JP4848091B2 - Gastrointestinal disease therapeutic agent or prophylactic agent containing diaminotrifluoromethylpyridine derivative - Google Patents

Description

〔式中、Ｘは−ＣＷ¹Ｒ¹基、−ＣＯＣＯＲ²基、−ＣＷ¹ＮＨＣＯＲ²基、−Ｃ（＝Ｗ¹）Ｗ²Ｒ³基又は−ＣＷ¹Ｎ（Ｒ⁴）Ｒ⁵基であり、Ｙはアルキル基、−ＣＷ³Ｒ⁶基、−ＣＯＣＯＲ⁷基、−ＮＨＣＯＲ⁷基、−Ｃ（＝Ｗ³）Ｗ⁴Ｒ⁸基、−（ＮＨ）_mＳＯ₂Ｒ⁹基、−（ＮＨ）_mＳＯ₂ＯＲ¹⁰基又は−（ＮＨ）_mＳＯ₂Ｎ（Ｒ¹¹）Ｒ¹²基であり、Ｒ¹、Ｒ⁶及びＲ⁹は各々独立して、置換されてもよい鎖式炭化水素基、置換されてもよい単環式炭化水素基、置換されてもよい多環式炭化水素基、置換されてもよい単環式複素環基又は置換されてもよい多環式複素環基であり、Ｒ²及びＲ⁷は各々独立して、置換されてもよいアルキル基、置換されてもよいアルコキシ基、置換されてもよいフェニル基又は置換されてもよいフェノキシ基であり、Ｒ³、Ｒ⁸及びＲ¹⁰は各々独立して、置換されてもよいアルキル基、置換されてもよいアルケニル基、置換されてもよいアルキニル基、置換されてもよいシクロアルキル基、置換されてもよいフェニル基又は置換されてもよいベンジル基であり、Ｒ⁴、Ｒ⁵、Ｒ¹¹及びＲ¹²は各々独立して、置換されてもよいアルキル基であり、Ｗ¹、Ｗ²、Ｗ³及びＷ⁴は各々独立して、酸素原子又は硫黄原子であり、ｍは０又は１である。但し、Ｘ及びＹの一方が−ＣＯＣＦ₂Ｘ¹基（Ｘ¹は水素原子、ハロゲン原子、アルキル基又はハロアルキル基である）であり、他方が−ＣＯＣＦ₂Ｘ²基（Ｘ²は水素原子、ハロゲン原子、アルキル基、ハロアルキル基又はアルキルカルボニル基である）又は−ＣＯＯＸ³基（Ｘ³は置換されてもよいアルキル基又は置換されてもよいフェニル基である）又は−ＣＯＸ⁴基（Ｘ⁴はアルキル基、ハロアルキル基、アルケニル基、アルキニル基、置換されてもよいフェニル基、フラニル基又はナフチル基である）である組合せの場合を除く〕で表されるジアミノトリフルオロメチルピリジン誘導体又はその塩を有効成分として含有する消化器疾患の治療剤又は予防剤を提供することにある。
【００１４】
式（Ｉ）中、Ｒ¹、Ｒ⁶及びＲ⁹に含まれる前記鎖式炭化水素基としてはアルキル基、アルケニル基、アルキニル基などが挙げられ、前記単環式炭化水素基としてはシクロアルキル基、シクロアルケニル基、フェニル基などが挙げられ、前記多環式炭化水素基としては、ナフチル基、テトラヒドロナフチル基、インダニル基のような縮合型多環式炭化水素基又はアダマンチル基、ノルアダマンチル基、ノルボルナニル基、ノルボルナノニル基のような架橋型多環式炭化水素基が挙げられ、前記単環式複素環基としてはピロリル基、フラニル基、チエニル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、チアジアゾリル基、ピロリニル基、ピロリジニル基、ジヒドロフラニル基、テトラヒドロフラニル基、ジヒドロチエニル基、テトラヒドロチエニル基、ピラゾリニル基、ヒダントイニル基、オキサゾリニル基、イソオキサゾリニル基、イソオキサゾリジニル基、チアゾリニル基、チアゾリジニル基、ジオキソラニル基、ジチオラニル基、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、ジヒドロピリジル基、テトラヒドロピリジル基、ピペリジニル基、ジヒドロオキソピリダジニル基、テトラヒドロオキソピリダジニル基、ジヒドロオキソピリミジニル基、テトラヒドロオキソピリミジニル基、ピペラジニル基、ジヒドロピラニル基，テトラヒドロピラニル基、ジオキサニル基、ジヒドロジチイニル基、ジチアニル基、モルホリニル基などが挙げられ、前記多環式複素環基としては、チエノチエニル基、ジヒドロシクロペンタチエニル基、インドリル基、ベンゾフラニル基、ベンゾチエニル基、ベンズオキサゾリル基、ベンズイソオキサゾリル基、ベンゾチアゾリル基、ベンズイミダゾリル基、テトラヒドロベンゾチエニル基、ジヒドロベンゾフラニル基、テトラヒドロベンズイソオキサゾリル基、ベンゾジオキソリル基、キノリニル基、イソキノリニル基、ベンゾジオキサニル基、キノキサリニル基のような縮合型多環式複素環基又はキヌクリジニル基のような架橋型多環式複素環基が挙げられる。
【００１５】
Ｒ¹、Ｒ⁶及びＲ⁹に含まれる置換されてもよい鎖式炭化水素基、Ｒ²及びＲ⁷に含まれる置換されてもよいアルキル基及び置換されてもよいアルコキシ基、Ｒ³、Ｒ⁸及びＲ¹⁰に含まれる置換されてもよいアルキル基、置換されてもよいアルケニル基及び置換されてもよいアルキニル基並びにＲ⁴、Ｒ⁵、Ｒ¹¹及びＲ¹²に含まれる置換されてもよいアルキル基並びにＸ³に含まれる置換されてもよいアルキル基の置換基としてはハロゲン原子、アルコキシ基、ハロアルコキシ基、アルキルチオ基、シクロアルキル基、シクロアルコキシ基、シクロアルケニル基、シクロアルケニルオキシ基、アルコキシカルボニル基、アルキルカルボニル基、アルキルカルボニルオキシ基、アリール基、アリールオキシ基、アリールチオ基、アミノ基、アルキル基で置換されたアミノ基などが挙げられ、それらの置換基又はそれらの置換基に付随する置換基の数は１ケであっても２ケ以上であってもよく、２ケ以上の場合それらの置換基は同一であっても異なってもよい。
【００１６】
また、Ｒ¹、Ｒ⁶ 及びＲ⁹ に含まれる置換されてもよい単環式炭化水素基、置換されてもよい多環式炭化水素基、置換されてもよい単環式複素環基及び置換されてもよい多環式複素環基、Ｒ²及びＲ⁷に含まれる置換されてもよいフェニル基及び置換されてもよいフェノキシ基、Ｒ³、Ｒ⁸ 及びＲ¹⁰に含まれる置換されてもよいシクロアルキル基、置換されてもよいフェニル基及び置換されてもよいベンジル基並びにＸ³に含まれる置換されてもよいフェニル基の置換基としてはハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ハロアルコキシ基、アルキルチオ基、シクロアルキル基、シクロアルコキシ基、シクロアルケニル基、シクロアルケニルオキシ基、アルコキシカルボニル基、アルキルカルボニル基、アルキルカルボニルオキシ基、アリール基、アリールオキシ基、アリールチオ基、アミノ基、アルキル基で置換されたアミノ基、シアノ基、ニトロ基などが挙げられ、それら置換基又はそれらの置換基に付随する置換基の数は１ケであっても２ケ以上であってもよく、２ケ以上の場合それらの置換基は同一であっても異なってもよい。
【００１７】
式（Ｉ）中、Ｘ及びＹに含まれるアルキル基並びにアルキル部分としては、炭素数１〜１８のもの、例えばメチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、デシル基、ノナデシル基などが挙げられ、それらは直鎖又は枝分れ脂肪鎖の構造異性のものも含む。Ｘ及びＹに含まれるアルケニル基ならびにアルケニル部分としては、炭素数が２〜１８のもの、例えばビニル基、プロペニル基、ブテニル基、ペンテニル基、ヘキセニル基、デセニル基、ノナデセニル基などが挙げられ、またそれらは直鎖又は枝分れ脂肪鎖の構造異性のものも含む。Ｘ及びＹに含まれるアルキニル基並びにアルキニル部分としては、炭素数が２〜１８のもの、例えばエチニル基、プロピニル基、ブチニル基、ペンチニル基、ヘキシニル基、デシニル基、ノナデシニル基などが挙げられ、またそれらは直鎖又は枝分れ脂肪鎖の構造異性のものも含む。Ｘ及びＹに含まれるシクロアルキル基並びにシクロアルキル部分としては、炭素数３〜８のもの、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロオクチル基などが挙げられる。Ｘ及びＹに含まれるシクロアルケニル基並びにシクロアルケニル部分としては、炭素数５〜８のもの、例えば、シクロペンテニル基、シクロヘキセニル基、シクロオクテニル基などが挙げられる。更にＸ及びＹに含まれるハロゲン原子としては弗素原子、塩素原子、臭素原子、沃素原子が挙げられる。Ｘ及びＹに含まれるアリール基並びにアリール部分としては、フェニル基、チエニル基、フラニル基、ピリジル基、ナフチル基、ベンゾチエニル基、ベンゾフラニル基、キノリニル基などが挙げられる。
【００１８】
本発明化合物の望ましい態様について下記する。式（Ｉ）において、Ｘが−ＣＷ¹Ｒ¹基又は−Ｃ（＝Ｗ¹）Ｗ²Ｒ³基であり、Ｙが−ＳＯ₂Ｒ⁹基である場合が望ましい。Ｒ¹及びＲ⁶は、置換されてもよいアルキル基、置換されてもよいアルケニル基、置換されてもよいシクロアルキル基、置換されてもよいシクロアルケニル基、置換されてもよいフェニル基、置換されてもよいテトラヒドロナフチル基、置換されてもよいインダニル基、置換されてもよいフラニル基又は置換されてもよいチエニル基が望ましく；アルキル基、ハロアルキル基、アルコキシカルボニルアルキル基、アルケニル基、ハロアルケニル基、シクロアルキル基、ハロゲン原子で置換されたシクロアルキル基、フェニル基、ハロゲン原子で置換されたフェニル基、アルキル基若しくはハロアルキル基で置換されたフェニル基、アルコキシ基若しくはハロアルコキシ基で置換されたフェニル基、テトラヒドロナフチル基、インダニル基、フラニル基又はチエニル基がさらに望ましい。Ｒ²及びＲ⁷は、置換されてもよいアルコキシ基又は置換されてもよいフェニル基が望ましく；アルコキシ基、ハロアルコキシ基、フェニル基又はハロゲン原子で置換されたフェニル基がさらに望ましい。Ｒ³、Ｒ⁸及びＲ¹⁰は、置換されてもよいアルキル基が望ましく；アルキル基又はハロアルキル基がさらに望ましい。Ｒ⁴、Ｒ⁵、Ｒ¹¹及びＲ¹²は、アルキル基が望ましい。Ｒ⁹は、置換されてもよいアルキル基、置換されてもよいアルケニル基、置換されてもよいシクロアルキル基、置換されてもよいシクロアルケニル基又は置換されてもよいフェニル基が望ましく；アルキル基、ハロアルキル基、フェニル基、ハロゲン原子で置換されたフェニル基、アルキル基若しくはハロアルキル基で置換されたフェニル基又はアルコキシ基若しくはハロアルコキシ基で置換されたフェニル基がさらに望ましい。
【００１９】
本発明化合物の中で望ましい化合物としては、前記式（Ｉ）において、Ｘがアルコキシカルボニルアルキルカルボニル基、アルケニルカルボニル基、チエニル基で置換されたアルケニルカルボニル基、シクロアルキルカルボニル基、インダニルカルボニル基、フランカルボニル基、チオフェンカルボニル基、テトラヒドロナフチルカルボニル基又はハロゲン原子若しくはハロアルキル基で置換されてもよいベンゾイル基であり、Ｙがアルキルスルホニル基である化合物が挙げられ、具体的には、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）-4-フルオロベンズアミド、Ｎ−（２−イソプロピルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）−３−フルオロベンズアミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）-2-フランカルボキサミド、Ｎ−（２−イソプロピルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）シクロペンタンカルボキサミド、Ｎ−（２−エチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）シクロヘキサンカルボキサミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）−５−インダンカルボキサミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）アセトキシアセタミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）クロトンアミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）−２−チオフェンカルボキサミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）−３−トリフルオロメチルベンズアミド、Ｎ−（２−エチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）−３−フルオロベンズアミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）−６−（１，２，３，４−テトラヒドロナフタレン）カルボキサミド、Ｎ−（２−エチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）クロトンアミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）−３−（２−チエニル）アクリルアミド又はこれらの塩が挙げられる。
【００２０】
さらに望ましい化合物としては、前記式（Ｉ）において、Ｘがシクロアルキルカルボニル基、フランカルボニル基又はハロゲンで置換されてもよいベンゾイル基であり、Ｙがアルキルスルホニル基である化合物が挙げられ、具体的にはＮ−（２−エチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）シクロヘキサンカルボキサミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）-4-フルオロベンズアミド、Ｎ−（２−イソプロピルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）−３−フルオロベンズアミド、Ｎ−（２−メチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）-2-フランカルボキサミド又はＮ−（２−イソプロピルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル）シクロペンタンカルボキサミド又はこれらの塩が挙げられる。
【００２１】
式（Ｉ）で表わされる化合物は、Ｙが−ＳＯ₂Ｒ⁹基（Ｒ⁹は前述の通りである）の場合、塩を形成してもよく、それらの塩としては、医薬上許容されるものであればよく、例えば、カリウム塩、ナトリウム塩のようなアルカリ金属塩、カルシウム塩のようなアルカリ土類金属塩、トリエタノールアミン塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機アミン塩などが挙げられる。又、これらの塩の中で結晶水をもつものもある。
【００２２】
式（Ｉ）で表わされる化合物は例えば日本特許第２７６２３２３号に記載の方法により製造することができる。更にこれらの化合物には、その置換基の種類によって幾何異性体が存在するが、本発明には各異性体（シス体、トランス体）及び異性体混合物が含まれる。
【００２３】
前記式（Ｉ）で表わされる本発明化合物は、消化器疾患の治療剤又は予防剤の有効成分として有用である。中でも、潰瘍性大腸炎(非特異性突発性大腸炎)、クローン病(限局性腸炎)、大腸クローン病(肉芽腫性大腸炎または限局性大腸炎)、腸管型ベーチェット病、感染性腸炎、虚血性腸炎、放射線腸炎、薬剤性腸炎、過敏性腸症候群等の炎症性腸疾患、胃潰瘍、十二指腸潰瘍等の消化性潰瘍及び胃炎の治療剤又は予防剤の有効成分として有用である。特に、前記潰瘍性大腸炎、クローン病、大腸クローン病又は腸管型ベーチェット病の治療剤又は予防剤の有効成分として有用であり、とりわけ潰瘍性大腸炎、クローン病の治療剤又は予防剤の有効成分として使用されるのが望ましい。また漢方薬等の他の薬剤と併用することでより有効となることが期待できる。
【００２４】
本発明化合物を潰瘍性大腸炎、クローン病、胃潰瘍、十二指腸潰瘍、胃炎等の消化器疾患治療剤の有効成分として投与する場合は、単独あるいは薬理的に許容される担体などと混合して、経口的又は非経口的な使用に適した製剤組成物、例えば、錠剤、粉末包装剤、カプセル剤、顆粒剤、注射剤、軟膏、吸入剤、注腸剤、坐剤等の形態で投与される。また、最近では胃粘膜や腸管粘膜に対する付着性を利用し、消化管内での滞留時間を延長させ、胃、十二指腸、大腸、小腸、直腸潰瘍薬等の有効成分を長時間に亘り高濃度でかつ効率的に作用させ得る経口投与用の消化管粘膜付着性マトリックスを坐剤基剤に含有させた製剤も報告されており(特開平5-132416号公報、特開平7-330582号公報)、これらを用いた投与も可能である。
【００２５】
経口的使用に適した製剤としては例えば錠剤、カプセル剤、粉末剤、顆粒剤、トローチのような固型組成物；シロップ懸濁液のような液状組成物等が挙げられる。錠剤、カプセル剤、粉末剤、顆粒剤、トローチのような固型組成物は、微結晶セルロース、アラビアゴム、トラガントゴム、ゼラチン、ポリビニルピロリドンのようなバインダー；澱粉、乳糖、カルボキシメチルセルロースのような賦形剤；アルギン酸、コーンスターチ、カルボキシメチルセルロースのような崩壊剤；ステアリン酸マグネシウム、軽質無水珪酸、コロイド二酸化ケイ素のような潤滑剤；スクロースのような甘味剤；ペパーミント、サリチル酸メチルのようなフレーバー剤；などを含有できる。シロップ、懸濁液のような液状組成物は、ソルビトール、ゼラチン、メチルセルロース、カルボキシメチルセルロース、落花生油のような植物油、レシチンのような乳化剤、その他必要があれば、甘味剤、保存剤、着色剤およびフレーバー剤などを含有でき、これらは、乾燥製剤としても提供できる。これらの製剤は、有効成分化合物を１〜９５重量％含むことが望ましい。
【００２６】
非経口的使用に適した製剤としては、例えば、注射剤等が挙げられる。注射剤としては、たとえば塩の形で通常の注射用水などに溶かしてもよいし、懸濁液又エマルジョン（医学上許容しうる油又は液体の混合物中）の注射しうる形にすることができる。この場合、抗菌剤のベンジルアルコールなど、抗酸化剤のアスコルビン酸など、医学上許される緩衝液又は浸透圧調節のための試薬を含有してもよい。この注射剤は有効成分化合物を０．１〜８重量％含むことが望ましい。
【００２７】
局所的又は経直腸的使用に適した製剤としては例えば吸入剤、軟膏、注腸剤、坐剤等が挙げられる。吸入剤としては、本発明化合物自体又は医学上許容される不活性担体とともにエアゾル又はネブライザー用の溶液に溶解させるか或は吸入用微粉末として、呼吸器管へ投与できる。吸入用微粉末の場合、粒子は５０ミクロン以下、好ましくは１０ミクロン以下である。又これら吸入剤として使用する場合、必要があれば他の抗喘息剤又は気管支拡張剤と併用することも可能である。
【００２８】
軟膏は通常使用される基剤等を添加し、慣用の方法により調製される。軟膏は有効成分化合物を０．１〜３０重量％含むことが望ましい。
【００２９】
坐剤は、当業界において周知の製剤用担体、例えばポリエチレングリコール、ラノリン、カカオ脂、脂肪酸トリグリセライド等を含有してもよい。坐剤は、有効成分化合物を０．１〜９５重量％含むことが望ましい。
【００３０】
前記経口的、非経口的、局所的又は経直腸的な使用に適した製剤組成物は、公知の方法により、患者に投与後、活性成分が急速に放出されるように、徐放的に放出されるように、あるいは遅れて放出されるように製剤化することができる。
【００３１】
本発明化合物の投与量は化合物の種類、投与方法、患者又は被処理動物の状況などに応じて変わることは勿論であり、一定の条件の下における適量と投与回数は専門医の判断によって決定されなければならないが、成人１日当たり、約０．１ｍｇ〜約１０ｇ、好ましくは約１ｍｇ〜約１ｇを投与するのが通常であろう。又、前記吸入法における１回当たりの本発明化合物の投与量は、約０．０１ｍｇ〜約１ｇが望ましい。
【００３２】
次に本発明の治療剤又は予防剤の具体的製剤例を挙げるが、本発明の製剤はこれらに限定されるものではない。
【００３３】

以上（１）〜（４）の成分を１錠として、錠剤に成型する。
【００３４】

上記（１）〜（４）を混合し、散剤、更に造粒により細粒剤或いは顆粒剤とする。又、これらをカプセルに封入し、カプセル剤とすることも可能である。
【００３５】

以上（１）〜（３）の成分を、１錠として硬ゼラチンカプセルにつめ、硬ゼラチンカプセル剤とする。
【００３６】

以上（１）〜（３）の成分を含むトリス緩衝液を凍結乾燥して注射剤とする。
【００３７】

以上（１）〜（８）の成分を軟膏の一般的調製法により調製し、皮膚用外用軟膏を得る。
【００３８】

マクロゴール４００に有効成分およびパラオキシ安息香酸メチルを加え、攪拌して混合したものに、精製水にリン酸二カリウムとリン酸二水素カリウムを加えたものを徐々に加えて注腸製剤を得る。
【００３９】

（１）を（２）に分散または溶解させ、坐剤として適切なサイズのプラスチックコンテナーに充填、シールした後、冷却固化させて坐剤を得る。
【００４０】

予め加熱溶解した（２）に（１）を混和させた後、坐剤として適切なサイズのプラスチックコンテナーに充填、シールした後、冷却固化させて坐剤を得る。
【００４１】
【実施例】
＜試験例１＞潰瘍性大腸炎モデルとしては、一般にトリニトロベンゼンスルホン酸(TNB)を用いられるが、本発明を完成するにあたっての薬効評価系としては、ラットのデキストラン硫酸ナトリウム(DSS)誘発潰瘍性大腸炎モデルを用いた。同モデルは、体重の増加抑制、血便の有無、貧血等の症状並びに大腸におけるびらん形成、さらに、小腸において病変が発現しない点等、多くの観点からヒト潰瘍性大腸炎に類似した実験モデルと位置づけられていることは周知である[日本薬理学雑誌、105巻、145-152頁(1995)]。同試験系に対するＮ−（２−エチルスルホニルアミノ−５−トリフルオロメチル−３−ピリジル)シクロヘキサンカルボキサミド・一ナトリウム塩・一水和物(以下化合物1と呼ぶ)の治療効果をみた。
【００４２】
化合物１は製剤品として用いた。製剤処方(1バイアルあたりの含有量)は以下の通りとした。

【００４３】
(1) 潰瘍性大腸炎の誘発方法
デキストラン硫酸ナトリウム(DSS:和光純薬工業製)の３%水溶液を吸水瓶に入れ、ラット [Crj: CD (SD)、雄、日本チャールスリバー、試験供試時7週齢]に11日間自由飲水させ大腸炎を惹起させた。11日後選抜基準(選抜日を含め2日以上連続して血便が認められるもののうち、選抜当日の体重減少が、前日の体重に比べて20 g未満かつヘモグロビン濃度が12g/dl以上)を満たす動物を選別し、各群間の平均体重に差が生じないように群分けした(10匹/群)。
【００４４】
非治療群および化合物１治療群では、群分け日に３％から１％DSS水溶液に切り替え、その後、14日間自由飲水させた。また、化合物１治療群には、群分け日から化合物1を経口ゾンデを用いて1日1回、14日間連日経口投与した (投与容量は10 ml/kg)。非治療群および正常群には注射用蒸留水（大塚製薬製）のみを同様に経口投与した。尚、正常群には実験開始から解剖日までDSS水溶液の代わりに注射用蒸留水を自由飲水させた。
【００４５】
注射用蒸留水（大塚製薬製）を用いて化合物1の10mg/ml水溶液を調製し、所望の投与量となるようにラットに投与した。
【００４６】
(2) 評価方法
大腸の長さおよび大腸粘膜のびらん面積
採血後直ちに大腸（結腸および直腸）を摘出し、十分弛緩させた状態で定規を用いてその長さを測定した。
【００４７】
測定終了後直ちに固定液を腸内に注入して、ほぼ均等になるように管腔を拡張させた状態で１時間以上仮固定した。その後、腸間膜付着部に沿って腸管を切開し、10％中性緩衝ホルマリン水溶液中に伸展させた状態で１週間以上本固定した。流水中で約５分間水洗し、さらに精製水で３回水洗した後、前処理として3 %酢酸水溶液に約５分間浸漬した。その後、1％アルシアンブルー(ナカライテスク製)（３％酢酸水溶液に溶解）液中に浸漬して約20分間染色した後、アルシアンブルーの溶出が無くなるまで3 %酢酸水溶液で４〜５回洗浄した。本操作により、大腸は濃淡のある青色に染色されるが、びらん部位は濃青色に染色されることから、その部位の面積を画像解析装置（汎用画像処理“Win ROOF、Version 3.1”三谷商事製）を用いて解析し、びらん面積とした。
【００４８】
非治療群のびらん面積を１００として、化合物1治療群のびらん抑制率を求めた。
びらん抑制率（％）＝[1-(化合物1治療群のびらん面積の平均値／非治療群のびらん面積の平均値)]×100
【００４９】
病理組織学的検査： 大腸、脾臓、腸間膜および腸間膜リンパ節、大腿骨骨髄を10％中性緩衝ホルマリン水溶液[ホルマリン(キシダ化学製)、リン酸水素二ナトリウム(和光純薬工業製)およびリン酸二水素ナトリウム二水和物(和光純薬工業製)を用いて自家調製した]で固定した後、常法に従ってヘマトキシリン・エオジン(メルク製)重染色を施した病理組織標本を作製し、鏡検した(オリンパス光学工業製BX50使用)。
【００５０】
(3)結果
大腸のびらん面積：化合物 1を100、10および1 mg/kg/dayの投与量で2週間にわたり毎日一回経口投与した結果、大腸のびらん面積において非治療群に比して各々62、56および45％の抑制率を示し、著明なびらん抑制効果が認められた (第１表)。なお正常群においては大腸のびらんは認められなかった。
【００５１】
【表１】
第１表 びらん面積に対する効果

【００５２】
大腸の長さ： また、化合物1は、大腸の長さの検討からびらんの随伴病変である腸壁肥厚を軽減することが示され、さらに、びらんによる下血が原因の貧血も軽減した。
【００５３】
病理組織学的検討： 病理組織学的検討の結果、化合物１治療群では、びらん発生域の粘膜下織における炎症の顕著な軽減が認められた。さらに、粘膜の再生によって正常な組織再構築が行われ、粘膜組織としての強度および機能が回復する傾向が認められた。
【００５４】
＜試験例2＞Trinitrobenzen sulfonic acid (TNBS) 誘発ラットクローン病モデルに対する治療効果：TNBS誘発ラットクローン病モデルに対する化合物１の治療効果は以下の方法で検討した。
【００５５】
（１）SDラット、雄、12週齡をネンブタール麻酔下で開腹し、回盲部から10cm下部の結腸内にTNBS溶液（TNBS 160 mg/ml-エタノール）を1 ml/kg投与し、閉腹してモデルを作製し、非治療群および化合物１治療群に6匹ずつ分配した。正常群の動物にはこれらの処置は行わなかった。モデル作製後、化合物１が無水物換算で10 mg/kg/dayの投与量になるように、蒸留水で希釈した試験例１の化合物１製剤品を7日間にわたり、化合物１治療群の動物に1日1回経口投与した。投与期間終了後、肉眼変化、小腸重量、小腸組織内ミエロペルオキシダーゼ（小腸MPO）を観察または測定した。肉眼変化は種々の変化を数値化して集計した。小腸重量と体重から小腸重量体重比も算出した。その結果を第２表に示した。
【００５６】
【表２】
第２表 検査結果

統計学的評価
正常群と非治療群の比較 #, ##, ### : P<0.05, P<0.01, P<0.001
非治療群と治療群の比較 *, **, *** : P<0.05, P<0.01, P<0.001
【００５７】
非治療群では、小腸重量、小腸重量体重比、肉眼スコアおよび小腸MPOで数値の上昇が認められ、小腸における炎症反応および組織傷害が認められた。化合物１治療群ではこれらの検査値の上昇を抑制し、小腸における炎症反応および組織傷害を軽減することが示された。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a therapeutic agent and a preventive agent which contain a diaminotrifluoromethylpyridine derivative or a salt thereof as an active ingredient and are effective for digestive organ diseases such as inflammatory bowel disease, gastritis and peptic ulcer.
[0002]
[Prior art]
In Japanese Patent No. 2762323 and US Pat. No. 5,229,403, a diaminotrifluoromethylpyridine derivative or a salt thereof is phospholipase A.₂It has an inhibitory action and is described as being useful as an active ingredient of anti-inflammatory agents or anti-pancreatitis agents. The publication also discloses (1) phospholipase A in platelets and inflammatory cells.₂Is secreted or activated by stimulation and contributes to the production of metabolites of platelet activating factor (PAF) and arachidonic acid. (2) Metabolites of arachidonic acid have various pathologies such as rheumatoid arthritis and osteoarthritis. Inflammatory symptoms such as tendonitis, bursitis, psoriasis and related skin inflammation; nasal and bronchial airway disorder symptoms such as allergic rhinitis and allergic bronchial asthma; immediate hypersensitivity reactions such as allergic conjunctivitis (3) On the other hand, phospholipase A secreted from the pancreas₂Is activated in the intestine and exerts digestive action, but once activated in the pancreas, it is considered to be one of the factors causing pancreatitis, (4) and the diaminotrifluoromethylpyridine derivative is phospholipase A₂Phospholipase A such as inflammatory symptoms, nasal / bronchial airway disorder symptoms, immediate hypersensitivity reactions, pancreatitis, etc.₂It is effective for the treatment of pathological conditions related to the above, and can be used as an anti-inflammatory agent, bronchial asthma treatment agent, anti-allergic agent, anti-pancreatitis agent, anti-nephritis agent, anti-multi-organ disorder agent, etc. .
[0003]
In US Pat. No. 5,492,908, these compounds can be used as therapeutic agents for rheumatoid arthritis. Furthermore, in Japanese Patent Application Laid-Open No. 10-298076, some of them have a carcinogenic inhibitory effect. It is described that it is effective as an anticancer agent.
[0004]
[Problems to be solved by the invention]
Among gastrointestinal diseases, diseases requiring new therapeutic agents include inflammatory bowel disease, gastritis, and peptic ulcer. Inflammatory bowel disease means enteritis that occurs in the small intestine (including duodenum, jejunum, ileum) or large intestine (including cecum, colon, rectum), infectious enteritis, ischemic enteritis, radiation enteritis, In addition to enteritis such as drug-induced enteritis and irritable bowel syndrome, ulcerative colitis (nonspecific idiopathic colitis), Crohn's disease (localized enteritis), colonic Crohn's disease (granuloma) Ulcerative colitis or localized colitis), intractable inflammatory bowel diseases such as intestinal Behcet's disease, and enteritis in which not only the cause is unknown but the disease itself has not yet been identified.
[0005]
Human ulcerative colitis is a nonspecific idiopathic inflammatory bowel disease that forms erosions and ulcers in the mucosal layer or submucosa of the large intestine from the rectum to the cecum. In recent years, the number of patients has increased rapidly. Clinical symptoms include characteristic findings such as diarrhea, bloody stool, abdominal pain, and weight loss, and are intractable diseases that repeat relapse and remission. Although there are still many unclear points regarding the detailed etiology and pathology, immunopathological mechanisms and psychological factors are considered to be involved. On the other hand, Crohn's disease is a disease in which inflammation spreads not only to the mucosa but also to the entire intestinal wall, and non-diffuse and non-continuous lesions occur in all digestive tracts from the oral cavity to the anus. Is still unknown. In addition to malnutrition during the course, various gastrointestinal and extraintestinal symptoms such as intestinal stenosis, intestinal perforation, abdominal abscess, major bleeding, etc. often occur, and the postoperative recurrence rate is high. It is also a disease.
[0006]
The main medical treatments for ulcerative colitis are steroid hormones, salazosulfapyridine (SASP) [sarazopyrine (registered trademark)], and metronidazole [fragile (registered trademark)] [New England Journal of Medicine 25, 1499 (1980), Merck Manual 17th edition, 309 (1999)]. SASP is an azo compound of 5-aminosalicylic acid (5-ASA) and sulfapyridine, but has a lesion in the large intestine, especially as a first-line drug for mild to moderate active ulcerative colitis In some cases, the effect in severe cases is relatively weak, and even in light cases, combined treatment with other agents such as steroids is often performed. Furthermore, it is pointed out that the effect in the acute phase of inflammation is insufficient. In spite of various reports on its mechanism of action, including prostaglandin synthesis inhibitory activity, leukotriene synthesis inhibitory activity, leukocyte chemotaxis inhibitory activity, active oxygen production inhibitory / erasant effect, immunosuppressive effect and anti-inflammatory effect. There are many unclear points. In addition, taking this drug has side effects such as liver dysfunction, nausea / vomiting, headache, fever, hemolytic anemia, male infertility, abdominal discomfort, skin rash, lymphadenopathy, granulocytopenia, and folic acid deficiency. It is expressed and its frequency reaches 10-20% [Gastrointestinal Pharmacology, Vol. 21, pp. 643-658 (1992)]. In order to reduce these side effects, mesalazine, a sustained-release preparation coated to produce 5-ASA at the intestinal pH, has been developed and used clinically. Problems have been reported, and their effects do not exceed those of SASP [Pharmacology and Treatment, Vol. 22, pp. 93-121 (1994)]. On the other hand, corticosteroids such as predonin and Linderon are commonly used as steroids, but on the other hand, there are problems with other side effects associated with viral / bacterial infections and suppression of pituitary / adrenocortical functions. Since it is very difficult to prescribe, it is generally necessary to carefully administer it under hospitalization management. Examples of effective therapeutic agents for Crohn's disease include SASP, 5-ASA, mercaptopurine, corticosteroids, metronidazole, etc., all of which are said to have insufficient clinical effects.
[0007]
Recently, for these inflammatory bowel diseases, lipoxygenase inhibitor, thromboxane A₂Receptor antagonist, thromboxane A₂Synthetic enzyme inhibitors, active oxygen scavengers, interleukin 1 (IL-1) antagonists (JP 9-157182 A), new therapeutic agents such as neutralizing antibodies against tumor necrosis factor (TNF-α), and leukocyte removal Development of therapies is underway, but the development of more effective and safe therapeutic agents is desired.
[0008]
On the other hand, peptic ulcers such as gastric ulcers and duodenal ulcers have various symptoms depending on the site of the ulcer and the age of the patient, but the pathogenesis has been classically thought to be mainly due to excessive secretion of gastric acid. As a gastric acid hypersecretion inhibitor, H₂H having receptor antagonism₂Blockers (cimetidine, ranitidine, famotidine, loxazine acetate, nizatidine, etc.) and proton pump inhibitors (PPI: omeprazole, lanzoprazole) have been clinically applied. There is no objection to the dramatic improvement in the healing rate of gastric and duodenal ulcers due to the advent of these drugs, and it is the main treatment for peptic ulcers. However, even after treating ulcers temporarily with these drugs, many clinical cases have been reported in which ulcers recur at a high rate as long as Helicobacter pylori bacteria are present in the digestive tract, as described later. [New England Journal of Medicene, 328, 308 (1993)]. H₂For blockers and long-term PPI users, the prevalence of non-steroidal anti-inflammatory drugs has been associated with a high rate of peptic ulcer formation.
[0009]
Recently, Helicobacter pylori has been shown to be an important pathogenic factor in the development of gastritis, gastric ulcer, duodenal ulcer and gastric cancer [American Journal of Gastroenterology, 82, 2283 (1987)] For patients with peptic ulcer, treatment with antibacterial agents has been given in addition to gastric acid secretion inhibitors, regardless of whether the disease is initially occurring or recurring. There are various theories about the action of Helicobacter pylori, but one theory is that urease produced from Helicobacter pylori decomposes urea present in the stomach to produce ammonia under acidic conditions, and the resulting ammonia is produced in the stomach. It has been reported that direct damage to the mucous membrane is the cause [Journal of Dairy Science, Vol. 67, p. 481 (1984)]. Various treatments have been devised for eradication of Helicobacter pylori, mainly bismuth preparations, antibacterial agents, and antiprotozoal agents. However, the use of these agents alone provides sufficient sterilization effects. However, multi-drug combination therapy is mainly performed. For example, in Europe and the United States, the classic triple combination therapy of bismuth, metronidazole, and tetracycline is performed, and a sterilization rate of 90% or more is obtained, but compliance is poor due to the frequent occurrence of side effects and complicated administration methods. Is not popular. In addition, two-drug combination therapy with PPI and antibacterial agents such as amoxicillin and clarithromycin, and a short-term triple combination therapy in which regular doses of omeprazole, clarithromycin and nitroimidazole were combined for 1 week were developed. However, there are cases where stable sterilization rates cannot be obtained, and there are cases where recurrence occurs due to the appearance of resistant bacteria, and the dose of antibacterial agents is large, so the burden on patients is heavy and often diarrhea It is known to have side effects such as nausea and nausea, and is generally recognized as a problem to be solved.
[0010]
Gastritis caused by gastric mucosal injury is broadly divided into acute erosive gastritis, chronic erosive gastritis, and non-erosive gastritis, post-gastrectomy gastritis and other gastritis syndromes. The etiology varies, but there are many parts in common with the case of peptic ulcer described above.₂The use of blockers, proton pump inhibitors, and Helicobacter pylori disinfectants alone or in combination has become the mainstream. From recent research, as a novel therapeutic agent for peptic ulcer or gastritis, for example, an anti-helicobacter agent that adheres to the gastrointestinal mucosa containing an antibacterial substance and an anti-ulcer substance (JP-A-7-126189, JP-A-10-167985) A cholecystokinin antagonist (JP-A-8-259447), a mucin production promoter containing lactoferrin as an active ingredient (JP-A-9-12473), H₂It has been reported that aminoalkylpyridyloxy derivatives (Japanese Patent Laid-Open No. 11-92373) having a receptor antagonistic action and a gastric mucosa protective action are effective.
[0011]
In addition, JP-A-11-12171 discloses 1,4-benzodioxin derivatives having selective β3 receptor agonist activity, and JP-A-10-330346 discloses a linear form having a free radical scavenging action. Nitron derivatives are further disclosed in Japanese Patent Application Laid-Open No. 10-101576, wherein drugs containing glycetine and glutamine (or glutamine derivatives) as active ingredients are effective for treating various digestive diseases. Therefore, development of a drug having an excellent therapeutic effect is demanded.
[0012]
As a result of intensive studies on the pharmacological action of diaminotrifluoromethylpyridine derivatives or salts thereof, the present inventors have found that these compounds are excellent for gastrointestinal diseases such as inflammatory bowel disease, gastritis, and peptic ulcer. As a result, the present invention was completed.
[0013]
The present invention provides a compound of formula (I);
[Chemical 2]

[Where X is -CW¹R¹Group, -COCOR²Group, -CW¹NHCOR²-C (= W¹) W²R^ThreeGroup or -CW¹N (R^Four) R^FiveY is an alkyl group, -CW^ThreeR⁶Group, -COCOR⁷Group, -NHCOR⁷-C (= W^Three) W^FourR⁸Group,-(NH)_mSO₂R⁹Group,-(NH)_mSO₂OR^TenGroup or-(NH)_mSO₂N (R¹¹) R¹²R and R¹, R⁶And R⁹Each independently represents a chain hydrocarbon group that may be substituted, a monocyclic hydrocarbon group that may be substituted, a polycyclic hydrocarbon group that may be substituted, or a monocyclic heterocycle that may be substituted. A cyclic group or an optionally substituted polycyclic heterocyclic group, R²And R⁷Are each independently an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted phenyl group or an optionally substituted phenoxy group, and R^Three, R⁸And R^TenEach independently represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group or a substituted A good benzyl group, R^Four, R^Five, R¹¹And R¹²Are each independently an optionally substituted alkyl group, and W¹, W², W^ThreeAnd W^FourAre each independently an oxygen atom or a sulfur atom, and m is 0 or 1. However, one of X and Y is -COCF₂X¹Group (X¹Is a hydrogen atom, a halogen atom, an alkyl group or a haloalkyl group, and the other is —COCF₂X²Group (X²Is a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group or an alkylcarbonyl group) or —COOX^ThreeGroup (X^ThreeIs an optionally substituted alkyl group or an optionally substituted phenyl group) or -COX^FourGroup (X^FourIs a combination of an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an optionally substituted phenyl group, a furanyl group, or a naphthyl group), or a diaminotrifluoromethylpyridine derivative or a salt thereof It is providing the therapeutic agent or preventive agent of a digestive organ disease which contains as an active ingredient.
[0014]
In formula (I), R¹, R⁶And R⁹Examples of the chain hydrocarbon group contained in the above include an alkyl group, an alkenyl group, and an alkynyl group, and examples of the monocyclic hydrocarbon group include a cycloalkyl group, a cycloalkenyl group, and a phenyl group. The cyclic hydrocarbon group includes a condensed polycyclic hydrocarbon group such as a naphthyl group, a tetrahydronaphthyl group, and an indanyl group, or a bridged polycyclic carbon group such as an adamantyl group, a noradamantyl group, a norbornanyl group, and a norbornanyl group. Examples of the monocyclic heterocyclic group include pyrrolyl group, furanyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyrrolinyl group, pyrrolidinyl group. , Dihydrofuranyl group, tetrahydrofuranyl group, dihydride Thienyl group, tetrahydrothienyl group, pyrazolinyl group, hydantoinyl group, oxazolinyl group, isoxazolinyl group, isoxazolidinyl group, thiazolinyl group, thiazolidinyl group, dioxolanyl group, dithiolanyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, Pyrazinyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, dihydrooxopyridazinyl group, tetrahydrooxopyridazinyl group, dihydrooxopyrimidinyl group, tetrahydrooxopyrimidinyl group, piperazinyl group, dihydropyranyl group, tetrahydropyrani group Group, dioxanyl group, dihydrodithiinyl group, dithianyl group, morpholinyl group and the like. Examples of the polycyclic heterocyclic group include thienothienyl group, dihydrocyclopentathenyl. , Indolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzimidazolyl group, tetrahydrobenzothienyl group, dihydrobenzofuranyl group, tetrahydrobenzisoxazolyl group, Examples thereof include a condensed polycyclic heterocyclic group such as a benzodioxolyl group, a quinolinyl group, an isoquinolinyl group, a benzodioxanyl group, and a quinoxalinyl group, or a bridged polycyclic heterocyclic group such as a quinuclidinyl group.
[0015]
R¹, R⁶And R⁹An optionally substituted chain hydrocarbon group, R²And R⁷An optionally substituted alkyl group and an optionally substituted alkoxy group, R^Three, R⁸And R^TenAn optionally substituted alkyl group, an optionally substituted alkenyl group and an optionally substituted alkynyl group, and R^Four, R^Five, R¹¹And R¹²An optionally substituted alkyl group and X^ThreeExamples of the substituent of the alkyl group which may be substituted include a halogen atom, alkoxy group, haloalkoxy group, alkylthio group, cycloalkyl group, cycloalkoxy group, cycloalkenyl group, cycloalkenyloxy group, alkoxycarbonyl group, alkyl Examples include a carbonyl group, an alkylcarbonyloxy group, an aryl group, an aryloxy group, an arylthio group, an amino group, an amino group substituted with an alkyl group, and the like, and the number of substituents attached to these substituents. May be 1 or 2 or more, and in the case of 2 or more, their substituents may be the same or different.
[0016]
R¹, R⁶ And R⁹ A monocyclic hydrocarbon group which may be substituted, a polycyclic hydrocarbon group which may be substituted, a monocyclic heterocyclic group which may be substituted and a polycyclic heterocyclic group which may be substituted , R²And R⁷An optionally substituted phenyl group and an optionally substituted phenoxy group, R^Three, R⁸ And R^TenAn optionally substituted cycloalkyl group, an optionally substituted phenyl group and an optionally substituted benzyl group, and X^ThreeThe substituent of the phenyl group which may be substituted is a halogen atom, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkylthio group, cycloalkyl group, cycloalkoxy group, cycloalkenyl group, cycloalkenyloxy group , Alkoxycarbonyl group, alkylcarbonyl group, alkylcarbonyloxy group, aryl group, aryloxy group, arylthio group, amino group, amino group substituted with alkyl group, cyano group, nitro group, etc. The number of substituents associated with these substituents may be 1 or 2 or more, and in the case of 2 or more, these substituents may be the same or different.
[0017]
In the formula (I), the alkyl group and the alkyl moiety contained in X and Y are those having 1 to 18 carbon atoms, such as methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, An octyl group, a decyl group, a nonadecyl group, etc. are mentioned, and these include structural isomers of straight or branched fatty chains. Examples of the alkenyl group and the alkenyl moiety contained in X and Y include those having 2 to 18 carbon atoms, such as vinyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, decenyl group, and nonadecenyl group. They include linear or branched fatty chain structural isomers. Examples of the alkynyl group and alkynyl moiety contained in X and Y include those having 2 to 18 carbon atoms, such as ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, decynyl group, and nonadecynyl group. They include linear or branched fatty chain structural isomers. Examples of the cycloalkyl group and the cycloalkyl moiety contained in X and Y include those having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Examples of the cycloalkenyl group and cycloalkenyl moiety contained in X and Y include those having 5 to 8 carbon atoms, such as a cyclopentenyl group, a cyclohexenyl group, and a cyclooctenyl group. Furthermore, examples of the halogen atom contained in X and Y include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the aryl group and aryl moiety contained in X and Y include a phenyl group, a thienyl group, a furanyl group, a pyridyl group, a naphthyl group, a benzothienyl group, a benzofuranyl group, and a quinolinyl group.
[0018]
Desirable embodiments of the compound of the present invention will be described below. In the formula (I), X is —CW¹R¹Group or -C (= W¹) W²R^ThreeAnd Y is -SO₂R⁹The group is desirable. R¹And R⁶Is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted phenyl group, an optionally substituted tetrahydro A naphthyl group, an optionally substituted indanyl group, an optionally substituted furanyl group or an optionally substituted thienyl group is desirable; an alkyl group, a haloalkyl group, an alkoxycarbonylalkyl group, an alkenyl group, a haloalkenyl group, a cycloalkyl group A cycloalkyl group substituted with a halogen atom, a phenyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with an alkyl group or a haloalkyl group, a phenyl group substituted with an alkoxy group or a haloalkoxy group, tetrahydronaphthyl Group, indanyl group, furanyl group or Enyl group is more preferable. R²And R⁷Is preferably an optionally substituted alkoxy group or an optionally substituted phenyl group; more preferably an alkoxy group, a haloalkoxy group, a phenyl group or a phenyl group substituted with a halogen atom. R^Three, R⁸And R^TenIs preferably an optionally substituted alkyl group; more preferably an alkyl group or a haloalkyl group. R^Four, R^Five, R¹¹And R¹²Is preferably an alkyl group. R⁹Is preferably an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group or an optionally substituted phenyl group; an alkyl group, a haloalkyl More desirable are a group, a phenyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with an alkyl group or a haloalkyl group, or a phenyl group substituted with an alkoxy group or a haloalkoxy group.
[0019]
Preferred compounds among the compounds of the present invention include those in the formula (I) wherein X is an alkoxycarbonylalkylcarbonyl group, an alkenylcarbonyl group, an alkenylcarbonyl group substituted with a thienyl group, a cycloalkylcarbonyl group, an indanylcarbonyl group, Examples include a furancarbonyl group, a thiophenecarbonyl group, a tetrahydronaphthylcarbonyl group, or a benzoyl group that may be substituted with a halogen atom or a haloalkyl group, and a compound in which Y is an alkylsulfonyl group. Specifically, N- (2 -Methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -4-fluorobenzamide, N- (2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl) -3-fluorobenzamide, N- (2 -Methylsulfur Nylamino-5-trifluoromethyl-3-pyridyl) -2-furancarboxamide, N- (2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclopentanecarboxamide, N- (2-ethylsulfonylamino- 5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -5-indanecarboxamide, N- (2-methylsulfonylamino-5-tri Fluoromethyl-3-pyridyl) acetoxyacetamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) crotonamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3) -Pyridyl) -2-thiophenecarboki N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -3-trifluoromethylbenzamide, N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) -3 -Fluorobenzamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -6- (1,2,3,4-tetrahydronaphthalene) carboxamide, N- (2-ethylsulfonylamino-5) -Trifluoromethyl-3-pyridyl) crotonamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -3- (2-thienyl) acrylamide or salts thereof.
[0020]
More desirable compounds include compounds in which, in the formula (I), X is a cycloalkyl group, a furancarbonyl group or a benzoyl group optionally substituted with a halogen, and Y is an alkylsulfonyl group. N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -4-fluorobenzamide, N -(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl) -3-fluorobenzamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -2-furancarboxamide or N -(2-Isopropylsulfonylamino-5-trifluoro) Methyl-3-pyridyl) cyclopentanecarboxamide or salts thereof.
[0021]
In the compound represented by the formula (I), Y is —SO.₂R⁹Group (R⁹In the case of the above), a salt may be formed as long as it is pharmaceutically acceptable, for example, an alkali metal salt such as potassium salt or sodium salt, calcium Examples include alkaline earth metal salts such as salts, organic ethanol salts such as triethanolamine salts, and tris (hydroxymethyl) aminomethane salts. Some of these salts have water of crystallization.
[0022]
The compound represented by the formula (I) can be produced, for example, by the method described in Japanese Patent No. 2762323. Further, these compounds have geometric isomers depending on the kind of substituents, but the present invention includes each isomer (cis isomer, trans isomer) and isomer mixtures.
[0023]
The compound of the present invention represented by the formula (I) is useful as an active ingredient of a therapeutic or prophylactic agent for digestive system diseases. Among them, ulcerative colitis (nonspecific idiopathic colitis), Crohn's disease (localized enterocolitis), colonic Crohn's disease (granulomatous colitis or localized colitis), intestinal Behcet's disease, infectious enteritis, false It is useful as an active ingredient of a therapeutic or preventive agent for hematologic enteritis, radiation enteritis, drug enteritis, inflammatory bowel diseases such as irritable bowel syndrome, peptic ulcers such as gastric ulcer and duodenal ulcer, and gastritis. In particular, it is useful as an active ingredient of a therapeutic or prophylactic agent for the ulcerative colitis, Crohn's disease, colonic Crohn's disease or intestinal Behcet's disease, and in particular, an active ingredient of a therapeutic or prophylactic agent for ulcerative colitis or Crohn's disease It is desirable to be used as It can also be expected to be more effective when used in combination with other drugs such as Chinese medicine.
[0024]
When the compound of the present invention is administered as an active ingredient of a therapeutic agent for digestive diseases such as ulcerative colitis, Crohn's disease, gastric ulcer, duodenal ulcer, gastritis, etc., alone or mixed with a pharmacologically acceptable carrier or the like, The pharmaceutical composition is suitable for oral or parenteral use, such as tablets, powder packaging, capsules, granules, injections, ointments, inhalants, enemas, suppositories and the like. In addition, recently, by utilizing the adhesion to the gastric mucosa and intestinal mucosa, the residence time in the gastrointestinal tract is extended, and active ingredients such as the stomach, duodenum, large intestine, small intestine, rectal ulcer drugs and the like are used at a high concentration over a long period of time. Preparations containing a gastrointestinal mucosa-adhesive matrix for oral administration that can be efficiently acted on in a suppository base have also been reported (JP-A-5-324416, JP-A-7-330582), and these Can also be administered.
[0025]
Examples of preparations suitable for oral use include solid compositions such as tablets, capsules, powders, granules, and troches; liquid compositions such as syrup suspensions. Solid compositions such as tablets, capsules, powders, granules and lozenges are shaped into binders such as microcrystalline cellulose, gum arabic, tragacanth gum, gelatin, polyvinylpyrrolidone; and shapes such as starch, lactose, carboxymethylcellulose Agents; disintegrating agents such as alginic acid, corn starch, carboxymethyl cellulose; lubricants such as magnesium stearate, light anhydrous silicic acid, colloidal silicon dioxide; sweeteners such as sucrose; flavoring agents such as peppermint and methyl salicylate; Can be contained. Liquid compositions such as syrups, suspensions include vegetable oils such as sorbitol, gelatin, methylcellulose, carboxymethylcellulose, peanut oil, emulsifiers such as lecithin, and other sweeteners, preservatives, colorants and A flavoring agent etc. can be contained and these can also be provided as a dry formulation. These preparations preferably contain 1 to 95% by weight of the active ingredient compound.
[0026]
Examples of preparations suitable for parenteral use include injections and the like. As an injection, for example, it may be dissolved in ordinary water for injection in the form of a salt, or it can be made into an injectable form of a suspension or emulsion (in a mixture of medically acceptable oils or liquids). . In this case, it may contain a medically acceptable buffer solution or a reagent for adjusting osmotic pressure, such as an antibacterial agent benzyl alcohol, an antioxidant ascorbic acid and the like. This injection preferably contains 0.1 to 8% by weight of the active ingredient compound.
[0027]
Examples of preparations suitable for topical or rectal use include inhalants, ointments, enemas, suppositories and the like. As an inhalant, the compound of the present invention itself or a medically acceptable inert carrier can be dissolved in an aerosol or nebulizer solution or administered as a fine powder for inhalation to the respiratory tract. In the case of fine powder for inhalation, the particles are 50 microns or less, preferably 10 microns or less. In addition, when used as an inhalant, if necessary, it can be used in combination with other anti-asthma agents or bronchodilators.
[0028]
An ointment is prepared by a conventional method with the addition of a commonly used base. The ointment preferably contains 0.1 to 30% by weight of the active ingredient compound.
[0029]
Suppositories may contain pharmaceutical carriers well known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglycerides and the like. The suppository preferably contains 0.1 to 95% by weight of the active ingredient compound.
[0030]
The pharmaceutical composition suitable for oral, parenteral, topical or rectal use is released in a known manner in a controlled manner so that the active ingredient is released rapidly after administration to the patient. Or can be formulated to be released later.
[0031]
The dose of the compound of the present invention varies depending on the type of compound, the administration method, the condition of the patient or the animal to be treated, and the appropriate dose and the number of administrations under certain conditions must be determined by the judgment of a specialist. However, it will normally be administered from about 0.1 mg to about 10 g, preferably from about 1 mg to about 1 g, per adult day. In addition, the dose of the compound of the present invention per dose in the inhalation method is preferably about 0.01 mg to about 1 g.
[0032]
Next, specific formulation examples of the therapeutic agent or prophylactic agent of the present invention will be given, but the formulation of the present invention is not limited thereto.
[0033]

The above components (1) to (4) are molded into a tablet as one tablet.
[0034]

Said (1)-(4) is mixed, and it is set as a fine granule or a granule by a powder and also granulation. It is also possible to encapsulate these into capsules.
[0035]

The above components (1) to (3) are packed into a hard gelatin capsule as one tablet to obtain a hard gelatin capsule.
[0036]

The Tris buffer containing the components (1) to (3) above is lyophilized to obtain an injection.
[0037]

The components (1) to (8) above are prepared by a general method for preparing ointments to obtain an external ointment for skin.
[0038]

An enema preparation is obtained by gradually adding an active ingredient and methyl parahydroxybenzoate to Macrogol 400, stirring and mixing them, and gradually adding dipotassium phosphate and potassium dihydrogen phosphate to purified water.
[0039]

(1) is dispersed or dissolved in (2), filled into a plastic container of an appropriate size as a suppository, sealed, and then cooled and solidified to obtain a suppository.
[0040]

(1) is mixed with (2), which has been heated and dissolved in advance, and then filled and sealed in a plastic container of an appropriate size as a suppository, and then cooled and solidified to obtain a suppository.
[0041]
【Example】
<Test Example 1> Trinitrobenzenesulfonic acid (TNB) is generally used as an ulcerative colitis model, but as a medicinal evaluation system for completing the present invention, rat dextran sulfate sodium (DSS) -induced ulcerability A colitis model was used. This model is positioned as an experimental model similar to human ulcerative colitis from many viewpoints, including suppression of weight gain, presence or absence of bloody stool, symptoms such as anemia, erosion formation in the large intestine, and the absence of lesions in the small intestine. It is well known [Japanese Journal of Pharmacology, Vol. 105, pp. 145-152 (1995)]. The therapeutic effect of N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide monosodium salt monohydrate (hereinafter referred to as Compound 1) on the same test system was observed.
[0042]
Compound 1 was used as a preparation. The formulation (content per vial) was as follows.

[0043]
(1) How to induce ulcerative colitis
A 3% aqueous solution of sodium dextran sulfate (DSS: manufactured by Wako Pure Chemical Industries, Ltd.) is placed in a water-absorbing bottle and allowed to drink freely for 11 days in rats [Crj: CD (SD), male, Charles River, Japan, 7 weeks old at the time of test test]. And caused colitis. Animals that meet the selection criteria after 11 days (of which bloody stool is observed continuously for 2 days or more including the selection day, the weight loss on the day of selection is less than 20 g and the hemoglobin concentration is 12 g / dl or more compared to the previous day) Were selected and divided into groups so that there was no difference in average body weight between groups (10 animals / group).
[0044]
In the non-treated group and the compound 1 treated group, the group was switched from 3% to 1% DSS aqueous solution on the day of grouping, and then allowed to drink freely for 14 days. In the Compound 1 treatment group, Compound 1 was orally administered once daily for 14 days using an oral sonde from the day of grouping (dosing volume was 10 ml / kg). For the non-treated group and the normal group, only distilled water for injection (manufactured by Otsuka Pharmaceutical) was orally administered in the same manner. The normal group was allowed to freely drink distilled water for injection instead of the DSS aqueous solution from the start of the experiment to the day of dissection.
[0045]
A 10 mg / ml aqueous solution of Compound 1 was prepared using distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) and administered to rats so as to obtain a desired dose.
[0046]
(2) Evaluation methods
Large intestine length and erosion area of large intestine mucosa
Immediately after blood collection, the large intestine (colon and rectum) was removed, and its length was measured using a ruler in a sufficiently relaxed state.
[0047]
Immediately after completion of the measurement, a fixative was injected into the intestine, and temporarily fixed for 1 hour or more in a state where the lumen was expanded to be almost uniform. Thereafter, the intestinal tract was incised along the mesentery adhering portion, and was permanently fixed for 1 week or more in a state of being extended in a 10% neutral buffered formalin aqueous solution. After washing with running water for about 5 minutes and further with purified water three times, it was immersed in a 3% aqueous acetic acid solution for about 5 minutes as a pretreatment. Then, after immersing in 1% Alcian Blue (manufactured by Nacalai Tesque) (dissolved in 3% acetic acid aqueous solution) and dyeing for about 20 minutes, 4-5 times with 3% acetic acid aqueous solution until elution of Alcian blue disappears Washed. By this operation, the large intestine is stained in light blue, but the erosion part is dyed in dark blue, so the area of that part is image analysis device (general-purpose image processing “Win ROOF, Version 3.1” manufactured by Mitani Corp. ) Was used as the erosion area.
[0048]
Taking the erosion area of the non-treated group as 100, the erosion inhibition rate of the Compound 1 treated group was determined.
Erosion inhibition rate (%) = [1- (average value of erosion area of compound 1 treatment group / average value of erosion area of non-treatment group)] × 100
[0049]
Histopathological examination: 10% neutral buffered formalin aqueous solution [formalin (manufactured by Kishida Chemical), disodium hydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.), large intestine, spleen, mesentery and mesenteric lymph nodes, femur bone marrow ) And sodium dihydrogen phosphate dihydrate (manufactured by Wako Pure Chemical Industries, Ltd.)], and then prepared a histopathological specimen with hematoxylin and eosin (Merck) overstaining according to conventional methods And then microscopically examined (using Olympus BX50).
[0050]
(3)result
Colon erosion area: Compound 1 was orally administered once daily for 2 weeks at doses of 100, 10 and 1 mg / kg / day, resulting in a colon erosion area of 62, 56 and The inhibition rate was 45%, and a significant erosion-inhibiting effect was observed (Table 1). In the normal group, no erosion of the large intestine was observed.
[0051]
[Table 1]
Table 1 Effect on erosion area

[0052]
Colon length: In addition, Compound 1 was shown to reduce intestinal wall thickening, an associated lesion of erosion, from examination of the length of the large intestine. Furthermore, anemia caused by erosion caused by erosion was also reduced.
[0053]
Histopathological examination: As a result of the histopathological examination, the compound 1 treatment group showed a marked reduction in inflammation in the submucosal tissue in the erosion area. Furthermore, normal tissue reconstruction was carried out by regeneration of the mucous membrane, and the strength and function as the mucosal tissue tended to be restored.
[0054]
<Test Example 2>Trinitrobenzen sulfonic acid (TNBS) Therapeutic effect on induced rat Crohn's disease model:The therapeutic effect of Compound 1 on the TNBS-induced rat Crohn's disease model was examined by the following method.
[0055]
(1) SD rats, males, 12-week-old rats were laparotomized under Nembutal anesthesia, TNBS solution (TNBS 160 mg / ml-ethanol) was administered 1 ml / kg into the colon 10 cm below the ileocecal region, and the abdomen was closed A model was created and distributed to the untreated group and the Compound 1 treated group by 6 mice. The normal group of animals did not receive these treatments. After preparation of the model, the compound 1 preparation of Test Example 1 diluted with distilled water so that the dose of Compound 1 is 10 mg / kg / day in terms of anhydride is applied to the animals in the Compound 1 treatment group for 7 days. It was orally administered once a day. At the end of the administration period, gross changes, small intestine weight, and myeloperoxidase (small intestine MPO) in the small intestine tissue were observed or measured. Macroscopic changes were tabulated with various changes. The small intestine weight / body weight ratio was also calculated from the small intestine weight and body weight. The results are shown in Table 2.
[0056]
[Table 2]
Table 2 Test results

Statistical evaluation
Comparison between normal and untreated groups #, ##, ###: P <0.05, P <0.01, P <0.001
Comparison between non-treated group and treated group *, **, ***: P <0.05, P <0.01, P <0.001
[0057]
In the non-treated group, increased values were observed in the small intestine weight, small intestine weight-to-body ratio, macroscopic score, and small intestine MPO, and inflammatory reactions and tissue damage were observed in the small intestine. In the Compound 1 treatment group, it was shown that the increase in these test values was suppressed and the inflammatory reaction and tissue injury in the small intestine were reduced.

Claims (1)

A therapeutic or prophylactic agent for ulcerative colitis or Crohn's disease containing N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide or a salt thereof as an active ingredient.