Lysergic acid derivatives with modified LSD-like activity

Abstract

A composition of a compound generally represented by Figure 1A for use in substance-assisted therapy. A method of administering a pharmaceutically effective amount of a compound of Figure 1A to a mammal, which interacts with the serotonin 5-HT2A receptor and induces a psychotropic effect, thereby altering neurotransmission in said mammal, particularly a human. A method of treating an individual by administering a pharmaceutically effective amount of a compound of Figure 1A to said individual.

Description

[Technical Field]

[0001] The present invention relates to both the substance definition and synthesis of lysergic acid derivatives with modified LSD-like activity for use in substance-assisted psychotherapy. [Background technology]

[0002] Psychedelic drugs are substances that induce unique subjective effects, including dreamlike altered consciousness, altered emotions, heightened introspective abilities, visual imagery, pseudohallucinations, synesthesia, mystical experiences, disembodiment, and spontaneous dissolution ( Liechti, 2017 ; Passie, Halpern, Stichtenoth, Emrich, & Hintzen, 2008 ).

[0003] Psychedelic drugs, primarily lysergic acid diethylamide (LSD) and psilocybin, are currently being investigated as potential pharmaceutical agents. Initial clinical trials have demonstrated that steroids can be effective against a range of conditions, including addiction ( Bogenschutz, 2013 ; Bogenschutz et al., 2015 ; Garcia-Romeu et al., 2019 ; Garcia-Romeu, Griffiths, & Johnson, 2014 ; Johnson, Garcia-Romeu, Cosimano, & Griffiths, 2014 ; Johnson, Garcia-Romeu, & Griffiths, 2016 ; Krebs & Johansen, 2012 ), anxiety related to life-threatening illness ( Gasser et al., 2014 ; Gasser, Kirchner, & Passie, 2015 ), and depression ( R. Carhart-Harris et al., 2021 ; R. R. Carhart-Harris, Bolstridge, et al., 2016 ; Davis et al., 2021 ; R. R. Griffiths et al., 2016 ). The potential efficacy of LSD and psilocybin in treating depression (R.R. Griffiths et al., 2016; Roseman, Nutt, & Carhart-Harris, 2017; Ross et al., 2016), and anxiety (R.R. Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016). Several trials investigating the therapeutic effects of LSD, psilocybin, and other psychedelics are also ongoing. There is also evidence that ayahuasca brew, a hallucinogenic drug containing the active psychedelic substance N,N-dimethyltryptamine (DMT) (Dominguez-Clave et al., 2016), may alleviate depression (Dos Santos et al., 2016; Palhano-Fontes et al., 2019; Sanches et al., 2016). In contrast, there is no comparable therapeutic research or elaborate conception of using psychedelic lysergic acid derivatives other than LSD to treat medical conditions.

[0004] While no psychedelics are currently approved for medical use, psilocybin and LSD are already being used in special therapeutic use programs (Schmid, Gasser, Oehen, & Liechti, 2021). LSD is a serotonergic psychedelic drug similar to psilocybin, with similar acute effects but a significantly longer duration of action (8–12 hours for LSD vs. 6 hours for psilocybin) (Becker et al., 2022; Holze et al., 2022; Holze, Vizeli, et al., 2021).

[0005] A potentially important drawback of LSD is its long duration of acute effects, resulting in the need for prolonged patient supervision and associated costs. On the other hand, LSD has advantages over psilocybin and other shorter-acting substances. Notably, LSD use has a long history (Nichols, 2016), and substantial information exists regarding its safety pharmacology (Holze, Caluori, Vizeli, & Liechti, 2021; Nichols & Grob, 2018). The pharmacology of LSD has been well studied (Holze, Caluori, et al., 2021; Holze et al., 2019; Holze, Vizeli, et al., 2021; Holze et al., 2020; Nichols, 2018b; Vizeli et al., 2021), and LSD is one of the most potent psychedelic drugs known in vivo, resulting in the desired effects being sufficiently produced at very low doses (Luethi & Liechti, 2018). Therefore, it is desirable to design LSD analogs that have similar pharmacological properties to LSD in terms of potency, efficacy, and safety, but with similar or preferably different rapid metabolism and therefore a shorter duration of action than classical LSD.

[0006] Novel lysergic acid derivatives may be equally suitable or even superior for treating medical conditions. Specifically, existing psychedelic treatments, such as LSD, psilocybin, and DMT, are not suitable for use in all patients for whom psychedelic-assisted therapy is considered. In general, the availability of several substances with distinct properties is important, and their current lack poses a therapeutic challenge. This will increase for patients in need of psychedelic-assisted therapy, and the demand for such treatments will increase once the efficacy of the first treatments is demonstrated in large-scale clinical trials. For example, some patients may respond with strong adverse reactions to existing treatments, such as psilocybin, exhibiting undesirable effects including headache, nausea / vomiting, anxiety, cardiovascular stimulation, or significant mood dysphoria (Davis et al., 2021; R.R. Griffiths et al., 2016; Holze et al., 2022; Ross et al., 2016). On the other hand, the long duration of action of LSD may be a limiting factor in some cases, and increased treatment session times can contribute significantly to healthcare costs. Furthermore, such long treatment sessions require lengthy planning. Therefore, new compounds with psychedelic-like effects are needed.

[0007] Structurally, LSD, unlike psilocybin, is an ergoline derivative. Although they share some structural features, such as a tryptamine core, the primary pharmacophore of LSD remains significantly different from psychedelic tryptamines such as psilocybin and DMT, and their binding modes and overall pharmacological profiles are distinct (Cao et al., 2022; Rickli, Moning, Hoener, & Liechti, 2016; Wacker et al., 2017). Psychedelics from the ergoline, tryptamine, and phenethylamine classes are all thought to elicit acute psychedelic effects primarily through common stimulation of the 5-HT2A receptor. All serotonergic psychotropic drugs, including LSD, psilocybin, DMT, and mescaline, are agonists at the 5-HT2A receptor (Rickli et al., 2016) and therefore may produce similar overall effects. However, there are differences in how these substances interact with the 5-HT2A receptor at the binding site, and some compounds bind to the receptor but do not produce subjective effects (Cao et al., 2022). Furthermore, there are differences in receptor activation profiles and subsequent signaling pathway activation patterns among substances, which may induce different subjective effects. Furthermore, LSD potently stimulates not only the 5-HT2A receptor but also the 5-HT2B / C, 5-HT1, and D1-3 receptors (Rickli et al., 2016). Psilocin, an active metabolite present in the human body derived from the prodrug psilocybin, also stimulates the 5-HT2A receptor but also inhibits the 5-HT transporter (SERT) (Rickli et al., 2016). Mescaline binds to the 5-HT2A, 5-HT2C, 5-HT1A, and α2A receptors at similar, but significantly lower, concentration ranges. In contrast to LSD, psilocybin and mescaline do not exhibit affinity for D2 receptors (Rickli et al., 2016). Taken together, LSD may have greater dopaminergic activity than psilocybin and mescaline, and psilocybin may have additional effects on SERT. Mescaline and its derivatives, in contrast to psilocybin, do not interact with SERT.In summary, the pharmacological profiles of psychedelic drugs may differ at the 5-HT2A receptor, but apparently also with regard to additional effects at other receptors, which may translate into different, even unique, effect profiles for each substance.

[0008] In humans, the subjective effects of a psychotropic dose of LSD appear within 15–60 minutes, peak between 2–4 hours, and last for 8–12 hours in a dose-dependent manner. The plasma half-life is approximately 4 hours (Holze et al., 2019; Holze et al., 2022; Holze, Vizeli, et al., 2021). The long duration of action of LSD reflects its presence in plasma and is therefore related to the concentration-time curve and plasma half-life in a particular subject (Holze et al., 2019). Similarly, for psilocybin, the presence of the unconjugated form of its active metabolite, psilocin, in plasma defines its duration of action in humans. The plasma half-life of unconjugated psilocin averages 2 hours (Becker et al., 2022), consistent with psilocybin's shorter duration of action compared to LSD. Therefore, compounds structurally related to LSD that have shorter plasma half-lives can be expected to have a similarly shorter duration of action.

[0009] The acute subjective effects of psychedelics are mostly positive in most humans (R.L. Carhart-Harris, Kaelen, et al., 2016; Dolder, Schmid, Mueller, Borgwardt, & Liechti, 2016; Dolder et al., 2017; Holze et al., 2019; Schmid et al., 2015). However, negative subjective effects, such as anxiety, are also seen in many humans (Davis et al., 2021; R.R. Griffiths et al., 2016; Ross et al., 2016), likely depending on the dose used (Holze et al., 2022), personality traits (set), environment (physical and social), and other factors (Studerus, Gamma, Kometer, & Vollenweider, 2012). Inducing an overall positive acute response to psychedelics is important because several studies have shown that more positive experiences predict greater long-term therapeutic effects of psychedelics (Garcia-Romeu et al., 2014; R.R. Griffiths et al., 2016; Ross et al., 2016). Even in healthy subjects, more positive acute responses to psychedelics, including LSD, have been shown to be associated with more positive long-term effects on wellness (R. Griffiths, Richards, Johnson, McCann, & Jesse, 2008; Schmid & Liechti, 2018).

[0010] LSD has associated acute side effects of varying severity depending on the subject treated, including elevated blood pressure, nausea and vomiting, elevated body temperature and blood sugar, numbness, tremors, negative bodily sensations, and mood changes (Holze, Caluori, et al., 2021). Such side effects of a substance are often related to interactions with pharmacological targets. For example, interactions with adrenergic receptors can result in inappropriate clinical cardiostimulatory properties. Furthermore, changes in the relative activation profile of serotonin 5-HT receptors and other targets alter the quality of psychotropic effects. The binding potency, binding mode, and potency of activating subsequent signaling pathways at the 5-HT2A receptor, as well as changes in the lipophilicity of the molecule, can largely determine the clinical dose required to induce psychotropic effects. Modifications that alter the metabolic stability of a compound can also significantly alter the duration of action of the substance.

[0011] New LSD-based derivatives, i.e., lysergic acid-based derivatives, are needed to provide substances with improved effect profiles, including, but not limited to, more positive effects, fewer side effects, different qualitative effects, and altered duration of acute effects. Summary of the Invention

[0012] The present invention provides compositions of compounds generally represented by FIG. 1A and termed "lysergic acid amides" for use in substance-supported therapy.

[0013] Thus, Class 1 is the lysergic acid amides represented in Figures 2A-2G, 3A-3H, 4A-4G, 5A-5C, and 6A-6C, where R' consists of the substituents shown in the subclasses designated Classes 1a-1n, and R consists of: a) R8', b) any of the substituents of subclasses 1a to 1n and as defined in the specific classes of R8′=1a to 1l, c) hydrogen, C1-C5 alkyl, branched C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkylcycloalkyl, C2-C5 alkenyl, branched C3-C5 alkenyl, C2-C5 alkynyl, branched C4-C5 alkynyl, or d) As specifically indicated in classes 1a to 1n; If it is defined,

[0014] In Class 1a, a subclass of Class 1, the substituent R8' consists of F1-F11 fluorine-substituted C1-C5 alkyl groups or branched C3-C5 alkyl groups, each optionally in combination with D1-D10 deuterons, and / or hydroxy and / or carbonyl;

[0015] In Class 1b, a subclass of Class 1, the substituent R8' consists of F1 to F13 fluorine-substituted C3 to C7 alkenyl groups, optionally in combination with D1 to D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl, and the double bond is away from the nitrogen;

[0016] In Class 1c, a subclass of Class 1, the substituent R8' is in combination with F1 to F11 fluorine-substituted C3 to C6 cycloalkyl groups, optionally D1 to D10 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1 to C3 alkyl and / or deuterated and non-deuterated C1 to C3 alkenyl;

[0017] In Class 1d, a subclass of Class 1, the substituent R8' is in combination with F1 to F11 fluorine-substituted C3 to C6 cycloalkyl groups, optionally D1 to D10 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1 to C3 alkyl and / or deuterated and non-deuterated C1 to C3 alkenyl;

[0018] In Class 1e, a subclass of Class 1, wherein the substituent R8' consists of F1-F11 fluorine-substituted C3-C7 alkynyl groups, optionally in combination with D1-D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl, with a triple bond separating the amide nitrogen;

[0019] In Class 1f, a subclass of Class 1, wherein the substituent R8' consists of a F0-F7 fluorine-substituted C2-C4 alkenyl group attached to the nitrogen through an unsaturated moiety, forming an enamide, optionally in combination with a D1-D7 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl;

[0020] In Class 1g, a subclass of Class 1, wherein the substituent R' consists of an F1-F5 fluorine-substituted C2-C4 alkylalkynyl group attached to the nitrogen at an unsaturated moiety, forming an ynamide, optionally in combination with D1-D4 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl;

[0021] In Class 1h, a subclass of Class 1, wherein the substituent R8' consists of F1 to F13 fluorine-substituted C1-3-O-C1-3 alkoxyalkyl groups, optionally in combination with D1 to D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl;

[0022] In Class 1i, a subclass of Class 1, the substituent R8' consists of an F0-F7 fluorine-substituted C1-C3 alkoxy group or a C3-C4 cycloalkoxy group, each optionally in combination with a D1-D7 deuteron, and / or nitrile, and / or hydroxy and / or carbonyl;

[0023] In Class 1j, a subclass of Class 1, the substituent R8' consists of a nitrile bonded to a C1-C3 alkyl group, optionally in combination with F1-F7 fluorine, and / or D1-D7 deuteron, and / or hydroxy and / or carbonyl;

[0024] In Class 1k, a subclass of Class 1 wherein the substituent R8 consists of a C1-C3 alkyl group containing D1-D6 deuterons in combination with optional F1-F6 fluorines, optionally in combination with hydroxy and / or carbonyl; R8' consists of hydrogen, a C1-C6 alkyl or a C3-C5 cycloalkyl or a C4-C7 cycloalkylalkyl group, optionally in combination with hydroxy and / or carbonyl;

[0025] In Class 11, a subclass of Class 1, the substituent R8 consists of a C1-C3 alkyl group containing D1-D7 deuterons or F1-F7 fluorines, or D1-D6 deuterons in combination with optional F1-F6 fluorines, optionally in combination with hydroxy and / or carbonyl; R8' consists of a C2-C8 alkenyl or C2-C8 alkynyl group, optionally in combination with nitrile, and / or hydroxy and / or carbonyl;

[0026] In Class 1m, a subclass of Class 1, wherein the substituents R8 and R8' are joined together to form an azacycloalkane having an amide nitrogen, consisting of a C3-C6 alkylene group containing D1-D10 deuterons or F1-F10 fluorines, or D1-D9 deuterons in combination with optional F1-F9 fluorines, optionally in combination with nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl, and / or deuterated and non-deuterated C2-C3 alkynyl groups;

[0027] In Class 1n, a subclass of Class 1, the substituents R8 and R8' are linked to each other to form an azacycloalkane having an amide nitrogen, consisting of a C3-C6 alkylene group having attached non-deuterated or deuterated C1-C3 alkenyl and / or non-deuterated or deuterated C2-C3 alkynyl groups, the azacycloalkane-forming alkylene groups optionally further combined with nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl groups.

[0028] The present invention provides compositions of compounds for use in substance-assisted therapy, generally represented by Figure 1A and termed "lysergic acid amides," also represented by Class 2, consisting of 6-substituted 6-nor-lysergic acid diethylamides as depicted in Figures 4A-5C, where R6 consists of the substituents set forth in the subclasses termed Classes 2a-2i, whereby R6 consists of:

[0029] In Class 2a, a subclass of Class 2, the substituent R6 consists of F1-F11 fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl groups, each optionally in combination with D1-D10 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl;

[0030] In Class 2b, a subclass of Class 2, the substituent R6 consists of F1 to F13 fluorine-substituted C3 to C7 alkenyl groups, optionally in combination with D1 to D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl, and the alkenyl double bond is spaced from the nitrogen;

[0031] In Class 2c, a subclass of Class 2, the substituent R6 consists of an F1-F11 fluorine-substituted C3-C7 alkynyl group having a triple bond distal to the N6 nitrogen, optionally in combination with a D1-D10 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl. When the substituent R6 contains at least one nitrile, one hydroxy, or one carbonyl group, R6 can also consist of a C3-C7 alkynyl group having a triple bond distal to the N6 nitrogen, optionally in combination with a D1-D10 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl;

[0032] In Class 2d, a subclass of Class 2, the substituent R6 consists of C3-C6 cycloalkyl groups, optionally in combination with F1-F11 fluorines, and / or D1-D11 deuterons, and / or nitriles, and / or hydroxy, and / or carbonyls, and / or deuterated and non-deuterated C1-C3 alkyls, and / or deuterated and non-deuterated C1-C3 alkenyls and / or deuterated and non-deuterated C2-C3 alkynyls;

[0033] In Class 2e, a subclass of Class 2, substituent R6 consists of F1 to F17 fluorine-substituted C4 to C9 cycloalkylalkyl groups, optionally in combination with D1 to D16 deuterons, and / or nitriles, and / or hydroxy, and / or carbonyls, and / or deuterated and non-deuterated C1 to C3 alkyls, and / or deuterated and non-deuterated C1 to C3 alkenyls and / or deuterated and non-deuterated C2 to C3 alkynyls. If the substituent R6 is not a cyclopropylmethyl attached to the N6 nitrogen of the ergoline structure by an exocyclic methylene unit, or is a cyclopropylmethyl attached to the N6 nitrogen of the ergoline structure by an exocyclic methylene unit and contains at least one nitrile, one hydroxyl or one carbonyl group, R6 may also consist of a C4-C9 cycloalkylalkyl group, optionally in combination with D1-D17 deuterons, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C1-C3 alkynyl groups;

[0034] In Class 2f, a subclass of Class 2, wherein the substituent R6 consists of a F0-F7 fluorine-substituted C2-C4 alkenyl group attached to the nitrogen at an unsaturated moiety, forming an enamide, optionally in combination with a D1-D7 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl;

[0035] Within Class 2g, a subclass of Class 2, the substituent R6 consists of a C3-C6 oxacycloalkyl, a C3-C9 oxacycloalkylalkyl, a C3-C6 thiacycloalkyl, or a C3-C9 thiacycloalkylalkyl group, each optionally in combination with F1-F19 fluorine, and / or D1-D19 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl;

[0036] In Class 2h, a subclass of Class 2, the substituent R6 consists of F0-F11 fluorine-substituted C1-C5 alkoxy or C3-C6 cycloalkoxy, or C2-C6 alkenoxy groups, each optionally in combination with D1-D11 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl;

[0037] In Class 2i, a subclass of Class 2, the substituent R6 consists of an aryl, heteroaryl, arylmethyl, or heteroarylmethyl group, each optionally bonded to F0-F7 fluorines and / or D1-D7 deuterons, and / or one or more of the following substituents, which themselves may be optionally fluorinated and / or deuterated: halogen, nitrile, nitro, hydroxy, carbonyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 alkenoxy, C3-C6 alkynoxy, methylenedioxy, C1-C4 alkylthio, C3-C6 alkenylthio, C3-C6 alkynylthio, C3-C6 cycloalkylthio. Furthermore, the R6 substituents defined above for Class 2i may be further cyclized.

[0038] The present invention provides compositions of compounds, generally represented by FIG. 1A and termed "lysergic acid amides," for use in substance-assisted therapy, also represented by Class 3 (FIG. 6A), consisting of any possible combination of substituents R8 and R8' from Class 1 and its subclasses 1a-1n (FIGS. 2A-3H) with substituent R6 from Class 2 and its subclasses 2a-2i (FIGS. 4A-5C).

[0039] The present invention provides compositions of compounds, generally represented by Figure 1A and termed "lysergic acid amides," for use in substance-assisted therapy. These compounds are also represented by Class 4 (Figure 6B), consisting of any possible combination of substituents R8 and R8' from Class 1 and its subclasses 1a-1n (Figures 2A-3H) with substituent R6 from Class 2 and its subclasses 2a-2i (Figures 4A-5C), with combinations of N1 nitrogen substituents on the ergoline moiety from the following groups: a) any acyl; b) unsubstituted and substituted carbamoyl; c) amide-linked amino acids; d) alkyl, alkenyl, or alkynyl; e) alkoxy, alkenoxy, or alkynoxy; f) any of the substituents described in a)-e) substituted with one or more fluorine atoms; g) any of the substituents described in a)-e) substituted with one or more deuteron atoms; and h) any of the substituents described in a)-e) substituted with one or more fluorine atoms and one or more deuteron atoms.

[0040] The present invention provides a composition of matter, generally depicted in FIG. 1A, termed "lysergic acid amide," for use in substance-assisted therapy. This is also represented by Class 5 (Figure 6C), which consists of a mono- to fully deuterated ergoline core structure, further composed of any possible combination of substituents R and R from Class 1 and its subclasses 1a-1n (Figures 2A-3H) with substituent R from Class 2 and its subclasses 2a-2i (Figures 4A-5C), with a combination of N nitrogen substituents on the ergoline moiety from the following groups: a) hydrogen; b) any acyl; c) unsubstituted and substituted carbamoyl; d) amide-linked amino acids; e) alkyl, alkenyl, or alkynyl; f) alkoxy, alkenoxy, or alkynoxy; g) any of the substituents described in a)-f) substituted with one or more fluorine atoms; h) any of the substituents described in a)-f) substituted with one or more deuteron atoms; or i) any of the substituents described in a)-f) substituted with one or more fluorine atoms and one or more deuteron atoms.

[0041] The present invention provides a method for altering neurotransmission by administering to a mammal a pharmaceutically effective amount of a compound of FIG. 1A to interact with the serotonin 5-HT2A receptor in a mammal, particularly a human, and inducing a psychoactive effect.

[0042] The present invention provides a method of treating an individual by administering to the individual a pharmaceutically effective amount of a compound of Figure 1A, thereby treating the individual.

[0043] The present disclosure will be more fully appreciated, and many of the attendant advantages will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, in which: [Brief explanation of the drawings]

[0044] [Figure 1] A shows the general chemical structure of lysergic acid derivatives within the scope of the present invention, more specifically, lysergic acid amides with various substituents at the 1-position (defined as R1), 6-position (defined as R6), and 8-position attached amide moieties (defined as R8 and R8'); B shows the ergoline core structure along with its numbering; and C shows the chemical structure of LSD and its stereochemical designation. [Figure 2] A indicates compounds defined as class 1, B indicates compounds of subclass 1a, C indicates compounds of subclass 1b, D indicates compounds of subclass 1c, E indicates compounds of subclass 1d, F indicates compounds of subclass 1e, and G indicates compounds of subclass 1f. [Figure 3] A indicates a compound of subclass 1g, B indicates a compound of subclass 1h, C indicates a compound of subclass 1i, D indicates a compound of subclass 1j, E indicates a compound of subclass 1k, F indicates a compound of subclass 11, G indicates a compound of subclass 1m, and H indicates a compound of subclass 1n. [Figure 4]A indicates a compound defined as class 2, B indicates a compound of subclass 2a, C indicates a compound of subclass 2b, D indicates a compound of subclass 2c, E indicates a compound of subclass 2d, F indicates a compound of subclass 2e, and G indicates a compound of subclass 2f. [Figure 5] A denotes compounds of subclass 2g, B denotes compounds of subclass 2h, and C denotes compounds of subclass 2j. [Figure 6] A indicates class 3 compounds, B indicates class 4 compounds, and C indicates class 5 compounds. [Figure 7] A to N represent preparation examples of lysergic acid derivatives shown in FIG. 1, where A represents compound 2a, B represents compound 2b, C represents compound 2c, D represents compound 2d, E represents compound 2e, F represents compound 2f, G represents compound 2g, H represents compound 2h, I represents compound 2i, J represents compound 2j, K represents compound 2k, L represents compound 21, M represents compound 2m, and N represents compound 2n. [Figure 8] A to N represent preparation examples of lysergic acid derivatives shown in FIG. 1, where A represents compound 12a, B represents compound 12b, C represents compound 12c, D represents compound 12d, E represents compound 12e, F represents compound 12f, G represents compound 12g, H represents compound 13, I represents compound 14a, J represents compound 14b, K represents compound 14c, L represents compound 16a, M represents compound 16b, and N represents compound 16c. [Figure 9] The synthetic routes to lysergic acid derivatives 2a-2k, 2l, and 2m are summarized below. [Figure 10] The synthetic route to lysergic acid derivative 2n is summarized below. [Figure 11] The synthetic routes to lysergic acid derivatives 12a-12g, 13, and 14a-14c are summarized below. [Figure 12] The synthetic routes to lysergic acid derivatives 16a-16c are summarized below. [Figure 13] A to J are graphs showing the metabolism of 10 novel lysergic acid derivatives, where A represents compound 2c, B represents compound 2d, C represents compound 2e, D represents compound 2h, E represents compound 2j, F represents compound 21, G represents compound 2n, H represents compound 12c, I represents compound 16a, and J represents compound 16b. [Figure 14] The receptor interactions of novel lysergic acid derivatives are described, compared with LSD and psilocin. DETAILED DESCRIPTION OF THE INVENTION

[0045] The present invention provides compositions of compounds termed "lysergic acid amides" for use in substance-assisted therapy, generally represented by Figure 1A. To better understand the problem, such compounds are depicted in Figures 2A-6C.

[0046] Thus, Class 1 is the lysergic acid amides depicted in Figures 2A-3H, where R' consists of the substituents shown in the subclasses designated Classes 1a-1n, and R consists of: a) R8', b) any of the substituents of subclasses 1a to 1n and as defined in the specific classes of R8′=1a to 1l, c) hydrogen, C1-C5 alkyl, branched C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkylcycloalkyl, C2-C5 alkenyl, branched C3-C5 alkenyl, C2-C5 alkynyl, branched C4-C5 alkynyl, or d) As specifically indicated in classes 1a to 1n; If it is defined,

[0047] In Class 1a, a subclass of Class 1, the substituent R8' consists of F1-F11 fluorine-substituted C1-C5 alkyl groups or branched C3-C5 alkyl groups, each optionally in combination with D1-D10 deuterons, and / or hydroxy and / or carbonyl;

[0048] In Class 1b, a subclass of Class 1, the substituent R8' consists of F1 to F13 fluorine-substituted C3 to C7 alkenyl groups, optionally in combination with D1 to D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl, and the double bond is away from the nitrogen;

[0049] In Class 1c, a subclass of Class 1, the substituent R8' is in combination with F1 to F11 fluorine-substituted C3 to C6 cycloalkyl groups, optionally D1 to D10 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1 to C3 alkyl and / or deuterated and non-deuterated C1 to C3 alkenyl;

[0050] In Class 1d, a subclass of Class 1, the substituent R8' is in combination with F1 to F11 fluorine-substituted C3 to C6 cycloalkyl groups, optionally D1 to D10 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1 to C3 alkyl and / or deuterated and non-deuterated C1 to C3 alkenyl;

[0051] In Class 1e, a subclass of Class 1, wherein the substituent R8' consists of F1-F11 fluorine-substituted C3-C7 alkynyl groups, optionally in combination with D1-D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl, with a triple bond separating the amide nitrogen;

[0052] In Class 1f, a subclass of Class 1, wherein the substituent R8' consists of a F0-F7 fluorine-substituted C2-C4 alkenyl group attached to the nitrogen through an unsaturated moiety, forming an enamide, optionally in combination with a D1-D7 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl;

[0053] In Class 1g, a subclass of Class 1, wherein the substituent R' consists of an F1-F5 fluorine-substituted C2-C4 alkylalkynyl group attached to the nitrogen at an unsaturated moiety, forming an ynamide, optionally in combination with D1-D4 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl;

[0054] In Class 1h, a subclass of Class 1, wherein the substituent R8' consists of F1 to F13 fluorine-substituted C1-3-O-C1-3 alkoxyalkyl groups, optionally in combination with D1 to D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl;

[0055] In Class 1i, a subclass of Class 1, the substituent R8' consists of an F0-F7 fluorine-substituted C1-C3 alkoxy group or a C3-C4 cycloalkoxy group, each optionally in combination with a D1-D7 deuteron, and / or nitrile, and / or hydroxy and / or carbonyl;

[0056] In Class 1j, a subclass of Class 1, the substituent R8' consists of a nitrile bonded to a C1-C3 alkyl group, optionally in combination with F1-F7 fluorine, and / or D1-D7 deuteron, and / or hydroxy and / or carbonyl;

[0057] In Class 1k, a subclass of Class 1, wherein the substituent R8 consists of a C1-C3 alkyl group containing D1-D6 deuterons in combination with optional F1-F6 fluorines, optionally in combination with hydroxy and / or carbonyl; R8' consists of hydrogen, a C1-C6 alkyl, or a C3-C5 cycloalkyl, or a C4-C7 cycloalkylalkyl group, optionally in combination with hydroxy and / or carbonyl;

[0058] In Class 11, a subclass of Class 1, wherein the substituent R8 consists of a C1-C3 alkyl group containing D1-D7 deuterons or F1-F7 fluorines, or D1-D6 deuterons combined with optional F1-F6 fluorines, optionally in combination with hydroxy and / or carbonyl; R8' consists of a C2-C8 alkenyl or C2-C8 alkynyl group, optionally in combination with nitrile, and / or hydroxy and / or carbonyl;

[0059] In Class 1m, a subclass of Class 1, wherein the substituents R8 and R8' are bonded to each other to form an azacycloalkane having an amide nitrogen, consisting of a C3-C6 alkylene group containing D1-D10 deuterons or F1-F10 fluorines, or D1-D9 deuterons in combination with optional F1-F9 fluorines, optionally in combination with nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl, and / or deuterated and non-deuterated C2-C3 alkynyl groups;

[0060] In Class 1n, a subclass of Class 1, the substituents R8 and R8' are linked to each other to form an azacycloalkane having an amide nitrogen, consisting of a C3-C6 alkylene group having attached non-deuterated or deuterated C1-C3 alkenyl and / or non-deuterated or deuterated C2-C3 alkynyl groups, the azacycloalkane-forming alkylene groups optionally further combined with nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl groups.

[0061] The present invention also provides compositions of compounds for use in substance-assisted therapy, generally represented by Figure 1A, termed "lysergic acid amides," also represented by Class 2, which consist of 6-substituted 6-nor-lysergic acid diethylamides as shown in Figures 4A-5C, where R6 consists of the substituents set forth in the subclasses termed Classes 2a-2i, and R6 consists of:

[0062] In Class 2a, a subclass of Class 2, the substituent R6 consists of F1-F11 fluorine-substituted C1-C5 alkyl or branched C3-C5 alkyl groups, each optionally in combination with D1-D10 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl;

[0063] In Class 2b, a subclass of Class 2, the substituent R6 consists of F1 to F13 fluorine-substituted C3 to C7 alkenyl groups, optionally in combination with D1 to D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl, and the alkenyl double bond is spaced from the nitrogen;

[0064] In Class 2c, a subclass of Class 2, the substituent R6 consists of an F1-F11 fluorine-substituted C3-C7 alkynyl group having a triple bond distal to the N6 nitrogen, optionally in combination with a D1-D10 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl. When the substituent R6 contains at least one nitrile, one hydroxy, or one carbonyl group, R6 can also consist of a C3-C7 alkynyl group having a triple bond distal to the N6 nitrogen, optionally in combination with a D1-D10 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl;

[0065] In Class 2d, a subclass of Class 2, the substituent R6 consists of C3-C6 cycloalkyl groups, optionally in combination with F1-F11 fluorines, and / or D1-D11 deuterons, and / or nitriles, and / or hydroxy, and / or carbonyls, and / or deuterated and non-deuterated C1-C3 alkyls, and / or deuterated and non-deuterated C1-C3 alkenyls and / or deuterated and non-deuterated C2-C3 alkynyls;

[0066] In Class 2e, a subclass of Class 2, substituent R6 consists of F1 to F17 fluorine-substituted C4 to C9 cycloalkylalkyl groups, optionally in combination with D1 to D16 deuterons, and / or nitriles, and / or hydroxy, and / or carbonyls, and / or deuterated and non-deuterated C1 to C3 alkyls, and / or deuterated and non-deuterated C1 to C3 alkenyls and / or deuterated and non-deuterated C2 to C3 alkynyls. If the substituent R6 is not a cyclopropylmethyl attached to the N6 nitrogen of the ergoline structure by an exocyclic methylene unit, or is a cyclopropylmethyl attached to the N6 nitrogen of the ergoline structure by an exocyclic methylene unit and contains at least one nitrile, one hydroxyl or one carbonyl group, R6 may also consist of a C4-C9 cycloalkylalkyl group, optionally in combination with D1-D17 deuterons, and / or nitrile, and / or hydroxyl, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C1-C3 alkynyl groups;

[0067] In Class 2f, a subclass of Class 2, wherein the substituent R6 consists of a F0-F7 fluorine-substituted C2-C4 alkenyl group attached to the nitrogen at an unsaturated moiety, forming an enamide, optionally in combination with a D1-D7 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl;

[0068] Within Class 2g, a subclass of Class 2, the substituent R6 consists of a C3-C6 oxacycloalkyl, a C3-C9 oxacycloalkylalkyl, a C3-C6 thiacycloalkyl, or a C3-C9 thiacycloalkylalkyl group, each optionally in combination with F1-F19 fluorine, and / or D1-D19 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl;

[0069] In Class 2h, a subclass of Class 2, the substituent R6 consists of F0-F11 fluorine-substituted C1-C5 alkoxy or C3-C6 cycloalkoxy, or C2-C6 alkenoxy groups, each optionally in combination with D1-D11 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl;

[0070] In Class 2i, a subclass of Class 2, the substituent R6 consists of an aryl, heteroaryl, arylmethyl, or heteroarylmethyl group, each optionally in combination with F0-F7 fluorines and / or D1-D7 deuterons, and / or one or more of the following substituents, which themselves may be optionally fluorinated and / or deuterated: halogen, nitrile, nitro, hydroxy, carbonyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 alkenoxy, C3-C6 alkynoxy, methylenedioxy, C1-C4 alkylthio, C3-C6 alkenylthio, C3-C6 alkynylthio, C3-C6 cycloalkylthio. Furthermore, the R6 substituents defined above for Class 2i may be further cyclized.

[0071] The present invention provides compositions of compounds, generally represented by FIG. 1A and termed "lysergic acid amides," for use in substance-assisted therapy, also represented by Class 3 (FIG. 6A), consisting of any possible combination of substituents R8 and R8' from Class 1 and its subclasses 1a-1n (FIGS. 2A-3H) with substituent R6 from Class 2 and its subclasses 2a-2i (FIGS. 4A-5C).

[0072] The present invention also provides compositions of compounds generally represented by FIG. 1A and termed "lysergic acid amides," for use in substance-assisted therapy, also represented by Class 4 (FIG. 6B), consisting of any possible combination of substituents R and R from Class 1 and its subclasses 1a-1n (FIGS. 2A-3H) with substituent R from Class 2 and its subclasses 2a-2i (FIGS. 4A-5C), with a combination of N1 nitrogen substituents on the ergoline structure from the following groups: a) any acyl, b) unsubstituted and substituted carbamoyl, c) amide-linked amino acids, d) alkyl, alkenyl, or alkynyl, e) alkoxy, alkenoxy, or alkynoxy, f) any of the substituents described in a) through e) substituted with one or more fluorine atoms, g) any of the substituents described in a) through e) substituted with one or more deuteron atoms, or h) any of the substituents described in a) through e) substituted with one or more fluorine atoms and one or more deuteron atoms.

[0073] The present invention provides compositions of compounds for use in substance-assisted therapy, generally represented in FIG. 1A and termed "lysergic acid amides," which are also represented by Class 5 (FIG. 6C), comprised of a mono- to fully deuterated ergoline core structure, further comprising any possible combination of substituents R8 and R8′ from Class 1 and its subclasses 1a-1n (FIGS. 2A-3H) and substituent R6 from Class 2 and its subclasses 2a-2i (FIGS. 4A-5C), on the ergoline moiety from the following groups: having a combination of N1 nitrogen substituents of: a) hydrogen; b) any acyl; c) unsubstituted and substituted carbamoyl; d) amide-linked amino acids; e) alkyl, alkenyl, or alkynyl; f) alkoxy, alkenoxy, or alkynoxy; g) any of the substituents described in a) to f) substituted with one or more fluorine atoms; h) any of the substituents described in a) to f) substituted with one or more deuteron atoms; i) any of the substituents described in a) to f) substituted with one or more fluorine atoms and one or more deuteron atoms.

[0074] The compound represented by Figure 1A is a basic compound that forms an acid addition salt with an inorganic or organic acid. Therefore, such salts form pharmaceutically acceptable inorganic or organic salts with a pharmaceutically acceptable inorganic or organic base. The acid that forms such a salt can be selected from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as carbonic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, and benzoic acid. Thus, examples of such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, formate, acetate, propionate, decanoate, caprylate, acrylate, isobutyrate, caprate, heptanoate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, sulfonate, phenylacetate, citrate, lactate, glycolate, tartrate, methanesulfonate, propanesulfonate, mandelate, and the like. Any hydrate form and any ratio of the compound represented in FIG. 1A to a pharmacologically acceptable inorganic or organic acid can be formed. Preferred pharmaceutically acceptable salts are those formed with tartaric acid and maleic acid.

[0075] Any of the pharmaceutically acceptable salts may also contain one or more deuteron or fluorine atoms and include any stereoisomers.

[0076] General chemical terms used in Figures 1A-12 have their usual meanings. The attachment of a generically named substituent to a molecule can occur at any part of the substituent. For example, the term "alkyl" includes unbranched and branched alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like. In another example, the term "cycloalkyl" includes groups such as cyclopropyl, cyclobutyl, and cyclopentyl. In yet another example, the term "alkylcycloalkyl" is used as "cycloalkylalkyl" and includes groups such as those outlined above, consisting of an alkyl or bonded to a cycloalkyl, as outlined above. Some examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, (2-methylcyclopropyl)methyl, and the like. The term "oxacycloalkyl" includes groups such as oxetane, tetrahydrofuran, and the like. Additionally, the term "alkenyl" includes unbranched and branched alkenyl groups, including groups such as vinyl (ethenyl), 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl, groups having cis, trans, E, or Z configurations, in any combination or purity. Additionally, the term "alkenyl" also includes alkylidenes, such as methylidene and ethylidene. Thus, the number 1 in "C1-C3 alkenyl" or "C1-C3 alkenyl" can be used for methylidene, for example, when an H2C= group is attached to the ring. The term "alkylalkenyl" consists of any combination and branching of alkenyl groups with alkyl groups having cis, trans, E, or Z configurations, in any combination or purity. Examples of such terms are 1-prop-2-enyl, 2-prop-1-enyl, 1-but-2-enyl, 1-but-3-enyl, 1-methyl-1-prop-2-enyl, etc. The term "alkynyl" includes unbranched and branched alkynyl groups, including groups such as ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 3-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, phenylethynyl, and the like.The term "alkylalkynyl" consists of any combination and branching of an alkynyl group with an alkyl group. The term "alkylene" defines any unbranched or branched alkyl group that serves as a connection between two molecular entities, substituents, or groups, or as an entity that allows for the construction of a cycle with molecular entities, substituents, or groups. Some examples include methylene, ethylene, propylene, or methylpropylene, and examples of rings include aziridine, azetidine, and oxetane. A phenyl group is defined as a substituent that can have zero or any number of substituents, such as deuterons, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, methylthio, hydroxy, nitrile, and methylenedioxy. Such phenyl groups can be further cyclized. An aryl group is defined as a substituent containing one or more aromatic (cyclized) homocyclic rings, such as phenyl or naphthyl. Heteroaryl groups are defined as any aromatic ring system, such as thiophene, furan, pyrrole, selenophene, pyrazole, oxazole, thiazole, isoxazole, isothiazole, benzothiophene, benzofuran, pyridine, pyrimidine, pyrazine, etc. Such heteroaryl groups can be further cyclized. A benzyl substituent defines a phenylmethyl group, which can have no or any number of substituents on the methylene or phenyl units, such as deuterons, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, methylthio, hydroxy, nitrile, methylenedioxy, etc. Such benzyl groups can be further cyclized. Heteroarylmethyl consists of a heteroaryl group, as defined before being attached to the methylene unit, which can have no or any number of substituents on the methylene or phenyl units, such as deuterons, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, methylthio, hydroxy, nitrile, methylenedioxy, etc. Such heteroarylmethyl groups can be further cyclized. The term "halogen" includes fluorine, chlorine, bromine, and iodine substituents, and the number of halogens may be as high as one chemically possible, which corresponds to a fully halogenated substituent, also known as the term "polyhalogenated."The term "deuterated" includes the number of deuteron atoms, which can be as many as chemically possible, and corresponds to a fully deuterated substituent, also known as "multiple deuterated." Any ratio and additional stereoisomers resulting from the introduction of fluorine and / or deuterium atoms are included. Terms such as "F0-F11 fluoride" or "D0-D5 deuterated" correspond to unfluorinated to up to undeca-fluorinated (11 fluorine atoms) and undeuterated to pentadeuterated (5 deuterons), respectively. Similarly, "F0-F11 fluoride" is also used as an example. 11 The term "A" is used in conjunction with the term "fluorine," which means that the substituent may also not contain fluorine and may therefore be non-fluorinated. m -A n (where m and n are numbers from zero to 99 and indicate the amount of atom A) describes, in total, the number of atoms A in a given group or substituent. An example of such a term is C3-C6 cycloalkylalkyl, meaning it can include cyclopropyl, cyclobutyl, cyclopropylmethyl, or cyclobutylethyl, or any other cycloalkylalkyl group consisting of 3 to 6 carbons. In a similar manner, an example would be "C 1~3 -OC 1~3 " represents an alkoxyalkyl group consisting of an alkyl group having 1 to 3 carbon atoms bonded to an oxygen atom which is itself bonded to an alkyl group having 1 to 3 carbon atoms. Representative alkoxyalkyl groups may be, by way of example, methoxymethyl, methoxyethyl, ethoxymethyl, and the like. The number of atoms or substituents may be indicated either in plain text or in subscript. Thus, by way of example, "C 1~3 -OC 1~3 is used equivalently to "C1-3-O-C1-3." The term "lysergic acid derivative" is used synonymously with the terms "lysergic acid amide," "lysergic acid amides," or "substituted lysergic acid amide," or "lysergic acid derivative," all of which refer to the compounds of the present invention.

[0077] Those skilled in the art will understand that the compounds of the present invention have at least two chiral carbons and therefore can exist as racemates, as individual enantiomers, diastereomers, or epimers, and as mixtures of individual enantiomers, diastereomers, or epimers in any ratio. Those skilled in the art will also understand that compounds of the present invention in which R, R, R, or R′ in FIG. 1A comprises a chiral substituent have additional asymmetric centers creating the additional optical isomers described above, and that such compounds are within the scope of the invention. While it is a preferred embodiment of the present invention that the compounds of the present invention exist as pure diastereomers having the 5R,8R absolute configuration within the ergoline core structure, the present invention also contemplates compounds of the present invention existing as racemates or mixtures of pure forms of individual enantiomers or diastereomers.

[0078] Those skilled in the art will also recognize that certain of the compounds of the present invention possess at least one double bond that results in cis / trans or E / Z configurational isomerism, depending on the substituents on that double bond. While it is a preferred embodiment of the present invention that the compounds of the present invention are used as pure configurational isomers, the present invention also contemplates compounds of the present invention existing as individual cis / trans or E / Z mixtures, respectively.

[0079] Individual enantiomers, diastereomers, and epimers can be prepared by non-chiral or chiral chromatography of the racemic, enantiomeric, or diastereomeric or epimeric mixtures of the compounds represented in Figure 1A, or by crystallization fractionation of a racemic, enantiomerically, diastereomeric, or epimer-enriched compound of the present invention and its salt prepared from a chiral or non-chiral acid. Alternatively, the compound of the present invention can be regenerated by reacting the compound of the present invention with a chiral or non-chiral auxiliary and an enantiomer, diastereomer, or epimer separated by chromatography or crystallization, followed by removal of the chiral or non-chiral auxiliary. Furthermore, separation of enantiomers, diastereomers, or epimers can be carried out at any convenient point in the synthesis of the compounds of the present invention. The compounds of the present invention can also be prepared by chiral synthesis. The compounds themselves are pharmacologically acceptable acid addition salts thereof.

[0080] Individual cis / trans or E / Z configurational isomers can be obtained either by selective synthesis or by separation techniques that address the different physicochemical properties of the configurational isomers by applying techniques such as chromatography, crystallization, distillation, or extraction.

[0081] For patients who have adverse reactions to other psychedelics, lysergic acid derivatives may be useful as an alternative treatment. For some patients, lysergic acid derivatives may also be useful because they require an experience different from that achieved with phenethylamines, psilocybin, or LSD, or because the patient is not amenable to treatment with these existing a priori approaches. Thus, the lysergic acid derivatives in Figure 1A may serve as an alternative treatment option that is sufficiently similar to other psychedelics to be therapeutic, yet has sufficiently different properties to provide additional benefits or avoid the adverse effects of other psychedelics.

[0082] Based on the structural relationships, the compounds of FIG. 1A described in this invention are expected to have pharmacological properties generally similar to LSD.

[0083] This assumption is further emphasized by the handful of known and psychopharmacologically described lysergic acid derivatives, such as the N6-modified compounds ETH-LAD, PRO-LAD, ALL-LAD, the amide-modified compounds DAM-57, LPD-824, or LSM-775, and the N1-derivatized compounds ALD-52, OML-632, and MLD-41, which have shown psychotropic effects in humans (Abramson, 1959; A. Shulgin & Shulgin, 1991).

[0084] The present invention provides compounds of Figure 1A that are pharmacologically active and enable altered neurotransmission and / or the production of neurogenesis. More specifically, but not by way of limitation, the compounds interact with serotonin (5-HT, 5-hydroxytryptamine) 5-HT2A and 5-HT2C receptors in a mammal by administering a pharmaceutically effective amount of the compound of Figure 1A to a mammal in need of such interaction.

[0085] Thus, the present invention provides a method for altering neurotransmission by administering to a mammal a pharmaceutically effective amount of a compound of FIG. 1A to enhance serotonin 5-HT2A receptor interaction and induce a psychoactive effect in the mammal.

[0086] The present invention provides a method of treating an individual by administering to the individual a pharmaceutically effective amount of a compound of Figure 1A, thereby treating the individual.

[0087] The condition or disease being treated may include, but is not limited to, anxiety disorders (including anxiety in advanced disease such as cancer, and generalized anxiety disorder), depression (including postpartum depression, major depressive disorder, and treatment-resistant depression), headache disorders (including cluster headaches and migraines), obsessive-compulsive disorder (OCD), personality disorders (including conduct disorder), stress disorders (including adjustment disorder and post-traumatic stress disorder), substance disorders (alcohol dependence or withdrawal, nicotine dependence or withdrawal, opioid dependence or withdrawal, cocaine dependence or withdrawal, methamphetamine dependence or withdrawal), other addictions (including drug disorders, eating disorders, and body dysmorphic disorders), pain, neurodegenerative disorders (such as dementia, Alzheimer's disease, Parkinson's disease), autism spectrum disorders, eating disorders, or neurological disorders (such as stroke).

[0088] The neuronal interactions of the compounds depicted in Figure 1A can be used in mammals for substance-assisted psychotherapy, where the compounds induce psychotropic effects to enhance psychotherapy. A preferred mammal is a human.

[0089] The intensity and quality of psychotropic effects, including psychedelic or empathogenic (also called entactogenic or MDMA-like) effects (Holze et al., 2020), the quality of perceptual changes such as imagery, daydreaming, eyes-closed or eyes-open visuals, as well as changes in bodily sensations, pharmacologically active doses, and duration of action, may be different from or similar to those of LSD.

[0090] LSD and some of its modified derivatives are known to interact with serotonin 5-HT2A, 5-HT2C, 5-HT1A, and dopamine receptors (Nichols, Frescas, Marona-Lewicka, & Kurrasch-Orbaugh, 2002; Rickli et al., 2016; Watts et al., 1995).

[0091] LSD and some of its modified derivatives are also known to substitute for LSD in two-lever drug discrimination assays (Nichols et al., 2002).

[0092] Among the known lysergic acid derivatives with psychotropic properties, three structural regions of the original LSD molecule have been primarily investigated.

[0093] One structural feature previously investigated is substitution of the N1 of the LSD molecule, resulting in N-acyl (e.g., N-acetyl, N-propionyl, N-butyryl), N-alkyl (e.g., N-methyl), or N-methoxy-substituted LSD derivatives (Abramson, 1959; Halberstadt et al., 2020).

[0094] Some of these substituents undergo rapid metabolism, the compounds behave as prodrugs, and it was found that only after N1 deprotection did the compounds exhibit activity at the target receptor and possess psychotropic properties.

[0095] The second structural feature of the original LSD molecule that has been previously modified to obtain psychotropic compounds is the N6-substituent. Similarly, the N6-methyl group has been replaced with alkyl, aryl, propargyl, phenethyl, branched alkyl, and alkylcycloalkyl (Hoffman & Nichols, 1985; Huang, Marona-Lewicka, Pfaff, & Nichols, 1994; Nichols, 2018a; Nichols et al., 2002; Nichols, Monte, Huang, & Marona-Lewicka, 1996; Oberlender, Pfaff, Johnson, Huang, & Nichols, 1992; Pfaff, Huang, Marona-Lewicka, Oberlender, & Nichols, 1994; A. Shulgin & Shulgin, 1991) and WO2021019023A1, WO2021175816A1. Some of the compounds have been investigated in humans and only mentioned as being psychotropic, and only three such compounds have been described as psychedelic, at least in anecdotal reports (A. Shulgin & Shulgin, 1991).

[0096] A third structural feature of the original LSD molecule that was modified to yield potentially psychotropic compounds, or that was only mentioned theoretically, was the substituent of the amide group attached to the C8 atom of LSD. Thus, N-monoalkyl, branched N-monoalkyl, symmetrical and asymmetric N,N-dialkyl, N-alkyl-N-alkenyl, N,N-dialkenyl, N,N-dialkynyl, N-ethyl-N-(2,2,2-trifluoroethyl), N-ethyl-N-(2-methoxyethyl), N-cycloalkyl, N-alkyl-N-cycloalkyl, N-alkyl-N-cycloalkyl, or N-oxacycloalkyl derivatives have been described or mentioned theoretically. (Brandt et al.,2020;Huang et al.,1994;Nichols,2018a;Nichols et al.,2002;Nichols et al.,1996;Oberlender et al.,1992;Pfaff et al.,1994;Watts et al. al., 1995) and WO2021019023A1, WO2021175816A1.

[0097] However, some of these compounds have only been described theoretically and have not been chemically prepared or investigated biologically or psychopharmacologically, and therefore the extent to which some of these compounds exhibit psychoactive, generally, or psychedelic, properties more specifically, remains unclear.

[0098] Regarding the aforementioned structural modifications of the original LSD molecule, i.e., the combination of N1, N6, and amide functions attached to C8, few compounds are known, with one of the few exceptions being the N1-propionyl version of ETH-LAD (Brandt et al., 2017). Other compounds have only been described theoretically, for example in WO2021019023A1 and WO2021175816A1, but their preparation and chemical characterization have not been described.

[0099] One of the main reasons for this is the ongoing search for N,N-diethylamide-substituted derivatives of lysergic acid, based on the finding that if even one of the ethyl groups in the original LSD molecule is immediately replaced with, for example, a methyl, propyl, or isopropyl group, the subsequent compound loses significant psychotropic potency. Little structural modification of the N,N-diethylamide moiety allows at least some of the psychotropic properties to be retained, the nature of which remains elusive and not fully explained.

[0100] Another reason for the very limited number of chemically prepared and biologically investigated samples of lysergic acid derivatives bearing amides other than N,N-diethylamide in combination with N6 substituents other than N-methyl is the cumbersome accessibility of these compounds. Given the existing and previously discussed structure-activity relationships, there appeared to be little interest in undertaking synthetic efforts to obtain additional examples of compounds with this extremely rare pharmacophore combination, provided that N,N-diethylamide was not used as the amide substituent.

[0101] One reason the N6 substituents in the aforementioned compounds are primarily methyl is the use of lysergic acid as the starting material. This acid is chemically bound in nature, primarily in the ergot fungus, as a chemical moiety from which the ergotamine compound can be isolated. Hydrolysis of ergotamine and subsequent purification yields pure lysergic acid, a compound that is chemically accessible only through extraordinary effort.

[0102] Another reason contributing to the widespread retention of the "original" 6-methyl substituent may be the synthetic conditions used in the past to remove this methyl group: the classical von Braun reaction, which applies cyanogen bromide in boiling tetrachloromethane, both of which are very difficult compounds to handle.

[0103] In summary, virtually all lysergic acid derivatives with known psychotropic properties contain either a N,N-diethylamide pharmacophore in which the N6 substituent varies, or the amide moiety is varied, with the N6 substituent being retained as N6-methyl.

[0104] The psychotropic properties of the psychotropic lysergic acid derivatives known so far have often not been described in detail, and it remains unclear whether they act as stimulants, entactogens, or psychedelics (Holze et al., 2020) or a combination thereof.

[0105] In the case of the psychedelic properties of previously known lysergic acid derivatives, the psychopharmacological properties (e.g., subjective effect profile compared to other substances) have only been described in detail and clinically for LSD (Holze et al., 2022; Holze, Vizeli, et al., 2021; Holze et al., 2020). Therefore, it remains unclear whether any of the previously described lysergic acid derivatives may be suitable within the scope of the invention referred to herein.

[0106] Some of the lysergic acid compounds of the present invention, depicted in FIG. 1A, exhibit in vitro pharmacological activity at relevant targets (5-HT2A receptors, data in Liechti et al.) and exhibit psychedelic effects, as compared to LSD.

[0107] The introduction of one fluorine into one of the N-ethylamide substituents is expected to preserve the psychedelic properties of the LSD molecule (e.g., compound TRALA-04).

[0108] The introduction of one fluorine at the N6 substituent of ET-LAD preserves the psychedelic properties of the LSD molecule (such as in the compound TRALA-15).

[0109] In conclusion, the combination of these structural features is also likely to lead to lysergic acid derivatives with psychedelic properties.

[0110] The several psychedelically active lysergic acid derivatives known to date all exhibit similar durations of action, varying only slightly, mainly in the range of 8–12 hours. Duration of action depends primarily on elimination half-life (Holze et al., 2019; Holze et al., 2022; Holze, Vizeli, et al., 2021), although receptor occupancy and kinetics may also play a role (Wacker et al., 2017).

[0111] The metabolism of the original LSD molecule has been investigated in human biological fluids (Canezin et al., 2001). The main metabolic attack was identified as a) the diethylamide moiety, either N-monodeethylation or monohydroxylation of one of the ethyl groups, b) N6-demethylation to form 6-norLSD, and c) oxidation / hydroxylation of the indole moiety. More recently, Vizeli et al. demonstrated that the genetic influence of CYP2D6 on the pharmacokinetics and acute subjective effects of LSD occurs in healthy subjects (Vizeli et al., 2021). The main metabolite of LSD in humans is 2-oxo-3-hydroxy-LSD (Luethi, Hoener, Krahenbuhl, Liechti, & Duthaler, 2019), and therefore, the main metabolic attack occurs at the indole moiety of LSD.

[0112] Because the duration of psychedelic action of the original LSD molecule is quite long, sometimes undesirably long, the inventors have chosen, by option but not limitation, an "anti-stability approach" that opposes the usual methods for optimizing pharmacologically active molecules. In classical medicinal chemistry, one goal is to maintain or increase biological activity while also increasing metabolic stability. For some compounds of the present invention, represented in Figure 1A, the inventors have introduced atoms or functional groups that can increase metabolic susceptibility. Using this metabolic enhancement strategy, destabilizing substituents and restabilizing them by adding specific atoms or groups may enable fine-tuning of metabolism while retaining the psychedelic properties of the original LSD molecule.

[0113] Since it is also within the scope of the present invention to access psychedelic lysergic acid derivatives with a shorter duration of action compared to the original LSD molecule, two regions have been identified for modification in the structure represented in FIG. 1A, but are not limited to these.

[0114] Substitution at N1 of the original LSD molecule requires a metabolically labile group at this position that would release the parent compound upon metabolism if psychedelic properties were the primary characteristic. The reason for this is that, based on existing SARs, few substituents at this position appear to be capable of conferring agonistic serotonin 5-HT2A receptor ligands, the primary site responsible for the psychedelic properties of lysergic acid derivatives (Halberstadt et al., 2020). Therefore, most N1-substituted LSD or similar compounds function solely as prodrugs, liberating the parent compound. Therefore, the duration of action is either unchanged or prolonged rather than shortened. One of the few exceptions where N1 substitution can result in a metabolically unchanged active compound is N1-substituted 1-methyl-LSD (Abramson, 1959), but this remains unclear at present, and this compound showed significantly lower potency in humans. Nevertheless, the N1 substituent is within the scope of the present invention as it may contribute to modifying the duration and nature of action of the lysergic acid derivatives represented by FIG. 1A by co-influencing the physicochemical and potentially absorption, distribution, metabolism, and excretion (ADME) properties.

[0115] The aforementioned "antistability approach" was applied to the N6 nitrogen of some lysergic acid derivatives represented in Figure 1A. Metabolism can result in, but is not limited to, degradation to polar conjugates and / or completely unsubstituted N6 nitrogen lysergic acid derivative structures (i.e., secondary amines). N6-demethylation of LSD (i.e., 6-norLSD) is known to result in alterations of its in vivo pharmacological properties (Fehr, Stadler, & Hofmann, 1970) and CH535236A, as well as loss of its 5-HT2A binding affinity (factor 30) and displacement potential in LSD-trained rats, even at 20-fold the full active dose of LSD (Hoffmann, 1987). However, more recent binding assays have shown that norLSD retains high-potency binding to 5-HT2A receptors but not 5-HT2C receptors (Luethi et al., 2019), indicating that this molecule, as well as the analogs and prodrugs described herein, may be associated with psychotropic properties. Therefore, the currently designed and synthesized compounds require further investigation to clarify their psychotropic properties. The formation of metabolites other than the N6-deprotected form in the compound depicted in Figure 1A may also result in the inactivation of the parent compound, thus affecting its duration of action.

[0116] Furthermore, the aforementioned "antistability approach" was applied to some amide groups of lysergic acid derivatives represented in Figure 1A. Thus, amide substituents within the scope of the present invention may undergo or result in a different or more rapid metabolism than the diethylamide of the original LSD molecule, resulting in inactivation of the psychotropic properties of the parent compound and thus affecting the duration of action.

[0117] Differential metabolism induced by different N1, N6, or amide substituents from the original LSD molecule can also occur at any part of the chemical structure of the compounds of the present invention depicted in Figure 1A, and is not limited to the various substituents themselves.

[0118] The "antistability approach" in no way limits the scope of the present invention, and for compounds represented in FIG. 1A does not necessarily require a metabolism different, faster, slower, or similar to that of the parent LSD molecule, as other mechanisms for the compounds of the present invention may lead to different or similar durations of action, intensity and quality of psychotropic effects, including psychedelic or empathogenic effects, quality of perceptual changes such as imagery, daydreaming, and eyes-closed or eyes-open visuals, and altered bodily sensations and / or pharmacologically active doses.

[0119] The aforementioned modifications can occur on the N6 or on the amide moiety, or any combination thereof.

[0120] Not only can receptor interactions, receptor profiles, subsequent signaling cascades, receptor heterodimerization, and overall psychological and psychedelic effects be altered by the structural modifications depicted in Figure 1, but metabolism can also be enhanced by, for example, but not limited to, potentially highly unstable N-alkoxy compounds, geminal amino ether compounds, geminal amide ether (N-alkoxymethyl derivatives of amides) compounds, vinyl or ethynyl compounds (i.e., enamides, ynamides, enamines, ynamines) on the N1, N6, or amide nitrogen, all of which can be made more or less susceptible to metabolism by introducing alkyl groups, fluorine atoms, or deuterium atoms into these functional groups, independently and in any combination, at either the vinyl, allyl, or gamma positions, or at either the ethynyl or propargyl positions, as previously described. Furthermore, nitrile groups can also be introduced into any of these positions on the aforementioned substituents, with alkylnitriles, alkenylnitriles, or alkynylnitriles (each with or without fluorine and / or deuterium substituents) also being options. Additionally, independently fluorinated, deuterated, or nitrile-substituted N-allyl or N-propargyl groups are also within the scope of the present invention. Thus, the present invention also enables the synthesis of psychedelic compounds that are metabolically stable and have a relatively short duration of action compared to longer acting compounds.

[0121] Any of the aforementioned substituents attached to N1, N6, or amide can be further combined with a substituent attached to amide or N6 or N1 consisting of alkyl, alkenyl, or alkynyl, cycloalkyl, alkylcycloalkyl, benzyl, heteroarylmethyl (each with or without one or several fluorine, deuterium atoms, or nitrile groups).

[0122] In another embodiment, any of the aforementioned structural modifications can be combined with one or several fluorine and / or deuterium atoms in any combination on the entire lysergic acid core, i.e., the ergoline core structure. While not limiting, mention is made of the introduction of deuterium at C8 of the ergoline structure to stabilize the lysergic acid derivatives depicted in Figure 1A from epimerization. Epimerization can occur depending on the chemical / biological environment and is driven by factors such as pH and, in some cases, enzymatic activity. Only the 5R,8R epimer of LSD possesses psychotropic properties, while its 5R,8S epimer (also known as iso-LSD) is known to be inactive up to a few milligrams. The remaining two epimers (5S,8R and 5S,8S configurations) are also psychoactively inactive.

[0123] The chemical stability of the aforementioned functional groups, such as enamides, ynamides, alkoxyamides (also known as Weinreb amides), geminal N-amide ethers, enamines, ynamines, alkoxyamines, or geminal amino ethers, to acidic, basic, or any other chemical conditions depends on factors such as pH, solvent, temperature, surface, nucleophilicity, or electrophilicity of the reaction partners, or gas entrapment in the environment. Metabolic stability in a biological environment, such as the human body, is further driven by factors such as absorption rate, exposure to enzymes, enzyme activity, genetic polymorphisms, retention time in the body, such as the gastrointestinal tract, and distribution rate or transit time throughout the body. All of these aspects can be influenced by modifications introduced into the compound to produce the desired effect and duration of effect in humans.

[0124] The stability of a functional group, a substituent, or generally a molecule, to the aforementioned factors can be greatly influenced and modified by the specific incorporation of stabilizing or destabilizing atoms or groups. Furthermore, the overall metabolic stability of a compound is also governed by properties such as overall lipophilicity, three-dimensional structure, dissociation constant, solubility, steric accessibility, and steric bulk density.

[0125] Fluorine is a strong electron-withdrawing atom, and its incorporation into a substituent can significantly reduce electron richness. Furthermore, it affects the dipole moment, dissociation constants of acidic and basic groups, lipophilicity, pH value, and, to some extent, steric properties of fluorine-containing molecules. Therefore, fluorine can change the physicochemical properties, and its incorporation into a molecule can dramatically affect interactions with biological targets, chemical / metabolic stability, and metabolic pathways. Furthermore, fluorine atoms incorporated into molecules enable so-called multipolar interactions with partially charged functional groups. This makes fluorine an excellent tool for medicinal chemistry.

[0126] Deuterium is a stable isotope of hydrogen. The slightly different metric incorporated into a molecule can affect its physicochemical properties. This can lead to the observation of kinetic isotope effects, inverse kinetic isotope effects, and stereoisotope effects. Because the chemical bonds involving deuterium are stronger and of different lengths compared to protium (hydrogen), such compounds exhibit significantly different biological reactions. Therefore, the incorporation of deuterons into a molecule can significantly affect its biological stability.

[0127] Thus, both fluorine and deuterons can be used to replace or be added to substituents to modify the overall stability and biological properties of the compounds of the present invention represented by Classes 1 through 5 depicted in Figure 1A and Figures 2A-6C. Substitutions can be made with one or more fluorine atoms, or one or more deuteron atoms, or any combination of fluorine and deuteron atoms.

[0128] Analogous to these medicinal chemistry concepts, the biological properties of the compounds of the present invention (ADME, target selectivity and target interaction, mode of action, duration of action, psychodynamic processes, and qualitative perception, e.g., psychedelic or empathogenic potency compared to the original LSD molecule) can be influenced not only by the aforementioned application of fluorine or deuterons to functional groups such as enamides, ynamides, alkoxyamides, geminal N-amido ethers, enamines, ynamines, alkoxyamines, or geminal amino ethers, but also by their introduction into simpler substituents, such as alkyl, alkenyl, or alkynyl, cycloalkyl, oxacycloalkyl, alkylcycloalkyl, alkyloxacycloalkyl, benzyl, or heteroarylmethyl substituents attached to N1, N6, or to the amide functional group attached to C8 of the ergoline core structure (Figure 1A). Other atoms or groups of atoms can be used in a similar manner to all of these substituents, as outlined in Figures 2A-6C.

[0129] Previous structure-activity relationships (Brandt et al., 2020; Huang et al., 1994; Nichols, 2018a; Nichols et al., 2002; Nichols et al., 1996; Oberlender et al., 1992; Pfaff et al., 1994; Watts et al., 1995) indicate that the amide functional group of lysergic acid amide cannot tolerate groups larger than an N,N-diethyl substituent without loss of biological activity, such as receptor affinity at receptors such as the 5-HT2A receptor, which is associated with psychotropic effects in humans. Using groups larger than that size, or smaller groups such as methyl groups, results in a dramatic loss of 5-HT2A receptor binding specificity and human potency. When modifying the N6 substituent, examples found in the literature (Hoffman & Nichols, 1985; Huang et al., 1994; Nichols, 2018a; Nichols et al., 2002; Nichols et al., 1996; Oberlender et al., 1992; Pfaff et al., 1994; A. Shulgin & Shulgin, 1991) have shown that expansion of the N6-methyl group is tolerated to some extent to retain in vivo potency, as demonstrated, for example, by drug identification studies or anecdotal reports based on human administration. However, the inventors do not simply intend to access compounds with in vitro or in vivo potencies equal to or greater than those of the prototypical LSD itself. Indeed, a more favorable overall profile may be more relevant, and lower potency in no way limits the use of such compounds.

[0130] LSD is typically administered orally. Buccal or nasal absorption, as well as intravenous or intramuscular administration, have also been used. While the compounds represented in Figure 1A can be administered orally (i.e., absorbed in the gastrointestinal tract), for certain compounds within the scope of the present invention, preferred routes of administration may be buccal, nasal, intestinal, intravenous, or intramuscular. These routes of administration may alter the duration of action of the compound itself and may result in a more rapid onset of drug effects. For some compounds, there are also important differences that can be expected between oral and parenteral administration. For example, a compound may be destroyed or converted to LSD by gastric or intestinal fluids or enzymes after oral administration, but may undergo different metabolism when used parenterally. Therefore, any change in structure may have different effects upon oral and parenteral administration.

[0131] While all of the lysergic acid derivatives depicted in Figure 1A are useful for optimizing the overall biological and clinical efficacy profile of psychedelics, certain classes of compounds, e.g., compounds that are the free base, salts, hydrochloride salts, where applicable, racemates, single enantiomers, single diastereomers, single epimers, or mixtures of enantiomers or diastereomers or epimers in any ratio, or individual cis / trans or E / Z configurational isomers, or mixtures of these configurational isomers in any ratio, will be understood to be combined to form additional preferred classes.

[0132] Synthetic access to the compounds of the present invention is illustrated in Figures 9-12 and detailed in the "Compound Preparation" section.

[0133] The group presented in the Preparation section, i.e., compounds 2a-2m, 12a-12g, 13, 14a-14c, and 16a-16c shown in Figures 7A-8N, exemplify lysergic acid derivatives depicted in Figure 1A that are contemplated within the scope of the present invention.

[0134] A general approach to several lysergic acid derivatives in Class 1 is outlined in Figures 9-10. Commercially and synthetically available lysergic acid (1) or lysergic acid monohydrate is activated using an amide coupling reagent such as CDI, TBTU, TCFH, TFFH, T3P, COMU, or any other suitable coupling reagent (Figure 9) in a suitable solvent such as DMF, dimethylacetamide, DCM, or THF, EtOAc, dioxane, acetonitrile, or mixtures thereof. Alternatively, activation can occur with reagents such as POCl3 or trifluoroacetic anhydride. The activated intermediate is then reacted with a primary or secondary amine. This amine can be used as a free base or a salt. In the case of the free base, the amine can be used in excess of the activated lysergic acid or as one equivalent, along with a non-nucleophilic base such as triethylamine (NEt3), N-methylmorpholine (NMM), or N,N-diisopropylethylamine (DIPEA). If the amine to be coupled is applied in salt form, e.g., as its hydrochloride salt, it can be used in one equivalent or excess relative to the activated lysergic acid, and a non-nucleophilic base, as outlined above, can be used to separate the amine from its salt. The reaction temperature can range from 0 to 120°C, more preferably from 20 to 100°C. After a reaction time sufficient to allow amide formation, the corresponding amide formed is separated from the reaction mixture by extraction, chromatography, or crystallization of the compound itself or its salt, or a combination of these methods.

[0135] Compounds of class 1 (Figures 2A-3H) containing an enamide group (e.g., subclass 1f) can be accessed via different routes (Figure 9). In one embodiment, the corresponding primary or secondary 2-(phenylthiol)ethylamine is coupled with an activated lysergic acid derivative suitable for amide coupling. The 2-phenylthioethylamine may contain additional substituents at any part of the molecule. The corresponding amide containing the 2-(phenylthiol)ethyl group is then oxidized to the corresponding sulfoxide, which is then reacted in pyrolysis to give the corresponding enamide (Taniguchi et al., 2005). The sulfoxide group is chiral and may have either the R or S configuration, or any mixture of stereoisomers. The pyrolysis is catalyzed with a suitable base (e.g., NaHCO3, KHCO3, Na2CO3, or K2CO3) and carried out in a suitable solvent (e.g., toluene, or dimethylated or trimethylated benzenes, e.g., ortho-, meta-, or para-xylene), although any other solvent chemically inert to the reaction being carried out can be used, most preferably xylene. The temperature applied is 40-200°C, more preferably 100-150°C.

[0136] Access to sulfoxides can also be achieved as follows: Phenylvinyl sulfoxide or a substituted analog is reacted with a primary amine R—NH in a suitable organic solvent such as THF, dioxane, ethyl acetate, or dichloromethane to form the corresponding N-(2-phenylsulfinylethyl)-R-amine (Hu, Chan, He, Ho, & Wong, 2014). The resulting amine is then coupled with the aforementioned lysergic acid or lysergic acid hydrate to yield an amide suitable for thermolysis to form the enamide. As noted above, the sulfoxide group is chiral and may have either the R or S configuration, or any mixture of stereoisomers.

[0137] In another embodiment for accessing enamides (e.g., subclass 1f), an aldehyde is coupled with a primary aldehyde to form an imine, which is then coupled with an activated lysergic acid derivative suitable for amide coupling and subsequent elimination (Goldin & Wong, 1981; He, Zhao, Wang, & Wang, 2014; Kulyashova & M., 2016; Meuzelaar, van Vliet, Neeleman, Maat, & Sheldon, 1997). The coupled intermediate is then eliminated to the corresponding enamide.

[0138] Another embodiment for accessing such enamides (e.g., subclass 1f) is the formation of an oxazoline followed by lithiation and alkylation, which leads to ring opening and formation of the enamide (Xu, Xiao-Yu, Wang, & Tang, 2017).

[0139] Furthermore, enamides (e.g., subclass 1f) can be accessed by direct elimination, for example, using lithium bis(trimethylsilyl)amide (LiHMDS) (Spiess, Berger, Kaiser, & Maulide, 2021).

[0140] Fluorinated enamides (e.g., subclass 1f) shown in class 1 (Figure 2G) can also be accessed by applying elimination procedures using strong bases such as butyllithium (BuLi), lithium diisopropylamide (LDA), or LiHDMS on 2,2,2-trifluoroethyl or 2-bromo-2,2-difluoroethyl substituents attached to the amide group of the corresponding lysergic acid amide compounds (Meiresonne, Verniest, De Kimpe, & Mangelinckx, 2015; Riss & Aigbirhio, 2011).

[0141] Formation of ynamides (e.g., subclass 1g) outlined in class 1 (Figure 3A) can be achieved by elimination procedures using a strong base such as, but not limited to, LiHDMS on 2,2,2-trifluoroethyl or 2-bromo-2,2-difluoroethyl substituents attached to the amide group of the corresponding lysergic acid amide compounds (Meiresonne et al., 2015).

[0142] Class 2 compounds (Figures 4A-5C) can be obtained starting from the corresponding 6-nor LSD or any other 6-nor compound. The preparation of 6-nor LSD (Figure 11) is well documented by applying the classical von Braun reaction, in which cyanogen bromide in boiling tetrachloromethane is applied, both of which are problematic compounds to handle, and the formed aminonitrile is reduced by elemental zinc in acetic acid solution (Fehr et al., 1970). Herein, we used an alternative method described in WO2006128658A1 to prepare the pyrrolidine analog of LSD. Analogously, LSD is treated with an oxidizing agent such as meta-chloroperoxybenzoic acid (mCPBA) in dichloromethane under cooling, and the formed N-oxide is then reduced by adding FeSO4. This is a fairly safe and easy-to-handle reaction, and the reaction is very rapid. Furthermore, the yields are comparable to or even superior to those of the von Braun reaction. Other oxidizing agents, such as HO or cumyl hydroperoxide in organic solvents such as alcohol, ethyl acetate, or dichloromethane, can also be used. After a separation step, which can be performed by extraction, chromatography, or crystallization of the compound itself or its salt, or a combination of these methods, the resulting 6-nor LSD or any other 6-nor compound, such as 6-nor TRALA-02, as shown in Figure 12, can be used in reactions to access compounds represented by Class 2 (Figures 4A-5C). The LSD recovered from the above N-demethylation reaction or any other recovered lysergic acid derivative can be recycled to an N-demethylation reaction, as outlined above, to further increase the amount of desired 6-nor LSD or other 6-nor compound. This cyclical process can be repeated as many times as the technique and / or compound requirements allow.

[0143] Some compounds represented by class 2, as shown in Figures 4A-5C, can be obtained by reacting 6-nor LSD or another 6-nor compound with a correspondingly substituted R6 containing a leaving group substituted at the basic N6 nitrogen of 6-nor LSD or another 6-nor compound. The leaving group can be, for example, a halogen, mesylate, tosylate, or triflate. Furthermore, reductive amination can also be applied using an appropriate carbonyl compound and a reducing compound such as NaBH4 or Na(OAc)3BH or NaBH3CN, or by using hydrogen in a suitable solvent with or without a catalyst.

[0144] In the case of lysergic acid derivatives with strongly electron-withdrawing substituents, such as the secondary N6 of 6-nor LSD or other derivatives with an NH at the 6-position, the nucleophilicity of the secondary amine may not be sufficiently high for use as a nucleophile. In such cases, the lysergic acid derivative must be appropriately protected or the electrophile must be activated to selectively deprotonate the N6. In such methods, the use of transition metals or transition metal oxides or salts such as silver salts to promote N-alkylation can be useful. Preferably, AgNO3 or AgOTf (AgCF3SO3) is added to the reaction mixture of the corresponding secondary N6 amine and alkylating agent in an organic solvent such as tetrahydrofuran (THF), dioxane, methanol (MeOH), ethanol (EtOH), isopropyl alcohol (iPrOH), or dichloromethane (DCM). The mixture can be maintained at 0-100°C, more preferably 20-100°C.

[0145] It is well known that in certain cases, the 2,2,2-trifluoroethyl substituent cannot be simply introduced into amines by applying one of the above methods due to its extremely deactivated reactivity (i.e., due to the electron-withdrawing properties of fluorine). Even 2,2,2-trifluoroethyl triflate, a compound much more reactive than 2,2,2-trifluoroethyl iodide, exhibits extremely low reactivity in nucleophilic substitution with amines. Such a substituent can be introduced into amines using a synthetic equivalent, illustratively 2,2,2-trifluoroacetaldehyde ethyl hemiacetal (alternative name: 1-ethoxy-2,2,2-trifluoroethanol) (Mimura, Kawada, Yamashita, Sakamato, & Kikugawa, 2010). The formed intermediate is then reduced with a suitable reducing agent, such as NaBH, Na(OAc)BH, or NaBHCN.

[0146] Enamine compounds of Class 2 (Subclass 2f) shown in Figure 4G can be obtained by reacting the corresponding carbonyl compound with 6-nor LSD, followed by removal or absorption of water to form an imine, and optionally, the addition of a non-nucleophilic base. Alternatively, such enamines can also be obtained by reacting fluorinated 1-halo-1-alkenes with 6-nor LSD or another 6-nor compound in a direct halo substitution reaction (WO2006046417A1).

[0147] Furthermore, enamine compounds represented by class 2 (subclass 2f) shown in Figure 4G can be obtained, for example, by reacting N6-substituted N6-2,2,2-trifluoroethyl-6-norLSD with a strong base such as LDA or BuLi (Riss & Aigbirhio, 2011).

[0148] Alkoxyamine compounds, also known as N-hydroxyethers, represented by Class 2 (Subclass 2h) depicted in Figure 5B can be obtained by reacting 6-norLSD with an oxidizing agent (e.g., HO or mCPBA in an organic solvent) to form the corresponding 6-norLSD-N-hydroxylamine, followed by deprotonation of the N-hydroxylamine with a base such as LDA, KOtBU, BuLi, or LiHDMS, and then reacting this deprotonated intermediate with a corresponding substituted R containing a leaving group that is replaced by the deprotonated oxygen of 6-norLSD-N-hydroxylamine. The leaving group can be a halogen, mesylate, tosylate, or triflate, or other suitable leaving group.

[0149] Arylamines or heteroarylamines represented by class 2 (subclass 2i) depicted in Figure 5C can be obtained by reacting 6-nor LSD or another 6-nor compound with the corresponding aryl or heteroaryl halide, triflate, for example, in a process commonly described as the Buchwald-Hartwig amination.

[0150] Benzylamines and (heteroarylmethyl)amines represented by class 2 (subclass 2i) depicted in Figure 5C can be obtained by reacting 6-nor LSD or another 6-nor compound with the corresponding aryl or (heteroarylmethyl)halide in a classical substitution reaction, or by reacting with the corresponding aldehyde by way of reductive amination in a suitable solvent, in the presence or absence of a catalyst, by applying reducing conditions such as NaBH, Na(OAc)BH, or NaBHCN, as well as hydrogen.

[0151] The N6 substituent can also consist of a cycloalkane or oxacycloalkane (subclasses 2d and 2g in Figure 4E and Figure 5A). These substituents can be introduced by reductive amination of 6-nor LSD or another 6-nor compound with the corresponding oxo-cycloalkane or oxo-oxacycloalkane and a reducing compound, such as NaBH, Na(OAc)BH, or NaBHCN, as well as hydrogen in the presence or absence of a catalyst in a suitable solvent.

[0152] Furthermore, these cycloalkane substituents, represented by subclasses 2d and 2g in Figures 4E and 5A, can also be introduced by a substitution reaction by reacting a 6-nor LSD or another 6-nor compound with a correspondingly substituted R6 cycloalkane or oxacycloalkane containing a leaving group that replaces the basic N6 nitrogen of the 6-nor LSD. The leaving group can be, for example, a halogen, mesylate, tosylate, or triflate.

[0153] Further access to compounds represented by subclasses 2d and 2g in Figures 4E and 5A is achieved by the use of 6-nor LSD or another 6-nor compound, which can be reacted with a cycloalkane or oxacycloalkane containing geminal substituted alkoxy-(trialkylsilyloxy) substitution, for example, under acidic conditions such as the use of acetic acid, and using reducing compounds such as NaBH, Na(OAc)BH, or NaBHCN as well as hydrogen, and in the presence or absence of a catalyst, in a suitable solvate.

[0154] Compounds of Class 3 (Figure 6A) can be obtained by combining any of the synthetic routes described above. In addition, suitable protecting groups can be first introduced at the carboxyl functionality attached to N1, N6, or C8 of other underivatized ergoline structures such as LSD, 6-norLSD, or N6-norergotamine, N6-deprotected intermediates, N6-deprotected lysergic acid, N6-deprotected lysergic acid esters, or suitably transformed compounds.

[0155] Class 4 compounds (Figure 6B) can be obtained by corresponding functionalization of N1 of the ergoline core structure by using Class 1, Class 2, or Class 3 compounds, and vice versa.

[0156] Class 5 compounds (Figure 6C) can be obtained by using Class 1, Class 2, or Class 3 compounds that have at least one deuteron atom in the ergoline core structure, and by correspondingly functionalizing N1 of the ergoline core structure, or vice versa.

[0157] Select synthesized lysergic acid derivatives are currently being investigated for their primary psychotropic effects in vitro (data on file from Liechti et al.). The primary target of psychedelic drugs is the 5-HT2A receptor (Holze, Vizeli, et al., 2021), where they typically bind with high affinity (Rickli et al., 2016). Furthermore, binding potency at the 5-HT2A receptor typically predicts that human doses of psychedelic drugs will confer psychotropic effects for many compounds (Luethi & Liechti, 2018). Furthermore, the psychedelic effects of psilocybin in humans have been shown to correlate with 5-HT2A receptor occupancy measurements using positron emission tomography (Madsen et al., 2019). Therefore, interactions with this target are relevant and highly predictive of psychedelic activity for most psychedelic drugs. However, this may not be true for all substances within this class.

[0158] Additional receptors, such as serotonergic 5-HT1A and 5-HT2C or dopaminergic D2 receptors, are thought to moderate the effects of psychedelics (Rickli et al., 2016). Although some psychedelics, such as psilocybin, do not act directly on dopaminergic receptors, they nevertheless possess some dopaminergic properties (Vollenweider, Vontobel, Hell, & Leenders, 1999), possibly by releasing dopamine in the striatum via activation of 5-HT1A receptors (Ichikawa & Meltzer, 2000). Furthermore, although LSD has activity at D2 receptors (Rickli et al., 2016), and some of its behavioral effects in animals may be related to this target (Marona-Lewicka, Thisted, & Nichols, 2005), its acute psychotropic effects in humans occur primarily when not entirely mediated via 5-HT2 receptors (Holze, Vizeli, et al., 2021; Preller et al., 2017).

[0159] The compound's activity at monoamine transporters is thought to mediate MDMA-like empathogenic effects (Hysek et al., 2012). Importantly, LSD is a high-affinity 5-HT2A receptor ligand, requiring extremely low doses to induce psychotropic effects in humans. Even doses of 0.1 mg or less can have unusually strong psychedelic effects in humans, and this is likely true for substances developed within the scope of this invention, although higher or lower potencies are possible for some lysergic acid compounds and will be further evaluated clinically. Key results of preliminary pharmacological profiling of the compounds described herein were as follows:

[0160] Several of the lysergic acid derivatives depicted in Figure 1A have demonstrated high binding affinity in ongoing studies at the serotonin 5-HT2A receptor, indicating activity as psychedelic drugs.

[0161] Microsomal studies of some of the lysergic acid derivatives depicted in Figure 1A revealed differential metabolic stability compared to LSD, as shown in Figures 13A–13J. In particular, derivatives 2l (TRALA-12), 12c (TRALA-17), 16a (TRALA-26), and 16b (TRALA-27) were metabolized significantly faster than LSD over a 4-hour microsomal incubation. Substance 2l exhibited much faster metabolism, with the majority of the substance being metabolized after only 30 minutes. Given its rapid metabolism, it is unlikely to be orally active, but is a candidate for intravenous administration, particularly as an infusion, where a short-lasting or sustained effect that can be rapidly terminated upon cessation of the infusion is expected. The metabolic profiles of 12c, 16a, and 16b all exhibited significantly faster microsomal metabolism than LSD, and appear promising among the derivatives tested for oral administration, with expected shorter durations of action compared to LSD. However, when selecting promising drug candidates for therapeutic use, in addition to metabolic profile, 5-HT activity should be considered. 2A It is important to note that other factors, such as receptor activity, must be considered. Additionally, in vivo experiments are needed to further evaluate the clinical pharmacokinetics of these substances.

[0162] The receptor interaction profiles of the novel compounds at their primary targets, as well as those relative to LSD and psilocin (the prodrug and active metabolite of the psychedelic psilocybin), were determined and are shown in Figure 14. Many of the novel compounds exhibited higher binding affinity compared to LSD at the receptor responsible for the psychedelic effects of psychedelics (h5-HT2A), as evidenced by similar or lower Ki values than LSD. Similarly, many of the novel compounds also exhibited similar or higher receptor activation potencies compared to LSD at the 5-HT2A receptor, responsible for their acute and therapeutic effects, as evidenced by lower or similar EC50 values for h5-HT2A receptor activation compared to LSD. Some of the novel compounds exhibited lower binding and / or receptor activation potencies at the 5-HT2B receptor compared to LSD, indicating a similar or reduced risk of cardiotoxicity (cardiac valve fibrosis), as the 5-HT2B receptor is thought to mediate this adverse effect of serotonergic drugs when used chronically at high doses.

[0163] Taken together, the in vitro profiles of lysergic acid derivatives shown in Figure 1A compared with psilocin and LSD indicate their overall psychedelic properties when used in humans. Thus, some lysergic acid derivatives may exert a profile of acute psychedelic effects that may be more beneficial for some patients, including, but not limited to, a more overall positive effect, a variety of perceptual effects, more emotional effects, reduced anxiety, reduced cardiac stimulation, and fewer side effects. Among other properties, lysergic acid derivatives may have less nausea, longer-lasting effects, and shorter-lasting effects compared with LSD.

[0164] The use of LSD presents several problems that can be resolved using the compounds described herein. Specifically, the effects of prolonged psychedelic experiences may be limited in some cases. The derivatives shown in Figure 1A are more easily metabolized and therefore may have a shorter duration of action. Furthermore, psychedelics like psilocybin or LSD can produce side effects, including nausea and vomiting, cardiovascular stimulation, and elevated body temperature. Novel compounds may reduce nausea, cardiac stimulation, thermogenesis, and / or other adverse responses. LSD has a longer duration of action. Substances currently under development are designed to have similar qualitative effects to LSD with a shorter duration of action, or to have a longer duration of action but other qualitative effects reflected by their structural changes and related pharmacological properties. In particular, less metabolically stable compounds have been created to reduce plasma half-life and duration of action in humans. Other modifications of the chemical structure are designed to create substances with qualitative effects different from those of LSD and to produce subjective effects known to those knowledgeable in the field that are believed to be beneficial in supporting psychotherapy, including feelings of empathy, openness, trust, insight, and connection.

[0165] The compounds depicted in Figure 1A have a shorter, similar, or longer duration of action in humans compared to the original LSD molecule, which is caused by modifications to the molecular structure of Figure 1A.

[0166] The groups presented in the Preparation section, i.e., compounds 2a-2m, 12a-12g, 13, 14a-14c, and 16a-16c (see Figures 7A-7N and 8A-8N), exemplify lysergic acid derivatives depicted in Figure 1A that are contemplated within the scope of the compounds of the present invention.

[0167] The compounds according to the invention depicted in FIG. 1A allow for modification of the mode of action, psychodynamic processes, and qualitative perceptions, for example with respect to psychedelic or empathogenic potency, compared to the original LSD molecule.

[0168] The compounds of the present invention depicted in FIG. 1A can produce imagery, daydreams, and closed- or open-eye visuals of similar or different quality compared to the original LSD molecule.

[0169] The compounds of the present invention depicted in FIG. 1A may have potency at similar, lower, or higher doses compared to the original LSD molecule.

[0170] The compounds of the present invention depicted in FIG. 1A may induce similar or more favorable physical sensations compared to the original LSD molecule.

[0171] The modified properties can be individually tailored to the patient's needs. This can be targeted not only by changing the compound's receptor profile, but also by modifying ADME (absorption, distribution, metabolism, and excretion) by introducing more, similar, or fewer substituents at the N1, N6, or C8 carboxamide of the ergoline structure, as in the compounds represented in Figure 1A. Furthermore, stability can also be altered by introducing one or more deuterons into the ergoline core structure, as represented by class 5 in Figure 6C.

[0172] Preparation of compounds

[0173] A general approach to several lysergic acid derivatives in Class 1 is outlined in Figures 9-10. Commercially and synthetically available lysergic acid (1) or lysergic acid monohydrate is activated using an amide coupling reagent such as CDI, TBTU, TCFH, TFFH, T3P, COMU, or any other suitable coupling reagent (Figure 9) in a suitable solvent such as DMF, dimethylacetamide, DCM, or THF, EtOAc, dioxane, acetonitrile, or mixtures thereof. Alternatively, activation can occur with reagents such as POCl3 or trifluoroacetic anhydride. The activated intermediate is then reacted with a primary or secondary amine. This amine can be used as a free base or a salt. In the case of the free base, the amine can be used in excess of the activated lysergic acid or as one equivalent, along with a non-nucleophilic base such as triethylamine (NEt3), N-methylmorpholine (NMM), or N,N-diisopropylethylamine (DIPEA). If the amine to be coupled is applied in salt form, e.g., as its hydrochloride salt, it can be used in one equivalent or excess relative to the activated lysergic acid, and a non-nucleophilic base, as outlined above, can be used to separate the amine from its salt. The reaction temperature can range from 0 to 120°C, more preferably from 20 to 100°C. After a reaction time sufficient to allow amide formation, the corresponding amide formed is separated from the reaction mixture by extraction, chromatography, or crystallization of the compound itself or its salt, or a combination of these methods.

[0174] Compounds of class 1 (Figures 2A-3H) containing an enamide group (e.g., subclass 1f) can be accessed via different routes (Figure 9). In one embodiment, the corresponding primary or secondary 2-(phenylthiol)ethylamine is coupled with an activated lysergic acid derivative suitable for amide coupling. The 2-phenylthioethylamine may contain additional substituents at any part of the molecule. The corresponding amide containing the 2-(phenylthiol)ethyl group is then oxidized to the corresponding sulfoxide, which is then reacted in pyrolysis to give the corresponding enamide (Taniguchi et al., 2005). The sulfoxide group is chiral and may have either the R or S configuration, or any mixture of stereoisomers. The pyrolysis is catalyzed with a suitable base (e.g., NaHCO3, KHCO3, Na2CO3, or K2CO3) and carried out in a suitable solvent (e.g., toluene, or dimethylated or trimethylated benzenes, e.g., ortho-, meta-, or para-xylene), although any other solvent chemically inert to the reaction being carried out can be used, most preferably xylene. The temperature applied is 40-200°C, more preferably 100-150°C.

[0175] Access to sulfoxides can also be achieved as follows: Phenylvinyl sulfoxide or a substituted analog is reacted with a primary amine R-NH2 in a suitable organic solvent, such as THF, dioxane, ethyl acetate, or dichloromethane, to form the corresponding N-(2-phenylsulfinylethyl)-R-amine (Hu et al., 2014). The resulting amine is then coupled with the aforementioned lysergic acid or lysergic acid hydrate to yield an amide suitable for thermolysis to form the enamide. As noted above, the sulfoxide group is chiral and may have either the R or S configuration, or any mixture of stereoisomers.

[0176] In another embodiment for accessing enamides (e.g., subclass 1f), an aldehyde is coupled with a primary aldehyde to form an imine, which is then coupled with an activated lysergic acid derivative suitable for amide coupling and subsequent elimination (Golding & Wong, 1981; He et al., 2014; Kulyashova & M., 2016; Meuzelaar et al., 1997). The coupled intermediate is then eliminated to the corresponding enamide.

[0177] Another embodiment for accessing such enamides (e.g., subclass 1f) is the formation of an oxazoline followed by lithiation and alkylation, which leads to ring opening and formation of the enamide (Xu et al., 2017).

[0178] Furthermore, enamides (e.g., subclass 1f) can be accessed by direct elimination using, for example, LiHMDS ( Spiess et al., 2021 ).

[0179] Fluorinated enamides (e.g., subclass 1f) shown in class 1 (Figures 2A–3H) can also be obtained by applying elimination procedures using strong bases such as BuLi, LDA, or LiHDMS on 2,2,2-trifluoroethyl or 2-bromo-2,2-difluoroethyl substituents attached to the amide group of the corresponding lysergic acid amide compounds (Meiresonne et al., 2015; Riss & Aigbirhio, 2011).

[0180] Formation of ynamides (e.g., subclass 1g) outlined in class 1 (Figures 2A–3H) can be achieved by elimination procedures using a strong base such as, but not limited to, LiHDMS on 2,2,2-trifluoroethyl or 2-bromo-2,2-difluoroethyl substituents attached to the amide group of the corresponding lysergic acid compound (Meiresonne et al., 2015).

[0181] Class 2 compounds (Figures 4A-5C) can be obtained starting from the corresponding 6-nor LSD or any other 6-nor compound. The preparation of 6-nor LSD (Figure 11) is well documented, applying the classical von Braun reaction, in which cyanogen bromide in boiling tetrachloromethane is applied, both of which are problematic compounds to handle, and the formed aminonitrile is reduced by elemental zinc in acetic acid solution (Fehr et al., 1970). Herein, we used an alternative method described in WO2006128658A1 to prepare the pyrrolidine analog of LSD. Analogously, LSD is treated with an oxidizing agent such as mCPBA in dichloromethane under cooling, and the formed N-oxide is then reduced by adding FeSO4. This is a fairly safe and easy-to-handle reaction, and the reaction is very rapid. Furthermore, the yields are comparable to or even superior to those of the von Braun reaction. Other oxidizing agents, such as HO or cumyl hydroperoxide in organic solvents such as alcohol, ethyl acetate, or dichloromethane, can also be used. After a separation step, which can be performed by extraction, chromatography, or crystallization of the compound itself or its salt, or a combination of these methods, the resulting 6-nor LSD, or any other 6-nor compound, such as 6-nor TRALA-02 (e.g., as shown in Figure 12), can be used in reactions to access compounds represented by Class 2 (Figures 4A-5C). The LSD recovered from the above N-demethylation reaction, or any other recovered lysergic acid derivative, can be recycled to an N-demethylation reaction, as outlined above, to further increase the amount of desired 6-nor LSD or other 6-nor compound. This cyclical process can be repeated as many times as the technique and / or compound requirements allow.

[0182] Some compounds represented by class 2, as shown in Figures 4A-5C, can be obtained by reacting 6-nor LSD or another 6-nor compound with a correspondingly substituted R6 containing a leaving group substituted at the basic N6 nitrogen of 6-nor LSD or another 6-nor compound. The leaving group can be, for example, a halogen, mesylate, tosylate, or triflate. Furthermore, reductive amination can also be applied using an appropriate carbonyl compound and a reducing compound such as NaBH4 or Na(OAc)3BH or NaBH3CN, or by using hydrogen in a suitable solvent with or without a catalyst.

[0183] In the case of lysergic acid derivatives with strongly electron-withdrawing substituents, such as the secondary N6 of 6-nor LSD, or other derivatives with an NH at the 6-position, the nucleophilicity of the secondary amine may not be sufficiently high for use as a nucleophile. In such cases, the lysergic acid derivative must be appropriately protected or the electrophile must be activated to selectively deprotonate the N6. In such methods, the use of transition metals or transition metal oxides or salts such as silver salts to promote N-alkylation can be useful. Preferably, AgNO3 or AgOTf (AgCF3SO3) is added to the reaction mixture of the corresponding secondary N6 amine and alkylating agent in an organic solvent (e.g., THF, dioxane, or alcohol (e.g., MeOH, EtOH, iPrOH, or DCM)). The mixture can be maintained at 0-100°C, more preferably 20-100°C.

[0184] It is well known that in certain cases, the 2,2,2-trifluoroethyl substituent cannot be simply introduced into amines by applying one of the above methods due to its extremely deactivated reactivity (i.e., due to the electron-withdrawing properties of fluorine). Even 2,2,2-trifluoroethyl triflate, a compound much more reactive than 2,2,2-trifluoroethyl iodide, exhibits extremely low reactivity in nucleophilic substitution with amines. Such a substituent can be introduced into amines using a synthetic equivalent, illustratively 2,2,2-trifluoroacetaldehyde ethyl hemiacetal (alternative name: 1-ethoxy-2,2,2-trifluoroethanol) (Mimura et al., 2010). The formed intermediate is then reduced with a suitable reducing agent, such as NaBH, Na(OAc)BH, or NaBHCN.

[0185] Enamine compounds of Class 2 (Subclass 2f) shown in Figure 4G can be obtained by reacting the corresponding carbonyl compound with 6-nor LSD, followed by removal or absorption of water to form an imine, and optionally, the addition of a non-nucleophilic base. Alternatively, such enamines can also be obtained by reacting fluorinated 1-halo-1-alkenes with 6-nor LSD or another 6-nor compound in a direct halo substitution reaction (WO2006046417A1).

[0186] Furthermore, enamine compounds represented by class 2 (subclass 2f) depicted in Figure 4G can be obtained by, for example, allowing the reaction of N6-substituted N6-2,2,2-trifluoroethyl-6-norLSD with a strong base such as LDA or BuLi (Riss & Aigbirhio, 2011).

[0187] Alkoxyamine compounds, also known as N-hydroxyethers, represented by Class 2 (Subclass 2h) depicted in Figure 5B can be obtained by reacting 6-norLSD with an oxidizing agent (e.g., HO or mCPBA in an organic solvent) to form the corresponding 6-norLSD-N-hydroxylamine, then deprotonating the N-hydroxylamine with a base such as LDA, KOtBU, BuLi, or LiHDMS, and then reacting this deprotonated intermediate with a corresponding substituted R containing a leaving group that is replaced by the deprotonated oxygen of 6-norLSD-N-hydroxylamine. The leaving group can be a halogen, mesylate, tosylate, or triflate, or other suitable leaving group.

[0188] Arylamines or heteroarylamines represented by class 2 (subclass 2i) depicted in Figure 5C can be obtained by reacting 6-nor LSD or another 6-nor compound with the corresponding aryl or heteroaryl halide, triflate, for example, in a process commonly described as the Buchwald-Hartwig amination.

[0189] Benzylamines and (heteroarylmethyl)amines represented by class 2 (subclass 2i) depicted in Figure 5C can be obtained by reacting 6-nor LSD or another 6-nor compound with the corresponding aryl or (heteroarylmethyl)halide in a classical substitution reaction, or by reacting with the corresponding aldehyde by way of reductive amination in a suitable solvent, in the presence or absence of a catalyst, by applying reducing conditions such as NaBH, Na(OAc)BH, or NaBHCN, as well as hydrogen.

[0190] The N6 substituent can also consist of a cycloalkane or oxacycloalkane (subclasses 2d and 2g in Figure 4E and Figure 5A). These substituents can be introduced by reductive amination of 6-nor LSD or another 6-nor compound with the corresponding oxo-cycloalkane or oxo-oxacycloalkane and a reducing compound, such as NaBH, Na(OAc)BH, or NaBHCN, as well as hydrogen in the presence or absence of a catalyst in a suitable solvent.

[0191] Furthermore, these cycloalkane substituents, represented by subclasses 2d and 2g in Figures 4E and 5A, can also be introduced by a substitution reaction by reacting a 6-nor LSD or another 6-nor compound with a correspondingly substituted R6 cycloalkane or oxacycloalkane containing a leaving group that replaces the basic N6 nitrogen of the 6-nor LSD. The leaving group can be, for example, a halogen, mesylate, tosylate, or triflate.

[0192] Further access to compounds represented by subclasses 2d and 2g in Figures 4E and 5A is achieved by the use of 6-nor LSD or another 6-nor compound, which can be reacted with a cycloalkane or oxacycloalkane containing geminal substituted alkoxy-(trialkylsilyloxy) substitution, for example, under acidic conditions such as the use of acetic acid, and using reducing compounds such as NaBH, Na(OAc)BH, or NaBHCN as well as hydrogen, and in the presence or absence of a catalyst, in a suitable solvate.

[0193] Compounds of Class 3 (Figure 6A) can be obtained by combining any of the synthetic routes described above. In addition, suitable protecting groups can be first introduced at the carboxyl functionality attached to N1, N6, or C8 of other underivatized ergoline structures such as LSD, 6-norLSD, or N6-norergotamine, N6-deprotected intermediates, N6-deprotected lysergic acid, N6-deprotected lysergic acid esters, or suitably transformed compounds.

[0194] Class 4 compounds (Figure 6B) can be obtained by corresponding functionalization of N1 of the ergoline core structure by using Class 1, Class 2, or Class 3 compounds, and vice versa.

[0195] Class 5 compounds (Figure 6C) can be obtained by using Class 1, Class 2, or Class 3 compounds that have at least one deuteron atom in the ergoline core structure, and by correspondingly functionalizing N1 of the ergoline core structure, or vice versa.

[0196] Detailed description of the chemical preparation of the compounds

[0197] General preparation and equipment information: NMR was performed using a Bruker NMR ( 1 H: 300MHz and 19 F: 282 MHz at ambient temperature. Reaction control was performed by silica gel TLC (F 254Analysis was performed under basic and acidic conditions by HPLC UV and MS (Agilent 1100, UV 210 nm and 313 nm, Waters SQD, ESI+ mode) (solvent: A: either 0.02% NH4OH in water or 0.05% TFA in water; B: acetonitrile, gradient 5% to 95% B, reverse-phase C18 HPLC column). All reactions, workups, drying steps, and storage were performed excluding sunlight and light sources such as neon lights or light bulbs containing wavelengths in the blue and / or UV spectrum. Work was performed either in light-free labware or under orange to red light (UV-free LED). This helps prevent compound decomposition. Additionally, to further protect the compounds from decomposition, reactions and some purifications can be performed under protective gases such as nitrogen or argon. Purification was performed using silica gel column chromatography and a mixture of alcohol (MeOH or EtOH) and dichloromethane, optionally with additional organic solvents such as 0.1%–1% NH4OH (5%) or 0.1%–1% NEt3. Preparative TLC (silica gel) using the aforementioned solvents was also performed in a similar manner. Work safety: Appropriate personal protective equipment and a fume hood with a movable glass window were used for laboratory work. Contamination, for example, on gloves or surfaces, can be quickly detected by having a long-wavelength UV lamp (e.g., 366 nm) on hand, preventing further distribution of the active substance. Compounds with an intact lysergic acid amide moiety typically exhibit strong bluish fluorescence, even in trace amounts. Rapid deactivation of potential central effects of these compounds can be achieved, for example, by using a mixture of bleach and dilute alcohol.

[0198] To evaluate the biological properties of the compounds of the present invention, proper purity and identity confirmation and determination of epimeric identity are crucial. For some compounds, TLC or a single HPLC is not sufficient to make the determination, so we did not rely on TLC or a single HPLC analysis, but instead set up a more detailed evaluation of the analysis.

[0199] Purity checks of the final compounds were performed on two different HPLC systems using different columns and different eluents at 195 nm and 313 nm (reaction control: 210 nm and 313 nm). Very low absorption wavelengths reveal organic contaminants, while higher wavelengths, which roughly correspond to the characteristic local maxima of these compounds, reveal whether structurally related contaminants are present. Furthermore, 1 H-NMR, and, where applicable, 19 F-NMR was further helpful in determining purity.

[0200] The identity of the final compound was checked by HPLC-MS, as well as 1 H-NMR, and, where applicable, 19 F-NMR was performed. See instructions below for important notes on NMR analysis and interpretation.

[0201] General method for amide coupling. To a suspension of 286 mg (1 mmol) of lysergic acid monohydrate (note: water-free lysergic acid can be used as well) in 4 mL of anhydrous DMF, 258 mg (1.59 mmol) of 1,1'-carbonyldiimidazole (CDI) was added in one portion. After a few minutes, the suspension became clear. After 30 min, HPLC-UV and MS-based activation was checked by dissolving a minimal sample of the reaction mixture in anhydrous MeOH. Results indicated clean and complete formation of the methyl ester (lysergic acid methyl ester appeared as two epimers). Therefore, the amine to be coupled (1.05–1.5 equiv.) as either the free base or the hydrochloride salt was premixed with diisopropylethylamine (DIPEA; 435 μL, 2.5 equiv.) in 2 mL of anhydrous DMF. The clear amine solution was added in one portion to the above activated lysergic acid solution. Note: In some cases, a large excess of free amine (up to 10 equivalents, without DIPEA) forced the reaction to favor the C8-epimer ratio much more toward the desired pharmacologically active 8R-carboxamide epimer. This method was used to force the epimer ratio depending on the availability of the amine used and for economic reasons. After reaction control (TLC: DCM / MeOH 9 / 1 and HPLC MS with UV at 210 nm and 313 nm) showed complete or nearly complete conversion (Note: In all cases, a mixture of C8-epimers was formed based on interpretation of UV absorption at 313 nm, with 8R:8S ratios ranging from 8:2 to 4:6. For less nucleophilic amines, such as di(2,2-difluoroethyl)amine, reaction times of up to 4 days were required), the DMF was removed under vacuum using a powerful vacuum pump at 40 °C. After extraction, the reaction mixture was either directly partitioned between water (40 mL) and 40 mL of 1:1 heptane / EtOAc (40 mL). The layers were separated, and the very dark aqueous layer was further extracted with 1:1 heptane / EtOAc (2 × 20 mL). The combined cognac-colored organic layers were further washed with water (3 × 20 mL) and dried by slow filtration through a pad of NaSO. After evaporation of the organic volatiles, a green to brown residue was obtained as crude product.This was purified by either column chromatography or preparative TLC as described in the general section to obtain the corresponding lysergic acid amide derivative as a free base. As a general observation, and consistent with (Bailey, Verner, & Legault, 1973; Hoehn, Nichols, McCorvy, Neven, & Kais, 2017; Hoffman & Nichols, 1985; Stachulski, Nichols, & Scheinmann, 1996), under normal-phase chromatographic conditions, the first compound eluted from the silica gel exhibited blue fluorescence under long-wavelength UV and corresponded to the pharmacologically active compound with the 8R-carboxamide configuration, and thus to the desired C8 epimer. The second, always highly polar, compound emitting blue fluorescence corresponded to the 8S-carboxamide epimer, also known as the isocompound. This was confirmed by LCMS for mass (reverse order of elution was observed on a reversed-phase column), by NMR for structural evidence, by comparing the separated lysergic acid derivatives with the separated iso-lysergic acid derivatives, and by existing literature, e.g., (Brandt et al., 2017; Hoehn et al., 2017; Hoffman & Nichols, 1985; Stachulski et al., 1996). We did not rely solely on TLC analysis because not all lysergic acid derivatives separate well from their iso-lysergic acid derivatives under HPLC conditions (rarely, no clear separation occurred). 1 H-NMR analysis was also used to check for proper epimer separation. Generally, rotation around the amide C-N bond is hindered, which can lead to more complex spectra. It is important to note that in the case of the H9 proton, in symmetrically substituted amides, 1H-NMR usually revealed only a single signal (usually around 6.3-6.4 ppm, singlet to multiplet). Most asymmetrically substituted amides showed two signals for this H9 proton (usually around 6.3-6.4 ppm, sometimes singlet to multiplet), in a ratio that was not 1:1. To prove the absence of 8S-configured impurities (isocompounds) that could contaminate the desired 8R-configured derivative, in addition to HPLC UV and MS analysis, in which the 8R / 8S epimers are not necessarily separated by baseline, isocompounds were also analyzed. 1 H-NMR analysis and spectral comparison also revealed two signals between approximately 6.3 and 6.4 ppm, indicating a non-1:1 ratio of H9 protons, but both signals had different chemical shifts than the two H9 signals from the 8R-configured compound. This conclusively demonstrated the epimeric purity of the asymmetric amide. The desired free base product was dried under high vacuum to remove residual NH3 or NEt3, yielding a solid or foam with a golden, brown, or beige appearance. The resulting iso-compound (the isolated compound with the 8S-carboxamide configuration) is also worth separating; it can easily epimerize at the C8 center to give a mixture of 8R- and 8S-carboxamides by applying a base to an appropriate solvent using known procedures (GB579484A). The resulting epimeric mixture can then be separated by the purification steps described above. This easily increases the yield of the lysergic acid derivative with the desired 8R-carboxamide configuration. For larger batches, it may be worth repeating this procedure several times to maximize yield.

[0202] General procedure for the formation of hemitartrate or tartrate salts. Note: Only the conversion of the desired 8R-carboxamide epimer to the salt is described; the C8 epimers (so-called iso compounds with 8S configuration) were either kept as their free base or 1A portion was also converted to a salt for H-NMR spectral comparison. A 10% solution of (+)-tartaric acid in anhydrous methanol was prepared (precise weighing required to calculate the volume). The purified lysergic acid amide derivative as a free base was dissolved in a minimum amount of anhydrous MeOH, with slight warming if necessary, and neutralized with 0.5 (for the hemitartrate) to 1 mol equivalent (for the tartrate) of the (+)-tartaric acid solution described above. Alternatively, neutralization can be performed by directly adding the (+)-tartaric acid solution to the free base foam. Anhydrous diethyl ether (EtO) was then added until maximum precipitation was achieved. The resulting suspension was allowed to stand for the required time, either at ambient temperature or in the refrigerator, depending on the ease of suspension formation. The liquid layer was carefully decanted or removed using a clogged Pasteur pipette (e.g., cotton wool), and the residue was rinsed with 1:1 MeOH / EtO and finally EtO, followed by drying overnight under high vacuum. The remaining crystalline lysergic acid amide hemitartrate or tartrate salt appeared white to off-white. Determination of the exact tartaric acid content was performed using a 1 This can be done by H-NMR (ratio of lysergic acid derivative to tartaric acid: this can be 1:0.5 to a maximum of 1:1, or even more if excess tartaric acid is inadvertently used and not properly removed). 1 Comments on the H-NMR spectrum (see also existing literature, e.g., (Bailey et al., 1973; Hoehn et al., 2017; Hoffman & Nichols, 1985; Stachulski et al., 1996)): As observed on the free base of lysergic acid derivatives, the H9 proton 1H-NMR revealed only a single signal (approximately 6.3-6.4 ppm, sometimes singlet to multiplet) for symmetrically substituted amides. Asymmetrically substituted amides showed two signals (approximately 6.3-6.4 ppm, sometimes singlet to multiplet) for this H9 proton, with a ratio that was not 1:1. To prove the absence of 8S configuration impurities (isocompounds), in addition to HPLC UV and MS analyses, in which the 8R / 8S epimers were not necessarily separated by baseline, isocompounds were also analyzed. 1 H-NMR measurements and spectral comparison showed that the H9 protons were not in a 1:1 ratio, but had different chemical shifts than the two H9 signals from the 8R-configured compound, conclusively demonstrating the epimeric purity of the asymmetric amide.

[0203] General procedure for N6 alkylation with alkyl halides, adapted from (Hoffman & Nichols, 1985). To a mixture of 97 μmol (for 6-nor LSD, this corresponds to 30 mg) of the free base of the N6-nor compound and 26.8 mg (2.0 equiv.) of K2CO3 in 0.5 mL of anhydrous DMF, 116 μmol (1.3 equiv.) of the corresponding alkyl halide was added under nitrogen. Reaction control (TLC: DCM / MeOH 9 / 1, sometimes by adding 0.1% NEt3, or by HPLC UV and MS) showed complete conversion after 1 hour. (Note: N6 alkylation is much faster than C8 epimerization, and therefore, at ambient temperature under the selected reaction conditions, workup of the mixture was performed as previously demonstrated (Stachulski et al.). (e.g., 1996), virtually no epimerization occurred. If the alkylation of N6 was very slow (e.g., less than about 20% conversion in one day), the reaction could be driven to completion by adding a second, and possibly a third, equivalent of alkylating agent after one, two, and three days, respectively. Therefore, after stirring for the required time, the reaction mixture was concentrated under high vacuum at 40 °C to remove most of the volatiles, including DMF. The residue was dissolved in the eluent used for chromatography as described in the general section and purified by silica gel column chromatography. A solvent system of DCM / MeOH / NEt3 = 98 / 2 / 0.1 was suitable for most compounds. After drying the free base products under high vacuum to remove residual NH3 or NEt3, solids or foams with a golden, brown, or beige appearance were obtained. If necessary, the products could be further purified by dissolving them in a hot solvent such as benzene, filtering if necessary, and then adding heptane to precipitate them from the filtered and cooled solution (Hoffman & Nichols, 1985). Such precipitate is then collected by filtration and dried under high vacuum. If desired, the free base compound can be converted to a pharmaceutically acceptable salt.In some cases, we observed very weak salt properties, and in the case of certain tartrate salts, it was even possible to completely separate the tartaric acid from the lysergic acid amide derivatives by precipitation of the tartaric acid from the solution.

[0204] Example - Amide coupling of lysergic acid with secondary amines and conversion to their salts: Preparation of lysergic acid derivatives 2a-l.

[0205] 9,10-didehydro-N-methyl-N-propyn-3-yl-6-methylergoline-8R-carboxamide (TRALA-01), 2a. According to the general amide coupling method described, from 286 mg of lysergic acid monohydrate (AT Shulgin & Shulgin, 1997), 258 mg of CDI, and 276 mg of N-methyl-propargylamine (4 equivalents), no DIPEA was used. Yield: 77 mg (24%) of TRALA-01 as a beige amorphous solid, and 75 mg (18%) of iso-TRALA-01 as a grayish-greenish solid. Tartrate salt formation according to the general method described yielded 62 mg of 2a tartrate product as an off-white solid. Analytical data for 2a as the tartrate salt: 1 H-NMR (DMSO-d6): (Related interpretation complications: see General Chapter, Amide Couplings) ca. 2.50 (s, N(6)Me, superimposed with DMSO), 2.59 (m, 1H), 2.92 (s, 1H), 3.11 (m, 2H), 3.23 (t, 1H), 3.25-3.44 (m, ca. 2H), 3.51 (m, ca. 2H), 3.89-4.38 (m, ca. 3H), 4.23 (s, tartaric acid), 6.28 (ca. 60%) / 6.35 (ca. 40%) (2 x s, total = H9; note; epimeric purity proof of ergoline structure C9: see General Chapter, Amide Couplings), 7.00-7.11 (m, 3 arom. H), 7.17-7.23 (m, 1 arom. H), 10.75 (bs, NH). LCMS (M+H): Expected for 2a: M=319.41; Found: 320.3.

[0206] 9,10-didehydro-N-ethyl-N-propyn-3-yl-6-methylergoline-8R-carboxamide (TRALA-02), 2b. According to the general amide coupling method described, 286 mg of lysergic acid monohydrate, 258 mg of CDI, 180 mg of N-ethyl-propargylamine hydrochloride (1.5 equivalents), and 435 μL of DIPEA (2.5 equivalents) were used. Yield: 110 mg (33%) of TRALA-02 as a brownish amorphous solid and 116 mg (35%) of iso-TRALA-02 as a brown solid. Tartrate salt formation according to the general method described yielded 104 mg of 2b tartrate product as an off-white solid. Analytical data for 2b as the tartrate salt: 1 H-NMR (DMSO-d6): (Related interpretation complications: see general chapter, Amide Coupling) 1.11 / 1.25 (2 x t, total = 3H), 2.54 (s, N(6)Me, superimposed with DMSO), 2.69 (t, ca. 1H), 3.04-3.21 (m, ca. 3H), 3.35-3.65 (m, ca. 4H), 3.96 (m, ca. 1H), 4.21 (m, ca. 1H), 4.24 (s, tartaric acid), 4.35 (m, 1H), 6.25 (ca. 50%) / 6.36 (ca. 50%) (2 x s, total = H9. Note: Proof of epimeric purity of ergoline structure C9: see general chapter, amide coupling), 7.00-7.11 (m, 3 arom. H), 7.17-7.23 (m, 1 arom. H), 10.74 (bs, NH). LCMS (M+H): Expected for 2b: M = 333.43; Found: 334.2. Analytical data for iso-2b as the tartrate salt: 1H-NMR (DMSO-d6): 1.10 / 1.26 (2 x t, total = 3H), 2.64 (s, N(6)Me), 2.76 (t, ca. 1H), 2.98 (m, ca. 1H), 3.13 (m, ca. 1H), 3.27-3.67 (m, ca. 4H), 3.87 (m, ca. 1H), 4.16 (m, ca. 1H), 4.20 (s, tartrate), 4.39 (m, 1H), 6.32 (ca. 55%) / 6.39 (ca. 45%) (2 x s, total = H9; Note: Proof of epimeric purity of ergoline structure C9: see general chapter, Amide Coupling), 7.07 (bs, 3 arom. H), 7.14-7.23 (m, 1 arom. H), 10.76 (bs, NH). LCMS (M+H): expected for iso-2b: M=333.43; found: 334.2.

[0207] 9,10-Didehydro-N-(cyanomethyl)-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-03), 2c. According to the general amide coupling method described, from 286 mg of lysergic acid monohydrate, 258 mg of CDI, and 168 mg of 2-(ethylamino)acetonitrile (2 equivalents), no DIPEA was used. Yield: 30 mg (9%) of TRALA-03 as a beige amorphous solid and 104 mg (31%) of iso-TRALA-03 as a brown mass. Tartrate salt formation according to the general method described yielded 31 mg of 2b tartrate product as an off-white solid. Analytical data for 2c as the tartrate salt: 1 H-NMR (DMSO-d6): (Related interpretation complications: see general chapter, amide coupling) 1.13 / 1.26 (2 x t, total = 3H), 2.52 (m, ca. 1H, superimposed with DMSO), 2.56 (s, N(6)Me, superimposed with DMSO), 2.71 (t, ca. 1H), 3.15 (m, ca. 2H), 3.59 (m, ca. 3H), 3.96 (m, ca. 1H), 4.27 (s, tartaric acid), 4.41 (m, ca. 2H), 6.28 (s, H9), 7.03-7.10 (m, 3 arom. H), 7.19-7.24 (m, 1 arom. H), 10.74 (bs, NH). LCMS (M+H): Expected for 2c: M = 334.42; Found: 335.2.

[0208] 9,10-didehydro-N-ethyl-N-(2-fluoroethyl)-6-methylergoline-8R-carboxamide (TRALA-04), 2d. According to the general amide coupling method described, 573 mg of lysergic acid monohydrate, 517 mg of CDI, 255 mg of N-ethyl-(2-fluoroethyl)amine hydrochloride (1 equivalent), and 523 μL of DIPEA (1.5 equivalents) were used. Yield: 153 mg (22%) of TRALA-04 as a beige foam and 156 mg (23%) of iso-TRALA-04 as a brown foam. Tartrate salt formation according to the general method described yielded 158 mg of 2d tartrate as an off-white solid. Analytical data for 2d as the tartrate salt: 1 H-NMR (DMSO-d6): (Related interpretation complications: see general chapter, Amide Couplings) 1.07 / 1.21 (2 x t, total = 3H), 2.52 (m, ca. 1H, superimposed with DMSO), 2.54 (s, N(6)Me, superimposed with DMSO), 2.69 (t, ca. 1H), 3.01-3.19 (m, ca. 2.5H), 3.41 (m, ca. 1H), 3.53 (m, ca. 2.5H), 3.62-3.95 (m, ca. 2.5H), 4.23 (s, tartaric acid), 4.59 (t x q, 2H), 6.27 (s, H9), 7.00-7.11 (m, 3 arom. H), 7.17-7.23 (m, 1 arom. H), 10.73 (bs, NH). 19 F-NMR (DMSO-d6): -221.29, -222.13. LCMS (M+H): expected for 2d: M=341.43; found: 342.3.

[0209] 9,10-didehydro-N-(2,2-difluoroethyl)-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-05), 2e. According to the general amide coupling method described, 492 mg of lysergic acid monohydrate, 444 mg of CDI, 250 mg of N-(2,2-difluoroethyl)ethylamine hydrochloride (1 equivalent), and 448 μL of DIPEA (1.5 equivalents) were used. Yield: 202 mg (33%) of TRALA-05 as a golden foam and 252 mg (41%) of iso-TRALA-05 as a brown mass. According to the general method described, tartrate salt formation yielded 204 mg of 2e tartrate salt as an off-white solid. Analytical data for 2e as the tartrate salt: 1 H-NMR (DMSO-d6): (Related interpretation complications: see general chapter, Amide Coupling) 1.08 / 1.23 (2 x t, total = 3H), 2.53 (s, N(6)Me), superimposed with DMSO), 2.62 (m, approx. 1.5H, superimposed with DMSO / N(6)Me), 3.02-3.19 (m, approx. 2.5H), 3.41 (m, approx. 1H), 3.54 (m, approx. 2.5H), 3.74 (t x m, 1.5H), 3.93 (m, 1.5H), 4.25 (s, tartrate), 6.15 (t x m, 1H), 6.24 (minor) / 6.26 (major) (2 x s, total = H9) Note: Epimeric purity proof for ergoline structure C9: see general chapter, amide coupling), 7.00-7.11 (m, 3 arom. H), 7.17-7.24 (m, 1 arom. H), 10.73 (bs, NH). 19 F-NMR (DMSO-d6): -120.46 (major), -122.04 (trace). LCMS (M+H): Expected for 2e: M = 359.42, Found: 360.3. Analytical data for iso-2e as the tartrate salt: 1H-NMR (DMSO-d6): (Related interpretation complications: see General Chapter, Amide Couplings) 1.05 / 1.23 (2 x t, total = 3H), 2.64 (m, N(6)Me), 2.77 (m, 1H), 2.97 (m, 1H), 3.13 (m, 1H), 3.32 (m, ca. 2H), 3.48-3.78 (m, ca. 4H), 3.81-4.10 (m, 1.8H), 4.22 (s, tartrate), 6.11 (t x m, 1H), 6.30 (s, H9; Note: Proof of epimeric purity of ergoline structure C9: see General Chapter, Amide Couplings), 7.07 (m, 3 arom. H), 7.21 (m, 1 arom. H), 10.76 (bs, NH). 19 F-NMR (DMSO-d6): -120.46 (major), -121.87 (trace). LCMS (M+H): expected for iso-2e: M = 359.42, found: 360.3.

[0210] 9,10-didehydro-N-ethyl-N-(2,2,2-trifluoroethyl)-6-methylergoline-8R-carboxamide (TRALA-06), 2f. According to the general amide coupling method described, 573 mg of lysergic acid monohydrate, 517 mg of CDI, 328 mg of N-(2,2,2-trifluoroethyl)ethyleneamine hydrochloride (1 equivalent), and 522 μL of DIPEA (1.5 equivalents) were used. Yield: 128 mg (17%) of TRALA-06 as a yellowish foam and 170 mg (23%) of iso-TRALA-06 as a brown mass. According to the general method described, tartrate salt formation yielded 108 mg of 2f tartrate salt as an off-white solid. Analytical data for 2f as the tartrate salt: 1H-NMR (DMSO-d6): (Related interpretation complications: see general chapter, Amide Coupling) 1.09 / 1.23 (2xt, total = 3H), 2.54 (s, N(6)Me), superimposed with DMSO), 2.67 (m, ca. 1H, superimposed with DMSO / N(6)Me), 2.99-3.20 (m, ca. 3H), 3.54 (m, ca. 3H), 3.96 (m, 1H), 4.24 (m, ca. 1.5H, superimposed with tartaric acid), 4.26 (s, tartaric acid), 4.47 (m, ca. 0.5H), 6.21 (minor) / 6.24 (major) (2x s, total = H9, Note: Epimeric purity proof for ergoline structure C9: see general chapter, amide coupling), 6.99-7.12 (m, 3arom.H), 7.17-7.23 (m, 1arom.H), 10.74 (bs, NH). 19 F-NMR (DMSO-d6): -68.27 (major), -69.38 (trace). LCMS (M+H): expected for 2f: M = 377.41, found: 378.3.

[0211] 9,10-didehydro-N-methyl-N-(2,2,2-trifluoroethyl)-6-methylergoline-8R-carboxamide (TRALA-07), 2 g. According to the general amide coupling method described, 573 mg of lysergic acid monohydrate, 517 mg of CDI, 299 mg of N-(2,2,2-trifluoroethyl)methylamine hydrochloride (1 equivalent), and 522 μL of DIPEA (1.5 equivalents) were used. Yield: 108 mg (15%) of TRALA-07 as a yellow foam and 174 mg (24%) of iso-TRALA-07 as a brown foam. According to the general method described, tartrate salt formation yielded 86 mg of 2 g tartrate salt as an off-white solid. Analytical data for 2 g as tartrate salt: 1H-NMR (DMSO-d6): (Related interpretation complications: see general chapter, Amide Coupling) 2.54 (s, N(6)Me, superimposed with DMSO), 2.63 (m, approx. 1.5H, superimposed with DMSO / N(6)Me), 2.97-3.20 (m, 3H), 3.28 (s, CONMe), 3.52 (dxd, 1H), 4.15 (m, 1H), 4.24 (m, 2H), 4.26 (s, tartrate), 4.53 (m, approx. 0.5H), 4.69 (dxt, 2H), 6.23 (minor) / 6.29 (major) (2x s, total = H9; Note: Epimeric purity proof for ergoline structure C9: see general chapter, amide coupling), 7.01-7.12 (m, 3 arom. H), 7.17-7.23 (m, 1 arom. H), 10.73 (bs, NH). 19 F-NMR (DMSO-d6): -68.62 (major), -69.36 (trace). LCMS (M+H): Expected for 2g: M = 363.39, Found: 364.3. Analytical data for iso-2g as the tartrate salt: 1 H-NMR (DMSO-d6): (Related interpretation complications: see General Chapter, Amide Couplings) 2.61 (s, N(6)Me), 2.73 (t, 1H), 2.94 (m, approx. 1.6H), 3.08 (dxd, approx. 1.3H), 3.29 (s, CONMe), 3.42 (m, approx. 1H), 3.94 (m, 1H), 4.21 (m, approx. 2H, superimposed from tartaric acid), 4.26 (s, tartaric acid), 6.27 (minor) / 6.33 (major) (2x s, total = H9; note: proof of epimeric purity of ergoline structure C9: see General Chapter, Amide Couplings), 7.01-7.12 (m, 3 arom. H), 7.16-7.24 (m, 1 arom. H), 10.75 (bs, NH). 19 F-NMR (DMSO-d6): -68.52 (major), -69.13 (trace). LCMS (M+H): expected for iso-2g: M = 363.39, found: 364.3.

[0212] 9,10-didehydro-N,N-di(2-fluoroethyl)-6-methylergoline-8R-carboxamide (TRALA-08), 2h. According to the general amide coupling method described, 492 mg of lysergic acid monohydrate, 444 mg of CDI, 250 mg of di(2-fluoroethyl)amine hydrochloride (1 equivalent), and 448 μL of DIPEA (1.5 equivalents) were used. Yield: 80 mg (13%) of TRALA-08 as a beige foam and 161 mg (26%) of iso-TRALA-08 as a beige foam. Tartrate salt formation according to the general method described yielded 76 mg of 2h tartrate salt as an off-white solid. Analytical data for 2h as the tartrate salt: 1 H-NMR (DMSO-d₆): 2.57 (s, NMe, superimposed with DMSO), 2.68 (t, 1H), 3.03-3.21 (m, 3H), 3.52 (dxd, 1H), 3.70 (dxm, 2H), 3.87 (dxt, 2H), 3.98 (m, 1H), 4.24 (s, tartaric acid), 4.53 (dxt, 2H), 4.69 (dxt, 2H), 6.28 (s, H₆), 7.01-7.12 (m, 3 arom. H), 7.18-7.23 (m, 1 arom. H), 10.73 (bs, NH). 19 F-NMR (DMSO-d): -221.98, -222.95. LCMS (M+H): expected for 2h: M = 359.42, found: 360.3.

[0213] 9,10-didehydro-N,N-bis(2,2-difluoroethyl)-6-methylergoline-8R-carboxamide (TRALA-09), 2i. According to the general amide coupling method described, 394 mg of lysergic acid monohydrate, 356 mg of CDI, 250 mg of bis(2,2-difluoroethyl)amine hydrochloride (1 equivalent), and 360 μL of DIPEA (1.5 equivalents) were used. Yield: 33 mg (6%) of TRALA-09 as brown mass and 44 mg (8%) of iso-TRALA-09 as brown mass. According to the general method described, tartrate salt formation yielded 18 mg of 2i tartrate salt as an off-white solid. Analytical data for 2i as the tartrate salt: 1H-NMR (DMSO-d6): (related interpretation complications: see general chapter, amide coupling) ca. 2.50 (NMe, superimposed with DMSO), 2.64 (t, 1H), 3.03-3.28 (m, 3H), 3.52 (dxd, 1H), 3.86 (txt, 2H), 3.97-4.15 (m, 3H), 4.27 (s, tartaric acid), 6.24 (s, H9), 6.25 (5.97-6.53: sharply resolved txm; 2x CHF2), 7.02-7.14 (m, 3arom. H), 7.18-7.25 (m, 1arom. H), 10.74 (bs, NH). 19 F-NMR (DMSO-d): -121.26, -121.29, -122.87. LCMS (M+H): expected for 2i: M = 395.40, found: 396.2.

[0214] 9,10-Didehydro-N-ethyl-N-(methoxy)-6-methylergoline-8R-carboxamide (TRALA-10), 2j. Following the general amide coupling procedure described, with 1.14 g of lysergic acid monohydrate, 1.04 g of CDI, 0.51 g of N-methoxy-ethylamine hydrochloride (1 equivalent), and 1.04 mL of DIPEA (1.5 equivalents). Yield: 113 mg (17%) of TRALA-10 as a yellow foam and 146 mg (22%) of iso-TRALA-10 as a brown foam. Tartrate salt formation according to the general procedure described yielded 74 mg of 2j tartrate as an off-white solid. Analytical data for 2j as the tartrate salt: 1 H-NMR (DMSO-d6): (Related interpretation complications: see general chapter, amide coupling): 1.13 (t, 3H), 2.56 (s, NMe, superimposed with DMSO), 2.62 (m, ca. 1H), 3.06-3.18 (m, 3H), 3.52 (dxd, 2H), 3.66 (q, 2H), 3.76 (s, OMe), 3.93 (m, 1H), 4.25 (s, tartaric acid), 6.30 (s, H9), 7.01-7.12 (m, 3arom. H), 7.18-7.23 (m, 1arom. H), 10.73 (bs, NH). LCMS (M+H): Expected for 2j: M = 325.41, found: 326.3.

[0215] 9,10-Didehydro-6-methylergoline-8R-((RS)-2-ethynylazetidide) (TRALA-11), 2k. According to the general amide coupling method described, with 243 mg of lysergic acid monohydrate, 220 mg of CDI, 100 mg of (RS)-2-ethynylazetidine hydrochloride (1 equivalent), and 222 μL of DIPEA (1.5 equivalents). Yield: 52 mg (19%) of TRALA-11 as a beige foam and 90 mg (32%) of iso-TRALA-11 as a beige foam. Tartrate salt formation according to the general method described, yield: 45 mg of 2k tartrate was obtained as an off-white solid. Analytical data for 2k as the tartrate salt (related interpretation complications: see General, Amide Coupling chapter): 1 H-NMR (DMSO-d6): 2.24 (m, 1H), 2.48-2.62 (m, ca. 3H, superimposed with DMSO and NMe), 2.52 (s, superimposed with NMe and DMSO), 3.12 (m, 1H), 3.18 (s, CCH), 3.52 (m, 2H), 3.75 (m, 1H), 3.86 (m, ca. 1.5H), 4.25 (s, tartaric acid), 4.27 (m, ca. 0.5H), 4.83 (m, ca. 0.5H), 4.32 (m, ca. 0.5H), 6.26 (minor) / 6.35 (major) (2x s, total = H9; Note: The azetidine moiety contains a stereocenter that is presumed to be racemic; Epimeric purity proof for ergoline structure C9: see general chapter, amide coupling) 7.01-7.11 (m, 3arom.H), 7.21 (m, 1arom.H), 10.73 (bs, NH). LCMS (M+H): expected for 2k: M = 331.42, found: 332.2.

[0216] 9,10-didehydro-N-(2-fluoroethyl)-N-(methoxy)-6-methylergoline-8R-carboxamide (TRALA-14), 2n. 1.) Preparation of N-methoxy-2-fluoroethylamine hydrochloride (10; adapted from US20100029670A1). To a solution of 1.0 g (8.39 mmol) of ethyl N-methoxycarbamate (8) in 5 mL of anhydrous DMF was added 0.352 g (8.81 mmol) of 60% NaH dispersed in mineral oil under nitrogen and ice cooling. After stirring for 5 minutes, the mixture was allowed to stir at ambient temperature for 1 hour. Next, 1.46 g (8.39 mmol) of 1-fluoro-2-iodomethane was added, and the mixture was heated to 75 °C for 6 hours. The mixture was cooled to ambient temperature, mixed with water and EtOAc (70 mL each), and the layers were separated. The organic layer was further washed once with water (1 x 70 mL), dried over MgSO4 and concentrated in vacuo to give 1.05 g (75%) of Intermediate 9 as a yellow oil. 1 H-NMR (CDCl3): 1.33 (t, CH2CH3), 3.75 (s, OCH3), 3.81 (dxt, CH2CH2F), 4.24 (q, CH2CH3), 4.59 (dxt, CH2F). 19 F-NMR (CDCl): -224.0. Intermediate 9 (1.03 g) was mixed with 1.5 mL of EtOH, 1.5 mL of water, and 1.25 g of KOH, and the mixture was heated to 75 °C for 5 h. The flask (25 mL) was sealed with a septum attached to a Teflon tube. The other end of the tube was placed in a small gas-washing bottle containing 2 M aqueous HCl. After the reaction time, the mixture was heated to 90 °C, and the residual product was forced into the gas-washing bottle using a slow stream of nitrogen (balloon, needle, over 1 h). The 2 M HCl solution containing the product was concentrated in vacuo, and the remaining semi-solid was coevaporated with MeOH, rapidly dried under high vacuum, and then triturated with EtO / hexane and filtered. After drying, 326 mg (40%) of N-methoxy-2-fluoroethylamine hydrochloride (10) was obtained as a rose-colored solid. 1 H-NMR (soluble in CDCl3): 3.66 (dxt, CH2CH2F), 4.12 (s, OCH3), 4.89 (dxt, CH2F). 19F-NMR (CDCl3): -223.2. 2.) Amide coupling reaction: According to the general amide coupling method described, from 248 mg of lysergic acid monohydrate, 155 mg (1.1 eq.) of CDI, 123.5 mg of N-methoxy-2-fluoroethylamine hydrochloride (10; 1.1 eq.), and 377 μL of DIPEA (2.5 eq.), a solution of amine 10 and DIPEA in DMF was added dropwise under ice cooling, and the reaction mixture was allowed to warm to ambient temperature over several hours. Yield: 21 mg (7%) of TRALA-14 was obtained as a golden-beige solid. Analytical data for 2n: 1 H-NMR(CDCl3):2.62(s,NMe),3.24(m,2H),3.57(dxd,1H),3.81(s,OMe),3.95(dxt,1H),4.04(dxt,1H),4.10(bm,1H),4.24(m,1H) ),4.57(t,1H),4.73(t,1H),6.47(s,H9)6.92(m,1arom.H),7.14-7.26(m,3arom.H),7.55(m,0.5H),7.73(m,0.5H),7.98(bs,NH). 19 F-NMR (CDCl3): -222.5. LCMS (M+H): expected for 2n: M=343.40, found: 344.2.

[0217] Example - Preparation of enamides of lysergic acid, derivatives 2l-m.

[0218] 1.) Amide formation

[0219] 9,10-didehydro-N-ethyl-N-(2-(phenylthio)ethyl)-6-methylergoline-8R-carboxamide, 4. According to the general amide coupling method described, 974 mg of lysergic acid monohydrate, 880 mg of CDI, 885 μL of N-ethyl-2-(phenylthiol)ethanamine (3; 1.1 eq.) and 885 μL of DIPEA (1.5 eq.) were used. Yield: 550 mg (38%) of the title product was obtained as a golden foam. Analytical data for 4: 1H-NMR(CDCl3):1.12-1.32(m,3H),2.59-2.78(m,4H),2.92(t,1H),3.04(m,1H),3.10-3.32(m,3H),3.40- 3.68(m,5H),3.89(bm,1H),6.30 / 6.37(2xs,H9)6.93(t,1arom.H),7.15-7.49(m,8arom.H),8.00(bs,NH). LCMS(M+H): Expected value for 4: M=431.60; Actual value: 432.3.

[0220] 2.) Sulfoxide formation

[0221] 9,10-didehydro-N-ethyl-N-(2-(phenylsulfinyl)ethyl)-6-methylergoline-8R-carboxamide, 5. To an ice-cold solution of 405 mg (0.94 mmol) of 4 in 20 mL of DCM, 81 μL of 37% aqueous HCl (1.05 equiv.) was added. Next, a solution of 211 mg (1.0 equiv.) of meta-chloroperbenzoic acid (mCPBA) in 20 mL of DCM was added over 5 min. After 20 min, LCMS analysis revealed the sulfoxide (50%; a small second peak with the same mass corresponds to the N-oxide), which was then separated and purified. 1 H-NMR confirmed the identity) and showed the formation of a double oxidation product (20%) along with the starting material (30%), and the reaction was quenched with 20 mL of 10% aqueous NaSO. After vigorous stirring for 5 min, the layers were separated, the aqueous layer was further extracted with DCM (2 x 20 mL), and the combined organic layers were dried over NaSO and concentrated in vacuo. The greenish-black residue (547 mg) was purified by silica gel chromatography (DCM / MeOH / NEt). Yield: 54 mg (13%) of the title product was obtained as an off-white foam, based on 258 mg of recovered starting material. Analytical data for 5: 1 H-NMR (CDCl 3、Note: The sulfoxide has an additional chiral center, adding complexity: 1.15-1.36 (m, 3H), 2.58-2.78 (m, 4H), 2.80-2.95 (bm, 1H), 2.95-3.20 (m, approx. 2.5H), 3.25-3.38 (m, approx. 2.5H), 3.5-3.8 (m, 5H), 3.93 (bm, 1H), 6.23 / 6.27 (both minor) and 6.32 / 6.38 (both major) (each s, H9; total = 1H), 6.94 (m, 1arom. H), 7.15-7.27 (m, 3arom. H), 7.50-7.61 (m, 3arom. H), 7.65-7.72 (m, 2arom. H), 7.95 (bs, NH). LCMS (M+H): Expected for 5: M=447.60; Found: 448.2.

[0222] 3.) Pyrolysis

[0223] 9,10-Didehydro-N-ethenyl-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-12), 2L. A mixture of 54 mg (0.121 mmol) of 9,10-didehydro-N-ethyl-N-(2-(phenylsulfinyl)ethyl)-6-methylergoline-8R-carboxamide (5) and 51 mg (5 equiv.) of NaHCO3 in 8 mL of m-xylene was heated to 130-140 °C under nitrogen. After a total of 2 days, approximately 25% conversion (LCMS) was observed between the starting material and some decomposition products. The volatiles were removed under high vacuum at 50 °C, and the residue was purified by first dissolving in 1 mL of DCM / MeOH / NEt3 (90 / 10 / 0.2) and filtering through a 1 cm-high silica gel pad using 70 mL of the same solvent system. This removed most of the dark color. The eluate was concentrated in vacuo, and the residue was further purified by silica gel chromatography using the same solvent system starting with 98% DCM. Approximately 2 mg of the title product was obtained. Analysis by either basic or acidic HPLC MS (see general section) showed the same purity (approximately 85%), demonstrating the stability of the product to these conditions. LCMS (M+H): Expected for 21: M = 321.43; Found: 322.2. 1H-NMR (CDCl): Signals followed spectra obtained by alternative routes (e.g., 6–7–5–2l, Figure 9; LCMS retention times were similar), but 1 H-NMR also showed significant impurities herein.

[0224] 4.) Enamides via Base-Promoted Elimination Reactions (Microscale)

[0225] 9,10-didehydro-N-(2,2-difluoroethenyl)-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-13), 2m. This reaction could be carried out using either LDA or BuLi, and no epimerization was observed. A solution of 7 mg (18.5 μmol) of TRALA-06 (2f) in 0.2 mL of anhydrous THF was cooled to -100 °C under nitrogen (liquid nitrogen, acetone / THF 4:1 mixture as cooling bath). Next, 2.0 equivalents of 1.6 M BuLi, or in a second experiment, 2.0 equivalents of a freshly prepared THF solution of lithium diisopropylamide (from BuLi and diisopropylamine in THF), was added within 30 seconds. Both basic and acidic HPLC MS from samples hydrolyzed in water and diluted with MeOH showed 30% product formation from unchanged starting material (by UV absorbance integration at 313 nm and e / z = 358 relative to the starting material); no significant decomposition was observed, and the product remained unchanged. To further test chemical stability, a hydrolyzed sample stored overnight at ambient temperature (hence, basic conditions) remained unchanged. Another hydrolyzed sample was acidified by the addition of excess tartaric acid, and reanalysis after storage for 24 hours showed the same product distribution as after the first hydrolysis of the reaction. LCMS (M+H): Expected for 2m: M = 357.41, Found: 358.3.

[0226] Example - Alternative route to enamides of lysergic acid: Preparation of derivative 2l.

[0227] 1.) Hydroamination

[0228] N-Ethyl-2-(phenylsulfinyl)ethanamine, 7. The procedure was adapted from (Hu et al., 2014). To 2 M ethylamine in anhydrous THF (6 mL, 12 mmol), 1.33 mL (10 mmol) of phenylvinyl sulfoxide (6) was added, and the clear solution was stirred under nitrogen for 18 h. The volatiles were removed in vacuo at 50 °C, and the remaining viscous orange oil was purified by silica gel chromatography (DCM / MeOH / NEt3 = 100 / 0 / 0.5 to 95 / 5 / 0.5). Yield: 1.72 g (72%) of the title product was obtained as a colorless oil. Analytical data for 7: 1 H-NMR (CDCl3; note: sulfoxide has a chiral center; enantiomeric ratio not determined): 1.11 (t, CH3), 2.67 (q, NHCH2), 2.96 (m, CH2), 3.13 (m, CH2), 7.48-7.57 (m, 3 arom.H), 7.62-7.67 (m, 2 arom.H). LCMS (M+H): expected for 7: 197.30; found: 198.1.

[0229] 2.) Amide formation

[0230] 9,10-didehydro-N-ethyl-N-(2-(phenylsulfinyl)ethyl)-6-methylergoline-8R-carboxamide, 5. According to the general amide coupling method described, 394 mg of lysergic acid monohydrate, 356 mg of CDI, 272 mg of N-ethyl-2-(phenylsulfinyl)ethanamine (7; 1.0 eq.) and 356 μL of DIPEA (1.5 eq.) were used. Yield: 191 mg (31%) of the title product was obtained as a beige solid. Analytical data for 5: 1 H-NMR (CDCl 3;Note: The sulfoxide has an additional chiral center, adding complexity; due to its synthetic route, it may be racemic rather than racemic as described here: 1.15-1.36 (m, 3H), 2.58-2.78 (m, 4H), 2.80-2.95 (bm, 1H), 2.95-3.20 (m, ca. 2.5H), 3.25-3.38 (m, ca. 2.5H), 3.5-3.8 (m, 5H) ), 3.93 (bm, 1H), 6.23 / 6.27 (both minor; first major) and 6.32 / 6.38 (both major) (H9; total = 1H), 6.92 / 6.94 (m, 1arom.H), 7.15-7.27 (m, 3arom.H), 7.50-7.61 (m, 3arom.H), 7.65-7.72 (m, 2arom.H), 7.95 (bs, NH). LCMS (Note: The same retention time was obtained for sulfoxide 5 obtained via an alternative route. See section "2.) Sulfoxide Formation"; M+H): Expected for 5: 447.60, found: 448.2.

[0231] 3.) Pyrolysis

[0232] 9,10-Didehydro-N-ethenyl-N-ethyl-6-methylergoline-8R-carboxamide (TRALA-12), 2 L. A mixture of 180 mg (0.402 mmol) of 9,10-didehydro-N-ethyl-N-(2-(phenylsulfinyl)ethyl)-6-methylergoline-8R-carboxamide (5) and 283 mg (5 equiv.) of K2CO3 in 26 mL of m-xylene was heated to 130-140 °C under nitrogen. After a total of 22 h, approximately 40% conversion (LCMS) was observed between starting material and only trace amounts of decomposition products. Longer heating induced progressive decomposition. The volatiles were removed under high vacuum at 50 °C, and the residue was purified by first dissolving it in 5 mL of DCM / MeOH / NEt3 = 90 / 10 / 0.1 and filtering it through a silica gel pad (1 cm high) using 150 mL of the same solvent system. This removed most of the dark color. The eluate was concentrated by i.v., and the residue was further purified by silica gel chromatography using DCM / MeOH / NEt3 = 98 / 2 / 0.1 to 90 / 10 / 0.1 as the eluent. The crude product (24 mg) eluted first (followed by the starting material, recovered: 89 mg) and was further purified by silica gel preparative TLC using DCM / MeOH / NEt3 = 98 / 2 / 0.1 as the eluent. Finally, 9 mg (7%) of the title product 2l was obtained. Analysis by HPLC MS under either basic or acidic conditions showed the same purity (approximately 90%), demonstrating the product's stability under these conditions. 1H-NMR (CDCl3): (Related interpretation complications: see general chapter, amide coupling) 1.3 (m; superimposed with some Et2O and impurities, CH2CH3), 2.63 (s, NMe), 2.74 (txm, 1H), 2.87 (m, 1H), 3.16 (dxd, 1H), 3.28 (bm, 1H), 3.56 (dxd, 1H), 3.78 (m, 2H), 4.10 (bm, 1H), 4.43 (d, 1H), 4.62 (d, 1H), 6.34-6.44 (two superimposed s, H9; total = 1H; Note: Proof of epimeric purity of ergoline structure C9: see general chapter, amide coupling), 6.93 (m, 1arom. H), 7.03 (dxd, 1H), 7.15-7.27 (m, 3arom. H), 7.95 (bs, NH). LCMS (M+H): Expected for 2l: M = 321.43; Found: 322.2.

[0233] Example - Preparation of N6-substituted derivatives of 6-nor-lysergic acid diethylamide, derivatives 12a-g.

[0234] 1.) Synthesis of LSD

[0235] 9,10-Didehydro-N,N-diethyl-6-methylergoline-8R-carboxamide (LSD), 2o. According to the general amide coupling method described, 3.52 g of lysergic acid monohydrate, 3.18 g of CDI, and 13.4 mL of diethylamine (10 equivalents; no DIPEA was used). Yield: 1.64 g (41%) of LSD as a beige foam and 0.65 g (16%) of iso-LSD as a brown sticky mass. Analytical data for 2o (LSD) as the free base according to the literature: 1H-NMR (CDCl3): 1.19 (t, 1xCH2CH3), 1.26 (t, 1xCH2CH3), 2.63 (s, NMe), 2.72 (txm, 1H), 2.93 (t, 1H), 3.08 (dxd, 1H), 3.26 (bm, 1H), superposition of 3.47 and 3.57 (m and dxd, total 5H), 3.92 (bm, 1H), 6.37 (s (hint of triplet)), H9. Note: The separated epimer iso-LSD showed this signal as t at 6.31), 6.93 (t, 1arom.H), 7.14-7.27 (m, 3arom.H), 7.99 (bs, NH). LCMS (M+H): Expected for 2o: M = 323.41, found: 324.3.

[0236] 2.) N6-demethylation of LSD: Preparation of 6-nor LSD.

[0237] 9,10-Didehydro-N,N-diethylergoline-8R-carboxamide (6-nor LSD), 11. This is adapted from (WO2006128658A1). To an ice-cold solution of 1.35 g (4.17 mmol) of LSD (2o) in 40 mL of DCM, 1.13 g (1.2 equiv.) of mCPBA 77% (wet) was added. After stirring for 10 min (Note: LCMS analysis showed clean and complete formation of the N-oxide intermediate as two chromatographically well-separated epimers with e / z = 340. This is because the N-oxide group possesses an additional chiral center), a freshly prepared solution of 580 mg (0.5 equiv.) of FeSO4 heptahydrate in 3.0 mL of MeOH pA was quickly added. The cooling bath was removed and stirring was continued at ambient temperature until the N-oxide completely disappeared. (Note: The reason for the incomplete conversion of the N-oxide to the desired product is that one of the N-oxide epimers reverts to the starting material LSD more rapidly than the rate of N-demethylation; see, e.g., (McCamley, Ripper, Singer, & Scammells, 2003). For example, by changing the reaction conditions for forming the N-oxide of LSD, the epimeric ratio of the N-oxides can be influenced, thus increasing the rate of N-demethylation. Unpublished results on file.) After 3.5 h, the reaction mixture was poured into 50 mL of 0.1 M ethylenediaminetetraacetic acid (EDTA) solution at pH = 9 (adjusted with 25% aqueous NH4OH). After vigorous shaking, the layers were filtered through a small Celite pad and then separated, and the aqueous layer was further extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The dark brown residue was purified by silica gel chromatography (DCM / MeOH / NH3 = 95 / 5 / 0.1 to 90 / 10 / 0.1). 449 mg of recovered LSD (2o; first elution) and 587 mg (46%) of 6-nor LSD (11) were obtained as a tan solid. The recovered LSD (2o) could be easily reused in the same reaction, resulting in essentially the same yield of the desired 6-nor LSD (11) each time (the reaction was repeated twice from the recovered LSD). 1H-NMR (CDCl3): 1.20 (t, 1 x CH2CH3), 1.30 (t, 1 x CH2CH3), 2.81 (t x m, 1H), 3.23-3.58 (m, 8H), 3.69 (m, 1H), 3.96 (m, 1H), 6.38 (t, H9), 6.92 (t, 1 arom. H), 7.15-7.26 (m, 3 arom. H), 7.97 (bs, N1H). LCMS (M+H): expected for 11: M = 309.41; found: 310.3.

[0238] 3.) N6-Alkylation of 6-nor LSD: Preparation of compounds 12a-g.

[0239] 9,10-Didehydro-N,N-diethyl-6-(2-fluoroethyl)ergoline-8R-carboxamide (TRALA-15), 12a. Following the general procedure for N6 alkylation described, a total of 28.5 μL (3 × 9.5 μL, second addition on day 2, third addition on day 3) of 1-fluoro-2-iodoethane iodide was added to 30 mg of 6-nor LSD (11), reaction time: 3 days. Yield: 9 mg (26%) of TRALA-15 was obtained as a beige foam. Analytical data for 12a as the free base: 1 H-NMR(CDCl3):1.20(t,1xCH2CH3),1.27(t,1xCH2CH3),2.73(t,1H),2.85-3.11(m,2H),3.18-3.63(m,8H), 3.87(bm,1H),4.68(dxm,CH2F,2H),6.36(s,H9),6.91(t,1arom.H),7.14-7.25(m,3arom.H),8.04(bs,NH). 19 F-NMR (CDCl3): -219.0 (s). LCMS (M+H): expected for 12a: M=355.46; found: 356.3.

[0240] 9,10-Didehydro-N,N-diethyl-6-(3-fluoropropyl)ergoline-8R-carboxamide (TRALA-16), 12b. Following the general procedure for N6 alkylation described, a total of 35.4 μL (2 × 17.7 μL, second addition on day 2) of 1-bromo-3-fluoropropane and 50 mg of 6-norLSD (11) were used. Reaction time: 2 days. Yield: 12 mg (20%) of TRALA-16 as a yellow solid. Analytical data for 12b as the free base: 1 H-NMR(CDCl3):1.20(t,1xCH2CH3),1.27(t,1xCH2CH3),1.9-2.1(bm,2H),2.60-2.84(m,2H),2.84-2.98(m,2H),3.14(bm,2H) ,3.4-3.6(m,6H),3.82(bm,1H),4.61(dxm,CH2F,2H)),6.35(s,H9),6.93(s,1arom.H),7.15-7.26(m,3arom.H),7.94(bs,NH). 19 F-NMR (CDCl3): -220.3 (s). LCMS (M+H): expected for 12b: M=369.49; found: 370.4.

[0241] 9,10-Didehydro-N,N-diethyl-6-(2-fluoro-1-propen-3-yl)ergoline-8R-carboxamide (TRALA-17), 12c. Following the general procedure for N6 alkylation described above, a total of 33.9 μL (3 × 11.3 μL, second addition on day 2, third addition on day 3) of 3-bromo-2-fluoro-1-propene and 30 mg of 6-norLSD (11) were used. Reaction time: 3 days. Yield: 20 mg (56%) of TRALA-17 was obtained as a yellow foam. Analytical data for 12c as the free base: 1 H-NMR(CDCl3):1.21(t,1xCH2CH3),1.27(t,1xCH2CH3),2.75(t,1H),2.99(t,1H),3.22-3.62(m,8H),3.72(dxd,1H), 3.85(bm,1H),4.58(dxd,1H),4.77(dxd,1H),6.37(s,H9),6.91(t,1arom.H),7.14-7.26(m,3arom.H),8.09(bs,NH).19 F-NMR (CDCl3): -97.7 (s). LCMS (M+H): expected for 12c: M=367.47; found: 368.3.

[0242] 9,10-Didehydro-N,N-diethyl-6-((RS)-(2,2-difluorocyclopropyl)methyl)ergoline-8R-carboxamide (TRALA-18), 12d. Following the general procedure for N6 alkylation described above, a total of 60 mg (3 x 20 mg, second addition on day 2, third addition on day 3) of rac.2-(bromomethyl)-1,1-difluorocyclopropane and 30 mg of 6-nor LSD (11) were obtained, reaction time: 3 days. Yield: 11 mg (28%) of TRALA-18 was obtained as a yellowish solid. Analytical data for 12d as the free base: 1 H-NMR(CDCl3):1.11(m,1H),1.21(t,1xCH2CH3),1.28(t,1xCH2CH3),1.53,(m,1H),1.84(m,1H),2.62-3.28(m ,5H),3.38-3.68(m,6H),3.87(bm,1H),6.37(s,H9),6.92(s,1arom.H),7.14-7.25(m,3arom.H),8.05(bs,NH). 19 F-NMR (CDCl3): -128.7 (m: -128.15; -128.71; -128.75; -129.31), -142.4 (m: -141.63; -142.18; -142.58; -143.14). LCMS (M+H): expected for 12d: M = 399.49; found: 400.3.

[0243] 9,10-Didehydro-N,N-diethyl-6-(cyanomethyl)ergoline-8R-carboxamide (TRALA-19), 12e. Following the general procedure for N6 alkylation described, a total of 24.4 μL (2 × 12.4 μL, second addition on day 2) of chloroacetonitrile and 50 mg of 6-nor LSD (11) were used, reaction time: 2 days. Yield: 33 mg of a yellow foam (still containing some impurities (approximately 15%) based on NMR analysis). Therefore, the product was further purified by preparative TLC (DCM / MeOH / NEt3 = 98 / 2 / 0.2) to give 7 mg (13%) of TRALA-19 as a yellow foam. Analytical data for 12e as the free base: 1 H-NMR (CDCl3): 1.21 (t, 1xCH2CH3), 1.27 (t, 1xCH2CH3), 2.71 (txm, 1H), 3.08 (dxd, 1H), 3.30 (t, 1H), 3.37-3.57 (m, 5H), 3.72 (bm, 1H), 3.76 (d, 1H), 3.91 (bm, 1H), 4.07 (d, 1H), 6.37 (s, H9), 6.94 (t, 1arom. H), 7.15-7.26 (m, 3arom. H), 8.06 (bs, NH). LCMS (M+H): expected for 12e: M = 348.45, found: 349.2.

[0244] 9,10-Didehydro-N,N-diethyl-6-(2-oxopropyl)ergoline-8R-carboxamide (TRALA-20), 12f. Following the general procedure for N6 alkylation described, a total of 27.9 μL (3 × 9.3 μL, second addition on day 2, third addition on day 3) of chloroacetone and 30 mg of 6-norLSD (11) were used. Reaction time: 2 days. Yield: 18 mg (51%) of TRALA-20 was obtained as a yellow-beige foam. Analytical data for 12f as the free base: 1H-NMR (CDCl3): 1.19 (t, 1xCH2CH3), 1.27 (t, 1xCH2CH3), 2.26 (s, 3H), 2.78 (t, 1H), 2.95 (t, 1H), 3.09 (dxd, 1H), 3.28-3.60 (m, 7H), 3.81-3.95 (m, 2H), 6.39 (s, H9), 6.90 (t, 1arom. H), 7.13-7.25 (m, 3arom. H), 8.12 (bs, NH). LCMS (M+H): expected for 12f: M = 365.48; found: 366.3.

[0245] 9,10-didehydro-N,N-diethyl-6-benzylergoline-8R-carboxamide (TRALA-21), 12 g. Following the general procedure for alkylation of N6 described above, with 13.8 μL of benzyl bromide and 30 mg of 6-nor LSD (11), reaction time: 2.5 h. Yield: 16 mg (41%) of TRALA-21 was obtained as a beige foam. Analytical data for 12 g as the free base: 1 H-NMR(CDCl3):1.14(m,2xCH2CH3),2.83(m,2H),3.10(dxd,1H),3.25-3.52(m,5H)),3.57(m,1H),3.73(m,2H),4.36(d, 1H),6.38(s,H9),6.92(t,1arom.H),7.13-7.23(m,3arom.H),7.24-7.38(m,3arom.H),7.44(m,2arom.H),8.14(bs,NH). LCMS (M+H): Expected value for 12g: M=399.54, Actual value: 400.3.

[0246] 9,10-Didehydro-N,N-diethyl-6-cyclopropylergoline-8R-carboxamide (TRALA-22), 13. The procedure was adapted from WO2009068214. To a solution of 42.2 mg (136.2 μmol) of 6-nor LSD (11) in 0.45 mL of anhydrous MeOH, followed by 41.1 μL (1.5 equiv.) of 1-ethoxy-1-trimethylsiloxycyclopropane, 8.7 μL (1.1 equiv.) of glacial acetic acid, and 18 mg (2 equiv.) of NaBH3CN (beware of HCN vapors when opening the bottle), the mixture was heated to 60 °C for 4 h under nitrogen. The mixture was cooled to ambient temperature, stripped of volatiles, and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated in vacuo. The remaining crude product was purified by silica gel chromatography using DCM / MeOH / NEt3 = 98 / 2 / 0.1 as the eluent. Yield: 20 mg (42%) of TRALA-22 was obtained as a beige foam. Analytical data for 13 as the free base: 1 H-NMR(CDCl3):0.51(m,1H),0.62(m,1H),0.82(m,about 2H),1.24(m,2xCH2CH3),1.87(m,1H),2.72(m,1H),3.01(t,1H),3.36(dxd, 1H),3.42-3.56(m,4H),3.63(m,1H),3.76-3.93(m,2H),6.39(s,H9),6.92(t,1arom.H),7.13-7.25(m,3arom.H),8.15(bs,NH). LCMS(M+H): Expected value for 13: M=349.48; Actual value: 350.3.

[0247] 9,10-Didehydro-N,N-diethyl-6-cyclobutylergoline-8R-carboxamide (TRALA-23), 14a. To a solution of 42.2 mg (136.2 μmol) of 6-nor LSD (11) and 15.2 μL (1.5 equiv.) of cyclobutanone in 0.45 mL of anhydrous dichloromethane was added 57.6 mg (2 equiv.) of NaBH(OAc)3, and the mixture was stirred at ambient temperature under nitrogen for 2 h. The mixture was diluted with water, stirred for 10 min, diluted with DCM, and added with 1 M NaOH to a final pH of 8–9. The layers were separated, and the aqueous layer was further extracted with 2x diluted DCM. The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The remaining crude product was purified by silica gel chromatography using DCM / MeOH / NEt3 = 98 / 2 / 0.1 as eluent. Yield: 13 mg (26%) of TRALA-23 was obtained as a yellow foam. Analytical data for 14a as the free base: 1 H-NMR (CDCl3): 1.24 (m, 2 x CH2CH3), 1.72 (m, 2H), 2.11 (m, 2H), 2.31 (m, 2H), 2.73 (m, 2H), 3.23 (d x d, 1H), 3.36-3.60 (m, 7H), 3.80 (m, 1H), 6.36 (s, H9), 6.90 (t, 1 arom. H), 7.13-7.24 (m, 3 arom. H), 8.06 (bs, NH). LCMS (M+H): expected for 14a: M = 363.51; found: 364.4.

[0248] 9,10-Didehydro-N,N-diethyl-6-(3-oxetanyl)ergoline-8R-carboxamide (TRALA-24), 14b. From 42.2 mg (136.2 μmol) of 6-nor LSD (11) and 12 μL (1.5 equiv.) of 3-oxetanone in 0.45 mL of anhydrous dichloromethane and 57.6 mg (2 equiv.) of NaBH(OAc) as described for compound X. Yield: 23 mg (46%) of TRALA-24 was obtained as a beige-yellow foam. Analytical data for 14b as the free base: 1H-NMR(CDCl3):1.20(t,CH2CH3),1.29(t,CH2CH3),2.79(m,2H),2.97(m,2H),3.38-3.63(m,5H),3.83(m,1H), 4.13(p,1H),4.70(t,1H),4.86(m,3H),6.38(s,H9),6.87(t,1arom.H),7.13-7.23(m,3arom.H),8.16(bs,NH). LCMS(M+H): Expected value for 14b: M=365.48; Actual value: 366.4.

[0249] 9,10-Didehydro-N,N-diethyl-6-((oxetan-3-yl)methyl)ergoline-8R-carboxamide (TRALA-25), 14c. From 42.2 mg (136.2 μmol) of 6-nor LSD (11) and 17.6 mg (1.5 equiv.) of oxetane-3-carbaldehyde in 0.45 mL of anhydrous dichloromethane and 57.6 mg (2 equiv.) of NaBH(OAc) as described for compound X. Yield: 25 mg (48%) of TRALA-25 was obtained as a beige foam. Analytical data for 14c as the free base: 1 H-NMR(CDCl3):1.20(t,CH2CH3),1.29(t,CH2CH3),2.79(m,2H),2.97(m,2H),3.38-3.63(m,5H),3.83(m,1H), 4.13(p,1H),4.70(t,1H),4.86(m,3H),6.38(s,H9),6.87(t,1arom.H),7.13-7.23(m,3arom.H),8.16(bs,NH). LCMS (M+H): Expected value for 14c: M=379.51; Actual value: 380.4.

[0250] Example 6 - Preparation of N6-substituted derivatives of norTRALA-02, derivatives 16a-c.

[0251] 1.) N6-Demethylation of TRALA-02: Preparation of 6-norTRALA-02.

[0252] 9,10-Didehydro-N-ethyl-N-propyn-3-ylergoline-8R-carboxamide (6-norTRALA-02), 15. The procedure described for 6-norLSD (11) was followed exactly using 366 mg (1.1 mmol) of TRALA-02 (2b), 295 mg (1.2 equiv.) of mCPBA in 11 mL of DCM, and 153 mg (0.5 equiv.) of FeSO4 heptahydrate in 0.8 mL of MeOH. The crude product was purified by silica gel chromatography using DCM / MeOH / NEt3 = 95 / 5 / 0.1 as the eluent. The recovered starting material (2b; 67 mg; 18%) eluted first, followed by the title compound 15. Yield: 172 mg (49%) obtained as a tan solid. Analytical data for 15 as the free base: 1 H-NMR (CDCl3): 1.21 (2 x t, total = 3H), 2.31 (m, 1H), 2.84 (t x m, 1H), 3.28-3.43 (m, ca. 3H), 3.55-3.87 (m, ca. 4H), 3.99 (m, 1H), 4.28 (m, 2H), 6.38 (ca. 60%) / 6.48 (ca. 40%) (2 x s, total = H9; Note: Proof of epimeric purity of ergoline structure C9: see General Chapter, Amide Coupling), 6.93 (s, 1 arom. H), 7.15-7.27 (m, 3 arom. H), 7.96 (bs, N1H). LCMS (M+H): expected for 15: M = 319.41; found: 320.3.

[0253] 2.) N6-Alkylation of 6-norTRALA-02: Preparation of compounds 16a-c.

[0254] 9,10-Didehydro-N-ethyl-N-propyn-3-yl-6-(2-fluoroethyl)ergoline-8R-carboxamide (TRALA-26), 16a. Following the general procedure for N6 alkylation described above, a total of 28.5 μL (3 × 9.5 μL, second addition on day 2, third addition 8 h after day 2) of 1-fluoro-2-iodoethane and 31 mg of 6-norTRALA-02 (15) were added. Reaction time: 6 days. Yield: 15 mg (42%) of TRALA-26 as a yellow-beige foam. Analytical data for 16a as the free base: 1H-NMR (CDCl3): 1.32 (m, 3H), 2.31 (m, 1H), 2.73 (t, 1H), 2.99 (m, 2H), 3.28 (m, 2H), 3.45-3.75 (m, 4H), 3.92 (m, 1H), 4.26 (m, 2H), 4.59 (m, 1H), 4.75 (m, 1H), 6.36 (ca. 55%) / 6.45 (ca. 45%) (2 x s, total = H9; note: proof of epimeric purity of ergoline structure C9: see general chapter, amide coupling), 6.91 (t, 1aromatic H), 7.14-7.26 (m, 3aromatic H), 8.03 (bs, NH). 19 F-NMR (CDCl3): -218.99, -219.03. LCMS (M+H): expected for 16a: M=365.45; found: 366.2.

[0255] 9,10-Didehydro-N-ethyl-N-propyn-3-yl-6-(2-fluoro-1-propen-3-yl)ergoline-8R-carboxamide (TRALA-27), 16b. Following the general procedure for N6 alkylation described, a total of 33.9 μL (3 × 11.3 μL, second addition on day 2, third addition 8 h later on day 3) of 3-bromo-2-fluoro-1-propene and 31 mg of 6-norTRALA-02 (15) were obtained, reaction time: 6 days. Yield: 12 mg (33%) of TRALA-27 was obtained as a yellow foam. Analytical data for 16b as the free base: 1 H-NMR (CDCl3): 1.31 (m, 3H), 2.31 (m, 1H), 2.74 (t x m, 1H), 3.01 (m, 1H), 3.31 (m, 2H), 3.48-3.78 (m, 5H), 3.89 (m, 1H), 4.27 (m, 2H), 4.59 (d x d, 1H), 4.78 (d x d, 1H), 6.37 (ca. 60%) / 6.45 (ca. 40%) (2 x s, total = H9; Note: Proof of epimeric purity of ergoline structure C9: see General Chapter, Amide Couplings), 6.92 (t, 1aromatic H), 7.14-7.26 (m, 3aromatic H), 7.99 (bs, NH). 19 F-NMR (CDCl3): -97.77, -97.85. LCMS (M+H): expected for 16b: M=377.41, found: 378.3.

[0256] 9,10-Didehydro-N-ethyl-N-propyn-3-yl-6-((RS)-(2,2-difluorocyclopropyl)methyl)ergoline-8R-carboxamide (TRALA-28), 16c. Following the general procedure for N6 alkylation described, a total of 59.4 μL (3 × 19.8 μL, second addition on day 2, third addition 8 h later on day 3) of rac.2-(bromomethyl)-1,1-difluorocyclopropane and 31 mg of 6-norTRALA-02 (15) were obtained, reaction time: 6 days. Yield: 13 mg (33%) of TRALA-28 was obtained as a yellow foam. Analytical data for 16c as the free base: 1 H-NMR (CDCl3): 1.11 (m, 1H), 1.31 (m, 3H), 1.52 (m, 1H), 1.84 (m, 1H), 2.31 (m, 1H), 2.61-3.35 (m, 5H), 3.47-3.78 (m, 4H), 3.91 (m, 1H), 4.29 (m, 2H), 6.37 (ca. 50%) / 6.45 (ca. 50%) (2 x s, total = H9; note: proof of epimeric purity of ergoline structure C9: see general chapter, amide coupling), 6.92 (s, 1 arom. H), 7.14-7.26 (m, 3 arom. H), 8.00 (bs, NH). 19 F-NMR (CDCl3): -141.65, -141.73, -142.20, -142.28, -142.57, -142.60, -143.13, -143.16. LCMS (M+H): expected for 16c: M=409.48; found: 410.3.

[0257] Microsomal Assay: The purpose of this experiment was to investigate the microsomal stability of 10 novel lysergamides (Figures 13A-13J) to make predictions regarding whether any of the derivatives may be clinically metabolized more rapidly than lysergic acid diethylamide (LSD). Test substances were incubated with human liver microsomes for 4 hours, and metabolic degradation was then measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Briefly, LSD and derivatives (10 nM) were incubated for 4 hours in the presence of pooled human liver microsomes. The microsome reaction mixture contained 464.5 μL of phosphate-buffered saline, 25 μL of nicotinamide adenine dinucleotide phosphate (NADPH) solution A (1:20 dilution, product no. 451220, lot no. 0344003, Corning Life Sciences BV), 5 μL of solution B (1:100 dilution, product no. 451200, lot no. 0342002; Corning Life Sciences BV), 5 μL of liver microsomes (150 donor, 20 mg / mL, product no. 452117, lot no. 38296; Corning Life Sciences BV, Amsterdam, The Netherlands), and 0.5 μL of test drug (10 μM). Samples (50 μL) were taken 2 min before microsome incubation (t0) and 0.5, 1, 2, 3, and 4 h after the start of the microsome reaction. A total of five assays were performed per substance. The amount (peak area) of test substance exposed to human liver microsomes for 4 hours was compared with that at a concentration of 10 nM (t0, 100% peak area). The linear regression slope was plotted to compare the degradation of the derivatives and LSD. None of the TRALA derivatives were metabolized to LSD (data not shown).

[0258] Throughout this application, various publications, including U.S. patents, are referenced by author, year, and patent number. Full citations for the publications are set forth herein. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0259] The present invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of words described rather than of limitation.

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Claims

1. A pharmacologically active compound comprising: characterized in that it exhibits the structural composition represented by FIG. 1A, Furthermore, it is characterized by being part of Class 1 to Class 5, Such compounds are represented as shown in Figures 2A-6C, Class 1 is the lysergic acid amides depicted in Figures 2A-2G and 3A-3H, where R8' consists of the substituents shown in the subclasses designated subclasses 1a-1n, and R8 consists of: a) R8', b) any of the substituents of subclasses 1a to 1n and as defined in the specific classes of R8′=1a to 1l; c) hydrogen, C １ ~C ５ Alkyl, branched C １ ~C ５ Alkyl, C ３ ~C ５ Cycloalkyl, C １ ~C ５ Alkylcycloalkyl, C ２ ~C ５ Alkenyl, branched C ３ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, branched C ４ ~C ５ alkynyl, or d) As specified in subclasses 1a-1n: If it is defined, In subclass 1a, the substituent R8' is F １ ~F １１ Fluorine-substituted C １ ~C ５ Alkyl or branched C ３ ~C ５ alkyl groups, each of which is optionally D １ ~D １０ combined with deuterons, and / or hydroxy and / or carbonyl, In subclass 1b, the substituent R8' consists of F1-F13 fluorine-substituted C3-C7 alkenyl groups, optionally in combination with D1-D12 deuterons, and / or nitriles, and / or hydroxy and / or carbonyls, with a double bond separating the nitrogen; In subclass 1c, the substituents R8' consist of F1-F11 fluorine-substituted C3-C6 cycloalkyl groups, optionally in combination with D1-D10 deuterons, and / or nitriles, and / or hydroxy, and / or carbonyls, and / or deuterated and non-deuterated C1-C3 alkyls and / or deuterated and non-deuterated C1-C3 alkenyls; In subclass 1d, the substituents R8' consist of F1-F17 fluorine-substituted C3-C6 cycloalkylalkyl groups, optionally in combination with D1-D10 deuterons, and / or nitriles, and / or hydroxy, and / or carbonyls, and / or deuterated and non-deuterated C1-C3 alkyls and / or deuterated and non-deuterated C1-C3 alkenyls; In subclass 1e, the substituent R8' consists of F1-F11 fluorine-substituted C3-C7 alkynyl groups, optionally in combination with D1-D12 deuterons, and / or nitriles, and / or hydroxy and / or carbonyls, with a triple bond separating the amide nitrogen; In subclass 1f, the substituent R8' consists of an F0-F7 fluorine-substituted C2-C4 alkenyl group attached to the nitrogen through an unsaturated moiety to form an enamide, optionally in combination with D1-D7 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl; In subclass 1g, the substituent R8' consists of an F1-F5 fluorine-substituted C2-C4 alkylalkynyl group attached to the nitrogen at the unsaturated moiety, forming an ynamide, optionally in combination with D1-D4 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl; Within Class 1h, a subclass of Class 1 wherein the substituent R8' consists of F1 to F13 fluorine substituted C1-3-O-C1-3 alkoxyalkyl groups, optionally in combination with D1 to D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl; In subclass 1i, the substituents R8' consist of F0-F7 fluorine-substituted C1-C3 alkoxy or C3-C4 cycloalkoxy groups, each optionally in combination with D1-D7 deuterons, and / or nitriles, and / or hydroxy and / or carbonyls; In subclass 1j, the substituent R8' consists of a nitrile bonded to a C1-C3 alkyl group, optionally in combination with F1-F7 fluorine, and / or D1-D7 deuteron, and / or hydroxy and / or carbonyl; In subclass 1k, the substituents R8 consist of C1-C3 alkyl groups containing D1-D6 deuterons in combination with optional F1-F6 fluorines, optionally in combination with hydroxy and / or carbonyl; and R8' consists of hydrogen, C1-C6 alkyl, or C3-C5 cycloalkyl or C4-C7 cycloalkylalkyl groups, optionally in combination with hydroxy and / or carbonyl; In subclass 11, the substituents R8 consist of C1-C3 alkyl groups containing D1-D7 deuterons or F1-F7 fluorines, or D1-D6 deuterons in combination with any of F1-F6 fluorines, optionally in combination with hydroxy and / or carbonyl; and R8' consists of C2-C8 alkenyl or C2-C8 alkynyl groups, optionally in combination with nitrile, and / or hydroxy and / or carbonyl; In subclass 1m, the substituents R8 and R8' are linked together to form an azacycloalkane having the amide nitrogen, consisting of a C3-C6 alkylene group containing D1-D10 deuterons or F1-F10 fluorines, or D1-D9 deuterons in combination with optional F1-F9 fluorines, optionally in combination with nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl groups; In subclass 1n, the substituents R8 and R8' are linked together to form an azacycloalkane having the amide nitrogen, consisting of a C3-C6 alkylene group to which is attached a non-deuterated or deuterated C1-C3 alkenyl and / or a non-deuterated or deuterated C2-C3 alkynyl group, the azacycloalkane-forming alkylene group optionally further combined with nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl groups; Class 2 is the lysergic acid amides depicted in Figures 4A-4G and 5A-5C, further characterized by consisting of 6-substituted 6-norlysergic acid diethylamides, wherein R6 consists of the substituents shown in the subclasses designated subclasses 2a-2i, whereby R6 is characterized as follows: In subclass 2a, the substituent R6 is F １ ~F １１ Fluorine-substituted C １ ~C ５ Alkyl or branched C ３ ~C ５ alkyl groups, each of which is optionally D １ ~D １０ in combination with deuterons, and / or nitriles, and / or hydroxy and / or carbonyls, In subclass 2b, a subclass of class 2 wherein the substituent R6 consists of F1-F13 fluorine substituted C3-C7 alkenyl groups, optionally in combination with D1-D12 deuterons, and / or nitriles, and / or hydroxy and / or carbonyls, and the alkenyl double bond is spaced from the nitrogen; In subclass 2c, the substituent R6 consists of an F1-F11 fluorine substituted C3-C7 alkynyl group having a triple bond distal to the N6 nitrogen, optionally in combination with D1-D10 deuterons, and / or nitriles, and / or hydroxy and / or carbonyl; when the substituent R6 contains at least one nitrile, one hydroxy, or one carbonyl group, R6 can also consist of a C3-C7 alkynyl group having said triple bond distal to the N6 nitrogen, optionally in combination with D1-D10 deuterons, and / or nitriles, and / or hydroxy and / or carbonyl; In subclass 2d, the substituent R6 consists of C3-C6 cycloalkyl groups, optionally in combination with F1-F11 fluorine, and / or D1-D11 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl; In subclass 2e, the substituent R6 consists of F1 to F17 fluorine-substituted C4 to C9 cycloalkylalkyl groups, optionally in combination with D1 to D16 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1 to C3 alkyl, and / or deuterated and non-deuterated C1 to C3 alkenyl and / or deuterated and non-deuterated C2 to C3 alkynyl, and the substituent R6 is not cyclopropylmethyl attached to the N6 nitrogen of the ergoline structure by the exocyclic methylene unit; or When R6 is a cyclopropylmethyl attached to the N6 nitrogen of the ergoline structure by an exocyclic methylene unit and contains at least one nitrile, one hydroxy, or one carbonyl group, R6 may also consist of a C4-C9 cycloalkylalkyl group, optionally in combination with D1-D17 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C1-C3 alkynyl groups; In subclass 2f, the substituent R6 consists of an F0-F7 fluorine-substituted C2-C4 alkenyl group attached to the nitrogen at the unsaturated moiety to form an enamide, optionally in combination with a D1-D7 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl; In subclass 2g, the substituent R6 consists of C3-C6 oxacycloalkyl, C3-C9 oxacycloalkylalkyl, C3-C6 thiacycloalkyl, or C3-C9 thiacycloalkylalkyl groups, each optionally in combination with F1-F19 fluorine, and / or D1-D19 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl; In subclass 2h, the substituent R6 consists of F0-F11 fluorine-substituted C1-C5 alkoxy or C3-C6 cycloalkoxy groups or C2-C6 alkenoxy groups, each optionally in combination with D1-D11 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl; In sub-class 2i, the R6 substituent consists of aryl, heteroaryl, arylmethyl, or heteroarylmethyl groups, each optionally in combination with F0-F7 fluorines, and / or D1-D7 deuterons, and / or one or more of the following substituents, which themselves can be optionally fluorinated and / or deuterated: halogen, nitrile, nitro, hydroxy, carbonyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 alkenoxy, C3-C6 alkynoxy, methylenedioxy, C1-C4 alkylthio, C3-C6 alkenylthio, C3-C6 alkynylthio, C3-C6 cycloalkylthio; and the R6 substituents defined above for Class 2i can be further cyclized; Class 3 is the lysergic acid amides depicted in Figure 6A, further characterized by any possible combination of the substituents R8 and R8' of Class 1 and its subclasses 1a to 1n (Figures 2A to 3H) with the substituent R6 of Class 2 and its subclasses 2a to 2i (Figures 4A to 5C); Class 4 is the lysergic acid amides depicted in Figure 6B, further characterized by consisting of any possible combination of the substituents R8 and R8' of Class 1 and its subclasses 1a-1n (Figures 2A-3H) and the substituent R6 of Class 2 and its subclasses 2a-2i (Figures 4A-5C), and having a combination of N1 nitrogen substituents on the ergoline moiety from the group: a) any acyl; b) unsubstituted and substituted carbamoyl; c) amide-linked amino acids; d) alkyl, alkenyl, or alkynyl; e) alkoxy, alkenoxy, or alkynoxy; f) any of the substituents described in a) to e) substituted with one or more fluorine atoms; g) any of the substituents described in a) to e) substituted with one or more deuteron atoms; h) any of the substituents described in a) to e) substituted with one or more fluorine atoms and one or more deuteron atoms; and Class 5 (FIG. 6C) consists of mono- to fully deuterated ergoline core structures and further comprises any possible combination of the substituents R8 and R8′ of Class 1 and its subclasses 1a-1n (FIGS. 2A-3H) with the substituent R6 of Class 2 and its subclasses 2a-2i (FIGS. 4A-5C), with combinations of N1 nitrogen substituents on the ergoline moiety from the following groups: a) hydrogen, b) any acyl, c) unsubstituted and substituted carbamoyl, d) amide-linked amino acids, e) alkyl, alkenyl, or alkynyl, f) alkoxy, alkenoxy, or alkynoxy, g) any of the substituents described in a) through f) substituted with one or more fluorine atoms, h) any of the substituents described in a) through f) substituted with one or more deuteron atoms, and i) any of the substituents described in a) through f) substituted with one or more fluorine atoms and one or more deuteron atoms.

2. 10. The pharmacologically active compound of claim 1, further characterized in that the compound is a free base.

3. 10. The pharmacologically active compound of claim 1, further characterized in that the compound is a salt thereof.

4. 4. The pharmacologically active compound of claim 3, further characterized in that the compound is a tartrate or hemitartrate salt thereof.

5. 5. The pharmacologically active compound of claim 4, further characterized in that said compound is a pharmacologically acceptable acid addition salt thereof.

6. 10. The pharmacologically active compound of claim 1, further characterized in that the compound is selected from the group consisting of a racemate, single enantiomers, diastereomers, epimers, and mixtures of enantiomers or diastereomers or epimers in any ratio, single and mixed E or Z configuration isomers in any ratio, single and mixed cis or trans configuration isomers in any ratio, and any combination thereof.

7. 1. A method of altering neurotransmission, comprising: administering to a mammal a pharmaceutically effective amount of a composition of a pharmacologically active compound, The compound is characterized by exhibiting a structural composition represented by FIG. 1A, Furthermore, it is characterized by being part of Class 1 to Class 5, Such compounds are represented as shown in Figures 2A-6C, Class 1 is the lysergic acid amides depicted in Figures 2A-2G and 3A-3H, where R8' consists of the substituents shown in the subclasses designated subclasses 1a-1n, and R8 consists of: a) R8', b) any of the substituents of subclasses 1a to 1n and as defined in the specific classes of R8′=1a to 1l; c) hydrogen, C １ ~C ５ Alkyl, branched C １ ~C ５ Alkyl, C ３ ~C ５ Cycloalkyl, C １ ~C ５ Alkylcycloalkyl, C ２ ~C ５ Alkenyl, branched C ３ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, branched C ４ ~C ５ alkynyl, or d) As specified in subclasses 1a-1n: If it is defined, In subclass 1a, the substituent R8' is F １ ~F １１ Fluorine-substituted C １ ~C ５ Alkyl or branched C ３ ~C ５ alkyl groups, each of which is optionally D １ ~D １０ combined with deuterons, and / or hydroxy and / or carbonyl, In subclass 1b, the substituent R8' consists of F1-F13 fluorine-substituted C3-C7 alkenyl groups, optionally in combination with D1-D12 deuterons, and / or nitriles, and / or hydroxy and / or carbonyls, with a double bond separating the nitrogen; In subclass 1c, the substituents R8' consist of F1-F11 fluorine-substituted C3-C6 cycloalkyl groups, optionally in combination with D1-D10 deuterons, and / or nitriles, and / or hydroxy, and / or carbonyls, and / or deuterated and non-deuterated C1-C3 alkyls and / or deuterated and non-deuterated C1-C3 alkenyls; In subclass 1d, the substituents R8' consist of F1-F17 fluorine-substituted C3-C6 cycloalkylalkyl groups, optionally in combination with D1-D10 deuterons, and / or nitriles, and / or hydroxy, and / or carbonyls, and / or deuterated and non-deuterated C1-C3 alkyls and / or deuterated and non-deuterated C1-C3 alkenyls; In subclass 1e, the substituent R8' consists of F1-F11 fluorine-substituted C3-C7 alkynyl groups, optionally in combination with D1-D12 deuterons, and / or nitriles, and / or hydroxy and / or carbonyls, with a triple bond separating the amide nitrogen; In subclass 1f, the substituent R8' consists of an F0-F7 fluorine-substituted C2-C4 alkenyl group attached to the nitrogen through an unsaturated moiety to form an enamide, optionally in combination with D1-D7 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl; In subclass 1g, the substituent R8' consists of an F1-F5 fluorine-substituted C2-C4 alkylalkynyl group attached to the nitrogen at the unsaturated moiety, forming an ynamide, optionally in combination with D1-D4 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl; Within Class 1h, a subclass of Class 1 wherein the substituent R8' consists of F1 to F13 fluorine substituted C1-3-O-C1-3 alkoxyalkyl groups, optionally in combination with D1 to D12 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl; In subclass 1i, the substituents R8' consist of F0-F7 fluorine-substituted C1-C3 alkoxy or C3-C4 cycloalkoxy groups, each optionally in combination with D1-D7 deuterons, and / or nitriles, and / or hydroxy and / or carbonyls; In subclass 1j, the substituent R8' consists of a nitrile bonded to a C1-C3 alkyl group, optionally in combination with F1-F7 fluorine, and / or D1-D7 deuteron, and / or hydroxy and / or carbonyl; In subclass 1k, the substituents R8 consist of C1-C3 alkyl groups containing D1-D6 deuterons in combination with optional F1-F6 fluorines, optionally in combination with hydroxy and / or carbonyl; and R8' consists of hydrogen, C1-C6 alkyl, or C3-C5 cycloalkyl or C4-C7 cycloalkylalkyl groups, optionally in combination with hydroxy and / or carbonyl; In subclass 11, the substituents R8 consist of C1-C3 alkyl groups containing D1-D7 deuterons or F1-F7 fluorines, or D1-D6 deuterons in combination with any of F1-F6 fluorines, optionally in combination with hydroxy and / or carbonyl; and R8' consists of C2-C8 alkenyl or C2-C8 alkynyl groups, optionally in combination with nitrile, and / or hydroxy and / or carbonyl; In subclass 1m, the substituents R8 and R8' are linked together to form an azacycloalkane having the amide nitrogen, consisting of a C3-C6 alkylene group containing D1-D10 deuterons or F1-F10 fluorines, or D1-D9 deuterons in combination with optional F1-F9 fluorines, optionally in combination with nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl groups; In subclass 1n, the substituents R8 and R8' are linked together to form an azacycloalkane having the amide nitrogen, consisting of a C3-C6 alkylene group to which is attached a non-deuterated or deuterated C1-C3 alkenyl and / or a non-deuterated or deuterated C2-C3 alkynyl group, the azacycloalkane-forming alkylene group optionally further combined with nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl groups; Class 2 is the lysergic acid amides depicted in Figures 4A-4G and 5A-5C, further characterized by consisting of 6-substituted 6-norlysergic acid diethylamides, wherein R6 consists of the substituents shown in the subclasses designated subclasses 2a-2i, whereby R6 is characterized as follows: In subclass 2a, the substituent R6 is F １ ~F １１ Fluorine-substituted C １ ~C ５ Alkyl or branched C ３ ~C ５ alkyl groups, each of which is optionally D １ ~D １０ in combination with deuterons, and / or nitriles, and / or hydroxy and / or carbonyls, In subclass 2b, a subclass of class 2 wherein the substituent R6 consists of F1-F13 fluorine substituted C3-C7 alkenyl groups, optionally in combination with D1-D12 deuterons, and / or nitriles, and / or hydroxy and / or carbonyls, and the alkenyl double bond is spaced from the nitrogen; In subclass 2c, the substituent R6 consists of an F1-F11 fluorine substituted C3-C7 alkynyl group having a triple bond distal to the N6 nitrogen, optionally in combination with D1-D10 deuterons, and / or nitriles, and / or hydroxy and / or carbonyl; when the substituent R6 contains at least one nitrile, one hydroxy, or one carbonyl group, R6 can also consist of a C3-C7 alkynyl group having said triple bond distal to the N6 nitrogen, optionally in combination with D1-D10 deuterons, and / or nitriles, and / or hydroxy and / or carbonyl; In subclass 2d, the substituent R6 consists of C3-C6 cycloalkyl groups, optionally in combination with F1-F11 fluorine, and / or D1-D11 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl; In subclass 2e, the substituent R6 consists of F1 to F17 fluorine-substituted C4 to C9 cycloalkylalkyl groups, optionally in combination with D1 to D16 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1 to C3 alkyl, and / or deuterated and non-deuterated C1 to C3 alkenyl and / or deuterated and non-deuterated C2 to C3 alkynyl, and the substituent R6 is not cyclopropylmethyl attached to the N6 nitrogen of the ergoline structure by the exocyclic methylene unit; or When R6 is a cyclopropylmethyl attached to the N6 nitrogen of the ergoline structure by an exocyclic methylene unit and contains at least one nitrile, one hydroxy, or one carbonyl group, R6 may also consist of a C4-C9 cycloalkylalkyl group, optionally in combination with D1-D17 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C1-C3 alkynyl groups; In subclass 2f, the substituent R6 consists of an F0-F7 fluorine-substituted C2-C4 alkenyl group attached to the nitrogen at the unsaturated moiety to form an enamide, optionally in combination with a D1-D7 deuteron, and / or a nitrile, and / or a hydroxy and / or a carbonyl; In subclass 2g, the substituent R6 consists of C3-C6 oxacycloalkyl, C3-C9 oxacycloalkylalkyl, C3-C6 thiacycloalkyl, or C3-C9 thiacycloalkylalkyl groups, each optionally in combination with F1-F19 fluorine, and / or D1-D19 deuterons, and / or nitrile, and / or hydroxy, and / or carbonyl, and / or deuterated and non-deuterated C1-C3 alkyl, and / or deuterated and non-deuterated C1-C3 alkenyl and / or deuterated and non-deuterated C2-C3 alkynyl; In subclass 2h, the substituent R6 consists of F0-F11 fluorine-substituted C1-C5 alkoxy or C3-C6 cycloalkoxy groups or C2-C6 alkenoxy groups, each optionally in combination with D1-D11 deuterons, and / or nitrile, and / or hydroxy and / or carbonyl; In sub-class 2i, the R6 substituent consists of aryl, heteroaryl, arylmethyl, or heteroarylmethyl groups, each optionally in combination with F0-F7 fluorines, and / or D1-D7 deuterons, and / or one or more of the following substituents, which themselves can be optionally fluorinated and / or deuterated: halogen, nitrile, nitro, hydroxy, carbonyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 alkenoxy, C3-C6 alkynoxy, methylenedioxy, C1-C4 alkylthio, C3-C6 alkenylthio, C3-C6 alkynylthio, C3-C6 cycloalkylthio; and the R6 substituents defined above for Class 2i can be further cyclized; Class 3 is the lysergic acid amides depicted in Figure 6A, further characterized by any possible combination of the substituents R8 and R8' of Class 1 and its subclasses 1a to 1n (Figures 2A to 3H) with the substituent R6 of Class 2 and its subclasses 2a to 2i (Figures 4A to 5C); Class 4 is the lysergic acid amides depicted in Figure 6B, further characterized by consisting of any possible combination of the substituents R8 and R8' of Class 1 and its subclasses 1a-1n (Figures 2A-3H) and the substituent R6 of Class 2 and its subclasses 2a-2i (Figures 4A-5C), and having a combination of N1 nitrogen substituents on the ergoline moiety from the group: a) any acyl; b) unsubstituted and substituted carbamoyl; c) amide-linked amino acids; d) alkyl, alkenyl, or alkynyl; e) alkoxy, alkenoxy, or alkynoxy; f) any of the substituents described in a) to e) substituted with one or more fluorine atoms; g) any of the substituents described in a) to e) substituted with one or more deuteron atoms; h) any of the substituents described in a) to e) substituted with one or more fluorine atoms and one or more deuteron atoms; and Class 5 (FIG. 6C) consists of mono- to fully deuterated ergoline core structures, further consisting of any possible combination of the R8 and R8′ substituents of Class 1 and its subclasses 1a-1n (FIGS. 2A-3H) with the R6 substituent of Class 2 and its subclasses 2a-2i (FIGS. 4A-5C), with a combination of N1 nitrogen substituents on the ergoline moiety from the following group: a) hydrogen, b) any acyl, c) unsubstituted and substituted carbamoyl, d) amide-linked amino acids, e) alkyl, alkenyl, or alkynyl, f) alkoxy, alkenoxy, or alkynoxy, g) any of the substituents described in a) through f) substituted with one or more fluorine atoms, h) any of the substituents described in a) through f) substituted with one or more deuteron atoms, i) any of the substituents described in a) through f) substituted with one or more fluorine atoms and one or more deuteron atoms. Lysergic acid increasing the interaction of serotonin 5-HT2A and 5-HT2C receptors in the mammal; and inducing a psychotropic effect.

8. 8. The method of claim 7, wherein the compound is selected from the group consisting of a racemate, a single enantiomer, a diastereomer, or a mixture of enantiomers or diastereomers or epimers in any ratio, a single and mixed E or Z configuration isomer in any ratio, a single and mixed cis or trans configuration isomer in any ratio, and any combination thereof.

9. 8. The method of claim 7, wherein the psychotropic effect comprises a psychedelic or empathogenic effect having a similar or different intensity, quality of effect, or duration of effect in a mammal compared to LSD.

10. 8. The method of claim 7, wherein the compound is administered to a mammal for substance-assisted psychotherapy.

11. 8. The method of claim 7, wherein the compound is administered to allow for varying dose potency compared to LSD.

12. 8. The method of claim 7, wherein the compound is administered to allow for adjustment and individualization of treatment according to the mammal's treatment needs.

13. The method of claim 7, wherein the mammal is a human.

14. 1. A method of treating an individual, comprising: administering to said individual a pharmaceutically effective amount of a compound described in FIG. 1A; and treating said individual.

15. 2. The pharmacologically active compound of claim 1, wherein the compound is selected from the group consisting of Compound 21, Compound 12c, Compound 16a, and Compound 16b, and further characterized in that the compound is metabolized more rapidly than LSD, resulting in a shorter duration of acute action.

16. 2. The pharmacologically active compound of claim 1, wherein said compound is selected from the group consisting of compounds 2a-2n, 12a-12g, 13, 14a-c, and 16a-c, and said compound is similar in potency to LSD such that similar low doses have psychotropic and therapeutic activity.

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