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WO2024097944A2 - Tryptamine derivatives - Google Patents

Tryptamine derivatives Download PDF

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Publication number
WO2024097944A2
WO2024097944A2 PCT/US2023/078615 US2023078615W WO2024097944A2 WO 2024097944 A2 WO2024097944 A2 WO 2024097944A2 US 2023078615 W US2023078615 W US 2023078615W WO 2024097944 A2 WO2024097944 A2 WO 2024097944A2
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Prior art keywords
chloride
dpt
crystalline
crystalline form
purified
Prior art date
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Ceased
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PCT/US2023/078615
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French (fr)
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WO2024097944A3 (en
Inventor
Andrew R. Chadeayne
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Caamtech Inc
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Caamtech Inc
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Publication of WO2024097944A2 publication Critical patent/WO2024097944A2/en
Publication of WO2024097944A3 publication Critical patent/WO2024097944A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/395—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

Definitions

  • This disclosure relates to ⁇ 2-[4-(methanesulfonyloxy)-lH-indol-3-yl]ethyl ⁇ dipropylazanium chloride (4-(methylsulfonyloxy)-/V,A/-di-n-propyltryptammonium chloride or 4-(methylsulfonyloxy)- DPT chloride), crystalline 4-(methylsulfonyloxy)-DPT chloride, and specific crystalline forms thereof, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride; to pharmaceutical compositions containing 4-(methylsulfonyloxy)-DPT chloride or crystalline 4-(methylsulfonyloxy)-DPT chloride, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride; and to methods of treatment/therapeutic uses of 4-(methylsulfonyloxy)-DPT chloride or crystalline 4- (methylsulfony
  • This disclosure further relates to dipropyl(2- ⁇ 4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3- yl ⁇ ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-A/,/V-di-n-propyltryptammonium chloride or 4-(4-trifluoromethylbenzoyloxy)-DPT chloride), crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, and specific crystalline forms thereof, including crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride; to pharmaceutical compositions containing 4-(4- trifluoromethylbenzoyloxy)-DPT chloride or crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride; and
  • This disclosure further relates to ⁇ 2-[4-(4-fluorobenzoyloxy)-lH-indol-3- yl]ethyl ⁇ dipropylazanium chloride (4-(4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride or 4-(4-fluorobenzoyloxy)-DPT chloride), crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, and specific crystalline forms thereof, including crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride; to pharmaceutical compositions containing 4-(4-fluorobenzoyloxy)-DPT chloride or crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride; and to methods of treatment/therapeutic uses of 4-(4-fluorobenzoyloxy)-DPT chlor
  • This disclosure further relates to (2- ⁇ 4-[(2,2-dimethylpropanoyl)oxy]-lH-indol-3 yl ⁇ ethyl)dipropylazanium chloride (4-pivaloyloxy-/V,A/-di-n-propyltryptammonium chloride or 4-PivO- DPT chloride), crystalline 4-PivO-DPT chloride, and specific crystalline forms thereof, including crystalline form 1 of 4-PivO-DPT chloride; to pharmaceutical compositions containing 4-PivO-DPT chloride or crystalline 4-PivO-DPT chloride, including crystalline form 1 of 4-PivO-DPT chloride; and to methods of treatment/therapeutic uses of 4-PivO-DPT chloride or crystalline 4-PivO-DPT chloride, including crystalline form 1 of 4-PivO-DPT chloride.
  • This disclosure further relates to dimethyl( ⁇ 2-[4-(propanoyloxy)-lH-indol-3-yl]ethyl ⁇ )azanium (2E)-3-carboxyprop-2-enoate (4-propanoyloxy-/V,A/-dimethyltryptammonium hydrofumarate or 4- Pro-DMT hydrofumarate), crystalline 4-Pro-DMT hydrofumarate, and specific crystalline forms thereof, including crystalline form 1 of 4-Pro-DMT hydrofumarate; to pharmaceutical compositions containing 4-Pro-DMT hydrofumarate or crystalline 4-Pro-DMT hydrofumarate, including crystalline form 1 of 4-Pro-DMT hydrofumarate; and to methods of treatment/therapeutic uses of 4-Pro-DMT hydrofumarate or crystalline 4-Pro-DMT hydrofumarate, including crystalline form 1 of 4-Pro-DMT hydrofumarate.
  • This disclosure further relates to (2- ⁇ 4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3- yl ⁇ ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n- propyltryptammonium chloride hydrate or 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate), crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and specific crystalline forms thereof, including crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate; to pharmaceutical compositions containing 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate or crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT
  • 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 ⁇ 2-[4-(methanesulfonyloxy)-lH-indol-3-yl]ethyl ⁇ dipropylazanium chloride (4-(methylsulfonyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(methylsulfonyloxy)- DPT chloride), crystalline 4-(methylsulfonyloxy)-DPT chloride, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of 4-(methylsulfonyloxy)- DPT chloride, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride.
  • XRPD X-ray powder diffraction
  • This disclosure further relates to dipropyl(2- ⁇ 4-[4-(trifluoromethyl)benzoyloxy]-lH- indol-3-yl ⁇ ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-N,N-di-n-propyltryptam monium chloride or 4-(4-trifluoromethylbenzoyloxy)-DPT chloride), crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride.
  • XRPD X-ray powder diffraction
  • This disclosure further relates to ⁇ 2-[4-(4-fluorobenzoyloxy)-lH-indol-3- yl]ethyl ⁇ dipropylazanium chloride (4-(4-fluorobenzoyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(4-fluorobenzoyloxy)-DPT chloride), crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of 4-(4-fluorobenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride.
  • XRPD X-ray powder diffraction
  • This disclosure further relates to (2- ⁇ 4-[(2,2-dimethylpropanoyl)oxy]-lH-indol-3 yl ⁇ ethyl)dipropylazanium chloride (4-pivaloyloxy-N,N-di-n-propyltryptammonium chloride or 4-PivO- DPT chloride), crystalline 4-PivO-DPT chloride, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of 4-PivO-DPT chloride, including crystalline form 1 of 4-PivO-DPT chloride.
  • XRPD X-ray powder diffraction
  • This disclosure further relates to dimethyl( ⁇ 2-[4-(propanoyloxy)-lH-indol-3- yl]ethyl ⁇ )azanium (2E)-3-carboxyprop-2-enoate (4-propanoyloxy-A/,A/-dimethyltryptammonium hydrofumarate or 4-Pro-DMT hydrofumarate), crystalline 4-Pro-DMT hydrofumarate, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of 4-Pro-DMT hydrofumarate, including crystalline form 1 of 4-Pro-DMT hydrofumarate.
  • XRPD X-ray powder diffraction
  • This disclosure further relates to (2- ⁇ 4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3- yl ⁇ ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n- propyltryptammonium chloride hydrate or 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate), crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and specific crystalline forms thereof.
  • this disclosure pertains to particular crystalline forms of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, including crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate.
  • XRPD X-ray powder diffraction
  • the disclosure further relates to a composition comprising 4-(methylsulfonyloxy)-
  • DPT chloride crystalline 4-(methylsulfonyloxy)-DPT chloride, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, and at least one excipient.
  • the disclosure further relates to a composition
  • a composition comprising 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, or specific crystalline forms thereof, such as crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, and at least one excipient.
  • the disclosure further relates to a composition comprising 4-(4-fluorobenzoyloxy)-
  • DPT chloride crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, or specific crystalline forms thereof, such as crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, and at least one excipient.
  • the disclosure further relates to a composition
  • a composition comprising 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, or specific crystalline forms thereof, such as crystalline form 1 of 4- PivO-DPT chloride, and at least one excipient.
  • the disclosure further relates to a composition
  • a composition comprising 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, or specific crystalline forms thereof, such as crystalline form 1 of 4-Pro-DMT hydrofumarate, and at least one excipient.
  • the disclosure further relates to a composition
  • a composition comprising 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-[ (4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and at least one excipient.
  • the disclosure also provides a composition comprising 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4- (methylsulfon)-D
  • 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT
  • 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofuma
  • 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 4-(methylsulfonyloxy)-
  • FIG. 2 shows the molecular structure of crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-N,N-di-n-propyltryptammonium chloride.
  • FIG. 3 shows the molecular structure of crystalline form 1 of 4-(4-fluorobenzoyloxy)-
  • FIG. 4 shows the molecular structure of crystalline form 1 of 4-pivaloyloxy-N,N-di-n- propyltryptammonium chloride.
  • FIG. 5 shows the molecular structure of crystalline form 1 of 4-propanoyloxy-/V,/V- dimethyltryptammonium hydrofumarate.
  • FIG. 6 shows the molecular structure of crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate.
  • FIG. 7 shows the unit cell of crystalline form 1 of 4-(methylsulfonyloxy)-N,N-di-n- propyltryptammonium chloride along the a-axis.
  • FIG. 8 shows the unit cell of crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-
  • N,N-di-n-propyltryptammonium chloride along the b-axis.
  • FIG. 9 shows the unit cell of crystalline form 1 of 4-(4-fluorobenzoyloxy)-N,N-di-n- propyltryptammonium chloride along the b-axis.
  • FIG. 10 shows the unit cell of crystalline form 1 of 4-pivaloyloxy-N,N-di-n- propyltryptammonium chloride along the a-axis.
  • FIG. 11 shows the unit cell of crystalline form 1 of 4-propanoyloxy-A/,/V- dimethyltryptammonium hydrofumarate along the b-axis.
  • FIG. 12 shows the unit cell of crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-
  • N,N-di-n-propyltryptammonium chloride hydrate along the a-axis.
  • FIG. 13 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(methylsulfonyloxy)-N,N-di-n-propyltryptammonium chloride.
  • FIG. 14 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-N,N-di-n-propyltryptammonium chloride.
  • FIG. 15 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(4-fluorobenzoyloxy)-N,N-di-n-propyltryptammonium chloride.
  • FIG. 16 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-pivaloyloxy-N,N-di-n-propyltryptammonium chloride.
  • FIG. 17 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-propanoyloxy-A/,/V-dimethyltryptammonium hydrofumarate.
  • FIG. 18 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate.
  • This disclosure relates to ⁇ 2-[4-(methanesulfonyloxy)-lH-indol-3- yl]ethyl ⁇ dipropylazanium chloride (4-(methylsulfonyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(methylsulfonyloxy)-DPT chloride), crystalline 4-(methylsulfonyloxy)-DPT chloride, dipropyl(2- ⁇ 4-[4- (trifluoromethyl)benzoyloxy]-lH-indol-3-yl ⁇ ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)- N,N-di-n-propyltryptammonium chloride or 4-(4-trifluoromethylbenzoyloxy)-DPT chloride), crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride,
  • 4-PivO-DPT chloride has the following chemical formula:
  • 4-Pro-DMT hydrofumarate has the following chemical formula:
  • Methods of the disclosure also relate to the administration of a therapeutically effective amount of 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form
  • 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4- (methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate,
  • 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
  • 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-
  • 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4- (methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific
  • 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]- DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride
  • 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.
  • 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. In the central nervous
  • 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.
  • 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.
  • 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.
  • compositions comprising an effective amount of 4-
  • the disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form
  • a composition or a pharmaceutical composition of the disclosure may be in any form which contains 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of
  • the composition may be, for example, a tablet, capsule, liquid suspension, injectable, topical, or transdermal.
  • the compositions generally contain, for example, about 1% to about 99% by weight of 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)s
  • the composition may be between about 5% and about 75% by weight of 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-
  • 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.
  • this disclosure provides a composition
  • a composition comprising: a first component comprising 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1
  • compositions having as a first component 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)
  • 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.
  • a pharmaceutical formulation of the disclosure may comprise, consist essentially of, or consist of (a) 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline
  • a pharmaceutical formulation of the disclosure may comprise a composition containing 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methyl)-methyl
  • 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.
  • the disclosure provides a pharmaceutical formulation comprising as (a) 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[
  • 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
  • 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, 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-yl
  • 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.
  • 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 0- carboline, pinoline, harmane, harmine, harmaline, harmalol, tetrahydroharmine, 9-methyl-0- 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.
  • 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.
  • 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4- (methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyl
  • 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.
  • a solid dosage form 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-D
  • 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 hydrocarbon-based 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. In such solid dosage forms, 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, intravagi na lly, 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.
  • E4 A composition comprising crystalline 4-pivaloyloxy-A/,A/-di-n- propyltryptammonium chloride according to any one of E1-E3 and an excipient.
  • E5. A composition comprising crystalline 4-pivaloyloxy-A/,/ ⁇ /-di-n- propyltryptammonium chloride according to any one of E1-E3 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.
  • E6 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 4- pivaloyloxy-A/,A/-di-n-propyltryptammonium chloride according to any one of E1-E3.
  • a method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E4 or E5.
  • 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 crystalline 4- pivaloyloxy-A/,A/-di-n-propyltryptammonium chloride according to any one of E1-E3.
  • 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 E4 or E5.
  • E13 A composition comprising crystalline 4-(methylsulfonyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of E10-E12 and an excipient.
  • E14 A composition comprising crystalline 4-(methylsulfonyloxy)-/V,/V-di-n- propyltryptammonium chloride according to any one of E10-E12 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.
  • E15 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 4- (methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E10-E12.
  • E16 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E13 or E14.
  • E17 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 4- (methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E10-E12.
  • E18 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 E13 or E14.
  • E20 Crystalline dipropyl(2- ⁇ 4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3- yl ⁇ ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-A/,/V-di-n-propyltryptammonium chloride).
  • E21 Crystalline form 1 of dipropyl(2- ⁇ 4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3- yl ⁇ ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride).
  • E23 A composition comprising 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to E19 and an excipient.
  • E24 A composition comprising crystalline 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of E20-E22 and an excipient.
  • a composition comprising 4-(4-trifluoromethylbenzoyloxy)-A/,/V-di-n- propyltryptammonium chloride according to 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.
  • E26 A composition comprising crystalline 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of E20-E22 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.
  • E27 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 4-(4- trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to E19.
  • E28 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 4- (4-trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E20- E22.
  • E29 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E23 or E25.
  • E30 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E24 or E26.
  • E31 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 4-(4- trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to E19.
  • E32 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 4- (4-trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E20- E22.
  • E33 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 E23 or E25.
  • 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 E24 or E26.
  • E36 Crystalline form 1 of ⁇ 2-[4-(4-fluorobenzoyloxy)-lH-indol-3- yl]ethyl ⁇ dipropylazanium chloride (4-(4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride). [00142] E37.
  • E38 A composition comprising crystalline 4-(4-fluorobenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of E35-E37 and an excipient. [00144] E39.
  • a composition comprising crystalline 4-(4-fluorobenzoyloxy)-/V,/V-di-n- propyltryptammonium chloride according to any one of E35-E37 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.
  • E40 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 4- (4-fluorobenzoyloxy)-/V,A/-di-n-propyltryptammonium chloride according to any one of E35-E37.
  • E41 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E38 or E39.
  • E42 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 4- (4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E35-E37.
  • E43 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 E38 or E39.
  • E45 Crystalline form 1 of dimethyl( ⁇ 2-[4-(propanoyloxy)-lH-indol-3- yl]ethyl ⁇ )azanium (2E)-3-carboxyprop-2-enoate (4-propanoyloxy-A/,A/-dimethyltryptammonium hydrofumarate).
  • E47 A composition comprising crystalline 4-propanoyloxy-A/,/V- dimethyltryptammonium hydrofumarate according to any one of E44-E46 and an excipient.
  • E48 A composition comprising crystalline 4-propanoyloxy-A/,/V- dimethyltryptammonium hydrofumarate according to any one of E44-E46 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.
  • E49 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 4- propanoyloxy-/V,/V-dimethyltryptammonium hydrofumarate according to any one of E44-E46.
  • E50 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E47 or E48.
  • E51 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 4- propanoyloxy-/V,/V-dimethyltryptammonium hydrofumarate according to any one of E44-E46.
  • E52 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 E47 or E48.
  • E53 (2- ⁇ 4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3-yl ⁇ ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate). [00159] E54.
  • E58 A composition comprising crystalline 4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n- propyltryptammonium chloride hydrate according to any one of E54-E56 and an excipient.
  • a composition comprising 4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n- propyltryptammonium chloride hydrate according to E53 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.
  • E60 A composition comprising crystalline 4-[(4-nitrophenyl)sulfonyloxy]-M,A/-di-n- propyltryptammonium chloride hydrate according to any one of E54-E56 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.
  • E61 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 4-[(4- nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate according to E53.
  • E62 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 4- [(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n-propyltryptammonium chloride hydrate according to any one of E54-E56.
  • E63 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E57 or E59.
  • E64 A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E58 or E60.
  • E65 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 4-[(4- nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate according to E53.
  • E66 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 4- [(4-nitrophenyl)sulfonyloxy]-A/,/V-di-n-propyltryptammonium chloride hydrate according to any one of E54-E56.
  • E67 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 E57 or E59.
  • E68 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 E58 or E60.
  • Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by methanesulfonyl chloride (1.5 equiv.) in a dropwise manner.
  • the resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (per TLC). The typical reaction times were between 1.5 to 2h.
  • the reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine.
  • Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by 4-(trifluoromethyl)benzoyl chloride (1.5 equiv.) in a dropwise manner.
  • the resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (per TLC). The typical reaction times were between 1.5 to 2h.
  • the reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine.
  • Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by 4-fluorobenzoyl chloride (1.5 equiv.) in a dropwise manner.
  • the resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (per TLC). The typical reaction times were between 1.5 to 2h.
  • the reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine.
  • Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by pivaloyl chloride (1.5 equiv.) in a dropwise manner.
  • the resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (perTLC). The typical reaction times were between 1.5 to 2h.
  • the reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine.
  • Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by 4-nitrobenzenesulfonyl chloride (1.5 equiv.) in a dropwise manner.
  • the resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (per TLC). The typical reaction times were between 1.5 to 2h.
  • the reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine.
  • FIG. 1 shows the molecular structure of crystalline form 1 of 4-(methylsulfonyloxy)- DPT chloride, showing the atomic labeling.
  • FIG. 2 shows the molecular structure of crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, showing the atomic labeling.
  • FIG. 3 shows the molecular structure of crystalline form 1 of 4-(4-fluorobenzoyloxy)- DPT chloride, showing the atomic labeling.
  • FIG. 4 shows the molecular structure of crystalline form 1 of 4-PivO-DPT chloride, showing the atomic labeling.
  • FIG. 5 shows the molecular structure of crystalline form 1 of 4-Pro-DMT hydrofumarate, showing the atomic labeling.
  • FIG. 6 shows the molecular structure of crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, showing the atomic labeling.
  • FIG. 7 shows the unit cell of crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride along the a-axis.
  • FIG. 8 shows the unit cell of crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)- DPT chloride along the b-axis.
  • FIG. 9 shows the unit cell of crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride along the b-axis.
  • FIG. 10 shows the unit cell of crystalline form 1 of 4-PivO-DPT chloride along the a- axis.
  • FIG. 11 shows the unit cell of crystalline form 1 of 4-Pro-DMT hydrofumarate along the b-axis.
  • FIG. 12 shows the unit cell of crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate along the a-axis.
  • FIG. 13 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride 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. 13. 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 7.6,
  • FIG. 14 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride 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. 14. 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 7.6, 9.8, and 10.8 °20 ⁇ O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 14.
  • FIG. 15 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride generated from its single crystal data.
  • Table 6 lists the angles, °20 ⁇ O.2°20, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 15. 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 7.4,
  • FIG. 16 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-PivO-DPT chloride generated from its single crystal data.
  • Table 7 lists the angles, °20 ⁇ O.2°20, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 16. 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 6.8, 8.1, and 10.1 °20 ⁇ O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 16.
  • FIG. 17 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-Pro-DMT hydrofumarate generated from its single crystal data.
  • Table 8 lists the angles, °20 ⁇ 0.2°26, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 17. 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 9.8, 15.8, and 18.6 °20 ⁇ O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 17.
  • FIG. 18 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate generated from its single crystal data.
  • Table 9 lists the angles, °20 ⁇ O.2°20, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 18. 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 14.3, 17.1, and 20.6 °20 ⁇ 0.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 18.

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Abstract

This disclosure relates to {2-[4-(methanesulfonyloxy)-1H-indol-3-yl]ethyl}dipropylazanium chloride (4-(methylsulfonyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(methylsulfonyloxy)-DPT chloride), crystalline 4-(methylsulfonyloxy)-DPT chloride, dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-1H-indol-3-yl}ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)- N,N-di-n-propyltryptammonium chloride or 4-(4-trifluoromethylbenzoyloxy)-DPT chloride), crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, {2-[4-(4-fluorobenzoyloxy)-1H-indol-3-yl]ethyl}dipropylazanium chloride (4-(4-fluorobenzoyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(4-fluorobenzoyloxy)-DPT chloride), crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, (2-{4-[(2,2-dimethylpropanoyl)oxy]-1H-indol-3 yl}ethyl)dipropylazanium chloride (4-pivaloyloxy-N,N-di-n-propyltryptammonium chloride or 4-PivO-DPT chloride), crystalline 4-PivO-DPT chloride,dimethyl({2-[4-(propanoyloxy)-1H-indol-3-yl]ethyl})azanium (2E)-3-carboxyprop-2-enoate (4-propanoyloxy-N,N-dimethyltryptammonium hydrofumarate or 4-Pro-DMT hydrofumarate), crystalline 4-Pro-DMT hydrofumarate, (2-{4-[(4-nitrobenzenesulfonyl)oxy]-1H-indol-3-yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate or 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate), crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and specific crystalline forms thereof, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate; to compositions containing the same; and to methods of treatment using them.

Description

TRYPTAMINE DERIVATIVES
Cross-Reference to Related Applications
[001] This application claims priority to U.S. Provisional Application No. 63/422,582, filed on November 4, 2022; U.S. Provisional Application No. 63/383,716, filed on November 15, 2022; U.S. Provisional Application No. 63/383,717, filed on November 15, 2022; U.S. Provisional Application No. 63/383,718, filed on November 15, 2022; U.S. Provisional Application No. 63/383,719, filed on November 15, 2022; and U.S. Provisional Application No. 63/383,720, filed on November 15, 2022; the disclosures of which are each incorporated herein by reference.
Technical Field
[002] This disclosure relates to {2-[4-(methanesulfonyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4-(methylsulfonyloxy)-/V,A/-di-n-propyltryptammonium chloride or 4-(methylsulfonyloxy)- DPT chloride), crystalline 4-(methylsulfonyloxy)-DPT chloride, and specific crystalline forms thereof, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride; to pharmaceutical compositions containing 4-(methylsulfonyloxy)-DPT chloride or crystalline 4-(methylsulfonyloxy)-DPT chloride, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride; and to methods of treatment/therapeutic uses of 4-(methylsulfonyloxy)-DPT chloride or crystalline 4- (methylsulfonyloxy)-DPT chloride, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride. [003] This disclosure further relates to dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3- yl}ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-A/,/V-di-n-propyltryptammonium chloride or 4-(4-trifluoromethylbenzoyloxy)-DPT chloride), crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, and specific crystalline forms thereof, including crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride; to pharmaceutical compositions containing 4-(4- trifluoromethylbenzoyloxy)-DPT chloride or crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride; and to methods of treatment/therapeutic uses of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride or crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride.
[004] This disclosure further relates to {2-[4-(4-fluorobenzoyloxy)-lH-indol-3- yl]ethyl}dipropylazanium chloride (4-(4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride or 4-(4-fluorobenzoyloxy)-DPT chloride), crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, and specific crystalline forms thereof, including crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride; to pharmaceutical compositions containing 4-(4-fluorobenzoyloxy)-DPT chloride or crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride; and to methods of treatment/therapeutic uses of 4-(4-fluorobenzoyloxy)-DPT chloride or crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride.
[005] This disclosure further relates to (2-{4-[(2,2-dimethylpropanoyl)oxy]-lH-indol-3 yl}ethyl)dipropylazanium chloride (4-pivaloyloxy-/V,A/-di-n-propyltryptammonium chloride or 4-PivO- DPT chloride), crystalline 4-PivO-DPT chloride, and specific crystalline forms thereof, including crystalline form 1 of 4-PivO-DPT chloride; to pharmaceutical compositions containing 4-PivO-DPT chloride or crystalline 4-PivO-DPT chloride, including crystalline form 1 of 4-PivO-DPT chloride; and to methods of treatment/therapeutic uses of 4-PivO-DPT chloride or crystalline 4-PivO-DPT chloride, including crystalline form 1 of 4-PivO-DPT chloride.
[006] This disclosure further relates to dimethyl({2-[4-(propanoyloxy)-lH-indol-3-yl]ethyl})azanium (2E)-3-carboxyprop-2-enoate (4-propanoyloxy-/V,A/-dimethyltryptammonium hydrofumarate or 4- Pro-DMT hydrofumarate), crystalline 4-Pro-DMT hydrofumarate, and specific crystalline forms thereof, including crystalline form 1 of 4-Pro-DMT hydrofumarate; to pharmaceutical compositions containing 4-Pro-DMT hydrofumarate or crystalline 4-Pro-DMT hydrofumarate, including crystalline form 1 of 4-Pro-DMT hydrofumarate; and to methods of treatment/therapeutic uses of 4-Pro-DMT hydrofumarate or crystalline 4-Pro-DMT hydrofumarate, including crystalline form 1 of 4-Pro-DMT hydrofumarate.
[007] This disclosure further relates to (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3- yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n- propyltryptammonium chloride hydrate or 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate), crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and specific crystalline forms thereof, including crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate; to pharmaceutical compositions containing 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate or crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, including crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate; and to methods of treatment/therapeutic uses of 4- [(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate or crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, including crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate.
Background of the Invention
[008] 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. This is important because the API's molecular weight is used to calculate the concentration of compositions comprising that API. Thus, 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.
Summary of the Invention
[009] This disclosure relates to {2-[4-(methanesulfonyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4-(methylsulfonyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(methylsulfonyloxy)- DPT chloride), crystalline 4-(methylsulfonyloxy)-DPT chloride, and specific crystalline forms thereof. In one embodiment, this disclosure pertains to particular crystalline forms of 4-(methylsulfonyloxy)- DPT chloride, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride. In one embodiment, crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride is characterized by at least one of: a monoclinic, P2i/c space group at a temperature of about 297(2) K; unit cell dimensions a = 9.5556(9) A, b = 8.7264(7) A, c = 23.485(2) A, a = 90°, 0 = 99.337(3)°, and y = 90°; an X-ray powder diffraction (XRPD) pattern substantially similar to FIG. 13; and an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.6, 9.4, and 11.1 °20 ± 0.2 °20.
[0010] This disclosure further relates to dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH- indol-3-yl}ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-N,N-di-n-propyltryptam monium chloride or 4-(4-trifluoromethylbenzoyloxy)-DPT chloride), crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, and specific crystalline forms thereof. In one embodiment, this disclosure pertains to particular crystalline forms of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride. In one embodiment, crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride is characterized by at least one of: a monoclinic, C2/c space group at a temperature of about 297(2) K; unit cell dimensions a = 23.438(3) A, b = 12.5821(16) A, c = 16.449(2) A, a = 90°, 0 = 94.071(4)°, and y = 90°; an X-ray powder diffraction (XRPD) pattern substantially similar to FIG. 14; and an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.6, 9.8, and 10.8 °20 ± 0.2 °20. [0011] This disclosure further relates to {2-[4-(4-fluorobenzoyloxy)-lH-indol-3- yl]ethyl}dipropylazanium chloride (4-(4-fluorobenzoyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(4-fluorobenzoyloxy)-DPT chloride), crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, and specific crystalline forms thereof. In one embodiment, this disclosure pertains to particular crystalline forms of 4-(4-fluorobenzoyloxy)-DPT chloride, including crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride. In one embodiment, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride is characterized by at least one of: a monoclinic, C2/c space group at a temperature of about 297(2) K; unit cell dimensions a = 23.9959(18) A, b = 11.5242(8) A, c = 16.3685(13) A, a = 90°, 0 = 97.197(3)°, and y = 90°; an X-ray powder diffraction (XRPD) pattern substantially similar to FIG. 15; and an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.4, 10.4, and 20.2 °20 ± 0.2 °20.
[0012] This disclosure further relates to (2-{4-[(2,2-dimethylpropanoyl)oxy]-lH-indol-3 yl}ethyl)dipropylazanium chloride (4-pivaloyloxy-N,N-di-n-propyltryptammonium chloride or 4-PivO- DPT chloride), crystalline 4-PivO-DPT chloride, and specific crystalline forms thereof. In one embodiment, this disclosure pertains to particular crystalline forms of 4-PivO-DPT chloride, including crystalline form 1 of 4-PivO-DPT chloride. In one embodiment, crystalline form 1 of 4-PivO-DPT chloride is characterized by at least one of: a triclinic, Pl space group at a temperature of about 297(2) K; unit cell dimensions a = 7.6697(5) A, b = 11.1491(8) A, c = 13.1430(9) A, a = 83.007(2)°, 0 = 82.786(2)°, and y = 77.733(2)°; an X-ray powder diffraction (XRPD) pattern substantially similar to FIG. 16; and an X-ray powder diffraction pattern characterized by at least two peaks selected from 6.8, 8.1, and 10.1 °20 ± 0.2 °20.
[0013] This disclosure further relates to dimethyl({2-[4-(propanoyloxy)-lH-indol-3- yl]ethyl})azanium (2E)-3-carboxyprop-2-enoate (4-propanoyloxy-A/,A/-dimethyltryptammonium hydrofumarate or 4-Pro-DMT hydrofumarate), crystalline 4-Pro-DMT hydrofumarate, and specific crystalline forms thereof. In one embodiment, this disclosure pertains to particular crystalline forms of 4-Pro-DMT hydrofumarate, including crystalline form 1 of 4-Pro-DMT hydrofumarate. In one embodiment, crystalline form 1 of 4-Pro-DMT hydrofumarate is characterized by at least one of: a monoclinic, P2i/n space group at a temperature of about 297(2) K; unit cell dimensions a = 11.7169(19) A, b = 11.4642(16) A, c = 15.287(2) A, a = 90°, 0 = 107.076(5)°, and y = 90°; an X-ray powder diffraction (XRPD) pattern substantially similar to FIG. 17; and an X-ray powder diffraction pattern characterized by at least two peaks selected from 9.8, 15.8, and 18.6 °20 ± 0.2 °20.
[0014] This disclosure further relates to (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3- yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n- propyltryptammonium chloride hydrate or 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate), crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and specific crystalline forms thereof. In one embodiment, this disclosure pertains to particular crystalline forms of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, including crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate. In one embodiment, crystalline form 1 of 4-[ (4- nitrophenyljsu lfonyloxy]-DPT chloride hydrate is characterized by at least one of: a triclinic, Pl space group at a temperature of about 297(2) K; unit cell dimensions a - 7.4130(10) A, b = 8.3525(12) A, c = 20.183(3) A, a = 100.340(5)°, 0 = 95.403(5)°, and y = 90.495(5)°; an X-ray powder diffraction (XRPD) pattern substantially similar to FIG. 18; and an X-ray powder diffraction pattern characterized by at least two peaks selected from 14.3, 17.1, and 20.6 °20 ± 0.2 °20.
[0015] The disclosure further relates to a composition comprising 4-(methylsulfonyloxy)-
DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, and at least one excipient.
[0016] The disclosure further relates to a composition comprising 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, or specific crystalline forms thereof, such as crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, and at least one excipient.
[0017] The disclosure further relates to a composition comprising 4-(4-fluorobenzoyloxy)-
DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, or specific crystalline forms thereof, such as crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, and at least one excipient.
[0018] The disclosure further relates to a composition comprising 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, or specific crystalline forms thereof, such as crystalline form 1 of 4- PivO-DPT chloride, and at least one excipient.
[0019] The disclosure further relates to a composition comprising 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, or specific crystalline forms thereof, such as crystalline form 1 of 4-Pro-DMT hydrofumarate, and at least one excipient.
[0020] The disclosure further relates to a composition comprising 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-[ (4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and at least one excipient.
[0021] The disclosure also provides a composition comprising 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4- (methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, 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; and at least one excipient.
[0022] 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or a composition according to this disclosure.
[0023] 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and to administering a pharmaceutical composition or a composition according to the invention. [0024] As used herein, the term "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.). In one embodiment, 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. In one embodiment, 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. In one embodiment, identifying a person in need of treatment comprises performing a psychiatric evaluation. In one embodiment, 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.
Description of the Figures
[0025] FIG. 1 shows the molecular structure of crystalline form 1 of 4-(methylsulfonyloxy)-
N,N-di-n-propyltryptammonium chloride.
[0026] FIG. 2 shows the molecular structure of crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-N,N-di-n-propyltryptammonium chloride.
[0027] FIG. 3 shows the molecular structure of crystalline form 1 of 4-(4-fluorobenzoyloxy)-
N,N-di-n-propyltryptammonium chloride.
[0028] FIG. 4 shows the molecular structure of crystalline form 1 of 4-pivaloyloxy-N,N-di-n- propyltryptammonium chloride.
[0029] FIG. 5 shows the molecular structure of crystalline form 1 of 4-propanoyloxy-/V,/V- dimethyltryptammonium hydrofumarate.
[0030] FIG. 6 shows the molecular structure of crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate.
[0031] FIG. 7 shows the unit cell of crystalline form 1 of 4-(methylsulfonyloxy)-N,N-di-n- propyltryptammonium chloride along the a-axis.
[0032] FIG. 8 shows the unit cell of crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-
N,N-di-n-propyltryptammonium chloride along the b-axis.
[0033] FIG. 9 shows the unit cell of crystalline form 1 of 4-(4-fluorobenzoyloxy)-N,N-di-n- propyltryptammonium chloride along the b-axis.
[0034] FIG. 10 shows the unit cell of crystalline form 1 of 4-pivaloyloxy-N,N-di-n- propyltryptammonium chloride along the a-axis. [0035] FIG. 11 shows the unit cell of crystalline form 1 of 4-propanoyloxy-A/,/V- dimethyltryptammonium hydrofumarate along the b-axis.
[0036] FIG. 12 shows the unit cell of crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-
N,N-di-n-propyltryptammonium chloride hydrate along the a-axis.
[0037] FIG. 13 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(methylsulfonyloxy)-N,N-di-n-propyltryptammonium chloride.
[0038] FIG. 14 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-N,N-di-n-propyltryptammonium chloride.
[0039] FIG. 15 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(4-fluorobenzoyloxy)-N,N-di-n-propyltryptammonium chloride.
[0040] FIG. 16 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-pivaloyloxy-N,N-di-n-propyltryptammonium chloride.
[0041] FIG. 17 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-propanoyloxy-A/,/V-dimethyltryptammonium hydrofumarate.
[0042] FIG. 18 shows the simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate.
Detailed Description
[0043] Compounds
[0044] This disclosure relates to {2-[4-(methanesulfonyloxy)-lH-indol-3- yl]ethyl}dipropylazanium chloride (4-(methylsulfonyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(methylsulfonyloxy)-DPT chloride), crystalline 4-(methylsulfonyloxy)-DPT chloride, dipropyl(2-{4-[4- (trifluoromethyl)benzoyloxy]-lH-indol-3-yl}ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)- N,N-di-n-propyltryptammonium chloride or 4-(4-trifluoromethylbenzoyloxy)-DPT chloride), crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, {2-[4-(4-fluorobenzoyloxy)-lH-indol-3- yl]ethyl}dipropylazanium chloride (4-(4-fluorobenzoyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(4-fluorobenzoyloxy)-DPT chloride), crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, (2-{4-[(2,2- dimethylpropanoyl)oxy]-lH-indol-3 yl}ethyl)dipropylazanium chloride (4-pivaloyloxy-N,N-di-n- propyltryptammonium chloride or 4-PivO-DPT chloride), crystalline 4-PivO-DPT chloride, dimethyl({2-[4-(propanoyloxy)-lH-indol-3-yl]ethyl})azanium (2E)-3-carboxyprop-2-enoate (4- propanoyloxy-/V,/V-dimethyltryptammonium hydrofumarate or 4-Pro-DMT hydrofumarate), crystalline 4-Pro-DMT hydrofumarate, (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3- yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n- propyltryptammonium chloride hydrate or 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate), crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and specific crystalline forms thereof, including crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate; to pharmaceutical compositions containing 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate according to the disclosure. The therapeutic uses of 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate according to the disclosure are described below as well as compositions containing them. 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]- DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)- DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and some exemplary methods used to characterize them are described below.
[0045] 4-(methylsulfonyloxy)-DPT chloride has the following chemical formula:
Figure imgf000012_0001
[0046] 4-(4-trifluoromethylbenzoyloxy)-DPT chloride has the following chemical formula:
Figure imgf000012_0002
[0047] 4-(4-fluorobenzoyloxy)-DPT chloride has the following chemical formula:
Figure imgf000012_0003
[0048] 4-PivO-DPT chloride has the following chemical formula:
Figure imgf000013_0001
[0049] 4-Pro-DMT hydrofumarate has the following chemical formula:
Figure imgf000013_0002
[0050] 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate has the following chemical formula:
Figure imgf000013_0003
[0051] Methods of Treatment and Therapeutic Uses
[0052] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, and specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate according to the disclosure, and the methods and the compositions (e.g., pharmaceutical compositions) are used to regulate the activity of a neurotransmitter receptor by administering a therapeutically effective dose of 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure. In one embodiment, 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4- (4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate according to the disclosure, and the methods and the compositions (e.g., pharmaceutical compositions) are used to treat inflammation and/or pain by administering a therapeutically effective dose of 4-(methylsulfonyloxy)- DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4- (methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure. [0053] Methods of the disclosure also relate to the administration of a therapeutically effective amount of 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate to prevent or treat a disease or condition, such as those discussed below for a subject in need of treatment. 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate may be administered neat or as a composition comprising 4-(methylsulfonyloxy)-DPT chloride, crystalline 4- (methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate as discussed below.
[0054] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4- (methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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).
[0055] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate.
[0056] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4- (methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate including the exemplary embodiments discussed above.
[0057] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]- DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)- DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure, including the exemplary embodiments discussed herein. Generally speaking, 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.
[0058] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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). 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. p38-alpha is involved with the regulation of pro-inflammatory cytokines, including TNF-a. In the central nervous
Y1 system, p38-alpha regulates neuronal death and neurite degeneration, and it is a common target of Alzheimer's disease therapies. 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.
[0059] As used herein, the term "modulating activity of a mitogen-activated protein kinase" refers to changing, manipulating, and/or adjusting the activity of a mitogen-activated protein kinase. In one embodiment, modulating the activity of a MAPK can influence neural health, neurogenesis, neural growth and differentiation, and neurodegenerative diseases.
[0060] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure may be used to modulate neurogenesis, comprising administering a composition of the invention. As used herein, the term "modulating neurogenesis" refers to changing, manipulating, and/or adjusting the growth and development of neural tissue. In one embodiment, neurogenesis comprises adult neurogenesis, in which new neural stem cells are generated from neural stem cells in an adult animal. In one embodiment, modulating neurogenesis comprises increasing and/or enhancing the rate at which new neural tissue is developed.
[0061] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure may be used to modulate neurite outgrowth, comprising administering a composition of the invention. As used herein, the term "modulating neurite outgrowth" refers to changing, manipulating, and/or adjusting the growth and development of neural projections, or "neurites." In one embodiment, neurogenesis comprises modulating the growth of new neurites, the number of neurites per neuron, and/or neurite length. In one embodiment, modulating neurite outgrowth comprises increasing and/or enhancing the rate and/or length at which neurites develop.
[0062] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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. In some embodiments, the disorder is a male sexual dysfunction disorder. In some embodiments, the disorder is a female sexual dysfunction disorder.
[0063] 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride,
4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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. [0064] Compositions
[0065] The disclosure also relates to compositions comprising an effective amount of 4-
(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate and an excipient (e.g., a pharmaceutically-acceptable excipient). In another embodiment, the disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate and a pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier). As discussed above, 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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.
[0066] A composition or a pharmaceutical composition of the disclosure may be in any form which contains 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate. The composition may be, for example, a tablet, capsule, liquid suspension, injectable, topical, or transdermal. The compositions generally contain, for example, about 1% to about 99% by weight of 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure and, for example, 99% to 1% by weight of at least one suitable pharmaceutically acceptable excipient. In one embodiment, the composition may be between about 5% and about 75% by weight of 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure, with the rest being at least one suitable pharmaceutically acceptable excipient or at least one other adjuvant, as discussed below.
[0067] Published US applications US 2018/0221396 Al and US 2019/0142851 Al disclose 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. According to this disclosure, 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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. Accordingly, this disclosure provides a composition comprising: a first component comprising 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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.
[0068] When used in such compositions as a first component comprising 4-
(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate according to the disclosure. In some embodiments, 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. 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.
[0069] Within the context of this disclosure, the term "purified" means separated from other materials, such as plant or fungal material, e.g., protein, chitin, cellulose, or water. In one embodiment, the term "purified" refers to a compound substantially free of other materials. In one embodiment, the term "purified" refers to a compound that is substantially free from a second tryptamine compound. In one embodiment, the term "purified" refers to a compound substantially free from histidine. In one embodiment, the term "purified" refers to a compound substantially free from a biological material, such as mold, fungus, plant matter, or bacteria. In one embodiment, the term "purified" refers to a compound substantially free from a paralytic.
[0070] In one embodiment, 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. In one embodiment, a "purified" psilocybin derivative is partially or completely isolated from other psilocybin derivatives present in a source material, such as a psilocybin-containing mushroom. In one example, "purified" baeocystin is substantially free from psilocybin and/or psilocin. By contrast, traditional psilocybin mushroom extracts (aka crude extracts or fruit body extracts) would be expected to contain an unpredictable and varying amount of psilocybin, psilocin, baeocystin, norbaeocystin, salts thereof, or combinations thereof. Other examples of 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. Similarly, the term "cannabis extracts" or "cannabinoid extracts" traditionally refers to whole plants (aka crude or full spectrum extracts) which have not been subjected to further purification to eliminate unwanted molecules that naturally occur in the cannabis plant. For example, a "cannabis extract comprising cannabidiol" could be expected to include cannabidiol (aka "CBD") and also varying amounts of other compounds, including cannabinoids, terpenes, and other biological material.
[0071] In one embodiment, the term "purified" refers to a compound or composition that has been crystallized.
[0072] In one embodiment, 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.
[0073] In one embodiment, the term "purified" refers to a compound or composition that has been distilled.
[0074] In one embodiment, the term "purified" refers to a compound or composition that has been sublimed.
[0075] In one embodiment, 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.
[0076] In one embodiment, the term "purified" refers to a compound that is between 80-
100% pure.
[0077] In one embodiment, the term "purified" refers to a compound that is between 90-
100% pure.
[0078] In one embodiment, the term "purified" refers to a compound that is between 95-
100% pure.
[0079] In one embodiment, the term "purified" refers to a compound that is between 99-
100% pure.
[0080] In one embodiment, the term "purified" refers to a compound that is between 99.9-
100% pure.
[0081] 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.
[0082] A pharmaceutical formulation of the disclosure may comprise, consist essentially of, or consist of (a) 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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) a pharmaceutically acceptable excipient. In some embodiments, 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]- DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)- DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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.
[0083] A pharmaceutical formulation of the disclosure may comprise a composition containing 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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. Published US applications US 2018/0221396 Al and US 2019/0142851 Al disclose 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. According to this disclosure composition containing 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure may be
T1 used in place of a "purified psilocybin derivative" in the compositions described in US 2018/0221396 Al and US 2019/0142851 Al. Accordingly, the disclosure provides a pharmaceutical formulation comprising as (a) 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4- PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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.
[0084] 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. Some examples of specific 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-T; N,N-dimethyl-4-hydroxy-T; N,N-dimethyl-5-hydroxy-T; N, N-dipropyl-4- hydroxy-T; N-ethyl-4-hydroxy-N-methyl-T; 4-hydroxy-N-isopropyl-N-methyl-T; 4-hydroxy-N-methyl- N-propyl-T; 4-hydroxy-N,N-tetramethylene-T; ibogaine; N,N-diethyl-L; N-butyl-N-methyl-T; N,N- diisopropyl-4,5-methylenedioxy-T; N,N-diisopropyl-5,6-methylenedioxy-T; N,N-dimethyl-4,5- methylenedioxy-T; N,N-dimethyl-5,6-methylenedioxy-T; N-isopropyl-N-methyl-5,6-methylenedioxy- T; N,N-diethyl-2-methyl-T; 2-N,N-trimethyl-T; N-acetyl-5-methoxy-T; N,N-diethyl-5-methoxy-T; N,N- diisopropyl-5-methoxy-T; 5-methoxy-N, N-dimethyl-T; N-isopropyl-4-methoxy-N-methyl-T; N- isopropyl-5-methoxy-N-methyl-T; 5,6-dimethoxy-N-isopropyl-N-methyl-T; 5-methoxy-N-methyl-T; 5- methoxy-N,N-tetramethylene-T; 6-methoxy-l-methyl-l,2,3,4-tetrahydro-C; 5-methoxy-2-N,N- trimethyl-T; N,N-dimethyl-5-methylthio-T; N-isopropyl-N-methyl-T; alpha-methyl-T; N-ethyl-T; N- methyl-T; 6-propyl-N L; N,N-tetramethylene-T; tryptamine; 7-methoxy-l-methyl-l,2,3,4-tetrahydro- C; and alpha, N-dimethyl-5-methoxy-T. For additional information regarding these compounds see Shulgin, A. T., & Shulgin, A. (2016). Tihkal: The Continuation. Berkeley, Calif.: Transform Press. In one embodiment, 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, phenethylamine, psicaine, oxazepam, reboxetine, serenic, serotonin, sertraline, temazepam, tramadol, triazolam, a tryptamine, venlafaxine, vortioxetine, and/or derivatives thereof. In an exemplary embodiment, the serotonergic drug is 3,4-methylenedioxymethamphetamine.
[0085] 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, incorporated here by reference. In one embodiment, the 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.
[0086] 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. Examples of 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 monomethylether (CBGAM); cannabigerovarin (CBGV); cannabigerovarinic acid (CBGVA); cannabinodiol (CBND); cannabinodivarin (CBVD); cannabinol (CBN); cannabinol methylether (CBNM); cannabinol-C2 (CBN-C2); cannabinol-C4 (CBN- C4); cannabinolic acid (CBNA); cannabiorcol (CBN-C1); cannabivarin (CBV); cannabitriol (CBT); cannabitriolvarin (CBTV); 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol; cannabicitran (CBTC); cannabiripsol (CBR); 8,9-dihydroxy-delta-6a-tetrahydrocannabinol; delta-8-tetrahydrocannabinol (A8-THC); delta-8-tetrahydrocannabinolic acid (A8-THCA); delta-9-tetrahydrocannabinol (THC); delta- 9-tetrahydrocannabinol-C4 (THC-C4); delta-9-tetrahydrocannabinolic acid A (THCA-A); delta-9- tetrahydrocannabinolic acid B (THCA-B); delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4); delta-9- tetrahydrocannabiorcol (THC-C1); delta-9-tetrahydrocannabiorcolic acid (THCA-C1); delta-9- tetrahydrocannabivarin (THCV); delta-9-tetrahydrocannabivarinic acid (THCVA); 10-oxo-delta-6a- tetrahydrocannabinol (OTHC); cannabichromanon (CBCF); cannabifuran (CBF); cannabiglendol; delta-9-cis-tetrahydrocannabinol (cis-THC); trihydroxy-delta-9-tetrahydrocannabinol (triOH-THC); dehydrocannabifuran (DCBF); and 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl- 2,6-methano-2H-l-benzoxocin-5-methanol. In one embodiment, the purified cannabinoid is chosen from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBVD, CBDVA, CBG, CBGA, CBGV, or CBGVA.
[0087] 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. In one embodiment, 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, eudesmol, eugenol, euphol, farnesene, farnesol, fenchone, geraniol, geranyl acetate, guaia-l(10),ll-diene, guaiacol, guaiol, guaiene, gurjunene, herniarin, hexanaldehyde, hexanoic acid, humulene, ionone, ipsdienol, isoamyl acetate, isoamyl alcohol, isoamyl formate, isoborneol, isomyrcenol, isoprene, isopulegol, isovaleric acid, lavandulol, limonene, gamma-linolenic acid, linalool, longifolene, lycopene, menthol, methyl butyrate, 3-mercapto-2-methylpentanal, beta-mercaptoethanol, mercaptoacetic acid, methyl salicylate, methylbutenol, methyl-2-methylvalerate, methyl thiobutyrate, myrcene, gamma- muurolene, nepetalactone, nerol, nerolidol, neryl acetate, nonanaldehyde, nonanoic acid, ocimene, octanal, octanoic acid, pentyl butyrate, phellandrene, phenylacetaldehyde, phenylacetic acid, phenylethanethiol, phytol, pinene, propanethiol, pristimerin, pulegone, retinol, rutin, sabinene, squalene, taxadiene, terpineol, terpine-4-ol, terpinolene, thujone, thymol, umbelliferone, undecanal, verdoxan, or vanillin. In one embodiment, 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.
[0088] As used herein, the term "adrenergic drug" refers to a compound that binds, blocks, or otherwise influences (e.g., via an allosteric reaction) activity at an adrenergic receptor. In one embodiment, an adrenergic drug binds to an adrenergic receptor. In one embodiment, an adrenergic drug indirectly affects an adrenergic receptor, e.g., via interactions affecting the reactivity of other molecules at the adrenergic receptor. In one embodiment, an adrenergic drug is an agonist, e.g., a compound activating an adrenergic receptor. In one embodiment, an adrenergic drug is an antagonist, e.g., a compound binding but not activating an adrenergic receptor, e.g., blocking a receptor. In one embodiment, an adrenergic drug is an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation. In one embodiment, an adrenergic drug acts (either directly or indirectly) at more than one type of receptor (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.).
[0089] In one embodiment, 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. In one embodiment, 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.
[0090] As used herein, 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. In one embodiment, a dopaminergic drug binds to a dopamine receptor. In one embodiment, a dopaminergic drug indirectly affects a dopamine receptor, e.g., via interactions affecting the reactivity of other molecules at the dopamine receptor. In one embodiment, a dopaminergic drug is an agonist, e.g., a compound activating a dopamine receptor. In one embodiment, a dopaminergic drug is an antagonist, e.g., a compound binding but not activating a dopamine receptor, e.g., blocking a receptor. In one embodiment, a dopaminergic drug is an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation. In one embodiment, a dopaminergic drug acts (either directly or indirectly) at more than one type of receptor (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.). [0091] In one embodiment, a dopaminergic drug is a dopamine transporter inhibitor. In one embodiment, a dopaminergic drug is a vesicular monoamine transporter inhibitor. In one embodiment, 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.
[0092] As used herein, the term "monoamine oxidase inhibitor" (MAOI) refers to a compound that blocks the actions of monoamine oxidase enzymes. In one embodiment, a MAOI inhibits the activity of one or both monoamine oxidase A and monoamine oxidase B. In one embodiment a MAOI is a reversible inhibitor of monoamine oxidase A. In one embodiment a MAOI is a drug chosen from isocarboxazid, phenelzine, or tranylcypromine. In one embodiment, a MAOI is 0- carboline, pinoline, harmane, harmine, harmaline, harmalol, tetrahydroharmine, 9-methyl-0- carboline, or 3-carboxy-tetrahydrononharman.
[0093] In one embodiment, the compositions and methods disclosed herein include one or more purified erinacine molecules. In one embodiment, the compositions and methods disclosed herein comprise purified erinacine A. In one embodiment, the compositions and methods disclosed herein comprise erinacine B. In one embodiment, the compositions and methods disclosed herein comprise erinacine C. In one embodiment, the compositions and methods disclosed herein comprise erinacine D. In one embodiment, the compositions and methods disclosed herein comprise erinacine E. In one embodiment, the compositions and methods disclosed herein comprise erinacine F. In one embodiment, the compositions and methods disclosed herein comprise erinacine G. In one embodiment, the compositions and methods disclosed herein comprise erinacine H. In one embodiment, the 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.
[0094] In one embodiment, the compositions and methods disclosed herein include one or more purified hericenone molecules. In one embodiment, the compositions and methods disclosed herein comprise purified hericenone A. In one embodiment, the compositions and methods disclosed herein comprise purified hericenone B. In one embodiment, the compositions and methods disclosed herein comprise purified hericenone C. In one embodiment, the compositions and methods disclosed herein comprise purified hericenone D. In one embodiment, the compositions and methods disclosed herein comprise purified hericenone E. In one embodiment, the compositions and methods disclosed herein comprise purified hericenone F. In one embodiment, the compositions and methods disclosed herein comprise purified hericenone G. In one embodiment, the compositions and methods disclosed herein comprise purified hericenone H. [0095] Exemplary compositions of 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-
(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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. 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure may be any one of the exemplary embodiments described above including the crystalline forms as disclosed herein. Table 1
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
[0096] Exemplary pharmaceutical compositions of 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]- DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)- DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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 and an excipient with exemplary molar ratios of 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate to the second compound are shown in Table 2. 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure may be any one of the exemplary embodiments described above including the crystalline forms as disclosed herein.
Table 2
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
[0097] An "effective amount" or a "therapeutically effective amount" of 4-
(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure is generally in the range of about 0.1 to about 100 mg daily (oral dose), of about 0.1 to about 50 mg daily (oral dose), of about 0.25 to about 25 mg daily (oral dose), of about 0.1 to about 5 mg daily (oral dose), or of about 0.5 to about 2.5 mg daily (oral dose). 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. 4- (methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure and pharmaceutical compositions containing it may be used in combination with other agents that are generally administered to a patient being treated for psychological and other disorders discussed above. They may also be co-formulated with one or more of such agents in a single pharmaceutical composition.
[0098] Depending on the type of pharmaceutical composition, 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 4-(methylsulfonyloxy)-DPT chloride, crystalline 4- (methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate of the disclosure, or produce undesirable biological effects or otherwise interact in a deleterious manner with any other component(s) of the pharmaceutical composition.
[0099] The pharmaceutical 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. In a solid dosage form, 4-(methylsulfonyloxy)-DPT chloride, crystalline 4-(methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4-trifluoromethylbenzoyloxy)- DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4-fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro- DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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, glucose, mannitol, and silicic acid, (b) binders, such as, for example, cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, such as, for example, glycerol, (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, such as, for example, paraffin, (f) absorption accelerators, such as, for example, quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like, (h) adsorbents, such as, for example, kaolin and bentonite, and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. In some embodiments, the excipient is not water. In some embodiments, the excipient is not a solvent (e.g., EtOH, diethyl ether, ethyl acetate, or hydrocarbon-based solvents (e.g., hexanes). In some embodiments, 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.
[00100] 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. If desired, 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.
[00101] 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.
[00102] 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. [00103] Solid dosage forms for oral administration, which includes capsules, tablets, pills, powders, and granules, may be used. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier).
[00104] Administration of 4-(methylsulfonyloxy)-DPT chloride, crystalline 4- (methylsulfonyloxy)-DPT chloride, 4-(4-trifluoromethylbenzoyloxy)-DPT chloride, crystalline 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline 4-(4- fluorobenzoyloxy)-DPT chloride, 4-PivO-DPT chloride, crystalline 4-PivO-DPT chloride, 4-Pro-DMT hydrofumarate, crystalline 4-Pro-DMT hydrofumarate, 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, crystalline 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate, or specific crystalline forms thereof, such as crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride, crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride, crystalline form 1 of 4-PivO-DPT chloride, crystalline form 1 of 4-Pro-DMT hydrofumarate, and crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate 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. Thus, administration may be, for example, orally, buccally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravagi na lly, 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.
[00105] Exemplary Embodiments
[00106] El. Crystalline (2-{4-[(2,2-dimethylpropanoyl)oxy]-lH-indol-3- yl}ethyl)dipropylazanium chloride (4-pivaloyloxy-A/,A/-di-n-propyltryptammonium chloride). [00107] E2. Crystalline form 1 of (2-{4-[(2,2-dimethylpropanoyl)oxy]-lH-indol-3- yl}ethyl)dipropylazanium chloride (4-pivaloyloxy-/V,A/-di-n-propyltryptammonium chloride). [00108] E3. Crystalline form 1 of 4-pivaloyloxy-A/,/V-di-n-propyltryptammonium chloride according to E2, characterized by at least one of: a triclinic crystal system at a temperature of about 297 K; a Pl space group at a temperature of about 297 K; unit cell dimensions a = 7.6697(5) A, b = 11.1491(8) A, c = 13.1430(9) A, a = 83.007(2)°, 0 =
82.786(2)°, and y = 77.733(2)°; an X-ray powder diffraction pattern substantially similar to FIG. 16; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 6.8, 8.1, and 10.1 °20 ± 0.2 °20.
[00109] E4. A composition comprising crystalline 4-pivaloyloxy-A/,A/-di-n- propyltryptammonium chloride according to any one of E1-E3 and an excipient.
[00110] E5. A composition comprising crystalline 4-pivaloyloxy-A/,/\/-di-n- propyltryptammonium chloride according to any one of E1-E3 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.
[00111] E6. 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 4- pivaloyloxy-A/,A/-di-n-propyltryptammonium chloride according to any one of E1-E3.
[00112] E7. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E4 or E5.
[00113] 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 crystalline 4- pivaloyloxy-A/,A/-di-n-propyltryptammonium chloride according to any one of E1-E3.
[00114] E9. 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 E4 or E5.
[00115] E10. Crystalline {2-[4-(methanesulfonyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4-(methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride).
[00116] Ell. Crystalline form 1 of {2-[4-(methanesulfonyloxy)-lH-indol-3- yl]ethyl}dipropylazanium chloride (4-(methylsulfonyloxy)-A/,/V-di-n-propyltryptammonium chloride).
[00117] E12. Crystalline form 1 of 4-(methylsulfonyloxy)-/V,/V-di-n-propyltryptammonium chloride according to Ell, characterized by at least one of: a monoclinic crystal system at a temperature of about 297 K; a P2i/c space group at a temperature of about 297 K; unit cell dimensions a = 9.5556(9) A, b = 8.7264(7) A, c = 23.485(2) A, a = 90°, 0 = 99.337(3)°, and y = 90°; an X-ray powder diffraction pattern substantially similar to FIG. 13; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.6, 9.4, and 11.1 °20 ± 0.2 °20.
[00118] E13. A composition comprising crystalline 4-(methylsulfonyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of E10-E12 and an excipient.
[00119] E14. A composition comprising crystalline 4-(methylsulfonyloxy)-/V,/V-di-n- propyltryptammonium chloride according to any one of E10-E12 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.
[00120] E15. 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 4- (methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E10-E12.
[00121] E16. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E13 or E14.
[00122] E17. 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 4- (methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E10-E12.
[00123] E18. 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 E13 or E14.
[00124] E19. Dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3-yl}ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-/V,/V-di-n-propyltryptam monium chloride).
[00125] E20. Crystalline dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3- yl}ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-A/,/V-di-n-propyltryptammonium chloride).
[00126] E21. Crystalline form 1 of dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3- yl}ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride).
[00127] E22. Crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to E21, characterized by at least one of: a monoclinic crystal system at a temperature of about 297 K; a C2/c space group at a temperature of about 297 K; unit cell dimensions a = 23.438(3) A, b = 12.5821(16) A, c = 16.449(2) A, a = 90°, 0 = 94.071(4)°, and y = 90°; an X-ray powder diffraction pattern substantially similar to FIG. 14; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.6, 9.8, and 10.8 °20 ± 0.2 °20.
[00128] E23. A composition comprising 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to E19 and an excipient.
[00129] E24. A composition comprising crystalline 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of E20-E22 and an excipient.
[00130] E25. A composition comprising 4-(4-trifluoromethylbenzoyloxy)-A/,/V-di-n- propyltryptammonium chloride according to 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.
[00131] E26. A composition comprising crystalline 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of E20-E22 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.
[00132] E27. 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 4-(4- trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to E19.
[00133] E28. 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 4- (4-trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E20- E22.
[00134] E29. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E23 or E25. [00135] E30. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E24 or E26.
[00136] E31. 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 4-(4- trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to E19.
[00137] E32. 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 4- (4-trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E20- E22.
[00138] E33. 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 E23 or E25.
[00139] 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 E24 or E26.
[00140] E35. Crystalline {2-[4-(4-fluorobenzoyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4-(4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride).
[00141] E36. Crystalline form 1 of {2-[4-(4-fluorobenzoyloxy)-lH-indol-3- yl]ethyl}dipropylazanium chloride (4-(4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride). [00142] E37. Crystalline form 1 of 4-(4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to E36, characterized by at least one of: a monoclinic crystal system at a temperature of about 297 K; a C2/c space group at a temperature of about 297 K; unit cell dimensions a = 23.9959(18) A, b = 11.5242(8) A, c = 16.3685(13) A, a = 90°, 0 = 97.197(3)°, and y = 90°; an X-ray powder diffraction pattern substantially similar to FIG. 15; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.4, 10.4, and 20.2 °20 ± 0.2 °20.
[00143] E38. A composition comprising crystalline 4-(4-fluorobenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of E35-E37 and an excipient. [00144] E39. A composition comprising crystalline 4-(4-fluorobenzoyloxy)-/V,/V-di-n- propyltryptammonium chloride according to any one of E35-E37 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.
[00145] E40. 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 4- (4-fluorobenzoyloxy)-/V,A/-di-n-propyltryptammonium chloride according to any one of E35-E37.
[00146] E41. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E38 or E39.
[00147] E42. 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 4- (4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of E35-E37.
[00148] E43. 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 E38 or E39.
[00149] E44. Crystalline dimethyl({2-[4-(propanoyloxy)-lH-indol-3-yl]ethyl})azanium (2E)-3- carboxyprop-2-enoate (4-propanoyloxy-/V,/V-dimethyltryptammonium hydrofumarate).
[00150] E45. Crystalline form 1 of dimethyl({2-[4-(propanoyloxy)-lH-indol-3- yl]ethyl})azanium (2E)-3-carboxyprop-2-enoate (4-propanoyloxy-A/,A/-dimethyltryptammonium hydrofumarate).
[00151] E46. Crystalline form 1 of 4-propanoyloxy-/V,A/-dimethyltryptammonium hydrofumarate according to E45, characterized by at least one of: a monoclinic crystal system at a temperature of about 297 K; a Pl-jct space group at a temperature of about 297 K; unit cell dimensions a = 11.7169(19) A, b = 11.4642(16) A, c = 15.287(2) A, a = 90°, p = 107.076(5)°, and y = 90°; an X-ray powder diffraction pattern substantially similar to FIG. 17; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 9.8,
15.8, and 18.6 °20 ± 0.2 °20. [00152] E47. A composition comprising crystalline 4-propanoyloxy-A/,/V- dimethyltryptammonium hydrofumarate according to any one of E44-E46 and an excipient.
[00153] E48. A composition comprising crystalline 4-propanoyloxy-A/,/V- dimethyltryptammonium hydrofumarate according to any one of E44-E46 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.
[00154] E49. 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 4- propanoyloxy-/V,/V-dimethyltryptammonium hydrofumarate according to any one of E44-E46.
[00155] E50. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E47 or E48.
[00156] E51. 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 4- propanoyloxy-/V,/V-dimethyltryptammonium hydrofumarate according to any one of E44-E46. [00157] E52. 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 E47 or E48.
[00158] E53. (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3-yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate). [00159] E54. Crystalline (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3- yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n- propyltryptammonium chloride hydrate).
[00160] E55. Crystalline form 1 of (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3- yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n- propyltryptammonium chloride hydrate).
[00161] E56. Crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-A/,/V-di-n- propyltryptammonium chloride hydrate according to E55, characterized by at least one of: a triclinic crystal system at a temperature of about 297 K; a Pl space group at a temperature of about 297 K; unit cell dimensions a = 7.4130(10) A, b = 8.3525(12) A, c = 20.183(3) A, a = 100.340(5)°, 0 = 95.403(5)°, and y = 90.495(5)°; an X-ray powder diffraction pattern substantially similar to FIG. 18; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 14.3, 17.1, and 20.6 ’26 ± 0.2 °20.
[00162] E57. A composition comprising 4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n- propyltryptammonium chloride hydrate according to E53 and an excipient.
[00163] E58. A composition comprising crystalline 4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n- propyltryptammonium chloride hydrate according to any one of E54-E56 and an excipient.
[00164] E59. A composition comprising 4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n- propyltryptammonium chloride hydrate according to E53 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.
[00165] E60. A composition comprising crystalline 4-[(4-nitrophenyl)sulfonyloxy]-M,A/-di-n- propyltryptammonium chloride hydrate according to any one of E54-E56 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.
[00166] E61. 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 4-[(4- nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate according to E53. [00167] E62. 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 4- [(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n-propyltryptammonium chloride hydrate according to any one of E54-E56.
[00168] E63. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E57 or E59.
[00169] E64. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to E58 or E60.
[00170] E65. 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 4-[(4- nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate according to E53. [00171] E66. 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 4- [(4-nitrophenyl)sulfonyloxy]-A/,/V-di-n-propyltryptammonium chloride hydrate according to any one of E54-E56.
[00172] E67. 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 E57 or E59.
[00173] E68. 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 E58 or E60.
Examples
[00174] The preparation and characterization of each of crystalline form 1 of {2-[4- (methanesulfonyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4-(methylsulfonyloxy)-N,N-di-n- propyltryptammonium chloride or 4-(methylsulfonyloxy)-DPT chloride), crystalline form 1 of dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3-yl}ethyl)azanium chloride (4-(4- trifluoromethylbenzoyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(4- trifluoromethylbenzoyloxy)-DPT chloride), crystalline form 1 of {2-[4-(4-fluorobenzoyloxy)-lH-indol- 3-yl]ethyl}dipropylazanium chloride (4-(4-fluorobenzoyloxy)-N,N-di-n-propyltryptammonium chloride or 4-(4-fluorobenzoyloxy)-DPT chloride), crystalline form 1 of (2-{4-[(2,2- dimethylpropanoyl)oxy]-lH-indol-3 yl}ethyl)dipropylazanium chloride (4-pivaloyloxy-N,N-di-n- propyltryptammonium chloride or 4-PivO-DPT chloride), crystalline form 1 of dimethyl({2-[4- (propanoyloxy)-lH-indol-3-yl]ethyl})azanium (2E)-3-carboxyprop-2-enoate (4-propanoyloxy-A/,/V- dimethyltryptammonium hydrofumarate or 4-Pro-DMT hydrofumarate), and crystalline form 1 of (2- {4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3-yl}ethyl)dipropylazanium chloride hydrate (4-[(4- nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate or 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate) are described below.
[00175] Single Crystal X-Ray Diffraction (SCXRD) 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 OLEX2 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.
[00176] Preparation and Characterization of Crystalline form 1 of 4-(methylsulfonyloxy)-N,N- di-n-propyltryptammonium chloride
[00177] Synthesis
[00178] All the reactions were performed in oven-dried glassware under nitrogen or argon. Thin-layer chromatography (TLC) was performed using aluminum backed silica coated plates. TLC plates were visualized under ultraviolet light.
[00179] Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by methanesulfonyl chloride (1.5 equiv.) in a dropwise manner. The resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (per TLC). The typical reaction times were between 1.5 to 2h. The reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine. The resulting organic layer was dried using sodium sulfate and reduced under pressure to afford a residue which was dissolved in toluene (10 mL). The residue after salt formation in toluene was subjected to column chromatography (DCM : MeOH) to obtain the desired sulfonate compound. Off white solid, Yield 51%.
[00180] NMR and HRMS
[001] All the aH and 13C NMRs were recorded on Bruker AVANCE III HD 400 MHz High-Performance Digital NMR spectrometer XH (400 MHz), 13C (101 MHz) with complete proton decoupling for 13C. Chemical shifts were analyzed on MestReNova software. Chemical shifts are reported in parts per million with the solvent resonance as the internal standard: D2O (1H: 64.79 ppm); and CDCI3 (13C: 877.23 ppm). High Resolution Mass Spectrometry (HRMS) were recorded on a Waters Q.Tof-1 spectrometer using electrospray ionization.
[00181] XH NMR (400 MHz, Deuterium Oxide) 6 7.46 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 3.41 (s, 3H), 3.40 - 3.35 (m, 2H), 3.28 - 3.20 (m, 2H), 3.12 - 3.02 (m, 4H), 1.71 - 1.52 (m, 4H), 0.85 (t, J = 7.4 Hz, 6H).
[00182] 13C NMR (101 MHz, Chloroform-d) 6 142.6, 139.1, 125.2, 122.0, 119.5, 111.8, 111.1,
108.0, 54.5, 54.4, 37.8, 20.9, 17.1, 11.2. [00183] HRMS ( ES+) m/z calc, for [C17H27N2O3SH: 339.1737; found: 339.1733.
[00184] Crystallization
[00185] Single crystals suitable for X-ray diffraction were grown from the slow evaporation of an aqueous solution.
[00186] Single Crystal Characterization
[00187] The single crystal data and structure refinement parameters for the crystalline form 1 structure of 4-(methylsulfonyloxy)-DPT chloride are reported in Table 3, below.
[00188] Preparation and Characterization of Crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-N,N-di-n-propyltryptammonium chloride
[00189] Synthesis
[00190] All the reactions were performed in oven-dried glassware under nitrogen or argon. Thin-layer chromatography (TLC) was performed using aluminum backed silica coated plates. TLC plates were visualized under ultraviolet light.
[00191] Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by 4-(trifluoromethyl)benzoyl chloride (1.5 equiv.) in a dropwise manner. The resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (per TLC). The typical reaction times were between 1.5 to 2h. The reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine. The resulting organic layer was dried using sodium sulfate and reduced under pressure to afford a residue which was dissolved in toluene (10 mL). To the resulting solution was added HCI in ether (2M, 1.1 equiv.) dropwise and stirred at room temperature for 15 min. The contents were then reduced under pressure and the residue was suspended in ether and sonicated to afford solid which was then filtered and dried under vacuum to yield hydrochloride salt of desired DPT ester. Solid, Yield 70%.
[00192] NMR and HRMS
[00193] All the 1H and 13C NMRs were recorded on Bruker AVANCE III HD 400 MHz High- Performance Digital NM R spectrometer 3H (400 MHz), 13C (101 MHz) with complete proton decoupling for 13C. Chemical shifts were analyzed on MestReNova software. Chemical shifts are reported in parts per million with the solvent resonance as the internal standard: D2O (1H: 64.79 ppm); and CDCI3 (13C: 677.23 ppm). High Resolution Mass Spectrometry (HRMS) were recorded on a Waters Q.Tof-1 spectrometer using electrospray ionization.
[00194] 1H NMR (400 MHz, Deuterium Oxide) 6 8.40 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.27 - 7.19 (m, 2H), 6.93 (d, J = 8.3 Hz, 1H), 3.23 (d, J = 7.5 Hz, 2H), 2.96 (d, J = 7.5 Hz, 2H), 2.76 (q, J = 4.5 Hz, 2H), 1.40 (h, J = 7.4 Hz, 4H), 0.67 (t, J = 7.4 Hz, 6H). [00195] 13C NMR (101 MHz, Chloroform-d) 6 164.5, 143.4, 138.7, 135.8, 135.5, 132.7, 130.7,
126.2 (q, J = 3.7 Hz), 124.0, 122.5, 119.2, 112.4, 110.5, 108.2, 54.3, 53.9, 21.2, 16.7, 10.9.
[00196] HRMS (ES+) m/z calc, for [C24H2SF3N2O2]+: 433.2097; found: 433.2094.
[00197] Crystallization
[00198] Single crystals suitable for X-ray diffraction were grown from the slow evaporation of a methylene chloride/methanol/hexanes solution.
[00199] Single Crystal Characterization
[00200] The single crystal data and structure refinement parameters for the crystalline form 1 structure of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride are reported in Table 3, below.
[00201] Preparation and Characterization of Crystalline form 1 of 4-(4-fluorobenzoyloxy)- N,N-di-n-propyltrvptammonium chloride
[00202] Synthesis
[00203] All the reactions were performed in oven-dried glassware under nitrogen or argon. Thin-layer chromatography (TLC) was performed using aluminum backed silica coated plates. TLC plates were visualized under ultraviolet light.
[00204] Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by 4-fluorobenzoyl chloride (1.5 equiv.) in a dropwise manner. The resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (per TLC). The typical reaction times were between 1.5 to 2h. The reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine. The resulting organic layer was dried using sodium sulfate and reduced under pressure to afford a residue which was dissolved in toluene (10 mL). To the resulting solution was added HCI in ether (2M, 1.1 equiv.) dropwise and stirred at room temperature for 15 min. The contents were then reduced under pressure and the residue was suspended in ether and sonicated to afford solid which was then filtered and dried under vacuum to yield hydrochloride salt of desired DPT ester. Solid, yield 68%.
[00205] NMR and HRMS
[00206] All the 1H and 13C NMRs were recorded on Bruker AVANCE III HD 400 MHz High- Performance Digital NMR spectrometer 1H (400 MHz), 13C (101 MHz) with complete proton decoupling for 13C. Chemical shifts were analyzed on MestReNova software. Chemical shifts are reported in parts per million with the solvent resonance as the internal standard: D2O (XH: 64.79 ppm); and CDCh (13C: 677.23 ppm). High Resolution Mass Spectrometry (HRMS) were recorded on a Waters Q.Tof-1 spectrometer using electrospray ionization. [00207] 3H NMR (400 MHz, Deuterium Oxide) 6 8.30 (dd, J = 8.9, 5.4 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 8.8 Hz, 2H), 7.28 - 7.18 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 3.23 (t, J = 7.5 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.85 - 2.72 (m, 4H), 1.43 (h, J = 7.4 Hz, 4H), 0.70 (t, J = 7.4 Hz, 6H).
[00208] 13C NMR (101 MHz, Chloroform-d) 6 164.7, 143.6, 138.7, 133.0 (d, J = 9.3 Hz), 124.1,
122.5, 119.4, 116.5, 116.3, 112.6, 110.2, 108.4, 54.4, 53.9, 21.2, 16.7, 11.0.
[00209] HRMS (ES+) m/z calc, for [C23H28FN2O2R: 383.2129; found: 383.2151.
[00210] Crystallization
[00211] Single crystals suitable for X-ray diffraction studies were grown from the slow evaporation of a methylene chloride/methanol/hexanes solution.
[00212] Single Crystal Characterization
[00213] The single crystal data and structure refinement parameters for the crystalline form 1 structure of 4-(4-fluorobenzoyloxy)-DPT chloride are reported in Table 3, below.
[00214] Preparation and Characterization of Crystalline form 1 of 4-pivaloyloxy-N,N-di-n- propyltryptammonium chloride
[00215] Synthesis
[00216] All the reactions were performed in oven-dried glassware under nitrogen or argon. Thin-layer chromatography (TLC) was performed using aluminum backed silica coated plates. TLC plates were visualized under ultraviolet light.
[00217] Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by pivaloyl chloride (1.5 equiv.) in a dropwise manner. The resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (perTLC). The typical reaction times were between 1.5 to 2h. The reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine. The resulting organic layer was dried using sodium sulfate and reduced under pressure to afford a residue which was dissolved in toluene (10 mL). To the resulting solution was added HCI in ether (2M, 1.1 equiv.) dropwise and stirred at room temperature for 15 min. The contents were then reduced under pressure and the residue was suspended in ether and sonicated to afford solid which was then filtered and dried under vacuum to yield hydrochloride salt of desired DPT ester. White solid, Yield 46%.
[00218] NMR and HRMS
[00219] All the 3H and 13C NMRs were recorded on Bruker AVANCE III HD 400 MHz High- Performance Digital NMR spectrometer aH (400 MHz), 13C (101 MHz) with complete proton decoupling for 13C. Chemical shifts were analyzed on MestReNova software. Chemical shifts are reported in parts per million with the solvent resonance as the internal standard: D2O (1H: 64.79 ppm), and CDCI3 (13C: 677.23 ppm). Coupling constants are reported in Hertz (Hz). Abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd=doublet of doublet. High Resolution Mass Spectrometry (HRMS) were recorded on a Waters Q.Tof-1 spectrometer using electrospray ionization.
[00220] XH NMR (400 MHz, Deuterium Oxide) 8 7.38 (d, J = 8.7 Hz, 1H), 7.26 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 3.47 (t, J = 6.7 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H), 3.01 (dt, J = 9.6, 5.4 Hz, 4H), 1.55 (h, J = 7.0 Hz, 4H), 1.36 (s, 9H), 0.79 (t, J = 7.4 Hz, 6H).
[00221] 13C NMR (101 MHz, Chloroform-d) 6 177.9, 144.5, 138.7, 123.0, 122.3, 119.4, 112.1,
109.8, 108.5, 54.4, 52.7, 39.4, 27.4, 21.1, 16.8, 11.1.
[00222] HRMS (ES+) m/z calc, for [C2IH33N2O2]+: 345.2537; found: 345.2567.
[00223] Crystallization
[00224] Single crystals suitable for X-ray diffraction studies were grown from the slow evaporation of a methylene chloride/methanol/hexanes solution.
[00225] Single Crystal Characterization
[00226] The single crystal data and structure refinement parameters for the crystalline form 1 structure of 4-PivO-DPT chloride are reported in Table 3, below.
[00227] Preparation and Characterization of Crystalline form 1 of 4-propanoyloxy-/\/,/\/- dimethyltryptammonium hydrofumarate
[00228] Crystallization
[00229] Single crystals suitable for X-ray diffraction studies were grown from the slow evaporation of an aqueous solution of a commercial sample (Indole Shop).
[00230] Single Crystal Characterization
[00231] The single crystal data and structure refinement parameters for the crystalline form 1 structure of 4-Pro-DMT hydrofumarate are reported in Table 3, below.
[00232] Preparation and Characterization of Crystalline form 1 of 4-((4- nitrophenyl)sulfonyloxyl-N,N-di-n-propyltrvptammonium chloride hydrate
[00233] Synthesis
[00234] All the reactions were performed in oven-dried glassware under nitrogen or argon. Thin-layer chromatography (TLC) was performed using aluminum backed silica coated plates. TLC plates were visualized under ultraviolet light.
[00235] Triethylamine (2 equiv.) was added to a reaction vial containing 3-(2- (dipropylamino)ethyl)-lH-indol-4-ol (0.4 mmol, 1 equiv.) in anhydrous DCM (8 mL) at 0 °C followed by 4-nitrobenzenesulfonyl chloride (1.5 equiv.) in a dropwise manner. The resulting contents were then stirred at room temperature under nitrogen until the disappearance of the starting material (per TLC). The typical reaction times were between 1.5 to 2h. The reaction contents were then diluted with DCM (20 mL) and washed twice with cold water followed by brine. The resulting organic layer was dried using sodium sulfate and reduced under pressure to afford a residue which was dissolved in toluene (10 mL). The residue after salt formation in toluene was subjected to column chromatography (DCM : MeOH) to obtain the desired sulfonate compound. Yellow solid, Yield 46%. [00236] NMR and HRMS
[00237] All the 1H and 13C NMRs were recorded on Bruker AVANCE III HD 400 MHz High- Performance Digital NMR spectrometer 3H (400 MHz), 13C (101 MHz) with complete proton decoupling for 13C. Chemical shifts were analyzed on MestReNova software. Chemical shifts are reported in parts per million with the solvent resonance as the internal standard D2O (1H: 64.79 ppm); and CDCI3 (13C: 677.23 ppm). Coupling constants are reported in Hertz (Hz). Abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd=doublet of doublet. High Resolution Mass Spectrometry (HRMS) were recorded on a Waters Q.Tof-1 spectrometer using electrospray ionization.
[00238] 3H NMR (400 MHz, Deuterium Oxide) 6 8.37 (d, J = 9.1 Hz, 2H), 8.06 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 6.99 (t, 7 = 8.1 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 3.43 - 3.34 (m, 2H), 3.22 - 3.13 (m, 2H), 3.15 - 3.03 (m, 4H), 1.64 (dt, J = 13.6, 7.0 Hz, 4H), 0.87 (t, J = 7.4 Hz, 6H). [00239] 13C NMR (101 MHz, Chloroform-d) 6 151.1, 142.5, 141.2, 139.0, 130.1, 129.0, 128.2,
125.4, 124.5, 121.9, 111.7, 111.4, 54.5, 54.4, 20.9, 17.1, 11.2.
[00240] HRMS (ES+) m/z calc, for [C22H28N3O5S]+: 446.1744; found: 446.1767.
[00241] Crystallization
[00242] Crystals suitable for X-ray diffraction studies were grown by the slow evaporation on an aqueous solution.
[00243] Single Crystal Characterization
[00244] The single crystal data and structure refinement parameters for the crystalline form 1 structure of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate are reported in Table 3, below.
Table 3
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
[00245] FIG. 1 shows the molecular structure of crystalline form 1 of 4-(methylsulfonyloxy)- DPT chloride, showing the atomic labeling.
[00246] FIG. 2 shows the molecular structure of crystalline form 1 of 4-(4- trifluoromethylbenzoyloxy)-DPT chloride, showing the atomic labeling.
[00247] FIG. 3 shows the molecular structure of crystalline form 1 of 4-(4-fluorobenzoyloxy)- DPT chloride, showing the atomic labeling.
[00248] FIG. 4 shows the molecular structure of crystalline form 1 of 4-PivO-DPT chloride, showing the atomic labeling.
[00249] FIG. 5 shows the molecular structure of crystalline form 1 of 4-Pro-DMT hydrofumarate, showing the atomic labeling.
[00250] FIG. 6 shows the molecular structure of crystalline form 1 of 4-[(4- nitrophenyl)sulfonyloxy]-DPT chloride hydrate, showing the atomic labeling.
[00251] FIG. 7 shows the unit cell of crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride along the a-axis.
[00252] FIG. 8 shows the unit cell of crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)- DPT chloride along the b-axis.
[00253] FIG. 9 shows the unit cell of crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride along the b-axis.
[00254] FIG. 10 shows the unit cell of crystalline form 1 of 4-PivO-DPT chloride along the a- axis.
[00255] FIG. 11 shows the unit cell of crystalline form 1 of 4-Pro-DMT hydrofumarate along the b-axis.
[00256] FIG. 12 shows the unit cell of crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate along the a-axis. [00257] Simulated Powder X-ray Diffraction (PXRD) Pattern
[00258] FIG. 13 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride 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. 13. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal. For example, the cocrystal may be characterized by at least two peaks selected from the peaks at 7.6,
9.4, and 11.1 °20 ± O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 13.
[00259] Simulated Powder X-ray Diffraction (PXRD) Pattern
[00260] FIG. 14 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride 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. 14. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal. For example, the cocrystal may be characterized by at least two peaks selected from the peaks at 7.6, 9.8, and 10.8 °20 ± O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 14.
[00261] Simulated Powder X-ray Diffraction (PXRD) Pattern
[00262] FIG. 15 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride generated from its single crystal data. Table 6 lists the angles, °20 ± O.2°20, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 15. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal. For example, the cocrystal may be characterized by at least two peaks selected from the peaks at 7.4,
10.4, and 20.2 °20 ± O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 15.
[00263] Simulated Powder X-ray Diffraction (PXRD) Pattern
[00264] FIG. 16 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-PivO-DPT chloride generated from its single crystal data. Table 7 lists the angles, °20 ± O.2°20, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 16. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal. For example, the cocrystal may be characterized by at least two peaks selected from the peaks at 6.8, 8.1, and 10.1 °20 ± O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 16.
[00265] Simulated Powder X-ray Diffraction (PXRD) Pattern
[00266] FIG. 17 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-Pro-DMT hydrofumarate generated from its single crystal data. Table 8 lists the angles, °20 ± 0.2°26, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 17. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal. For example, the cocrystal may be characterized by at least two peaks selected from the peaks at 9.8, 15.8, and 18.6 °20 ± O.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 17.
[00267] Simulated Powder X-ray Diffraction (PXRD) Pattern
[00268] FIG. 18 shows a simulated X-ray powder diffraction pattern (XRPD) for crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate generated from its single crystal data. Table 9 lists the angles, °20 ± O.2°20, and d-spacing of the peaks identified in the experimental XRPD pattern of FIG. 18. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal. For example, the cocrystal may be characterized by at least two peaks selected from the peaks at 14.3, 17.1, and 20.6 °20 ± 0.2°20 or their corresponding d-spacing as well as by an XRPD pattern substantially similar to FIG. 18.
Table 4: Crystalline form 1 of 4-(methylsulfonyloxy)-DPT chloride
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Table 5: Crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-DPT chloride
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000074_0001
Table 6: Crystalline form 1 of 4-(4-fluorobenzoyloxy)-DPT chloride
Figure imgf000074_0002
Figure imgf000075_0001
Figure imgf000076_0001
Table 7: Crystalline form 1 of 4-PivO-DPT chloride
Figure imgf000076_0002
Figure imgf000077_0001
Figure imgf000078_0001
Table 8: Crystalline form 1 of 4-Pro-DMT hydrofumarate
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
Table 9: Crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-DPT chloride hydrate
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000082_0001
References
Dolomanov, 0. V., Bourhis, L J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.
Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8.

Claims

The claimed invention is:
1. Crystalline (2-{4-[(2,2-dimethylpropanoyl)oxy]-lH-indol-3-yl}ethyl)dipropylazanium chloride (4- pivaloyloxy-/V,A/-di-n-propyltryptammonium chloride).
2. Crystalline form 1 of (2-{4-[(2,2-dimethylpropanoyl)oxy]-lH-indol-3-yl}ethyl)dipropylazanium chloride (4-pivaloyloxy-/V,/V-di-n-propyltryptammonium chloride).
3. Crystalline form 1 of 4-pivaloyloxy-A/,A/-di-n-propyltryptammonium chloride according to claim 2, characterized by at least one of: a triclinic crystal system at a temperature of about 297 K; a Pl space group at a temperature of about 297 K; unit cell dimensions a = 7.6697(5) A, b = 11.1491(8) A, c = 13.1430(9) A, a = 83.007(2)°, 0 = 82.786(2)°, and y = 77.733(2)°; an X-ray powder diffraction pattern substantially similar to FIG. 16; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 6.8, 8.1, and 10.1 °20 ± 0.2 ’20.
4. A composition comprising crystalline 4-pivaloyloxy-/V,/V-di-n-propyltryptammonium chloride according to any one of claims 1-3 and an excipient.
5. A composition comprising crystalline 4-pivaloyloxy-A/,A/-di-n-propyltryptammonium chloride according to any one of claims 1-3 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.
6. 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 4- pivaloyloxy-/V,A/-di-n-propyltryptammonium chloride according to any one of claims 1-3.
7. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to claim 4.
8. A method of preventing or treating a psychological disorder comprising the step of: administering to a subject in need thereof a composition according to claim 5.
9. 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 4- pivaloyloxy-/V,A/-di-n-propyltryptammonium chloride according to any one of claims 1-3.
10. 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 claim 4.
11. 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 claim 5.
12. Crystalline {2-[4-(methanesulfonyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4- (methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride).
13. Crystalline form 1 of {2-[4-(methanesulfonyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4- (methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride).
14. Crystalline form 1 of 4-(methylsulfonyloxy)-/V,A/-di-n-propyltryptammonium chloride according to claim 13, characterized by at least one of: a monoclinic crystal system at a temperature of about 297 K; a P2i/c space group at a temperature of about 297 K; unit cell dimensions a = 9.5556(9) A, b = 8.7264(7) A, c = 23.485(2) A, a = 90°, p = 99.337(3)°, and y = 90°; an X-ray powder diffraction pattern substantially similar to FIG. 13; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.6, 9.4, and 11.1 °20 ± 0.2 °20.
15. A composition comprising crystalline 4-(methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of claims 12-14 and an excipient.
16. A composition comprising crystalline 4-(methylsulfonyloxy)-A/,A/-di-n-propyltryptammonium chloride according to any one of claims 12-14 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.
17. Dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3-yl}ethyl)azanium chloride (4-(4- trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride).
18. Crystalline dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3-yl}ethyl)azanium chloride (4- (4-trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptam monium chloride).
19. Crystalline form 1 of dipropyl(2-{4-[4-(trifluoromethyl)benzoyloxy]-lH-indol-3-yl}ethyl)azanium chloride (4-(4-trifluoromethylbenzoyloxy)-/V,A/-di-n-propyltryptam monium chloride).
20. Crystalline form 1 of 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to claim 19, characterized by at least one of: a monoclinic crystal system at a temperature of about 297 K; a C2/c space group at a temperature of about 297 K; unit cell dimensions a = 23.438(3) A, b = 12.5821(16) A, c = 16.449(2) A, a = 90°, 0 = 94.071(4)°, and y = 90°; an X-ray powder diffraction pattern substantially similar to FIG. 14; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.6, 9.8, and 10.8 °20 ± 0.2 °20.
21. A composition comprising 4-(4-trifluoromethylbenzoyloxy)-/V,/V-di-n-propyltryptammonium chloride according to claim 17 and an excipient.
22. A composition comprising crystalline 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of claims 18-20 and an excipient.
23. A composition comprising 4-(4-trifluoromethylbenzoyloxy)-/V,/V-di-n-propyltryptammonium chloride according to claim 17 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.
24. A composition comprising crystalline 4-(4-trifluoromethylbenzoyloxy)-A/,A/-di-n- propyltryptammonium chloride according to any one of claims 18-20 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.
25. Crystalline {2-[4-(4-fluorobenzoyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4-(4- fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride).
26. Crystalline form 1 of {2-[4-(4-fluorobenzoyloxy)-lH-indol-3-yl]ethyl}dipropylazanium chloride (4- (4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride).
27. Crystalline form 1 of 4-(4-fluorobenzoyloxy)-A/,A/-di-n-propyltryptammonium chloride according to claim 26, characterized by at least one of: a monoclinic crystal system at a temperature of about 297 K; a C2/c space group at a temperature of about 297 K; unit cell dimensions a = 23.9959(18) A, b = 11.5242(8) A, c = 16.3685(13) A, a = 90°, P = 97.197(3)°, and y = 90°; an X-ray powder diffraction pattern substantially similar to FIG. 15; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 7.4, 10.4, and 20.2 °20 ± 0.2 ”20.
28. A composition comprising crystalline 4-(4-fluorobenzoyloxy)-/V,/V-di-n-propyltryptammonium chloride according to any one of claims 25-27 and an excipient.
29. A composition comprising crystalline 4-(4-fluorobenzoyloxy)-A/,M-di-n-propyltryptammonium chloride according to any one of claims 25-27 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.
30. Crystalline dimethyl({2-[4-(propanoyloxy)-lH-indol-3-yl]ethyl})azanium (2E)-3-carboxyprop-2- enoate (4-propanoyloxy-A/,/V-dimethyltryptammonium hydrofumarate).
31. Crystalline form 1 of dimethyl({2-[4-(propanoyloxy)-lH-indol-3-yl]ethyl})azanium (2E)-3- carboxyprop-2-enoate (4-propanoyloxy-A/,A/-dimethyltryptammonium hydrofumarate).
32. Crystalline form 1 of 4-propanoyloxy-/V,A/-dimethyltryptammonium hydrofumarate according to claim 31, characterized by at least one of: a monoclinic crystal system at a temperature of about 297 K; a P2i/n space group at a temperature of about 297 K; unit cell dimensions a = 11.7169(19) A, b = 11.4642(16) A, c = 15.287(2) A, a = 90°, 0 = 107.076(5)°, and y = 90°; an X-ray powder diffraction pattern substantially similar to FIG. 17; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 9.8, 15.8, and 18.6 °20 ± 0.2 °20.
33. A composition comprising crystalline 4-propanoyloxy-A/,A/-dimethyltryptammonium hydrofumarate according to any one of claims 30-32 and an excipient.
34. A composition comprising crystalline 4-propanoyloxy-A/,/V-dimethyltryptammonium hydrofumarate according to any one of claims 30-32 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.
35. (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3-yl}ethyl)dipropylazanium chloride hydrate (4-[(4- nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate).
36. Crystalline (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3-yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n-propyltryptammonium chloride hydrate).
37. Crystalline form 1 of (2-{4-[(4-nitrobenzenesulfonyl)oxy]-lH-indol-3-yl}ethyl)dipropylazanium chloride hydrate (4-[(4-nitrophenyl)sulfonyloxy]-/V,/V-di-n-propyltryptammonium chloride hydrate).
38. Crystalline form 1 of 4-[(4-nitrophenyl)sulfonyloxy]-A/,A/-di-n-propyltryptammonium chloride hydrate according to claim 37, characterized by at least one of: a triclinic crystal system at a temperature of about 297 K; a Pl space group at a temperature of about 297 K; unit cell dimensions a = 7.4130(10) A, b = 8.3525(12) A, c = 20.183(3) A, a = 100.340(5)°, 0 = 95.403(5)°, and y = 90.495(5)°; an X-ray powder diffraction pattern substantially similar to FIG. 18; or an X-ray powder diffraction pattern characterized by at least two peaks selected from 14.3, 17.1, and 20.6 °20 ± 0.2 °20.
39. A composition comprising 4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate according to claim 35 and an excipient.
40. A composition comprising crystalline 4-[(4-nitrophenyl)sulfonyloxy]-/V,/V-di-n- propyltryptammonium chloride hydrate according to any one of claims 36-38 and an excipient.
41. A composition comprising 4-[(4-nitrophenyl)sulfonyloxy]-N,N-di-n-propyltryptammonium chloride hydrate according to claim 35 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.
42. A composition comprising crystalline 4-[(4-nitrophenyl)sulfonyloxy]-/V,A/-di-n- propyltryptammonium chloride hydrate according to any one of claims 36-38 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.
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