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EP4584248A2 - Dérivés de tryptamine - Google Patents

Dérivés de tryptamine

Info

Publication number
EP4584248A2
EP4584248A2 EP23864037.9A EP23864037A EP4584248A2 EP 4584248 A2 EP4584248 A2 EP 4584248A2 EP 23864037 A EP23864037 A EP 23864037A EP 4584248 A2 EP4584248 A2 EP 4584248A2
Authority
EP
European Patent Office
Prior art keywords
iodide
crystalline
hydrogenoxalate
dpt
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP23864037.9A
Other languages
German (de)
English (en)
Inventor
Andrew R. Chadeayne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Caamtech Inc
Original Assignee
Caamtech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Caamtech Inc filed Critical Caamtech Inc
Publication of EP4584248A2 publication Critical patent/EP4584248A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C07C55/07—Salts thereof

Definitions

  • This disclosure relates to [2-(l-methyl-lH-indol-3-yl)ethyl]dipropylazanium iodide (1-methyl- M,A/-di-n-propyltryptammonium iodide or 1-Me-DPT iodide), crystalline 1-Me-DPT iodide, and specific crystalline forms thereof, including crystalline form 1 of 1-Me-DPT iodide; to pharmaceutical compositions containing 1-Me-DPT iodide or crystalline 1-Me-DPT iodide, including crystalline form 1 of 1-Me-DPT iodide; and to methods of treatment/therapeutic uses of 1-Me-DPT iodide or crystalline 1-Me-DPT iodide, including crystalline form 1 of 1-Me-DPT iodide.
  • This disclosure further relates to 2-(2-methyl-lH-indol-3-yl)ethan-l-aminium hydrogen oxalate (2-methyltryptammonium hydrogenoxalate or 2-Me-T hydrogenoxalate), crystalline 2-Me-T hydrogenoxalate, and specific crystalline forms thereof, including crystalline form 1 of 2-Me-T hydrogenoxalate; to pharmaceutical compositions containing 2-Me-T hydrogenoxalate or crystalline 2-Me-T hydrogenoxalate, including crystalline form 1 of 2-Me-T hydrogenoxalate; and to methods of treatment/therapeutic uses of 2-Me-T hydrogenoxalate or crystalline 2-Me-T hydrogenoxalate, including crystalline form 1 of 2-Me-T hydrogenoxalate.
  • an active pharmaceutical ingredient 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.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2- Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate, 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogen oxa I ate, and to administering a pharmaceutical composition or a composition according to the invention.
  • a mitogen- activated protein kinase MAPK
  • 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.
  • FIG. 1 shows the molecular structure of crystalline form 1 of l-methyl-A/,A/-di-n- propyltryptammonium iodide.
  • FIG. 5 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of l-methyl-/V,/V-di-n-propyltryptammonium iodide.
  • FIG. 6 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 2-methyltryptammonium hydrogenoxalate.
  • 2-Me-T hydrogenoxalate or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate.
  • a brain disorder e.g., Huntington's disease, Alzheimer's disease, dementia, and Parkinson's disease
  • 2-Me-T hydrogenoxalate or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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 an inflammation and/or pain by administering to a subject in need thereof a therapeutically effective amount of 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate of the disclosure, including the exemplary embodiments discussed herein.
  • treatable "pain” includes nociceptive, neuropathic, and mix-type.
  • 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-T hydrogenoxalate or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate of the disclosure may be used to modulate activity of a mitogen-activated protein kinase (MAPK), comprising administering a composition of the invention.
  • 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).
  • 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-T hydrogenoxalate or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate of the disclosure may be used to modulate neurogenesis, comprising administering a composition of the invention.
  • 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.
  • 2-Me-T hydrogenoxalate or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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.
  • 2-Me-T hydrogenoxalate or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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.
  • 2-Me-T hydrogenoxalate or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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.
  • 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 1-Me-
  • DPT iodide crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate and an excipient (e.g., a pharmaceutically- acceptable excipient).
  • an excipient e.g., a pharmaceutically- acceptable excipient
  • 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2- Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate.
  • 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate of the disclosure and, for example, 99% to 1% by weight of at least one suitable pharmaceutically acceptable excipient.
  • this disclosure provides a composition
  • a composition comprising: a first component comprising 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2- Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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 amounts or by combination in a therapeutically effective amount to treat a disease, disorder, or condition as described herein.
  • compositions having as a first component 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline
  • 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-
  • the term “purified” refers to a compound that is between 90-
  • the term “purified” refers to a compound that is between 95-
  • the term “purified” refers to a compound that is between 99-
  • 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 (e.g., via an allosteric reaction) activity at a serotonin receptor as described in paragraphs [0245]-[0253] of US 2018/0221396 Al and [0305]-[0311] US 2019/0142851 Al as well as the disclosed exemplary embodiments.
  • 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 [01 ll]-[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.
  • l-Me-DPT iodide, crystalline l-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of l-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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 l-Me-DPT iodide, crystalline l-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of l-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me- T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate of the disclosure and a serotonergic drug, a purified psilocybin derivative, a purified cannabinoid, or a purified terpene, each present in a therapeutically effective amount using purposefully engineered and unnaturally occurring molar ratios.
  • 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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) 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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, disorder, or condition as described herein.
  • a serotonergic drug refers to a compound that binds to, blocks, or otherwise influences (e.g., via an allosteric reaction) activity at a serotonin receptor as described in paragraphs [0245]-[0253] of US 2018/0221396 Al and [0305]-[0311] US 2019/0142851 Al as well as the disclosed exemplary embodiments.
  • Some exemplary serotonergic drugs include SSRIs and SNRIs.
  • serotonergic drugs include the following molecules, including any salts, solvates, or polymorphs thereof: 6-a Ilyl-N, N-diethyl-N L; 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-
  • 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
  • a 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.,
  • compositions of 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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.
  • 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogenoxalate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate 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 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate of the disclosure, or produce undesirable biological effects or otherwise interact in a deleterious manner with any other component(s) of the pharmaceutical composition.
  • 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 of 1-Me-DPT iodide, crystalline 1-Me-DPT iodide, 2-Me-T hydrogenoxalate, crystalline 2-Me-T hydrogen oxa I ate, or specific crystalline forms thereof, such as crystalline form 1 of 1-Me-DPT iodide, and crystalline form 1 of 2-Me-T hydrogenoxalate of the disclosure in pure form or in an appropriate pharmaceutical composition may be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration may be, for example, orally, buccally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, or intrasystemically, in the form of solid, semi-solid, 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 l-methyl-A/,A/-di-n-propyltryptammonium iodide according to El and an excipient.
  • a composition comprising l-methyl-A/,/V-di-n-propyltryptammonium 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 l-methyl-A/,A/-di-n-propyltryptammonium 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 crystalline 1- methyl-/V,M-di-n-propyltryptammonium 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.
  • 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.
  • E17 Crystalline 2-(2-methyl-lH-indol-3-yl)ethan-l-aminium hydrogen oxalate (2- methyltryptammonium hydrogenoxalate).
  • E20 A composition comprising crystalline 2-methyltryptammonium hydrogenoxalate according to any one of E17-E19 and an excipient.
  • 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 2- methyltryptammonium hydrogenoxalate according to any one of E17-E19.
  • FIG. 1 shows the molecular structure of crystalline form 1 of 1-Me-DPT iodide, showing the atomic labeling.
  • FIG. 3 shows the unit cell of crystalline form 1 of 1-Me-DPT iodide along the c-axis.

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Abstract

La présente invention concerne de l'iodure de [2-(1-méthyl-1H-indol-3-yl)éthyl]dipropylazanium (iodure de 1-méthyl-/V,/V-di-n-propyltryptammonium ou iodure de 1-Me-DPT), de l'iodure de 1-Me-DPT cristallin, de l'oxalate de 2-(2-méthyl-1H-indol-3-yl)éthan-1-aminium (hydrogénooxalate de 2-méthyltryptammonium ou hydrogénooxalate de 2-Me-T), de l'oxalate de 2-Me-T cristallin, et des formes cristallines spécifiques de celui-ci, y compris la forme cristalline 1 d'iodure de 1-Me-DPT, et la forme cristalline 1 d'oxalate de 2-Me-T-T-hydrogénoxalate ; des compositions les contenant ; et des procédés de traitement les utilisant.
EP23864037.9A 2022-09-08 2023-09-08 Dérivés de tryptamine Withdrawn EP4584248A2 (fr)

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