Psychedelic compounds, methods of their preparation and uses thereof

Abstract

The invention provides synthetic compounds having psychedelic bioactivity, compositions comprising them, methods of their preparation and uses thereof in the treatment of diseases, symptoms and disorders.

Description

PSYCHEDELIC COMPOUNDS, METHODS OF THEIR PREPARATION ANDUSES THEREOFBACKGROUND OF THE INVENTION

[0001] N,N-Dimethyltryptamine (DMT orN,N-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including humans, and which is both a derivative and a structural analog of tryptamine. DMT is used as a psychedelic drug and prepared by various cultures for ritual purposes as an entheogen.

[0002] DMT has a rapid onset, intense effects, and a relatively short duration of action. DMT can be inhaled, ingested, or injected and its effects depend on the dose, as well as the mode of administration. When inhaled or injected, the effects last a short period of time: about five to 15 minutes. Effects can last three hours or more. DMT can produce vivid "projections" of mystical experiences involving euphoria and dynamic pseudohallucinations of geometric forms.

[0003] DMT is a functional analog and structural analog of other psychedelic tryptamines such as O-acetylpsilocin (4-AcO-DMT), psilocybin (4-PO-DMT), psilocin (4-HO-DMT), O-methylbufotenin (5-MeO-DMT), and bufotenin (5-HO-DMT). Parts of the structure of DMT occur within some important biomolecules like serotonin and melatonin, making them structural analogs of DMT.

[0004] Dimethyltryptamine (DMT), an endogenous ligand of sigma- 1 receptors (Sig- 1 Rs), acts against systemic hypoxia. Research demonstrates DMT reduces the number of apoptotic and ferroptotic cells in mammalian forebrain and supports astrocyte survival in an ischemic environment. According to these data, DMT may be considered as adjuvant pharmacological therapy in the management of acute cerebral ischemia, Parkinson’ s disease,Major Depressive Disorder and as a psychoplastogen, capable of promoting rapid and sustained neuroplasticity that may have wide-ranging therapeutic benefit.SUMMARY OF THE INVENTION

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

[0006] Wherein R1 and R2 are each selected from H, straight or branched Cl - C5 alkyl, straight or branched C21 - C5 alkenyl, straight or branched C2 - C5 alkynyl, and a moiety of formula (II)

[0007] wherein each of R13 - R22 are each selected from H, halogen (i.e. F, Cl, Br, I), straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl, a chemical protecting group;

[0008] R3 - R6 are H or each of R3 and R4 together and / or R5 and R6 together are =0;

[0009] R7 - R12 are each selected from null, H or halogen;

[0010] X is selected from C or N; wherein when X is N then R9 is null;

[0011] provided that at least one of R1 and R2 is different than H;

[0012] provided that when both R3 and R4 together and R5 and R6 together are =0 than X is N, R9 is null or at least one of R7 - R12 is different than H; and

[0013] provided that when R1 and R2 are each straight or branched Cl - C3 alkyl then at least one of R7 - R12 is different than H.

[0014] In some embodiments, R1 and R2 are each a straight or branched Cl - C5 alkyl, provided that when R1 and R2 are each straight or branched Cl - C3 alkyl then at least one of R7 - R12 is different than H.

[0015] In some embodiments, at least one of R7 - R12 is a halogen. In other embodiments, R11 is halogen. In some embodiments R11 is F. In other embodiments R11 is Br.

[0016] In some embodiments, R3 and R4 together and R5 and R6 together are =0; X is N, R9 is null.

[0017] In some embodiments, R3 and R4 together and R5 and R6 together are =0; R11 is halogen.

[0018] In some embodiments, R1 and R2 are each a straight or branched Cl - C5 alkyl; R3 - R6 are H; and R11 is halogen.

[0019] In some embodiments, Rl, R3 - R12 are H and R2 is a moiety of formula (II)

[0020] wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl, straight or branched C2 - C8 alkenyl, straight or branched C2 - C8 alkynyl.

[0021] In some embodiments, Rl, R3 - R12 are H and R2 is a moiety of formula (II)

[0022] wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl provided that at least one of R13 - R22 is different than H.

[0023] In some embodiments, a compound of the invention is selected from:9

[0024] The invention further provides a compound for use in the treatment of disease, symptom or condition selected from depression, including resistant depression, stress including PTSD (post-traumatic stress disorder), cerebral ischemia and any combinations thereof, wherein said compound having the general formula (I):

[0025] Wherein Rl and R2 are each selected from H, straight or branched Cl - C5 alkyl, straight or branched C21 - C5 alkenyl, straight or branched C2 - C5 alkynyl, -C(=O)CR23R24R25 wherein R23 - R25 is selected from H or halogen; and a moiety of formula (II)

[0026] wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl, a chemical protecting group; or R1 and R2 together with the nitrogen atom they are connected to form a 5 - 6 membered heterocyclic ring;

[0027] R3 - R6 are H or R3 and R4 together is =0 and / or R5 and R6 together is =0;

[0028] R7 - R12 are each selected from H, halogen.

[0029] In some embodiments, R1 and R2 are each a straight or branched Cl - C5 alkyl.

[0030] In some embodiments, R3 - R6 are H.

[0031] In some embodiments, at least one of R7 - R12 is a halogen. In some embodiments, R11 is halogen. In some embodiments halogen is selected from F, Cl, Br and I. In other embodiments halogen is F. In other embodiments halogen is Br.

[0032] In some embodiments, R1 and R2 are each a straight or branched Cl - C5 alkyl; R3 - R6 are H; and R11 is halogen.

[0033] In some embodiments, Rl, R3 - R12 are H and R2 is a moiety of formula (II)

[0034] wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl, straight or branched C2 - C8 alkenyl, straight or branched C2 - C8 alkynyl.

[0035] In some embodiments, Rl, R3 - R12 are H and R2 is a moiety of formula (II)

[0036] wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl provided that at least one of R13 - R22 is different than H.

[0037] In some embodiments, R3 - R12 are H; and Rl and R2 together with the nitrogen atom they are connected to form a 5 - 6 membered heterocyclic ring.

[0038] In some embodiments, R7 - R12 are H or halogen; R3 and R4 are =0 and R5 and R6 are =0; Rl and R2 are each straight or branched Cl- C5 alkyl or together with the nitrogen atom they are connected to form a 5 - 6 membered heterocyclic ring.

[0039] In some embodiments, Rl, R3 -R12 are H or halogen; R2 is -C(=O)-C1-C5 alkyl optionally substituted with at least one halogen.

[0040] In some embodiments, a compound of the invention is selected from:

[0041]

[0042] In another aspect the invention provides a compound having the general formula(Ill):

[0043] Wherein R23 and R24 are each a phenyl, a straight or branched Cl - C5 alkyl substituted with at least one group selected from a phenyl, a halogenated phenyl, an indolyl, a halogenated indolyl; and R25 - R34 are each selected from H, straight or branched Cl - C5 alkoxy.

[0044] In some embodiments, R25, R27, R29, R30, R32 R34 are each a straight or branched Cl - C5 alkoxy.

[0045] In some embodiments, R23 and R24 are each a phenyl.

[0046] In some embodiments, R23 and R24 are each straight or branched Cl - C5 alkyl substituted with at least one phenyl.

[0047] In some embodiments, R23 and R24 are each straight or branched Cl - C5 alkyl substituted with at least one halogenated phenyl (i.e. a phenyl ring substituted by at least one halogen).

[0048] In some embodiments, R23 and R24 are each straight or branched Cl - C5 alkyl substituted with at least one indolyl.

[0049] In some embodiments, R23 and R24 are each straight or branched Cl - C5 alkyl substituted with at least one halogenated indolyl (i.e. a indolyl ring substituted by at least one halogen).

[0050] In some embodiments, a compound of the invention is selected from:

[0051] The invention further provides a composition comprising at least one compound as disclosed herein above.

[0052] The invention further provides a composition as disclosed herein above, for use in the treatment of disease, symptom or condition associated with depression, including resistant depression.

[0053] The invention further provides a composition as disclosed herein above, for use in the treatment of disease, symptom or condition associated with stress including PTSD.

[0054] The invention further provides a composition as disclosed herein above, for use in the treatment of disease, symptom or condition associated with cerebral ischemia.

[0055] The invention provides a method of treating a disease, symptom or condition associated with depression, including resistant depression; said method comprising administering to a subject in need thereof at least one compound as disclosed herein above and below.

[0056] The invention provides a method of treating a disease, symptom or condition associated with stress including PTSD; said method comprising administering to a subject in need thereof at least one compound as disclosed herein above and below.

[0057] The invention provides a method of treating a disease, symptom or condition associated with cerebral ischemia; said method comprising administering to a subj ect in need thereof at least one compound as disclosed herein above and below.

[0058] When relating to “resistant depression" it should be understood to relate to treatment-resistant depression (TRD) which is a major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration.

[0059] When referring to “cerebral ischemia" it should be understood to relate to brain ischemia which is a condition in which there is insufficient blood flow to the brain to meet metabolic demand. This condition leads to poor oxygen supply or cerebral hypoxia and thus leads to the death of brain tissue or cerebral infarction / ischemic stroke. Cerebral ischemia is a sub-type of stroke along with subarachnoid hemorrhage and intracerebral hemorrhage.

[0060] When referring to “ post-traumatic stress disorder (PTSD)” it should be understood to relate to a mental and behavioral disorder that develops from experiencing a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a person's life or well-being. Symptoms of PTSD may include disturbing thoughts, feelings, or dreams related to the events, mental or physical distress to trauma-related cues, attempts to avoid trauma-related cues, alterations in the way a person thinks and feels, and an increase in the fight-or-flight response. These symptoms last for more than a month after the event. A person with PTSD is at a higher risk of suicide and intentional self-harm.

[0061] The term “ straight or branched Ci - Cs alkyl” should be understood to encompass any straight or branched saturated hydrocarbon chain having 1, 2, 3, 4, 5 carbon atoms, wherein only sigma bonds connect between the atoms of the chain, and wherein one hydrogen atom is removed from any carbon atom of the chain. The term “straight or branched Ci - Cs alkyl” should be understood to encompass any straight or branched saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8 carbon atoms, wherein only sigma bonds connect between the atoms of the chain, and wherein one hydrogen atom is removed from any carbon atom of the chain.

[0062] The term “straight or branched C2 - C5 alkenyl" should be understood to encompass any straight or branched unsaturated hydrocarbon chain having 2, 3, 4, 5 carbon atoms, wherein at least one double bond connects two carbon atoms at any point of the hydrocarbon chain, and wherein one hydrogen atom is removed from any carbon atom of the chain. The term “straight or branched C2 - Cs alkenyl” should be understood to encompass any straight or branched unsaturated hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8 carbon atoms, wherein at least one double bond connects two carbon atoms at any point ofthe hydrocarbon chain, and wherein one hydrogen atom is removed from any carbon atom of the chain.

[0063] The term “straight or branched C2 - C5 alkynyF should be understood to encompass any straight or branched unsaturated hydrocarbon chain having 2, 3, 4, 5 carbon atoms, wherein at least one triple bond connects two carbon atoms at any point of the hydrocarbon chain, and wherein one hydrogen atom is removed from any carbon atom of the chain. The term “straight or branched C2 - Cs alkynyF should be understood to encompass any straight or branched unsaturated hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8 carbon atoms, wherein at least one triple bond connects two carbon atoms at any point of the hydrocarbon chain, and wherein one hydrogen atom is removed from any carbon atom of the chain.

[0064] As used herein the term “Ci-Cs alkoxyF refers to a functional group -OR wherein R is a Ci-Cs alkyl group.

[0065] As used herein, the term "phenyl" refers to an aromatic ring functional group - CeHs. As used herein, the term "halogenated phenyl" refers to an aromatic ring functional group -C6H4X wherein X is a halogen group being substituted at any position on the phenyl ring.

[0066] As used herein, the term "indolyl" refers to an aromatic heterocyclic functional group -CxHxN (a functional group of indoline being connected via any position either from the aromatic, saturated rings or the nitrogen atom thereof). As used herein, the term "halogenated indolyl " refers to an aromatic ring functional group -CxH?NX wherein X is a halogen group being substituted at any position on the indolyl ring.

[0067] The term “5 - 6 membered heterocyclic ring" refers to a ring system (that may be aromatic, saturated or non-saturated ring system) having 1 or 2 rings (fused or connected)wherein at least one of the carbon atoms of the ring system is replaced by a heteroatom (N, O, P, S) and wherein two hydrogen atoms were removed, thus having two open valencies for bonding. The total number of members in said ring is 5 or 6.

[0068] The present invention relates to pharmaceutical compositions comprising a compound of the subject invention in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The auxiliaries must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

[0069] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration or administration via an implant. The compositions may be prepared by any method well- known in the art of pharmacy.

[0070] Such methods include the step of bringing in association compounds used in the invention or combinations thereof with any auxiliary agent. The auxiliary agent(s), also named accessory ingredient(s), include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, anti-oxidants, and wetting agents.

[0071] Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragees, or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a bolus or paste. The compositions can further be processed into a suppository or enema for rectal administration.

[0072] The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material, including instructions for the use of the composition for a use as hereinbefore described.

[0073] For parenteral administration, suitable compositions include aqueous and nonaqueous sterile injection. The compositions may be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example, water, prior to use. For transdermal administration, e.g., gels, patches, or sprays can be contemplated. Compositions or formulations suitable for pulmonary administration e.g., by nasal inhalation, include fine dust or mists, which may be generated by means of metered dose pressurized aerosols, nebulizers or insufflators.

[0074] The exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.

[0075] As used herein, the term "effective amount" means the amount of a drug or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, slowing the progression of, or a decrease in the rate of advancement of a disease or disorder, condition or symptom. The term also includes within its scope amounts effective to enhance normal physiological function.DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0076] 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.

[0077] Materials and General Remarks:

[0078] Unless otherwise stated, reactions were performed in oven-dried glassware fitted with rubber septa under inert atmosphere (N2) and were stirred with teflon-coated magnetic stirring bars. 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 used as commercial grade and used as received with no further drying. Tetrahydrofuran (THF) and diethyl ether (Et2O) were used from a solvent purification system. All other reagents were used as received unless otherwise noted. Thin layer chromatography (TLC) was performed using silica gel 60 F-254 precoated plates (0.25 mm) and visualized by UV irradiation ^=232 nm, CAM stain, KMnCU stain, and other stains. Silica gel of particle size 230-400 mesh was used for flash chromatography, Flash chromatography (FC) was performed using CombiFlash, with SiCb columns. ’H and13C NMR spectra were recorded on 400, 500 MHz spectrometers with13C operating frequencies of 101, 126 MHz,nB operating frequencies of 128, 160 MHz,19F operating frequencies of 376, 471 MHz respectively. ’H and13C NMR spectra were referenced to TMS as an internal standard with a deuterated solvent unless otherwise stated. Chemical shifts (6) are reported in ppm relative to the residual solvents (CDCL) signal (6 = 7.26 for ’H NMR and 6 = 77.16for13C NMR) and (DMSO-tL) signal (6 = 2.50 (ppm) forXH NMR and 6 = 39.5 (septet) for13C NMR). Data for1H NMR spectra are reported as follows: chemical shift (multiplicity, coupling constants, and number of hydrogen). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentate), m (multiplet), brs (broad singlet). High- Resolution Mass Spectrometry (HRMS) using acetonitrile or methanol as solvent.

[0079] Synthesis of Modified N,N-Dim ethyltryptamine [2a and 2b]:

[0080] Products la and lb were prepared according to a literature reported procedure with slight modifications. In a three necked 250 ml flask, indole (10.5 mmol, 1 equiv) was added and dissolved in 20 mL Et2O and cooled to 0 °C in an ice bath. Then a solution of oxalyl chloride (2.75 ml, 21 mmol, 2 equiv) in Et2O (5.0 ml) was added in a dropwise addition for 30 min, and the solution was kept for 2 more hours at rt. Then a solution of diisopropylamine (12.5 ml, 90 mmol) in Et2O (50 ml) was added to the reaction mixture through a dropping funnel at 0 °C. A white solid starts to form at this point, the mixture was stirred for another 2 hours at 0 °C. The precipitate was filtered and washed with water (20 mL) and diethyl ether (20 mL x 2), collected and further dried in high vacuum to give the desired products as a white solid.

[0081] To a well-stirred suspension of LiAlH4 (0.30 g, 8 mmol) in THF (15 mL), la / lb (2 mmol, 1 equiv) in THF (10 mL) solution was added in small portions, and the mixture was refluxed for 5 h in an oil bath. After that, the mixture was cooled in an external ice bath, and a 2 M aqueous solution of NaOH was added until a clear solution was observed. The participated solids were removed via filtration, and the filtrate was dried over anhydrous MgSCU, filtered and concentrated under vacuum (by evaporator) to give the desired products 2a and 2b.NN-00-139

[0082] / V-(2-(5-bromo- / H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine (2a) :Prepared according to general procedure A, product 2a was isolated in (50% yield) as an orange solid. 'H NMR (400 MHZ, DMSO-tL) 8: 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, 1H), 3.12 - 3.04 (m, 2H), 2.75 - 2.62 (m, 4H), 0.99 (d, J= 6.5 Hz, 12H).13C NMR (101 MHz, DMSO-tL) 6:134.85, 129.24, 124.37, 123.19, 120.53, 113.41, 110.81, 60.78, 46.06, 29.22, 20.59.NN -00-143

[0083] N-(2-(5-fluoro-lH-indol-3-yl)ethyl)-N-isopropylpropan-2-amine (2b)Prepared according to general procedure A, product 2b was isolated in (66% yield) as abrown solid. 'H NMR (400 MHZ, DMSO-tL) 8: 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).13C NMR (101 MHz, DMSO-tL) 6:132.83, 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, 20.71.19F NMR (376 MHz, DMSO-tL) 6:-125.8.

[0084] General Procedure and Characterization for Double Amination (4):

[0085] An oven dried screw capped vail equipped with magnetic stir barr and septum was sequentially charged with PPhs (0.80 mmol; 1.1 equiv), MeCN (2 mL) and TfOH (0.87 mmol; 1.2 equiv.) under N2 atmosphere. The reaction mixture was stirred for 3 minutes, then charged with 1,3,5-trimethoxybenzene (0.73 mmol; 1.0 equiv) and terephthal aldehyde (0.73 mmol; 1.0 equiv) at room temperature. The reaction mixture transferred to 45 °C oil bath and stirring was continued for 24 hours. Then the solvent was removed under vacuum by evaporator. To the crude mixture was added minimum amount of ethanol and precipitated with diethyl ether / pentane (10 mL) and solids were collected by filtration and washed with cold diethyl ether / pentane (3 X 4 mL) to obtain pure phosphonium salt (NN-00-146) that was used to the next step.

[0086] An oven dried screw capped vail equipped with magnetic stir barr was sequentially charged with phosphonium salt (NN-00-146) (0.16 mmol; 1 equiv), DMSO (3 mL) and benzyl amine (0.64 mmol; 4.0 equiv) at room temperature without special care of inert atmosphere. The reaction mixture was transferred to 60 °C oil bath and stirred for 24 h. Then the reaction mixture was diluted with saturated sodium chloride (5 mL) and organic mixture was extracted into EtO Ac (10 mL). The organic phase was washed with water, dried over MgSO4, evaporated under reduced pressure (by evaporator) and the crude mixture was purified by column chromatography on silica to obtain the pure product 4 (knb-03-81).

[0087] 1,1 '-(l,4-Phnylene)bis(N- >&i 7^\-l-(2,4,6-triniethoxyphenyl)methanannne)(4): Prepared according to general procedure B product 4 was isolated in (78% yield) as a white solid. R / = 0.60 (10 % MeOH in CH2C12). 'H NMR (400 CDCh) 8: 7.27 - 7.23 (m, 8H) (for both diastereomers), 7.21 - 7.16 (m, 16H) (for both diastereomers), 7.14 - 7.08 (m, 4H) (for both diastereomers), 6.04 (s, 8H) (for both diastereomers), 5.33 (s, 4H) (for both diastereomers), 3.70 (s, 12H) (for both diastereomers), 3.68 - 3.60 (m, 8H) (for both diastereomers), 3.59 (s, 24H) (for both diastereomers), 3.03 (brs, 4H) (for both diastereomers).13C NMR (101 MHz, CDCh) 6: 160.15 (for both diastereomers), 159.24 (for one diastereomer), 159.23 (for another diastereomer), 141.48 (for both diastereomers), 140.76 (for both diastereomers), 128.50 (for both diastereomers), 128.13 (for both diastereomers), 126.67 (for both diastereomers), 126.38 (for both diastereomers), 111.93 (for one diastereomer), 111.87 (for another diastereomer), 91.16 (for both diastereomers),55.71 (for both diastereomers), 55.69 (for both diastereomers), 55.31 (for both diastereomers), 51.80 (for both diastereomers).

[0088] 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 are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

CLAIMS[00089] What is claimed is:

1. A compound having the general formula (I):WhereinRl and R2 are each selected from H, straight or branched Cl - C5 alkyl, straight or branched C21 - C5 alkenyl, straight or branched C2 - C5 alkynyl, and a moiety of formula (II)wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl, a chemical protecting group;R3 - R6 are H or each of R3 and R4 together and / or R5 and R6 together areR7 - R12 are each selected from null, H or halogen;X is selected from C or N; wherein when X is N then R9 is null; provided that at least one of R1 and R2 is different than H; provided that when both R3 and R4 together and R5 and R6 together are =0 than X is N, R9 is null or at least one of R7 - R12 is different than H; and provided that when R1 and R2 are each straight or branched Cl - C3 alkyl then at least one of R7 - R12 is different than H.

2. A compound according to claim 1, wherein R1 and R2 are each a straight or branched Cl - C5 alkyl.

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

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

5. A compound according to claim 1, wherein R3 and R4 together and R5 and R6 together are =0; X is N, R9 is null.

6. A compound according to claim 1, wherein R3 and R4 together and R5 and R6 together are =0; R11 is halogen.

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

8. A compound according to claim 1, wherein Rl, R3 - R12 are H and R2 is a moiety of formula (II)wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl, straight or branched C2 - C8 alkenyl, straight or branched C2 - C8 alkynyl.

9. A compound according to claim 1, wherein Rl, R3 - R12 are H and R2 is a moiety of formula (II)wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl provided that at least one of R13 - R22 is different than H.

10. A compound according to any one of claims 1 to 9, selected from:

11. A compound having the general formula (III):U)Wherein R23 and R24 are each a phenyl, a straight or branched Cl - C5 alkyl substituted with at least one group selected from a phenyl, a halogenated phenyl, an indolyl, a halogenated indolyl;R25 - R34 are each selected from H, straight or branched Cl - C5 alkoxy.

12. A compound according to claim 11, wherein R25, R27, R29, R30, R32 R34 are each a straight or branched Cl - C5 alkoxy.

13. A compound according to claims 11 or 12, wherein R23 and R24 are each a phenyl.

14. A compound according to claims 11 or 12, wherein R23 and R24 are each straight or branched Cl - C5 alkyl substituted with at least one phenyl.

15. A compound according to claims 11 or 12, wherein R23 and R24 are each straight or branched Cl - C5 alkyl substituted with at least one halogenated phenyl.

16. A compound according to claims 11 or 12, wherein R23 and R24 are each straight or branched Cl - C5 alkyl substituted with at least one indolyl.

17. A compound according to any one of claims 11 to 16, being selected from:

18. A composition comprising at least one compound according to any one of claims 1 to 17.

19. A composition according to claim 18, for use in the treatment of disease, symptom or condition associated with depression, including resistant depression.

20. A composition according to claim 18, for use in the treatment of disease, symptom or condition associated with stress including PTSD.

21. A composition according to claim 18, for use in the treatment of disease, symptom or condition associated with cerebral ischemia.

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

23. A method of treating a disease, symptom or condition associated with stress including PTSD; said method comprising administering to a subject in need thereof at least one compound according to any one of claims 1 to 17.

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

25. A compound for use in the treatment of disease, symptom or condition selected from depression, including resistant depression, stress including PTSD, cerebral ischemia and any combinations thereof, wherein said compound having the general formula (I):Wherein Rl and R2 are each selected from H, straight or branched Cl - C5 alkyl, straight or branched C21 - C5 alkenyl, straight or branched C2 - C5 alkynyl, -C(=O)CR23R24R25 wherein R23 -R25 is selected from H or halogen; and a moiety of formula (II)wherein each of R13 - R22 are each selected from H, halogen, straight or branched Cl - C8 alkoxy, straight or branched Cl - C8 alkyl, a chemical protecting group; or R1 and R2 together with the nitrogen atom they are connected to form a 5 - 6 membered heterocyclic ring;R3 - R6 are H or R3 and R4 together is =0 and / or R5 and R6 together is =0; R7 - R12 are each selected from H, halogen.

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