JP5584238B2 - Pharmaceutical use of indole derivatives or pharmacologically acceptable salts thereof - Google Patents

Description

The present invention relates to a pharmaceutical composition containing an indole derivative having an EP ₁ receptor antagonistic activity useful as a pharmaceutical, or a pharmacologically acceptable salt thereof, and a pharmaceutical use thereof.

  With the development of an aging society and stress society, the number of patients with lower urinary tract dysfunction (LUTD) is increasing. LUTD is a general term for urinary storage disorder and dysuria, and the symptoms that develop from LUTD are lower urinary tract symptoms (LUTS). One type of LUTS is overactive bladder syndrome (OABs). OABs are also sometimes referred to as overactive bladder (OAB). In any case, it is a disease defined as “a symptom syndrome requiring urgency of urine, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential”. These symptoms associated with OABs interfere with overall life such as work, daily life, and mental activity, and lower the quality of life (QOL). Currently, anticholinergic drugs are first-line drugs for the treatment of OABs. However, anticholinergic drugs need to be used with sufficient consideration for antimuscarinic effects such as dry mouth and residual urine, and are not necessarily effective for all patients (for example, non-patent literature). 1). Under such circumstances, development of a therapeutic agent having a mechanism different from that of an anticholinergic agent is desired (see, for example, Non-Patent Document 1).

In recent years, the role of urothelium has attracted attention in LUTS, especially in OABs. In LUTS, it has become clear that various chemical mediators are released in urothelial cells and cause a micturition reflex through a receptor of the bladder sensory nerve ending. Among them, prostaglandin E ₂ (PGE ₂ ), one of chemical transmitters, binds to prostaglandin E receptor 1 (EP ₁ receptor) of afferent nerves (particularly C fibers) in the urothelium. Increases the micturition reflex. PGE ₂ also contracts the bladder by binding to the EP ₁ receptor present in bladder smooth muscle. In fact, it has been reported that an EP ₁ receptor antagonist suppresses both the enhancement of micturition reflex and the enhancement of afferent nerve activity by PGE ₂ (see, for example, Non-Patent Document 2 and Non-Patent Document 3). ). These suggest that PGE ₂ is involved in bladder smooth muscle contraction and bladder sensory nerve enhancement via the EP ₁ receptor. Furthermore, EP ₁ receptor antagonists have also been reported to increase bladder capacity without increasing residual urine volume (see, for example, Non-Patent Document 4).

In addition to EP ₁ , there are four subtypes of receptors for PGE ₂ , EP ₂ , EP ₃ and EP ₄ . The EP ₁ receptor is present in the lung, skeletal muscle, kidney collecting duct and the like in addition to the bladder and urothelium (see, for example, Non-Patent Document 2). However, it is expected that therapeutic agents for a desired disease can be developed by changing the selectivity of the PGE ₂ receptor subtype and the target organ or target tissue of the drug.

  Now, a compound represented by the general formula (A) is disclosed as a classic complement pathway inhibitor (see, for example, Patent Document 1).

〔式中、Ｒ’、Ｒ”は独立して水素原子または低級アルキル基を表す。〕
しかし、これら化合物がＥＰ_１受容体拮抗作用を有することは、記載も示唆も一切ない
。

[Wherein, R ′ and R ″ each independently represents a hydrogen atom or a lower alkyl group.]
However, there is no description or suggestion that these compounds have an EP ₁ receptor antagonistic action.

Examples of indole derivatives having EP ₁ receptor antagonistic activity include compounds represented by chemical structural formula (B) (6- (6-chloro-3-isobutylindol-1-yl) pyridine-2-carboxylate sodium) and The analog is disclosed (for example, see Non-Patent Document 5).

  However, these compounds differ from the compounds of the present invention in chemical structural formulas in the position and type of substituents. There is no description that it is useful for the treatment of lower urinary tract symptoms.

US Pat. No. 4,510,158

Seki adult, "The Journal of Japanese Pharmacology", 2007, 129, p. 368-373 Xiaojun Wang, et al., `` Biomedical Research '', 2008, 29, p. 105-111 Masahito Kawatani, “PAIN RESEARCH”, 2004, 19, p. 185-190 Masanobu Maekawa, “The Journal of the Japan Urological Function Society”, 2008, 19, p. 169 Adrian Hall, et al., `` Bioorganic & Medicinal Chemistry Letters '', 2008, p.2684-2690

The present invention includes a pharmaceutical use of a compound having EP ₁ receptor antagonistic activity or a pharmacologically acceptable salt thereof, and a compound having EP ₁ receptor antagonistic activity or a pharmacologically acceptable salt thereof. It is an object to provide a pharmaceutical composition.

The present inventors diligently studied to find a compound having an EP ₁ receptor antagonistic action. As a result, it has been found that the compound (I) of the present invention or a pharmacologically acceptable salt thereof has a strong EP ₁ receptor antagonistic activity, and has led to the present invention.

〔式中、
Ａは、以下のａ）〜ｈ）：

からなる群から選択される基であり；
Ｗ^１およびＷ^２は、一方が窒素原子であり、他方が＝ＣＨ−または窒素原子であり；
Ｗ^３は、酸素原子または硫黄原子であり；
Ｗ^４は、＝ＣＨ−または窒素原子であり；
Ｘは、水素原子またはハロゲン原子であり；
Ｙは、Ｃ_１−６アルキレン基またはハロＣ_１−６アルキレン基であり；
Ｒ^Ｎは、水素原子またはＣ_１−６アルキル基であり；
Ｒ^１は、水素原子、Ｃ_１−６アルキル基またはＣ_７−１０アラルキル基であり；
Ｒ^２は、以下のｉ）〜ｍ）：
ｉ）分枝鎖のＣ_３−６アルキル基、
ｊ）Ｃ_３−６シクロアルキル基、
ｋ）非置換もしくは以下からなる群：ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基およびシアノ基から独立して選択される１〜５個の基で環が置換されるフェニル基、
ｌ）非置換もしくは以下からなる群：ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基およびシアノ基から独立して選択される１〜４個の基で環が置換される６員環の芳香族複素環基，および
ｍ）非置換もしくは以下からなる群：ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基およびシアノ基から独立して選択される１〜３個の基で環が置換される５員環の芳香族複素環基
からなる群から選択される基であり；
Ｒ^３は、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基、ハロＣ_１−６アルコキシ基、Ｃ_１−６アルキルスルファニル基、Ｃ_１−６アルキルスルフィニル基、Ｃ_１−６アルキルスルホニル基、
Ｃ_３−６シクロアルキル基、シアノ基、アミノ基またはニトロ基であり；
Ｒ^４は、水素原子、ハロゲン原子、Ｃ_１−６アルキル基またはＣ_１−６アルコキシ基であり；
Ｒ^５は、水素原子、ハロゲン原子、Ｃ_１−６アルキル基またはＣ_１−６アルコキシ基を表す。ただし、（＊）を付された結合はＹと結合し、（＊＊）を付された結合はＣＯ_２Ｒ^１と結合することを表す。〕。
〔２〕Ａが、以下のａ）〜ｄ）：

からなる群から選択される基である、（１）記載のＥＰ_１受容体拮抗薬。
〔３〕Ａが、以下のａ）〜ｃ）：

からなる群から選択される基であり、
Ｗ^１が、窒素原子であり；
Ｗ^２が、＝ＣＨ−あり；
Ｘが、水素原子である、（２）記載のＥＰ_１受容体拮抗薬。
〔４〕Ｒ^２が、以下のａ）〜ｃ）：
ａ）分枝鎖のＣ_３−６アルキル基、
ｂ）フェニル基、および
ｃ）５員環の芳香族複素環基もしくは６員環の芳香族複素環基
からなる群から選択される基であり；
Ｒ^３が、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、Ｃ_１−６アル
コキシ基、ハロＣ_１−６アルコキシ基またはシアノ基であり；
Ｒ^４が水素原子であり；
Ｒ^５が水素原子である、（３）記載のＥＰ_１受容体拮抗薬。
〔５〕Ｒ^１が水素原子である、（４）記載のＥＰ_１受容体拮抗薬。
〔６〕Ｙがメチレン基であり、Ｒ^Ｎが水素原子である、（５）記載のＥＰ_１受容体拮抗薬。
〔７〕Ｒ^２が、フェニル基、５員環の芳香族複素環基または６員環の芳香族複素環である、（６）記載のＥＰ_１受容体拮抗薬。
〔８〕Ｒ^３がハロゲン原子またはＣ_１−６アルコキシ基である、（７）記載のＥＰ_１受容体拮抗薬。
〔９〕Ｒ^２が、イソプロピル基、イソブチル基、ｓｅｃ−ブチル基またはｔｅｒｔ−ブチル基である、（６）記載のＥＰ_１受容体拮抗薬。
〔１０〕Ｒ^３がハロゲン原子またはＣ_１−６アルコキシ基である、（９）記載のＥＰ_１受容体拮抗薬。
〔１１〕Ａが、以下の式

で表される基である、（２）記載のＥＰ_１受容体拮抗薬。
〔１２〕Ｒ^１が、水素原子である、（１１）記載のＥＰ_１受容体拮抗薬。
〔１３〕Ｒ^２が、以下のａ）〜ｄ）：

からなる群から選択される基であり；
Ｗ^５は、窒素原子または−ＣＲ^９ｃ＝であり；
Ｒ^６ａ、Ｒ^６ｂ、Ｒ^６ｃ、Ｒ^６ｄ、Ｒ^６ｅ、Ｒ^７ａ、Ｒ^７ｂ、Ｒ^７ｃ、Ｒ^７ｄ、Ｒ^８ａ、Ｒ^８ｂ、Ｒ^８ｃ、Ｒ^９ａ、Ｒ^９ｂおよびＲ^９ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基またはシアノ基である、（３）記載のＥＰ_１受容体拮抗薬。
〔１４〕Ｒ^１が、水素原子である、（１３）記載のＥＰ_１受容体拮抗薬。
〔１５〕（１）〜（１４）の何れか一項に記載のＥＰ_１受容体拮抗薬を含有する、下部尿路症状の治療または予防薬。
〔１６〕以下からなる群：抗コリン薬、α_１アンタゴニスト、βアゴニスト、５α−リダクターゼ阻害薬、ＰＤＥ阻害薬、アセチルコリンエステラーゼ阻害薬、抗男性ホルモン、プロゲステロン系ホルモン、ＬＨ−ＲＨアナログ、ニューロキニン阻害薬、抗利尿薬、カルシウムチャネルブロッカー、平滑筋直接作用薬、三環系抗うつ薬、Ｋチャネル調節薬、ナトリウムチャネルブロッカー、Ｈ_１ブロッカー、セロトニン再取り込み阻害薬、ノルエピネフリン再取り込み阻害薬、ドーパミン再取り込み阻害薬、ＧＡＢＡアゴニスト、ＴＲＰＶ１調節薬、エンドセリン拮抗薬、５−ＨＴ_１Ａアンタゴニスト、α_１アゴニスト、オピオイドアゴニスト、Ｐ_２Ｘアンタゴニスト、ＣＯＸ阻害薬、σアゴニストおよびムスカリンアゴニストから選択される少なくとも１種の薬剤とを組み合わせて使用する、（１５）記載の下部尿路症状の治療または予防薬。
〔１７〕（１）〜（１４）の何れか一項に記載のＥＰ_１受容体拮抗薬を含有する医薬組成物。
〔１８〕以下からなる群：抗コリン薬、α_１アンタゴニスト、βアゴニスト、５α−リダクターゼ阻害薬、ＰＤＥ阻害薬、アセチルコリンエステラーゼ阻害薬、抗男性ホルモン、プロゲステロン系ホルモン、ＬＨ−ＲＨアナログ、ニューロキニン阻害薬、抗利尿薬、カルシウムチャネルブロッカー、平滑筋直接作用薬、三環系抗うつ薬、Ｋチャネル調節薬、ナトリウムチャネルブロッカー、Ｈ_１ブロッカー、セロトニン再取り込み阻害薬、ノルエピネフリン再取り込み阻害薬、ドーパミン再取り込み阻害薬、ＧＡＢＡアゴニスト、ＴＲＰＶ１調節薬、エンドセリン拮抗薬、５−ＨＴ_１Ａアンタゴニスト、α_１アゴニスト、オピオイドアゴニスト、Ｐ_２Ｘアンタゴニスト、ＣＯＸ阻害薬、σアゴニストおよびムスカリンアゴニストから選択される少なくとも１種の薬剤とを組み合わせて使用する、（１７）記載の医薬組成物。
〔１９〕下部尿路症状の予防または治療用の医薬組成物を製造するための、（１）〜（１４）の何れか一項に記載の化合物、またはその薬理学的に許容される塩の使用。 That is, the means for solving the above problems are as follows.
[1] EP ₁ receptor antagonist containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof

[Where,
A represents the following a) to h):

A group selected from the group consisting of:
One of W ¹ and W ² is a nitrogen atom, and the other is ═CH— or a nitrogen atom;
W ³ is an oxygen atom or a sulfur atom;
W ⁴ is ═CH— or a nitrogen atom;
X is a hydrogen atom or a halogen atom;
Y is a C _1-6 alkylene group or a halo C _1-6 alkylene group;
^RN is a hydrogen atom or a C _1-6 alkyl group;
R ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _7-10 aralkyl group;
R ² represents the following i) to m):
i) a branched C _3-6 alkyl group,
j) a C _3-6 cycloalkyl group,
k) unsubstituted or selected from the group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group and a cyano group A phenyl group wherein the ring is substituted with 1 to 5 groups,
l) unsubstituted or independently selected from the group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group and a cyano group A 6-membered aromatic heterocyclic group in which the ring is substituted with 1-4 groups, and m) unsubstituted or a group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 It consists of a 5-membered aromatic heterocyclic group in which the ring is substituted with 1 to 3 groups independently selected from an alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group and a cyano group A group selected from the group;
R ³ is a halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, hydroxy C _1-6 alkyl group, C _1-6 alkoxy group, halo C _1-6 alkoxy group, C _1-6 alkyl A sulfanyl group, a C _1-6 alkylsulfinyl group, a C _1-6 alkylsulfonyl group,
A C _3-6 cycloalkyl group, a cyano group, an amino group or a nitro group;
R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group;
R ⁵ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group. However, the bond marked with (*) is bonded to Y, and the bond marked with (**) is bonded to CO ₂ R ¹ . ].
[2] A is the following a) to d):

The EP ₁ receptor antagonist according to (1), which is a group selected from the group consisting of:
[3] A is the following a) to c):

A group selected from the group consisting of:
W ¹ is a nitrogen atom;
W ² is ═CH—;
The EP ₁ receptor antagonist according to (2), wherein X is a hydrogen atom.
[4] R ² is the following a) to c):
a) a branched C _3-6 alkyl group,
a group selected from the group consisting of b) a phenyl group, and c) a 5-membered aromatic heterocyclic group or a 6-membered aromatic heterocyclic group;
R ³ is a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a halo C _1-6 alkoxy group or a cyano group;
R ⁴ is a hydrogen atom;
The EP ₁ receptor antagonist according to (3), wherein R ⁵ is a hydrogen atom.
[5] The EP ₁ receptor antagonist according to (4), wherein R ¹ is a hydrogen atom.
[6] The EP ₁ receptor antagonist according to (5), wherein Y is a methylene group and ^RN is a hydrogen atom.
[7] The EP ₁ receptor antagonist according to (6), wherein R ² is a phenyl group, a 5-membered aromatic heterocyclic group or a 6-membered aromatic heterocyclic ring.
[8] The EP ₁ receptor antagonist according to (7), wherein R ³ is a halogen atom or a C _1-6 alkoxy group.
[9] The EP ₁ receptor antagonist according to (6), wherein R ² is an isopropyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.
[10] The EP ₁ receptor antagonist according to (9), wherein R ³ is a halogen atom or a C _1-6 alkoxy group.
[11] A is the following formula

The EP ₁ receptor antagonist according to (2), which is a group represented by:
[12] The EP ₁ receptor antagonist according to (11), wherein R ¹ is a hydrogen atom.
[13] R ² is the following a) to d):

A group selected from the group consisting of:
W ⁵ is a nitrogen atom or —CR ^9c =;
R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^7a , R ^7b , R ^7c , R ^7d , R ^8a , R ^8b , R ^8c , R ^9a , R ^9b and R ^9c are each independently EP ₁ acceptance according to (3), which is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group or a cyano group Body antagonist.
[14] The EP ₁ receptor antagonist according to (13), wherein R ¹ is a hydrogen atom.
[15] A therapeutic or prophylactic agent for lower urinary tract symptoms, comprising the EP ₁ receptor antagonist according to any one of (1) to (14).
[16] the group consisting of: anticholinergics, alpha ₁ antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitory drugs, anti-diuretics, calcium channel blockers, smooth muscle direct action, tricyclic antidepressants, K channel modulating agents, sodium channel blockers, H ₁ blockers, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine re Selected from uptake inhibitors, GABA agonists, TRPV1 modulators, endothelin antagonists, 5-HT _1A antagonists, α ₁ agonists, opioid agonists, P ₂ X antagonists, COX inhibitors, σ agonists and muscarinic agonists The therapeutic or prophylactic agent for lower urinary tract symptoms according to (15), which is used in combination with at least one pharmaceutical agent.
[17] A pharmaceutical composition comprising the EP ₁ receptor antagonist according to any one of (1) to (14).
[18] the group consisting of: anticholinergics, alpha ₁ antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitory drugs, anti-diuretics, calcium channel blockers, smooth muscle direct action, tricyclic antidepressants, K channel modulating agents, sodium channel blockers, H ₁ blockers, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine re Selected from uptake inhibitors, GABA agonists, TRPV1 modulators, endothelin antagonists, 5-HT _1A antagonists, α ₁ agonists, opioid agonists, P ₂ X antagonists, COX inhibitors, σ agonists and muscarinic agonists The pharmaceutical composition according to (17), which is used in combination with at least one drug.
[19] A compound of any one of (1) to (14) or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating lower urinary tract symptoms. use.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof exhibited a strong EP ₁ receptor antagonism in, for example, an EP ₁ receptor antagonism confirmation test. Therefore, the compound (I) of the present invention, or a pharmacologically acceptable salt thereof, treats lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs), etc., based on EP ₁ receptor antagonism. Useful as a drug or prophylactic.

  Terms used in this specification will be described.

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

The “C _1-6 alkyl group” means an alkyl group having 1 to 6 carbon atoms which may be branched. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, Examples thereof include 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group and the like. In R ³ , a methyl group, an ethyl group or a propyl group is preferable, a methyl group or an ethyl group is more preferable, and a methyl group is further preferable. In ^RN , a methyl group is preferable.

The “branched C _3-6 alkyl group” means a branched alkyl group having 3 to 6 carbon atoms. For example, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-ethyl A propyl group, an isohexyl group, etc. are mentioned. Preferably, they are isopropyl group, isobutyl group, sec-butyl group, tert-butyl group or 1-ethylpropyl group. More preferably, they are isopropyl group, isobutyl group, sec-butyl group, or tert-butyl group. More preferred is a tert-butyl group.

The “C _1-6 alkoxy group” means an alkoxy group having 1 to 6 carbon atoms which may be branched. Examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group. In R ³ , a methoxy group or an ethoxy group is preferable, and a methoxy group is more preferable.

The “halo C _1-6 alkyl group” means a C _1-6 alkyl group substituted with 1 to 5 same or different halogen atoms. For example, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-chloroethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group 2,2,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 2,2,2-trichloroethyl group, 3-fluoropropyl group, 2-fluoropropyl group, -Fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1-difluoropropyl group, 1-fluorobutyl group, 1-fluoropentyl group or 1-fluorohexyl group . Preferably, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group or 2,2 , 2-trifluoroethyl group. More preferably, they are a monofluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 1,1-difluoroethyl group, a 1,2-difluoroethyl group, or a 2,2,2-trifluoroethyl group. More preferably, it is a monofluoromethyl group or a trifluoromethyl group.

“Hydroxy C _1-6 alkyl group” means a C _1-6 alkyl group substituted with a hydroxyl group. For example, a hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1,1-dimethylmethyl group, 2-hydroxyethyl group, 2-hydroxy-2-methylpropyl group, 3-hydroxypropyl group and the like can be mentioned.

The “C _1-6 alkylsulfanyl group” means a group represented by (C _1-6 alkyl) -S—. Examples thereof include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, a butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group.

The “C _1-6 alkylsulfinyl group” means a group represented by (C _1-6 alkyl) -S (═O) —. Examples thereof include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, a butylsulfinyl group, a pentylsulfinyl group, and a hexylsulfinyl group.

The “C _1-6 alkylsulfonyl group” means a group represented by (C _1-6 alkyl) -SO ₂ —. Examples thereof include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, and a hexanesulfonyl group.

The “C _3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms. For example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. are mentioned. Preferably, it is a cyclopropyl group or a cyclopentyl group. R ³ is more preferably a cyclopropyl group.

The “halo C _1-6 alkoxy group” means a C _1-6 alkoxy group substituted with 1 to 5 same or different halogen atoms. For example, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-chloroethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 1,1-difluoroethoxy group, 1,2-difluoroethoxy Group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2,2,2-trichloroethoxy group, 3-fluoropropoxy group, 2-fluoropropoxy group, 1-fluoropropoxy group, 3,3-difluoropropoxy group, 2,2-difluoropropoxy group, 1,1-difluoropropoxy group, 4-fluorobutoxy group, 5-fluoropentyloxy group, 6-fluorohexyloxy group, etc. Is mentioned. Preferably, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 1,1-difluoroethoxy group, 1,2-difluoroethoxy group or 2,2 , 2-trifluoroethoxy group. More preferably, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 1,1-difluoroethoxy group, 1,2-difluoroethoxy group or 2,2,2-trifluoroethoxy group It is. More preferred is a difluoromethoxy group or a trifluoromethoxy group.

The “C _7-10 aralkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with an aryl group. For example, benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like can be mentioned.

  The “5- or 6-membered aromatic heterocyclic group” means a 5- or 6-membered ring group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring. . For example, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, furyl group, pyrrolyl group, thienyl group, imidazolyl group, pyrazolyl group, 1,2,4-triazolyl group, isothiazolyl group, isoxazolyl group, oxazolyl group, thiazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group and the like can be mentioned. Preferably, it is a 5-membered aromatic heterocyclic group. More preferred is a 2-furyl group, a 3-furyl group, a 2-thienyl group or a 3-thienyl group. More preferred is a 3-furyl group or a 3-thienyl group.

  The “5-membered aromatic heterocyclic group” means a 5-membered ring group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring. For example, furyl group, pyrrolyl group, thienyl group, imidazolyl group, pyrazolyl group, 1,2,4-triazolyl group, isothiazolyl group, isoxazolyl group, oxazolyl group, thiazolyl group, 1,3,4-oxadiazolyl group, 1,2 , 4-oxadiazolyl group and the like. 2-furyl group, 3-furyl group, 2-thienyl group or 3-thienyl group is preferable. More preferred is a 3-furyl group or a 3-thienyl group.

  The “6-membered aromatic heterocyclic group” means a 6-membered ring group containing 1 to 4 nitrogen atoms in the ring. For example, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, etc. are mentioned. A pyridyl group is preferable, and a 3-pyridyl group is more preferable.

The “C _1-6 alkylene group” means a divalent straight chain or branched saturated hydrocarbon chain having 1 to 6 carbon atoms. For _{example, -CH 2 -, - CH 2} CH 2 -, - CH (CH 3) -, - (CH 2) 3 -, - CH (CH 3) CH 2 -, - CH 2 CH (CH 3) -, _{-CH (CH 2 CH 3) -} , - C (CH 3) 2 -, - (CH 2) 4 -, - CH (CH 3) - (CH 2) 2 -, - (CH 2) 2 -CH ( _{CH 3) -, - CH (} CH 2 CH 3) -CH 2 -, - C (CH 3) 2 CH 2 -, - CH 2 -C (CH 3) 2 -, - CH (CH 3) -CH ( _{CH 3) -, - (CH} 2) 5 -, - CH (CH 3) - (CH 2) 3 -, - C (CH 3) 2 CH 2 CH 2 -, - (CH 2) 6 -, - C (CH ₃ ) ₂ (CH ₂ ) ₃ — and the like can be mentioned.

The “C _1-5 alkylene group” means a divalent straight chain or branched saturated hydrocarbon chain having 1 to 5 carbon atoms. For _{example, -CH 2 -, - (CH} 2) 2 -, - CH (CH 3) -, - (CH 2) 3 -, - CH 2 -CH (CH 3) -, - C (CH 3) 2 - , — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ — and the like.

The “halo C _1-6 alkylene group” means a group in which a hydrogen atom of a C _1-6 alkylene group is substituted with 1 to 4 halogen atoms. The halogen atom for substituting a hydrogen atom is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. Examples of such halo C _1-6 alkylene groups include —CHF—, —CF ₂ —, —CF ₂ CH ₂ —, CH ₂ CF ₂ —, CF ₂ CF ₂ —, —CCl ₂ —, —CCl. ₂ CH ₂ —, —CH ₂ CCl ₂ —, —CCl ₂ CCl ₂ —, and the like.

  Hereinafter, the present invention will be described in more detail.

  When one or more asymmetric carbon atoms are present in the compound (I) of the present invention, the present invention relates to a compound in which each asymmetric carbon atom is in the R configuration, a compound in the S configuration, and any combination thereof. Any compound is included. Also included within the scope of the present invention are those racemates, racemic mixtures, single enantiomers and diastereomeric mixtures. When geometric isomerism exists in the compound (I) of the present invention, the present invention includes any of the geometric isomers.

  Compound (I) of the present invention can be converted into a pharmacologically acceptable salt thereof according to a conventional method as necessary. Such a salt can be an acid addition salt or a salt with a base.

  Such acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzene Organic acids such as sulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid and aspartic acid The acid addition salt of can be mentioned.

  Examples of the salt with a base include a salt with an inorganic base such as sodium salt, potassium salt, calcium salt and magnesium salt, and a salt with an organic base such as piperidine, morpholine, pyrrolidine, arginine and lysine.

  Further, the compound (I) of the present invention or a pharmacologically acceptable salt thereof includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.

The “EP ₁ receptor antagonism” as used in the present invention means an action of inhibiting the binding of prostaglandin E ₂ (PGE ₂ ) to prostaglandin E receptor 1 (EP ₁ receptor).
EP ₁ receptor antagonism decreases the inflow of calcium into the cell and decreases or suppresses the intracellular calcium concentration. As a result, the EP ₁ receptor antagonism exhibits actions such as smooth muscle relaxation and suppression of sensory nerve stimulation. In particular, EP ₁ receptor antagonists are useful as therapeutic or prophylactic agents for symptoms such as LUTS, especially OABs, by acting on the bladder, urothelium and the like.
Moreover, EP ₁ receptor antagonism can be evaluated by the efficacy of inhibiting the amount of calcium inflow into cells by PGE ₂ . This efficacy can be evaluated by an in vitro test or an in vivo test according to “Pharmacological Test Examples” described in JP-A-2008-214224.

  In the compound (I) of the present invention or a pharmacologically acceptable salt thereof, preferred substituents are as follows.

(I-1) A is preferably a benzene ring, a pyridine ring or a thiazole ring.
(I-2) Y is preferably a methylene group, —CH (CH ₃ ) — or —C (CH ₃ ) ₂ —, more preferably a methylene group.
(I-3) R ¹ is preferably a hydrogen atom or a C _1-6 alkyl group, and more preferably a hydrogen atom.
(I-4) R ² is preferably a tert-butyl group, a phenyl group, a 5-membered aromatic heterocyclic group or a 6-membered aromatic heterocyclic group, a group consisting of the following: a halogen atom, C _1- A phenyl group in which the ring is substituted with 1 to 3 groups independently selected from a ₆ alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group and a cyano group 1 to independently selected from the group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group, and a cyano group. A 6-membered aromatic heterocyclic group in which the ring is substituted by two groups, or a group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl Group, C _1-6 alkoxy It is a 5-membered aromatic heterocyclic group in which the ring is substituted with 1 to 2 groups independently selected from the Si group and the cyano group. More preferably, a tert-butyl group, a phenyl group, a 3-furyl group, a 3-thienyl group, or the following a) to d):

からなる群から選択される基である（式中、
Ｒ^６ａ、Ｒ^６ｂ、Ｒ^６ｃ、Ｒ^６ｄおよびＲ^６ｅは以下のｅ）〜ｇ）：
ｅ）Ｒ^６ａ、Ｒ^６ｂ、Ｒ^６ｃ、Ｒ^６ｄおよびＲ^６ｅの内の１つの基はハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、その他の４つの基は水素原子、
ｆ）Ｒ^６ａ、Ｒ^６ｂ、Ｒ^６ｃ、Ｒ^６ｄおよびＲ^６ｅの内の２つの基は、それぞれ独立して、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、その他の３つの基は水素原子、および
ｇ）Ｒ^６ａ、Ｒ^６ｂ、Ｒ^６ｃ、Ｒ^６ｄおよびＲ^６ｅの内の３つの基は、それぞれ独立して、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、その他の２つの基は水素原子からなる群から選択される基であり、
Ｒ^７ａ、Ｒ^７ｂ、Ｒ^７ｃおよびＲ^７ｄは以下のｈ）およびｉ）：
ｈ）Ｒ^７ａ、Ｒ^７ｂ、Ｒ^７ｃおよびＲ^７ｄの内の１つの基はハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、その他の３つの基は水素原子、および
ｉ）Ｒ^７ａ、Ｒ^７ｂ、Ｒ^７ｃおよびＲ^７ｄの内の２つの基は、それぞれ独立して、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、その他の２つの基は水素原子
からなる群から選択される基であり、
Ｒ^８ａ、Ｒ^８ｂ、およびＲ^８ｃは以下のｊ）およびｋ）：
ｊ）Ｒ^８ａ、Ｒ^８ｂおよびＲ^８ｃの内の１つの基は、ハロゲン原子、Ｃ_１−６アルキル基
、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、その他の２つの基は水素原子、および
ｋ）Ｒ^８ａ、Ｒ^８ｂおよびＲ^８ｃの内の２つの基は、それぞれ独立して、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、その他は水素原子
からなる群から選択される基であり、
Ｒ^９ａおよびＲ^９ｂは、ｗ^５が−ＣＲ^９ｃ＝である場合、Ｒ^９ａ、Ｒ^９ｂおよびＲ^９ｃの内の１つの基が、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、その他の２つの基が水素原子であり、ｗ^５が窒素原子である場合、Ｒ^９ａおよびＲ^９ｂの内の１つの基が、ハロゲン原子、Ｃ_１−６アルキル基、ハロＣ_１−６アルキル基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−６アルコキシ基もしくはシアノ基であり、他方の基が水素原子である）。さらに好ましくはｔｅｒｔ−ブチル基またはフェニル基である。
（Ｉ−５）Ｒ^３は、好ましくは塩素原子、フッ素原子、メチル基、トリフルオロメチル基、メトキシ基、エトキシ基またはトリフルオロメトキシ基であり、より好ましくは塩素原子、フッ素原子、メチル基、メトキシ基、エトキシ基またはトリフルオロメトキシ基であり、さらに好ましくは塩素原子またはメトキシ基であり、特に好ましくはメトキシ基である。
（Ｉ−６）Ｒ^Ｎは、好ましくは水素原子またはメチル基であり、より好ましくは水素原子である。

A group selected from the group consisting of:
R ^6a , R ^6b , R ^6c , R ^6d and R ^6e are the following e) to g):
e) one of R ^6a , R ^6b , R ^6c , R ^6d and R ^6e is a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, C _1-6 alkoxy group or cyano group, the other four groups are hydrogen atoms,
f) Two groups out of R ^6a , R ^6b , R ^6c , R ^6d and R ^6e are each independently a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _{1 A -6} alkyl group, a C _1-6 alkoxy group or a cyano group, the other three groups are hydrogen atoms, and g) three groups of R ^6a , R ^6b , R ^6c , R ^6d and R ^6e are Each independently a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group or a cyano group, and the other two groups are A group selected from the group consisting of hydrogen atoms,
R ^7a , R ^7b , R ^7c and R ^7d are h) and i) below:
h) one of R ^7a , R ^7b , R ^7c and R ^7d is a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 An alkoxy group or a cyano group, the other three groups are hydrogen atoms, and i) two groups of R ^7a , R ^7b , R ^7c and R ^7d are each independently a halogen atom, C _{1- 6} alkyl group, halo C _1-6 alkyl group, hydroxy C _1-6 alkyl group, C _1-6 alkoxy group or cyano group, and the other two groups are groups selected from the group consisting of hydrogen atoms ,
R ^8a , R ^8b , and R ^8c are the following j) and k):
j) One of R ^8a , R ^8b and R ^8c is a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, or a C _1-6 alkoxy group. Or a cyano group, the other two groups are hydrogen atoms, and k) two of R ^8a , R ^8b and R ^8c are each independently a halogen atom, a C _1-6 alkyl group, a halo A C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group or a cyano group, and the others are groups selected from the group consisting of hydrogen atoms,
R ^9a and R ^9b are such that when w ⁵ is —CR ^9c =, one of R ^9a , R ^9b and R ^9c is a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl Group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group or a cyano group, when the other two groups are a hydrogen atom and w ⁵ is a nitrogen atom, R ^9a and R ^9b One group is a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group or a cyano group, and the other group is a hydrogen atom is there). More preferred is a tert-butyl group or a phenyl group.
(I-5) R ³ is preferably a chlorine atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a trifluoromethoxy group, more preferably a chlorine atom, a fluorine atom, a methyl group, It is a methoxy group, an ethoxy group or a trifluoromethoxy group, more preferably a chlorine atom or a methoxy group, and particularly preferably a methoxy group.
(I-6) ^RN is preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom.

  A preferred embodiment of the compound (I) of the present invention or a pharmacologically acceptable salt thereof is a compound comprising a combination of preferred substituents described in (I-1) to (I-6).

Embodiment 1
As a preferred embodiment of the present invention,
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is a phenyl group or a 5-membered aromatic heterocyclic group;
R ³ is a methoxy group or an ethoxy group;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
6- (6-Methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 4-1), 3- (6-methoxy-2-phenyl-1H-indole-3- Ylmethyl) benzoic acid (Example 4-2), 3- (6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) benzoic acid (Example 4-12), 6- (6- Ethoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 4-34), 6- (6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) ) Pyridine-2-carboxylic acid (Example 11-1), 6- [2- (3-Fluorophenyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 1) -5), 6- (2-furan-3-yl-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 11-10), 6- [2- (4-fluoro Phenyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Examples 11-13), 3- (2-furan-3-yl-6-methoxy-1H-indole-3- Ylmethyl) benzoic acid (Examples 11-15), 6- (6-methoxy-2-thiophen-2-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 11-17), 6 -[6-Methoxy-2- (5-methylthiophen-3-yl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 11-20), 6- [2- (3-chlorophenyl) ) 6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 11-21), 6- (6-methoxy-2-thiazol-5-yl-1H-indol-3-ylmethyl) pyridine 2-carboxylic acid (Examples 11-24), 6- [6-methoxy-2- (3-methoxyphenyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Examples 11-34) , 6- [2- (3,4-Difluorophenyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 16-2), 6- [6-Methoxy-2- (3,4,5-trifluorophenyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 16-6), 2-fluoro-3- (6-methoxy-2-phen Nyl-1H-indol-3-ylmethyl) benzoic acid (Example 16-9), 6- (6-methoxy-5-methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid ( Examples 16-12), 6- (5-chloro-6-methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-13), 6- (5-fluoro) -6-methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-16), 2-fluoro-5- (6-methoxy-2-phenyl-1H-indole- 3-ylmethyl) benzoic acid (Examples 16-18), 6- (6-methoxy-5-methyl-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridin-2- Rubonic acid (Examples 16-24), 6- (5-Fluoro-6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-28) , 6- (5-Chloro-6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-29), 6- [6-Ethoxy-2 -(4-Fluorophenyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 16-60), 6- (6-Ethoxy-2-thiophen-3-yl-1H-indole-3 -Ylmethyl) pyridine-2-carboxylic acid (Examples 16-61), 6- (6-Ethoxy-5-fluoro-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyrid 2-carboxylic acid (Example 16-79), 6- (6-ethoxy-5-methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-84), 6- [2- (4-Fluorophenyl) -6-methoxy-5-methyl-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 16-85), 6- (6-Ethoxy-5 -Methyl-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-93).

Embodiment 2
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is an unsubstituted phenyl group;
R ³ is a methoxy group;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
6- (6-Methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 4-1), 3- (6-methoxy-2-phenyl-1H-indole-3- Ylmethyl) benzoic acid (Example 4-2), 2-fluoro-3- (6-methoxy-2-phenyl-1H-indol-3-ylmethyl) benzoic acid (Example 16-9), 6- (6- Methoxy-5-methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-12), 6- (5-chloro-6-methoxy-2-phenyl-1H-indole -3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-13), 6- (5-fluoro-6-methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-cal Phosphate (Example 16-16), 2-fluoro-5- (6-methoxy-2-phenyl--1H- indol-3-ylmethyl) benzoic acid (Example 16-18).

Embodiment 3
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is a substituted phenyl group;
R ³ is a methoxy group;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
6- [2- (3-Fluorophenyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 11-5), 6- [2- (4-fluorophenyl)- 6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Examples 11-13), 6- [2- (3-chlorophenyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine 2-carboxylic acid (Examples 11-21), 6- [6-methoxy-2- (3-methoxyphenyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Examples 11-34) , 6- [2- (3,4-difluorophenyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 16-2), 6- [6-methoxy -2- (3,4,5-trifluorophenyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 16-6), 6- [2- (5-fluoropyridine-3- Yl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 16-11), 6- [2- (4-fluorophenyl) -6-methoxy-5-methyl-1H -Indol-3-ylmethyl] pyridine-2-carboxylic acid (Examples 16-85).

Embodiment 4
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is an optionally substituted 5-membered aromatic heterocyclic group;
R ³ is a methoxy group;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
3- (6-Methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) benzoic acid (Example 4-12), 6- (6-Methoxy-2-thiophen-3-yl-1H- Indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 11-1), 6- (2-furan-3-yl-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid ( Example 11-10), 3- (2-furan-3-yl-6-methoxy-1H-indol-3-ylmethyl) benzoic acid (Example 11-15), 6- (6-methoxy-2-thiophene) 2-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 11-17), 6- [6-methoxy-2- (5-methylthiophen-3-yl) -1H-indole -3 [Ilmethyl] pyridine-2-carboxylic acid (Examples 11-20), 6- (6-methoxy-5-methyl-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid ( Examples 16-24), 6- (5-Fluoro-6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-28), 6- (5-Chloro-6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-29).

Embodiment 5
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is a 6-membered aromatic heterocyclic group which may have a substituent;
R ³ is a methoxy group;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
6- (6-Methoxy-2-pyridin-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 11-11), 6- [2- (5-fluoropyridine-3- Yl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 16-11), 6- (6-methoxy-5-methyl-2-pyridin-3-yl-1H- Indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-66).

Embodiment 6
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is a phenyl group which may have a substituent or a 5-membered aromatic heterocyclic group which may have a substituent;
R ³ is a halogen atom;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
6- (6-Chloro-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 4-17), 6- (6-Chloro-5-methoxy-2-phenyl-1H- Indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-23), 6- (6-chloro-5-fluoro-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2 -Carboxylic acid (Examples 16-52), 6- (6-chloro-5-methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-59), 6- (6-Chloro-5-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-86), 6- (6-Chloro-5-methyl- -Thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-92), 6- (6-chloro-2-furan-3-yl-5-methoxy-1H- Indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-105).

Embodiment 7
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is isopropyl, isobutyl, sec-butyl or tert-butyl;
R ³ is a methoxy group or an ethoxy group;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
6- (2-tert-butyl-5-chloro-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-89), 6- (2-tert-butyl-5- Fluoro-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-97), 6- (2-tert-butyl-6-methoxy-5-methyl-1H-indole-3) -Ylmethyl) pyridine-2-carboxylic acid (Examples 16-98), 6- (2-sec-butyl-5-chloro-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (implementation) Examples 16-107), 6- (5-Chloro-2-isopropyl-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-109) , 6- (5-fluoro-2-isopropyl-6-methoxy -1H- indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 18-1).

Embodiment 8
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is a tert-butyl group, a phenyl group or a 5-membered aromatic heterocyclic group;
R ³ is a chlorine atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a trifluoromethoxy group;
^RN is a methyl group.

Embodiment 9
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a C _1-6 alkyl group;
R ² is a tert-butyl group, a phenyl group or a 5-membered aromatic heterocyclic group;
R ³ is a chlorine atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a trifluoromethoxy group;
^RN is a hydrogen atom or a methyl group.

Embodiment 10
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is a phenyl group which may have a substituent, a 5-membered aromatic heterocyclic group which may have a substituent or a 6-membered aromatic heterocyclic group which may have a substituent. Yes;
R ³ is a cyclopropyl group;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
6- (6-Cyclopropyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-8), 6- [6-cyclopropyl-2- (4-fluorophenyl) -1H-Indol-3-ylmethyl] pyridine-2-carboxylic acid (Examples 16-62), 6- (6-Cyclopropyl-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2 -Carboxylic acid (Examples 16-65), 6- (6-cyclopropyl-2-pyridin-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-67), 6 -(6-Cyclopropyl-5-fluoro-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-68), 6- [6-cyclo (Lopyl-5-fluoro-2- (4-fluorophenyl) -1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-74), 6- (6-cyclopropyl-5-fluoro-2) -Thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-75), 6- (6-cyclopropyl-5-fluoro-2-pyridin-3-yl-1H) -Indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-76), 6- (6-Cyclopropyl-5-methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid Acid (Example 16-100), 6- (6-Cyclopropyl-5-methyl-2-pyridin-3-yl-1H-indol-3-ylmethyl) pyridine-2 Carboxylic acid (Examples 16-101), 6- (6-Cyclopropyl-5-methyl-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-102) ).

Embodiment 11
Another preferred embodiment of the present invention includes:
Y is a methylene group;
A is a benzene ring or a pyridine ring;
R ¹ is a hydrogen atom;
R ² is a phenyl group which may have a substituent, a 5-membered aromatic heterocyclic group which may have a substituent or a 6-membered aromatic heterocyclic group which may have a substituent. Yes;
R ³ is a methyl group;
^RN is a hydrogen atom.

Specific compounds included in this embodiment include the following compounds.
6- (6-Methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 4-35), 6- (6-Methyl-2-thiophen-3-yl-1H- Indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-21), 6- (5,6-dimethyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example) 16-44), 6- [2- (4-fluorophenyl) -6-methyl-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Examples 16-48), 6- (5,6- Dimethyl-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-51), 6- (5-fluoro-6-methyl-2-phenyl-1H-in Ol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-53), 6- [5-fluoro-2- (4-fluorophenyl) -6-methyl-1H-indol-3-ylmethyl] pyridine 2-carboxylic acid (Examples 16-54), 6- (5-fluoro-6-methyl-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16) -56), 6- (5,6-dimethyl-2-pyridin-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-58), 6- (5-methoxy- 6-Methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid (Examples 16-78), 6- (5-methoxy-6-methyl-2-thiophen-3-yl-1H) Indol-3-ylmethyl) pyridine-2-carboxylic acid (Example 16-108).

Process for producing compound (I) of the present invention

  The compound (I) of the present invention or a pharmacologically acceptable salt thereof is a method shown in the following schemes 1 to 2 or 4, or a method equivalent thereto, or a method described in the literature or a method equivalent thereto, etc. Can be manufactured according to.

[A] Synthesis of Compounds (Ia) to (Id) Compound (I) of the present invention can be produced as compounds (Ia) to (Id) by the method shown in Schemes 1-2 or 4. In addition, when a protective group is required, it can implement by combining operation of introduction and removal suitably according to a conventional method.

^{(Wherein, R 2, R 3, R} 4, R 5, A, and Y are, are the same as defined above, ^{R K} is _{C 1-6} alkyl group or a _{C 7-10} aralkyl group, ^{X 1} is It represents a leaving group such as a chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, Y ¹ represents a single bond or a C _1-5 alkylene group, and R ^L represents C _1-6. Represents an alkyl group.)

Step 1-1
Compound (Ia) is obtained by reacting compound (1) and compound (2) in a solvent in the presence of a reducing agent and an acid. Examples of the solvent used include methylene chloride and tetrahydrofuran. Examples of the reducing agent include triethylsilane, and examples of the acid include trifluoroacetic acid, acetic acid, trimethylsilyl = trifluoromethanesulfonate, boron trifluoride / ethyl ether complex, and the like. The reaction temperature is usually −70 ° C. to 50 ° C., and the reaction time is usually 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, and the reaction temperature.
Moreover, the compound (2) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, the method according to them, etc.

Step 1-2
Compound (Ib) is obtained by treating compound (Ia) according to a method such as alkaline hydrolysis generally used in organic synthesis. Examples of the solvent used include methanol, ethanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The reaction temperature is usually room temperature to solvent reflux temperature, and the reaction time is usually 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. In addition, this process can also consider the method by acid hydrolysis and hydrogenolysis, Theodora W. et al. Greene & Peter G. M.M. It can also be carried out according to the method described in Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.

Step 1-3
Compound (4) is obtained by reacting compound (1) and compound (3) in a solvent in the presence of a base. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylimidazolidinone, 1-methyl-2-pyrrolidone, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the base include sodium hydride, cesium carbonate, potassium carbonate, potassium tert-butoxide, lithium bis (trimethylsilyl) amide and the like. The reaction temperature is usually −20 ° C. to solvent reflux temperature, and the reaction time is usually 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. In this step, an additive such as sodium iodide may be used as necessary.
Moreover, the compound (3) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, the method according to them, etc.

Step 1-4
In the same manner as in Step 1-3, compound (Ic) can be obtained from compound (Ia) and compound (3).

Step 1-5
In the same manner as in Step 1-1, compound (Ic) can be obtained from compound (4) and compound (2).

Step 1-6
Compound (Id) is obtained by hydrolyzing compound (Ic) in the same manner as in Step 1-2.

  Compound (1) can be obtained by the method shown in the following scheme 3.

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ^K , A and Y are as defined above, and X ² is a chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy group, methane Represents a leaving group such as a sulfonyloxy group.)

Step 2-1
Compound (7) is obtained by reacting compound (5) and compound (6) in a solvent in the presence of a base. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylimidazolidinone, 1-methyl-2-pyrrolidone, tetrahydrofuran and the like, and the base includes sodium hydride. Cesium carbonate, potassium carbonate, potassium tert-butoxide, 1,8-diazabicycloundeca [5.4.0] -7-ene (DBU), lithium bis (trimethylsilyl) amide, and the like. The reaction temperature is usually −20 ° C. to solvent reflux temperature, and the reaction time is usually 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. In this step, an additive such as sodium iodide may be used as necessary.

Step 2-2
Compound (Ia) is obtained by reacting compound (7) in a solvent or without a solvent under acidic conditions. Examples of the solvent used include methylene chloride and tetrahydrofuran, and examples of the acid include trifluoroacetic acid, acetic acid, hydrogen chloride, sulfuric acid and the like. The reaction temperature is usually from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 24 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 2-3
Compound (Ib) is obtained by hydrolyzing compound (Ia) in the same manner as in Step 1-2.

  Compound (5) can be obtained according to steps 3-6 to 3-8 shown in the following scheme 3.

[B] Synthesis of Compound (1) and Compound (5)

  The compound (1) used in Scheme 1 and the compound (5) used in Scheme 2 are obtained by the method shown in Scheme 3.

^{(Wherein, R 2, R 3, R} 4 and ^{R 5} are the same as defined above, ^{X 3} represents a leaving group such as chlorine atom, bromine atom, iodine atom, trifluoromethanesulfonyloxy group, ^{X 4} X ⁵ represents a halogen atom such as a chlorine atom or a bromine atom.)

Step 3-1
Compound (9) is obtained by acylating compound (8) with trifluoroacetic anhydride. Such acylation reactions are well known to those skilled in the art and are described in Theodora W., et al. Greene & Peter G. M.M. It can also be carried out according to the method described in Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.
Moreover, the compound (8) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, the method according to them, etc.

Step 3-2
Compound (1) is obtained by reacting compound (9) and compound (10) in a solvent in the presence of a base, a copper catalyst, and a palladium catalyst. Examples of the solvent used include tetrahydrofuran, acetonitrile, N, N-dimethylformamide and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine, potassium carbonate, potassium phosphate and the like. Examples of the palladium catalyst include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and examples of the copper catalyst include copper (I) iodide. The reaction temperature is usually room temperature to solvent reflux temperature, and the reaction time is usually 30 minutes to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like. This step can also be performed in the absence of a palladium catalyst. In that case, an amino acid derivative such as N, N-dimethylglycine or L-proline may be used as an additive.

Step 3-3
Compound (12) is obtained by reacting compound (11) with halomethane in a solvent in the presence of a base and triphenylphosphine. Examples of the solvent used include methylene chloride and tetrahydrofuran. Examples of the halomethane used include carbon tetrabromide, carbon tetrachloride, and chloroform. Examples of the base include potassium tert-butoxide. The reaction temperature is usually room temperature to solvent reflux temperature, and the reaction time is usually 30 minutes to 24 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. In addition, this process can be performed in absence of a base, when carbon tetrabromide is used as halomethane.
In addition, the compound (11) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, the method according to them, etc.

Step 3-4
Compound (13) is obtained by reducing compound (12) by a general catalytic reduction method or a reduction method using a metal or a metal salt.
1) The catalytic reduction method can be carried out by using compound (12) in a solvent in a solvent under a hydrogen atmosphere. Examples of the solvent used include methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid and the like. Examples of the catalyst include palladium carbon powder, rhodium carbon powder, platinum carbon powder, platinum carbon powder doped with vanadium, and preferably platinum carbon powder doped with vanadium. The reaction temperature is usually room temperature to solvent reflux temperature, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but may be treated for 1 hour to 3 days.
2) The reduction method using a metal or a metal salt can be performed by using compound (12) in a solvent under acidic conditions and using a reducing agent. Examples of the solvent used include methanol, ethanol, tetrahydrofuran and the like. Examples of the acid include acetic acid, ammonium chloride, hydrochloric acid, sulfuric acid and the like. Examples of the reducing agent include tin (II) chloride dihydrate, iron, zinc and the like. The reaction temperature is usually room temperature to solvent reflux temperature, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but may be treated for 30 minutes to 3 days.

Step 3-5
Compound (1) is obtained by reacting compound (13) with compound (14) in a solvent in the presence of a base and a palladium catalyst. Examples of the solvent used include toluene, tetrahydrofuran, 1,4-dioxane, ethanol, water, a mixed solvent thereof and the like. Examples of the base include potassium phosphate, potassium phosphate monohydrate, potassium carbonate, cesium carbonate, cesium fluoride, sodium carbonate and the like. Examples of the palladium catalyst include bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0) and the like. The reaction temperature is usually room temperature to solvent reflux temperature, and the reaction time is usually 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. In addition, you may perform this process, adding ligands, such as 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, as needed.

Step 3-6
Compound (16) is obtained by reacting compound (15) with N, O-dimethylhydroxylamine hydrochloride in a solvent under basic conditions. Examples of the solvent used include tetrahydrofuran and methylene chloride, and examples of the base include triethylamine, pyridine, N, N-diisopropylethylamine and the like. The reaction temperature is usually −20 ° C. to room temperature, and the reaction time is usually 30 minutes to 24 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
In addition, the compound (15) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, the method according to them, etc.

Step 3-7
Compound (18) is obtained by tert-butoxycarbonylating compound (17) with di-tert-butyl dicarbonate. Such reactions are well known to those skilled in the art and are described in Theodora W., et al. Greene & Peter G. M.M. It can also be carried out according to the method described in Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.
In addition, the compound (17) used at this process can use a commercial item, and can also manufacture it according to the method of literature description or the method according to them.

Step 3-8
After lithiation of compound (18) with alkyllithium in a solvent, compound (16) is added to obtain compound (5). Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, diethyl ether, and the like. Examples of the alkyl lithium include n-butyl lithium, sec-butyl lithium, tert-butyl lithium, and the like. -Butyl lithium is preferred. The reaction temperature is usually −78 ° C. to room temperature, and the reaction time is usually 30 minutes to 6 hours, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like.

Step 3-9
In the same manner as in Step 2-2, compound (1) can be obtained from compound (5).

  Compound (Ia) can also be obtained by the method shown in Scheme 4 below.

(Wherein R ² , R ³ , R ⁴ , R ⁵ , A, R ^K , Y and Y ¹ are as defined above.)

Step 4-1
Compound (19) is obtained by reacting compound (1) and compound (2) in a solvent in the presence of a base. Examples of the solvent used include methylene chloride, tetrahydrofuran, acetonitrile and the like. Examples of the base include 1,8-diazabicycloundeca [5.4.0] -7-ene (DBU), sodium hydroxide, sodium methoxide, sodium ethoxide and the like. The reaction temperature is usually −20 ° C. to 50 ° C., and the reaction time is usually 30 minutes to 3 days, although it varies depending on the raw material and solvent used and the reaction temperature.
Moreover, the compound (2) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, the method according to them, etc.

Step 4-2
Compound (Ia) is obtained by reacting compound (19) with a reducing agent in a solvent. Examples of the solvent used include acetonitrile, ethyl acetate, and tetrahydrofuran. Examples of the reducing agent include sodium iodide / trialkylchlorosilane (for example, trimethylchlorosilane, triethylchlorosilane, t-butyldimethylchlorosilane) and the like. The reaction temperature is −30 ° C. to room temperature, and the reaction time is usually 10 minutes to 24 hours, although it varies depending on the raw material used, the solvent, and the reaction temperature.
Compound (Ia) can also be obtained by reacting compound (19) with a reducing agent in a solvent under acidic conditions. Examples of the solvent used include tetrahydrofuran, methylene chloride, a mixed solvent thereof and the like. Examples of the reducing agent include triethylsilane, and examples of the acid include trifluoroacetic acid, acetic acid, trimethylsilyl = trifluoromethanesulfonate, boron trifluoride / ethyl ether complex, and the like. The reaction temperature is usually −70 ° C. to 50 ° C., and the reaction time is usually 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, and the reaction temperature.

  The scheme shown above is an illustration of a method for producing the compound (I) of the present invention or a production intermediate thereof. These can be variously modified into schemes that can be easily understood by those skilled in the art.

  Further, when a protective group is required depending on the type of functional group, it can be carried out by appropriately combining introduction and desorption operations according to a conventional method. Regarding the type, introduction and removal of protecting groups, see, for example, Theodora W. et al. Greene & Peter G. M.M. Reference can be made to Wuts, “Greene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.

  The compound (I) of the present invention or a pharmacologically acceptable salt thereof, and an intermediate used for producing the compound, if necessary, are isolated and purified well known to those skilled in the art. It can be isolated and purified by means such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography, and the like.

Pharmaceutical composition containing compound (I) of the present invention or a pharmaceutically acceptable salt thereof

  The pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof may be used in various dosage forms depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.

These pharmaceutical compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents. Further, when used in combination with drugs other than the EP ₁ receptor antagonist, simultaneously or separately each of active ingredients, it can be prepared by formulating the same manner as described above.

Process for producing the pharmaceutical composition of the present invention

  Production examples of a pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient are shown below, but the pharmaceutical composition of the present invention is not limited thereto. .

In the pharmaceutical composition of the present invention, for example, the active ingredient is 0.01 to 1000 mg of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof, and the following composition:
a) Content of active ingredient: 1 to 20% (wt / wt) based on the total weight of the pharmaceutical composition;
b) Magnesium stearate content: 0.1-2.0% (wt / wt) based on the total weight of the pharmaceutical composition; and c) Corn starch content: based on the total weight of the pharmaceutical composition 78-98.9% (wt / wt);
Consists of. The mixture of a) to c) can be mixed at room temperature and filled into hard gelatin capsules to produce hard capsules.

Pharmaceutical use of the compound (I) of the present invention or a pharmacologically acceptable salt thereof

Compound (I) or a pharmaceutically acceptable salt of the present invention exhibit a strong EP ₁ receptor antagonism in the EP ₁ receptor antagonistic activity confirmatory test and the like. Therefore, the compound (I) of the present invention can suppress or decrease the intracellular calcium concentration. Therefore, the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof is a therapeutic agent for a disease or symptom caused by activation of EP ₁ receptor by PGE ₂ stimulating action, or Can be used as a prophylactic agent.

Examples of diseases that activate the EP ₁ receptor by PGE ₂ stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, osteoporosis, cancer, and the like. The pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease. More preferably, it is LUTS.

  The causative diseases of lower urinary tract symptoms include overactive bladder (OAB), prostatic hypertrophy (BPH), cystitis such as interstitial cystitis, prostatitis and the like.

  “Lower urinary tract symptoms” means urine storage symptoms, urination symptoms, post-urination symptoms, and the like. The compound (I) of the present invention or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of urinary retention symptoms.

  "Urine accumulation symptoms" include urinary urgency, daytime frequent urination, night frequent urination, urinary incontinence (such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturnal urine, persistent incontinence) Bladder perception (increased bladder perception, decreased bladder perception, lack of bladder perception, nonspecific bladder perception, etc.) is included. Compound (I) of the present invention or a pharmacologically acceptable salt thereof is urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception, or It is preferably used for the treatment or prevention of nonspecific bladder perception. More preferred are urinary urgency, daytime frequent urination, nocturia, urge incontinence, or increased bladder perception. In addition, the compound (I) of the present invention or a pharmacologically acceptable salt thereof is particularly preferable for the treatment or prevention of OABs.

Combination or combination of the compound (I) of the present invention or a pharmacologically acceptable salt thereof

The compound (I) of the present invention or a pharmacologically acceptable salt thereof can also be used in appropriate combination with at least one drug other than the EP ₁ receptor antagonist.

Examples of the drug that can be used in combination with the compound (I) of the present invention or a pharmacologically acceptable salt thereof include overactive bladder (OAB), prostatic hypertrophy (PD) having a mechanism of action different from that of the EP ₁ receptor antagonist. BPH), cystitis such as interstitial cystitis, therapeutic agents for prostatitis and the like. Such agents, anticholinergics, alpha ₁ antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitors , anti-diuretics, calcium channel blockers, smooth muscle direct action, tricyclic antidepressants, K channel modulating agents, sodium channel blockers, H ₁ blockers, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake Inhibitors, GABA agonists, TRPV1 modulators, endothelin antagonists, 5-HT _1A antagonists, α ₁ agonists, opioid agonists, P ₂ X antagonists, COX inhibitors, σ agonists, muscarinic agonists and the like. Preferably, anticholinergics, alpha ₁ antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, progesterone-based hormone, antidiuretic agents, smooth muscle direct agonists or tricyclic antidepressants. More preferred are anticholinergic agents, α ₁ antagonists, β agonists, smooth muscle direct acting agents or tricyclic antidepressants. More preferred are anticholinergic agents, α ₁ antagonists or tricyclic antidepressants. Most preferred is an anticholinergic agent.

  Moreover, although it illustrates concretely as follows about the chemical | medical agent used in combination, the content of this invention is not limited to these. In addition, specific compounds include free forms thereof and other pharmacologically acceptable salts.

  Examples of the “anticholinergic agent” include oxybutynin, propiverine, solifenacin, tolterodine, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantheline and the like. Oxybutynin, propiverine, solifenacin, tolterodine or imidafenacin is preferable. More preferred is oxybutynin, propiverine, solifenacin, tolterodine or imidafenacin. More preferred is solifenacin or imidafenacin.

Examples of the “α ₁ antagonist” include urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin, alfuzosin, doxazosin, CR-2991, feduxin and the like. Preferably, urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin or feduxin. More preferred is tamsulosin, silodosin or prazosin. More preferred is tamsulosin or silodosin. Most preferred is silodosin. .

  Examples of the “β agonist” include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, solabegron and the like. Preferably, mirabegron or KUC-7383. More preferred is mirabegron.

  Examples of the “5α-reductase inhibitor” include dutasteride, TF-505, finasteride, and izonsteride. Preferred is dutasteride or izonsteride.

  Examples of the “PDE inhibitor” include tadalafil, vardenafil, sildenafil, avanafil, UK-369003, T-0156, AKP-002, etazolate and the like. Tadalafil, vardenafil, sildenafil or avanafil is preferred.

  Examples of the “acetylcholinesterase inhibitor” include distigmine, donepezil, Z-338, rivastigmine, ganstigmine, BGC-20-1259, galantamine, itopride, NP-61, SPH-1286, tolserine, ZT-1 and the like. .

  Examples of the “anti-androgen” include gestroneone, oxendron, bicalutamide, BMS-641988, CB-03-01, CH-489789, flutamide, MDV-3100, nilutamide, TAK-700, YM-580 and the like.

  Examples of “progesterone hormones” include chromazinone and allylestrenol.

  Examples of the “LH-RH analog” include AEZS-108, buserelin, deslorelin, goserelin, histrelin, leuprorelin, lutropin, nafarelin, triptorelin, AEZS-019, cetrorelix, degarelix, elagorix, ganilelex, ozalelix, PTD-634, PTD-634 -385, Teverelix, TAK-448, TAK-683 and the like.

  Examples of the “neurokinin inhibitor” include KRP-103, aprepitant, AV-608, Casopitant, CP-122721, DNK-333, fosprepitant, LY-686017, netpitant, olbepitant, lolapitant, TA-5538, T-2328, Vestipitant, AZD-2624, Z-501, 1144814, MEN-15596, MEN-11420, SAR-102779, SAR-102279, Saleduant, SSR-241586, and the like.

  Examples of the “antidiuretic” include desmopressin, VA-106483 and the like.

  Examples of “calcium channel blockers” include amlodipine, cilnidipine, propiverine, temiverine, PD-29985, alanidipine, azelnidipine, balnidipine, benidipine, bevantolol, clevidipine, CYC-381, diltiazem, efonidipine, fasudil, felodipine, gabamil, dipapine, gabamil Examples include rasidipine, lercanidipine, romeridine, manidipine, MEM-1003, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, SB-751689, verapamil, YM-58483, ziconotide and the like.

  Examples of the “smooth muscle direct acting drug” include flavoxate.

  Examples of the “tricyclic antidepressant” include imipramine, clomipramine, amitriptyline and the like. Preferably, imipramine is used.

  Examples of the “K channel modulator” include nicorandil, NIP-141, NS-4591, NS-1643, andlast, diazoxide, ICA-105665, minoxidil, pinacidil, tyrisolol, VRX-698 and the like.

  Examples of the “sodium channel blocker” include bepridil, dronedarone, propafenone, safinamide, SUN-N8075, SMP-986, 1014802, 552-02, A-803467, brivaracetam, cibenzoline, eslicarbazepine, F-15845, flecainide Phosphenytoin, lacosamide, lamotrigine, levobupivacaine, M-58373, mexiletine, moracidin, nerispyridine, NW-3509, oxcarbazepine, pilsicainide, pirmenol, propafenone, NW-1029, ropivacaine, banacarant, etc. it can.

Examples of “H ₁ blocker” include acribastine, alcaftadine, bepotatin, belastine, cetirizine, desloratadine, ebastine, efletirizine, epinastine, fexofenadine, GSK-835726, levocabastine, levocetirizine, loratadine, mequitadine, mizolastine, NBI-7, 43 Examples thereof include ReN-1869, terfenadine, UCB-35440, vapitadine, YM-344484, diphenhydramine, chlorpheniramine and the like.

  Examples of “serotonin reuptake inhibitors” include UCB-46331, 424887, AD-337, BGC-20-1259, BMS-505130, citalopram, dapoxetine, desvenlafaxine, DOV-102303, DOV-216303, DOV-21947 , Duloxetine, escitalopram, F-2695, F-98214-TA, fluoxetine, fluvoxamine, IDN-5491, milnacipran, minaprine, NS-2359, NSD-644, paroxetine, PF-184298, SD-726, SEP-225289 , SEP-227162, SEP-228425, SEP-228432, sertraline, sibutramine, tesofensin, tramadol, trazodone, UCB-46331, venlafaqui Mention may be made of down, Birazodon, the WAY-426, WF-516 and the like.

  Examples of “norepinephrine reuptake inhibitors” include AD-337, desvenlafaxine, DOV-102676, DOV-216303, DOV-21947, duloxetine, F-2695, F-98214-TA, milnacipran, NS-2359. , NSD-644, PF-184298, SD-726, SEP-225289, SEP-227162, SEP-228425, SEP-228432, Sibutramine, Tesofensin, Tramadol, Venlafaxine, Bupropion, Radafaxin, Atomoxetine, DDP-225, LY -2216684, nevogramin, NRI-193, reboxetine, tapentadol, WAY-256805, WAY-260022, and the like.

  Examples of “dopamine reuptake inhibitors” include DOV-102777, DOV-216303, DOV-21947, IDN-5491, NS-2359, NSD-644, SEP-225289, SEP-228425, SEP-228432, sibutramine, tesofensin, Examples include tramadol, brassofensin, bupropion, NS-27100, radafaxin, safinamide and the like.

  “GABA agonists” include retigabine, eszopiclone, indipron, pagoclone, SEP-225441, acamprosate, baclofen, AZD-7325, BL-1020, brotizolam, DP-VPA, progabide, propofol, topiramate, zopiclone, EVT-201, AZD-3043, ganaxolone, NS-11394, albaclofen, AZD-3355, GS-39783, ADX-71441, ADX-71943 and the like can be mentioned.

  “TRPV1 modulators” include capsaicin, resiniferatoxin, DE-096, GRC-6221, AMG-8562, JTS-653, SB-705498, A-4256619, A-784168, ABT-102, AMG-628. AZD-1386, JNJ-17203212, NGD-8243, PF-38664086, SAR-115740, SB-784443, and the like.

  Examples of the “endothelin antagonist” include SB-234551, ACT-064992, ambrisentan, atrasentan, bosentan, clazosentan, darsentan, fundsentan, S-0139, TA-0201, TBC-3711, dibotentane, BMS-509701, PS -433540 and the like.

Examples of the “5-HT _1A antagonist” include espindolol, lecozotan, lurasidone, E-2110, REC-0206, SB-649915, WAY-426, WF-516 and the like.

Examples of the “α ₁ agonist” include CM-2236, armodafinil, midodrine, modafinil and the like.

  “Opioid agonists” include morphine, TRK-130, DPI-125, DPI-3290, fentanyl, LIF-301, loperamide, loperamide oxide, remifentanil, tapentadol, WY-16225, oxycodone, PTI-202, PTI-721 , ADL-5747, ADL-5858, DPI-221, DPI-353, IPP-102199, SN-11, ADL-10-0101, ADL-10-0116, asimadoline, buprenorphine, CR-665, CR-845, eptazosin Nalbuphine, nalflaphine, pentazocine, XEN-0548, W-212393, ZP-120, nalmefene and the like.

Examples of the “P ₂ X antagonist” include A-740003, AZ-1157312, AZD-9056, GSK-1482160, GSK-31481A, and the like.

  Examples of the “COX inhibitor” include aceclofenac, ST-679, aspirin, bromfenac, dexketoprofen, flurbiprofen, FYO-750, ibuprofen, ketoprofen, ketorolac, lycoferon, lornoxicam, loxoprofen, LT-NS001, diclofenac, Nabumetone, naproxen, oxaprozin, piroxicam, pranoprofen, suprofen, tenoxicam, thiaprofenic acid, tolfenamic acid, zaltoprofen, 644784, ABT-963, ajuremic acid, apricoxib, celecoxib, cimicoxib, etlicoxib, igiroxicam, meloximod , RO-26-2198, valdecoxib, etc. It can be.

  Examples of the “σ agonist” include ANAVEX-27-1041, PRS-013, SA-4503, ANAVEX-2-73, silamesine, ANAVEX-7-1037, and ANAVEX-1-41.

  Examples of the “muscarinic agonist” include AC-260584, cevimeline, MCD-386, NGX-267, NGX-292, subcomerin, pilocarpine, bethanechol and the like.

When the compound (I) of the present invention or a pharmacologically acceptable salt thereof and one or more of the above drugs are used in combination, the present invention includes the following 1) to 5):
1) Simultaneous administration with combination drug,
2) As separate formulations, co-administration by the same route of administration,
3) As separate formulations, co-administration by different routes of administration,
It includes any one method of administration selected from 4) administration at different times by the same route of administration as separate formulations, or 5) administration at different times by different routes of administration as separate formulations. Moreover, when administering at different time as a separate formulation like 4) or 5), there is no restriction | limiting in particular about the administration order of the compound (I) of this invention, and said agent.

  In addition, the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be used in combination with one or more of the above drugs as appropriate, thereby providing an additive effect in preventing or treating the above diseases. The above advantageous effects can be obtained. Similarly, it is possible to reduce the amount of use compared to the case of using it alone, or to reduce the side effects of the drugs used in combination, or to avoid or reduce the side effects of the drugs used in combination.

Usage and dosage of compound (I) of the present invention

  The medicament of the present invention can be administered systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.).

When using the pharmaceutical composition organism of the present invention for actual treatment, the dose of compound (I) or a pharmacologically acceptable salt thereof which is an active ingredient of the EP ₁ receptor antagonist of the present invention which is an active ingredient thereof Is appropriately determined depending on the age, sex, weight, disease, degree of treatment, etc. of the patient. For example, in the case of oral administration, an adult (with a body weight of 60 kg) in the range of about 0.01 to 1000 mg per day, and in the case of parenteral administration, in the range of about 0.001 to 300 mg per day for an adult, once or several times And can be administered as appropriate. In addition, the dose of the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be reduced according to the dose of a drug other than the EP ₁ receptor antagonist.

  EXAMPLES Hereinafter, although an Example and a manufacture example demonstrate this invention further in detail, the scope of the present invention is not limited to these.

Of the symbols used in each production example, each example, and each table, Ref. No. Is the production example number, Ex. No. Example number, STRC chemical structural formula, Physical data are physical properties, IH-NMR means hydrogen jittery magnetic resonance spectrum, CDCl3 chloroform -d, DMSO-d6 means dimethylsulfoxide -d _6. MS means mass spectrometry, and ESI means measurement by electrospray ionization.

(Production Example 1-1)
N- (2-bromo-5-trifluoromethoxyphenyl) -2,2,2-trifluoroacetamide

  Under ice cooling, trifluoroacetic anhydride (0.79 mL) and pyridine (0.61 mL) were added to a solution of 2-bromo-5-trifluoromethoxyaniline (0.98 g) in tetrahydrofuran (10 mL). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (1.30 g).

1H-NMR (CDCl3) δ ppm: 8.60-8.30 (2H, m), 7.65 (1H, d, J = 8.9Hz), 7.10-7.00 (1H, m)

  The following production examples 1-2 to 1-3 were obtained in the same manner as in Production Example 1-1 using the corresponding aniline derivatives. These structural formulas and physical property values are shown in Table 1.

(Production Example 2-1)
2-Phenyl-6-trifluoromethoxy-1H-indole

  To a solution of N- (2-bromo-5-trifluoromethoxyphenyl) -2,2,2-trifluoroacetamide (0.513 g) in acetonitrile (10 mL) was added bis (triphenylphosphine) palladium (II) dichloride (30. 7 mg), copper iodide (16.6 mg) and triethylamine (0.51 mL) were added and the mixture was stirred at 120 ° C. for 10 minutes under microwave irradiation. After cooling to room temperature, potassium carbonate (0.503 g) was added to the reaction mixture, and the mixture was stirred at 120 ° C. for 10 minutes under microwave irradiation. The reaction mixture was filtered through Celite (registered trademark), and insoluble materials were removed by filtration. Ethyl acetate and saturated brine were added to the filtrate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (0.233 g).

1H-NMR (CDCl3) δ ppm: 8.50-8.35 (1H, br), 7.70-7.55 (3H, m), 7.50-7.30 (3H, m), 7.05-6.95 (1H, m), 6.85-6.80 (1H , m)

  The following Preparation Examples 2-2 to 2-3 were obtained in the same manner as in Preparation Example 2-1, using the corresponding trifluoroacetanilide derivative. These structural formulas and physical property values are shown in Table 2.

(Production Example 3-1)
tert-butyl = (5-methoxy-2-methylphenyl) carbamate

  Di-tert-butyl dicarbonate (4.80 g) was added to a tetrahydrofuran (80 mL) solution of 5-methoxy-2-methylaniline (2.74 g) at room temperature, and the solution was heated to reflux at 75 ° C. overnight. After allowing to cool, the solution was concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (4.00 g).

1H-NMR (CDCl3) δ ppm: 7.65-7.45 (1H, m), 7.02 (1H, d, J = 8.4Hz), 6.55 (1H, dd, J = 8.4, 2.7Hz), 6.27 (1H, br s ), 3.80 (3H, s), 2.17 (3H, s), 1.53 (9H, s)

  Using the corresponding 2-methylaniline derivative, the following Production Examples 3-2 to 3-6 were obtained in the same manner as in Production Example 3-1. These structural formulas and physical property values are shown in Table 3.

(Production Example 4-1)
tert-butyl = [5-methoxy-2- (2-oxo-2-phenylethyl) phenyl] carbamate

  Under an argon gas atmosphere, a solution of tert-butyl = (5-methoxy-2-methylphenyl) carbamate (3.87 g) in tetrahydrofuran (70 mL) was maintained at an internal temperature of −50 ° C. or lower, and a sec-butyllithium solution (1.04 mol / L n-hexane-cyclohexane solution, 31.36 mL) was added dropwise over 19 minutes. The solution was stirred for 20 minutes while maintaining the internal temperature at -48 ° C. While maintaining the internal temperature at −40 ° C. or lower, a solution of N-methoxy-N-methylbenzamide (2.69 g) in tetrahydrofuran (32 mL) was added to the solution over 15 minutes. The solution was stirred for 20 minutes while maintaining the internal temperature at -40 ° C or lower, and further stirred for 1 hour and 20 minutes at room temperature. Under ice cooling, 2 mol / L hydrochloric acid was added to the mixture, the mixture was stirred at room temperature for 5 minutes, and then ethyl acetate was added. The organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) and then aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to give the title compound (2. 49 g) was obtained.

1H-NMR (CDCl3) δ ppm: 8.10-8.00 (2H, m), 7.90-7.70 (1H, br), 7.65-7.40 (4H, m), 7.09 (1H, d, J = 8.5Hz), 6.59 ( 1H, dd, J = 8.5, 2.6Hz), 4.19 (2H, s), 3.79 (3H, s),
1.53 (9H, s)

  The following Preparation Examples 4-2 to 4-11 were obtained in the same manner as in Production Example 4-1, using the corresponding tert-butyl = (2-methylphenyl) carbamate derivative. These structural formulas and physical property values are shown in Tables 4 and 5.

(Production Example 5-1)
6-Methoxy-2-phenyl-1H-indole

  A solution of tert-butyl = [5-methoxy-2- (2-oxo-2-phenylethyl) phenyl] carbamate (170 mg) in trifluoroacetic acid (0.80 mL) -methylene chloride (2.0 mL) at room temperature overnight. Stir. The solvent was distilled off under reduced pressure. Methylene chloride was added to the residue, and then a saturated aqueous sodium bicarbonate solution was added to the solution. The organic layer was separated and concentrated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (80.1 mg).

1H-NMR (CDCl3) δ ppm: 8.30-8.10 (1H, br), 7.65-7.35 (5H, m), 6.91 (1H, d, J = 2.0Hz), 6.85-6.70 (2H, m), 3.87 ( 3H, s)

  The following production examples 5-2 to 5-10 were obtained in the same manner as in Production Example 5-1, using the corresponding ketone. These structural formulas and physical property values are shown in Tables 6 and 7.

(Production Example 6-1)
Methyl = 6- [2- (2-tert-butoxycarbonylamino-4-methoxyphenyl) -3-oxo-3-phenylpropyl] pyridine-2-carboxylate

  Under ice cooling, a solution of tert-butyl = [5-methoxy-2- (2-oxo-2-phenylethyl) phenyl] carbamate (2.39 g) in N, N-dimethylformamide (50 mL) was added under an argon gas atmosphere. Sodium hydride (content: about 55%, 321 mg) was added. The suspension was stirred for 30 minutes at room temperature under an argon gas atmosphere. At room temperature, methyl 6-chloromethylpyridine-2-carboxylic acid (1.37 g) in N, N-dimethylformamide (15 mL) was added over 5 minutes under an argon gas atmosphere, and the mixture was added at room temperature. The mixture was stirred for 3 hours under an argon gas atmosphere. Water was added to the reaction mixture, then ethyl acetate was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The collected organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (3.27 g).

MS (ESI, m / z): 491 (M + H) +

  The following production examples 6-2 to 6-6 were obtained in the same manner as in Production Example 6-1, using the corresponding ketone. These structural formulas and physical property values are shown in Table 8.

(Production Example 7)
2,2,2-trifluoro-N- (5-methoxy-2-trimethylsilanylethynylphenyl) acetamide

  At room temperature, 2,2,2-trifluoro-N- (2-iodo-5-methoxyphenyl) acetamide (500 mg), ethynyltrimethylsilane (157 mg) and triethylamine (0.403 mL) in acetonitrile (8.0 mL) Was added bis (triphenylphosphine) palladium (II) dichloride (25 mg) and copper iodide (14 mg), and the mixture was stirred under an argon gas atmosphere for 4 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (361 mg).

1H-NMR (CDCl3) δ ppm: 9.00-8.80 (1H, br), 8.00 (1H, d, J = 2.5Hz), 7.39 (1H, d, J = 8.7Hz), 6.70 (1H, dd, J = 8.7, 2.5Hz), 3.85 (3H, s), 0.28 (9H, s)

(Production Example 8)
N- (2-ethynyl-5-methoxyphenyl) -2,2,2-trifluoroacetamide

  Under a room temperature, a solution of 2,2,2-trifluoro-N- (5-methoxy-2-trimethylsilanylethynylphenyl) acetamide (360 mg) in tetrahydrofuran (2.0 mL) was added to tetrabutylammonium fluoride (1.0 mol / mol). L tetrahydrofuran solution, 1.37 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (210 mg).

1H-NMR (CDCl3) δ ppm: 8.90-8.65 (1H, br), 8.01 (1H, d, J = 2.5Hz), 7.43 (1H, d, J
= 8.7Hz), 6.73 (1H, dd, J = 8.7, 2.5Hz), 3.85 (3H, s), 3.53 (1H, s)

(Production Example 9-1)
6-Methoxy-2-thiazol-4-yl-1H-indole

N- (2-ethynyl-5-methoxyphenyl) -2,2,2-trifluoroacetamide (209 mg), 4-bromothiazole (0.115 mL) and triethylamine (0.298 mL) in acetonitrile (5.0 mL) To the mixture was added bis (triphenylphosphine) palladium (II) dichloride (18 mg) and copper iodide (10 mg), and the mixture was stirred at 120 ° C. for 10 minutes under microwave irradiation. After cooling to room temperature, potassium carbonate (297 mg) was added to the mixture and the mixture was stirred at 120 ° C. for 10 minutes under microwave irradiation. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (60.0 mg).
The structural formula and spectral data of the title compound are shown in Table 9.

  The following Preparation Example 9-2 was obtained in the same manner as in Preparation Example 9-1 using the corresponding starting material. These structural formulas and spectral data are shown in Table 9.

(Production Example 10-1)
Ethyl = 6-[(6-chloro-2-pyridin-3-yl-1H-indol-3-yl) hydroxymethyl] pyridine-2-carboxylate

Suspension of 6-chloro-2-pyridin-3-yl-1H-indole (62.6 mg) and ethyl 6-formylpyridine-2-carboxylate (49.2 mg) at room temperature in methylene chloride (2.7 mL) To the solution was added 1,8-diazabicycloundeca [5.4.0] -7-ene (0.004 mL) and the mixture was stirred overnight. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluent: hexane-ethyl acetate-methanol) to give the title compound (84.1 mg).
The structural formula and spectral data of the title compound are shown in Table 10.

  The following Production Examples 10-2 to 10-3 were obtained in the same manner as in Production Example 10-1, using the corresponding starting materials. These structural formulas and spectral data are shown in Table 10.

(Production Example 11-1)
5-methylthiophene-3-carboxylic acid methoxymethylamide

To a solution of 5-methylthiophene-3-carboxylic acid (0.500 g) in tetrahydrofuran (10 mL) at room temperature was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.738 g) and N-methyl. Morpholine (1.20 mL) was added. The mixture was stirred for 1 hour and then N, O-dimethylhydroxylamine hydrochloride (0.376 g) was added. The mixture was stirred for 23 hours. Water and diethyl ether were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with diethyl ether and the organic layers were combined. The collected organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (0.626 g).
The structural formula and spectrum data of the title compound are shown in Table 11.

  The following Preparation Example 11-2 was obtained in the same manner as in Production Example 11-1 using the corresponding starting material. These structural formulas and spectral data are shown in Table 11.

(Production Example 12)
5-Methylfuran-2-carboxylic acid methoxymethylamide

  Under ice cooling, pyridine (0.670 mL) was added to a suspension of 5-methylfuran-2-carbonyl chloride (0.573 g) and N, O-dimethylhydroxylamine hydrochloride (0.426 g) in methylene chloride (15 mL). In addition, the solution was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.670 g).

1H-NMR (CDCl3) δ ppm: 7.05 (1H, d, J = 3.4Hz), 6.15-6.05 (1H, m), 3.75 (3H, s), 3.34 (3H, s), 2.39 (3H, s)

(Production Example 13-1)
tert-butyl = [5-methoxy-2- (2-oxo-2-thiophen-3-yl-ethyl) phenyl] carbamate

A sec-butyllithium solution (1.07 mol / L) was added to a tetrahydrofuran (6.0 mL) solution of tert-butyl = (5-methoxy-2-methylphenyl) carbamate (0.596 g) at −43 ° C. in an argon gas atmosphere. n-Hexane-cyclohexane solution (4.7 mL) was added dropwise over 5 minutes. The mixture was stirred at the same temperature for 30 minutes, and a solution of 5-methylthiophene-3-carboxylic acid methoxymethylamide (0.430 g) in tetrahydrofuran (4.0 mL) was added dropwise to the mixture. The mixture was stirred at -45 ° C for 30 minutes and at room temperature for 1 hour. Under ice-cooling, 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with diethyl ether. The aqueous layer was extracted with diethyl ether and the organic layers were combined. The collected organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (0.424 g).
The structural formula and spectrum data of the title compound are shown in Table 12.

  The following Preparation Examples 13-2 to 13-23 were obtained in the same manner as in Preparation Example 13-1, using the corresponding starting materials. These structural formulas and spectral data are shown in Tables 12-16.

(Production Example 14-1)
Ethyl = 6- [2- (2-tert-butoxycarbonylamino-4-methoxyphenyl) -3-oxo-3-thiophen-3-ylpropyl] pyridine-2-carboxylate

Under ice cooling, tert-butyl = [5-methoxy-2- (2-oxo-2-thiophen-3-yl-ethyl) phenyl] carbamate (0.387 g) N, N-dimethylformamide (5.5 mL) Sodium hydride (55% content, 49.0 mg) was added to the solution under an argon gas atmosphere, and the mixture was stirred for 30 minutes under the same conditions. Under ice-cooling, ethyl 6-chloromethylpyridinecarboxylate (0.222 g) was added to the mixture, and the mixture was stirred under the same conditions for 20 minutes and then at room temperature for 6 hours. The reaction mixture was poured into a cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The collected organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (0.425 g).
The structural formula and spectral data of the title compound are shown in Table 17.

  The following Preparation Examples 14-2 to 14-24 were obtained in the same manner as in Preparation Example 14-1, using the corresponding starting materials. These structural formulas and spectral data are shown in Tables 17-22.

(Production Example 15)
Ethyl = 3- (6-methoxy-2-pyridin-3-yl-1H-indole-3-carbonyl) benzoate

  At room temperature, 2,2,2-trifluoro-N- (2-iodo-5-methoxyphenyl) acetamide (200 mg), 3-ethynylpyridine (65.2 mg) and triethylamine (0.161 mL) in acetonitrile (8. 0 mL) solution was added bis (triphenylphosphine) palladium (II) dichloride (12 mg) and copper iodide (7 mg), and the mixture was stirred overnight under an argon gas atmosphere. To the reaction mixture were added potassium carbonate (240 mg) and ethyl 3-iodobenzoic acid (0.106 mL), and the mixture was stirred overnight at 50 ° C. in a carbon monoxide gas atmosphere. After cooling to room temperature, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (128 mg).

1H-NMR (CDCl3) δ ppm: 9.00-6.70 (12H, m), 4.32 (2H, q, J = 7.2Hz), 3.89 (3H, s), 1.36 (3H, t, J = 7.2Hz)
MS (ESI, m / z) = 401 (M + H) +

(Production Example 16)
(2-Phenyl-1H-indol-6-yl) methanol

  Under ice-cooling, a solution of 2-phenyl-1H-indole-6-carboxylic acid in tetrahydrofuran (5.0 mL) was added to a suspension of lithium aluminum hydride (80% content, 96.0 mg) in tetrahydrofuran (5.0 mL). In addition, the mixture was stirred under the same conditions for 5 minutes and then at room temperature for 2 hours. Under ice-cooling, lithium aluminum hydride (content 80%, 48.0 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours, then at 50 ° C. for 5 hours, and further overnight at room temperature. After cooling to room temperature, the reaction mixture was poured into chilled 1 mol / L hydrochloric acid and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The collected organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (121 mg).

1H-NMR (CDCl3) δ ppm: 8.45-8.25 (1H, br), 7.75-7.55 (3H, m), 7.50-7.30 (4H, m), 7.13 (1H, dd, J = 8.2, 1.4Hz), 6.85-6.80 (1H, m), 4.80 (2H, s)

(Production Example 17)
2-Phenyl-1H-indol-6-ylmethyl-acetate

  At room temperature, acetic anhydride (0.034 mL) was added to a solution of (2-phenyl-1H-indol-6-yl) methanol (20.0 mg) and pyridine (0.058 mL) in methylene chloride (0.5 mL). The mixture was stirred for 2 hours. 0.5 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (18.7 mg).

1H-NMR (CDCl3) δ ppm: 8.39 (1H, s), 7.75-7.55 (3H, m), 7.55-7.30 (4H, m), 7.13 (1H, dd, J = 8.1, 1.3Hz), 6.85- 6.80 (1H, m), 5.22 (2H, s), 2.11 (3H, s)
MS (ESI, m / z) = 266 (M + H) +

(Production Example 18)
Ethyl = 6- (6-acetoxymethyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylate

  A suspension of 2-phenyl-1H-indol-6-ylmethyl acetate (87.0 mg) and ethyl 6-formylpyridine-2-carboxylate (64.8 mg) in methylene chloride (3.3 mL) under ice cooling. Triethylsilane (0.157 mL) and trifluoroacetic acid (0.038 mL) were sequentially added to the mixture, and the mixture was stirred under the same conditions for 2 hours and at room temperature for 4 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (66.9 mg).

1H-NMR (CDCl3) δ ppm: 8.24 (1H, s), 8.00-7.85 (1H, m), 7.70-7.55 (3H, m), 7.50-7.30 (5H, m), 7.20-7.10 (1H, m ), 7.08 (1H, dd, J = 8.2, 1.4Hz), 5.21 (2H, s), 4.57 (2H, s), 4.51 (2H, q, J = 7.1Hz), 2.10 (3H, s), 1.47 (3H, t, J = 7.1Hz)
MS (ESI, m / z) = 429 (M + H) +

(Production Example 19)
4-Cyclopropyl-1-iodo-2-nitrobenzene

Under ice cooling, a solution of sodium nitrite (522 mg) in water (5.0 mL) was slowly added to a suspension of 4-cyclopropyl-2-nitroaniline (1.23 g) in concentrated hydrochloric acid (5.0 mL). The mixture was stirred for 30 minutes under the same conditions. A solution of potassium iodide (2.28 g) in water (10 mL) was added dropwise to the mixture. The mixture was stirred at room temperature for 30 minutes and at 60 ° C. for 1.5 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture, and the organic layer was separated. The layer was washed successively with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (1.66 g).
The structural formula and spectrum data of the title compound are shown in Table 58.

(Production Example 20)
5-cyclopropyl-2-iodoaniline

At room temperature, 4-cyclopropyl-1-iodo-2-nitrobenzene (1.65 g), iron (III) chloride hexahydrate (77.2 mg), activated carbon (27.4 mg, wet) in methanol (20 mL) Hydrazine monohydrate (0.83 mL) was added to the suspension. The mixture was stirred at 70 ° C. overnight. After cooling to room temperature, hydrazine monohydrate (0.28 mL) was added to the mixture. The mixture was stirred at 70 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was filtered through Celite (registered trademark), and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.41 g).
The structural formula and spectrum data of the title compound are shown in Table 58.

(Production Example 21)
3-Ethoxy-4-fluoroaniline

Under ice-cooling, 10% palladium-carbon (675 mg, wet) was added to a solution of 2-ethoxy-1-fluoro-4-nitrobenzene (2.25 g) in tetrahydrofuran (25 mL) -ethanol (25 mL), and the suspension was The mixture was stirred overnight at room temperature under a hydrogen gas atmosphere. The suspension was filtered through Celite (registered trademark), and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (2.01 g).
The structural formula and spectrum data of the title compound are shown in Table 58.

(Production Example 22-1)
2-Bromo-4-methyl-5-trifluoromethylaniline

Under ice-cooling, tetra-n-butylammonium tribromide (1.93 g) was added to a solution of 4-methyl-3-trifluoromethylaniline (701 mg) in methylene chloride (13 mL), and the suspension was stirred at room temperature for 1. Stir for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated. The layer was concentrated under reduced pressure to give the title compound (2.19 g).
The structural formula and spectrum data of the title compound are shown in Table 58.

  The following production examples 22-2 to 22-4 were obtained in the same manner as in Production Example 22-1 using the corresponding starting materials. These structural formulas and physical property values are shown in Table 58.

(Production Example 23)
The following production examples 23-1 to 23-18 were obtained in the same manner as in Production Example 1-1 using the corresponding aniline derivatives. These structural formulas and physical property values are shown in Tables 59 to 61.

(Production Example 24)
The following Preparation Examples 24-1 to 24-49 were obtained in the same manner as in Preparation Example 2-1, using the corresponding trifluoroacetanilide derivative. These structural formulas and physical property values are shown in Tables 61 to 68.

(Production Example 25-1)
5-Methyl-2-phenyl-1H-indole-6-ol

Under ice cooling, boron tribromide (1 mol / L methylene chloride solution, 3.3 mL) was added to a suspension of 6-methoxy-5-methyl-2-phenyl-1H-indole (197 mg) in methylene chloride (4.2 mL). Was dripped. The mixture was stirred under ice cooling for 20 minutes and then at room temperature for 1 hour. The reaction mixture was slowly poured into ice. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (180 mg).
The structural formula and spectrum data of the title compound are shown in Table 69.

  The following Preparation Examples 25-2 to 25-4 were obtained in the same manner as in Preparation Example 25-1, using the corresponding starting materials. These structural formulas and physical property values are shown in Table 69.

(Production Example 26-1)
2-tert-butyl-6-ethoxy-1H-indole

At room temperature, ethyl iodide (0.085 mL) was added to a suspension of 2-tert-butyl-1H-indol-6-ol (133 mg) and potassium carbonate (117 mg) in N, N-dimethylformamide (3.0 mL). In addition, the suspension was stirred overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (74.5 mg).
The structural formula and spectrum data of the title compound are shown in Table 69.

  The following Preparation Examples 26-2 to 26-4 were obtained in the same manner as in Preparation Example 26-1 using the corresponding starting materials. These structural formulas and physical property values are shown in Table 69.

(Production Example 27)
6-Difluoromethoxy-2-phenyl-1H-indole

At room temperature, a solution of 2-phenyl-1H-indol-6-ol (250 mg) in N, N-dimethylformamide (2.0 mL) was added to sodium chlorodifluoroacetate (182 mg), sodium hydroxide (47.8 mg), water ( 0.024 mL) was added and the mixture was stirred at 125 ° C. for 6.5 hours. After allowing to cool, sodium chlorodifluoroacetate (364 mg), sodium hydroxide (95.6 mg) and water (0.047 mL) were added to the mixture, and the mixture was stirred at 125 ° C. overnight. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (7.2 mg).
The structural formula and spectral data of the title compound are shown in Table 70.

(Production Example 28)
3- (6-Methoxy-1H-indol-2-yl) benzamide

To a suspension of 6-methoxy-1H-indole (500 mg), palladium (II) acetate (76.1 mg) and cesium acetate (1.76 g) at room temperature in N, N-dimethylacetamide (1.7 mL) was added 3- Iodobenzamide (1.05 g) was added and the mixture was stirred at 130 ° C. under an argon gas atmosphere for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The mixture was filtered through Celite (registered trademark), and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate-methanol). A mixed solvent of hexane-diisopropyl ether was added to the obtained crude product, and the suspension was stirred at room temperature for 15 minutes. The precipitate was collected by filtration, washed with the same mixed solvent, and dried under reduced pressure to give the title compound (169 mg).
The structural formula and spectral data of the title compound are shown in Table 70.

(Production Example 29)
3- (6-Methoxy-1H-indol-2-yl) benzonitrile

Under ice cooling, trifluoroacetic anhydride was added to a suspension of 3- (6-methoxy-1H-indol-2-yl) benzamide (100 mg) in methylene chloride (1.0 mL) -tetrahydrofuran (1.0 mL) under an argon gas atmosphere. (0.068 mL) and triethylamine (0.117 mL) were sequentially added, and the suspension was stirred at room temperature for 5.5 hours. At room temperature, trifluoroacetic anhydride (0.016 mL) was added to the suspension and the mixture was stirred for 1.5 hours. Ethyl acetate and 2 mol / L hydrochloric acid were added to the reaction mixture, and the organic layer was separated. The layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate-methanol) to obtain the title compound (44.1 mg).
The structural formula and spectral data of the title compound are shown in Table 70.

(Production Example 30-1)
2-tert-butyl-5,6-dimethyl-1H-indole

Under reflux, 1-bromo-3,3-dimethyl-2-butanone (0.405 mL) was divided into four portions every 5 minutes in a solution of 3,4-dimethylaniline (1.20 g) in ethanol (3.0 mL). Added. The mixture was refluxed overnight. After cooling to room temperature, 2 mol / L hydrochloric acid was added to the mixture, then water and ethyl acetate were added, and the organic layer was separated. The layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (38.1 mg).
The structural formula and spectral data of the title compound are shown in Table 70.

  The following Production Examples 30-2 to 30-3 were obtained in the same manner as in Production Example 30-1, using the corresponding starting materials. These structural formulas and physical property values are shown in Table 70.

(Production Example 31)
The following production examples 31-1 to 31-40 were obtained in the same manner as in Production Example 10-1, using the corresponding starting materials. These structural formulas and physical property values are shown in Tables 71 to 78.

(Production Example 32)
The following Preparation Examples 32-1 to 32-2 were obtained in the same manner as in Preparation Example 11-1, using the corresponding starting materials. Table 79 shows these structural formulas and physical property values.

(Production Example 33)
The following Preparation Examples 33-1 to 33-3 were obtained in the same manner as in Production Example 12-1, using the corresponding starting materials. Table 79 shows these structural formulas and physical property values.

(Production Example 34)
N-methoxy-N-methyl-3-propylbenzamide

At room temperature, 10% palladium-carbon (55.3 mg, wet) was added to a solution of 3-allyl-N-methoxy-N-methylbenzamide (340 mg) in tetrahydrofuran (10.5 mL), and the suspension was charged with hydrogen gas. Stir overnight under atmosphere. The suspension was filtered through Celite (registered trademark), and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (355 mg).
The structural formula and spectrum data of the title compound are shown in Table 79.

(Production Example 35)
5-cyclopropyl-2-methylaniline

At room temperature, 5-bromo-2-methylaniline (372 mg), cyclopropylboronic acid monohydrate (270 mg), tricyclohexylphosphine (56.0 mg), potassium phosphate (1.49 g) in toluene (8.0 mL) ) -Palladium (II) (22.4 mg) was added to a water (0.4 mL) suspension, and the mixture was stirred at 100 ° C. for 6 hours under an argon gas atmosphere. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (256 mg).
The structural formula and spectrum data of the title compound are shown in Table 79.

(Production Example 36)
The following production examples 36-1 to 36-4 were obtained in the same manner as in Production Example 3-1, using the corresponding 2-methylaniline derivative. These structural formulas and physical property values are shown in Table 80.

(Production Example 37)
tert-butyl = [5-cyclopropyl-2- (2-hydroxy-3,3-dimethylbutyl) phenyl] carbamate

Under an argon gas atmosphere, a solution of tert-butyl = (5-cyclopropyl-2-methylphenyl) carbamate (495 mg) in tetrahydrofuran (7.0 mL) at −40 ° C. at a sec-butyllithium solution (1.03 mol / L n− Hexane-cyclohexane solution (4.70 mL) was added slowly. The mixture was stirred at −40 ° C. for 15 minutes. A solution of trimethylacetaldehyde (purity 90%, 0.32 mL) in tetrahydrofuran (1.0 mL) was added dropwise to the mixture. The mixture was stirred at −40 ° C. for 15 minutes and at room temperature for 1 hour. Water was added to the reaction mixture, then 1 mol / L hydrochloric acid and ethyl acetate were added, and the organic layer was separated. The layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (544 mg).
The structural formula and spectrum data of the title compound are shown in Table 80.

(Production Example 38)
1- (2-Amino-4-cyclopropylphenyl) -3,3-dimethylbutan-2-ol

At room temperature, trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl = [5-cyclopropyl-2- (2-hydroxy-3,3-dimethylbutyl) phenyl] carbamate (540 mg) in methylene chloride (5.0 mL). ) Was added. The mixture was stirred for 2 hours. The reaction mixture was poured into 5% aqueous sodium bicarbonate solution. Ethyl acetate was added to the mixture and the organic layer was separated. The layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (351 mg).
The structural formula and spectrum data of the title compound are shown in Table 80.

(Production Example 39)
2-tert-butyl-6-cyclopropyl-1H-indole

1- (2-Amino-4-cyclopropylphenyl) -3,3-dimethylbutan-2-ol (350 mg), 2-bromo-1,3,5-trimethylbenzene (0.269 mL) and carbonic acid at room temperature Tetrakistriphenylphosphine palladium (0) (86.6 mg) was added to a suspension of potassium (413 mg) in N, N-dimethylformamide (10 mL), and the mixture was stirred at 150 ° C. for 5 hours under an argon gas atmosphere. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (286 mg).
The structural formula and spectrum data of the title compound are shown in Table 80.

(Production Example 40)
The following production examples 40-1 to 40-31 were obtained in the same manner as in Production Example 4-1, using the corresponding tert-butyl = (2-methylphenyl) carbamate derivative. These structural formulas and physical property values are shown in Tables 81 to 85.

(Production Example 41)
Using corresponding ketones, the following Production Examples 41-1 to 41-5 were obtained in the same manner as in Production Example 5-1. These structural formulas and physical property values are shown in Table 86.

(Production Example 42)
Ethyl-2-chloro-3-methylbenzoate

Under ice-cooling, concentrated sulfuric acid (0.43 mL) was added to an ethanol (4.3 mL) solution of 2-chloro-3-methylbenzoic acid (147 mg) in an argon gas atmosphere. The mixture was refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. The layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (182 mg).
The structural formula and spectrum data of the title compound are shown in Table 86.

(Production Example 43)
Ethyl 3-bromomethyl-2-chlorobenzoate

At room temperature, ethyl 2-chloro-3-methylbenzoate (166 mg) in tetrachloromethane (4.2 mL) was added to N-bromosuccinimide (149 mg) and benzoyl peroxide (content 75%, 13.0 mg). ) Was added and the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (153 mg).
The structural formula and spectrum data of the title compound are shown in Table 86.

(Production Example 44)
Using corresponding ketones, the following Production Examples 44-1 to 44-20 were obtained in the same manner as in Production Example 6-1. These structural formulas and physical property values are shown in Tables 87 to 90.

(Production Example 45)
Using the corresponding ketone and the corresponding bromide as the alkylating agent, the following Production Examples 45-1 to 45-9 were obtained in the same manner as in Production Example 6-1. These structural formulas and physical property values are shown in Tables 91 to 92.

(Production Example 46)
Using the corresponding ketone, using the corresponding bromide as the alkylating agent, and further adding sodium iodide as an additive, the following Production Examples 46-1 to 46-5 were obtained in the same manner as in Production Example 6-1. . These structural formulas and physical property values are shown in Table 93.

(Production Example 47-1)
5-Fluoro-2-isopropyl-6-methoxy-1H-indole

  The title compound was obtained in the same manner as in Production Example 30-1 using the corresponding starting material.

1H-NMR (CDCl3) δ ppm: 7.81 (1H, s), 7.20 (1H, d, J = 11.6Hz), 6.89 (1H, d, J = 7.1Hz), 6.14 (1H, s), 3.90 (3H , s), 3.15-2.95 (1H, m), 1.34 (6H, d, J = 6.7Hz)

(Production Example 47-2)
2-Isopropyl-6-methoxy-5-methyl-1H-indole

  The title compound was obtained in the same manner as in Production Example 30-1 using the corresponding starting material.

1H-NMR (CDCl3) δ ppm: 7.73 (1H, s), 7.25 (1H, s), 6.78 (1H, s), 6.09 (1H, s), 3.84 (3H, s), 3.10-2.95 (1H, m), 2.28 (3H, s), 1.33 (6H, d, J = 6.9Hz)

(Example 1-1)
Methyl = 6- (6-methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylate

  Methyl = 6- [2- (2-tert-butoxycarbonylamino-4-methoxyphenyl) -3-oxo-3-phenylpropyl] pyridine-2-carboxylate (3.27 g) in trifluoroacetic acid (10 mL)- A solution of methylene chloride (25 mL) was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution was added to the mixture. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (1.49 g).

1H-NMR (CDCl3) δ ppm: 8.10 (1H, br s), 8.00-7.90 (1H, m) 7.65-7.15 (8H, m), 6.92 (1H, d, J = 2.2Hz), 6.74 (1H, dd, J = 8.7, 2.2Hz), 4.56 (2H, s), 4.04 (3H, s), 3.86 (3H, s)

  The following Examples 1-2 to 1-6 were obtained in the same manner as Example 1-1 using the corresponding ketone. These structural formulas and physical property values are shown in Table 23.

(Example 2-1)
Methyl = 3- (6-methoxy-2-phenyl-1H-indol-3-ylmethyl) benzoate

  Under ice cooling, to a solution of triethylsilane (0.204 mL) and trifluoroacetic acid (0.049 mL) in methylene chloride (1.5 mL) was added 6-methoxy-2-phenyl-1H-indole (95.0 mg) and methyl = A solution of m-formylbenzoate (76.9 mg) in methylene chloride (1.8 mL) was added. The solution was stirred for 0.5 hours under the same conditions, then at room temperature overnight. A 2 mol / L aqueous sodium hydroxide solution was added to the solution, and then water was added. The organic layer was separated and concentrated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (111 mg).

1H-NMR (CDCl3) δ ppm: 8.05-7.80 (3H, m), 7.55-7.15 (8H, m), 6.90 (1H, d, J = 2.2Hz), 6.72 (1H, dd, J = 8.7, 2.2 Hz), 4.28 (2H, s), 3.88 (3H, s), 3.85 (3H, s)

  The following Examples 2-2 to 2-26 were obtained in the same manner as in Example 2-1, using the corresponding indole derivatives. These structural formulas and physical property values are shown in Tables 24-28.

(Example 3-1)
Methyl = 3- (6-chloro-1-methyl-2-phenyl-1H-indol-3-ylmethyl) benzoate

  At room temperature, a solution of methyl 3- (6-chloro-2-phenyl-1H-indol-3-ylmethyl) benzoate (112 mg) in N, N-dimethylformamide (15 mL) was added with sodium hydride (content 55%, 13.6 mg) was added under an argon gas atmosphere and the mixture was stirred at room temperature under an argon gas atmosphere for 0.5 hours. Methyl iodide (0.030 mL) was added to the mixture at room temperature, and the mixture was stirred at room temperature overnight under an argon gas atmosphere. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (41.2 mg).

1H-NMR (CDCl3) δ ppm: 7.85-7.75 (2H, m), 7.50-7.20 (9H, m), 7.03 (1H, dd, J = 8.4, 1.8Hz), 4.07 (2H, s), 3.87 ( 3H, s), 3.59 (3H, s)

  The following Examples 3-2 to 3-12 were obtained in the same manner as in Example 3-1, using the corresponding indole derivatives. These structural formulas and physical property values are shown in Tables 29 to 31.

(Example 4-1)
6- (6-Methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid

  A solution of methyl 6- (6-methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylate (0.427 g) in methanol (3.0 mL) -tetrahydrofuran (1.5 mL) at room temperature. 2mol / L sodium hydroxide aqueous solution (1.43mL) was added, and the solution was stirred at 65 ° C for 1 hour. After cooling to room temperature, 2 mol / L hydrochloric acid was added to the mixture. The mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was sonicated and then stirred for 15 minutes. The precipitate was collected by filtration to give the title compound (0.405 g).

1H-NMR (DMSO-d6) δ ppm: 11.18 (1H, br s), 7.90-7.70 (4H, m), 7.50-7.25 (5H, m), 6.87 (1H, d, J = 2.1Hz), 6.62 (1H, dd, J = 8.7, 2.1Hz), 4.38 (2H, s), 3.77 (3H, s)
MS (ESI, m / z): 359 (M + H) +

  The following Examples 4-2 to 4-44 were obtained in the same manner as in Example 4-1, using the corresponding esters. These structural formulas and physical property values are shown in Tables 32 to 40.

(Example 5-1)
Ethyl = 6- (6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylate

At room temperature, ethyl 6- [2- (2-tert-butoxycarbonylamino-4-methoxyphenyl) -3-oxo-3-thiophen-3-ylpropyl] pyridine-2-carboxylate (0.411 g) To a methylene chloride (4.0 mL) solution was added trifluoroacetic acid (0.80 mL) and the solution was stirred for 1 hour. Under ice-cooling, 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was stirred. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (0.189 g).
The structural formula and spectrum data of the title compound are shown in Table 41.

  The following Examples 5-2 to 5-24 were obtained in the same manner as in Example 5-1, using the corresponding ketone. These structural formulas and spectral data are shown in Tables 41 to 46.

(Example 6-1)
Methyl = 6- (6-fluoro-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylate

Under ice cooling, 6-fluoro-2-phenyl-1H-indole (88.9 mg), methyl 6-formylpyridine-2-carboxylate (76.5 mg) and triethylsilane (0.200 mL) in methylene chloride (2 0.0 mL) solution was added dropwise trifluoroacetic acid (0.049 mL). The mixture was stirred at the same temperature for 5 minutes and then at room temperature for 14 hours. Under ice-cooling, 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was stirred. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (73.8 mg).
The structural formula and spectral data of the title compound are shown in Table 47.

  The following Examples 6-2 to 6-10 were obtained in the same manner as in Example 6-1, using the corresponding indole derivatives. These structural formulas and spectral data are shown in Tables 47 and 48.

(Example 7)
Ethyl = 3- (6-methoxy-2-pyridin-3-yl-1H-indol-3-ylmethyl) benzoate

  Under ice-cooling, ethyl 3- (6-methoxy-2-pyridin-3-yl-1H-indole-3-carbonyl) benzoate (0.12 g) in tetrahydrofuran (1.5 mL) -ethanol (1.5 mL) To the solution was added 10% palladium-carbon (125 mg, wet) and the mixture was stirred at room temperature overnight under a hydrogen atmosphere and then at 40 ° C. for 8 hours. The reaction mixture was filtered through Celite (registered trademark), and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. A methylene chloride (3 mL) solution was added to the residue, then triethylsilane (0.105 mL) and trifluoroacetic acid (0.277 mL) were sequentially added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (41.8 mg).

1H-NMR (CDCl3) δ ppm: 8.85-8.70 (1H, m), 8.65-8.50 (1H, m), 8.10 (1H, s), 8.00-7.70 (3H, m), 7.40-7.20 (4H, m ), 6.93 (1H, d, J = 2.2Hz), 6.75 (1H, dd, J = 8.7, 2.2Hz), 4.35 (2H, q, J = 7.1Hz), 4.28 (2H, s), 3.86 (3H , s), 1.37 (3H, t, J = 7.1Hz)
MS (ESI, m / z) = 387 (M + H) +

(Example 8-1)
Ethyl = 6- (6-chloro-2-pyridin-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylate

At room temperature, ethyl 6-[(6-chloro-2-pyridin-3-yl-1H-indol-3-yl) hydroxymethyl] pyridine-2-carboxylate (72.0 mg) in methylene chloride (1.5 mL ) Triethylsilane (0.034 mL) and trifluoroacetic acid (0.163 mL) were sequentially added to the solution, and the mixture was stirred for 7 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (49.5 mg).
The structural formula and spectral data of the title compound are shown in Table 49.

  The following Example 8-2 was obtained in the same manner as in Example 8-1, using the corresponding alcohol. These structural formulas and spectral data are shown in Table 49.

Example 9
Ethyl = 2 (6-methoxy-2-phenyl-1H-indol-3-ylmethyl) thiazole-4-carboxylate

  To a solution of ethyl 2- [hydroxy- (6-methoxy-2-phenyl-1H-indol-3-yl) methyl] thiazole-4-carboxylate (69.0 mg) in methylene chloride (1.7 mL) at room temperature. Triethylsilane (0.135 mL) was added under an argon gas atmosphere. Boron trifluoride-ethyl ether complex (0.107 mL) was slowly added dropwise to the mixture under ice cooling. The mixture was stirred under the same conditions for 10 minutes and at room temperature for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The organic layer was separated, and the layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by aminopropylated silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain the title compound (17.0 mg).

1H-NMR (CDCl3) ppm: 8.13 (1H, br s), 7.99 (1H, s), 7.60-7.30 (6H, m), 6.93 (1H, d, J = 2.1Hz), 6.79 (1H, dd, J = 8.7, 2.1Hz), 4.61 (2H, s), 4.45 (2H, q, J = 7.2Hz), 3.87 (3H, s), 1.43 (3H, t, J = 7.2Hz)
MS (ESI, m / z) = 393 (M + H) +

(Example 10)
6- (6-Hydroxymethyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid

  To a solution of ethyl 6- (6-acetoxymethyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylate (66.0 mg) in tetrahydrofuran (1 mL) -ethanol (0.5 mL) at room temperature. A 2 mol / L aqueous sodium hydroxide solution (0.31 mL) was added and the mixture was stirred at 30 ° C. overnight. The reaction mixture was concentrated under reduced pressure. After adding water to the residue, 2 mol / L hydrochloric acid (0.31 mL) was added dropwise, and the mixture was stirred for 20 minutes. The precipitate was collected by filtration to give the title compound (41.4 mg).

1H-NMR (CDCl3) δ ppm: 11.29 (1H, s), 7.90-7.70 (4H, m), 7.55-7.25 (6H, m), 6.95-6.85 (1H, m), 5.15-5.10 (1H, m ), 4.60-4.50 (2H, m), 4.38 (2H, s)
MS (ESI, m / z) = 359 (M + H) +

(Example 11-1)
6- (6-Methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid

Ethyl = 6- (6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylate (0.187 g) in tetrahydrofuran (3.6 mL) -ethanol (1.8 mL) A 1 mol / L aqueous sodium hydroxide solution (1.4 mL) was added to the solution, and the mixture was stirred at 60 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure. The residue was diluted with water, and 1 mol / L hydrochloric acid (1.4 mL) was added to the mixture under ice cooling. The precipitate was collected by filtration to give the title compound (0.171 g).
The structural formula and spectral data of the title compound are shown in Table 50.

  The following Examples 11-2 to 11-38 were obtained in the same manner as in Example 11-1, using the corresponding ester. These structural formulas and spectral data are shown in Tables 50-57.

(Example 12)
The following Examples 12-1 to 12-34 were obtained in the same manner as Example 1-1 using the corresponding ketone. These structural formulas and physical property values are shown in Tables 94 to 99.

(Example 13)
The following Examples 13-1 to 13-35 were obtained in the same manner as in Example 2-1, using the corresponding indole derivatives. These structural formulas and physical property values are shown in Tables 100 to 106.

(Example 14-1)
Ethyl = 6- (5-fluoro-6-methoxy-2-pyridin-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylate

Under ice-cooling, ethyl 6-[(5-fluoro-6-methoxy-2-pyridin-3-yl-1H-indol-3-yl) hydroxymethyl] pyridine-2-carboxylate (81.0 mg) and triethyl To a solution of silane (0.120 mL) in methylene chloride (1.9 mL) was slowly added trifluoroacetic acid (0.059 mL). The mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated. The layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by aminopropylated silica gel column chromatography (elution solvent: methylene chloride-methanol) to obtain the title compound (70.5 mg).
Table 106 shows the structural formula and spectral data of the title compound.

  The following Examples 14-2 to 14-15 were obtained in the same manner as Example 14-1 using the corresponding starting materials. These structural formulas and physical property values are shown in Tables 106 to 108.

(Example 15-1)
Methyl = 6- (6-methoxy-5-methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylate

Under ice cooling, triethylsilane (0.063 mL) was added to a suspension of sodium iodide in acetonitrile (0.30 mL) under an argon gas atmosphere, and the mixture was stirred for 5 minutes under the same conditions. Methyl = 6- [hydroxy- (6-methoxy-5-methyl-2-phenyl-1H-indol-3-yl) methyl] pyridine-2-carboxylate (50.0 mg) in acetonitrile (1 mL) was added to the mixture. A turbid solution was added and the mixture was stirred for 1 hour under the same conditions. Under ice cooling, ethyl acetate and water were added to the mixture, and then sodium bicarbonate was added. The organic layer was separated, and the layer was washed successively with 9% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (40.9 mg).
Table 109 shows the structural formula and spectrum data of the title compound.

  The following Examples 15-2 to 15-25 were obtained in the same manner as Example 15-1 using the corresponding starting materials. These structural formulas and physical property values are shown in Tables 109 to 113.

(Example 16)
The following Examples 16-1 to 16-109 were obtained in the same manner as in Example 4-1, using the corresponding esters. These structural formulas and physical property values are shown in Tables 114 to 135.

(Example 17)
The following Examples 17-1-17-2 were obtained in the same manner as in Example 2-1, using the corresponding starting materials. These structural formulas and physical property values are shown in Table 136.

(Example 18)
The following Examples 18-1-18-2 were obtained in the same manner as in Example 4-1, using the corresponding starting materials. These structural formulas and physical property values are shown in Table 136.

(Example 19)
EP ₁ receptor antagonism confirmation test

(1) Preparation of rat EP ₁ expression vector Using Rat Kidney BD Marathon-Ready cDNA (Nippon Becton Dickinson Co., Ltd.) as a template, the forward primer shown in SEQ ID NO: 1 and the reverse primer shown in SEQ ID NO: 2 were used. The first PCR was performed using KOD-Plus-Ver2.0 (Toyobo Co., Ltd.). Further, using this amplification product as a template, a forward primer shown in SEQ ID NO: 3 and a reverse primer shown in SEQ ID NO: 4 were used, and a second PCR was performed in the same manner. The amplification product obtained by the second PCR was incorporated into a vector (pcDNA3.1 D / V5-His-TOPO (registered trademark), Invitrogen Corporation). By a conventional method, the vector incorporating this amplification product was introduced into E. coli (One-shot TOP10 competent cell, Invitrogen) and transformed. The transformed Escherichia coli was cultured on an LB agar medium for 1 day. After the culture, colonies were selected and cultured in an LB liquid medium containing 50 μg / mL ampicillin. After culture, the vector was purified using QIAprep Spin Miniprep Kit (Qiagen). When the base sequence (SEQ ID NO: 5) of the insertion site of this vector was compared with the base sequence (Ptger ₁ ) of rat EP ₁ registered under the accession number NM — 013100 of a known database (NCBI), all except one base were identical. It was. Further, the amino acid sequence translated by this base sequence completely matched the amino acid sequence of the rat EP ₁ receptor registered under NCBI accession number NP — 037232. Therefore, it was confirmed that the cloned gene sequence was the base sequence of rat EP ₁ receptor, and the obtained amino acid sequence was rat EP ₁ receptor. PcDNA3.1 D / V5-His-TOPO (registered trademark) into which the nucleic acid shown in SEQ ID NO: 5 was inserted was used as a rat EP ₁ expression vector.

(2) Preparation of rat EP ₁ receptor-expressing cells

(2-1) COS-1 cell culture COS-1 cells (Dainippon Sumitomo Pharma Co., Ltd.) are penicillin-streptomycin solutions (Invitrogen Corporation, final concentration: 100 U / mL as benzylpenicillin; 100 μg / mL as streptomycin) as antibiotics, D-MEM liquid medium (containing high glucose and L-glutamine, supplemented with MEM non-essential amino acids (Invitrogen Corporation, final concentration: 0.1 mM) and fetal calf serum (Sanko Junyaku Co., Ltd., final concentration: 10%), Invitrogen Corp.) was cultured in an incubator under 5% CO ₂ gas conditions at 37 ° C. until confluence.

(2-2) Passage of COS-1 cells Cells that reached confluence were detached with 0.05% trypsin / 0.53 mM EDTA · 4Na (Invitrogen Corporation) and resuspended in the liquid medium. The resuspended cells were diluted with the above liquid medium so that the spread ratio was 1: 4 to 1: 8 and cultured.

(2-3) Preparation of Rat EP ₁ Expression Vector Introducing Cells Cells that have reached confluence are detached with 0.05% trypsin / 0.53 mM EDTA · 4Na, MEM non-essential amino acids (final concentration: 0.1 mM) and Resuspended in D-MEM liquid medium (containing high glucose and L-glutamine, Invitrogen Corporation) supplemented with fetal bovine serum (final concentration: 10%). This resuspended cell suspension was poly D-lysine coated 96 well microplate (BD BioCoat (registered trademark), Nippon Becton Dickinson Co., Ltd.) in each well 5 × 10 ⁴ cells / well, liquid The medium volume was adjusted to 100 μL and seeded. After seeding, the cells were cultured at 37 ° C. in an incubator with 5% CO ₂ gas. When the cells for introduction of the rat EP ₁ expression vector were adhered (about 2 hours after seeding), the rat EP ₁ expression vector was introduced by the following procedure.

(2-4) Rat EP ₁ expression vector introduction

For the introduction of rat EP ₁ expression vector, using Lipofectamine 2000 (Invitrogen Corporation). The rat EP ₁ expression vector was diluted with 200ng / 25μL / to be well OPTI-MEM (R) I Reduced-Serum Medium (Invitrogen, Inc.). At the same time, Lipofectamine 2000 (Invitrogen Corporation) is diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) so as to be 0.5 μL / 25 μL / well, and incubated at room temperature for 5 minutes. did. After incubation for 5 minutes, diluted rat EP ₁ expression vector and diluted Lipofectamine 2000 were mixed and incubated at room temperature for 30 minutes for complex formation of rat EP ₁ expression vector / Lipofectamine 2000. After incubation for 30 minutes, the rat EP ₁ expression vector / Lipofectamine 2000 complex was dispensed into the rat EP ₁ expression vector introduction cells at 50 μL / well. The cells into which the rat EP ₁ expression vector / Lipofectamine 2000 complex was dispensed were cultured at 37 ° C. for 20 hours in an incubator under 5% CO ₂ gas conditions. After culturing for 20 hours, the cells were used as rat EP ₁ receptor-expressing cells for measurement of intracellular calcium concentration.

(3) Examination of the inhibitory effect on the increase in intracellular calcium concentration

Using the rat EP ₁ receptor-expressing cells, the inhibitory effect of each test compound on the increase in intracellular calcium concentration induced by prostaglandin E ₂ was examined by Method A or Method B shown below.

Method A:
A 10 mM dimethyl sulfoxide solution of each test compound was diluted with an assay buffer (20 mM HEPES / Hank's Balanced Salt Solution (HBSS), pH 7.2).
Rat EP ₁ receptor-expressing cells were washed with assay buffer. Fluorescent calcium indicator (Fluo-4 NW Calcium Assay Kit (Molecular Probes): prepared by the same protocol, Invitrogen Corp., containing 2.5 mM probenecid) 100 μL was added to each well and in an incubator at 37 ° C. for 60 minutes. Incubated at Thereafter, all cell supernatant was aspirated and washed with assay buffer. After washing, 100 μL of assay buffer containing 2.5 mM probenecid was added to each well, and the intracellular calcium concentration was measured immediately.
The intracellular calcium concentration was measured as a fluorescence signal using FlexStation (registered trademark) (manufactured by Molecular Devices). 50 μL of each test compound (final concentration: 1 nM to 10 μM) diluted with an assay buffer 20 seconds after the start of reading of the fluorescent signal was added to each well, and the fluorescent signal was measured for 60 seconds. Then added 50μL prostaglandin _{E 2} buffer solution to each well (final concentration 10 nM), was measured for 60 seconds the fluorescence signal.

Method B:
A 10 mM dimethyl sulfoxide solution of each test compound was diluted with an assay buffer (20 mM HEPES / Hank's Balanced Salt Solution (HBSS), pH 7.2).
Rat EP ₁ receptor-expressing cells were washed with assay buffer. Fluorescent calcium indicator (Calcium kit II, Fluo4 (Dojindo Laboratories Co., Ltd.): Prepared by the same product protocol, Invitrogen Co., Ltd., containing 2.5 mM probenecid) 100 μL was added to each well, and at 37 ° C. for 60 minutes. Incubated in incubator. Thereafter, the intracellular calcium concentration was measured immediately.
The intracellular calcium concentration was measured as a fluorescence signal using FDSS (registered trademark) 7000 (manufactured by Hamamatsu Photonics). 20 seconds after the start of reading the fluorescence signal, 50 μL of each test compound (final concentration: 1 nM to 10 μM) was added to each well, and the fluorescence signal was measured for 60 seconds. Then added 50μL prostaglandin _{E 2} buffer solution to each well (final concentration 10 nM), was measured for 60 seconds the fluorescence signal.

In Method A or Method B, 100% of the fluorescence signal obtained when prostaglandin E _{2 was} added when assay buffer was added instead of test compound, obtained when neither test compound nor prostaglandin E ₂ was added. The signal obtained was taken as 0%, and the concentration showing 50% inhibition from the concentration-response curve of the test compound was taken as the IC ₅₀ value. As values of EP ₁ receptor antagonism, IC ₅₀ values of the obtained test compounds are shown in Tables 137 to 138 below. Further, sodium 6- (6-chloro-3-isobutylindol-1-yl) pyridine-2-carboxylate (Compound 12 g) described in Non-Patent Document 5 was similarly tested as Comparative Example 1. The results are shown in Table 138.

As shown in Table 137 and Table 138, it was revealed that the compound of the present invention exhibits a strong EP ₁ receptor antagonistic action as compared with Comparative Example 1.

(Example 20)
Inhibitory effect of compounds on sarprostone-induced bladder contraction

  Female SD rats were used. Under urethane anesthesia (1.25 g / kg, subcutaneous administration), a tracheal cannula (Size8, HBIKI) and a femoral vein cannula for administration (PE50 with a 23G needle) were inserted. A bladder cannula (PE50) was inserted from the top of the bladder. The bladder cannula was connected to a three-way stopcock, one connected to a pressure transducer, and the other connected to a syringe filled with saline. Saline was infused into the bladder at an infusion rate of 3.6 mL / hour, and the bladder contraction pressure at the time of infusion was recorded with a recorder (RECTI-HORITZ-8K, NEC Corporation). Ten minutes after stabilization of the bladder contraction pressure during urination, sarprostone was administered subcutaneously (0.3 mg / kg). Thereafter, when the bladder contraction pressure became constant, the test drug (1.0 mg / kg) was intravenously administered. The average bladder contraction pressure for 10 minutes before administration of salprostone was used as a reference value (0%). The average bladder contraction pressure for 10 minutes immediately before administration of the test drug was defined as the maximum bladder contraction pressure (100%). Average bladder contraction pressure was measured for 5 minutes before and after 15 minutes and 60 minutes after administration of the test drug. The ratio of this measured value with respect to the maximum bladder contraction pressure was calculated by the following formula, and was defined as the average bladder contraction rate after administration of the test drug: (average bladder contraction rate (%) after test drug administration) = (test drug) Average bladder contraction pressure after administration) / (maximum bladder contraction pressure). Further, the difference between the maximum bladder contraction rate (100%) and the average bladder contraction rate (%) after administration of the test drug was calculated by the following formula, and was taken as the bladder contraction suppression rate of the test drug: (bladder contraction suppression rate) = 100%-(mean bladder contraction rate (%) after test drug administration). The results are shown in Table 139.

(Example 21) Inhibitory effect by combined use of compounds on sarprostone-induced bladder contraction

Instead of the test drug of Example 20, Compound (I) or a pharmacologically acceptable salt thereof and a drug other than the EP ₁ receptor antagonist are administered at the time when the bladder contraction pressure becomes constant. The intravenous cannula is administered intravenously simultaneously or separately. The bladder contraction inhibition rate when compound (I) or a pharmacologically acceptable salt thereof and a drug other than an EP ₁ receptor antagonist are used in combination can be calculated in the same manner as in Example 20.

  As a result of the above, the compound of the present invention was shown to have a strong and sustained suppression of bladder contraction even when administered in vivo.

Since the compound of the present invention has a strong EP ₁ receptor antagonism, it is useful as a therapeutic or prophylactic agent for diseases or symptoms caused by the activation of EP ₁ receptor by the stimulating action of PGE ₂ . Among them, it is useful as a therapeutic or prophylactic agent for lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs).

<Sequence Listing 1>
SEQ ID NO: 1 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<Sequence Listing 2>
SEQ ID NO: 2 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<Sequence Listing 3>
SEQ ID NO: 3 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<SEQ ID NO: 4>
SEQ ID NO: 4 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<SEQ ID NO: 5>
SEQ ID NO: 5 is a DNA sequence for expressing the rat EP ₁ receptor amplified using the primers of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

Claims (20)

A pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof , wherein the compound is an EP ₁ receptor antagonist

[Where,
A represents the following a) to h):

A group selected from the group consisting of:
One of W ¹ and W ² is a nitrogen atom, and the other is ═CH— or a nitrogen atom;
W ³ is an oxygen atom or a sulfur atom;
W ⁴ is ═CH— or a nitrogen atom;
X is a hydrogen atom or a halogen atom;
Y is a C _1-6 alkylene group or a halo C _1-6 alkylene group;
^RN is a hydrogen atom or a C _1-6 alkyl group;
R ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _7-10 aralkyl group;
R ² represents the following i) to m):
i) a branched C _3-6 alkyl group,
j) a C _3-6 cycloalkyl group,
k) unsubstituted or selected from the group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group and a cyano group A phenyl group wherein the ring is substituted with 1 to 5 groups,
l) unsubstituted or independently selected from the group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group and a cyano group A 6-membered aromatic heterocyclic group in which the ring is substituted with 1-4 groups, and m) unsubstituted or a group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 It consists of a 5-membered aromatic heterocyclic group in which the ring is substituted with 1 to 3 groups independently selected from an alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group and a cyano group A group selected from the group;
R ³ is a halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, hydroxy C _1-6 alkyl group, C _1-6 alkoxy group, halo C _1-6 alkoxy group, C _1-6 alkyl A sulfanyl group, a C _1-6 alkylsulfinyl group, a C _1-6 alkylsulfonyl group, a C _3-6 cycloalkyl group, a cyano group, an amino group, or a nitro group;
R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group;
R ⁵ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group. ]. A is the following a) to d):

The pharmaceutical composition according to claim 1, which is a group selected from the group consisting of: A is the following a) to c):

A group selected from the group consisting of:
W ¹ is a nitrogen atom;
W ² is ═CH—;
The pharmaceutical composition according to claim 2, wherein X is a hydrogen atom. R ² is the following a) to c):
a) a branched C _3-6 alkyl group,
a group selected from the group consisting of b) a phenyl group, and c) a 5-membered aromatic heterocyclic group or a 6-membered aromatic heterocyclic group;
R ³ is a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a halo C _1-6 alkoxy group or a cyano group;
R ⁴ is a hydrogen atom;
The pharmaceutical composition according to claim 3, wherein R ⁵ is a hydrogen atom. The pharmaceutical composition according to claim 4, wherein R ¹ is a hydrogen atom. The pharmaceutical composition according to claim 5, wherein Y is a methylene group and ^RN is a hydrogen atom. The pharmaceutical composition according to claim 6, wherein R ² is a phenyl group, a 5-membered aromatic heterocyclic group or a 6-membered aromatic heterocyclic ring. The pharmaceutical composition according to claim 7, wherein R ³ is a halogen atom or a C _1-6 alkoxy group. The pharmaceutical composition according to claim 6, wherein R ² is an isopropyl group, an isobutyl group, a sec-butyl group or a tert-butyl group. The pharmaceutical composition according to claim 9, wherein R ³ is a halogen atom or a C _1-6 alkoxy group. A is the following formula

The pharmaceutical composition of Claim 2 which is group represented by these . The pharmaceutical composition according to claim 11, wherein R ¹ is a hydrogen atom. R ² represents the following a) to d):

A group selected from the group consisting of:
W ⁵ is a nitrogen atom or —CR ^9c =;
R ^6a , R ^6b , R ^6c , R ^6d , R ^6e , R ^7a , R ^7b , R ^7c , R ^7d , R ^8a , R ^8b , R ^8c , R ^9a , R ^9b and R ^9c are each independently And a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a hydroxy C _1-6 alkyl group, a C _1-6 alkoxy group or a cyano group . . The pharmaceutical composition according to claim 13, wherein R ¹ is a hydrogen atom. 3- (6-methoxy-2-phenyl-1H-indol-3-ylmethyl) benzoic acid,
6- (6-Chloro-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid,
6- (6-ethyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid,
6- (6-Ethoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid,
6- (2-phenyl-6-trifluoromethyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid,
6- [2- (3-fluorophenyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [2- (4-fluorophenyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methoxy-2- (5-methylthiophen-3-yl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- (6-methoxy-2-thiazol-5-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid,
2-fluoro-3- (6-methoxy-2-phenyl-1H-indol-3-ylmethyl) benzoic acid,
6- [2- (5-fluoropyridin-3-yl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- (5-chloro-6-methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid,
6- (5-fluoro-6-methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid, and
6- (5-chloro-6-methoxy-2-thiophen-3-yl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid,
A pharmaceutical composition comprising a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof, wherein the compound is EP ₁ A pharmaceutical composition which is a receptor antagonist. A pharmaceutical composition comprising 6- (6-methoxy-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid, or a pharmacologically acceptable salt thereof, wherein the compound is EP ₁ A pharmaceutical composition which is a receptor antagonist. A pharmaceutical composition comprising 6- (6-methyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid, or a pharmacologically acceptable salt thereof, wherein the compound is EP ₁ A pharmaceutical composition which is a receptor antagonist. A pharmaceutical composition comprising 6- (6-cyclopropyl-2-phenyl-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, comprising the compound EP ₁ A pharmaceutical composition which is a receptor antagonist. A therapeutic or prophylactic agent for lower urinary tract symptoms, comprising the pharmaceutical composition according to any one of claims 1 to 18 . Group consisting of: anticholinergics, alpha ₁ antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitors, anti diuretics, calcium channel blockers, smooth muscle direct action, tricyclic antidepressants, K channel modulating agents, sodium channel blockers, H ₁ blockers, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors , GABA agonist, TRPV1 modulator, endothelin antagonist, 5-HT _1A antagonist, α ₁ agonist, opioid agonist, P ₂ X antagonist, COX inhibitor, σ agonist and muscarinic agonist The therapeutic or prophylactic agent for lower urinary tract symptoms according to claim 19 , wherein both are used in combination with one kind of drug.