JPWO2014069554A1 - Quinuclidinamide derivative and its pharmaceutical use - Google Patents

Abstract

The present invention provides a novel compound having a potent central nicotinic acetylcholine receptor activation action, and provides an antipruritic agent that exhibits a medicinal effect with a new action mechanism against pruritus. It is aimed. The present invention provides a quinuclidineamide derivative represented by the following or a pharmacologically acceptable salt thereof.

Description

  The present invention relates to a quinuclidinamide derivative and a pharmaceutical use thereof.

  The nicotinic acetylcholine receptor is a homo or hetero pentamer receptor composed of a combination of α, β, γ, δ and ε subunits, and is widely distributed in central and peripheral tissues. Nicotinic acetylcholine receptors expressed in the central nervous system such as the brain, medulla, and spinal cord are called central nicotinic acetylcholine receptors and are known to have subtypes such as α7, α4β2, α4β4, α3β2, and α3β4. However, the major subtypes have been shown to be α4β2 and α7. The α4β2 subtype is a heteropentamer composed of two α4 subunits and three β2 subunits, and is expressed in the cerebral cortex, thalamus, and hippocampus. The α7 subtype is composed of five α7 subunits. It is reported that it is expressed in the cerebral cortex and hippocampus (Non-patent Document 1).

  There have been various reports on compounds that activate central nicotinic acetylcholine receptors (Patent Literature 1 and Non-Patent Literatures 2 to 6). As a compound that activates α4β2 subtype and α7 subtype, varenicline (7,8,9,10-tetrahydro-6H-6,10-methanopyrazino [2,3-h] [3] benzazepine) has been reported ( Non-patent document 2) and its tartrate salt is marketed as a smoking cessation aid. As a compound that activates the α4β2 subtype, (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine has been reported (Non-patent Document 3), which is effective in neuropathic pain in diabetic patients. On the other hand, it has been reported that it exerts an analgesic action (Non-patent Document 4). The compound that activates the α7 subtype includes N- (2 (S)-(pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] octa-3 (R) -yl) -1-benzofuran. -2-Carboxamide has been reported (Non-Patent Document 5), and recently, it has been reported that phase II clinical trials improved cognitive impairment and negative symptoms in schizophrenia (Non-Patent Document 6).

  Thus, it is said that the central nicotinic acetylcholine receptor is involved in various diseases, and its activation can be expected to improve the pathological condition or ameliorate symptoms. On the other hand, the nicotinic acetylcholine receptor Acetylcholine and nicotine that activates are also known as substances that cause pruritus in the skin (Non-patent Documents 7 and 8).

  Pruritus is a skin-specific sensation, often caused by skin disease as the primary disease, but certain medical diseases (malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, gout, thyroid disease) , Blood disease and iron deficiency), hemodialysis, peritoneal dialysis, pregnancy, parasitic infection and multiple sclerosis occur as the primary disease, drug allergy (drug itch) and mental stress (psychogenic pruritus) ).

  Although the mechanism of pruritus has not been fully elucidated yet, endogenous stimulators such as histamine, substance P, bradykinin, proteinase, prostaglandin or opioid peptides are present in the epidermis-dermis boundary in vivo. It is thought that it acts on the multi-stimulus-responsive nerve endings (itch receptors), and the resulting impulses are transmitted in the order of the spinal thalamic tract, thalamus, and cerebral cortex, resulting in perception as pruritus (non- Patent Document 9). Itching has also been thought to be a weak pain, but now it is becoming clear that pruritus and pain are transmitted through different neural pathways and occur in different mechanisms. (Non-Patent Documents 10 and 11).

  In the treatment of pruritus, antihistamines are mainly used as internal preparations, and opioid κ receptor agonists are sometimes used for hemodialysis patients. As external preparations, antihistamines, corticosteroids, immunosuppressants, or nonsteroidal anti-inflammatory agents are used.

  Patent Documents 2 to 5 disclose quinuclidine amide derivatives that activate central nicotinic acetylcholine receptors, but there is disclosure and suggestion that these derivatives have medicinal effects against pruritus. It has not been.

International Publication No. 2010/132423 International Publication No. 2001/060821 International Publication No. 2004/064836 International Publication No. 2002/017358 International Publication No. 2005/111033

Buccafusco, Molecular Interventions, 2004, Vol. 4, p. 285-295 Mihalak et al., Molecular Pharmacology, 2006, 70, p. 801-805 Donnelly-Roberts et al., Journal of Pharmacology and Experimental Therapeutics, 1998, 285, p. 777-786 Rowbotham et al., Pain, 2009, 146, p. 245-252 Hauser et al., Biochemical Pharmacology, 2009, vol. 78, p. 803-812 Targacept, April 7, 2011 press release, http: // www. target. com / wt / page / pr — 1302179429 Vogelsang et al., Acta Dermato-Veneerologica, 1995, vol. 75, p. 434-436 Smith et al., Skin Pharmacology, 1992, Vol. 5, p. 69-76 Yoshiki Miyaji, “Approach to the treatment of cutaneous pruritus”, Advanced Medical Company, 1996, p. 22-33 Sun et al., Nature, 2007, 448, p. 700-703 Liu et al., Nature Neuroscience, 2010, Vol. 13, p. 1460-1462

  However, there is a lack of a lineup of drugs that can activate central nicotinic acetylcholine receptors and exhibit significant medicinal effects, and the development of new compounds that strongly activate central nicotinic acetylcholine receptors is eagerly desired. Has been.

  In pruritus, there are many clinical conditions in which existing drugs such as antihistamines are not sufficiently effective, and the development of antipruritic drugs with new mechanisms of action is eagerly desired.

  Therefore, an object of the present invention is to provide a novel compound having a potent central nicotinic acetylcholine receptor activation action. A further object of the present invention is to provide an antipruritic agent that exhibits a medicinal effect with a new mechanism of action against pruritus.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found a novel quinuclidineamide derivative that strongly activates a central nicotinic acetylcholine receptor, and also receives a central nicotinic acetylcholine receptor. Newly discovered that activating the body is effective against pruritus, and the above-mentioned novel quinuclidinamide derivatives are antipruritic based on the mechanism of action that activates the central nicotinic acetylcholine receptor It has been clarified experimentally that the present invention is exhibited, and the present invention has been completed.

［式中、Ａは、以下の一般式（ＩＩ−１）〜（ＩＩ−９）で表される置換基からなる群から選択される置換基を表す。

（式中、Ｒ^１は、それぞれ独立して、水素原子、水素原子が１〜６個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基若しくは炭素数３〜６のシクロアルキル基、又は、水素原子がＲ^２で置換されていてもよい炭素数６〜１０のアリール基若しくは環構成原子数５〜１０のヘテロアリール基を表し、Ｒ^２は、ハロゲン原子、ヒドロキシル基、又は、水素原子が１〜６個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基若しくは炭素数１〜６のアルキルオキシ基を表し、Ｒ^３は、水素原子、又は、水素原子が１〜６個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基若しくは炭素数３〜６のシクロアルキル基を表し、Ｚは、水素原子がＲ^４で置換されていてもよい炭素数６〜１０のアリール基又は環構成原子数５〜１０のヘテロアリール基を表し、Ｒ^４は、ハロゲン原子、ヒドロキシル基、二トリル基、アミノ基、アセチルアミノ基、ニトロ基、又は、水素原子が１〜６個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基若しくは炭素数１〜６のアルキルオキシ基を表す。）］That is, the present invention provides a quinuclidineamide derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

[Wherein, A represents a substituent selected from the group consisting of substituents represented by the following general formulas (II-1) to (II-9).

(In the formula, each R ¹ independently represents a hydrogen atom, a C 1-6 alkyl group in which the hydrogen atom may be substituted with 1 to 6 halogen atoms, or a C 3-6 cycloalkyl. Represents a group, or an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R ² , and R ² represents a halogen atom, a hydroxyl group, or Represents a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a C 1-6 alkyloxy group in which a hydrogen atom may be substituted with 1-6 halogen atoms, R ³ represents a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which the hydrogen atom may be substituted with 1 to 6 halogen atoms, and Z represents hydrogen atom is replaced by R ⁴ There represents a heteroaryl group the aryl group or ring structure atoms 5 to 10 carbon atoms which may 6-10, R ⁴ is a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, Alternatively, the alkyl group having 1 to 6 carbon atoms, the cycloalkyl group having 3 to 6 carbon atoms, or the alkyloxy group having 1 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms is represented. ]]

In the quinuclidinamide derivative, A is preferably a substituent selected from the group consisting of substituents represented by the following general formulas (II-1) to (II-5).

  In this case, a strong central nicotinic acetylcholine receptor activating effect is exhibited.

In the quinuclidinamide derivative, each R ¹ is independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ³ is a halogen atom having 1 to 6 hydrogen atoms or hydrogen atoms. An alkyl group having 1 to 6 carbon atoms which may be substituted with an atom, and Z is a phenyl group, naphthyl group, pyridyl group, thienyl group or imidazolyl group in which a hydrogen atom may be substituted with R ⁴ , R ⁴ is a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, or a hydrogen atom having 1 to 6 carbon atoms that may be substituted with 1 to 6 halogen atoms An alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms is more preferable.

  In this case, a stronger central nicotinic acetylcholine receptor activation effect is exhibited.

In the quinuclidinamide derivative, R ¹ is a hydrogen atom, R ³ is a methyl group, and Z is a phenyl group, a pyridyl group, or a hydrogen atom in which the hydrogen atom may be substituted with R ⁴ A thienyl group and R ⁴ is a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, or a hydrogen atom in which a hydrogen atom may be substituted with 1 to 6 halogen atoms More preferably, they are a 1-6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkyloxy group.

  In this case, a stronger central nicotinic acetylcholine receptor activation effect is exhibited.

  The present invention also provides a medicament comprising the above quinuclidineamide derivative or a pharmacologically acceptable salt thereof as an active ingredient.

  The present invention also provides a central nicotinic acetylcholine receptor activator containing the quinuclidineamide derivative or a pharmacologically acceptable salt thereof as an active ingredient. The central nicotinic acetylcholine receptor is preferably an α7 subtype.

  The present invention also provides an antidiarrheal agent containing the above quinuclidineamide derivative or a pharmacologically acceptable salt thereof as an active ingredient.

  The quinuclidinamide derivative of the present invention and a pharmacologically acceptable salt thereof have a strong central nicotinic acetylcholine receptor activation action, and the pathological condition is improved by activating the central nicotinic acetylcholine receptor. Or it can be used as a medicine for a disease for which remission of symptoms is expected. In addition, the quinuclidine amide derivative of the present invention and a pharmacologically acceptable salt thereof exhibit an excellent antipruritic effect based on the central nicotinic acetylcholine receptor activation action, and treat existing drugs. The antipruritic effect can also be expected for pruritus showing resistance, and it can contribute to the improvement of the patient's QOL and the stop of the “scratch scratch cycle”.

It is a figure which shows the effect of the compound of Example 1 with respect to substance P induced scratching | fracture behavior. FIG. 14 shows the effect of the compound of Example 66 on substance P-induced scratching behavior. It is a figure which shows the effect | action of the nicotinic acetylcholine receptor antagonist (mecamylamine hydrochloride) with respect to the substance P-induced scratching behavior inhibitory effect of varenicline tartrate.

［式中、Ａは、以下の一般式（ＩＩ−１）〜（ＩＩ−９）で表される置換基からなる群から選択される置換基を表す。

（式中、Ｒ^１は、それぞれ独立して、水素原子、水素原子が１〜６個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基若しくは炭素数３〜６のシクロアルキル基、又は、水素原子がＲ^２で置換されていてもよい炭素数６〜１０のアリール基若しくは環構成原子数５〜１０のヘテロアリール基を表し、Ｒ^２は、ハロゲン原子、ヒドロキシル基、又は、水素原子が１〜６個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基若しくは炭素数１〜６のアルキルオキシ基を表し、Ｒ^３は、水素原子、又は、水素原子が１〜６個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基若しくは炭素数３〜６のシクロアルキル基を表し、Ｚは、水素原子がＲ^４で置換されていてもよい炭素数６〜１０のアリール基又は環構成原子数５〜１０のヘテロアリール基を表し、Ｒ^４は、ハロゲン原子、ヒドロキシル基、二トリル基、アミノ基、アセチルアミノ基、ニトロ基、又は、水素原子が１〜６個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基若しくは炭素数１〜６のアルキルオキシ基を表す。）］The quinuclidineamide derivative of the present invention is characterized by being represented by the following general formula (I).

[Wherein, A represents a substituent selected from the group consisting of substituents represented by the following general formulas (II-1) to (II-9).

(In the formula, each R ¹ independently represents a hydrogen atom, a C 1-6 alkyl group in which the hydrogen atom may be substituted with 1 to 6 halogen atoms, or a C 3-6 cycloalkyl. Represents a group, or an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R ² , and R ² represents a halogen atom, a hydroxyl group, or Represents a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a C 1-6 alkyloxy group in which a hydrogen atom may be substituted with 1-6 halogen atoms, R ³ represents a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which the hydrogen atom may be substituted with 1 to 6 halogen atoms, and Z represents hydrogen atom is replaced by R ⁴ There represents a heteroaryl group the aryl group or ring structure atoms 5 to 10 carbon atoms which may 6-10, R ⁴ is a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, Alternatively, the alkyl group having 1 to 6 carbon atoms, the cycloalkyl group having 3 to 6 carbon atoms, or the alkyloxy group having 1 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms is represented. ]]

  The following terms used in this specification are defined as follows unless otherwise specified.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  The “C 1-6 alkyl group” means a linear saturated hydrocarbon group having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms. Examples of the linear saturated hydrocarbon group include a methyl group, an ethyl group, a 1-propyl group, and a 1-butyl group. Examples of the branched saturated hydrocarbon group include an isopropyl group and an isobutyl group. Or a tert-butyl group is mentioned.

  “C3-C6 cycloalkyl group” means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

  The “C 1-6 alkyloxy group” means a group in which the above C 1-6 alkyl group is bonded to an oxygen atom, such as a methoxy group, ethoxy group, 1-propyloxy group, 1 -A butyloxy group, an isopropyloxy group, an isobutyloxy group, or a tert- butyloxy group is mentioned.

  “H 1 is an alkyl group having 1 to 6 carbon atoms optionally substituted with 1 to 6 halogen atoms” means a carbon atom in which a hydrogen atom is optionally substituted with 1 to 6 halogen atoms Represents a straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms, for example, methyl group, ethyl group, 1-propyl group, isopropyl group 1-butyl group, 2-butyl group, tert-butyl group, 2-methyl-1-propyl group, 2,2-dimethyl-1-propyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group , Trifluoromethyl group, 2-fluoroethyl group, trifluoroethyl group, pentafluoroethyl group, trichloromethyl group or trichloroethyl group.

  "The C3-C6 cycloalkyl group in which the hydrogen atom may be substituted with 1 to 6 halogen atoms" means the carbon atom in which the hydrogen atom may be substituted with 1 to 6 halogen atoms Represents a cyclic saturated hydrocarbon group having 3 to 6, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a 4,4-difluorocyclohexyl group.

  “Hydrogen atom optionally substituted with 1 to 6 halogen atoms is an alkyloxy group having 1 to 6 carbon atoms” means that a hydrogen atom bonded through an ether bond at the end of a single bond is 1 to 1 This means a group in which an alkyl group having 1 to 6 carbon atoms which may be substituted with 6 halogen atoms is bonded to an oxygen atom, such as a methoxy group, an ethoxy group, a 1-propyloxy group, an isopropyloxy group, 1 -Butyloxy group, 2-butyloxy group, trifluoromethoxy group, 2-trifluoroethoxy group or 2-fluoroethoxy group can be mentioned.

  Examples of the “C6-C10 aryl group” include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

  The term “heteroaryl group having 5 to 10 ring atoms” means a ring containing 1 to 4 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom. Means a heterocyclic aromatic group having 5 to 10 member atoms, for example, thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, triazolyl group Oxadiazolyl group, tetrazolyl group, pyridyl group, 1-oxypyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, indolyl group, indazolyl group, benzothienyl group, thienopyridyl group, benzofuryl group, furopyridyl group, benzothiazolyl group, Thiazolopyridyl group, benzimidazolyl group, imidazo Lysyl group, benzoxazolyl group, oxazolopyridyl group include a quinolyl group or an isoquinolyl group.

Examples of the “C6-C10 aryl group in which the hydrogen atom may be substituted with R ² ” include, for example, a phenyl group, a naphthyl group, a chlorophenyl group, a dichlorophenyl group, a fluorophenyl group, a bromophenyl group, and an iodophenyl group. , Toluyl group, trifluoromethylphenyl group, hydroxyphenyl group or methoxyphenyl group.

Examples of the “heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R ² ” include, for example, chlorothienyl group, methylthienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, Oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, 1-oxypyridyl, chloropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, chloropyrazinyl, triazinyl, indolyl Group, indazolyl group, benzothienyl group, chlorobenzothienyl group, fluorobenzothienyl group, hydroxybenzothienyl group, thienopyridyl group, benzofuryl group, furopyridyl group, benzothiazolyl group, thiazolopyridyl group, benzimidazole A zolyl group, an imidazopyridyl group, a benzoxazolyl group, an oxazolopyridyl group, a quinolyl group or an isoquinolyl group can be mentioned.

Examples of the “aryl group having 6 to 10 carbon atoms in which the hydrogen atom may be substituted with R ⁴ ” include, for example, a phenyl group, a naphthyl group, a chlorophenyl group, a dichlorophenyl group, a fluorophenyl group, a bromophenyl group, and an iodophenyl group. , Toluyl group, trifluoromethylphenyl group, hydroxyphenyl group, methoxyphenyl group, cyanophenyl group, aminophenyl group, acetylamino group or nitrophenyl group.

Examples of the “heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R ⁴ ” include, for example, chlorothienyl group, methylthienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, Oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, 1-oxypyridyl, chloropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, chloropyrazinyl, triazinyl, indolyl Group, indazolyl group, benzothienyl group, chlorobenzothienyl group, fluorobenzothienyl group, hydroxybenzothienyl group, thienopyridyl group, benzofuryl group, furopyridyl group, benzothiazolyl group, thiazolopyridyl group, benzimidazole A zolyl group, an imidazopyridyl group, a benzoxazolyl group, an oxazolopyridyl group, a quinolyl group or an isoquinolyl group can be mentioned.

In the quinuclidinamide derivative, A is preferably a substituent selected from the group consisting of substituents represented by the following general formulas (II-1) to (II-5).

In the quinuclidinamide derivative, each R ¹ is independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ³ is a halogen atom having 1 to 6 hydrogen atoms or hydrogen atoms. Is an alkyl group having 1 to 6 carbon atoms which may be substituted with, and Z is a phenyl group, a naphthyl group, a pyridyl group, a thienyl group or an imidazolyl group in which a hydrogen atom may be substituted with R ⁴ , R ⁴ is a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, or a hydrogen atom having 1 to 6 carbon atoms that may be substituted with 1 to 6 halogen atoms It is more preferably an alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms.

In the quinuclidinamide derivative, R ¹ is a hydrogen atom, R ³ is a methyl group, and Z is a phenyl group, a pyridyl group, or a hydrogen atom in which the hydrogen atom may be substituted with R ⁴ , Or a thienyl group, and R ⁴ is a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, or a carbon atom in which a hydrogen atom may be substituted with 1 to 6 halogen atoms More preferably, they are a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkyloxy group.

  The quinuclidine amide derivative represented by the above general formula (I) (hereinafter referred to as quinuclidine amide derivative (I)) may have optical isomers or diastereomers. As well as racemic and diastereomeric mixtures.

  Examples of the “pharmacologically acceptable salt” of the quinuclidinamide derivative (I) include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate. Acid salt or oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate , Benzoate, ascorbate, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartic acid Organic salts such as salts, glutamates or cinnamates are mentioned, but hydrochlorides, sulfates, hydrobromides, maleates, benzoates or methanesulfonates are preferred.

  The quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof may be an anhydride, or may form a solvate such as a hydrate. Here, the solvate is preferably a pharmacologically acceptable solvate. The pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferable. Examples of the solvent constituting the solvate include water, alcohol solvents such as methanol, ethanol, and n-propanol, N, N′-dimethylformamide (hereinafter referred to as DMF), and dimethyl sulfoxide (hereinafter referred to as DMSO).

  The quinuclidineamide derivative (I) can be produced by an appropriate method based on characteristics derived from the basic skeleton and the type of substituent. The starting materials and reagents used for the production of these compounds can be generally purchased or can be produced by known methods.

  The quinuclidineamide derivative (I) and the intermediates and starting materials used for the production thereof can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.

  When the quinuclidineamide derivative (I) contains an optical isomer or a stereoisomer, each isomer can be obtained as a single compound by a known method. Known methods include, for example, crystallization, enzyme resolution, or chiral chromatography.

[式中、Ｙは、炭素数１〜６のアルキル基を表し、Ａは、上記定義に同じである。]For example, as shown in Scheme 1, the quinuclidine amide derivative (I) is subjected to a hydrolysis reaction of the ester derivative (III) in the presence of an acid or a base (first step), followed by the presence of a condensing agent and a base. The carboxylic acid derivative (IV) obtained in the first step can be obtained by a condensation reaction (second step) with quinuclidin-3-amine (V).

[Wherein Y represents an alkyl group having 1 to 6 carbon atoms, and A has the same definition as above. ]

  Examples of the acid used for the hydrolysis reaction include hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid, and hydrogen chloride or sulfuric acid is preferable.

  Examples of the base used for the hydrolysis reaction include cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, and tert-butyloxy sodium, and potassium hydroxide or sodium hydroxide is preferable.

  The amount of the acid or base used for the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, relative to the ester derivative (III).

  The reaction solvent used for the hydrolysis reaction is appropriately selected according to the type of acid or base used, but is not particularly limited as long as it does not inhibit the reaction. For example, tetrahydrofuran (hereinafter referred to as THF), 1, 4 -Ether solvents such as dioxane, ethylene glycol dimethyl ether or dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic such as DMF or DMSO Examples include polar solvents, ketone solvents such as acetone or methyl ethyl ketone, nitrile solvents such as acetonitrile or propionitrile, alcohol solvents such as methanol, ethanol or 2-propanol, water, or a mixed solvent thereof. Nord, alcohol solvents such as ethanol or 2-propanol are preferred.

  The concentration of the ester derivative (III) used for the hydrolysis reaction at the start of the reaction is preferably 0.01 mmol / L to 1 mol / L.

  The reaction temperature of the hydrolysis reaction is preferably −78 to 200 ° C., more preferably −20 to 100 ° C.

  Although the reaction time of a hydrolysis reaction is suitably selected according to conditions, such as reaction temperature, it is preferable that it is 1 to 30 hours.

  Examples of the condensing agent used in the condensation reaction include cyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, N, N-carbodiimidazole, O- (7-azabenzotriazol-1-yl. ) -1,1,3,3-tetramethyluronium hexafluorophosphate or ortho- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate HBTU), and HBTU is preferred.

  Examples of the base used in the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, and methyl lithium. Alternatively, alkyl lithium such as butyl lithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof may be mentioned, and an organic base such as triethylamine or diisopropylethylamine is preferable.

  The amount of the condensing agent used for the condensation reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the carboxylic acid derivative (IV).

  The amount of the base used for the condensation reaction is preferably 1 to 100 equivalents, more preferably 2 to 30 equivalents, relative to the carboxylic acid derivative (IV).

  The amount of quinuclidin-3-amine (V) used in the condensation reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the carboxylic acid derivative (IV).

  The quinuclidin-3-amine (V) used for the condensation reaction may be a free form or a salt such as hydrochloride.

  The reaction solvent used in the condensation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxy Examples include ether solvents such as ethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile. , Halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferred.

  The concentration of the carboxylic acid derivative (IV) used for the condensation reaction at the start of the reaction is preferably 0.01 mmol / L to 1 mol / L.

  The reaction temperature of the condensation reaction is preferably −78 to 200 ° C., more preferably 0 to 100 ° C.

  Although the reaction time of a condensation reaction is suitably selected according to conditions, such as reaction temperature, it is preferable that it is 6 to 48 hours.

[式中、Ｘは、ハロゲン原子を表し、Ｒ^１、Ｙ及びＺは、上記定義に同じである。]When the ester derivative (III) shown in Scheme 1 is an ester derivative (III-a) in which A is a substituent represented by the above general formula (II-1), for example, as shown in Scheme 2 In the presence of a metal catalyst, a base and a ligand, it can be obtained by a coupling reaction of a pyrazole derivative (VI) and an aryl halide (VII).

[Wherein, X represents a halogen atom, and R ¹ , Y and Z are the same as defined above]. ]

  The coupling reaction is appropriately selected depending on the type of pyrazole derivative (VI) to be used, etc. For example, the method described in known literature (Journal of Medicinal Chemistry, 2005, Vol. 48, p. 306-311) or It can carry out according to the method according to this.

  Examples of the metal catalyst used in the coupling reaction include copper iodide, copper sulfate, copper acetate, copper oxide, bis (dibenzylideneacetone) palladium (0), tetrakistriphenylphosphine palladium (0), or manganese fluoride. However, copper iodide or copper oxide is preferred.

  Examples of the base used for the coupling reaction include potassium carbonate, sodium hydrogen carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, potassium phosphate and sodium tert-butyloxy, and potassium carbonate or cesium carbonate is preferable.

  Examples of the ligand used in the coupling reaction include N, N′-dimethylethylenediamine, N, N′-dimethylglycine, 1,10-phenanthroline, or trans-1,2-diaminocyclohexane. N′-dimethylethylenediamine or 1,10-phenanthroline is preferred.

  The amount of the metal catalyst used for the coupling reaction is preferably 0.01 to 1 equivalent, more preferably 0.01 to 0.5 equivalent, relative to the pyrazole derivative (VI).

  The amount of the base used for the coupling reaction is preferably 1 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the pyrazole derivative (VI).

  The amount of the ligand used for the coupling reaction is preferably 0.01 to 1 equivalent, more preferably 0.01 to 0.5 equivalent, relative to the pyrazole derivative (VI).

  The amount of aryl halide (VII) used in the coupling reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the pyrazole derivative (VI).

  The reaction solvent used in the coupling reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, THF, 1,4-dioxane, ethylene glycol dimethyl ether or Ether solvents such as dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF or DMSO, or methanol, Examples include alcohol solvents such as ethanol or 2-propanol, but ether solvents such as THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxyethane, or aromatic hydrocarbon solvents such as benzene or toluene are preferred. Arbitrariness.

  The concentration of the pyrazole derivative (VI) used for the coupling reaction at the start of the reaction is preferably 0.01 mmol / L to 1 mol / L.

  The reaction temperature of the coupling reaction is preferably −78 to 200 ° C., more preferably 0 to 150 ° C.

  The reaction time of the coupling reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 6 to 60 hours.

［式中、Ｗは、炭素数１〜６のアルキル基を表し、Ｙ及びＺは、上記定義に同じである。]Among the ester derivatives (III-a) shown in Scheme 2, an ester derivative (III-b) in which R ¹ is a hydrogen atom is, for example, a ketoacetal derivative (VIII) in the presence of an acid as shown in Scheme 3. ) Hydrolysis reaction of acetal (first step), followed by aminomethyleneation reaction of ketoaldehyde derivative (IX) obtained in the first step with dimethylformamide dimethyl acetal (XI) (second step), Subsequently, the 2-formyl-3-aminoacrylate derivative (X) obtained in the second step can be obtained by a cyclization reaction (third step) with the hydrazine derivative (XII).

[Wherein W represents an alkyl group having 1 to 6 carbon atoms, and Y and Z are the same as defined above. ]

  Examples of the acid used for the acetal hydrolysis reaction include formic acid, hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid, with trifluoroacetic acid being preferred.

  The amount of the acid used in the acetal hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, relative to the ketoacetal derivative (VIII).

  The reaction solvent used for the acetal hydrolysis reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, THF, 1,4-dioxane, ethylene glycol Ether solvents such as dimethyl ether or dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF or DMSO, methanol, Alcohol solvents such as ethanol or 2-propanol, water, or a mixed solvent thereof may be used, but alcohol solvents such as methanol, ethanol or 2-propanol are preferable.

  The concentration of the ketoacetal derivative (VIII) used in the acetal hydrolysis reaction at the start of the reaction is preferably 0.01 mmol / L to 1 mol / L.

  The reaction temperature of the acetal hydrolysis reaction is preferably −78 to 200 ° C., more preferably −20 to 100 ° C.

  The reaction time of the acetal hydrolysis reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 1 to 30 hours.

  The amount of dimethylformamide dimethyl acetal (IX) used in the aminomethylene reaction is preferably 1 to 20 equivalents and more preferably 3 to 10 equivalents with respect to the ketoaldehyde derivative (IX).

  The aminomethylene reaction is preferably performed without a solvent. When a reaction solvent is used, it is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, ether such as THF, 1,4-dioxane or ethylene glycol dimethyl ether Solvent, aromatic hydrocarbon solvent such as benzene or toluene, aprotic polar solvent such as DMF or DMSO, or alcohol solvent such as methanol, ethanol or 2-propanol. -Ether solvents such as dioxane or ethylene glycol dimethyl ether are preferred.

  The concentration of the ketoaldehyde derivative (IX) used for the aminomethylene reaction at the start of the reaction is preferably 0.1 mmol / L to 10 mol / L.

  The reaction temperature of the aminomethylene reaction is preferably 0 to 200 ° C, and more preferably 20 to 120 ° C.

  The reaction time of the aminomethylene reaction is appropriately selected according to conditions such as reaction temperature, but is preferably 0.5 to 12 hours.

  The amount of the hydrazine derivative (XII) used for the cyclization reaction is preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the 2-formyl-3-aminoacrylate derivative (X). preferable.

  The hydrazine derivative (XII) used for the cyclization reaction may be a salt such as hydrochloride.

  The reaction solvent used for the cyclization reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, aprotic polar solvents such as DMF or DMSO, methanol , Alcohol solvents such as ethanol or 2-propanol, or nitrile solvents such as acetonitrile or propionitrile, but alcohol solvents such as methanol, ethanol or 2-propanol are preferred.

  The concentration of 2-formyl-3-aminoacrylate derivative (X) used for the cyclization reaction at the start of the reaction is preferably 0.01 mmol / L to 10 mol / L.

  The reaction temperature of the cyclization reaction is preferably 0 to 200 ° C, more preferably 20 to 120 ° C.

  The reaction time of the cyclization reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 12 hours.

  Among the ester derivatives (III) shown in Scheme 1, an ester derivative (III-c) in which A is a substituent represented by the general formula (II-2) is, for example, as shown in Scheme 4 Below, esterification reaction of 4-imidazolecarboxylic acid derivative (XIII) and alcohol (XV) (first step), followed by ester derivative obtained in the first step in the presence of a metal catalyst, a base and a ligand It can be obtained by a coupling reaction (second step) between (XIV) and aryl halide (VII).

［式中、Ｙ、Ｚ及びＲ^１は、上記定義に同じである。]

Wherein Y, Z and R ¹ are the same as defined above. ]

  Examples of the acid used for the esterification reaction include hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid, and hydrogen chloride or sulfuric acid is preferable.

  The amount of acid used for the esterification reaction is preferably 0.01 to 1 equivalent, more preferably 0.05 to 0.5 equivalent, relative to the 4-imidazolecarboxylic acid derivative (XIII).

  Examples of the alcohol (XV) used in the esterification reaction include methanol, ethanol, 2-propanol, and tert-butyl alcohol, and methanol or ethanol is preferable.

  The reaction solvent used for the esterification reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, THF, 1,4-dioxane, ethylene glycol dimethyl ether or Ether solvents such as dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF or DMSO, alcohol (XV) , Water, or a mixed solvent thereof, alcohol (XV) is preferred.

  The concentration of 4-imidazolecarboxylic acid derivative (XIII) used in the esterification reaction at the start of the reaction is preferably 0.01 mmol / L to 1 mol / L.

  The reaction temperature for the esterification reaction is preferably −78 to 200 ° C., more preferably −20 to 100 ° C.

  The reaction time of the esterification reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 1 to 30 hours.

  The coupling reaction is appropriately selected depending on the type of ester derivative (XIV) to be used and the like. For example, the method described in known literature (Journal of Medicinal Chemistry, 2008, 51, p. 5243-5263) or It can carry out according to the method according to this.

  Examples of the metal catalyst used in the coupling reaction include copper iodide, copper sulfate, copper acetate, copper oxide, bis (dibenzylideneacetone) palladium (0), tetrakistriphenylphosphine palladium (0), or manganese fluoride. However, copper iodide or copper oxide is preferred.

  Examples of the base used for the coupling reaction include potassium carbonate, sodium hydrogen carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, potassium phosphate and sodium tert-butyloxy, and potassium carbonate or cesium carbonate is preferable.

  Examples of the ligand used in the coupling reaction include N, N′-dimethylethylenediamine, N, N′-dimethylglycine, 1,10-phenanthroline, or trans-1,2-diaminocyclohexane. N′-dimethylethylenediamine or 1,10-phenanthroline is preferred.

  The amount of the metal catalyst used for the coupling reaction is preferably 0.01 to 1 equivalent, more preferably 0.01 to 0.5 equivalent, relative to the ester derivative (XIV).

  The amount of the base used for the coupling reaction is preferably 1 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the ester derivative (XIV).

  The amount of the ligand used in the coupling reaction is preferably 0.01 to 1 equivalent, more preferably 0.01 to 0.5 equivalent, relative to the ester derivative (XIV).

  1-10 equivalent is preferable with respect to ester derivative (XIV), and, as for the quantity of the aryl halide used for a coupling reaction, it is more preferable that it is 1-3 equivalent.

  The reaction solvent used in the coupling reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, THF, 1,4-dioxane, ethylene glycol dimethyl ether or Ether solvents such as dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF or DMSO, or methanol, Examples include alcohol solvents such as ethanol or 2-propanol, but ether solvents such as THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxyethane, or aromatic hydrocarbon solvents such as benzene or toluene are preferred. Arbitrariness.

  The concentration of the ester derivative (XIV) used for the coupling reaction at the start of the reaction is preferably 0.01 mmol / L to 1 mol / L.

  The reaction temperature of the coupling reaction is preferably −78 to 200 ° C., more preferably 0 to 150 ° C.

  The reaction time of the coupling reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 6 to 60 hours.

  The coupling reaction may be performed under microwave irradiation conditions depending on the type of ester derivative (XIV) used.

Among the ester derivatives (III) shown in scheme 1, A is a substituent represented by the general formula (II-3) or (II-8), and R ³ is R ^3a (III-d ) Or (III-e), for example, as shown in Scheme 5, by an alkylation reaction (first step) of imidazole derivative (XVI) and halogenated alkyl derivative (XVIII) in the presence of a base, An imidazole derivative (XVII-a) or (XVII-b), followed by the reaction of a chloroformate after deprotonation of the N-alkylimidazole derivative (XVII-d) or (XVII-e) in the presence of a base, It can be synthesized by an alkoxycarbonylation reaction (second step).

［式中、Ｒ^３ａは、炭素数１〜６のアルキル基を表し、Ｙ、Ｚ及びＲ^１は、上記定義に同じである。]

[Wherein R ^3a represents an alkyl group having 1 to 6 carbon atoms, and Y, Z and R ¹ are the same as defined above. ]

  Although the alkylation reaction varies depending on the type of substrate, it can be performed, for example, according to a method described in a known document (Journal of Medicinal Chemistry, 1988, Vol. 31, p.323-329) or a method analogous thereto.

  Examples of the base used for the alkylation reaction include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, tert-butyloxy sodium, and tert-butyloxy potassium.

  1-10 equivalent is preferable with respect to imidazole derivative (XVI), and, as for the quantity of the base used for alkylation reaction, 1-3 equivalent is more preferable.

  1-10 equivalent is preferable with respect to imidazole derivative (XVI), and, as for the quantity of the alkyl halide used for alkylation reaction, 1-5 equivalent is more preferable.

  The reaction solvent used in the alkylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxy Ether solvents such as ethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF or DMSO, acetonitrile or propionitrile A nitrile solvent such as THF, 1,4-dioxane, an ether solvent such as ethylene glycol dimethyl ether or dimethoxyethane, or an aprotic polar solvent such as DMF or DMSO is preferred.

  The concentration of the imidazole derivative (XVI) used for the alkylation reaction at the start of the reaction is preferably 0.01 mmol / L to 1 mol / L.

  The reaction temperature of the alkylation reaction is preferably -78 to 200 ° C, more preferably 0 to 150 ° C.

  The reaction time of the alkylation reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 6 to 60 hours.

  The alkoxycarbonylation reaction varies depending on the type of the substrate, but can be performed, for example, according to a method described in a known document (Journal of Organic Chemistry, 1987, Vol. 52, p. 3493-3501) or a method analogous thereto.

  Examples of the base used for the alkoxycarbonylation reaction include sodium hydride, potassium hydride, potassium hydroxide, tert-butyloxysodium, n-butyllithium, and sec-butyllithium, and n-butyllithium is preferable. .

  Examples of the chloroformate used for the alkoxycarbonylation reaction include methyl chloroformate, ethyl chloroformate or propyl chloroformate, and methyl chloroformate or ethyl chloroformate is preferred.

  1-10 equivalent is preferable with respect to N-alkyl imidazole derivative (XVII-d) or (XVII-e), and, as for the quantity of the base used for alkoxycarbonylation reaction, 1-3 equivalent is more preferable.

  1-10 equivalent is preferable with respect to N-alkyl imidazole derivative (XVII-d) or (XVII-e), and, as for the quantity of the chloroformate used for alkoxycarbonylation reaction, 1-3 equivalent is more preferable.

  The reaction solvent used in the alkoxycarbonylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, THF, 1,4-dioxane, ethylene glycol dimethyl ether or Examples include ether solvents such as dimethoxyethane, and aromatic hydrocarbon solvents such as benzene or toluene, and ether solvents such as THF, 1,4-dioxane, ethylene glycol dimethyl ether, or dimethoxyethane are preferable.

  The concentration of the N-alkylimidazole derivative (XVII-d) or (XVII-e) used in the alkoxycarbonylation reaction at the start of the reaction is preferably 0.01 mmol / L to 1 mol / L.

  The reaction temperature of the alkoxycarbonylation reaction is preferably -78 to 200 ° C, more preferably 0 to 100 ° C.

  Although the reaction time of alkoxycarbonylation reaction is suitably selected according to conditions, such as reaction temperature, it is preferable that it is 1 to 60 hours.

  The medicament, central nicotinic acetylcholine receptor activator and antipruritic agent of the present invention are characterized by containing the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. .

  The quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof is characterized by activating a central nicotinic acetylcholine receptor (preferably an α7 subtype of the central nicotinic acetylcholine receptor). It is said. Since the central nicotinic acetylcholine receptor is involved in various diseases, and it is known that its activation can be expected to improve the pathological condition or ameliorate symptoms, the quinuclidine amide derivative (I) or a drug thereof Physiologically acceptable salt is used as a medicament for a disease for which improvement of pathological condition or amelioration of symptoms can be expected by activating central nicotinic acetylcholine receptor (preferably, α7 subtype of central nicotinic acetylcholine receptor) be able to.

  The “central nicotinic acetylcholine receptor” is a nicotinic acetylcholine receptor expressed in the central nervous system such as the brain, medulla and spinal cord. Central nicotinic acetylcholine receptor, neuronal nicotinic acetylcholine receptor Also called receptor or neuronal nicotinic acetylcholine receptor.

  Examples of the subtype of the central nicotinic acetylcholine receptor activated by the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof include α7, α4β2, α4β4, α3β2 and α3β4. Type is preferred.

  “Activating the central nicotinic acetylcholine receptor” means that when a ligand binds to the receptor, the channel portion of the receptor opens, and a cation flows from the outside of the cell. It means to promote polarization or transmission of intracellular signals.

  The fact that the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof activates the central nicotinic acetylcholine receptor is described in Dunlop et al. (Biochemical Pharmacology, 2007, Vol. 74, p. 1172) can be evaluated in an in vitro experimental system using cells expressing a central nicotinic acetylcholine receptor. For example, expressing α7 subtype, one of central nicotinic acetylcholine receptors, in GH4C1 cells derived from rat pituitary gland, and measuring the fluorescence intensity of the fluorescent indicator to increase intracellular calcium concentration due to the action of the compound In this method, the strength of activation is evaluated.

  Compounds known to activate central nicotinic acetylcholine receptors (preferably the α7 subtype of central nicotinic acetylcholine receptors) (eg, varenicline tartrate, N- (1-azabicyclo [2. 2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride and compounds of Reference Examples 51 to 60, as shown in Reference Examples 61 and 62, the central nicotinic acetylcholine receptor When activated, it exhibits an excellent inhibitory effect against pruritus. Therefore, it is clear that a compound that activates the central nicotinic acetylcholine receptor (preferably the α7 subtype of the central nicotinic acetylcholine receptor) exerts an excellent inhibitory effect on pruritus. In addition, varenicline tartrate, N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride, and central nicotinic acetylcholine described in Reference Examples 51-60 The characteristics of the compound that activates the receptor are shown below.

  Varenicline (7,8,9,10-tetrahydro-6H-6,10-methanopyrazino [2,3-h] [3] benzazepine) and derivatives thereof are described in WO 99/35131 and the like. It mainly exhibits α4β2 and α7 subtype activation effects (Mihalak et al., Molecular Pharmacology, 2006, 70, p.801). (R) -2-Chloro-5- (2-azetidinylmethoxy) pyridine and derivatives thereof are described in WO 98/25920 and the like, and mainly exhibit an α4β2 subtype activating action (Donnelly). -Roberts et al., Journal of Pharmacology and Experimental Therapeutics, 1998, 285, p.777). N- (2 (S)-(pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] octa-3 (R) -yl) -1-benzofuran-2-carboxamide and its derivatives are international Publication No. 09/018505, etc., and mainly exhibits an α7 subtype activation effect (Hauser et al., Biochemical Pharmacology, 2009, Vol. 78, p. 803). N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide and its derivatives are described in European Publication No. 311724 and the like, mainly α7 subtype activity (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219). (R) -7-Chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and its derivatives are described in International Publication No. 03/055878, etc. The type activating effect is shown (International Publication No. 2010/132423). 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester and its derivatives are described in European Publication No. 1231212 and the like, and mainly have an α7 subtype activation action. (Biton et al., Neuropsychopharmacology, 2007, vol. 32, p. 1). 2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine and its derivatives are described in O'Donnell et al. (Journal of Medicinal Chemistry, 2010, Vol. 53, p. 1222), etc., and mainly exhibits an α7 subtype activation action (O'Donnell et al., Journal of Medicinal Chemistry, 2010, Vol. 53, p. 122). 1222). 5- (4-morpholinyl) -N- (4- (3-pyridyl) phenyl) pentanamide and derivatives thereof are described in WO 06/008133 and the like, and mainly have an α7 subtype activation action. (Haydar et al., Bioorganic & Medicinal Chemistry, 2009, Vol. 17, p. 5247). Cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole and its derivatives are described in WO 05/028477, etc. It exhibits an α7 subtype activation effect (Tietje et al., CNS Neuroscience & Therapeutics, 2008, Vol. 14, p. 65). (-)-N- (1-azabicyclo [2,2,2] octa-3 (S) -yl) carbamic acid 1 (S)-(2-fluorophenyl) ethyl ester and its derivatives are described in Jiang et al. Synthetic Communications, 2009, Vol. 39, p. 2640) and the like, which mainly show α7 subtype activation (Feuerbach et al., Neuroscience Letters, 2007, Vol. 416, p. 61). ). N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxamide and derivatives thereof are disclosed in International Publication No. 02/100857 and the like. It is described and mainly exhibits an α7 subtype activating effect (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219). N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide and its derivatives are described in WO 03 / No. 042210 and the like, mainly exhibiting an α7 subtype activation action (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219).

  Therefore, the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof has an activating action on a central nicotinic acetylcholine receptor (preferably an α7 subtype of the central nicotinic acetylcholine receptor). Therefore, based on the said action mechanism, the inhibitory effect outstanding with respect to the pruritus is exhibited, and it can use as an antipruritic agent.

  “Itching” is a skin-specific sensation with a desire to scratch, such as atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis Skin diseases such as sebum deficiency, senile skin pruritus, insect bite, photosensitivity, urticaria, urticaria, shingles, impetigo, eczema, ringworm, lichen, psoriasis, scabies or acne vulgaris Examples include pruritus, malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, blood disease, hemodialysis, peritoneal dialysis or multiple sclerosis, or pruritus caused by drug or psychosis. It is done. In addition, pruritus is roughly divided into itch mediated by histamine and pruritus not mediated by histamine (refractory pruritus). The antipruritic agent of the present invention is particularly itch free from histamine (refractory pruritus). It is effective against. Examples of pruritus without histamine (refractory pruritus) include atopic dermatitis, contact dermatitis, sebum deficiency, senile pruritus, urticaria, psoriasis, malignant tumor, liver disease, chronic kidney disease, renal failure In the case of blood diseases, hemodialysis, peritoneal dialysis, multiple sclerosis, etc., there is a pruritus that is resistant to treatment with antihistamines.

  The antipruritic effect of the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof can be evaluated in an in vivo experimental system using an pruritus model animal, and various kinds represented by histamine, chloroquine or substance P A pruritus model that uses as an index the scratching behavior of a mouse caused by a causative substance is common. For example, Togashi et al. (European Journal of Pharmacology, 2002, Vol. 435, p. 259) and Andoh et al. (European Journal of Pharmacology, 2002, Vol. 436, p. 35). Substance P-induced scratching behavior using mice and spontaneous scratching using NC / Nga mice described in Takano et al. (European Journal of Pharmacology, 2003, Vol. 471, p. 223). Behavior can be used as one of the intractable pruritus models not mediated by histamine.

  In addition, since the scratching behavior of mice induced by substance P is suppressed by an opioid μ receptor antagonist, it is recognized not as a pain-related reaction but as a pruritus-related reaction (Journal of Pharmaceutical Therapies and Experimental Therapeutics, 1998). Year, 286, p. 1140-1145).

  Moreover, the substance P-induced scratching behavior of mice is not suppressed by the immunosuppressive agent tacrolimus (Biological & Pharmaceutical Bulletin, 2008, Vol. 31, p. 752) and the anti-inflammatory agents indomethacin and diclofenac. Scratch behavior is suppressed by steroids that are involved as an initiator and inhibit its production (Journal of Investigative Dermatology, 2001, 117, pp. 1621-1626). Substance P-induced scratch behavior is exogenous. Substance P and endogenous leukotriene B4 are induced by acute nerve stimulation, and can be used as an itching model that does not involve immune or inflammatory reactions. Is shall.

  The quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof is administered to a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human), particularly a human. In this case, it can be used as a useful medicament (in particular, a central nicotinic acetylcholine receptor activator or antipruritic agent). When clinically using the quinuclidinamide derivative (I) or a pharmacologically acceptable salt thereof as a pharmaceutical, the quinuclidinamide derivative (I) or a pharmacologically acceptable salt thereof is used as it is. Alternatively, additives such as excipients, stabilizers, preservatives, buffering agents, solubilizers, emulsifiers, diluents or tonicity agents may be appropriately mixed. Moreover, said pharmaceutical can be manufactured by a normal method using these pharmaceutical carriers as appropriate. Examples of the above-mentioned pharmaceutical administration forms include oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or liquids, or topical administration. Examples include ointments, creams, patches, and the like. Further, it may be a known continuous preparation.

  The above medicament preferably contains 0.001 to 90% by weight, preferably 0.01 to 70% by weight, of the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. Is more preferable. The dose is appropriately selected according to symptoms, age, body weight, sex, administration method, etc. As the amount of active ingredient for adults, 0.001 mg to 5 g per day for injections, 0.01 mg to 10 g for oral preparations Each can be administered once or in several divided doses.

  Examples of the pharmacologically acceptable carrier or diluent of the above-mentioned pharmaceutical include, for example, binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride, tragacanth, etc.), excipients (sugar, lactose, corn starch, calcium phosphate, etc. Sorbitol, glycine, etc.) or lubricants (magnesium stearate, polyethylene glycol, talc, silica, etc.).

  The above medicines may be used in combination with or in combination with other drugs in order to supplement or enhance the therapeutic or preventive effect or reduce the dose.

  As a drug that can be used in combination when the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof is used as an antipruritic agent, for example, it is usually used for the treatment of the following primary diseases that cause itching Drugs.

  Examples of skin diseases that are the primary diseases of pruritus include atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, senile Skin pruritus, insect bites, photosensitivity, urticaria, urticaria, herpes, impetigo, eczema, ringworm, lichen, psoriasis, scabies or acne vulgaris. In addition, examples of other primary diseases include malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, pregnancy, and multiple sclerosis. Furthermore, it is also known that hemodialysis, peritoneal dialysis or drugs cause pruritus, pregnancy or parasitic infection causes pruritus, or psychogenic pruritus.

  Examples of drugs used for the treatment of atopic dermatitis include steroid external preparations (betamethasone, beclomethasone, clobetasone or prednisolone, etc.), calcineurin inhibitory (immunosuppressive) external preparations (tacrolimus, etc.), nonsteroidal anti-inflammatory external preparations, antihistamines (Diphenhydramine, chlorpheniramine, cetirizine or oxatomide, loratadine, etc.), cyclosporine, oral steroids or humectants (urea, hirudoid, petrolatum, etc.). Examples of drugs used for the treatment of multiple sclerosis include corticosteroids (such as prednisolone or methylprednisolone), immunosuppressants (methotrexate, azathioprine, cyclophosphamide, cyclosporin A, tacrolimus, mizoribine, etc.) Interferon preparations (such as interferon α or interferon β), sphingosine-1-phosphate receptor modulators (FTY-720), copolymer I, immunoglobulin, T cell receptor vaccine, adhesion molecule inhibitor, TNFα inhibitor, relieve spasticity Examples include drugs (tizanidine, eperisone, afroqualone, baclofen, dantrolene, etc.) or analgesics (indomethacin, diclofenac, etc.).

  The following examples further illustrate the present invention in detail but are not to be construed to limit the scope thereof.

  In addition, the commercially available compound was used about the compound which is not described in the synthesis method by the compound used for the synthesis | combination of an Example compound. The solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruplex line), quint, respectively. (Quintet), sept (sevent), m (multiple line), br (wide), dd (double double line), dt (double triple line), ddd (double double line) , Dq (double quadruple line), td (triple double line), and tt (triple triple line). The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology). The amine silica gel used was an amine silica gel DM1020 manufactured by Fuji Silysia Chemical, and the chromatography used was YFLC W-prep2XY (Yamazensha). As the microwave reactor, monowave 300 (manufactured by Anton Paar) was used.

エチル ３，３−ジエトキシプロパノエート（２．６ｇ，１４ｍｍｏｌ）をジクロロメタン（１４ｍＬ）に溶解し、トリフルオロ酢酸（８．０ｍＬ，１００ｍｍｏｌ）、蒸留水（８．０ｍＬ）を室温で加え、同温で撹拌した。２時間後、反応溶液をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物にジメチルホルムアミドジメチルアセタール（９．２ｍＬ，６８ｍｍｏｌ）を加え、８０℃で撹拌した。２時間後、反応溶液を室温まで冷却し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０〜２５／７５，クロロホルムのみ〜クロロホルム／メタノール＝９５／５）で精製し、表題化合物（０．９５ｇ、４１％）を黄色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．３１（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．１６（３Ｈ，ｓ），３．３２（３Ｈ，ｓ），４．２３（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．７４（１Ｈ，ｓ），９．７１（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：１７２．Reference Example 1 Synthesis of ethyl 3- (dimethylamino) -2-formyl acrylate:

Ethyl 3,3-diethoxypropanoate (2.6 g, 14 mmol) was dissolved in dichloromethane (14 mL), and trifluoroacetic acid (8.0 mL, 100 mmol) and distilled water (8.0 mL) were added at room temperature. Stir at warm. After 2 hours, the reaction solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Dimethylformamide dimethyl acetal (9.2 mL, 68 mmol) was added to the obtained crude product, and the mixture was stirred at 80 ° C. After 2 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-25 / 75, chloroform only-chloroform / methanol = 95/5) to give the title compound (0.95 g, 41%) Was obtained as a yellow liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.31 (3H, t, J = 7.2 Hz), 3.16 (3H, s), 3.32 (3H, s), 4.23 (2H, q, J = 7.2 Hz), 7.74 (1H, s), 9.71 (1H, s).
MS (ESI) [M + H] ⁺ : 172.

エチル ３−（ジメチルアミノ）−２−ホルミルアクリレート（０．３８ｇ，２．２ｍｍｏｌ）をエタノール（１５ｍＬ）に溶解し、フェニルヒドラジン（０．２４ｇ，２．２ｍｍｏｌ）を室温で加え、８０℃で撹拌した。３時間後、反応溶液を室温まで冷却し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ〜ヘキサン／酢酸エチル＝７８／２２）で精製し、表題化合物（０．４７ｇ、９８％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．３８（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．３４（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．３３−７．３９（１Ｈ，ｍ），７．４６−７．５３（２Ｈ，ｍ），７．６７−７．７３（２Ｈ，ｍ），８．１０（１Ｈ，ｂｒｓ），８．４１（１Ｈ，ｂｒｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２１７．Reference Example 2 Synthesis of ethyl 1-phenyl-1H-pyrazole-4-carboxylate:

Ethyl 3- (dimethylamino) -2-formyl acrylate (0.38 g, 2.2 mmol) is dissolved in ethanol (15 mL), phenylhydrazine (0.24 g, 2.2 mmol) is added at room temperature, and the mixture is stirred at 80 ° C. did. After 3 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane only to hexane / ethyl acetate = 78/22) to obtain the title compound (0.47 g, 98%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.38 (3H, t, J = 7.2 Hz), 4.34 (2H, q, J = 7.2 Hz), 7.33-7.39 (1H, m), 7.46-7 .53 (2H, m), 7.67-7.73 (2H, m), 8.10 (1H, brs), 8.41 (1H, brs).
MS (ESI) [M + H] ⁺ : 217.

  In the same manner as in Reference Example 2, the following compounds of Reference Example 3 to Reference Example 27 were synthesized.

エチル ３−オキソ−３−フェニルプロパノエート（０．５０ｇ，２．６ｍｍｏｌ）にジメチルホルムアミドジメチルアセタール（１．７ｍＬ，１３ｍｍｏｌ）を室温で加え、８０℃で撹拌した。２時間後、反応溶液を室温まで冷却し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９７／３）で精製した。Reference Example 28 Synthesis of ethyl 1,5-diphenyl-1H-pyrazole-4-carboxylate:

Diethylformamide dimethyl acetal (1.7 mL, 13 mmol) was added to ethyl 3-oxo-3-phenylpropanoate (0.50 g, 2.6 mmol) at room temperature, and the mixture was stirred at 80 ° C. After 2 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform only to chloroform / methanol = 97/3).

The above product was dissolved in ethanol (15 mL), phenylhydrazine (0.33 g, 2.3 mmol) was added at room temperature, and the mixture was stirred at 80 ° C. After 3 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane only to hexane / ethyl acetate = 88/12) to obtain the title compound (0.54 g, 72%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.22 (3H, t, J = 7.2 Hz), 4.21 (2H, q, J = 7.2 Hz), 7.19-7.22 (2H, m), 7.26-7 .38 (8H, m), 8.19 (1H, s).
MS (ESI) [M + H] ⁺ : 293.

エチル １Ｈ−ピラゾール−４−カルボキシレート（０．５８ｇ，４．１ｍｍｏｌ）を１，４−ジオキサン（１４ｍＬ）に溶解し、炭酸カリウム（０．８６ｇ，６．２ｍｍｏｌ）、Ｎ，Ｎ’−ジメチルエチレンジアミン（０．３６ｍＬ，３．３ｍｍｏｌ）、ヨウ化銅（Ｉ）（０．１６ｇ，０．８３ｍｍｏｌ）、１−ブロモ−２−ニトロベンゼン（１．０ｇ，５．０ｍｍｏｌ）を室温で加え、１００℃で撹拌した。６時間後、反応溶液を室温まで冷却し、セライトで濾過した。濾液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ〜ヘキサン／酢酸エチル＝６７／３３）で精製し、表題化合物（０．２７ｇ、２５％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．３７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．３４（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．５７−７．６４（２Ｈ，ｍ），７．７０−７．７６（１Ｈ，ｍ），７．９６（１Ｈ，ｄｄ，Ｊ＝１．６，８．０Ｈｚ），８．１１（１Ｈ，ｓ），８．２２（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２６２．Reference Example 29 Synthesis of ethyl 1- (2-nitrophenyl) -1H-pyrazole-4-carboxylate:

Ethyl 1H-pyrazole-4-carboxylate (0.58 g, 4.1 mmol) is dissolved in 1,4-dioxane (14 mL), potassium carbonate (0.86 g, 6.2 mmol), N, N′-dimethylethylenediamine. (0.36 mL, 3.3 mmol), copper (I) iodide (0.16 g, 0.83 mmol), 1-bromo-2-nitrobenzene (1.0 g, 5.0 mmol) was added at room temperature, and 100 ° C. Stir. After 6 hours, the reaction solution was cooled to room temperature and filtered through celite. Distilled water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 67/33) to obtain the title compound (0.27 g, 25%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.37 (3H, t, J = 7.2 Hz), 4.34 (2H, q, J = 7.2 Hz), 7.57-7.64 (2H, m), 7.70-7 .76 (1H, m), 7.96 (1H, dd, J = 1.6, 8.0 Hz), 8.11 (1H, s), 8.22 (1H, s).
MS (ESI) [M + H] ⁺ : 262.

  The following compounds of Reference Example 30 to Reference Example 40 were synthesized by the same procedure as in Reference Example 29.

Reference Example 41 Synthesis of 1-methyl-4-phenyl-1H-imidazole and 1-methyl-5-phenyl-1H-imidazole:
5-Phenyl-1H-imidazole (2.5 g, 17 mmol) was dissolved in DMF (15 mL), tert-butyloxysodium (1.8 g, 19 mmol) was added at room temperature, and the mixture was stirred at the same temperature. After 15 minutes, iodomethane (1.2 mL, 19 mmol) was added and stirred at room temperature. After 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 23/77 to ethyl acetate only), 1-methyl-4-phenyl-1H-imidazole (1.8 g, 64%) and 1 -Methyl-5-phenyl-1H-imidazole (0.52 g, 19%) was obtained as a white solid, respectively.

^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：３．７３（３Ｈ，ｓ），７．１７（１Ｈ，ｂｒｓ），７．２０−７．２７（１Ｈ，ｍ），７．３７（２Ｈ，ｄｄ，Ｊ＝８．０，８．０Ｈｚ），７．４７（１Ｈ，ｂｒｓ），７．７５（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：１５９．1-methyl-4-phenyl-1H-imidazole:

¹ H-NMR (400 MHz, CDCl ₃ )
δ: 3.73 (3H, s), 7.17 (1H, brs), 7.20-7.27 (1H, m), 7.37 (2H, dd, J = 8.0, 8.0 Hz) ), 7.47 (1H, brs), 7.75 (2H, d, J = 8.0 Hz).
MS (ESI) [M + H] ⁺ : 159.

^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：３．６８（３Ｈ，ｓ），７．１０（１Ｈ，ｂｒｓ），７．３５−７．４７（５Ｈ，ｍ），７．５２（１Ｈ，ｂｒｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：１５９．1-methyl-5-phenyl-1H-imidazole:

¹ H-NMR (400 MHz, CDCl ₃ )
δ: 3.68 (3H, s), 7.10 (1H, brs), 7.35-7.47 (5H, m), 7.52 (1H, brs).
MS (ESI) [M + H] ⁺ : 159.

１−メチル−４−フェニル−１Ｈ−イミダゾール（０．４８ｇ，３．０ｍｍｏｌ）をＴＨＦ（１５ｍＬ）に溶解し、ｎ−ブチルリチウム（２．６Ｎヘキサン溶液，１．４ｍＬ，３．６ｍｍｏｌ）を−７８℃で加え、０℃で撹拌した。２０分後、クロロギ酸エチル（０．３８ｍＬ，３．９ｍｍｏｌ）を−７８℃で加え、０℃で攪拌した。２時間後、反応溶液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝８８／１２〜５６／３４）で精製し、表題化合物（０．１２ｇ、１７％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．４６（３Ｈ，ｔ，Ｊ＝６．８Ｈｚ），４．０６（３Ｈ，ｓ），４．４６（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），７．２４−７．４０（４Ｈ，ｍ），７．７７−７．８２（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２３１．Reference Example 42 Synthesis of ethyl 1-methyl-4-phenyl-1H-imidazole-2-carboxylate:

1-methyl-4-phenyl-1H-imidazole (0.48 g, 3.0 mmol) was dissolved in THF (15 mL), and n-butyllithium (2.6N hexane solution, 1.4 mL, 3.6 mmol) was It added at 78 degreeC and stirred at 0 degreeC. After 20 minutes, ethyl chloroformate (0.38 mL, 3.9 mmol) was added at −78 ° C. and stirred at 0 ° C. Two hours later, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 88 / 12-56 / 34) to give the title compound (0.12 g, 17%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.46 (3H, t, J = 6.8 Hz), 4.06 (3H, s), 4.46 (2H, t, J = 6.8 Hz), 7.24-7.40 (4H , M), 7.77-7.82 (2H, m).
MS (ESI) [M + H] ⁺ : 231.

  The following compound of Reference Example 43 was synthesized by the same procedure as Reference Example 42.

１Ｈ−イミダゾール−４−カルボン酸（１．０ｇ，８．９ｍｍｏｌ）をメタノール（１０ｍＬ）に溶解し、濃硫酸（１．０ｍＬ，１９ｍｍｏｌ）を室温で加え、８０℃で撹拌した。８時間後、反応溶液を室温まで冷却し、飽和炭酸水素ナトリウム水溶液を加え、中和し、減圧濃縮した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をＤＭＳＯ（５．０ｍＬ）に溶解し、炭酸セシウム（２．７ｇ，８．１ｍｍｏｌ）、１，１０−フェナントロリン（０．５９ｇ，３．３ｍｍｏｌ）、酸化銅（Ｉ）（０．２３ｇ，１．６ｍｍｏｌ）、ヨードベンゼン（１．３ｇ，６．５ｍｍｏｌ）を室温で加え、マイクロウェーブ照射下、１００℃で撹拌した。４０分後、反応溶液を室温まで冷却し、セライトで濾過した。濾液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３６／６４〜酢酸エチルのみ）で精製し、表題化合物（０．１２ｇ、７％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：３．９４（３Ｈ，ｓ），７．４０−７．４７（３Ｈ，ｍ），７．５０−７．５６（２Ｈ，ｍ），７．８６（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２０３．Reference Example 44 Synthesis of methyl 1-phenyl-1H-imidazole-4-carboxylate:

1H-imidazole-4-carboxylic acid (1.0 g, 8.9 mmol) was dissolved in methanol (10 mL), concentrated sulfuric acid (1.0 mL, 19 mmol) was added at room temperature, and the mixture was stirred at 80 ° C. After 8 hours, the reaction solution was cooled to room temperature, neutralized with a saturated aqueous sodium hydrogen carbonate solution, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in DMSO (5.0 mL), cesium carbonate (2.7 g, 8.1 mmol), 1,10-phenanthroline (0.59 g, 3.3 mmol), copper (I) oxide ( 0.23 g, 1.6 mmol) and iodobenzene (1.3 g, 6.5 mmol) were added at room temperature, and the mixture was stirred at 100 ° C. under microwave irradiation. After 40 minutes, the reaction solution was cooled to room temperature and filtered through celite. Distilled water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 36/64 to ethyl acetate alone) to obtain the title compound (0.12 g, 7%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 3.94 (3H, s), 7.40-7.47 (3H, m), 7.50-7.56 (2H, m), 7.86 (1H, d, J = 1.2 Hz) ), 7.97 (1H, d, J = 1.2 Hz).
MS (ESI) [M + H] ⁺ : 203.

  The following compound of Reference Example 45 was synthesized by the same procedure as Reference Example 44.

メチル １Ｈ−イミダゾール−４−カルボキシレート（１００ｍｇ、０．７９ｍｍｏｌ）をＤＭＳＯ（１．０ｍＬ）に溶解し、１−フルオロ−２−ヨードベンゼン（０．１９ｍＬ、１．６ｍｍｏｌ）、炭酸セシウム（６５０ｍｇ、２．０ｍｍｏｌ）、１，１０−フェナントロリン（１４０ｍｇ、０．７９ｍｍｏｌ）、酸化銅（Ｉ）（５７ｍｇ、０．４０ｍｍｏｌ）を室温で加え、マイクロウェーブ照射下、１２０℃で撹拌した。３０分後、反応溶液を室温まで冷却し、セライトで濾過した。濾液にアンモニア水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０〜４０／６０）で精製し、表題化合物（２６ｍｇ、１５％）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：３．９４（３Ｈ，ｓ），７．２８−７．３４（２Ｈ，ｍ），７．４０−７．４５（２Ｈ，ｍ），７．８３（１Ｈ，ｔ，Ｊ＝１．６Ｈｚ），７．９４（１Ｈ，ｔ，Ｊ＝１．６Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２２１．Reference Example 46 Synthesis of methyl 1- (2-fluorophenyl) -1H-imidazole-4-carboxylate:

Methyl 1H-imidazole-4-carboxylate (100 mg, 0.79 mmol) was dissolved in DMSO (1.0 mL) and 1-fluoro-2-iodobenzene (0.19 mL, 1.6 mmol), cesium carbonate (650 mg, 2.0 mmol), 1,10-phenanthroline (140 mg, 0.79 mmol) and copper (I) oxide (57 mg, 0.40 mmol) were added at room temperature, and the mixture was stirred at 120 ° C. under microwave irradiation. After 30 minutes, the reaction solution was cooled to room temperature and filtered through celite. Aqueous ammonia was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-40 / 60) to give the title compound (26 mg, 15%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 3.94 (3H, s), 7.28-7.34 (2H, m), 7.40-7.45 (2H, m), 7.83 (1H, t, J = 1.6 Hz) ), 7.94 (1H, t, J = 1.6 Hz).
MS (ESI) [M + H] ⁺ : 221.

メチル １Ｈ−イミダゾール−４−カルボキシレート（１００ｍｇ，０．７９ｍｍｏｌ）をジクロロメタン（３．０ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．４２ｍＬ，２．４ｍｍｏｌ）、ピリジン−Ｎ−オキシド（７５ｍｇ，０．７９ｍｍｏｌ）、ヘキサフルオロリン酸ブロモトリピロリジノホスホニウム（４１０ｍｇ，０．８７ｍｍｏｌ）を０℃で加え、同温で撹拌した。３時間後、飽和炭酸水素ナトリウム水溶液を０℃で加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝８０／２０〜２０／８０）で精製し、表題化合物（７０ｍｇ、４４％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：３．９５（３Ｈ，ｓ），７．３３（１Ｈ，ｄｄ，Ｊ＝５．２，７．６Ｈｚ），７．４２（１Ｈ，ｄｄ，Ｊ＝０．８，８．４Ｈｚ），７．８９（１Ｈ，ｄｄｄ，Ｊ＝１．６，７．６，８．４Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），８．３８（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）８．５３（１Ｈ，ｄｄｄ，Ｊ＝０．８，１．６，５．２Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２０４．Reference Example 47 Synthesis of methyl 1- (pyridin-2-yl) -1H-imidazole-4-carboxylate:

Methyl 1H-imidazole-4-carboxylate (100 mg, 0.79 mmol) was dissolved in dichloromethane (3.0 mL), diisopropylethylamine (0.42 mL, 2.4 mmol), pyridine-N-oxide (75 mg, 0.79 mmol). ), Bromotripyrrolidinophosphonium hexafluorophosphate (410 mg, 0.87 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature. After 3 hours, a saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C., and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by amine silica gel column chromatography (hexane / ethyl acetate = 80/20 to 20/80) to give the title compound (70 mg, 44%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 3.95 (3H, s), 7.33 (1H, dd, J = 5.2, 7.6 Hz), 7.42 (1H, dd, J = 0.8, 8.4 Hz), 7 .89 (1H, ddd, J = 1.6, 7.6, 8.4 Hz), 8.33 (1H, d, J = 1.6 Hz), 8.38 (1H, d, J = 1.6 Hz) ) 8.53 (1H, ddd, J = 0.8, 1.6, 5.2 Hz).
MS (ESI) [M + H] ⁺ : 204.

エチル １−フェニル−１Ｈ−ピラゾール−４−カルボキシレート（４７０ｍｇ，２．２ｍｍｏｌ）をメタノール（７．０ｍＬ）に溶解し、水酸化ナトリウム水溶液（１．０Ｎ，６．５ｍＬ，６．５ｍｍｏｌ）を室温で加え、５０℃で撹拌した。３時間後、反応溶液を減圧濃縮し、酢酸エチルで抽出した。水層に１．０Ｎ塩酸を加え、ｐＨ＝５とした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮し、表題化合物（０．３９ｇ、９５％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：７．３５−７．４１（１Ｈ，ｍ），７．４７−７．５３（２Ｈ，ｍ），７．７０−７．７４（２Ｈ，ｍ），８．１７（１Ｈ，ｂｒｓ），８．４７（１Ｈ，ｂｒｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：１８９．Reference Example 48 Synthesis of 1-phenyl-1H-pyrazole-4-carboxylic acid:

Ethyl 1-phenyl-1H-pyrazole-4-carboxylate (470 mg, 2.2 mmol) is dissolved in methanol (7.0 mL), and aqueous sodium hydroxide solution (1.0 N, 6.5 mL, 6.5 mmol) is dissolved at room temperature. And stirred at 50 ° C. After 3 hours, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. 1.0N hydrochloric acid was added to the aqueous layer to adjust to pH = 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (0.39 g, 95%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 7.35-7.41 (1H, m), 7.47-7.53 (2H, m), 7.70-7.74 (2H, m), 8.17 (1H, brs), 8.47 (1H, brs).
MS (ESI) [M + H] ⁺ : 189.

（Ｒ）−キヌクリジン−３−アミン二塩酸塩（２．０ｇ，１０ｍｍｏｌ）をクロロホルム（５０ｍＬ）に溶解し、ジイソプロピルエチルアミン（７．０ｍＬ，４０ｍｍｏｌ）を０℃で加え、同温で撹拌した。１時間後、クロロギ酸エチル（１．２ｍＬ，１２ｍｍｏｌ）を０℃で加え、同温で撹拌した。０．５時間後、反応溶液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９７／３）で精製した。Reference Example 49 Synthesis of (R) -N-methylquinuclidin-3-amine:

(R) -quinuclidine-3-amine dihydrochloride (2.0 g, 10 mmol) was dissolved in chloroform (50 mL), diisopropylethylamine (7.0 mL, 40 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature. After 1 hour, ethyl chloroformate (1.2 mL, 12 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature. After 0.5 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 97/3).

The above product was dissolved in THF (25 mL), lithium aluminum hydride (0.48 g, 13 mmol) was added at room temperature, and the mixture was stirred at 70 ° C. After 4 hours, a saturated aqueous Rochelle salt solution was added, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 89/11) to obtain the title compound (350 mg, 25%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.23-1.52 (2H, m), 1.63-2.00 (3H, m), 2.37-2.44 (4H, m), 2.58-2.64 (1H M), 2.68-2.90 (4H, m), 3.07-3.16 (1H, m).
MS (ESI) [M + H] ⁺ : 141.

１−フェニル−１Ｈ−ピラゾール−４−カルボン酸（４００ｍｇ，２．２ｍｍｏｌ）をクロロホルム（２０ｍＬ）に溶解し、ジイソプロピルエチルアミン（１．５ｍＬ，８．５ｍｍｏｌ）、ＨＢＴＵ（１２００ｍｇ，３．２ｍｍｏｌ）、（Ｒ）−キヌクリジン−３−アミン二塩酸塩（４２０ｍｇ，２．２ｍｍｏｌ）を室温で加え、同温で撹拌した。１６時間後、反応溶液に蒸留水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９９／１）及びシリカゲルクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝５０／５０）で精製し、表題化合物（３８０ｍｇ、６１％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．５２−１．６０（１Ｈ，ｍ），１．６８−１．８０（３Ｈ，ｍ），２．０２−２．０８（１Ｈ，ｍ），２．５５−２．６４（１Ｈ，ｍ），２．７８−２．９８（４Ｈ，ｍ），３．４１−３．５０（１Ｈ，ｍ），４．１０−４．２０（１Ｈ，ｍ），５．８９−５．９６（１Ｈ，ｍ），７．３３−７．３８（１Ｈ，ｍ），７．４５−７．５２（２Ｈ，ｍ），７．６８−７．７３（２Ｈ，ｍ），７．９４（１Ｈ，ｓ），８．３８（１Ｈ，ｓ）．ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２９７．Example 1 Synthesis of (R) -1-phenyl-N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide:

1-phenyl-1H-pyrazole-4-carboxylic acid (400 mg, 2.2 mmol) was dissolved in chloroform (20 mL), and diisopropylethylamine (1.5 mL, 8.5 mmol), HBTU (1200 mg, 3.2 mmol), ( R) -Quinuclidin-3-amine dihydrochloride (420 mg, 2.2 mmol) was added at room temperature and stirred at the same temperature. After 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 99/1) and silica gel chromatography (chloroform only to chloroform / methanol = 50/50) to give the title compound (380 mg, 61 %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.52-1.60 (1H, m), 1.68-1.80 (3H, m), 2.02-2.08 (1H, m), 2.55-2.64 (1H) M), 2.78-2.98 (4H, m), 3.41-3.50 (1H, m), 4.10-4.20 (1H, m), 5.89-5.96. (1H, m), 7.33-7.38 (1H, m), 7.45-7.52 (2H, m), 7.68-7.73 (2H, m), 7.94 (1H , S), 8.38 (1H, s). MS (ESI) [M + H] ⁺ : 297.

  The following compounds of Example 2 to Example 9, Reference Example 50 and Comparative Examples 1 to 3 were synthesized according to the same procedure as Example 1.

３−メチル−１−フェニル−１Ｈ−ピラゾール−４−カルボアルデヒド（２４０ｍｇ，１．９ｍｍｏｌ）をｔｅｒｔ−ブチルアルコール（１０ｍＬ）と蒸留水（２０ｍＬ）の混合溶媒に溶解し、リン酸二水素ナトリウム（１．９ｇ，１６ｍｍｏｌ）を室温で加え、同温で攪拌した。１時間後、亜塩素酸ナトリウム（２．９ｇ，３２ｍｍｏｌ）を室温で加え、同温で撹拌した。１６時間後、飽和亜硫酸水素ナトリウム水溶液を室温で加え、同温で攪拌した。０．５時間後、反応溶液に１．０Ｎ水酸化ナトリウム水溶液を加え、ｐＨ＝１０とした後、酢酸エチルで抽出した。水層に１．０Ｎ塩酸を加え、ｐＨ＝５とした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をクロロホルム（５．０ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．７３ｍＬ，４．２ｍｍｏｌ）、ＨＢＴＵ（４７０ｍｇ，１．２ｍｍｏｌ）、（Ｒ）−キヌクリジン−３−アミン二塩酸塩（２１０ｍｇ，１．０ｍｍｏｌ）を室温で加え、同温で撹拌した。１６時間後、反応溶液に蒸留水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９５／５）で精製し、表題化合物（１６０ｍｇ、９％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．４８−１．６０（１Ｈ，ｍ），１．６６−１．７８（１Ｈ，ｍ），１．９６−２．０５（３Ｈ，ｍ），２．５５−２．６２（４Ｈ，ｍ），２．７８−２．９５（４Ｈ，ｍ），３．３８−３．４７（１Ｈ，ｍ），４．０９−４．１８（１Ｈ，ｍ），５．９５−６．０５（１Ｈ，ｍ），７．２６−７．３４（１Ｈ，ｍ），７．４４（２Ｈ，ｄｄ，Ｊ＝８．０，８．０Ｈｚ），７．６５（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．２７（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３１１．Example 10 Synthesis of (R) -3-methyl-1-phenyl-N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide:

3-Methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (240 mg, 1.9 mmol) was dissolved in a mixed solvent of tert-butyl alcohol (10 mL) and distilled water (20 mL), and sodium dihydrogen phosphate ( 1.9 g, 16 mmol) was added at room temperature and stirred at the same temperature. After 1 hour, sodium chlorite (2.9 g, 32 mmol) was added at room temperature and stirred at the same temperature. After 16 hours, a saturated aqueous sodium hydrogensulfite solution was added at room temperature, and the mixture was stirred at the same temperature. After 0.5 hour, 1.0N aqueous sodium hydroxide solution was added to the reaction solution to adjust to pH = 10, followed by extraction with ethyl acetate. 1.0N hydrochloric acid was added to the aqueous layer to adjust to pH = 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in chloroform (5.0 mL), diisopropylethylamine (0.73 mL, 4.2 mmol), HBTU (470 mg, 1.2 mmol), (R) -quinuclidin-3-amine dihydrochloride. (210 mg, 1.0 mmol) was added at room temperature and stirred at the same temperature. After 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 95/5) to obtain the title compound (160 mg, 9%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.48-1.60 (1H, m), 1.66-1.78 (1H, m), 1.96-2.05 (3H, m), 2.55-2.62 (4H) M), 2.78-2.95 (4H, m), 3.38-3.47 (1H, m), 4.09-4.18 (1H, m), 5.95-6.05. (1H, m), 7.26-7.34 (1H, m), 7.44 (2H, dd, J = 8.0, 8.0 Hz), 7.65 (2H, d, J = 8. 0 Hz), 8.27 (1 H, s).
MS (ESI) [M + H] ⁺ : 311.

エチル １，５−ジフェニル−１Ｈ−ピラゾール−４−カルボキシレート（５４０ｍｇ，１．８ｍｍｏｌ）をメタノール（６．０ｍＬ）に溶解し、１．０Ｎ水酸化ナトリウム水溶液（５．５ｍＬ，５．５ｍｍｏｌ）を室温で加え、５０℃で撹拌した。３時間後、反応溶液を減圧濃縮し、酢酸エチルで逆抽出した。水層に１．０Ｎ塩酸を加え、ｐＨ＝５とした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をクロロホルム（１８ｍＬ）に溶解し、ジイソプロピルエチルアミン（１．３ｍＬ，７．４ｍｍｏｌ）、ＨＢＴＵ（１１００ｍｇ，２．８ｍｍｏｌ）、（Ｒ）−キヌクリジン−３−アミン二塩酸塩（３７０ｍｇ，１．８ｍｍｏｌ）を室温で加え、同温で撹拌した。１６時間後、反応溶液に蒸留水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９９／１）で精製し、表題化合物（６２０ｍｇ、９１％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：０．８７−０．９８（１Ｈ，ｍ），１．１８−１．２６（１Ｈ，ｍ），１．５３−１．６４（２Ｈ，ｍ），１．７０−１．７６（１Ｈ，ｍ），２．０３−２．０８（１Ｈ，ｍ），２．２８−２．３８（１Ｈ，ｍ），２．６３−２．７４（３Ｈ，ｍ），３．１７−３．２５（１Ｈ，ｍ），３．９４−４．０２（１Ｈ，ｍ），５．４３−５．５２（１Ｈ，ｍ），７．１９−７．２９（５Ｈ，ｍ），７．３５−７．４１（２Ｈ，ｍ），７．４４−７．５０（３Ｈ，ｍ），８．２３（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３７３．Example 11 Synthesis of (R) -1,5-diphenyl-N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide:

Ethyl 1,5-diphenyl-1H-pyrazole-4-carboxylate (540 mg, 1.8 mmol) is dissolved in methanol (6.0 mL), and 1.0N aqueous sodium hydroxide solution (5.5 mL, 5.5 mmol) is dissolved. It added at room temperature and stirred at 50 degreeC. After 3 hours, the reaction solution was concentrated under reduced pressure and back-extracted with ethyl acetate. 1.0N hydrochloric acid was added to the aqueous layer to adjust to pH = 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in chloroform (18 mL), diisopropylethylamine (1.3 mL, 7.4 mmol), HBTU (1100 mg, 2.8 mmol), (R) -quinuclidin-3-amine dihydrochloride (370 mg). , 1.8 mmol) at room temperature and stirred at the same temperature. After 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 99/1) to obtain the title compound (620 mg, 91%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 0.87-0.98 (1H, m), 1.18-1.26 (1H, m), 1.53-1.64 (2H, m), 1.70-1.76 (1H M), 2.03-2.08 (1H, m), 2.28-2.38 (1H, m), 2.62-2.74 (3H, m), 3.17-3.25. (1H, m), 3.94-4.02 (1H, m), 5.43-5.52 (1H, m), 7.19-7.29 (5H, m), 7.35-7 .41 (2H, m), 7.44-7.50 (3H, m), 8.23 (1H, s).
MS (ESI) [M + H] ⁺ : 373.

  The following compounds of Example 12 to Example 52 were synthesized according to the same procedure as Example 11.

エチル １Ｈ−ピラゾール−４−カルボキシレート（０．５８ｇ，４．１ｍｍｏｌ）を１，４−ジオキサン（１４ｍＬ）に溶解し、炭酸カリウム（０．８６ｇ，６．２ｍｍｏｌ）、Ｎ，Ｎ’−ジメチルエチレンジアミン（０．３６ｍＬ，３．３ｍｍｏｌ）、ヨウ化銅（Ｉ）（０．１６ｇ，０．８３ｍｍｏｌ）、１−ブロモ−４−ニトロベンゼン（１．０ｇ，５．０ｍｍｏｌ）を室温で加え、１００℃で撹拌した。６時間後、反応溶液をセライトで濾過した。濾液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ〜ヘキサン／酢酸エチル＝６７／３３）で精製した。Example 53 Synthesis of (R) -1- (4-nitrophenyl) -N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide:

Ethyl 1H-pyrazole-4-carboxylate (0.58 g, 4.1 mmol) is dissolved in 1,4-dioxane (14 mL), potassium carbonate (0.86 g, 6.2 mmol), N, N′-dimethylethylenediamine. (0.36 mL, 3.3 mmol), copper (I) iodide (0.16 g, 0.83 mmol), 1-bromo-4-nitrobenzene (1.0 g, 5.0 mmol) was added at room temperature, and 100 ° C. Stir. After 6 hours, the reaction solution was filtered through celite. Distilled water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane only to hexane / ethyl acetate = 67/33).

The above product was dissolved in ethanol (5.0 mL), 1.0 N aqueous sodium hydroxide solution (4.6 mL, 4.6 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. After 4 hours, the reaction solution was concentrated under reduced pressure and back-extracted with ethyl acetate. 1.0N hydrochloric acid was added to the aqueous layer to adjust to pH = 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in chloroform (8.0 mL), and diisopropylethylamine (1.1 mL, 6.1 mmol), HBTU (0.70 g, 1.8 mmol), (R) -quinuclidine-3-amine Hydrochloride (0.31 g, 1.5 mmol) was added at room temperature and stirred at the same temperature. After 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 95/5) to obtain the title compound (62 mg, 4%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.50-1.60 (1H, m), 1.66-1.80 (3H, m), 2.02-2.07 (1H, m), 2.55-2.64 (1H M), 2.76-2.96 (4H, m), 3.40-3.46 (1H, m), 4.12-4.20 (1H, m), 5.98-6.06. (1H, m), 7.91 (2H, d, J = 9.6 Hz), 8.01 (1H, s), 8.37 (2H, d, J = 9.6 Hz), 8.50 (1H , S).
MS (ESI) [M + H] ⁺ : 342.

（Ｒ）−１−（２−ニトロフェニル）−Ｎ−（キヌクリジン−３−イル）−１Ｈ−ピラゾール−４−カルボキシアミド（１５０ｍｇ，０．４４ｍｍｏｌ）をエタノール（４．０ｍＬ）に溶解し、パラジウム−炭素（１０％ｗｅｔ，２４ｍｇ，０．０２２ｍｍｏｌ）を室温で加え、水素雰囲気下、同温で撹拌した。１６時間後、反応溶液をセライトで濾過し、濾液を減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝８９／１１）で精製し、表題化合物（９９ｍｇ、７２％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．６８−１．７８（３Ｈ，ｍ），２．０１−２．０７（１Ｈ，ｍ），２．５４−２．６２（１Ｈ，ｍ），２．７７−２．９６（４Ｈ，ｍ），３．４２−３．５０（１Ｈ，ｍ），４．１０−４．１９（１Ｈ，ｍ），４．５７−４．６３（１Ｈ，ｍ），５．８７−５．９４（１Ｈ，ｍ），６．７８−６．８６（２Ｈ，ｍ），７．１２−７．２２（２Ｈ，ｍ），７．９８（１Ｈ，ｓ），８．１４（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３１２．Example 54 Synthesis of (R) -1- (2-aminophenyl) -N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide:

(R) -1- (2-nitrophenyl) -N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide (150 mg, 0.44 mmol) was dissolved in ethanol (4.0 mL) and palladium was added. -Carbon (10% wet, 24 mg, 0.022 mmol) was added at room temperature and stirred at the same temperature under a hydrogen atmosphere. After 16 hours, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 89/11) to obtain the title compound (99 mg, 72%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.68-1.78 (3H, m), 2.01-2.07 (1H, m), 2.54-2.62 (1H, m), 2.77-2.96 (4H) M), 3.42-3.50 (1H, m), 4.10-4.19 (1H, m), 4.57-4.63 (1H, m), 5.87-5.94. (1H, m), 6.78-6.86 (2H, m), 7.12-7.22 (2H, m), 7.98 (1H, s), 8.14 (1H, s).
MS (ESI) [M + H] ⁺ : 312.

  The following compounds of Example 55 and Example 56 were synthesized according to the same procedure as Example 54.

（Ｒ）−１−（２−アミノフェニル）−Ｎ−（キヌクリジン−３−イル）−１Ｈ−ピラゾール−４−カルボキシアミド（８０ｍｇ，０．２６ｍｍｏｌ）をジクロロメタン（１．０ｍＬ）に溶解し、トリエチルアミン（０．１１ｍＬ，０．７７ｍｍｏｌ）、無水酢酸（０．０７３ｍＬ，０．７７ｍｍｏｌ）を室温で加え、同温で撹拌した。１６時間後、反応溶液に飽和炭酸水素ナトリウム水溶液を加え、中和した後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝６９／３１）で精製し、表題化合物（３９ｍｇ、４３％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．４７−１．５８（１Ｈ，ｍ），１．６７−１．７６（３Ｈ，ｍ），２．００−２．０５（１Ｈ，ｍ），２．１２（３Ｈ，ｓ），２．５５−２．６４（１Ｈ，ｍ），２．７５−２．９５（４Ｈ，ｍ），３．３８−３．４８（１Ｈ，ｍ），４．１０−４．２０（１Ｈ，ｍ），６．１２−６．２２（１Ｈ，ｍ），７．１３−７．２０（１Ｈ，ｍ），７．２７−７．３２（１Ｈ，ｍ），７．３５−７．４２（１Ｈ，ｍ），８．０８（１Ｈ，ｓ），８．２２（１Ｈ，ｓ），８．３６−８．４４（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３５４．Example 57 Synthesis of (R) -1- (2-acetamidophenyl) -N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide:

(R) -1- (2-aminophenyl) -N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide (80 mg, 0.26 mmol) was dissolved in dichloromethane (1.0 mL) and triethylamine was dissolved. (0.11 mL, 0.77 mmol) and acetic anhydride (0.073 mL, 0.77 mmol) were added at room temperature and stirred at the same temperature. After 16 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to neutralize it, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 69/31) to obtain the title compound (39 mg, 43%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.47-1.58 (1H, m), 1.67-1.76 (3H, m), 2.00-2.05 (1H, m), 2.12 (3H, s), 2.55-2.64 (1H, m), 2.75-2.95 (4H, m), 3.38-3.48 (1H, m), 4.10-4.20 (1H, m) ), 6.12-6.22 (1H, m), 7.13-7.20 (1H, m), 7.27-7.32 (1H, m), 7.35-7.42 (1H) M), 8.08 (1H, s), 8.22 (1H, s), 8.36-8.44 (1H, m).
MS (ESI) [M + H] ⁺ : 354.

  The following compounds of Example 58 and Example 59 were synthesized according to the same procedure as Example 57.

（Ｒ）−１−フェニル−Ｎ−（キヌクリジン−３−イル）−１Ｈ−ピラゾール−４−カルボキシアミド（１５０ｍｇ，０．５１ｍｍｏｌ）をジエチルエーテル（５．０ｍＬ）に溶解し、塩化水素−１，４−ジオキサン溶液（４．０Ｎ，０．１６ｍＬ，０．６６ｍｍｏｌ）を０℃で加え、室温で撹拌した。１０分後、反応溶液を濾過し、濾取した固体をジエチルエーテルで洗浄、乾燥し、表題化合物（１１０ｍｇ、６７％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，Ｄ_２Ｏ）
δ：１．９２−２．０２（１Ｈ，ｍ），２．０６−２．１４（２Ｈ，ｍ），２．１８−２．２８（１Ｈ，ｍ），２．３６−２．４２（１Ｈ，ｍ），３．２４−３．５０（５Ｈ，ｍ），３．７９−３．８７（１Ｈ，ｍ），４．４０−４．４６（１Ｈ，ｍ），７．４６−７．５２（１Ｈ，ｍ），７．５９（２Ｈ，ｄｄ，Ｊ＝７．６，８．４Ｈｚ），７．７０（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），８．１８（１Ｈ，ｓ），８．６５（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２９７．Example 60 Synthesis of (R) -1-phenyl-N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide hydrochloride:

(R) -1-phenyl-N- (quinuclidin-3-yl) -1H-pyrazole-4-carboxamide (150 mg, 0.51 mmol) was dissolved in diethyl ether (5.0 mL), and hydrogen chloride-1, 4-Dioxane solution (4.0 N, 0.16 mL, 0.66 mmol) was added at 0 ° C. and stirred at room temperature. After 10 minutes, the reaction solution was filtered, and the collected solid was washed with diethyl ether and dried to give the title compound (110 mg, 67%) as a white solid.
¹ H-NMR (400 MHz, D ₂ O)
δ: 1.92-2.02 (1H, m), 2.06-2.14 (2H, m), 2.18-2.28 (1H, m), 2.36-2.42 (1H M), 3.24-3.50 (5H, m), 3.79-3.87 (1H, m), 4.40-4.46 (1H, m), 7.46-7.52. (1H, m), 7.59 (2H, dd, J = 7.6, 8.4 Hz), 7.70 (2H, d, J = 7.6 Hz), 8.18 (1H, s), 8 .65 (1H, s).
MS (ESI) [M + H] ⁺ : 297.

  The following compounds of Example 61 to Example 80 and Comparative Example 4 were synthesized according to the same procedure as Example 60.

(Example 81) Human central nicotinic acetylcholine receptor α7 subtype (hereinafter, human α7 receptor) operability test:
Using cells stably expressing human α7 receptor, the human α7 receptor agonist activity of quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof was evaluated.

PCI-neo-hCHRNA7 in which the coding region of the human α7 receptor gene (CHRNA7 gene; NCBI Reference Sequence NM — 000076.3) was cloned into the mammalian cell expression vector pCI-neo (Promega) was introduced into GH4C1 cells. Rat pituitary-derived GH4C1 cells were purchased from ATCC (American Type Culture Collection). A single clone was obtained by limiting dilution from the cells into which the expression vector pCI-neo-hCHRNA7 was introduced, and human α7 receptor stably expressing cells (α7 / GH4C1 cells) were prepared. α7 / GH4C1 cells are 2.5% fetal bovine serum (invitrogen, # 26140-079), 15% horse serum (Invitrogen, # 16050-122), 100 U / mL penicillin, 100 μg / mL streptomycin and 100 μg / mL Geneticin ( The culture was maintained in a 37 ° C., 5% CO ₂ incubator using F-10 neutral mixture (Invitrogen, # 11550-043) containing invitrogen, # 10131-027).

α7 / GH4C1 cells are suspended in the above culture medium (without Geneticin) and seeded at 8 × 10 ⁴ cells in each well of 96 well black plate (Becton Dickinson, # 356640) at 37 ° C., 5% Cultivated overnight in CO ₂ and used for the following evaluation.

  Evaluation of human α7 receptor operability was performed by measuring an increase in intracellular calcium concentration due to activation of human α7 receptor. For the measurement of intracellular calcium concentration, FLIPR (registered trademark) Calcium 5 Assay Kit (Molecular Devices, # R8185) was used. As an assay buffer, 2.5 mmol / L probenecid (Sigma, #Sigma) was added to Hank's balanced salt solution (hereinafter referred to as HBSS; Invitrogen, # 14065-056) containing 20 mmol / L HEPES (pH 7.4) (Amresco, # J848). 8761) was used.

Remove the medium from the plate on which the cells were seeded, add 100 μL of assay buffer to each well, and add 100 μL of component A (fluorescent indicator; included in the kit) dissolved in the assay buffer according to the instructions attached to the kit. The cells were cultured at 37 ° C. and 5% CO ₂ for 45 minutes, and further allowed to stand at room temperature for 15 minutes under light shielding. Using FLIPR® TETRA (Molecular Devices), 50 μL of PNU-120596, which is a PAM (positive allosteric modulator) of human α7 receptor, was automatically added to each well to increase detection sensitivity (final concentration 3 μmol / L). ) After measuring the fluorescence intensity for 10 minutes at an excitation wavelength of 470-495 nm and a fluorescence wavelength of 515-575 nm, 50 μL of the test compound was automatically added, and the fluorescence intensity was measured for 5 minutes at the same wavelength. Each test compound was evaluated at a common ratio of 3 and n = 3 for each concentration. The fluorescence intensity when the test compound was not added was defined as 0% response value, and the fluorescence intensity when nicotine (Sigma, # N3876) (final concentration 10 μmol / L) showing human α7 receptor agonist activity was added instead of the test compound. The maximum response rate (%) of each test compound was determined as a 100% response value. EC ₅₀ value of each test compound (representing 50% response to the maximum response rate) by non-linear regression using the response rate (%) at each concentration converted to 100% as the maximum response rate (%) of each test compound Concentration). PNU-120596, each test compound and nicotine were dissolved in DMSO and diluted with assay buffer, and the final concentration of DMSO in the reaction system was 0.2% or less.

The EC ₅₀ values for each test compound are shown in Table 22. As is clear from the results in Table 22, the quinuclidinamide derivative (I) or a pharmacologically acceptable salt thereof exhibited a strong human α7 receptor activating action. On the other hand, the compounds of Comparative Examples 1 to 4 showed very weak human α7 receptor activation action.

  Therefore, it is clear that the quinuclidinamide derivative (I) or a pharmacologically acceptable salt thereof has a strong human α7 receptor activating action.

(Example 82) Inhibitory effect of a compound that activates central nicotinic acetylcholine receptor on substance P-induced scratching behavior:
Substance P-induced scratching behavior of mice, which is an intractable pruritus model, was induced based on the method described in the known literature (Togashi et al., European Journal of Pharmacology, 2002, Vol. 435, p. 259, etc.). In addition, the evaluation of the scratching behavior is automatically detected using MicroAct (Neuroscience) based on the method described in a publicly known document (Hashimoto et al., Allergy International, 2004, Vol. 53, p.349). I went there.

  Specifically, a neodymium magnet coated with parafilm on the back of both hindlimbs of male ICR mice (Japan SLC, Inc.) of 5-7 weeks of age under isoflurane anesthesia at least 5 days prior to drug efficacy evaluation. 1 mm in diameter and 3 mm in length) was inserted. On the day before or 2 days before the medicinal evaluation date, the back of the neck of the mouse was shaved with a clipper under isoflurane anesthesia. At least 1 hour before the start of the measurement of the number of scratches, mice (6 to 8 weeks old) were housed one by one in the measurement chamber (diameter 11 cm, height 18 cm) and habituated. After acclimatization, substance P (5 mmol / L) or its buffer phosphate buffered saline (hereinafter PBS) was intradermally administered to the back of the neck (0.05 mL / site), and the number of scratching behaviors was measured immediately after. Started. The number of scratching behaviors was recorded by amplifying the current induced by the movement of the magnet inserted into the hind limb in a round coil around the measurement chamber. The measurement was performed in an unattended environment, and the efficacy evaluation was performed using the number of scratching behaviors for 15 minutes after the start of the measurement as an index.

  30 minutes before the start of the measurement of the number of scratching behaviors, the test compound or its solvent was orally administered in a volume of 10 mL / kg. The compound of Example 1 or Example 66, which is a test compound, was used after being dissolved in distilled water. A group (test compound: 0 mg / kg, substance P: 0 nmol / site) administered with only the solvent was a “non-induced control group”, and a group administered with substance P but not administered a test compound (test compound: 0 mg / kg, Substance P: 250 nmol / site) is the “induction control group”, substance P and the group administered with the test compound (test compound: 1, 10 or 100 mg / kg, substance P: 250 nmol / site) are “the compound administration of Example 1” Group "or" Compound administration group of Example 66 ".

  FIG. 1 shows the effect of the compound of Example 1 on the number of scratching actions. The vertical axis represents the number of scratching actions for 15 minutes (average value ± standard error, n = 6 to 10). The horizontal axis shows the non-induced control group, the induced control group, and the compound administration group (1, 10 or 100 mg / kg) of Example 1. The symbol “#” in the figure indicates statistical significance in comparison with the induction control group (#p <0.05, Student's t test), and the symbol “*” indicates statistical comparison with the induction control group. It is shown to be clinically significant (* p <0.025, Williams test (one side)).

  FIG. 2 shows the effect of the compound of Example 66 on the number of scratching actions. The vertical axis represents the number of scratching actions for 15 minutes (average value ± standard error, n = 5 to 8). The horizontal axis shows the non-induced control group, the induced control group, and the compound administration group of Example 66 (1, 10 or 100 mg / kg). The symbol “#” in the figure indicates statistical significance in comparison with the induction control group (#p <0.05, Student's t test), and the symbol “*” indicates statistical comparison with the induction control group. It is shown to be clinically significant (* p <0.025, Williams test (one side)).

  Administration of the compound of Example 1 (10 or 100 mg / kg) or the compound of Example 66 (10 or 100 mg / kg) significantly suppressed substance P-induced scratching behavior. Therefore, it is clear that the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof significantly suppresses substance P-induced scratching behavior known as an intractable pruritus model and has an excellent antipruritic effect. It is.

  From these results, it was revealed that the quinuclidineamide derivative (I) or a pharmacologically acceptable salt thereof has an excellent antipruritic action.

ジイソプロピルアゾジカルボキシレート（０．１９ｍＬ，１．０ｍｍｏｌ）をＴＨＦ（２．５ｍＬ）に溶解し、トリフェニルホスフィン（０．２６ｇ，１．０ｍｍｏｌ）を０℃で加え、同温で攪拌した。０．５時間後、反応溶液に１−（ｔｅｒｔ−ブトキシカルボニル）−２−（Ｒ）−アゼチジニルメタノール（０．１９ｇ，１．０ｍｍｏｌ）、６−クロロピリジン−３−オール（０．１３ｇ，１．０ｍｍｏｌ）を室温で加え、同温で攪拌した。４時間後、反応溶液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９５／５〜７０／３０）で精製し、表題化合物（０．２７ｇ、９０％）を黄色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．４１（９Ｈ，ｓ），２．２３−２．４０（２Ｈ，ｍ），３．８７−３．９１（２Ｈ，ｍ），４．０９−４．１４（１Ｈ，ｍ），４．２８−４．３７（１Ｈ，ｍ），４．４７−４．５４（１Ｈ，ｍ），７．２１−７．２８（２Ｈ，ｍ），８．１０（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ）．
ＭＳ（ＥＳＩ）：２９９［Ｍ＋Ｈ］^＋．Reference Example 51 Synthesis of (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine hydrochloride (hereinafter referred to as the compound of Reference Example 51):
[First step]
Synthesis of 2-chloro-5-((1- (tert-butoxycarbonyl))-2- (R) -azetidinylmethoxy) pyridine:

Diisopropyl azodicarboxylate (0.19 mL, 1.0 mmol) was dissolved in THF (2.5 mL), triphenylphosphine (0.26 g, 1.0 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature. After 0.5 hour, 1- (tert-butoxycarbonyl) -2- (R) -azetidinylmethanol (0.19 g, 1.0 mmol), 6-chloropyridin-3-ol (0.13 g) was added to the reaction solution. , 1.0 mmol) at room temperature and stirred at the same temperature. After 4 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5-70 / 30) to give the title compound (0.27 g, 90%) as a yellow liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.41 (9H, s), 2.23-2.40 (2H, m), 3.87-3.91 (2H, m), 4.09-4.14 (1H, m), 4.28-4.37 (1H, m), 4.47-4.54 (1H, m), 7.21-7.28 (2H, m), 8.10 (1H, d, J = 3) .6 Hz).
MS (ESI): 299 [M + H] ^< +>.

２−クロロ−５−（（１−（ｔｅｒｔ−ブトキシカルボニル））−２−（Ｒ）−アゼチジニルメトキシ）ピリジン（０．２７ｇ，０．９０ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に溶解し、トリフルオロ酢酸（２．５ｍＬ，３３ｍｍｏｌ）を室温で加え、同温で攪拌した。２時間後、反応溶液に１．０Ｎ水酸化ナトリウム水溶液をｐＨ＝１０となるまで加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝８５／１５）で精製し、表題化合物（０．１２ｇ、５６％）を黄色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：２．２１−２．４３（２Ｈ，ｍ），３．４２−３．４８（１Ｈ，ｍ），３．６８−３．７５（１Ｈ，ｍ），３．９７−４．０６（２Ｈ，ｍ），４．２３−４．３１（１Ｈ，ｍ），７．２１−７．２２（２Ｈ，ｍ），８．０６−８．０８（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：１９９［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine:

2-Chloro-5-((1- (tert-butoxycarbonyl))-2- (R) -azetidinylmethoxy) pyridine (0.27 g, 0.90 mmol) was dissolved in dichloromethane (10 mL) and trifluoro Acetic acid (2.5 mL, 33 mmol) was added at room temperature and stirred at the same temperature. After 2 hours, 1.0N aqueous sodium hydroxide solution was added to the reaction solution until pH = 10, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 85/15) to obtain the title compound (0.12 g, 56%) as a yellow liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 2.21-2.43 (2H, m), 3.42-3.48 (1H, m), 3.68-3.75 (1H, m), 3.97-4.06 (2H M), 4.23-4.31 (1H, m), 7.21-7.22 (2H, m), 8.06-8.08 (1H, m).
MS (ESI): 199 [M + H] ⁺

（Ｒ）−２−クロロ−５−（２−アゼチジニルメトキシ）ピリジン（０．１２ｇ，０．６１ｍｍｏｌ）を酢酸エチル（１．０ｍＬ）に溶解し、塩化水素−酢酸エチル溶液（４．０Ｎ，０．１８ｍＬ，０．６８ｍｍｏｌ）を室温で加え、同温で攪拌した。０．５時間後、得られた固体を濾取し、ヘキサンで洗浄し、乾燥することで、表題化合物（０．１０ｇ、７０％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，Ｄ_２Ｏ）
δ：２．６３−２．７２（２Ｈ，ｍ），４．０２−４．１８（２Ｈ，ｍ），４．４０（２Ｈ，ｄ，Ｊ＝４．０Ｈｚ），４．９０−４．９７（１Ｈ，ｍ），７．４６（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５６（１Ｈ，ｄｄ，Ｊ＝２．８，８．８Ｈｚ），８．１２−８．１５（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：１９９［Ｍ＋Ｈ］^＋ [Third step]
Synthesis of the compound of Reference Example 51:

(R) -2-chloro-5- (2-azetidinylmethoxy) pyridine (0.12 g, 0.61 mmol) was dissolved in ethyl acetate (1.0 mL), and a hydrogen chloride-ethyl acetate solution (4.0 N) was dissolved. , 0.18 mL, 0.68 mmol) was added at room temperature and stirred at the same temperature. After 0.5 hour, the resulting solid was collected by filtration, washed with hexane, and dried to give the title compound (0.10 g, 70%) as a white solid.
¹ H-NMR (400 MHz, D ₂ O)
δ: 2.63-2.72 (2H, m), 4.02-4.18 (2H, m), 4.40 (2H, d, J = 4.0 Hz), 4.90-4.97 (1H, m), 7.46 (1H, d, J = 8.8 Hz), 7.56 (1H, dd, J = 2.8, 8.8 Hz), 8.12-8.15 (1H, m).
MS (ESI): 199 [M + H] ⁺

３−キヌクリジノン塩酸塩（６．０ｇ，３７ｍｍｏｌ）に水酸化カリウム（２．３ｇ，４１ｍｍｏｌ）をメタノール（３６ｍＬ）に溶解し、３−ピリジンアルデヒド（４．４ｇ，４１ｍｍｏｌ）を室温で加え、同温で攪拌した。１６時間後、反応溶液に蒸留水（３０ｍＬ）を加え、４℃まで冷却し１６時間放置した。得られた固体を濾取し、蒸留水で洗浄し、乾燥することで表題化合物（７．６ｇ、９６％）を黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：２．００−２．０８（４Ｈ，ｍ），２．６４−２．６８（１Ｈ，ｍ），２．９４−３．０４（２Ｈ，ｍ），３．１３−３．２２（２Ｈ，ｍ），６．９８（１Ｈ，ｓ），７．２８−７．３２（１Ｈ，ｍ），８．４４−８．５０（１Ｈ，ｍ），８．５１−８．５５（１Ｈ，ｍ），９．０４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
ＭＳ（ＥＳＩ）：２１５［Ｍ＋Ｈ］^＋ Reference Example 52 N- (2 (S)-(pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] octa-3 (R) -yl) -1-benzofuran-2-carboxamide ( Hereinafter, the synthesis of the compound of Reference Example 52):
[First step]
Synthesis of 2- (3-pyridinyl) methylene-1-azabicyclo [2.2.2] octane-3-one:

Potassium hydroxide (2.3 g, 41 mmol) was dissolved in 3-quinuclidinone hydrochloride (6.0 g, 37 mmol) in methanol (36 mL), and 3-pyridinealdehyde (4.4 g, 41 mmol) was added at room temperature. And stirred. After 16 hours, distilled water (30 mL) was added to the reaction solution, cooled to 4 ° C., and allowed to stand for 16 hours. The obtained solid was collected by filtration, washed with distilled water, and dried to give the title compound (7.6 g, 96%) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 2.00 to 2.08 (4H, m), 2.64-2.68 (1H, m), 2.94 to 3.04 (2H, m), 3.13-3.22 (2H) M), 6.98 (1H, s), 7.28-7.32 (1H, m), 8.44-8.50 (1H, m), 8.51-8.55 (1H, m ), 9.04 (1H, d, J = 2.0 Hz).
MS (ESI): 215 [M + H] ⁺

２−（３−ピリジニル）メチレン−１−アザビシクロ［２．２．２］オクタン−３−オン（７．６ｇ，３６ｍｍｏｌ）をメタノール（８０ｍＬ）に溶解し、パラジウム−炭素（１０％ｗｅｔ，０．６４ｇ，０．６０ｍｍｏｌ）、塩酸（６．０Ｎ，９．０ｍＬ，５４ｍｍｏｌ）を室温で加え、水素雰囲気下、同温で攪拌した。１６時間後、反応溶液をセライトで濾過し、濾液を減圧濃縮した。得られた粗生成物に２．０Ｎ水酸化ナトリウム水溶液をｐＨ＝１０となるまで加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０−５９／４１，クロロホルムのみ〜クロロホルム／メタノール＝７８／２２）で精製し、表題化合物（５．４ｇ、７１％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．９２−２．１０（４Ｈ，ｍ），２．４７−２．５１（１Ｈ，ｍ），２．７３−２．９２（３Ｈ，ｍ），３．０５−３．２４（３Ｈ，ｍ），３．２９−３．３５（１Ｈ，ｍ），７．２０−７．２４（１Ｈ，ｍ），７．５７−７．６２（１Ｈ，ｍ），８．４４−８．４８（１Ｈ，ｍ），８．５２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
ＭＳ（ＥＳＩ）：２１７［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of 2-((3-pyridinyl) methyl) -1-azabicyclo [2.2.2] octane-3-one:

2- (3-Pyridinyl) methylene-1-azabicyclo [2.2.2] octane-3-one (7.6 g, 36 mmol) was dissolved in methanol (80 mL) and palladium-carbon (10% wet, 0. 0). 64 g, 0.60 mmol) and hydrochloric acid (6.0 N, 9.0 mL, 54 mmol) were added at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere. After 16 hours, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. To the resulting crude product, 2.0N aqueous sodium hydroxide solution was added until pH = 10, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-59 / 41, chloroform only to chloroform / methanol = 78/22) to give the title compound (5.4 g, 71%) Was obtained as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.92-2.10 (4H, m), 2.47-2.51 (1H, m), 2.73-2.92 (3H, m), 3.05-3.24 (3H M), 3.29-3.35 (1H, m), 7.20-7.24 (1H, m), 7.57-7.62 (1H, m), 8.44-8.48. (1H, m), 8.52 (1H, d, J = 2.0 Hz).
MS (ESI): 217 [M + H] ⁺

２−（（３−ピリジニル）メチル）−１−アザビシクロ［２．２．２］オクタン−３−オン（５．０ｇ，２３ｍｍｏｌ）をメタノール（３４ｍＬ）に溶解し、二塩化亜鉛（６３０ｍｇ，４．６ｍｍｏｌ）を室温で加え、同温で攪拌した。０．５時間後、反応溶液にギ酸アンモニウム（１７ｇ，２８０ｍｍｏｌ）を室温で加え、同温で攪拌した。１時間後、反応溶液にナトリウムシアノボロヒドリド（２．９ｇ，４６ｍｍｏｌ）を室温で加え、同温で攪拌した。１６時間後、反応溶液を５０℃に昇温し、攪拌した。３時間後、反応溶液に蒸留水、５．０Ｎ水酸化ナトリウム水溶液を加え、中和した後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝８９／１１）で精製した。得られた粗精製物に対し、メタノール（１６ｍＬ）、（＋）−ジ−パラトルオイル−（Ｄ）−酒石酸（４．０ｇ，１０ｍｍｏｌ）を室温で加え、９０℃で攪拌した。１時間後、反応溶液を減圧濃縮し、メタノール（４．０ｍＬ）を室温で加え、９０℃に昇温し溶解した。反応溶液を１時間かけて室温、４時間かけて５℃、続いて０℃にゆっくり冷却し、１６時間放置した。得られた沈殿物を濾取し、メタノール（３．０ｍＬ）を用いて再結晶した。得られた固体に２．０Ｎ水酸化ナトリウム水溶液（３．０ｍＬ）、クロロホルム（３．０ｍＬ）を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた無色液体をジクロロメタン（２．０ｍＬ）に溶解し、これをＨＢＴＵ（０．６０ｇ，１．６ｍｍｏｌ）、トリエチルアミン（０．７３ｍＬ，１．６ｍｍｏｌ）、ベンゾフラン−２−カルボン酸（０．１７ｇ，１．１ｍｍｏｌ）のジクロロメタン（２．０ｍＬ）溶液に室温で加え、同温で攪拌した。１６時間後、反応溶液に蒸留水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９９／１）で精製し、表題化合物（０．２１ｇ、３％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．５０−１．５９（１Ｈ，ｍ），１．６６−１．８４（３Ｈ，ｍ），２．００−２．０６（１Ｈ，ｍ），２．７２−２．８２（２Ｈ，ｍ），２．９２−２．９９（４Ｈ，ｍ），３．０５−３．１４（１Ｈ，ｍ），３．９４−３．９９（１Ｈ，ｍ），６．５５−６．６０（１Ｈ，ｍ），７．１２−７．１６（１Ｈ，ｍ），７．２９−７．３２（１Ｈ，ｍ），７．４０−７．４５（２Ｈ，ｍ），７．５１（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．５６−７．６０（１Ｈ，ｍ），７．６７（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．３５（１Ｈ，ｄｄ，Ｊ＝１．６，４．４Ｈｚ），８．５１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）：３６２［Ｍ＋Ｈ］^＋ [Third step]
Synthesis of the compound of Reference Example 52:

2-((3-Pyridinyl) methyl) -1-azabicyclo [2.2.2] octane-3-one (5.0 g, 23 mmol) was dissolved in methanol (34 mL) and zinc dichloride (630 mg, 4. 6 mmol) was added at room temperature and stirred at the same temperature. After 0.5 hour, ammonium formate (17 g, 280 mmol) was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature. After 1 hour, sodium cyanoborohydride (2.9 g, 46 mmol) was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature. After 16 hours, the reaction solution was heated to 50 ° C. and stirred. Three hours later, distilled water and 5.0N aqueous sodium hydroxide solution were added to the reaction solution for neutralization, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 89/11). Methanol (16 mL) and (+)-di-paratoluoyl- (D) -tartaric acid (4.0 g, 10 mmol) were added to the obtained crude product at room temperature, and the mixture was stirred at 90 ° C. After 1 hour, the reaction solution was concentrated under reduced pressure, methanol (4.0 mL) was added at room temperature, and the mixture was heated to 90 ° C. and dissolved. The reaction solution was slowly cooled to room temperature over 1 hour, 5 ° C. over 4 hours, then to 0 ° C. and left for 16 hours. The resulting precipitate was collected by filtration and recrystallized from methanol (3.0 mL). To the obtained solid, 2.0N aqueous sodium hydroxide solution (3.0 mL) and chloroform (3.0 mL) were added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained colorless liquid was dissolved in dichloromethane (2.0 mL), and this was dissolved in HBTU (0.60 g, 1.6 mmol), triethylamine (0.73 mL, 1.6 mmol), benzofuran-2-carboxylic acid (0.17 g). , 1.1 mmol) in dichloromethane (2.0 mL) at room temperature and stirred at the same temperature. After 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform only to chloroform / methanol = 99/1) to obtain the title compound (0.21 g, 3%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.50-1.59 (1H, m), 1.66-1.84 (3H, m), 2.00-2.06 (1H, m), 2.72-2.82 (2H M), 2.92-2.99 (4H, m), 3.05-3.14 (1H, m), 3.94-3.99 (1H, m), 6.55-6.60. (1H, m), 7.12-7.16 (1H, m), 7.29-7.32 (1H, m), 7.40-7.45 (2H, m), 7.51 (1H , D, J = 8.4 Hz), 7.56-7.60 (1H, m), 7.67 (1H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 1. 6, 4.4 Hz), 8.51 (1H, d, J = 2.4 Hz).
MS (ESI): 362 [M + H] ⁺

Reference Example 53 Synthesis of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide hydrochloride (hereinafter referred to as compound of Reference Example 53):

７−クロロ−１−ベンゾチオフェン−２−カルボキシリックアシッド（２１０ｍｇ，１．０ｍｍｏｌ）をクロロホルム（１０ｍＬ）に溶解し、ＨＢＴＵ（５７０ｍｇ，１．５ｍｍｏｌ）、ジイソプロピルエチルアミン（０．７０ｍＬ，４．０ｍｍｏｌ）、（Ｒ）−キヌクリジン−３−アミン塩酸塩（２００ｍｇ，１．０ｍｍｏｌ）を室温で加え、同温で攪拌した。１６時間後、反応溶液に蒸留水、１．０Ｎ水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９０／１０）で精製し、表題化合物（１７０ｍｇ、５３％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）
δ：１．２２−１．３８（１Ｈ，ｍ），１．５３−１．６２（２Ｈ，ｍ），１．７５−１．８２（２Ｈ，ｍ），２．６３−２．７３（４Ｈ，ｍ），２．８４−２．９４（１Ｈ，ｍ），３．０７−３．１８（１Ｈ，ｍ），３．９０−４．００（１Ｈ，ｍ），７．４９（１Ｈ，ｄｄ，Ｊ＝７．６，８．０Ｈｚ），７．５９（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．３１（１Ｈ，ｓ），８．６２−８．６６（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３２１［Ｍ＋Ｈ］^＋ [First step]
Synthesis of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide:

7-Chloro-1-benzothiophene-2-carboxyl acid (210 mg, 1.0 mmol) was dissolved in chloroform (10 mL), HBTU (570 mg, 1.5 mmol), diisopropylethylamine (0.70 mL, 4.0 mmol). , (R) -quinuclidin-3-amine hydrochloride (200 mg, 1.0 mmol) was added at room temperature and stirred at the same temperature. After 16 hours, distilled water and 1.0N aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 90/10) to obtain the title compound (170 mg, 53%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ: 1.22-1.38 (1H, m), 1.53-1.62 (2H, m), 1.75-1.82 (2H, m), 2.63-2.73 (4H M), 2.84-2.94 (1H, m), 3.07-3.18 (1H, m), 3.90-4.00 (1H, m), 7.49 (1H, dd) , J = 7.6, 8.0 Hz), 7.59 (1H, d, J = 7.6 Hz), 7.96 (1H, d, J = 8.0 Hz), 8.31 (1H, s) , 8.62-8.66 (1H, m).
MS (ESI): 321 [M + H] ⁺

（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキシアミド（１７０ｍｇ，０．５３ｍｍｏｌ）を酢酸エチル（２．０ｍＬ）に溶解し、塩化水素−酢酸エチル溶液（４．０Ｍ，０．２０ｍＬ，０．８０ｍｍｏｌ）を加え、室温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで表題化合物（１７０ｍｇ、９０％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）
δ：１．７０−１．７８（１Ｈ，ｍ），１．８６−１．９４（２Ｈ，ｍ），２．１０−２．１９（２Ｈ，ｍ），３．１８−３．３５（５Ｈ，ｍ），３．６３−３．７２（１Ｈ，ｍ），４．２７−４．３６（１Ｈ，ｍ），７．５０（１Ｈ，ｄ，Ｊ＝７．６，８．０Ｈｚ），７．６１（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．９８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．３８（１Ｈ，ｓ），９．０７−９．１０（１Ｈ，ｍ），９．８０−９．８５（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３２１［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of the compound of Reference Example 53:

(R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide (170 mg, 0.53 mmol) was dissolved in ethyl acetate (2.0 mL), and hydrogen chloride-acetic acid was dissolved. Ethyl solution (4.0 M, 0.20 mL, 0.80 mmol) was added and stirred at room temperature. After 10 minutes, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to give the title compound (170 mg, 90%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ: 1.70-1.78 (1H, m), 1.86-1.94 (2H, m), 2.10-2.19 (2H, m), 3.18-3.35 (5H) M), 3.63-3.72 (1H, m), 4.27-4.36 (1H, m), 7.50 (1H, d, J = 7.6, 8.0 Hz), 7 .61 (1H, d, J = 7.6 Hz), 7.98 (1H, d, J = 8.0 Hz), 8.38 (1H, s), 9.07-9.10 (1H, m) , 9.80-9.85 (1H, m).
MS (ESI): 321 [M + H] ⁺

１，４−ジアザビシクロ［３．２．２］ノナン二塩酸塩（２３０ｍｇ，１．２ｍｍｏｌ）をジクロロメタン（１２ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．４０ｍＬ，２．４ｍｍｏｌ）を室温で加え、同温で１時間攪拌した。トリホスゲン（１１０ｍｇ，０．３８ｍｍｏｌ）をジクロロメタン（１２ｍＬ）に溶解し、４−ブロモフェノール（２００ｍｇ，１．２ｍｍｏｌ）とジイソプロピルエチルアミン（０．２０ｍＬ，１．２ｍｍｏｌ）のＴＨＦ（１２ｍＬ）溶液を室温でゆっくり加え、同温で攪拌した。１時間後、この溶液に先ほど調製した１，４−ジアザビシクロ［３．２．２］ノナン二塩酸塩溶液を室温でゆっくり加え、同温で攪拌した。４時間後、反応溶液に蒸留水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９５／５〜７０／３０，クロロホルムのみ〜クロロホルム／メタノール＝９０／１０）で精製し、表題化合物（０．２４ｇ、６５％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．６８−１．８１（２Ｈ，ｍ），２．００−２．１４（２Ｈ，ｍ），２．９５−３．１９（６Ｈ，ｍ），３．７２−３．８５（２Ｈ，ｍ），４．３４−４．４５（１Ｈ，ｍ），６．９８−７．０６（２Ｈ，ｍ），７．４４−７．５０（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３２６［Ｍ＋Ｈ］^＋ Reference Example 54 Synthesis of 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester hydrochloride (hereinafter referred to as the compound of Reference Example 54):
[First step]
Synthesis of 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester:

1,4-diazabicyclo [3.2.2] nonane dihydrochloride (230 mg, 1.2 mmol) was dissolved in dichloromethane (12 mL), and diisopropylethylamine (0.40 mL, 2.4 mmol) was added at room temperature. For 1 hour. Triphosgene (110 mg, 0.38 mmol) was dissolved in dichloromethane (12 mL), and a solution of 4-bromophenol (200 mg, 1.2 mmol) and diisopropylethylamine (0.20 mL, 1.2 mmol) in THF (12 mL) was slowly added at room temperature. In addition, the mixture was stirred at the same temperature. After 1 hour, the 1,4-diazabicyclo [3.2.2] nonane dihydrochloride solution prepared previously was slowly added to this solution at room temperature and stirred at the same temperature. After 4 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 95/5 to 70/30, chloroform only to chloroform / methanol = 90/10) to give the title compound (0.24 g, 65%) Was obtained as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.68-1.81 (2H, m), 2.00-2.14 (2H, m), 2.95-3.19 (6H, m), 3.72-3.85 (2H) M), 4.34-4.45 (1H, m), 6.98-7.06 (2H, m), 7.44-7.50 (2H, m).
MS (ESI): 326 [M + H] ⁺

１，４−ジアザビシクロ［３．２．２］ノナン−４−カルボキシリックアシッド ４−ブロモフェニルエステル（２５０ｍｇ，０．７５ｍｍｏｌ）を酢酸エチル（４．０ｍＬ）に溶解し、塩化水素−酢酸エチル溶液（４．０Ｎ，０．２８ｍＬ，１．１ｍｍｏｌ）を室温で加え、同温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、表題化合物（２４０ｍｇ、８８％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）
δ：１．９５−２．２６（４Ｈ，ｍ）、３．３２−３．４７（６Ｈ，ｍ），３．８１−３．８５（１Ｈ，ｍ），３．９４−４．００（１Ｈ，ｍ），４．３５−４．５６（１Ｈ，ｍ），７．１４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）１０．２−１１．０（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３２６［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of the compound of Reference Example 54:

1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester (250 mg, 0.75 mmol) was dissolved in ethyl acetate (4.0 mL), and a hydrogen chloride-ethyl acetate solution ( 4.0N, 0.28 mL, 1.1 mmol) was added at room temperature and stirred at the same temperature. After 10 minutes, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the title compound (240 mg, 88%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ: 1.95-2.26 (4H, m), 3.32-3.47 (6H, m), 3.81-3.85 (1H, m), 3.94-4.00 (1H) M), 4.35-4.56 (1H, m), 7.14 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz) 10.2- 11.0 (1H, m).
MS (ESI): 326 [M + H] ⁺

６−メチル−２−ニトロピリジン−３−オール（１．６ｇ，１０ｍｍｏｌ）をエタノール（２０ｍＬ）に溶解し、パラジウム−炭素（１０％ｗｅｔ，０．４０ｇ，０．３８ｍｍｏｌ）、酢酸（０．０５０ｍＬ，０．８７ｍｍｏｌ）を室温で加え、水素雰囲気下、同温で攪拌した。６時間後、反応溶液をセライトで濾過し、濾液を減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝８８／１２）で精製し、表題化合物（１．２ｇ、９３％）を黄色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：２．３２（３Ｈ，ｓ），６．３８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），６．８２−６．８６（１Ｈ，ｍ）．Reference Example 55 2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine hydrochloride (hereinafter referred to as the compound of Reference Example 55) ) Synthesis:
[First step]
Synthesis of 2-amino-6-methylpyridin-3-ol:

6-Methyl-2-nitropyridin-3-ol (1.6 g, 10 mmol) was dissolved in ethanol (20 mL), palladium-carbon (10% wet, 0.40 g, 0.38 mmol), acetic acid (0.050 mL). , 0.87 mmol) at room temperature and stirred at the same temperature under a hydrogen atmosphere. After 6 hours, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 88/12) to obtain the title compound (1.2 g, 93%) as a yellow liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 2.32 (3H, s), 6.38 (1H, d, J = 8.0 Hz), 6.82-6.86 (1H, m).

２−アミノ−６−メチルピリジン−３−オール（１．２ｇ，９．７ｍｍｏｌ）をエタノール（２５ｍＬ）に溶解し、カリウムエチルキサンテート（３．１ｇ，１９ｍｍｏｌ）を室温で加え、８０℃で攪拌した。４時間後、反応溶液を減圧濃縮し、蒸留水を加え、酢酸をｐＨ＝５となるまで加えた。得られた固体を濾取し、蒸留水で洗浄し、乾燥することで表題化合物（１．２ｇ、７７％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：２．４５（３Ｈ，ｓ），７．０３−７．０７（１Ｈ，ｍ），７．６４−７．７０（１Ｈ，ｍ）．[Second step]
Synthesis of 5-methyloxazolo [4,5-b] pyridine-2-thiol:

2-Amino-6-methylpyridin-3-ol (1.2 g, 9.7 mmol) was dissolved in ethanol (25 mL), potassium ethyl xanthate (3.1 g, 19 mmol) was added at room temperature, and the mixture was stirred at 80 ° C. did. After 4 hours, the reaction solution was concentrated under reduced pressure, distilled water was added, and acetic acid was added until pH = 5. The obtained solid was collected by filtration, washed with distilled water, and dried to give the title compound (1.2 g, 77%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 2.45 (3H, s), 7.03-7.07 (1H, m), 7.64-7.70 (1H, m).

５−メチルオキサゾロ［４，５−ｂ］ピリジン−２−チオール（１．２ｇ，７．５ｍｍｏｌ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（１．０ｇ，７．５ｍｍｏｌ）、ヨウ化メチル（０．５６ｍＬ，９．０ｍｍｏｌ）を室温で加え、同温で攪拌した。３時間後、反応溶液に蒸留水を加え、酢酸エチルで抽出した。有機層を蒸留水、飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝８８／１２−６５／３５，クロロホルムのみ〜クロロホルム／メタノール＝９８／２）で精製し、表題化合物（１．２ｇ、９０％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）
δ：２．５３（３Ｈ，ｓ），２．７７（３Ｈ，ｓ），７．１８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．９４（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．[Third step]
Synthesis of 5-methyl-2- (methylthio) oxazolo [4,5-b] pyridine:

5-Methyloxazolo [4,5-b] pyridine-2-thiol (1.2 g, 7.5 mmol) is dissolved in DMF (20 mL), potassium carbonate (1.0 g, 7.5 mmol), methyl iodide (0.56 mL, 9.0 mmol) was added at room temperature and stirred at the same temperature. After 3 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 88 / 12-65 / 35, chloroform only to chloroform / methanol = 98/2) to give the title compound (1.2 g, 90%) Was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ: 2.53 (3H, s), 2.77 (3H, s), 7.18 (1H, d, J = 8.0 Hz), 7.94 (1H, d, J = 8.0 Hz).

１，４−ジアザビシクロ［３．２．２］ノナン二塩酸塩（９００ｍｇ，４．５ｍｍｏｌ）に、水酸化ナトリウム水溶液（１．０Ｎ，１１ｍＬ，１１ｍｍｏｌ）を室温で加え、同温で攪拌した。２時間後、反応溶液をクロロホルム−メタノール混合溶液（９：１）で抽出した。有機層を蒸留水、飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物に対し、イソプロピルアルコール（２．７ｍＬ）、５−メチル−２−（メチルチオ）オキサゾロ［４，５−ｂ］ピリジン（３００ｍｇ，１．７ｍｍｏｌ）を室温で加え、１００℃で攪拌した。２２時間後、得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９５／５）で精製し、表題化合物（３２０ｍｇ、７４％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）
δ：１．７４−１．８５（２Ｈ，ｍ），２．１０−２．２１（２Ｈ，ｍ），２．５３（３Ｈ，ｓ），２．９５−３．０６（２Ｈ，ｍ），３．１０−３．１９（４Ｈ，ｍ），３．９５（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），４．５３−４．５７（１Ｈ，ｍ），６．７２（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．２８（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．
ＭＳ（ＥＳＩ）：２５９［Ｍ＋Ｈ］^＋ [Fourth step]
Synthesis of 2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine:

To 1,4-diazabicyclo [3.2.2] nonane dihydrochloride (900 mg, 4.5 mmol) was added an aqueous sodium hydroxide solution (1.0 N, 11 mL, 11 mmol) at room temperature, and the mixture was stirred at the same temperature. After 2 hours, the reaction solution was extracted with a chloroform-methanol mixed solution (9: 1). The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the obtained crude product, isopropyl alcohol (2.7 mL) and 5-methyl-2- (methylthio) oxazolo [4,5-b] pyridine (300 mg, 1.7 mmol) were added at room temperature, and the mixture was added at 100 ° C. Stir. After 22 hours, the resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 95/5) to obtain the title compound (320 mg, 74%) as a white solid.
¹ H-NMR (400 MHz, CD ₃ OD)
δ: 1.74-1.85 (2H, m), 2.10-2.21 (2H, m), 2.53 (3H, s), 2.95-3.06 (2H, m), 3.10-3.19 (4H, m), 3.95 (2H, t, J = 6.0 Hz), 4.53-4.57 (1H, m), 6.72 (1H, d, J = 7.6 Hz), 7.28 (1H, d, J = 7.6 Hz).
MS (ESI): 259 [M + H] ⁺

２−（１，４−ジアザビシクロ［３．２．２］ノナ−４−イル）−５−メチルオキサゾロ［４，５−ｂ］ピリジン（３２０ｍｇ，１．２ｍｍｏｌ）を酢酸エチル（１．０ｍＬ）に溶解し、塩化水素−酢酸エチル溶液（４．０Ｍ，０．４７ｍＬ，１．９ｍｍｏｌ）を室温で加え、同温で攪拌した。０．５時間後、得られた白色固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで表題化合物（２９０ｍｇ、８０％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：２．０５−２．１７（２Ｈ，ｍ），２．２２−２．３４（２Ｈ，ｍ），２．４９（３Ｈ，ｓ），３．３５−３．４４（４Ｈ，ｍ），３．４８−３．５４（２Ｈ，ｍ），４．０９−４．１２（２Ｈ，ｍ），４．５９−４．６５（１Ｈ，ｍ），６．９９（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．８２−７．８７（１Ｈ，ｍ），１１．４−１１．５（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２５９［Ｍ＋Ｈ］^＋
２５９[Fifth step]
Synthesis of the compound of Reference Example 55:

2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine (320 mg, 1.2 mmol) in ethyl acetate (1.0 mL) Then, a hydrogen chloride-ethyl acetate solution (4.0 M, 0.47 mL, 1.9 mmol) was added at room temperature, and the mixture was stirred at the same temperature. After 0.5 hour, the obtained white solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the title compound (290 mg, 80%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 2.05-2.17 (2H, m), 2.22-2.34 (2H, m), 2.49 (3H, s), 3.35-3.44 (4H, m), 3.48-3.54 (2H, m), 4.09-4.12 (2H, m), 4.59-4.65 (1H, m), 6.99 (1H, d, J = 8) .0Hz), 7.82-7.87 (1H, m), 11.4-11.5 (1H, m).
MS (ESI): 259 [M + H] ⁺
259

４−ブロモアニリン（２．８ｇ，１７ｍｍｏｌ）をジクロロメタン（６０ｍＬ）に溶解し、トリエチルアミン（２．３ｍＬ，１７ｍｍｏｌ）を室温で加え、５−ブロモペンタノイルクロライド（２．４ｍＬ，１８ｍｍｏｌ）を０℃でゆっくり加え、同温で攪拌した。３時間後、反応溶液を室温まで昇温し、０．４０Ｎ炭酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮することで、表題化合物（５．５ｇ、９９％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．８５−２．００（４Ｈ，ｍ），２．４０（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．４５（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），７．０８−７．１２（１Ｈ，ｍ），７．３９−７．４３（４Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３３６［Ｍ＋Ｈ］^＋ Reference Example 56 Synthesis of 5- (4-morpholinyl) -N- (4- (3-pyridyl) phenyl) pentanamide hydrochloride (hereinafter referred to as the compound of Reference Example 56):
[First step]
Synthesis of 5-bromo-N- (4-bromophenyl) pentanamide:

4-Bromoaniline (2.8 g, 17 mmol) was dissolved in dichloromethane (60 mL), triethylamine (2.3 mL, 17 mmol) was added at room temperature, and 5-bromopentanoyl chloride (2.4 mL, 18 mmol) was added at 0 ° C. Slowly added and stirred at the same temperature. After 3 hours, the reaction solution was warmed to room temperature, 0.40N aqueous sodium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (5.5 g, 99%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.85-2.00 (4H, m), 2.40 (2H, t, J = 6.8 Hz), 3.45 (2H, t, J = 6.0 Hz), 7.08-7 .12 (1H, m), 7.39-7.43 (4H, m).
MS (ESI): 336 [M + H] ⁺

５−ブロモ−Ｎ−（４−ブロモフェニル）ペンタンアミド（２．７ｇ，８．１ｍｍｏｌ）を２−ブタノン（６０ｍＬ）に溶解し、ヨウ化ナトリウム（１．２ｇ，８．１ｍｍｏｌ）、モルホリン（０．７８ｍＬ，８．９ｍｍｏｌ）を室温で加え、７０℃で攪拌した。６時間後、反応溶液に１．０Ｎ水酸化ナトリウム水溶液を加え、減圧濃縮した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ−ヘキサン／酢酸エチル＝８０／２０，クロロホルムのみ〜クロロホルム／メタノール＝９５／５）で精製し、表題化合物（２．３ｇ、８３％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．５３−１．６２（２Ｈ，ｍ），１．７２−１．８０（２Ｈ，ｍ），２．３５−２．４５（８Ｈ，ｍ），３．６７−３．７２（４Ｈ，ｍ），７．１６−７．２１（１Ｈ，ｍ），７．３９−７．４２（４Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３４２［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of 5-morpholin-4-yl-pentanoic acid (4-bromophenyl) amide:

5-Bromo-N- (4-bromophenyl) pentanamide (2.7 g, 8.1 mmol) was dissolved in 2-butanone (60 mL), sodium iodide (1.2 g, 8.1 mmol), morpholine (0 .78 mL, 8.9 mmol) was added at room temperature, and the mixture was stirred at 70 ° C. After 6 hours, 1.0N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 80/20, chloroform only to chloroform / methanol = 95/5) to give the title compound (2.3 g, 83%). Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.53-1.62 (2H, m), 1.72-1.80 (2H, m), 2.35-2.45 (8H, m), 3.67-3.72 (4H M), 7.16-7.21 (1H, m), 7.39-7.42 (4H, m).
MS (ESI): 342 [M + H] ⁺

５−モルホリン−４−イル−ペンタノイックアシッド（４−ブロモフェニル）アミド（５００ｍｇ，１．５ｍｍｏｌ）をアセトニトリル（８．０ｍＬ）に溶解し、ピリジン−３−ボロニックアシッド（２００ｍｇ，１．６ｍｍｏｌ）、炭酸ナトリウム水溶液（０．４Ｍ，８．０ｍＬ）、テトラキストリフェニルホスフィンパラジウム（８５ｍｇ，０．０７３ｍｍｏｌ）を室温で加え、マイクロウェーブ照射下、９０℃で攪拌した。２０分後、反応溶液を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝８０／２０）で精製し、表題化合物（３５０ｍｇ、７１％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）
δ：１．４０−１．５０（２Ｈ，ｍ），１．５４−１．６５（２Ｈ，ｍ），２．２４−２．３６（８Ｈ，ｍ），３．５２−３．６７（４Ｈ，ｍ），７．４２−７．４７（１Ｈ，ｍ），７．６５−７．７３（４Ｈ，ｍ），８．００−８．０５（１Ｈ，ｍ），８．４９−８．５４（１Ｈ，ｍ），８．８３−８．８７（１Ｈ，ｍ），９．９８−１０．０（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３４０［Ｍ＋Ｈ］^＋ [Third step]
Synthesis of 5- (4-morpholinyl) -N- (4- (3-pyridyl) phenyl) pentanamide:

5-Morpholin-4-yl-pentanoic acid (4-bromophenyl) amide (500 mg, 1.5 mmol) was dissolved in acetonitrile (8.0 mL) to give pyridine-3-boronic acid (200 mg, 1.6 mmol). ), An aqueous sodium carbonate solution (0.4 M, 8.0 mL) and tetrakistriphenylphosphine palladium (85 mg, 0.073 mmol) were added at room temperature, and the mixture was stirred at 90 ° C. under microwave irradiation. After 20 minutes, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform only to chloroform / methanol = 80/20) to obtain the title compound (350 mg, 71%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ: 1.40-1.50 (2H, m), 1.54-1.65 (2H, m), 2.24-2.36 (8H, m), 3.52-3.67 (4H) M), 7.42-7.47 (1H, m), 7.65-7.73 (4H, m), 8.00-8.05 (1H, m), 8.49-8.54. (1H, m), 8.83-8.87 (1H, m), 9.98-10.0 (1H, m).
MS (ESI): 340 [M + H] ⁺

５−（４−モルホリニル）−Ｎ−（４−（３−ピリジル）フェニル）ペンタンアミド（３６０ｍｇ，１．０ｍｍｏｌ）をメタノール（２．０ｍＬ）に溶解し、塩酸（１．０Ｎ，１．０ｍＬ，１．０ｍｍｏｌ）を室温で加え、同温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、表題化合物（３４０ｍｇ、８７％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）
δ：１．５９−１．７８（４Ｈ，ｍ），２．３９−２．４５（２Ｈ，ｍ），２．９６−３．１４（４Ｈ，ｍ），３．３３−３．４２（２Ｈ，ｍ），３．７１−３．８１（２Ｈ，ｍ），３．８８−３．９６（２Ｈ，ｍ），７．７８−７．８２（４Ｈ，ｍ），７．８６−７．９４（１Ｈ，ｍ），８．５５−８．６５（１Ｈ，ｍ），８．７１−８．７６（１Ｈ，ｍ），９．１０−９．１４（１Ｈ，ｍ），１０．３−１０．４（１Ｈ，ｍ），１０．７−１０．８（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３４０［Ｍ＋Ｈ］^＋ [Fourth step]
Synthesis of the compound of Reference Example 56:

5- (4-morpholinyl) -N- (4- (3-pyridyl) phenyl) pentanamide (360 mg, 1.0 mmol) was dissolved in methanol (2.0 mL) and hydrochloric acid (1.0 N, 1.0 mL, 1.0 mmol) was added at room temperature and stirred at the same temperature. After 10 minutes, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to give the title compound (340 mg, 87%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ: 1.59-1.78 (4H, m), 2.39-2.45 (2H, m), 2.96-3.14 (4H, m), 3.33-3.42 (2H) M), 3.71-3.81 (2H, m), 3.88-3.96 (2H, m), 7.78-7.82 (4H, m), 7.86-7.94. (1H, m), 8.55-8.65 (1H, m), 8.71-8.76 (1H, m), 9.10-9.14 (1H, m), 10.3-10 .4 (1H, m), 10.7-10.8 (1H, m).
MS (ESI): 340 [M + H] ⁺

３−クロロ−６−フェニルピリダジン（０．９０ｇ，４．７ｍｍｏｌ）をＤＭＳＯ（５．０ｍＬ）に溶解し、ｔｅｒｔ−ブチル ｃｉｓ−ヘキサヒドロピロロ［３，４−ｃ］ピロール−２（１Ｈ）−カルボキシレート（１．０ｇ，４．７ｍｍｏｌ）、ジイソプロピルエチルアミン（２．９ｍＬ，１６ｍｍｏｌ）を室温で加え、１０５℃で攪拌した。２１時間後、反応溶液を４０℃まで冷却し、蒸留水を加え、攪拌した。１時間後、得られた固体を濾取し、蒸留水、ジエチルエーテルで洗浄し、乾燥することで表題化合物（０．９８ｇ、５７％）を茶色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）
δ：１．４６（９Ｈ，ｓ），３．０７−３．１６（２Ｈ，ｍ），３．３０−３．３５（２Ｈ，ｍ），３．４６−３．５２（２Ｈ，ｍ），３．６２−３．７２（２Ｈ，ｍ），３．７７−３．８４（２Ｈ，ｍ），７．００−７．０５（１Ｈ，ｍ），７．３７−７．４３（１Ｈ，ｍ），７．４３−７．５０（２Ｈ，ｍ），７．８１−７．８６（１Ｈ，ｍ），７．８９−７．９４（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３６７［Ｍ＋Ｈ］^＋ Reference Example 57 Synthesis of cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole fumarate (compound of Reference Example 57):
[First step]
Synthesis of tert-butyl cis-5- (6-phenylpyridazin-3-yl) -hexahydro-pyrrolo [3,4-c] -pyrrole-2 (1H) -carboxylate:

3-Chloro-6-phenylpyridazine (0.90 g, 4.7 mmol) was dissolved in DMSO (5.0 mL) and tert-butyl cis-hexahydropyrrolo [3,4-c] pyrrole-2 (1H)- Carboxylate (1.0 g, 4.7 mmol) and diisopropylethylamine (2.9 mL, 16 mmol) were added at room temperature, and the mixture was stirred at 105 ° C. After 21 hours, the reaction solution was cooled to 40 ° C., distilled water was added and stirred. After 1 hour, the obtained solid was collected by filtration, washed with distilled water and diethyl ether, and dried to obtain the title compound (0.98 g, 57%) as a brown solid.
¹ H-NMR (400 MHz, CD ₃ OD)
δ: 1.46 (9H, s), 3.07-3.16 (2H, m), 3.30-3.35 (2H, m), 3.46-3.52 (2H, m), 3.62-3.72 (2H, m), 3.77-3.84 (2H, m), 7.00-7.05 (1H, m), 7.37-7.43 (1H, m ), 7.43-7.50 (2H, m), 7.81-7.86 (1H, m), 7.89-7.94 (2H, m).
MS (ESI): 367 [M + H] ⁺

ｔｅｒｔ−ブチル ｃｉｓ−５−（６−フェニルピリダジン−３−イル）−ヘキサヒドロ−ピロロ［３，４−ｃ］−ピロール−２（１Ｈ）−カルボキシレート（０．５０ｇ，１．４ｍｍｏｌ）をギ酸（２．５ｍＬ）に溶解し、ホルマリン水溶液（３０％，０．０８９ｍＬ，１．５ｍｍｏｌ）を室温で加え、１００℃で攪拌した。１時間後、反応溶液を室温まで冷却し、減圧濃縮した後、飽和炭酸水素ナトリウム水溶液を加え、中和した。クロロホルムで抽出した後、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９５／５）で精製し、表題化合物（０．２９ｇ、７６％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）
δ：２．２８（３Ｈ，ｓ），２．４４−２．５０（２Ｈ，ｍ），２．７５−２．８０（２Ｈ，ｍ），３．００−３．０８（２Ｈ，ｍ），３．４５−３．５２（２Ｈ，ｍ），３．６２−３．６８（２Ｈ，ｍ），７．０１（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），７．３１−７．４４（３Ｈ，ｍ），７．７８（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），７．８５（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．
ＭＳ（ＥＳＩ）：２８１［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole:

tert-Butyl cis-5- (6-phenylpyridazin-3-yl) -hexahydro-pyrrolo [3,4-c] -pyrrole-2 (1H) -carboxylate (0.50 g, 1.4 mmol) was added to formic acid ( 2.5 mL), a formalin aqueous solution (30%, 0.089 mL, 1.5 mmol) was added at room temperature and stirred at 100 ° C. After 1 hour, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added for neutralization. After extraction with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 95/5) to obtain the title compound (0.29 g, 76%) as a white solid.
¹ H-NMR (400 MHz, CD ₃ OD)
δ: 2.28 (3H, s), 2.44-2.50 (2H, m), 2.75-2.80 (2H, m), 3.00-3.08 (2H, m), 3.45-3.52 (2H, m), 3.62-3.68 (2H, m), 7.01 (1H, d, J = 9.6 Hz), 7.31-7.44 (3H M), 7.78 (1H, d, J = 9.6 Hz), 7.85 (2H, d, J = 8.0 Hz).
MS (ESI): 281 [M + H] ⁺

ｃｉｓ−２−メチル−５−（６−フェニルピリダジン−３−イル）パーヒドロピロロ［３，４−ｃ］ピロール（０．２９ｇ，１．０ｍｍｏｌ）をメタノール−ジエチルエーテル混合溶液（１／１０，１０ｍＬ）に溶解し、フマル酸（０．１２ｇ，１．０ｍｍｏｌ）のメタノール−ジエチルエーテル混合溶液（１／１０，１０ｍＬ）を室温で加え、同温で攪拌した。１時間後、得られた固体を濾取し、ジエチルエーテル、ヘキサンで洗浄し、乾燥することで、表題化合物（３６０ｍｇ、８８％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）
δ：２．３２（３Ｈ，ｓ），２．５８−２．６４（２Ｈ，ｍ），２．６８−２．７６（２Ｈ，ｍ），２．９５−３．０５（２Ｈ，ｍ），３．４３−３．４９（２Ｈ，ｍ），３．６４−３．７１（２Ｈ，ｍ），６．５６（２Ｈ，ｓ），７．０１（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），７．３５−７．５０（３Ｈ，ｍ），７．９１（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），８．００（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ）．
ＭＳ（ＥＳＩ）：２８１［Ｍ＋Ｈ］^＋ [Third step]
Synthesis of the compound of Reference Example 57:

Cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole (0.29 g, 1.0 mmol) was mixed with a methanol-diethyl ether mixed solution (1/10, 10 mL), fumaric acid (0.12 g, 1.0 mmol) in methanol-diethyl ether mixed solution (1/10, 10 mL) was added at room temperature, and the mixture was stirred at the same temperature. After 1 hour, the obtained solid was collected by filtration, washed with diethyl ether and hexane, and dried to give the title compound (360 mg, 88%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ: 2.32 (3H, s), 2.58-2.64 (2H, m), 2.68-2.76 (2H, m), 2.95-3.05 (2H, m), 3.43-3.49 (2H, m), 3.64-3.71 (2H, m), 6.56 (2H, s), 7.01 (1H, d, J = 9.6 Hz), 7.35-7.50 (3H, m), 7.91 (1H, d, J = 9.6 Hz), 8.00 (2H, d, J = 7.2 Hz).
MS (ESI): 281 [M + H] ⁺

（Ｒ）−メチルオキシアザボロリジン（０．３２ｇ，１．２ｍｍｏｌ）をｔｅｒｔ−ブチルアルコール（６０ｍＬ）に溶解し、Ｎ，Ｎ−ジエチルアニリンボラン（２．６ｇ，１６ｍｍｏｌ）を室温で加え、１−（２−フルオロフェニル）エタノン（２．０ｇ，１４ｍｍｏｌ）のｔｅｒｔ−ブチルアルコール溶液（１５０ｍＬ）を４５℃で加え、攪拌した。１時間後、反応溶液を室温まで冷却し、メタノールを加え、減圧濃縮した。得られた粗生成物に１．０Ｎ塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ〜ヘキサン／酢酸エチル＝８５／１５）で精製し、表題化合物（１．９ｇ、９２％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．５２（３Ｈ，ｄ，Ｊ＝６．８Ｈｚ），５．１７−５．２４（１Ｈ，ｍ），６．９８−７．０５（１Ｈ，ｍ），７．１５（１Ｈ，ｄｄｄ，Ｊ＝１．２，７．６，７．６Ｈｚ），７．２１−７．２８（１Ｈ，ｍ），７．４９（１Ｈ，ｄｄｄ，Ｊ＝１．６，７．６，７．６Ｈｚ）．Reference Example 58 (-)-N- (1-azabicyclo [2,2,2] octa-3 (S) -yl) carbamic acid 1 (S)-(2-fluorophenyl) ethyl ester (hereinafter, Synthesis of Compound of Reference Example 58:
[First step]
Synthesis of (S) -1- (2-fluorophenyl) ethanol:

(R) -Methyloxyazaborolidine (0.32 g, 1.2 mmol) is dissolved in tert-butyl alcohol (60 mL), and N, N-diethylaniline borane (2.6 g, 16 mmol) is added at room temperature. A tert-butyl alcohol solution (150 mL) of-(2-fluorophenyl) ethanone (2.0 g, 14 mmol) was added at 45 ° C. and stirred. After 1 hour, the reaction solution was cooled to room temperature, methanol was added, and the mixture was concentrated under reduced pressure. 1.0N hydrochloric acid was added to the obtained crude product, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane only to hexane / ethyl acetate = 85/15) to obtain the title compound (1.9 g, 92%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.52 (3H, d, J = 6.8 Hz), 5.17-5.24 (1H, m), 6.98-7.05 (1H, m), 7.15 (1H, ddd) , J = 1.2, 7.6, 7.6 Hz), 7.21-7.28 (1H, m), 7.49 (1H, ddd, J = 1.6, 7.6, 7.6 Hz). ).

１，１’−カルボニルジイミダゾール（３．３ｇ，２０ｍｍｏｌ）をＴＨＦ（１６ｍＬ）に溶解し、（Ｓ）−１−（２−フルオロフェニル）エタノール（１．９ｇ，１３ｍｍｏｌ）のＴＨＦ溶液（４．０ｍＬ）を５０℃でゆっくり加え、同温で攪拌した。４時間後、反応溶液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０〜７０／３０）で精製し、表題化合物（３．１ｇ、９９％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．７５（３Ｈ，ｄ，Ｊ＝６．４Ｈｚ），６．３３（１Ｈ，ｑ，Ｊ＝６．４Ｈｚ），７．０６−７．１３（２Ｈ，ｍ），７．１８（１Ｈ，ｄｄｄ，Ｊ＝１．２，７．２，７．６Ｈｚ），７．３１−７．４６（３Ｈ，ｍ），８．１６（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：２３５［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of imidazole-1-carboxylic acid (S) -1- (2-fluorophenyl) ethyl ester:

1,1′-carbonyldiimidazole (3.3 g, 20 mmol) was dissolved in THF (16 mL), and (S) -1- (2-fluorophenyl) ethanol (1.9 g, 13 mmol) in THF (4. 0 mL) was slowly added at 50 ° C. and stirred at the same temperature. After 4 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-70 / 30) to give the title compound (3.1 g, 99%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.75 (3H, d, J = 6.4 Hz), 6.33 (1H, q, J = 6.4 Hz), 7.06-7.13 (2H, m), 7.18 (1H , Ddd, J = 1.2, 7.2, 7.6 Hz), 7.31-7.46 (3H, m), 8.16 (1H, s).
MS (ESI): 235 [M + H] ⁺

３−アミノキヌクリジン二塩酸塩（１．４ｇ，７．０ｍｍｏｌ）をＴＨＦ（１４ｍＬ）に溶解し、ｎ−ブチルリチウム−ヘキサン溶液（２．６Ｎ，５．２ｍＬ，１４ｍｍｏｌ）を０℃でゆっくり加え、室温で撹拌した。１時間後、イミダゾール−１−カルボキシリックアシッド （Ｓ）−１−（２−フルオロフェニル）エチルエステル（１．５ｇ，６．４ｍｍｏｌ）を０℃でゆっくり加え、室温で撹拌した。１時間後、反応溶液を５５℃に昇温し、攪拌した。２時間後、反応溶液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９８／２）で精製し、表題化合物（４８０ｍｇ、２６％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．３６−１．５０（１Ｈ，ｍ），１．５５（３Ｈ，ｄ，Ｊ＝６．４Ｈｚ），１．５３−１．６５（３Ｈ，ｍ），１．８３−１．９０（１Ｈ，ｍ），２．４４−２．５２（１Ｈ，ｍ），２．６９−２．８５（４Ｈ，ｍ），３．２８−３．３８（１Ｈ，ｍ），３．６６−３．７４（１Ｈ，ｍ），４．８４−４．９４（１Ｈ，ｍ），６．０１−６．０８（１Ｈ，ｍ），７．００−７．０６（１Ｈ，ｍ），７．１３（１Ｈ，ｄｄ，Ｊ＝６．８，７．６Ｈｚ），７．２２−７．２９（１Ｈ，ｍ），７．３７（１Ｈ，ｄｄ，Ｊ＝５．２，６．８Ｈｚ）．
ＭＳ（ＥＳＩ）：２９３［Ｍ＋Ｈ］^＋ [Third step]
Synthesis of the compound of Reference Example 58:

3-Aminoquinuclidine dihydrochloride (1.4 g, 7.0 mmol) was dissolved in THF (14 mL), and n-butyllithium-hexane solution (2.6 N, 5.2 mL, 14 mmol) was slowly added at 0 ° C. Added and stirred at room temperature. After 1 hour, imidazole-1-carboxylic acid (S) -1- (2-fluorophenyl) ethyl ester (1.5 g, 6.4 mmol) was slowly added at 0 ° C. and stirred at room temperature. After 1 hour, the reaction solution was heated to 55 ° C. and stirred. Two hours later, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 98/2) to obtain the title compound (480 mg, 26%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.36-1.50 (1H, m), 1.55 (3H, d, J = 6.4 Hz), 1.53-1.65 (3H, m), 1.83-1.90 (1H, m), 2.44-2.52 (1H, m), 2.69-2.85 (4H, m), 3.28-3.38 (1H, m), 3.66-3 .74 (1H, m), 4.84-4.94 (1H, m), 6.01-6.08 (1H, m), 7.00-7.06 (1H, m), 7.13 (1H, dd, J = 6.8, 7.6 Hz), 7.22-7.29 (1H, m), 7.37 (1H, dd, J = 5.2, 6.8 Hz).
MS (ESI): 293 [M + H] ⁺

フロ［２，３−ｃ］ピリジン−５−カルボキシリックアシッド（０．１６ｇ，１．０ｍｍｏｌ）をクロロホルム（１０ｍＬ）に溶解し、ＨＢＴＵ（０．５７ｇ，１．５ｍｍｏｌ）、ジイソプロピルエチルアミン（０．７０ｍＬ，４．０ｍｍｏｌ）、（Ｒ）−キヌクリジン−３−アミン塩酸塩（０．２０ｇ，１．０ｍｍｏｌ）を室温で加え、同温で攪拌した。１６時間後、反応溶液に蒸留水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９８／２）で精製し、表題化合物（０．１８ｍｇ、６６％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．４０−１．５５（１Ｈ，ｍ），１．６５−１．７４（２Ｈ，ｍ），１．８０−１．９０（１Ｈ，ｍ），２．０２−２．０６（１Ｈ，ｍ），２．６３−２．７０（１Ｈ，ｍ），２．７５−３．００（４Ｈ，ｍ），３．３９−３．４６（１Ｈ，ｍ），４．１２−４．２０（１Ｈ，ｍ），６．８９−６．９２（１Ｈ，ｍ），７．８０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）８．２５−８．３５（１Ｈ，ｍ），８．４６−８．４９（１Ｈ，ｍ），８．７５−８．７８（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２７２［Ｍ＋Ｈ］^＋ Reference Example 59 N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxyamide dihydrochloride (hereinafter referred to as Reference Example 59) Synthesis of compound:
[First step]
Synthesis of N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxamide:

Furo [2,3-c] pyridine-5-carboxylic acid (0.16 g, 1.0 mmol) was dissolved in chloroform (10 mL), HBTU (0.57 g, 1.5 mmol), diisopropylethylamine (0.70 mL). , 4.0 mmol), (R) -quinuclidin-3-amine hydrochloride (0.20 g, 1.0 mmol) was added at room temperature, and the mixture was stirred at the same temperature. After 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 98/2) to obtain the title compound (0.18 mg, 66%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.40-1.55 (1H, m), 1.65-1.74 (2H, m), 1.80-1.90 (1H, m), 2.02-2.06 (1H M), 2.63-2.70 (1H, m), 2.75-3.00 (4H, m), 3.39-3.46 (1H, m), 4.12-4.20. (1H, m), 6.89-6.92 (1H, m), 7.80 (1H, d, J = 2.0 Hz) 8.25-8.35 (1H, m), 8.46- 8.49 (1H, m), 8.75-8.78 (1H, m).
MS (ESI): 272 [M + H] ⁺

Ｎ−（１−アザビシクロ［２．２．２］オクタ−３（Ｒ）−イル）フロ［２，３−ｃ］ピリジン−５−カルボキシアミド（１８０ｍｇ，０．６６ｍｍｏｌ）を酢酸エチル（２．０ｍＬ）に溶解し、塩化水素−酢酸エチル溶液（４．０Ｍ，０．５０ｍＬ，２．０ｍｍｏｌ）を室温で加え、同温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、表題化合物（１９０ｍｇ、８４％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，Ｄ_２Ｏ）
δ：１．７６−２．１８（４Ｈ，ｍ），２．２６−２．３２（１Ｈ，ｍ），３．１５−３．３５（５Ｈ，ｍ），３．６８−３．７６（１Ｈ，ｍ），４．３５−４．４０（１Ｈ，ｍ），７．０１−７．０５（１Ｈ，ｍ），８．００−８．０４（１Ｈ，ｍ），８．３２−８．３４（１Ｈ，ｍ），８．８０−８．８２（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２７２［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of the compound of Reference Example 59:

N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxamide (180 mg, 0.66 mmol) was added to ethyl acetate (2.0 mL). ), A hydrogen chloride-ethyl acetate solution (4.0 M, 0.50 mL, 2.0 mmol) was added at room temperature, and the mixture was stirred at the same temperature. After 10 minutes, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the title compound (190 mg, 84%) as a white solid.
¹ H-NMR (400 MHz, D ₂ O)
δ: 1.76-2.18 (4H, m), 2.26-2.32 (1H, m), 3.15-3.35 (5H, m), 3.68-3.76 (1H M), 4.35-4.40 (1H, m), 7.01-7.05 (1H, m), 8.00-8.04 (1H, m), 8.32-8.34. (1H, m), 8.80-8.82 (1H, m).
MS (ESI): 272 [M + H] ⁺

２，３−ジヒドロ［ｂ］［１，４］ジオキシン−６−カルボキシリックアシッド（０．１８ｇ，１．０ｍｍｏｌ）をクロロホルム（１０ｍＬ）に溶解し、ＨＢＴＵ（０．５７ｇ，１．５ｍｍｏｌ）、ジイソプロピルエチルアミン（０．７０ｍＬ，４．０ｍｍｏｌ）、（Ｒ）−キヌクリジン−３−アミン塩酸塩（０．２０ｇ，１．０ｍｍｏｌ）を室温で加え、同温で攪拌した。１６時間後、反応溶液に蒸留水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し、減圧濃縮した。得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９８／２）で精製し、表題化合物（０．２２ｍｇ、７６％）を無色液体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）
δ：１．４４−１．５５（１Ｈ，ｍ），１．６５−１．７６（３Ｈ，ｍ），１．９８−２．０３（１Ｈ，ｍ），２．５１−２．５８（１Ｈ，ｍ），２．７５−２．９０（４Ｈ，ｍ），３．３７−３．４６（１Ｈ，ｍ），４．０５−４．１４（１Ｈ，ｍ），４．２５−４．３５（４Ｈ，ｍ），６．０８−６．１８（１Ｈ，ｍ），６．８６−６．９０（１Ｈ，ｍ），７．２４−７．３１（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２８９［Ｍ＋Ｈ］^＋ Reference Example 60 N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide hydrochloride (hereinafter, Synthesis of the compound of Reference Example 60:
[First step]
Synthesis of N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide:

2,3-dihydro [b] [1,4] dioxin-6-carboxylic acid (0.18 g, 1.0 mmol) was dissolved in chloroform (10 mL), and HBTU (0.57 g, 1.5 mmol), diisopropyl was dissolved. Ethylamine (0.70 mL, 4.0 mmol) and (R) -quinuclidin-3-amine hydrochloride (0.20 g, 1.0 mmol) were added at room temperature, and the mixture was stirred at the same temperature. After 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by amine silica gel column chromatography (chloroform only to chloroform / methanol = 98/2) to obtain the title compound (0.22 mg, 76%) as a colorless liquid.
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 1.44 to 1.55 (1H, m), 1.65 to 1.76 (3H, m), 1.98 to 2.03 (1H, m), 2.51 to 2.58 (1H) M), 2.75-2.90 (4H, m), 3.37-3.46 (1H, m), 4.05-4.14 (1H, m), 4.25-4.35. (4H, m), 6.08-6.18 (1H, m), 6.86-6.90 (1H, m), 7.24-7.31 (2H, m).
MS (ESI): 289 [M + H] ⁺

Ｎ−（１−アザビシクロ［２．２．２］オクタ−３（Ｒ）−イル）−２，３−ジヒドロ−１，４−ベンゾジオキシン−６−カルボキシアミド（２２０ｍｇ，０．７６ｍｍｏｌ）を酢酸エチル（２．０ｍＬ）に溶解し、塩化水素−酢酸エチル溶液（４．０Ｎ，０．２８ｍＬ，１．１ｍｍｏｌ）を室温で加え、同温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、表題化合物（１１０ｍｇ、４３％）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）
δ：１．６４−１．７４（１Ｈ，ｍ），１．８２−１．９１（２Ｈ，ｍ），１．９７−２．１６（２Ｈ，ｍ），３．１０−３．３５（５Ｈ，ｍ），３．５５−３．６３（１Ｈ，ｍ），４．２２−４．３０（５Ｈ，ｍ），６．９１−６．９５（１Ｈ，ｍ），７．４０−７．４６（２Ｈ，ｍ），８．４２−８．４５（１Ｈ，ｍ），１０．２−１０．３（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２８９［Ｍ＋Ｈ］^＋ [Second step]
Synthesis of the compound of Reference Example 60:

N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide (220 mg, 0.76 mmol) in ethyl acetate (2.0 mL), a hydrogen chloride-ethyl acetate solution (4.0 N, 0.28 mL, 1.1 mmol) was added at room temperature, and the mixture was stirred at the same temperature. After 10 minutes, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to give the title compound (110 mg, 43%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ )
δ: 1.64-1.74 (1H, m), 1.82-1.91 (2H, m), 1.97-2.16 (2H, m), 3.10-3.35 (5H) M), 3.55-3.63 (1H, m), 4.22-4.30 (5H, m), 6.91-6.95 (1H, m), 7.40-7.46. (2H, m), 8.42-8.45 (1H, m), 10.2-10.3 (1H, m).
MS (ESI): 289 [M + H] ⁺

Reference Example 61 Compound that activates central nicotinic acetylcholine receptor (Varenicline tartrate, N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride Suppressive effect on substance P-induced scratching behavior of the salt and the compounds of Reference Examples 51-60:
Induction of substance P-induced scratching behavior and measurement of the number of times were performed in the same manner as in Example 82.

  The test compound or its solvent was administered at a volume of 10 mL / kg 30 to 60 minutes before the start of measurement of the number of scratching behaviors. Varenicline tartrate (Tocris Bioscience) was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 60 minutes before the start of measurement of the number of scratching behaviors. N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride (PNU-282987) hydrate (Sigma-Aldrich) is dissolved in PBS, It was administered intraperitoneally at a dose of 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 51 was dissolved in PBS and administered intraperitoneally at a dose of 0.1 or 0.3 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 52 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 53 was dissolved in distilled water and orally administered at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 54 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 55 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 56 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 57 was dissolved in PBS and administered intraperitoneally at a dose of 0.3, 1 or 3 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 58 was suspended in 0.5% methylcellulose and orally administered at a dose of 10 or 30 mg / kg 60 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 59 was dissolved in PBS and administered intraperitoneally at a dose of 0.1, 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 60 was dissolved in PBS and administered intraperitoneally at a dose of 0.1, 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors.

  A group (test compound: 0 mg / kg, substance P: 0 nmol / site) administered with only the solvent was a “non-induced control group”, and a group administered with substance P but not administered a test compound (test compound: 0 mg / kg, Substance P: 250 nmol / site) was designated as “induction control group”, and a group administered with substance P and test compound was designated as “test compound administration group”.

The inhibition rate (%) of scratching behavior by the test compound was calculated from the following formula.
Inhibition rate (%) = [1- (A−C) / (B−C)] × 100
Here, A, B, and C represent the average values of the number of scratching behaviors of the test compound administration group, the induced control group, and the non-induced control group, respectively.

  As a statistical treatment, Dunnett's test was performed as a test of the test compound administration group with respect to the induction control group. The significance level was 5% (both sides).

  Tables 23 and 24 show the effect of each test compound on the number of scratching actions. * Mark in a table | surface shows that it is statistically significant compared with an induction | guidance | derivation control group (* p <0.05, Dunnett test).

  From these results, it is clear that a compound that activates the central nicotinic acetylcholine receptor significantly suppresses substance P-induced scratching behavior known as an intractable pruritus model and has an excellent antipruritic effect.

(Reference Example 62) Action of a nicotinic acetylcholine receptor antagonist on the inhibitory effect of varenicline on substance P-induced scratching behavior Induction and frequency measurement of substance P-induced scratching behavior was carried out in the same manner as in Example 82.

  Varenicline tartrate (0.3 mg / mL, Tocris Bioscience), mecamylamine hydrochloride (0.3 mg / mL, Tocris Bioscience), a mixed solution of varenicline tartrate and mecamylamine hydrochloride (both 0.3 mg / mL) or these PBS as a solvent was administered intraperitoneally at a volume of 10 mL / kg 60 minutes before the start of measurement of the number of scratching behaviors.

  The evaluation results are shown in FIG. The vertical axis represents the number of scratching actions for 15 minutes (average value ± standard error, n = 5 to 8). The horizontal axis represents the non-induced control group (test compound: 0 mg / kg, substance P: 0 nmol / site), the induced control group (test compound: 0 mg / kg, substance P: 250 nmol / site), the varenicline tartrate-administered group (valenicline). Tartrate: 3 mg / kg, substance P: 250 nmol / site), mecamylamine hydrochloride administration group (mecamylamine hydrochloride: 3 mg / kg, substance P: 250 nmol / site) and varenicline tartrate + mecamylamine hydrochloride administration group (valenicline tartrate) : 3 mg / kg, mecamylamine hydrochloride: 3 mg / kg, substance P: 250 nmol / site). The * mark in the figure indicates that it is statistically significant in comparison with the induction control group (* p <0.05, Aspin-Welch t-test), and the # mark indicates the varenicline tartrate administration group. (#P <0.05, Aspin-Welch t test).

  When mecamylamine hydrochloride, which is a nicotinic acetylcholine receptor antagonist, was used in combination, the effect of inhibiting substance P-induced scratching behavior of varenicline tartrate completely disappeared. From these results, it was clarified that the effect of suppressing the scratching behavior of the compound that activates the central nicotinic acetylcholine receptor is a result of specific activation of the nicotinic acetylcholine receptor.

  Further, this substance P-induced scratching behavior is considered to be an itching model that is induced by exogenous substance P and endogenous leukotriene B4 acutely stimulating nerves and does not mediate immune reaction or inflammatory reaction. (Andoh et al., European Journal of Pharmacology, 1998, 353, p. 93; Andoh et al., Journal of Investigative Dermatology, 2001, 117, p. 1621). As a result of a single administration of a compound that activates the central nicotinic acetylcholine receptor 30 to 60 minutes before the induction of substance P-induced scratching behavior, the result was that the scratching behavior was suppressed. This suggests that the activation of the gene directly suppressed the conduction and / or transmission of impulses by pruritus stimulation.

  Since the quinuclidineamide derivative of the present invention or a pharmacologically acceptable salt thereof has a strong central nicotinic acetylcholine receptor activation action, the pathological condition is improved by activating the central nicotinic acetylcholine receptor. Alternatively, it can be used as a medicine for a disease for which symptom remission is expected, and further, it exhibits an antipruritic effect based on the mechanism of action, and can be used as an antidiarrheal agent.

Claims (8)

A quinuclidinamide derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

[Wherein, A represents a substituent selected from the group consisting of substituents represented by the following general formulas (II-1) to (II-9).

(In the formula, each R ¹ independently represents a hydrogen atom, a C 1-6 alkyl group in which the hydrogen atom may be substituted with 1 to 6 halogen atoms, or a C 3-6 cycloalkyl. Represents a group or an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R ² ;
R ² represents a halogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a carbon number, in which a hydrogen atom may be substituted with 1 to 6 halogen atoms. Represents an alkyloxy group of 1-6,
R ³ represents a hydrogen atom or a C 1-6 alkyl group or a C 3-6 cycloalkyl group in which the hydrogen atom may be substituted with 1 to 6 halogen atoms,
Z represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R ⁴ ;
R ⁴ represents a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, or an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms. Group, a C3-C6 cycloalkyl group or a C1-C6 alkyloxy group. ]] The quinuclidineamide derivative according to claim 1, wherein A is a substituent selected from the group consisting of substituents represented by the following general formulas (II-1) to (II-5) or a pharmacology thereof: Acceptable salt.

Each R ¹ is independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
R ³ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms in which the hydrogen atom may be substituted with 1 to 6 halogen atoms,
Z is a phenyl group, a naphthyl group, a pyridyl group, a thienyl group or an imidazolyl group in which a hydrogen atom may be substituted with R ⁴ ;
R ⁴ represents a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, or an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms. The quinuclidine amide derivative or pharmacologically acceptable salt thereof according to claim 2, which is a group, a cycloalkyl group having 3 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms. R ¹ is a hydrogen atom;
R ³ is a methyl group,
Z is a phenyl group, a pyridyl group or a thienyl group in which a hydrogen atom may be substituted with R ⁴ ;
R ⁴ represents a halogen atom, a hydroxyl group, a nitrile group, an amino group, an acetylamino group, a nitro group, or an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms. The quinuclidine amide derivative or pharmacologically acceptable salt thereof according to claim 3, which is a group, a cycloalkyl group having 3 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms.   The pharmaceutical which contains the quinuclidinamide derivative as described in any one of Claims 1-4, or its pharmacologically acceptable salt as an active ingredient.   A central nicotinic acetylcholine receptor activator comprising the quinuclidinamide derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.   The central nicotinic acetylcholine receptor activator according to claim 6, wherein the central nicotinic acetylcholine receptor is α7 subtype.   An antidiarrheal agent containing the quinuclidineamide derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.

Images