JP2023520256A - Therapeutic compositions containing deuterated or partially deuterated N,N-dimethyltryptamine compounds - Google Patents

Abstract

The present invention relates to N,N-dimethyltryptamine compounds, α-prothio,α-deutero-N,N-dimethyltryptamine compounds, α,α-dideutero-N,N-dimethyltryptamine compounds, and pharmaceutical compositions of these compounds. There is provided deuterated N,N-dimethyltryptamine compound(s) for use in therapy, selected from acceptable salts, preferably said deuterated N,N-dimethyltryptamine compound comprising: It has an increased half-life compared to that of non-deuterated N,N-dimethyltryptamine. In particular, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof; each R1 is independently selected from H and D; R2 is selected from CH3 and CD3; R3 is selected from CH3 and CD3; each yH is independently selected from H and D . Also provided are methods of synthesizing the compounds of the invention and methods of using such compositions in treating psychiatric or neurological disorders, such as major depressive disorder. [Selection figure] None

Description

Field of Invention

The present invention relates to N,N-dimethyltryptamine compounds, α-prothio,α-deutero-N,N-dimethyltryptamine compounds, α,α-dideutero-N,N-dimethyltryptamine compounds, and pharmaceutical compositions of these compounds. There is provided deuterated N,N-dimethyltryptamine compound(s) for use in therapy selected from acceptable salts, preferably the deuterated N,N-dimethyltryptamine compound is selected from non- It has a long half-life compared to that of deuterated N,N-dimethyltryptamine.

ここで、前記化合物中の重水素：プロチウムの比は、水素において天然に見られるものよりも大きく；
各R¹は、HおよびDから独立して選択され；
R²は、CH₃およびCD₃から選択され；
R³は、CH₃およびCD₃から選択され；及び、
各^yHは、HおよびDから独立して選択される。 In particular, the present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof;

wherein the deuterium:protium ratio in said compound is greater than that found naturally in hydrogen;
each R ¹ is independently selected from H and D;
^R2 is selected from _CH3 and _CD3 ;
^R3 is selected from _CH3 and _CD3 ; and
Each ^y H is independently selected from H and D.

Also provided are methods of synthesizing the compounds of the invention and methods of using such compositions in the treatment of psychiatric or neurological disorders, such as major depressive disorder.

Background of the Invention

Classical hallucinogens have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin (2017), The Therapeutic Potential of Psychedelic Drugs: Past, Present and Future, Neuropsychopharmacology 42, 2105-2113). In particular, psilocybin has demonstrated significant improvement in various depression and anxiety rating scales in a randomized, double-blind trial (Griffiths et al. (2016), Psilocybin produces substantial and sustained decreases). in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial, Journal of Psychopharmacology 30(12), 1181-1197).

N,N-Dimethyltryptamine (DMT) is also understood to have therapeutic value as a short-acting hallucinogen, but its very short duration of action (less than 20 minutes) makes it an effective treatment. is restricted. Administration protocols have been developed to extend the immersive psychedelic 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). However, these protocols carry the risk of toxic accumulation in patients who metabolize DMT poorly (for further discussion see Strassman et al (1994), Dose response study of N,N-dimethyltryptamine in humans, Arch Gen Psychiatry 51). , 85).

α,α,β,β-tetradeutero-N,N-dimethyltryptamine exhibits dynamic isotope effects (kinetic isotope effect). Substitution of deuterium for hydrogen at the ^sp3 carbon center is known to produce a 'dynamic isotope effect' due to the difference in bond strength between the CH and CD bonds. Half-life of α,α,β,β-tetradeutero-N,N-dimethyltryptamine in rodent brain suggests keeping patients in the DMT space for longer than is required for treatment (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).

To controllably modify the pharmacokinetic profile of N,N-dimethyltryptamine, thereby allowing for more flexible therapeutic applications, the present invention provides α,α,β,β-tetradeutero-N It is based in part on the ability to apply knowledge of dynamic isotope effects exhibited by ,N-dimethyltryptamine. In particular, deuterated N,N-dimethyltryptamine analogues (especially containing at least one deuterium atom in the alpha position [i.e., at least one deuterium atom attached to the carbon atom to which the dimethylamino moiety is attached) By providing a separate drug composition comprising N,N-dimethyltryptamine), the present invention allows therapeutic optimization without resorting to clinical infusion protocols or concomitant therapy with monoamine oxidase inhibitors. Compositions and methods that allow fine-tuned single doses to maintain the patient in complete isolation from the outside world (referred to herein as the "DMT space") for a controlled duration of time. I will provide a. The present invention provides a clinically applicable solution that reduces clinical complexity and increases clinical flexibility in the administration of therapy using DMT.

Furthermore, we have determined that between the degree of deuteration, the H:D ratio of the input reducing agent in the synthetic methods disclosed herein, and the effect on the enhancement (i.e., increase) of the metabolic half-life of the parent compound. A quantifiable relationship was observed. Such technical effects include deuterated N,N-dimethyltryptamine compositions (i.e., isolated multiple deuterium-containing N,N-dimethyltryptamine compounds; or N,N-dimethyltryptamine and its heavy a composition comprising two or more compounds selected from hydrogenated analogues, especially those deuterated at the α- and/or N,N-dimethyl positions, or pharmaceutically acceptable salts thereof); It can be used to quantitatively increase the precision in preparation.

Viewed from a first aspect, therefore, the present invention provides an N,N-dimethyltryptamine compound, α-prothio,α-deutero-N,N-dimethyltryptamine compound, α,α-dideutero-N,N-dimethyltryptamine. and pharmaceutically acceptable salts of these compounds, deuterated N,N-dimethyltryptamine compound(s) for use in therapy, preferably said deuterated Deuterated N,N-dimethyltryptamine compounds have a longer half-life compared to that of non-deuterated N,N-dimethyltryptamine.

式中、化合物中の重水素：プロチウムの比は、水素において天然に見られるものよりも大きく：
各R¹は、H及びDから独立して選択され；
R²は、CH₃及びCD₃から選択され；
R³は、CH₃及びCD₃から選択され；
各^yHは、H及びDから独立して選択される。 Viewed from a second aspect, the present invention provides a deuterated N,N-dimethyltryptamine compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy:

where the deuterium:protium ratio in the compound is greater than that found naturally in hydrogen:
each R ¹ is independently selected from H and D;
^R2 is selected from _CH3 and _CD3 ;
^R3 is selected from _CH3 and _CD3 ;
Each ^y H is independently selected from H and D.

In preferred embodiments of the second aspect, each R ¹ is H. In a first embodiment of the second aspect, both ^y H are D. In a second embodiment of the second aspect both ^R2 and ^R3 are _CD3 .

式中、R¹は、H及びDから選択され；
R²は、CH₃及びCD₃から選択され；
R³は、CH₃及びCD₃から選択され；及び
各^yHは、H及びDから独立して選択される。 Viewed from a third aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is reacted with _LiAlH4 and/or _LiAlD4 . can be obtained by synthetic methods including

wherein R ¹ is selected from H and D;
^R2 is selected from _CH3 and _CD3 ;
^R3 is selected from _CH3 and _CD3 ; and each ^yH is independently selected from H and D.

Viewed from a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound or composition according to any one of the first to third aspects in combination with a pharmaceutically acceptable excipient. offer.

Viewed from a fifth aspect, the present invention provides a compound or composition according to any one of the first to fourth aspects for use in a method of psychedelic psychotherapy.

Viewed from a sixth aspect, the invention provides a compound or composition according to any one of the first to fifth aspects for use in a method of treating a neurological or psychological disorder in a patient. offer.

Viewed from a seventh aspect, the present invention provides a neurological or psychological treatment comprising administering to a patient in need thereof a compound or composition according to any one of the first to fourth aspects. Methods of treating physical disorders are provided.

Viewed from an eighth aspect, the invention provides a compound according to any one of the first to fourth aspects for the manufacture of a medicament for use in a method of treating a neurological or psychological disorder in a patient. or provide a use of the composition.

Viewed from a ninth aspect, the invention provides a process for preparing a compound according to any of the first to third aspects of the invention, comprising deuterated or non-deuterated 2-(3-indolyl) -N,N-dimethylacetamide is provided with a reducing agent consisting essentially of lithium aluminum hydride and/or lithium aluminum deuteride.

Viewed from a tenth aspect, the present invention provides a compound selected from compounds 1-5 or a pharmaceutically acceptable salt thereof.

Further aspects and embodiments of the invention will become apparent from the description below.

FIG. 1 shows the predicted pharmacokinetic profile of partially deuterated DMT compared to non-deuterated and fully deuterated DMT. Predicted A) plasma and B) brain tissue concentrations indicate an extended half-life of partially deuterated DMT. The hatched area indicates effect site concentrations (>60 ng/mL) experienced as complete dissociation from the environment, termed the 'DMT space'. 2 plots the calculated in vitro half-lives for DMT and six deuterated-containing compositions described in Example 1. FIG. A) Linear regression analysis. The half-life r ² value was 0.754 and the slope was found to be significantly different from zero (p=0.01). B) Half-lives of deuterated analogues are shown as percent change from (non-deuterated) DMT (dashed line). FIG. 3 shows the in vitro intrinsic clearance of DMT as described in Example 1 and six deuterium-containing compositions. A) Linear regression analysis. The intrinsic clearance r ² value was 0.7648 and the slope was found to be significantly different from zero (p=0.01). B) Intrinsic clearance of deuterated analogs is shown as percent change from (non-deuterated) DMT (dashed line). In vitro intrinsic clearance (A) and halving of DMT (SPL026) and six _D2 -deuterated SPL028 analogue blends in human hepatocytes with and without MAO-A/B inhibitor combinations. Phase (B) (described in the Examples section).

Detailed description of the invention

Throughout this specification, one or more aspects of the invention can be combined with one or more features described herein to define separate embodiments of the invention.

In this specification, references to the singular form of a noun include the plural form of the noun and vice versa unless the context indicates to the contrary.

Throughout this specification, the term "comprising," or variations such as "comprises," or "comprising," mean the inclusion of a recited element, integer or step, or group of elements, integers or steps. is understood not to mean the exclusion of any other element, integer or step, or any other group of elements, integers or steps.

The present invention relates to N,N-dimethyltryptamine compounds, α-prothio,α-deutero-N,N-dimethyltryptamine compounds, α,α-dideutero-N,N-dimethyltryptamine compounds, and pharmaceutical compositions of these compounds. A deuterated N,N-dimethyltryptamine compound selected from acceptable salts is provided.

As used herein, the term deuterated N,N-dimethyltryptamine compound refers to N,N-dimethyltryptamine having a deuterium composition greater than the deuterium composition found naturally in hydrogen (about 1.6%). means a tryptamine compound. As used herein, the term non-deuterated N,N-dimethyltryptamine compound refers to N,N-dimethyltryptamine having a deuterium composition equal to or lower than the deuterium composition found naturally in hydrogen. means a tryptamine compound.

As used herein, the term N,N-dimethyltryptamine compound means a compound of Formula Ia wherein each ^x H is independently selected from protium (H) and deuterium (D). . For example, the N,N-dimethyltryptamine compound can contain 0, 1, or 2 deuterium atoms at the β-position. For the avoidance of doubt, the present invention does not include compounds of Formula Ia in which each ^x H is H.

As used herein, the term α-prothio,α-deutero-N,N-dimethyltryptamine compounds means that each ^x H is independently selected from protium (H) and deuterium (D) , means a compound of formula Ib. For example, the α-prothio, α-deutero-N,N-dimethyltryptamine compound can contain 0, 1, or 2 deuterium atoms in the β-position.

As used herein, the term α,α-dideutero-N,N-dimethyltryptamine compounds are compounds of the formula wherein each ^x H is independently selected from protium (H) and deuterium (D) Ic compound. For example, an α,α-dideutero-N,N-dimethyltryptamine compound can contain 0, 1, or 2 deuterium atoms in the β-position.

A protium atom (H) is a hydrogen atom with zero neutrons. A deuterium atom (D) is a hydrogen atom with one neutron.

The inventors have found that the compounds of the invention exhibit first-order kinetic isotopic effects when one or two deuterium atoms are located on the α-carbon of the N,N-dimethyltryptamine compounds. discovered. This first-order kinetic isotope effect is exhibited to its greatest extent by the α,α-dideutero-N,N-dimethyltryptamine compounds and to a lesser extent by the α-prothio,α-deutero-N,N-dimethyltryptamine compounds. The results showed that the fold change in half-life of the α-prothio,α-deutero-N,N-dimethyltryptamine compounds compared to the analogous N,N-dimethyltryptamine compounds was similar to that of the analogous α,α-dideutero- about half that of the N,N-dimethyltryptamine compound.

a mixture of two or more compounds selected from N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine compounds, and α-prothio,α-deutero-N,N-dimethyltryptamine compounds The therapeutic benefits of first-order kinetic isotope effects can be applied to varying degrees using compositions comprising.

Accordingly, the present invention provides 2 compounds selected from N,N-dimethyltryptamine compounds, α,α-dideutero-N,N-dimethyltryptamine compounds and α-prothio,α-deutero-N,N-dimethyltryptamine compounds. Compositions comprising more than one compound are provided.

The inventors have also discovered that the compounds of the invention exhibit second order kinetic isotopic effects when the N,N-dimethyl group is deuterated. When such N,N-dimethyl groups contain one or more deuterium atoms and are also mono- or -dideuterated in the α-position, the secondary kinetic isotope is the primary kinetic isotope It is synergistic with body effects, resulting in more than a 14-fold increase in half-life compared to non-deuterated N,N-dimethyltryptamine (see Example 3).

N,N-dimethyltryptamine and all its deuterated analogs freely form addition salts with anionic counterions. Throughout this specification, N,N-dimethyltryptamine compounds (particularly N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine compounds, and α-prothio,α-deutero-N,N- dimethyltryptamine compound) equally means any pharmaceutically acceptable salt (eg, fumarate).

Typically, acidic reagents can be used to prepare salts of the N,N-dimethyltryptamine compounds, particularly pharmaceutically acceptable salts. Examples of suitable acidic reagents are selected from the group consisting of fumaric acid, hydrochloric acid, tartaric acid, citric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, lactic acid, tartaric acid and gluconic acid. The N,N-dimethyltryptamine compound (particularly as a compound of the invention), often in the form of a salt, in compositions of the invention or used in accordance with various aspects of the invention and embodiments thereof, is , fumarate, hydrochloride, tartrate or citrate, especially fumarate.

Compounds of the first aspect of the invention, and compounds of the second and third (and optionally other) aspects of the invention, may be in free base or salt form (e.g., as described herein). salts, etc.) and optionally as solvates thereof (eg, hydrates).

Embodiments of the first aspect provide compositions comprising 2% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 5% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises 10% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises 15% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises 20% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises 25% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 30% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises 50% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises 60% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 75% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises up to 90% by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises up to 95% by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises up to 96% by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises up to 97% by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises up to 98% by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises up to 99% by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises up to 99.5% by weight of one or more deuterated N,N-dimethyltryptamine compounds. In a preferred embodiment of the first aspect, the composition comprises up to 99.9% by weight of one or more deuterated N,N-dimethyltryptamine compounds.

Thus, from the foregoing, it can be seen that, according to certain embodiments of the first aspect of the invention, particularly those discussed in the following eight paragraphs, the composition comprises 2% to 90%, 2 % to 95%, 2% to 96%, 2% to 97%, 2% to 98%, such as 5% to 90%, 5% to 95%, 5% to 96%, 5% to 97%, 5 %~98%; 10%~90%, 10%~95%, 10%~96%, 10%~97%, 10%~98%; 15%~90%, 15%~95%, 15%~ 96%, 15%-97%, 15%-98%; 20%-90%, 20%-95%, 20%-96%, 20%-97%, 20%-98%; 25%-90% , 25%-95%, 25%-96%, 25%-97%, 25%-98%; 30%-90%, 30%-95%, 30%-96%, 30%-97%, 30 %~98%; 50%~90%, 50%~95%, 50%~96%, 50%~97%, 50%~98%; 60%~90%, 60%~95%, 60%~ 96%, 60%-97%, 60%-98%; or 75%-90%, 75%-95%, 75%-96%, 75%-97%, 75%-98%, 75%- 90% to 99%, 90% to 99.9%, 99% to 99.9% (all % by weight) of one or more deuterated N,N-dimethyltryptamine compounds.

Whenever a composition contains 2% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds, such composition contains 95% or less (or 96% or less, 97% or less) or 98% by weight or less) of one or more deuterated N,N-dimethyltryptamine compounds.

In preferred embodiments, the one or more partially deuterated N,N-dimethyltryptamine compounds constitute up to 50% by weight of the total composition.

According to another preferred embodiment of the first aspect of the present invention, the composition comprises up to 50% by weight, based on the total weight of the composition, of an α,α-dideutero-N,N-dimethyltryptamine compound, one or more compounds selected from α-prothio, α-deutero-N,N-dimethyltryptamine compounds, and pharmaceutically acceptable salts thereof. In such embodiments, such compositions contain 2% or more, e.g., 5% or more, 10% or more, 15% or more, by weight of the total composition of the one or more compounds. , 20% or more, 25% or more, or 30% or more.

According to certain embodiments, compositions of the invention include all embodiments described herein, including embodiments comprising N,N-dimethyltryptamine, N, A practice consisting essentially of one or more compounds selected from N-dimethyltryptamine, and deuterated analogues thereof (particularly those deuterated at the α-position), or pharmaceutically acceptable salts thereof. Forms include, but are not limited to. A composition consisting essentially of one or more compounds selected from N,N-dimethyltryptamine and its deuterated analogs means that the composition contains additional ingredients (other than the N,N-dimethyltryptamine compound). However, it is meant that the presence of these additional ingredients does not materially affect the essential properties of the composition. In particular, compositions that consist essentially of N,N-dimethyltryptamine compounds do not contain substantial amounts of other pharmaceutically active substances (ie, substantial amounts of other drugs).

The compositions of the invention may contain from 2% to 98% by weight of N,N-dimethyltryptamine, preferably from 5% to 95% by weight of N,N-dimethyltryptamine. Preferred compositions of the present invention contain 10% to 90% N,N-dimethyltryptamine, or 15% to 85% N,N-dimethyltryptamine, or 20% to 80% N, N-dimethyltryptamine, or 25% to 75% by weight of N,N-dimethyltryptamine, or 30% to 70% by weight of N,N-dimethyltryptamine, or 40% to 60% by weight of N,N- Contains dimethyltryptamine.

The compositions of the present invention preferably contain from 5% to 99.9% by weight of α,α-dideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyl Contains deuterated N,N-dimethyltryptamine compounds selected from tryptamines.

An aspect of the present invention is a composition obtained by reducing 2-(3-indolyl)-N,N-dimethylacetamide with a reducing agent consisting essentially of lithium aluminum hydride and/or lithium aluminum deuteride A composition obtained by reduction of a substance is provided. In both aspects, the reducing agent may be dissolved or suspended in the liquid medium. Although available in solid (powder) form, typically due to its strong reactivity with water and protective solvents (such as alcohols), lithium aluminum hydride (or lithium aluminum deuteride) is often , in dry aprotic solvents (such as ether), often under an inert atmosphere. Such precautions and suitable protocols are well known to those skilled in the art.

Accordingly, the present invention provides a composition comprising 2-(3-indolyl)-N,N-dimethylacetamide with a reducing agent (optionally a liquid medium) consisting essentially of lithium aluminum hydride and/or lithium aluminum deuteride. It is understood to provide a composition obtained by reconstituting the liquid (dissolved or suspended therein). The invention also provides a composition obtained by such a reduction, or more generally by a reduction according to the second or third aspect of the invention.

With particular reference to the compositions of the first aspect of the invention, the amounts of the N,N-dimethyltryptamine compounds described herein, mutatis mutandis, are those of the second and second aspects of the invention. It should also be understood that it can be applied to the composition of the third aspect.

According to certain embodiments, by stating that the reducing agent consists essentially of lithium aluminum hydride and/or lithium aluminum deuteride, the reducing agent may contain additional components, although the presence of these components does not substantially affect the essential properties of the reducing agent (especially stability and reducibility).

According to a fourth aspect of the invention there is provided a pharmaceutical composition comprising a composition as defined according to the first to third aspects of the invention in combination with a pharmaceutically acceptable excipient.

Pharmaceutical compositions of the invention comprise a composition of the invention (a composition according to any one of the first to third aspects) in combination with one or more pharmaceutically acceptable excipients. Suitable pharmaceutical compositions can be prepared by those skilled in the art using pharmaceutically acceptable excipients, examples of pharmaceutically acceptable excipients can be found in Gennaro et. : The Science and Practice of Pharmacy, ^20th Edition, Lippincott, Williams and Wilkins, 2000 (specifically part 5: pharmaceutical manufacturing). Suitable excipients are also described in Handbook of Pharmaceutical Excipients, ^2nd Edition; Editors A. Wade and PJ Weller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1994.

Pharmaceutical compositions of the present invention are expected to exhibit superior oral bioavailability compared to non-deuterated N,N-dimethyltryptamine. Thus, the compounds or compositions of the present invention can be compressed or otherwise formulated into solid dosage units such as tablets, capsules, orally disintegrating tablets, thin films, buccal patches and buccal tablets, or capsules. Or it can be processed into suppositories. When formulated as an orally disintegrating tablet, the compounds or compositions of the invention are compatible with the ^Zydis® platform. ^Zydis® tablets are manufactured by lyophilizing or freeze-drying a free base compound or composition of the invention in a matrix. The product obtained is very lightweight. Such an embodiment of the formulation comprises physically suspending particles of the compound or composition of the invention (preferably having a particle size of less than 50 μm) in an aqueous matrix and then lyophilizing. . Orally disintegrating tablets formulated in this way dissolve rapidly when placed in the oral cavity.

Pharmaceutically suitable solutions also allow the compounds to be prepared in the form of solutions, suspensions, emulsions, or as sprays. The use of conventional excipients such as fillers, colorants, polymeric binders and the like is contemplated for preparing dosage units including tablets. Generally, any pharmaceutically acceptable excipient can be used.

Suitable fillers for the preparation and administration of pharmaceutical compositions include lactose, starch, cellulose and derivatives thereof, etc., or mixtures thereof used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used containing pharmaceutically acceptable dispersing agents and/or wetting agents such as propylene glycol or butylene glycol, etc.).

For parenteral administration, aqueous solutions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents such as propylene glycol or butylene glycol. Formulations suitable for inhaled, transdermal, mucosal or transmembrane administration comprise the free base of the deuterated N,N-dimethyltryptamine compound, typically with one or more biocompatible excipients. include. Such formulations achieve longer lasting therapeutic effects than comparable formulations of non-deuterated N,N-dimethyltryptamine.

Thus, one aspect of the invention is selected from N,N-dimethyltryptamine compounds, α,α-dideutero-N,N-dimethyltryptamine compounds, α-prothio,α-deutero-N,N-dimethyltryptamine compounds Provided are parenteral formulations comprising the free base of one or more deuterated N,N-dimethyltryptamine compounds together with biocompatible excipients. In a preferred embodiment, the deuterated N,N-dimethyltryptamine compound is a compound of Formula I, wherein the deuterium:protium ratio in the compound is greater than that found naturally in hydrogen; ^R1 is independently selected from H and D; ^R2 _is selected from _CH3 and CD3; ^R3 is selected from _CH3 and _CD3 ; each ^y H is independently from H and D selected by

Typically, biocompatible excipients include solvents. Preferably, the solvent is selected from any one or a combination of two or more of propylene glycol, glycerin, polyethylene glycol, water, ethanol and triacetin. For preferred inhalable formulations the solvent is selected from propylene glycol, glycerin and polyethylene glycol, or any mixture thereof. Preferably, the solvent is a mixture of propylene glycol and glycerin in a weight ratio of about 50:50 to about 30:70. The free base concentration is from about 1 mg/mL to about 1000 mg/mL. Preferably, the biocompatible excipient comprises a taste-masking agent.

In preferred embodiments, the formulation has an oxygen content of less than 2 ppm. In embodiments, the formulation is stored in a container configured to prevent transmission of ultraviolet light.

The invention also provides a pharmaceutical composition of the invention in combination with packaging material suitable for the composition, the packaging material including instructions for use of the pharmaceutical composition.

The compositions of the invention are useful in therapy and can be administered to a patient in need thereof. As used herein, the term "patient" preferably refers to human patients, but may also refer to domesticated mammals. The term does not include mammals used in laboratories.

According to a sixth aspect of the invention there is provided a composition according to any one of the first to fourth aspects for use in a method of treating a psychiatric or neurological disorder in a patient. A seventh aspect of the invention is a method of treating a psychiatric or neurological disorder comprising administering to a patient in need thereof a composition defined according to any one of the first to fourth aspects wherein an eighth aspect is defined according to any one of the first through fourth aspects in the manufacture of a medicament for use in a method of treating a psychiatric or neurological disorder in a patient provided is the use of the composition. In embodiments of the sixth to eighth aspects of the invention, the psychiatric or neurological disorder is (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) schizophrenia disorder, (iv) (v) anxiety disorders; (vi) substance abuse; (vii) deprivation disorders; and (viii) brain injury disorders.

As used herein, the term "psychiatric disorder" refers to a current distress (e.g., distressing symptoms) or disability (i.e., one or more of the functions) occurring in an individual and present clinically significant behavioral or psychological syndromes or patterns associated with disability in critical areas of the body) or associated with significantly increased risk of suffering death, pain, disability, or significant loss of freedom is.

As used herein, the term "neurological disorder" refers to diseases of the central and peripheral nervous system.

Diagnostic criteria for psychiatric and neurological disorders referred to herein are provided, for example, in the "Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5)", the contents of which are incorporated herein by reference. incorporated into.

As used herein, the term "obsessive-compulsive disorder" is defined by the presence of either obsessions or compulsions (generally both). This condition can lead to significant impairment and/or distress. Obsessions are defined as unwanted, intrusive thoughts, images, or impulses that repeatedly enter a person's mind. A compulsion is a repetitive behavior or mental act that a person feels compelled to do. Typically, obsessive-compulsive disorder (OCD) manifests as one or more obsessions driven by compulsions. For example, an obsession with germs leads to a compulsion (urge) to clean. The compulsions may be obvious and observable, such as checking that a door is locked, or they may be implicit, unobservable, such as repeating a phrase in your head. can be any of the

As used herein, the term "depressive disorder" includes major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients. .

As used herein, the term "major depressive disorder (MDD); also called major depression or clinical depression" refers to most of the day, most of the day, over a period of two weeks or more. Defined as the daily presence of 5 or more of the following symptoms (also referred to herein as a "major depressive episode"):
- Depressed mood, e.g. feeling sad, empty or crying (in children and adolescents, depressed mood may manifest as persistent irritability);
- Markedly diminished interest or lack of pleasure in all or most activities;
Significant weight loss, weight gain, or decreased or increased appetite in the absence of diet (no expected weight gain in children);
Insomnia or increased desire to sleep;
- restlessness or slowness of movement observable by others;
- Fatigue or decreased energy;
Feelings of worthlessness or excessive or inappropriate guilt;
- Difficulty making decisions or difficulty thinking or concentrating;
• Recurrent thoughts of death or suicide, or suicide attempts At least one symptom must be either depressed mood or loss of interest or pleasure.

Persistent depressive disorder, also known as dysthymia, is defined as patients exhibiting the following two characteristics:
A. Has depressed mood most of the time, almost every day, for at least 2 years.
Children and adolescents may experience irritable moods, lasting at least a year.
B. During depression, a person experiences at least two of the following symptoms:
Either overeating or anorexia Excessive or disturbed sleep Fatigue or decreased energy Low self-esteem Difficulty concentrating or making decisions

As used herein, the term "treatment-resistant depression" describes MDD that fails to achieve an adequate response to adequate treatment with standard care therapies.

As used herein, "bipolar disorder," also known as manic depression, is a disorder that causes abnormal shifts in mood, energy, activity level, and ability to perform daily tasks.

There are two defined subcategories of bipolar disorder, all of which involve distinct changes in mood, energy, and activity levels. These moods range from periods of extreme "up", elation, and energetic behavior (known as manic episodes, further defined below) to periods of very sad "down" or hopelessness. (known as depressive episodes). A less severe manic period is known as a hypomanic episode.

Bipolar I disorder is defined by a manic episode lasting at least 7 days or by severe manic symptoms such that a person requires immediate hospital care. Depressive episodes also usually occur, typically lasting at least two weeks. Depressive episodes with mixed features (having depressive and manic symptoms simultaneously) can also occur.

Bipolar II disorder is defined by a pattern of depressive and hypomanic episodes, but not the terminal manic episodes described above.

As used herein, "bipolar depression" is experiencing depressive symptoms with previous or coexisting manic episodes but does not meet clinical criteria for bipolar disorder defined as an individual.

As used herein, the term "anxiety disorders (anxiety)" includes generalized anxiety disorder, phobias, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

As used herein, "generalized anxiety disorder (GAD)" means a chronic disorder characterized by long-lasting anxiety that is not specific to one object or situation. People with GAD experience persistent, non-specific fears and anxieties and become overly concerned with the mundane of everyday life. GAD is characterized by chronic excessive anxiety with three or more of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbance.

A "phobia" is defined as a constant fear of an object or situation that the affected person goes to great lengths to avoid (typically disproportionate to the actual danger involved). If the feared object or situation cannot be completely avoided, the affected person endures it with significant distress and serious impairment in social or occupational activities.

A patient suffering from "panic disorder" is defined as someone who experiences one or more short attacks of intense fear and anxiety (also called panic attacks), often with tremors, tremors, confusion, dizziness, and nausea. , and/or dyspnea. A panic attack is defined as fear or discomfort that begins abruptly and peaks in less than 10 minutes.

"Social anxiety disorder" is defined as intense fear and avoidance of negative public scrutiny, public embarrassment, embarrassing situations, or social interaction. Social anxiety often presents with specific physical symptoms, including redness, sweating, and difficulty speaking.

"Post-traumatic stress disorder" (PTSD) is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, natural disasters, rape, hostage situations, child abuse, bullying, or serious accidents. Common symptoms include hyperarousal, flashbacks, avoidance behavior, anxiety, anger, and depression.

As used herein, the term "substance abuse" means patterned use of a drug in which the user consumes the substance in amounts or in a manner that is detrimental to themselves or others.

As used herein, the term "avolition disorder" refers to a disorder whose symptoms include decreased motivation to initiate and perform voluntary and purposeful activities.

As used herein, the term "brain injury disorder" refers to injuries to the brain that occur after birth and are not congenital, degenerative, or hereditary. The term includes traumatic brain injuries, eg from motor vehicle accidents or sports injuries, and acquired brain injuries such as ischemic stroke, transient ischemic stroke, hemorrhagic stroke, brain tumors, meningitis or encephalitis.

In preferred embodiments of the sixth to eighth aspects of the invention, the psychiatric or neurological disorder is (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse, (v) deprivation disorder; and (vi) brain injury disorder.

According to particular embodiments of the sixth to eighth aspects of the invention, the depressive disorder is major depressive disorder. According to an even more particular embodiment, the major depressive disorder is treatment-resistant major depressive disorder.

Compositions containing the deuterated N,N-dimethyltryptamine compounds of the present invention can be synthesized according to the reaction scheme (synthesis scheme) shown in Scheme 1 on a gram scale to multi-kilogram scale.

The relative proportions of N,N-dimethyltryptamine compounds to deuterated N,N-dimethyltryptamine compounds and partially deuterated N,N-dimethyltryptamine compounds are determined by the amount of lithium aluminum hydride and aluminum deuteride in the reducing agent. It may be controlled by varying the ratio with lithium. one or more of N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine in the above compositions. The relative proportions may be further varied by adding to

A particular advantage of the present invention, particularly but not limited to the compositions obtained according to its third aspect and the method of its ninth aspect, is that the reduction described for these aspects of the invention is followed by It is possible to obtain particularly high purities without the need for chromatographic purification (eg column chromatography), thereby increasing the efficiency of preparing the compositions of the invention. Furthermore, not using chromatography to achieve high purity makes scale-up more efficient and therefore cost effective.

Identification of the compositions obtained by the method of the invention can be accomplished by chromatographic separation of the components of the mixture by conventional means available to those skilled in the art, optionally in combination with spectroscopy and/or mass spectroscopy. can.

Another composition is the non-hydrogenated N,N-dimethyltryptamine obtained according to Scheme 1 when the reducing agent is exclusively lithium aluminum hydride and from Scheme 1 when the reducing agent is exclusively lithium aluminum deuteride Obtained by mixing with the resulting deuterated N,N-dimethyltryptamine compound.

The compositions described above may be further modified by the addition of one or more deuterated N,N-dimethyltryptamine compounds. Stocks of such deuterated N,N-dimethyltryptamine compounds can be obtained, for example, from the chromatographic separations described above. In this way, for example, compounds of the tenth aspect of the invention can be obtained.

Although identification of the compositions resulting from the reductions described herein can be accomplished by chromatographic separation of the components of the mixture in combination with spectroscopy and/or mass spectroscopy, certain advantages of the present invention are According to the embodiment, it is not necessary to do so. This is because, as already suggested, in addition to the purities achievable according to the present invention, the degree of deuteration (in other words, deuterium in the N,N-dimethyltryptamine compounds in the compositions of the present invention) ) and the metabolic half-life of the resulting composition. The degree of deuteration can be controlled via the amount of deuterium-containing reducing agent used in the method of the invention, through which (according to certain embodiments) the composition of the invention is , can be obtained in a predictable manner through enhancement of the metabolic half-life of the parent compound (non-deuterated N,N-dimethyltryptamine) and is therefore controllable.

In particular, as detailed in Example 1 and related FIGS. resulting in reduced clearance and longer half-life, where there is a linear relationship between molecular weight (188.3-190.3 g/mol) and half-life, and synergistic first- and second-order kinetics has been demonstrated to provide a predictable relationship between molecular weight and half-life of compounds and compositions of Formula I (where R ¹ is H and ranges from 188.3 to 196.3 grams/ moles).

Compositions of such type constitute a particular embodiment of the first aspect of the invention. According to certain of these embodiments, the composition comprises N,N-dimethyltryptamine, α-prothio,α-deutero-N,N-dimethyltryptamine, and α,α-dideutero-N,N-dimethyltryptamine. wherein the composition may be in the form of a pharmaceutically acceptable salt, wherein the N,N-dimethyltryptamine present in the composition consists essentially of two or three compounds selected from , α-prothio, α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine have an average molecular weight of 188.28 to 190.28.

According to a further particular aspect, the composition comprises N,N-bis(trideutero)dimethyltryptamine (compound 5), α-prothio,α-deutero-N,N-bis(trideutero)dimethyltryptamine (compound 2), and one, two or three compounds selected from α,α-dideutero-N,N-bis(trideutero)dimethyltryptamine (Compound 1), said compounds being pharmaceutically acceptable wherein N,N-bis(trideutero)dimethyltryptamine, α-prothio, α-deutero-N,N-bis(trideutero)dimethyltryptamine, and ,α,α-dideutero-N,N-bis(trideutero)dimethyltryptamine has a molecular weight or average molecular weight of 188.9-196.3. In a preferred embodiment of this aspect, the composition comprises N,N-bis(trideutero)dimethyltryptamine (compound 5), preferably α-prothio,α-deutero-N,N-bis(trideutero)dimethyltryptamine (compound 2), and more preferably α,α-dideutero-N,N-bis(trideutero)dimethyltryptamine (compound 1) (in order of increasing metabolic stability).

As used herein, average molecular weight refers to N,N-dimethyltryptamine compounds, α-prothio,α-deutero-N,N-dimethyltryptamine compounds, and α,α-dideutero-N,N-dimethyl Means the weight average of the molecular weights of tryptamine compounds, as determined by a suitable mass spectrometry technique, e.g. LC-MS SIM (selected ion monitoring), ignoring any weight contribution due to pharmaceutically acceptable salt formation (as applicable). case).

It is understood that the provision of compositions having such specific average molecular weights can be accomplished by those skilled in the art through the teachings herein (especially when varying the level of deuteration at the α-position: By adjusting the relative proportions of lithium aluminum hydride:lithium aluminum deuteride used in stage 2 and when varying the level of deuteration at the N,N-dimethyl positions, the by adjusting the relative proportions of dimethylamine:deuterated dimethylamine).

In this connection, the composition comprises N,N-dimethyltryptamine and/or α-prothio,α-deutero-N,N-dimethyltryptamine/α,α-dideutero-N,N-dimethyltryptamine. A statement that the composition consists essentially of a mixture of means that In particular, the compositions do not contain substantial amounts of other pharmaceutically active compounds, including other N,N-dimethyltryptamine compounds. Accordingly, substantial amounts of other deuterated N,N-dimethyltryptamine compounds, particularly β-prothio,β-deutero-N,N-dimethyltryptamine compounds and β,β-dideutero-N,N-dimethyltryptamine compounds β-prothio, β-deutero-N,N-dimethyltryptamine and β,β-dideutero-N,N-dimethyltryptamine and one or two deuterium atoms instead of hydrogen atoms in the α position β-Prothio, β-deutero-N,N-dimethyltryptamine compounds having atoms and β,β-dideutero-N,N-dimethyl having 1 or 2 deuterium atoms instead of hydrogen atoms in the α position A tryptamine compound is not present in the composition of such embodiments.

In other words, and to put it another way, a composition according to one particular embodiment comprises N,N-dimethyltryptamine, α-prothio, α-deutero-N,N-dimethyltryptamine, and α,α- comprising a drug substance comprising a biologically active ingredient consisting essentially of one or more of didutero-N,N-dimethyltryptamines, wherein the biologically active ingredient is between 188.3 and 190.3 A compound having an average molecular weight and included in a drug substance is optionally in the form of a pharmaceutically acceptable salt. A composition according to a second particular embodiment comprises N,N-bis(trideutero)dimethyltryptamine (compound 5), α-prothio,α-deutero-N,N-bis(trideutero)dimethyltryptamine (compound 2), and α,α-dideutero-N,N-bis(trideutero)dimethyltryptamine (Compound 1), wherein biological The active ingredient has an average molecular weight of 188.9-196.3, and the drug substance may be in the form of a pharmaceutically acceptable salt.

Compositions according to these particular embodiments contain α-prothio,α-deutero-N,N-dimethyl in amounts greater than those found in non-isotopically enriched N,N-dimethyltryptamine. It will be understood to include one or more of tryptamine compounds and α,α-dideutero-N,N-dimethyltryptamine compounds. Also, the higher the proportion of α-prothio,α-deutero-N,N-dimethyltryptamine compound and α,α-dideutero-N,N-dimethyltryptamine compound in these particular embodiments, the higher the composition average It will be appreciated that the molecular weight is high.

According to a more particular embodiment, N,N-dimethyltryptamine, α-prothio,α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyl present in the composition The average molecular weight of tryptamine is 188.9-189.7, eg 188.90-189.70.

An even more specific embodiment of the specific embodiments described herein includes N,N-dimethyltryptamine, α-prothio,α-deutero-N,N-dimethyltryptamine present in the composition. and α,α-dideutero-N,N-dimethyltryptamine having an average molecular weight of 188.9 to 189.7, wherein the compounds contained in the compositions are optionally in the form of pharmaceutically acceptable salts. which reduces N,N-dimethyltryptamine, α-prothio,α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine present in the composition to , are understood to exist in the form of pharmaceutically acceptable salts. Such salts may be salts as described elsewhere herein, and according to an even more particular embodiment, the composition is in the form of the fumarate salt.

Methods by which compounds of Formula I may be produced are described below, said methods being suitable for producing high purity compounds of Formula I. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 99%-100% pure by HPLC, eg, 99.5%-100% pure by HPLC. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 99.9%-100% pure by HPLC, eg, 99.95%-100% pure by HPLC.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, produces no more than two impurity peaks by HPLC. In some embodiments, when a compound of Formula I or a pharmaceutically acceptable salt thereof produces impurity peaks by HPLC, no impurity peaks above 0.2% are present. In some embodiments, there are no impurity peaks by HPLC above 0.1%.

In some embodiments, compounds of Formula I are in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts often comprise a compound of formula I and a suitable acid. Compounds ^of Formula I are typically protonated at -N( ^R2R3 ) ₂ to form -[ ^NHR2R3 ] ⁺ and the ^resulting positive charge is offset with an anion.

P.H. Stahl and C.G. Wermuth, in "Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich: Wiley-VCH/VHCA, 2002," provide an overview of pharmaceutical salts and the acids contained therein. Acids described in this review are suitable components of pharmaceutically acceptable salts of Formula I.

In some embodiments, the acid is 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, decanoic acid , hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecyl sulfate, 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, lactobionic 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.

Often the acid is any one selected from fumaric acid, tartaric acid, citric acid and hydrochloric acid. In some embodiments, the acid is fumaric acid, i.e. the pharmaceutically acceptable salt is fumarate.

式中、
各R¹は、H及びDから独立して選択され；
R²は、CH₃及びCD₃から選択され；
R³は、CH₃及びCD₃から選択され；
各^yHは、H及びDから独立して選択される。 Also disclosed herein are synthetic methods for making the compounds of Formula I or pharmaceutically acceptable salts thereof. The method includes stage 2 and optionally stage 1, stage 1:
(i) reacting a compound of Formula III with two or more coupling agents to form an active compound;
(ii) reacting the active compound with an amine having the formula ( ^R2 ) _2NH to produce a compound of formula II;
wherein stage 2 comprises reacting the compound of formula II with _LiAlD4 or with _LiAlH4 and _LiAlD4 ;

During the ceremony,
each R ¹ is independently selected from H and D;
^R2 is selected from _CH3 and _CD3 ;
^R3 is selected from _CH3 and _CD3 ;
Each ^y H is independently selected from H and D.

For the avoidance of doubt, the embodiment of the first aspect of the invention relating to a compound of formula I or a pharmaceutically acceptable salt thereof is, mutatis mutandis, a compound of formula I of said synthetic method (and compounds of formulas III and II).

The synthetic method avoids the problematic use of oxalyl chloride and uses compounds of formula III, which may be derived from auxin derivatives. Auxins of formula III of high quality and purity are commercially available on a large scale and/or can be readily synthesized via Fischer, Bartoli, Japp-Klingemann or Larock syntheses (e.g. MB Smith and J. March, 2020, March's Advanced Organic Chemistry, ^8th edition, Wiley, New Jersey). The method is efficient, scalable, current good manufacturing practices (cGMP) compatible, and suitable for the production of high purity compounds of Formula I. For example, the method is suitable for producing compounds of formula I on a batch scale ranging from 1 g to 100 kg, and is suitable for producing compounds of formula I with >99.9% purity and greater than 65% overall yield. Are suitable.

Compounds of Formula II are prepared by reacting a compound ^of Formula III with two or more coupling agents to form an active compound, and reacting the active compound with an amine having the formula ^R2R3NH . be. While not intending to be bound by theory, it is understood that the nitrogen atom of the amine is attached to the carbon atom of the carbonyl of Formula III, resulting in the formation of the compound of Formula II. For the avoidance of doubt, the ^R2 and ^R3 groups of Formula II and Formula I are derived from the ^R2 and ^R3 groups of the amine. Thus, as noted above, ^R2 and ^R3 of Formulas II and I are independently selected from _CH3 and _CD3 .

Compounds of formula I are prepared by reacting compounds of formula II with _LiAlD4 or with _LiAlH4 and _LiAlD4 . Without intending to be bound by theory, the hydride or deuteride ion provided by LiAlD ₄ or by LiAlH ₄ and LiAlD ₄ binds to the carbonyl carbon atom of formula II to form the compound of formula I. understood to result in formation. For the avoidance of doubt, the ^xH groups of Formula I are derived from the hydride or deuteride ions provided by _LiAlD4 or by _LiAlH4 and _LiAlD4 .

As mentioned above, the method includes Stage 1 and Stage 2. Stage 1 is:
(i) reacting a compound of Formula III with two or more coupling agents to form an active compound; and
(ii) reacting ^the active compound with an amine having the formula ^R2R3NH to produce a compound of formula II.

The term "coupling agent" refers to an agent that promotes the chemical reaction between amines and carboxylic acids. The two or more coupling agents are reacted with a carboxylic acid activating agent, i.e., the carboxylic acid moiety of Formula III to form an activated moiety derived from the original carboxylic acid moiety (which is more It may also contain agents that form compounds containing amines that are readily reactive with amines).

The active compound is the product of the reaction between the compound of formula III and two or more coupling agents. When the two or more coupling agents include a carboxylic acid activator, the active compound has an activating moiety derived from the original carboxylic acid moiety of Formula III, which reacts with the amine rather than the original carboxylic acid moiety. easy).

Two or more coupling agents may include a carboxylic acid activator. The two or more coupling agents may contain additional coupling agents.

Additional coupling agents (also referred to herein as "additives") are agents that increase the reactivity of the coupling agent. The additive reacts with the reaction product of formula III and the coupling agent (said product is a compound containing an activated moiety) to make it more reactive with the amine than the original activated moiety, and further activated. It may also be a compound capable of producing a compound containing the moiety.

The additive reacts with the reaction product of formula III and the coupling agent (said product is a compound containing an activated moiety) to make it more reactive with the amine than the original activated moiety, and further activated. may have the ability to produce active compounds including moieties.

Often the two or more coupling agents comprise a carboxylic acid activator and an additional coupling agent.

At least one of the two or more coupling agents is a carbodiimide coupling agent, a phosphonium coupling agent, and 3-(diethoxy-phosphoryloxy)-1,2,3-benzo[d]triazine-4(3H )-ones (DEPBT) and may be selected from, for example, carbodiimide coupling agents or phosphonium coupling agents. At least one of the two or more coupling agents may be a carbodiimide coupling agent.

A carbodiimide coupling agent is a coupling agent that contains a carbodiimide group (R'-N=C=NR"), where R' and R" are heteroatoms (typically is a hydrocarbyl group optionally substituted by nitrogen). Often R' and R" are independently selected from _C1 - _C6 alkyl, _C5 - _C6 cycloalkyl, _C1 - _C6 alkylamino and _morpholinoC1 - _C6 alkyl. where _C1 - _C6 alkyl is _C3 alkyl, _C5 - _C6 cycloalkyl is cyclohexyl, _C1 - _C6 alkylamino is dimethylaminopropyl, and/or morpholino _C1 -C ₆ alkyl is morpholinoethyl.

Carbodiimide coupling agents include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), and 1-cyclohexyl-(2-morpholinoethyl)carbodiimide It may be any one selected from the group consisting of met-p-toluenesulfonate (CMCT).The carbodiimide coupling agent is dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and (N-( 3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), often the carbodiimide coupling agent is N-(3-dimethylaminopropyl )-N'-ethylcarbodiimide (EDC), typically the hydrochloride salt (EDC.HCl).EDC or EDC.HCl is non-toxic, highly water-soluble, and suitable for Stage 1 work. It is particularly preferred as it facilitates their substantially complete removal in the up and wash steps.

Phosphonium coupling agents comprise a phosphonium cation and a counterion, typically a hexafluorophosphate anion. The phosphonium cation may be of the formula [PR ^a ₃ R ^b ] ⁺ where R ^a is di(C ₁ -C ₆ )alkylamino or pyrrolidinyl and R ^b is halo or hydrocarbyl group (optionally substituted with nitrogen and/or oxygen atoms). Often R ^b is bromo, benzotriazol-1-yloxy, or 7-aza-benzotriazol-1-yloxy.

Phosphonium coupling agents include benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP), and benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP). Fluorophosphate (PyBOP), 7-aza-benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyAOP), and ethylcyano(hydroxyimino)acetato-O ₂ )tri-(1-pyrrolidinyl)-phosphonium hexafluoro Any one selected from the group consisting of phosphates (PyOxim) may be used.

At least one of the two or more coupling agents is 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-azabenzo-1,2,3-triazene (HODhat), and 3-hydroxy-4-oxo -3,4-dihydro-5-azepine may be an additional coupling agent selected from the group consisting of benzo-1,3-diazines (HODhad).

At least one of the two or more coupling agents is 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) ) may be an additional coupling agent selected from the group consisting of:

At least one of the two or more coupling agents may be an additional coupling agent that is 1-hydroxybenzotriazole.

The two or more coupling agents may consist of a coupling agent and an additional coupling agent, wherein said coupling agent and additional coupling agent are as described in the embodiments above. There may be.

An advantage of using both the coupling agent and the additional coupling agent is the increased rate of formation of the compound of formula II from the compound of formula III and the amine having the formula ( ^R2 ) _2NH . Additionally, the potential for unwanted side reactions can be reduced when an additional coupling agent is used in conjunction with the carbodiimide coupling agent. For example, reaction of a compound of Formula III with a carbodiimide coupling reagent likely forms an O-acylisourea. It can undergo rearrangements to form N-acylureas, stable compounds that react poorly with amines. Additional coupling reagents can react with O-acylureas prior to rearrangement to N-acylureas to produce compounds that react with amines rather than inactive N-acylureas.

Thus, two or more coupling agents may consist of a carbodiimide coupling agent and an additional coupling agent.

The two or more coupling agents are from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), typically hydrochloride (EDC.HCl), and 1-hydroxybenzotriazole (HOBt). You can become

Often an excess of coupling agent is used relative to the compound of formula III. The ratio of coupling agent to compound of formula III is from about 1:1 to about 3:1, typically from about 1:1 to about 2:1, most typically from about 1:1 to about 1.5:1. may be

Often an excess of additional coupling agent relative to the compound of formula III is used. Sometimes the ratio of additional coupling agent to compound of formula III is from about 1:1 to about 3:1, typically from about 1:1 to about 2:1, most typically from about 1:1 to It is approximately 1.5:1.

When the two or more coupling agents comprise a coupling agent and an additional coupling agent, the ratio of coupling agent to compound of formula III and the ratio of additional coupling agent to compound of formula III is about 1 :1 to about 1.5:1.

As described above, Stage 1 involves reacting an active compound (the reaction product of a compound of formula III and two or more coupling agents) with an amine having the formula ^R2R3NH to give a compound ^of formula II including generating ^R2 and ^R3 of Formula II and Formula I are independently selected from _CH3 and _CD3 .

The ratio of amine to compound of formula III employed in this method is often about ≧1:1. Sometimes the ratio of amine to compound of Formula III is from about 1:1 to about 3:1, typically from about 1:1 to about 2:1.

Sometimes Stage 1 further comprises isolating the compound of Formula II. A person skilled in the art knows techniques in the art suitable for isolating compounds of Formula II. For example, a compound of Formula II may be extracted into an organic solvent such as dichloromethane or ethyl acetate, washed with an aqueous solution such as basic aqueous solution, and concentrated. Isolated compounds of Formula II may be recrystallized to increase purity. A person skilled in the art knows techniques suitable for recrystallization of compounds of Formula II. For example, the compound of formula II is dissolved in a minimal amount of solvent at a particular temperature (eg, ambient temperature (eg, 15-25° C.), or heated temperature (temperature at which heat is applied to the solution)) to obtain The resulting solution can be cooled to facilitate precipitation. Alternatively, or in addition, the volume of the solution may be reduced to facilitate precipitation (eg, by simple evaporation at ambient temperature and pressure). Alternatively, or in addition, an anti-solvent (in which the compound of formula II is less soluble in the solvent already present) may be used.

Isolated compounds of Formula II are stable and can be stored as solids in air at ambient temperature (eg, about 20° C.). They may, but need not, be stored under inert conditions, eg under nitrogen or argon, or at low temperatures, eg a refrigerator or freezer.

Typically, Stage 1 steps (i) and (ii) are carried out in a suitable solvent. Those skilled in the art can assess 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 (i) and (ii) of Stage 1 are performed in dichloromethane.

Steps (i) and (ii) of Stage 1 are carried out at suitable temperatures and those skilled in the art can assess which temperatures are suitable for these steps. Stage 1 steps (i) and (ii) are often carried out at a temperature of about 10°C to about 30°C. In some embodiments, Stage 1 steps (i) and (ii) are performed at room temperature (about 20° C.).

Sometimes Stage 1 of the method includes the following steps:
(1) contacting a compound of Formula III with 1 to 1.5 equivalents of an additional coupling agent and 1 to 1.5 equivalents of a carbodiimide coupling agent to produce a first composition; and (2) a second One composition is contacted with 1-2 equivalents of an amine having the formula R ² R ³ NH to form a second composition.

Often 1 g or more, eg 1 g to 100 kg or 1 g to 1 kg of the compound of formula III is used in the method.

The contacting of steps (i) and (ii) is often carried out in the presence of a first solvent, eg 5 to 20 volumes of the first solvent. The first solvents were dichloromethane (DCM), acetone, isopropyl alcohol (IPA), isopropyl acetate (iPrOAc), tert-butyl methyl ether (TBME), 2-methyltetrahydrofuran (2-MeTHF) and ethyl acetate (EtOAc). Any one may be selected. Typically the first solvent is DCM.

Often step (i) further comprises agitating or stirring the first composition. The first composition may be stirred or stirred for at least 30 minutes, such as 30 minutes to 3 hours or 30 minutes to 2 hours, preferably at least 1 hour, such as 1-3 hours or 1-2 hours. . The first composition may be maintained at a temperature of 10°C to 30°C.

The amine of step (ii) is often dissolved in a solvent such as tetrahydrofuran (THF) or ether prior to contact. The amine may be present in the solvent at a concentration of about 2M. Typically the amine of step (ii) is dissolved in THF.

Optionally, step (ii) further comprises agitating or stirring the second composition. The second composition may be stirred or stirred for at least 30 minutes, such as 30 minutes to 3 hours or 30 minutes to 2 hours, preferably at least 1 hour, such as 1-3 hours or 1-2 hours. . The second composition may be maintained at a temperature of 10°C to 30°C.

Step (ii) further comprises contacting the second composition with a basic aqueous solution to form a third composition, for example, the second composition is added to 2-10 volumes of a basic aqueous solution, such as It may comprise contacting with an aqueous solution comprising potassium carbonate.

Optionally, step (ii) further comprises agitating or stirring the third composition. The third composition may be stirred or stirred for at least 1 minute, such as 1-15 minutes or 1-10 minutes, preferably at least 5 minutes, such as 5-15 minutes or 5-10 minutes. The third composition may be maintained at a temperature of 10°C to 30°C.

If the third composition comprises an organic component and an aqueous component, step (ii) may further comprise separating the organic component from the aqueous component. The organic component may be separated from the aqueous component within 8 hours of contacting in step (i).

Sometimes Stage 1 of the method includes the following steps:
i. adding to a first vessel 1 g or more of a compound of formula III and 1 to 1.5 equivalents of an additional coupling agent;
ii. to a first vessel, add 5-20 volumes of a first solvent selected from DCM, acetone, IPA, iPrOAc, TBME, 2-MeTHF and EtOAc;
iii. adding 1 to 1.5 equivalents of a carbodiimide coupling agent to the first vessel;
iv. agitating the contents of the first container for at least 30 minutes, preferably at least 1 hour (e.g., 1-2 hours) at 10°C to 30°C;
v. To a first vessel is added 1-2 equivalents of an amine having the formula R ² R ³ NH (where the amine is preferably dissolved in an ethereal solvent).
vi. the contents of the first container are further stirred for at least 30 minutes, preferably at least 1 hour (eg 1-2 hours) at 10°C to 30°C;
vii. adding 2 to 10 volumes of a basic aqueous solution to the first container;
viii. further stirring the contents of the first container for at least 1 minute, preferably at least 5 minutes (e.g. 5-10 minutes) at 10°C to 30°C;
ix. An immiscible organic fraction is separated from the aqueous fraction (wherein the organic fraction comprises the compound of Formula II).
x. Removing the Organic Fraction Containing the Compound of Formula II Where steps (i)-(x) are performed within a single period of 8 hours.

Often the first solvent is DCM.
Often the amine is dimethylamine. Amines may be dissolved in THF, for example, at a concentration of 2M.
Often the basic aqueous solution contains potassium carbonate.

Sometimes, the first stage of the method further comprises the steps of:
xi. drying the organic fraction using a drying agent such as a drying agent selected from calcium chloride, magnesium sulfate, and sodium sulfate;
xii. filtering the organic fraction,
xiii. Concentrating the organic fraction, e.g., under vacuum (e.g., under pressure of less than 1 atmosphere),
xiv. placing the concentrated organic fraction in a second vessel;
xv. 2-10 volumes of a second solvent is added to the second vessel, where the second solvent is selected from IPA, EtOAc, IPrOAc, acetonitrile (MeCN), TBME, THF, 2-MeTHF and toluene. is done),
xvi. agitating the contents of the second vessel at a temperature of 45° C. to 55° C. for at least 1 hour, preferably at least 2 hours (eg 2-3 hours);
xvii. cooling the contents of the second container to a temperature of 15°C to 25°C;
xviii. filtering the contents of the second container to obtain a filtrate, wherein the filtrate comprises the compound of Formula II; and
xix. Dry the filtrate.

The drying agent in step (xi) is typically magnesium sulfate. Often the solvent in step (xv) is selected from TBME and IPA.

Stage 2 of the process involves reacting the compound of formula II with _LiAlD4 or with _LiAlH4 and _LiAlD4 to produce the compound of formula I. _LiAlD4 , or a mixture of _LiAlH4 and _LiAlD4 , may be reacted with the compound of Formula II. In a preferred embodiment, Stage 2 of the method comprises reacting the compound of formula II with a mixture of _LiAlH4 and _LiAlD4 . Such mixtures include LiAlD ₄ and contain 0.1-99.9% hydride. A mixture of 2% to 98% lithium aluminum hydride or 2% to 98% lithium aluminum deuteride may be used. Sometimes the mixture of _LiAlH4 and _LiAlD4 consists essentially of 98% _LiAlD4 ^/ 2% _LiAlH4 . Sometimes such mixtures are essentially 95% _LiAlD4 ^/ 5% _LiAlH4 , 95% _LiAlD4 ^/ 5% LiAlH4, 85% _LiAlD4 ^/ 15% _LiAlH4 , 80% _LiAlD4 ^/ 20% LiAlH4 _{. 4} , 75% _LiAlD4 ^/ 25% _LiAlH4 , 70% _LiAlD4 ^/ 30% _LiAlH4 , 65%LiAlD4 ^/ 35% _{LiAlH4 ,} 60% _LiAlD4 ^/ 40% _LiAlH4 , 55% _LiAlD4 ^/ 45%LiAlH ₄ , 50% _LiAlD4 ^/ 50% _LiAlH4 , 45% _LiAlD4 ^/ 55%LiAlH4, 40% _LiAlD4 ^/ 60%LiAlH4 _, 35% _LiAlD4 ^/ 65%LiAlH4 ^{, 30%LiAlD4/} _{70 % LiAlH 4} , 25% _LiAlD4 ^/ 75% _LiAlH4 , 20% _LiAlD4 ^/ 80%LiAlH4, 15% _LiAlD4 ^/ 85% _LiAlH4 , 10 _{% LiAlD4} ^/ 90%LiAlH4, _{5 %} LiAlD4 ^/ 95%LiAlH ₄ , or 2% _LiAlD4 ^/ 98% _LiAlH4 .

A mixture consisting essentially of certain percentages of LiAlH ₄ and LiAlD ₄ means that the mixture may contain additional components (other than LiAlH ₄ and LiAlD ₄ ), but the presence of these additional components may means that it does not materially affect the characteristics of In particular, the mixture consisting essentially of LiAlH ₄ and LiAlD ₄ does not contain substantial amounts of substances that are detrimental to the reduction of the compound of formula II (to yield the compound of formula I) (e.g. the compound of formula I LiAlH ₄ and LiAlD ₄ , the compound of formula II and/or the compound of formula I in a manner that inhibits the reduction of the compound of formula II to form ).

The amount of LiAlH ₄ or LiAlD ₄ included in the binary mixture depends on the degree of deuteration desired in the compound of formula I. For example, if a compound of Formula I is sought in which one ^yH is protium and the other is deuterium, a mixture of 50% _LiAlH4 and 50% _LiAlD4 may be preferred. Alternatively, about half of the compounds contain two deuterium atoms in the alpha position (i.e., ^y H are both deuterium) and about half of the compounds contain one deuterium atom and one protium atom in the alpha position ( That is, one ^yH is deuterium and the other protium) If a mixture of compounds of formula I is desired, a mixture of 25% _LiAlH4 and 75% _LiAlD4 may be preferred.

The amount of LiAlD ₄ or LiAlH ₄ and LiAlD ₄ used relative to compounds of formula II is often ≦1:1. For the avoidance of doubt, the ratio of _LiAlD4 or LiAlH4 and _{LiAlD4 to} the compound of formula II refers to the total amount of _LiAlD4 or _LiAlH4 and _LiAlD4 used relative to the amount of compound II. In particular, the ratio of LiAlD ₄ or LiAlH ₄ and LiAlD ₄ : compound of formula II is from 0.5:1 to 1:1, eg from 0.8:1 to 1:1. Typically the ratio of LiAlH ₄ and/or LiAlD ₄ : compound of formula II is 0.9:1.

Typically, Stage 2 of the method is carried out in a suitable solvent. Those skilled in the art can assess which solvents are suitable for Stage 2. Examples of suitable solvents include ethers such as THF and diethyl ether. Stage 2 is often performed in THF.

LiAlD ₄ or LiAlH ₄ and LiAlD ₄ are often provided as a solution or suspension of LiAlD ₄ or LiAlH ₄ and LiAlD ₄ in a suitable solvent (such as an ether, such as THF or diethyl ether, typically THF). be done.

Stage 2 of the method is carried out at suitable temperatures and those skilled in the art can assess which temperatures are suitable for these steps. Stage 2 is often carried out at a temperature of about -5°C to about 65°C.

Stage 2 typically further comprises isolating the compound of Formula I. Those skilled in the art know suitable techniques for isolating compounds of Formula I. For example, the reaction is quenched (e.g., with an aqueous solution of a tartrate salt such as Rochelle's salt), a compound of formula I is extracted into an organic solvent (such as an ether, such as THF or diethyl ether), and an aqueous solution such as a basic aqueous solution. can be washed with and concentrated. Isolated compounds of formula I may be recrystallized. A person skilled in the art knows techniques suitable for recrystallization of compounds of Formula I. Examples of recrystallization techniques described for recrystallization of compounds of formula II apply mutatis mutandis to recrystallization of compounds of formula I.

Often about 1 g or more, for example from about 1 g to about 100 kg, or from about 1 g to about 1 kg of the compound of formula II is used in the method.

Typically, Stage 2 of the process comprises contacting the compound of formula II with about 0.8 to about 1 equivalent, such as about 0.9 equivalents of _LiAlD4 or _LiAlH4 and _LiAlD4 to form the first compound. including doing

Contacting is typically carried out in the presence of a solvent (such as an ether, eg THF or diethyl ether, typically THF).

Frequently, contacting comprises adding _LiAlD4 , or _LiAlH4 and _LiAlD4 dropwise to a compound of formula II, wherein _LiAlD4 or _LiAlH4 and _LiAlD4 are in a suitable solvent (such as an ether, e.g. provided as a solution or suspension of LiAlD ₄ or LiAlH ₄ and LiAlD ₄ in THF or diethyl ether). _LiAlD4 or _LiAlH4 and _LiAlD4 may be provided as a 2.4M or 2M solution or suspension of _LiAlD4 or _LiAlH4 and _LiAlD4 in THF. Sometimes _LiAlD4 or _LiAlH4 and _LiAlD4 are provided as a 2M solution or suspension of _LiAlD4 or _LiAlH4 and _LiAlD4 in THF.

Contacting is often carried out at a temperature of about -5°C to about 65°C.

Stage 2 often further comprises agitating or stirring the first composition. The first composition may be stirred or stirred for about 1 hour to about 6 hours, typically about 2 hours. The first composition may be stirred or stirred at a temperature of about 55°C to about 65°C. Often the first composition is stirred or stirred 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.

Typically, the compound of formula II is combined with about 0.9 equivalents of LiAlD_Fourand or LiAlH_Fourand LiAlD_Fourcome into contact with

Stage 2 of the method of the invention may comprise the following steps:
i. adding 1 g or more (e.g., 1 g to 1 kg) of a compound of Formula II to a third container;
ii. adding 5 to 20 volumes of ether solvent to a third vessel;
iii. Into a third container, 0.8-1 equivalent of LiAlD ₄ solution or LiAlH ₄ and LiAlD ₄ solutions in ether solvent at a temperature of −5° C. to 65° C. over at least 15 minutes (eg, 15-30 minutes). to drip the
iv. agitate the contents of the third vessel at 55° C. to 65° C. for 1 hour to 6 hours, preferably 2 hours; and
v. cooling the contents of the third vessel to 10°C to 30°C;
wherein the contents of the third container comprise a compound of Formula I;

Often the ether solvent is THF. Typically 0.9 equivalents of _LiAlD4 or _LiAlH4 and _LiAlD4 are added to the third vessel in step (iii). _LiAlD4 or _LiAlH4 and _LiAlD4 are typically added as 2.4M or 2M THF solutions to the third vessel. Sometimes _LiAlD4 or _LiAlH4 and _LiAlD4 are added as a 2M solution in THF to a third vessel.

Sometimes Stage 2 of the method includes a workup that includes the following steps:
vi. Place 5-20 volumes of an aqueous solution of tartrate (e.g., Rochelle's salt) in a fourth container,
vii. A composition comprising a crude compound of Formula I is heated at 15° C. to 25° C. for at least 15 minutes (eg, 15 minutes to 1 hour), preferably at least 30 minutes (eg, 30 minutes to 1 hour), and subjected to a fourth and
viii. The contents of the fourth vessel are stirred at 15°C to 25°C for at least 30 minutes (eg, 30 minutes to 1 hour).

For the avoidance of doubt, the composition comprising the crude compound of Formula I refers to the contents of the third container upon completion of step (v) of Stage 2 above.

Stage 2 of the method may further include the following steps:
ix. Separating the organic fraction from the aqueous fraction (wherein the organic fraction comprises the compound of Formula I)
x. removing the aqueous fraction from the fourth container;
xi. In a fourth vessel, add 5-20 volumes of brine solution (brine).
xii. agitating the contents of the fourth container at a temperature of 15° C. to 25° C. for at least 5 minutes (eg, 5 to 15 minutes);
xiii. removing the organic fraction containing the compound of formula I as the free base;
xiv. drying the organic fraction using a drying agent such as a drying agent selected from calcium chloride, magnesium sulfate, and sodium sulfate;
xv. filtering the organic fraction, and
xvi. Concentrate the organic fraction under vacuum (eg, under a pressure of less than 1 atmosphere).

The isolated compound of Formula I (produced by Stage 2) is stable and can be stored as a solid in air at ambient temperature, eg, about 20°C. They may, but need not, be stored under inert conditions, eg, under nitrogen or argon, or at low temperatures, eg, in a refrigerator or freezer. Sometimes the compound of formula I is stored dissolved in a solvent, for example ethanol. Sometimes compounds of formula I are stored in the solvent for more than 8 hours, typically for more than 12 hours.

As noted above, the compounds of Formula I may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts may be formed from compounds of Formula I by reaction with a suitable acid. Accordingly, the method may further comprise Stage 3 of reacting the compound of Formula I with an acidic reagent to produce a pharmaceutically acceptable salt of the compound of Formula I. Acidic reagents may be suitable for crystallizing pharmaceutically acceptable salts of compounds of Formula I.

For the avoidance of doubt, when a reagent is expressed herein as an equivalent number, this is the molar equivalent of a compound of Formula III, Formula II or Formula I for the reagent in Stage 1, Stage 2 or Stage 3, respectively. Regarding.

A method of synthesizing a compound of Formula I or a pharmaceutically acceptable salt thereof often comprises Stage 1, Stage 2 and Stage 3, wherein Stage 1 is:
(i) reacting a compound of Formula III with two or more coupling agents to form an active compound;
(ii) reacting the active compound with ^an amine having the formula ^R2R3NH to produce a compound of formula II; and (iii) isolating the compound of formula II;
including.
stage 2 comprises reacting the compound of formula II with _LiAlD4 or with _LiAlH4 and _LiAlD4 ; and stage 3 comprises reacting the compound of formula I with a pharmaceutically acceptable salt of the compound of formula I including reacting with a suitable acidic reagent to crystallize.

Occasionally, a ratio of ≧1:1 of acidic reagent:compound of formula I is used. Often the ratio of acidic reagent to compound of formula I is 1:1.

Typically, Stage 3 of the method is carried out in a suitable solvent. Those skilled in the art can assess which solvents are suitable for Stage 3. Examples of suitable solvents include ethanol, IPA, iPrOAc and MeCN. Stage 3 is often performed in ethanol.

Stage 3 of the method of the invention is carried out at suitable temperatures and the skilled person can assess which temperatures are suitable for these steps.

Stage 3 of the method often involves contacting the compound of Formula I with an acidic reagent to form a first composition. Often stage 3 contacting is carried out at a temperature of 70-100°C, such as 70-90°C or 70-80°C. Sometimes stage 3 contacting is performed at a temperature of about 75°C.

Stage 3 often further comprises isolating the pharmaceutically acceptable salt of Formula I. The person skilled in the art knows techniques suitable for isolation of such compounds. For example, when a compound is dissolved in a suspension, it may be separated from some of the other components of the suspension by filtration (eg, hot filtration). A pharmaceutically acceptable salt of Formula I may precipitate from the filtrate. Those skilled in the art are familiar with methods of promoting precipitation of a compound from solution, such as cooling the solution, concentrating the solution, and/or adding the compound in crystalline form to the solution to facilitate nucleation and removal of the compound from solution. know how to promote further crystal growth (ie, seeding). A pharmaceutically acceptable salt of Formula I may be recrystallized. Those skilled in the art know techniques suitable for recrystallization of pharmaceutically acceptable salts of Formula I. Examples of recrystallization techniques described for recrystallization of compounds of Formula II apply mutatis mutandis to recrystallization of pharmaceutically acceptable salts of Formula I.

Stage 3 of the method may include the following steps:
i. adding at least one equivalent of an acidic reagent suitable for crystallizing a pharmaceutically acceptable salt of the compound of Formula I to a fifth vessel;
ii. dissolving the compound of Formula I as the free base in 5-20 volumes of a solvent (e.g., a solvent selected from ethanol, IPA, iPrOAc and MeCN) and adding the solution to a fifth reaction vessel;
iii. agitating the contents of the fifth vessel at a temperature of 72°C or higher (e.g., 72-90°C);
iv. filtering the contents of the fifth container;
v. Add the filtrate to the sixth vessel and cool the contents to a temperature of 67° C. to 73° C.
vi. optionally, seeding the sixth container with a pharmaceutically acceptable salt of the compound of Formula I in crystalline form;
vii. agitating the contents of the sixth vessel at a temperature of 67° C. to 73° C. for at least 30 minutes (eg, 30 minutes to 1 hour);
viii. cooling the contents of the sixth vessel to a temperature of -5°C to 5°C at a rate of 2-8°C per hour; and
ix. The contents of the sixth container are filtered to produce a filter cake comprising a pharmaceutically acceptable salt of the compound of Formula I.

Often the solvent in step (ii) is ethanol. Often the cooling rate in step (viii) is 5°C per hour.

As noted above, pharmaceutically acceptable salts often comprise a compound of Formula I and a suitable acid. The acids listed above as suitable components of the pharmaceutically acceptable salts of the invention apply mutatis mutandis to the acidic reagent in Stage 3 of the process.

Often the acidic reagent is any selected from fumaric acid, tartaric acid, citric acid and hydrochloric acid, such as fumaric acid.

The synthetic method disclosed herein uses significantly less _LiAlD4 than other syntheses known in the art because the method substitutes deuterium at the α-position but not the β-position, thus It is particularly useful for preparing therapeutic deuterated substituted dialkyltryptamines. LiAlD ₄ is one of the most expensive and difficult reagents to make in this synthesis. Additionally, the optimized methods disclosed herein reduce the required amount of _LiAlD4 or of _LiAlH4 and _LiAlD4 from, for example, 2 equivalents to 0.9 equivalents, which is equivalent to the deuterated compound of Formula I. increase economic efficiency in the production of In this regard, compounds of Formula I are less expensive than known deuterated analogues, which are typically deuterated at both the α- and β-positions by the synthetic methods disclosed herein. manufactured to

The synthetic methods disclosed herein are efficient and compounds of formula I can be produced in overall yields of 50% to 100%, eg, 60% to 100%, or 65% to 100%.

Each and every patent and non-patent reference mentioned herein is hereby incorporated by reference in its entirety, as if the entire contents of each reference were set forth herein in its entirety. incorporated.
The invention may be further understood with reference to the following non-limiting examples.

Example 1
In a first example, we show that the first-order kinetic isotopic effects induced on N,N-dimethyltryptamine when the α-position is enriched with one or two deuteriums are observed in human hepatocytes. The assay demonstrates a linear relationship between average molecular weight and half-life.

Use of Human Hepatocytes to Assess In Vitro Intrinsic Clearance of Deuterated DMT Analog Blends Against DMT In vitro measurements of intrinsic clearance are a valuable model for predicting in vivo liver clearance. The liver is the major organ of drug metabolism in the body, containing both phase I and phase II drug-metabolizing enzymes present in intact cells.

Sample synthesis
220.9 g of N,N-DMT (as free base) was prepared as N,N-DMT fumarate salt using the chemistry shown in Scheme 1. An additional 4-6 g of six partially deuterated mixtures were also prepared using modified conditions.

Synthesis of DMT
Stage 1: Coupling of indole-3-acetic acid and dimethylamine
A 5 L vessel under _N2 was charged with indole-3-acetic acid (257.0 g, 1.467 mol), hydroxybenzotriazole (HOBt, ~20% wet) (297.3 g, 1.760 mol), and dichloromethane (2313 mL), giving a milky white color. A suspension was obtained. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 337.5 g, 1.760 mol) was then charged portionwise over 5 minutes at 16-22°C. After the reaction mixture was stirred at ambient temperature for 2 hours, 2M dimethylamine in THF (1100 mL, 2.200 mol) was added dropwise at 20-30° C. over 20 minutes. The resulting solution was stirred at ambient temperature for 1 hour, where HPLC showed 1.1% indole-3-acetic acid and 98.1% of the target product (referred to as Stage 1). 10% K ₂ CO ₃ (1285 ml) was then added to the reaction mixture and stirred for 5 minutes. The layers were separated and the upper aqueous layer was extracted with dichloromethane (643 mL x 2). The organic extracts were combined and washed with saturated brine (643 mL). The organic extract was then dried over _MgSO4 , filtered and concentrated in vacuo at 45°C. This gave 303.1 g of crude stage 1 as an off-white sticky solid. This crude material was then slurried in tert-butyl methyl ether (TBME, 2570 mL) at 50° C. for 2 hours, then cooled to ambient temperature, filtered and washed with TBME (514 mL×2). The filter cake was then vacuum dried at 50° C. to give 266.2 g (yield=90%) of stage 1 as an off-white solid (purity 98.5% by HPLC and >95% by NMR). ).

Stage 2: Preparation of DMT
A 5 L vessel under _N2 was charged with Stage 1 (272.5 g, 1.347 mol) and tetrahydrofuran (THF, 1363 mL) to give an off-white suspension. 2.4 M LiAlH ₄ in THF (505.3 mL, 1.213 mol) was then added dropwise over 35 minutes at 20-56° C. to give an amber solution. The solution was heated to 60° C. for 2 h, where HPLC showed stage 1 (ND), target product bracket (designated stage 2 92.5%), impurity 1 (2.6%), impurity 2 (1.9%). showed that. The complete reaction mixture was cooled to ambient temperature and then added dropwise to a solution of 25% Rochelle's salt (aq) (2725 mL) over 30 minutes at 20-30°C. The resulting milky white suspension was stirred at 20-25° C. for 1 hour, 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 _MgSO4 , filtered and concentrated in vacuo at 45°C. The resulting crude oil was azeotroped from ethanol (545 mL x 2). This gave 234.6 g of stage 2 (yield=92%) with a purity of 95.0% by HPLC and >95% by NMR.

Stage 3a(i)-(iii): Preparation of seed crystals of DMT fumarate
(i) Stage 2 (100 mg) was placed in 8 volumes of isopropyl acetate and warmed to 50° C. before charging fumaric acid (1 eq) as an ethanol solution. The flask was then aged at 50° C. for 1 hour before cooling to room temperature and stirring overnight to give a white suspension. The solid was isolated by filtration and dried at 50° C. for 4 hours to give 161 mg of product (>99% yield). Purity by HPLC was 99.5% and purity by NMR was >95%.

(ii) Substituting isopropyl alcohol for isopropyl acetate in method (i) gave a white suspension after stirring overnight. The solid was isolated by filtration and dried at 50° C. for 4 hours to give 168 mg of product (>99% yield). Purity by HPLC was 99.8% and purity by NMR was >95%.

Substituting tetrahydrofuran for isopropyl acetate in method (i), a white suspension was obtained after stirring overnight. The solid was isolated by filtration and dried at 50° C. for 4 hours to give 161 mg of product (>99% yield). Purity by HPLC was 99.4% and purity by NMR was >95%.

Analysis by X-ray powder diffraction showed that the product of each of methods (i)-(iii) was the same, designated pattern A.

Stage 3b: Preparation of DMT Fumarate
A 5 L flanged flask under _N2 was charged with fumaric acid (152.7 g, 1.315 mol) and Stage 2 (248.2 g, 1.315 mol) as a solution in ethanol (2928 mL). The mixture was heated to 75°C to give a dark brown solution. The solution was polish filtered into a preheated (80° C.) 5 L jacketed vessel. The solution was then cooled to 70°C and seeded with pattern A (0.1 wt%), allowing the seeds to mature for 30 minutes before cooling to 0°C at a rate of 5°C/hour. After stirring for an additional 4 hours at 0° C., the batch was filtered, washed with cold ethanol (496 mL×2) and then dried at 50° C. overnight. This gave 312.4 g (yield=78%) of stage 3 with a purity of 99.9% by HPLC and >95% by NMR. XRPD: Pattern A

Synthesis of Deuterated Mixtures of DMT Compounds A modified synthesis method for stage 2 using a solid _LiAlH4 / _LiAlD4 mixture was adopted, using 1.8 equivalents of _LiAlH4 / _LiAlD4 vs 0.9 equivalents of non-deuterated DMT. We used the method described above for

Representative Synthesis of Deuterated (1:1 LiAlH ₄ :LiAlD ₄ ) DMT Compositions
A 250 mL three-necked flask under _N2 was charged with _LiAlH4 (1.013 g, 26.7 mmol), _LiAlD4 (1.120 g, 26.7 mmol), THF (100 ml). The resulting suspension was stirred for 30 minutes before stage 1 (6 g, 29.666 mmol) was charged in portions over 15 minutes at 20-40°C. The reaction mixture was then heated to reflux (66° C.) for 2 hours where HPLC showed no stage 1 left. The mixture was cooled to 0° C. and quenched with 25% Rochelle's salt (aq) (120 mL) over 30 min below 30° C. The resulting milky suspension was stirred for 1 hour and then allowed to separate. The lower aqueous layer was removed and the upper organic layer was washed with saturated brine (30 mL). The organics were then dried over _MgSO4 , filtered and concentrated in vacuo. This gave 4.3 g of crude material. The crude material was then taken up in ethanol (52 mL) and charged with fumaric acid (2.66 g, 22.917 mmol) before heating to 75°C. The resulting solution was cooled to ambient temperature overnight and then further cooled to 0-5° C. for 1 hour. The solid was isolated by filtration and washed with cold ethanol (6.5 mL x 2). The filter cake was dried at 50° C. overnight to give 5.7 g (yield=63%) of product with 99.9% purity by HPLC and >95% purity by NMR.

In Vitro Intrinsic Clearance of Deuterated DMT Compounds and Compositions
In vitro measurement of human hepatocyte 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, thereby providing a valuable model for the study of drug metabolism. In particular, CLint in hepatocytes is a measure of the metabolic potential of a compound and can be related to liver clearance in vivo by also taking into account plasma protein binding and hepatic blood flow. CLint can therefore be used as an indicator of the relative metabolic stability of a compound and compared with other external probe substrates. Furthermore, in vitro measurement of CLint (hepatic metabolic clearance is known to be a problem) can be a valuable tool for understanding different pharmacokinetic behaviors of compounds in vivo.

Assay method
Human (gender-mixed) hepatocytes pooled from 10 donors were used to examine the in vitro intrinsic clearance of SPL026 and SL028 analogues in three separate experiments:
First experiment - human (gender-mixed) hepatocytes; 545,000 cells/mL final organic concentration 1.05% (consisting of 80.74% MeCN and 19.26% DMSO)
• Second experiment - human (gender-mixed) hepatocytes; 427,000 cells/mL final organic concentration 1% (consisting of 84.7% MeCN and 15.3% DMSO).
・Third experiment - human (gender-mixed) hepatocytes; 362,000 cells/mL
Mouse CD-1 (male) hepatocytes 1% final organic concentration (consisting of 84.7% MeCN and 15.3% DMSO).

Assay preparation • Hepatocyte buffer is prepared as 26.2 mM _NaHCO3 , 9 mM Na HEPES, 2.2 mM D-fructose and DMEM in MilliQ water.
• Compound and marker stocks are prepared at 10 mM in DMSO and further diluted to 100-fold assay concentration in 91:9 acetonitrile:DMSO.
• Rapidly thaw hepatocytes in a 37°C water bath and, once thawed, decant into hepatocyte buffer. After centrifuging the cells and removing the supernatant, they are counted and resuspended at the final assay concentration.

Assay Procedure A concentration of 5 μM was used for all test compounds, as well as sumatriptan, serotonin, benzylamine controls, with two replicate incubations per compound in each experiment. This concentration was chosen to maximize the signal-to-noise ratio while being below the Michaelis constant (Km) for the monoamine oxidase enzyme (MAO). Diltiazem and diclofenac controls were used at a laboratory validated concentration of 1 μM.

Add hepatocytes to pre-warmed incubation tubes (37°C). Pre-prepared 100x assay compound stocks are then added to the incubation tubes and mixed carefully. Samples are taken at 7 time points (2, 4, 8, 15, 30, 45 and 60 minutes). At each time point, a small aliquot was removed from the incubation and quenched (1:4 with ice-cold acidified methanol or acetonitrile [containing internal standard]).

Incubation tubes are rocked at 37° C. for the duration of the experiment.
Typical final incubation conditions are nominally about 500,000 viable cells/mL, about 0.9% (v/v) acetonitrile (MeCN), and about 0.1% (v/v) DMSO (see section 2 above). 1 μM compound in buffer containing specific assay concentrations outlined).

Mix the quenched sample thoroughly and allow the proteins to precipitate at -20°C for a minimum of 12 hours. The samples are then centrifuged at 4°C. Supernatants are transferred to new 96-well plates for analysis.

Liquid chromatography-mass spectrometry (LC-MS/MS)
The following LC-MS/MS conditions were used for analysis:

MRM transitions:
D0 = mass-to-charge ratio 189.136 > 144.179 (method determined from SPL026 analysis)
D1 = mass-to-charge ratio 190.136 > 59.17 (method determined from SPL028ii analysis)
D2 = mass-to-charge ratio 191.137 > 60.169 (method determined from SPL028i analysis)
・D6 = mass-to-charge ratio 195.17 > 64.127
・D8 = mass-to-charge ratio 197.2 > 146.17

MRM transitions were either free of deuterium (D0 transitions) or of DMT samples containing high levels of D1, D2, D6 or D8 deuteration (D1, D2, D6 and D8 transitions, respectively). Determined from preliminary analysis.

The resulting concentration-time profile was then used to calculate intrinsic clearance (CLint) and half-life (t _1/2 ). To do this, the MS peak area or MS peak area/IS response for each analyte is plotted on the y-axis against the time of sampling (minutes) on the x-axis on a natural logarithmic scale. The slope of this line is the elimination rate constant. This is converted to half-life by -ln(2)/slope. Intrinsic clearance is calculated from the slope/elimination rate constant, the formula is CLint = (-1000*slope)/cell density (1E6 cells/ml), giving units of microliters/min/million cells.

Clearance of six _D2DMT analog blends (SPL028i-SPL028vi) with and without MAO inhibitors to six different α,α-dideutero-N,N-dimethyltryptamine ( _D2DMT ) compounds. The contribution of MAO was estimated from in vitro intrinsic clearance using human (gender-mixed) hepatocytes (545,000 cells/mL; final organic concentration of 1.05% [consisting of 80.74% MeCN and 19.26% DMSO]) from 10 donors. Via assays, irreversible combined MAO-A/B inhibitors (100 nM clorgyline and 100 nM deprenyl/selegiline: added as a cassette) were investigated.

The deuteration effect data were fit to two separate linear models using linear regression analysis (one-way ANOVA), showing that the deuterium enrichment at the α-carbon of DMT correlated with the fraction of D ₂ -deuteration and A linear decrease in intrinsic clearance was demonstrated with increasing molecular weight (MW) (using the equation below).

96.6% of _D2 -DMT (SPL028i) showed the greatest change in metabolic stability (approximately two-fold change in intrinsic clearance and half-life) compared to SPL026 in the first hepatocyte assay (Table 3 and Table 4). The metabolic stability of the deuterated intermediate blends (SPL028ii-SPL028vi) increased in a manner that correlated with increasing levels of deuteration and molecular weight (Tables 3 and 4).

Table 3: In vitro intrinsic clearance of SPL026 and six _D2 -deuterated SPL028 analogue blends in human hepatocytes. Fold change in intrinsic clearance from SPL026 for each deuterated compound with/without inhibitor. to emphasize Compounds are ordered by molecular weight

Table 4: In vitro half-life of SPL026 and six _D2 -deuterated SPL028 analogue blends in human hepatocytes. Fold change in half-life from SPL026 for each deuterated compound with/without inhibitor. to emphasize Compounds are ordered by molecular weight

Contribution of MAO (see also Figure 4)
A two-way ANOVA was performed to determine the effect of MAO inhibitors and compound deuteration on intrinsic clearance. A significant effect of MAO inhibitor on intrinsic clearance F(1,6)=11.42, p=0.0149 and a significant effect of deuteration on intrinsic clearance F(1,6)=9.996, p=0.006 was observed. .

Inclusion of a MAO inhibitor was shown to have the least effect on the metabolism of SPL026 (DMT), resulting in approximately 4% slower intrinsic clearance (Table 5). The MAO inhibitor was also shown to have a slight effect on the 96.6% _D2 -deuterated analogue (SPL028i) (approximately 5% faster intrinsic clearance observed in the presence of the MAO inhibitor) ( Table 5). These results indicate that MAO enzymes do not significantly contribute to the metabolism of SPL026 and SPL028i in human hepatocytes.

MAO inhibitors were shown to have greater inhibitory effects on intrinsic clearance for the remaining five D ₂ -deuterated analog blends (SPL028ii-SPL028vi). For these five compounds, with the exception of SPL028vi, the inhibitory effect of MAO inhibitors was shown to increase linearly with increasing deuterium level and molecular weight (Table 3). 49% _D2 -deuterated SPL028iv showed the greatest change in intrinsic clearance (49%) when containing the MAO inhibitor (Table 5), while 36.8% _D2 -deuterated SPL028iii showed the greatest change in metabolic stability (approximately two-fold) compared to SPL026 in cell fractions (Tables 3 and 4).

Table 5: In vitro intrinsic clearance and half-life of SPL026 and six _D2 -deuterated SPL028 analog blends in human hepatocytes (with and without MAO-A/B inhibitor combination). The percent change (%) values represent the % change in metabolic stability with MAO inhibitor versus no inhibitor (measured for intrinsic clearance and half-life separately). The compounds are ordered in order of increasing molecular weight.

These results indicate that increasing the deuteration level at the α-carbon of DMT decreases the MAO enzymatic metabolism of the compound.

Clearance of Six _D2DMT Analog Blends (SPL028i-SPL028vi) and One _D6 -DMT (SPL028vii) Analog Blend
Synthesis of d6 _- DMT: 028vii (compound 5)

EDC.HCl (15.7 g, 81.90 mmol) was added to DCM (108 mL) containing 3-indoleacetic acid (12.0 g, 68.50 mmol) and _HOBt.H2O (1.16 g, 75.75 mmol) at room temperature. After the reaction was stirred for 1 hour, N,N-diisopropylethylamine (DIPEA) (35.6 mL, 205.75 mmol) and _d6 -dimethylamine.HCl (9.0 g, 102.76 mmol) were added (temperature was kept below 30°C). maintained). After the reaction was stirred at room temperature for 1 hour, analysis by HPLC indicated 65.6% product and 28.9% remaining 3-indoleacetic acid. DIPEA (11.9 mL, 68.78 mmol) was added and the reaction was stirred at room temperature for 1 hour. HPLC showed no change in conversion. Aqueous potassium carbonate solution (6.0 g in 54 mL water) was added and the phases were separated. The aqueous phase was extracted with DCM (2 x 30 mL). The combined organics were washed with brine (2 x 30 mL) then aqueous citric acid solution (20 w/w%, 50 mL), dried over _MgSO4 and filtered. The filtrate was stripped and the resulting solid was slurried in TBME (120 mL) and isolated by filtration. Purification by flash column chromatography gave 8.34 g of the desired product (58% yield). ¹ H NMR confirmed the identity of the product.

_LiAlH4 (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) at <30 <0>C. The resulting reaction was heated to 60-65° C. and stirred for 2 hours. HPLC analysis showed complete consumption of Stage 1 and 97.3% product formation. The reaction was cooled to room temperature and quenched in aqueous Rochelle's salt solution (10 g in 30 mL water) at <30.degree. After stirring for 1 hour, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over _MgSO4 , filtered and stripped (azeotroped with ethanol, 20 mL) to give the desired product as an amber oil (3.97 g). rice field. ¹ H NMR confirmed the identity of the product and showed that 8.5% ethanol was present (no THF) and yielded 3.63 g, 97% activity.

The free base of d ₆ -DMT (3.6 g activity, 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. (solids crystallized during heating and did not re-dissolve). The resulting suspension was cooled to 0-5° C. and stirred for 1 hour. The solid was isolated by filtration, washed with ethanol (2 x 7 mL) and dried. Further drying in a 50° C. vacuum oven gave the desired d ₆ -DMT fumarate salt (4.98 g, 87%).

Synthesis of d8 _- DMT: 028viii (compound 1)
For stage 1 (coupling of 3-indoleacetic acid and d ₆ -dimethylamine) see above.

_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) at <30 <0>C. The resulting reaction was heated to 60-65° C. and stirred for 2 hours. HPLC analysis showed complete consumption of Stage 1 and 97.3% product formation. The reaction was cooled to room temperature and quenched in aqueous Rochelle's salt solution (10 g in 30 mL water) at <30.degree. After stirring for 1 hour, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over _MgSO4 , filtered and stripped (azeotroped with ethanol, 20 mL) to give the desired product as an amber oil (4.01 g). Obtained. ¹ H NMR confirmed the identity of the product, showing that 8.6% ethanol was present (no THF) and yielded 3.66 g, 97% activity.

Compound 1 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. (solids crystallized during heating and did not re-dissolve). The resulting suspension was cooled to 0-5° C. and stirred for 1 hour. The solid was isolated by filtration, washed with ethanol (2 x 7 mL) and dried. Further drying in a 50° C. vacuum oven gave the desired compound 1 as the fumarate salt (4.62 g, 81%).

Evaluation of the degree of deuteration This is achieved by LCMS-SIM (SIM = Single Ion Monitoring), the analysis of the three deuterated N,N- of dimethyltryptamine compounds (N,N-dimethyltryptamine (D0), α-prothio,α-deutero-N,N-dimethyltryptamine (D1), and α,α-dideutero-N,N-dimethyltryptamine (D2)) A separate ion count is given for each mass. The percentage of each component was then calculated from these ion counts. for example,

In vitro human liver-specific clearance of six α,α-dideutero-N,N-dimethyltryptamine (D ₂ DMT) compounds and one N,N-bis(trideutero-dimethyl)tryptamine (D ₆ DMT, SPL028vii) was measured using human (gender-mixed) hepatocytes from 10 donors (427,000 cells/mL; final organic concentration 1% [consisting of 84.7% MeCN and 15.3% DMSO]), methyl group deuteration vs. We investigated the effect of α-carbon deuteration on metabolic stability.

Table 6. In vitro intrinsic clearance and half-life of six _D2 -deuterated DMT and _D6 -deuterated DMT analogue blends in human hepatocytes. Arranged in order of increasing molecular weight.

線形回帰モデルは、以下の式を使用して分子量にもフィッティングされ、６種類のD₂-重水素化SPL028ブレンドに関して、分子量が固有クリアランスの強力な予測因子であることを明らかにした。

Data from a linear regression model fit to six D ₂ -deuterides show that deuterium enrichment at the α-carbon of DMT linearly increases intrinsic clearance with increasing deuteration level and molecular weight. confirms the previous finding of lowering

A linear regression model was also fitted to molecular weight using the following equation, revealing that molecular weight is a strong predictor of intrinsic clearance for the six _D2 -deuterated SPL028 blends.

Initial hepatocyte data did not suggest a relationship between molecular weight and intrinsic clearance of D ₂ -deuterated and D ₆ -deuterated SPL028 blends (r ² =0.0395).

[Example 2]
In a second example, we recognize the potential for increased half-life when N,N-dimethyltryptamine is deuterated at the N,N-dimethyl position.

Clearance of two D2DMT ₍ SPL028i and SPL028ii) blends, one D6DMT ₍ SPL028vii, Compound 5), and one D8 _- DMT (SPL028viii, Compound 1) analogs Further human hepatocyte assays were performed. , conducted with two _D2 -deuterated SLP028 analogue blends and two additional deuterated analogues ( _D6DMT and _D8DMT ), human (gender-mixed) from 10 donors. In vitro intrinsic clearance was measured using hepatocytes (362,000 cells/mL).

Table 7. In vitro intrinsic clearance and half-life of two D ₂ -deuterated DMT, D ₆ -deuterated DMT, and D ₈ -deuterated DMT analog blends in human hepatocytes. Arranged in order of increasing molecular weight.

Although the presence of a possible second-order kinetic isotope effect was observed in the data, linear regression models did not support molecular weight and intrinsic clearance for SPL026, SPL028i, SPL028ii, SPL029vii, and SPL028viii in the human hepatocyte assay. did not support a predictive relationship between (r ² =0.0445).

[Example 3]
In a third example, we provide evidence that an additional protective effect is observed between _D2 -deuterated SPL028i and _D8 -deuterated SPL028viii (compound 1). Data demonstrate metabolic stability when deuterium is present in both the alpha and N,N-dimethyl positions of compounds of Formula I, or of any other compound or composition of any aspect of the invention. Supports synergy against

Use of liver mitochondrial fractions to model human metabolism of deuterated DMT Given the predicted half-life of DMT in humans (5 min), we have determined the large amount of DMT before it reaches the human liver. Predict that the part will be disassembled. Therefore, alternative non-tissue or organ-specific in vitro assays were sought as more suitable systems for modeling human metabolism of DMT. Analysis of non-tissue or organ-specific human metabolism can be performed in human liver mitochondrial fractions.

The following assays performed on human liver mitochondrial (HLMt) fractions revealed enhanced fold changes between SPL026 and _D2 -deuterated SPL028i compared to those expected in hepatocyte studies. Then predict.

In vitro human mitochondrial fraction-specific clearance of SPL026 (DMT) with/without MAO-A and MAO-B inhibitors
In an in vitro measurement of the intrinsic clearance of SPL026, a selective and irreversible MAO-A inhibitor (100 nM clorgyline) and a MAO-B inhibitor (100 nM deprenyl/selegiline) were administered separately to 0.5 mg/mL human liver mitochondrial fractions. added. The MAO-A substrate serotonin and the MAO-B substrate benzylamine were added as positive controls to confirm the presence of MAO-A and MAO-B and the action of clorgyline and deprenyl inhibitors.

Table 8. Intrinsic clearance and half-life of SPL026 in human liver mitochondrial fraction

The half-life and intrinsic clearance of SPL026 were significantly increased in the presence of an MAO-A inhibitor (clorgyline), resulting in a 10-fold increase in intrinsic clearance compared to data for SPL026 in the absence of MAO inhibitor. rice field. Deprenyl (MAO-B inhibitor) showed no difference in human mitochondrial intrinsic clearance compared to fractions without inhibitor. These results suggest a role for MAO-A (but not MAO-B) in the metabolism of SPL026.

Intrinsic clearance of in vitro human mitochondrial fractions of SPL026 (DMT), SPL028i (96.6% D2 _- DMT), SPL028iii (36.8% D2 _- DMT), SPL028vii (compound 5), and SPL028viii (compound 1) For in vitro measurements, SPL026, SPL028i, SPL028iii and SPL028viii were added separately to 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 to confirm the presence of MAO-A and MAO-B. The experiment was repeated with the same material and also with SPL028ii and SPL028vii.

Table 9. Intrinsic clearance and half-life of SPL026, SPL028i, SPL028ii, SPL028iii, SPL028vii, and SPL028viii in human liver mitochondrial fractions.

Half-life increased with increasing deuteration levels of the SPL028 compound when compared to SPL026. D ₈ -deuterated SPL028viii (compound 1) showed the greatest half-life change (14-fold increase when averaged over both replicates) compared to SPL026. The 96.6% _D2 -deuterated SPL028i also showed a large change in half-life compared to SPL026 (10-fold increase when averaged over both replicates). 36.80% _D2 -deuterated SPL028iii showed a smaller change in clearance (3.6-fold increase) compared to SPL026. An independent Welch t-test was performed for each deuterated compound and compared to SPL026 and the results are shown in Table 10.

Table 10. T-test showing the significance of the half-life extension of SPL028(i-viii)

Conclusion
Complete deuteration of the α-position of N,N-dimethyltryptamine increases metabolic stability ten-fold via first-order kinetic isotope effects in the human mitochondrial fraction assay.
N,N-dimethyldeuteration potentially increases metabolic stability in human hepatocyte assays via second-order kinetic isotope effects.
Most unexpectedly, deuteration primary and secondary isotopic effects at both the α- and N,N-dimethyl positions synergistically increased metabolic stability in compound 1 and in human mitochondrial fraction assays. It showed a 14-fold increase in metabolic stability.

Claims (34)

A deuterated N,N-dimethyltryptamine compound or composition comprising one or more deuterated N,N-dimethyltryptamine compounds for use in therapy, wherein the or each compound comprises N, selected from N-dimethyltryptamine compounds, α,α-dideutero-N,N-dimethyltryptamine compounds, α-prothio,α-deutero-N,N-dimethyltryptamine compounds, and pharmaceutically acceptable salts of these compounds A compound or composition that is A deuterated N,N-dimethyltryptamine compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy:

wherein the deuterium:protium ratio in the compound is greater than that found naturally in hydrogen, and each ^R is independently selected from H and D;
^R2 is selected from _CH3 and _CD3 ;
^R3 is selected from _CH3 and _CD3 ;
Each ^yH is independently selected from H and D. 3. The deuterated N,N-dimethyltryptamine compound of claim 2, wherein each ^R1 is H. 4. The deuterated N,N-dimethyltryptamine compound of claim 2 or 3, wherein both ^yH are D. A deuterated N,N-dimethyltryptamine compound according to any one of claims 2 to 4, wherein both R ² and R ³ are CD ₃ . 6. A deuterated N,N-dimethyltryptamine compound or composition according to any one of claims 1 to 5, wherein the or each compound is in the form of a pharmaceutically acceptable salt. 7. A deuterated N,N-dimethyltryptamine compound or composition according to claim 6, wherein the pharmaceutically acceptable salt is the fumarate salt. A deuterated N,N-dimethyltryptamine compound or composition according to claim 1, wherein the or each compound is selected from compounds 1-5:

9. Any one of claims 1-8, wherein said deuterated N,N-dimethyltryptamine compound has an increased half-life compared to non-deuterated N,N-dimethyltryptamine in a human hepatocyte assay. A deuterated N,N-dimethyltryptamine compound or composition according to . 10. The deuterated N,N-dimethyltryptamine compound of any one of claims 1-9, wherein said deuterated N,N-dimethyltryptamine compound has an increased half-life compared to non-deuterated N,N-dimethyltryptamine in a mitochondrial fraction assay. A deuterated N,N-dimethyltryptamine compound or composition according to . ^The deuterated-N, An N-dimethyltryptamine compound, or a composition comprising said compound. The deuterated N,N-dimethyl of claim 11, wherein R ² and R ³ are CH ₃ and said compound or composition has a molecular weight or average molecular weight of 189.2 to 190.3 grams/mole. A tryptamine compound, or a composition comprising such a compound. 12. The deuterated-N of claim 11, wherein one or both of R ² and R ³ is CD ₃ and said compound or composition has a molecular weight or average molecular weight of 189.2 to 196.3 grams/mole. , N-dimethyltryptamine compounds or compositions comprising such compounds. 14. The deuterated-N of claim 11 or 13, wherein both R ² and R ³ are CD ₃ and the compound or composition has a molecular weight or average molecular weight of 194.3 to 196.3 grams/mole. , N-dimethyltryptamine compounds or compositions comprising such compounds. A deuterated N,N-dimethyltryptamine compound or composition according to any one of claims 1 to 14, in the form of a pharmaceutical formulation (pharmaceutical dosage form, pharmaceutical dosage form). 16. A deuterated N,N-dimethyltryptamine compound or composition according to claim 15, wherein said pharmaceutical formulation is a parenteral formulation. 16. A deuterated N,N-dimethyltryptamine compound or composition according to claim 15, wherein said pharmaceutical formulation is a solid formulation (solid dosage form, solid dosage form). Deuterated N,N-dimethyl according to any one of claims 15 to 17, wherein said pharmaceutical formulation comprises a total of 0.001 mg to 100 mg deuterated N,N-dimethyltryptamine compound or composition. A tryptamine compound or composition. A deuterated N,N-dimethyltryptamine compound or composition according to any one of claims 1-18 for use in a method of treating a psychiatric or neurological disorder in a patient. said psychiatric or neurological disorder is (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) schizophrenic disorder, (iv) schizophrenic disorder, (v) anxiety disorder, (vi) substance abuse 20. The deuterated N,N-dimethyltryptamine compound of claim 19, which is selected from: , (vii) Depression Disorder, and (viii) Brain Injury Disorder. 21. The deuterated N,N-dimethyltryptamine compound of claim 20, wherein said disorder is major depressive disorder. 21. The deuterated N,N-dimethyltryptamine compound of claim 20, wherein said disorder is treatment-resistant depression. A method of synthesizing a deuterated N,N-dimethyltryptamine compound of formula (I) or a pharmaceutically acceptable salt thereof comprising:

comprising reacting a compound of formula (II) with _LiAlH4 and/or _LiAlD4 ,

During the ceremony,
R ¹ is selected from H and D;
^R2 is selected from _CH3 and _CD3 ; and ^R3 is selected from _CH3 and _CD3 ;
Method. A process according to claim 23, wherein a ratio of LiAlH ₄ and/or LiAlD ₄ : compound of formula (II) of 0.8:1 to 2:1 is used. 25. A method according to claim 23 or claim 24, wherein the compound of formula (II) is made by the steps of:
(i) reacting a compound of formula (III) with two or more coupling agents to form an active compound;

and (ii) reacting ^the active compound with an amine having the formula ^R2R3NH or ^R2R3ND , wherein ^R1 , ^{R2 and R3} are as defined in claim 23. ). 26. The method of claim 25, wherein said two or more coupling agents comprise additional coupling agents. 27. The method of claim 26, wherein said two or more coupling agents comprise carbodiimides. the carbodiimide is selected from the group consisting of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.HCl, dicyclohexylcarbodiimide, and diisopropylcarbodiimide; 28. The method of claim 27, wherein 29. The method of claim 28, wherein said carbodiimide is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.HCl. the additional coupling agent is 1-hydroxybenzotriazole, hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, N-hydroxysuccinimide, 1-hydroxy-7-aza-1H- 30. The method of any one of claims 26-29, selected from the group consisting of benzotriazole, ethyl 2-cyano-2-(hydroxyimino)acetate and 4-(N,N-dimethylamino)pyridine. . 31. The method of claim 30, wherein said additional coupling agent is 1-hydroxybenzotriazole. A method according to any one of claims 23-31, which is a method of synthesizing a compound or composition according to any one of claims 1-22. 33. The method of claim 32, wherein the or each deuterated N,N-dimethyltryptamine compound is a pharmaceutically acceptable salt. 34. The method of claim 33, further comprising reacting the compound of formula (I) with an acidic reagent to produce a pharmaceutically acceptable salt of the or each deuterated N,N-dimethyltryptamine compound. Method.

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