CA3149602A1 - Alkyl quarternary ammonium tryptamines and their therapeutic uses - Google Patents

Abstract

The invention relates to a compound of formula (I): The invention also relates to crystalline compounds of formula (I). The invention relates to compositions comprising, consisting essentially of, or consisting of a compound of formula (I) and an excipient. The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) where the excipient is a pharmaceutically acceptable carrier. The invention further relates to therapeutic uses of compounds of formula (I).

Description

ALKYL QUARTERNARY AMMONIUM TRYPTAMI NES AND THEIR THERAPEUTIC USES
Related Applications [001] This application claims priority to US application 62/891,388, filed August 25, 2019; to US
application 63/007,653, filed April 9, 2020; and to US application 63/053,976, filed July 20, 2020; each of which are incorporated herein by reference.
Technical Field

[002] This disclosure relates to alkyl quaternary ammonium tryptamines, compositions and pharmaceutical corn positions containing them as well as their use in treating various diseases.
Background

[003] N,N-dimethyltryptamine (DMT) and its derivatives have been used by humans for centuries because of their psychoactive, entheogenic, or hallucinogenic effects, or combinations thereof (Cameron & Olson, 2018). Psilocybin, the 4-phosphate variant of DMT, is arguably its most studied derivative. Psilocybin is one of several naturally occurring psychoactive tryptamines found in "magic"
mushrooms. When consumed by humans, psilocybin serves as a prodrug of psilocin. Upon digestion, psilocybin hydrolyses to generate psilocin, the 4-hydroxy derivative of DMT.
Psilocin is a potent serotonin 2a-agonist, which is responsible for its psychoactive properties (Dinis-Oliveira, 2017; Nichols, 2012).

[004] Psychoactive tryptamines like DMT and psilocin have garnered significant interest recently because of their potential for treating mood disorders, including depression, anxiety, addiction, and post-traumatic stress disorder (PTSD) (Johnson & Griffiths, 2017; Carhart-Harris & Goodwin, 2017).
Altering the chemical structure within this class of compounds can dramatically influence the potency and action of the drugs. For example, merely changing the N,N-dialkyl groups on DMT can modify its psychoactive properties: increasing the chain length of the two alkyl groups of the tryptamine to larger than n-butyl dramatically reduces or eliminates the psychoactive effects (Bradley & Johnston, 1970).

[005] The synthesis of N-methyl-N-isopropyltryptamine (MiPT) was reported in 1981 (Repke et aL, 1981). In 1985, Repke and co-workers reported that of the compounds in the series of N,N-dialky1-4-hy-droxytryptamines, the N-methyl-N-isopropyl derivative (4-HO-Mi PT) is the most potent based upon qualitative effects on humans (Repke et aL, 1985). Later quantitative studies showed the N-methyl-N-isopropyl derivatives of DMT and psilocin to be more potent as serotonin-1A, -2A and -2B receptors compared to the analogous dimethyl compounds (McKenna et aL, 1990).

Njt "Ann -0-Hick34 cis

[006] New psychoactive tryptamines have been identified in "magic mushrooms" as recently as 2017. (Lentz, et al., 2017.) Until this year, there was no general synthetic method for producing useful amounts of the minor psychoactive tryptamines. (Sherwood, Halberstadt, et al.) One of these minor components is aeruginascin, (Jensen, et al., 2006) the N-trimethyl analogue of psilocybin. The limited exposure of humans to Inocybe aeruginascens mushrooms, the only known species in which aeruginascin has been found, has resulted in hallucinations that exhibited only euphoric experiences. (Gartz, 1989). This is in contrast to psilocybin and psilocin mushrooms, which often lead to dysphoric moods during the psychedelic experience. Despite these observations, the pharmacological activity of aeruginascin has remained unexplored.

[007] Even with this previous work, there is a need to develop new psilocybin derivatives with improved properties for treatment of psychological disorders.
Summary of the Invention

[008] The invention relates to a compound of formula (I):

X-Rg R

(I) wherein R1, R2 and R3 are each independently a straight chain or branched C1-05 alkyl or C2- C6 alkenyl, R4 is hydrogen, hydroxyl, C1-C6 alkoxy, -0C(0)Rs, or-0C(0)0R5, Rs is a straight chain or branched C1-C6 alkyl, Rs is 114 or a straight chain or branched Ci-Cs alkyl with the proviso that Rs is not hydroxyl when RI, R2 and R3 are all methyl, 117., Its and R9 are each independently hydrogen or a straight chain or branched Ci-C6 alkyl, and X- is a pharmaceutically acceptable anion. The invention also provides a method of making compounds of formula (I).

[009] The invention relates to compositions comprising, consisting essentially of, or consisting of a compound of formula (I) and an excipient. The invention also relates pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) where the excipient is a pharmaceutically acceptable carrier. The invention further 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 a compound of formula (I) or of a pharmaceutical composition containing the compound.

[010] The invention also relates to a composition comprising, consisting essentially of, or consisting of as a first active component: a compound of formula (I) of the disclosure; and as a second active component selected from (a) a sertonergic drug, (b) a purified psilocybin derivative, (c) one or two purified cannabinoids and (d) a purified terpene; and a pharmaceutically acceptable excipient.

[011] The invention also relates to methods of preventing or treating inflammation and/or pain comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), and to administering a pharmaceutical composition or a composition according to the invention.
Brief Description of the Figures

[012] FIG. 1 is the fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of crystalline 4-AcO-TMT iodide.

[013] FIG. 2 is the simulated X-ray Powder Diffraction Pattern (XRPD) for 4-AcO-TMT iodide from its single crystal structure.

[014] FIG. 3 is the fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of crystalline 4-HO-TMT iodide.

[015] FIG. 4 is the simulated X-ray Powder Diffraction Pattern (XRPD) for 4-AcO-TMT iodide from its single crystal structure.

[016] FIG. 5 shows the molecular structure of crystalline DM PT iodide.

[017] FIG. 6 shows the packing of crystalline DMPT iodide.

[018] FIG. 7 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline DMPT iodide from its single crystal data.

[019] FIG. 8 shows the molecular structure of crystalline DMALT iodide.

[020] FIG. 9 shows the packing of crystalline DMALT iodide.

[021] FIG. 10 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline DMALT iodide from its single crystal data.

[022] FIG. 11 shows the molecular structure of crystalline 4-AcO-DMET iodide hemihydrate showing the atomic labelling.

[023] FIG. 12 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline 4-AcO-DMET iodide hemihydrate from its single crystal data.

[024] FIG. 13 shows the molecular structure of crystalline 4-AcO-DMPT iodide showing the atomic labelling.

[025] FIG. 14 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline 4-AcO-DMPT iodide from its single crystal data.

[026] FIG. 15 shows the molecular structure of 4-HO-DM PT iodide showing the atomic labelling.

[027] FIG. 16 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline 4-HO-DM PT iodide from its single crystal data.
Detailed Description

[028] Compounds of the Invention

[029] This invention relates to alkyl quaternary ammonium tryptamine compounds of formula (I):

\ R
nr--- 3 X-Re In formula (I), R1, R2 and R3 are each independently a straight chain or branched Ci-C6 alkyl, for example a straight chain Ci-C6 alkyl, or a C2-C6alkenyl, for example allyl. In some embodiments, R1, R2 and R3 are each independently a straight chain or branched Ci-C4 alkyl, for example a straight chain C1-C4 alkyl, or a C2-C4 alkenyl. R1, R2 and R3 may each independently be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In other embodiments, RI, R2 and R3 are each methyl, are each ethyl, or a mixture of methyl and ethyl groups. R4 is hydrogen, hydroxyl, C1-05alkoxy., -0C(0)R5 or -0C(0)0115.

When R4 is a Ci-C6alkoxy group, or in some embodiments a C1-C4 alkoxy group, it may be a straight chain or branched Ci-C6alkoxy group or Ci-C4 alkoxy group, for example a straight chain, and may be methoxy or ethoxy. Rs is a straight chain or branched Cr-Cs alkyl or C1-C4 alkyl, for example a straight chain Ci-C4 alkyl. In some embodiments, Rs is selected from methyl, ethyl, n-propyl or n-butyl, and for example is methyl or ethyl. R6 is R4 or a straight chain or branched Cr-C4 alkyl, with the exemplary embodiments just discussed and with the proviso that R6 is not hydroxyl when R1, R2 and R3 are all methyl. R7, Rs and Rg are each independently hydrogen or a straight chain or branched C1-C4 alkyl, for example a straight chain CrC4 alkyl. In some embodiments, 116, R7, R8 and Rg are each independently selected hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. In other embodiments, R6, R7, R8 and Rg are each independently hydrogen, methyl, ethyl. The anion, X-, may be any pharmaceutically acceptable anion, for example, Cl-, r, Br-, ascorbate, hydrofumarate, fumarate, maleate, and the like. A preferred anion. X-, is iodide, F. When the pharmaceutically acceptable anion is a di-anion it balances two of the ammonium cations.

[030] Preferred compounds of formula (I) are those where RI, R2 and R3 are each independently a Ci-Cis alkyl or a C2-C4 alkenyl; 114 is hydrogen, hydroxyl, Ci-C4 alkoxy, -0C(0)R5 or -0C(0)0R5; Rs is selected from methyl, ethyl, n-propyl and n-butyl; R6, R7, R8 and Rg are each independently hydrogen, methyl, or ethyl; and X- is Cl-, l-, Br, ascorbate, hydrofumarate, fumarate, or maleate.
Other preferred compounds are those where R1, R2 and 113 are each independently methyl, ethyl, propyl or allyl; Its is hydrogen, hydroxyl, or -0C(0)R5; Rs is methyl or ethyl; 116, R7, and R9 are each independently hydrogen; R8 is hydrogen or methyl; and X- is r.
[0311 Exemplary compounds of formula (I) are:
N
0>
H (la), \ /

OH I-0 \
11 (lb) o \NI
--Ao i-0 \
VI 00, o N
0 \
ri (Id), \ 0----Kr I
0 \
ri (le), Lre \
(If), se k.
\
Ogb 1, ii .k) N, les Nir /
rfCeN tre 32 ;A
(11)/
\
p8 \ ..........................................
zr.:7-tt4N
rtE
Ckt 11 V, -(0), and -------------------------------- 7 \
-c*E.
(1k).
[032] A compound of formula (I) 1\
rR3 X-Re Re R

(I) may be prepared formula (II) (below) with XR3, where X is I, by refluxing in an appropriate organic solvent, such as methanol or THF, under an inert atmosphere.

Ri\N

R3 opRe (II) In a preferred embodiment, XR3 is ICH3 or ICH2CH3. When R4 or Rfi are hydroxyl they can be converted to esters, -0C(0)R5, or carbonate esters, -0C(0)0R5, as is known in the art.
Hydroxyl groups may be introduced by hydrolysis of a corresponding ester. Other pharmaceutically acceptable salts may be prepared by anion exchange techniques known in the art to exchange the iodide anion for a desired pharmaceutically acceptable anion. For example, the iodide anion may be exchanged using an anion exchange resin.
[0331 Methods of Treatment and Therapeutic Uses [034] In one embodiment, the compounds of formula (I), the methods, and the pharmaceutical compositions of the invention are used to regulate the activity of a neurotransmitter receptor by administering a therapeutically effective dose of a compound formula (I).
Methods of the invention administer a therapeutically effective amount of a compound of formula (I) to prevent or treat a psychological disorder such as those discussed below. Compounds of formula (I) may be administered neat or as a pharmaceutical composition comprising a compound of formula (I) as discussed below.
[035] Compounds of formula (I) may be used to prevent and/or treat a psychological disorder. The invention provides a method for preventing and/or treating a psychological disorder by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), including the preferred embodiments discussed above. 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).
[036] Compounds of formula (I) may be used to prevent and/or treat a brain disorder. The invention provides a method for preventing and/or treating a brain disorder by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), including the preferred embodiments discussed above. The brain disorder may be chosen from Huntington's disease, Alzheimer's disease, dementia, and Parkinson's disease.
[037] Compounds of formula (I) 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 invention provides a method for preventing and/or treating these disorders by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), including the preferred embodiments discussed above.

[038] A compound of formula (I) according to the invention 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 invention 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 a compound of formula (I), including the preferred embodiments discussed herein. Generally speaking, treatable "pain" includes nociceptive, neuropathic, and mix-type.
A method of the invention 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 invention 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 invention 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.
[039] Compositions [040] The invention relates to compositions comprising, consisting essentially of, or consisting of an effective amount of a compound of formula (I), including its preferred embodiments discussed above, and an excipient. In another embodiment of the invention, the invention also relates to pharmaceutical compositions comprising, consisting essentially of, or consisting of a therapeutically effective amount of a compound of formula (I) according to the invention, including its preferred embodiments discussed above, and a pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier). As discussed above, a compound of formula (I) according to the invention 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.
[041] A composition or a pharmaceutical composition of the invention may be in any form which contains a compound of formula (I) according to the invention. 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 a compound of formula (I) 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 a compound of formula (I) with the rest being at least one suitable pharmaceutically acceptable excipient or at least one other adjuvant, as discussed below.
[042] 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 serotonergic drug, 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 invention, a compound of formula (I) of the invention, and the preferred embodiments described herein, 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 invention provides a composition comprising as a first component: a compound of formula (I) of the disclosure; and as a second component selected from (a) a sertonergic 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 therapeutic effective amounts or by combination in a therapeutically effective amount to treat a disease, disorder or condition as described herein.
[043] 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 [0305140311] US 2019/0142851 Al 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-l-methyl-C, 7-Methyoxy-1-methyl-C, N,N-Dibuty1-4-hydroxy-T, N,N-Diethyl-4-hydroxy-T, N,N-Diisopropy1-4-hydroxy-T, N,N-Dimethy1-4-hydroxy-T, N,N-Dimethy1-5-hydroxy-T, N, N-Dipropy1-4-hydroxy-T, N-Ethy1-4-hydroxy-N-methyl-T, 4-Hydroxy-N-isopropyl-N-methyl-T, 4-Hydroxy-N-methyl-N-propyl-T, 4-Hydroxy-N,N-tetramethylene-T lbogaine, N,N-Diethyl-L, N-Butyl-N-methyl-T, N,N-Diisopropy1-4,5-methylenedioxy-T, N,N-Diisopropy1-5,6-methylenedioxy-T, N,N-Dimethy1-4,5-methylenedioxy-T, N,N-Dimethy1-5,6-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-Diisopropy1-5-methoxy-T, 5-Methoxy-N,N-dimethyl-T, N-Isopropyl-4-methoxy-N-methyl-T, N-Isopropy1-5-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-methy1-1,2,3,4-tetrahydro-C, 5-Methoxy-2,N,N-trimethyl-T, N,N-Dimethy1-5-methylthio-T, N-Isopropyl-N-methyl-T, alpha-Methyl-T, N-Ethyl-T, N-Methyl-T, 6-Propyl-N 1_, N,N-Tetramethylene-T, Tryptamine, and 7-Methoxy-1-methy1-1,2,3,4-tetrahydro-C, alpha,N-Dimethy1-5-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, psic.aine, oxazepam, reboxetine, serenic, serotonin, sertraline, temazepam, tramadol, triazolam, a tryptamine, venlafaxine, vortioxetine, and/or derivatives thereof.
[044] Exemplary psilocybin derivatives include but are not limited to psilocybin itself and the psilocybin derivates described in paragraphs [0081]-[0109] of US 2018/0221396 Al and [082]-[0110] US
2019/0142851 Al 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-y11 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-indo1-4-yl] dihydrogen phosphate, [3-(2-trimethylaminoethyl)-1H-indo1-4-yl] dihydrogen phosphate, and 4-hydroxy-N,N,N-trimethyltryptamine.
[045] Exemplary cannabinoids include but are not limited to the cannabinoids described in paragraphs [0111]40159] of US 2018/0221396 Al and [0112]10160] US 2019/0142851 Al 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 (CRC), 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 (CRT), Cannabiripsol (CBR), 8,9-Dihydroxy-delta-6a-tetrahydrocannabinol, Delta-8-tetrahydrocannabinol (.DELTA.8-THC), Delta-8-tetrahydrocannabinolic acid (.DELTA.8-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), 10-0xo-delta-6a-tetrahydrocannabinol (OTHC), Cannabichromanon (CBCF), Cannabifuran (CBF), Cannabiglendol, Delta-9-cis-tetrahydrocannabinol (cis-THC), Tryhydroxy-delta-9-tetrahydrocannabinol (tri0H-THC), Dehydrocannabifuran (DCBF), and 3,4,5,6-Tetrahydro-7-hydroxy-alpha-alpha-2-trimethy1-9-n-propy1-2,6-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.
[046] Exemplary terpenes include but are not limited to the terpenes described in paragraphs [0160]-[0238] of US 2018/0221396 Al and [0161]40300] US 2019/0142851 Al 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, hornyl acetate, borneol, cadinene, cafestol, caffeic acid, camphene, camphor, capsaicin, carene, carotene, carvacrol, carvone, alpha-caryophyllene, beta-caryophyllene, caryophyllene oxide, cedrene, cedrene epoxide, cecanal, cedrol, cembrene, cinnamaldehyde, cinnamic acid, citronella!, citronellol, cymene, eicosane, elemene, estragole, ethyl acetate, ethyl cinnamate, ethyl maltol, eucalypto1/1,8-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, beta-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, beta-caryophyllene, cedrene, cymene, elemene, eucalyptol, eudesmol, farnesene, fenchol, geraniol, guaiacol, humulene, isoborneol, limonene, linalool, menthol, beta-myrcene, nerolidol, ocimene, phellandrene, phytol, pinene, pulegone, sabinene, terpineol, terpinolene, or valencene.
[047] A "therapeutically effective amount" of a compound of formula (I) according to the invention 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. A compound of formula (I) according to the invention 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.
[048] 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 the salt of ritonavir or produce undesirable biological effects or otherwise interact in a deleterious manner with any other component(s) of the pharmaceutical composition.
[049] The pharmaceutical compositions of the invention 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., 1994), which is incorporated herein by reference. In a solid dosage form, a compound of formula (I) 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.
[1:1501 Excipients or pharmaceutically acceptable adjuvants known in the pharmaceutical formulation art may also be used in the pharmaceutical compositions of the invention.
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 invention 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.
[0511 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.
[052] 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.

[053] 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).
[054] Administration of a compound of formula (I) 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.
[055] Examples [056] Example 1: 4-Acetoxy-N,N,N-trimethyltryptammonium Iodide (4-AcO-TMT
iodide) [057] 4-acetoxy-N,N-dimethyltryptammine (4-AcO-DMT) fumarate was stirred in a 1:1 solution of methanol and iodomethane and heated to reflux for four hours. Solvent is removed in vacua, and a white powder is obtained after triturating and washing the resulting residue with tetrahydrofuran. 1H NMR (400 MHz, D20): 57.46 (d, J = 8.1 Hz, 1H, ArH), 7.33 (s, 1H, ArH), 7.27 (t, I = 8.0 Hz, 1H, ArH), 6.90 (d, J = 7.8 Hz, 1H, ArH), 3.63 (t, J = 7.5 Hz, 2H, Cl-!2), 3.27 (t, J = 8.6 Hz, 2H, CH2), 321 (s, 9H, NC!-!3), 2.47 (s, 3H, C(0)CH4.
Unit Cell: a = 7.8459(9) A, b = 9.8098(12) A, c = 11.0823(12) A, a = 909, f3 =
101.069(3)9, y = 90`1, V =
837.10(17) A3.
[058] Second Preparation of 4-AcO-TMT iodide: 250 mg of 4-acetoxy-N,N-dimethyltryptammonium (4-AcO-DMT) fumarate was dissolved in 10 mL of methanol in a 50 mL round bottom flask, and 10 ml_ of iodomethane was then added. The mixture was stirred for 24 hours under an atmosphere of dinitrogen.
The solvent was removed in vacuo. The resulting powder was washed with diethyl ether and filtered to yield 313 mg of yellow powder. This powder was dissolved in 75 mL of acetone.
The solution was heated with stirring and reduced in volume to 40 mL. The mixture was cooled in an ice bath, yielding a white precipitate. The powder was filtered to yield 142 mg of white powder (53.01%
yield). 1H NMR (400 MHz, D20): 6 7.46 (d, 3 = 8.6 Hz, 1 H, ArH), 7.34 (s, 1 H, ArH), 7.22 (t, J = 7.8 Hz, 1 H, ArH), 6.95 (d, 3 = 8.3 Hz, 1H, ArH) 3.63 (t, J = 7.9 Hz, 2 H, Cl-i2), 3.28 (t,1 = 8.0 Hz, 2 H, Cl-I2), 3.21 (s, 9 H, CH3), 2.47 (s, 3 H, C(0)C1-13); 13C NMR (100 MHz, D20): 6 174.32 (C=0), 143.59 (ArC), 139.28 (ArC), 125.82 (ArC), 123.01 (ArC), 119.11 (ArC), 112.92 (ArC), 111.13 (ArC), 107.32 (ArC), 67.64 (NCH2), 53.73 (NCH3), 21.25 (CH2), 20.48 (C(0)CH3). Elemental analysis calcd. for CisH21N2021: C 46.40, H 5.45, N
7.22; Found: C 46.17, H
5.35, N 7.11.
[059] X-Ray data collection and refinement details for 4-AcO-TMT iodide:
Crystals suitable for X-ray diffraction studies were grown from the slow evaporation of an aqueous solution. All operations were performed on a Bruker D8 Venture CMOS diffractometer, using Mo Ka radiation with a TRIUMPH
monochromator at a temperature of 298 K. Data collection was carried out using the Bruker APEX3 software. Cell refinement and data reduction were performed with the SAINT
program. The structure solution was done with SHELKS and structure refinement was performed with SHELXL. Further refinement and molecular graphics were generated using the OLEX2 and Mercury CSD software.
[060] All non-hydrogen atoms were refined anisotropically (XL) by full matrix least squares on F2.
Hydrogen atom H1 was found from a Fourier difference map, and refined with a fixed distance of 0.87 A.
Isotropic displacement parameters were set to 1.20 times Ueci of the parent N
atoms. The remaining hydrogen atoms were placed in calculated positions and then refined with a riding model with C-H
lengths of 0.93 A (sp2), 0.96 A (0-6) and 0.97 A (cm) with isotropic displacement parameters set to 1.20 (sp2 and CH2) and 1.50 (CH3) times IJE.q of the parent C atom. Further details are in Table 1. FIG. 11s the fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of 4-AcO-TMT iodide.
Table 1. Crystal data and structure refinement for 4-AcO-TMT iodide.
Empirical formula C15H21IN202 Formula weight 388.24 Temperature/K 299.05 Crystal system Monoclinic Space group P21 a/A 7.8459(9) b/A 9.8098(12) c/A 11.0823(12) PP 101.069(3) Volume/A3 837.10(17) pcakg/cm3 1.540 Rim ncl 1.916 F(000) 388.0 Crystal size/mm3 0.2 x 0.1 x 0.05 Radiation MoKa (A. = 0.71073) 20 range for data collection/9 5.866 to 50.852 Index ranges -9 .1-19,-11 Reflections collected 18328 Independent reflections 3076 [Rim = 0.0424, Rsigma = 0.02981 Data/restraints/parameters 3076/2/189 Goodness-of-fit on F2 1.064 Final R indexes [I 2o (I)] R1 = 0.0300, wR2 =
0.0548 Final R indexes [all data] R1= 0.0396, wR2 = 0.0583 Largest cliff. peak/hole / e 0.51/-0.40 Flack parameter -0.001(11) [061] FIG. 2 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline 4-Acetoxy-N,N,N-trimethyltryptammonium Iodide (4-AcO-TMT iodide) from its single crystal data.
Crystalline 4-Acetoxy-N,N,N-trimethyltryptammonium Iodide (4-AcO-TMT iodide) may be characterized by the XRPD peaks at 8.1, 14.6 and 19.8 -n 0.29213 as well as by an XRPD pattern substantially similar to Fla 2.
[062] Example 2: 4-Hydroxy-N,N,N-trimethyltryptammonium (4-HO-TMT) Iodide [063] 4-acetoxy-N,N,N-trimethyltryptammonium (4-AcO-TMT) iodide was stirred in a 1:1 solution of water and acetic acid in air for 12 hours. Solvent is removed in vacua, and a white powder is obtained after triturating and washing the resulting residue with tetrahydrofuran. 1H
NMR (400 MHz, D20): 6 7.18 (s, 1H, ArH), 7.12-7.06 (m, 2H, ArH), 6.57 (dd, J = 6.0, 2.4 Hz, 1H, ArH), 3.62 (t, J = 7.8 Hz, 2H, CH4, 3.37 (t, 3 = 8.1 Hz 2H, CH2), 3.19 (s, 9H, NCH3). Unit Cell: a = 11.3057(9) A, b =
11.2370(10) A, c= 12.7785(10) A, a = 909, p = 113.087(2)9, y = 909, V = 1493.4(2) A3.
[064] Second preparation of 4-HO-TMT iodide: 95 mg of 4-Ac0 TMT iodide was dissolved in 4 mL of deionized (DI) water in a 50 mL round bottom flask. 20 mL of acetic acid was added to the mixture, and it was refluxed under an atmosphere of dinitrogen for 2 days. Solvent was removed in vacuo to obtain a green/blue oil. 3 mL of methanol and 20 mL of ethyl acetate were added to the green/blue oil, leaving a green/blue powder that was removed via filtration. Solvent was removed in vacua. The resulting oil was dissolved n 5 mL of ethanol, and 30 mL of pentane was added to generate a precipitate. The resulting powder was isolated via filtration to give 53.1 g (60% yield) to give an off-white powder. 1H NMR (400 MHz, D20): 6 7.19 (s, 1 H, ArH), 7.12-7.07 (m, 2 H, ArH), 6.56 (dd, J = 5.9, 2.5 Hz, 1 H, ArH), 3.66-3.62 (m, 2 H, CH2), 3.40-3.36 (m, 2 H, CH2), 3.20 (s, 9 H, CH4; nc NMR (100 MHz, D20):
5 150.62 (ArC), 139.37 (ArC), 123.89 (ArC), 123.86 (ArC), 116.56 (ArC), 108.72 (ArC), 105.23 (ArC), 104.43 (ArC), 68.20 (NCH2), 53.59 (NCH3), 21.20 (Cl-I2). Elemental analysis calcd. For C13H19N201: C
45.10, H 5.53, N 8.09; Found: C
44.84, H 5.23, N 7.98.

[065] X-Ray data collection and refinement details for 4-HO-TMT iodide:
Crystals suitable for X-ray diffraction studies were grown from the slow evaporation of an aqueous solution. All operations were performed on a Bruker D8 Venture CMOS diffractometer, using Mo Ka radiation with a TRIUMPH
monochromator at a temperature of 200 K. Data collection was carried out using the Bruker APEX3 software. Cell refinement and data reduction were performed with the SAINT
program. The structure solution was done with SHELXS and structure refinement was performed with SHEXL. Further refinement and molecular graphics were generated using the OLEX2 and Mercury CSD software.
[066] All non-hydrogen atoms were refined anisotropically (XL) by full matrix least squares on F2.
Hydrogen atom H1 and HlA were found from a Fourier difference map, and refined with a fixed distance of 0.86 A and 0.85 A respectively. Isotropic displacement parameters were set to 1.20 times Ueq of the parent N atom, and 1.50 times Unq of the parent 0 atom. The remaining hydrogen atoms were placed in calculated positions and then refined with a riding model with C¨H lengths of 0.95 A (spl, 0.98 A (Cl-I2) and 0.99 A (GO with isotropic displacement parameters set to 1.20 (sp2 and Cl-h) and 1.50 (CH3) times Uet, of the parent C atom. Further details are in Table 2. FIG. 3 is the fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of 4-HO-TMTI.
Table 2. Crystal data and structure refinement for 4-HO-TMT iodide.
Empirical formula C13H19IN20 Formula weight 346.20 Temperature/K 200.0 Crystal system Monoclinic Space group P2i/n a/A 11.3057(9) b/A 11.2370(10) c/A 12.7785(10) a.r 90 13P 113.087(2) Yie 90 Volume/A3 1493.4(2) pcakg/cm3 1.540 it/mm_i 2.133 F(000) 688.0 Crystal size/mm3 0.4 x 0.2 x 0.1 Radiation MoKa (X = 0.71073) 20 range for data collection/. 6.164 to 52.884 Index ranges ¨13 5 h 5 14, ¨14 5 k 5 14, ¨15 5 I 5 15 Reflections collected 29269 Independent reflections 3063 [Rim = 0.0564, Rsignia = 0.0277]

Data/restraints/parameters 3063/2/161 Goodness-of-fit on F2 1.073 Final R indexes [I 2, (I)] R1 = 0.0368, wR2 =
0.0797 Final R indexes [all data] Ri = 0.0574, wR2 =
0.0885 Largest cliff. peak/hole / e A-3 1.05/-0.93 [067] FIG. 4 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline 4-Hydroxy-N,N,N-trimethyltryptammonium Iodide (4-HO-TMT iodide) from its single crystal data.
Crystalline 4-Hydroxy-N,N,N-trimethyltryptammonium Iodide (4-HO-TMT iodide) may be characterized by the XRPD peaks at 17.0, 18.1 and19.5 20 0.2 20 as well as by an XRPD pattern substantially similar to FIG. 4.
[068] Example 3: Cellular Assays [069] Cellular assays were performed by Eurofins CEREP SA, Celle-Levescault, France. All receptors were separately expressed in HEK-293 cells. Cell membrane homogenates (30 lig protein) are incubated for 60 min (5-HT1A, 5-EIT2A, 5-HT2B) or 120 min (5-HT3) at 22 C with radiolabeled ligand in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCI (pH 7.4), 5 mM MgCl2, 10 p.M
pargyline and 0.1% ascorbic acid. For 5-HT3, the buffer contained 50 mM Tris-HCI (pH 7.4), 5 mM MgCl2, and 1mM EDTA. Binding was reported as the K1 for the inhibition of binding of well-characterized orthosteric ligands. The ligands used for each receptor were:
5-HT1A: [3H] 8-0H-DPAT
5-HT2A: [125.] tri = 1 5-HT2R: [1251] ( )D01 5-HT3: [3H] BRL 43694 [070] Nonspecific binding was determined in the presence of 1 p.M unlabeled ligand listed above.
Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM
Tris-HCI using a 96-sample cell harvester (Unifilter, Packard). The filters were dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control radioligand specific binding.
[071] The IC50 values and Hill coefficients (nH) were determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting Y=D-F[ (A-D) / (1+(C/C50) nil) ] where Y = specific binding, A = left asymptote of the curve, D = right asymptote of the curve, C = compound concentration, Co = ICso, and nH = slope factor.

[072] Analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot 4.0 for Windows (0 1997 by SPSS Inc.). The inhibition constants (KO were calculated using the Cheng Prusoff equation: K= ICso (1+LAD), where L = concentration of radioligand in the assay, and KD =
affinity of the radioligand for the receptor. A scatchard plot was used to determine the Kr).
[073] The results in terms of inhibition constants (K) are shown in Table 3.
The aeruginascin active metabolite, 4-HO-TMTI, shows activity at 5-HT1A, 5-HT2A and 5-HT2B. Counter to the prevailing theory that aeruginascin should function as a powerful 5-1-11-3 agonist, there is no activity observed at this receptor. The aeruginascin functional analogue, 4-AcO-TMTI shows no activity at any of the receptors.
For comparison, psilocybin, the pro-drug of psilocin, shows no activity at 5-HT1A, 5-HT2A, nor 5-HT3, but does show itself to be a potent 5-HT2B agonist. Psilocin, its active metabolite, shows activity at 5-HT1A
and 5-HT2A that is more active though comparable to 4-HO-TMTI. (Roth et al.) It is significantly more potent than 4-HO-TMTI at the 5-HT2B receptor, and in fact, psi locybin is more active at this receptor as well.
Table 3. Inhibition constants (K) in nM units.
Compound 5-HTIA 5-HT2A 5-HT2B 5-HT3 4-HO-TMTI 4,400 670 120 >10,000 4-Ac0->10,000 >10,000 >10,000 >10,000 TMTI
Psilocint 567.4 107.2 4.6 >10,000 Psilocybint >10,000 >10,000 98.7 >10,000 [074] Example 4: N,N-di-methyl-N-propyl-tryptammonium (DMPT) iodide [075] N,N-di-methyl-N-propyl-tryptammonium (DMPT) iodide was prepared by mixing 101 mg of a commercial sample of N-methyl-N-propyl-tryptamine (The Ind le Shop) and 4 ml of methyl iodide in 4 mL of methanol. The mixture was refluxed for twelve hours under an atmosphere of nitro-gen. The solvent was removed in vacuo, and the remaining residue was recrystallized from ethanol to yield colorless single crystals suitable for X-ray diffraction studies. The product was also characterized by nuclear magnetic resonance. 1H N MR (400 MHz, D20): d 7.69 (d, I = 8.0 Hz, 1 H, ArH), 7.55 (d, J = 8.2 Hz, 1 H, ArH), 7.33-7.28 (m, 2 H, Ad-1), 7.22 (t, J = 7.0 Hz, 1 H, ArH), 3.60 (m, 2 H, Cl-h), 3.36 (m, 4 H, Cl-I2), 3.17 (s, 6 H, CH3), 1.82 (m, 2 H, Cl-I2), 0.97 (t, J = 7.0 Hz, 3 H, Cl-I3).
[076] The molecular structure of crystalline DMPT iodide is shown in FIG. 5.
Crystal data, data collection and structure refinement details are summarized in Table 4. The asymmetric unit contains one N,N-di-methyl-N-n-propyl tryptammonium (C15H23N21 cation and one iodide anion. The indole ring of the cation is near, planar with a mean deviation from planarity of 0.011 A.
The ethyl-ammonium arm is turned away from the plane with a C7¨C8¨C9¨C10 torsion angle of 89.1 (4) .
The DMPT cation and the iodide anion are held together in the asymmetric unit via N(1)¨H(1)-1(1) hydrogen bonds, between the indole nitrogen and the iodide. The packing of crystalline DMPT iodide is shown in FIG. 6.
[077] Crystal data, data collection and structure refinement details are summarized in Table 4.
Table 4: Crystalline DM PT Iodide Chemical formula I-C3H23N2 Mr 358.25 Crystal system, space group Monoclinic, P21/c Temperature (K) 303 a, 13, C (A) 7.4471 (6), 9.9016 (9), 22.052 (2) [3 el 94.184(3) V (A3) 1621.8 (2) Radiation type Mo Ka m (mm-1) 1.96 Crystal size (mm) 0_40 x 0.14 x 0_12 Diffractometer Bruker D8 Venture CMOS
Absorption correction Multi-scan SADABS201612 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.0600 before and 0.0507 after correction. The Ratio of minimum to maximum transmission is 0.8362. The I/2 correction factor is Not present.
Trniny Trnax 0.470, 0.562 No. of measured, independent and 44530, 3071, 2362 observed [I> 2s(I)] reflections Rint 0.036 (sin q/l)max (k1) 0.611 RIF2> 2s(F2)], wR(F2), S 0.028, 0.054, 1.13 No. of reflections 3071 No. of parameters 170 No. of restraints 1 H-atom treatment H atoms treated by a mixture of independent and constrained refinement DiPmax,13Pmin (e A-3) 0.53, -0.47 Absolute structure ¨
Absolute structure parameter ¨
Computer programs: APEX3 (Bruker, 2018), SAINT (Bruker, 2018), SHELXT2014 (Sheldrick, 2015a), SHELXL2018 (Sheldrick, 2015b), 01ex2 (Dolomanov et at, 2009), pubICIF
(Westrip, 2010).
Table 5 Hydrogen-bond geometry (A, 2) for Crystalline DMPT Iodide D¨H---A D¨H H---A D---A D¨H---A
N1¨H1===11 0.86 (1) 2.91 (2) 3.733 (3) 162 (3) [078] FIG. 7 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline N,N-dimethyl-N-propyl (DMPT) iodide from its single crystal data. Crystalline N,N-dimethyl-N-propyl (DMPT) iodide may be characterized by the XRPD peaks at 8.0, 17. 9 and 23.3 20 0.2 20 as well as by an XRPD pattern substantially similar to FIG. 7.
[079] Example 5: N,N-di-methyl-N-allyl-tryptammonium (DMALT) iodide [080] N,N-di-methyl-N-allyl-tryptammonium (DMALT) iodide was prepared by mixing 101 mg of a commercial sample of N-allyl-N-methyl-tryptamine (The Indole Shop) with 4 mL
of methyl iodide in 4 mL
of methanol. The mixture was refluxed for twelve hours under an atmosphere of nitrogen. The solvent was removed in vacuo, and the remaining residue was recrystallized from acetone to yield colorless crystals suitable for X-ray diffraction studies. The product was also characterized by nuclear magnetic resonance. 1H NMR (400 MHz, D20): d 7.69 (d, J = 7.8 Hz, 1 H, ArH), 7.55 (d, J
= 8.2 Hz, 1 H, ArH), 7.32-7.28 (m, 1 H, ArH), 7.22 (t, 1 = 7.2 Hz, 1 H, ArH), 6.13-6.03 (m, 1 H, CH), 5.77-5.71 (m, 2 H, CH2), 4.04 (d, 1 = 7.3 Hz, 1 H, CH2), 3.61-3.56 (m, 2 H, CH2), 3.37-3.32 (m, 2 H, CH2), 3.17 (s, 6 H, CH3).
[0811 The molecular structure of crystalline DMALT iodide is shown in FIG. 8.
The asymmetric unit contains one N-allyl-N,N-di-methyl-tryptammonium (C15E1211421 cation and one iodide anion. The indole ring of the cation is near planar, with a mean deviation from planarity of 0.013 A. The ethyl-ammonium arm is turned away from the plane with a C7¨C8¨C9¨C10 torsion angle of 101.9 (9)*. The allyl group is disordered over two orientations with a 0.30(4) to 0.70(4) occupancy ratio for C14, C15 and C14A, C15A, respectively. The DMALT structure is very similar to that of DMPT, with the ions held together in the asymmetric unit through N(1)¨H(1)-1(1) hydrogen bonds. The packing of crystalline DMALT iodide is shown in FIG. 9.
[082] Crystal data, data collection and structure refinement details are summarized in Table 6.

Table 6: Crystalline DMALT Iodide Chemical formula 0.5(1)Ø5(C151-121N2) Mr 178.12 Crystal system, space group Monoclinic, P21 Temperature (K) 303 a, b, c (A) 73471 (8), 9.9672 (9), 10.9499 (11) fi (e) 94.671 (3) V (A3) 799.20 (14) Radiation type Mo Ka m (mm-1) 1.99 Crystal size (mm) 0.39 x 0.22 x 0.15 Diffractometer Bruker 08 Venture CMOS
Absorption correction Multi-scan SADABS2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.0671 before and 0.0484 after correction. The Ratio of minimum to maximum transmission is 0.8154. The 1/2 correction factor is Not present.
;lin/ Tmax 0.608, 0.745 No. of measured, independent and 26314, 3038, 2868 observed [I> 25(1)] reflections Rint 0.031 (sin q/l)max (k1) 0.611 RIF2> 2s(F2)1, wR(F2), S 0.027, 0.071, 1.13 No. of reflections 3038 No. of parameters 174 No. of restraints 5 H-atom treatment H-atom parameters constrained DPmax, DPmm (e k3) 0.46, -0.48 Absolute structure Refined as an inversion twin.
Absolute structure parameter 0.29 (5) Computer programs: APEX3 (Bruker, 2018), SAINT (Bruker, 2018), SHELXT2014 (Sheldrick, 2015a), SHELXL2018 (Sheldrick, 2015b), Olex2 (Dolomanov et at, 2009), pubICIF
(Westrip, 2010).
Table 7 Hydrogen-bond geometry (A, 2) for Crystalline MALT Iodide D¨H---A D¨H H---A D--A
D¨H---A

N1-H1-11 0.86 2.95 3.727 (6) 152 [083] FIG. 10 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline NN-dimethyl-N-ally1 (DMALT) iodide from its single crystal data. Crystalline N,N-dimethyl-N-allyl(DMALT) iodide may be characterized by the XRPD peaks at 12.0, 18.5 and 23.4 020 0.2 29 as well as by an XRPD pattern substantially similar to FIG.10.
[084] Example 6: 4-acetoxy-NN-dimethyl-N-ethyltryptammonium (4-AcO-DMET) iodide [085] Synthesis: 300 mg of 4-acetoxy-N,N-dimethyl- tryptammonium (4-AcO-DMT) fumarate was dissolved in 30 ml of tetrahydrofuran, and 6 ml of iodoethane was added. The mixture was refluxed overnight under an atmosphere of nitrogen. This resulted in the precipitation of a white powder from the yellow solution. The precipitate was isolated via vacuum filtration to give white powder, which was washed with diethyl ether to yield 303 mg of pure product (91% yield). 1H NMR
(400 MHz, D20): 5 7.46 (dd, J = 8.2, 0.7 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.25 (t, 1 = 7.9 Hz, 1 H, ArH), 6.90 (dd, 1 = 7.7, 0.7 Hz, 1 H, ArH), 3.58-3.54 (m, 2 H, CH2), 3.46 (q, 1 = 7.3 Hz, 2 H, CH2), 3.25-3.20 (m, 2 H, CH2), 3.12 (s, 6 H, CH3), 2.47 (s, 3 H, (CO)CH4, 1.38-1.35 (m, 3 H, CH4; 13C NMR (100 MHz, 020): 5 174.3(C0), 143.6 (ArC), 139.2(ArC), 125.7 (ArC), 123.0 (ArC), 119.1 (Ara 112.9 (ArC), 111.1 (ArC), 107.4 (ArC), 64.6 (AkC), 60.6 (Aka 50.7 (AkC), 21.3 (AkC), 19.9 (AkC), 8.1 (AkC).
[086] 4-AcO-DMET iodide was recrystallized by slow evaporation of an ethanol solution to yield crystals suitable for X-ray diffraction studies. Crystal data, data collection and structure refinement details are summarized in Table 8. FIG. 11 shows the molecular structure of crystalline 4-AcO-DMET
iodide hemihydrate showing the atomic labelling. Displacement ellipsoids are drawn at the 50%
probability level. There are two distinct tryptammonium cations and two iodides in the asymmetric unit.
The solvate water molecule is modeled at 50% occupancy.
Table 8 Crystal data 2(1)-2(C16H23N202)-0.5(H20) F(000) = 818 Mr= 81333 Dx = 1.471 Mg m-3 Monoclinic, P21 Mo Ka radiation, I = 0.71073 A
a = 11.8538 (8) A Cell parameters from 9080 reflections Li = 10.3179 (7) A q = 3.0-25.7 c = 15.0132 (10) A m = 1.75 mm-1 = 90.611 (2) T= 297 K
V= 1836.1 (2) A3 BLOCK, colourless Z= 2 0.23 x 0.22 x 0.21 mm Data collection Bruker D8 Venture CMOS 6527 reflections with I> 2s(!) diffractometer f and w scans Rint = 0.029 Absorption correction: multi-scan qmax = 25.7 , gram = 2.7 SADABS2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.0602 before and 0.0524 after correction.
The Ratio of minimum to maximum transmission is 0.9438. The 1/2 correction factor is Not present.
Trnm = 0.531, Tmax = 0.562 h = -141 14 47080 measured reflections k = -12.12 6821 independent reflections I = -18 18 Refinement Refinement on F2 Hydrogen site location: mixed Least-squares matrix: full H atoms treated by a mixture of independent and constrained refinement R1F2> 2s(F2)] = 0.029 w = 1/[52(F02) + (0.0298P)2+ 1.2326P]
where P= (F02 + 2F/)/3 wR(F2) = 0.072 (D/s). = 0.001 S = 1.05 Drimax = 0.66 e k3 6821 reflections Mims, = -0.46 e k3 410 parameters Absolute structure: Flack x determined using 2968 quotients [(1+)-(1-)1/[(1-04-(1-)]
(Parsons, Flack and Wagner, Ada Cryst.
B69 (2013) 249-259).
6 restraints Absolute structure parameter: -0.009 (5) [087] FIG. 12 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline 4-acetoxy-N,N-dimethyl-N-ethyltryptammonium (4-AcO-DMET) iodide hemihydrate from its single crystal data.

Crystalline 4-acetoxy-N,N-dimethyl-N-ethyltryptammonium (4-Ac0-DMET) iodide hemihydrate may be characterized by the XRPD peaks at 11.4, 14.6 and 19.2 020 0.2 20 as well as by an XRPD pattern substantially similar to FIG. 12.
[088] Example 7: 4-hydroxy-N,N-dimethyl-N-ethyltryptammonium (4-HO-DMET) iodide [089] Synthesis: 150 mg of 4-AcO-DMET iodide was dissolved in 2 mL of DI
water, and 10 ml_ of acetic acid was added. The mixture was refluxed overnight under an atmosphere of nitrogen. The solvent was removed via distillation, yielding an orange sticky oil. The oil was dissolved in a small volume of tetrahydrofuran and acetone. Hexanes was added to the solution, producing a white precipitate. The powder was isolated via vacuum filtration to give 90 mg (67% yield) of pure product. 1H NMR (400 MHz, D20):45 7.19 (s, 1 H, ArH), 7.12-7.07 (m, 2 H, ArH), 6.59-6.54 (m, 1 H, ArH), 3.60-3.56 (m, 2 H, CH2), 3.46 (q, l = 7.3 Hz, 2 H, CH2), 3.35-3.31 (m, 2 H, CH2), 3.12 (s, 6 H, CH3), 1.39 (t, 1 = 7.3 Hz, 3 H, CH4; 13C NMR
(100 MHz, D20): 5 150.6 (ArC), 139.3(ArC), 1219 (ArC), 116.6 (ArC), 108.8 (ArC), 1052 (ArC), 104.4 (Ara 65.0 (AkC), 60.3 (AkC), 50.7 (AkC), 20.7 (AkC), 8.0 (AkC).
[090] Example 8: 4-acetoxy-N,N-dimethyl-N-n-propyltryptammonium (4-AcO-DMPT) iodide [091] Synthesis: 323 mg of 4-AcO-DMT fumarate was dissolved in 30 mL of tetrahydrofuran, and 6 mL
of 1-iodopropane was added. The mixture was refluxed overnight under an atmosphere of nitrogen. This resulted in the precipitation of a white powder from the yellow solution. The precipitate was isolated via vacuum filtration to give a white powder, which was washed with diethyl ether to yield 314 mg of pure product (85% yield). 3-H NMR (400 MHz, 020): 57.46 (dd, I = 8.2, 0.5 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.26 (t, .1 = 7.9 Hz, 1 H, ArH), 6.90 (d, J = 7.7 Hz, 1 H, ArH), 3.61-3.57 (m, 2 H, CH2), 3.35-3.29 (m, 2 H, CH2), 3.27-3.21 (m, 2 H, CH2), 3.14 (s, 6 H, CH3), 2.47 (s, 3 H, (CO)CH3), 1.81-1.72 (m, 2 H, CH2), 0.91 (t, 1= 7.3 Hz, 3 H, CH3); 13C NMR (100 MHz, D20): 5 174.3(C0), 143.6 (ArC), 139.3(ArC), 125.8 (ArC), 123.0 (ArC), 119.1 (ArC), 112.9 (ArC), 111.1 (ArC), 107.5 (ArC), 66.4 (AkC), 65.1 (AkC), 51.3 (AkC), 21.3 (AkC), 20.1 (AkC), 16.3 (AkC), 10.4 (AkC).
[092] 4-AcO-DMPT iodide was recrystallized by slow evaporation of an ethanol solution to yield crystals suitable for X-ray diffraction studies. Crystal data, data collection and structure refinement details are summarized in Table 9. FIG. 13 shows the molecular structure of crystalline 4-AcO-DMPT
iodide showing the atomic labelling. Displacement ellipsoids are drawn at the 50% probability level.
Dashed bonds indicate a disordered component in the structure.
Table 9 Crystal data 1=C17H25N202 F(000) = 420 Mr= 416.29 Dx = 1.495 Mg m-3 Monoclinic, P21 Mo Ka radiation, I = 0.71073 A
a = 7.7067 (4) A Cell parameters from 9480 reflections b = 10.3424 (4) A q = 2.7-25.7 c = 11.6302(6) A m = 1.74 mm-1 13= 94.222 (2r T= 273 K
V= 924.48 (8) A3 BLOCK, colourless Z=2 0.23 x 0.2 x 0.07 mm Data collection Bruker D8 Venture CMOS 3251 reflections with I> 25(/) diffractometer f and w scans flint = 0.030 Absorption correction: multi-scan climax = 25.8%
chain = 2.7 SADA852016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.0659 before and 0.0527 after correction.
The Ratio of minimum to maximum transmission is 0.8900. The 1/2 correction factor is Not present.
Trnbn = 0.663, Tmax = 0.745 h = 9 9 32264 measured reflections k = -12.12 3428 independent reflections / = -149.4 Refinement Refinement on F2 Hydrogen site location: mixed Least-squares matrix: full H atoms treated by a mixture of independent and constrained refinement R1F2> 2s(F2)] = 0.035 w = 1/Es2u,-02.
1 + (0.0233P)2+ 1.32821'1 where P = (F02 + 2Fc2)/3 wR(P)= 0.081 (D/s)max <0.001 S = 1.04 Minim = 1.09 e 3428 reflections Dtimin = -0.78 e A-3 243 parameters Absolute structure: Flack x determined using 1473 quotients [(l+)-(I-)]/[(14-)+(1-)]
(Parsons, Flack and Wagner, Acta Cryst_ B69 (2013) 249-259).
35 restraints Absolute structure parameter: 0.009 (7) [093] FIG. 14 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline 4-acetoxy-N,N-dimethyl-N-n-propyltryptammonium (4-AcO-DMPT) iodide from its single crystal data. Crystalline 4-acetoxy-N,N-dimethyl-N-n-propyltryptammonium (4-AcO-DMPT) iodide may be characterized by the XRPD peaks at 11.5, 16.7 and 19.8 '20 0.2 28 as well as by an XRPD pattern substantially similar to FIG.
14.
[094] Example 9: 4-hydroxy-NN-dimethyl-N-n-propyltryptammonium (4-HO-DMPT) iodide [095] Synthesis: 200 mg of 4-AcO-DMPT iodide was dissolved in 3 mL of deionized (DI) water, and 10 mL of acetic acid was added. The mixture was refluxed overnight under an atmosphere of nitrogen. The solvent was removed via distillation, yielding an orange sticky oil. The oil was dissolved in a small volume of tetrahydrofuran and acetone. Hexanes was then added to the solution, producing a light green precipitate. This powder was isolated via vacuum filtration and washed with diethyl ether to give 157 mg (87 A yield) of pure product. 1H NMR (400 MHz, D20): 6 7.17 (s, 1 H, ArH), 7.12-7.07 (m, 2 H, ArH), 6.57-6.55 (m, 1 H, ArH), 3.57-3.53 (in, 2 H, CH2), 3.32-3.26 (m, 4 H, CH2), 3.11 (s, 6 H, CH3), 1.85-1.75 (m, 2 H, CH2), 0.95 (t, .1 = 7.3 Hz, 3 H, CH4; 13C NMR (100 MHz, D20): 5 150.6 (ArC), 139.3(ArC), 123.9 (ArC), 116.7 (ArC), 108.9 (ArC), 105.2 (ArC), 104.4 (ArC), 66.1 (AkC), 65.4 (AkC), 51.3 (AkC), 20.8 (AkC), 16.2 (AkC), 10.4 (AkC).
[096] 4-HO-DMPT iodide was recrystallized by slow evaporation of an ethanol solution to yield crystals suitable for X-ray diffraction studies. Crystal data, data collection and structure refinement details are summarized in Table 10. FIG. 15 shows the molecular structure of 4-HO-DMPT
iodide showing the atomic labelling. Displacement ellipsoids are drawn at the 50% probability level.
Table 10 Crystal data 1-C151-123N20 F(000) = 752 Mr= 374.25 Dx = 1.487 Mg m-3 Monoclinic, P21/c Mo Ka radiation, I = 0.71073 A
a = 9.4296 (8) A Cell parameters from 9954 reflections b = 14.1816 (11) A q = 2.7-25.7 c = 13.2586 (10) A m = 1.91 mm' 13= 109.423 (3) T= 297 K
V= 1672.1 (2) A3 BLOCK, colourless Z=4 0.25 x 0.2 x 0.19 mm Data collection Bruker D8 Venture CMOS 2808 reflections with I> 25(/) diffractometer f and w scans Rint = 0.025 Absorption correction: multi-scan climax = 25.7%
chain = 2.7*
5ADA852016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.0578 before and 0.0440 after correction.
The Ratio of minimum to maximum transmission is 0.9109. The 1/2 correction factor is Not present.
Trnir = 0.679, Tmax = 0.745 h = -11 11 38248 measured reflections k = -17 17 3102 independent reflections / = -16 16 Refinement Refinement on F2 Hydrogen site location: mixed Least-squares matrix: full H atoms treated by a mixture of independent and constrained refinement R[F2> 2s(F2)] = 0.027 w = 1/(52(F02) + (0.0259P)2+ 1.432211 where P = (F02 + 2Fc2)13 wR(F2)= 0.069 (D/s), = 0.001 S = 1.05 Dñmax = 0.85 e 3102 reflections Dñmm = -0.64 e 182 parameters Extinction correction: SHELXL201813 (Sheldrick 2018), Fe=kFc[1+0.001xFc213/sin(2q)14/4 16 restraints Extinction coefficient: 0.0082 (16) Primary atom site location: structure-invariant direct methods [097] FIG. 16 is a simulated x-ray powder diffraction (XRPD) pattern of crystalline 4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium (4-HO-DMPT) iodide from its single crystal data. Crystalline 4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium (4-HO-DMPT) iodide may be characterized by the XRPD peaks at 115, 18.9 and 19.9 20 0.2 20 as well as by an XRPD pattern substantially similar to FIG.
16.
[098] Example 10: 4-acetoxy-N,N-dimethyl-N-isopropyltryptammonium (4-AcO-DM1PT) iodide [099] Synthesis: 320 mg of 4-AcO-DMT fumarate was dissolved in 30 ml of tetrahydrofuran, and 12 mL of 2-iodopropane was added. The mixture was retluxed overnight under an atmosphere of nitrogen.
A mixture of orange/yellow solid and yellow liquid was obtained. The liquid was decanted and the remaining solid was triturated with ethyl acetate to yield a white powder. The powder was isolated via vacuum filtration to give 151 mg of pure product (41% yield). NMR (400 MHz, D20): 67.46 (dd, J=
8.2, 0.7 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.26 (t, 1= 7.9 Hz, 1 H, ArH), 6.89 (dd, 3 = 7.7, 0.6 Hz, 1 H, ArH), 3.86-3.76 (sep, 3= 6.6 Hz, 1 H, CH), 3.57-3.53 (m, 2 H, CH2), 3.26-3.22 (m, 2 H, CH2), 3.07 (s, 6 H, CH3), 2.47 (s, 3 H, (CO)CH4, 1.41 (d, J= 6.6 Hz, 6 H, CH3); 13C NMR (100 MHz, D20):
5 174.2(C0), 143.6 (ArC), 139.2 (ArC), 125.7 (ArC), 123.0 (ArC), 119.1 (ArC), 113.0 (ArC), 111.1 (ArC), 107.5 (ArC), 66.0 (AkC), 63.5 (AkC), 48.1 (AkC), 21.3 (AkC), 19.7 (AkC), 16.2 (AkC).
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Cameron, L P. & Olson, D. E. (2018). AG Chem. Neurosci. 9, 2344-2357.
Carhart-Harris, R. L. & Goodwin, G. M. (2017). Neuropsychopharmacology, 42, 2105-2113.
Dinis-Oliveira, R. J. (2017). Drug Metab. Rev. 49,84-91.
Johnson, M. W. & Griffiths, R. R. (2017). Neurotherapeutics 14, 734-740.
McKenna, D. J., Repke, D. B., Lo, L & Peroutka, S. J. (1990).
Neuropharmacology, 29, 193-198.
Nichols, D. E. (2012). WiREs Membr. Transp. Signal. 1, 559-579.
Repke, D. B., Grotjahn, 11 B. & Shulgin, A. T. (1985). J. Med. Chem. 28, 892-896.
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31

Claims (22)

The claimed invention is:

1. A compound of formula (I):

RIN. f R
NI. 3 X

Rg Re 0/1 \ Re N
H

(1) wherein R1, R2 and R3 are each independently a straight chain or branched C1-C6 alkyl or C2-C6alkenyl, R4 is hydrogen, hydroxyl, C1-C6 alkoxy, -OC(0)Rs or -0C(0)0R5, Rs is a straight chain or branched C1-C6 alkyl, R6 is R4 or a straight chain or branched C1-C6 alkyl with the proviso that R6 is not hydroxyl when R1, R2 and R3 are all methyl, R7, Rs and R9 are each independently hydrogen or a straight chain or branched C1-C6 alkyl, and X- is a pharmaceutically acceptable anion.

2. A compound of formula (I) according to claim 1 wherein:
R1, R2 and R3 are each independently a straight chain or branched C1-C4 alkyl or a C2-Ca alkenyl;
R4 is hydrogen, hydroxyl, C1-C4 alkoxyõ -0C(0)R5 or -0C(0)0115;
Rs is selected from methyl, ethyl, n-propyl and n-butyl;
R6,, R7,, Rg and R9 are each independently hydrogen, methyl, or ethyl; and X- is Cl-, r, Br, ascorbate, hydrofumarate, furnarate, or rnaleate.

3. A compound of formula (I) according to claim 2 wherein:
Rj., R2 and R3 are each independently methyl, ethyl, propyl or allyl;
R4 is hydrogen, hydroxyl, or -0C(0)Rs;
!Isis methyl or ethyl;
R6,, R7,, and R9 are each independently hydrogen;
Rs is hydrogen or methyl; and X- is I-.

4. A compound of formula (I) according to claim 1 wherein the compound is 4-Acetoxy-N,N,N-trimethyltryptammonium iodide.

5. A compound of formula (I) according to claim 4 wherein the compound is crystalline 4-Acetoxy-N,N,N-trimethyltryptammonium iodide characterized by:
a monoclinic, P21 crystal system space group at a temperature of about 299 K, unit cell dimensions a = 7.8459 (9) A, b = 9.8098(12) A, c = 11.0823(12) A, a=
90 , 0 =
101.069(3)% and y = 90%
an XRPD pattern having peaks at 8.1, 14.6 and 19.8 20 o.r2e, or an XRPD pattern substantially similar to FIG. 2.

6. A compound of formula (I) according to claim 1 wherein the compound is 4-Hydroxy-N,N,N-trimethyltryptammonium iodide.

7. A compound of formula (I) according to claim 6 wherein the compound is crystalline 4-Hydroxy-N,N,N-trimethyltryptammonium iodide characterized by:
a monoclinic, P21.1n crystal system space group at a temperature of about 200 K, unit cell dimensions a = 11.3057(9) A, b = 11.2370(10) A, c = 12.7785(10) A, a= 90% 0 =
113.087(2)% and y = 900 , an XRPD pattern having peaks at 17.0, 18.1 and19.5 20 o.r2e, or an XRPD pattern substantially similar to FIG. 4.

8. A compound of formula (I) according to claim 1 wherein the compound is N,N-dimethyl-N-propyltryptammonium iodide.

9. A compound of formula (I) according to claim 8 wherein the compound is crystalline N,N-dimethyl-N-propyltryptammonium iodide characterized by:
a monoclinic, PZilc crystal system space group at a temperature of about 303 K, unit cell dimensions a = 7.4471 (6) A, b = 9.9016 (9) A, c = 22.052 (2) A, and 13 = 94.184 (2) , an XRPD having peaks at 8.0, 17. 9 and 23.3 29 0.2 20, or an XRPD pattern substantially similar to FIG. 7.

10. A compound of formula (I) according to claim 1 wherein the compound is N,N-dimethyl-N-allyltryptammonium iodide.

11. A compound of formula (I) according to claim 10 wherein the compound is crystalline N,N-dimethyl-N-allyltryptammonium iodide characterized by:
a monoclinic, P21 crystal system space group at a temperature of about 303 K, unit cell dirnensions a = 7.3471 (8) A, b = 9.9672 (9) A, c = 10.9499 (11) A, and 13 = 94.671 (2)%
an XRPD pattern having peaks at 12.0, 183 and 23.4 .2e 0r2e, or an XRPD pattern substantially similar to FIG. 10.

12. A compound of formula (I) according to claim 1 wherein the compound is 4-acetoxy-N,N-dimethyl-N-ethyltryptammonium iodide.

13. A compound of formula (I) according to claim 12 wherein the compound is crystalline 4-acetoxy-N,N-dimethyl-N-ethyltryptammonium iodide as a hemihydrate characterized by:
a monoclinic, P21 crystal system space group at a temperature of about 297 K, unit cell dimensions a = 11.8538 (8) A, b = 10.3179 (7) A, c = 15.0132 (10) A, and 13 = 90.611 (2) , an XRPD pattern having peaks at 11.4, 14.6 and 19.2 020 o.r2e, or an XRPD pattern substantially similar to FIG. 12.

14. A compound of formula (I) according to claim 1 wherein the compound is 4-acetoxy-N,N-dimethyl-N-n-propyltryptamrnonium iodide.

15. A compound of formula (I) according to claim 14 wherein the compound is crystalline 4-acetoxy-N,N-dirnethyl-N-n-propyltryptammonium iodide characterized by:
a monoclinic, P21 crystal systern space group at a temperature of about 273 K, unit cell dimensions a = 7.7067 (4) A, b = 10.3424 (4) A, c = 11.6302 (6) A, and 13 = 94.222 (2) , an XRPD pattern haying peaks at 11.5, 16.7 and 19.8 020 o.r2e, or an XRPD pattern substantially similar to FIG. 14.

16. A compound of formula (I) according to claim 1 wherein the cornpound is 4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium iodide.

17. A compound of formula (I) according to claim 16 wherein the compound is crystalline 4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium iodide characterized by:
a monoclinic, P21/c crystal system space group at a temperature of about 273 K, unit cell dirnensions o = 9.4296 (8) A, b = 14.1816 (11) A, c = 13.2586 (10) A, and 13 = 109.423 or, an XRPD pattern having peaks at 12.5, 18.9 and 19.9 .2e 0r2e, or an XRPD pattern substantially similar to FIG. 16.

18. A composition comprising, consisting essentially of, or consisting of a compound according to any one of clairns 1-17 and an excipient

19. A composition of claim 18 wherein the composition is a pharmaceutical composition comprising, consisting essentially of, or consisting of a therapeutically effective amount of a compound according to any one of clairns 1-17 and a pharmaceutically acceptable excipient

20. A composition comprising, consisting essentially of, or consisting of as a first active component: a cornpound according to any one of claims 1-17; and as a second active component selected frorn (a) a sertonergic drug, (b) a purified psilocybin derivative, (c) one or two purified cannabinoids and (d) a purified terpene; and a pharmaceutically acceptable excipient.

21. A method of preventing or treating a psychological disorder comprising the step of:
administering to a subject in need thereof a therapeutically effective arnount of a compound according to any one of claims 1-17 or a composition according to any one of claims 18-20.

22. 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 a compound according to any one of claims 1-17 or a composition according to any one of claims 18-20.