Magic compounds, methods of making and uses thereof

Abstract

The present invention provides synthetic compounds having magical biological activity, compositions comprising them, processes for their preparation and their use in the treatment of diseases, symptoms and conditions.

Description

Background Technology

[0001] N,N-Dimethyltryptamine (DMT or N,N-DMT, SPL026) is a substituted tryptamine found in many plants and animals, including humans. It is both a derivative and a structural analog of tryptamine. DMT has been used as a hallucinogenic drug and has been prepared by various cultures for ritual purposes as a hallucinogen.

[0002] DMT has a rapid onset of action, a strong effect, and a relatively short duration of action. DMT can be inhaled, ingested, or injected, and its effects depend on the dosage and route of administration. When inhaled or injected, the effect lasts for a short time: approximately 5 to 15 minutes. The effect may last for three hours or longer. DMT can produce vivid “projections” of mystical experiences, including euphoria and dynamic pseudo-hallucinations of geometric shapes.

[0003] DMT is a functional and structural analogue of other hallucinogenic trypsin-like compounds, such as O-acetylated dephosphorylated psilocybin (4-AcO-DMT), psilocybin (4-PO-DMT), dephosphorylated psilocybin (4-HO-DMT), O-methylbufotenine (5-MeO-DMT), and bufotenine (5-HO-DMT). Parts of the DMT structure are present in some important biomolecules, such as serotonin and melatonin, making them structural analogues of DMT.

[0004] Dimethyltryptamine (DMT) is an endogenous ligand for sigma-1 receptors (Sig-1Rs) and can counteract systemic hypoxia. Studies have shown that DMT can reduce the number of apoptotic and ferroptotic cells in the mammalian forebrain and support the survival of astrocytes in ischemic environments. Based on these data, DMT could be considered as an adjunct therapy for acute cerebral ischemia, Parkinson's disease, and major depressive disorder. It is also a psychotropic drug that can promote rapid and sustained neuroplasticity, potentially offering broad therapeutic benefits. Summary of the Invention

[0005] This invention provides a compound having the general formula (I):

[0006] (I) R1 and R2 are each selected from H, straight-chain or branched C1-C5 alkyl, straight-chain or branched C2-C5 alkenyl, straight-chain or branched C2-C5 ynyl, and part (II).

[0007] (II) R13-R22 are each selected from H, halogens (i.e. F, Cl, Br, I), straight-chain or branched C1-C8 alkoxy groups, straight-chain or branched C1-C8 alkyl groups, and chemical protecting groups. R3-R6 are H, or R3 and R4 together and / or R5 and R6 together form =O; R7 to R12 are each selected from empty, H, or halogen; X is selected from C or N; where R9 is empty when X is N. The condition is that at least one of R1 and R2 is different from H; The condition is that when R3 and R4 together, and R5 and R6 together, form = 0, X is N, R9 is empty, or at least one of R7 to R12 is different from H; and The condition is that when R1 and R2 are each straight-chain or branched C1-C3 alkyl groups, at least one of R7-R12 is different from H.

[0008] In some embodiments, R1 and R2 are each straight-chain or branched C1-C5 alkyl groups, provided that when R1 and R2 are both straight-chain or branched C1-C3 alkyl groups, at least one of R7-R12 is different from H.

[0009] In some embodiments, at least one of R7 to R12 is a halogen. In other embodiments, R11 is a halogen. In some embodiments, R11 is F. In other embodiments, R11 is Br.

[0010] In some implementations, R3 and R4 together, and R5 and R6 together, form =0; X is N, and R9 is empty.

[0011] In some implementations, R3 and R4 together, and R5 and R6 together, form =O; R11 is a halogen.

[0012] In some embodiments, R1 and R2 are each straight-chain or branched C1-C5 alkyl groups; R3 to R6 are H; and R11 is a halogen.

[0013] In some embodiments, R1, R3-R12 are H, and R2 is part (II).

[0014] (II) Each of R13-R22 is selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, straight-chain or branched C2-C8 alkenyl, and straight-chain or branched C2-C8 alkynyl.

[0015] In some embodiments, R1, R3-R12 are H, and R2 is part (II).

[0016] (II) R13-R22 are each selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, provided that at least one of R13-R22 is different from H.

[0017] In some embodiments, the compounds of the present invention are selected from: 1 2 3 4 5 6 7 8 9 10 11 12 The present invention also provides a compound for treating diseases, symptoms, or conditions selected from depression (including resistant depression), stress including post-traumatic stress disorder (PTSD), cerebral ischemia, and any combination thereof, wherein the compound has the general formula (I):

[0024] (I) R1 and R2 are each selected from H, straight-chain or branched C1-C5 alkyl, straight-chain or branched C2-C5 alkenyl, straight-chain or branched C2-C5 alkynyl, -C(=O)CR23R24R25, wherein R23-R25 are selected from H or halogens; and part of formula (II)

[0025] (II) R13-R22 are each selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, chemical protecting group; or R1 and R2 together with the nitrogen atom to which they are attached form a 5-6 membered heterocycle; R3-R6 are H, or R3 and R4 together form =O and / or R5 and R6 together form =O; R7 to R12 are each selected from H and halogens.

[0026] In some embodiments, R1 and R2 are each a straight-chain or branched C1-C5 alkyl group.

[0027] In some implementations, R3-R6 are H.

[0028] In some embodiments, at least one of R7 to R12 is a halogen. In some embodiments, R11 is a halogen. In some embodiments, the halogen is selected from F, Cl, Br, and I. In other embodiments, the halogen is F.

[0029] In some embodiments, R1 and R2 are each straight-chain or branched C1-C5 alkyl groups; R3 to R6 are H; and R11 is a halogen.

[0030] In some embodiments, R1, R3-R12 are H, and R2 is part (II).

[0031] (II) Each of R13-R22 is selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, straight-chain or branched C2-C8 alkenyl, and straight-chain or branched C2-C8 alkynyl.

[0032] In some embodiments, R1, R3-R12 are H, and R2 is part (II).

[0033] (II) R13-R22 are each selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, provided that at least one of R13-R22 is different from H.

[0034] In some embodiments, R3-R12 are H; R1 and R2 together with the nitrogen atom to which they are attached form a 5-6 membered heterocycle.

[0035] In some embodiments, R7–R12 are H or halogens; R3 and R4 form =O, R5 and R6 form =O; R1 and R2 are each straight-chain or branched C1-C5 alkyl groups, or together with the nitrogen atom to which they are attached, form a 5-6 membered heterocycle.

[0036] In some embodiments, R1, R3-R12 are H or halogens; R2 is an -C(=O)-C1-C5 alkyl group optionally substituted with at least one halogen.

[0037] In some embodiments, the compounds of the present invention are selected from: 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 In another aspect, the present invention provides a compound having the general formula (III):

[0050] (III) R23 and R24 are each phenyl groups, straight-chain or branched C1-C5 alkyl groups substituted with at least one group selected from phenyl, halophenyl, indole, or haloindole; R25-R34 are each selected from H, straight-chain or branched C1-C5 alkoxy groups.

[0051] In some embodiments, R25, R27, R29, R30, R32, and R34 are each straight-chain or branched C1-C5 alkoxy groups.

[0052] In some embodiments, R23 and R24 are each phenyl.

[0053] In some embodiments, R23 and R24 are each straight-chain or branched C1-C5 alkyl groups substituted with at least one phenyl group.

[0054] In some embodiments, R23 and R24 are each straight-chain or branched C1-C5 alkyl groups substituted with at least one halophenyl group (i.e., benzene rings substituted with at least one halogen).

[0055] In some embodiments, R23 and R24 are each straight-chain or branched C1-C5 alkyl groups substituted with at least one indole group.

[0056] In some embodiments, R23 and R24 are each straight-chain or branched C1-C5 alkyl groups substituted with at least one haloindolyl group (i.e., indole rings substituted with at least one halogen).

[0057] In some embodiments, the compounds of the present invention are selected from: 37, 38, 39, 40.

[0058] The present invention further provides a composition comprising at least one compound as described above.

[0059] The present invention also provides a composition as described above for treating diseases, symptoms or conditions associated with depression, including resistant depression.

[0060] The present invention also provides a composition as described above for treating stress-related illnesses, symptoms or conditions, including post-traumatic stress disorder (PTSD).

[0061] The present invention also provides a composition as described above for treating diseases, symptoms or conditions associated with cerebral ischemia.

[0062] The present invention provides a method for treating diseases, symptoms or conditions associated with depression, including resistant depression; the method comprising administering at least one compound as disclosed above and below to a subject in need.

[0063] The present invention provides a method for treating stress-related diseases, symptoms or conditions, including post-traumatic stress disorder; the method comprising administering at least one compound as disclosed above and below to a subject in need.

[0064] The present invention provides a method for treating diseases, symptoms or conditions associated with cerebral ischemia; the method comprising administering at least one compound as disclosed above and below to a subject in need.

[0065] When “resistant depression” is mentioned, it should be understood to refer to treatment-resistant depression (TRD), a severe form of depression in which the affected person does not respond adequately to at least two different antidepressants for a sufficient dose and duration.

[0066] When "cerebral ischemia" is mentioned, it should be understood as related to cerebral ischemia, a condition where the blood flow to the brain is insufficient to meet its metabolic needs. This leads to insufficient oxygen supply or cerebral hypoxia, resulting in brain tissue death or cerebral infarction / ischemic stroke. Cerebral ischemia is a subtype of stroke, classified alongside subarachnoid hemorrhage and cerebral hemorrhage.

[0067] When we talk about "Post-Traumatic Stress Disorder (PTSD)," it should be understood as a mental and behavioral disorder that develops in response to a traumatic event, such as sexual assault, war, traffic accidents, child abuse, domestic violence, or other threats to a person's life or well-being. Symptoms of PTSD may include disturbing thoughts, feelings, or dreams related to the event; mental or physical distress in response to trauma-related cues; attempts to avoid trauma-related cues; altered ways of thinking and feeling; and an increased fight-or-flight response. These symptoms can persist for more than a month after the event. People with PTSD have a higher risk of suicide and intentional self-harm.

[0068] The term "straight-chain or branched C1-C5 alkyl" should be understood to include any straight-chain or branched saturated hydrocarbon chain having 1, 2, 3, 4, or 5 carbon atoms, wherein only σ bonds connect the atoms of the chain, and one hydrogen atom is removed from any carbon atom of the chain. The term "straight-chain or branched C1-C8 alkyl" should be understood to include any straight-chain or branched saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, wherein only σ bonds connect the atoms of the chain, and one hydrogen atom is removed from any carbon atom of the chain.

[0069] The term "straight-chain or branched C2-C5 alkenyl" should be understood to include any straight-chain or branched unsaturated hydrocarbon chain having 2, 3, 4, or 5 carbon atoms, wherein at least one double bond connects two carbon atoms at any point in the hydrocarbon chain, and one hydrogen atom is removed from any carbon atom in the chain. The term "straight-chain or branched C2-C8 alkenyl" should be understood to include any straight-chain or branched unsaturated hydrocarbon chain having 2, 3, 4, 5, 6, 7, or 8 carbon atoms, wherein at least one double bond connects two carbon atoms at any point in the hydrocarbon chain, and one hydrogen atom is removed from any carbon atom in the chain.

[0070] The term "straight-chain or branched C2-C5 ynyl group" should be understood to include any straight-chain or branched unsaturated hydrocarbon chain having 2, 3, 4, or 5 carbon atoms, wherein at least one triple bond connects two carbon atoms at any point in the hydrocarbon chain, and one hydrogen atom is removed from any carbon atom in the chain. The term "straight-chain or branched C2-C8 ynyl group" should be understood to include any straight-chain or branched unsaturated hydrocarbon chain having 2, 3, 4, 5, 6, 7, or 8 carbon atoms, wherein at least one triple bond connects two carbon atoms at any point in the hydrocarbon chain, and one hydrogen atom is removed from any carbon atom in the chain.

[0071] As used herein, the term “C1-C8 alkoxy” refers to the functional group -OR, where R is a C1-C8 alkyl group.

[0072] As used herein, the term "phenyl" refers to the aromatic ring functional group -C6H5. As used herein, the term "halogenated phenyl" refers to the aromatic ring functional group -C6H4X, where X is a halogen group substituted at any position on the benzene ring.

[0073] As used herein, the term "indolyl" refers to the aromatic heterocyclic functional group -C8H8N (the functional group of indoline is connected through an aromatic saturated ring or any position of its nitrogen atom). As used herein, the term "haloindolyl" refers to the aromatic ring functional group -C8H7NX, where X is a halogen group substituted at any position on the indolyl ring.

[0074] The term "5-6 membered heterocycle" refers to a ring system (which can be aromatic, saturated, or unsaturated) having one or two rings (fused or linked), wherein at least one carbon atom of the ring system is substituted by a heteroatom (N, O, P, S), and two hydrogen atoms are removed, resulting in two open valences. The total number of members in the ring is 5 or 6.

[0075] This invention relates to pharmaceutical compositions comprising a mixture of the compounds of the invention with pharmaceutically acceptable adjuvants and optionally other therapeutic agents. The adjuvants must be "acceptable," meaning compatible with the other components of the composition and harmless to the receptor.

[0076] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, oral, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration or via implantation. The compositions may be prepared by any method well known in the pharmaceutical field.

[0077] Such methods include the step of combining the associative compound or a combination thereof used in this invention with any adjuvants. Adjuvants, also known as auxiliary ingredients, include conventional ingredients in the art such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, and wetting agents.

[0078] Pharmaceutical compositions suitable for oral administration may be in discrete dosage units, such as pills, tablets, coated formulations, or capsules, or in powder or granule form, or in solution or suspension form. The active ingredient may also be presented in the form of pills or pastes. The composition may be further processed into suppositories or enemas for rectal administration.

[0079] The present invention also includes combinations of pharmaceutical compositions and packaging materials as described above, including instructions for the use of the composition as described above.

[0080] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injectable solutions. The compositions can be packaged in single-dose or multi-dose containers, such as sealed vials and ampoules, and can be stored under lyophilized (freeze-dried) conditions requiring only the addition of a sterile liquid carrier (e.g., water) before use. For transdermal administration, gels, patches, or sprays may be considered, for example. Compositions or formulations suitable for pulmonary administration, such as by nasal inhalation, include fine dust or mists that can be generated by metered-dose pressurized aerosols, nebulizers, or inhalers.

[0081] The exact dosage and administration regimen of the composition will depend on the therapeutic or nutritional effect to be achieved and may vary depending on the specific formulation, route of administration, and the age and condition of the individual taking the composition.

[0082] As used herein, the term "effective amount" means an amount of a drug or pharmaceutical composition that will elicit a biological or medical response in a tissue, system, animal, or human, such as that sought by an investigator or clinician. Furthermore, the term "therapeuticly effective amount" means any amount that, compared to a corresponding subject who has not received that amount, improves the treatment, healing, prevention, or improvement of a disease, disorder, or side effect, slows the progression of the disease or disorder, condition, or symptom, or reduces the rate of its progression. Within its scope, the term also includes amounts that effectively enhance normal physiological function. Detailed Implementation

[0083] 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.

[0084] Materials and general instructions: Unless otherwise specified, reactions were carried out in dried glassware with rubber diaphragms under an inert atmosphere (N2) and stirred with a Teflon-coated magnetic stir bar. Materials and chemicals were purchased from Sigma-Aldrich Inc., Combi-Blocks Inc., Alfa Aesar, and other commercial suppliers. Liquid reagents and solvents were transferred via syringe using standard Schlenk techniques. Solvents DMSO, methanol, and acetonitrile were commercial grade and used directly without further drying. Tetrahydrofuran (THF) and diethyl ether (Et2O) from solvent purification systems were used. All other reagents were used as is unless otherwise specified. Thin-layer chromatography (TLC) was performed using pre-coated silica gel 60 F-254 plates (0.25 mm) and analyzed by... Visualization was achieved through 232nm UV irradiation, CAM staining, KMnO4 staining, and other staining methods. Silica gel with a particle size of 230-400 mesh was used for rapid chromatography, employing a CombiFlash and SiO2 column for rapid chromatography (FC). 1 H and 13 The C10 NMR spectra were recorded on a 400 MHz and a 500 MHz spectrometer, respectively. 13 C operates at frequencies of 101 and 126 MHz. 11 B operates at frequencies of 128 and 160 MHz. 19 The F operates at frequencies of 376 and 471 MHz. Unless otherwise specified, 1 H and 13 All C NMR spectra were referenced to TMS as an internal standard for the deuterated solvent. The signal relative to the residual solvent (CDCl3) was... 1 The δ value of H NMR is 7.26. 13 The C NMR signal (δ=77.16) and the (DMSO-d6) signal ( 1 The δ value of the H NMR is 2.50 (ppm). 13 The C NMR value is δ = 39.5 (sepet), and the chemical shift (δ) is expressed in ppm. 1 The data from the 1H NMR spectra are reported as follows: chemical shifts (multiplicity, coupling constant, and number of hydrogen atoms). Abbreviations are as follows: s (singleton), d (doublet), t (triplet), q (quartet), p (pentetet), m (multiplet), brs (broad singlet). High-resolution mass spectrometry (HRMS) using acetonitrile or methanol as solvents.

[0085] Synthesis of modified N,N-dimethyltryptamine [2a and 2b]:

[0086] Products 1a and 1b were prepared according to a procedure reported in the literature, with slight modifications. In a 250 mL three-necked flask, indole (10.5 mmol, 1 equivalent) was dissolved in 20 mL of Et₂O and cooled to 0 °C in an ice bath. C. Then, add dropwise a solution of oxalyl chloride (2.75 ml, 21 mmol, 2 equivalents) in 5.0 ml of Et₂O over 30 minutes and maintain at room temperature for another 2 hours. Then at 0 At temperature C, a solution of diisopropylamine (12.5 ml, 90 mmol) in Et₂O₃ (50 ml) was added to the reaction mixture using a dropping funnel. A white solid began to form at this point. The mixture was then heated to 0°C. Stir for another 2 hours at C. Filter the precipitate, wash with water (20 mL) and ether (20 mL x 2), collect and dry under high vacuum to obtain the desired white solid product.

[0087]

[0088] A solution of 1a / 1b (2 mmol, 1 equivalent) in 10 mL of THF was added in portions to a well-stirred suspension of LiAlH4 (0.30 g, 8 mmol) in 15 mL of THF, and the mixture was refluxed in an oil bath for 5 hours. The mixture was then cooled in an external ice bath, and 2 M NaOH aqueous solution was added until a clear solution was observed. The solids were removed by filtration, the filtrate was dried over anhydrous MgSO4, filtered, and concentrated under vacuum (via an evaporator) to give the desired products 2a and 2b.

[0089]

[0090] N-(2-(5-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropyl-2-amine (2a): Prepared according to general procedure A, yielding an orange solid product 2a (50% yield). 1 H NMR (400 MHZ, DMSO-d6) δ: 11.01 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H, 7.22 (d), J=2.4 Hz, 1H, 7.15 (dd, J=8.6, 2.0 Hz, 1Hs), 3.12-3.04 (m, 2H), 2.75-2.62 (m, 4H), 0.99 (d, J / 6.5 Hz, 12H). 13 C NMR (101 MHz, DMSO-d6) delta: 134.85, 129.24, 124.37, 123.19, 120.53, 113.41, 110.81, 60.78, 46.06, 29.22, 20.59.

[0091]

[0092] N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N-isopropylpropyl-2-amine (2b): prepared according to general procedure A, yielding a brown solid product 2b (66% yield). 1 H NMR (400 MHZ, DMSO-d6) δ: 10.87 (s, 1H), 7.31 (dd, J=8.8, 4.6 Hz, 1H); 7.22 (d, J=2.4 Hz, 1H, 7.19-7.15 (m, 1H), 6.93-6.83 (m, 1H), 3.04 (hept, J=6.6 Hz, 2H), 2.72-2.58 (m, 4H), 0.98 (d, J=6.5 Hz, 12H). 13 C NMR (101 MHz, DMSO-d6) δ: 132.83, 127.58, 124.68, 124.63, 113.39, 112.21, 108.91, 108.64 , 102.86, 102.64, 102.59, 48.07, 48.02, 45.94, 45.89, 27.48, 27.43, 20.76, 20.71. 19 F NMR (376 MHz, DMSO-d6) delta: -125.8.

[0093] General procedures and characteristics of double amination (4):

[0094] Under a nitrogen atmosphere, PPh3 (0.80 mmol; 1.1 equivalents), MeCN (2 mL), and TfOH (0.87 mmol; 1.2 equivalents) were sequentially added to a dried screw-top container equipped with a magnetic stir bar and a diaphragm. The reaction mixture was stirred for 3 minutes, and then 1,3,5-trimethoxybenzene (0.73 mmol; 1.0 equivalents) and terephthalaldehyde (0.73 mol; 1.0 equivalents) were added at room temperature. The reaction mixture was transferred to a 45°C oil bath and stirred for 24 hours. The solvent was then removed under vacuum using an evaporator. A minimum amount of ethanol was added to the crude mixture, and precipitation was performed with diethyl ether / pentane (10 mL). The solid was collected by filtration and washed with cold diethyl ether / heptane (3 x 4 mL) to obtain pure phosphonium salt (NN-00-146) for the next step.

[0095]

[0096] At room temperature, without particular attention to an inert atmosphere, phosphonium salt (NN-00-146) (0.16 mmol; 1 equivalent), DMSO (3 mL), and benzylamine (0.64 mmol; 4.0 equivalent) were sequentially added to a dried screw-cap jar equipped with a magnetic stir bar. The reaction mixture was transferred to a 60°C oil bath and stirred for 24 hours. The reaction mixture was then diluted with saturated sodium chloride (5 mL), and the organic mixture was extracted into EtOAc (10 mL). The organic phase was washed with water, dried over MgSO4, evaporated under reduced pressure (via an evaporator), and the crude mixture was purified by silica gel column chromatography to give pure product 4 (knb-03-81).

[0097] 1,1'-(1,4-phenylene)bis(N-benzyl-1-(2,4,6-trimethoxyphenyl)methylamine) (4): Prepared according to general procedure B, product 4 was isolated as a white solid (yield 78%). f =0.60 (10% MeOH in CH2Cl2). 1 ¹H NMR (400 CDCl₃) δ: 7.27–7.23 (m, 8H) (two diastereomers), 7.21–7.16 (m, 16H) (two diastereomers), 7.14–7.08 (m, 4H) (two diastereomers), 6.04 (s, 8H) (two diastereomers), 5.33 (s, 4H) (two diastereomers), 3.70 (s, 12H) (two diastereomers), 3.68–3.60 (m, 8H) (two diastereomers), 3.59 (s, 24H) (two diastereomers), 3.03 (brs, 4H) (two diastereomers). 13 C NMR (101 MHz, CDCl3) δ: 160.15 (two diastereomers), 159.24 (one diastereomer), 159.23 (another diastereomer), 141.48 (two diastereomers), 140.76 (two diastereomers), 128.50 (two diastereomers), 128.13 (two diastereomers), 126.67 (two diastereomers), 126.38 (two diastereomers), 111.93 (one diastereomer), 111.87 (another diastereomer), 91.16 (two diastereomers), 55.71 (two diastereomers), 55.69 (two diastereomers), 55.31 (two diastereomers), 51.80 (two diastereomers).

[0098] While certain features of the invention have been described and illustrated herein, many modifications, substitutions, alterations, and equivalents will be readily apparent to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all modifications and alterations consistent with the true spirit of the invention.

Claims

1. A compound having the general formula (I): （I） in, R1 and R2 are each selected from H, straight-chain or branched C1-C5 alkyl, straight-chain or branched C2-C5 alkenyl, straight-chain or branched C2-C5 ynyl, and part (II). (II) R13-R22 are each selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, and chemical protecting groups; R3-R6 are H, or R3 and R4 together and / or R5 and R6 together form =O; R7 to R12 are each selected from empty, H, or halogen; X is selected from C or N; where R9 is empty when X is N. The condition is that at least one of R1 and R2 is different from H; The condition is that when R3 and R4 together, and R5 and R6 together, form = 0, X is N, R9 is empty, or at least one of R7-R12 is different from H; and The condition is that when R1 and R2 are each straight-chain or branched C1-C3 alkyl groups, at least one of R7-R12 is different from H.

2. The compound according to claim 1, wherein R1 and R2 are each straight-chain or branched C1-C5 alkyl groups.

3. The compound according to claim 1, wherein at least one of R7-R12 is a halogen.

4. The compound according to any one of the preceding claims, wherein R11 is a halogen.

5. The compound according to claim 1, wherein R3 and R4 together and R5 and R6 together form =O; X is N, and R9 is empty.

6. The compound according to claim 1, wherein R3 and R4 together and R5 and R6 together form =O; R11 is a halogen.

7. The compound according to claim 1, wherein R1 and R2 are each straight-chain or branched C1-C5 alkyl groups; R3-R6 are H; and R11 is a halogen.

8. The compound according to claim 1, wherein R1, R3-R12 are H, and R2 is part (II). (II) Each of R13-R22 is selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, straight-chain or branched C2-C8 alkenyl, and straight-chain or branched C2-C8 alkynyl.

9. The compound according to claim 1, wherein R1, R3-R12 are H, and R2 is part (II). (II) R13-R22 are each selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, provided that at least one of R13-R22 is different from H.

10. The compound according to any one of claims 1 to 9, wherein the compound is selected from: 。 11. A compound having the general formula (III): (III) R23 and R24 are each phenyl, or straight-chain or branched C1-C5 alkyl groups substituted with at least one group selected from phenyl, halophenyl, indole, or haloindole; R25-R34 are each selected from H, or straight-chain or branched C1-C5 alkoxy groups.

12. The compound according to claim 11, wherein R25, R27, R29, R30, R32, and R34 are each straight-chain or branched C1-C5 alkoxy groups.

13. The compound according to claim 11 or 12, wherein R23 and R24 are each phenyl.

14. The compound according to claim 11 or 12, wherein R23 and R24 are each straight-chain or branched C1-C5 alkyl groups substituted with at least one phenyl group.

15. The compound according to claim 11 or 12, wherein R23 and R24 are each straight-chain or branched C1-C5 alkyl groups substituted with at least one halophenyl group.

16. The compound according to claim 11 or 12, wherein R23 and R24 are each straight-chain or branched C1-C5 alkyl groups substituted with at least one indole group.

17. The compound according to any one of claims 11-16, wherein the compound is selected from: ， ， ， 。 18. A composition comprising at least one compound according to any one of claims 1 to 17.

19. The composition of claim 18, for treating diseases, symptoms or conditions associated with depression, including resistant depression.

20. The composition of claim 18, for treating stress-related illnesses, symptoms, or conditions, including PTSD.

21. The composition according to claim 18, for treating diseases, symptoms or conditions related to cerebral ischemia.

22. A method for treating a disease, symptom, or condition associated with depression, including resistant depression; said method comprising administering to a subject in need at least one compound according to any one of claims 1 to 17.

23. A method for treating stress-related illnesses, symptoms, or conditions, including post-traumatic stress disorder; said method comprising administering to a subject in need at least one compound according to any one of claims 1 to 17.

24. A method for treating a disease, symptom, or condition associated with cerebral ischemia; said method comprising administering to a subject in need at least one compound according to any one of claims 1 to 17.

25. A compound for treating a disease, symptom, or condition selected from depression, including resistant depression; stress, including post-traumatic stress disorder (PTSD); cerebral ischemia; and any combination thereof, wherein the compound has the general formula (I): （I） R1 and R2 are each selected from H, straight-chain or branched C1-C5 alkyl, straight-chain or branched C2-C5 alkenyl, straight-chain or branched C2-C5 alkynyl, -C(=O)CR23R24R25, wherein R23-R25 are selected from H or halogens; and part of formula (II) (II) R13-R22 are each selected from H, halogen, straight-chain or branched C1-C8 alkoxy, straight-chain or branched C1-C8 alkyl, chemical protecting group; or R1 and R2 together with the nitrogen atom to which they are attached form a 5-6 membered heterocycle; R3-R6 are H, or R3 and R4 together form =O and / or R5 and R6 together form =O; R7-R12 are each selected from H and halogens.

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