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WO2024206109A1 - Dérivés de tryptamine - Google Patents

Dérivés de tryptamine Download PDF

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Publication number
WO2024206109A1
WO2024206109A1 PCT/US2024/021071 US2024021071W WO2024206109A1 WO 2024206109 A1 WO2024206109 A1 WO 2024206109A1 US 2024021071 W US2024021071 W US 2024021071W WO 2024206109 A1 WO2024206109 A1 WO 2024206109A1
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WO
WIPO (PCT)
Prior art keywords
crystalline
iodide
hydrogenoxalate
serotonin
hydromaleate
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PCT/US2024/021071
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Inventor
Andrew R. Chadeayne
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Caamtech Inc
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Caamtech Inc
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Publication of WO2024206109A1 publication Critical patent/WO2024206109A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This disclosure relates to trimethyl[2-(2-methyl-lH-indol-3-yl)ethyl]azanium iodide (2-methyl- /V,/V,/V-trimethyltryptammonium iodide or 2-Me-TMT iodide), crystalline 2-Me-TMT iodide, and specific crystalline forms thereof, including crystalline form 1 of 2-Me-TMT iodide; to pharmaceutical compositions containing 2-Me-TMT iodide or crystalline 2-Me-TMT iodide, including crystalline form 1 of 2-Me-TMT iodide; and to methods of treatment/therapeutic uses of 2-Me-TMT iodide or crystalline 2- Me-TMT iodide, including crystalline form 1 of 2-Me-TMT iodide.
  • This disclosure further relates to [2-(5-hydroxy-lH-indol-3-yl)ethyl](methyl)azanium hydrogenoxalate (5-hydroxy-/V-methyltryptammonium hydrogenoxalate or 5-HO-NMT hydrogenoxalate), crystalline 5-HO-NMT hydrogenoxalate, and specific crystalline forms thereof, including crystalline form 1 of 5-HO-NMT hydrogenoxalate; to pharmaceutical compositions containing 5-HO-NMT hydrogenoxalate or crystalline 5-HO-NMT hydrogenoxalate, including crystalline form 1 of 5- HO-NMT hydrogenoxalate; and to methods of treatment/therapeutic uses of 5-HO-NMT hydrogenoxalate or crystalline 5-HO-NMT hydrogenoxalate, including crystalline form 1 of 5-HO-NMT hydrogenoxalate.
  • This disclosure further relates to 2-(5-hydroxy-lH-indol-3-yl)ethan-l-aminium (2E)-3- carboxyprop-2-enoate (serotonin hydromaleate), crystalline serotonin hydromaleate, and specific crystalline forms thereof, including crystalline form 1 of serotonin hydromaleate; to pharmaceutical compositions containing serotonin hydromaleate or crystalline serotonin hydromaleate, including crystalline form 1 of serotonin hydromaleate; and to methods of treatment/therapeutic uses of serotonin hydromaleate or crystalline serotonin hydromaleate, including crystalline form 1 of serotonin hydromaleate.
  • Obtaining specific salts or crystalline forms of an active pharmaceutical ingredient (API) is extremely useful in drug development. It permits better characterization of the drug candidate's chemical and physical properties. Crystalline forms often have better chemical and physical properties than the API in its amorphous state. Such crystalline forms may possess more favorable pharmaceutical and pharmacological properties or be easier to process. Additionally, preparing a crystalline API and solving its crystal structure provides the gold standard for chemical characterization and determining the molecular formula (and molecular weight) of the API. Accordingly, preparing a crystalline form with an accompanying crystal structure thereof prevents potential ambiguities and/or inaccuracies in the API's molecular weight.
  • API's molecular weight is used to calculate the concentration of compositions comprising that API.
  • inaccuracies in molecular weight may lead to errors in the calculations pertaining to dosing, potency, toxicity, etc. in all downstream in vitro and in vivo assays that correlated the concentration of the API with a measured property. Accordingly, there remains a need to obtain and characterize crystalline forms of APIs, such as tryptamines and other psychedelic drug compounds.
  • This disclosure relates to trimethyl[2-(2-methyl-lH-indol-3-yl)ethyl]azanium iodide (2-methyl- A/,/V,/V-trimethyltryptammonium iodide or 2-Me-TMT iodide), crystalline 2-Me-TMT iodide, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of 2-Me-TMT iodide, including crystalline form 1 of 2-Me-TMT iodide.
  • XRPD X-ray powder diffraction
  • This disclosure further relates to [2-(5-hydroxy-lH-indol-3-yl)ethyl](methyl)azanium hydrogenoxalate (5-hydroxy-A/-methyltryptammonium hydrogenoxalate or 5-HO-NMT hydrogenoxalate), crystalline 5-HO-NMT hydrogenoxalate, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of 5-HO-NMT hydrogenoxalate, including crystalline form 1 of 5-HO-NMT hydrogenoxalate.
  • XRPD X-ray powder diffraction
  • This disclosure further relates to 2-(5-hydroxy-lH-indol-3-yl)ethan-l-aminium (2E)-3- carboxyprop-2-enoate (serotonin hydromaleate), crystalline serotonin hydromaleate, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of serotonin hydromaleate, including crystalline form 1 of serotonin hydromaleate.
  • XRPD X-ray powder diffraction
  • the disclosure further relates to a composition
  • a composition comprising 2-Me-TMT iodide, crystalline 2-Me- TMT iodide, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, and at least one excipient.
  • the disclosure further relates to a composition
  • a composition comprising 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 5-HO-NMT hydrogenoxalate, and at least one excipient.
  • the disclosure further relates to a composition
  • a composition comprising serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of serotonin hydromaleate, and at least one excipient.
  • the disclosure also provides a composition comprising 2-Me-TMT iodide, crystalline 2-
  • a serotonergic drug
  • the disclosure also relates to a method of preventing or treating a psychological disorder comprising the step of administering to a subject in need thereof a therapeutically effective amount of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5- HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate, or a composition according to this disclosure.
  • the disclosure further relates to a method of preventing or treating inflammation and/or pain, preventing or treating a neurological disorder, modulating activity of a mitogen-activated protein kinase (MAPK), modulating neurogenesis, or modulating neurite outgrowth comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of 2- Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate, and to administering a pharmaceutical composition or a composition according to the invention.
  • a subject in need thereof refers to a person requiring a composition to treat a particular disease or condition (e.g., inflammation, pain, a psychological disorder, modulating activity at a receptor, etc.).
  • the "subject in need thereof” may be identified by analyzing, diagnosing, and/or determining whether the person (or subject) requires the composition for treatment of a particular disease or condition.
  • identifying a person in need of treatment comprises diagnosing a person with a medical condition, e.g., a neurological disorder, a chemical imbalance, a hereditary condition, etc.
  • identifying a person in need of treatment comprises performing a psychiatric evaluation.
  • identifying a person in need of treatment comprises performing a blood test. In one embodiment, identifying a person in need of treatment comprises determining whether a person has a compulsive disorder. In one embodiment, identifying a person in need of treatment comprises self-identifying as having a compulsive disorder.
  • FIG. 1 shows the molecular structure of crystalline form 1 of 2-Me-TMT iodide.
  • FIG. 2 shows the molecular structure of crystalline form 1 of 5-HO-NMT hydrogenoxalate.
  • FIG. 3 shows the molecular structure of crystalline form 1 of serotonin hydromaleate.
  • FIG. 4 shows the unit cell of crystalline form 1 of 2-Me-TMT iodide along the o-axis.
  • FIG. 5 shows the unit cell of crystalline form 1 of 5-HO-NMT hydrogenoxalate along the o-axis.
  • FIG. 6 shows the unit cell of crystalline form 1 of serotonin hydromaleate along the o- axis.
  • FIG. 7 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form l of 2-Me-TMT iodide.
  • FIG. 8 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form
  • FIG. 9 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form
  • This disclosure relates to trimethyl[2-(2-methyl-lH-indol-3-yl)ethyl]azanium iodide (2- methyl-A/,A/,/ ⁇ /-trimethyltryptammonium iodide or 2-Me-TMT iodide), crystalline 2-Me-TMT iodide, [2-(5- hydroxy-lH-indol-3-yl)ethyl](methyl)azanium hydrogenoxalate (5-hydroxy-/V-methyltryptammonium hydrogenoxalate or 5-HO-NMT hydrogenoxalate), crystalline 5-HO-NMT hydrogenoxalate, 2-(5-hydroxy- lH-indol-3-yl)ethan-l-aminium (2E)-3-carboxyprop-2-enoate (serotonin hydromaleate), crystalline serotonin hydromaleate, and specific crystalline forms thereof, such as crystalline form 1 of 2-Me
  • 2-Me-TMT iodide crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate, and some exemplary methods used to characterize them are described below.
  • 5-HO-NMT hydrogenoxalate has the following chemical formula:
  • Serotonin hydromaleate has the following chemical formula:
  • compositions are used to regulate the activity of a neurotransmitter receptor by administering a therapeutically effective dose of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate according to the disclosure, and the methods and the compositions are used to treat inflammation and/or pain by administering a therapeutically effective dose of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO- NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TM
  • Methods of the disclosure also relate to the administration of a therapeutically effective amount of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5- HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate to prevent or treat a disease or condition, such as those discussed below for a subject in need of treatment.
  • 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to prevent and/or treat a psychological disorder.
  • the disclosure provides a method for preventing and/or treating a psychological disorder by administering to a subject in need thereof a therapeutically effective amount of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5- HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure, including the exemplary embodiments discussed herein.
  • the psychological disorder may be chosen from: depression; psychotic disorder; schizophrenia; schizophreniform disorder (acute schizophrenic episode); schizoaffective disorder; bipolar I disorder (mania, manic disorder, manic-depressive psychosis); bipolar II disorder; major depressive disorder; major depressive disorder with psychotic feature (psychotic depression); delusional disorders (paranoia); shared psychotic disorder (shared paranoia disorder); brief psychotic disorder (other and unspecified reactive psychosis); psychotic disorder not otherwise specified (unspecified psychosis); paranoid personality disorder; schizoid personality disorder; schizotypal personality disorder; anxiety disorder; social anxiety disorder; substance-induced anxiety disorder; selective mutism; panic disorder; panic attacks; agoraphobia; attention deficit syndrome; post-traumatic stress disorder (PTSD); premenstrual dysphoric disorder (PMDD); and premenstrual syndrome (PMS).
  • depression depression
  • psychotic disorder schizophrenia
  • schizophreniform disorder acute schizophrenic episode
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to prevent and/or treat a brain disorder.
  • the disclosure provides a method for preventing and/or treating a brain disorder (e.g., Huntington's disease, Alzheimer's disease, dementia, and Parkinson's disease) by administering to a subject in need thereof a therapeutically effective amount of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate.
  • a brain disorder e.g., Huntington's disease, Alzheimer's disease, dementia, and Parkinson's disease
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to prevent and/or treat developmental disorders, delirium, dementia, amnestic disorders and other cognitive disorders, psychiatric disorders due to a somatic condition, drug-related disorders, schizophrenia and other psychotic disorders, mood disorders, anxiety disorders, somatoform disorders, factitious disorders, dissociative disorders, eating disorders, sleep disorders, impulse control disorders, adjustment disorders, or personality disorders.
  • the disclosure provides a method for preventing and/or treating these disorders by administering to a subject in need thereof a therapeutically effective amount of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate including the exemplary embodiments discussed above.
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to prevent and/or treat inflammation and/or pain, such as for example inflammation and/or pain associated with inflammatory skeletal or muscular diseases or conditions.
  • the disclosure provides a method for preventing and/or treating an inflammation and/or pain by administering to a subject in need thereof a therapeutically effective amount of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5- HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure, including the exemplary embodiments discussed herein.
  • treatable "pain” includes nociceptive, neuropathic, and mix-type.
  • a method of the disclosure may reduce or alleviate the symptoms associated with inflammation, including but not limited to treating localized manifestation of inflammation characterized by acute or chronic swelling, pain, redness, increased temperature, or loss of function in some cases.
  • a method of the disclosure may reduce or alleviate the symptoms of pain regardless of the cause of the pain, including but not limited to reducing pain of varying severity, i.e., mild, moderate and severe pain, acute pain and chronic pain.
  • a method of the disclosure is effective in treating joint pain, muscle pain, tendon pain, burn pain, and pain caused by inflammation such as rheumatoid arthritis.
  • Skeletal or muscular diseases or conditions which may be treated include but are not limited to musculoskeletal sprains, musculoskeletal strains, tendinopathy, peripheral radiculopathy, osteoarthritis, joint degenerative disease, polymyalgia rheumatica, juvenile arthritis, gout, ankylosing spondylitis, psoriatic arthritis, systemic lupus erythematosus, costochondritis, tendonitis, bursitis, such as the common lateral epicondylitis (tennis elbow), medial epicondylitis (pitchers elbow) and trochanteric bursitis, temporomandibular joint syndrome, and fibromyalgia.
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to modulate activity of a mitogen-activated protein kinase (MAPK), comprising administering a composition of the invention.
  • MPK mitogen-activated protein kinase
  • MAPKs provide a wide-ranging signaling cascade that allow cells to quickly respond to biotic and abiotic stimuli.
  • exemplary MAPKs include, but are not limited to, Tropomyosin Receptor Kinase A (TrkA), P38-alpha, and c-Jun N-Terminal Kinase 3 (JNK3).
  • TrkA is a high affinity catalytic receptor of nerve growth factor (NGF) protein. TrkA regulates NGF response, influencing neuronal differentiation and outgrowth as well as programmed cell death.
  • NGF nerve growth factor
  • p38-alpha is involved with the regulation of pro-inflammatory cytokines, including TNF-a.
  • JNK3 is a neuronal-specific protein isoform of the JNKs. It is involved with the regulation of apoptosis. JNK3 also plays a role in modulating the response of cytokines, growth factors, and oxidative stress.
  • modulating activity of a mitogen-activated protein kinase refers to changing, manipulating, and/or adjusting the activity of a mitogen-activated protein kinase.
  • modulating the activity of a MAPK can influence neural health, neurogenesis, neural growth and differentiation, and neurodegenerative diseases.
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to modulate neurogenesis, comprising administering a composition of the invention.
  • the term "modulating neurogenesis” refers to changing, manipulating, and/or adjusting the growth and development of neural tissue.
  • neurogenesis comprises adult neurogenesis, in which new neural stem cells are generated from neural stem cells in an adult animal.
  • modulating neurogenesis comprises increasing and/or enhancing the rate at which new neural tissue is developed.
  • 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to modulate neurite outgrowth, comprising administering a composition of the invention.
  • the term “modulating neurite outgrowth” refers to changing, manipulating, and/or adjusting the growth and development of neural projections, or "neurites.”
  • neurogenesis comprises modulating the growth of new neurites, the number of neurites per neuron, and/or neurite length.
  • modulating neurite outgrowth comprises increasing and/or enhancing the rate and/or length at which neurites develop.
  • 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to prevent and/or treat sexual health disorders including, but not limited to, hypoactive sexual desire disorder, hyperactive sexual desire disorder, orgasmic disorder, arousal disorder, vaginismus, and dyspareunia.
  • the disorder is a male sexual dysfunction disorder.
  • the disorder is a female sexual dysfunction disorder.
  • 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used to prevent and/or treat women's health disorders including, but not limited to, menstrual cramping, dysmenorrhea, post-hysterectomy pain, vaginal or vulvar vestibule mucosa disorder, menopausal- related disorders, vaginal atrophy, or vulvar vestibulitis.
  • compositions comprising an effective amount of 2-Me- TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate and an excipient (e.g., a pharmaceutically-acceptable excipient).
  • an excipient e.g., a pharmaceutically-acceptable excipient
  • the disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate and a pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier).
  • a pharmaceutically acceptable excipient also known as a pharmaceutically acceptable carrier
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2- Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be, for example, therapeutically useful to prevent and/or treat the psychological disorders, brain disorders, pain, and inflammation as well as the other disorders described herein.
  • a composition or a pharmaceutical composition of the disclosure may be in any form which contains 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate.
  • the composition may be, for example, a tablet, capsule, liquid suspension, injectable, topical, or transdermal.
  • compositions generally contain, for example, about 1% to about 99% by weight of 2-Me-TMT iodide, crystalline 2-Me- TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure and, for example, 99% to 1% by weight of at least one suitable pharmaceutically acceptable excipient.
  • the composition may be between about 5% and about 75% by weight of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO- NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure, with the rest being at least one suitable pharmaceutically acceptable excipient or at least one other adjuvant, as discussed below.
  • compositions comprising a combination of a first purified psilocybin derivative with a second purified psilocybin derivative, with one or two purified cannabinoids or with a purified terpene. Various ratios of these components in the composition are also disclosed.
  • the disclosures of US 2018/0221396 Al and US 2019/0142851 Al are incorporated herein by reference.
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used as the "first purified psilocybin derivative" in the compositions described in US 2018/0221396 Al and US 2019/0142851 Al.
  • this disclosure provides a composition
  • a composition comprising: a first component comprising 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure; at least one second component selected from at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, and (d) a purified terpene; and at least one pharmaceutically- acceptable excipient or at least one other adjuvant.
  • Such a composition may be a pharmaceutical composition wherein the components are present individually in therapeutically effective
  • compositions When used in such compositions as a first component comprising 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure with a second component selected from at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, and (d) a purified terpene, the compositions represent particular embodiments of the invention.
  • compositions having as a first component 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure with a second component selected from at least one of (e) an adrenergic drug, (f) a dopaminergic drug, (g) a monoamine oxidase inhibitor, (h) a purified erinacine, and (i) a purified hericenone represent additional particular embodiments of the invention represented by the compositions having 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenox
  • the first and second components can be administered at the same time (e.g., together in the same composition), or at separate times over the course of treating a patient in need thereof.
  • a composition may be a pharmaceutical composition wherein the components are present individually in therapeutically effective amounts or by combination in a therapeutically effective amount to treat a disease, disorder, or condition as described herein.
  • the term “purified” means separated from other materials, such as plant or fungal material, e.g., protein, chitin, cellulose, or water.
  • the term “purified” refers to a compound substantially free of other materials.
  • the term “purified” refers to a compound that is substantially free from a second tryptamine compound.
  • the term “purified” refers to a compound substantially free from histidine.
  • the term “purified” refers to a compound substantially free from a biological material, such as mold, fungus, plant matter, or bacteria.
  • the term “purified” refers to a compound substantially free from a paralytic.
  • the term "purified” refers to a compound which has been separated from other compounds that are typically co-extracted when the purified compound is extracted from a naturally occurring organism.
  • a "purified" psilocybin derivative is partially or completely isolated from other psilocybin derivatives present in a source material, such as a psilocybin-containing mushroom.
  • "purified" baeocystin is substantially free from psilocybin and/or psilocin.
  • psilocybin mushroom extracts aka crude extracts or fruit body extracts
  • traditional psilocybin mushroom extracts would be expected to contain an unpredictable and varying amount of psilocybin, psilocin, baeocystin, norbaeocystin, salts thereof, or combinations thereof.
  • unpurified psilocybin derivatives would include mycelium containing psilocybin derivatives and/or naturally occurring fungal material such as biological material and/or structural material such as chitin.
  • cannabidiol cannabidiol
  • CBD cannabidiol
  • the term "purified" refers to a compound or composition that has been crystallized.
  • the term "purified" refers to a compound or composition that has been chromatographed, for example by gas chromatography, liquid chromatography (e.g., LC, HPLC, etc.), etc.
  • the term "purified" refers to a compound or composition that has been distilled.
  • the term "purified" refers to a compound or composition that has been sublimed.
  • the term "purified" refers to a compound or composition that has been subject to two or more steps chosen from crystallization, chromatography, distillation, or sublimation.
  • the term “purified” refers to a compound that is between 80-100% pure.
  • the term “purified” refers to a compound that is between 90-100% pure.
  • the term “purified” refers to a compound that is between 95-100% pure.
  • the term “purified” refers to a compound that is between 99-100% pure.
  • the term “purified” refers to a compound that is between 99.9-
  • a serotonergic drug refers to a compound that binds to, blocks, or otherwise influences
  • Exemplary psilocybin derivatives include but are not limited to psilocybin itself and the psilocybin derivatives described in paragraphs [0081]-[0109] of US 2018/0221396 Al and [0082]-[0110] US 2019/0142851 Al as well as the disclosed exemplary embodiments.
  • Exemplary cannabinoids include but are not limited to the cannabinoids described in paragraphs [0111]-[0145] of US 2018/0221396 Al and [0112]-[0146] US 2019/0142851 Al as well as the disclosed exemplary embodiments.
  • Exemplary terpenes include but are not limited to the terpenes described in paragraphs [0160]-[0238] of US 2018/0221396 Al and [0161]-[0300] US 2019/0142851 Al as well as the disclosed exemplary embodiments.
  • a pharmaceutical formulation of the disclosure may comprise, consist essentially of, or consist of (a) 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5- HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure and (b) at least one second active compound selected from a serotonergic drug, a purified psilocybin derivative, a purified cannabinoid, a purified terpene, an adrenergic drug, a dopaminergic drug, a monoamine oxidase inhibitor, a purified erinacine, and a purified hericenone, and (c)
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate and the second active compound(s) are each present in a therapeutically effective amount using purposefully engineered and unnaturally occurring molar ratios.
  • Exemplary molar ratios of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure to the second active compound in a composition of the disclosure include but are not limited to from about 0.1:100 to about 100:0.1, from about 1:100 to about 100:1, from about 1:50 to about 50:1, from about 1:25 to about 25:1, from about 1:20 to about 20:1, from about 1:10 to about 10:1, from about 1:5 to about 5:1, from about 1:2 to about 2:1 or may be about 1:1.
  • a pharmaceutical formulation of the disclosure may comprise a composition containing
  • compositions comprising a combination of a purified psilocybin derivative with a second purified psilocybin derivative, with one or two purified cannabinoids or with a purified terpene.
  • composition containing 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5- HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be used in place of a "purified psilocybin derivative" in the compositions described in US 2018/0221396 Al and US 2019/0142851 Al.
  • the disclosure provides a pharmaceutical formulation comprising as (a) 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO- NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure and at least one second component selected from (a) a purified psilocybin derivative, (b) a purified cannabinoid, and (c) a purified terpene; and at least one pharmaceutically-acceptable excipient or at least one other adjuvant, as described herein.
  • Such a composition may be a pharmaceutical composition wherein the components are present individually in therapeutically effective amounts or by combination in a therapeutically effective amount to treat a disease
  • a serotonergic drug refers to a compound that binds to, blocks, or otherwise influences
  • Some exemplary serotonergic drugs include SSRIs and SNRIs.
  • serotonergic drugs include the following molecules, including any salts, solvates, or polymorphs thereof: 6-allyl-N,N-diethyl-NL; N,N-dibutyl-T; N,N-diethyl-T; N,N-diisopropyl-T; 5-methyoxy-alpha-methyl-T; N,N- dimethyl-T; 2,alpha-dimethyl-T; alpha, N-dimethyl-T; N,N-dipropyl-T; N-ethyl-N-isopropyl-T; alpha-ethyl- T; 6-N,N-Triethyl-NL; 3,4-dihydro-7-methoxy-l-methyl-C; 7-methyoxy-l-methyl-C; N,N-dibutyl-4- hydroxy-T; N,N-diethyl-4-hydroxy-T; N,N-diisopropyl-4-hydroxy-T;
  • a serotonergic drug is chosen from alprazolam, amphetamine, aripiprazole, azapirone, a barbiturate, bromazepam, bupropion, buspirone, a cannabinoid, chlordiazepoxide, citalopram, clonazepam, clorazepate, dextromethorphan, diazepam, duloxetine, escitalopram, fluoxetine, flurazepam, fluvoxamine, lorazepam, lysergic acid diethylamide, lysergamide, 3,4- methylenedioxymethamphetamine, milnacipran, mirtazapine, naratriptan, paroxetine, pethidine, phene
  • Exemplary psilocybin derivatives include but are not limited to psilocybin itself and the psilocybin derivatives described in paragraphs [0081]-[0109] of US 2018/0221396 Al and [082]-[0110] US 2019/0142851 Al as well as the disclosed exemplary embodiments, incorporated here by reference.
  • compositions disclosed herein comprise one or more purified psilocybin derivatives chosen from: [3-(2-dimethylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate; 4- hydroxytryptamine; 4-hydroxy-N,N-dimethyltryptamine; [3-(2-methylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate; 4-hydroxy-N-methyltryptamine; [3-(aminoethyl)-lH-indol-4-yl] dihydrogen phosphate; [3-(2-trimethylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate; and 4-hydroxy-N,N,N- trimethyltryptamine.
  • purified psilocybin derivatives chosen from: [3-(2-dimethylaminoethyl)-lH-indol-4-y
  • Exemplary cannabinoids include but are not limited to the cannabinoids described in paragraphs [0111]-[0145] of US 2018/0221396 Al and [0112]-[0146] US 2019/0142851 Al as well as the disclosed exemplary embodiments.
  • cannabinoids within the context of this disclosure include the following molecules: cannabichromene (CBC); cannabichromenic acid (CBCA); cannabichromevarin (CBCV); cannabichromevarinic acid (CBCVA); cannabicyclol (CBL); cannabicyclolic acid (CBLA); cannabicyclovarin (CBLV); cannabidiol (CBD); cannabidiol monomethylether (CBDM); cannabidiolic acid (CBDA); cannabidiorcol (CBD-C1); cannabidivarin (CBDV); cannabidivarinic acid (CBDVA); cannabielsoic acid B (CBEA-B); cannabielsoin (CBE); cannabielsoin acid A (CBEA-A); cannabigerol (CBG); cannabigerol monomethylether (CBGM); cannabigerolic acid (CBGA); cannabigerolic acid
  • the purified cannabinoid is chosen from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBVD, CBDVA, CBG, CBGA, CBGV, or CBGVA.
  • Exemplary terpenes include but are not limited to the terpenes described in paragraphs [0160]-[0238] of US 2018/0221396 Al and [0161]-[0300] US 2019/0142851 Al as well as the disclosed exemplary embodiments.
  • a purified terpene is chosen from acetanisole, acetyl cedrene, anethole, anisole, benzaldehyde, bornyl acetate, borneol, cadinene, cafestol, caffeic acid, camphene, camphor, capsaicin, carene, carotene, carvacrol, carvone, caryophyllene, caryophyllene, caryophyllene oxide, cedrene, cedrene epoxide, cecanal, cedrol, cembrene, cinnamaldehyde, cinnamic acid, citronellal, citronellol, cymene, eicosane, elemene, estragole, ethyl acetate, ethyl cinnamate, ethyl maltol, eucalyptol/l,8-cineole, eudes
  • a purified terpene is chosen from bornyl acetate, alpha-bisabolol, borneol, camphene, camphor, carene, caryophyllene, cedrene, cymene, elemene, eucalyptol, eudesmol, farnesene, fenchol, geraniol, guaiacol, humulene, isoborneol, limonene, linalool, menthol, myrcene, nerolidol, ocimene, phellandrene, phytol, pinene, pulegone, sabinene, terpineol, terpinolene, or valencene.
  • adrenergic drug refers to a compound that binds, blocks, or otherwise influences (e.g., via an allosteric reaction) activity at an adrenergic receptor.
  • an adrenergic drug binds to an adrenergic receptor.
  • an adrenergic drug indirectly affects an adrenergic receptor, e.g., via interactions affecting the reactivity of other molecules at the adrenergic receptor.
  • an adrenergic drug is an agonist, e.g., a compound activating an adrenergic receptor.
  • an adrenergic drug is an antagonist, e.g., a compound binding but not activating an adrenergic receptor, e.g., blocking a receptor.
  • an adrenergic drug is an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation.
  • an adrenergic drug acts (either directly or indirectly) at more than one type of receptor (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.).
  • an adrenergic drug is an antidepressant. In one embodiment, an adrenergic drug is a norepinephrine transporter inhibitor. In one embodiment, an adrenergic drug is a vesicular monoamine transporter inhibitor.
  • an adrenergic drug is chosen from adrenaline, agmatine, amoxapine, aptazapine, atomoxetine, bupropion, clonidine, doxepin, duloxetine, esmirtazpine, mianserin, ketanserin, mirabegron, mirtazapine, norepinephrine, phentolamine, phenylephrine, piperoxan, reserpine, ritodrine, setiptiline, tesofensine, timolol, trazodone, trimipramine, or xylazine.
  • the term "dopaminergic drug” refers to a compound that binds, blocks, or otherwise influences (e.g., via an allosteric reaction) activity at a dopamine receptor.
  • a dopaminergic drug binds to a dopamine receptor.
  • a dopaminergic drug indirectly affects a dopamine receptor, e.g., via interactions affecting the reactivity of other molecules at the dopamine receptor.
  • a dopaminergic drug is an agonist, e.g., a compound activating a dopamine receptor.
  • a dopaminergic drug is an antagonist, e.g., a compound binding but not activating a dopamine receptor, e.g., blocking a receptor.
  • a dopaminergic drug is an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation.
  • a dopaminergic drug acts (either directly or indirectly) at more than one type of receptor (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.).
  • a dopaminergic drug is a dopamine transporter inhibitor.
  • a dopaminergic drug is a vesicular monoamine transporter inhibitor.
  • a dopaminergic drug is chosen from amineptine, apomorphine, benzylpiperazine, bromocriptine, cabergoline, chlorpromazine, clozapine, dihydrexidine, domperidone, dopamine, fluphenazine, haloperidol, ketamine, loxapine, methamphetamine, olanzapine, pemoline, perphenazine, pergolide, phencyclidine, phenethylamine, phenmetrazine, pimozide, piribedil, a psychostimulant, reserpine, risperidone, ropinirole, tetrabenazine, or thioridazine.
  • a MAOI refers to a compound that blocks the actions of monoamine oxidase enzymes.
  • a MAOI inhibits the activity of one or both monoamine oxidase A and monoamine oxidase B.
  • a MAOI is a reversible inhibitor of monoamine oxidase A.
  • a MAOI is a drug chosen from isocarboxazid, phenelzine, or tranylcypromine.
  • a MAOI is -carboline, pinoline, harmane, harmine, harmaline, harmalol, tetrahydroharmine, 9-methyl-P-carboline, or 3-carboxy- tetrahydrononharman.
  • the compositions and methods disclosed herein include one or more purified erinacine molecules.
  • the compositions and methods disclosed herein comprise purified erinacine A.
  • the compositions and methods disclosed herein comprise erinacine B.
  • the compositions and methods disclosed herein comprise erinacine C.
  • the compositions and methods disclosed herein comprise erinacine D.
  • the compositions and methods disclosed herein comprise erinacine E.
  • the compositions and methods disclosed herein comprise erinacine F.
  • the compositions and methods disclosed herein comprise erinacine G.
  • the compositions and methods disclosed herein comprise erinacine H.
  • compositions and methods disclosed herein comprise erinacine I. In one embodiment, the compositions and methods disclosed herein comprise erinacine J. In one embodiment, the compositions and methods disclosed herein comprise erinacine K In one embodiment, the compositions and methods disclosed herein comprise erinacine P. In one embodiment, the compositions and methods disclosed herein comprise erinacine Q. In one embodiment, the compositions and methods disclosed herein comprise erinacine R. In one embodiment, the compositions and methods disclosed herein comprise erinacine S.
  • the compositions and methods disclosed herein include one or more purified hericenone molecules.
  • the compositions and methods disclosed herein comprise purified hericenone A.
  • the compositions and methods disclosed herein comprise purified hericenone B.
  • the compositions and methods disclosed herein comprise purified hericenone C.
  • the compositions and methods disclosed herein comprise purified hericenone D.
  • the compositions and methods disclosed herein comprise purified hericenone E.
  • the compositions and methods disclosed herein comprise purified hericenone F.
  • the compositions and methods disclosed herein comprise purified hericenone G.
  • the compositions and methods disclosed herein comprise purified hericenone H.
  • compositions of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure and a second compound selected from a serotonergic drug, a purified psilocybin derivative, a purified cannabinoid, a purified terpene, an adrenergic drug, a dopaminergic drug, a monoamine oxidase inhibitor, a purified erinacine, and a purified hericenone in exemplary molar ratios are shown in Table 1.
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5- HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be any one of the exemplary embodiments described above including the crystalline forms as disclosed herein.
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5-HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be any one of the exemplary embodiments described above including the crystalline forms as disclosed herein.
  • the actual amount required for treatment of any particular patient may depend upon a variety of factors including, for example, the disease being treated and its severity; the specific pharmaceutical composition employed; the age, body weight, general health, sex, and diet of the patient; the mode of administration; the time of administration; the route of administration; and the rate of excretion; the duration of the treatment; any drugs used in combination or coincidental with the specific compound employed; and other such factors well known in the medical arts. These factors are discussed in Goodman and Gilman's "The Pharmacological Basis of Therapeutics," Tenth Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173 (2001), which is incorporated herein by reference.
  • the pharmaceutically acceptable carrier may be chosen from any one or a combination of carriers known in the art.
  • the choice of the pharmaceutically acceptable carrier depends upon the pharmaceutical form and the desired method of administration to be used.
  • Exemplary carriers include those that do not substantially alter the structure or activity of 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5- HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure, or produce undesirable biological effects or otherwise interact in a deleterious manner with any other component(s) of the pharmaceutical composition.
  • compositions of the disclosure may be prepared by methods know in the pharmaceutical formulation art, for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990), which is incorporated herein by reference.
  • 2-Me-TMT iodide, crystalline 2-Me-TMT iodide, 5-HO-NMT hydrogenoxalate, crystalline 5- HO-NMT hydrogenoxalate, serotonin hydromaleate, crystalline serotonin hydromaleate, or specific crystalline forms thereof, such as crystalline form 1 of 2-Me-TMT iodide, crystalline form 1 of 5-HO-NMT hydrogenoxalate, and crystalline form 1 of serotonin hydromaleate of the disclosure may be admixed with at least one pharmaceutically acceptable excipient such as, for example, sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose
  • the dosage forms may also comprise buffering agents.
  • the excipient is not water.
  • the excipient is not a solvent (e.g., EtOH, diethyl ether, ethyl acetate, or hydrocarbonbased solvents (e.g., hexanes).
  • the dosage form is substantially free of water and/or solvents, for example less than about 5% water by mass, less than 2% water by mass, less than 1% water by mass, less than 0.5% water by mass, or less than 0.1% water by mass.
  • Excipients or pharmaceutically acceptable adjuvants known in the pharmaceutical formulation art may also be used in the pharmaceutical compositions of the disclosure. These include, but are not limited to, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms may be ensured by inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like.
  • a pharmaceutical composition of the disclosure may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • Solid dosage forms as described above may be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner.
  • Non-limiting examples of embedded compositions that may be used are polymeric substances and waxes.
  • the active compounds may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Suspensions in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Solid dosage forms for oral administration which includes capsules, tablets, pills, powders, and granules, may be used.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier).
  • administration may be, for example, orally, buccally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, or intrasystemically, in the form of solid, semisolid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, such as, for example, in unit dosage forms suitable for simple administration of precise dosages.
  • One route of administration may be oral administration, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • E5. A composition comprising 2-methyl-/V,A/,A/-trimethyltryptammonium iodide according to El and an excipient.
  • E6 A composition comprising crystalline 2-methyl-W,/ ⁇ /,/ ⁇ /-trimethyltryptammonium iodide according to any one of E2-E4 and an excipient.
  • a composition comprising 2-methyl-A/,A/,A/-trimethyltryptammonium iodide according to El as a first component and a second component selected from at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, (d) a purified terpene, (e) an adrenergic drug, (f) a dopaminergic drug, (g) a monoamine oxidase inhibitor, (h) a purified erinacine, and (i) a purified hericenone.
  • E8 A composition comprising crystalline 2-methyl-/ ⁇ Z,/ ⁇ / / / ⁇ /-trimethyltryptammonium iodide according to any one of E2-E4 as a first component and a second component selected from at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, (d) a purified terpene, (e) an adrenergic drug, (f) a dopaminergic drug, (g) a monoamine oxidase inhibitor, (h) a purified erinacine, and (i) a purified hericenone.
  • a method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a therapeutically effective amount of 2-methyl-A/,/ ⁇ /, N- trimethyltryptammonium iodide according to El.
  • a method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline 2- methyl-W,/V,/V-trimethyltryptammonium iodide according to any one of E2-E4
  • Ell. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E5 or E7.
  • E12. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E6 or E8.
  • a method of preventing or treating inflammation and/or pain comprising the step of: administering to a subject in need thereof a therapeutically effective amount of 2-methyl-A/ / /V / / ⁇ /- trimethyltryptammonium iodide according to El.
  • E14 A method of preventing or treating inflammation and/or pain comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline 2- methyl-A/,/ ⁇ /,/ ⁇ /-trimethyltryptammonium iodide according to any one of E2-E4.
  • E15 A method of preventing or treating inflammation and/or pain comprising the step of: administering to a subject in need thereof a composition according to E5 or E7.
  • E16 A method of preventing or treating inflammation and/or pain comprising the step of: administering to a subject in need thereof a composition according to E6 or E8.
  • E20 A composition comprising crystalline 5-hydroxy-/V-methyltryptammonium hydrogenoxalate according to any one of E17-E19 and an excipient.
  • E21 A composition comprising crystalline 5-hydroxy-/V-methyltryptammonium hydrogenoxalate according to any one of E17-E19 as a first component and a second component selected from at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, (d) a purified terpene, (e) an adrenergic drug, (f) a dopaminergic drug, (g) a monoamine oxidase inhibitor, (h) a purified erinacine, and (i) a purified hericenone.
  • E22 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline 5- hydroxy-W-methyltryptammonium hydrogenoxalate according to any one of E17-E19.
  • E23 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E20 or E21.
  • E24 A method of preventing or treating inflammation and/or pain comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline 5- hydroxy-W-methyltryptammonium hydrogenoxalate according to any one of E17-E19.
  • E25 A method of preventing or treating inflammation and/or pain comprising the step of: administering to a subject in need thereof a composition according to E20 or E21.
  • E29 A composition comprising crystalline serotonin hydromaleate according to any one of E26-E28 and an excipient.
  • E30 A composition comprising crystalline serotonin hydromaleate according to any one of E26-E28 as a first component and a second component selected from at least one of (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) a purified cannabinoid, (d) a purified terpene, (e) an adrenergic drug, (f) a dopaminergic drug, (g) a monoamine oxidase inhibitor, (h) a purified erinacine, and (i) a purified hericenone.
  • E31 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline serotonin hydromaleate according to any one of E26-E28.
  • E32 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E29 or E30.
  • E33 A method of preventing or treating inflammation and/or pain comprising the step of: administering to a subject in need thereof a therapeutically effective amount of crystalline serotonin hydromaleate according to any one of E26-E28.
  • E34 A method of preventing or treating inflammation and/or pain comprising the step of: administering to a subject in need thereof a composition according to E29 or E30.
  • SCXRD Single Crystal X-Ray Diffraction Characterization: Data were collected on a Bruker D8 Venture CMOS Diffractometer equipped with an Oxford Cryosystems Cryostream cooling device and using Mo Ka radiation. Structures were solved using the Bruker SHELXTL program and refined with the SHELXTL program as part of the Bruker SHELXTL suite, or 0LEX2 software. Unless otherwise stated, hydrogen atoms attached to carbon were placed geometrically and allowed to refine with a riding isotropic displacement parameter. Hydrogen atoms attached to a heteroatom were located in a difference Fourier synthesis and were allowed to refine freely with an isotropic displacement parameter.
  • FIG. 1 shows the molecular structure of crystalline form 1 of 2-Me-TMT iodide, showing the atomic labeling.
  • FIG. 2 shows the molecular structure of crystalline form 1 of 5-HO-NMT hydrogenoxalate, showing the atomic labeling.
  • FIG. 3 shows the molecular structure of crystalline form 1 of serotonin hydromaleate, showing the atomic labeling.
  • FIG. 4 shows the unit cell of crystalline form 1 of 2-Me-TMT iodide along the o-axis.
  • FIG. 5 shows the unit cell of crystalline form 1 of 5-HO-NMT hydrogenoxalate along the o-axis.
  • FIG. 6 shows the unit cell of crystalline form 1 of serotonin hydromaleate along the flaxis.
  • FIG. 7 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 2-Me-TMT iodide generated from its single crystal data.
  • Table 4 lists the angles, °20 ⁇ O.2°20, and d- spacing of the peaks identified in the experimental XRPD pattern of FIG. 7. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal.
  • the cocrystal may be characterized by at least two peaks selected from the peaks at 6.6, 7.5, and 20.5 °29 ⁇ 0.2°29 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 7.
  • FIG. 8 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 5-HO-NMT hydrogenoxalate generated from its single crystal data.
  • Table 5 lists the angles, °20 + O.2°20, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 8. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal.
  • the cocrystal may be characterized by at least two peaks selected from the peaks at 8.9, 15, and 19.4 °20 ⁇ O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 8.
  • FIG. 9 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of serotonin hydromaleate generated from its single crystal data.
  • Table 6 lists the angles, °20 ⁇ 0.2°29, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 9. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal.
  • the cocrystal may be characterized by at least two peaks selected from the peaks at 10, 11.7, and 15.1 °20 ⁇ O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 9.

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Abstract

La présente divulgation concerne de l'iodure de triméthyl[2-(2-méthyl-lH-indol-3-yl)éthyl]azanium (iodure de 2- méthyl-/V,/V,/V-triméthyltryptammonium ou iodure de 2-Me-TMT), de l'iodure de crystalline 2-Me-TMT, de [2-(5- hydroxy-lH-indol-3-yl)éthyl](méthyl)azanium hydrogénoxalate (5-hydroxy-/V-méthyltryptammonium hydrogénoxalate ou 5-HO-NMT hydrogénoxalate), de 5-HO-NMT hydrogénoxalate crystallin, 2-(5-hydroxy- lH-indol-3-yl)éthan-l-aminium (2E)-3-carboxyprop-2-enoate (hydromaléate de sérotonine), de l'hydromaléate de sérotonine cristallin, et des formes cristallines spécifiques associées, telles que la forme cristalline 1 de l'iodure de 2-Me-TMT, la forme cristalline 1 de l'hydrogénooxalate de 5-HO-NMT, et la forme cristalline 1 de l'hydromaléate de sérotonine, des compositions les contenant, et des procédés de traitement les utilisant.
PCT/US2024/021071 2023-03-24 2024-03-22 Dérivés de tryptamine Pending WO2024206109A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210300870A1 (en) * 2020-03-23 2021-09-30 Caamtech Llc Crystalline n-methyl tryptamine derivatives
US20220160737A1 (en) * 2019-11-19 2022-05-26 Turtle Bear Holdings, Llc Tryptamine compositions for enhancing neurite outgrowth
US20230086574A1 (en) * 2021-09-08 2023-03-23 Small Pharma Ltd 5-methoxy-n,n-dimethyltryptamine crystalline forms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220160737A1 (en) * 2019-11-19 2022-05-26 Turtle Bear Holdings, Llc Tryptamine compositions for enhancing neurite outgrowth
US20210300870A1 (en) * 2020-03-23 2021-09-30 Caamtech Llc Crystalline n-methyl tryptamine derivatives
US20230086574A1 (en) * 2021-09-08 2023-03-23 Small Pharma Ltd 5-methoxy-n,n-dimethyltryptamine crystalline forms

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