CRYSTALLINE NORPSILOCIN COMPOUNDS

Abstract

The disclosure relates to norpsilocin compounds, compositions containing those crystalline compounds, and methods of treatment using them. The norpsilocin compounds include crystalline 4-hydroxy-N-methyltryptamine (“crystalline 4-HO-NMT” or “crystalline norpsilocin freebase”), crystalline 4-hydroxy-N-methyltryptammonium fumarate (“crystalline norpsilocin fumarate”), and 4-hydroxy-N-methyltryptammonium fumarate (“norpsilocin fumarate”) and their compositions and uses.

Claims

1-10. (canceled)

11. A composition comprising crystalline 4-hydroxy-N-methyltryptammonium fumarate (norpsilocin fumarate) and an excipient.

12. (canceled)

13. A composition comprising crystalline 4-hydroxy-N-methyltryptammonium fumarate (norpsilocin fumarate) and a second component selected from (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) one or two purified cannabinoids and (d) a purified terpene.

14. (canceled)

15. (canceled)

16. 4-hydroxy-N-methyltryptammonium fumarate (norpsilocin fumarate).

17. A composition comprising 4-hydroxy-N-methyltryptammonium fumarate (norpsilocin fumarate) according to claim 16 and an excipient.

18. A composition comprising 4-hydroxy-N-methyltryptammonium fumarate (norpsilocin fumarate) according to claim 16 and a second component selected from (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) one or two purified cannabinoids and (d) a purified terpene.

19. 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-hydroxy-N-methyltryptammonium fumarate (norpsilocin fumarate) according to claim 16.

20. 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 17.

21. 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-hydroxy-N-methyltryptammonium fumarate (norpsilocin fumarate) according to claim 16.

22. 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 17.

23. 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 18.

24. 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 18.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0021] FIG. 1 shows the molecular structure of crystalline norpsilocin freebase.

[0022] FIG. 2 shows the packing of crystalline norpsilocin freebase.

[0023] FIG. 3 shows a simulated x-ray power diffraction (XRPD) of crystalline norpsilocin freebase.

[0024] FIG. 4 shows the molecular structure of crystalline norpsilocin fumarate.

[0025] FIG. 5 shows the indole N—H, methylammonium N—H, and phenol O—H hydrogen bonds with the oxygen atoms of the norpsilocin fumarate dianion.

[0026] FIG. 6 shows the packing of crystalline norpsilocin fumarate.

[0027] FIG. 7 shows a simulated x-ray power diffraction (XRPD) of crystalline norpsilocin fumarate.

DETAILED DESCRIPTION

[0028] The disclosure relates to norpsilocin compounds and to pharmaceutical compositions containing them. The norpsilocin compounds according to the disclosure include crystalline 4-hydroxy-N-methyltryptamine (“crystalline 4-HO-NMT” or “crystalline norpsilocin freebase”), crystalline 4-hydroxy-N-methyltryptammonium fumarate (“crystalline norpsilocin fumarate”), and 4-hydroxy-N-methyltryptammonium fumarate (“norpsilocin fumarate”). The therapeutic uses of the norpsilocin compounds according to the disclosure, are described below as well as compositions containing them. The norpsilocin compounds according to the disclosure, and the methods used to characterize them are described below.

[0029] Norpsilocin freebase is a compound of formula (I):

##STR00001##

[0030] Norpsilocin fumarate is a compound of formula (II):

##STR00002##

[0031] Methods of Treatment and Therapeutic Uses

[0032] In one embodiment, crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate, according to the disclosure, and the methods and the compositions—particularly the pharmaceutical compositions—of the disclosure are used to regulate the activity of a neurotransmitter receptor by administering a therapeutically effective dose of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure. In another embodiment, crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate, according to the disclosure, and the methods and the compositions—particularly the pharmaceutical compositions—of the disclosure are used to treat inflammation and/or pain by administering a therapeutically effective dose of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure.

[0033] Methods of the disclosure administer a therapeutically effective amount of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure to prevent or treat a disease or condition, such as those discussed below. Crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate may be administered neat or as a pharmaceutical composition comprising crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate as discussed below.

[0034] Crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate, according to 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 crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure, including the preferred 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).

[0035] Crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate according to 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 by administering to a subject in need thereof a therapeutically effective amount of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure, including the preferred embodiments discussed herein. The brain disorder may be chosen from Huntington's disease, Alzheimer's disease, dementia, and Parkinson's disease.

[0036] Crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate according to 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 crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure, including the preferred embodiments discussed herein.

[0037] Crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate according to 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. Accordingly, the disclosure relates to a method for preventing and/or treating inflammation and/or pain by administering to a subject in need thereof a therapeutically effective amount of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure, including the preferred 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.

[0038] Compositions

[0039] The disclosure also relates to compositions comprising an effective amount of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure, including its preferred embodiments discussed above, and an excipient. In another embodiment of the disclosure, the disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure, including its preferred embodiments discussed above, and a pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier). As discussed above, crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate according to 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 discussed above.

[0040] A composition or a pharmaceutical composition of the disclosure may be in any form which contains crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure. 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 crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate 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 crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate with the rest being at least one suitable pharmaceutically acceptable excipient or at least one other adjuvant, as discussed below.

[0041] Published US applications US 2018/0221396 A1 and US 2019/0142851 A1 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 A1 and US 2019/0142851 A1 are incorporated herein by reference. According to this disclosure, crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure may be used as the “first purified psilocybin derivative” in the compositions described in US 2018/0221396 A1 and US 2019/0142851 A1. Accordingly, this disclosure provides a composition comprising as a first component: crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate of the disclosure; and as a second component selected from (a) a serotonergic drug, (b) a purified psilocybin derivative, (c) one or two purified cannabinoids and (d) a purified terpene; with the rest being at least one suitable pharmaceutical excipient or at least one other adjuvant, as discussed below. Such a composition may be a pharmaceutical composition wherein the components are present individually in therapeutically effective amounts or by combination in a therapeutically effective amount to treat a disease, disorder, or condition as described herein. A serotonergic drug refers to a compound that binds to, blocks, or otherwise influences (e.g., via an allosteric reaction) activity at a serotonin receptor as described in paragraphs [0245]-[0253] of US 2018/0221396 A1 and [0305]-[0311] US 2019/0142851 A1 as well as the disclosed preferred embodiments, incorporated here by reference. Exemplary psilocybin derivatives include but are not limited to psilocybin itself and the psilocybin derivates described in paragraphs [0081]-[0109] of US 2018/0221396 A1 and [082]-[0110] US 2019/0142851 A1 as well as the disclosed preferred embodiments. Exemplary cannabinoids include but are not limited to the cannabinoids described in paragraphs [0111]-[0159] of US 2018/0221396 A1 and [0112]-[0160] US 2019/0142851 A1 as well as the disclosed preferred embodiments. Exemplary terpenes include but are not limited to the terpenes described in paragraphs [0160]-[0238] of US 2018/0221396 A1 and [0161]-[0300] US 2019/0142851 A1 as well as the disclosed preferred embodiments.

[0042] A pharmaceutical formulation of the disclosure may comprise, consist essentially of, or consist of (a) crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate and (b) a second active compound selected from a serotonergic drug, a purified psilocybin derivative, a purified cannabinoid, or a purified terpene and (c) a pharmaceutically acceptable excipient. Crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate and the second active compound are each present in a therapeutically effective amount using a purposefully engineered and unnaturally occurring molar ratios. Exemplary molar ratios of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate to the second active compound in a composition of the disclosure include but are not limited to from about 0.1:100 to about 100:01, 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.

[0043] A pharmaceutical formulation of the disclosure may comprise a composition 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 a purposefully engineered and unnaturally occurring molar ratios. Published US applications US 2018/0221396 A1 and US 2019/0142851 A1 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. The disclosures of US 2018/0221396 A1 and US 2019/0142851 A1 are incorporated herein by reference. According to this disclosure composition containing crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate as discussed above may be used in place of a “purified psilocybin derivative” in the compositions described in US 2018/0221396 A1 and US 2019/0142851 A1. Accordingly, the disclosure provides a pharmaceutical formulation comprising as (a) crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate and as a second component selected from (a) a purified psilocybin derivative, (b) one or two purified cannabinoids and (c) a purified terpene; with the rest being at least one suitable pharmaceutical excipient or at least one other adjuvant, as discussed below. Such a composition may be a pharmaceutical composition wherein the components are present individually in therapeutic effective amounts or by combination in a therapeutically effective amount to treat a disease, disorder, or condition as described herein.

[0044] 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 A1 and [0305]-[0311] US 2019/0142851 A1 as well as the disclosed preferred embodiments, incorporated here by reference. Some exemplary serotonergic drugs include the following molecules: 6-Allyl-N,N-diethyl-NL, N,N-Dibutyl-T, N,N-Diethyl-T, N,N-Diisopropyl-T, 5-Methyoxy-alpha-methyl-T, N,N-Dimethyl-T, 2,alpha-Dimethyl-T, alpha,N-Dimethyl-T, N,N-Dipropyl-T, N-Ethyl-N-isopropyl-T, alpha-Ethyl-T, 6,N,N-Triethyl-NL, 3,4-Dihydro-7-methoxy-1-methyl-C, 7-Methyoxy-1-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-1-methyl-1,2,3,4-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, and 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-C, 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 a preferred embodiment, the serotonergic drug is 3,4-methylenedioxymethamphetamine.

[0045] Exemplary psilocybin derivatives include but are not limited to psilocybin itself and the psilocybin derivates described in paragraphs [0081]-[0109] of US 2018/0221396 A1 and [082]-[0110] US 2019/0142851 A1 as well as the disclosed preferred embodiments, incorporated here by reference. In one embodiment, the compositions disclosed herein comprise one or more purified psilocybin derivatives chosen from: [3-(2-Dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, 4-hydroxy-N,N-dimethyltryptamine, [3-(2-methylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-N-methyltryptamine, [3-(aminoethyl)-1H-indol-4-yl] dihydrogen phosphate, [3-(2-trimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, and 4-hydroxy-N,N,N-trimethyltryptamine.

[0046] Exemplary cannabinoids include but are not limited to the cannabinoids described in paragraphs [0111]-[0159] of US 2018/0221396 A1 and [0112]-[0160] US 2019/0142851 A1 as well as the disclosed preferred embodiments, incorporated here by reference. 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 (CBDV), Cannabinol (CBN), Cannabinol methylether (CBNM), Cannabinol-C2 (CBN-C2), Cannabinol-C4 (CBN-C4), Cannabinolic acid (CBNA), Cannabiorcool (CBN-C1), Cannabivarin (CBV), Cannabitriol (CBT), Cannabitriolvarin (CBTV), 10-Ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, Cannbicitran (CBT), Cannabiripsol (CBR), 8,9-Dihydroxy-delta-6a-tetrahydrocannabinol, Delta-8-tetrahydrocannabinol (Δ8-THC), Delta-8-tetrahydrocannabinolic acid (Δ8-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), Tryhydroxy-delta-9-tetrahydrocannabinol (triOH-THC), Dehydrocannabifuran (DCBF), and 3,4,5,6-Tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-metha-no-2H-1-benzoxocin-5-methanol. In one embodiment, the purified cannabinoid is chosen from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBGV, or CBGVA.

[0047] Exemplary terpenes include but are not limited to the terpenes described in paragraphs [0160]-[0238] of US 2018/0221396 A1 and [0161]-[0300] US 2019/0142851 A1 as well as the disclosed preferred embodiments, incorporated here by reference. 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/1,8-cineole, eudesmol, eugenol, euphol, farnesene, farnesol, fenchone, geraniol, geranyl acetate, guaia-1(10),11-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.

[0048] Exemplary compositions of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate and a second compound selected from a serotonergic drug, a purified psilocybin derivative, a purified cannabinoid, or a purified terpene in exemplary molar ratios are shown in Table 1.

TABLE-US-00001 TABLE 1 Molar ratio of Molar ratio of Molar ratio of crystalline crystalline crystalline norpsilocin norpsilocin norpsilocin freebase, freebase, freebase, crystalline crystalline crystalline norpsilocin norpsilocin norpsilocin fumarate, or fumarate, or fumarate, or norpsilocin norpsilocin norpsilocin fumarate: second fumarate: second fumarate: second Second Compound compound compound compound 3,4- About 1:100 to About 1:25 to About 1:5 to about methylenedioxymethamphetamine about 100:1 about 25:1 5:1 Citalopram About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Escitalopram About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Fluoxetine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Paroxetine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Sertraline About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 [3-(2-Dimethylaminoethyl)-1H- About 1:100 to About 1:25 to About 1:5 to about indol-4-yl] dihydrogen phosphate about 100:1 about 25:1 5:1 4-hydroxytryptamine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 4-hydroxy-N,N-dimethyltryptamine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 [3-(2-methylaminoethyl)-1H-indol- About 1:100 to About 1:25 to About 1:5 to about 4-yl] dihydrogen phosphate about 100:1 about 25:1 5:1 4-hydroxy-N-methyltryptamine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 [3-(aminoethyl)-1H-indol-4-yl] About 1:100 to About 1:25 to About 1:5 to about dihydrogen phosphate about 100:1 about 25:1 5:1 [3-(2-trimethylaminoethyl)-1H- About 1:100 to About 1:25 to About 1:5 to about indol-4-yl] dihydrogen phosphate about 100:1 about 25:1 5:1 4-hydroxy-N,N,N- About 1:100 to About 1:25 to About 1:5 to about trimethyltryptamine about 100:1 about 25:1 5:1 THC About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 CBC About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 CBD About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 CBG About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Myrcene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Pinene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Caryophyllene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Limonene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Humulene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Linalool About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1

[0049] Exemplary pharmaceutical compositions of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate and a second compound selected from a serotonergic drug, a purified psilocybin derivative, a purified cannabinoid, or a purified terpene and an excipient with exemplary molar ratios of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate to the second compound are shown in Table 2.

TABLE-US-00002 TABLE 2 Molar ratio of Molar ratio of Molar ratio of crystalline crystalline crystalline norpsilocin norpsilocin norpsilocin freebase, freebase, freebase, crystalline crystalline crystalline norpsilocin norpsilocin norpsilocin fumarate, or fumarate, or fumarate, or norpsilocin norpsilocin norpsilocin fumarate: second fumarate: second fumarate: second Second Compound compound compound compound 3,4- About 1:100 to About 1:25 to About 1:5 to about methylenedioxymethamphetamine about 100:1 about 25:1 5:1 Citalopram About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Escitalopram About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Fluoxetine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Paroxetine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Sertraline About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 [3-(2-Dimethylaminoethyl)-1H- About 1:100 to About 1:25 to About 1:5 to about indol-4-yl] dihydrogen phosphate about 100:1 about 25:1 5:1 4-hydroxytryptamine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 4-hydroxy-N,N-dimethyltryptamine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 [3-(2-methylaminoethyl)-1H-indol- About 1:100 to About 1:25 to About 1:5 to about 4-yl] dihydrogen phosphate about 100:1 about 25:1 5:1 4-hydroxy-N-methyltryptamine About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 [3-(aminoethyl)-1H-indol-4-yl] About 1:100 to About 1:25 to About 1:5 to about dihydrogen phosphate about 100:1 about 25:1 5:1 [3-(2-trimethylaminoethyl)-1H- About 1:100 to About 1:25 to About 1:5 to about indol-4-yl] dihydrogen phosphate about 100:1 about 25:1 5:1 4-hydroxy-N,N,N- About 1:100 to About 1:25 to About 1:5 to about trimethyltryptamine about 100:1 about 25:1 5:1 THC About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 CBC About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 CBD About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 CBG About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Myrcene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Pinene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Caryophyllene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Limonene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Humulene About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1 Linalool About 1:100 to About 1:25 to About 1:5 to about about 100:1 about 25:1 5:1

[0050] An “effective amount” or a “therapeutically effective amount” of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate 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. Crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate 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.

[0051] 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. Preferred carriers include those that do not substantially alter crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate, or produce undesirable biological effects or otherwise interact in a deleterious manner with any other component(s) of the pharmaceutical composition.

[0052] 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, crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate 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, alignates, 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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).

[0057] Administration of crystalline norpsilocin freebase, crystalline norpsilocin fumarate, or norpsilocin fumarate 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, intravaginally, intravesically, or intrasystemically, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, such as, for example, in unit dosage forms suitable for simple administration of precise dosages. One route of administration may be oral administration, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.

Examples

[0058] The preparation of crystalline norpsilocin freebase and crystalline norpsilocin fumarate are discussed below.

[0059] Preparation of Crystalline Norpsilocin Freebase and Crystalline Norpsilocin Fumarate

[0060] Single crystals of norpsilocin freebase suitable for X-ray analysis were obtained from the slow evaporation of an acetone solution of a commercial sample of 4-hydroxy-N-methyltryptamine (Angene).

[0061] The norpsilocin fumarate was synthesized by starting with 101 mg of 4-hydroxy-N-methyltryptamine which was dissolved in 10 mL of methanol. 62 mg of fumaric acid was added to the solution and it was stirred overnight under reflux. The solvent was removed in vacuo to yield a dark blue powder. The powder was triturated with diethyl ether and then recrystallized in acetone to yield colorless crystals suitable for X-ray analysis.

[0062] .sup.1H NMR (400 MHz, D.sub.2O): δ 7.12 (s, 1H, ArH), 7.10-7.07 (m, 2H, ArH), 6.66 (s, 2H, CH), 6.56 (dd, J=5.5, 2.8 Hz, 1H, ArH), 3.41 (t, J=6.8 Hz, 2H, CH.sub.2), 3.26 (t, J=6.8 Hz, CH.sub.2), 2.70 (s, 3H, CH.sub.3).

[0063] .sup.13C NMR (100 MHz, D.sub.2O): δ 171.0 (COOH), 149.7 (ArC), 138.5 (ArC), 134.2 (CH), 123.0 (ArC), 122.8 (ArC), 115.6 (ArC), 108.4 (ArC), 104.1 (ArC), 103.4 (ArC), 50.3 (CH.sub.2), 32.4 (CH.sub.2), 22.7 (CH.sub.3).

[0064] Single crystal data, data collection and structure refinement details for crystalline norpsilocin freebase and crystalline norpsilocin fumarate are summarized in Table 3. The data for crystalline norpsilocin fumarate in Table 3 relates to the asymmetric unit.

TABLE-US-00003 TABLE 3 Norpsilocin Freebase Norpsilocin Fumarate Chemical formula C.sub.11H.sub.14N.sub.2O C.sub.11H.sub.15N.sub.2O•C.sub.2HO.sub.2 M.sub.r 190.24 248.28 Crystal system, space group Monoclinic, P2.sub.1/c Triclinic, P1 Temperature (K) 297 297 a, b, c (Å) 9.4060 (16), 8.8436 (15), 12.144 7.7363 (10), 9.7146 (12), 9.7854 (2) (13) α (°) 105.524 (4) β (°) 100.601 (7) 110.554 (4) γ (°) 97.167 (4) V (Å.sup.3) 993.0 (3) 643.69 (14) z 4 2 Radiation type Mo Kα Mo Kα μ (mm.sup.−1) 0.08 0.09 Crystal size (mm) 0.35 × 0.2 × 0.1 0.24 × 0.19 × 0.03 F(000) 408 264 D.sub.x (Mg m.sup.−3) 1.273 1.281 λ (Å) 0.71073 0.71073 θ (°) 2.9-26.0 2.7-25.5 BLOCK Colourless Colourless Diffractometer Bruker D8 Venture CMOS Bruker D8 Venture CMOS Absorption correction Absorption correction: multi-scan Absorption correction: multi-scan SADABS2016/2 (Bruker, 2016/2) SADABS2016/2 (Bruker, 2016/2) was used for absorption was used for absorption correction. wR2(int) was 0.0546 correction. wR2(int) was 0.0541 before and 0.0457 after before and 0.0477 after correction. The Ratio of minimum correction. The Ratio of minimum to maximum transmission is to maximum transmission is 0.9612. The λ/2 correction factor is 0.9187. The λ/2 correction factor Not present. is Not present. T.sub.min, T.sub.max 0.716, 0.745 0.685, 0.745 No. of measured, independent 35681, 1955, 1687 14395, 2365, 1774 and observed [l > 2σ(l)] reflections R.sub.int 0.031 0.046 θ.sub.max, θ.sub.min (°) 26.1, 3.2 25.5, 2.7 h −11.fwdarw.11 −9.fwdarw.9 k −10.fwdarw.10 −11.fwdarw.11 l −14.fwdarw.15 −11.fwdarw.11 Refinement F.sup.2 F.sup.2 Least-squares matrix Full Full R[F.sup.2 > 2σ(F.sup.2)], wR(F.sup.2), S 0.053, 0.146, 1.08 0.039, 0.098, 1.11 No. of reflections 1955 2365 No. of parameters 137 181 No. of restraints 3 4 Hydrogen site location Mixed Mixed H-atom treatment H atoms treated by a mixture of H atoms treated by a mixture of independent and constrained independent and constrained refinement refinement w 1/[σ.sup.2(F.sub.o.sup.2) + (0.0686P).sup.2 + 0.560P] 1/[σ.sup.2(F.sub.o.sup.2) + (0.0428P).sup.2 + 0.1031P] where P = (F.sub.o.sup.2 + 2F.sub.c.sup.2)/3 where P = (F.sub.o.sup.2 + 2F.sub.c.sup.2)/3 (Δ/σ).sub.max <0.001 <0.001 Δρ.sub.max, Δρ.sub.min (e Å.sup.−3 ) 0.59, −0.22 0.15, −0.15 Extinction Correction SHELXL2018/3 (Sheldrick 2018), Fc* = kFc[1 + 0.001 × Fc.sup.2λ.sup.3/sin(2θ)].sup.−1/4 Extinction Coefficient 0.035 (8) Data collection: APEX3 (Bruker, 2018). Cell refinement: SAINT (Bruker, 2018) for umd2019e_a; SAINT (Bruker, 2018 for umd2025f_a. Data reduction: SAINT for umd2019e_a; SAINT (Bruker, 2018) for umd2025f_a. Program(s) used to solve structure: SHELXT2014 (Sheldrick 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: pubICIF (Westrip, 2010).

[0065] The molecular structure of crystalline norpsilocin freebase is shown in FIG. 1. The asymmetric unit contains one full 4-hydroxy-N-methyltryptamine (C.sub.11H.sub.14N.sub.2O) molecule. The indole ring system of the tryptamine is near planar with an r.m.s. deviation from planarity of 0.015 Å. The ethylamine arm of the tryptamine is slightly turned, with a C7-C8-C9-C10 torsion angle of 26.7 (3°).

[0066] The tryptamine molecules of the norpsilocin freebase are held in an infinite two-dimensional network along the (100) plane through a series of N—H . . . O and O—H . . . N hydrogen bonds. The phenol O—H hydrogen bonds with the nitrogen of the methylamine of another tryptamine molecule. The indole N—H hydrogen bonds with the phenol oxygen of another tryptamine molecule. The packing of crystalline norpsilocin freebase is shown in FIG. 2.

[0067] FIG. 3 is a simulated x-ray powder diffraction (XRPD) of crystalline norpsilocin freebase from its single crystal data. Crystalline norpsilocin freebase may be characterized by the XRPD peaks at 9.6, 12.4, and 17.9°2θ±0.2°2θ as well as by an XRPD pattern substantially similar to FIG. 3.

[0068] The molecular structure of crystalline norpsilocin fumarate is shown in FIG. 4. The asymmetric unit contains one full 4-hydroxy-N-methyltryptammonium (C.sub.11H.sub.15N.sub.2O.sup.+) cation and one half of a fumarate (C.sub.4H.sub.2O.sub.4.sup.2−) dianion. The indole ring system of the tryptamine is near planar with an r.m.s. deviation from planarity of 0.009 Å. Unlike norpsilocin freebase, the ethyl ammonium arm also stays in the same plane of the indole. The planarity of all of the nonhydrogen atoms of the tryptamine have an r.m.s. deviation from planarity of only 0.043 Å. The fumarate itself is also near planar, with an r.m.s. deviation from planarity of 0.050 Å.

[0069] The tryptammonium cations and the fumarate dianions of the norpsilocin fumarate are held together in an infinite three-dimensional framework through a series of N—H . . . O and O—H . . . O hydrogen bonds. The indole N—H, methylammonium N—H, and phenol O—H all hydrogen bond with the oxygen atoms of the fumarate dianion are shown in FIG. 5. The six-membered rings of the indoles stack with parallel slipped π-π interactions [intercentroid distance=3.6465 (15) Å, interplanar distance=3.4781 (16) Å, and slippage=1.095 (3) Å]. The packing of crystalline norpsilocin fumarate is shown in FIG. 6.

[0070] FIG. 7 is a simulated x-ray powder diffraction (XRPD) of crystalline norpsilocin fumarate from its single crystal data. Crystalline norpsilocin fumarate may be characterized by the XRPD peaks at 11.5, 13.9, and 16.2°2θ±0.2°2θ as well as by an XRPD pattern substantially similar to FIG. 7.

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