JP2002030084A - 1-azabicycloalkane compound and pharmaceutical use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound having α7-nicotine receptor agonism or α7-nicotine receptor partial agonism, therefore useful as a therapeutic or prophylactic agent for such diseases as Alzheimer's disease, recognition dysfunction, attention-defective hyperkinesia, anxiety, depression, schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease and Huntington's disease. SOLUTION: This new compound is an 1-azabicycloalkane compound of the general formula (I) (wherein, the definitions of the respective symbols are such as to be described in the specification), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 1-azabicycloalkane compound for providing a medicament useful for diseases of the central nervous system.

[0002]

BACKGROUND OF THE INVENTION Nicotine receptors are known to have many subtypes, and to date at least 11 subtypes (α2-9 and β2-4) have been identified (reviewed). : Trends in Pharmacological Scie
nces, 12: 34-40, 1991; Progress in Neurobiology, 5
3: 199-237,1997). It is known that nicotine receptors exist as pentamers of these subtypes, form ion channels, and take in calcium ions and the like into cells. There are mainly two subtypes (α4
β2 and α7) are known to exist, but α4β
The 2 nicotine receptor is formed as a hetero-oligomer of the α4 subunit and the β2 subunit, and the α7 nicotine receptor is formed as a homo-oligomer of the α7 subunit. These subtypes (α4β2 nicotine receptor and α7 nicotine receptor) are distributed in a wide range of regions in the brain (cerebral cortex, hippocampus, etc.). Nicotine receptors (α4β2 nicotine receptor and α7 nicotine receptor) in the central nervous system are known to be involved in various physiological functions such as neural development / differentiation, formation of learning and memory, and reward. (Review: Brain Research
Reviews, 26: 198-216, 1998; Trends in Neuroscience
s, 22: 555-561, 1999; MolecularNeurobiology, 20: 1-1
6, 1999). The nicotine receptor present at the presynapse
It is known to play an important role in the release of various neurotransmitters (acetylcholine, dopamine, glutamate, etc.) (Review: Trends in Phar
macological Sciences, 20: 92-98, 1997; Annual Revie
ws of Neuroscience 22: 443-485, 1999; Molecular Neu
robiology, 20: 1-16, 1999). In addition, it is known that the nicotine receptor present in the postsynapse plays an important role in cholinergic neurotransmission (reviewed by Tren)
ds in Pharmacological Sciences, 22: 555-561, 1999;
Molecular Neurobiology, 20: 1-16, 1999).

[0003] On the other hand, the acetylcholine system is one of the major neurotransmitters of the central nervous system, and is known to play an important role in regulating neural activity in the cerebral cortex and hippocampus. It has been pointed out that it may be involved in the pathology of the disease. For example, in the cerebral cortex and hippocampus of the autopsy brain of Alzheimer's disease patients, decreased nicotinic receptors (α4β2 nicotine receptor and α7 nicotine receptor) among acetylcholine systems have been reported (Journa).
l of Neurochemistry, 46: 288-293, 1986; Alzheimer's
Disease Reviews, 3: 20-27, 1998; Alzheimer's Disea
se Reviews, 3: 28-34, 1998). Furthermore, the mR of α7 nicotine receptor in lymphocytes of Alzheimer's disease patients
It has been reported that the amount of NA is significantly increased as compared to the amount of α7 nicotine receptor mRNA in lymphocytes of normal subjects (Alzheimer's Research, 3: 29-36, 1997).
It has also been reported that the amount of α7 nicotine receptor mRNA in the hippocampus of Alzheimer's disease patients is significantly increased as compared to the amount of α7 nicotine receptor mRNA in the hippocampus of normal subjects (Molecular Brain). Research, 66:
94-103, 1999). In this report, mRNA levels of other subtypes (α3 and α4) were not different between normal brain and Alzheimer's disease patient's brain. It is suggested that it plays an important role in the pathology. In a test using a primary culture system of rat cerebral cortex, it has been reported that nicotine exerts a neuroprotective effect on amyloid β peptide through α7 nicotine receptor (Annuals of Neurology, 42: 159-163). ,
1997). One of the mechanisms of neurotoxicity caused by amyloid β peptide is oxidative stress theory by a radical reaction, and it has been suggested that nicotine receptor stimulation may regulate intracellular oxidative stress. Therefore, α
It is highly likely that 7 nicotine receptor is involved in the pathogenesis of Alzheimer's disease or the site of action as a therapeutic agent.

On the other hand, the association between schizophrenic patients and α7 nicotine receptor has attracted attention (review: Harvard Reviews).
of Psychiatry, 2: 179-192, 1994; Schizophrenia Bull
etin, 22: 431-445, 1996; Schizophrenia Bulletin, 24:
189-202, 1998; Trends in Neurosciences, 22: 555-56
1, 1999). It has also been reported that the number of α7 nicotine receptors in autopsy brains (such as hippocampus and frontal cortex) of schizophrenic patients is decreased (Schizophrenia Bulletin, 22: 431-44).
5, 1996; Schizophrenia Bulletin, 24: 189-202,1998;
NeuroReport, 10: 1779-1782, 1999). In addition, it has been reported that the abnormality of sensory gating observed in schizophrenic patients is improved by administration of nicotine, and that this phenomenon is related to α7 nicotine receptor. Therefore, it is highly likely that α7 nicotine receptor is involved in the pathogenesis of schizophrenia. By the way, the mechanism of the pathogenesis of schizophrenia is not clear at present, but the hypothesis that the neurotransmitter system of glutamate, one of the excitatory amino acids, is reduced has been widely proposed (review: Harvard Reviews of Psychiatry, 3: 241-253,
1996; American Journal of Psychiatry, 148: 1301-13
08, 1991; Archives of General Psychiatry, 52: 998-1
007, 1995). Agonists of the α7 nicotine receptor release glutamate from the presynapse to activate the reduced glutamate neurotransmitter system, and the symptoms seen in schizophrenic patients (positive symptoms, negative symptoms, cognitive function) Obstacles). Thus, it is highly likely that the α7 nicotine receptor is involved in the site of action of the therapeutic agent for schizophrenia.

[0005] Furthermore, since the α7 nicotine receptor is also present in the reward system considered to be involved in smoking dependence, agonists of the α7 nicotine receptor are also involved in the suppression of smoking. (Trends in Neuroscience
s, 22: 555-561, 1999; NeuroReport, 10: 697-702, 199
9; Neurosciences, 85: 1005-1009, 1998). From these, α7 nicotine receptor agonist or α7 nicotine receptor partial agonist is used for Alzheimer's disease, cognitive dysfunction,
A compound that is useful as a therapeutic or prophylactic agent for attention deficit hyperactivity disorder, anxiety, depression, schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease, Huntington's disease, etc. and is an α4β2 nicotine receptor agonist It is considered to have an advantage as compared with. Thus, agonists or partial agonists that are selective for the α7 nicotine receptor are desirable. Further, since this drug has a neuroprotective effect, it is also useful as a treatment or prevention for a neurodegenerative disease in which cholinergic neurotransmission is abnormal. In addition, it can be used to help control smoking.

As the preceding α7 nicotine receptor partial agonist, 3-[(2,4-dimethoxy) benzylidene] anabaseine (development code GTS-21: WO94 / 0528)
8) Spiro [1-] as an α7 nicotine receptor agonist
Azabicyclo [2.2.2] octane-3,5′-oxazolidin-2′-one] (development code AR-R 17779: WO96)
/ 06098), all of which are known to have problems such as low affinity for α7 receptor and low brain translocation. Also, WO97 / 30998
The publication discloses an azabicycloester compound of carbamic acid, which is an agonist of α7 nAChR (α7 nicotine acetylcholine receptor), but the affinity of this compound for the receptor is not strong. Further, as a structural analog of the present compound, a 1-azacycloalkane compound having an affinity for a muscarinic receptor (JP-A-4-226)
No. 981), an azabicyclo compound as a calcium channel antagonist (Japanese Patent Publication No. 7-503463), and a quinuclidine derivative as a squalene synthetase inhibitor (Japanese Patent Publication No. 8-500998 and Japanese Patent Publication No. 8-504)
No. 803), 3- (2-oxo-2-phenylethyl)
Quinuclidine and 3- (2-phenylethyl) quinuclidine (Khim. Geterotsikl. Soedin. 1983, 3rd.
381-385 (Chemical Abstract, 100: 2256)
3w)) are known. However, none of these are aimed at α7 nicotine receptor agonists.

[0007]

SUMMARY OF THE INVENTION The present invention has a potent α7 nicotine receptor agonistic action or α7 nicotine receptor partial agonistic action, and has Alzheimer's disease, cognitive dysfunction, attention deficit hyperactivity disorder, anxiety, and depression. , Schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease, Huntington's disease, and other therapeutic or prophylactic agents, therapeutic or preventive agents for neurodegenerative diseases with abnormal cholinergic neurotransmission, and smoking cessation drugs To provide a novel compound useful as a compound.

[0008]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a 1-azabicycloalkane compound represented by the following general formula (I), an optically active form thereof, or a pharmaceutically acceptable salt thereof. Has a selective and strong affinity for the α7 nicotine receptor, and particularly has a selective and strong α7 nicotine receptor agonistic action or an α7 nicotine receptor partial agonistic action. Therefore, the compound of the present invention has Alzheimer's disease, cognitive dysfunction,
Drugs for the treatment or prevention of attention deficit hyperactivity disorder, anxiety, depression, schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease, Huntington's disease, and neurodegenerative diseases in which cholinergic neurotransmission is abnormal It may be useful as a therapeutic or prophylactic agent, and as a smoking cessation drug. The present invention is as follows. 1. General formula (I)

[0009]

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Wherein X is absent or O, S
Or NH. Y represents CH ₂ or C ＝ O. m
Represents 1 or 2. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. Or a pharmaceutically acceptable salt thereof. 2. 2. The 1-azabicycloalkane compound according to the above 1, wherein the bicyclic aromatic heterocycle is benzothiophene, benzofuran, benzothiazole or benzimidazole, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

3. The 1-azabicycloalkane compound according to the above 1, which is selected from the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. (1) 3-((benzo [b] thiophen-2-yl) methoxy) -1-azabicyclo [2.2.2] octane (2) (R) -3-((benzo [b] thiophen-2-
Yl) methoxy) -1-azabicyclo [2.2.2] octane (3) (S) -3-((benzo [b] thiophen-2-
Yl) methoxy) -1-azabicyclo [2.2.2] octane (4) 3-((benzo [b] thiophen-3-yl) methoxy) -1-azabicyclo [2.2.2] octane (5) 3-((2-naphthyl) methoxy) -1-azabicyclo [2.2.2] octane (6) 3-((1-naphthyl) methoxy) -1-azabicyclo [2.2.2] octane (7) 3- (2- (benzo [b] thiophen-2-yl) ethyl) -1-azabicyclo [2.2.2] octane (8) (+)-3- (2- (benzo [b] thiophene-
2-yl) ethyl) -1-azabicyclo [2.2.2]
Octane (9) (-)-3- (2- (benzo [b] thiophene-
2-yl) ethyl) -1-azabicyclo [2.2.2]
Octane (10) 3- (2- (benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.
2.2] Octane (11) (+)-3- (2- (benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane (12) (- ) -3- (2- (Benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane (13) 3- (2- (benzothiazol-2-yl) )-
2-oxoethyl) -1-azabicyclo [2.2.2]
Octane (14) 3- (2- (1-methylbenzimidazole-
2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane (15) 3- (2- (benzo [b] furan-2-yl)
-2-oxoethyl) -1-azabicyclo [2.2.
2] octane (16) 3-((benzo [b] thiophen-2-yl)
Methyl) -1-azabicyclo [2.2.2] octane (17) 3-((benzo [b] thiophen-2-yl)
Carbonyl) -1-azabicyclo [2.2.2] octane (18) 3- (3- (benzo [b] thiophen-2-yl) propyl) -1-azabicyclo [2.2.2] octane (19) 3- (3- (benzo [b] thiophen-2-yl) -3-oxopropyl) -1-azabicyclo [2.
2.2] Octane

4. An α7 nicotine receptor ligand comprising a 1-azabicycloalkane compound of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 5. An α7 nicotine receptor agonist or an α7 nicotine receptor partial agonist comprising a 1-azabicycloalkane compound of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 6. A drug for improving cognitive impairment comprising a 1-azabicycloalkane compound of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 7. An anti-dementia drug comprising a 1-azabicycloalkane compound of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 8. A therapeutic agent for schizophrenia comprising a 1-azabicycloalkane compound of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 9. A drug for ameliorating the negative symptoms of schizophrenia, comprising a 1-azabicycloalkane compound of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 10. A therapeutic agent for attention deficit hyperactivity disorder comprising a 1-azabicycloalkane compound of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 11. A remedy for Alzheimer's disease comprising a 1-azabicycloalkane compound of the general formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Specific examples of each group in the above general formula (I) are as follows. The bicyclic aromatic heterocycle in Ar represents a structure in which an aromatic heterocycle and a benzene ring or the same or different aromatic heterocycles share a part of each other's rings and are condensed, and are benzoxazole, benzothiazole , 1,2-benzisoxazole, 1,2-benzisothiazole, indole, 1-benzofuran, 1-
Benzothiophene, quinoline, isoquinoline, quinazoline and the like can be mentioned. Ar can be bonded to Y from any carbon atom on the ring.

The substituent of the bicyclic aromatic heterocyclic ring includes
(1) halogen selected from fluorine, chlorine, bromine and iodine, (2) methyl, ethyl, propyl, isopropyl,
Alkyl having 1 to 4 carbon atoms selected from butyl, isobutyl, tertiary butyl and the like; and (3) alkyl having 1 to 4 carbon atoms selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy and the like. Alkoxy having an oxygen atom, (4) C1-C4 such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, etc. Haloalkyl,
(5) hydroxy, (6) amino, (7) dimethylamino, diethylamino, N-methyl-N-ethylamino,
Dialkylamino each independently having an alkyl having 1 to 4 carbon atoms selected from pyrrolidin-1-yl, piperidin-1-yl and the like, wherein the alkyl moiety may form a ring;
(8) nitro, (9) cyano, (10) formyl, acetyl, propionyl, 2-methylpropionyl, butyryl and the like, acyl having 1 to 4 carbon atoms selected from alkyl and carbonyl, (11) carboxylic acid, (1
2) esters composed of alkoxy and carbonyl having 1 to 4 carbon atoms selected from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, etc., (13) carbamoyl, (14) N-alkylcarbamoyl or N, N-dialkylcarbamoyl composed of monoalkylamino or dialkylamino and carbonyl; (15) acylamino or diacylamino composed of acyl (as defined above) and amino; (16) thiol; 17) Alkylthio composed of alkyl having 1 to 4 carbon atoms selected from methylthio, ethylthio, propylthio, butylthio and the like and a sulfur atom, (18) alkoxycarbonylamido composed of ester and amino No, (19) Sulfamoyl, (2
0) N-alkylsulfamoyl or N, N-dialkylsulfamoyl composed of monoalkylamino or dialkylamino and sulfone, and the like;
One or more, preferably 1 to 3 arbitrary carbon atoms of Ar may be substituted. When the same or different substituents described above exist on adjacent carbon atoms on Ar, a new ring may be formed between the adjacent substituents.

Preferred compounds included in the general formula (I) are as follows. The number indicates the embodiment number. (1) 3-((benzo [b] thiophen-2-yl) methoxy) -1-azabicyclo [2.2.2] octane,
(2) (R) -3-((benzo [b] thiophen-2-
Yl) methoxy) -1-azabicyclo [2.2.2] octane, (3) (S) -3-((benzo [b] thiophen-2-yl) methoxy) -1-azabicyclo [2.
2.2] octane, (5) 3-((2-naphthyl) methoxy) -1-azabicyclo [2.2.2] octane,
(7) 3- (2- (benzo [b] thiophen-2-yl) ethyl) -1-azabicyclo [2.2.2] octane, (8) (+)-3- (2- (benzo [b ] Thiophen-2-yl) ethyl) -1-azabicyclo [2.2.
2] octane, (9) (−)-3- (2- (benzo [b] thiophen-2-yl) ethyl) -1-azabicyclo [2.2.2] octane, (10) 3- (2- (Benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane, (1
1) (+)-3- (2- (benzo [b] thiophene-2)
-Yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane, (12) (-)-3- (2-
(Benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane,
(13) 3- (2- (benzothiazol-2-yl)-
2-oxoethyl) -1-azabicyclo [2.2.2]
Octane, (15) 3- (2- (benzo [b] furan-
2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane.

The compounds of the general formula (I) and the pharmaceutically acceptable salts thereof include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid,
Phosphoric acid, nitric acid, etc. or organic acid (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid , Camphorsulfonic acid, ascorbic acid, etc.). In addition, oxalate may be used for the purpose of crystallization of the compound. Since the compound of general formula (I) and the hydrate or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate, these hydrates (1/2 hydrate, 1/3 hydrate, monohydrate, 3
/ 2 hydrate, 2 hydrate, 3 hydrate, etc.) and solvates are also included in the present invention. When the compound of the formula (I) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are included in the present invention.

The compound of the present invention contained in the general formula (I) can be synthesized by the following method. In the reaction formulas, the definition of each symbol is as defined above unless otherwise specified. Synthesis method 1

[0018]

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A compound of the formula (1) and a compound of the formula (2), wherein J is a chlorine atom, a bromine atom, an iodine atom, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, methanesulfonyloxy and the like. Suitable leaving groups generally used in the above are shown as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tertiary butoxide, sodium, potassium, potassium carbonate, potassium hydrogen carbonate, carbonate In the presence of a suitable base generally used in organic synthetic chemistry such as sodium, sodium bicarbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, butyllithium, and the like, Suitable solvents that do not hinder the progress (benzene, toluene , Xylene, dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, or a mixture thereof) at room temperature to the reflux temperature of the solvent for 0.1 to 48 hours. The compound represented by the formula (3) can be obtained by deprotecting boron using a suitable acid generally used in organic synthetic chemistry such as sulfuric acid. Synthesis method 2

[0020]

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An appropriate solvent (benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide) which does not hinder the progress of the reaction between the compound of formula (4) and N, O-dimethylhydroxylamine , N-methyl-2-pyrrolidone, methylene chloride, chloroform, ethylene dichloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, or a mixed solvent thereof) in a suitable base (triethylamine, In the presence of pyridine, dimethylaminopyridine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, etc., at −78 ° C. to the reflux temperature of the solvent, a suitable condensing agent (diethyl cyanophosphate, benzotriazo Le-1-yloxy - tris (dimethylamino) phosphonium hexafluorophosphate (Bop reagent), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide (WSCI), 1, 3
-Dicyclohexylcarbodiimide (DCCD), etc.)
And reacting for 0.1 to 48 hours to obtain the compound represented by the formula (5). The compound of the formula (5) can be prepared by converting the compound (4) into a suitable solvent which does not inhibit the progress of the reaction (benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide,
A suitable base (triethylamine, pyridine, dimethylaminopyridine) in dimethyl sulfoxide, N-methyl-2-pyrrolidone, methylene chloride, chloroform, ethylene dichloride, or any mixture thereof, which does not inhibit the progress of the reaction , Diisopropylethylamine,
A mixture formed by adding an appropriate acid chloride (pivaloyl chloride, isobutyl chlorocarbonate, ethyl chlorocarbonate, etc.) at −20 ° C. to 10 ° C. in the presence of potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, etc. N, O-dimethylhydroxylamine is added to the acid anhydride to obtain 0
It can also be obtained by reacting at a temperature of from 0 ° C. to the reflux temperature of the solvent for 0.1 to 48 hours. Further, the compound of the formula (5) may be a compound suitable for the compound (4) by a halogenating agent (such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, thionyl bromide) or 1,1 It can also be obtained by obtaining a reactive intermediate using '-carbonylbis-1H-imidazole and the like, and reacting the reactive intermediate with N, O-dimethylhydroxylamine.

A compound of the formula (6) wherein M is lithium,
A metal such as magnesium chloride or magnesium bromide) and a compound of formula (5) in a solvent that does not hinder the progress of the reaction (diethyl ether, diisopropyl ether,
Tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof) at a temperature of −78 ° C. to the reflux temperature of the solvent.
The compound of formula (7) can be obtained by reacting for 1 to 24 hours. The compound of formula (7) is added with triethylsilane in trifluoroacetic acid and added at 0 ° C. to the reflux temperature of the solvent to give 0.1 g.
The compound of formula (8) can be obtained by reacting for 1 to 24 hours. The compound of the formula (8) is obtained from the compound of the formula (7) once using an appropriate reducing agent such as sodium borohydride, lithium aluminum hydride, diisobutyl aluminum hydride or the like, and the alcohol is converted to acetonitrile. It can also be obtained by dissolving, adding sodium iodide and chlorotrimethylsilane and reacting at 0 ° C. to the reflux temperature of the solvent for 0.1 to 24 hours.

The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method. When the resulting product is racemic, for example, by fractional recrystallization of a salt with an optically active acid,
Alternatively, it can be divided into a desired optically active substance by passing through a column filled with an optically active carrier. Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using an optically active raw material compound or the like. Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

When the 1-azabicycloalkane compound of the present invention, its optical isomer or its pharmaceutically acceptable salt is used as a medicament, the compound of the present invention is converted into a pharmaceutically acceptable carrier (excipient, binder, disintegrating agent). Composition, preparation (tablet, pill, capsule, granule, powder, syrup, emulsion, elixir) Preparations, suspensions, solutions, injections, drops, suppositories and the like). The pharmaceutical composition can be formulated according to a usual method. In this specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono- or di- or triglycerides.

Suppositories for rectal administration are solid at normal temperature, such as cocoa butter and polyethylene glycols, but liquid at the intestinal tract and a suitable nonirritating excipient in the rectum. It can be manufactured by mixing with a substance that melts and releases a drug. Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills, and capsules. In such dosage forms, the active ingredient compound may comprise at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar,
Alginate, chitin, chitosan, pectin,
It can be mixed with tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also comprise, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbins, ascorbic acid And antioxidants such as α-tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavorants, perfumes and the like. Tablets and pills can also be prepared with enteric coating. Solutions for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which include inert diluents commonly used in the art, such as water. It may be.

The compound of general formula (I), an optical isomer or a pharmaceutically acceptable salt thereof has a selective and potent α7 nicotine receptor agonistic action or α7 nicotine receptor partial agonistic action, and is useful for Alzheimer's disease, cognition Dysfunction, attention deficit hyperactivity disorder, anxiety, depression, schizophrenia, epilepsy,
It is effective as a therapeutic or preventive agent for pain, Tourette's syndrome, Parkinson's disease, Huntington's disease, etc., a therapeutic or preventive agent for neurodegenerative diseases in which cholinergic neurotransmission is abnormal, and a smoking cessation drug. The dosage is age,
Determined according to body weight, general health, gender, diet, administration time, administration method, excretion rate, drug combination, the extent of the condition of the patient being treated at that time, and other factors, . The compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof can be safely used with low toxicity, and its daily dose depends on the condition and weight of the patient, the type of the compound, the administration route, etc. Depends on
For example, parenterally, subcutaneously, intravenously, intramuscularly, or rectally, about 0.01 to 50 mg / person / day, preferably 0.1 mg / person / day.
01-20 mg / person / day, orally about 0.01-150 mg / person / day, preferably 0.1-1
Desirably, 00 mg / person / day is administered. Also, α
This compound having a selective and strong affinity for 7 nicotine receptor, as a ligand of α7 nicotine receptor,
It is useful as a compound for labeling α7 nicotine receptor in the brain.

[0027]

The present invention will be described below in more detail with reference to Examples, Formulation Examples and Experimental Examples, but the present invention is not limited thereto. Example 1

[0028]

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0.5 g of the 1-azabicyclo [2.2.2] octane-3-ol-borane complex was dissolved in 5 ml of dimethylformamide, and sodium hydride (60 ml) was added under ice cooling.
%) And stirred for 30 minutes. 2 in the reaction solution
0.77 g of -chloromethylbenzo [b] thiophene was added, and the mixture was further stirred for 1 hour. After the completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and dried over sodium sulfate. The residue obtained by concentrating the solvent was subjected to silica gel chromatography, and the hexane: ethyl acetate = 9: 1 effluent was concentrated to give 3-((benzo [b] thiophen-2-yl) methoxy) -1-. 0.3 g of azabicyclo [2.2.2] octane-borane complex was obtained. This compound was dissolved in 10 ml of acetone, 3N hydrochloric acid was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the residue obtained by concentrating the solvent, extracted with ethyl acetate, and dried over sodium sulfate. The residue obtained by concentrating the solvent was dissolved in ethyl acetate, hydrochloric acid-ether was added, and the precipitated crystals were collected by filtration to give 3-((benzo [b] thiophen-2-yl) methoxy) -1-azabicyclo. [2.2.2] Octane hydrochloride / hemihydrate 0.17 g was obtained. Melting point 201-2
03 ° C Example 2

[0030]

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(R) -1-Azabicyclo [2.2.2]
The reaction was carried out in the same manner as in Example 1 using 0.065 g of the octane-3-ol-borane complex, and (R) -3-((benzo [b] thiophen-2-yl) methoxy) -1-azabicyclo [2. 2.2] Octane hydrochloride 0.021 g was obtained. Melting point 211-212 [deg.] C. [Α] _D = −52 ° (c =
0.23, MeOH) Example 3

[0032]

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(S) -1-Azabicyclo [2.2.2]
The reaction was carried out in the same manner as in Example 1 using 0.37 g of the octane-3-ol-borane complex, and (S) -3-((benzo [b] thiophen-2-yl) methoxy) -1-azabicyclo [2. 2.2] Octane hydrochloride 0.061 g was obtained. Melting point 211-213 ° C. [Α] _D = + 56 ° (c =
0.25, MeOH) Example 4

[0034]

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The reaction was carried out in the same manner as in Example 1 by using 0.77 g of 3-chloromethylbenzo [b] thiophene.
((Benzo [b] thiophen-3-yl) methoxy)-
1-azabicyclo [2.2.2] octane hydrochloride • 3 /
0.155 g of dihydrate was obtained. Melting point 153-156 ° C Example 5

[0036]

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Reaction was carried out in the same manner as in Example 1 using 0.74 g of 2-chloromethylnaphthalene, and 3-((2-naphthyl) methoxy) -1-azabicyclo [2.2.2] octane hydrochloride / 1 water 0.103 g of the hydrate was obtained. Melting point 187
-189 ° C Example 6

[0038]

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The reaction was carried out in the same manner as in Example 1 using 0.74 g of 1-chloromethylnaphthalene, and 0.1 g of 3-((1-naphthyl) methoxy) -1-azabicyclo [2.2.2] octane hydrochloride was used. I got Melting point 191-194 ° C Example 7

[0040]

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3- (2- (benzo [b] thiophene-2)
-Yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane 1.2 g
0 ml, triethylsilane 1.7 ml was added,
Stirred at room temperature for 5 days. Dilute the reaction with 30 ml of water,
The mixture was made alkaline with sodium carbonate, and the desired product was extracted three times with chloroform. The organic layer is dried over sodium sulfate,
The residue obtained by concentration was subjected to silica gel column chromatography, and hexane: ethyl acetate = 7: 3 to 6: 4.
The effluent was concentrated. The residue was dissolved in acetone, 32% hydrochloric acid / methanol was added to adjust the hydrochloride, the solvent was distilled off under reduced pressure, isopropanol was added, and the precipitated crystals were collected by filtration to give 3- (2- (benzo [b] b). Thiophen-2-yl)
0.105 g of (ethyl) -1-azabicyclo [2.2.2] octane hydrochloride 1/4 hydrate was obtained. Melting point 218-
220 ° C

Example 8 (+)-3- (2- (Benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.
2.2] Octane (0.28 g) was dissolved in methanol (10 ml), and sodium borohydride (0.038 g) was added thereto under ice-cooling, followed by stirring at room temperature. After completion of the reaction, a saturated aqueous solution of sodium carbonate was added to the reaction system, and the product was extracted twice with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 0.13 g of an alcohol.
0.4 g of sodium iodide was dissolved in 5 ml of acetonitrile, 0.34 ml of chlorotrimethylsilane was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the resulting yellow suspension was added 0.13 g of an alcohol at room temperature, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, an aqueous solution of sodium sulfite was added, and the mixture was made alkaline with saturated aqueous sodium carbonate. The product was extracted twice with chloroform, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
An oil was obtained by silica gel column chromatography. Dissolve the oil in isopropanol and add 32% hydrochloric acid
Methanol was added and the resulting crystals were collected by filtration to give (+)-3-
(2- (benzo [b] thiophen-2-yl) ethyl)
-1-Azabicyclo [2.2.2] octane hydrochloride • 1
0.060 g of / 4 hydrate was obtained. Melting point 248-250
° C, [α] _D = + 41.2 ° (c = 0.25, MeO
H)

Example 9 (-)-3- (2- (benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.
2.2] Octane was reacted in the same manner as in Example 8 using 0.31 g of (octane) to give (-)-3- (2- (benzo [b] thiophen-2-yl) ethyl) -1-azabicyclo [2.2 .
2] 0.015 g of octane hydrochloride was obtained. Melting point 228-
232 ° C., [α] _D = −36.4 ° (c = 0.25, M
OH) Example 10

[0044]

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0.76 g of benzo [b] thiophene was dissolved in 10 ml of tetrahydrofuran, and −78 was added under a nitrogen atmosphere.
2. 1.6N n-butyllithium hexane solution at ℃.
5 ml was added and the mixture was stirred for 10 minutes. Here, N-methyl-N-methoxy-2- (1-azabicyclo [2.2.
2] 5 ml of a tetrahydrofuran solution of 1.0 g of octane-3-yl) acetamide was added dropwise, and the mixture was stirred at -78 ° C for 15 minutes. After completion of the reaction, water was added to the reaction solution, and extracted twice with chloroform. The organic layer was dried over sodium sulfate, and the residue obtained by concentrating the solvent was subjected to silica gel column chromatography, and the chloroform effluent was concentrated to obtain an oil. The obtained oil was dissolved in isopropyl alcohol, 32% hydrochloric acid-methanol was added, and the precipitated crystals were collected by filtration to give 3- (2- (benzo [b] thiophene-).
0.23 g of 2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane hydrochloride was obtained. 247-249 ° C

Example 11 3- (2- (benzo [b] thiophen-2-yl) -2
-Oxoethyl) -1-azabicyclo [2.2.2] octane is added to 30 ml of a warm ethanol solution of 2.9 g of L-malic acid, and 20 ml of a warm ethanol solution of 1.3 g of L-malic acid.
The solution was returned to room temperature, and the precipitated crystals were collected by filtration. 3.5 g of the obtained crystals were recrystallized three times using ethanol-water to obtain (+)-3- (2- (benzo [b] thiophene-2).
0.72 g of L-malate of -yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane
Obtained. A saturated aqueous solution of sodium carbonate was added to the resulting malate, the target substance was extracted twice with chloroform, the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated, and the obtained crystals were dissolved in methanol. -Crystals precipitated by adding methanol are collected by filtration and (+)-3- (2- (benzo [b] thiophen-2-yl) -2-oxoethyl)-
1-azabicyclo [2.2.2] octane hydrochloride / 1
0.28 g of pentahydrate was obtained. 226-227 ° C,
[Α] _D = −36.2 ° (c = 0.25, MeOH)

Example 12 The filtrates obtained in Example 11 were mixed, the solvent was distilled off under reduced pressure, a saturated aqueous solution of sodium carbonate was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated. To a solution of 1.15 g of the obtained residue in 10 ml of a warm ethanol solution, 0.54 g of D-malic acid was added.
Was added, and the precipitated crystals were collected by filtration. The obtained crystal was recrystallized three times using ethanol-water, and-)-3- (2- (benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.2 .2] Octane D-malate was obtained. A saturated aqueous solution of sodium carbonate was added to the resulting malate, the target substance was extracted twice with chloroform, the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated, and the obtained crystals were dissolved in methanol. -Crystals precipitated by adding methanol are collected by filtration and (-)-3- (2- (benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane. 0.28 g of the hydrochloride was obtained.
230 ° -232 ° C., [α] _D = −36.0 ° (c =
0.25, MeOH) Example 13

[0048]

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2.23 g of benzothiazole, N-methyl-N-methoxy-2- (1-azabicyclo [2.2.
2] Octane-3-yl) acetamide was reacted in the same manner as in Example 10 using 1.0 g of 3- (2- (benzothiazol-2-yl) -2-oxoethyl) -1-azabicyclo [2. 2.2] Octane hydrochloride 0.24 g was obtained. Melting point 274-275 ° C

[0050]

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2.2 g of 1-methylbenzimidazole,
N-methyl-N-methoxy-2- (1-azabicyclo [2.2.2] octan-3-yl) acetamide 1.0
Using g, the reaction was carried out in the same manner as in Example 10, and 3- (2-
0.6 g of (1-methylbenzimidazol-2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane trihydrochloride was obtained. Melting point 246-247 ° C Example 15

[0052]

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1.95 g of benzo [b] furan, N-methyl-N-methoxy-2- (1-azabicyclo [2.2.
2] Using 1.0 g of octane-3-yl) acetamide, the reaction was carried out in the same manner as in Example 10 to give 3- (2- (benzo [b] furan-2-yl) -2-oxoethyl) -1-.
0.6 g of azabicyclo [2.2.2] octane hydrochloride / 1/5 hydrate was obtained. Melting point 288-290 ° C Example 16

[0054]

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The reaction was carried out in the same manner as in Example 8 using 1.0 g of 3-((benzo [b] thiophen-2-yl) carbonyl) -1-azabicyclo [2.2.2] octane.
-((Benzo [b] thiophen-2-yl) methyl)-
1-Azabicyclo [2.2.2] octane hydrochloride was obtained. Melting point 264-265 ° C Example 17

[0056]

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5.4 g of benzothiophene, N-methyl-
N-methoxy-2- (1-azabicyclo [2.2.2]
The reaction was carried out in the same manner as in Example 10 using 2.0 g of octane-3-yl) carboxamide to give 3-((benzo [b] thiophen-2-yl) carbonyl) -1-azabicyclo [2.2.2] octane. Hydrochloride 1/5 hydrate 1.0g
g was obtained. Melting point 236-238 ° C Example 18

[0058]

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3- (3- (benzo [b] thiophene-2
-Yl) -3-oxopropyl) -1-azabicyclo [2.2.2] octane was reacted in the same manner as in Example 8 using 1.0 g to give 3- (3- (benzo [b] thiophene-
2-yl) propyl) -1-azabicyclo [2.2.
2] 0.146 g of octane hydrochloride 1/4 hydrate was obtained. Melting point 176-178 ° C Example 19

[0060]

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2.93 g of benzothiophene, N-methyl-N-methoxy-3- (1-azabicyclo [2.2.
2] The reaction was carried out in the same manner as in Example 10 using 1.65 g of octane-3-yl) propanamide to give 3- (3- (benzo [b] thiophen-2-yl) -3-oxopropyl) -1-. 1.6 g of azabicyclo [2.2.2] octane hydrochloride 1/5 hydrate was obtained. 280-282 ° C

Formulation Formulation Example 1 0.5 part of the compound of Example 1, 25 parts of lactose, 35 parts of crystalline cellulose and 3 parts of corn starch were thoroughly mixed, and then kneaded well with a binder made with 2 parts of corn starch. The kneaded mixture is sieved through 16 mesh and placed in an oven for 5 minutes.
After drying at 0 ° C., the mixture is sieved with 24 mesh. The kneaded powder thus obtained, 8 parts of corn starch, 11 parts of crystalline cellulose and 9 parts of talc were mixed well, and then compressed and compressed to obtain 1 part.
Tablets containing 0.5 mg of active ingredient per tablet are obtained.

Formulation Example 2 1.0 mg of the compound of Example 1 and 9.0 m of sodium chloride
g in water for injection and filtered to remove pyrogens,
The filtrate is aseptically transferred to an ampoule, sterilized, and melt-sealed to give an injection containing 1.0 mg of the active ingredient.

The excellent pharmacological activity of the compounds of the general formula (I) is proved by the following series of tests. Experimental Example 1: Affinity for α7 nicotine receptor ([ ¹²⁵
I] α-bungarotoxin binding) Rat hippocampus was homogenized with 15 volumes of a cooled 0.32 M sucrose solution, and 1,000 G for 10 minutes (4 ° C).
Centrifuge. The supernatant is taken, centrifuged at 20,000 G for 20 minutes (4 ° C.), the precipitate is homogenized with cold distilled water, and centrifuged at 8,000 G for 20 minutes (4 ° C.). After centrifuging the supernatant at 40,000 G for 20 minutes (4 ° C.), the pellet is again homogenized with cooled distilled water and centrifuged at 40,000 G for 20 minutes (4 ° C.). Store the final sediment in the freezer (-80 ° C). On the day of the binding test, the precipitate was cooled in a buffer solution (118 mM aqueous sodium chloride solution, 4.8 mM aqueous potassium chloride solution, 2.
5 mM calcium chloride aqueous solution, 1.2 mM magnesium sulfate aqueous solution, 20 mM Na-HEPES buffer,
(pH 7.5) to prepare a hippocampal membrane preparation. Previously reported (Briggs CA et al., Functional characterization of
the novel neural nicotinic acetylcholine receptor
ligand GTS-21 in vitro and in vivo.Pharmacolo. B
iochem. Behav. 57 (1/2): 231-241, 1997) and [ ¹²⁵ I] αbungarotoxin (> 7.4 TBq /
mmol, IM-109, Amersham), hippocampal membrane preparation, buffer (118 mM aqueous sodium chloride solution, 4.8)
mM potassium chloride aqueous solution, 2.5 mM calcium chloride aqueous solution, 1.2 mM magnesium sulfate aqueous solution, 20 mM
Na-HEPES buffer, pH 7.5), test compounds are incubated at 37 ° C. for 3 hours. The reaction is
Quickly use Cell Harvester (Brandale)
Suction-filter on Whatman GF / B filters (pretreated with a 0.5% aqueous solution of polyethyleneimine in 0.1% bovine serum albumin for a minimum of 3 hours) and wash three times with cold buffer. Radioactivity bound to the filter ( ¹²⁵ I)
Is measured with a gamma counter. Non-specific binding is
1 μM α-bungarotoxin (Wako Pure Chemical Industries, Ltd.) or 100 μM (−)-nicotine (Research Biochemic)
als Int., USA). Specific binding was 50-70% of total binding. As a result of this test, the IC ₅₀ values of the compound of the present invention and the control compound are shown below. The compound number indicates the example number. Comparative compounds are the following compounds A and B
It is. Comparative compound A: AR-R 17779 (WO96 / 06098) Comparative compound B: 3-benzyloxy-1-azabicyclo [2.2.2] octane (Compound 2 of JP-A-4-226981)

[0065]

[Table 1]

Experimental Example 2: Affinity for α4β2 nicotine receptor ([ ³ H] Cytisine binding) Rat cerebral cortex was homogenized with 15 volumes of a cooled 0.32 M sucrose solution, and 1,000 G for 10 minutes ( 4
C) centrifuge. Take the supernatant and incubate at 20,000 G for 20
After centrifugation for 4 minutes (4 ° C.), the precipitate is homogenized with cold distilled water and centrifuged at 8,000 G for 20 minutes (4 ° C.). After centrifuging the supernatant at 40,000 G for 20 minutes (4 ° C.), the pellet is again homogenized with cooled distilled water and centrifuged at 40,000 G for 20 minutes (4 ° C.). Store the final sediment in the freezer (-80 ° C). On the day of the binding test, the precipitate was cooled with a buffer solution (120 mM aqueous sodium chloride solution, 5 mM aqueous potassium chloride solution, 2.5 mM
mM calcium chloride solution, 1 mM magnesium sulfate solution, 50 mM Tris-HCl buffer, pH 7.4)
To prepare a membrane preparation of the cerebral cortex.

[ ³ H] Cytisine (555 GBq-1.48)
TBq / mmol, NET-1054, NEN Life Science Produ
cts, USA), cerebral cortical membrane preparation, buffer solution (120 mM sodium chloride solution, 5 mM potassium chloride solution, 2.5
mM calcium chloride solution, 1 mM magnesium sulfate solution, 50 mM Tris-HCl buffer, pH7.
4) Incubate the test compound for 75 minutes at 4 ° C. The reaction was quickly filtered using a Brandel Cell Harvester onto a Whatman GF / B filter (pretreated with a 0.5% aqueous solution of polyethyleneimine containing 0.1% bovine serum albumin for at least 3 hours) and cooled. Wash three times with the buffer solution. After placing the filter in a vial and adding a liquid scintillator, the radioactivity (tritium) bound to the filter is measured with a liquid scintillation counter. A liquid scintillator is added, and the radioactivity (tritium) is measured with a liquid scintillation counter. Non-specific binding is determined in the presence of 10 μM (−)-nicotine (Research Biochemicals Int., USA). Specific binding was greater than 80% of total binding. As a result of this test, the IC ₅₀ value of the compound of the present invention was 1000 nM or more, and the affinity for α4β2 nicotine receptor was very weak. That is, the compound of the present invention is a compound having a selective affinity for the α7 nicotine receptor.

Experimental Example 3: Agonist activity for α7 nicotine receptor (electrophysiological test on PC12 cells) PC12 cells (purchased from Dainippon Pharmaceutical Co., Ltd.) were
The seeds were seeded on agen-coated 35 mm ² culture dishes, cultured for 1 to 3 days, and then electrophysiologically measured. Nystatin perforated patch clamp method (Akaike N. and Harata N., Jap. J. Physi
ol., Vol. 44, pp. 433-473, 1994), under the condition that PC12 cells were fixed with a membrane potential (V _H = -70 mV), an external solution instantaneous exchange method (Y-tube method, Murase et al., Brain R
es. Vol. 525, pp. 84-91, 1990), the test compound solution (dissolved in extracellular solution) was administered, and the amplitude of the evoked transient inward current (α7 receptor response) was measured. The extracellular fluid and the pipette fluid used for the measurement have the following composition. Extracellular solution: 135 mM sodium chloride, 2 mM potassium chloride, 1 mM magnesium chloride, 5 mM calcium chloride, 10 mM glucose, 12 mM HEPES were added, and the pH was adjusted to 7.4 with Tris buffer. Pipette solution: 150 mM cesium chloride, 10 mM H
A solution prepared by adding a 1/25 volume of a 1% nystatin / methanol solution to a solution adjusted to pH = 7.2 with Tris buffer by adding EPES was used as a pipette internal solution. Analysis of current response is performed using software (pCLAMP software ver.6, Axon
Instruments), and the peak value of the transient inward current through the α7 nicotine receptor was measured for each cell.
For relative comparison with a control drug, the magnitude of the response of the test compound was expressed as a percentage, with the magnitude of the 10 mM response of choline, which is a total agonist of α7 nicotine receptor, in the same cells as 100%. As a result, as shown in FIG.
It showed partial agonist activity on nicotine receptor.

[0069]

The compound of formula (I), an optical isomer or a pharmaceutically acceptable salt thereof has a selective and potent α7 nicotine receptor agonistic action or α7 nicotine receptor partial agonistic action, and has Alzheimer's disease. Treatment or prevention of cognitive dysfunction, attention deficit hyperactivity disorder, anxiety, depression, schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease, Huntington's disease, abnormal cholinergic neurotransmission It is effective as a therapeutic or preventive drug for neurodegenerative diseases, and as a smoking cessation drug. In addition, the compound of the present invention is excellent in oral absorption and brain localization, and has good properties as a central nervous system drug.

[Brief description of the drawings]

FIG. 1 is a diagram showing the results of Experimental Example 3.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Atsushi Numata 3-25-25 Koyata, Iruma-shi, Saitama F-Term in the Drug Discovery Laboratory, Welphide Co., Ltd. 4C064 AA06 CC01 DD01 EE03 FF01 GG05 4C086 AA01 AA02 AA03 CB17 MA01 MA04 NA14 ZA15 ZA16 ZA18 ZC02

Claims (11)

[Claims] 1. A compound of the general formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. Or a pharmaceutically acceptable salt thereof. 2. The 1-azabicycloalkane compound according to claim 1, wherein the bicyclic aromatic heterocycle is benzothiophene, benzofuran, benzothiazole or benzimidazole, an optical isomer thereof or a pharmaceutically acceptable salt thereof. 3. The 1-azabicycloalkane compound according to claim 1, which is selected from the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. (1) 3-((benzo [b] thiophen-2-yl) methoxy) -1-azabicyclo [2.2.2] octane (2) (R) -3-((benzo [b] thiophen-2-
Yl) methoxy) -1-azabicyclo [2.2.2] octane (3) (S) -3-((benzo [b] thiophen-2-
Yl) methoxy) -1-azabicyclo [2.2.2] octane (4) 3-((benzo [b] thiophen-3-yl) methoxy) -1-azabicyclo [2.2.2] octane (5) 3-((2-naphthyl) methoxy) -1-azabicyclo [2.2.2] octane (6) 3-((1-naphthyl) methoxy) -1-azabicyclo [2.2.2] octane (7) 3- (2- (benzo [b] thiophen-2-yl) ethyl) -1-azabicyclo [2.2.2] octane (8) (+)-3- (2- (benzo [b] thiophene-
2-yl) ethyl) -1-azabicyclo [2.2.2]
Octane (9) (-)-3- (2- (benzo [b] thiophene-
2-yl) ethyl) -1-azabicyclo [2.2.2]
Octane (10) 3- (2- (benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.
2.2] Octane (11) (+)-3- (2- (benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane (12) (- ) -3- (2- (Benzo [b] thiophen-2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane (13) 3- (2- (benzothiazol-2-yl) )-
2-oxoethyl) -1-azabicyclo [2.2.2]
Octane (14) 3- (2- (1-methylbenzimidazole-
2-yl) -2-oxoethyl) -1-azabicyclo [2.2.2] octane (15) 3- (2- (benzo [b] furan-2-yl)
-2-oxoethyl) -1-azabicyclo [2.2.
2] octane (16) 3-((benzo [b] thiophen-2-yl)
Methyl) -1-azabicyclo [2.2.2] octane (17) 3-((benzo [b] thiophen-2-yl)
Carbonyl) -1-azabicyclo [2.2.2] octane (18) 3- (3- (benzo [b] thiophen-2-yl) propyl) -1-azabicyclo [2.2.2] octane (19) 3- (3- (benzo [b] thiophen-2-yl) -3-oxopropyl) -1-azabicyclo [2.
2.2] Octane 4. A compound of the general formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. A) azabicycloalkane compound represented by the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof; 5. A compound of the general formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. ), An α7 nicotine receptor agonist or an α7 nicotine receptor partial agonist comprising an optical isomer or a pharmaceutically acceptable salt thereof. 6. A compound of the general formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. A) -azabicycloalkane compound represented by the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof; 7. A compound of the general formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. An anti-dementia drug comprising a 1-azabicycloalkane compound represented by the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 8. A compound of the general formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. A) -Azabicycloalkane compound represented by the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof; 9. A compound of the general formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. A schizophrenia negative symptom ameliorating agent comprising a 1-azabicycloalkane compound represented by the following formula), an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 10. A compound of the formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. A therapeutic agent for attention-deficit / hyperactivity disorder comprising a 1-azabicycloalkane compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof. 11. A compound of the general formula (I) (Wherein X is absent or represents O, S or NH. Y represents CH ₂ or C = O. M is 1 or 2
Is shown. n shows 0 or the integer of 1-3. Ar represents a bicyclic aromatic heterocyclic ring which may have a substituent or a naphthyl group which may have a substituent. A) -Azabicycloalkane compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof, for the treatment of Alzheimer's disease.