Psychoactive compounds, methods for their preparation and their use in treatment of psychiatric disorders

Abstract

The present invention provides psychially active compounds. Compositions comprising them, processes for their preparation and their use in the treatment of mental diseases or conditions.

Description

Background Technology

[0001] Psychedelic compounds, or psychoactive compounds, are a class of natural and synthetic compounds, including psilocybin, MDMA (3,4-methylenedioxymethylamphetamine), ibogline, and DMT (dimethyltryptamine). Some psychedelics have been used by indigenous communities for centuries or even millennia. Others were first synthesized in the early 20th century. By the mid-20th century, clinicians were using psychedelics as an adjunct to psychotherapy and reported various benefits. However, in the 1970s, they were classified as Group 1 controlled substances, reportedly having no currently accepted medical use and a high potential for abuse; this hindered mainstream research on these compounds for decades.

[0002] In the late 1990s, the U.S. Drug Enforcement Administration (DEA) allowed some researchers to study a limited number of psychedelics, which enabled research to resume. Clinical trials have been conducted, and mounting evidence supports the use of psychedelics (such as serocillin and MDMA) to treat depression, post-traumatic stress disorder, and end-of-life anxiety. The Category I status of most psychedelics sets a ceiling for many policy recommendations.

[0003] Most psychedelic drugs are classified and legally regulated as substances with no or very limited medical use, high potential for abuse, and lacking generally accepted safety profiles when used under medical supervision. The potential health risks of these substances include inducing psychotic breaks in individuals with or predisposing to mental illness. Therefore, participation in contemporary psychedelic research typically excludes individuals with a personal or family history of mental illness or bipolar disorder.

[0004] Another risk associated with psychedelic drugs is persistent hallucinogenic perception disorder (HPPD), sometimes referred to as "flashbacks," but HPPD is rarer and clinically more severe than the flashbacks or visual distortions sometimes described within days of illicit psychedelic use. However, adverse effects such as delirium or HPPD are believed to occur at a relatively low rate in the general population, and these effects are typically associated with the use of illicitly obtained psychedelic substances, often involving polydrug abuse in unsupervised, uncontrolled settings. Given these concerns, it is noteworthy that lifelong use of classic psychedelic drugs at the population level is associated with reduced psychological distress; therefore, potential individual cases of harm may be masked by cases where people experience benefits or no harm.

[0005] The most common adverse reactions to psychedelic drugs administered under clinical supervision are limited to the period of drug action, such as anxiety, fear, and acute increases in heart rate and blood pressure. Without careful supervision, fear responses may lead to dangerous behaviors (e.g., fleeing the research site). Furthermore, delayed-onset headaches are sometimes caused by serocillin use, but can also be caused by other classic psychedelics. Although there is some overlap between the adverse reactions of MDMA and classic psychedelics, the cardiovascular effects of MDMA (e.g., tachycardia) are generally greater, while classic psychedelics are more likely to cause adverse psychological reactions. It is important to note that acute adverse reactions are easily managed, and as mentioned earlier, no new clinical studies have reported long-term harm.

[0006] There is a need to find a compound that can be used to treat mental illnesses or conditions safely and without the abuse risks and side effects associated with known psychedelics. Summary of the Invention

[0007] This invention provides compounds selected from the following:

[0008] .

[0009] The present invention also provides compounds selected from the following: .

[0010] In another aspect, the present invention provides compounds selected from the following: .

[0011] The present invention further provides a pharmaceutical composition comprising at least one compound as disclosed herein and any combination thereof.

[0012] The present invention further provides a pharmaceutical composition comprising at least one compound as disclosed above and below, and any combination thereof, for use as an adjunct to psychedelic therapy.

[0013] When referring to "psychedelic-assisted therapy," it should be understood that it includes a treatment, in some embodiments of a mental illness or condition (including any of its symptoms), involving the administration of the composition of the present invention to a patient under the supervision of a caregiver such as a physician, psychiatrist, psychologist, nurse, etc. In some embodiments, the patient is also administered at least one further pharmaceutical composition before, during, or after the administration of the composition of the present invention. In some embodiments, the at least one further pharmaceutical composition is a composition for treating mental or psychological psychotic disorders or conditions.

[0014] The present invention further provides a pharmaceutical composition comprising at least one compound as disclosed herein and any combination thereof, for the treatment of mental illness or condition (including any of its symptoms). In some embodiments, the mental illness is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, addiction (to alcohol, food, drugs, gambling, etc.), psychotic attack, and any combination thereof.

[0015] The present invention further provides a method for treating a mental illness or condition (including any of its symptoms) in a subject in need, wherein the subject is given a composition comprising at least one compound as disclosed above and below, and any combination thereof.

[0016] In some embodiments, the patient is a child aged 5 to 18 years. In some embodiments, the patient is an adult over 18 years of age. In other embodiments, the patient is an elderly person over 80 years of age.

[0017] The terminology used in this article Treatment "Including eliminating, substantially inhibiting, slowing or reversing the progression of the disease, substantially improving the clinical or external symptoms of the disease, or substantially preventing the occurrence of the clinical or external symptoms of the disease."

[0018] Therefore, another aspect of the invention provides the use of one or more compounds as described herein, their enantiomers, hydrates, solvates, prodrugs, or any pharmaceutically acceptable salts in the preparation of a medicament.

[0019] In this document, "pharmaceutical composition" refers to a formulation of the compound described herein with other chemical components, such as pharmaceutically acceptable and suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0020] In the following text, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the applied compound. Examples of carriers include, but are not limited to, propylene glycol, saline solutions, emulsions and mixtures of organic solvents and water, as well as solid (e.g., powdered solids) and gaseous carriers.

[0021] The term "excipient" in this document refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0022] For drug preparation and administration techniques, please refer to Remington Pharmaceutical Science (Mack Publishing Co., Easton, PA, latest edition), the contents of which are incorporated herein by reference.

[0023] Therefore, the pharmaceutical compositions used according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, said carriers containing excipients and adjuvants that facilitate the processing of the compound into a pharmaceutically usable formulation. A suitable formulation depends on the chosen route of administration. Dosage can vary depending on the dosage form used and the route of administration employed. The exact formulation, route of administration, and dosage can be selected by the attending physician based on the patient's condition (see, for example, Fingl et al., 1975, *Pharmacological Basis of Therapeutics*, Chapter 1, page 1). The pharmaceutical composition can be formulated for administration via one or more routes, depending on whether local or systemic treatment or administration is chosen, and the area to be treated. Administration can be by oral, inhalation, or parenteral (e.g., by intravenous infusion or intraperitoneal, subcutaneous, intramuscular, or intravenous injection) or local (including ocular, vaginal, rectal, or nasal administration).

[0024] Topically applied formulations may include, but are not limited to, lotions, ointments, gels, creams, suppositories, drops, liquids, sprays, and powders.

[0025] Conventional drug carriers, aqueous, powder or oil-based matrices, thickeners, etc., may be necessary or desirable.

[0026] Compositions intended for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, pills, capsules, or tablets. Thickeners, diluents, flavoring agents, dispersants, emulsifiers, or binders may be required.

[0027] Parenteral formulations may include, but are not limited to, sterile solutions, and may also contain buffers, diluents, and other suitable additives. The intended treatment is a sustained-release composition.

[0028] Of course, the amount of the composition to be administered will depend on the subject receiving treatment, the severity of the condition, the method of administration, and the prescribing physician's judgment.

[0029] If desired, the compositions of the present invention may be provided in the form of a packaging or dispenser device, such as an FDA (U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredient. The packaging may, for example, contain metal or plastic foil, such as, but not limited to, blister packs or pressurized containers (for inhalation). The packaging or dispenser device may be accompanied by instructions for use. The packaging or dispenser may also be accompanied by a notification associated with the container, in the form prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval of the composition form for human or veterinary administration. For example, such notification may be an FDA-approved prescription drug label or an approved product insert.

[0030] Compositions comprising the compounds of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of medical symptoms, diseases, or conditions associated with the mental illnesses or conditions detailed above.

[0031] Therefore, according to one embodiment of the present invention, the pharmaceutical composition of the present invention is packaged in packaging material and is marked by printing inside or on the packaging material for treating medical conditions, diseases or ailments as defined above related to mental illness or condition (or any symptoms associated therewith).

[0032] According to any of the methods, uses, and further embodiments of the compositions described herein, the compounds of the present invention can be used in combination with other active ingredients commonly used to treat mental illnesses and conditions. Attached Figure Description

[0033] The subject matter of this invention is specifically pointed out and explicitly claimed at the end of the specification. However, the organization, operation, purpose, features, and advantages of this invention can be best understood by reading the following detailed description in conjunction with the accompanying drawings, in which: Figure 1A and Figure 1B This study demonstrates the dose-dependent response of Flp-In 293 T-REx cells stably expressing r5HT2a to serotonin, as detected by live-cell calcium imaging. Figure 1A Pseudo-color images of calcium before (baseline; left panel) and 20 seconds after (serotonin application; 1 nM, 10 nM, 1000 nM; right panel); scale bar indicates intracellular calcium levels. Figure 1B Intracellular calcium levels (y-axis) and nanomolar concentrations (x-axis) were estimated by increasing the F340 / F380 ratio to indicate dose response. The estimated EC50 for serotonin was 0.79 nM (n=4 compartment replicates per concentration).

[0034] Figure 2 Prism analysis of a repeat r5HT2a response to serotonin, as detected by live-cell calcium imaging, is shown. Intracellular calcium levels over time are observed in Flp-In 293 T-REx cells stably expressing r5HT2a in response to a test compound (10 μM) followed by serotonin (1 μM) to identify serotonin-sensitive cells.

[0035] Figure 3A and Figure 3B Data on the activation of the 5HT2a receptor by the synthetic psychoactive compounds of the present invention are shown. Figure 3AThe graph displays a normalized bar chart, representing the mean (± SEM) ratio of calcium responses induced by different psychedelic compounds (10 μM; blue bars) as measured by live-cell calcium imaging. Each bar represents the mean of 50–150 cells. Statistical significance is [value missing]. p ≤ 0.0001 (multiple comparison tests were performed after ANOVA). Figure 3B Concentration-response relationships of rat 5HT2a stably expressed in Flp-in T-REx 293 cells to serotonin (5-HT, hollow circles) or GD-I-46 (solid circles). Each point represents the mean (±SEM) response of 50–150 cells. Solid lines (5-HT, cyan; GD-I-46, orange) conform to the Hill equation, with EC50 and nH of 5-HT at 0.0015 ± 0.0002 μM and 0.7, respectively, and EC50 and nH of GD-I-46 at 0.83 ± 0.13 μM and 0.8, respectively.

[0036] Figure 4 The graph displays a normalized bar chart, representing the mean (± SEM) ratio of calcium responses induced by different psychedelic compounds (10 μM; purple bars) relative to serotonin (1 μM; 5-HT), as measured by live-cell calcium imaging. Each bar represents the mean of 50–150 cells. Statistical significance is [not specified]. p ≤ 0.0001 (multiple comparison tests were performed after ANOVA).

[0037] Figure 5 This displays data on the activation of human 5HT2a receptors by the synthetic psychoactive compounds of the present invention. The normalized bar graph represents the calcium content of the compounds obtained from [the present invention] as determined by live-cell calcium imaging. Figure 4 Mean (± SEM) ratios of calcium responses induced by four successful psychedelic compounds (1–10 μM). Each bar represents the mean of 50–150 cells.

[0038] Figure 6 The graph displays a normalized bar chart representing the mean (± SEM) ratio of calcium responses induced by different psychedelic compounds (10 μM; blue bars) relative to serotonin (1 μM; 5-HT), as determined by live-cell calcium imaging. Each bar represents the mean of 50–150 cells.

[0039] Figure 7 This invention demonstrates the activation of the 5HT2a receptor by the synthetic psychoactive compound. The concentration-response relationship of human 5HT2a stably expressed in Flp-in T-REx 293 cells to MM-I-06 is shown. Each point represents the mean (±SEM) response of 50–150 cells. The solid line conforms to the Hill equation, with the EC50 and nH of MM-I-06 being 501 nM and 0.8, respectively.

[0040] It should be understood that, for the sake of simplicity and clarity, the elements shown in the figures are not necessarily drawn to scale. For example, the dimensions of some elements may be exaggerated relative to others for clarity. Furthermore, where deemed appropriate, reference numerals may be repeated in the figures to indicate corresponding or similar elements. Detailed Implementation

[0041] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, those skilled in the art will understand that the invention can be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the invention.

[0042] Synthesis of GD-I-46 (G-1): 2-(1H-indol-3-yl)ethyl-1-amine (1.00 equivalent) was added in a single batch to a solution of 1,2-cyclohexanedione (1.00 equivalent) in methanol (0.3 M). The solution was stirred at 80°C for 12 hours. The mixture was concentrated under high vacuum. The product GD-I-46 (G-1) was purified by rapid chromatography with DCM / MeOH to obtain the corresponding product. α - Enamino ketone. Purity 74%.

[0043] Synthesis of MM-I-006 (G-2): 2-(6-fluoro-1H-indol-3-yl)ethyl-1-amine (1.00 equivalent) was added in a single batch to a solution of 1,2-cyclohexanedione (1.00 equivalent) in methanol (0.3 M). The solution was stirred at 80°C for 12 hours. The mixture was concentrated under high vacuum. The product MM-I-006 (G-2) was purified by rapid chromatography with DCM / MeOH to obtain the corresponding product. α - Enamino ketone. Purity 92%.

[0044]

[0045] Cell culture:Flp-In 293 T-REx cells expressing stable rat or human 5-HT2A (serotonin) receptors were homogeneously cultured with antibiotics (200 mg / mL hygromycin B Gold and 10 mg / mL blastomycin; InvivoGen) at 37°C and 5% CO2 in DuPont modified Eagle medium (DMEM) (referred to as Full DMEM in this paper) (Sigma-Aldrich, Missouri, USA) supplemented with 10% fetal bovine serum (FBS), 1% penicillin-streptomycin, 2 mM L-alanyl-L-glutamine and 25 mM HEPES (pH 7.3; Biological Industries, Israel).

[0046] Live-cell calcium imaging: Flp-In 293 T-REx cells expressing stable rat 5-HT2A (serotonin) receptors were spotted onto poly-D-lysine (0.2 mg / mL)-coated imaging chambers (µ-slide, 8-well, Ibidi, Germany) 3–4 hours before loading Fura-2AM solution. Subsequently, the cells were loaded in the dark for 60 minutes with Ringer's salt solution (mM: 140 NaCl, 2.5 KCl, 1.8 CaCl2, 2 MgSO4, 20 HEPES, 5 D-glucose, pH 7.4, adjusted with NaOH) containing 10 µM / mL Fura-2AM (a membrane permeability calcium indicator – Invitrogen) and 2 µM / mL Pluronic acid solution. The cells were then washed three times with Ringer's solution and incubated for 15–30 minutes before recording. Calcium imaging was performed using an Olympus fluorescence microscope (IX 73, Olympus, Japan) equipped with an ORCA-Flash4.0 LT imaging camera (Figure 1). Cells were illuminated with a xenon arc lamp, and the excitation wavelength (340 / 380 nm) was selected using a Lambda DG-4 monochromatic wavelength converter (Sutter Instrument). Fluorescence emission at 510 nm (>480 nm) was captured using a front-illuminated inner-line CCD camera. Background-corrected images were monitored and collected every 4 seconds during the experiments. Experiments were conducted at room temperature.

[0047] Data Analysis: Calcium imaging analysis was performed using MetaFluor fluorescence imaging software (Molecular Devices, California, USA). All statistical data, including concentration-response and standard deviation analyses, were calculated using Prism 5 software (GraphPad Software, La Jolla, California, USA). Figure 2 -Figure 3, Figure 5 ).

[0048] result: Rat 5HT2a and human 5HT2a cell lines were established for analysis. Three batches of compounds from this invention were screened. Figure 3A , Figure 4 , Figure 6 As shown in the results below, this system was able to activate and enhance the sensitivity of different compounds to the rat 5HT2a receptor. Furthermore, following the first two rounds of screening, the most successful compounds on human 5HT were evaluated. Figures 5-7 ).

[0049] Although certain features of the invention have been described and illustrated herein, many modifications, substitutions, variations, and equivalents will now occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and variations that fall within the true spirit and scope of the invention.

Claims

1. Selected from the following compounds: 。 2. Selected from the following compounds: 。 3. Selected from the following compounds: 。 4. A composition comprising at least one compound according to claim 1.

5. The composition according to claim 4, used as an adjunct to psychedelic therapy.

6. The composition according to claim 4, used for treating mental illness or condition.

7. The composition of claim 6, wherein the mental illness or condition is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, psychotic episode, and any combination thereof.

8. A method for treating a mental illness in a subject in need, wherein the subject is given the composition according to claim 4.

9. The method of claim 8, wherein the mental illness or condition is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, and any combination thereof.

10. A composition comprising at least one compound according to claim 2.

11. The composition according to claim 10, used as an adjunct to psychedelic therapy.

12. The composition according to claim 10, used for treating mental illness or condition.

13. The composition of claim 12, wherein the mental illness or condition is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, psychotic episode, and any combination thereof.

14. A method for treating a mental illness in a subject in need, wherein the subject is given the composition according to claim 10.

15. The method of claim 14, wherein the mental illness is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, psychotic episode, and any combination thereof.

16. A composition comprising at least one compound according to claim 3.

17. The composition according to claim 16, used as an adjunct to psychedelic therapy.

18. The composition according to claim 16, used for treating mental illness or condition.

19. The composition of claim 18, wherein the mental illness or condition is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, psychotic episode, and any combination thereof.

20. The composition of claim 18, wherein the treatment is administered to a child, adult, or elderly patient.

Images