Antagonists of n-methyl-d-aspartate receptors and use thereof

Abstract

The invention provides compounds of general formula I wherein „-----„ represents a single or double bond. R1 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein in the alkyl or cycloalkyl group, one CH2 group can be replaced by an oxygen atom; R2 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, wherein in the alkyl or cycloalkyl group, one CH2 group can be replaced by an oxygen atom; or R1 and R2 together with the nitrogen atom to which they are bound form a 5- to 6-membered heterocyclic aliphatic ring which can comprise one additional oxygen atom and which may be optionally substituted with C1-C4 alkyl. The compounds are suitable for treatment of neurodegenerative diseases.

Description

[0001]Antagonists of N-methyl-D-aspartate receptors and use thereof Field of Art The present invention relates to new compounds, antagonists of N-methyl-D-aspartate (NMDA) receptors, method of preparation thereof and therapeutic use thereof. Background Art N-methyl-D-aspartate receptors (NMDAR) play a key role in excitatory transmission, synapse development, and synaptic plasticity in the mammalian central nervous system (CNS). The most common conventional NMDARs found in the adult forebrain are heterodimeric GluN1 / GluN2A and GluN1 / GluN2B receptors. These receptors have an ion channel that opens when activated by specific agonists, but under physiological conditions, at resting membrane potentials (e.g., -60 mV), can be blocked by endogenous Mg2+or pharmacological drugs from the group of NMDAR blockers. Clinically, a large number of psychiatric and neurological disorders, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD) or epilepsy, are associated with altered NMDAR function. Other diseases are then caused by the presence of pathogenic mutations in the ion channel of this receptor, including encephalopathy, mental retardation or disorders of sensory functions. Direct pharmacological modulation of NMDARs by specific open-channel blockers, such as memantine or ketamine, has been shown to positively alter the symptoms of these CNS disorders. Memantine is approved for the treatment of AD, while ketamine is used as an anesthetic and has antidepressant effects. The mechanism of action of these substances is defined not only by the affinity and binding site in the ion channel, but also by the binding or release from binding kinetics or the presence of specific mutations in the ion channel that may affect the resulting ability to block the open channel and thereby suppress NMDAR activation. Another key factor in receptor physiology is Mg2+, and structural data confirmed that the binding site for Mg2+in the ion channel overlaps with the binding site for memantine or ketamine. The open-channel blockers thus compete with Mg2+, which in physiological conditions is present in the extracellular fluid at a concentration of about 1 mM. Thus, Mg2+may decrease the efficiency of the NMDAR open-channel blocker (i.e., increase the IC50value). Other clinically used substances that are able to block the open NMDAR channel include e.g. dextramethorphan with antitussive and neuroprotective effects, the antiviral amantadine with a therapeutic effect on neuropsychiatric symptoms, and tomoxetine used for attention disorders and the treatment of hyperactivity. Also known is the high-affinity dizocilpine (syn. MK-801) (Kd=37 nM) (WONG, E., J. A. KEMP, T. PRIESTLEY, A. R. KNIGHT, G. N. WOODRUFF AND L. L. IVERSEN The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proceedings of the National Academy of Sciences, 1986, 83(18), 7104-7108), which, however, because of a virtually irreversible binding (MCKAY, S., C.P. BENGTSON, H. BADING, D.J. WYLLIE AND G.E. HARDINGHAM Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+and memantine under conditions of agonist exposure. Neuropharmacology, 2013, 74, 119-125) in the NMDAR ion channel has only a limited use for inducing schizophrenia symptoms in laboratory animal models. WO 2007018460 discloses dibenzocycloheptane derivatives substituted by piperazine which are intended for the treatment of obesity, psychiatric and neurologic disorders. Disclosure of the Invention The present invention addresses the problems of the state of the art by providing compounds capable of effectively blocking the open NMDAR channel in physiologically relevant conditions, thus even in the presence of 1 mM Mg2+. Moreover, this structural type of compounds also effectively inhibits NMDARs with a mutation inside the ion channel and, unlike the structurally similar compound dizocilpine (MK- 801), does not irreversibly block the NMDAR ion channel. Compounds of the invention can therefore be used for the treatment of neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease). The present invention relates to compounds of the general formula I, I wherein „-----„ represents a single or double bond; R1 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein in the alkyl or cycloalkyl group, one CH2group can be replaced by an oxygen atom; R2 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, wherein in the alkyl or cycloalkyl group, one CH2group can be replaced by an oxygen atom; or R1 and R2 together with the nitrogen atom to which they are bound form a 5- to 6-membered heterocyclic aliphatic ring which can comprise one additional oxygen atom and which may be optionally substituted with C1-C4 alkyl. In a preferred embodiment, R1 is selected from H and C1-C6 alkyl. Preferably, the alkyl wherein one CH2group is replaced by an oxygen atom is hydroxy-C1-C5-alkyl, methoxy-C1-C4-alkyl. Alkyl is a saturated hydrocarbon with 1 to 6 carbon atoms. Alkyl can be linear or branched. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terc-butyl. Cycloalkyl is a saturated hydrocarbon with 3 to 6 carbon atoms, containing one cycle. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Examples of a heterocyclic 5- to 6-membered aliphatic ring formed by the substituents R1 and R2 and the nitrogen atom to which R1 and R2 are bound are piperidinyl, morpholinyl, pyrrolidinyl. The organic compounds of the general formula I can be in the form of pharmaceutically acceptable salts with alkali metals, ammonia or amines, or addition salts with acids. The compounds according to the invention are preferably selected from the compounds listed in Table 1. Table 1: Compound Structure Compound name number 1NHN-methyl-10,11-dihydro-5H- dibenzo[a,d][7]annulene-5-amine 2 N-ethyl-10,11-dihydro-5H- NH dibenzo[a,d][7]annulene-5-amine 3 N-isopropyl-10,11-dihydro-5H- NH dibenzo[a,d][7]annulene-5-amine 4 N-cyclopropyl-10,11-dihydro-5H- NH dibenzo[a,d][7]annulene-5-amine N-butyl-10,11-dihydro-5H- dibenzo[a,d][7]annulene-5-amine NH N-isobutyl-10,11-dihydro-5H- dibenzo[a,d][7]annulene-5-amine NH N-cyclohexyl-10,11-dihydro-5H- NH dibenzo[a,d][7]annulene-5-amine 1-(10,11-dihydro-5H-dibenzo[a,d][7]annulene- 5-yl)piperidine N 4-(10,11-dihydro-5H-dibenzo[a,d][7]annulene- 5-yl)morfoline N N-cyclobutyl-10,11-dihydro-5H- NH dibenzo[a,d][7]annulene-5-amine N-(2-metoxyethyl)-10,11-dihydro-5H- dibenzo[a,d][7]annulene-5-amine NH N,N-diethyl-10,11-dihydro-5H- N dibenzo[a,d][7]annulene-5-amine 1-(10,11-dihydro-5H-dibenzo[a,d][7]annulene- N 5-yl)pyrrolidine HO 2-((10,11-dihydro-5H- dibenzo[a,d][7]annulene-5-yl)amino)ethanol NH NH N-methyl-5H-dibenzo[a,d][7]annulene-5- amine N-ethyl-5H-dibenzo[a,d][7]annulene-5-amine NH N-isopropyl-5H-dibenzo[a,d][7]annulene-5- NH amine N-cyclopropyl-5H-dibenzo[a,d][7]annulene-5- NH amine N-butyl-5H-dibenzo[a,d][7]annulene-5-amine NH N-isobutyl-5H-dibenzo[a,d][7]annulene-5- amine NH 23 N-cyclohexyl-5H-dibenzo[a,d][7]annulene-5- NH amine 24 1-(5H-dibenzo[a,d][7]annulene-5-yl)piperidine N 25 O 4-(5H-dibenzo[a,d][7]annulene-5-yl)morfoline N 26 N-cyclobutyl-5H-dibenzo[a,d][7]annulene-5- NH amine 27 N-(2-metoxyethyl)-5H- O dibenzo[a,d][7]annulene-5-amine NH 28 1-(5H-dibenzo[a,d][7]annulene-5- N yl)pyrrolidine 29 HO 2-((5H-dibenzo[a,d][7]annulene-5- yl)amino)ethanol NH Compounds of the general formula I act antagonistically on NMDARs. Compounds of the general formula I are useful for the symptomatic treatment of neurodegenerative diseases, in particular of Alzheimer's disease, Huntington's disease or Parkinson's disease. Compounds of the general formula I may be administered in the form of a pharmaceutical composition comprising at least one compound of the general formula I and at least one pharmaceutically acceptable excipient. Suitable excipients include fillers such as saccharides, starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid and salts thereof, solvents, binders, etc. Suitable excipients are known to the person skilled in the art of pharmaceutical formulation. For the preparation of the compounds according to the present invention, the procedure according to scheme 1 can be used: Scheme 1 Scheme 1 describes the synthesis of N-substituted 10,11-dihydro-5H-dibenzo[a,d]annulene-5-amines and 5H-dibenzo[a,d]annulene-5-amines. The reaction conditions are: i) acetonitrile, 40 °C, 3 h; ii) HCl (aq.), MeOH, 25 °C, 1 h. Examples The invention is further described by way of the following examples, which are merely illustrative and shall not be construed as limiting the present invention. General chemical methods Chemicals necessary for the synthesis were purchased from Sigma Aldrich Co. LLC and Fluorochem Ltd. and were used without further purification. Reactions were monitored using TLC, which was performed on aluminum plates covered with silica gel 60 F254 (Merck, Prague, Czech Republic). A PuriFlash Gen5, 5.250 instrument (Interchim, Montluçon, France) (silica gel 100, 60 Å, 230–400-mesh ASTM, Sigma-Aldrich, Prague, Czech Republic) was used for column chromatography. A Dionex Ultimate 3000 LC-MS analytical system coupled with an Orbitrap Q Exactive Plus spectrometer (Thermo Fisher Scientific, Bremen, Germany) was used for mass spectrometry determination. The LC- MS system consists of a HHG-3400RS binary pump connected to a vacuum degasser, a TCC-3000 heated column compartment, a WTS-3000 autosampler and a VWD-3000 ultraviolet detector. The quadrupole mass spectrometer was equipped with an electron spray ionization source and data were recorded in positive mode with the following parameters: spray voltage was 3.2 kV, capillary temperature was 350 °C, gas temperature was 300 °C.1H and13C NMR spectra were determined at room temperature in deuterated chloroform (CDCl3) or in methanol (Methanol-d4) on a Bruker Avance NEO 500 MHz NMR spectrometer (499.87 MHz for1H and 125.71 MHz for13C). Chemical shifts (δ) of protons in1H NMR and carbons in13C NMR spectra are given in units of ppm. The reference standard for the shift in1H NMR spectra was the central peak of DMSO-d6at δ = 2.50 ppm, the CDCl3peak at δ = 7.26 ppm, and the methanol-d4peak at δ = 3.21 ppm. In the13C NMR spectra, the internal standard was the DMSO-d6peak at δ = 39.43 ppm, the CDCl3peak at δ = 77.00 ppm, and the methanol-d4peak δ = 47.6 ppm. Interaction constants (J) are given in Hz. The spin multiplicity of signals in1H NMR spectra is expressed as bs (broad singlet), s (singlet), d (doublet), dd (doublet of doublet), t (triplet) or m (multiplet). Chemical shifts are shown in ppm (parts per million, δ), relative to the signals of the listed solvents. Melting points were determined on an automatic melting point meter M-565 (Büchi, Flawil, Switzerland). Example 1 – method for the preparation of compounds of the general formula I Compounds were prepared according to Scheme 1. Commercially available amine R1-NH-R2 (3 eq.) was dissolved in 10 milliliters of dry acetonitrile. Commercially available 5-chlorodibenzosuberane (1 eq., for synthesis of (1-16)) or 5-chloro-5H-dibenzo[a,d][7]annulene (1 eq., for synthesis of (17-29)) was dissolved in 5 milliliters of dry acetonitrile and was added dropwise to the reaction mixture under an argon atmosphere. The reaction mixture was heated to 40 °C and stirred for three hours. The solvent was subsequently evaporated and the resulting mixture was purified on an automatic flash chromatography column (eluent CHCl3 / MeOH with additive 1% NH3, gradient 98:2 94:6). The compounds of the general formula I were obtained as free bases. In the following step, conversion to the corresponding hydrochloride salts took place by dissolving the compound of the general formula I in 5 milliliters of dry methanol, the mixture was cooled to 0 °C in an ice bath and 1 milliliter of concentrated HCl was added. The reaction mixture was stirred at laboratory temperature for 1 hour. The solvent was evaporated and residual water was removed by performing repeated azeotropic distillations with dry ethanol. The resulting brownish oily substance was washed with ice-cold acetone and the products were obtained as white to yellowish crystalline substances. By this procedure, compounds 1-29 were prepared, the characterization of which is given below. For biological testing, the compounds were converted to hydrochloride salts: N-methyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (1) Yield: 17 %. White crystalline substance. Melting point: 238.9 – 241.6 °C.1H NMR (500 MHz, Metanol-d4): δ 7.54 (dd, J = 7.5, 1.4 Hz, 2H); 7.42 (td, J = 7.5, 1.4 Hz, 2H); 7.37 – 7.31 (m, 4H); 5.43 (s, 1H); 3.52 – 3.41 (m, 2H); 3.14 – 3.02 (m, 2H); 2.63 (s, 3H).13C NMR (126 MHz, MeOD) δ 140.31; 131.64; 131.07; 130.13; 126.74; 32.15; 31.21. HRMS (ESI+): [M + H]+: calculated for C16H18N+(m / z): 224.14337; found: 224.14308. LC-MS purity 99 %. N-ethyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (2) Yield 51 %. White crystalline substance. Melting point: 226.0 – 230.6 °C.1H NMR (500 MHz, Methanol-d4) δ 7.54 (dd, J = 7.5, 1.4 Hz, 2H); 7.41 (td, J = 7.5, 1.4 Hz, 2H); 7.37 – 7.30 (m, 4H); 5.48 (s, 1H); 3.54 – 3.41 (m, 2H); 3.14 – 2.99 (m, 4H); 1.34 (t, J = 7.3 Hz, 3H).13C NMR (126 MHz, MeOD) δ 131.02; 130.05; 126.69; 42.00; 32.10; 10.02. HRMS (ESI+): [M + H]+: calculated for C17H20N+(m / z): 238.15902; found: 238.15881. LC-MS purity 99 %. N-isopropyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (3) Yield 52 %. White crystalline substance. Melting point: 202.2 – 205.9 °C.1H NMR (500 MHz, Methanol-d4) δ 7.56 (dd, J = 7.5, 1.4 Hz, 2H); 7.42 (td, J = 7.5, 1.4 Hz, 2H); 7.36 – 7.30 (m, 4H); 5.56 (s, 1H); 3.51 – 3.40 (m, 2H); 3.34 – 3.31 (m, 1H); 3.14 – 3.02 (m, 2H); 1.40 (d, J = 6,6 Hz, 6H).13C NMR (126 MHz, MeOD) δ 140.32; 132.23; 131.07; 130.04; 126.70; 50.09; 32.05; 18.13. HRMS (ESI+): [M + H]+: calculated for C18H22N+(m / z): 252.17467; found: 252.17441. LC-MS purity 99 %. N-cyklopropyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (4) Yield 62 %. White crystalline substance. Melting point: 204.6 – 208.6 °C.1H NMR (500 MHz, Methanol-d4) δ 7.59 (dd, J = 7.5, 1.4 Hz, 2H); 7.42 (td, J = 7.5, 1.4 Hz, 2H); 7.37 – 7.30 (m, 4H); 5.61 (s, 1H); 3.55 – 3.42 (m, 2H); 3.14 – 3.01 (m, 2H); 2.64 – 2.56 (m, 1H); 0.96 – 0.91 (m, 2H); 0.88 – 0.82 (m, 2H).13C NMR (126 MHz, MeOD) δ 129.14; 128.31; 124.90; 30.43; 28.01; 1.42. HRMS (ESI+): [M + H]+: calculated for C18H20N+(m / z): 250,15902; found: 250,15881. LC-MS purity 99 %. N-butyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (5) Yield 57 %. White crystalline substance. Melting point: 220.4 – 225.0 °C.1H NMR (500 MHz, Methanol-d4) δ 7.54 (dd, J = 7.5, 1.4 Hz, 2H); 7.42 (td, J = 7.5, 1.4 Hz, 2H); 7.38 – 7.30 (m, 4H); 5.49 (s, 1H); 3.52 – 3.41 (m, 2H); 3.15 – 3.02 (m, 2H); 2.97 – 2.88 (m, 2H); 1.78 – 1.67 (m, 2H); 1.42 – 1.31 (m, 2H); 0.94 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, MeOD) δ 131.02; 130.08; 126.70; 46.57; 32.10; 27.49; 19.57; 12.42. HRMS (ESI+): [M + H]+: calculated for C19H24N+(m / z): 266.19032; found: 266.18967. LC-MS purity 99 %. N-isobutyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (6) Yield 24 %. White crystalline substance. Melting point: 195.6 – 199.2 °C.1H NMR (500 MHz, Methanol-d4) δ 7.54 (dd, J = 7.5, 1.4 Hz, 2H); 7.42 (td, J = 7.5, 1.4 Hz, 2H); 7.37 – 7.30 (m, 4H); 5.52 (s, 1H); 3.51 – 3.40 (m, 2H); 3.18 – 3.04 (m, 2H); 2.81 – 2.72 (m, 2H); 2.17 – 2.05 (m, 1H); 1.00 (d, J = 6.7 Hz, 6H).13C NMR (126 MHz, MeOD) δ 131.02; 130.11; 126.69; 53.92; 32.10; 25.40; 19.20. HRMS (ESI+): [M + H]+: calculated for pro C19H24N+(m / z): 266.19032; found: 266.18994. LC-MS purity 99 %. N-cyklohexyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (7) Yield 19 %. White crystalline substance. Melting point: 218.4 – 224.3 °C.1H NMR (500 MHz, Methanol-d4) δ 7.55 (dd, J = 7.5, 1.4 Hz, 2H); 7.41 (td, J = 7.5, 1.4 Hz, 2H); 7.37 – 7.29 (m, 4H); 5.61 (s, 1H); 3.51 – 3.40 (m, 2H); 3.15 – 3.02 (m, 2H); 3.00 – 2.90 (m, 1H); 2.26 – 2.17 (m, 2H); 1.90 – 1.81 (m, 2H); 1.72 – 1.64 (m, 1H); 1.52 – 1.37 (m, 2H); 1.31 – 1.14 (m, 3H).13C NMR (126 MHz, MeOD) δ 140.35; 132.33; 131.04; 130.00; 126.68; 56.89; 32.07; 29.14; 24.55; 24.25. HRMS (ESI+): [M + H]+: calculated for C21H26N+(m / z): 292.20597; found: 292.20572. LC-MS purity 96 %. 1-(10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-yl)piperidine hydrochloride (8) Yield 38 %. White crystalline substance. Melting point: 200.1 – 213.3 °C.1H NMR (500 MHz, Methanol-d4) δ 7.52 (dd, J = 7.5, 1.4 Hz, 2H); 7.43 (td, J = 7.5, 1.4 Hz, 2H); 7.39 – 7.27 (m, 4H); 5.36 (s, 1H); 3.56 – 3.44 (m, 2H); 3.41 – 3.34 (m, 2H); 3.14 – 3.01 (m, 4H); 2.01 – 1.89 (m, 2H); 1.87 – 1.74 (m, 3H); 1.64 – 1.50 (m, 1H).13C NMR (126 MHz, MeOD) δ 139.95; 132.86; 131.24; 130.73; 130.48; 126.51; 77.49; 52.63; 31.85; 22.52; 21.16. HRMS (ESI+): [M + H]+: calculated for C20H24N+(m / z): 278.19032; found: 278.19012. LC-MS purity 99 %. 1-(10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-yl)-4-methylpiperazine dihydrochloride (9) – comparative compound Yield 33 %. White crystalline substance. Melting point: 228.7 °C (decomposition).1H NMR (500 MHz. Methanol-d4) δ 7.26 – 7.19 (m.4H); 7.17 (dd. J = 7.5.1.4 Hz. 2H); 7.12 (td. J = 7.5. 1.4 Hz.2H); 4.16 (s. 1H); 4.02 – 3.92 (m. 2H); 3.26 – 3.08 (m. 4H); 2.89 – 2.77 (m.2H); 2.67 – 2.47 (m. 4H).13C NMR (126 MHz. MeOD) δ 139.64; 137.79; 130.66; 130.61; 128.00; 125.50; 77.69; 53.71; 48.68; 42.06; 31.42. HRMS (ESI+): [M + H]+: calculated for C20H25N2+(m / z): 293.20122; found: 293.20096. LC-MS purity 99 %. 4-(10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-yl)morfoline hydrochloride (10) Yield 60 %. White crystalline substance. Melting point: 185.6 – 191.2 °C.1H NMR (500 MHz, Methanol-d4) δ 7.53 (dd, J = 7.5, 1.4 Hz, 2H); 7.44 (dt, J = 7.5, 1.4 Hz, 2H); 7.41 – 7.28 (m, 4H); 5.44 (s, 1H); 4.10 – 3.95 (m, 2H); 3.91 – 3.77 (m, 2H); 3.62 – 3.48 (m, 2H); 3.32 – 3.19 (m, 4H); 3.16 – 2.99 (m, 2H).13C NMR (126 MHz, MeOD) δ 140.23; 133.05; 131.31; 130.70; 129.91; 126.58; 78.60; 63.45; 51.73; 31.94. HRMS (ESI+): [M + H]+: calculated for C19H22NO+(m / z): 280.16959; found: 280.16928. LC-MS purity 95 %. N-cyklobutyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (11) Yield 66 %. White crystalline substance. Melting point: 225.2 – 232.0 °C.1H NMR (500 MHz, DMSO- d6) δ 9.82 (bs, 2H); 7.64 – 7.51 (dd, J = 7.5, 1.4 Hz, 2H); 7.42 – 7.31 (dt, J = 7.5, 1.4 Hz, 2H); 7.31 – 7.21 (m, 4H); 5.36 (s, 1H); 3.65 – 3.42 (m, 3H); 3.01 – 2.83 (m, 2H); 2.37 – 2.22 (m, 2H); 1.99 – 1.83 (m, 2H); 1.76 – 1.56 (m, 2H).13C NMR (126 MHz, DMSO) δ 131.18; 126.78; 65.55; 51.09; 32.23; 26.86; 15.38. HRMS (ESI+): [M + H]+: calculated for C19H22N+(m / z): 264.17467; found: 264.17444. LC-MS purity 99 %. N-(2-methoxyethyl)-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (12) Yield 56 %. White crystalline substance. Melting point: 205.8 – 211.2 °C.1H NMR (500 MHz, Methanol-d4) δ 7.53 (dd, J = 7.5, 1.4 Hz, 2H); 7.41 (td, J = 7.5, 1.4 Hz, 2H); 7.36 – 7.30 (m, 4H); 5.57 (s, 1H); 3.63 (t, J = 5.1 Hz, 2H); 3.52 – 3.41 (m, 2H); 3.38 (s, 3H); 3.14 (t, J = 5.1 Hz, 2H); 3.12 – 3.04 (m, 2H).13C NMR (126 MHz, MeOD) δ 131.02; 130.05; 126.68; 66.61; 57.81; 45.92; 32.07. HRMS (ESI+): [M + H]+: calculated for C18H22NO+(m / z): 268.16959; found: 268.16934. LC-MS purity 99 %. N,N-diethyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (13) Yield 55 %. White crystalline substance. Melting point: 166.2 – 172.4 °C.1H NMR (500 MHz, DMSO- d6) δ 9.87 (s, 1H); 7.55 (dd, J = 7.5, 1.4 Hz, 2H); 7.39 (td, J = 7.5, 1.4 Hz, 2H); 7.30 (dd, J = 7.5, 1.4 Hz, 2H); 7.27 (td, J = 7.5, 1.4 Hz, 2H); 5.51 (d, J = 8,8 Hz, 1H); 3.75 – 3.63 (m, 2H); 3.16 – 3.06 (m, 2H); 3.02 – 2.89 (m, 4H); 1.25 (t, J = 7.2 Hz, 6H).13C NMR (126 MHz, DMSO) δ 140.32; 132.94; 132.20; 131.77; 130.63; 126.78; 71.95; 44.32; 31.83; 8.10. HRMS (ESI+): [M + H]+: calculated for C19H24N+(m / z): 226.19032; found: 266.19046. LC-MS purity 99 %. 1-(10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-yl)-4-ethylpiperazine dihydrochloride (14) – comparative compound Yield 36 %. White crystalline substance. Melting point: 239,3 °C (decomposition).1H NMR (500 MHz, Methanol-d4) δ 7,26 – 7,19 (m, 4H); 7,16 (dd, J = 7,5, 1,4 Hz, 2H); 7,11 (td, J = 7,5, 1,4 Hz, 2H); 4,14 (s, 1H); 4,04 – 3,90 (m, 2H); 3,24 – 2,96 (m, 6H); 2,89 – 2,75 (m, 2H); 2,67 – 2,42 (m, 4H); 1,28 (t, J = 7,3 Hz, 3H).13C NMR (126 MHz, MeOD) δ 139,63; 137,94; 130,64; 130,60; 127,96; 125,48; 77,84; 51,64; 51,50; 48,81; 31,43; 8,47. HRMS (ESI+): [M + H]+: calculated for C21H27N2+(m / z): 307,21687; found: 307,21658. LC-MS purity 99 %. 1-(10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-yl)pyrrolidine hydrochloride (15) Yield 38 %. White crystalline substance. Melting point: 222.3 – 228.9 °C.1H NMR (500 MHz, Methanol-d4) δ 7.54 (dd, J = 7.5, 1.4 Hz, 2H); 7.43 (td, J = 7.5, 1.4 Hz, 2H); 7.38 – 7.28 (m, 4H); 5.41 (s, 1H); 3.64 – 3.52 (m, 2H); 3.32 – 3.28 (m, 4H); 3.15 – 3.03 (m, 2H); 2.28 – 2.14 (m, 2H); 2.12 – 1.97 (m, 2H).13C NMR (126 MHz, MeOD) δ 139.82; 132.12; 132.05; 131.24; 130.37; 126.63; 75.86; 54.00; 31.98; 22.18. HRMS (ESI+): [M + H]+: calculated for C19H22N+(m / z): 264.17467; found: 264.17435. LC-MS purity 99 %. 2-((10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-yl)amino)ethanol hydrochloride (16) Yield 53 %. White crystalline substance. Melting point: 183.1 – 186.8 °C.1H NMR (500 MHz, Methanol-d4) δ 7.54 (dd, J = 7.5, 1.4 Hz, 2H); 7.41 (td, J = 7.5, 1.4 Hz, 2H); 7.36 – 7.30 (m, 4H); 5.60 (s, 1H); 3.84 – 3.78 (m, 2H); 3.54 – 3.43 (m, 2H); 3.15 – 3.02 (m, 4H).13C NMR (126 MHz, MeOD) δ 131.02; 130.02; 126.67; 56.35; 32.11. HRMS (ESI+): [M + H]+: calculated for C17H20NO+(m / z): 254.15394; found: 254.15373. LC-MS purity 99 %. N-methyl-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (17) Yield 43 %. White crystalline substance. Melting point: 208.7 – 233.7 °C.1H NMR (500 MHz, Methanol-d4) δ 7.75 – 7.69 (m, 2H); 7.66 – 7.60 (m, 2H); 7.60 – 7.54 (m, 4H); 7.25 (s, 2H); 5.66 (s, 1H); 2.36 (s, 3H).13C NMR (126 MHz, MeOD) δ 133.62; 130.91; 130.44; 130.35; 130.26; 129.54; 129.46; 68.17; 30.74. HRMS (ESI+): [M + H]+: calculated for (m / z): 222.12772; found: 222.12752. LC- MS purity 98 %. N-ethyl-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (18) Yield 44 %. White crystalline substance. Melting point: 189.0 – 192.9 °C.1H NMR (500 MHz, Methanol-d4) δ 7.76 – 7.71 (m, 2H); 7.64 – 7.60 (m, 2H); 7.59 – 7.53 (m, 4H); 7.25 (s, 2H); 5.76 (s, 1H); 2.70 (q, J = 7.3 Hz, 2H); 1.21 (t, J = 7.3 Hz, 3H).13C NMR (126 MHz, MeOD) δ 133.83; 130.98; 130.44; 130.32; 130.20; 129.47; 129.43; 66.44; 41.31; 9.54. HRMS (ESI+): [M + H]+: calculated for C17H18N+(m / z): 236.14337; found: 236.14259. LC-MS purity 99 %. N-isopropyl-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (19) Yield 41 %. White crystalline substance. Melting point: 189.5 – 191.7 °C.1H NMR (500 MHz, Methanol-d4) δ 7.80 – 7.74 (m, 2H); 7.64 – 7.59 (m, 2H); 7.58 – 7.51 (m, 4H); 7.27 (s, 2H); 5.87 (s, 1H); 2.95 (hept, J = 6.6 Hz, 1H); 1.21 (d, J = 6.6 Hz, 6H).13C NMR (126 MHz, MeOD) δ 133.97; 131.29; 130.58; 130.10; 129.98; 129.44; 129.36; 64.73; 50.03; 17.97. HRMS (ESI+): [M + H]+: calculated for C18H20N+(m / z): 250.15902; found: 250.1583694%. LC-MS purity 96 %. N-cyklopropyl-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (20) Yield 68 %. White crystalline substance. Melting point: 195.5 – 204.0 °C.1H NMR (500 MHz, Methanol-d4) δ 7.79 – 7.74 (m, 2H); 7.64 – 7.59 (m, 2H); 7.59 – 7.53 (m, 4H); 7.24 (s, 2H); 5.84 (s, 1H); 2.17 – 2.08 (m, 1H); 0.83 – 0.76 (m, 2H); 0.75 – 0.69 (m, 2H).13C NMR (126 MHz, MeOD) δ 132.36; 129.43; 128.97; 128.87; 128.54; 127.90; 127.81; 66.85; 27.47; 1.42. HRMS (ESI+): [M + H]+: calculated for C18H18N+(m / z): 248.14337; found: 248.14290. LC-MS purity 98 %. N-butyl-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (21) Yield 57 %. White crystalline substance. Melting point: 202.7 – 208.2 °C.1H NMR (500 MHz, Methanol-d4) δ 7.76 – 7.71 (m, 2H); 7.65 – 7.60 (m, 2H); 7.59 – 7.53 (m, 4H); 7.26 (s, 2H); 5.77 (s, 1H); 2.65 – 2.56 (m, 2H); 1.64 – 1.53 (m, 2H); 1.31 – 1.18 (m, 2H); 0.87 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, MeOD) δ 133.81; 130.96; 130.45; 130.35; 130.20; 129.49; 129.44; 66.73; 45.85; 26.99; 19.46; 12.33. HRMS (ESI+): [M + H]+: calculated for C19H22N+(m / z): 264.17467; found: 264.17410. LC-MS purity 99 %. N-isobutyl-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (22) Yield 42 %. White crystalline substance. Melting point: 183.6 – 187.4 °C.1H NMR (500 MHz, Methanol-d4) δ 7.77 – 7.72 (m, 2H); 7.65 – 7.61 (m, 2H); 7.60 – 7.54 (m, 4H); 7.28 (s, 2H); 5.79 (s, 1H); 2.45 (d, J = 7.1 Hz, 2H); 2.01 – 1.90 (m, 1H); 0.88 (d, J = 6.7 Hz, 6H).13C NMR (126 MHz, MeOD) δ 133.71; 130.88; 130.52; 130.38; 130.17; 129.50; 66.78; 53.04; 24.81; 18.98. HRMS (ESI+): [M + H]+: calculated for pro C19H22N+(m / z): 264.17467; found: 264.17392. LC-MS purity 99 %. N-cyklohexyl-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (23) Yield 74 %. White crystalline substance. Melting point: 199.8 – 208.2 °C.1H NMR (500 MHz, Methanol-d4) δ 7.78 – 7.73 (m, 2H); 7.65 – 7.60 (m, 2H); 7.59 – 7.52 (m, 4H); 7.27 (s, 2H); 5.91 (s, 1H); 2.63 – 2.52 (m, 1H); 1.98 – 1.90 (m, 2H); 1.83 – 1.73 (m, 2H); 1.65 – 1.57 (m, 1H); 1.36 – 1.24 (m, 2H); 1.18 – 1.03 (m, 3H).13C NMR (126 MHz, MeOD) δ 133.98; 131.24; 130.58; 130.11; 130.00; 129.43; 129.38; 64.60; 56.85; 28.94; 24.41; 24.24. HRMS (ESI+): [M + H]+: calculated for C21H24N+(m / z): 290.19032; found: 290.18954. LC-MS purity 99 %. 1-(5H-dibenzo[a,d][7]annulene-5-yl)piperidine hydrochloride (24) Yield 44 %. White crystalline substance. Melting point: 169.8 – 172.0 °C.1H NMR (500 MHz, DMSO- d6) δ 8.52 – 8.40 (m, 1H); 7.86 – 7.81 (m, 2H); 7.69 – 7.64 (m, 2H); 7.60 – 7.53 (m 4H); 6.26 – 6.15 (m, 1H); 2.78 – 2.61 (m, 4H); 1.86 – 1.73 (m, 2H); 1.70 – 1.58 (m, 2H); 1.56 – 1.36 (m, 2H).13C NMR (126 MHz, DMSO) δ 134.55; 132.18; 131.15; 130.70; 130.13; 129.82; 51.28; 21.71; 20.74. HRMS (ESI+): [M + H]+: calculated for C20H22N+(m / z): 276.17467; found: 276.17404. LC-MS purity 99 %. 4-(5H-dibenzo[a,d][7]annulene-5-yl)morfoline hydrochloride (25) Yield 52 %. White crystalline substance. Melting point: 171.1 – 175.7 °C.1H NMR (500 MHz, Methanol-d4) δ 7.79 – 7.73 (m, 2H); 7.69 – 7.64 (m, 2H); 7.63 – 7.57 (m, 4H); 7.28 (s, 2H); 5.92 (s, 1H); 3.96 – 3.85 (m, 3H); 3.74 – 3.65 (m, 2H); 3.28 – 3.22 (m, 1H); 3.18 – 3.09 (m, 2H); 2.78 – 2.69 (m, 2H).13C NMR (126 MHz, MeOD) δ 134.14; 131.67; 130.48; 130.45; 130.05; 129.50; 128.77; 127.90; 76.97; 63.49; 62.42; 51.12; 43.26. HRMS (ESI+): [M + H]+: calculated for C19H20NO+(m / z): 278.15394; found: 278.15356. LC-MS purity 97 %. N-cyklobutyl-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (26) Yield 64 %. White crystalline substance. Melting point: 217.7 – 227.1 °C.1H NMR (500 MHz, Methanol-d4) δ 7.74 – 7.69 (m, 2H); 7.63 – 7.59 (m, 2H); 7.58 – 7.52 (m, 4H); 7.25 (s, 2H); 5.63 (s, 1H); 3.40 – 3.34 (m, 1H); 2.15 – 2.03 (m, 2H); 2.02 – 1.92 (m, 2H); 1.83 – 1.64 (m, 2H).13C NMR (126 MHz, MeOD) δ 134.03; 130.94; 130.51; 130.21; 130.13; 129.47; 129.43; 65.83; 50.94; 26.44; 14.42. HRMS (ESI+): [M + H]+: calculated for C19H20N+(m / z): 262.15902; found: 262.15839. LC-MS purity 99 %. N-(2-methoxyethyl)-5H-dibenzo[a,d][7]annulene-5-amine hydrochloride (27) Yield 52 %. White crystalline substance. Melting point: 189.1 – 195.8 °C.1H NMR (500 MHz, Methanol-d4) δ 7.74 – 7.71 (m, 2H); 7.64 – 7.61 (m, 2H); 7.59 – 7.53 (m, 4H); 7.27 (s, 2H); 5.81 (s, 1H); 3.52 – 3.46 (m, 2H); 3.32 (s, 3H); 2.90 – 2.81 (m, 2H).13C NMR (126 MHz, MeOD) δ 133.67; 130.97; 130.48; 130.33; 130.18; 129.48; 66.81; 66.18; 57.75; 45.17. HRMS (ESI+): [M + H]+: calculated for C18H20NO+(m / z): 266.15394; found: 266.15411. LC-MS purity 99%. 1-(5H-dibenzo[a,d][7]annulene-5-yl)pyrrolidine hydrochloride (28) Yield 58 %. White crystalline substance. Melting point: 170.1 – 178.3 °C.1H NMR (500 MHz, Methanol-d4) δ 7.76 – 7.73 (m, 2H); 7.66 – 7.62 (m, 2H); 7.59 – 7.56 (m, 4H); 7.30 (s, 2H); 5.74 (s, 1H); 3.15 – 3.05 (m, 2H); 2.88 – 2.80 (m, 2H); 2.19 – 2.08 (m, 2H); 1.99 – 1.88 (m, 2H).13C NMR (126 MHz, MeOD) δ 133.63; 131.06; 130.51; 130.50; 130.19; 129.67; 129.49; 74.64; 53.89; 22.66. HRMS (ESI+): [M + H]+: calculated for C19H20N+(m / z): 262.15902; found: 262.15942. LC-MS purity 99%. 2-((5H-dibenzo[a,d][7]annulene-5-yl)amino)ethanol hydrochloride (29) Yield 69 %. White crystalline substance. Melting point: 181.5 – 190.3 °C.1H NMR (500 MHz, Methanol-d4) δ 7.75 – 7.70 (m, 2H); 7.66 – 7.61 (m, 2H); 7.60 – 7.53 (m, 4H); 7.28 (s, 2H); 5.85 (s, 1H); 3.69 – 3.63 (m, 2H); 2.80 – 2.73 (m, 2H).13C NMR (126 MHz, MeOD) δ 133.62; 131.03; 130.49; 130.29; 130.20; 129.51; 129.47; 66.60; 55.92; HRMS (ESI+): [M + H]+: calculated for C17H18NO+(m / z): 252.13829; found: 252.13858. LC-MS purity 99 %. Example 2: In vitro testing: determination of relative inhibitory activity for GluN1 / GluN2A and GluN1 / GluN2B NMDAR subtypes Relative inhibition for the prepared derivatives of the general formula I was determined on the two main NMDAR subtypes, GluN1 / GluN2A and GluN1 / GluN2B, according to a previously published protocol (Hansen, K. B., Wollmuth, L. P., Bowie, D., Furukawa, H., Menniti, F. S., Sobolevsky, A. I., Swanson, G. T., Swanger, S. A., Greger, I. H., Nakagawa, T., McBain, C. J., Jayaraman, V., Low, C. M., Dell'Acqua, M. L., Diamond, J. S., Camp, C. R., Perszyk, R. E., Yuan, H., Traynelis, S. F., 2021. Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels. Pharmacol Rev 73, 298- 487) at a concentration of the tested compounds of 3 µM and a membrane potential of -60 mV. As can be seen from Table 2, all tested compounds of the general formula I are able to block both NMDAR subtypes. Table 2: Inhibitory effect on human GluN1 / GluN2A and GluN1 / GluN2B NMDAR subtypes for selected compounds of the general formula I at a membrane potential of -60 mV. Results are expressed as relative inhibition at a final concentration of 3 µM (0% = no inhibition, 100% = complete inhibition). SEM = standard deviation. Compound GluN1 / GluN2A GluN1 / GluN2B RIa(%) ± SEM RIa(%) ± SEM 1 82.34 ± 3.25 70.97 ± 1.75 2 34.05 ± 4.60 51.84 ± 3.39 3 52.23 ± 5.23 76.92 ± 3.57 4 40.11 ± 3.42 53.57 ± 3.16 5 76.43 ± 4.03 85.79 ± 2.19 6 76.79 ± 2.99 91.62 ± 0.99 7 79.42 ± 2.06 85.95 ± 3.13 10 73.68 ± 3.00 84.17 ± 2.95 11 34.90 ± 4.80 66.63 ± 3.90 12 49.80 ± 3.27 62.14 ± 3.44 13 47.96 ± 5.18 49.67 ± 4.47 15 68.43 ± 4.84 75.00 ± 3.14 17 54.32 ± 3.11 68.93 ± 3.57 18 39.93 ± 4.78 59.85 ± 3.15 19 75.62 ± 2.36 76.05 ± 2.22 20 45.00 ± 3.55 57.18 ± 3.27 21 81.12 ± 2.62 79.19 ± 2.84 22 93.17 ± 1.11 91.77 ± 0.71 23 92.12 ± 1.48 92.37 ± 1.82 24 29.85 ± 2.73 58.40 ± 4.37 25 31.90 ± 4.16 57.65 ± 3.47 26 77.52 ± 2.81 89.15 ± 4.63 27 35.63 ± 1.09 60.00 ± 4.39 28 48.56 ± 2.99 85.53 ± 0.21 29 38.17 ± 3.80 48.78 ± 4.13 9 (comparative) 6.78 ± 1.67 3.43 ± 1.33 14 (comparative) 9.70 ± 2.41 9.49 ± 2.17 Example 3: In vitro testing: determination of absolute inhibitory activity for compounds 22 and 26 on GluN1 / GluN2A and GluN1 / GluN2B NMDAR subtypes Absolute inhibition for the most effective compound from Table 3 (compound 22) and another selected compound 26 was determined on the two main NMDAR subtypes present in the adult brain, GluN1 / GluN2A and GluN1 / GluN2B, according to a previously published protocol (KONECNY, J., A. MISIACHNA, M. HRABINOVA, L. PULKRABKOVA, M. BENKOVA, L. PRCHAL, T. KUCERA, T. KOBRLOVA, V. FINGER AND M. KOLCHEVA Pursuing the complexity of Alzheimer’s disease: discovery of fluoren-9-amines as selective butyrylcholinesterase inhibitors and n-methyl-d-aspartate receptor antagonists. Biomolecules, 2020, 11(1), 3.) at various concentrations, at a membrane potential of -60 mV or +40 mV. Table 3: The inhibitory efficiency of compounds 22 and 26 on the human GluN1 / GluN2A and GluN1 / GluN2B receptor at a membrane potential of -60 mV or +40 mV, expressed as IC50value. Compound IC50(-60 mV) IC50(-60 mV) IC50(+40 mV) IC50(+40 mV) µM µM µM µM GluN1 / GluN2A GluN1 / GluN2B GluN1 / GluN2A GluN1 / GluN2B 22 0.36 ± 0.06 0.16 ± 0.01 22.37 ± 3.43 11.67 ± 1.23 26 0.68 ± 0.07 0.62 ± 0.07 38.30 ± 3.70 16.11 ± 1.59 Memantine 1.34 ± 0.08 0.78 ± 0.09 39.84 ± 1.41 25.63 ± 1.36 Amantadine 52.6 ± 4.55 33 ± 2.04 449 ± 19 359 ± 32.8 Ketamine 0.50 ± 0.06 0.51 ± 0.05 53.3 ± 8.6 15.2 ± 0.60 Tomoxetine 8.29 ± 0.97 2.10 ± 0.15 84.5 ± 4.73 20.05 ± 2.5 Example 4: In vitro testing: determination of absolute inhibitory activity for NMDAR under specific physiological conditions With respect to practical applicability, it should be noted that the function of NMDAR under physiological conditions is regulated by the level of Mg2+, which blocks the ion channel of this receptor. It is also known that some mutations in the channel cause disease or render already approved drugs ineffective. Therefore, we tested the inhibitory efficiency for compound 26, which was found to best pass into the CNS in a laboratory rat model (see Example 8), regarding efficiency in the presence of a physiological level of Mg2+(Table 4) and also in the presence of the hGluN2A-N615S mutation, causing epileptic seizures in adult mice (Table 8). As can be seen from Table 4, compound 26 is in all cases a more effective blocker than the reference drug memantine. It is then clear from Table 5 that compound 26 has a higher efficiency on this mutated NMDAR both in the presence and in the absence of 1 mM Mg2+compared to the reference memantine. Table 4: Inhibitory efficiency of compound 26 in the presence of 1 mM Mg2+on the human GluN1 / GluN2A and GluN1 / GluN2B receptor at a membrane potential of -60mV or +40mV, expressed as IC50value. Compound IC50(-60 mV) IC50(-60 mV) IC50(+40 mV) IC50(+40 mV) µM µM µM µM GluN1 / GluN2A GluN1 / GluN2B GluN1 / GluN2A GluN1 / GluN2B 26 4.40 ±0.62 3.62 ± 0.09 35.13 ± 3.10 15.35 ± 1.05 Memantine 11.75 ±0.53 8.05 ± 0.42 36.31 ±1.78 22.67 ± 1.84 Amantadine 382 ± 24.5 359 ± 48 617 ± 47.3 414 ± 31 Ketamine 7.32 ± 0.22 6.12 ± 0.84 49.5 ± 9.7 23.9 ± 1.24 Tomoxetine 25.14 ± 0.64 17.6 ± 1.5 88.15 ± 4.31 31.9 ± 1.14 Table 5: Inhibitory efficiency of compound 26 on the human mutated GluN1 / GluN2A-N615S receptor at various membrane potentials in the presence / absence Mg2+, expressed as IC50value. Receptor Compound IC50(µM) 0 mM Mg2+1 mM Mg2+-60 mV +40 mV -60 mV +40 mV hGluN1- 26 0.47 ± 0.05 12.13 ± 0.59 0.55 ± 0.04 10.95 ± 1.08 4a / Memantine 2.50 ± 0.36 40.25 ± 5.92 7.78 ± 0.59 44.89 ± 1.13 hGluN2A- N615S Example 5: Binding of compound 26 in the NMDA receptor ion channel Kinetics of inhibitor binding expressed as binding rate (Ton) and unbinding rate (Toff) are also important for the clinical effect of NMDAR ion channel inhibitors, as the structurally most similar high-affinity dizocilpine is clinically unusable due to practically irreversible binding (unbinding in the order of hours) in ion channels. Table 6 shows the values for Tonand Tofffor compound 26 which penetrates the brain best, and also for compounds 16 and 22, memantine and dizocipline. It was found that compounds of the invention (16, 22, 26) bind with high affinity into the open NMDAR channel, but in contrast to dizocilpine they are still able to unbind and thus do not cause a permanent blockade leading to undesirable psychomimetic effects in vivo. Table 6: Binding kinetics of compounds 26, 22, 16 (10 µM) and reference compounds to the GluN1 / GluN2A NMDAR ion channel at -60 mV, Glu (1 mM), Gly (100 µM). Binding rate (Ton) and unbinding rate (Toff) are expressed in seconds (s). Compound Ton(s) Toff(s) 16 1.3 1.8 22 3.4 14 26 0.8 8.3 Memantine 0.1 0.8 Ketamine 0.1 1.0 Dizocilpine 0.3 Irreversible / unmeasurable Example 6: Ion channel binding mechanism The mechanism of binding to the ion channel was further studied in this example. Ion channel blockers can enter this channel either directly or via a so-called membrane-to-channel (MCI) pathway (Wilcox MR, Nigam A, Glasgow NG, Narangoda C, Phillips MB, Patel DS, Mesbahi-Vasey S, Turcu AL, Vázquez S, Johnson JW. Inhibition of NMDA receptors through a membrane-to-channel path. Nat Commun., 2022, 13(1), 4114), where they can form depots and gradually enter the channel to release the substance. This mechanism was studied using a published methodology (Kolcheva M, Ladislav M, Netolicky J, Kortus S, Rehakova K, Krausova BH, Hemelikova K, Misiachna A, Kadkova A, Klima M, Chalupska D, Horak M. The pathogenic N650K variant in the GluN1 subunit regulates the trafficking, conductance, and pharmacological properties of NMDA receptors. Neuropharmacology, 2023, 222, 109297). The results clearly demonstrate that compared to the reference compounds mematine and ketamine, the compounds 22 and 26 show a unique mechanism of binding through the membrane pathway to a far greater extent (Table 7). Table 7: Mechanism of membrane permeation binding (the so-called membrane-to-channel, MCI) of compounds 22, 26 (100 µM) and reference compound to the GluN1 / GluN2A NMDAR ion channel. Value 1 = no membrane permeation, value 0 = permeation via membrane. Compound MCI (100 μM) 22 0.31 ± 0.04 26 0.28 ± 0.01 Memantine 0.57 ± 0.07 Ketamine 0.92 ± 0.03 Example 7: Permeation of the compounds 16, 22 and 26 through hematoencephalic barrier in in vivo rat model Given the intended use for CNS disease treatment, it is critical that the compounds cross the blood-brain barrier. This was studied in a rat model according to a published methodology (GORECKI, L., A. MISIACHNA, J. DAMBORSKY, R. DOLEZAL, J. KORABECNY, L. CEJKOVA, K. HAKENOVA, M. CHVOJKOVA, J. Z. KARASOVA AND L. PRCHAL Structure-activity relationships of dually- acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors. European Journal of Medicinal Chemistry, 2021, 219, 113434). After administration of 5 mg / kg i.p., we have determined the concentrations of the compounds in plasma and brain after 15 min (table 8). As can be seen, the substances pass through the blood-brain barrier, and are thus suitable for the treatment of CNS diseases. Table 8: Concentration of the compounds 16, 22 and 26 in plasma and brain of the rats within 15 min of i.p. administration of a dose of 5mg / kg Compound Cplasma(nM) Cbrain(nM) 16 423 1672 22 171 485 26 204 1694

Claims

CLAIMS 1. Compound of general formula II wherein „-----„ represents a single bond or a double bond; R1 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein in the alkyl or cycloalkyl group, one CH2group can be replaced by an oxygen atom; R2 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, wherein in the alkyl or cycloalkyl group, one CH2group can be replaced by an oxygen atom; or R1 and R2 together with the nitrogen atom to which they are bound form a 5- to 6-membered heterocyclic aliphatic ring which can comprise one additional oxygen atom and which may be optionally substituted with C1-C4 alkyl, or pharmaceutically acceptable salts thereof with alkali metals, ammonia or amines, or addition salts thereof with acids.

2. Compound of general formula I according to claim 1, selected from the group consisting of: N-cyclopropyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine, N-cyclohexyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine, N-cyclobutyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-amine, N-cyclopropyl-5H-dibenzo[a,d][7]annulene-5-amine, N-cyclohexyl-5H-dibenzo[a,d][7]annulene-5-amine, N-cyclobutyl-5H-dibenzo[a,d][7]annulene-5-amine, or pharmaceutically acceptable salts thereof with alkali metals, ammonia or amines, or addition salts thereof with acids.

3. Compound of general formula I according to claim 1 or 2 for use in the treatment of neurodegenerative disease.

4. Compound of general formula I for use according to claim 3, wherein the neurodegenerative disease is selected from Alzheimer's disease, Huntington's disease and Parkinson's disease.

5. Method of treatment of a neurodegenerative disease, comprising the step of administering at least one compound of general formula II wherein „-----„ represents a single bond or a double bond. R1 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein in the alkyl or cycloalkyl group, one CH2group can be replaced by an oxygen atom; R2 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, wherein in the alkyl or cycloalkyl group, one CH2group can be replaced by an oxygen atom; or R1 and R2 together with the nitrogen atom to which they are bound form a 5- to 6-membered heterocyclic aliphatic ring which can comprise one additional oxygen atom and which may be optionally substituted with C1-C4 alkyl, or pharmaceutically acceptable salts thereof with alkali metals, ammonia or amines, or addition salts thereof with acids, to a subject in need of such treatment.

6. The method according to claim 5, wherein the neurodegenerative disease is selected from Alzheimer's disease, Huntington's disease and Parkinson's disease.

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