JPWO2004014861A1 - 4-Substituted quinoline-8-carboxylic acid amide derivatives and their pharmacologically acceptable addition salts - Google Patents

4-Substituted quinoline-8-carboxylic acid amide derivatives and their pharmacologically acceptable addition salts Download PDF

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JPWO2004014861A1
JPWO2004014861A1 JP2004527322A JP2004527322A JPWO2004014861A1 JP WO2004014861 A1 JPWO2004014861 A1 JP WO2004014861A1 JP 2004527322 A JP2004527322 A JP 2004527322A JP 2004527322 A JP2004527322 A JP 2004527322A JP WO2004014861 A1 JPWO2004014861 A1 JP WO2004014861A1
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志賀　太
太 志賀
高野　安雄
安雄 高野
石山　順一
順一 石山
剛 安楽
剛 安楽
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩を有効成分とするポリ（ＡＤＰ−リボース）合成酵素阻害作用を有する化合物を提供する。一般式（１）で表される４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。Provided is a compound having a poly (ADP-ribose) synthetase inhibitory activity, which comprises a 4-substituted quinoline-8-carboxylic acid amide derivative and a pharmacologically acceptable addition salt thereof as active ingredients. A 4-substituted quinoline-8-carboxylic acid amide derivative represented by the general formula (1) and a pharmacologically acceptable addition salt thereof.

Description

本発明は、４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩およびこれらを有効成分として含有するポリ（ＡＤＰ−リボース）合成酵素阻害剤に関する。  The present invention relates to a 4-substituted quinoline-8-carboxylic acid amide derivative, a pharmacologically acceptable addition salt thereof, and a poly (ADP-ribose) synthase inhibitor containing these as active ingredients.

ポリ（ＡＤＰ−リボース）合成酵素（ｐｏｌｙ（ＡＤＰ−ｒｉｂｏｓｅ）ｐｏｌｙｍｅｒａｓｅ；以下、「ＰＡＲＰ」と略す。別名：ｐｏｌｙ（ＡＤＰ−ｒｉｂｏｓｅ）ｓｙｎｔｈｅｔａｓｅ）は、核内ＤＮＡ機能調節タンパク質であり、ＤＮＡの損傷を認識することで活性化を受け、細胞内必須構成要素であるＮＡＤ（ｎｉｃｏｔｉｎａｍｉｄｅ ａｄｅｎｉｎｅ ｄｉｎｕｃｌｅｏｔｉｄｅ）を酵素基質として、ポリ（ＡＤＰ−リボース）をＤＮＡ−ポリメラーゼ等のアクセプタータンパク質に逐次転移させる酵素である。従って、ＰＡＲＰの過剰な活性化は、電子伝達系に必須なＮＡＤの枯渇に基づく細胞内エネルギー生産能の低下を惹起し、細胞死を招くと考えられている（Ｃ．Ｓｚａｂｏ，Ｆｒｅｅ Ｒａｄｉｃ．Ｂｉｏｌ．Ｍｅｄ．，２１，８５５（１９９６））。また、ＰＡＲＰがインターロイキン−１β変換酵素様プロテアーゼファミリーの一つであるカスパーゼ−３の基質となって限定分解されることから、アポトーシス関連酵素としても注目を集めている。
更に、ＰＡＲＰ−ノックアウトマウスを用いた実験で、このノックアウトマウスの脳より採取した培養神経細胞が、一酸化窒素およびＮＭＤＡ（Ｎ−ｍｅｔｈｙｌ−Ｄ−ａｓｐａｒｔａｔｅ）等の興奮性アミノ酸による障害に対して抵抗性を示すこと、またこのノックアウトマウスは脳虚血による梗塞巣を約８０％以上抑制することが報告されている（Ｍ．Ｊ．Ｌ．Ｅｌｉａｓｓｏｎ ｅｔ ａｌ．，Ｎａｔｕｒｅ Ｍｅｄ．，３，１０８９（１９９７））。これらのことからＰＡＲＰ阻害剤は、脳梗塞や神経変性疾患（アルツハイマー病、ハンチントン舞踏病、パーキンソン病等）に有効であると考えられている。これ以外にも、糖尿病、心筋梗塞や急性腎不全等の虚血あるいは虚血−再潅流による疾患、敗血症性ショック等の循環器系疾患、慢性関節リュウマチや多発性硬化症といった炎症性疾患にも有効であるとの報告がある（Ｃ．Ｓｚａｂｏ ｅｔ ａｌ．，Ｔｒｅｎｄ Ｐｈａｒｍａｃｏｌ Ｓｃｉ．，１９，２８７（１９９８））。またＰＡＲＰ阻害剤は、ＨＩＶを含む抗レトロウイルス剤（Ｇ．Ａ．Ｃｏｌｅ ｅｔ ａｌ．，Ｂｉｏｃｈｅｍ．Ｂｉｏｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．，１８０，５０４（１９９１））や抗癌療法の増感剤（Ｃ．Ａｒｕｎｄｅｌ−Ｓｕｔｏ，ｅｔ ａｌ．，Ｒａｄｉａｔ．Ｒｅｓ．，１２６，３６７（１９９１）；Ｓ．Ｂｏｕｌｔｏｎ ｅｔ ａｌ．，Ｂｒ．Ｊ．Ｃａｎｃｅｒ，７２，８４９（１９９５））としても有用であることが報告されている。
以上のことから、ＰＡＲＰ阻害活性を有する化合物は、ＰＡＲＰの過剰な活性化に起因する疾患、例えば、種々の虚血性疾患（脳梗塞、心筋梗塞、急性腎不全等）、炎症性疾患（炎症性腸疾患、多発性脳硬化症、関節炎、慢性関節リュウマチ等）、神経変性疾患（アルツハイマー病、ハンチントン舞踏病、パーキンソン病等）、糖尿病、敗血症性ショック、頭部外傷等の予防および／または治療剤として有用であることが期待される。
４−置換キノリン−８−カルボン酸アミド誘導体の類似構造化合物としては、特開昭６２−４８６６９号には抗腫瘍活性を有する化合物として一般式（３）

Figure 2004014861
（式中、Ｒ１とＲ２は別個に水素原子または低級アルキル基、ハロゲン、ＣＦ３、ＣＮ、ＳＯ２ＣＨ３、ＮＯ２、ＯＨ、ＮＨ２、ＯＲ３、ＮＨＲ３（Ｒ３は水酸基、アミノ基などを表す）などを表し、ＹはＣ（ＮＨ）ＮＨ２、ＮＨＣ（ＮＨ）ＮＨ２またはＮＲ４Ｒ５（Ｒ４とＲ５は水素原子または水酸基、アミノ基などを表し、ｎは２〜６を表す）を表す）で表される化合物（置換基の説明は一部を抜粋した）が、特開平１０−２９１９８８号には異常骨代謝による骨疾患の治療に有用な化合物として一般式（４）
Figure 2004014861
（式中、Ｒ１は置換されていてもよい複素環基またはアリール基を表し、Ｒ２は水素原子または低級アルキル基を表し、Ｒ３は水素原子、ハロゲン原子などを表し、Ｒ４は置換されたアミノ基、置換されたヒドラジノ基、置換または非置換の複素環基などを表し、Ｒ５、Ｒ６およびＲ７は水素原子、ハロゲン原子または低級アルキル基を表し、Ａは−ＣＯＮＨ−、−ＮＨＣＯ−などを表す）で表される化合物（置換基の説明は一部を抜粋した）が知られている。しかしながらこれら化合物は、いずれもキノリン８位が２級カルボン酸アミドであり、１級カルボン酸アミドを特徴とする本発明化合物とは構造が異なり、ＰＡＲＰ阻害活性についても何ら記載がない。
また、特開平４−２２５９５９号にはアンギオテンシンＩＩ拮抗作用を有する化合物として一般式（５）
Figure 2004014861
（式中、Ｒ１は水素原子、Ｃ１〜Ｃ８アルキル基、フェニル基などを表し、Ｒ２は水素原子、Ｃ１〜Ｃ８アルキル基、フェニル基、カルボキシ基などを表し、Ｒ３、Ｒ４は独立して水素原子、Ｃ１〜Ｃ４アルキル基、ハロゲン原子、トリフルオロメチル基、ヒドロキシ基、アミノ基、カルバモイル基、最大７個までの炭素原子を有するＮ−アルキルカルバモイル基およびジ−（Ｎ−アルキル）カルバモイル基などを表し、Ｒ５は水素原子、Ｃ１〜Ｃ４アルキル基、Ｃ１〜Ｃ４アルコキシ基、ハロゲン原子などを表し、Ｘは、所望ならば、Ｃ１〜Ｃ４アルキル基、Ｃ１〜Ｃ４アルコキシ基などを表し、Ｒａは、所望ならば、一個以上のフッ素原子を有してもよいＣ１〜Ｃ４アルキル基を表し、Ｚは１Ｈ−テトラゾール−５−イル基などを表す）で表される化合物（置換基の説明は一部を抜粋した）が、特開平８−３１４４号にはカリウムチャンネルオープナーとして強い血管拡張作用を有する化合物として一般式（６）
Figure 2004014861
（式中、ＡおよびＢは同一または異なってＮまたはＣＨを表し、Ｒ１およびＲ２は水素原子、低級アルキル基、低級ハロアルキル基、低級アルコキシ基、ハロゲン原子、シアノ基、ニトロ基、アシル基、カルボキシル基、アミド基などを表し、Ｒ３は水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいアリール基を表し、Ｒ４は飽和または不飽和の複素環基、置換基を有してもよいアミノ基、低級アルコキシ基、アリールオキシ基などを表す）で表される化合物（置換基の説明は一部を抜粋した）が、ＷＯ９６／０９２９４号には一般式（７）
Figure 2004014861
（式中、ＸはＮまたはＣＨを表し、Ｙは基Ｗ（ＣＨ２）、（ＣＨ２）Ｗ、Ｗ（ＷはＯ、Ｓ（Ｏ）ｍを表し、ｍは０〜２を表す）、またはＮＲａ（Ｒａは水素またはＣ１〜Ｃ８アルキル基を表す）を表し、Ｒ１、Ｒ２、Ｒ３およびＲ３‘は同一であるか、または異なっていてもよく、各々はアミノ、水素、ハロゲン、ヒドロキシ、カルボキシ、カルバモイル、ウレイド、Ｎ−Ｃ１〜Ｃ４アルキルカルバモイル、Ｎ，Ｎ−ジ［Ｃ１〜Ｃ４アルキル］カルバモイル基などを表し、各Ｒ４は水素、ハロゲン、トリフルオロメチル、Ｃ１〜Ｃ４アルキル基、Ｃ１〜Ｃ４アルコキシ基などを表し、Ｒ５は水素、ハロゲン、トリフルオロメチル、Ｃ１〜Ｃ４アルキル基、Ｃ１〜Ｃ４アルコキシ基を表し、Ｒ６は基ＺＲ７を表す）で表される化合物（置換基の説明は一部を抜粋した）が、ＷＯ９７／０３０６９号には一般式（８）
Figure 2004014861
（式中、ＸはＮまたはＣＨを表し、Ｙは基Ｗ（ＣＨ２）、（ＣＨ２）ＷまたはＷ（ＷはＯ、Ｓ（Ｏ）ｍを表し、ｍは０〜２を表す）、またはＮＲａ（Ｒａは水素またはＣ１〜Ｃ８アルキル基を表す）を表し、Ｕは５〜１０員の一または二環系を表し、Ｒ１、Ｒ２、Ｒ３およびＲ３‘は同一または異なるものであり、それぞれアミノ、水素、ハロゲン、ヒドロキシ、カルボキシ、カルバモイル、ウレイド、Ｎ−Ｃ１〜Ｃ４アルキルカルバモイル、Ｎ，Ｎ−ジ［Ｃ１〜Ｃ４アルキル］カルバモイル基などを表し、Ｒ５は水素、ハロゲン、トリフルオロメチル、Ｃ１〜Ｃ４アルキル基、Ｃ１〜Ｃ４アルコキシ基を表す）で表される化合物（置換基の説明は一部を抜粋した）が知られているが、これらの明細書中にも本発明化合物の特徴であるキノリン８位に一級カルボン酸アミド（カルバモイル基）を有する化合物は開示されておらず、ＰＡＲＰ阻害活性を有することも記されていない。
またＥＰ３９９２６７号にはＫ＋／Ｈ＋−ＡＴＰアーゼおよび胃酸分泌を抑制する化合物として一般式（９）
Figure 2004014861
（式中、Ｒ１は水素原子、ヒドロキシ基もしくはＣ１〜Ｃ４アルコキシ基によって置換されていてもよいＣ１〜Ｃ４アルキル基を表し、Ｒ２は水素原子またはＣ１〜Ｃ６アルキル基を表し、Ｒ３は１〜３個のＣ１〜Ｃ４アルキル基および／または１〜２個のハロゲン原子によって置換されていてもよいチエニル基などを表し、Ｒ４は水素原子またはＣ１〜Ｃ４アルキル基などを表し、Ｒ５はヒドロキシ基、アミノ基、Ｃ１〜Ｃ４アルキルアミノ基、Ｃ１〜Ｃ６アルコキシカルボニル基、アミノカルボニル基、ジ（Ｃ１〜Ｃ６アルキル）アミノカルボニル基などを表し、Ｒ６は水素原子またはＣ１〜Ｃ４アルキル基などを表す）で表される化合物（置換基の説明は一部を抜粋した）が知られているが、本発明化合物の特徴であるキノリン８位に一級カルボン酸アミド（カルバモイル基）を有する化合物としては、２−メチル−４−（（３−メチル−２−チエニル）メチルアミノ）キノリン−８−カルボン酸アミド（Ｒ１＝ＣＨ３，Ｒ２＝Ｒ４＝Ｒ６＝Ｈ，Ｒ３＝３−ｍｅｔｈｙｌ−２−ｔｈｉｅｎｙｌ，Ｒ５＝ＣＯＮＨ２）が唯一開示されているもののＰＡＲＰ阻害活性を有することは記されていない。
一方、現在知られているＰＡＲＰ阻害活性を有する化合物としては、表１記載の一般式（１０）〜（２５）で表される化合物（置換基の説明は省略した）が挙げられるが、これらはいずれも環状アミド構造を有する化合物であり、１級カルボン酸アミドを特徴とする本発明化合物とは構造を異にするものである。また開示された化合物のＰＡＲＰ阻害活性も十分であるとはいえない。
Figure 2004014861
次に１級カルボン酸アミドを有したＰＡＲＰ阻害活性を有する化合物としては、ＷＯ９７／４７７１号には一般式（２６）
Figure 2004014861
（式中、Ｒは水素原子、アルキル基、ヒドロキシアルキル基（例えば、ヒドロキシエチル基）、アシル基（例えば、アセチル基、ベンゾイル基）、置環基を有してもよいアリール基（例えば、フェニル基）あるいはアラルキル（例えば、ベンジル基、カルボキシベンジル基）を表し、Ｒ’は水素原子、アルキル基、ヒドロキシアルキル基（例えば、ヒドロキシエチル基）、アシル基（例えば、アセチル基、ベンゾイル基）、置環基を有してもよいアリール基（例えば、フェニル基）あるいはアラルキル（例えば、ベンジル基、カルボキシベンジル基）を表す）で表される化合物が知られているが、キノリン−８−カルボン酸アミドを特徴とする本発明化合物とは構造を異にするものである。また開示された化合物のＰＡＲＰ阻害活性も十分であるとは言えない。
更にＷＯ９９／５９９７３号には一般式（２７）
Figure 2004014861
（式中、Ｙは縮合した５員若しくは６員の、芳香あるいは非芳香の炭化水素環であるか、酸素原子、硫黄原子、窒素原子を含むヘテロ環を構成する原子であり、Ｙと他のヘテロ原子は無置換あるいはアルキル基、アルケニル基、シクロアルキル基、シクロアルケニル基、アラルキル基、アリール基、カルボキシ基、ハロゲン原子で置換されていてもよく、Ｘは環Ｙの１位であり、ＣＯ２Ｒ５あるいは、
Figure 2004014861
から選択され、Ｒ７は水素原子、アルキル基、アルケニル基、シクロアルキル基などを表し、Ｒ１は水素原子、アルキル基、アルケニル基、シクロアルキル基などを表し、Ｒ３、Ｒ４およびＲ５は独立して、アルキル基、アルケニル基、シクロアルキル基、アミノ基、水酸基などを表す）で表される化合物が知られているが、本発明化合物の特徴であるキノリン−８−カルボン酸アミドを包含するものではなく、本発明化合物とは構造を異にするものである。また開示された化合物のＰＡＲＰ阻害活性も十分であるとは言えない。
１級カルボン酸アミドを有したＰＡＲＰ阻害活性を有する類似化合物としては、更に表２記載の一般式（２８）〜（３６）で表される化合物（置換基の説明は省略した）が知られているが、いずれもキノリン−８−カルボン酸アミドを特徴とする本発明化合物とは構造を異にするものである。また開示された化合物のＰＡＲＰ阻害活性も十分であるとはいえない。
Figure 2004014861
本発明はＰＡＲＰの過剰な活性化に起因する疾患、例えば、種々の虚血性疾患（脳梗塞、心筋梗塞、急性腎不全等）、炎症性疾患（炎症性腸疾患、多発性脳硬化症、関節炎、慢性関節リュウマチ等）、神経変性疾患（アルツハイマー病、ハンチントン舞踏病、パーキンソン病等）、糖尿病、敗血症性ショック、頭部外傷等の予防および／または治療剤として開発が期待されるＰＡＲＰ阻害活性を有する新規な化合物を提供することにある。Poly (ADP-ribose) synthetase (hereinafter abbreviated as “PARP”, also known as poly (ADP-ribose) synthetase) is a protein that regulates DNA function in the nucleus and damages DNA. It is an enzyme that is activated by recognition and sequentially transfers poly (ADP-ribose) to an acceptor protein such as DNA-polymerase using NAD (nicotinamide adenine dinucleotide) as an enzyme substrate as an enzyme substrate. Therefore, excessive activation of PARP is thought to cause a decrease in intracellular energy production ability based on depletion of NAD essential for the electron transport system, leading to cell death (C. Szabo, Free Radic. Biol). Med., 21 , 855 (1996)). In addition, since PARP is limitedly decomposed as a substrate of caspase-3, which is one of the interleukin-1β converting enzyme-like protease family, it is also attracting attention as an apoptosis-related enzyme.
Furthermore, in an experiment using a PARP-knockout mouse, cultured neurons collected from the brain of the knockout mouse were resistant to damage caused by excitatory amino acids such as nitric oxide and NMDA (N-methyl-D-aspartate). It is reported that this knockout mouse suppresses infarct caused by cerebral ischemia by about 80% or more (MJL Eliasson et al., Nature Med., 3 , 1089 (1997). )). Therefore, PARP inhibitors are considered to be effective for cerebral infarction and neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.). Other than this, there are also diseases caused by ischemia or ischemia-reperfusion such as diabetes, myocardial infarction and acute renal failure, cardiovascular diseases such as septic shock, inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. There are reports that it is effective (C. Szabo et al., Trend Pharmacol Sci., 19 , 287 (1998)). In addition, PARP inhibitors include antiretroviral agents including HIV (GA Cole et al., Biochem. Biophys. Res. Commun., 180 , 504 (1991)) and sensitizers for anticancer therapy (C.I. Arundel-Suto, et al., Radiat.Res., 126 , 367 (1991); S. Boulton et al., Br. J. Cancer, 72, 849 (1995)). Yes.
Based on the above, compounds having PARP inhibitory activity are diseases caused by excessive activation of PARP, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory) Intestinal diseases, multiple encephalopathy, arthritis, rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.), diabetes, septic shock, head trauma, etc. It is expected to be useful as
As a compound having a similar structure to a 4-substituted quinoline-8-carboxylic acid amide derivative, Japanese Patent Application Laid-Open No. 62-48669 discloses a compound represented by the general formula (3)
Figure 2004014861
(In the formula, R 1 and R 2 are each independently a hydrogen atom or a lower alkyl group, halogen, CF 3 , CN, SO 2 CH 3 , NO 2 , OH, NH 2 , OR 3 , NHR 3 (R 3 is a hydroxyl group, Y represents C (NH) NH 2 , NHC (NH) NH 2 or NR 4 R 5 (R 4 and R 5 represent a hydrogen atom or a hydroxyl group, an amino group, etc., and n represents (Representing a part of the explanation of substituents), JP-A-10-291988 discloses a compound useful as a compound for treating bone diseases caused by abnormal bone metabolism. Formula (4)
Figure 2004014861
(In the formula, R 1 represents an optionally substituted heterocyclic group or aryl group, R 2 represents a hydrogen atom or a lower alkyl group, R 3 represents a hydrogen atom, a halogen atom, etc., and R 4 represents a substituted group. A substituted amino group, a substituted hydrazino group, a substituted or unsubstituted heterocyclic group, etc., R 5 , R 6 and R 7 represent a hydrogen atom, a halogen atom or a lower alkyl group, A represents —CONH—, A compound represented by —NHCO— or the like (the description of substituents is partially extracted) is known. However, all of these compounds are secondary carboxylic acid amides at the 8-position of quinoline and have different structures from the compounds of the present invention characterized by primary carboxylic acid amides, and there is no description of PARP inhibitory activity.
JP-A-4-225959 discloses a compound having the general formula (5) as an angiotensin II antagonism.
Figure 2004014861
(In the formula, R 1 represents a hydrogen atom, a C 1 -C 8 alkyl group, a phenyl group, etc., R 2 represents a hydrogen atom, a C 1 -C 8 alkyl group, a phenyl group, a carboxy group, etc., R 3 , R 4 is independently a hydrogen atom, C 1 -C 4 alkyl group, halogen atom, trifluoromethyl group, hydroxy group, amino group, carbamoyl group, N-alkylcarbamoyl group having up to 7 carbon atoms and di- -(N-alkyl) carbamoyl group or the like, R 5 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a halogen atom, or the like, and X is, if desired, C 1- Represents a C 4 alkyl group, a C 1 -C 4 alkoxy group, and the like, Ra represents a C 1 -C 4 alkyl group which may have one or more fluorine atoms, if desired, and Z represents 1H-tetrazole- 5 A compound represented by yl represents a group and the like) (the description of the substituents the excerpt) has the general formula as compounds in JP-A-8-3144 having strong vasodilating activity as potassium channel openers (6)
Figure 2004014861
(In the formula, A and B are the same or different and each represents N or CH, and R 1 and R 2 are hydrogen atom, lower alkyl group, lower haloalkyl group, lower alkoxy group, halogen atom, cyano group, nitro group, acyl group. R 3 represents a hydrogen atom, a lower alkyl group that may have a substituent, or an aryl group that may have a substituent, and R 4 represents a saturated or unsaturated complex. A compound represented by a cyclic group, an amino group which may have a substituent, a lower alkoxy group, an aryloxy group, etc. (the description of the substituent is partially extracted) is disclosed in WO 96/09294. General formula (7)
Figure 2004014861
(Wherein X represents N or CH, Y represents a group W (CH 2 ), (CH 2 ) W, W (W represents O, S (O) m, m represents 0 to 2)), or NR a (R a represents hydrogen or C 1 -C 8 alkyl group) represents, R 1, R 2, R 3 and R 3 'may be the identical or different, each amino , Hydrogen, halogen, hydroxy, carboxy, carbamoyl, ureido, N—C 1 -C 4 alkylcarbamoyl, N, N-di [C 1 -C 4 alkyl] carbamoyl group and the like, each R 4 represents hydrogen, halogen, trifluoromethyl, C 1 -C 4 alkyl group, C 1 -C 4 represents an alkoxy group, R 5 is hydrogen, halogen, trifluoromethyl, C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group R 6 represents the group ZR 7 ) The compounds represented (excerpts of the explanation of substituents) are described in WO 97/03069, but the general formula (8)
Figure 2004014861
Wherein X represents N or CH, Y represents a group W (CH 2 ), (CH 2 ) W or W (W represents O, S (O) m, m represents 0-2), or NR a (R a represents hydrogen or C 1 -C 8 alkyl group) represents, U is represents one or bicyclic 5- to 10-membered, R 1, R 2, R 3 and R 3 ' be the same or different, each represents an amino, hydrogen, halogen, hydroxy, carboxy, carbamoyl, ureido, N-C 1 ~C 4 alkylcarbamoyl, N, N-di [C 1 -C 4 alkyl] carbamoyl group, etc. , R 5 represents a compound represented by hydrogen, halogen, trifluoromethyl, a C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy group) (explanation of substituents is partly extracted) However, the compounds of the present invention are also described in these specifications. A compound having a primary carboxylic acid amide (carbamoyl group) at the 8-position of quinoline, which is a feature of the above, is not disclosed, nor is it described that it has PARP inhibitory activity.
EP 399267 discloses a compound represented by the general formula (9) as a compound that suppresses K + / H + -ATPase and gastric acid secretion.
Figure 2004014861
(Wherein, R 1 represents a hydrogen atom, a hydroxy group or a C 1 ~C 4 C 1 may be substituted by an alkoxy group -C 4 alkyl group, R 2 represents a hydrogen atom or a C 1 -C 6 alkyl group R 3 represents 1 to 3 C 1 -C 4 alkyl groups and / or a thienyl group optionally substituted by 1 to 2 halogen atoms, and R 4 represents a hydrogen atom or C 1- C 4 represents an alkyl group, R 5 is hydroxy group, amino group, C 1 -C 4 alkylamino group, C 1 -C 6 alkoxycarbonyl group, aminocarbonyl group, di (C 1 -C 6 alkyl) aminocarbonyl A compound represented by a group such as R 6 represents a hydrogen atom or a C 1 to C 4 alkyl group, etc. (the description of the substituent is partially extracted) is known. Special The compound having a quinoline 8-position primary carboxylic acid amide (carbamoyl) is 2-methyl-4 - ((3-methyl-2-thienyl) methylamino) quinoline-8-carboxylic acid amide (R 1 = CH3, R 2 = R 4 = R 6 = H, R 3 = 3-methyl-2-thienyl, R 5 = CONH 2 ) is the only one disclosed but is not described as having PARP inhibitory activity.
On the other hand, examples of the currently known compounds having PARP inhibitory activity include compounds represented by the general formulas (10) to (25) shown in Table 1 (the explanation of substituents is omitted). All of them are compounds having a cyclic amide structure, and are different in structure from the compound of the present invention characterized by primary carboxylic acid amide. Moreover, it cannot be said that the PARP inhibitory activity of the disclosed compound is sufficient.
Figure 2004014861
Next, as a compound having a primary carboxylic acid amide and having a PARP inhibitory activity, WO 97/4771 discloses a general formula (26).
Figure 2004014861
Wherein R is a hydrogen atom, an alkyl group, a hydroxyalkyl group (for example, hydroxyethyl group), an acyl group (for example, acetyl group, benzoyl group), or an aryl group (for example, phenyl) Group) or aralkyl (for example, benzyl group, carboxybenzyl group), R ′ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group (for example, hydroxyethyl group), an acyl group (for example, acetyl group, benzoyl group), A compound represented by an aryl group (for example, phenyl group) or aralkyl (for example, benzyl group, carboxybenzyl group) which may have a ring group is known, but quinoline-8-carboxylic acid amide is known. The compound of the present invention, which is characterized by the above, has a different structure. Moreover, it cannot be said that the PARP inhibitory activity of the disclosed compound is sufficient.
Further, WO99 / 59973 describes the general formula (27)
Figure 2004014861
Wherein Y is a condensed 5-membered or 6-membered aromatic or non-aromatic hydrocarbon ring, or an atom constituting a heterocycle containing an oxygen atom, a sulfur atom, or a nitrogen atom; The heteroatom may be unsubstituted or substituted with an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkenyl group, an aralkyl group, an aryl group, a carboxy group, or a halogen atom, X is the 1-position of ring Y, and CO 2 R 5 or
Figure 2004014861
R 7 represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, or the like; R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, or the like; R 3 , R 4, and R 5 Independently represents an alkyl group, an alkenyl group, a cycloalkyl group, an amino group, a hydroxyl group, etc.), but the quinoline-8-carboxylic acid amide, which is a feature of the compound of the present invention, is known. It is not intended to be included, and is different in structure from the compound of the present invention. Moreover, it cannot be said that the PARP inhibitory activity of the disclosed compound is sufficient.
As similar compounds having primary carboxylic acid amide and having PARP inhibitory activity, compounds represented by the general formulas (28) to (36) shown in Table 2 are further known (substituents are omitted). However, all of them are different in structure from the compound of the present invention characterized by quinoline-8-carboxylic acid amide. Moreover, it cannot be said that the PARP inhibitory activity of the disclosed compound is sufficient.
Figure 2004014861
The present invention relates to diseases caused by excessive activation of PARP, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebral sclerosis, arthritis) Rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.), diabetes, septic shock, head injury, etc. It is to provide a novel compound having the above.

本発明者らは、新規なＰＡＲＰ阻害活性を有する化合物を求めて、鋭意研究を重ねた結果、本発明の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩に優れたＰＡＲＰ阻害活性を見出した。
すなわち、本発明によって、一般式（１）

Figure 2004014861
［式中、Ｒ１はハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基、または一般式（２）
Figure 2004014861
（式中、環Ａｒは、フェニル基、ナフチル基、５員若しくは６員の複素環及びその縮合環を表し、
Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表す）を表し、
Ｒ２、Ｒ３、Ｒ４は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基（ハロゲン原子で置換されてもよい低級アルコキシ基、置換基を有してもよいアミノ基、ニトロ基、シアノ基を表し、
Ｘは酸素原子、硫黄原子、ＮＲ１３（ここで、Ｒ１３は水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表す）を表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ７は水素原子、ハロゲン原子、水酸基、置換基を有してもよい環状アルキル基、置換基を有してもよい低級アルコキシ基、カルボキシ基、低級アルコキシカルボニル基、ＮＲ１１Ｒ１２、ＣＯＮＲ１１Ｒ１２、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して５員若しくは６員の複素環及びその縮合環（これらは複素環、縮合環上に置換基を有してもよい）を表し、
ｎは０〜３を表す］で表される４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩、一般式（１−ｄ）
Figure 2004014861
［式中、Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ２ａ、Ｒ３ａ、Ｒ４ａは同一または異なって、水素原子、ハロゲン原子を表し、
Ｘａは酸素原子、ＮＨを表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して５員若しくは６員の複素環及びその縮合環（これらは複素環、縮合環上に置換基を有してもよい）を表し、
ｎは０〜３を表す］で表される４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩、および一般式（１−ｅ）
Figure 2004014861
［式中、Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ２ａ、Ｒ３ａ、Ｒ４ａは同一または異なって、水素原子、ハロゲン原子を表し、
Ｘａは酸素原子、ＮＨを表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して５員若しくは６員の複素環及びその縮合環（これらは複素環、縮合環上に置換基を有してもよい）を表し、
ｎは０〜３を表す］で表される４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩に優れたＰＡＲＰ阻害活性を有することを見出し、本発明を完成するに至った。
本発明化合物の一般式（１）において、好ましくは、Ｒ１が一般式（２）である化合物が挙げられる。
更に好ましくは、Ｒ１が一般式（２）で示される化合物の内、Ｒ２、Ｒ３、Ｒ４が同一または異なって、水素原子、ハロゲン原子であり、Ｒ７が水酸基、ＮＲ１１Ｒ１２である化合物が挙げられる。
特に好ましくは、Ｒ１が一般式（２）で示される化合物の内、環Ａｒがフェニル基であり、Ｒ２、Ｒ４が水素原子であり、Ｒ３が水素原子またはハロゲン原子であり、Ｘが酸素原子、ＮＲ１３であり、Ｒ１３が水素原子である化合物が挙げられる。
これら好ましい化合物としては、例えば、以下の表３〜５記載の化合物を挙げることができるが、本発明はこれら化合物またはその薬理上許容される付加塩に限定されるものではない。
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
上記表３〜５において、更に好ましい化合物としては、例示番号１１〜１３、１５、１６、１８〜３８、４２〜７５、７９〜１１６、１２０〜１７３、１７７〜２１４、２１８〜２７４、２７８〜２９６の化合物を挙げることができる。
特に好ましい化合物としては、例示番号１１〜１３、１５、１６、１８〜３２、３６〜３８、４２〜４７、５６〜７５、７９〜１１０、１１４〜１１６、１２０〜１３３、１５２〜１６７、１７１〜１７３、１７７〜１９０、１９４〜２３３、２５１〜２７１、２７８〜２９３の化合物を挙げることができる。
本発明の一般式（１）の文中において『ハロゲン原子で置換されてもよい低級アルキル基』および『ハロゲン原子で置換されてもよい低級アルコキシ基』における『ハロゲン原子』とは、フッ素、塩素、臭素、ヨウ素が挙げられ、『低級アルキル基』とは、メチル、エチル、ｎ−プロピル、ｉｓｏ−プロピルなどの直鎖若しくは分岐した炭素数１〜６のものが挙げられ、『低級アルコキシ基』とは、メトキシ、エトキシ、プロポキシなどの直鎖若しくは分岐した炭素数１〜４のものが挙げられる。また文中において、『置換基を有してもよい環状アルキル基』、『置換基を１個以上有してもよいアラルキル基』、『置換基を有してもよいフェニル基』、『置換基を有してもよいナフチル基』および『置換基を有してもよい５員若しくは６員の複素環及びその縮合環』における『置換基』とは、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、低級アルキルチオ基、低級アルコキシカルボニル基、ニトロ基、置換基を有してもよいアミノ基、シアノ基、カルボキシル基、アルデヒド基、ヒドロキシ基で置換された低級アルキル基、カルボキシ基で置換された低級アルキル基、ハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基で置換されてもよいアミノ基で置換された低級アルキル基、置換基を有しても良い５員若しくは６員の環状アミノ基で置換された低級アルキル基、ヒドロキシ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、ハロゲン原子で置換されてもよい低級アルキル基または置換基を有してもよいアラルキル基で置換されてもよいアミノ基で置換された低級アルコキシ基、置換基を有しても良い５員若しくは６員の環状アミノ基で置換された低級アルコキシ基などが挙げられ、『低級アルコキシカルボニル基』とは、メトキシカルボニル、エトキシカルボニルなどの直鎖若しくは分岐した炭素数１〜６のものが挙げられ、『置換基を有してもよいアミノ基』とは、アシル基、ハロゲン原子で置換されていてもよい低級アルキルスルホニル基、アリールスルホニル基、例えばアセチル、メタンスルホニル、フェニルスルホニルなどによって置換されてもよく、またハロゲン原子で置換されていてもよい低級アルキル基、置換基を有してもよいフェニル基、置換基を有してもよいアラルキル基によって置換されていてもよいアミノ基が挙げられ、『置換基を有しても良い５員若しくは６員の環状アミノ基』における『５員若しくは６員の環状アミノ基』とは、ピロリジル、ピペリジル、ピペラジル、モルホリル、チオモルホリルなどが挙げられる。ここで言う置換基とは上記で説明した『置換基』を指す。
また『環状アルキル基』とは、シクロプロピル、シクロペンチル、シクロヘキシルなどの炭素数３〜７のものが挙げられ、『５員若しくは６員の複素環及びその縮合環』における『複素環』とは、置換基を１個以上有してもよい飽和若しくは不飽和の単環式又は多環式の窒素、酸素、硫黄原子を１個以上含有し得る複素環式基であり、例えばピロリジル、ピペリジル、ピペラジル、モルホリル、チオモルホリル、フラニル、チエニル、ピラゾリル、イミダゾリル、オキサゾリル、チアゾリル、ピリジル、ピリミジル、ピリダジル、ピラチルなどが挙げられ、『その縮合環』とは、上記『複素環』のベンゼン縮合環（例えば、インドリル、テトラヒドロキノリル、ベンズオキサゾリジニル、ベンゾチアゾリジニル、ベンゾフラニル、ベンゾチエニル、ベンズイミダゾリル、キノリル、イソキノリル、キナゾリル、キノキサリル、シンノリルなどが挙げられる）あるいは上記『複素環』より任意に選ばれた２つの環より成る縮合環（例えば、イミダゾピリジン、ピラゾロピリジン、イミダゾピリミジンなどが挙げられる）を指す。
本発明の一般式（１）で表される化合物は、必要に応じて薬理上許容される塩とすることができる。薬理上許容される塩としては、例えば、塩酸、臭化水素酸、硫酸等の無機酸塩、酢酸、フマル酸、シュウ酸、クエン酸、メタンスルホン酸、トシル酸等の有機酸塩、およびナトリウム塩、カリウム塩、カルシウム塩、アンモニウム塩等の塩基塩が挙げられる。
また本発明の一般式（１）で表される化合物とその薬理上許容される塩は、その分子内塩、それらの無水物、水和物または溶媒和物であってもよい。
本発明のＰＡＲＰ阻害活性を有する、一般式（１）で表される化合物は、公知化合物から公知の方法の組合せにより合成することができる。例えば、一般式（１）で表される化合物の内、Ｘが酸素原子、硫黄原子である一般式（１−ｈ）で表される化合物は、以下に示す方法（製造法Ｉ）により容易に合成することができる。
＜製造法Ｉ＞
Figure 2004014861
上記式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ１１、Ｒ１２、ｎは前述したものと同意義を表し、Ｘｂは酸素原子、硫黄原子を表し、Ｒ１４はハロゲン原子で置換されてもよい低級アルキル基、置換基を１個以上有してもよいアラルキル基を表す。
一般式（３７）で表される化合物から一般式（３８）で表される化合物への変換（工程Ｉ−Ａ）は、Ｃｏｎｒａｄ−Ｌｉｍｐａｃｈの合成法と呼ばれ、４（１Ｈ）−キノロンを構築する反応の一つであり、適当な溶媒、例えば、クロロホルム、ベンゼン、トルエン等の溶媒中、適当な酸、例えば、酢酸、メタンスルホン酸、トシル酸、三フッ化ホウ素ジエチルエーテル錯体等の存在下、一般式（４１）
Figure 2004014861
（式中、Ｒ１、Ｘｂは前述したものと同意義を表し、Ｒ１５はハロゲン原子で置換されてもよい低級アルコキシ基、置換基を１個以上有してもよいアラルキルオキシ基または４−（低級アルコキシ）アニリノ基を表す）で表される化合物を用い、５〜７２時間加熱環流することにより、脱水縮合させた後、例えば、ジフェニルエーテル、ニトロベンゼン等の高沸点溶媒中、あるいは硫酸、ポリリン酸などの強酸中、１００〜２５０℃にて０．５〜３時間反応させることにより行うことができる。
一般式（３８）で表される化合物から一般式（３９）で表される化合物への変換（工程Ｉ−Ｂ）は、適当な溶媒、例えば、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、テトラヒドロフランなどの溶媒中、適当な塩基、例えば、炭酸ナトリウム、炭酸カリウム、トリエチルアミン、ピリジンなどの存在下、一般式（４２）
Figure 2004014861
（式中、Ｒ５、Ｒ６、Ｒ７、ｎは前述したものと同意義を表し、Ｙはハロゲン原子またはハロゲン原子で置換されていてもよい低級アルキルスルホニルオキシ基を表す）で表される化合物を用い、２０〜８０℃にて１〜２４時間反応させることにより行うことができる。
一般式（３９）で表される化合物から一般式（１−ｈ）で表される化合物への変換（工程Ｉ−Ｃ）は、適当な溶媒、例えば、水、メタノール、エタノール等の溶媒中、適当なアルカリ、例えば、水酸化カリウム、水酸化ナトリウム、炭酸カリウム等を用いて２０〜１００℃で０．５〜１０時間反応させてカルボン酸とし、無溶媒あるいは適当な溶媒、例えば、ジクロロメタン、クロロホルム、テトラヒドロフランなどの溶媒中、適当なハロゲン化剤、例えば塩化チオニル、オキシ塩化リンなどを用いて０〜１３０℃で１〜１０時間反応させて酸ハロゲン化物に変換後、適当な溶媒、例えば、水、メタノール、テトラヒドロフラン等の溶媒中、アンモニアを用いて、０〜６０℃で０．１〜３時間反応させることにより行うことができる。また、適当な溶媒、例えば、水、メタノール、エタノール等の溶媒中、アンモニアを用いて、１００〜１５０℃で５〜４８時間反応させても行うことができる。
一般式（３８）で表される化合物から一般式（４０）で表される化合物への変換（工程Ｉ−Ｄ）は、適当な溶媒、例えば、水、メタノール、エタノール等の溶媒中、アンモニアを用いて、１００〜１５０℃で５〜４８時間反応させることにより行うことができる。
一般式（４０）で表される化合物から一般式（１−ｈ）で表される化合物への変換（工程Ｉ−Ｅ）は、工程Ｉ−Ｂに準じて行うことができる。
一般式（１−ｈ）で表される化合物の内、Ｒ７がハロゲン原子である化合物は、工程Ｉ−Ｆにより、一般式（１−ｈ）で表される化合物の内、Ｒ７がＮＲ１１Ｒ１２である一般式（１−ｉ）で表される化合物に変換することができる。すなわち、適当な溶媒、例えば、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、テトラヒドロフランなどの溶媒中（必要に応じて適当なヨウ化塩、例えば、ヨウ化ナトリウム、ヨウ化カリウムを添加してもよい）、一般式（４３）
Figure 2004014861
（式中、Ｒ１１、Ｒ１２は前述したものと同意義を表す）で表される化合物を用い、６０〜１８０℃にて１〜２４時間反応させることにより行うことができる。
一般式（１−ｈ）で表される化合物の内、Ｒ７が低級アルコキシカルボニル基である化合物は、工程Ｉ−Ｇにより、一般式（１−ｈ）で表される化合物の内、Ｒ７がカルボキシ基である一般式（１−ｊ）で表される化合物に変換することができる。すなわち、適当な溶媒、例えば、水、メタノール、エタノール等の溶媒中、適当なアルカリ、例えば、水酸化カリウム、水酸化ナトリウム、炭酸カリウム等を用いて２０〜１００℃で０．５〜１０時間反応させることにより行うことができる。
一般式（１−ｈ）で表される化合物の内、Ｒ７がＣＯＮＲ１１Ｒ１２である一般式（１−ｋ）で表される化合物は、一般式（１−ｊ）で表される化合物から、工程Ｉ−Ｈより変換することができる。すなわち、適当な溶媒、例えば、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、テトラヒドロフランなどの溶媒中、適当な縮合剤、例えば１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド、ジシクロヘキシルカルボジイミドなどの存在下（必要に応じて適当な塩基、例えば、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等を添加してもよい）、一般式（４３）
Figure 2004014861
（式中、Ｒ１１、Ｒ１２は前述したものと同意義を表す）で表される化合物を用い、０〜８０℃で１〜３６時間反応させることにより行うことができる。
また本発明のＰＡＲＰ阻害活性を有する、一般式（１）で表される化合物の内、ＸがＮＲ１３である一般式（１−ｌ）で表される化合物は、例えば、下記の方法（製造法ＩＩ）により容易に合成することができる。
＜製造法ＩＩ＞
Figure 2004014861
上記式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ１３、Ｒ１４、ｎは前述したものと同意義を表し、Ｚはハロゲン原子を表す。
一般式（４４）で表される化合物は、一般式（３８）で表される化合物の内、Ｘｂが酸素原子である一般式（３８−ａ）で表される化合物から、工程ＩＩ−Ａにより変換することができる。すなわち、無溶媒あるいは適当な溶媒、例えば、ベンゼン、クロロホルム、１，２−ジクロロエタンなどの溶媒中、適当なハロゲン化剤、例えば、塩化チオニル、オキシ塩化リン、オキシ臭化リンなどを用い、６０〜１３０℃にて０．５〜６時間反応させることにより行うことができる。
一般式（４４）で表される化合物から一般式（４５）で表される化合物への変換（工程ＩＩ−Ｂ）は、無溶媒あるいは適当な溶媒、例えば、水、メタノール、エタノール等の溶媒中、アンモニアを用いて、１００〜１５０℃で５〜４８時間反応させることにより行うことができる。
また、無溶媒あるいは適当な溶媒、例えば、ジクロロメタン（クロロホルム等の溶媒中、三塩化ホウ素あるいは三臭化ホウ素を用いて、０〜６０℃で１〜２４時間反応させてカルボン酸とし、無溶媒あるいは適当な溶媒、例えば、ジクロロメタン、クロロホルム、テトラヒドロフランなどの溶媒中、適当なクロル化剤、例えば塩化チオニル、オキシ塩化リンなどを用いて２０〜１３０℃で１〜１０時間反応させて酸塩化物に変換後、適当な溶媒、例えば、水、メタノール、テトラヒドロフラン等の溶媒中、アンモニアを用いて、０〜６０℃で０．１〜３時間反応させても行うことができる。
一般式（３８−ａ）で表される化合物から一般式（４６）で表される化合物への変換（工程ＩＩ−Ｃ）は、適当な溶媒、例えば、水、メタノール、エタノール等の溶媒中、適当なアルカリ、例えば、水酸化カリウム、水酸化ナトリウム、炭酸カリウム等を用いて２０〜１００℃で０．５〜１０時間反応させることにより行うことができる。
一般式（４６）で表される化合物から一般式（４５）で表される化合物への変換（工程ＩＩ−Ｄ）は、無溶媒あるいは適当な溶媒、例えば、ベンゼン、クロロホルム、１，２−ジクロロエタンなどの溶媒中、適当なハロゲン化剤、例えば、塩化チオニル、オキシ塩化リン、オキシ臭化リンなどを用い、６０〜１３０℃にて０．５〜６時間反応させて酸ハロゲン化物とした後、適当な溶媒、例えば、水、メタノール、テトラヒドロフラン等の溶媒中、アンモニアを用いて、０〜６０℃で０．１〜３時間反応させることにより行うことができる。
一般式（４５）で表される化合物から一般式（１）で表される化合物の内、ＸがＮＲ１３である一般式（１−ｌ）で表される化合物への変換（工程ＩＩ−Ｅ）は、適当な溶媒、例えば、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリジノン、１，３−ジメチル−２−イミダゾリジノンなどの溶媒中（必要に応じて適当なヨウ化塩、例えば、ヨウ化ナトリウム、ヨウ化カリウムを添加してもよい）、一般式（４７）
Figure 2004014861
（式中、Ｒ５、Ｒ６、Ｒ７、Ｒ１３、ｎは前述したものと同意義を表す）で表される化合物を用い、８０〜１８０℃にて１〜２４時間反応させることにより行うことができる。
一般式（１）で表される化合物、または製造法ＩおよびＩＩにおける合成中間体である一般式（３８）〜（４０）、（４４）〜（４６）で表される化合物の内、Ｒ１が一般式（２）である化合物において、Ｒ８、Ｒ９およびＲ１０を必要に応じて他の置換基に変換することも公知の方法により行うことができる。例えば、一般式（１）で表される化合物の内、Ｒ１が一般式（２）であり、Ｒ８、Ｒ９またはＲ１０のいずれか一つ以上がハロゲン原子で置換されてもよい低級アルコキシ基である化合物は、無溶媒あるいは適当な溶媒、例えば水、酢酸あるいはこれらの混液等中、適当な酸、例えば塩酸、臭化水素酸等を用い、６０〜１１０℃で１〜２４時間反応させた後、無溶媒あるいは適当な溶媒、例えば、ジクロロメタン、クロロホルム、テトラヒドロフランなどの溶媒中、適当なクロル化剤、例えば塩化チオニル、オキシ塩化リンなどを用いて２０〜１３０℃で１〜１０時間反応させ、更に適当な溶媒、例えば、水、メタノール、テトラヒドロフランあるいはこれらの混液等の溶媒中、アンモニアを用いて、０〜６０℃で０．１〜３時間反応させることにより、一般式（１）で表される化合物の内、Ｒ１が一般式（２）であり、Ｒ８、Ｒ９またはＲ１０のいずれか一つ以上が水酸基である化合物に変換することができ、更に適当な溶媒、例えば、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド等中、適当なアルキル化剤、例えば、ヨードエタン、ブロモ酢酸エチルなどを用い、適当な塩基、例えば、炭酸カリウム、トリエチルアミン、ピリジンなどの存在下（必要に応じて適当なヨウ化塩、例えば、ヨウ化ナトリウム、ヨウ化カリウムを添加してもよい）、０〜８０℃にて１〜２４時間反応させることにより、一般式（１）で表される化合物の内、Ｒ１が一般式（２）であり、Ｒ８、Ｒ９またはＲ１０のいずれか一つ以上がハロゲン原子で置換されてもよい低級アルコキシ基あるいは低級アルコキシカルボニル基で置換された低級アルコキシ基である化合物に変換することができる。
また、一般式（１）で表される化合物の内、Ｒ１が一般式（２）であり、Ｒ８、Ｒ９またはＲ１０のいずれか一つ以上がニトロ基である化合物は、適当な溶媒、例えば、メタノール、エタノール、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当な触媒、例えば、パラジウム−炭素、白金−炭素などを用い、常圧または必要に応じて加圧下、２０〜８０℃にて１〜７２時間水素添加反応に付すことにより、一般式（１）で表される化合物の内、Ｒ１が一般式（２）であり、Ｒ８、Ｒ９またはＲ１０のいずれか一つ以上がアミノ基である化合物に変換することができ、更に適当な溶媒、例えば、クロロホルム、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミドあるいはこれらの混液等中、適当なアシル化剤、例えば、無水酢酸、塩化アセチルなどを用い、無塩基あるいは適当な塩基、例えば、トリエチルアミン、ピリジンなどの存在下、０〜８０℃にて１〜２４時間反応させることにより、一般式（１）で表される化合物の内、Ｒ１が一般式（２）であり、Ｒ８、Ｒ９またはＲ１０のいずれか一つ以上が置換基を有してもよいアミノ基である化合物に変換することができる。
一般式（１）で表される化合物、または製造法ＩおよびＩＩにおける合成中間体である一般式（３８）〜（４０）、（４４）〜（４６）で表される化合物の内、Ｒ１が一般式（２）である化合物において、Ｒ８、Ｒ９およびＲ１０を必要に応じて他の置換基に変換する方法は、これらに限定されるものではない。
本発明の一般式（１）で表される４−置換キノリン−８−カルボン酸アミド誘導体及びその付加塩は優れたＰＡＲＰ阻害活性を示す。本願発明化合物を治療又は予防剤として使用する場合には、単独あるいは適時薬理学的に許容される賦形剤、希釈剤等と混合し、錠剤、カプセル剤、顆粒剤、散剤もしくはシロップ剤等により経口的に、あるいは注射剤もしくは経皮吸収剤、座薬等により非経口的に投与することができる。
また、本発明化合物は他の薬物と組み合わせて用いることができる。この場合併用投与であっても、配合剤として用いても良い。組み合わせに用いられる薬物としては、血栓溶解剤、抗血小板薬、脳保護薬、抗浮腫薬、抗凝固薬、解熱薬、脳循環代謝改善薬、抗てんかん薬、抗うつ薬、抗炎症薬、ＡＣＥ阻害薬、消炎鎮痛薬又は血糖調節薬等が挙げられる。
また、本発明化合物は外科的療法、低体温療法や高圧酸素療法等の際にも併用して用いることができる。As a result of earnest research, the present inventors have sought for a novel compound having PARP inhibitory activity. As a result, the 4-substituted quinoline-8-carboxylic acid amide derivative of the present invention and its pharmacologically acceptable addition salt are excellent. PARP inhibitory activity was found.
That is, according to the present invention, the general formula (1)
Figure 2004014861
[Wherein R 1 Is a lower alkyl group which may be substituted with a halogen atom, a cyclic alkyl group which may have a substituent, an aralkyl group which may have a substituent, or the general formula (2)
Figure 2004014861
(Wherein the ring Ar represents a phenyl group, a naphthyl group, a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof,
R 8 , R 9 , R 10 Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 11 R 12 A lower alkyl group substituted with an N group, an optionally substituted cyclic alkyl group, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R 11 R 12 A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5- or 6-membered heterocyclic ring and its condensed ring Represents
R 2 , R 3 , R 4 Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom (a lower alkoxy group which may be substituted with a halogen atom, an amino group which may have a substituent, nitro A group, a cyano group,
X is oxygen atom, sulfur atom, NR 13 (Where R 13 Represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent.
R 5 , R 6 Are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, or a lower alkyl group substituted with a hydroxy group,
R 7 Is a hydrogen atom, a halogen atom, a hydroxyl group, a cyclic alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a carboxy group, a lower alkoxycarbonyl group, NR 11 R 12 , CONR 11 R 12 A phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent and a condensed ring thereof,
R 11 , R 12 Are the same or different and each represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, a cyclic alkyl group which may have a substituent, an aralkyl group which may have a substituent, or R 11 And R 12 And a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof (which may have a substituent on the heterocyclic ring or the condensed ring),
n represents 0-3] 4-substituted quinoline-8-carboxylic acid amide derivatives and their pharmacologically acceptable addition salts, general formula (1-d)
Figure 2004014861
[Wherein R 8 , R 9 , R 10 Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 11 R 12 A lower alkyl group substituted with an N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R 11 R 12 A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5- or 6-membered heterocyclic ring and its condensed ring Represents
R 2a , R 3a , R 4a Are the same or different and each represents a hydrogen atom or a halogen atom,
X a Represents an oxygen atom, NH,
R 5 , R 6 Are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, or a lower alkyl group substituted with a hydroxy group,
R 11 , R 12 Are the same or different and each represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, a cyclic alkyl group which may have a substituent, an aralkyl group which may have a substituent, or R 11 And R 12 And a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof (which may have a substituent on the heterocyclic ring or the condensed ring),
n represents 0 to 3], a 4-substituted quinoline-8-carboxylic acid amide derivative, a pharmacologically acceptable addition salt thereof, and the general formula (1-e)
Figure 2004014861
[Wherein R 8 , R 9 , R 10 Are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 11 R 12 A lower alkyl group substituted with an N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R 11 R 12 A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5- or 6-membered heterocyclic ring and its condensed ring Represents
R 2a , R 3a , R 4a Are the same or different and each represents a hydrogen atom or a halogen atom,
X a Represents an oxygen atom, NH,
R 5 , R 6 Are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, or a lower alkyl group substituted with a hydroxy group,
R 11 , R 12 Are the same or different and each represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, a cyclic alkyl group which may have a substituent, an aralkyl group which may have a substituent, or R 11 And R 12 And a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof (which may have a substituent on the heterocyclic ring or the condensed ring),
In order to complete the present invention, the present invention has found that the 4-substituted quinoline-8-carboxylic acid amide derivative represented by n represents 0 to 3] and a pharmacologically acceptable addition salt thereof have excellent PARP inhibitory activity. It came.
In the general formula (1) of the compound of the present invention, preferably R 1 Are compounds represented by the general formula (2).
More preferably, R 1 Of the compounds represented by the general formula (2), R 2 , R 3 , R 4 Are the same or different and are a hydrogen atom or a halogen atom, and R 7 Is a hydroxyl group, NR 11 R 12 The compound which is is mentioned.
Particularly preferably, R 1 Of the compounds represented by the general formula (2), the ring Ar is a phenyl group, and R 2 , R 4 Is a hydrogen atom and R 3 Is a hydrogen atom or a halogen atom, X is an oxygen atom, NR 13 And R 13 In which is a hydrogen atom.
Examples of these preferable compounds include the compounds shown in Tables 3 to 5 below, but the present invention is not limited to these compounds or pharmacologically acceptable addition salts thereof.
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
Figure 2004014861
In the said Tables 3-5, as an example number 11-13, 15, 16, 18-38, 42-75, 79-116, 120-173, 177-214, 218-274, 278-296 as a more preferable compound. Can be mentioned.
As particularly preferred compounds, exemplary numbers 11 to 13, 15, 16, 18 to 32, 36 to 38, 42 to 47, 56 to 75, 79 to 110, 114 to 116, 120 to 133, 152 to 167, 171 to 173, 177-190, 194-233, 251-271, 278-293 can be mentioned.
In the sentence of the general formula (1) of the present invention, the “halogen atom” in the “lower alkyl group optionally substituted with a halogen atom” and the “lower alkoxy group optionally substituted with a halogen atom” means fluorine, chlorine, Examples of the “lower alkyl group” include linear or branched ones having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, etc., and “lower alkoxy group” May be linear or branched ones having 1 to 4 carbon atoms, such as methoxy, ethoxy and propoxy. In the text, “cyclic alkyl group which may have a substituent”, “aralkyl group which may have one or more substituents”, “phenyl group which may have substituents”, “substituents” The “substituent” in “optionally substituted naphthyl group” and “optionally substituted 5- or 6-membered heterocyclic ring and condensed ring thereof” is substituted with a halogen atom, a hydroxyl group or a halogen atom. May be a lower alkyl group, a lower alkoxy group optionally substituted with a halogen atom, a lower alkylthio group, a lower alkoxycarbonyl group, a nitro group, an amino group optionally having a substituent, a cyano group, a carboxyl group, an aldehyde group A lower alkyl group substituted with a hydroxy group, a lower alkyl group substituted with a carboxy group, a lower alkyl group optionally substituted with a halogen atom, or an aralkyl optionally having a substituent A lower alkyl group substituted with an amino group which may be substituted with a dialkyl group, a lower alkyl group substituted with a 5- or 6-membered cyclic amino group which may have a substituent, a lower alkyl group substituted with a hydroxy group An alkoxy group, a lower alkoxy group substituted with a carboxy group, a lower alkyl group optionally substituted with a halogen atom, or a lower alkoxy group substituted with an amino group optionally substituted with an aralkyl group optionally having a substituent And a lower alkoxy group substituted with a 5- or 6-membered cyclic amino group which may have a substituent, and the “lower alkoxycarbonyl group” is a straight or branched chain such as methoxycarbonyl and ethoxycarbonyl The “amino group optionally having substituent (s)” may be substituted with an acyl group or a halogen atom. A lower alkyl group which may be substituted with a primary alkylsulfonyl group, an arylsulfonyl group such as acetyl, methanesulfonyl, phenylsulfonyl, etc., which may be substituted with a halogen atom, an optionally substituted phenyl group, An amino group which may be substituted by an aralkyl group which may have a substituent is mentioned, and “5-membered or 6-membered cyclic amino group which may have a substituent” Examples of the “cyclic amino group” include pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl and the like. The substituent mentioned here refers to the “substituent” described above.
Examples of the “cyclic alkyl group” include those having 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl and the like, and the “heterocycle” in the “5-membered or 6-membered heterocycle and condensed ring thereof” A heterocyclic group which may contain one or more saturated or unsaturated monocyclic or polycyclic nitrogen, oxygen and sulfur atoms which may have one or more substituents, such as pyrrolidyl, piperidyl, piperazyl , Morpholyl, thiomorpholyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyratyl, etc., and “the condensed ring” means the benzene condensed ring (for example, indolyl) of the above “heterocycle” , Tetrahydroquinolyl, benzoxazolidinyl, benzothiazolidinyl, benzofuranyl, benzothie Benzimidazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, etc.) or a condensed ring composed of two rings arbitrarily selected from the above-mentioned “heterocycle” (eg, imidazopyridine, pyrazolopyridine, imidazopyrimidine Etc.).
The compound represented by the general formula (1) of the present invention can be converted into a pharmacologically acceptable salt as necessary. Examples of pharmacologically acceptable salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid and sulfuric acid, organic acid salts such as acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid and tosylic acid, and sodium. Examples of the base salt include salts, potassium salts, calcium salts, and ammonium salts.
Further, the compound represented by the general formula (1) of the present invention and a pharmacologically acceptable salt thereof may be an inner salt, an anhydride, a hydrate or a solvate thereof.
The compound represented by the general formula (1) having the PARP inhibitory activity of the present invention can be synthesized from a known compound by a combination of known methods. For example, among the compounds represented by the general formula (1), the compound represented by the general formula (1-h) in which X is an oxygen atom or a sulfur atom can be easily prepared by the following method (Production Method I). Can be synthesized.
<Production Method I>
Figure 2004014861
In the above formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 12 , N are as defined above, and X b Represents an oxygen atom or a sulfur atom, R 14 Represents a lower alkyl group which may be substituted with a halogen atom, or an aralkyl group which may have one or more substituents.
The conversion from the compound represented by the general formula (37) to the compound represented by the general formula (38) (step IA) is called Conrad-Limpach synthesis method and constructed 4 (1H) -quinolone. In the presence of a suitable acid such as acetic acid, methanesulfonic acid, tosylic acid, boron trifluoride diethyl ether complex, etc. in a suitable solvent such as chloroform, benzene or toluene. And general formula (41)
Figure 2004014861
(Wherein R 1 , X b Represents the same meaning as described above, and R 15 Represents a lower alkoxy group which may be substituted with a halogen atom, a aralkyloxy group which may have one or more substituents or a 4- (lower alkoxy) anilino group). After dehydrating condensation by heating and refluxing for a period of time, for example, the reaction is carried out at 100 to 250 ° C. for 0.5 to 3 hours in a high boiling point solvent such as diphenyl ether or nitrobenzene, or in a strong acid such as sulfuric acid or polyphosphoric acid. Can be performed.
Conversion of the compound represented by the general formula (38) to the compound represented by the general formula (39) (Step IB) is carried out by using a suitable solvent such as N, N-dimethylformamide, N, N-dimethyl. In the presence of a suitable base such as sodium carbonate, potassium carbonate, triethylamine, pyridine or the like in a solvent such as acetamide or tetrahydrofuran, the compound of the general formula (42)
Figure 2004014861
(Wherein R 5 , R 6 , R 7 N represents the same meaning as described above, and Y represents a halogen atom or a lower alkylsulfonyloxy group which may be substituted with a halogen atom). It can be performed by reacting for 24 hours.
The conversion from the compound represented by the general formula (39) to the compound represented by the general formula (1-h) (step IC) is carried out in a suitable solvent, for example, a solvent such as water, methanol, ethanol, etc. The reaction is carried out at 20 to 100 ° C. for 0.5 to 10 hours using a suitable alkali such as potassium hydroxide, sodium hydroxide, potassium carbonate, etc. to give a carboxylic acid, and there is no solvent or a suitable solvent such as dichloromethane or chloroform. In a solvent such as tetrahydrofuran, a suitable halogenating agent such as thionyl chloride or phosphorus oxychloride is reacted at 0 to 130 ° C. for 1 to 10 hours to convert to an acid halide, and then a suitable solvent such as water The reaction can be carried out by using ammonia in a solvent such as methanol or tetrahydrofuran at 0 to 60 ° C. for 0.1 to 3 hours. Moreover, it can carry out also by making it react at 100-150 degreeC for 5-48 hours using ammonia in suitable solvents, for example, solvents, such as water, methanol, and ethanol.
The conversion from the compound represented by the general formula (38) to the compound represented by the general formula (40) (Step ID) is carried out by using ammonia in a suitable solvent, for example, water, methanol, ethanol or the like. And can be carried out by reacting at 100 to 150 ° C. for 5 to 48 hours.
Conversion from the compound represented by the general formula (40) to the compound represented by the general formula (1-h) (step IE) can be performed according to step IB.
Of the compounds represented by the general formula (1-h), R 7 Is a halogen atom, the compound represented by general formula (1-h) is represented by R in Step IF. 7 Is NR 11 R 12 Can be converted to a compound represented by the general formula (1-i). That is, in an appropriate solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran or the like (adding an appropriate iodide salt such as sodium iodide or potassium iodide as necessary. General formula (43)
Figure 2004014861
(Wherein R 11 , R 12 Can be carried out by reacting at 60 to 180 ° C. for 1 to 24 hours.
Of the compounds represented by the general formula (1-h), R 7 Is a lower alkoxycarbonyl group, the compound represented by general formula (1-h) is represented by R in Step IG. 7 Can be converted to a compound represented by the general formula (1-j), wherein is a carboxy group. That is, the reaction is carried out at 20 to 100 ° C. for 0.5 to 10 hours using an appropriate alkali such as potassium hydroxide, sodium hydroxide, potassium carbonate or the like in an appropriate solvent such as water, methanol or ethanol. Can be performed.
Of the compounds represented by the general formula (1-h), R 7 Is CONR 11 R 12 The compound represented by the general formula (1-k) can be converted from the compound represented by the general formula (1-j) by Step IH. That is, a suitable condensing agent such as 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide in a suitable solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran or the like. , Dicyclohexylcarbodiimide and the like (a suitable base such as triethylamine, pyridine, 4-dimethylaminopyridine and the like may be added if necessary), and is represented by the general formula (43)
Figure 2004014861
(Wherein R 11 , R 12 Can be performed by reacting at 0 to 80 ° C. for 1 to 36 hours.
Of the compounds represented by the general formula (1) having PARP inhibitory activity of the present invention, X is NR. 13 The compound represented by the general formula (1-l) can be easily synthesized by, for example, the following method (Production Method II).
<Production Method II>
Figure 2004014861
In the above formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 13 , R 14 , N represents the same meaning as described above, and Z represents a halogen atom.
Among the compounds represented by the general formula (38), the compound represented by the general formula (44) is X b Can be converted by the step II-A from the compound represented by the general formula (38-a) in which is an oxygen atom. That is, using a suitable halogenating agent such as thionyl chloride, phosphorous oxychloride, phosphorous oxybromide in a solvent-free or suitable solvent such as benzene, chloroform, 1,2-dichloroethane, etc. It can carry out by making it react at 130 degreeC for 0.5 to 6 hours.
Conversion from the compound represented by the general formula (44) to the compound represented by the general formula (45) (Step II-B) is carried out without solvent or in a suitable solvent such as water, methanol, ethanol or the like. The reaction can be performed by using ammonia at 100 to 150 ° C. for 5 to 48 hours.
Further, there is no solvent or an appropriate solvent, for example, dichloromethane (boron trichloride or boron tribromide in a solvent such as chloroform and the like, and reaction is carried out at 0 to 60 ° C. for 1 to 24 hours to obtain a carboxylic acid. Conversion to an acid chloride by reacting at 20 to 130 ° C. for 1 to 10 hours with an appropriate chlorinating agent such as thionyl chloride or phosphorus oxychloride in an appropriate solvent such as dichloromethane, chloroform or tetrahydrofuran. Thereafter, the reaction can be carried out by reacting at 0 to 60 ° C. for 0.1 to 3 hours using ammonia in a suitable solvent such as water, methanol, tetrahydrofuran or the like.
Conversion from the compound represented by the general formula (38-a) to the compound represented by the general formula (46) (step II-C) is carried out in a suitable solvent, for example, a solvent such as water, methanol, ethanol, etc. It can carry out by making it react at 20-100 degreeC for 0.5 to 10 hours using a suitable alkali, for example, potassium hydroxide, sodium hydroxide, potassium carbonate etc.
Conversion from the compound represented by the general formula (46) to the compound represented by the general formula (45) (step II-D) can be performed without a solvent or an appropriate solvent such as benzene, chloroform, 1,2-dichloroethane. In a solvent such as, a suitable halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide and the like is reacted at 60 to 130 ° C. for 0.5 to 6 hours to obtain an acid halide, It can carry out by making it react at 0-60 degreeC for 0.1 to 3 hours using ammonia in suitable solvents, for example, water, methanol, tetrahydrofuran, etc. solvent.
Of the compounds represented by the general formula (1) from the compound represented by the general formula (45), X is NR. 13 Is converted to a compound represented by the general formula (1-l) (step II-E) using a suitable solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2. -In a solvent such as pyrrolidinone, 1,3-dimethyl-2-imidazolidinone (a suitable iodide salt such as sodium iodide or potassium iodide may be added as necessary), and represented by the general formula (47 )
Figure 2004014861
(Wherein R 5 , R 6 , R 7 , R 13 , N represents the same meaning as described above), and the reaction is performed at 80 to 180 ° C. for 1 to 24 hours.
Of the compounds represented by the general formula (1) or the compounds represented by the general formulas (38) to (40) and (44) to (46) which are synthetic intermediates in the production methods I and II, R 1 In the compound of general formula (2) 8 , R 9 And R 10 Can be converted to other substituents as necessary by a known method. For example, among the compounds represented by the general formula (1), R 1 Is the general formula (2) and R 8 , R 9 Or R 10 A compound in which any one or more of them is a lower alkoxy group which may be substituted with a halogen atom is a suitable acid such as hydrochloric acid, bromide in a solvent-free or suitable solvent such as water, acetic acid or a mixture thereof. After reacting at 60 to 110 ° C. for 1 to 24 hours using hydrogen acid or the like, a suitable chlorinating agent such as thionyl chloride, oxyl in a solvent-free or suitable solvent such as dichloromethane, chloroform, tetrahydrofuran or the like. The reaction is carried out at 20 to 130 ° C. for 1 to 10 hours using phosphorus chloride or the like, and further 0 to 0 to 60 ° C. using ammonia in a suitable solvent such as water, methanol, tetrahydrofuran or a mixture thereof. Among the compounds represented by the general formula (1) by reacting for 1 to 3 hours, R 1 Is the general formula (2) and R 8 , R 9 Or R 10 Can be converted to a compound in which at least one of them is a hydroxyl group, and in a suitable solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, etc., a suitable alkylating agent such as iodoethane. , Ethyl bromoacetate and the like in the presence of a suitable base such as potassium carbonate, triethylamine, pyridine and the like (a suitable iodide salt such as sodium iodide and potassium iodide may be added as necessary. ), By reacting at 0 to 80 ° C. for 1 to 24 hours, among the compounds represented by the general formula (1), R 1 is General formula (2), R 8 , R 9 Or R 10 Any one or more of the above can be converted to a compound which is a lower alkoxy group substituted with a halogen atom or a lower alkoxy group substituted with a lower alkoxycarbonyl group.
Of the compounds represented by the general formula (1), R 1 Is the general formula (2) and R 8 , R 9 Or R 10 A compound in which any one or more of nitro groups is a suitable catalyst such as palladium-carbon, platinum in an appropriate solvent such as methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof. -Of the compounds represented by the general formula (1), by subjecting to hydrogenation reaction at 20 to 80 ° C. for 1 to 72 hours using carbon or the like under normal pressure or if necessary, R 1 Is the general formula (2) and R 8 , R 9 Or R 10 Any one or more of the above can be converted to a compound having an amino group, and a suitable acylating agent such as chloroform, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof can be used. The reaction is represented by the general formula (1) by reacting at 0 to 80 ° C. for 1 to 24 hours in the presence of an abasic or appropriate base such as triethylamine or pyridine using acetic anhydride or acetyl chloride. R 1 Is the general formula (2) and R 8 , R 9 Or R 10 Any one or more of the above can be converted to a compound which is an amino group which may have a substituent.
Of the compounds represented by the general formula (1) or the compounds represented by the general formulas (38) to (40) and (44) to (46) which are synthetic intermediates in the production methods I and II, R 1 In the compound of general formula (2) 8 , R 9 And R 10 The method for converting to other substituents as necessary is not limited thereto.
The 4-substituted quinoline-8-carboxylic acid amide derivative represented by the general formula (1) of the present invention and an addition salt thereof exhibit excellent PARP inhibitory activity. When the compound of the present invention is used as a therapeutic or prophylactic agent, it can be used alone or mixed with timely pharmacologically acceptable excipients, diluents, etc. It can be administered orally or parenterally by injection, transdermal absorption agent, suppository or the like.
The compound of the present invention can be used in combination with other drugs. In this case, it may be used in combination or as a compounding agent. Drugs used in combination include thrombolytic agents, antiplatelet drugs, brain protective drugs, antiedema drugs, anticoagulants, antipyretic drugs, cerebral circulation metabolism improving drugs, antiepileptic drugs, antidepressants, anti-inflammatory drugs, ACE Inhibitors, anti-inflammatory analgesics, blood glucose regulators and the like.
The compound of the present invention can also be used in combination for surgical therapy, hypothermia therapy, hyperbaric oxygen therapy and the like.

以下に、参考例、実施例および試験例を示し、本発明をさらに詳細に説明するが、本発明の範囲は、これらに限定されるものではない。
＜参考例１＞ １，４−ジヒドロ−４−オキソ−２−フェニルキノリン−８−カルボン酸メチル

Figure 2004014861
アントラニル酸メチル（３７．８ｇ，２５０ｍｍｏｌ）およびベンゾイル酢酸エチル（４８．１ｇ，２５０ｍｍｏｌ）のベンゼン（２００ｍＬ）溶液に、メタンスルホン酸（２．５０μＬ）を加え、４８時間加熱還流した。反応液を半量まで濃縮後、石油エーテルを加え、結晶を濾取し、石油エーテル−ベンゼン（１：１）にて洗浄後、乾燥することにより、淡黄色粉末を１６．１ｇ得た。これを２６０℃加温下、ジフェニルエーテル（１００ｍＬ）に加え、同温にて３０分間撹拌した。冷後、析出晶を濾取し、石油エーテル−ベンゼン（１：１）にて洗浄後、乾燥することにより、黄褐色粉末の表題化合物を１１．６ｇ得た。収率１７％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．９９（３Ｈ，ｓ），６．６２（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．４８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６４−７．６８（３Ｈ，ｍ），７．８７−７．９０（２Ｈ，ｍ），８．３８−８．４３（２Ｈ，ｍ），１１．９８（１Ｈ，ｓ）．
＜参考例２〜１２＞ 参考例１と同様の方法により、下記表６記載の化合物を得た。
Figure 2004014861
《参考例２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．８７（３Ｈ，ｓ），３．９９（３Ｈ，ｓ），６．５７（１Ｈ，ｓ），７．２１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４６（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．８４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．３８（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．４１（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），１１．９３（１Ｈ，ｓ）．
《参考例３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．８８（３Ｈ，ｓ），３．９９（３Ｈ，ｓ），６．６４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．２１（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），７．４０−７．４９（３Ｈ，ｍ），７．５７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．３８−８．４３（２Ｈ，ｍ），１１．９３（１Ｈ，ｓ）．
《参考例４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．００（３Ｈ，ｓ），６．７２（１Ｈ，ｓ），７．５１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．１５（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．４１−８．４８（４Ｈ，ｍ），１２．００（１Ｈ，ｓ）．
《参考例５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．００（３Ｈ，ｓ），６．７２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．５０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．９４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．４０−８．４７（３Ｈ，ｍ），８．６４（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），１１．９８（１Ｈ，ｓ）．
《参考例６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．４０（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），３．９２（３Ｈ，ｓ），４．４５（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），６．５７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．６３−７．６５（３Ｈ，ｍ），７．８６−７．８８（３Ｈ，ｍ），７．９３（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ），１１．７８（１Ｈ，ｓ）．
《参考例７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：２．４８（３Ｈ，ｓ），３．９８（３Ｈ，ｓ），６．５８（１Ｈ，ｔ，Ｊ＝１．０Ｈｚ），７．６３−７．６７（３Ｈ，ｍ），７．８６−７．８９（２Ｈ，ｍ），８．２３（２Ｈ，ｓ），１１．８７（１Ｈ，ｓ）．
《参考例８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．００（３Ｈ，ｓ），６．６６（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．６４−７．６８（３Ｈ，ｍ），７．８７−７．８９（２Ｈ，ｍ），８．３１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），１１．８５（１Ｈ，ｓ）．
《参考例９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．００（３Ｈ，ｓ），６．６２（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．６５−７．６８（３Ｈ，ｍ），７．８７−７．９０（２Ｈ，ｍ），８．１１（１Ｈ，ｄｄ，Ｊ＝８．３，２．９Ｈｚ），８．２１（１Ｈ，ｄｄ，Ｊ＝８．８，３．４Ｈｚ），１１．８６（１Ｈ，ｓ）．
《参考例１０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．８７（３Ｈ，ｓ），４．００（３Ｈ，ｓ），６．５８（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．２１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．８４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．１０（１Ｈ，ｄｄ，Ｊ＝８．３，２．９Ｈｚ），８．１９（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），１１．８２（１Ｈ，ｓ）．
《参考例１１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．８８（３Ｈ，ｓ），４．００（３Ｈ，ｓ），６．６５（１Ｈ，ｓ），７．２１（１Ｈ，ｄｄ，Ｊ＝８．３，２．０Ｈｚ），７．４０（１Ｈ，ｓ），７．４２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５７（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），８．１１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．２１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），１１．８２（１Ｈ，ｓ）．
《参考例１２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．０１（３Ｈ，ｓ），６．７３（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），８．１２−８．１８（３Ｈ，ｍ），８．２４（１Ｈ，ｄｄ，Ｊ＝８．６，３．１Ｈｚ），８．４５−８．４８（２Ｈ，ｍ），１１．８９（１Ｈ，ｓ）．
＜参考例１３＞ ２−（３，４−ジフルオロフェニル）−１，４−ジヒドロ−４−オキソキノリン−８−カルボン酸メチル
Figure 2004014861
アントラニル酸メチル（４２５μＬ，３．２８ｍｍｏｌ）および３，４−ジフルオロ−Ｎ−（４−メトキシフェニル）ベンゾイル酢酸アミド（１．００ｇ，３．２８ｍｍｏｌ）のベンゼン（３０ｍＬ）溶液に、メタンスルホン酸（１０．０μＬ）を加え、４８時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝４：１］に付し、黄色アモルファスを５９２ｍｇ得た。これを２５０℃加温下、ジフェニルエーテル（６ｍＬ）に加え、同温にて３０分間撹拌した。冷後、ヘキサンを加え、析出晶を濾取し、ヘキサンにて洗浄後、乾燥した。得られた粗結晶をクロマトレックスＮＨカラムクロマトグラフィ［ヘキサン−酢酸エチル＝３：２］に付し、淡黄色粉末の表題化合物を１２４ｍｇ得た。収率１２％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．９９（３Ｈ，ｓ），６．６４（１Ｈ，ｓ），７．４９（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７５（２Ｈ，ｄ−ｌｉｋｅ ｂｒ，Ｊ＝３．４Ｈｚ），８．０５（１Ｈ，ｄｄ，Ｊ＝１１．３，７．３Ｈｚ），８．３９−８．４３（２Ｈ，ｍ），１１．８９（１Ｈ，ｓ）．
＜参考例１４＞ ２−（４−ブロモフェニル）−１，４−ジヒドロ−４−オキソキノリン−８−カルボン酸メチル
Figure 2004014861
４−ブロモ−Ｎ−（４−メトキシフェニル）ベンゾイル酢酸アミドを用い、参考例１３と同様の方法により、淡褐色粉末の表題化合物を得た。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．９９（３Ｈ，ｓ），６．６３（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．４９（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．８２−７．８８（４Ｈ，ｍ），８．３９−８．４４（２Ｈ，ｍ），１１．９４（１Ｈ，ｓ）．
＜参考例１５＞ １，４−ジヒドロ−４−オキソ−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
参考例１の化合物（５００ｍｇ，１．７９ｍｍｏｌ）の飽和アンモニア−エタノール（１０ｍＬ）溶液を封管中、１２０℃にて１９時間撹拌した。冷後、反応液を半量まで濃縮し、結晶を濾取し、アセトンにて洗浄後、風乾することにより、黄褐色粉末の表題化合物を２７４ｍｇ得た。収率５８％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：６．５８（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．４４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６３−７．６４（３Ｈ，ｍ），７．８５−７．８７（２Ｈ，ｍ），８．３３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．６７（１Ｈ，ｓ），１３．５５（１Ｈ，ｓ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１６Ｈ１２Ｎ２Ｏ２・１／１０Ｈ２Ｏ：Ｃ，７２．２２；Ｈ，４．６２；Ｎ，１０．５３（％）．
Ｆｏｕｎｄ：Ｃ，７２．２６；Ｈ，４．６９；Ｎ，１０．４２（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：２６４．０９０９（＋１．０ｍｍｕ）．
＜参考例１６＞ ４−クロロ−２−フェニルキノリン−８−カルボン酸メチル
Figure 2004014861
参考例１の化合物（４．００ｇ，１４．３ｍｍｏｌ）にオキシ塩化リン（１５ｍＬ）を加え、１時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣に酢酸エチルを加え、水洗後、無水硫酸ナトリウムで乾燥し、溶媒を留去した。得られた残渣をアルミナカラムクロマトグラフィ［酢酸エチル−ヘキサン＝１：１］に付し、淡黄色粉末の表題化合物を３．４０ｇ得た。収率８０％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．００（３Ｈ，ｓ），７．５５−７．６１（３Ｈ，ｍ），７．８１（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），８．０９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），８．３２−８．３８（３Ｈ，ｍ），８．５３（１Ｈ，ｓ）．
＜参考例１７〜２７＞ 参考例１６と同様の方法により、下記表７記載の化合物を得た。
Figure 2004014861
《参考例１７の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：３．９０（３Ｈ，ｓ），４．０９（３Ｈ，ｓ），７．０４（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．５９（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），８．００（１Ｈ，ｓ），８．０４（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），８．１８（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），８．３３（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
《参考例１８の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：３．９４（３Ｈ，ｓ），４．０９（３Ｈ，ｓ），７．０３−７．０６（１Ｈ，ｍ），７．４３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６４（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），７．７４−７．７６（１Ｈ，ｍ），７．８６（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），８．０５（１Ｈ，ｓ），８．０６（１Ｈ，ｄｄ，Ｊ＝６．９，１．５Ｈｚ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
《参考例１９の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：４．０８（３Ｈ，ｓ），７．６３−７．６７（３Ｈ，ｍ），８．０２（１Ｈ，ｓ），８．０６−８．１１（３Ｈ，ｍ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
《参考例２０の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：４．１０（３Ｈ，ｓ），７．７２（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），８．１１（１Ｈ，ｓ），８．１３（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），８．３８−８．４３（５Ｈ，ｍ）．
《参考例２１の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：４．０９（３Ｈ，ｓ），７．３０（１Ｈ，ｄｔ，Ｊ＝９．８，８．３Ｈｚ），７．６６（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），７．９１−７．９５（１Ｈ，ｍ），７．９８（１Ｈ，ｓ），８．０８−８．１４（２Ｈ，ｍ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
《参考例２２の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：１．４９（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），４．０１（３Ｈ，ｓ），４．５６（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），７．４５−７．５３（３Ｈ，ｍ），７．５７（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ），７．６９（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ），８．０２（１Ｈ，ｓ），８．１７−８．１９（２Ｈ，ｍ）．
《参考例２３の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：２．６１（３Ｈ，ｓ），４．０８（３Ｈ，ｓ），７．４７−７．５４（３Ｈ，ｍ），７．９１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．０２（１Ｈ，ｓ），８．１２（１Ｈ，ｄｄ，Ｊ＝２．０，１．０Ｈｚ），８．１９−８．２１（２Ｈ，ｍ）．
《参考例２４の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：４．０９（３Ｈ，ｓ），７．５０−７．５５（３Ｈ，ｍ），８．００（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．０７（１Ｈ，ｓ），８．１８−８．２０（２Ｈ，ｍ），８．３３（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
《参考例２５の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：４．０９（３Ｈ，ｓ），７．４９−７．５５（３Ｈ，ｍ），７．８３（１Ｈ，ｄｄ，Ｊ＝８．３，２．９Ｈｚ），７．９９（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），８．０８（１Ｈ，ｓ），８．１８−８．２０（２Ｈ，ｍ）．
《参考例２６の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：３．８９（３Ｈ，ｓ），４．０９（３Ｈ，ｓ），７．０３（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．８１（１Ｈ，ｄｄ，Ｊ＝８．３，２．９Ｈｚ），７．９５（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），８．０２（１Ｈ，ｓ），８．１５（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）．
《参考例２７の化合物》
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：３．９３（３Ｈ，ｓ），４．０９（３Ｈ，ｓ），７．０４（１Ｈ，ｄｄ，Ｊ＝８．３，２．４Ｈｚ），７．４３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８１−７．８５（２Ｈ，ｍ），７．９８（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），８．０５（１Ｈ，ｓ）．
＜参考例２８＞ ４−クロロ−２−（３，４−ジフルオロフェニル）−６−フルオロキノリン−８−カルボン酸メチル
Figure 2004014861
３，４−ジフルオロベンゾイル酢酸エチル（１．１４ｇ，５．００ｍｍｏｌ）および５−フルオロアントラニル酸メチル（１．６９ｇ，１０．０ｍｍｏｌ）のベンゼン（２５ｍＬ）溶液に、メタンスルホン酸（１０．０μＬ）を加え、４８時間加熱還流した。冷後、反応液を減圧濃縮し、ジイソプロピルエーテルを加え、結晶を濾取し、ジイソプロピルエーテルにて洗浄後、乾燥することにより、淡褐色粉末を得た。これにジフェニルエーテル（１５ｍＬ）を加え、２５０℃にて３０分間撹拌した。冷後、ヘキサンを加え、析出晶を濾取し、酢酸エチルにて洗浄後、乾燥することにより、黄褐色粉末を得た。これにオキシ塩化リン（２ｍＬ）を加え、１時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣にジクロロメタンを加え、飽和炭酸水素ナトリウム水溶液にて洗浄後、無水硫酸ナトリウムにて乾燥し、溶媒を留去することにより、無色粉末の表題化合物を１７６ｍｇ得た。収率１０％。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：４．１０（３Ｈ，ｓ），７．２７−７．３４（１Ｈ，ｍ），７．８４−７．９２（２Ｈ，ｍ），７．９７−７．９９７（１Ｈ，ｍ），８．００（１Ｈ，ｓ），８．０５−８．１１（１Ｈ，ｍ）．Hereinafter, the present invention will be described in more detail with reference examples, examples and test examples, but the scope of the present invention is not limited thereto.
Reference Example 1 Methyl 1,4-dihydro-4-oxo-2-phenylquinoline-8-carboxylate
Figure 2004014861
Methanesulfonic acid (2.50 μL) was added to a benzene (200 mL) solution of methyl anthranilate (37.8 g, 250 mmol) and ethyl benzoyl acetate (48.1 g, 250 mmol), and the mixture was heated to reflux for 48 hours. The reaction solution was concentrated to half volume, petroleum ether was added, the crystals were collected by filtration, washed with petroleum ether-benzene (1: 1), and dried to obtain 16.1 g of a pale yellow powder. This was added to diphenyl ether (100 mL) with heating at 260 ° C., and stirred at the same temperature for 30 minutes. After cooling, the precipitated crystals were collected by filtration, washed with petroleum ether-benzene (1: 1) and dried to obtain 11.6 g of the title compound as a tan powder. Yield 17%.
1 H-NMR (DMSO-d 6 , δ): 3.99 (3H, s), 6.62 (1H, d, J = 1.5 Hz), 7.48 (1H, t, J = 7.8 Hz) ), 7.64-7.68 (3H, m), 7.87-7.90 (2H, m), 8.38-8.43 (2H, m), 11.98 (1H, s).
<Reference Examples 2 to 12> By the same method as Reference Example 1, the compounds shown in Table 6 below were obtained.
Figure 2004014861
<< Compound of Reference Example 2 >>
1 H-NMR (DMSO-d 6 , δ): 3.87 (3H, s), 3.99 (3H, s), 6.57 (1H, s), 7.21 (2H, d, J = 8.8 Hz), 7.46 (1 H, t, J = 7.8 Hz), 7.84 (2 H, d, J = 8.8 Hz), 8.38 (1 H, dd, J = 7.8, 1) .5 Hz), 8.41 (1H, dd, J = 7.8, 1.5 Hz), 11.93 (1H, s).
<< Compound of Reference Example 3 >>
1 H-NMR (DMSO-d 6 , δ): 3.88 (3H, s), 3.99 (3H, s), 6.64 (1H, d, J = 2.0 Hz), 7.21 ( 1H, dd, J = 7.8, 2.0 Hz), 7.40-7.49 (3H, m), 7.57 (1H, t, J = 7.8 Hz), 8.38-8.43. (2H, m), 11.93 (1H, s).
<< Compound of Reference Example 4 >>
1 H-NMR (DMSO-d 6 , δ): 4.00 (3H, s), 6.72 (1H, s), 7.51 (1H, t, J = 7.8 Hz), 8.15 ( 2H, d, J = 8.8 Hz), 8.41-8.48 (4H, m), 12.00 (1H, s).
<< Compound of Reference Example 5 >>
1 H-NMR (DMSO-d 6 , δ): 4.00 (3H, s), 6.72 (1H, d, J = 2.0 Hz), 7.50 (1H, t, J = 7.8 Hz) ), 7.94 (1H, t, J = 7.8 Hz), 8.34 (1H, d, J = 8.8 Hz), 8.40-8.47 (3H, m), 8.64 (1H) , T, J = 2.0 Hz), 11.98 (1H, s).
<< Compound of Reference Example 6 >>
1 H-NMR (DMSO-d 6 , δ): 1.40 (3H, t, J = 7.3 Hz), 3.92 (3H, s), 4.45 (2H, q, J = 7.3 Hz) ), 6.57 (1H, d, J = 2.0 Hz), 7.63-7.65 (3H, m), 7.86-7.88 (3H, m), 7.93 (1H, d) , J = 2.9 Hz), 11.78 (1H, s).
<< Compound of Reference Example 7 >>
1 H-NMR (DMSO-d 6 , δ): 2.48 (3H, s), 3.98 (3H, s), 6.58 (1H, t, J = 1.0 Hz), 7.63- 7.67 (3H, m), 7.86-7.89 (2H, m), 8.23 (2H, s), 11.87 (1H, s).
<< Compound of Reference Example 8 >>
1 H-NMR (DMSO-d 6 , δ): 4.00 (3H, s), 6.66 (1H, d, J = 1.5 Hz), 7.64-7.68 (3H, m), 7.87-7.89 (2H, m), 8.31 (1H, d, J = 2.5 Hz), 8.33 (1H, d, J = 2.4 Hz), 11.85 (1H, s ).
<< Compound of Reference Example 9 >>
1 H-NMR (DMSO-d 6 , δ): 4.00 (3H, s), 6.62 (1H, d, J = 1.5 Hz), 7.65-7.68 (3H, m), 7.87-7.90 (2H, m), 8.11 (1H, dd, J = 8.3, 2.9 Hz), 8.21 (1H, dd, J = 8.8, 3.4 Hz) , 11.86 (1H, s).
<< Compound of Reference Example 10 >>
1 H-NMR (DMSO-d 6 , δ): 3.87 (3H, s), 4.00 (3H, s), 6.58 (1H, d, J = 1.5 Hz), 7.21 ( 2H, d, J = 8.8 Hz), 7.84 (2H, d, J = 8.8 Hz), 8.10 (1H, dd, J = 8.3, 2.9 Hz), 8.19 (1H , Dd, J = 8.8, 2.9 Hz), 11.82 (1H, s).
<< Compound of Reference Example 11 >>
1 H-NMR (DMSO-d 6 , δ): 3.88 (3H, s), 4.00 (3H, s), 6.65 (1H, s), 7.21 (1H, dd, J = 8.3, 2.0 Hz), 7.40 (1 H, s), 7.42 (1 H, d, J = 8.3 Hz), 7.57 (1 H, t, J = 8.3 Hz), 8. 11 (1H, d, J = 8.3 Hz), 8.21 (1H, d, J = 8.3 Hz), 11.82 (1H, s).
<< Compound of Reference Example 12 >>
1 H-NMR (DMSO-d 6 , δ): 4.01 (3H, s), 6.73 (1H, d, J = 1.2 Hz), 8.12-8.18 (3H, m), 8.24 (1H, dd, J = 8.6, 3.1 Hz), 8.45-8.48 (2H, m), 11.89 (1H, s).
Reference Example 13 Methyl 2- (3,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-8-carboxylate
Figure 2004014861
To a solution of methyl anthranilate (425 μL, 3.28 mmol) and 3,4-difluoro-N- (4-methoxyphenyl) benzoylacetamide (1.00 g, 3.28 mmol) in benzene (30 mL) was added methanesulfonic acid (10 0.0 μL) and heated to reflux for 48 hours. After cooling, the residue obtained by concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography [hexane-ethyl acetate = 4: 1] to obtain 592 mg of yellow amorphous. This was added to diphenyl ether (6 mL) with heating at 250 ° C., and stirred at the same temperature for 30 minutes. After cooling, hexane was added, and the precipitated crystals were collected by filtration, washed with hexane and dried. The resulting crude crystals were subjected to chromatolex NH column chromatography [hexane-ethyl acetate = 3: 2] to obtain 124 mg of the title compound as a pale yellow powder. Yield 12%.
1 H-NMR (DMSO-d 6 , δ): 3.99 (3H, s), 6.64 (1H, s), 7.49 (1H, t, J = 7.8 Hz), 7.75 ( 2H, d-like br, J = 3.4 Hz), 8.05 (1H, dd, J = 11.3, 7.3 Hz), 8.39-8.43 (2H, m), 11.89 ( 1H, s).
Reference Example 14 Methyl 2- (4-bromophenyl) -1,4-dihydro-4-oxoquinoline-8-carboxylate
Figure 2004014861
The title compound was obtained as a light brown powder in the same manner as in Reference Example 13 using 4-bromo-N- (4-methoxyphenyl) benzoylacetamide.
1 H-NMR (DMSO-d 6 , δ): 3.99 (3H, s), 6.63 (1H, d, J = 2.0 Hz), 7.49 (1H, t, J = 7.8 Hz) ), 7.82-7.88 (4H, m), 8.39-8.44 (2H, m), 11.94 (1H, s).
Reference Example 15 1,4-Dihydro-4-oxo-2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
A saturated ammonia-ethanol (10 mL) solution of the compound of Reference Example 1 (500 mg, 1.79 mmol) was stirred at 120 ° C. for 19 hours in a sealed tube. After cooling, the reaction mixture was concentrated to half volume, and the crystals were collected by filtration, washed with acetone, and then air-dried to obtain 274 mg of the title compound as a tan powder. Yield 58%.
1 H-NMR (DMSO-d 6 , δ): 6.58 (1H, d, J = 1.5 Hz), 7.44 (1H, t, J = 7.8 Hz), 7.63-7.64 (3H, m), 7.85-7.87 (2H, m), 8.33 (1H, d, J = 7.8 Hz), 8.33 (1H, d, J = 7.8 Hz), 8 .67 (1H, s), 13.55 (1H, s).
Anal. Calcd. for C 16 H 12 N 2 O 2 1/10 H 2 O: C, 72.22; H, 4.62; N, 10.53 (%).
Found: C, 72.26; H, 4.69; N, 10.42 (%).
HR-MS (m / z): 264.0909 (+1.0 mmu).
Reference Example 16 Methyl 4-chloro-2-phenylquinoline-8-carboxylate
Figure 2004014861
Phosphorous oxychloride (15 mL) was added to the compound of Reference Example 1 (4.00 g, 14.3 mmol), and the mixture was heated to reflux for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to alumina column chromatography [ethyl acetate-hexane = 1: 1] to obtain 3.40 g of the title compound as a pale yellow powder. Yield 80%.
1 H-NMR (DMSO-d 6 , δ): 4.00 (3H, s), 7.55-7.61 (3H, m), 7.81 (1H, dd, J = 8.3, 7 .3 Hz), 8.09 (1 H, dd, J = 7.3, 1.5 Hz), 8.32-8.38 (3 H, m), 8.53 (1 H, s).
<Reference Examples 17 to 27> By the same method as Reference Example 16, the compounds shown in Table 7 below were obtained.
Figure 2004014861
<< Compound of Reference Example 17 >>
1 H-NMR (CDCl 3 , δ): 3.90 (3H, s), 4.09 (3H, s), 7.04 (2H, d, J = 9.3 Hz), 7.59 (1H, dd, J = 8.3, 7.3 Hz), 8.00 (1H, s), 8.04 (1H, dd, J = 7.3, 1.5 Hz), 8.18 (2H, d, J = 9.3 Hz), 8.33 (1H, dd, J = 8.3, 1.5 Hz).
<< Compound of Reference Example 18 >>
1 H-NMR (CDCl 3 , δ): 3.94 (3H, s), 4.09 (3H, s), 7.03-7.06 (1H, m), 7.43 (1H, t, J = 7.8 Hz), 7.64 (1H, dd, J = 8.3, 7.3 Hz), 7.74-7.76 (1H, m), 7.86 (1H, t, J = 2) .0Hz), 8.05 (1H, s), 8.06 (1H, dd, J = 6.9, 1.5Hz), 8.37 (1H, dd, J = 8.3, 1.5Hz) .
<< Compound of Reference Example 19 >>
1 H-NMR (CDCl 3 , δ): 4.08 (3H, s), 7.63-7.67 (3H, m), 8.02 (1H, s), 8.06-8.11 ( 3H, m), 8.37 (1H, dd, J = 8.3, 1.5 Hz).
<< Compound of Reference Example 20 >>
1 H-NMR (CDCl 3 , δ): 4.10 (3H, s), 7.72 (1H, dd, J = 8.3, 7.3 Hz), 8.11 (1H, s), 8. 13 (1H, dd, J = 7.3, 1.5 Hz), 8.38-8.43 (5H, m).
<< Compound of Reference Example 21 >>
1 H-NMR (CDCl 3 , δ): 4.09 (3H, s), 7.30 (1H, dt, J = 9.8, 8.3 Hz), 7.66 (1H, dd, J = 8) .3, 7.3 Hz), 7.91-7.95 (1 H, m), 7.98 (1 H, s), 8.08-8.14 (2 H, m), 8.37 (1 H, dd) , J = 8.3, 1.5 Hz).
<< Compound of Reference Example 22 >>
1 H-NMR (CDCl 3 , δ): 1.49 (3H, t, J = 7.3 Hz), 4.01 (3H, s), 4.56 (2H, q, J = 7.3 Hz), 7.45-7.53 (3H, m), 7.57 (1H, d, J = 2.9 Hz), 7.69 (1H, d, J = 2.9 Hz), 8.02 (1H, s ), 8.17-8.19 (2H, m).
<< Compound of Reference Example 23 >>
1 H-NMR (CDCl 3 , δ): 2.61 (3H, s), 4.08 (3H, s), 7.47-7.54 (3H, m), 7.91 (1H, d, J = 2.0 Hz), 8.02 (1H, s), 8.12 (1H, dd, J = 2.0, 1.0 Hz), 8.19-8.21 (2H, m).
<< Compound of Reference Example 24 >>
1 H-NMR (CDCl 3 , δ): 4.09 (3H, s), 7.50-7.55 (3H, m), 8.00 (1H, d, J = 2.5 Hz), 8. 07 (1H, s), 8.18-8.20 (2H, m), 8.33 (1H, d, J = 2.0 Hz).
<< Compound of Reference Example 25 >>
1 H-NMR (CDCl 3 , δ): 4.09 (3H, s), 7.49-7.55 (3H, m), 7.83 (1H, dd, J = 8.3, 2.9 Hz) ), 7.99 (1H, dd, J = 8.8, 2.9 Hz), 8.08 (1H, s), 8.18-8.20 (2H, m).
<< Compound of Reference Example 26 >>
1 H-NMR (CDCl 3 , δ): 3.89 (3H, s), 4.09 (3H, s), 7.03 (2H, d, J = 8.8 Hz), 7.81 (1H, dd, J = 8.3, 2.9 Hz), 7.95 (1H, dd, J = 8.8, 2.9 Hz), 8.02 (1H, s), 8.15 (2H, d, J = 8.8 Hz).
<< Compound of Reference Example 27 >>
1 H-NMR (CDCl 3 , δ): 3.93 (3H, s), 4.09 (3H, s), 7.04 (1H, dd, J = 8.3, 2.4 Hz), 7. 43 (1H, t, J = 7.8 Hz), 7.71 (1H, d, J = 7.8 Hz), 7.81-7.85 (2H, m), 7.98 (1H, dd, J = 8.8, 2.9 Hz), 8.05 (1H, s).
Reference Example 28 Methyl 4-chloro-2- (3,4-difluorophenyl) -6-fluoroquinoline-8-carboxylate
Figure 2004014861
To a solution of ethyl 3,4-difluorobenzoyl acetate (1.14 g, 5.00 mmol) and methyl 5-fluoroanthranilate (1.69 g, 10.0 mmol) in benzene (25 mL) was added methanesulfonic acid (10.0 μL). In addition, the mixture was heated to reflux for 48 hours. After cooling, the reaction solution was concentrated under reduced pressure, diisopropyl ether was added, the crystals were collected by filtration, washed with diisopropyl ether and dried to obtain a light brown powder. Diphenyl ether (15 mL) was added thereto, and the mixture was stirred at 250 ° C. for 30 minutes. After cooling, hexane was added, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried to obtain a tan powder. To this was added phosphorus oxychloride (2 mL), and the mixture was heated to reflux for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound as a colorless powder. 176 mg was obtained. Yield 10%.
1 H-NMR (CDCl 3 , δ): 4.10 (3H, s), 7.27-7.34 (1H, m), 7.84-7.92 (2H, m), 7.97- 7.997 (1H, m), 8.00 (1H, s), 8.05-8.11 (1H, m).

＜参考例２９＞ ４−クロロ−２−フェニルキノリン−８−カルボン酸アミド

Figure 2004014861
参考例１６の化合物（１．００ｇ，３．３６ｍｍｏｌ）の飽和アンモニア−エタノール（１０ｍＬ）溶液を封管中、１２０℃にて２０時間撹拌した。冷後、反応液にジイソプロピルエーテルを加え、結晶を濾取し、ジイソプロピルエーテルにて洗浄後、風乾することにより、無色粉末の表題化合物を７１２ｍｇ得た。収率７５％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．５７−７．６５（３Ｈ，ｍ），７．８６（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），８．０６（１Ｈ，ｓ），８．２２（２Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．４２（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５１（１Ｈ，ｓ），８．５７（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），９．８０（１Ｈ，ｓ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１６Ｈ１１ＣｌＮ２Ｏ：Ｃ，６７．９７；Ｈ，３．９２；Ｎ，９．９１（％）．
Ｆｏｕｎｄ：Ｃ，６８．１２；Ｈ，３．９２；Ｎ，９．９８（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：２８２．０５６１（＋０．１ｍｍｕ）．
＜参考例３０〜３９＞ 参考例２９と同様の方法により、下記表８記載の化合物を得た。
Figure 2004014861
《参考例３０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．８７（３Ｈ，ｓ），７．１６（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．８２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．０４（１Ｈ，ｓ），８．１９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．３９（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．４６（１Ｈ，ｓ），８．５５（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），９．８６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
《参考例３１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．８２（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．８７（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），８．０１（１Ｈ，ｓ），８．１８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．４１（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５１（１Ｈ，ｄｄ，Ｊ＝６．９，１．５Ｈｚ），８．５３（１Ｈ，ｓ），９．４８（１Ｈ，ｓ）．
《参考例３２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．９１（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），８．０１（１Ｈ，ｓ），８．４２−８．５０（６Ｈ，ｍ），９．２４（１Ｈ，ｓ）．
《参考例３３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．７０（１Ｈ，ｄｔ，Ｊ＝１０．８，８．３Ｈｚ），７．８６（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），８．０１（１Ｈ，ｄ，Ｊ＝１．０Ｈｚ），８．１１−８．１４（１Ｈ，ｍ），８．２９−８．３４（１Ｈ，ｍ），８．４１（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．４６（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），８．５７（１Ｈ，ｓ），９．２７（１Ｈ，ｓ）．
《参考例３４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．０１（３Ｈ，ｓ），７．５６−７．６２（３Ｈ，ｍ），７．６５（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ），８．１２（１Ｈ，ｓ），８．１５−８．１８（３Ｈ，ｍ），８．４６（１Ｈ，ｓ），９．８８（１Ｈ，ｓ）．
《参考例３５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：２．６２（３Ｈ，ｓ），７．５８−７．６３（３Ｈ，ｍ），８．０３（１Ｈ，ｓ），８．１８−８．２０（２Ｈ，ｍ），８．４３（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．４６（１Ｈ，ｓ），９．８６（１Ｈ，ｓ）．
《参考例３６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．６０−７．６３（３Ｈ，ｍ），８．１８−８．２３（３Ｈ，ｍ），８．３８−８．４０（２Ｈ，ｍ），８．５７（１Ｈ，ｓ），９．５８（１Ｈ，ｓ）．
《参考例３７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．５８−７．６４（３Ｈ，ｍ），８．１３（１Ｈ，ｄｄ，Ｊ＝８．８，３．４Ｈｚ），８．２０−８．２２（３Ｈ，ｍ），８．３２（１Ｈ，ｄｄ，Ｊ＝９．３，２．９Ｈｚ），８．５６（１Ｈ，ｓ），９．６８（１Ｈ，ｄ，Ｊ＝１．０Ｈｚ）．
《参考例３８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．８７（３Ｈ，ｓ），７．１５（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．１０（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），８．１７（２Ｈ，ｄ，Ｊ＝９．３，２．９Ｈｚ），８．５１（１Ｈ，ｓ），９．７６（１Ｈ，ｓ）．
《参考例３９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．６６−７．７３（１Ｈ，ｍ），８．０９−８．１５（３Ｈ，ｍ），８．２２−８．３３（２Ｈ，ｍ），８．６１（１Ｈ，ｓ），９．１８（１Ｈ，ｓ）．
＜参考例４０＞ ４−クロロ−２−（４−ヒドロキシフェニル）キノリン−８−カルボン酸
Figure 2004014861
参考例１７の化合物（１２５ｍｇ，３８１μｍｏｌ）のジクロロメタン（４ｍＬ）溶液に１ｍｏｌ／Ｌ三臭化ホウ素−ジクロロメタン溶液（１．９１ｍＬ，１．９１ｍｍｏｌ）を加え、１６時間加熱還流した。冷後、少量づつ水を添加した。析出晶を濾取し、水、酢酸エチルにて順次洗浄後、風乾することにより、黄色粉末の表題化合物を１０８ｍｇ得た。収率９５％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．０２（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．８９（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），８．０８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．４９（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５４（１Ｈ，ｓ），８．６１（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ）．
＜参考例４１〜４３＞ 参考例４０と同様の方法により、下記表９記載の化合物を得た。
Figure 2004014861
《参考例４１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．０４（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），７．４５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５６（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），７．６４（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．９５（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），８．５３（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５６（１Ｈ，ｓ），８．６３（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），９．９７（１Ｈ，ｓ）．
《参考例４２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．０２（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），７．４３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５６（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），７．６３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．２４（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），８．３６（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），８．５８（１Ｈ，ｓ），９．９４（１Ｈ，ｓ），１５．５０−１６．３０（１Ｈ，ｂｒ）．
《参考例４３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．００（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．０６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．２０（１Ｈ，ｄｄ，Ｊ＝９．３，２．９Ｈｚ），８．３４（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），８．５７（１Ｈ，ｓ），９．９０−１０．９０（１Ｈ，ｂｒ）．
＜参考例４４＞ １，４−ジヒドロ−２−（３−メトキシフェニル）−４−オキソキノリン−８−カルボン酸
Figure 2004014861
参考例３の化合物（８２５ｍｇ，２．６７ｍｍｏｌ）のメタノール（２５ｍＬ）に１ｍｏｌ／Ｌ水酸化カリウム（５．８７ｍＬ，５．８７ｍｍｏｌ）を加え、１時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣を水に溶解後、濃塩酸を用いてｐＨ２とした。析出晶を濾取し、水洗後、風乾することにより、淡褐色粉末の表題化合物を７５４ｍｇ得た。収率９６％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．８８（３Ｈ，ｓ），６．７５（１Ｈ，ｓ），７．２０（１Ｈ，ｄｄ，Ｊ＝８．３，２．０Ｈｚ），７．４２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．４５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５６（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．４０−８．４４（２Ｈ，ｍ）．
＜参考例４５＞ １，４−ジヒドロ−２−（３−ニトロフェニル）−４−オキソキノリン−８−カルボン酸
Figure 2004014861
参考例５の化合物（３．２４ｇ，１０．０ｍｍｏｌ）を用い、参考例４４と同様の方法により、黄白色粉末の表題化合物を３．０７ｇ得た。収率９９％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：６．９１（１Ｈ，ｂｒｓ），７．５５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．９３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．３７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．４２−８．４７（３Ｈ，ｍ），８．６７（１Ｈ，ｓ）．
＜参考例４６＞ １，４−ジヒドロ−６−フルオロ−２−（４−ニトロフェニル）−４−オキソキノリン−８−カルボン酸
Figure 2004014861
参考例１２の化合物（４．７９ｇ，１４．０ｍｍｏｌ）を用い、参考例４４と同様の方法により、黄白色粉末の表題化合物を４．５１ｇ得た。収率９８％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：６．９４（１Ｈｓ），８．０８（１Ｈ，ｄｄ，Ｊ＝８．６，３．１Ｈｚ），８．１５（２Ｈ，ｄ，Ｊ＝９．２Ｈｚ），８．２３（１Ｈ，ｄｄ，Ｊ＝８．６，３．１Ｈｚ），８．４４（２Ｈ，ｄ，Ｊ＝９．２Ｈｚ）．
＜参考例４７＞ ４−クロロ−２−（４−ヒドロキシフェニル）キノリン−８−カルボン酸アミド
Figure 2004014861
参考例４０の化合物（１０６ｍｇ，３５４μｍｏｌ）に塩化チオニル（３ｍＬ）を加え、１時間加熱還流した。冷後、減圧濃縮して得られた残渣をテトラヒドロフランに懸濁後、氷冷撹拌下、濃アンモニア水（５ｍＬ）に滴下し、同温にて３０分間撹拌した。析出晶を濾去し、溶媒を留去した。得られた残渣に少量の水を加え、結晶を濾取し、水洗後、風乾することにより、褐色粉末の表題化合物を４９．６ｍｇ得た。収率４７％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：６．９７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．８０（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），８．００（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．０８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．３８（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．４０（１Ｈ，ｓ），８．５６（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），９．９５（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），１０．１３（１Ｈ，ｓ）．
＜参考例４８〜５０＞ 参考例４７と同様の方法により、下記表１０記載の化合物を得た。
Figure 2004014861
《参考例４８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：６．９９（１Ｈ，ｄｄ，Ｊ＝８．３，２．５Ｈｚ），７．４０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．６１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８６（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．０５（１Ｈ，ｓ），８．４０（１Ｈ，ｓ），８．４２（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．０Ｈｚ），９．８６（１Ｈ，ｓ）．
《参考例４９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：６．９９（１Ｈ，ｄｄ，Ｊ＝８．３，２．５Ｈｚ），７．４０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５５（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），７．６１（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），８．１３（１Ｈ，ｄｄ，Ｊ＝８．８，２．９Ｈｚ），８．２２（１Ｈ，ｓ），８．３４（１Ｈ，ｄｄ，Ｊ＝９．３，２．９Ｈｚ），８．４５（１Ｈ，ｓ），９．７６（１Ｈ，ｓ），９．８６（１Ｈ，ｂｒｓ）．
《参考例５０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：６．９５（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．０４−８．０８（３Ｈ，ｍ），８．２９（１Ｈ，ｄｄ，Ｊ＝９．３，２．９Ｈｚ），８．４３（１Ｈ，ｓ），９．８５（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ）．
＜参考例５１＞ ４−クロロ−２−（３−メトキシフェニル）キノリン−８−カルボン酸アミド
Figure 2004014861
参考例４４の化合物（７５２ｍｇ，２．５５ｍｍｏｌ）に塩化チオニル（５ｍＬ）を加え、１時間加熱還流した。冷後、減圧濃縮して得られた残渣をテトラヒドロフランに溶解後、氷冷撹拌下、濃アンモニア水（１０ｍＬ）に滴下し、同温にて３０分間撹拌した。析出晶を濾取し、水洗後、風乾することにより、淡褐色粉末の表題化合物を７７１ｍｇ得た。収率９７％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．８９（３Ｈ，ｓ），７．１６（１Ｈ，ｄｄ，Ｊ＝７．８，２．５Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７６（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），７．８０（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．１１（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），８．４３（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５４（１Ｈ，ｓ），８．５７（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），９．８２（１Ｈ，ｄ，Ｊ＝１．０Ｈｚ）．
＜参考例５２＞ ４−クロロ−２−（３−ニトロフェニル）キノリン−８−カルボン酸アミド
Figure 2004014861
参考例４５の化合物（３．０７ｇ，９．８９ｍｍｏｌ）を用い、参考例５１と同様の方法により、淡褐色粉末の表題化合物を３．１９ｇ得た。収率９８％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：７．８７−７．９３（２Ｈ，ｍ），８．０７（１Ｈ，ｓ），８．４０−８．４７（３Ｈ，ｍ），８．６８（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），８．６９（１Ｈ，ｓ），９．０３（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），９．２０（１Ｈ，ｓ）．
＜参考例５３＞ ４−クロロ−６−フルオロ−２−（４−ニトロフェニル）キノリン−８−カルボン酸アミド
Figure 2004014861
参考例４６の化合物（４．５０ｇ，１３．７ｍｍｏｌ）を用い、参考例５１と同様の方法により、淡褐色粉末の表題化合物を４．４１ｇ得た。収率９３％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：８．１５（１Ｈ，ｄｄ，Ｊ＝８．６，３．１Ｈｚ），８．１０−８．２０（１Ｈ，ｂｒ），８．２７（１Ｈ，ｄｄ，Ｊ＝８．６，３．０Ｈｚ），８．４３（２Ｈ，ｄ，Ｊ＝９．２Ｈｚ），８．４８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．６９（１Ｈ，ｓ），９．１４（１Ｈ，ｂｒｓ）．
＜参考例５４〜５９＞ 参考例１と同様の方法により、下記表１１記載の化合物を得た。
Figure 2004014861
《参考例５４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：３．９９（３Ｈ，ｓ），６．６９（１Ｈ，ｓ），７．５０（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．１０（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．４２（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），１１．９９（１Ｈ，ｓ）．
《参考例５５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：４．０１（３Ｈ，ｓ），６．６９（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．４３−７．５５（４Ｈ，ｍ），７．８０（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．９６−８．０１（４Ｈ，ｍ），１２．０５（１Ｈ，ｓ）．
《参考例５６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：３．７５（３Ｈ，ｓ），３．９０（６Ｈ，ｓ），３．９７（３Ｈ，ｓ），６．６５（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．１４（２Ｈ，ｓ），７．４６（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），８．３６−８．４１（２Ｈ，ｍ），１１．８０（１Ｈ，ｓ）．
《参考例５７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：４．０２（３Ｈ，ｓ），６．７６（１Ｈ，ｓ），７．５０（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６７（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．０６（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），８．１２（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），８．１９（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．４２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．５１（１Ｈ，ｓ），１２．１０（１Ｈ，ｓ）．
《参考例５８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：４．００（３Ｈ，ｓ），６．５７（１Ｈ，ｓ），７．３４（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．４６（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．８３（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．９５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．２８（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１１．９６（１Ｈ，ｓ）．
《参考例５９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：３．９８（３Ｈ，ｓ），６．６１（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．４１（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．６４−７．６７（３Ｈ，ｍ），７．８６−７．８８（２Ｈ，ｍ），８．２５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），１２．２９（１Ｈ，ｓ）．
＜参考例６０〜６５＞ 参考例４４と同様の方法により、下記表１２記載の化合物を得た。
Figure 2004014861
《参考例６０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：６．８７（１Ｈ，ｓ），７．５５（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），８．０２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．１２（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．４２−８．４７（２Ｈ，ｍ），１３．００−１４．００（１Ｈ，ｂｒ）．
《参考例６１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：６．８６（１Ｈ，ｓ），７．４４（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．５１−７．５６（３Ｈ，ｍ），７．７９−７．８１（２Ｈ，ｍ），７．９５−８．０１（４Ｈ，ｍ），８．４３−８．４７（２Ｈ，ｍ）．
《参考例６２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：３．７８（３Ｈ，ｓ），３．９３（６Ｈ，ｓ），６．９９（１Ｈ，ｓ），７．２３（２Ｈ，ｓ），７．５８（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），８．４７（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ）．
《参考例６３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：６．８８（１Ｈ，ｂｒｓ），７．５３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６４−７．６９（２Ｈ，ｍ），７．９８（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．０６（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），８．１２（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），８．１９（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．４３−８．４７（２Ｈ，ｍ），８．５１（１Ｈ，ｓ）．
《参考例６４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：７．１１（１Ｈ，ｓ），７．３４（１Ｈ，ｄｄ，Ｊ＝４．９，３．７Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．８８（１Ｈ，ｔ，Ｊ＝２．４Ｈｚ），７．９６（１Ｈ，ｔ，Ｊ＝１．２Ｈｚ），８．４１（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），８．４９（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ）．
《参考例６５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：６．６７（１Ｈ，ｂｒｓ），７．４４（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．６３−７．６６（３Ｈ，ｍ），７．８７−７．８９（２Ｈ，ｍ），８．２９（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．
＜参考例６６〜７１＞ 参考例５１と同様の方法により、下記表１３記載の化合物を得た。
Figure 2004014861
《参考例６６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：７．８９（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．９８（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．０２（１Ｈ，ｓ），８．４２−８．４５（３Ｈ，ｍ），８．５１（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），８．５９（１Ｈ，ｓ），９．４１（１Ｈ，ｓ）．
《参考例６７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：７．４５（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．５３（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．８１（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．８６（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．９３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．０７（１Ｈ，ｓ），８．３３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．４３（１Ｈ，ｄｄ，Ｊ＝８．６，１．２Ｈｚ），８．５６（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），８．５８（１Ｈ，ｓ），９．７３（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
《参考例６８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：３．７７（３Ｈ，ｓ），３．９４（６Ｈ，ｓ），７．５３（２Ｈ，ｓ），７．８５（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），８．１７（１Ｈ，ｓ），８．４２（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５９（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．６３（１Ｈ，ｓ），９．９６（１Ｈ，ｓ）．
《参考例６９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：７．６３−７．６７（２Ｈ，ｍ），７．８７（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），８．０２−８．１５（４Ｈ，ｍ），８．３４（１Ｈ，ｄｄ，Ｊ＝８．６，１．８Ｈｚ），８．４４（１Ｈ，ｄｄ，Ｊ＝８．６，１．２Ｈｚ），８．５７（１Ｈ，ｄｄ，Ｊ＝７．３，１．８Ｈｚ），８．６９（１Ｈ，ｓ），８．８６（１Ｈ，ｓ），９．８０（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ）．
《参考例７０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：７．３０（１Ｈ，ｄｄ，Ｊ＝４．９，３．７Ｈｚ），７．８１（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．８９（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．１７（１Ｈ，ｓ），８．２１（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），８．３９（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），８．５６（１Ｈ，ｓ），８．６２（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），９．８０（１Ｈ，ｓ）．
《参考例７１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：７．６０−７．６３（３Ｈ，ｍ），７．９０（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．９９（１Ｈ，ｂｒｓ），８．２４−８．２６（３Ｈ，ｍ），８．５０（１Ｈ，ｓ），９．１１（１Ｈ，ｂｒｓ）．
＜参考例７２＞ １，４−ジヒドロ−４−オキソ−２−（４−トリフルオロメチルフェニル）キノリン−８−カルボン酸アミド
Figure 2004014861
参考例５４の化合物（９２６ｍｇ，２．６７ｍｍｏｌ）を用い、参考例１５と同様の方法により、淡黄色粉末の表題化合物を７０３ｍｇ得た。収率７９％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：６．６４（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．４５（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．９９（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．０７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．３３（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），８．６７（１Ｈ，ｓ），１３．６７（１Ｈ，ｓ）．
＜参考例７３＞ ２−（４−ビフェニル）−１，４−ジヒドロ−４−オキソキノリン−８−カルボン酸アミド
Figure 2004014861
参考例５５の化合物（５７０ｍｇ，１．６０ｍｍｏｌ）を用い、参考例１５と同様の方法により、淡褐色粉末の表題化合物を４９６ｍｇ得た。収率９１％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，▲ａ▼）：６．６５（１Ｈ，ｓ），７．４２−７．４７（２Ｈ，ｍ），７．５３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．９５（４Ｈ，ｓ），８．０５（１Ｈ，ｓ），８．３３−８．３６（２Ｈ，ｍ），８．６８（１Ｈ，ｓ），１３．６２（１Ｈ，ｓ）．
＜実施例１＞ ４−メトキシ−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
工程１：参考例１の化合物（６００ｍｇ，２．１５ｍｍｏｌ）および炭酸カリウム（５９４ｍｇ，４．３０ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）懇濁液に、ヨードメタン（１６１μＬ，２．５８ｍｍｏｌ）を加え、室温にて３時間撹拌した。反応液に水を加え、酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝４：１］に付し、黄白色粉末の４−メトキシ−２−フェニルキノリン−８−カルボン酸メチルを５５９ｍｇ得た。収率８９％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．９７（３Ｈ，ｓ），４．２０（３Ｈ，ｓ），７．５２−７．６１（４Ｈ，ｍ），７．６６（１Ｈ，ｓ），７．９３（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），８．２７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．３１−８．３３（２Ｈ，ｍ）．
工程２：４−メトキシ−２−フェニルキノリン−８−カルボン酸メチル（２５７ｍｇ，８７６μｍｏｌ）の飽和アンモニア−エタノール（１０ｍＬ）溶液を封管中、１２０℃にて２０時間撹拌した。冷後、溶媒を留去して得られた残渣に酢酸エチルを加え、結晶を濾取し、酢酸エチルにて洗浄後、乾燥した。これをシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝１：２］に付し、無色粉末の表題化合物を５６．１ｍｇ得た。収率２３％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．２２（３Ｈ，ｓ），７．５７−７．７０（５Ｈ，ｍ），７．９８（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１８（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５５（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１７Ｈ１４Ｎ２Ｏ２：Ｃ，７３．３７；Ｈ，５．０７；Ｎ，１０．０７（％）．
Ｆｏｕｎｄ：Ｃ，７３．０７；Ｈ，５．１１；Ｎ，１０．０２（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：２７８．１０８７（＋３．２ｍｍｕ）．
＜実施例２〜４＞ 実施例１と同様の方法により、下記表１４記載の化合物を得た。
Figure 2004014861
《実施例２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．５４（３Ｈ，ｔ，Ｊ＝６．９Ｈｚ），４．５２（２Ｈ，ｑ，Ｊ＝６．９Ｈｚ），７．５７−７．６２（４Ｈ，ｍ），７．６７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．９５（１Ｈ，ｓ），８．１５−８．１７（２Ｈ，ｍ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．０Ｈｚ），１０．５６（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１７Ｈ１４Ｎ２Ｏ２・１／３Ｈ２Ｏ：Ｃ，７２．４７；Ｈ，５．６３；Ｎ，９．３９（％）．
Ｆｏｕｎｄ：Ｃ，７２．２５；Ｈ，５．４８；Ｎ，９．４９（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：２９２．１１６７（−４．４ｍｍｕ）．
《実施例３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．４８（６Ｈ，ｔ，Ｊ＝５．９Ｈｚ），５．２６−５．３２（１Ｈ，ｍ），７．５５−７．６８（５Ｈ，ｍ），７．９５（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．１５−８．１７（２Ｈ，ｍ），８．３６（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５９（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１７Ｈ１４Ｎ２Ｏ２・１／５Ｈ２Ｏ：Ｃ，７３．６２；Ｈ，５．９８；Ｎ，９．０４（％）．
Ｆｏｕｎｄ：Ｃ，７３．５０；Ｈ，５．９３；Ｎ，８．９５（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３０６．１３８７（＋１．９ｍｍｕ）．
《実施例４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．７８（３Ｈ，ｓ），５．５２（２Ｈ，ｓ），７．０２（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５８−７．６８（４Ｈ，ｍ），７．７９（１Ｈ，ｓ），７．９８（１Ｈ，ｄ，Ｊ＝３．４Ｈｚ），８．１７−８．１９（２Ｈ，ｍ），８．３５（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５４（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３８４．１４６１（−１．３ｍｍｕ）．
＜実施例５＞ ２−フェニル−４−プロポキシキノリン−８−カルボン酸アミド
Figure 2004014861
参考例１５の化合物（１００ｍｇ，３７８μｍｏｌ）および炭酸カリウム（１０４ｍｇ，７５６μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）懸濁液に、１−ヨードプロパン（４４．３μＬ，４５４μｍｏｌ）を加え、室温にて６時間撹拌した。反応液に水を加え、酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣に少量の酢酸エチルを加え、結晶を濾取し、酢酸エチルにて洗浄後、風乾することにより、黄白色粉末の表題化合物を７６．４ｍｇ得た。収率６６％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．１２（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．９２−１．９９（２Ｈ，ｍ），４．４２（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），７．５５−７．６１（３Ｈ，ｍ），７．６３（１Ｈ，ｓ），７．６８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１５−８．１８（２Ｈ，ｍ），８．３９（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１９Ｈ１８Ｎ２Ｏ２：Ｃ，７４．４９；Ｈ，５．９２；Ｎ，９．１４（％）．
Ｆｏｕｎｄ：Ｃ，７４．５３；Ｈ，５．９６；Ｎ，９．１５（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３０６．１３７９（＋１．１ｍｍｕ）．
＜実施例６〜１１＞ 実施例５と同様の方法により、下記表１５記載の化合物を得た。
Figure 2004014861
《実施例６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．１９（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），４．７７（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．５７−７．６３（３Ｈ，ｍ），７．７０−７．７３（２Ｈ，ｍ），７．９９（１Ｈ，ｄ，Ｊ＝３．４Ｈｚ），８．１８（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．４０（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５１（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１８Ｈ１５ＣｌＮ２Ｏ２：Ｃ，６６．１６；Ｈ，４．６３；Ｎ，８．５７（％）．
Ｆｏｕｎｄ：Ｃ，６６．０５；Ｈ，４．５４；Ｎ，８．６３（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３２６．０８３６（＋１．４ｍｍｕ）．
《実施例７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：２．３６−２．４２（２Ｈ，ｍ），３．９６（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），４．５８（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．５７−７．６４（３Ｈ，ｍ），７．６６−７．７０（２Ｈ，ｍ），７．９８（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．１８（２Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．４３（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５５（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１９Ｈ１７ＣｌＮ２Ｏ２・１／１０Ｈ２Ｏ：Ｃ，６６．６１；Ｈ，５．０６；Ｎ，８．１８（％）．
Ｆｏｕｎｄ：Ｃ，６６．５４；Ｈ，５．０５；Ｎ，８．１９（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３４０．０９８０（＋０．１ｍｍｕ）．
《実施例８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：２．０５（４Ｈ，ｂｒｓ），３．８１（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），４．５０（２Ｈ，ｂｒｓ），７．５７−７．７１（５Ｈ，ｍ），７．９８（１Ｈ，ｓ），８．１７（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），８．３８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．５９（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１０．５６（１Ｈ，ｓ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３５４．１１４９（＋１．４ｍｍｕ）．
《実施例９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．７７（３Ｈ，ｓ），５．３７（２Ｈ，ｓ），７．５７−７．６４（３Ｈ，ｍ），７．６８（１Ｈ，ｓ），７．７２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１５−８．１８（２Ｈ，ｍ），８．４１（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．４５（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１９Ｈ１６Ｎ２Ｏ４・１／４Ｈ２Ｏ：Ｃ，６６．９５；Ｈ，４．８８；Ｎ，８．２２（％）．
Ｆｏｕｎｄ：Ｃ，６６．９２；Ｈ，４．７４；Ｎ，８．２０（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３３６．１１４０（＋２．９ｍｍｕ）．
《実施例１０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．９０−３．９４（２Ｈ，ｍ），４．４７（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），５．１４（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．５５−７．７０（５Ｈ，ｍ），７．９７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１７（２Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．４８（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，２．０Ｈｚ），１０．５８（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１８Ｈ１６Ｎ２Ｏ３・１／４Ｈ２Ｏ：Ｃ，６９．１１；Ｈ，５．３２；Ｎ，８．９５．
Ｆｏｕｎｄ：Ｃ，６９．１１；Ｈ，５．１８；Ｎ，８．９２．
ＨＲ−ＭＳ（ｍ／ｚ）：３０８．１１８３（＋２．２ｍｍｕ）．
《実施例１１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．４０（３Ｈ，ｓ），３．８７−３．８９（２Ｈ，ｍ），４．６０（２Ｈ，ｔ，Ｊ＝４．４Ｈｚ），７．５５−７．６４（３Ｈ，ｍ），７．６７−７．７１（２Ｈ，ｍ），７．９８（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１６−８．１８（２Ｈ，ｍ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，２．０Ｈｚ），１０．５５（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１８Ｈ１６Ｎ２Ｏ３：Ｃ，７０．７９；Ｈ，５．６３；Ｎ，８．６９（％）．
Ｆｏｕｎｄ：Ｃ，７０．５９；Ｈ，５．５９；Ｎ，８．７４（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３２２．１３３１（＋１．４ｍｍｕ）．
＜実施例１２＞ ４−［２−（ジエチルアミノ）エトキシ］−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
工程１：参考例１の化合物（３００ｍｇ，１．０７ｍｍｏｌ）および炭酸カリウム（２９６ｍｇ，２．１４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）懸濁液に、１−ブロモ−２−クロロエタン（２６７μＬ，３．２１ｍｍｏｌ）を加え、室温にて１０時間撹拌した。反応液に水を加え、酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル＝４：１］に付し、淡黄色粘凋性液体の４−（２−クロロエトキシ）−２−フェニルキノリン−８−カルボン酸メチルを３１８ｍｇ得た。収率８７％
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：４．０２（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），４．０８（３Ｈ，ｓ），４．５６（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．２４（１Ｈ，ｓ），７．４７−７．５４（４Ｈ，ｍ），８．０３（１Ｈ，ｄｄ，Ｊ＝６．９，１．５Ｈｚ），８．１９−８．２１（２Ｈ，ｍ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
工程２：４−（２−クロロエトキシ）−２−フェニルキノリン−８−カルボン酸メチル（２８０ｍｇ，８１９μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）溶液に、ジエチルアミン（４２４μＬ，４．１０ｍｍｏｌ）次いでヨウ化ナトリウム（１２．３ｍｇ，８１．９μｍｏｌ）を加え、８０℃にて２４時間撹拌した。反応液に水を加え、酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［ヘキサン−酢酸エチル−トリエチルアミン＝５：１：１］に付し、黄褐色粘凋性液体の４−［２−（ジエチルアミノ）エトキシ］−２−フェニルキノリン−８−カルボン酸メチルを２９９ｍｇ得た。収率９６％
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ）：１．１３（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．７２（４Ｈ，ｑ，Ｊ＝７．３Ｈｚ），３．０８（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），４．０８（３Ｈ，ｓ），４．３６（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．２９（１Ｈ，ｓ），７．４６−７．５３（４Ｈ，ｍ），８．０１（１Ｈ，ｄｄ，Ｊ＝６．９，１．５Ｈｚ），８．２０−８．２２（２Ｈ，ｍ），８．３２（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ）．
工程３：４−［２−（ジエチルアミノ）エトキシ］−２−フェニルキノリン−８−カルボン酸メチル（２９９ｍｇ，７９０μｍｏｌ）の飽和アンモニア−エタノール（１０ｍＬ）溶液を封管中、１２０℃にて２０時間撹拌した。冷後、溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル−ヘキサン−トリエチルアミン＝４：２：１］に付し、無色粉末の表題化合物を３２．８ｍｇ得た。収率１１％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．０３（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．６３（４Ｈ，ｑ，Ｊ＝７．３Ｈｚ），３．００（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），４．５０（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．５７−７．６３（３Ｈ，ｍ），７．６７５（１Ｈ，ｓ），７．６８４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝３．４Ｈｚ），８．１８（２Ｈ，ｄ，Ｊ＝６．４Ｈｚ），８．３５（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２５Ｎ３Ｏ２：Ｃ，７２．７０；Ｈ，６．９３；Ｎ，１１．５６（％）．
Ｆｏｕｎｄ：Ｃ，７２．４５；Ｈ，６．８３；Ｎ，１１．４５（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３６３．１９４７（＋０．１ｍｍｕ）．
＜実施例１３＞ ４−［３−（ジエチルアミノ）プロポキシ］−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
実施例７の化合物（１８７ｍｇ，５４９μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）溶液に、ヨウ化ナトリウム（８．２３ｍｇ，５４．９μｍｏｌ）次いでジエチルアミン（２８３μＬ，２．７４ｍｍｏｌ）を加え、８０℃にて２４時間撹拌した。反応液を減圧濃縮して得られた残渣をシリカグルカラムクロマトグラフィ［酢酸エチル−ヘキサン（２：１）→酢酸エチル−ヘキサン−トリエチルアミン（４：２：１）］に付し、無色粉末の表題化合物を１４４ｍｇ得た。収率６９％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：０．９６（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．０２（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），２．６５（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），４．４９（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．５７−７．６１（３Ｈ，ｍ），７．６３（１Ｈ，ｓ），７．６８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１６（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３８（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２３Ｈ２７Ｎ３Ｏ２・１／５Ｈ２Ｏ：Ｃ，７２．４９；Ｈ，７．２５；Ｎ，１１．０３（％）．
Ｆｏｕｎｄ：Ｃ，７２．５６；Ｈ，７．１４；Ｎ，１１．１６（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３７７．２１３０（＋０．１ｍｍｕ）．
＜実施例１４＞ ４−［４−（ジエチルアミノ）ブトキシ］−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
実施例８の化合物（２２９ｍｇ，６４５μｍｏｌ）を用い、実施例１３と同様の方法により、淡褐色粉末の表題化合物を３０．８ｍｇ得た。収率１２％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：０．９５（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．６２−１．６９（２Ｈ，ｍ），１．９４（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），４．４７（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），７．５５−７．６１（３Ｈ，ｍ），７．６４（１Ｈ，ｓ），７．６８（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．１６（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５８（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２４Ｈ２９Ｎ３Ｏ２・１／３Ｈ２Ｏ：Ｃ，７２．５２；Ｈ，７．５２；Ｎ，１０．５７（％）．
Ｆｏｕｎｄ：Ｃ，７２．５８；Ｈ，７．５６；Ｎ，１０．５４（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３９１．２２６４（＋０．５ｍｍｕ）．
＜実施例１５＞ ２−フェニル−４−［２−（ピロリジン−１−イル）エトキシ］キノリン−８−カルボン酸アミド
Figure 2004014861
実施例６の化合物（１５０ｍｇ，４５９μｍｏｌ）およびピロリジン（１９２μＬ，２．３０ｍｍｏｌ）を用い、実施例１３と同様の方法により、淡褐色粉末の表題化合物を３６．２ｍｇ得た。収率２２％
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７０−１．７３（４Ｈ，ｍ），２．６３（４Ｈ，ｂｒｓ），３．０１（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），４．５６（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．５７−７．６３（３Ｈ，ｍ），７．６７−７．７１（２Ｈ，ｍ），７．９７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１８（２Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．３６（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５６（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２３Ｎ３Ｏ２・１／５Ｈ２Ｏ：Ｃ，７２．３９；Ｈ，６．４６；Ｎ，１１．５１（％）．
Ｆｏｕｎｄ：Ｃ，７２．３３；Ｈ，６．３８；Ｎ，１１．５０（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３６２．１８７５（＋０．６ｍｍｕ）．
＜実施例１６＞ ４−［２−（（Ｒ）−３−ヒドロキシピロリジン−１−イル）エトキシ］−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
実施例６の化合物（１００ｍｇ，３０６μｍｏｌ）および（Ｒ）−３−ピロリジノール（１２７μＬ，１．５３ｍｍｏｌ）を用い、実施例１３と同様の方法により、淡褐色粉末の表題化合物を９６．９ｍｇ得た。収率８２％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．５２−１．６０（１Ｈ，ｍ），１．９６−２．０５（１Ｈ，ｍ），２．５５−２．６４（１Ｈ，ｍ），２．７３−２．７９（１Ｈ，ｍ），２．８６−２．９０（１Ｈ，ｍ），２．９６−３．０３（１Ｈ，ｍ），４．１９−４．２５（１Ｈ，ｍ），４．５４（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），４．７３（１Ｈ，ｔ，Ｊ＝４．４Ｈｚ），７．５５−７．６３（３Ｈ，ｍ），７．６７−７．７１（２Ｈ，ｍ），７．９７（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．１８（２Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．３６（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，２．０Ｈｚ），１０．５６（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２３Ｎ３Ｏ３・１／２Ｈ２Ｏ：Ｃ，６８．３８；Ｈ，６．２６；Ｎ，１０．８７（％）．
Ｆｏｕｎｄ：Ｃ，６８．３７；Ｈ，６．２６；Ｎ，１０．８７（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３７８．１８４２（＋２．５ｍｍｕ）．
＜実施例１７＞ ２−フェニル−４−［３−（ピロリジン−１−イル）プロポキシ］キノリン−８−カルボン酸アミド
Figure 2004014861
実施例７の化合物（１９２ｍｇ，５６３μｍｏｌ）およびピロリジン（２３５μＬ，２．８２ｍｍｏｌ）を用い、実施例１３と同様の方法により、黄褐色粉末の表題化合物を８４．０ｍｇ得た。収率３８％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．６９（４Ｈ，ｔ，Ｊ＝２．９Ｈｚ），２．０８−２．１１（２Ｈ，ｍ），２．６６（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），４．５０（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），７．５７−７．７０（５Ｈ，ｍ），７．９７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１７（２Ｈ，ｄ，Ｊ＝６．８Ｈｚ），８．３８（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２３Ｈ２５Ｎ３Ｏ２・Ｈ２Ｏ：Ｃ，７０．２１；Ｈ，６．９２；Ｎ，１０．６８（％）．
Ｆｏｕｎｄ：Ｃ，７０．１５；Ｈ，６．８１；Ｎ，１０．７２（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３７６．２０４６（＋２．１ｍｍｕ）．
＜実施例１８＞ ４−［２−（イミダゾール−１−イル）エトキシ］−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
実施例６の化合物（１６４ｍｇ，５０２μｍｏｌ）およびイミダゾール（１０３ｍｇ，１．５１ｍｍｏｌ）を用い、実施例１３と同様の方法により、無色粉末の表題化合物を８３．８ｍｇ得た。収率４７％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．６０（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），４．７３（２Ｈ，ｔ，Ｊ＝４．４Ｈｚ），６．９２（１Ｈ，ｓ），７．３６（１Ｈ，ｓ），７．５７−７．６３（４Ｈ，ｍ），７．６９（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．８４（１Ｈ，ｓ），７．９７（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．１４−８．１７（２Ｈ，ｍ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．４９（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３５８．１４２５（−０．５ｍｍｕ）．
＜実施例１９＞ ４−（カルボキシメトキシ）−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
実施例９の化合物（１３３ｍｇ，３９５μｍｏｌ）のメタノール（４ｍＬ）懸濁液に、１ｍｏｌ／Ｌ水酸化カリウム水溶液（８６９μＬ，８６９μｍｏｌ）を加え、１時間加熱還流した。冷後、溶媒を留去して得られた残渣を水に溶解し、４ｍｏｌ／Ｌ塩酸にてｐＨ３とした。析出晶を濾取し、水洗後、乾燥することにより、無色粉末の表題化合物を１１６ｍｇ得た。収率９１％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：５．３２（２Ｈ，ｓ），７．６５−７．６７（３Ｈ，ｍ），７．７６−７．８０（２Ｈ，ｍ），８．１４（１Ｈ，ｂｒｓ），８．１７（２Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．４７（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．６５（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１０．１９（１Ｈ，ｂｒｓ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３２３．１０３５（＋０．３ｍｍｕ）．
＜実施例２０＞ ２−フェニル−４−［（ピロリジン−１−イル）カルボニルメトキシ］キノリン−８−カルボン酸アミド
Figure 2004014861
実施例１９の化合物（１３６ｍｇ，４２２μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（５ｍＬ）溶液に、ピロリジン（３５．２μＬ，４２２μｍｏｌ）、１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド（９７．０ｍｇ，５０６μｍｏｌ）および４−ジメチルアミノピリジン（５．１６ｍｇ，４２．２μｍｏｌ）を順次加え、室温にて９時間撹拌した。反応液に水を加え、酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥後、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル］に付し、無色粉末の表題化合物を３２．３ｍｇ得た。収率２０％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７９−１．６４（２Ｈ，ｍ），１．９１−１．９６（２Ｈ，ｍ），３．３６（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．５７（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），５．２９（２Ｈ，ｓ），７．５５−７．６４（４Ｈ，ｍ），７．７０（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．１１−８．１３（２Ｈ，ｍ），８．４２（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．５２（１Ｈ，ｄ，Ｊ＝３．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２０Ｈ２１Ｎ３Ｏ：Ｃ，７０．３８；Ｈ，５．６４；Ｎ，１１．１９（％）．
Ｆｏｕｎｄ：Ｃ，７０．１３；Ｈ，５．６５；Ｎ，１１．１５（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３７５．１６０７（＋２．４ｍｍｕ）．
＜実施例２１＞ ４−［２−（ジメチルアミノ）エチル］アミノ−２−フェニルキノリン−８−カルボン酸アミド
Figure 2004014861
参考例２９の化合物（１５０ｍｇ，５３１μｍｏｌ）のＮ，Ｎ−ジメチルアセトアミド（５ｍＬ）溶液に、ヨウ化ナトリウム（７．９６ｍｇ，５３．１μｍｏｌ）次いでＮ，Ｎ−ジメチルエチレンジアミン（２９１μＬ，２．６５ｍｍｏｌ）を加え、２４時間加熱還流した。冷後、反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィ［酢酸エチル−ヘキサン−トリエチルアミン（４：２：１）→酢酸エチル−メタノール−トリエチルアミン（８：１：１）］に付し、淡褐色粉末の表題化合物を２４．９ｍｇ得た。収率１４％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：２．３２（６Ｈ，ｓ），２．７０（２Ｈ，ｂｒｓ），３．５０−３．６０（２Ｈ，ｂｒ），７．０５（１Ｈ，ｓ），７．４３（１Ｈ，ｂｒｓ），７．４３−７．５９（４Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．０７（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．４２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．５４（１Ｈ，ｄｄ，Ｊ＝７．３，１．０Ｈｚ），１１．１２（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３３４．１７９２（−０．１ｍｍｕ）．
＜実施例２２〜５８＞ 実施例２１と同様の方法により、下記表１６記載の化合物を得た。
Figure 2004014861
《実施例２２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：０．９９（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．５８（４Ｈ，ｑ，Ｊ＝７．３Ｈｚ），２．７５（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．４３−３．５４（２Ｈ，ｍ），７．０５（１Ｈ，ｓ），７．４３（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．５２−７．５９（４Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０５（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．３８（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．５３（１Ｈ，ｄ，Ｊ＝６．４Ｈｚ），１１．１２（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２６Ｎ４Ｏ・１／３Ｈ２Ｏ：Ｃ，７１．７１；Ｈ，７．２９；Ｎ，１５．２１（％）．
Ｆｏｕｎｄ：Ｃ，７１．５７；Ｈ，７．１８；Ｎ，１５．３０（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３６２．２１０２（−０．５ｍｍｕ）．
《実施例２３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：０．８５（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．１９（３Ｈ，ｔ，Ｊ＝６．９Ｈｚ），２．４１（４Ｈ，ｑ，Ｊ＝７．３Ｈｚ），２．６２（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．４９−３．５２（４Ｈ，ｍ），７．５４−７．６２（５Ｈ，ｍ），７．９０（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．０８（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３０（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．５２（１Ｈ，ｄ，Ｊ＝６．４Ｈｚ），１１．６８（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２４Ｈ３０Ｎ４Ｏ：Ｃ，７３．８１；Ｈ，７．７４；Ｎ，１４．３５（％）．
Ｆｏｕｎｄ：Ｃ，７３．７４；Ｈ，７．８６；Ｎ，１４．４１（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３６２．２１０２（−０．５ｍｍｕ）．
《実施例２４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：０．９７（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．８１−１．８８（２Ｈ，ｍ），３．４６−３．５０（２Ｈ，ｍ），７．０１（１Ｈ，ｓ），７．５０−７．５９（４Ｈ，ｍ），７．８４（１Ｈ，ｓ），８．０３−８．０６（２Ｈ，ｍ），８．３７（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），８．５４（１Ｈ，ｄｄ，Ｊ＝７．３，１．０Ｈｚ），１１．１５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２３Ｈ２８Ｎ４Ｏ・２／５Ｈ２Ｏ：Ｃ，７２．００；Ｈ，７．５７；Ｎ，１４．６０（％）．
Ｆｏｕｎｄ：Ｃ，７１．８８；Ｈ，７．６２；Ｎ，１４．８６（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３７６．２２８１（＋１．８ｍｍｕ）．
《実施例２５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．６９−１．７２（４Ｈ，ｍ），２．５３−２．５６（４Ｈ，ｍ），２．７８（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５８（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），７．０５（１Ｈ，ｓ），７．５０−７．５９（５Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．０５−８．０７（２Ｈ，ｍ），８．４４（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５４（１Ｈ，ｄｄ，Ｊ＝７．３，１．０Ｈｚ），１１．１４（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２４Ｎ４Ｏ・１／３Ｈ２Ｏ：Ｃ，７２．１１；Ｈ，６．７８；Ｎ，１５．２９（％）．
Ｆｏｕｎｄ：Ｃ，７２．２２；Ｈ，６．６８；Ｎ，１５．１２（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３６０．１９６２（＋１．２ｍｍｕ）．
《実施例２６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．３５−１．４５（２Ｈ，ｍ），１．４９−１．５５（４Ｈ，ｍ），２．６４（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５５（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），７．０６（１Ｈ，ｓ），７．４２（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．５０−７．５９（４Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０６（２Ｈ，ｄ，Ｊ＝６．８Ｈｚ），８．４１（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５３（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１１．１３（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２３Ｈ２６Ｎ４Ｏ・１／２Ｈ２Ｏ：Ｃ，７２．０４；Ｈ，７．１０；Ｎ，１４．６１（％）．
Ｆｏｕｎｄ：Ｃ，７２．１２；Ｈ，６．９４；Ｎ，１４．６５（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３７４．２１５０（＋４．４ｍｍｕ）．
《実施例２７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：２．６９（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５６−３．６１（６Ｈ，ｍ），７．０７（１Ｈ，ｓ），７．４３（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．５２−７．５９（４Ｈ，ｍ），７．８２（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０６−８．０８（２Ｈ，ｍ），８．４３（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５４（１Ｈ，ｄｄ，Ｊ＝７．３，１．０Ｈｚ），１１．１２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２４Ｎ４Ｏ・２／５Ｈ２Ｏ：Ｃ，６８．８７；Ｈ，６．３１；Ｎ，１４．６０（％）．
Ｆｏｕｎｄ：Ｃ，６８．９２；Ｈ，６．４９；Ｎ，１４．３３（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３７６．１９１７（＋１．８ｍｍｕ）．
《実施例２８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：０．９７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．４１−１．５０（２Ｈ，ｍ），１．６８−１．７６（２Ｈ，ｍ），３．３８−３．４７（２Ｈ，ｍ），７．００（１Ｈ，ｓ），７．５０−７．５９（５Ｈ，ｍ），７．８２（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０４−８．０６（２Ｈ，ｍ），８．４８（１Ｈ，ｄｄ，Ｊ＝８．３，１．５Ｈｚ），８．５３（１Ｈ，ｄｄ，Ｊ＝７．３，１．０Ｈｚ），１１．１５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２０Ｈ２１Ｎ３Ｏ・１／３Ｈ２Ｏ：Ｃ，７３．８２；Ｈ，６．７１；Ｎ，１２．９１（％）．
Ｆｏｕｎｄ：Ｃ，７３．８６；Ｈ，６．５８；Ｎ，１２．８８（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３１９．１６９５（＋１．０ｍｍｕ）．
《実施例２９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｓ），２．５６（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．５４−３．５７（２Ｈ，ｍ），３．８５（３Ｈ，ｓ），７．００（１Ｈ，ｓ），７．１１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４３（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．５０（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．０２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４０（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１１．１７（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２３Ｈ２６Ｎ４Ｏ２・１／５Ｈ２Ｏ：Ｃ，７０．１０；Ｈ，６．７５；Ｎ，１４．２２（％）．
Ｆｏｕｎｄ：Ｃ，７０．１４；Ｈ，６．９０；Ｎ，１４．１７（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９１．２１２２（−１．２ｍｍｕ）．
《実施例３０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｔ，Ｊ＝２．９Ｈｚ），２．５６（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５６−３．５９（２Ｈ，ｍ），３．８６（３Ｈ，ｓ），７．０４（１Ｈ，ｓ），７．０９（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），７．４６−７．５５（３Ｈ，ｍ），７．５８（１Ｈ，ｔ，Ｊ＝１．５Ｈｚ），７．６４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．４２−８．４４（１Ｈ，ｍ），８．５３（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１１．１４（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２３Ｈ２６Ｎ４Ｏ２・１／３Ｈ２Ｏ：Ｃ，６９．６７；Ｈ，６．７８；Ｎ，１４．１３（％）．
Ｆｏｕｎｄ：Ｃ，６９．６１；Ｈ，６．８３；Ｎ，１３．９２（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９１．２１６７（＋３．３ｍｍｕ）．
《実施例３１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｓ），２．５６（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．５３−３．５６（２Ｈ，ｍ），６．９２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．９６（１Ｈ，ｓ），７．３０−７．４０（１Ｈ，ｍ），７．４８（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．９１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．３９（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５０（１Ｈ，ｄ，Ｊ＝６．４Ｈｚ），９．８７（１Ｈ，ｓ），１１．２４（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３７７．１９８５（＋０．７ｍｍｕ）．
《実施例３２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｔ，Ｊ＝３．４Ｈｚ），２．５５（４Ｈ，ｓ），２．７７（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．５６（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），６．９１（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），６．９５（１Ｈ，ｓ），７．３４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４２−７．５４（４Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．４２−８．４４（１Ｈ，ｍ），８．５４（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），９．７０（１Ｈ，ｓ），１１．１５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２４Ｎ４Ｏ２・１／２Ｈ２Ｏ：Ｃ，６８．５５；Ｈ，６．５４；Ｎ，１４．５４（％）．
Ｆｏｕｎｄ：Ｃ，６８．５７；Ｈ，６．４４；Ｎ，１４．４４（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３７６．１９１１（＋１．２ｍｍｕ）．
《実施例３３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｔ，Ｊ＝３．４Ｈｚ），２．５１（４Ｈ，ｓ），２．７９（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５５−３．６０（２Ｈ，ｍ），７．０４（１Ｈ，ｓ），７．５２−７．５６（２Ｈ，ｍ），７．７６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８２（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．４４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．５２（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．８９（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２３ＢｒＮ４Ｏ・１／３Ｈ２Ｏ：Ｃ，５９．３３；Ｈ，５．３１；Ｎ，１２．５８（％）．
Ｆｏｕｎｄ：Ｃ，５９．３７；Ｈ，５．１７；Ｎ，１２．４２（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：４３８．１０５５（−０．１ｍｍｕ）．
《実施例３４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７０（４Ｈ，ｔ，Ｊ＝３．４Ｈｚ），２．５５（４Ｈ，ｓ），２．７９（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５８−３．６２（２Ｈ，ｍ），７．１５（１Ｈ，ｓ），７．５８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６４（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），７．８５（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．３２（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），８．４０（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．４７（１Ｈ，ｄｄ，Ｊ＝８．８，１．５Ｈｚ），８．５３（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１０．６８（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４０６．１８９４（＋１．５ｍｍｕ）．
《実施例３５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｔ，Ｊ＝３．４Ｈｚ），２．５６（４Ｈ，ｓ），２．７９（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．６１（２Ｈ，ｑ，Ｊ＝５．４Ｈｚ），７．１７（１Ｈ，ｓ），７．５５−７．６３（２Ｈ，ｍ），７．８４−７．９１（２Ｈ，ｍ），８．３６（１Ｈ，ｄｄ，Ｊ＝７．８，１．５Ｈｚ），８．４７（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５１−８．５４（２Ｈ，ｍ），８．８３（１Ｈ，ｔ，Ｊ＝１．５Ｈｚ），１０．６５（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２３Ｎ５Ｏ３・１／３Ｈ２Ｏ：Ｃ，６４．２２；Ｈ，５．８０；Ｎ，１７．０２（％）．
Ｆｏｕｎｄ：Ｃ，６４．４６；Ｈ，５．９０；Ｎ，１６．７３（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４０６．１８６０（−１．９ｍｍｕ）．
《実施例３６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７０（４Ｈ，ｓ），２．５５（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５７−３．６０（２Ｈ，ｍ），７．０７（１Ｈ，ｓ），７．５１−７．５６（１Ｈ，ｍ），７．６０−７．６７（１Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），７．９３−７．９６（１Ｈ，ｍ），８．１０−８．１６（１Ｈ，ｍ），８．４４（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４９−８．５１（１Ｈ，ｍ），１０．７３（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２２Ｆ２Ｎ４Ｏ：Ｃ，６６．６５；Ｈ，５．５９；Ｎ，１４．１３（％）．
Ｆｏｕｎｄ：Ｃ，６６．３５；Ｈ，５．８７；Ｎ，１４．３１（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９７．１８６４（＋２．４ｍｍｕ）．
《実施例３７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７２（４Ｈ，ｓ），２．５８（４Ｈ，ｓ），２．８０（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５５−３．６５（２Ｈ，ｍ），３．９４（３Ｈ，ｓ），６．５５（１Ｈ，ｓ），７．０２（１Ｈ，ｓ），７．３８（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．４９−７．５７（３Ｈ，ｍ），７．８２（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．９１（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０２（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），８．１５（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ），８．６２（１Ｈ，ｓ），１１．２１（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３９０．２０５３（−０．３ｍｍｕ）．
《実施例３８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．６８−１．７８（４Ｈ，ｍ），２．５１（３Ｈ，ｓ），２．５３（４Ｈ，ｓ），２．７９（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．４１−３．５９（２Ｈ，ｍ），７．０１（１Ｈ，ｓ），７．３８（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），７．４８−７．５７（３Ｈ，ｍ），７．８０（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０３−８．０５（２Ｈ，ｍ），８．２５（１Ｈ，ｓ），８．３８（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），１１．１６（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２３Ｈ２６Ｎ４Ｏ・１／４Ｈ２Ｏ：Ｃ，７２．８９；Ｈ，７．０５；Ｎ，１４．７８（％）．
Ｆｏｕｎｄ：Ｃ，７２．８４；Ｈ，７．０５；Ｎ，１４．７８（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３７４．２１２２（＋１．６ｍｍｕ）．
《実施例３９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｔ，Ｊ＝３．４Ｈｚ），２．５６（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５５−３．６０（２Ｈ，ｍ），７．０８（１Ｈ，ｓ），７．５２−７．６３（４Ｈ，ｍ），８．０２−８．０７（３Ｈ，ｍ），８．４１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），８．６３（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），１１．０１（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２３ＣｌＮ４Ｏ：Ｃ，６６．９１；Ｈ，５．８７；Ｎ，１４．１９（％）．
Ｆｏｕｎｄ：Ｃ，６６．７１；Ｈ，５．８７；Ｎ，１４．０４（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９５．１６０９（−２．９ｍｍｕ）．
《実施例４０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．６９−１．７１（４Ｈ，ｍ），２．５６（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５５−３．６０（２Ｈ，ｍ），７．０７（１Ｈ，ｓ），７．４４（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），７．５０−７．５９（３Ｈ，ｍ），８．０４−８．０６（２Ｈ，ｍ），８．２９（１Ｈ，ｄｄ，Ｊ＝９．２，２．９Ｈｚ），８．３４（１Ｈ，ｄｄ，Ｊ＝９．８，２．９Ｈｚ），１１．０９（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２３ＦＮ４Ｏ・１／５Ｈ２Ｏ：Ｃ，６９．１６；Ｈ，６．１７；Ｎ，１４．６６（％）．
Ｆｏｕｎｄ：Ｃ，６９．２７；Ｈ，６．０２；Ｎ，１４．６５（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３７９．１９４０（＋０．６ｍｍｕ）．
《実施例４１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｓ），２．５７（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．５７（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），３．８５（３Ｈ，ｓ），７．０２（１Ｈ，ｓ），７．１１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３７（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），８．０１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．０４（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），８．２５−８．３３（２Ｈ，ｍ），１１．１５（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２３Ｈ２５ＦＮ４Ｏ２・２／５Ｈ２Ｏ：Ｃ，６６．４６；Ｈ，６．２６；Ｎ，１３．４８（％）．
Ｆｏｕｎｄ：Ｃ，６６．４５；Ｈ，６．１２；Ｎ，１３．４３（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４０９．２０３９（−０．１ｍｍｕ）．
《実施例４２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｍ），２．５５（４Ｈ，ｓ），２．７７（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５５（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），６．９２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．９８（１Ｈ，ｓ），７．３３（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．９１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．００（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．２４−８．３１（２Ｈ，ｍ），９．９０（１Ｈ，ｓ），１１．２１（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９５．１８６４（−１．９ｍｍｕ）．
《実施例４３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．６９−１．７２（４Ｈ，ｍ），２．５５（４Ｈ，ｓ），２．７７（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５５（２Ｈ，ｑ，Ｊ＝５．９Ｈｚ），６．９１（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），６．９７（１Ｈ，ｓ），７．３４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４０−７．４５（３Ｈ，ｍ），８．０５（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．２７−８．３５（２Ｈ，ｍ），９．７０（１Ｈ，ｓ），１１．１１（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９５．１９０５（＋２．２ｍｍｕ）．
《実施例４４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１（４Ｈ，ｓ），２．５５（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５８（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），７．０９（１Ｈ，ｓ），７．４５（１Ｈ，ｓ），７．６３（１Ｈ，ｄｄ，Ｊ＝８．８，８．６Ｈｚ），７．９３（１Ｈ，ｓ），８．０５（１Ｈ，ｓ），８．１３（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），８．２５（１Ｈ，ｄｄ，Ｊ＝９．３，２．９Ｈｚ），８．３４（１Ｈ，ｄｄ，Ｊ＝９．８，２．９Ｈｚ），１０．６８（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２２Ｈ２１Ｆ３Ｎ４Ｏ：Ｃ，６３．７６；Ｈ，５．１１；Ｎ，１３．５２（％）．
Ｆｏｕｎｄ：Ｃ，６３．５０；Ｈ，５．１６；Ｎ，１３．６５（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４１５．１７７４（＋２．８ｍｍｕ）．
《実施例４５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．５０−３．６０（２Ｈ，ｍ），３．６５−３．７５（２Ｈ，ｍ），４．９０（１Ｈ，ｓ），７．０７（１Ｈ，ｓ），７．５３−７．５８（４Ｈ，ｍ），８．０５（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．５３（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），１１．１４（１Ｈ，ｓ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１８Ｈ１７Ｎ３Ｏ２・１／２Ｈ２Ｏ Ｃ，６８．３４；Ｈ，５．７４；Ｎ，１３．２８（％）．
Ｆｏｕｎｄ：Ｃ，６８．３０；Ｈ，５．６６；Ｎ，１３．１６（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３０７．１３３５（＋１．４ｍｍｕ）．
《実施例４６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．３０（３Ｈ，ｄ，Ｊ＝６．４Ｈｚ），３．４６−３．５２（１Ｈ，ｍ），３．６０−３．６５（１Ｈ，ｍ），３．９９−４．０６（１Ｈ，ｍ），４．８９（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．０７（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．０９（１Ｈ，ｓ），７．５０−７．５９（４Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０４−８．０６（２Ｈ，ｍ），８．５４（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１１．１６（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１９Ｈ１９Ｎ３Ｏ２・１／１０Ｈ２Ｏ：Ｃ，７０．６１；Ｈ，５．９９；Ｎ，１３．００（％）．
Ｆｏｕｎｄ：Ｃ，７０．５８；Ｈ，５．９５；Ｎ，１３．０４（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３２１．１４７９（＋０．１ｍｍｕ）．
《実施例４７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６７（４Ｈ，ｔ，Ｊ＝５．９Ｈｚ），３．９１−３．９５（１Ｈ，ｍ），４．８７（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．９６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１３（１Ｈ，ｓ），７．５０−７．５９（４Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０４（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．５１（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．５４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１１．１６（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３３７．１４４３（＋１．６ｍｍｕ）．
《実施例４８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．４３（３Ｈ，ｓ），３．６４−３．６８（２Ｈ，ｍ），３．７２−３．７６（１Ｈ，ｍ），５．１５（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．３４（１Ｈ，ｓ），７．３５（１Ｈ，ｓ），７．５３−７．６０（４Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），７．９８−８．００（２Ｈ，ｍ），８．３５（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５４（１Ｈ，ｄｄ，Ｊ＝７．３，１．０Ｈｚ），１１．０７（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２０Ｈ２１Ｎ３Ｏ３・Ｈ２Ｏ：Ｃ，６５．０３；Ｈ，６．２８；Ｎ，１１．３７（％）．
Ｆｏｕｎｄ：Ｃ，６４．７５；Ｈ，６．０９；Ｎ，１１．２３（％）．
ＨＲ−ＭＳ（ｍ／ｚ）：３５１．１５８５（＋０．２ｍｍｕ）．
《実施例４９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．８７−１．９２（２Ｈ，ｍ），３．５１（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），３．５８（２Ｈ，ｑ，Ｊ＝５．９Ｈｚ），４．６６（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．０４（１Ｈ，ｓ），７．５０−７．５９（５Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．０４−８．０６（２Ｈ，ｍ），８．４５（１Ｈ，ｄｄ，Ｊ＝８．３，１．０Ｈｚ），８．５３（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１１．１５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：３２１．１５０２（＋２．４ｍｍｕ）．
《実施例５０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６３−３．６９（４Ｈ，ｍ），３．８７（３Ｈ，ｓ），３．９１−３．９６（１Ｈ，ｍ），４．８５（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．９５（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．１０（１Ｈ，ｄｄ，Ｊ＝８．３，２．４Ｈｚ），７．１２（１Ｈ，ｓ），７．４６−７．５７（３Ｈ，ｍ），７．６２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．５０−８．５５（２Ｈ，ｍ），１１．１６（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ２０Ｈ２１Ｎ３Ｏ４・１／４Ｈ２Ｏ：Ｃ，６４．５９；Ｈ，５．８３；Ｎ，１１．３０（％）．
Ｆｏｕｎｄ：Ｃ，６４．４９；Ｈ，５．８３；Ｎ，１１．５７（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３６８．１６２５（＋１．５ｍｍｕ）．
《実施例５１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６４−３．６７（４Ｈ，ｍ），３．８５−３．９５（１Ｈ，ｍ），４．８６（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．９０−６．９５（２Ｈ，ｍ），７．０４（１Ｈ，ｓ），７．３５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４１−７．４５（２Ｈ，ｍ），７．５５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．８３（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），８．４９−８．５５（２Ｈ，ｍ），９．７０（１Ｈ，ｓ），１１．１６（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３５４．１４７４（＋２．０ｍｍｕ）．
《実施例５２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６６（４Ｈ，ｔ，Ｊ＝５．９Ｈｚ），３．８０−３．９０（１Ｈ，ｍ），４．８３（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．８３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．９３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．０４（１Ｈ，ｓ），７．４８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．９０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４５−８．４７（１Ｈ，ｍ），８．５０−８．５２（１Ｈ，ｍ），９．８６（１Ｈ，ｓ），１１．２４（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３５４．１４２１（−３．３ｍｍｕ）．
《実施例５３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６０−３．６９（４Ｈ，ｍ），３．８７−３．９２（１Ｈ，ｍ），４．８１（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．８２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．９３（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．０５（１Ｈ，ｓ），７．８９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．２６（１Ｈ，ｄｄ，Ｊ＝９．８，２．９Ｈｚ），８．３９（１Ｈ，ｄｄ，Ｊ＝１０．３，２．９Ｈｚ），９．８８（１Ｈ，ｓ），１１．２２（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８３．１３６９（＋１．３ｍｍｕ）．
《実施例５４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６２−３．７３（４Ｈ，ｍ），４．００−４．０５（１Ｈ，ｍ），４．８３（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．０８（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２５（１Ｈ，ｓ），７．５７（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．８５−７．８９（２Ｈ，ｍ），８．３５−８．３８（１Ｈ，ｍ），８．５０−８．５６（３Ｈ，ｍ），８．８１（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），１０．６７（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１９Ｈ１８Ｎ４Ｏ５：Ｃ，５９．６８；Ｈ，４．７４；Ｎ，１４．６５（％）．
Ｆｏｕｎｄ：Ｃ，５９．４４；Ｈ，４．７７；Ｎ，１４．５４（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８３．１３８９（＋３．４ｍｍｕ）．
《実施例５５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６３−３．６７（４Ｈ，ｍ），３．８５（３Ｈ，ｓ），３．９０−４．００（１Ｈ，ｍ），４．８２（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．８６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０９（１Ｈ，ｓ），７．１２（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．９９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．０３（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），８．２７（１Ｈ，ｄｄ，Ｊ＝９．８，３．４Ｈｚ），８．４２（１Ｈ，ｄｄ，Ｊ＝１０．３，３．４Ｈｚ），１１．１６（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８６．１５４４（＋２．８ｍｍｕ）．
《実施例５６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６０−３．７０（４Ｈ，ｍ），３．８７−３．９２（１Ｈ，ｍ），４．８４（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．９１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０６（１Ｈ，ｓ），７．３３−７．４４（３Ｈ，ｍ），８．０４（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．３０（１Ｈ，ｄｄ，Ｊ＝９．８，２．９Ｈｚ），８．４３（１Ｈ，ｄｄ，Ｊ＝１０．３，３．４Ｈｚ），９．７１（１Ｈ，ｓ），１１．１３（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１９Ｈ１８ＦＮ３Ｏ４・１／４Ｈ２Ｏ：Ｃ，６０．７１；Ｈ，４．９６；Ｎ，１１．１８（％）．
Ｆｏｕｎｄ：Ｃ，６０．６８；Ｈ，５．００；Ｎ，１１．１７（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３７２．１３７１（＋１．２ｍｍｕ）．
《実施例５７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６０−３．６９（４Ｈ，ｍ），３．８７−３．９２（１Ｈ，ｍ），４．８２（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．８２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．９３（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．０５（１Ｈ，ｓ），７．８９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．２６（１Ｈ，ｄｄ，Ｊ＝９．３，２．９Ｈｚ），８．３９（１Ｈ，ｄｄ，Ｊ＝１０．３，２．９Ｈｚ），９．８８（１Ｈ，ｓ），１１．２２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ．ｆｏｒ Ｃ１９Ｈ１８ＦＮ３Ｏ４・２／３Ｈ２Ｏ：Ｃ，５９．５３；Ｈ，５．０８；Ｎ，１０．９６（％）．
Ｆｏｕｎｄ：Ｃ，５９．３９；Ｈ，４．９７；Ｎ，１０．８６（％）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３７２．１３５６（−０．４ｍｍｕ）．
《実施例５８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６２−３．７０（４Ｈ，ｍ），３．９０−４．１０（１Ｈ，ｍ），４．８２（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．０６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２４（１Ｈ，ｓ），８．０３（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），８．２７−８．３０（３Ｈ，ｍ），８．４０（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．４７（１Ｈ，ｄｄ，Ｊ＝１０．３，２．９Ｈｚ），１０．６３（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４０１．１２６１（＋０．０ｍｍｕ）．
＜実施例５９＞ ２−（４−アミノフェニル）−４−（１，３−ジヒドロキシプロパン−２−イル）アミノキノリン−８−カルボン酸アミド
Figure 2004014861
実施例５３の化合物（１．００ｇ，２．６２ｍｍｏｌ）のメタノール−Ｎ，Ｎ−ジメチルアセトアミド（１：１、３０ｍＬ）懸濁液に、１０％パラジウム−炭素（１００ｍｇ）を加え、水素気流下（常圧）、室温にて３時間撹拌した。セライトを用いて、触媒を濾去し、溶媒を留去した。得られた残渣をクロマトレックスＮＨカラムクロマトグラフィ［酢酸エチル−メタノール＝１０：１］に付し、淡黄色粉末の表題化合物を２１２ｍｇ得た。収率２３％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６５（４Ｈ，ｔ，Ｊ＝５．９Ｈｚ），３．６０−３．９０（１Ｈ，ｍ），４．８３（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），５．５６（２Ｈ，ｓ），６．６８−６．７３（３Ｈ，ｍ），６．９９（１Ｈ，ｓ），７．４３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６−７．７９（３Ｈ，ｍ），８．４０−８．４２（１Ｈ，ｍ），８．４８−８．４９（１Ｈ，ｍ），１１．３９（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３５３．１６０８（−０．５ｍｍｕ）．
＜実施例６０＞ ２−（４−アミノフェニル）−４−（１，３−ジヒドロキシプロパン−２−イル）アミノ−６−フルオロキノリン−８−カルボン酸アミド
Figure 2004014861
実施例５８の化合物（２．４５ｇ，６．１２ｍｍｏｌ）を用い、実施例５６と同様の方法により、黄褐色粉末の表題化合物を１．６２ｇ得た。収率７１％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．５９−３．６９（４Ｈ，ｍ），３．８５−３．８９（１Ｈ，ｍ），４．８１（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），５．５８（２Ｈ，ｓ），６．６８−６．７３（３Ｈ，ｍ），７．００（１Ｈ，ｓ），７．７６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．９８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．２４（１Ｈ，ｄｄ，Ｊ＝９．８，２．９Ｈｚ），８．３４（１Ｈ，ｄｄ，Ｊ＝１０．３，２．９Ｈｚ），１１．３８（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３７１．１５４７（−０．５ｍｍｕ）．
＜実施例６１＞ ４−（２−クロロエトキシ）−２−（４−トリフルオロメチルフェニル）キノリン−８−カルボン酸アミド
Figure 2004014861
参考例７２の化合物（４００ｍｇ，１．２０ｍｍｏｌ）および１−ブロモ−２−クロロエタン（１２０μＬ，１．４４ｍｍｏｌ）を用い、実施例５と同様の方法により、無色粉末の表題化合物を１３６ｍｇ得た。収率２９％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．２０（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），４．７８（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．７３−７．７７（２Ｈ，ｍ），７．９７−７．９９（３Ｈ，ｍ），８．３７−８．４２（３Ｈ，ｍ），８．５７−８．５９（１Ｈ，ｍ），１０．１５（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９５．０７６３（−１．１ｍｍｕ）．
＜実施例６２＞ ２−（４−ビフェニル）−４−（２−クロロエトキシ）キノリン−８−カルボン酸アミド
Figure 2004014861
参考例７３の化合物（４９３ｍｇ，１．４５ｍｍｏｌ）および１−ブロモ−２−クロロエタン（１４５μＬ，１．７４ｍｍｏｌ）を用い、実施例５と同様の方法により、無色粉末の表題化合物を２６９ｍｇ得た。収率４６％。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：４．１８（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），４．７８（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．４２（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．５２（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７４（１Ｈ，ｓ），７．７９（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．９０（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．００（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），８．２７（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．３９（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），８．５９（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），１０．４８（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９５．０７６３（−１．１ｍｍｕ）．
＜実施例６３〜６８＞ 実施例６１または実施例６２の化合物を用い、実施例１３と同様の方法により、下記表１７記載の化合物を得た。
Figure 2004014861
《実施例６３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．６９−１．７２（４Ｈ，ｍ），２．６０−２．６３（４Ｈ，ｍ），３．００（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），４．５６（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．６９−７．７３（２Ｈ，ｍ），７．９５−７．９７（３Ｈ，ｍ），８．３５−８．３８（３Ｈ，ｍ），８．５６（１Ｈ，ｄｄ，Ｊ＝７．３，１．８Ｈｚ），１０．２０（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２３Ｈ２２Ｆ３Ｎ３Ｏ２：Ｃ，６４．３３；Ｈ，５．１６；Ｎ，９．７８．
Ｆｏｕｎｄ：Ｃ，６４．１９；Ｈ，５．１２；Ｎ，９．９３．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４３０．１７５８（＋１．６ｍｍｕ）．
《実施例６４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．０３（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．６３（４Ｈ，ｑ，Ｊ＝７．３Ｈｚ），３．００（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），４．５１（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．７２（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．７５（１Ｈ，ｓ），７．９６−７．９８（３Ｈ，ｍ），８．３５−８．４０（３Ｈ，ｍ），８．５７（１Ｈ，ｄｄ，Ｊ＝７．３，１．８Ｈｚ），１０．２１（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２３Ｈ２４Ｆ３Ｎ３Ｏ２・３／１０Ｈ２Ｏ：Ｃ，６３．２４；Ｈ，５．６８；Ｎ，９．６２．
Ｆｏｕｎｄ：Ｃ，６３．２１；Ｈ，５．５２；Ｎ，９．６４．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４３２．１８６６（−３．３ｍｍｕ）．
《実施例６５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：２．３５（３Ｈ，ｓ），２．９５（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），３．６５（２Ｈ，ｓ），４．５９（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．２４−７．３６（５Ｈ，ｍ），７．７１−７．７５（２Ｈ，ｍ），７．９６−７．９８（３Ｈ，ｍ），８．３４−８．３８（３Ｈ，ｍ），８．５８（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），１０．２１（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２７Ｈ２４Ｆ３Ｎ３Ｏ２・１／４Ｈ２Ｏ：Ｃ，６７．００；Ｈ，５．１０；Ｎ，８．６８．
Ｆｏｕｎｄ：Ｃ，６６．９７；Ｈ，４．９８：Ｎ，８．６８．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４８０．１９００９（＋１．０ｍｍｕ）．
《実施例６６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７１−１．７３（４Ｈ，ｍ），２．６２−２．６３（４Ｈ，ｍ），３．０２（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），４．５８（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．４３（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．５３（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．６９（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．７３（１Ｈ，ｓ），７．８０（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．９１（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．００（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），８．２８（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．３７（１Ｈ，ｄ，Ｊ＝６．７Ｈｚ），８．５９（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１０．５４（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２８Ｈ２７Ｎ３Ｏ２：Ｃ，７６．８６；Ｈ，６．２２；Ｎ，９．６０．
Ｆｏｕｎｄ：Ｃ，７６．８１；Ｈ，６．２５；Ｎ，９．６８．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４３８．２１８５（＋０．４ｍｍｕ）．
《実施例６７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：２．７６（４Ｈ，ｔ，Ｊ＝４．９Ｈｚ），３．０２（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），４．６５（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．７７（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），６．９４（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１８−７．２２（２Ｈ，ｍ），７．４１−７．４５（１Ｈ，ｍ），７．５３（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．７７−７．８２（３Ｈ，ｍ），７．９０−７．９２（２Ｈ，ｍ），８．０１（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），８．２８−８．３１（２Ｈ，ｍ），８．３９（１Ｈ，ｄｄ，Ｊ＝８．６，１．８Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，１．８Ｈｚ），１０．５５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｅｄ ｆｏｒ Ｃ２８Ｈ２７Ｎ３Ｏ２・１／４Ｈ２Ｏ：Ｃ，７６．５９；Ｈ，６．１４；Ｎ，１０．５１．
Ｆｏｕｎｄ：Ｃ，７６．５７；Ｈ，６．１９；Ｎ，１０．７４．
ＨＲ−ＭＳ（ｍ／ｚ）：５２８．２５１７（−０．８ｍｍｕ）．
《実施例６８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：０．８７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．２８−１．３４（２Ｈ，ｍ），１．４１−１．４７（２Ｈ，ｍ），２．３３（３Ｈ，ｓ），２．４７（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．９３（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），４．５６（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．４３（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．５３（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６８（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．７３（１Ｈ，ｓ），７．８０−７．８２（１Ｈ，ｍ），７．９１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．０１（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），８．２９（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．３６（１Ｈ，ｄｄ，Ｊ＝８．６，１．８Ｈｚ），８．６０（１Ｈ，ｄｄ，Ｊ＝７．３，１．８Ｈｚ），１０．５５（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２９Ｈ３１Ｎ３Ｏ２：Ｃ，７６．７９；Ｈ，６８９；Ｎ，９．２６．
Ｆｏｕｎｄ：Ｃ，７６．５９；Ｈ，６．９６；Ｎ，９．３６．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４５４．２５２５（＋３．１ｍｍｕ）．
＜実施例６９〜８２＞ 実施例２１と同様の方法により、下記表１８記載の化合物を得た。
Figure 2004014861
《実施例６９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７３（４Ｈ，ｓ），２．５５（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．７Ｈｚ），３．５９（２Ｈ，ｑ，Ｊ＝６．７Ｈｚ），７．１１（１Ｈ，ｓ），７．５５−７．６１（２Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），７．９２（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．２６（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．４６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．５３（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１０．８３（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
ＨＲ−ＭＳ（ｍ／ｚ）：４０２．１１１０（−２．５ｍｍｕ）．
《実施例７０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６５−３．６９（４Ｈ，ｍ），３．９０−４．００（１Ｈ，ｍ），４．８５（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．０６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１９（１Ｈ，ｓ），７．５７（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．８２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．９３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．２４（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．５４（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），１０．８５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４０６．１３６７（−１．１ｍｍｕ）．
《実施例７１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．６８−１．７２（４Ｈ，ｍ），２．５４−２．５５（４Ｈ，ｍ），２．７８（２Ｈ，ｔ，Ｊ＝６．７Ｈｚ），３．５６−３．６１（２Ｈ，ｍ），７．０９（１Ｈ，ｓ），７．４０（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．４９−７．５５（４Ｈ，ｍ），７．７６−７．７８（２Ｈ，ｍ），７．８４−７．８６（３Ｈ，ｍ），８．１５（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．４３（１Ｈ，ｄｄ，Ｊ＝８．６，１．２Ｈｚ），８．５３（１Ｈ，ｄ，Ｊ＝７．３，１．８Ｈｚ），１１．１２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２８Ｈ２８Ｎ４Ｏ・１／１０Ｈ２Ｏ：Ｃ，７６．７２；Ｈ，６．４８；Ｎ，１２．７８．
Ｆｏｕｎｄ：Ｃ，７６．６０；Ｈ，６．５６；Ｎ，１２．６６．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４３７．２３２７（−１．４ｍｍｕ）．
《実施例７２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６７（４Ｈ，ｓ），３．９１−３．９８（１Ｈ，ｍ），４．８６（２Ｈ，ｓ），６．９６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１８（１Ｈ，ｓ），７．４１（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．４９−７．５５（３Ｈ，ｍ），７．７６−７．７８（２Ｈ，ｍ），７．８５−７．８７（３Ｈ，ｍ），８．１３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５０−８．５５（２Ｈ，ｍ），１１．１３（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４１４．１７９２（−２．６ｍｍｕ）．
《実施例７３の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６８（４Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．４０−７．４４（１Ｈ，ｍ），７．５０−７．５６（３Ｈ，ｍ），７．６１（１Ｈ，ｓ），７．７７−７．７９（２Ｈ，ｍ），７．８５−７．８８（３Ｈ，ｍ），８．１７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．４８（１Ｈ，ｄｄ，Ｊ＝７．９，１．２Ｈｚ），８．５４（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），１１．１２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２５Ｈ２３Ｎ３Ｏ２・３／１０Ｈ２Ｏ：Ｃ，７４．５４；Ｈ，５．９０；Ｎ，１０．４３．
Ｆｏｕｎｄ：Ｃ，７４．５０；Ｈ，５．９０；Ｎ，１０．４１．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３９８．１８８８（＋２．０ｍｍｕ）．
《実施例７４の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．０７（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），３．７０−３．７５（２Ｈ，ｍ），７．１０（１Ｈ，ｓ），７．２１−７．２４（１Ｈ，ｍ），７．３１−７．４０（４Ｈ，ｍ），７．４３（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．５０−７．５６（３Ｈ，ｍ），７．６５（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．８５−７．８７（３Ｈ，ｍ），８．１５（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．４６（１Ｈ，ｄｄ，Ｊ＝８．６，１．２Ｈｚ），８．５４（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），１１．１２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２５Ｈ２３Ｎ３Ｏ２・１／３Ｈ２Ｏ：Ｃ，８０．１５；Ｈ，５．７５；Ｎ，９．３５．
Ｆｏｕｎｄ：Ｃ，８０．１６；Ｈ，５．８４；Ｎ，９．６１．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４４４．２０７６（＋０．１ｍｍｕ）．
《実施例７５の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：０．９５−１．１０（２Ｈ，ｍ），１．１５−１．３０（３Ｈ，ｍ），１．６０−１．７５（３Ｈ，ｍ），１．８０−１．９０（３Ｈ，ｍ），７．０４（１Ｈ，ｓ），７．４０−７．４４（１Ｈ，ｍ），７．５０−７．５８（４Ｈ，ｍ），７．７７−７．７９（２Ｈ，ｍ），７８６−７．８８（３Ｈ，ｍ），８．１４−８．１６（２Ｈ，ｍ），８．５０−８．５５（２Ｈ，ｍ），１１．１５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２９Ｈ２９Ｎ３Ｏ・１／６Ｈ２Ｏ：Ｃ，７９．４２；Ｈ，６．７４；Ｎ，９．５８．
Ｆｏｕｎｄ：Ｃ，７９．４４；Ｈ，６．８０；Ｎ，９．５４．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４３６．２４０９（＋２．０ｍｍｕ）．
《実施例７６の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７０（４Ｈ，ｓ），２．５７（４Ｈ，ｓ），２．７８（２Ｈ，ｔ，Ｊ＝６．９Ｈｚ），３．５８−３．６２（２Ｈ，ｍ），３．７５（３Ｈ，ｓ），３．９１（６Ｈ，ｓ），７．０３（１Ｈ，ｓ），７．３３（２Ｈ，ｓ），７．４７−７．５４（２Ｈ，ｍ），７．９２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．４１−８．４３（１Ｈ，ｍ），８．５２（１Ｈ，ｄｄ，Ｊ＝７．３，１．５Ｈｚ），１１．２４（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４５１．２３３６（−０．９ｍｍｕ）．
《実施例７７の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６５−３．６９（４Ｈ，ｍ），３．７５（３Ｈ，ｓ），３．９１（６Ｈ，ｓ），３．９５−４．０５（１Ｈ，ｍ），４．８４（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．９２（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１０（１Ｈ，ｓ），７．２９（２Ｈ，ｓ），７．５２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．９０（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．４９−８．５３（２Ｈ，ｍ），１１．２５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４２８．１７９０（−０．９ｍｍｕ）．
《実施例７８の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．７０−１．７３（４Ｈ，ｍ），２．５６−２．５９（４Ｈ，ｍ），２．８２（２Ｈ，ｔ，Ｊ＝６．７Ｈｚ），３．６３（２Ｈ，ｑ，Ｊ＝６．１Ｈｚ），７．２３（１Ｈ，ｓ），７．５１−７．５７（２Ｈ，ｍ），７．６０−７．６２（２Ｈ，ｍ），７．８７（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．０１（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），８．０８−８．１１（２Ｈ，ｍ），８．２０（１Ｈ，ｄｄ，Ｊ＝８．６，１．８Ｈｚ），８．４７（１Ｈ，ｄｄ，Ｊ＝８．６，１．２Ｈｚ），８．５５（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），８．６５（１Ｈ，ｓ），１１．１７（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：４１１．２２１４（＋２．９ｍｍｕ）．
《実施例７９の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６７−３．７３（４Ｈ，ｍ），４．００−４．０６（１Ｈ，ｍ），４．８７（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．９９（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３１（１Ｈ，ｓ），７．５５（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．５９−７．６４（２Ｈ，ｍ），７．８６（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），８．００−８．０３（１Ｈ，ｍ），８．０８−８．１１（２Ｈ，ｍ），８．１９（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５３−８．５６（１Ｈ，ｍ），８．６２（１Ｈ，ｓ），１１．１９（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３８８．１６４６（−１．５ｍｍｕ）．
《実施例８０の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：１．６９−１．７２（４Ｈ，ｍ），２．５４−２．５７（４Ｈ，ｍ），２．７８（２Ｈ，ｔ，Ｊ＝６．７Ｈｚ），３．５６（２Ｈ，ｑ，Ｊ＝６．７Ｈｚ），７．１１（１Ｈ，ｓ），７．２４（１Ｈ，ｄｄ，Ｊ＝４．９，３．７Ｈｚ），７．４５−７．５１（２Ｈ，ｍ），７．７３−７．７４（１Ｈ，ｍ），７．９２（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），８．００（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），８．３９（１Ｈ，ｄｄ，Ｊ＝８．６，１．２Ｈｚ），８．５１（１Ｈ，ｄｄ，Ｊ＝７．３，１．２Ｈｚ），１０．７８（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ２０Ｈ２２Ｎ４ＯＳ：Ｃ，６５．５５；Ｈ，６．０５；Ｎ，１５．２９．
Ｆｏｕｎｄ：Ｃ，６５．４０；Ｈ，６．１１；Ｎ，１５．１８．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３６７．１５８５（−０．７ｍｍｕ）．
《実施例８１の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６１−３．６９（４Ｈ，ｍ），３．９１−３．９５（１Ｈ，ｍ），４．８４（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．９４（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１７（１Ｈ，ｓ），７．２４（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．４９（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．７４（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．９２（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），８．４７（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５２（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），１０．７９（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ１７Ｈ１７Ｎ３Ｏ３Ｓ・１／５Ｈ２Ｏ：Ｃ，５８．８４；Ｈ，５．０５；Ｎ，１２．１１．
Ｆｏｕｎｄ：Ｃ，５８．８１；Ｈ，５．０７；Ｎ，１２．１９．
ＨＲ−ＦＡＢ＋（ｍ／ｚ）：３４４．１０７９（＋１．０ｍｍｕ）．
《実施例８２の化合物》
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ）：３．６０−３．６６（２Ｈ，ｍ），３．７２−３．７６（２Ｈ，ｍ），３．９２（１Ｈ，ｂｒｓ），５．１０（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．２２（１Ｈ，ｓ），７．５４−７．６０（４Ｈ，ｍ），７．９１（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ），７．９５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．０４（２Ｈ，ｄ，Ｊ＝６．７Ｈｚ），８．３８（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），１０．７１（１Ｈ，ｄ，Ｊ＝４．３Ｈｚ）．
Ａｎａｌ．Ｃａｌｃｄ ｆｏｒ Ｃ１９Ｈ１８ＣｌＮ３Ｏ３・１／１０Ｈ２Ｏ：Ｃ，６１．０８；Ｈ，４．９１；Ｎ，１１．２５．
Ｆｏｕｎｄ：Ｃ，６１．０１；Ｈ，５．１３；Ｎ，１１．５０．
ＨＲ−ＭＳ（ｍ／ｚ）：３７１．１０４４（＋０．８ｍｍｕ）．
＜試験例＞
（ＰＡＲＰ活性に対する阻害実験）
ＰＡＲＰ（Ｔｒｅｖｉｇｅｎ ４６６７−０５０−０１）５０ｍｍｏｌ／Ｌトリス−ＨＣｌ（ｐＨ７．８）、１００ｍｍｏｌ／Ｌ ＫＣｌおよび１ｍｍｏｌ／Ｌジチオスレイトールより成る緩衝液にて３５倍希釈して実験に用いた。
１１７．６ｍｍｏｌ／Ｌ トリス−ＨＣｌ（ｐＨ８．０）、１１．８ｍｍｏｌ／Ｌ ＭｇＣｌ２、５．９ｍｍｏｌ／Ｌジチオスレイトールおよび０．４ｍｍｏｌ／Ｌ ＮＡＤより成る緩衝液７６．５μＬ、［１４Ｃ］ＮＡＤ（ＮＥＮ Ｌｉｆｅ Ｓｃｉｅｎｃｅ Ｐｒｏｄｕｃｔｓ，Ｉｎｃ．ＮＥＣ７４３、３７０ｋＢｑ／ｍｌ）２．５μＬ、活性化ＤＮＡ（Ｔｒｅｖｉｇｅｎ ４６６７−５０−０６）１μＬ、被験化合物または被験化合物溶剤１０μＬおよび３５倍希釈したＰＡＲＰ溶液１０μＬをプラスティック試験管に入れ、よく混合した後、水浴中にて２５℃に加温した。１０分後、氷冷２０％トリクロロ酢酸１ｍＬの添加により反応を中止し、試験管を氷上に一夜静置した。吸引濾過により、沈殿をガラス繊維フィルター上に集め、５％トリクロロ酢酸で５回洗浄した。フィルター上の放射活性を液体シンチレーションカウンターで測定した。被験化合物非存在下における酵素活性を１００％とし、これを５０％に低下させる被験化合物の濃度（ＩＣ５０値）を算出した。
Figure 2004014861
上記結果、表１９に示すように本発明の新規な４−置換キノリン−８−カルボン酸アミド誘導体は、優れたＰＡＲＰ阻害活性を有することが確認された。
産業上利用可能性
以上のことから、本願発明化合物は新規な４−置換キノリン−８−カルボン酸アミド誘導体およびその塩から構成され、優れたＰＡＲＰ阻害活性を持つことが明らかとなった。
ＰＡＲＰ阻害活性を有する化合物は、ＰＡＲＰの過剰な活性化に起因する疾患、例えば、種々の虚血性疾患（脳梗塞、心筋梗塞、急性腎不全等）、炎症性疾患（炎症性腸疾患、多発性脳硬化症、関節炎、慢性関節リュウマチ等）、神経変性疾患（アルツハイマー病、ハンチントン舞踏病、パーキンソン病等）、糖尿病、敗血症性ショック、頭部外傷等の予防および／または治療剤として有用である。Reference Example 29 4-Chloro-2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
A saturated ammonia-ethanol (10 mL) solution of the compound of Reference Example 16 (1.00 g, 3.36 mmol) was stirred at 120 ° C. for 20 hours in a sealed tube. After cooling, diisopropyl ether was added to the reaction solution, and the crystals were collected by filtration, washed with diisopropyl ether and air-dried to obtain 712 mg of the title compound as a colorless powder. Yield 75%.
1 H-NMR (DMSO-d 6 , Δ): 7.57-7.65 (3H, m), 7.86 (1H, dd, J = 8.3, 7.3 Hz), 8.06 (1H, s), 8.22 (2H) , Dd, J = 7.8, 1.5 Hz), 8.42 (1H, dd, J = 8.3, 1.5 Hz), 8.51 (1H, s), 8.57 (1H, dd, J = 7.3, 1.5 Hz), 9.80 (1H, s).
Anal. Calcd. for C 16 H 11 ClN 2 O: C, 67.97; H, 3.92; N, 9.91 (%).
Found: C, 68.12; H, 3.92; N, 9.98 (%).
HR-MS (m / z): 282.0561 (+0.1 mmu).
<Reference Examples 30 to 39> The compounds shown in Table 8 below were obtained in the same manner as in Reference Example 29.
Figure 2004014861
<< Compound of Reference Example 30 >>
1 H-NMR (DMSO-d 6 , Δ): 3.87 (3H, s), 7.16 (2H, d, J = 9.3 Hz), 7.82 (1H, t, J = 7.8 Hz), 8.04 (1H, s) ), 8.19 (2H, d, J = 8.8 Hz), 8.39 (1H, dd, J = 8.3, 1.5 Hz), 8.46 (1H, s), 8.55 (1H) , Dd, J = 7.3, 1.5 Hz), 9.86 (1H, d, J = 2.0 Hz).
<< Compound of Reference Example 31 >>
1 H-NMR (DMSO-d 6 , Δ): 7.82 (2H, d, J = 8.8 Hz), 7.87 (1H, t, J = 7.3 Hz), 8.01 (1H, s), 8.18 (2H, d) , J = 8.8 Hz), 8.41 (1H, dd, J = 8.3, 1.5 Hz), 8.51 (1H, dd, J = 6.9, 1.5 Hz), 8.53 ( 1H, s), 9.48 (1H, s).
<< Compound of Reference Example 32 >>
1 H-NMR (DMSO-d 6 , Δ): 7.91 (1H, t, J = 7.3 Hz), 8.01 (1H, s), 8.42-8.50 (6H, m), 9.24 (1H, s).
<< Compound of Reference Example 33 >>
1 H-NMR (DMSO-d 6 , Δ): 7.70 (1H, dt, J = 10.8, 8.3 Hz), 7.86 (1H, dd, J = 8.3, 7.3 Hz), 8.01 (1H, d, J = 1.0 Hz), 8.11-8.14 (1H, m), 8.29-8.34 (1 H, m), 8.41 (1 H, dd, J = 8.3, 1.5 Hz) ), 8.46 (1H, dd, J = 7.3, 1.5 Hz), 8.57 (1H, s), 9.27 (1H, s).
<< Compound of Reference Example 34 >>
1 H-NMR (DMSO-d 6 , Δ): 4.01 (3H, s), 7.56-7.62 (3H, m), 7.65 (1H, d, J = 2.9 Hz), 8.12 (1H, s), 8.15-8.18 (3H, m), 8.46 (1H, s), 9.88 (1H, s).
<< Compound of Reference Example 35 >>
1 H-NMR (DMSO-d 6 , Δ): 2.62 (3H, s), 7.58-7.63 (3H, m), 8.03 (1H, s), 8.18-8.20 (2H, m), 8. 43 (1H, d, J = 2.0 Hz), 8.46 (1 H, s), 9.86 (1 H, s).
<< Compound of Reference Example 36 >>
1 H-NMR (DMSO-d 6 , Δ): 7.60-7.63 (3H, m), 8.18-8.23 (3H, m), 8.38-8.40 (2H, m), 8.57 (1H, s) ), 9.58 (1H, s).
<< Compound of Reference Example 37 >>
1 H-NMR (DMSO-d 6 , Δ): 7.58-7.64 (3H, m), 8.13 (1H, dd, J = 8.8, 3.4 Hz), 8.20-8.22 (3H, m), 8 .32 (1H, dd, J = 9.3, 2.9 Hz), 8.56 (1H, s), 9.68 (1H, d, J = 1.0 Hz).
<< Compound of Reference Example 38 >>
1 H-NMR (DMSO-d 6 , Δ): 3.87 (3H, s), 7.15 (2H, d, J = 8.8 Hz), 8.10 (1H, dd, J = 8.8, 2.9 Hz), 8.17 (2H, d, J = 9.3, 2.9 Hz), 8.51 (1H, s), 9.76 (1H, s).
<< Compound of Reference Example 39 >>
1 H-NMR (DMSO-d 6 , Δ): 7.66-7.73 (1H, m), 8.09-8.15 (3H, m), 8.22-8.33 (2H, m), 8.61 (1H, s) ), 9.18 (1H, s).
Reference Example 40 4-Chloro-2- (4-hydroxyphenyl) quinoline-8-carboxylic acid
Figure 2004014861
A 1 mol / L boron tribromide-dichloromethane solution (1.91 mL, 1.91 mmol) was added to a solution of the compound of Reference Example 17 (125 mg, 381 μmol) in dichloromethane (4 mL), and the mixture was heated to reflux for 16 hours. After cooling, water was added in small portions. The precipitated crystals were collected by filtration, washed successively with water and ethyl acetate, and then air-dried to obtain 108 mg of the title compound as a yellow powder. Yield 95%.
1 H-NMR (DMSO-d 6 , Δ): 7.02 (2H, d, J = 8.8 Hz), 7.89 (1H, t, J = 7.3 Hz), 8.08 (2H, d, J = 8.8 Hz), 8 .49 (1H, dd, J = 8.3, 1.5 Hz), 8.54 (1H, s), 8.61 (1H, dd, J = 7.3, 1.5 Hz).
<Reference Examples 41-43> By the method similar to Reference Example 40, the compounds shown in Table 9 below were obtained.
Figure 2004014861
<< Compound of Reference Example 41 >>
1 H-NMR (DMSO-d 6 , Δ): 7.04 (1H, dd, J = 8.3, 1.5 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.56 (1H, t, J = 2. 0 Hz), 7.64 (1H, t, J = 8.3 Hz), 7.95 (1H, dd, J = 8.3, 7.3 Hz), 8.53 (1H, dd, J = 8.3) 1.5Hz), 8.56 (1H, s), 8.63 (1H, dd, J = 7.3, 1.5 Hz), 9.97 (1H, s).
<< Compound of Reference Example 42 >>
1 H-NMR (DMSO-d 6 , Δ): 7.02 (1H, dd, J = 7.8, 2.0 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.56 (1H, t, J = 2. 0 Hz), 7.63 (1H, t, J = 7.8 Hz), 8.24 (1H, dd, J = 8.8, 2.9 Hz), 8.36 (1H, dd, J = 8.8). , 2.9 Hz), 8.58 (1H, s), 9.94 (1H, s), 15.50-16.30 (1H, br).
<< Compound of Reference Example 43 >>
1 H-NMR (DMSO-d 6 , Δ): 7.00 (2H, d, J = 8.8 Hz), 8.06 (2H, d, J = 8.8 Hz), 8.20 (1H, dd, J = 9.3, 2.). 9 Hz), 8.34 (1H, dd, J = 8.8, 2.9 Hz), 8.57 (1H, s), 9.90-10.90 (1H, br).
Reference Example 44 1,4-Dihydro-2- (3-methoxyphenyl) -4-oxoquinoline-8-carboxylic acid
Figure 2004014861
1 mol / L potassium hydroxide (5.87 mL, 5.87 mmol) was added to methanol (25 mL) of the compound of Reference Example 3 (825 mg, 2.67 mmol), and the mixture was heated to reflux for 1 hour. After cooling, the residue obtained by concentrating the reaction solution under reduced pressure was dissolved in water and adjusted to pH 2 with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and air-dried to obtain 754 mg of the title compound as a light brown powder. Yield 96%.
1 H-NMR (DMSO-d 6 , Δ): 3.88 (3H, s), 6.75 (1H, s), 7.20 (1H, dd, J = 8.3, 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.45 (1 H, d, J = 7.8 Hz), 7.51 (1 H, t, J = 7.8 Hz), 7.56 (1 H, t, J = 7.8 Hz) , 8.40-8.44 (2H, m).
Reference Example 45 1,4-Dihydro-2- (3-nitrophenyl) -4-oxoquinoline-8-carboxylic acid
Figure 2004014861
Using the compound of Reference Example 5 (3.24 g, 10.0 mmol), 3.07 g of the title compound as a yellowish white powder was obtained in the same manner as in Reference Example 44. Yield 99%.
1 H-NMR (DMSO-d 6 , Δ): 6.91 (1H, brs), 7.55 (1H, t, J = 7.8 Hz), 7.93 (1H, t, J = 7.8 Hz), 8.37 (1H, d , J = 7.8 Hz), 8.42-8.47 (3H, m), 8.67 (1H, s).
Reference Example 46 1,4-Dihydro-6-fluoro-2- (4-nitrophenyl) -4-oxoquinoline-8-carboxylic acid
Figure 2004014861
Using the compound of Reference Example 12 (4.79 g, 14.0 mmol), 4.51 g of the title compound as a pale yellow powder was obtained in the same manner as in Reference Example 44. Yield 98%.
1 H-NMR (DMSO-d 6 , Δ): 6.94 (1Hs), 8.08 (1H, dd, J = 8.6, 3.1 Hz), 8.15 (2H, d, J = 9.2 Hz), 8.23 (1H , Dd, J = 8.6, 3.1 Hz), 8.44 (2H, d, J = 9.2 Hz).
Reference Example 47 4-Chloro-2- (4-hydroxyphenyl) quinoline-8-carboxylic acid amide
Figure 2004014861
To the compound of Reference Example 40 (106 mg, 354 μmol) was added thionyl chloride (3 mL), and the mixture was heated to reflux for 1 hour. After cooling, the residue obtained by concentration under reduced pressure was suspended in tetrahydrofuran, dropped into concentrated aqueous ammonia (5 mL) with stirring under ice cooling, and stirred at the same temperature for 30 minutes. The precipitated crystals were removed by filtration and the solvent was distilled off. A small amount of water was added to the resulting residue, and the crystals were collected by filtration, washed with water and air-dried to obtain 49.6 mg of the title compound as a brown powder. Yield 47%.
1 H-NMR (DMSO-d 6 , Δ): 6.97 (2H, d, J = 8.8 Hz), 7.80 (1H, t, J = 7.3 Hz), 8.00 (1H, d, J = 2.0 Hz), 8 .08 (2H, d, J = 8.3 Hz), 8.38 (1H, dd, J = 8.3, 1.5 Hz), 8.40 (1H, s), 8.56 (1H, dd, J = 7.3, 1.5 Hz), 9.95 (1H, d, J = 2.4 Hz), 10.13 (1H, s).
<Reference Examples 48 to 50> By the same method as Reference Example 47, the compounds shown in Table 10 below were obtained.
Figure 2004014861
<< Compound of Reference Example 48 >>
1 H-NMR (DMSO-d 6 , Δ): 6.99 (1H, dd, J = 8.3, 2.5 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.56 (1H, d, J = 2. 0 Hz), 7.61 (1 H, d, J = 7.8 Hz), 7.86 (1 H, t, J = 7.8 Hz), 8.05 (1 H, s), 8.40 (1 H, s) , 8.42 (1H, dd, J = 8.3, 1.5 Hz), 8.59 (1H, dd, J = 7.3, 1.0 Hz), 9.86 (1H, s).
<< Compound of Reference Example 49 >>
1 H-NMR (DMSO-d 6 , Δ): 6.99 (1H, dd, J = 8.3, 2.5 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.55 (1H, t, J = 2. 0 Hz), 7.61 (1 H, d, J = 6.8 Hz), 8.13 (1 H, dd, J = 8.8, 2.9 Hz), 8.22 (1 H, s), 8.34 ( 1H, dd, J = 9.3, 2.9 Hz), 8.45 (1H, s), 9.76 (1H, s), 9.86 (1H, brs).
<< Compound of Reference Example 50 >>
1 H-NMR (DMSO-d 6 , Δ): 6.95 (2H, d, J = 8.3 Hz), 8.04-8.08 (3H, m), 8.29 (1H, dd, J = 9.3, 2.9 Hz) , 8.43 (1H, s), 9.85 (1H, d, J = 2.9 Hz).
Reference Example 51 4-Chloro-2- (3-methoxyphenyl) quinoline-8-carboxylic acid amide
Figure 2004014861
Thionyl chloride (5 mL) was added to the compound of Reference Example 44 (752 mg, 2.55 mmol), and the mixture was heated to reflux for 1 hour. After cooling, the residue obtained by concentration under reduced pressure was dissolved in tetrahydrofuran, then dropwise added to concentrated aqueous ammonia (10 mL) with stirring under ice cooling, and stirred at the same temperature for 30 minutes. The precipitated crystals were collected by filtration, washed with water and air-dried to obtain 771 mg of the title compound as a light brown powder. Yield 97%.
1 H-NMR (DMSO-d 6 , Δ): 3.89 (3H, s), 7.16 (1H, dd, J = 7.8, 2.5 Hz), 7.53 (1H, t, J = 7.8 Hz), 7.76. (1H, t, J = 2.0 Hz), 7.80 (1H, d, J = 7.8 Hz), 7.87 (1H, t, J = 7.8 Hz), 8.11 (1H, d, J = 1.5 Hz), 8.43 (1H, dd, J = 8.3, 1.5 Hz), 8.54 (1H, s), 8.57 (1H, dd, J = 7.3, 1) .5 Hz), 9.82 (1H, d, J = 1.0 Hz).
Reference Example 52 4-Chloro-2- (3-nitrophenyl) quinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Reference Example 45 (3.07 g, 9.89 mmol), 3.19 g of the title compound as a light brown powder was obtained in the same manner as in Reference Example 51. Yield 98%.
1 H-NMR (DMSO-d 6 , Δ): 7.87-7.93 (2H, m), 8.07 (1H, s), 8.40-8.47 (3H, m), 8.68 (1H, d, J = 5). .4 Hz), 8.69 (1 H, s), 9.03 (1 H, t, J = 2.0 Hz), 9.20 (1 H, s).
Reference Example 53 4-Chloro-6-fluoro-2- (4-nitrophenyl) quinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Reference Example 46 (4.50 g, 13.7 mmol), 4.41 g of the title compound as a light brown powder was obtained in the same manner as in Reference Example 51. Yield 93%.
1 H-NMR (DMSO-d 6 , Δ): 8.15 (1H, dd, J = 8.6, 3.1 Hz), 8.10-8.20 (1H, br), 8.27 (1H, dd, J = 8.6, 3.0 Hz), 8.43 (2H, d, J = 9.2 Hz), 8.48 (2H, d, J = 8.6 Hz), 8.69 (1H, s), 9.14 (1H, brs).
<Reference Examples 54 to 59> The compounds shown in Table 11 below were obtained in the same manner as in Reference Example 1.
Figure 2004014861
<< Compound of Reference Example 54 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 3.99 (3H, s), 6.69 (1H, s), 7.50 (1H, t, J = 7.9 Hz), 8.03 (2H, d, J = 8) .6 Hz), 8.10 (2H, d, J = 7.9 Hz), 8.42 (2H, t, J = 7.9 Hz), 11.99 (1H, s).
<< Compound of Reference Example 55 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 4.01 (3H, s), 6.69 (1H, d, J = 1.8 Hz), 7.43-7.55 (4H, m), 7.80 (2H, d) , J = 7.9 Hz), 7.96-8.01 (4H, m), 12.05 (1H, s).
<< Compound of Reference Example 56 >>
1 H-NMR (DMSO-d 6 , (A)): 3.75 (3H, s), 3.90 (6H, s), 3.97 (3H, s), 6.65 (1H, d, J = 1.8 Hz), 7. 14 (2H, s), 7.46 (1H, t, J = 7.9 Hz), 8.36-8.41 (2H, m), 11.80 (1H, s).
<< Compound of Reference Example 57 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 4.02 (3H, s), 6.76 (1H, s), 7.50 (1H, t, J = 7.9 Hz), 7.67 (2H, t, J = 4) .9 Hz), 7.96 (1 H, d, J = 8.6 Hz), 8.06 (1 H, t, J = 4.9 Hz), 8.12 (1 H, t, J = 5.5 Hz), 8 .19 (1H, d, J = 8.6 Hz), 8.42 (1H, d, J = 7.3 Hz), 8.45 (1H, d, J = 7.9 Hz), 8.51 (1H, s), 12.10 (1H, s).
<< Compound of Reference Example 58 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 4.00 (3H, s), 6.57 (1H, s), 7.34 (1H, t, J = 4.9 Hz), 7.46 (1H, t, J = 7) .9 Hz), 7.83 (1H, d, J = 3.7 Hz), 7.95 (1H, d, J = 4.9 Hz), 8.28 (2H, d, J = 7.3 Hz), 11 .96 (1H, s).
<< Compound of Reference Example 59 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 3.98 (3H, s), 6.61 (1H, d, J = 1.8 Hz), 7.41 (1H, d, J = 8.6 Hz), 7.64-7 .67 (3H, m), 7.86-7.88 (2H, m), 8.25 (1H, d, J = 7.9 Hz), 12.29 (1H, s).
<Reference Examples 60 to 65> By the same method as Reference Example 44, the compounds shown in Table 12 below were obtained.
Figure 2004014861
<< Compound of Reference Example 60 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 6.87 (1H, s), 7.55 (1H, t, J = 7.9 Hz), 8.02 (2H, d, J = 8.6 Hz), 8.12 (2H , D, J = 7.9 Hz), 8.42-8.47 (2H, m), 13.00-14.00 (1H, br).
<< Compound of Reference Example 61 >>
1 H-NMR (DMSO-d 6 , (A)): 6.86 (1H, s), 7.44 (1H, t, J = 7.3 Hz), 7.51-7.56 (3H, m), 7.79-7.81 (2H, m), 7.95-8.01 (4H, m), 8.43-8.47 (2H, m).
<< Compound of Reference Example 62 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 3.78 (3H, s), 3.93 (6H, s), 6.99 (1H, s), 7.23 (2H, s), 7.58 (1H, t, J = 7.9 Hz), 8.47 (2H, t, J = 7.9 Hz).
<< Compound of Reference Example 63 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 6.88 (1H, brs), 7.53 (1H, t, J = 7.9 Hz), 7.64-7.69 (2H, m), 7.98 (1H, d) , J = 8.6 Hz), 8.06 (1H, t, J = 4.9 Hz), 8.12 (1H, t, J = 5.5 Hz), 8.19 (1H, d, J = 8. 6 Hz), 8.43-8.47 (2H, m), 8.51 (1H, s).
<< Compound of Reference Example 64 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 7.11 (1H, s), 7.34 (1H, dd, J = 4.9, 3.7 Hz), 7.59 (1H, t, J = 7.9 Hz), 7 .88 (1H, t, J = 2.4 Hz), 7.96 (1H, t, J = 1.2 Hz), 8.41 (1H, dd, J = 7.9, 1.2 Hz), 8. 49 (1H, dd, J = 7.3, 1.2 Hz).
<< Compound of Reference Example 65 >>
1 H-NMR (DMSO-d 6 , (A)): 6.67 (1H, brs), 7.44 (1H, d, J = 7.9 Hz), 7.63-7.66 (3H, m), 7.87-7.89 (2H, m), 8.29 (1H, d, J = 7.9 Hz).
<Reference Examples 66 to 71> By the same method as Reference Example 51, the compounds shown in Table 13 below were obtained.
Figure 2004014861
<< Compound of Reference Example 66 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 7.89 (1H, t, J = 7.3 Hz), 7.98 (2H, d, J = 7.9 Hz), 8.02 (1H, s), 8.42-8 .45 (3H, m), 8.51 (1H, dd, J = 7.3, 1.2 Hz), 8.59 (1H, s), 9.41 (1H, s).
<< Compound of Reference Example 67 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 7.45 (1H, d, J = 7.3 Hz), 7.53 (2H, t, J = 7.3 Hz), 7.81 (2H, d, J = 7.3 Hz) , 7.86 (1H, t, J = 7.3 Hz), 7.93 (2H, d, J = 8.6 Hz), 8.07 (1H, s), 8.33 (2H, d, J = 8.6 Hz), 8.43 (1H, dd, J = 8.6, 1.2 Hz), 8.56 (1H, dd, J = 7.3, 1.2 Hz), 8.58 (1H, s) ), 9.73 (1H, d, J = 2.4 Hz).
<< Compound of Reference Example 68 >>
1 H-NMR (DMSO-d 6 , (A)): 3.77 (3H, s), 3.94 (6H, s), 7.53 (2H, s), 7.85 (1H, t, J = 7.9 Hz), 8. 17 (1H, s), 8.42 (1H, d, J = 8.6 Hz), 8.59 (1H, d, J = 7.3 Hz), 8.63 (1H, s), 9.96 ( 1H, s).
<< Compound of Reference Example 69 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 7.63-7.67 (2H, m), 7.87 (1H, t, J = 7.9 Hz), 8.02-8.15 (4H, m), 8.34 (1H, dd, J = 8.6, 1.8 Hz), 8.44 (1H, dd, J = 8.6, 1.2 Hz), 8.57 (1H, dd, J = 7.3, 1 .8 Hz), 8.69 (1 H, s), 8.86 (1 H, s), 9.80 (1 H, d, J = 1.2 Hz).
<< Compound of Reference Example 70 >>
1 H-NMR (DMSO-d 6 , ▲ a ▼): 7.30 (1H, dd, J = 4.9, 3.7 Hz), 7.81 (1H, t, J = 7.3 Hz), 7.89 (1H, d, J = 4.9 Hz), 8.17 (1 H, s), 8.21 (1 H, d, J = 3.7 Hz), 8.39 (1 H, dd, J = 7.9, 1.2 Hz), 8. 56 (1H, s), 8.62 (1H, dd, J = 7.3, 1.2 Hz), 9.80 (1H, s).
<< Compound of Reference Example 71 >>
1 H-NMR (DMSO-d 6 , A): 7.60-7.63 (3H, m), 7.90 (1H, d, J = 8.6 Hz), 7.99 (1H, brs), 8.24-8.26. (3H, m), 8.50 (1H, s), 9.11 (1H, brs).
Reference Example 72 1,4-Dihydro-4-oxo-2- (4-trifluoromethylphenyl) quinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Reference Example 54 (926 mg, 2.67 mmol), 703 mg of the title compound as a pale yellow powder was obtained in the same manner as in Reference Example 15. Yield 79%.
1 H-NMR (DMSO-d 6 , ▲ a ▼): 6.64 (1H, d, J = 1.8 Hz), 7.45 (1H, t, J = 7.9 Hz), 7.99 (2H, d, J = 7.9 Hz) , 8.07 (2H, d, J = 8.6 Hz), 8.33 (1H, t, J = 7.3 Hz), 8.67 (1H, s), 13.67 (1H, s).
Reference Example 73 2- (4-biphenyl) -1,4-dihydro-4-oxoquinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Reference Example 55 (570 mg, 1.60 mmol), 496 mg of the title compound as a light brown powder was obtained in the same manner as in Reference Example 15. Yield 91%.
1 H-NMR (DMSO-d 6 , ▲ a ▼): 6.65 (1H, s), 7.42-7.47 (2H, m), 7.53 (1H, t, J = 7.9 Hz), 7.79 (2H, d) , J = 7.9 Hz), 7.95 (4H, s), 8.05 (1H, s), 8.33-8.36 (2H, m), 8.68 (1H, s), 13. 62 (1H, s).
Example 1 4-Methoxy-2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
Process 1 : Iodomethane (161 μL, 2.58 mmol) was added to an N, N-dimethylformamide (10 mL) suspension of the compound of Reference Example 1 (600 mg, 2.15 mmol) and potassium carbonate (594 mg, 4.30 mmol) at room temperature. For 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography [hexane-ethyl acetate = 4: 1] to obtain 559 mg of methyl 4-methoxy-2-phenylquinoline-8-carboxylate as a pale yellow powder. Yield 89%.
1 H-NMR (DMSO-d 6 , Δ): 3.97 (3H, s), 4.20 (3H, s), 7.52-7.61 (4H, m), 7.66 (1H, s), 7.93 (1H, dd, J = 7.3, 1.5 Hz), 8.27 (1H, dd, J = 8.3, 1.5 Hz), 8.31-8.33 (2H, m).
Process 2 : Saturated ammonia-ethanol (10 mL) solution of methyl 4-methoxy-2-phenylquinoline-8-carboxylate (257 mg, 876 μmol) was stirred at 120 ° C. for 20 hours in a sealed tube. After cooling, the solvent was distilled off and ethyl acetate was added to the resulting residue. The crystals were collected by filtration, washed with ethyl acetate and dried. This was subjected to silica gel column chromatography [hexane-ethyl acetate = 1: 2] to obtain 56.1 mg of the title compound as a colorless powder. Yield 23%.
1 H-NMR (DMSO-d 6 , Δ): 4.22 (3H, s), 7.57-7.70 (5H, m), 7.98 (1H, d, J = 3.9 Hz), 8.18 (2H, d, J = 6.9 Hz), 8.37 (1H, dd, J = 8.3, 1.5 Hz), 8.59 (1H, dd, J = 7.3, 1.5 Hz), 10.55 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 17 H 14 N 2 O 2 : C, 73.37; H, 5.07; N, 10.07 (%).
Found: C, 73.07; H, 5.11; N, 10.02 (%).
HR-MS (m / z): 278.187 (+3.2 mmu).
<Examples 2 to 4> By the same method as in Example 1, the compounds shown in Table 14 below were obtained.
Figure 2004014861
<< Compound of Example 2 >>
1 H-NMR (DMSO-d 6 , Δ): 1.54 (3H, t, J = 6.9 Hz), 4.52 (2H, q, J = 6.9 Hz), 7.57-7.62 (4H, m), 7.67. (1H, t, J = 7.8 Hz), 7.95 (1H, s), 8.15-8.17 (2H, m), 8.37 (1H, dd, J = 8.3, 1.. 5 Hz), 8.59 (1 H, dd, J = 7.3, 1.0 Hz), 10.56 (1 H, d, J = 3.9 Hz).
Anal. Calcd. for C 17 H 14 N 2 O 2 ・ 1 / 3H 2 O: C, 72.47; H, 5.63; N, 9.39 (%).
Found: C, 72.25; H, 5.48; N, 9.49 (%).
HR-MS (m / z): 292.1167 (-4.4 mmu).
<< Compound of Example 3 >>
1 H-NMR (DMSO-d 6 , Δ): 1.48 (6H, t, J = 5.9 Hz), 5.26-5.32 (1H, m), 7.55-7.68 (5H, m), 7.95 (1H , D, J = 4.4 Hz), 8.15-8.17 (2H, m), 8.36 (1H, dd, J = 7.8, 1.5 Hz), 8.59 (1H, dd, J = 7.3, 1.5 Hz), 10.59 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 17 H 14 N 2 O 2 ・ 1 / 5H 2 O: C, 73.62; H, 5.98; N, 9.04 (%).
Found: C, 73.50; H, 5.93; N, 8.95 (%).
HR-MS (m / z): 306.1387 (+1.9 mmu).
<< Compound of Example 4 >>
1 H-NMR (DMSO-d 6 , Δ): 3.78 (3H, s), 5.52 (2H, s), 7.02 (2H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.3 Hz) ), 7.58-7.68 (4H, m), 7.79 (1H, s), 7.98 (1H, d, J = 3.4 Hz), 8.17-8.19 (2H, m ), 8.35 (1H, dd, J = 7.8, 1.5 Hz), 8.59 (1H, dd, J = 7.3, 1.5 Hz), 10.54 (1H, d, J = 3.9 Hz).
HR-MS (m / z): 384.1461 (-1.3 mmu).
Example 5 2-Phenyl-4-propoxyquinoline-8-carboxylic acid amide
Figure 2004014861
To a suspension of the compound of Reference Example 15 (100 mg, 378 μmol) and potassium carbonate (104 mg, 756 μmol) in N, N-dimethylformamide (10 mL) was added 1-iodopropane (44.3 μL, 454 μmol) at room temperature. Stir for 6 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was distilled off. A small amount of ethyl acetate was added to the resulting residue, and the crystals were collected by filtration, washed with ethyl acetate, and then air-dried to obtain 76.4 mg of the title compound as a pale yellow powder. Yield 66%.
1 H-NMR (DMSO-d 6 , Δ): 1.12 (3H, t, J = 7.3 Hz), 1.92-1.99 (2H, m), 4.42 (2H, t, J = 6.4 Hz), 7.55 −7.61 (3H, m), 7.63 (1H, s), 7.68 (1H, t, J = 7.8 Hz), 7.97 (1H, d, J = 3.9 Hz), 8 15-8.18 (2H, m), 8.39 (1H, dd, J = 8.3, 1.5 Hz), 8.60 (1H, dd, J = 7.3, 1.5 Hz), 10.57 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 19 H 18 N 2 O 2 : C, 74.49; H, 5.92; N, 9.14 (%).
Found: C, 74.53; H, 5.96; N, 9.15 (%).
HR-MS (m / z): 306.1379 (+1.1 mmu).
<Examples 6 to 11> By the same method as that in Example 5, the compounds shown in Table 15 below were obtained.
Figure 2004014861
<< Compound of Example 6 >>
1 H-NMR (DMSO-d 6 , Δ): 4.19 (2H, t, J = 4.9 Hz), 4.77 (2H, t, J = 4.9 Hz), 7.57-7.63 (3H, m), 7.70. -7.73 (2H, m), 7.99 (1H, d, J = 3.4 Hz), 8.18 (2H, d, J = 6.9 Hz), 8.40 (1H, d, J = 8.3 Hz), 8.60 (1H, dd, J = 7.3, 1.5 Hz), 10.51 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 18 H 15 ClN 2 O 2 : C, 66.16; H, 4.63; N, 8.57 (%).
Found: C, 66.05; H, 4.54; N, 8.63 (%).
HR-MS (m / z): 326.0836 (+1.4 mmu).
<< Compound of Example 7 >>
1 H-NMR (DMSO-d 6 , Δ): 2.36-2.42 (2H, m), 3.96 (2H, t, J = 6.4 Hz), 4.58 (2H, t, J = 5.9 Hz), 7.57 −7.64 (3H, m), 7.66-7.70 (2H, m), 7.98 (1H, d, J = 4.4 Hz), 8.18 (2H, dd, J = 7. 8, 1.5 Hz), 8.43 (1 H, dd, J = 8.3, 1.5 Hz), 8.60 (1 H, dd, J = 7.3, 1.5 Hz), 10.55 (1 H , D, J = 3.9 Hz).
Anal. Calcd. for C 19 H 17 ClN 2 O 2 ・ 1 / 10H 2 O: C, 66.61; H, 5.06; N, 8.18 (%).
Found: C, 66.54; H, 5.05; N, 8.19 (%).
HR-MS (m / z): 340.0980 (+0.1 mmu).
<< Compound of Example 8 >>
1 H-NMR (DMSO-d 6 , Δ): 2.05 (4H, brs), 3.81 (2H, t, J = 5.9 Hz), 4.50 (2H, brs), 7.57-7.71 (5H, m), 7.98 (1H, s), 8.17 (1H, d, J = 6.8 Hz), 8.38 (1H, d, J = 7.8 Hz), 8.59 (1H, d, J = 7) .3 Hz), 10.56 (1 H, s).
HR-MS (m / z): 354.1149 (+1.4 mmu).
<< Compound of Example 9 >>
1 H-NMR (DMSO-d 6 , Δ): 3.77 (3H, s), 5.37 (2H, s), 7.57-7.64 (3H, m), 7.68 (1H, s), 7.72 (1H, t, J = 7.8 Hz), 7.99 (1H, d, J = 3.9 Hz), 8.15-8.18 (2H, m), 8.41 (1H, dd, J = 8.3) 1.5Hz), 8.60 (1H, dd, J = 7.3, 1.5Hz), 10.45 (1H, d, J = 4.4Hz).
Anal. Calcd. for C 19 H 16 N 2 O 4 ・ 1 / 4H 2 O: C, 66.95; H, 4.88; N, 8.22 (%).
Found: C, 66.92; H, 4.74; N, 8.20 (%).
HR-MS (m / z): 336.1140 (+2.9 mmu).
<< Compound of Example 10 >>
1 H-NMR (DMSO-d 6 , Δ): 3.90-3.94 (2H, m), 4.47 (2H, t, J = 4.9 Hz), 5.14 (1H, t, J = 5.9 Hz), 7.55 −7.70 (5H, m), 7.97 (1H, d, J = 3.9 Hz), 8.17 (2H, dd, J = 8.3, 1.5 Hz), 8.48 (1H, dd, J = 8.3, 1.5 Hz), 8.60 (1H, dd, J = 7.3, 2.0 Hz), 10.58 (1H, d, J = 4.4 Hz).
Anal. Calcd. for C 18 H 16 N 2 O 3 ・ 1 / 4H 2 O: C, 69.11; H, 5.32; N, 8.95.
Found: C, 69.11; H, 5.18; N, 8.92.
HR-MS (m / z): 308.1183 (+2.2 mmu).
<< Compound of Example 11 >>
1 H-NMR (DMSO-d 6 , Δ): 3.40 (3H, s), 3.87-3.89 (2H, m), 4.60 (2H, t, J = 4.4 Hz), 7.55-7.64 (3H) M), 7.67-7.71 (2H, m), 7.98 (1H, d, J = 3.9 Hz), 8.16-8.18 (2H, m), 8.37 (1H). , Dd, J = 8.3, 1.5 Hz), 8.60 (1H, dd, J = 7.3, 2.0 Hz), 10.55 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 18 H 16 N 2 O 3 : C, 70.79; H, 5.63; N, 8.69 (%).
Found: C, 70.59; H, 5.59; N, 8.74 (%).
HR-MS (m / z): 322.1331 (+1.4 mmu).
Example 12 4- [2- (Diethylamino) ethoxy] -2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
Process 1 Into a suspension of the compound of Reference Example 1 (300 mg, 1.07 mmol) and potassium carbonate (296 mg, 2.14 mmol) in N, N-dimethylformamide (10 mL), 1-bromo-2-chloroethane (267 μL, 3. 21 mmol) was added and stirred at room temperature for 10 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography [hexane-ethyl acetate = 4: 1] to give 318 mg of methyl 4- (2-chloroethoxy) -2-phenylquinoline-8-carboxylate as a pale yellow viscous liquid. Obtained. Yield 87%
1H-NMR (CDCl 3 , Δ): 4.02 (2H, t, J = 5.9 Hz), 4.08 (3H, s), 4.56 (2H, t, J = 5.9 Hz), 7.24 (1H, s) ), 7.47-7.54 (4H, m), 8.03 (1H, dd, J = 6.9, 1.5 Hz), 8.19-8.21 (2H, m), 8.37. (1H, dd, J = 8.3, 1.5 Hz).
Process 2 : Methyl 4- (2-chloroethoxy) -2-phenylquinoline-8-carboxylate (280 mg, 819 μmol) in N, N-dimethylformamide (10 mL), diethylamine (424 μL, 4.10 mmol) and then sodium iodide (12.3 mg, 81.9 μmol) was added, and the mixture was stirred at 80 ° C. for 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography [hexane-ethyl acetate-triethylamine = 5: 1: 1] to give a tan viscous liquid 4- [2- (diethylamino) ethoxy] -2-phenylquinoline-8. -299 mg of methyl carboxylate was obtained. Yield 96%
1 H-NMR (CDCl 3 , Δ): 1.13 (6H, t, J = 7.3 Hz), 2.72 (4H, q, J = 7.3 Hz), 3.08 (2H, t, J = 5.9 Hz), 4 .08 (3H, s), 4.36 (2H, t, J = 5.9 Hz), 7.29 (1H, s), 7.46-7.53 (4H, m), 8.01 (1H) , Dd, J = 6.9, 1.5 Hz), 8.20-8.22 (2H, m), 8.32 (1H, dd, J = 8.3, 1.5 Hz).
Process 3 : A saturated ammonia-ethanol (10 mL) solution of methyl 4- [2- (diethylamino) ethoxy] -2-phenylquinoline-8-carboxylate (299 mg, 790 μmol) was stirred at 120 ° C. for 20 hours in a sealed tube. After cooling, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography [ethyl acetate-hexane-triethylamine = 4: 2: 1] to obtain 32.8 mg of the title compound as a colorless powder. Yield 11%.
1 H-NMR (DMSO-d 6 , Δ): 1.03 (6H, t, J = 7.3 Hz), 2.63 (4H, q, J = 7.3 Hz), 3.00 (2H, t, J = 5.9 Hz), 4 .50 (2H, t, J = 5.9 Hz), 7.57-7.63 (3H, m), 7.675 (1H, s), 7.684 (1 H, t, J = 7.8 Hz) 7.97 (1H, d, J = 3.4 Hz), 8.18 (2H, d, J = 6.4 Hz), 8.35 (1H, dd, J = 8.3, 1.5 Hz), 8.59 (1H, dd, J = 7.3, 1.5 Hz), 10.57 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 22 H 25 N 3 O 2 : C, 72.70; H, 6.93; N, 11.56 (%).
Found: C, 72.45; H, 6.83; N, 11.45 (%).
HR-MS (m / z): 363. 1947 (+0.1 mmu).
Example 13 4- [3- (Diethylamino) propoxy] -2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
To a solution of the compound of Example 7 (187 mg, 549 μmol) in N, N-dimethylformamide (10 mL) was added sodium iodide (8.23 mg, 54.9 μmol) and then diethylamine (283 μL, 2.74 mmol), and the mixture was heated to 80 ° C. And stirred for 24 hours. The residue obtained by concentrating the reaction solution under reduced pressure was subjected to silica glu column chromatography [ethyl acetate-hexane (2: 1) → ethyl acetate-hexane-triethylamine (4: 2: 1)] to give the title compound as a colorless powder. 144 mg was obtained. Yield 69%.
1 H-NMR (DMSO-d 6 , Δ): 0.96 (6H, t, J = 7.3 Hz), 2.02 (2H, t, J = 6.4 Hz), 2.65 (2H, t, J = 6.9 Hz), 4 .49 (2H, t, J = 5.9 Hz), 7.57-7.61 (3H, m), 7.63 (1H, s), 7.68 (1H, t, J = 7.8 Hz) 7.97 (1 H, d, J = 3.9 Hz), 8.16 (2 H, d, J = 6.9 Hz), 8.38 (1 H, dd, J = 8.3, 1.5 Hz), 8.59 (1H, dd, J = 7.3, 1.5 Hz), 10.57 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 23 H 27 N 3 O 2 ・ 1 / 5H 2 O: C, 72.49; H, 7.25; N, 11.03 (%).
Found: C, 72.56; H, 7.14; N, 11.16 (%).
HR-MS (m / z): 377.2130 (+0.1 mmu).
Example 14 4- [4- (Diethylamino) butoxy] -2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Example 8 (229 mg, 645 μmol), 30.8 mg of the title compound as a light brown powder was obtained in the same manner as in Example 13. Yield 12%.
1 H-NMR (DMSO-d 6 , Δ): 0.95 (6H, t, J = 7.3 Hz), 1.62-1.69 (2H, m), 1.94 (2H, t, J = 6.9 Hz), 4.47. (2H, t, J = 6.4 Hz), 7.55-7.61 (3H, m), 7.64 (1H, s), 7.68 (1H, t, J = 7.3 Hz), 7 .97 (1H, d, J = 4.4 Hz), 8.16 (2H, d, J = 6.9 Hz), 8.37 (1H, dd, J = 8.3, 1.5 Hz), 8. 59 (1H, dd, J = 7.3, 1.5 Hz), 10.58 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 24 H 29 N 3 O 2 ・ 1 / 3H 2 O: C, 72.52; H, 7.52; N, 10.57 (%).
Found: C, 72.58; H, 7.56; N, 10.54 (%).
HR-MS (m / z): 391.2264 (+0.5 mmu).
Example 15 2-Phenyl-4- [2- (pyrrolidin-1-yl) ethoxy] quinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Example 6 (150 mg, 459 μmol) and pyrrolidine (192 μL, 2.30 mmol), 36.2 mg of the title compound as a light brown powder was obtained in the same manner as in Example 13. Yield 22%
1 H-NMR (DMSO-d 6 , Δ): 1.70-1.73 (4H, m), 2.63 (4H, brs), 3.01 (2H, t, J = 5.9 Hz), 4.56 (2H, t, J = 5.9 Hz), 7.57-7.63 (3H, m), 7.67-7.71 (2H, m), 7.97 (1H, d, J = 3.9 Hz), 8.18. (2H, dd, J = 8.3, 1.5 Hz), 8.36 (1H, dd, J = 8.3, 1.5 Hz), 8.59 (1H, dd, J = 7.3, 1) .5 Hz), 10.56 (1 H, d, J = 3.9 Hz).
Anal. Calcd. for C 22 H 23 N 3 O 2 ・ 1 / 5H 2 O: C, 72.39; H, 6.46; N, 11.51 (%).
Found: C, 72.33; H, 6.38; N, 11.50 (%).
HR-FAB + (m / z): 362.1875 (+0.6 mmu).
Example 16 4- [2-((R) -3-Hydroxypyrrolidin-1-yl) ethoxy] -2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Example 6 (100 mg, 306 μmol) and (R) -3-pyrrolidinol (127 μL, 1.53 mmol), 96.9 mg of the title compound as a light brown powder was obtained in the same manner as in Example 13. Yield 82%.
1 H-NMR (DMSO-d 6 , Δ): 1.52-1.60 (1H, m), 1.96-2.05 (1H, m), 2.55-2.64 (1H, m), 2.73-2.79. (1H, m), 2.86-2.90 (1H, m), 2.96-3.03 (1H, m), 4.19-4.25 (1H, m), 4.54 (2H , T, J = 5.9 Hz), 4.73 (1H, t, J = 4.4 Hz), 7.55-7.63 (3H, m), 7.67-7.71 (2H, m) 7.97 (1H, d, J = 4.4 Hz), 8.18 (2H, dd, J = 8.3, 1.5 Hz), 8.36 (1H, dd, J = 8.3, 1) .5 Hz), 8.59 (1H, dd, J = 7.3, 2.0 Hz), 10.56 (1H, d, J = 4.4 Hz).
Anal. Calcd. for C 22 H 23 N 3 O 3 ・ 1 / 2H 2 O: C, 68.38; H, 6.26; N, 10.87 (%).
Found: C, 68.37; H, 6.26; N, 10.87 (%).
HR-FAB + (m / z): 378.1842 (+2.5 mmu).
Example 17 2-Phenyl-4- [3- (pyrrolidin-1-yl) propoxy] quinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Example 7 (192 mg, 563 μmol) and pyrrolidine (235 μL, 2.82 mmol), the title compound as a tan powder was obtained in the same manner as in Example 13 to obtain 84.0 mg. Yield 38%.
1 H-NMR (DMSO-d 6 , Δ): 1.69 (4H, t, J = 2.9 Hz), 2.08-2.11 (2H, m), 2.66 (2H, t, J = 6.9 Hz), 4.50 (2H, t, J = 6.4 Hz), 7.57-7.70 (5H, m), 7.97 (1H, d, J = 3.9 Hz), 8.17 (2H, d, J = 6.8 Hz), 8.38 (1 H, dd, J = 7.8, 1.5 Hz), 8.60 (1 H, dd, J = 7.3, 1.5 Hz), 10.57 (1 H, d , J = 3.9 Hz).
Anal. Calcd. for C 23 H 25 N 3 O 2 ・ H 2 O: C, 70.21; H, 6.92; N, 10.68 (%).
Found: C, 70.15; H, 6.81; N, 10.72 (%).
HR-FAB + (m / z): 376.2046 (+2.1 mmu).
<Example 18> 4- [2- (imidazol-1-yl) ethoxy] -2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Example 6 (164 mg, 502 μmol) and imidazole (103 mg, 1.51 mmol), the title compound as a colorless powder was obtained in the same manner as in Example 13 to obtain 83.8 mg. Yield 47%.
1 H-NMR (DMSO-d 6 , Δ): 4.60 (2H, t, J = 4.9 Hz), 4.73 (2H, t, J = 4.4 Hz), 6.92 (1H, s), 7.36 (1H, s) ), 7.57-7.63 (4H, m), 7.69 (1H, t, J = 7.8 Hz), 7.84 (1H, s), 7.97 (1H, d, J = 3) 0.9 Hz), 8.14-8.17 (2H, m), 8.37 (1H, dd, J = 8.3, 1.5 Hz), 8.59 (1H, dd, J = 7.3) 1.5 Hz), 10.49 (1 H, d, J = 3.9 Hz).
HR-MS (m / z): 358.1425 (-0.5 mmu).
Example 19 4- (Carboxymethoxy) -2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
To a suspension of the compound of Example 9 (133 mg, 395 μmol) in methanol (4 mL) was added 1 mol / L potassium hydroxide aqueous solution (869 μL, 869 μmol), and the mixture was heated to reflux for 1 hour. After cooling, the residue obtained by evaporating the solvent was dissolved in water and adjusted to pH 3 with 4 mol / L hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to give 116 mg of the title compound as a colorless powder. Yield 91%.
1 H-NMR (DMSO-d 6 , Δ): 5.32 (2H, s), 7.65-7.67 (3H, m), 7.76-7.80 (2H, m), 8.14 (1H, brs), 8. 17 (2H, dd, J = 7.8, 1.5 Hz), 8.47 (1H, d, J = 8.8 Hz), 8.65 (1H, d, J = 7.3 Hz), 10.19 (1H, brs).
HR-FAB + (m / z): 323.1035 (+0.3 mmu).
Example 20 2-Phenyl-4-[(pyrrolidin-1-yl) carbonylmethoxy] quinoline-8-carboxylic acid amide
Figure 2004014861
To a solution of the compound of Example 19 (136 mg, 422 μmol) in N, N-dimethylformamide (5 mL), pyrrolidine (35.2 μL, 422 μmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (97 0.04 mg, 506 μmol) and 4-dimethylaminopyridine (5.16 mg, 42.2 μmol) were sequentially added, and the mixture was stirred at room temperature for 9 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography [ethyl acetate] to obtain 32.3 mg of the title compound as a colorless powder. Yield 20%.
1 H-NMR (DMSO-d 6 , Δ): 1.79-1.64 (2H, m), 1.91-1.96 (2H, m), 3.36 (2H, t, J = 6.8 Hz), 3.57 (2H) , T, J = 6.8 Hz), 5.29 (2H, s), 7.55-7.64 (4H, m), 7.70 (1H, t, J = 7.3 Hz), 7.97. (1H, d, J = 4.4 Hz), 8.11-8.13 (2H, m), 8.42 (1H, dd, J = 8.3, 1.5 Hz), 8.60 (1H, dd, J = 7.3, 1.5 Hz), 10.52 (1H, d, J = 3.4 Hz).
Anal. Calcd. for C 20 H 21 N 3 O: C, 70.38; H, 5.64; N, 11.19 (%).
Found: C, 70.13; H, 5.65; N, 11.15 (%).
HR-MS (m / z): 375.1607 (+2.4 mmu).
Example 21 4- [2- (Dimethylamino) ethyl] amino-2-phenylquinoline-8-carboxylic acid amide
Figure 2004014861
To a solution of the compound of Reference Example 29 (150 mg, 531 μmol) in N, N-dimethylacetamide (5 mL), sodium iodide (7.96 mg, 53.1 μmol) and then N, N-dimethylethylenediamine (291 μL, 2.65 mmol) were added. In addition, the mixture was heated to reflux for 24 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [ethyl acetate-hexane-triethylamine (4: 2: 1) → ethyl acetate-methanol-triethylamine (8: 1: 1)]. 24.9 mg of the title compound was obtained as a light brown powder. Yield 14%.
1 H-NMR (DMSO-d 6 , Δ): 2.32 (6H, s), 2.70 (2H, brs), 3.50-3.60 (2H, br), 7.05 (1H, s), 7.43 (1H, brs), 7.43-7.59 (4H, m), 7.83 (1H, d, J = 3.9 Hz), 8.07 (2H, d, J = 6.9 Hz), 8.42 ( 1H, d, J = 7.8 Hz), 8.54 (1H, dd, J = 7.3, 1.0 Hz), 11.12 (1H, d, J = 4.4 Hz).
HR-MS (m / z): 334.1792 (-0.1 mmu).
<Examples 22 to 58> In the same manner as in Example 21, the compounds shown in Table 16 below were obtained.
Figure 2004014861
<< Compound of Example 22 >>
1 H-NMR (DMSO-d 6 , Δ): 0.99 (6H, t, J = 7.3 Hz), 2.58 (4H, q, J = 7.3 Hz), 2.75 (2H, t, J = 6.9 Hz), 3 .43-3.54 (2H, m), 7.05 (1H, s), 7.43 (1H, t, J = 4.9 Hz), 7.52-7.59 (4H, m), 7 .84 (1H, d, J = 4.4 Hz), 8.05 (2H, d, J = 7.3 Hz), 8.38 (1H, d, J = 7.3 Hz), 8.53 (1H, d, J = 6.4 Hz), 11.12 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 22 H 26 N 4 O · 1 / 3H 2 O: C, 71.71; H, 7.29; N, 15.21 (%).
Found: C, 71.57; H, 7.18; N, 15.30 (%).
HR-MS (m / z): 362.2102 (-0.5 mmu).
<< Compound of Example 23 >>
1 H-NMR (DMSO-d 6 , Δ): 0.85 (6H, t, J = 7.3 Hz), 1.19 (3H, t, J = 6.9 Hz), 2.41 (4H, q, J = 7.3 Hz), 2 .62 (2H, t, J = 6.8 Hz), 3.49-3.52 (4H, m), 7.54-7.62 (5H, m), 7.90 (1H, d, J = 3.9 Hz), 8.08 (2H, d, J = 6.9 Hz), 8.30 (1H, d, J = 7.3 Hz), 8.52 (1H, d, J = 6.4 Hz), 11.68 (1H, d, J = 3.9 Hz).
Anal. Calcd for C 24 H 30 N 4 O: C, 73.81; H, 7.74; N, 14.35 (%).
Found: C, 73.74; H, 7.86; N, 14.41 (%).
HR-MS (m / z): 362.2102 (-0.5 mmu).
<< Compound of Example 24 >>
1 H-NMR (DMSO-d 6 , Δ): 0.97 (6H, t, J = 7.3 Hz), 1.81-1.88 (2H, m), 3.46-3.50 (2H, m), 7.01 (1H) , S), 7.50-7.59 (4H, m), 7.84 (1H, s), 8.03-8.06 (2H, m), 8.37 (1H, dd, J = 8 .3, 1.0 Hz), 8.54 (1H, dd, J = 7.3, 1.0 Hz), 11.15 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 23 H 28 N 4 O.2 / 5H 2 O: C, 72.00; H, 7.57; N, 14.60 (%).
Found: C, 71.88; H, 7.62; N, 14.86 (%).
HR-MS (m / z): 376.2281 (+1.8 mmu).
<< Compound of Example 25 >>
1 H-NMR (DMSO-d 6 , Δ): 1.69-1.72 (4H, m), 2.53-2.56 (4H, m), 2.78 (2H, t, J = 6.9 Hz), 3.58 (2H , Q, J = 6.4 Hz), 7.05 (1H, s), 7.50-7.59 (5H, m), 7.84 (1H, d, J = 4.9 Hz), 8.05 −8.07 (2H, m), 8.44 (1H, dd, J = 8.3, 1.5 Hz), 8.54 (1H, dd, J = 7.3, 1.0 Hz), 11. 14 (1H, d, J = 4.4 Hz).
Anal. Calcd. for C 22 H 24 N 4 O · 1 / 3H 2 O: C, 72.11; H, 6.78; N, 15.29 (%).
Found: C, 72.22; H, 6.68; N, 15.12 (%).
HR-MS (m / z): 360.1962 (+1.2 mmu).
<< Compound of Example 26 >>
1 H-NMR (DMSO-d 6 , Δ): 1.35-1.45 (2H, m), 1.49-1.55 (4H, m), 2.64 (2H, t, J = 6.9Hz), 3.55 (2H , Q, J = 6.4 Hz), 7.06 (1H, s), 7.42 (1H, t, J = 4.9 Hz), 7.50-7.59 (4H, m), 7.83 (1H, d, J = 4.4 Hz), 8.06 (2H, d, J = 6.8 Hz), 8.41 (1H, dd, J = 8.3, 1.5 Hz), 8.53 ( 1H, dd, J = 7.3, 1.5 Hz), 11.13 (1H, d, J = 4.4 Hz).
Anal. Calcd. for C 23 H 26 N 4 O ・ 1 / 2H 2 O: C, 72.04; H, 7.10; N, 14.61 (%).
Found: C, 72.12; H, 6.94; N, 14.65 (%).
HR-MS (m / z): 374.2150 (+4.4 mmu).
<< Compound of Example 27 >>
1 H-NMR (DMSO-d 6 , Δ): 2.69 (2H, t, J = 6.9 Hz), 3.56-3.61 (6H, m), 7.07 (1H, s), 7.43 (1H, t, J = 4.9 Hz), 7.52-7.59 (4 H, m), 7.82 (1 H, d, J = 4.4 Hz), 8.06-8.08 (2 H, m), 8.43 (1H, dd, J = 8.3, 1.5 Hz), 8.54 (1H, dd, J = 7.3, 1.0 Hz), 11.12 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 22 H 24 N 4 O.2 / 5H 2 O: C, 68.87; H, 6.31; N, 14.60 (%).
Found: C, 68.92; H, 6.49; N, 14.33 (%).
HR-MS (m / z): 376.1919 (+1.8 mmu).
<< Compound of Example 28 >>
1 H-NMR (DMSO-d 6 , Δ): 0.97 (3H, t, J = 7.3 Hz), 1.41-1.50 (2H, m), 1.68-1.76 (2H, m), 3.38-3 .47 (2H, m), 7.00 (1H, s), 7.50-7.59 (5H, m), 7.82 (1H, d, J = 4.4 Hz), 8.04-8 .06 (2H, m), 8.48 (1H, dd, J = 8.3, 1.5 Hz), 8.53 (1H, dd, J = 7.3, 1.0 Hz), 11.15 ( 1H, d, J = 4.9 Hz).
Anal. Calcd. for C 20 H 21 N 3 O · 1 / 3H 2 O: C, 73.82; H, 6.71; N, 12.91 (%).
Found: C, 73.86; H, 6.58; N, 12.88 (%).
HR-MS (m / z): 319.1695 (+1.0 mmu).
<< Compound of Example 29 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, s), 2.56 (4H, s), 2.78 (2H, t, J = 6.8 Hz), 3.54-3.57 (2H, m), 3.85 (3H, s), 7.00 (1H, s), 7.11 (2H, d, J = 8.8 Hz), 7.43 (1H, d, J = 5.4 Hz), 7. 50 (1H, d, J = 8.3 Hz), 7.82 (1H, d, J = 4.9 Hz), 8.02 (2H, d, J = 8.3 Hz), 8.40 (1H, d , J = 8.3 Hz), 8.52 (1H, d, J = 7.3 Hz), 11.17 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 23 H 26 N 4 O 2 ・ 1 / 5H 2 O: C, 70.10; H, 6.75; N, 14.22 (%).
Found: C, 70.14; H, 6.90; N, 14.17 (%).
HR-FAB + (m / z): 391.2122 (-1.2 mmu).
<< Compound of Example 30 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, t, J = 2.9 Hz), 2.56 (4H, s), 2.78 (2H, t, J = 6.9 Hz), 3.56-3.59 (2H, m), 3.86 (3H, s), 7.04 (1H, s), 7.09 (1H, dd, J = 7.8, 2.0 Hz), 7.46-7.55. (3H, m), 7.58 (1H, t, J = 1.5 Hz), 7.64 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 4.9 Hz) , 8.42-8.44 (1H, m), 8.53 (1H, dd, J = 7.3, 1.5 Hz), 11.14 (1H, d, J = 4.4 Hz).
Anal. Calcd. for C 23 H 26 N 4 O 2 ・ 1 / 3H 2 O: C, 69.67; H, 6.78; N, 14.13 (%).
Found: C, 69.61; H, 6.83; N, 13.92 (%).
HR-FAB + (m / z): 391.2167 (+3.3 mmu).
<< Compound of Example 31 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, s), 2.56 (4H, s), 2.78 (2H, t, J = 6.8 Hz), 3.53-3.56 (2H, m), 6.92 (2H, d, J = 8.3 Hz), 6.96 (1H, s), 7.30-7.40 (1 H, m), 7.48 (1 H, t, J = 8.3 Hz) ), 7.78 (1H, d, J = 4.9 Hz), 7.91 (2H, d, J = 8.8 Hz), 8.39 (1H, d, J = 8.3 Hz), 8.50 (1H, d, J = 6.4 Hz), 9.87 (1H, s), 11.24 (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 377.1985 (+0.7 mmu).
<< Compound of Example 32 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, t, J = 3.4 Hz), 2.55 (4H, s), 2.77 (2H, t, J = 6.8 Hz), 3.56 (2H, t , J = 6.3 Hz), 6.91 (1H, dd, J = 7.8, 1.5 Hz), 6.95 (1H, s), 7.34 (1H, t, J = 7.8 Hz) , 7.42-7.54 (4H, m), 7.83 (1H, d, J = 4.9 Hz), 8.42-8.44 (1H, m), 8.54 (1H, dd, J = 7.3, 1.5 Hz), 9.70 (1H, s), 11.15 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 22 H 24 N 4 O 2 ・ 1 / 2H 2 O: C, 68.55; H, 6.54; N, 14.54 (%).
Found: C, 68.57; H, 6.44; N, 14.44 (%).
HR-MS (m / z): 376.1911 (+1.2 mmu).
<< Compound of Example 33 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, t, J = 3.4 Hz), 2.51 (4H, s), 2.79 (2H, t, J = 6.9 Hz), 3.55-3.60 (2H, m), 7.04 (1H, s), 7.52-7.56 (2H, m), 7.76 (2H, d, J = 8.3 Hz), 7.82 (1H, d , J = 4.4 Hz), 8.01 (2H, d, J = 8.8 Hz), 8.44 (1H, d, J = 7.3 Hz), 8.52 (1H, dd, J = 7. 3, 1.5 Hz), 10.89 (1 H, d, J = 4.9 Hz).
Anal. Calcd. for C 22 H 23 BrN 4 O · 1 / 3H 2 O: C, 59.33; H, 5.31; N, 12.58 (%).
Found: C, 59.37; H, 5.17; N, 12.42 (%).
HR-MS (m / z): 438.155 (-0.1 mmu).
<< Compound of Example 34 >>
1 H-NMR (DMSO-d 6 , Δ): 1.70 (4H, t, J = 3.4 Hz), 2.55 (4H, s), 2.79 (2H, t, J = 6.9 Hz), 3.58-3.62. (2H, m), 7.15 (1H, s), 7.58 (1H, t, J = 7.8 Hz), 7.64 (1H, t, J = 5.4 Hz), 7.85 (1H , D, J = 4.4 Hz), 8.32 (2H, d, J = 9.3 Hz), 8.40 (2H, d, J = 8.8 Hz), 8.47 (1H, dd, J = 8.8, 1.5 Hz), 8.53 (1H, dd, J = 7.3, 1.5 Hz), 10.68 (1H, d, J = 4.4 Hz).
HR-FAB + (m / z): 406.1894 (+1.5 mmu).
<< Compound of Example 35 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, t, J = 3.4 Hz), 2.56 (4H, s), 2.79 (2H, t, J = 6.9 Hz), 3.61 (2H, q) , J = 5.4 Hz), 7.17 (1H, s), 7.55-7.63 (2H, m), 7.84-7.91 (2H, m), 8.36 (1H, dd) , J = 7.8, 1.5 Hz), 8.47 (1H, d, J = 8.3 Hz), 8.51-8.54 (2H, m), 8.83 (1H, t, J = 1.5 Hz), 10.65 (1 H, d, J = 4.4 Hz).
Anal. Calcd. for C 22 H 23 N 5 O 3 ・ 1 / 3H 2 O: C, 64.22; H, 5.80; N, 17.02 (%).
Found: C, 64.46; H, 5.90; N, 16.73 (%).
HR-FAB + (m / z): 406.1860 (-1.9 mmu).
<< Compound of Example 36 >>
1 H-NMR (DMSO-d 6 , Δ): 1.70 (4H, s), 2.55 (4H, s), 2.78 (2H, t, J = 6.9 Hz), 3.57-3.60 (2H, m), 7.07 (1H, s), 7.51-7.56 (1H, m), 7.60-7.67 (1H, m), 7.83 (1H, d, J = 3.9 Hz), 7.93-7.96 (1H, m), 8.10-8.16 (1H, m), 8.44 (1H, d, J = 8.3 Hz), 8.49-8.51 (1H , M), 10.73 (1H, d, J = 4.4 Hz).
Anal. Calcd. for C 22 H 22 F 2 N 4 O: C, 66.65; H, 5.59; N, 14.13 (%).
Found: C, 66.35; H, 5.87; N, 14.31 (%).
HR-FAB + (m / z): 397.1864 (+2.4 mmu).
<< Compound of Example 37 >>
1 H-NMR (DMSO-d 6 , Δ): 1.72 (4H, s), 2.58 (4H, s), 2.80 (2H, t, J = 6.9 Hz), 3.55 to 3.65 (2H, m), 3.94 (3H, s), 6.55 (1H, s), 7.02 (1H, s), 7.38 (1H, t, J = 4.9 Hz), 7.49-7.57 ( 3H, m), 7.82 (1H, d, J = 2.4 Hz), 7.91 (1H, d, J = 4.4 Hz), 8.02 (1H, d, J = 6.8 Hz), 8.15 (1H, d, J = 2.9 Hz), 8.62 (1H, s), 11.21 (1H, d, J = 4.4 Hz).
HR-MS (m / z): 390.053 (-0.3 mmu).
<< Compound of Example 38 >>
1 H-NMR (DMSO-d 6 , Δ): 1.68-1.78 (4H, m), 2.51 (3H, s), 2.53 (4H, s), 2.79 (2H, t, J = 6.9 Hz), 3.41-3.59 (2H, m), 7.01 (1H, s), 7.38 (1H, t, J = 5.4 Hz), 7.48-7.57 (3H, m), 7.80 (1H, d, J = 4.4 Hz), 8.03-8.05 (2H, m), 8.25 (1H, s), 8.38 (1H, d, J = 2.0 Hz) ), 11.16 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 23 H 26 N 4 O ・ 1 / 4H 2 O: C, 72.89; H, 7.05; N, 14.78 (%).
Found: C, 72.84; H, 7.05; N, 14.78 (%).
HR-MS (m / z): 374.2122 (+1.6 mmu).
<< Compound of Example 39 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, t, J = 3.4 Hz), 2.56 (4H, s), 2.78 (2H, t, J = 6.9 Hz), 3.55-3.60 (2H, m), 7.08 (1H, s), 7.52-7.63 (4H, m), 8.02-8.07 (3H, m), 8.41 (1H, d, J = 2.4 Hz), 8.63 (1H, d, J = 2.4 Hz), 11.01 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 22 H 23 ClN 4 O: C, 66.91; H, 5.87; N, 14.19 (%).
Found: C, 66.71; H, 5.87; N, 14.04 (%).
HR-FAB + (m / z): 395.1609 (-2.9 mmu).
<< Compound of Example 40 >>
1 H-NMR (DMSO-d 6 , Δ): 1.69-1.71 (4H, m), 2.56 (4H, s), 2.78 (2H, t, J = 6.9 Hz), 3.55 to 3.60 (2H) M), 7.07 (1H, s), 7.44 (1H, t, J = 5.4 Hz), 7.50-7.59 (3H, m), 8.04-8.06 (2H) M), 8.29 (1H, dd, J = 9.2, 2.9 Hz), 8.34 (1H, dd, J = 9.8, 2.9 Hz), 11.09 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 22 H 23 FN 4 O · 1 / 5H 2 O: C, 69.16; H, 6.17; N, 14.66 (%).
Found: C, 69.27; H, 6.02; N, 14.65 (%).
HR-FAB + (m / z): 379.1940 (+0.6 mmu).
<< Compound of Example 41 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, s), 2.57 (4H, s), 2.78 (2H, t, J = 6.4 Hz), 3.57 (2H, q, J = 6.4 Hz). ), 3.85 (3H, s), 7.02 (1H, s), 7.11 (2H, d, J = 8.8 Hz), 7.37 (1H, t, J = 4.9 Hz), 8.01 (2H, d, J = 8.8 Hz), 8.04 (1H, d, J = 5.4 Hz), 8.25-8.33 (2H, m), 11.15 (1H, d , J = 4.4 Hz).
Anal. Calcd. for C 23 H 25 FN 4 O 2 ・ 2 / 5H 2 O: C, 66.46; H, 6.26; N, 13.48 (%).
Found: C, 66.45; H, 6.12; N, 13.43 (%).
HR-FAB + (m / z): 409.2039 (-0.1 mmu).
<< Compound of Example 42 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, m), 2.55 (4H, s), 2.77 (2H, t, J = 6.9 Hz), 3.55 (2H, q, J = 6.4 Hz). ), 6.92 (2H, d, J = 8.3 Hz), 6.98 (1H, s), 7.33 (1H, t, J = 4.9 Hz), 7.91 (2H, d, J = 8.8 Hz), 8.00 (1 H, d, J = 4.9 Hz), 8.24-8.31 (2 H, m), 9.90 (1 H, s), 11.21 (1 H, d , J = 4.9 Hz).
HR-FAB + (m / z): 395.1864 (-1.9 mmu).
<< Compound of Example 43 >>
1 H-NMR (DMSO-d 6 , Δ): 1.69-1.72 (4H, m), 2.55 (4H, s), 2.77 (2H, t, J = 6.9 Hz), 3.55 (2H, q, J = 5.9 Hz), 6.91 (1H, dd, J = 7.3, 1.5 Hz), 6.97 (1H, s), 7.34 (1H, t, J = 7.8 Hz), 7 .40-7.45 (3H, m), 8.05 (1H, d, J = 4.4 Hz), 8.27-8.35 (2H, m), 9.70 (1H, s), 11 .11 (1H, d, J = 4.4 Hz).
HR-FAB + (m / z): 395.1905 (+2.2 mmu).
<< Compound of Example 44 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71 (4H, s), 2.55 (4H, s), 2.78 (2H, t, J = 6.9 Hz), 3.58 (2H, q, J = 6.4 Hz). ), 7.09 (1H, s), 7.45 (1H, s), 7.63 (1H, dd, J = 8.8, 8.6 Hz), 7.93 (1H, s), 8. 05 (1H, s), 8.13 (1H, t, J = 8.3 Hz), 8.25 (1H, dd, J = 9.3, 2.9 Hz), 8.34 (1H, dd, J = 9.8, 2.9 Hz), 10.68 (1H, d, J = 3.9 Hz).
Anal. Calcd. for C 22 H 21 F 3 N 4 O: C, 63.76; H, 5.11; N, 13.52 (%).
Found: C, 63.50; H, 5.16; N, 13.65 (%).
HR-FAB + (m / z): 415.1774 (+2.8 mmu).
<< Compound of Example 45 >>
1 H-NMR (DMSO-d 6 , Δ): 3.50-3.60 (2H, m), 3.65-3.75 (2H, m), 4.90 (1H, s), 7.07 (1H, s), 7. 53-7.58 (4H, m), 8.05 (1H, d, J = 7.3 Hz), 8.45 (1H, d, J = 8.8 Hz), 8.53 (1H, d, J = 6.8 Hz), 11.14 (1 H, s).
Anal. Calcd. for C 18 H 17 N 3 O 2 ・ 1 / 2H 2 OC, 68.34; H, 5.74; N, 13.28 (%).
Found: C, 68.30; H, 5.66; N, 13.16 (%).
HR-MS (m / z): 307.1335 (+1.4 mmu).
<< Compound of Example 46 >>
1 H-NMR (DMSO-d 6 , Δ): 1.30 (3H, d, J = 6.4 Hz), 3.46-3.52 (1H, m), 3.60-3.65 (1H, m), 3.99-4 .06 (1H, m), 4.89 (1H, d, J = 5.9 Hz), 7.07 (1H, d, J = 8.3 Hz), 7.09 (1H, s), 7.50 -7.59 (4H, m), 7.83 (1H, d, J = 4.4Hz), 8.04-8.06 (2H, m), 8.54 (2H, d, J = 7. 3 Hz), 11.16 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 19 H 19 N 3 O 2 ・ 1 / 10H 2 O: C, 70.61; H, 5.99; N, 13.00 (%).
Found: C, 70.58; H, 5.95; N, 13.04 (%).
HR-MS (m / z): 321.1479 (+0.1 mmu).
<< Compound of Example 47 >>
1 H-NMR (DMSO-d 6 , Δ): 3.67 (4H, t, J = 5.9 Hz), 3.91-3.95 (1H, m), 4.87 (2H, t, J = 5.9 Hz), 6.96 (1H, d, J = 7.8 Hz), 7.13 (1H, s), 7.50-7.59 (4H, m), 7.83 (1H, d, J = 4.4 Hz), 8 .04 (2H, d, J = 7.3 Hz), 8.51 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J = 7.3 Hz), 11.16 (1H, d, J = 4.4 Hz).
HR-MS (m / z): 337.1443 (+1.6 mmu).
<< Compound of Example 48 >>
1 H-NMR (DMSO-d 6 , Δ): 1.43 (3H, s), 3.64-3.68 (2H, m), 3.72-3.76 (1H, m), 5.15 (2H, t, J = 5) .9 Hz), 6.34 (1 H, s), 7.35 (1 H, s), 7.53-7.60 (4 H, m), 7.84 (1 H, d, J = 4.4 Hz), 7.98-8.00 (2H, m), 8.35 (1H, d, J = 8.3 Hz), 8.54 (1H, dd, J = 7.3, 1.0 Hz), 11.07 (1H, d, J = 4.4 Hz).
Anal. Calcd. for C 20 H 21 N 3 O 3 ・ H 2 O: C, 65.03; H, 6.28; N, 11.37 (%).
Found: C, 64.75; H, 6.09; N, 11.23 (%).
HR-MS (m / z): 351.1585 (+0.2 mmu).
<< Compound of Example 49 >>
1 H-NMR (DMSO-d 6 , Δ): 1.87-1.92 (2H, m), 3.51 (2H, q, J = 6.4 Hz), 3.58 (2H, q, J = 5.9 Hz), 4.66 (1H, d, J = 4.9 Hz), 7.04 (1H, s), 7.50-7.59 (5H, m), 7.83 (1H, d, J = 4.4 Hz), 8 .04-8.06 (2H, m), 8.45 (1H, dd, J = 8.3, 1.0 Hz), 8.53 (1H, dd, J = 7.3, 1.5 Hz), 11.15 (1H, d, J = 4.9 Hz).
HR-MS (m / z): 321.1502 (+2.4 mmu).
<< Compound of Example 50 >>
1 H-NMR (DMSO-d 6 , Δ): 3.63-3.69 (4H, m), 3.87 (3H, s), 3.91-3.96 (1H, m), 4.85 (2H, t, J = 5) .9 Hz), 6.95 (1 H, d, J = 8.3 Hz), 7.10 (1 H, dd, J = 8.3, 2.4 Hz), 7.12 (1 H, s), 7.46 -7.57 (3H, m), 7.62 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 4.9 Hz), 8.50-8.55 (2H, m), 11.16 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 20 H 21 N 3 O 4 ・ 1 / 4H 2 O: C, 64.59; H, 5.83; N, 11.30 (%).
Found: C, 64.49; H, 5.83; N, 11.57 (%).
HR-FAB + (m / z): 368.1625 (+1.5 mmu).
<< Compound of Example 51 >>
1 H-NMR (DMSO-d 6 , Δ): 3.64-3.67 (4H, m), 3.85-3.95 (1H, m), 4.86 (2H, t, J = 5.9 Hz), 6.90-6 .95 (2H, m), 7.04 (1H, s), 7.35 (1H, t, J = 7.8 Hz), 7.41-7.45 (2H, m), 7.55 (1H) , T, J = 7.8 Hz), 7.83 (1H, d, J = 5.4 Hz), 8.49-8.55 (2H, m), 9.70 (1H, s), 11.16. (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 3544.1474 (+2.0 mmu).
<< Compound of Example 52 >>
1 H-NMR (DMSO-d 6 , Δ): 3.66 (4H, t, J = 5.9 Hz), 3.80-3.90 (1H, m), 4.83 (2H, t, J = 5.9 Hz), 6.83 (1H, d, J = 7.8 Hz), 6.93 (2H, d, J = 8.3 Hz), 7.04 (1H, s), 7.48 (1H, t, J = 7.8 Hz) 7.77 (1H, d, J = 4.9 Hz), 7.90 (2H, d, J = 8.3 Hz), 8.45-8.47 (1H, m), 8.50-8. 52 (1H, m), 9.86 (1H, s), 11.24 (1H, d, J = 4.4 Hz).
HR-FAB + (m / z): 354.1421 (-3.3 mmu).
<< Compound of Example 53 >>
1 H-NMR (DMSO-d 6 , Δ): 3.60-3.69 (4H, m), 3.87-3.92 (1H, m), 4.81 (2H, t, J = 5.9 Hz), 6.82 (1H , D, J = 8.3 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.05 (1H, s), 7.89 (2H, d, J = 8.3 Hz), 7 .99 (1H, d, J = 4.4 Hz), 8.26 (1H, dd, J = 9.8, 2.9 Hz), 8.39 (1H, dd, J = 10.3, 2.9 Hz) ), 9.88 (1H, s), 11.22 (1H, d, J = 4.4 Hz).
HR-FAB + (m / z): 383.1369 (+1.3 mmu).
<< Compound of Example 54 >>
1 H-NMR (DMSO-d 6 , Δ): 3.62-3.73 (4H, m), 4.00-4.05 (1H, m), 4.83 (2H, t, J = 5.9 Hz), 7.08 (1H , D, J = 8.3 Hz), 7.25 (1H, s), 7.57 (1H, t, J = 8.3 Hz), 7.85-7.89 (2H, m), 8.35. -8.38 (1H, m), 8.50-8.56 (3H, m), 8.81 (1H, t, J = 2.0 Hz), 10.67 (1H, d, J = 4. 4 Hz).
Anal. Calcd. for C 19 H 18 N 4 O 5 : C, 59.68; H, 4.74; N, 14.65 (%).
Found: C, 59.44; H, 4.77; N, 14.54 (%).
HR-FAB + (m / z): 383.1389 (+3.4 mmu).
<< Compound of Example 55 >>
1 H-NMR (DMSO-d 6 , Δ): 3.63-3.67 (4H, m), 3.85 (3H, s), 3.90-4.00 (1H, m), 4.82 (2H, t, J = 5) .9 Hz), 6.86 (1 H, d, J = 7.8 Hz), 7.09 (1 H, s), 7.12 (2 H, d, J = 8.8 Hz), 7.99 (2 H, d) , J = 8.8 Hz), 8.03 (1H, d, J = 4.4 Hz), 8.27 (1H, dd, J = 9.8, 3.4 Hz), 8.42 (1H, dd, J = 10.3, 3.4 Hz), 11.16 (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 386.1544 (+2.8 mmu).
<< Compound of Example 56 >>
1 H-NMR (DMSO-d 6 , Δ): 3.60-3.70 (4H, m), 3.87-3.92 (1H, m), 4.84 (2H, t, J = 5.9 Hz), 6.91 (2H) , D, J = 7.8 Hz), 7.06 (1H, s), 7.33-7.44 (3H, m), 8.04 (1H, d, J = 4.9 Hz), 8.30. (1H, dd, J = 9.8, 2.9 Hz), 8.43 (1H, dd, J = 10.3, 3.4 Hz), 9.71 (1H, s), 11.13 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 19 H 18 FN 3 O 4 ・ 1 / 4H 2 O: C, 60.71; H, 4.96; N, 11.18 (%).
Found: C, 60.68; H, 5.00; N, 11.17 (%).
HR-FAB + (m / z): 372.371 (+1.2 mmu).
<< Compound of Example 57 >>
1 H-NMR (DMSO-d 6 , Δ): 3.60-3.69 (4H, m), 3.87-3.92 (1H, m), 4.82 (2H, t, J = 5.9 Hz), 6.82 (1H , D, J = 7.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.05 (1H, s), 7.89 (2H, d, J = 8.8 Hz), 7 .99 (1H, d, J = 4.9 Hz), 8.26 (1H, dd, J = 9.3, 2.9 Hz), 8.39 (1H, dd, J = 10.3, 2.9 Hz) ), 9.88 (1H, s), 11.22 (1H, d, J = 4.9 Hz).
Anal. Calcd. for C 19 H 18 FN 3 O 4 ・ 2 / 3H 2 O: C, 59.53; H, 5.08; N, 10.96 (%).
Found: C, 59.39; H, 4.97; N, 10.86 (%).
HR-FAB + (m / z): 372.1356 (-0.4 mmu).
<< Compound of Example 58 >>
1 H-NMR (DMSO-d 6 , Δ): 3.62-3.70 (4H, m), 3.90-4.10 (1H, m), 4.82 (2H, t, J = 5.9 Hz), 7.06 (1H , D, J = 7.8 Hz), 7.24 (1H, s), 8.03 (1H, d, J = 3.9 Hz), 8.27-8.30 (3H, m), 8.40. (2H, d, J = 8.8 Hz), 8.47 (1H, dd, J = 10.3, 2.9 Hz), 10.63 (1H, d, J = 3.9 Hz).
HR-FAB + (m / z): 401.1261 (+0.0 mmu).
Example 59 2- (4-Aminophenyl) -4- (1,3-dihydroxypropan-2-yl) aminoquinoline-8-carboxylic acid amide
Figure 2004014861
To a suspension of the compound of Example 53 (1.00 g, 2.62 mmol) in methanol-N, N-dimethylacetamide (1: 1, 30 mL), 10% palladium-carbon (100 mg) was added, and hydrogen gas flow ( The mixture was stirred at room temperature for 3 hours. The catalyst was removed by filtration using Celite, and the solvent was distilled off. The obtained residue was subjected to chromatolex NH column chromatography [ethyl acetate-methanol = 10: 1] to obtain 212 mg of the title compound as a pale yellow powder. Yield 23%.
1 H-NMR (DMSO-d 6 , Δ): 3.65 (4H, t, J = 5.9 Hz), 3.60-3.90 (1H, m), 4.83 (2H, t, J = 5.9 Hz), 5.56 (2H, s), 6.68-6.73 (3H, m), 6.99 (1H, s), 7.43 (1H, d, J = 7.8 Hz), 7.76-7.79. (3H, m), 8.40-8.42 (1H, m), 8.48-8.49 (1H, m), 11.39 (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 353.1608 (-0.5 mmu).
Example 60 2- (4-Aminophenyl) -4- (1,3-dihydroxypropan-2-yl) amino-6-fluoroquinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Example 58 (2.45 g, 6.12 mmol), 1.62 g of the title compound as a tan powder was obtained in the same manner as in Example 56. Yield 71%.
1 H-NMR (DMSO-d 6 , Δ): 3.59-3.69 (4H, m), 3.85-3.89 (1H, m), 4.81 (2H, t, J = 5.9 Hz), 5.58 (2H) , S), 6.68-6.73 (3H, m), 7.00 (1H, s), 7.76 (2H, d, J = 8.8 Hz), 7.98 (1H, d, J = 4.9 Hz), 8.24 (1H, dd, J = 9.8, 2.9 Hz), 8.34 (1H, dd, J = 10.3, 2.9 Hz), 11.38 (1H, d, J = 5.9 Hz).
HR-FAB + (m / z): 371.1547 (-0.5 mmu).
Example 61 4- (2-Chloroethoxy) -2- (4-trifluoromethylphenyl) quinoline-8-carboxylic acid amide
Figure 2004014861
Using the compound of Reference Example 72 (400 mg, 1.20 mmol) and 1-bromo-2-chloroethane (120 μL, 1.44 mmol), 136 mg of the title compound as a colorless powder was obtained in the same manner as in Example 5. Yield 29%.
1 H-NMR (DMSO-d 6 , Δ): 4.20 (2H, t, J = 4.9 Hz), 4.78 (2H, t, J = 4.9 Hz), 7.73-7.77 (2H, m), 7.97. -7.99 (3H, m), 8.37-8.42 (3H, m), 8.57-8.59 (1H, m), 10.15 (1H, d, J = 3.7 Hz) .
HR-FAB + (m / z): 395.0763 (-1.1 mmu).
Example 62 2- (4-Biphenyl) -4- (2-chloroethoxy) quinoline-8-carboxylic acid amide
Figure 2004014861
By using the compound of Reference Example 73 (493 mg, 1.45 mmol) and 1-bromo-2-chloroethane (145 μL, 1.74 mmol) in the same manner as in Example 5, 269 mg of the title compound as a colorless powder was obtained. Yield 46%.
1 H-NMR (DMSO-d 6 , Δ): 4.18 (2H, t, J = 4.9 Hz), 4.78 (2H, t, J = 4.9 Hz), 7.42 (1H, t, J = 7.3 Hz), 7 .52 (2H, t, J = 7.9 Hz), 7.70 (1H, t, J = 7.9 Hz), 7.74 (1H, s), 7.79 (1H, d, J = 7. 9 Hz), 7.90 (1 H, d, J = 8.6 Hz), 8.00 (1 H, d, J = 4.3 Hz), 8.27 (1 H, d, J = 8.6 Hz), 8. 39 (1H, dd, J = 7.9, 1.2 Hz), 8.59 (1H, dd, J = 7.3, 1.2 Hz), 10.48 (1H, d, J = 4.3 Hz) .
HR-FAB + (m / z): 395.0763 (-1.1 mmu).
<Examples 63 to 68> Using the compound of Example 61 or Example 62, the compounds shown in Table 17 below were obtained in the same manner as in Example 13.
Figure 2004014861
<< Compound of Example 63 >>
1 H-NMR (DMSO-d 6 , Δ): 1.69-1.72 (4H, m), 2.60-2.63 (4H, m), 3.00 (2H, t, J = 5.5 Hz), 4.56 (2H) , T, J = 5.5 Hz), 7.69-7.73 (2H, m), 7.95-7.97 (3H, m), 8.35-8.38 (3H, m), 8 .56 (1H, dd, J = 7.3, 1.8 Hz), 10.20 (1H, d, J = 3.7 Hz).
Anal. Calcd for C 23 H 22 F 3 N 3 O 2 : C, 64.33; H, 5.16; N, 9.78.
Found: C, 64.19; H, 5.12; N, 9.93.
HR-FAB + (m / z): 430.1758 (+1.6 mmu).
<< Compound of Example 64 >>
1 H-NMR (DMSO-d 6 , Δ): 1.03 (6H, t, J = 7.3 Hz), 2.63 (4H, q, J = 7.3 Hz), 3.00 (2H, t, J = 5.5 Hz), 4 .51 (2H, t, J = 5.5 Hz), 7.72 (2H, t, J = 7.3 Hz), 7.75 (1H, s), 7.96-7.98 (3H, m) , 8.35-8.40 (3H, m), 8.57 (1H, dd, J = 7.3, 1.8 Hz), 10.21 (1H, d, J = 3.7 Hz).
Anal. Calcd for C 23 H 24 F 3 N 3 O 2 ・ 3 / 10H 2 O: C, 63.24; H, 5.68; N, 9.62.
Found: C, 63.21; H, 5.52; N, 9.64.
HR-FAB + (m / z): 432.1866 (-3.3 mmu).
<< Compound of Example 65 >>
1 H-NMR (DMSO-d 6 , Δ): 2.35 (3H, s), 2.95 (2H, t, J = 5.5 Hz), 3.65 (2H, s), 4.59 (2H, t, J = 5.5 Hz) ), 7.24-7.36 (5H, m), 7.71-7.75 (2H, m), 7.96-7.98 (3H, m), 8.34-8.38 (3H) M), 8.58 (1H, dd, J = 7.3, 1.2 Hz), 10.21 (1H, d, J = 3.7 Hz).
Anal. Calcd for C 27 H 24 F 3 N 3 O 2 ・ 1 / 4H 2 O: C, 67.00; H, 5.10; N, 8.68.
Found: C, 66.97; H, 4.98: N, 8.68.
HR-FAB + (m / z): 480.19009 (+1.0 mmu).
<< Compound of Example 66 >>
1 H-NMR (DMSO-d 6 , Δ): 1.71-1.73 (4H, m), 2.62-2.63 (4H, m), 3.02 (2H, t, J = 5.5 Hz), 4.58 (2H) , T, J = 5.5 Hz), 7.43 (1H, t, J = 7.3 Hz), 7.53 (2H, t, J = 7.3 Hz), 7.69 (1H, t, J = 7.3 Hz), 7.73 (1H, s), 7.80 (1H, d, J = 7.9 Hz), 7.91 (1H, d, J = 8.6 Hz), 8.00 (1H, d, J = 4.3 Hz), 8.28 (1H, d, J = 8.6 Hz), 8.37 (1H, d, J = 6.7 Hz), 8.59 (1H, d, J = 7) .3 Hz), 10.54 (1 H, d, J = 4.3 Hz).
Anal. Calcd for C 28 H 27 N 3 O 2 : C, 76.86; H, 6.22; N, 9.60.
Found: C, 76.81; H, 6.25; N, 9.68.
HR-FAB + (m / z): 438.2185 (+0.4 mmu).
<< Compound of Example 67 >>
1 H-NMR (DMSO-d 6 , Δ): 2.76 (4H, t, J = 4.9 Hz), 3.02 (2H, t, J = 5.5 Hz), 4.65 (2H, t, J = 5.5 Hz), 6 .77 (1H, t, J = 7.3 Hz), 6.94 (2H, d, J = 7.9 Hz), 7.18-7.22 (2H, m), 7.41-7.45 ( 1H, m), 7.53 (2H, t, J = 7.3 Hz), 7.70 (1H, t, J = 7.3 Hz), 7.77-7.82 (3H, m), 7. 90-7.92 (2H, m), 8.01 (1H, d, J = 4.3 Hz), 8.28-8.31 (2H, m), 8.39 (1H, dd, J = 8) .6, 1.8 Hz), 8.60 (1H, dd, J = 7.3, 1.8 Hz), 10.55 (1H, d, J = 4.9 Hz).
Anal. Caled for C 28 H 27 N 3 O 2 ・ 1 / 4H 2 O: C, 76.59; H, 6.14; N, 10.51.
Found: C, 76.57; H, 6.19; N, 10.74.
HR-MS (m / z): 528.2517 (-0.8 mmu).
<< Compound of Example 68 >>
1 H-NMR (DMSO-d 6 , Δ): 0.87 (3H, t, J = 7.3 Hz), 1.28-1.34 (2H, m), 1.41-1.47 (2H, m), 2.33 (3H , S), 2.47 (2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 5.5 Hz), 4.56 (2H, t, J = 5.5 Hz), 7 .43 (1H, t, J = 7.3 Hz), 7.53 (2H, t, J = 7.9 Hz), 7.68 (1H, t, J = 7.9 Hz), 7.73 (1H, s), 7.80-7.82 (1H, m), 7.91 (2H, d, J = 8.6 Hz), 8.01 (1H, d, J = 4.3 Hz), 8.29 ( 2H, d, J = 7.9 Hz), 8.36 (1H, dd, J = 8.6, 1.8 Hz), 8.60 (1H, dd, J = 7.3, 1.8 Hz), 10 .55 (1H, d, J = 4.3 Hz).
Anal. Calcd for C 29 H 31 N 3 O 2 : C, 76.79; H, 689; N, 9.26.
Found: C, 76.59; H, 6.96; N, 9.36.
HR-FAB + (m / z): 454.2525 (+3.1 mmu).
<Examples 69 to 82> In the same manner as in Example 21, the compounds shown in Table 18 below were obtained.
Figure 2004014861
<< Compound of Example 69 >>
1 H-NMR (DMSO-d 6 , Δ): 1.73 (4H, s), 2.55 (4H, s), 2.78 (2H, t, J = 6.7 Hz), 3.59 (2H, q, J = 6.7 Hz) ), 7.11 (1H, s), 7.55-7.61 (2H, m), 7.83 (1H, d, J = 4.4 Hz), 7.92 (2H, d, J = 7) .9 Hz), 8.26 (2 H, d, J = 7.9 Hz), 8.46 (1 H, d, J = 7.9 Hz), 8.53 (1 H, d, J = 7.3 Hz), 10 .83 (1H, d, J = 4.3 Hz).
HR-MS (m / z): 402.1110 (-2.5 mmu).
<< Compound of Example 70 >>
1 H-NMR (DMSO-d 6 , Δ): 3.65-3.69 (4H, m), 3.90-4.00 (1H, m), 4.85 (2H, t, J = 5.5 Hz), 7.06 (1H , D, J = 7.9 Hz), 7.19 (1H, s), 7.57 (1H, t, J = 7.9 Hz), 7.82 (1H, d, J = 4.9 Hz), 7 .93 (2H, d, J = 7.9 Hz), 8.24 (2H, d, J = 7.9 Hz), 8.54 (2H, d, J = 7.9 Hz), 10.85 (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 406.1367 (-1.1 mmu).
<< Compound of Example 71 >>
1 H-NMR (DMSO-d 6 , Δ): 1.68-1.72 (4H, m), 2.54-2.55 (4H, m), 2.78 (2H, t, J = 6.7 Hz), 3.56-3 .61 (2H, m), 7.09 (1H, s), 7.40 (1H, t, J = 7.3 Hz), 7.49-7.55 (4H, m), 7.76-7 .78 (2H, m), 7.84-7.86 (3H, m), 8.15 (2H, d, J = 7.9 Hz), 8.43 (1H, dd, J = 8.6) 1.2 Hz), 8.53 (1H, d, J = 7.3, 1.8 Hz), 11.12 (1H, d, J = 4.9 Hz).
Anal. Calcd for C 28 H 28 N 4 O · 1 / 10H 2 O: C, 76.72; H, 6.48; N, 12.78.
Found: C, 76.60; H, 6.56; N, 12.66.
HR-FAB + (m / z): 437.2327 (-1.4 mmu).
<< Compound of Example 72 >>
1 H-NMR (DMSO-d 6 , Δ): 3.67 (4H, s), 3.91-3.98 (1H, m), 4.86 (2H, s), 6.96 (1H, d, J = 7.9 Hz), 7.18 (1H, s), 7.41 (1H, t, J = 7.3 Hz), 7.49-7.55 (3H, m), 7.76-7.78 (2H, m), 7.85-7.87 (3H, m), 8.13 (2H, d, J = 8.6 Hz), 8.50-8.55 (2H, m), 11.13 (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 414.1792 (-2.6 mmu).
<< Compound of Example 73 >>
1 H-NMR (DMSO-d 6 , Δ): 3.68 (4H, d, J = 1.8 Hz), 7.40-7.44 (1H, m), 7.50-7.56 (3H, m), 7.61 (1H) , S), 7.77-7.79 (2H, m), 7.85-7.88 (3H, m), 8.17 (2H, d, J = 8.6 Hz), 8.48 (1H) , Dd, J = 7.9, 1.2 Hz), 8.54 (1H, dd, J = 7.3, 1.2 Hz), 11.12 (1H, d, J = 4.9 Hz).
Anal. Calcd for C 25 H 23 N 3 O 2 ・ 3 / 10H 2 O: C, 74.54; H, 5.90; N, 10.43.
Found: C, 74.50; H, 5.90; N, 10.41.
HR-FAB + (m / z): 398.1888 (+2.0 mmu).
<< Compound of Example 74 >>
1 H-NMR (DMSO-d 6 , Δ): 3.07 (2H, t, J = 7.3 Hz), 3.70-3.75 (2H, m), 7.10 (1H, s), 7.21-7.24 (1H , M), 7.31-7.40 (4H, m), 7.43 (1H, d, J = 7.3 Hz), 7.50-7.56 (3H, m), 7.65 (1H , T, J = 5.5 Hz), 7.78 (2H, d, J = 7.3 Hz), 7.85-7.87 (3H, m), 8.15 (2H, d, J = 7. 9 Hz), 8.46 (1 H, dd, J = 8.6, 1.2 Hz), 8.54 (1 H, dd, J = 7.3, 1.2 Hz), 11.12 (1 H, d, J = 4.9 Hz).
Anal. Calcd for C 25 H 23 N 3 O 2 ・ 1 / 3H 2 O: C, 80.15; H, 5.75; N, 9.35.
Found: C, 80.16; H, 5.84; N, 9.61.
HR-FAB + (m / z): 444.2076 (+0.1 mmu).
<< Compound of Example 75 >>
1 H-NMR (DMSO-d 6 , Δ): 0.95-1.10 (2H, m), 1.15-1.30 (3H, m), 1.60-1.75 (3H, m), 1.80-1.90 (3H, m), 7.04 (1H, s), 7.40-7.44 (1H, m), 7.50-7.58 (4H, m), 7.77-7.79 (2H , M), 786-7.88 (3H, m), 8.14-8.16 (2H, m), 8.50-8.55 (2H, m), 11.15 (1H, d, J = 4.9 Hz).
Anal. Calcd for C 29 H 29 N 3 O · 1 / 6H 2 O: C, 79.42; H, 6.74; N, 9.58.
Found: C, 79.44; H, 6.80; N, 9.54.
HR-FAB + (m / z): 436.2409 (+2.0 mmu).
<< Compound of Example 76 >>
1 H-NMR (DMSO-d 6 , Δ): 1.70 (4H, s), 2.57 (4H, s), 2.78 (2H, t, J = 6.9 Hz), 3.58-3.62 (2H, m), 3.75 (3H, s), 3.91 (6H, s), 7.03 (1H, s), 7.33 (2H, s), 7.47-7.54 (2H, m), 7 .92 (1H, d, J = 4.9 Hz), 8.41-8.43 (1H, m), 8.52 (1H, dd, J = 7.3, 1.5 Hz), 11.24 ( 1H, d, J = 4.4 Hz).
HR-FAB + (m / z): 451.2336 (-0.9 mmu).
<< Compound of Example 77 >>
1 H-NMR (DMSO-d 6 , Δ): 3.65-3.69 (4H, m), 3.75 (3H, s), 3.91 (6H, s), 3.95-4.05 (1H, m), 4. 84 (2H, t, J = 5.5 Hz), 6.92 (1H, d, J = 7.9 Hz), 7.10 (1H, s), 7.29 (2H, s), 7.52 ( 1H, t, J = 7.9 Hz), 7.90 (1H, d, J = 4.9 Hz), 8.49-8.53 (2H, m), 11.25 (1H, d, J = 4) .9 Hz).
HR-FAB + (m / z): 428.1790 (-0.9 mmu).
<< Compound of Example 78 >>
1 H-NMR (DMSO-d 6 , Δ): 1.70-1.73 (4H, m), 2.56 to 2.59 (4H, m), 2.82 (2H, t, J = 6.7 Hz), 3.63 (2H) , Q, J = 6.1 Hz), 7.23 (1H, s), 7.51-7.57 (2H, m), 7.60-7.62 (2H, m), 7.87 (1H) , D, J = 4.9 Hz), 8.01 (1H, t, J = 5.5 Hz), 8.08-8.11 (2H, m), 8.20 (1H, dd, J = 8. 6,1.8 Hz), 8.47 (1H, dd, J = 8.6, 1.2 Hz), 8.55 (1H, dd, J = 7.3, 1.2 Hz), 8.65 (1H , S), 11.17 (1H, d, J = 4.9 Hz).
HR-FAB + (m / z): 411.2214 (+2.9 mmu).
<< Compound of Example 79 >>
1 H-NMR (DMSO-d 6 , Δ): 3.67-3.73 (4H, m), 4.00-4.06 (1H, m), 4.87 (2H, t, J = 5.5 Hz), 6.99 (1H , D, J = 8.6 Hz), 7.31 (1H, s), 7.55 (1H, t, J = 7.9 Hz), 7.59-7.64 (2H, m), 7.86 (1H, d, J = 4.3 Hz), 8.00-8.03 (1H, m), 8.08-8.11 (2H, m), 8.19 (1H, d, J = 8. 6 Hz), 8.53-8.56 (1 H, m), 8.62 (1 H, s), 11.19 (1 H, d, J = 4.3 Hz).
HR-FAB + (m / z): 388.1646 (-1.5 mmu).
<< Compound of Example 80 >>
1 H-NMR (DMSO-d 6 , Δ): 1.69-1.72 (4H, m), 2.54-2.57 (4H, m), 2.78 (2H, t, J = 6.7 Hz), 3.56 (2H , Q, J = 6.7 Hz), 7.11 (1H, s), 7.24 (1H, dd, J = 4.9, 3.7 Hz), 7.45-7.51 (2H, m) , 7.73-7.74 (1H, m), 7.92 (1H, d, J = 4.3 Hz), 8.00 (1H, d, J = 3.7 Hz), 8.39 (1H, dd, J = 8.6, 1.2 Hz), 8.51 (1H, dd, J = 7.3, 1.2 Hz), 10.78 (1H, d, J = 4.3 Hz).
Anal. Calcd for C 20 H 22 N 4 OS: C, 65.55; H, 6.05; N, 15.29.
Found: C, 65.40; H, 6.11; N, 15.18.
HR-FAB + (m / z): 367.1585 (-0.7 mmu).
<< Compound of Example 81 >>
1 H-NMR (DMSO-d 6 , Δ): 3.61-3.69 (4H, m), 3.91-3.95 (1H, m), 4.84 (2H, t, J = 5.5 Hz), 6.94 (1H , D, J = 7.9 Hz), 7.17 (1H, s), 7.24 (1H, d, J = 4.9 Hz), 7.49 (1H, t, J = 7.3 Hz), 7 .74 (1H, d, J = 4.9 Hz), 7.92 (1H, d, J = 4.3 Hz), 7.99 (1H, d, J = 3.7 Hz), 8.47 (1H, d, J = 8.6 Hz), 8.52 (1H, d, J = 7.3 Hz), 10.79 (1H, d, J = 4.9 Hz).
Anal. Calcd for C 17 H 17 N 3 O 3 S ・ 1 / 5H 2 O: C, 58.84; H, 5.05; N, 12.11.
Found: C, 58.81; H, 5.07; N, 12.19.
HR-FAB + (m / z): 344.1079 (+1.0 mmu).
<< Compound of Example 82 >>
1 H-NMR (DMSO-d 6 , Δ): 3.60-3.66 (2H, m), 3.72-3.76 (2H, m), 3.92 (1H, brs), 5.10 (2H, t, J = 4) .9 Hz), 7.22 (1 H, s), 7.54-7.60 (4 H, m), 7.91 (1 H, d, J = 4.3 Hz), 7.95 (1 H, d, J = 7.9 Hz), 8.04 (2 H, d, J = 6.7 Hz), 8.38 (1 H, d, J = 7.9 Hz), 10.71 (1 H, d, J = 4.3 Hz) .
Anal. Calcd for C 19 H 18 ClN 3 O 3 ・ 1 / 10H 2 O: C, 61.08; H, 4.91; N, 11.25.
Found: C, 61.01; H, 5.13; N, 11.50.
HR-MS (m / z): 371.1044 (+0.8 mmu).
<Test example>
(Inhibition experiment on PARP activity)
PARP (Trevigen 4667-050-01) was diluted 35-fold with a buffer solution consisting of 50 mmol / L Tris-HCl (pH 7.8), 100 mmol / L KCl and 1 mmol / L dithiothreitol and used in the experiment.
117.6 mmol / L Tris-HCl (pH 8.0), 11.8 mmol / L MgCl 2 76.5 μL of a buffer consisting of 5.9 mmol / L dithiothreitol and 0.4 mmol / L NAD, [ 14 C] 2.5 μL of NAD (NEN Life Science Products, Inc. NEC743, 370 kBq / ml), 1 μL of activated DNA (Trevigen 4667-50-06), 10 μL of test compound or test compound solvent, and 10 μL of 35-fold diluted PARP solution After putting in a plastic test tube and mixing well, it was heated to 25 ° C. in a water bath. After 10 minutes, the reaction was stopped by adding 1 mL of ice-cold 20% trichloroacetic acid, and the test tube was left on ice overnight. The precipitate was collected on a glass fiber filter by suction filtration and washed 5 times with 5% trichloroacetic acid. Radioactivity on the filter was measured with a liquid scintillation counter. The concentration of the test compound that reduces the enzyme activity in the absence of the test compound to 100% and reduces it to 50% (IC 50 Value).
Figure 2004014861
As a result, as shown in Table 19, it was confirmed that the novel 4-substituted quinoline-8-carboxylic acid amide derivative of the present invention has excellent PARP inhibitory activity.
Industrial applicability
From the above, it has been clarified that the compound of the present invention is composed of a novel 4-substituted quinoline-8-carboxylic acid amide derivative and a salt thereof and has an excellent PARP inhibitory activity.
Compounds having PARP inhibitory activity are diseases caused by excessive activation of PARP, such as various ischemic diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.), inflammatory diseases (inflammatory bowel disease, multiple diseases) It is useful as a preventive and / or therapeutic agent for encephalopathy, arthritis, rheumatoid arthritis, etc.), neurodegenerative diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.), diabetes, septic shock, head trauma and the like.

Claims (16)

一般式（１）
Figure 2004014861
［式中、Ｒ１はハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基、または一般式（２）
Figure 2004014861
（式中、環Ａｒは、フェニル基、ナフチル基、５員若しくは６員の複素環及びその縮合環を表し、
Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表す）を表し、
Ｒ２、Ｒ３、Ｒ４は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、置換基を有してもよいアミノ基、ニトロ基、シアノ基を表し、
Ｘは酸素原子、硫黄原子、ＮＲ１３（ここで、Ｒ１３は水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表す）を表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ７は水素原子、ハロゲン原子、水酸基、置換基を有してもよい環状アルキル基、置換基を有してもよい低級アルコキシ基、カルボキシ基、低級アルコキシカルボニル基、ＮＲ１１Ｒ１２、ＣＯＮＲ１１Ｒ１２、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
ｎは０〜３を表す］で表される４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。General formula (1)
Figure 2004014861
[Wherein, R 1 represents a lower alkyl group which may be substituted with a halogen atom, a cyclic alkyl group which may have a substituent, an aralkyl group which may have a substituent, or a general formula (2)
Figure 2004014861
(Wherein the ring Ar represents a phenyl group, a naphthyl group, a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof,
R 8 , R 9 , and R 10 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxy group, or an R 11 R 12 N group. Substituted with a lower alkyl group substituted with, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, or an R 11 R 12 N group A lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group which may have a substituent, a nitro group, or a substituent. A good amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5-membered or 6-membered complex Represents a ring and its condensed ring),
R 2 , R 3 and R 4 are the same or different and have a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkoxy group which may be substituted with a halogen atom, or a substituent. Represents an amino group, a nitro group, or a cyano group,
X is an oxygen atom, a sulfur atom, NR 13 (wherein R 13 has a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or a substituent. Represents a good aralkyl group)
R 5 and R 6 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group that may be substituted with a halogen atom, or a lower alkyl group that is substituted with a hydroxy group;
R 7 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyclic alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a carboxy group, a lower alkoxycarbonyl group, NR 11 R 12 or CONR 11. R 12 represents a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent, and a condensed ring thereof,
R 11 and R 12 are the same or different and each represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent. Or a 5-membered or 6-membered heterocyclic ring optionally bonded to R 11 and R 12 and a substituent thereof, and a condensed ring thereof,
n represents 0-3] 4-substituted quinoline-8-carboxylic acid amide derivative and its pharmacologically acceptable addition salt. 一般式（１−ａ）
Figure 2004014861
［式中、環Ａｒは、フェニル基、ナフチル基、５員若しくは６員の複素環及びその縮合環を表し、
Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ２、Ｒ３、Ｒ４は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、置換基を有してもよいアミノ基、ニトロ基、シアノ基を表し、
Ｘは酸素原子、硫黄原子、ＮＲ１３（ここで、Ｒ１３は水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表す）を表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ７は水素原子、ハロゲン原子、水酸基、置換基を有してもよい環状アルキル基、置換基を有してもよい低級アルコキシ基、カルボキシ基、低級アルコキシカルボニル基、ＮＲ１１Ｒ１２、ＣＯＮＲ１１Ｒ１２、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
ｎは０〜３を表す］で表される請求項１記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。Formula (1-a)
Figure 2004014861
[Wherein, the ring Ar represents a phenyl group, a naphthyl group, a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof,
R 8 , R 9 , and R 10 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxy group, or an R 11 R 12 N group. Substituted with a lower alkyl group substituted with, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, or an R 11 R 12 N group A lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group which may have a substituent, a nitro group, or a substituent. A good amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5-membered or 6-membered complex Represents a ring and its condensed ring,
R 2 , R 3 and R 4 are the same or different and have a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkoxy group which may be substituted with a halogen atom, or a substituent. Represents an amino group, a nitro group, or a cyano group,
X is an oxygen atom, a sulfur atom, NR 13 (wherein R 13 has a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or a substituent. Represents a good aralkyl group)
R 5 and R 6 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group that may be substituted with a halogen atom, or a lower alkyl group that is substituted with a hydroxy group;
R 7 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyclic alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a carboxy group, a lower alkoxycarbonyl group, NR 11 R 12 or CONR 11. R 12 represents a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-membered heterocyclic ring which may have a substituent, and a condensed ring thereof,
R 11 and R 12 are the same or different and each represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent. Or a 5-membered or 6-membered heterocyclic ring optionally bonded to R 11 and R 12 and a substituent thereof, and a condensed ring thereof,
The 4-substituted quinoline-8-carboxylic acid amide derivative according to claim 1 and a pharmacologically acceptable addition salt thereof, wherein n represents 0 to 3. 一般式（１−ｂ）
Figure 2004014861
［式中、環Ａｒは、フェニル基、ナフチル基、５員若しくは６員の複素環及びその縮合環を表し、
Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ２、Ｒ３、Ｒ４は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、置換基を有してもよいアミノ基、ニトロ基、シアノ基を表し、
Ｘは酸素原子、硫黄原子、ＮＲ１３（ここで、Ｒ１３は水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表す）を表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
ｎは０〜３を表す］で表される請求項１記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。Formula (1-b)
Figure 2004014861
[Wherein, the ring Ar represents a phenyl group, a naphthyl group, a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof,
R 8 , R 9 , and R 10 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxy group, or an R 11 R 12 N group. Substituted with a lower alkyl group substituted with, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, or an R 11 R 12 N group A lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group which may have a substituent, a nitro group, or a substituent. A good amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5-membered or 6-membered complex Represents a ring and its condensed ring,
R 2 , R 3 and R 4 are the same or different and have a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkoxy group which may be substituted with a halogen atom, or a substituent. Represents an amino group, a nitro group, or a cyano group,
X is an oxygen atom, a sulfur atom, NR 13 (wherein R 13 has a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or a substituent. Represents a good aralkyl group)
R 5 and R 6 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group that may be substituted with a halogen atom, or a lower alkyl group that is substituted with a hydroxy group;
R 11 and R 12 are the same or different and each represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent. Or a 5-membered or 6-membered heterocyclic ring optionally bonded to R 11 and R 12 and a substituent thereof, and a condensed ring thereof,
The 4-substituted quinoline-8-carboxylic acid amide derivative according to claim 1 and a pharmacologically acceptable addition salt thereof, wherein n represents 0 to 3. 一般式（１−ｃ）
Figure 2004014861
［式中、環Ａｒは、フェニル基、ナフチル基、５員若しくは６員の複素環及びその縮合環を表し、
Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ２、Ｒ３、Ｒ４は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、置換基を有してもよいアミノ基、ニトロ基、シアノ基を表し、
Ｘは酸素原子、硫黄原子、ＮＲ１３（ここで、Ｒ１３は水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表す）を表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
ｎは０〜３を表す］で表される請求項１記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。Formula (1-c)
Figure 2004014861
[Wherein, the ring Ar represents a phenyl group, a naphthyl group, a 5-membered or 6-membered heterocyclic ring and a condensed ring thereof,
R 8 , R 9 , and R 10 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group that may be substituted with a halogen atom, a lower alkyl group that is substituted with a hydroxy group, or an R 11 R 12 N group. Substituted with a lower alkyl group substituted with, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, or an R 11 R 12 N group A lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group which may have a substituent, a nitro group, or a substituent. A good amino group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5-membered or 6-membered complex Represents a ring and its condensed ring,
R 2 , R 3 and R 4 are the same or different and have a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkoxy group which may be substituted with a halogen atom, or a substituent. Represents an amino group, a nitro group, or a cyano group,
X is an oxygen atom, a sulfur atom, NR 13 (wherein R 13 has a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or a substituent. Represents a good aralkyl group)
R 5 and R 6 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group that may be substituted with a halogen atom, or a lower alkyl group that is substituted with a hydroxy group;
R 11 and R 12 are the same or different and each represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent. Or a 5-membered or 6-membered heterocyclic ring optionally bonded to R 11 and R 12 and a substituent thereof, and a condensed ring thereof,
The 4-substituted quinoline-8-carboxylic acid amide derivative according to claim 1 and a pharmacologically acceptable addition salt thereof, wherein n represents 0 to 3. 一般式（１−ｄ）
Figure 2004014861
［式中、Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ２ａ、Ｒ３ａ、Ｒ４ａは同一または異なって、水素原子、ハロゲン原子を表し、
Ｘａは酸素原子、ＮＨを表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
ｎは０〜３を表す］で表される請求項１記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。Formula (1-d)
Figure 2004014861
[Wherein, R 8 , R 9 and R 10 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 11 A lower alkyl group substituted with an R 12 N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R 11 R 12 A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An amino group which may have, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-optional which may have a substituent Represents a member heterocyclic ring and its condensed ring,
R 2a , R 3a and R 4a are the same or different and each represents a hydrogen atom or a halogen atom,
X a represents oxygen atom, a NH,
R 5 and R 6 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group that may be substituted with a halogen atom, or a lower alkyl group that is substituted with a hydroxy group;
R 11 and R 12 are the same or different and each represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent. Or a 5-membered or 6-membered heterocyclic ring optionally bonded to R 11 and R 12 and a substituent thereof, and a condensed ring thereof,
The 4-substituted quinoline-8-carboxylic acid amide derivative according to claim 1 and a pharmacologically acceptable addition salt thereof, wherein n represents 0 to 3. 一般式（１−ｅ）
Figure 2004014861
［式中、Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ２ａ、Ｒ３ａ、Ｒ４ａは同一または異なって、水素原子、ハロゲン原子を表し、
Ｘａは酸素原子、ＮＨを表し、
Ｒ５、Ｒ６は同一または異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
ｎは０〜３を表す］で表される請求項１記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。Formula (1-e)
Figure 2004014861
[Wherein, R 8 , R 9 and R 10 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 11 A lower alkyl group substituted with an R 12 N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R 11 R 12 A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An amino group which may have, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-optional which may have a substituent Represents a member heterocyclic ring and its condensed ring,
R 2a , R 3a and R 4a are the same or different and each represents a hydrogen atom or a halogen atom,
X a represents oxygen atom, a NH,
R 5 and R 6 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group that may be substituted with a halogen atom, or a lower alkyl group that is substituted with a hydroxy group;
R 11 and R 12 are the same or different and each represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent. Or a 5-membered or 6-membered heterocyclic ring optionally bonded to R 11 and R 12 and a substituent thereof, and a condensed ring thereof,
The 4-substituted quinoline-8-carboxylic acid amide derivative according to claim 1 and a pharmacologically acceptable addition salt thereof, wherein n represents 0 to 3. 一般式（１−ｆ）
Figure 2004014861
［式中、Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ３ａは水素原子、ハロゲン原子を表し、
Ｘａは酸素原子、ＮＨを表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表す］で表される請求項１記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。Formula (1-f)
Figure 2004014861
[Wherein, R 8 , R 9 and R 10 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 11 A lower alkyl group substituted with an R 12 N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R 11 R 12 A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An amino group which may have, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-optional which may have a substituent Represents a member heterocyclic ring and its condensed ring,
R 3a represents a hydrogen atom or a halogen atom,
X a represents oxygen atom, a NH,
R 11 and R 12 are the same or different and each represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent. Or a 5- or 6-membered heterocyclic ring which may have a substituent by bonding together with R 11 and R 12 and a condensed ring thereof. -8-carboxylic acid amide derivatives and pharmacologically acceptable addition salts thereof. 一般式（１−ｇ）
Figure 2004014861
［式中、Ｒ８、Ｒ９、Ｒ１０は同一または異なって、水素原子、ハロゲン原子、水酸基、ハロゲン原子で置換されてもよい低級アルキル基、ヒドロキシ基で置換された低級アルキル基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルキル基、置換基を有してもよい環状アルキル基、ハロゲン原子で置換されてもよい低級アルコキシ基、ヒドロキシ基で置換された低級アルコキシ基、Ｒ１１Ｒ１２Ｎ基で置換された低級アルコキシ基、カルボキシ基で置換された低級アルコキシ基、低級アルコキシカルボニル基で置換された低級アルコキシ基、置換基を有してもよいアラルキルオキシ基、ニトロ基、置換基を有してもよいアミノ基、置換基を有してもよいフェニル基、置換基を有してもよいナフチル基、置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表し、
Ｒ３ａは水素原子、ハロゲン原子を表し、
Ｘａは酸素原子、ＮＨを表し、
Ｒ５ａは水素原子、ヒドロキシメチル基を表し、
Ｒ１１、Ｒ１２は同一または異なって、水素原子、ハロゲン原子で置換されてもよい低級アルキル基、置換基を有してもよい環状アルキル基、置換基を有してもよいアラルキル基を表すか、あるいはＲ１１とＲ１２とで共に結合して置換基を有してもよい５員若しくは６員の複素環及びその縮合環を表す］で表される請求項１記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩。General formula (1-g)
Figure 2004014861
[Wherein, R 8 , R 9 and R 10 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, R 11 A lower alkyl group substituted with an R 12 N group, a cyclic alkyl group optionally having a substituent, a lower alkoxy group optionally substituted with a halogen atom, a lower alkoxy group substituted with a hydroxy group, R 11 R 12 A lower alkoxy group substituted with an N group, a lower alkoxy group substituted with a carboxy group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, an aralkyloxy group optionally having a substituent, a nitro group, a substituent An amino group which may have, a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a 5-membered or 6-optional which may have a substituent Represents a member heterocyclic ring and its condensed ring,
R 3a represents a hydrogen atom or a halogen atom,
X a represents oxygen atom, a NH,
R 5a represents a hydrogen atom or a hydroxymethyl group,
R 11 and R 12 are the same or different and each represents a hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, a cyclic alkyl group that may have a substituent, or an aralkyl group that may have a substituent. Or a 5- or 6-membered heterocyclic ring which may have a substituent by bonding together with R 11 and R 12 and a condensed ring thereof. -8-carboxylic acid amide derivatives and pharmacologically acceptable addition salts thereof. 一般式（１）で表される化合物が２−フェニル−４−［２−（ピロリジン−１−イル）エチル］アミノキノリン−８−カルボン酸アミド、２−（４−ヒドロキシフェニル）−４−［２−（ピロリジン−１−イル）エチル］アミノキノリン−８−カルボン酸アミド、２−（３−ヒドロキシフェニル）−４−［２−（ピロリジン−１−イル）エチル］アミノキノリン−８−カルボン酸アミド、６−フルオロ−２−（４−ヒドロキシフェニル）−４−［２−（ピロリジン−１−イル）エチル］アミノキノリン−８−カルボン酸アミド、６−フルオロ−２−（３−ヒドロキシフェニル）−４−［２−（ピロリジン−１−イル）エチル］アミノキノリン−８−カルボン酸アミド、４−（１，３−ジヒドロキシプロパン−２−イル）アミノ−６−フルオロ−２−（４−ヒドロキシフェニル）キノリン−８−カルボン酸アミド、４−（１，３−ジヒドロキシプロパン−２−イル）アミノ−６−フルオロ−２−（３−ヒドロキシフェニル）キノリン−８−カルボン酸アミドである請求項１記載の化合物。The compound represented by the general formula (1) is 2-phenyl-4- [2- (pyrrolidin-1-yl) ethyl] aminoquinoline-8-carboxylic acid amide, 2- (4-hydroxyphenyl) -4- [ 2- (Pyrrolidin-1-yl) ethyl] aminoquinoline-8-carboxylic acid amide, 2- (3-hydroxyphenyl) -4- [2- (pyrrolidin-1-yl) ethyl] aminoquinoline-8-carboxylic acid Amido, 6-fluoro-2- (4-hydroxyphenyl) -4- [2- (pyrrolidin-1-yl) ethyl] aminoquinoline-8-carboxylic acid amide, 6-fluoro-2- (3-hydroxyphenyl) -4- [2- (Pyrrolidin-1-yl) ethyl] aminoquinoline-8-carboxylic acid amide, 4- (1,3-dihydroxypropan-2-yl) amino-6-fluoro 2- (4-hydroxyphenyl) quinoline-8-carboxylic acid amide, 4- (1,3-dihydroxypropan-2-yl) amino-6-fluoro-2- (3-hydroxyphenyl) quinoline-8-carboxylic acid The compound of claim 1 which is an amide. 請求項１から９のいずれか１項に記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩の一種以上を有効成分として含有することを特徴とするポリ（ＡＤＰ−リボース）合成酵素阻害剤。A poly (ADP) comprising as an active ingredient at least one of the 4-substituted quinoline-8-carboxylic acid amide derivative according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof. Ribose) synthase inhibitor. 請求項１から９のいずれか１項に記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩の一種以上を有効成分として含有することを特徴とする医薬。A medicament comprising as an active ingredient at least one of the 4-substituted quinoline-8-carboxylic acid amide derivative according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof. 請求項１から９のいずれか１項に記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩の一種以上を有効成分として含有することを特徴とする、虚血性疾患（脳梗塞、心筋梗塞、急性腎不全等）の予防および／または治療剤。10. Ischemic, comprising as an active ingredient at least one of the 4-substituted quinoline-8-carboxylic acid amide derivative according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof. A preventive and / or therapeutic agent for diseases (cerebral infarction, myocardial infarction, acute renal failure, etc.). 請求項１から９のいずれか１項に記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩の一種以上を有効成分として含有することを特徴とする、炎症性疾患（炎症性腸疾患、多発性脳硬化症、関節炎、慢性関節リュウマチ等）の予防および／または治療剤。Inflammatory, comprising as an active ingredient at least one of the 4-substituted quinoline-8-carboxylic acid amide derivative according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof. A preventive and / or therapeutic agent for diseases (inflammatory bowel disease, multiple encephalopathy, arthritis, rheumatoid arthritis, etc.). 請求項１から９のいずれか１項に記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩の一種以上を有効成分として含有することを特徴とする、神経変性疾患（アルツハイマー病、ハンチントン舞踏病、パーキンソン病等）の予防および／または治療剤。10. A neurodegeneration comprising at least one of the 4-substituted quinoline-8-carboxylic acid amide derivative according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof as an active ingredient. A preventive and / or therapeutic agent for diseases (Alzheimer's disease, Huntington's chorea, Parkinson's disease, etc.). 請求項１から９のいずれか１項に記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩の一種以上を有効成分として含有することを特徴とする、糖尿病およびその合併症の予防および／または治療剤。It comprises one or more of the 4-substituted quinoline-8-carboxylic acid amide derivative according to any one of claims 1 to 9 and a pharmacologically acceptable addition salt thereof as an active ingredient. Preventive and / or therapeutic agent for the complication. 請求項１から９のいずれか１項に記載の４−置換キノリン−８−カルボン酸アミド誘導体とその薬理上許容される付加塩の一種以上を有効成分として含有することを特徴とする、頭部外傷の治療剤。10. A head comprising, as an active ingredient, one or more of the 4-substituted quinoline-8-carboxylic acid amide derivative according to claim 1 and a pharmacologically acceptable addition salt thereof. A treatment for trauma.
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