Nicotinic acetylcholine receptor ligand

Abstract

Compounds of general formula (I), pharmaceutical compositions containing the compounds, uses of the compositions, and methods for producing the compounds are disclosed. The compounds are nicotinic acetylcholine receptor (nAChR) ligands and can be used for the prevention and / or suppression of cough. JPEG2025517615000020.jpg2734(I)

Description

Technical Field

[0001] Nicotinic acetylcholine receptors (nAChRs) have been extensively characterized for their functions in peripheral and central neurons involved in the regulation of neurotransmission. nAChRs typically associated with the central nervous system (CNS) have been shown to occur in several subtypes. The most common nAChR subtypes are the α4β2 and α7 subtypes. The α7 nAChR belongs to a family of acetylcholine-dependent cation channels and exhibits a distinct biophysical and pharmacological profile compared to other nAChR subtypes.

[0002] These receptors are mainly expressed in neuronal tissue, but some types of immune cells also express α7 nAChR mRNA. Examples of such immune cells that express α7 nAChR mRNA include macrophages, T cells, B cells, microglia, monocytes, and dendritic cells. The immunological response to protect against excessive inflammation can be regulated by the CNS via the cholinergic anti-inflammatory pathway in which acetylcholine is released from the vagus nerve. As a result, acetylcholine activates postsynaptic α7 nAChRs in intrinsic tissues including the splenic nerve after stimulation, which then inhibits inflammatory cytokines.

Background Art

[0003] Various nicotine compounds are known to interact with the α7 nAChR and have thus been proposed for therapy. However, the drawbacks of these known nicotine compounds are associated with various undesirable side effects, for example, by stimulating muscle and ganglion receptors.

[0004] There is a need for compounds, compositions, and methods for preventing or treating various conditions or disorders, such as CNS disorders, including alleviating the symptoms of these disorders without associated side effects. More specifically, there is a need for compounds, compositions, and methods that affect CNS function without significantly affecting nicotinic receptor subtypes that can induce undesirable side effects, such as significant activity in the cardiovascular and skeletal muscle sites. SUMMARY OF THE INVENTION

[0005] According to an aspect of the invention, a compound of general formula (I),

Chemical formula

[0006] According to another aspect of the invention, a compound of general formula (I),

Chemical formula

[0007] Also provided are a pharmaceutical composition comprising a compound of general formula (I), the use of a composition comprising a compound of general formula (I), and a method for producing a compound of general formula (I) as defined in the appended independent claims, which should be referred to herein. Preferred or advantageous features of the invention are set out in the dependent claims and are further described below.

[0008] Advantageously, the compounds of general formula (I) of the present invention act on the central nervous system without inducing potentially undesirable side effects of nicotinic receptor subtypes. These potentially undesirable side effects can include significant activity at the cardiovascular and skeletal muscle sites.

[0009] More specifically, the compounds of general formula (I) of the present invention are α7 nAChR agonists, which provide a novel non-narcotic approach to therapy in patients with acute and chronic cough. As described below, the potential application of selective α7 nAChR agonists as antitussives according to the present invention was demonstrated in in vivo experiments by inhibiting the cough response in guinea pigs induced by citric acid.

[0010] Furthermore, the α7 nAChR agonists described herein may be beneficial for the treatment of cough origin. In preclinical studies of lung diseases, α7 nAChR agonists showed anti-inflammatory effects in models of acute lung injury, antigen challenge, and gram-negative bacterial infection.

[0011] According to another aspect of the present invention, a compound of general formula (I),

Chemical formula

[0012] According to yet another aspect of the present invention, a compound of general formula (I),

Chemical formula

[0013] As used herein, the term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine, or iodine.

[0014] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms in the ring. Common aryl groups include C 6 ~C 14 aryl, for example C 6 ~C 10 aryl. C 6 ~C 14Non-limiting examples of an aryl group include a phenyl group, a naphthyl group, a phenanthrenyl group, an anthracenyl group, an indenyl group, an azulenyl group, a biphenyl group, a biphenylylenyl group, and a fluorenyl group. An "optionally substituted aryl group" may include substituents described herein.

[0015] As used herein, the term "heteroaryl" refers to an aromatic group having 5 to 14 ring atoms (e.g., 5 to 10 ring atoms) and containing carbon atoms and 1, 2, or 3 oxygen, nitrogen, or sulfur heteroatoms. Examples of heteroaryl groups include, but are not limited to, thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl including 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl (pyridinyl) including 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrenyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl. When a heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom may be in the form of an N-oxide, for example, pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide. An "optionally substituted heteroaryl group" may include substituents described herein.

[0016] Optionally, one or both of the carbocyclic or heterocyclic aromatic rings of the aryl group of general formula (I), or each aromatic ring, the aryl of the optionally substituted aryl of general formula (I), and the heteroaryl of the optionally substituted heteroaryl of general formula (I) are 3- to 10-membered rings, for example 5- to 10-membered rings. For example, one or both of the carbocyclic or heterocyclic aromatic rings of the aryl group of general formula (I), or each aromatic ring, the aryl of the optionally substituted aryl of general formula (I), and the heteroaryl of the optionally substituted heteroaryl of general formula (I) may be 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, or 10-membered rings.

[0017] Optionally, one or both of the aryl groups of general formula (I), and each aryl or heteroaryl of general formula (I) are monocyclic. For example, one or both of the aryl groups of general formula (I), and each aryl or heteroaryl of general formula (I) may independently be selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. In one embodiment, R 1 does not contain phenyl.

[0018] Optionally, one or both of the aryl groups of general formula (I), and each aryl or heteroaryl of general formula (I) is polycyclic. For example, one or both of the aryl groups of general formula (I), each aryl or heteroaryl of general formula (I) is independently naphthalenyl, anthracenyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzodioxolanyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, purinyl, thienopyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, naphthyridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and azulenyl selected from the group consisting of.

[0019] Optionally, one or both aryl groups of general formula (I), each aryl or heteroaryl of general formula (I) is independently acenaphthylene, acephenanthrylene, acridine, anthracene, anthracene, 9,10-anthraquinone, 9(10H)-anthracenone, anthraquinone, anthrone, benz[e]acephenanthrylene, benz[c]acridine, benz[a]anthracene, 7H-benz[de]anthracen-7-one, benzanthrone, benz[b]chrysene, benz[c]chrysene, benz[g]chrysene, benz[c]cinnoline, benz[a]dibenzothiophene, benz[b]fluoranthene, benz[ghi]fluoranthene, benz[j]fluoranthene, benz[k]fluoranthene, 11H-benz[a]fluorene, 11H-benz[b]fluorene, 7H-benz[c]fluorene, benz[h]naphtho[1,2-f]quinoline, benz[b]naphtho[2,1-d]thiophene, benz[rst]pentaphene, benz[ghi]perylene, benz[c]phenanthrene, benz[a]pyrene, benz[e]pyrene, benz[f]quinoline, benz[h]quinoline, benz[b]triphenylene, biphenylene, 9H-carbazole, chrysene, coronene, 4H-cyclopenta[def]phenanthrene, cyclopenta[cd]pyrene, dibenz[a,h]acridine, dibenz[a,j]acridine, dibenz[c,h]acridine, dibenz[a,c]anthracene, dibenz[a,h]anthracene, dibenz[a,j]anthracene, 7H-dibenzo[a,g]carbazole, 13H-dibenzo[a,i]carbazole, 7H-dibenzo[c,g]carbazole, dibenz[b,def]chrysene, dibenz[def,mno]chrysene, dibenz[def,p]chrysene, dibenz[b,h]phenanthrene, dibenz[a,e]pyrene, dibenz[a,h]pyrene, dibenz[a,i]pyrene, dibenz[a,1]pyrene, dibenzothiophene, fluoranthene, 9H-fluorene, 9H-fluoren-9-one, indeno[1,2,3-cd]pyrene, 1H-indole, isoquinoline, naphthacene, naphthalene, naphtho[1,2,3,4-def]chrysene, naphtho[2,It is selected from the group consisting of quinoline, pentaphene, perylene, 1H-phenalene, phenanthraquinone, phenanthralene, 9,10-phenanthrenion, phenanthridine, 1,10-phenanthroline, phenanthro[4,5-bcd]thiophene, phenazine, phenazone, picene, pyrene, quinoline, triphenylene, and 9H-xanthene.,

[0020] Optionally, one or both of the aryl groups of general formula (I), and each aryl or heteroaryl of general formula (I) are substituted with, for example, 1, 2, or 3 substituents.,

[0021] Optionally, the substituents are independently alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br, or I), --OR’, --NR’R’’, ‐‐CF3, --CN, --NO 2 、-SR’、--N 3 、‐C(=O)NR’R’’, -NR’C(=O)R’’’, ‐C(=O)R’’, -C(=O)R’, -C(=O)OR’, -OC(=O)R’, -O(CR’R’’’’), -C(=O)R’, -SO 2 R’、および-SO 2 NR’R’’ selected from the group consisting of, wherein R’ and R’’ are independently hydrogen or lower alkyl. Lower alkyl may be methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. For example, the substituent may be a linear or branched alkyl containing C 1 ~C 8 、preferably C 1 ~C 5 、e.g., methyl, ethyl or isopropyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl).

[0022] Optionally, R’ and R’’ are joined to form a cyclic functional group.,

[0023] Optionally, the substituents are independently selected from the group consisting of cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

[0024] Optionally, R of general formula (I) 1 is selected from 1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0025] Optionally, R of general formula (I) 2 is selected from indolyl, benzofuranyl, benzothiazolyl, and phenyl.

[0026] Optionally, R of general formula (I) 1 and R 2 may be fused. Thus, R of general formula (I) 1 and R 2 may be joined together to form an optionally substituted aryl group. R of general formula (I) 1 and R 2 may together form a carbocyclic or heterocyclic aromatic ring. R of general formula (I) 1 and R 2 may together form a monocyclic or polycyclic group. For example, R of general formula (I) 1 and R 2 may together form a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered, 15-membered, 16-membered, or 17-membered ring.

[0027] Optionally, one or both aryl groups of general formula (I) may contain a carbocyclic or heterocyclic aromatic ring. Optionally, one or both aryl groups of general formula (I) may be an optionally substituted carbocyclic or heterocyclic aromatic ring.

[0028] Optionally, R of general formula (I) 1 and R 2Together, they may optionally form an optionally substituted aryl or an optionally substituted heteroaryl. In this case, R in general formula (I) 1 and R 2 may each independently be an optionally substituted aryl or an optionally substituted heteroaryl. Thus, R in general formula (I) 1 and R 2 may be joined together to form an optionally substituted aryl group or an optionally substituted heteroaryl group. R in general formula (I) 1 and R 2 may together form a monocyclic or polycyclic group. For example, R in general formula (I) 1 and R 2 may together form a 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered ring, or 17-membered ring.

[0029] Optionally, the compound is selected from the group consisting of: 4-(3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene, and 4-(6-phenylpyridazin-3-yl)-1-azabicyclo[3.2.2]non-3-ene.

[0030] Advantageously, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene significantly reduces the citric acid-induced cough count compared to the saline control.

[0031] Furthermore, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene also showed a significant improvement in cough latency at a dose about 20 - 30 times lower than that of codeine, which is regarded as a "representative" narcotic antitussive.

[0032] Accordingly, in a preferred embodiment of the present invention, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene or a pharmaceutically acceptable salt thereof is provided.

[0033] In a preferred embodiment of the present invention, a compound of the following formula or a pharmaceutically acceptable salt thereof is provided.

Chemical formula

[0034] Optionally, the pharmaceutically acceptable salt is selected from one or more of chloride, bromide, sulfate, phosphate, and nitrate, acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, ascorbate and other organic acid addition salts, salts containing acidic amino acids such as aspartate or glutamate, or hydrates or ethanol solvates.

[0035] Optionally, the compound of general formula (I) may exist in unsolvated form as well as in solvated forms including hydrated forms. "Hydrate" refers to a complex formed by the combination of water molecules with the molecules or ions of a solute. "Solvate" refers to a complex formed by the combination of solvent molecules with the molecules or ions of a solute. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Solvates are meant to include hydrates. Some examples of solvents include, but are not limited to, methanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. Generally, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Optionally, the compound of general formula (I) may exist as a solid material in, for example, multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the intended uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0036] "Tautomers" refer to compounds generated by the phenomenon in which a proton of one atom of a molecule shifts to another atom (see Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992)). Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. The compounds described herein may have one or more tautomers and thus may include various isomers. All such isomeric forms of these compounds are expressly included in the present invention.

[0037] "Isomers" means compounds that have the same molecular formula but differ in the nature or sequence of the bonds between their atoms or in the arrangement of those atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". "Stereoisomers" and "(a plurality of) stereoisomers" refer to compounds that have one or more asymmetric centers or double bonds with asymmetric substitution and thus exist in different stereoisomeric forms when they can be produced as individual stereoisomers or mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers (mirror image isomers)". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers may be characterized by the absolute configuration of their asymmetric center, by the R sequence rule and S sequence determination rule of Cahn and Prelog, or in a manner in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as the (+) isomer or (-) isomer, respectively). A chiral compound can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture". Unless otherwise indicated, this specification is intended to include individual stereoisomers as well as mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the discussion in Chapter 4 of Advanced Organic Chemistry, 6th edition J. March, John Wiley and Sons, New York, 2007).

[0038] The present invention also encompasses isotopically labeled compounds that are identical to those recited herein but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include 2H (deuterium, D), 3 3H (tritium),11 C, 13C, 1 4 C, 1 5 N, 1 8 F, 31P, 32 P, 35 S, 36 Cl, and 125 I and the like, but not limited to these, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. Unless otherwise specified, when a position is specifically designated as H or hydrogen, the position is understood to have hydrogen in its naturally occurring isotope composition or its isotopes, such as deuterium (D) or tritium ( 3 H). Certain isotope-labeled compounds of the present invention (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. Tritiated compounds (i.e., 3 H) and carbon-14 (i.e., 14 C) and fluorine-18 (i.e., 18 F) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased half-life in vivo or reduced dosing requirements) and may thus be preferred in some situations. The isotope-labeled compounds of the present invention can generally be prepared by substituting an isotope-labeled reagent for a non-isotope-labeled reagent according to procedures similar to those described herein.

[0039] According to the present invention, there is also provided a pharmaceutical composition comprising a compound described herein and a pharmaceutically or therapeutically acceptable excipient or carrier, e.g., a pharmaceutical composition comprising a compound of general formula (I) and a pharmaceutically or therapeutically acceptable excipient or carrier. For example, the pharmaceutical composition may comprise 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene or a pharmaceutically acceptable salt thereof.

[0040] Pharmaceutically acceptable excipients or carriers may include fillers, binders, disintegrants, lubricants, glidants, complexing agents, solubilizing agents, and surfactants, which may be selected to facilitate the administration of the compound by a particular route. Examples of carriers include various sugars such as calcium carbonate, calcium phosphate, lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, etc. The carrier may also include, as a solvent, or for example, a sterile solution of water for injection (WFI), physiological saline, dextrose solution, Hank's solution, Ringer's solution, vegetable oil, mineral oil, animal oil, polyethylene glycol, a physiologically compatible liquid for suspensions including liquid paraffin, etc. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, microcrystalline cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowax C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor oil, mineral oil, polyethylene glycol (e.g., PEG 400 or PEG 4000 - 8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylic acid divinylbenzene copolymer, doxate sodium, cyclodextrin (e.g., 2-hydroxypropyl -.Delta-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, di-fatty acid esters of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan ester Tween (registered trademark)), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, e.g., sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or spray-dried lactose, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrate dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropylmethylcellulose), HPC (hydroxypropylcellulose), hydroxyethylcellulose, etc.

[0041] According to the present invention, there is also provided a compound described herein for use in the treatment of a disease or disorder, e.g., a compound of general formula (I) for use in the treatment of a disease or disorder. For example, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder.

[0042] According to the present invention, there are also provided compounds described herein for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR), for example, compounds of general formula (I) for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR). For example, 4-(3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene or a pharmaceutically acceptable salt thereof may be for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0043] Advantageously, the compounds described herein, for example, compounds of general formula (I), competitively inhibit the binding of radio-labeled α-bungarotoxin to the human α7 nAChR subtype with an equilibrium constant (Ki) value of 1 to 1000 nM. Accordingly, the compounds described herein, for example, compounds of general formula (I), are suitable for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0044] For example, the expression "mediated by" such as "mediated by nAChR" is understood to mean linked to the activity of nAChR.

[0045] For example, the expression "mediated by" can be understood to mean controlled, for example, by "transcriptional control or translational control", or "transcriptional control or translational control", for example, upregulation or downregulation. Preferably, the expression "mediated by nAChR" can be understood to be related to the activation (i.e., opening) of the nAChR ion channel. More specifically, a conformational change in the nAChR ion channel can occur upon binding of a compound that opens the hydrophobic gate and then leads to a four-fold symmetric twist of the M1-M4 domains that allows the passage of ions. For example, this process involves monovalent Na + and K + ions, as well as Ca 2+It can be permeable to ions. Advantageously, the ability of nAChR to change intracellular calcium levels can lead to the activation of different downstream intracellular pathways such as neuronal signaling and plasticity. Furthermore, the expression "mediated" can be understood to include, for example, the promotion of intracellular signaling via a G-protein binding cluster contained in the intracellular loop of the α7 subunit.

[0046] Optionally, the compounds described herein, for example, the compounds of general formula (I), can desensitize nAChR. Therefore, the compounds described herein, for example, the compounds of general formula (I), can be suitable for desensitizing nAChR. Accordingly, the compounds described herein, for example, the compounds of general formula (I), for use as nAChR desensitizing agents are also provided.

[0047] More specifically, nAChR can be rapidly converted to a closed state after activation and then to a desensitized state. Desensitization is the loss of the biological response to agonist stimulation. When the ligand is washed out, the receptor may return to the basal or resting allosteric state.

[0048] According to the present invention, there is also provided the use of the compounds described herein, for example, the use of the compounds of general formula (I) in the manufacture of a medicament for the treatment of a disease or disorder.

[0049] According to the present invention, there is also provided a method for treating a disease or disorder, comprising the step of administering to a patient in need thereof a compound described herein, or a pharmaceutical composition described herein. For example, there is provided a method for treating a disease or disorder, comprising the step of administering to a patient in need thereof a compound of general formula (I), or a pharmaceutical composition comprising a compound of general formula (I). For example, the method for treating a disease or disorder can include the step of administering 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene, or a pharmaceutical composition described herein, to a patient in need thereof.

[0050] Optionally, the disease or disorder is a disease or disorder mediated by the α7 nAChR.

[0051] Optionally, the disease or disorder is selected from cognitive and neurodegenerative diseases, psychotic disorders such as schizophrenia, acute nociceptive, neuropathic, or inflammatory pain, and mood disorders such as depression and inflammation.

[0052] For example, the disease or disorder is i) pain including one or more of acute, neural, inflammatory, neuropathic, chronic pain, severe chronic pain, postoperative pain, cancer-related pain, angina, kidney or gallbladder contusion, menstruation, migraine, gout, arthritis, rheumatic disease, tenosynovitis, vasculitis, trigeminal neuralgia or herpes neuralgia, painful diabetic neuropathy, causalgia, low back pain, fibromyalgia syndrome, and brachial plexus palsy; ii) metabolic syndrome, weight gain, type I diabetes, type II diabetes, or diabetic neuropathy; iii) psoriasis, asthma, atherosclerosis, idiopathic pulmonary fibrosis, inflammation including one or more of chronic and acute inflammation, psoriasis, endotoxemia, acute gouty arthritis, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, allograft rejection, chronic transplant rejection, asthma, atherosclerosis, mononuclear phagocyte-dependent lung injury, atopic dermatitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute chest syndrome in sickle cell disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute cholangitis, aphthous stomatitis, ileitis, glomerulonephritis, lupus nephritis, thrombosis, and graft-versus-host reaction, and / or iv) selected from the group consisting of cognition including one or more of age-related memory impairment, mild cognitive impairment, pre-senile dementia, early-onset Alzheimer's disease, senile dementia, Alzheimer's type dementia, Alzheimer's type mild to moderate dementia, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive impairment in schizophrenia, and cognitive dysfunction in schizophrenia.

[0053] The pharmaceutical compositions can be for use in improving any of their conditions, diseases, and symptoms associated with disorders.

[0054] Preferably, the treatment is for preventing and / or suppressing cough, for improving the progression of cough, the symptoms of cough, and the recurrence of cough. The treatment may be for treating the origin of cough. Hereinafter, "cough" is understood to be related to expelling air from the lungs, for example, from the lungs of a subject, for example, a human subject. Advantageously, the compounds of the present invention, for example, the compounds of general formula (I), can be used as antitussives. Accordingly, there are also provided compounds described herein for use as antitussives, such as compounds of general formula (I) for use as antitussives. More specifically, an antitussive can inhibit cough through a central mechanism, or a peripheral mechanism, or a mixture of the two mechanisms.

[0055] The pharmaceutical compositions described herein can be used as selective α7nAChR agonists. The pharmaceutical compositions described herein can also be used as antitussives. The pharmaceutical compositions described herein can also be used as anti-inflammatory agents, for example, as anti-inflammatory agents for acute lung injury, antigen challenge and / or Gram-negative bacterial infection. As a result, the pharmaceutical compositions described herein can be for use in the treatment of inflammation, for example, the treatment of acute lung injury, the treatment of antigen challenge, and / or the treatment of Gram-negative bacterial infections.

[0056] The compounds described herein can also be used as adjuvant therapies in combination with existing therapies, for example, in the management of any of the aforementioned types of diseases and disorders. In such situations, it is preferred to administer the active ingredient in a manner that minimizes the effect on nAChR.

[0057] Including subtypes such as those related to muscle and ganglia. This can be achieved by targeted drug delivery and / or by adjusting the dosage such that the desired effect is obtained without reaching the threshold dosage required to achieve significant side effects.

[0058] Optionally, for the uses, compounds or methods described herein, the compounds may be administered orally.

[0059] Optionally, for the uses, compounds or methods described herein, the compounds may be such that they are administered in dry powder form. Preferably, the compound is dry powder 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene, for example, dry powder insufflated 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene.

[0060] Optionally, for the uses, compounds or methods described herein, the compounds may be such that they are administered in spray form. Preferably, the compound is atomized 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene.

[0061] Optionally, for the uses, compounds or methods described herein, the compounds may be administered orally at a dose of 0.1 mg to 1 g / kg per day.

[0062] For example, the compound may be administered orally at a dose of at least about 0.00001 mg / kg per day, at least about 0.0001 mg / kg per day, at least about 0.001 mg / kg per day, at least about 0.01 mg / kg per day, at least about 0.1 mg / kg per day, at least about 0.2 mg / kg per day, at least about 0.3 mg / kg per day, at least about 0.4 mg / kg per day, at least about 0.5 mg / kg per day. The compound may include any range from a given endpoint.

[0063] For example, the compound may be orally administered at a dosage of about 0.01 g / kg or less per day, about 0.1 g / kg or less per day, about 0.5 g / kg or less per day, about 0.9 g / kg or less per day, about 1 g / kg or less per day, about 1.1 g / kg or less per day, about 1.2 g / kg or less per day, about 1.5 g / kg or less per day, about 2 g / kg or less per day. The compound may include any range from a given endpoint.

[0064] For example, the compound may be orally administered at a dosage of at least about 0.00001 mg / kg per day to about 2 g / kg per day, at least about 0.0001 mg / kg / day to about 1.5 g / kg / day or less, at least about 0.001 mg / kg per day to about 1.2 g / kg per day or less, at least about 0.01 mg / kg / day to about 1.1 g / kg or less, at least about 0.1 mg / kg per day to about 1 g / kg per day or less, at least about 0.2 mg / kg / day to about 0.9 g / kg / day or less, at least about 0.3 mg / kg / day to about 0.5 g / kg / day or less, at least about 0.4 mg / kg per day to about 0.1 g / kg per day or less, at least about 0.5 mg / kg per day to about 0.01 g / kg or less per day. The compound may include any range from a given endpoint.

[0065] For example, a compound, use, or method for use described herein may be such that the compound is orally administered at 0.1 mg / kg per day, 0.2 mg / kg per day, 0.3 mg / kg per day, 0.4 mg / kg per day, 0.5 mg / kg per day, 1 mg / kg per day, 2 mg / kg per day, 3 mg / kg per day, 4 mg / kg per day, 5 mg / kg per day, 10 mg / kg per day, 15 mg / kg per day, 20 mg / kg per day, 25 mg / kg per day, 30 mg / kg per day, 35 mg / kg per day, 40 mg / kg per day, 45 mg / kg per day, 50 mg / kg per day, 100 mg / kg per day, 150 mg / kg per day, 200 mg / kg per day, 250 mg / kg per day, 300 mg / kg per day, 350 mg / kg per day, 400 mg / kg per day, 450 mg / kg per day, 500 mg / kg per day, 550 mg / kg per day, 600 mg / kg per day, 650 mg / kg per day, 700 mg / kg per day, 750 mg / kg per day, 800 mg / kg per day, 850 mg / kg per day, 900 mg / kg per day, 950 mg / kg per day, 1000 mg / kg per day, 1100 mg / kg per day, 1200 mg / kg per day, 1300 mg / kg per day, 1400 mg / kg per day, 1500 mg / kg per day, 1600 mg / kg per day, 1700 mg / kg per day, 1800 mg / kg per day, 1900 mg / kg per day, 2000 mg / kg per day. The compound may include any range from a given endpoint.

[0066] Optionally, a compound, use, or method for use described herein may be such that the compound is orally administered at 5 mg to 2 g per day.

[0067] For example, the compound may be orally administered at a dose of at least about 0.1 mg / day, at least about 1 mg / day, at least about 3 mg / day, at least about 4 mg / day, at least about 5 mg / day, at least about 5.1 mg / day, at least about 6 mg / day, at least about 10 mg / day, at least about 50 mg / day. The compound may include any range from a given endpoint.

[0068] For example, the compound may be orally administered at a dosage of about 0.2 g / day or less, about 0.5 g / day or less, about 1 g / day or less, about 1.5 g / day or less, about 2 g / day or less, about 2.5 g / day or less, about 3 g / day or less, about 5 g / day or less, or about 10 g / day or less. The compound may include any range from a given endpoint.

[0069] For example, the compound may be orally administered at a dosage of at least about 0.1 mg / day to about 10 g / day or less, at least about 1 mg / day to about 5 g / day or less, at least about 3 mg / day to about 3 g / day or less, at least about 4 mg / day to about 2.5 g / day or less, at least about 5 mg / day to about 2 g / day or less, at least about 5.1 mg / day to about 1.5 g / day or less, at least about 6 mg / day to about 1 g / day or less, at least about 10 mg / day to about 0.5 g / day or less, or at least about 50 mg / day to about 0.2 g / day or less. The compound may include any range from a given endpoint.

[0070] For example, the compound may be orally administered at a dosage of 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, 1400 mg / day, 1500 mg / day, 1600 mg / day, 1700 mg / day, 1800 mg / day, 1900 mg / day, 2000 mg / day, 2100 mg / day, 2200 mg / day, 2300 mg / day, 2400 mg / day, or 2500 mg / day. The compound may include any range from a given endpoint.

[0071] The expression "about" with respect to a numerical value is understood to be ± 10%, preferably ± 5%, for example ± 10% w / w, preferably ± 5% w / w, of the average.

[0072] Optionally, the compounds, uses, or methods for use described herein may be such that the composition is in the form of a tablet. The tablet may be a film-coated tablet. The compounds, uses, or methods for use described herein may be such that the composition is in the form of a capsule, for example a gelatin capsule.

[0073] Optionally, the uses, uses, or methods described herein may be such that the compound is administered parenterally, topically, rectally, transmucosally, or enterally.

[0074] According to the present invention, there is also provided a method for producing a compound of general formula (I) shown in Scheme (I).

Chemical formula

[0075] Optionally, R 1 and R 2 are as defined above. For example, for a compound of general formula (I), R 1 and R 2 are each independently optionally substituted aryl groups which may be the same or different, one or both of the aryl groups contain a carbocyclic or heterocyclic aromatic ring, one or both of the aryl groups are monocyclic or polycyclic, and R 1 and R 2 are optionally fused. Alternatively, for a compound of general formula (I), R 1 is optionally substituted aryl or optionally substituted heteroaryl, and R 2 is halogen, triflate, optionally substituted aryl, optionally substituted heteroaryl, or absent.

[0076] As will be apparent to those skilled in the art, the compounds of formula (I) include 4-substituted 1-azabicyclo[3.2.2]non-3-ene. The methods by which the compounds of the present invention can be prepared can vary, but the compounds can be advantageously prepared using intermediates generated during the synthesis of the target compounds shown in Scheme (I) above.

[0077] Other synthetic strategies will be apparent to those skilled in the art, but aryl-substituted 1-azabicyclo[3.2.2]non-3-ene can be prepared starting from quinuclidin-3-one. The Buchner-Curtius-Schlotterbeck reaction can be used to promote one carbon ring expansion of quinuclidin-3-one after triflation and Suzuki coupling with halogenated aryls. The various combinations of aryl groups in formula (I) can be achieved via the Suzuki cross-coupling reaction.

[0078] Specific examples of the compound Examples of representative compounds of the present invention include, but are not limited to, the following compounds. 4-(3-Pyridyl)-1-azabicyclo[3.2.2]non-3-ene

Chemical formula

Chemical formula

Chemical formula

[0079] [Numbered paragraph] Aspects of the present invention are described in the following numbered paragraphs. 1. Compounds of general formula (I), [Chemistry] (I), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently an optionally substituted aryl group, which may be the same or different, and one or both of the aryl groups contain a carbocyclic or heterocyclic aromatic ring, and one or both of the aryl groups are monocyclic or polycyclic, wherein R 1 and R 2 are optionally fused, a compound.

[0080] 2. The compound according to numbered paragraph 1, wherein the aromatic ring or each aromatic ring of the carbocyclic or heterocyclic aromatic ring of one or both of the aryl groups is a 3- to 10-membered ring, such as a 5-membered ring or a 6-membered ring.

[0081] 3. The compound according to numbered paragraph 1 or numbered paragraph 2, wherein one or both of the aryl groups are monocyclic.

[0082] 4. The compound according to numbered paragraph 3, wherein one or both of the aryl groups are independently selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.

[0083] 5. The compound according to either numbered paragraph 1 or numbered paragraph 2, wherein one or both of the aryl groups are polycyclic.

[0084] 6. The compound according to numbered paragraph 5, wherein one or both aryl groups are independently selected from the group consisting of naphthalenyl, anthracenyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzodioxolanyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, purinyl, thienopyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, naphthyridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and azulenyl.

[0085] 7. The compound according to any of the preceding numbered paragraphs, wherein one or both aryl groups are substituted with, for example, 1, 2, or 3 substituents.

[0086] 8. The substituents are independently alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br or I), --OR’, --NR’R’’, ‐‐CF3, --CN, --NO 2 , --SR’, --N 3 , ‐C(=O)NR’R’’, --NR’C(=O)R’’, ‐‐C(=O)R’, --C(=O)OR’, --OC(=O)R’, --O(CR’R’’), --C(=O)R’, --SO 2 R’, and --SO 2 NR’R’’ selected from the group consisting of, wherein R’ and R’’ are each hydrogen, lower alkyl (e.g., C 1 ~C 8 linear or branched alkyl including, preferably C 1 ~C 5 , such as methyl, ethyl or isopropyl), cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl), and wherein R’ and R’’ are optionally combined to form a cyclic functional group, the compound according to numbered paragraph 7.

[0087] 9. The compound according to numbered paragraph 8, wherein the substituent is independently selected from the group consisting of cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

[0088] 10. R 1 is as defined in any of the preceding numbered paragraphs, selected from 1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0089] 11. R 2 is as defined in any of the preceding numbered paragraphs, selected from indolyl, benzofuranyl, benzothiazolyl, and phenyl.

[0090] 12. The compound is 4-(3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene, and 4-(6-phenylpyridazin-3-yl)-1-azabicyclo[3.2.2]non-3-ene, and is selected from the group consisting of any one of the preceding numbered paragraphs.

[0091] 13. The compound according to numbered paragraph 12, wherein the compound is 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene.

[0092] 14. The pharmaceutically acceptable salt is selected from one or more of chlorides, bromides, sulfates, phosphates, and nitrates; organic acid addition salts such as acetates, galactarates, propionates, succinates, lactates, glycolates, malates, tartrates, citrates, maleates, fumarates, methanesulfonates, p-toluenesulfonates, ascorbates; salts containing acidic amino acids such as aspartates or glutamates, or hydrates or ethanol solvates, and is the compound according to any of the preceding numbered paragraphs.

[0093] 15. A compound of general formula (I),

Chem.

[0094] 16. A pharmaceutical composition comprising a compound according to any one of numbered paragraphs 1 to 15 and a pharmaceutically or therapeutically acceptable excipient or carrier.

[0095] 17. A compound according to any one of numbered paragraphs 1 to 15 for use in the treatment of a disease or disorder.

[0096] 18. A compound according to any one of numbered paragraphs 1 to 15 for use in the treatment of a disease or disorder mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0097] 19. Use of a compound according to any one of numbered paragraphs 1 to 15 in the manufacture of a medicament for the treatment of a disease or disorder.

[0098] 20. A method of treating a disease or disorder, comprising administering to a patient in need thereof a compound according to any one of numbered paragraphs 1 to 15 or a pharmaceutical composition according to numbered paragraph 16.

[0099] 21. The compound, use as described in numbered paragraph 17 or numbered paragraph 18, use as described in numbered paragraph 19, or method as described in numbered paragraph 20, for the use wherein the treatment is for preventing and / or suppressing cough, for the progression of cough, for improving the symptoms of cough, and for improving the recurrence of cough.

[0100] 22. The compound, use as described in numbered paragraph 17 or numbered paragraph 18, use as described in numbered paragraph 19, or method as described in paragraph 20, for the use wherein the disease or disorder is selected from cognitive and neurodegenerative diseases, psychotic disorders such as schizophrenia, acute nociceptive, neuropathic, or inflammatory pain, and mood disorders such as depression and inflammation.

[0101] 23. The compound, use, or method for the use as described in numbered paragraph 21 or numbered paragraph 22, wherein the compound is administered orally.

[0102] 24. The compound, use, or method for the use as described in numbered paragraph 23, wherein the compound is administered orally at a dose of 0.1 mg to 1 g / kg per day.

[0103] 25. The compound, use, or method for the use as described in numbered paragraph 23, wherein the compound is administered orally at a dose of at least about 0.00001 mg / kg per day, at least about 0.0001 mg / kg per day, at least about 0.001 mg / kg per day, at least about 0.01 mg / kg per day, at least about 0.1 mg / kg per day, at least about 0.2 mg / kg per day, at least about 0.3 mg / kg per day, at least about 0.4 mg / kg per day, at least about 0.5 mg / kg per day.

[0104] 26. The compound, use or method for use according to numbered paragraph 23, wherein the compound is orally administered at a dose of about 0.01 g / kg or less per day, about 0.1 g / kg or less per day, about 0.5 g / kg or less per day, about 0.9 g / kg or less per day, about 1 g / kg or less per day, about 1.1 g / kg or less per day, about 1.2 g / kg or less per day, about 1.5 g / kg or less per day, about 2 g / kg or less per day.

[0105] 27. The compound, use or method for use according to numbered paragraph 23, wherein the compound is orally administered at a dose of at least about 0.00001 mg / kg to about 2 g / kg or less per day, at least about 0.0001 mg / kg to about 1.5 g / kg or less per day, at least about 0.001 mg / kg to about 1.2 g / kg or less per day, at least about 0.01 mg / kg to about 1.1 g / kg or less per day, at least about 0.1 mg / kg to about 1 g / kg or less per day, at least about 0.2 mg / kg to about 0.9 g / kg or less per day, at least about 0.3 mg / kg to about 0.5 g / kg or less per day, at least about 0.4 mg / kg to about 0.1 g / kg or less per day, at least about 0.5 mg / kg to about 0.01 g / kg or less per day.

[0106] 28. The compound, use or method for use according to numbered paragraph 23, wherein the compound is orally administered at 5 mg to 2 g per day.

[0107] 29. The compound, use or method for use according to numbered paragraph 23, wherein the compound is orally administered at a dose of at least about 0.1 mg / day, at least about 1 mg / day, at least about 3 mg / day, at least about 4 mg / day, at least about 5 mg / day, at least about 5.1 mg / day, at least about 6 mg / day, at least about 10 mg / day, at least about 50 mg / day.

[0108] 30. A compound, a compound for use, or a method for use according to numbered paragraph 23, wherein the compound is orally administered at a dose of about 0.2 g / day or less, about 0.5 g / day or less, about 1 g / day or less, about 1.5 g / day or less, about 2 g / day or less, about 2.5 g / day or less, about 3 g / day or less, about 5 g / day or less, about 10 g / day or less.

[0109] 31. A compound, a use or a method for use according to numbered paragraph 23, wherein the compound is orally administered at a dose of at least about 0.1 mg / day to about 10 g / day or less, at least about 1 mg / day to about 5 g / day or less, at least about 3 mg / day to about 3 g / day or less, at least about 4 mg / day to about 2.5 g / day or less, at least about 5 mg / day to about 2 g / day or less, at least about 5.1 mg / day to about 1.5 g / day or less, at least about 6 mg / day to about 1 g / day or less, at least about 10 mg / day to about 0.5 g / day or less, at least about 50 mg / day to about 0.2 g / day or less.

[0110] 32. A compound, a use for use according to any one of numbered paragraphs 23 to 31, wherein the composition is in the form of a tablet. Or a method.

[0111] 33. A compound, a use or a method for use according to numbered paragraph 21 or numbered paragraph 22, wherein the compound is administered parenterally, topically, rectally, transmucosally, or enterally.

[0112] 34. A method for producing a compound of general formula (I) shown in Scheme (I),

Chemical formula

Brief Description of the Drawings

[0113]

Figure 1A

Figure 1B

Figure 2

Figure 3

[0114] [Experiment] Synthesis examples of the compounds described in Examples 1 to 5, as well as the biological activity examples of Examples 6 and 7, are provided to illustrate the present invention and should not be construed as limiting its scope. In these examples, all parts and percentages are by weight unless otherwise stated. The reaction yields are reported as mole percentages.

Example

[0115] Example 1 (reference): 1-azabicyclo[3.2.2]nonan-4-one (CAS: 30708-54-4)

Chemical formula

[0116] Example 2: 1-azabicyclo[3.2.2]non-3-en-4-yl trifluoromethanesulfonate [Chemical formula] A solution of 1-azabicyclo[3.2.2]nonan-4-one (5.00 g, 35.9 mmol, 1.00 equivalent) in tetrahydrofuran (30 mL) was added to a solution of lithium dimethylamide (2.00 M, 23.3 mL, 1.30 equivalents) in tetrahydrofuran (10 mL) at -78 °C, and the mixture was stirred at -78 °C for 30 minutes. Then, a solution of bis(trifluoromethanesulfonyl)aniline (16.6 g, 46.7 mmol, 1.30 equivalents) in tetrahydrofuran (5 mL) was added to the mixture. The reaction mixture was quenched by adding saturated NaHCO 3 (10 mL), and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , dichloromethane / methanol = 1 / 0 to 10 / 1). 1-Azabicyclo[3.2.2]non-3-en-4-yl trifluoromethanesulfonate (10.0 g, crude) was obtained as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 5.65 - 5.63 (m, 1H), 3.62 (d, J = 2.9 Hz, 2H), 3.15 - 3.05 (m, 4H), 2.48 - 2.47 (m, 1H), 2.24 - 2.21 (m, 2H), 1.88 - 1.84 (m, 2H).

[0117] Example 3: 4-(3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene ​​​​1 - Azabicyclo[3.2.2]nona - 3 - en - 4 - yl trifluoromethanesulfonate (1.00 g, 3.69 mmol, 1.00 equiv), pyridine - 3 - boronic acid (679 mg, 5.53 mmol, 1.50 equiv), K 2 CO 3 (1.53 g, 11.0 mmol, 3.00 equiv), Pd(dppf)Cl 2 (134 mg, 184 μmol, 0.0500 equiv) in water (2 mL) and dioxane (10 mL) was stirred at 90 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 1 / 0 - 5 / 1; (1% NH3·H2O)) and preparative HPLC (basic conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 17% - 45%, 10 min). 4 - (3 - Pyridyl)-1 - azabicyclo[3.2.2]nona - 3 - ene (16.0 mg, 79.62 μmol, 2.16% yield, 99.67% purity) was obtained as a pale yellow gum. 1H NMR (400 MHz, CD3OD): δ 8.49 (d, J = 2.0 Hz, 1H), 8.38 (dd, J = 1.5, 4.8 Hz, 1H), 7.78 (td, J = 1.9, 8.0 Hz, 1H), 7.37 (dd, J = 4.9, 7.9 Hz, 1H), 5.86 (dt, J = 1.5, 3.1 Hz, 1H), 3.75 (d, J = 3.1 Hz, 2H), 3.13 - 3.07 (m, 4H), 2.79 - 2.78 (m, 1H), 2.18 - 2.13 (m, 2H), 2.06 - 2.02 (m, 2H). LCMS: m / z = 201 (M + 1)+.

[0118] Example 4: 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene A solution of 1 - azabicyclo[3.2.2]nona - 3 - en - 4 - yl trifluoromethanesulfonate (500 mg, 1.84 mmol, 1.00 equiv) and 2 - phenyl - 5 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyridine (570 mg, 2.03 mmol, 1.10 equiv) in water (2 mL) and dioxane (10 mL) was added with K​​2 CO 3 (764 mg, 5.53 mmol, 3.00 equivalents) and Pd(dppf)Cl 2 (67.4 mg, 92.1 μmol, 0.0500 equivalent) were added. The mixture was stirred at 90 °C for 10 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , dichloromethane / methanol = 1 / 0 to 10 / 1). 4-(6-Phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene (150 mg, 529 μmol, yield 28.7%, purity 97.1%) was obtained as a brown solid. 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 1H), 7.93 - 7.82 (m, 3H), 7.50 - 7.43 (m, 3H), 7.16 - 6.89 (m, 1H), 5.92 (s, 1H), 3.87 (d, J = 3.2 Hz, 2H), 3.26 - 3.20 (m, 4H), 2.91 (s, 1H), 2.26 - 2.09 (m, 4H). LCMS: m / z = 277 (M+1)+.

[0119] [Example 5: 4-(6-Phenylpyridazin-3-yl)-1-azabicyclo[3.2.2]non-3-ene] Step 1: To a solution of 1-azabicyclo[3.2.2]non-3-en-4-yl trifluoromethanesulfonate (0.500 g, 1.84 mmol, 1.00 equivalent) and bis(pinacolato)diboron (467 mg, 1.84 mmol, 1.00 equivalent) in dioxane (10 mL) were added potassium acetate (361 mg, 3.68 mmol, 2.00 equivalents) and Pd(dppf)Cl 2 (67.3 mg, 92.0 μmol, 0.0500 equivalent). The mixture was stirred at 80 °C for 12 h. 3-Chloro-6-phenylpyridazine (420 mg, 2.21 mmol, 1.20 equivalents), K 2 CO 3 (762 mg, 5.52 mmol, 3.00 equivalents), and Pd(dppf)Cl 2(67.3 mg, 92.0 μmol, 0.0500 eq) was added to the mixture, and the mixture was stirred at 90 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , dichloromethane / methanol = 1 / 0 to 10 / 1). 4-(6-Phenylpyridazin-3-yl)-1-azabicyclo[3.2.2]non-3-ene (50.8 mg, 177 μmol, yield 9.63%, purity 96.7%) was obtained as a gray solid. 1H NMR (400 MHz, CD3OD): δ 8.11 - 8.07 (m, 2H), 7.93 (d, J = 9.0 Hz, 1H), 7.57 - 7.54 (m, 2H), 7.18 - 6.93 (m, 2H), 6.43 - 6.42 (m, 1H), 4.03 (d, J = 3.3 Hz, 2H), 3.65 - 3.64 (m, 1H), 3.32 - 3.29 (m, 2H), 3.28 - 3.26 (m, 2H), 2.25 - 2.09 (m, 4H). LCMS: m / z = 278 (M+1)+.

[0120] [Example 6: Biological Activity] The compounds described in Examples 3 - 5 competitively inhibited the binding of radiolabeled α-bungarotoxin to the human α7 nAChR subtype with equilibrium constant (Ki) values of 1 - 1000 nM.

[0121] Human recombinant nicotinic acetylcholine α7 receptor was expressed in SH-SY5Y cells. A 20 μg aliquot of the membrane was incubated with 0.4 nM [125I]α-bungarotoxin in modified phosphate buffer pH 7.4 at 37 °C for 120 min. Nonspecific binding was estimated in the presence of 1 μM α-bungarotoxin. The membrane was filtered, washed, and then the filter was counted to determine specifically bound [125I]α-bungarotoxin. IC 50 values were determined by non-linear least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK). The Ki value was the observed IC of the tested compound 50, using the concentration of the radioactive ligand used in the assay and the historical value of the KD of the ligand (0.40 nM [125I] α-bungarotoxin), was calculated using the Cheng and Prusoff equation. The Ki values are shown in nM for each compound tested in Table 1 below.

[0122] Table 1

Table 1

[0123] [Example 7: In Vivo Cough Induction Experiment] Materials and Methods As shown in Figure 1, cough induction is performed by placing a guinea pig in a whole body plethysmograph (WBP) equipped with an Aeroneb™ vibrating mesh nebulizer and including a pressure transducer and a detection device (EMKA Technologies). A primary microphone (EMKA Technologies) is provided for acoustic confirmation of the cough frequency in the form of a digital trace using EMKA software. The data acquisition software (iOX2, version 2.10.5.28, EMKA Technologies, France) displays the pressure signal detected from the pressure transducer and calculates both the cough frequency and intensity measured during the test period.

[0124] A secondary microphone (T1 True Wireless Earphone, QCY®) is also placed inside the chamber and connected to a smartphone via Bluetooth, enabling the observer to hear audible sounds during the test. A bias flow rate of 2 L / min is used to continuously draw either air (during the fresh air period) or aerosolized citric acid from the nebulizer into the WBP and discharge it through the exhaust pipe. The chamber pressure inside the WBP is set to -10 to -30 Pa relative to the ambient pressure.

[0125] Before the citrate challenge, guinea pigs are administered vehicle control, positive control, or test compound (if applicable) at different doses (intraperitoneal injection) (Table 2) and individually placed in the WBP for at least 5 minutes for acclimation.

[0126]

Table 2

[0127] The procedure was as follows. Injection → Mouse in a box with citrate for 10 minutes (count coughs) → Box, then fill with air for 5 minutes (count coughs) → Mouse moves to recovery cage.

[0128] Aerosol is generated using an appropriate concentration of citrate and delivered to the WBP for 10 minutes while recording the pressure measurement values constantly. The average concentration of citrate was 1283.1 ± 137.2 μg / L. When the citrate challenge is completed, the guinea pigs are recovered and the cough count recording is continued for an additional 5 minutes. Thereafter, the guinea pigs are carefully monitored in the recovery cage for complete recovery from the challenge, and there were no adverse events before returning the animals to the home cage. The cough count (CCnt) is recorded for at least 10 minutes starting from the citrate challenge, and the cough incubation period (CIP) is defined as the time it takes to cough for the first time after the citrate challenge.

[0129] The cough response during the citrate challenge and recovery after treatment is carefully monitored using the following: - Continuous pressure monitoring (Plethysmography monitoring software) - Acoustic confirmation of cough using a microphone (primary and secondary) - Visual confirmation of cough by changes in posture.

[0130] Statistical analysis and data presentation Data are analyzed using one-way ANOVA (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001) when compared to the saline control, and each column represents the mean ± SEM.

[0131] Figures 2 and 3 relate to the evaluation of the antitussive efficacy of 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene using a chemically induced cough in vivo model in guinea pigs.

[0132] Figures 2A and 3A show the mean ± SEM, and Figures 2B and 3B show the results of each replicate, respectively.

[0133] [Results] As shown in Figure 2 for cough count, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene, an exemplary compound of the present invention, significantly reduced the citric acid-induced cough count compared to the saline control.

[0134] More specifically, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene significantly reduced the citric acid-induced cough count at low concentration (1.5 mg / kg, cough count = 3, p < 0.0001), medium concentration (5 mg / kg, cough count = 6, p < 0.05), and high concentration (15 mg / kg, cough count = 7, p < 0.05) compared to the saline control (0.9% sodium chloride, cough count = 13).

[0135] The decrease in citric acid-induced cough count by 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene was similar to that of 30 mg / kg of codeine. However, at 1.5 mg / kg to 15 mg / kg, the dose of 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene was about 20 to 30 times lower compared to the dose of 30 mg / kg of codeine.

[0136] Furthermore, as shown in Figure 3 for the latency period, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene showed a significant improvement in the cough latency period.

[0137] More specifically, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene significantly increased the cough latency at low concentration (1.5 mg / kg, 504 seconds, p<0.05) and high concentration (15 mg / kg, 491 seconds, p<0.05) compared with the physiological saline control (0.9% sodium chloride, 232 seconds).

[0138] The increase in cough latency by 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene was similar to that by 30 mg / kg of codeine. However, at 1.5 mg / kg to 15 mg / kg, the dose of 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene was about 20 to 30 times lower than the dose of 30 mg / kg of codeine.

[0139] Conclusion 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene, an exemplary compound of the present invention, significantly reduced the citric acid-induced cough count compared with the physiological saline control (see Figure 2).

[0140] Furthermore, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]non-3-ene also showed a significant improvement in cough latency at a dose about 20 to 30 times lower than that of codeine, which is considered a "representative" narcotic antitussive (see Figure 3).

Claims

1. Compounds of general formula (I), (I) or a pharmaceutically acceptable salt thereof R 1 However, it is an arbitrarily substituted aryl or an arbitrarily substituted heteroaryl, R 2 However, it is either a halogen, a triflate, an optionally substituted aryl, an optionally substituted heteroaryl, or none at all. Or in the formula, R 1 and R 2 A compound in which both atoms form an optionally substituted aryl or optionally substituted heteroaryl molecule.

2. The compound according to claim 1, wherein the aforementioned or each aryl or heteroaryl is a 5- to 10-membered ring, for example, a 5-membered ring or a 6-membered ring.

3. The compound according to claim 1, wherein one or both of the aryl group or heteroaryl group are monocyclic.

4. The compound according to claim 3, wherein one or both of the aryl group or heteroaryl group are independently selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyridadinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.

5. The compound according to claim 1, wherein one or both of the aryl group and / or heteroaryl group are polycyclic.

6. The compound according to claim 5, wherein one or both of the aryl group and / or heteroaryl group are independently selected from the group consisting of naphthalenyl, anthracenyl, indolidinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzodioxolanil, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, purinyl, thienopyrazinyl, quinolinyl, isoquinolinyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridine, pteridinyl, carbazolyl, acridinyl, naphthyridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and azurenyl.

7. One or both of the aryl or heteroaryl groups are substituted, for example with one, two or three substituents, optionally said substituents being alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br or I), --OR', --NR'R'', --CF 3 , --CN, --NO 2 , --SR', --N 3 , -C(=O)NR'R'', --NR'C(=O)R'', --C(=O)R', --C(=O)OR', --OC(=O)R', --O(CR'R''), --C(=O)R', --SO 2 R', and --SO 2 NR'R'' selected from the group consisting of, wherein R' and R'' are each hydrogen, lower alkyl (e.g., C 1 ~C 8 linear or branched alkyl including, preferably C 1 ~C 5 , for example methyl, ethyl or isopropyl), cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl), wherein R' and R'' are optionally combined to form a cyclic functional group, the compound according to claim 1.

8. The compound according to claim 7, wherein the substituent is independently selected from the group consisting of cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

9. R 1 However, selected from 1,3,4-thiadiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl, and / or R 2 The compound according to claim 1, wherein the compound is selected from indolyl, benzofuranyl, benzothiazolyl, and phenyl.

10. The aforementioned compound, 4-(3-pyridyl)-1-azabicyclo[3.2.2]nona-3-ene, 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]nona-3-ene, and Selected from the group consisting of 4-(6-phenylpyridazin-3-yl)-1-azabicyclo[3.2.2]nona-3-ene, For example, the compound according to claim 1, wherein the compound is 4-(6-phenyl-3-pyridyl)-1-azabicyclo[3.2.2]nona-3-ene.

11. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically or therapeutically acceptable excipient or carrier.

12. A pharmaceutical composition comprising the compound described in claim 1 for use in the treatment of a disease or disorder.

13. A pharmaceutical composition comprising the compound according to claim 1 for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR).

14. The pharmaceutical composition for use according to claim 12, wherein the treatment is for the prevention and / or suppression of cough, progression of cough, improvement of cough symptoms, and improvement of cough recurrence.

15. A method for producing a compound of general formula (I) shown in scheme (I), Scheme (I), In the formula, R 1 and R 2 However, the method is as defined in claim 1.

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