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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P25/00—Drugs for disorders of the nervous system
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  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/31—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings
  • C07C211/32—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings containing dibenzocycloheptane or dibenzocycloheptene ring systems or condensed derivatives thereof
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  • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
  • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
  • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
  • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
  • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
  • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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  • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
  • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

• 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.
• 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 Mg 2+ or pharmacological drugs from the group of NMDAR blockers.
• endogenous Mg 2+ or pharmacological drugs from the group of NMDAR blockers.
• 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.
• NMDARs 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.
• Mg 2+ Another key factor in receptor physiology is Mg 2+ , and structural data confirmed that the binding site for Mg 2+ in the ion channel overlaps with the binding site for memantine or ketamine.
• the open-channel blockers thus compete with Mg 2+ , which in physiological conditions is present in the extracellular fluid at a concentration of about 1 mM.
• Mg 2+ may decrease the efficiency of the NMDAR open-channel blocker (i.e., increase the IC 50 value).
• Other clinically used substances that are able to block the open NMDAR channel include e.g.
• 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 Mg 2+ . 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 antique----- remind 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 CH 2 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 CH 2 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.
• R1 is selected from H and C1-C6 alkyl.
• the alkyl wherein one CH 2 group 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.
• cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
• 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.
• 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.
• 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.
• 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.
• 1 H and 13 C NMR spectra were determined at room temperature in deuterated chloroform (CDCl 3 ) or in methanol (Methanol-d 4 ) on a Bruker Avance NEO 500 MHz NMR spectrometer (499.87 MHz for 1 H and 125.71 MHz for 13 C). Chemical shifts ( ⁇ ) of protons in 1 H NMR and carbons in 13 C NMR spectra are given in units of ppm.
• 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 CHCl 3 /MeOH with additive 1% NH 3 , gradient 98:2 94:6).
• the compounds of the general formula I were obtained as free bases.
• 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.
• 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.
• MISIACHNA M. HRABINOVA, L. PULKRABKOVA, M. BENKOVA, L. PRCHAL, T. KUCERA, T. KOBRLOVA, V. FINGER AND M. KOLCHEVA
• 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 IC 50 value.
• Compound IC 50 (-60 mV) IC 50 (-60 mV)
• IC 50 (+40 mV) IC 50 (+40 mV) ⁇ M ⁇ M ⁇ M 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
• Table 4 Inhibitory efficiency of compound 26 in the presence of 1 mM Mg 2+ on the human GluN1/GluN2A and GluN1/GluN2B receptor at a membrane potential of -60mV or +40mV, expressed as IC 50 value.
• Receptor Compound IC 50 ( ⁇ M) 0 mM Mg 2+ 1 mM Mg 2+ -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 (T on ) and unbinding rate (T off ) 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 T on and T off for 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 ⁇ M) and reference compounds to the GluN1/GluN2A NMDAR ion channel at -60 mV, Glu (1 mM), Gly (100 ⁇ M).
• Binding rate (T on ) and unbinding rate (T off ) are expressed in seconds (s).
• 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.
• MCI membrane-to-channel pathway
• 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.

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