JP2004161662A - 1h-imidazoquinoline derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a compound having inhibitory action on production of tumor necrosis factor (TNF). <P>SOLUTION: The 1H-imidazoquinoline derivative represented by the general formula (R<SP>1</SP>is a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, an acetyloxy group, a halogen atom, a nitro group, an amino group or an cyano group; R<SP>2</SP>is a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group or a halogen atom; R<SP>3</SP>is a hydrogen atom, a lower alkyl group, a halogenoalkyl group or a halogen atom; R<SP>4</SP>is a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group or a halogen atom; X is CH or N; R<SP>1</SP>and R<SP>2</SP>are not hydrogen atoms at the same time) or its salt has excellent inhibitory action on production of TNF and is extremely useful as a prophylactic or a therapeutic agent for diseases caused by TNF. <P>COPYRIGHT: (C)2004,JPO

Description

（式中、Ｒ^１はハロゲン原子・水酸基・アルコキシカルボニル基から選択される置換基を有してもよいアルコキシ基，水素原子，水酸基，アルキル基，ハロゲノアルキル基，アシルオキシ基，ハロゲン原子，ニトロ基，アミノ基，シアノ基を表し、Ｒ^２は水素原子，水酸基，アルキル基，アルコキシ基，ハロゲン原子，ニトロ基を表し、Ｒ^３は水素原子，アルキル基，ハロゲノアルキル基，ハロゲン原子を表し、Ｒ^４は水素原子，水酸基，アルキル基，アルコキシ基，アラルキルオキシ基，ハロゲン原子を表し、ＸはＣＨで示される基又は窒素原子を表す。ここでＲ^１とＲ^２が同時に水素原子を表すことはない。ただし、ここでＸがＣＨで示される基を表し、（ａ）Ｒ^１及びＲ^４が同時に水素原子を表し、Ｒ^３がメチル基のとき、Ｒ^２はフッ素原子ではなく、（ｂ）Ｒ^１及びＲ^４が同時に水素原子を表し、Ｒ^３が塩素原子のとき、Ｒ^２はメチル基，メトキシ基，フッ素原子ではなく、（ｃ）Ｒ^１がフッ素原子で、Ｒ^３が塩素原子のとき、Ｒ^２とＲ^４は同時に水素原子を表すことはなく、（ｄ）Ｒ^１及びＲ^４が同時に水素原子を表し、Ｒ^３がトリフルオロメチル基のとき、Ｒ^２はメチル基，メトキシ基，フッ素原子，ヨウ素原子ではなく、（ｅ）Ｒ^１が水素原子で、Ｒ^３がトリフルオロメチル基で、Ｒ^４が塩素原子又はメチル基のとき、Ｒ^２は水酸基又はメトキシ基ではなく、（ｆ）Ｒ^２が水素原子で、Ｒ^３がトリフルオロメチル基で、Ｒ^４が塩素原子又はメチル基のとき、Ｒ^１は水酸基又はメトキシ基ではなく、（ｇ）Ｒ^１が水素原子で、Ｒ^３がメチル基で、Ｒ^４が塩素原子のとき、Ｒ^２は水酸基又はメトキシ基ではなく、（ｈ）Ｒ^２が水素原子で、Ｒ^３がメチル基で、Ｒ^４が塩素原子のとき、Ｒ^１は水酸基又はメトキシ基ではない。）
で示される新規な１Ｈ−イミダゾキノリン誘導体、又はその塩に関するものである。
【０００６】
本発明の第二の態様によれば、前記一般式（Ｉ）で示される化合物中、
（１） Ｒ^３がアルキル基で、Ｒ^４がアルキル基又はフッ素原子である化合物、又はその塩
（２） Ｒ^１が水酸基で、Ｒ^４がフッ素原子である化合物、又はその塩
（３） Ｒ^２が水酸基で、Ｒ^４がフッ素原子である化合物、又はその塩
（４） Ｒ^２がアルコキシ基で、Ｒ^４が塩素原子以外のハロゲン原子である化合物、又はその塩
（５） Ｒ^３がハロゲン原子で、Ｒ^４がアルキル基又はハロゲン原子である化合物、又はその塩
（６） Ｒ^３がハロゲノアルキル基で、Ｒ^４がフッ素原子である化合物、又はその塩が提供される。
【０００７】
更に、本発明の好ましい態様によれば、以下の（ａ）〜（ｎ）の中から選ばれる化合物又はその塩が提供される。
（ａ）４，７−ジクロロ−２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｂ）４，７−ジクロロ−２−（２−ヒドロキシフェニル）−１−［２−（１−ピペラジニル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｃ）２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｄ）２−（２−ヒドロキシフェニル）−１−［２−（１−ピペラジニル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｅ）７−フルオロ−２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｆ）７−フルオロ−２−（２−ヒドロキシフェニル）−１−［２−（１−ピペラジニル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｇ）２−（２−ヒドロキシフェニル）−４−メチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｈ）２−（２−ヒドロキシフェニル）−４−メチル−１−［２−（１−ピペラジニル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｉ）２−（２−ヒドロキシフェニル）−７−メチル−１−［２−（１−ピペラジニル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｊ）７−クロロ−４−メチル−２−（２−ニトロフェニル）−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｋ）４−クロロ−２−（２−ヒドロキシフェニル）−７−メチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｌ）４−クロロ−７−フルオロ−２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｍ）２−（２−ヒドロキシフェニル）−４，７−ジメチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（ｎ）７−フルオロ−２−（２−ヒドロキシフェニル）−４−メチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
【０００８】
【発明の実施の形態】
以下、本発明の前記一般式（Ｉ）で示される化合物について具体的に説明する。
本発明の前記一般式（Ｉ）中、Ｒ^１で示されるハロゲン原子・水酸基・アルコキシカルボニル基から選択される置換基を有してもよいアルコキシ基における置換基において、置換基の個数，種類及び置換位置は特に限定されず、２個以上の置換基が存在する場合には、それらは互いに同一でも異なっていてもよい。置換可能なハロゲン原子としては、例えば、フッ素原子，塩素原子，臭素原子，ヨウ素原子が挙げられ、アルコキシカルボニル基としては、例えば、メトキシカルボニル基，エトキシカルボニル基，ｎ−プロポキシカルボニル基，ｎ−ブトキシカルボニル基等が挙げられる。
【０００９】
前記一般式（Ｉ）において、Ｒ^１，Ｒ^２及びＲ^４で示されるアルコキシ基としては、例えば、メトキシ基，エトキシ基，ｎ−プロポキシ基，イソプロポキシ基，ｎ−ブトキシ基，イソブトキシ基，ｓｅｃ−ブトキシ基，ｔｅｒｔ−ブトキシ基等が挙げられ、Ｒ^１，Ｒ^２，Ｒ^３及びＲ^４で示されるアルキル基としては、例えば、メチル基，エチル基，ｎ−プロピル基，イソプロピル基，ｎ−ブチル基，イソブチル基，ｓｅｃ−ブチル基，ｔｅｒｔ−ブチル基，ｎ−ペンチル基，イソペンチル基，ネオペンチル基，ｎ−ヘキシル基等が挙げられる。
【００１０】
前記一般式（Ｉ）において、Ｒ^１及びＲ^３で示されるハロゲノアルキル基としては、例えばトリフルオロメチル基，トリクロロメチル基，トリブロモメチル基，ペンタフルオロエチル基，ペンタクロロエチル基，ペンタブロモエチル基等が挙げられ、Ｒ^１で示されるアシルオキシ基としては、アセチルオキシ基，プロピオニルオキシ基等が挙げられ、Ｒ^１，Ｒ^２，Ｒ^３及びＲ^４で示されるハロゲン原子としては、フッ素原子，塩素原子，臭素原子，ヨウ素原子が挙げられ、Ｒ^４で示されるアラルキルオキシ基としては、例えば、ベンジルオキシ基，フェネチルオキシ基等が挙げられる。
【００１１】
本発明の前記一般式（Ｉ）で示される化合物は必要に応じて塩、好ましくは薬理学的に許容しうる塩に変換することも、又は生成した塩から遊離塩基に変換することもできる。本発明化合物の塩としては、酸付加塩が挙げられ、例えば、塩酸，臭化水素酸，ヨウ化水素酸，硫酸，硝酸，燐酸等の鉱酸塩、あるいはギ酸，酢酸，プロピオン酸，酪酸，イソ酪酸，吉草酸，イソ吉草酸，ピバル酸，トリフルオロ酢酸，アクリル酸，オレイン酸，マレイン酸，フマル酸，クエン酸，シュウ酸，コハク酸，酒石酸，リンゴ酸，マロン酸，乳酸，グルタル酸，セバシン酸，グルコン酸，エナント酸，カプリル酸，ノナン酸，カプリン酸，ラウリン酸，パルミチン酸，ミリスチン酸，ステアリン酸，ヘプタデカン酸，ウンデカン酸，マンデル酸，グリコール酸，ソルビン酸，メタンスルホン酸，エタンスルホン酸，ベンゼンスルホン酸，安息香酸，フタル酸，テレフタル酸，ケイ皮酸，ｐ−トルエンスルホン酸，ニコチン酸，ピクリン酸，アジピン酸，アスパラギン酸，グルタミン酸，１０−カンファースルホン酸及びこれらの光学活性体等の有機酸塩が挙げられる。
【００１２】
本発明の前記一般式（Ｉ）で示される化合物中、１個又は２個以上の不斉炭素を有する化合物には光学異性体，ジアステレオ異性体が存在し得るが、本発明にはこれら光学活性体及びその混合物，ラセミ体並びにそれらの塩も包含される。
【００１３】
本発明の前記一般式（Ｉ）で示される化合物又はその塩は、製造条件により任意の結晶形として存在することができ、又、任意の水和物又は溶媒和物として存在することができるが、これらの結晶形や水和物又は溶媒和物及びそれらの混合物も本発明の範囲に包含される。
【００１４】
本発明の好ましい化合物としては、例えば、以下の化合物及びそれらの塩を挙げることができるが、本発明はこれらの例に限定されることはない。
（１） ４，７−ジクロロ−２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（２） ４，７−ジクロロ−２−（２−ヒドロキシフェニル）−１−［２−（１−ピペラジニル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（３） ２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（４） ２−（２−ヒドロキシフェニル）−１−［２−（１−ピペラジニル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（５） ７−フルオロ−２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（６） ７−フルオロ−２−（２−ヒドロキシフェニル）−１−［２−（１−ピペラジニル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（７） ２−（２−ヒドロキシフェニル）−４−メチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（８） ２−（２−ヒドロキシフェニル）−４−メチル−１−［２−（１−ピペラジニル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（９） ２−（２−ヒドロキシフェニル）−７−メチル−１−［２−（１−ピペラジニル）エチル］−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（１０） ７−クロロ−４−メチル−２−（２−ニトロフェニル）−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（１１） ４−クロロ−２−（２−ヒドロキシフェニル）−７−メチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（１２） ４−クロロ−７−フルオロ−２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（１３） ２−（２−ヒドロキシフェニル）−４，７−ジメチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
（１４） ７−フルオロ−２−（２−ヒドロキシフェニル）−４−メチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
【００１５】
本発明の前記一般式（Ｉ）で示される新規な１Ｈ−イミダゾキノリン誘導体は、例えば以下の方法により製造することができるが、本発明化合物の製造方法はこれらの方法に限定されるわけではない。
【００１６】
本発明化合物の第一の製造方法として、前記一般式（Ｉ）で示される化合物は、以下の様にして製造することができる。
【化３】

（式中、Ｂｏｃはｔｅｒｔ−ブトキシカルボニル基を表し、Ｒ^１，Ｒ^２，Ｒ^３，Ｒ^４及びＸは前述と同意義を表す。）
【００１７】
即ち、工程１においては、一般式（ＩＩ）の化合物と次の一般式（ＩＶ）
【化４】

（式中、Ｒ^１及びＲ^２は前述と同意義を表す。）
で示される化合物を、２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノンの存在下、アセトニトリル，１，４−ジオキサン，テトラヒドロフラン，１，２−ジクロロエタン，トルエン等の溶媒中、０℃から溶媒の還流温度の間で反応することにより、一般式（ＩＩＩ）の化合物を得ることができる。
【００１８】
次に工程２においては、一般式（ＩＩＩ）の化合物を、酢酸エチル，塩化メチレン，１，２−ジクロロエタン，１，４−ジオキサン，メタノール，エタノール，ｎ−プロパノール，Ｎ，Ｎ−ジメチルホルムアミド，テトラヒドロフラン，水，又はこれらの混合溶媒等の溶媒中で、例えば、塩酸，塩化水素酢酸エチル溶液，塩化水素エタノール溶液，硫酸，臭化水素酸，トリフルオロ酢酸，ｐ−トルエンスルホン酸，メタンスルホン酸等の酸を用いて、０℃から溶媒の還流温度の間で反応することにより、前記一般式（Ｉ）の化合物を得ることができる。
【００１９】
本発明化合物の第二の製造方法として、一般式（Ｉ）の化合物の内、Ｒ^１としてアミノ基を有する化合物は、Ｒ^１がニトロ基である前記一般式（ＩＩＩ）の化合物を適当な還元法、例えば、白金，ラネーニッケル，パラジウム炭素等の金属触媒を用いた接触還元法、塩化ニッケルと水素化ホウ素ナトリウムを用いた還元法、鉄粉と塩酸を用いた還元法等を用いて、水，メタノール，エタノール，テトラヒドロフラン等の溶媒又はこれらの混合溶媒中、０℃から溶媒の還流温度の間で還元反応を行なって、Ｒ^１がアミノ基である前記一般式（ＩＩＩ）の化合物へと変換した後、第一の製造方法の工程２と同様の脱保護反応を行うことにより得ることができる。
【００２０】
本発明化合物の第三の製造方法として、一般式（Ｉ）の化合物の内、Ｒ^１として置換基を有してもよいアルコキシ基又はアシルオキシ基を有する化合物は、Ｒ^１が水酸基である前記一般式（Ｉ）の化合物を、ハロゲン化アルキル，クロロ酢酸エチル，２−クロロエタノール，２−ブロモエタノール等の適当なアルキル化試薬や塩化アセチル，無水酢酸等の適当なアシル化試薬を用いて、Ｎ，Ｎ−ジメチルホルムアミド，塩化メチレン，テトラヒドロフラン，トルエン，ピリジン，ニトロベンゼン，１，２−ジクロロエタン，１，４−ジオキサン，メタノール，エタノール，ｎ−プロパノール又はこれらの混合溶媒等の溶媒の存在下又は非存在下、トリエチルアミン，炭酸カリウム等の塩基の存在下又は非存在下に、０℃から２００℃の間で反応を行うことにより得ることができる。あるいは、Ｒ^１が水酸基である前記一般式（ＩＩＩ）の化合物を同様に処理した後、更に第一の製造方法の工程２と同様の反応を行うことにより、Ｒ^１が置換基を有してもよいアルコキシ基又はアシルオキシ基である一般式（Ｉ）の化合物を得ることができる。
【００２１】
本発明化合物の第四の製造方法として、一般式（Ｉ）の化合物の内、Ｒ^４として水酸基を有する化合物は、Ｒ^４がベンジルオキシ基である前記一般式（ＩＩＩ）の化合物を、白金，パラジウム炭素，ラネーニッケル，パールマンズ試薬等の金属触媒を用いて、水，メタノール，エタノール，ｎ−プロパノール，酢酸，又はこれらの混合溶媒中、塩酸等の酸の存在下又は非存在下、室温から溶媒の還流温度の間で、水素源として水素ガス，シクロヘキセン，シクロヘキサジエン，ギ酸，ギ酸アンモニウム，２−プロパノール等を用いて，常圧から２００Ｐａの水素圧で、水素化分解反応を行い、更に第一の製造方法の工程２と同様の脱保護反応を行うことにより得ることができる。
【００２２】
本発明化合物の第五の製造方法として、一般式（Ｉ）の化合物の内、Ｒ^４としてアルコキシ基又はアラルキルオキシ基を有する化合物は、Ｒ^４が水酸基である前記一般式（ＩＩＩ）の化合物を、ハロゲン化アルキル，ハロゲン化ベンジル等の適当なアルキル化試薬を用いて、Ｎ，Ｎ−ジメチルホルムアミド，塩化メチレン，テトラヒドロフラン，トルエン，ピリジン，ニトロベンゼン，１，２−ジクロロエタン，１，４−ジオキサン，メタノール，エタノール，ｎ−プロパノール又はこれらの混合溶媒等の溶媒の存在下又は非存在下、トリエチルアミン，炭酸カリウム等の塩基の存在下又は非存在下に、０℃から２００℃の間で反応を行うことにより、Ｒ^４がアルコキシ基又はアラルキルオキシ基である前記一般式（ＩＩＩ）の化合物へと変換し、更に第一の製造方法の工程２と同様の脱保護反応を行うことにより得ることができる。
【００２３】
本発明化合物の製造方法において、一般式（ＩＩ）で示される化合物は、例えば、特開２０００−１１９２７１号公報、特開２００２−１６１０９５号公報、特願２００１−２４８４６８号に開示されており、これらの文献に記載の方法に従って製造できる。尚、一部新規の化合物については、その製造方法を参考例として記載した。
【００２４】
この様にして製造される前記一般式（Ｉ）で示される新規な１Ｈ−イミダゾキノリン誘導体、又はその塩を有効成分とする医薬は、通常、カプセル剤，錠剤，細粒剤，顆粒剤，散剤，シロップ剤，ドライシロップ剤，液剤等の経口投与製剤、あるいは注射剤，坐剤，点眼剤，眼軟膏剤，点耳剤，点鼻剤，外皮用剤，吸入剤等の非経口投与製剤として投与される。
【００２５】
これらの製剤は、本発明の前記一般式（Ｉ）で示される化合物、及びその塩、並びにそれらの水和物，溶媒和物からなる群から選ばれる１種又は２種以上の化合物と、薬理学的，製剤学的に許容しうる添加物の１種又は２種以上を加え、常法により製造できる。例えば、経口投与製剤及び坐剤にあっては、賦形剤（乳糖，Ｄ−マンニトール，トウモロコシデンプン，結晶セルロース等），崩壊剤（カルボキシメチルセルロース，カルボキシメチルセルロースカルシウム，部分アルファー化デンプン，クロスカルメロースナトリウム，クロスポビドン等），結合剤（ヒドロキシプロピルセルロース，ヒドロキシプロピルメチルセルロース，ポリビニルピロリドン等），滑沢剤（ステアリン酸マグネシウム，タルク，硬化油，ジメチルポリシロキサン，含水二酸化ケイ素，軽質無水ケイ酸，カルナウバロウ等），コーティング剤（ヒドロキシプロピルメチルセルロース，白糖，酸化チタン等），可塑剤（クエン酸トリエチル，ポリエチレングリコール，グリセリン脂肪酸エステル等），基剤（ポリエチレングリコール，ハードファット等）等の製剤用成分が、注射剤あるいは点眼剤，点耳剤等にあっては水性あるいは用時溶解型剤型を構成しうる溶解剤ないし溶解補助剤（注射用水，生理食塩水，プロピレングリコール等），ｐＨ調節剤（無機又は有機の酸あるいは塩基），等張化剤（塩化ナトリウム，ブドウ糖，グリセリン等），安定化剤（安息香酸，クエン酸，亜硫酸水素ナトリウム等）等の製剤用成分が、又、眼軟膏剤，外皮用剤にあっては、軟膏剤，クリーム剤，貼付剤として適切な製剤用成分（白色ワセリン，マクロゴール，グリセリン，流動パラフィン，グリセリン脂肪酸エステル，ポリエチレングリコール脂肪酸エステル，カルボキシビニルポリマー，アクリル系粘着剤，ゴム系粘着剤，シリコン樹脂，綿布等）が、吸入剤にあっては噴射剤（二酸化炭素，プロパン，窒素等），溶解補助剤（エタノール，プロピレングリコール等），界面活性剤（トリオレイン酸ソルビタン等），賦形剤（乳糖等）が使用される。
【００２６】
本発明化合物又はその塩のヒトに対する投与量は、例えば、通常成人の場合、一日量として、経口投与で０．１〜１０００ｍｇ程度、非経口投与で０．０１〜５００ｍｇ程度を１日１回又は数回に分けて投与することができる。もっとも、その投与量は治療又は予防の目的、疾患の部位や種類、投与経路・剤形、患者の年齢や症状などに応じて、適宜増減することが望ましい。
【００２７】
【実施例】
以下、本発明を参考例及び実施例によって説明するが、本発明はこれらの例に限定されるものではない。
尚、例における略語はそれぞれ次の意味を表す。Ｂｏｃ： ｔｅｒｔ−ブトキシカルボニル，Ｍｅ：メチル，Ｅｔ：エチル，ｎ−Ｐｒ：ｎ−プロピル，ｉｓｏ−Ｐｒ：イソプロピル，Ｂｎ：ベンジル，Ａｃ：アセチル，ＤＭＳＯ−ｄ_６：ジメチルスルホキシド−ｄ_６，ａｑ．：水性，ＡＴＲ：全反射測定法
【００２８】
参考例１
４’−フルオロ−２−ニトロ−２’−（ペンタフルオロプロピオンアミド）アセトフェノン
２’−アミノ−４’−フルオロ−２−ニトロアセトフェノン５．００ｇのテトラヒドロフラン３０ｍｌ溶液に、氷冷下ペンタフルオロプロピオン酸無水物５．２ｍｌを滴下し、１時間室温で攪拌した。反応混合物に水を加え、析出結晶を濾取して、水及びジイソプロピルエーテルとｎ−ヘプタンの混液で順次洗浄し、７．６５ｇの淡黄色結晶を得た。酢酸エチルとジイソプロピルエーテルの混液から再結晶して、融点１４３．５〜１４４℃の無色結晶を得た。
元素分析値 Ｃ_１１Ｈ_６Ｆ_６Ｎ_２Ｏ_４
理論値（％）Ｃ，３８．３９； Ｈ，１．７６； Ｎ，８．１４
実験値（％）Ｃ，３８．１０； Ｈ，１．９６； Ｎ，７．８４
【００２９】
参考例２
７−フルオロ−３−ニトロ−２−ペンタフルオロエチル−４−キノリノール
４’−フルオロ−２−ニトロ−２’−（ペンタフルオロプロピオンアミド）アセトフェノン７．５０ｇのテトラヒドロフラン７５ｍｌ溶液に、４−（ジメチルアミノ）ピリジン３．２０ｇを加えて１時間還流した。反応混合物を氷水に注ぎ、濃塩酸を加えてｐＨ２に調整後、ジイソプロピルエーテルを加え、析出した結晶を濾取し、水とジイソプロピルエーテルで順次洗浄して４．００ｇの褐色結晶を得た。酢酸エチルとメタノールの混液から再結晶して、淡褐色結晶を得た。
ＮＭＲスペクトル δ（ＤＭＳＯ−ｄ_６）ｐｐｍ：７．４６（１Ｈ，ｄｄｄ，Ｊ＝１０，９，２．５Ｈｚ），７．６３（１Ｈ，ｄｄ，Ｊ＝１０，２．５Ｈｚ），８．３４（１Ｈ，ｄｄ，Ｊ＝９，６．５Ｈｚ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１５４８，１３６７
マススペクトルｍ／ｚ：３２５（Ｍ^＋−１）
【００３０】
参考例３
７−メチル−３−ニトロ−４−キノリノール
２’−アミノ−４’−メチル−２−ニトロアセトフェノン８．００ｇのＮ，Ｎ−ジメチルホルムアミド３０ｍｌ溶液に、氷冷下Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタール１６．４ｍｌを加えて室温で１４時間攪拌した。反応混合物に水を加え、１０％塩酸を加えてｐＨ２に調整後、析出した結晶を濾取し、水とジエチルエーテルで順次洗浄して８．３６ｇの淡褐色結晶を得た。Ｎ，Ｎ−ジメチルホルムアミドと水の混液から再結晶して、融点３００℃以上の淡褐色結晶を得た。
元素分析値 Ｃ_１０Ｈ_８Ｎ_２Ｏ_３
理論値（％）Ｃ，５８．８２； Ｈ，３．９５； Ｎ，１３．７２
実験値（％）Ｃ，５８．６０； Ｈ，３．９７； Ｎ，１３．５７
【００３１】
参考例４
７−ベンジルオキシ−３−ニトロ−２−トリフルオロメチル−４−キノリノール
６０％水素化ナトリウム１．４５ｇのＮ，Ｎ−ジメチルホルムアミド６０ｍｌ懸濁液中に、室温攪拌下、ベンジルアルコール３．８０ｍｌを滴下後、７−フルオロ−３−ニトロ−２−トリフルオロメチル−４−キノリノール５．００ｇを少量ずつ加え、混合物を６０℃で４時間攪拌した。反応混合物に氷水を加え、１０％塩酸を加えて酸性にして、析出した結晶を濾取し、水とジイソプロピルエーテルで順次洗浄して５．６０ｇの淡黄褐色結晶を得た。酢酸エチルから再結晶して、融点２７５〜２７７℃（分解）の淡黄色板状晶を得た。
元素分析値 Ｃ_１７Ｈ_１１Ｆ_３Ｎ_２Ｏ_４
理論値（％）Ｃ，５６．０５； Ｈ，３．０４； Ｎ，７．６９
実験値（％）Ｃ，５５．８６； Ｈ，３．１６； Ｎ，７．６０
【００３２】
参考例５
４−クロロ−７−フルオロ−３−ニトロ−２−ペンタフルオロエチルキノリン７−フルオロ−３−ニトロ−２−ペンタフルオロエチル−４−キノリノール３．８４ｇとオキシ塩化リン１１ｍｌの混合物を５時間還流した。放冷後、反応混合物を少量ずつ氷水中に注いで攪拌し、トルエンで抽出した。トルエン層を水洗し、脱水後、溶媒を留去して２．５０ｇの褐色結晶を得た。
ＮＭＲスペクトル δ（ＣＤＣｌ_３）ｐｐｍ：７．７３（１Ｈ，ｄｄｄ，Ｊ＝９，８．５，２．５Ｈｚ），７．９６（１Ｈ，ｄｄ，Ｊ＝８．５，２．５Ｈｚ），８．４２（１Ｈ，ｄｄ，Ｊ＝９，５．５Ｈｚ）
ＩＲスペクトル ν（ＫＢｒ）ｃｍ^−１：１５５０，１３２１
【００３３】
参考例５の方法に従って、参考例６の化合物を得た。
【００３４】
参考例６
４−クロロ−７−メチル−３−ニトロキノリン
性状 淡褐色結晶
融点 １００〜１０２．５℃
ＮＭＲスペクトル δ（ＣＤＣｌ_３）ｐｐｍ：２．６４（３Ｈ，ｓ），７．６４（１Ｈ，ｄｄ，Ｊ＝８．５，１Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝１Ｈｚ），８．３２（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），９．２４（１Ｈ，ｓ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１５１４，１３３８
マススペクトルｍ／ｚ：２２３，２２５（Ｍ^＋＋１，３：１）
【００３５】
参考例７
２，４，７−トリクロロ−３−ニトロキノリン
７−クロロ−４−ヒドロキシ−３−ニトロキノリン−２（１Ｈ）−オン７．４５ｇと二塩化フェニルホスホリル１７．３ｍｌの混合物を１４０℃で１．５時間攪拌した。反応混合物を水中に注ぎ、析出した結晶を濾取し、水で洗浄して８．４０ｇの淡褐色結晶を得た。酢酸エチルから再結晶して、融点１１９．５〜１２０．５℃の無色結晶を得た。
元素分析値 Ｃ_９Ｈ_３Ｃｌ_３Ｎ_２Ｏ_２・１／８Ｈ_２Ｏ
理論値（％）Ｃ，３８．６４； Ｈ，１．１７； Ｎ，１０．０１
実験値（％）Ｃ，３９．０２； Ｈ，１．２７； Ｎ，９．６４
【００３６】
参考例８
４−［２−［（２，７−ジクロロ−３−ニトロキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
２，４，７−トリクロロ−３−ニトロキノリン２．００ｇ，トリエチルアミン１．２ｍｌ及びＮ，Ｎ−ジメチルホルムアミド６ｍｌの混合物に、室温攪拌下、４−（２−アミノエチル）−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル２．１０ｇのＮ，Ｎ−ジメチルホルムアミド２ｍｌ溶液を滴下し、室温で３０分間攪拌した。反応混合物に氷水を加えて酢酸エチルで抽出した。抽出液を水及び飽和食塩水で順次洗浄後、脱水し、溶媒を留去した。残渣をジイソプロピルエーテルで洗浄して、２．８８ｇの黄色結晶を得た。酢酸エチルから再結晶して、融点１９４〜１９５℃の黄色板状晶を得た。
元素分析値 Ｃ_２１Ｈ_２６Ｃｌ_２Ｎ_４Ｏ_４・１／８Ｈ_２Ｏ
理論値（％）Ｃ，５３．４８； Ｈ，５．６１； Ｎ，１１．８８
実験値（％）Ｃ，５３．７７； Ｈ，５．６４； Ｎ，１１．５０
【００３７】
参考例８の方法に従って、参考例９〜１２の化合物を得た。
【００３８】
参考例９
４−［２−［（７−フルオロ−３−ニトロ−２−ペンタフルオロエチルキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
性状 黄色結晶（再結晶溶媒：ＭｅＯＨ）
融点 １６８〜１６９℃
元素分析値 Ｃ_２３Ｈ_２６Ｆ_６Ｎ_４Ｏ_４
理論値（％）Ｃ，５１．４９； Ｈ，４．８９； Ｎ，１０．４４
実験値（％）Ｃ，５１．２９； Ｈ，４．８９； Ｎ，１０．２３
【００３９】
参考例１０
４−［２−［（７−メチル−３−ニトロキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
性状 黄色針状晶（再結晶溶媒：ＭｅＯＨ）
融点 １５０〜１５１℃
元素分析値 Ｃ_２２Ｈ_３０Ｎ_４Ｏ_４
理論値（％）Ｃ，６３．７５； Ｈ，７．３０； Ｎ，１３．５２
実験値（％）Ｃ，６３．６４； Ｈ，７．２４； Ｎ，１３．４６
【００４０】
参考例１１
４−［２−［（７−ベンジルオキシ−３−ニトロ−２−トリフルオロメチルキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル性状 黄色板状晶（再結晶溶媒：ＡｃＯＥｔ−ｉｓｏ−Ｐｒ_２Ｏ）
融点 １９５〜１９６℃
元素分析値 Ｃ_２９Ｈ_３３Ｆ_３Ｎ_４Ｏ_５
理論値（％）Ｃ，６０．６２； Ｈ，５．７９； Ｎ，９．７５
実験値（％）Ｃ，６０．５０； Ｈ，５．７６； Ｎ，９．５５
【００４１】
参考例１２
４−［２−［（７−フルオロ−３−ニトロ−２−トリフルオロメチルキノリン−４−イル）アミノ］エチル］−１−ピペラジンカルボン酸ｔｅｒｔ−ブチル
性状 黄色液体
ＮＭＲスペクトル δ（ＤＭＳＯ−ｄ_６）ｐｐｍ：１．３９（９Ｈ，ｓ），２．３６（４Ｈ，ｔ，Ｊ＝５Ｈｚ），２．６３（２Ｈ，ｔ，Ｊ＝６Ｈｚ），３．２５（４Ｈ，ｔ，Ｊ＝５Ｈｚ），３．４３（２Ｈ，ｑ，Ｊ＝６Ｈｚ），７．７０（１Ｈ，ｄｄｄ，Ｊ＝１０，９，２．５Ｈｚ），７．８０（１Ｈ，ｄｄ，Ｊ＝１０，２．５Ｈｚ），７．８５（１Ｈ，ｂｒｓ），８．５４（１Ｈ，ｄｄ，Ｊ＝９，６Ｈｚ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１６８９
マススペクトルｍ／ｚ：４８６（Ｍ^＋−１）
【００４２】
参考例１３
４−［２−［（３−アミノ−２，７−ジクロロキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
塩化ニッケル・６水和物０．７１ｇのメタノール１５ｍｌ溶液中に氷冷攪拌下、水素化ホウ素ナトリウム０．１２ｇを添加した後、内温５℃以下で４−［２−［（２，７−ジクロロ−３−ニトロキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル２．７８ｇのメタノール６０ｍｌとテトラヒドロフラン２０ｍｌの懸濁液を加えた。続いて、内温５℃以下で水素化ホウ素ナトリウム０．６７ｇを少量ずつ添加し、室温で１時間攪拌した。反応混合物の不溶物を濾去し、濾液を濃縮した後、残渣に１０％塩化アンモニウム水溶液を加えて酢酸エチルで抽出した。抽出液は水と飽和食塩水で順次洗浄後、脱水し、溶媒を留去した。得られた暗褐色液体を酢酸エチル−ｎ−ヘプタン（１：３→２：５）を溶出溶媒としたシリカゲルカラムクロマトグラフィーで精製した後、ジイソプロピルエーテルで洗浄して１．８１ｇの淡黄色結晶を得た。酢酸エチルから再結晶して、融点１５２〜１５３℃の淡黄色針状晶を得た。
元素分析値 Ｃ_２１Ｈ_２８Ｃｌ_２Ｎ_４Ｏ_２
理論値（％）Ｃ，５７．４０； Ｈ，６．４２； Ｎ，１２．７５
実験値（％）Ｃ，５７．３４； Ｈ，６．４０； Ｎ，１２．６９
【００４３】
参考例１３の方法に従って、参考例１４〜１７の化合物を得た。
【００４４】
参考例１４
４−［２−［（３−アミノ−７−フルオロ−２−ペンタフルオロエチルキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
性状 黄色結晶（再結晶溶媒：ＡｃＯＥｔ−ｉｓｏ−Ｐｒ_２Ｏ）
融点 １２２〜１２３℃
元素分析値 Ｃ_２３Ｈ_２８Ｆ_６Ｎ_４Ｏ_２
理論値（％）Ｃ，５４．５４； Ｈ，５．５７； Ｎ，１１．０６
実験値（％）Ｃ，５４．３５； Ｈ，５．４８； Ｎ，１０．７８
【００４５】
参考例１５
４−［２−［（３−アミノ−７−メチルキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
性状 黄褐色結晶（再結晶溶媒：ＡｃＯＥｔ−ｉｓｏ−Ｐｒ_２Ｏ）
融点 １４２．５〜１４４．５℃
元素分析値 Ｃ_２２Ｈ_３２Ｎ_４Ｏ_２・１／４Ｈ_２Ｏ
理論値（％）Ｃ，６７．９２； Ｈ，８．４２； Ｎ，１４．４０
実験値（％）Ｃ，６８．３２； Ｈ，８．３８； Ｎ，１４．０２
【００４６】
参考例１６
４−［２−［（３−アミノ−７−ベンジルオキシ−２−トリフルオロメチルキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
性状 淡黄色液体
ＮＭＲスペクトル δ（ＤＭＳＯ−ｄ_６）ｐｐｍ：０．９１−１．０３（２Ｈ，ｍ），１．３８（９Ｈ，ｓ），１．４６−１．６３（５Ｈ，ｍ），２．５８−２．７０（２Ｈ，ｍ），３．３１（２Ｈ，ｑ，Ｊ＝７Ｈｚ），３．８１−３．９２（２Ｈ，ｍ），４．７１（２Ｈ，ｓ），５．２３（２Ｈ，ｓ），５．２９（１Ｈ，ｔ，Ｊ＝６．５Ｈｚ），７．２３（１Ｈ，ｄｄ，Ｊ＝９，２．５Ｈｚ），７．２８（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．３３（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．４０（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．４９（２Ｈ，ｄ，Ｊ＝７．５Ｈｚ），８．０３（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１６８２
マススペクトルｍ／ｚ：５４３（Ｍ^＋−１）
【００４７】
参考例１７
４−［２−［（３−アミノ−７−フルオロ−２−トリフルオロメチルキノリン−４−イル）アミノ］エチル］−１−ピペラジンカルボン酸ｔｅｒｔ−ブチル
性状 黄色液体
ＮＭＲスペクトル δ（ＤＭＳＯ−ｄ_６）ｐｐｍ：１．３９（９Ｈ，ｓ），２．３２（４Ｈ，ｔ，Ｊ＝５Ｈｚ），２．４７（２Ｈ，ｔ，Ｊ＝６Ｈｚ），３．２４（４Ｈ，ｔ，Ｊ＝５Ｈｚ），３．３５（２Ｈ，ｑ，Ｊ＝６Ｈｚ），５．１３（２Ｈ，ｓ），５．４３（１Ｈ，ｔ，Ｊ＝６Ｈｚ），７．４３（１Ｈ，ｄｄｄ，Ｊ＝１０．５，１０，３Ｈｚ），７．５３（１Ｈ，ｄｄ，Ｊ＝１０．５，３Ｈｚ），８．２１（１Ｈ，ｄｄ，Ｊ＝１０，６Ｈｚ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１６９０
マススペクトルｍ／ｚ：４５８（Ｍ^＋＋１）
【００４８】
参考例１８
４−［２−［４，７−ジクロロ−２−（２−ヒドロキシフェニル）−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
４−［２−［（３−アミノ−２，７−ジクロロキノリン−４−イル）アミノ］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル１．７１ｇ，サリチルアルデヒド０．６２ｇ及び２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン０．１９ｇのテトラヒドロフラン１７ｍｌ溶液を室温で５日間攪拌した。反応混合物に水及び炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。抽出液を炭酸水素ナトリウム水溶液，水，飽和食塩水で順次洗浄後、脱水し、溶媒を留去した。得られた液体を、酢酸エチル−ｎ−ヘプタン（１：３→３：５）を溶出溶媒としたシリカゲルカラムクロマトグラフィーで精製して、淡黄褐色液体０．６２ｇを得た。
ＮＭＲスペクトル δ（ＤＭＳＯ−ｄ_６）ｐｐｍ：０．７４−０．８８（２Ｈ，ｍ），１．１７−１．３１（３Ｈ，ｍ），１．３６（９Ｈ，ｓ），１．６７（２Ｈ，ｑ，Ｊ＝７Ｈｚ），２．４１−２．５８（２Ｈ，ｍ），３．６７−３．７８（２Ｈ，ｍ），４．５７（２Ｈ，ｔ，Ｊ＝７Ｈｚ），７．０４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．０９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．４７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．４９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．７９（１Ｈ，ｄｄ，Ｊ＝９，２Ｈｚ），８．１６（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．４１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．１４（１Ｈ，ｓ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１６８９
マススペクトルｍ／ｚ：５３９，５４１，５４３（Ｍ^＋−１；９：６：１）
【００４９】
参考例１８の方法に従って、参考例１９〜４９の化合物を得た。
【００５０】
【表１】

【００５１】
【表２】

【００５２】
【表３】

【００５３】
【表４】

【００５４】
【表５】

【００５５】
【表６】

【００５６】
参考例５０
４−［２−［７−メチル−２−（２−イソプロポキシフェニル）−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
４−［２−［２−（２−ヒドロキシフェニル）−７−メチル−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル０．５０ｇ，炭酸カリウム０．２３ｇのＮ，Ｎ−ジメチルホルムアミド２．５ｍｌ懸濁液に、ヨウ化イソプロピル０．３４ｇのＮ，Ｎ−ジメチルホルムアミド０．５ｍｌ溶液を滴下し、室温で２４時間攪拌した。反応混合物に水を加えて、析出した結晶を濾取し、水で洗浄して無色結晶０．５４ｇを得た。酢酸エチルとジイソプロピルエーテルの混液から再結晶して融点１１９〜１２０℃の無色結晶を得た。
元素分析値 Ｃ_３３Ｈ_３９Ｆ_３Ｎ_４Ｏ_３
理論値（％）Ｃ，６６．４３； Ｈ，６．５９； Ｎ，９．３９
実験値（％）Ｃ，６６．１０； Ｈ，６．５６； Ｎ，９．１７
【００５７】
参考例５０の方法に従って、参考例５１〜５４の化合物を得た。
【表７】

【００５８】
参考例５５
４−［２−［２−（２−アセチルオキシフェニル）−７−ベンジルオキシ−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
氷冷下、４−［２−［７−ベンジルオキシ−２−（２−ヒドロキシフェニル）−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル６．８２ｇとトリエチルアミン２．２ｍｌのテトラヒドロフラン６０ｍｌ溶液に、塩化アセチル０．８３ｍｌを滴下し、室温で３０分間攪拌した。反応混合物に氷水を加えて、酢酸エチルで抽出し、抽出液を水と飽和食塩水で順次洗浄後、脱水し、溶媒を留去して、淡黄色液体７．４２ｇを得た。
ＮＭＲスペクトル δ（ＤＭＳＯ−ｄ_６）ｐｐｍ：０．８０−０．９２（２Ｈ，ｍ），１．２５−１．３６（３Ｈ，ｍ），１．３６（９Ｈ，ｓ），１．７０（２Ｈ，ｑ，Ｊ＝７Ｈｚ），２．０２（３Ｈ，ｓ），２．４３−２．６０（２Ｈ，ｍ），３．７２−３．８１（２Ｈ，ｍ），４．５８（２Ｈ，ｔ，Ｊ＝７Ｈｚ），５．３８，（２Ｈ，ｓ），７．３６（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．４３（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．４５（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．５４（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．５４（２Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．６４（１Ｈ，ｄｄ，Ｊ＝９，２．５Ｈｚ），７．７２（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．７９（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．８４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．４１（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１７６９，１６８４
マススペクトルｍ／ｚ：６８９（Ｍ^＋＋１）
【００５９】
参考例５５の方法に従って、参考例５６の化合物を得た。
【００６０】
参考例５６
４−［２−［２−（２−アセチルオキシフェニル）−７−クロロ−４−メチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
性状：無色液体
ＮＭＲスペクトル δ（ＣＤＣｌ_３）ｐｐｍ：０．９８−１．１０（２Ｈ，ｍ），１．３０−１．５０（３Ｈ，ｍ），１．４４（９Ｈ，ｓ），１．８０（２Ｈ，ｑ，Ｊ＝８Ｈｚ），２．０４（３Ｈ，ｓ），２．５２−２．６５（２Ｈ，ｍ），３．０２（３Ｈ，ｓ），３．９２−４．１０（２Ｈ，ｍ），４．４６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），７．３４（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４５（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．５５−７．６５（３Ｈ，ｍ），８．０５（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．２４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１７７２，１６９２
マススペクトルｍ／ｚ：５６３，５６５（Ｍ^＋＋１；３：１）
【００６１】
参考例５７
４−［２−［２−（２−アセチルオキシフェニル）−７−ヒドロキシ−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
４−［２−［２−（２−アセチルオキシフェニル）−７−ベンジルオキシ−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル０．３０ｇとシクロヘキセン０．１４ｍｌのエタノール９ｍｌ溶液に、パールマンズ試薬３０ｍｇを加えて、１時間還流した。触媒を濾去し、濾液を濃縮後、残渣を酢酸エチル−ｎ−ヘプタン（１：４→１：１）を溶出溶媒としたシリカゲルカラムクロマトグラフィーで精製して、無色液体０．２６ｇを得た。
ＮＭＲスペクトル δ（ＤＭＳＯ−ｄ_６）ｐｐｍ：０．７９−０．９１（２Ｈ，ｍ），１．２４−１．３６（３Ｈ，ｍ），１．３６（９Ｈ，ｓ），１．６９（２Ｈ，ｑ，Ｊ＝７Ｈｚ），２．０２（３Ｈ，ｓ），２．４４−２．６１（２Ｈ，ｍ），３．７０−３．８１（２Ｈ，ｍ），４．５５（２Ｈ，ｔ，Ｊ＝７Ｈｚ），７．４４（１Ｈ，ｄｄ，Ｊ＝８，１Ｈｚ），７．４６（１Ｈ，ｄｄ，Ｊ＝９，２．５Ｈｚ），７．５３（１Ｈ，ｔｄ，Ｊ＝８，１Ｈｚ），７．５６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．７１（１Ｈ，ｔｄ，Ｊ＝８，１Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝８，１Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．２５（１Ｈ，ｓ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１７６９，１６８６
マススペクトルｍ／ｚ：５９９（Ｍ^＋＋１）
【００６２】
参考例５８
４−［２−［２−（２−ヒドロキシフェニル）−７−メトキシ−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
４−［２−［２−（２−アセチルオキシフェニル）−７−ヒドロキシ−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル０．６０ｇと炭酸カリウム０．１７ｇのＮ，Ｎ−ジメチルホルムアミド６ｍｌ懸濁液に、氷冷攪拌下、ヨウ化メチル０．１３ｍｌを滴下し、室温で２．５時間攪拌した。反応混合物に１０％水酸化ナトリウム水溶液１．５ｍｌを加えて、室温で２．５時間攪拌した後、水を加え酢酸エチルで抽出した。抽出液を水と飽和食塩水で順次洗浄し、脱水後、溶媒を留去した。残渣を酢酸エチル−ｎ−ヘプタン（１：４→１：１）を溶出溶媒としたシリカゲルカラムクロマトグラフィーで精製して、無色液体０．２３ｇを得た。
ＮＭＲスペクトル δ（ＤＭＳＯ−ｄ_６）ｐｐｍ：０．７５−０．８７（２Ｈ，ｍ），１．２０−１．３６（３Ｈ，ｍ），１．３６（９Ｈ，ｓ），１．６６（２Ｈ，ｑ，Ｊ＝７Ｈｚ），２．４３−２．５８（２Ｈ，ｍ），３．６９−３．７９（２Ｈ，ｍ），３．８３（３Ｈ，ｓ），４．４５（２Ｈ，ｔ，Ｊ＝７Ｈｚ），７．１８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．２９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．４４（１Ｈ，ｄｄ，Ｊ＝９，２．５Ｈｚ），７．５４（１Ｈ，ｄｄ，Ｊ＝８，１．５Ｈｚ），７．５５（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．６４（１Ｈ，ｔｄ，Ｊ＝８，１．５Ｈｚ），８．３１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．２１（１Ｈ，ｓ）
ＩＲスペクトル ν（ＡＴＲ）ｃｍ^−１：１６８７
マススペクトルｍ／ｚ：５６９（Ｍ^＋−１）
【００６３】
参考例５９
４−［２−［２−（２−アミノフェニル）−７−クロロ−４−メチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル
氷冷攪拌下、塩化ニッケル・６水和物０．２５ｇのメタノール２５ｍｌ溶液中に、水素化ホウ素ナトリウム０．０４ｇを添加した後、４−［２−［７−クロロ−４−メチル−２−（２−ニトロフェニル）−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル］エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル１．１７ｇのメタノール１０ｍｌ溶液を加えた。続いて、水素化ホウ素ナトリウム０．２０ｇを少量ずつ添加し、室温で３０分間攪拌した。反応混合物中の不溶物を濾去し、濾液を濃縮した後、残渣に１０％塩化アンモニウム水溶液を加えて酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、脱水し、溶媒を留去した。得られた残渣を酢酸エチルとジイソプロピルエーテルの混液で洗浄して１．００ｇの淡褐色結晶を得た。２−プロパノールから再結晶して、融点１８２〜１８３℃の無色結晶を得た。
元素分析値 Ｃ_２９Ｈ_３４ＣｌＮ_５Ｏ_２
理論値（％）Ｃ，６６．９７； Ｈ，６．５９； Ｎ，１３．４７
実験値（％）Ｃ，６６．８０； Ｈ，６．５１； Ｎ，１３．４６
【００６４】
実施例１
４，７−ジクロロ−２−（２−ヒドロキシフェニル）−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン・７／２フマル酸塩４−［２−（４，７−ジクロロ−２−（２−ヒドロキシフェニル）−１Ｈ−イミダゾ［４，５−ｃ］キノリン−１−イル）エチル］−１−ピペリジンカルボン酸ｔｅｒｔ−ブチル０．５８ｇとトリフルオロ酢酸１．５ｍｌの１，２−ジクロロエタン３ｍｌ溶液を、室温で３０分間攪拌した。反応混合物を濃縮し、残渣に２−プロパノールを加えて、析出した結晶を濾取し、０．４５ｇのトリフルオロ酢酸塩を得た。得られた塩に水を加え水酸化ナトリウム水溶液でアルカリ性とした後に、酢酸エチルと２−プロパノールの混液で抽出した。抽出液を脱水後、溶媒を留去して、酢酸エチルとジイソプロピルエーテルの混液で洗浄して、０．３６ｇの遊離塩基を得た。更に、常法によりフマル酸塩とし、エタノールから再結晶して、融点２１５〜２１８℃（分解）の淡褐色針状晶を得た。
元素分析値 Ｃ_２３Ｈ_２２Ｃｌ_２Ｎ_４Ｏ・７／２Ｃ_４Ｈ_４Ｏ_４・２Ｈ_２Ｏ
理論値（％）Ｃ，５０．２９； Ｈ，４．５６； Ｎ，６．３４
実験値（％）Ｃ，５０．３３； Ｈ，４．２３； Ｎ，６．０３
【００６５】
実施例１の方法に従って、実施例２〜４１の化合物を得た。
【００６６】
【表８】

【００６７】
【表９】

【００６８】
【表１０】

【００６９】
【表１１】

【００７０】
【表１２】

【００７１】
【表１３】

【００７２】
実施例４２
７−クロロ−２−［２−（２−ヒドロキシエトキシ）フェニル］−４−メチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン
７−クロロ−２−（２−ヒドロキシフェニル）−４−メチル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン０．５８ｇとトリエチルアミン０．２３ｍｌのＮ，Ｎ−ジメチルホルムアミド２．５ｍｌ溶液を５０℃で攪拌しながら、２−ブロモエタノール０．１２ｍｌのＮ，Ｎ−ジメチルホルムアミド０．５ｍｌ溶液を滴下後、５０℃で５時間攪拌した。反応混合物に水を加え、析出した結晶を濾取し、水で洗浄して、０．２８ｇの無色結晶を得た。メタノールから再結晶して、融点１１１〜１１２℃の無色結晶を得た。
元素分析値 Ｃ_２６Ｈ_２９ＣｌＮ_４Ｏ_２・５／２Ｈ_２Ｏ
理論値（％）Ｃ，６１．２３； Ｈ，６．７２； Ｎ，１０．９９
実験値（％）Ｃ，６１．１３； Ｈ，６．３２； Ｎ，１１．０５
【００７３】
以下、本発明化合物の優れた効果の一例として、ヒト細胞におけるＴＮＦ−αの産生阻害作用の試験結果を示す。尚、対照化合物としては、特開２０００−１１９２７１号公報に開示されている４−クロロ−２−フェニル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン（対照化合物Ａ）、特開２００２−１６１０９５号公報に開示されている１−［２−（２−モルホリニル）エチル］−２−（２−ピロリル）−４−トリフルオロメチル−１Ｈ−イミダゾ［４，５−ｃ］キノリン（対照化合物Ｂ）、特願２００１−２４８４６８号に開示されている７−クロロ−４−メチル−２−フェニル−１−［２−（４−ピペリジル）エチル］−１Ｈ−イミダゾ［４，５−ｃ］キノリン（対照化合物Ｃ）を用いた。
【００７４】
１．培養用の血液細胞の調製
健康な成人志願者に静脈穿刺して、ノボ・ヘパリン注 １０００ （ノボ・ノルディスク 社製）を１７０μｌ 含有するプラスチック試験管中へ全血を約５０ｍｌ採取した。これから末梢血単核細胞（ＰＢＭＣ：Ｐｅｒｉｐｈｅｒａｌ Ｂｌｏｏｄ Ｍｏｎｏｎｕｃｌｅａｒ Ｃｅｌｌ ）をＬｅｕｃｏＰＲＥＰ^ＴＭ（Ｂｅｃｔｏｎ Ｄｉｃｋｉｎｓｏｎ社製）細胞分離管によって調製し、２ｍＭ Ｌ−グルタミン（Ｌｉｆｅ Ｔｅｃｈｎｏｌｏｇｉｅｓ 社製）、２．５Ｕ／ｍｌペニシリン−２．５μｇ／ｍｌストレプトマイシン溶液（Ｌｉｆｅ Ｔｅｃｈｎｏｌｏｇｉｅｓ社製）を含有し、１０％牛胎児血清（Ｉｎｔｅｒｇｅｎ Ｃｏｍｐａｎｙ社製）を添加したＲＰＭＩ−１６４０ 培地（日水製薬株式会社製）中で、細胞密度１×１０^６個／ｍｌとなるように培養した。
２．被験化合物の調製
被験化合物は滅菌超純水やジメチルスルホキシドあるいは０．１Ｍ塩酸で可能なかぎり２０μＭとなるよう溶解してから生理食塩水で系列希釈して用いた。化合物は１０^−１１Ｍ〜１０^−５Ｍの濃度範囲で試験した。
３．細胞の薬物処置
予め１０μｌの被験化合物を添加した９６穴（平底）Ｍｉｃｒｏ Ｔｅｓｔ ＩＩＩ^ＴＭ ｔｉｓｓｕｅ ｃｕｌｔｕｒｅ ｐｌａｔｅ（Ｂｅｃｔｏｎ Ｄｉｃｋｉｎｓｏｎ社製）細胞培養用プレートに、先に調製した培地中のＰＢＭＣ１８０μｌを添加した。その３０分後更に、２０μｇ／ｍｌのリポポリサッカライド（ＬＰＳ）１０μｌを添加し、プレートにプラスチック製の蓋をして、５％二酸化炭素雰囲気において３７℃で１６時間インキュベートした。
【００７５】
４．ヒトＴＮＦ−αの定量
サンドイッチ法によるエンザイムイムノアッセイ法を構築して培養上清中のヒトＴＮＦ−αを定量した。９６ウェルのマイクロタイタープレートに希釈した抗サイトカイン抗体（捕捉抗体、又は一次抗体）を入れ、コーティングとした。ウェルの洗浄後、培養上清を適宜希釈してウェルに入れインキュベーションした。その後、サイトカインに対する検出抗体（又は二次抗体）、検出抗体に対するＨＲＰ（西洋わさびペルオキシターゼ；ｈｏｒｓｅｒａｄｉｓｈ ｐｅｒｏｘｉｄａｓｅ）抱合抗体（又は三次抗体）を、洗浄工程を挟みながら順次入れた。最終洗浄後、各ウェルにテトラメチルベンジジン溶液（ＤＡＫＯ社製）を入れ発色反応を開始した。０．５Ｍ硫酸で発色反応を停止した後、各ウェルの４５０ｎｍでの吸光度をＭ−Ｖｍａｘ ^ＴＭマイクロプレートリーダー（Ｍｏｌｅｃｕｌａｒ Ｄｅｖｉｃｅｓ社製）で測定した。サイトカインの濃度は定量ソフトウェアＳｏｆｔｍａｘ ^ＴＭ（Ｍｏｌｅｃｕｌａｒ Ｄｅｖｉｃｅｓ社製）で組換えサイトカインを標準品として使った検量線と比較して決定した。ヒトＴＮＦ−αの定量にはモノクローナル抗ヒトＴＮＦ−α（ＥＮＤＯＧＥＮ社製）、ポリクローナルウサギ抗ヒトＴＮＦ−α（Ｐｈａｒｍａ Ｂｉｏｔｅｃｈｎｏｌｏｇｉｅ Ｈａｎｎｏｖｅｒ社製）、ペルオキシダーゼ抱合ロバ抗ウサギＩｇＧ（Ｊａｃｋｓｏｎ ＩｍｍｕｎｏＲｅｓ． Ｌａｂｓ社製）、組換えヒトＴＮＦ−α（ＩＮＴＥＲＧＥＮ社製）をそれぞれ、捕捉、検出、ＨＲＰ抱合抗体及び検量線用の標準品に用いた。
各被験化合物の活性は、ＬＰＳと被験化合物で処理したときのヒトＴＮＦ−αの誘導量を、５０％抑制する濃度ＩＣ_５０値（ｎＭ）で表した。結果を表１４に示す。
【００７６】
【表１４】

【００７７】
これらの結果から、本発明化合物は優れたＴＮＦ−αの産生阻害作用を示すことが明らかである。
【００７８】
【発明の効果】
本発明化合物は優れたＴＮＦ−αの産生阻害作用を示し、ＴＮＦ−αに起因する疾患の予防又は治療剤として極めて有用である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel 1H-imidazoquinoline derivative which has a potent tumor necrosis factor (TNF) -α production inhibitory activity and is useful as a medicament for preventing or treating TNF-α-mediated diseases in humans or animals. Or a salt thereof.
These TNF-α-mediated diseases include, for example, chronic inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, etc.), allergic rhinitis, atopic dermatitis, contact dermatitis, asthma, sepsis, septic shock , Various autoimmune diseases [autoimmune blood diseases (eg, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, etc.), autoimmune bowel diseases (eg, ulcerative colitis, Crohn's disease, etc.), autologous Immune keratitis (eg, keratoconjunctivitis sicca, spring conjunctivitis, etc.), endocrine ocular disorders, Graves' disease, sarcoidosis, multiple sclerosis, systemic lupus erythematosus, polychondritis, scleroderma, active chronic hepatitis, severe Myasthenia, psoriasis, interstitial lung fibrosis, etc.], diabetes, cancer cachexia, AIDS cachexia, and the like.
[0002]
[Prior art]
As compounds similar to the compound of the present invention, there are compounds having several 1H-imidazoquinoline skeletons. For example, in Journal of Medicinal Chemistry, vol. 11, p. 87 (1968), 1- (2-piperidinoethyl) -1H-imidazo [4,5-c] quinoline is disclosed in Japanese Patent No. 60-123488 discloses 1-isobutyl-1H-imidazo [4,5-c] quinolin-4-amine (generic name: imiquimod, imiquimod) as a compound having an antiviral action, and Hungarian published patent 34479. No. (Japanese Patent No. 190109) discloses 1- (2-diethylaminoethyl) -1H-imidazo [4,5-c] quinoline as a compound having an analgesic / anticonvulsant action.
Further, according to the earlier invention of the present applicant, JP-A-2000-119271 discloses a compound having a cytokine inhibitory action such as TNF-α or IL-1β similar to the compound of the present invention. Phenyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline and the like are disclosed in JP-A-2002-161095 as 1- [2- (2-morpholinyl) ethyl. 2- (2-pyrrolyl) -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline and the like are disclosed in Japanese Patent Application No. 2001-248468, which discloses 7-chloro-4-methyl-2-phenyl. Although -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline and the like have been disclosed, there is still room for improvement in the action of these compounds.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel compound which has more excellent characteristics and pharmacological activity than the above-mentioned 1H-imidazo [4,5-c] quinoline derivative and is useful as a medicine.
[0004]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to solve these problems, and as a result, have found a novel 1H-imidazoquinoline derivative having a more excellent TNF-α production inhibitory effect than the previously applied 1H-imidazoquinoline derivative. Completed the invention.
[0005]
That is, the present invention provides the following general formula (I)
Embedded image

(Where R¹Is an alkoxy group which may have a substituent selected from a halogen atom, a hydroxyl group and an alkoxycarbonyl group, a hydrogen atom, a hydroxyl group, an alkyl group, a halogenoalkyl group, an acyloxy group, a halogen atom, a nitro group, an amino group, a cyano group And R²Represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a halogen atom, or a nitro group;³Represents a hydrogen atom, an alkyl group, a halogenoalkyl group, or a halogen atom;⁴Represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an aralkyloxy group, or a halogen atom, and X represents a group represented by CH or a nitrogen atom. Where R¹And R²Does not simultaneously represent a hydrogen atom. Here, X represents a group represented by CH, and (a) R¹And R⁴Represents a hydrogen atom at the same time;³Is a methyl group, R²Is not a fluorine atom, and (b) R¹And R⁴Represents a hydrogen atom at the same time;³Is a chlorine atom, R²Is not a methyl group, a methoxy group or a fluorine atom, but (c) R¹Is a fluorine atom and R³Is a chlorine atom, R²And R⁴Does not represent a hydrogen atom at the same time, and (d) R¹And R⁴Represents a hydrogen atom at the same time;³Is a trifluoromethyl group,²Is not a methyl, methoxy, fluorine or iodine atom, but (e) R¹Is a hydrogen atom and R³Is a trifluoromethyl group, and R⁴Is a chlorine atom or a methyl group;²Is not a hydroxyl or methoxy group, and (f) R²Is a hydrogen atom and R³Is a trifluoromethyl group, and R⁴Is a chlorine atom or a methyl group;¹Is not a hydroxyl group or a methoxy group, and (g) R¹Is a hydrogen atom and R³Is a methyl group and R⁴Is a chlorine atom, R²Is not a hydroxyl or methoxy group, and (h) R²Is a hydrogen atom and R³Is a methyl group and R⁴Is a chlorine atom, R¹Is not a hydroxyl group or a methoxy group. )
Or a novel 1H-imidazoquinoline derivative or a salt thereof.
[0006]
According to a second aspect of the present invention, in the compound represented by the general formula (I),
(1) R³Is an alkyl group, and R⁴Is an alkyl group or a fluorine atom, or a salt thereof
(2) R¹Is a hydroxyl group and R⁴Is a fluorine atom, or a salt thereof
(3) R²Is a hydroxyl group and R⁴Is a fluorine atom, or a salt thereof
(4) R²Is an alkoxy group, and R⁴Is a halogen atom other than a chlorine atom, or a salt thereof
(5) R³Is a halogen atom and R⁴Is a alkyl group or a halogen atom, or a salt thereof
(6) R³Is a halogenoalkyl group, and R⁴Is a fluorine atom, or a salt thereof.
[0007]
Further, according to a preferred embodiment of the present invention, there is provided a compound selected from the following (a) to (n) or a salt thereof.
(A) 4,7-dichloro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(B) 4,7-dichloro-2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -1H-imidazo [4,5-c] quinoline
(C) 2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(D) 2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(E) 7-Fluoro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(F) 7-Fluoro-2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(G) 2- (2-hydroxyphenyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(H) 2- (2-hydroxyphenyl) -4-methyl-1- [2- (1-piperazinyl) ethyl] -1H-imidazo [4,5-c] quinoline
(I) 2- (2-hydroxyphenyl) -7-methyl-1- [2- (1-piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(J) 7-chloro-4-methyl-2- (2-nitrophenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(K) 4-chloro-2- (2-hydroxyphenyl) -7-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(1) 4-chloro-7-fluoro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(M) 2- (2-hydroxyphenyl) -4,7-dimethyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(N) 7-Fluoro-2- (2-hydroxyphenyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
[0008]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the compound represented by the general formula (I) of the present invention will be specifically described.
In the general formula (I) of the present invention, R¹In the substituents of the alkoxy group which may have a substituent selected from a halogen atom, a hydroxyl group, and an alkoxycarbonyl group, the number, type and position of the substituent are not particularly limited, and two or more substituents may be substituted. If groups are present, they can be identical or different from one another. Examples of the substitutable halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group and an n-butoxy group. And a carbonyl group.
[0009]
In the general formula (I), R¹, R²And R⁴Examples of the alkoxy group represented by are methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, and the like.¹, R², R³And R⁴Examples of the alkyl group represented by are, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, Examples include a neopentyl group and an n-hexyl group.
[0010]
In the general formula (I), R¹And R³Examples of the halogenoalkyl group represented by are trifluoromethyl group, trichloromethyl group, tribromomethyl group, pentafluoroethyl group, pentachloroethyl group, pentabromoethyl group and the like.¹Examples of the acyloxy group represented by R include an acetyloxy group and a propionyloxy group.¹, R², R³And R⁴Examples of the halogen atom represented by R include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.⁴Examples of the aralkyloxy group represented by include a benzyloxy group and a phenethyloxy group.
[0011]
The compound represented by the general formula (I) of the present invention can be converted into a salt, preferably a pharmacologically acceptable salt, or the resulting salt can be converted into a free base, if necessary. Examples of the salt of the compound of the present invention include acid addition salts, for example, mineral salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or formic acid, acetic acid, propionic acid, butyric acid, and the like. Isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, acrylic acid, oleic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, malonic acid, lactic acid, glutaric acid , Sebacic acid, gluconic acid, enanthic acid, caprylic acid, nonanoic acid, capric acid, lauric acid, palmitic acid, myristic acid, stearic acid, heptadecanoic acid, undecanoic acid, mandelic acid, glycolic acid, sorbic acid, methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, benzoic acid, phthalic acid, terephthalic acid, cinnamic acid, p-toluenesulfonic acid, nicotinic acid, picic acid Phosphate, adipic acid, aspartic acid, glutamic acid, camphorsulfonic acid and organic acid salts such as those optically active form thereof.
[0012]
Among the compounds represented by the above general formula (I) of the present invention, compounds having one or more asymmetric carbons may exist as optical isomers and diastereoisomers. The active substances and their mixtures, racemates and salts thereof are also included.
[0013]
The compound of the present invention represented by the general formula (I) or a salt thereof may exist as an arbitrary crystal form or as an arbitrary hydrate or solvate depending on the production conditions. , Their crystal forms, hydrates or solvates, and mixtures thereof are also included in the scope of the present invention.
[0014]
Preferred compounds of the present invention include, for example, the following compounds and salts thereof, but the present invention is not limited to these examples.
(1) 4,7-dichloro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(2) 4,7-dichloro-2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -1H-imidazo [4,5-c] quinoline
(3) 2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(4) 2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(5) 7-Fluoro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(6) 7-fluoro-2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(7) 2- (2-hydroxyphenyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(8) 2- (2-hydroxyphenyl) -4-methyl-1- [2- (1-piperazinyl) ethyl] -1H-imidazo [4,5-c] quinoline
(9) 2- (2-hydroxyphenyl) -7-methyl-1- [2- (1-piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline
(10) 7-chloro-4-methyl-2- (2-nitrophenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(11) 4-chloro-2- (2-hydroxyphenyl) -7-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(12) 4-chloro-7-fluoro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(13) 2- (2-hydroxyphenyl) -4,7-dimethyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
(14) 7-fluoro-2- (2-hydroxyphenyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
[0015]
The novel 1H-imidazoquinoline derivative represented by the general formula (I) of the present invention can be produced, for example, by the following method, but the production method of the compound of the present invention is not limited to these methods. .
[0016]
As a first method for producing the compound of the present invention, the compound represented by the general formula (I) can be produced as follows.
Embedded image

(Wherein Boc represents a tert-butoxycarbonyl group;¹, R², R³, R⁴And X have the same meaning as described above. )
[0017]
That is, in the step 1, the compound of the general formula (II) and the following general formula (IV)
Embedded image

(Where R¹And R²Is as defined above. )
In a solvent such as acetonitrile, 1,4-dioxane, tetrahydrofuran, 1,2-dichloroethane, and toluene in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The compound of the general formula (III) can be obtained by reacting at a temperature between ℃ and the reflux temperature of the solvent.
[0018]
Next, in step 2, the compound of the general formula (III) is converted into ethyl acetate, methylene chloride, 1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, n-propanol, N, N-dimethylformamide, tetrahydrofuran. Water, or a solvent such as a mixed solvent thereof, for example, hydrochloric acid, ethyl acetate in hydrogen chloride, ethanol in hydrogen chloride, sulfuric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. The compound of the general formula (I) can be obtained by reacting with the acid of the formula (1) between 0 ° C. and the reflux temperature of the solvent.
[0019]
As a second method for producing the compound of the present invention, among the compounds of the general formula (I), R¹A compound having an amino group as R¹A compound of the general formula (III) wherein is a nitro group, for example, a catalytic reduction method using a metal catalyst such as platinum, Raney nickel or palladium carbon, a reduction method using nickel chloride and sodium borohydride The reaction is carried out in a solvent such as water, methanol, ethanol, tetrahydrofuran or a mixed solvent thereof at a temperature between 0 ° C. and the reflux temperature of the solvent by a reduction method using iron powder and hydrochloric acid.¹Can be obtained by performing the same deprotection reaction as in Step 2 of the first production method after converting into the compound of the above general formula (III) in which is an amino group.
[0020]
As a third method for producing the compound of the present invention, among the compounds of the general formula (I), R¹As the compound having an alkoxy group or an acyloxy group which may have a substituent as¹Is a hydroxyl group, by converting a compound of the above general formula (I) into a suitable alkylating reagent such as an alkyl halide, ethyl chloroacetate, 2-chloroethanol or 2-bromoethanol, or a suitable acylation such as acetyl chloride or acetic anhydride. Using a reagent, a solvent such as N, N-dimethylformamide, methylene chloride, tetrahydrofuran, toluene, pyridine, nitrobenzene, 1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, n-propanol or a mixed solvent thereof The reaction can be carried out at 0 ° C. to 200 ° C. in the presence or absence of a base such as triethylamine or potassium carbonate. Alternatively, R¹Is a hydroxyl group, the compound of the above general formula (III) is treated in the same manner, and the same reaction as in step 2 of the first production method is further carried out, whereby R¹Is a compound of the general formula (I) in which is an alkoxy group or an acyloxy group which may have a substituent.
[0021]
As a fourth method for producing the compound of the present invention, among the compounds of the general formula (I), R⁴A compound having a hydroxyl group as R⁴Is a benzyloxy group, water, methanol, ethanol, n-propanol, acetic acid, or a mixture thereof using a metal catalyst such as platinum, palladium carbon, Raney nickel, or Pearlman's reagent. In a solvent, in the presence or absence of an acid such as hydrochloric acid, between room temperature and the reflux temperature of the solvent, hydrogen gas, cyclohexene, cyclohexadiene, formic acid, ammonium formate, 2-propanol and the like are used as a hydrogen source. It can be obtained by performing a hydrocracking reaction at a hydrogen pressure of 200 Pa to 200 Pa and further performing a deprotection reaction similar to step 2 of the first production method.
[0022]
As a fifth production method of the compound of the present invention, among the compounds of the general formula (I), R⁴Having an alkoxy group or an aralkyloxy group as R⁴Is a hydroxyl group, using a suitable alkylating reagent such as an alkyl halide or a benzyl halide, using N, N-dimethylformamide, methylene chloride, tetrahydrofuran, toluene, pyridine, nitrobenzene, In the presence or absence of a solvent such as 1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, n-propanol or a mixed solvent thereof, in the presence or absence of a base such as triethylamine and potassium carbonate By performing the reaction between 0 ° C. and 200 ° C., R⁴Is an alkoxy group or an aralkyloxy group, and the compound is subjected to the same deprotection reaction as in Step 2 of the first production method.
[0023]
In the method for producing the compound of the present invention, the compound represented by the general formula (II) is disclosed in, for example, JP-A-2000-119271, JP-A-2002-161095, and Japanese Patent Application No. 2001-248468. Can be produced according to the method described in the literature. In addition, about a some novel compound, the manufacturing method was described as a reference example.
[0024]
The thus-produced pharmaceutical containing the novel 1H-imidazoquinoline derivative represented by the above general formula (I) or a salt thereof as an active ingredient is usually in the form of capsules, tablets, fine granules, granules, powders. , Syrups, dry syrups, liquids, etc., or parenteral formulations such as injections, suppositories, eye drops, eye ointments, ear drops, nasal drops, dermatological agents, inhalants, etc. Is done.
[0025]
These preparations contain one or more compounds selected from the group consisting of the compounds of the present invention represented by the above general formula (I), salts thereof, and hydrates and solvates thereof, One or more of physically and pharmaceutically acceptable additives can be added to produce the compound by a conventional method. For example, in the preparation for oral administration and suppositories, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, partially pregelatinized starch, croscarmellose sodium) , Crospovidone, etc.), binders (hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, hydrogenated oil, dimethylpolysiloxane, hydrous silicon dioxide, light anhydrous silicic acid, carnauba wax, etc.) ), Coating agent (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), plasticizer (triethyl citrate, polyethylene glycol, glycerin fatty acid ester, etc.), base material (polyethylene) Ingredients for preparations such as recall, hard fat, etc. are used in injections or eye drops, ear drops, etc., solubilizers or solubilizers which can constitute aqueous or ready-to-use dissolvable dosage forms (water for injection, physiological Saline, propylene glycol, etc.), pH regulator (inorganic or organic acid or base), tonicity agent (sodium chloride, glucose, glycerin, etc.), stabilizer (benzoic acid, citric acid, sodium bisulfite, etc.) And other ophthalmic ointments and dermatological preparations, ophthalmic ointments, creams, patches, and other suitable pharmaceutical ingredients (white petrolatum, macrogol, glycerin, liquid paraffin, glycerin fatty acid ester) , Polyethylene glycol fatty acid ester, carboxyvinyl polymer, acrylic adhesive, rubber adhesive, silicone resin, cotton cloth, etc.) The propellant (carbon dioxide, propane, nitrogen and the like), solubilizers (ethanol, propylene glycol, etc.), surfactants (sorbitan trioleate, etc.), excipients (lactose, etc.) are used.
[0026]
The dose of the compound of the present invention or a salt thereof to a human is, for example, usually about 0.1 to 1000 mg for oral administration and about 0.01 to 500 mg for parenteral administration once a day as a daily dose for an adult. Alternatively, it can be administered in several divided doses. However, the dose is desirably increased or decreased according to the purpose of treatment or prevention, the site and type of the disease, the administration route and dosage form, the age and symptoms of the patient, and the like.
[0027]
【Example】
Hereinafter, the present invention will be described by reference examples and examples, but the present invention is not limited to these examples.
The abbreviations in the examples have the following meanings. Boc: tert-butoxycarbonyl, Me: methyl, Et: ethyl, n-Pr: n-propyl, iso-Pr: isopropyl, Bn: benzyl, Ac: acetyl, DMSO-d₆: Dimethyl sulfoxide-d₆, Aq. : Aqueous, ATR: Total reflection measurement
[0028]
Reference Example 1
4'-fluoro-2-nitro-2 '-(pentafluoropropionamido) acetophenone
5.2 ml of pentafluoropropionic anhydride was added dropwise to a solution of 5.00 g of 2'-amino-4'-fluoro-2-nitroacetophenone in 30 ml of tetrahydrofuran under ice cooling, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed sequentially with water and a mixed solution of diisopropyl ether and n-heptane to obtain 7.65 g of pale yellow crystals. Recrystallization from a mixture of ethyl acetate and diisopropyl ether gave colorless crystals having a melting point of 143.5 to 144 ° C.
Elemental analysis value C₁₁H₆F₆N₂O₄
Theory (%) C, 38.39; H, 1.76; N, 8.14
Experimental value (%) C, 38.10; H, 1.96; N, 7.84
[0029]
Reference Example 2
7-fluoro-3-nitro-2-pentafluoroethyl-4-quinolinol
To a solution of 4.50 g of 4'-fluoro-2-nitro-2 '-(pentafluoropropionamido) acetophenone in 75 ml of tetrahydrofuran was added 3.20 g of 4- (dimethylamino) pyridine, and the mixture was refluxed for 1 hour. The reaction mixture was poured into ice water, adjusted to pH 2 by adding concentrated hydrochloric acid, diisopropyl ether was added, and the precipitated crystals were collected by filtration and washed sequentially with water and diisopropyl ether to obtain 4.00 g of brown crystals. Recrystallization from a mixture of ethyl acetate and methanol gave pale brown crystals.
NMR spectrum δ (DMSO-d₆) Ppm: 7.46 (1H, ddd, J = 10, 9, 2.5 Hz), 7.63 (1H, dd, J = 10, 2.5 Hz), 8.34 (1H, dd, J = 9) , 6.5 Hz)
IR spectrum ν (ATR) cm^-1: 1548, 1367
Mass spectrum m / z: 325 (M⁺-1)
[0030]
Reference Example 3
7-methyl-3-nitro-4-quinolinol
To a solution of 8.00 g of 2'-amino-4'-methyl-2-nitroacetophenone in 30 ml of N, N-dimethylformamide was added 16.4 ml of N, N-dimethylformamide dimethyl acetal under ice-cooling, followed by stirring at room temperature for 14 hours. did. After water was added to the reaction mixture and 10% hydrochloric acid was added to adjust the pH to 2, the precipitated crystals were collected by filtration and washed sequentially with water and diethyl ether to obtain 8.36 g of light brown crystals. Recrystallization from a mixture of N, N-dimethylformamide and water gave light brown crystals having a melting point of 300 ° C. or higher.
Elemental analysis value C₁₀H₈N₂O₃
Theory (%) C, 58.82; H, 3.95; N, 13.72
Experimental value (%) C, 58.60; H, 3.97; N, 13.57
[0031]
Reference example 4
7-benzyloxy-3-nitro-2-trifluoromethyl-4-quinolinol
To a suspension of 1.45 g of 60% sodium hydride in 60 ml of N, N-dimethylformamide was added dropwise 3.80 ml of benzyl alcohol while stirring at room temperature, and then 7-fluoro-3-nitro-2-trifluoromethyl-4 was added. -Quinolinol 5.00 g was added in small portions and the mixture was stirred at 60 ° C for 4 hours. Ice water was added to the reaction mixture, and the mixture was acidified with 10% hydrochloric acid. The precipitated crystals were collected by filtration and washed sequentially with water and diisopropyl ether to obtain 5.60 g of pale yellow-brown crystals. Recrystallization from ethyl acetate gave pale yellow plate-like crystals having a melting point of 275-277 ° C (decomposition).
Elemental analysis value C₁₇H₁₁F₃N₂O₄
Theory (%) C, 56.05; H, 3.04; N, 7.69
Experimental value (%) C, 55.86; H, 3.16; N, 7.60
[0032]
Reference example 5
4-Chloro-7-fluoro-3-nitro-2-pentafluoroethylquinoline A mixture of 3.84 g of 7-fluoro-3-nitro-2-pentafluoroethyl-4-quinolinol and 11 ml of phosphorus oxychloride was refluxed for 5 hours. . After cooling, the reaction mixture was poured little by little into ice water and stirred, and extracted with toluene. The toluene layer was washed with water, and after dehydration, the solvent was distilled off to obtain 2.50 g of brown crystals.
NMR spectrum δ (CDCl₃) Ppm: 7.73 (1H, ddd, J = 9, 8.5, 2.5 Hz), 7.96 (1H, dd, J = 8.5, 2.5 Hz), 8.42 (1H, dd) , J = 9, 5.5 Hz)
IR spectrum ν (KBr) cm^-1: 1550, 1321
[0033]
According to the method of Reference Example 5, the compound of Reference Example 6 was obtained.
[0034]
Reference Example 6
4-chloro-7-methyl-3-nitroquinoline
Properties Light brown crystal
Melting point 100-102.5 ° C
NMR spectrum δ (CDCl₃) Ppm: 2.64 (3H, s), 7.64 (1H, dd, J = 8.5, 1 Hz), 7.99 (1H, d, J = 1 Hz), 8.32 (1H, d, J = 8.5 Hz), 9.24 (1H, s)
IR spectrum ν (ATR) cm^-1: 1514, 1338
Mass spectrum m / z: 223, 225 (M⁺+1,3: 1)
[0035]
Reference Example 7
2,4,7-trichloro-3-nitroquinoline
A mixture of 7.45 g of 7-chloro-4-hydroxy-3-nitroquinolin-2 (1H) -one and 17.3 ml of phenylphosphoryl dichloride was stirred at 140 ° C. for 1.5 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and washed with water to obtain 8.40 g of light brown crystals. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 119.5 to 120.5 ° C.
Elemental analysis value C₉H₃Cl₃N₂O₂・ 1 / 8H₂O
Theory (%) C, 38.64; H, 1.17; N, 10.01
Experimental value (%) C, 39.02; H, 1.27; N, 9.64
[0036]
Reference Example 8
Tert-Butyl 4- [2-[(2,7-dichloro-3-nitroquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate
To a mixture of 2.00 g of 2,4,7-trichloro-3-nitroquinoline, 1.2 ml of triethylamine and 6 ml of N, N-dimethylformamide was added 4- (2-aminoethyl) -1-piperidinecarboxylic acid under stirring at room temperature. A solution of 2.10 g of tert-butyl in 2 ml of N, N-dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dehydrated, and the solvent was distilled off. The residue was washed with diisopropyl ether to obtain 2.88 g of yellow crystals. Recrystallization from ethyl acetate gave yellow platelets with a melting point of 194-195 ° C.
Elemental analysis value C₂₁H₂₆Cl₂N₄O₄・ 1 / 8H₂O
Theory (%) C, 53.48; H, 5.61; N, 11.88.
Experimental value (%) C, 53.77; H, 5.64; N, 11.50
[0037]
According to the method of Reference Example 8, the compounds of Reference Examples 9 to 12 were obtained.
[0038]
Reference Example 9
Tert-Butyl 4- [2-[(7-fluoro-3-nitro-2-pentafluoroethylquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate
Properties Yellow crystals (recrystallization solvent: MeOH)
Melting point 168-169 ° C
Elemental analysis value C₂₃H₂₆F₆N₄O₄
Theory (%) C, 51.49; H, 4.89; N, 10.44
Experimental value (%) C, 51.29; H, 4.89; N, 10.23
[0039]
Reference Example 10
Tert-Butyl 4- [2-[(7-methyl-3-nitroquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate
Properties Yellow needles (recrystallization solvent: MeOH)
Melting point 150-151 ° C
Elemental analysis value C₂₂H₃₀N₄O₄
Theory (%) C, 63.75; H, 7.30; N, 13.52
Experimental value (%) C, 63.64; H, 7.24; N, 13.46
[0040]
Reference Example 11
4- [2-[(7-Benzyloxy-3-nitro-2-trifluoromethylquinolin-4-yl) amino] ethyl] -tert-butyl 4-piperidinecarboxylate Yellow plate-like crystal (recrystallization solvent: AcOEt-iso-Pr₂O)
195-196 ° C
Elemental analysis value C₂₉H₃₃F₃N₄O₅
Theory (%) C, 60.62; H, 5.79; N, 9.75
Experimental value (%) C, 60.50; H, 5.76; N, 9.55
[0041]
Reference Example 12
Tert-Butyl 4- [2-[(7-fluoro-3-nitro-2-trifluoromethylquinolin-4-yl) amino] ethyl] -1-piperazinecarboxylate
Properties Yellow liquid
NMR spectrum δ (DMSO-d₆) Ppm: 1.39 (9H, s), 2.36 (4H, t, J = 5 Hz), 2.63 (2H, t, J = 6 Hz), 3.25 (4H, t, J = 5 Hz) , 3.43 (2H, q, J = 6 Hz), 7.70 (1H, ddd, J = 10, 9, 2.5 Hz), 7.80 (1H, dd, J = 10, 2.5 Hz), 7.85 (1H, brs), 8.54 (1H, dd, J = 9.6 Hz)
IR spectrum ν (ATR) cm^-1: 1689
Mass spectrum m / z: 486 (M⁺-1)
[0042]
Reference Example 13
Tert-Butyl 4- [2-[(3-amino-2,7-dichloroquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate
0.12 g of sodium borohydride was added to a solution of 0.71 g of nickel chloride hexahydrate in 15 ml of methanol under ice-cooling with stirring, and then 4- [2-[(2,7- A suspension of 2.78 g of tert-butyl dichloro-3-nitroquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate in 60 ml of methanol and 20 ml of tetrahydrofuran was added. Subsequently, 0.67 g of sodium borohydride was added little by little at an internal temperature of 5 ° C. or lower, and the mixture was stirred at room temperature for 1 hour. The insoluble matter of the reaction mixture was removed by filtration, and the filtrate was concentrated. Then, a 10% aqueous ammonium chloride solution was added to the residue, followed by extraction with ethyl acetate. The extract was washed successively with water and saturated saline, dehydrated, and the solvent was distilled off. The resulting dark brown liquid was purified by silica gel column chromatography using ethyl acetate-n-heptane (1: 3 → 2: 5) as an eluting solvent, and washed with diisopropyl ether to give 1.81 g of pale yellow crystals. Obtained. Recrystallization from ethyl acetate gave pale yellow needles with a melting point of 152-153 ° C.
Elemental analysis value C₂₁H₂₈Cl₂N₄O₂
Theory (%) C, 57.40; H, 6.42; N, 12.75
Experimental value (%) C, 57.34; H, 6.40; N, 12.69
[0043]
According to the method of Reference Example 13, the compounds of Reference Examples 14 to 17 were obtained.
[0044]
Reference Example 14
Tert-Butyl 4- [2-[(3-amino-7-fluoro-2-pentafluoroethylquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate
Properties Yellow crystals (recrystallization solvent: AcOEt-iso-Pr₂O)
Melting point 122-123 ° C
Elemental analysis value C₂₃H₂₈F₆N₄O₂
Theory (%) C, 54.54; H, 5.57; N, 11.06
Experimental value (%) C, 54.35; H, 5.48; N, 10.78
[0045]
Reference Example 15
Tert-Butyl 4- [2-[(3-amino-7-methylquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate
Properties Yellow-brown crystal (recrystallization solvent: AcOEt-iso-Pr₂O)
142.5-144.5 ° C
Elemental analysis value C₂₂H₃₂N₄O₂・ 1 / 4H₂O
Theory (%) C, 67.92; H, 8.42; N, 14.40
Experimental value (%) C, 68.32; H, 8.38; N, 14.02
[0046]
Reference Example 16
Tert-Butyl 4- [2-[(3-amino-7-benzyloxy-2-trifluoromethylquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate
Property Light yellow liquid
NMR spectrum δ (DMSO-d₆) Ppm: 0.91-1.03 (2H, m), 1.38 (9H, s), 1.46-1.63 (5H, m), 2.58-2.70 (2H, m) , 3.31 (2H, q, J = 7 Hz), 3.81-3.92 (2H, m), 4.71 (2H, s), 5.23 (2H, s), 5.29 (1H) , T, J = 6.5 Hz), 7.23 (1H, dd, J = 9, 2.5 Hz), 7.28 (1H, d, J = 2.5 Hz), 7.33 (1H, t, J = 7.5 Hz), 7.40 (2H, t, J = 7.5 Hz), 7.49 (2H, d, J = 7.5 Hz), 8.03 (1H, d, J = 9 Hz)
IR spectrum ν (ATR) cm^-1: 1682
Mass spectrum m / z: 543 (M⁺-1)
[0047]
Reference Example 17
Tert-Butyl 4- [2-[(3-amino-7-fluoro-2-trifluoromethylquinolin-4-yl) amino] ethyl] -1-piperazinecarboxylate
Properties Yellow liquid
NMR spectrum δ (DMSO-d₆) Ppm: 1.39 (9H, s), 2.32 (4H, t, J = 5 Hz), 2.47 (2H, t, J = 6 Hz), 3.24 (4H, t, J = 5 Hz) , 3.35 (2H, q, J = 6 Hz), 5.13 (2H, s), 5.43 (1H, t, J = 6 Hz), 7.43 (1H, ddd, J = 10.5, 7.53 (1H, dd, J = 10.5, 3 Hz), 8.21 (1H, dd, J = 1,6 Hz)
IR spectrum ν (ATR) cm^-1: 1690
Mass spectrum m / z: 458 (M⁺+1)
[0048]
Reference Example 18
Tert-Butyl 4- [2- [4,7-dichloro-2- (2-hydroxyphenyl) -1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylate
1.71 g of tert-butyl 4- [2-[(3-amino-2,7-dichloroquinolin-4-yl) amino] ethyl] -1-piperidinecarboxylate, 0.62 g of salicylaldehyde and 2,3-dichloro A solution of 0.19 g of -5,6-dicyano-1,4-benzoquinone in 17 ml of tetrahydrofuran was stirred at room temperature for 5 days. Water and aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with an aqueous solution of sodium hydrogen carbonate, water and saturated saline, then dehydrated, and the solvent was evaporated. The obtained liquid was purified by silica gel column chromatography using ethyl acetate-n-heptane (1: 3 → 3: 5) as an eluting solvent to obtain 0.62 g of a pale yellowish brown liquid.
NMR spectrum δ (DMSO-d₆) Ppm: 0.74-0.88 (2H, m), 1.17-1.31 (3H, m), 1.36 (9H, s), 1.67 (2H, q, J = 7 Hz) , 2.41-2.58 (2H, m), 3.67-3.78 (2H, m), 4.57 (2H, t, J = 7 Hz), 7.04 (1H, t, J = 8 Hz), 7.09 (1 H, d, J = 8 Hz), 7.47 (1 H, t, J = 8 Hz), 7.49 (1 H, d, J = 8 Hz), 7.79 (1 H, dd, J = 9.2 Hz, 8.16 (1 H, d, J = 2 Hz), 8.41 (1 H, d, J = 9 Hz), 10.14 (1 H, s)
IR spectrum ν (ATR) cm^-1: 1689
Mass spectrum m / z: 539, 541, 543 (M⁺-1; 9: 6: 1)
[0049]
According to the method of Reference Example 18, the compounds of Reference Examples 19 to 49 were obtained.
[0050]
[Table 1]

[0051]
[Table 2]

[0052]
[Table 3]

[0053]
[Table 4]

[0054]
[Table 5]

[0055]
[Table 6]

[0056]
Reference Example 50
4- [2- [7-methyl-2- (2-isopropoxyphenyl) -4-trifluoromethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid tert-butyl
4- [2- [2- (2-hydroxyphenyl) -7-methyl-4-trifluoromethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid tert To a suspension of 0.50 g of -butyl and 0.23 g of potassium carbonate in 2.5 ml of N, N-dimethylformamide was added dropwise a solution of 0.34 g of isopropyl iodide in 0.5 ml of N, N-dimethylformamide. Stirred for hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with water to obtain 0.54 g of colorless crystals. Recrystallization from a mixture of ethyl acetate and diisopropyl ether gave colorless crystals having a melting point of 119 to 120 ° C.
Elemental analysis value C₃₃H₃₉F₃N₄O₃
Theory (%) C, 66.43; H, 6.59; N, 9.39
Experimental value (%) C, 66.10; H, 6.56; N, 9.17
[0057]
According to the method of Reference Example 50, the compounds of Reference Examples 51 to 54 were obtained.
[Table 7]

[0058]
Reference Example 55
4- [2- [2- (2-acetyloxyphenyl) -7-benzyloxy-4-trifluoromethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid Tert-butyl acid
Under ice cooling, 4- [2- [7-benzyloxy-2- (2-hydroxyphenyl) -4-trifluoromethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1 0.83 ml of acetyl chloride was added dropwise to a solution of 6.82 g of tert-butyl piperidinecarboxylate and 2.2 ml of triethylamine in 60 ml of tetrahydrofuran, followed by stirring at room temperature for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, then dehydrated, and the solvent was distilled off to obtain 7.42 g of a pale yellow liquid.
NMR spectrum δ (DMSO-d₆) Ppm: 0.80-0.92 (2H, m), 1.25-1.36 (3H, m), 1.36 (9H, s), 1.70 (2H, q, J = 7 Hz) , 2.02 (3H, s), 2.43-2.60 (2H, m), 3.72-3.81 (2H, m), 4.58 (2H, t, J = 7 Hz), 5 .38, (2H, s), 7.36 (1H, t, J = 7.5 Hz), 7.43 (2H, t, J = 7.5 Hz), 7.45 (1H, d, J = 7) 7.5 Hz), 7.54 (1H, t, J = 7.5 Hz), 7.54 (2H, d, J = 7.5 Hz), 7.64 (1H, dd, J = 9, 2.5 Hz) , 7.72 (1H, t, J = 7.5 Hz), 7.79 (1H, d, J = 7.5 Hz), 7.84 (1H, d, J = 2.5 Hz), 8.41 ( 1H, d, J = 9Hz)
IR spectrum ν (ATR) cm^-1: 1769, 1684
Mass spectrum m / z: 689 (M⁺+1)
[0059]
According to the method of Reference Example 55, the compound of Reference Example 56 was obtained.
[0060]
Reference Example 56
4- [2- [2- (2-acetyloxyphenyl) -7-chloro-4-methyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid tert- Butyl
Properties: colorless liquid
NMR spectrum δ (CDCl₃) Ppm: 0.98-1.10 (2H, m), 1.30-1.50 (3H, m), 1.44 (9H, s), 1.80 (2H, q, J = 8 Hz) , 2.04 (3H, s), 2.52-2.65 (2H, m), 3.02 (3H, s), 3.92-4.10 (2H, m), 4.46 (2H , T, J = 8 Hz), 7.34 (1H, d, J = 8.5 Hz), 7.45 (1H, t, J = 7.5 Hz), 7.55-7.65 (3H, m) , 8.05 (1H, d, J = 8.5 Hz), 8.24 (1H, d, J = 2.5 Hz)
IR spectrum ν (ATR) cm^-11772, 1692
Mass spectrum m / z: 563, 565 (M⁺+1; 3: 1)
[0061]
Reference Example 57
4- [2- [2- (2-acetyloxyphenyl) -7-hydroxy-4-trifluoromethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid tert-butyl
4- [2- [2- (2-acetyloxyphenyl) -7-benzyloxy-4-trifluoromethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid To a solution of 0.30 g of tert-butyl acid and 0.14 ml of cyclohexene in 9 ml of ethanol, 30 mg of Pearlman's reagent was added, and the mixture was refluxed for 1 hour. After removing the catalyst by filtration and concentrating the filtrate, the residue was purified by silica gel column chromatography using ethyl acetate-n-heptane (1: 4 → 1: 1) as an eluting solvent to obtain 0.26 g of a colorless liquid. .
NMR spectrum δ (DMSO-d₆) Ppm: 0.79-0.91 (2H, m), 1.24-1.36 (3H, m), 1.36 (9H, s), 1.69 (2H, q, J = 7 Hz) , 2.02 (3H, s), 2.44-2.61 (2H, m), 3.70-3.81 (2H, m), 4.55 (2H, t, J = 7 Hz), 7 .44 (1H, dd, J = 8, 1 Hz), 7.46 (1H, dd, J = 9, 2.5 Hz), 7.53 (1H, td, J = 8, 1 Hz), 7.56 ( 1H, d, J = 2.5 Hz), 7.71 (1H, td, J = 8, 1 Hz), 7.78 (1H, dd, J = 8, 1 Hz), 8.33 (1H, d, J) = 9Hz), 10.25 (1H, s)
IR spectrum ν (ATR) cm^-1: 1769, 1686
Mass spectrum m / z: 599 (M⁺+1)
[0062]
Reference Example 58
4- [2- [2- (2-hydroxyphenyl) -7-methoxy-4-trifluoromethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid tert -Butyl
4- [2- [2- (2-acetyloxyphenyl) -7-hydroxy-4-trifluoromethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid To a suspension of 0.60 g of tert-butyl and 0.17 g of potassium carbonate in 6 ml of N, N-dimethylformamide was added dropwise 0.13 ml of methyl iodide under ice cooling and stirring, followed by stirring at room temperature for 2.5 hours. To the reaction mixture was added 1.5 ml of a 10% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2.5 hours. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dehydrated, and the solvent was distilled off. The residue was purified by silica gel column chromatography using ethyl acetate-n-heptane (1: 4 → 1: 1) as an eluting solvent to obtain 0.23 g of a colorless liquid.
NMR spectrum δ (DMSO-d₆) Ppm: 0.75-0.87 (2H, m), 1.20-1.36 (3H, m), 1.36 (9H, s), 1.66 (2H, q, J = 7 Hz) , 2.43-2.58 (2H, m), 3.69-3.79 (2H, m), 3.83 (3H, s), 4.45 (2H, t, J = 7 Hz), 7 .18 (1H, t, J = 8 Hz), 7.29 (1H, d, J = 8 Hz), 7.44 (1H, dd, J = 9, 2.5 Hz), 7.54 (1H, dd, J = 8, 1.5 Hz), 7.55 (1H, d, J = 2.5 Hz), 7.64 (1H, td, J = 8, 1.5 Hz), 8.31 (1H, d, J = 9Hz), 10.21 (1H, s)
IR spectrum ν (ATR) cm^-1: 1687
Mass spectrum m / z: 569 (M⁺-1)
[0063]
Reference Example 59
Tert-Butyl 4- [2- [2- (2-aminophenyl) -7-chloro-4-methyl-1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylate
Under ice-cooling and stirring, 0.04 g of sodium borohydride was added to a solution of 0.25 g of nickel chloride hexahydrate in 25 ml of methanol, and then 4- [2- [7-chloro-4-methyl-2-methyl-2-hydrate] was added. A solution of 1.17 g of tert-butyl (2-nitrophenyl) -1H-imidazo [4,5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylate in 10 ml of methanol was added. Subsequently, 0.20 g of sodium borohydride was added little by little, and the mixture was stirred at room temperature for 30 minutes. After the insolubles in the reaction mixture were removed by filtration, the filtrate was concentrated, and a 10% aqueous ammonium chloride solution was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated saline, dehydrated, and the solvent was distilled off. The obtained residue was washed with a mixture of ethyl acetate and diisopropyl ether to obtain 1.00 g of pale brown crystals. Recrystallization from 2-propanol gave colorless crystals having a melting point of 182-183 ° C.
Elemental analysis value C₂₉H₃₄ClN₅O₂
Theory (%) C, 66.97; H, 6.59; N, 13.47.
Experimental value (%) C, 66.80; H, 6.51; N, 13.46
[0064]
Example 1
4,7-Dichloro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline.7 / 2 fumarate 4- [2 0.58 g of tert-butyl- (4,7-dichloro-2- (2-hydroxyphenyl) -1H-imidazo [4,5-c] quinolin-1-yl) ethyl] -1-piperidinecarboxylate and trifluoro A solution of 1.5 ml of acetic acid in 3 ml of 1,2-dichloroethane was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, 2-propanol was added to the residue, and the precipitated crystals were collected by filtration to obtain 0.45 g of trifluoroacetate. After water was added to the obtained salt to make it alkaline with an aqueous sodium hydroxide solution, the mixture was extracted with a mixed solution of ethyl acetate and 2-propanol. After the extract was dehydrated, the solvent was distilled off, and the extract was washed with a mixed solution of ethyl acetate and diisopropyl ether to obtain 0.36 g of a free base. Further, it was converted into a fumarate by a conventional method, and recrystallized from ethanol to obtain light brown needles having a melting point of 215 to 218 ° C (decomposition).
Elemental analysis value C₂₃H₂₂Cl₂N₄O.7 / 2C₄H₄O₄・ 2H₂O
Theory (%) C, 50.29; H, 4.56; N, 6.34
Experimental value (%) C, 50.33; H, 4.23; N, 6.03
[0065]
According to the method of Example 1, the compounds of Examples 2-41 were obtained.
[0066]
[Table 8]

[0067]
[Table 9]

[0068]
[Table 10]

[0069]
[Table 11]

[0070]
[Table 12]

[0071]
[Table 13]

[0072]
Example 42
7-chloro-2- [2- (2-hydroxyethoxy) phenyl] -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline
0.58 g of 7-chloro-2- (2-hydroxyphenyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline and 0.23 ml of triethylamine A 2.5 ml solution of N, N-dimethylformamide was stirred at 50 ° C., a solution of 0.12 ml of 2-bromoethanol in 0.5 ml of N, N-dimethylformamide was added dropwise, and the mixture was stirred at 50 ° C. for 5 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with water to obtain 0.28 g of colorless crystals. Recrystallization from methanol gave colorless crystals with a melting point of 111-112 ° C.
Elemental analysis value C₂₆H₂₉ClN₄O₂・ 5 / 2H₂O
Theory (%) C, 61.23; H, 6.72; N, 10.99
Experimental value (%) C, 61.13; H, 6.32; N, 11.05
[0073]
Hereinafter, as an example of the excellent effects of the compound of the present invention, test results of the TNF-α production inhibitory action in human cells are shown. In addition, as a control compound, 4-chloro-2-phenyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] disclosed in JP-A-2000-119271. Quinoline (Control Compound A), 1- [2- (2-morpholinyl) ethyl] -2- (2-pyrrolyl) -4-trifluoromethyl-1H-imidazo [disclosed in JP-A-2002-161095. 4,5-c] quinoline (control compound B), 7-chloro-4-methyl-2-phenyl-1- [2- (4-piperidyl) ethyl] -1H disclosed in Japanese Patent Application No. 2001-248468. -Imidazo [4,5-c] quinoline (control compound C) was used.
[0074]
1. Preparation of blood cells for culture
About 50 ml of whole blood was collected by venipuncture from a healthy adult volunteer into a plastic test tube containing 170 μl of Novo Heparin Injection 1000 (manufactured by Novo Nordisk). From now on, peripheral blood mononuclear cells (PBMC: Peripheral Blood Mononuclear Cell) will be converted to LeucoPREP.^TM(Becton Dickinson) prepared by a cell separation tube, containing 2 mM L-glutamine (Life Technologies), 2.5 U / ml penicillin-2.5 μg / ml streptomycin solution (Life Technologies), and containing 10% In RPMI-1640 medium (manufactured by Nissui Pharmaceutical Co., Ltd.) supplemented with fetal calf serum (manufactured by Intergen Company), the cell density was 1 × 10⁶The cells were cultured so as to obtain the number of cells / ml.
2. Preparation of test compound
The test compound was dissolved in sterile ultrapure water, dimethyl sulfoxide, or 0.1 M hydrochloric acid to a concentration of 20 μM as much as possible, and serially diluted with physiological saline before use. The compound is 10^-11M-10^-5M was tested in the concentration range.
3. Cell drug treatment
96-well (flat bottom) Micro Test III pre-added with 10 μl of test compound^TMTo a tissue culture plate (manufactured by Becton Dickinson) cell culture plate, 180 μl of PBMC in the previously prepared medium was added. Thirty minutes later, 10 μl of 20 μg / ml lipopolysaccharide (LPS) was further added, the plate was covered with a plastic lid, and the plate was incubated at 37 ° C. in a 5% carbon dioxide atmosphere for 16 hours.
[0075]
4. Quantification of human TNF-α
An enzyme immunoassay by the sandwich method was constructed to quantify human TNF-α in the culture supernatant. A diluted anti-cytokine antibody (capture antibody or primary antibody) was placed in a 96-well microtiter plate and coated. After washing the wells, the culture supernatant was diluted appropriately and incubated in the wells. Thereafter, a detection antibody (or a secondary antibody) for the cytokine and an HRP (horseradish peroxidase; horseradish peroxidase) conjugated antibody (or a tertiary antibody) for the detection antibody were sequentially added while sandwiching a washing step. After the final washing, a tetramethylbenzidine solution (manufactured by DAKO) was added to each well to start a color development reaction. After stopping the color reaction with 0.5 M sulfuric acid, the absorbance at 450 nm of each well was determined by M-Vmax.^TMThe measurement was performed using a microplate reader (Molecular Devices). The concentration of cytokines is determined by the quantification software Softmax.^TM(Molecular Devices) and determined by comparing with a calibration curve using a recombinant cytokine as a standard. For quantification of human TNF-α, monoclonal anti-human TNF-α (manufactured by ENDOGEN), polyclonal rabbit anti-human TNF-α (manufactured by Pharma Biotechnologies Hanover), peroxidase-conjugated donkey anti-rabbit IgG (manufactured by Jackson ImmunoRes. Labs.) Recombinant human TNF-α (manufactured by INTERGEN) was used as a standard for capture, detection, HRP-conjugated antibody and calibration curve, respectively.
The activity of each test compound was determined by the concentration IC at which the amount of human TNF-α induced by treatment with LPS and the test compound was inhibited by 50%.₅₀Value (nM). Table 14 shows the results.
[0076]
[Table 14]

[0077]
From these results, it is clear that the compound of the present invention exhibits an excellent TNF-α production inhibitory action.
[0078]
【The invention's effect】
The compound of the present invention exhibits an excellent TNF-α production inhibitory action, and is extremely useful as an agent for preventing or treating diseases caused by TNF-α.

Claims (8)

The following general formula

(In the formula, R ¹ is an alkoxy group optionally having a substituent selected from a halogen atom, a hydroxyl group, and an alkoxycarbonyl group, a hydrogen atom, a hydroxyl group, an alkyl group, a halogenoalkyl group, an acyloxy group, a halogen atom, and a nitro group. , An amino group, a cyano group, R ² represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a halogen atom, and a nitro group; R ³ represents a hydrogen atom, an alkyl group, a halogenoalkyl group, a halogen atom; ⁴ represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an aralkyloxy group, or a halogen atom, and X represents a group represented by CH or a nitrogen atom, wherein R ¹ and R ² simultaneously represent a hydrogen atom. no. However, in this case represents a X is a group represented by CH, it represents (a) ^{R 1} and ^{R 4} are simultaneously hydrogen atom when ^{R 3} is a methyl group, ^{R 2} Is not a fluorine atom, (b) R ¹ and R ⁴ represent a hydrogen atom at the same time, and when R ³ is a chlorine atom, R ² is not a methyl group, a methoxy group or a fluorine atom, and (c) R ¹ is a fluorine atom When R ³ is a chlorine atom, R ² and R ⁴ do not represent a hydrogen atom at the same time. (D) When R ¹ and R ⁴ represent a hydrogen atom at the same time and R ³ is a trifluoromethyl group , ^{R 2} is not a methyl group, a methoxy group, a fluorine atom, an iodine atom, (e) ^{R 1} is hydrogen atom, ^{R 3} is a trifluoromethyl group, when ^{R 4} is a chlorine atom or a methyl group, ^{R 2} Is not a hydroxyl group or a methoxy group, and (f) when R ² is a hydrogen atom, R ³ is a trifluoromethyl group, and R ⁴ is a chlorine atom or a methyl group, R ¹ is not a hydroxyl group or a methoxy group, and (g) ) R ¹ is a hydrogen atom, R ³ is a methyl group, When R ⁴ is a chlorine atom, R ² is not a hydroxyl group or a methoxy group. (H) When R ² is a hydrogen atom, R ³ is a methyl group and R ⁴ is a chlorine atom, R ¹ is a hydroxyl group or a methoxy group. is not.)
Or a 1H-imidazoquinoline derivative represented by the formula: or a salt thereof. The compound according to claim 1, wherein R ³ is an alkyl group, and R ⁴ is an alkyl group or a fluorine atom, or a salt thereof. The compound according to claim 1, wherein R ¹ is a hydroxyl group and R ⁴ is a fluorine atom, or a salt thereof. The compound according to claim 1, wherein R ² is a hydroxyl group and R ⁴ is a fluorine atom, or a salt thereof. The compound according to claim 1, wherein R ² is an alkoxy group and R ⁴ is a halogen atom other than a chlorine atom, or a salt thereof. The compound according to claim 1, wherein R ³ is a halogen atom, and R ⁴ is an alkyl group or a halogen atom, or a salt thereof. The compound according to claim 1, wherein R ³ is a halogenoalkyl group and R ⁴ is a fluorine atom, or a salt thereof. A compound selected from the following (a) to (n), or a salt thereof.
(A) 4,7-dichloro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline (b) 4,7-dichloro -2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -1H-imidazo [4,5-c] quinoline (c) 2- (2-hydroxyphenyl) -1- [2 -(4-Piperidyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline (d) 2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline (e) 7-fluoro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -4-tri Fluoromethyl-1H-imidazo [ , 5-c] quinoline (f) 7-fluoro-2- (2-hydroxyphenyl) -1- [2- (1-piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c ] Quinoline (g) 2- (2-hydroxyphenyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline (h) 2- (2- (Hydroxyphenyl) -4-methyl-1- [2- (1-piperazinyl) ethyl] -1H-imidazo [4,5-c] quinoline (i) 2- (2-hydroxyphenyl) -7-methyl-1- [2- (1-Piperazinyl) ethyl] -4-trifluoromethyl-1H-imidazo [4,5-c] quinoline (j) 7-chloro-4-methyl-2- (2-nitrophenyl) -1- [2- (4-piperidyl) ethyl] 1H-imidazo [4,5-c] quinoline (k) 4-chloro-2- (2-hydroxyphenyl) -7-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4 5-c] quinoline (l) 4-chloro-7-fluoro-2- (2-hydroxyphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline ( m) 2- (2-Hydroxyphenyl) -4,7-dimethyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline (n) 7-fluoro-2- (2-Hydroxyphenyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline