JPWO2005011674A1 - Preventive and / or therapeutic agent for bronchial asthma - Google Patents

Abstract

Formula (I) [wherein R1 represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkoxy, and X1-X2-X3 represents CR5 = CR6-CR7 = CR8 (formula R5, R6, R7 and R8 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, etc.), etc. , —CH═CH—, — (CH 2) p — (wherein p represents an integer of 0 to 2), —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —OCH 2 —, and R 2 represents a hydrogen atom Or a pharmacologically acceptable salt thereof as an active ingredient, and a prophylactic and / or therapeutic agent for bronchial asthma, which represents a substituted or unsubstituted lower alkyl, etc. To provide a tachykinin inhibitors.

Description

  The present invention relates to a prophylactic and / or therapeutic agent for bronchial asthma containing a tricyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.

The main pathology of bronchial asthma consists of inflammatory symptoms such as abnormal contraction of airway smooth muscle, vascular leakage, secretory gland stimulation, and increased vascular permeability. As therapeutic agents for bronchial asthma, inhaled β stimulants having a tracheal smooth muscle relaxing action and inhaled steroids having an anti-inflammatory action are often used. Inhaled β-stimulants have a fast-acting and remarkable effect, but it has been reported that the effect may be attenuated by continuous use and may cause sudden death [The New England Journal, Of Medicine (The New England Journal of Medicine), Vol. 326, p. 501-506 (1992)]. Inhaled steroids, on the other hand, have excellent anti-inflammatory effects and are excellent drugs. However, steroids have been reported to have serious side effects such as growth disorders in children [American Journal of Respiratory Medicine.・ American Journal of Respiratory and Critical Care Medicine, Vol. 151, p. 1715-1719 (1995)], safety for long-term use has not been established. In addition, since an inhalant is complicated to use, a highly safe oral preparation is desired.
In the airways of bronchial asthma patients, tachykinin is released from the end of sensory nerves distributed around smooth muscle, secretory glands, capillaries, etc. due to various risk factors such as antigen, viral infection, exercise, smoke, cold air, stress, etc. Inspired, effects such as smooth muscle contraction, increased secretion, increased vascular permeability are induced. From these facts, tachykinin is considered to be deeply involved in the pathology of bronchial asthma, and tachykinin inhibitors are considered to be usable as therapeutic agents for bronchial asthma [Lancet, Vol. 1, p. 242-245 (1986)].
On the other hand, a group of compounds having the same structure as the compound used in the present invention has an action of extending the interval of micturition that occurs when the bladder is full, and is used in various diseases or conditions including neurogenic bladder and unstable bladder. It is known to be useful for the treatment or improvement of frequent urination, urinary incontinence, urgency and residual urine (WO 97/14672, WO 98/46587).

｛式中、Ｒ^１は水素原子、ハロゲン、置換もしくは非置換の低級アルキルまたは置換もしくは非置換の低級アルコキシを表し、
Ｘ^１−Ｘ^２−Ｘ^３は、ＣＲ^５＝ＣＲ^６−ＣＲ^７＝ＣＲ^８［式中、Ｒ^５、Ｒ^６、Ｒ^７及びＲ^８は、同一または異なって水素原子、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルコキシまたは置換もしくは非置換の低級アルカノイルアミノを表す］、Ｎ（Ｏ）_ｍ＝ＣＲ^６−ＣＲ^７＝ＣＲ^８（式中、Ｒ^６、Ｒ^７及びＲ^８はそれぞれ前記と同義であり、ｍは０または１を表す）、ＣＲ^５＝ＣＲ^６−Ｎ（Ｏ）_ｍ＝ＣＲ^８（式中、Ｒ^５、Ｒ^６、Ｒ^８及びｍはそれぞれ前記と同義である）、ＣＲ^５＝ＣＲ^６−ＣＲ^７＝Ｎ（Ｏ）_ｍ（式中、Ｒ^５、Ｒ^６、Ｒ^７及びｍはそれぞれ前記と同義である）、ＣＲ^５＝ＣＲ^６−Ｏ（式中、Ｒ^５及びＲ^６はそれぞれ前記と同義である）、ＣＲ^５＝ＣＲ^６−Ｓ（式中、Ｒ^５及びＲ^６はそれぞれ前記と同義である）、Ｏ−ＣＲ^７＝ＣＲ^８（式中、Ｒ^７及びＲ^８はそれぞれ前記と同義である）、Ｓ−ＣＲ^７＝ＣＲ^８（式中、Ｒ^７及びＲ^８はそれぞれ前記と同義である）またはＯ−ＣＲ^７＝Ｎ（式中、Ｒ^７は前記と同義である）を表し、
Ｙは−ＣＨ_２Ｓ−、−ＣＨ_２ＳＯ−、−ＣＨ_２ＳＯ_２−、−ＣＨ_２Ｏ−、−ＣＨ＝ＣＨ−、−（ＣＨ_２）_ｐ−（式中、ｐは０〜２の整数を表す）、−ＳＣＨ_２−、−ＳＯＣＨ_２−、−ＳＯ_２ＣＨ_２−または−ＯＣＨ_２−を表し、
Ｒ^２は水素原子、アミノ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルコキシ、モノ（置換もしくは非置換の低級アルキル）置換アミノ、ジ（置換もしくは非置換の低級アルキル）置換アミノ、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアラルキルアミノ、置換もしくは非置換のアリールアミノまたは置換もしくは非置換の複素環基を表す｝で表される三環式化合物またはその薬理学的に許容される塩を有効成分として含有する気管支喘息の予防及び／または治療剤。
（２）前記（１）に記載の三環式化合物またはその薬理学的に許容される塩を有効成分として含有するタキキニン抑制剤。
（３）式（Ｉａ）

［式中、Ｒ^１及びＸ^１−Ｘ^２−Ｘ^３はそれぞれ前記と同義であり、Ｙ^ａは−ＣＨ_２ＳＯ_２−、−ＳＣＨ_２−、−ＳＯＣＨ_２−、−ＳＯ_２ＣＨ_２−または−ＯＣＨ_２−を表し、
Ｙ^ａが−ＣＨ_２ＳＯ_２−、−ＳＣＨ_２−、−ＳＯＣＨ_２−または−ＳＯ_２ＣＨ_２−であるときに、
Ｒ^２ａは水素原子、アミノ、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルコキシ、モノ（置換もしくは非置換の低級アルキル）置換アミノ、ジ（置換もしくは非置換の低級アルキル）置換アミノ、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアラルキルアミノ、置換もしくは非置換のアリールアミノ、置換もしくは非置換の脂環式複素環基または置換もしくは非置換の含窒素複素環基を表し、
Ｙ^ａが−ＯＣＨ_２−であるときに、
Ｒ^２ａは水素原子、アミノ、トリフルオロメチル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルコキシ、モノ（置換もしくは非置換の低級アルキル）置換アミノ、ジ（置換もしくは非置換の低級アルキル）置換アミノ、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアラルキルアミノ、置換もしくは非置換のアリールアミノ、置換もしくは非置換の脂環式複素環基、置換もしくは非置換の含窒素複素環基または式（ＩＩ）

（式中、ｎは０または１であり、Ｒ^３及びＲ^４は、同一または異なって水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の環状アルキル、置換もしくは非置換のアリールまたは置換もしくは非置換のアラルキルを表すか、Ｒ^３及びＲ^４が隣接する炭素原子と一緒になって環状アルキルを形成してもよく、Ｑはハロゲン、アミノ、ヒドロキシまたは置換もしくは非置換の低級アルコキシを表す）を表す］で表される三環式化合物またはその薬理学的に許容される塩を有効成分として含有する気管支喘息の予防及び／または治療剤。
（４）Ｙ^ａが−ＣＨ_２ＳＯ_２−、−ＳＣＨ_２−、−ＳＯＣＨ_２−または−ＳＯ_２ＣＨ_２−である前記（３）記載の気管支喘息の予防及び／または治療剤。
（５）Ｙ^ａが−ＯＣＨ_２−である前記（３）記載の気管支喘息の予防及び／または治療剤。
（６）Ｙ^ａが−ＣＨ_２ＳＯ_２−、−ＳＯ_２ＣＨ_２−または−ＯＣＨ_２−である前記（３）記載の気管支喘息の予防及び／または治療剤。
（７）Ｙ^ａが−ＣＨ_２ＳＯ_２−または−ＳＯ_２ＣＨ_２−である前記（３）記載の気管支喘息の予防及び／または治療剤。
（８）Ｙ^ａが−ＣＨ_２ＳＯ_２−である前記（３）記載の気管支喘息の予防及び／または治療剤。
（９）Ｒ^１が水素原子、ハロゲンまたは置換もしくは非置換の低級アルコキシである前記（３）〜（８）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（１０）Ｒ^１が水素原子である前記（３）〜（８）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（１１）Ｘ^１−Ｘ^２−Ｘ^３がＳ−ＣＲ^７＝ＣＲ^８（式中、Ｒ^７及びＲ^８はそれぞれ前記と同義である）である前記（３）〜（１０）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（１２）Ｘ^１−Ｘ^２−Ｘ^３がＣＲ^５＝ＣＲ^６−ＣＲ^７＝ＣＲ^８（式中、Ｒ^５、Ｒ^６、Ｒ^７及びＲ^８はそれぞれ前記と同義である）である前記（３）〜（１０）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（１３）Ｒ^２ａが式（ＩＩ）

（式中、ｎ、Ｒ^３、Ｒ^４及びＱはそれぞれ前記と同義である）である前記（３）〜（１２）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（１４）ｎが０である前記（１３）記載の気管支喘息の予防及び／または治療剤。
（１５）Ｒ^３がメチルであり、Ｒ^４がトリフルオロメチルであり、Ｑがヒドロキシである前記（１４）記載の気管支喘息の予防及び／または治療剤。
（１６）Ｒ^１が水素原子であり、Ｙ^ａが−ＣＨ_２ＳＯ_２−であり、Ｘ^１−Ｘ^２−Ｘ^３がＳ−ＣＲ^７＝ＣＲ^８（式中、Ｒ^７及びＲ^８はそれぞれ前記と同義である）であり、Ｒ^２ａが式（ＩＩＩ）

である前記（３）記載の気管支喘息の予防及び／または治療剤。
（１７）前記（３）〜（１６）のいずれかに記載の三環式化合物またはその薬理学的に許容される塩を有効成分として含有するタキキニン抑制剤。
（１８）式（Ｉｂ）

［式中、Ｒ^１及びＸ^１−Ｘ^２−Ｘ^３はそれぞれ前記と同義であり、Ｙ^ｂは−ＣＨ_２Ｏ−、−ＣＨ_２Ｓ−、−ＣＨ_２ＳＯ−、−ＣＨ＝ＣＨ−または−（ＣＨ_２）_ｐ−（式中、ｐは前記と同義である）を表し、Ｒ^２ｂは式（ＩＩＩ）

を表す］で表される三環式化合物またはその薬理学的に許容される塩を有効成分として含有する気管支喘息の予防及び／または治療剤。
（１９）Ｘ^１−Ｘ^２−Ｘ^３がＣＲ^５＝ＣＲ^６−ＣＲ^７＝ＣＲ^８（式中、Ｒ^５、Ｒ^６、Ｒ^７及びＲ^８はそれぞれ前記と同義である）またはＣＲ^５＝ＣＲ^６−ＣＲ^７＝Ｎ（式中、Ｒ^５、Ｒ^６及びＲ^７はそれぞれ前記と同義である）である前記（１８）記載の気管支喘息の予防及び／または治療剤。
（２０）Ｘ^１−Ｘ^２−Ｘ^３がＣＲ^５＝ＣＲ^６−Ｏ（式中、Ｒ^５及びＲ^６はそれぞれ前記と同義である）またはＣＲ^５＝ＣＲ^６−Ｓ（式中、Ｒ^５及びＲ^６はそれぞれ前記と同義である）である前記（１８）記載の気管支喘息の予防及び／または治療剤。
（２１）Ｘ^１−Ｘ^２−Ｘ^３がＯ−ＣＲ^７＝ＣＲ^８（式中、Ｒ^７及びＲ^８はそれぞれ前記と同義である）またはＳ−ＣＲ^７＝ＣＲ^８（式中、Ｒ^７及びＲ^８はそれぞれ前記と同義である）である前記（１８）記載の気管支喘息の予防及び／または治療剤。
（２２）Ｙ^ｂが−ＣＨ_２Ｏ−である前記（１８）〜（２１）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（２３）Ｙ^ｂが−（ＣＨ_２）_ｐ−（式中、ｐは前記と同義である）である前記（１８）〜（２１）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（２４）ｐが０である前記（２３）記載の気管支喘息の予防及び／または治療剤。
（２５）ｐが２である前記（２３）記載の気管支喘息の予防及び／または治療剤。
（２６）Ｙ^ｂが−ＣＨ＝ＣＨ−である前記（１８）〜（２１）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（２７）Ｙ^ｂが−ＣＨ_２Ｓ−または−ＣＨ_２ＳＯ−である前記（１８）〜（２１）のいずれかに記載の気管支喘息の予防及び／または治療剤。
（２８）前記（１８）〜（２７）のいずれかに記載の三環式化合物またはその薬理学的に許容される塩を有効成分として含有するタキキニン抑制剤。
（２９）気管支喘息の予防及び／または治療剤の製造のための、前記（１）、（３）〜（１６）及び（１８）〜（２７）のいずれかに記載の三環式化合物またはその薬理学的に許容される塩の使用。
（３０）タキキニン抑制剤の製造のための、前記（１）、（３）〜（１６）及び（１８）〜（２７）のいずれかに記載の三環式化合物またはその薬理学的に許容される塩の使用。
（３１）前記（１）、（３）〜（１６）及び（１８）〜（２７）のいずれかに記載の三環式化合物またはその薬理学的に許容される塩の有効量を投与する工程を含む、気管支喘息の予防及び／または治療方法。
（３２）前記（１）、（３）〜（１６）及び（１８）〜（２７）のいずれかに記載の三環式化合物またはその薬理学的に許容される塩の有効量を投与する工程を含む、タキキニンの作用抑制方法。
以下、式（Ｉ）で表される化合物を化合物（Ｉ）という。他の式番号で表される化合物についても同様である。
式（Ｉ）の各基の定義において、低級アルキルとしては、例えば直鎖または分岐している炭素数１〜８のアルキル、より具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ペンチル、ヘキシル、１，２，２−トリメチルプロピル、ヘプチル、オクチル等が挙げられる。
ハロゲンは、フッ素、塩素、臭素、ヨウ素の各原子を意味する。
低級アルコキシ、モノ（低級アルキル）置換アミノ及びジ（低級アルキル）置換アミノにおける低級アルキル部分は、前記低級アルキルと同義である。
低級アルカノイルアミノにおける低級アルカノイルとしては、例えば炭素数１〜６のアルカノイル、より具体的にはホルミル、アセチル、プロパノイル、ブタノイル、ペンタノイル、２，２−ジメチルプロパノイル、ヘキサノイル等が挙げられる。
低級アルケニルとしては、例えば直鎖または分岐している炭素数２〜６のアルケニル、より具体的にはビニル、アリル、１−プロペニル、メタクリル、１−ブテニル、クロチル、ペンテニル、ヘキセニル等が挙げられる。
アリール及びアリールアミノのアリール部分としては、例えばフェニル、ナフチル等が挙げられ、ヘテロアリールとしては、例えばピリジル、フリル、チエニル、キノリル、イミダゾリル、ベンゾイミダゾリル、チアゾリル等が挙げられる。
アラルキルアミノのアラルキル部分としては、例えば炭素数７〜１２のアラルキル、より具体的にはベンジル、フェネチル、ナフチルメチル等が挙げられる。
複素環基としては、例えば脂環式複素環基、含窒素複素環基等が挙げられる。脂環式複素環基としては、例えばテトラヒドロフリル、テトラヒドロチエニル、クロマニル等が挙げられる。含窒素複素環基は、例えば１つまたは２つの窒素原子をその環内に含む複素環基であり、さらに酸素、硫黄等のヘテロ原子を含んでいてもよく、例えばピロリジニル、ピペコリニル、ピペラジニル、ピペリジル、モルホリニル、チオモルホリニル、オキサゾリル等が挙げられる。
置換低級アルキル、置換低級アルコキシ、モノ（置換低級アルキル）置換アミノ、ジ（置換低級アルキル）置換アミノ、置換低級アルカノイルアミノ及び置換低級アルケニルにおける置換基としては、同一または異なって、置換数１〜置換可能な数の（好ましくは１〜６の、より好ましくは１〜４の）、例えばハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、環状アルキル、置換環状アルキル［該置換環状アルキルにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる］、アリール、置換アリール（該置換アリールにおける置換基は、後記の置換アリールにおける置換基と同義である）、アラルキル、置換アラルキル（該置換アラルキルにおける置換基は、後記の置換アラルキルにおける置換基と同義である）、低級アルコキシ、置換低級アルコキシ［該置換低級アルコキシにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる］等が挙げられる。また、上記の置換低級アルキルにおいては、該低級アルキルにおける同一炭素原子上に２つの置換基を有し、該２つの置換基が該炭素原子と一緒になって脂肪族環を形成していてもよい。なお置換低級アルキルが置換メチルまたは置換エチルである場合は、その置換基は、さらに同一または異なって例えば置換数１〜３の、低級アルキルまたは置換低級アルキル［該置換低級アルキルにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる］であってもよい。
置換低級アルキル、置換低級アルコキシ、モノ（置換低級アルキル）置換アミノ、ジ（置換低級アルキル）置換アミノ、置換低級アルカノイルアミノ及び置換低級アルケニルにおける置換基の定義において、ハロゲンは前記と同義であり、低級アルキル、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ及び低級アルコキシにおける低級アルキル部分は、前記低級アルキルと同義であり、アリールは前記と同義である。環状アルキル及び脂肪族環の環状アルキル部分としては、例えば炭素数３〜８の環状アルキル、より具体的にはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。アラルキルとしては、例えば炭素数７〜１２のアラルキル、より具体的にはベンジル、フェネチル、ナフチルメチル等が挙げられる。
置換アリール、置換ヘテロアリール、置換アラルキルアミノ及び置換アリールアミノにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、アミノ、低級アルキル等が挙げられる。
置換アリール、置換ヘテロアリール、置換アラルキルアミノ及び置換アリールアミノにおける置換基の定義において、ハロゲン及び低級アルキルはそれぞれ前記と同義である。
置換複素環基における置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、低級アルキル等が挙げられる。
置換複素環基における置換基の定義において、ハロゲン及び低級アルキルはそれぞれ前記と同義である。
式（Ｉａ）及び式（Ｉｂ）の各基の定義において、低級アルキルとしては、例えば直鎖または分岐している炭素数１〜６のアルキル、より具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ペンチル、ヘキシル、１，２，２−トリメチルプロピル等が挙げられる。
ハロゲンは、フッ素、塩素、臭素、ヨウ素の各原子を意味する。
低級アルコキシ、モノ（低級アルキル）置換アミノ及びジ（低級アルキル）置換アミノにおける低級アルキル部分は、前記低級アルキルと同義である。
低級アルケニルとしては、例えば直鎖または分岐している炭素数２〜６のアルケニル、より具体的にはビニル、アリル、１−プロペニル、メタクリル、１−ブテニル、クロチル、ペンテニル、ヘキセニル等が挙げられる。
アリール及びアリールアミノのアリール部分としては、例えばフェニル、ナフチル等が包含され、ヘテロアリールとしては、例えばピリジル、フリル、チエニル、キノリル、イミダゾリル、ベンゾイミダゾリル、チアゾリル等が挙げられる。
アラルキル及びアラルキルアミノのアラルキル部分としては、例えば炭素数７〜１２のアラルキル、より具体的にはベンジル、フェネチル、ナフチルメチル等が挙げられる。
脂環式複素環基としては、例えばテトラヒドロフリル、テトラヒドロチエニル、クロマニル等が挙げられる。含窒素複素環基は、例えば１つまたは２つの窒素原子をその環内に含む複素環基であり、さらに酸素、硫黄等のヘテロ原子を含んでいてもよく、且つその環内の窒素原子が隣接するカルボニル基と結合している複素環基を表し、例えばピロリジニル、ピペコリニル、ピペラジニル、ピペリジル、モルホリニル、チオモルホリニル、オキサゾリル等が挙げられる。
環状アルキルとしては、例えば炭素数３〜８の環状アルキル、より具体的にはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。
置換低級アルキル、置換低級アルコキシ、モノ（置換低級アルキル）置換アミノ、ジ（置換低級アルキル）置換アミノ、置換低級アルケニル及び置換環状アルキルにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる。また置換低級アルキルが、置換メチルまたは置換エチルである場合は、その置換基は、さらに同一または異なって例えば置換数１〜３の、低級アルキル、置換低級アルキル［該置換低級アルキルにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる］、環状アルキル、置換環状アルキル［該置換環状アルキルにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる］、アリール、置換アリール［該置換アリールにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる］、アラルキル、置換アラルキル［該置換アラルキルにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる］、置換低級アルコキシ［該置換低級アルコキシにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、ニトロ、アミノ、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ、低級アルコキシ等が挙げられる］等であってもよい。さらに置換メチルまたは置換エチルの、メチルまたはエチルにおける同一炭素原子上に２つの置換基を有し、該２つの置換基が該炭素原子と一緒になって脂肪族環を形成していてもよい。
置換低級アルキル、置換低級アルコキシ、モノ（置換低級アルキル）置換アミノ、ジ（置換低級アルキル）置換アミノ、置換低級アルケニル及び置換環状アルキルにおける置換基の定義において、ハロゲン、環状アルキル、アリール及びアラルキルはそれぞれ前記と同義であり、低級アルキル、モノ（低級アルキル）置換アミノ、ジ（低級アルキル）置換アミノ及び低級アルコキシにおける低級アルキル部分は、前記低級アルキルと同義であり、脂肪族環の環状アルキル部分は前記環状アルキルと同義である。
置換アリール、置換ヘテロアリール、置換アラルキル、置換アラルキルアミノ及び置換アリールアミノにおける置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、アミノ、低級アルキル等が挙げられる。
置換アリール、置換ヘテロアリール、置換アラルキル、置換アラルキルアミノ及び置換アリールアミノにおける置換基の定義において、ハロゲン及び低級アルキルはそれぞれ前記と同義である。
置換脂環式複素環基及び置換含窒素複素環基における置換基としては、同一または異なって例えば置換数１〜３の、ハロゲン、ヒドロキシ、低級アルキル等が挙げられる。
置換脂環式複素環基及び置換含窒素複素環基における置換基の定義において、ハロゲン及び低級アルキルはそれぞれ前記と同義である。
化合物（Ｉ）、化合物（Ｉａ）及び化合物（Ｉｂ）の薬理学的に許容される塩としては、薬理学的に許容される酸付加塩が挙げられ、例えば塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩、リン酸塩等の無機酸塩、ギ酸塩、酢酸塩、安息香酸塩、マレイン酸塩、フマル酸塩、コハク酸塩、酒石酸塩、クエン酸塩、シュウ酸塩、グリオキシル酸塩、アスパラギン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩等の有機酸塩が挙げられる。
タキキニン抑制剤におけるタキキニン抑制とは、タキキニンの遊離抑制、タキキニン受容体に結合することによるタキキニンの作用抑制等を意味する。
本発明で用いられる三環式化合物は、前記刊行物に開示された方法、またはそれらに準じて製造することができ、有機合成化学で常用される精製法、例えば中和、濾過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して単離・精製することができる。
本発明で用いられる三環式化合物の塩を取得したいとき、当該三環式化合物が塩の形で得られる場合には、そのまま精製すればよく、また、遊離塩基の形で得られる場合には、当該遊離塩基を適当な溶媒に溶解または懸濁し、酸を加えて塩を形成させれば良い。
なお、本発明で用いられる三環式化合物の中には光学異性体が存在し得るものもあるが、全ての可能な立体異性体及びそれらの混合物も、本発明の気管支喘息の予防及び／もしくは治療剤またはタキキニン抑制剤の有効成分として用いることができる。
また、本発明で用いられる三環式化合物またはその薬理学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、これら付加物も本発明の気管支喘息の予防及び／もしくは治療剤またはタキキニン抑制剤の有効成分として用いることができる。
タキキニン抑制活性は、電気刺激により誘発されるモルモット気管支標本の平滑筋収縮を測定する系で評価できる［ジャーナル・オブ・ファーマシー・アンド・ファーマコロジー（Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｙ ａｎｄ Ｐｈａｒｍａｃｏｌｏｇｙ）、第４２巻、ｐ．１３１−１３４（１９９０年）］
次に、化合物（Ｉ）の代表的化合物の薬理作用を、試験例により説明する。試験化合物としては、（Ｓ）−（＋）−３，３，３−トリフルオロ−２−ヒドロキシ−２−メチル−Ｎ−（５，５，１０−トリオキソ−４，１０−ジヒドロチエノ［３，２−ｃ］［１］ベンゾチエピン−９−イル）プロパンアミド［（Ｓ）−（＋）−３，３，３−ｔｒｉｆｌｕｏｒｏ−２−ｈｙｄｒｏｘｙ−２−ｍｅｔｈｙｌ−Ｎ−（５，５，１０−ｔｒｉｏｘｏ−４，１０−ｄｉｈｙｄｒｏｔｈｉｅｎｏ［３，２−ｃ］［１］ｂｅｎｚｏｔｈｉｅｐｉｎ−９−ｙｌ）ｐｒｏｐａｎ−ａｍｉｄｅ］を用いた。以下、上記化合物を本明細書において、化合物１という。なお、化合物１は、ＷＯ９８／４６５８７中の化合物（１−２５）と同一化合物である。
試験例１：電気刺激誘発気管支筋収縮反応に対する抑制作用
試験にはモルモット（ハートレー系、雄性、日本エスエルシー社）を用いた。電気刺激誘発気管支筋収縮反応は、池村らの方法［ブリティッシュ・ジャーナル・オブ・ファーマコロジー（Ｂｒｉｔｉｓｈ Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｙ）、第１１７巻、ｐ．９６７−９７３（１９９６年）］に準じて実施した。すなわち、モルモットより摘出した左右の主気管支は、周囲に付着している結合組織や脂肪を取り除いた後、軟骨にそって切断し長さ約２ｍｍのリング標本にした。標本は、混合ガス（９５％ Ｏ_２，５％ ＣＯ_２）を通気した３７℃のインドメタシン（５μｍｏｌ／Ｌ）を含むＫｒｅｂｓ−Ｈｅｎｓｅｌｅｉｔ栄養液［組成（×１ｍｍｏｌ／Ｌ）：ＮａＣｌ １１８．４；ＫＣｌ ４．７；ＣａＣｌ_２ ２．５；ＫＨ_２ＰＯ_４ １．２；ＭｇＳＯ_４ １．２；ＮａＨＣＯ_３ ２５．０；ｇｌｕｃｏｓｅ １１．１］を満たしたイージーマグヌス装置（いわしや、京都）に懸垂した。標本の収縮反応はＦＤピックアップ（ＴＢ−６１１Ｔ、ＴＢ−６１２Ｔ、日本光電、東京）、プレアンプ（ＡＰ−６２１Ｇ、日本光電、東京）を介し等尺性（静止張力：０．５ｇ）に測定し、レコーダー（ＬＲ４２２０、横河電気、東京）上に記録した。標本は約３０分間安定化させた後、実験を開始した。フィールド電気刺激による気管支筋収縮反応は、電気刺激装置（ＳＥＮ−３３０１、日本光電、東京）、棒状双極白金電極（電極幅７ｍｍ、いわしや、京都）を用い矩形波パルスによるフィールド電気刺激（刺激条件：電圧１５ボルト、頻度８ヘルツ、持続時間０．５ミリ秒、通電時間１５秒）により誘発させた。この条件での刺激により、素早い立ち上がりのアセチルコリンの関与する収縮反応（コリナージック収縮）とその後に緩やかな立ち上がりのタキキニンの関与する収縮反応（タキキナージック収縮）からなる二相性の収縮反応が観察された。化合物１の評価には安定した収縮反応が２回見られた標本を用い、プレ収縮反応（２回目をプレ収縮とする）を観察後、化合物１を添加し３０分間前処置を行った後、収縮反応（ポスト収縮反応）を観察した。収縮反応は収縮高を指標にし、抑制率を以下の式から算出した。化合物１は、３、１０及び３０ｍｍｏｌ／Ｌの濃度でジメチルスルホキシド（ＤＭＳＯ）に溶解し、最終濃度３、１０及び３０μｍｏｌ／Ｌとした（ＤＭＳＯ濃度０．１％）。なお別途溶媒処置群を設けた。溶媒処置群には化合物１投与群と同量の溶媒を加えた。

タキキナージック収縮及びコリナージック収縮に対する化合物１の抑制率を図１に示す。化合物１はタキキナージック収縮に対して、有意な抑制作用を示し、３、１０及び３０μｍｏｌ／Ｌでの抑制率はそれぞれ、３２．１±１０．７％、５５．２±１１．４％及び８７．１±３．６％であった。溶媒のタキキナージック収縮に対する抑制作用は７．９±８．０％であった。また化合物１はコリナージック収縮に対しては、最高濃度の３０μｍｏｌ／Ｌでの抑制率が３３．０±５．７％であり、タキキナージック収縮に対するよりも抑制作用が弱く、タキキナージック収縮に対する選択的な抑制作用が認められた。
試験例２：マウスの抗原誘発気道過敏性発現に及ぼす影響
雄性ＢＡＬＢ／ｃマウス（日本チャールスリバー）に、０．１ｍｇ／ｍＬの卵白アルブミン（以下、ＯＡ）及び１０ｍｇ／ｍＬの水酸化アルミニウムを含む生理食塩液０．２ｍＬを７日間間隔で２回腹腔内投与することにより感作した。最終感作の１週間後より４日間、生理食塩液に溶解した２ｗ／ｖ％ＯＡ溶液を超音波ネブライザー（ＮＥ−Ｕ１７、オムロン）にて２０分間マウスに噴霧した（抗原噴霧）。陰性対照群のマウスには同様の方法で生理食塩液を噴霧した。化合物１投与群には、抗原噴霧をした４日間、抗原噴霧の１時間前に０．５ｗ／ｖ％メチルセルロース水溶液に懸濁した試験化合物を経口投与した。陰性対照群及び陽性対照群には、０．５ｗ／ｖ％メチルセルロース水溶液を経口投与した。なお、各群７匹または８匹のマウスを用いた。最終抗原噴霧の約２４時間後、メサコリンに対するマウスの気道反応性を、呼吸機能測定装置（ＢｉｏＳｙｓｔｅｍ ＸＡ、Ｂｕｘｃｏ）を用いて測定した。始めに無処置状態におけるｅｎｈａｎｃｅｄ ｐａｕｓｅ（Ｐｅｎｈ）を３０秒毎に３分間測定し、その平均値を算出した（ｂａｓｅｌｉｎｅ）。その後、生理食塩液およびメサコリン（１．５、３．１、６．３および１２．５ｍｇ／ｍＬ）を順次、超音波ネブライザー（ＮＥ−Ｕ１２、オムロン）を用いてマウスに３分間吸入させ、それぞれの噴霧直後のＰｅｎｈを３０秒毎に３分間測定し、その平均値を算出した。
抗原噴霧により気道過敏性の発現が誘導された。化合物１（３０ｍｇ／ｋｇ）は気道過敏性の発現を有意に抑制した。
化合物（Ｉ）、化合物（Ｉａ）、化合物（Ｉｂ）またはそれらの薬理学的に許容される塩を含有する医薬製剤は、活性成分としてこれら化合物単独で、または任意の他の治療のための有効成分との混合物として含有することができる。また、それら医薬製剤は、活性成分を薬理学的に許容される一種もしくはそれ以上の担体と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。
投与経路は、治療に際し最も効果的なものを使用するのが望ましく、経口または、例えば気管内、静脈内等の非経口を挙げることができる。
投与形態としては、錠剤、カプセル剤、注射剤等がある。
経口投与に適当な、例えば錠剤、カプセル剤等は、乳糖、ブドウ糖、蔗糖、マンニット等の賦形剤、澱粉、アルギン酸ソーダ等の崩壊剤、ステアリン酸マグネシウム、タルク等の滑沢剤、ポリビニルアルコール、ヒドロキシプロピルセルロース、ゼラチン等の結合剤、脂肪酸エステル等の界面活性剤、グリセリン等の可塑剤等を用いて製造できる。
注射剤に適当な製剤は、好ましくは受容者の血液と等張である活性化合物を含む滅菌水性剤からなる。例えば、注射剤の場合は、塩溶液、ブドウ糖溶液または塩水とブドウ糖溶液の混合物からなる担体等を用いて注射用の溶液を調製する。
また、これら非経口剤においても、経口剤で例示した希釈剤、防腐剤、フレーバー類、賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、可塑剤等から選択される１種もしくはそれ以上の補助成分を添加することもできる。
化合物（Ｉ）、化合物（Ｉａ）、化合物（Ｉｂ）またはそれらの薬理学的に許容される塩の投与量及び投与回数は、投与形態、患者の年齢、体重、治療すべき症状の性質または重篤度により異なるが、通常経口の場合、成人一人当り０．０１ｍｇ〜１ｇ、好ましくは０．０５〜５０ｍｇを一日一回ないし数回投与する。吸入や静脈内投与等の非経口投与の場合、成人一人当り０．００１〜１００ｍｇ、好ましくは０．０１〜１０ｍｇを一日一回ないし数回投与する。しかしながら、これら投与量及び投与回数に関しては、前述の種々の条件により変動する。An object of the present invention is to provide a preventive and / or therapeutic agent for bronchial asthma containing a tricyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.
The present invention relates to the following (1) to (32).
(1) Formula (I)

{Wherein R ¹ represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxy,
X ¹ -X ² -X ³ is CR ⁵ = CR ⁶ -CR ⁷ = CR ⁸ [wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and represent a hydrogen atom, halogen, hydroxy, nitro , Amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted lower alkanoylamino], N (O _{^{) m = CR 6 -CR 7 =}} CR 8 ( ^wherein, R 6, ^{R 7} and ^{R 8} have the same meanings as defined above, m represents 0 or ^{1), CR 5 = CR 6} -N (O) _m = CR ^{8 (wherein,} R ^5, R 6, ^{R 8} and m are the same meanings as defined above, ^{respectively), CR 5 = CR 6 -CR} 7 = N (O) m ( ^wherein, R 5, ^{R 6} , same and each ^{R 7} and m the In ^a), in ^CR 5 = CR 6 -O (wherein, ^{R 5} and ^{R 6} are respectively the same as the ^{aforementioned), CR 5 = CR 6 -S} ( wherein, ^{R 5} and ^{R 6} each as defined above O-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above), S-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above), Or O—CR ⁷ ═N (wherein R ⁷ is as defined above),
Y is _{-CH 2 S -, - CH 2} SO -, - CH 2 SO 2 -, - CH 2 O -, - CH = CH -, - (CH 2) p - ( wherein, p is 0-2 represents an _{integer), - SCH 2 -, -} SOCH 2 -, - SO 2 CH 2 - or -OCH ₂ - represents,
R ² is a hydrogen atom, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono (substituted or unsubstituted lower alkyl) -substituted amino, di (substituted or unsubstituted Substituted lower alkyl) represents a substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino or substituted or unsubstituted heterocyclic group} A prophylactic and / or therapeutic agent for bronchial asthma comprising a tricyclic compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient.
(2) A tachykinin inhibitor comprising the tricyclic compound or the pharmacologically acceptable salt thereof according to (1) as an active ingredient.
(3) Formula (Ia)

[In the formula, ^{R 1} and ^X 1 ^-X 2 ^{-X 3} have the same meanings as defined above, ^{Y a} is _{-CH 2 SO 2 -, - SCH} 2 -, - SOCH 2 -, - SO 2 CH 2 - or -OCH ₂ - represents the,
Y ^a is _{-CH 2 SO 2 -, - SCH} 2 -, - SOCH 2 - or _-SO 2 CH ₂ - when it is,
R ^2a is a hydrogen atom, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono (substituted or unsubstituted lower alkyl) -substituted amino, di (substituted or unsubstituted Substituted lower alkyl) substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alicyclic heterocyclic group Or a substituted or unsubstituted nitrogen-containing heterocyclic group,
When Y ^a is —OCH ₂ —,
R ^2a is a hydrogen atom, amino, trifluoromethyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono (substituted or unsubstituted lower alkyl) substituted amino, di (substituted or unsubstituted lower alkyl) ) Substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted Substituted nitrogen-containing heterocyclic group or formula (II)

Wherein n is 0 or 1, and R ³ and R ⁴ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted aryl, or substituted Or an unsubstituted aralkyl, or R ³ and R ⁴ together with the adjacent carbon atoms may form a cyclic alkyl, Q represents halogen, amino, hydroxy or substituted or unsubstituted lower alkoxy ]. A prophylactic and / or therapeutic agent for bronchial asthma containing the tricyclic compound represented by the above or a pharmacologically acceptable salt thereof as an active ingredient.
(4) ^{Y a} is _{-CH 2 SO 2 -, - SCH} 2 -, - SOCH 2 - or _-SO 2 CH ₂ - in which the (3) prevention and / or therapeutic agent for bronchial asthma description.
(5) The preventive and / or therapeutic agent for bronchial asthma according to (3), wherein Y ^a is —OCH ₂ —.
(6) The agent for preventing and / or treating bronchial asthma according to (3) above, wherein Y ^a is —CH ₂ SO ₂ —, —SO ₂ CH ₂ — or —OCH ₂ —.
(7) The preventive and / or therapeutic agent for bronchial asthma according to (3) above, wherein Y ^a is —CH ₂ SO ₂ — or —SO ₂ CH ₂ —.
(8) The preventive and / or therapeutic agent for bronchial asthma according to (3), wherein Y ^a is —CH ₂ SO ₂ —.
(9) The prophylactic and / or therapeutic agent for bronchial asthma according to any one of (3) to (8), wherein R ¹ is a hydrogen atom, halogen, or substituted or unsubstituted lower alkoxy.
(10) The prophylactic and / or therapeutic agent for bronchial asthma according to any one of (3) to (8), wherein R ¹ is a hydrogen atom.
(11) X ¹ -X ² -X ³ is S-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above), The preventive and / or therapeutic agent for bronchial asthma as described.
(12) X ¹ -X ² -X ³ is CR ⁵ = CR ⁶ -CR ⁷ = CR ⁸ (wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above), respectively ( The prophylactic and / or therapeutic agent for bronchial asthma according to any one of 3) to (10).
(13) R ^2a is represented by formula (II)

(Wherein n, R ³ , R ⁴ and Q are as defined above, respectively), the preventive and / or therapeutic agent for bronchial asthma according to any one of (3) to (12).
(14) The prophylactic and / or therapeutic agent for bronchial asthma according to (13), wherein n is 0.
(15) The prophylactic and / or therapeutic agent for bronchial asthma according to (14), wherein R ³ is methyl, R ⁴ is trifluoromethyl, and Q is hydroxy.
(16) R ¹ is a hydrogen atom, Y ^a is —CH ₂ SO ₂ —, X ¹ —X ² —X ³ is S—CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are each And R ^2a is represented by formula (III).

The prophylactic and / or therapeutic agent for bronchial asthma according to (3) above.
(17) A tachykinin inhibitor containing the tricyclic compound or the pharmacologically acceptable salt thereof according to any one of (3) to (16) as an active ingredient.
(18) Formula (Ib)

[In the formula, ^{R 1} and ^X 1 ^-X 2 ^{-X 3} have the same meanings as defined above, ^{Y b} is _{-CH 2 O -, - CH 2} S -, - CH 2 SO -, - CH = CH- or — (CH ₂ ) _p — (wherein p is as defined above), R ^2b is the formula (III)

A prophylactic and / or therapeutic agent for bronchial asthma comprising a tricyclic compound represented by the formula: or a pharmacologically acceptable salt thereof as an active ingredient.
(19) X ¹ -X ² -X ³ is CR ⁵ = CR ⁶ -CR ⁷ = CR ⁸ (wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above) or CR ⁵ = The prophylactic and / or therapeutic agent for bronchial asthma according to (18), wherein CR ⁶ -CR ⁷ = N (wherein R ⁵ , R ⁶ and R ⁷ are as defined above).
(20) X ¹ -X ² -X ³ is CR ⁵ = CR ⁶ -O (wherein R ⁵ and R ⁶ are as defined above) or CR ⁵ = CR ⁶ -S (wherein R ⁵ And R ⁶ are as defined above, respectively, for preventing and / or treating bronchial asthma according to (18).
(21) X ¹ -X ² -X ³ is O-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above) or S-CR ⁷ = CR ⁸ (wherein R ⁷ And R ⁸ has the same meaning as defined above), and a prophylactic and / or therapeutic agent for bronchial asthma according to (18).
(22) The prophylactic and / or therapeutic agent for bronchial asthma according to any one of (18) to (21), wherein Y ^b is —CH ₂ O—.
(23) The prophylactic and / or therapeutic agent for bronchial asthma according to any one of (18) to (21), wherein Y ^b is — (CH ₂ ) _p — (wherein p is as defined above). .
(24) The preventive and / or therapeutic agent for bronchial asthma according to (23), wherein p is 0.
(25) The preventive and / or therapeutic agent for bronchial asthma according to (23), wherein p is 2.
(26) The prophylactic and / or therapeutic agent for bronchial asthma according to any one of (18) to (21), wherein Y ^b is —CH═CH—.
(27) The agent for preventing and / or treating bronchial asthma according to any one of (18) to (21), wherein Y ^b is —CH ₂ S— or —CH ₂ SO—.
(28) A tachykinin inhibitor containing the tricyclic compound or the pharmacologically acceptable salt thereof according to any one of (18) to (27) as an active ingredient.
(29) The tricyclic compound according to any one of (1), (3) to (16), and (18) to (27) or a production thereof for the production of a prophylactic and / or therapeutic agent for bronchial asthma Use of pharmacologically acceptable salts.
(30) The tricyclic compound according to any one of (1), (3) to (16) and (18) to (27) for the production of a tachykinin inhibitor or a pharmacologically acceptable product thereof. Use of salt.
(31) A step of administering an effective amount of the tricyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1), (3) to (16) and (18) to (27). A method for preventing and / or treating bronchial asthma.
(32) A step of administering an effective amount of the tricyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1), (3) to (16) and (18) to (27). A method for suppressing the action of tachykinin, comprising:
Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds represented by other formula numbers.
In the definition of each group of the formula (I), as the lower alkyl, for example, linear or branched alkyl having 1 to 8 carbon atoms, more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, hexyl, 1,2,2-trimethylpropyl, heptyl, octyl and the like.
Halogen means each atom of fluorine, chlorine, bromine and iodine.
The lower alkyl moiety in lower alkoxy, mono (lower alkyl) -substituted amino and di (lower alkyl) -substituted amino has the same meaning as the aforementioned lower alkyl.
Examples of the lower alkanoyl in the lower alkanoylamino include alkanoyl having 1 to 6 carbon atoms, more specifically formyl, acetyl, propanoyl, butanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl and the like.
Examples of the lower alkenyl include linear or branched alkenyl having 2 to 6 carbon atoms, more specifically vinyl, allyl, 1-propenyl, methacryl, 1-butenyl, crotyl, pentenyl, hexenyl and the like.
Examples of the aryl moiety of aryl and arylamino include phenyl and naphthyl, and examples of the heteroaryl include pyridyl, furyl, thienyl, quinolyl, imidazolyl, benzimidazolyl and thiazolyl.
Examples of the aralkyl moiety of aralkylamino include aralkyl having 7 to 12 carbon atoms, more specifically benzyl, phenethyl, naphthylmethyl and the like.
Examples of the heterocyclic group include an alicyclic heterocyclic group and a nitrogen-containing heterocyclic group. Examples of the alicyclic heterocyclic group include tetrahydrofuryl, tetrahydrothienyl, chromanyl and the like. The nitrogen-containing heterocyclic group is, for example, a heterocyclic group containing one or two nitrogen atoms in the ring, and may further contain a heteroatom such as oxygen or sulfur. For example, pyrrolidinyl, pipecolinyl, piperazinyl, piperidyl , Morpholinyl, thiomorpholinyl, oxazolyl and the like.
Substituents in substituted lower alkyl, substituted lower alkoxy, mono (substituted lower alkyl) substituted amino, di (substituted lower alkyl) substituted amino, substituted lower alkanoylamino and substituted lower alkenyl are the same or different and have 1 to substituted substituents. Possible number (preferably 1-6, more preferably 1-4), eg halogen, hydroxy, nitro, amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, cyclic alkyl, substituted Cyclic alkyl [substituents in the substituted cyclic alkyl are the same or different, for example, halogen, hydroxy, nitro, amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, lower Alkoxy, etc.], aryl, substituted aryl (in the substituted aryl Are the same as the substituents in the substituted aryl described later), aralkyl, substituted aralkyl (the substituent in the substituted aralkyl is synonymous with the substituent in the substituted aralkyl described later), lower alkoxy, substituted lower alkoxy [Substituents in the substituted lower alkoxy are the same or different, for example, halogen, hydroxy, nitro, amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, lower alkoxy, etc. having 1 to 3 substituents. And the like. The above substituted lower alkyl may have two substituents on the same carbon atom of the lower alkyl, and the two substituents may form an aliphatic ring together with the carbon atom. Good. When the substituted lower alkyl is substituted methyl or substituted ethyl, the substituent is further the same or different, for example, a lower alkyl having 1 to 3 substituents or a substituted lower alkyl [as the substituent in the substituted lower alkyl, For example, halogen, hydroxy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino, lower alkoxy and the like having 1 to 3 substituents may be used.
In the definitions of substituents in substituted lower alkyl, substituted lower alkoxy, mono (substituted lower alkyl) substituted amino, di (substituted lower alkyl) substituted amino, substituted lower alkanoylamino and substituted lower alkenyl, halogen is as defined above, The lower alkyl part in alkyl, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino and lower alkoxy has the same meaning as the lower alkyl, and aryl has the same meaning as described above. Examples of the cyclic alkyl and the cyclic alkyl portion of the aliphatic ring include cyclic alkyl having 3 to 8 carbon atoms, more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of aralkyl include aralkyl having 7 to 12 carbon atoms, and more specifically benzyl, phenethyl, naphthylmethyl, and the like.
Substituents in substituted aryl, substituted heteroaryl, substituted aralkylamino and substituted arylamino are the same or different and include, for example, halogen, hydroxy, amino, lower alkyl and the like having 1 to 3 substituents.
In the definition of substituents in substituted aryl, substituted heteroaryl, substituted aralkylamino and substituted arylamino, halogen and lower alkyl are as defined above.
Examples of the substituent in the substituted heterocyclic group are the same or different and include, for example, halogen, hydroxy, lower alkyl having 1 to 3 substituents.
In the definition of the substituent in the substituted heterocyclic group, halogen and lower alkyl are as defined above.
In the definition of each group of the formula (Ia) and the formula (Ib), as the lower alkyl, for example, linear or branched alkyl having 1 to 6 carbon atoms, more specifically, methyl, ethyl, propyl, isopropyl, Examples include butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, 1,2,2-trimethylpropyl and the like.
Halogen means each atom of fluorine, chlorine, bromine and iodine.
The lower alkyl moiety in lower alkoxy, mono (lower alkyl) -substituted amino and di (lower alkyl) -substituted amino has the same meaning as the aforementioned lower alkyl.
Examples of the lower alkenyl include linear or branched alkenyl having 2 to 6 carbon atoms, more specifically vinyl, allyl, 1-propenyl, methacryl, 1-butenyl, crotyl, pentenyl, hexenyl and the like.
Examples of the aryl moiety of aryl and arylamino include phenyl and naphthyl, and examples of heteroaryl include pyridyl, furyl, thienyl, quinolyl, imidazolyl, benzimidazolyl, thiazolyl and the like.
Examples of the aralkyl moiety of aralkyl and aralkylamino include aralkyl having 7 to 12 carbon atoms, more specifically benzyl, phenethyl, naphthylmethyl and the like.
Examples of the alicyclic heterocyclic group include tetrahydrofuryl, tetrahydrothienyl, chromanyl and the like. The nitrogen-containing heterocyclic group is, for example, a heterocyclic group containing one or two nitrogen atoms in the ring, may further contain a heteroatom such as oxygen or sulfur, and the nitrogen atom in the ring is It represents a heterocyclic group bonded to an adjacent carbonyl group, and examples thereof include pyrrolidinyl, pipecolinyl, piperazinyl, piperidyl, morpholinyl, thiomorpholinyl, oxazolyl and the like.
Examples of the cyclic alkyl include cyclic alkyl having 3 to 8 carbon atoms, more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Substituents in substituted lower alkyl, substituted lower alkoxy, mono (substituted lower alkyl) substituted amino, di (substituted lower alkyl) substituted amino, substituted lower alkenyl and substituted cyclic alkyl may be the same or different, for example having 1 to 3 substituents. Halogen, hydroxy, nitro, amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, lower alkoxy and the like. When the substituted lower alkyl is substituted methyl or substituted ethyl, the substituent is further the same or different, for example, a lower alkyl having 1 to 3 substituents, a substituted lower alkyl [as the substituent in the substituted lower alkyl, And the same or different, for example, halogen, hydroxy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino, lower alkoxy and the like having 1 to 3 substitutions], cyclic alkyl, substituted cyclic Alkyl [substituents in the substituted cyclic alkyl may be the same or different, for example, halogen, hydroxy, nitro, amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, lower alkoxy, having 1 to 3 substituents. Etc.], aryl, substituted aryl [substitution in the substituted aryl Are the same or different and include, for example, halogen, hydroxy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino, lower alkoxy and the like having 1 to 3 substituents], aralkyl, substituted Aralkyl [Substituents in the substituted aralkyl are the same or different, for example, halogen, hydroxy, nitro, amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, lower alkoxy, etc. Substituted lower alkoxy [substituents in the substituted lower alkoxy are the same or different, for example, halogen, hydroxy, nitro, amino, mono (lower alkyl) substituted amino, di (lower Alkyl) substituted amino, lower alkoxy, etc.] It may be. Furthermore, in substituted methyl or substituted ethyl, it may have two substituents on the same carbon atom in methyl or ethyl, and the two substituents may be combined with the carbon atom to form an aliphatic ring.
In the definitions of substituents in substituted lower alkyl, substituted lower alkoxy, mono (substituted lower alkyl) substituted amino, di (substituted lower alkyl) substituted amino, substituted lower alkenyl and substituted cyclic alkyl, halogen, cyclic alkyl, aryl and aralkyl are each As defined above, the lower alkyl part in lower alkyl, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino and lower alkoxy is as defined above, and the cyclic alkyl part of the aliphatic ring is as defined above. Synonymous with cyclic alkyl.
Substituents in substituted aryl, substituted heteroaryl, substituted aralkyl, substituted aralkylamino and substituted arylamino are the same or different, and examples thereof include halogen, hydroxy, amino, lower alkyl, etc. having 1 to 3 substituents.
In the definitions of substituents in substituted aryl, substituted heteroaryl, substituted aralkyl, substituted aralkylamino and substituted arylamino, halogen and lower alkyl are as defined above.
Examples of the substituent in the substituted alicyclic heterocyclic group and the substituted nitrogen-containing heterocyclic group are the same or different and include, for example, halogen, hydroxy, lower alkyl and the like having 1 to 3 substituents.
In the definition of the substituent in the substituted alicyclic heterocyclic group and the substituted nitrogen-containing heterocyclic group, halogen and lower alkyl are as defined above.
Examples of pharmacologically acceptable salts of Compound (I), Compound (Ia) and Compound (Ib) include pharmacologically acceptable acid addition salts such as hydrochloride, hydrobromide, Inorganic acid salts such as hydroiodide, nitrate, sulfate, phosphate, formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, sulphate Organic acid salts such as acid salts, glyoxylate salts, aspartates, methanesulfonates, ethanesulfonates, and benzenesulfonates.
The tachykinin inhibition in the tachykinin inhibitor means inhibition of tachykinin release, inhibition of action of tachykinin by binding to tachykinin receptors, and the like.
The tricyclic compounds used in the present invention can be produced according to the methods disclosed in the above-mentioned publications or pursuant thereto, and purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, and washing. , Drying, concentration, recrystallization, various chromatographies and the like for isolation and purification.
When it is desired to obtain a salt of the tricyclic compound used in the present invention, if the tricyclic compound is obtained in the form of a salt, it may be purified as it is, or if it is obtained in the form of a free base. The free base may be dissolved or suspended in a suitable solvent, and an acid may be added to form a salt.
Although some of the tricyclic compounds used in the present invention may have optical isomers, all possible stereoisomers and mixtures thereof may be used for the prevention and / or bronchial asthma of the present invention. It can be used as an active ingredient of a therapeutic agent or a tachykinin inhibitor.
In addition, the tricyclic compound or a pharmacologically acceptable salt thereof used in the present invention may exist in the form of an adduct with water or various solvents, and these adducts are also used in the bronchial asthma of the present invention. It can be used as an active ingredient of a preventive and / or therapeutic agent or tachykinin inhibitor.
Tachykinin inhibitory activity can be evaluated in a system that measures smooth muscle contraction of guinea pig bronchial specimens induced by electrical stimulation [Journal of Pharmacy and Pharmacology, Vol. 42, p. 131-134 (1990)]
Next, the pharmacological action of a representative compound of compound (I) will be described with reference to test examples. Test compounds include (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10-trioxo-4,10-dihydrothieno [3,2 -C] [1] benzothiepin-9-yl) propanamide [(S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10-trioxo- 4,10-dihydrothieno [3,2-c] [1] benzothiepin-9-yl) propan-amide] was used. Hereinafter, the above compound is referred to as Compound 1 in this specification. Compound 1 is the same compound as Compound (1-25) in WO98 / 46587.
Test Example 1: Inhibitory effect on electrical stimulation-induced bronchomuscular contraction response In the test, guinea pigs (Hartley, male, Nippon SLC) were used. The electrical stimulation-induced bronchomuscular contraction reaction was determined by the method of Ikemura et al. [British Journal of Pharmacology, Vol. 117, p. 967-973 (1996)]. That is, the left and right main bronchi removed from the guinea pig were removed along the cartilage after removing the connective tissue and fat adhering to the surroundings to obtain a ring specimen having a length of about 2 mm. The specimen was a Krebs-Henseleit nutrient solution containing 37 ° C. indomethacin (5 μmol / L) aerated with a mixed gas (95% O ₂ , 5% CO ₂ ) [composition (× 1 mmol / L): NaCl 118.4; KCl. 4.7; CaCl ₂ 2.5; KH ₂ PO ₄ 1.2; MgSO ₄ 1.2; NaHCO ₃ 25.0; glucose 11.1] suspended in an easy magnus apparatus (Iwashiya, Kyoto) . The contraction reaction of the specimen was measured isometrically (static tension: 0.5 g) via an FD pickup (TB-611T, TB-612T, Nihon Kohden, Tokyo) and a preamplifier (AP-621G, Nihon Kohden, Tokyo) Recorded on a recorder (LR4220, Yokogawa Electric, Tokyo). The specimen was allowed to stabilize for about 30 minutes before starting the experiment. Bronchomuscular contraction reaction by field electrical stimulation is based on electrical stimulation device (SEN-3301, Nihon Kohden, Tokyo), rod-shaped bipolar platinum electrode (electrode width 7mm, Iwashiya, Kyoto), and field electrical stimulation (stimulation condition) : Voltage 15 volts, frequency 8 hertz, duration 0.5 milliseconds, energization time 15 seconds). By the stimulation under this condition, a biphasic contraction reaction consisting of a contraction reaction involving fast rising acetylcholine (corinacic contraction) and a subsequent contraction reaction involving moderately rising tachykinin (tachykinic contraction) was observed. For the evaluation of Compound 1, a sample in which a stable contraction reaction was observed twice was used, and after observing a precontraction reaction (the second precontraction), Compound 1 was added and a pretreatment was performed for 30 minutes. Contraction reaction (post-contraction reaction) was observed. The contraction reaction was calculated from the following formula using the contraction height as an index. Compound 1 was dissolved in dimethyl sulfoxide (DMSO) at concentrations of 3, 10 and 30 mmol / L to give final concentrations of 3, 10 and 30 μmol / L (DMSO concentration 0.1%). Separately, a solvent treatment group was provided. The same amount of solvent as in the compound 1 administration group was added to the solvent treatment group.

The inhibition rate of Compound 1 against tachykinic contraction and corinacic contraction is shown in FIG. Compound 1 has a significant inhibitory effect on tachykinic contraction, and the inhibition rates at 3, 10 and 30 μmol / L are 32.1 ± 10.7%, 55.2 ± 11.4% and 87.87, respectively. 1 ± 3.6%. The inhibitory action against the tachykinic shrinkage of the solvent was 7.9 ± 8.0%. In addition, Compound 1 has a suppression rate of 33.0 ± 5.7% at the maximum concentration of 30 μmol / L with respect to corinergic contraction, and its inhibitory action is weaker than that of tachykinic contraction, and selectively suppresses tachykinic contraction. The effect was recognized.
Test Example 2: Effects on antigen-induced airway hypersensitivity expression in mice Male BALB / c mice (Nippon Charles River) contain 0.1 mg / mL ovalbumin (hereinafter referred to as OA) and 10 mg / mL aluminum hydroxide. Sensitization was performed by intraperitoneally administering 0.2 mL of physiological saline twice at intervals of 7 days. One week after the final sensitization, mice were sprayed with an ultrasonic nebulizer (NE-U17, OMRON) for 20 minutes for 2 days (antigen spraying) with a 2 w / v% OA solution dissolved in physiological saline. Negative control group mice were sprayed with physiological saline in the same manner. The compound 1 administration group was orally administered a test compound suspended in a 0.5 w / v% aqueous methylcellulose solution for 1 day before antigen spraying for 4 days after antigen spraying. A 0.5 w / v% methylcellulose aqueous solution was orally administered to the negative control group and the positive control group. In addition, 7 or 8 mice were used for each group. Approximately 24 hours after the final antigen spray, the airway reactivity of mice to mesacolin was measured using a respiratory function measuring device (BioSystem XA, Buxco). First, the enhanced pause (Penh) in the untreated state was measured every 30 seconds for 3 minutes, and the average value was calculated (baseline). Thereafter, physiological saline and mesacolin (1.5, 3.1, 6.3, and 12.5 mg / mL) were sequentially inhaled to the mouse for 3 minutes using an ultrasonic nebulizer (NE-U12, OMRON). Penh immediately after spraying was measured every 30 seconds for 3 minutes, and the average value was calculated.
The expression of airway hypersensitivity was induced by antigen spraying. Compound 1 (30 mg / kg) significantly suppressed the expression of airway hypersensitivity.
A pharmaceutical preparation containing Compound (I), Compound (Ia), Compound (Ib) or a pharmaceutically acceptable salt thereof is effective as an active ingredient for these compounds alone or for any other treatment. It can be contained as a mixture with the components. In addition, these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmacologically acceptable carriers.
It is desirable to use the administration route that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intratracheal and intravenous administration.
Administration forms include tablets, capsules, injections and the like.
Suitable for oral administration, for example, tablets, capsules, etc. are excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol , Hydroxypropylcellulose, a binder such as gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin.
Formulations suitable for injection consist of sterile aqueous preparations containing an active compound that is preferably isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of salt water and a glucose solution.
Also in these parenteral agents, one kind selected from diluents, preservatives, flavors, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for oral agents. Or more auxiliary components can be added.
The dose and frequency of administration of compound (I), compound (Ia), compound (Ib) or a pharmacologically acceptable salt thereof are determined depending on the dosage form, patient age, body weight, nature or severity of the condition to be treated. Although it varies depending on the severity, in the case of oral administration, 0.01 mg to 1 g, preferably 0.05 to 50 mg per adult is administered once to several times a day. In the case of parenteral administration such as inhalation and intravenous administration, 0.001 to 100 mg, preferably 0.01 to 10 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.

FIG. 1 is a graph showing the action of Compound 1 on the contractile response induced by field electrical stimulation in guinea pig bronchi, where the vertical axis represents the inhibition rate (%) and the horizontal axis represents the concentration of Compound 1 (μmol /). Six specimens each were used. The value means mean value ± standard error.
-○-: Corinergic contraction---: Takikinic contraction *: P <0.05 (Williams test compared to solvent administration group)
***: P <0.001 (Williams test compared to solvent administration group)
FIG. 2 is a graph showing the effect of Compound 1 on the expression of antigen-induced airway hypersensitivity in mice, where the vertical axis represents enhanced pause (Penh) and the horizontal axis represents mesacholine concentration (mg / mL).
-○-: Negative control group-●-: Positive control group-◆-: 3 mg / kg administration group of compound 1-▲-: 10 mg / kg administration group of compound 1-■-: 30 mg / kg administration group of compound 1 #: P <0.05 (Student t test or Aspin-Welch test compared to negative control group)
*: P <0.05 (Steel test compared to positive control group)
**: P <0.01 (Steel test compared to positive control group)
EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the scope of the present invention is not limited by these examples.

Example 1: Tablet A tablet having the following composition was prepared by a conventional method.
250 g of Compound 1, 1598.5 g of mannitol, 100 g of sodium starch glycolate, 10 g of light anhydrous silicic acid, 40 g of magnesium stearate and 1.5 g of yellow iron sesquioxide were mixed by a conventional method. Using this mixture, tableting was carried out with a tableting machine (Purepress Correct-12, manufactured by Kikusui Co., Ltd.) having a punch with a diameter of 8 mm to obtain tablets (containing 25 mg of active ingredient per tablet).
Formulation Compound 1 25 mg
Mannitol 159.85 mg
Starch sodium glycolate 10 mg
Light anhydrous silicic acid 1 mg
Magnesium stearate 4 mg
Yellow ferric oxide 0.15 mg
200 mg
Example 2: Capsule A capsule having the following composition was prepared by a conventional method.
500 g of Compound 1, 300 g of lactose, 100 g of light anhydrous silicic acid and 100 g of sodium lauryl sulfate were mixed by a conventional method. This mixture was filled into a hard capsule No. 1 (100 mg capacity per capsule) by a capsule filling machine (manufactured by Zanasi, LZ-64 type) to obtain a capsule (containing 50 mg of active ingredient per capsule).
Formulation Compound 1 50 mg
Lactose 30 mg
Light anhydrous silicic acid 10 mg
Sodium lauryl sulfate 10 mg
100 mg
Example 3: Injection The injection which consists of the following compositions is prepared by a conventional method.
1 g of Compound 1 and 5 g of D-mannitol are added to and mixed with distilled water for injection. Further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 6, and then the total volume is made up to 1000 mL with distilled water for injection. . The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 mg of active ingredient per vial).
Formulation Compound 1 2 mg
D-mannitol 10 mg
Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount
Distilled water for injection
2.00 mL

  The present invention provides a prophylactic and / or therapeutic agent for bronchial asthma containing a tricyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.

Claims (32)

Formula (I)

{Wherein R ¹ represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxy,
X ¹ -X ² -X ³ is CR ⁵ = CR ⁶ -CR ⁷ = CR ⁸ [wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and represent a hydrogen atom, halogen, hydroxy, nitro , Amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted lower alkanoylamino], N (O _{^{) m = CR 6 -CR 7 =}} CR 8 ( ^wherein, R 6, ^{R 7} and ^{R 8} have the same meanings as defined above, m represents 0 or ^{1), CR 5 = CR 6} -N (O) _m = CR ^{8 (wherein,} R ^5, R 6, ^{R 8} and m are the same meanings as defined above, ^{respectively), CR 5 = CR 6 -CR} 7 = N (O) m ( ^wherein, R 5, ^{R 6} , same and each ^{R 7} and m the In ^a), in ^CR 5 = CR 6 -O (wherein, ^{R 5} and ^{R 6} are respectively the same as the ^{aforementioned), CR 5 = CR 6 -S} ( wherein, ^{R 5} and ^{R 6} each as defined above O-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above), S-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above), Or O—CR ⁷ ═N (wherein R ⁷ is as defined above),
Y is _{-CH 2 S -, - CH 2} SO -, - CH 2 SO 2 -, - CH 2 O -, - CH = CH -, - (CH 2) p - ( wherein, p is 0-2 represents an _{integer), - SCH 2 -, -} SOCH 2 -, - SO 2 CH 2 - or -OCH ₂ - represents,
R ² is a hydrogen atom, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono (substituted or unsubstituted lower alkyl) -substituted amino, di (substituted or unsubstituted Substituted lower alkyl) represents a substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino or substituted or unsubstituted heterocyclic group} A prophylactic and / or therapeutic agent for bronchial asthma comprising a tricyclic compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient. A tachykinin inhibitor comprising the tricyclic compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. Formula (Ia)

[In the formula, ^{R 1} and ^X 1 ^-X 2 ^{-X 3} have the same meanings as defined above, ^{Y a} is _{-CH 2 SO 2 -, - SCH} 2 -, - SOCH 2 -, - SO 2 CH 2 - or -OCH ₂ - represents the,
_{^{Y a -CH 2 SO 2 -,}} - SCH 2 -, - SOCH 2 - or _-SO 2 CH ₂ - when it is,
R ^2a is a hydrogen atom, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono (substituted or unsubstituted lower alkyl) -substituted amino, di (substituted or unsubstituted Substituted lower alkyl) substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alicyclic heterocyclic group Or a substituted or unsubstituted nitrogen-containing heterocyclic group,
When Y ^a is —OCH ₂ —,
R ^2a is a hydrogen atom, amino, trifluoromethyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono (substituted or unsubstituted lower alkyl) substituted amino, di (substituted or unsubstituted lower alkyl) ) Substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted Substituted nitrogen-containing heterocyclic group or formula (II)

Wherein n is 0 or 1, and R ³ and R ⁴ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted aryl, or substituted Or an unsubstituted aralkyl, or R ³ and R ⁴ together with the adjacent carbon atoms may form a cyclic alkyl, Q represents halogen, amino, hydroxy or substituted or unsubstituted lower alkoxy ]. A prophylactic and / or therapeutic agent for bronchial asthma containing the tricyclic compound represented by the above or a pharmacologically acceptable salt thereof as an active ingredient. Y ^a is _{-CH 2 SO 2 -, - SCH} 2 -, - SOCH 2 - or _-SO 2 CH ₂ - prevention and / or therapeutic agent for bronchial asthma ranging 3 according claims is. Y ^a is -OCH ₂ - prevention and / or therapeutic agent for bronchial asthma ranging 3 according claims is. The prophylactic and / or therapeutic agent for bronchial asthma according to claim 3, wherein Y ^a is -CH ₂ SO _2- , -SO ₂ CH ₂ -or -OCH _2- . The preventive and / or therapeutic agent for bronchial asthma according to claim 3, wherein Y ^a is -CH ₂ SO ₂ -or -SO ₂ CH _2- . The agent for preventing and / or treating bronchial asthma according to claim 3, wherein Y ^a is -CH ₂ SO _2- . The prophylactic and / or therapeutic agent for bronchial asthma according to any one of claims 3 to 8, wherein R ¹ is a hydrogen atom, halogen, or substituted or unsubstituted lower alkoxy. The prophylactic and / or therapeutic agent for bronchial asthma according to any one of claims 3 to 8, wherein R ¹ is a hydrogen atom. The bronchial asthma according to any one of claims 3 to 10, wherein X ¹ -X ² -X ³ is S-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above). Prophylactic and / or therapeutic agent. X ¹ -X ² -X ³ is CR ⁵ = CR ⁶ -CR ⁷ = CR ⁸ (wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above), 11. The preventive and / or therapeutic agent for bronchial asthma according to any one of 10. R ^2a is the formula (II)

(Wherein n, R ³ , R ⁴ and Q have the same meanings as described above, respectively). The preventive and / or therapeutic agent for bronchial asthma according to any one of claims 3 to 12. The prophylactic and / or therapeutic agent for bronchial asthma according to claim 13, wherein n is 0. The prophylactic and / or therapeutic agent for bronchial asthma according to claim 14, wherein R ³ is methyl, R ⁴ is trifluoromethyl, and Q is hydroxy. R ¹ is a hydrogen atom, Y ^a is —CH ₂ SO ₂ —, X ¹ —X ² —X ³ is S—CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above, respectively). And R ^2a is of formula (III)

The prophylactic and / or therapeutic agent for bronchial asthma according to claim 3. A tachykinin inhibitor comprising the tricyclic compound according to any one of claims 3 to 16 or a pharmacologically acceptable salt thereof as an active ingredient. Formula (Ib)

[In the formula, ^{R 1} and ^X 1 ^-X 2 ^{-X 3} have the same meanings as defined above, ^{Y b} is _{-CH 2 O -, - CH 2} S -, - CH 2 SO -, - CH = CH- or — (CH ₂ ) _p — (wherein p is as defined above), R ^2b is the formula (III)

A prophylactic and / or therapeutic agent for bronchial asthma comprising a tricyclic compound represented by the formula: or a pharmacologically acceptable salt thereof as an active ingredient. X ¹ -X ² -X ³ is ^{CR 5 = CR 6 -CR 7 =} CR 8 ( ^{wherein, R 5, R 6, R} 7 and ^{R 8} each have the same meanings as defined above) or ^CR 5 = ^{CR 6} - The prophylactic and / or therapeutic agent for bronchial asthma according to claim 18, wherein CR ⁷ = N (wherein R ⁵ , R ⁶ and R ⁷ are as defined above). X ¹ -X ² -X ³ is CR ⁵ = CR ⁶ -O (wherein R ⁵ and R ⁶ are as defined above) or CR ⁵ = CR ⁶ -S (wherein R ⁵ and R ⁶ 19. The agent for preventing and / or treating bronchial asthma according to claim 18, wherein each is as defined above. X ¹ -X ² -X ³ is O-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are as defined above) or S-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ 19. The agent for preventing and / or treating bronchial asthma according to claim 18, wherein each is as defined above. Y ^b is the prevention and / or therapeutic agent for bronchial asthma according to any one of claims _-CH 2 O-a is 18-21. Y ^b is - _{(CH 2) p} - (wherein, p is the same meaning as defined above) the prevention and / or therapeutic agent for bronchial asthma according to any one of claims 18 to 21 claims is. The preventive and / or therapeutic agent for bronchial asthma according to claim 23, wherein p is 0. 24. The preventive and / or therapeutic agent for bronchial asthma according to claim 23, wherein p is 2. Prevention and / or therapeutic agent for bronchial asthma according to any one of claims 18 to 21 Y ^b is -CH = CH-. Y ^b is the prevention and / or therapeutic agent for bronchial asthma according to any one of claims _-CH 2 S- or _-CH 2 SO- 18 to 21. A tachykinin inhibitor comprising the tricyclic compound according to any one of claims 18 to 27 or a pharmacologically acceptable salt thereof as an active ingredient. Use of the tricyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3 to 16, and 18 to 27 for the manufacture of a prophylactic and / or therapeutic agent for bronchial asthma. Use of the tricyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3 to 16, and 18 to 27 for the production of a tachykinin inhibitor. Prevention and / or treatment of bronchial asthma comprising the step of administering an effective amount of the tricyclic compound or pharmacologically acceptable salt thereof according to any one of claims 1, 3 to 16, and 18 to 27. Method. A method for suppressing the action of tachykinin, comprising a step of administering an effective amount of the tricyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1, 3 to 16, and 18 to 27.

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