CN116056763A

CN116056763A - Therapeutic compositions comprising deuterated or partially deuterated N, N-dimethyltryptamine compounds

Info

Publication number: CN116056763A
Application number: CN202180046463.XA
Authority: CN
Inventors: P·兰德斯; T·本威; Z·乔尔; M·雷泽尔; E·詹姆斯
Original assignee: Smar Pharmaceutical Co ltd
Current assignee: Smar Pharmaceutical Co ltd
Priority date: 2020-06-02
Filing date: 2021-04-23
Publication date: 2023-05-02
Anticipated expiration: 2041-04-23
Also published as: CA3179161A1; AU2021204158A1; AU2021204158B2; KR20230007547A; IL298541A; ES2928395T3; JP7288154B2; JP2023520256A; CA3179161C; KR102589605B1; MX2022014900A; PL3902541T3; CN116056763B; NZ794833A; IL298541B1

Abstract

The present invention provides deuterated N, N-dimethyltryptamine compounds or a plurality of deuterated N, N-dimethyltryptamine compounds selected from the group consisting of N, N-dimethyltryptamine compounds, alpha-protons, alpha-deuterated-N, N-dimethyltryptamine compounds, alpha-dideutero-N, N-dimethyltryptamine compounds, and pharmaceutically acceptable salts of these compounds, preferably wherein the deuterated N, N-dimethyltryptamine compounds have an increased half-life when compared to the half-life of non-deuterated N, N-dimethyltryptamine. In particular, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof; wherein the ratio of deuterium to protium in the compound is greater than the ratio naturally occurring in hydrogen; each R ¹ Independently selected from H and D; r is R ² Selected from CH ₃ And CD (compact disc) ₃ ；R ³ Selected from CH ₃ And CD (compact disc) ₃ The method comprises the steps of carrying out a first treatment on the surface of the And each is provided with ^y H is independently selected from H and D. Also provided are methods of synthesizing the compounds of the invention, as well as methods of using such compositions in the treatment of mental or neurological disorders, such as major depressive disorder.

Description

Therapeutic compositions comprising deuterated or partially deuterated N, N-dimethyltryptamine compounds

Technical Field

The present invention provides deuterated N, N-dimethyltryptamine compounds or a plurality of deuterated N, N-dimethyltryptamine compounds selected from the group consisting of N, N-dimethyltryptamine compounds, alpha-protons, alpha-deuterated-N, N-dimethyltryptamine compounds, alpha-dideutero-N, N-dimethyltryptamine compounds, and pharmaceutically acceptable salts of these compounds, preferably wherein the deuterated N, N-dimethyltryptamine compounds have an increased half-life when compared to the half-life of non-deuterated N, N-dimethyltryptamine.

In particular, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof;

wherein the ratio of deuterium to protium in the compound is greater than the ratio naturally occurring in hydrogen;

each R ¹ Independently selected from H and D;

R ² selected from CH ₃ And CD (compact disc) ₃ ；

R ³ Selected from CH ₃ And CD (compact disc) ₃ The method comprises the steps of carrying out a first treatment on the surface of the And

each of which is ^y H is independently selected from H and D.

Methods of synthesizing the compounds of the invention are also provided, as are methods of using such compositions in the treatment of mental or neurological disorders, such as major depressive disorder.

Background

Classical hallucinogens have shown preclinical and clinical promise in the treatment of psychotic disorders (Carhart-Harris and Goodwin (2017), the Therapeutic Potential of Psychedelic Drugs: past, present and Future, neuropyschopharmacology 42, 2105-2113). In particular, in a randomized, double-blind study, nupharin (psilocybin) has shown significant improvement in a series of depression and anxiety ratings scales (Griffiths et al (2016), psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomised double-blind three, journal of Psychopharmacology (12), 1181-1197).

N, N-Dimethyltryptamine (DMT) is also understood to have therapeutic value as a short-acting hallucinogen, however its duration of action (less than 20 minutes) is too short to limit effective treatment. Dosing regimens have been developed to extend the immersive illusion experience of DMT (Galimore 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 regimens have the risk of toxic accumulation in patients with poor DMT metabolism (see Strassman et al (1994), dose response study of N, N-dimethyltryptamine in humans, arch Gen Psychiatry 51,85 for further discussion).

The α, α, β, β -tetradeutero-N, N-dimethyltryptamine is known to exhibit a kinetic isotope effect, which exhibits a significant difference in its in vivo pharmacokinetic properties compared to N, N-dimethyltryptamine. Known as sp ³ Substitution of deuterium for hydrogen at the carbon center creates a "kinetic isotope effect" due to the bond strength difference between CH and CD bonds. The half-life of α, α, β, β -tetradeutero-N, N-dimethylprimary amine in rodent brain was first demonstrated in 1982 (Barker et al (1982), comparison of the brain levels of N, N-dimethyltryptamine and α, α, α0, α1-tetradeutero-N, N-dimethyltryptamine following intraperitoneal injection, biochemical Pharmacology,31 (15), 2513-2516), suggesting that administration of α, α, β, β -tetradeutero-N, N-dimethylprimary amine alone will maintain the patient in the DMT space for longer than is therapeutically necessary.

Summary of The Invention

The present invention is based in part on the knowledge of the kinetic isotope effects exhibited by the application of α, α, β, β -tetradeutero-N, N-dimethylprimary amines to controllably alter the pharmacokinetic properties of N, N-dimethylprimary amines, thereby allowing for more flexible therapeutic applications. In particular, by providing separate pharmaceutical substance compositions comprising deuterated N, N-dimethyltryptamine analogues, in particular N, N-dimethyltryptamine comprising at least one deuterium atom in the alpha position (i.e. attached to the carbon atom to which the dimethylaminobase is attached), the present invention provides compositions and methods that enable fine tuning of a single dose to maintain complete separation of the patient from the outside world (referred to herein as "DMT space") for a therapeutically optimized duration without clinically relying on infusion protocols or combination therapies with monoamine oxidase inhibitors. The present invention provides a clinically applicable solution that reduces clinical complexity and increases clinical flexibility in administering DMT-assisted therapies.

Furthermore, we have observed a quantifiable relationship between the degree of deuteration (and represented by the H: D ratio of the input reducing agent in the synthetic methods disclosed herein) and the effect on enhancing (i.e., increasing) the metabolic half-life of the parent compound. Such a technical effect may be used to quantitatively enhance the accuracy with which deuterated N, N-dimethyltryptamine compositions (that is, isolated deuterium-containing N, N-dimethyltryptamine compounds or compositions comprising more than one type of compound selected from the group consisting of N, N-dimethyltryptamine and deuterated analogs thereof, particularly those compounds deuterated at the alpha and/or N, N-dimethyl positions, or pharmaceutically acceptable salts of such compounds) may be prepared.

Thus, viewed from a first aspect, the present invention provides a deuterated N, N-dimethyltryptamine compound or a plurality of deuterated N, N-dimethyltryptamine compounds selected from the group consisting of N, N-dimethyltryptamine compounds, alpha-protons, alpha-deuterated-N, N-dimethyltryptamine compounds, alpha-dideutero-N, N-dimethyltryptamine compounds, and pharmaceutically acceptable salts of these compounds for therapeutic use, preferably wherein the deuterated N, N-dimethyltryptamine compound has an increased half-life compared to the half-life of non-deuterated N, N-dimethyltryptamine.

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 therapeutic use:

wherein the ratio of deuterium to protium in the compound is greater than the ratio naturally occurring in hydrogen:

each R ¹ Independently selected from H and D;

R ² selected from CH ₃ And CD (compact disc) ₃ ；

R ³ Selected from CH ₃ And CD (compact disc) ₃ ；

Each of which is ^y H is independently selected from H and D.

In a preferred embodiment of the second aspect, each R ¹ Is H. In a main embodiment of the second aspect, two ^y H is D. In a minor embodiment of the second aspect, R ² And R is ³ Are all CD ₃ 。

Viewed from a third aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is obtainable by a process comprising reacting a compound of formula (II) with LiAlH ₄ And/or LiAlD ₄ The method for synthesizing the catalyst is obtained by a synthetic method of reaction,

wherein R is ¹ Is selected from the group consisting of H and D,

R ² selected from CH ₃ And CD (compact disc) ₃ ；

R ³ Selected from CH ₃ And CD (compact disc) ₃ ；

And each of ^y H is independently selected from H and D.

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

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

Viewed from a sixth aspect the present invention provides a compound or composition as defined according to any one of the first to fifth aspects for use in a method of treatment of a neurological or psychiatric disorder in a patient.

Viewed from a seventh aspect the present invention provides a method of treating a neurological or psychiatric disorder comprising administering to a patient in need thereof a compound or composition as defined according to any one of the first to fourth aspects.

Viewed from an eighth aspect the present invention provides the use of a compound or composition as defined in any one of the first to fourth aspects in the manufacture of a medicament for use in a method of treating a neurological or psychiatric disorder in a patient.

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

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

Other aspects and embodiments of the invention will be apparent from the discussion that follows.

Brief Description of Drawings

Fig. 1 depicts predicted pharmacokinetic properties of partially deuterated DMT as compared to non-deuterated DMT and fully deuterated DMT. Predicted a) plasma concentration and B) brain tissue concentration, show an increase in half-life of the partially deuterated DMT. The shaded area depicts the concentration of effector sites (> 60 ng/mL) that undergo complete separation from the outside world (referred to as the "DMT space").

Figure 2 plots calculated in vitro half-lives of DMT and 6 deuterium containing compositions described in example 1. A) Linear regression analysis. The half-life r2 value is 0.754; where the slope was found to be significantly different from zero, p=0.01. B) The half-life of deuterated analogs varies as a percentage relative to (non-deuterated) DMT (dashed line).

FIG. 3 is an implementationIn vitro intrinsic clearance of DMT and 6 deuterium containing compositions described in example 1. A) Linear regression analysis. R of intrinsic clearance ² The value is 0.7648; where the slope was found to be significantly different from zero, p=0.01. B) The intrinsic clearance of deuterated analogs varies as a percentage relative to (non-deuterated) DMT (dashed line).

FIG. 4DMT (SPL 026) and 6 different D ₂ In vitro intrinsic clearance (A) and half-life (B) of deuterated SPL028 analog blends in human hepatocytes in the presence and absence of MAO-A/B inhibitor combinations as described in the examples section below.

Detailed Description

Throughout the specification, one or more aspects of the invention may be combined with one or more features described in the specification to define different embodiments of the invention.

Unless the context implies otherwise, references herein to singular nouns encompass plural nouns and vice versa.

Throughout this specification, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

The present invention provides deuterated N, N-dimethyltryptamine compounds selected from the group consisting of N, N-dimethyltryptamine compounds, alpha-protons, alpha-deuterated-N, N-dimethyltryptamine compounds, alpha-dideutero-N, N-dimethyltryptamine compounds, and pharmaceutically acceptable salts of these compounds.

As used herein, the term deuterated N, N-dimethyltryptamine compound means an N, N-dimethyltryptamine compound having a deuterium composition that is greater than that naturally occurring in hydrogen (about 1.6%). The term non-deuterated N, N-dimethyltryptamine compound as used herein means an N, N-dimethyltryptamine compound having a composition equal to or less than the deuterium naturally occurring in hydrogen.

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

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

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

Protium atoms (H) are hydrogen atoms with zero neutrons. Deuterium atoms (D) are hydrogen atoms with one neutron.

The inventors have found that the compounds of the present invention exhibit a first order kinetic isotope effect when one or two deuterium atoms are located on the alpha carbon of an N, N-dimethyltryptamine compound. The α, α -dideutero-N, N-dimethyltryptamine compound exhibits its greatest degree of this first order kinetic isotope effect, while the α -proton, α -deutero-N, N-dimethyltryptamine compound exhibits a lesser degree of this first order kinetic isotope effect, such that the fold change in half-life of the α -proton, α -deutero-N, N-dimethyltryptamine compound is about half the half-life of the analogous α, α -dideutero-N, N-dimethyltryptamine compound compared to the analogous N, N-dimethyltryptamine compound.

A composition comprising a mixture of two or more compounds selected from the group consisting of N, N-dimethyltryptamine, α -dideutero-N, N-dimethyltryptamine compounds and α -protons, α -deutero-N, N-dimethyltryptamine compounds may be used to apply the therapeutic benefit of the primary kinetic isotope effect to a variable extent.

Accordingly, the present invention provides a composition comprising two or more compounds selected from the group consisting of N, N-dimethyltryptamine compounds, α -dideutero-N, N-dimethyltryptamine compounds, and α -proton, α -deutero-N, N-dimethyltryptamine compounds.

The inventors have also found that the compounds of the invention exhibit a secondary kinetic isotope effect when N, N-dimethyl is deuterated. When such N, N-dimethyl groups contain one or more deuterium and the a position is also mono-or di-deuterated, the secondary kinetic isotope cooperates with the primary kinetic isotope effect to produce a half-life increase greater than 14-fold compared to non-deuterated N, N-dimethylprimary amine (see example 3).

N, N-dimethyltryptamine and all its deuterated analogs are free to form addition salts with anionic counterions. Throughout the specification, N-dimethyltryptamine compounds (in particular N, N-dimethyltryptamine, α -dideutero-N, N-dimethyltryptamine compounds and α -protons, α -deutero-N, N-dimethyltryptamine compounds) are likewise meant to be any pharmaceutically acceptable salt, such as fumarate.

In general, acidic reagents can be used to prepare salts, particularly pharmaceutically acceptable salts, of N, N-dimethyltryptamine compounds. Examples of suitable acidic reagents are selected from 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. Typically, when in salt form, the N, N-dimethyltryptamine compound used in the compositions of the present invention or otherwise in accordance with aspects of the present invention and embodiments thereof (particularly as a compound of the present invention) is a fumarate, hydrochloride, tartrate or citrate salt, particularly a fumarate salt.

Thus, the compounds of the first aspect of the invention and the compounds of the second and third (and, as the case may be) aspects of the invention may be present in free base or salt form (such as a salt as described herein), optionally as a solvate (e.g. hydrate) thereof.

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

Thus, it will be appreciated from the foregoing that, in particular, those embodiments discussed in the following eight paragraphs, the composition comprises from 2% to 90%, from 2% to 95%, from 2% to 96%, from 2% to 97%, from 2% to 98%, for example from 5% to 90%, from 5% to 95%, from 5% to 96%, from 5% to 97%, from 5% to 98% by weight; 10% to 90%, 10% to 95%, 10% to 96%, 10% to 97%, 10% to 98%;15% to 90%, 15% to 95%, 15% to 96%, 15% to 97%, 15% to 98%;20% to 90%, 20% to 95%, 20% to 96%, 20% to 97%, 20% to 98%;25% to 90%, 25% to 95%, 25% to 96%, 25% to 97%, 25% to 98%;30% to 90%, 30% to 95%, 30% to 96%, 30% to 97%, 30% to 98%;50% to 90%, 50% to 95%, 50% to 96%, 50% to 97%, 50% to 98%;60% to 90%, 60% to 95%, 60% to 96%, 60% to 97%, 60% to 98%; or 75% to 90%, 75% to 95%, 75% to 96%, 75% to 97%, 75% to 98%, 75% to 99%, 90% to 99.9%, 99% to 99.9% of one or more deuterated N, N-dimethyltryptamine compounds.

It will be appreciated that wherever the composition comprises 2 wt% or more of one or more deuterated N, N-dimethyltryptamine compounds, such a composition may comprise up to 95 wt% of one or more deuterated N, N-dimethyltryptamine compounds, or up to 96 wt%, up to 97 wt% or up to 98 wt% of one or more deuterated N, N-dimethyltryptamine compounds.

In a preferred embodiment, the one or more partially deuterated N, N-dimethyltryptamine compounds comprise up to 50 wt.% of the total composition.

According to other preferred embodiments of the first aspect of the present invention, the composition comprises up to 50 wt%, based on the total weight of the composition, of one or more compounds selected from the group consisting of α, α -dideutero-N, N-dimethyltryptamine compounds, α -protons, α -deutero-N, N-dimethyltryptamine compounds and pharmaceutically acceptable salts thereof. It will be appreciated that in such embodiments, such compositions may comprise 2% or more, e.g., 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, or 30% or more of the one or more compounds, by weight of the total composition.

According to specific embodiments, the compositions of the present invention, including all embodiments described herein, including but not limited to those comprising N, N-dimethylprimary amine, consist essentially of one or more compounds selected from the group consisting of N, N-dimethylprimary amine and deuterated analogs thereof, particularly those compounds deuterated at the alpha position, or pharmaceutically acceptable salts of such compounds. A composition consisting essentially of one or more compounds selected from the group consisting of N, N-dimethyltryptamine and deuterated analogs thereof means that the composition may comprise additional components (in addition to the N, N-dimethyltryptamine compound) but the presence of these additional components does not substantially affect the essential characteristics of the composition. In particular, a composition consisting essentially of an N, N-dimethyltryptamine compound will not contain substantial amounts of other pharmaceutical active substances (i.e. substantial amounts of other pharmaceutical substances).

The composition of the present invention may comprise 2 to 98 wt% of N, N-dimethylprimary amine, and preferably comprises 5 to 95 wt% of N, N-dimethylprimary amine. Preferred compositions of the present invention comprise 10 to 90 wt% of N, N-dimethylprimary amine, or 15 to 85 wt% of N, N-dimethylprimary amine, or 20 to 80 wt% of N, N-dimethylprimary amine, or 25 to 75 wt% of N, N-dimethylprimary amine, or 30 to 70 wt% of N, N-dimethylprimary amine, or 40 to 60 wt% of N, N-dimethylprimary amine.

The composition of the present invention preferably comprises 5 to 99.9 wt% of a deuterated N, N-dimethyltryptamine compound selected from the group consisting of α, α -dideutero-N, N-dimethyltryptamine and α, α, β, β -tetradeutero-N, N-dimethyltryptamine.

Aspects of the present invention provide compositions obtainable by reducing 2- (3-indolyl) -N, N-dimethylacetamide with a reducing agent consisting essentially of lithium aluminum hydride and/or lithium aluminum deuteride. In both aspects, the reducing agent may be dissolved or suspended in the liquid medium. Typically, lithium aluminum hydride (or lithium aluminum deuteride), although available in solid (powder) form, is typically operated under an inert atmosphere, typically in a dry aprotic solvent such as an ether, due to the strong reactivity with water and a protective solvent such as an alcohol. The skilled person is familiar with such precautions and appropriate protocols.

It will be appreciated that the present invention thus provides a composition obtainable by reducing a composition comprising 2- (3-indolyl) -N, N-dimethylacetamide with a reducing agent consisting essentially of lithium aluminum hydride and/or lithium aluminum deuteride, optionally dissolved or suspended in a liquid medium. The present invention also provides a composition obtainable by such reduction, or more generally, by reduction according to the second or third aspect of the invention.

It will also be appreciated that the amounts of N, N-dimethyltryptamine compounds described herein with specific reference to the composition of the first aspect of the present invention may be applied mutatis mutandis to the compositions of the second and third aspects of the present invention.

According to a specific embodiment, by stating that the reducing agent consists essentially of lithium aluminum hydride and/or lithium aluminum deuteride, it is meant that the reducing agent may comprise additional components, but that the presence of these components does not substantially affect the essential characteristics of the reducing agent (in particular stability and reduction propensity).

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

The pharmaceutical composition of the invention comprises the composition of the invention (according to any of the first to third aspects of the invention) in combination with one or more pharmaceutically acceptable excipients. Suitable pharmaceutical compositions may be prepared by the skilled artisan, with examples of pharmaceutically acceptable excipients including, but not limited to, those described in Gennaro et al, remmington, the Science and Practice of Pharmacy, 20 th edition, lippincott, williams and Wilkins,2000 (specifically section 5: pharmaceutical manufacturing). Suitable excipients are also described in Handbook of Pharmaceutical Excipients, 2 nd edition; wade and P.J.Weller, eds. American Pharmaceutical Association, washington, the Pharmaceutical Press, london, 1994.

The 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 may be compressed or otherwise formulated into solid dosage units such as tablets, capsules, orally disintegrating tablets, films, buccal tablets and buccal tablets, or processed into capsules or suppositories. When formulated as orally disintegrating tablets, the compounds or compositions of the invention are combined with

The platforms are compatible. />

Tablets are prepared by lyophilizing or freeze-drying the free base compound or composition of the invention in a matrix. The resulting product is very light weight. Such embodiments of the formulation comprise particles of the compound or composition of the invention physically suspended in a water-soluble matrix (which is then lyophilized), preferably having a particle size of less than 50 μm. Orally disintegrating tablets formulated in this manner dissolve rapidly upon placement in the mouth.

The compounds may also be prepared in the form of solutions, suspensions, emulsions or sprays with the aid of pharmaceutically suitable liquids. For the preparation of dosage units, including tablets, it is contemplated to use conventional additives such as fillers, colorants, polymeric binders, and the like. Generally, any pharmaceutically acceptable additive may be used.

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

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

Accordingly, aspects of the present invention provide parenteral formulations comprising one or more free bases of deuterated N, N-dimethyltryptamine compounds selected from the group consisting of N, N-dimethyltryptamine compounds, α -dideutero-N, N-dimethyltryptamine compounds, α -protons, α -deuterated-N, N-dimethyltryptamine compounds, and biocompatible excipients. In a preferred embodiment, the deuterated N, N-dimethyltryptamine compound is a compound of formula I wherein the ratio of deuterium to protium in the compound is greater than the ratio naturally occurring in hydrogen; each R ¹ Independently selected from H and D; r is R ² Selected from CH ₃ And CD (compact disc) ₃ ；R ³ Selected from CH ₃ And CD (compact disc) ₃ The method comprises the steps of carrying out a first treatment on the surface of the And each of ^y H is independently selected from H and D.

Typically, the biocompatible excipient comprises a solvent. Preferably, the solvent is selected from any one or a combination of two or more of propylene glycol, glycerol, polyethylene glycol, water, ethanol and triacetin. For preferred inhalable formulations, the solvent is selected from propylene glycol, glycerin and polyethylene glycol, or mixtures 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 concentration of the free base is from about 1mg/mL to about 1000mg/mL. Preferably, the biocompatible excipient comprises a taste masking agent.

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

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

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

According to a sixth aspect of the present invention there is provided a composition as defined according to any one of the first to fourth aspects for use in a method of treating a psychotic disorder or neurological disorder in a patient. A seventh aspect of the present invention provides a method of treating a psychotic or neurological disorder, comprising administering to a patient in need thereof a composition as defined according to any of the first to fourth aspects, and an eighth aspect provides the use of a composition as defined according to any of the first to fourth aspects in the manufacture of a medicament for use in a method of treating a psychotic or neurological disorder in a patient. In an embodiment of the sixth to eighth aspects of the invention, the mental or neurological disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) schizophrenic disorder, (iv) schizophrenic disorder, (v) anxiety disorder, (vi) substance abuse, (vii) motivational disorder, and (viii) brain injury disorder.

The term "mental disorder" as used herein is a clinically significant behavioral or psychological syndrome or pattern that occurs in an individual and is associated with current distress (e.g., pain symptoms) or disability (i.e., damage in one or more important areas of function) or with a significantly increased risk of suffering from death, pain, disability, or significant loss of freedom.

The term "neurological disorder" as used herein means a disease of the central and peripheral nervous system.

Diagnostic criteria for mental and neurological disorders mentioned herein are provided, for example, in Diagnostic and Statistical Manual of Mental Disorders, fifth edition, (DSM-5), the contents of which are incorporated herein by reference.

The term "obsessive-compulsive disorder (obsessive-compulsive disorder)" as used herein is defined as the presence of compulsive thinking (obsessions) or compulsive behavior (compusions), but generally both. These symptoms can lead to significant functional impairment and/or distress. Forced thinking is defined as unwanted invasive thinking, images or impulses that repeatedly enter the human brain. Compulsive behavior is repetitive or psychological behavior that a person feels is driven to perform. In general, obsessive-compulsive disorder (OCD) is manifested as one or more compulsive thoughts that drive the taking of compulsive actions. For example, forced thinking about pathogens may drive the cleaning of forced behavior. The compulsive behavior may be noticeable and observable by others, such as checking that the door is locked, or hidden psychological behavior that cannot be observed, such as repeating a phrase in the brain of a person.

The term "depressive disorder" as used herein includes major depressive disorder, persistent depressive disorder, bipolar depression, and depression in an end patient (terminally ill patient).

The term "major depressive disorder" (MDD, also referred to as major depression or clinical depression) as used herein is defined as five or more of the following symptoms (also referred to herein as "major depressive episodes") occurring almost daily for a period of two weeks or more, most of the time of the day:

depressed mood, such as sadness, empty or tearing (in children and young teenagers, depressed mood may appear as persistent irritability);

interest in all or most activities is significantly reduced or no pleasure is felt;

significant weight loss, weight gain, or loss or gain in appetite when not eating (in children, weight gain as expected is not expected);

insomnia or increase in sleep desire;

agitation or slow behavior that others can observe;

fatigue or energy loss;

non-valuable feeling, or excessive or improper guilt;

making decisions difficult, or thinking or focusing attention difficult;

repeat thinking of death or suicide, or attempt to suicide.

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

Persistent depressive disorder, also known as dysthymia, is defined as a patient exhibiting two characteristics:

A. there is a depressed mood for at least two years almost most of the time every day. Children and adolescents may have a irritable mood and a time frame of at least one year.

B. When depressed, humans experience at least two of the following symptoms:

overeating or lack of appetite.

Hypersomnia or difficulty sleeping.

Fatigue, lack of energy.

Self-esteem difference.

It is difficult to focus on or make decisions.

The term "refractory depression" as used herein describes MDD that fails to achieve an appropriate response with appropriate treatment with standard of care therapy.

As used herein, a 'bipolar disorder', also referred to as mania-depression, is a disorder that results in abnormal changes in mood, energy, activity level, and ability to perform daily tasks.

There are two sub-categories of defined bipolar disorders; they all involve significant changes in emotion, energy and activity levels. These emotions range from extremely "excited (up)", excited and energetic behaviors (called manic episodes, and defined further below) to very sad, "depressed" or destinated periods (called depressive episodes). The less severe manic phase is called hypomanic episode.

Bipolar I disorder-defined as a manic episode lasting at least 7 days, or as a manic symptom severe enough to require immediate hospitalization in a human. Typically, depressive episodes also occur, typically lasting at least 2 weeks. Depressive episodes with mixed features (both depressive and manic symptoms) are also possible.

Bipolar II disorder-defined as the pattern of depressive and hypomanic episodes, but not the overall manic episodes described above.

As used herein, "bipolar depression" is defined as an individual experiencing symptoms of depression with prior or concurrent episodes of manic symptoms, but not meeting clinical criteria for bipolar disorder.

The term "anxiety disorder" as used herein includes generalized anxiety disorder, phobia, panic disorder, social anxiety disorder, and post traumatic stress disorder.

As used herein, "generalized anxiety disorder" (GAD) means a chronic disorder characterized by long-term anxiety that is not focused on any one subject or condition. Those with GAD experience non-specific persistent fear and concern and become overly concerned about daily transactions. GAD is characterized by chronic excessive anxiety with three or more of the following symptoms: agitation, fatigue, concentration problems, irritability, muscle tension and sleep disturbances.

"phobia" is defined as the persistent fear of a subject or condition that an affected person will struggle to avoid, often disproportionate to the actual risk posed. If the fear of the subject or condition is not completely avoided, the affected person will suffer from significant pain and significant disturbance to social or professional activity.

Patients suffering from "panic disorder" are defined as patients experiencing one or more brief episodes of intense phobia and anxiety (also known as panic attacks), often characterized by tremors, jolts, confusion, dizziness, nausea, and/or dyspnea. Panic attacks are defined as fear or discomfort that suddenly appears and peaks in less than ten minutes.

"social anxiety disorder" is defined as intense fear and avoidance of negative public inspection, public embarrassment, shame or social interaction. Social anxiety is often manifested as specific physical symptoms including flushing, sweating, and difficulty speaking.

"post traumatic stress disorder" (PTSD) is an anxiety disorder caused by traumatic experience. Post-traumatic stress can be caused by extreme conditions such as combat, natural disasters, rape, altered personality conditions (hostage situation), abuse of children, spoofing, or even serious accidents. Common symptoms include excessive vigilance, flashback, avoidance behavior, anxiety, anger, and depression.

The term "substance abuse" as used herein means the patterned use of drugs in which a user consumes these substances in amounts or methods that are harmful to themselves or to others.

The term "motivational deficit disorder (avolition disorder)" as used herein refers to a disorder that includes reduced motivation as a symptom to initiate and conduct a self-directed purposeful activity.

The term "brain injury disorder" as used herein refers to brain injury that occurs after birth and is not congenital, degenerative, or genetic. The term includes traumatic brain injury, e.g., from a car accident or sports injury, as well as acquired brain injury, such as ischemic stroke, transient ischemic stroke, hemorrhagic stroke, brain tumor, meningitis, or encephalitis.

In a preferred embodiment of the sixth to eighth aspects of the invention, the mental or neurological disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse, (v) motivational deficit disorder, and (vi) brain injury disorder.

According to a specific embodiment of the sixth to eighth aspects of the invention, the depressive disorder is major depressive disorder. According to yet a more specific embodiment, the major depressive disorder is a refractory major depressive disorder.

The composition comprising the deuterated N, N-dimethyltryptamine compound of the present invention may be synthesized on a gram scale up to a thousands of gram scale according to the reaction scheme (synthesis scheme) provided in scheme 1.

The relative proportions of the N, N-dimethyltryptamine compound to the deuterated N, N-dimethyltryptamine compound and the partially deuterated N, N-dimethyltryptamine compound can be controlled by varying the ratio of lithium aluminum hydride to lithium aluminum deuteride in the reducing agent. The relative proportions may be further altered by adding one or more of N, N-dimethylprimary amine, α -dideutero-N, N-dimethylprimary amine, and α, α, β, β -tetradeutero-N, N-dimethylprimary amine to the composition described above.

A particular advantage of the present invention, in particular but not limited to the compositions obtainable according to the third aspect thereof and the method of the ninth aspect thereof, is that the reduction described according to these aspects of the invention allows a particularly high purity to be obtained without the need for subsequent chromatographic purification (e.g. column chromatography), thereby increasing the efficiency with which the composition of the invention can be prepared. Furthermore, the ability to avoid the use of chromatography in order to obtain high purity makes scale-up more efficient and thus cost-effective.

If desired, confirmation of the composition obtained by the method of the invention can be achieved by chromatographic separation of the components of the mixture in combination with spectroscopic and/or mass spectrometry analysis by conventional means used by the skilled person.

Alternative compositions may be obtained by mixing non-deuterated N, N-dimethyltryptamine (obtainable from scheme 1 when the reducing agent is only lithium aluminum hydride) with deuterated N, N-dimethyltryptamine compounds (obtainable from scheme 1 when the reducing agent is only lithium aluminum deuteride).

The compositions described above may be further improved by the addition of one or more deuterated N, N-dimethyltryptamine compounds. Such a stock solution of deuterated N, N-dimethyltryptamine compounds may for example be obtained from the chromatographic separation described above. For example, the compound of the tenth aspect of the present invention may be obtained in this manner.

While confirmation of the composition resulting from the reduction described herein may be achieved by chromatographic separation of the components of the mixture in combination with spectroscopy and/or mass spectrometry analysis, a particular benefit of the present invention is that this may not be necessary depending on the particular embodiment. This is because, in addition to the purity achievable according to the invention, we have as mentioned above realized that there is a quantifiable relationship between the degree of deuteration (or in other words the amount or proportion of deuterium in the N, N-dimethyltryptamine compound in the composition of the invention) and the metabolic half-life of the resulting composition. The degree of deuteration may be controlled by the amount of deuterium-containing reducing agent used in the methods of the present invention by which (according to specific embodiments) the compositions of the present invention may be obtained and thus the enhancement of the metabolic half-life of the parent compound (non-deuterated N, N-dimethyltryptamine) is controlled in a predictable manner.

In particular, as detailed in example 1 and related figures 2 and 3, the inventors have demonstrated that increasing deuterium enrichment at the α -carbon of N, N-dimethylprimary amine increases metabolic stability, resulting in reduced clearance and longer half-life, where there is a linear relationship between molecular weight and half-life between 188.3 and 190.3 g/mole, and between 188.3 and 196.3 g/mole, synergistic primary and secondary kinetic isotope effects are where R ¹ Compounds and compositions of formula I that are H provide a predictable relationship between molecular weight and half-life.

Compositions of this type constitute a particular embodiment of the first aspect of the invention. According to these embodiments, the composition consists essentially of two or three compounds selected from the group consisting of N, N-dimethylprimary amine, α -proton, α -deuterated-N, N-dimethylprimary amine and α, α -dideutero-N, N-dimethylprimary amine, the composition optionally being in the form of a pharmaceutically acceptable salt, wherein the average molecular weight of the N, N-dimethylprimary amine, α -proton, α -deuterated-N, N-dimethylprimary amine and α, α -dideutero-N, N-dimethylprimary amine present in the composition is 188.28 to 190.28.

According to a further specific aspect, the composition consists essentially of one, two or three compounds selected from the group consisting of N, N-bis (tridentate) dimethylprimary amine (compound 5), α -proton, α -deutero-N, N-bis (tridentate) dimethylprimary amine (compound 2) and α, α -dideutero-N, N-bis (tridentate) dimethylprimary amine (compound 1), optionally in the form of a pharmaceutically acceptable salt, wherein the molecular weight or average molecular weight of the N, N-bis (tridentate) dimethylprimary amine, α -proton, α -deutero-N, N-bis (tridentate) dimethylprimary amine and α, α -dideutero-N, N-bis (tridentate) dimethylprimary amine present in the composition is 188.9 to 196.3. In a preferred embodiment of this aspect, the composition consists essentially of one compound selected from the group consisting of N, N-bis (tridentate) dimethylprimary amine (compound 5), preferably α -proton, α -deutero-N, N-bis (tridentate) dimethylprimary amine (compound 2) and more preferably α, α -dideutero-N, N-bis (tridentate) dimethylprimary amine (compound 1), in order to increase metabolic stability.

As used herein, average molecular weight means a weighted average of the molecular weights of the N, N-dimethyltryptamine compound, the α -proton, the α -deutero-N, N-dimethyltryptamine compound and the α, α -dideutero-N, N-dimethyltryptamine compound, as measured by a suitable mass spectrometry technique (e.g., LC-MS SIM (selective ion monitoring)), omitting any weight contribution by forming a pharmaceutically acceptable salt, where applicable.

It will be appreciated by those skilled in the art from the teachings herein that compositions having such specific average molecular weights can be obtained by adjusting the relative proportions of lithium aluminum hydride to lithium aluminum deuteride used in stage 2, particularly when changing the deuteration level at the α -position, and by adjusting the relative proportions of dimethylamine to deuterated dimethylamine used in stage 1 when changing the deuteration level at the N, N-dimethyl position.

In this context, by stating that the composition consists essentially of N, N-dimethylprimary amine and an α -proton, α -deuterated-N, N-dimethylprimary amine and a mixture of one or both of α, α -dideutero-N, N-dimethylprimary amine, it is meant that the composition may comprise additional components other than these, but the presence of such additional components does not substantially affect the essential characteristics of the composition. In particular, the composition will not contain substantial amounts of other pharmaceutically active compounds, including other N, N-dimethyltryptamine compounds. Thus, there are no substantial amounts of other deuterated N, N-dimethyltryptamine compounds, in particular β -proton, β -deuterated-N, N-dimethyltryptamine compounds and β, β -dideutero-N, N-dimethyltryptamine compounds, such as β -proton, β -deuterated-N, N-dimethyltryptamine and β, β -dideutero-N, N-dimethyltryptamine compounds, and β -proton, β -deuterated-N, N-dimethyltryptamine compounds having one or two deuterium atoms in the α position instead of a hydrogen atom, respectively.

In other words, and alternatively, the composition according to one particular embodiment constitutes a pharmaceutical substance comprising a bioactive ingredient consisting essentially of one or more of N, N-dimethylprimary amine, alpha-proton, alpha-deuterated-N, N-dimethylprimary amine and alpha, alpha-dideutero-N, N-dimethylprimary amine, wherein the bioactive ingredient has an average molecular weight of 188.3 to 190.3, and wherein the compound contained in the pharmaceutical substance is optionally in the form of a pharmaceutically acceptable salt. The composition according to the second specific embodiment constitutes a bioactive ingredient consisting essentially of one or more of N, N-bis (tridentate) dimethylprimary amine (compound 5), α -proton, α -deuterated-N, N-bis (tridentate) dimethylprimary amine (compound 2) and α, α -dideutero-N, N-bis (tridentate) dimethylprimary amine (compound 1), wherein the bioactive ingredient has an average molecular weight of 188.9 to 196.3, and wherein the pharmaceutical substance is optionally in the form of a pharmaceutically acceptable salt.

It will be appreciated that compositions according to these embodiments comprise one or more of an α -proton, α -deuterated-N, N-dimethyltryptamine compound and an α, α -dideutero-N, N-dimethyltryptamine compound in an amount greater than that present in isotopically unaccumulated N, N-dimethyltryptamine. It is also understood that in these embodiments, the greater the ratio of alpha-proton, alpha-deuterated-N, N-dimethyltryptamine compound to alpha, alpha-dideutero-N, N-dimethyltryptamine compound, the higher the average molecular weight of the composition.

According to a more specific embodiment, the N, N-dimethylprimary amine, the α -proton, the α -deutero-N, N-dimethylprimary amine and the α, α -dideutero-N, N-dimethylprimary amine present in the composition have an average molecular weight of from 188.9 to 189.7, such as from 188.90 to 189.70.

According to still more specific embodiments of the specific embodiments described herein, including compositions wherein the average molecular weight of N, N-dimethylprimary amine, α -proton, α -deuterated-N, N-dimethylprimary amine and α, α -dideutero-N, N-dimethylprimary amine present in the composition is 188.9 to 189.7, the compounds included in the composition are optionally in the form of pharmaceutically acceptable salts, whereby it is understood that the N, N-dimethylprimary amine, α -proton, α -deuterated-N, N-dimethylprimary amine and α, α -dideutero-N, N-dimethylprimary amine present in the composition are present in the form of pharmaceutically acceptable salts. Such salts may be as described elsewhere herein, and according to yet more particular embodiments, the composition is in the form of a fumarate salt.

The methods by which the compounds of formula I can be prepared are described below and are suitable for preparing the compounds of formula I in high purity. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, has an HPLC purity of 99% to 100%, such as 99.5% to 100%. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, has an HPLC purity of 99.9% to 100%, such as 99.95% to 100%.

In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, produces two or fewer HPLC impurity peaks. In some embodiments, where the compound of formula I, or a pharmaceutically acceptable salt thereof, produces an HPLC impurity peak, the impurity peak is not greater than 0.2%. In some embodiments, the HPLC impurity peak is not greater than 0.1%.

In some embodiments, the compound of formula I is in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts generally comprise the compound of formula I and a suitable acid. The compounds of formula I are generally represented by the formula-N (R ² R ³ ) ₂ Is protonated to form- [ NHR ] ² R ³ ] ⁺ And the resulting positive charge is counterbalanced with an anion.

A review of pharmaceutically acceptable salts and acids contained therein is provided in P.H.Stahl and C.G.Wermuth in Handbook of Pharmaceutical Salts:Properties, selection and Use, weinheim/Zulrich:Wiley-VCH/VHCA, 2002. The acids described in this review are suitable components for the pharmaceutically acceptable salts of formula I.

In some embodiments, the acid is any one selected from the group consisting of: fumaric acid, tartaric acid, citric acid, hydrochloric acid, acetic acid, lactic acid, gluconic acid, 1-hydroxy-2-naphthoic acid, 2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutarate, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, 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, palmitic acid, pamoic acid, phosphoric acid, propionic acid, glutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanic acid, toluenesulfonic acid, and undecylenic acid.

Generally, 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 the fumarate salt.

Also disclosed herein are synthetic methods for preparing the compounds of formula I or pharmaceutically acceptable salts thereof. The method comprises a stage 2 and optionally a stage 1, wherein stage 1 comprises:

(i) Reacting a compound of formula III with two or more coupling agents to produce an activated compound;

(ii) Contacting an activating compound with a compound having the formula (R ² ) ₂ Amine reaction of NH to produce a compound of formula II;

and wherein stage 2 comprises reacting the compound of formula II with LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ The reaction is carried out,

wherein:

each R ¹ Independently selected from H and D;

R ² selected from CH ₃ And CD (compact disc) ₃ ；

R ³ Selected from CH ₃ And CD (compact disc) ₃ ；

Each of which is ^y H is independently selected from H and D.

For the avoidance of doubt, embodiments relating to the compound of formula I or a pharmaceutically acceptable salt thereof of the first aspect of the invention are also applicable mutatis mutandis to compounds of formula I (and hence compounds of formulae III and II) of the synthetic process.

The synthetic method avoids the use of problematic oxalyl chloride and employs a compound of formula III, which may be derived from an auxin derivative. High quality and purity auxins of formula III are commercially available on a large scale and/or can be readily synthesized via Fischer (Fischer) synthesis, bartoli synthesis, japp-Klingemann synthesis or Larock synthesis (see, e.g., M.B. Smith and J.March,2020,March's Advanced Organic Chemistry, 8 th edition, wiley, new Jersey). The process is efficient, scalable, compatible with current good manufacturing practice (Current Good Manufacturing Practices) (cGMP), and suitable for preparing compounds of formula I in high purity. For example, the process is suitable for preparing compounds of formula I on a batch scale ranging from 1g to 100kg, and for preparing compounds of formula I having a purity of >99.9% and a total yield of 65% or more.

The compound of formula II is prepared as follows: reacting a compound of formula III with two or more coupling agents to produce an activated compound, and reacting the activated compound with a compound of formula R ² R ³ Amine reaction of NH. Without wishing to be bound by theory, it is understood that the nitrogen atom of the amine is bound to the carbon atom of the carbonyl group of formula III, resulting in the formation of the compound of formula II. For the avoidance of doubt, R of formulae II and I ² And R is ³ R groups derived from amines ² And R is ³ A group. Thus, as described above, R of formulas II and I ² And R is ³ Independently selected from CH ₃ And CD (compact disc) ₃ 。

Compounds of formula I are prepared by reacting a compound of formula II with LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ And reacting to prepare the catalyst. Without wishing to be bound by theory, it is understood that the light source is composed of LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ The provided hydrogen or deuterium ions bind to the carbon atom of the carbonyl group of formula II, resulting in the formation of the compound of formula I. For the avoidance of doubt, formula I ^x The H groups being derived from LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ The provided hydrogen ions or deuterium ions.

As described above, the method includes stage 1 and stage 2. Stage 1 comprises:

(i) Reacting a compound of formula III with two or more coupling agents to produce an activated compound; and

(ii) Allowing the activating compound to have the formula R ² R ³ The amine of NH reacts to produce a compound of formula II.

The term "coupling agent" refers to an agent that facilitates a chemical reaction between an amine and a carboxylic acid. The two or more coupling agents may comprise carboxylic acid activators, i.e., agents that react with the carboxylic acid moiety of formula III to produce a compound comprising an activated moiety derived from the original carboxylic acid moiety that is more likely to react with an amine than the original carboxylic acid moiety.

The activating compound is the product of the reaction between a compound of formula III and the two or more coupling agents. In the case where the two or more coupling agents comprise carboxylic acid activators, the activating compound comprises an activating moiety derived from the original carboxylic acid moiety of formula III, which is more likely to react with the amine than the original carboxylic acid moiety.

The two or more coupling agents may comprise a carboxylic acid activator. The two or more coupling agents may comprise additive coupling agents (additive coupling agent).

Additive coupling agents (also referred to herein as "additives") are agents that enhance the reactivity of the coupling agent. The additive may be a compound capable of reacting with the reaction product of formula III and a coupling agent (the product being a compound comprising an activating moiety) to produce a compound comprising even more activating moieties that are more likely to react with the amine than the original activating moiety.

The additive is capable of reacting with the reaction product of formula III and the coupling agent (the product being a compound comprising an activating moiety) to produce an activated compound comprising an even more activating moiety that is more likely to react with the amine than the original activating moiety.

Typically, the two or more coupling agents comprise a carboxylic acid activator and an additive coupling agent.

At least one of the two or more coupling agents may be selected from the group consisting of: carbodiimide coupling agents, phosphonium coupling agents, and 3- (diethoxy-phosphoryloxy) -1,2, 3-benzo [ d ] triazin-4 (3H) -one (DEPBT), such as carbodiimide coupling agents or phosphonium coupling agents. At least one of the two or more coupling agents may be a carbodiimide coupling agent.

Carbodiimide coupling agents are coupling agents comprising carbodiimide groups R '-n=c=n-R ", wherein R' and R" are hydrocarbyl groups optionally substituted with heteroatoms (typically nitrogen) selected from nitrogen, sulfur and oxygen. Typically, R 'and R' are independently selected from C ₁ -C ₆ Alkyl, C ₅ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkylamino and morpholino C ₁ -C ₆ An alkyl group. In general, C ₁ -C ₆ Alkyl is C ₃ Alkyl, C ₅ -C ₆ Cycloalkyl is cyclohexyl, C ₁ -C ₆ Alkylamino is dimethylaminopropyl, and/or morpholino C ₁ -C ₆ Alkyl is morpholinoethyl.

The carbodiimide coupling agent may be any one selected from the group consisting of Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N- (3-dimethylaminopropyl) -N' -Ethylcarbodiimide (EDC), and 1-cyclohexyl- (2-morpholinoethyl) carbodiimide methyl-p-toluenesulfonate (CMCT).

The phosphonium coupling agent comprises a phosphonium cation and a counter ion, typically a hexafluorophosphate anion. The phosphonium cations may have the formula [ PR ] ^a ₃ R ^b ] ⁺ Wherein R is ^a Is two (C) ₁ -C ₆ ) Alkylamino or pyrrolidinyl, and R ^b Is halogen or hydrocarbyl optionally substituted with nitrogen and/or oxygen atoms. In general, R ^b Is bromo, benzotriazol-1-yloxy or 7-aza-benzotriazol-1-yloxy.

The phosphonium coupling agent may be any selected from the group consisting of: benzotriazol-1-yloxy-tris (dimethylamino) -hexafluorophosphate (BOP), bromo-tripyrrolidinyl-hexafluorophosphate (PyBrOP), benzotriazol-1-yloxy-tripyrrolidinyl-hexafluorophosphate (PyBOP), 7-aza-benzotriazol-1-yloxy-tripyrrolidinyl hexafluorophosphate (PyAOP) and ethylcyano (oximino) acetoxy-O ₂ ) Tris- (1-pyrrolidinyl) -hexafluorophosphate phosphonium (PyOxim).

At least one of the two or more coupling agents may be an additive coupling agent selected from the group consisting of: 1-hydroxybenzotriazole (HOBt), hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazine (HOOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl 2-cyano-2- (oximino) 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-aza

Benzo-1, 3-diazine (HODhad).

At least one of the two or more coupling agents may be an additive coupling agent selected from the group consisting of: 1-hydroxybenzotriazole (HOBt), hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazine (HOOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl 2-cyano-2- (oximino) acetate (Oxyma Pure) and 4- (N, N-dimethylamino) pyridine (DMAP).

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

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

The benefit of using both coupling agents and additive coupling agents is derived from the compound of formula III and a compound having the formula (R ² ) ₂ The rate at which NH amines form compounds of formula II increases. In addition, when an additive coupling agent is used together with a carbodiimide coupling agent, the possibility of undesired side reactions can be reduced. For example, the reaction of a compound of formula III with a carbodiimide coupling reagent may form an O-acylisourea. This may undergo rearrangement to form an N-acyl urea, which is a stable compound that is unlikely to react with amines. The additive coupling reagent may react with the O-acyl urea prior to rearrangement to the N-acyl urea and produce a compound that continues to react with the amine instead of the inactive N-acyl urea.

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

The two or more coupling agents may consist of N- (3-dimethylaminopropyl) -N' -Ethylcarbodiimide (EDC) (typically as hydrochloride salt (edc.hcl)) and 1-hydroxybenzotriazole (HOBt).

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

Typically, an excess of additive coupling agent is used relative to the compound of formula III. Sometimes, the ratio of additive 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, and most typically from about 1:1 to about 1.5:1.

Where the two or more coupling agents comprise a coupling agent and an additive coupling agent, a ratio of coupling agent to compound of formula III to additive coupling agent to compound of formula III of from about 1:1 to about 1.5:1 may be used.

As described above, stage 1 comprises reacting an activating compound (the product of the reaction of a compound of formula III with two or more coupling agents) with a catalyst of formula R ² R ³ The amine of NH reacts to produce a compound of formula II. R of formulae II and I ² And R is ³ Independently selected from CH ₃ And CD (compact disc) ₃ 。

The ratio of amine to compound of formula III employed in the process is generally about.gtoreq.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. The skilled person is aware of the art suitable for isolating compounds of formula II. For example, the compound of formula II may be extracted into an organic solvent such as dichloromethane or ethyl acetate, washed with an aqueous solution such as an aqueous alkaline solution, and concentrated. To increase purity, the isolated compound of formula II may be recrystallized. The skilled person is aware of techniques suitable for recrystallization of compounds of formula II. For example, the compound of formula II may be dissolved in a minimum amount of solvent at a particular temperature (e.g., at ambient temperature (e.g., 15 ℃ to 25 ℃) or at an elevated temperature where heat is applied to the solution), and the resulting solution cooled to promote precipitation. Alternatively or additionally, the volume of the solution may be reduced to facilitate precipitation, for example by simple evaporation at ambient temperature and pressure. Alternatively or additionally, an anti-solvent (in which the compound of formula II is less soluble than in the solvent already present) may be used.

The isolated compound of formula II is stable and can be stored as a solid in air at ambient temperature (e.g., at about 20 ℃). They may, but need not, be stored under inert conditions, such as under nitrogen or argon, or at reduced temperatures, such as in a refrigerator or freezer.

Typically, steps (i) and (ii) of stage 1 are carried out in a suitable solvent. The skilled person is able to evaluate which solvents are suitable for these steps. Examples of suitable solvents include Dichloromethane (DCM), acetone, isopropyl alcohol (IPA), isopropyl acetate (iPrOAc), tert-butyl methyl ether (TBME), 2-methyltetrahydrofuran (2-MeTHF) and ethyl acetate (EtOAc). In some embodiments, steps (i) and (ii) of stage 1 are performed in methylene chloride.

Steps (i) and (ii) of stage 1 are carried out at suitable temperatures and the skilled person is able to evaluate which temperatures are suitable for these steps. Typically, steps (i) and (ii) of stage 1 are carried out at a temperature of from about 10 ℃ to about 30 ℃. In some embodiments, steps (i) and (ii) of stage 1 are performed at room temperature (about 20 ℃).

Sometimes stage 1 of the method comprises the steps of:

(1) Contacting a compound of formula III with 1 to 1.5 equivalents of an additive coupling agent and 1 to 1.5 equivalents of a carbodiimide coupling agent to produce a first composition; and

(2) Combining the first composition with 1 to 2 equivalents of a compound having formula R ² R ³ The amine of NH is contacted to produce a second composition.

Typically, 1g or more, such as 1g to 100kg or 1g to 1kg of a compound of formula III is employed in the process.

The contacting of steps i, and ii is typically performed in the presence of a first solvent, such as 5 to 20 volumes of the first solvent. The first solvent may be selected from any one of Dichloromethane (DCM), acetone, isopropyl alcohol (IPA), isopropyl acetate (iPrOAc), tert-butyl methyl ether (TBME), 2-methyltetrahydrofuran (2-MeTHF) and ethyl acetate (EtOAc). Typically, the first solvent is DCM.

Typically, step i. Further comprises stirring or agitating the first composition. The first composition may be stirred or agitated for at least 30 minutes, such as 30 minutes to 3 hours or 30 minutes to 2 hours, preferably at least 1 hour, for example 1 to 3 hours or 1 to 2 hours. The first composition may be maintained at a temperature of 10 ℃ to 30 ℃.

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

Sometimes, step ii. Further comprises stirring or agitating the second composition. The second composition may be stirred or agitated for at least 30 minutes, such as 30 minutes to 3 hours or 30 minutes to 2 hours, preferably at least 1 hour, for example 1 to 3 hours or 1 to 2 hours. The second composition may be maintained at a temperature of 10 ℃ to 30 ℃.

The step ii may further comprise contacting the second composition with an aqueous alkaline solution to produce a third composition, for example contacting the second composition with 2 to 10 volumes of an aqueous alkaline solution such as an aqueous solution comprising potassium carbonate.

Sometimes, step ii. Further comprises stirring or agitating the third composition. The third composition may be stirred or agitated for at least 1 minute, such as 1 to 15 minutes or 1 to 10 minutes, preferably at least 5 minutes, for example 5 to 15 minutes or 5 to 10 minutes. The third composition may be maintained at a temperature of 10 ℃ to 30 ℃.

In the case that 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 the contacting of step i.

Sometimes stage 1 of the method comprises the steps of:

i. 1g or more of a compound of formula III and 1 to 1.5 equivalents of an additive coupling agent are added to a first vessel,

adding 5 to 20 volumes of a first solvent selected from DCM, acetone, IPA, iPrOAc, TBME, 2-MeTHF and EtOAc to the first vessel,

adding 1 to 1.5 equivalents of a carbodiimide coupling agent to the first vessel,

Stirring the contents of the first vessel at 10 to 30 ℃ for at least 30 minutes, preferably at least 1 hour (such as 1 to 2 hours),

v. adding 1 to 2 equivalents of a compound of formula R to the first vessel ² R ³ NH, wherein the amine is preferably dissolved in an ether solvent,

the contents of the first vessel are further stirred at 10 to 30 ℃ for at least 30 minutes, preferably at least 1 hour (such as 1 to 2 hours),

adding 2 to 10 volumes of an aqueous alkaline solution to the first vessel,

the contents of the first vessel are further stirred at 10 to 30 ℃ for at least 1 minute, preferably at least 5 minutes (such as 5 to 10 minutes),

allowing separation of the immiscible organic fraction from the aqueous fraction, wherein the organic fraction comprises a compound of formula II, and

removing an organic fraction comprising the compound of formula II,

wherein steps i.through x.are performed during a single 8 hour period.

Typically, the first solvent is DCM.

Typically, the amine is dimethylamine. The amine may be dissolved in THF, for example, at a concentration of 2M.

Typically, the aqueous alkaline solution comprises potassium carbonate.

Sometimes stage 1 of the method further comprises the steps of:

drying the organic fraction with a drying agent, for example a drying agent selected from the group consisting of calcium chloride, magnesium sulfate and sodium sulfate,

The organic fraction is filtered off and the organic fraction is filtered,

concentrating the organic fraction e.g. under vacuum such as at a pressure of less than 1 atmosphere,

adding the concentrated organic fraction to a second vessel,

xv. adding 2 to 10 volumes of a second solvent to the second container, wherein the second solvent is selected from IPA, etOAc, IPrOAc, acetonitrile (MeCN), TBME, THF, 2-mechf and toluene,

stirring the contents of the second vessel at a temperature of 45 to 55 ℃ for at least 1 hour, preferably at least 2 hours (such as 2 to 3 hours),

xvii cooling the contents of the second vessel to a temperature of from 15 ℃ to 25 ℃,

xviii filtering the contents of the second vessel to obtain a filtrate, wherein the filtrate comprises the compound of formula II, and

drying the filtrate.

The drying agent of step xi. Is typically magnesium sulfate. Typically, the solvent of step xv. is selected from TBME and IPA.

Stage 2 of the process comprises reacting a compound of formula II with LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ To produce the compound of formula I. Can make LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ Is reacted with a compound of formula II. In a preferred embodiment, stage 2 of the process comprises reacting a compound of formula (la)Compounds of II and LiAlH ₄ And LiAlD ₄ Is prepared by the reaction of the mixture of the above components. Such a mixture comprises LiAlD ₄ And comprises 0.1% to 99.9% of a hydride. Mixtures of 2% to 98% lithium aluminum hydride or 2% to 98% lithium aluminum deuteride may be employed. Sometimes LiAlH ₄ And LiAlD ₄ Is essentially composed of 98% LiAlD ₄ /2％ LiAlH ₄ Composition is prepared. Sometimes, such a mixture consists essentially of: 95% LiAlD ₄ /5％ LiAlH ₄ 、95％ LiAlD ₄ /5％ LiAlH ₄ 、85％LiAlD ₄ /15％ LiAlH ₄ 、80％ LiAlD ₄ /20％ LiAlH ₄ 、75％ LiAlD ₄ /25％LiAlH ₄ 、70％ LiAlD ₄ /30％ LiAlH ₄ 、65％ LiAlD ₄ /35％ LiAlH ₄ 、60％LiAlD ₄ /40％ LiAlH ₄ 、55％ LiAlD ₄ /45％ LiAlH ₄ 、50％ LiAlD ₄ /50％LiAlH ₄ 、45％ LiAlD ₄ /55％ LiAlH ₄ ,40％ LiAlD ₄ /60％ LiAlH ₄ 、35％LiAlD ₄ /65％ LiAlH ₄ 、30％ LiAlD ₄ /70％ LiAlH ₄ 、25％ LiAlD ₄ /75％LiAlH ₄ 、20％ LiAlD ₄ /80％ LiAlH ₄ 、15％ LiAlD ₄ /85％ LiAlH ₄ 、10％LiAlD ₄ /90％ LiAlH ₄ 、5％ LiAlD ₄ /95％ LiAlH ₄ Or 2% LiAlD ₄ /98％LiAlH ₄ 。

Essentially by a specified percentage of LiAlH ₄ And LiAlD ₄ Composition of LiAlH ₄ And LiAlD ₄ Meaning that the mixture may contain additional components (in addition to LiAlH ₄ And LiAlD ₄ Outside) but the presence of these additional components does not substantially affect the essential characteristics of the mixture. In particular, it is substantially composed of LiAlH ₄ And LiAlD ₄ The resulting mixture will not contain substantial amounts of reagents detrimental to the reduction of the compound of formula II to produce the compound of formula I (e.g., with LiAlH in a manner that inhibits the reduction of the compound of formula II to produce the compound of formula I ₄ And LiAlD ₄ Compounds of formula IIAnd/or a substantial amount of reagent reacted with the compound of formula I).

LiAlH contained in a mixture of both ₄ Or LiAlD ₄ The amount of (c) depends on the degree of deuteration sought in the compound of formula I. For example, in seeking one of them ^y In the case of a compound of formula I wherein H is protium and the other is deuterium, 50% LiAlH may be preferred ₄ And 50% LiAlD ₄ Is a mixture of (a) and (b). Alternatively, it is sought that about half of the compounds contain two deuterium atoms in the α -position (i.e. two ^y H is deuterium) and about half of the compounds contain one deuterium atom and one protium atom in the alpha-position (i.e., one ^y H is deuterium and the other is protium) may preferably be 25% LiAlH ₄ And 75% LiAlD ₄ Is a mixture of (a) and (b).

LiAlD used ₄ Or LiAlH ₄ And LiAlD ₄ The amount of (2) is generally.ltoreq.1:1 relative to the compound of the formula II. For the avoidance of doubt, liAlD ₄ Or LiAlH ₄ And LiAlD ₄ The ratio relative to the compound of formula II refers to the LiAlD used ₄ Or LiAlH ₄ And LiAlD ₄ Relative to the total amount of compound II. Sometimes LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ The ratio of the compounds of formula II is 0.5:1 to 1:1, such as 0.8:1 to 1:1. In general, liAlH ₄ And/or LiAlD ₄ The ratio of the compounds of formula II is 0.9:1.

Typically, stage 2 of the process is carried out in a suitable solvent. The skilled person can evaluate which solvents are suitable for stage 2. Examples of suitable solvents include ethers such as THF and diethyl ether. Typically, stage 2 is carried out in THF.

In general, liAlD ₄ Or LiAlH ₄ And LiAlD ₄ As LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ Provided as a solution or suspension in a suitable solvent such as an ether (e.g., THF or diethyl ether, typically THF).

Stage 2 of the process is carried out at a suitable temperature and the skilled person is able to evaluate which temperatures are suitable for these steps. Typically, stage 2 is conducted at a temperature of from about-5 ℃ to about 65 ℃.

Typically, stage 2 further comprises isolating the compound of formula I. The skilled person is aware of the art suitable for isolating compounds of formula I. For example, in quenching the reaction (e.g., with an aqueous solution of a tartrate salt such as Rochelle's salt), the compound of formula I may be extracted into an organic solvent such as an ether (e.g., THF or diethyl ether), washed with an aqueous solution such as an aqueous alkaline solution, and concentrated. The isolated compound of formula I may be recrystallized. The skilled person is aware of techniques suitable for recrystallization of compounds of formula I. Examples of recrystallization techniques described in relation to the recrystallization of compounds of formula II are applied, mutatis mutandis, to the recrystallization of compounds of formula I.

Typically, about 1g or more, such as about 1g to about 100kg or about 1g to about 1kg of the compound of formula II is employed in the process.

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 equivalent, of LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ Contacting to produce a first composition.

The contacting is generally carried out in the presence of a solvent such as an ether (e.g., THF or diethyl ether, typically THF).

Typically, contacting includes contacting LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ Drop wise addition to a compound of formula II wherein LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ As LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ Provided as a solution or suspension in a suitable solvent such as ether (e.g., THF or diethyl ether). LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ Can be used as LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ A 2.4M or 2M solution or suspension in THF. Sometimes LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ Can be used as LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ A 2M solution or suspension in THF is provided.

The contacting is typically carried out at a temperature of from about-5 ℃ to about 65 ℃.

Typically, stage 2 further comprises stirring or agitating the first composition. The first composition may be stirred or agitated for about 1 hour to about 6 hours, typically about 2 hours. The first composition may be stirred or agitated at a temperature of about 55 ℃ to about 65 ℃. Typically, the first composition is stirred or agitated at a temperature of about 55 ℃ to about 65 ℃ and then cooled to a temperature of about 10 ℃ to about 30 ℃.

Typically, the compound of formula II is combined with about 0.9 equivalent of LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ And (3) contact.

Stage 2 of the method of the invention may comprise the steps of:

i. 1g or more (such as 1g to 1 kg) of a compound of formula II is added to a third vessel,

adding 5 to 20 volumes of an ether solvent to a third vessel,

dropwise adding 0.8 to 1 equivalent of LiAlD to the third vessel at a temperature of-5 ℃ to 65 ℃ over at least 15 minutes (e.g., 15 to 30 minutes) ₄ Or LiAlH ₄ And LiAlD ₄ A solution in an ether solvent, wherein the solvent is selected from the group consisting of,

stirring the contents of the third vessel at 55 ℃ to 65 ℃ for 1 to 6 hours, preferably 2 hours, and

cooling the contents of the third vessel to 10 ℃ to 30 ℃,

wherein the contents of the third container comprise a compound of formula I.

Typically, the ether solvent is THF. Typically, 0.9 equivalent of LiAlD will be used in step iii ₄ Or LiAlH ₄ And LiAlD ₄ Added to the third container. LiAlD is usually used ₄ Or LiAlH ₄ And LiAlD ₄ Added to the third vessel as a 2.4M or 2M solution in THF. Sometimes LiAlD is used ₄ Or LiAlH ₄ And LiAlD ₄ Added to the third vessel as a 2M solution in THF.

Sometimes stage 2 of the method comprises a post-treatment comprising the steps of:

adding 5 to 20 volumes of an aqueous solution of tartrate salt such as rochelle salt to a fourth vessel,

Adding a composition comprising the crude compound of formula I to a fourth vessel at a temperature of between 15 ℃ and 25 ℃ for at least 15 minutes (such as 15 minutes to 1 hour), preferably at least 30 minutes (such as 30 minutes to 1 hour), and

the contents of the fourth vessel are stirred at 15 ℃ to 25 ℃ for at least 30 minutes (such as 30 minutes to 1 hour).

For the avoidance of doubt, a composition comprising a crude compound of formula I refers to the contents of the third vessel upon completion of step v. of stage 2 described above.

Stage 2 of the method may further comprise the steps of:

allowing separation of an organic fraction from an aqueous fraction, wherein the organic fraction comprises a compound of formula I,

removing the aqueous fraction from the fourth vessel,

adding 5 to 20 volumes of saline solution to a fourth vessel,

stirring the contents of the fourth vessel at a temperature of 15 to 25 ℃ for at least 5 minutes (such as 5 to 15 minutes),

removing an organic fraction comprising the compound of formula I as free base,

drying the organic fraction using a drying agent, such as a drying agent selected from the group consisting of calcium chloride, magnesium sulfate and sodium sulfate,

xv. filtering the organic fraction, and

the organic fraction is concentrated, for example, under vacuum, such as at a pressure of less than 1 atmosphere.

The isolated compound of formula I (produced via stage 2) is stable and can be stored as a solid in air at ambient temperature (e.g., at about 20 ℃). They may, but need not, be stored under inert conditions, such as under nitrogen or argon, or at reduced temperatures, such as in a refrigerator or freezer. Sometimes, the compound of formula I is stored in a solvent, for example dissolved in ethanol. Sometimes, the compound of formula I is stored in a solvent for more than 8 hours, typically more than 12 hours.

As described 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. Thus, the method may further comprise stage 3, wherein the compound of formula I is reacted with an acidic reagent to produce a pharmaceutically acceptable salt of the compound of formula I. The acidic agent may be suitable for crystallizing a pharmaceutically acceptable salt of the compound of formula I.

For the avoidance of doubt, where the reagent is expressed herein as an equivalent number, this is the molar equivalent of a compound of formula III, formula II or formula I relative to the reagent in stage 1, stage 2 or stage 3 respectively.

The process for the synthesis of a compound of formula I or a pharmaceutically acceptable salt thereof generally comprises stage 1, stage 2 and stage 3, wherein stage 1 comprises:

(ii) By reacting an activating compound with R ² R ³ Amine reaction of NH to produce a compound of formula II; and

(iii) Isolating a compound of formula II:

stage 2 comprises reacting a compound of formula II with LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ Reacting; and

stage 3 comprises the step of reacting the compound of formula I with an acidic reagent suitable for crystallizing a pharmaceutically acceptable salt of the compound of formula I.

In some cases, a ratio of acidic reagent to compound of formula I of 1:1 or more is used. Typically, the ratio of acidic reagent to compound of formula I is 1:1.

Typically, stage 3 of the process is carried out in a suitable solvent. The skilled person can evaluate which solvents are suitable for stage 3. Examples of suitable solvents include ethanol, IPA, iPrOAc and MeCN. Stage 3 is typically carried out in ethanol.

Stage 3 of the process of the invention is carried out at a suitable temperature and the skilled person is able to evaluate which temperatures are suitable for these steps.

Stage 3 of the process generally comprises contacting the compound of formula I with an acidic reagent to produce a first composition. Typically, the contacting of stage 3 is performed at a temperature of from 70 ℃ to 100 ℃, e.g., from 70 ℃ to 90 ℃ or from 70 ℃ to 80 ℃. Sometimes, the contacting of stage 3 is performed at a temperature of about 75 ℃.

Typically, stage 3 further comprises isolating the pharmaceutically acceptable salt of formula I. The skilled artisan is aware of techniques in the art that are suitable for the isolation of such compounds. For example, where the compound is dissolved in a suspension, it may be separated from some of the other components of the suspension via filtration (such as thermal filtration). The pharmaceutically acceptable salts of formula I may be precipitated from the filtrate. The skilled artisan is aware of methods of promoting precipitation of a compound from a solution, such as cooling the solution, concentrating the solution, and/or adding a crystalline form of the compound to the solution to promote nucleation and growth (i.e., seeding) of additional crystals of the compound from the solution. Pharmaceutically acceptable salts of formula I may be recrystallized. The skilled person is aware of techniques suitable for recrystallization of pharmaceutically acceptable salts of formula I. Examples of recrystallization techniques described with respect to recrystallization of compounds of formula II are applied, mutatis mutandis, to recrystallization of pharmaceutically acceptable salts of formula I.

Stage 3 of the method may include the steps of:

i. adding to the fifth vessel at least one equivalent of an acidic reagent suitable for crystallizing a pharmaceutically acceptable salt of the compound of formula I,

Dissolving a compound of formula I as a free base in 5 to 20 volumes of a solvent such as a solvent selected from ethanol, IPA, iPrOAc and MeCN, and adding the solution to a fifth reaction vessel,

stirring the contents of the fifth vessel at a temperature above 72 c (such as 72 c to 90 c),

filtering the contents of the fifth vessel,

v. adding the filtrate to a sixth vessel and cooling the contents to a temperature of 67 to 73 ℃,

optionally seeding the sixth vessel with a crystalline form of a pharmaceutically acceptable salt of the compound of formula I,

stirring the contents of the sixth vessel at a temperature of 67 ℃ to 73 ℃ for at least 30 minutes (such as 30 minutes to 1 hour),

cooling the contents of the sixth vessel to a temperature of-5 ℃ to 5 ℃ at a rate of 2 ℃ to 8 ℃/hour, and

filtering the contents of the sixth vessel to produce a filter cake comprising a pharmaceutically acceptable salt of the compound of formula I.

Typically, the solvent of step ii is ethanol. Typically, the cooling rate in step viii is 5 ℃/hr.

As described above, the pharmaceutically acceptable salts generally comprise the compounds of formula I and a suitable acid. The acids listed above as suitable components of the pharmaceutically acceptable salts of the invention are applied mutatis mutandis to the acidic reagent of stage 3 of the process.

Typically, the acidic agent is any one selected from fumaric acid, tartaric acid, citric acid and hydrochloric acid, such as fumaric acid.

The synthetic methods disclosed herein are particularly useful for preparing therapeutic deuterated substituted dialkano-primary amines because the methods employ significantly less LiAlD than other syntheses known in the art ₄ Because the method replaces deuterium in the alpha position rather than in the beta position. In this synthesis, liAlD ₄ Is one of the most expensive and difficult to prepare reagents. In addition, the optimization methods disclosed herein reduce LiAlD ₄ Or LiAlH ₄ And LiAlD ₄ For example, from 2 equivalents to 0.9 equivalents, which increases the economic efficiency of preparing deuterated compounds of formula I. In view of this, the compounds of formula I are prepared via the synthetic methods disclosed herein less expensively than known deuterated analogs (which are typically deuterated in both the alpha and beta positions).

The synthetic methods disclosed herein are highly efficient; the compounds of formula I may be prepared in total yields of 50% to 100%, such as 60% to 100% or 65% to 100%.

Each of the patent and non-patent references mentioned herein is hereby incorporated by reference in its entirety as if each reference were set forth in its entirety herein.

The invention may be further understood with reference to the following non-limiting examples:

example 1

In a first example, the inventors demonstrated that the primary kinetic isotope effect imparted to N, N-dimethyltryptamine when enriched with one or two deuterium at the alpha position exhibits a linear relationship between average molecular weight and half-life in a human hepatocyte assay.

Evaluation of in vitro intrinsic clearance of deuterated DMT analog blends relative to DMT using human hepatocytes

In vitro determination of intrinsic clearance is a valuable model for predicting liver clearance in vivo. The liver is the major organ of drug metabolism in the body and contains phase I and II drug metabolizing enzymes present in intact cells.

Synthesis of samples

220.9g of N, N-DMT (as the free base) was prepared as N, N-DMT fumarate using the chemistry depicted in scheme 1. Additional 4-6g of six partially deuterated mixtures were also prepared using modified conditions.

Synthesis of DMT

Stage 1: coupling of indole-3-acetic acid and dimethylamine

At N ₂ Indole-3-acetic acid (257.0 g,1.467 mol), hydroxybenzotriazole (HOBt,. About.20% moisture) (297.3 g,1.760 mol) and methylene chloride (2313 mL) were added to a 5L vessel to give a milky white suspension. Then, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 337.5g,1.760 mol) was added in portions over 5 minutes at 16℃to 22 ℃. The reaction mixture was stirred at ambient temperature for 2 hours, then 2M dimethylamine (1100 ml,2.200 mol) in THF was added dropwise over 20 minutes at 20 ℃ -30 ℃. The resulting solution was stirred at ambient temperature for 1 hour, wherein HPLC indicated 1.1% indole-3-acetic acid and 98.1% of the target product (referred to as stage 1). Then 10% K was added to the reaction mixture ₂ CO ₃ (1285 mL) and stirred 5And (3) minutes. The layers were separated and the upper aqueous layer was extracted with dichloromethane (643 ml×2). The organic extracts were combined and washed with saturated brine (643 mL). The organic extract was then subjected to MgSO ₄ Dried, filtered and concentrated in vacuo at 45 ℃. This provided 303.1g of crude stage 1 as an off-white viscous solid. The crude material was then subjected to slurrying in t-butyl methyl ether (TBME, 2570 mL) at 50 ℃ for 2 hours, then cooled to ambient temperature, filtered and washed with TBME (514 ml×2). The filter cake was then dried in vacuo at 50 ℃ to give stage 1.2 g (yield=90%) as an off-white solid with HPLC purity 98.5% and NMR purity > 95%.

Stage 2: preparation of DMT

At N ₂ Next, stage 1 (272.5 g,1.347 mol) and tetrahydrofuran (THF, 1363 mL) were added to a 5L vessel to give an off-white suspension. Then 2.4M LiAlH in THF was added dropwise over 35 minutes at 20℃to 56 ℃ ₄ (505.3 mL,1.213 mol) to give an amber solution. The solution was heated to 60 ℃ for 2 hours, with HPLC indicating stage 1ND, the target product (referred to as stage 2, 92.5%), impurity 1 (2.6%), impurity 2 (1.9%). The complete reaction mixture was cooled to ambient temperature and then added drop wise to a solution of 25% Rochelle salt (Rochelle' ssalt) (aqueous solution) (2725 mL) at 20 ℃ -30 ℃ over 30 minutes. The resulting milky suspension was allowed to stir at 20 ℃ to 25 ℃ 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 MgSO ₄ Dried, filtered and concentrated in vacuo at 45 ℃. The resulting crude oil was subjected to azeotropy with ethanol (545 ml×2). This provided 234.6g (yield = 92%) of stage 2, hplc purity 95.0%, and NMR purity>95%. Stages 3a (i) - (iii): preparation of seed crystals of DMT fumarate

(i) Stage 2 (100 mg) was partitioned in 8 volumes of isopropyl acetate and warmed to 50 ℃ and then fumaric acid (1 eq) in ethanol was added. The flask was then allowed to age at 50 ℃ for 1 hour, then cooled to room temperature and stirred overnight to give a white suspension. The solid was isolated by filtration and dried at 50 ℃ for 4 hours to provide 161mg of product (> 99% yield). HPLC purity was 99.5% and NMR purity >95%.

(ii) Isopropyl acetate was replaced with isopropyl alcohol in method (i), and after stirring overnight a white suspension was obtained. The solid was isolated by filtration and dried at 50 ℃ for 4 hours to provide 168mg of product (> 99% yield). HPLC purity was 99.8% and NMR purity >95%.

In process (i) isopropyl acetate was replaced with tetrahydrofuran, after stirring overnight a white suspension was obtained. The solid was isolated by filtration and dried at 50 ℃ for 4 hours to provide 161mg of product (> 99% yield). HPLC purity was 99.4% and NMR purity >95%.

Analysis by X-ray powder diffraction showed that the product of each of methods 9 i) to (iii) was identical, labeled as pattern a.

Stage 3b: preparation of DMT fumarate

At N ₂ Next, a solution of fumaric acid (152.7 g,1.315 mol) and stage 2 (248.2 g,1.315 mol) in ethanol (2928 mL) was added to a 5L flanged flask. The mixture was heated to 75 ℃ to give a dark brown solution. The solution was finely filtered (polish filter) into a 5L jacketed vessel that was preheated (80 ℃). The solution was then cooled to 70 ℃ and seeded with mode a (0.1 wt%) to mature the seed for 30 minutes, then cooled to 0 ℃ at a rate of 5 ℃/hour. After stirring for an additional 4 hours at 0 ℃, the batch was filtered and washed with cold ethanol (496 mL x 2) and then dried overnight at 50 ℃. This provided 312.4g (yield = 78%) of stage 3, 99.9% purity by HPLC, and purity by NMR>95%. XRPD: mode a.

Synthesis of deuterated mixtures of DMT compounds

By using solid LiAlH in stage 2 ₄ /LiAlD ₄ Improved synthesis of mixtures using 1.8 equivalents of LiAlH ₄ /LiAlD ₄ Whereas the above method for non-deuterated DMT was used at 0.9 equivalent.

₄ ₄ Representative synthesis of deuterated (1:1 lialh: liald) DMT compositions: At N ₂ Next, liA was added to a 250mL 3-necked flasklH ₄ (1.013g，26.7mmol)、LiAlD ₄ (1.120 g,26.7 mmol) and THF (100 mL). The resulting suspension was stirred for 30 minutes and then stage 1 (6 g,29.666 mmol) was added in portions over 15 minutes at 20℃to 40 ℃. The reaction mixture was then heated to reflux (66 ℃) for 2 hours, wherein HPLC indicated no phase 1 remained. The mixture was cooled to 0deg.C and cooled to 0deg.C<Quenched with 25% Rochelle's salt (aq) (120 mL) at 30 ℃ for 30 minutes. 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 passed over MgSO ₄ Dried, filtered and concentrated in vacuo. This provided 4.3g of crude material. The crude product was then partitioned in ethanol (52 mL) and fumaric acid (2.66 g,22.917 mmol) was added, followed by heating to 75deg.C. The resulting solution was allowed to cool to ambient temperature overnight and then further cooled to 0 ℃ to 5 ℃ for 1 hour. The solid was isolated by filtration and washed with cold ethanol (6.5 ml×2). The filter cake was dried overnight at 50 ℃ to provide 5.7g (yield = 63%) of product with HPLC purity of 99.9% and NMR purity>95％。

TABLE 1

In vitro intrinsic clearance of deuterated DMT compounds and compositions

Intrinsic clearance of human hepatocytes

In vitro determination of intrinsic clearance (CLint) is a valuable model for predicting in vivo clearance. The liver contains phase I and II drug metabolizing enzymes present in intact cells and thus provides a valuable model for the study of drug metabolism. In particular, CLint in hepatocytes is a measure of the potential of a compound to undergo metabolism and can be correlated with in vivo liver clearance by taking into account both plasma protein binding and liver blood flow. Thus, CLint can be used as an indicator of the relative metabolic stability of the compound and compared to other external probe substrates. Furthermore, where liver metabolic clearance is known to be an issue, measurement of CLint in vitro can be a useful means of understanding the different pharmacokinetic behavior of a compound in vivo.

Measurement method

In vitro intrinsic clearance of SPL026 and SL028 analogs was studied in three separate experiments using human (mixed sex) hepatocytes pooled from 10 donors:

first experiment-human (mixed sex) hepatocytes; 545000 cells/mL. Final organics concentration 1.05%, consisting of 80.74% MeCN and 19.26% DMSO

Second experiment-human (mixed sex) hepatocytes; 427000 cells/mL. The final organic concentration was 1%, consisting of 84.7% MeCN and 15.3% DMSO.

Third experiment-human (mixed sex) hepatocytes; 362000 cells/mL mouse CD-1 (Male) hepatocytes

Final organic concentration 1%, consisting of 84.7% MeCN and 15.3% DMSO

Preparation for measurement

Preparation of hepatocyte buffer as 26.2mM NaHCO in MilliQ water ₃ 9mM Na HEPES, 2.2mM D-fructose and DMEM.

Compound and marker stock solutions were prepared at 10mM in DMSO and further diluted to 100 x assay concentration in 91:9 acetonitrile in DMSO.

The hepatocytes were quickly thawed in a water bath at 37 ℃ and once thawed, poured into hepatocyte buffer. Cells were centrifuged and the supernatant removed, then counted and resuspended at the final assay concentration.

Measurement program

All test compounds as well as sumatriptan, serotonin, benzylamine controls were incubated 2 replicates of each compound in each experiment using a concentration of 5 μm. The concentration is chosen so as to maximize the signal-to-noise ratio while maintaining the Miq constant (K) of monoamine oxidase (MAO) _m ) And (3) downwards. Diltiazem and diclofenac controls were used at laboratory-verified concentrations of 1 μm.

Hepatocytes were added to pre-warmed incubation tubes (37 ℃). The pre-prepared 100 x assay compound stock solution was then added to the incubation tube and carefully mixed. Samples were taken at 7 time points (2, 4, 8, 15, 30, 45 and 60 minutes). At each time point, small aliquots were removed from the incubation and quenched with ice-cold acidified methanol or acetonitrile containing internal standard at 1:4.

Throughout the experiment, the incubation tube was orbitally shaken at 37 ℃.

Standard final incubation conditions were 1. Mu.M compound in buffer containing nominally 50 ten thousand viable cells/mL, 0.9% (v/v) acetonitrile (MeCN) and 0.1% (v/v) DMSO (specific assay concentrations outlined above, part 2).

The quenched samples were thoroughly mixed and the protein precipitated at-20 ℃ for a minimum of 12 hours. The sample was then centrifuged at 4 ℃. The supernatant was transferred to a fresh 96-well plate for analysis.

Liquid chromatography-mass spectrometry (LC-MS/MS)

Analysis was performed using the following LC-MS/MS conditions:

instrument: thermo TSQQuantiva with Thermo Vanquish UPLC system

Column: luna Omega 2.1X105 mm 2.6 μm

Solvent a: h ₂ O+0.1% formic acid

Solvent B: acetonitrile +0.1% formic acid

Flow rate: 0.8ml/min

Sample injection volume: 1 μl

Column temperature: 65 DEG C

Gradient:

time (minutes)	% solvent B
		0.00	5.0
0.90	75.0
		1.36	99.0
1.36	5.0
		1.80	5.0

MS parameters:

positive ion spray voltage: 4000V

Evaporator temperature: 450 DEG C

Ion transfer tube temperature: 365 DEG C

Sheath gas: 54

Auxiliary gas: 17

Purge gas: 1

Residence time of 8ms

MRM transition:

d0=mass to charge ratio 189.136>144.179 (method determined by SPL026 analysis)

D1=mass to charge ratio 190.136>59.17 (method determined by SPL028ii analysis)

D2=mass to charge ratio 191.137>60.169 (method determined by SPL028i analysis)

D6=mass to charge ratio 195.17>64.127

D8=mass to charge ratio 197.2>146.17

MRM transitions were determined from preliminary analysis of DMT samples containing no deuterium (for D0 transitions) or high levels of D1, D2, D6 or D8 deuteration (for D1, D2, D6 and D8 transitions, respectively).

The resulting concentration-time curves were then used to calculate intrinsic clearance (CLint) and half-life (t 1/2). To this end, the MS peak area or MS peak area/IS response for each analyte IS plotted on a natural log (log) scale on the y-axis versus sampling time (min) on the X-axis. The slope of the line is the elimination rate constant. This is converted to half-life by-ln (2)/slope. Intrinsic clearance was calculated from the slope/elimination rate constant and the formula clint= (-1000 slope)/cell density in 1E6 cells/ml to give units of microliters/minute/million cells.

Six different D with and without MAO inhibitors ₂ Clearance of DMT analog blends (SPL 028i-SPL028 vi)

Six different alphA, -dideuterio-N, N-dimethyltryptamine (D) were examined by measuring in vitro intrinsic clearance using irreversible, combined MAO-A/B inhibitors (100 nM of clojiline and 100nM of amphetamine/selegiline added as cassettes), viA the use of human (mixed sex) hepatocytes (545000 cells/mL; final organics concentration 1.05%, consisting of 80.74% MeCN and 19.26% DMSO) from 10 donors ₂ DMT) MAO contribution of the compound.

Deuterated effect

Fitting the data to two separate linear models using linear regression analysis (one-way ANOVA) revealed deuterium enrichment at the alpha-carbon of DMT with D ₂ Percent deuteration (formula: y=d ₂ *-6.04+12.9，r ² =0.748) and Molecular Weight (MW) (using the formula: y=mw 79.5+98.8, r ² =0.811) while linearly decreasing the intrinsic clearance.

96.6％D ₂ -DMT (SPL 028 i) observed a 2-fold change in the maximal change in metabolic stability, intrinsic clearance and half-life compared to SPL026 in initial hepatocyte studies (tables 3 and 4). The metabolic stability of the deuterated intermediate blend (SPL 028ii-SPL028 vi) increased in a manner correlated with increased deuteration levels and molecular weight (tables 3 and 4).

TABLE 3 SPL026 and 6 different D in human hepatocytes ₂ The in vitro intrinsic clearance of deuterated SPL028 analog blends, highlighting the presence and absence of inhibitorsIn the case, the intrinsic clearance of each deuterated compound varies with respect to the multiple of SPL 026. The compounds are ordered by molecular weight.

TABLE 4 SPL026 and 6 different D in human hepatocytes ₂ The in vitro half-life of deuterated SPL028 analog blends highlights the fold change in the intrinsic clearance of each deuterated compound relative to SPL026 with and without inhibitors. The compounds are ordered by molecular weight.

Contribution of MAO (see also FIG. 4)

Two-way ANOVA was performed to determine the effect of MAO inhibitors and deuteration of the compound on intrinsic clearance. MAO inhibitors had a significant effect on intrinsic clearance, F (1, 6) =11.42, p=0.0149, and deuteration had a significant effect on intrinsic clearance, F (1, 6) =9.996, p=0.006.

Inclusion of MAO inhibitors showed minimal effect on SPL026 (DMT) metabolism, resulting in a slower intrinsic clearance of-4% (table 5). MAO inhibitor pair 96.6% D is also shown ₂ Deuterated analogs (SPL 028 i) had a small effect, which was observed to be-5% faster intrinsic clearance in the presence of MAO inhibitors (table 5). These results indicate that the MAO enzyme does not significantly promote the metabolism of SPL026 and SPL028i in human liver hepatocytes.

Showing MAO inhibitor vs. the remaining five D ₂ The intrinsic clearance of the deuterated analog blend (SPL 028ii-SPL028 vi) has greater inhibition. For these five compounds, inhibition by the MAO inhibitor showed a linear increase with increasing deuteration level and molecular weight, except SPL028vi (table 3). In the case of MAO inhibitor, 49% D ₂ Maximum change in intrinsic clearance was observed for deuterated SPL028iv (49%) (table 5), whereas in the cell fraction with inhibitor, 36.8% D relative to SPL026 ₂ Deuterated SPL028iii observed the greatest change in metabolic stability (-2-fold) (tables 3 and 4).

TABLE 5SPL026 and 6 different D ₂ The in vitro intrinsic clearance and half-life of deuterated SPL028 analog blends in human hepatocytes with and without the combination of MAO-A/B inhibitors. The percent change (%) value represents the change in metabolic stability comprising the MAO inhibitor relative to the metabolic stability without the MAO inhibitor, as measured by intrinsic clearance and half-life, respectively. The compounds are ordered by molecular weight increase.

These results indicate that increasing deuteration levels at the alpha-carbon of DMT decreases the MAO enzyme metabolism of the compound.

Six types of D ₂ DMT analog blend (SPL 028i-SPL028 vi) and a D ₆ Clearance of-DMT (SPL 028 vii) analog blends

d ₆ -DMT:028vii (Synthesis of Compound 5)

Stage 1

EDC.HCl (15.7 g,81.90 mmol) was added to 3-indoleacetic acid (12.0 g,68.50 mmol) and HOBt.H in DCM (108 mL) at room temperature ₂ O (1.16 g,75.75 mmol). The reaction was stirred for 1 hour before N, N-Diisopropylethylamine (DIPEA) (35.6 mL,205.75 mmol) and d were added ₆ Dimethylamine HCl (9.0 g,102.76 mmol) (temperature maintained below 30 ℃). The reaction was stirred at room temperature for 1 hour, after which HPLC analysis indicated 65.6% product, 28.9% 3-indoleacetic acid remained. DIPEA (11.9 mL,68.78 mmol) was added and the reaction was stirred at room temperature for 1 hour. HPLC indicated no change in conversion. Aqueous potassium carbonate (6.0 g in 54mL of water) was added and the phases separated. The aqueous phase was extracted with DCM (2X 30 mL). The combined organics were washed with brine (2X 30 mL), then with aqueous citric acid (20 w/w%,50 mL), over MgSO ₄ Drying and filtering. The filtrate was stripped and the resulting solid was slurried in TBME (120 mL) and isolated by filtration. By means of a fast columnPurification by chromatography gave 8.34g of the desired product (58% yield). ¹ H NMR confirmed the identity of the product.

Stage 2

At the position of<At 30 ℃, liAlH is added ₄ (1M in THF, 17.3mL,17.28 mmol) was added to a suspension of stage 1 (4.0 g,19.20 mmol) in THF (10 mL). The resulting reaction was heated to 60 ℃ to 65 ℃ and stirred for 2 hours. HPLC analysis indicated complete consumption of stage 1, forming 97.3% of product. The reaction was cooled to room temperature and cooled to room temperature<Quenched into aqueous rochelle salt (10 g in 30mL of water) at 30 ℃. After stirring for 1 hour, the phases are separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), over MgSO ₄ Dried, filtered and stripped (azeotroped with ethanol, 20 mL) to give the desired product (3.97 g) as an amber oil. ¹ H NMR confirmed the identity of the product and indicated the presence of 8.5% ethanol (no THF) to give an effective yield of 3.63g, 97%.

Stage 3

D at room temperature ₆ -DMT free base (3.6 g active, 18.53 mmol) was dissolved in ethanol (43 mL). Fumaric acid (2.15 g,18.53 mmol) was added and the solution was heated to 75 ℃ (the solid crystallized during heating and did not redissolve). The resulting suspension was cooled to 0 ℃ to 5 ℃ and stirred for 1 hour. The solid was isolated by filtration, washed with ethanol (2X 7 mL) and drained. Further drying in a vacuum oven at 50℃gives the desired d ₆ -DMT fumarate (4.98 g, 87%).

d ₈ -DMT:028viii Synthesis of Compound 1

For stage 1 (3-indoleacetic acid with d) ₆ Coupling of dimethylamine), see above.

Stage 2

At the position of<At 30 ℃, liAlD is added ₄ (1M in THF, 17.3mL,17.28 mmol) was added to a suspension of stage 1 (4.0 g,19.20 mmol) in THF (10 mL). The resulting reaction was heated to 60 ℃ to 65 ℃ and stirred for 2 hours. HPLC analysis indicated complete consumption of stage 1, forming 97.3% of product. The reaction was cooled to room temperature and cooled to room temperature<Quenched into aqueous rochelle salt (10 g in 30mL of water) at 30 ℃. After stirring for 1 hour, the phases are separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), over MgSO ₄ Dried, filtered and stripped (azeotroped with ethanol, 20 mL) to give the desired product (4.01 g) as an amber oil. ¹ H NMR confirmed the identity of the product and indicated the presence of 8.6% ethanol (no THF) to give an effective yield of 3.66g, 97%.

Stage 3

Compound 1 free base (3.6 g active material, 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 ℃ (the solid crystallized during heating and did not redissolve). The resulting suspension was cooled to 0 ℃ to 5 ℃ and stirred for 1 hour. The solid was isolated by filtration, washed with ethanol (2X 7 mL) and drained. Further drying in a vacuum oven at 50 ℃ afforded the desired compound 1 (4.62 g, 81%) as the fumarate salt.

Assessment of the degree of deuteration

This was achieved by LCMS-SIM (sim=single ion monitoring), analysis of the retention time at N, N-dimethyltryptamine gave separate ion counts for the respective masses of the three deuterated N, N-dimethyltryptamine compounds (N, N-dimethyltryptamine (D0), α -proton, α -deuterated-N, N-dimethyltryptamine (D1) and α, α -dideutero-N, N-dimethyltryptamine (D2)). The percentage of each component was then calculated from these ion counts.

For example,% d0= [ D0/(d0+d1+d2) ]×100.

HPLC parameters

The system comprises: agilent 1100/1200 series liquid chromatography or equivalent

Column: triart Phenyl; 150X 4.6mm,3.0 μm particle size (Ex: YMC, part number: TPH12S03-1546 PTH)

Mobile phase a: water trifluoroacetic acid (100:0.05%)

Mobile phase B: acetonitrile trifluoroacetic acid (100:0.05%)

Flow rate: 1.0mL/min

Stop time: run time after 31 minutes: 4 minutes

Sample injection volume: 5 μl wash vial: N/A

Column temperature: 30 ℃, combined wavelength: 200nm, (4 nm) reference: N/A

Mass spectral parameters

The system comprises: agilent 6100 series quadrupole LC-MS or equivalent

Drying gas flow rate: 12.0L/min dry gas temperature: 350 DEG C

Atomizer pressure: 35psig

Fragmentation voltage: 110. gain: 1.00

The MS-SIM range is the target mass + -0.1 m/z

Six different alpha, -dideutero-N, N-dimethylprimary amines (D ₂ DMT) compound and an N, N-bis (tridentate-dimethyl) tryptamine (D) ₆ In vitro human liver intrinsic clearance of DMT, SPL028 vii) to study the in vitro human (mixed sex) hepatocytes (427000 cells) from 10 donors were used/mL; final organic concentration 1%, consisting of 84.7% MeCN and 15.3% DMSO), methyl deuteration versus alpha-carbon deuteration on metabolic stability.

Names of Compounds	Intrinsic clearance (μL/min/million cells)	Half-life (min)
			SPL028v	14.1	119
SPL028vi	13.4	126.8
			SPL028ii	9.1	191.1
SPL028iii	8.2	213.9
			SPL028iv	7.7	223.9
SPL028i	6.3	258.3
			SPL028vii(D ₆ )	13.3	122.2
Diltiazem (A)	15.3	15.0
			Diltiazem (B)	17.2	18.2
Diclofenac (A)	155.0	154.0
			Diclofenac (B)	150.1	154.3

TABLE 6.6 different D ₂ Deuterated DMT and D ₈ In vitro intrinsic clearance and half-life of deuterated DMT analog blends in human hepatocytes, ordered by increasing molecular weight levels

With six different D ₂ The data of the deuterated linear regression model fit confirm the previous findings that deuterium enrichment at the alpha-carbon of DMT follows D ₂ Deuteration level (y=d ₂ *-8.07+12.9，r ² =0.690) and an increase in molecular weight while linearly decreasing intrinsic clearance. Also using the formula y=mw 13.9+6.06, r ² =0.923 by fitting a linear regression model to the molecular weights, it was revealed that the molecular weights were 6 different D ₂ Strong predictors of intrinsic clearance of deuterated SPL028 blends.

Initial hepatocyte data did not indicate D ₂ Deuteration and D ₆ Molecular weight and intrinsic clearance of deuterated SPL028 blendsRelation between r ² ＝0.0395。

Example 2

In a second example, the inventors detected that half-life may be increased when N, N-dimethyltryptamine is deuterated at the N, N-dimethyl position.

Two kinds D ₂ DMT (SPL 028i and SPL028 ii) blend, a D ₆ DMT (SPL 028vii, compound 5) and a D ₈ Clearance of-DMT (SPL 028viii, compound 1) analogs

By two kinds of D ₂ Deuterated SLP028 analog blend and two additional deuterated analogs: d (D) ₆ DMT and D ₈ DMT was further assayed for human hepatocytes to measure in vitro intrinsic clearance (362000 cells/mL) using human (mixed sex) hepatocytes from 10 donors.

TABLE 7 two different D ₂ Deuterated DMT, D ₆ Deuterated DMT and D ₈ In vitro intrinsic clearance and half-life of deuterated DMT analog blends in human hepatocytes, ordered by increasing molecular weight levels

It was noted in the data that there may be a secondary kinetic isotope effect, however in human hepatocyte assays, the linear regression model does not support a predictive relationship between molecular weight and intrinsic clearance of SPL026, SPL028i, SPL028ii, SPL029vii and SPL028viii, r2=0.0445.

Example 3

In a third embodiment, the inventors provide that in D ₂ Deuterated SPL028i and D ₈ Evidence of additional protection was observed between deuterated SPL028viii (compound 1). The data support a synergistic effect on metabolic stability when deuterium is present at both the a-position and the N, N-dimethyl position of the compound of formula I or any other compound or composition of any aspect of the invention.

Modeling human metabolism of deuterated DMT using liver mitochondrial fractions

Considering the predicted half-life of DMT in humans for 5 minutes, the inventors expect DMT to be largely decomposed before reaching the human liver. Thus, alternative in vitro assays that are not tissue or organ specific are sought as more suitable systems for mimicking human DMT metabolism. Analysis of non-tissue or organ specific human metabolism can be performed in human liver mitochondrial fractions.

Compared to fold-change predicted in hepatocyte studies, SPL026 and D were predicted by the following assay on human liver mitochondrial (HLMt) fractions ₂ Enhanced fold change between deuterated SPL028 i.

Intrinsic clearance of in vitro human mitochondrial fraction of SPL026 (DMT) with/without MAO-A and MAO-B inhibitors

The intrinsic clearance of SPL026 was determined in vitro by adding A selective and irreversible MAO-A inhibitor (100 nM clojiline) and A MAO-B inhibitor (100 nM amphetamine/selegiline) to 0.5mg/mL human liver mitochondrial fraction, respectively. The addition of the MAO-A substrate serotonin and MAO-B substrate benzylamine as positive controls confirmed the presence of MAO-A and MAO-B and the effect of the clomazone and propynylamphetamine inhibitors.

TABLE 8 intrinsic clearance and half-life of SPL026 in human liver mitochondrial fraction

SPL026 half-life and intrinsic clearance with the MAO-A inhibitor (clojiline) were significantly increased compared to SPL026 datA without the MAO inhibitor, resulting in A10-fold increase in intrinsic clearance. The amphetamine (MAO-B inhibitor) showed no difference in intrinsic clearance of human mitochondria relative to the inhibitor-free fraction. These results indicate that MAO-A, but not MAO-B, plays A role in the metabolism of SPL 026.

SPL026(DMT)、SPL028i(96.6％ D ₂ -DMT)、SPL028iii(36.8％D ₂ Intrinsic clearance of human mitochondrial fractions in vitro of-DMT), SPL028vii (Compound 5) and SPL028viii (Compound 1)

SPL026, SPL028i, SPL028iii and SPL028viii were added to 0.5mg/mL human liver mitochondrial fraction, respectively, and their intrinsic clearance was determined in vitro. The MAO-A substrate 'serotonin' and the MAO-B substrate 'benzylamine' were added as positive controls and the presence of MAO-A and MAO-B was confirmed. Experiments were repeated with the same substances and also with SPL028iii and SPL028 vii.

TABLE 9 intrinsic clearance and half-life of SPL026, SPL028i, SPL028ii, SPL028iii, SPL028vii and SPL028viii in human liver mitochondrial fractions

The half-life of SPL028 compounds increases with increased deuteration levels when compared to SPL 026. D relative to SPL026 ₈ The maximum change in half-life of deuterated SPL028viii (compound 1) was observed (average increase in two replicates by 14-fold). 96.6% D compared to SPL026 ₂ Deuterated SPL028i also showed a large change in half-life (10-fold increase in average of two replicates). 36.80% D compared to SPL026 ₂ Deuterated SPL028iii showed a smaller change in clearance (3.6 fold increase). Independent Welch t-test was performed for each deuterated compound as compared to SPL026, and the results are provided in table 10.

Table 10 shows t-test of the significance of the half-life extension of SPL028 (i-viii)

Conclusion(s)

In the human mitochondrial fraction assay, complete deuteration at the α position of N, N-dimethyltryptamine increases metabolic stability by a factor of 10 via the primary kinetic isotope effect.

In human hepatocyte assays, N-dimethyl deuteration potentially increases metabolic stability via secondary kinetic isotope effects.

Most unexpectedly, in the human mitochondrial fraction assay, the primary and secondary isotopic effects of deuteration at both the α -position and the N, N-dimethyl position in compound 1 synergistically increase metabolic stability, showing a 14-fold increase in metabolic stability.

Claims

1. A deuterated N, N-dimethyltryptamine compound or a composition comprising one or more deuterated N, N-dimethyltryptamine compounds wherein the or each compound is selected from the group consisting of an N, N-dimethyltryptamine compound, an α, α -dideutero-N, N-dimethyltryptamine compound, an α -proton, an α -deuterated-N, N-dimethyltryptamine compound, and pharmaceutically acceptable salts of these compounds for use in therapy.

2. A deuterated N, N-dimethyltryptamine compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy:

and wherein:

each R ¹ Independently selected from H and D;

R ² selected from CH ₃ And CD (compact disc) ₃ ；

R ³ Selected from CH ₃ And CD (compact disc) ₃ ；

Each of which is ^y H is independently selected from H and D.

3. The deuterated N, N-dimethyltryptamine compound of claim 2 wherein each R ¹ Is H.

4. The deuterated N, N-dimethyltryptamine compound of claim 2 or 3 wherein two of them ^y H is D.

5. The deuterated N, N-dimethyltryptamine compound of any of the claims 2 to 4 wherein R ² And R is ³ Are all CD ₃ 。

6. The deuterated N, N-dimethyltryptamine compound or composition of any of the claims 1 to 5, wherein the compound or each compound is in the form of a pharmaceutically acceptable salt.

7. The deuterated N, N-dimethyltryptamine compound or composition of claim 6 wherein the pharmaceutically acceptable salt is a fumarate salt.

8. The deuterated N, N-dimethyltryptamine compound or composition of claim 1 wherein the or each compound is selected from the group consisting of compounds 1 to 5:

9. the deuterated N, N-dimethyltryptamine compound or composition of any of claims 1-8, wherein said deuterated N, N-dimethyltryptamine compound has an increased half-life in a human hepatocyte assay as compared to non-deuterated N, N-dimethyltryptamine.

10. The deuterated N, N-dimethyltryptamine compound or composition of any of the claims 1-9, wherein said deuterated N, N-dimethyltryptamine compound has an increased half-life as compared to non-deuterated N, N-dimethyltryptamine in a mitochondrial fraction assay.

11. The deuterated N, N-dimethyltryptamine compound of any of the claims 2 to 10 or comprisingCompositions of said compounds, wherein R ¹ Is H, and the compound or composition has a molecular weight or average molecular weight of 188.9 to 196.3 g/mol.

12. The deuterated N, N-dimethyltryptamine compound of claim 11 or a composition comprising the compound, wherein R ² And R is ³ Is CH ₃ And the compound or composition has a molecular weight or average molecular weight of 189.2 to 190.3 g/mole.

13. The deuterated N, N-dimethyltryptamine compound of claim 11 or a composition comprising the compound, wherein R ² And R is ³ One or both of which are CDs ₃ And the compound or composition has a molecular weight or average molecular weight of 189.2 to 196.3 g/mole.

14. The deuterated N, N-dimethyltryptamine compound of claim 11 or 13 or a composition comprising said compound, wherein R ² And R is ³ Are all CD ₃ And the compound or composition has a molecular weight or average molecular weight of 194.3 to 196.3 g/mol.

15. The deuterated N, N-dimethyltryptamine compound or composition of any preceding claim in the form of a pharmaceutical dosage form.

16. The deuterated N, N-dimethyltryptamine compound or composition of claim 15 wherein the pharmaceutical dosage form is a parenteral dosage form.

17. The deuterated N, N-dimethyltryptamine compound or composition of claim 15 wherein the pharmaceutical dosage form is a solid dosage form.

18. The deuterated N, N-dimethyltryptamine compound or composition of any of the claims 15-17, wherein the pharmaceutical dosage form comprises a total of 0.001mg to 100mg of the deuterated N, N-dimethyltryptamine compound or composition.

19. The deuterated N, N-dimethyltryptamine compound or composition of any of the claims 1 to 18 for use in a method of treating a mental or neurological disorder in a patient.

20. The deuterated N, N-dimethyltryptamine compound of claim 19, wherein the mental or neurological disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorders, (iii) schizophrenic disorders, (iv) schizophrenic disorders, (v) anxiety disorders, (vi) substance abuse, (vii) motivational deficiency disorders, and (viii) brain injury disorders.

21. The deuterated N, N-dimethyltryptamine compound of claim 20 wherein the disorder is major depressive disorder.

22. The deuterated N, N-dimethyltryptamine compound of claim 20 wherein the disorder is refractory depression.

23. A method of synthesizing a deuterated N, N-dimethyltryptamine compound of formula (I):

comprising reacting a compound of formula (II) with LiAlH ₄ And/or LiAlD ₄ The reaction is carried out,

wherein R is ¹ Is selected from the group consisting of H and D,

R ² selected from CH ₃ And CD (compact disc) ₃ ；

And R is ³ Selected from CH ₃ And CD (compact disc) ₃ 。

24. The method of claim 23, wherein 0.8:1 to 2:1 LiAlH is used ₄ And/or LiAlD ₄ Ratio of the compounds of formula (II).

25. The method of claim 23 or 24, wherein the compound of formula (II) is prepared by:

(i) Allowing a compound of formula (III)

/>

Reacting with two or more coupling agents to produce an activating compound; and

(ii) Allowing the activating compound to have the formula R ² R ³ NH or R ² R ³ The amine reaction of ND is carried out,

wherein R is ¹ 、R ² And R is ³ As defined in claim 23.

26. The method of claim 25, wherein the two or more coupling agents comprise additive coupling agents.

27. The method of claim 26, wherein the two or more coupling agents comprise a carbodiimide.

28. The method of claim 27, wherein the carbodiimide is selected from the group consisting of N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide HCl, dicyclohexylcarbodiimide, and diisopropylcarbodiimide.

29. The method of claim 28, wherein the carbodiimide is N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide HCl.

30. The method of any one of claims 26 to 29, wherein the additive coupling agent is selected from the group consisting of 1-hydroxybenzotriazole, hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazine, N-hydroxysuccinimide, 1-hydroxy-7-aza-1H-benzotriazole, ethyl 2-cyano-2- (oximino) acetate, and 4- (N, N-dimethylamino) pyridine.

31. The method of claim 30, wherein the additive coupling agent is 1-hydroxybenzotriazole.

32. The method of any one of claims 23 to 31, which is a method of synthesizing a compound or composition as defined in any one of claims 1 to 22.

33. The method as recited in claim 32, wherein the or each deuterated N, N-dimethyltryptamine compound is a pharmaceutically acceptable salt.

34. The method as recited in claim 33, further comprising reacting a compound of formula (I) with an acidic reagent to prepare the or each deuterated N, N-dimethyltryptamine compound as a pharmaceutically acceptable salt thereof.