JP2015027999A - Medicine containing phenyl triazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug to be used for prevention or therapy of diseases, such as dementia, alzheimer disease, attention deficit/hyperactivity, schizophrenia, epilepsy, central convulsion, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorders, parasomnia, sleep-related movement disorders, insomnia, depression or allergic rhinitis, by inhibition of bonding of histamine to histamine H3 receptor.SOLUTION: A preventive or therapeutic agent contains a phenyl triazole derivative compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. [In the formula, the ring P is a specific triazole group; Q is a specific piperidyl oxy group or a specific aminopropyl oxy group; and Ris H, a halogen atom or a C1 to 6 alkyl.]

Description

  The present invention relates to a novel phenyltriazole derivative and pharmaceutical use thereof, in particular, a prophylactic or therapeutic agent for histamine H3 receptor-related diseases.

  Histamine is usually stored in intracellular granules such as mast cells, lungs, liver, and gastric mucosa, and is released to the outside by external stimuli such as binding of antigens to cell surface antibodies. For example, when mast cells are stimulated with an antigen that has entered from the outside, histamine is released from the mast cells and causes an allergic reaction by stimulating histamine H1 (H1) receptors present on blood vessels and smooth muscles. Also, histamine released from ECL cells on the gastric mucosa stimulates histamine H2 (H2) receptors on mural cells and promotes gastric acid secretion. Based on these facts, H1 receptor antagonists or H2 receptor antagonists have been developed as therapeutic agents for allergic diseases or gastric ulcers, and are now widely used as pharmaceuticals.

  Furthermore, it has been clarified that histamine acts as a neurotransmitter on a histamine receptor (histamine H3 (H3) receptor) present in the central nerve and peripheral nerve and exhibits various physiological functions. This receptor was cloned in 1999 and its gene sequence and amino acid sequence were clarified, but the amino acid sequence homology with H1 receptor and H2 receptor was as low as 22% and 21.4%, respectively. (Refer nonpatent literature 1). It has been shown that the H3 receptor exists in the presynaptic membrane and functions as an autoreceptor that controls histamine synthesis and release (see Non-Patent Document 2). It has also been clarified that the H3 receptor controls the release of histamine and other neurotransmitters such as acetylcholine, serotonin, dopamine, and noradrenaline (see Non-Patent Document 3). Furthermore, the H3 receptor has been suggested to be active in the absence of agonists and this activity can be inhibited by compounds that act as inverse agonists. These facts suggest that H3 receptor antagonists or inverse agonists can increase the release of neurotransmitters controlled by H3 receptors and can be therapeutic agents for various diseases associated with abnormal release. ing.

In fact, experimental results using animal models show that H3 receptor antagonists or inverse agonists are dementia, Alzheimer's disease (see Non-Patent Documents 4 and 5), attention deficit / hyperactivity disorder (Non-Patent Document 6). Reference), schizophrenia (see Non-Patent Document 7), epilepsy, central convulsions and the like.
In addition, H3 receptor has been shown to be involved in eating behavior (see Non-Patent Document 8), and H3 receptor antagonists or inverse agonists are indicated as obesity, diabetes, hyperlipidemia, etc. Metabolic diseases are also envisaged.

  Histamine has been shown to regulate the daily rhythm in the brain and maintain a balance between arousal and sleep (see Non-Patent Documents 9 and 10), an H3 receptor antagonist, or an inverse agonist Diseases associated with sleep disorders such as narcolepsy, sleep apnea syndrome, circadian rhythm disorders, and depression are also envisaged.

  Furthermore, it has been shown that the H3 receptor is present in the sympathetic nerve of the nasal mucosa, and it has been reported that nasal congestion is markedly improved by the combined use of the H3 receptor antagonist and the H1 receptor antagonist ( Non-patent document 11). This indicates that the H3 receptor antagonist or inverse agonist may be useful for the treatment of allergic rhinitis and the like alone or in combination with the H1 receptor antagonist.

  H3 receptor antagonists or inverse agonists are summarized in multiple reviews (see Non-Patent Documents 12 to 15), and these can be referred to. Initially, many imidazole compounds using histamine itself as a lead compound were reported, but concerns about the inhibitory action of the drug metabolizing enzyme cytochrome P450 (CYP) and the like have been shown, and they have not been developed as pharmaceutical products.

  Recently, many literatures and patents on non-imidazole H3 receptor antagonists or inverse agonists have been reported (see Patent Literatures 1 to 10).

  In addition, histamine H3 receptor antagonists having a 5-membered aromatic ring such as a pyrazole ring have been reported (see Patent Documents 11 to 15). However, there are no reports on compounds having the structure disclosed in the present invention.

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  The present invention relates to phenyltriazole derivatives, and more particularly, has a strong inhibitory action on the binding of histamine to histamine H3 receptor, and is a disorder caused by histamine H3 receptor such as dementia, Alzheimer's disease, attention deficit Hyperactivity, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder An object of the present invention is to provide a phenyltriazole derivative or a pharmaceutically acceptable salt thereof useful for the prevention or treatment of diseases such as sleep-related complications, sleep-related movement disorders, insomnia, depression, or allergic rhinitis. .

As a result of intensive studies for the above purpose, the present inventors have found that a compound having a phenyltriazole skeleton (hereinafter referred to as “phenyltriazole derivative”) has a potent inhibitory activity on the binding of histamine to the histamine H3 receptor. The present invention was completed.
Hereinafter, the present invention will be described in detail. The embodiment of the present invention (hereinafter, the embodiment of the compound is referred to as “the compound of the present invention”) is as follows.
That is, the present invention

(1) Formula (I)

[式（Ｉ）中、環Ｐは、下記式（ＩＩ）又は（ＩＩＩ）で表される基を示し、

[In Formula (I), Ring P represents a group represented by the following Formula (II) or (III);

Ｑは、下記式（Ａ）又は（Ｂ）で表される基を示し、

Q represents a group represented by the following formula (A) or (B),

Ｒ¹は、水素原子、ハロゲン原子又はＣ₁〜Ｃ₆アルキルを示し、
Ｒ²は、水素原子、ヒドロキシ、シアノ、カルボキシ、Ｃ₁〜Ｃ₆アルキル、Ｃ₂〜Ｃ₇アルカノイル、Ｃ₁〜Ｃ₆アルキルスルホニル（ここで該Ｃ₁〜Ｃ₆アルキル、Ｃ₂〜Ｃ₇アルカノイル又はＣ₁〜Ｃ₆アルキルスルホニルは、ハロゲン原子、ヒドロキシ及びＣ₁〜Ｃ₆アルコキシからなる群より選ばれる１〜３個の基で置換されてもよい。）、Ｃ₁〜Ｃ₆アルコキシ、Ｃ₃〜Ｃ₇シクロアルキル、Ｃ₂〜Ｃ₇アルコキシカルボニル（ここで、該Ｃ₁〜Ｃ₆アルコキシ、Ｃ₃〜Ｃ₇シクロアルキル又はＣ₂〜Ｃ₇アルコキシカルボニルは、ハロゲン原子、ヒドロキシ、Ｃ₁〜Ｃ₆アルキル及びＣ₁〜Ｃ₆アルコキシからなる群より選ばれる１〜３個の基で置換されてもよい。）、−（ＣＨ₂）_n−Ｃ（＝Ｏ）ＮＲ^1AＲ^1B又は−Ｓ（＝Ｏ）₂ＮＲ^2AＲ^2Bを示し、
Ｒ^1A及びＲ^1Bは、同一又は異なって、水素原子、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₇シクロアルキルを示し、
又はＲ^1A及びＲ^1Bは、隣接する窒素原子と一緒になって互いに結合した３〜７員の飽和複素環（該飽和複素環は、ハロゲン原子及びＣ₁〜Ｃ₆アルキルからなる群より選ばれる１又は２個の基で置換されてもよい。）を形成してもよく、
ｎは、０又は１を示し、
Ｒ^2A及びＲ^2Bは、同一又は異なって、水素原子、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₇シクロアルキルを示し、
又はＲ^2A及びＲ^2Bは、隣接する窒素原子と一緒になって互いに結合した３〜７員の飽和複素環（該飽和複素環は、ハロゲン原子及びＣ₁〜Ｃ₆アルキルからなる群より選ばれる１又は２個の基で置換されてもよい。）を形成してもよく、
Ｒ³は、水素原子又はＣ₁〜Ｃ₆アルキルであり、
Ｒ⁴は、Ｃ₁〜Ｃ₆アルキル（該Ｃ₁〜Ｃ₆アルキルは１又は２個のＣ₃〜Ｃ₇シクロアルキルで置換されてもよい。）又はＣ₃〜Ｃ₇シクロアルキル（該Ｃ₃〜Ｃ₇シクロアルキルは１又は２個のＣ₁〜Ｃ₆アルキルで置換されてもよい。）を示し、
Ｒ⁵及びＲ⁶は、同一又は異なって、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₇シクロアルキルを示し、
又はＲ⁵及びＲ⁶は、隣接する窒素原子と一緒になって互いに結合した３〜７員の飽和複素環（該飽和複素環は１又は２個のＣ₁〜Ｃ₆アルキルで置換されてもよい。）を形成してもよい。]
で表される化合物（ただし、Ｎ，Ｎ−ジメチル−３−［４−（１Ｈ−１，２，４−トリアゾール−１−イル）フェノキシ］プロパン−１−アミンを除く）、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、肥満、糖尿病、高脂血症、ナルコレプシー、特発性過眠症、行動誘発性睡眠不足症候群、睡眠時無呼吸症候群、概日リズム障害、睡眠時随伴症、睡眠関連運動障害、不眠症、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（２）環Ｐが式（ＩＩ）

R ¹ represents a hydrogen atom, a halogen atom or C ₁ -C ₆ alkyl;
R ² is a hydrogen atom, hydroxy, cyano, carboxy, C ₁ -C ₆ alkyl, C ₂ -C ₇ alkanoyl, C ₁ -C ₆ alkylsulfonyl (wherein the C ₁ -C ₆ alkyl, C ₂ -C ₇ alkanoyl or C ₁ -C ₆ alkylsulfonyl, halogen atoms, with 1 to 3 substituents selected from the group consisting of hydroxy and C ₁ -C ₆ alkoxy may be substituted.), C ₁ ~C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ alkoxycarbonyl (wherein said C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl or C ₂ -C ₇ alkoxycarbonyl, halogen atom, hydroxy, C _{1 to} C ₆ alkyl and ₁ to 3 groups selected from the group consisting of C _{1 to} C ₆ alkoxy may be substituted.), — (CH ₂ ) _n —C (═O) NR ^1A R ^1B or -S (= O) ₂ NR ^2A R ^2B is shown,
R ^1A and R ^1B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
Or R ^1A and R ^1B are 3 to 7-membered saturated heterocycles bonded to each other together with adjacent nitrogen atoms (the saturated heterocycle is selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyls) May be substituted with 1 or 2 groups),
n represents 0 or 1,
R ^2A and R ^2B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
Or R ^2A and R ^2B are 3 to 7-membered saturated heterocycles bonded to each other together with adjacent nitrogen atoms (the saturated heterocycle is selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyls) May be substituted with 1 or 2 groups),
R ³ is a hydrogen atom or C ₁ -C ₆ alkyl,
R ⁴ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with 1 or 2 C ₃ -C ₇ cycloalkyl) or C ₃ -C ₇ cycloalkyl (the C ₃ -C ₇ cycloalkyl may be substituted with 1 or 2 C ₁ -C ₆ alkyl.)
R ⁵ and R ⁶ are the same or different and each represents C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
Or R ⁵ and R ⁶ are 3- to 7-membered saturated heterocycles bonded together with adjacent nitrogen atoms (the saturated heterocycle may be substituted with 1 or 2 C ₁ -C ₆ alkyls). May be formed). ]
Or a pharmaceutically acceptable salt thereof, except for N, N-dimethyl-3- [4- (1H-1,2,4-triazol-1-yl) phenoxy] propan-1-amine, Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, Preventive or therapeutic agent for idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep-related comorbidity, sleep-related movement disorder, insomnia, depression, or allergic rhinitis ,
(2) Ring P is represented by formula (II)

（式中、Ｒ²及びＲ³は、（１）に定義した通りである）
である、（１）に記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、肥満、糖尿病、高脂血症、ナルコレプシー、特発性過眠症、行動誘発性睡眠不足症候群、睡眠時無呼吸症候群、概日リズム障害、睡眠時随伴症、睡眠関連運動障害、不眠症、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（３）Ｑが式（Ａ）

(Wherein R ² and R ³ are as defined in (1)).
Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy characterized by containing the compound according to (1) or a pharmaceutically acceptable salt thereof as an active ingredient , Central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorders, sleep-related complications, sleep-related movement disorders, Preventive or therapeutic agent for insomnia, depression, or allergic rhinitis,
(3) Q is the formula (A)

（式中、Ｒ⁴は、（１）に定義した通りである）
である、（１）又は（２）に記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、肥満、糖尿病、高脂血症、ナルコレプシー、特発性過眠症、行動誘発性睡眠不足症候群、睡眠時無呼吸症候群、概日リズム障害、睡眠時随伴症、睡眠関連運動障害、不眠症、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（４）Ｒ¹が水素原子である、（１）〜（３）のいずれか１つに記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、肥満、糖尿病、高脂血症、ナルコレプシー、特発性過眠症、行動誘発性睡眠不足症候群、睡眠時無呼吸症候群、概日リズム障害、睡眠時随伴症、睡眠関連運動障害、不眠症、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（５）Ｒ²が、Ｃ₁〜Ｃ₆アルキル（ここで該Ｃ₁〜Ｃ₆アルキルは、ヒドロキシ及びＣ₁〜Ｃ₆アルコキシからなる群より選ばれる１〜３個の基で置換されてもよい。）、Ｃ₁〜Ｃ₆アルコキシ、Ｃ₃〜Ｃ₇シクロアルキル（ここで、該Ｃ₁〜Ｃ₆アルコキシ又はＣ₃〜Ｃ₇シクロアルキルは、ヒドロキシ、Ｃ₁〜Ｃ₆アルキル及びＣ₁〜Ｃ₆アルコキシからなる群より選ばれる１〜３個の基で置換されてもよい。）、又は−Ｃ（＝Ｏ）ＮＲ^1AＲ^1Bであり、
Ｒ^1A及びＲ^1Bは、同一又は異なって、水素原子、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₇シクロアルキルを示し、又はＲ^1A及びＲ^1Bは、隣接する窒素原子と一緒になって互いに結合した３〜７員の飽和複素環（該飽和複素環は、ハロゲン原子及びＣ₁〜Ｃ₆アルキルからなる群より選ばれる１又は２個の基で置換されてもよい。）を形成してもよい、（１）〜（４）のいずれか１つに記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、肥満、糖尿病、高脂血症、ナルコレプシー、特発性過眠症、行動誘発性睡眠不足症候群、睡眠時無呼吸症候群、概日リズム障害、睡眠時随伴症、睡眠関連運動障害、不眠症、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（６）Ｒ³が水素原子である、（１）〜（５）のいずれか１つに記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、肥満、糖尿病、高脂血症、ナルコレプシー、特発性過眠症、行動誘発性睡眠不足症候群、睡眠時無呼吸症候群、概日リズム障害、睡眠時随伴症、睡眠関連運動障害、不眠症、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（７）Ｒ⁴がＣ₃〜Ｃ₇シクロアルキルである、（１）〜（６）のいずれか１つに記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、肥満、糖尿病、高脂血症、ナルコレプシー、特発性過眠症、行動誘発性睡眠不足症候群、睡眠時無呼吸症候群、概日リズム障害、睡眠時随伴症、睡眠関連運動障害、不眠症、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（８）エチル １−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキシラート、
１−シクロブチル−４−｛４−［４−（メトキシメチル）−１Ｈ−１，２，３−トリアゾール−１−イル］フェノキシ｝ピペリジン、
１−シクロブチル−４−［４−（４−エトキシ−１Ｈ−１，２，３−トリアゾール−１−イル）フェノキシ］ピペリジン、
１−シクロブチル−４−［４−（４−シクロプロピル−１Ｈ−１，２，３−トリアゾール−１−イル）フェノキシ］ピペリジン、
１−（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）エタノン、
２−（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）プロパン−２−オール、
４−［４−（４−ｔｅｒｔ−ブチル−１Ｈ−１，２，３−トリアゾール−１−イル）フェノキシ］−１−シクロブチルピペリジン、
（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）（ピロリジン−１−イル）メタノン、
（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−５−メチル−１Ｈ−１，２，３−トリアゾール−４−イル）（ピロリジン−１−イル）メタノン、
アゼチジン−１−イル（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−５−メチル−１Ｈ−１，２，３−トリアゾール−４−イル）メタノン、
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−Ｎ，５−ジメチル−１Ｈ−１，２，３−トリアゾール−４−カルボキサミド、
２−（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）−１−（ピロリジン−１−イル）エタノン、
１−（アゼチジン−１−イル）−２−（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）エタノン、
２−（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）−Ｎ−メチルアセトアミド、
［１−（４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝フェニル）−１Ｈ−１，２，３−トリアゾール−４−イル］（ピロリジン−１−イル）メタノン、
アゼチジン−１−イル［１−（４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝フェニル）−１Ｈ−１，２，３−トリアゾール−４−イル］メタノン、
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボン酸、
アゼチジン−１−イル（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）メタノン、
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−Ｎ−メチル−１Ｈ−１，２，３−トリアゾール−４−カルボキサミド、
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキサミド、
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボニトリル、
（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）メタノール、
１−シクロブチル−４−［４−（１Ｈ−１，２，３−トリアゾール−１−イル）フェノキシ］ピペリジン、
エチル １−（４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝フェニル）−１Ｈ−１，２，３−トリアゾール−４−カルボキシラート、
（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）（モルホリン−４−イル）メタノン、
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−Ｎ，Ｎ−ジメチル−１Ｈ−１，２，３−トリアゾール−４−カルボキサミド、
エチル １−｛４−［（１−ｔｅｒｔ−ブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキシラート、
（１−｛４−［（１−ｔｅｒｔ−ブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）（ピロリジン−１−イル）メタノン、
アゼチジン−１−イル（１−｛４−［（１−ｔｅｒｔ−ブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−イル）メタノン、
１−｛４−［（１−ｔｅｒｔ−ブチルピペリジン−４−イル）オキシ］フェニル｝−Ｎ−メチル−１Ｈ−１，２，３−トリアゾール−４−カルボキサミド、
１−｛４−［（１−ｔｅｒｔ−ブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキサミド、
１−｛４−［（１−ｔｅｒｔ−ブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボニトリル、
エチル １−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボキシラート、
（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−イル）（ピロリジン−１−イル）メタノン、
アゼチジン−１−イル（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−イル）メタノン、
（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−イル）（ピペリジン−１−イル）メタノン、
Ｎ−ｔｅｒｔ−ブチル−１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボキサミド、
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボン酸、
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボキサミド、
１−（１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−イル）エタノン、
及び１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボニトリルからなる群より選ばれる、（１）に記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、肥満、糖尿病、高脂血症、ナルコレプシー、特発性過眠症、行動誘発性睡眠不足症候群、睡眠時無呼吸症候群、概日リズム障害、睡眠時随伴症、睡眠関連運動障害、不眠症、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
である。

(Wherein R ⁴ is as defined in (1)).
Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, integration characterized by containing as an active ingredient the compound according to (1) or (2), or a pharmaceutically acceptable salt thereof Ataxia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep-related complications, sleep Preventive or therapeutic agent for related movement disorders, insomnia, depression, or allergic rhinitis,
(4) Dementia characterized by containing as an active ingredient the compound according to any one of (1) to (3), wherein R ¹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. , Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea Preventive or therapeutic agent for syndrome, circadian rhythm disorder, parasomnia, sleep-related movement disorder, insomnia, depression, or allergic rhinitis,
(5) R ² is C ₁ -C ₆ alkyl (wherein the C ₁ -C ₆ alkyl is substituted with 1 to 3 groups selected from the group consisting of hydroxy and C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl (wherein the C ₁ -C ₆ alkoxy or C ₃ -C ₇ cycloalkyl is hydroxy, C ₁ -C ₆ alkyl and C _1). -C ₆ optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy.), or -C (= O) a NR ^1A R ^1B,
R ^1A and R ^1B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl, or R ^1A and R ^1B together with the adjacent nitrogen atom Forming a bonded 3 to 7 membered saturated heterocyclic ring (which may be substituted with one or two groups selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyl). The compound according to any one of (1) to (4), or a pharmaceutically acceptable salt thereof as an active ingredient, comprising dementia, Alzheimer's disease, attention deficit / multiple Dyskinetics, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep Episodic disorder, sleep-related movement disorder, insomnia, depression, young Ku is allergic rhinitis prophylactic or therapeutic agent,
(6) Dementia comprising, as an active ingredient, the compound according to any one of (1) to (5), wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. , Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea Preventive or therapeutic agent for syndrome, circadian rhythm disorder, parasomnia, sleep-related movement disorder, insomnia, depression, or allergic rhinitis,
(7) The compound according to any one of (1) to (6), wherein R ⁴ is C _{3 to} C ₇ cycloalkyl, or a pharmaceutically acceptable salt thereof as an active ingredient Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome Preventive or therapeutic agent for sleep apnea syndrome, circadian rhythm disorder, sleep-related comorbidity, sleep-related movement disorder, insomnia, depression, or allergic rhinitis,
(8) ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate,
1-cyclobutyl-4- {4- [4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] phenoxy} piperidine,
1-cyclobutyl-4- [4- (4-ethoxy-1H-1,2,3-triazol-1-yl) phenoxy] piperidine,
1-cyclobutyl-4- [4- (4-cyclopropyl-1H-1,2,3-triazol-1-yl) phenoxy] piperidine,
1- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) ethanone,
2- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) propan-2-ol,
4- [4- (4-tert-butyl-1H-1,2,3-triazol-1-yl) phenoxy] -1-cyclobutylpiperidine,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (pyrrolidin-1-yl) methanone,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -5-methyl-1H-1,2,3-triazol-4-yl) (pyrrolidin-1-yl) methanone,
Azetidin-1-yl (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -5-methyl-1H-1,2,3-triazol-4-yl) methanone,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N, 5-dimethyl-1H-1,2,3-triazole-4-carboxamide,
2- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) -1- (pyrrolidin-1-yl) ethanone ,
1- (azetidin-1-yl) -2- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) ethanone ,
2- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) -N-methylacetamide,
[1- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1H-1,2,3-triazol-4-yl] (pyrrolidin-1-yl) methanone ,
Azetidin-1-yl [1- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1H-1,2,3-triazol-4-yl] methanone,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylic acid,
Azetidin-1-yl (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanone,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N-methyl-1H-1,2,3-triazole-4-carboxamide,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxamide,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carbonitrile,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanol,
1-cyclobutyl-4- [4- (1H-1,2,3-triazol-1-yl) phenoxy] piperidine,
Ethyl 1- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1H-1,2,3-triazole-4-carboxylate,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (morpholin-4-yl) methanone,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N, N-dimethyl-1H-1,2,3-triazole-4-carboxamide,
Ethyl 1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate,
(1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (pyrrolidin-1-yl) methanone,
Azetidin-1-yl (1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanone,
1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -N-methyl-1H-1,2,3-triazole-4-carboxamide,
1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxamide,
1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carbonitrile,
Ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylate,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) (pyrrolidin-1-yl) methanone,
Azetidin-1-yl (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) methanone,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) (piperidin-1-yl) methanone,
N-tert-butyl-1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxamide;
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylic acid,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxamide,
1- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) ethanone,
And 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carbonitrile, according to (1), A compound or a pharmaceutically acceptable salt thereof as an active ingredient, characterized by dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, Hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep-related complications, sleep-related movement disorders, insomnia, depression, or allergic Preventive or therapeutic agent for rhinitis,
It is.

  The compound of the present invention has an excellent histamine H3 receptor antagonistic action.

  Terms used herein are as defined below.

  In the present invention, the “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

“C ₁ -C ₆ alkyl” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec A group such as -butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl is shown.

“C ₃ -C ₇ cycloalkyl” refers to a group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

“C ₁ -C ₆ alkoxy” refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, A group such as sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy or n-hexyloxy is shown.

“C ₂ -C ₇ alkanoyl” refers to a carbonyl group to which an alkyl group having 1 to 6 carbon atoms is bonded. A group such as dimethylpentanoyl or heptanoyl is shown.

“C ₂ -C ₇ alkoxycarbonyl” refers to a carbonyl group to which a linear or branched alkoxy group having 1 to 6 carbon atoms is bonded. For example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, A group such as isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl or n-hexyloxycarbonyl is shown.

“C ₁ -C ₆ alkylsulfonyl” refers to a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, such as methylsulfonyl, n-propylsulfonyl, isobutylsulfonyl, n-hexylsulfonyl. Etc. are shown.

“3-7 membered saturated heterocyclic ring bonded to each other together with the adjacent nitrogen atom” includes the nitrogen atom and further includes one heteroatom selected from O, N, and S A saturated monocyclic or spiro ring composed of 3 to 7 ring atoms is preferable, and examples thereof include 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-azepanyl and morpholino.

Preferred embodiments of the compound of the present invention are shown below.
In a preferred embodiment of the compound of formula (I) of the present invention, ring P is formula (II).

（式中、Ｒ²は、水素原子、ヒドロキシ、シアノ、カルボキシ、Ｃ₁〜Ｃ₆アルキル、Ｃ₂〜Ｃ₇アルカノイル、Ｃ₁〜Ｃ₆アルキルスルホニル（ここで該Ｃ₁〜Ｃ₆アルキル、Ｃ₂〜Ｃ₇アルカノイル又はＣ₁〜Ｃ₆アルキルスルホニルは、ハロゲン原子、ヒドロキシ及びＣ₁〜Ｃ₆アルコキシからなる群より選ばれる１〜３個の基で置換されてもよい。）、Ｃ₁〜Ｃ₆アルコキシ、Ｃ₃〜Ｃ₇シクロアルキル、Ｃ₂〜Ｃ₇アルコキシカルボニル、（ここで、該Ｃ₁〜Ｃ₆アルコキシ、Ｃ₃〜Ｃ₇シクロアルキル又はＣ₂〜Ｃ₇アルコキシカルボニルは、ハロゲン原子、ヒドロキシ、Ｃ₁〜Ｃ₆アルキル及びＣ₁〜Ｃ₆アルコキシからなる群より選ばれる１〜３個の基で置換されてもよい。）、−（ＣＨ₂）_n−Ｃ（＝Ｏ）ＮＲ^1AＲ^1B又は−Ｓ（＝Ｏ）₂ＮＲ^2AＲ^2Bを示し、
Ｒ^1A及びＲ^1Bは、同一又は異なって、水素原子、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₇シクロアルキルを示し、
又はＲ^1A及びＲ^1Bは、隣接する窒素原子と一緒になって互いに結合した３〜７員の飽和複素環（該飽和複素環は、ハロゲン原子及びＣ₁〜Ｃ₆アルキルからなる群より選ばれる１又は２個の基で置換されてもよい。）を形成してもよく、
ｎは、０又は１を示し、
Ｒ^2A及びＲ^2Bは、同一又は異なって、水素原子、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₇シクロアルキルを示し、
又はＲ^2A及びＲ^2Bは、隣接する窒素原子と一緒になって互いに結合した３〜７員の飽和複素環（該飽和複素環は、ハロゲン原子及びＣ₁〜Ｃ₆アルキルからなる群より選ばれる１又は２個の基で置換されてもよい。）を形成してもよい、
Ｒ³は、水素原子又はＣ₁〜Ｃ₆アルキルである）。
式（ＩＩ）におけるＲ²は、好ましくは、Ｃ₁〜Ｃ₆アルキル（ここで該Ｃ₁〜Ｃ₆アルキルは、ヒドロキシ及びＣ₁〜Ｃ₆アルコキシからなる群より選ばれる１〜３個の基で置換されてもよい。）、Ｃ₁〜Ｃ₆アルコキシ、Ｃ₃〜Ｃ₇シクロアルキル（ここで、該Ｃ₁〜Ｃ₆アルコキシ又はＣ₃〜Ｃ₇シクロアルキルは、ヒドロキシ、Ｃ₁〜Ｃ₆アルキル及びＣ₁〜Ｃ₆アルコキシからなる群より選ばれる１〜３個の基で置換されてもよい。）、又は−Ｃ（＝Ｏ）ＮＲ^1AＲ^1Bであり、
Ｒ^1A及びＲ^1Bは、同一又は異なって、水素原子、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₇シクロアルキルを示し、又はＲ^1A及びＲ^1Bは、隣接する窒素原子と一緒になって互いに結合した３〜７員の飽和複素環（該飽和複素環は、ハロゲン原子及びＣ₁〜Ｃ₆アルキルからなる群より選ばれる１又は２個の基で置換されてもよい。）を形成してもよい。
式（ＩＩ）におけるＲ³は、好ましくは、水素原子である。
本発明の式（Ｉ）の化合物の好ましい１つの態様は、Ｑが式（Ａ）である。

(In the formula, R ² represents a hydrogen atom, hydroxy, cyano, carboxy, C ₁ -C ₆ alkyl, C ₂ -C ₇ alkanoyl, C ₁ -C ₆ alkylsulfonyl (wherein the C ₁ -C ₆ alkyl, C ₂ -C ₇ alkanoyl or C ₁ -C ₆ alkylsulfonyl, halogen atoms, with 1 to 3 substituents selected from the group consisting of hydroxy and C ₁ -C ₆ alkoxy may be substituted.), C ₁ ~ C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ alkoxycarbonyl, wherein the C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl or C ₂ -C ₇ alkoxycarbonyl is halogen May be substituted with 1 to 3 groups selected from the group consisting of atom, hydroxy, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy.), — (CH ₂ ) _n —C (═O) NR ^1A R ^1B or -S (= O It indicates ₂ NR ^2A R ^2B,
R ^1A and R ^1B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
Or R ^1A and R ^1B are 3 to 7-membered saturated heterocycles bonded to each other together with adjacent nitrogen atoms (the saturated heterocycle is selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyls) May be substituted with 1 or 2 groups),
n represents 0 or 1,
R ^2A and R ^2B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
Or R ^2A and R ^2B are 3 to 7-membered saturated heterocycles bonded to each other together with adjacent nitrogen atoms (the saturated heterocycle is selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyls) May be substituted with 1 or 2 groups).
R ³ is a hydrogen atom or C ₁ -C ₆ alkyl).
R ² in formula (II) is preferably C ₁ -C ₆ alkyl (wherein the C ₁ -C ₆ alkyl is selected from 1 to 3 groups selected from the group consisting of hydroxy and C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl (wherein the C ₁ -C ₆ alkoxy or C ₃ -C ₇ cycloalkyl is hydroxy, C ₁ -C 7). ₆ may be substituted with 1 to 3 groups selected from the group consisting of C ₁ -C ₆ alkoxy), or —C (═O) NR ^1A R ^1B ;
R ^1A and R ^1B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl, or R ^1A and R ^1B together with the adjacent nitrogen atom Forming a bonded 3 to 7 membered saturated heterocyclic ring (which may be substituted with one or two groups selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyl). Also good.
R ³ in formula (II) is preferably a hydrogen atom.
In one preferred embodiment of the compound of formula (I) of the present invention, Q is formula (A).

（式中、Ｒ⁴は、Ｃ₁〜Ｃ₆アルキル（該Ｃ₁〜Ｃ₆アルキルは１又は２個のＣ₃〜Ｃ₇シクロアルキルで置換されてもよい。）又はＣ₃〜Ｃ₇シクロアルキル（該Ｃ₃〜Ｃ₇シクロアルキルは１又は２個のＣ₁〜Ｃ₆アルキルで置換されてもよい。）を示す） を示す。）
式（Ａ）におけるＲ⁴は好ましくは、Ｃ₃〜Ｃ₇シクロアルキルであり、さらに好ましくは、シクロブチルである。
本発明の式（Ｉ）の化合物の好ましい１つの態様は、Ｒ¹が水素原子である。

Wherein R ⁴ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with 1 or 2 C ₃ -C ₇ cycloalkyl) or C ₃ -C ₇ cyclo. Alkyl (wherein the C ₃ -C ₇ cycloalkyl may be substituted with 1 or 2 C ₁ -C ₆ alkyl). )
R ⁴ in formula (A) is preferably C ₃ -C ₇ cycloalkyl, more preferably cyclobutyl.
In one preferred embodiment of the compound of formula (I) of the present invention, R ¹ is a hydrogen atom.

  Desirable profiles of the compounds of the present invention include excellent medicinal properties, excellent pharmacokinetics (good oral absorption and no accumulation in specific tissues), and excellent physical properties as pharmaceuticals. And low toxicity. The preferred compound of the present invention is expected to have excellent brain transportability because of its low recognition as a substrate for P-glycoprotein, which is an efflux transporter that controls drug transportability to the brain.

  In the present invention, pharmaceutically acceptable salts include, for example, salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, succinic acid, lactic acid, tartaric acid, fumaric acid , Maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandel A salt with an organic acid such as acid, galactaric acid or naphthalene-2-sulfonic acid, or one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion or aluminum ion Salt, ammonia, arginine, lysine, piperazine, choline, diethylamine, 4- E cycloalkenyl cyclohexylamine, 2-aminoethanol, salts with amines such as benzathine.

  The compounds of the present invention may also exist as various solvates. Moreover, it may be a hydrate from the viewpoint of applicability as a medicine.

  The compounds of the present invention include all forms such as enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like. The individual isomers are known methods, for example the use of optically active starting materials or intermediates, optically selective or diastereoselective reactions in the production of intermediates or final products, or intermediates or final products. It can be obtained by separation using chromatography in the production of

  The compounds of the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, sulfur atoms, halogen atoms and the like are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful in, for example, metabolism and pharmacokinetic studies, biological analysis as receptor ligands, and the like.

  A compound of the present invention, or a pharmaceutically acceptable salt thereof, can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical formulation. Examples of the carrier, excipient, and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water Various oils such as syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like are included.

  In addition, additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary are mixed with the above carriers, excipients or diluents, and tablets are prepared by conventional formulation techniques. , Pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches and the like. The compound of the present invention can be orally or parenterally administered to an adult patient in an amount of 0.001 to 500 mg once a day or divided into several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

  A medicament containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is useful as a histamine H3 receptor antagonist or inverse agonist.

  In addition, a medicament containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, Diabetes mellitus, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorders, sleep-related comorbidities, sleep-related movement disorders, insomnia, depression, or It is useful as a prophylactic or therapeutic agent for allergic rhinitis.

The compound of the present invention can be produced by a known organic chemical method. The method according to the following reaction formula is an example of the production method of the compound of the present invention, and is not limited thereto. In the following reaction formulas 1 to 4, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^1A , R ^1B and n are as defined above. X, Y ¹ , Y ² , and Y ³ are the same or different and are a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, A leaving group such as an organic sulfonyloxy group such as a trifluoromethanesulfonyloxy group or a hydroxyl group is shown.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 1 is demonstrated. This production process is a process for producing the compound (IA) of the present invention from the compound (1).
(Reaction Formula 1)

(Step 1a)
Step 1a is a step for obtaining compound (3) by condensing compound (1) and compound (2) by a coupling reaction. Compounds (1) and (2) are known compounds or can be easily synthesized from known compounds.
When Y ¹ is a leaving group such as a halogen atom or an organic sulfonyloxy group, the coupling reaction generally involves alkylation of the hydroxy group of the phenol in the presence or absence of a base in a solvent or without a solvent. It can be implemented by a conventional method. Moreover, additives, such as potassium iodide and sodium bromide, can be added as needed. Examples of the base used in this reaction include organic bases such as pyridine, triethylamine and diisopropylethylamine; alkali metal alkoxides such as tert-butoxypotassium; potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, hydroxide Examples include inorganic bases such as potassium and sodium hydride. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and 2-propanol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; hydrocarbons such as toluene and benzene. Halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; ketones such as acetone and 2-butanone; dimethyl sulfoxide Acetonitrile, water or a mixed solvent thereof. The reaction temperature in this reaction is usually 0 ° C to 200 ° C, preferably 15 ° C to 150 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 16 hours.
When Y ¹ is a hydroxyl group, the coupling reaction includes Mitsunobu reaction. For example, organophosphorus compounds such as triphenylphosphine and tributylphosphine and diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditertbutyl azodicarboxylate And a method in which it is carried out in a solvent in the presence of a reagent combined with an azo compound such as phosphine or a phosphorus ylide reagent such as cyanomethyltributylphosphorane. Examples of the solvent used in this reaction include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; Examples thereof include amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; ketones such as acetone and 2-butanone; dimethyl sulfoxide; acetonitrile or a mixed solvent thereof. The reaction temperature in this reaction is usually 0 ° C to 150 ° C, preferably 15 ° C to 100 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 16 hours.

(Step 2a)
Step 2a is a step of converting compound (3) to azide compound (4). The conversion reaction can be carried out by a general method in which the reaction is carried out in a solvent in the presence of sodium azide, a catalyst and its ligand. For example, (Liang et al., Synlett, 2005, 14, 2209-2213) It can implement according to the method of description or the method according to it. In addition, this reaction is preferably performed in the presence of a base. Examples of the catalyst used in this reaction include a copper catalyst. More specifically, copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper bromide (I ), Copper sulfate (II) and the like. Examples of the ligand used in this reaction include ligands generally used in reactions using a copper catalyst, such as N, N′-dimethylethylenediamine, N, N′-dimethylcyclohexane-1,2-diamine, and 2-aminopyridine. 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol, triphenylphosphine, tri-tert-butylphosphine and the like. It is done. Examples of the base used in this reaction include potassium carbonate, potassium phosphate, potassium hydroxide, tert-butoxy potassium, tert-butoxy sodium, cesium carbonate, sodium ascorbate, sodium carbonate, sodium hydroxide, sodium bicarbonate, Examples include sodium acetate, sodium methoxide, tetrabutylammonium hydroxide and the like. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and 2-propanol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; hydrocarbons such as toluene and benzene. Halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; ketones such as acetone and 2-butanone; dimethyl sulfoxide Acetonitrile, water or a mixed solvent thereof. The reaction temperature in this reaction is usually 0 ° C to 200 ° C, preferably 40 ° C to 150 ° C, and the reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 6 hours.

(Step 3a)
Step 3a is a step for producing the compound (IA) of the present invention by a cycloaddition reaction between the compound (4) and the compound (5). Compound (5) is a known compound or a compound that can be easily synthesized from a known compound. The reaction can be carried out by a general method for carrying out the reaction in a solvent or without a solvent. For example, it can be carried out according to the method described in (Synthesis, 2011, pp. 223-228) or a method analogous thereto. Moreover, this reaction can be performed in presence of a catalyst, a ligand, and a base. Examples of the catalyst used in this reaction include a copper catalyst. More specifically, copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper bromide (I ), Copper sulfate (II) and the like. Examples of the ligand used in this reaction include ligands generally used in reactions using a copper catalyst, such as N, N′-dimethylethylenediamine, N, N′-dimethylcyclohexane-1,2-diamine, and 2-aminopyridine. 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol, triphenylphosphine, tri-tert-butylphosphine and the like. It is done. Examples of the base used in this reaction include potassium carbonate, potassium phosphate, potassium hydroxide, tert-butoxy potassium, tert-butoxy sodium, cesium carbonate, sodium ascorbate, sodium carbonate, sodium hydroxide, sodium bicarbonate, Examples include sodium acetate, sodium methoxide, tetrabutylammonium hydroxide and the like. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and 2-propanol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; hydrocarbons such as toluene and benzene. Halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; ketones such as acetone and 2-butanone; dimethyl sulfoxide Acetonitrile, water or a mixed solvent thereof. The reaction temperature in this reaction is usually 0 ° C to 200 ° C, preferably 40 ° C to 150 ° C, and the reaction time is usually 30 minutes to 48 hours, preferably 30 minutes to 6 hours.

Compound (IA-2) can be produced from compound (IA-1) of the present invention according to the method shown in Reaction Scheme 2.
(Reaction Formula 2)

(Step 4a)
Step 4a is a step for obtaining the compound (6) of the present invention in which R ² = carboxy group by converting the ethoxycarbonyl group of the compound (IA-1) of the present invention into a carboxylic acid by hydrolysis. The hydrolysis reaction can be carried out by a general ester hydrolysis reaction, for example, a method of reacting in the presence or absence of a strong acid in a solvent, a method of reacting in a solvent in the presence of a base, etc. (T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4th edition, John Wiley and Sons) or a method analogous thereto. The reaction temperature in this reaction is usually 0 ° C to 120 ° C, preferably 15 ° C to 80 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Step 5a)
Step 5a is a step for condensing the carboxylic acid compound (6) and the amine compound (7) by a coupling reaction to obtain the compound (IA-2) of the present invention. Compound (7) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be performed by a general method of amidation of a carboxylic acid. For example, a method in which a carboxylic acid is led to a carboxylic acid halide such as carboxylic acid chloride or carboxylic acid bromide and then reacted with an amine, A method of reacting a mixed acid anhydride obtained from chlorocarbonate or the like with an amine, a method of reacting an carboxylic acid with an amine after being led to an active ester such as 1-benzotriazolyl ester or succinimidyl ester, and dehydrating a carboxylic acid Examples thereof include a method of reacting with an amine in the presence of a condensing agent. These reactions can all be performed in a solvent in the presence or absence of a base. Examples of the dehydrating condensing agent used in this reaction include 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, diphenylphosphoryl azide, carbonyldiimidazole and the like. -Activators such as hydroxybenzotriazole and hydroxysuccinimide can be used. Examples of the base used in this reaction include pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. Examples of the solvent used in this reaction include ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof. Among these, toluene, Tetrahydrofuran or N, N-dimethylformamide is preferred. The reaction temperature in this reaction is usually 0 ° C to 120 ° C, preferably 15 ° C to 40 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Step 6a)
Step 6a is a step for obtaining compound (IA-2) by an ester-amide exchange reaction between compound (IA-1) of the present invention and amine compound (7). All of these reactions can be carried out in the presence or absence of a base, without solvent, or in a solvent. Moreover, additives, such as aluminum chloride and sodium methoxide, can be added as needed. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and 2-propanol, ethers such as tetrahydrofuran and 1,4-dioxane, hydrocarbons such as toluene and benzene, and halogens such as chloroform and dichloromethane. Hydrocarbons; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or these A mixed solvent is mentioned, Of these, toluene, tetrahydrofuran or N, N-dimethylformamide is preferable. The reaction temperature in this reaction is usually 0 ° C to 120 ° C, preferably 40 ° C to 120 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

Hereinafter, the manufacturing method of the compound of this invention shown by Reaction formula 3 is demonstrated. This production process is a process for producing the compound (IB) of the present invention from the compound (1).
(Reaction Formula 3)

(Step 1b)
Step 1b is a step for obtaining compound (9) by a coupling reaction between compound (1) and compound (8). Compound (8) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be carried out by the same method as in step 1a.

(Step 2b)
Step 2b is a step for obtaining compound (10) from compound (9). This reaction can be carried out by the same method as in Step 2a.

(Step 3b)
Step 3b is a step for obtaining compound (IB) by cycloaddition reaction between compound (10) and compound (5). This reaction can be carried out by the same method as in Step 3a.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 4 is demonstrated. This production process is a process for producing the compound (IB-2) of the present invention from the compound (1B-1).
(Reaction Formula 4)

(Step 4b)
Step 4b is a step for obtaining the compound (11) of the present invention in which R ² = carboxy group by converting the ethoxycarbonyl group of the compound (IB-1) to carboxylic acid by hydrolysis. This reaction can be carried out by the same method as in Step 4a.

(Step 5b)
Step 5b is a step for condensing the carboxylic acid compound (11) and the amine compound (7) by a coupling reaction to obtain the compound (IB-2) of the present invention. This reaction can be carried out by the same method as in Step 5a.

(Step 6b)
Step 6b is a step for obtaining compound (IB-2) by an ester-amide exchange reaction between compound (IB-1) of the present invention and amine compound (7). This reaction can be carried out in the same manner as in Step 6a.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 5 is demonstrated. This production process is a process for producing the compound (IC) of the present invention from the compound (12).
(Reaction Formula 5)

Step 7 is a step for obtaining compound (14) from compound (12) and compound (13). Compounds (12) and (13) are known compounds or compounds that can be easily synthesized from known compounds. The reaction can be carried out by a general aromatic nucleophilic substitution reaction, for example, according to the method described in (Journal of Medicinal Chemistry, 2008, 51, 6889) or a method analogous thereto. Examples of the conditions used in this reaction include a method of reacting in a solvent or without a solvent in the presence or absence of a base. Examples of the base used include organic bases such as pyridine, triethylamine and diisopropylethylamine; alkali metal alkoxides such as tert-butoxypotassium; potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, hydrogen And inorganic bases such as sodium hydride. Examples of the solvent used in this reaction include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof . The reaction temperature in this reaction is usually 0 ° C to 200 ° C, preferably 15 ° C to 150 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 16 hours.

  Step 8 is a step of obtaining compound (15) from compound (14). The reaction can be carried out by reacting compound (14) in a solvent under the conditions of the reduction reaction. For example, the method described in (Journal of American Chemical Society, 1944, 66, 1442) or a method analogous thereto. It can be carried out according to the method. The conditions for the reduction reaction used in this reaction include, for example, a method in which a catalyst such as Raney nickel or palladium carbon is added and reacted in a hydrogen atmosphere at normal pressure or under pressure, lithium aluminum hydride, sodium borohydride and the like. Examples include a method of reacting with a metal hydride complex, a method of reacting with iron (0), zinc chloride (II) or tin (II) in the presence of an acid such as acetic acid or ammonium chloride, or a combination of these conditions. . Examples of the solvent used in this reaction include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; hydrocarbons such as toluene and benzene; chloroform and dichloromethane. Halogenated hydrocarbons such as N, N-dimethylformamide, N, N-dimethylacetamide, amides such as N-methyl-2-pyrrolidone, ketones such as acetone and 2-butanone, dimethyl sulfoxide, acetonitrile or the like The mixed solvent is mentioned. The reaction temperature in this reaction is usually 0 ° C to 200 ° C, preferably 15 ° C to 150 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 16 hours.

Step 9 is a step for obtaining compound (16) from compound (15). The reaction can be carried out by a general diazotization reaction, for example, by the method described in (Journal of Organic Chemistry, 2005, 70, 1050) or a method analogous thereto. The conditions used in this reaction include a method in which a compound (15) is reacted with a nitrite such as sodium nitrite or a nitrite such as isoamyl nitrite in the presence of an acid in a solvent or without a solvent. It is done. Examples of the acid used include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and Lewis acids such as boron trifluoride, trimethylaluminum, and aluminum chloride. Examples of the solvent used in this reaction include water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; hydrocarbons such as toluene and benzene; chloroform. Halogenated hydrocarbons such as dichloromethane, or a mixed solvent thereof. The reaction temperature in this reaction is usually −10 ° C. to 200 ° C., preferably −10 ° C. to 50 ° C., and the reaction time is usually 15 minutes to 48 hours, preferably 15 minutes to 5 hours.

Step 10 is a step for obtaining compound (IC) from compound (16). This reaction can be carried out by a cyclization reaction between the diazo compound (16) and the isonitrile compound (17). Examples of the conditions used in this reaction include a reaction carried out in the presence or absence of a base, in a solvent, or without a solvent. Examples of the base to be used include organic bases such as pyridine, triethylamine and diisopropylethylamine; alkali metal alkoxides such as tert-butoxy potassium; sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide And inorganic bases such as potassium hydroxide. Examples of the solvent used in this reaction include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof . The reaction temperature in this reaction is usually 0 ° C to 200 ° C, preferably 15 ° C to 150 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 16 hours.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 6 is demonstrated. This production process is a process for producing the compound (IC-1) of the present invention from the compound (1C).
(Reaction Formula 6)

(Step 11)
Step 11 is a step for obtaining the compound (18) of the present invention by converting the ethoxycarbonyl group of the compound (IC) into a carboxylic acid by hydrolysis. This reaction can be carried out by the same method as in Step 4a.

(Step 12)
Step 5b is a step for condensing the carboxylic acid compound (18) and the amine compound (7) by a coupling reaction to obtain the compound (IC-1) of the present invention. This reaction can be carried out by the same method as in Step 5a.

(Step 13)
Step 13 is a step for obtaining compound (IC-1) by ester-amide exchange reaction between compound (IC) of the present invention and amine compound (7). This reaction can be carried out in the same manner as in Step 6a.

EXAMPLES Examples and test examples are shown below to specifically describe the present invention, but the present invention is not limited to these.
Each instrument data described in the examples was measured with the following measuring instruments.
MS spectrum: micromass Platform LC or micromass GCT
NMR spectrum: [ ¹ H-NMR] 600 MHz: JNM-ECA600 (JEOL)

Example 1
Preparation of ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate (Compound No. 1)

１−シクロブチル−４−（４−ヨードフェノキシ）ピペリジン（１．０ ｇ、ＷＯ２００８０７２７０３に記載の方法に従って合成できる）、アジ化ナトリウム（０．３２ ｇ）、Ｎ，Ｎ’−ジメチルエチレンジアミン（０．０４９ ｇ）、ヨウ化銅（０．０５３ ｇ）、アスコルビン酸ナトリウム（０．０２７ ｇ）、エタノール（９．０ ｍL）及び水（１．０ ｍＬ）の混合液を７０℃にて２時間攪拌した。反応混合物を室温まで放冷し、水を加え、クロロホルムにて抽出した。有機層を減圧下濃縮した。アジド化合物を主成分とする混合物を得た（０．８３ ｇ）。
MS (ESI pos.) m/z : 273 [M+H]⁺
残渣（０．８０ ｇ）、プロピオール酸エチル（５７６ ｍｇ）、ヨウ化銅（５５．９ ｍｇ）、アスコルビン酸ナトリウム（１１６ ｍｇ）のトルエン（５．０ ｍL）懸濁液を封管中７０℃にて撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨ型シリカゲル、展開溶媒：ｎ−ヘキサン／酢酸エチル＝８０／２０〜２０／８０）にて精製し、無色固体の表題化合物（０．２７１ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.44 (t, J=7.22 Hz, 3 H) 1.64 - 1.77 (m, 2 H) 1.80 - 1.95 (m, 4 H) 1.98 - 2.09 (m, 4 H) 2.12 - 2.26 (m, 2 H) 2.63 (br. s., 2 H) 2.75 (t, J=7.64 Hz, 1 H) 4.39 (br. s., 1 H) 4.47 (q, J=7.16 Hz, 2 H) 7.01 - 7.06 (m, 2 H) 7.60 - 7.65 (m, 2 H) 8.41 (s, 1 H); MS (ESI pos.) m/z : 371 [M+H]⁺

1-cyclobutyl-4- (4-iodophenoxy) piperidine (1.0 g, which can be synthesized according to the method described in WO2008077033), sodium azide (0.32 g), N, N′-dimethylethylenediamine (0.049 g), a mixture of copper iodide (0.053 g), sodium ascorbate (0.027 g), ethanol (9.0 mL) and water (1.0 mL) was stirred at 70 ° C. for 2 hours. . The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. A mixture mainly containing an azide compound was obtained (0.83 g).
MS (ESI pos.) M / z: 273 [M + H] ⁺
A toluene (5.0 mL) suspension of the residue (0.80 g), ethyl propiolate (576 mg), copper iodide (55.9 mg), and sodium ascorbate (116 mg) was placed in a sealed tube at 70 ° C. Was stirred at. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH type silica gel, developing solvent: n-hexane / ethyl acetate = 80/20 to 20/80) to obtain the title compound (0.271 g) as a colorless solid. .
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.44 (t, J = 7.22 Hz, 3 H) 1.64-1.77 (m, 2 H) 1.80-1.95 (m, 4 H) 1.98-2.09 (m, 4 H ) 2.12-2.26 (m, 2 H) 2.63 (br. S., 2 H) 2.75 (t, J = 7.64 Hz, 1 H) 4.39 (br. S., 1 H) 4.47 (q, J = 7.16 Hz , 2 H) 7.01-7.06 (m, 2 H) 7.60-7.65 (m, 2 H) 8.41 (s, 1 H); MS (ESI pos.) M / z: 371 [M + H] ⁺

  The compounds shown in Table 1 below (Compound Nos. 2 to 7) were produced in the same manner as shown in Example 1.

(Example 2)
(1- {4-[(1-Cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (pyrrolidin-1-yl) methanone (Compound No. 8) Manufacturing of

実施例１で合成したエチル １−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキシラート（０．０７０ｇ）及びピロリジン（２．０ ｍL）の混合物を封管中９０℃にて５時間撹拌した。反応混合物を室温まで放冷し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸ナトリウムにて乾燥後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨ型シリカゲル、展開溶媒：ｎ−ヘキサン／酢酸エチル＝８０／２０〜０／１００）にて精製し、無色固体の表題化合物（０．０２２ ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.64 - 1.77 (m, 2 H) 1.80 - 1.98 (m, 6 H) 1.98 - 2.10 (m, 6 H) 2.19 (br. s., 2 H) 2.64 (br. s., 2 H) 2.75 (d, J=7.84 Hz, 1 H) 3.70 (t, J=7.02 Hz, 2 H) 4.18 (t, J=6.81 Hz, 2 H) 4.39 (br. s., 1 H) 7.00 - 7.06 (m, 2 H) 7.59 - 7.66 (m, 2 H) 8.45 (s, 1 H); MS (ESI pos.) m/z : 396 [M+H]⁺

Ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate (0.070 g) and pyrrolidine synthesized in Example 1 (2.0 mL) of the mixture was stirred in a sealed tube at 90 ° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH type silica gel, developing solvent: n-hexane / ethyl acetate = 80/20 to 0/100) to obtain the title compound (0.022 g) as a colorless solid. It was.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.64-1.77 (m, 2 H) 1.80-1.98 (m, 6 H) 1.98-2.10 (m, 6 H) 2.19 (br. S., 2 H) 2.64 (br. s., 2 H) 2.75 (d, J = 7.84 Hz, 1 H) 3.70 (t, J = 7.02 Hz, 2 H) 4.18 (t, J = 6.81 Hz, 2 H) 4.39 (br. s ., 1 H) 7.00-7.06 (m, 2 H) 7.59-7.66 (m, 2 H) 8.45 (s, 1 H); MS (ESI pos.) M / z: 396 [M + H] ⁺

  The following compounds shown in Table 2-1 and Table 2-2 (Compound Nos. 9 to 16) were produced in the same manner as in Example 2.

Example 3
Preparation of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylic acid hydrochloride (Compound No. 17)

実施例１で製造したエチル １−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキシラート（０．２７ ｇ）と濃塩酸（１．０ ｍL）の混合液を１００℃にて５時間撹拌した。反応混合物を減圧下濃縮後、残渣にテトラヒドロフラン（１．０ ｍL）を加え０℃にて撹拌後、析出物をろ取し、無色固体の標題化合物を（０．２７ ｇ）得た。
1H NMR (600 MHz, DMSO-d₆) δ ppm 1.62 - 1.83 (m, 2 H) 1.87 - 2.00 (m, 1 H) 2.02 - 2.11 (m, 1 H) 2.12 - 2.22 (m, 3 H) 2.26 (d, J=13.21 Hz, 1 H) 2.30 - 2.42 (m, 2 H) 2.80 - 3.01 (m, 2 H) 3.19 - 3.28 (m, 1 H) 3.56 - 3.67 (m, 1 H) 3.69 - 3.80 (m, 1 H) 4.62 - 4.92 (m, 1 H) 7.17 - 7.28 (m, 2 H) 7.82 - 7.97 (m, 2 H) 9.30 (s, 1 H) 10.85 (br. s., 1 H) 13.29 (br. s., 1 H); MS (ESI pos.) m/z : 343 [M+H]⁺

Ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate (0.27 g) prepared in Example 1 A mixture of concentrated hydrochloric acid (1.0 mL) was stirred at 100 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, tetrahydrofuran (1.0 mL) was added to the residue, and the mixture was stirred at 0 ° C. The precipitate was collected by filtration to give the title compound as a colorless solid (0.27 g).
1H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.62-1.83 (m, 2 H) 1.87-2.00 (m, 1 H) 2.02-2.11 (m, 1 H) 2.12-2.22 (m, 3 H) 2.26 (d, J = 13.21 Hz, 1 H) 2.30-2.42 (m, 2 H) 2.80-3.01 (m, 2 H) 3.19-3.28 (m, 1 H) 3.56-3.67 (m, 1 H) 3.69-3.80 (m, 1 H) 4.62-4.92 (m, 1 H) 7.17-7.28 (m, 2 H) 7.82-7.97 (m, 2 H) 9.30 (s, 1 H) 10.85 (br. s., 1 H) 13.29 (br. S., 1 H); MS (ESI pos.) M / z: 343 [M + H] ⁺

Example 4
Preparation of azetidin-1-yl (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanone (Compound No. 18)

実施例３で製造した１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボン酸（０．１０ ｇ）、アゼチジン塩酸塩（０．０３７ ｇ）、１−｛３−（ジメチルアミノ）プロピル｝−３−エチルカルボジイミド塩酸塩（０．０７６ｇ）、１−ヒドロキシベンゾトリアゾール水和物（０．０６１ｇ）及びトリエチルアミン（０．１１ ｍL）をＮ，Ｎ−ジメチルホルムアミド（１．０ ｍL）に加えて懸濁液とし、室温にて１６時間撹拌した。反応混合物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。有機層を硫酸ナトリウムにて乾燥後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム／メタノール＝１００／０〜９５／５）にて精製した。得られた固体をジイソプロピルエーテルにて洗浄し、表題化合物（０．０５８ ｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.64 - 1.77 (m, 2 H) 1.88 (d, J=9.50 Hz, 4 H) 1.96 - 2.26 (m, 6 H) 2.39 - 2.47 (m, 2 H) 2.64 (br. s., 2 H) 2.75 (br. s., 1 H) 4.22 - 4.29 (m, 2 H) 4.39 (br. s., 1 H) 4.80 (t, J=7.64 Hz, 2 H) 7.00 - 7.05 (m, 2 H) 7.62 (d, J=9.08 Hz, 2 H) 8.42 (s, 1 H); MS (ESI pos.) m/z : 382 [M+H]⁺

1- {4-[(1-Cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylic acid (0.10 g), azetidine, prepared in Example 3 Hydrochloride (0.037 g), 1- {3- (dimethylamino) propyl} -3-ethylcarbodiimide hydrochloride (0.076 g), 1-hydroxybenzotriazole hydrate (0.061 g) and triethylamine (0 .11 mL) was added to N, N-dimethylformamide (1.0 mL) to form a suspension and stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 100/0 to 95/5). The obtained solid was washed with diisopropyl ether to give the title compound (0.058 g) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.64-1.77 (m, 2 H) 1.88 (d, J = 9.50 Hz, 4 H) 1.96-2.26 (m, 6 H) 2.39-2.47 (m, 2 H ) 2.64 (br. S., 2 H) 2.75 (br. S., 1 H) 4.22-4.29 (m, 2 H) 4.39 (br. S., 1 H) 4.80 (t, J = 7.64 Hz, 2 H) 7.00-7.05 (m, 2 H) 7.62 (d, J = 9.08 Hz, 2 H) 8.42 (s, 1 H); MS (ESI pos.) M / z: 382 [M + H] ⁺

(Example 5)
Preparation of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N-methyl-1H-1,2,3-triazole-4-carboxamide (Compound No. 19)

実施例４と同様の手法により、アゼチジン塩酸塩の代わりにメチルアミン塩酸塩を用いて無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.62 - 1.78 (m, 2 H) 1.81 - 1.94 (m, 4 H) 1.99 - 2.10 (m, 4 H) 2.12 - 2.24 (m, 2 H) 2.58 - 2.69 (m, 2 H) 2.70 - 2.80 (m, 1 H) 3.05 (d, J=5.37 Hz, 3 H) 4.39 (br. s., 1 H) 7.02 - 7.06 (m, 2 H) 7.18 (br. s., 1 H) 7.61 (d, J=9.08 Hz, 2 H) 8.39 (s, 1 H); MS (ESI pos.) m/z : 356 [M+H]⁺

In the same manner as in Example 4, methylamine hydrochloride was used in place of azetidine hydrochloride to give the title compound as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.62-1.78 (m, 2 H) 1.81-1.94 (m, 4 H) 1.99-2.10 (m, 4 H) 2.12-2.24 (m, 2 H) 2.58- 2.69 (m, 2 H) 2.70-2.80 (m, 1 H) 3.05 (d, J = 5.37 Hz, 3 H) 4.39 (br. S., 1 H) 7.02-7.06 (m, 2 H) 7.18 (br s., 1 H) 7.61 (d, J = 9.08 Hz, 2 H) 8.39 (s, 1 H); MS (ESI pos.) m / z: 356 [M + H] ⁺

(Example 6)
Preparation of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxamide (Compound No. 20)

実施例４と同様の手法により、アゼチジン塩酸塩の代わりにアンモニア水を用いて無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.62 - 2.27 (m, 12 H) 2.56 - 2.82 (m, 3 H) 4.40 (br. s., 1 H) 5.60 (br. s., 1 H) 7.00 - 7.12 (m, 3 H) 7.59 - 7.65 (m, 2 H) 8.42 (s, 1 H); MS (ESI pos.) m/z : 342 [M+H]⁺

In the same manner as in Example 4, a colorless solid title compound was obtained using ammonia water instead of azetidine hydrochloride.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.62-2.27 (m, 12 H) 2.56-2.82 (m, 3 H) 4.40 (br. S., 1 H) 5.60 (br. S., 1 H) 7.00-7.12 (m, 3 H) 7.59-7.65 (m, 2 H) 8.42 (s, 1 H); MS (ESI pos.) M / z: 342 [M + H] ⁺

(Example 7)
Preparation of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carbonitrile hydrochloride (Compound No. 21)

実施例６で製造した１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキサミド（０．１ ｇ）をＮ，Ｎ−ジメチルホルムアミド（１．０ ｍL）に加えて溶液とし、氷冷下塩化チオニル（０．３４８ ｇ）を滴下し、室温まで昇温しながら３時間撹拌した。反応混合物に水及びエタノールを加え、析出した結晶を濾取した。得られた粗結晶をエタノールから再結晶して無色結晶の表題化合物（０．０６０ ｇ）を得た。
1H NMR (600 MHz, DMSO-d₆) δ ppm 1.63 - 1.82 (m, 2 H) 1.82 - 1.95 (m, 1 H) 2.04 - 2.14 (m, 2 H) 2.14 - 2.23 (m, 2 H) 2.23 - 2.36 (m, 2 H) 2.82 - 3.02 (m, 2 H) 3.19 - 3.49 (m, 2 H) 3.58 - 3.81 (m, 1 H) 4.64 - 4.94 (m, 1 H) 7.21 - 7.32 (m, 2 H) 7.78 - 7.91 (m, 2 H) 9.65 (s, 1 H) 10.42 (br. s., 1 H); MS (ESI pos.) m/z : 324 [M+H]⁺

1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxamide (0.1 g) prepared in Example 6 was replaced with N, A solution was added to N-dimethylformamide (1.0 mL), thionyl chloride (0.348 g) was added dropwise under ice cooling, and the mixture was stirred for 3 hours while warming to room temperature. Water and ethanol were added to the reaction mixture, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from ethanol to obtain colorless crystals of the title compound (0.060 g).
1H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.63-1.82 (m, 2 H) 1.82-1.95 (m, 1 H) 2.04-2.14 (m, 2 H) 2.14-2.23 (m, 2 H) 2.23 -2.36 (m, 2 H) 2.82-3.02 (m, 2 H) 3.19-3.49 (m, 2 H) 3.58-3.81 (m, 1 H) 4.64-4.94 (m, 1 H) 7.21-7.32 (m, 2 H) 7.78-7.91 (m, 2 H) 9.65 (s, 1 H) 10.42 (br. S., 1 H); MS (ESI pos.) M / z: 324 [M + H] ⁺

(Example 8)
Production of (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanol (Compound No. 22)

実施例１と同様の方法でプロピオール酸エチルの代わりに2-プロピン-1-オールを用いて無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.44 - 2.27 (m, 12 H) 2.61 (d, J=12.39 Hz, 2 H) 2.71 - 2.83 (m, 1 H) 4.30 - 4.43 (m, 1 H) 4.87 (d, J=6.19 Hz, 2 H) 6.93 - 7.05 (m, 2 H) 7.48 - 7.64 (m, 2 H) 7.87 (s, 1 H); MS (ESI pos.) m/z : 329 [M+H]+

In the same manner as in Example 1, 2-propyn-1-ol was used in place of ethyl propiolate to obtain the title compound as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.44-2.27 (m, 12 H) 2.61 (d, J = 12.39 Hz, 2 H) 2.71-2.83 (m, 1 H) 4.30-4.43 (m, 1 H ) 4.87 (d, J = 6.19 Hz, 2 H) 6.93-7.05 (m, 2 H) 7.48-7.64 (m, 2 H) 7.87 (s, 1 H); MS (ESI pos.) M / z: 329 [M + H] +

Example 9
Preparation of 1-cyclobutyl-4- [4- (1H-1,2,3-triazol-1-yl) phenoxy] piperidine (Compound No. 23)

１−シクロブチル−４−（４−ヨードフェノキシ）ピペリジン（０．１ ｇ、ＷＯ２００８０７２７０３に記載の方法に従って合成できる）、アジ化ナトリウム（０．０３３ ｇ）、Ｎ，Ｎ’−ジメチルエチレンジアミン（４．９ ｍｇ）、ヨウ化銅（５．３ ｍｇ）、アスコルビン酸ナトリウム（２．３ ｍｇ）、エタノール（０．９ ｍＬ）及び水（０．１ ｍＬ）の混合液を７０℃にて２時間攪拌した。反応混合物を室温まで放冷し、炭酸カリウム（５８ ｍｇ）、エチニルトリメチルシラン（３３ ｍｇ）を加え、７０℃にて４時間攪拌した。反応混合物を室温まで放冷し、アンモニア水を加え酢酸エチルにて抽出後、得られた有機層をアンモニア水、飽和食塩水にて順次洗浄した。有機層を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨ型シリカゲル、展開溶媒：クロロホルム）にて精製した。得られた固体をジイソプロピルエーテルにて洗浄し、表題化合物（０．０５０ ｇ）を無色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.46 - 2.41 (m, 11 H) 2.53 - 2.91 (m, 4 H) 4.30 - 4.51 (m, 1 H) 7.00 - 7.05 (m, 2 H) 7.62 (d, J=9.08 Hz, 2 H) 7.83 (d, J=0.83 Hz, 1 H) 7.90 (d, J=0.83 Hz, 1 H); MS (ESI pos.) m/z : 299 [M+H]+

1-cyclobutyl-4- (4-iodophenoxy) piperidine (0.1 g, which can be synthesized according to the method described in WO2008077033), sodium azide (0.033 g), N, N′-dimethylethylenediamine (4.9 mg), copper iodide (5.3 mg), sodium ascorbate (2.3 mg), ethanol (0.9 mL) and water (0.1 mL) were stirred at 70 ° C. for 2 hours. . The reaction mixture was allowed to cool to room temperature, potassium carbonate (58 mg) and ethynyltrimethylsilane (33 mg) were added, and the mixture was stirred at 70 ° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, aqueous ammonia was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with aqueous ammonia and saturated brine. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH type silica gel, developing solvent: chloroform). The obtained solid was washed with diisopropyl ether to give the title compound (0.050 g) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.46-2.41 (m, 11 H) 2.53-2.91 (m, 4 H) 4.30-4.51 (m, 1 H) 7.00-7.05 (m, 2 H) 7.62 ( d, J = 9.08 Hz, 2 H) 7.83 (d, J = 0.83 Hz, 1 H) 7.90 (d, J = 0.83 Hz, 1 H); MS (ESI pos.) m / z: 299 (M + H ] +

(Example 10)
Preparation of ethyl 1- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1H-1,2,3-triazole-4-carboxylate (Compound No. 24)

実施例１と同様の手法により、１−シクロブチル−４−（４−ヨードフェノキシ）ピペリジンの代わりに、（２Ｒ）−１−［３−（４−ヨードフェノキシ）プロピル］−２−メチルピロリジン（ＷＯ２００９０６３９５３に記載の方法に従って合成できる）を用いて、黄色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.91 - 1.02 (m, 3 H) 1.25 - 1.37 (m, 4 H) 1.52 - 2.24 (m, 8 H) 2.87 (dt, J=11.97, 8.05 Hz, 1 H) 3.06 (td, J=8.46, 2.48 Hz, 1 H) 3.91 - 4.06 (m, 2 H) 4.35 (q, J=7.02 Hz, 2 H) 6.86 - 6.96 (m, 2 H) 7.45 - 7.57 (m, 2 H) 8.29 (s, 1 H); MS (ESI pos.) m/z : 359 [M+H]+

In the same manner as in Example 1, instead of 1-cyclobutyl-4- (4-iodophenoxy) piperidine, (2R) -1- [3- (4-iodophenoxy) propyl] -2-methylpyrrolidine (WO20099063953) was used. To give the title compound as a yellow solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.91-1.02 (m, 3 H) 1.25-1.37 (m, 4 H) 1.52-2.24 (m, 8 H) 2.87 (dt, J = 11.97, 8.05 Hz, 1 H) 3.06 (td, J = 8.46, 2.48 Hz, 1 H) 3.91-4.06 (m, 2 H) 4.35 (q, J = 7.02 Hz, 2 H) 6.86-6.96 (m, 2 H) 7.45-7.57 (m, 2 H) 8.29 (s, 1 H); MS (ESI pos.) m / z: 359 [M + H] +

(Example 11)
(1- {4-[(1-Cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (morpholin-4-yl) methanone (Compound No. 25) Manufacturing of

実施例４と同様の手法により、アゼチジン塩酸塩の代わりにモルホリンを用いて無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.57 - 2.32 (m, 12 H) 2.58 - 2.83 (m, 3 H) 3.77 - 3.86 (m, 6 H) 4.35 - 4.46 (m, 3 H) 7.01 - 7.07 (m, 2 H) 7.60 - 7.65 (m, 2 H) 8.43 (s, 1 H); MS (ESI pos.) m/z : 412 [M+H]+

In the same manner as in Example 4, the title compound was obtained as a colorless solid using morpholine instead of azetidine hydrochloride.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.57-2.32 (m, 12 H) 2.58-2.83 (m, 3 H) 3.77-3.86 (m, 6 H) 4.35-4.46 (m, 3 H) 7.01- 7.07 (m, 2 H) 7.60-7.65 (m, 2 H) 8.43 (s, 1 H); MS (ESI pos.) M / z: 412 [M + H] +

(Example 12)
Preparation of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N, N-dimethyl-1H-1,2,3-triazole-4-carboxamide (Compound No. 26)

実施例４と同様の手法により、アゼチジン塩酸塩の代わりにジメチルアミン（２．０Ｍ ＴＨＦ溶液）を用いて無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.63 - 2.29 (m, 12 H) 2.57 - 2.80 (m, 3 H) 3.16 (s, 3 H) 3.60 (s, 3 H) 4.34 - 4.43 (m, 1 H) 7.01 - 7.05 (m, 2 H) 7.63 (d, J=9.08 Hz, 2 H) 8.41 (s, 1 H); MS (ESI pos.) m/z : 370 [M+H]+

In the same manner as in Example 4, the title compound was obtained as a colorless solid using dimethylamine (2.0 M THF solution) instead of azetidine hydrochloride.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.63-2.29 (m, 12 H) 2.57-2.80 (m, 3 H) 3.16 (s, 3 H) 3.60 (s, 3 H) 4.34-4.43 (m, 1 H) 7.01-7.05 (m, 2 H) 7.63 (d, J = 9.08 Hz, 2 H) 8.41 (s, 1 H); MS (ESI pos.) M / z: 370 [M + H] +

(Example 13)
Preparation of ethyl 1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate (Compound No. 27)

実施例１と同様の手法により、１−シクロブチル−４−（４−ヨードフェノキシ）ピペリジンの代わりに、１−（ｔｅｒｔ−ブチル）−４−（４−ヨードフェノキシ）ピペリジン（ＷＯ２００８０７２７２４に記載の方法に従って合成できる）を用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.03 - 1.19 (m, 9 H) 1.45 (t, J=7.22 Hz, 3 H) 1.86 (br. s., 2 H) 2.06 (d, J=6.61 Hz, 2 H) 2.46 (br. s., 2 H) 2.90 (br. s., 2 H) 4.37 (br. s., 1 H) 4.48 (q, J=7.16 Hz, 2 H) 6.95 - 7.11 (m, 2 H) 7.55 - 7.69 (m, 2 H) 8.42 (s, 1 H); MS (ESI pos.) m/z : 373 [M+H]+

In the same manner as in Example 1, instead of 1-cyclobutyl-4- (4-iodophenoxy) piperidine, 1- (tert-butyl) -4- (4-iodophenoxy) piperidine (in accordance with the method described in WO20080772724) was used. The title compound was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.03-1.19 (m, 9 H) 1.45 (t, J = 7.22 Hz, 3 H) 1.86 (br. S., 2 H) 2.06 (d, J = 6.61 Hz, 2 H) 2.46 (br. S., 2 H) 2.90 (br. S., 2 H) 4.37 (br. S., 1 H) 4.48 (q, J = 7.16 Hz, 2 H) 6.95-7.11 (m, 2 H) 7.55-7.69 (m, 2 H) 8.42 (s, 1 H); MS (ESI pos.) m / z: 373 [M + H] +

(Example 14)
(1- {4-[(1-tert-Butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (pyrrolidin-1-yl) methanone (Compound No. 28 )Manufacturing of

実施例２と同様の手法により、エチル １−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキシラートの代わりに、実施例１３で製造したエチル １−［４−（１−ｔｅｒｔ−ブチルピペリジン−４−イル）オキシフェニル］トリアゾール−４−カルボキシラートを用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, DMSO-d6) d ppm 1.00 (s, 9 H) 1.49 - 1.63 (m, 2 H) 1.75 - 1.84 (m, 2 H) 1.87 - 1.98 (m, 4 H) 2.25 - 2.34 (m, 2 H) 2.76 - 2.84 (m, 2 H) 3.46 - 3.51 (m, 2 H) 3.87 - 3.92 (m, 2 H) 4.33 - 4.44 (m, 1 H) 7.11 (d, J=9.08 Hz, 2 H) 7.81 (d, J=9.08 Hz, 2 H) 9.11 (s, 1 H); MS (ESI pos.) m/z : 398 [M+H]+

In the same manner as in Example 2, instead of ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate, Using the ethyl 1- [4- (1-tert-butylpiperidin-4-yl) oxyphenyl] triazole-4-carboxylate prepared in Example 13, the title compound was obtained as a colorless solid.
1H NMR (600 MHz, DMSO-d6) d ppm 1.00 (s, 9 H) 1.49-1.63 (m, 2 H) 1.75-1.84 (m, 2 H) 1.87-1.98 (m, 4 H) 2.25-2.34 ( m, 2 H) 2.76-2.84 (m, 2 H) 3.46-3.51 (m, 2 H) 3.87-3.92 (m, 2 H) 4.33-4.44 (m, 1 H) 7.11 (d, J = 9.08 Hz, 2 H) 7.81 (d, J = 9.08 Hz, 2 H) 9.11 (s, 1 H); MS (ESI pos.) M / z: 398 [M + H] +

(Example 15)
Of azetidin-1-yl (1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanone (Compound No. 29) Manufacturing

実施例１４と同様の手法により、ピロリジンの代わりにアゼチジンを用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, DMSO-d6) d ppm 0.99 (s, 9 H) 1.48 - 1.61 (m, 2 H) 1.86 - 1.97 (m, 2 H) 2.29 (d, J=7.43 Hz, 4 H) 2.73 - 2.85 (m, 2 H) 4.01 - 4.05 (m, 2 H) 4.31 - 4.41 (m, 1 H) 4.53 - 4.58 (m, 2 H) 7.10 (d, J=9.08 Hz, 2 H) 7.79 (d, J=9.08 Hz, 2 H) 9.12 (s, 1 H); MS (ESI pos.) m/z : 384 [M+H]+

In the same manner as in Example 14, the title compound was obtained as a colorless solid using azetidine instead of pyrrolidine.
1H NMR (600 MHz, DMSO-d6) d ppm 0.99 (s, 9 H) 1.48-1.61 (m, 2 H) 1.86-1.97 (m, 2 H) 2.29 (d, J = 7.43 Hz, 4 H) 2.73 -2.85 (m, 2 H) 4.01-4.05 (m, 2 H) 4.31-4.41 (m, 1 H) 4.53-4.58 (m, 2 H) 7.10 (d, J = 9.08 Hz, 2 H) 7.79 (d , J = 9.08 Hz, 2 H) 9.12 (s, 1 H); MS (ESI pos.) M / z: 384 [M + H] +

(Example 16)
Preparation of 1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -N-methyl-1H-1,2,3-triazole-4-carboxamide (Compound No. 30)

実施例１６と同様の手法により、ピロリジンの代わりにメチルアミン（９．８Ｍ メタノール溶液）を用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, DMSO-d6) d ppm 0.96 (s, 9 H) 1.52 (d, J=9.08 Hz, 2 H) 1.89 (br. s., 2 H) 2.27 (br. s., 2 H) 2.73 (d, J=4.54 Hz, 3 H) 2.75 - 2.82 (m, 2 H) 4.30 - 4.41 (m, 1 H) 7.07 (d, J=9.08 Hz, 2 H) 7.76 (d, J=9.08 Hz, 2 H) 8.50 (d, J=4.54 Hz, 1 H) 9.07 (s, 1 H); MS (ESI pos.) m/z : 358 [M+H]+

In the same manner as in Example 16, the title compound was obtained as a colorless solid using methylamine (9.8 M methanol solution) instead of pyrrolidine.
1H NMR (600 MHz, DMSO-d6) d ppm 0.96 (s, 9 H) 1.52 (d, J = 9.08 Hz, 2 H) 1.89 (br. S., 2 H) 2.27 (br. S., 2 H ) 2.73 (d, J = 4.54 Hz, 3 H) 2.75-2.82 (m, 2 H) 4.30-4.41 (m, 1 H) 7.07 (d, J = 9.08 Hz, 2 H) 7.76 (d, J = 9.08 Hz, 2 H) 8.50 (d, J = 4.54 Hz, 1 H) 9.07 (s, 1 H); MS (ESI pos.) M / z: 358 [M + H] +

(Example 17)
Preparation of 1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxamide (Compound No. 31)

実施例１３で製造したエチル １−［４−（１−ｔｅｒｔ−ブチルピペリジン−４−イル）オキシフェニル]トリアゾール−４−カルボキシラート（０．３０ ｇ）、６規定水酸化ナトリウム水溶液（０．４０ ｍＬ）および、エタノール（２．０ ｍＬ）の混合液を６０℃にて３時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、減圧下濃縮した。残渣に１−｛３−（ジメチルアミノ）プロピル｝−３−エチルカルボジイミド塩酸塩（０．３１ ｇ）、１−ヒドロキシベンゾトリアゾール水和物（０．２５ ｇ）及びＮ，Ｎ−ジメチルホルムアミド（２．０ ｍL）を加えて懸濁液とし、室温にて１６時間撹拌した。２８％アンモニア水溶液（０．２ ｍＬ）を加えて室温にて１６時間撹拌した。反応混合物に水を加え、析出物を濾取した。この粗結晶をエタノール−水から再結晶し、無色固体の表題化合物（０．０８６ ｇ）を得た。
1H NMR (600 MHz, DMSO-d6) d ppm 1.00 (s, 9 H) 1.50 - 1.62 (m, 2 H) 1.89 - 1.98 (m, 2 H) 2.24 - 2.32 (m, 2 H) 2.74 - 2.85 (m, 2 H) 4.32 - 4.45 (m, 1 H) 7.11 (d, J=9.50 Hz, 2 H) 7.56 (br.s, 1/2 H) 7.78 (d, J=9.08 Hz, 2 H) 7.93 (br.s, 1/2 H) 9.08 (s, 1 H); MS (ESI pos.) m/z : 344 [M+H]+

Ethyl 1- [4- (1-tert-butylpiperidin-4-yl) oxyphenyl] triazole-4-carboxylate (0.30 g), 6N aqueous sodium hydroxide solution (0.40) prepared in Example 13 mL) and ethanol (2.0 mL) were stirred at 60 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. 1- {3- (Dimethylamino) propyl} -3-ethylcarbodiimide hydrochloride (0.31 g), 1-hydroxybenzotriazole hydrate (0.25 g) and N, N-dimethylformamide (2 (0.0 mL) was added to form a suspension and stirred at room temperature for 16 hours. A 28% aqueous ammonia solution (0.2 mL) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration. The crude crystals were recrystallized from ethanol-water to obtain the title compound (0.086 g) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) d ppm 1.00 (s, 9 H) 1.50-1.62 (m, 2 H) 1.89-1.98 (m, 2 H) 2.24-2.32 (m, 2 H) 2.74-2.85 ( m, 2 H) 4.32-4.45 (m, 1 H) 7.11 (d, J = 9.50 Hz, 2 H) 7.56 (br.s, 1/2 H) 7.78 (d, J = 9.08 Hz, 2 H) 7.93 (br.s, 1/2 H) 9.08 (s, 1 H); MS (ESI pos.) m / z: 344 [M + H] +

(Example 18)
Preparation of 1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carbonitrile (Compound No. 32)

実施例７と同様の手法により、１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキサミドの代わりに、１−［４−（１−ｔｅｒｔ−ブチルピペリジン−４−イル)オキシフェニル]トリアゾール−４−カルボキサミドを用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09 (br. s., 9 H) 1.83 (br. s., 2 H) 2.02 (br. s., 2 H) 2.43 (br. s., 2 H) 2.87 (br. s., 2 H) 4.27 - 4.42 (m, 1 H) 6.99 - 7.09 (m, 2 H) 7.58 (d, J=9.08 Hz, 2 H) 8.30 (s, 1 H); MS (ESI pos.) m/z : 326 [M+H]+

In the same manner as in Example 7, instead of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxamide, [4- (1-tert-Butylpiperidin-4-yl) oxyphenyl] triazole-4-carboxamide was used to give the title compound as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09 (br. S., 9 H) 1.83 (br. S., 2 H) 2.02 (br. S., 2 H) 2.43 (br. S., 2 H) 2.87 (br. S., 2 H) 4.27-4.42 (m, 1 H) 6.99-7.09 (m, 2 H) 7.58 (d, J = 9.08 Hz, 2 H) 8.30 (s, 1 H); MS (ESI pos.) M / z: 326 [M + H] +

(Example 19)
Preparation of ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylate (Compound No. 33)

水素雰囲気下、１−シクロブチル−４−（４−ニトロフェノキシ）ピペリジン（５．５ ｇ，Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ ２００８年，５１巻，６８８９頁に記載の方法に従って合成できる）、５％パラジウム−炭素（０．５５ ｇ）及び、メタノール（５５ ｍＬ）を混合、懸濁液とし、室温にて４時間撹拌した。反応混合物をセライト（登録商標）濾過した。濾液を減圧下濃縮した。残渣に１規定塩酸水溶液（４．９ ｍＬ）を加え、溶液とした。この溶液に氷冷下、亜硝酸ナトリウム（１２５ ｍｇ）、水（０．５２ ｍＬ）の混合溶液を滴下し、２０分間撹拌した。この反応混合物を、イソシアノ酢酸エチル（１．８ ｇ）、酢酸ナトリウム（１２．１ ｇ）、メタノール（８７．０ ｍＬ）及び水（１１．０ ｍＬ）の混合液に、氷冷下滴下し１時間撹拌した。反応混合物に水を加え、減圧下濃縮後、クロロホルムにて抽出した。有機層を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨ型シリカゲル、展開溶媒：ヘキサン／酢酸エチル＝８８／１２〜０／１０）にて精製した。褐色油状の表題化合物（１．７ ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.40 (t, J=7.22 Hz, 3 H) 1.57 - 1.70 (m, 2 H) 1.74 - 1.88 (m, 4 H) 1.91 - 2.04 (m, 4 H) 2.12 (br. s., 2 H) 2.57 (br. s., 2 H) 2.69 (t, J=7.64 Hz, 1 H) 4.32 (br. s., 1 H) 4.44 - 4.49 (m, 2 H) 6.91 - 7.01 (m, 2 H) 7.52 - 7.62 (m, 2 H) 8.43 (s, 1 H); MS (ESI pos.) m/z : 371 [M+H]+

1-cyclobutyl-4- (4-nitrophenoxy) piperidine (5.5 g, can be synthesized according to the method described in Journal of Medicinal Chemistry 2008, 51, 6889) under a hydrogen atmosphere, 5% palladium-carbon ( 0.55 g) and methanol (55 mL) were mixed to form a suspension and stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. A 1N aqueous hydrochloric acid solution (4.9 mL) was added to the residue to prepare a solution. To this solution, a mixed solution of sodium nitrite (125 mg) and water (0.52 mL) was added dropwise under ice cooling, and the mixture was stirred for 20 minutes. The reaction mixture was added dropwise to a mixture of ethyl isocyanoacetate (1.8 g), sodium acetate (12.1 g), methanol (87.0 mL) and water (11.0 mL) under ice-cooling. Stir for hours. Water was added to the reaction mixture, concentrated under reduced pressure, and extracted with chloroform. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH type silica gel, developing solvent: hexane / ethyl acetate = 88/12 to 0/10). The title compound (1.7 g) was obtained as a brown oil.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.40 (t, J = 7.22 Hz, 3 H) 1.57-1.70 (m, 2 H) 1.74-1.88 (m, 4 H) 1.91-2.04 (m, 4 H ) 2.12 (br. S., 2 H) 2.57 (br. S., 2 H) 2.69 (t, J = 7.64 Hz, 1 H) 4.32 (br. S., 1 H) 4.44-4.49 (m, 2 H) 6.91-7.01 (m, 2 H) 7.52-7.62 (m, 2 H) 8.43 (s, 1 H); MS (ESI pos.) M / z: 371 [M + H] +

(Example 20)
(1- {4-[(1-Cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) (pyrrolidin-1-yl) methanone (Compound No. 34) Manufacturing of

実施例２と同様の手法により、エチル １−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，３−トリアゾール−４−カルボキシラートの代わりに、実施例１９で製造したエチル １−［４−（１−シクロブチルピペリジン−４−イル）オキシフェニル］−１，２，４−トリアゾール−３−カルボキシラートを用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.62 - 1.74 (m, 2 H) 1.79 - 2.08 (m, 12 H) 2.16 (d, J=2.89 Hz, 2 H) 2.62 (br. s., 2 H) 2.69 - 2.78 (m, 1 H) 3.72 (t, J=6.81 Hz, 2 H) 3.92 (t, J=6.61 Hz, 2 H) 4.35 (br. s., 1 H) 6.95 - 7.05 (m, 2 H) 7.51 - 7.61 (m, 2 H) 8.44 (s, 1 H); MS (ESI pos.) m/z : 396 [M+H]+

In the same manner as in Example 2, instead of ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate, Using ethyl 1- [4- (1-cyclobutylpiperidin-4-yl) oxyphenyl] -1,2,4-triazole-3-carboxylate prepared in Example 19 gave the title compound as a colorless solid. It was.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.62-1.74 (m, 2 H) 1.79-2.08 (m, 12 H) 2.16 (d, J = 2.89 Hz, 2 H) 2.62 (br. S., 2 H) 2.69-2.78 (m, 1 H) 3.72 (t, J = 6.81 Hz, 2 H) 3.92 (t, J = 6.61 Hz, 2 H) 4.35 (br. S., 1 H) 6.95-7.05 (m , 2 H) 7.51-7.61 (m, 2 H) 8.44 (s, 1 H); MS (ESI pos.) M / z: 396 [M + H] +

(Example 21)
Preparation of azetidin-1-yl (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) methanone (Compound No. 35)

実施例２０と同様の手法により、ピロリジンの代わりにアゼチジンを用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.53 - 1.77 (m, 2 H) 1.81 - 1.94 (m, 4 H) 1.97 - 2.08 (m, 4 H) 2.17 (br. s., 2 H) 2.30 - 2.41 (m, 2 H) 2.62 (br. s., 2 H) 2.74 (t, J=7.84 Hz, 1 H) 4.27 (t, J=7.84 Hz, 2 H) 4.36 (br. s., 1 H) 4.66 (t, J=7.64 Hz, 2 H) 6.99 (d, J=8.26 Hz, 2 H) 7.57 (d, J=9.08 Hz, 2 H) 8.43 (d, J=0.83 Hz, 1 H); MS (ESI pos.) m/z : 382 [M+H]+

In the same manner as in Example 20, azetidine was used in place of pyrrolidine to obtain the title compound as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.53-1.77 (m, 2 H) 1.81-1.94 (m, 4 H) 1.97-2.08 (m, 4 H) 2.17 (br. S., 2 H) 2.30 -2.41 (m, 2 H) 2.62 (br. S., 2 H) 2.74 (t, J = 7.84 Hz, 1 H) 4.27 (t, J = 7.84 Hz, 2 H) 4.36 (br. S., 1 H) 4.66 (t, J = 7.64 Hz, 2 H) 6.99 (d, J = 8.26 Hz, 2 H) 7.57 (d, J = 9.08 Hz, 2 H) 8.43 (d, J = 0.83 Hz, 1 H) ; MS (ESI pos.) M / z: 382 [M + H] +

(Example 22)
(1- {4-[(1-Cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) (piperidin-1-yl) methanone (Compound No. 36) Manufacturing of

実施例２０と同様の手法により、ピロリジンの代わりにピペリジンを用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.55 - 1.73 (m, 8 H) 1.79 - 1.94 (m, 4 H) 1.97 - 2.08 (m, 4 H) 2.16 (br. s., 2 H) 2.62 (br. s., 2 H) 2.74 (t, J=7.84 Hz, 1 H) 3.68 (d, J=5.78 Hz, 2 H) 3.75 (t, J=4.95 Hz, 2 H) 4.35 (br. s., 1 H) 6.91 - 7.05 (m, 2 H) 7.49 - 7.61 (m, 2 H) 8.43 (s, 1 H); MS (ESI pos.) m/z : 410 [M+H]+

In the same manner as in Example 20, the title compound was obtained as a colorless solid using piperidine instead of pyrrolidine.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.55-1.73 (m, 8 H) 1.79-1.94 (m, 4 H) 1.97-2.08 (m, 4 H) 2.16 (br. S., 2 H) 2.62 (br. s., 2 H) 2.74 (t, J = 7.84 Hz, 1 H) 3.68 (d, J = 5.78 Hz, 2 H) 3.75 (t, J = 4.95 Hz, 2 H) 4.35 (br. s ., 1 H) 6.91-7.05 (m, 2 H) 7.49-7.61 (m, 2 H) 8.43 (s, 1 H); MS (ESI pos.) M / z: 410 [M + H] +

(Example 23)
Preparation of N-tert-butyl-1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxamide (Compound No. 37)

実施例２０と同様の手法により、ピロリジンの代わりにｔｅｒｔ−ブチルアミンを用いて、無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.42 (s, 9 H) 1.54 - 1.67 (m, 2 H) 1.70 - 1.86 (m, 4 H) 1.89 - 2.01 (m, 4 H) 2.06 - 2.13 (m, 2 H) 2.46 - 2.58 (m, 2 H) 2.61 - 2.71 (m, 1 H) 4.20 - 4.34 (m, 1 H) 6.92 (d, J=9.08 Hz, 3 H) 7.52 (d, J=9.08 Hz, 2 H) 8.31 (s, 1 H); MS (ESI pos.) m/z : 398 [M+H]+

In the same manner as in Example 20, using tert-butylamine instead of pyrrolidine, the title compound was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.42 (s, 9 H) 1.54-1.67 (m, 2 H) 1.70-1.86 (m, 4 H) 1.89-2.01 (m, 4 H) 2.06-2.13 ( m, 2 H) 2.46-2.58 (m, 2 H) 2.61-2.71 (m, 1 H) 4.20-4.34 (m, 1 H) 6.92 (d, J = 9.08 Hz, 3 H) 7.52 (d, J = 9.08 Hz, 2 H) 8.31 (s, 1 H); MS (ESI pos.) M / z: 398 [M + H] +

(Example 24)
Preparation of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylic acid hydrochloride (Compound No. 38)

実施例１９にて製造したエチル １−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボキシラート（０．６０ ｇ）及び濃塩酸（６．０ ｍＬ）の混合液を１００℃にて５時間撹拌した。反応混合物を室温まで放冷後、減圧下濃縮した。残渣にテトラヒドロフラン（２．０ ｍＬ）を加え、氷冷下３０分間撹拌した。析出物を濾取した。無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.63 - 1.74 (m, 2 H) 1.75 - 1.82 (m, 2 H) 1.84 - 1.92 (m, 2 H) 1.92 - 1.99 (m, 2 H) 2.00 - 2.17 (m, 4 H) 2.72 (t, J=7.79 Hz, 1 H) 2.77 - 2.84 (m, 2 H) 2.98 - 3.05 (m, 2 H) 4.22 (br. s., 1 H) 6.31 (d, J=9.17 Hz, 1 H) 6.60 (dd, J=8.71, 2.75 Hz, 1 H) 6.78 (d, J=2.75 Hz, 1 H) 6.86 (d, J=8.71 Hz, 1 H) 7.44 (dd, J=8.71, 2.75 Hz, 1 H) 8.04 (d, J=2.75 Hz, 1 H); MS (ESI pos.) m/z : 343 [M+H]+

Ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylate (0.60 g) prepared in Example 19 And concentrated hydrochloric acid (6.0 mL) were stirred at 100 ° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. Tetrahydrofuran (2.0 mL) was added to the residue, and the mixture was stirred for 30 minutes under ice cooling. The precipitate was collected by filtration. The title compound was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.63-1.74 (m, 2 H) 1.75-1.82 (m, 2 H) 1.84-1.92 (m, 2 H) 1.92-1.99 (m, 2 H) 2.00- 2.17 (m, 4 H) 2.72 (t, J = 7.79 Hz, 1 H) 2.77-2.84 (m, 2 H) 2.98-3.05 (m, 2 H) 4.22 (br. S., 1 H) 6.31 (d , J = 9.17 Hz, 1 H) 6.60 (dd, J = 8.71, 2.75 Hz, 1 H) 6.78 (d, J = 2.75 Hz, 1 H) 6.86 (d, J = 8.71 Hz, 1 H) 7.44 (dd , J = 8.71, 2.75 Hz, 1 H) 8.04 (d, J = 2.75 Hz, 1 H); MS (ESI pos.) M / z: 343 [M + H] +

(Example 25)
Preparation of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxamide (Compound No. 39)

実施例２４で製造した１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボン酸塩酸塩（０．３０ ｇ）、１−｛３−（ジメチルアミノ）プロピル｝−３−エチルカルボジイミド塩酸塩（０．２３ ｇ）、１−ヒドロキシベンゾトリアゾール水和物（０．１８ ｇ）、トリエチルアミン（０．１６ ｇ）及び、Ｎ，Ｎ−ジメチルホルムアミド（０．６ ｍL）を加えて懸濁液とし、室温にて３０分間撹拌した。反応混合液にアンモニア（０．２３ ｍＬ、７Ｍ メタノール溶液）を加え室温にて１６時間撹拌した。反応混合物に水を加え、クロロホルムにて抽出した。有機層を無水硫酸マグネシウムにて乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＮＨ型シリカゲル、展開溶媒：酢酸エチル）にて精製した。無色固体の表題化合物（０．０９３ ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.54 - 1.66 (m, 2 H) 1.70 - 1.85 (m, 4 H) 1.96 (br. s., 4 H) 2.05 - 2.16 (m, 2 H) 2.48 - 2.59 (m, 2 H) 2.62 - 2.72 (m, 1 H) 4.23 - 4.34 (m, 1 H) 5.51 - 5.62 (m, 1 H) 6.86 - 6.96 (m, 3 H) 7.52 (d, J=9.08 Hz, 2 H) 8.37 (s, 1 H); MS (ESI pos.) m/z : 342 [M+H]+

1- {4-[(1-Cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylic acid hydrochloride (0.30 g) prepared in Example 24 1- {3- (dimethylamino) propyl} -3-ethylcarbodiimide hydrochloride (0.23 g), 1-hydroxybenzotriazole hydrate (0.18 g), triethylamine (0.16 g), and N, N-dimethylformamide (0.6 mL) was added to form a suspension and stirred at room temperature for 30 minutes. Ammonia (0.23 mL, 7M methanol solution) was added to the reaction mixture, followed by stirring at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH type silica gel, developing solvent: ethyl acetate). The title compound (0.093 g) was obtained as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.54-1.66 (m, 2 H) 1.70-1.85 (m, 4 H) 1.96 (br. S., 4 H) 2.05-2.16 (m, 2 H) 2.48 -2.59 (m, 2 H) 2.62-2.72 (m, 1 H) 4.23-4.34 (m, 1 H) 5.51-5.62 (m, 1 H) 6.86-6.96 (m, 3 H) 7.52 (d, J = 9.08 Hz, 2 H) 8.37 (s, 1 H); MS (ESI pos.) M / z: 342 [M + H] +

(Example 26)
Preparation of 1- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) ethanone hydrochloride (Compound No. 40)

実施例２４で製造した１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボン酸 塩酸塩（０．４０ ｇ）、１−｛３−（ジメチルアミノ）プロピル｝−３−エチルカルボジイミド塩酸塩（０．２４ ｇ）、１−ヒドロキシベンゾトリアゾール水和物（０．１６ ｇ）、トリエチルアミン（０．２１ ｇ）、Ｎ，Ｏ−ジメチルヒドロキシルアミン塩酸塩（０．１２ ｇ）及び、Ｎ，Ｎ−ジメチルホルムアミド（５．０ ｍL）を加えて懸濁液とし、室温にて１６時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水にて順次洗浄後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム／メタノール＝１０／０〜９／１）にて精製した。無色固体の１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−Ｎ−メトキシ−Ｎ−メチル−１Ｈ−１，２，４−トリアゾール−３−カルボキサミド（０．３３ ｇ）を得た。ＭＳ （ＥＳＩ ｐｏｓ．） ｍ／ｚ ： ３８６ ［Ｍ＋Ｈ］⁺
１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−Ｎ−メトキシ−Ｎ−メチル−１Ｈ−１，２，４−トリアゾール−３−カルボキサミド（０．１０ ｇ）のテトラヒドロフラン（３．０ ｍＬ）溶液に−７８℃にてメチルリチウム（０．５２ ｍＬ，１．０Ｍジエチルエーテル溶液）を滴下し、２時間撹拌後、室温に昇温し１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムにて抽出後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム／メタノール＝１０／０〜９／１）にて精製した。得られた非晶質の固体を酢酸エチル（２．０ ｍＬ）に溶解後、塩酸（１．０ ｍＬ，４Ｍ酢酸エチル溶液）を滴下し、室温にて１０分間撹拌した。この反応混合物を減圧下濃縮し、無色固体の表題化合物（１２．０ ｍｇ）を得た。
1H NMR (600 MHz, DMSO-d6) d ppm 1.65 - 1.80 (m, 2 H) 2.04 - 2.40 (m, 8 H) 2.62 (s, 3 H) 2.83 - 2.99 (m, 3 H) 3.20 - 3.26 (m, 1 H) 3.39 - 3.45 (m, 1 H) 3.71 - 3.80 (m, 1 H) 7.23 (dd, J=18.58, 9.08 Hz, 2 H) 7.84 (dd, J=11.15, 9.08 Hz, 2 H) 9.34 (s, 1 H); MS (ESI pos.) m/z : 341 [M+H]+

1- {4-[(1-Cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylic acid hydrochloride prepared in Example 24 (0.40 g) 1- {3- (dimethylamino) propyl} -3-ethylcarbodiimide hydrochloride (0.24 g), 1-hydroxybenzotriazole hydrate (0.16 g), triethylamine (0.21 g), N , O-dimethylhydroxylamine hydrochloride (0.12 g) and N, N-dimethylformamide (5.0 mL) were added to form a suspension and stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 10/0 to 9/1). 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N-methoxy-N-methyl-1H-1,2,4-triazole-3-carboxamide (0.33) as a colorless solid g) was obtained. MS (ESI pos.) M / z: 386 [M + H] ⁺
1- {4-[(1-Cyclobutylpiperidin-4-yl) oxy] phenyl} -N-methoxy-N-methyl-1H-1,2,4-triazole-3-carboxamide (0.10 g) Methyl lithium (0.52 mL, 1.0 M diethyl ether solution) was added dropwise to a tetrahydrofuran (3.0 mL) solution at −78 ° C., stirred for 2 hours, then warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, extracted with chloroform, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 10/0 to 9/1). The obtained amorphous solid was dissolved in ethyl acetate (2.0 mL), hydrochloric acid (1.0 mL, 4M ethyl acetate solution) was added dropwise, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure to give the title compound (12.0 mg) as a colorless solid.
1H NMR (600 MHz, DMSO-d6) d ppm 1.65-1.80 (m, 2 H) 2.04-2.40 (m, 8 H) 2.62 (s, 3 H) 2.83-2.99 (m, 3 H) 3.20-3.26 ( m, 1 H) 3.39-3.45 (m, 1 H) 3.71-3.80 (m, 1 H) 7.23 (dd, J = 18.58, 9.08 Hz, 2 H) 7.84 (dd, J = 11.15, 9.08 Hz, 2 H ) 9.34 (s, 1 H); MS (ESI pos.) M / z: 341 [M + H] +

(Example 27)
Preparation of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carbonitrile (Compound No. 41)

実施例２５にて製造した１−｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝−１Ｈ−１，２，４−トリアゾール−３−カルボキサミド（０．０６０ ｇ）のＮ，Ｎ−ジメチルホルムアミド（０．６ ｍL）溶液に、氷冷下塩化チオニル(０．２１ ｇ)を加え、室温にて２時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて抽出後、減圧下濃縮した。残渣を分取薄層クロマトグラフィー（ＮＨ型シリカゲル，展開溶媒：ヘキサン／酢酸エチル＝１／１）にて精製し、無色固体の表題化合物（０．０２５ ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.61 - 1.74 (m, 2 H) 1.77 - 1.91 (m, 4 H) 1.95 - 2.06 (m, 4 H) 2.07 - 2.21 (m, 2 H) 2.54 - 2.63 (m, 2 H) 2.67 - 2.77 (m, 1 H) 4.32 - 4.40 (m, 1 H) 7.00 (d, J=9.08 Hz, 2 H) 7.52 (d, J=9.08 Hz, 2 H) 8.47 (s, 1 H); MS (ESI pos.) m/z : 324 [M+H]+

N of 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxamide (0.060 g) prepared in Example 25 , N-dimethylformamide (0.6 mL) was added with thionyl chloride (0.21 g) under ice-cooling and stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (NH type silica gel, developing solvent: hexane / ethyl acetate = 1/1) to obtain the title compound (0.025 mg) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.61-1.74 (m, 2 H) 1.77-1.91 (m, 4 H) 1.95-2.06 (m, 4 H) 2.07-2.21 (m, 2 H) 2.54- 2.63 (m, 2 H) 2.67-2.77 (m, 1 H) 4.32-4.40 (m, 1 H) 7.00 (d, J = 9.08 Hz, 2 H) 7.52 (d, J = 9.08 Hz, 2 H) 8.47 (s, 1 H); MS (ESI pos.) m / z: 324 [M + H] +

(Test Example 1: Rat H3 receptor binding test)
The frontal cortex excised from the rat was mixed with a 50 mM Tris-HCl buffer (pH 7) containing a protease inhibitor (Complete EDTA-free, Roche Diagnostics) and 5 mM EDTA using a Teflon (registered trademark) homogenizer. Homogenized in 4). The homogenate was centrifuged at 48,000 × g for 15 minutes. The supernatant was removed, and the pellet was suspended in 50 mM Tris-HCl buffer (pH 7.4) containing 5 mM EDTA, and further centrifuged at 48,000 × g for 15 minutes. The supernatant was removed, and the pellet was suspended in 50 mM Tris-HCl buffer (pH 7.4) containing 5 mM EDTA to obtain a membrane fraction. Membrane fraction (75 μg of protein in the final reaction solution), N-α-methyl [ ³ H] histamine (Perkin Elmer, final concentration 0.75 nM), and test drug were mixed and reacted at room temperature for 1 hour. . After completion of the reaction, the reaction mixture was suction filtered through a 96-well GF / C filter plate treated with 0.3% polyethyleneimine, and the filter was washed 5 times with 50 mM Tris-HCl buffer (pH 7.4) containing 5 mM EDTA. Washed. After washing, the filter was dried, a scintillator was added, and the residual radioactivity on the filter was measured with a top count (Perkin Elmer).
The residual radioactivity in the presence of 10 μM thioperamide was defined as nonspecific binding, and the difference from the residual radioactivity in the absence of thioperamide was defined as specific binding. The test drug was dissolved and diluted in DMSO, and the test drug concentration (IC ₅₀ ) at which specific binding was inhibited by 50% was determined from the dose response curve obtained from the residual radioactivity in the presence of each concentration. The IC ₅₀ values of the example compounds are shown in Table 3.

(Test Example 2: [ ³⁵ S] GTP-γ-S binding test)
The frontal cortex excised from the rat was homogenized in 30 mM Tris-HCl buffer (pH 7.4) containing 2.5 mM calcium chloride dihydrate using a Teflon (registered trademark) homogenizer. The homogenate was centrifuged at 48,000 × g for 15 minutes. The supernatant was removed, and the pellet was suspended in 30 mM Tris-HCl buffer (pH 7.4) containing 2.5 mM calcium chloride dihydrate and further centrifuged at 48,000 × g for 15 minutes. The supernatant was removed, the pellet was suspended in 30 mM Tris-HCl buffer (pH 7.4) containing 2.5 mM calcium chloride dihydrate, incubated at 37 ° C. for 30 minutes, and then at 48,000 × g. Centrifuge for 15 minutes. The supernatant was removed, and the pellet was suspended in 20 mM HEPES buffer (pH 7.4) containing 100 mM sodium chloride and 10 mM magnesium chloride to obtain a membrane fraction. Membrane fraction (20 μg of protein in the final reaction solution), GDP (final concentration 300 μM), adenosine deaminase (final concentration 1 U / mL), R (−)-α-methylhistamine (final concentration 300 nM), and test compound Mix and react at 30 ° C. for 20 minutes. After the reaction, [ ³⁵ S] GTP-γ-S (final concentration 0.3 nM) was further added, and the reaction was continued for 90 minutes. After completion of the reaction, the reaction mixture was suction filtered through a 96-well GF / C filter plate, and the filter was washed three times with 20 mM HEPES buffer (pH 7.4) containing 100 mM sodium chloride and 10 mM magnesium chloride. After washing, the filter was dried, a scintillator was added, and the residual radioactivity on the filter was measured with a top count (Perkin Elmer).
The residual radioactivity in the absence of R (−)-α-methylhistamine was defined as nonspecific binding, and the difference from the residual radioactivity in the presence of R (−)-α-methylhistamine was defined as specific binding. . The test drug was dissolved and diluted in DMSO, and the test drug concentration (IC ₅₀ ) at which specific binding was inhibited by 50% was determined from the dose response curve obtained from the residual radioactivity in the presence of each concentration. As a result, Compound 8 of the present invention showed an activity with an IC _{50 of} 100 nM or less.

Test Example 3: Rat pharmacokinetic study
Using SD rats, compounds 8, 19 and 22 were orally administered at a single dose of 3 mg / kg, and tissue distribution in plasma, brain and cerebrospinal fluid was confirmed 1 hour after administration. High-performance liquid chromatography / tandem mass spectrometer API4000 (LC-MS / MS, AB Sciex) was used for quantification. As a result, the brain / plasma transfer ratio of Compound 8 was 3.0, the cerebrospinal fluid / plasma transfer ratio was 0.2, the brain concentration was 45.7 ng / g, and the cerebrospinal fluid concentration was 2.9 ng / mL. Met. Compound 19 had a brain / plasma transition ratio of 4.4, a cerebrospinal fluid / plasma transition ratio of 0.7, a brain concentration of 820 ng / g, and a cerebrospinal fluid concentration of 134 ng / mL. Compound 22 had a brain / plasma transition ratio of 1.5, a cerebrospinal fluid / plasma transition ratio of 0.5, a brain concentration of 209 ng / g, and a cerebrospinal fluid concentration of 67.6 ng / mL.

Test Example 4: P-glycoprotein substrate recognition test
LLC-GA5-COL300 cells (pig kidney-derived cultured renal epithelial cell line LLC-PK1-derived Human MDR1 expression system) were cultured on the transwell. Immediately before the test, the test was replaced with Hank's balanced salt solution (HBSS). The evaluation compound solution adjusted to a final concentration of 10 μM was added to the donor side of LLC-GA5-COL300 cells, and after a certain period of time, a certain amount was collected from the acceptor side. The compound concentration in the sample was measured by LC-MS / MS. From the accumulated permeation amount of the compound to the acceptor side, the membrane permeation coefficient (× 10 ⁻⁶ cm / sec) of each of Apical → Basal and Basal → Apical is calculated, and P-glycoprotein substrate recognition property is calculated from the ratio (Efflux Ratio) Evaluated. Table 4 shows the Efflux Ratio values of the example compounds.

  According to the present invention, it has a strong binding inhibitory action on histamine H3 receptor, and is a disorder caused by histamine H3 receptor, such as dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, Central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep-related complications, sleep-related movement disorders, insomnia It is possible to provide a medicinal product useful for the prevention or treatment of diseases such as infectious diseases, depression, or allergic rhinitis, which is considered to contribute greatly to the development of the pharmaceutical industry.

Claims (8)

Formula (I)

[In Formula (I), Ring P represents a group represented by the following Formula (II) or (III);

Q represents a group represented by the following formula (A) or (B),

R ¹ represents a hydrogen atom, a halogen atom or C ₁ -C ₆ alkyl;
R ² is a hydrogen atom, hydroxy, cyano, carboxy, C ₁ -C ₆ alkyl, C ₂ -C ₇ alkanoyl, C ₁ -C ₆ alkylsulfonyl (wherein the C ₁ -C ₆ alkyl, C ₂ -C ₇ alkanoyl or C ₁ -C ₆ alkylsulfonyl, halogen atoms, with 1 to 3 substituents selected from the group consisting of hydroxy and C ₁ -C ₆ alkoxy may be substituted.), C ₁ ~C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, C ₂ -C ₇ alkoxycarbonyl (wherein said C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl or C ₂ -C ₇ alkoxycarbonyl, halogen atom, hydroxy, C _{1 to} C ₆ alkyl and ₁ to 3 groups selected from the group consisting of C _{1 to} C ₆ alkoxy may be substituted.), — (CH ₂ ) _n —C (═O) NR ^1A R ^1B or -S (= O) ₂ NR ^2A R ^2B is shown,
R ^1A and R ^1B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
Or R ^1A and R ^1B are 3 to 7-membered saturated heterocycles bonded to each other together with adjacent nitrogen atoms (the saturated heterocycle is selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyls) May be substituted with 1 or 2 groups),
n represents 0 or 1,
R ^2A and R ^2B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
Or R ^2A and R ^2B are 3 to 7-membered saturated heterocycles bonded to each other together with adjacent nitrogen atoms (the saturated heterocycle is selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyls) May be substituted with 1 or 2 groups),
R ³ is a hydrogen atom or C ₁ -C ₆ alkyl,
R ⁴ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with 1 or 2 C ₃ -C ₇ cycloalkyl) or C ₃ -C ₇ cycloalkyl (the C ₃ -C ₇ cycloalkyl may be substituted with 1 or 2 C ₁ -C ₆ alkyl.)
R ⁵ and R ⁶ are the same or different and each represents C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
Or R ⁵ and R ⁶ are 3- to 7-membered saturated heterocycles bonded together with adjacent nitrogen atoms (the saturated heterocycle may be substituted with 1 or 2 C ₁ -C ₆ alkyls). May be formed). ]
Or a pharmaceutically acceptable salt thereof, except for N, N-dimethyl-3- [4- (1H-1,2,4-triazol-1-yl) phenoxy] propan-1-amine, Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, Preventive or therapeutic agent for idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep-related comorbidity, sleep-related movement disorder, insomnia, depression, or allergic rhinitis . Ring P is of formula (II)

(Wherein R ² and R ³ are as defined in claim 1)
A dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy characterized by comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient , Central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorders, sleep-related complications, sleep-related movement disorders, A preventive or therapeutic agent for insomnia, depression, or allergic rhinitis. Q is the formula (A)

(Wherein R ⁴ is as defined in claim 1).
A dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient , Epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep-related complications, sleep-related exercise Preventive or therapeutic agent for disorder, insomnia, depression, or allergic rhinitis. The compound according to any one of claims 1 to 3, wherein R ¹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof as an active ingredient, dementia, Alzheimer's disease, caution Deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm A preventive or therapeutic agent for disorder, parasomnia, sleep-related movement disorder, insomnia, depression, or allergic rhinitis. R ² is C ₁ -C ₆ alkyl (wherein the C ₁ -C ₆ alkyl may be substituted with 1 to 3 groups selected from the group consisting of hydroxy and C ₁ -C ₆ alkoxy) , C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl (wherein said C ₁ -C ₆ alkoxy or C ₃ -C ₇ cycloalkyl, hydroxy, C ₁ -C ₆ alkyl and C ₁ -C ₆ May be substituted with 1 to 3 groups selected from the group consisting of alkoxy.), Or —C (═O) NR ^1A R ^1B ;
R ^1A and R ^1B are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl, or R ^1A and R ^1B together with the adjacent nitrogen atom Forming a bonded 3 to 7 membered saturated heterocyclic ring (which may be substituted with one or two groups selected from the group consisting of halogen atoms and C ₁ -C ₆ alkyl). A dementia, Alzheimer's disease, attention deficit / hyperactivity characterized by containing the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient Disease, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep-associated Sickness, sleep-related movement disorders, insomnia, depression, youth Prophylactic or therapeutic agent for allergic rhinitis. The compound according to any one of claims 1 to 5, wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof as an active ingredient, dementia, Alzheimer's disease, caution Deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm A preventive or therapeutic agent for disorder, parasomnia, sleep-related movement disorder, insomnia, depression, or allergic rhinitis. The compound according to any one of claims 1 to 6, wherein R ⁴ is C _{3 to} C ₇ cycloalkyl, or a pharmaceutically acceptable salt thereof as an active ingredient, dementia , Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea Preventive or therapeutic agent for syndrome, circadian rhythm disorder, sleep-related comorbidity, sleep-related movement disorder, insomnia, depression, or allergic rhinitis. Ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate,
1-cyclobutyl-4- {4- [4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] phenoxy} piperidine,
1-cyclobutyl-4- [4- (4-ethoxy-1H-1,2,3-triazol-1-yl) phenoxy] piperidine,
1-cyclobutyl-4- [4- (4-cyclopropyl-1H-1,2,3-triazol-1-yl) phenoxy] piperidine,
1- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) ethanone,
2- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) propan-2-ol,
4- [4- (4-tert-butyl-1H-1,2,3-triazol-1-yl) phenoxy] -1-cyclobutylpiperidine,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (pyrrolidin-1-yl) methanone,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -5-methyl-1H-1,2,3-triazol-4-yl) (pyrrolidin-1-yl) methanone,
Azetidin-1-yl (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -5-methyl-1H-1,2,3-triazol-4-yl) methanone,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N, 5-dimethyl-1H-1,2,3-triazole-4-carboxamide,
2- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) -1- (pyrrolidin-1-yl) ethanone ,
1- (azetidin-1-yl) -2- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) ethanone ,
2- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) -N-methylacetamide,
[1- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1H-1,2,3-triazol-4-yl] (pyrrolidin-1-yl) methanone ,
Azetidin-1-yl [1- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1H-1,2,3-triazol-4-yl] methanone,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylic acid,
Azetidin-1-yl (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanone,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N-methyl-1H-1,2,3-triazole-4-carboxamide,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxamide,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carbonitrile,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanol,
1-cyclobutyl-4- [4- (1H-1,2,3-triazol-1-yl) phenoxy] piperidine,
Ethyl 1- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1H-1,2,3-triazole-4-carboxylate,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (morpholin-4-yl) methanone,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -N, N-dimethyl-1H-1,2,3-triazole-4-carboxamide,
Ethyl 1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxylate,
(1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) (pyrrolidin-1-yl) methanone,
Azetidin-1-yl (1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazol-4-yl) methanone,
1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -N-methyl-1H-1,2,3-triazole-4-carboxamide,
1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carboxamide,
1- {4-[(1-tert-butylpiperidin-4-yl) oxy] phenyl} -1H-1,2,3-triazole-4-carbonitrile,
Ethyl 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylate,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) (pyrrolidin-1-yl) methanone,
Azetidin-1-yl (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) methanone,
(1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) (piperidin-1-yl) methanone,
N-tert-butyl-1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxamide;
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxylic acid,
1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carboxamide,
1- (1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazol-3-yl) ethanone,
And 1- {4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} -1H-1,2,4-triazole-3-carbonitrile. A compound or a pharmaceutically acceptable salt thereof as an active ingredient, characterized by dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, obesity, diabetes, Hyperlipidemia, narcolepsy, idiopathic hypersomnia, behavior-induced sleep deprivation syndrome, sleep apnea syndrome, circadian rhythm disorder, sleep-related complications, sleep-related movement disorders, insomnia, depression, or allergic A preventive or therapeutic agent for rhinitis.