WO2021041407A1 - Alkyl quarternary ammonium tryptamines and their therapeutic uses - Google Patents

Alkyl quarternary ammonium tryptamines and their therapeutic uses Download PDF

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Publication number
WO2021041407A1
WO2021041407A1 PCT/US2020/047791 US2020047791W WO2021041407A1 WO 2021041407 A1 WO2021041407 A1 WO 2021041407A1 US 2020047791 W US2020047791 W US 2020047791W WO 2021041407 A1 WO2021041407 A1 WO 2021041407A1
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Prior art keywords
compound
iodide
formula
dimethyl
xrpd pattern
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PCT/US2020/047791
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French (fr)
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Andrew R. Chadeayne
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Caamtech Inc
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Caamtech Inc
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Priority to EP20858480.5A priority Critical patent/EP4017859A4/en
Priority to AU2020337903A priority patent/AU2020337903A1/en
Priority to CA3149602A priority patent/CA3149602A1/en
Publication of WO2021041407A1 publication Critical patent/WO2021041407A1/en
Priority to US17/495,069 priority patent/US20220112162A1/en
Anticipated expiration legal-status Critical
Priority to US18/544,954 priority patent/US20240116867A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • 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).
  • 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.
  • 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).
  • MiPT N-methyl-N-isopropyltryptamine
  • the invention relates to a compound of formula (I): wherein R 1 , R 2 and R 3 are each independently a straight chain or branched C 1 ⁇ C 6 alkyl or C 2 ⁇ C 6 alkenyl, R 4 is hydrogen, hydroxyl, C 1 ⁇ C 6 alkoxy, ⁇ OC(O)R 5, or ⁇ OC(O)OR 5 , R 5 is a straight chain or branched C 1 ⁇ C 6 alkyl, R 6 is R 4 or a straight chain or branched C 1 ⁇ C 6 alkyl with the proviso that R 6 is not hydroxyl when R 1 , R 2 and R 3 are all methyl, R 7 , R 8 and R 9 are each independently hydrogen or a straight chain or branched C 1 ⁇ C 6 alkyl, and X ⁇ is a pharmaceutically acceptable anion.
  • R 1 , R 2 and R 3 are each independently a straight chain or branched C 1 ⁇ C 6 alkyl or C 2 ⁇ C 6 alkeny
  • the invention also provides a method of making 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 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.
  • the invention also relates to a composition
  • 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.
  • 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.
  • FIG. 1 is the fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of crystalline 4 ⁇ AcO ⁇ TMT iodide.
  • FIG. 2 is the simulated X ⁇ ray Powder Diffraction Pattern (XRPD) for 4 ⁇ AcO ⁇ TMT iodide from its single crystal structure.
  • FIG. 3 is the fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of crystalline 4 ⁇ HO ⁇ TMT iodide.
  • FIG. 4 is the simulated X ⁇ ray Powder Diffraction Pattern (XRPD) for 4 ⁇ AcO ⁇ TMT iodide from its single crystal structure.
  • FIG. 5 shows the molecular structure of crystalline DMPT iodide.
  • FIG. 6 shows the packing of crystalline DMPT iodide.
  • FIG. 7 is a simulated x ⁇ ray powder diffraction (XRPD) pattern of crystalline DMPT iodide from its single crystal data.
  • FIG. 8 shows the molecular structure of crystalline DMALT iodide.
  • FIG. 9 shows the packing of crystalline DMALT iodide.
  • FIG. 10 is a simulated x ⁇ ray powder diffraction (XRPD) pattern of crystalline DMALT iodide from its single crystal data.
  • FIG. 10 is a simulated x ⁇ ray powder diffraction (XRPD) pattern of crystalline DMALT iodide from its single crystal data.
  • FIG. 11 shows the molecular structure of crystalline 4 ⁇ AcO ⁇ DMET iodide hemihydrate showing the atomic labelling.
  • FIG. 12 is a simulated x ⁇ ray powder diffraction (XRPD) pattern of crystalline 4 ⁇ AcO ⁇ DMET iodide hemihydrate from its single crystal data.
  • FIG. 13 shows the molecular structure of crystalline 4 ⁇ AcO ⁇ DMPT iodide showing the atomic labelling.
  • FIG. 14 is a simulated x ⁇ ray powder diffraction (XRPD) pattern of crystalline 4 ⁇ AcO ⁇ DMPT iodide from its single crystal data.
  • FIG. 12 is a simulated x ⁇ ray powder diffraction (XRPD) pattern of crystalline 4 ⁇ AcO ⁇ DMPT iodide from its single crystal data.
  • FIG. 15 shows the molecular structure of 4 ⁇ HO ⁇ DMPT iodide showing the atomic labelling.
  • FIG. 16 is a simulated x ⁇ ray powder diffraction (XRPD) pattern of crystalline 4 ⁇ HO ⁇ DMPT iodide from its single crystal data.
  • XRPD x ⁇ ray powder diffraction
  • This invention relates to alkyl quaternary ammonium tryptamine compounds of formula (I):
  • R 1 , R 2 and R 3 are each independently a straight chain or branched C 1 ⁇ C 6 alkyl, for example a straight chain C 1 ⁇ C 6 alkyl, or a C 2 ⁇ C 6 alkenyl, for example allyl.
  • R 1 , R 2 and R 3 are each independently a straight chain or branched C 1 ⁇ C 4 alkyl, for example a straight chain C 1 ⁇ C 4 alkyl, or a C 2 ⁇ C 4 alkenyl.
  • R 1 , R 2 and R 3 may each independently be selected from methyl, ethyl, n ⁇ propyl, isopropyl, n ⁇ butyl, isobutyl and tert ⁇ butyl.
  • R 1 , R 2 and R 3 are each methyl, are each ethyl, or a mixture of methyl and ethyl groups.
  • R 4 is hydrogen, hydroxyl, C 1 ⁇ C 6 alkoxy ⁇ ⁇ OC(O)R 5 or ⁇ OC(O)OR 5 .
  • R 4 is a C 1 ⁇ C 6 alkoxy group, or in some embodiments a C 1 ⁇ C 4 alkoxy group, it may be a straight chain or branched C 1 ⁇ C 6 alkoxy group or C 1 ⁇ C 4 alkoxy group, for example a straight chain, and may be methoxy or ethoxy.
  • R 5 is a straight chain or branched C 1 ⁇ C 6 alkyl or C 1 ⁇ C 4 alkyl, for example a straight chain C 1 ⁇ C 4 alkyl.
  • R 5 is selected from methyl, ethyl, n ⁇ propyl or n ⁇ butyl, and for example is methyl or ethyl.
  • R 6 is R 4 or a straight chain or branched C 1 ⁇ C 4 alkyl, with the exemplary embodiments just discussed and with the proviso that R 6 is not hydroxyl when R 1 , R 2 and R 3 are all methyl.
  • R 7 , R 8 and R 9 are each independently hydrogen or a straight chain or branched C 1 ⁇ C 4 alkyl, for example a straight chain C 1 ⁇ C 4 alkyl.
  • R 6 , R 7 , R 8 and R 9 are each independently selected hydrogen, methyl, ethyl, n ⁇ propyl, isopropyl, n ⁇ butyl and isobutyl. In other embodiments, R 6 , R 7 , R 8 and R 9 are each independently hydrogen, methyl, ethyl.
  • the anion, X ⁇ may be any pharmaceutically acceptable anion, for example, Cl ⁇ , I ⁇ , Br ⁇ , ascorbate, hydrofumarate, fumarate, maleate, and the like.
  • a preferred anion, X ⁇ is iodide, I ⁇ .
  • Preferred compounds of formula (I) are those where R 1 , R 2 and R 3 are each independently a C 1 ⁇ C 4 alkyl or a C 2 ⁇ C 4 alkenyl; R 4 is hydrogen, hydroxyl, C 1 ⁇ C 4 alkoxy ⁇ ⁇ OC(O)R 5 or ⁇ OC(O)OR 5 ; R 5 is selected from methyl, ethyl, n ⁇ propyl and n ⁇ butyl; R 6 , R 7 , R 8 and R 9 are each independently hydrogen, methyl, or ethyl; and X ⁇ is Cl ⁇ , I ⁇ , Br ⁇ , ascorbate, hydrofumarate, fumarate, or maleate.
  • R 1 , R 2 and R 3 are each independently methyl, ethyl, propyl or allyl;
  • R 4 is hydrogen, hydroxyl, or ⁇ OC(O)R 5 ;
  • R 5 is methyl or ethyl;
  • R 6 , R 7 , and R 9 are each independently hydrogen;
  • R 8 is hydrogen or methyl;
  • X ⁇ is I ⁇ .
  • a compound of formula (I) may be prepared formula (II) (below) with XR 3 , where X is I, by refluxing in an appropriate organic solvent, such as methanol or THF, under an inert atmosphere.
  • XR 3 is ICH 3 or ICH 2 CH 3 .
  • R 4 or R 6 are hydroxyl they can be converted to esters, ⁇ OC(O)R 5 , or carbonate esters, ⁇ OC(O)OR 5 , 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.
  • the iodide anion may be exchanged using an anion exchange resin.
  • 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.
  • 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 (
  • 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.
  • 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.
  • 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.
  • 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.
  • musculoskeletal sprains musculoskeletal strains
  • tendinopathy peripheral radiculopathy
  • osteoarthritis joint degenerative disease
  • polymyalgia rheumatica juvenile arthritis
  • gout ankylosing spondy
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 A1 and US 2019/0142851 A1 are incorporated herein by reference.
  • a compound of formula (I) of the invention may be used as the “first purified psilocybin derivative” in the compositions described in US 2018/0221396 A1 and US 2019/0142851 A1.
  • 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.
  • 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 ⁇
  • 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, phenethyl-N-methylenedioxymethamphetamine, milnacipran, mirtazapine, naratriptan, paroxetine, pethidine, pheneth
  • 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.
  • 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.
  • purified psilocybin derivatives chosen from: [3 ⁇ (2 ⁇ Dimethylaminoethyl
  • 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.
  • cannabinoids within the context of this disclosure include the following molecules: Cannabichromene (CBC), Cannabichromenic acid (CBCA), Cannabichromevarin (CBCV), Cannabichromevarinic acid (CBCVA), Cannabicyclol (CBL), Cannabicyclolic acid (CBLA), Cannabicyclovarin (CBLV), Cannabidiol (CBD), Cannabidiol monomethylether (CBDM), Cannabidiolic acid (CBDA), Cannabidiorcol (CBD ⁇ C1), Cannabidivarin (CBDV), Cannabidivarinic acid (CBDVA), Cannabielsoic acid B (CBEA ⁇ B), Cannabielsoin (CBE), Cannabielsoin acid A (CBEA ⁇ A), Cannabigerol (CBG), Cannabigerol monomethylether (CBGM), Cannabigerolic acid (CBGA), Cannabigerolic acid
  • the purified cannabinoid is chosen from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBGV, or CBGVA.
  • Exemplary terpenes include but are not limited to the terpenes described in paragraphs [0160] ⁇ [0238] of US 2018/0221396 A1 and [0161] ⁇ [0300] US 2019/0142851 A1 as well as the disclosed preferred embodiments, incorporated here by reference.
  • 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, alpha ⁇ caryophyllene, beta ⁇ 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,
  • 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.
  • 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.
  • 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.
  • 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., 1990), which is incorporated herein by reference.
  • 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, alg
  • a pharmaceutically acceptable excipient
  • the dosage forms may also comprise buffering agents.
  • 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.
  • 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.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • Solid dosage forms as described above may be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner.
  • Non ⁇ limiting examples of embedded compositions that may be used are polymeric substances and waxes.
  • the active compounds may also be in microencapsulated form, if appropriate, with one or more of the above ⁇ mentioned excipients.
  • Suspensions in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar ⁇ agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar ⁇ agar and tragacanth, or mixtures of these substances, and the like.
  • Solid dosage forms for oral administration which includes capsules, tablets, pills, powders, and granules, may be used.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier).
  • pharmaceutically acceptable excipient also known as a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • 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 vacuo, and a white powder is obtained after triturating and washing the resulting residue with tetrahydrofuran.
  • FIG. 1 is the fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of 4 ⁇ AcO ⁇ TMT iodide. [061] FIG.
  • 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 °2q ⁇ 0.2°2q as well as by an XRPD pattern substantially similar to FIG. 2.
  • 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 vacuo, and a white powder is obtained after triturating and washing the resulting residue with tetrahydrofuran.
  • Second preparation of 4 ⁇ HO ⁇ TMT iodide 95 mg of 4 ⁇ AcO 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 vacuo.
  • DI deionized
  • FIG. 3 is the fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of 4 ⁇ HO ⁇ TMTI. [067] FIG.
  • 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 °2q ⁇ 0.2°2q as well as by an XRPD pattern substantially similar to FIG. 4.
  • Example 3 Cellular Assays [069] Cellular assays were performed by Eurofins CEREP SA, Celle ⁇ Lévescault, France. All receptors were separately expressed in HEK ⁇ 293 cells. Cell membrane homogenates (30 ⁇ g protein) are incubated for 60 min (5 ⁇ HT 1A , 5 ⁇ HT 2A , 5 ⁇ HT 2B ) or 120 min (5 ⁇ HT 3 ) at 22°C with radiolabeled ligand in the absence or presence of the test compound in a buffer containing 50 mM Tris ⁇ HCl (pH 7.4), 5 mM MgCl 2 , 10 ⁇ M pargyline and 0.1% ascorbic acid.
  • the buffer contained 50 mM Tris ⁇ HCl (pH 7.4), 5 mM MgCl 2 , and 1mM EDTA. Binding was reported as the K i for the inhibition of binding of well ⁇ characterized orthosteric ligands.
  • the ligands used for each receptor were: 5 ⁇ HT 1A : [ 3 H] 8 ⁇ OH ⁇ DPAT 5 ⁇ HT 2A : [ 125 I] ( ⁇ )DOI 5 ⁇ HT 2B : [ 125 I] ( ⁇ )DOI 5 ⁇ HT 3 : [ 3 H] BRL 43694 [070]
  • Nonspecific binding was determined in the presence of 1 ⁇ M unlabeled ligand listed above.
  • L concentration of radioligand in the assay
  • K D affinity of the radioligand for the receptor.
  • a scatchard plot was used to determine the K D .
  • the results in terms of inhibition constants (K i ) are shown in Table 3.
  • the aeruginascin functional analogue, 4 ⁇ AcO ⁇ TMTI shows no activity at any of the receptors.
  • psilocybin the pro ⁇ drug of psilocin
  • Psilocin shows activity at 5 ⁇ HT 1A , 5 ⁇ HT 2A , nor 5 ⁇ HT 3 , but does show itself to be a potent 5 ⁇ HT 2B agonist.
  • Psilocin its active metabolite, shows activity at 5 ⁇ HT 1A and 5 ⁇ HT 2A 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 ⁇ HT 2B receptor, and in fact, psilocybin is more active at this receptor as well.
  • 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 Indole 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.
  • DMPT N,N ⁇ di ⁇ methyl ⁇ N ⁇ propyl ⁇ tryptammonium
  • the asymmetric unit contains one N,N ⁇ di ⁇ methyl ⁇ N ⁇ n ⁇ propyl tryptammonium (C 15 H 23 N 2 + ) 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)°.
  • 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.
  • 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 molecular structure of crystalline DMALT iodide is shown in FIG. 8.
  • the asymmetric unit contains one N ⁇ allyl ⁇ N,N ⁇ di ⁇ methyl ⁇ tryptammonium (C 15 H 21 N 2 + ) cation and one iodide anion.
  • the indole ring of the cation is near planar, with a mean deviation from planarity of 0.013 ⁇ .
  • 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) ⁇ I(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.
  • FIG. 10 is a simulated x ⁇ ray powder diffraction (XRPD) pattern of crystalline N,N ⁇ dimethyl ⁇ N ⁇ allyl (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 °2q ⁇ 0.2°2q as well as by an XRPD pattern substantially similar to FIG.10.
  • Example 6 4 ⁇ acetoxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ ethyltryptammonium (4 ⁇ AcO ⁇ DMET) iodide
  • 4 ⁇ acetoxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ ethyltryptammonium (4 ⁇ AcO ⁇ DMET) iodide 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.
  • 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 Data collection Refinement [087] FIG. 11
  • Crystalline 4 ⁇ acetoxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ ethyltryptammonium (4 ⁇ AcO ⁇ DMET) iodide hemihydrate may be characterized by the XRPD peaks at 11.4, 14.6 and 19.2 °2q ⁇ 0.2°2q as well as by an XRPD pattern substantially similar to FIG. 12.
  • Example 7 4 ⁇ hydroxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ ethyltryptammonium (4 ⁇ HO ⁇ DMET) iodide
  • 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.
  • Example 8 4 ⁇ acetoxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ n ⁇ propyltryptammonium (4 ⁇ AcO ⁇ DMPT) iodide
  • 4 ⁇ AcO ⁇ DMPT 4 ⁇ acetoxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ n ⁇ propyltryptammonium (4 ⁇ AcO ⁇ DMPT) iodide
  • 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 Data collection Refinement [093] FIG.
  • 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 °2q ⁇ 0.2°2q as well as by an XRPD pattern substantially similar to FIG. 14.
  • 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 Data collection Refinement [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.
  • XRPD simulated x ⁇ ray powder diffraction
  • Crystalline 4 ⁇ hydroxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ n ⁇ propyltryptammonium (4 ⁇ HO ⁇ DMPT) iodide may be characterized by the XRPD peaks at 12.5, 18.9 and 19.9 °2q ⁇ 0.2°2q as well as by an XRPD pattern substantially similar to FIG. 16.
  • Example 10 4 ⁇ acetoxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ isopropyltryptammonium (4 ⁇ AcO ⁇ DMiPT) iodide
  • 4 ⁇ AcO ⁇ DMiPT 4 ⁇ acetoxy ⁇ N,N ⁇ dimethyl ⁇ N ⁇ isopropyltryptammonium (4 ⁇ AcO ⁇ DMiPT) iodide
  • 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 refluxed 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).

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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 TRYPTAMINES 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 compositions 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‐dialkyl-4-hy‐ droxytryptamines, the N‐methyl‐N‐isopropyl derivative (4‐HO‐MiPT) 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).          
Figure imgf000004_0001
  [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): 
Figure imgf000004_0002
wherein  R1, R2 and R3 are each independently a straight chain or branched C1‐C6 alkyl or C2‐ C6 alkenyl,   R4 is hydrogen, hydroxyl, C1‐C6 alkoxy, ‐OC(O)R5, or ‐OC(O)OR5,  R5 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, R8 and R9 are each independently hydrogen or a straight chain or branched C1‐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 DMPT 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‐DMPT iodide showing the atomic labelling.  [027]     FIG. 16 is a simulated x‐ray powder diffraction (XRPD) pattern of crystalline 4‐HO‐DMPT 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): 
Figure imgf000006_0001
In formula (I), R1, R2 and R3 are each independently a straight chain or branched C1‐C6 alkyl, for example  a straight chain C1‐C6 alkyl, or a C2‐C6 alkenyl, for example allyl.  In some embodiments, R1, R2 and R3 are  each independently a straight chain or branched C1‐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, R1, R2 and R3 are each methyl, are each ethyl, or  a mixture of methyl and ethyl groups.  R4 is hydrogen, hydroxyl, C1‐C6 alkoxy¸ ‐OC(O)R5 or ‐OC(O)OR5.   When R4 is a C1‐C6 alkoxy group, or in some embodiments a C1‐C4 alkoxy group, it may be a straight chain  or branched C1‐C6 alkoxy group or C1‐C4 alkoxy group, for example a straight chain, and may be methoxy  or ethoxy. R5 is a straight chain or branched C1‐C6 alkyl or C1‐C4 alkyl, for example a straight chain C1‐C4  alkyl. In some embodiments, R5 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 C1‐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, R8 and  R9 are each independently hydrogen or a straight chain or branched C1‐C4 alkyl, for example a straight  chain C1‐C4 alkyl.  In some embodiments, R6, R7, R8 and R9 are each independently selected hydrogen,  methyl, ethyl, n‐propyl, isopropyl, n‐butyl and isobutyl.  In other embodiments, R6, R7, R8 and R9 are each  independently hydrogen, methyl, ethyl. The anion, X‐, may be any pharmaceutically acceptable anion,  for example, Cl‐, I‐, Br‐, ascorbate, hydrofumarate, fumarate, maleate, and the like.  A preferred anion, X‐,  is iodide, I‐.  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 R1, R2 and R3 are each independently a C1‐ C4 alkyl or a C2‐C4 alkenyl; R4 is hydrogen, hydroxyl, C1‐C4 alkoxy¸ ‐OC(O)R5 or ‐OC(O)OR5; R5 is selected  from methyl, ethyl, n‐propyl and n‐butyl; R6, R7, R8 and R9 are each independently hydrogen, methyl, or  ethyl; and X‐ is Cl‐, I‐, Br‐, ascorbate, hydrofumarate, fumarate, or maleate.  Other preferred compounds  are those where R1, R2 and R3 are each independently methyl, ethyl, propyl or allyl; R4 is hydrogen,  hydroxyl, or ‐OC(O)R5; R5 is methyl or ethyl; R6, R7, and R9 are each independently hydrogen; R8 is  hydrogen or methyl; and X‐ is I‐.  [031]     Exemplary compounds of formula (I) are: 
Figure imgf000007_0001
 
Figure imgf000008_0001
 
Figure imgf000009_0001
 
Figure imgf000010_0001
  [032]     A compound of formula (I) 
Figure imgf000010_0002
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.  
Figure imgf000010_0003
In a preferred embodiment, XR3 is ICH3 or ICH2CH3.  When R4 or R6 are hydroxyl they can be converted to  esters, ‐OC(O)R5, or carbonate esters, ‐OC(O)OR5, 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.      [033]     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 A1 and US 2019/0142851 A1 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  A1 and US 2019/0142851 A1 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 A1  and US 2019/0142851 A1.  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 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.  [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 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.    [045]     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 (.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‐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.  [046]     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,  alpha‐caryophyllene, beta‐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, 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., 1990), 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.   [050]     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.  [051]     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 vacuo, and a white  powder is obtained after triturating and washing the resulting residue with tetrahydrofuran. 1H NMR (400  MHz, D2O): d 7.46 (d, J = 8.1 Hz, 1H, ArH), 7.33 (s, 1H, ArH), 7.27 (t, J = 8.0 Hz, 1H, ArH), 6.90 (d, J = 7.8 Hz,  1H, ArH), 3.63 (t, J = 7.5 Hz, 2H, CH2), 3.27 (t, J = 8.6 Hz, 2H, CH2), 3.21 (s, 9H, NCH3), 2.47 (s, 3H, C(O)CH3).  Unit Cell: a = 7.8459(9) Å, b = 9.8098(12) Å, c = 11.0823(12) Å, a = 90°, b = 101.069(3)°,  g = 90°, V =  837.10(17) Å3.   [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).  1 ,  D2O): d 7.46 (d, J = 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, J = 8.3 Hz,  1H, ArH) 3.63 (t, J = 7.9 Hz, 2 H, CH2), 3.28 (t, J = 8.0 Hz, 2 H, CH2), 3.21 (s, 9 H, CH3), 2.47 (s, 3 H,  C(O)CH3); 13C NMR (100 MHz, D2O): d 174.32 (C=O), 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(O)CH3). Elemental analysis calcd. for C15H21N2O2I: 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 SHELXS 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 Å.  Isotropic displacement parameters were set to 1.20 times Ueq 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 Å (sp2), 0.96 Å (CH3) and 0.97 Å (CH2) with isotropic displacement parameters set to 1.20  (sp2 and CH2) and 1.50 (CH3) times Ueq of the parent C atom. Further details are in Table 1. FIG. 1 is the  fully labelled displacement ellipsoid representation (50%) of the asymmetric unit of 4‐AcO‐TMT iodide.   
Figure imgf000019_0001
Figure imgf000020_0001
  [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 °2q ± 0.2°2q as well as by an XRPD pattern substantially similar to FIG. 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 vacuo, and a white powder is obtained  after triturating and washing the resulting residue with tetrahydrofuran. 1H NMR (400 MHz, D2O): d 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, CH2), 3.37  (t, J = 8.1 Hz 2H, CH2), 3.19 (s, 9H, NCH3). Unit Cell: a = 11.3057(9) Å, b = 11.2370(10) Å, c = 12.7785(10)  Å, a = 90°, b = 113.087(2)°, g = 90°, V = 1493.4(2) Å3.  [064]     Second preparation of 4‐HO‐TMT iodide: 95 mg of 4‐AcO 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 vacuo. 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, D2O): d 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, CH3); 13C NMR (100 MHz, D2O): d 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 (CH2). Elemental analysis calcd. For C13H19N2OI: 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 H1A were found from a Fourier difference map, and refined with a fixed distance  of 0.86 Å and 0.85 Å respectively. Isotropic displacement parameters were set to 1.20 times Ueq of the  parent N atom, and 1.50 times Ueq of the parent O atom. The remaining hydrogen atoms were placed in  calculated positions and then refined with a riding model with C–H lengths of 0.95 Å (sp2), 0.98 Å (CH2)  and 0.99 Å (CH3) with isotropic displacement parameters set to 1.20 (sp2 and CH2) and 1.50 (CH3) times  Ueq 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. 
Figure imgf000021_0001
Figure imgf000022_0001
  [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 °2q ± 0.2°2q 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‐Lévescault, France. All receptors  were separately expressed in HEK‐293 cells. Cell membrane homogenates (30 µg protein) are incubated  for 60 min (5‐HT1A, 5‐HT2A, 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‐HCl (pH 7.4), 5 mM MgCl2, 10 µM  pargyline and 0.1% ascorbic acid. For 5‐HT3, the buffer contained 50 mM Tris‐HCl (pH 7.4), 5 mM MgCl2,  and 1mM EDTA.  Binding was reported as the Ki for the inhibition of binding of well‐characterized  orthosteric ligands. The ligands used for each receptor were:   5‐HT1A: [ 3H] 8‐OH‐DPAT  5‐HT2A: [ 125I] (±)DOI   5‐HT2B: [ 125I] (±)DOI   5‐HT3: [3H] BRL 43694  [070]     Nonspecific binding was determined in the presence of 1 µM 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‐HCl 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+[ (A‐ D) / (1+(C/C50) nH) ] where Y = specific binding, A = left asymptote of the curve, D = right asymptote of the  curve, C = compound concentration, C50 = IC50, 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® (© 1997 by  SPSS Inc.). The inhibition constants (Ki) were calculated using the Cheng Prusoff equation: Ki= IC50  (1+L/KD), 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 KD.  [073]     The results in terms of inhibition constants (Ki) 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‐HT3 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, psilocybin is more active at this receptor as  well. 
Figure imgf000023_0001
  [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 Indole 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 NMR (400 MHz, D2O): d 7.69 (d, J = 8.0 Hz, 1 H, ArH), 7.55 (d, J = 8.2 Hz,  1 H, ArH), 7.33‐7.28 (m, 2 H, ArH), 7.22 (t, J = 7.0 Hz, 1 H, ArH), 3.60 (m, 2 H, CH2), 3.36 (m, 4 H, CH2),  3.17 (s, 6 H, CH3), 1.82 (m, 2 H, CH2), 0.97 (t, J = 7.0 Hz, 3 H, CH3).  [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 (C15H23N2 +) 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)∙∙∙I(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.   
Figure imgf000024_0001
C S
Figure imgf000025_0001
  [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 °2q ± 0.2°2q 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, D2O): 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, J = 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, J  = 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).  [081]     The molecular structure of crystalline DMALT iodide is shown in FIG. 8. The asymmetric unit  contains one N‐allyl‐N,N‐di‐methyl‐tryptammonium (C15H21N2 +) cation and one iodide anion. The indole  ring of the cation is near planar, with a mean deviation from planarity of 0.013 Å. 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)∙∙∙I(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. 
Figure imgf000026_0001
Computer programs: APEX3 (Bruker, 2018), SAINT (Bruker, 2018), SHELXT2014 (Sheldrick, 2015a),  SHELXL2018 (Sheldrick, 2015b), Olex2 (Dolomanov et al., 2009), publCIF (Westrip, 2010). 
Figure imgf000026_0002
Figure imgf000027_0001
  [083]     FIG. 10 is a simulated x‐ray powder diffraction (XRPD) pattern of crystalline N,N‐dimethyl‐N‐allyl  (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 °2q ± 0.2°2q as well as by an XRPD pattern  substantially similar to FIG.10.   [084]     Example 6: 4‐acetoxy‐N,N‐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, D2O): d 7.46  (dd, J = 8.2, 0.7 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.25 (t, J = 7.9 Hz, 1 H, ArH), 6.90 (dd, J = 7.7, 0.7 Hz, 1 H,  ArH), 3.58‐3.54 (m, 2 H, CH2), 3.46 (q, J = 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)CH3), 1.38‐1.35 (m, 3 H, CH3);  13C NMR (100 MHz, D2O): d 174.3(CO), 143.6 (ArC), 139.2(ArC),  125.7 (ArC), 123.0 (ArC), 119.1 (ArC), 112.9 (ArC), 111.1 (ArC), 107.4 (ArC), 64.6 (AkC), 60.6 (AkC), 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 
Figure imgf000027_0002
Figure imgf000028_0001
  Data collection 
Figure imgf000028_0002
  Refinement 
Figure imgf000028_0003
  [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‐AcO‐DMET) iodide hemihydrate may be  characterized by the XRPD peaks at 11.4, 14.6 and 19.2 °2q ± 0.2°2q 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,  D2O): d 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, J = 7.3 Hz, 2 H, CH2), 3.35‐3.31 (m, 2 H, CH2), 3.12 (s, 6 H, CH3), 1.39 (t, J = 7.3 Hz, 3 H, CH3); 13C NMR  (100 MHz, D2O): d 150.6 (ArC), 139.3(ArC), 123.9 (ArC), 116.6 (ArC), 108.8 (ArC), 105.2 (ArC), 104.4 (ArC),  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). 1H NMR (400 MHz, D2O): d 7.46 (dd, J = 8.2, 0.5 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.26  (t, J = 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, J = 7.3  Hz, 3 H, CH3); 13C NMR (100 MHz, D2O): d 174.3(CO), 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 
Figure imgf000030_0001
  Data collection 
Figure imgf000030_0002
  Refinement 
Figure imgf000030_0003
Figure imgf000031_0001
  [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 °2q ± 0.2°2q as well as by an XRPD pattern substantially similar to FIG.  14.  [094]     Example 9: 4‐hydroxy‐N,N‐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% yield) of pure product. 1H NMR (400 MHz, D2O): d 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 (m, 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, J = 7.3 Hz, 3 H, CH3);  13C NMR (100 MHz, D2O): d 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 
Figure imgf000031_0002
Figure imgf000032_0001
  Data collection 
Figure imgf000032_0002
  Refinement 
Figure imgf000032_0003
  [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 12.5, 18.9 and 19.9 °2q ± 0.2°2q as well as by an XRPD pattern substantially similar to FIG.  16.  [098]     Example 10: 4‐acetoxy‐N,N‐dimethyl‐N‐isopropyltryptammonium (4‐AcO‐DMiPT) 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 refluxed 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). 1H NMR (400 MHz, D2O): d 7.46 (dd, J =  8.2, 0.7 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.26 (t, J = 7.9 Hz, 1 H, ArH), 6.89 (dd, J = 7.7, 0.6 Hz, 1 H, ArH),  3.86‐3.76 (sep, J = 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)CH3), 1.41 (d, J = 6.6 Hz, 6 H, CH3); 13C NMR (100 MHz, D2O): d 174.2(CO), 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).    References  Bradley, R. J. & Johnston, V. S. (1970). Origin and Mechanism of Hallucinations, edited by W. Keup, pp.  333–344. New York: Plenum Press.     Cameron, L. P. & Olson, D. E. (2018). ACS 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, D. B. & Shulgin, A. T. (1985). J. Med. Chem. 28, 892–896.  C. Lenz, J. Wick and D. Hoffmeister, J. Nat. Prod., 2017, 80, 2835‐2838.  A. M. Sherwood, A. L. Halberstadt, A. K. Klein, J. D. McCorvy, K. W. Kaylo, R. B. Kargbo and P.  Meisenheimer, J. Nat. Prod., Article ASAP, DOI: 10.1021/acs.jnatprod.9b01061.  N. Jensen, J. Gartz and H. Laatsch, Planta Med., 2006, 72, 665‐666.  J. Gartz, Int. J. Crude Drug Res., 1989, 27, 141‐144.  B. L. Roth, W. K. Kroeze, S. Patel and E. Lopez, The Neuroscientist, 2000, 6, 252‐262.   

Claims

The claimed invention is:  1.  A compound of formula (I): 
Figure imgf000034_0001
wherein  R1, R2 and R3 are each independently a straight chain or branched C1‐C6 alkyl or C2‐C6 alkenyl,   R4 is hydrogen, hydroxyl, C1‐C6 alkoxy, ‐OC(O)R5 or ‐OC(O)OR5,  R5 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, R8 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‐C4 alkenyl;   R4 is hydrogen, hydroxyl, C1‐C4 alkoxy¸ ‐OC(O)R5 or ‐OC(O)OR5;   R5 is selected from methyl, ethyl, n‐propyl and n‐butyl;   R6, R7, R8 and R9 are each independently hydrogen, methyl, or ethyl; and   X‐ is Cl‐, I‐, Br‐, ascorbate, hydrofumarate, fumarate, or maleate.     
3.  A compound of formula (I) according to claim 2 wherein:   R1, R2 and R3 are each independently methyl, ethyl, propyl or allyl;   R4 is hydrogen, hydroxyl, or ‐OC(O)R5;   R5 is methyl or ethyl;   R6, R7, and R9 are each independently hydrogen;   R8 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) Å, b = 9.8098(12) Å, c = 11.0823(12) Å, a = 90°, b =  101.069(3)°, and g = 90°,  an XRPD pattern having peaks at 8.1, 14.6 and 19.8 °2q ± 0.2°2q, 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/n crystal system space group at a temperature of about 200 K,   unit cell dimensions  = 11.3057(9) Å, b = 11.2370(10) Å, c = 12.7785(10) Å, a = 90°, b =  113.087(2)°, and g = 90°,  an XRPD pattern having peaks at 17.0, 18.1 and19.5 °2q ± 0.2°2q, 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, P21/c crystal system space group at a temperature of about 303 K,   unit cell dimensions a = 7.4471 (6) Å, b = 9.9016 (9) Å, c = 22.052 (2) Å, and b = 94.184 (2)°,  an XRPD having peaks at 8.0, 17. 
9 and 23.3 °2q ± 0.2°2q, 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 dimensions a = 7.3471 (8) Å, b = 9.9672 (9) Å, c = 10.9499 (11) Å, and b = 94.671 (2)°,  an XRPD pattern having peaks at 12.0, 18.5 and 23.4 °2q ± 0.2°2q, 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) Å, b = 10.3179 (7) Å, c = 15.0132 (10) Å, and b = 90.611 (2)°,  an XRPD pattern having peaks at 11.4, 14.6 and 19.2 °2q ± 0.2°2q, 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‐propyltryptammonium iodide.   
15.  A compound of formula (I) according to claim 14 wherein the compound is crystalline 4‐acetoxy‐ N,N‐dimethyl‐N‐n‐propyltryptammonium iodide characterized by:  a monoclinic, P21 crystal system space group at a temperature of about 273 K,   unit cell dimensions a = 7.7067 (4) Å, b = 10.3424 (4) Å, c = 11.6302 (6) Å, and b = 94.222 (2)°,  an XRPD pattern having peaks at 11.5, 16.7 and 19.8 °2q ± 0.2°2q, or   an XRPD pattern substantially similar to FIG. 14.   
16.  A compound of formula (I) according to claim 1 wherein the compound 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 dimensions a = 9.4296 (8) Å, b = 14.1816 (11) Å, c = 13.2586 (10) Å, and b = 109.423  (3)°,  an XRPD pattern having peaks at 12.5, 
18.9 and 19.9 °2q ± 0.2°2q, 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 claims 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 claims 1‐17 and a pharmaceutically acceptable excipient.   
20.  A composition comprising, consisting essentially of, or consisting of as a first active component: a  compound according to any one of claims 1‐17; 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.   
21.  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  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.       
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