Psychoactive compounds, methods of their preparation and uses thereof in the treatment of mental disorders

Abstract

The invention provides psychoactive compounds. Compositions comprising them and methods of their preparation and use in the treatment of metal diseases or disorders.

Description

PSYCHOACTIVE COMPOUNDS, METHODS OF THEIR PREPARATION AND USES THEREOF IN THE TREATMENT OF MENTAL DISORDERSBACKGROUND OF THE INVENTION

[0001] Psychedelic compounds or psychoactive compounds are a class of natural and synthetic compounds that includes psilocybin, MDMA (3,4- methylenedioxymethamphetamine), ibogaine and DMT (dimethyltryptamine). Some psychedelics have been used by Indigenous communities for hundreds or thousands of years. Others were first synthesized in the early 20th century. By the middle of the 20th century, clinicians used psychedelics as adjuncts to psychotherapy, reporting a variety of benefits. However, in the 1970s they were categorized as schedule I controlled substances, which are said to have no currently accepted medical use and a high potential for abuse; this blocked mainstream research on these compounds for decades.

[0002] In the late 1990s, the US Drug Enforcement Administration (DEA) permitted some researchers to study limited amounts of psychedelics, which allowed research to resume. Clinical trials have been conducted and a growing body of evidence supports the use of psychedelics, such as psilocybin and MDMA, in the treatment of depression, post- traumatic stress disorder and anxiety toward the end of life. The schedule I status of most psychedelics imposes a ceiling on many policy recommendations.

[0003] Most psychedelic drugs are classified and legally scheduled as having no or very limited medical purpose, a high potential for abuse and a lack of accepted safety for use under medical supervision. Potential health risks of these substances include the precipitation of psychotic breaks in patients with psychotic disorders or a predisposition to these disorders. Thus, participation in contemporary psychedelic research typically excludes people with a personal or family history of psychosis or bipolar disorder.

[0004] A further risk associated with psychedelic drugs is Hallucinogen Persisting Perception Disorder (HPPD), sometimes known as “flashbacks,” although HPPD is more uncommon and more clinically severe than the flashbacks or visual distortions sometimes described in the days following illicit use of psychedelics. However, the incidence of adverse effects such as psychosis or HPPD in the general population is believed to be relatively low, and these effects are generally associated with the use of illicitly procured psychedelic substances, which often involves polysubstance use in uncontrolled settings without supervision. In light of these concerns, it is worth noting that lifetime use of classic psychedelics at the population level is associated with decreased psychological distress; thus, potential individual instances of harm may be overshadowed by instances in which people experience benefit or no harm.

[0005] The most common adverse effects from the administration of psychedelics under clinical supervision are limited to the time of drug action, such as acute increases in anxiety, fear, heart rate and blood pressure. Without careful supervision, fearful responses could lead to dangerous behaviour (e.g., fleeing the study site). In addition, delayed-onset headache is sometimes caused by psilocybin use and possibly by other classic psychedelics. Although adverse effects of MDMA overlap somewhat with those of classic psychedelics, cardiovascular effects (e.g., tachycardia) are generally greater with MDMA, whereas adverse psychological reactions are more likely with classic psychedelics. It is important to note that acute adverse effects are readily managed, and that, as described previously, none of the new clinical research studies have reported long-term harms.

[0006] There is a need for finding compounds that have safe and therapeutic effect without the risk of abuse and side-effects associated with known psychedelics for the treatment of mental disease or disorders.SUMMARY OF THE INVENTION

[0007] The invention provides compounds selected from:

[0008] The invention further provides compounds selected from:

[0010] The invention further provides a pharmaceutical composition comprising at least one of compounds as disclosed herein above and below and any combinations thereof.

[0011] The invention further provides a pharmaceutical composition comprising at least one of compounds as disclosed herein above and below and any combinations thereof, for use in psychedelic-assisted therapy.

[0012] When referring to “psychedelic-assisted therapy” it should be understood to encompass a therapy treatment, in some embodiments of metal diseases or disorders (including any symptoms thereof), that involves the supervised (by a care giver such as medical doctor, psychiatric doctor, psychologist, nurse and so forth) administration of a composition of the invention to a patient. In some embodiments, said patient is administered at least one further pharmaceutical composition either, before during or after administration of a composition of the invention. In some embodiments, said at least one further pharmaceutical composition is a composition used in the treatment of mental or psychological psychotic diseases or disorders.

[0013] The invention further provides a pharmaceutical composition comprising at least one of compounds as disclosed herein above and below and any combinations thereof, for use in the treatment of a mental disease or disorder (including any symptoms thereof). In some embodiments, said metal disorder is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, addiction (to alcohol, food, drugs, gambling and so forth), psychotic attack, and any combinations thereof.

[0014] The invention further provides a method of treating mental disease or disorder (including any symptoms thereof) in a subject in need thereof wherein said subject is administered with a composition comprising at least one compound as disclosed herein above and below and any combinations thereof.

[0015] In some embodiments, said patient is a child between the age of 5 to 18 years. In some embodiments, said patient is an adult above the age of 18 years. In other embodiments, said patient is an elderly person above the age of 80 years.

[0016] As used herein, the terms “treating" and “treatment" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or external symptoms of a condition or substantially preventing the appearance of clinical or external symptoms of a condition.

[0017] Accordingly, another aspect of the present invention provides a use of one or more of the compounds as presented herein, as well enantiomers, hydrates, solvates, prodrugs or any pharmaceutically acceptable salts thereof, in the preparation of a medicament.

[0018] As used herein a “pharmaceutical composition” refers to a preparation of the compounds presented herein, with other chemical components such as pharmaceutically acceptable and suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0019] Hereinafter, the term “pharmaceutically acceptable carrier” refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Examples, without limitations, of carriers are: propylene glycol, saline, emulsions and mixtures of organic solvents with water, as well as solid (e.g., powdered) and gaseous carriers.

[0020] Herein the term “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0021] Techniques for formulation and administration of drugs may be found in “Remington’s Pharmaceutical Sciences” Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

[0022] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see e.g., Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. I p. I). The pharmaceutical composition may be formulated for administration in either one or more of routes depending on whether local or systemic treatment or administration is of choice, and on the area to be treated. Administration may be done orally, by inhalation, or parenterally, for example by intravenous drip or intraperitoneal, subcutaneous, intramuscular or intravenous injection, or topically (including ophtalmically, vaginally, rectally, intranasally).

[0023] Formulations for topical administration may include but are not limited to lotions, ointments, gels, creams, suppositories, drops, liquids, sprays and powders.

[0024] Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0025] Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, pills, caplets, capsules or tablets. Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable.

[0026] Formulations for parenteral administration may include, but are not limited to, sterile solutions which may also contain buffers, diluents and other suitable additives. Slow release compositions are envisaged for treatment.

[0027] The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0028] Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA (the U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as, but not limited to a blister pack or a pressurized container (for inhalation). The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.

[0029] Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a medical condition, disease or disorder associated with mental disease or disorder, as is detailed hereinabove.

[0030] Thus, according to an embodiment of the present invention, the pharmaceutical composition of the present invention is being packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment of a medicalcondition, disease or disorder associated with mental disease or disorder (or any symptoms associate therefrom), as is defined hereinabove.

[0031] According to further embodiments of the any of the methods, uses and compositions presented herein, the compounds of the present invention can be combined with other active ingredients which are commonly used to treat mental diseases and disorders.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0033] Figures 1A and IB show the dose-dependent Flp-In 293 T-REx cells stably expressing r5HT2a response to serotonin detected by live-cell calcium imaging. (Fig. 1A) Pseudo-colored calcium images of before (Basal; left images) and after 20s (after serotonin application; InM, lOnM, lOOOnM; right images); Scale bar indicates levels of intracellular calcium. (Fig. IB) Dose response indicated by increase in F340 / F380 ratio to estimate intracellular levels of calcium (y-axis) and concentration in nano-molar (x-axis). Estimated EC50 for serotonin is 0.79 nM (n=4 chamber repeats per concentration).

[0034] Figure 2 shows the prism analysis of one repeat of r5HT2a response to Serotonin detected by live-cell calcium imaging. Changes with time of intracellular calcium levels in Flp-In 293 T-REx cells stably expressing r5HT2a in response to a tested compound (10 pM) followed by an application of Serotonin (1 pM) for recognition of Serotonin sensitive cells.

[0035] Figures 3A and 3B show the activated the 5HT2a receptor data for the synthetic psychoactive compounds of the invention. Fig. 3A shows the normalized bar graph represents the average (± SEM) ratio of the calcium response evoked by different psychedelic compounds (lOpM; blue bars) as determined by live-cells calcium imaging. Each bar represents an average of 50-150 cells. Statistical significance is ****p < 0.0001 (ANOVA followed by a multiple comparison test). Fig. 3B shows the concentrationresponse relationships for serotonin (5-HT, empty circles) or GD-I-46 (circles) of rat 5HT2a stably expressed in Flp-in T-REx 293 cells. Each point represents the average (±SEM) response of 50-150 cells. The solid lines (5-HT, cyan; GD-I-46, orange) fits the Hill equation with EC50 and nH of 0.0015 ± 0.0002 pM and 0.7 for 5-HT, and EC50 and nH of 0.83 ± 0.13 pM and 0.8 for GD-I-46.

[0036] Figure 4 shows the normalized bar graph represents the average (± SEM) ratio of the calcium response evoked by different psychedelic compounds (lOpM; purple bars) relative to serotonin (IpM; 5-HT)) as determined by live-cells calcium imaging. Each bar represents an average of 50-150 cells. Statistical significance is ****p < 0.0001 (ANOVA followed by a multiple comparison test).

[0037] Figure 5 shows data of synthetic psychoactive compounds of the invention activate the human 5HT2a receptor. Normalized bar graphs represent the average (± SEM) ratio of the calcium response evoked by four successful psychedelic compounds (1-1 OpM) from Fig. 4, as determined by live-cells calcium imaging. Each bar represents an average of 50-150 cells.

[0038] Figure 6 shows the normalized bar graph represents the average (± SEM) ratio of the calcium response evoked by different psychedelic compounds (lOpM; blue bars)relative to serotonin (IpM; 5-HT)) as determined by live-cells calcium imaging. Each bar represents an average of 50-150 cells.

[0039] Figure 7 shows the synthesized psychoactive compound of the invention activated the 5HT2a receptor. Concentration-response relationships for MM-I-06 of Human 5HT2a stably expressed in Flp-in T-REx 293 cells. Each point represents the average (±SEM) response of 50-150 cells. The solid line fits the Hill equation with EC50 and nH of 501 nM and 0.8 respectively for MM-I-06.

[0040] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0041] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may 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 present invention.

[0042] Synthesis of GD-I-46 (G-l}: To a solution of 1,2-cyclohexadione (1.00 equiv.) in MeOH (0.3 M), was added 2-(lH-indol-3-yl)ethan-l-amine (1.00 equiv.) in one portion. The solution was left to stir for 12 hours at 80 °C. The mixture was concentrated under high vacuum. The product GD-I-46 (G-l) was purified by flash chromatography with DCM / MeOH, to yield the corresponding a-enaminone. Purity 74%.

[0043] Synthesis ofMM-I-006 (G-2): To a solution of 1,2-cyclohexadione (1.00 equiv.) in MeOH (0.3 M), was added 2-(6-fluoro-lH-indol-3-yl)ethan-l-amine (1.00 equiv.) in one portion. The solution was left to stir for 12 hours at 80 °C. The mixture was concentrated under high vacuum. The product MM-I-006 (G-2) was purified by flash chromatography with DCM / MeOH, to yield the corresponding a-enaminone. Purity 92%.

[0044] Cell culturing: Homogenously expressing Flp-In 293 T-REx cells which express stable rat or human 5-HT2A (serotonin) receptor were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Sigma-Aldrich, MO, USA) supplemented with 10% fetal bovine serum (FBS), 1% Penicillin-Streptomycin, 2 mM L-Alanyl L-Glutamine, and 25 mMHEPES (pH 7.3; Biological Industries, Israel) (herein: Full DMEM) with antibiotics (200mg / mL Hygromycin B Gold and lOmg / mL Blasticidin ;InvivoGen) at 37°C and 5% CO2.

[0045] Live cell calcium imaging: Flp-In 293 T-REx cells which express stable rat 5- HT2A (serotonin) receptor were spotted on poly-D-lysine (0.2 mg / mL)-coated imaging chambers (p-slide, 8 well, Ibidi, Germany) 3-4 hours before being loaded with Fura-2AM solution. Subsequently, they were loaded with lOpM / mL Fura-2AM (a membrane-permeant calcium indicator - Invitrogen) and 2pM / mL Pluronic acid solution in Ringer's salt solution (in mM: 140 NaCl, 2.5 KC1, 1.8 CaC12, 2 MgSO4, 20 HEPES, and 5 D-glucose, pH 7.4, with NaOH) for 60 minutes in a dark place. Then, the cells were washed three times with Ringer's solution and incubated for 15-30 minutes before the recordings. Calcium imaging was performed using an Olympus fluorescence microscope (IX 73, Olympus, Japan) equipped with an imaging ORCA-Flash4.0 LT camera (Figure 1). Cells were illuminated with a xenon arc lamp, and excitation wavelengths (340 / 380 nm) were selected by a Lambda DG-4 monochromatic wavelength changer (Sutter Instrument). Fluorescence emission at 510 nm (>480 nm) was captured with a front-illuminated interline CCD camera. Background-corrected images were monitored and collected every 4 seconds during the experiment. The experiments were conducted at room temperature.

[0046] Data Analysis: Calcium imaging analysis was performed using MetaFluor Fluorescence Imaging Software (Molecular Devices, CA, USA). All statistical data, including concentration-response and standard deviation analysis, were calculated using Prism 5 software (GraphPad Software, La Jolla, CA, USA) (Figures 2-3, 5).

[0047] Results: The rat 5HT2a and human 5HT2a cell lines were established for analysis. Three batches of compounds of the invention were screened (Fig. 3a, Fig. 4, Fig. 6). As demonstrated in the results below, the system enabled the activation and sensitivity of the different compounds to the rat 5HT2a receptors. Furthermore, after the screening of the first two batches the most successful compounds on human 5HT (Fig. 5-7) were evaluated.

[0048] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims areintended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

CLAIMS[00049] What is claimed is:

1. A compound selected from:

2. A compound selected from:

3. A compound selected from:

4. A composition comprising at least one compound according to claim 1.

5. A composition according to claim 4, for use in psychedelic-assisted therapy.

6. A composition according to claim 4, for use in the treatment of a mental disease or disorder.

7. A composition according to claim 6, wherein said mental disease or disorder is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, psychotic attack and any combinations thereof.

8. A method of treating mental disorder in a subject in need thereof wherein said subject is administered with a composition according to claim 4.

9. A method according to claim 8, wherein said metal disease or disorder is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder and any combinations thereof.

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

11. A composition according to claim 10, for use in psychedelic-assisted therapy.

12. A composition according to claim 10, for use in the treatment of a mental disease or disorder.

13. A composition according to claim 12, wherein said mental disease or disorder is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, psychotic attack, and any combinations thereof.

14. A method of treating mental disorder in a subject in need thereof wherein said subject is administered with a composition according to claim 10.

15. A method according to claim 14, wherein said metal disorder is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, psychotic attack, and any combinations thereof.

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

17. A composition according to claim 16, for use in psychedelic-assisted therapy.

18. A composition according to claim 16, for use in the treatment of a mental disease or disorder.

19. A composition according to claim 18, wherein said mental disease or disorder is selected from major depressive disorder, anxiety disorder, post-traumatic stress disorder, psychotic attack, and any combinations thereof.

20. A composition according to claim 18, wherein said treatment is administered to a child, an adult or an elderly patient.

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