Deuterated or partially deuterated N,N-dimethyltryptamine compounds

Abstract

The present invention relates to compounds of formula (I) as defined herein, which comprise a higher proportion of deuterium to protium than is naturally present in hydrogen; and to compositions comprising these compounds and optionally analogous compounds of formula (I) that are not deuterium-enriched, including pharmaceutical compositions. These compounds and compositions can be used in therapy, particularly in the treatment of mental or neurological disorders. Varying the amounts of the different compounds within the compositions of the present invention allows the therapeutic effect of the compositions to be adjusted. A particularly efficient synthetic method is also provided, which is capable of obtaining compounds of formula (I) and related compounds of formula (I').

Description

Field of the Invention

[0001] The present invention relates to compounds of formula (I) as defined herein which comprise a greater proportion of deuterium to protium than is naturally present in hydrogen; and to compositions comprising these compounds and optionally analogous compounds of formula (I) which are not deuterium-enriched, including pharmaceutical compositions. These compounds and compositions can be used in therapy, in particular in the treatment of mental or neurological disorders. Altering the amounts of the different compounds within the compositions of the present invention allows adjustment of the therapeutic effect of the compositions. Also provided is a synthetic method capable of obtaining compounds of formula (I) and related compounds of formula (I’).

[0002] Background of the Invention

[0004] Classical hallucinogens have shown preclinical and clinical promise in the treatment of mental disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). In particular, in a randomized double-blind study, psilocybin has shown significant improvement in a range of depression and anxiety rating scales (Griffiths et al., Journal of Psychopharmacology, 30(12), 1181-1197 (2016)). The efficacy of psilocybin has been shown in depression (R.L. Carhart-Harris et al., Psychopharmacology, 2018, 235, 399-408), end-of-life anxiety (R.R. Griffiths et al., J. Psychopharmacol., 2016, 30, 12, 1181-1197) and addiction (M.W. Johnson, A. Garcia-Romeu and R.R. Griffiths, Am. J. Drug Alcohol Abuse, 2017, 43, 1, 55-60), and is currently being investigated for several other mental health disorders resulting from psychologically disruptive patterns of thought processing (anorexia nervosa: NCT#NCT04052568).

[0005] 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is an endogenous tryptamine present in human blood, urine, and spinal fluid (S.A. Barker, E.H. McIlhenny, and R. Strassman, Drug Test. Anal., 2012, 4, 7-8, 617-635; F. Benington, R.D. Morin, and L.C. Clark, J. Med. Sci., 1965, 2, 397–403; F. Franzen, and H. Gross, Nature, 206, 1052; R.B. Guchhait., J. Neurochem., 1976, 26, 1, 187–190), and has been shown to have protective and therapeutically relevant effects. Antidepressant properties have been shown in rodents administered 5-MeO-DMT (M.S. Riga et al., Neuropharmacology, 2017, 113, A, 148-155). Additionally, users of 5-MeO-DMT administered in a variety of forms have reported therapeutic effects of its use, including improved post-traumatic stress disorder, depression, and anxiety (A.K. Davis et al., J. Psychopharmacol., 2018, 32, 7, 779-792). 5-MeO-DMT has also shown potential for treating substance use disorders (V. Dakic et al., Sci. Rep., 2017, 7, 12863).

[0006] N,N-Dimethyltryptamine (DMT) is also understood to have therapeutic value as a short-acting hallucinogen. A review of studies on the biosynthesis and metabolism of DMT in the brain and peripheral tissues, methods and results for DMT detection in body fluids and the brain, new sites of action of DMT, and new data on the possible physiological and therapeutic effects of DMT was provided by S.A. Barker in Front. Neurosci., 12, 536, 1-17 (2018). In that review, DMT was described as having possible therapeutic effects in the treatment of depression, obsessive-compulsive disorder, and substance use disorders.

[0007] N-Methyltryptamine (NMT) is commonly extracted from the bark, twigs, and leaves of several plant genera together with DMT and 5-MeO-DMT. NMT has been reported to have hallucinogenic properties: inhaling NMT at 50–100 mg produces “visual effects” that last for 15–30 seconds (Shulgin, A. and Shulgin, A., 2002, THIKAL: the continuation, Transform Press).

[0008] The duration of action of DMT (at 20 minutes) is short, which limits effective therapies. Although dosing regimens have been developed to extend the immersive hallucinogenic experience of DMT (Gallimore and Strassman (2016), A model for the application of target-controlled intravenous infusion for a prolonged immersive DMT psychedelic experience, Frontiers in Pharmacology, 7:211), these regimens may pose a risk of cumulative toxicity to patients with poor DMT metabolism (for further discussion, see Strassman et al. (1994), Dose response study of N,N-dimethyltryptamine in humans, Arch Gen Psychiatry 51, 85).

[0009] It should be understood that DMT and its substituted analogs (such as 5-MeO-DMT) are mainly inactivated via a deamination pathway mediated by monoamine oxidase (MAO). MAO-mediated DMT metabolism via oxidative deamination provides indole-3-acetic acid (IAA) (O. Suzuki et al. Inhibition of type A and type B monoamine oxidases by naturally occurring xanthones, Planta Med., 42:17-21 (1981) and J. Riba, et al., Metabolism and urinary disposition of N,N-dimethyltryptamine after oral and smoked administration: a comparative study, Drug Test. Anal., 7(5):401-406 (2015)).

[0010] DMT-N-oxide (DMT-NO) is the second most abundant metabolite of DMT formed via N-oxidation. Additional minor metabolites have also been identified, including N-methyltryptamine (NMT), 2-methyl-1,2,3,4-tetrahydro-β-carboline (MTHBC), and THBC (see review by Barker (2018) above). The production of alternative metabolites such as DMT-NO and NMT is thought to be independent of MAO activity (S.A. Barker et al., In vivo metabolism of α,α,β,β-tetradeutero-N,N-dimethyltryptamine in rodent brain, Biochem. Pharmacol, 33(9):1395-400 (1984)). It does not yet appear to be clear which enzymes are responsible for the formation of N-oxides and other metabolites.

[0011] Given the important role of MAO in the metabolic inactivation of DMT and its substituted analogs such as 5-MeO-DMT, DMT and substituted analogs such as 5-MeO-DMT are typically administered with monoamine oxidase inhibitors (MAOIs) to prevent inactivation of the compounds before they reach their target sites in the body, allowing for extended and increased exposure to the compounds. However, since MAOIs can cause hypertension when taken with certain foods or drugs, patients using MAOIs typically require patients to restrict their diet and avoid some other drugs.

[0012] Naturally occurring hydrogen contains approximately 0.02 mole percent deuterium and 99.98% protium. The physicochemical properties between protium and deuterium are small but measurable. Deuterium is slightly less lipophilic than protium, has a smaller molar volume, and the carbon-deuterium bond is shorter than the carbon-protium bond. Compared to H, deuterium maintains the 3D surface, shape, and spatial flexibility unchanged.

[0013] These properties suggest that incorporating deuterium into DMT is expected to gradually decrease lipophilicity and increase basicity in a non-additive manner, depending on the stereochemical position, while also retaining the biochemical potency and selectivity of the parent compound. In addition, enrichment of the hydrogen atoms of DMT with deuterium is expected to result in a change in compound stability, measured as the deuterium kinetic isotope effect (DKIE).

[0014] The difference in stability of isotopically substituted molecules is called the primary kinetic isotope effect (KIE), and for deuterium, it can be defined as the deuterium kinetic isotope effect (DKIE). DKIE is quantified as the ratio of the reaction rate constants (kH / kD) and typically ranges from 1 (when deuterium has no effect on the reaction) to 7, with a theoretical limit of 9.

[0015] Since enzymatic catalytic transformations are multi-step, in order to observe a high DKIE, it is necessary that the C-H cleavage step is at least partially rate-limiting. Other kinetic models such as quantum mechanical tunneling have been used to explain secondary DKIEs. Although this is typically much smaller than the primary effect (typically 1.1 - 1.2), the mechanism can still result in a larger effect.

[0016] Barker et al. demonstrated that deuterium substitution of the hydrogen atoms at the α and β-positions of the ethylamine side chain of DMT (α,α,β,β-tetradeutero-DMT, D 4 DMT) has a KIE in vivo (S.A. Barker et al., 1982, Comparison of the brain levels of N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine following intraperitoneal injection, Biochemical Pharmacology, 31(15), 2513 - 2516 (1982)). When compared to an equidose of DMT, D 4 DMT was found to have a shorter onset time and enhanced behavioral interference effects. However, kinetic data quantifying the DKIE have not been reported (S.A. Barker et al., ibid (1982); S.A. Barker et al., ibid (1984); and J.M. Beaton et al., A Comparison of the Behavioral Effects of Proteo- and Deutero-N,N-Dimethyltryptamine. Pharmacol. Biochem. Behav, 1982. 16(5):811 - 4 (1982)).

[0017] The synthesis of α,α,-bisdeutero-DMT (D 2 DMT) has been reported in the literature (P.E. Morris and C. Chiao (Journal of Labelled Compounds And Radiopharmaceuticals, Vol. XXXIII, No. 6, 455 - 465 (1993)). However, biological or metabolic data have not been published.

[0018] In WO 2020 / 245133 A1 (Small Pharma Ltd, published on December 10, 2020), the knowledge of the kinetic isotope effect exhibited by α,α,β,β-tetradeuterated-N,N-dimethyltryptamine was used to controllably alter the pharmacokinetic properties of N,N-dimethyltryptamine, thus allowing for more flexible therapeutic applications.

[0019] G.N. Rossi et al., J. Pschedelic Stud., 3(1), 1 - 6(2019); G. de Oliveira Silveria et al., Molecules, 25, 2072, 1 - 11(2020); and C.D.R. Oliveira et al., Bioanalysis, 2012, 4(14), 1731 - 1738) describe the use of N,N-(dimethyl-d 6 )-tryptamine (d 6 -DMT) as an internal standard in the bioanalysis of plasma samples of DMT. However, no mention is made of the possibility of using d 6 -DMT itself as a therapeutically active substance.

[0020] Given the therapeutic potential of DMT and substituted analogues, there is still a need in the art for alternative compounds, such as compounds having improved bioavailability, extended and / or improved pharmacokinetics and / or improved pharmacodynamics, for use in psychotherapy, particularly for the development of clinically applicable hallucinogenic drug substances to assist psychotherapy. The present invention addresses this need. Summary of the Invention

[0021] DMT is metabolized very rapidly in the human body. Using modeling data from Timmerman (C. Timmermann et al., DMT Models the Near-Death Experience, Front. Psychol 9:1424(2018) and C. Timmermann et al., Neural correlates of the DMT experience assessed with multivariate EEG, Sci. Rep. 9:16324(2019)), we calculated that DMT has a half-life of approximately 5 minutes and a clearance rate of 24483 ml / min, which corresponds to 350 ml / min / kg based on a 70 kg person. This clearance rate is much greater than the average human liver blood flow, which is 20 ml / min / kg in the case of a cardiac output of 71 ml / min / kg. Based on these calculations, we inferred that DMT is largely metabolized before reaching the human liver.

[0022] In the studies described herein, we have demonstrated that the intrinsic clearance and half-life values of deuterated DMT compounds in human liver mitochondrial fractions containing substantial amounts of MAO are different from those in hepatocytes such as human liver microsomes and whole-cell hepatocytes. In addition, these pharmacokinetic parameters also vary depending on the presence or absence of deuterium substitution at the carbon atom adjacent to the dimethylamino moiety of DMT (α-deuteration) or at the carbon atoms of the methyl groups (methyl-deuteration).

[0023] Specifically, we found that α-deuteration causes an increase in the metabolic stability of human hepatocytes (compared to the parent compound: non-deuterated DMT), while methyl-deuteration has a minimal effect on the metabolic stability of such systems. On the other hand, a significantly greater increase in metabolic stability in the mitochondrial fraction was found in the case of a representative deuterated DMT with complete methyl-deuteration compared to the corresponding compound without methyl-deuteration.

[0024] The liver contains both phase I and phase II drug-metabolizing enzymes present in intact cells, making hepatocytes a valuable in vitro model for drug metabolism studies to predict in vivo clearance. However, liver fractions such as human liver microsomes and whole-cell hepatocytes contain significant amounts of cytochrome P450 enzymes, the major location of which in the body is in the liver. The human liver mitochondrial fraction, although of liver origin, contains fewer cytochrome P450 enzymes than whole-cell hepatocytes but, as previously mentioned, contains substantial amounts of MAO. Although whole-cell hepatocytes also contain substantial amounts of MAO, MAO is more evenly distributed throughout the body (more evenly than cytochrome P450 enzymes) and is present in most cell types.

[0025] The enhanced metabolic stability in the human liver mitochondrial fraction conferred by methyl-deuteration compared to non-deuterated or only α-deuterated DMT indicates that mitochondrial enzymes are more stable to metabolism and thus have higher in vivo metabolic stability.

[0026] Accordingly, and in a first aspect, the present invention provides a compound of formula (I) for use in therapy:

[0027]

[0028] Wherein:

[0029] R 1 is independently selected from –R 4 、-OH、-OR 4 、-O(CO)R 4 、monohydrogen phosphate, -F, -Cl, -Br and –I;

[0030] n is selected from 0, 1, 2, 3 or 4;

[0031] R 2 is C(x H) 3 ;

[0032] R 3 is C( x H) 3 or H;

[0033] Each R 4 is independently selected from C 1 -C 4 alkyl; and

[0034] each x H and y H is independently protium or deuterium,

[0035] wherein the ratio of deuterium:protium in the C( x H) 3 moiety of the compound is greater than the ratio found in naturally occurring hydrogen,

[0036] or a pharmaceutically acceptable salt thereof.

[0037] It should be understood that the only DMT compound having methyl deuteration described to date is N,N-bis(trideuteriomethyl)tryptamine (i.e., d 6 -DMT), and there is no suggestion in the art of the utility of methyl deuteration in providing therapeutically active DMT. Thus, in a second aspect, the present invention provides a compound or a pharmaceutically acceptable salt as defined in the first aspect of the present invention, which is not the free base of N,N-bis(trideuteriomethyl)tryptamine, 5-hydroxy-N-monotrideuteriomethyltryptamine (also known as N-methyl-serotonin-D 3 , CAS No. 1794811-18-9), or N-monotrideuteriomethyltryptamine (also known as N-methyl-tryptamine-D 3 , CAS No. 1794745-39-0), but which can be, for example, a pharmaceutically acceptable salt of N,N-bis(trideuteriomethyl)tryptamine, 5-hydroxy-N-monotrideuteriomethyltryptamine, or N-monotrideuteriomethyltryptamine.

[0038] In a third aspect, the present invention provides a composition comprising a first compound, which is a compound or a pharmaceutically acceptable salt as defined in the first or second aspect of the present invention, and a second compound, which is (i) a compound or a pharmaceutically acceptable salt as defined in the first aspect of the present invention, but which is different from the first compound by the y identity of H and / or the 3 identity of R; or (ii) a compound or a pharmaceutically acceptable salt as defined in the first aspect of the present invention, except that each x H and y H represents hydrogen.

[0039] From a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound as defined in the first or second aspect of the present invention, or a composition according to the third aspect of the present invention, in combination with a pharmaceutically acceptable excipient.

[0040] From a fifth aspect, the present invention provides a compound as defined in the first or second aspect of the present invention, or a composition according to the third or fourth aspect of the present invention, for use in a method of treating a mental or neurological disorder in a patient.

[0041] From a sixth aspect, the present invention provides a method of treatment comprising administering to a patient in need thereof a compound as defined in the first or second aspect of the present invention, or a composition according to the third or fourth aspect of the present invention.

[0042] From a seventh aspect, the present invention provides a method for including synthesizing a compound of formula (I') or a pharmaceutically acceptable salt thereof:

[0043]

[0044] Including reacting a compound of formula (II):

[0045]

[0046] with LiAlH 4 and / or LiAlD 4 wherein:

[0047] R 1 is independently selected from –R 4 , -OPR, -OR 4 , -F, -Cl, -Br and –I;

[0048] PR is a protecting group,

[0049] n is selected from 0, 1, 2, 3 or 4, preferably 1, 2, 3 or 4;

[0050] R 2 is C( x H) 3 ;

[0051] R 3 is C( x H) 3 or H;

[0052] Each R 4 is independently selected from C 1 -C 4 alkyl; and

[0053] Eachx H and y H are each independently protium or deuterium,

[0054] wherein the ratio of deuterium:protium in the C( x H) 3 moiety in the compound of formula (I’) is greater than the ratio found in naturally occurring hydrogen,

[0055] or a pharmaceutically acceptable salt thereof.

[0056] Optionally, a compound of formula (I’) in which R 1’ is –OPR is converted to a compound of formula (I) using chemical methods known to those skilled in the art.

[0057] Further aspects and embodiments of the invention will be apparent from the following discussion. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 : Semi-logarithmic plot of mean DMT (SPL026) and d 8 -DMT (SPL028viii) concentrations over time following a 2 mg / kg intravenous fumarate dose in vivo.

[0059] Figure 2 : Semi-logarithmic plot of mean SPL026 and SPL028viii concentrations over time following a 1 mg / kg intravenous fumarate dose (added as a cassette) in vivo.

[0060] Figure 3: Plot of mean DMT (SPL026) and d 8 -DMT (SPL028viii) concentrations over time following a 3.5 mg / kg intramuscular fumarate dose (added as a cassette) in vivo. Figure 3A – Linear plot, Figure 3B – Semi-logarithmic plot. DETAILED DESCRIPTION

[0061] In this specification, one or more aspects of the invention may be combined with one or more of the features described in the specification to define different embodiments of the invention.

[0062] In the following discussion, many terms are mentioned, and unless the context clearly indicates otherwise, these terms should be understood to have the meanings provided below. The nomenclature used herein to define compounds, particularly the compounds described herein, is intended to be in accordance with the rules of the International Union of Pure and Applied Chemistry (IUPAC) for chemical compounds, specifically the "IUPAC Compendium of Chemical Terminology (the Gold Book)" (see A.D. Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287 - 2311). To avoid doubt, if the rules of the IUPAC organization are contrary to the definitions provided herein, the definitions herein shall prevail.

[0063] Unless the context otherwise implies, references herein to the singular of a noun include the plural of the noun and vice versa. For example, "a compound of formula (I)" refers to one or more compounds of formula (I).

[0064] Throughout this specification, the word "comprise" or variants such as "comprises" or "comprising" will be understood to imply the inclusion of the stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The term "comprising" includes within its scope the term "consisting of".

[0065] The term "consisting of" or its variants shall be understood to imply the inclusion of the stated element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0066] When defining a number or value, the term "about" as used herein refers to a value within ±5% of the specified value. For example, if a temperature range of about 15°C to about 25°C is mentioned, temperatures from 14.25°C to 26.25°C are included.

[0067] To avoid doubt, where a number or value is specified herein without the term "about", the number or value should be understood according to standard numerical rounding conventions, depending on the number of decimal places. For example, an integer such as 194 should be understood to include values ≥193.5 and <194.5. Similarly, a number specified to one decimal place, such as 196.3, should be understood to include values ≥196.25 and <196.35.

[0068] The term "hydrocarbyl" defines a monovalent group derived from a hydrocarbon by removing a hydrogen atom from any carbon atom, where the term "hydrocarbon" refers to a compound consisting solely of hydrogen and carbon. In the case of a hydrocarbyl group disclosed as optionally containing one or more heteroatoms, any carbon or hydrogen atom on the hydrocarbyl group may be replaced by a heteroatom or a functional group containing a heteroatom, provided that the valence is satisfied. The one or more heteroatoms may be selected from the group consisting of nitrogen, sulfur, and oxygen.

[0069] Oxygen and sulfur heteroatoms or functional groups containing these heteroatoms may replace –H or –CH 2 - of the hydrocarbyl group, provided that when replacing –H, the oxygen or the oxygen-containing functional group binds to the carbon initially bonded to -H as =O (replacing two –H) or –OH (replacing one –H), and the sulfur or the sulfur-containing functional group binds to the carbon atom initially bonded to –H as =S (replacing two –H) or –SH (replacing one –H). When a methylene group (-CH 2 -) is replaced, oxygen binds as -O- to the carbon atom initially bonded to -CH 2 -, and sulfur binds as -S- to the carbon atom initially bonded to -CH 2 -.

[0070] Nitrogen heteroatoms or functional groups containing nitrogen heteroatoms may replace –H, -CH 2 -, or -CH=, provided that when replacing –H, the nitrogen or the nitrogen-containing functional group binds to the carbon initially bonded to -H as ≡N (replacing three –H), =NH (replacing two –H), or –NH 2 (replacing one –H); when -CH 2 - is replaced, the nitrogen or the nitrogen-containing functional group binds as -NH- to the carbon atom initially bonded to –CH 2 -; and when -CH= is replaced, nitrogen binds as -N= to the carbon atom initially bonded to -CH=.

[0071] The term "alkyl" is well known in the art and defines a monovalent group derived from an alkane by removing a hydrogen atom from any carbon atom, where the term "alkane" is intended to define an acyclic branched or unbranched hydrocarbon having the general formula C n H 2n+2 where n is an integer ≥ 1. C 1 -C 4 alkyl refers to any one selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0072] The term "cycloalkyl" defines all monovalent groups derived from cycloalkanes by removing a hydrogen atom from a ring carbon atom. The term "cycloalkane" defines saturated monocyclic and polycyclic branched or unbranched hydrocarbons, where the monocyclic cycloalkane has the general formula C nH 2n , where n is an integer of ≥3. Typically, the cycloalkyl group is C 5 -C 6 cycloalkyl group, such as cyclopentyl or cyclohexyl.

[0073] The term "alkylamino" refers to an alkyl group in which any one hydrogen atom is substituted by a primary (-NH 2 ), secondary (-NRH) or tertiary (-NR 2 ) amino group, where R is, or each R is independently a hydrocarbon group. Typically, any one hydrogen atom is substituted by a tertiary amino group, where each R is independently C 1 -C 4 alkyl group.

[0074] The term "acetoxy" (usually abbreviated as OAc) defines a monovalent group derived from acetic acid by removing a hydrogen atom from the OH moiety. The term "methoxy" (usually abbreviated as OMe) defines a monovalent group derived from methanol by removing a hydrogen atom from the OH moiety. The term hydrogen phosphate defines a divalent group of the formula HPO 4 , which is derived from phosphoric acid by removing protons from two of the three OH moieties, and thus represents a substituent of the formula -OP(O)(OH)O - .

[0075] Hydrogen, as used herein, means that in a variety of similar compounds, unless the context clearly dictates otherwise, the isotopes of hydrogen so represented are present in their natural abundances. For example, in a particular compound x H and y H are specified to represent hydrogen, the isotopes of hydrogen in a variety of such compounds x H and y H are present in their natural abundances.

[0076] In the case where a compound (such as a compound of formula (I)) is substituted by hydrogen phosphate (i.e., in R 1In the case of monohydrogen phosphate, it should be understood that "monohydrogen phosphate" also includes protonated or unprotonated analogs, that is, it also includes dihydrogen phosphate and phosphate. This is to reflect that psilocybin (also known as [3-(2-dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate) and analogs thereof, such as [3-(2-methylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, in water usually contain monohydrogen phosphate. Since the pKa values of the two terminal phosphate ester oxygen atoms are estimated to be 1.3 and 6.5, it is generally understood that this is the main form. Further, it should be understood that psilocybin and its analogs in the form of monohydrogen phosphate exist as zwitterions (i.e., inner salts), in which the nitrogen atom of the dimethylamino (or monomethylamino) moiety is protonated. To avoid ambiguity, the zwitterion is considered separately from the salt, that is, the pharmaceutically acceptable salts of the present invention refer to salts containing the compound of formula (I) of the present invention and an acid. For example, the salt can be a salt of the compound of formula (I) and fumaric acid.

[0077] The compounds of formula (I) described herein, for example, in the compositions according to the third and fourth aspects of the present invention, can be used in therapy and can be administered to a patient in need. As used herein, the term "patient" preferably refers to a mammal. Typically, the mammal is a human, but can also refer to a domesticated mammal. The term does not include laboratory mammals.

[0078] The terms "treatment" and "therapy" define a therapeutic treatment of a patient in order to slow down or stop the rate of progression of a disorder, or to improve or cure the disorder. It also includes the prevention of a disorder due to the treatment or therapy. The mention of prevention herein is not intended to require complete prevention of the disorder: rather, its development can be hindered by the treatment or therapy according to the present invention. Typically, the treatment or therapy is not prophylactic, and the compound or composition is administered to a patient suffering from a diagnosed or suspected disorder.

[0079] Psychedelic-assisted psychotherapy means the treatment of mental disorders by psychological means, which is enhanced by one or more protocols in which the patient undergoes a psychedelic experience. The psychedelic experience is characterized by a startling perception of aspects of thought previously unknown and can include one or more changes in perceptions of hallucinations, synesthesia, altered states of consciousness or focused awareness, changes in thought patterns, trance or hypnotic states, and mystical states.

[0080] As understood in the art, psychological, psychiatric, or neurological disorders are disorders that may be associated with one or more cognitive impairments. As used herein, the term 'mental disorder' is a clinically significant behavioral or psychological syndrome or pattern that occurs in an individual and is associated with present distress (e.g., pain symptoms) or disability (i.e., impairment in one or more important areas of functioning) or with a significantly increased risk of death, pain, disability, or loss of freedom.

[0081] Diagnostic criteria for the psychiatric or neurological disorders mentioned herein are provided in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5).

[0082] As used herein, the term 'obsessive-compulsive disorder' (OCD) is defined as the presence of obsessions or compulsions, but usually both are present. These symptoms can lead to severe functional impairment and / or distress. Obsessions are defined as unwanted, intrusive thoughts, images, or impulses that repeatedly enter a person's mind. Compulsions are repetitive behaviors or mental acts that a person feels driven to perform. Typically, OCD presents as one or more obsessions that drive the performance of compulsions. For example, an obsession with bacteria may drive the compulsion to clean, or an obsession with food may drive the compulsion to overeat, undereat, or vomit after eating (i.e., an obsession with food may manifest itself as an eating disorder). Compulsions can be overt and observable by others, such as checking if a door is locked, or covert mental acts that cannot be observed, such as repeating a phrase in one's mind.

[0083] The term 'eating disorder' includes anorexia nervosa, bulimia nervosa, and binge eating disorder (BED). Symptoms of anorexia nervosa include eating too little and / or exercising too much in order to maintain weight as low as possible. Symptoms of bulimia nervosa include eating a large amount of food in a very short period of time (i.e., binge eating), and then deliberately vomiting, using laxatives, eating too little, and / or exercising too much to prevent weight gain. Symptoms of BED include frequently eating large amounts of food until uncomfortably full, and thus feeling upset or guilty.

[0084] As used herein, the term 'depression' includes major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients.

[0085] As used herein, the term'major depressive disorder' (MDD, also known as major depression or clinical depression) is defined as the presence of five or more of the following symptoms (also referred to herein as a'major depressive episode') on most days, nearly every day, for a period of two weeks or longer:

[0086] · Depressed mood, such as feeling sad, empty, or tearful (in children and adolescents, depressed mood may present as persistent irritability);

[0087] · Markedly diminished interest or pleasure in all, or almost all, activities;

[0088] · Weight gain when not dieting, or significant weight loss when appetite decreases or increases (in children, failure to make expected weight gain);

[0089] · Insomnia or hypersomnia;

[0090] · Psychomotor agitation or retardation that can be observed by others;

[0091] · Fatigue or loss of energy;

[0092] · Feelings of worthlessness, or excessive or inappropriate guilt;

[0093] · Difficulty making decisions, or difficulty thinking or concentrating;

[0094] · Recurrent thoughts of death or suicide, or suicide attempts.

[0095] At least one of these symptoms must be depressed mood or loss of interest or pleasure.

[0096] Persistent depressive disorder, also known as dysthymia, is defined as a patient who exhibits the following two characteristics:

[0097] A. Depressed mood for most of the day, nearly every day, for at least two years. In children and adolescents, irritable mood may be present, and the time frame is at least one year.

[0098] B. When depressed, the patient experiences at least two of the following symptoms:

[0099] · Either overeating or lack of appetite.

[0100] · Hypersomnia or difficulty sleeping.

[0101] · Fatigue, lack of energy.

[0102] · Low self-esteem.

[0103] · Difficulty concentrating or making decisions.

[0104] As used herein, the term "treatment-resistant major depressive disorder" describes MDD that fails to achieve an adequate response to appropriate treatment with standard care therapies.

[0105] As used herein, "bipolar disorder", also known as manic-depressive illness, is a disorder that results in abnormal shifts in mood, energy, activity levels, and the ability to perform daily tasks.

[0106] Bipolar disorder has two defined subclasses; all of these involve marked shifts in mood, energy, and activity levels. These moods range from extreme "up," elated, and energetic behavior (termed manic episodes and further defined below) to periods of profound sadness, "down," or despair (termed depressive episodes). Less severe manic periods are called hypomanic episodes.

[0107] Bipolar I disorder—is defined as a manic episode that lasts at least 7 days, or manic symptoms that are severe enough to require immediate hospitalization of the patient. Typically, depressive episodes also occur, typically lasting at least 2 weeks. Depressive episodes with mixed features (having both depressive and manic symptoms) are also possible.

[0108] Bipolar II disorder—is defined as a pattern of depressive and hypomanic episodes, but not the full manic episodes described above.

[0109] As used herein, "bipolar depression" is defined as an individual who experiences depressive symptoms with previous or co-existing manic symptoms, but does not meet the clinical criteria for bipolar disorder.

[0110] As used herein, the term "anxiety disorder" includes generalized anxiety disorder, phobias, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

[0111] "Generalized anxiety disorder" (GAD) as used herein refers to a chronic disorder characterized by persistent anxiety that is not focused on any one object or situation. Those with GAD experience nonspecific, ongoing fear and worry and become overly concerned about day-to-day matters. GAD is characterized by chronic excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbances.

[0112] A "phobia" is defined as a persistent fear of an object or situation that the affected person will go to great lengths to avoid, usually out of proportion to the actual danger posed. If the feared object or situation cannot be completely avoided, the affected person will experience significant distress and substantial interference with social or occupational activities.

[0113] A patient with "panic disorder" is defined as experiencing one or more brief episodes of intense terror and fear (also called panic attacks), typically manifested as trembling, shaking, confusion, dizziness, nausea, and / or difficulty breathing. A panic attack is defined as a sudden onset of fear or discomfort that peaks within less than ten minutes.

[0114] "Social anxiety disorder" is defined as an intense fear of and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety typically presents with specific physical symptoms, including blushing, sweating, and difficulty speaking.

[0115] "Post-traumatic stress disorder" (PTSD) is an anxiety disorder caused by a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, natural disasters, rape, hostage situations, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, re-experiencing, avoidance behavior, anxiety, anger, and depression.

[0116] As used herein, the term "post-partum depression" (PPD, also known as postnatal depression) is a form of depression experienced by either parent of a newborn. Symptoms typically appear within 4 weeks of the baby's birth and often include extreme sadness, fatigue, anxiety, loss of interest or pleasure in hobbies and activities, irritability, and changes in sleep or eating patterns.

[0117] As used herein, the term "substance abuse" means a patterned use of a drug in which the user consumes the substance in amounts or by methods that are harmful to themselves or others.

[0118] As used herein, the term "anhedonia disorder" refers to a disorder that includes symptoms of decreased motivation to initiate and execute self-directed, purposeful activities.

[0119] In various aspects, the present invention relates to compounds of formula (I). The compounds of formula (I) (and each of the compounds of formula (I'), (II), and N(H)R 2 R 3 described herein) contain a C( x H) 3 moiety (and in some embodiments two such moieties) in which the deuterium:protium ratio is greater than its natural isotopic abundance, i.e., the relevant compounds contain a methyl group in which the percentage of deuterium in the hydrogen atoms of the compound of the formula is greater than its natural isotopic abundance in hydrogen, which is about 0.02 mol%.

[0120] In the compounds of formula (I), according to specific embodiments of at least the first to sixth aspects of the present invention, R 1 is independently selected from –OR 4 , -O(CO)R 4 , monohydrogen phosphate, and -OH. In specific embodiments of these and other embodiments, R 4 is methyl.

[0121] Sometimes, according to any relevant aspect or embodiment of the present invention, in the compounds of formula (I), (I') and (II) (formulas (I') and (II) are described below), n is 0 or 1. According to some embodiments, n is 0. According to some embodiments, n is 1.

[0122] wherein n is 1, R 1 (or in the compounds of formula (I') and (II), R 1’ ) is at the 4-position or 5-position. For the avoidance of doubt, positions 4 and 5 refer to these positions in the labeled structure of DMT depicted below:

[0123]

[0124] According to some embodiments of at least the first to sixth aspects of the present invention, in the compounds of formula (I), n is 0; or n is 1 and R 1 is selected from 5-methoxy, 5-bromo, 4-acetoxy, 4-hydrogen phosphate, 4-hydroxy and 5-hydroxy.

[0125] According to some embodiments of all aspects of the present invention, n is 0; or n is 1, and R 1 , or the appropriate R 1’ , is 5-methoxy.

[0126] Sometimes, in the compounds described herein having y H moieties, these are deuterium (in other words, hydrogen in which the proportion of deuterium has been increased to more than its natural abundance); sometimes these y H moieties are protium (in other words, hydrogen in which the proportion of deuterium has not been increased to more than its natural abundance).

[0127] For the avoidance of doubt, x H or y H being deuterium means that the relevant atom is deuterium-enriched, i.e., due to this enrichment, the hydrogen atoms of the resulting compound contain a greater percentage of deuterium than is naturally present in hydrogen, which is about 0.02 mol%.

[0128] In cases where the compounds described herein are indicated as or described as being deuterium-substituted, the relevant compounds are deuterium-enriched, the amount depending on the percentage of deuterium available in the reagent from which the compound is derived. For example, and as described herein, the d 6 -dimethylamino or d 3 -monomethylamino moieties of the compounds of formula (I), (I') and (II), where –NR 2 R 3 are –N(CD 3 ) 2 and –N(H)CD 3 , respectively, can be derived from dimethyl-d7 -amine, dimethyl-d 6 -amine or methyl-d 3 -amine (usually available as the HCl salt), which is available from chemical suppliers with a purity of deuterium in the range from 98% to 99%. Thus, the resulting d 6 -dimethylamino or d 3 -monomethylamino substituent has a deuterium purity between 98% and 99%. This means that, as will be understood by the person skilled in the art, not all compounds of formula (I) (for example) will contain d 6 -dimethylamino or d 3 -monomethylamino substituent – some may contain d 0 -d 5 dimethylamino or d 0 -d 3 -monomethylamino substituent, but the average purity of deuterium is about 98% to 99%.

[0129] Sometimes, in the related compounds described herein, R 2 and R 3 are both C( x H) 3 and, in some of these embodiments, the two C( x H) 3 are the same. According to the specific embodiment, R 2 and R 3 are both CD 3 .

[0130] According to a second aspect of the present invention, there is provided a compound of formula (I), provided that the compound is not the free base of N,N-bis(trideuteriomethyl)tryptamine (d 6 -DMT), 5-hydroxy-N-monotrideuteriomethyltryptamine (also known as N-methyl-serotonin-D 3 , CAS No. 1794811-18-9), or N-monotrideuteriomethyltryptamine (also known as N-methyl-tryptamine-D 3 , CAS No. 1794745-39-0). However, the compounds of the present invention may be bis(trideuteriomethyl)tryptamine, N-methyl-serotonin-D 3 , or N-methyl-tryptamine-D 3Pharmaceutically acceptable salts thereof, such as bis(trideuteriomethyl)tryptamine fumarate; or other N,N-bis(trideuteriomethyl)tryptamines of formula (I), such as 5-methoxy-N,N-bis(trideuteriomethyl)tryptamine or a pharmaceutically acceptable salt thereof. In a further embodiment, according to the second aspect of the present invention, the compound of formula (I) is not N,N-bis(trideuteriomethyl)tryptamine, 5-hydroxy-N-monotrideuteriomethyltryptamine, N-monotrideuteriomethyltryptamine or 4-hydroxy-N,N-bis(trideuteriomethyl)tryptamine (also known as 4-hydroxy-N,N-dimethyltryptamine-d 6 or dimethyl-4-hydroxytryptamine (psilocin)-d 6 ).

[0131] In some embodiments, the compound is a compound of formula (I) wherein n is 0 and wherein the compound has a molecular weight of from 188.9 to 196.3 g / mol (as the free base), or from 189.2 to 196.3 g / mol (as the free base), preferably from 194.3 to 196.3 g / mol (as the free base).

[0132] In some embodiments, the compound is a compound of formula (I) wherein n is 1, R 1 is 5-methoxy and wherein the compound has a molecular weight of from 224.3 to 226.4 g / mol (as the free base); or wherein n is 1, R 1 is 5-hydroxy and wherein the compound has a molecular weight of from 210.3 to 212.3 g / mol (as the free base).

[0133] The compounds of formula (I), including the specific embodiments just described (including those wherein n = 0 and n = 1, wherein R 1 is 5-methoxy), for example, are synthesized according to the reaction scheme set forth in Scheme 1 below:

[0134]

[0135] Scheme 1. Synthetic route for the preparation of an example of a compound of formula (I) (wherein n = 0): (i) SOCl 2 in Et 2 O, -78 °C; (ii) N(H)R 2 in Et 2 O; (iii) LiAlH 3 and / or LiAlD 2 in Et 2 O, CH 2 Cl 4 . 4

[0136] ​Scheme 1 depicts the synthesis of a compound of formula (I) where n = 0. Variations of the described chemical substances (e.g., related to the synthesis of a compound of formula (I) where n is not 0) are well within the normal capabilities of a person skilled in the art using his or her common general knowledge and / or the teachings herein.

[0137] The chemical method depicted in Scheme 1 was reported by P.E. Morris and C. Chiao (see above). Deuterated compounds according to aspects of the present invention or deuterated compounds used according to aspects of the present invention, or non-deuterated compounds that can be used in embodiments of the third to sixth aspects of the present invention as described herein and are actually relevant to the present invention, can also be synthesized according to the chemical method depicted in Scheme 2 or variations of this chemical method.

[0138]

[0139] Scheme 2. Additional synthetic routes for the preparation of an example of a compound of formula (I) (where n = 0): (Stage 1) (1) CH 2 Cl 2 HOBt / EDC [usually (i) HOBt in CH 2 Cl 2 , EDC.HCl], (2) 2M N(H)R in THF 2 R 3 ; (Stage 2) THF, LiAlH 4 and / or LiAlD 4 , usually quenched with Rochelle's salt; (Stage 3) EtOH, fumaric acid (fumaric acid, recrystallized from ethanol).

[0140] As in Scheme 1, Scheme 2 depicts the synthesis of a compound of formula (I) where n = 0. Implementing the described chemical substances and their variations (extensively discussed above for the seventh aspect of the present invention) is well within the normal capabilities of a person skilled in the art.

[0141] It should be understood that the formation of the fumarate salt depicted in Stage 3 of Scheme 2 can be varied to provide other pharmaceutically acceptable salts, and this salt formation step can also be carried out on one or more of the final products depicted in Scheme 1.

[0142] The ratio of lithium aluminum hydride and lithium aluminum deuteride as reducing agents can be varied to control the yThe relative amounts of protium and deuterium of H (see, for example, WO 2020 / 245133A1 (Small Pharma Ltd), supra). If desired, the ratios of protium and deuterium at these positions can be further varied, for example, by adding one or more of a protiated or deuterated compound to the compositions described herein, to provide the compositions according to the invention in a controlled manner.

[0143] It will be seen from Scheme 1 step (ii) and Scheme 2 stage 1 that the introduction of an amine moiety (-NR 2 R 3 ) into the compound can be achieved. It should be understood that the synthesis of the compound of formula (I) (which contains at least one C( x H) 3 moiety where the percentage of deuterium is greater than its natural isotopic abundance in hydrogen) can be achieved by using appropriate commercially available deuterated monomethylamine and dimethylamine. In particular, the use of commercially available d 7 -dimethylamine (i.e., DN(CD 3 ) 2 ), d 6 -dimethylamine (i.e., bis(trideuteriomethyl)amine) and d 3 -methylamine (i.e., trideuteriomethylamine) allows the obtaining of the compound of formula (I) and, according to the seventh aspect of the invention, allows the obtaining of the compound of formula (I’), where -NR 2 R 3 is -N(CD 3 ) 2 and –N(H)CD 3 .

[0144] If desired, the confirmation of the composition obtained from the reduction steps in Schemes 1 and 2 can be achieved by chromatographically separating the components of the mixture by conventional means at the disposal of the person skilled in the art, in combination with spectroscopic and / or mass spectrometric analysis.

[0145] Alternative compositions can be obtained by mixing the undeuterated compound obtainable from Scheme 1 or 2 when the reducing agent is only lithium aluminum hydride with the α,α-dideuterated compound obtainable from Scheme 1 or 2 when the reducing agent is only lithium aluminum deuteride. It should be understood that when referring to a reducing agent that is only lithium aluminum hydride or lithium aluminum deuteride, this refers to the ideal case and ultimately depends on the purity of the relevant reagent, as discussed above.

[0146] The compositions described above can be further modified by adding one or more α-monodeuterated compounds. Stock solutions of such compounds can be obtained, for example, from the chromatographic separations described above.

[0147] Scheme 3 depicts chemical substances known in the art for the synthesis of DMT, which can be deployed / modified to synthesize the compound of formula (I), wherein the substituent R 1 represents hydrogen (i.e., where n = 0) or the substituent R 1 as defined herein, and R 2 and R 3 as defined herein. Although there will generally be no more than one R 1 group, the presence of multiple R 1 moieties is not excluded.

[0148]

[0149] Scheme 3. Additional synthetic routes for preparing optionally R 1 -substituted compounds of formula (I): (i) oxalyl chloride (ClC(O)C(O)Cl); (ii) N(H)R 2 R 3 ; (iii) LiAlH 4 and / or LiAlD 4 ; (iv) formaldehyde, sodium cyanoborohydride; (v) additional pharmaceutically acceptable acids, such as fumaric acid, to form salts of the compound or composition of formula (I); (vi) SOCl 2 , Et 2 O; (vii) N(H)R 2 R 3 .

[0150] As in Schemes 1 and 2, Scheme 3 illustrates how an amine moiety (-NR 2 R 3 ) can be introduced into the compound, and how in step (iii) the relative ratio of protium to deuterium in the compound can be controlled by varying the ratio of lithium aluminum hydride to lithium aluminum deuteride (i.e., the composition of the substituent y H) (see again, for example, WO 2020 / 245133 A1 (Small Pharma Ltd), supra). Step (iv) can be used to introduce the C( x H) 3 moiety as R 2 and R 3 , where the amount of deuterium can be controlled by using a mixture of sodium borohydride and sodium borodeuteride or sodium borodeuteride (see, for example, the synthesis of DMT-d 6 described by Oliveira et al. (supra).

[0151] Tryptamines are generally synthesized using methods adapted from the pioneering publication TiHKAL: The Continuation (Berkeley, CA, Transform Press, 1997) by Alexander Shulgin. Several alternative methods for synthesizing DMT are disclosed herein; a three-step route starting from indole using (1) oxalyl chloride, (2) dimethylamine, and (3) lithium aluminum hydride has been widely adopted (see the top synthetic route depicted in Scheme 3), and a similar route has been used to scale up psilocybin under GMP control (see, for example, WO 2019 / 073379 A1). Oxalyl chloride is highly toxic and corrosive. It is severely irritating to the eyes, skin, and respiratory tract, and its violent reaction with water makes it difficult to handle on a large scale.

[0152] P.E. Morris and C. Chiao (supra) (again see the bottom synthetic route depicted in Scheme 1 as well as Scheme 3 (steps (vi), (vii), and (iii))) reported the synthesis of DMT from auxin (a phytohormone and natural product, and the compound first depicted in both Schemes 1 and 2). While the oxalyl chloride route can be used to prepare the compounds of formula (I), an advantageous feature of the present invention is to avoid this and provide high-purity compounds of formula (I) without sacrificing yield. This is the chemistry depicted in Scheme 2, and the seventh aspect of the present invention relates to this chemistry, and this chemistry can be modified by using a starting material containing R 1 (or a starting material containing R 1’ ) to provide a compound of formula (I) containing R 1 , for example, by modifying the chemistry described in Scheme 2 using protecting groups also described herein.

[0153] Specifically, and according to the seventh aspect of the present invention, there is provided a method comprising synthesizing a compound of formula (I’) or a pharmaceutically acceptable salt thereof:

[0154]

[0155] which comprises reacting a compound of formula (II):

[0156]

[0157] with LiAlH 4 and / or LiAlD 4 , wherein:

[0158] R 1 is independently selected from –R 4 , -OPR, -OR 4 , -F, -Cl, -Br, and –I;

[0159] PR is a protecting group,

[0160] n is selected from 0, 1, 2, 3 or 4;

[0161] R 2 is C( x H) 3 ;

[0162] R 3 is C( x H) 3 or H;

[0163] Each R 4 is independently selected from C 1 -C 4 alkyl; and

[0164] Each x H and y H is independently protium or deuterium,

[0165] wherein the ratio of deuterium to protium in the C( x H) 3 moiety in the compound of formula (I') is greater than the ratio found in naturally occurring hydrogen,

[0166] or a pharmaceutically acceptable salt thereof.

[0167] It should be understood that the reduction of the amide carbonyl in the compound of formula (II) corresponds to stage 2 in Scheme 2, and one or more optional substituents R may be present in the compounds of formula (I') and (II) 1’ .

[0168] In the compounds of formula (I') and (II), PR is a protecting group. In other words, where the R 1’ group represents OPR, which represents a protected hydroxyl group. It is well known to those skilled in the art that it can be advantageous to protect sensitive or reactive groups on any relevant molecule during a synthetic sequence. This is achieved by means of protecting groups, a concept with which those skilled in the art are fully familiar. For example, suitable protecting groups and the manner of using these protecting groups are described by T.W. Greene and P.G.M. Wuts in 'Protective Groups in Organic Synthesis' 5th Edition, John Wiley and Sons, 2014.

[0169] When preparing a compound of formula (I') with an –OPR group, after reduction of the compound of formula (II) as described in the method of the seventh aspect of the present invention, this can and typically is removed using deprotection methods well known in the art (again see T.W. Greene and P.G.M. Wutts, supra). If desired, the hydroxyl group thus revealed can be converted to -OR 4 、-O(CO)R 4 、or a monohydrogen phosphate moiety (as defined herein). Such reactions represent specific embodiments of the seventh aspect of the present invention.

[0170] According to such an embodiment, the method of the seventh aspect of the present invention further comprises, in the case where the compound of formula (I') contains an –OPR group, removing the protecting group and optionally (but typically) converting the resulting –OH group to -OR 4 、-O(CO)R 4 、or a monohydrogen phosphate moiety.

[0171] For example, to synthesize a compound of formula (I) having a hydroxyl, monohydrogen phosphate or acetyl substituent, lithium aluminum hydride and lithium aluminum deuteride in a desired ratio can be used to reduce benzyloxy 2-(3-indolyl)-oxoacetamide having suitable R 2 and R 3 groups to produce benzyloxy-N,N-dimethyltryptamine (optionally deuterated one or two times at the α-position). The benzyl protecting group can then be removed, for example, by hydrogenation with hydrogen and palladium on carbon to form the corresponding hydroxy-tryptamine (optionally deuterated at the α-position). The hydroxyl group can be converted to a monohydrogen phosphate or acetyl group by reaction with tetra-O-benzyl-pyrophosphate (followed by removal of the benzyl protecting group) or by reaction with acetic anhydride (or other acid anhydrides, acyl halides or other methods of converting the –OH group to -O(CO)R 4 moiety). For additional information on this synthetic strategy, see D.E. Nichols and S. Frescas, Synthesis, 1999, 6, 935-938.

[0172] In a specific embodiment of the method of the seventh aspect of the present invention, R1' in formula (I') and (II) is not OPR, i.e., is independently selected from –R 4 、-OR 4 、-F、-Cl、-Br and -I. The compound of formula (I') according to such an embodiment represents a subset of the compound of formula (I) as defined in the first aspect of the present invention. In an even more specific embodiment of the method of the seventh aspect of the present invention, including the embodiments described below, there is no R 1’ substituent (i.e., n = 0) or R 1’ is 5-OMe (i.e., n = 1).

[0173] In Scheme 2, Stage 1 involves reacting the depicted carboxylic acid reactant with two or more coupling agents to produce an activated compound, and reacting the activated compound with an amine to produce the depicted amide. Stage 2 involves reacting the amide with LiAlH 4 and / or LiAlD 4 and corresponds to the method of the seventh aspect of the present invention. Stage 3 depicts optional salt formation. Any deprotection (removal) and transformation of protecting groups as described immediately above will typically occur after Stage 2 and before Stage 3, where desired / appropriate.

[0174] Advantageously, the method of the seventh aspect of the present invention avoids the use of problematic oxalyl chloride and employs starting materials that can be derived from auxin (indole-3-acetic acid). High-quality and pure auxin (derivatives of the carboxylic acid starting material depicted in Scheme 2 (comprising one or more substituents R 1(‘) )) are commercially available on a large scale and / or can be readily synthesized via Fischer synthesis, Bartoli synthesis, Japp-Klingemann synthesis, or Larock synthesis (see, for example, M.B. Smith and J. March’s Advanced Organic Chemistry, 8th Edition, Wiley, New Jersey, March 2020).

[0175] The method of Scheme 2 represents an exemplary embodiment of the seventh aspect of the present invention, which is efficient, scalable, compatible with Current Good Manufacturing Practices (cGMP), and suitable for preparing high-purity compounds of formula (I). For example, the method is suitable for preparing compounds of formula (I) on a batch scale ranging from 1 g to 100 kg, and for preparing compounds of formula (I) having a purity of >99.9% and an overall yield of 50% or higher.

[0176] From the foregoing discussion, it will be understood that, according to a specific embodiment, the method of the seventh aspect of the present invention may further comprise preparing a compound of formula (II) by:

[0177] (i) reacting a compound of formula (III)

[0178] wherein R 1’ and n are as defined for formula (I’),

[0179] with two or more coupling agents to produce an activated compound; and

[0180] (ii) React the activated compound with an amine having the formula R 2 R 3 NH or R 2 R 3 ND, where the definitions of n, R 1’ 、R 2 and R 3 correspond to those in the compound of formula (II).

[0181] It should be understood that the starting materials depicted in Scheme 2 are examples of compounds of formula (III) where n = 0.

[0182] Generally, n herein will be 0 or 1, typically (but not necessarily) 0. Examples of suitable starting materials of formula (III) where n is 1 include, for example, 4- and 5-hydroxyindoleacetic acids, and 4- and 5-methoxyindoleacetic acids.

[0183] To avoid doubt, where reagents are expressed as equivalents herein, this is in terms of molar equivalents of the reaction compounds for the reagents in Stages 1 to 3 of Scheme 2.

[0184] The term "coupling agent" refers to a reagent that promotes the chemical reaction between an amine and a carboxylic acid. In some embodiments, the two or more coupling agents comprise a carboxylic acid activator, i.e., a reagent that reacts with the carboxylic acid moiety in Stage 1 (i.e., in the compound of formula (III)) to produce a compound comprising an activated moiety derived from the original carboxylic acid moiety, which activated moiety is more likely to react with an amine than the original carboxylic acid moiety.

[0185] An additive coupling agent (also referred to herein as an "additive") is a reagent that enhances the reactivity of a coupling agent. In some embodiments, an additive is a compound that is capable of reacting with the reaction product of the starting carboxylic acid and the coupling agent (the product being a compound comprising an activated moiety) to produce a compound comprising an even more activated moiety that is more likely to react with an amine than the original activated moiety.

[0186] Unless the context indicates otherwise, amine means a secondary amine.

[0187] High performance liquid chromatography (HPLC) is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. For a review of HPLC, see A.M. Sabir et al., Int. Res. J. Pharm., 2013, 4, 4, 39 - 46.

[0188] Solvents referred to herein include MeCN (acetonitrile), DCM (dichloromethane), acetone, IPA (isopropanol), iPrOAc (isopropyl acetate), TBME (tert-butyl methyl ether), THF (tetrahydrofuran), 2-MeTHF (2-methyltetrahydrofuran), EtOAc (ethyl acetate), ethanol, and toluene. As used herein, the term ether solvent means a solvent containing an alkyl-O-alkyl moiety, where the two alkyl components may be linked. Ether solvents include diethyl ether, TBME, THF, and 2-MeTHF.

[0189] A desiccant is a chemical used to remove water from an organic compound in solution. Examples of desiccants include calcium chloride, magnesium sulfate, and sodium sulfate. The desiccant described herein is typically magnesium sulfate.

[0190] Acidic reagents suitable for crystallizing the pharmaceutically acceptable salts of the compounds of formula (I) (or (I')) are acids that form non-toxic acid anions. Examples include hydrochloride, hydrobromide, sulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, and gluconate.

[0191] An aqueous basic solution means a weak base suitable for work-up, such as a 10% potassium carbonate solution.

[0192] As described above, Scheme 2 depicts an advantageous method for synthesizing a compound of formula (I) (or (I')) or a pharmaceutically acceptable salt thereof, which includes Stage 1 and Stage 2. Stage 1 includes:

[0193] (i) reacting a starting carboxylic acid (auxin or its derivative) with two or more coupling agents to produce an activated compound; and

[0194] (ii) reacting the activated compound with an amine having the formula (R 2 )(R 3 )NH to produce a compound of formula (II).

[0195] The activated compound is the product of the reaction between the auxin starting material and two or more coupling agents. In the case where the two or more coupling agents include a carboxylic acid activator, the activated compound contains an activated moiety derived from the original carboxylic acid moiety, which is more likely to react with an amine than the original carboxylic acid moiety.

[0196] In some embodiments, the two or more coupling agents include a carboxylic acid activator. In some embodiments, the two or more coupling agents include an addition coupling agent. In some embodiments, the additive is capable of reacting with the reaction product of the starting carboxylic acid and the coupling agent (the product is a compound containing an activated moiety) to produce an activated compound containing an even more activated moiety that is more likely to react with an amine than the original activated moiety.

[0197] Typically, the two or more coupling agents include a carboxylic acid activator and an addition coupling agent.

[0198] In some embodiments, at least one of the two or more coupling agents is selected from the group consisting of carbodiimide coupling agents, phosphonium coupling agents, and 3-(diethoxy-phosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), such as a carbodiimide coupling agent or a phosphonium coupling agent. In some embodiments, at least one of the two or more coupling agents is a carbodiimide coupling agent.

[0199] A carbodiimide coupling agent is a coupling agent containing a carbodiimide group R'-N=C=N-R", where R' and R" are hydrocarbon groups optionally substituted with heteroatoms selected from nitrogen, sulfur, and oxygen (usually nitrogen). Typically, R' and R" are independently selected from C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl, C 1 -C 6 alkylamino, and morpholino C 1 -C 6 alkyl. Typically, C 1 -C 6 alkyl is C 3 alkyl, C 5 -C 6 cycloalkyl is cyclohexyl, C 1 -C 6 alkylamino is dimethylaminopropyl and / or morpholino C 1 -C 6 alkyl is morpholinoethyl.

[0200] In some embodiments, the carbodiimide coupling agent is any one selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), and 1-cyclohexyl-(2-morpholinoethyl)carbodiimide methyl p-toluenesulfonate (CMCT). In some embodiments, the carbodiimide coupling agent is any one selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC). Typically, the carbodiimide coupling agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), typically as the hydrochloride salt (EDC·HCl). EDC or EDC·HCl is particularly preferred because they are non-toxic and highly water-soluble, facilitating their almost complete removal during the post-treatment and washing steps in Stage 1.

[0201] The phosphonium coupling agent comprises a phosphonium cation and a counterion, typically a hexafluorophosphate anion. In some embodiments, the phosphonium cation has the formula [PR a 3 R b + , wherein R a is bis(C 1 -C 6 )alkylamino or pyrrolidino, and R b is a halogen or a hydrocarbyl group optionally substituted with nitrogen and / or oxygen atoms. Typically, R b is bromo, benzotriazol-1-yloxy or 7-azabenzotriazol-1-yloxy.

[0202] In some embodiments, the phosphonium coupling agent is selected from the group consisting of benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP), benzotriazol-1-yloxy-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxy-tris(pyrrolidinium) hexafluorophosphate (PyAOP), and ethyl cyano(hydroxyimino)acetato-O 2 )tris(1-pyrrolidino)-phosphonium hexafluorophosphate (PyOxim).

[0203] In some embodiments, at least one of the two or more coupling agents is an addition coupling agent selected from the group consisting of 1-hydroxybenzotriazole (HOBt), hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma Pure), 4-(N,N-dimethylamino)pyridine (DMAP), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt), 3-hydroxy-4-oxo-3,4-dihydro-5-azabenzotri-1,2,3-triene (HODhat), and 3-hydroxy-4-oxo-3,4-dihydro-5-azabenzotri-1,3-diazine (HODhad).

[0204] ​In some embodiments, at least one of the two or more coupling agents is an addition coupling agent selected from the group consisting of 1-hydroxybenzotriazole (HOBt), hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma Pure), and 4-(N,N-dimethylamino)pyridine (DMAP).

[0205] In some embodiments, at least one of the two or more coupling agents is an addition coupling agent which is 1-hydroxybenzotriazole.

[0206] In some embodiments, the two or more coupling agents consist of a coupling agent and an addition coupling agent, wherein the coupling agent and the addition coupling agent can be as described in the above embodiments.

[0207] The benefit of using both a coupling agent and an addition coupling agent is to increase the formation rate of the stage 1 product from the starting materials and the amine having the formula (R 2 )(R 3 )NH. Additionally, when an addition coupling agent is used with a carbodiimide coupling agent, the likelihood of an unwanted side reaction can be reduced. For example, the reaction of a starting carboxylic acid with a carbodiimide coupling reagent may form an O-acylisourea. This can undergo rearrangement to form an N-acylurea, which is a stable compound that is less likely to react with an amine. The addition coupling agent can react with the O-acylurea before rearrangement to N-acylurea and produce a compound that continues to react with the amine rather than the inactive N-acylurea.

[0208] Thus, in some embodiments, the two or more coupling agents consist of a carbodiimide coupling agent and an addition coupling agent.

[0209] In a specific embodiment, the two or more coupling agents consist of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) (usually as the hydrochloride (EDC.HCl)) and 1-hydroxybenzotriazole (HOBt).

[0210] Typically, an excess of the coupling agent relative to the starting carboxylic acid is used. In some embodiments, the ratio of coupling agent:starting carboxylic acid is from about 1:1 to about 3:1, typically from about 1:1 to about 2:1, and most typically from about 1:1 to about 1.5:1.

[0211] Typically, an excess of the addition coupling agent relative to the starting carboxylic acid is used. In some embodiments, the ratio of addition coupling agent:starting carboxylic acid is from about 1:1 to about 3:1, typically from about 1:1 to about 2:1, and most typically from about 1:1 to about 1.5:1.

[0212] In some embodiments, when the two or more coupling agents include a coupling agent and an addition coupling agent, a coupling agent:starting carboxylic acid and addition coupling agent:starting carboxylic acid ratio of from about 1:1 to about 1.5:1 is used.

[0213] As described above, Stage 1 of Scheme 2 involves reacting the starting carboxylic acid of the activated compound (e.g., of formula (III)) (the product of reaction with two or more coupling agents) with an amine having the formula (R 2 )(R 3 )NH to produce the product of Stage 1.

[0214] The amine:starting carboxylic acid ratio employed in the process is typically about ≥1:1. In some embodiments, the amine:starting carboxylic acid ratio is from about 1:1 to about 3:1, typically from about 1:1 to about 2:1.

[0215] In some embodiments, Stage 1 further includes isolating the resulting compound (the amide of formula (II)). Those skilled in the art are aware of techniques applicable in the art for isolating such compounds. For example, such amides can be extracted into an organic solvent such as dichloromethane or ethyl acetate, washed with an aqueous solution such as an aqueous basic solution, and concentrated. To increase purity, the isolated amide can be recrystallized. Those skilled in the art are aware of techniques applicable to doing so. For example, the amide can be dissolved in a minimal amount of solvent at a specific temperature (e.g., at ambient temperature (e.g., from about 15 °C to about 25 °C) or at an elevated temperature where heat is applied to the solution), and the resulting solution is cooled to promote precipitation. Alternatively or additionally, the volume of the solution can be reduced to promote precipitation, e.g., by simple evaporation at ambient temperature and pressure. Alternatively or additionally, an anti-solvent (in which the solubility of the amide is lower than the solubility of the solvent already present) can be used.

[0216] The isolated amides are stable and can be stored as solids in air at ambient temperature, e.g., from about 15 °C to about 25 °C. They can, but need not, be stored under inert conditions, e.g., under nitrogen or argon, or at a reduced temperature, e.g., in a refrigerator or freezer.

[0217] Typically, steps (1) and (2) of Stage 1 of Scheme 2 (e.g., but not necessarily (1) CH 2 Cl 2 / HOBt / EDC and (2) 2M N(H)R 2 R 3(The illustrative conditions mentioned in the legend of Scheme 2 above) are carried out in a suitable solvent. A person skilled in the art can evaluate which solvents are suitable for these steps. Examples of suitable solvents include dichloromethane (DCM), acetone, isopropyl alcohol (IPA), isopropyl acetate (iPrOAc), tert-butyl methyl ether (TBME), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate (EtOAc). In some embodiments, steps (1) and (2) of Stage 1 are carried out in dichloromethane.

[0218] Steps (1) and (2) of Stage 1 are carried out at a suitable temperature, and a person skilled in the art can evaluate which temperatures are suitable for these steps. Generally, steps (1) and (2) of Stage 1 are carried out at a temperature of about 10 °C to about 30 °C. In some embodiments, steps (1) and (2) of Stage 1 are carried out at room temperature (e.g., at about 20 °C to about 30 °C (usually about 20 °C)).

[0219] In a specific embodiment, Stage 1 of the method depicted in Scheme 2 and thus in the specific embodiments of the seventh aspect of the present invention (involving the reaction of the compound of formula (III)) comprises the following steps:

[0220] (1) contacting the starting carboxylic acid of formula (III) with 1 to 1.5 equivalents of an addition coupling agent and 1 to 1.5 equivalents of a carbodiimide coupling agent to produce a first composition; and

[0221] (2) contacting the first composition with 1 to 2 equivalents of an amine having the formula R 2 R 3 NH or R 2 R 3 ND to produce a second composition.

[0222] In some embodiments, 1 g or more, such as 1 g to 100 kg or 1 g to 1 kg of the starting compound (carboxylic acid) is employed in the method of the present invention.

[0223] In some embodiments, the contacting in steps (1) and (2) is carried out in the presence of a first solvent such as 5 to 20 volumes of the first solvent. The first solvent can be selected from any one of dichloromethane (DCM), acetone, isopropyl alcohol (IPA), isopropyl acetate (iPrOAc), tert-butyl methyl ether (TBME), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate (EtOAc). Generally, the first solvent is DCM.

[0224] In some embodiments, step (1) further comprises stirring or agitating the first composition. The first composition can be stirred or agitated for at least 30 minutes, such as 30 minutes to 3 hours or 30 minutes to 2 hours, preferably at least 1 hour, for example 1 to 3 hours or 1 to 2 hours. The first composition can be maintained at a temperature of 10°C to 30°C.

[0225] In some embodiments, prior to the contacting, the amine of step (2) is dissolved in a solvent such as tetrahydrofuran (THF) or an ether. The amine can be present in the solvent at a concentration of about 2M. Typically, the amine of step (2) is dissolved in THF.

[0226] In some embodiments, step (2) further comprises stirring or agitating the second composition. The second composition can be stirred or agitated for at least 30 minutes, such as 30 minutes to 3 hours or 30 minutes to 2 hours, preferably at least 1 hour, for example 1 to 3 hours or 1 to 2 hours. The second composition can be maintained at a temperature of 10°C to 30°C.

[0227] In some embodiments, step (2) further comprises contacting the second composition with an aqueous basic solution to produce a third composition, for example contacting the second composition with 2 to 10 volumes of an aqueous basic solution such as an aqueous solution containing potassium carbonate.

[0228] In some embodiments, step (2) further comprises stirring or agitating the third composition. The third composition can be stirred or agitated for at least 1 minute, such as 1 to 15 minutes or 1 to 10 minutes, preferably at least 5 minutes, for example 5 to 15 minutes or 5 to 10 minutes. The third composition can be maintained at a temperature of 10°C to 30°C.

[0229] In some embodiments, in the case where the third composition comprises an organic component and an aqueous component, step (2) further comprises separating the organic component from the aqueous component. In some embodiments, the organic component is separated from the aqueous component within 8 hours of the contacting step (1).

[0230] In even more specific embodiments, stage 1 in the method of the seventh aspect of the present invention comprises the following steps:

[0231] i. Add 1 g or more of the starting carboxylic acid of formula (III) and 1 to 1.5 equivalents of an addition coupling agent to a first container,

[0232] ii. Add 5 to 20 volumes of a first solvent selected from DCM, acetone, IPA, iPrOAc, TBME, 2-MeTHF, and EtOAc to the first container,

[0233] iii. Add 1 to 1.5 equivalents of a carbodiimide coupling agent to the first container,

[0234] iv. Stir the contents of the first container at 10°C to 30°C for at least 30 minutes, preferably at least 1 hour (such as 1 to 2 hours),

[0235] v. Add 1 to 2 equivalents of an amine having the formula R 2 R 3 NH or R 2 R 3 ND, wherein the amine is preferably dissolved in an ether solvent,

[0236] vi. Further stir the contents of the first container at 10°C to 30°C for at least 30 minutes, preferably at least 1 hour (such as 1 to 2 hours),

[0237] vii. Add 2 to 10 volumes of an aqueous basic solution to the first container,

[0238] viii. Further stir the contents of the first container between 10°C and 30°C for at least 1 minute, preferably at least 5 minutes (such as 5 to 10 minutes),

[0239] ix. Allow the immiscible organic fraction to separate from the aqueous fraction, wherein the organic fraction contains the amide product of stage 1, and

[0240] x. Remove the organic fraction containing the amide product,

[0241] wherein steps i. to x. are carried out within a single 8-hour period.

[0242] In some embodiments, the first solvent is DCM.

[0243] In some embodiments, the amine is dimethylamine. In some embodiments, the amine is dissolved in THF, for example, at a concentration of 2M.

[0244] In some embodiments, the aqueous basic solution contains potassium carbonate.

[0245] In even more specific embodiments, stage 1 of the method of Scheme 2 further comprises the following steps:

[0246] xi. Dry the organic fraction with a drying agent, such as a drying agent selected from calcium chloride, magnesium sulfate, and sodium sulfate,

[0247] xii. Filter the organic fraction,

[0248] xiii. Concentrate the organic fraction, for example, under vacuum, such as at a pressure of less than 1 atmosphere,

[0249] xiv. Add the concentrated organic fraction to a second container,

[0250] xv. Add 2 to 10 volumes of a second solvent to the second container, wherein the second solvent is selected from IPA, EtOAc, IPrOAc, acetonitrile (MeCN), TBME, THF, 2-MeTHF, and toluene,

[0251] xvi. Stir the contents of the second container at a temperature of 45 °C to 55 °C for at least 1 hour, preferably at least 2 hours (such as 2 to 3 hours),

[0252] xvii. Cool the contents of the second container to a temperature of 15 °C to 25 °C,

[0253] xviii. Filter the contents of the second container to obtain a filtrate, wherein the filtrate contains the amide product of stage 1, and

[0254] xix. Dry the filtrate.

[0255] In some embodiments, the drying agent in step xi. is magnesium sulfate. In some embodiments, the solvent in step xv. is selected from TBME and IPA.

[0256] Stage 2 of the method of Scheme 2 involves reacting the amide product of stage 1 (the compound of formula (II)) with LiAlH 4 and / or LiAlD 4 to produce the compound of formula (I’). Optionally, as described above, it may be desirable to convert certain compounds of formula (I’) to the compounds of formula (I) as described herein.

[0257] As described above, LiAlH 4 , LiAlD 4 or a mixture of the two can be reacted with the amide. In a preferred embodiment, stage 2 of the method involves reacting the amide with a mixture of LiAlH 4 and LiAlD 4 . Such mixtures can contain LiAlD 4 and contain 0.1% to 99.9% hydride. Mixtures of lithium aluminum hydride or lithium aluminum deuteride of 2% to 98% can be employed. Sometimes, the mixture of LiAlH 4 and LiAlD 4 consists essentially of 98% LiAlD 4 / 2% LiAlH 4 . Sometimes, such mixtures consist essentially of 95% LiAlD 4 / 5% LiAlH 4 , 95% LiAlD 4 / 5% LiAlH 4 , 85% LiAlD 4 / 15%LiAlH 4 、80%LiAlD 4 / 20%LiAlH 4 、75%LiAlD 4 / 25%LiAlH 4 、70%LiAlD 4 / 30%LiAlH 4 、65%LiAlD 4 / 35%LiAlH 4 、60%LiAlD 4 / 40%LiAlH 4 、55%LiAlD 4 / 45%LiAlH 4 、50%LiAlD 4 / 50%LiAlH 4 、45%LiAlD 4 / 55%LiAlH 4 、40%LiAlD 4 / 60%LiAlH 4 、35%LiAlD 4 / 65%LiAlH 4 、30%LiAlD 4 / 70%LiAlH 4 、25%LiAlD 4 / 75%LiAlH 4 、20%LiAlD 4 / 80%LiAlH 4 、15%LiAlD 4 / 85%LiAlH 4 、10%LiAlD 4 / 90%LiAlH 4 、5%LiAlD 4 / 95%LiAlH 4 , or 2% LiAlD 4 / 98%LiAlH 4 composition.

[0258] Essentially composed of the specified percentage of LiAlH 4 and LiAlD 4 Composition of LiAlH 4 and LiAlD 4 A mixture means that the mixture may contain further components (in addition to LiAlH 4 and LiAlD 4 In particular, the mixture is essentially composed of LiAlH 4and LiAlD 4 The mixture consisting of will not contain an amount of material of a reagent that would impair the reduction of the amide to produce the compound of formula (I') (e.g., in a manner that inhibits the reduction of the carbonyl moiety of the amide of formula (II) to produce the compound of formula (I')) that reacts with LiAlH 4 and LiAlD 4 , the amide reactant, and / or the compound of formula (I')).

[0259] The amount of LiAlH 4 or LiAlD 4 contained in the mixture of the two depends on the degree of α-deuteration sought in the compounds of formula (I') (and (I)). For example, in the case of seeking a compound of formula (I(')) in which one y H is protium and the other is deuterium, a 50% LiAlH 4 and 50% LiAlD 4 mixture may be preferred. Alternatively, in the case of seeking a mixture of compounds of formula (I')) in which approximately half of the compounds contain two deuterium atoms at the α-position (i.e., both x H's are deuterium) and approximately half of the compounds contain one deuterium atom and one protium atom at the α-position (i.e., one y H is deuterium and the other is protium), a 25% LiAlH 4 and 75% LiAlD 4 mixture may be preferred.

[0260] The amount of LiAlH 4 and / or LiAlD 4 employed, relative to the amide being reduced in stage 2 of Scheme 2, is typically ≤1:1. For the avoidance of doubt, the ratio of LiAlH 4 and / or LiAlD 4 to the amide refers to the total amount of LiAlH 4 and / or LiAlD 4 used relative to the amide of formula (II). In some embodiments, the ratio of LiAlH 4 and / or LiAlD 4 : the compound of formula (II) is 0.5:1 to 1:1, such as 0.8:1 to 1:1. In some embodiments, the ratio of LiAlH 4 and / or LiAlD 4 : the compound of formula (II) is 0.9:1.

[0261] Typically, Stage 2 of Scheme 2 is carried out in a suitable solvent. A person skilled in the art can evaluate which solvents are suitable for this. Examples of suitable solvents include ethers such as THF and diethyl ether. In some embodiments, Stage 2 is carried out in THF.

[0262] In some embodiments, LiAlH 4 and / or LiAlD 4 is provided as a solution or suspension of LiAlH 4 and / or LiAlD 4 in a suitable solvent such as an ether, for example THF or diethyl ether, typically THF.

[0263] Stage 2 of Scheme 2 is carried out at a suitable temperature, and a person skilled in the art can evaluate which temperatures are suitable for these steps. Generally, Stage 2 of Scheme 2 is carried out at a temperature of from about -5 °C to about 65 °C.

[0264] In some embodiments, Stage 2 of Scheme 2 further comprises separating the compound resulting from the reduction by techniques known to a person skilled in the art suitable for doing so. For example, when quenching the reaction (e.g., with an aqueous solution of a tartrate such as Rochelle's salt), the product resulting from Stage 3 of Scheme 2 can be extracted into an organic solvent (such as an ether, for example THF or diethyl ether), washed with an aqueous solution such as an aqueous basic solution and concentrated. The separated compound from Stage 2 of Scheme 2 can be recrystallized. Techniques known to a person skilled in the art are suitable for such recrystallization. Examples of recrystallization techniques described for the recrystallization of the compound resulting from Stage 2 of Scheme 2 are applicable, mutatis mutandis, to the recrystallization of the salts (resulting from Stage 3) of these compounds.

[0265] In some embodiments, about 1 g or more, such as from about 1 g to about 100 kg or from about 1 g to about 1 kg of the compound resulting from Stage 2 of Scheme 2 is employed.

[0266] In a specific embodiment, Stage 2 of Scheme 2 comprises contacting the compound resulting from Stage 1 (i.e., the compound of formula (II)) with about 0.8 to about 1 equivalent, such as about 0.9 equivalent, of LiAlH 4 and / or LiAlD 4 to produce a first composition.

[0267] In some embodiments, the contacting is carried out in the presence of a solvent such as an ether, for example THF or diethyl ether, typically THF.

[0268] In some embodiments, the contacting comprises adding LiAlH 4 and / or LiAlD 4 dropwise to the amide, wherein LiAlH 4 and / or LiAlD4 As a solution or suspension of LiAlH 4 and / or LiAlD 4 in a suitable solvent (such as an ether, for example THF or diethyl ether) is provided. In some embodiments, LiAlH 4 and / or LiAlD 4 is provided as a 2.4 M or 2 M solution or suspension of LiAlH 4 and / or LiAlD 4 in THF. In some embodiments, LiAlH 4 and / or LiAlD 4 is provided as a 2 M solution or suspension of LiAlH 4 and / or LiAlD 4 in THF.

[0269] In some embodiments, the contacting is carried out at a temperature of about -5 °C to about 65 °C.

[0270] In some embodiments, Stage 2 further comprises stirring or agitating the first composition. The first composition may be stirred or agitated for about 1 hour to about 6 hours, typically about 2 hours. The first composition may be stirred or agitated at a temperature of about 55 °C to about 65 °C. In some embodiments, the first composition is stirred or agitated at a temperature of about 55 °C to about 65 °C and then cooled to a temperature of about 10 °C to about 30 °C.

[0271] In some embodiments, the amide is contacted with about 0.9 equivalents of LiAlH 4 and / or LiAlD 4

[0272] In a specific embodiment, Stage 2 of Scheme 2 comprises the following steps:

[0273] i. Add 1 g or more (such as 1 g to 1 kg) of the amide to be reduced to a third container,

[0274] ii. Add 5 to 20 volumes of an ether solvent to the third container,

[0275] iii. At a temperature of -5 °C to 65 °C, add dropwise to the third container over at least 15 minutes (such as 15 to 30 minutes) a 0.8 to 1 equivalent solution of LiAlH 4 and / or LiAlD 4 in an ether solvent,

[0276] iv. Stir the contents of the third container at 55 °C to 65 °C for 1 hour to 6 hours, preferably 2 hours, and

[0277] ​vi. Cool the contents of the third container to 10 °C to 30 °C,

[0278] wherein the contents of the third container comprise a compound of formula (I’).

[0279] In some embodiments, the ether solvent is THF. In some embodiments, in step iii, 0.9 equivalents of LiAlH 4 and / or LiAlD 4 is added to the third container. LiAlH 4 and / or LiAlD 4 is typically added to the third container as a 2.4 M or 2 M solution in THF. In some embodiments, LiAlH 4 and / or LiAlD 4 is added to the third container as a 2 M solution in THF.

[0280] In even more specific embodiments, stage 2 of Scheme 2 includes a work-up comprising the following steps:

[0281] vi. Add an aqueous solution of 5 to 20 volumes of a tartrate (such as Rochelle salt) to the fourth container,

[0282] vii. At 15 °C to 25 °C, add the composition comprising the crude compound of formula (I) to the fourth container over at least 15 minutes (such as 15 minutes to 1 hour), preferably over at least 30 minutes (such as 30 minutes to 1 hour), and

[0283] viii. Stir the contents of the fourth container at 15 °C to 25 °C for at least 30 minutes (such as 30 minutes to 1 hour).

[0284] For the avoidance of doubt, the composition comprising the crude compound of formula (I’) refers to the contents of the third container at the completion of step v. of stage 2 described above.

[0285] In further specific embodiments, stage 2 of Scheme 2 further includes the following steps:

[0286] ix. Allow the organic fraction to separate from the aqueous fraction, wherein the organic fraction comprises the compound of formula (I’),

[0287] x. Remove the aqueous fraction from the fourth container,

[0288] xi. Add 5 to 20 volumes of a brine solution to the fourth container,

[0289] xii. Stir the contents of the fourth container at a temperature of 15 °C to 25 °C for at least 5 minutes (such as 5 to 15 minutes).

[0290] xiii. Remove the organic fraction containing the compound of formula (I’) as the free base,

[0291] xiv. Dry the organic fraction using a desiccant, such as a desiccant selected from calcium chloride, magnesium sulfate, and sodium sulfate,

[0292] xv. Filter the organic fraction, and

[0293] xvi. Concentrate the organic fraction, for example under vacuum, such as at a pressure of less than 1 atmosphere.

[0294] The isolated compound of formula (I’) (produced via Stage 2) is stable and can be stored as a solid in air at ambient temperature, for example at about 20 °C. They can, but need not, be stored under inert conditions, such as under nitrogen or argon, or at a reduced temperature, such as in a refrigerator or freezer. In some embodiments, the compound of formula (I) is stored in a solvent, for example dissolved in ethanol. In some embodiments, the compound of formula (I’) is stored in a solvent for more than 8 hours, typically more than 12 hours.

[0295] As described above, the method of Scheme 2 provides a method for synthesizing a compound of formula (I’) or a pharmaceutically acceptable salt thereof, or a method comprising the synthesis of a compound of formula (I’) or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for synthesizing a pharmaceutically acceptable salt of formula (I’), or a method comprising the synthesis of a pharmaceutically acceptable salt of formula (I’). The pharmaceutically acceptable salt can be formed from the compound of formula (I’) by reaction with a suitable acid. Thus, in some optional embodiments, the method of Scheme 2 includes Stage 3 (as depicted in Scheme 2), wherein in some embodiments the compound of formula (I’) is reacted with an acidic reagent to produce a pharmaceutically acceptable salt of the compound of formula (I’), the acidic reagent being suitable for crystallizing the pharmaceutically acceptable salt of the compound of formula (I’). It should be understood that in embodiments in which the compound of formula (I’) contains the moiety OPR, the protecting group PR will typically be removed and the resulting hydroxyl group is optionally manipulated as described herein prior to Stage 3 (formation of the pharmaceutically acceptable salt).

[0296] Thus, in some embodiments, the present invention provides a method for synthesizing a compound of formula (I) or (I’) or a pharmaceutically acceptable salt thereof, which comprises Stage 1, Stage 2, and Stage 3, wherein Stage 1 comprises:

[0297] (i) Reacting a carboxylic acid (such as the carboxylic acid of formula (III)) with two or more coupling agents to produce an activated compound;

[0298] (ii) Reacting the activated compound with a compound having R 2 R 3NH or R 2 R 3 the amine reaction of ND to produce an amide (e.g., an amide of formula (II)); and

[0299] (iii) separating the amide;

[0300] Stage 2 involves reacting the amide with LiAlH 4 and / or LiAlD 4 ; and

[0301] Stage 3 involves the step of reacting a compound (e.g., a compound of formula (I) or (I')) with an acidic reagent suitable for crystallizing a pharmaceutically acceptable salt of the compound of formula (I) or (I').

[0302] In some embodiments, a ratio of acidic reagent:compound of formula (I) or (I') of ≥1:1 is used. Typically, the ratio of acidic reagent:compound of formula (I(')) is 1:1.

[0303] Typically, Stage 3 of the method is carried out in a suitable solvent. A person skilled in the art can evaluate which solvents are suitable for Stage 3. Examples of suitable solvents include ethanol, IPA, iPrOAc and MeCN. In some embodiments, Stage 3 is carried out in ethanol.

[0304] Stage 3 of the method of the present invention is carried out at a suitable temperature, and a person skilled in the art can evaluate which temperatures are suitable for these steps.

[0305] In some embodiments, Stage 3 of the method involves contacting a compound of formula (I) (or (I')) with an acidic reagent to produce a first composition. Typically, the contacting in Stage 3 is carried out at a temperature of from 70 °C to 100 °C, such as from 70 °C to 90 °C or from 70 °C to 80 °C. In some embodiments, the contacting in Stage 3 is carried out at a temperature of about 75 °C.

[0306] In some embodiments, Stage 3 further includes separating a pharmaceutically acceptable salt of (I) or (I’). Those skilled in the art are aware of the techniques in the art applicable to separating such compounds. For example, in the case where the compound is dissolved in a suspension, it can be separated from some other components of the suspension via filtration such as hot filtration. The pharmaceutically acceptable salt of formula (I) or (I’) can be precipitated from the filtrate. Those skilled in the art are aware of methods to promote the precipitation of a compound from a solution, such as cooling the solution, concentrating the solution, and / or adding a crystalline form of the compound to the solution to promote nucleation of the compound from the solution and further growth of the crystals (i.e., seeding). The pharmaceutically acceptable salt of formula (I) or (I’) can be recrystallized. Those skilled in the art are aware of techniques applicable to recrystallizing the pharmaceutically acceptable salt of formula (I) or (I’). Examples of the recrystallization techniques described for the recrystallization of the contents produced by Stage 2 are applicable, mutatis mutandis, to the recrystallization of the pharmaceutically acceptable salt of formula (I) or (I’).

[0307] In a more specific embodiment, Stage 3 of the method of the present invention includes the following steps:

[0308] i. Adding at least one equivalent of an acidic reagent suitable for crystallizing the pharmaceutically acceptable salt of the compound of formula (I) or (I’) to a fifth container,

[0309] ii. Dissolving the compound of formula (I) or (I’) as a free base in 5 to 20 volumes of a solvent such as a solvent selected from ethanol, IPA, iPrOAc, and MeCN, and adding the solution to the fifth reaction container,

[0310] iii. Stirring the contents of the fifth container at a temperature higher than 72 °C (such as 72 °C to 90 °C),

[0311] iv. Filtering the contents of the fifth container,

[0312] v. Adding the filtrate to a sixth container and cooling the contents to a temperature of 67 °C to 73 °C,

[0313] vi. Optionally seeding the sixth container with a crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) or (I’),

[0314] vii. Stirring the contents of the sixth container at a temperature of 67 °C to 73 °C for at least 30 minutes (such as 30 minutes to 1 hour),

[0315] viii. Cooling the contents of the sixth container to a temperature of -5 °C to 5 °C at a rate of 2 °C to 8 °C per hour, and

[0316] ix. Filter the contents of the sixth vessel to produce a filter cake comprising a pharmaceutically acceptable salt of the compound of formula (I) or (I’).

[0317] In some embodiments, the solvent in step ii. is ethanol. In some embodiments, the cooling rate in step viii. is 5 °C / hour.

[0318] P. H. Stahl and C. G. Wermuth provided a review of pharmaceutical salts and the acids contained therein in Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. The acids described in this review are suitable acidic reagents for providing pharmaceutically acceptable salts according to aspects of the present invention or for use in pharmaceutically acceptable salts for uses according to aspects of the present invention.

[0319] In some embodiments, the acidic reagent is any one selected from the group consisting of fumaric acid, tartaric acid, citric acid, hydrochloric acid, acetic acid, lactic acid, gluconic acid, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanic acid, toluenesulfonic acid, and undecylenic acid.

[0320] Generally, the acidic reagent is any one selected from fumaric acid, tartaric acid, citric acid, and hydrochloric acid. In a specific embodiment, the acidic reagent is fumaric acid.

[0321] The amide produced in Stage 2 is produced when reacting the starting carboxylic acid with two or more coupling agents to produce an activated compound and reacting the activated compound with an amine having the formula R 2 R 3 NH or R 2 R 3 ND. For the avoidance of doubt, the amide produced in Stage 1 and the R of the compound of formula (I) or (I’) produced in Stage 2 (and Stage 3) 2and R 3 The group is derived from formula R 2 R 3 R of the amine of NH 2 and R 3 group.

[0322] The compound of formula (I') is produced when a compound of formula (II) is reacted with LiAlH 4 and / or LiAlD 4 Without wishing to be bound by theory, the hydride or deuteride ions provided by LiAlH 4 and / or LiAlD 4 bind to the carbon atom of the carbonyl group of formula (II), resulting in the formation of the compound of formula (I'). For the avoidance of doubt, the y H group in formulas ((I) and (I') is derived from the hydride or deuteride ions provided by LiAlH 4 and / or LiAlD 4 .

[0323] In some embodiments, at least one y H is deuterium, i.e., the compound of formula (I') is produced when a compound of formula (II) is reacted with LiAlD 4 or LiAlD 4 and a mixture of LiAlH 4 .

[0324] The method of the seventh aspect of the present invention is particularly useful for allowing the obtaining of therapeutically useful α-deuterated compounds (i.e., wherein there is more deuterium at the α-position than the natural preponderance, except for methyl (R 2 and / or R 3 ), because the method employs significantly less LiAlD 4 than the related syntheses known in the art, since the method substitutes deuterium at the α-position but not at the β-position. LiAlD 4 is one of the most expensive and difficult-to-prepare reagents in this synthesis. In addition, the optimized method of the present invention reduces the requirements for LiAlH 4 and / or LiAlD 4 , for example from 2 equivalents to 0.9 equivalents, which improves the economic efficiency of preparing the deuterated compounds of formula (I) and / or (I'). In view of this, via the method of the present invention, the preparation of the compounds of formula (I') and (I') is less costly than other related deuterated compounds typically deuterated at both the α- and β-positions.

[0325] As described above, the method of the seventh aspect of the present invention is applicable to the production of high-purity compounds of formula (I) and (I'). In some embodiments, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof is produced at an HPLC purity of 99% to 100%, such as at an HPLC purity of 99.5% to 100%. In some embodiments, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof is produced at an HPLC purity of 99.9% to 100%, such as at an HPLC purity of 99.95% to 100%.

[0326] The chemical substances described in connection with the seventh aspect of the present invention and Scheme 2 detail the chemical substances for pre-GMP and GMP batches that can be used for the efficient synthesis of DMT-based drug substances, including the compound of formula (I). In particular, the coupling agents HOBt and EDC.HCl can be used to increase the yield of Step 1 from less than 70% to greater than 90%. This enables the effective scaling of drug substance batches under GMP standards, with an overall yield of 65% and higher.

[0327] A series of DMT-based drug substances are prepared using a modified version of Scheme 2 below (with reference to the labeling of formula (I)), each selectively enriched in deuterium in a GMP-compatible route, some according to formula (I) and others for use in the present invention (e.g., in its third aspect):

[0328]

[0329]

[0330] * And thus the synthesis of (undeuterated) DMT is described in the following experimental section.

[0331] Similarly, the GMP-compatible chemical substances of Scheme 2 are used to prepare a similar series of 5-OMeDMT-based drug substances (see Scheme 4), each selectively enriched in deuterium, some according to formula (I) and others for use in the present invention (e.g., its third aspect).

[0332]

[0333] Scheme 4. GMP-compatible route for 5-OMeDMT-based drug substances

[0334] The compounds are again described with reference to the labeling of formula (I) in the following table (in all compounds described below, n = 1 and R 1 = 5-OMe)

[0335]

[0336] *And thus the synthesis of (undeuterated) 5-OMeDMT is described in the following experimental section.

[0337] According to a third aspect of the invention, there is provided a composition comprising a first compound which is a compound as defined according to the first aspect of the invention or a pharmaceutically acceptable salt thereof, and a second compound which is (i) a compound as defined according to the first aspect of the invention or a pharmaceutically acceptable salt thereof, but which differs from the first compound by y the identity of H and / or R 3 ; or (ii) a compound as defined according to the first aspect of the invention or a pharmaceutically acceptable salt thereof, except that each x H and y H represents hydrogen.

[0338] Generally, the second compound differs from the first compound only by y the identity of H and / or R 3 ; and / or by x H and y H which represent hydrogen.

[0339] For example, the first compound and the second compound may differ by y the identity of H, and in an embodiment differ only by y the identity of H. As described in WO 2020 / 245133 A1 (published 10 December 2020, Small Pharma Ltd), there is a quantifiable relationship between the degree of α-deuteration and the H:D ratio of the input reducing agent in the synthesis method indirectly disclosed therein, and the effect on enhancing the metabolic half-life of DMT. Such technical information can be used to prepare compositions comprising a plurality of compounds of formula (I) described herein, wherein the compounds or salts differ from each other only by y the identity of H.

[0340] From the above discussion of the synthesis method, it should be understood that in reducing the precursor amide (the carbonyl of which is converted to the C( y H) 2 moiety of formula (I) and (I')), this can be readily achieved in a controlled manner by using a mixture of lithium aluminium hydride and lithium aluminium deuteride. For example, if desired, a mixture of compounds of formula (I) (where n = 0) containing a controlled proportion of compounds which differ only by α-mono- and / or α,α-di-deuteration (i.e. differ only by 2 R and 3 R groups) can be prepared by reducing 2-(3-indolyl)-acetamide having the desired y H identity) with a desired ratio of lithium aluminium hydride and lithium aluminium deuteride.

[0341] Alternatively or additionally, the compounds (or pharmaceutically acceptable salts thereof) in the compositions of the third aspect of the present invention may be different from each other by the identity of R 3 , for example, only by the identity of R 3 and / or only by the identity of y H. In the case where a compound is present in a composition in which R 2 is the same as R 3 , different R 3 can be achieved. In this case, this is typically but not necessarily CD 3 ; and there is another compound in which R 3 is H.

[0342] The binding of the dimethylamino-containing compound of formula (I) (i.e., the compound of formula (I) in which R 3 is not H) to the serotonin receptor in vivo is expected to be different in selectivity and strength from the binding of the monomethylamino compound of formula (I) (i.e., in which R 3 is H). It is expected that altering the relative amounts of the dimethylamino- and monomethylamino-containing compounds (in which the proportion of deuterium in the N-methyl in at least one is greater than its natural isotopic abundance and hydrogen) in the compositions of the present invention allows for the modulation of pharmacokinetics and thus the therapeutic effect of the composition. This provides an additional element for controlling the metabolism of the compounds of formula (I).

[0343] Alternatively or additionally (for compositions comprising compounds of formula (I) that are different from each other by the identity of y H and / or R 3 ), the compositions of the third aspect of the present invention may comprise a compound as defined in the first aspect of the present invention or a pharmaceutically acceptable salt thereof, except for each x H representing hydrogen and y H, in other words, analogs of the compounds of formula (I) that are not deuterium-enriched or pharmaceutically acceptable salts thereof. As described in WO 2020 / 245133 A1 (Small Pharma Ltd, supra), mixtures of DMT and its α- and / or β-deuterated analogs, as well as clinical effectiveness, are described. In the same way, mixtures of the compounds of formula (I) and their deuterated analogs can be used to controllably alter the pharmacokinetic properties of the compounds of formula (I) described herein, thus allowing for more flexible therapeutic applications.

[0344] Combining different compounds in these ways to provide the compositions according to the third aspect of the present invention, except for increasing the deuterium atoms in the methyl groups of DMT or the methyl groups of NMT and their R 1In addition to the ratios in the -substituted derivatives, additional variables are provided, i.e., through these variables, the pharmacokinetics of the parent non-deuterated compounds corresponding to those of formula (I) can be altered.

[0345] In particular, it is contemplated that altering the relative amounts of the compounds within the compositions of the invention will modulate the pharmacokinetics of the compositions and thus their therapeutic effects. In those compositions that include compounds of formula (I) in which R 3 is H, for example, greater concentrations of these compounds may be more readily administered because larger amounts of the monomethyltryptamine compounds are generally better tolerated in vivo (relative to their dimethyltryptamine counterparts). The relative amounts of the different compounds within the compositions of the invention can be determined in part by the medical practitioner based on the metabolic characteristics of the patient to whom the composition is intended to be administered. For example, relatively greater amounts of the compounds of formula (I) in which R 3 is H may be more suitable for patients with higher metabolisms.

[0346] In some embodiments, the compositions of the third aspect of the invention comprise compounds of formula (I) in which, in each of them, one y H is H and the other is D. In some embodiments, the compositions comprise compounds of formula (I) in which, in each of them, each y H is H. Sometimes, the compositions comprise compounds of formula (I) in which, in each of them, each y H is D.

[0347] To avoid doubt, the above embodiments do not exclude the presence of additional compounds of formula (I) or their non-deuterated analogs.

[0348] In a specific embodiment, the compositions of the third aspect of the invention comprise two or three compounds of formula (I) that differ from each other only in y the definition of H, i.e., a population of compounds of formula (I) is provided in which the C( y H) 2 moiety is CH 2 , CD 2 , or CH. In a specific embodiment of these, NR 2 R 3 is N(CD 3 ) 2 or N(CH 3 )(CD 3 ), typically N(CD 3 ) 2 .

[0349] The compositions of the present invention can be quantified at least in part by their average molecular weight. As used herein, average molecular weight means the weighted average of the molecular weights of a compound or composition (e.g., a composition comprising two or more compounds of formula (I) that differ from each other only in the degree of deuteration), as measured by appropriate mass spectrometry techniques such as LC-MS SIM (selective ion monitoring). In some embodiments, the average molecular weight is a weighted average.

[0350] It should be understood that the average molecular weight can be used to characterize the available compounds and compositions of the present invention obtainable by the teachings herein, particularly by adjusting the relative ratios of lithium aluminum hydride and lithium aluminum deuteride in the exemplified reductions. It should be further understood that the greater the degree of deuteration, the higher the average molecular weight of the composition.

[0351] In some embodiments, the composition consists essentially of a compound of formula (I) optionally together with its undeuterated analogue. This means that the composition does not contain a substantial amount of other pharmaceutically active compounds (including other dimethyltryptamine compounds). In other specific embodiments, the composition consists essentially of a compound of formula (I). In other words, and alternatively, the compositions according to these specific embodiments constitute a pharmaceutical substance comprising a biologically active ingredient consisting essentially of a mixture of compounds of formula (I).

[0352] According to specific embodiments, the compositions of the present invention and the compositions for use and for uses according to related aspects of the present invention are substances that do not exist (e.g., detectable amounts of dimethyltryptamine), particularly in the case where one or both of R 2 and R 3 is CD 3 of.

[0353] In some embodiments, the compositions of the present invention have an oxygen content of less than 2 ppm, such as from 0.1 ppm to 2 ppm. A person skilled in the art can determine the oxygen content using any suitable technique known in the art, such as using a dissolved oxygen meter (e.g., Jenway 970 Enterprise Dissolved Oxygen Meter, available from Keison Products: http: / / www.keison.co.uk / products / jenway / 970.pdf). Compositions of the present invention having an oxygen content of less than 2 ppm are particularly advantageous for the preparation of dosage forms for oral or nasal administration, since the reduced oxygen content improves the formation of odorous impurities and / or degradation products from the compounds of formula (I).

[0354] The composition can be stored in any suitable container. In some embodiments, to improve the degradation of the composition, the composition of the present invention is stored in a container suitable for preventing ultraviolet light penetration, such as an amber glass vial. In other cases, the container for storing the composition is not suitable (and can be made of, for example, clear glass) for protection against ultraviolet light, and if desired, secondary packaging (e.g., a package in which the container containing the formulation can be placed) provides the protection.

[0355] To improve the degradation of the composition, it may be desirable to minimize the total oxygen content within the container in which the composition is stored, with the oxygen within the container being balanced between the composition and the headspace (if any) within the container. Thus, it may be desirable to store the composition under an inert atmosphere, for example, by purging the headspace to reduce its oxygen content from about 20% typically present in air to less than, for example, 0.5%. Generally, the container is airtight and the composition is stored under an inert atmosphere such as in nitrogen or argon, typically nitrogen. The composition can be stored at room temperature, for example, at about 20°C to about 30°C (usually about 20°C) or at a colder temperature, for example, at about 2°C to about 8°C. Alternatively, to further improve the degradation of the composition, it can be stored at a temperature below room temperature, such as in a refrigerator or freezer.

[0356] As described above, in its fourth aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined according to the first aspect or the second aspect of the present invention, or a combination of a composition according to the third aspect of the present invention with a pharmaceutically acceptable excipient.

[0357] Examples of pharmaceutically acceptable excipients that may be included in the pharmaceutical compositions of the present invention include, but are not limited to, those described in Gennaro et al., Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000 (particularly Part 5: Pharmaceutical Manufacturing). Suitable pharmaceutically acceptable excipients are also described in Handbook of Pharmaceutical Excipients, 2nd Edition; Editors A. Wade and P. J. Weller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1994. M. F. Powell, T. Nguyen and L. Baloian provide a review of excipients suitable for parenteral administration (administration other than by oral or digestive tract) in PDA J. Pharm. Sci. Technol., 52, 238 - 311 (1998). The compositions include those suitable for oral, nasal, topical (including buccal, sublingual and transdermal), parenteral (including subcutaneous, intravenous and intramuscular) or rectal administration.

[0358] With the aid of a pharmaceutically suitable liquid, the compositions of the present invention can be prepared in the form of a solution, suspension, emulsion, or as a spray. Aqueous suspensions, isotonic saline solutions and sterile injectable solutions containing pharmaceutically acceptable dispersing agents and / or wetting agents such as propylene glycol or butylene glycol can be used.

[0359] The present invention also provides a combination of the compositions of the present invention with a packaging material suitable for the compositions, the packaging material including instructions for use of the compositions.

[0360] According to some embodiments, the pharmaceutical compositions of the present invention are suitable for parenteral administration, i.e., suitable for administration other than by oral or digestive tract, such as by inhalation or nasal, topical (including buccal, sublingual and transdermal), subcutaneous, intravenous or intramuscular administration. In fact, the pharmaceutical compositions for intramuscular administration show significantly improved bioavailability, as measured by the area under the curve (see Figure 3A and 3B)Measured. Suitability for (i.e., use in) parenteral administration means that such compositions meet the pharmacopeial requirements for sterility, contaminants, and pyrogens (see, e.g., The United States Pharmacopeial Convention, General Requirements / <1>Injections, page 33). Sometimes, pharmaceutical compositions contain inhibitors of microbial growth (e.g., antimicrobial preservatives) and / or antioxidants.

[0361] Pharmaceutical compositions suitable for injection generally have a pH of about 3 to 9 and an osmotic weight concentration of about 250 to about 600 mOsm / Kg. I. Usach et al. reported in Adv. Ther., 36, 2986 - 2996 (2019) that pH values above 9 are associated with tissue necrosis (death of cells within the tissue), while values below 3 are reported to cause pain and phlebitis (inflammation of the vein). A weight osmolarity greater than 600 mOsm / Kg has also been reported to cause pain.

[0362] As described herein, it is also contemplated that the compounds and compositions of the present invention have greater oral bioavailability than the compounds corresponding to formula (I), but without deuterium enrichment in the methyl groups corresponding to R 2 or R 3 . Thus, according to specific embodiments, the pharmaceutical compositions of the present invention are in the form of oral dosage forms.

[0363] "Oral dosage form" means a specific configuration (such as, for example, a tablet or a capsule) containing a specific dose of a compound or composition, where the configuration is suitable for oral administration. Oral dosage forms can be solid dosage forms, such as tablets, capsules, sachets, powders or granules, or liquid or semi - solid oral dosage forms, such as syrups, solutions, ampoules, or dispersions. Typically, oral dosage forms are solid dosage forms, usually tablets or capsules.

[0364] According to still further embodiments, the pharmaceutical compositions of the present invention are presented in a form suitable for inhalation. Inhalable formulations preferably contain a compound of formula (I) in free base form.

[0365] To avoid doubt, inhalable formulations are capable of being aerosolized and entering the patient's lungs by the patient's inhalation. In other words, inhalable formulations are suitable for pulmonary administration. Inhalable formulations can be inhaled in the form of vapors, aerosols, or gases. Generally, inhalable formulations are inhaled in the form of vapors or aerosols.

[0366] "Free base" means that the amine within the compound of formula (I) or its non-deuterated analog (e.g., in addition to the compounds of formula (I) as discussed above, it may also be present in the compositions of the present invention) is in its unprotonated form, as opposed to the conjugated acid (protonated) form of the amine. Thus, salts of the compounds of formula (I) or their non-deuterated analogs are excluded from the scope of the free base. To avoid doubt, zwitterions containing the protonated form of the amine and a negatively charged substituent bound to DMT (such as psilocybin in zwitterionic form) are excluded from the scope of the free base.

[0367] A pharmaceutical composition suitable for inhalation comprises a solvent in which the free base is at least partially soluble. The solvent is typically a liquid at ambient temperature and pressure (in particular at about 20 °C and about 1 bar). In more specific embodiments, the solvent is capable of forming a vapor or aerosol containing the free base upon application of heat, e.g., the solvent may be suitable for use in an electronic vapor device (EVD). An EVD typically includes a power supply portion and a cartridge. The power supply portion generally contains a power source such as a battery, and the cartridge generally contains a heater and a reservoir capable of accommodating an inhalable formulation. The heater is typically in contact with the inhalable formulation (e.g., via a wick) and is typically configured to heat the inhalable formulation to produce a vapor or aerosol.

[0368] In some embodiments, the solvent is volatile (having a boiling point ≤ 100 °C, such as 50 °C to 100 °C). Such a solvent may be capable of evaporating under the airflow of an evaporator (such as a Volcano Medic Vaporizer) at a temperature of 30 °C to 70 °C, e.g., 55 °C. Evaporation of the solvent leaves a residue of the free base, which can then be evaporated into a vapor or aerosol at a higher temperature (e.g., at a temperature of about 150 °C to 250 °C, such as 210 °C) under the airflow of the evaporator and inhaled.

[0369] In some embodiments, the solvent is any one or a combination of two or more selected from the group consisting of propylene glycol (propane-1,2-diol), glycerol, polyethylene glycol, water, propylene glycol (propane-1,3-diol), butylene glycol (butane-1,3-diol), butane-2,3,-diol, butane-1,2-diol, ethanol, and triacetin.

[0370] In some embodiments, the solvent is selected from propylene glycol, glycerol, and polyethylene glycol, or a mixture thereof. Typically, the solvent is a mixture of propylene glycol and glycerol in a ratio of about 50:50 (propylene glycol:glycerol) to about 10:90 by weight, such as about 50:50 to about 20:80 or about 50:50 to about 30:70 by weight. In some embodiments, the solvent is a mixture of propylene glycol and glycerol in a ratio of about 50:50 to about 30:70 by weight.

[0371] Typically, the glycerol is vegetable glycerol, i.e., glycerol derived from vegetable oils.

[0372] A pharmaceutical composition suitable for inhalation or nasal administration typically contains a taste-masking agent. The purpose of the taste-masking agent is to make the taste or odor of the formulation more appealing to the patient. In some embodiments, a pharmaceutically acceptable excipient contains a taste-masking agent. When a pharmaceutically acceptable excipient contains a solvent and a taste-masking agent, the taste-masking agent is typically at least partially soluble in the solvent, and upon application of heat, the solvent is generally capable of forming a vapor or aerosol containing the free base and the taste-masking agent. Typically, the taste-masking agent is suitable for evaporation into a vapor or aerosol under the gas flow of an evaporator (e.g., at a temperature of about 150°C to 250°C, such as 210°C). The taste-masking agent is typically a liquid or solid at ambient temperature and pressure. Advantageously, the taste-masking agent has no adverse effect on the bioavailability of the free base, e.g., it is advantageous that the free base is stable when stored in the presence of the taste-masking agent.

[0373] In some embodiments, the taste-masking agent is any one or a combination of two or more selected from the group consisting of flavoring agents, glucose, fructose, sorbitol, mannitol, honey, saccharin, sucrose, xylitol, erythritol, maltitol, sucralose, neotame, trehalose, and tagatose. In some embodiments, the flavoring agent is menthol, vanilla, wintergreen, mint, maple, apricot, peach, raspberry, walnut, butterscotch, wild cherry, chocolate, anise, citrus plants such as orange or lemon, or licorice flavoring.

[0374] Examples of additional pharmaceutically acceptable excipients that can be included in compositions suitable for inhalation or other means include, but are not limited to, those described in Gennaro et al., Remmington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000 (especially Part 5: Pharmaceutical Manufacturing). Suitable pharmaceutical excipients are also described in Handbook of Pharmaceutical Excipients, 2nd Edition; Editors A. Wade and P.J. Weller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1994. M.F. Powell, T. Nguyen and L. Baloian provided a review of excipients suitable for parenteral administration in PDA J. Pharm. Sci. Technol., 52, 238 - 311 (1998). All soluble excipients listed in this review article are excipients suitable for use in inhalable formulations.

[0375] As described in detail herein, the present invention has therapeutic uses. In some embodiments, the therapy is psychedelic-assisted psychotherapy, i.e., the therapy related to the first aspect of the present invention treats mental disorders by psychological means, which are enhanced by one or more protocols, wherein the patient is subjected to a psychedelic experience induced by administration of a compound of formula (I).

[0376] In its fifth aspect, the present invention provides a compound as defined in the first aspect, second aspect or a composition of the third or fourth aspect for use in a method of treating a mental or neurological disorder in a patient.

[0377] In another aspect, the present invention provides the use of a compound as defined in the first aspect, second aspect or a composition of the third aspect for the preparation of a medicament. In some embodiments of this aspect, the medicament is for use in a method of treating a mental or neurological disorder in a patient, including those disorders described immediately below.

[0378] In some embodiments, the mental or neurological disorder is selected from (i) obsessive-compulsive disorder, (ii) depression, (iii) schizophrenia, (iv) schizoid disorder, (v) anxiety disorder, (vi) substance abuse, and (vii) anhedonia disorder. Generally, the mental or neurological disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depression, (iii) anxiety disorder, (iv) substance abuse, and (v) anhedonia disorder.

[0379] In some embodiments, the disorder is selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, obsessive-compulsive disorder, and eating disorders such as compulsive eating disorder.

[0380] In some embodiments, the mental or neurological disorder is major depressive disorder. In some embodiments, the mental or neurological disorder is treatment-resistant depression.

[0381] In some embodiments, the therapy or treatment method includes parenteral administration, such as inhalation or pulmonary administration of a formulation.

[0382] To avoid doubt, the embodiments related to the fifth aspect of the present invention are applicable, mutatis mutandis, to the treatment methods of the sixth aspect of the present invention. For example, the method can be used to treat disorders selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse, and (v) anhedonia disorder.

[0383] To treat a disorder, an effective amount of a compound of formula (I) is administered, i.e., an amount sufficient to reduce or halt the rate of progression of the disorder, or to improve or cure the disorder and thus produce the desired therapeutic or inhibitory effect.

[0384] Each and every reference mentioned herein is hereby incorporated by reference in its entirety as if the entire content of each reference were set forth herein in its entirety.

[0385] The present invention can be further understood with reference to the following examples.

[0386] Examples

[0387] Overview

[0388] A series of in vitro drug metabolism and pharmacokinetics (DMPK) experiments were conducted on human and animal tissues with respect to N,N-dimethyltryptamine (DMT, SPL026), N,N-hexadeuterio-dimethyltryptamine (D 6 -DMT, SPL028vii) and α,α-bis-deuterio-N,N-hexadeuterio-dimethyltryptamine (D 8 -DMT, SPL028viii) to study the metabolic characteristics and stability of each isotope mixture.

[0389] Deuterium substitution of the methyl groups of DMT shows a DKIE, which can be attributed to disruption of metabolic pathways such as demethylation and N-oxidation, or via a secondary DKIE mechanism. It is also noteworthy that the lower deuterated species D 0 to D 5This is advantageous for analytical method development and validation as well as CMC aspects of pharmaceutical product development of the compounds and compositions of the present invention.

[0390] Experiment

[0391] A series of in vitro experiments were conducted on the deuterium-rich DMT compounds SPL028vii and SPL028viii (see the following table) to study the deuterium kinetic isotope effect (DKIE) in human and animal tissues as an indicator of in vivo clearance.

[0392] Research Description Tested Compounds In vitro Intrinsic Clearance in Human Hepatocytes <![CDATA[SPL026, SPL028vii(D 6 ),SPL028viii(D 8 )]]> In vitro Intrinsic Clearance in Human Mitochondrial Fraction <![CDATA[SPL026, SPL028viii(D 8 )]]> In vitro Intrinsic Clearance in Human Mitochondrial Fraction <![CDATA[SPL026, SPL028vii(D 6 ),SPL028viii(D 8 )]]>

[0393] Overview of in vitro DMPK experiments of SPL026 and SPL028 deuterated analogs

[0394] Chemical substance

[0395] Synthesis of DMT (SPL026)

[0396] Stage 1: Coupling of indole-3-acetic acid and dimethylamine

[0397] Under N 2 Into a 5 L vessel were added indole-3-acetic acid (257.0 g, 1.467 mol), hydroxybenzotriazole (HOBt) (~20% wet) (297.3 g, 1.760 mol), and dichloromethane (DCM) (2313 mL) to obtain a milky suspension. Then ethyl carbodiimide hydrochloride (EDC·HCl) (337.5 g, 1.760 mol) was added in portions over 5 minutes at 16 °C - 22 °C. The reaction mixture was stirred at ambient temperature for 2 hours, and then 2 M dimethylamine in tetrahydrofuran (THF) (1100 mL, 2.200 mol) was added dropwise over 20 minutes at 20 °C - 30 °C. The resulting solution was stirred at ambient temperature for 1 hour, where HPLC indicated 1.1% indole-3-acetic acid and 98.1% of Stage 1. Then 10% K 2 CO 3 (1285 mL) was added and stirred for 5 minutes. The layers were separated, and the upper aqueous layer was extracted with DCM (643 mL × 2). The organic extracts were combined and washed with saturated brine (643 mL). Then the organic extracts were passed through MgSO 4Dry, filter and concentrate in vacuo at 45 °C. This afforded 303.1 g of crude Stage 1 as an off-white viscous solid. The crude material was then slurried in methyl tert-butyl ether (TBME) (2570 mL) at 50 °C for 2 h, then cooled to ambient temperature, filtered and washed with TBME (514 mL × 2). The filter cake was then dried in vacuo at 50 °C to afford 226.2 g (yield = 90%) of Stage 1 as an off-white solid with HPLC purity of 98.5% and NMR purity >95%.

[0398] Stage 2: Preparation of DMT

[0399] Under N 2 to a 5 L vessel was added Stage 1 (272.5 g, 1.347 mol) and THF (1363 mL) to give an off-white suspension. Then 2.4 M LiAlH 4 (505.3 mL, 1.213 mol) in THF was added dropwise over 35 min at 20 °C - 56 °C to give an amber solution. The solution was heated to 60 °C for 2 h, where HPLC indicated Stage 1 ND, Stage 2 92.5%, Impurity 1 2.6%, Impurity 2 1.9%. The complete reaction mixture was cooled to ambient temperature and then added dropwise over 30 min at 20 °C - 30 °C to a solution of 25% Rochelle's salt (aqueous solution) (2725 mL). The resulting milky suspension was allowed to stir at 20 °C - 25 °C for 1 h, after which the layers were separated and the upper organic layer was washed with saturated brine (681 mL). The organic layer was then dried over MgSO 4 dried, filtered and concentrated in vacuo at 45 °C. The resulting crude oil was subjected to azeotropy with ethanol (545 mL × 2). This afforded 234.6 g of Stage 2 (yield = 92%) with HPLC purity of 95.0% and NMR purity >95%.

[0400] Stage 3a (i) - (iii): Preparation of Seeds of DMT Fumarate

[0401] (i) Dissolve Stage 2 (100 mg) in 8 volumes of isopropyl acetate and warm to 50 °C, then add fumaric acid (1 equiv) as a solution in ethanol. The flask was then allowed to age at 50 °C for 1 h, then cooled to room temperature and stirred overnight, yielding a white suspension. The solid was separated by filtration and dried at 50 °C for 4 h to afford 161 mg of product (>99% yield). The purity was determined by HPLC to be 99.5% and by NMR to be >95%.

[0402] (ii) In method (i), isopropyl acetate replaces isopropanol, and a white suspension is obtained after stirring overnight. The solid is separated by filtration and dried at 50 °C for 4 h to afford 168 mg of the product (>99% yield). The purity is determined to be 99.8% by HPLC and >95% by NMR.

[0403] In method (i), isopropyl acetate replaces tetrahydrofuran, and a white suspension is obtained after stirring overnight. The solid is separated by filtration and dried at 50 °C for 4 h to afford 161 mg of the product (>99% yield). The purity is determined to be 99.4% by HPLC and >95% by NMR.

[0404] By X-ray powder diffraction analysis, it is shown that the products in each of methods (i) to (iii) are the same, which is labeled as pattern A.

[0405] Stage 3b: Preparation of DMT fumarate

[0406] Under N 2 To a 5 L flange flask, fumaric acid (152.7 g, 1.315 mol) and stage 2 (248.2 g, 1.315 mol) as a solution in ethanol (2928 mL) are added. The mixture is heated to 75 °C to obtain a dark brown solution. The solution is finely filtered into a preheated (80 °C) 5 L jacketed vessel. Then the solution is cooled to 70 °C and seeded with mode A (0.1 wt%), allowing the seeds to mature for 30 min and then cooled to 0 °C at a rate of 5 °C / h. After stirring for an additional 4 h at 0 °C, the batch is filtered and washed with cold ethanol (496 mL × 2), and then dried overnight at 50 °C. This affords 312.4 g of stage 3 with 99.9% HPLC purity and >95% NMR purity (yield = 78%). XRPD: pattern A.

[0407] Synthesis of 5-MeO-DMT

[0408] Stage 1: Coupling of 5-methoxyindole-3-acetic acid and dimethylamine

[0409] Under N 2Under the following conditions, 5-methoxyindole-3-acetic acid (3.978 g, 19.385 mmol), HOBt (~20% wet) (3.927 g, 23.261 mmol) and DCM (40 mL) were added to a 100 mL three-necked flask. Then, at <30 °C, EDC·HCl (4.459 g, 23.261 mmol) was added portionwise over 15 minutes. The reaction mixture was stirred at ambient temperature for 1 hour, and then 2 M dimethylamine (14.54 mL, 29.078 mmol) was added dropwise over 15 minutes at <25 °C. After stirring for 1 hour, HPLC indicated no starting material (SM, i.e., 5-methoxyindole-3-acetic acid) remaining. Then 10% K 2 CO 3 (20 mL) was added to the reaction mixture, stirred for 5 minutes and then allowed to separate. The lower aqueous layer was removed and back-extracted with DCM (10 mL × 2). The organic extracts were combined, washed with saturated brine (10 mL), and then dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo at 45 °C to afford 3.898 g of the active product with 95.7% HPLC purity (yield = 87%).

[0410] Stage 2: Preparation of 5-MeO-DMT

[0411] Under N 2 atmosphere, the Stage 1 methoxy derivative (3.85 g, 16.586 mmol) and THF (19.25 mL) were added to a 100 mL three-necked flask. Then, at <40 °C, 2.4 M LiAlH 4 in THF (6.22 mL, 14.927 mmol) was added dropwise over 30 minutes. The reaction mixture was heated to 60 °C for 1 hour, during which HPLC indicated 0.1% SM (Stage 1 methoxy derivative) remaining. Then the reaction mixture was cooled to ambient temperature and quenched dropwise into 25% Rochelle's salt (38.5 mL) at <30 °C over 30 minutes. The resulting suspension was stirred for 1 hour and then allowed to separate. Then the lower aqueous layer was removed, and the upper organic layer was washed with saturated brine (9.6 mL). Then the organic matter was dried over MgSO 4 , filtered and concentrated in vacuo, and then subjected to an azeotrope with EtOH (10 mL × 2). This afforded 3.167 g of the active product with 91.5% HPLC purity (yield = 88%).

[0412] Stage 3: Preparation of 5-MeO-DMT fumarate

[0413] Under N 2Under the following conditions, a solution of fumaric acid (1.675 g, 14.430 mmol) and the stage 2 methoxy derivative (3.15 g, 14.430 mmol) in EtOH (37.8 mL) was added to a 50 mL three-necked flask. The mixture was then heated to 75 °C for 1 hour, which did not produce a solution as expected. The mixture was further heated to reflux (78 °C), which still failed to provide a solution. Therefore, the suspension was cooled to 0 °C - 5 °C, filtered and washed with EtOH (8 mL × 2), and then dried at 50 °C overnight. This provided 3.165 g of material with 99.9% HPLC purity (yield = 65%).

[0414] Example 1d 6 -Dimethyltryptamine

[0415] d 6 Synthesis of -DMT (SPL028vii)

[0416] Stage 1

[0417]

[0418] At room temperature, EDC.HCl (15.7 g, 81.90 mmol) was added to 3-indoleacetic acid (12.0 g, 68.50 mmol) and HOBt.H 2 O (1.16 g, 75.75 mmol) in DCM (108 mL). The reaction was stirred for 1 hour, after which N,N-diisopropylethylamine (DIPEA) (35.6 mL, 205.75 mmol) and d 6 -dimethylamine.HCl (9.0 g, 102.76 mmol) were added (temperature maintained below 30 °C). The reaction was stirred at room temperature for 1 hour, after which HPLC analysis indicated 65.6% of the product and 28.9% of the 3-indoleacetic acid remaining. DIPEA (11.9 mL, 68.78 mmol) was added and the reaction was stirred at room temperature for 1 hour. HPLC indicated no change in the conversion. An aqueous potassium carbonate solution (6.0 g in 54 mL of water) was added and the phases were separated. The aqueous phase was extracted with DCM (2 × 30 mL). The combined organic matter was washed with brine (2 × 30 mL) and then with an aqueous citric acid solution (20 w / w%, 50 mL), dried over MgSO 4 and filtered. The filtrate was stripped and the resulting solid was slurried in TBME (120 mL) and separated by filtration. Purification by flash column chromatography gave 8.34 g of the desired product (58% yield). 1 1H NMR confirmed the identity of the product.

[0419] Stage 2

[0420]

[0421] At <30 °C, LiAlH 4 (1 M, in THF, 17.3 mL, 17.28 mmol) was added to a suspension of Stage 1 (4.0 g, 19.20 mmol) in THF (10 mL). The resulting reaction was heated to 60 °C - 65 °C and stirred for 2 h. HPLC analysis indicated complete consumption of Stage 1, forming 97.3% of the product. The reaction was cooled to room temperature and quenched at <30 °C into Rochelle's salt aqueous solution (10 g, in 30 mL of water). After stirring for 1 h, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organic matters were washed with brine (20 mL), dried over MgSO 4 and filtered and removed (azeotroped with ethanol, 20 mL) to obtain the desired product (3.97 g) as an amber oil. 1 1H NMR confirmed the identity of the product and indicated the presence of 8.5% ethanol (no THF), giving a 97% yield of the active substance at 3.63 g.

[0422] Stage 3

[0423]

[0424] d 6 -DMT free base (3.6 g active, 18.53 mmol) was dissolved in ethanol (43 mL) at room temperature. Fumaric acid (2.15 g, 18.53 mmol) was added and the solution was heated to 75 °C (the solid crystallized during heating and did not redissolve). The resulting suspension was cooled to 0 °C - 5 °C and stirred for 1 h. The solid was separated by filtration, washed with ethanol (2 × 7 mL) and drained. It was further dried in a vacuum oven at 50 °C to obtain the desired d 6 -DMT fumarate (4.98 g, 87%).

[0425] Example 2: d 8 -Dimethyltryptamine

[0426] d 8 -DMT (SPL028viii) Synthesis

[0427] Stage 1 (coupling of 3-indoleacetic acid and d 6 -dimethylamine) was carried out according to the method described in Stage 1 of Example 1 above.

[0428] Stage 2

[0429]

[0430] At <30 °C, LiAlD4 (1M, in THF, 17.3 mL, 17.28 mmol) was added to a suspension of Stage 1 (4.0 g, 19.20 mmol) in THF (10 mL). The resulting reaction was heated to 60 °C - 65 °C and stirred for 2 h. HPLC analysis indicated complete consumption of Stage 1, forming 97.3% of the product. The reaction was cooled to room temperature and quenched at <30 °C into Rochelle's salt aqueous solution (10 g, in 30 mL of water). After stirring for 1 h, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over MgSO 4 4, filtered, and stripped (azeotroped with ethanol, 20 mL) to afford the desired product (4.01 g) as an amber oil. 1 1H NMR confirmed the identity of the product and indicated the presence of 8.6% ethanol (no THF), giving a 97% isolated yield of the active product at 3.66 g.

[0431] Stage 3

[0432]

[0433] The d 8 -DMT free base (3.6 g active, 18.53 mmol) was dissolved in ethanol (43 mL) at room temperature. Fumaric acid (2.15 g, 18.53 mmol) was added and the solution was heated to 75 °C (the solid crystallized during heating and did not redissolve). The resulting suspension was cooled to 0 °C - 5 °C and stirred for 1 h. The solid was separated by filtration, washed with ethanol (2 × 7 mL), and drained. It was further dried in a vacuum oven at 50 °C to afford the desired d 8 -DMT fumarate (4.62 g, 81%).

[0434] Example 3: d 6 -5-Methoxydimethyltryptamine

[0435] d 6 Synthesis of d

[0436] Stage 1

[0437] The coupling of 5-methoxy-3-indoleacetic acid and d 6 -dimethylamine was carried out on a 20 g scale by a method similar to that described for Stage 1 in Example 1 above. Purification by flash column chromatography gave a light brown solid (87%) with 97.8% HPLC purity. Molecular weight: 238.32.

[0438] Stage 2

[0439] According to the method described in Stage 2 of Example 1, the product of Stage 1 of Example 3 was reacted with LiAlH in THF 4 The reaction was carried out on a 9 g scale to produce d as an amber oil with a yield of 8.22 g (7.40 g active, 87.3%) and an HPLC purity of 98.4% 6 -5-MeO-DMT. Molecular weight: 224.34

[0440] Stage 3

[0441] d 6 The fumarate of d-5-MeO-DMT was prepared according to the method described in Stage 3 of Example 1. 6.04 g (65%) of an off-white solid with an HPLC purity of 99.61% was obtained. NMR and XRPD data indicated that the hemi-salt was isolated. Molecular weight: 564.74 (as the hemi-salt)

[0442] Example 4: d 8 -5-methoxydimethyltryptamine

[0443] d 8 Synthesis of d-5-MeO-DMT

[0444] Stage 1

[0445] The coupling of 5-methoxy-3-indoleacetic acid and d-dimethylamine was carried out on a 20 g scale by a method similar to that described in Stage 1 of Example 1 above. Purification by flash column chromatography gave a light brown solid with an HPLC purity of 97.8% (87%). Molecular weight: 238.32 6 Stage 2

[0446] According to the method described in Stage 2 of Example 2, the product of Stage 1 of Example 4 was reacted with LiAlD in THF

[0447] The reaction was carried out on a 9 g scale. Purification gave 8.12 g (7.58 g active product, 88.7%) of the product d-5-MeO-DMT as an amber oil with an HPLC purity of 97.9%. Molecular weight: 226.35 4 Stage 3 8 The fumarate of d-5-MeO-DMT was prepared according to the method described in Stage 3 of Example 1. 9.6 g of the product d-5-MeO-DMT fumarate with an HPLC purity of 99.71% was obtained. Molecular weight: 342.42

[0448] Stage 3

[0449] d 8 The fumarate of d-5-MeO-DMT was prepared according to the method described in Stage 3 of Example 1. 9.6 g of the product d-5-MeO-DMT fumarate with an HPLC purity of 99.71% was obtained. Molecular weight: 342.42 8 -5-MeO-DMT fumaric acid. Molecular weight: 342.42

[0450] D6 -5-Hydroxy-N,N-dimethyltryptamine and d 8 -5-Hydroxy-N,N-dimethyltryptamine can be prepared using 5-hydroxyindole-3-acetic acid as a starting material by a method similar to that described for Examples 3 and 4, respectively.

[0451] Assessment of Deuteration Level

[0452] This is achieved by LCMS-SIM (SIM = single ion monitoring), where the analysis gives the individual ion counts for each mass of the deuterated N,N-dimethyltryptamine compound at the retention time of N,N-dimethyltryptamine. The percentage of each component is then calculated from these ion counts.

[0453] For example, %D0 = [D0 / (D0 + D1 + D2)] × 100.

[0454] HPLC Parameters

[0455] System: Agilent 1100 / 1200 series liquid chromatography or equivalent

[0456] Column: Triart Phenyl; 150 x 4.6 mm, 3.0 μm particle size (Ex: YMC, part number: TPH12S03-1546PTH)

[0457]

[0458]

[0459] Mass Spectrometry Parameters

[0460] System: Agilent 6100 series quadrupole LC-MS or equivalent

[0461] Drying gas flow rate: 12.0 L / min Drying gas temperature: 350 °C

[0462] Nebulizer pressure: 35 psig

[0463] Fragmentation voltage: 110 Gain: 1.00

[0464]

[0465]

[0466] Example 5: Intrinsic Clearance in Human Hepatocytes

[0467] The in vitro determination of intrinsic clearance (Clint) is a valuable model for predicting in vivo clearance. The liver contains both phase I and phase II drug-metabolizing enzymes present in intact cells and thus provides a valuable model for the study of drug metabolism. In particular, Clint in hepatocytes is a measure of the potential of a compound to undergo metabolism and can also be related to in vivo hepatic clearance by considering plasma protein binding and hepatic blood flow. Thus, Clint can be used as an indicator of the relative metabolic stability of a compound and compared to other external probe substrates. In addition, the measurement of in vitro Clint (in cases where known hepatic metabolic clearance is an issue) can be a useful means of understanding the different pharmacokinetic behaviors of compounds in vivo.

[0468] Determination method

[0469] In three separate experiments, human (mixed gender) hepatocytes pooled from 10 donors were used to study the in vitro intrinsic clearance of DMT (SPL026) and deuterated DMT (SPL028) analogs:

[0470] · The first experiment - human (mixed gender) hepatocytes; 545,000 cells / mL. Final organic concentration 1.05%, consisting of 80.74% MeCN and 19.26% DMSO

[0471] · The second experiment - human (mixed gender) hepatocytes; 427,000 cells / mL. Final organic concentration 1%, consisting of 84.7% MeCN and 15.3% DMSO.

[0472] · The third experiment - human (mixed gender) hepatocytes; 362,000 cells / mL

[0473] Mouse CD-1 (male) hepatocytes

[0474] · Final organic concentration 1%, consisting of 84.7% MeCN and 15.3% DMSO

[0475] Assay preparation

[0476] · Hepatocyte buffer was prepared as 26.2 mM NaHCO in MilliQ water 3 , 9 mM Na HEPES, 2.2 mM D-fructose, and DMEM.

[0477] · Compound and marker stock solutions were prepared at 10 mM in DMSO and further diluted to 100× the assay concentration in 91:9 acetonitrile:DMSO.

[0478] · Rapidly thaw the hepatocytes in a water bath at 37 °C. Once thawed, immediately decant into hepatocyte buffer. Centrifuge the cells and remove the supernatant, then count and resuspend at the final assay concentration.

[0479] Assay procedure

[0480] Use a concentration of 5 μM for all test compounds, as well as sumatriptan, serotonin, and benzylamine controls. In each experiment, incubate each compound twice at this concentration. This concentration was chosen to maximize the signal-to-noise ratio while remaining below the Michaelis constant (K m ) of monoamine oxidase (MAO). Use diltiazem and diclofenac controls at a laboratory-verified concentration of 1 μM.

[0481] Add hepatocytes to pre-warmed incubation tubes (37 °C). Then add the pre-prepared 100× assay compound stock solution to the incubation tubes and mix carefully. Collect samples at 7 time points (2, 4, 8, 15, 30, 45, and 60 minutes). At each time point, remove a small aliquot from the incubation and quench with ice-cold acidified methanol or acetonitrile containing an internal standard at a ratio of 1:4.

[0482] Throughout the experiment, incubate the tubes on an orbital shaker at 37 °C.

[0483] The standard final incubation conditions are 1 μM compound (the specific assay concentration outlined in Part 2 above) in a buffer nominally containing ~500,000 viable cells / mL, ~0.9% (v / v) acetonitrile (MeCN), and ~0.1% (v / v) DMSO.

[0484] Mix the quenched samples thoroughly and precipitate the protein at -20 °C for at least 12 hours. Then centrifuge the samples at 4 °C. Transfer the supernatant to a fresh 96-well plate for analysis.

[0485] Liquid chromatography - mass spectrometry (LC-MS / MS)

[0486] Use the following LC-MS / MS conditions for analysis: Instrument: Thermo TSQ Quantiva with a Thermo Vanquish UPLC system

[0487] Column: Luna Omega 2.1x50 mm 2.6 μm

[0488] Solvent A: H 2 O + 0.1% formic acid

[0489] Solvent B: acetonitrile + 0.1% formic acid

[0490] Flow rate: 0.8 ml / min

[0491] Injection volume: 1 μl

[0492] Column temperature: 65 °C

[0493] Gradient:

[0494] Time (minutes) Solvent B % 0.00 5.0 0.90 75.0 1.36 99.0 1.36 5.0 1.80 5.0

[0495] MS parameters:

[0496] Positive ion spray voltage: 4000 V

[0497] Evaporator temperature: 450 °C

[0498] Ion transfer tube temperature: 365 °C

[0499] Sheath gas: 54

[0500] Auxiliary gas: 17

[0501] Purge gas: 1

[0502] Dwell time 8 ms

[0503] MRM transitions:

[0504] · D0 = mass-to-charge ratio 189.136 > 144.179

[0505] · D6 = mass-to-charge ratio 195.17 > 64.127

[0506] · D8 = mass-to-charge ratio 197.2 > 146.17

[0507] The MRM transitions are determined by preliminary analysis of DMT samples that do not contain deuterium (for the D0 transition) or contain high levels of D 6 or D 8 deuteration (for the D 6 and D 8 transitions) respectively.

[0508] Then the resulting concentration-time curves are used to calculate the intrinsic clearance (CLint) and half-life (t 1 / 2 ). For this purpose, the MS peak area or MS peak area / IS response of each analyte is plotted against the sampling time (min) on the X-axis on a natural logarithm scale on the y-axis. The slope of the line is the elimination rate constant. This is converted to the half-life by -ln(2) / slope. The intrinsic clearance is calculated by slope / elimination rate constant, and the formula is CLint = (-1000 * slope) / cell density (in units of 1E6 cells / ml) to obtain the units of microliters per minute per million cells.

[0509] D 6 -DMT (SPL028vii) and D 8 -DMT (SPL028viii) clearance rate

[0510] Using D 6 -DMT and D 8 -DMT to perform additional human hepatocyte assays to measure the in vitro intrinsic clearance rate using human (mixed gender) hepatocytes (362,000 cells / mL) from 10 donors.

[0511]

[0512] D in human hepatocytes 6 -deuterated DMT and D 8 -in vitro intrinsic clearance rate and half-life of deuterated DMT analog blends.

[0513] Intrinsic clearance rate of SPL026 (19.4 μL / min / million cells) – Intrinsic clearance rate of SPL028vii (17.1 μL / min / million cells) = 2.3 μL / min / million cells. The intrinsic clearance rate of SPL028vii shows a 1.1-fold change compared to DMT (SPL026).

[0514] D 8 -The intrinsic clearance rate of deuterated DMT (SPL028viii) shows a 2.1-fold change compared to DMT (SPL026).

[0515] Using liver mitochondrial fractions to simulate human metabolism of deuterated DMT

[0516] Given that the predicted half-life of DMT in humans is 5 minutes, the inventors expected that DMT would be largely decomposed before reaching the human liver. Therefore, an alternative in vitro assay was selected as a more appropriate system to simulate human metabolism of DMT. The following assays performed on human liver mitochondrial (HLMt) fractions predict an enhanced fold change between SPL026 and D 8 -deuterated SPL028viii.

[0517] Contribution of MAO-A and MAO-B to in vitro intrinsic clearance rate of human liver mitochondrial fractions

[0518] Human liver mitochondrial (HLMt) fractions contain high amounts of MAO enzymes and thus provide a useful model system to measure the clearance rate of MAO substrates.

[0519] A series of studies were performed using HLMt to evaluate the effect of MAO on the metabolism of DMT and deuterated DMT analogs in vitro.

[0520] Intrinsic Clearance of SPL026 (DMT) and SPL028viii (D 8 -DMT) in Human Mitochondrial Fraction In Vitro

[0521] The in vitro determination of the intrinsic clearance of SPL026 and SPL028viii was added separately to a human liver mitochondrial fraction at 0.5 mg / mL. The MAO-A substrate "serotonin" and the MAO-B substrate "benzylamine" were added as positive controls, and the presence and functional activity of MAO-A and MAO-B were confirmed.

[0522]

[0523] Intrinsic Clearance and Half-Life of SPL026 and SPL028viii in Human Liver Mitochondrial Fraction

[0524] D 8 -deuterated SPL028viii showed a 14.8-fold increase relative to SPL026.

[0525] D 0 、D 6 and D 8 Human and Rat Hepatocyte Stability of 5-MeO-DMT Analogs

[0526]

[0527] The test compound (5 μM) was incubated with cryopreserved hepatocytes in suspension. Samples were taken at 6 time points over the course of a 60-min experiment, and the test compound was analyzed by LC-MS / MS.

[0528] Before adding each test compound (final substrate concentration 1 μM; final DMSO concentration 0.25%), cryopreserved pooled hepatocyte suspensions from human and rat species (final cell density of 0.5 × 10 6 viable cells / mL in Williams E medium supplemented with 2 mM L-glutamine and 25 mM HEPES) were pre-incubated at 37 °C to initiate the reaction. The final incubation volume was 500 μL.

[0529] Each species included two control compounds. Each compound was incubated at 37 °C for 0, 5, 10, 20, 40, and 60 min. The reaction was stopped by transferring the incubation to acetonitrile at a 1:3 ratio at the appropriate time points. The terminated plates were centrifuged at 3,000 rpm for 30 min at 4 °C to precipitate the proteins.

[0530] After protein precipitation, the sample supernatants were pooled in a cassette of up to 4 compounds, internal standards were added and the samples were analysed using Cyprotex generic LC-MS / MS conditions.

[0531] From a plot of the ln peak area ratio (compound peak area / internal standard peak area) against time, the slope of the line was determined. Subsequently, the half-life (t 1 / 2 ) and intrinsic clearance (CLint) were calculated using the following equations:

[0532] Elimination rate constant (k) = (-slope)

[0533]

[0534]

[0535] where V = incubation volume (μL) / number of cells

[0536] CLint values below the lower limit of assay sensitivity (calculated based on t1 / 2 > 3 × incubation time) were classified as below the limit of quantification (<LOQ). Two control compounds for each species were included in the assay and if the values of these compounds were not within the specified limits, the results were unacceptable and the experiment was repeated.

[0537] Results

[0538]

[0539]

[0540]

[0541] NC – not calculated as only 1 replicate value of the internal standard was tested.

[0542] SEM (standard error of the mean)

[0543]

[0544] Deuteration of both human and rat hepatocytes resulted in a decrease in intrinsic clearance and an increase in half-life compared to 5-MeO-DMT. Compared to 5-MeO-DMT, D 8 Deuteration had the greatest effect on increasing in vitro metabolic stability, resulting in a 1.8-fold change in half-life and intrinsic clearance in both human and rat tissues.

[0545] Example 6: In vivo study of pharmacokinetic (PK) properties

[0546] In rats, a preclinical in vivo study of the pharmacokinetic (PK) properties of N,N-dimethyltryptamine (DMT, SPL026) and α,α-bis-deuterio-N,N-hexadeuterio-dimethyltryptamine (D 8 DMT, SPL028viii) after intravenous (IV) and intramuscular (IM) administration.

[0547] Test compounds

[0548]

[0549] Methods

[0550] Thirteen male and three female (7-8 weeks old) Sprague Dawley rats (body weight 250–300 g) were dosed as follows:

[0551]

[0552] Housing and husbandry

[0553]

[0554]

[0555] Dosing regimen

[0556]

[0557] A 2 mg / kg IV dose of SPL026 fumarate was administered to male and female rats to determine whether there were any differences in the metabolic stability of DMT between male and female animals. A 2 mg / kg IV dose of SPL028viii fumarate was administered only to different male rats in order to compare the metabolic stability of d 8 -DMT compared to DMT.

[0558] A cassette dose of 1 mg / kg SPL026 fumarate and 1 mg / kg SPL028viii fumarate was administered as a single IV dose to four different male animals, and a separate cassette dose of 3.5 mg / kg SPL026 fumarate and 3.5 mg / kg SPL028viii fumarate was administered as a single IM dose to three different male animals to allow for a direct inter-animal comparison of SPL026 and SPL028viii and thus avoid confounding effects of inter-animal variability.

[0559] Dosing procedure

[0560] Animals were weighed on the morning of dosing and dosed based on body weight and the specified dose volume.

[0561] · The IV administration device consists of a syringe of appropriate size and a winged needle. During administration, the dose is directly dispensed into the lateral tail vein not used for blood collection.

[0562] · The IM administration device will consist of an insulin syringe of appropriate size. The injection site is shaved on the morning of the day of administration. During administration, the dose will be directly dispensed into the thigh muscle.

[0563] PK Sampling

[0564] After administration, serial whole blood samples (approximately 200 μL) will be collected from the lateral tail vein via an indwelling cannula into separate K 2 EDTA-treated containers. Samples will be collected at the following times after administration:

[0565] Before IV administration, 1, 5, 10, 15, 30, 45, 60, 120, and 180 minutes

[0566] Before IM administration, 5, 10, 25, 30, 45, 60, 90, 120, and 180 minutes

[0567] The blood samples will be placed on a cooling block and then centrifuged at 10,000 g for 2 minutes at approximately 4 °C, and the resulting plasma withdrawn. All samples will be stored at approximately -80 °C.

[0568] Bioanalysis

[0569] Bioanalysis of DMT and d8-DMT in rat K 2 EDTA plasma will be performed using LC-MS / MS. The following table details the 2 qualified methods:

[0570]

[0571] Quantify the concentration of DMT and d 8 -DMT using 20.0 μL of rat plasma with a target lower limit of quantitation (LLOQ) of approximately 0.310 ng / mL of DMT and d 8 -DMT, and check for qualification using the following method:

[0572] · Determine linearity – Prepare calibration curves in duplicate, containing ≥8 concentration levels as well as control blanks and zero (IS only). Acceptance criteria - At least 75% of the calibration standards (non-zero samples) must be within ≤±20% relative error (RE) of their prepared nominal concentration (≤±25% RE at the lower limit of quantitation).

[0573] · Sensitivity - The minimum signal-to-noise ratio at the LLOQ concentration must be 5:1.

[0574] · Precision and accuracy - A single analytical run containing QCs at low, medium, and high concentrations in replicates (n = 6). Acceptance criteria - Intra-run precision (CV) and accuracy (RE) ≤ 20%.

[0575] · Selectivity - Qualitative assessment of the chromatograms of control blank matrices from at least one source for the presence of potential interfering peaks. Acceptance criteria - The response of any co-eluting interference must be ≤ 25% of the peak area of the LLOQ calibration standard. The response of any co-eluting interference must be less than 5% of the peak area of the zero sample of the internal standard.

[0576] · Stability - The stability of the QC Med matrix in replicates (minimum n = 3) will be evaluated for at least 2 hours only at the sample handling temperature of DMT. Acceptance criteria - Precision (CV) and accuracy (RE) ≤ 20%.

[0577] · Carryover - Evaluated in at least one control blank matrix sample (carryover blank) analyzed immediately after the ULOQ calibration standard. Acceptance criteria - Analyte carryover should be ≤ 25% of the analyte peak area in the LLOQ standard. Internal standard carryover should be ≤ 5% of the internal standard peak area in the LLOQ standard sample.

[0578] PK parameters

[0579] DMT (SPL026) and d in plasma 8 - The pharmacokinetic parameters of DMT (SPL028viii) were derived by non-compartmental analysis of the plasma concentration-time curves for each animal.

[0580] Results

[0581] The results are presented in Figure 1 through 3. These data indicate that after IV and IM administration, d 8 - DMT (SPL028viii) has greater overall exposure compared to DMT (SPL026).

[0582] Figure 1 A semi-logarithmic plot of the mean SPL026 and SPL028viii concentrations over time after a 2 mg / kg IV fumarate dose is shown.

[0583] Figure 2 A semi-logarithmic plot of the mean SPL026 and SPL028viii concentrations over time after a 1 mg / kg IV fumarate dose (added as a cassette) is shown.

[0584] Figure 3 shows the mean DMT (SPL026) and d after a 3.5 mg / kg intramuscular fumarate dose (added as a cassette) in vivo 8-DMT (SPL028viii) concentration vs. time linear and semi-log plots. Figure 3A – Linear plot, Figure 3B – Semi-log plot, SEM error bars.

[0585] ANOVA for paired comparisons was performed to analyze the effect of dose groups on PK parameters. After equal IV and IM doses were administered to two groups, there was a statistically significant difference in the area under the mean curve (AUC 0-inf ) extrapolated from time 0 to infinity between the SPL026 and SPL028viii groups, indicating that the total systemic exposure of SPL028viii was significantly higher than that of SPL026 after single IV and IM doses. There was no significant difference in AUC 0-inf between the male and female groups of SPL026, indicating that there were no significant differences in the metabolism and elimination of SPL026 with respect to animal gender.

[0586] <![CDATA[AUC 0-inf (min.ng / mL)]]> P - value SPL026 (male) vs. SLP026 (female) 0.5784 SPL026 (male) vs. SPL028viii (male) 0.0002*** SLP026 (female) vs. SPL028viii (male) 0.0013**

[0587] After IM administration, it was found that the Cmax of d 8 -DMT (SPL028viii) was significantly higher (p = 0.005**) when compared to DMT (SPL026).

[0588] The present invention is further illustrated by the following embodiments.

[0589] E1. A compound of formula (I):

[0590]

[0591] Wherein:

[0592] R 1 is independently selected from –R 4 , -OH, -OR 4 , -O(CO)R 4 , monohydrogen phosphate, -F, -Cl, -Br, and –I;

[0593] n is selected from 0, 1, 2, 3, or 4;

[0594] R 2 is C( x H) 3 ;

[0595] R 3 is C( x H) 3 or H;

[0596] Each R 4 is independently selected from C 1 -C 4 alkyl; and

[0597] Each x H and y H are independently protium or deuterium,

[0598] wherein the ratio of deuterium:protium in the C( x H) 3 moiety in said compound is greater than its naturally occurring ratio in hydrogen,

[0599] or a pharmaceutically acceptable salt thereof,

[0600] which is used in therapy.

[0601] The compound of E2.E1 for said use, wherein R 1 is independently selected from –OR 4 , -O(CO)R 4 , monohydrogen phosphate and -OH.

[0602] The compound of E3.E1 or E2 for said use, wherein R 4 is methyl.

[0603] The compound of E4. Any of the foregoing embodiments for said use, wherein n is 1.

[0604] The compound of E5.E4 for said use, wherein, R 1 is at the 4-position or 5-position.

[0605] The compound of E6.E1 for said use, wherein n is 0, or n is 1 and R 1 is selected from 5-methoxy, 5-bromo, 4-acetoxy, 4-monohydrogen phosphate, 4-hydroxy and 5-hydroxy.

[0606] The compound of E7.E1 for said use, wherein n is 0.

[0607] The compound of E8. Any of the foregoing embodiments for said use, wherein both y H are deuterium.

[0608] The compound of E9. Any of the foregoing embodiments for said use, wherein both y H are protium.

[0609] The compound of E10. Any of the foregoing embodiments for said use, wherein R 2 and R 3 are both C( x H) 3 .

[0610] The compound of E11.E10 for said use, wherein both C( x H)3 The same.

[0611] A compound of E12.E10 for the said use, wherein R 2 and R 3 are both CD 3 .

[0612] E13. A compound of any of the foregoing embodiments for the said use, which is in the form of a pharmaceutically acceptable salt.

[0613] E14. A compound of any of the foregoing embodiments for the said use, wherein the pharmaceutically acceptable salt is fumarate.

[0614] E15. A compound as defined in any one of E1 to E11, or a pharmaceutically acceptable salt thereof, which is not N,N-bis(trideuteriomethyl)tryptamine.

[0615] E16. A compound as described in E15, which is in the form of a pharmaceutically acceptable salt.

[0616] E17. A compound as described in E15 or E16, which is a pharmaceutically acceptable salt of N,N-bis(trideuteriomethyl)tryptamine.

[0617] E18. A compound as described in any one of E15 to E17, wherein the pharmaceutically acceptable salt is fumarate.

[0618] E19. A composition comprising a first compound, which is a compound as defined in any of the foregoing embodiments or a pharmaceutically acceptable salt thereof, and a second compound, which is (i) a compound as defined in any of the foregoing embodiments or a pharmaceutically acceptable salt thereof, but which is different from the first compound by y the identity of H and / or R 3 ; or (ii) a compound as defined in any of the foregoing claims or a pharmaceutically acceptable salt thereof, but each x H and y H represents hydrogen.

[0619] E20. A composition as described in E19, wherein the second compound is different from the first compound only by y the identity of H and / or R 3 ; and / or x H and y H which represent hydrogen.

[0620] E21. A composition as described in E19 or E20, which comprises two or three compounds of formula (I) that differ from each other only by y the definition of H.

[0621] E22. The composition as described in E21, which comprises wherein said C( y H) 2 moiety is CH 2 , CD 2 or three compounds of CHD.

[0622] E23. The composition as described in E19 or E20, wherein some of said compounds are different from each other by the identity of R 3 , wherein in some compounds R 3 is H and in other compounds R 2 and R 3 are the same.

[0623] E24. The composition as described in any one of E19 to E23, wherein said compounds are in the form of pharmaceutically acceptable salts.

[0624] E25. The composition as described in any one of E19 to E24, wherein said pharmaceutically acceptable salt is fumarate.

[0625] E26. A pharmaceutical composition, which comprises a combination of a compound as described in any one of E1 to E14 or any one of E15 to E18 or a composition as described in any one of E19 to E25 and a pharmaceutically acceptable excipient.

[0626] E27. The pharmaceutical composition as described in E26, which is in the form of an oral dosage form.

[0627] E28. A compound as described in any one of E1 to E14 or any one of E15 to E18 or a composition as described in any one of E19 to E27, which is used in a method for treating mental or neurological disorders in a patient.

[0628] E29. The compound or composition for the use as described in E28, wherein the mental or neurological disorder is selected from (i) obsessive-compulsive disorder, (ii) depression, (iii) schizophrenia, (iv) schizoid disorder, (v) anxiety disorder, (vi) substance abuse, and (vii) anhedonia disorder.

[0629] E30. The compound or composition for the use as described in E28 or E29, wherein the disorder is major depressive disorder.

[0630] E31. The compound or composition for the use as described in E28 or E29, wherein the disorder is treatment-resistant depression.

[0631] E32. The compound or composition for the use as described in any one of E28 to E31, which comprises oral administration of the compound or composition.

[0632] E33. A method of treatment, which comprises administering to a patient in need thereof a compound as described in any one of E1 to E14 or any one of E15 to E18 or a composition as described in any one of E19 to E27.

[0633] E34. The method as described in E33, which is a method as described in any one of E28 to E32.

[0634] E35. A method for synthesizing a compound of formula (I’) or a pharmaceutically acceptable salt thereof:

[0635]

[0636] which comprises reacting a compound of formula (II):

[0637]

[0638] with LiAlH 4 and / or LiAlD 4 wherein:

[0639] R 1 is independently selected from –R 4 , -OPR, -OR 4 , -F, -Cl, -Br and –I;

[0640] PR is a protecting group,

[0641] n is selected from 0, 1, 2, 3 or 4;

[0642] R 2 is C( x H) 3 ;

[0643] R 3 is C( x H) 3 or H;

[0644] each R 4 is independently selected from C 1 -C 4 alkyl; and

[0645] each x H and y H is independently protium or deuterium,

[0646] wherein the ratio of deuterium:protium in the C( x H) 3 moiety of the compound of formula (I’) is greater than its naturally occurring ratio in hydrogen,

[0647] or a pharmaceutically acceptable salt thereof.

[0648] E36. The method as described in E35, wherein LiAlH in a ratio of 0.8:1 to 1:1 is used 4 and / or LiAlD 4 : the ratio of the compound of formula (II).

[0649] E37. The method as described in E35 or E36, wherein the compound of formula (II) is prepared by:

[0650] (i) reacting a compound of formula (III)

[0651]

[0652] with two or more coupling agents to produce an activated compound; and

[0653] (ii) reacting the activated compound with an amine having the formula R 2 R 3 NH or R 2 R 3 ND,

[0654] wherein R 1’ , n, R 2 and R 3 are as defined in claim 35.

[0655] E38. The method as described in E37, wherein the two or more coupling agents comprise addition coupling agents.

[0656] E39. The method as described in E38, wherein the two or more coupling agents comprise carbodiimides.

[0657] E40. The method as described in E39, wherein the carbodiimide is selected from the group consisting of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, dicyclohexylcarbodiimide, and diisopropylcarbodiimide.

[0658] E41. The method as described in E40, wherein the carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.HCl.

[0659] E42. The method as described in any one of E38 to E41, wherein the addition coupling agent is selected from the group consisting of 1-hydroxybenzotriazole, hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, N-hydroxysuccinimide, 1-hydroxy-7-azabenzotriazole, ethyl 2-cyano-2-(hydroxyimino)acetate, and 4-(N,N-dimethylamino)pyridine.

[0660] E43. The method as described in any one of E38 to E41, wherein the addition coupling agent is 1-hydroxybenzotriazole.

[0661] E44. The method according to any one of E35 to E43, which is a method for synthesizing a compound of formula (I) according to any one of E1 to E12, wherein the method further comprises, when R 1’ is OPR, removing the protecting group PR and optionally converting the resulting hydroxyl group to -OR 4 、-O(CO)R 4 、monohydrogen phosphate.

[0662] E45. The method according to E44, wherein the compound of formula (I) is a pharmaceutically acceptable salt.

[0663] E46. The method according to E44, which further comprises reacting the compound of formula (I) with an acidic reagent to produce a pharmaceutically acceptable salt of the compound of formula (I).

[0664] E47. The method according to E46, wherein the acidic reagent is fumaric acid.

[0665] The present invention is further illustrated by the following embodiments

[0666] E’1. A composition comprising a compound of formula I and a compound of formula II:

[0667]

[0668] wherein:

[0669] each x H is independently selected from protium and deuterium;

[0670] n is selected from 0, 1, 2, 3 and 4;

[0671] each R 1 is independently selected from -R 3 、-OH、-OR 3 、-O(CO)R 3 、monohydrogen phosphate、-F、-Cl、-Br and –I; and

[0672] each R 3 is independently selected from C 1 -C 4 alkyl.

[0673] E’2. The composition according to E’1, which comprises about 5% to about 95% by weight of the compound of formula I.

[0674] E’3. The composition according to E’1 or E’2, which comprises a compound of formula I and a compound of formula II, in which one x H is H and the other is D.

[0675] E’4. The composition according to any one of E’1 to 3, which comprises a compound of formula I and a compound of formula II, each of which x H is H.

[0676] E’5. The composition according to any one of E’1 to 4, which comprises a compound of formula I and a compound of formula II, each of which x H is D.

[0677] E’6. The composition according to any one of E’1 to 5, wherein R 1 is independently selected from -OR 3 、-O(CO)R 3 、monohydrogen phosphate and -OH.

[0678] E’7. The composition according to any one of E’1 to 6, wherein R 3 is methyl.

[0679] E’8. The composition according to any one of E’1 to 7, wherein n is 1.

[0680] E’9. The composition according to E’8, wherein R 1 is at the 4-position or 5-position.

[0681] E’10. The composition according to any one of E’1 to 5, wherein n is 0, or n is 1 and R 1 is selected from 5-methoxy, 4-acetoxy, 4-monohydrogen phosphate, 4-hydroxy and 5-hydroxy.

[0682] E’11. The composition according to any one of E’1 to 5, wherein n is 0, or n is 1 and R 1 is 5-methoxy.

[0683] E’12. The composition according to any one of E’1 to 11, which comprises a compound of formula I and a compound of formula II, in which x H, n and R 1 are the same.

[0684] E’13. The composition according to any one of E’1 to 12, which comprises two compounds of formula I that differ from each other only by x the definition of H.

[0685] E’14. The composition according to any one of E’1 to 13, which comprises two compounds of formula II that differ from each other only by x the definition of H.

[0686] E’15. The composition according to any one of E’1 to 14, wherein the compound is in the form of a pharmaceutically acceptable salt.

[0687] E’16. The composition according to E’15, wherein the pharmaceutically acceptable salt is fumarate.

[0688] E’17. A pharmaceutical composition comprising a combination of the composition according to any one of E’1 to 16 and a pharmaceutically acceptable excipient.

[0689] E’18. The composition according to any one of E’1 to 17, which is for use in therapy.

[0690] E’19. The composition according to any one of E’1 to 17, which is for use in a method of treating a mental or neurological disorder in a patient.

[0691] E’20. The composition according to E’19 for said use, wherein the mental or neurological disorder is selected from (i) obsessive-compulsive disorder, (ii) depression, (iii) schizophrenia, (iv) schizoid disorder, (v) anxiety disorder, (vi) substance abuse, and (vii) anhedonia disorder.

[0692] E’21. A method of treatment comprising administering to a patient in need thereof a composition according to any one of E’1 to 17.

[0693] E’22. The method according to E’21, which is the method according to E’19 or E’20.

[0694] E’23. A chemical library comprising a plurality of compositions according to any one of E’1 to 17.

[0695] E’24. Use of a compound of formula III as an internal standard in a determination for quantifying the amount of a target compound in a sample:

[0696]

[0697] wherein:

[0698] each x H is independently selected from protium and deuterium;

[0699] n is selected from 0, 1, 2, 3, and 4;

[0700] each R 1 is independently selected from -R 3 、-OH、-OR 3 、-O(CO)R 3 、monohydrogen phosphate, -F, -Cl, -Br, and –I; and

[0701] each R3 independently selected from C 1 -C 4 alkyl;

[0702] R 4 is protium or –CD 3 ,

[0703] wherein when each x H is protium, n is 1, 2, 3 or 4, and R 4 is –CD 3 .

[0704] E’25. The use according to E’24, wherein the target compound comprises a compound of formula IV:

[0705]

[0706] wherein:

[0707] each x H is independently selected from protium and deuterium;

[0708] n is selected from 0, 1, 2, 3 and 4;

[0709] each R 1 is independently selected from -R 3 , -OH, -OR 3 , -O(CO)R 3 , monohydrogen phosphate, -F, -Cl, -Br and –I; and

[0710] each R 3 is independently selected from C 1 -C 4 alkyl;

[0711] R 5 is protium or methyl; and

[0712] the compound of formula IV and the compound of formula III differ from each other only in the number of deuterium atoms.

[0713] E’26. The use according to E’25, wherein R 5 is methyl and the compound of formula IV has an average molecular weight 5.5 to 6.5 g / mol less than the average molecular weight of the compound of formula III.

[0714] E’27. The use according to E’25, wherein R 5 is protium and the compound of formula IV has an average molecular weight 2.5 to 3.5 g / mol less than the average molecular weight of the compound of formula III.

[0715] E’28. Use according to any one of E’25 to 28, wherein at least one of the compounds of formula IV x H is D.

[0716] E’29. Use according to any one of E’24 to 28, wherein at least one of the compounds of formula III x H is D.

[0717] E’30. Use according to any one of E’24 to 27, wherein H of the compound of formula III x is defined as in any one of E’3 to 5.

[0718] E’31. Use according to any one of E’24 to 30, wherein n, R of the compound of formula III 1 and R 3 are defined as in any one of E’6 to 11.

[0719] E’32. Use according to E’24, wherein the sample comprises a compound of formula I and a compound of formula II as described in any one of E’1 to 14, and wherein the compound of formula III and the compound of formula I or the compound of formula II differ only by the number of deuterium atoms contained therein.

[0720] E’33. A method for quantifying the amount of a target compound in a sample, the method comprising adding a known amount of the compound of E’24 to the sample.

[0721] E’34. The method according to claim 33, wherein the internal standard and the target compound are defined as in any one of E’25 to 32.

[0722] E’35. The method according to E’33 or E’34, wherein the sample has been previously obtained from a subject, and the target compound has been administered to the subject prior to obtaining the sample.

[0723] E’36. The method according to E’35, wherein a plurality of samples are obtained from the subject at different times after administration of the target compound, and the method comprises adding a known amount of the compound of E’24 to each of the samples, and quantifying the amount of the target compound in each of the samples.

[0724] E’37. The method according to E’36, wherein the method further comprises calculating the half-life of the target compound in the subject.

[0725] E’38. The compound according to E’24, wherein when each x H is protium, n is 1, 2, 3 or 4.

[0726] Compound as described in E’38, wherein x H, n, R 1 and R 3 are as defined in any one of E’3 to 11.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I)， Wherein: R 1 is methoxy; n is selected from 0 and 1; R 2 is CD 3 ; R 3 is CH 3 or CD 3 ; and Each y H is deuterium.

2. The compound according to claim 1, wherein n is 0.

3. The compound according to claim 1, wherein n is 1 and R 1 is 5-methoxy.

4. The compound according to claim 1, wherein R 2 and R 3 are both CD 3 .

5. The compound according to any one of claims 1 to 4, in the form of a pharmaceutically acceptable salt.

6. The compound according to claim 5, wherein the pharmaceutically acceptable salt is fumarate.

7. The compound according to claim 1 or 2, wherein n is 0, and wherein the compound has a molecular weight of 188.9 to 196.3 g / mol as the free base.

8. The compound according to claim 1 or 2, wherein n is 0, and wherein the compound has a molecular weight of 189.2 to 196.3 g / mol as the free base.

9. The compound according to claim 5, Wherein: n is 1, R 1 is 5-methoxy, and wherein the compound has a molecular weight of from 224.3 to 226.4 grams per mole as the free base; or n is 1, R 1 is 5-hydroxy, and wherein the compound has a molecular weight of from 210.3 to 212.3 grams per mole as the free base.

10. A composition comprising (a) a first compound which is a compound as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and (b) a second compound which is: (i) a compound as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, but which differs from the first compound by y the identity of H and / or 3 the identity of R, where y H is independently protium or deuterium; or (ii) a compound as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, except that each y H represents hydrogen.

11. A composition comprising the compound as defined in any one of claims 1 to 9 or the composition as defined in claim 10 in combination with a pharmaceutically acceptable excipient.

12. Use of the compound as defined in any one of claims 1 to 9 or the composition as defined in claim 10 or 11 in the manufacture of a medicament for psychedelic-assisted psychotherapy.

13. Use of the compound as defined in any one of claims 3 to 6 and 9 or the composition as defined in claim 10 or 11 in the manufacture of a medicament for treating a mental or neurological disorder in a patient.

14. The use according to claim 13, wherein the mental or neurological disorder is selected from (i) obsessive-compulsive disorder, (ii) depression, (iii) schizophrenia, (iv) schizoid disorder, (v) anxiety disorder, (vi) substance abuse, and (vii) anhedonia disorder.

15. The use according to claim 13, wherein the mental or neurological disorder is selected from (i) major depressive disorder and (ii) treatment-resistant depression.

16. The use according to claim 13 or claim 14, wherein the medicament is formulated for oral administration of the compound or composition.

17. A method for synthesizing a compound of formula (I') or a pharmaceutically acceptable salt thereof: (I’) Which comprises reacting a compound of formula (II) or a pharmaceutically acceptable salt thereof: (II) React with LiAlD 4 react Wherein: R 1’ is methoxy; PR is a protecting group, n is 1; R 2 is CD 3 ; R 3 is CH 3 or CD 3 ; and Each y H is deuterium.

18. The method according to claim 17, wherein a ratio of LiAlD 4 : the compound of formula (II) is used in a ratio of 0.8:1 to 1:

1.

19. The method according to claim 17 or 18, which is a method for synthesizing a compound of formula (I) according to any one of claims 1 to 9, wherein the method further comprises, when R 1’ is OPR, removing the protecting group PR and optionally converting the resulting hydroxyl group into a methoxy group.

20. The method according to claim 19, which further comprises reacting the compound of formula (I) with an acidic reagent to produce a pharmaceutically acceptable salt of the compound of formula (I).

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