portion defined below may be substituted with multiple substituents, and the corresponding definitions are intended to include those substituted portions within the scope described below. Unless otherwise stated, the term “substituted” is defined as follows. It should be further understood that the terms “group” and “free radical” may be considered interchangeable when used herein. The articles “an” and “a” may be used herein to refer to one or more (i.e., at least one) grammatical object of the article. For example, “analyte” means one or more analogs.

[0067] "Cyano" refers to the CN group.

[0068] "Hydroxyl" or "hydroxyl group" refers to the OH group.

[0069] As used in this article, "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group (“alkyl”). In the embodiments, the alkyl group has 1 to 12 carbon atoms (“C”). 1-12 Alkyl group”). In the embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group (“C”). In the embodiments, the alkyl group has 1 to 9 carbon atoms (“C”). 1-9 Alkyl group (“C”). In the embodiments, the alkyl group has 1 to 8 carbon atoms (“C”).1-8 Alkyl group (“C”). In the embodiments, the alkyl group has 1 to 7 carbon atoms (“C”). 1-7 Alkyl group (“C6”). In the embodiments, the alkyl group has 1 to 6 carbon atoms (“C6”). 1-6 Alkyl group, also referred to herein as "lower alkyl group"). In embodiments, the alkyl group has 1 to 5 carbon atoms ("C1 to 5 C2"). 1-5 Alkyl group (“C”). In the embodiments, the alkyl group has 1 to 4 carbon atoms (“C”). 1-4 Alkyl group (“C”). In the embodiments, the alkyl group has 1 to 3 carbon atoms (“C”). 1-3 Alkyl group (“C”). In the embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In the embodiments, the alkyl group has one carbon atom (“C1 alkyl”). 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, the alkyl group may optionally be independently substituted in each case, i.e., unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (“substituted alkyl”); for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In embodiments, the alkyl group is an unsubstituted C10. 1-10 Alkyl group (e.g., -CH3). In embodiments, the alkyl group is a substituted C-molecule. 1-10 Alkyl. Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), i-Pr(-CH(CH3)2), n-Pr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0070] As used herein, “alkenyl” refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2-20 Alkenyl group (“Alkenyl”). In the embodiments, the alkenyl group does not contain any triple bonds. In the embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2-10 Alkenyl group (“Alkenyl”). In the embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In the embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8Alkenyl group (“Alkenyl”). In the embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In the embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In the embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In the embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In the embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 Alkenyl group (“C2-alkenyl”). In embodiments, the alkenyl group has two carbon atoms (“C2-alkenyl”). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”), for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In embodiments, the alkenyl group is an unsubstituted C10 group. 2-10 Alkenyl group. In the embodiments, the alkenyl group is a substituted C group. 2-10 Alkenyl group.

[0071] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array), which has 6–14 ring carbon atoms and zero heteroatoms ("C") in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”, e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C”). 14 "Aromatic", such as anthracene.

[0072] Typical aryl groups include, but are not limited to, groups derived from acenaphthene, acenaphthene, acenaphthylphenanthrene, anthracene, azulene, benzene, phenanthrene, fluorene, benzo[a]hexane, hexane, benzo[a]cyclohexene, asymmetric indarene, symmetric indarene, indene, indene, naphthalene, benzo[a]octabenzene, octane, octane, olebenzene, pent-2,4-diene, benzo[a]pentabenzene, benzo[a]cyclopentadiene, pentabenzene, perylene, phenanthracene, phenanthrene, sepium, heptabenzene, pyrene, pyrene-anthracene, rubigin, benzo[a]phenanthrene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl. Unless otherwise specified, the aryl group may optionally be independently substituted in each case, i.e., unsubstituted (“unsubstituted aryl”) or substituted by one or more substituents (“substituted aryl”). In embodiments, the aryl group is an unsubstituted C[a] 6-14 Aryl group. In the embodiments, the aryl group is a substituted C group. 6-14 Aryl.

[0073] "Heteroaryl" refers to a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array), wherein the aromatic ring system has a cyclic carbon atom and 1 to 8 cyclic heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.

[0074] "Heteroaryl" also includes ring systems in which a heteroaryl group as defined above is fused with one or more aryl groups, wherein the linkage is on the heteroaryl group or one or more aryl groups, and in this case, the number of ring members represents the total number of ring members in the fused (aryl / heteroaryl) ring system. When substitution is indicated in this case, unless otherwise stated, substitution may occur on the heteroaryl group or one or more aryl groups. For bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the linkage may be on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0075] In one embodiment, a heteroaryl group is a 5- to 10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In another embodiment, a heteroaryl group is a 5- to 9-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In yet another embodiment, a heteroaryl group is a 5- to 8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In yet another embodiment, a heteroaryl group is a 5- to 6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In one embodiment, the 5- to 6-membered heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another embodiment, the 5- to 6-membered heteroaryl group has 1 to 2 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In yet another embodiment, the 5- to 6-membered heteroaryl group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, the heteroaryl group may optionally be independently substituted in each case, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In one embodiment, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl group. In yet another embodiment, the heteroaryl group is a substituted 5- to 14-membered heteroaryl group.

[0076] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirheptatrienyl, oxaheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0077] "Heterocyclic group" refers to a group having a 3- to 12-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 12-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided the valence allows. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxacyclopropyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrobutyl, oxacyclobutyl, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopranyl, oxothiocyclopentyl, dithiocyclopentyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0078] In one embodiment, the heterocyclic group is a 5- to 12-membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclic group”). In another embodiment, the heterocyclic group is a 5- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclic group”). In yet another embodiment, the heterocyclic group is a 5- to 8-membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclic group”). In yet another embodiment, the heterocyclic group is a 5- to 6-membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclic group”). In one embodiment, the 5- to 6-membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In another embodiment, the 5- to 6-membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In yet another embodiment, the 5- to 6-membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0079] In embodiments, the heterocyclic group can be a monocyclic (“monocyclic heterocyclic group”) or polycyclic (“polycyclic heterocyclic group”) containing a fused, bridged, or spirocyclic system, and can be saturated or partially unsaturated. The heterocyclic polycyclic system can include one or more heteroatoms in one or two rings. “Hypercyclic group” also includes ring systems in which the heterocyclic group as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic group or the heterocyclic group ring, and in this case, the number of ring members represents the total number of ring members in the entire ring system. When substitution is indicated in this case, unless otherwise stated, substitution can occur on the heterocyclic group or one or more carbocyclic groups. Unless otherwise specified, the heterocyclic group is optionally substituted independently in each case, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted by one or more substituents (“substituted heterocyclic group”). In embodiments, the heterocyclic group is an unsubstituted 3- to 12-membered heterocyclic group. In embodiments, the heterocyclic group is a substituted 3- to 12-membered heterocyclic group.

[0080] As used herein, "alkoxy" refers to the group -OR, where R is an alkyl group as defined herein. 1-6 Alkoxy groups refer to the -OR group, where each R is a C as defined herein. 1-6 Alkyl group. Exemplary C 1-6 Alkyl groups are as described above.

[0081] "O" refers to =O. When a group or atom other than aryl and heteroaryl is substituted with an oxo radical, it is intended to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl group is substituted with an oxo radical, it is intended to indicate that the resonance structure / tautomerism involving the heteroatom provides a carbon atom capable of forming two geminal radicals, which then form a double bond with an oxygen radical.

[0082] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In the embodiments, the halogen group is fluorine or chlorine.

[0083] Xelosiben and psilocybin derivatives in the compositions of the present invention

[0084] In embodiments, the serozepine-containing compositions of the present invention comprise crystalline serozepine. In embodiments, the crystalline serozepine is aqueous or anhydrous. In embodiments, serozepine is a mixture of one or more crystalline forms. In embodiments, the serozepine is anhydrous serozepine with a crystalline purity of at least 80%, or at least 90%, or at least 95%, or at least 99%. In embodiments, as measured on a Cu X-ray source, the X-ray diffraction pattern of anhydrous serozepine has one or more peaks at 10.1°±0.2°2 θ, 11.5°±0.2°2 θ, 12.1°±0.2°2 θ, 14.6°±0.2°2 θ, 19.6°±0.2°2 θ, 20.5°±0.2°2 θ, and 25.8°±0.2°2 θ. In embodiments, anhydrous serozepine has according to... Figure 18 The X-ray diffraction pattern is shown. In the embodiments, serozepine contains no more than 20% hydrated serozepine, or no more than 10%, or no more than 5%, or no more than 1%, or substantially no hydrated serozepine. In the embodiments, the hydrated serozepine is serozepine trihydrate. The purity of serozepine crystals is measured in molar units of serozepine molecules.

[0085] This disclosure also provides extended-release compositions comprising psilocybin 4-O-carbamate, which further prolong the action of psilocybin by releasing it from the carbamate prodrug at a slower rate than the phosphate prodrug present in bisoprene. In embodiments, the invention also provides compositions of psilocybin 4-O-polyethylene glycol derivatives (e.g., PEGn-psilocybin). “PEGn” represents an oligomer consisting of n ethylene glycol monomers connected by ether bonds to the 4-hydroxy position of psilocybin and methoxy-terminated, for example, PEG8-psilocybin represents an oligomer consisting of eight ethylene glycol monomers connected by ether bonds to the 4-hydroxy position of psilocybin and methoxy-terminated. It has been found that PEGylated psilocybin cannot cross the blood-brain barrier in amounts comparable to unmodified psilocybin, and therefore cannot or is unlikely to induce hallucinations after oral administration.

[0086] In the implementation scheme, the psilocybin derivative is a compound of formula I:

[0087] Or its pharmaceutically acceptable salt.

[0088] in:

[0089] T is hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclic, wherein T is optionally substituted at one or more positions with one or more of the following: deuterium, halogen, alkyl, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate ester.

[0090] n is in the range of 1 to 100.

[0091] In the embodiments, T is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or two of a halogen, CF3, hydroxyl, nitro or cyano group.

[0092] In the implementation scheme, T is hydrogen, CH3, or CH2CH3. In the implementation scheme, T is CH3.

[0093] In the implementation scheme, n is in the range of 1 to 20. In the implementation scheme, n is in the range of 1 to 12. In the implementation scheme, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0094] Xelosine can be any suitable pharmaceutical salt thereof. Xelosine and psilocybin derivatives are described, for example, in International Patent Application Nos. PCT / US2020 / 021400 and PCT / US2022 / 028559, the contents of which are incorporated herein by reference in their entirety. In embodiments, the psilocybin derivatives include psilocybin derivatives, such as 4-O-polyethylene glycolated psilocybin, such as PEGn-psilocybin, wherein n is in the range of 1 to 20, or psilocybin-4-O-carbamate as otherwise described herein.

[0095] In the implementation scheme, the naked head cinnamon derivative is a compound of formula (II):

[0096] Or its pharmaceutically acceptable salt.

[0097] in:

[0098] R1 and R2, each time appearing independently, are hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclic, optionally substituted at one or more positions with the following: deuterium, halogroup, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate ester, or of the formula (CH3-(OCH2CH2)). n -) a methoxy polyethylene glycol chain, wherein n is contained between 1 and 100.

[0099] In the embodiments, R1 is optionally replaced by a halogen, alkyl ester, hydroxyl, alkoxy, amino, alkylamino, nitro, cyano, thiol, thioalkyl, or of the formula (CH3-(OCH2CH2)). n -) a methoxy polyethylene glycol chain substituted with C1-C8 alkyl groups, wherein n is included between 1 and 20.

[0100] In the embodiments, R1 is optionally replaced by a halogen, alkyl ester, hydroxyl, alkoxy, amino, alkylamino, or of the formula (CH3-(OCH2CH2)). n -) a methoxy polyethylene glycol chain substituted with C1-C8 alkyl groups, wherein n is included between 1 and 20.

[0101] In the embodiments, R1 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or two of a halogen, CF3, hydroxyl, nitro or cyano group.

[0102] In the embodiments, R1 is a C2-C4 alkyl group optionally substituted with 1, 2 or 3 fluorine groups.

[0103] In the embodiments, R1 is a C2-C6 alkyl group optionally substituted with a carboxyl, methyl, or ethyl ester group.

[0104] In the implementation plan, R1 is , , , , , or .

[0105] In the implementation scheme, the naked ginseng derivative of formula (II) is selected from the following:

[0106]

[0107]

[0108] In an embodiment, the naked head cinnamon derivative (e.g., according to formula (I) or formula (II)) is its hydrochloride salt.

[0109] In one embodiment, the composition comprises seroceridine or a psilocybin derivative. In another embodiment, the composition comprises about 0.1 mg to about 10 mg, or about 0.1 mg to about 7 mg of seroceridine or a psilocybin derivative. In the embodiments, the composition comprises about 0.1 mg to about 6 mg, or about 0.1 mg to about 5 mg, or about 0.1 mg to about 4 mg, or about 0.1 mg to about 3 mg, or about 0.1 mg to about 2 mg, or about 0.1 mg to 1 mg, or about 0.2 mg to about 6 mg, or about 0.2 mg to about 5 mg, or about 0.2 mg to about 4 mg, or about 0.2 mg to about 3 mg, or about 0.2 mg to about 2 mg, or about 0.2 mg to 1 mg, or about 0.3 mg to about 6 mg, or about 0.3 mg to about 5 mg, or about 0.3 mg to about 4 mg, or about 0.3 mg to about 3 mg, or about 0.3 mg to about 2 mg, or about 0.3 mg to 1 mg, or about 0.4 mg to about 6 mg, or about 0.4 mg to about 5 mg, or about 0.4 mg to about 4 mg, or about 0.4 mg to about 3 mg, or about 0.4 mg to about 2 mg, or about 0.4 mg to 1 mg. mg of seroceridine or psilocybin derivative. In embodiments, the composition comprises about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg, such as about 0.5 mg of seroceridine or psilocybin derivative.

[0110] In an embodiment, the composition comprises an amount of psilocybin derivative (e.g., a derivative of formula (I) or formula (II)) of about 20 mg to about 1000 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 1000 mg, or about 500 mg to about 1000 mg.

[0111] Xelocepin or psilocybin derivatives can be administered in different dosage regimens. In one embodiment, the composition is administered once daily, twice daily, or three times daily. In other embodiments, xelocepin is administered once every other week, once weekly, twice weekly, three times weekly, four times weekly, five times weekly, or six times weekly.

[0112] In one embodiment, the extended-release composition contains 0.5 mg of serocepin in the tablet.

[0113] The compositions disclosed herein

[0114] In embodiments, the extended-release composition of psilocybin is obtained using a mixture of amorphous and crystalline forms of psilocybin or a pure monocrystalline form. In embodiments, the psilocybin derivative, such as 4-O-polyethylene glycolated psilocybin, such as PEG8-psilocybin, is substantially unable to cross the blood-brain barrier and therefore does not induce CNS hallucinations, or psilocybin-4-O-carbamate, is used to further prolong the action of psilocybin through its slow release in vivo from the carbamate prodrug.

[0115] In embodiments, the present invention provides an extended-release composition comprising about 0.01 mg to about 20 mg of serocepin, or said composition being provided as described in USP <711> The following dissolution characteristics were measured:

[0116] Approximately 15% to 35% of the seroprecept is released within approximately 0.5 hours;

[0117] Approximately 45% to 64% of the serosides were released within approximately 2 hours;

[0118] Approximately 65% ​​to 85% of the serosides were released within approximately 4 hours; and

[0119] No less than approximately 80% of the serosides were released within approximately 10 hours.

[0120] In an embodiment, the present invention provides an extended-release composition comprising about 0.01 mg to about 40 mg of any of the above-mentioned psilocybin derivatives, wherein the composition provides a release from USP <711> The following dissolution curves were measured:

[0121] Approximately 15% to approximately 35% of the said psilocybin derivatives are released within approximately 0.5 hours;

[0122] Approximately 45% to approximately 64% of the said psilocybin derivatives are released within approximately 2 hours;

[0123] Approximately 65% ​​to approximately 85% of the said psilocybin derivatives are released within approximately 4 hours; and

[0124] No less than about 80% of the said naked head cinnamon derivative is released within about 10 hours.

[0125] In the implementation scheme, approximately 15% to approximately 30% of serocepin or psilocybin derivatives are released within approximately 0.5 hours. Alternatively, approximately 15% to approximately 25%, or approximately 20% to approximately 35%, or approximately 20% to approximately 30%, or approximately 25% to approximately 35% of serocepin are released within approximately 0.5 hours.

[0126] In the implementation scheme, approximately 45% to approximately 60% of the psilocybin or psilocybin derivative is released within approximately 2 hours. In the implementation scheme, approximately 45% to approximately 55%, or approximately 50% to approximately 64%, or approximately 50% to approximately 60%, or approximately 55% to approximately 64% of the psilocybin is released within approximately 0.5 hours.

[0127] In the implementation scheme, approximately 65% ​​to approximately 80% of the psilocybin or psilocybin derivative is released within approximately 4 hours. In the implementation scheme, approximately 65% ​​to approximately 75%, or approximately 70% to approximately 85%, or approximately 70% to approximately 80%, or approximately 75% to approximately 85% of the psilocybin is released within approximately 0.5 hours.

[0128] In the implementation plan, no less than about 85%, or about 90%, or about 95% of the serosol or psilocybin derivatives are released within about 10 hours.

[0129] In the implementation plan, according to USP <705> The dissolution rate of the compositions disclosed herein was determined using the following parameters:

[0130]

[0131] In the embodiments, the application of the composition provides an AUC in the range of about 1 to about 2 μg·h / L, or about 2 to about 3 μg·h / L, or about 3 to about 4 μg·h / L, or about 4 to about 6 μg·h / L, or about 5 to about 8 μg·h / L, or about 8 to about 12 μg·h / L. 0-24In the embodiments, the application of the composition provides an AUC in the range of about 1 μg·h / L, about 2 μg·h / L, about 3 μg·h / L, about 4 μg·h / L, about 5 μg·h / L, about 6 μg·h / L, about 7 μg·h / L, about 8 μg·h / L, about 9 μg·h / L, about 10 μg·h / L, about 11 μg·h / L, or about 12 μg·h / L (inclusive). 0-24 .

[0132] In the embodiments, the application of the composition provides about 0.2 to about 0.5 μg / L, or about 0.5 to about 1.0 μg / L, or about 0.8 to about 1.2 μg / L, or about 1.2 to about 1.6 μg / L of C. max In the embodiments, the application of the composition provides about 0.2 μg / L, about 0.3 μg / L, about 0.4 μg / L, about 0.5 μg / L, about 0.6 μg / L, about 0.7 μg / L, about 0.8 μg / L, about 0.9 μg / L, about 1.0 μg / L, about 1.1 μg / L, about 1.2 μg / L, about 1.3 μg / L, about 1.4 μg / L, about 1.5 μg / L, or about 1.6 μg / L (inclusive of all ranges therein) of C. max .

[0133] In the embodiments, the application of the composition provides a T of about 2 to about 6 hours, or about 3 to about 6 hours, or about 3 to about 5 hours, or about 4 to about 5 hours. max In the embodiments, the application of the composition provides a T (time) of about 2 h, about 3 h, about 4 h, about 5 h, or about 6 h. max (Including all ranges in between).

[0134] In the embodiments, the application of the composition provides a T of about 1 to about 2 hours. 1 / 2 .

[0135] In the implementation scheme, the application of the composition provides T max It is an equivalent immediate-release formulation of T max More than twice (e.g., 2-3 times).

[0136] In the implementation scheme, a sustained-release form of the psilocybin composition is achieved by formulating a psilocybin or psilocybin derivative, such as 4-O-polyethylene glycolated psilocybin, such as PEG8-psilocybin, or psilocybin-4-O-carbamate, which cannot cross the blood-brain barrier and therefore does not induce CNS hallucinations, to further prolong the action of psilocybin through its slow release from the carbamate prodrug in vivo.

[0137] In the implementation scheme, on a molar basis, the psilocybin derivative crosses the blood-brain barrier at a rate of less than 30%, or less than 20%, or less than 10%, or less than 5% compared to psilocybin.

[0138] In the embodiments, the extended-release serocerin or psilocybin derivative composition comprises a controlled-release polymer, a diluent, a binder, and a lubricant and / or a flow aid.

[0139] In one embodiment, the controlled-release polymer comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, or mixtures thereof. In another embodiment, the controlled-release polymer comprises hydroxypropyl methylcellulose. In yet another embodiment, the controlled-release polymer is hydroxypropyl methylcellulose. In a further embodiment, the composition comprises two different controlled-release polymers. In yet another embodiment, the composition comprises two hydroxypropyl methylcellulose polymers.

[0140] In one embodiment, the composition comprises about 5 wt% to about 45 wt% of a controlled-release polymer. In another embodiment, the composition comprises about 10 wt% to about 45 wt%, or about 15 wt% to about 45 wt%, or about 20 wt% to about 45 wt%, or about 5 wt% to about 43 wt%, or about 10 wt% to about 43 wt%, or about 15 wt% to about 43 wt%, or about 20 wt% to about 43 wt%, or about 5 wt% to about 40 wt%, or about 10 wt% to about 40 wt%, or about 15 wt% to about 40 wt%, or about 20 wt% to about 40 wt%, or about 5 wt% to about 35 wt%, or about 10 wt% to about 35 wt%, or about 15 wt% to about 35 wt%, or about 20 wt% to about 35 wt% of a controlled-release polymer.

[0141] In some embodiments, the composition comprises a diluent. In some embodiments, the diluent includes lactose, cellulose (e.g., microcrystalline cellulose), starch, calcium sulfate (e.g., calcium sulfate dihydrate), mannitol, sorbitol, dibasic calcium phosphate, or mixtures thereof. In some embodiments, the diluent comprises lactose monohydrate. In some embodiments, the diluent comprises lactose monohydrate and microcrystalline cellulose. In some embodiments, the diluent is lactose monohydrate.

[0142] In an embodiment, the composition comprises 5 wt% to about 90% of a diluent. In an example, the composition comprises about 10 wt% to about 90 wt%, or about 20 wt% to about 90 wt%, or about 30 wt% to about 90 wt%, or about 5 wt% to about 80 wt%, or about 10 wt% to about 80 wt%, or about 20 wt% to about 80 wt%, or about 30 wt% to about 80 wt%, or about 5 wt% to about 70 wt%, or about 10 wt% to about 70 wt%, or about 20 wt% to about 70 wt%, or about 30 wt% to about 70 wt% of a diluent.

[0143] In one embodiment, the composition comprises a binder. In another embodiment, the binder comprises at least one of starch, partially or fully pregelatinized starch, gelatin, polyethylene glycol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, microcrystalline cellulose, or mixtures thereof.

[0144] In one embodiment, the adhesive comprises partially pregelatinized starch. In another embodiment, the adhesive is pregelatinized starch.

[0145] In one embodiment, the composition comprises about 2 wt% to about 20 wt% of an adhesive. In another embodiment, the composition comprises about 5 wt% to about 20 wt%, or about 5 wt% to about 15 wt% of an adhesive.

[0146] In some embodiments, the composition comprises a lubricant and / or a flow aid. In some embodiments, the lubricant and / or flow aid includes colloidal silica, stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, povidone, crospovidone, or talc. In some embodiments, the lubricant and / or flow aid comprises colloidal silica. In some embodiments, the lubricant and / or flow aid comprises magnesium stearate. In some embodiments, the lubricant and / or flow aid comprises colloidal silica and magnesium stearate.

[0147] In one embodiment, the composition comprises 0.1 wt% to about 10 wt% of a lubricant and / or a flow aid. In another embodiment, the composition comprises 0.2 wt% to about 10 wt%, or about 0.5 wt% to about 10 wt%, or about 1 wt% to about 10 wt%, or about 0.1 wt% to about 8 wt%, or about 0.2 wt% to about 8 wt%, or about 0.5 wt% to about 8 wt%, or about 1 wt% to about 8 wt%, or about 0.1 wt% to about 5 wt%, or about 0.2 wt% to about 5 wt%, or about 0.5 wt% to about 5 wt%, or about 1 wt% to about 5 wt% of a lubricant and / or a flow aid.

[0148] In embodiments, administration of the extended-release psilocybin composition of the present invention provides a therapeutically effective, non-hallucinogenic dose of psilocybin or psilocybin derivatives, either as a single dose or in a multiple-dose regimen. In embodiments, administration of the extended-release psilocybin composition of the present invention provides a peak plasma concentration (C0) of less than about 10 ng / mL of psilocybin. max In the implementation scheme, the administration of the prolonged-release serocerin composition provides less than about 8 ng / mL, or about 6 ng / mL, or about 5 ng / mL, or about 4 ng / mL, or about 3 ng / mL, or about 2 ng / mL of psilocybin C. max In the embodiments, the administration of the extended-release serocerin composition provides approximately 0.05 ng / mL to approximately 2 ng / mL of psilocybin C. max Approximately 0.2 ng / mL to approximately 2 ng / mL, or approximately 0.5 ng / mL to approximately 2 ng / mL, or approximately 1 ng / mL to approximately 2 ng / mL.

[0149] In embodiments, administration of the extended-release seroceridine composition of the present invention provides a time (T0) at which peak drug concentration of psilocybin is reached for at least about 1 hour (e.g., at least about 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2.0 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, 3 hours, or 4 hours). max In the implementation scheme, the application of the extended-release seroceridine composition provides no more than 24 hours (e.g., no more than about 12 hours, or about 10 hours, or about 8 hours) of psilocybin T. max .

[0150] In embodiments, compared to immediately released xelocepine compositions containing the same dose of xelocepine, the extended-release xelocepine compositions of the present invention provide reduced C60%. max And / or the increased T max In the implementation scheme, the application of the prolonged release serozepine composition provides psilocybin C. max Compared to an equivalent dose of thelocebin from an immediately released composition, C max Less than 10%, less than 15%, or less than 20%. In the embodiments, the application of the prolonged release serocerin composition provides psilocybin C. max Compared to an equivalent dose of thelocebin from an immediately released composition, C max Less than 25%, less than 35%, less than 50%. In the embodiments, the application of the prolonged-release selozepine composition provides selozepine C. max Compared to an equivalent dose of psilocybin from an immediately released composition, psilocybin Cmax Approximately 10%, 15%, 20%, 25%, 35%, or 50% lower.

[0151] In the implementation scheme, the application of the prolonged release of the serocerin composition provides naupliine T max Compared to an equivalent dose of thelocebin from an immediately released composition, T max At least 10%, at least 15%, or at least 20%. In the embodiments, the application of the prolonged release serocerin composition provides psilocybin T. max Compared to an equivalent dose of thelocebin from an immediately released composition, T max At least 100%, at least 50%, or at least 35%. In the embodiments, the application of the prolonged release serocerin composition provides psilocybin T. max Compared to an equivalent dose of thelocebin from an immediately released composition, T max Approximately 10%, approximately 15%, approximately 20%, approximately 35%, approximately 50%, or approximately 100%.

[0152] The pharmacokinetics of conventional selocilbin are disclosed, for example, in Holze et al., “Pharmacokinetics and pharmacodynamics of Oral Psilocybin Administration in Healthy Participants.” Clinical. Drugs and Therapy. 113:4-822 (2023).

[0153] In an embodiment, the extended-release composition of the present invention comprises about 0.01 mg to about 20 mg of serocepin, wherein said composition meets USP <905> Or the minimum content uniformity requirements provided in European Pharmacopoeia 2.9.40.

[0154] Treatment

[0155] In one embodiment, the extended-release composition disclosed herein is administered for the treatment of metabolic disorders. In another embodiment, the metabolic disorders are prediabetes, type II diabetes, obesity, metabolic dysfunction-related fatty liver disease (MASLD and MetALD), metabolic dysfunctional steatohepatitis (MASH), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, nonalcoholic steatohepatitis (NASH), dyslipidemia, or sarcopenia.

[0156] In the implementation scheme, sarcopenia is associated with metabolic disorders, or sarcopenia is associated with aging or disease of organs and systems, or the treatment of such diseases. In the implementation scheme, the disorder and disease are neuropsychiatric or neurodegenerative diseases or disorders and their symptoms. In the implementation scheme, visual impairment associated with ischemic stroke can be treated by administration of a therapeutically effective amount of a compound or composition as otherwise described herein. In the implementation scheme, cellular senescence can be treated by administration of a therapeutically effective amount of a compound or composition as otherwise described herein.

[0157] In an embodiment, the method of the present invention comprises administering to a patient in need about 0.001 mg / kg to about 0.1 mg / kg, for example about 0.005 mg / kg to about 0.1 mg / kg, of a compound or composition described herein, such as serocepin or psilocybin derivatives, for example in the extended release composition of the present invention.

[0158] It has been found that, compared to immediate-release formulations of selociline, prolonged-release formulations of selociline provide improved pharmacokinetic parameters (i.e., reduced C60 of psilocybin). max And / or the increased T max ).

[0159] In the implementation scheme, the application of the prolonged release serocerin composition provides no more than about 10 ng / mL of psilocybin C. max In the implementation scheme, the administration of the prolonged-release serocerin composition provides not more than about 8 ng / mL, or about 6 ng / mL, or about 5 ng / mL, or about 4 ng / mL, or about 3 ng / mL, or about 2 ng / mL, or about 1 ng / mL, or about 0.5 ng / mL of psilocybin C. max In the embodiments, the administration of the prolonged-release serocerin composition provides at least about 0.1 ng / mL, for example at least about 0.2 ng / mL, or about 0.5 ng / mL, or about 1 ng / mL of psilocybin C. max .

[0160] The extended-release composition of psilocybin allows for a prolonged duration of therapeutic, non-hallucinogenic blood levels of psilocybin, thus allowing for less frequent administration or a more sustained effect. Therefore, in embodiments, administration of the extended-release psilocybin composition provides at least about 1 hour (e.g., at least about 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2.0 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, 3 hours, or 4 hours) of psilocybin T. maxIn the embodiments, the application of the extended-release serocerin composition provides no more than 24 hours (e.g., no more than about 12 hours, or about 10 hours, or about 8 hours, or about 4 hours, or about 2 hours) of psilocybin T. max .

[0161] Compared to immediately released compositions, prolonged-release compositions provide reduced C60 levels. max And / or the increased T max In the implementation scheme, the application of the prolonged release serozepine composition provides psilocybin C. max Compared to an equivalent dose of thelocebin from an immediately released composition, C max Less than 10%, less than 15%, or less than 20%. In the embodiments, the application of the prolonged release serocerin composition provides psilocybin C. max Compared to an equivalent dose of thelocebin from an immediately released composition, C max Less than 25%, less than 35%, less than 50%. In the embodiments, the application of the extended-release serocepin composition provides psilocybin C. max Compared to an equivalent dose of thelocebin from an immediately released composition, C max Approximately 10%, 15%, 20%, 25%, 35%, or 50% lower.

[0162] In the implementation scheme, the application of the prolonged release of the serocerin composition provides naupliine T max Compared to an equivalent dose of thelocebin from an immediately released composition, T max At least 10%, at least 15%, or at least 20%. In the embodiments, the application of the prolonged release serocerin composition provides psilocybin T. max Compared to an equivalent dose of thelocebin from an immediately released composition, T max At least 100%, at least 50%, or at least 35%. In the embodiments, the application of the prolonged release serocerin composition provides psilocybin T. max Compared to an equivalent dose of thelocebin from an immediately released composition, T max Approximately 10%, approximately 15%, approximately 20%, approximately 35%, approximately 50%, or approximately 100%.

[0163] The pharmacokinetics of conventional selocebin are disclosed, for example, in Holze et al., “Pharmacokinetics and pharmacodynamics of Oral Psilocybin Administration in Healthy Participants.” Clin. Pharm. & Therap. 113:4-822 (2023).

[0164] Example

[0165] The invention is further illustrated by referring to the following embodiments. These embodiments are illustrative and should not be construed as limiting the scope of the invention in any way.

[0166] Example 1. Xelosipine composition

[0167] The exemplary serozepine composition of the present invention was prepared using amorphous serozepine as follows:

[0168] Composition A

[0169]

[0170] Composition B

[0171]

[0172] Composition C

[0173]

[0174] Composition D

[0175]

[0176] The above composition was directly compressed to form 200 mg tablets, which were then coated with a 3.0 wt% (6.0 mg) Opadry II full film coating system (purple).

[0177] According to USP <905> Assess the content uniformity of tablets containing composition A:

[0178]

[0179] All compositions exhibited good stability in aging tests.

[0180] Dissolution tests were performed on composition AD. The dissolution medium was prepared as follows: 6.8 g of potassium dihydrogen phosphate and 0.9 g of sodium hydroxide granules were transferred to a 1 L flask and dissolved in 1 L of water to obtain a solution with a pH of 6.8 ± 0.05, which was adjusted as needed with sodium hydroxide or phosphoric acid. The dissolution apparatus was designed according to USP. <711> Equipped with a paddle mixer. Test tablets under the following conditions:

[0181]

[0182] Xelosibenzyl in aliquots of the sample was tested by HPLC using ammonium formate as the mobile phase. The following dissolution was observed for composition A with the following specifications:

[0183]

[0184] The change in the dissolution of composition A over time is shown in the figure. Figure 1 middle.

[0185] Measure the solubility properties of composition B:

[0186]

[0187] Measure the solubility properties of composition C:

[0188]

[0189] Measure the solubility properties of composition D:

[0190]

[0191] Example 2. Xelosipine composition

[0192] The exemplary serocepin composition of the present invention was prepared using the hydrous crystalline form of serocepin (serocepin trihydrate) as follows:

[0193]

[0194]

[0195] For film coating, Opadry is mixed with purified water to form a 15% w / w suspension. The actual quantities for items 9 and 10 are weighed 50% over the required amount. Purified water is a processing aid and is removed during processing.

[0196] Blending uniformity:

[0197] Table 1: Blending uniformity of the final blend.

[0198]

[0199] Content uniformity:

[0200] Table 2: Content uniformity.

[0201]

[0202] Example 3. Pharmacokinetic profile of prolonged release of selocillin using a simulation-based method.

[0203] Pharmacokinetic (PK) / pharmacodynamic (PD) modeling studies were conducted to simulate the typical pharmacokinetic characteristics of prolonged-release xelocebin tablets. This modeling is based on PK and PD literature data of immediately released (IR) psilocybin (RTBrown, CRNicholas, NVCozzi, MCGassman, KMCooper, D.Muller, CDThomas, SJHetzel, KMHenriquez, ASRibaudo and PRHutson. Pharmacokinetics of escalating doses of oral psilocybin in healthy adults. Clinical Pharmacokinetics, 56(12): 1543–1154, 2017; MKMadsen, PMFisher, D.Burmester, A.Dyssegaard, DSStenbæk, S.Kristiansen, SSJohansen, S.Lehel, K.Linnet, C.Svarer, D.Erritzoe, B.Ozenne and GMKnudsen. Psychedelic effects of psilocybin correlate with serotonin 2a receptor occupancy and plasm:psilocinlevel. Neuropsychopharmacology,44(7):1328–1334, 2019) and known in vitro dissolution parameters of extended-release (ER) psilocin formulations. The simulations performed showed that, with 2 mg IR psilocin C max Compared to 2 mg ER selocebin C max It may be about 20% lower (0.99 ng / ml vs. 1.2 ng / ml), with almost the same AUC. 0-24 Furthermore, in this model, the half-lives of the two formulations for IR and MR are similar, as shown in the table below. Figure 2As reported in [the study]. These simulations suggest that, when the same dose is administered, ER cilostabene is less likely to result in increased drug exposure compared to IR cilostabene, and due to C [the specific drug level]. max The risk of hallucinogenic effects is lower.

[0204] Table 1. Average simulated exposures for immediate release seroconvertin (IR) and extended (modified) release seroconvertin (MR).

[0205]

[0206] Source: .. / .. / .. / Simulations / params-combined-byDOSE-Fnorm.csv

[0207] AUC over time 0 to 24 hours 0-24 Area under the concentration-time curve, C max Maximum observed concentration, IR for immediate release, MR for modified release, T 1 / 2 Terminal half-life, T at maximum observed concentration max time

[0208] Example 4. Pharmacokinetic characteristics and CNS activity of 4-O-polyethylene glycolated psilocybin derivatives (PEG4, PEG6, PEG8 and PEG10-psilocybin)

[0209] Pharmacokinetic studies were conducted on compounds PEG4, PEG6, PEG8, and PEG10-psilonisin to evaluate the major PK parameters of the derivatives after oral administration. The compounds were administered orally to c57BL6 mice at a dose of 50 mg / kg, and blood samples were collected at nine time points between 0 and 48 h.

[0210] Derivatives with shorter PEG chains (4 and 6 units) showed significantly higher C values ​​than PEG8 and PEG10-psilocybin. max And AUC, characterized by higher bioavailability ( Figure 3 ).

[0211] The compound was administered to c57BL6 mice via oral feeding at a dose of 50 mg / kg, and blood was collected at nine time points between 0 and 48 h.

[0212] Derivatives with shorter PEG chains (4 and 6 units) showed significantly higher C values ​​than PEG8 and PEG10-psilocybin. max And AUC, characterized by higher bioavailability ( Figure 3 ).

[0213] Furthermore, unlike serosibin ( Figure 4 All the compounds had poor permeability to the BBB, because even in the presence of retained 5-HT2A activity (Figure 5), they could not induce a head twitching response in mice when administered at a hallucinogenic dose of 3 mg / kg.

[0214] Example 5. Synthesis and pharmacokinetic characteristics of psilocybin-4-O-carbamates (IleMe-carbamate psilocybin and CF3-Et-carbamate psilocybin)

[0215] The structures of the compounds in the following examples were characterized by one or more of the following methods: ¹H NMR, ¹³C NMR, mass spectrometry, and HPLC-UV. ¹H NMR spectra were determined using a Bruker Avance III HD 400 spectrometer operating at 400 MHz. The chemical shift reference signal for residual protons in deuterated chloroform was as follows: CDCl₃ = 7.25 ppm. Peak multiplicity was specified as follows: s, singlet; d, doublet; t, triplet; and m, multiplet. Coupling constants are given in Hertz (Hz).

[0216] Mass spectrometry (MS) data were obtained using an Agilent 6550iFunnel Q-TOF LC / MS system mass spectrometer with ESI ionization and TOF mass analyzers.

[0217] UPLC purity was determined on an Agilent Infinity 1290 system equipped with a DAD and a ZORBAX Eclipse XDB-C18 (2.1 × 50 mm, 1.8 µm) column, with an eluent system of water + 0.1% TFA and ACN + 0.1% TFA, with a gradient from 5% ACN to 100% over 10 minutes, λ = 254 nm.

[0218] In the examples below, the reagents and solvents may be purchased from commercial suppliers and may be used without further purification, unless otherwise stated.

[0219] PSI was synthesized according to the method described in the literature (see 10.1055 / s-1999-3490, the entire contents of which are incorporated herein by reference) without modification.

[0220] Example A: 4-Nitrophenyl Carbamate

[0221] Example A describes a method for preparing 4-nitrobenzene carbamate, as shown in Scheme 1, reaction i.

[0222] Under a nitrogen atmosphere, a solution of DMAP (14.8 mmol, 2.0 equivalent) in anhydrous DCM (8 mL) was slowly added to an ice-cold solution of appropriate amine hydrochloride (7.38 mmol, 1.0 equivalent) and bis(4-nitrophenyl) carbonate (BPNC, 7.38 mmol, 1.0 equivalent) in anhydrous DCM (14 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured into 0.5 M hydrochloric acid aqueous solution (50 mL) and extracted with DCM (50 mL). The aqueous phase was further extracted three times with 40 mL of DCM. The combined organic fractions were dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by rapid chromatography, eluting with DCM as the eluent system to give the product as a white solid.

[0223] Example B: PSI-carbamate

[0224] Example B describes a method for preparing PSI-carbamate, as shown in Scheme 1, reaction ii.

[0225] To a chilled solution of 4-nitrobenzene carbamate (3 mmol, 2.0 equivalent) and psilocybin (1.5 mmol, 1.0 equivalent) in anhydrous THF (16 mL), a solution of DMAP (1.8 mmol, 1.2 equivalent) in anhydrous THF (5 mL) was added. The reaction mixture was stirred at room temperature for 24 hours. The mixture was poured into a 2:1 aqueous solution of NH4Cl / salt (50 mL) and extracted with ethyl acetate (100 mL). The aqueous phase was further extracted three times with ethyl acetate (50 mL). The collected organic fraction was dehydrated with sodium sulfate, evaporated under reduced pressure, and purified by silica gel column chromatography using DCM / MeOH 97:3 to DCM / MeOH 9:1 + 1% NH3 (8 M in MeOH) to obtain a colorless oily product. The oil was reconstituted in DCM (10 mL) and treated with 2 M HCl in Et2O solution (1.8 mmol, 1.5 equivalent). After evaporating the solvent under reduced pressure, the product is obtained as a white crystalline solid.

[0226] Option 1

[0227]

[0228] Using scheme 1, a series of compounds were synthesized:

[0229] Synthesis of 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl isobutylcarbamate (i-buPSI)

[0230]

[0231] 78% yield. HRMS(ESI) m / z: for C 17 H 26 N3O2 + [M+H + The requirement is 304.2020; the measured value is 304.2015.

[0232] 1 H NMR(400MHz, CDCl3)δ 8.44 (s, 1H), 7.15–7.05 (m, 2H), 6.99 (dd, J=6.1, 2.5Hz, 1H), 6.80 (d, J=2.3Hz, 1H), 6.41 (t, J=6.2Hz, 1H), 3.09 (t, J=6.4Hz, 2H), 2.98–2.88 (m, 2H), 2.67–2.57 (m, 2H), 2.31 (s, 6H), 1.91–1.77 (m, 1H), 0.96 (d, J=6.7Hz, 6H). 13 C NMR (101MHz, CDCl3) δ 155.47, 144.86, 138.72, 122.25, 122.16, 120.24, 113.05, 112.36, 108.62, 61.18, 48.88, 45.28, 28.92, 25.41, 20.18. UPLC purity >99%

[0233] (((3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)oxy)carbonyl)-L-isoleucine methyl ester Synthesis of (IleMePSI)

[0234]

[0235] 92% yield. HRMS(ESI) m / z: C 20 H 30 N3O4 + [M+H + The theoretical value is 376.2231; the measured value is 376.2236.

[0236] 1H NMR(400MHz, CDCl3)δ 11.91(s, 1H), 9.15(s, 1H), 7.15(d, J=8.1Hz, 1H), 7.06(t, J=7.9Hz, 1H), 6.87(d, J =7.7Hz, 1H), 6.78 (d, J=7.8Hz, 1H), 6.55 (d, J=2.4Hz, 1H), 4.29 (dd, J=7.8, 5.3Hz, 1H), 3.71(s, 3H), 3.14–2.87(m, 4H), 2.80(s, 3H), 2.72(s, 3H), 2.06–1.91(m, 1H), 1.57–1.43 (m, 1H), 1.37–1.22 (m, 1H), 0.99 (d, J=6.9Hz, 3H), 0.94 (t, J=7.4Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.17, 155.48, 144.04, 138.78, 123.79, 122.31, 119.49, 112.61, 109.37, 108.17, 77.16, 59.40, 58.89, 52.20, 42.96, 42.93, 37.09, 25.44, 21.89, 15.80, 11.52. UPLC purity >99%.

[0237] (((3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)oxy)carbonyl)-L-isoleucine (IlePSI) Synthesis

[0238]

[0239] 85% yield. HRMS(ESI) m / z: for C 19 H 28 N3O4 + [M+H + The required value is 362.2074; the measured value is 362.2072.

[0240] 1H NMR (400MHz, acetone) δ 11.11(s,1H), 10.31(s,1H), 7.36(d,J=8.5Hz,1H),7.28–7.21(m,2H), 7.07(t,J=7.9Hz,1H), 6.82–6.78(m,1H), 4.27–4.19(m,1H), 3.52–3.43(m,2H), 3.36–3.27(m,2H), 3.09–3.06(m,1H), 3.04(s,6H), 1.69–1.58(m,1H),1.45–1.34(m,1H), 1.07(d,J=6.9Hz,3H), 0.96(t,J=7.4Hz,3H). 13C NMR (101 MHz, acetone) δ 174.29, 156.15, 145.41, 139.93, 124.75, 122.53, 121.04, 113.21, 109.82, 109.63, 60.22, 59.56, 43.40, 37.52, 26.00, 22.44, 16.22, 11.85. UPLC purity >99%.

[0241] Synthesis of 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2-fluoroethyl)carbamate (CFEtPSI) become

[0242]

[0243] 88% yield. HRMS(ESI) m / z: C 15 H 21 FN3O2 + [M+H + The theoretical value is 294.1612; the measured value is 294.1615.

[0244] 1H NMR(400MHz,MeOD)δ 7.27(dd,J=8.2,0.8Hz,1H), 7.22(s,1H), 7.10(t,J=7.9Hz,1H), 6.76(dd,J=7.7,0.8Hz,1H), 4.62(t,J=4.8Hz,1H), 4.50(t,J=4.8Hz,1H),3.57(t,J=4.9Hz,1H), 3.50(t,J=4.9Hz,1H), 3.45–3.36(m,2H), 3.23–3.15(m,2H),2.89(s,6H). 13C NMR (101MHz, MeOD) δ 157.78, 145.24, 140.64, 125.58, 123.03, 121.13, 113.34, 110.49, 108.45, 84.27, 82.61, 60.05, 43.57, 42.90, 42.69, 22.99. UPLC purity >99%.

[0245] 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2,2-difluoroethyl)carbamate (CF2EtPSI) Synthesis

[0246]

[0247] 87% yield. HRMS(ESI) m / z: C 15 H 20 F2N3O2 + [M+H + The theoretical value is 312.1518; the measured value is 312.1520.

[0248] 1 H NMR(400MHz,MeOD)δ 7.28(d, J=8.1Hz, 1H), 7.12(s, 1H), 7.07(t, J=7.9Hz, 1H), 6.75(d, J=7.6Hz, 1H), 6.21-5.87(m, 1H), 3.61 (td, J=15.7, 3.5Hz, 2H), 3.25 (dd, J=9.4, 6.2Hz, 2H), 3.09 (dd, J=9.2, 6.3Hz, 2H), 2.77 (s, 6H). 13C NMR (101MHz, MeOD) δ 157.71, 145.03, 140.33, 125.56, 122.90, 120.92, 118.08, 115.69, 113.30, 113.24, 110.62, 108.50, 108.46, 59.73, 44.45, 44.19, 43.94, 43.42, 22.79. UPLC purity >99%.

[0249] 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2,2,2-trifluoroethyl)carbamate Synthesis of (CF3EtPSI)

[0250]

[0251] 87% yield. HRMS(ESI) m / z: C 15 H 19 F3N3O2 + [M+H + The theoretical value is 330.1424; the measured value is 330.1419.

[0252] 1 H NMR (400MHz, acetone) δ 11.73(s,1H), 10.40(s,1H), 8.24(t,J=6.6Hz,1H), 7.27(d,J=8.1Hz,1H), 7.22(d,J=2.4Hz,1H), 7.09(t,J=7.9Hz,1H), 6.96(d,J=7.7Hz,1H), 4.11–3.89(m,2H), 3.39(dd,J=12.9,5.6Hz,2H), 3.34–3.25(m,2H), 2.98(s,6H). 13C NMR (101 MHz, acetone) δ 161.89, 161.56, 155.99, 145.27, 139.90, 130.03, 127.27, 124.95, 124.50, 122.52, 120.32, 112.94, 109.89, 109.31, 59.64, 43.76, 43.41, 43.16, 43.07, 42.73, 22.67. UPLC purity >99%.

[0253] 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(3,3,3-trifluoropropyl)carbamate Synthesis of (CF3PrPSI)

[0254]

[0255] 86% yield. HRMS(ESI) m / z: C 16 H 21 F3N3O2 + [M+H + The theoretical value is 344.1580; the measured value is 344.1581.

[0256] 1H NMR (400MHz, acetone) δ 11.85(s,1H), 10.35(s,1H), 7.74(t,J=5.9Hz,1H),7.27–7.17(m,2H), 7.07(t,J=7.9Hz,1H), 6.97(d,J=7.7Hz,1H), 3.57–3.47(m,2H), 3.42–3.27(m,4H), 2.98(s,6H), 2.65–2.50(m,2H). 13C NMR (101 MHz, acetone) δ 155.57, 145.53, 139.85, 129.02, 126.28, 124.73, 124.56, 122.50, 120.34, 112.94, 109.50, 59.71, 43.20, 35.31, 34.63, 34.36, 34.09, 33.81, 22.76. UPLC purity >99%.

[0257] Example C: Pharmacokinetic Study of the Selected Carbamate

[0258] Pharmacokinetic studies were conducted on the compounds IleMe-carbamate psilocybin and CF3-Et-carbamate psilocybin to evaluate the major PK parameters of the derivatives after oral administration. The compounds were administered orally to c57BL6 mice at a dose of 50 mg / kg, and blood samples were collected at nine time points between 0 and 48 hours. Figure 6 As shown, CF3-Et carbamate psilocybin exhibits significantly higher bioavailability compared to IleMe-carbamate psilocybin. Both compounds are able to release small amounts of psilocybin over time, suggesting they may serve as a reservoir for psilocybin to assess prolonged effects without reaching high hallucinogenic concentrations in the CNS.

[0259] Example 6. In vivo metabolism of PEG8-naphthoside

[0260] C57BL6 mice fed a high-fructose, high-fat (HFHFD) diet for 17 weeks were administered a low dose of PEG8-psilonisin (0.11 mg / kg, equivalent to 0.05 mg / kg selosine) daily for 12 weeks. PEG8-psilonisin treatment reduced body weight gain in this animal model. Figure 7 This improved glucose tolerance, as shown by the results of the oral glucose tolerance test and fasting blood glucose levels. Figure 8 It reduced hepatic steatosis. Figure 9 ).

[0261] Example 7. Treatment of visual impairment with seroceridine

[0262] Mice treated with selocillin showed improved performance in tasks associated with post-stroke visual impairment. A photothrombotic stroke model was designed to induce ischemic injury in a given cortical region via photoactivation of a pre-injected photosensitive dye. Upon irradiation, the dye was activated and produced singlet oxygen, which disrupted components of the endothelial cell membrane, subsequently leading to platelet aggregation and thrombus formation, ultimately resulting in local blood flow disruption. 0.2 ml of rose red dye, which exhibits cytotoxicity upon photoexposure (using white laser light with an absorption peak at 560 nm), was injected intraperitoneally.

[0263] Treatment with 0.05 mg / kg cilostabin daily for 30 days was well tolerated, as no signs of distress were observed in the animals, and there was no change in body weight compared to mice injected with 0.9% saline solution (control). Figure 11 ).

[0264] Regarding animal behavior, the study investigated whether long-term treatment with microdose cilostabene affected levels of anxiety-like, depression-like, obsessive-compulsive / obsessive-compulsive behaviors, social behavior, memory and learning, and visual performance. Notably, treatment with 0.05 mg / kg cilostabene for 30 days either did not alter animal behavior or induced interesting pharmacological effects. In fact, anxiolytic-like effects of cilostabene were observed, measured as increased time spent in the light portion of the light / dark box test, shortened latency for selecting the first arm in the T-maze test, and reduced combing time in the open field test. A test investigating spatial memory and learning was conducted in the Cued Water Morris Test. Over the three days of the experiment, animals treated with cilostabene showed significantly shorter times to reach the underwater platform with a flag protruding from the water's surface compared to animals treated with the medium. Furthermore, on days 1 and 2 of the experiment, mice treated with cilostabene reached the platform more times per day than mice treated with saline solution (control). Finally, in novel suppressive feeding, a behavioral paradigm used to evaluate the potential anxiolytic activity of a novel compound but also responding to long-term antidepressant treatment, it was found that while there was no difference in the latency required for selocillin and mediator-treated mice to reach the center of the enclosure and begin feeding, selocillin-treated mice consumed significantly less food in their cages than control animals. It is speculated that this latter effect may be secondary to selocillin's anxiolytic-like activity, which was observed in other tests where animals did not crave food in a rapid / forced manner when faced with it, or secondary to selocillin's role at the circuit level regulating feeding behavior. Results of behavioral studies conducted to evaluate selocillin administration are shown in... Figure 12 middle.

[0265] An in vitro experiment on occipital lobe stroke and treatment with selocillin was conducted, analyzing the size of the lesions 45 days after treatment. Figure 13 ) and the spike density was determined by counting the area surrounding the lesion (between 100 and 200 μm) and the distal area of ​​the lesion (between 400 and 700 μm). Figure 10 Neuronal plasticity processes. Significant repair of post-stroke lesions (reduced lesion volume) was found only in animals treated with 0.05 mg / Kg selocillin at 24 hours post-stroke compared to 24 hours post-stroke. Figure 13 The reduction in stroke area volume may be partly due to increased neuroplasticity observed in animals treated with selocillin for 45 days. In fact, as... Figure 14 As described in the study, in the hemisphere of mice subjected to photothrombotic stroke, mice treated with selocillin 24 hours post-stroke showed significantly higher spine density in both the perilesional and distal regions compared to mice receiving the mediator (control). No significant effect on spine density was observed when selocillin treatment was initiated 14 days post-stroke.

[0266] Example 8. Serocerin and psilocybin improve parameters indicating neurological dysfunction and have in vivo bioactivity on the expression of ALS-related genes.

[0267] Studies of seroxibin were conducted in G93A SOD1 mice. These studies indicate that:

[0268] 1) In vivo biological activity of ALS-related gene expression

[0269] 2) Improved gripping function (indicating neuroprotective effects)

[0270] 3) Improves grip strength (indicating the maintenance of muscle function) Figure 15 ).

[0271] Example 9. Serocerin and psilocybin improve cellular senescence

[0272] Psib is naturally found in *Phyllostachys* fungi and is converted in vivo into its metabolically active form, psin. Growing evidence suggests that it modulates inflammation and neuroprotection, both of which are dysregulated in aging. Therefore, we evaluated the effects of low concentrations of psib and psin in a doxorubicin (Doxo)-induced cellular senescence model in WI-38 human lung fibroblasts. Pretreatment with both Psib and Psin significantly prevented Doxo-induced SA-β-Gal positivity, indicating senescence prevention. The results of these studies can be found in Figure 16.

[0273] To understand the biochemical events underlying the in vitro anti-aging effects of Psib and Psin, cells were subjected to Western blot analysis after pretreatment with Psib or Psin for 48 hours, followed by exposure to 100 nM DOXO for 48 hours. Psib and Psin ameliorated p38 phosphorylation, a kinase responding to oxidative stress. Furthermore, Psib and Psin prevented doxorubicin-induced histone H3 cleavage, a post-translational modification occurring during aging. The results of the Western blot are shown in Figure 17.

[0274] Example 10. Human seroxipen test

[0275] To evaluate the safety, tolerability, and efficacy of selocillin in human patients, a randomized, double-blind, placebo-controlled study was designed and conducted. Volunteers were recruited according to the following inclusion criteria:

[0276] BMI 24.99-50 kg / m 2 This includes end values;

[0277] At the time of screening, the body weight should be between 55 and 300 kg (inclusive);

[0278] Based on historically stable weight (±5 kg) (subject-reported) and historically stable physical activity in the 3 months prior to screening (subject-reported);

[0279] Fatty liver disease: fatty liver disease associated with metabolic dysfunction: MASLD, formerly known as NAFLD, and MetALD (patients with metabolic dysfunction and limited alcohol consumption (20 to 60 g per day) (Rinella et al. 2023)).

[0280] Magnetic resonance imaging proton density fat fraction (MRI PDFF) ≥ 8% indicates liver fat content (LFC);

[0281] ALT is between 21 and 75 U / L, including the extreme values;

[0282] AST is between 21 and 75 U / L, including extreme values;

[0283] Fiber scan showed liver stiffness <14 kPa;

[0284] Type 2 diabetes diagnosed by any of the following criteria: fasting blood glucose >126 mg / dL; any random glucose level >200 mg / dL; glucose level >200 mg / dL at 120 minutes after an OGTT 75; HbA1c ≥6.5%;

[0285] HbA1c levels between 6% and 10% (between 42 mmol / mol and 86 mmol / mol); and

[0286] There are no circulating autoantibodies against GAD.

[0287] Approximately 3 months prior to randomization, patients should undergo one of the following stabilizing therapies: a) metformin monotherapy; b) DPP4 inhibitor monotherapy; c) combination therapy of metformin and a DPP4 inhibitor; or d) no antidiabetic medication.

[0288] Dyslipidemia is defined as fasting serum lipid levels:

[0289] Triglycerides >150 mg / dl

[0290] HDL cholesterol <40 mg / dl (men) or <50 mg / dl (women)

[0291] LDL cholesterol >100 mg / dl

[0292] These three changes can exist individually or in combination.

[0293] Any treatment with statins or PSK9 inhibitors must be stable for approximately 3 months prior to randomization.

[0294] A history of stable physical activity within 3 months prior to screening (subject-reported).

[0295] GFR > 45 mL / min / 1.73 m 2 .

[0296] Thirty-six participants were randomly assigned to receive 2 mg cilostabene once daily. Another thirty-six participants received 2 mg cilostabene twice daily, and the final thirty-six participants received a placebo. Medication was administered in 0.5 mg adjusted-release cilostabene oral tablets, four tablets once or twice daily before breakfast or dinner, as directed.

[0297] The full analysis cluster will be used for all analyses of efficacy endpoints and will consist of all randomly assigned patients who received any trial treatment and had baseline weight measurements and were assessed on day 120±7.

[0298] Sample size estimates were determined using a hypothetical Cohen effect size of 0.8 (group comparisons) and the previously established significance level of 5.0% (two-sided) and power requirement of 80%. Taking into account the estimated 20% dropout rate and block randomization, a total sample size of 36 individuals per study group (108 subjects in total) was recommended to achieve 30 completed subjects per group.

[0299] Changes in whole-body fat mass (FM) measured by dual-energy X-ray absorptiometry (DXA) from baseline to day 180 ± 7 will be compared between treatment groups. Differences in the least-squares mean with standard error, 90% confidence intervals for the differences in the least-squares mean, and corresponding p-values ​​will be presented. Furthermore, the size of Cohen's d-effect and its 90% confidence interval will be estimated to measure the size of the REL-P11 effect compared to placebo. For efficacy assessment, whole-body FM measured by dual-energy X-ray absorptiometry (DXA) fat mass at baseline and day 180 ± 7 are required. Patients who prematurely discontinue the trial will not be replaced. All analyses are based on available data, and no imputation will be made for missing data.

[0300] Based on PK sampling, the PK curve of the major metabolite of REL-P11 (glucoside) was estimated (the observed maximum plasma concentration [C]). max ], trough concentration [C trough ], area under the concentration-time curve (AUC), and apparent terminal elimination half-life at steady state [t] 1 / 2 For the first 45 subjects, PK sampling and psilocybin plasma concentrations will be performed before the first dose and at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours (just before the second dose). For subjects 46–90, PK sampling and psilocybin plasma concentrations will be performed before the first dose and at Tmax ± 15 minutes on day 1 of treatment. For all subjects, psilocybin plasma concentrations will also be assessed only once on days 14, 30, 60, 90, 120, 150, and 180 ± 7 and 194 ± 2.

[0301] The primary efficacy endpoint was the change in total lipid mass (FM) from baseline to day 120 ± 7, as measured by dual-energy X-ray absorptiometry (DXA). Secondary efficacy endpoints included the following changes from baseline to day 120 ± 7: body composition, including boneless lean body mass as measured by DXA; MRI-derived liver fat fraction; MRI-derived subcutaneous and abdominal visceral adipose tissue; Metabolic state 1: efficacy endpoints related to glucose metabolism and insulin sensitivity: HbA1c levels, homeostasis model assessment [HOMA2], quantitative insulin sensitivity test [QUICKI], and Matsuda index; Metabolic state 2: laboratory efficacy endpoints related to weight loss; weight and BMI; waist circumference and waist-to-hip ratio; blood pressure; physical performance, including hand grip strength as measured by a dynamometer; and liver stiffness as measured by Fibroscan.

[0302] Laboratory efficacy endpoints included improvements in parameters related to metabolic disease and liver laboratory parameters. Specifically, changes relative to baseline were assessed in the following areas: serum lipid levels; high-sensitivity C-reactive protein (hsCRP) levels; interleukin-6 levels; leptin levels; adiponectin levels; ALT; AST; αGT; platelet count; FIB4 index; hs-CRP; APO-B; ceramides; dihydroceramides; sphingosine; free fatty acids (total); and glycosylated ceramides.

[0303] By incorporating via reference

[0304] For all purposes, all references, articles, publications, patents, patent publications and patent applications cited herein are incorporated herein in their entirety by reference. However, any reference, article, publication, patent, patent publication and patent application cited herein is not and should not be construed as an admission or in any way implying that they constitute valid prior art or are part of common general knowledge in any country of the world.

Claims

1. A prolonged-release composition comprising about 0.01 mg to about 20 mg of serocerin or a psilocybin derivative, wherein said composition is provided as described in USP <711> The following dissolution characteristics were measured: Approximately 15% to 35% of the seroprecept is released within approximately 0.5 hours; Approximately 45% to 64% of the serosides were released within approximately 2 hours; Approximately 65% ​​to 85% of the serosides were released within approximately 4 hours; and No less than approximately 80% of the serosides were released within approximately 10 hours.

2. The composition of claim 1, wherein the extended release composition comprises serozepine, and the serozepine comprises anhydrous serozepine with a crystalline purity of at least 80%.

3. The composition according to claim 1, wherein the composition comprises a psilocybin derivative, wherein the psilocybin derivative has formula I: Or its pharmaceutically acceptable salt. in T is hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclic, wherein T is optionally substituted at one or more positions by one or more of the following: deuterium, halogen, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate ester; n is in the range of 1 to 100.

4. The composition according to claim 3, wherein T is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by one or two of a halogen, methyl, CF3, hydroxyl, nitro or cyano group.

5. The composition according to claim 3, wherein T is hydrogen, CH3 or CH2CH3.

6. The composition according to any one of claims 3-5, wherein n is in the range of 1 to 20.

7. The composition according to any one of claims 3-5, wherein n is in the range of 1 to 12.

8. The composition according to any one of claims 3-5, wherein n is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

9. The composition according to claim 1, wherein the composition comprises a psilocybin derivative, wherein the psilocybin derivative has formula II: Or its pharmaceutically acceptable salt. in: R1 and R2, each time appearing independently, are hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclic, optionally substituted at one or more positions with the following: deuterium, halogroup, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate ester, or of the formula (CH3-(OCH2CH2)). n -) a methoxy polyethylene glycol chain, wherein n is contained between 1 and 100.

10. The composition according to claim 9, wherein R1 is optionally halogenated, alkyl ester, hydroxyl, alkoxy, amino, alkylamino, nitro, cyano, thiol, thioalkyl, or of the formula (CH3-(OCH2CH2)). n -) a methoxy polyethylene glycol chain substituted with C1-C8 alkyl groups, wherein n is included between 1 and 20.

11. The composition according to claim 9, wherein R1 is optionally halogenated, alkyl ester, hydroxyl, alkoxy, amino, alkylamino, or of the formula (CH3-(OCH2CH2)). n -) a methoxy polyethylene glycol chain substituted with C1-C8 alkyl groups, wherein n is included between 1 and 20.

12. The composition according to claim 9, wherein R1 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or two of a halogen, CF3, hydroxyl, nitro or cyano group.

13. The composition according to claim 9, wherein R1 is a C2-C4 alkyl group, optionally substituted with one, two or three fluorine groups.

14. The composition according to claim 9, wherein R1 is a C2-C6 alkyl group, optionally substituted with a carboxyl, methyl, or ethyl ester group.

15. The composition according to claim 9, wherein R1 is , , , , , or .

16. The composition according to any one of claims 9-15, wherein R2 is hydrogen or CH3.

17. The composition according to any one of claims 3-16, wherein the psilocybin derivative is its hydrochloride.

18. The composition according to claims 1-17, wherein the composition comprises a controlled-release polymer, a diluent, a binder, a lubricant, and / or a flow aid.

19. The composition of claim 18, wherein the controlled-release polymer comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, or a mixture thereof.

20. The composition of claim 18, wherein the controlled-release polymer comprises hydroxypropyl methylcellulose.

21. The composition of claim 20, wherein the composition comprises two different hydroxypropyl methylcellulose polymers.

22. The composition according to any one of claims 18-20, wherein the composition comprises about 5 wt% to about 45 wt% of the controlled-release polymer.

23. The composition according to any one of claims 18-22, wherein the diluent comprises lactose, microcrystalline cellulose, starch, calcium sulfate dihydrate, mannitol, sorbitol, dibasic calcium phosphate, or a mixture thereof.

24. The composition of claim 23, wherein the diluent comprises lactose monohydrate.

25. The composition according to claim 23 or claim 24, wherein the diluent comprises lactose monohydrate and microcrystalline cellulose.

26. The composition according to any one of claims 18-25, comprising about 5 wt% to about 90 wt% of a diluent.

27. The composition of claim 26, comprising about 10 wt% to about 80 wt% of a diluent.

28. The composition according to claim 26 or claim 27, comprising about 30 wt% to about 70 wt% of a diluent.

29. The composition according to any one of claims 18-28, wherein the binder comprises at least one of starch, partially or fully pregelatinized starch, gelatin, polyethylene glycol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, microcrystalline cellulose, or mixtures thereof.

30. The composition of claim 29, wherein the adhesive comprises partially pregelatinized starch.

31. The composition according to any one of claims 18-30, wherein the composition comprises about 2% by weight to about 20% by weight of an adhesive.

32. The composition according to any one of claims 18-31, wherein the lubricant and / or flow aid comprises colloidal silica, stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, povidone, crospovidone, or talc.

33. The composition of claim 32, wherein the lubricant and / or flow aid comprises colloidal silica.

34. The composition according to claim 32 or claim 33, wherein the lubricant and / or flow aid comprises magnesium stearate.

35. The composition according to any one of claims 5-21, wherein the composition comprises about 0.1% by weight to about 10% by weight of a lubricant and / or a flow aid.

36. Compounds according to Formula II: Or its pharmaceutically acceptable salt. in: R1 and R2, each time appearing independently, are hydrogen, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclic, optionally substituted at one or more positions with the following: deuterium, halogroup, alkyl ester, hydroxyl, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclic, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate ester, or of the formula (CH3-(OCH2CH2)). n -) methoxy polyethylene glycol chains, where the value of n is between 1 and 100.

37. The compound of claim 36, wherein R1 is a C1-C8 alkyl group, optionally coated with a halogen, alkyl ester, hydroxyl group, alkoxy group, amino group, alkylamino group, nitro group, cyano group, thiol group, thioalkyl group, or of the formula (CH3-(OCH2CH2)). n The methoxy polyethylene glycol chain is substituted with n, where the value of n is between 1 and 20.

38. The compound according to claim 36, wherein R1 is a C1-C8 alkyl group, optionally coated with a halogen, alkyl ester, hydroxyl group, alkoxy group, amino group, alkylamino group, or of the formula (CH3-(OCH2CH2)). n The methoxy polyethylene glycol chain is substituted with n, where the value of n is between 1 and 20.

39. The compound of claim 36, wherein R1 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or two of a halogen, CF3, hydroxyl, nitro or cyano group.

40. The compound according to claim 36, wherein R1 is a C2-C4 alkyl group optionally substituted with 1, 2 or 3 fluorine groups.

41. The compound according to claim 36, wherein R1 is a C2-C6 alkyl group, optionally substituted with a carboxyl, methyl, or ethyl ester group.

42. The compound according to claim 36, wherein R1 is , , , , , or .

43. The compound according to any one of claims 36-42, wherein R2 is hydrogen or CH3.

44. The compound according to any one of claims 36-43, wherein the compound is its hydrochloride salt.

45. A method for treating patients in need of prediabetes, type II diabetes, obesity, metabolic dysfunction-related fatty liver disease (MASLD and MetALD), metabolic dysfunction-related steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), dyslipidemia, or sarcopenia, said method comprising administering to said patient a therapeutically effective amount of the composition according to any one of claims 1-35 or the compound according to any one of claims 36-44.

46. ​​A method for treating stroke and its defects in a patient in need, the method comprising administering to the patient a therapeutically effective amount of the composition according to any one of claims 1-35 or the compound according to any one of claims 36-44.

47. A method for treating ALS and its defects in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a composition according to any one of claims 1-35 or a compound according to any one of claims 36-44.

48. A method for treating aging in a patient in need, the method comprising administering to the patient a therapeutically effective amount of the composition according to any one of claims 1-35 or the compound according to any one of claims 36-44.

49. The method according to claims 45-48, wherein the dose delivered by administration contains no more than about 10 ng / mL (e.g., no more than about 8 ng / mL, 6 ng / mL, 5 ng / mL, 4 ng / mL, 3 ng / mL, 2 ng / mL, 1 ng / mL, 0.5 ng / mL or 0.1 mg / mL) of psilocybin or a psilocybin derivative C. max .

50. The method according to claims 45-49, wherein the dose provided by administration has at least about 0.01 ng / mL of psilocybin or a psilocybin derivative C. max .

51. The method according to any one of claims 45-50, wherein the dose delivered by administration has a duration of at least about 1.5 h (e.g., at least about 1.7 h, 1.8 h, 1.9 h, 2 h, 2.1 h, 2.2 h, 2.3 h, 2.4 h, or 2.5 h) of seroceridine or psilocybin derivative T. max .

52. The method of claim 51, wherein the dose provided by administration has a dose of psilocybin or a psilocybin derivative T for no more than about 24 h (e.g., no more than about 12 h or about 8 h). max .

53. The method according to any one of claims 45 to 52, wherein the provided psilocybin or psilocybin derivative is applied to C max Compared to C doses of equivalent serocerin or psilocybin derivatives not administered with a prolonged-release composition max At least 10% smaller.

54. The method according to any one of claims 45 to 53, wherein the administration of T-method provides psilocybin or a psilocybin derivative. max Compared to T doses of equivalent serocerin or psilocybin derivatives not administered with prolonged-release compositions max At least 10% larger.

55. The method according to any one of claims 45-54, wherein the serocerin or psilocybin derivative is administered in combination with a GLP-1 agonist.

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