JPH0995485A5 - - Google Patents

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Publication number: JPH0995485A5
Authority: JP; Japan
Prior art keywords: group; added; pyrimidin; benzyl; chlorobenzoyl
Prior art date: 1996-03-15
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

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JP1996059508A

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Japanese (ja)

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JPH0995485A (en

Filing date

1996-03-15

Publication date

2004-12-09

1996-03-15 Application filed filed Critical

1996-03-15 Priority to JP8059508A priority Critical patent/JPH0995485A/en

1996-03-15 Priority claimed from JP8059508A external-priority patent/JPH0995485A/en

1997-04-08 Publication of JPH0995485A publication Critical patent/JPH0995485A/en

2004-12-09 Publication of JPH0995485A5 publication Critical patent/JPH0995485A5/ja

Status Withdrawn legal-status Critical Current

Description

【発明の詳細な説明】
【０００１】
【発明の属する技術分野】
本発明は、抗腫瘍作用を有する新規なケトン誘導体またはその塩、その製造法および医薬用途に関する。
【０００２】
【従来の技術】
従来より難治性固形癌として知られているすい臓癌は、発見の時点で既に転移や癌性腹膜炎を起こしている場合もあるために手術が不可能であることが多く、また手術が可能であっても予後はよくない。このような進行癌患者や術後患者に対しては、５−フルオロウラシル（５−ＦＵ）の単独投与もしくは５−ＦＵおよびマイトマイシンなどの化学療法剤を用いる多剤併用療法が行われている。また、難治性固形腫瘍として知られているホルモン非依存性癌（特に前立腺癌、乳癌など）、その再発癌もしくは転移癌に対しては、アドリアマイシン、シスプラチン、マイトマイシン、５−ＦＵなどの化学療法剤の単独投与あるいはこれらの多剤併用療法が行われている。さらに、肺癌の治療には、多くの場合シスプラチン、カルボプラチン、エトポシド、マイトマイシン、サイクロホスファミドなどの多剤併用療法が行われている。しかしながら、現状としては、これらの薬剤を用いた治療法は十分満足できるものとはいえない。
一方、ジアリールケトン誘導体では、抗炎症、鎮痛、解熱剤（ケトプロフェン、チアプロフェニックアシッド）、抗高脂血症治療剤（フェノフィブレイト）が医薬品として開発されている。そのほか、特公平６−７６２、特開昭６０−５４３７０、特開昭６１−１１２０５７、１１２０５８、１３０２７５、２６８６７２、特開昭６２−１２３１７６、特開昭６３−１１２５６６、特開昭６４−３４９７１、特開平１−２５０３６１、特開平３−２２０１７７には殺ダニ、殺虫剤としての記載が、特開昭６１−２６００１８には抗アレルギー剤としての記載がある。ピリミジン誘導体としては、特開平１−１９０６７０、２６１３７１に殺虫、殺ダニ剤の記載が、特開平６−７３０２２に除草剤の記載がある。アゾール誘導体としては、特公昭５４−２１３３９、特公昭６２−２０１６７に抗原虫剤の記載が、特開昭５１−７６４３１に殺菌剤の記載がある。イミダゾール誘導体としては、特公平５−２９３５１、特公表平５−５０４３５９にアンギオテンシンII阻害剤の記載が、特開昭５１−７６２７３、特開昭５２−８３５５６、特開昭５１−１４３６６７に抗菌剤の記載が、特開昭５９−１１８７７２に抗コクシジウム剤の記載が、特公表平３−５０１０２０に利尿、抗炎症剤の記載がある。トリアゾール誘導体としては、特公昭６０−２８８０４、特開昭５５−５７５７４に殺菌剤の記載が、特公平６−２５１７２に抗コクシジウム剤の記載がある。ピリジン誘導体としては、特開平３−４４３７２に殺虫剤の記載が、特公平５−２５５２５６に重合開始剤の記載が、特公平４−１４１０７に抗ウイルス剤の記載が、特開昭４９−１０００９１に血糖低下剤の記載がある。ピラゾロピリミジン誘導体としては、特開昭６３−２４６３７７に抗高脂血症剤の記載がある。テトラゾール誘導体としては、特公昭５５−１２６９に抗高血圧剤、抗浮腫剤、抗高尿酸剤の記載がある。ピラゾール誘導体としては、特開昭５０−１２６８３０に除草剤の記載が、特開平４−２１７６６８に殺菌剤の記載がある。オキサジアゾール誘導体としては、特開昭６２−１６４６７３に除草剤の記載がある。チアジアゾール誘導体としては、特開昭６１−８０２９２７に抗真菌剤の記載がある。ニコチン誘導体としては、特公昭６１−２６９９３に抗高脂血症剤の記載がある。ピペラジン誘導体としては、特公昭５９−３６９８７に抗炎症剤の記載がある。フェノキシ酢酸誘導体としては、特開昭５２−３９６５９に抗高血圧剤、抗浮腫剤、抗リュウマチ剤の記載がある。ウラシル誘導体としては、特開平５−４３５５５に殺虫、殺ダニ剤の記載がある。その他特開昭５１−１０８０５５、特開昭６２−２４０６３９、特公表昭６３−５０２５１１、特開昭５３−１２４６８２、特開平４−２２４８６２、２３０２８２、特開平６−１３５９７７が知られている。また、抗腫瘍作用を有する化合物を記載したものにＷＯ９４１８１６８（インドール誘導体）、特開昭６４−６８３２１（トリアゾール誘導体）、特開平３−５６４１７（トリアゾール誘導体）、特開平１−２８７０７４、２９０６６３、２９０６７０（イミダゾール誘導体）、特公平５−７１５９４（５−フルオロウラシル誘導体）がある。
【０００３】
【発明が解決しようとする課題】
従来の抗腫瘍化合物は治療効果が十分とはいえないので、これらとは化学構造が相違し、例えばすい臓癌、前立腺癌、乳癌、肺癌などの難治性固形腫瘍の治療およびこれらの癌の他臓器への遠隔転移の予防などに優れた効果を有する医薬品の開発が望まれている。
【０００４】
【課題を解決するための手段】
本発明者らは、かかる現状に鑑み、種々鋭意検討した結果、一般式
Ａ−Ｚ−Ａr¹−ＣＯ−Ａr² 〔I〕
〔式中、Ａは置換されていてもよい縮合ピリミジノンまたは縮合ピリダジノン環；Ａr¹およびＡr²はそれぞれ置換されていてもよい環；Ｚは２価の基を示す。〕で表される新規なケトン誘導体またはその塩を初めて合成し、得られた化合物がその特異な化学構造に基づいて、予想外にも優れた抗腫瘍作用を有しており、例えばすい臓癌細胞、前立腺癌細胞、乳癌細胞、肺癌細胞などの固形腫瘍細胞に対して優れた増殖抑制作用を示し、難治性固形腫瘍の予防、治療に有用であること、さらにヘリコバクター・ピロリ菌の除菌効果を有し、これに基づく疾患の予防、治療に有用であることを見出し、これらに基づいて本発明を完成した。
【０００５】
すなわち、本発明は、
（１）化合物〔I〕またはその塩、
（２）Ａが（i）Ｃ_6-14芳香族炭化水素、Ｃ_5-10シクロアルカンあるいはモノ−またはジ−複素環（環の構成原子として炭素以外に窒素、酸素および硫黄から選ばれた１ないし４個のヘテロ原子を含む）と（ii）ピリミジノンまたはピリダジノン環とが縮合して形成される置換されていてもよい縮合ピリミジノンまたは縮合ピリダジノン環である前記(1)記載の化合物、
（３）Ａが置換されていてもよいピロロ〔２,３−d〕ピリミジン−４−オン、ピロロ〔３,２−d〕ピリミジン−４−オン、ピロロ〔３,４−d〕ピリミジン−４−オン、ピラゾロ〔３,４−d〕ピリミジン−４−オン、ピラゾロ〔４,３−d〕ピリミジン−７−オン、６−オキソプリン、イミダゾ〔１,２−a〕ピリミジン−５−オン、イミダゾ〔１，２−a〕ピリミジン−７−オン、チエノ〔２,３−d〕ピリミジン−４−オン、チエノ〔３,４−d〕ピリミジン−４−オン、チエノ〔３,２−d〕ピリミジン−４−オン、フロ〔２,３−d〕ピリミジン−４−オン、フロ〔３,４−d〕ピリミジン−４−オン、フロ〔３,２−d〕ピリミジン−４−オン、イソキサゾロ〔５,４−d〕ピリミジン−４−オン、イソキサゾロ〔４,５−d〕ピリミジン−７−オン、オキサゾロ〔５,４−d〕ピリミジン−４−オン、オキサゾロ〔４,５−d〕ピリミジン−７−オン、チアゾロ〔５,４−d〕ピリミジン−４−オン、チアゾロ〔４,５−d〕ピリミジン−７−オン、イソチアゾロ〔５,４−d〕ピリミジン−４−オン、イソチアゾロ〔４,５−d〕ピリミジン−７−オン、トリアゾロ〔４,５−d〕ピリミジン−４−オン、１,２,４−トリアゾロ〔１,５−a〕ピリミジン−７−オン、ジヒドロシクロペンタ〔d〕ピリミジン−４−オン、５Ｈまたは７Ｈ−シクロペンタ〔d〕ピリミジン−４−オン、ピリド〔２,３−d〕ピリミジン−４−オン、ピリド〔３,２−d〕ピリミジン−４−オン、ピリド〔４,３−d〕ピリミジン−４−オン、ピリド〔３,４−d〕ピリミジン−４−オン、プテリジン−４−オン、キナゾリン−４−オン、ピリド〔１,２−a〕ピリミジン−４−オン、ピリミド〔１，２−a〕ピリミジン−４−オン、チアゾロ〔３，２−ａ〕ピリミジン−５−オン、オキサゾロ〔３，２−ａ〕ピリミジン−５−オン、ピロロ〔１，２−a〕ピリミジン−４−オン、ピリミド〔３，４−a〕ピリミジン−４−オン、ピリミド〔４，５−d〕ピリミジン−４−オン、ピリミド〔５，４−d〕ピリミジン−４−オン、ピリダジノ〔２，３−a〕ピリミジン−４−オン、ピリダジノ〔４，３−d〕ピリミジン−４−オン、ピリダジノ〔３，４−d〕ピリミジン−４−オン、キサンチン、尿酸、ピロロ〔３，２−d〕ピリミジン−２，４−ジオン、ピロロ〔２，３−d〕ピリミジン−２，４−ジオン、ピロロ〔３，４−d〕ピリミジン−２，４−ジオン、ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン、ピリミド〔２，１−ｂ〕〔１，３〕オキサジン−６−オン、イミダゾ〔２，１−ｂ〕キナゾリン−５−オン、シクロペント〔ｄ〕イミダゾ〔１，２−ａ〕ピリミジン−５−オン、シクロペント〔ｄ〕イミダゾ〔１，２−ａ〕ピリミジン−５−オン、ピリダジノ〔４,５−b〕−１,５−オキサゼピン−９（８Ｈ）−オン、ピリダジノ〔４,５−b〕−１,４−オキサジン−８（７Ｈ）−オン、ピロロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン、ピロロ〔２，３−d〕ピリダジン−７（６Ｈ）−オン、ピロロ〔２,３−d〕ピリダジン−４（５Ｈ）−オン、イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン、イミダゾ〔４,５−c〕ピリダジン−６（５Ｈ）−オン、ピラゾロ〔４,３−d〕ピリダジン−４（５Ｈ）−オン、ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン、トリアゾロ〔４,５−d〕ピリダジン−４（５Ｈ）−オン、ピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン、チアゾロ〔４，５−d〕ピリダジン−７（６Ｈ）−オン（これらは部分的に還元されていてもよい）である前記(1)記載の化合物、
（４）Ａが（i）Ｃ_6-14芳香族炭化水素、Ｃ_5-10シクロアルカンあるいはモノ−またはジ−複素環（環の構成原子として炭素以外に窒素、酸素および硫黄から選ばれた１ないし４個のヘテロ原子を含む）と（ii）ピリミジノン環とが縮合して形成される置換されていてもよい縮合ピリミジノン環である前記(1)記載の化合物、
（５）縮合ピリミジノン環がピロロ〔２，３−ｄ〕ピリミジン−４−オン、キナゾリン−４−オン、ピリド〔１，２−ａ〕ピリミジン−４−オン、チアゾロ〔３，２−ａ〕ピリミジン−５−オン、ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オンまたはイミダゾ〔２，１−ｂ〕キナゾリン−５−オン（これらは部分的に還元されていてもよい）である前記(4)記載の化合物、
（６）Ｚが−ＮＨ−、−Ｏ−または−Ｓ−を含んでいてもよい２価のＣ_1-6脂肪族炭化水素基である前記(1)記載の化合物、
（７）Ａｒ¹およびＡｒ²がそれぞれ置換されていてもよい芳香族環である前記(1)記載の化合物、
（８）Ａｒ¹がパラ置換ベンゼンである前記(1)記載の化合物、
（９）Ａｒ²−が置換されていてもよいフェニル、ピリジル、インドリル、ピロリル、チエニル、ピペリジノ、ピペラジノまたはモルホリノ基である前記(1)記載の化合物、
（１０）Ａｒ²−が置換されていてもよいフェニル基である前記(8)記載の化合物、
（１１）Ａｒ²−が置換されていてもよいピペリジノ、ピペラジノまたはモルホリノ基である前記(8)記載の化合物、
（１２）Ａｒ²がハロゲン、Ｃ_1-10アルキル、Ｃ_2-10アルケニル、Ｃ_2-10アルキニル、Ｃ_3-10シクロアルキル、Ｃ_3-6シクロアルキル−Ｃ_1-6アルキル、Ｃ_1-10アルコキシ、Ｃ_2-10アルケニルオキシ、Ｃ_2-10アルキニルオキシ、Ｃ_6-14アリールオキシ、Ｃ_7-16アラルキルオキシ、Ｃ_1-10アルキルチオ、Ｃ_2-10アルケニルチオ、Ｃ_2-10アルキニルチオ、Ｃ_6-14アリールチオ、Ｃ_7-16アラルキルチオ、Ｃ_1-10アルキルスルフィニル、Ｃ_2-10アルケニルスルフィニル、Ｃ_2-10アルキニルスルフィニル、Ｃ_6-14アリールスルフィニル、Ｃ_1-10アルキルスルホニル、Ｃ_2-10アルケニルスルホニル、Ｃ_2-10アルキニルスルホニル、Ｃ_6-14アリールスルホニル、カルバモイルオキシ、モノ−またはジ−Ｃ_1-10アルキルカルバモイルオキシ、ホスホノオキシ、モノ−またはジ−Ｃ_1-10アルキルホスホノオキシ、オキソ、ニトロ、シアノ、スルホ、ヒドロキシル、アミノ、モノ−またはジ−Ｃ_1-10アルキルアミノ、モノ−またはジ−Ｃ_7-16アラルキルアミノ、環状アミノ、カルボキシル、メルカプト、カルバモイル、モノ−またはジ−Ｃ_1-10アルキルカルバモイル、モノ−またはジ−Ｃ_6-14アリールカルバモイル、Ｃ_1-10アルコキシ−カルボニル、Ｃ_2-10アルケニルオキシ−カルボニル、Ｃ_2-10アルキニルオキシ−カルボニル、Ｃ_6-14アリールオキシ−カルボニル、Ｃ_1-10アルキルスルホニルアミノ、Ｃ_7-16アラルキル、Ｃ_6-14アリール、スチリル、Ｃ_6-14アリールイミノ、芳香族複素環、ホルミル、Ｃ_1-10アルキル−カルボニル、Ｃ_2-10アルケニル−カルボニル、Ｃ_2-10アルキニル−カルボニル、Ｃ_6-14アリール−カルボニル、Ｃ_1- ₁₀アシルアミノ、−ＣＯ−Ｑ（Ｑは置換アミノを示す）およびＣ_1-10アシルオキシから選ばれた１ないし５個の置換基で置換されていてもよく、これらの置換基は、さらにハロゲン、Ｃ_1-6アルキル、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_3-6シクロアルキル、カルボキシル、ヒドロキシル、シアノ、ニトロ、スルホ、ホスホノ、オキソ、Ｃ_1-6アルコキシ、Ｃ_1-3アルキレンジオキシ、Ｃ_6-10アリールオキシ、Ｃ_7-14アラルキルオキシ、メルカプト、Ｃ_1-6アルキルチオ、Ｃ_6-10アリールチオ、Ｃ_7-14アラルキルチオ、カルバモイル、モノ−またはジ−Ｃ_1-6アルキルカルバモイル、アミノ、モノ−またはジ−Ｃ_1-6アルキルアミノ、環状アミノ、モノ−またはジ−Ｃ_7-14アラルキルアミノ、Ｃ_6-10アリール、Ｃ_7-14アラルキル、ホルミル、Ｃ_1-6アルキル−カルボニル、Ｃ_6-10アリール−カルボニル、Ｃ_1-6アルコキシ−カルボニル、Ｃ_1-6アシルオキシ、芳香族複素環および芳香族複素環チオから選ばれた１ないし３個の置換基で置換されていてもよく、またさらにこれらの置換基はハロゲン、Ｃ_1-6アルキル、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_3-6シクロアルキル、カルボキシル、ヒドロキシル、シアノ、ニトロ、スルホ、ホスホノ、オキソ、Ｃ_1-6アルコキシ、Ｃ_1-3アルキレンジオキシ、Ｃ_6-10アリールオキシ、Ｃ_7-14アラルキルオキシ、メルカプト、Ｃ_1-6アルキルチオ、Ｃ_6-10アリールチオ、Ｃ_7-14アラルキルチオ、カルバモイル、モノ−またはジ−Ｃ_1-6アルキルカルバモイル、アミノ、モノ−またはジ−Ｃ_1-6アルキルアミノ、環状アミノ、モノ−またはジ−Ｃ_7-14アラルキルアミノ、Ｃ_6-10アリール、Ｃ_7-14アラルキル、ホルミル、Ｃ_1-6アルキル−カルボニル、Ｃ_6-10アリール−カルボニル、Ｃ_1-6アルコキシ−カルボニル、Ｃ_1-6アシルオキシ、芳香族複素環および芳香族複素環チオから選ばれた１ないし３個の置換基で置換されていてもよい環である前記(1)記載の化合物、
【０００６】
（１３）一般式
【化１５】
〔式中、Ａは置換されていてもよい縮合ピリミジノンまたはピリダジノン環；Ａｒ²は置換されていてもよい環；Ｚ^aは−ＮＨ−、−Ｏ−または−Ｓ−を含んでいてもよい２価のＣ_1-6脂肪族炭化水素基を示す。〕で表される化合物またはその塩、
（１４）Ａが式
【化１６】
〔式中、Ａ¹およびＡ²はそれぞれ置換されていてもよい５ないし８員の同素または複素環；Ｒ¹およびＲ²はそれぞれ水素、ハロゲン、Ｃ_1-6アルキル基、ハロ−Ｃ_1-6アルキル基、ヒドロキシル基、Ｃ_1-6アルコキシ基、ハロ−Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロ−Ｃ_1-6アルキルチオ基を示す。〕で表される環である前記(13)記載の化合物、
（１５）Ａが式
【化１７】
〔式中の記号は前記(14)記載と同意義を示す。〕で表される環である前記(13)記載の化合物、
（１６）Ａが式
【化１８】
〔式中の記号は前記(14)記載と同意義を示す。〕で表される環である前記(13)記載の化合物、
（１７）Ｒ¹およびＲ²がそれぞれ水素またはＣ_1-6アルキル基である前記(14)記載の化合物、
（１８）５ないし８員の同素または複素環が環の構成原子として炭素以外に窒素、酸素および硫黄から選ばれた１ないし４個のヘテロ原子を含んでいてもよい５ないし８員環である前記(14)記載の化合物、
（１９）５ないし８員環が(i)シクロペンタン、シクロヘキサン、シクロヘプタン、ベンゼンまたは(ii)イミダゾール、ピリジン、チアジン、チアゾール、オキサゾール、チオフェン、ピロール、ピラゾール、ピラジン、ピリミジン（これらは部分的に還元されていてもよい）である前記(18)記載の化合物、
（２０）Ｚ^aが−Ｏ−または−Ｓ−を含んでいてもよいＣ_1-6アルキレン基である前記(13)記載の化合物、
（２１）Ａｒ²−が置換されていてもよいフェニル、ピリジル、インドリル、ピロリル、チエニル、ピペリジノ、ピペラジノまたはモルホリノ基である前記(13)記載の化合物、
（２２）Ａｒ²−が置換されていてもよいフェニル基である前記(13)記載の化合物、
（２３）Ａｒ²−が置換されていてもよいピペリジノ、ピペラジノまたはモルホリノ基である前記(13)記載の化合物、
【０００７】
（２４）Ａが式
【化１９】
〔式中の記号は前記(14)記載と同意義を示す。〕；Ｚ^aが−Ｏ−または−Ｓ−を含んでいてもよいＣ_1-6アルキレン；Ａｒ²−が置換されていてもよいフェニル基である前記(13)記載の化合物、
（２５）Ｚ^aが−Ｏ−ＣＨ₂−または−ＣＨ₂−である前記(24)記載の化合物、
（２６）Ａが式
【化２０】
〔式中の記号は前記(14)記載と同意義を示す。〕；Ｚ^aが−Ｏ−または−Ｓ−を含んでいてもよいＣ_1-6アルキレン基；Ａｒ²−が置換されていてもよいフェニル基である前記(13)記載の化合物、
（２７）Ｚ^aが−Ｏ−ＣＨ₂−または−ＣＨ₂−である前記(26)記載の化合物、
（２８）一般式
【化２１】
〔式中、ｎは０ないし３の整数、その他の記号は前記(13)記載と同意義を示す。〕で表される前記(13)記載の化合物、
（２９）ｎが１ないし３の整数である前記(28)記載の化合物、
（３０）一般式
【化２２】
〔式中の記号は前記(13)記載と同意義を示す。〕で表される前記(28)記載の化合物、
（３１）Ａｒ²−が置換されていてもよいフェニル基である前記(28)記載の化合物、
（３２）置換されていてもよいフェニル基がＣ_1-6アルキル、ハロ−Ｃ_1-6アルキル、Ｃ_1-6アルコキシ、ハロ−Ｃ_1-6アルコキシ、Ｃ_1-6アルキルチオ、ハロ−Ｃ_1-6アルキルチオ、ハロゲン、アミノ、モノ−またはジ−Ｃ_1-6アルキルアミノ、Ｃ_1-6アシルアミノ、Ｃ_1-6アルキル−カルボニル、Ｃ_6-10アリール−カルボニル、Ｃ_7-14アラルキル−カルボニル、Ｃ_1-6アルコキシ−カルボニル、Ｃ_1-6アシルオキシ、カルバモイルオキシ、モノ−またはジ−Ｃ_1-6アルキルカルバモイルオキシ、シアノ、ニトロ、カルバモイルおよびモノ−またはジ−Ｃ_1-6アルキルカルバモイルから選ばれた１ないし５個の置換基で置換されていてもよいフェニル基である前記(31)記載の化合物、
（３３）Ａｒ²−が置換されていてもよいピペリジノまたはピペラジノ基である前記(28)記載の化合物、
（３４）Ａｒ²が式
【化２３】
〔式中、Ｒ^aは置換基を示す。〕で表される環である前記(28)記載の化合物、
（３５）Ｒ^aがハロゲン、Ｃ_1-6アルキル基、ハロ−Ｃ_1-6アルキル基、Ｃ_1-6アルコキシ基またはハロ−Ｃ_1-6アルコキシ基である前記(34)記載の化合物、
（３６）Ｚ^aが−Ｏ−ＣＨ₂−である前記(35)記載の化合物、
（３７）Ｒ¹がメチル基である前記(36)記載の化合物、
【０００８】
（３８）一般式
【化２４】
〔式中、ｎは０ないし３の整数、その他の記号は前記(13)記載と同意義を示す。〕で表される前記(13)記載の化合物、
（３９）Ａｒ²−が置換されていてもよいフェニル基である前記(38)記載の化合物、
（４０）置換されていてもよいフェニル基がＣ_1-6アルキル、ハロ−Ｃ_1-6アルキル、Ｃ_1-6アルコキシ、ハロ−Ｃ_1-6アルコキシ、Ｃ_1-6アルキルチオ、ハロ−Ｃ_1-6アルキルチオ、ハロゲン、アミノ、モノ−またはジ−Ｃ_1-6アルキルアミノ、Ｃ_1-6アシルアミノ、Ｃ_1-6アルキル−カルボニル、Ｃ_6-10アリール−カルボニル、Ｃ_7-14アラルキル−カルボニル、Ｃ_1-6アルコキシ−カルボニル、Ｃ_1-6アシルオキシ、カルバモイルオキシ、モノ−またはジ−Ｃ_1-6アルキルカルバモイルオキシ、シアノ、ニトロ、カルバモイルおよびモノ−またはジ−Ｃ_1-6アルキルカルバモイルから選ばれた１ないし５個の置換基で置換されていてもよいフェニル基である前記(39)記載の化合物、
（４１）Ａｒ²−が置換されていてもよいピペリジノまたはピペラジノ基である前記(38)記載の化合物、
（４２）Ａｒ²が式
【化２５】
〔式中、Ｒ^aは置換基を示す。〕で表される環である前記(38)記載の化合物、
（４３）Ｒ^aがハロゲン、Ｃ_1-6アルキル基、ハロ−Ｃ_1-6アルキル基、Ｃ_1-6アルコキシ基またはハロ−Ｃ_1-6アルコキシ基である前記(42)記載の化合物、
（４４）Ｚ^aが−Ｏ−ＣＨ₂−である前記(38)記載の化合物、
（４５）Ｒ¹がメチル基である前記(38)記載の化合物、
【０００９】
（４６）一般式
【化２６】
〔式中、Ａｒ³は環；Ｗは結合手、カルボニル基または−ＮＲ³−（Ｒ³は水素またはＣ_1-6アルキル基）、−Ｏ−または−Ｓ−を含んでいてもよい２価のＣ_1-6脂肪族炭化水素基；Ｔは置換されていてもよい第１ないし第３級アミノ基；その他の記号は前記と同意義を示す。〕で表される前記(1)記載の化合物、
（４７）Ｔがハロゲン、Ｃ_1-6アルキル、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_3-6シクロアルキル、カルボキシル、ヒドロキシル、シアノ、ニトロ、スルホ、ホスホノ、オキソ、Ｃ_1-6アルコキシ、Ｃ_1-3アルキレンジオキシ、Ｃ_6-10アリールオキシ、Ｃ_7-14アラルキルオキシ、メルカプト、Ｃ_1-6アルキルチオ、Ｃ_6-10アリールチオ、Ｃ_7-14アラルキルチオ、カルバモイル、モノ−またはジ−Ｃ_1-6アルキルカルバモイル、アミノ、モノ−またはジ−Ｃ_1-6アルキルアミノ、環状アミノ、モノ−またはジ−Ｃ_7-14アラルキルアミノ、Ｃ_6-10アリール、Ｃ_7-14アラルキル、ホルミル、Ｃ_1-6アルキル−カルボニル、Ｃ_6-10アリール−カルボニル、Ｃ_1-6アルコキシ−カルボニル、Ｃ_1-6アシルオキシ、芳香族複素環および芳香族複素環チオから選ばれた１ないし３個の置換基で置換されていてもよいピペリジノ、ピペラジノまたはモルホリノ基である前記(46)記載の化合物、
（４８）Ｗが結合手、−(ＣＨ₂)_1-3−または−Ｏ−(ＣＨ₂)_1-3−である前記(46)記載の化合物、
（４９）Ａが式
【化２７】
〔式中の記号は前記(14)記載と同意義を示す。〕で表される環である前記(46)記載の化合物、
（５０）Ｚが−Ｏ−または−Ｓ−を含んでいてもよい２価のＣ_1-6脂肪族炭化水素基である前記(46)記載の化合物、
（５１）Ａｒ³が式
【化２８】
である前記(46)記載の化合物、
（５２）一般式
Ｄ−Ａｌｋ−Ｅ−Ａｒ¹−ＣＯ−Ａｒ²
〔式中、Ｄは置換されていてもよいキナゾリン−５−オン、ピリド〔１，２−ａ〕ピリミジン−４−オン、イミダゾ〔１，２−ａ〕ピリミジン−５−オン、チアゾロ〔３，２−ａ〕ピリミジン−５−オン、オキサゾロ〔３，２−ａ〕ピリミジン−５−オンまたはピリド〔１，２−ａ〕ピリミジン−４−オン（これらは部分的に還元されていてもよい）；ＡｌｋはＣ_1-3アルキレン基；Ｅは結合手、−ＮＲ−、−Ｏ−、−Ｓ−、−ＮＲ−ＣＨ₂−、−Ｏ−ＣＨ₂−または−Ｓ−ＣＨ₂−（Ｒは水素、Ｃ_1-6アルキル基またはＣ_2-6アルケニル基を示す）；その他の記号は前記と同意義を示す。〕で表される前記(1)記載の化合物、
（５３）１−〔４−（４−クロロベンゾイル）ベンジル〕−６，７，８，９−テトラヒドロイミダゾ〔２，１−ｂ〕キナゾリン−５（１Ｈ）−オンまたはその塩、
（５４）３−メチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オンまたはその塩、
（５５）７−〔４−（４−メトキシベンゾイル）ベンジルオキシ〕−６−メチル−２，３−ジヒドロ−５Ｈ−チアゾロ〔１，２−ａ〕ピリミジン−５−オンまたはその塩、
【００１０】
（５６）ａ）Ａ−Ｙ^aまたはその塩とＹ−Ａｒ¹−ＣＯ−Ａｒ²またはその塩を反応させるか、
ｂ）Ａまたはその塩とＸ−Ｚ−Ａｒ¹−ＣＯ−Ａｒ²またはその塩とを反応させるか、
ｃ）Ａ−Ｘまたはその塩とＨＺ−Ａｒ¹−ＣＯ−Ａｒ²またはその塩とを反応させるか、
ｄ）Ａ^aまたはその塩とＡ^b−Ｚ−Ａｒ¹−ＣＯ−Ａｒ²またはその塩とを反応させるか、または
ｅ）Ａ−Ｚ−Ａｒ¹またはその塩とＸ−ＣＯ−Ａｒ²またはその塩
〔式中、ＹおよびＹ^aは互いに一緒になって形成されるＺで表される２価の基；Ａ^aおよびＡ^bは互いに一緒になって形成されるＡで表される置換されていてもよい縮合ピリミジノンまたは縮合ピリダジノン環；Ｘは反応性基；その他の記号は前記と同意義を示す。〕とを反応させることを特徴とする前記(1)記載の化合物の製造法、
（５７）前記(1)記載の化合物を含有することを特徴とする医薬、
（５８）癌の治療を目的とする前記(57)記載の医薬、および
（５９）ヘリコバクター・ピロリ除菌を目的とする前記(57)記載の医薬などに関する。
【００１１】
前記〔I〕式中、Ａは置換されていてもよい縮合ピリミジノンまたは縮合ピリダジノン環を示す。
Ａで表される「縮合ピリミジノン環」としては、例えば（i）１または２個の環状炭化水素および／または複素環と（ii）ピリミジノン環とが縮合して形成される縮合ピリミジノン環を示し、例えば環の構成原子として炭素、窒素、酸素および硫黄から選ばれた９ないし１４個の原子から構成された縮合ピリミジノン環が好ましい。
該「環状炭化水素」とは、例えば５ないし１０員の単環式炭化水素またはこれらが互いに縮合した縮合２環式炭化水素などを示す。好ましい「環状炭化水素」としては、例えばＣ_6-14芳香族炭化水素（例えば、ベンゼン、ナフタレンなど）、Ｃ_5-10シクロアルカン（例えば、シクロペンタン、シクロヘキサン、シクロヘプタン、インダン、テトラリンなど）などが挙げられる。
該「複素環」とは、例えば炭素以外に窒素、酸素および硫黄から選ばれたヘテロ原子を１または２種、好ましくは１ないし４個含む５ないし１０員の単環式複素環またはこれらと他の環（例えば、前記環状炭化水素または単環式複素環など）が縮合した縮合２環式複素環などを示す。このましい「複素環」としては、例えばイミダゾール、チアゾール、オキサゾール、ピロール、イソオキサゾール、イソチアゾール、ピラゾール、トリアゾール、ピリジン、ピリミジン、ピリダジン、ピラジン、チオフェン、フラン、チアジン、インドール、イソインドール、プリン、キノリン、イソキノリンなどが用いられ、これらは部分的に還元されていてもよい。
【００１２】
該「縮合ピリミジノン環」の具体例としては、例えばピロロ〔２,３−d〕ピリミジン−４−オン、ピロロ〔３,２−d〕ピリミジン−４−オン、ピロロ〔３,４−d〕ピリミジン−４−オン、ピラゾロ〔３,４−d〕ピリミジン−４−オン、ピラゾロ〔４,３−d〕ピリミジン−７−オン、６−オキソプリン、イミダゾ〔１,２−a〕ピリミジン−５−オン、イミダゾ〔１，２−a〕ピリミジン−７−オン、チエノ〔２,３−d〕ピリミジン−４−オン、チエノ〔３,４−d〕ピリミジン−４−オン、チエノ〔３,２−d〕ピリミジン−４−オン、フロ〔２,３−d〕ピリミジン−４−オン、フロ〔３,４−d〕ピリミジン−４−オン、フロ〔３,２−d〕ピリミジン−４−オン、イソキサゾロ〔５,４−d〕ピリミジン−４−オン、イソキサゾロ〔４,５−d〕ピリミジン−７−オン、オキサゾロ〔５,４−d〕ピリミジン−４−オン、オキサゾロ〔４,５−d〕ピリミジン−７−オン、チアゾロ〔５,４−d〕ピリミジン−４−オン、チアゾロ〔４,５−d〕ピリミジン−７−オン、イソチアゾロ〔５,４−d〕ピリミジン−４−オン、イソチアゾロ〔４,５−d〕ピリミジン−７−オン、トリアゾロ〔４,５−d〕ピリミジン−４−オン、１,２,４−トリアゾロ〔１,５−a〕ピリミジン−７−オン、ジヒドロシクロペンタ〔d〕ピリミジン−４−オン、５Ｈまたは７Ｈ−シクロペンタ〔d〕ピリミジン−４−オン、ピリド〔２,３−d〕ピリミジン−４−オン、ピリド〔３,２−d〕ピリミジン−４−オン、ピリド〔４,３−d〕ピリミジン−４−オン、ピリド〔３,４−d〕ピリミジン−４−オン、プテリジン−４−オン、キナゾリン−４−オン、ピリド〔１,２−a〕ピリミジン−４−オン、ピリミド〔１，２−a〕ピリミジン−４−オン、チアゾロ〔３，２−a〕ピリミジン−５−オン、オキサゾロ〔３，２−a〕ピリミジン−５−オン、ピロロ〔１，２−a〕ピリミジン−４−オン、ピリミド〔３，４−a〕ピリミジン−４−オン、ピリミド〔４，５−d〕ピリミジン−４−オン、ピリミド〔５，４−d〕ピリミジン−４−オン、ピリダジノ〔２，３−a〕ピリミジン−４−オン、ピリダジノ〔４，３−d〕ピリミジン−４−オン、ピリダジノ〔３，４−d〕ピリミジン−４−オン、キサンチン、尿酸、ピロロ〔３，２−d〕ピリミジン−２，４−ジオン、ピロロ〔２，３−d〕ピリミジン−２，４−ジオン、ピロロ〔３，４−d〕ピリミジン−２，４−ジオン、ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン、ピリミド〔２，１−ｂ〕〔１，３〕オキサジン−６−オン、イミダゾ〔２，１−ｂ〕キナゾリン−５−オン、シクロペント〔ｄ〕イミダゾ〔１，２−ａ〕ピリミジン−５−オン、シクロペント〔ｄ〕イミダゾ〔１，２−ａ〕ピリミジン−５−オンなどが挙げられる。
【００１３】
Ａで表される「縮合ピリダジノン環」としては、例えば（i）１または２個の環状炭化水素および／または複素環と（ii）ピリダジノン環とが縮合して形成される縮合ピリダジノン環を示し、例えば環の構成原子として炭素、窒素、酸素および硫黄から選ばれた９ないし１４個の原子から構成された縮合ピリダジノン環が好ましい。
該「環状炭化水素」および「複素環」は、例えば前記と同様のものなどが用いられる。
該「縮合ピリダジノン環」の具体例としては、例えばピリダジノ〔４,５−b〕−１,５−オキサゼピン−９（８Ｈ）−オン、ピリダジノ〔４,５−b〕−１,４−オキサジン−８（７Ｈ）−オン、ピロロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン、ピロロ〔２，３−d〕ピリダジン−７（６Ｈ）−オン、ピロロ〔２,３−d〕ピリダジン−４（５Ｈ）−オン、イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン、イミダゾ〔４,５−c〕ピリダジン−６（５Ｈ）−オン、ピラゾロ〔４,３−d〕ピリダジン−４（５Ｈ）−オン、ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン、トリアゾロ〔４,５−d〕ピリダジン−４（５Ｈ）−オン、ピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン、チアゾロ〔４，５−d〕ピリダジン−７（６Ｈ）−オンなどが挙げられる。
該「縮合ピリミジノンおよび縮合ピリダジノン環」は部分的に還元されていてもよい。
【００１４】
該「縮合ピリミジノンおよび縮合ピリダジノン環」が有していてもよい置換基（−Ｌとする）としては、例えばハロゲン原子、アルキル基、アルケニル基、アルキニル基、シクロアルキル基、シクロアルキル−アルキル基、アルコキシ基、アルケニルオキシ基、アルキニルオキシ基、アリールオキシ基、アラルキルオキシ基、アルキルチオ基、アルケニルチオ基、アルキニルチオ基、アリールチオ基、アラルキルチオ基、アルキルスルフィニル基、アルケニルスルフィニル基、アルキニルスルフィニル基、アリールスルフィニル基、アルキルスルホニル基、アルケニルスルホニル基、アルキニルスルホニル基、アリールスルホニル基、カルバモイルオキシ基、モノ−またはジ−アルキルカルバモイルオキシ基、ホスホノオキシ基、モノ−またはジ−アルキルホスホノオキシ基、オキソ基、ニトロ基、シアノ基、スルホ基、ヒドロキシル基、アミノ基、モノ−またはジ−アルキルアミノ基、モノ−またはジ−アラルキルアミノ基、環状アミノ基、カルボキシル基、メルカプト基、カルバモイル基、モノ−またはジ−アルキルカルバモイル基、モノ−またはジ−アリールカルバモイル基、アルコキシ−カルボニル基、アルケニルオキシ−カルボニル基、アルキニルオキシ−カルボニル基、アリールオキシ−カルボニル、アルキルスルホニルアミノ基、アラルキル基、アリール基、スチリル基、アリールイミノ基、芳香族複素環基、ホルミル基、アルキル−カルボニル基、アルケニル−カルボニル基、アルキニル−カルボニル基、アリール−カルボニル基、アシルアミノ基、−ＣＯ−Ｑ（Ｑは置換アミノ基）、アシルオキシ基などが挙げられる。これらの置換基は、「縮合ピリミジノン環および縮合ピリダジノン環」上の置換可能な位置に置換され、その置換基の数は１ないし５個、好ましくは１ないし３個である。ただし、その置換基の数が２個以上の場合は同一または異なっていてもよい。これら「縮合ピリミジノンおよび縮合ピリダジノン環」上の置換基の具体例を次に記載する。
【００１５】
該「ハロゲン原子」とは、例えばフッ素、塩素、臭素、ヨウ素などを示す。
該「アルキル基」とは、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、イソヘキシル、１,１−ジメチルブチル、２,２−ジメチルブチルなどのＣ_1-10アルキル基などを示す。
該「アルケニル基」とは、例えば、ビニル、アリル、２−ブテニル、イソプロペニル、２−ペンテニル、３−ペンテニル、４−ペンテニル、２−ヘキセニル、３−ヘキセニル、４−ヘキセニル、５−ヘキセニルなどのＣ_2-10アルケニル基などを示す。
該「アルキニル基」とは、例えば、エチニル、１−プロピニル、プロパルギル、１−ヘキシニル、２−ヘキシニル、３−ヘキシニル、４−ヘキシニルなどのＣ_2-10アルキニル基などを示す。
該「シクロアルキル基」とは、例えばシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルなどのＣ_3-10シクロアルキル基などを示す。
該「シクロアルキル−アルキル基」とは、例えばシクロプロピルメチルなどのＣ_3-6シクロアルキル−Ｃ_1-6アルキル基などを示す。
該「アルコキシ基」とは、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec−ブトキシ、ペンチルオキシ、ヘキシルオキシなどのＣ_1-10アルコキシ基などを示す。
【００１６】
該「アルケニルオキシ基」とは、例えばアリルオキシ、イソプロペニルオキシなどのＣ_2-10アルケニルオキシ基などを示す。
該「アルキニルオキシ基」とは、例えばプロパルギルオキシなどのＣ_2-10アルキニルオキシ基などを示す。
該「アリールオキシ基」とは、例えばフェノキシなどのＣ_6-14アリールオキシ基などを示す。
該「アラルキルオキシ基」とは、例えばベンジルオキシなどのＣ_7-16アラルキルオキシ基などを示す。
該「アルキルチオ基」とは、例えばメチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、ペンチルチオ、ヘキシルチオなどのＣ_1-10アルキルチオ基などを示す。
該「アルケニルチオ基」とは、例えばアリルチオ、イソプロペニルチオなどのＣ_2-10アルケニルチオ基などを示す。
該「アルキニルチオ基」とは、例えばプロパルギルチオなどのＣ_2-10アルキニルチオ基などを示す。
該「アリールチオ基」とは、例えばフェニルチオなどのＣ_6-14アリールチオ基などを示す。
該「アラルキルチオ基」とは、例えばベンジルチオなどのＣ_7-16アラルキルチオ基などを示す。
【００１７】
該「アルキルスルフィニル基」とは、例えばメチルスルフィニル、エチルスルフィニル、などのＣ_1-10アルキルスルフィニル基などを示す。
該「アルケニルスルフィニル基」とは、例えばアリルスルフィニル、イソプロペニルスルフィニルなどのＣ_2-10アルケニルスルフィニル基などを示す。
該「アルキニルスルフィニル基」とは、例えばプロパルギルスルフィニルなどのＣ_2-10アルキニルスルフィニル基などを示す。
該「アリールスルフィニル基」とは、例えばベンゼンスルフィニルなどのＣ_6-14アリールスルフィニル基などを示す。
該「アルキルスルホニル基」とは、例えばメチルスルホニル、エチルスルホニル、プロピルスルホニルなどのＣ_1-10アルキルスルホニル基などを示す。
該「アルケニルスルホニル基」とは、例えばアリルスルホニル、イソプロペニルスルホニルなどのＣ_2-10アルケニルスルホニル基などを示す。
該「アルキニルスルホニル基」とは、例えばプロパルギルスルホニルなどのＣ_2-10アルキニルスルホニル基などを示す。
該「アリールスルホニル基」とは、例えばベンゼンスルホニルなどのＣ_6-14アリールスルホニル基などを示す。
該「モノ−またはジ−アルキルカルバモイルオキシ基」とは、例えばメチルカルバモイルオキシ、エチルカルバモイルオキシ、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシなどのモノ−またはジ−Ｃ_1-6アルキルカルバモイルオキシ基などを示す。
該「モノ−またはジ−アルキルホスホノオキシ基」とは、例えばメチルホスホノオキシ、ジメチルホスホノオキシ、ジエチルホスホノオキシなどのモノ−またはジ−Ｃ_1-6アルキルホスホノオキシ基などを示す。
該「モノ−またはジ−アルキルアミノ基」とは、例えばメチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどのモノ−またはジ−Ｃ_1-10アルキルアミノ基などを示す。
【００１８】
該「モノ−またはジ−アラルキルアミノ基」とは、例えばベンジルアミノなどのモノ−またはジ−Ｃ_7-16アラルキルアミノ基などを示す。
該「環状アミノ基」とは、例えばピロリジノ、ピペリジノ、ピペラジノ、モルホリノなどの５または６員環状アミノ基などを示す。
該「モノ−またはジ−アルキルカルバモイル基」とは、例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイルなどのモノ−またはジ−Ｃ_1-10アルキルカルバモイル基などを示す。
該「モノ−またはジ−アリールカルバモイル基」とは、例えばフェニルカルバモイルなどのモノ−またはジ−Ｃ_6-14アリールカルバモイル基などを示す。
該「アルコキシ−カルボニル基」とは、例えばメトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニルなどのＣ_1-10アルコキシ−カルボニル基などを示す。
該「アルケニルオキシ−カルボニル基」とは、例えばアリルオキシカルボニル、イソプロペニルオキシカルボニルなどのＣ_2-10アルケニルオキシ−カルボニル基などを示す。
該「アルキニルオキシ−カルボニル基」とは、例えばプロパルギルオキシカルボニルなどのＣ_2-10アルキニルオキシ−カルボニル基などを示す。
該「アリールオキシ−カルボニル基」とは、例えばフェノキシカルボニルなどのＣ_6-14アリールオキシ−カルボニル基などを示す。
該「アルキルスルホニルアミノ基」とは、例えばメチルスルホニルアミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、ブチルスルホニルアミノなどのＣ_1-10アルキルスルホニルアミノ基などを示す。
該「アラルキル基」とは、例えばベンジル、フェネチル、ジフェニルメチル、トリフェニルメチル、１−ナフチルメチル、２−ナフチルメチル、２−ジフェニルエチル、３−フェニルプロピル、４−フェニルブチル、５−フェニルペンチルなどのＣ_7-16アラルキル基などを示す。
該「アリール基」とは、例えばフェニル、１−ナフチル、２−ナフチル、ビフェニル、２−アンスリルなどのＣ_6-14アリール基などを示す。
該「アリールイミノ基」とは、例えばフェニルイミノなどのＣ_6-14アリールイミノ基などを示す。
【００１９】
該「芳香族複素環基」とは、例えば炭素以外に窒素、酸素および硫黄から選ばれたヘテロ原子を１ないし４個含む５ないし１０員の芳香族複素環基または縮合２環式芳香族複素環基などを示し、具体的には、２−チエニル、３−チエニル、２−ピリジル、３−ピリジル、４−ピリジル、２−フリル、３−フリル、２−キノリル、４−キノリル、８−キノリル、３−イソキノリル、４−イソキノリル、ピラジニル、２−ピリミジニル、３−ピロリル、１−イミダゾリル、２−イミダゾリル、１−ピラゾリル、２−チアゾリル、４−チアゾリル、５−チアゾリル、３−イソチアゾリル、４−イソチアゾリル、３−イソオキサゾリル、３−ピリダジニル、２−ピリドン−１−イル、３−ピリドン−１−イル、１−イソインドリル、２−イソインドリル、１−インドリル、３−インドリル、１−テトラゾリル、２−テトラゾリル、５−テトラゾリル、２−ピリミジニル、４−ピリミジニル、５−ピリミジニル、２−プリニル、６−プリニル、７−プリニル、８−プリニル、９−プリニル、１−キサンチニル、３−キサンチニル、７−キサンチニル、８−キサンチニル、２−キナゾリニル、４−キナゾリニル、５−キナゾリニル、６−キナゾリニル、７−キナゾリニル、８−キナゾリニル、４(３Ｈ)−キナゾリノン−２−イル、４(３Ｈ)−キナゾリノン−３−イル、４(３Ｈ)−キナゾリノン−５−イル、４(３Ｈ)−キナゾリノン−６−イル、４(３Ｈ)−キナゾリノン−７−イル、４(３Ｈ)−キナゾリノン−８−イルなどが用いられる。
該「アルキル−カルボニル基」とは、例えばアセチル、プロピオニル、ブチリル、バレリルなどのＣ_1-10アルキル−カルボニル基などを示す。
該「アルケニル−カルボニル基」とは、例えばアクリロイルなどのＣ_2-10アルケニル−カルボニル基などを示す。
該「アルキニル−カルボニル基」とは、例えばプロピオロイルなどのＣ_2-10アルキニル−カルボニル基などを示す。
該「アリール−カルボニル基」とは、例えばベンゾイルなどのＣ_6-14アリールカルボニル基などを示す。
該「アシルアミノ基」とは、例えばホルミルアミノ、アセチルアミノ、プロピオニルアミノ、ブチリルアミノ、ベンゾイルアミノなどのＣ_1-10アシルアミノ基などを示す。
該「−ＣＯ−Ｑ」の「Ｑ」で表される「置換アミノ基」とは、例えばモノ−またはジ−Ｃ_1-6アルキルアミノ基（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノなど）、環状アミノ基（例えば、ピロリジノ、ピペリジノ、ピペラジノ、モルホリノなどの５ないし８員の環状アミノ基など）などを示す。
該「アシルオキシ基」とは、例えばホルミルオキシ、アセトキシ、プロピオニルオキシなどのＣ_1-10アシルオキシ基などを示す。
【００２０】
前記置換基「−Ｌ」は、さらにこれらの置換基の置換可能な位置にハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素など）、Ｃ_1-6アルキル基（例えば、メチル、エチル、プロピル、イソプロピルなど）、Ｃ_2-6アルケニル基（例えば、ビニル、アリルなど）、Ｃ_2-6アルキニル基（例えば、エチニル、プロパルギルなど）、Ｃ_3-6シクロアルキル基（例えば、シクロプロピル、シクロペンチル、シクロヘキシルなど）、カルボキシル基、ヒドロキシル基、シアノ基、ニトロ基、スルホ基、ホスホノ基、オキソ基、Ｃ_1-6アルコキシ基（例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシなど）、Ｃ_6-10アリールオキシ基（例えば、フェノキシなど）、Ｃ_7-14アラルキルオキシ基（例えば、ベンジルオキシなど）、メルカプト基、Ｃ_1-6アルキルチオ基（例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオなど）、Ｃ_6-10アリールチオ基（例えば、フェニルチオなど）、Ｃ_7-14アラルキルチオ基（例えば、ベンジルチオなど）、カルバモイル基、モノ−またはジ−Ｃ_1-6アルキルカルバモイル基（例えば、メチルカルバモイル、ジメチルカルバモイルなど）、アミノ基、モノ−またはジ−Ｃ_1-6アルキルアミノ基（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノなど）、環状アミノ基（例えば、ピロリジノ、ピペリジノ、ピペラジノ、モルホリノなど）、モノ−またはジ−Ｃ_7-14アラルキルアミノ基（例えば、ベンジルアミノなど）、Ｃ_6-10アリール基（例えば、フェニル、１−ナフチル、２−ナフチルなど）、Ｃ_7-14アラルキル基（例えば、ベンジルなど）、ホルミル基、Ｃ_1-6アルキル−カルボニル基（例えば、アセチル、プロピオニル、ブチリル、バレリルなど）、Ｃ_6-10アリール−カルボニル基（例えば、ベンゾイルなど）、Ｃ_1-6アルコキシ−カルボニル基（例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニルなど）、アシルオキシ基（例えば、ホルミルオキシ、アセトキシなど）および芳香族複素環または芳香族複素環チオ基（「芳香族複素環基は、例えば炭素以外に窒素原子、酸素および硫黄から選ばれたヘテロ原子を１ないし４個含む５ないし１０員の芳香族複素環基または縮合２環式芳香族炭化水素基などを示し、具体的には、２−チエニル、３−チエニル、２−ピリジル、３−ピリジル、４−ピリジル、２−フリル、３−フリル、２−キノリル、４−キノリル、８−キノリル、３−イソキノリル、４−イソキノリル、ピラジニル、２−ピリミジニル、３−ピロリル、１−イミダゾリル、２−イミダゾリル、１−ピラゾリル、２−チアゾリル、４−チアゾリル、５−チアゾリル、３−イソチアゾリル、４−イソチアゾリル、３−イソキオサゾリル、３−ピリダジニル、２−ピリドン−１−イル、３−ピリドン−１−イル、１−イソインドリル、２−イソインドリル、１−インドリル、３−インドリル、１−テトラゾリル、２−テトラゾリル、５−テトラゾリル、２−ピリミジニル、４−ピリミジニル、５−ピリミジニル、２−プリニル、６−プリニル、７−プリニル、８−プリニル、９−プリニル、１−キサンチニル、３−キサンチニル、７−キサンチニル、８−キサンチニル、２−キナゾリニル、４−キナゾリニル、５−キナゾリニル、６−キナゾリニル、７−キナゾリニル、８−キナゾリニル、４(３Ｈ)−キナゾリノン−２−イル、４(３Ｈ)−キナゾリノン−３−イル、４(３Ｈ)−キナゾリノン−５−イル、４(３Ｈ)−キナゾリノン−６−イル、４(３Ｈ)−キナゾリノン−７−イル、４(３Ｈ)−キナゾリノン−８−イルなど）などから選ばれた１ないし３個の置換基（−Ｍとする）を有していてもよい。前記の置換基（−Ｍ）はさらにその置換基上に前記のような置換基「−Ｍ」を有することによって置換基（−Ｍ−Ｍ）となっていてもよい。つまり「Ａ」は置換基：−Ｌ−Ｍ−Ｍを有していてもよい。
Ａがヒドロキシル基やメルカプト基を有する場合、それらの互変異性体であるケト型やチオン型も本発明の化合物に含まれる。
【００２１】
前記〔I〕式中、Ａｒ¹およびＡｒ²はそれぞれ置換されていてもよい環を示す。
用語「置換されていてもよい環」の「環」とは、例えば環状炭化水素、複素環などを示す。
該「環状炭化水素」としては、例えば炭素数６ないし１４の単環式あるいは縮合多環式炭化水素などが用いられ、具体的にはＣ_6-10芳香族炭化水素（例えば、ベンゼン、ナフタレンなど）、Ｃ_6-10シクロアルカン（例えば、シクロヘキサンなど）などが汎用され、特にベンゼンなどが好ましい。
該「複素環」としては、例えば炭素以外に窒素、酸素および硫黄から選ばれた１種または２種、好ましくは１個ないし４個のヘテロ原子を含む単環式複素環、さらに他の環（例えば、前記環状炭化水素または単環式複素環など）と縮合して形成される縮合２環式または３環式複素環を形成しているものも用いられる。該「単環式複素環」としては、例えば６員の単環式複素環（例えば、フラン、チオフェン、ピロール、ピリジン、ピラゾール、イミダゾール、オキサゾール、チアゾール、ピラジン、ピリミジン、ピリダジン、イソオキサゾール、イソチアゾール、トリアゾールなど）および５または６員の環状アミノ（例えば、ピロリジン、イミダゾリジン、ピラゾリジン、ピペリジン、ピペラジン、モルホリンなど）などが挙げられる。該「縮合２環式または３環式複素環」としては、例えばベンゾフラン、インドール、インダゾール、キノリン、ベンゾチアゾール、クマリン、イソキノリンなどが挙げられ、好ましくは、ピリジン、ピペリジン、ピペラジン、ピリミジン、モルホリンである。Ａr¹とＡr²は同一または異なっていてもよい。
【００２２】
該「置換されていてもよい環」の「環」が有していてもよい置換基としては、例えば前記Ａで表される「縮合ピリミジノン環または縮合ピリダジノン環」が有していてもよい置換基と同様のものなどが用いられる。これらの置換基は、環上の置換可能な位置に置換され、その置換基の数は１ないし５個、好ましくは１ないし３個である。ただし、その置換基の数が２個以上の場合は同一または異なっていてもよい。Ａr¹およびＡr²の置換基の数は合わせて５個以内のものが好ましい。Ａｒ²は、例えばハロゲン原子、Ｃ_1-10アルキル基、Ｃ_2-10アルケニル基、Ｃ_1-10アルコキシ基、Ｃ_6-14アリールオキシ基、Ｃ_7-16アラルキルオキシ基、Ｃ_1-10アルキルチオ基、カルバモイルオキシ基、モノ−またはジ−Ｃ_1-10アルキルカルバモイルオキシ基、ホスホノオキシ基、モノ−またはジ−Ｃ_1-10アルキルホスホノオキシ基、ニトロ基、シアノ基、ヒドロキシル基、アミノ基、モノ−またはジ−Ｃ_1-10アルキルアミノ基、環状アミノ基、カルボキシル基、メルカプト基、カルバモイル基、モノ−またはジ−Ｃ_1-10アルキルカルバモイル基、Ｃ_1-10アルコキシ−カルボニル基、Ｃ_6-14アリルオキシ−カルボニル基、Ｃ_7-16アラルキル基、Ｃ_6-14アリール基、ホルミル基、Ｃ_1-10アルキル−カルボニル基、Ｃ_6-14アリール−カルボニル基、Ｃ_1-10アシルアミノ基およびＣ_1-10アシルオキシ基から選ばれた１ないし５個の置換基を有する場合が好ましく、これらの置換基は１ないし３個のハロゲン原子、Ｃ_1-6アルキル基、カルボキシル基、ヒドロキシル基、オキソ基、Ｃ_1-6アルコキシ基、Ｃ_1-3アルキレンジオキシ基、Ｃ_6-10アリールオキシ基、Ｃ_7-14アラルキルオキシ基、メルカプト基、Ｃ_1-6アルキルチオ基、カルバモイル基、モノ−またはジ−Ｃ_1-6アルキルカルバモイル基、アミノ基、モノ−またはジ−Ｃ_1-6アルキルアミノ基、環状アミノ基、Ｃ_6-10アリール基、Ｃ_7-14アラルキル基、ホルミル基、Ｃ_1-6アルキル−カルボニル基、Ｃ_6-10アリール−カルボニル基、Ｃ_1-6アルコキシ−カルボニル基、Ｃ_1-6アシルオキシ基、芳香族複素環基または芳香族複素環チオ基、これらの置換基はさらに１ないし３個のハロゲン原子、Ｃ_1-6アルキル基、オキソ基、Ｃ_1-6アルコキシ基、アミノ基あるいはモノ−またはジ−Ｃ_1-6アルキルアミノ基を有していてもよい。
前記〔I〕式中、Ｚは２価の基を示す。該「２価の基」とは、例えば縮合ピリミジノンまたは縮合ピリダジノン環と環（Ａｒ¹）を炭素、窒素、酸素および硫黄などから選ばれた１ないし５個（好ましくは、１ないし３個）の原子で結ばれた基、例えば−ＮＨ−、−Ｏ−、−Ｓ−またはこれらの基を任意の位置に含んでいてもよい２価の脂肪族基（例えば、炭素数１ないし６個の直鎖状または分枝状の脂肪族基）などを示し、具体的には、例えば−ＣＨ₂−、−ＮＨ−、−Ｏ−、−Ｓ−、−ＣＨ₂ＣＨ₂−、−ＣＨ₂−ＮＨ−、−ＣＨ₂−Ｏ−、−ＣＨ₂−Ｓ−、−ＣＨ₂ＣＨ₂ＣＨ₂−、−ＮＨ−ＣＨ₂ＣＨ₂−、−ＣＨ₂−ＮＨ−ＣＨ₂−、−Ｏ−ＣＨ₂ＣＨ₂−、−ＣＨ₂−Ｏ−ＣＨ₂−、−Ｓ−ＣＨ₂ＣＨ₂−、−ＣＨ₂−Ｓ−ＣＨ₂−（これらの結合する向きは任意である）などが挙げられる。
【００２３】
該「２価の基」は、例えばＣ_1-6アルキル基（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチルなど）、Ｃ_2-6アルケニル基（例えば、ビニル、アリル、イソプロペニルなど）、Ｃ_2-6アルキニル基（例えば、プロパルギル、エチニルなど）、Ｃ_1-6アルコキシ基（例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシなど）、Ｃ_1-6アルキルチオ基（例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオなど）、Ｃ_1-6アシル基（例えば、ホルミル、アセチルなど）、アミノ基、ハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素など）、ヒドロキシル基、メルカプト基およびオキソ基などから選ばれた１ないし３個の置換基を有していてもよい。
Ｚで表される「２価の基」が連続した炭素を含む場合、それら炭素−炭素結合は不飽和結合（例えば２重結合）であってもよい。例えば、−ＣＨ＝ＣＨ−、−ＣＨ₂−ＣＨ＝ＣＨ−などが挙げられる。
【００２４】
前記〔I〕式中のＡ、Ａｒ¹、Ａｒ²およびＺの好ましい例示を以下に示す。
（１）Ａ：
（Ａ−１）「置換されていてもよいピリミジノン環」；用語「置換されていてもよいピリミジノン環」は前記と同意義を示す。
（Ａ−２）「置換されていてもよいピロロ〔２，３−ｄ〕ピリミジン−４−オン、キナゾリン−４−オン、ピリド〔１，２−ａ〕ピリミジン−４−オン、チアゾロ〔３，２−ａ〕ピリミジン−５−オン、ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オンまたはイミダゾ〔２，１−ｂ〕キナゾリン−５−オン」；用語「置換されていてもよい」は、前記「縮合ピリミジノン環」が有していてもよい置換基と同様のものなどが用いられる。
【００２５】
（Ａ−３）式
【化２９】
〔式中、Ａ¹およびＡ²はそれぞれ置換されていてもよい５ないし８員の同素または複素環；Ｒ¹およびＲ²はそれぞれ水素、ハロゲン、Ｃ_1-6アルキル基、ハロ−Ｃ_1-6アルキル基、ヒドロキシル基、Ｃ_1-6アルコキシ基、ハロ−Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロ−Ｃ_1-6アルキルチオ基、好ましくは水素またはＣ_1-6アルキル基を示す。〕で表される環；用語「５ないし８員の同素または複素環」は、炭素以外に窒素、酸素および硫黄から選ばれた１ないし４個のヘテロ原子を含んでいてもよい環を示し、具体的にはシクロペンタン、シクロヘキサン、シクロヘプタン、ベンゼンあるいはイミダゾール、ピリジン、チアジン、チアゾール、オキサゾール、チオフェン、ピロール、ピラゾール、ピラジン、ピリミジン（これらは部分的に還元されていてもよい）、またこれらは前記Ｒ¹およびＲ²で表されるような置換基を１ないし３個有していてもよい、用語「ハロゲン」は、例えばフッ素、塩素、臭素、ヨウ素などを示し、用語「Ｃ_1-6アルキル基」は、例えばメチル、エチル、プロピル、イソプロピルなどを示し、用語「ハロ−Ｃ_1-6アルキル基」は、例えばトリフルオロメチルなどを示し、用語「Ｃ_1-6アルコキシ基」は、例えばメトキシ、エトキシ、プロポキシ、イソプロポキシなどを示し、用語「ハロ−Ｃ_1-6アルコキシ基」は、例えばトリフルオロメトキシなどを示し、用語「Ｃ_1-6アルキルチオ基」は、例えばメチルチオ、エチルチオ、プロピルチオ、イソプロピルチオなどを示し、用語「ハロ−Ｃ_1-6アルキルチオ基」は、例えばトリフルオロメチルチオなどを示す。
【００２６】
（Ａ−４）式
【化３０】
〔式中の記号は前記(A-3)と同意義を示す。〕で表される環。
【００２７】
（Ａ−５）式
【化３１】
〔式中の記号は前記(A-3)と同意義を示す。〕で表される環。
【００２８】
（Ａ−６）式
【化３２】
〔式中、ｎは０ないし３の整数、その他の記号は前記(A-3)と同意義を示す。〕で表される環。
【００２９】
（Ａ−７）式
【化３３】
〔式中、ｎは０ないし３の整数、その他の記号は前記(A-3)と同意義を示す。〕で表される環。
【００３０】
（Ａ−８）式
【化３４】
〔式中、Ｒ¹は前記(A-3)と同意義を示す。〕で表される環。
【００３１】
（２）Ｚ：
（Ｂ−１）−ＮＨ−、−Ｏ−または−Ｓ−を含んでいてもよい２価のＣ_1-6脂肪族炭化水素基（Ｚ^aと表すこともある）；用語「２価のＣ_1-6脂肪族炭化水素基」としては、例えばＣ_1-6アルキレン基（例えば、メチレン、エチレン、トリメチレン、テトラメチレンなど）またはＣ_2-6アルケニレン基（例えば、ビニレン、プロペニレンなど）などが用いられる。
（Ｂ−２）−Ｏ−または−Ｓ−を含んでいてもよい２価のＣ_1-6脂肪族炭化水素基；用語「２価のＣ_1-6脂肪族炭化水素基」は、例えば前記と同様のものなどが用いられる。
（Ｂ−３）−Ｏ−または−Ｓ−を含んでいてもよいＣ_1-6アルキレン基；用語「Ｃ_1-6アルキレン基」としては、例えば、メチレン、エチレン、トリメチレン、テトラメチレンなどが用いられ、メチレンの場合が汎用される。
（Ｂ−４）−Ｏ−を含んでいてもよいＣ_1-6アルキレン基；用語「Ｃ_1-6アルキレン基」としては、例えば、メチレン、エチレン、トリメチレン、テトラメチレンなどが用いられ、メチレンの場合が汎用される。
（Ｂ−５）Ｃ_2-6アルケニレン基；用語「Ｃ_2-6アルケニレン基」としては、例えばビニレンなどが用いられる。
（Ｂ−６）−Ｓ−ＣＨ₂−、−Ｏ−ＣＨ₂−または−ＣＨ₂−。
（Ｂ−７）−Ｏ−ＣＨ₂−または−ＣＨ₂−。
【００３２】
（３）Ａｒ¹：
（Ｃ−１）置換されていてもよい芳香族環；用語「芳香族環」は、例えばＣ_6-10芳香族炭化水素（例えば、ベンゼン、ナフタレンなど）またはピリジンなどが用いられる。用語「置換されていてもよい」は、前記Ａが有していてもよい置換基と同様のものなどが用いられる。
（Ｃ−２）パラ置換ベンゼン。
（４）Ａｒ²：
（Ｄ−１）置換されていてもよい芳香環；用語「芳香環」は、例えばＣ_6-10芳香族炭化水素（例えば、ベンゼン、ナフタレンなど）、ピリジン、インドール、ピロール、イミダゾール、チオフェン、ピラジン、ピリミジン、プリン、キノリン、イソキノリンなどが用いられる。用語「置換されていてもよい」は、例えば前記Ａが有していてもよい置換基と同様のものなどが用いられる。
（Ｄ−２）置換されていてもよいフェニル、ピリジル、インドリル、ピロリル、チエニル、ピペリジノ、ピペラジノまたはモルホリノ基；用語「置換されていてもよい」は、例えば前記Ａが有していてもよい置換基と同様のものなどが用いられる。
（Ｄ−３）置換されていてもよいフェニル基；用語「置換されていてもよい」は、例えば前記Ａが有していてもよい置換基と同様のものなどが用いられる。
（Ｄ−４）置換されていてもよいピペリジノ、ピペラジノまたはモルホリノ基；用語「置換されていてもよい」は、例えば前記Ａが有していてもよい置換基と同様のものなどが用いられる。
（Ｄ−５）置換されていてもよいピペリジノまたはピペラジノ基；用語「置換されていてもよい」は、例えば前記Ａが有していてもよい置換基と同様のものなどが用いられる。
【００３３】
（Ｄ−６）Ｃ_1-6アルキル、ハロ−Ｃ_1-6アルキル、Ｃ_1-6アルコキシ、ハロ−Ｃ_1-6アルコキシ、Ｃ_1-6アルキルチオ、ハロ−Ｃ_1-6アルキルチオ、ハロゲン、アミノ、モノ−またはジ−Ｃ_1-6アルキルアミノ、Ｃ_1-6アシルアミノ、Ｃ_1-6アルキル−カルボニル、Ｃ_6-10アリール−カルボニル、Ｃ_7-14アラルキル−カルボニル、Ｃ_1-6アルコキシ−カルボニル、Ｃ_1-6アシルオキシ、カルバモイルオキシ、モノ−またはジ−Ｃ_1-6アルキルカルバモイルオキシ、シアノ、ニトロ、カルバモイルおよびモノ−またはジ−Ｃ_1-6アルキルカルバモイルから選ばれた１ないし５個の置換基で置換されていてもよいフェニル基；用語「Ｃ_1-6アルキル」は、例えばメチル、エチル、プロピル、イソプロピルなどを示し、用語「ハロ−Ｃ_1-6アルキル」は、例えばトリフルオロメチルなどを示し、用語「Ｃ_1-6アルコキシ」は、例えばメトキシ、エトキシ、プロポキシ、イソプロポキシなどを示し、用語「ハロ−Ｃ_1-6アルコキシ」は、例えばトリフルオロメトキシなどを示し、用語「Ｃ_1-6アルキルチオ」は、例えばメチルチオ、エチルチオ、プロピルチオ、イソプロピルチオなどを示し、用語「ハロ−Ｃ_1-6アルキルチオ」は、例えばトリフルオロメチルチオなどを示し、用語「ハロゲン」は、例えばフッ素、塩素、臭素、ヨウ素などを示し、用語「モノ−またはジ−Ｃ_1-6アルキルアミノ」は、例えばメチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノなどを示し、用語「Ｃ_1-6アシルアミノ」は、例えばホルミルアミノ、アセチルアミノなどを示し、用語「Ｃ_1-6アルキル−カルボニル」は、例えばアセチル、プロピオニルなどを示し、用語「Ｃ_6-10アリール−カルボニル」は、例えばベンゾイルなどを示し、用語「Ｃ_7-14アラルキル−カルボニル」は、例えばベンジルカルボニルなどを示し、用語「Ｃ_1-6アルコキシ−カルボニル」は、例えばメトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニルなどを示し、用語「Ｃ_1-6アシルオキシ」は、例えばホルミルオキシ、アセトキシなどを示し、用語「モノ−またはジ−Ｃ_1-6アルキルカルバモイルオキシ」は、例えばメチルカルバモイルオキシ、ジメチルカルバモイルオキシなどを示し、用語「モノ−またはジ−Ｃ_1-6アルキルカルバモイル」は、例えばメチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイルなどを示す。
【００３４】
（Ｄ−７）式
【化３５】
〔式中、Ｒ^aは前記Ａが有していてもよい置換基と同意義を示す。〕で表される基；Ｒ^aの好ましい例としては、例えばハロゲン（例えば、フッ素、塩素、臭素、ヨウ素など）、Ｃ_1-6アルキル基（例えば、メチル、エチル、プロピル、イソプロピルなど）、ハロ−Ｃ_1-6アルキル基（例えば、トリフルオロメチルなど）、Ｃ_1-6アルコキシ基（例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシなど）またはハロ−Ｃ_1-6アルコキシ基（例えば、トリフルオロメトキシなど）などが挙げられる。
【００３５】
（Ｄ−８）式
【化３６】
〔式中、Ｒ^aは前記と同意義を示す。〕で表される基。
【００３６】
（Ｄ−９）式
【化３７】
〔式中、Ａｒ³は環；Ｗは結合手、カルボニルまたは−ＮＲ³−、−Ｏ−または−Ｓ−を含んでいてもよい２価のＣ_1-6脂肪族炭化水素基、Ｒ³は水素またはＣ_1-6アルキル基；Ｔは置換されていてもよい第１ないし第３級アミノ基を示す。〕で表される基；Ａｒ³で表される用語「環」は、前記Ａｒ¹およびＡｒ²と同様のものなどが用いられる。Ａｒ³の好ましいものとしては、例えばピペリジノ、ピペラジノ、フェニルまたはピリジルであり、より好ましいものとして式
【化３８】
などが挙げられる。用語「２価のＣ_1-6脂肪族炭化水素基」は、前記(B-1)で記載されるものなどが用いられ、好ましくは−ＣＨ₂−、−ＣＨ₂ＣＨ₂−、−Ｏ−ＣＨ₂ＣＨ₂−などが汎用される。用語「第１ないし第３級アミノ基」は、例えばモノ−またはジ−Ｃ_1-6アルキルアミノ（例えば、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノなど）、モノ−またはジ−Ｃ_6-10アリールアミノ（例えば、フェニルアミノ、ジフェニルアミノなど）、環状アミノ（例えば、ピペリジノ、ピペラジノ、モルホリノなど）などを示し、好ましくは環状アミノ（例えば、ピペリジノ、ピペラジノなど）などが汎用される。該「第１ないし第３級アミノ基」は、前記−Ｍのような置換基を１ないし３個有していてもよい。
【００３７】
好ましい組み合わせを以下に示す（／は組み合わせの区切りを示す）。
（Ａ−１），（Ｂ−１），（Ｃ−１），（Ｄ−１）／（Ａ−２），（Ｂ−１），（Ｃ−２），（Ｄ−１）／（Ａ−３），（Ｂ−１），（Ｃ−２），（Ｄ−１）／（Ａ−４），（Ｂ−１），（Ｃ−２），（Ｄ−１）／（Ａ−５），（Ｂ−１），（Ｃ−２），（Ｄ−１）／（Ａ−６），（Ｂ−１），（Ｃ−２），（Ｄ−１）／（Ａ−７），（Ｂ−１），（Ｃ−２），（Ｄ−１）／（Ａ−２），（Ｂ−２），（Ｃ−２），（Ｄ−１）／（Ａ−３），（Ｂ−２），（Ｃ−２），（Ｄ−１）／（Ａ−４），（Ｂ−２），（Ｃ−２），（Ｄ−１）／（Ａ−５），（Ｂ−２），（Ｃ−２），（Ｄ−１）／（Ａ−６），（Ｂ−２），（Ｃ−２），（Ｄ−１）／（Ａ−７），（Ｂ−２），（Ｃ−２），（Ｄ−１）／（Ａ−２），（Ｂ−３），（Ｃ−２），（Ｄ−１）／（Ａ−３），（Ｂ−３），（Ｃ−２），（Ｄ−１）／（Ａ−４），（Ｂ−３），（Ｃ−２），（Ｄ−１）／（Ａ−５），（Ｂ−３），（Ｃ−２），（Ｄ−１）／（Ａ−６），（Ｂ−３），（Ｃ−２），（Ｄ−１）／（Ａ−７），（Ｂ−３），（Ｃ−２），（Ｄ−１）／（Ａ−２），（Ｂ−４），（Ｃ−２），（Ｄ−１）／（Ａ−３），（Ｂ−４），（Ｃ−２），（Ｄ−１）／（Ａ−４），（Ｂ−４），（Ｃ−２），（Ｄ−１）／（Ａ−５），（Ｂ−４），（Ｃ−２），（Ｄ−１）／（Ａ−６），（Ｂ−４），（Ｃ−２），（Ｄ−１）／（Ａ−７），（Ｂ−４），（Ｃ−２），（Ｄ−１）／（Ａ−２），（Ｂ−５），（Ｃ−２），（Ｄ−１）／（Ａ−３），（Ｂ−５），（Ｃ−２），（Ｄ−１）／（Ａ−４），（Ｂ−５），（Ｃ−２），（Ｄ−１）／（Ａ−５），（Ｂ−５），（Ｃ−２），（Ｄ−１）／（Ａ−６），（Ｂ−５），（Ｃ−２），（Ｄ−１）／（Ａ−７），（Ｂ−５），（Ｃ−２），（Ｄ−１）／（Ａ−３），（Ｂ−３），（Ｃ−２），（Ｄ−２）／（Ａ−４），（Ｂ−３），（Ｃ−２），（Ｄ−２）／（Ａ−４），（Ｂ−３），（Ｃ−２），（Ｄ−２）／（Ａ−５），（Ｂ−３），（Ｃ−２），（Ｄ−２）／（Ａ−６），（Ｂ−３），（Ｃ−２），（Ｄ−２）／（Ａ−７），（Ｂ−３），（Ｃ−２），（Ｄ−２）／（Ａ−３），（Ｂ−５），（Ｃ−２），（Ｄ−２）／（Ａ−４），（Ｂ−５），（Ｃ−２），（Ｄ−２）／（Ａ−５），（Ｂ−５），（Ｃ−２），（Ｄ−２）／（Ａ−６），（Ｂ−５），（Ｃ−２），（Ｄ−２）／（Ａ−７），（Ｂ−５），（Ｃ−２），（Ｄ−２）／（Ａ−３），（Ｂ−３），（Ｃ−２），（Ｄ−３）／（Ａ−３），（Ｂ−３），（Ｃ−２），（Ｄ−４）／（Ａ−４），（Ｂ−３），（Ｃ−２），（Ｄ−３）／（Ａ−４），（Ｂ−３），（Ｃ−２），（Ｄ−４）／（Ａ−５），（Ｂ−３），（Ｃ−２），（Ｄ−３）／（Ａ−６），（Ｂ−３），（Ｃ−２），（Ｄ−６）／（Ａ−７），（Ｂ−３），（Ｃ−２），（Ｄ−６）／（Ａ−６），（Ｂ−４），（Ｃ−２），（Ｄ−６）／（Ａ−７），（Ｂ−４），（Ｃ−２），（Ｄ−６）／（Ａ−６），（Ｂ−６），（Ｃ−２），（Ｄ−５）／（Ａ−７），（Ｂ−６），（Ｃ−２），（Ｄ−５）／（Ａ−６），（Ｂ−７），（Ｃ−２），（Ｄ−６）／（Ａ−７），（Ｂ−７），（Ｃ−２），（Ｄ−６）／（Ａ−６），（Ｂ−７），（Ｃ−２），（Ｄ−７）／（Ａ−７），（Ｂ−７），（Ｃ−２），（Ｄ−７）／（Ａ−６），（Ｂ−７），（Ｃ−２），（Ｄ−８）／（Ａ−７），（Ｂ−７），（Ｃ−２），（Ｄ−８）／（Ａ−１），（Ｂ−１），（Ｃ−１），（Ｄ−９）／（Ａ−２），（Ｂ−１），（Ｃ−２），（Ｄ−９）／（Ａ−３），（Ｂ−１），（Ｃ−２），（Ｄ−９）／（Ａ−４），（Ｂ−１），（Ｃ−２），（Ｄ−９）／（Ａ−５），（Ｂ−１），（Ｃ−２），（Ｄ−９）／（Ａ−６），（Ｂ−１），（Ｃ−２），（Ｄ−９）／（Ａ−７），（Ｂ−１），（Ｃ−２），（Ｄ−９）／（Ａ−８），（Ｂ−１），（Ｃ−２），（Ｄ−９）／（Ａ−３），（Ｂ−２），（Ｃ−２），（Ｄ−９）／（Ａ−４），（Ｂ−２），（Ｃ−２），（Ｄ−９）／（Ａ−５），（Ｂ−２），（Ｃ−２），（Ｄ−９）／（Ａ−６），（Ｂ−２），（Ｃ−２），（Ｄ−９）／（Ａ−７），（Ｂ−２），（Ｃ−２），（Ｄ−９）／（Ａ−８），（Ｂ−２），（Ｃ−２），（Ｄ−９）／（Ａ−３），（Ｂ−４），（Ｃ−２），（Ｄ−９）／（Ａ−４），（Ｂ−４），（Ｃ−２），（Ｄ−９）／（Ａ−５），（Ｂ−４），（Ｃ−２），（Ｄ−９）／（Ａ−６），（Ｂ−４），（Ｃ−２），（Ｄ−９）／（Ａ−７），（Ｂ−４），（Ｃ−２），（Ｄ−９）／（Ａ−８），（Ｂ−４），（Ｃ−２），（Ｄ−９）／（Ａ−３），（Ｂ−６），（Ｃ−２），（Ｄ−９）／（Ａ−４），（Ｂ−６），（Ｃ−２），（Ｄ−９）／（Ａ−５），（Ｂ−６），（Ｃ−２），（Ｄ−９）／（Ａ−６），（Ｂ−６），（Ｃ−２），（Ｄ−９）／（Ａ−７），（Ｂ−６），（Ｃ−２），（Ｄ−９）／（Ａ−８），（Ｂ−６），（Ｃ−２），（Ｄ−９）／（Ａ−３），（Ｂ−７），（Ｃ−２），（Ｄ−９）／（Ａ−４），（Ｂ−７），（Ｃ−２），（Ｄ−９）／（Ａ−５），（Ｂ−７），（Ｃ−２），（Ｄ−９）／（Ａ−６），（Ｂ−７），（Ｃ−２），（Ｄ−９）／（Ａ−７），（Ｂ−７），（Ｃ−２），（Ｄ−９）／（Ａ−８），（Ｂ−７），（Ｃ−２），（Ｄ−９）などが挙げられる。
化合物〔I〕またはその塩の中でさらに好ましい化合物として、下記の化合物などが挙げられる。
【００３８】
（１）一般式：Ｂ−Ｚ−Ａｒ¹−ＣＯ−Ａｒ² 〔I−a〕
〔式中、Ｂは置換されていてもよい(1)ピロロ〔２,３−d〕ピリミジン−４−オン、(2)ピロロ〔３,２−d〕ピリミジン−４−オン、(3)ピロロ〔３,４−d〕ピリミジン−４−オン、(4)ピラゾロ〔３,４−d〕ピリミジン−４−オン、(5)ピラゾロ〔４,３−d〕ピリミジン−７−オン、(6)６−オキソプリン、(7)チエノ〔２,３−d〕ピリミジン−４−オン、(8)チエノ〔３,４−d〕ピリミジン−４−オン、(9)チエノ〔３,２−d〕ピリミジン−７−オン、(10)フロ〔２,３−d〕ピリミジン−４−オン、(11)フロ〔３,４−d〕ピリミジン−４−オン、(12)フロ〔３,２−d〕ピリミジン−７−オン、(13)イソキサゾロ〔５,４−d〕ピリミジン−４−オン、(14)イソキサゾロ〔４,５−d〕ピリミジン−７−オン、(15)オキサゾロ〔５,４−d〕ピリミジン−４−オン、(16)オキサゾロ〔４,５−d〕ピリミジン−７−オン、(17)チアゾロ〔５,４−d〕ピリミジン−４−オン、(18)チアゾロ〔４,５−d〕ピリミジン−７−オン、(19)イソチアゾロ〔５,４−d〕ピリミジン−４−オン、(20)イソチアゾロ〔４,５−d〕ピリミジン−７−オン、(21)トリアゾロ〔４,５−d〕ピリミジン−４−オン、(22)１,２,４−トリアゾロ〔１,５−a〕ピリミジン−７−オン、(23)ジヒドロシクロペンタ〔d〕ピリミジン−４−オン、(24)５Ｈまたは７Ｈ−シクロペンタ〔d〕ピリミジン−４−オン、(25)ピリド〔２,３−d〕ピリミジン−４−オン、(26)ピリド〔３,２−d〕ピリミジン−４−オン、(27)ピリド〔４,３−d〕ピリミジン−４−オン、(28)ピリド〔３,４−d〕ピリミジン−４−オン、(29)プテリジン−４−オン、(30)ピロロ〔１，２−a〕ピリミジン−４−オン、(31)ピリミド〔３，４−a〕ピリミジン−４−オン、(32)ピリミド〔４，５−d〕ピリミジン−４−オン、(33)ピリミド〔５，４−d〕ピリミジン−４−オン、(34)ピリダジノ〔２，３−a〕ピリミジン−４−オン、(35)ピリダジノ〔４，３−d〕ピリミジン−４−オン、(36)ピリダジノ〔３，４−d〕ピリミジン−４−オン、(37)キサンチン、(38)尿酸、(39)ピロロ〔３，２−d〕ピリミジン−２，４−ジオン、(40)ピロロ〔２，３−d〕ピリミジン−２，４−ジオン、(41)ピロロ〔３，４−d〕ピリミジン−２，４−ジオン、(42)ピリダジノ〔４,５−b〕−１,５−オキサゼピン−９（８Ｈ）−オン、(43)ピリダジノ〔４,５−b〕−１,４−オキサジン−８（７Ｈ）−オン、(44)ピロロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン、(45)ピロロ〔２，３−d〕ピリダジン−７（６Ｈ）−オン、(46)ピロロ〔２,３−d〕ピリダジン−４（５Ｈ）−オン、(47)イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン、(48)イミダゾ〔４,５−c〕ピリダジン−６（５Ｈ）−オン、(49)ピラゾロ〔４,３−d〕ピリダジン−４（５Ｈ）−オン、(50)ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン、(51)トリアゾロ〔４,５−d〕ピリダジン−４（５Ｈ）−オン、(52)ピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オンまたは(53)チアゾロ〔４，５−d〕ピリダジン−７（６Ｈ）−オン；その他の記号は前記と同意義を示す。〕で表される化合物またはその塩。
Ｂが有していてもよい置換基としては、例えばＡが有していてもよい置換基と同様のものなどが用いられる。
【００３９】
（２）一般式：Ｄ−Ａｌｋ−Ｅ−Ａｒ¹−ＣＯ−Ａｒ² 〔I−b〕
〔式中、Ｄは置換されていてもよい(1)キナゾリン−５−オン、(2)ピリド〔１，２−a〕ピリミジン−４−オン、(3)イミダゾ〔１，２−a〕ピリミジン−５−オン、(4)チアゾロ〔３，２−a〕ピリミジン−５−オン、(5)オキサゾロ〔３，２−a〕ピリミジン−５−オンまたは(6)ピリド〔１，２−a〕ピリミジン−４−オン；
ＡｌｋはＣ_1-3アルキレン基（例えば、−ＣＨ₂−、−ＣＨ₂ＣＨ₂−など）；
Ｅは結合手、−Ｓ−、−Ｏ−、−ＮＲ−、−Ｓ−ＣＨ₂−、−Ｏ−ＣＨ₂−または−ＮＲ−ＣＨ₂−〔Ｒは水素原子、Ｃ_1-6アルキル基（例えば、メチル、エチル、プロピル、イソプロピルなど）またはＣ_2-6アルケニル基（例えば、ビニル、アリエウなど）を示す。〕；その他の記号は前記と同意義を示す。〕で表される化合物またはその塩。
Ｄが有していてもよい置換基としては、例えばＡが有していてもよい置換基と同様のものなどが用いられる。
（３）置換されていてもよいイミダゾ〔１，２−a〕ピリミジン−５−オンの１位に−Ｚ−Ａｒ¹−ＣＯ−Ａｒ²を有する化合物またはその塩。
イミダゾ〔１，２−a〕ピリミジン−５−オンが有していてもよい置換基としては、Ａが有していてもよい置換基と同様のものなどが用いられる。Ｚ、Ａｒ¹、Ａｒ²は前記と同意義を示す。
化合物〔I〕またはその塩は、例えば以下に示される方法などによって製造される。
【００４０】
〔反応スキーム〕
（１式）
ＨＺ−Ａr¹ ＋Ｘ−ＣＯ−Ａr² → ＨＺ−Ａr¹−ＣＯ−Ａr²
ＨＺ−Ａr¹−ＣＯ−Ｘ＋Ａr² → ＨＺ−Ａr¹−ＣＯ−Ａr²
（２式）
Ｙ−Ａr¹ ＋Ｘ−ＣＯ−Ａr² → Ｙ−Ａr¹−ＣＯ−Ａr²
Ｙ−Ａr¹−ＣＯ−Ｘ＋Ａr² → Ｙ−Ａr¹−ＣＯ−Ａr²
（３式）
Ａ−Ｙ^a ＋Ｙ−Ａr¹−ＣＯ−Ａr² → Ａ−Ｚ−Ａr¹−ＣＯ−Ａr²
（４式）
Ａ＋Ｘ−Ｚ−Ａr¹−ＣＯ−Ａｒ → Ａ−Ｚ−Ａr¹−ＣＯ−Ａr²
Ａ−Ｘ＋ＨＺ−Ａr¹−ＣＯ−Ａr² → Ａ−Ｚ−Ａr¹−ＣＯ−Ａr²
（５式）
Ａ^a ＋Ａ^b−Ｚ−Ａr¹−ＣＯ−Ａr² → Ａ−Ｚ−Ａr¹−ＣＯ−Ａr²
（６式）
Ａ−Ｚ−Ａr¹ ＋ＸＣＯ−Ａr² → Ａ−Ｚ−Ａr¹−ＣＯ−Ａr²
〔反応スキーム中、−ＣＯ−Ｘはカルボキシル基の反応性誘導体、ＹおよびＹ^aは両者が反応してＺで表わされる２価の基、Ｘ−Ｚ−はＺの反応性誘導体、Ａ^aおよびＡ^bは両者が反応してＡで表される縮合ピリミジノンまたは縮合ピリダジノン環を示す。〕
【００４１】
前記（１式）において、−ＣＯ−Ｘで表されるカルボキシル基の反応性誘導体としては、例えば酸ハロゲン化物（例えば、酸クロリド、酸ブロミドなど）、酸無水物（Ａr²ＣＯＯＨの無水物やギ酸などとの混合酸無水物など）が挙げられる。反応は通常ルイス酸（例えば、塩化アルミニウム、臭化アルミニウム、塩化スズ、塩化アンチモン、塩化チタン、三弗化ホウ素など）の存在下で行われる。この時用いる溶媒は、反応に不活性なものなら特に限定されないが、例えば二硫化炭素やハロゲン化炭化水素などが汎用される。ＨＺ−Ａr¹やＡｒ²が液体の場合、ＨＺ−Ａr¹またはＡｒ²をそのまま溶媒として用いてもよい。反応温度は０℃〜溶媒の沸点の範囲であるが、２０〜８０℃が一般的である。反応時間は１〜１２時間程度である。用いる触媒の量は反応基質により異なるが、用いるカルボキシル基の反応性誘導体の１〜５倍である。前記（２式）も（１式）と同様の条件で進行する。前記（２式）および（３式）において、ＹおよびＹ^aで表される基は、炭素−炭素結合生成反応、窒素−炭素結合生成反応、酸素−炭素結合生成反応、硫黄−炭素結合生成反応などで、Ｚで表される２価の基を生成する基である。ＹやＹ^aからＺで表される２価の基を生成する反応例としては、例えばウィテッヒ反応、グリニヤール反応、アルドール反応、クライゼン反応、遷移金属を用いた炭素−炭素結合生成反応、アミノ基のアルキル化またはアリール化による窒素−炭素結合生成反応、アルコールのＯ−アルキル化による酸素−炭素結合生成反応、メルカプタンのＳ−アルキル化による硫黄−炭素結合生成反応などが挙げられる。アミノ基、アルコールおよびメルカプタンのアルキル化は、通常いづれも塩基の存在下で有利に進行する。用いられる塩基としては、例えば水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、水素化ナトリウム、ナトリウムメトキシド、ナトリウムエトキシドなどが挙げられる。この時用いる溶媒は、アミノ基、メルカプタンのアルキル化の場合は、例えばアルコール類（例えば、メタノール、エタノール、プロパノールなど）、アミド類（例えば、ジメチルホルムアミド、ジメチルアセトアミド、１−メチル−２−ピロリドンなど）、ジメチルスルホキシドなどが一般的である。アルコールのアルキル化には、アミド類、ジメチルスルホキシドが汎用される。これらの反応は、０℃〜溶媒の沸点の範囲、好ましくは室温〜溶媒の沸点で進行し、１〜１０時間、通常５時間程度で反応は終了する。また、Ｙ、Ｙ^aの一方がアミノ基で他方がカルボン酸またはその誘導体の時は、アミド結合の生成によりＺを生成してもよい。この時用いられる方法は、通常のアミド結合生成反応である。前記（４式）はＡで表される縮合ピリミジノン、縮合ピリダジノン環がアミノ基を有する場合、アミノ基にＺを結合させる工程を示す。Ｘ−Ｚ−で表されるＺの反応性誘導体としては、例えばＸがハロゲン（例えば、塩素、臭素、ヨウ素など）、アルキルまたはアリールスルホニルオキシ基（例えば、メタンスルホニルオキシ、パラトルエンスルホニルオキシなど）などが挙げられる。反応は通常、塩基の存在下で行われる。塩基としては、例えば水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、水素化ナトリウム、ナトリウムメトキシド、ナトリウムエトキシドなどが用いられる。この時用いる溶媒は、反応に不活性なものであればよく、例えばメタノール、エタノール、ジメチルスルホキシド、ジメチルフォルムアミド、ジメチルアセトアミドなどが汎用される。反応温度は、０℃〜溶媒の沸点で、反応は１〜１０時間、通常５時間程度で終了する。前記（５式）はＡで表される縮合ピリミジノン、縮合ピリダジノン環を形成する段階で、これらの環の前駆物質Ａ^aまたはＡ^bが既に−Ｚ−Ａr¹−ＣＯ−Ａr²を有している場合を示す。なお、前記（６式）に示した様に、Ａ−Ｚ−Ａr¹の部分を合成した後に、−ＣＯ−Ａr²で表される部分を導入してもよい。
【００４２】
本発明の原料化合物、製造中間体は、塩を形成していてもよく、製造過程においては特に限定されないが、例えば無機酸（例えば、塩酸、硫酸、リン酸など）、有機酸（例えば、酢酸、プロピオン酸、クエン酸、酒石酸、りんご酸、蓚酸など）、アルカリ金属（例えば、ナトリウム、カリウムなど）、アルカリ土類金属（例えば、カルシウム、マグネシウムなど）、有機塩基（例えば、トリエチルアミン、ピペリジンなど）などが用いられる。
また、前記本発明の各反応および原料化合物合成の各反応において、原料化合物が置換基としてアミノ基、カルボキシル基、ヒドロキシル基を有する場合、これらの基にペプチド化学などで一般的に用いられるような保護基が導入されていてもよく、反応後に必要に応じて保護基を除去することにより目的化合物を得ることができる。
アミノ基の保護基としては、例えばＣ_1-6アルキル−カルボニル基（例えば、ホルミル、アセチル、エチルカルボニルなど）、ベンジル基、tert−ブチルオキシカルボニル基、ベンジルオキシカルボニル基、９−フルオレニルメチルオキシカルボニル基、アリルオキシカルボニル基、フェニルカルボニル基、Ｃ_1-6アルキルオキシカルボニル基（例えば、メトキシカルボニル、エトキシカルボニルなど）、Ｃ_7-10アラルキル−カルボニル基（例えば、ベンジルカルボニルなど）、トリチル基、フタロイル基、Ｎ，Ｎ−ジメチルアミノメチレン基などが用いられる。これらの基は、１ないし３個のハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素など）、ニトロ基などで置換されていてもよい。
【００４３】
カルボキシル基の保護基としては、例えばＣ_1-6アルキル基（例えば、メチル、エチル、ｎ−プロピル、イソプロピル、ブチル、tert−ブチルなど）、フェニル基、シリル基、ベンジル基、アリル基などが用いられる。これらの基は、１ないし３個のハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素など）、ニトロ基などで置換されていてもよい。
ヒドロキシル基の保護基としては、例えばメトキシメチル基、アリル基、tert−ブチル基、Ｃ_7-10アラルキル基（例えば、ベンジルなど）、Ｃ_1-6アルキル−カルボニル基（例えば、ホルミル、アセチル、エチルカルボニルなど）、ベンゾイル基、Ｃ_7-10アラルキル−カルボニル基（例えば、ベンジルカルボニルなど）、ピラニル基、フラニル基、トリアルキルシリル基などが用いられる。これらの基は、１ないし３個のハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素など）、Ｃ_1-6アルキル基（例えば、メチル、エチル、ｎ−プロピルなど）、フェニル基、Ｃ_7-10アラルキル基（例えば、ベンジルなど）、ニトロ基などで置換されていてもよい。
また、これらの保護基の除去方法としては、それ自体公知またはそれに準じる方法が用いられるが、例えば酸、塩基、還元、紫外光、ヒドラジン、フェニルヒドラジン、Ｎ−メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウムなどを使用する方法などが用いられる。
【００４４】
前記反応によって、目的物が遊離の状態で得られる場合には、常法に従って塩に変換してもよく、また塩として得られる場合には、常法に従って遊離体または他の塩に変換することもできる。かくして得られる化合物〔I〕またはその塩は、公知の手段例えば転溶、濃縮、溶媒抽出、分溜、結晶化、再結晶、クロマトグラフィーなどにより反応溶液から単離、精製することができる。
なお、化合物〔I〕またはその塩がジアステレオマー、コンフォーマーなどとして存在する場合には、所望により、前記分離、精製手段によりそれぞれを単離することができる。また、化合物〔I〕またはその塩がラセミ体である場合には、通常の光学分割手段によりｄ体、ｌ体に分離することができる。
化合物〔I〕が、塩基性基を含む場合、自体公知の方法により、酸付加塩、とりわけ薬理学的に許容される酸付加塩として得ることができる。このような酸としては、例えば無機酸（例えば、塩酸、硫酸、リン酸など）あるいは有機酸（例えば、酢酸、プロピオン酸、クエン酸、酒石酸、りんご酸、蓚酸など）などが挙げられる。化合物〔I〕が酸性基を有する場合、塩基との塩、とりわけ薬理学的に許容される塩基との塩とすることができる。このような塩基としては、アルカリ金属（例えば、ナトリウム、カリウムなど）、アルカリ土類金属（例えば、カルシウム、マグネシウムなど）、有機塩基（例えば、トリエチルアミン、ピペリジンなど）が挙げられる。
【００４５】
化合物〔I〕またはその塩は、優れた抗腫瘍作用を有しておりかつ毒性が低く、副作用も少ないので、哺乳動物（例えば、ヒト、ウシ、ウマ、イヌ、ネコ、サル、マウス、ラットなど）に対して、例えば前立腺癌、すい臓癌、肺癌などの固形癌の原発癌に対する抗腫瘍剤として用いることができるほか、転移抑制作用、外科手術後の再発予防作用、癌に伴う諸症状（例えば、痛み、悪液質など）の改善作用を有しており臨床上の有用性が高い。さらに化合物〔I〕またはその塩の投与による療法は、種々の化学療法剤（例えば、イホスファミド、リン酸エストラムスチン、塩酸ニムスチンなどのアルキル化剤、フルオロウラシル、テガフールなどの代謝拮抗剤、マイトマイシン、塩酸ドキソルビシン、ブレオマイシン、硫酸ペプロマイシン、塩酸アクラルビシン、ネオカルチノスタチンなどの抗生物質、その他シスプラチン、カルボプラチンなど）、ＢＲＭ（ＩＬ−２、ＩＦＮ−α、ＩＦＮ−β、ＩＦＮ−γ、ＴＮＦ−αなど）、血管新生阻害剤などによる療法、温熱療法、前立腺癌などの場合にはホルモン療法（除睾術、エストロゲン、リン酸ジエチルスチルベストロール、ＬＨＲＨ−アゴニスト、ＬＨＲＨ−アンタゴニスト投与など）との併用効果がある。さらに、化合物〔I〕またはその塩は、ヘリコバクター・ピロリ菌（Helicobacter Pylori）に対して優れた除菌効果も有するので、ヘリコバクター・ピロリ菌に起因する感染症の予防および治療剤として用いることができる。該「感染症」としては、例えば十二指腸潰瘍、胃潰瘍、食道炎、胃炎、胃癌などが挙げられる。また、化合物〔I〕またはその塩と抗潰瘍剤および抗菌剤から選ばれた１ないし３種の薬剤との併用は、ヘリコバクター・ピロリ菌に起因する消化器系疾患に対する優れた治療法である。該「抗潰瘍剤」としては、例えばプロトンポンプ阻害剤（例えば、ランソプラゾール、オメプラゾール、パントプラゾール、パリプラゾール、レミノプラゾールなど）、Ｈ₂−受容体拮抗剤（例えば、シメチジン、ラニチジン、ファモチジンなど）などが挙げられる。該「抗菌剤」としては、例えばアモキシシリン、クラリスロマイシン、テトラサイクリン、メトロニダゾール、チニダゾールなどが挙げられる。該「消化器系疾患」とは、例えば十二指腸潰瘍、胃潰瘍、食道炎、胃炎、胃癌などが挙げられる。
化合物〔I〕またはその塩は、そのままあるいは自体公知（例えば、日本薬局方第１２改正記載）の方法にしたがって、医学的に許容される担体を混合した医薬組成物、例えば錠剤（糖衣錠、フィルムコーティング錠を含む）、散剤、顆粒剤、カオウセル剤、カプセル剤（ソフトカプセルを含む）、溶剤、点滴剤、注射剤、外用剤（例えば、経鼻投与剤、経皮投与製剤など）、坐剤（例えば、直腸座剤、腔座剤など）、徐放剤などとして、経口的または非経口的に安全に投与することができ、その投与量は、投与対象、投与ルート、疾患などによっても異なるが、例えば、成人の前立腺癌の患者に経口的に投与する場合、有効成分（化合物〔I〕またはその塩）として、０.１ないし２０mg／kg、好ましくは、０.２ないし１０mg／kgを１日１ないし数回に分けて投与するのがよい。
【００４６】
医薬的に許容される担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤、増粘剤；液状製剤における溶剤、分散剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤などとして配合される。また必要に応じて、防腐剤、抗酸化剤、着色剤、甘味剤などの添加物を用いることもできる。賦形剤の好適な例としては、例えば乳糖、白糖、Ｄ−マンニトール、デンプン、結晶セルロース、軽質無水ケイ酸などが挙げられる。滑沢剤の好適な例としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカなどが挙げられる。結合剤の好適な例としては、例えば結晶セルロース、白糖、Ｄ−マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドンなどが挙げられる。崩壊剤の好適な例としては、例えばデンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウムなどが挙げられる。増粘剤の好適な例としては、例えば天然ガム類、セルロース誘導体、アクリル酸重合体などが挙げられる。溶剤の好適な例としては、例えば注射用水、アルコール、プロピレングリコール、マルクゴール、ゴマ油、トウモロコシ油などが挙げられる。分散剤の好適な例としては、例えば、ツイーン（Tween）８０，ＨＣＯ６０，ポリエチレングリコール、カルボキシメチルセルロース、アルギン酸ナトリウムなどが挙げられる。溶解補助剤の好適な例としては、例えばポリエチレングリコール、プロピレングリコール、Ｄ−マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウムなどが挙げられる。懸濁化剤の好適な例としては、例えばステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸クセリセリン、などの界面活性剤；例えばポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロースなどの親水性高分子などが挙げられる。等張化剤の好適な例としては、例えば塩化ナトリウム、グリセリン、Ｄ−マンニトールなどが挙げられる。緩衝剤の好適な例としては、例えばリン酸塩、酢酸塩、炭酸塩、クエン酸塩などの緩衝液などが挙げられる。無痛化剤の好適な例としては、例えばベンジルアルコールなどが挙げられる。防腐剤の好適な例としては、例えばパラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸などが挙げられる。抗酸化剤の好適な例としては、例えば亜流酸塩、アスコルビン酸などが挙げられる。
【００４７】
本発明の医薬製剤の具体例を以下に示す。
（１）錠剤、散剤、顆粒剤、カオウセル剤：
化合物〔I〕またはその塩に、例えば賦形剤、崩壊剤、結合剤または滑沢剤などを添加して圧縮成型し、次いで必要により、味のマスキング、腸溶性あるいは持続性の目的のためのコーティングを行うことにより製造することができる。
（２）注射剤：
化合物〔I〕またはその塩を、例えば分散剤、保存剤、等張化剤などと共に水性注射剤として、あるいはオリーブ油、ゴマ油、綿実油、コーン油等の植物油、プロピレングリコール等に溶解、懸濁あるいは乳化して油性注射剤として成型することにより製造することができる。
（３）外用剤：
化合物〔I〕またはその塩を固状、半固状または液状の組成物とすることにより製造される。例えば、上記固状の組成物は、化合物〔I〕またはその塩をそのまま、あるいは賦形剤、増粘剤などを添加、混合して粉状とすることにより製造される。上記液状の組成物は、注射剤の場合とほとんど同様で、油性あるいは水性懸濁剤とすることにより製造される。半固状の組成物は、水性または油性のゲル剤、あるいは軟膏状のものがよい。また、これらの組成物は、いずれも緩衝剤、防腐剤などを含んでいてもよい。
（４）座剤：
化合物〔I〕またはその塩を油性または水性の固状、半固状あるいは液状の組成物とすることにより製造される。このような組成物に用いる油性基剤としては、例えば、高級脂肪酸のグリセリド（例えば、カカオ脂、ウイテプゾル類など）、中級脂肪酸（例えば、ミグリオール類など）、あるいは植物油（例えば、ゴマ油、大豆油、綿実油など）などが挙げられる。水性ゲル基剤としては、例えば天然ガム類、セルロース誘導体、ビニール重合体、アクリル酸重合体などが挙げられる。
【００４８】
【発明の実施の形態】
【実施例】
本発明はさらに下記の参考例、実施例、製剤例、試験例で詳しく説明されるが、これらの例は単なる実施であって本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。参考例、実施例中の略号は次の意味を有する。
s：シングレット，d：ダブレット，t：トリプレット，q：クワルテット，dd：ダブルダブレット，dt：ダブルトリプレット，m：マルチプレット，br：幅広い，J：カップリング定数，室温：０〜３０℃。
参考例１
２−メルカプト−３−メチル−６,７−ジヒドロ−５Ｈ−シクロペンタ〔d〕ピリミジン−４−オン
２−エトキシカルボニルシクロペンタノン（３１.２ｇ）とメチルチオウレア（１８.０ｇ）の混合溶液に、濃硫酸５滴を加え１００℃で２日間加熱させた。生じた沈殿物を濾取し、エタノールで洗浄後乾燥して無色粉末状の表題化合物（１０.２ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：1.98(2H,m), 2.55(2H,t,J=7.2Hz), 2.74(2H,t,J=7.8Hz), 3.52(3H,s).
【００４９】
参考例２
１,７−ジメチル−２−メルカプト−６−オキソプリン
１,７−ジメチルキサンチン（５００mg）とオキシ塩化リン（１０ml)の混合物を５時間加熱還流した後濃縮し、残渣をエタノール（１５ml）に溶解させ、チオ尿素（１.０６ｇ）を加え１５時間還流させた。冷後生じた沈殿物を濾取し、エタノールで洗浄後乾燥して黄色固体の表題化合物（２９０mg）を得た。
¹H-NMR(DMSO-d₆)δ：3.60(3H,s), 3.89(3H,s), 8.07(1H,s), 13.54(1H,brs).
参考例３
９−ヒドロキシ−２,３−ジメチル−４Ｈ−ピリド〔１,２−a〕ピリミジン−４−オン
２−アミノ−３−ヒドロキシピリジン（１１ｇ）、２−メチルアセト酢酸エチル（１４.４ｇ）、ポリりん酸（２０ml）および酢酸（４０ml）の混合物を４時間１００℃で加熱撹拌した。反応液を氷水にあけ、水酸化ナトリウム水溶液でpＨを４にし、つづいて炭酸カリウムでpＨ７にした。生じた沈殿物をクロロホルムで抽出し、水で洗浄後、乾燥、濃縮して褐色固体の表題化合物（３.６３ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：2.25(3H,s), 2.49(3H,s), 6.97(1H,dd,J=7.4,6.8Hz), 7.05(1H,dd,J=7.4,1.6Hz), 8.47(1H,dd,J=6.8,1.6Hz).
【００５０】
参考例４
７−〔４−（４−クロロベンゾイル）ベンジル〕−２,６−ジクロロプリン
２,６−ジクロロプリン（３.２５ｇ）のジメチルホルムアミド（３４ml）に炭酸カリウム（２.８５ｇ）と臭化４−（４−クロロベンゾイル）ベンジル（５.３２ｇ）を加え、室温で２４時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１〜１：３）で精製し、表題化合物（１.３７ｇ，１９％）を無水粉末として得た。
¹H-NMR(CDCl₃)δ：5.76(2H,s), 7.21-7.85(8H,m), 8.33(1H,s).
IR(KBr)：1655, 1600, 1580, 1530, 1400, 1270, 1230, 1170, 1090, 990, 925,750 cm^-1.
参考例５
７−〔４−（４−クロロベンゾイル）ベンジル〕−２,６−ジエトキシプリン
７−〔４−（４−クロロベンゾイル）ベンジル〕−２,６−ジクロロプリン（１.１２ｇ）のエタノール（３０ml）溶液にナトリウムエトキシド（１.８３ｇ）を加え室温で９６時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをエーテルとヘキサンで洗い、表題化合物（０.７８ｇ，６７％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ：1.34(3H,t,J=7.0Hz), 1.50(3H,t,J=7.0Hz), 4.50(2H,q,J=7.0Hz), 4.55(2H,q,J=7.0Hz), 5.53(2H,s), 7.25-7.80(8H,m), 7.98(1H,s).
IR(KBr)：2980, 1660, 1620, 1570, 1490, 1450, 1380, 1345, 1300, 1190, 1140, 1120, 1090, 1065, 930 cm^-1.
【００５１】
参考例６
１−〔４−（４−クロロベンゾイル）ベンジル〕−４,５−ジメトキシカルボニル−イミダゾール
アルゴン雰囲気下、水素化ナトリウム（８１６mg）をヘキサン（１０ml）で洗浄し、ＤＭＦ（３０ml）に溶解した。その後、反応溶液を０℃に冷却し、１Ｈ−イミダゾール−４,５−ジカルボン酸ジメチル（３.１７ｇ）を加え、０℃にて１５分、室温にて１.５時間撹拌した後、再び０℃に冷却した。この反応液に４−（４−クロロ−ベンゾイル）ベンジルブロミド（５.１４ｇ）を加えて室温にて１時間撹拌した。氷を加えて、酢酸エチル（１５０ml）にて希釈した後、有機層を、水（１００ml）にて４回洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー（担体１００ｇ；ジクロロメタン：エーテル＝１０：２−２：１）にて精製を行い、表題化合物を４.０６ｇ（収率５９％）得た。
¹H-NMR(CDCl₃)δ：3.86(3H,s), 3.94(3H,s), 5.52(2H,s), 7.26(2H,d,J=7.2Hz),7.47(2H,d,J=8.6Hz), 7.64-7.80(5H,m).
【００５２】
参考例７
１−〔４−（４−クロロベンゾイル）ベンジル〕イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）、７（６Ｈ）−ジオン
１−〔４−（４−クロロベンゾイル）ベンジル〕−４,５−ジメトキシカルボニルイミダゾール（３.３１ｇ）をメタノール（２０ml）に溶解した後、ヒドラジン−水和物（１.６８ｇ）を加えて、５時間加熱還流した。得られた結晶をろ別した後、水（１００ml）に懸濁し、濃塩酸（１０ml）を加えて８０℃にて３０分撹拌した。結晶をろ別した後、減圧下乾燥し、表題化合物を２.６７ｇ（収率８８％）得た。
¹H-NMR(DMSO-d₆)δ：5.78(2H,s), 7.45-7.77(8H,m), 8.49(1H,s).
参考例８
１−〔４−（４−クロロベンゾイル）ベンジル〕−４,７−ジクロロイミダゾ〔４,５−d〕ピリダジン
１−〔４−（４−クロロベンゾイル）ベンジル〕−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）、７（６Ｈ）−ジオン（２.５７ｇ）をオキシ塩化リン（３３.２ｇ）に溶解し、２時間加熱還流した。オキシ塩化リンを減圧下留去し、飽和炭酸水素ナトリウム水溶液を加えて、析出した結晶をろ別した。得られた結晶を水にて洗浄し、減圧下乾燥した後、シリカゲルカラムクロマトグラフィー（担体３０ｇ；ジクロロメタン：酢酸エチル＝１：０−４：１）にて精製を行い、表題化合物を２.１７ｇ（収率７７％）得た。
¹H-NMR(CDCl₃)δ：5.85(2H,s), 7.26(2H,d,J=8.6Hz), 7.46(2H,d,J=8.4Hz), 7.72(2H,d,J=8.6Hz), 7.80(2H,d,J=8.4Hz), 8.24(1H,s).
ＩＲ（ＫＢr）：1654, 754 cm^-1.
【００５３】
参考例９
３−〔４−（４−クロロベンゾイル）ベンジルアミノ〕−１−プロパノール
３−アミノ−１−プロパノール（３.００ｇ）のエタノール（４０ml）溶液に４−（４−クロロベンゾイル）ベンジルブロミド（３.１０ｇ）を加えて４.５時間加熱還流した。室温まで冷却後、溶媒を減圧下に留去し、残渣を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：クロロホルム／メタノール＝９／１〕で精製して表題化合物を白色粉末（１.３６ｇ：収率４５％）として得た。
¹H-NMR(CDCl₃)δ：1.76(2H,quintet,J=5.6Hz), 2.29(2H,m), 2.93(2H,t,J=5.6Hz), 3.83(2H,t,J=5.6Hz), 3.90(2H,s), 7.41-7.50(4H,m), 7.71-7.78(4H,m).
ＩＲ（ＫＢr）：3255, 3140, 2840, 1660, 1600 cm^-1.
参考例１０
２−tert−ブチル−４−クロロ−５−〔Ｎ−（３−ヒドロキシプロピル）−（４−（４−クロロベンゾイル）ベンジル）アミノ〕−３（２Ｈ）−ピリダジノン
２−tert−ブチル−４,５−ジクロロ−３（２Ｈ）−ピリダジノン（４７３mg）および３−〔４−（４−クロロベンゾイル）ベンジルアミノ〕−１−プロパノール（１.３０ｇ）をジオキサン（５ml）／水（５ml）の混合溶媒に溶解後、１００℃で６４時間撹拌した。室温まで冷却後水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下に留去し、残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝４／１→２／１〕で精製して表題化合物を白色粉末（１２０mg：収率１２％）として得た。
¹H-NMR(CDCl₃)δ：1.63(9H,s), 1.83-1.98(3H,m), 3.51(2H,t,J=7.2Hz), 3.70(2H,m), 4.71(2H,m), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.60(1H,s), 7.75(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
【００５４】
参考例１１
２,３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２,３−d〕ピリダジン−４（５Ｈ）−オン
メチルヒドラジン（４.７２ｇ）と３−カルボエトキシ−４,５−ジクロロ−２−ホルミルピロール（４.７２ｇ）のエタノール（５０ml）溶液を２時間加熱還流した。室温まで冷却後、濃硫酸（０.５ml）を加えさらに２１時間加熱還流した。室温まで冷却して析出した結晶をろ取し、エタノールおよびエーテルで洗浄後、減圧下乾燥して表題化合物を褐色粉末（３.２９ｇ：収率８１％）として得た。
¹H-NMR(DMSO-d₆)δ：3.66(3H,s), 8.11(1H,s),
ＩＲ（ＫＢr）：3080, 2980, 1630, 1570 cm^-1.
【００５５】
参考例１２
エチル１−〔４−（４−クロロベンゾイル）ベンジル〕−５−（ジエトキシメチル）イミダゾール−４−カルボキシレート（Ａ）およびエチル１−〔４−（４−クロロベンゾイル）ベンジル〕−４−（ジエトキシメチル）イミダゾール−５−カルボキシレート（Ｂ）
氷浴で冷却した６０％油性水素化ナトリウム（３６３mg）のＤＭＦ（１５ml）懸濁液に、エチル５−（ジエトキシメチル）イミダゾール−４−カルボキシレート（２.００ｇ）のＤＭＦ（２５ml）溶液を滴下注入した。室温で４５分撹拌後、４−（４−クロロベンゾイル）ベンジルブロミド（２.８１ｇ）のＤＭＦ（１５ml）溶液を加えて６０℃でさらに３時間撹拌した。飽和塩化アンモニウム水溶液を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／２〕で精製して表題化合物（Ａ）を白色粉末（２.１８ｇ：収率５６％）としておよび表題化合物（Ｂ）を褐色油状物（１.１３ｇ：収率２９％）として得た。
（Ａ）：¹H-NMR(CDCl₃)δ：1.13(6H,t,J=7.0Hz), 1.42(3H,t,J=7.0Hz), 3.43-3.59(2H,m), 3.70-3.87(2H,m), 4.39(2H,q,J=7.0Hz), 5.53(2H,s), 6.41(1H,s), 7.28(2H,d,J=8.4Hz), 7.41(1H,s), 7.46(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.74(2H,d,J=8.6Hz).
IR(KBr)：3120, 3050, 2980, 2950, 2900, 1700, 1660 cm^-1.
（Ｂ）：¹H-NMR(CDCl₃)δ：1.25(6H,t,J=7.2Hz), 1.32(3H,t,J=7.0Hz), 3.61-3.85(4H,m), 4.30(2H,q,J=7.2Hz), 5.57(2H,s), 6.08(1H,s), 7.24(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.68-7.77(5H,m).
【００５６】
参考例１３
エチル１−〔４−（４−クロロベンゾイル）ベンジル〕−５−ホルミルイミダゾール−４−カルボキシレート
エチル１−〔４−（４−クロロベンゾイル）ベンジル〕−５−（ジエトキシメチル）イミダゾール−４−カルボキシレート（１.７０ｇ）を２０％含水酢酸（１５ml）に溶解し、室温で２３時間撹拌した。水で希釈後、酢酸エチルで抽出した。抽出液を水、飽和重曹水、水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下に留去して、表題化合物を白色粉末（１.３７ｇ：収率９５％）として得た。
¹H-NMR(CDCl₃)δ：1.45(3H,t,J=7.2Hz), 4.47(2H,q,J=7.2Hz), 5.65(2H,s), 7.28(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.69-7.77(5H,m), 10.51(1H,s).
ＩＲ（ＫＢr）：3100, 2980, 1740, 1710, 1675, 1610, 1590 cm^-1.
【００５７】
参考例１４
エチル１−〔４−（４−クロロベンゾイル）ベンジル〕−４−ホルミルイミダゾール−５−カルボキシレート
エチル１−〔４−（４−クロロベンゾイル）ベンジル〕−４−（ジエトキシメチル）イミダゾール−５−カルボキシレート（１.２０ｇ）を２０％含水酢酸（１０ml）に溶解し、室温で８時間撹拌した。水で希釈後、酢酸エチルで抽出した。抽出液を水、飽和重曹水、水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下に留去して、残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〕で精製して表題化合物を白色粉末（６７１mg：収率６７％）として得た。
¹H-NMR(CDCl₃)δ：1.38(3H,t,J=7.0Hz), 4.41(2H,q,J=7.0Hz), 5.66(2H,s), 7.26(2H,d,J=8.8Hz), 7.46(2H,d,J=8.8Hz), 7.70-7.79(5H,m), 10.42(1H,s).
ＩＲ（ＫＢr）：3000, 1720, 1685, 1655, 1610, 1580 cm^-1.
【００５８】
参考例１５
２−ヒドロキシ−３−メチルピリド〔１,２−a〕ピリミジン−４−オン
２−アミノピリジン(９.７１ｇ)と２−メチルマロン酸ジメチル（１９.７０ｇ）の混合物に濃塩酸(１０滴)を加え１５０℃で１時間撹拌した後室温まで放冷した。反応液にヘキサンと酢酸エチルを加え、析出した淡黄色固体をろ取した。収量０.４０３ｇ（２.２％）
¹H-NMR(CDCl₃-CD₃OD)δ：2.09(3H,s), 7.31-7.50(2H,m), 9.12(1H,m).
IR(KBr)ν：3358, 3167, 1666, 1622, 1126, 769, 621 cm^-1.
参考例１６
２−メルカプト−６,７−ジメトキシ−３−メチルキナゾリン−４−オン
２−アミノ−４,５−ジメトキシ安息香酸（２０.０ｇ）とイソチオシアン酸メチル（７.２３ｇ）のエタノール溶液の３０分間還流した。析出した無色針状晶の表題化合物をろ取した。収量１１.７７ｇ（４７％）
¹H-NMR(CDCl₃)δ：3.67(3H,s), 3.85(3H,s), 3.89(3H,s), 6.93(1H,s), 7.31(1H,s).
IR(KBr)ν：1648，1622，1402，1273，1209，1092，1028 cm^-1.
【００５９】
参考例１７
２−アミノ−６−メチル安息香酸
６−メチル−２−ニトロ安息香酸（１４．２５ｇ）のメタノール溶液（１５０ml）にパラジウム−炭素（１.４０ｇ）を加えた後、常温、常圧で水素（５.３１）を添加した。触媒をろ去した後ろ液を減圧濃縮し淡黄色固体の表題化合物（１５.１２ｇ；収率１００％）を得た。
¹H-NMR(CDCl₃)δ：2.47(3H,s), 6.50(2H,t,J=8.1Hz), 7.00-7.07(4H,m).
IR(KBr)ν：2927, 2645, 1645, 1599, 1545, 1470, 1394, 1334, 1288, 1236, 813, 775, 580, 419 cm^-1.
参考例１８
２−メルカプト−３,５−ジメチルキナゾリン−４−オン
参考例１７で得られた２−アミノ−６−メチル安息香酸（１４.１２ｇ）とイソチオシアン酸メチル（７.２２ｇ）のエタノール溶液の１時間還流した。析出した無色針状晶の表題化合物をろ取した。収量７.７２ｇ（４０.０％）
¹H-NMR(CDCl₃)δ：2.47(3H,s), 6.50(2H,t,J=8.1Hz), 7.00-7.07(4H,m).
IR(KBr)ν：3286, 1660, 1614, 1537, 1474, 1431, 1385, 1271, 1109, 1049, 991, 795, 691, 665, 420 cm^-1.
【００６０】
参考例１９
Ｎ,Ｎ−ジメチルフェニルアセトアミド
塩化フェニルアセチル（２５ml）を５０％ジメチルアミン水溶液に氷冷下滴下した。溶媒を減圧除去した後残渣を酢酸エチルに溶かし、有機層を飽和重曹水で洗浄後ＭgＳＯ₄で乾燥し減圧濃縮した。表題化合物を無色油状物として得た。
収量２８.９０ｇ（９５％）
¹H-NMR(CDCl₃)δ：2.95(3H,s), 2.98(3H,s), 3.71(2H,s), 7.26-7.30(5H,m).
IR(Neat)ν：3466, 2937, 1643, 1495, 1450, 1398, 1266, 1132, 1068, 733, 700, 598 cm^-1.
参考例２０
７−〔４−（４−クロロベンゾイル）ベンジル〕−４−メトキシ−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン
アルゴン気流中、６０％油性水素化ナトリウム（２２０mg）を乾燥ジメチルホルムアミド（５ml）に懸濁し、氷冷撹拌下、４−メトキシ−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン（１.０５ｇ）の粉末を少量ずつ加えた。全量添加後、３０分撹拌し、４−（４−クロロベンゾイル）ベンジルブロミド（１.６３ｇ）のジメチルホルムアミド（５ml）溶液を加え室温に戻した後、２時間撹拌した。反応液に水（５０ml）を加え析出物を濾取し、水洗後乾燥した。このものをフラッシュカラムクロマトグラフィー（シリカゲル；ヘキサン−酢酸エチル；９：１）で精製することにより表題化合物（１.１９ｇ）を得た。
¹H-NMR(CDCl₃)δ：2.33(3H,d,J=1.2Hz), 2.60(3H,s), 4.08(3H,s), 5.36(2H,s),6.57(1H,d,J=1.2Hz), 7.28(2H,d,J=8.6Hz), 7.44(2H,d,J=8.6Hz), 7.70(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz).
IR(KBr)：3430, 3100, 2920, 1650, 1600, 1590, 1560, 1530, 1480, 1455, 1430, 1395, 1335, 1300, 1280, 1240, 1190, 1170, 1145, 1100, 1090 cm^-1.
【００６１】
参考例２１
７−〔４−（４−クロロベンゾイル）ベンジル〕−４−メトキシ−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン
アルゴン雰囲気下、４−メトキシ−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン（０.５４ｇ）を乾燥１,２−ジメトキシエタン（以下ＤＭＥ）（１０ml）に溶解し、氷冷撹拌下、６０％油性水素化ナトリウム（１３２mg）を２回に分けて添加した。全量添加後、３０分撹拌し、４−（４−クロロベンゾイル）ベンジルブロミド（１.１１ｇ）のＤＭＥ（５ml）溶液を加え室温に戻した後、１夜撹拌した。反応液に酢酸エチルを加え飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；ヘキサン−酢酸エチル；９：１）で精製することにより表題化合物（０.９４１ｇ）を得た。
¹H-NMR(CDCl₃)δ：2.61(3H,s), 4.10(3H,s), 5.44(2H,s), 6.49(1H,d,J=3.6Hz),6.87(1H,d,J=3.6Hz), 7.29(2H,d,J=8.6Hz), 7.44(2H,d,J=8.6Hz), 7.72(4H,d,J=8.6Hz).
IR(KBr)：3450, 3120, 3000, 2960, 2930, 1660, 1610, 1590, 1560, 1510, 1460, 1390, 1380, 1335, 1280, 1260, 1240, 1170, 1155, 1090, 1065 cm^-1.
【００６２】
参考例２２
６−ｔ−ブチル−ピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン
２−ホルミル−３−ピリジンカルボン酸エチル（１.３ｇ）を酢酸−水（１：１）（５ml）に溶解し、ｔ−ブチルヒドラジン塩酸塩（１.８ｇ）を加え、１時間還流撹拌した。反応液を室温まで冷却し、飽和重曹水でpＨ５.０に調製した後、ジクロロメタンで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥する。これを濃縮して得られた残渣を酢酸（２ml）に溶解し、１時間還流撹拌した。反応液を冷却し、飽和重曹水でpＨ５.０に調製した後、ジクロロメタンで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製した。白色粉末１.２ｇ
¹H-NMR(CDCl₃)δ：1.73(9H,s), 7.64(1H,dd,J=8.2 and 4.4Hz), 8.38(1H,s), 8.69(1H,d,J=8.2Hz), 9.03(1H,d,J=4.4Hz).
参考例２３
６−ｔ−ブチル−１,２,３,４−テトラヒドロピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン
６−ｔ−ブチルピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン（９５５mg）を酢酸（２０ml）に溶解し、酸化白金（９４mg）を加え、水素雰囲気下室温で７時間撹拌した。触媒を濾去し、濾液を濃縮乾固した後、残渣をジエチルエーテルで洗浄し、乾燥した。白色粉末９１１mg
¹H-NMR(CDCl₃)δ：1.63(9H,s), 1.8-2.0(2H,m), 2.54(2H,t,J=6.2Hz), 3.28(2H,t,J=5.4Hz), 4.24(1H,br s), 7.19(1H,s).
【００６３】
参考例２４
６−メチルピリド〔２，３−d〕ピリダジン−５（６Ｈ）−オン
２−ホルミル−３−ピリジンカルボン酸エチル（５１９mg）をエタノール（３ml）に溶解し、メチルヒドラジン（２６７mg）を加え、２時間還流撹拌した。反応液を濃縮乾固した後、残渣をジエチルエーテル−アセトンで洗浄し、乾燥した。黄色粉末３９１mg
¹H-NMR(DMSO-d₆)δ：3.75(3H,s), 7.86(1H,dd,J=8.4 and 4.4Hz), 8.48(1H,s),8.62(1H,d,J=8.4Hz), 9.14(1H,d,J=4.4Hz).
参考例２５
６−メチル−１,２,３,４−テトラヒドロピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン
６−メチルピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン（４０２mg）を酢酸（１５ml）に溶解し、酸化白金（５０mg）を加え、水素雰囲気下室温で１５時間撹拌した。触媒を濾去し、濾液を濃縮乾固した後、残渣をアセトンで洗浄し、乾燥した。白色粉末２５０mg
¹H-NMR(CDCl₃)δ：1.8-2.0(2H,m), 2.58(2H,t,J=6.4Hz)，3.29(2H,t,J=5.6Hz),3.69(3H,s). 4.30(1H,br s), 7.23(1H,s).
【００６４】
参考例２６
２−ｔ−ブチル−４−クロロ−５−ジメチルアミノ−３（２Ｈ）−ピリダジノン
２−ｔ−ブチル−４,５−ジクロロ−３（２Ｈ）−ピリダジノン（４.４ｇ）をエタノール−水（２：１）（４５ml）に溶解し、５０％ジメチルアミン（７.２ｇ）を加え、室温で１５時間撹拌した。エタノールを留去した後、ジエチルエーテルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮乾固した後、残渣をｎ−ヘキサンで洗浄し、乾燥した。白色粉末４.４ｇ
¹H-NMR(CDCl₃)δ：1.63(9H,s), 3.10(6H,s), 7.57(1H,s).
参考例２７
２−ｔ−ブチル−５−ジメチルアミノ−３（２Ｈ）−ピリダジノン
２−ｔ−ブチル−４−クロロ−５−ジメチルアミノ−３（２Ｈ）−ピリダジノン（４．３ｇ）をメタノール（４０ml）に溶解し、１０％パラジウムカーボン（５０％含水）（４３０mg）を加え、水素雰囲気下室温で４８時間撹拌した。触媒を濾去し、濾液を濃縮した後、飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮乾固した後、残渣をｎ−ヘキサンで洗浄し、乾燥した。白色粉末３.４ｇ
¹H-NMR(CDCl₃)δ：1.63(9H,s), 2.98(6H,s), 5.65(1H,d,J=3.0Hz), 7.55(1H,d,J=3.0Hz).
【００６５】
参考例２８
２−ｔ−ブチル−５−ジメチルアミノ−４−ホルミル−３（２Ｈ）−ピリダジノン
オキシ塩化リン（６.５ｇ）をＤＭＦ（１５ml）に氷冷下滴下し、室温で３０分間撹拌した。続いて２−ｔ−ブチル−５−ジメチルアミノ−３（２Ｈ）−ピリダジノン（３.３ｇ）／ＤＭＦ（４０ml）を氷冷下滴下し、７０℃で１時間撹拌した。反応液を氷−重曹水に徐々に加えた後、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮乾固した後、残渣をｎ−ヘキサンで洗浄し、乾燥した。黄色粉末３.７ｇ
¹H-NMR(CDCl₃)δ：1.63(9H,s), 3.10(6H,s), 7.71(1H,s), 10.27(1H,s).
参考例２９
５−ｔ−ブチル−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン
２−ｔ−ブチル−５−ジメチルアミノ−４−ホルミル−３（２Ｈ）−ピリダジノン（３.５ｇ）をヒドラジン（５.１ｇ）／エタノール（３０ml）に加え、４０時間還流撹拌した。エタノール、ヒドラジンを留去した後、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮乾固した後、残渣をｎ−ヘキサン−ジエチルエーテルで洗浄し、乾燥した。白色粉末１.９ｇ
¹H-NMR(CDCl₃)δ：1.71(9H,s), 8.19(1H,s), 8.32(1H,s).
【００６６】
参考例３０
５−メチル−１Ｈ−トリアゾロ〔４,５−ｄ〕ピリダジン−４（５Ｈ）−オン
４,５−ジアミノ−２−メチル−３（２Ｈ）−ピリダジノン（２８０mg）を水（１０ml）に溶解し、濃塩酸（０.５ml）を氷冷下で加え、続いて亜硝酸ナトリウム（２９０mg）／水（５ml）を１０℃以下で滴下し、１０℃以下で１時間、次に１００℃で１時間撹拌した。反応液を１６時間冷蔵庫で放置した後、析出物を濾取し、水洗し、乾燥した。白色粉末２６２mg
¹H-NMR(DMSO-d₆)δ：3.76(3H,s), 8.71(1H,s).
参考例３１
５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
メチルヒドラジン（４．８４ｇ）と３−エトキシカルボニル−２−ホルミルピロール（３．３４ｇ）のエタノール（３０ｍｌ）溶液を２時間加熱還流した。室温まで冷却後、濃硫酸（０．７ｍｌ）を加えさらに１９時間加熱還流した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ジクロロメタン／メタノール＝１９／１〕で精製して表題化合物を白色粉末（１．８１ｇ：収率６１％）として得た。
¹H-NMR(DMSO-d₆) δ :3.68(3H,s), 6.65(1H,d,J=2.8Hz), 7.42(1H,t,J=2.8Hz),8.17(1H,s), 12.02(1H,m).
IR(KBr): 3200, 3100, 1640.
【００６７】
参考例３２
２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
メチルヒドラジン（１．８２ｇ）と３−エトキシカルボニル−４，５−ジメチル−２−ホルミルピロール（３．８５ｇ）のエタノール（４０ｍｌ）溶液を２時間加熱還流した。室温まで冷却後、濃硫酸（０．７ｍｌ）を加えさらに１３時間加熱還流した。室温まで冷却して析出した結晶をろ取し、エタノールおよびエーテルで洗浄後、減圧下乾燥して表題化合物を淡黄色粉末（３．６４ｇ：収率１００％）として得た。
¹ H-NMR(DMSO-d₆) δ :2.26(6H,s), 3.62(3H,s), 7.98(1H,s), 11.6-11.7(1H,m).
参考例３３
２−ｔ−ブチル−５−ジメチルアミノ−４−（１−ヒドロキシ）エチル−３（２Ｈ）−ピリダジノン
２−ｔ−ブチル−５−ジメチルアミノ−４−ホルミル−３（２Ｈ）−ピリダジノン（３．２ｇ）をＴＨＦ（４５ｍｌ）に溶解し、３．０Ｍ臭化メチルマグネシウム／ジエチルエーテル（７．１ｍｌ）を氷冷下滴下し、５０℃で３０分間撹拌した。反応液に１Ｎ塩酸（２２ｍｌ）を氷冷下加えた後、飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥する。これを濃縮乾燥した。黄色油状物３．５ｇ
¹H-NMR(CDCl₃)δ: 1.63(9H,s), 1.63(3H,d,J=6.6Hz), 2.91(6H,s), 4.93(1H,dq,J=6.6Hz and 11.0Hz), 5.55(1H,d,J=11.0Hz), 7.65(1H,s)
【００６８】
参考例３４
４−アセチル−２−ｔ−ブチル−５−ジメチルアミノ−３（２Ｈ）−ピリダジノン
２−ｔ−ブチル−５−ジメチルアミノ−４−（１−ヒドロキシ）エチル−３（２Ｈ）−ピリダジノン（３．４ｇ）をトルエンに溶解し、活性二酸化マンガン（１７．０ｇ）を加え、８０℃で２４時間撹拌した。酸化剤を濾去し、濾液を濃縮した後、残渣をｎ−ヘキサン−ジエチルエーテルで洗浄し、乾燥した。黄色粉末２．５ｇ
¹H-NMR(CDCl₃)δ: 1.62(9H,s), 2.63(3H,s), 2.92(6H,s), 7.62(1H,s)
参考例３５
５−ｔ−ブチル−３−メチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン
４−アセチル−２−ｔ−ブチル−５−ジメチルアミノ−３（２Ｈ）−ピリダジノン（２．５ｇ）をヒドラジン（３．２ｇ）／エタノール（３０ｍｌ）に加え、６時間還流撹拌した。エタノール、ヒドラジンを留去した後、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮乾固した後、残渣をｎ−ヘキサン−ジエチルエーテルで洗浄し、乾燥した。白色粉末１．７ｇ
¹H-NMR(CDCl₃)δ: 1.70(9H,s), 2.74(3H,s), 8.10(1H,s)
【００６９】
参考例３６
５−ジメチルアミノ−４−（１−ヒドロキシ）エチル−２−メチル−３（２Ｈ）−ピリダジノン
５−ジメチルアミノ−４−ホルミル−２−メチル−３（２Ｈ）−ピリダジノン（３６２ｍｇ）をＴＨＦ（１０ｍｌ）に溶解し、３．０Ｍ臭化メチルマグネシウム／ジエチルエーテル（１．０ｍｌ）を氷冷下滴下し、５０℃で３０分間撹拌した。反応液に１Ｎ塩酸（３ｍｌ）を氷冷下加えた後、飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮乾燥した。黄色油状物３７１ｍｇ
¹H-NMR(CDCl₃)δ： 1.64(3H,d,J=6.6Hz), 2.94(6H,s), 3.72(3H,s), 4.93(1H,dq,J=6.6Hz and 11.4Hz), 5.31(1H,d,J=11.4Hz), 7.66(1H,s)
参考例３７
４−アセチル−５−ジメチルアミノ−２−メチル−３（２Ｈ）−ピリダジノン
５−ジメチルアミノ−４−（１−ヒドロキシ）エチル−２−メチル−３（２Ｈ）−ピリダジノン（３５５ｍｇ）をクロロホルムに溶解し、活性二酸化マンガン（２．０ｇ）を加え、５０℃で２４時間撹拌した。酸化剤を濾去し、濾液を濃縮した後、残渣をｎ−ヘキサン−ジエチルエーテルで洗浄し、乾燥した。黄色粉末１７８ｍｇ
¹H-NMR(CDCl₃)δ: 2.67(3H,s), 2.94(6H,s), 3.69(3H,s), 7.66(1H,s)
【００７０】
参考例３８
３，５−ジメチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン
４−アセチル−５−ジメチルアミノ−２−メチル−３（２Ｈ）−ピリダジノン（１３７ｍｇ）をヒドラジン（２２４ｍｇ）／エタノール（５ｍｌ）に加え、６時間還流撹拌した。エタノール、ヒドラジンを留去した後、残渣をジエチルエーテルで洗浄し、乾燥した。白色粉末１１４ｇ
¹H-NMR(CDCl₃)δ: 2.57(3H,s), 3.64(3H,s), 8.30(1H,s)
参考例３９
１−メチル−２−メルカプト−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
金属ナトリウム（１．２１ｇ）を無水エタノール（５０ｍｌ）に溶解し、これにＮ−メチルチオ尿素（４．９６ｇ）を加え、５０℃、３０分撹拌し溶解した。次いでエチル２−シアノ−４，４−ジエトキシブチレート（１１．４７ｇ）のエタノール（１０ｍｌ）溶液を加え、１００℃、５時間還流した。減圧下溶媒留去後、水（２０ｍｌ）を加えて溶解し、更に１０％塩酸（７５ｍｌ）を加え１夜撹拌放置した。析出した沈殿物を瀘取、水、エタノール、エーテル洗浄後、乾燥することにより表題化合物（６．８ｇ）を得た。
¹H-NMR(DMSO-d₆)δ: 3.82(3H,s), 6.41-6.44(1H,m), 6.92-6.95(1H,s), 12.02(1H,s), 12.06(1H,s)
【００７１】
参考例４０
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−２,３−ジエトキシカルボニル−ピロール
アルゴン雰囲気下、１Ｈ−ピロール−２,３−ジカルボン酸ジエチル（４.７９ｇ）をＤＭＥ（１００ml）に溶解し、反応溶液を０℃に冷却した。水素化ナトリウム（９９０mg）を加え、室温にて０.５時間撹拌した後、再び０℃に冷却した。この反応溶液に４−（４−クロロ−ベンゾイル）ベンジルブロミド（８.５３ｇ）を加えて室温にて１４時間撹拌した。水を加えて、酢酸エチル（５００ml）にて希釈した後、有機層を、重曹水（３００ml）にて２回洗浄し、飽和食塩水（１００ml）にて洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー（担体２５０ｇ：ヘキサン：酢酸エチル＝６：１−１：１）にて精製を行い、表題化合物を９.５６ｇ（収率９６％）得た。
¹H-NMR(CDCl₃)δ: 1.26(3H,t,J=7.1Hz), 1.35(3H,t,J=7.0Hz), 4.26(2H,q,J=7.1Hz), 4.30(2H,q,J=7.1Hz), 5.49(2H,s), 6.57(1H,d,J=3.0Hz), 6.88(1H,d,J=3.2Hz), 7.19(2H,d,J=8.4Hz), 7.45(2H,d,J=8.6Hz), 7.72(4H,d,J=8.8Hz)
参考例４１
３−エチル−５−メチル−２−メルカプトキナゾリン−４−オン
６−メチルアントラニル酸（１４.９７ｇ，０.０９９mol）とイソチオシアン酸エチル（１５.００ml，０.１７１mol）のエタノール溶液（２００ml）を５時間撹拌、還流し、放冷後析出した無色針状晶をろ過した。９.６３ｇ（４３.０％）
¹H-NMR(CDCl₃)δ： 1.37(3H,t,J=7.0Hz), 2.80(3H,s), 4.57(2H,q,J=7.0Hz), 6.96(1H,d,J=8.0Hz), 7.08(1H,d,J=8.0Hz), 7.49(1H,t,J=8.0Hz)
IR(KBr)：3188, 3130, 2981, 1693, 1618, 1549, 1468, 1338, 1232, 1117, 775cm^-1
【００７２】
参考例４２
７−〔４−（４−フルオロベンゾイル）ベンジル〕−４−メトキシ−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン
アルゴン雰囲気下、４−メトキシ−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン（４.１８ｇ）を乾燥ＤＭＥ（１２０ml）に溶解し、氷冷撹拌下、６０％油性水素化ナトリウム（０.８８ｇ）を３回に分けて添加した。全量添加後、３０分撹拌し、４−（４−フルオロベンゾイル）ベンジルブロミド（６.７４ｇ）の乾燥ＤＭＥ（２０ml）溶液を加え室温に戻した後、２時間撹拌した。減圧下溶媒を留去し、残渣を酢酸エチルに溶解し、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮すると無色針状晶が析出した。この物を濾取、酢酸エチルで洗浄後乾燥することにより表題化合物（７.０７ｇ）を得た。
¹H-NMR(CDCl₃)δ: 2.33(3H,d,J=1.2Hz), 2.61(3H,s), 4.09(3H,s), 5.37(2H,s),6.58(1H,d,J=1.2Hz), 7.15(2H,t,J=8.6Hz), 7.29(2H,d,J=8.4Hz), 7.71(2H,d,J=8.4Hz), 7.82(2H,dd,J=5.4Hz,8.8Hz)
参考例４３
７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１５．０６ｇ）をメタノール（７１４ml）に懸濁し、２８％ナトリウムメチラート／メタノール溶液（１８．４ml）を加え溶解した。５０℃にて撹拌下、ラネーニッケルを加えた。触媒を濾去し、濾液を１規定塩酸（９０ml）で中和した。減圧下溶媒を濃縮し、析出した沈殿物を濾取、水、メタノール、エーテルで洗浄後、乾燥することにより表題化合物（８．１ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：6.44(1H,d,J=3.0Hz), 7.03(1H,d,J=3.0Hz), 7.83(1H,s), 11.80(1H,brs).
【００７３】
参考例４４
５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１５．０６ｇ）をメタノール（７１４ml）に懸濁し、２８％ナトリウムメチラート／メタノール溶液（１８．４ml）を加え溶解した。５０℃にて撹拌下、ラネーニッケルを加えた。触媒を濾去し、濾液を１規定塩酸（９０ml）で中和した、減圧下溶媒を濃縮し、析出した沈殿物を濾取、水、メタノール、エーテルで洗浄後、乾燥することにより表題化合物（８．１ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：6.44(1H,d,J=3.0Hz), 7.03(1H,d,J=3.0Hz), 7.83(1H,s), 11.80(1H,brs).
参考例４５
３−イソプロピル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．０ｇ）をＤＭＦ（３５ml）に加温溶解した。次いで、無水炭酸カリウム（１．０２ｇ）とヨウ化イソプロピル（１．１ml）を加え５５℃、１３時間撹拌した。不溶物を濾去し、減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトクラフィー（シリカゲル；ヘキサン：酢酸エチル４：１→１：１）にて精製することにより表題化合物（１１０mg）を得た。
¹H-NMR(CDCl₃)δ：1.48(6H,d,J=7.0Hz), 5.31(1H,m), 6.74(1H,dd,J=2.2Hz,3.4Hz), 6.96(1H,dd,J=2.2Hz,3.4Hz), 7.95(1H,s), 9.20(1H,brs).
【００７４】
参考例４６
３−プロピル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．０ｇ）をＤＭＦ（３５ml）に加温溶解した。次いで、無水炭酸カリウム（１．０２ｇ）とヨウ化プロピル（１．０８ml）を加え５５℃、２０時間撹拌した。不溶物を濾去し、減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトクラフィー（シリカゲル；ヘキサン：酢酸エチル４：１→１：１）にて精製することにより表題化合物（５２１mg）を得た。
¹H-NMR(CDCl₃)δ：0.96(3H,t,J=7.4Hz), 1.73-1.92(2H,m), 4.01(2H,t,J=7.4Hz), 6.71(1H,dd,J=2.2Hz,3.4Hz), 7.01(1H,dd,J=2.2Hz,3.4Hz), 7.94(1H,s).
参考例４７
Ｎ−tert−ブトキシカルボニル−４−ピペリドン
４−ピペリドン−塩酸塩（５.２２ｇ）をテトラヒドロフラン（１００ml）に懸濁させ、Ｎ,Ｎ−ジメチルアミノピリジン（２０８mg）を加え氷冷下さらにトリエチルアミン（１８.９ml）を加えた。室温で１.５時間撹拌後、二炭酸−ジ−tert−ブチル（１４.８４ｇ）を加えた。室温で２０時間撹拌後トリエチルアミン（９.４ml）、二炭酸−ジ−tert−ブチル（１４.８４ｇ）を追加した。４日間撹拌後ＴＨＦを留去し、酢酸エチルで希釈し、１０％クエン酸、水、重層水、水、食塩水で洗浄後、硫酸マグネシウムで乾燥した。濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２／１）より精製し、黄色粉末の表題化合物（４.２４ｇ）を得た。
¹H-NMR(CDCl₃)δ：1.50(9H,s), 2.45(4H,t,J=6.2Hz), 3.73(4H,t,J=6.2Hz).
【００７５】
参考例４８
エチルＮ−tert−ブトキシカルボニル−４−ピペリジデンアセテート
水素化ナトリウム（４１２mg）をテトラヒドロフラン（５ml）に懸濁させ、ジエチルホスホノ酢酸エチル（２.１８ml）を氷冷下、滴下した。室温で３０分間撹拌後、さらにＮ−tert−ブトキシカルボニル−４−ピペリドン（１.００ｇ）／ＴＨＦ（５ml）溶液を加えた。室温で１時間撹拌後、氷冷下、水を加えた。酢酸エチルで希釈し、重層水、食塩水で洗浄後、硫酸マグネシウムで乾燥した。濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝４／１）より精製し、白色粉末の表題化合物（１.４０ｇ）を得た。
IR(KBr)ν（cm^-1）：2924, 1709, 1680, 1429, 1166.
¹H-NMR(CDCl₃)δ：1.28(3H,t,J=7.0Hz), 1.47(9H,s), 2.28(2H,t,J=5.6Hz), 3.48(2H,t,J=5.8Hz), 3.51(2H,t,J=5.6Hz), 4.15(2H,q,J=7.0Hz), 5.71(1H,s).
参考例４９
エチルＮ−tert−ブトキシカルボニル−４−ピペリジルアセテート
エチルＮ−tert−ブトキシカルボニル−４−ピペリジデンアセテート（１.２０ｇ）をエタノール（１０ml）に溶かし、Ｐd／Ｃ（１８０mg）を加えた。窒素置換後、水素ガスを注入した。室温で２時間撹拌後、触媒をろ去した。濃縮し、白色粉末の表題化合物（１.１８ｇ）を得た。
IR(Neat)ν（cm^-1）：1736, 1695, 1421, 1286, 1159.
¹H-NMR(CDCl₃)δ：1.1-1.3(2H,m), 1.26(3H,t,J=7.2Hz), 1.45(9H,s), 1.6-2.0(3H,m), 2.23(2H,d,J=7.0Hz), 2.72(2H,t,J=12.0Hz), 4.0-4.1(2H,m), 4.13(2H,q,J=7.2Hz).
【００７６】
参考例５０
Ｎ−tert−ブトキシカルボニル−４−（２−ヒドロキシエチル）ピペリジン
エチルＮ−tert−ブトキシカルボニル−４−ピペリジルアセテート（１.１８ｇ）をジエチルエーテル（２０ml）に溶かしメタノール（０.１９ml）を加えた。氷冷下さらに水素化ほう素リチウム（１２３mg）を加えた。室温で１５時間撹拌後、氷冷下、水を加えた。酢酸エチルで希釈し、食塩水で洗浄後、硫酸マグネシウムで乾燥した。濃縮し、無色オイルの表題化合物（０.９６ｇ）を得た。
IR(Neat)ν（cm^-1）：3350, 2927, 1697, 1672, 1429, 1169.
¹H-NMR(CDCl₃)δ：1.0-1.4(4H,m), 1.45(9H,s), 1.5-1.8(4H,m), 2.69(2H,t,J=13.3Hz), 3.6-3.8(2H,brm), 4.0-4.2(2H,brm).
参考例５１
Ｎ−tert−ブトキシカルボニル−４−（２−ブロモエチル）ピペリジン
Ｎ−tert−ブトキシカルボニル−４−（２−ヒドロキシエチル）ピペリジン（０.９２ｇ）をジクロロメタン（２０ml）に溶かし、四臭化炭素（１.６２ｇ）を加えた。氷冷下さらにトリフェニルホスフィン（１.５８ｇ）をゆっくりと加えた。室温で２時間撹拌後、ジクロロメタンで留去し、酢酸エチルで希釈した。重層水を加え、不溶物をろ去した。酢酸エチルで抽出し、食塩水で洗浄後、硫酸マグネシウムで乾燥した。濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝８／１）より精製し、無色オイルの表題化合物（１.３４ｇ）を得た。
IR(Neat)ν（cm^-1）：2926, 1691, 1425, 1242, 1167.
¹H-NMR(CDCl₃)δ：1.0-1.3(3H,m), 1.45(9H,s), 1.6-1.9(4H,m), 2.6-2.8(2H,brm), 3.45(2H,t,J=6.8Hz), 4.0-4.2(2H,brm).
【００７７】
実施例１
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン
ケミカル・ファーマシューティカル・ブルタン（Chem. Pharm. Bull.）、１７巻、２３５７頁、１９６９年の方法で合成した２−メルカプト−３−メチル−４（３Ｈ）−キナゾリノン（１.０ｇ）と水酸化ナトリウム（２５０mg）の５０％エタノール（１５ml）−ジメチルホルムアミド（１５ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１.８ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、酢酸エチル−メタノールから再結晶して無色固体の表題化合物（１.２９ｇ）を得た。
¹H-NMR(CDCl₃)δ：3.61(3H,s), 4.62(2H,s), 7.35-7.50(3H,m), 7.55-7.80(8H,m), 8.24(1H,d,J=8.0Hz).
IR(KBr)：1670, 1645, 1550 cm^-1.
【００７８】
実施例２
２−〔４−（４−フルオロベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン
２−メルカプト−３−メチル−４（３Ｈ）−キナゾリノン（１.０ｇ）と水酸化ナトリウム（２５０mg）の５０％エタノール（１５ml）−ジメチルホルムアミド（１５ml）溶液に、４−（４−フルオロベンゾイル）ベンジルブロミド（１.５５ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（１.８５ｇ）を得た。
¹H-NMR(CDCl₃)δ：3.61(3H,s), 4.62(2H,s), 7.15(2H,t,J=8.6Hz), 7.40(1H,dt,J=8.2,1.4Hz), 7.58-7.90(8H,m), 8.23(1H,dd,J=8.0,1.4Hz).
IR(KBr)：1670, 1645, 1550 cm^-1.
実施例３
２−〔３−（４−クロロベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン
２−メルカプト−３−メチル−４（３Ｈ）−キナゾリノン（１.０ｇ）と水酸化ナトリウム（２５０mg）の５０％エタノール（１５ml）−ジメチルホルムアミド（１５ml）溶液に、３−（４−クロロベンゾイル）ベンジルブロミド（１.８ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（２.２２ｇ）を得た。
¹H-NMR(CDCl₃)δ：3.59(3H,s), 4.59(2H,s), 7.34-7.52(5H,m), 7.61-7.80(5H,m), 7.96(1H,d,J=2.0Hz), 8.22(1H,dd,J=8.0,1.4Hz).
IR(KBr)：1660, 1650, 1525 cm^-1.
【００７９】
実施例４
２−〔４−（２,４−ジクロロベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン
２−メルカプト−３−メチル−４（３Ｈ）−キナゾリノン（１.０ｇ）と水酸化ナトリウム（２５０mg）の５０％エタノール（１５ml）−ジメチルホルムアミド（１５ml）溶液に、４−（２,４−ジクロロベンゾイル）ベンジルブロミド（１.８８ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（２.１６ｇ）を得た。
¹H-NMR(CDCl₃)δ：3.59(3H,s), 4.59(2H,s), 7.25-7.80(10H,m), 8.22(1H,dd,J=8.2,1.4Hz).
IR(KBr)：1670, 1650, 1550 cm^-1.
【００８０】
実施例５
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３−メチル−６,７−ジヒドロ−５Ｈ−シクロペンタ〔d〕ピリミジン−４（３Ｈ）−オン
参考例１で得られた２−メルカプト−３−メチル−６,７−ジヒドロ−５Ｈ−シクロペンタ〔d〕ピリミジン−４（３Ｈ）−オン（１.０ｇ）と水酸化ナトリウム（２２０mg）の５０％エタノール（１５ml）−ジメチルホルムアミド（８ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１.７５ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（１.１５ｇ）を得た。
¹H-NMR(CDCl₃)δ：2.06(2H,quint,J=7.4Hz), 2.79(2H,t,J=7.4Hz), 2.84(2H,t,J=7.4Hz), 3.49(3H,s), 4.50(2H,s), 7.46(2H,d,J=8.6Hz), 7.54(2H,d,J=8.6Hz),7.74(4H,d,J=8.6Hz).
IR(KBr)：1670, 1645, 1495 cm-1．
【００８１】
実施例６
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−１，７−ジメチル−６−オキソプリン
参考例２で得られた１,７−ジメチル−２−メルカプト−６−オキソプリン（２８６mg）と水酸化ナトリウム（６０mg）の５０％エタノール（１０ml）−ジメチルホルムアミド（１５ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（４８０mg）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（５３５mg）を得た。
¹H-NMR(CDCl₃)δ：3.57(3H,s), 4.05(3H,s), 4.63(2H,s), 7.45(2H,d,J=8.4Hz),7.61(2H,d,J=8.4Hz), 7.73(1H,s), 7.74(4H,d,J=8.4Hz).
IR(KBr)：1680, 1650, 1490 cm^-1.
【００８２】
実施例７
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３−メチルチェノ〔３,２−d〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチルチェノ〔３,２−d〕ピリミジン−４（３Ｈ）−オン（１.０ｇ）と水酸化ナトリウム（２０５mg）の５０％エタノール（１２ml）−ジメチルホルムアミド（２０ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１.５６ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（１.４９７ｇ）を得た。
¹H-NMR(CDCl₃)δ：3.61(3H,s), 4.58(2H,s), 7.23(1H,d,J=5.2Hz), 7.45(2H,d,J=8.6Hz), 7.59(2H,d,J=8.2Hz), 7.70-7.80(5H,m).
IR(KBr)：1665, 1645, 1510 cm^-1.
【００８３】
実施例８
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３−メチル−５,６,７,８−テトラヒドロ−ベンズ〔b〕チェノ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチル−５,６,７,８−テトラヒドロ−ベンズ〔b〕チェノ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（５００mg）と水酸化ナトリウム（７５mg）の５０％エタノール（５ml）−ジメチルホルムアミド（５ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（５６５mg）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（４９７mg）を得た。
¹H-NMR(CDCl₃)δ：1.72-1.94(4H,m), 2.75(2H,m), 2.98(2H,m), 3.53(3H,s), 4.53(2H,s), 7.45(2H,d,J=8.6Hz), 7.56(2H,d,J=8.4Hz), 7.74(4H,d,J=8.6Hz).
IR(KBr)：1670, 1660, 1510 cm^-1.
【００８４】
実施例９
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−５−メチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン
６−メルカプト−５−メチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オンカリウム塩（１.０ｇ）のジメチルホルムアミド（１０ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１.３９３ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（１.６４７ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：3.53(3H,s), 4.58(2H,s), 7.50(2H,t,J=8.6Hz), 7.65(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 7.79(1H,s).
IR(KBr)：3200, 1660, 1640, 1575, 1280 cm^-1.
【００８５】
実施例１０
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−１,５−ジメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オンおよび６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−２,５−ジメチル−２Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−５−メチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン（１.０ｇ）のジメチルホルムアミド（２０ml）懸濁液に、６０％水素化ナトリウム（１９７mg）を加え室温で１０分間撹拌させ透明溶液になった後、ヨウ化メチル（５１５mg）を加え室温で１時間撹拌した。反応液を濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３／２）にて精製して無色固体の６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−１,５−ジメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン（１２０mg）および無色固体の６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−２,５−ジメチル−２Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン（５７０mg）を得た。
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−１,５−ジメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン
¹H-NMR(CDCl₃)δ：3.54(3H,s), 4.06(3H,s), 4.60(2H,s), 7.46(2H,d,J=8.6Hz),7.61(2H,d,J=8.4Hz), 7.75(4H,d,J=8.6Hz), 7.99(1H,s).
IR(KBr)：1680, 1645, 1570 cm^-1.
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−２,５−ジメチル−２Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン
¹H-NMR(CDCl₃)δ:3.57(3H,s), 3.97(3H,s), 4.57(2H,s), 7.47(2H,d,J=8.6Hz),7.59(2H,d,J=8.4Hz), 7.75(2H,d,J=8.6Hz), 7.78(2H,d,J=8.4Hz), 8.00(1H,s).
IR(KBr)：1700, 1660, 1550 cm^-1.
【００８６】
実施例１１
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３,５−ジメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン
６−メルカプト−３,５−ジメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オンカリウム塩（８００mg）のジメチルホルムアミド（１２ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１.０５ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（１.０８６ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：2.44(3H,s), 3.42(3H,s), 4.60(2H,s), 7.63(2H,d,J=8.6Hz), 7.71(4H,s), 7.75(2H,d,J=8.6Hz), 13.29(1H,brs).
IR(KBr)：3210, 1660, 1575, 1550, 1280 cm^-1.
【００８７】
実施例１２
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−１,３,５−トリメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オンおよび６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−２,３,５−トリメチル−２Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３,５−ジメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン（５００mg）のジメチルホルムアミド（１５ml）懸濁液に、６０％水素化ナトリウム（５５mg）を加え室温で１０分間撹拌させ透明溶液になった後、ヨウ化メチル（２３５mg）を加え室温で１時間撹拌した。反応液を濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３／２）にて精製して無色固体の６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−１,３,５−トリメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン（９０mg）および無色固体の６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−２,３,５−トリメチル−２Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン（１７０mg）を得た。
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−１,３,５−トリメチル−１Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン
¹H-NMR(CDCl₃)δ：2.66(3H,s), 3.51(3H,s), 3.91(3H,s), 4.59(2H,s), 7.46(2H,d,J=8.8Hz), 7.60(2H,d,J=8.4Hz), 7.70-7.80(4H,m).
IR(KBr)：1680, 1645, 1585, 1520 cm^-1.
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−２,３,５−ジメチル−２Ｈ−ピラゾロ〔３,４−d〕ピリミジン−４（５Ｈ）−オン
¹H-NMR(CDCl₃)δ:2.55(3H,s), 3.54(3H,s), 3.88(3H,s), 4.55(2H,s), 7.47(2H,d,J=8.6Hz), 7.58(2H,d,J=8.2Hz), 7.75(2H,d,J=8.6Hz), 7.77(2H,d,J=8.2Hz).
ＩＲ（ＫＢr）：1695, 1660, 1550 cm^-1.
【００８８】
実施例１３
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３,５−ジメチル−イソオキサゾロ〔５,４−d〕ピリミジン−４（５Ｈ）−オン
６−メルカプト−３,５−ジメチル−イソオキサゾロ〔５,４−d〕ピリミジン−４（５Ｈ）−オン（８００mg）と水酸化ナトリウム（１６５mg）の５０％エタノール（１０ml）−ジメチルホルムアミド（１０ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１.２５ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２／１）にて精製して無色固体の表題化合物（４７０mg）を得た。
¹H-NMR(CDCl₃)δ：2.57(3H,s), 3.55(3H,s), 4.59(2H,s), 7.46(2H,d,J=8.6Hz),7.58(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.76(2H,d,J=8.6Hz).
IR(KBr)：1715, 1690, 1650, 1590, 1525 cm^-1.
【００８９】
実施例１４
９−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−２,３−ジメチル−４Ｈ−ピリド〔１,２−a〕ピリミジン−４−オン
参考例３で得られた９−ヒドロキシ−２,３−ジメチル−４Ｈ−ピリド〔１,２−a〕ピリミジン−４−オン（５００mg）と炭酸カリウム（３７５mg）のアセトン（１５ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（８９６mg）を加え、反応液を室温で一夜撹拌させた。反応液を濃縮し得られた残渣を水および酢酸エチルで洗浄し、メタノールから再結晶して無色固体の表題化合物（４１５mg）を得た。
¹H-NMR(DMSO-d₆)δ：2.14(3H,s), 2.43(3H,s), 7.16(1H,t,J=7.2Hz), 7.31(1H,d,J=7.4Hz), 7.63(2H,d,J=8.0Hz), 7.68(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz), 8.50(1H,d,J=7.0Hz).
IR(KBr)：1630, 1480, 1280 cm^-1.
【００９０】
実施例１５
７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン
テオフィリン（１.８０ｇ）のジメチルホルムアミド（２０ml）溶液に炭酸カリウム（１.６６ｇ）と臭化４−（４−クロロベンゾイル）ベンジル（３.１０ｇ）を加えて室温で１４時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：４）で精製し、表題化合物（２.７９ｇ，６８％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ：3.41(3H,s), 3.63(3H,s), 5.59(2H,s), 7.38-7.50(4H,m), 7.65(1H,s), 7.68-7.81(4H,m).
IR(KBr)：3110, 1690, 1650, 1400, 1280, 1230 cm^-1.
実施例１６
７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン塩酸塩
７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン（１００mg）のメタノール（４ml）溶液に４Ｎ塩酸（１ml）を加え、室温で１０分間撹拌した。反応液にエーテルを加え、析出物質をろ過して表題化合物（８４mg，７７％）を白色粉末として得た。
¹H-NMR(CDCl₃)δ：3.45(3H,s), 3.70(3H,s), 5.70(2H,s), 7.42-7.83(8H,m), 8.47(1H,s).
IR(KBr)：3010, 2950, 1710, 1675, 1660 cm^-1.
【００９１】
実施例１７
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−メチルキサンチン
３−メチルキサンチン(１.０６ｇ)のジメチルホルムアミド(２６ml)溶液に炭酸カリウム(１.０６ｇ)と臭化４−（４−クロロベンゾイル）ベンジル(１.９８ｇ)を加えて室温で２４時間撹拌した。反応液に水と酢酸エチルを加え、浮遊物を濾過し、そのろ過物の水溶液に１Ｎ塩酸水溶液を加え、クロロホルムで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し溶媒を留去した。残さを酢酸エチルで洗い、表題化合物（２３９mg，１０％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ：3.54(3H,s), 3.57(3H,s), 7.41-7.52(4H,m), 7.68-7.81(5H,m).
IR(KBr)：3450, 3160, 3040, 2820, 1685, 1585, 1540, 1375, 1280, 1230, 1190, 925, 750 cm^-1.
実施例１８
１−〔４−（４−クロロベンゾイル）ベンジル〕−３,７−ジメチルキサンチン
テオブロミン（０.９０ｇ）のジメチルホルムアミド（２０ml）に水素化ナトリウム（２４０ml）と臭化４−（４−クロロベンゾイル）ベンジル（１.５５ｇ）を加え、室温で１８時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをエーテルで洗い、表題化合物（１.３７ｇ，６７％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ：3.60(3H,s), 4.00(3H,s), 5.27(2H,s), 7.38-7.79(8H,m).
IR(KBr):3310, 2940, 1710, 1655, 1645, 1600, 1580, 1545, 1280, 930 cm^-1.
【００９２】
実施例１９
８−クロロ−７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン
８−クロロテオフィリン（２.１５ｇ）のジメチルホルムアミド（２０ml）溶液に炭酸カリウム（１.６６ｇ）と臭化４−（４−クロロベンゾイル）ベンジル（３.１０ｇ）を加えて室温で２０時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをエーテルで洗い、表題化合物（３.３４ｇ，７５％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ：3.41(3H,s), 3.57(3H,s), 5.64(2H,s), 7.41-7.52(4H,m), 7.68-7.80(4H,m).
IR(KBr):2940, 1710, 1660, 1580, 1530, 1445, 1400, 1370, 1280, 740 cm^-1.
実施例２０
７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチル−８−メトキシキサンチン
８−クロロ−７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン（８６６mg）のジメチルホルムアミド（４０ml）溶液にナトリウムメトキシド（１０ml，２８％メタノール溶液）を加え、室温で３０分間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で抽出し、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをエーテルで洗い、表題化合物（４７０mg，５４％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ：3.40(3H,s), 3.54(3H,s), 4.17(3H,s), 5.36(2H,s), 7.38-7.78(8H,m).
IR(KBr)：2950, 1705, 1670, 1655, 1610, 1525, 1460, 1410, 1285 cm^-1.
【００９３】
実施例２１
７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチル尿酸
７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチル−８−メトキシキサンチン（４００mg）に濃塩酸（８ml）を室温で加え、１３０℃で１時間撹拌した。放冷後、析出物をろ取し、水とエーテルで洗い、表題化合物（３３３mg，８６％）を無色粉末として得た。
¹H-NMR(CDCl₃+5%CD₃OD)δ：3.36(3H,s), 3.45(3H,s), 5.23(2H,s), 7.40-7.80(8H,m).
IR(KBr)：3450, 2950, 2710, 1680, 1550, 1280, 1185, 740 cm^-1.
実施例２２
１−〔４−（４−クロロベンゾイル）ベンジル〕−４,６−ジメチル−トリアゾロ〔４,５−d〕ピリミジン−５,７−ジオン
塩化Ｎ,Ｎ−ジメチルアジドホスゲンイミニウム(１.７０ｇ)の塩化メチレン(４０ml)溶液に４−アミノ−１,３−ジメチルウラシル(１.５５ｇ)を加えて３時間加熱還流し、反応液を濃縮した。残さをジメチルホルムアミド（３０ml）溶液に炭酸カリウム（６.９１ｇ）と臭化４−（４−クロロベンゾイル）ベンジル（３.１０ｇ）を加え、室温で１８時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１〜１：１）で精製し、表題化合物（０.９２ｇ，２２％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ：3.41(3H,s), 3.66(3H,s), 5.93(2H,s), 7.39-7.80(8H,m).
IR(KBr)：1710, 1680, 1560, 1270, 925, 745 cm^-1.
【００９４】
実施例２３
７−〔３−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン
テオフィリン（１.８０ｇ）のジメチルホルムアミド（５０ml）溶液に炭酸カリウム（１.６６ｇ）と臭化３−（４−クロロベンゾイル）ベンジル（３.１０ｇ）を加えて室温で２４時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さを再結晶（アセトン−ヘキサン）し、表題化合物（１.６４ｇ，４０％）を白色粉末として得た。
¹H-NMR(CDCl₃)δ：3.40(3H,s), 3.60(3H,s), 5.57(2H,s), 7.42-7.79(9H,m).
IR(KBr)：1700, 1660, 1550, 1290, 750 cm^-1.
実施例２４
７−〔４−（２,４−ジクロロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン
テオフィリン（１.８０ｇ）のジメチルホルムアミド（２０ml）溶液に炭酸カリウム（１.６６ｇ）と臭化４−（２,４−ジクロロベンゾイル）ベンジル（３.３３ｇ）を加えて室温で２４時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さを再結晶（酢酸エチル）し、表題化合物（３.３８ｇ，７６％）を白色粉末として得た。
¹H-NMR(CDCl₃)δ：3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.25-7.84(8H,m).
IR(KBr)：1700, 1660, 1290, 930, 745 cm^-1.
【００９５】
実施例２５
７−〔４−（４−フルオロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン
テオフィリン（１.８０ｇ）のジメチルホルムアミド（２０ml）溶液に炭酸カリウム（１.６６ｇ）と臭化４−（４−フルオロベンゾイル）ベンジル（２.９３ｇ）を加えて室温で２４時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをエーテルで洗い、表題化合物（２.７９ｇ，７４％）を白色粉末として得た。
¹H-NMR(CDCl₃)δ：3.41(3H,s), 3.60(3H,s), 5.59(2H,s), 7.08-7.86(9H,m).
IR(KBr)：1700, 1660, 1640, 1590, 1545, 1270, 1230 cm^-1.
実施例２６
７−〔４−（２−クロロベンゾイル）ベンジル〕−１,３−ジメチルキサンチン
テオフィリン（０.９０ｇ）のジメチルホルムアミド（２０ml）溶液に炭酸カリウム（０.８３ｇ）と臭化４−（２−クロロベンゾイル）ベンジル（１.５５ｇ）を加えて室温で１３時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをエーテルで洗い、表題化合物（１.７０ｇ，８３％）を針状結晶として得た。
¹H-NMR(CDCl₃)δ：3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.30-7.48(6H,m), 7.63(1H,s), 7.76-7.85(2H,m).
IR(KBr)：3100, 1700, 1660, 1540, 1430, 1285, 740 cm^-1.
【００９６】
実施例２７
７−〔４−（４−クロロベンゾイル）ベンジル〕キサンチン塩酸塩
１,３−ジエトキシ−７−〔４−（４−クロロベンゾイル）ベンジル〕プリン（１００mg）に濃塩酸（１０ml）を室温で加え、１３０℃で２時間撹拌した。放冷後、析出物をろ過し、水とエーテルで洗い、表題化合物（７３mg，７３％）を無色粉末として得た。
¹H-NMR(CDCl₃+5%CD₃OD)δ：5.59(2H,s), 7.45-7.55(4H,m), 7.70-7.90(4H,m), 8.05(1H,s).
IR(KBr)：2950, 2760, 1710, 1650, 1575, 1270 cm^-1.
実施例２８
７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３,８−トリメチルキサンチン
１,３,８−トリメチルキサンチン（０.９７ｇ）のジメチルホルムアミド（２０ml）溶液に炭酸カリウム（０.８３ｇ）と臭化４−（４−クロロベンゾイル）ベンジル（１.５５ｇ）を加えて室温で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをアセトンで洗い、表題化合物（１.３４ｇ，６１％）を白色粉末として得た。
¹H-NMR(CDCl₃)δ：2.46(3H,s), 3.41(3H,s), 3.60(3H,s), 5.63(2H,s), 7.25-7.80(8H,m).
IR(KBr)：2950, 1705, 1660, 1610, 1590, 1545, 1490, 1410, 1395, 1290, 1270, 1090, 925, 755, 745 cm^-1.
【００９７】
実施例２９
７−〔４−（４−クロロベンゾイル）ベンジル〕−１,３−ジメチル−８−エチルキサンチン
１,３−ジメチル−８−エチルキサンチン（４１６mg）のジメチルホルムアミド（１０ml）溶液に炭酸カリウム（３３２mg）と臭化４−（４−クロロベンゾイル）ベンジル（６１９mg）を加えて室温で２１時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さを再結晶（酢酸エチル−エーテル）し、表題化合物（５８４mg，６７％）を白色粉末として得た。
¹H-NMR(CDCl₃)δ：1.30(3H,t,J=7.6Hz), 2.72(2H,q,J=7.6Hz), 3.40(3H,s), 3.61(3H,s), 5.64(2H,s), 7.21-7.80(8H,m).
IR(KBr)：1700, 1600, 1650, 1410, 1280 cm^-1.
実施例３０
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３−メチルピリド〔２,３−d〕ピリミジン−４−オン
３−メチルピリド〔２,３−d〕ピリミジン−４−オン−２−チオン（１９３mg）のジメチルホルムアミド（５ml）溶液に水素化ナトリウム（６０mg）と臭化４−（４−クロロベンゾイル）ベンジル（３１０mg）を加えて室温で３０分間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さを再結晶（酢酸エチル−エーテル−ヘキサン）し、表題化合物（１６２mg，３８％）を白色粉末として得た。
¹H-NMR(CDCl₃)δ：3.62(3H,s), 4.73(2H,s), 7.26-7.79(9H,m), 8.54-8.61(1H,m), 8.90-8.95(1H,m).
ＩＲ（ＫＢr）：1680, 1645, 1580, 1550, 1425, 1285, 1270, 1080, 725 cm^-1.
【００９８】
実施例３１
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−イミダゾ〔４,５−d〕ピリダジン−７（６Ｈ）−オンおよび１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−７−クロロ−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４,７−ジクロロ−イミダゾ〔４,５−d〕ピリダジン（２．００６g）をジオキサン（２０ml）に溶解し、水酸化ナトリウム水溶液（水酸化ナトリウム３.７８ｇ／水３０ml）を加えて１５時間加熱還流した。水（１００ml）を加えて、酢酸（５ml）を加えた後、析出した結晶をろ取した。得られた結晶をシリカゲルカラムクロマトグラフィー（担体５０ｇ；ジクロロメタン：酢酸エチル−１０：１−１：１）にて精製を行い、表題化合物１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−イミダゾ〔４,５−d〕ピリダジン−７（６Ｈ）−オンを１.３２ｇ（収率６９％）、表題化合物１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−７−クロロ−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オンを４４１mg（収率２３％）得た。
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−イミダゾ〔４,５−d〕ピリダジン−７（６Ｈ）−オン
¹H-NMR(CDCl₃)δ：5.80(2H,s), 7.51(2H,d,J=8.4Hz), 7.60(2H,d,J=8.8Hz), 7.73(4H,d,J=8.8Hz), 8.69(1H,s).
IR(KBr)：3101, 2933, 1672, 1533, 742 cm^-1.
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−７−クロロ−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン
¹H-NMR(CDCl₃)δ：5.86(2H,s), 7.31(2H,d,J=8.4Hz), 7.61(2H,d,J=8.8Hz), 7.74(4H,d,J=8.6Hz), 8.62(1H,s).
IR(KBr)：3116, 2926, 1676, 1533, 739 cm^-1.
【００９９】
実施例３２
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−６−メチル−イミダゾ〔４,５−d〕ピリダジン−７（６Ｈ）−オン
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−イミダゾ〔４,５−d〕ピリダジン−７（６Ｈ）−オン（９６３mg）ＤＭＦ（１５ml）に溶解し、炭酸カリウム（９８５mg）を加えた後、よう化メチル（０.４５ml）を加え、室温にて６５時間撹拌した。水（５０ml）を加えて析出した結晶をろ取した後、得られた結晶をシリカゲルカラムクロマトグラフィー（担体３０ｇ；ジクロロメタン：エーテル−１：０−３：１）にて精製を行い、表題化合物を６５５mg（収率６６％）得た。
¹H-NMR(CDCl₃)δ：3.86(3H,s), 5.81(2H,s), 7.45(2H,d,J=7.8Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.01(1H,s).
IR(neat)：2949，1666，1537，741 cm^-1．
実施例３３
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−５−メチル−７−クロロ−イミダゾ〔４，５−d〕ピリダジン−４（５Ｈ）−オン
実施例３２と同様にして、１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−７−クロロ−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン（４２４mg）をＤＭＦ（７ml）に溶解し、炭酸カリウム（４６５mg）を加えた後、よう化メチル（０.２ml）を加え、室温にて６５時間撹拌した。水（５０ml）を加えて析出した結晶をろ取した後、得られた結晶をシリカゲルカラムクロマトグラフィー（担体３０ｇ；酢酸エチル：メタノール＝１：０−２０：１）にて精製を行い、表題化合物を２１８mg（収率５０％）得た。
¹H-NMR(CDCl₃)δ：3.87(3H,s), 5.74(2H,s), 7.23(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.72(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.01(1H,s).
IR(neat)：2951, 1672, 1529, 739 cm^-1.
【０１００】
実施例３４
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−メトキシ−６−メチル−イミダゾ〔４,５−d〕ピリダジン−７（６Ｈ）−オン
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−６−メチル−イミダゾ〔４,５−d〕ピリダジン−７（６Ｈ）−オン（７２mg）をメタノール（５ml）に溶解し、２８％ナトリウムメトキシド／メタノール溶液（１.０ml）を加えた後、５時間加熱還流した。多量の水を加えて結晶を析出させ、水にて洗浄した後、減圧下乾燥し表題化合物を５０mg（収率７０％）得た。
¹H-NMR(CD₃OD)δ:3.71(3H,s), 4.00(3H,s), 5.85(2H,s), 7.50(2H,d,J=8.6Hz),7.52(2H,d,J=8.8Hz), 7.74(2H,d,J=8.8Hz), 7.75(2H,d,J=8.6Hz), 8.42(1H,s).
IR(neat)：2945, 1660, 1561, 1269, 1234, 739 cm^-1.
実施例３５
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−５−メチル−７−メトキシ−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン
実施例７と同様にして、１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−５−メチル−７−クロロ−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン（５２mg）をメタノール（５ml）に溶解し、２８％ナトリウムメトキシド／メタノール溶液（０.５ml）を加えた後、３時間加熱還流した。多量の水を加えて結晶を析出させ、水にて洗浄した後、減圧下乾燥し表題化合物を２０mg（収率３９％）得た。
¹H-NMR(CD₃OD)δ：3.73(3H,s), 3.97(3H,s), 5.70(2H,s), 7.41(2H,d,J=8.4), 7.51(2H,d,J=8.8Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 8.36(1H,s).
IR(neat)：2947, 1660, 1568, 1272, 737 cm^-1.
【０１０１】
実施例３６
８−tert−ブチル−５−〔４−（４−クロロベンゾイル）ベンジル〕−２,３,４,５−テトラヒドロピリダジノ〔４,５−b〕−１，４−オキサゼピン−９（８Ｈ）−オン
金属ナトリウム（６.５mg）をエタノール（１ml）に溶解して調整したナトリウムエトキシドエタノール溶液に、２−tert−ブチル−４−クロロ−５−〔４−（４−クロロベンゾイル）ベンジル−Ｎ−（３−ヒドロキシプロピル）アミノ〕−３（２Ｈ）−ピリダジノン（９１mg）のエタノール（５ml）溶液を加え、４６時間加熱還流した。室温まで冷却後水を加え、酢酸エチルで抽出した。抽出液を水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下に留去し、残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１→１／２〕で精製して表題化合物を白色粉末（１２０mg：収率１２％）として得た。
¹H-NMR(CDCl₃)δ：1.62(9H,s), 2.06(2H,quintet,J=6.2Hz), 3.55(2H,t,J=6.2Hz), 4.42(2H,t,J=6.2Hz), 4.55(2H,m), 7.32(1H,s), 7.41(2H,d,J=8.4Hz), 7.48(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz).
【０１０２】
実施例３７
１−〔４−（４−クロロベンゾイル）ベンジル〕−２,３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２,３−d〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６mg）のＤＭＦ（１０ml）懸濁液に、２,３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２,３−d〕ピリダジン−４（５Ｈ）−オン（４０４mg）のＤＭＦ（７０ml）溶液を滴下注入した。室温で３時間撹拌後、４−（４−クロロベンゾイル）ベンジルブロミド（６８１mg）のＤＭＦ（１５ml）溶液を加えて室温でさらに１８時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝２／１→１／１〕で精製して表題化合物を白色粉末（３５１mg：収率３９％）として得た。
¹H-NMR(DMSO-d₆)δ：3.68(3H,s), 5.73(2H,s), 7.30(2H,d,J=8.6Hz), 7.61(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 8.71(1H,s).
IR(KBr)：3055, 3040, 2990, 2960, 1660, 1640, 1605 cm^-1.
【０１０３】
実施例３８
１−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−１Ｈ−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン
メチルヒドラジン（４７２mg）とエチル１−〔４−（４−クロロベンゾイル）ベンジル〕−５−ホルミルイミダゾール−４−カルボキシレート(１.０３ｇ)のエタノール(２０ml)溶液を３時間加熱還流した。室温まで冷却後、濃硫酸（０.２ml）を加えさらに２１時間加熱還流した。水で希釈後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、溶媒を減圧下に留去し、残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：クロロホルム／メタノール＝１９／１〕で精製して表題化合物を白色粉末（６６mg：収率７％）として得た。
¹H-NMR(CDCl₃)δ:3.90(3H,s), 5.47(2H,s), 7.31(2H,d,J=8.4Hz), 7.48(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 7.92(1H,s), 8.00(1H,s).
【０１０４】
実施例３９
３−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−３Ｈ−イミダゾ〔４,５−d〕ピリダジン−４（５Ｈ）−オン
メチルヒドラジン（２０９mg）とエチル１−〔４−（４−クロロベンゾイル）ベンジル〕−４−ホルミルイミダゾール−５−カルボキシレート（６０１ｇ）のエタノール（１０ml）溶液を２.５時間加熱還流した。室温まで冷却後、濃硫酸（０.１ml）を加えさらに１５時間加熱還流した。水で希釈後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、溶媒を減圧下に留去し、残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝２／１〕で精製して表題化合物を白色粉末（１１５mg：収率２０％）として得た。
¹H-NMR(CDCl₃)δ：3.88(3H,s), 5.81(2H,s), 7.46(4H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz), 7.97(1H,s), 8.33(1H,s).
IR(KBr)：3100, 2950, 1650, 1600, 1580, 1540 cm^-1.
【０１０５】
実施例４０
２−〔４−（４−クロロベンゾイル）−ベンジルオキシ〕−３−メチルピリド〔１,２−a〕ピリミジン−４−オン
参考例１５で得られた２−ヒドロキシ−３−メチルピリド〔１,２−a〕ピリミジン−４−オン(０.３１ｇ)と臭化４−（４−クロロベンゾイル）ベンジル(０.５６ｇ)のジメチルホルムアミド（１０.０ml）溶液に炭酸カリウム（０.２５ｇ）を加え８０℃で３０分間撹拌した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、有機層を硫酸マグネシウムで乾燥した後減圧下濃縮した。残渣をメタノールから再結晶し無色針状晶の表題化合物（０.２２４ｇ；収率３１％）を得た。
¹H-NMR(CDCl₃)δ：2.23(3H,s), 5.62(2H,s), 7.10(1H,t,J=7.4Hz), 7.45-7.82(10H,m), 9.08(1H,d,J=7.4Hz).
IR(KBr)ν：1689, 1657, 1581, 1431, 1284, 1174, 1088, 930, 748 cm^-1.
【０１０６】
実施例４１
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−６,７−ジメトキシ−３−メチルキナゾリン−４−オン
参考例１６で得られた２−メルカプト−６,７−ジメトキシ−３−メチルキナゾリン−４−オン（０.９９８ｇ）と臭化４−（４−クロロベンゾイル）ベンジル（１.２６ｇ）のエタノール（１５.０ml）−ＴＨＦ（５.０ml）混合溶液に１Ｎ−水酸化ナトリウム（３.９０ml）を加え７０℃で終夜撹拌した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、有機層を硫酸マグネシウムで乾燥した後減圧下濃縮した。残渣を酢酸エチルから再結晶し無色針状晶の表題化合物（１.０６ｇ；収率５６％）を得た。
¹H-NMR(CDCl₃)δ:3.60(3H,s), 3.99(3H,s), 4.02(3H,s), 4.61(2H,s), 7.00(1H,s), 7.46(2H,d,J=8.6Hz), 7.56(1H,s), 7.60(2H,d,J=8.0Hz), 7.73-7.78(4H,m).
IR(KBr)：1660, 1610, 1549, 1497, 1271, 1076, 1022, 928, 781, 743 cm^-1.
【０１０７】
実施例４２
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３,５−ジメチルキナゾリン−４−オン
参考例１８で得られた２−メルカプト−３,５−ジメチルキナゾリン−４−オン（１.０５ｇ）と臭化４−（４−クロロベンゾイル）ベンジル（１.６０ｇ）のエタノール（１５.０ml）−ＴＨＦ（１５.０ml）−ＤＭＦ（５.０ml）混合溶液に１Ｎ−水酸化ナトリウム（５.１０ml）を加え７０℃で３０分間撹拌した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、有機層を硫酸マグネシウムで乾燥した後減圧下濃縮した。残渣を酢酸エチルから再結晶し無色針状晶の表題化合物（１.５４ｇ；収率７０％）を得た。
¹H-NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.16(1H,d,J=7.0Hz),7.42-7.47(2H,m), 7.53(2H,d,J=8.2Hz), 7.61(2H,d,J=8.6Hz), 7.72-7.77(4H,m).
IR(KBr)：1666, 1554, 1466, 1408, 1306, 1277, 1090, 928 cm^-1.
【０１０８】
実施例４３
２−〔４−（２,４−ジクロロベンゾイル）ベンジルチオ〕−３,５−ジメチルキナゾリン−４−オン
参考例１８で得られた２−メルカプト−３,５−ジメチルキナゾリン−４−オン（０.５１１ｇ）のエタノール（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム（２.６０ml）を加えた後、臭化４−（２,４−ジクロロベンゾイル）ベンジル（０.８７２ｇ）を加え６０℃で３.５時間撹拌した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、有機層を硫酸マグネシウムで乾燥した後減圧下濃縮した。残渣を酢酸エチルから再結晶し無色針状晶の表題化合物（０.８２５ｇ；収率６９％）を得た。
¹H-NMR(CDCl₃)δ：2.84(3H,s), 3.53(3H,s), 4.57(2H,s), 7.15(1H,d,J=6.8Hz),7.32-7.54(5H,m), 7.59(2H,d,J=8.2Hz), 7.75(2H,d,J=8.2Hz).
IR(KBr)：1672, 1581, 1554, 1464, 1417, 1306, 1282, 1092, 930 cm^-1.
【０１０９】
実施例４４
２−〔３−（４−クロロベンゾイル）ベンジルチオ〕−３,５−ジメチルキナゾリン−４−オン
参考例１８で得られた２−メルカプト−３,５−ジメチルキナゾリン−４−オン（０.５２２ｇ）のエタノール（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム（２.５０ml）を加えた後、臭化３−（４−クロロベンゾイル）ベンジル（０.７７０ｇ）を加え６０℃で３.５時間撹拌した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、有機層を硫酸マグネシウムで乾燥した後減圧下濃縮した。残渣を酢酸エチルから再結晶し無色針状晶の表題化合物（０.８７７ｇ；収率８１％）を得た。
¹H-NMR(CDCl₃)δ：2.84(3H,s), 3.53(3H,s), 4.57(2H,s), 7.15(1H,d,J=7.2Hz),7.30-7.55(5H,m), 7.65-7.74(4H,m), 7.96(1H,bs).
IR(KBr)：1666, 1581, 1554, 1466, 1306, 1090, 733 cm^-1.
【０１１０】
実施例４５
２−〔４−（４−フルオロベンゾイル）ベンジルチオ〕−３,５−ジメチルキナゾリン−４−オン
参考例１８で得られた２−メルカプト−３,５−ジメチルキナゾリン−４−オン（０.４９２ｇ）のエタノール（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム（２.５０ml）を加えた後、臭化４−（４−フルオロベンゾイル）ベンジル（０.７００ｇ）を加え６０℃で３.５時間撹拌した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、有機層を硫酸マグネシウムで乾燥した後減圧下濃縮した。残渣を酢酸エチルから再結晶し無色針状晶の表題化合物（０.７１７ｇ；収率７２％）を得た。
¹H-NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.10-7.20(3H,m), 7.46-7.63(4H,m), 7.72-7.87(4H,m).
IR(KBr):1666, 1601, 1554, 1464, 1414, 1304, 1277, 1234, 1153, 1092cm^-1.
【０１１１】
実施例４６
７−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７−〔４−（４−クロロベンゾイル）ベンジル〕−４−メトキシ−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン（０.６７１ｇ）をジオキサン（８ml）に溶解し、４,４'−チオビス（６−ｔ−ブチル−ｍ−クレゾール）（７.２mg）を添加後、０.５規定塩酸（１.１２ml）を加え１０５℃、３６時間撹拌した。再度０.５規定塩酸（１.１２ml）を加え、同温度にて２４時間撹拌後、水（３０ml）を加え析出物を濾取乾燥した。このものをフラッシュカラムクロマトグラフィー（クロロホルム）で精製することにより表題化合物（０.３１２ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：2.24(3H,s), 2.51(3H,d,J=1.0Hz), 5.33(2H,s), 6.83(1H,d,J=1.0Hz), 7.43(2H,d,J=8.2Hz), 7.60(2H,d,J=8.6Hz), 7.71(2H,d,J=8.2Hz), 7.73(2H,d,J=8.6Hz), 12.01(1H,s).
IR(KBr)：3430, 3220, 3030, 2920, 2830, 1660, 1605, 1570, 1545, 1520, 1460, 1410, 1305, 1280, 1205, 1180, 1170, 1135, 1035, 1085, 1010 cm^-1.
【０１１２】
実施例４７
７−〔４−（４−クロロベンゾイル）ベンジル〕−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７−〔４−（４−クロロベンゾイル）ベンジル〕−４−メトキシ−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン（０.６１５ｇ）をジオキサン（６ml）に溶解し、４,４'−チオビス（６−ｔ−ブチル−ｍ−クレゾール）（７mg）を添加後、０.５規定塩酸（１.２ml）を加え１０５℃、３６時間撹拌した。再度０.５規定塩酸（１.２ml）を加え、同温度にて２４時間撹拌後、室温に戻した。析出物を濾取しメタノール、エーテル洗浄後乾燥することにより表題化合物（０.４０５ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：2.53(3H,s), 5.42(2H,s), 6.44(1H,d,J=3.4Hz), 7.15(1H,d,J=3.4Hz), 7.45(2H,d,J=8.0Hz), 7.60(2H,d,J=8.4Hz), 7.72(2H,d,J=8.0Hz), 7.73(2H,d,J=8.4Hz), 12.18(1H,s).
IR(KBr)：3450, 2920, 2840, 1670, 1640, 1605, 1550, 1405, 1310, 1280, 1230, 1205, 1140, 1085 cm^-1.
【０１１３】
実施例４８
７−〔４−（４−クロロベンゾイル）ベンジル〕−３,５−ジメチル−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（２５４mg）を乾燥ＤＭＥ（１０ml）、乾燥ジメチルホルムアミド（６ml）に溶解し、氷冷下６０％油性水素化ナトリウム（２６.４mg）を添加した。３０分撹拌し、ヨウ化メチル（９８mg）を加え室温に戻し２.５時間撹拌した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をフラッシュカラムクロマトグラフィー（クロロホルム）で精製することにより表題化合物（１７６mg）を得た。
¹H-NMR(CDCl₃)δ:2.39(3H,s), 2.56(3H,s), 3.56(3H,s), 5.29(2H,s), 6.47(1H,d,J=1.0Hz), 7.29(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.73(4H,d,J=8.4Hz).
IR(KBr)：3450，3050，3030，1665，1650，1605，1590，1570，1535，1515，1485，1410，1340，1310，1280，1270，1230，1180，1150，1080 cm^-1．
【０１１４】
実施例４９
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−d〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７−〔４−（４−クロロベンゾイル）ベンジル〕−２−メチルチオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（８２mg）を乾燥ＤＭＥ（１０ml）、乾燥ジメチルホルムアミド（４ml）に溶解し、氷冷下６０％油性水素化ナトリウム（９.６mg）を添加した。３０分撹拌し、ヨウ化メチル（３４mg）を加え室温に戻し２.５時間撹拌した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をフラッシュカラムクロマトグラフィー（ヘキサン−酢酸エチル；４：１）で精製することにより表題化合物（３０mg）を得た。
¹H-NMR(CDCl₃)δ：2.58(3H,s), 3.60(3H,s), 5.37(2H,s), 6.67(1H,d,J=3.4Hz),6.75(1H,d,J=3.4Hz), 7.30(2H,d,J=8.0Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.0Hz).
IR(KBr)：3430, 3100, 3050, 3000, 2920, 1670, 1650, 1606, 1580, 1540, 1495, 1465, 1410, 1350, 1295, 1275, 1215, 1170, 1085 cm^-1.
【０１１５】
実施例５０
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−５−メチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
５−メチル−２−メルカプト−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（１.３６ｇ）をジメチルホルムアミド（３０ml）に溶解し、１規定水酸化ナトリウム（７.５ml）を加え、氷冷下４−（４−クロロベンゾイル）ベンジルブロミド（２.４８ｇ）のジメチルホルムアミド（１０ml）溶液を滴下した。室温に戻した後、４時間撹拌し反応液を氷水（２５０ml）に加え析出した沈殿物を濾取、水洗後乾燥した。この物をフラッシュカラムクロマトグラフィー（３−５％エタノール含クロロホルム）で精製することにより表題化合物（１.５７ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：2.23(3H,s), 4.50(2H,s), 6.65(1H,s), 7.60(2H,d,J=8.6Hz), 7.64(2H,d,J=8.6Hz), 7.69(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 11.42(1H,s), 11.95(1H,s).
IR(KBr)：3420, 3180, 3100, 3020, 2920, 2830, 1660, 1600, 1580, 1545, 1515, 1480, 1430, 1400, 1360, 1300, 1280, 1235, 1170, 1085, 1065, 1010 cm^-1.
【０１１６】
実施例５１
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（８３６ml）をジメチルホルムアミド（２０ml）に溶解し、１規定水酸化ナトリウム（５ml）を加え、氷冷下４−（４−クロロベンゾイル）ベンジルブロミド（１.６３ｇ）のジメチルホルムアミド（５ml）溶液を滴下した。室温に戻した後、４時間撹拌し反応液を氷水（２００ml）に加え析出した沈殿物を濾取、水洗後乾燥した。この物をフラッシュカラムクロマトグラフィー（３−５％エタノール含クロロホルム）で精製することにより表題化合物（１.３３ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：4.52(2H,s), 6.34-6.37(1H,m), 6.91-6.95(1H,m), 7.61(2H,d,J=8.4Hz), 7.65(2H,d,J=8.4Hz), 7.70(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz),11.42(1H,s), 11.95(1H,s).
IR(KBr)：3430, 3220, 3100, 3030, 2960, 2900, 2840, 1650, 1605, 1565, 1410, 1350, 1300, 1280, 1270, 1215, 1170, 1140, 1090, 1015 cm^-1.
【０１１７】
実施例５２
２−〔４−（４−フルオロベンゾイル）ベンジル〕チオ−５−メチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
５−メチル−２−メルカプト−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（１.８２ｇ）をメタノール（２５ml）に懸濁し、１規定水酸化ナトリウム（１０.５ml）を加えて溶解した。氷冷下４−（４−フルオロベンゾイル）ベンジルブロミド（３.５１ｇ）のＤＭＥ（１０ml）溶液を滴下した。室温に戻した後、４時間撹拌し、結晶性沈殿物を濾取、水洗、５０％エタノール水、メタノール、エーテル洗浄後、乾燥した。この物をＤＭＥ（１,２−ジメトキシエタン）を用いて再結晶することにより表題化合物（２.７１ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：2.24(3H,s), 4.51(2H,s), 6.65(1H,s), 7.37(2H,t,J=8.8Hz), 7.64(2H,d,J=8.8Hz), 7.70(2H,d,J=8.8Hz), 7.81(2H,dd,J=5.6Hz,8.8Hz), 11.43(1H,s), 11.97(1H,s).
IR(KBr)：3430, 3180, 3120, 3060, 2980, 2920, 2830, 1650, 1600, 1580, 1545, 1500, 1455, 1435, 1410, 1300, 1280, 1235, 1180, 1155, 1120, 1065 cm^-1.
【０１１８】
実施例５３
２−〔４−（２,４−ジクロロベンゾイル）ベンジル〕チオ−５−メチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
５−メチル−２−メルカプト−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（１.３６ｇ）をメタノール（１８.７ml）に懸濁し、１規定水酸化ナトリウム（７.８８ml）を加えて溶解した。氷冷下４−（２,４−ジクロロベンゾイル）ベンジルブロミド（３.０９ｇ）のＤＭＥ（８ml）溶液を滴下した。室温に戻した後、４時間撹拌し、結晶性沈殿物を濾取、水洗、５０％エタノール水、メタノール、エーテル洗浄後、乾燥した。この物をＤＭＥ（１,２−ジメトキシエタン）を用いて再結晶することにより表題化合物（２.０３ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：2.23(3H,s), 4.48(2H,s), 6.65(1H,s), 7.53(1H,d,J=8.2Hz), 7.59(1H,dd,J=1.6Hz,8.8Hz), 7.64(2H,d,J=8.4Hz), 7.69(2H,d,J=8.4Hz), 7.80(1H,d,J=1.6Hz), 11.40(1H,s), 11.96(1H,s).
IR(KBr)：3430, 3270, 3130, 3080, 2920, 2820 1670, 1650, 1600, 1580, 1550, 1515, 1455, 1430, 1410, 1370, 1280, 1240, 1190, 1180, 1150, 1100, 1085, 1050 cm^-1.
【０１１９】
実施例５４
２−〔３−（４−クロロベンゾイル）ベンジル〕チオ−５−メチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
５−メチル−２−メルカプト−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（１.３６ｇ）をメタノール（１８.７ml）に懸濁し、１規定水酸化ナトリウム（７.８８ml）を加えて溶解した。氷冷下３−（４−クロロベンゾイル）ベンジルブロミド（２.７９ｇ）のＤＭＥ−ＤＭＦ（６：５；２２ml）溶液を滴下した。室温に戻した後、２０時間撹拌し、反応液を氷水（２００ml）に加え析出した沈殿物を濾取し、水洗、５０％エタノール水、メタノール、エーテル洗浄後、乾燥した。この物をフラッシュカラムクロマトグラフィー（１％メタノール含クロロホルム）で精製することにより表題化合物（１.９４ｇ）を得た。
¹H-NMR(DMSO-d₆)δ：2.25(3H,s), 4.50(2H,s), 6.65(1H,s), 7.50(2H,d,J=8.0Hz), 7.69(2H,d,J=8.6Hz), 7.51-7.82(4H,m), 11.38(1H,s), 11.95(1H,s).
IR(KBr)：3430, 3180, 3120, 3060, 2920, 2830, 1650, 1580, 1545, 1515, 1480, 1455, 1430, 1400, 1360, 1300, 1280, 1235, 1200, 1190, 1170, 1120, 1090, 1065, 1010 cm^-1.
【０１２０】
実施例５５
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３,５,７−トリメチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−５−メチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（６４０mg）を乾燥ＤＭＥ（１５.６ml）に懸濁し、氷冷撹拌下、６０％油性水素化ナトリウム（１４４mg）を２回に分けて添加した。次いでヨウ化メチル（５０９mg）を加え、室温に戻した後１夜撹拌放置した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（ヘキサン−酢酸エチル；４：１）で精製することにより表題化合物（５４２mg）を得た。
¹H-NMR(CDCl₃)δ:2.38(3H,s), 3.55(3H,s), 3.66(3H,s), 4.54(2H,s), 6.44(1H,d,J=1.0Hz), 7.46(2H,d,J=8.4Hz), 7.59(2H,d,J=8.4Hz), 7.75(4H,d,J=8.4Hz).
IR(KBr)：3430, 3110, 3060, 2920, 1680, 1660, 1605, 1580, 1540, 1515, 1460, 1400, 1300, 1275, 1225, 1200, 1170, 1090, 1050, 1010 cm^-1.
【０１２１】
実施例５６
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３,７−ジメチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（Ａ）
２−〔１−〔４−（４−クロロベンゾイル）フェニル〕エチル〕チオ−３,７−ジメチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（Ｂ）
アルゴン雰囲気下、２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（１.２ｇ）を乾燥ＤＭＥ（１５ml）に溶解し、氷冷撹拌下、６０％油性水素化ナトリウム（２８８mg）を２回に分けて添加した。次いでヨウ化メチル（１.１１ｇ）を加え、室温に戻した後１夜撹拌放置した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（ヘキサン−酢酸エチル；６：１→４：１→２.５：１）で精製することにより表題化合物（Ａ；４７０mg、Ｂ；９２mg）を得た。
化合物（Ａ）
¹H-NMR(CDCl₃)δ：3.59(3H,s), 3.74(3H,s), 4.56(2H,s), 6.60(1H,d,J=3.4Hz),6.71(1H,d,J=3.4Hz), 7.46(2H,d,J=8.6Hz), 7.59(2H,d,J=8.4Hz), 7.75(2H,d,J=8.6Hz), 7.76(2H,d,J=8.4Hz).
IR(KBr)：3450, 3120, 2980, 2930, 1700, 1660, 1605, 1585, 1540, 1510, 1460, 1400, 1300, 1270, 1220, 1170, 1105, 1090, 1050, 1010 cm^-1.
化合物（Ｂ）
¹H-NMR(CDCl₃)δ：1.83(3H,d,J=7.2Hz), 3.55(3H,s), 3.71(3H,s), 5.20(1H,q,J=7.2Hz), 6.57(1H,d,J=3.4Hz), 6.68(1H,d,J=3.4Hz), 7.45(2H,d,J=8.4Hz), 7.62(2H,d,J=8.4Hz), 7.74(2H,d,J=8.6Hz), 7.76(2H,d,J=8.6Hz).
IR(KBr)：3430，2970，2930，1680，1660，1600，1580，1540，1505，1460，1400，1300，1280，1210，1170，1100，1085，1040，1010 cm^-1．
【０１２２】
実施例５７
２−〔４−（４−フルオロベンゾイル）ベンジル〕チオ−３,５,７−トリメチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（Ａ）
２−〔１−〔４−（４−フルオロベンゾイル）フェニル〕エチル〕チオ−３,５,７−トリメチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（Ｂ）
アルゴン雰囲気下、２−〔４−（４−フルオロベンゾイル）ベンジル〕チオ−５−メチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（１.９７ｇ）を乾燥ＤＭＥ（５０ml）に懸濁し、氷冷撹拌下、６０％油性水素化ナトリウム（４２０mg）を２回に分けて添加した。室温１５分撹拌し、次いでヨウ化メチル（１.８５ｇ）を加え、室温に戻した後１夜撹拌放置した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（ヘキサン−酢酸エチル；４：１→２.５：１）で精製することにより表題化合物（Ａ；１.２９ｇ、Ｂ；７mg）を得た。
化合物（Ａ）
¹H-NMR(CDCl₃)δ：2.38(3H,d,J=1.2Hz), 3.54(3H,s), 3.66(3H,s), 4.54(2H,s),6.43(1H,d,J=1.2Hz), 7.15(2H,t,J=8.8Hz), 7.58(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.83(1H,dd,J=5.4Hz,8.8Hz).
IR(KBr)：3450, 3110, 3060, 2920, 1680, 1660, 1600, 1575, 1540, 1520, 1500, 1455, 1405, 1300, 1280, 1225, 1195, 1150, 1090, 1050 cm^-1.
化合物（Ｂ）
¹H-NMR(CDCl₃)δ：1.82(3H,d,J=7.2Hz), 2.37(3H,d,J=1.2Hz), 3.51(3H,s), 3.65(3H,s), 5.19(2H,q,J=7.2Hz), 6.42(1H,d,J=1.2Hz), 7.16(2H,t,J=8.8Hz), 7.62(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.84(2H,dd,J=5.6Hz,8.8Hz).
IR(KBr)：3430，3100，3060，2920，1680，1650，1595，1570，1540，1510，1445，1405，1305，1275，1225，1195，1150，1090，1045 cm^-1．
【０１２３】
実施例５８
２−〔４−（２，４−ジクロロベンゾイル）ベンジル〕チオ−３,５,７−トリメチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（Ａ）
２−〔１−〔４−（２,４−ジクロロベンゾイル）フェニル〕エチル〕チオ−３,５,７−トリメチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（Ｂ）
アルゴン雰囲気下、２−〔４−（２,４−ジクロロベンゾイル）ベンジル〕チオ−５−メチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（１.７８ｇ）を乾燥ＤＭＥ（５０ml）に懸濁し、６０％油性水素化ナトリウム（３３６mg）を２回に分けて添加した。室温１５分撹拌し、次いでヨウ化メチル（１.４８ｇ）を加え、室温に戻した後１夜撹拌放置した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（ヘキサン−酢酸エチル；４：１→２.５：１）で精製することにより表題化合物（Ａ；１.２８ｇ、Ｂ；２４mg）を得た。
化合物（Ａ）
¹H-NMR(CDCl₃)δ：2.37(3H,d,J=1.2Hz), 3.53(3H,s), 3.63(3H,s), 4.52(2H,s),6.43(1H,d,J=1.2Hz), 7.31(1H,d,J=8.2Hz), 7.37(1H,dd,J=1.8Hz,8.2Hz), 7.49(1H,d,J=1.8Hz), 7.57(2H,d,J=8.6Hz), 7.75(2H,d,J=8.6Hz).
IR(KBr)：3430, 3100, 3050, 2920, 1680, 1670, 1605, 1580, 1540, 1515, 1460, 1400, 1365, 1285, 1255, 1225, 1220, 1180, 1150, 1095, 1055 cm^-1.
化合物（Ｂ）
¹H-NMR(CDCl₃)δ：1.79(3H,d,J=7.2Hz), 2.35(3H,d,J=1.0Hz), 3.50(3H,s), 3.61(3H,s), 5.16(2H,q,J=7.2Hz), 6.41(1H,d,J=1.0Hz), 7.30(1H,d,J=8.2Hz), 7.36(1H,dd,J=1.8Hz,8.2Hz), 7.49(1H,d,J=1.8Hz), 7.60(2H,d,J=8.6Hz), 7.76(2H,d,J=8.6Hz).
IR(KBr)：3430，2920，1675，1600，1580，1570，1540，1520，1450，1405，1370，1310，1280，1240，1220，1195，1150，1100，1090，1050 cm^-1．
【０１２４】
実施例５９
２−〔３−（４−クロロベンゾイル）ベンジル〕チオ−３,５,７−トリメチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、２−〔３−（４−クロロベンゾイル）ベンジル〕チオ−５−メチル−７Ｈ−ピロロ〔２,３−d〕ピリミジン−４（３Ｈ）−オン（１.３１ｇ）を乾燥ＤＭＥ（３２ml）に懸濁し、氷冷撹拌下、６０％油性水素化ナトリウム（２６９mg）を２回に分けて添加した。１５分撹拌し、次いでヨウ化メチル（１.１８ｇ）を加え、室温に戻した後１夜撹拌放置した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（ヘキサン−酢酸エチル；４：１→２.５：１）で精製することにより表題化合物（９５０mg）を得た。
¹H-NMR(CDCl₃)δ：2.39(3H,d,J=1.0Hz), 3.53(3H,s), 3.54(3H,s), 4.52(2H,s),6.42(1H,d,J=1.0Hz), 7.36(2H,d,J=8.6Hz), 7.35-7.50(1H,m), 7.65-7.72(2H,m), 7.69(2H,d,J=8.6Hz), 7.97(1H,d,J=1.6Hz).
IR(KBr)：3450, 3100, 2920, 1680, 1640, 1600, 1580, 1540, 1515, 1455, 1430, 1405, 1290, 1280, 1245, 1225, 1200, 1170, 1130, 1105, 1090, 1040, 1010 cm^-1.
【０１２５】
実施例６０
６−ｔ−ブチル−１−〔４−（４−クロロベンゾイル）ベンジル〕−１,２,３,４−テトラヒドロピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン
６−ｔ−ブチル−１,２,３,４−テトラヒドロピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン（２０７mg）をＤＭＦ（５ml）に溶解し、水素化ナトリウム（６０％）（８０mg）を加え、室温で３０分間撹拌する。続いて４−（４−クロロベンゾイル）ベンジルブロミド（４６４mg）を加え、室温で１時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルクロマト（ジクロロメタン−酢酸エチル（４：１））で精製した。白色粉末１３９mg
¹H-NMR(CDCl₃)δ：1.63(9H,s), 1.9-2.1(2H,m), 2.64(2H,t,J=6.2Hz), 3.35(2H,t,J=5.6Hz), 4.61(2H,s), 7.34(2H,d,J=8.6Hz), 7.39(1H,s), 7.47(2H,d,J=8.6Hz), 7.76(2H,d,J=8.6Hz), 7.79(2H,d,J=8.6Hz).
IR(KBr)：1605, 1655 cm^-1.
【０１２６】
実施例６１
１−〔４−（４−クロロベンゾイル）ベンジル〕−６−メチル−１,２,３,４−テトラヒドロピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン
６−メチル−１,２,３,４−テトラヒドロピリド〔２,３−d〕ピリダジン−５（６Ｈ）−オン（１１６mg）をＤＭＦ（５ml）に溶解し、水素化ナトリウム（６０％）（５６mg）を加え、室温で３０分間撹拌した。続いて４−（４−クロロベンゾイル）ベンジルブロミド（３４１mg）を加え、室温で１時間撹拌する。反応液に水を加えた後、酢酸エチル−ＴＨＦで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルクロマト（酢酸エチル）で精製した。黄色アモルファス１６５mg
¹H-NMR(CDCl₃)δ：1.9-2.1(2H,m), 2.67(2H,t,J=6.4Hz), 3.37(2H,t,J=5.6Hz),3.70(3H,s), 4.63(2H,s), 7.32(2H,d,J=8.4Hz), 7.43(2H,d,J=8.4Hz), 7.49(1H,s), 7.75(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【０１２７】
実施例６２
５−ｔ−ブチル−１−〔４−（４−クロロベンゾイル）ベンジル〕−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（Ａ）
５−ｔ−ブチル−２−〔４−（４−クロロベンゾイル）ベンジル〕−２Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（Ｂ）
５−ｔ−ブチル−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（２８８mg）をＤＭＦ（５ml）に溶解し、４−（４−クロロベンゾイル）ベンジルブロミド（７１２１mg）、炭酸カリウム（３１８mg）を加え、室温で１５時間撹拌した。反応液をジエチルエーテルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製した後、さらに５−ｔ−ブチル−１−〔４−（４−クロロベンゾイル）ベンジル〕−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オンはｎ−ヘキサン−ジエチルエーテルで、５−ｔ−ブチル−２−〔４−（４−クロロベンゾイル）ベンジル〕−２Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オンはジエチルエーテルでそれぞれ洗浄し、乾燥した。
化合物（Ａ）：白色粉末１５９mg
¹H-NMR(CDCl₃)δ:1.69(9H,s), 5.61(2H,s), 7.33(2H,d,J=8.0Hz), 7.46(2H,d,J=8.4Hz), 7.73(2H,d,J=8.0Hz), 7.77(2H,d,J=8.4Hz), 7.95(1H,s), 8.23(1H,s).
IR(KBr)：1650, 1660 cm^-1.
Anal. Calcd : Ｃ６５.６３％，Ｈ５.０３％，Ｎ１３.３１％
Found : Ｃ６５.６１％，Ｈ５.０３％，Ｎ１２.９９％
化合物（Ｂ）：白色粉末２４５mg
¹H-NMR(CDCl₃)δ:1.68(9H,s), 5.59(2H,s), 7.38(2H,d,J=8.0Hz), 7.46(2H,d,J=8.4Hz), 7.73(2H,d,J=8.0Hz), 7.78(2H,d,J=8.4Hz), 8.20(1H,s), 8.22(1H,s).
IR(KBr)：1585, 1650, 1660 cm^-1.
【０１２８】
実施例６３
５−ｔ−ブチル−１−〔４−（４−フルオロベンゾイル）ベンジル〕−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（Ａ）
５−ｔ−ブチル−２−〔４−（４−フルオロベンゾイル）ベンジル〕−２Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（Ｂ）
５−ｔ−ブチル−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（２８８mg）をＤＭＦ（５ml）に溶解し、４−（４−フルオロベンゾイル）ベンジルブロミド（６７４mg）、炭酸カリウム（３１８mg）を加え、室温で１５時間撹拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製した後、さらに５−ｔ−ブチル−１−〔４−（４−フルオロベンゾイル）ベンジル〕−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オンはｎ−ヘキサン−ジエチルエーテルで、５−ｔ−ブチル−２−〔４−（４−フルオロベンゾイル）ベンジル〕−２Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オンはジエチルエーテルでそれぞれ洗浄し、乾燥した。
化合物（Ａ）：白色粉末１１５mg
¹H-NMR(DMSO-d₆)δ：1.63(9H,s), 5.81(2H,s), 7.3-7.5(4H,m), 7.7-7.9(4H,m),8.27(1H,s), 8.66(1H,s).
IR(KBr)：1650, 1665 cm^-1.
化合物（Ｂ）：白色粉末２３５mg
¹H-NMR(DMSO-d₆)δ：1.61(9H,s), 5.74(2H,s), 7.3-7.5(4H,m), 7.7-7.8(4H,m),8.33(1H,s), 8.89(1H,s).
IR(KBr)：1600, 1650, 1655 cm^-1.
【０１２９】
実施例６４
１−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（Ａ）
２−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−２Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（Ｂ）
５−メチル−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オン（１０１mg）をＤＭＦ（２ml）に溶解し、４−（４−クロロベンゾイル）ベンジルブロミド（３１０mg）、炭酸カリウム（１３８mg）を加え、室温で１５時間撹拌した。反応液を酢酸エチル−ＴＨＦで抽出し、有機層を無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル（１：４））で精製した後、さらに１−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−１Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オンはジエチルエーテル−酢酸エチルで、２−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−２Ｈ−ピラゾロ〔３,４−d〕ピリダジン−４（５Ｈ）−オンは酢酸エチルでそれぞれ洗浄し、乾燥した。
化合物（Ａ）：白色粉末２０mg
¹H-NMR(DMSO-d₆)δ：3.70(3H,s), 5.84(2H,s), 7.42(2H,d,J=8.4Hz), 7.60(2H,d,J=8.6Hz), 7.72(2H,d,J=8.4Hz), 7.73(2H,d,J=8.6Hz), 8.33(1H,s), 8.73(1H,s).
IR(KBr)：1655 cm^-1.
化合物（Ｂ）：白色粉末１３７mg
¹H-NMR(DMSO-d₆)δ：3.64(3H,s), 5.75(2H,s), 7.49(2H,d,J=7.6Hz), 7.61(2H,d,J=8.4Hz), 7.74(4H,br d), 8.38(1H,s), 8.94(1H,s).
IR(KBr)：1585, 1650 cm^-1.
【０１３０】
実施例６５
１−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−１Ｈ−トリアゾロ〔４,５−d〕ピリダジン−４（５Ｈ）−オン
５−メチル−１Ｈ−トリアゾロ〔４,５−d〕ピリダジン−４（５Ｈ）−オン（２２７mg）をＤＭＦ（５ml）に溶解し、４−（４−クロロベンゾイル）ベンジルブロミド（７１２mg）、炭酸カリウム（３１８mg）を加え、室温で２時間撹拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製した後、さらにジエチルエーテルで洗浄し、乾燥した。白色粉末１１０mg
¹H-NMR(CDCl₃)δ：3.89(3H,s), 5.90(2H,s), 7.42(2H,d,J=8.4Hz), 7.47(2H,d,J=8.8Hz), 7.73(2H,d,J=8.8Hz), 7.81(2H,d,J=8.4Hz), 7.96(1H,s).
IR(KBr)：1655, 1670 cm^-1.
【０１３１】
実施例６６
１−〔４−（４−フルオロベンゾイル）ベンジル〕−２，３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（１０ｍｌ）懸濁液に、２，３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（４０４ｍｇ）のＤＭＦ（７０ｍｌ）溶液を滴下注入した。室温で２時間撹拌後、４−（４−フルオロベンゾイル）ベンジルブロミド（６４５ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに１６時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〕で精製して表題化合物を白色粉末（３７１ｍｇ：収率４３％）として得た。
¹H-NMR(DMSO-d₆) δ :3.35(3H,s), 5.74(2H,s), 7.30(2H,t,J=8.0Hz), 7.38(2H,d,J=8.8Hz), 7.73(2H,d,J=8.0Hz), 7.81(2H,dd,J=5.4,8.8Hz), 8.59(1H,s).
IR(KBr) : 3050, 2950, 1650, 1640, 1600.
【０１３２】
実施例６７
２，３−ジクロロ−１−〔４−（２，４−ジクロロベンゾイル）ベンジル〕−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（１０ｍｌ）懸濁液に、２，３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（４０４ｍｇ）のＤＭＦ（７０ｍｌ）溶液を滴下注入した。室温で２時間撹拌後、４−（２，４−ジクロロベンゾイル）ベンジルブロミド（７５７ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに１６時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をエーテルで洗浄して表題化合物を黄褐色粉末（４７１ｍｇ：収率４９％）として得た。
¹H-NMR(DMSO-d₆) δ :3.67(3H,s), 5.73(2H,s), 7.27(2H,d,J=8.4Hz), 7.54(1H,d,J=8.2Hz), 7.60(1H,dd,J=2.2,8.2Hz), 7.73(2H,d,J=8.4Hz), 7.82(1H,d,J=2.2Hz), 8.55(1H,s).
IR(KBr) : 3050, 2950, 1665, 1600, 1580.
【０１３３】
実施例６８
１−〔３−（４−クロロベンゾイル）ベンジル〕−２，３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（７２ｍｇ）のＤＭＦ（１０ｍｌ）懸濁液に、２，３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（３０３ｍｇ）のＤＭＦ（５０ｍｌ）溶液を滴下注入した。室温で２．５時間撹拌後、３−（４−クロロベンゾイル）ベンジルブロミド（５１１ｍｇ）のＤＭＦ（１０ｍｌ）溶液を加えて室温でさらに１７時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〕で精製して表題化合物を白色粉末（１０４ｍｇ：収率１６％）として得た。
¹H-NMR(DMSO-d₆) δ :3.68(3H,s), 5.71(2H,s), 7.42(1H,dm,J=7.8Hz), 7.56(1H,t,J=7.8Hz), 7.61(2H,d,J=8.6Hz), 7.55-7.65(1H,m), 7.65-7.77(1H,m), 7.71(2H,d,J=8.6Hz), 8.59(1H,s).
IR(KBr) : 3050, 2950, 1660, 1630, 1580.
【０１３４】
実施例６９
２，３−ジクロロ−５−メチル−１−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（１０ｍｌ）懸濁液に、２，３−ジクロロ−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（４０４ｍｇ）のＤＭＦ（７０ｍｌ）溶液を滴下注入した。室温で２時間撹拌後、４−（４−トリフルオロメチルベンゾイル）ベンジルブロミド（７５４ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに１５時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〕で精製して表題化合物を白色粉末（４４８ｍｇ：収率４７％）として得た。
¹H-NMR(DMSO-d₆) δ ：3.68(3H,s), 5.75(2H,s), 7.31(2H,d,J＝8.2Hz), 7.78(2H,d,J＝8.2Hz), 7.91(4H,s), 8.58(1H,s).
IR(KBr) ： 3040, 2930, 1660, 1650, 1605.
【０１３５】
実施例７０
１−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（８ｍｌ）懸濁液に、５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（２９８ｍｇ）のＤＭＦ（１０ｍｌ）溶液を滴下注入した。室温で３０分間撹拌後、４−（４−クロロベンゾイル）ベンジルブロミド（７１２ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに１．５時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／２〕で精製して表題化合物を白色粉末（５０５ｍｇ：収率５７％）として得た。
¹H-NMR(DMSO-d₆) δ :3.68(3H,s), 5.65(2H,s), 6.74(1H,d,J=3.0Hz), 7.39(2H,d,J=8.4Hz), 7.61(2H,d,J=8.4Hz), 7.63(1H,d,J=3.0Hz), 7.73(4H,d,J=8.4Hz),8.45(1H,s).
IR(KBr) : 3050, 2940, 1650, 1600, 1580, 1540.
【０１３６】
実施例７１
１−〔４−（４−フルオロベンゾイル）ベンジル〕−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（１２０ｍｇ）のＤＭＦ（１０ｍｌ）懸濁液に、５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（３７３ｍｇ）のＤＭＦ（１０ｍｌ）溶液を滴下注入した。室温で１時間撹拌後、４−（４−フルオロベンゾイル）ベンジルブロミド（８０６ｍｇ）のＤＭＦ（２０ｍｌ）溶液を加えて室温でさらに１３時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ジクロロメタン／メタノール＝９９／１〕で精製して表題化合物を白色粉末（６１５ｍｇ：収率６８％）として得た。
¹H-NMR(DMSO-d₆) δ :3.68(3H,s), 5.64(2H,s), 6.74(1H,d,J=3.0Hz), 7.37(2H,t,J=9.0Hz), 7.39(2H,d,J=8.0Hz), 7.62(1H,d,J=3.0Hz), 7.72(2H,d,J=8.0Hz),7.80(2H,dd,J=5.4,9.0Hz), 8.45(1H,s).
IR(KBr) : 3040, 2990, 2940, 1650, 1600, 1540.
【０１３７】
実施例７２
１−〔４−（２，４−ジクロロベンゾイル）ベンジル〕−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（８ｍｌ）懸濁液に、５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（２９８ｍｇ）のＤＭＦ（１０ｍｌ）溶液を滴下注入した。室温で１時間撹拌後、４−（２，４−ジクロロベンゾイル）ベンジルブロミド（７５７ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに１．５時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／３〕で精製して表題化合物を白色粉末（５１１ｍｇ：収率６２％）として得た。
¹H-NMR(DMSO-d₆) δ :3.67(3H,s), 5.64(2H,s), 6.73(1H,d,J=3.0Hz), 7.36(2H,d,J=8.2Hz), 7.53(1H,d,J=8.2Hz), 7.60(1H,d,J=3.0Hz), 7.60(1H,dd,J=7.8,8.2Hz), 7.72(2H,d,J=8.2Hz), 7.81(2H,d,J=1.8Hz), 8.40(1H,s).
IR(KBr) : 3050, 2940, 1660, 1640, 1600, 1540.
【０１３８】
実施例７３
１−〔３−（４−クロロベンゾイル）ベンジル〕−５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（８ｍｌ）懸濁液に、５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（２９８ｍｇ）のＤＭＦ（１０ｍｌ）溶液を滴下注入した。室温で１時間撹拌後、３−（４−クロロベンゾイル）ベンジルブロミド（６８１ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに２時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／３〕で精製して表題化合物を白色粉末（６３０ｍｇ：収率８３％）として得た。
¹H-NMR(DMSO-d₆) δ :3.68(3H,s), 5.62(2H,s), 6.71(1H,d,J=3.0Hz), 7.53-7,73(9H,m), 8.47(1H,s).
IR(KBr) : 3100, 3040, 2960, 2850, 1650, 1580, 1540.
【０１３９】
実施例７４
５−メチル−１−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（８ｍｌ）懸濁液に、５−メチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（２９８ｍｇ）のＤＭＦ（１０ｍｌ）溶液を滴下注入した。室温で１時間撹拌後、４−（４−トリフルオロメチルベンゾイル）ベンジルブロミド（７５５ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに３時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／２〕で精製して表題化合物を淡褐色粉末（４３６ｍｇ：収率５３％）として得た。
¹H-NMR(CDCl₃) δ :3.86(3H,s), 5.43(2H,s), 6.95(1H,d,J=3.0Hz), 7.13(1H,d,J=3.0Hz), 7.22(2H,d,J=8.8Hz), 7.76(2H,d,J=8.8Hz), 7.80(2H,d,J=8.2Hz), 7.87(2H,d,J=8.2Hz), 7.93(1H,s).
IR(KBr) : 3100, 3050, 2950, 1660, 1640, 1605.
【０１４０】
実施例７５
１−〔４−（４−クロロベンゾイル）ベンジル〕−２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（１４４ｍｇ）のＤＭＦ（１２ｍｌ）懸濁液に、２．３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（５３２ｍｇ）のＤＭＦ（４５ｍｌ）溶液を滴下注入した。室温で３０分間撹拌後、４−（４−クロロベンゾイル）ベンジルブロミド（１．０２ｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに１．５時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／２〕で精製して表題化合物を淡黄色粉末（７１１ｍｇ：収率５８％）として得た。
¹H-NMR(CDCl₃) δ :2.23(3H,s), 2.48(3H,s), 3.83(3H,s), 5.35(2H,s), 7.04(2H,d,J=8.2Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.2Hz), 7.85(1H,s).
IR(KBr) : 3050, 2930, 1660, 1630, 1605, 1520.
【０１４１】
実施例７６
１−〔４−（４−フルオロベンゾイル）ベンジル〕−２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（８ｍｌ）懸濁液に、２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（３５４ｍｇ）のＤＭＦ（３０ｍｌ）溶液を滴下注入した。室温で１時間撹拌後、４−（４−フルオロベンゾイル）ベンジルブロミド（６４５ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに２時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〕で精製して表題化合物を白色粉末（６２８ｍｇ：収率８１％）として得た。
¹H-NMR(CDCl₃) δ :2.23(3H,s), 2.48(3H,s), 3.83(3H,s), 5.35(2H,s), 7.04(2H,d,J=8.4Hz), 7.16(2H,t,J=8.6Hz), 7.74(2H,d,J=8.4Hz), 7.78(2H,dd,J=3.0,8.6Hz), 7.86(1H,s).
IR(KBr) : 3055, 2940, 1650, 1610, 1595, 1510.
【０１４２】
実施例７７
１−〔４−（２，４−ジクロロベンゾイル）ベンジル〕−２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（８ｍｌ）懸濁液に、２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（３５４ｍｇ）のＤＭＦ（３０ｍｌ）溶液を滴下注入した。室温で１時間撹拌後、４−（２，４−ジクロロベンゾイル）ベンジルブロミド（７５７ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに１．５時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〕で精製して表題化合物を淡黄色粉末（６１２ｍｇ：収率７０％）として得た。
¹H-NMR(CDCl₃) δ :2.20(3H,s), 2.46(3H,s), 3.82(3H,s), 5.33(2H,s), 7.01(2H,d,J=8.6Hz), 7.30(1H,d,J=8.0Hz), 7.36(1H,dd,J=1.8,8.0Hz), 7.48(1H,d,J=1.8Hz), 7.75(2H,d,J=8.6Hz), 7.82(1H,s).
IR(KBr) : 3100, 2910, 1660, 1600, 1580, 1520.
【０１４３】
実施例７８
１−〔４−（４−トリフロオロメチルベンゾイル）ベンジル〕−２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（９６ｍｇ）のＤＭＦ（８ｍｌ）懸濁液に、２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（３５４ｍｇ）のＤＭＦ（３０ｍｌ）溶液を滴下注入した。室温で１時間撹拌後、４−（４−トリフルオロメチルベンゾイル）ベンジルブロミド（７５５ｍｇ）のＤＭＦ（１５ｍｌ）溶液を加えて室温でさらに１．５時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〕で精製して表題化合物を淡黄色粉末（５６６ｍｇ：収率６４％）として得た。
¹H-NMR(CDCl₃) δ:2.23(3H,s), 2.48(3H,s), 3.82(3H,s), 5.36(2H,s), 7.05(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.77(2H,d,J=8.0Hz), 7.84(1H,s), 7.86(2H,d,J=8.0Hz).
IR(KBr) : 3050, 2910, 1660, 1600, 1570, 1520.
【０１４４】
実施例７９
１−〔４−（４−メトキシベンゾイル）ベンジル〕−２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン
氷浴で冷却した６０％油性水素化ナトリウム（２８８ｍｇ）のＤＭＦ（２４ｍｌ）懸濁液に、２，３，５−トリメチル−１Ｈ−ピロロ〔２，３−ｄ〕ピリダジン−４（５Ｈ）−オン（１．０６ｇ）のＤＭＦ（９０ｍｌ）溶液を滴下注入した。室温で１時間撹拌後、４−（４−メトキシベンゾイル）ベンジルブロミド（２．４０ｇ）のＤＭＦ（３０ｍｌ）溶液を加えて室温でさらに２時間撹拌した。水を加え反応を停止後、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー〔展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１→１／２〕で精製して表題化合物を淡黄色粉末（１．７０ｇ：収率７１％）として得た。
¹H-NMR(CDCl₃) δ :2.23(3H,s), 2.48(3H,s), 3.83(3H,s), 3.89(3H,s), 5.34(2H,s), 6.96(2H,d,J=8.6Hz), 7.03(2H,d,J=8.0Hz), 7.72(2H,d,J=8.0Hz), 7.80(2H,d,J=8.6Hz), 7.83(1H,s).
IR(KBr) : 3050, 2910, 1660, 1635, 1600, 1570, 1520.
【０１４５】
実施例８０
５−ｔ−ブチル−１−〔３−（４−クロロベンゾイル）ベンジル〕−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（Ａ）
５−ｔ−ブチル−２−〔３−（４−クロロベンゾイル）ベンジル〕−２Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（Ｂ）
５−ｔ−ブチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（２８８ｍｇ）をＤＭＦ（５ｍｌ）に溶解し、３−（４−クロロベンゾイル）ベンジルブロミド（７１２ｍｇ）、炭酸カリウム（３１８ｍｇ）を加え、室温で１５時間撹拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製した後、さらに５−ｔ−ブチル−１−〔３−（４−クロロベンゾイル）ベンジル〕−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オンはジエチルエーテルで、５−ｔ−ブチル−２−〔３−（４−クロロベンゾイル）ベンジル〕−２Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オンはｎ−ヘキサン−ジエチルエーテルでそれぞれ洗浄し、乾燥した。
化合物Ａ：白色粉末１７２ｍｇ
¹H-NMR(DMSO-d₆) δ: 1.62(9H,s), 5.78(2H,s), 7.5-7.7(8H,m), 8.25(1H,s), 8.66(1H,s)
Anal.Calcd. : C 65.63%, H 5.03%, N 13.31%
Found : C 65.88%, H 4.97%, N 13.47%
化合物Ｂ：白色粉末４２ｍｇ
¹H-NMR(DMSO-d₆)δ：1.61(9H,s), 5.72(2H,s), 7.5-7.8(8H,m), 8.33(1H,s), 8.88(1H,s)
Anal.Calcd. : C 65.63%, H 5.03%, N 13.31%
Found : C 65.75%, H 4.90%, N 13.41%
【０１４６】
実施例８１
５−ｔ−ブチル−１−〔４−（２，４−ジクロロベンゾイル）ベンジル〕−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（Ａ）
５−ｔ−ブチル−２−〔４−（２，４−ジクロロベンゾイル）ベンジル〕−２Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（Ｂ）
５−ｔ−ブチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（２８８ｍｇ）をＤＭＦ（５ｍｌ）に溶解し、４−（２，４−ジクロロベンゾイル）ベンジルブロミド（７９１ｍｇ）、炭酸カリウム（３１８ｍｇ）を加え、室温で１５時間撹拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製した後、さらに５−ｔ−ブチル−２−〔４−（２，４−ジクロロベンゾイル）ベンジル〕−２Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オンはｎ−ヘキサン−ジエチルエーテルで洗浄し、乾燥した。
化合物Ａ：白色粉末２０８ｍｇ
¹H-NMR(DMSO-d₆)δ: 1.62(9H,s), 5.81(2H,s), 7.44(2H,d,J=8.4Hz), 7.53(1H,d,J=8.2Hz), 7.60(1H,d,J=8.2Hz), 7.73(2H,d,J=8.4Hz), 7.81(1H,s), 8.26(1H,s), 8.63(1H,s)
化合物Ｂ：白色粉末２２０ｍｇ
¹H-NMR(DMSO-d₆)δ: 1.60(9H,s), 5.73(2H,s), 7.47(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.53(1H,d,J=8.2Hz), 7.60(1H,d,J=8.2Hz), 7.81(1H,s), 8.32(1H,s), 8.88(1H,s)
【０１４７】
実施例８２
５−ｔ−ブチル−１−〔４−（４−クロロベンゾイル）ベンジル〕−３−メチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン
５−ｔ−ブチル−３−メチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（５１６ｍｇ）をＤＭＦ（１０ｍｌ）に溶解し、４−（４−クロロベンゾイル）ベンジルブロミド（１．２ｇ）、炭酸カリウム（５２５ｍｇ）を加え、室温で１５時間撹拌した。反応液を酢酸エチル−ＴＨＦで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製した後、さらにｎ−ヘキサン−ジエチルエーテルで洗浄し、乾燥した。白色粉末５２７ｍｇ
¹H-NMR(DMSO-d₆)δ: 1.62(9H,s), 2.52(3H,s), 5.70(2H,s), 7.44(2H,d,J=8.4Hz), 7.61(2H,d,J=8.4Hz), 7.73,(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 8.56(1H,s)
【０１４８】
実施例８３
５−ｔ−ブチル−１−〔４−（４−フルオロベンゾイル）ベンジル〕−３−メチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（Ａ）
５−ｔ−ブチル−２−〔４−（４−フルオロベンゾイル）ベンジル〕−３−メチル−２Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（Ｂ）
５−ｔ−ブチル−３−メチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（５１６ｍｇ）をＤＭＦ（１０ｍｌ）に溶解し、４−（４−フルオロベンゾイル）ベンジルブロミド（１．１ｇ）、炭酸カリウム（５２５ｍｇ）を加え、室温で１５時間撹拌した。反応液をジエチルエーテルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製した後、さらに５−ｔ−ブチル−１−〔４−（４−フルオロベンゾイル）ベンジル〕−３−メチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オンはｎ−ヘキサン−ジエチルエーテルで、５−ｔ−ブチル−２−〔４−（４−フルオロベンゾイル）ベンジル〕−３−メチル−２Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オンはジエチルエーテル−酢酸エチルでそれぞれ洗浄し、乾燥した。
化合物Ａ：白色粉末５１３ｍｇ
¹H-NMR(DMSO-d₆)δ: 1.62(9H,s), 2.52(3H,s), 5.70(2H,s), 7.36(2H,dd,J=8.8Hz and 8.4Hz), 7.44(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.81(2H,dd,J=5.8Hz and 8.8Hz), 8.55(1H,s)
Anal.Calcd. : C 68.89%, H 5.54%, N 13.39%
Found : C 68.82%, H 5.52%, N 13.37%
化合物Ｂ：白色粉末２６２ｍｇ
¹H-NMR(DMSO-d₆)δ: 1.61(9H,s), 2.68(3H,s), 5.70(2H,s), 7.35(2H,d,J=8.4Hz), 7.37(2H,dd,J=8.8Hz and 9.2Hz), 7.71(2H,d,J=8.4Hz), 7.81(2H,dd,J=5.4Hz and 9.2Hz), 8.27(1H,S)
Anal.Calcd. : C 68.89%, H 5.54%, N 13.39%
Found : C 68.99%, H 5.41%, N 13.42%
【０１４９】
実施例８４
１−〔４−（４−クロロベンゾイル）ベンジル〕−３，５−ジメチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（Ａ）
２−〔４−（４−クロロベンゾイル）ベンジル〕−３，５−ジメチル−２Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（Ｂ）
３，５−ジメチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オン（９４ｍｇ）をＤＭＦ（２ｍｌ）に溶解し、４−（４−クロロベンゾイル）ベンジルブロミド（２７９ｍｇ）、炭酸カリウム（１２４ｍｇ）を加え、室温で１５時間撹拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮し、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル（１：４））で精製した後、さらに１−〔４−（４−クロロベンゾイル）ベンジル〕−３，５−ジメチル−１Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オンはｎ−ヘキサン−ジエチルエーテルで、２−〔４−（４−クロロベンゾイル）ベンジル〕−３，５−ジメチル−２Ｈ−ピラゾロ〔３，４−ｄ〕ピリダジン−４（５Ｈ）−オンはジエチルエーテルでそれぞれ洗浄し、乾燥した。
化合物Ａ：白色粉末９２ｍｇ
¹H-NMR(DMSO-d₆) δ: 2.52(3H,s), 3.67(3H,s), 5.73(2H,s), 7.41(2H,d,J=8.2Hz), 7.61(2H,d,J=8.8Hz), 7.72,(2H,d,J=8.2Hz), 7.73(2H,d,J=8.8Hz), 8.65(1H,s)
化合物Ｂ：白色粉末５４ｍｇ
¹H-NMR(DMSO-d₆) δ： 2.69(3H,s), 3.62(3H,s), 5.72(2H,s), 7.35(2H,d,J=8.2Hz), 7.61(2H,d,J=8.8Hz), 7.73(2H,d,J=8.2Hz), 7.74(2H,d,J=8.8Hz), 8.33(1H,s)
【０１５０】
実施例８５
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３−メチルプテリジン−４−オン
３−メチルプテリジン−４−オン−２−チオン(１９４ｍｇ)のエタノール(５ｍｌ)溶液に１Ｎ水酸化ナトリウム（１．２ｍｌ）水溶液と臭化４−（４−クロロベンゾイル）ベンジル（３１０ｍｇ）を加えて室温で２４時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、表題化合物（１１８ｍｇ，２８％）を白色粉末として得た。
¹H-NMR(CDCl₃)δ: 3.69 (3H, s), 4.73 (2H, s), 7.42-7.82 (8H, m), 8.77 (1H, d, J=2.2Hz), 8.91 (1H, d, J=2.2Hz).
IR(KBr)cm^-1 : 1700, 1650, 1545, 1530, 1410, 1400, 1280, 1170.
【０１５１】
実施例８６
７−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−１，３−ジメチルキサンチン
テオフィリン（１．８０ｇ）のジメチルホルムアミド（２０ｍｌ）溶液に炭酸カリウム（１．６６ｇ）と臭化４−（４−トリフルオロメチルベンゾイル）ベンジル（３．４３ｇ）を加えて室温で２０時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さに４Ｎ塩酸−酢酸エチル溶液を加え、析出物をろ取し、ろ取した化合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去し、表題化合物（１．５７ｇ，３６％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ： 3.41 (3H, s), 3.61 (3H, s), 5.61 (2H, s), 7.40-7.90 (9H, m).
IR(KBr)cm^-1 ： 1705, 1660, 1605, 1550, 1410, 1325, 1275, 1130, 1060.
【０１５２】
実施例８７
７−〔４−（１−インドリルカルボニル）ベンジル〕−１，３−ジメチルキサンチン
テオフィリン（１．８０ｇ）のジメチルホルムアミド（２０ｍｌ）溶液に炭酸カリウム（１．６６ｇ）と塩化４−（１−インドリルカルボニル）ベンジル（２．７０ｇ）を加えて室温で２２時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去し、表題化合物（２．２５ｇ，５４％）を無色粉末として得た。
¹H-NMR(CDCl₃)δ: 3.42 (3H, s), 3.62 (3H, s), 5.17 (2H, s), 6.62 (1H, d, J=3.0Hz), 7.22-7.80 (9H, m), 8.36-8.45 (1H, m).
IR(KBr)cm^-1 : 1700, 1650, 1540, 1450, 1380, 1340.
【０１５３】
実施例８８
６−クロロ−２−〔３−（４−クロロベンゾイル)ベンジル〕チオ−３，５，７−トリメチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
２−〔３−（４−クロロベンゾイル)ベンジル〕チオ−３，５，７−トリメチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（０．３５１ｇ）を乾燥ジクロロメタン（８ｍｌ）に溶解し、氷冷撹拌下、Ｎ−クロロコハク酸イミド（０．１１３ｇ）を添加した。２時間撹拌後、減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；クロロホルム）で精製することにより表題化合物（０．１０４ｇ）を得た。
¹H-NMR(CDCl₃) δ :2.36(3H,s), 3.53(3H,s), 3.56(3H,s), 4.51(2H,s), 7.40(2H,d,J=8.4Hz), 7.40-7.50(1H,m), 7.62-7.73(2H,m), 7.71(2H,d,J=8.4Hz), 7.97(1H,s)
【０１５４】
実施例８９
６−クロロ−７−〔４−（４−クロロベンゾイル)ベンジル〕−３，５−ジメチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
７−〔４−（４−クロロベンゾイル)ベンジル〕−３，５−ジメチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（８８ｍｇ）を乾燥ジクロロメタン（３ｍｌ）に溶解し、氷冷撹拌下、Ｎ−クロロコハク酸イミド（２８ｍｇ）を添加した。２時間撹拌後、減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；クロロホルム）で精製することにより表題化合物（５５ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :2.38(3H,s), 2.56(3H,s), 3.56(3H,s), 5.39(2H,s), 7.33(2H,d,J=8.2Hz), 7.45(2H,d,J=8.2Hz), 7.73(4H,d,J=8.6Hz)
【０１５５】
実施例９０
７−〔４−（４−クロロベンゾイル)ベンジル〕−３−エチル−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７−〔４−（４−クロロベンゾイル)ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン(２．４６ｇ)を乾燥ＤＭＥ(７２．５ｍｌ)、乾燥ジメチルホルムアミド（７２．５ｍｌ）に溶解し、氷冷下６０％油性水素化ナトリウム（２５５ｍｇ）を２回に分けて添加した。３０分撹拌し、ヨウ化エチル（１．０９ｇ）を加え室温に戻し１夜撹拌放置した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；ジクロロメタン→メタノール：ジクロロメタン；１：４９）で精製することにより表題化合物（１．０４ｇ）を得た。
¹H-NMR(CDCl₃) δ :1.36(3H,t,J=7.0Hz), 2.39(3H,s), 2.56(3H,s), 4.19(2H,q,J=7.0Hz), 5.28(2H,s), 6.46(1H,s), 7.31(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.74(4H,d,J=8.6Hz)
【０１５６】
実施例９１
７−〔４−（４−フルオロベンゾイル)ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７−〔４−（４−フルオロベンゾイル)ベンジル〕−４−メトキシ−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン（６．７５ｇ）をジオキサン（４５ｍｌ）に溶解し、４，４'−チオビス（６−ｔ−ブチル−ｍ−クレゾール）（７５ｍｇ）を添加後、０．５規定塩酸（１２ｍｌ）を加え１０５℃、２３時間撹拌した。再度０．５規定塩酸（１２ｍｌ）を加え、同温度にて２２時間撹拌後、１規定塩酸（３ｍｌ）とジオキサン（６ｍｌ）を加え、同温度にて２４時間撹拌した。室温放置後、析出した結晶を瀘取し、メタノール、ＤＭＥ、エーテル洗浄後、乾燥することにより表題化合物（５．３５ｇ）を得た。
¹H-NMR(DMSO-d₆) δ: 2.24(3H,S), 2.52(3H,s), 5.34(2H,s), 6.84(1H,s), 7.37(2H,t,J=8.2Hz), 7.43(2H,d,J=8.2Hz), 7.71(2H,d,J=8.2Hz), 7.81(2H,dd,J=5.6Hz,8.6Hz), 12.06(1H,s)
【０１５７】
実施例９２
３，５−ジメチル−７−〔４−（４−フルオロベンゾイル)ベンジル〕−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７−〔４−（４−フルオロベンゾイル)ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．８５ｇ）を乾燥ＤＭＥ（５０ｍｌ）、乾燥ジメチルホルムアミド（５０ｍｌ）に溶解し、氷冷下６０％油性水素化ナトリウム（１７６ｍｇ）を２回に分けて添加した。３０分撹拌し、ヨウ化メチル（６８１ｍｇ）を加え室温に戻し１夜時間撹拌した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；酢酸エチル：ヘキサン；１：５．６→１：２．３）で精製することにより表題化合物（１．３１ｇ）を得た。
¹H-NMR(CDCl₃) δ :2.40(3H,d,J=1.0Hz), 2.57(3H,s), 3.57(3H,s), 5.29(2H,s), 6.47(1H,d,J=1.0Hz), 7.16(2H,t,J=8.8Hz)，7.30(2H,d,J=8.2Hz), 7.74(2H,d,J=8.2Hz), 7.83(2H,dd,J=5.4Hz,8.8Hz）
【０１５８】
実施例９３
３−エチル−７−〔４−（４−フルオロベンゾイル）ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、７−〔４−（４−フルオロベンゾイル)ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．８５ｇ）を乾燥ＤＭＥ（５０ｍｌ）、乾燥ジメチルホルムアミド（５０ｍｌ）に溶解し、氷冷下６０％油性水素化ナトリウム（１７６ｍｇ）を２回に分けて添加した。３０分撹拌し、ヨウ化エチル（７４９ｍｇ）を加え室温に戻し１夜撹拌放置した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；酢酸エチル：ヘキサン；１：５．６→１：２．３）で精製することにより表題化合物（８６７ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :1.36(3H,t,J=7.2Hz), 2.40(3H,d,J=1.0Hz), 2.56(3H,s), 4.19(2H,q,J=7.2Hz), 5.29(2H,s), 6.47(1H,d,J=1.0Hz), 7.16(2H,t,J=8.6Hz), 7.31(2H,d,J=8.2Hz), 7.74(2H,d,J=8.2Hz), 7.83(2H,dd,J=5.4Hz,8.6Hz)
【０１５９】
実施例９４
７−〔４−（４−クロロベンゾイル)ベンジル〕−３，５−ジメチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
７−〔４−（４−クロロベンゾイル)ベンジル〕−３，５−ジメチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（８００ｍｇ）をＤＭＥ（１２０ｍｌ）、エタノール（１２ｍｌ）に溶解し、酢酸（６７２ｍｇ）を加えたあと４０℃に加温した。ＴＬＣ（薄層クロマトグラフィー）にて原料が消滅するまでラネーニッケルを加えた。触媒を瀘去し、減圧下溶媒を留去して得られた残渣を酢酸エチルに溶解後、飽和炭酸水素ナトリウム水溶液、ついで飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒留去し放置することにより結晶が析出した。この物を瀘取しエタノール、ヘキサン洗浄後、乾燥することにより表題化合物（６０８ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :2.43(3H,d,J=1.0Hz), 3.57(3H,s), 5.34(2H,s), 6.60(1H,d,J=1.0Hz), 7.26(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.73(4H,d,J=8.4Hz), 7.84(1H,s)
【０１６０】
実施例９５
３，５−ジメチル−７−〔４−（４−フルオロベンゾイル)ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
３，５−ジメチル−７−〔４−（４−フルオロベンゾイル)ベンジル〕−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（７５５ｍｇ）をＤＭＥ（１００ｍｌ）、エタノール（１０ｍｌ）に溶解し、酢酸（５６０ｍｇ）を加えたあと４０℃に加温した。ＴＬＣ（薄層クロマトグラフィー）にて原料が消滅するまでラネーニッケルを加えた。触媒を瀘去し、減圧下溶媒を留去して得られた残渣を酢酸エチルに溶解後、飽和炭酸水素ナトリウム水溶液、ついで飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒留去し放置することにより結晶が析出した。この物を瀘取しエタノール、ヘキサン洗浄後、乾燥することにより表題化合物（５１２ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :2.43(3H,d,J=1.0Hz), 3.57(3H,s), 5.34(2H,s), 6.60(1H,d,J=1.0Hz), 7.15(2H,d,J=8.8Hz), 7.26(2H,d,J=8.0Hz), 7.73(2H,d,J=8.0Hz), 7.82(2H,dd,J=5.6Hz,8.8Hz), 7.84(1H,s)
【０１６１】
実施例９６
７−〔４−（４−クロロベンゾイル)ベンジル〕−３−エチル−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
７−〔４−（４−クロロベンゾイル)ベンジル〕−３−エチル−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（５００ｍｇ）をＤＭＥ（６５ｍｌ）、エタノール（６ｍｌ）に溶解し、酢酸（３３６ｍｇ）を加えたあと４０℃に加温した。ＴＬＣ（薄層クロマトグラフィー）にて原料が消滅するまでラネーニッケルを加えた。触媒を瀘去し、減圧下溶媒を留去して得られた残渣を酢酸エチルに溶解後、飽和炭酸水素ナトリウム水溶液、ついで飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒留去し放置することにより結晶が析出した。この物を瀘取しエタノール、ヘキサン洗浄後、乾燥することにより表題化合物（３７０ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :1.41(3H,t,J=7.2Hz), 2.43(3H,d,J=1.0Hz), 4.06(2H,q,J=7.2Hz), 5.34(2H,s), 6.59(1H,d,J=1.0Hz), 7.27(2H,d,J=8.6Hz), 7.45(2H,d,J=8.6Hz), 7.73(4H,d,J=8.6Hz)
【０１６２】
実施例９７
３−エチル−７−〔４−（４−フルオロベンゾイル)ベンジル〕−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
３−エチル−７−〔４−（４−フルオロベンゾイル)ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（３４４ｍｇ）をＤＭＥ（５０ｍｌ）、エタノール（２ｍｌ）に溶解し、酢酸（２２４ｍｇ）を加えたあと４０℃に加温した。ＴＬＣ（薄層クロマトグラフィー）にて原料が消滅するまでラネーニッケルを加えた。触媒を瀘去し、減圧下溶媒を留去して得られた残渣を酢酸エチルに溶解後、飽和炭酸水素ナトリウム水溶液、ついで飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒留去し放置することにより結晶が析出した。この物を瀘取しエタノール、ヘキサン洗浄後、乾燥することにより表題化合物（２３０ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :1.41(3H,t,J=7.2Hz), 2.44(3H,d,J=1.2Hz), 4.06(2H,q,J=7.2Hz), 5.34(2H,s), 6.59(1H,d,J=1.2Hz), 7.15(2H,t,J=8.8Hz), 7.27(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.82(2H,dd,J=5.6Hz,8.8Hz), 7.84(1H,s)
【０１６３】
実施例９８
２−〔４−（４−フルオロベンゾイル)ベンジル〕チオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン(２．５１ｇ)をメタノール(６７．５ｍｌ)に懸濁し、１規定水酸化ナトリウム(１５．７５ｍｌ)を加え溶解した。氷冷下４−（４−フルオロベンゾイル)ベンジルブロミド(５．０６ｇ)のＤＭＥ(１５ｍｌ)溶液を滴下した。室温に戻した後、一夜撹拌放置した。反応液を減圧下溶媒留去して、得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；酢酸エチル：ヘキサン；１：４→１：１→酢酸エチル）で精製することにより表題化合物（２．４３ｇ）を得た。
¹H-NMR(DMSO-d₆) δ :4.53(2H,s), 6.38(1H,brs), 6.94(1H,brs), 7.42(2H,t,J=8.8Hz), 7.68(4H,s), 7.82(2H,dd,J=5.6Hz,8.8Hz), 11.81(1H,s), 12.13(1H,s)
【０１６４】
実施例９９
３，７−ジメチル−２−〔４−（４−フルオロベンゾイル)ベンジル〕チオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
アルゴン雰囲気下、２−〔４−（４−フルオロベンゾイル)ベンジル〕チオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（８１８ｍｇ）を乾燥ＤＭＥ（２１．５ｍｌ）に溶解し、氷冷撹拌下、６０％油性水素化ナトリウム（１８１ｍｇ）を２回に分けて添加した。次いでヨウ化メチル（７９４ｍｇ）を加え、室温に戻した後、一夜撹拌放置した。反応液に酢酸エチルを加え飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（ヘキサン−酢酸エチル；４：１→３：２）で精製することにより表題化合物（６４０ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :3.59(3H,s), 3.74(3H,s), 4.56(2H,s), 6.61(1H,d,J=3.4Hz), 6.72(1H,d,J=3.4HZ), 7.17(2H,t,J=8.9Hz), 7.60(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.84(2H,dd,J=5.4Hz,8.9Hz)
【０１６５】
実施例１００
５，６−ジクロロ−３，７−ジメチル−２−〔４−（４−フルオロベンゾイル)ベンジル〕チオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
３，７−ジメチル−２−〔４−（４−フルオロベンゾイル)ベンジル〕チオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（２０４ｍｇ）を乾燥ジクロロメタン（７．５ｍｌ）に溶解し、氷冷撹拌下、Ｎ−クロロコハク酸イミド（１４１ｍｇ）を添加した。２時間撹拌後、減圧下溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；ジクロロメタン）で精製することにより表題化合物（１２５ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :3.56(3H,s), 3.69(3H,s), 4.53(2H,s), 7.17(2H,t,J=8.6Hz), 7.57(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.84(2H,dd,J=5.4Hz,8.6Hz)
【０１６６】
実施例１０１
５−ジメチルアミノメチル−２−〔４−（４−フルオロベンゾイル)ベンジル〕チオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（Ａ）
６−ジメチルアミノメチル−２−〔４−（４−フルオロベンゾイル)ベンジル〕チオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（Ｂ）
２−〔４−（４−フルオロベンゾイル)ベンジル〕チオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（５７０ｍｇ）を８０％酢酸水溶液（１５ｍｌ）に溶解し、３７％ホルマリン水溶液（２４４ｍｇ）、次いで５０％ジメチルアミン水溶液（２７０ｍｇ）を加え、６０℃、１３時間撹拌した。減圧下溶媒留去後、水（１５ｍｌ）に溶解し、濃アンモニア水にてアルカリ性としたあとクロロホルム抽出した。飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒留去後、フラッシュカラムクロマトグラフィー（シリカゲル；エタノール：クロロホルム；１：４９→７％アンモニア含エタノール：クロロホルム；１：１９→１：９）精製することにより表題化合物（３６ｍｇ；化合物Ａ）、（２３３ｍｇ；化合物Ｂ）を得た。
化合物Ａ
¹H-NMR(DMSO-d₆) δ :2.36(6H,brs), 3.76(2H,s), 4.47(2H,s), 6.84(1H,s), 7.37(2H,t,J=8.8Hz), 7.65(4H,s), 7.81(2H,dd,J=5.6Hz,8.8Hz), 11.47(1H,s)
化合物Ｂ
¹H-NMR(DMSO-d₆) δ :2.14(6H,brs), 3.39(2H,s), 4.50(2H,s), 6.19(1H,s), 7.37(2H,t,J=8.8Hz), 7.68(4H,s), 7.81(2H,dd,J=5.6Hz,8.8Hz), 11.77(1H,s), 12.06(1H,s)
【０１６７】
実施例１０２
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−１，７−ジメチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
アルゴン雰囲気下、２−〔４−（４−クロロベンゾイル)ベンジル〕チオ−１−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン（１０３ｍｇ）を乾燥ＤＭＳＯ（２０ｍｌ）に加温溶解し、室温に戻した後、６０％油性水素化ナトリウム（１１ｍｇ）を添加し、２０分撹拌した。次いでヨウ化メチル（４２．６ｍｇ）を加え、１夜撹拌放置した。反応液に水（２００ｍｌ）に注加し、析出した沈殿物を瀘取、乾燥後フラッシュカラムクロマトグラフィー（シリカゲル；クロロホルム→エタノール：クロロホルム；１：４９）で精製することにより表題化合物（４７ｍｇ）を得た。
¹H-NMR(CDCl₃) δ :3.94(6H,s), 4.65(2H,s), 6.48(1H,d,J=3.4Hz), 6.62(1H,d,J=3.4HZ), 7.46(2H,d,J=8.8Hz), 7.58(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.8Hz)
【０１６８】
実施例１０３
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−ピロロ〔２,３−ｄ〕ピリダジン−４(５Ｈ)，７(６Ｈ)−ジオン
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−２,３−ジエトキシカルボニル−ピロール（３.３１ｇ）をエタノール（７０ml）に溶解した後、無水ヒドラジン（１０.５４ｇ）を加えて３時間加熱還流した。減圧下溶媒を留去し、得られた結晶を水（１５０ml）に懸濁し、濃塩酸（３０ml）を加えて８５℃にて３０分撹拌した。結晶を水、メタノール、エーテルで洗浄して減圧下乾燥し、表題化合物を１.４６ｇ（収率８１％）得た。
¹H-NMR(DMSO-d₆) δ :5.83(2H,s), 6.54(1H,d,J=3.0Hz), 7.20-7.75(9H,m), 11.2(2H,brs)
【０１６９】
実施例１０４
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４,７−ジクロロ−ピロロ〔２,３−ｄ〕ピリダジン
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−ピロロ〔２,３−ｄ〕ピリダジン−４(５Ｈ)，７(６Ｈ)−ジオン（１.４６ｇ）をオキシ塩化リン（４４.７ｇ）に溶解し、２時間加熱還流した。オキシ塩化リンを減圧下留去し、飽和炭酸水素ナトリウム水溶液を加えて洗浄し、析出した結晶をろ取した。得られた結晶を酢酸エチルに溶解し、無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。その後、シリカゲルカラムクロマトグラフィー（担保４０ｇ：ジクロロメタン：エーテル＝１：０−９：１）にて精製を行い、酢酸エチル−エーテルより再結晶を行い、表題化合物を１.２３ｇ（収率７６％）得た。
¹H-NMR(CDCl₃) δ :5.89(2H,s), 6.87(1H,d,J=3.0Hz), 7.15(2H,d,J=8.0Hz), 7.45(1H,d,J=3.0Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz)
【０１７０】
実施例１０５
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−ピロロ〔２,３−ｄ〕ピリダジン−７(６Ｈ)−オン(Ａ)
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−７−クロロ−ピロロ〔２,３−ｄ〕ピリダジン−４(５Ｈ)−オン(Ｂ)
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４,７−ジクロロ−ピロロ〔２,３−ｄ〕ピリダジン（１.０８ｇ）をジオキサン（１５ml）に溶解し、水酸化ナトリウム（４.４２ｇ）、水（５ml）を加えて６９時間加熱還流した。水（１２０ml）を加えた後、析出した結晶をろ取した。得られた結晶をシリカゲルカラムクロマトグラフィー（担体５０ｇ：ジクロロメタン：エーテル＝１：０−９：１、酢酸エチル：メタノール＝１：９）にて精製を行い、表題化合物１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−ピロロ〔２,３−ｄ〕ピリダジン−７(６Ｈ)−オンを４１６mg（収率４０％）、表題化合物１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−７−クロロ−ピロロ〔２,３−ｄ〕ピリダジン−４(５Ｈ)−オンを１９６mg（収率１９％）得た。
化合物Ａ
¹H-NMR(CDCl₃) δ :5.87(2H,s), 6.59(1H,d,J=2.9Hz), 7.23(1H,d,J=3.0Hz), 7.37(2H,d,J=8.3Hz), 7.45(2H,d,J=8.7Hz), 7.73(2H,d,J=8.7Hz), 7.75(2H,d,J=8.3Hz), 10.02(1H,brs)
化合物Ｂ
¹H-NMR(CDCl₃) δ :5.80(2H,s), 7.04(1H,d,J=3.0Hz), 7.13(2H,d,J=8.6Hz), 7.19(1H,d,J=3.0Hz), 7.46(2H,d,J=8.8Hz), 7.73(2H,d,J=8.8Hz), 7.77(2H,d,J=8.4Hz), 10.18(1H,brs)
【０１７１】
実施例１０６
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−６−メチル−ピロロ〔２,３−ｄ〕ピリダジン−７(６Ｈ)−オン
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−４−クロロ−ピロロ〔２,３−ｄ〕ピリダジン−７(６Ｈ)−オン（８３０mg）をＤＭＦ（２０ml）に溶解し、炭酸カリウム（２.１１ｇ）を加えた後、よう化メチル（０.１３ml）を加え、室温にて９５時間撹拌した。水（５０ml）を加えて酢酸エチル（２００ml）で抽出した後、有機層を、水（１００ml）にて３回洗浄し、飽和食塩水（１００ml）にて洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、得られた結晶を酢酸エチルで洗浄して、表題化合物を７４２mg（収率８４％）得た。
¹H-NMR(CDCl₃) δ :3.82(3H,s), 5.89(2H,s), 6.54(1H,d,J=3.0Hz), 7.19(1H,d,J=3.0Hz), 7.34(2H,d,J=8.2Hz), 7.45(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.2Hz)
【０１７２】
実施例１０７
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−５−メチル−７−クロロ−ピロロ〔２,３−ｄ〕ピリダジン−４(５Ｈ)−オン
１−〔４−（４−クロロ−ベンゾイル）ベンジル〕−７−クロロ−ピロロ〔２,３−ｄ〕ピリダジン−４(５Ｈ)−オン（３５２mg）をＤＭＦ（１５ml）に溶解し、炭酸カリウム（８５８mg）を加えた後、よう化メチル（０.０６ml）を加え、室温にて１６時間撹拌した。水（３０ml）を加えて酢酸エチル（２００ml）で抽出した後、有機層を、水（１００ml）にて３回洗浄し、飽和食塩水（１００ml）にて洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、得られた結晶をヘキサンで洗浄して、表題化合物を２９０mg（収率８０％）得た。
¹H-NMR(CDCl₃) δ :3.83(3H,s), 5.77(2H,s), 7.01(1H,d,J=3.0Hz), 7.13(2H,d,J=8.2Hz), 7.16(1H,d,J=3.0Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz)
【０１７３】
実施例１０８
１,３−ジメチル−７−〔４−（４−メトキシベンゾイル）ベンジル〕キサンチン
テオフィリン（１.８４ｇ）をＤＭＦ（２０ml）に溶解し、炭酸カリウム（１.４２ｇ）を加え、ｐ−メトキシベンゾイルベンジルブロミド（３.７８ｇ）を加えて、室温で１４時間撹拌た。水を加えて酢酸エチル（１２００ml）で希釈した後、有機層を、水（５００ml）にて２回洗浄し、飽和食塩水（５００ml）にて洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、得られた結晶を酢酸エチルで洗浄して、表題化合物を２.８３ｇ（収率６９％）得た。
¹H-NMR(CDCl₃) δ :2.44(3H,s), 3.89(3H,s), 6.96(2H,d,J=9.0Hz), 7.28(2H,d,J=8.0Hz), 7.68(2H,d,J=8.2Hz), 7.82(2H,d,J=8.8Hz)
【０１７４】
実施例１０９
７−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−６−メチル−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
６−メチル−２−ヒドロキシ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン（３６５mg）と炭酸カリウム（５２６mg）のジメチルホルムアミド（１０ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（６６４mg）を加え、反応液を８０℃で２時間撹拌させた。反応液を濃縮し、残渣に水／酢酸エチルを加え、酢酸エチルで抽出し、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝２：１：１）で精製し、酢酸エチルから再結晶して無色固体の表題化合物（４００mg）を得た。
IR(KBr)ν：1670, 1640, 1565, 1490 cm^-1.
NMR(CDCl₃)δ：2.11(3H,s), 5.53(2H,s), 6.92(1H,d,J=4.9Hz), 7.47(2H,d,J=8.5Hz), 7.55(2H,d,J=8.2Hz), 7.76(2H,d,J=8.2Hz), 7.80(2H,d,J=8.5Hz), 7.98(1H,d,J=4.9Hz).
【０１７５】
実施例１１０
７−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−２，３，６−トリメチル−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
２，３，６−トリメチル−２−ヒドロキシ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン（３８２mg）と炭酸カリウム（３５７mg）のジメチルホルムアミド（１０ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（５８１mg）を加え、反応液を８０℃で２時間撹拌させた。反応液を濃縮し、残渣に水／酢酸エチルを加え、酢酸エチルで抽出し、酢酸エチルから再結晶して無色固体の表題化合物（２６６mg）を得た。
IR(KBr)ν：1665, 1580, 1500 cm^-1.
NMR(CDCl₃)δ：2.04(3H,s), 2.27(3H,s), 2.73(3H,s), 5.48(2H,s), 7.46(2H,d,J=8.4Hz), 7.53(2H,d,J=8.2Hz), 7.76(2H,d,J=8.4Hz), 7.79(2H,d,J=8.2Hz).
【０１７６】
実施例１１１
５−〔４−（４−クロロベンゾイル）ベンジル〕−１，３−ジメチル−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン
１，３−ジメチル−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン（０．４０２ｇ，２．２４mmol）と臭化４−（４−クロロベンゾイル）ベンジル（１．２０ｇ，３．８８mmol）のＤＭＦ（５ml）溶液に炭酸カリウム（０．７３ｇ，５．２８mmol）を加え６０℃で２時間撹拌した。溶媒を減圧除去した後残渣に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラム（展開溶媒：イソプロピルエーテル：酢酸エチル：塩化メチレン＝２：１：１）で精製した後、酢酸エチルから再結晶し無色針状晶を得た。
０．３６０ｇ（３９％）
IR(KBr)ν：1693, 1653, 1549, 1466, 1434, 1406, 1267, 1065, 1016, 962, 922, 856, 744, 669, 503 cm^-1.
NMR(CDCl₃)δ：3.40(3H,s), 3.49(3H,s), 5.66(2H,s), 6.00(1H,d,J=3.0Hz), 7.01(1H,d,J=3.0Hz), 7.29(2H,d,J=8.6Hz), 7.45(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz).
【０１７７】
実施例１１２
１，３−ジメチル−５−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン
１，３−ジメチル−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン（０．４０５ｇ，２．２６mmol）と臭化４−（４−トリフルオロメチルベンゾイル）ベンジル（２．０１ｇ）のＤＭＦ（５ml）溶液に炭酸カリウム（０．８２ｇ，５．９３mmol）を加え６０℃で２時間撹拌した。溶媒を減圧除去した後残渣に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラム（展開溶媒：イソプロピルエーテル：酢酸エチル：塩化メチレン＝２：１：１）で精製した後、酢酸エチルから再結晶し無色針状晶を得た。
０．３９８ｇ（４０％）
IR(KBr)ν：1695, 1651, 1468, 1408, 1319, 1277, 1164, 1063, 10146, 926, 759 cm^-1.
【０１７８】
実施例１１３
３,５−ジメチル−２−〔４−（３−インドリルカルボニル）ベンジルチオ〕−キナゾリン−４−オン
３,５−ジメチル−２−メルカプトキナゾリン−４−オン（０.４９７ｇ，２.４１mmol）のＥtＯＨ(１０.０ml)−ＴＨＦ(１０.０ml)混合溶液に１Ｎ−水酸化ナトリウム水溶液（２.５ml）を加えた後臭化４−（３−インドリルカルボニル）ベンジル（０.６５０ｇ，２.４１mmol）を加え室温で２.５時間撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル：ＴＨＦ＝１：１）で精製し淡い赤色固体を得た。０.１７８ｇ（１７％）。
¹H-NMR(CDCl₃) δ :2.76(3H,s), 4.65(2H,s), 7.18-7.28(4H,m), 7.48(2H,d,J=7.6Hz), 7.58-7.83(4H,m), 7.93(1H,dd,J=6.2,3.0Hz), 8.27(1H,m)
IR(KBr) : 3149, 1670, 1602, 1556, 1431, 1309, 1213, 1092, 750 cm^-1
【０１７９】
実施例１１４
３,５−ジメチル−２−〔４−（３,４,５−トリメトキシベンゾイル）ベンジルチオ〕−キナゾリン−４−オン
３,５−ジメチル−２−メルカプトキナゾリン−４−オン（０.４９７ｇ，２.４１mmol）のＥtＯＨ（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２.５ml）を加えた後臭化４−（３,４,５−ｔトリメトキシベンゾイル）ベンジル（０.９７０ｇ，２.５２mmol）を加え室温で終夜撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０.９８３ｇ（８３％）
¹H-NMR(CDCl₃) δ :2.85(3H,s), 3.55(3H,s), 3.86(6H,s), 3.94(3H,s), 4.60(2H,s), 7.04(2H,s), 7.15(1H,d,J=7.2Hz), 7.44(1H,d,J=7.2Hz), 7.51(1H,t,J=7.2Hz), 7.61(2H,d,J=8.0Hz), 7.78(2H,d,J=8.0Hz)
IR(KBr) : 1672, 1581, 1556, 1500, 1462, 1414, 1333, 1234, 1126, 1093, 1001, 806, 773, 696 cm^-1
【０１８０】
実施例１１５
３,５−ジメチル−２−〔４−（４−メトキシベンゾイル）ベンジルチオ〕−キナゾリン−４−オン
３,５−ジメチル−２−メルカプトキナゾリン−４−オン（０.４９５ｇ，２.４１mmol）のＥtＯＨ（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２.５ml）を加えた後臭化４−（４−メトキシベンゾイル）ベンジル（純度８４％，０.９６０ｇ，２.５２mmol）を加え室温で１.５時間撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０.７３６ｇ（７１％）
¹H-NMR(CDCl₃) δ :2.85(3H,s), 3.55(3H,s), 3.89(3H,s), 4.60(2H,s), 6.95(2H,d,J=6.8Hz), 7.15(1H,d,J=6.2Hz), 7.44(1H,d,J=6.2Hz), 7.55(1H,t,J=6.2Hz), 7.59(2H,d,J=6.8Hz), 7.72(2H,d,J=8.0Hz), 7.82(2H,d,J=8.0Hz)
IR(KBr) : 1672, 1601, 1554, 1462, 1417, 1308, 1255, 1173, 1090, 1030, 928 cm^-1
【０１８１】
実施例１１６
３,５−ジメチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−キナゾリン−４−オン
３,５−ジメチル−２−メルカプトキナゾリン−４−オン（０.４９５ｇ，２.４１mmol）のＥtＯＨ（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２.５ml）を加えた後臭化４−（４−トリフルオロメチルベンゾイル）ベンジル（純度６３.４％，１.３７ｇ，２.５２mmol）を加え室温で終夜撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をメタノールから再結晶し無色針状晶を得た。１.２１８ｇ
¹H-NMR(CDCl₃) δ :2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.16(1H,d,J=7.2Hz), 7.32(2H,d,J=8.2Hz), 7.43(1H,d,J=7.2Hz), 7.55(1H,t,J=7.2Hz), 7.63(2H,d,J=8.0Hz), 7.88(2H,d,J=8.0Hz)
IR(KBr) : 1671, 1556, 1410, 1325, 1297, 1171, 1130, 1066, 930, 860, 690 cm^-1
【０１８２】
実施例１１７
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３−エチル−５−メチルキナゾリン−４−オン
３−エチル−５−メチル−２−メルカプトキナゾリン−４−オン（０.５０６ｇ，２.３０mmol）のＥtＯＨ（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２.７ml）を加えた後臭化４−（４−クロロベンゾイル）ベンジル（０.７２０ｇ，２.３３mmol）を加え室温で５時間撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０.６９５ｇ（６７％）
¹H-NMR(CDCl₃) δ :1.35(3H,t,J=7.2Hz), 2.84(3H,s), 4.13(2H,q,J=7.2Hz), 4.59(2H,s), 7.14(1H,d,J=8.0Hz), 7.41-7.54(4H,m), 7.60(2H,d,J=8.0Hz), 7.73(2H,d,J=6.8Hz), 7.74(2H,d,J=8.0Hz)
IR(KBr) : 1668, 1551, 1276, 1221, 1097, 926, 731 cm^-1
【０１８３】
実施例１１８
２−〔４−（４−フルオロベンゾイル）ベンジルチオ〕−３−エチル−５−メチルキナゾリン−４−オン
３−エチル−５−メチル−２−メルカプトキナゾリン−４−オン（０.５０６ｇ，２.３０mmol）のＥtＯＨ（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２.７ml）を加えた後臭化４−（４−フルオロベンゾイル）ベンジル（０.７１５ｇ，２.４４mmol）を加え室温で５時間撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をメタノールから再結晶し無色針状晶を得た。０.８０３ｇ（８１％）
¹H-NMR(CDCl₃) δ :1.35(3H,t,J=7.2Hz), 2.85(3H,s), 4.13(2H,q,J=7.2Hz), 4.59(2H,s), 7.10-7.20(3H,m), 7.42(1H,d,J=7.0Hz), 7.54(1H,t,J=7.0Hz), 7.74(2H,d,J=8.4Hz), 7.76-7.87(2H,m)
IR(KBr) ：1666, 1599, 1552, 1450, 1412, 1371, 1277, 1225, 1153, 1103, 856，808, 777, 734, 698 cm-¹
【０１８４】
実施例１１９
３−エチル−５−メチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−キナゾリン−４−オン
３−エチル−５−メチル−２−メルカプトキナゾリン−４−オン（０．５０７ｇ，２.３０mmol）のＥtＯＨ（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２.７ml）を加えた後臭化４−（４−トリフルオロメチルベンゾイル）ベンジル（純度：６３％，１.２８ｇ，２.３５mmol）を加え室温で５時間撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をメタノールから再結晶し無色針状晶を得た。０.８１１ｇ（７３％）
¹H-NMR(CDCl₃) δ :1.35(3H,t,J=7.2Hz), 2.85(3H,s), 4.12(2H,q,J=7.2Hz), 4.60(2H,s), 7.14(1H,d,J=7.0Hz), 7.42(1H,t,J=7.0Hz), 7.54(1H,t,J=7.0Hz), 7.63(2H,d,J=8.0Hz), 7.74(2H,d,J=8.0Hz), 7.78(2H,d,J=8.0Hz), 7.88(2H,d,J=8.0Hz)
IR(KBr) : 1670, 1552, 1321, 1171, 1130, 1065, 930 cm^-1
【０１８５】
実施例１２０
３−エチル−２−〔４−（４−メトキシベンゾイル）ベンジルチオ〕−５−メチルキナゾリン−４−オン
３−エチル−５−メチル−２−メルカプトキナゾリン−４−オン（０.５０７ｇ，２.３０mmol）のＥtＯＨ（１０.０ml）−ＴＨＦ（１０.０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２.７ml）を加えた後臭化４−（４−メトキシベンゾイル）ベンジル（純度：８４％，０.８４０ｇ，２.３１mmol）を加え室温で５時間撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をメタノールから再結晶し無色針状晶を得た。０.８２６ｇ（８１％）
¹H-NMR(CDCl₃) δ :1.35(3H,t,J=7.0Hz), 2.85(3H,s), 3.89(3H,s), 4.14(2H,q,J=7.0Hz), 4.59(2H,s), 6.96(2H,d,J=8.8Hz), 7.15(1H,d,J=7.2Hz), 7.43(1H,d,J=7.2Hz), 7.54(1H,t,J=7.2Hz), 7.58(2H,d,J=8.1Hz), 7.73(2H,d,J=8.1Hz), 7.82(2H,d,J=8.8Hz)
IR(KBr) : 1674, 1601, 1552, 1257, 1173, 1103, 1028, 930, 851, 811, 781 cm^-1
【０１８６】
実施例１２１
２−〔４−（４−フルオロベンゾイル）ベンジルオキシ〕−３−メチルピリド〔１,２−ａ〕ピリミジン−４−オン
２−ヒドロキシ−３−メチルピリド〔１,２−ａ〕ピリミジン−４−オン（０.４８０ｇ，２.７２mmol）と臭化４−（４−フルオロベンゾイル）ベンジル（０.９００ｇ，３.０７mmol）のＤＭＦ（１０.０ml）−ＤＭＳＯ（１０.０ml）混合溶液に炭酸カリウム（０.８００ｇ，５.７８mmol）を加え室温で２.５時間撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０.４２５ｇ（４０.２％）
¹H-NMR(CDCl₃) δ :2.23(3H,s), 5.63(2H,s), 7.11-7.21(2H,m), 7.45-7.61(4H,m), 7.64-7.89(5H,m), 9.09(1H,d,J=7.2Hz)
IR(KBr) : 1670, 1578, 1531, 1477, 1279, 1165, 926, 854, 762 cm^-1
【０１８７】
実施例１２２
２−〔４−（２−エトキシカルボニルベンゾイル）ベンジルオキシ〕−３−メチルピリド〔１,２−ａ〕ピリミジン−４−オン
２−ヒドロキシ−３−メチルピリド〔１,２−ａ〕ピリミジン−４−オン（０.２７７ｇ，１.５７mmol）と臭化４−（２−エトキシカルボニルベンゾイル）ベンジル（０.５６５ｇ，１.６３mmol）のＤＭＦ（１０.０ml）−ＤＭＳＯ（１０.０ml）混合溶液に炭酸カリウム（０.３６０ｇ，２.６０mmol）を加え室温で終夜撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル：ヘキサン＝２：１）で精製し無色不定形固体を得た。０.３４５ｇ（５４.０％）
¹H-NMR(CDCl₃) δ :1.05(3H,t,J=7.2Hz), 2.20(3H,s), 4.08(2H,q,J=7.2Hz), 5.59(2H,s), 7.10(1H,dt,J=7.2,1.4Hz), 7.41(1H,dt,J=6.6,2.0Hz), 7.51-7.81(8H,m), 8.07(1H,dd,J=6.8,1.6Hz), 9.07(1H,dd,J=6.8,1.6Hz)
IR(KBr) : 1716, 1674, 1635, 1576, 1531, 1479, 1281, 1165, 769 cm^-1
【０１８８】
実施例１２３
２−〔４−（１−インドリルカルボニル）ベンジルオキシ〕−３−メチルピリド〔１,２−ａ〕ピリミジン−４−オン
２−ヒドロキシ−３−メチルピリド〔１,２−ａ〕ピリミジン−４−オン（０.２５８ｇ，１.４６mmol）と塩化４−（１−インドリルカルボニル）ベンジル（０.４３０ｇ，１.５９mmol）のＤＭＦ（１０.０ml）−ＤＭＳＯ（５.０ml）混合溶液に炭酸カリウム（０.３３０ｇ，２.３９mmol）を加え室温で終夜撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０.１９ｇ（３３.０％）
¹H-NMR(CDCl₃-DMSO-d₆) δ :2.24(3H,s), 5.64(2H,s), 6.62(1H,m), 7.12(1H,t,J=7.7Hz), 7.27-7.40(4H,m), 7.49-7.80(6H,m), 8.42(1H,d,J=7.7Hz), 9.09(2H,d,J=7.7Hz)
IR(KBr) : 1676, 1578, 1533, 1450, 1336, 1282, 1169, 754 cm^-1
【０１８９】
実施例１２４
３−メチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルオキシ〕−ピリド〔１,２−ａ〕ピリミジン−４−オン
２−ヒドロキシ−３−メチルピリド〔１,２−ａ〕ピリミジン−４−オン（０.２５０ｇ，１.４２mmol）と臭化４−（４−トリフルオロメチルベンゾイル）ベンジル（純度：６３.４％，０.８５２ｇ，２.４８mmol）のＤＭＦ（１０.０ml）−ＤＭＳＯ（５.０ml）混合溶液に炭酸カリウム（０.３６０ｇ，２.６０mmol）を加え室温で終夜撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０.２１ｇ（３４.０％）
¹H-NMR(CDCl₃) δ :2.23(3H,s), 5.63(2H,s), 7.12(1H,t,J=6.8Hz), 7.50(1H,d,J=8.8Hz), 7.61(2H,d,J=8.3Hz), 7.68(1H,m), 7.76(2H,d,J=8.1Hz), 7.84(2H,d,J=8.1Hz), 7.91(2H,d,J=8.3Hz), 9.09(1H,d,J=7.2Hz)
IR(KBr) : 1672, 1578, 1531, 1479, 1325, 1279, 1167, 1128, 1065, 914, 744cm^-1
【０１９０】
実施例１２５
２−〔４−（４−フルオロベンゾイル）ベンジル〕チオ−３−メチルチエノ〔３,２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチルチエノ〔３,２−ｄ〕ピリミジン−４（３Ｈ）−オン（１.０ｇ）と水酸化ナトリウム（２０５mg）の５０％エタノール（１２ml）−ジメチルホルムアミド（２０ml）溶液に、４−（４−フルオロベンゾイル）ベンジルブロミド（１.４８ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（１.４４ｇ）を得た。
¹H-NMR(CDCl₃) δ :3.62(3H,s), 4.58(2H,s), 7.16(2H,t,J=8.6Hz), 7.24(1H,d,J=5.2Hz), 7.59(2H,d,J=8.4Hz), 7.70-7.90(5H,m)
IR(KBr) : 1670, 1640, 1500 cm^-1
【０１９１】
実施例１２６
２−〔４−（４−フルオロベンゾイル）ベンジル〕チオ−３−メチル−６,７−ジヒドロ−５Ｈ−シクロペンタ〔ｄ〕ピリミジン−４(３Ｈ)−オン
参考例１で得られた２−メルカプト−３−メチル−６,７−ジヒドロ−５Ｈ−シクロペンタ〔ｄ〕ピリミジン−４(３Ｈ)−オン（１.０ｇ）と水酸化ナトリウム（２２０mg）の５０％エタノール（１５ml）−ジメチルホルムアミド（８ml）溶液に、４−（４−フルオロベンゾイル）ベンジルブロミド（２.１１ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄し、メタノールから再結晶して無色固体の表題化合物（１.２３５ｇ）を得た。
¹H-NMR(CDCl₃) δ :2.07(2H,quint,J=7.4Hz), 2.80(2H,t,J=7.8Hz), 2.84(2H,t,J=7.8Hz), 3.50(3H,s), 4.50(2H,s), 7.17(2H,t,J=8.4Hz), 7.54(2H,d,J=8.0Hz), 7.74(2H,d,J=8.0Hz), 7.85(2H,dd,J=8.4,5.6Hz)
IR(KBr) : 1660, 1650, 1595, 1495 cm^-1
【０１９２】
実施例１２７
６−〔４−（４−フルオロベンゾイル）ベンジル〕チオ−５−メチル−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オン
６−メルカプト−５−メチル−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オンカリウム塩（１.０ｇ）のジメチルホルムアミド（２０ml）溶液に、４−（４−フルオロベンゾイル）ベンジルブロミド（１.７４５ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄して、無色固体の表題化合物（１.４６７ｇ）を得た。
¹H-NMR(DMSO-d₆) δ :3.45(3H,s), 4.63(2H,s), 7.39(2H,t,J=8.8Hz), 7.72(4H,s), 7.83(2H,dd,J=8.8,5.4Hz), 8.03(1H,s), 13.67(1H,brs)
IR(KBr) : 3200, 1670, 1640, 1575 cm^-1
【０１９３】
実施例１２８
６−〔４−（４−クロロベンゾイル）ベンジル〕チオ−５−エチル−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オン
６−メルカプト−５−エチル−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オンカリウム塩（１.０ｇ）のジメチルホルムアミド（２５ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１.３１ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水、メタノールで洗浄して無色固体の表題化合物（１.７１４ｇ）を得た。
¹H-NMR(DMSO-d₆) δ :1.24(3H,t,J=7.0Hz), 4.07(2H,q,J=7.0Hz), 4.62(2H,s), 7.60(2H,d,J=8.0Hz), 7.70-7.80(7H,m)
IR(KBr) : 3100, 1660, 1580, 1540 cm^-1
【０１９４】
実施例１２９
１−〔４−（４−クロロベンゾイル）ベンジル〕−５−エチル−６−メチルチオ−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オン (Ａ)
２−〔４−（４−クロロベンゾイル）ベンジル〕−５−エチル−６−メチルチオ−２Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オン (Ｂ)
５−エチル−６−メルカプト−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オンカリウム塩（５.０ｇ）のジメチルホルムアミド（４０ml）溶液に、ヨウ化メチル（３.６５ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を濃縮し得られた残渣に水を加え生じた結晶をろ取し、水で洗浄して無色固体の５−エチル−６−メチルチオ−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オン（２.９０８ｇ）を得た。
¹H-NMR(DMSO-d₆) δ :1.24(3H,t,J=7.0Hz), 2.61(3H,s), 4.08(2H,q,J=7.0Hz), 8.09(1H,brs)
５−エチル−６−メチルチオ−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オン（１.０ｇ）のジメチルホルムアミド（２０ml）溶液に、６０％水素化ナトリウム（２３０mg）を加え室温で１０分間撹拌し、つづいて４−（４−クロロベンゾイル）ベンジルブロミド（１.４６ｇ）を加え、反応液を室温で１時間撹拌させた。反応液濃縮し得られた残渣を酢酸エチルに溶解させ、水、飽和食塩水で洗浄し、乾燥後溶媒を留去し、得られた残渣にヘキサン：酢酸エチル＝３：１の溶液を加え、生じた結晶をろ取して無色固体の２−〔４−（４−クロロベンゾイル）ベンジル〕−５−エチル−６−メチルチオ−２Ｈ−ピラゾロ〔３,４−ｄ）ピリミジン−４(５Ｈ)−オン(Ｂ)（５３０mg）を得た。
¹H-NMR(CDCl₃) δ :1.34(3H,t,J=7.0Hz), 2.65(3H,s), 4.17(2H,q,J=7.0Hz), 5.48(2H,s), 7.41(2H,d,J=8.4Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.4Hz), 8.06(1H,s)
IR(KBr) : 1695, 1650, 1570 cm^-1
またろ液を濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝３／２／１）にて精製して、メタノールから結晶化させて無色固体の１−〔４−（４−クロロベンゾイル）ベンジル〕−５−エチル−６−メチルチオ−１Ｈ−ピラゾロ〔３,４−ｄ〕ピリミジン−４(５Ｈ)−オン(Ａ)（１６０mg）を得た。
¹H-NMR(CDCl₃) δ :1.35(3H,t,J=7.0Hz), 2.63(3H,s), 4.20(2H,q,J=7.0Hz), 5.54(2H,s), 7.43(2H,d,J=8.0Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.75(2H,d,J=8.0Hz), 8.05(1H,s)
IR(KBr) : 1695, 1645, 1540 cm^-1
【０１９５】
実施例１３０
７−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−６−メチル−２,３−ジヒドロ−５Ｈ−チアゾロ〔３,２−ａ〕ピリミジン−５−オン
７−ヒドロキシ−６−メチル−２,３−ジヒドロ−５Ｈ−チアゾロ〔３,２−ａ〕−５−オン（１.０ｇ）と炭酸カリウム（７５０mg）のジメチルホルムアミド（１５ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（２.０ｇ）を加え、反応液を６０℃で２時間撹拌させた。反応液を濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）にて精製し、イソプロピルエーテルから再結晶して無色固体の表題化合物（２００mg）を得た。
¹H-NMR(CDCl₃) δ :1.97(3H,s), 3.47(2H,t,J=7.8Hz), 4.46(2H,t,J=7.8Hz), 5.43(2H,s), 7.46(2H,d,J=8.0Hz), 7.50(2H,d,J=8.0Hz), 7.76(2H,d,J=8.0Hz), 7.78(2H,d,J=8.0Hz)
IR(KBr) : 1650, 1515, 1390 cm^-1
【０１９６】
実施例１３１
１−〔４−（４−クロロベンゾイル）ベンジル〕−６−（３−ジメチルアミノプロピルチオ）−５−エチル−１，５−ジヒドロ−４Ｈ−ピラゾロ〔３，４−ｄ〕ピリミジン−４−オン塩酸塩（Ａ）
２−〔４−（４−クロロベンゾイル）ベンジル〕−６−（３−ジメチルアミノプロピルチオ）−５−エチル−２，３−ジヒドロ−４Ｈ−ピラゾロ〔３，４−ｄ〕ピリミジン−４−オン塩酸塩（Ｂ）
５−エチル−６−メルカプト−１，５−ジヒドロ−４Ｈ−ピラゾロ〔３，４−ｄ〕ピリミジン−４−オンカリウム塩（２．０ｇ）のジメチルホルムアミド（２５ml）溶液に２８％ナトリウムメチラート（１．７５ml）を加え、つづいて３−ジメチルアミノプロピルクロリド塩酸塩（１．６２ｇ）を加え６０℃で１日撹拌した。反応液に６０％水素化ナトリウム（２３２mg）を加え室温で１０分間撹拌し、つぎに４−（４−クロロベンゾイル）ベンジルブロミド（１．７７８ｇ）を加え、反応液を室温で３０分間撹拌した。反応液を濃縮し、残渣を酢酸エチルに溶解させ、水洗、乾燥、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール／濃アンモニア水＝５０／１／０．１）にて精製後、塩酸酢酸エチル溶液にて塩酸塩として無色固体の表題化合物（Ａ）（５１８mg）および（Ｂ）（２６２mg）を得た。
化合物（Ａ）
IR(KBr)ν：1710, 1650, 1545 cm^-1.
NMR(CDCl₃)δ：1.34(3H,t,J=7.0Hz), 2.31(2H,m), 2.73(6H,d,J=4.6Hz), 3.03(2H,m), 3.41(2H,t,J=7.0Hz), 4.17(2H,q,J=7.0Hz), 5.61(2H,s), 7.35(2H,d,J=8.2Hz), 7.46(2H,d,J=8.6Hz), 7.73(4H,d,J=8.6Hz), 8.07(1H,s).
化合物（Ｂ）
IR(KBr)ν：1695, 1655, 1580 cm^-1.
NMR(CDCl₃)δ：1.33(3H,t,J=7.0Hz), 2.30-2.50(2H,m), 2.83(6H,d,J=4.4Hz), 3.19(2H,m), 3.41(2H,t,J=7.0Hz), 4.15(2H,q,J=7.0Hz), 5.48(2H,s), 7.40(2H,d,J=8.2Hz), 7.47(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.07(1H,s).
【０１９７】
実施例１３２
５−エチル−１−〔４−（４−メトキシベンゾイル）ベンジル〕−６−メチルチオ−１，５−ジヒドロ−４Ｈ−ピラゾロ〔３，４−ｄ〕ピリミジン−４−オン（Ａ）
５−エチル−２−〔４−（４−メトキシベンゾイル）ベンジル〕−６−メチルチオ−２，５−ジヒドロ−４Ｈ−ピラゾロ〔３，４−ｄ〕ピリミジン−４−オン（Ｂ）
５−エチル−６−メチルチオ−１，５−ジヒドロ−４Ｈ−ピラゾロ〔３，４−ｄ〕ピリミジン−４−オン（９００mg）のジメチルホルムアミド（２０ml）溶液に６０％水素化ナトリウム（２０７mg）を加え室温で１０分間撹拌し、つぎに４−（４−メトキシベンゾイル）ベンジルブロミド（１．３１ｇ）を加え、反応液を室温で３０分間撹拌した。反応液を濃縮し、残渣を酢酸エチルに溶解させ、水洗、乾燥、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝３／２／１）にて精製して無色固体の表題化合物（Ａ）（４００mg）および（Ｂ）（３６６mg）を得た。
化合物（Ａ）
IR(KBr)ν：1695, 1645, 1595, 1550, 1495, 1315, 1260, 1170 cm^-1.
NMR(CDCl₃)δ：1.35(3H,t,J=7.2Hz), 2.63(3H,s), 3.89(3H,s), 4.19(2H,q,J=7.2Hz), 5.54(2H,s), 6.95(2H,d,J=8.8Hz), 7.41(2H,d,J=8.0Hz), 7.73(2H,d,J=8.0Hz), 7.80(2H,d,J=8.8Hz), 8.05(1H,s).
化合物（Ｂ）
IR(KBr)ν：1695, 1650, 1600, 1575, 1515, 1315, 1280, 1170 cm^-1.
NMR(CDCl₃)δ：1.34(3H,t,J=7.0Hz), 2.65(3H,s), 3.89(3H,s), 4.17(2H,q,J=7.0Hz), 5.47(2H,s), 6.96(2H,d,J=8.8Hz), 7.40(2H,d,J=8.0Hz), 7.75(2H,d,J=8.0Hz), 7.81(2H,d,J=8.8Hz), 8.06(1H,s).
【０１９８】
実施例１３３
７−〔４−（４−クロロベンゾイル）ベンジル〕−１−エチル−３−メチルキサンチン
ジャーナル・オブ・アメリカン・ケミカル・ソサイエティー（J. Am. Chem. Soc., ７５，１１４(１９５３)）に合成法が記載されている１−エチル−３−メチルキサンチン（３８５mg）のジメチルホルムアミド（１０ml）溶液に炭酸カリウム（４１５mg）と臭化４−（４−クロロベンゾイル）ベンジル（６１９mg）を加えて室温で１４時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：４）で精製し、さらに再結晶（酢酸エチル−エーテル−ヘキサン）し、表題化合物（２０７mg，２５％）を無色粉末として得た。
IR(KBr)：1695, 1660, 1650, 1600, 1580, 1545, 1455, 1380, 1270, 1230, 1090, 930, 740 cm^-1.
¹H-NMR(CDCl₃)δ：1.25(3H,t,J=7.0Hz), 3.60(3H,s), 4.08(2H,q,H=7.0Hz), 5.60(2H,s), 7.40-7.53(4H,m), 7.64(1H,s), 7.70-7.85(4H,m).
【０１９９】
実施例１３４
２−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
４−（４−クロロベンゾイル）ベンジルアルコール（１．０ｇ）のジメチルホルムアミド（２０ml）溶液に６０％水素化ナトリウム（２１０mg）を加え室温で１０分間撹拌し、つぎに２−クロロ−３，５−ジメチル−４（３Ｈ）−キナゾリノン（８５０mg）を加え、反応液を室温で１時間つづいて８０℃で１０分間撹拌した。反応液を濃縮し、残渣を酢酸エチルに溶解させ、水洗、乾燥、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝４／１／１）にて精製して無色固体の表題化合物（３５０mg）を得た。
IR(KBr)ν：1680, 1665, 1630, 1600 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.53(3H,s), 5.61(2H,s), 7.09(1H,d,J=8.0Hz), 7.34(1H,d,J=8.0Hz), 7.42-7.53(3H,m), 7.60(2H,d,J=8.2Hz), 7.76(2H,d,J=8.6Hz), 7.82(2H,d,J=8.2Hz).
【０２００】
実施例１３５
３，５−ジメチル−２−〔４−（４−フルオロベンゾイル）ベンジルオキシ〕−４（３Ｈ）−キナゾリノン
４−（４−フルオロベンゾイル）ベンジルアルコール（１．０ｇ）のジメチルホルムアミド（２０ml）溶液に６０％水素化ナトリウム（２１０mg）を加え室温で１０分間撹拌し、つぎに２−クロロ−３，５−ジメチル−４（３Ｈ）−キナゾリノン（９０７mg）を加え、反応液を室温で１時間撹拌した。反応液を濃縮し、残渣を酢酸エチルに溶解させ、水洗、乾燥、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３／１）にて精製して無色固体の表題化合物（５６０mg）を得た。
IR(KBr)ν：1675, 1660, 1630, 1595 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.53(3H,s), 5.61(2H,s), 7.09(1H,d,J=8.2Hz), 7.17(2H,t,J=8.6Hz), 7.35(1H,d,J=8.2Hz), 7.50(1H,t,J=8.2Hz), 7.61(2H,d,J=8.2Hz), 7.82(2H,d,J=8.2Hz), 7.86(2H,dd,J=8.6,5.4Hz).
【０２０１】
実施例１３６
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３，５，６−トリメチルチエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３，５，６−トリメチルチエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．１３ｇ）と水酸化ナトリウム（２０５mg）の５０％メタノール（１６ml）−ジメチルホルムアミド（４ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１．６９ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水で洗浄し、酢酸エチルから再結晶して無色固体の表題化合物（１．４２５ｇ）を得た。
IR(KBr)ν：1680, 1655, 1525, 1275, 1090 cm^-1.
NMR(CDCl₃)δ：2.37(3H,s), 2.45(3H,s), 3.54(3H,s), 4.53(2H,s), 7.46(2H,d,J=8.2Hz), 7.56(2H,d,J=8.2Hz), 7.74(4H,d,J=8.2Hz).
【０２０２】
実施例１３７
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３，５−ジメチルチエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
３，５−ジメチル−２−メルカプト−チエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．０６ｇ）と水酸化ナトリウム（２０５mg）の５０％メタノール（１６ml）−ジメチルホルムアミド（４ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（１．６９ｇ）を加え、反応液を室温で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水で洗浄し、酢酸エチルから再結晶して無色固体の表題化合物（８７８mg）を得た。
IR(KBr)ν：1680, 1645, 1515, 1285, 1090 cm^-1.
NMR(CDCl₃)δ：2.55(3H,s), 3.55(3H,s), 4.55(2H,s), 6.67(1H,s), 7.46(2H,d,J=7.8Hz), 7.57(2H,d,J=8.2Hz), 7.74(4H,d,J=8.2Hz).
【０２０３】
実施例１３８
３，５−ジメチル−２−〔４−〔４−〔〔１−（２−ジメチルアミノエチル）−１Ｈ−テトラゾール−５−イル〕チオメチル〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１．０３ｇ）、４，４'−ビス（ブロモメチル）ベンゾフェノン（１．７５ｇ）、１−（２−ジメチルアミノエチル）−５−メルカプト−１Ｈ−テトラゾール（８６５mg）、１規定水酸化ナトリウム水溶液（１１ml）のジメチルホルムアミド（２０ml）溶液を室温で３０分間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール／アンモニア水＝５０／１／０．１）で精製し、メタノールから結晶化して無色固体の表題化合物（３３７mg）を得た。
IR(KBr)ν：1670, 1650, 1605, 1580, 1555, 1305, 1280 cm^-1.
NMR(CDCl₃)δ：2.22(6H,s), 2.69(2H,t,J=6.4Hz), 2.84(3H,s), 3.54(3H,s), 4.24(2H,t,J=6.4Hz), 4.58(2H,s), 4.59(2H,s), 7.15(1H,d,J=7.2Hz), 7.40-7.63(6H,m), 7.70-7.80(4H,m).
【０２０４】
実施例１３９
３，５−ジメチル−２−〔４−〔４−〔（３，５，６−トリメチル−３Ｈ−ピリミジン−４−オン−２−イル）チオメチル〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１．０３ｇ）、４，４'−ビス（ブロモメチル）ベンゾフェノン（１．７５ｇ）、３，５，６−トリメチル−２−メルカプト−３Ｈ−ピリミジン−４−オン（９６０mg）、１規定水酸化ナトリウム水溶液（１１ml）のジメチルホルムアミド（２０ml）溶液を室温で３０分間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝３／１／１）で精製し、メタノールから結晶化して無色固体の表題化合物（６６２mg）を得た。
IR(KBr)ν：1660, 1555, 1520 cm^-1.
NMR(CDCl₃)δ：2.03(3H,s), 2.28(3H,s), 2.85(3H,s), 3.47(3H,s), 3.54(3H,s), 4.47(2H,s), 4.59(2H,s), 7.15(1H,d,J=7.2Hz), 7.40-7.63(6H,m), 7.75(2H,d,J=8.0Hz), 7.76(2H,d,J=8.2Hz).
【０２０５】
実施例１４０
３，５−ジメチル−２−〔４−（４−トルオイル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１９７mg）、４−（４−トルオイル）ベンジルブロミド（３３６mg）、１規定水酸化ナトリウム水溶液（１ml）のジメチルホルムアミド（１０ml）溶液を室温で３０分間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝５／１／１）で精製し、メタノールから結晶化して無色固体の表題化合物（１４０mg）を得た。
IR(KBr)ν：1665, 1650, 1605, 1580, 1555, 1310, 1280 cm^-1.
NMR(CDCl₃)δ：2.44(3H,s), 2.85(3H,s), 3.55(3H,s), 4.59(2H,s), 7.15(1H,d,J=8.2Hz), 7.27(2H,d,J=8.0Hz), 7.40-7.63(4H,m), 7.70(2H,d,J=8.2Hz), 7.75(2H,d,J,=8.2Hz).
【０２０６】
実施例１４１
３，５−ジメチル−２−〔４−〔４−〔（チアゾリジン−２−イル）チオメチル〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１．０３ｇ）、４，４'−ビス（ブロモメチル）ベンゾフェノン（１．７５ｇ）、２−メルカプトチアゾリン（６００mg）、１規定水酸化ナトリウム水溶液（１１ml）のジメチルホルムアミド（２０ml）溶液を室温で３０分間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝３／１／１）で精製し、メタノールから結晶化して無色固体の表題化合物（４８９mg）を得た。
IR(KBr)ν：1660, 1605, 1580, 1555, 1305, 1280 cm^-1.
NMR(CDCl₃)δ：2.84(3H,s), 3.43(2H,t,J=8.2Hz), 3.55(3H,s), 4.23(2H,t,J=8.2Hz), 4.41(2H,s), 4.59(2H,s), 7.15(1H,d,J=7.0Hz), 7.40-7.63(6H,m), 7.74(2H,d,J=8.0Hz), 7.76(2H,d,J=8.2Hz).
【０２０７】
実施例１４２
３，５−ジメチル−２−〔４−〔４−〔（１−メチル−１Ｈ−テトラゾール−５−イル）チオメチル〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１．０３ｇ）、４，４'−ビス（ブロモメチル）ベンゾフェノン（１．７５ｇ）、１−メチル−５−メルカプト−１Ｈ−テトラゾール（７００mg）、１規定水酸化ナトリウム水溶液（５．５ml）のジメチルホルムアミド（２０ml）溶液を室温で３０分間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール／アンモニア水＝５０／１／０．１）で精製し、メタノールから結晶化して無色固体の表題化合物（６０３mg）を得た。
IR(KBr)ν：1665, 1605, 1580, 1555, 1305, 1280 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 3.86(3H,s), 4.60(2H,s), 4.61(2H,s), 7.16(1H,d,J=6.6Hz), 7.40-7.63(6H,m), 7.75(4H,d,J=8.0Hz).
【０２０８】
実施例１４３
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−メルカプト−４（３Ｈ）−キナゾリノン（１．７８ｇ）、４−（４−クロロベンゾイル）ベンジルブロミド（３．０７ｇ）、１規定水酸化ナトリウム水溶液（１０．５ml）のエタノール（２０ml）溶液を室温で３０分間撹拌させた。反応液に水を加え生じた沈殿物をろ取し、水、メタノール、酢酸エチルで洗浄し、乾燥後酢酸エチルから再結晶して無色固体の表題化合物（３．２４ｇ）を得た。
IR(KBr)ν：1690, 1660, 1580, 1560 cm^-1.
NMR(CDCl₃)δ：4.58(2H,s), 7.33-7.80(11H,m), 8.14(1H,d,J=8.0Hz), 12.30(1H,brs).
【０２０９】
実施例１４４
３，５−ジメチル−２−〔４−〔４−（４−メチルピペラジニルメチル）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１．０３ｇ）、４，４'−ビス（ブロモメチル）ベンゾフェノン（１．７５ｇ）、Ｎ−メチルピペラジン（５００mg）、１規定水酸化ナトリウム水溶液（５．５ml）のジメチルホルムアミド（３５ml）溶液を室温で３０分間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール／アンモニア水＝４０／１／０．１）で精製して無色アモルファス状の表題化合物（１８０mg）を得た。
IR(KBr)ν：1670, 1605, 1580, 1555, 1305, 1280 cm^-1.
NMR(CDCl₃)δ：2.31(3H,s), 2.35-2.60(8H,m), 2.85(3H,s)，3.55(3H,s), 3.58(2H,s), 4.60(2H,s), 7.16(1H,d,J=7.0Hz), 7.40-7.63(6H,m), 7.75(2H,d,J=8.0Hz), 7.77(2H,d,J=8.2Hz).
【０２１０】
実施例１４５
３，５−ジメチル−２−〔４−〔４−（４−フェニルピペラジニルメチル）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１．０３ｇ）、４，４'−ビス（ブロモメチル）ベンゾフェノン（１．７５ｇ）、フェニルピペラジン（８１０mg）、１規定水酸化ナトリウム水溶液（５．５ml）のジメチルホルムアミド（３５ml）溶液を６０℃で１時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝４／１／１）で精製し、イソプロピルエーテルより結晶化させて、無色固体の表題化合物（３７２mg）を得た。
IR(KBr)ν：1685, 1655, 1600, 1550, 1305, 1260, 1190 cm^-1.
NMR(CDCl₃)δ：2.64(4H,t,J=5.0Hz), 2.85(3H,s), 3.22(4H,t,J=5.0Hz), 3.55(3H,s), 3.64(2H,s), 4.60(2H,s), 6.80-7.00(3H,m), 7.15(1H,d,J=7.0Hz), 7.20-7.32(2H,m), 7.40-7.65(6H,m), 7.76(2H,d,J=8.2Hz), 7.78(2H,d,J=8.2Hz).
【０２１１】
実施例１４６
２−〔４−（４−アセトキシベンゾイル）ベンジルチオ〕−３，５−ジメチルチエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
３，５−ジメチル−２−メルカプト−チエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．４０ｇ）と１規定水酸化ナトリウム水溶液（６．７ml）のエタノール（１３ml）−ジメチルホルムアミド（２５ml）溶液に、４−（４−アセトキシベンゾイル）ベンジルブロミド（２．６８ｇ）を加え、反応液を室温から６０℃で１時間撹拌させた。反応液を水にあけ酢酸エチルで抽出し、水で洗浄、乾燥後濃縮し、メタノールから再結晶して無色固体の表題化合物（８８７mg）を得た。
IR(KBr)ν：1750, 1680, 1650, 1600, 1520, 1195 cm^-1.
NMR(CDCl₃)δ：2.44(3H,s), 2.55(3H,s), 3.55(3H,s), 4.54(2H,s), 6.67(1H,s), 7.21(2H,d,J=8.6Hz), 7.56(2H,d,J=8.2Hz), 7.77(2H,d,J=8.2Hz), 7.84(2H,d,J=8.6Hz).
【０２１２】
実施例１４７
３，５−ジメチル−２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕チエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
２−〔４−（４−アセトキシベンゾイル）ベンジルチオ〕−３，５−ジメチルチエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．４０ｇ）と１規定水酸化ナトリウム水溶液（６．７ml）のテトラヒドロフラン（２０ml）溶液を室温で１０分間撹拌させた。反応液を濃縮後水に溶解させ１規定塩酸で酸性にし、生じた沈殿物を酢酸エチルで抽出し、水で洗浄、乾燥後濃縮し、メタノール／酢酸エチルから再結晶して無色固体の表題化合物（７７５mg）を得た。
IR(KBr)ν：3320, 1645, 1600, 1580, 1520, 1310, 1280 cm^-1.
NMR(CDCl₃)δ：2.55(3H,d,J=1.2Hz), 3.55(3H,s), 4.55(2H,s), 5.59(1H,s), 6.67(1H,d,J=1.2Hz), 6.91(2H,d,J=8.6Hz), 7.55(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.78(2H,d,J=8.6Hz).
【０２１３】
実施例１４８
３，５−ジメチル−２−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジルチオ〕チエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
３，５−ジメチル−２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕チエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン(４２２mg)、１−（２−クロロエチル）モルホリン塩酸塩(２０５mg)、炭酸カリウム(４１４mg)のジメチルホルムアミド（１０ml）溶液を６０℃で２４時間撹拌させた。反応液を濃縮後水に溶解させ、酢酸エチルで抽出し、水で洗浄、乾燥後濃縮し、ヘキサン／イソプロピルエーテルから結晶化して淡黄色固体の表題化合物（４９５mg）を得た。
IR(KBr)ν：1680, 1650, 1600, 1530, 1310, 1265, 1170, 1120 cm^-1.
NMR(CDCl₃)δ：2.55(3H,d,J=1.2Hz), 2.59(4H,t,J=4.6Hz), 2.84(2H,t,J=5.8Hz), 3.55(3H,s), 3.75(4H,t,J=4.6Hz), 4.19(2H,t,J=5.8Hz), 4.55(2H,s), 6.67(1H,d,J=1.2Hz), 6.96(2H,d,J=9.0Hz), 7.55(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.81(2H,d,J=9.0Hz).
【０２１４】
実施例１４９
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３−メチル−５，６，７，８−テトラヒドロ−４（３Ｈ）−キナゾリノン
２−メルカプト−３−メチル−５，６，７，８−テトラヒドロ−４（３Ｈ）−キナゾリノン（９８０mg）、４−（４−クロロベンゾイル）ベンジルブロミド（１．５３ｇ）、１規定水酸化ナトリウム水溶液（５．５ml）のエタノール（１０ml）、ジメチルホルムアミド（５ml）溶液を室温で３０分間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、メタノール／酢酸エチルから再結晶して無色固体の表題化合物（１．２７ｇ）を得た。
IR(KBr)ν：1655, 1520, 1410, 1280, 1270 cm^-1.
NMR(CDCl₃)δ：1.65-1.85(4H,m), 2.40-2.65(4H,m), 3.47(3H,s), 4.47(2H,s), 7.46(2H,d,J=8.2Hz), 7.55(2H,d,J=8.2Hz), 7.74(2H,d,J=8.2Hz), 7.75(2H,d,J=8.2Hz).
【０２１５】
実施例１５０
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３−フルオロメチル−４（３Ｈ）キナゾリノン
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン（１．０ｇ）のジメチルホルムアミド（３０ml）懸濁液に６０％水素化ナトリウム（１００mg）を加え、溶液が透明になった後フルオロメチルブロミド（５００mg）を加え、反応液を室温で３０分間撹拌させた。溶媒を濃縮し、残渣を酢酸エチルに溶解させ、水で洗浄し、乾燥後シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル／クロロホルム＝５／１／１）にて精製し、メタノールから再結晶して無色固体の表題化合物（５００mg）を得た。
IR(KBr)ν: 1695, 1650, 1605, 1580, 1555 cm^-1.
NMR(CDCl₃)δ：4.63(2H,s), 6.21(2H,d,J=51.2Hz), 7.38-7.80(11H,m), 8.24(1H,d,J=7.8Hz).
【０２１６】
実施例１５１
３，５−ジメチル−２−〔４−〔４−〔（１，３−ジメチルキサンチン−７−イル）メチル〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
４，４'−ビス（ブロモメチル）ベンゾフェノン（１．７５ｇ）、テオフィリン（９００mg）、炭酸カリウム（８２８mg）のジメチルホルムアミド（４０ml）溶液を４０℃で１時間撹拌させ、つぎに３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１．０３ｇ）を加え６０℃で１時間撹拌した。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して無色固体の表題化合物（７８７mg）を得た。
IR(KBr)ν: 1700, 1660, 1605, 1555 cm^-1.
NMR(CDCl₃)δ：2.84(3H,s), 3.40(3H,s), 3.54(3H,s), 3.60(3H,s), 4.58(2H,s), 5.58(2H,s), 7.15(1H,d,J=7.2Hz), 7.35-7.80(11H,m).
【０２１７】
実施例１５２
３−メチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−チエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（１．０ｇ）と１規定水酸化ナトリウム水溶液（５．１mg）のエタノール（１０ml）溶液に、４−（４−トリフルオロメチルベンゾイル）ベンジルブロミド（１．７３ｇ）を加え、反応液を６０℃で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水で洗浄し、酢酸エチル／ヘキサンから再結晶して無色固体の表題化合物（１．１１ｇ）を得た。
IR(KBr)ν：1670, 1655, 1510, 1330, 1120 cm^-1.
NMR(CDCl₃)δ：3.61(3H,s), 4.58(2H,s), 7.23(1H,ｄ,Ｊ=5.2Hz), 7.61(2H,ｄ,J=8.0Hz), 7.70-7.81(5H,m), 7.88(2H,d,J=8.0Hz).
【０２１８】
実施例１５３
２−〔４−（４−アセトキシベンゾイル）ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（１．９８ｇ）と１規定水酸化ナトリウム水溶液（１０ml）のエタノール（３０ml）溶液に、４−（４−アセトキシベンゾイル）ベンジルブロミド（３．９５ｇ）を加え、反応液を６０℃で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水で洗浄し、酢酸エチルから再結晶して無色固体の表題化合物（３．８７ｇ）を得た。
IR(KBr)ν：1760, 1670, 1655, 1505, 1225 cm^-1.
NMR(CDCl₃)δ：2.35(3H,s), 3.62(3H,s), 4.58(2H,s), 7.21(2H,d,J=8.6Hz), 7.25(1H,d,J=5.2Hz), 7.59(2H,d,J=8.2Hz), 7.72-7.90(5H,m).
【０２１９】
実施例１５４
２−〔４−（４−ヒドロキシベンゾイル〕ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−〔４−（４−アセトキシベンゾイル）ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（３．５１ｇ）のＴＨＦ（２０ml）溶液に、１規定水酸化ナトリウム水溶液（１０ml）を加え、反応液を室温で３０分間撹拌させた。反応液を濃縮し、残渣を水に溶解させ、１規定塩酸を加えて生じた沈殿物をろ取し、水で洗浄、乾燥して無色固体の表題化合物（３．２２ｇ）を得た。
IR(KBr)ν：3200(br), 1660, 1630, 1605, 1505, 1280 cm^-1.
NMR(CDCl₃)δ：3.61(3H,s), 4.58(2H,s), 6.91(2H,d,J=8.6Hz), 7.25(1H,d,J=5.6Hz), 7.56(2H,d,J=8.2Hz), 7.68-7.80(5H,m).
【０２２０】
実施例１５５
３−メチル−２−〔４−〔４−（４−フェニルピペラジニルメチル）ベンゾイル〕ベンジルチオ〕−チエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（９９０mg）、４，４'−ビス（ブロモメチル）ベンゾフェノン（１．７５ｇ）、フェニルピペラジン（８１０mg）、炭酸カリウム（８２８mg）のジメチルホルムアミド（３０ml）溶液を６０℃で２間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール／アンモニア水＝２５０／１／０．１）で精製して、淡黄色シロップ状の表題化合物（４２８mg）を得た。
IR(Neat)ν：1670, 1600, 1535, 1505, 1275 cm^-1.
NMR(CDCl₃)δ：2.64(4H,t,J=4.8Hz), 3.22(4H,t,J=4.8Hz), 3.61(3H,s), 3.64(2H,s), 4.58(2H,s), 6.80-6.96(3H,m), 7.20-7.31(3H,m), 7.48(2H,d,J=8.2Hz), 7.58(2H,d,J=8.4Hz), 7.70-7.82(5H,m).
【０２２１】
実施例１５６
３−メチル−２−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジルチオ〕−チエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（４０８mg）、１−（２−クロロエチル）モルホリン塩酸塩（２０５mg）、炭酸カリウム（４１４mg）のジメチルホルムアミド（１０ml）溶液を６０℃で１５時間撹拌させた。反応液を濃縮後水／酢酸エチルにあけ、生じた沈殿物をろ取し、水で洗浄後乾燥して無色固体の表題化合物（４１０mg）を得た。
IR(KBr)ν：1670, 1645, 1595, 1505, 1260 cm^-1.
NMR(CDCl₃)δ：2.59(4H,t,J=4.6Hz), 2.84(2H,t,J=5.7Hz), 3.61(3H,s), 3.74(4H,t,J=4.6Hz), 4.19(2H,t,J=5.7Hz), 4.58(2H,s), 6.96(2H,d,J=8.8Hz), 7.24(1H,d,J=5.2Hz), 7.56(2H,d,J=8.4Hz), 7.69-7.85(5H,m).
【０２２２】
実施例１５７
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（１．９８ｇ）と１規定水酸化ナトリウム水溶液（１０．５ml）のエタノール（３０ml）溶液に、４−（６−クロロニコチノイル）ベンジルブロミド（３．３５ｇ）を加え、反応液を６０℃で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水で洗浄し、酢酸エチルから再結晶して淡黄色固体の表題化合物（３．１９４ｇ）を得た。
IR(KBr)ν：1670, 1655, 1510, 1290 cm^-1.
NMR(CDCl₃)δ：3.62(3H,s), 4.59(2H,s), 7.24(1H,d,J=5.2Hz), 7.48(1H,d,J=8.0Hz), 7.63(2H,d,J=8.4Hz), 7.75(1H,d,J=5.2Hz), 7.77(2H,d,J=8.4Hz), 8.09(1H,dd,J=2.6, 8.4Hz), 8.76(1H,d,J=2.6Hz).
【０２２３】
実施例１５８
３−メチル−２−〔４−〔６−（４−ピペリジノピペリジニル）ニコチノイル〕ベンジルチオ〕−チエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン塩酸塩
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（４２７mg）と４−ピペリジノピペリジン（２０２mg）のピリジン（１０ml）溶液を８０℃で１０時間撹拌させた。反応液を濃縮し残渣をクロロホルムに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール／アンモニア水＝５０／１／０．１）で精製し、塩酸酢酸エチル溶液で塩酸塩として、無色固体の表題化合物（３７３mg）を得た。
IR(KBr)ν：1660, 1640, 1600, 1535, 1505 cm^-1.
NMR(CDCl₃)δ：1.80-2.41(6H,m), 2.50-2.92(4H,m), 3.30-3.60(7H,m), 3.62(3H,s), 4.59(2H,s), 4.88(2H,m), 7.20-7.30(2H,m), 7.60-7.80(5H,m), 8.38(1H,brd,J=8.8Hz), 8.47(1H,brs).
【０２２４】
実施例１５９
２−〔４−（２，４−ジクロロベンゾイル）ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（１．０ｇ）と１規定水酸化ナトリウム水溶液（５．５ml）のエタノール（２０ml）溶液に、４−（２，４−ジクロロベンゾイル）ベンジルブロミド（１．９１ｇ）を加え、反応液を６０℃で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水で洗浄し、酢酸エチルから再結晶して無色固体の表題化合物（１．６９ｇ）を得た。
IR(KBr)ν：1665, 1650, 1600, 1535, 1510, 1290 cm^-1.
NMR(CDCl₃)δ：3.60(3H,s), 4.56(2H,s), 7.22(1H,d,J=5.4Hz), 7.27-7.40(2H,m), 7.49(1H,d,J=2.0Hz), 7.57(2H,d,J=8.2Hz), 7.74(1H,d,J=5.4Hz), 7.76(2H,d,J=8.2Hz).
【０２２５】
実施例１６０
２−〔４−（１−インドリルカルボニル）ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−メルカプト−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（１．０ｇ）と１規定水酸化ナトリウム水溶液（５．５ml）のエタノール（２０ml）溶液に、４−（１−インドリルカルボニル）ベンジルクロリド（１．５ｇ）を加え、反応液を６０℃で１時間撹拌させた。反応液を水にあけ生じた結晶をろ取し、水で洗浄し、酢酸エチルから再結晶して無色固体の表題化合物（８０８mg）を得た。
IR(KBr)ν：1680, 1665, 1530, 1510, 1450, 1335 cm^-1.
NMR(CDCl₃)δ：3.62(3H,s), 4.60(2H,s), 6.61(1H,d,J=3.8Hz), 7.20-7.42(4H,m), 7.56-7.80(6H,m), 8.39(1H,d,J=8.4Hz).
【０２２６】
実施例１６１
３，５−ジメチル−２−〔４−〔４−（２−ピペリジノエトキシ）ベンゾイル〕ベンジルチオ〕チエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン塩酸塩
３，５−ジメチル−２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕チエノ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（２５５mg）、１−（２−クロロエチル）ピペリジン塩酸塩（１２２mg）、炭酸カリウム（２５０mg）のジメチルホルムアミド（８ml）溶液を６０℃で１５時間撹拌させた。反応液を濃縮後残渣を酢酸エチルに溶解させ、水で洗浄乾燥後、塩酸酢酸エチル溶液を加えて塩酸塩を沈殿させ、ろ取、乾燥して無色固体の表題化合物（２６８mg）を得た。
IR(KBr)ν：1680, 1640, 1595, 1515, 1310, 1250 cm^-1.
NMR(CDCl₃)δ：1.35-2.00(6H,m), 2.15-2.40(2H,m), 2.55(3H,d,J=1.2Hz), 2.82(2H,m), 3.43(2H,m), 3.55(3H,s), 3.67(2H,m), 4.55(2H,s), 4.69(2H,t,J=4.4Hz), 6.67(1H,d,J=1.2Hz), 6.97(2H,d,J=8.8Hz), 7.56(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.81(2H,d,J=8.8Hz), 12.64(1H,brs).
【０２２７】
実施例１６２
３−メチル−２−〔４−〔４−（２−ピペリジノエトキシ）ベンゾイル〕ベンジルチオ〕−チエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３−メチルチエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン（４０８mg）、１−（２−クロロエチル）ピペリジン塩酸塩（２０２mg）、炭酸カリウム（４１４mg）のジメチルホルムアミド（１０ml）溶液を６０℃で１５時間撹拌させた。反応液を濃縮後残渣を酢酸エチルに溶解させ、水で洗浄乾燥後、塩酸酢酸エチル溶液を加えて塩酸塩を沈殿させ、ろ取、乾燥して無色固体の表題化合物（４７１mg）を得た。
IR(KBr)ν：1680, 1635, 1600, 1535, 1505, 1300, 1280, 1250 cm^-1.
NMR(CDCl₃)δ：1.35-2.00(6H,m), 2.15-2.40(2H,m), 2.81(2H,m), 3.42(2H,m), 3.62(3H,s), 3.67(2H,m), 4.58(2H,s), 4.69(2H,t,J=4.4Hz), 6.97(2H,d,J=8.8Hz), 7.24(1H,d,J=5.2Hz), 7.58(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.75(1H,d,J=5.2Hz), 7.81(2H,d,J=8.8Hz), 12.65(1H,brs).
【０２２８】
実施例１６３
１−〔４−（４−クロロベンゾイル）ベンジル〕−６，７−ジメチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６，７−ジメチルイミダゾ〔１，２−ａ〕ピリミジン−５−オン（１．１０ｇ，６．７５mmol）と４−（４−クロロベンゾイル）ベンジルブロミド（１．６０ｇ，５．２０mmol）のＤＭＳＯ（２０．０ml)−溶液に炭酸カリウム（１．１６ｇ，８．３９mmol）を加え室温で終夜撹拌した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル）で精製し無色不定形固体を得た。これを酢酸エチルから再結晶し無色針状晶を得た。１．１６ｇ(５７％)
IR(KBr)ν：1655, 1583, 1522, 1279, 1223, 1090, 926, 733 cm^-1.
NMR(CDCl₃)δ：2.15(3H,s), 2.41(3H,s), 5.33(2H,s), 6.86(1H,d,J=2.8Hz), 7.48-7.41(4H,m), 7.54(1H,d,J=2.8Hz), 7.72(2H,d,J=7.8Hz), 7.77(2H,d,J=7.8Hz).
【０２２９】
実施例１６４
１−〔４−（２，４−ジクロロベンゾイル）ベンジル〕−６，７−ジメチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６，７−ジメチルイミダゾ〔１，２−ａ〕ピリミジン−５−オン（０．４０１ｇ，２．４６mmol）と４−（２，４−ジクロロベンゾイル）ベンジルブロミド（０．８６ｇ，２．５０mmol）のＤＭＳＯ（１０．０ml）−溶液に炭酸カリウム（０．３７６ｇ，２．７２mmol）を加え室温で終夜撹拌した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をメタノールから再結晶し無色針状晶を得た。０．５７８ｇ（５５％）
IR(KBr)ν：1659, 1581, 1521, 1284, 1223, 930, 733 cm^-1.
NMR(CDCl₃)δ：2.14(3H,s), 2.88(3H,s), 5.32(2H,s), 6.83(1H,d,J=2.8Hz), 7.32-7.39(4H,m), 7.48-7.54(2H,m), 7.78(2H,d,J=8.4Hz).
【０２３０】
実施例１６５
１−〔３−（４−クロロベンゾイル）ベンジル〕−６，７−ジメチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６，７−ジメチルイミダゾ〔１，２−ａ〕ピリミジン−５−オン（０．４０２ｇ，２．４７mmol）と３−（４−クロロベンゾイル）ベンジルブロミド（０．７６ｇ，２．４５mmol）のＤＭＳＯ（１０．０ml)溶液に炭酸カリウム（０．３６０ｇ，２．６０mmol）を加え室温で終夜撹拌した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０．３７３ｇ（３９％）
IR(KBr)ν：1657, 1583, 1522, 1281, 1221, 727 cm^-1.
NMR(CDCl₃)δ：2.15(3H,s), 2.38(3H,s), 5.31(2H,s), 6.85(1H,d,J=2.6Hz), 7.43-7.55(4H,m), 7.69-7.79(4H,m).
【０２３１】
実施例１６６
７−〔４−（４−クロロベンゾイル）ベンジル〕−１，３−ジエチルキサンチン
ジャーナル・オブ・アメリカン・ケミカル・ソサイエティー（J. Am. Chem. Soc., ７５，１１４(１９５３)）に合成法が記載されている１，３−ジエチルキサンチン（１９０mg）のジメチルホルムアミド（５ml）溶液に炭酸カリウム（１８９mg）と臭化４−（４−クロロベンゾイル）ベンジル（２８２mg）を加えて室温で１７時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製し、さらに再結晶（エーテル−ヘキサン）し、表題化合物（２１７mg，５４％）を無色粉末として得た。
IR(KBr)：1700, 1660, 1650, 1455, 1270 cm^-1.
¹H-NMR(CDCl₃)δ：1,25(3H,t,J=7.0Hz), 1.36(3H,t,J=7.0Hz), 4.07(2H,q,J=7.0Hz), 4.18(2H,q,J=7.0Hz), 5.59(1H,s), 7.41-7.52(4H,m), 7.63(1H,s), 7.69-7.83(4H,m).
【０２３２】
実施例１６７
６−クロロ−２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン
６−クロロ−３−メチル−２メルカプトキナゾリン−４−オン（０．５００ｇ，２．２１mmol）のＥtＯＨ（１０．０ml）−ＴＨＦ（１０．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２．５０ml）を加えた後、臭化４−（４−クロロベンゾイル）ベンジル（０．２６１ｇ，０．８４３mmol）を加え室温で終夜撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチル−メタノールから再結晶し無色針状晶を得た。０．２３０ｇ（６８％）
IR(KBr)ν：1741, 1672, 1549, 1470, 1410, 1308, 1297, 1082, 930, 832, 733cm^-1.
NMR(CDCl₃)δ：3.60(3H,s), 4.59(2H,s), 7.45(2H,d,J=8.4Hz), 7.53(1H,d,J=8.6Hz), 7.59(2H,d,J=8.4Hz), 7.63(1H,dd,J=8.6,2.2Hz), 7.75(2H,d,J=8.4Hz), 8.19(1H,d,J=2.2Hz).
【０２３３】
実施例１６８
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３，６−ジメチル−４（３Ｈ）−キナゾリノン
３，６−ジメチル−２メルカプトキナゾリン−４−オン（０．１６０ｇ，０．７７６mmol）のＥtＯＨ（５．０ml）−ＴＨＦ（５．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（１．０ml）を加えた後、臭化４−（４−クロロベンゾイル）ベンジル（０．２６１ｇ，０．８４３mmol）を加え室温で２時間撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０．２３０ｇ（６８％）
IR(KBr)ν：1678, 1549, 1489, 1406, 1311, 1286, 1136, 1072, 928, 829, 771, 730, 629, 534, 470 cm^-1.
NMR(CDCl₃)δ：2.47(3H,s), 3.60(3H,s), 4.60(2H,s), 7.43-7.52(4H,m), 7.60-7.63(2H,m), 7.72-7.77(4H,m), 8.03(1H,bs).
【０２３４】
実施例１６９
１−〔４−（４−クロロベンゾイル）ベンジル〕−６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５−オン（０．７１０ｇ，４．００mmol）と臭化４−（４−クロロベンゾイル）ベンジルブロミド（１．１２ｇ，３．６mmol）のＤＭＦ（１５．０ml)溶液に炭酸カリウム（０．６００ｇ，４．３mmol）を加え室温で終夜撹拌した。溶媒を減圧除去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：塩化メチレン：アセトン＝５：１）で精製し、得られた無色固体を酢酸エチル−ヘキサンから再結晶し針状晶を得た。０．２４３ｇ（１６％）
IR(KBr)ν：2968, 1659, 1585, 1522, 1417, 1367, 1279, 1213, 1173, 1088, 928, 689 cm^-1.
NMR(CDCl₃)δ：1.45(3H,t,J=7.4Hz), 2.43(3H,s), 2.66(2H,q,J=7.4Hz), 5.33(2H,s), 6.85(1H,d,J=2.7Hz), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.54(1H,d,J=2.7Hz), 7.75(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【０２３５】
実施例１７０
４，４'−ビス〔〔３，５−ジメチル−４（３Ｈ）−キナゾリノン−２−イル〕チオメチル〕ベンゾフェノン
３，５−ジメチル−２−メルカプトキナゾリン−４−オン（１．９８ｇ，９．６０mmol）のＥtＯＨ（１５．０ml）−ＴＨＦ（１５．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（１０．０ml）を加えた後、４，４'−ビス（ブロモメチル）ベンゾフェノン（３．５０ｇ）のＴＨＦ（２０ml）溶液を１時間かけて加えた。２０分間室温で撹拌した。溶媒を除去し残渣に酢酸エチルを加え、析出した無色固体をろ取した。この結晶を水、エタノールで洗浄後、減圧下乾燥し無色固体を得た。１．１０ｇ（４０％）
IR(KBr)ν：1670, 1554, 1462, 1415, 1306, 1277, 1090, 930, 808, 694 cm^-1.
NMR(CDCl₃)δ：2.58(6H,s), 3.54(6H,s), 4.58(4H,s), 7.15(2H,d,J=7.2Hz), 7.44(2H,d,J=7.2Hz), 7.54(2H,t,J=7.2Hz), 7.59(4H,d,J=8.4Hz), 7.75(4H,d,J=8.4Hz).
【０２３６】
実施例１７１
２−〔４−〔４−（ジメチルアミノメチル）ベンゾイル〕ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）−キナゾリノン塩酸塩
３，５−ジメチル−２−メルカプトキナゾリン−４−オン（１．９８ｇ，９．６０mmol）のＥtＯＨ（１５．０ml）−ＴＨＦ（１５．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（１０．０ml）を加えた後、４，４'−ビス（ブロモメチル）ベンゾフェノン（３．５０ｇ）のＴＨＦ（２０ml）溶液を１時間かけて加えた。２０分間室温で撹拌した後５０％ジメチルアミン水溶液を加え室温で１時間撹拌した。溶媒を除去し残渣に酢酸エチルを加え、析出した無色固体をろ去した。ろ液に塩酸を加え析出した無色固体をろ取し、この固体を水、エタノールで洗浄後、減圧乾燥した。０．７８９ｇ（１７％）
IR(KBr)ν：3413, 2931, 2551, 2470, 1695, 1554, 1466, 1416, 1306, 1279, 1089, 927, 864, 804, 773, 696 cm^-1.
NMR(CDCl₃)δ：2.82(6H,d,J=4.8Hz), 2.84(3H,s), 3.60(3H,s), 4.26(2H,d,J=5.4Hz), 4.91(2H,s), 7.22(1H,d,J=7.4Hz), 7.59(1H,d,J=8.0Hz), 7.64(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz), 7.81(1H,dd,J=8.0,7.4Hz), 7.82(2H,d,J=8.1Hz), 7.86(2H,d,J=8.1Hz).
【０２３７】
実施例１７２
２−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−３，７−ジメチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
３，７−ジメチルピリド〔１，２−ａ〕ピリミジン−２，４−ジオン（０．３０８ｇ，１．６２mmol）と４−（４−クロロベンゾイル）ベンジルブロミド（０．５１１ｇ，１．６５mmol）のＤＭＦ（１０．０ml）−ＤＭＳＯ（１０．０ml）混合溶液に炭酸カリウム（０．３１ｇ，２．２４mmol）を加え室温で終夜撹拌した。反応混合物に酢酸エチルを加え、飽和食塩水で洗浄後、有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０．２４６（３６％）
IR(KBr)ν：1726, 1657, 1604, 1554, 1464, 1409, 1308, 1279, 1184, 1089, 931, 864, 789, 694 cm^-1.
NMR(CDCl₃)δ：2.23(3H,s), 2.42(3H,s), 5.61(2H,s), 7.42(1H,d,J=8.8Hz), 7.47(2H,d,J=7.3Hz), 7.54-7.61(3H,m), 7.76(2H,d,J=7.3Hz), 7.80(2H,d,J=7.3Hz), 8.88(1H,s).
【０２３８】
実施例１７３
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−６−ヒドロキシ−３−メチル−４（３Ｈ）−キナゾリノン
６−ヒドロキシ−３−メチル−２メルカプトキナゾリン−４−オン（０．５１８ｇ，２．４９mmol）のＥtＯＨ（５．０ml）−ＴＨＦ（５．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２．５０ml）を加えた後、臭化４−（４−クロロベンゾイル）ベンジル（０．２６１ｇ，０．８４３mmol）を加え室温で１時間撹拌した。析出した結晶をろ取し、水、エタノールで洗浄後、減圧下乾燥し淡黄色固体を得た。０．８８ｇ（８１％）
IR(KBr)ν：3383, 1663, 1560, 1495, 1408, 1363, 1309, 1282, 1234, 1089, 1064, 930, 833 cm^-1.
NMR(CDCl₃)δ：3.48(3H,s), 4.62(2H,s), 7.24(1H,dd,J=8.8,2.8Hz), 7.37(1H,d,J=2.8Hz), 7.52(1H,d,J=8.8Hz), 7.60(2H,d,J=8.6Hz), 7.71(4H,s), 7.74(2H,d,J=8.6Hz).
【０２３９】
実施例１７４
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−６−メトキシ−３−メチル−４（３Ｈ）−キナゾリノン
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−６−ヒドロキシ−３−メチル−４（３Ｈ）−キナゾリノン（０．３０６ｇ，０．７００mmol）のＤＭＦ（５．０ml）溶液に炭酸カリウム（０．２５ｇ，１．４５mmol）とヨウ化メチル（０．１００ml，１．６１mmol）を加え室温で３時間撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥した後減圧濃縮し、残渣を酢酸エチル−メタノールから再結晶し無色針状晶を得た。０．２０２g（６４％）
IR(KBr)ν：1672, 1643, 1578, 1535, 1481, 1392, 1282, 1165, 1088, 928, 830 cm^-1.
NMR(CDCl₃)δ：3.61(3H,s), 3.91(3H,s), 4.59(2H,s), 7.31(1H,dd,J=8.8,2.8Hz), 7.44(1H,d,J=8.5Hz), 7.53(1H,d,J=8.8Hz), 7.59(1H,d,J=2.8Hz), 7.60(2H,d,J=8.5Hz), 7.33(2H,d,J=8.5Hz), 7.74(2H,d,J=8.5Hz).
【０２４０】
実施例１７５
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−６−イソプロポキシ−３−メチル−４（３Ｈ）−キナゾリノン
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−６−ヒドロキシ−３−メチル−４（３Ｈ）−キナゾリノン（０．３００ｇ，０．６８７mmol）のＤＭＦ（５．０ml）溶液に炭酸カリウム（０．２００ｇ，１．４５mmol）とヨウ化イソプロピル（０．２００ml，２．００mmol）を加え５０℃で１時間撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥した後、減圧濃縮し残渣を酢酸エチル−メタノールから再結晶し無色針状晶を得た。０．２３２g（７１％）
IR(KBr)ν：1674, 1581, 1557, 1485, 1365, 1313, 1281, 1226, 1112, 1066, 928, 833 cm^-1.
NMR(CDCl₃)δ：1.38(6H,d,J=6.0Hz), 3.60(3H,s), 4.59(2H,s), 4.69(1H,m), 7.27(1H,dd,J=9.0,3.0Hz), 7.43-7.50(3H,m), 7.55-7.62(3H,m), 7.73(2H,d,J=8.0Hz), 7.74(2H,d,J=8.0Hz).
【０２４１】
実施例１７６
６−ヒドロキシ−２−〔４−（４−メトキシベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン
６−ヒドロキシ−３−メチル−２メルカプトキナゾリン−４−オン（１．５２ｇ，７．３０mmol）のＥtＯＨ（１５．０ml）−ＴＨＦ（１５．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（７．５０ml）を加えた後、臭化４−（４−メトキシベンゾイル）ベンジル（２．３０ｇ，７．５０mmol）を加え室温で４時間撹拌した。析出した結晶をろ取し、水、エタノールで洗浄後、減圧下乾燥し淡黄色固体を得た。１．８３０ｇ（５８％）
IR(KBr)ν：3400, 1660, 1603, 1556, 1496, 1464, 1416, 1362, 1311, 1254, 1176, 1147, 1066, 1030, 930, 839, 775 cm^-1.
NMR(CDCl₃)δ：3.61(3H,s), 3.88(3H,s), 4.58(2H,s), 6.95(2H,d,J=9.0Hz), 7.29(1H,dd,J=8.9,2.8Hz), 7.54(1H,d,J=8.9Hz), 7.58(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.78(1H,d,J=2.8Hz), 7.81(2H,d,J=9.0Hz).
【０２４２】
実施例１７７
２−〔４−（４−メトキシベンゾイル）ベンジル〕チオ−６−メトキシ−３−メチル−４（３Ｈ）−キナゾリノン
６−ヒドロキシ−２−〔４−（４−メトキシベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン（０．４００ｇ，０．９２５mmol）のＤＭＦ（１０．０ml）溶液に炭酸カリウム（０．２６０ｇ，１．８８mmol）とヨウ化メチル（０．２００ml，３．２１mmol）を加え室温で２時間撹拌した。溶媒を除去した後残渣を酢酸エチルに溶かし、飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥後減圧濃縮し、残渣を酢酸エチルから再結晶し無色針状晶を得た。０．３３８ｇ（８２％）
IR(KBr)ν：2931, 1682, 1649, 1606, 1551, 1489, 1412, 1360, 1319, 1266, 1173, 1066, 1022, 931, 833, 779, 750 cm^-1.
NMR(CDCl₃)δ：3.61(3H,s), 3.88(3H,s), 3.91(3H,s), 4.59(2H,s), 6.95(2H,d,J=8.8Hz), 7.31(1H,dd,J=8.8,3.2Hz), 7.54(1H,d,J=8.8Hz), 7.58(2H,d,J=8.0Hz), 7.59(1H,d,J=3.2Hz), 7.73(2H,d,J=8.0Hz), 7.81(2H,d,J=8.8Hz).
【０２４３】
実施例１７８
６−イソプロポキシ−２−〔４−（４−メトキシベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン
６−ヒドロキシ−２−〔４−（４−メトキシベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン（０．４００ｇ，０．９２５mmol）のＤＭＦ（１０．０ml）溶液に炭酸カリウム（０．２６０ｇ，１．８８mmol）とヨウ化イソプロピル（０．３００ml，３．００mmol）を加え５０℃で８時間撹拌した。溶媒を除去した後残渣を酢酸エチルに溶かし、飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥後減圧濃縮し、残渣を酢酸エチルから再結晶し無色針状晶を得た。０．３４８ｇ（７９％）
IR(KBr)ν：1673, 1674, 1605, 1554, 1487, 1311, 1254, 1174, 145 , 1113, 1086, 841 cm^-1.
NMR(CDCl₃)δ：1.37(6H,d,J=6.4Hz), 3.60(3H,s), 3.88(3H,s), 4.59(2H,s), 6.59(2H,d,J=9.0Hz), 7.27(1H,dd,J=7.8,3.0Hz), 7.53(1H,d,J=7.8Hz), 7.58(2H,d,J=8.1Hz), 7.59(1H,d,J=3.0Hz), 7.72(2H,d,J=8.1Hz), 7.80(2H,d,J=9.0Hz).
【０２４４】
実施例１７９
２−〔４−（４−メトキシベンゾイル）ベンジル〕チオ−３，８−ジメチル−４（３Ｈ）−キナゾリノン
３，８−ジメチル−２メルカプトキナゾリン−４−オン（０．５０３ｇ，２．４４mmol）のＥtＯＨ（５．０ml）−ＴＨＦ（１０．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２．８０ml）を加えた後、臭化４−（４−メトキシベンゾイル）ベンジル（０．７４４ｇ，２．４４mmol）を加え室温で終夜撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥後減圧濃縮し、残渣を酢酸エチルから再結晶し無色針状晶を得た。０．６９６ｇ（６６％）
IR(KBr)ν:1682, 1585, 1558, 1458, 1404, 1327, 1275, 1084, 930, 764 cm^-1.
NMR(CDCl₃)δ：2.60(3H,s), 3.62(3H,s), 3.89(3H,s), 4.65(2H,s), 6.96(2H,d,J=8.8Hz), 7.28(1H,t,J=8.0Hz), 7.56(1H,d,J=8.0Hz), 7.59(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.82(2H,d,J=8.8Hz), 8.09(1H,d,J=8.0Hz).
【０２４５】
実施例１８０
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−３，８−ジメチル−４（３Ｈ）−キナゾリノン
３，８−ジメチル−２メルカプトキナゾリン−４−オン（０．５０４ｇ，２．４４mmol）のＥtＯＨ（５．０ml）−ＴＨＦ（１０．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２．８０ml）を加えた後、臭化４−（４−クロロベンゾイル）ベンジル（０．７６３ｇ，２．４６mmol）を加え室温で終夜撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥後減圧濃縮し、残渣を酢酸エチルから再結晶し無色針状晶を得た。０．７６８ｇ（７２％）
IR(KBr)ν：1682, 1663, 1585, 1458, 1404, 1327, 1275, 1084, 930, 764 cm^-1.
NMR(CDCl₃)δ：2.59(3H,s), 3.62(3H,s), 4.66(2H,s), 7.29(1H,t,J=7.6Hz), 7.45(2H,d,J=8.4Hz), 7.56(1H,d,J=7.6Hz), 7.61(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.75(2H,d,J=8.4Hz), 8.08(1H,d,J=7.6Hz).
【０２４６】
実施例１８１
１−〔４−（４−クロロベンゾイル）ベンジル〕−６−イソプロピル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６−イソプロピル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５−オン（０．４００ｇ，２．２３mmol）と臭化４−（４−クロロベンゾイル）ベンジルブロミド（０．７６２ｇ，２．４６mmol）のＤＭＦ（１５．０ml）溶液に炭酸カリウム（０．６００ｇ，４．５０mmol）を加え室温で終夜撹拌した。溶媒を減圧除去し、残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン：アセトン＝２０：１）で精製し無色アモルファスを得た。０．４８ｇ（５１％）
IR(KBr)ν：1659, 1585, 1512, 1408, 1367, 1279, 1088, 928, 735, 692 cm^-1.
NMR(CDCl₃)δ：1.39(6H,d,J=7.0Hz), 2.45(3H,s), 3.17(1H,m), 5.31(2H,s), 6.83(1H,d,J=2.6Hz), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.53(1H,d,J=2.6Hz), 7.73(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【０２４７】
実施例１８２
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−５−メトキシカルボニル−３−メチル−４（３Ｈ）−キナゾリノン
５−カルボキシ−３−メチル−２メルカプトキナゾリン−４−オン（０．５２０ｇ，２．２０mmol）のＥtＯＨ（１０．０ml）−ＴＨＦ（１０．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（４．４０ml）を加えた後、臭化４−（４−クロロベンゾイル）ベンジル（０．６３８ｇ，２．２１mmol）を加え室温で１時間撹拌した。反応溶液に塩酸を加え酸性とし析出した固体をろ取、水で洗浄した。この固体をＤＭＦ（２０ml）−水（５．０ml）に溶かし炭酸セシウム（１．４０ｇ，４．３０mmol）とヨウ化メチル（１．００ml）を加え室温で終夜撹拌した。溶媒を除去した後、残渣に酢酸エチルを加え、飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥し減圧濃縮し、残渣をシリカゲルカラム（塩化メチレン）で精製した後、酢酸エチル−エタノールから再結晶し無色針状晶を得た。
IR(KBr)ν：1734, 1674, 1593, 1554, 1441, 1408, 1323, 1282, 1203, 1082, 926, 818, 762 cm^-1.
NMR(CDCl₃)δ：3.58(3H,s), 4.01(3H,s), 4.61(2H,s), 7.34(1H,dd,J=6.6,1.8Hz), 7.46(2H,d,J=8.6Hz), 7.60(2H,d,J=8.2Hz), 7.68-7.77(6H,m).
【０２４８】
実施例１８３
２−〔４−（４−メトキシカルボニルベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２メルカプトキナゾリン−４−オン（５．００ｇ，２４．２mmol）のＥtＯＨ（１００．０ml）−ＴＨＦ（１００．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２５．０ml）を加えた後、臭化４−（４−メトキシカルボニルベンゾイル）ベンジル（８．０６ｇ，２４．２mmol）を加え室温で終夜撹拌した。析出した無色固体をろ取し、水で洗浄後、減圧下乾燥した。これを酢酸エチルから再結晶し無色針状晶を得た。１０．８９ｇ（９８％）
IR(KBr)ν：1722, 1658, 1554, 1431, 1275, 1093, 1020, 966, 928, 962, 715cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 3.95(3H,s), 4.60(2H,s), 7.15(1H,d,J=7.4Hz), 7.43(1H,d,J=7.4Hz), 7.62(2H,d,J=8.5Hz), 7.77(2H,d,J=8.6Hz), 7.79(1H,t,J=7.4Hz), 7.82(2H,d,J=8.5Hz), 8.14(2H,d,J=8.6Hz).
【０２４９】
実施例１８４
３，５−ジメチル−２−〔４−（４−（４−メチルピペラジノカルボニル）ベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
２−〔４−（４−カルボキシベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）−キナゾリノン（０．３２０ｇ，０．７２０mmol）のＤＭＦ（５．０ml）混合溶液にＤＥＰＣ（０．３７ｇ，２．２７mmol）と１−メチルピペラジン（０．２００ml，１．８０mmol）を加え室温で終夜撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥後減圧濃縮し、残渣をシリカゲルカラム（塩化メチレン：メタノール：アンモニア＝２０：１：０．１）で精製した。得られた固体をエタノールから再結晶し無色針状晶を得た。０．２０１ｇ（１８％）
IR(KBr)ν：1674, 1628, 1552, 1462, 1433, 1299, 1276, 1144, 1092, 931 cm^-1.
NMR(CDCl₃)δ：2.33(3H,s), 3.55(3H,s), 2.36(2H,m), 2.60(2H,m), 2.85(3H,s), 3.41(2H,m), 3.55(3H,s), 3.82(2H,m), 4.59(2H,s), 7.15(1H,d,J=6.6Hz), 7.40(1H,d,J=6.6Hz), 7.50(2H,d,J=8.0Hz), 7.51(1H,t,J=6.6Hz), 7.61(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz).
【０２５０】
実施例１８５
２−〔４−（２−クロロベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２メルカプトキナゾリン−４−オン（０．５１３ｇ，２．４９mmol）のＥtＯＨ（１０．０ml）−ＴＨＦ（１０．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２．７０ml）を加えた後、臭化４−（２−クロロベンゾイル）ベンジル（０．８００ｇ，２．５８mmol）を加え室温で終夜撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥後減圧濃縮し、残渣をメタノールから再結晶し無色針状晶を得た。０．７０４ｇ（６５％）
IR(KBr)ν：1678, 1659, 1599, 1552, 1286, 1240, 1089, 926, 860, 769, 692cm^-1.
NMR(CDCl₃)δ：2.84(3H,s), 3.53(3H,s), 4.57(2H,s), 7.14(1H,d,J=7.0Hz), 7.26-7.46(5H,m), 7.49(1H,t,J=7.0Hz), 7.58(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz).
【０２５１】
実施例１８６
３，５−ジメチル−２−〔４−（４−ニトロベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２メルカプトキナゾリン−４−オン（２．０３ｇ，９．７４mmol）のＥtＯＨ（３０．０ml）−ＴＨＦ（３０．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（１０．０ml）を加えた後、臭化４−（４−ニトロベンゾイル）ベンジル（３．５０ｇ，１０．９mmol）を加え室温で終夜撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をメタノールから再結晶し淡黄色針状晶を得た。０．３０７ｇ（７０％）
IR(KBr)ν：1678, 1660, 1558, 1522, 1414, 1346, 1307, 1277, 1249, 1088, 929, 858, 810, 708 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.15(1H,d,J=7.4Hz), 7.43(1H,d,J=7.4Hz), 7.54(1H,t,J=7.4Hz), 7.64(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 7.91(2H,d,J=8.4Hz), 8.33(2H,d,J=8.4Hz).
【０２５２】
実施例１８７
７−〔４−（４−クロロベンゾイル）ベンジル〕−１−エチル−３，８−ジメチルキサンチン
ジャーナル・オブ・アメリカン・ケミカル・ソサイエティー（J. Am. Chem. Soc., ７５，１１４(１９５３)）に合成法が記載されている１−エチル−３，８−ジメチルキサンチン（１７０mg）のジメチルホルムアミド（８ml）溶液に炭酸カリウム（１６９mg）と臭化４−（４−クロロベンゾイル）ベンジル（２７８mg）を加えて室温で２０時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さを再結晶（酢酸エチル−ヘキサン）し、表題化合物（８７mg，２４％）を無色粉末として得た。
IR(KBr)：1700, 1660, 1610, 1400, 1280, 1270 cm^-1.
¹H-NMR(CDCl₃)δ：1.25(3H,t,J=7.0Hz), 2.45(3H,s), 3.59(3H,s), 4.08(2H,q,J=7.0Hz), 5.63(2H,s), 7.25-7.81(8H,m).
【０２５３】
実施例１８８
２−〔４−（４−アミノベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−〔４−（４−ニトロベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン（１．００ｇ，２．２４mmol）の酢酸（３０．０ml）−ＴＨＦ（１５．０ml）混合溶液に鉄（２．００ｇ）を加え室温で終夜撹拌した。溶媒を除去した後、残渣に１Ｎ−水酸化ナトリウム（２０ml）を加えクロロホルムで抽出を行った。有機層をＭgＳＯ₄で乾燥した後減圧濃縮し、残渣を酢酸エチルから結晶化し淡黄色固体を得た。０．３８０ｇ（４１％）
IR(KBr)ν：352 , 1650, 1583, 1552, 1469, 1430, 1311, 1282, 1172, 1147, 1089, 928, 844 cm^-1.
NMR(DMSO-d₆)δ：2.76(3H,s), 3.46(3H,s), 4.63(2H,s), 6.12(2H,s), 6.59(2H,d,J=8.8Hz), 7.20(1H,d,J=7.4Hz), 7.44-7.67(8H,m).
【０２５４】
実施例１８９
１−〔４−（４−クロロベンゾイル）ベンジル〕−６，７，８，９−テトラヒドロイミダゾ〔２，１−ｂ〕キナゾリン−５（１Ｈ）−オン
６，７，８，９−テトラヒドロイミダゾ〔２，１−ｂ〕キナゾリン−５（１Ｈ）−オン（０．２３５ｇ，１．２４mmol）と臭化４−（４−クロロベンゾイル）−ベンジルブロミド（０．４１０ｇ，１．３２mmol）のＤＭＦ（１５．０ml）−ＤＭＳＯ（５ml）混合溶液に炭酸カリウム（０．２５０ｇ，１．８１mmol）を加え室温で終夜撹拌した。溶媒を減圧除去し、残渣を分取用ＴＬＣ（塩化メチレン：メタノール＝２０：１）で精製し無色アモルファスを得た。０．０８５ｇ（１６％）
IR(KBr)ν：2933, 1659, 1585, 1528, 1419, 1306, 1277, 1209, 1170, 1088, 928, 733 cm^-1.
NMR(CDCl₃)δ：1.82(4H,m), 2.64(2H,t,J=5.4Hz), 2.73(2H,t,J=5.4Hz), 5.32(2H,s), 6.84(1H,d,J=2.6Hz), 7.40(2H,d,J=8.1Hz), 7.46(2H,d,J=8.1Hz), 7.54(1H,d,J=2.6Hz), 7.73(2H,d,J=8.1Hz), 7.77(2H,d,J=8.1Hz).
【０２５５】
実施例１９０
１−〔４−（４−クロロベンゾイル）ベンジル〕−１，６，７，８−テトラヒドロ−５Ｈ−シクロペント〔ｄ〕イミダゾ〔１,２−ａ〕ピリミジン−５−オン
１，６，７，８−テトラヒドロ−５Ｈ−シクロペント〔ｄ〕イミダゾ〔１，２−ａ〕ピリミジン−５−オン（０．３４５ｇ，１．９６７mmol）と臭化４−（４−クロロベンゾイル）−ベンジルブロミド（０．０６５０ｇ，２．１０mmol）のＤＭＦ（１５．０ml）−ＤＭＳＯ（５ml）混合溶液に炭酸カリウム（０．３００ｇ，２．１７mmol）を加え室温で終夜撹拌した。溶媒を減圧除去し、残渣を分取用ＴＬＣ（塩化メチレン：メタノール＝２０：１）で精製し無色アモルファスを得た。０．２６０ｇ（３３％）
IR(Neat)ν：2954, 1675, 1660, 1579, 1522, 1417, 1279, 1240, 1173, 1089, 928, 849, 733 cm^-1.
NMR(CDCl₃)δ：2.13(2H,quint,J=7.2Hz), 2.89(4H,t,J=7.2Hz), 5.36(2H,s), 6.89(1H,d,J=2.6Hz), 7.39(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.61(1H,d,J=2.6Hz), 7.73(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
【０２５６】
実施例１９１
３，５−ジメチル−２−〔４−（４−（ｔ−ブトキシカルボニルメチル）カルバモイルベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
２−〔４−（４−カルボキシベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）キナゾリノン（０．４９５ｇ，１．１１mmol）とグリシンｔ−ブチルエステル塩酸塩（０．２３６ｇ，１．４１mmol）のＤＭＦ（１０．０ml）溶液にＤＥＰＣ（０．３６４ｇ，２．２３mmol）とトリエチルアミン（０．６０ml）を加え室温で３．５時間撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０．３５１ｇ（５５％）
IR(KBr)ν：3259, 2978, 1741, 1673, 1658, 1605, 1554, 1371, 1306, 1230, 1157, 1092, 931, 869, 808, 754 cm^-1.
NMR(CDCl₃)δ：1.52(9H,s), 2.85(3H,s), 3.55(3H,s), 4.17(2H,d,J=5.0Hz), 4.60(2H,s), 6.75(1H,t,J=5.0Hz), 7.15(1H,d,J=7.2Hz), 7.44(1H,d,J=7.2Hz), 7.55(1H,t,J=7.2Hz), 7.62(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 7.83(2H,d,J=8.6Hz), 7.92(2H,d,J=8.6Hz).
【０２５７】
実施例１９２
３，５−ジメチル−２−〔４−（４−（Ｎ−メトキシカルボニルメチル−Ｎ−メチルカルバモイル）ベンゾイル）ベンジル〕チオ−４(３Ｈ)−キナゾリノン
２−〔４−（４−カルボキシベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）キナゾリノン（０．５００ｇ，１．１２mmol）とＮ−メチルグリシンメチルエステル塩酸塩（０．１９９ｇ，１．４３mmol）のＤＭＦ（１０．０ml）溶液にＤＥＰＣ（０．３７４ｇ，２．２９mmol）とトリエチルアミン（０．６０ml）を加え室温で３時間撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラム（ヘキサン：酢酸エチル＝１：３）で精製した後、エタノールから結晶化し無色固体を得た。０．２５０ｇ（３８％）
IR(KBr)ν：2935, 1668, 1597, 1554, 1462, 1412, 1315, 1259, 1171, 1080, 1020, 930, 841, 769 cm^-1.
NMR(CDCl₃)δ：2.84(3H,s), 3.05(2/3×3H,s), 3.15(1/3×3H,s), 3.55(3H,s), 3.74(1/3×3H,s), 3.81(2/3×3H,s), 3.99(1/3×2H,s), 4.31(2/3×2H,s), 4.59(2H,s), 7.15(1H,d,J=7.6Hz), 7.40-7.66(6H,m), 7.67(2H,d,J=8.6Hz), 7.82(2H,d,J=8.4Hz).
【０２５８】
実施例１９３
３，５−ジメチル−２−〔４−（４−（４−ピペリジノピペリジノカルボニル）ベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
２−〔４−（４−カルボキシベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）キナゾリノン（０．４９５ｇ，１．１１mmol）のＤＭＦ（１０．０ml）溶液にＤＥＰＣ（０．３７０ｇ，２．２７mmol）を加え室温で１時間撹拌した後４−ピペリジノピペリジン（０．２７７ｇ，１．６５mmol）を加え終夜撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラム（イソプロピルエーテル：塩化メチレン：メタノール：アンモニア＝５：５：１：０．１）で精製し無色アモルファスを得た。０．２７０ｇ（４０％）
IR(KBr)ν：2931, 1664, 1631, 1608, 1554, 1508, 1448, 1306, 1277, 1092, 1016, 931, 864 cm^-1.
NMR(CDCl₃)δ：1.40-2.56(15H,m), 2.75-2.80(1H,m), 2.85(3H,s), 2.90-3.10(1H,m), 3.55(3H,s), 3.70-3.85(1H,m), 4.59(2H,s), 7.45-4.82(1H,m), 7.15(1H,d,J=7.8Hz), 7.46(1H,t,J=7.8Hz), 7.48(2H,d,J=8.0Hz), 7.49(1H,d,J=7.8Hz), 7.61(2H,d,J=8.0Hz), 7.65(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz).
【０２５９】
実施例１９４
１−〔４−（６−クロロニコチノイル）ベンジル〕−６，７−ジメチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン塩酸塩
６，７−ジメチルイミダゾ〔１，２−ａ〕ピリミジン−５−オン（０．９００ｇ，５．５mmol）と４−（６−クロロニコチノイル）ベンジルブロミド（１．９２ｇ，３．６mmol）のＤＭＦ（２０．０ml）−ＤＭＳＯ（１０．０ml）混合溶液に炭酸カリウム（２．１０ｇ，１５．２０mmol）を加えた室温で終夜撹拌した。溶媒を減圧除去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し淡黄色油状物を得た。この酢酸エチル溶液に４Ｎ−塩酸−酢酸エチルを加え析出した結晶をろ取し、減圧下乾燥した。１．４５ｇ（７０％）
IR(KBr)ν：2366, 1680, 1659, 1578, 1365, 1281, 1099, 926 cm^-1.
NMR(DMSO-d₆)δ：2.02(3H,s), 2.39(3H,s), 5.59(2H,s), 7.41(1H,t,J=8.4Hz), 7.56(2H,d,J=8.0Hz), 7.67-7.73(2H,m), 7.79(2H,d,J=8.0Hz), 8.16(1H,dd,J=8.4,2.6Hz), 8.69(1H,d,J=2.6Hz).
【０２６０】
実施例１９５
３，５−ジメチル−２−〔４−（４−ビス（ｔ−ブトキシカルボニルメチル）カルバモイル）ベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−〔４−（４−（ｔ−ブトキシカルボニルメチル）カルバモイルベンゾイル）ベンジル〕チオ−４（３Ｈ）キナゾリノン（０．５１１ｇ，０．８９４mmol）のＤＭＦ（１５．０ml）溶液に６０％−水素化ナトリウム（０．０４０ｇ，１．００mmol）とブロモ酢酸ｔ−ブチル（０．２１０ｇ，１．０８mmol）を加え室温で終夜撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラム（ヘキサン：酢酸エチル＝２：１）で精製し無色アモルファスを得た。０．２７０ｇ（４０％）
IR(KBr)ν：1741, 1662, 1556, 1153 cm^-1.
NMR(CDCl₃)δ：1.44(9H,s), 1.51(9H,s), 2.85(3H,s), 3.55(3H,s), 3.94(2H,s), 4.22(2H,s), 4.59(2H,s), 7.15(1H,d,J=7.0Hz), 7.43(1H,d,J=8.6Hz), 7.48-7.66(5H,m), 7.77(2H,d,J=8.6Hz), 7.79(2H,d,J=8.0Hz).
【０２６１】
実施例１９６
２−〔４−（６−クロロニコチノイル）ベンジルオキシ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
３−メチルピリド〔１，２−ａ〕ピリミジン−２，４−ジオン（１．５２０ｇ，８．６２mmol）と４−（６−クロロニコチノイル）ベンジルブロミド（３．００ｇ，９．６６mmol）のＤＭＦ（２５．０ml）−ＤＭＳＯ（１０．０ml）混合溶液に炭酸カリウム（３．５０ｇ，２５．３mmol）を加え室温で終夜撹拌した。反応混合物に水を加え、析出した結晶をエタノールで洗浄した後減圧下乾燥し、淡黄色固体を得た。２．４４ｇ（７０％）
IR(KBr)ν：1670, 1576, 1477, 1280, 1165, 1103, 924, 764 cm^-1.
NMR(CDCl₃)δ：2.28(3H,s), 5.63(2H,s), 7.12(1H,t,J=7.5Hz), 7.49(2H,d,J=8.4Hz), 7.62(2H,d,J=8.4Hz), 7.71(1H,t,J=8.4Hz), 7.82(2H,d,J=8.4Hz), 8.00(1H,dd,J=8.4,2.4Hz), 8.77(1H,d,J=2.4Hz), 9.08(1H,d,J=7.5Hz).
【０２６２】
実施例１９７
３−メチル−２−〔４−〔６−（４−ピペリジノピペリジノ）ニコチノイル〕ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−〔４−（６−クロロニコチノイル）ベンジルオキシ〕−３−メチル−ピリド〔１，２−ａ〕ピリミジン−４−オン（０．４９ｇ，１．２１mmol）と４−ピペリジノピペリジン（０．４０２ｇ，２．３９mmol）のピリジン（１５ml）溶液を９０℃で終夜撹拌した。溶媒を減圧除去し、残渣をシリカゲルカラムクロマトグラフィー（イソプロピルエーテル：塩化メチレン：メタノール：アンモニア＝５：５：１：０．１）で精製し淡黄色油状物を得た。０．３８ｇ（５９％）
IR(Neat)ν：2929, 2852, 1676, 1637, 1589, 1533, 1477, 1423, 1281, 1246, 1164, 1012, 922, 768 cm^-1.
NMR(CDCl₃)δ：1.42-1.76(8H,m), 1.92-1.99(2H,m), 2.23(3H,s), 2.48-2.58(5H,m), 2.87-3.01(2H,m), 4.49-4.60(2H,m), 5.61(2H,s), 6.68(1H,d,J=7.5Hz), 7.10(1H,t,J=7.5Hz), 7.49(1H,d,J=8.9Hz), 7.56(2H,d,J=8.1Hz), 7.68(1H,d,J=8.1Hz), 8.01(1H,dd,J=8.9,2.2Hz), 8.59(1H,d,J=2.2Hz), 9.08(1H,d,J=7.1Hz).
【０２６３】
実施例１９８
２−〔４−（２−クロロニコチノイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２メルカプトキナゾリン−４−オン（０．５１６ｇ，２．５０mmol）のＥtＯＨ（１０．０ml）−ＴＨＦ（１０．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（２．６０ml）を加えた後、臭化４−（２−クロロニコチノイル）ベンジル（０．８０７ｇ，２．６０mmol）を加え室温で３０分間撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し淡黄色針状晶を得た。０．８１０ｇ（７４％）
IR(KBr)ν：1670, 1549, 1460, 1402, 1304, 1280, 1284, 1161, 1086, 1036, 924, 864, 746, 694, 656 cm^-1.
NMR(CDCl₃)δ：2.84(3H,s), 3.54(3H,s), 4.58(2H,s), 7.14(1H,d,J=7.6Hz), 7.37(1H,dd,J=7.9,4.8Hz), 7.41(1H,d,J=7.6Hz), 7.51(1H,t,J=7.6Hz), 7.61(2H,d,J=8.4Hz), 7.71(1H,dd,J=7.9,2.0Hz), 7.76(2H,d,J=8.4Hz), 8.54(1H,dd,J=4.8,2.0Hz).
【０２６４】
実施例１９９
１−〔４−（６−クロロニコチノイル）ベンジル〕−６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５−オン（４．１９ｇ，２３．６０mmol）と４−（６−クロロニコチノイル）ベンジルブロミド（７．３６ｇ，２３．７０mmol）のＤＭＦ（１００．０ml）−ＤＭＳＯ（２０．０ml）混合溶液に炭酸カリウム（７．１０ｇ，５０．７０mmol）を加えた室温で終夜撹拌した。溶媒を減圧除去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製した。得られた無色油状物を酢酸エチルから結晶化し無色針状晶を得た。４．５９ｇ（４８％）
IR(KBr)ν：1655, 1581, 1520, 1414, 1282, 1217, 1103, 923 cm^-1.
NMR(CDCl₃)δ：1.15(3H,t,J=7.4Hz), 2.43(3H,s), 2.66(2H,q,J=7.4Hz), 5.35(2H,s), 6.86(1H,d,J=2.6Hz), 7.44(2H,d,J=8.0Hz), 7.53(1H,d,J=8.0Hz), 7.56(1H,d,J=2.6Hz), 7.81(2H,d,J=8.0Hz), 8.09(1H,dd,J=8.0,2.4Hz), 8.75(1H,d,J=2.4Hz).
【０２６５】
実施例２００
６−エチル−１−〔４−（４−メトキシカルボニルベンゾイル）ベンジル〕−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５−オン（４．００ｇ，２２．６mmol）と４−（４−メトキシカルボニルベンゾイル）ベンジルブロミド（１１．００ｇ，３３．０２mmol）のＤＭＦ（１００．０ml）−ＤＭＳＯ（２０．０ml）混合溶液に炭酸カリウム（７．１４ｇ，５１．７mmol）を加え室温で終夜撹拌した。溶媒を減圧除去した後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製した。得られた無色油状物を酢酸エチルから結晶化し無色針状晶を得た。４．５９ｇ（４８％）
IR(KBr)ν：1724, 1657, 1581, 1520, 1277, 1109, 928, 721 cm^-1.
NMR(CDCl₃)δ：1.15(3H,t,J=6.6Hz), 2.44(3H,s), 2.66(2H,q,J=6.6Hz), 3.97(3H,s), 5.34(2H,s), 6.86(1H,d,J=2.6Hz), 7.42(2H,d,J=8.0Hz), 7.56(1H,d,J=2.6Hz), 7.81(2H,d,J=8.0Hz), 7.82(2H,d,J=8.0Hz), 8.16(2H,d,J=8.0Hz).
【０２６６】
実施例２０１
２−〔４−（４−メトキシカルボニルベンゾイル）ベンジルオキシ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
３−メチルピリド〔１，２−ａ〕ピリミジン−２，４−ジオン（２．２０ｇ，１２．５mmol）と４−（４−メトキシカルボニルベンゾイル）ベンジルブロミド（７．０４ｇ，１２．７mmol）のＤＭＦ（４０．０ml）−ＤＭＳＯ（２０．０ml）混合溶液に炭酸カリウム（３．９２ｇ，２８．４mmol）を加え室温で終夜撹拌した。反応混合物に水を加え、析出した結晶をろ取し、これを酢酸エチルに溶かした後ＭgＳＯ₄で乾燥した。溶媒を減圧除去し、残渣を酢酸エチルから再結晶し無色針状晶を得た。２．６７ｇ（５０％）
IR(KBr)ν：1722, 1672, 1576, 1530, 1477, 1277, 1167, 1108 cm^-1.
NMR(CDCl₃)δ：2.23(3H,s), 3.97(3H,s), 5.63(2H,s), 7.11(1H,dt,J=6.7,1.5Hz), 7.49(1H,dd,J=8.7,1.5Hz), 7.60(2H,d,J=8.4Hz), 7.71(1H,ddd,J=8.7,6.7,1.5Hz), 7.84(2H,d,J=8.4Hz), 7.86(2H,d,J=8.4Hz), 8.17(2H,d,J=8.4Hz), 9.08(1H,dd,J=6.7,1.5Hz).
【０２６７】
実施例２０２
６−エチル−１−〔４−（６−（４−ピペリジノピペリジノ）ニコチノイル）ベンジル〕−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン３塩酸塩
１−〔４−（６−クロロニコチノイル）ベンジル〕−６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（０．８１０ｇ，１．９９mmol）と４−ピペリジノピペリジン（０．３７２ｇ，２．２１mmol）のピリジン（１０．０ml）溶液を９０℃で終夜撹拌した。溶媒を減圧除去した後、残渣をシリカゲルカラムクロマトグラフィー（ＴＨＦ：メタノール：アンモニア＝６０：１：０．１）で精製し淡黄色油状物を得た。これを酢酸エチルに溶かし４Ｎ−塩酸−酢酸エチルを加え、析出した結晶をろ取し減圧下乾燥した。０．５９６ｇ（４９％）
IR(KBr)ν：3383, 2937, 2615, 2519, 1643, 1595, 1554, 1444, 1321, 1273, 1240, 1178, 1008, 762, 723 cm^-1.
NMR(DMSO-d₆)δ：1.04(3H,t,J=7.4Hz), 1.72(2H,m), 1.82(2H,m), 2.23(2H,m), 2.38(3H,s), 2.51(2H,q,J=7.4Hz), 2.94(2H,m), 3.02(2H,m), 3.40(2H,m), 4.20(3H,m), 4.65(4H,m), 5.49(2H,s), 7.07(1H,m), 7.49-7.54(2H,m), 7.63-7.95(4H,m), 7.98(1H,m), 8.42(1H,m).
【０２６８】
実施例２０３
６−エチル−７−メチル−１−〔４−（６−（４−フェニルピペラジノ）ニコチノイル）ベンジル〕−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン３塩酸塩
６−エチル−７−メチル−１−〔４−（６−（４−フェニルピペラジノ）ニコチノイル）ベンジル〕−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（６９６mg）を酢酸エチル（１０．０ml）に溶かし、この溶液に４Ｎ−塩酸−酢酸エチルを加え生じた結晶をろ取し減圧下乾燥し淡黄色固体を得た。
０．６６７ｇ（８４％）
IR(KBr)ν:3412, 2681, 1703, 1647, 1595, 1446, 1284, 1257, 756, 692 cm^-1.
NMR(DMSO-d₆)δ：1.04(3H,t,J=7.4Hz), 2.39(3H,s), 2.51(2H,q,J=7.4Hz), 3.41(4H,bs), 4.00(4H,bs), 5.50(2H,s), 7.00(1H,m), 7.11(1H,d,J=9.0Hz), 7.22-7.38(4H,m), 7.51(2H,d,J=8.0Hz), 7.62-7.73(4H,m), 8.00(1H,dd,J=9.0,2.2Hz),8.46(1H,d,J=2.2Hz).
【０２６９】
実施例２０４
６−エチル−７−メチル−１−〔４−（６−（４−フェニルピペラジノ）ニコチノイル）ベンジル〕−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
１−〔４−（６−クロロニコチノイルベンジル〕−６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（０．８１０ｇ，１．９９mmol）と４−フェニルピペラジン（０．３５０ｇ，２．１６mmol）のピリジン（１０．０ml）溶液を９０℃で終夜撹拌した。溶媒を減圧除去した後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し淡黄色アモルファスを得た。０．９０７ｇ（８５％）
IR(KBr)ν：1657, 1589, 1518, 1417, 1282, 1225, 951, 824, 760 cm^-1.
NMR(CDCl₃)δ：1.15(3H,t,J=7.6Hz), 2.44(3H,s), 2.66(2H,q,J=7.6Hz), 3.31(4H,t,J=4.8Hz), 3.90(4H,t,J=4.8Hz), 5.32(2H,s), 6.72(1H,d,J=9.0Hz), 6.83(1H,d,J=2.6Hz), 6.91(1H,t,J=8.4Hz), 6.97(2H,d,J=8.4Hz), 7.30(2H,t,J=8.4Hz), 7.39(2H,d,J=8.2Hz), 7.54(1H,d,J=2.6Hz), 7.75(1H,d,
【０２７０】
実施例２０５
３−メチル−２−〔４−（６−（４−フェニルピペラジノ）ニコチノイル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−〔４−（６−クロロニコチノイル）ベンジルオキシ〕−３−メチル−ピリド〔１，２−ａ〕ピリミジン−４−オン（０．８０５ｇ，１．９８mmol）と４−フェニルピペラジン（０．４７８ｇ，２．９５mmol）のピリジン（１０ml）溶液を９０℃で終夜撹拌した。溶媒を減圧除去し、残渣に水を加え生じた結晶を減圧下乾燥し淡黄色固体を得た。０．３８ｇ（５９％）
IR(KBr)ν：1674, 1637, 1589, 1479, 1282, 1164 cm^-1.
NMR(CDCl₃)δ：2.22(3H,s), 3.32(4H,t,J=7.2Hz), 3.90(4H,t,J=7.2Hz), 5.62(2H,s), 6.73(1H,d,J=9.2Hz), 6.86-7.02(3H,m), 7.10(1H,dt,J=7.0,1.2Hz), 7.24-7.36(2H,m), 7.45-7.82(6H,m), 8.08(1H,dd,J=9.2,2.6Hz), 8.64(1H,d,J=2.2Hz), 9.08(1H,d,J=8.0Hz).
【０２７１】
実施例２０６
３，５−ジメチル−２−〔４−（４−（４−フェニルピペラジノカルボニル）ベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
２−〔４−（４−カルボキシベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）−キナゾリノン（０．４７２ｇ，１．０６mmol）のＤＭＦ（１０．０ml）溶液にＤＥＰＣ（０．３５６ｇ，２．１８mmol）を加え室温で１５分間撹拌した後４−フェニルピペラジン（０．３５ml，２．２９mmol）を加え室温で３時間撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をＴＨＦから再結晶し無色針状晶を得た。０．３６６ｇ（５９％）
IR(KBr)ν：1666, 1635, 1554, 1432, 1277, 1090, 729 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.05-3.35(2H,m), 3.55(3H,s), 3.59(1H,m), 3.95(1H,m), 4.60(2H,s), 6.88-6.98(3H,m), 7.15(1H,d,J=7.6Hz), 7.25-7.35(2H,m),7.43(1H,d,J=7.4Hz), 7.50-7.65(5H,m), 7.78(2H,d,J=8.4Hz), 7.83(2H,d,J=8.2Hz).
【０２７２】
実施例２０７
３，５−ジメチル−２−〔４−（４−（４−ヒドロキシピペリジノカルボニル）ベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
２−〔４−（４−カルボキシベンゾイル）ベンジル〕チオ−３，５−ジメチル−４（３Ｈ）−キナゾリノン（１．００ｇ，２．２６mmol）のＤＭＦ（１０．０ml）溶液にＤＥＰＣ（０．７５５ｇ，４．６３mmol）を加え室温で１０分間撹拌した後４−ヒドロキシピペリジン（０．５２２ｇ，５．１６mmol）を加え室温で４時間撹拌した。溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をＴＨＦから再結晶し無色針状晶を得た。０．７３５ｇ（６２％）
IR(KBr)ν：3425, 1664, 1608, 1554, 1448, 1305, 1277, 1088, 729 cm^-1.
NMR(CDCl₃)δ：1.40-2.10(4H,m), 2.81(3H,s), 3.10-3.80(3H,m), 3.55(3H,s), 4.01(1H,m), 4.10-4.30(1H,m), 4.59(2H,s), 7.15(1H,d,J=6.6Hz), 7.40-7.68(6H,m), 7.75-7.86(4H,m).
【０２７３】
実施例２０８
２−〔４−（４−カルボキシベンゾイル）ベンジルオキシ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−〔４−（４−メトキシカルボニルベンゾイル）ベンジルオキシ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（１．４８ｇ，３．４７mmol）のＤＭＦ（３０．０ml）溶液を９０℃に加熱し、１Ｎ−水酸化ナトリウム（４．００ml）を加え２時間撹拌した。塩酸を加え pＨ＝６とすると無色針状晶が析出し、これをろ取し減圧下、乾燥した。１．４０ｇ（９７％）
IR(KBr)ν：3421, 3050, 1716, 1691, 1579, 1527, 1408, 1282, 1257, 1178, 931, 788, 735 cm^-1.
NMR(DMSO-d₆)δ：2.09(3H,s), 5.63(2H,s), 7.32(1H,t,J=7.2Hz), 7.57(1H,d,J=8.8Hz), 7.67(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz), 7.83(2H,d,J=8.0Hz), 7.94(1H,dd,J=8.8,7.2Hz), 8.96(1H,d,J=7.2Hz).
【０２７４】
実施例２０９
１−〔４−（４−カルボキシベンゾイル）ベンジル〕−６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６−エチル−１−〔４−（４−メトキシカルボニルベンゾイル）ベンジル〕−７−メチルイミダゾール〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（１．９１ｇ，４．４５mmol）のＴＨＦ（３０．０ml）−メタノール（１０ml）混合溶液に１Ｎ−水酸化ナトリウム（５．００ml）を加え室温で３時間撹拌した。塩酸を加え pＨ＝４とすると無色針状晶が析出し、これをろ取し減圧下、乾燥した。０．９００ｇ（４９％）
IR(KBr)ν：3396, 3134, 2968, 1713, 1645, 1562, 1523, 1414, 1275, 1225, 931, 787, 717 cm^-1.
NMR(DMSO-d₆)δ：1.03(3H,t,J=7.4Hz), 2.33(3H,s), 3.33(2H,q,J=7.4Hz), 5.40(2H,s), 7.49(2H,d,J=8.4Hz), 7.58(1H,d,J=2.6Hz), 7.64(1H,d,J=2.6Hz), 7.76(2H,d,J=8.4Hz), 7.80(2H,d,J=8.4Hz), 8.09(2H,d,J=8.4Hz).
【０２７５】
実施例２１０
３−メチル−２−〔４−（４−（４−フェニルピペラジノカルボニル）ベンゾイル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−〔４−（４−カルボキシ）ベンゾイル）ベンジルオキシ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（０．４９５ｇ，１．２０mmol）のＤＭＦ（１５ml）溶液にＤＥＰＣ（０．７５mml，４．９１mmol）を加え室温で３０分間撹拌した後４−フェニルピペラジン（０．４３７ｇ，２．６８mmol）を加え終夜撹拌した。反応混合物に酢酸エチルを加え飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色針状晶を得た。０．３９４ｇ（５９％）
IR(KBr)ν：1668, 1635, 1529, 1477, 1281, 1165, 1012, 928, 731 cm^-1.
NMR(CDCl₃)δ:2.23(3H,s), 3.13(2H,bs), 3.24(2H,bs), 3.59(2H,bs), 3.97(2H,bs), 5.63(2H,s), 6.93(1H,t,J=7.8Hz), 6.95(2H,d,J=7.8Hz), 7.11(1H,t,J=7.0Hz), 7.31(2H,d,J=7.8Hz), 7.50(1H,d,J=7.0Hz), 7.56(2H,d,J=8.4Hz), 7.60(2H,d,J=8.4Hz), 7.71(1H,t,J=7.0Hz), 7.85(2H,d,J=8.4Hz), 7.87(2H,d,J=8.4Hz), 9.07(1H,d,J=7.0Hz).
【０２７６】
実施例２１１
６−エチル−７−メチル−１−〔４−（４−（４−フェニルピペラジノカルボニル）ベンゾイル）ベンジル〕−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
１−〔４−（４−カルボキシベンゾイル）ベンジル〕−６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（０．３０３ｇ，０．７２９mmol）のＤＭＦ（１５ml）溶液にＤＥＰＣ（０．４４mml，２．８８mmol）を加え室温で３０分間撹拌した後４−フェニルピペラジン（０．４０７ｇ，２．４９mmol）を加え終夜撹拌した。反応混合物に酢酸エチルを加え飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をＴＨＦから再結晶し無色針状晶を得た。０．３２９ｇ（８１％）
IR(KBr)ν：1653, 1587, 1520, 1435, 1277, 1221, 1011, 926, 729 cm^-1.
NMR(CDCl₃)δ：1.15(3H,t,J=7.2Hz), 2.43(3H,s), 2.66(2H,q,5.33(2H,s), 6.85(1H,d,J=2.6Hz), 6.92(1H,t,J=7.0Hz), 6.94(2H,d,J=7.0Hz), 7.30(2H,t,J=7.0Hz), 7.42(2H,d,J=8.4Hz), 7.55(2H,d,J=8.4Hz), 7.55(1H,d,J=2.6Hz), 7.82(2H,d,J=8.4Hz), 7.84(2H,d,J=8.4Hz).
【０２７７】
実施例２１２
３−メチル−２−〔４−（４−（４−ピペリジノピペリジノカルボニル）ベンゾイル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン２塩酸塩
２−〔４−（４−カルボキシベンゾイル）ベンジルオキシ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（０．３３３ｇ，０．８０４mmol）のＤＭＦ（１０ml）溶液にＤＥＰＣ（０．４２４mml，２．５２mmol）を加え室温で３０分間撹拌した後４−ピペリジノピペリジン（０．３４８ｇ，２．１３mmol）を加え２．５時間撹拌した。反応混合物に酢酸エチルを加え飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＴＨＦ：メタノール：アンモニア＝５０：１：０．１）で精製し無色油状物を得た。これを４Ｎ−塩酸−酢酸エチルで塩酸塩とした後水から凍結乾燥し無色粉末を得た。
IR(KBr)ν：3423, 2945, 1633, 1529, 1475, 1448, 1281, 1167, 1003, 930, 773 cm^-1.
NMR(DMSO-d₆)δ：1.30-1.60(2H,m), 1.60-2.00(6H,m), 2.00-2.30(2H,m), 2.80-3.10(4H,m), 3.60-3.80(4H,m), 4.50-4.70(1H,m), 7.33(1H,t,J=8.2Hz), 7.58(2H,d,J=8.0Hz), 7.68(2H,d,J=8.0Hz), 7.73(1H,d,J=8.2Hz), 7.79(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz), 7.95(1H,t,J=8.2Hz), 8.96(1H,d,J=8.2Hz).
【０２７８】
実施例２１３
６−エチル−７−メチル−１−〔４−（４−（４−ピペリジノピペリジノカルボニル）ベンゾイル）ベンジル〕−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン塩酸塩
１−〔４−（４−カルボキシベンゾイル）ベンジル〕−６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（０．３０２ｇ，０．７２７mmol）のＤＭＦ（１０ml）溶液にＤＥＰＣ（０．３１８mg，１．９５mmol）を加え室温で３０分間撹拌した後４−ピペリジノピペリジン（０．３３６ｇ，２．００mmol）を加え２．５時間撹拌した。反応混合物に酢酸エチルを加え飽和食塩水で洗浄後有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＴＨＦ：メタノール：アンモニア＝５０：１：０．１）で精製し無色油状物を得た。これを４Ｎ−塩酸−酢酸エチルで塩酸塩とした後、水から凍結乾燥し無色粉末を得た。
IR(KBr)ν：3456, 2960, 2690, 1703, 1657, 1601, 1510, 1452, 1278, 1225, 1171, 1034, 1003 cm^-1.
NMR(DMSO-d₆)δ：1.19(3H,t,J=7.0Hz), 1.35-1.55(2H,m), 1.60-2.00(6H,m), 2.05-2.30(2H,m), 2.38(3H,s), 2.47(2H,q,J=7.0Hz), 2.60-3.00(4H,m), 3.30-3.50(4H,m), 4.50-4.70(1H,m), 5.49(2H,s), 7.53(2H,d,J=8.2Hz), 7.57(2H,d,J=8.2Hz), 7.64(1H,d,J=2.8Hz), 7.68(1H,d,J=2.8Hz), 7.77(2H,d,J=8.2Hz), 7.78(2H,d,J=8.2Hz).
【０２７９】
実施例２１４
２−〔４−（４−クロロベンゾイル）ベンジル〕チオ−５−エチル−３−メチル−４（３Ｈ）−キナゾリノン
５−エチル−３−メチル−２メルカプトキナゾリン−４−オン（０．３０７ｇ，１．３９mmol）のＥtＯＨ（５．０ml）−ＴＨＦ（５．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（１．５０ml）を加えた後臭化４−（４−クロロベンゾイル）ベンジル（０．４３４ｇ，１．４０mmol）を加え室温で１．５時間撹拌した。反応液に水（１００ml）を加え析出した固体をろ取し、水で洗浄後減圧下乾燥した。この固体を酢酸エチルから再結晶し淡黄色針状晶を得た。０．３９８ｇ（６４％）
IR(KBr)ν：1666, 1583, 1554, 1441, 1311, 1277, 1090, 928, 822 cm^-1.
NMR(CDCl₃)δ：1.27(3H,t,J=7.2Hz), 2.29(2H,q,J=7.2Hz), 4.59(2H,s), 7.18(1H,d,J=8.0Hz), 7.44(1H,d,J=8.0Hz), 7.45(2H,d,J=7.2Hz), 7.58(1H,t,J=8.0Hz), 7.60(2H,d,J=7.2Hz), 7.72(2H,d,J=7.2Hz), 7.73(2H,d,J=7.2Hz).
【０２８０】
実施例２１５
５−エチル−２−〔４−（４−メトキシベンゾイル）ベンジル〕チオ−３−メチル−４（３Ｈ）−キナゾリノン
５−エチル−３−メチル−２メルカプトキナゾリン−４−オン（０．２９８ｇ，１．３５mmol)のＥtＯＨ（５．０ml）−ＴＨＦ（５．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（１．５０ml）を加えた後臭化４−（４−メトキシベンゾイル）ベンジル（０．４３０ｇ，１．４１mmol）を加え室温で４０分間撹拌した。反応液に水（１００ml）を加え析出した固体をろ取し、水で洗浄後減圧下乾燥した。この固体を酢酸エチルから再結晶し無色針状晶を得た。０．５７２ｇ（９５％）
IR(KBr)ν：1668, 1601, 1552, 1464, 1435, 1414, 1311, 1171, 1091, 1026, 928, 820 cm^-1.
NMR(CDCl₃)δ：1.27(3H,t,J=8.0Hz), 3.34(2H,q,J=8.0Hz), 3.56(3H,s), 3.88(3H,s), 4.59(2H,s), 6.95(2H,d,J=9.0Hz), 7.18(1H,d,J=8.8Hz), 7.54(1H,d,J=8.8Hz), 7.58(2H,d,J=8.4Hz), 7.59(1H,t,J=8.8Hz), 7.72(2H,d,J=8.4Hz), 7.81(2H,d,J=9.0Hz).
【０２８１】
実施例２１６
５−エチル−３−メチル−２−〔４−（４−ニトロベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
５−エチル−３−メチル−２メルカプトキナゾリン−４−オン（０．２９５ｇ，１．３４mmol)のＥtＯＨ（５．０ml）−ＴＨＦ（５．０ml）混合溶液に１Ｎ−水酸化ナトリウム水溶液（１．５０ml）を加えた後臭化４−（４−ニトロベンゾイル）ベンジル（０．４３４ｇ，１．３６mmol）を加え室温で４０分間撹拌した。反応液に水（１００ml）を加え析出した固体をろ取し、水で洗浄後減圧下乾燥した。この固体を酢酸エチルから再結晶し無色針状晶を得た。０．４０８ｇ（７０％）
IR(KBr)ν：1666, 1601, 1552, 1524, 1466, 1437, 1412, 1346, 1311, 1092, 929 cm^-1.
NMR(CDCl₃)δ:1.27(3H,t,J=7.6Hz), 3.29(2H,q,J=7.6Hz), 3.56(3H,s), 4.60(2H,s), 7.19(1H,d,J=8.4Hz), 7.44(1H,d,J=8.4Hz), 7.58(1H,t,J=8.4Hz), 7.64(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 7.91(2H,d,J=8.8Hz), 8.32(2H,d,J=8.8Hz).
【０２８２】
実施例２１７
２−〔４−（４−ジエチルホスホノオキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（２６８mg）、ジエチルホスホノクロリダート（０．１６ml）、トリエチルアミン（０．２８ml）のテトラヒドロフラン（８ml）溶液を室温で１４時間撹拌した。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、ヘキサンから結晶化させて無色固体の表題化合物（２７０mg）を得た。
IR(KBr)ν：1683, 1556, 1471, 1270, 1031 cm^-1.
NMR(CDCl₃)δ：1.37(3H,t,J=7.1Hz), 1.38(3H,t,J=7.0Hz), 2.85(3H,s), 3.55(3H,s), 4.23(2H,q,J=7.1Hz), 4.27(2H,q,J=7.0Hz), 4.60(2H,s), 7.16(1H,d,J=7.6Hz), 7.32(2H,d,J=8.0Hz), 7.44(1H,d,J=7.8Hz), 7.53(1H,d,J=7.2Hz), 7.61(2H,d,J=8.2Hz), 7.75(2H,d,J=8.4Hz), 7.81(7H,d,J=8.4Hz).
【０２８３】
実施例２１８
３，５−ジメチル−２−〔４−〔４−（２−ジメチルアミノエトキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン塩酸塩
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３０６mg）、ジメチルアミノエチルクロリド塩酸塩（２１８mg）、炭酸カリウム（３１６mg）のジメチルホルムアミド（５ml）溶液を８０℃で２０時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後、塩酸酢酸エチル溶液を加え、生じた塩酸塩の沈殿物をろ取して無色固体の表題化合物（１９３mg）を得た。
IR(KBr)ν：1641, 1600, 1473, 1303, 1170, 808 cm^-1.
NMR(DMSO-d₆)δ：2.76(3H,s), 2.87(6H,s), 3.46(3H,s), 3.56(2H,m), 4.47(2H,m), 4.65(2H,s), 7.14(2H,d,J=8.8Hz), 7.21(1H,d,J=7.6Hz), 7.47(1H,d,J=8.2Hz), 7.58-7.82(7H,m).
【０２８４】
実施例２１９
２−〔４−（４−アセトキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（９１７mg）、４−（４−アセトキシベンゾイル）ベンジルブロミド（１．７８５ｇ）、１規定水酸化ナトリウム水溶液（４．５ml）のメタノール（２０ml）溶液を室温で４時間撹拌させた。反応液を濃縮しクロロホルムで抽出し、水で洗浄、乾燥後濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝６／１）にて精製して無色固体の表題化合物（４．２６mg）を得た。
IR(KBr)ν：1754, 1670, 1652, 1558, 1471, 1303, 1193 cm^-1.
NMR(CDCl₃)δ：2.34(3H,s), 2.85(3H,s), 3.55(3H,s), 4.59(2H,s), 7.15(1H,d,J=7.6Hz), 7.21(2H,d,J=8.4Hz), 7.44(1H,d,J=7.4Hz), 7.50-7.64(3H,m), 7.77(2H,d,J=8.2Hz), 7.83(2H,d,J=8.8Hz).
【０２８５】
実施例２２０
３，５−ジメチル−２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（９５２mg）、４−（４−ｔ−ブチルジメチルシリルオキシベンゾイル）ベンジルブロミド（２．９０ｇ）、１規定水酸化ナトリウム水溶液（４．６ml）のメタノール（２０ml）溶液を室温で４時間撹拌させた。反応液を濃縮しクロロホルムで抽出し、水で洗浄、乾燥後濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１９／１）にて精製した。得られた２−〔４−（４−ｔ−ブチルジメチルシリルオキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノンをテトラヒドロフラン（１５ml）に溶解させ、テトラブチルアンモニウムフルオリドの１Ｍテトラヒドロフラン溶液（３．８ml）を加え、室温で１時間撹拌させた。反応液に水を加え生じた沈殿物をろ取し、水で洗浄後乾燥して無色固体の表題化合物（１．３３２ｇ）を得た。
IR(KBr)ν：1652, 1604, 1556, 1471, 1309, 1039 cm^-1.
NMR(DMSO-d₆)δ：2.75(3H,s), 3.45(3H,s), 4.63(2H,s), 6.87(2H,d,J=8.7Hz), 7.21(1H,d,J=7.3Hz), 7.46(1H,d,J=7.3Hz), 7.57-7.72(7H,m).
【０２８６】
実施例２２１
２−〔４−（４−ベンジルオキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン(３９５mg)、ベンジルブロミド(０．１３ml)、炭酸カリウム(４０８mg)のジメチルホルムアミド（５ml）溶液を６０℃で１時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、酢酸エチルから再結晶して無色固体の表題化合物（３４６mg）を得た。
IR(KBr)ν：1683, 1598, 1560, 1469, 1172, 1093 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 5.15(2H,s), 7.03(2H,d,J=8.9Hz), 7.16(1H,d,J=7.2Hz), 7.34-7.64(9H,m), 7.73(2H,d,J=8.4Hz), 7.81(2H,d,J=8.9Hz).
【０２８７】
実施例２２２
３，５−ジメチル−２−〔４−〔４−（２−ピロリジノエトキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン塩酸塩
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３８４mg）、１−（２−クロロエチル）ピロリジン塩酸塩（１８１mg）、炭酸カリウム（４１４mg）のジメチルホルムアミド（５ml）溶液を６０℃で６２時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後、塩酸酢酸エチル溶液を加え、生じた塩酸塩の沈殿物をろ取して無色固体の表題化合物（２２７mg）を得た。
IR(KBr)ν：1675, 1600, 1554, 1471, 1307, 1172, 1093 cm^-1.
NMR(DMSO-d₆)δ：1.78-2.12(4H,m), 2.75(3H,s), 3.02-3.24(2H,m), 3.46(3H,s), 3.50-3.68(4H,m), 4.43(2H,t,J=5.0Hz), 4.65(2H,s), 7.15(2H,d,J=8.8Hz), 7.22(1H,d,J=8.0Hz), 7.47(1H,d,J=7.8Hz), 7.58-7.82(7H,m).
【０２８８】
実施例２２３
３，５−ジメチル−２−〔４−〔４−（２−ピペリジノエトキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン塩酸塩
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３９９mg）、１−（２−クロロエチル）ピペリジン塩酸塩（１８５mg）、炭酸カリウム（３９２mg）のジメチルホルムアミド（５ml）溶液を６０℃で６２時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後、塩酸酢酸エチル溶液を加え、生じた塩酸塩の沈殿物をろ取して無色固体の表題化合物（３６８mg）を得た。
IR(KBr)ν：1675, 1598, 1554, 1309, 1147, 1093 cm^-1.
NMR(DMSO-d₆)δ：1.76-1.96(6H,m), 2.75(3H,s), 2.90-3.16(2H,m), 3.64(3H,s), 3.20-3.70(4H,m), 4.49(2H,t,J=4.4Hz), 4.65(2H,s), 7.14(2H,d,J=8.8Hz), 7.21(1H,d,J=6.8Hz), 7.47(1H,d,J=7.4Hz), 7.58-7.80(7H,m).
【０２８９】
実施例２２４
３，５−ジメチル−２−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン塩酸塩
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３６６mg）、４−（２−クロロエチル）モルホリン塩酸塩（１９２mg）、炭酸カリウム（３５６mg）のジメチルホルムアミド（５ml）溶液を６０℃で６２時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後、塩酸酢酸エチル溶液を加え、生じた塩酸塩の沈殿物をろ取して無色固体の表題化合物（３３７mg）を得た。
IR(KBr)ν：1683, 1600, 1558, 1471, 1305, 1172, 1095 cm^-1.
NMR(DMSO-d₆)δ：2.75(3H,s), 3.08-3.68(9H,m), 3.70-4.08(4H,m), 4.53(2H,t,J=4.5Hz), 4.65(2H,s), 7.15(2H,d,J=9.0Hz), 7.21(1H,d,J=7.2Hz), 7.47(1H,d,J=8.0Hz), 7.58-7.81(7H,m).
【０２９０】
実施例２２５
３，５−ジメチル−２−〔４−〔４−（３−ジメチルアミノプロポキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン塩酸塩
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３１１mg）、３−ジメチルアミノプロピルクロリド塩酸塩（２４９mg）、炭酸カリウム（３２２mg）のジメチルホルムアミド（５ml）溶液を６０℃で１８時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後、塩酸酢酸エチル溶液を加え、生じた塩酸塩の沈殿物をろ取して無色固体の表題化合物（１８５mg）を得た。
IR(KBr)ν：1675, 1558, 1471, 1305, 1172 cm^-1.
NMR(DMSO-d₆)δ：2.18(2H,m), 2.76(3H,s), 2.81(6H,s), 3.24(2H,m), 3.46(3H,s), 4.17(2H,m), 4.65(2H,s), 7.08(2H,d,J=8.2Hz), 7.23(1H,d,J=8.2Hz), 7.48(1H,d,J=7.8Hz), 7.58-7.82(7H,m).
【０２９１】
実施例２２６
２−〔４−〔４−（２−アセトキシエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（１．８８８ｇ）、４−〔４−（アセトキシエトキシ）ベンゾイル〕ベンジルブロミド（３．８９５ｇ）、１規定水酸化ナトリウム水溶液（１４．３ml）のメタノール（３０ml）溶液を室温で３０分間撹拌させた。反応液を濃縮しクロロホルムで抽出し、水で洗浄、乾燥後濃縮し、得られた残渣を酢酸エチルから再結晶して無色固体の表題化合物（２．５９７ｇ）を得た。
IR(KBr)ν：1737, 1668, 1600, 1554, 1174, 1085 cm^-1.
NMR(CDCl₃)δ：2.13(3H,s), 2.85(3H,s), 3.55(3H,s), 4.25(2H,m), 4.46(2H,m), 4.60(2H,s), 6.97(2H,d,J=9.0Hz), 7.15(1H,d,J=6.6Hz), 7.45(1H,d,J=6.8Hz), 7.50-7.64(3H,m), 7.73(2H,d,J=8.2Hz), 7.82(2H,d,J=8.8Hz).
【０２９２】
実施例２２７
３，５−ジメチル−２−〔４−〔４−（２−ヒドロキシエトキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−〔４−（２−アセトキシエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（１．７５ｇ）と１規定水酸化ナトリウム水溶液（１５ml）のメタノール（５０ml）ジクロロメタン（２５ml）溶液を室温で３時間撹拌させた。反応液からジクロロメタンで抽出し、乾燥濃縮後得られた残渣を酢酸エチルから再結晶して無色固体の表題化合物（１．２７８ｇ）を得た。
IR(KBr)ν：1683, 1600, 1553, 1471, 1305, 1093 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 4.02(2H,m), 4.17(2H,t,J=4.4Hz), 4.60(2H,s), 6.98(2H,d,J=8.8Hz), 7.15(1H,d,J=6.6Hz), 7.45(1H,d,J=6.6Hz), 7.52-7.63(3H,m), 7.73(2H,d,J=8.4Hz), 7.82(2H,d,J=8.8Hz).
【０２９３】
実施例２２８
３，５−ジメチル−２−〔４−〔４−（Ｎ，Ｎ−ジメチルカルバモイルオキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（４７８mg）、ジメチルカルバモイルクロリド（０．１５ml）、炭酸カリウム（３１５mg）のジメチルホルムアミド（７ml）溶液を５０℃で４８時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、酢酸エチルから再結晶して無色固体の表題化合物（３４６mg）を得た。
IR(KBr)ν：1733, 1670, 1602, 1562, 1471, 1160, 1091 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.04(3H,s), 3.13(3H,s), 3.55(3H,s), 4.59(2H,s), 7.15(1H,d,J=7.0Hz), 7.23(2H,d,J=8.8Hz), 7.44(1H,d,J=8.2Hz), 7.50-7.64(3H,m), 7.77(2H,d,J=8.2Hz), 7.81(2H,d,J=8.8Hz).
【０２９４】
実施例２２９
３，５−ジメチル−２−〔４−〔４−〔４−（４−ホルミルピペラジニルカルボニル）ベンジルオキシ〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン(４０２mg)、１−（４−クロロメチルベンゾイル）−４−ホルミルピペラジン(３５４mg)、炭酸カリウム(２６１mg)のジメチルホルムアミド（５ml）溶液を室温で２４時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して無色固体の表題化合物(３１０mg)を得た。
IR(KBr)ν：1670, 1600, 1558, 1456, 1307, 1172 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.35-3.80(8H,m), 3.55(3H,s), 4.60(2H,s), 5.19(2H,s), 7.02(2H,d,J=8.9Hz), 7.15(1H,d,J=7.2Hz), 7.42-7.61(8H,m), 7.73(2H,d,J=8.3Hz), 7.82(2H,d,J=8.9Hz), 8.12(1H,s).
【０２９５】
実施例２３０
２−〔４−〔４−（４−ベンジルオキシベンジルオキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３０９mg）、４−ベンジルオキシベンジルクロリド（２２４mg）、炭酸カリウム（２９５mg）のジメチルホルムアミド（５ml）溶液を室温で１４時間撹拌させた。反応液を濃縮し残渣をクロロホルムに溶解させ、水で洗浄し乾燥後濃縮して、クロロホルム／酢酸エチルから再結晶して無色固体の表題化合物（３５５mg）を得た。
IR(KBr)ν：1683, 160 , 1552, 1456, 1305, 1172, 1093 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 4.59(2H,s), 5.07(2H,s), 5.09(2H,s), 7.00(2H,d,J=8.6Hz), 7.01(2H,d,J=8.8Hz), 7.15(1H,d,J=7.2Hz), 7.32-7.62(11H,m), 7.73(2H,d,J=8.3Hz), 7.81(2H,d,J=8.8Hz).
【０２９６】
実施例２３１
３，５−ジメチル−２−〔４−〔４−（４−ピコリルオキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３６９mg）、４−ピコリルクロリド塩酸塩（１４４mg）、炭酸カリウム（３５０mg）のジメチルホルムアミド（５ml）溶液を室温で３日間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、酢酸エチル／クロロホルムから再結晶して無色固体の表題化合物（９９mg）を得た。
IR(KBr)ν：1670, 1600, 1554, 1471, 1305, 1170, 1093 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 5.18(2H,s), 7.01(2H,d,J=8.9Hz), 7.15(1H,d,J=6.8Hz), 7.37(2H,d,J=5.4Hz), 7.44(1H,d,J=8.0Hz), 7.50-7.64(3H,m), 7.73(2H,d,J=8.2Hz), 7.82(2H,d,J=8.9Hz), 8.65(2H,d,J=5.4Hz).
【０２９７】
実施例２３２
３，５−ジメチル−２−〔４−〔４−〔２−（４−メチルピペラジニル）エトキシ〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン２塩酸塩
２−〔４−〔４−（２−クロロエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（１７３mg）とメチルピペラジン（０．１２ml）のジメチルホルムアミド（５ml）溶液を１００℃で１５時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄後乾燥し、塩酸酢酸エチル溶液を加え、生じた塩酸塩の沈殿物をろ取し、乾燥して無色固体の表題化合物（１２２mg）を得た。
IR(KBr)ν：1670, 1600, 1558, 1471, 1307, 1172, 1093, 929 cm^-1.
NMR(DMSO-d₆)δ：2.76(3H,s), 3.46(3H,s), 2.80-3.70(13H,m), 4.16-4.40(2H,m), 4.65(2H,s), 7.10(2H,d,J=8.4Hz), 7.22(1H,d,J=7.4Hz), 7.47(1H,d,J=7.8Hz), 7.58-7.80(7H,m).
【０２９８】
実施例２３３
２−〔４−〔４−（２−クロロエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−〔４−〔４−（２−ヒドロキシエトキシ)ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン(６５１mg)の四塩化炭素(１５ml)懸濁液に、トリフェニルホスフィン(４７６mg)を加え４０時間還流させた。反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン）で精製し、酢酸エチルから再結晶して無色固体の表題化合物(３９１mg)を得た。
IR(KBr)ν：1670, 1600, 1554, 1307, 1174, 1093, 696 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 3.85(2H,t,J=5.9Hz), 4.31(2H,t,J=5.9Hz), 4.60(2H,s), 6.97(2H,d,J=8.9Hz), 7.15(1H,d,J=7.0Hz), 7.44(1H,d,J=8.2Hz), 7.50-7.64(3H,m), 7.73(2H,d,J=8.4Hz), 7.82(2H,d,J=8.9Hz).
【０２９９】
実施例２３４
３，５−ジメチル−２−〔４−（４−フェナシルオキシベンゾイル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（４１３mg）、フェナシルブロミド（３１５mg）、炭酸カリウム（４３６mg）のジメチルホルムアミド（７ml）溶液を室温で１５時間撹拌させた。反応液を濃縮し残渣をクロロホルムに溶解させ、水で洗浄し乾燥後濃縮して、クロロホルム／酢酸エチルから再結晶して無色固体の表題化合物（３１３mg）を得た。
IR(KBr)ν：1708, 1675, 1594, 1560, 1471, 1176, 1093 cm^-1.
NMR(CDCl₃)δ：2.85(3H,s), 3.54(3H,s), 4.59(2H,s), 5.38(2H,s), 6.98(2H,d,J=8.8Hz), 7.14(1H,d,J=7.0Hz), 7.40-7.67(7H,m), 7.72(2H,d,J=8.4Hz), 7.80(2H,d,J=8.8Hz), 8.01(2H,m).
【０３００】
実施例２３５
３，５−ジメチル−２−〔４−〔４−〔２−（４−ピペリジノピペリジノ）エトキシ〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン２塩酸塩
２−〔４−〔４−（２−クロロエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３７５mg）と４−ピペリジノピペリジン（４３４mg）のジメチルホルムアミド（５ml）溶液を１００℃で７時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄後乾燥濃縮して、塩酸酢酸エチル溶液を加え、生じた塩酸塩の沈殿物をろ取し乾燥して無色固体の表題化合物（３６８mg）を得た。
IR(KBr)ν：1670, 1598, 1558, 1457, 1307, 1172, 1093 cm^-1.
NMR(DMSO-d₆)δ: 2.76(3H,s), 3.46(3H,s), 1.80-3.80(21H,m), 4.50(2H,brs), 4.66(2H,s), 7.15(2H,d,J=8.8Hz), 7.22(1H,d,J=7.4Hz), 7.48(1H,d,J=7.6Hz), 7.58-7.83(7H,m).
【０３０１】
実施例２３６
３，５−ジメチル−２−〔４−〔４−〔２−（２−ジメチルアミノエチルアミノ）エトキシ〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン２塩酸塩
２−〔４−〔４−（２−クロロエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（２３７mg）と２−ジメチルアミノエチルアミン（１．１ml）のジメチルホルムアミド（５ml）溶液を１００℃で７時間撹拌させた。反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール／アンモニア水＝９／１／０．１）にて精製し、塩酸酢酸エチル溶液で塩酸塩として無色固体の表題化合物（１０４mg）を得た。
IR(KBr)ν：1652, 1600, 1558, 1457, 1305, 1172 cm^-1.
NMR(DMSO-d₆)δ：2.75(3H,s), 2.85(6H,brs), 3.30-3.60(9H,m), 4.36-4.46(2H,brs), 4.65(2H,s), 7.10-7.25(3H,m), 7.46(1H,d,J=8.0Hz), 7.56-7.84(7H,m), 9.58-9.82(1H,br).
【０３０２】
実施例２３７
３，５−ジメチル−２−〔４−〔４−（４−フェニルフェナシルオキシ）ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３９８mg）、４−フェニルフェナシルブロミド（２９０mg）、炭酸カリウム（４４０mg）のジメチルホルムアミド（７ml）溶液を室温で７２時間撹拌させた。反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／エーテル＝１０／１）で精製し、クロロホルム／酢酸エチルから再結晶して無色固体の表題化合物（２１７mg）を得た。
IR(KBr)ν：1675, 1600, 1558, 1471, 1305, 1093 cm^-1.
NMR(CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.59(2H,s), 5.41(2H,s), 7.01(2H,d,J=9.0Hz), 7.15(1H,d,J=7.0Hz), 7.41-7.78(13H,m), 7.81(2H,d,J=9.0Hz), 8.09(2H,d,J=8.6Hz).
【０３０３】
実施例２３８
３，５−ジメチル−２−〔４−〔４−〔２−（２−モルホリノエチルアミノ）エトキシ〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン２塩酸塩
２−〔４−〔４−（２−クロロエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（１６５mg）と４−（２−アミノエチル）モルホリン（５４３mg）のジメチルホルムアミド（７ml）溶液を１００℃で７時間撹拌させた。反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール／アンモニア水＝９／１／０．１）にて精製し、塩酸酢酸エチル溶液で塩酸塩として無色固体の表題化合物（１０１mg）を得た。
IR(KBr)ν：1646, 1602, 1558, 1307, 1174, 1147, 1108 cm^-1.
NMR(DMSO-d₆)δ：2.75(3H,s), 3.45(3H,s), 3.00-4.80(16H,m), 7.10-7.26(3H,m), 7.47(1H,d,J=8.0Hz), 7.58-7.82(7H,m).
【０３０４】
実施例２３９
３，５−ジメチル−２−〔４−〔４−〔２−〔Ｎ−〔２−（２−ピリジル）エチル〕−Ｎ−メチルアミノ〕エトキシ〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン２塩酸塩
２−〔４−〔４−（２−クロロエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３８１mg）、２−（２−メチルアミノエチル）ピリジン（０．１７ml）、トリエチルアミン（０．３３ml）のジメチルホルムアミド（７ml）溶液を１００℃で２１時間撹拌させた。反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール／アンモニア水＝９／１／０．１）にて精製し、塩酸酢酸エチル溶液で塩酸塩として無色固体の表題化合物（２５６mg）を得た。
IR(KBr)ν：1662, 1600, 1556, 1307, 1174, 1110 cm^-1.
NMR(DMSO-d₆)δ：2.75(3H,s), 2.97(3H,s), 3.45(3H,s), 3.46-4.20(6H,m), 4.56(2H,brs), 4.64(2H,s), 7.08-7.24(3H,m), 7.46(1H,d,J=8.4Hz), 7.56-7.80(7H,m), 7.87(1H,t,J=6.6Hz), 7.99(1H,d,J=7.8Hz), 8.45(1H,t,J=7.8Hz), 8.82(1H,d,J=5.4Hz).
【０３０５】
実施例２４０
３，５−ジメチル−２−〔４−〔４−〔４−（４−メチルピペラジニルカルボニル）ベンジルオキシ〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン塩酸塩
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（４０６mg）、１−（４−クロロメチルベンゾイル）−４−メチルピペラジン塩酸塩（１．１１９ｇ）、炭酸カリウム（７３９mg）のジメチルホルムアミド（１０ml）溶液を室温で４０時間撹拌させた。反応液を濃縮し残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝９／１）で精製し、塩酸酢酸エチル溶液で塩酸塩として無色固体の表題化合物（８６mg）を得た。
IR(KBr)ν：1652, 1600, 1558, 1471, 1307, 1172, 1093 cm^-1.
NMR(CDCl₃)δ：2.28-2.58(4H,m), 2.33(3H,s), 2.85(3H,s), 3.38-3.60(2H,m), 3.54(3H,s), 3.64-3.90(2H,m), 4.59(2H,s), 5.17(2H,s), 7.01(2H,d,J=8.8Hz),7.14(1H,d,J=7.0Hz), 7.40-7.62(8H,m), 7.72(2H,d,J=8.0Hz), 7.81(1H,d,J=8.8Hz).
【０３０６】
実施例２４１
６−エチル−７−メチル−１−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジル〕イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン塩酸塩
６−エチル−１−〔４−（４−ヒドロキシベンゾイル）ベンジル〕−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（１３６mg）、４−（２−クロロエチル）モルホリン塩酸塩（１５４mg）、炭酸カリウム（２０５mg）のジメチルホルムアミド（７ml）溶液を１００℃で６時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄後乾燥して、塩酸酢酸エチル溶液を加え生じた塩酸塩の沈殿物をろ取し乾燥して無色固体の表題化合物（１３２mg）を得た。
IR(KBr)ν：1699, 1652, 1598, 1176 cm^-1.
NMR(CDCl₃)δ：1.15(3H,t,J=7.4Hz), 2.63(2H,q,J=7.4Hz), 2.80(3H,s), 2.96-3.21(2H,m), 3.44-3.70(4H,m), 4.01(2H,d,J=12.0Hz), 4.30(2H,t,J=12.4Hz), 4.72(2H,m), 6.20(2H,s), 6.98(2H,d,J=8.8Hz), 7.10(1H,d,J=2.2Hz), 7.58-7.84(7H,m).
【０３０７】
実施例２４２
６−エチル−１−〔４−（４−ヒドロキシベンゾイル）ベンジル〕−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
６−エチル−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（３．９３ｇ）、４−（４−ｔ−ブチルジメチルシリルオキシベンゾイル）ベンジルブロミド（１４．７９ｇ）、炭酸カリウム（５．９７ｇ）のジメチルホルムアミド（２５ml）ジメチルスルホキシド（２５ml）溶液を室温で２０時間撹拌させた。反応液を濃縮し酢酸エチルで抽出し、水で洗浄、乾燥後濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝９／１）にて精製し、エタノール／酢酸エチルから再結晶して無色固体の表題化合物（９０９mg）を得た。
IR(KBr)ν：150 , 1596, 1456, 1168 cm^-1.
NMR(DMSO-d₆)δ：1.03(3H,t,J=7.2Hz), 2.34(3H,s), 2.52(2H,q,J=7.2Hz), 5.38(2H,s), 6.88(2H,d,J=8.6Hz), 7.45(2H,d,J=8.2Hz), 7.58-7.71(6H,m), 10.44(1H,s).
【０３０８】
実施例２４３
６−エチル−７−メチル−１−〔４−〔４−（４−ピコリルオキシ）ベンゾイル〕ベンジル〕イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン塩酸塩
６−エチル−１−〔４−（４−ヒドロキシベンゾイル）ベンジル〕−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン（１２６mg）、４−ピコリルクロリド塩酸塩（１５４mg）、炭酸カリウム（２７４mg）のジメチルホルムアミド（７ml）溶液を室温で１７時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１９／１）で精製し、塩酸酢酸エチル溶液で塩酸塩として無色固体の表題化合物（１４０mg）を得た。
IR(KBr)ν：1704, 1652, 1598, 1457, 1174, 929 cm^-1.
NMR(DMSO-d₆)δ：1.04(3H,t,J=7.2Hz), 2.46-2.62(5H,m), 5.46(2H,s), 5.61(2H,s), 7.21(2H,d,J=8.6Hz), 7.50(2H,d,J=8.0Hz), 7.62-7.88(6H,m), 8.11(2H,d,J=6.6Hz), 8.96(2H,d,J=6.6Hz).
【０３０９】
実施例２４４
３−メチル−２−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン塩酸塩
２−〔４−（４−ヒドロキシベンゾイル）ベンジルオキシ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（１０４mg）、４−（２−クロロエチル）モルホリン塩酸塩（９０mg）、炭酸カリウム（１７９mg）のジメチルホルムアミド（７ml）溶液を１００℃で２０時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄後乾燥濃縮し、塩酸酢酸エチル溶液を加え生じた塩酸塩をろ取し、乾燥して無色固体の表題化合物（２４mg）を得た。
IR(KBr)ν：1670, 1600, 1481, 1170, 927 cm^-1.
NMR(DMSO-d₆)δ：2.09(3H,s), 3.10-4.08(10H,m), 4.52(2H,m), 5.64(2H,s), 7.16(2H,d,J=8.6Hz), 7.34(1H,dt,J=7.0,1.4Hz), 7.56-7.84(7H,m), 7.95(1H,m), 8.97(1H,d,J=7.2Hz).
【０３１０】
実施例２４５
３−メチル−２−〔４−〔４−（４−ピコリルオキシ）ベンゾイル〕ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン塩酸塩
２−〔４−（４−ヒドロキシベンゾイル）ベンジルオキシ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（９６mg）、４−ピコリルクロリド塩酸塩（８９mg）、炭酸カリウム（１７８mg）のジメチルホルムアミド（７ml）溶液を室温で１３時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝２０／１）で精製し、塩酸酢酸エチル溶液で塩酸塩として無色固体の表題化合物（８７mg）を得た。
IR(KBr)ν：1666, 1598, 1461, 1172, 929 cm^-1.
NMR(DMSO-d₆)δ：2.09(3H,s), 5.60(2H,s), 5.63(2H,s), 7.22(2H,d,J=8.8Hz), 7.33(1H,t,J=6.9Hz), 7.56-7.86(7H,m), 7.93(1H,t,J=7.4Hz), 8.09(2H,t,J=5.8Hz), 8.95(3H,m).
【０３１１】
実施例２４６
２−〔４−（６−クロロニコチノイル）〕ベンジルチオ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−メルカプト−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（５９９mg）、４−（６−クロロニコチノイル）ベンジルブロミド（１．１７９ｇ）、炭酸カリウム（１．１４８ｇ）のジメチルホルムアミド（４０ml）溶液を室温で２時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄し乾燥後濃縮して、テトラヒドロフラン／酢酸エチルから再結晶して無色固体の表題化合物（３６７mg）を得た。
IR(KBr)ν：1672, 1577, 1461, 1103, 925, 765 cm^-1.
NMR(CDCl₃)δ：2.09(3H,s), 4.65(2H,s), 7.31(1H,td,J=7.0,1.4Hz), 7.65-7.80(6H,m), 7.93(1H,m), 8.14(1H,dd,J=8.2,2.4Hz), 8.69(1H,d,J=3.4Hz), 8.89(1H,d,J=7.0Hz).
【０３１２】
実施例２４７
３−メチル−２−〔４−〔６−（４−ピペリジノピペリジノ）ニコチノイル〕ベンジルチオ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン３塩酸塩
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（２８７mg）、４−ピペリジノピペリジン（１３７mg）、炭酸カリウム（１９４mg）のジメチルホルムアミド（１０ml）溶液を８０℃で２４時間撹拌させた。反応液を濃縮し残渣をクロロホルムに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９／１）で精製し、塩酸酢酸エチルで塩酸塩にして無色固体の表題化合物（２８mg）を得た。
IR(KBr)ν：1693, 1639, 1006, 765 cm^-1.
NMR(CDCl₃)δ：1.40-2.14(8H,m), 2.19(3H,s), 2.32-2.46(2H,m), 2.96-3.16(2H,m), 3.26-3.76(5H,m), 4.44-4.60(2H,m), 4.68(2H,s), 7.32(1H,td,J=6.3,1.6Hz), 7.54(1H,d,J=9.7Hz), 7.66-7.80(5H,m), 7.94(1H,m), 8.27(1H,d,J=2.2Hz),8.36(1H,dd,J=7.0,2.2Hz), 8.97(1H,d,J=6.3Hz).
【０３１３】
実施例２４８
３−メチル−２−〔４−〔４−（４−フェニルピペラジニルメチル）ベンゾイル〕ベンジルチオ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−メルカプト−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（２９８mg）、４，４'−ビス（ブロモメチル）ベンゾフェノン（９３４mg）、フェニルピペラジン塩酸塩（４０２mg）、炭酸カリウム（８５０mg）のジメチルホルムアミド（３０ml）溶液を室温で１０時間撹拌させた。反応液を濃縮し残渣をクロロホルムに溶解させ、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製して、無色固体の表題化合物（１４６mg）を得た。
IR(KBr)ν：1695, 1602, 1465, 1141, 763 cm^-1.
NMR(CDCl₃)δ：2.24(3H,s), 2.64(4H,m), 3.22(4H,m), 3.64(2H,s), 4.61(2H,s), 6.80-6.97(3H,m), 7.08(1H,td,J=8.8,1.8Hz), 7.21-7.32(2H,m), 7.43-7.62(5H,m), 7.66(1H,m), 7.76(4H,d,J=8.4Hz), 9.00(1H,d,J=7.0Hz).
【０３１４】
実施例２４９
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−メルカプト−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（２９２mg）、４−（４−ｔ−ブチルジメチルシリルオキシベンゾイル）ベンジルブロミド（８４３mg）、炭酸カリウム（４４３mg）のメタノール（１０ml）テトラヒドロフラン（１０ml）水（２ml）溶液を室温で４８時間撹拌させた。反応液を濃縮して得られた残渣を酢酸エチル、水で洗浄し、メタノール／テトラヒドロフラン／酢酸エチルから再結晶して淡黄色固体の表題化合物（２７６mg）を得た。
IR(KBr)ν：1660, 1600, 1556, 1452, 765 cm^-1.
NMR(DMSO-d₆)δ：2.10(3H,s), 4.63(2H,s), 6.46(2H,d,J=8.8Hz), 7.31(1H,td,J=6.9,1.6Hz), 7.44-7.62(6H,m), 7.70(1H,m), 7.94(1H,m), 8.90(1H,m).
【０３１５】
実施例２５０
３−メチル−２−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジルチオ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−〔４−（４−ヒドロキシベンゾイル）ベンジルチオ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（２１４mg）、４−（２−クロロエチル）モルホリン塩酸塩（１５７mg）、炭酸カリウム（２４７mg）のジメチルホルムアミド（７ml）溶液を８０℃で４時間撹拌させた。反応液を濃縮し残渣を酢酸エチルに溶解させ、水で洗浄後乾燥して、塩酸酢酸エチル溶液を加え生じた塩酸塩の沈殿物をろ取乾燥して、無色固体の表題化合物（１８２mg）を得た。
IR(KBr)ν：1658, 1600, 1463, 1172, 1143 cm^-1.
NMR(CDCl₃)δ：2.10(3H,s), 3.10-4.07(10H,m), 4.51(2H,s), 4.65(2H,s), 7.14(2H,d,J=7.0Hz), 7.32(1H,m), 7.58-7.82(7H,m), 7.94(1H,m), 8.89(1H,d,J=7.0Hz).
【０３１６】
実施例２５１
３−メチル−２−〔４−（４−ヒドロキシベンゾイル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−ヒドロキシ−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（３．１５８ｇ）、４−（４−ｔ−ブチルジメチルシリルオキシベンゾイル）ベンジルブロミド（１２．２４ｇ）、炭酸カリウム（５．０７ｇ）のジメチルホルムアミド（５０ml）溶液を室温で２４時間撹拌させた。反応液を濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／酢酸エチル＝１／２）にて精製し、クロロホルム／メタノール／酢酸エチルから再結晶して無色固体の表題化合物（３２５mg）を得た。
IR(KBr)ν：1646, 1604, 1575, 1475, 1170, 929 cm^-1.
NMR(DMSO-d₆)δ：2.09(3H,s), 5.62(2H,s), 6.89(2H,d,J=8.8Hz), 7.33(1H,dt,J=7.0,1.6Hz), 7.54-7.80(7H,m), 7.94(1H,m), 8.96(1H,d,J=6.8Hz).
【０３１７】
実施例２５２
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−エチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
アルゴン雰囲気下、２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．８２ｇ）をＤＭＦ（６０ml）に加温溶解した。次いで、無水炭酸カリウム（１．３８ｇ）とヨウ化エチル（１．２ml）を加え５５℃、３．５時間撹拌した。不溶物を濾去し、減圧下溶媒留去して得られた残渣にメタノールを加え、超音波を用いて微細化した。この物を濾取し、水、メタノール、エーテル洗浄後、乾燥すると３−エチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オンと４−エトキシ−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジンの混合物（５５：４５；１．３４ｇ）が得られた。この物はこれ以上精製する事なく次の反応に用いた。
アルゴン雰囲気下、上記混合物（１．１４ｇ）を乾燥ＤＭＦ（１０ml）に溶解し、次いで乾燥ＤＭＥ（１，２−ジメトキシエタン；４０ml）を加え、さらに６０％油性水素化ナトリウム（２５０mg）を添加した。３０分撹拌した後、４−（４−クロロベンゾイル）ベンジルブロミド（２．１９ｇ）のＤＭＥ（１０ml）溶液を滴下した。室温１５時間撹拌後、酢酸エチルと飽和食塩水を加え、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；酢酸エチル：ヘキサン；１：４）で精製することにより７−〔４−（４−クロロベンゾイル）ベンジル〕−４−エトキシ−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン（７２５mg）と表題化合物（９９４mg）を得た。
¹H-NMR(CDCl₃)δ：1.46(3H,t,J=7.0Hz), 2.60(3H,s), 4.59(2H,q,J=7.0Hz), 5.45(2H,s), 6.50(1H,d,J=3.4Hz), 6.87(1H,d,J=3.4Hz), 7.30(2H,d,J=8.2Hz), 7.45(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.73(2H,d,J=8.2Hz).
【０３１８】
実施例２５３
７−〔４−（４−クロロベンゾイル）ベンジル〕−２−メチルチオ−３−プロピル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
アルゴン雰囲気下、２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（０．９１ｇ）をＤＭＦ（３０ml）に加温溶解した。次いで、無水炭酸カリウム（０．６９１ｇ）とヨウ化プロピル（０．７２９ml）を加え６０℃、４時間撹拌した。不溶物を濾去し、減圧下溶媒留去して得られた残渣にメタノールを加え、超音波を用いて微細化した。この物を濾取し、水、メタノール、エーテル洗浄後、乾燥すると２−メチルチオ−３−プロピル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オンと２−メチルチオ−４−プロポキシ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジンの混合物（４５：５５；６０３mg）が得られた。この物はこれ以上精製する事なく次の反応に用いた。
アルゴン雰囲気下、上記混合物（５３８mg）を乾燥ＤＭＥ（１０ml）に溶解し、次いで６０％油性水素化ナトリウム（１０６mg）を添加した。３０分撹拌した後、４−（４−クロロベンゾイル）ベンジルブロミド（９６６mg）のＤＭＥ（２ml）溶液を滴下した。室温１３時間撹拌後、酢酸エチルと飽和食塩水を加え、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；酢酸エチル：ヘキサン；１：４）で精製することにより７−〔４−（４−クロロベンゾイル）ベンジル〕−２−メチルチオ−４−プロポキシ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン（３５３mg）と表題化合物（３６０mg）を得た。
¹H-NMR(CDCl₃)δ：1.01(3H,t,J=7.2Hz), 1.70-1.89(2H,m), 2.57(3H,s), 4.11(2H,t,J=7.2Hz), 5.36(2H,s), 6.65(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 7.32(2H,d,J=8.4Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.4Hz).
【０３１９】
実施例２５４
３−（２−アセトキシエチル）−７−〔４−（４−クロロベンゾイル）ベンジル〕−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
アルゴン雰囲気下、２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（１．８２ｇ）をＤＭＦ（６０ml）に加温溶解した。次いで、無水炭酸カリウム（２．０７ｇ）と酢酸ブロモエチル（３．３４ｇ）を加え７０℃、７時間撹拌した。不溶物を濾去し、減圧下溶媒留去して得られた残渣にメタノールを加え、超音波を用いて微細化した。この物を濾取し、水、メタノール、エーテル洗浄後、乾燥すると３−（２−アセトキシエチル）−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オンと４−（２−アセトキシエトキシ）−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジンの混合物（１：２；１．７１ｇ）が得られた。この物はこれ以上精製する事なく次の反応に用いた。
アルゴン雰囲気下、上記混合物（１．３４ｇ）を乾燥ＤＭＥ（３０ml）に溶解し、次いで６０％油性水素化ナトリウム（２２０mg）を添加した。３０分撹拌した後、４−（４−クロロベンゾイル）ベンジルブロミド（２．０２ｇ）のＤＭＥ（２ml）溶液を滴下した。室温１５時間撹拌後、酢酸エチルと飽和食塩水を加え、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒留去して得られた残渣をフラッシュカラムクロマトグラフィー（シリカゲル；酢酸エチル：ヘキサン；１：４→３：７）で精製することにより４−（２−アセトキシエトキシ）−７−〔４−（４−クロロベンゾイル）ベンジル〕−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン（９００mg）と表題化合物（４６０mg）を得た。
¹H-NMR(CDCl₃)δ：2.06(3H,s), 2.58(3H,s), 4.43(4H,s), 5.37(2H,s), 6.66(1H,d,J=3.6Hz), 6.77(1H,d,J=3.6Hz), 7.32(2H,d,J=8.4Hz), 7.46(2H,d,J=8.6Hz),7.73(2H,d,J=8.6Hz), 7.75(2H,d,J=8.4Hz).
【０３２０】
実施例２５５
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−（２−ヒドロキシエチル）−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
３−（２−アセトキシエチル）−７−〔４−（４−クロロベンゾイル）ベンジル〕−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン（４１０mg）をメタノール（８ml）とＤＭＥ（４ml）に溶解し、１規定水酸化ナトリウム水溶液（１．６４ml）を加え、２時間撹拌した。１規定塩酸（１．６４ml）を用いて中和後、沈殿物を濾取し、水、メタノール、エーテル洗浄した。この物を乾燥することにより表題化合物（２９５mg）を得た。
¹H-NMR(CDCl₃)δ：2.59(3H,s), 2.98(1H,t,J=5.4Hz), 3.99(2H,q,J=5.4Hz), 4.43(2H,t,J=5.4Hz), 5.38(2H,s), 6.67(1H,d,J=3.4Hz), 6.79(1H,d,J=3.4Hz), 7.32(2H,d,J=7.8Hz), 7.46(2H,d,J=8.2Hz), 7.74(2H,d,J=8.6Hz), 7.75(2H,d,J=8.4Hz).
【０３２１】
実施例２５６
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン（２２１mg）をＤＭＥ（１５ml）、エタノール（１．５ml）に溶解し、酢酸（１８５mg）を加えたあと４０℃に加温した。ＴＬＣ（博層クロマトグラフィー）にて原料が消滅するまでラネーＮi を加えた。触媒を濾去し、減圧下溶媒を留去して得られた残渣を酢酸エチルに溶解後、飽和炭酸水素ナトリウム水溶液、ついで飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒留去し放置することにより結晶が析出した。この物を濾取しエタノール、ヘキサン洗浄後、乾燥することにより表題化合物（１４９mg）を得た。
¹H-NMR(CDCl₃)δ：3.61(3H,s), 5.42(2H,s)，6.76(1H,d,J=3.4Hz), 6.88(1H,d,J=3.4Hz), 7.27(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.90(1H,s).
【０３２２】
実施例２５７
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−エチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−エチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン（２２１mg）をＤＭＥ（１５ml）、エタノール（１．５ml）に溶解し、酢酸（１８５mg）を加えたあと４０℃に加温した。ＴＬＣ（博層クロマトグラフィー）にて原料が消滅するまでラネーＮi を加えた。触媒を濾去し、減圧下溶媒を留去して得られた残渣を酢酸エチルに溶解後、飽和炭酸水素ナトリウム水溶液、ついで飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒留去し放置することにより結晶が析出した。この物を濾取しエタノール、ヘキサン洗浄後、乾燥することにより表題化合物（１４１mg）を得た。
¹H-NMR(CDCl₃)δ：1.41(3H,t,J=7.2Hz), 4.09(2H,q,J=7.2Hz), 5.42(2H,s), 6.76(1H,d,J=3.4Hz), 6.87(1H,d,J=3.4Hz), 7.28(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.89(1H,s).
【０３２３】
実施例２５８
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−プロピル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
アルゴン雰囲気下、３−プロピル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン（２４９mg）を乾燥ＤＭＥ（６ml）に溶解し、氷冷撹拌下、６０％油性水素化ナトリウム（６２mg）を添加した。３０分撹拌し、４−（４−クロロベンゾイル）ベンジルブロミド（５６４mg）の乾燥ＤＭＥ（２ml）溶液を加え室温に戻した後、２時間撹拌した。減圧下溶媒を留去し、残渣を酢酸エチルに溶解し、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮し、フラッシュカラムクロマト精製（シリカゲル；２１ｇ；ヘキサン：酢酸エチル；４：１→３：２）することにより無色粉末として表題化合物（５０７mg）を得た。
¹H-NMR(CDCl₃)δ：0.99(3H,t,J=7.4Hz), 1.74-1.93(2H,m), 3.99(2H,t,J=7.4Hz), 5.42(2H,s), 6.76(1H,d,J=3.4Hz), 6.87(1H,d,J=3.4Hz), 7.28(2H,d,J=8.6Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.87(1H,s).
【０３２４】
実施例２５９
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−イソプロピル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
アルゴン雰囲気下、３−イソプロピル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン（８９mg）を乾燥ＤＭＥ（２ml）に溶解し、氷冷撹拌下、６０％油性水素化ナトリウム（２２mg）を添加した。３０分撹拌し、４−（４−クロロベンゾイル）ベンジルブロミド（２０１mg）の乾燥ＤＭＥ（１ml）溶液を加え室温に戻した後、２時間撹拌した。減圧下溶媒を留去し、残渣を酢酸エチルに溶解し、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮し、フラッシュカラムクロマト精製（シリカゲル；１２ｇ；ヘキサン：酢酸エチル；４：１→３：２）することにより無色粉末として表題化合物（１８１mg）を得た。
¹H-NMR(CDCl₃)δ：1.47(6H,d,J=7.0Hz), 5.30(1H,q,J=7.0Hz), 5.42(2H,s), 6.76(1H,d,J=3.4Hz), 6.88(1H,d,J=3.4Hz), 7.29(2H,d,J=8.8Hz), 7.45(2H,d,J=8.8Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.95(1H,s).
【０３２５】
実施例２６０
２−〔４−（４−フルオロベンゾイル）ベンジル〕チオ−６−メチル−チアゾロ〔４，５−ｄ〕ピリダジン−７（６Ｈ）オン
５−アミノ−４−クロロ−２−メチル−３（２Ｈ）−ピリダジノン（６３８mg）をＤＭＦ（１０ml）に溶解し、６０％水素化ナトリウム（３８４mg）を加え、室温で１０分間撹拌した。続いて二硫化炭素（３６５mg）を加え、８０℃で１時間撹拌した。さらに４−（４−フルオロベンゾイル）ベンジルブロミド（１．４ｇ）を加え、室温で１時間撹拌した。反応液を酢酸エチル−ＴＨＦで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮した後、残渣をシリカゲルクロマト（ヘキサン−酢酸エチル(１：１)）で精製し、白色粉末１．２ｇを得た。
¹H-NMR(CDCl₃)δ：3.88(3H,s), 4.66(2H,s), 7.17(2H,dd,J=8.8 and 8.8Hz), 7.57(2H,d,J=8.2Hz), 7.76(2H,d,J=8.2Hz), 7.84(2H,dd,J=8.8 and 5.6Hz), 8.34(1H,s).
【０３２６】
実施例２６１
２−〔２−〔４−（４−クロロベンゾイル）フェニル〕ビニル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２，３，５−トリメチル−４（３Ｈ）−キナゾリノン（３７６mg）と４−（４−クロロベンゾイル）ベンズアルデヒド（１．１ｇ）の混合物に無水酢酸（０．５ml）を加え、１４０℃で２時間撹拌した。反応液を濃縮した後、残渣をジエチルエーテルで洗浄し、乾燥し、黄色粉末５０４mlを得た。
¹H-NMR(DMSO-d₆)δ：2.81(3H,s), 3.68(3H,s), 7.27(1H,d,J=7.8Hz), 7.54(1H,d,J=7.8Hz), 7.63(1H,d,J=15.2Hz), 7.66(1H,dd,J=7.8 and 7.8Hz), 7.66(2H,d,J=8.4Hz), 7.80(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 7.97(1H,d,J=15.2Hz), 8.02(2H,d,J=8.4Hz).
【０３２７】
実施例２６２
２−〔２−〔４−（４−クロロベンゾイル）フェニル〕エチル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２−〔２−〔４−（４−クロロベンゾイル）フェニル〕ビニル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン(１０４mg)をＴＨＦ−酢酸エチル−メタノール（２：１：１）(２０ml)に溶解し、１０％Ｐｄ／Ｃ（５０％含水）(１０mg)を加え、水素雰囲気下室温で２時間撹拌した。触媒を濾去し、濾液を濃縮した後、残渣を酢酸エチル−メタノールで洗浄し、乾燥し、白色粉末５３mgを得た。
¹H-NMR(CDCl₃)δ : 2.88(3H,s), 3.05-3.18(2H,m), 3.25-3.38(2H,m), 3.56(3H,s), 7.18-7.30(2H,m), 7.43(2H,d,J=8.6Hz), 7.46(2H,d,J=8.6Hz), 7.54(1H,dd,J=7.6 and 7.6Hz), 7.74(4H,d,J=8.6Hz).
【０３２８】
実施例２６３
３，５−ジメチル−２−〔２−〔４−（４−トリフルオロメチルベンゾイル）フェニル〕ビニル〕−４（３Ｈ）−キナゾリノン
２，３，５−トリメチル−４（３Ｈ）−キナゾリノン（５０８mg）と４−（４−トリフルオロメチルベンゾイル）ベンズアルデヒド（７５１mg）の混合物に無水酢酸（１．０ml）を加え、１４０℃で２時間撹拌した。反応液を濃縮した後、残渣をｎ−ヘキサン−ジエチルエーテルで洗浄し、乾燥し、黄色粉末８９８mgを得た。
¹H-NMR(DMSO-d₆)δ：2.81(3H,s), 3.69(3H,s), 7.26(1H,d,J=7.6Hz), 7.53(1H,d,J=7.6Hz), 7.63(1H,d,J=15.8Hz), 7.65(1H,dd,J=7.6 and 7.6Hz), 7.84(2H,d,J=8.4Hz), 7.96(4H,s), 7.97(1H,d,J=15.8Hz), 8.02(2H,d,J=8.4Hz).
【０３２９】
実施例２６４
３，５−ジメチル−２−〔２−〔４−（４−トリフルオロメチルベンゾイル）フェニル〕エチル〕−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−〔２−〔４−（４−トリフルオロメチルベンゾイル）フェニル〕ビニル〕−４（３Ｈ）−キナゾリノン（８９７mg）をＴＨＦ−酢酸エチル−メタノール（１：１：１）（６０ml）に溶解し、１０％Ｐｄ／Ｃ（５０％含水）（１７９mg）を加え、水素雰囲気下室温で２時間撹拌した。触媒を濾去し、濾液を濃縮した後、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル(２：１)）で精製し、さらに酢酸エチル−メタノールから再結晶し、白色粉末３０７mgを得た。
¹H-NMR(CDCl₃)δ：2.88(3H,s), 3.06-3.19(2H,m), 3.24-3.38(2H,m), 3.56(3H,s), 7.19-7.30(2H,m), 7.45(2H,d,J=8.4Hz), 7.54(1H,dd,J=7.4 and 7.4Hz), 7.75(2H,d,J=8.2Hz), 7.77(2H,d,J=8.4Hz), 7.88(2H,d,J=8.2Hz).
【０３３０】
実施例２６５
２−〔２−〔４−（４−アセトキシベンゾイル）フェニル〕ビニル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２，３，５−トリメチル−４（３Ｈ）−キナゾリノン（３７６mg）と４−（４−アセトキシベンゾイル）ベンズアルデヒド（５３７mg）の混合物に無水酢酸（０．５ml）を加え、１４０℃で２時間撹拌した。反応液を濃縮した後、残渣をｎ−ヘキサン−ジエチルエーテルで洗浄し、乾燥し、黄色粉末６５３mgを得た。
¹H-NMR(DMSO-d₆)δ：2.33(3H,s), 2.80(3H,s), 3.68(3H,s), 7.25(1H,d,J=7.6Hz), 7.35(2H,d,J=8.6Hz), 7.52(1H,d,J=7.6Hz), 7.60(1H,d,J=15.0Hz), 7.64(1H,dd,J=7.6 and 7.6Hz), 7.81(2H,d,J=8.2Hz), 7.84(2H,d,J=8.6Hz), 7.96(1H,d,J=15.0Hz), 8.00(2H,d,J=8.2Hz).
【０３３１】
実施例２６６
３，５−ジメチル−２−〔２−〔４−（４−ヒドロキシベンゾイル）フェニル〕エチル〕−４（３Ｈ）−キナゾリノン
２−〔２−〔４−（４−アセトキシベンゾイル）フェニル〕ビニル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（６３１mg）をＴＨＦ−酢酸エチル−メタノール（１：１：１）（５０ml）に溶解し、１０％Ｐｄ／Ｃ（５０％含水）（１２６mg）を加え、水素雰囲気下室温で２時間撹拌した。触媒を濾去し、濾液を濃縮した後、残渣をエタノール（１０ml）に懸濁し、１Ｎ水酸化ナトリウム水溶液（２．９ml）を加え、室温で２時間撹拌した。反応液を濃縮した後、残渣を水（２０ml）に懸濁し、１Ｎ塩酸（２．９ml）を加えて中和した。析出物を濾取し、水洗し、乾燥して白色粉末５３８mgを得た。
¹H-NMR(CDCl₃)δ：2.88(3H,s), 3.05-3.19(2H,m), 3.23-3.36(2H,m), 3.58(3H,s), 6.91(2H,d,J=8.4Hz), 7.18-7.32(2H,m), 7.38(2H,d,J=8.4Hz), 7.58(1H,dd,J=7.6 and 7.6Hz), 7.72(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【０３３２】
実施例２６７
３，５−ジメチル−２−〔２−〔４−〔４−（２−ジメチルアミノエトキシ）ベンゾイル〕フェニル〕エチル〕−４（３Ｈ）−キナゾリノン塩酸塩
３，５−ジメチル−２−〔２−〔４−（４−ヒドロキシベンゾイル）フェニル〕エチル〕−４（３Ｈ）−キナゾリノン（５３４mg）をＤＭＦ（１０ml）に溶解し、２−ジメチルアミノエチルクロリド（６９５mg）、炭酸カリウム（６７７mg）を加え、８０℃で４時間撹拌した。反応液を濃縮した後、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。２０mlまで濃縮した有機層に１Ｎ塩酸（２ml）を加え、水で抽出した。水層に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを１０mlまで濃縮した後、４Ｎ塩化水素／酢酸エチル（０．５ml）を加えた。析出物を濾取し、水洗、乾燥して白色粉末２４０mgを得た。
¹H-NMR(DMSO-d₆)δ：2.79(3H,s), 2.85(3H,s), 2.88(3H,s), 3.16-3.37(4H,m), 3.55(3H,s), 3.51-3.61(2H,m), 4.44-4.44(2H,m), 7.16(2H,d,J=8.8Hz), 7.31(1H,d,J=7.2Hz), 7.52-7.62(2H,m), 7.62(2H,d,J=8.8Hz), 7.66(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
【０３３３】
実施例２６８
２−〔２−〔４−（６−クロロニコチノイル）フェニル〕ビニル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２，３，５−トリメチル−４（３Ｈ）−キナゾリノン（１．１ｇ）と４−（６−クロロニコチノイル）ベンズアルデヒド（１．５ｇ）の混合物に無水酢酸（２ml）を加え、１４０℃で２時間撹拌した。反応液を濃縮した後、残渣をトルエン−ジエチルエーテルで洗浄し、乾燥し、黄色粉末１．４ｇを得た。
¹H-NMR(CDCl₃)δ：2.90(3H,s), 3.74(3H,s), 7.20-7.30(1H,m), 7.24(1H,d,J=15.6Hz), 7.51(1H,d,J=8.4Hz), 7.58-7.61(2H,m), 7.76(2H,d,J=8.4Hz), 7.87(2H,d,J=8.4Hz), 8.02(1H,d,J=15.6Hz), 8.12(1H,dd,J=2.6 and 8.4Hz), 8.79(1H,d,J=2.6Hz).
【０３３４】
実施例２６９
３，５−ジメチル−２−〔２−〔４−〔６−（２−ジメチルアミノエトキシ）ニコチノイル〕フェニル〕ビニル〕−４（３Ｈ）−キナゾリノン
２−ジメチルアミノエタノール（５３mg）をＤＭＦ（３ml）に溶解し、６０％水素化ナトリウム（２９mg）を加え、室温で１０分間撹拌した。続いて２−〔２−〔４−（６−クロロニコチノイル）フェニル〕ビニル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（２０８mg）を加え、室温で２時間撹拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。１０mlまで濃縮した有機層に１Ｎ塩酸（２ml）を加え、水層を抽出した。水層に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮乾固し、黄色粉末１６９mgを得た。
¹H-NMR(CDCl₃)δ：2.35(6H,s), 2.75(2H,t,J=5.7Hz), 2.90(3H,s), 3.73(3H,s),4.52(2H,t,J=5.7Hz), 6.91(1H,d,J=8.7Hz), 7.18-7.28(1H,m), 7.23(1H,d,J=15.3Hz), 7.57-7.60(2H,m), 7.73(2H,d,J=8.3Hz), 7.84(2H,d,J=8.3Hz), 8.01(1H,d,J=15.3Hz), 8.11(1H,dd,J=2.4 and 8.7Hz), 8.62(1H,d,J=2.4Hz).
【０３３５】
実施例２７０
３，５−ジメチル−２−〔２−〔４−〔６−（２−ジメチルアミノエトキシ）ニコチノイル〕フェニル〕エチル〕−４（３Ｈ）−キナゾリノン２塩酸塩
３，５−ジメチル−２−〔２−〔４−〔６−（２−ジメチルアミノエトキシ）ニコチノイル〕フェニル〕ビニル〕−４（３Ｈ）−キナゾリノン（１６７mg）を酢酸エチル−メタノール−酢酸（１０：１０：１）（１０．５ml）に溶解し、１０％Ｐｄ／Ｃ（５０％含水）（３４mg）を加え、水素雰囲気下室温で２時間撹拌した。触媒を濾去し、濾液を濃縮した後、残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを１０mlまで濃縮した後、４Ｎ塩化水素／酢酸エチル（０．１ml）を加えた。析出物を濾取し、酢酸エチル−エタノールで洗浄し、乾燥して白色粉末８５mgを得た。
¹H-NMR(DMSO-d₆)δ：2.79(3H,s), 2.86(6H,s), 3.13-3.40(4H,m), 3.56(3H,s), 3.51-3.61(2H,m), 4.73(2H,t,J=5.4Hz), 7.05(1H,d,J=8.6Hz), 7.33(1H,d,J=7.5Hz), 7.55-7.66(2H,m), 7.60(2H,d,J=8.7Hz), 7.72(2H,d,J=8.7Hz), 8.12(1H,dd,J=2.2 and 8.6Hz), 8.55(1H,d,J=2.2Hz).
【０３３６】
実施例２７１
３，５−ジメチル−２−〔２−〔４−〔６−（４−フェニル−１−ピペラジニル）ニコチノイル〕フェニル〕ビニル〕−４（３Ｈ）−キナゾリノン
２−〔２−〔４−（６−クロロニコチノイル）フェニル〕ビニル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３３３mg）をピリジン（５ml）に溶解し、フェニルピペラジン（１５６ml）を加え、９０℃で４時間撹拌した。反応液を濃縮した後、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮した後、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル(１：１)）で精製し、黄色粉末（１６２mg）を得た。
¹H-NMR(CDCl₃)δ：2.90(3H,s), 3.33(4H,t,J=5.2Hz), 3.74(3H,s), 3.92(4H,t,J=5.2Hz), 6.75(1H,d,J=9.1Hz), 6.92(1H,t,J=8.3Hz), 6.98(2H,d,J=8.3Hz), 7.18-7.26(1H,m), 7.21(1H,d,J=15.5Hz), 7.33(2H,d,J=8.3Hz), 7.57-7.60(2H,m), 7.72(2H,d,J=8.2Hz), 7.82(2H,d,J=8.2Hz), 8.01(1H,d,J=15.5Hz), 8.09(1H,dd,J=2.5 and 9.1Hz), 8.65(1H,d,J=2.5Hz).
【０３３７】
実施例２７２
３，５−ジメチル−２−〔２−〔４−〔６−（４−フェニル−１−ピペラジニル）ニコチノイル〕フェニル〕エチル〕−４(３Ｈ)−キナゾリノン２塩酸塩
３，５−ジメチル−２−〔２−〔４−〔６−（４−フェニル−１−ピペラジニル）ニコチノイル〕フェニル〕ビニル〕−４（３Ｈ）−キナゾリノン(１６０mg)をＴＨＦ−酢酸エチル−メタノール−酢酸（１０：５：５：１）(２１ml)に溶解し、１０％Ｐｄ／Ｃ（５０％含水）(６４mg)を加え、水素雰囲気下室温で６時間撹拌した。触媒を濾去し、濾液を濃縮した後、残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮した後、残渣をシリカゲルカラムクロマト（ｎ−ヘキサン−酢酸エチル(１：１)）で精製した。目的とする溶出画分を１０mlまで濃縮した後、４Ｎ塩化水素／酢酸エチル(０．１５ml)を加えた。析出物を濾取し、酢酸エチル−エタノールで洗浄し、乾燥して白色粉末１２９mgを得た。
¹H-NMR(DMSO-d₆)δ：2.80(3H,s), 3.16-3.54(8H,m), 3.60(3H,s), 3.91-4.08(4H,m), 6.99(1H,t,J=8.3Hz), 7.10-7.42(6H,m), 7.59-7.77(6H,m), 8.01(1H,dd,J=2.2 and 8.0Hz), 8.48(1H,d,J=2.2Hz).
【０３３８】
実施例２７３
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−メチル−１−プロピルキサンチン
３−メチル−７−〔４−（４−クロロベンゾイル）ベンジル〕キサンチン（６５７mg）、炭酸カリウム（２４２mg）、ヨウ化プロピル（４２７mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製し、酢酸エチルから再結晶して無色固体の表題化合物（３５２mg）を得た。
IR(KBr)ν：1700, 1665, 1650 cm^-1.
NMR(CDCl₃)δ：0.95(3H,t,J=7Hz), 1.66(2H,q,J=8Hz), 3.60(3H,s), 3.96(2H,t,J=7Hz), 5.59(2H,s), 7.42(2H,d,J=7Hz), 7.46(2H,d,J=8Hz), 7.75(5H,m).
【０３３９】
実施例２７４
１，７−ビス〔４−（４−クロロベンゾイル）ベンジル〕−３−メチルキサンチン
３−メチルキサンチン（２０４mg）、炭酸カリウム（３４０mg）、４−（４−クロロベンゾイル）ベンジルブロマイド（７５４mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製し、酢酸エチル／ヘキサンから再結晶して無色固体の表題化合物（１８４mg）を得た。
IR(KBr)ν：1700, 1660, 1645 cm^-1.
NMR(CDCl₃)δ：3.61(3H,s), 5.27(2H,s), 5.61(2H,s), 7.46(7H,m), 7.67(1H,s), 7.71(9H,m).
【０３４０】
実施例２７５
７−〔４−（４−クロロベンゾイル）ベンジル〕−１−イソプロピル−３−メチルキサンチン
３−メチル−７−〔４−（４−クロロベンゾイル）ベンジル〕キサンチン（５４４mg）、炭酸カリウム（２０２mg）、ヨウ化イソプロピル（３５６mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製し、アセトン／ヘキサンから再結晶して無色固体の表題化合物（３８mg）を得た。
IR(KBr)ν：1700, 1665, 1650 cm^-1.
NMR(CDCl₃)δ：1.50(6H,d,J=6Hz), 3.56(3H,s), 5.29(1H,spt,J=6Hz), 5.60(2H,s), 7.49(4H,m), 7.72(1H,s), 7.76(4H,m).
【０３４１】
実施例２７６
７−〔４−（４−クロロベンゾイル）ベンジル〕−１−ブチル−３−メチルキサンチン
３−メチル−７−〔４−（４−クロロベンゾイル）ベンジル〕キサンチン（６１２mg）、炭酸カリウム（２２８mg）、ヨウ化ブチル（４３０mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製し、酢酸エチルから再結晶して無色固体の表題化合物（１４７mg）を得た。
IR(KBr)ν：1700, 1680, 1655 cm^-1.
NMR(CDCl₃)δ：0.95(3H,t,J=7Hz), 1.39(2H,sec,J=7Hz), 1.63(2H,pent,J=7Hz),3.63(3H,s), 4.01(2H,t,J=7Hz), 5.64(2H,s), 7.46(4H,d,J=9Hz), 7.74(5H,d,J=9Hz).
【０３４２】
実施例２７７
７−〔４−（４−クロロベンゾイル）ベンジル〕−１−フルオロメチル−３−メチルキサンチン
３−メチル−７−〔４−（４−クロロベンゾイル）ベンジル〕キサンチン（９７５mg）、水素化ナトリウム（６１mg）、フルオロブロモメタン（１２１mg）のジメチルホルムアミド（１０ml）溶液を１０℃で１時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／２）で精製し、酢酸エチルから再結晶して無色固体の表題化合物（１２１mg）を得た。
IR(KBr)ν：1715, 1665, 1650 cm^-1.
NMR(CDCl₃)δ：3.61(3H,s), 5.58(2H,s), 6.14(2H,d,J=50Hz), 7.43(2H,d,J=8.2Hz), 7.47(2H,d,J=8.0Hz), 7.68-7.81(5H,m).
【０３４３】
実施例２７８
７−〔４−（４−ヒドロキシベンゾイル）ベンジル〕−１，３−ジメチルキサンチン
１，３−ジメチルキサンチン（７４２mg）、炭酸カリウム（５６９mg）、４−（４−ｔ−ブチルジメチルシロキシベンゾイル）ベンジルブロマイド（２２９２mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／３）で精製し、クロロホルム／イソプロピルエーテルから再結晶して無色固体の表題化合物（１７６３mg）を得た。
IR(KBr)ν：1700, 1655, 1645 cm^-1.
NMR(CDCl₃)δ：3.42(3H,s), 3.62(3H,s), 5.59(2H,s), 6.90(2H,d,J=8.8Hz), 7.40(2H,d,J=8.3Hz), 7.68(1H,s), 7.74(2H,d,J=8.4Hz).
【０３４４】
実施例２７９
７−〔４−（６−クロロニコチノイル）ベンジル〕−１，３−ジメチルキサンチン
１，３−ジメチルキサンチン（７１２mg）、炭酸カリウム（５７８mg）、４−（６−クロロニコチノイル）ベンジルブロマイド（１５１５mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／３）で精製し、クロロホルム／イソプロピルエーテルから再結晶して無色固体の表題化合物（１５６２mg）を得た。
IR(KBr)ν：1700, 1650 cm^-1.
NMR(CDCl₃)δ：3.40(3H,s), 3.61(3H,s), 5.61(2H,s), 7.45(1H,d,J=8.1Hz), 7.48(2H,d,J=8.1Hz), 7.67(1H,s), 7.80(2H,d,J=8.1Hz), 8.08(1H,dd,J=2.4,8.1Hz), 8.74(1H,d,J=2.3Hz).
【０３４５】
実施例２８０
７−〔４−（４−ブロモメチルベンゾイル）ベンジル〕−１，３−ジメチルキサンチン
１，３−ジメチルキサンチン（９９０mg）、炭酸カリウム（１３４８mg）、４−（４−ブロモメチルベンゾイル）ベンジルブロマイド（２００７mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／５）で精製し、酢酸エチル／イソプロピルエーテルから再結晶して無色固体の表題化合物（１０２１mg）を得た。
IR(KBr)ν：1700, 1650 cm^-1.
NMR(CDCl₃)δ：3.41(3H,s), 3.61(3H,s), 4.53(2H,s), 5.60(2H,s), 7.44(4H,m), 7.66(1H,s), 7.78(4H,m).
【０３４６】
実施例２８１
１．３−ジメチル−７−〔４−（４−（２−モルフォリノエトキシ）ベンゾイル）ベンジル〕キサンチン
７−〔４−（４−ヒドロキシベンゾイル）ベンジル〕−１，３−ジメチルキサンチン（１７０mg）、炭酸カリウム（２００mg）、１−クロロ−２−モルフォリノエタン塩酸塩（８７mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（クロロホルム／酢酸エチル／アセトン＝１／１／１）で精製し、表題化合物（９３mg）を得た。
IR(KBr)ν：1695, 1650 cm^-1.
NMR(CDCl₃)δ：2.59(4H,dd,J=4.7, Hz), 2.84(2H,t,J=7.0Hz), 3.41(3H,s), 3.61(3H,s), 3.75(4H,dd,J=4.7, Hz,), 4.19(2H,t,J=7.0Hz), 5.59(2H,s), 6.96(2H,d,J=9.0Hz), 7.43(2H,d,J=8.0Hz), 7.66(1H,s), 7.75(2H,d,J=8.0Hz), 7.79(2H,d,J=9.0Hz).
【０３４７】
実施例２８２
１，３−ジメチル−７−〔４−（６−（４−ピペリジノピペリジノ）ニコチノイル）ベンジル〕キサンチン
７−〔４−（６−クロロニコチノイル）ベンジル〕−１，３−ジメチルキサンチン（１９６mg）、４−ピペリジノピペリジン（１０２mg）のピリジン（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（酢酸エチル／アセトン／トリエチルアミン＝１／１／０．１）で精製し、表題化合物（１０８mg）を得た。
IR(KBr)ν：1695, 1660, 1590 cm^-1.
NMR(CDCl₃)δ：1.4-1.6(7H,m,br), 1.8-2.0(6H,m,br), 2.56(4H,m,br), 2.95(2H,m), 3.42(3H,s), 3.61(3H,s), 4.56(2H,m), 5.58(2H,s), 6.68(1H,d,J=9.1Hz),7.41(2H,d,J=8.1Hz), 7.65(1H,s), 7.74(2H,d,J=8.1Hz), 8.00(1H,dd,J=2.4,9.1Hz), 8.54(1H,d,J=2.4Hz).
【０３４８】
実施例２８３
１，３−ジメチル−７−〔４−（４−フェニルピペラジニルメチルベンゾイル）ベンジル〕キサンチン
７−〔４−（４−ブロモメチルベンゾイル）ベンジル〕−１，３−ジメチルキサンチン（２３２mg）、炭酸カリウム（１０９mg）、１−フェニルピペラジン（９２mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン／トリエチルアミン＝３／１／０．１）で精製し、クロロホルム／イソプロピルエーテルから再結晶して無色固体の表題化合物（２０mg）を得た。
IR(KBr)ν：1695, 1650 cm^-1.
NMR(CDCl₃)δ：2.64(4H,t,J=5.0Hz), 3.22(4H,t,J=5.0Hz), 3.41(3H,s), 3.61(3H,s), 3.65(2H,s), 5.60(2H,s), 6.91(3H,m), 7.27(2H,m), 7.42(2H,d,J=8.2Hz), 7.48(2H,d,J=8.2Hz), 7.66(1H,s), 7.76(2H,d,J=8.2Hz), 7.81(2H,d,J=8.2Hz).
【０３４９】
実施例２８４
７−〔４−（４−メチルベンゾイル）ベンジル〕−１，３−ジメチルキサンチン
１，３−ジメチルキサンチン（９９mg）、炭酸カリウム（１３５mg）、４−（４−メチルベンゾイル）ベンジルブロミド（２０１mg）のジメチルホルムアミド（１０ml）溶液を６０℃で５時間撹拌させた。反応液を水にあけ、酢酸エチルで抽出し、水で洗浄し乾燥後濃縮して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／５）で精製し、酢酸エチル／イソプロピルエーテルから再結晶して無色固体の表題化合物（９８mg）を得た。
IR(KBr)ν：1700, 1655 cm^-1.
NMR(CDCl₃)δ：2.44(3H,s), 3.41(3H,s), 3.60(3H,s), 5.59(2H,s), 7.27(2H,d,J=8.2Hz), 7.41(2H,d,J=8.2Hz), 7.68(1H,s), 7.69(2H,d,J=8.2Hz), 7.77(2H,d,J=8.2Hz).
【０３５０】
実施例２８５
７−〔４−（４−フルオロベンゾイル）ベンジルオキシ〕−３，６−ジメチル−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
３，６−ジメチル−７−ヒドロキシ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン（５１４mg）と炭酸カリウム（７４１mg）のジメチルホルムアミド（１０ml）溶液に、４−（４−フルオロベンゾイル）ベンジルブロミド（７８２mg）を加え、反応液を８０℃で２時間撹拌させた。反応液を濃縮し、残渣に水／酢酸エチルを加え、酢酸エチルで抽出して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２：１）で精製し、酢酸エチルから再結晶して無色固体の表題化合物（７６mg）を得た。
IR(KBr)ν：1640, 1590, 1385, 1340, 1300, 1270, 1245, 1145 cm^-1.
NMR(CDCl₃)δ：2.05(3H,s), 2.82(3H,d,J=1.2Hz), 5.50(2H,s), 6.35(1H,d,J=1.2Hz), 7.17(2H,t,J=8.6Hz), 7.45(2H,d,J=8.1Hz), 7.79(2H,d,J=8.1Hz), 7.86(2H,dd,J=5.5,8.6Hz).
【０３５１】
実施例２８６
７−〔４−（４−メトキシベンゾイル）ベンジルオキシ〕−３，６−ジメチル−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
３，６−ジメチル−７−ヒドロキシ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン（５３７mg）と炭酸カリウム（７４５mg）のジメチルホルムアミド（１０ml）溶液に、４−（４−メトキシベンゾイル）ベンジルブロミド（９７０mg）を加え、反応液を８０℃で２時間撹拌させた。反応液を濃縮し、残渣に水／酢酸エチルを加え、酢酸エチルで抽出して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２：１）で精製し、酢酸エチルから再結晶して無色固体の表題化合物（１０６mg）を得た。
IR(KBr)ν：1660, 1645, 1595, 1570, 1490 cm^-1.
NMR(CDCl₃)δ : 2.05(3H,s), 2.82(3H,s), 3.90(3H,s), 5.49(2H,s), 6.35(1H,s), 6.97(2H,d,J=8.5Hz), 7.52(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz), 7.84(2H,d,J=8.5Hz).
【０３５２】
実施例２８７
７−〔４−（４−ニトロベンゾイル）ベンジルオキシ〕−３，６−ジメチル−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
３，６−ジメチル−７−ヒドロキシ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン（５３７mg）と炭酸カリウム（６１８mg）のジメチルホルムアミド（１０ml）溶液に、４−（４−ニトロベンゾイル）ベンジルブロミド（９０９mg）を加え、反応液を８０℃で２時間撹拌させた。反応液を濃縮し、残渣に水／酢酸エチルを加え、酢酸エチルで抽出して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２：１）で精製し、酢酸エチルから再結晶して無色固体の表題化合物（１０５mg）を得た。
IR(KBr)ν：1665, 1515, 1500 cm^-1.
NMR(CDCl₃)δ：2.05(3H,s), 2.82(3H,s), 5.51(2H,s), 6.36(1H,s), 7.57(2H,d,J=8.1Hz), 7.83(2H,d,J=8.1Hz), 7.94(2H,d,J=8.2Hz), 8.35(2H,d,J=8.2Hz).
【０３５３】
実施例２８８
７−〔４−（６−クロロニコチノイル）ベンジルオキシ〕−３，６−ジメチル−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
３，６−ジメチル−７−ヒドロキシ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン（５２６mg）と炭酸カリウム（５７４mg）のジメチルホルムアミド（１０ml）溶液に、４−（６−クロロニコチノイル）ベンジルブロミド（８５２mg）を加え、反応液を８０℃で２時間撹拌させた。反応液を濃縮し、残渣に水／酢酸エチルを加え、酢酸エチルで抽出して、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２：１）で精製し、酢酸エチルから再結晶して無色固体の表題化合物（３００mg）を得た。
IR(KBr)ν：1665, 1640, 1570, 1490 cm^-1.
NMR(CDCl₃)δ：2.05(3H,s), 2.82(3H,s), 5.51(2H,s), 6.35(1H,s), 7.49(1H,d,J=8.4Hz), 7.57(2H,d,J=8.1Hz), 7.82(2H,d,J=8.1Hz), 8.10(1H,dd,J=2.2,8.4Hz), 8.78(1H,d,J=2.2Hz).
【０３５４】
実施例２８９
７−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−３−エチル−６−メチル−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
３−エチル−６−メチル−７−ヒドロキシ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン（２９８mg）と炭酸カリウム（３６３mg）のジメチルホルムアミド（１０ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（４５０mg）を加え、反応液を８０℃で２時間撹拌させた。反応液を濃縮し、残渣に水／酢酸エチルを加え、酢酸エチルで抽出し、酢酸エチルから再結晶して無色固体の表題化合物（２０５mg）を得た。
IR(KBr)ν：1670, 1640, 1570, 1490 cm^-1.
NMR(CDCl₃)δ：1.31(3H,t,J=7.2Hz), 2.06(3H,s), 3.34(2H,q,J=7.2Hz), 5.50(2H,s), 6.39(1H,s), 7.47(2H,d,J=8.1Hz), 7.54(2H,d,J=8.1Hz), 7.77(2H,d,J=8.1Hz), 7.80(2H,d,J=8.1Hz).
【０３５５】
実施例２９０
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
３，５−ジメチル−２−メルカプト−４（３Ｈ）−キナゾリノン（２.１ｇ）をメタノール−ＴＨＦ−水（３：３：１）（７０ml）に懸濁し、１Ｎ水酸化ナトリウム水溶液（１１ml）を加え、均一になるまで撹拌した。続いて４−（６−クロロニコチノイル）ベンジルブロミド（３.１ｇ）を加え、室温で３０分間撹拌した。反応液を濃縮した後、残渣を水、メタノール、ジイソプロピルエーテルで順次洗浄し、乾燥して白色粉末３．２ｇを得た。
IR(KBr)：1660, 1580, 1555 cm^-1.
NMR(CDCl₃)：δ 2.84(3H,s), 3.54(3H,s), 4.60(2H,s), 7.15(1H,d,J=7.8Hz), 7.43(1H,d,J=7.8Hz), 7.47(1H,d,J=8.2Hz), 7.54(1H,dd,J=7.8 and 7.8Hz), 7.64(2H,d,J=8.2Hz), 7.76(2H,d,J=8.2Hz), 8.07(1H,dd,J=2.2 and 8.2Hz), 8.75(1H,d,J=2.2Hz).
【０３５６】
実施例２９１
３，５−ジメチル−２−〔４−〔６−（４−メチル−１−ピペラジニル）ニコチノイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン・２塩酸塩
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（２１８mg）をピリジン（３ml）に溶解し、１−メチルピペラジン（７５mg）を加え、９０℃で３時間撹拌した。反応液を濃縮した後、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。１０mlまで濃縮した有機層に１Ｎ塩酸（１.２ml）を加え、水で抽出した。水層に飽和炭酸水素ナトリウム水溶液を加えて塩基性とし、再度酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。これを５mlまで濃縮した後、４Ｎ塩化水素／酢酸エチル（０.４ml）を加えた。析出物を濾集し、酢酸エチルで洗浄し、乾燥して白色粉末１８５mgを得た。
mp １８７−１８９℃
IR(KBr)：3450, 1660, 1640, 1600, 1550 cm^-1.
¹H-NMR(DMSO)：δ 2.75(3H,s), 2.85(3H,s), 2.96-3.20(2H,m), 3.45(3H,s), 3.30-3.59(4H,m), 4.51-4.63(2H,m), 4.64(2H,s), 7.06(1H,d,J=9.3Hz), 7.21(1H,d,J=7.7Hz), 7.47(1H,d,J=7.7Hz), 7.63(1H,dd,J=7.7 and 7.7Hz), 7.65(2H,d,J=8.6Hz), 7.71(2H,d,J=8.6Hz), 7.97(1H,dd,J=2.2 and 9.3Hz), 8.50(1H,d,J=2.2Hz).
【０３５７】
実施例２９２
３，５−ジメチル−２−〔４−〔６−（４−ピペリジノ−１−ピペリジニル）ニコチノイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン・２塩酸塩
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（４３６mg）をピリジン（５ml）に溶解し、４−ピペリジノピペリジン（２５２mg）を加え、９０℃で３時間撹拌した。反応液を濃縮した後、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮した後、残渣をシリカゲルクロマト（ジクロロメタン−メタノール（９：１））で精製した。これを酢酸エチル（５ml）に溶解し、４Ｎ塩化水素／酢酸エチル（０.８ml）を加えた。析出物を濾集し、酢酸エチル−エタノールで洗浄し、乾燥して白色粉末３９２mgを得た。
mp １４０−１４２℃
IR(KBr)：3400, 1710, 1660, 1640, 1600, 1550 cm^-1.
¹H-NMR(DMSO)：δ 1.28-2.03(8H,m), 2.13-2.30(2H,m), 2.75(3H,s), 2.79-3.13(4H,m), 3.29-3.56(3H,m), 3.45(3H,s), 4.65-4.75(2H,m), 4.65(2H,s), 7.10(1H,d,J=9.0Hz), 7.21(1H,d,J=7.9Hz), 7.47(1H,d,J=7.9Hz), 7.63(1H,dd,J=7.9 and 7.9Hz), 7.66(2H,d,J=8.4Hz), 7.71(2H,d,J=8.4Hz), 7.96(1H,dd,J=1.8 and 9.0Hz), 8.42(1H,d,J=1.8Hz).
【０３５８】
実施例２９３
３，５−ジメチル−２−〔４−〔６−（２−ピリミジニルチオ）ニコチノイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（２１４mg）をＤＭＦ（３ml）に溶解し、２−メルカプトピリミジン（６６mg）、Ｎ,Ｎ−ジイソプロピルエチルアミン（９６mg）を加え、１００℃で８時間撹拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮した後、残渣をシリカゲルクロマト（ｎ−ヘキサン−酢酸エチル（１：１））で精製し、さらにジエチルエーテルで洗浄し、乾燥して白色粉末８７mgを得た。
IR(KBr)：1660, 1580, 1550 cm-¹.
¹H-NMR(CDCl₃)：δ 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.11(1H,d,J=4.8Hz), 7.15(1H,d,J=7.7Hz), 7.43(1H,d,J=7.7Hz), 7.55(1H,dd,J=7.7 and 7.7Hz), 7.64(2H,d,J=8.3Hz), 7.81(2H,d,J-8.3Hz), 8.02(1H,d,J=8.3Hz), 8.12(1H,dd,J=2.2 and 8.3Hz), 8.60(2H,d,J=4.8Hz), 8.93(1H,d,J=2.2Hz).
【０３５９】
実施例２９４
５−〔４−（４−クロロベンゾイル）ベンジル〕−１，３，６−トリメチル−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン
１，３，６−トリメチル−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン（０．１２０ｇ，０．６２２mmol）と臭化４−（４−クロロベンゾイル）ベンジル（０．１５３ｇ，０．４９４mmol）のＤＭＦ（１０ml）溶液に炭酸カリウム（０．１２１ｇ，０．８７５mmol）を加え室温で終夜撹拌した。溶媒を減圧除去した後残渣に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、有機層をＭgＳＯ₄で乾燥し減圧濃縮した。残渣を酢酸エチルから再結晶し無色プリズム晶を得た。０．０８０ｇ（３８％）
IR(KBr)ν：1691, 1648, 1547, 1506, 1406, 1281, 1086, 928, 748 cm^-1.
NMR(CDCl₃)δ：2.25(3H,s), 3.39(3H,s), 3.47(3H,s), 5.72(2H,s), 5.83(1H,s), 7.12(2H,d,J=8.3Hz), 7.44(2H,d,J=8.6Hz), 7.71(2H,d,J=8.3Hz), 7.72(2H,d,J=8.6Hz).
【０３６０】
実施例２９５
３，５−ジメチル−２−〔４−〔６−［１−（２−ジメチルアミノエチル）−５−テトラゾリルチオ〕ニコチノイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例２９３と同様にして合成した。
mp １３４−１３５℃
IR(KBr)：1660, 1575, 1550 cm^-1.
¹H-NMR(CDCl₃)：δ 2.21(6H,s), 2.80(2H,t,J=6.2Hz), 2.84(3H,s), 3.54(3H,s), 4.51(2H,t,J=6.2Hz), 4.59(2H,s), 7.15(1H,d,J=7.8Hz), 7.42(1H,d,J=7.8Hz), 7.49(1H,d,J=8.4Hz), 7.54(1H,dd,J=7.8 and 7.8Hz), 7.63(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 8.02(1H,dd,J=2.2 and 8.4Hz), 8.71(1H,d,J=2.2Hz).
【０３６１】
実施例２９６
２−〔４−（４−クロロベンゾイル）フェニルチオメチル〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
mp １３１.５−１３２.５℃
IR(KBr)：1670, 1650, 1585, 1560 cm^-1.
¹H-NMR(CDCl₃)：δ 2.87(3H,s), 3.70(3H,s), 4.32(2H,s), 7.22(1H,d,J=7.8Hz), 7.43(1H,d,J=7.8Hz), 7.44(2H,d,J=8.8Hz), 7.55(1H,dd,J=7.8Hz and 7.8Hz),7.59(2H,d,J=8.5Hz), 7.68(2H,d,J=8.8Hz), 7.69(2H,.d,J=8.5Hz).
【０３６２】
実施例２９７
３，５−ジメチル−２−〔４−〔４−〔２−〔１−（２−ジメチルアミノエチル）−５−テトラゾリル〕チオエトキシ〕ベンゾイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−〔４−（２−クロロエトキシ）ベンゾイル〕ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（２４０mg）をＤＭＦ（３ml)に溶解し、ヨウ化ナトリウム（７５mg）を加え、９０℃で３０分間撹拌した。続いて１−（２−ジメチルアミノエチル）−５−メルカプトテトラゾール（１０４mg）、Ｎ,Ｎ−ジイソプロピルエチルアミン（９７mg）を加え、９０℃で３時間撹拌した。反応液を酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。これを濃縮した後、残渣をジエチルエーテル−酢酸エチルで洗浄し、乾燥して白色粉末１００mgを得た。
IR(KBr)：1670, 1600, 1550 cm^-1.
¹H-NMR(CDCl₃)：δ 2.26(6H,s), 2.77(2H,t,J=6.4Hz), 2.85(3H,s), 3.55(3H,s), 3.73(2H,t,J=6.0Hz), 4.32(2H,t,J=6.4Hz), 4.44(2H,t,J=6.0Hz), 4.60(2H,s), 6.97(2H,d,J=8.9Hz), 7.16(1H,d,J=7.7Hz), 7.45(1H,d,J=7.7Hz), 7.55(1H,dd,J=7.7 and 7.7Hz), 7.59(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.81(2H,d,J=8.9Hz).
【０３６３】
実施例２９８
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３−メチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)：1660, 1630, 1510 cm^-1.
¹H-NMR(CDCl₃)：δ 2.24(3H,s), 4.60(2H,s), 7.08(1H,dd,J=7.1 and 7.1Hz), 7.45(1H,d,J=8.6Hz), 7.53(1H,d,J=7.1Hz), 7.57(2H,d,J=8.0Hz), 7.68(1H,dd,J=7.1 and 7.1Hz), 7.73(2H,d,J=8.0Hz), 7.73(2H,d,J=8.6Hz), 9.00(1H,d,J=7.1Hz).
実施例２９９
３，５−ジメチル−２−〔４−（４−（２，２，２−トリフルオロエチルカルボニル）ベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン
表題の化合物を実施例２０６と同様にして合成した。
IR：(KBr)ν：3207, 1660, 1554, 1495, 1360, 1282, 1236, 1070, 930, 835, 746 cm^-1.
NMR(CDCl₃)δ(ppm)： 2.84(3H,s), 3.55(3H,s), 4.16(2H,dq,J=9.0, 6.8Hz), 6.46(1H,t,J=6.8Hz), 7.15(1H,d,J=7.0Hz), 7.43(1H,d,J=7.0Hz), 7.54(1H,t,J=7.0Hz), 7.62(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.84(2H,d,J=8.4Hz), 7.90(2H,d,J=8.4Hz).
【０３６４】
実施例３００
６−エチル−７−メチル−１−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
表題の化合物を実施例１６３と同様にして合成した。
IR：(KBr)ν：3097, 2971, 2489, 1695, 1658, 1596, 1450, 1410, 1331, 1279,1180, 1132, 1066, 860, 773, 687 cm^-1.
NMR：(DMSO-d₆)δ： 1.04(3H,t,J=7.4Hz), 2.35(3H,s), 3.69(2H,q,J=7.4Hz), 5.43(2H,s), 7.50(1H,d,J=2.8Hz), 7.60(1H,d,J=2.8Hz), 7.65(1H,d,J=2.8Hz), 7.77(2H,d,J=7.6Hz), 7.90(4H,s).
実施例３０１
２−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−３，６−ジメチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１２１と同様にして合成した。
IR：(KBr)ν：1672, 1589, 1547, 1484, 1331, 1279, 1163 cm^-1.
NMR：(CDCL₃)δ(ppm)： 2.21(3H,s), 3.10(3H,s), 5.57(2H,s), 6.63(1H,d,J=7.0Hz), 7.24(1H,d,J=9.0Hz), 7.39(1H,dd,J=9.0, 7.0Hz), 7.47(2H,d,J=8.3Hz), 7.57(2H,d,J=8.1Hz), 7.76(2H,d,J=8.3Hz), 7.47(2H,d,J=8.1Hz).
【０３６５】
実施例３０２
３，６−ジメチル−２−〔４−（４−フルオロベンゾイル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１２１と同様にして合成した。
IR：(KBr)ν：1672, 1593, 1547, 1485, 1331, 1279, 1279, 1230, 1161, 928, 854, 797, 760 cm^-1.
NMR：(CDCl₃)δ(ppm)： 2.12(3H,s), 3.10(3H,s), 5.57(2H,s), 6.63(1H,d,J=6.7Hz), 7.14(1H,d,J=8,5Hz), 7.23(2H,d,J=9.5Hz), 7.39(1H,dd,J=8.5, 6.7Hz), 7.57(2H,d,J=8.0Hz), 7.79(2H,d,J=8.0Hz), 7.85(2H,dd,J=9.5, 5.7Hz).
実施例３０３
２−〔４−（６−クロロニコチノイル）ベンジルオキシ〕−３，６−ジメチル−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１２１と同様にして合成した。
IR：(KBr)ν：1666, 1585, 1485, 1331, 1282, 1163 cm^-1.
NMR：(CDCl₃)δ(ppm)： 2.12(3H,s), 3.10(3H,s), 5.58(2H,s), 6.62(1H,d,J=7.4Hz), 7.23(1H,d,J=8,6Hz), 7.39(1H,dd,J=8.6, 7.4Hz), 7.48(1H,d,J=8.4Hz), 7.60(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 8.09(1H,dd,J=8.4, 2.6Hz), 8.77(1H,d,J=2.6Hz).
【０３６６】
実施例３０４
３，６−ジメチル−２−〔４−（４−ヒドロキシベンゾイル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１２１と同様にして合成した。
IR：(KBr)ν：3410, 2921, 1645, 1591, 1481, 1282, 1165, 926, 731 cm^-1.
NMR：(CDCl₃)δ(ppm)： 2.13(3H,s), 3.11(3H,s), 5.25(2H,s), 6.65(1H,d,J=6.6Hz), 7.04(2H,d,J=8,7Hz), 7.27(1H,d,J=8.8Hz), 7.41(1H,dd,J=8.8, 6.6Hz), 7.54(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.77(2H,d,J=8.7Hz).
実施例３０５
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−５−エチル−３−メチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR：(KBr)ν：1666, 1552, 1462, 1281, 1159, 1099, 926 cm^-1.
NMR：(CDCl₃)δ(ppm)： 1.27(3H,t,J=7.4Hz), 3.30(2H,q,J=7.4Hz), 3.56(3H,s), 4.60(2H,s), 7.19(1H,d,J=7.4Hz), 7.46(1H,t,J=7.4Hz), 7.47(1H,d,J=8.2Hz), 7.57(1H,d,J=7.4Hz), 7.65(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 8.08(1H,dd,J=8.4, 2.4Hz), 8.75(1H,d,J=2.4Hz).
【０３６７】
実施例３０６
３，６−ジメチル−２−〔４−〔６−（４−ピペリジノピペリジノ）ニコチノイル〕ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１９７と同様にして合成した。
IR：(KBr)ν：3423, 2937, 1643, 1549, 1483, 1446, 1331, 1282, 1238, 1177,1003 cm^-1.
NMR：(DMSO)δ(ppm)： 1.60-1.97(5H,m), 1.98(3H,s), 2.10-2.30(2H,m), 2.80-3.10(4H,m), 2.98(3H,s), 3.30-3.50(2H,m), 3.60-3.70(4H,m), 5.60(2H,s), 6.87(1H,d,J=7.2Hz), 7.00-7.09(2H,m), 7.30(1H,d,J=9.0Hz), 7.62(2H,d,J=7.6Hz), 7.71(2H,d,J=7.6Hz), 7.95(1H,dd,J=7.6, 2.2Hz), 8.46(1H,d,J=2.2Hz).
実施例３０７
３，６−ジメチル−２−〔４−〔６−（４−フェニルピペラジニル）ニコチノイル〕ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン３塩酸塩
表題の化合物を実施例１９７と同様にして合成した。
IR：(KBr)ν：3456, 1664, 1637, 1599, 1487, 1439, 1288, 1261, 1187 cm^-1.
NMR：(DMSO)δ(ppm)： 1.19(3H,s), 2.99(3H,s), 3.39(4H,m), 3.89(4H,m), 5.58(2H,s), 6.88(1H,d,J=8.0Hz), 6.95(1H,m), 7.07-7.20(3H,m), 7.28-7.35(3H,m), 7.60(1H,m), 7.62(2H,d,J=8.4Hz), 7.73(1H,d,J=8.4Hz), 8.00(1H,dd,J=8.8,2.2Hz), 8.49(1H,d,J=2.2Hz).
【０３６８】
実施例３０８
３，６−ジメチル−２−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン塩酸塩
表題の化合物を実施例１５６と同様にして合成した。
IR：(KBr)ν：1649, 1599, 1483, 1282, 1255, 1167, 928 cm^-1.
NMR：(CDCl₃)δ(ppm)： 2.12(3H,s), 2.60(4H,t,J=4.8Hz), 2.85(2H,t,J=6.0Hz), 3.75(4H,t,J=8.4Hz), 4.20(2H,t,J=6.0Hz), 5.56(2H,s), 6.63(1H,d,J=6.8Hz), 6.97(2H,d,J=8.8Hz), 7.25(1H,d,J=8.7Hz), 7.39(1H,dd,J=8.7, 6.8Hz), 7.55(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz), 7.82(2H,d,J=8.8Hz).
実施例３０９
５−エチル−３−メチル−２−〔４−〔６−（４−ピペリジノピペリジノ）ニコチノイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン３塩酸塩
表題の化合物を実施例１９７と同様にして合成した。
IR：(KBr)ν：3377, 2933, 2646, 2519, 1647, 1551, 1442, 1317, 1279, 1241,1180, 1093, 1003, 926, 822, 748 cm^-1.
NMR：(DMSO)δ(ppm)： 1.18(3H,t,J=7.2Hz), 1.50-1.90(7H,m), 2.10-2.30(2H,m), 2.80-3.10(4H,m), 3.22(2H,q,J=7.2Hz), 3.30-3.50(4H,m), 3.48(3H,s), 4.65(2H,s), 4.70(1H,m), 7.02(1H,d,J=8.4Hz), 7.22(1H,d,J=8.6Hz), 7.48(1H,d,J=9.0Hz), 7.64(1H,d,J=8.7Hz), 7.66(1H,dd,J=8.6, 8.4Hz), 7.71(2H,d,J=8.7Hz), 8.13(1H,dd,J=9.0, 2.6Hz), 8.45(1H,d,J=2.6Hz).
【０３６９】
実施例３１０
５−エチル−３−メチル−２−〔４−〔６−（４−フェニルピペラジニル）ニコチノイル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン３塩酸塩
表題の化合物を実施例１９７と同様にして合成した。
IR：(KBr)ν：3406, 1968, 1637, 1605, 1552, 1435, 1313, 1255, 1182, 1091,760, 696 cm^-1.
NMR：(DMSO)δ(ppm)： 1.18(3H,t,J=7.2Hz), 3.22(2H,q,J=7.2Hz), 3.40(4H,m),3.48(3H,s), 3.89(4H,m), 4.65(2H,s), 6.90-7.40(6H,m), 7.48(2H,d,J=8.0Hz), 7.64(2H,d,J=8.0Hz), 7.62-7.80(3H,m), 8.00(1H,m), 8.46(1H,m).
実施例３１１
３−（２−アセトキシエチル）−７−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
表題の化合物を実施例４９と同様にして合成した。
¹H-NMR(CDCl₃)δ：2.06(3H,s), 2.42(3H,s), 4.22-4.28(2H,m), 4.37-4.43(2H,m), 5.34(2H,s), 6.59(1H,s), 7.27(2H,d,J=8.2Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.2Hz), 7.80(1H,s).
【０３７０】
実施例３１２
７−〔４−（４−クロロベンゾイル）ベンジル〕−３−（２−ヒドロキシエチル）−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
３−（２−アセトキシエチル）−７−〔４−（４−クロロベンゾイル）ベンジル〕−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン（４６４mg）をメタノール（１２ml）に溶解し、１規定水酸化ナトリウム（２ml）加え、更にＤＭＥ（６ml）を加え均一な溶液とした。４時間撹拌し、１規定塩酸（２ml）を加え、減圧下溶媒を留去した。水を加え結晶を微細化した後、濾取、水、メタノール洗浄後、乾燥することより表題化合物（４０２mg）を結晶性粉末として得た。
¹H-NMR(CDCl₃)δ：2.42(3H,d,J=1.0Hz), 2.86(1H,t,J=4.4Hz), 3.97(2H,q,J=4.4Hz), 4.18(2H,t,J=4.4Hz), 5.34(2H,s), 6.60(1H,d,J=1.0Hz), 7.27(2H,d,J=8.2Hz), 7.45(2H,d,J=8.6Hz), 7.73(4H,d,J=8.4Hz), 7.80(1H,s).
【０３７１】
実施例３１３
５−〔４−（６−クロロニコチノイル）ベンジル〕−１，３−ジメチル−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン
表題の化合物を実施例１６３と同様にして合成した。
IR：(KBr)ν：1695, 1655, 1551, 1467, 1275, 1099, 922, 758 cm^-1.
¹H-NMR：(CDCl₃)δ：3.39(3H,s), 3.49(3H,s), 5.67(2H,s), 5.67(2H,s), 6.01(1H,d,J=3.0Hz), 7.02(1H,d,J=3.0Hz), 7.32(2H,d,J=8.4Hz), 7.46(1H,d,J=8.1Hz), 7.75(1H,d,J=8.4Hz), 8.06(1H,dd,J=8.1, 2.2Hz), 8.74(1H,d,J=2.2Hz).
実施例３１４
１，３−ジメチル−５−〔４−（４−フルオロベンゾイル）ベンジル〕−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン
表題の化合物を実施例１６３と同様にして合成した。
IR：(KBr)ν：1686, 1647, 1601, 1551, 1468, 1412, 1275, 1244, 1153, 1061,
928, 856, 746 cm^-1.
¹H-NMR：(CDCl₃)：δ3.40(3H,s), 3.49(3H,s), 5.66(2H,s), 6.01(1H,d,J=2.9Hz), 7.02(1H,d,J=2.9Hz), 7.15(2H,t,J=8.6Hz), 7.30(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.82(2H,dd,J=8.6, 5.4Hz).
【０３７２】
実施例３１５
１，３−ジメチル−５−〔４−〔６−（４−ピペリジノピペリジノ）ニコチノイル〕ベンジル〕−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン２塩酸塩
表題の化合物を実施例１９７と同様にして合成した。
IR：(KBr)ν：3417, 1689, 1641, 1551, 1464, 1269, 746 cm^-1.
¹H-NMR(DMSO-d₆)δ：1.40(2H,m), 1.68-1.82(8H,m), 2.20-2.26(2H,m), 2.80-3.00(5H,m), 3.22(3H,s), 3.39(3H,s), 4.64-4.69(2H,m), 4.64(2H,s), 6.24(1H,d,J=2.4Hz), 7.10(1H,d,J=9.1Hz), 7.34(2H,d,J=8.4Hz), 7.52(1H,d,J=2.4Hz), 7.65(2H,d,J=8.4Hz), 7.96(1H,dd,J=9.1, 2.2Hz), 8.40(1H,d,J=2.4Hz).
実施例３１６
１，３−ジメチル−５−〔４−〔６−（４−フェニルピペラジノ）ニコチノイル〕ベンジル〕−ピロロ〔３，２−ｄ〕ピリミジン−２，４−ジオン２塩酸塩
表題の化合物を実施例１９７と同様にして合成した。
IR：(KBr)ν：3413, 1691, 1641, 1549, 1464, 1255, 750 cm^-1.
¹H-NMR(DMSO-d₆)δ：3.22(3H,s), 3.39(4H,m), 3.57(3H,s), 5.65(2H,s), 6.24(1H,d,J=3.0Hz), 6.90-7.30(6H,m), 7.34(2H,d,J=8.0Hz), 7.52(1H,d,J=3.0Hz), 7.66(2H,d,J=8.0Hz), 7.98(1H,dd,J=9.0, 2.2Hz), 8.44(1H,d,J=2.2Hz).
【０３７３】
実施例３１７
２−〔４−（６−クロロニコチノイル）ベンジルチオ〕−６−ヒドロキシ−３−メチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR：(KBr)ν：3209, 1660, 1554, 1495, 1360, 1281, 1236, 1105, 1070, 928, 835, 748 cm^-1.
¹H-NMR(DMSO-d₆)δ(ppm)：3.48(3H,s), 4.63(2H,s), 7.27(1H,dd,J=8.8, 2.6Hz), 7.38(1H,d,J=2.7Hz), 7.52(1H,d,J=8.8Hz), 7.69(1H,d,J=8.2Hz), 7.75(4H,s), 8.13(1H,dd,J=8.2, 2.4Hz), 8.69(1H,d,J=2.4Hz).
実施例３１８
２−〔４−（４−フルオロベンゾイル）ベンジルチオ〕−６−ヒドロキシ−３−メチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR：(KBr)ν：3200, 1654, 1602, 1552, 1494, 1363, 1277, 1232, 1147, 1666,833 cm^-1.
¹H-NMR：(CDCl₃)δ：3.61(3H,s), 4.59(2H,s), 5.46(1H,brs), 6.51(1H,brs), 7.15(2H,t,J=8.8Hz), 7.30(1H,dd,J=8.8, 2.6Hz), 7.54(2H,d,J=8.8Hz), 7.60(2H,d,J=8.0Hz), 7.74(2H,d,J=8.0Hz), 7.78(1H,m), 7.82(1H,dd,J=5.4, 2.6Hz).
【０３７４】
実施例３１９
６−ヒドロキシ−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−３−メチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR：(KBr)ν：3346, 1678, 1610, 1556, 1493, 1323, 1143, 1063, 928, 833 cm^-1.
¹H-NMR(CDCl₃)δ：3.61(3H,s), 4.59(2H,s), 7.29(1H,dd,J=8.9, 3.0Hz), 7.53(1H,d,J=8.9Hz), 7.62(1H,d,J=8.2Hz), 7.72-7.79(6H,m), 7.87(2H,d,J=8.0Hz).
実施例３２０
３−メチル−６−（２，２，２−トリフルオロエチルアミノカルボニルオキシ）−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
６−ヒドロキシ−３−メチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕チオ−４（３Ｈ）−キナゾリノン（０.３００ｇ，０.６３８mmol）のＤＭＦ（５.０ml）溶液にクロロ炭酸４−ニトロフェノール（０.１９６ｇ，０.９７３mmol）とトリエチルアミン（０.２５ml）を加え室温で１時間撹拌した。２，２，２−トリフルオロエチルアミン（０.１４８ｇ，０.９８９mmol）を加えさらに１４時間撹拌し、溶媒を除去した後、残渣を酢酸エチルに溶かし、飽和食塩水で洗浄した。有機層をＭgＳＯ₄で乾燥後減圧濃縮し、残渣をシリカゲルカラム（イソプロピルエーテル：アセトン＝１０：１）で精製した後、ヘキサン−イソプロピルエーテルから再結晶し無色針状晶を得た。０.０８０ｇ（２１％）
IR：(KBr)ν：3305, 1726, 1674, 1552, 1483, 1412, 1333, 1284, 1246, 1159,1111, 1068, 1016, 933, 837, 773, 686 cm^-1.
¹H-NMR(CDCl₃)δ：3.60(3H,s), 3.92(2H,m), 4.60(2H,s), 5.46(1H,brs), 7.51(1H,dd,J=8.5, 2.5Hz), 7.61(1H,d,J=8.8Hz), 7.62(2H,d,J=8.0Hz), 7.74(2H,d,J=8.4Hz), 7.77(2H,d,J=8.0Hz), 7.87(2H,d,J=8.4Hz), 7.94(1H,d,J=2.5Hz).
【０３７５】
実施例３２１
２−（４−ベンゾイルベンジルチオ）−３，５−ジメチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR：(KBr)ν：1659, 1552, 1308, 1277, 1088, 931, 858, 802, 702 cm^-1.
¹H-NMR(CDCl₃)δ：2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.15(1H,d,J=7.2Hz),7.44-7.62(7H,m), 7.76-7.81(4H,m).
実施例３２２
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−５−メトキシメチル−３−メチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR：(KBr)ν：1660, 1552, 1435, 1404, 1308, 1281, 1086, 924, 804, 741, 687 cm^-1.
¹H-NMR(CDCl₃)δ:3.55(3H,s), 3.56(3H,s), 4.60(2H,s), 5.14(2H,s), 7.45(2H,d,J=8.6Hz), 7.52(1H,dd,J=7.4, 1.8Hz), 7.59-7.66(3H,m), 7.70-7.77(5H,m).
【０３７６】
実施例３２３
２−〔４−（４−フルオロベンゾイル）ベンジルチオ〕−５−メトキシメチル−３−メチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR：(KBr)ν：1663, 1589, 1555, 1439, 1408, 1308, 1279, 1234, 1084, 924, 852, 746, 687, 575 cm^-1.
¹H-NMR(CDCl₃)δ：3.55(3H,s), 3.56(3H,s), 4.60(2H,s), 5.14(2H,s), 7.15(2H,t,J=9.0Hz), 7.52(1H,dd,J=7.6, 2.0Hz), 7.60(2H,d,J=8.4Hz), 7.64(1H,m), 7.68(1H,t,J=7.6Hz), 7.74(2H,d,J=8.4Hz), 7.83(2H,dd,J=9.0, 5.4Hz).
実施例３２４
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３−メチル−５−（２，２，２−トリフルオロエトキシメチル）−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1676, 1645, 1558, 1443, 1409, 1309, 1157, 1088, 806, 693 cm^-1.
¹H-NMR(CDCl₃)δ：3.55(3H,s), 4.05(2H,q,J=8.4Hz), 4.60(2H,s), 5.36(2H,s),７.45(2H,d,J=8.4Hz), 7.54(1H,d,J=6.6Hz), 7.60(2H,d,J=8.4Hz), 7.61(1H,d,J=6.6Hz), 7.68(1H,t,J=6.6Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz).
【０３７７】
実施例３２５
２−〔４−（４−フルオロベンゾイル）ベンジルチオ〕−３−メチル−５−（２，２，２−トリフルオロエトキシメチル）−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1662, 1603, 1558, 1443, 1412, 1279, 1161, 1088, 964, 928, 851, 690 cm^-1.
¹H-NMR(CDCl₃)δ：3.55(3H,s), 4.04(2H,q,J=8.6Hz), 4.60(2H,s), 5.36(2H,s),7.15(2H,t,J=8.8Hz), 7.53-7.67(5H,m), 7.73(2H,d,J=8.4Hz), 7.84(2H,dd,J=8.8, 5.4Hz).
実施例３２６
５−メトキシメチル−３−メチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1660, 1560, 1408, 1315, 1279, 1161, 1134, 1086, 1063 cm^-1.
¹H-NMR(CDCl₃)δ：3.55(3H,s), 4.60(2H,s), 5.14(2H,s), 7.50(1H,d,J=8.4Hz),7.62(2H,d,J=8.0Hz), 7.68(1H,d,J=8.4Hz), 7.72-7.79(5H,m), 7.87(2H,d,J=8.0Hz).
【０３７８】
実施例３２７
３−メチル−５−（２，２，２−トリフルオロエトキシメチル）−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1678, 1659, 1554, 1331, 1282, 1169, 1128, 1090 cm^-1.
¹H-NMR(CDCl₃)δ：3.55(3H,s), 4.05(2H,q,J=8.8Hz), 4.61(2H,s), 5.36(2H,s),7.55(1H,d,J=7.8Hz), 7.62(2H,d,J=8.0Hz), 7.66(1H,d,J=7.8Hz), 7.72-7.79(5H,m).
実施例３２８
１−〔４−（４−フルオロベンゾイル）ベンジル〕−６，７，８，９−テトラヒドロイミダゾ〔２，１−ｂ〕キナゾリノン−５（１Ｈ）−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1657, 1589, 1527, 1418, 1277, 1213, 1159, 928 cm^-1.
¹H-NMR(CDCl₃)δ：1.82(4H,m), 2.65(2H,t,J=5.6Hz), 2.74(2H,t,J=5.6Hz), 5.33(2H,s), 6.85(1H,d,J=2.6Hz), 7.17(2H,d,J=8.2Hz), 7.40(2H,d,J=8.0Hz), 7.55(1H,d,J=2.6Hz), 7.78(2H,d,J=8.0Hz), 7.83(2H,dd,J=8.2, 4.8Hz).
【０３７９】
実施例３２９
１−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−６，７，８，９−テトラヒドロイミダゾ〔２，１−ｂ〕キナゾリノン−５（１Ｈ）−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1659, 1583, 1527, 1417, 1321, 1277, 1168, 1128, 1064, 928 cm^-1.
¹H-NMR(CDCl₃)δ：1.79-1.83(4H,m), 2.65(2H,t,J=5.8Hz), 2.73(2H,t,J=5.8Hz), 5.34(2H,s), 6.84(1H,d,J=2.6Hz), 7.42(2H,d,J=8.2Hz), 7.55(1H,d,J=2.6Hz), 7.76(2H,d,J=8.2Hz), 7.81(2H,d,J=8.4Hz), 7.88(2H,d,J=8.2Hz).
実施例３３０
３，６−ジメチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1672, 1599, 1549, 1487, 1331, 1276, 1167, 1113, 1063, 928, 802, 766 cm^-1.
¹H-NMR(CDCl₃)δ：2.12(3H,s), 3.10(3H,s), 5.58(2H,s), 6.62(1H,d,J=6.4Hz),7.24(1H,d,J=9.0Hz), 7.38(1H,dd,J=9.0, 6.4Hz), 7.58(2H,d,J=8.4Hz), 7.75(2H,d,J=8.4Hz), 7.82(2H,d,J=8.4Hz), 7.89(2H,d,J=8.4Hz).
【０３８０】
実施例３３１
３，６−ジメチル−２−〔４−（４−（４−フルオロフェニル）ピペラジノカルボニル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1678, 1632, 1595, 1487, 1444, 1331, 1282, 1234, 1163, 1012, 808 cm^-1.
¹H-NMR(CDCl₃)δ：2.10(3H,s), 3.10(3H,s), 3.11(4H,brs), 3.63(2H,brs), 3.87(2H,brs), 5.51(2H,s), 6.62(1H,d,J=7.2Hz), 6.88(2H,dd,J=8.7, 4.8Hz), 6.96(2H,d,J=8.0Hz), 7.24(1H,d,J=7.0Hz), 7.39(1H,dd,J=7.2, 6.6Hz), 7.44(2H,d,J=8.0Hz), 7.49(2H,d,J=8.7Hz).
実施例３３２
３，６−ジメチル−２−〔４−（４−（２−ピリジル）ピペラジノカルボニル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1674, 1632, 1595, 1551, 1485, 1435, 1375, 1332, 1279, 1238, 1163, 1010, 764 cm^-1.
¹H-NMR(CDCl₃)δ：2.10(3H,s), 3.10(3H,s), 3.59(6H,brs), 3.85(2H,brs), 5.52(2H,s), 6.61-6.71(3H,m), 7.24(1H,d,J=9.0Hz), 7.35-7.59(6H,m), 8.20(1H,d,J=5.4Hz), 7.39(1H,dd,J=7.2, 6.6Hz), 7.44(2H,d,J=8.0Hz), 7.49(2H,d,J=8.7Hz).
【０３８１】
実施例３３３
１−〔４−（４−クロロベンゾイル）ベンジル〕−１，６，７，８，９，１０−ヘキサヒドロシクロペント〔d〕イミダゾ〔１，２−ａ〕−ピリミジン−５−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：2918, 1655, 1584, 1520, 1308, 1277, 1190, 1090, 928, 696 cm^-1.
¹H-NMR(CDCl₃)δ：1.50-1.80(5H,m), 1.84(1H,m), 2.80-2.91(4H,m), 5.34(2H,s), 6.85(1H,d,J=2.6Hz), 7.40(2H,d,J=8.0Hz), 7.46(2H,d,J=8.4Hz), 7.56(1H,d,J=2.6Hz), 7.74(2H,d,J=8.4Hz), 7.77(2H,d,J=8.0Hz).
実施例３３４
１−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−１，６，７，８−テトラヒドロ−５Ｈ−シクロペント〔d〕イミダゾ〔１，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1657, 1570, 1520, 1475, 1327, 1277, 1167, 1128, 1063, 700 cm^-1.
¹H-NMR(CDCl₃)δ：2.15(2H,m), 2.90(2H,t,J=6.4Hz), 2.94(2H,t,J=7.4Hz), 5.37(2H,s), 6.89(1H,d,J=2.6Hz), 7.41(2H,d,J=8.2Hz), 7.63(1H,d,J=2.6Hz), 7.76(2H,d,J=8.2Hz), 7.82(2H,d,J=8.2Hz), 7.88(2H,d,J=8.2Hz).
【０３８２】
実施例３３５
１−〔４−（４−フルオロベンゾイル）ベンジル〕−１，６，７，８−テトラヒドロ−５Ｈ−シクロペント〔d〕イミダゾ〔１，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν:1664, 1581, 1525, 1410, 1279, 1225, 1151, 928, 852, 736 cm^-1.
¹H-NMR(CDCl₃)δ：2.13(2H,m), 2.90(2H,t,J=7.1Hz), 2.94(2H,t,J=7.1Hz), 5.36(2H,s), 6.88(1H,d,J=2.6Hz), 7.17(2H,d,J=8.7Hz), 7.39(1H,d,J=7.8Hz), 7.62(1H,d,J=2.6Hz), 7.65(2H,d,J=7.8Hz), 7.83(2H,dd,J=8.7, 5.4Hz).
実施例３３６
１−〔４−（４−フルオロベンゾイル）ベンジル〕−１，６，７，８，９，１０−ヘキサヒドロシクロペント〔d〕イミダゾ〔１，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1655, 1587, 1522, 1277, 1227, 930, 860, 739, 704 cm^-1.
¹H-NMR(CDCl₃)δ：1.50-1.72(4H,m), 1.80-2.00(2H,m), 2.86-2.91(4H,m), 5.34(2H,s), 6.86(1H,d,J=2.6Hz), 7.16(2H,d,J=8.8Hz), 7.41(2H,d,J=7.8Hz), 7.56(1H,d,J=2.6Hz), 7.78(2H,d,J=7.8Hz), 7.83(2H,dd,J=8.8, 5.6Hz).
【０３８３】
実施例３３７
１−〔４−（４−クロロベンゾイル）ベンジル〕−７−メチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1676, 1657, 1580, 1533, 1423, 1277, 1165, 1088, 926, 835, 746, 685 cm^-1.
¹H-NMR(CDCl₃)δ：2.93(3H,s), 5.36(2H,s), 5.97(1H,s), 6.88(1H,d,J=2.8Hz),7.41(2H,d,J=8.2Hz), 7.46(2H,d,J=9.0Hz), 7.59(1H,d,J=2.8Hz), 7.71(2H,d,J=9.0Hz), 7.78(2H,d,J=8.2Hz).
実施例３３８
１−〔４−（４−クロロベンゾイル）ベンジル〕−６，７−ジエチルイミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1655, 1576, 1460, 1412, 1360, 1275, 1207, 1169, 1084, 933, 734, 698 cm^-1.
¹H-NMR(CDCl₃)δ：1.16(3H,t,J=7.4Hz), 1.28(3H,t,J=7.4Hz), 2.66(2H,q,J=7.4Hz), 2.71(2H,q,J=7.4Hz), 5.33(2H,s), 6.87(1H,d,J=2.6Hz), 7.44(2H,d,J=8.0Hz), 7.46(2H,d,J=8.4Hz), 7.54(1H,d,J=2.6Hz), 7.73(2H,d,J=8.0Hz), 7.77(2H,d,J=8.4Hz).
【０３８４】
実施例３３９
６，７−ジエチル−１−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1668, 1585, 1514, 1410, 1331, 1115, 1066, 931, 847, 769, 706cm^-1.
¹H-NMR(CDCl₃)δ：1.16(3H,t,J=7.4Hz), 1.28(3H,t,J=7.4Hz), 2.66(2H,q,J=7.4Hz), 2.71(2H,q,J=7.4Hz), 5.33(2H,s), 6.87(1H,d,J=2.6Hz), 7.46(2H,d,J=8.4Hz), 7.54(1H,d,J=2.6Hz), 7.75(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 7.88(2H,d,J=8.4Hz).
実施例３４０
１−〔４−（４−クロロベンゾイル）ベンジル〕−７−メチル−６−プロピル−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν:1655, 1585, 1518, 1412, 1273, 1213, 1086, 924, 733, 698 cm^-1.
¹H-NMR(CDCl₃)δ：1.00(3H,t,J=7.4Hz), 1.58(2H,m), 2.43(3H,s), 2.60(2H,t,J=7.0Hz), 5.33(2H,s), 6.84(1H,d,J=2.6Hz), 7.41(2H,d,J=8.0Hz), 7.46(2H,d,J=8.8Hz), 7.54(1H,d,J=2.6Hz), 7.74(2H,d,J=8.8Hz), 7.78(2H,d,J=8.0Hz).
【０３８５】
実施例３４１
７−メチル−６−プロピル−１−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−イミダゾ〔１，２−ａ〕ピリミジン−５（１Ｈ）−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1655, 1578, 1520, 1414, 1321, 1279, 1221, 1176, 1140, 1065, 931, 708 cm^-1.
¹H-NMR(CDCl₃)δ：1.00(3H,t,J=7.8Hz), 1.55(2H,m), 2.43(3H,s), 2.60(2H,t,J=7.6Hz), 5.34(2H,s), 6.85(1H,d,J=2.6Hz), 7.42(2H,d,J=8.4Hz), 7.54(1H,d,J=2.6Hz), 7.75(2H,d,J=8.4Hz), 7.81(2H,d,J=8.0Hz), 7.88(2H,d,J=8.0Hz).
実施例３４２
３，５−ジメチル−２−〔４−（４−ホルミルピペラジニルカルボニル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1670, 1558, 1458, 1095, 1004 cm^-1.
¹H-NMR(CDCl₃)δ: 2.85(3H,s), 3.27-3.82(8H,m), 3.54(3H,s), 4.56(2H,s), 7.16(1H,d,J=6.7Hz), 7.34-7.60(6H,m), 8.11(1H,s).
【０３８６】
実施例３４３
３，５−ジメチル−２−〔４−（４−メチルピペラジニルカルボニル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1683, 1473, 1307, 1093 cm^-1.
¹H-NMR(CDCl₃)δ：2.82(3H,s), 2.85(3H,s), 3.53(3H,s), 2.60-4.21(8H,m), 4.55(2H,s), 7.16(1H,d,J=7.4Hz), 7.35-7.47(3H,m), 7.50-7.63(3H,m).
実施例３４４
３，５−ジメチル−２−〔４−〔４−（２−ヒドロキシエチル）ピペラジニルカルボニル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン塩酸塩
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1668, 1558, 1471, 1093, 989, 806 cm^-1.
¹H-NMR(CDCl₃)δ：2.75(3H,s), 3.00-3.86(15H,m), 4.60(2H,s), 7.21(1H,d,J=7.2Hz), 7.38-7.68(6H,m).
【０３８７】
実施例３４５
３，５−ジメチル−２−〔４−〔４−（２−ピリジル）ピペラジニルカルボニル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1677, 1625, 1592, 1305, 1095, 1012 cm^-1.
¹H-NMR(CDCl₃)δ：2.85(3H,s), 3.30-4.06(8H,m), 3.54(3H,s), 4.56(2H,s), 6.68(2H,m), 7.15(1H,d,J=6.6Hz), 7.36-7.60(7H,m), 8.20(1H,m).
実施例３４６
３，５−ジメチル−２−〔４−（４−ピペロニルピペラジニルカルボニル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1675, 1556, 1307, 1093, 1039 cm^-1.
¹H-NMR(CDCl₃)δ：2.26-2.58(4H,m), 2.84(3H,s), 3.30-3.56(2H,brs), 3.43(2H,s), 3.53(3H,s), 3.62-3.84(2H,brs), 4.54(2H,s), 5.94(2H,s), 6.73(2H,s), 6.84(1H,s), 7.14(1H,d,J=7.6Hz), 7.35(2H,d,J=8.2Hz), 7.39-7.58(4H,m).
【０３８８】
実施例３４７
２−〔４−（４−ベンジルピペラジニルカルボニル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1675, 1616, 1456, 1305, 1095, 933 cm^-1.
¹H-NMR(CDCl₃)δ：2.30-2.58(4H,m), 2.84(3H,s), 3.30-3.60(2H,m), 3.53(5H,s), 3.66-3.86(2H,m), 4.53(2H,s), 7.14(1H,d,J=7.0Hz), 7.24-7.58(11H,m).
実施例３４８
３，５−ジメチル−２−〔４−〔４−（４−フルオロフェニル）ピペラジニルカルボニル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1683, 1629, 1095, 1014 cm^-1.
¹H-NMR(CDCl₃)δ：2.85(3H,s), 2.80-3.24(4H,m), 3.54(3H,s), 3.30-4.04(4H,m), 4.55(2H,s), 6.83-7.04(4H,m), 7.15(1H,d,J=6.6Hz), 7.36-7.60(6H,m).
【０３８９】
実施例３４９
３，５−ジメチル−２−〔４−〔４−（２−ピリミジル）ピペラジニルカルボニル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1675, 1627, 1585, 1510, 1307, 1089 cm^-1.
¹H-NMR(CDCl₃)δ：2.85(3H,s), 3.38-4.02(8H,m), 3.54(3H,s), 4.56(2H,s), 6.55(1H,t,J=4.7H), 7.15(1H,d,J=6.6Hz), 7.41(2H,d,J=8.2Hz), 7.44(1H,d,J=8.2Hz), 7.50-7.59(3H,m), 8.33(2H,d,J=4.7Hz).
実施例３５０
３，５−ジメチル−２−（４−モルホリノカルボニルベンジルチオ）−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1670, 1629, 1550, 1427, 1112, 894 cm^-1.
¹H-NMR(CDCl₃)δ：2.85(3H,s), 3.30-3.89(8H,m), 3.53(3H,s), 4.54(2H,s), 7.15(1H,d,J=6.6Hz), 7.37(2H,d,J=8.4Hz), 7.43(1H,d,J=8.0Hz), 7.49-7.59(3H,m).
【０３９０】
実施例３５１
３，５−ジメチル−２−〔３−（４−メチルピペラジニルカルボニル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様に合成した。
IR(KBr)ν：1685, 1579, 1560, 1461, 1423, 1089 cm^-1.
¹H-NMR(CDCl₃)δ：2.28(3H,s), 2.10-2.58(4H,m), 2.84(3H,s), 3.26-3.55(2H,m), 3.53(3H,s), 3.86-3.60(2H,m), 4.54(2H,s), 7.14(1H,d,J=7.2Hz), 7.26-7.58(6H,m).
実施例３５２
２−〔４−（４−ヒドロキシメチルピペリジルカルボニル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２−〔４−（４−エトキシカルボニルピペリジルカルボニル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（３.５９３ｇ）をＴＨＦ（２５ml）に溶解し、ＬiＢＨ₄（２５４mg）を加えて３０分撹拌させた。１Ｎ塩酸および飽和食塩水で洗浄、乾燥後濃縮し、得られた残渣を酢酸エチルにて洗浄し、無色固体の表題化合物（１.８７１ｇ）を得た。
IR(KBr)ν：1668, 1601, 1558, 1471, 1450, 1307, 1097 cm^-1.
¹H-NMR(CDCl₃)δ：1.04-1.90(6H,m), 2.85(3H,s), 2.66-3.20(2H,m), 3.53(5H,s), 3.56-3.96(1H,s), 4.54(2H,s), 4.55-5.00(1H,m), 7.15(1H,d,J=7.0Hz), 7.35(2H,d,J=8.2Hz), 7.43(2H,d,J=7.2Hz), 7.46-7.58(6H,m).
【０３９１】
実施例３５３
２−〔４−（４−ブロモメチルピペリジルカルボニル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシメチルピペリジルカルボニル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（１.０８１ｇ）をジクロロメタン（２５ml）に溶解し、四臭化炭素（１.０５０ｇ）を加え、１０分かけてトリフェニルホスフィン（９８２mg）を加え、室温にて２時間撹拌させた。塩をろ別後濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）にて精製し、エーテルで洗浄して無色固体の表題化合物（４９６mg）を得た。
IR(KBr)ν：1666, 1550, 1435, 1305, 1095, 964 cm^-1.
¹H-NMR(CDCl₃)δ：1.08-1.50(2H,m), 1.75-2.06(3H,m), 2.85(3H,s), 2.50-3.14(2H,m), 3.32(2H,d,J=5.8Hz), 3.53(3H,s), 3.64-3.96(1H,m), 4.55(2H,s), 4.60-4.90(1H,m), 7.15(1H,d,J=7.0Hz), 7.34-7.60(6H,m).
【０３９２】
実施例３５４
３，５−ジメチル−２−〔４−（４−イソニコチノイルオキシメチルピペリジルカルボニル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
２−〔４−（４−ヒドロキシメチルピペリジルカルボニル）ベンジルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン（４１５mg）をＤＭＦ（１５ml）に溶解し、イソニコチン酸クロリド塩酸塩（２７０mg）を加え、５分かけてトリエチルアミン（０.４０ml）を加え、室温にて３時間撹拌させた。反応液を濃縮し、水および飽和重曹水溶液および飽和食塩水で洗浄、乾燥後濃縮した。ヘキサン／酢酸エチルから再結晶して無色固体の表題化合物（２４１mg）を得た。
IR(KBr)ν：1718, 1668, 1560, 1295, 1099 cm^-1.
¹H-NMR(CDCl₃)δ：1.16-2.22(5H,m), 2.85(3H,s), 2.56-3.20(2H,m), 3.53(3H,s), 3.55-4.04(1H,m), 4.26(2H,d,J=6.4Hz), 4.55(2H,s), 4.40-5.00(1H,m), 7.15(1H,d,J=7.2Hz), 7.31-7.60(6H,m), 7.83(2H,d,J=5.8Hz), 8.80(2H,d,J=5.8Hz).
【０３９３】
実施例３５５
３，５−ジメチル−２−〔４−〔４−〔４−（４−フルオロフェニル）ピペラジニルカルボニル〕ピペリジルカルボニル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1672, 1550, 1434, 1307, 1226 cm^-1.
¹H-NMR(CDCl₃)δ：1.54-1.92(6H,m), 2.85(3H,s), 2.70-3.16(7H,m), 3.53(3H,s), 3.60-3.82(4H,m), 4.54(2H,s), 6.84-7.04(4H,m), 7.14(1H,d,J=8.8Hz), 7.33-7.59(6H,m).
実施例３５６
３，５−ジメチル−２−〔４−（４−モルホリノカルボニルピペリジルカルボニル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１８４と同様にして合成した。
IR(KBr)ν：1731, 1681, 1556, 1411, 1272, 1085 cm^-1.
¹H-NMR(CDCl₃)δ：1.54-1.94(6H,m), 2.85(3H,s), 2.60-3.12(3H,m), 3.53(3H,s), 3.67(9H,m), 4.54(2H,m), 7.15(1H,d,J=7.2Hz), 7.33-7.59(6H,m).
【０３９４】
実施例３５７
２−〔５−〔２−〔４−（４−トリフルオロメチルフェニル）ピペラジニルカルボニル〕ピラジル〕メチルチオ〕−３，５−ジメチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１８４と同様にして合成した。
IR(KBr)ν：1675, 1558, 1448, 1307, 1116 cm^-1.
¹H-NMR(CDCl₃)δ：2.84(3H,s), 3.22(2H,m), 3.34(2H,m), 3.81(2H,m), 3.97(2H,m), 4.67(2H,s), 7.00-7.20(4H,m), 7.30-7.48(2H,m), 7.55(1H,t,J=7.6Hz), 8.87(1H,s), 8.96(1H,s).
実施例３５８
８−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−３，４−ジヒドロ−７−メチル−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1649, 1589, 1500, 1390, 1274 cm^-1.
¹H-NMR(CDCl₃)δ：1.99(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.9Hz), 4.10(2H,t,J=5.9Hz), 5.42(2H,s), 7.49(4H,m), 7.77(4H,m).
【０３９５】
実施例３５９
３，４−ジヒドロ−８−〔４−（４−フルオロベンゾイル）ベンジルオキシ〕−７−メチル−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1625, 1580, 1500, 1266, 1118 cm^-1.
¹H-NMR(CDCl₃)δ：1.99(3H,s), 2.59(2H,m), 3.17(2H,t,J=5.9Hz), 4.10(2H,t,J=5.9Hz), 5.42(2H,s), 7.17(2H,m), 7.52(2H,d,J=8.6Hz), 7.82(4H,m).
実施例３６０
３，４−ジヒドロ−７−メチル−８−〔４−（４−トリフルオロメチルベンゾイル）ベンジルオキシ〕−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1654, 1591, 1498, 1326, 1187, 1122 cm^-1.
¹H-NMR(CDCl₃)δ：1.99(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 4.10(2H,t,J=5.8Hz), 5.43(2H,s), 7.54(2H,d,J=8.4Hz), 7.84(6H,m).
【０３９６】
実施例３６１
３−メチル−２−〔４−〔４−（４−フルオロフェニル）ピペラジニルカルボニル〕ベンジルチオ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1673, 1633, 1510, 1284, 1236, 1170 cm^-1.
¹H-NMR(CDCl₃)δ: 2.21(3H,s), 2.90-3.26(4H,m), 3.42-4.04(4H,m), 5.57(2H,s), 6.82-7.16(5H,m), 7.50(5H,m), 7.70(1H,m), 9.08(1H,m).
実施例３６２
３−メチル−２−〔４−〔４−（２−ピリジル）ピペラジニルカルボニル〕ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1679, 1627, 1484, 1284, 1170 cm^-1.
¹H-NMR(CDCl₃)δ：2.22(3H,s), 3.44-4.06(8H,m), 5.57(2H,s), 6.69(2H,m), 7.11(1H,m), 7.48(6H,m), 7.71(1H,m), 8.21(1H,m), 9.08(1H,d,J=6.4Hz).
【０３９７】
実施例３６３
３−メチル−２−〔４−〔４−（２−ピリジル）ピペラジニルカルボニル〕ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1660, 1527, 1479, 1241, 1155 cm^-1.
¹H-NMR(CDCl₃)δ：1.80-2.08(4H,m), 2.01(3H,s), 2.84(2H,t,J=6.1Hz), 3.40-4.04(8H,m), 3.95(2H,t,J=6.1Hz), 5.40(2H,s), 6.69(2H,m), 7.40-7.58(5H,m), 8.21(1H,dd,J=1.8, 5.6Hz).
実施例３６４
８−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３，４−ジヒドロ−７−メチル−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1647, 1496, 1398, 1286 cm^-1.
¹H-NMR(CDCl₃)δ：2.00(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 4.07(2H,t,J=5.8Hz), 4.40(2H,s), 7.40-7.56(4H,m), 7.68-7.80(4H,m).
【０３９８】
実施例３６５
３，４−ジヒドロ−７−メチル−８−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1641, 1546, 1494, 1326, 1166, 1130 cm^-1.
¹H-NMR(CDCl₃)δ：2.00(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 4.07(2H,t,J=5.8Hz), 4.40(2H,s), 7.53(2H,d,J=8.2Hz), 7.76(4H,d,J=8.2Hz), 7.89(2H,d,J=8.2Hz).
実施例３６６
３，４−ジヒドロ−８−〔４−（４−フルオロベンゾイル）ベンジルチオ〕−７−メチル−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1646, 1596, 1498, 1396, 1155 cm^-1.
¹H-NMR(CDCl₃)δ：2.00(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 4.07(2H,t,J=5.8Hz), 4.40(2H,s), 7.08-7.23(2H,m), 7.51(2H,d,J=8.3Hz), 7.72(2H,d,J=8.3Hz), 7.76-7.96(2H,m).
【０３９９】
実施例３６７
３，５−ジメチル−２−〔４−〔４−〔Ｎ−〔２−（２−ピリジル）エチル〕−Ｎ−メチルアミノカルボニル〕ピペリジルカルボニル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１８４と同様にして合成した。
IR(KBr)ν：1675, 1556, 1434, 1307 cm^-1.
¹H-NMR(CDCl₃)δ：1.48-1.84(7H,m), 2.85(3H,s), 2.97(3H,s), 2.46-3.10(4H,m), 3.53(3H,s), 3.77(2H,m), 4.54(2H,s), 7.06-7.25(2H,m), 7.30-7.66(8H,m),8.54(1H,m).
実施例３６８
１−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−１，６，７，８，９，１０−ヘキサヒドロシクロペント〔d〕イミダゾ〔１，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：1654, 1581, 1326, 1278 cm^-1.
¹H-NMR(CDCl₃)δ：1.50-1.95(6H,m), 2.88(4H,m), 5.35(2H,s), 6.87(1H,d,J=2.7Hz), 7.43(2H,d,J=8.4Hz), 7.57(1H,d,J=2.7Hz), 7.72-7.92(6H,m).
【０４００】
実施例３６９
３，４−ジヒドロ−８−〔４−（４−メトキシベンゾイル）ベンジルオキシ〕−７−メチル−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1654, 1504, 1257, 1170, 1128 cm^-1.
¹H-NMR(CDCl₃)δ：1.99(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 3.89(3H,s),4.10(2H,t,J=5.8Hz), 5.42(2H,s), 6.97(2H,d,J=8.3Hz), 7.51(2H,d,J=8.3Hz), 7.73-7.84(4H,m).
実施例３７０
３−メチル−２−〔４−（４−シアノベンゾイル）ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１６３と同様にして合成した。
IR(KBr)ν：2227, 1658, 1535, 1276, 1149 cm^-1.
¹H-NMR(CDCl₃)δ：1.78-2.03(4H,m), 2.02(3H,s), 2.83(2H,t,J=6.4Hz), 3.95(2H,t,J=6.2Hz), 5.46(2H,s), 7.55(2H,d,J=8.4Hz), 7.75-7.93(6H,m).
【０４０１】
実施例３７１
６−メチル−７−〔４−（４−シアノベンゾイル）ベンジルオキシ〕−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：2231, 1600, 1523, 1392, 1278, 1143 cm^-1.
¹H-NMR(CDCl₃)δ：1.97(3H,s), 3.47(2H,t,J=7.7Hz), 4.47(2H,t,J=7.7Hz), 5.44(2H,s), 7.53(2H,d,J=8.0Hz), 7.75-7.92(6H,m).
実施例３７２
３，４−ジヒドロ−８−〔４−（４−ヒドロキシベンゾイル）ベンジルオキシ〕−７−メチル−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1645, 1585, 1498, 1278 cm^-1.
¹H-NMR(CDCl₃)δ：1.85(3H,s), 2.14(2H,m), 3.21(2H,m), 3.95(2H,m), 5.40(2H,s), 6.89(2H,d,J=8.6Hz), 7.54(2H,d,J=8.4Hz), 7.64-7.72(4H,m).
【０４０２】
実施例３７３
３，４−ジヒドロ−８−〔４−〔４−（Ｎ，Ｎ−ジメチルカルバモイルオキシ）ベンゾイル〕ベンジルオキシ〕−７−メチル−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1718, 1654, 1502, 1390, 1270 cm^-1.
¹H-NMR(CDCl₃)δ：1.99(3H,s), 2.26(2H,m), 3.05(3H,s), 3.13(3H,s), 3.17(2H,m), 4.10(2H,t,J=5.6Hz), 5.42(2H,s), 7.25(2H,d,J=9.0Hz), 7.52(2H,d,J=8.4Hz), 7.82(4H,m).
実施例３７４
３−メチル−２−〔４−（４−アセトキシベンゾイル）ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1758, 1646, 1527, 1199 cm^-1.
¹H-NMR(CDCl₃)δ：1.89(4H,m), 2.02(3H,s), 2.35(3H,s), 2.84(2H,t,J=6.2Hz),3.94(2H,t,J=6.2Hz), 5.45(2H,s), 5.42(2H,s), 7.22(2H,d,J=8.8Hz), 7.52(2H,d,J=8.4Hz), 7.76-7.90(4H,m).
【０４０３】
実施例３７５
３−メチル−２−〔４−（４−ヒドロキシベンゾイル）ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１４７と同様にして合成した。
IR(KBr)ν：1735, 1635, 1510, 1280, 1149 cm^-1.
¹H-NMR(CDCl₃)δ：1.81(4H,m), 1.87(3H,s), 2.81(2H,t,J=6.3Hz), 3.79(2H,t,J=5.9Hz), 5.46(2H,s), 6.90(2H,d,J=8.6Hz), 7.56(2H,d,J=8.2Hz), 7.62-7.73(4H,m).
実施例３７６
３−メチル−２−〔４−〔４−（Ｎ，Ｎ−ジメチルカルバモイルオキシ）ベンゾイル〕ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例２２８と同様にして合成した。
IR(KBr)ν：1716, 1658, 1602, 1527, 1396 cm^-1.
¹H-NMR(CDCl₃)δ：1.92(4H,m), 2.03(3H,s), 2.84(2H,t,J=6.3Hz), 3.05(3H,s),3.14(3H,s), 3.95(2H,t,J=6.3Hz), 5.45(2H,s), 7.25(2H,d,J=8.5Hz), 7.52(2H,d,J=8.5Hz), 7.82(4H,m).
【０４０４】
実施例３７７
３−メチル−２−〔４−（４−メチルピペラジニルカルボニル）ベンジルチオ〕−チエノ〔３，２−ｄ〕ピリミジン−４（３Ｈ）−オン塩酸塩
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1665, 1640, 1530, 1500, 1410, 1280, 1260 cm^-1.
¹H-NMR(DMSO-d₆)δ：2.80(3H,brs), 3.00-3.90(8H,m), 3.51(3H,s), 4.59(2H,s), 7.37(1H,d,J=5.2Hz), 7.43(2H,d,J=8.2Hz), 7.62(2H,d,J=8.2Hz), 8.16(1H,d,J=5.2Hz).
実施例３７８
３，６−ジメチル−７−〔４−（４−メチルピペラジニルカルボニル）ベンジルオキシ〕−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン塩酸塩
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1680, 1650, 1630, 1565, 1500 cm^-1.
¹H-NMR(DMSO-d₆)δ：1.90(3H,s), 2.69(3H,d,J=1.2Hz), 3.78(3H,s), 3.00-3.90(8H,m), 5.44(2H,s), 6.98(1H,d,J=1.2Hz), 7.48(2H,d,J=8.2Hz), 7.54(2H,d,J=8.2Hz).
【０４０５】
実施例３７９
３−メチル−２−〔４−（４−メチルピペラジニルカルボニル）ベンジルオキシ〕−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン塩酸塩
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1670, 1630, 1470, 1420 cm^-1.
¹H-NMR(DMSO-d₆)δ：2.07(3H,s), 2.80(3H,s), 3.00-3.85(8H,m), 5.57(2H,s), 7.15-7.70(6H,m), 8.00(1H,m), 5.97(1H,d,J=7.4Hz).
実施例３８０
３，５−ジメチル−２−〔４−〔４−（２−ピペリジノエチル）ピペラジニルカルボニル〕ベンジルチオ〕−４（３Ｈ）−キナゾリノン２塩酸塩
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1675, 1640, 1550, 1450, 1420 cm^-1.
¹H-NMR(DMSO-d₆＋D₂O)δ：1.50-1.85(6H,m), 2.75(3H,s), 2.95-4.15(16H,m), 3.59(3H,s), 4.59(2H,s), 7.22(1H,d,J=7.0Hz), 7.37-7.70(6H,m).
【０４０６】
実施例３８１
３，５−ジメチル−２−〔４−（４−シンナミルピペラジニルカルボニル）ベンジルチオ〕−４（３Ｈ）−キナゾリノン塩酸塩
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1675, 1630, 1550, 1420 cm^-1.
¹H-NMR(DMSO-d₆)δ：2.75(3H,s), 2.90-3.55(8H,m), 3.44(3H,s), 3.90(2H,m), 4.60(2H,s), 6.39(1H,dt,J=15.8, 7.0Hz), 6.83(1H,d,J=15.8Hz), 7.21(1H,d,J=7.4Hz), 7.30-7.70(11H,m).
実施例３８２
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−５−メチル−４（３Ｈ）−キナゾリノン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1670, 1585, 1560 cm^-1.
¹H-NMR(DMSO-d₆)δ：2.73(3H,s), 4.57(2H,s), 7.18(1H,d,J=7.2Hz), 7.44(1H,d,J=7.2Hz), 7.55-7.80(5H,m), 12.40(1H,brs).
【０４０７】
実施例３８３
２−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−３−メチル−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1650, 1640, 1595, 1520, 1135 cm^-1.
¹H-NMR(CDCl₃)δ：1.75-2.05(4H,m), 2.02(3H,s), 2.83(2H,t,J=6.8Hz), 3.95(2H,t,J=6.0Hz), 5.46(2H,s), 7.47(2H,d,J=8.6Hz), 7.52(2H,d,J=8.4Hz), 7.76(2H,d,J=8.6Hz), 7.78(2H,d,J=8.4Hz).
実施例３８４
２−〔４−（４−フルオロベンゾイル）ベンジルオキシ〕−３−メチル−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1650, 1640, 1590, 1525, 1270, 1130 cm^-1.
¹H-NMR(CDCl₃)δ：1.80-2.05(4H,m), 2.02(3H,s), 2.84(2H,t,J=6.4Hz), 3.95(2H,t,J=6.0Hz), 5.46(2H,s), 7.17(2H,t,J=8.6Hz), 7.52(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz), 7.86(2H,dd,J=8.6, 5.6Hz).
【０４０８】
実施例３８５
３−メチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1655, 1605, 1325, 1145 cm^-1.
¹H-NMR(CDCl₃)δ：1.80-2.00(4H,m), 2.02(3H,s), 2.83(2H,t,J=6.6Hz), 3.95(2H,t,J=6.0Hz), 5.47(2H,s), 7.54(2H,d,J=8.0Hz), 7.76(2H,d,J=8.6Hz), 7.82(2H,d,J=8.6Hz), 7.90(2H,d,J=8.0Hz).
実施例３８６
２−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−３，６−ジメチル−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1650, 1640, 1600, 1520, 1135 cm^-1.
¹H-NMR(CDCl₃)δ：1.34(3H,d,J=6.6Hz), 1.80-2.05(4H,m), 2.02(3H,s), 2.86(2H,m), 4.95(1H,m), 5.44(2H,s), 7.47(2H,d,J=8.6Hz), 7.52(2H,d,J=8.6Hz), 7.76(2H,d,J=8.6Hz), 7.78(2H,d,J=8.6Hz).
【０４０９】
実施例３８７
３，６−ジメチル−２−〔４−（４−フルオロベンゾイル）ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1650, 1595, 1520, 1270, 1135 cm^-1.
¹H-NMR(CDCl₃)δ：1.34(3H,d,J=6.6Hz), 1.80-2.05(4H,m), 2.02(3H,s), 2.65-3.00(2H,m), 4.96(1H,m), 5.44(2H,s), 7.16(2H,t,J=8.6Hz), 7.52(2H,d,J=8.4Hz), 7.77(2H,d,J-8.4Hz), 7.85(2H,dd,J=8.6, 5.4Hz).
実施例３８８
３，６−ジメチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1655, 1645, 1605, 1525, 1325, 1130 cm^-1.
¹H-NMR(CDCl₃)δ：1.34(3H,d,J=6.6Hz), 1.80-2.05(4H,m), 2.02(3H,s), 2.65-3.00(2H,m), 4.96(1H,m), 5.45(2H,s), 7.54(2H,d,J=8.0Hz), 7.76(2H,d,J=8.6Hz), 7.82(2H,d,J=8.6Hz), 7.90(2H,d,J=8.0Hz).
【０４１０】
実施例３８９
７−〔４−（４−フルオロベンゾイル）ベンジルオキシ〕−６−メチル−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1650, 1640, 1590, 1510, 1390, 1345, 1285, 1220, 1145 cm^-1.
¹H-NMR(CDCl₃)δ：1.98(3H,s), 3.47(2H,t,J=7.8Hz), 4.47(2H,t,J=7.8Hz), 5.44(2H,s), 7.17(2H,t,J=8.6Hz), 7.51(2H,d,J=8.2Hz), 7.78(2H,d,J=8.2Hz), 7.86(2H,dd,J=8.6, 5.4Hz).
実施例３９０
７−〔４−（４−メトキシベンゾイル）ベンジルオキシ〕−６−メチル−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1650, 1640, 1595, 1515, 1390, 1255 cm^-1.
¹H-NMR(CDCl₃)δ：1.98(3H,s), 3.47(2H,t,J=7.8Hz), 3.90(3H,s), 4.47(2H,t,J=7.8Hz), 5.43(2H,s), 6.97(2H,t,J=8.8Hz), 7.49(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 7.84(2H,d,J=8.8Hz).
【０４１１】
実施例３９１
６−メチル−７−〔４−（３，４，５−トリメトキシベンゾイル）ベンジルオキシ〕−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1645, 1595, 1580, 120 , 1390, 1330, 1230, 1125 cm^-1.
¹H-NMR(CDCl₃)δ：1.98(3H,s), 3.47(2H,t,J=7.8Hz), 3.88(6H,s), 3.94(3H,s),4.47(2H,t,J=7.8Hz), 5.44(2H,s), 7.07(2H,s), 7.51(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz).
【０４１２】
実施例３９２
７−〔４−（４−クロロベンゾイル）ベンジルチオ〕−６−メチル−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1645, 1545, 1500 cm^-1.
¹H-NMR(CDCl₃)δ(ppm)：1.99(3H,s), 3.45(2H,t,J=7.6Hz), 4.41(2H,s), 4.45(2H,t,J=7.6Hz), 7.45(2H,d,J=8.2Hz), 7.49(2H,d,J=8.0Hz), 7.72(2H,d,J=8.0Hz), 7.74(2H,d,J=8.2Hz).
実施例３９３
７−〔４−（４−フルオロベンゾイル）ベンジルチオ〕−６−メチル−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1645, 1600, 1595, 1550, 1500 cm^-1.
¹H-NMR(CDCl₃)δ(ppm)：1.99(3H,s), 3.45(2H,t,J=7.6Hz), 4.42(2H,s), 4.45(2H,t,J=7.6Hz), 7.16(2H,t,J=8.6Hz), 7.48(2H,d,J=8.2Hz), 7.72(2H,d,J=8.2Hz), 7.84(2H,dd,J=8.6, 5.4Hz),
【０４１３】
実施例３９４
２−〔４−（４−クロロベンゾイル）ベンジルチオ〕−３−メチル−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1645, 1605, 1560, 1520 cm^-1.
¹H-NMR(CDCl₃)δ：1.72-2.10(4H,m), 2.03(3H,s), 2.89(2H,t,J=6.2Hz), 3.92(2H,t,J=6.0Hz), 4.44(2H,s), 7.45(2H,d,J=8.6Hz), 7.50(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.74(2H,d,J=8.6Hz).
実施例３９５
３−メチル−２−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1645, 1560, 1520, 1320, 1160, 1120 cm^-1.
¹H-NMR(CDCl₃)δ：1.75-2.10(4H,m), 2.04(3H,s), 2.89(2H,t,J=6.3Hz), 3.92(2H,t,J=6.0Hz), 4.45(2H,s), 7.53(2H,d,J=8.2Hz), 7.75(4H,d,J=8.2Hz), 7.88(2H,d,J=8.2Hz).
【０４１４】
実施例３９６
２−〔４−（４−フルオロベンゾイル）ベンジルチオ〕−３−メチル−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1640, 1595, 1560, 1520, 1270, 1225 cm^-1.
¹H-NMR(CDCl₃)δ：1.80-2.10(4H,m), 2.04(3H,s), 2.90(2H,t,J=6.4Hz), 3.93(2H,t,J=5.9Hz), 4.45(2H,s), 7.16(2H,t,J=8.6Hz), 7.51(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.94(2H,dd,J=8.6, 5.4Hz).
実施例３９７
６−メチル−７−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1655, 1600, 1555, 1505, 1385, 1325, 1275, 1120, 1060 cm^-1.
¹H-NMR(CDCl₃)δ：1.99(3H,s), 3.46(2H,t,J=7.7Hz), 4.43(2H,s), 4.45(2H,t,J=7.7Hz), 7.51(2H,d,J=8.4Hz), 7.75(2H,d,J=8.2Hz), 7.76(2H,d,J=8.4Hz), 7.89(2H,d,J=8.2Hz).
【０４１５】
実施例３９８
３，６−ジメチル−７−〔４−（４−トリフルオロメチルベンゾイル）ベンジルチオ〕−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例１と同様にして合成した。
IR(KBr)ν：1660, 1650, 1530, 1485, 1320, 1170, 1110 cm^-1.
¹H-NMR(CDCl₃)δ：2.06(3H,s), 2.80(3H,d,J=1.2Hz), 4.49(2H,s), 6.35(1H,q,J=1.2Hz), 7.54(2H,d,J=8.2Hz), 7.75(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 7.88(2H,d,J=8.6Hz).
実施例３９９
２−〔２−〔４−（４−クロロベンゾイル）フェニル〕エチル〕−３−メチル−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
２−（２−フェニルエチル）−３−メチル−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン（１.０ｇ）のメチレンクロリド（１５ml）溶液に塩化アルミニウム（１.５１ｇ）を加え、つづいて４−クロロベンゾイルクロリド（９８０mg）のメチレンクロリド（５ml）溶液を加え室温で１５時間撹拌させた。反応液を１規定塩酸にあけ、酢酸エチルで抽出し、水、重曹水、食塩水で洗浄、乾燥後濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）にて精製し、ヘキサン・酢酸エチルから結晶化させて無色固体の表題化合物（４９５mg）を得た。
IR(KBr)ν：1650, 1600, 1530 cm^-1.
¹H-NMR(CDCl₃)δ：1.75-2.00(4H,m), 1.99(3H,s), 2.80-3.08(6H,m), 3.95(2H,t,J=6.0Hz), 7.33(2H,d,J=8.2Hz), 7.46(2H,d,J=8.6Hz), 7.71(2H,d,J=8.2Hz), 7.74(2H,d,J=8.6Hz).
【０４１６】
実施例４００
７−〔２−〔４−（４−クロロベンゾイル）フェニル〕エチル〕−６−メチル−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例３９９と同様にして合成した。
IR(KBr)ν：1650, 1510 cm^-1.
¹H-NMR(CDCl₃)δ：2.06(3H,s), 2.80(3H,d,J=1.2Hz), 4.49(2H,s), 6.35(1H,q,J=1.2Hz), 7.54(2H,d,J=8.2Hz), 7.75(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 7.88(2H,d,J=8.6Hz）．
実施例４０１
８−〔２−〔４−（４−クロロベンゾイル）フェニル〕エチル〕−７−メチル−３，４−ジヒドロ−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例３９９と同様にして合成した。
IR(KBr)ν：1645, 1500 cm^-1.
¹H-NMR(CDCl₃)δ：1.96(3H,s), 2.28(2H,m), 2.85(2H,m), 3.01(2H,m), 3.18(2H,t,J=6.0Hz), 4.10(2H,t,J=5.6Hz), 7.33(2H,d,J=8.2Hz), 7.47(2H,d,J=8.2Hz),7.71(2H,d,J=8.2Hz), 7.74(2H,d,J=8.2Hz).
【０４１７】
実施例４０２
６−メチル−７−〔４−（４−トリフルオロメチルベンゾイル）ベンジルオキシ〕−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1655, 1590, 1510, 1325, 1140 cm^-1.
¹H-NMR(CDCl₃)δ：1.98(3H,s), 3.48(2H,t,J=7.8Hz), 4.47(2H,t,J=7.8Hz), 5.45(2H,s), 7.53(2H,d,J=8.6Hz), 7.60-7.93(6H,m).
実施例４０３
２−〔４−（４−メトキシベンゾイル）ベンジルオキシ〕−３−メチル−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1660, 1645, 1600, 1530, 1280, 1255, 1150 cm^-1.
¹H-NMR(CDCl₃)δ：1.80-2.12(4H,m), 2.02(3H,s), 2.84(2H,t,J=6.4Hz), 3.90(3H,s), 3.95(2H,t,J=6.0Hz), 5.45(2H,s), 6.97(2H,d,J=8.8Hz), 7.51(2H,d,J=8.2Hz), 7.77(2H,d,J=8.2Hz), 7.84(2H,d,J=8.8Hz).
【０４１８】
実施例４０４
３−メチル−２−〔４−（４−メチルベンゾイル）ベンジルオキシ〕−６，７，８，９−テトラヒドロ−４Ｈ−ピリド〔１，２−ａ〕ピリミジン−４−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1650, 1600, 1530, 1270, 1145 cm^-1.
¹H-NMR(CDCl₃)δ：1.80-2.05(4H,m), 2.02(3H,s), 2.45(3H,s), 2.84(2H,t,J=6.5Hz), 3.94(2H,t,J=6.0Hz), 5.45(2H,s), 7.28(2H,d,J=8.4Hz), 7.50(2H,d,J=8.0Hz), 7.72(2H,d,J=8.0Hz), 7.79(2H,d,J=8.4Hz).
実施例４０５
６−メチル−７−〔４−（４−メチルベンゾイル）ベンジルオキシ〕−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1655, 1600, 1590, 1515, 1390, 1270 cm^-1.
¹H-NMR(CDCl₃)δ：1.98(3H,s), 2.45(3H,s), 3.47(2H,t,J=7.7Hz), 4.47(2H,t,J=7.7Hz), 5.43(2H,s), 7.29(2H,d,J=8.4Hz), 7.49(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.79(2H,d,J=8.4Hz).
【０４１９】
実施例４０６
７−メチル−８−〔４−（４−メチルベンゾイル）ベンジルオキシ〕−３，４−ジヒドロ−２Ｈ，６Ｈ−ピリミド〔２，１−ｂ〕〔１，３〕チアジン−６−オン
表題の化合物を実施例４０と同様にして合成した。
IR(KBr)ν：1645, 1585, 1495 cm^-1.
¹H-NMR(CDCl₃)δ：1.99(3H,s), 2.20-2.38(2H,m), 2.45(3H,s), 3.17(2H,t,J=6.0Hz), 4.10(2H,t,J=5.6Hz), 5.42(2H,s), 7.29(2H,d,J=8.2Hz), 7.51(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.79(2H,d,J=8.2Hz).
実施例４０７
３−エチル−２−メチルチオ−７−〔４−（３，４，５−トリメトキシベンゾイル）ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
表題の化合物を実施例４９と同様にして合成した。
¹H-NMR(CDCl₃)δ：1.36(3H,t,J=7.2Hz), 2.58(3H,s), 3.87(6H,s), 3.94(3H,s),4.22(2H,q,J=7.2Hz), 5.37(2H,s), 6.65(1H,d,J=3.4Hz), 6.77(1H,d,J=3.4Hz), 7.04(2H,s), 7.34(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【０４２０】
実施例４０８
７−〔４−（４−ｔ−ブチルジメチルシリルオキシベンゾイル）ベンジル〕−３−エチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
表題の化合物を実施例４９と同様にして合成した。
¹H-NMR(CDCl₃)δ：0.24(6H,s), 0.99(9H,s), 1.36(3H,t,J=7.2Hz), 2.57(3H,s),4.22(2H,q,J=7.2Hz), 5.35(2H,s), 6.65(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 6.89(2H,d,J=8.6Hz), 7.30(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.6Hz).
実施例４０９
３−エチル−７−〔４−（４−ヒドロキシベンゾイル）ベンジル〕−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
７−〔４−（４−ｔ−ブチルジメチルシリルオキシベンゾイル）ベンジル〕−３−エチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン（４.１０ｇ）をＴＨＦ（７６.８ml）に溶解し、１Ｍ−テトラブチルアンモニウムフルオライドのＴＨＦ溶液（７.６８ml）を加え３０分撹拌した。水を加えた後、ＴＨＦを留去し、酢酸エチルを加え分液した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒留去し、残渣をエーテルで微細化し濾取、エーテル、メタノール、ヘキサン洗浄後、乾燥することにより表題化合物（３.０ｇ）を結晶性粉末として得た。
¹H-NMR(Me₂SO-d₆)δ：1.24(3H,t,J=7.2Hz), 2.60(3H,s), 4.08(2H,q,J=7.2Hz), 5.41(2H,s), 6.47(1H,d,J=3.4Hz), 6.87(2H,d,J=8.6Hz), 7.19(1H,d,J=3.4Hz), 7.44(2H,d,J=8.0Hz), 7.63(2H,d,J=8.6Hz), 7.65(2H,d,J=8.0Hz).
【０４２１】
実施例４１０
７−〔４−〔４−（２−ジメチルアミノエトキシ）ベンゾイル〕ベンジル〕−３−エチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン・塩酸塩
表題の化合物を実施例１５６と同様にして合成した。
¹H-NMR（CDCl₃）δ：1.36(3H,t,J=7.2Hz), 2.35(6H,s), 2.58(3H,s), 2.76(2H,t,J=5.6Hz), 4.14(2H,t,J=5.6Hz), 4.22(2H,q,J=7.2Hz), 5.35(2H,s), 6.65(1H,d,H=3.4Hz), 6.75(1H,d,J=3.4Hz), 6.97(2H,d,J=8.8Hz), 7.30(2H,d,J=8.2Hz), 7.72(2H,d,J=8.2Hz), 7.79(2H,d,J=8.8Hz).
実施例４１１
３−エチル−２−メチルチオ−７−〔４−（４−ニコチノイルメトキシベンゾイル）ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
表題の化合物を実施例２３７と同様にして合成した。
¹H-NMR（CDCl₃）δ：1.23(3H,t,J=7.2Hz), 2.60(3H,s), 4.08(2H,q,J=7.2Hz), 5.42(2H,s), 5.78(2H,s), 6.47(1H,d,J=3.4Hz), 7.14(2H,d,J=8.8Hz), 7.20(1H,d,J=3.4Hz), 7.46(2H,d,J=8.2Hz), 7.59-7.64(1H,m), 7.69(2H,d,J=8.2Hz), 7.72(2H,d,J=8.8Hz), 8.32-8.39(1H,m), 8.88(1H,dd,J=1.6, 4.8Hz), 9.20(1H,d,J=1.6Hz).
【０４２２】
実施例４１２
３−エチル−２−メチルチオ−７−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン・塩酸塩
表題の化合物を実施例１５６と同様にして合成した。
¹H-NMR（CDCl₃）δ：1.36(3H,t,J=7.0Hz), 2.58(3H,s), 2.59(4H,t,J=4.7Hz), 2.84(2H,t,J=5.6Hz), 3.74(4H,t,J=4.7Hz), 4.19(2H,t,J=5.6Hz), 4.22(2H,q,J=7.0Hz), 5.35(2H,s), 6.66(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 6.96(2H,d,J=8.8Hz), 7.30(2H,d,J=8.2Hz), 7.72(2H,d,J=8.2Hz), 7.80(2H,d,J=8.8Hz).
実施例４１３
３−エチル−２−メチルチオ−７−〔４−〔４−（２−ピペリジノエトキシ）ベンゾイル〕ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン・塩酸塩
表題の化合物を実施例１５６と同様にして合成した。
¹H-NMR（CDCl₃）δ：1.36(3H,t,J=7.2Hz), 1.37-1.52(2H,m), 1.54-1.68(4H,m),2.51(4H,t,J=5.6Hz), 2.58(3H,s), 2.80(2H,t,J=6.2Hz), 4.18(2H,t,J=6.2Hz), 4.12(2H,q,J=7.2Hz), 5.35(2H,s), 6.65(1H,d,J=3.4Hz), 6.76(1H,d,J=3.4Hz), 6.96(2H,d,J=9.0Hz), 7.31(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.79(2H,d,J=9.0Hz).
【０４２３】
実施例４１４
７−〔４−（４−フルオロベンゾイル）ベンジル〕−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン
７−〔４−（４−フルオロベンゾイル）ベンジル〕−５−メチル−２−メチルチオ−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４（３Ｈ）−オン（７７５mg）をＤＭＥ（１００ml）、酢酸エチル（１００ml）、メタノール（８０ml）に溶解した。酢酸（２.５ml）を加えた後、ラネーニッケルを添加した。原料の消滅を確認し、触媒を濾去した。減圧下溶媒を留去し、エーテルにて結晶性粉末を微細化し、濾取、エーテル洗浄後、乾燥することにより表題化合物（５２９mg）を得た。
¹H-NMR(DMSO-d₆＋D₂O)δ：2.29(3H,s), 5.39(2H,s), 6.96(1H,s), 7.33(2H,d,J=8.1Hz), 7.37(2H,d,J=8.8Hz), 7.69(2H,d,J=8.1Hz), 7.80(2H,dd,J=5.6, 8.8Hz), 7.86(1H,s).
実施例４１５
３−エチル−７−〔４−（４−ヒドロキシベンゾイル）ベンジル〕−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
表題の化合物を実施例４９と同様にして合成した。
¹H-NMR（DMSO-d₆）δ：1.25(3H,t,J=7.2Hz), 2.30(3H,s), 3.96(2H,q,J=7.2Hz),5.366(2H,s), 6.87(2H,d,J=8.6Hz), 6.97(1H,s), 7.33(2H,d,J=8.2Hz), 7.63(4H,d,J=8.6Hz), 8.19(1H,s), 10.34(1H,s).
【０４２４】
実施例４１６
７−〔４−（６−クロロニコチノイル）ベンジル〕−３−エチル−５−メチル−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
表題の化合物を実施例４９と同様にして合成した。
¹H-NMR(CDCl₃)δ：1.41(3H,t,J=7.2Hz), 2.44(3H,d,J=1.0Hz), 4.05(2H,q,J=7.2Hz), 5.36(2H,s), 6.60(1H,d,J=1.0Hz), 7.30(2H,d,J=8.2Hz), 7.47(1H,d,J=8.4Hz), 7.75(2H,d,J=8.2Hz), 7.84(1H,s), 8.07(1H,dd,J=2.4, 8.4Hz), 8.74(1H,d,J=2.4Hz).
実施例４１７
３−エチル−５−メチル−７−〔４−（４−トリフルオロメチルベンゾイル）ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
表題の化合物を実施例４９と同様にして合成した。
¹H-NMR(CDCl₃)δ：1.41(3H,t,J=7.2Hz), 2.43(3H,s), 4.05(2H,q,J=7.2Hz), 5.35(2H,s), 6.59(1H,s), 7.28(2H,d,J=8.6Hz), 7.74(2H,d,J=8.0Hz), 7.76(2H,d,J=8.0Hz), 7.83(1H,s), 7.87(2H,d,J=8.6Hz).
【０４２５】
実施例４１８
３−エチル−５−メチル−７−〔４−（４−（４−フェニルピペラジノメチル）ベンゾイル）ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン
表題の化合物を実施例４９と同様にして合成した。
¹H-NMR(CDCl₃)δ：1.41(3H,t,J=7.2Hz), 2.44(3H,d,J=1.0Hz), 2.64(4H,t,J=5.1Hz), 3.22(4H,t,J=5.1Hz), 3.64(2H,s), 4.06(2H,q,J=7.2Hz), 5.34(2H,s), 6.60(1H,d,J=1.0Hz), 6.86(1H,t,J=8.0Hz), 6.93(2H,d,J=8.0Hz), 7.26(2H,d,J=8.4Hz), 7.27(2H,d,J=8.0Hz), 7.47(2H,d,J=8.2Hz), 7.76(2H,d,J=8.4Hz), 7.77(2H,d,J=8.2Hz), 7.83(1H,s).
実施例４１９
３−エチル−５−メチル−７−〔４−〔４−（２−モルホリノエトキシ）ベンゾイル〕ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン・塩酸塩
表題の化合物を実施例１５６と同様にして合成した。
¹H-NMR(CDCl₃)δ：1.40(3H,t,J=7.2Hz), 2.43(2H,d,J=1.2Hz), 2.59(4H,t,J=4.7Hz), 2.84(2H,t,J=5.7Hz), 3.74(4H,t,J=4.7Hz), 4.05(2H,q,J=7.2Hz), 4.19(2H,t,J=5.7Hz), 5.33(2H,s), 6.60(1H,d,J=1.2Hz), 6.95(2H,d,J=8.8Hz), 7.26(2H,d,J=8.2Hz), 7.71(2H,d,J=8.2Hz), 7.79(2H,d,J=8.8Hz), 7.84(1H,s).
【０４２６】
実施例４２０
３−エチル−５−メチル−７−〔４−〔６−（４−ピペリジノピペリジノ）ニコチノイル〕ベンジル〕−７Ｈ−ピロロ〔２，３−ｄ〕ピリミジン−４−オン・２塩酸塩
表題の化合物を実施例１５８と同様にして合成した。
¹H-NMR(CDCl₃)δ：1.41(3H,t,J=7.2Hz), 1.46-2.02(10H,m), 2.43(3H,s), 2.54(4H,t,J=5.1Hz), 2.55-2.67(1H,m), 2.93(2H,dt,J=2.6, 13.0Hz), 4.06(2H,q,J=7.2Hz), 4.54(2H,d,J=13.0Hz), 5.33(2H,s), 6.58(1H,s), 6.67(1H,d,J=9.0Hz), 7.25(2H,d,J=8.2Hz), 7.69(2H,d,J=8.2Hz), 7.83(1H,s), 8.00(1H,dd,J=2.2, 8.2Hz), 8.55(1H,d,J=2.2Hz).
実施例４２１
７−〔４−〔４−（４−Ｎ−tert−ブトキシカルボニルピペリジルメトキシ）ベンゾイル〕ベンジル〕−１，３−ジメチル−キサンチン
表題の化合物を実施例１５６と同様にして合成した。
IR(KBr)ν：1699, 1664, 1655, 1599, 1257 cm^-1.
¹H-NMR(CDCl₃)δ：1.2-1.4(2H,m), 1.47(9H,s), 1.7-2.1(3H,m), 2.76(2H,t,J=12.7Hz), 3.41(3H,s), 3.61(3H,s), 4.1-4.3(2H,brm), 5.59(2H,s), 6.93(2H,ABq,J=8.6Hz), 7.40(2H,ABq,J=7.9Hz), 7.65(1H,s), 7.74(2H,ABq,J=7.9Hz), 7.78(2H,ABq,J=8.6Hz).
【０４２７】
実施例４２２
１，３−ジメチル−７−〔４−〔４−（４−ピペリジルメトキシ）ベンゾイル〕ベンジル〕キサンチン塩酸塩
７−〔４−〔４−（４−Ｎ−tert−ブトキシカルボニルピペリジルメトキシ）ベンゾイル〕ベンジル〕−１，３−ジメチル−キサンチン（３６６mg）をテトラヒドロフラン（５ml）に溶かし、氷冷下、４規定塩酸／酢酸エチル（０.７８ml）を滴下した。５０℃で一晩撹拌後、さらに８時間還流した。反応液を濃縮後、析出物をろ取し、酢酸エチルで洗浄し、白色粉末の表題化合物（２２７mg）を得た。
IR(KBr)ν：1707, 1662, 1599, 1259, 1171 cm^-1.
¹H-NMR(DMSO-d₆)δ：1.3-1.7(2H,m), 1.8-2.2(3H,m), 2.8-3.0(2H,m), 3.2-3.5(2H,m), 3.22(3H,s), 3.45(3H,s), 3.98(2H,d,J=6.0Hz), 5.61(2H,s), 7.08(2H,ABq,J=8.8Hz), 7.46(2H,ABq,J=8.2Hz), 7.66(2H,ABq,J=8.2Hz), 7.72(2H,ABq,J=8.8Hz), 8.35(1H,s).
【０４２８】
実施例４２３
１，３−ジメチル−７−〔４−〔４−（４−Ｎ−メチルピペリジルメトキシ）ベンゾイル〕ベンジル〕キサンチン
１，３−ジメチル−７−〔４−〔４−（４−ピペリジルメトキシ）ベンゾイル〕ベンジル〕キサンチン塩酸塩（８２mg）をアセトニトリル／メタノール（２ml／１ml）に溶かし、３７％ホルムアルデヒド水溶液（０.０２ml）を加え、氷冷下さらに水素化シアノほう素ナトリウム（１６mg）を加えた。室温で１時間撹拌後、酢酸を加え pＨ５とした。反応液を濃縮し、残渣に酢酸エチル、重曹水を加え、酢酸エチル層を抽出した。食塩水で洗浄後、硫酸マグネシウムで乾燥した。濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／エタノール／トリエチルアミン＝２０／２／１）より精製し、白色粉末の表題化合物（３６mg）を得た。
IR(KBr)ν：1713, 1664, 1597, 1252, 1173, 758 cm^-1.
¹H-NMR(CDCl₃)δ：1.2-2.2(7H,m), 2.35(3H,s), 2.9-3.1(2H,m), 3.41(3H,s), 3.61(3H,s), 3.89(2H,d,J=5.4Hz), 5.59(2H,s), 6.92(2H,ABq,J=8.8Hz), 7.40(2H,ABq,J=8.2Hz), 7.65(1H,s), 7.7-7.9(4H,m).
【０４２９】
実施例４２４
７−〔４−〔４−〔１−（４−Ｎ−tert−ブトキシカルボニルピペリジル）エトキシ〕ベンゾイル〕ベンジル〕−１，３−キサンチン
表題の化合物を実施例１５６と同様にして合成した。
IR(KBr)ν：1705, 1664, 1254, 1176 cm^-1.
¹H-NMR(CDCl₃)δ：1.1-1.3(3H,brm), 1.6-1.8(4H,brm), 1.46(9H,s), 2.71(2H,t,J=13.7Hz), 3.42(3H,s), 3.61(3H,s), 4.0-4.2(4H,brm), 5.59(2H,s), 6.93(2H,ABq,J=8.8Hz), 7.40(2H,ABq,J=8.0Hz), 7.65(1H,s), 7.74(2H,ABq,J=8.0Hz), 7.78(2H,ABq,J=8.8Hz).
【０４３０】
実施例４２５
１，３−ジメチル−７−〔４−〔４−〔１−（４−ピペリジル）エトキシ〕ベンゾイル〕ベンジル〕キサンチン塩酸塩
７−〔４−〔４−〔１−（４−Ｎ−tert−ブトキシカルボニルピペリジル）エトキシ〕ベンゾイル〕ベンジル〕−１，３−キサンチン（４５４mg）をテトラヒドロフラン（１０ml）に溶かし、氷冷下４規定塩酸／酢酸エチル（０.９４ml）を滴下した。５０℃で一晩撹拌後、さらに二日間還流した。反応液を濃縮後、析出物をろ取し、酢酸エチル／エーテルで洗浄し、白色粉末の表題化合物（４０３mg）を得た。
IR(KBr)ν：1684, 1653, 1601, 1257 cm^-1.
¹H-NMR(DMSO-d₆)δ：1.2-2.0(7H,brm), 2.7-3.0(2H,brm), 3.21(3H,s), 3.2-3.3(2H,m), 3.44(3H,s), 4.1-4.2(2H,brm), 5.61(2H,s), 7.06(2H,ABq,J=9.0Hz), 7.45(2H,ABq,J=8.1Hz), 7.66(2H,ABq,J=8.1Hz), 7.71(2H,ABq,J=9.0Hz), 8.33(1H,s), 8.4-8.8(2H,brm).
【０４３１】
実施例４２６
１，３−ジメチル−７−〔４−〔４−〔１−（４−Ｎ−メチルピペリジル）エトキシ〕ベンゾイル〕ベンジル〕キサンチン
１，３−ジメチル−７−〔４−〔４−〔１−（４−ピペリジル）エトキシ〕ベンゾイル〕ベンジル〕キサンチン塩酸塩（２０２ml）をアセトニトリル／メタノール（４ml／２ml）に溶かし、３７％ホルムアルデヒド水溶液（０.０４５ml）を加え、氷冷下さらに水素化シアノほう素ナトリウム（３８mg）を加えた。室温で１.５時間撹拌後、酢酸を加え pＨとした。反応液を濃縮し、残渣に酢酸エチル、重曹水を加え、酢酸エチル層を抽出した。食塩水で洗浄後、硫酸マグネシウムで乾燥した。濃縮し、残渣をシリカゲルカラムクロマトグラフィーより精製し、白色粉末の表題化合物（３４mg，１８％）を得た。
IR(KBr)ν：1716, 1662, 1525, 1255 cm^-1.
¹H-NMR(CDCl₃)δ:1.2-2.1(9H,m), 2.29(3H,s), 2.8-3.0(2H,brm), 3.42(3H,s), 3.61(3H,s), 4.08(2H,t,J=6.3Hz), 5.59(2H,s), 6.93(2H,ABq,J=8.8Hz), 7.40(2H,ABq,J=7.6Hz), 7.65(1H,s), 7.75(2H,ABq,J=7.6Hz), 7.79(2H,ABq,J=8.8Hz).
【０４３２】
実施例４２７
７−〔４−（４−クロロベンゾイル）ベンジルオキシ〕−６−メチル−２，３−ジヒドロ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン
７−ヒドロキシ−６−メチル−２，３−ジヒドロキシ−５Ｈ−チアゾロ〔３，２−ａ〕ピリミジン−５−オン（１.０ｇ）と炭酸カリウム（７５０mg）のジメチルホルムアミド（１５ml）溶液に、４−（４−クロロベンゾイル）ベンジルブロミド（２.０ｇ）を加え、反応液を６０℃で２時間撹拌させた。反応液を濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）にて精製し、イソプロピルエーテルから再結晶して無色固体の表題化合物（２００mg）を得た。
IR(KBr)ν：1650, 1515, 1390 cm^-1.
¹H-NMR(CDCl₃)δ：1.97(3H,s), 3.47(2H,t,J=7.8Hz), 4.46(2H,t,J=7.8Hz), 5.43(2H,s), 7.46(2H,d,J=8.0Hz), 7.50(2H,d,J=8.0Hz), 7.76(2H,d,J=8.0Hz), 7.78(2H,d,J=8.0Hz).
【０４３３】
【製剤例】
製剤例１（１錠当たりの用量）
（１）実施例１５の化合物１０．０ｍｇ
（２）乳糖６０．０ｍｇ
（３）コーンスターチ３５．０ｍｇ
（４）ゼラチン３．０ｍｇ
（５）ステアリン酸マグネシウム２．０ｍｇ
実施例１５の化合物１０．０ｍｇと乳糖６０．０ｍｇおよびコーンスターチ３５．０ｍｇの混合物を１０重量％ゼラチン水溶液０．０３ｍｌ（ゼラチンとして３．０ｍｇ）を用い、１ｍｍメッシュの篩を通して顆粒化したのち、４０℃で乾燥し、再び篩過した。得られた顆粒をステアリン酸マグネシウム２．０ｍｇと混合し、圧縮した。得られた中心錠を蔗糖、二酸化チタン、タルクおよびアラビアゴムの懸濁液による糖衣でコーティングが施された錠剤をミツロウで艶出してコート錠を得た。
製剤例２（１錠当たりの用量）
（１）実施例１５の化合物１０．０ｍｇ
（２）乳糖７０．０ｍｇ
（３）コーンスターチ５０．０ｍｇ
（４）可溶性デンプン７．０ｍｇ
（５）ステアリン酸マグネシウム３．０ｍｇ
実施例１５の化合物１０．０ｍｇとステアリン酸マグネシウム３．０ｍｇを可溶性デンプンの水溶液０．０７ｍｌ（可溶性デンプンとして７．０ｍｇ）で顆粒化したのち、乾燥し、乳糖７０．０ｍｇおよびコーンスターチ５０．０ｍｇと混合した。混合物を圧縮して錠剤を得た。
【０４３４】
【試験例】
実験例１
in vitro での前立腺癌の細胞増殖抑制作用
前立腺癌細胞株ＰＣ−３を１０％ウシ胎児血清を含むＦ−１２Ｋ培地（フローラボラトリーズ〔Flow Laboratories〕社製あるいは大日本製薬社製）に浮遊させた細胞懸濁液を９６穴マイクロプレートに播き（５０００個／５０あるいは７５μｌ／ウェル）、５％炭酸ガスインキュベーター中３７℃で培養した。翌日、ジメチルホルムアミドに溶解して３倍段階希釈した各化合物溶液（５０あるいは２５μl／ウェル）を添加し（最終１００μｌ）、さらに３日間培養を行った。ＭＴＴ色素溶液を加え生存細胞数を定量した〔多田ら、ジャーナル・オブ・イムノロジカル・メソッズ（J. Immunol. Methods）、第９３巻、第１５７頁、（１９８６年）〕。化合物溶液を添加していない対照群の細胞量を１００％として、各化合物添加群の細胞量の割合を求め、生存細胞量を対照群の５０％抑制させるのに必要な化合物濃度（ＩＣ₅₀値）を算出した。これらを〔表１〕に示す。
【表１】
〔表１〕より、本発明の化合物は優れた前立腺癌細胞株（ＰＣ−３）の増殖抑制作用を有することが分かる。
【０４３５】
実験例２
皮下移植腫瘍に対する腫瘍増殖抑制作用
組織培養用シャーレを用いインビトロ（in vitro）で継代培養したヒト前立腺癌ＰＣ−３細胞株（以下、ＰＣ−３細胞と略記する）を０．０５％トリプシンで器壁からはがし、細胞を１０％血清を含むハムＦ１２Ｋ培地で洗った後、３Ｘ１０⁷／ｍｌになるようにＰＢＳ（リン酸緩衝液）に懸濁し、その１００μｌをＢＡＬＢ／ｃｎｕ／ｎｕマウス（７週齢、雄）の右側腹部中央に注射筒（２５Ｇ使用）を用いて移植した。移植２５日目に腫瘍サイズを測定し、平均腫瘍サイズが１６〜１７９mm³になるようにグループ分けをし、薬物投与を開始した。腫瘍サイズは長径（a）と短径（b）をキャリパーで測定し、計算値０．５ｘａｘｂ²から算出した。
本発明化合物を０．５％メチルセルロース／生理食塩水に懸濁し、投薬液量として１０μｌ／ｇマウス体重となるように調整し、背部皮下に投与した。投薬は月水金の週３回計３週間行い、移植４６日目に腫瘍増殖抑制作用の評価を以下の方法により行った。投薬開始前の腫瘍サイズを引いた腫瘍サイズの値を用い、薬物投与群（Ｔ）とコントロール群（Ｃ）との腫瘍体積比（Ｔ／Ｃ％）を求めた。結果を表２にて表す。薬物の投与量は１回当たりの薬物重量（ｍｇ／ｋｇ体重）で表した。
【表２】
〔表２〕より、本発明の化合物に、優れた腫瘍増殖抑制作用が認められた。
【０４３６】
実験例３
皮下移植腫瘍に対する腫瘍増殖抑制作用
組織培養用シャーレを用いインビトロ（in vitro）で継代培養したＰＣ−３細胞を０．０５％トリプシンで器壁からはがし、細胞を１０％血清を含むハムＦ１２Ｋ培地で洗った後、３Ｘ１０⁷／ｍｌになるようにＰＢＳに懸濁し、その１００μｌをＢＡＬＢ／ｃｎｕ／ｎｕマウス（７週齢、雄）の右側腹部中央に注射筒（２５Ｇ使用）を用いて移植した。移植３２日目に腫瘍サイズを測定し、平均腫瘍サイズが２７３〜２９３mm³になるようにグループ分けをし、薬物投与を開始した。腫瘍サイズは長径（a）と短径（b）をキャリパーで測定し、計算値０．５ｘａｘｂ²から算出した。
本発明化合物を０．５％メチルセルロース／生理食塩水に懸濁し、投薬液量として１０μｌ／ｇマウス体重となるように調整し、２１日間連続経口投与した。最終投与の翌日、移植５３日目に腫瘍増殖抑制作用の評価を以下の方法により行った。投薬開始前の腫瘍サイズを引いた腫瘍サイズの値を用い、薬物投与群（Ｔ）とコントロール群（Ｃ）との腫瘍体積比（Ｔ／Ｃ％）を求めた。結果を表３にて表す。薬物の投与量は１回当たりの薬物重量（ｍｇ／ｋｇ体重）で表した。
【表３】
〔表３〕より、本発明の化合物に、優れた腫瘍増殖抑制作用が認められた。
【０４３７】
実験例４
皮下移植腫瘍に対する腫瘍増殖抑制作用
組織培養用シャーレを用いインビトロ（in vitro）で継代培養したＰＣ−３細胞を０．０５％トリプシンで器壁からはがし、細胞を１０％血清を含むハムＦ１２Ｋ培地で洗った後、３Ｘ１０⁷／ｍｌになるようにＰＢＳに懸濁し、その１００μｌをＢＡＬＢ／ｃｎｕ／ｎｕマウス（７週齢、雄）の右側腹部中央に注射筒（２５Ｇ使用）を用いて移植した。移植３１日目に腫瘍サイズを測定し、平均腫瘍サイズが２７３〜２９３mm³になるようにグループ分けをし、薬物投与を開始した。腫瘍サイズは長径（a）と短径（b）をキャリパーで測定し、計算値０．５ｘａｘｂ²から算出した。
本発明化合物を０．５％メチルセルロース／生理食塩水に懸濁し、投薬液量として１０μｌ／ｇマウス体重となるように調整し、２１日間連続経口投与した。最終投与の翌日、移植５２日目に腫瘍増殖抑制作用の評価を以下の方法により行った。投薬開始前の腫瘍サイズを引いた腫瘍サイズの値を用い、薬物投与群（Ｔ）とコントロール群（Ｃ）との腫瘍体積比（Ｔ／Ｃ％）を求めた。結果を表４にて表す。薬物の投与量は１回当たりの薬物重量（ｍｇ／ｋｇ体重）で表した。
【表４】
〔表４〕より、本発明の化合物に、用量依存的に優れた腫瘍増殖抑制作用が認められた。
【０４３８】
【発明の効果】
本発明の化合物は、優れた抗腫瘍活性を示し、難治性固形腫瘍の治療および他臓器への遠隔転移の予防などに優れた効果を有する。Detailed Description of the Invention
【0001】
[Technical field to which the invention belongs]
The present invention relates to a novel ketone derivative or its salt having antitumor activity, its production method, and pharmaceutical use.
【0002】
[Prior art]
Pancreatic cancer, traditionally known as a refractory solid tumor, is often inoperable at the time of discovery because it may have already metastasized or developed peritonitis carcinomatosis. Even when surgery is possible, the prognosis is poor. For such patients with advanced cancer or postoperative patients, monotherapy with 5-fluorouracil (5-FU) or combination therapy with chemotherapy agents such as 5-FU and mitomycin is used. Furthermore, for hormone-independent cancers (particularly prostate cancer and breast cancer), known as refractory solid tumors, and their recurrent or metastatic cancers, monotherapy with chemotherapy agents such as adriamycin, cisplatin, mitomycin, and 5-FU or combination therapy with these agents is used. Furthermore, multidrug combination therapy with cisplatin, carboplatin, etoposide, mitomycin, and cyclophosphamide is often used to treat lung cancer. However, at present, treatments using these agents are not fully satisfactory.
Meanwhile, diaryl ketone derivatives have been developed as pharmaceuticals, including anti-inflammatory, analgesic, and antipyretic agents (ketoprofen, thiaprofenic acid) and antihyperlipidemic agents (fenofibrate). In addition, JP-B-6-762, JP-A-60-54370, JP-A-61-112057, 112058, 130275, 268672, JP-A-62-123176, JP-A-63-112566, JP-A-64-34971, JP-A-1-250361, and JP-A-3-220177 describe them as acaricides and insecticides, and JP-A-61-260018 describes them as antiallergic agents. As pyrimidine derivatives, JP-A-1-190670 and JP-A-261371 describe insecticides and acaricides, and JP-A-6-73022 describes herbicides.As azole derivatives, JP-B-54-21339 and JP-B-62-20167 describe antiprotozoal agents, and JP-A-51-76431 describes fungicides.As imidazole derivatives, JP-B-5-29351 and JP-B-5-504359 describe angiotensin II inhibitors, JP-A-51-76273, JP-A-52-83556 and JP-A-51-143667 describe antibacterial agents, JP-A-59-118772 describe anticoccidial agents, and JP-A-3-501020 describes diuretics and anti-inflammatory agents. As for triazole derivatives, fungicides are described in JP-B-60-28804 and JP-A-55-57574, and anticoccidial agents are described in JP-B-6-25172. As for pyridine derivatives, insecticides are described in JP-A-3-44372, polymerization initiators are described in JP-A-5-255256, antiviral agents are described in JP-A-4-14107, and hypoglycemic agents are described in JP-A-49-100091. As for pyrazolopyrimidine derivatives, antihyperlipidemic agents are described in JP-A-63-246377. As for tetrazole derivatives, antihypertensive agents, antiedema agents, and antihyperuric agents are described in JP-B-55-1269. As for pyrazole derivatives, herbicides are described in JP-A-50-126830, and fungicides are described in JP-A-4-217668. Oxadiazole derivatives are described as herbicides in JP 62-164673 A. Thiadiazole derivatives are described as antifungal agents in JP 61-802927 A. Nicotine derivatives are described as antihyperlipidemic agents in JP 61-26993 B. Piperazine derivatives are described as anti-inflammatory agents in JP 59-36987 B. Phenoxyacetic acid derivatives are described as antihypertensive agents, antiedema agents, and antirheumatic agents in JP 52-39659 A. Uracil derivatives are described as insecticides and acaricides in JP 5-43555 B. Other known compounds include those disclosed in JP-A-51-108055, JP-A-62-240639, JP-A-63-502511, JP-A-53-124682, JP-A-4-224862, JP-A-230282, and JP-A-6-135977. Compounds having antitumor activity are also disclosed in WO 9418168 (indole derivatives), JP-A-64-68321 (triazole derivatives), JP-A-3-56417 (triazole derivatives), JP-A-1-287074, JP-A-290663, JP-A-290670 (imidazole derivatives), and JP-B-5-71594 (5-fluorouracil derivatives).
【0003】
[Problem the invention aims to solve]
Conventional antitumor compounds do not have sufficient therapeutic effects, so there is a need to develop pharmaceuticals that have a different chemical structure and are highly effective in treating intractable solid tumors such as pancreatic cancer, prostate cancer, breast cancer, and lung cancer, as well as preventing distant metastasis of these cancers to other organs.
【0004】
[Means to solve the problem]
In light of this situation, the inventors have conducted extensive research and have concluded that the general formula
A-Z-Ar¹-CO-Ar²[I]
[Wherein A is an optionally substituted fused pyrimidinone or fused pyridazinone ring; Ar¹and Ar²[0013] The present inventors have synthesized for the first time a novel ketone derivative represented by the formula (I): wherein each of the formulas represents an optionally substituted ring; and Z represents a divalent group. They have also found that the resulting compound has an unexpectedly excellent antitumor effect due to its unique chemical structure, and exhibits an excellent growth inhibitory effect against solid tumor cells such as pancreatic cancer cells, prostate cancer cells, breast cancer cells, and lung cancer cells, making it useful for the prevention and treatment of intractable solid tumors, and further has an eradication effect against Helicobacter pylori, making it useful for the prevention and treatment of diseases associated with this. Based on these findings, the present invention has been completed.
【0005】
That is, the present invention is
(1) Compound [I] or a salt thereof,
(2) A is (i) C_6-14Aromatic hydrocarbons, C_5-10The compound according to (1), which is an optionally substituted fused pyrimidinone or fused pyridazinone ring formed by condensing a cycloalkane or a mono- or di-heterocycle (containing, in addition to carbon as ring-constituting atoms, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur) with (ii) a pyrimidinone or pyridazinone ring;
(3) A is optionally substituted pyrrolo[2,3-d]pyrimidin-4-one, pyrrolo[3,2-d]pyrimidin-4-one, pyrrolo[3,4-d]pyrimidin-4-one, pyrazolo[3,4-d]pyrimidin-4-one, pyrazolo[4,3-d]pyrimidin-7-one, 6-oxopurine, imidazo[1,2-a]pyrimidin-5-one, imidazo[1,2-a]pyrimidin-7-one, thieno[2,3-d]pyrimidin thieno[3,4-d]pyrimidin-4-one, thieno[3,2-d]pyrimidin-4-one, furo[2,3-d]pyrimidin-4-one, furo[3,4-d]pyrimidin-4-one, furo[3,2-d]pyrimidin-4-one, isoxazolo[5,4-d]pyrimidin-4-one, isoxazolo[4,5-d]pyrimidin-7-one, oxazolo[5,4-d]pyrimidin-4-one, oxazolo[4,5-d]pyrimidin-7-one -d]pyrimidin-7-one, thiazolo[5,4-d]pyrimidin-4-one, thiazolo[4,5-d]pyrimidin-7-one, isothiazolo[5,4-d]pyrimidin-4-one, isothiazolo[4,5-d]pyrimidin-7-one, triazolo[4,5-d]pyrimidin-4-one, 1,2,4-triazolo[1,5-a]pyrimidin-7-one, dihydrocyclopenta[d]pyrimidin-4-one, 5H or 7H -cyclopenta[d]pyrimidin-4-one, pyrido[2,3-d]pyrimidin-4-one, pyrido[3,2-d]pyrimidin-4-one, pyrido[4,3-d]pyrimidin-4-one, pyrido[3,4-d]pyrimidin-4-one, pteridin-4-one, quinazolin-4-one, pyrido[1,2-a]pyrimidin-4-one, pyrimido[1,2-a]pyrimidin-4-one, thiazolo[3,2-a]pyrimidin-5-one oxazolo[3,2-a]pyrimidin-5-one, pyrrolo[1,2-a]pyrimidin-4-one, pyrimido[3,4-a]pyrimidin-4-one, pyrimido[4,5-d]pyrimidin-4-one, pyrimido[5,4-d]pyrimidin-4-one, pyridazino[2,3-a]pyrimidin-4-one, pyridazino[4,3-d]pyrimidin-4-one, pyridazino[3,4-d]pyrimidin-4-one, xanthine, urine acid, pyrrolo[3,2-d]pyrimidine-2,4-dione, pyrrolo[2,3-d]pyrimidine-2,4-dione, pyrrolo[3,4-d]pyrimidine-2,4-dione, pyrimido[2,1-b][1,3]thiazin-6-one, pyrimido[2,1-b][1,3]oxazin-6-one, imidazo[2,1-b]quinazolin-5-one, cyclopenta[d]imidazo[1,2-a]pyrimidin-5-one, cyclopenta[d] Imidazo[1,2-a]pyrimidin-5-one, pyridazino[4,5-b]-1,5-oxazepin-9(8H)-one, pyridazino[4,5-b]-1,4-oxazin-8(7H)-one, pyrrolo[3,4-d]pyridazin-4(5H)-one, pyrrolo[2,3-d]pyridazin-7(6H)-one, pyrrolo[2,3-d]pyridazin-4(5H)-one, imidazo[4,5-d]pyridazin-4(5H)-one, The compound according to the above (1), which is midazo[4,5-c]pyridazin-6(5H)-one, pyrazolo[4,3-d]pyridazin-4(5H)-one, pyrazolo[3,4-d]pyridazin-4(5H)-one, triazolo[4,5-d]pyridazin-4(5H)-one, pyrido[2,3-d]pyridazin-5(6H)-one, or thiazolo[4,5-d]pyridazin-7(6H)-one (which may be partially reduced),
(4) A is (i) C_6-14Aromatic hydrocarbons, C_5-10The compound according to (1), which is an optionally substituted fused pyrimidinone ring formed by condensing a cycloalkane or a mono- or di-heterocycle (containing, in addition to carbon as ring-constituting atoms, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur) with (ii) a pyrimidinone ring;
(5) The compound according to (4) above, wherein the fused pyrimidinone ring is pyrrolo[2,3-d]pyrimidin-4-one, quinazolin-4-one, pyrido[1,2-a]pyrimidin-4-one, thiazolo[3,2-a]pyrimidin-5-one, pyrimido[2,1-b][1,3]thiazin-6-one, or imidazo[2,1-b]quinazolin-5-one (which may be partially reduced).
(6) Z is a divalent C group which may contain -NH-, -O-, or -S-._1-6The compound according to (1), which is an aliphatic hydrocarbon group.
(7) Ar¹and Ar²and (c) each represent an optionally substituted aromatic ring;
(8) Ar¹The compound according to (1), wherein
(9) Ar²The compound according to (1) above, wherein - is an optionally substituted phenyl, pyridyl, indolyl, pyrrolyl, thienyl, piperidino, piperazino or morpholino group;
(10) Ar²The compound according to (8) above, wherein - is an optionally substituted phenyl group.
(11) Ar²The compound according to (8) above, wherein - is an optionally substituted piperidino, piperazino or morpholino group;
(12) Ar²is halogen, C_1-10Alkyl, C_2-10Alkenyl, C_2-10Alkynyl, C_3-10Cycloalkyl, C_3-6Cycloalkyl-C_1-6Alkyl, C_1-10Alkoxy, C_2-10Alkenyloxy, C_2-10Alkynyloxy, C_6-14Aryloxy, C_7-16Aralkyloxy, C_1-10Alkylthio, C_2-10Alkenylthio, C_2-10Alkynylthio, C_6-14Arylthio, C_7-16Aralkylthio, C_1-10Alkylsulfinyl, C_2-10Alkenylsulfinyl, C_2-10Alkynylsulfinyl, C_6-14Arylsulfinyl, C_1-10Alkylsulfonyl, C_2-10Alkenylsulfonyl, C_2-10Alkynylsulfonyl, C_6-14Arylsulfonyl, carbamoyloxy, mono- or di-C_1-10Alkylcarbamoyloxy, phosphonooxy, mono- or di-C_1-10Alkylphosphonooxy, oxo, nitro, cyano, sulfo, hydroxyl, amino, mono- or di-C_1-10Alkylamino, mono- or di-C_7-16Aralkylamino, cyclic amino, carboxyl, mercapto, carbamoyl, mono- or di-C_1-10Alkylcarbamoyl, mono- or di-C_6-14Arylcarbamoyl, C_1-10Alkoxy-carbonyl, C_2-10Alkenyloxy-carbonyl, C_2-10Alkynyloxy-carbonyl, C_6-14Aryloxy-carbonyl, C_1-10Alkylsulfonylamino, C_7-16Aralkyl, C_6-14Aryl, styryl, C_6-14Arylimino, aromatic heterocycle, formyl, C_1-10Alkyl-carbonyl, C_2-10Alkenyl-carbonyl, C_2-10Alkynyl-carbonyl, C_6-14Aryl-carbonyl, C_1- ₁₀acylamino, —CO—Q (wherein Q represents a substituted amino) and C_1-10acyloxy, and these substituents may further be halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Cycloalkyl, carboxyl, hydroxyl, cyano, nitro, sulfo, phosphono, oxo, C_1-6Alkoxy, C_1-3Alkylenedioxy, C_6-10Aryloxy, C_7-14Aralkyloxy, mercapto, C_1-6Alkylthio, C_6-10Arylthio, C_7-14Aralkylthio, carbamoyl, mono- or di-C_1-6Alkylcarbamoyl, amino, mono- or di-C_1-6Alkylamino, cyclic amino, mono- or di-C_7-14Aralkylamino, C_6-10Aryl, C_7-14Aralkyl, Formyl, C_1-6Alkyl-carbonyl, C_6-10Aryl-carbonyl, C_1-6Alkoxy-carbonyl, C_1-6It may be substituted with 1 to 3 substituents selected from acyloxy, aromatic heterocycle and aromatic heterocyclethio, and these substituents may further be halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Cycloalkyl, carboxyl, hydroxyl, cyano, nitro, sulfo, phosphono, oxo, C_1-6Alkoxy, C_1-3Alkylenedioxy, C_6-10Aryloxy, C_7-14Aralkyloxy, mercapto, C_1-6Alkylthio, C_6-10Arylthio, C_7-14Aralkylthio, carbamoyl, mono- or di-C_1-6Alkylcarbamoyl, amino, mono- or di-C_1-6Alkylamino, cyclic amino, mono- or di-C_7-14Aralkylamino, C_6-10Aryl, C_7-14Aralkyl, Formyl, C_1-6Alkyl-carbonyl, C_6-10Aryl-carbonyl, C_1-6Alkoxy-carbonyl, C_1-6The compound according to (1), which is a ring optionally substituted with 1 to 3 substituents selected from acyloxy, an aromatic heterocycle, and an aromatic heterocyclethio.
【0006】
(13) General formula
[Chemical formula 15]
[Wherein A is an optionally substituted fused pyrimidinone or pyridazinone ring; Ar²is an optionally substituted ring; Z^ais a divalent C which may contain -NH-, -O- or -S-_1-6a compound represented by the formula (I) or a salt thereof,
(14) A is the formula
[Chemical formula 16]
[In the formula, A¹and A²each represents an optionally substituted 5- to 8-membered homocyclic or heterocyclic ring; R¹and R²are hydrogen, halogen, and C, respectively._1-6Alkyl group, halo-C_1-6Alkyl group, hydroxyl group, C_1-6Alkoxy group, halo-C_1-6Alkoxy group, C_1-6Alkylthio group or halo-C_1-6The compound according to the above (13), wherein the ring is represented by the formula (1):
(15) A is the formula
[Chemical formula 17]
The compound according to (13) above, which is a ring represented by the formula: [wherein the symbols have the same meanings as those described in (14) above.]
(16) A is the formula
[Chemical formula 18]
The compound according to (13) above, which is a ring represented by the formula: [wherein the symbols have the same meanings as those described in (14) above.]
(17) R¹and R²are each hydrogen or C_1-6The compound according to (14), which is an alkyl group.
(18) The compound according to (14), wherein the 5- to 8-membered homo- or heterocyclic ring is a 5- to 8-membered ring which may contain, in addition to carbon, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur as ring-constituting atoms;
(19) The compound according to (18), wherein the 5- to 8-membered ring is (i) cyclopentane, cyclohexane, cycloheptane, or benzene, or (ii) imidazole, pyridine, thiazine, thiazole, oxazole, thiophene, pyrrole, pyrazole, pyrazine, or pyrimidine (which may be partially reduced).
(20) Z^aC may contain -O- or -S-_1-6The compound according to (13), which is an alkylene group.
(21) Ar²The compound according to (13) above, wherein - is an optionally substituted phenyl, pyridyl, indolyl, pyrrolyl, thienyl, piperidino, piperazino or morpholino group;
(22) Ar²The compound according to the above (13), wherein - is an optionally substituted phenyl group.
(23) Ar²The compound according to (13) above, wherein - is an optionally substituted piperidino, piperazino, or morpholino group;
【0007】
(24) A is the formula
[Chemical formula 19]
[The symbols in the formula have the same meanings as described in (14) above.]; Z^aC may contain -O- or -S-_1-6Alkylene; Ar²The compound according to the above (13), wherein - is an optionally substituted phenyl group.
(25) Z^ais -O-CH₂—or —CH₂The compound according to (24),
(26) A is the formula
[C20]
[The symbols in the formula have the same meanings as described in (14) above.]; Z^aC may contain -O- or -S-_1-6Alkylene group; Ar²The compound according to the above (13), wherein - is an optionally substituted phenyl group.
(27) Z^ais -O-CH₂—or —CH₂The compound according to (26),
(28) General formula
[C21]
The compound according to (13) above, represented by the formula: [wherein n is an integer of 0 to 3, and the other symbols are as defined in (13) above.]
(29) The compound according to (28), wherein n is an integer of 1 to 3.
(30) General formula
[C22]
The compound described in (28) above, wherein the symbols in the formula are as defined in (13) above.
(31) Ar²The compound according to the above (28), wherein - is an optionally substituted phenyl group.
(32) An optionally substituted phenyl group is C_1-6Alkyl, halo-C_1-6Alkyl, C_1-6Alkoxy, halo-C_1-6Alkoxy, C_1-6Alkylthio, halo-C_1-6Alkylthio, halogen, amino, mono- or di-C_1-6Alkylamino, C_1-6Acylamino, C_1-6Alkyl-carbonyl, C_6-10Aryl-carbonyl, C_7-14Aralkyl-carbonyl, C_1-6Alkoxy-carbonyl, C_1-6Acyloxy, carbamoyloxy, mono- or di-C_1-6Alkylcarbamoyloxy, cyano, nitro, carbamoyl and mono- or di-C_1-6The compound according to (31), which is a phenyl group optionally substituted by 1 to 5 substituents selected from alkylcarbamoyl,
(33) Ar²The compound according to (28) above, wherein - is an optionally substituted piperidino or piperazino group.
(34) Ar²is the formula
[C23]
[In the formula, R^arepresents a substituent.],
(35) R^ais halogen, C_1-6Alkyl group, halo-C_1-6Alkyl group, C_1-6Alkoxy group or halo-C_1-6The compound according to (34), wherein the aryl group is an alkoxy group.
(36) Z^ais -O-CH₂The compound according to (35),
(37) R¹The compound according to (36) above, wherein
【0008】
(38) General formula
[C24]
The compound according to (13) above, represented by the formula: [wherein n is an integer of 0 to 3, and the other symbols are as defined in (13) above.]
(39) Ar²The compound according to the above (38), wherein - is an optionally substituted phenyl group.
(40) An optionally substituted phenyl group is C_1-6Alkyl, halo-C_1-6Alkyl, C_1-6Alkoxy, halo-C_1-6Alkoxy, C_1-6Alkylthio, halo-C_1-6Alkylthio, halogen, amino, mono- or di-C_1-6Alkylamino, C_1-6Acylamino, C_1-6Alkyl-carbonyl, C_6-10Aryl-carbonyl, C_7-14Aralkyl-carbonyl, C_1-6Alkoxy-carbonyl, C_1-6Acyloxy, carbamoyloxy, mono- or di-C_1-6Alkylcarbamoyloxy, cyano, nitro, carbamoyl and mono- or di-C_1-6The compound according to (39), which is a phenyl group optionally substituted by 1 to 5 substituents selected from alkylcarbamoyl,
(41) Ar²The compound according to (38), wherein - is an optionally substituted piperidino or piperazino group.
(42) Ar²is the formula
[C25]
[In the formula, R^arepresents a substituent.], the compound according to (38) above,
(43) R^ais halogen, C_1-6Alkyl group, halo-C_1-6Alkyl group, C_1-6Alkoxy group or halo-C_1-6The compound according to (42), wherein the aryl group is an alkoxy group.
(44) Z^ais -O-CH₂The compound according to (38),
(45) R¹The compound according to (38) above, wherein
【0009】
(46) General formula
[C26]
[In the formula, Ar³is a ring; W is a bond, a carbonyl group, or -NR³−(R³is hydrogen or C_1-6alkyl group), a divalent C_1-6an aliphatic hydrocarbon group; T is an optionally substituted primary, secondary or tertiary amino group; and the other symbols are as defined above.
(47) T is halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Cycloalkyl, carboxyl, hydroxyl, cyano, nitro, sulfo, phosphono, oxo, C_1-6Alkoxy, C_1-3Alkylenedioxy, C_6-10Aryloxy, C_7-14Aralkyloxy, mercapto, C_1-6Alkylthio, C_6-10Arylthio, C_7-14Aralkylthio, carbamoyl, mono- or di-C_1-6Alkylcarbamoyl, amino, mono- or di-C_1-6Alkylamino, cyclic amino, mono- or di-C_7-14Aralkylamino, C_6-10Aryl, C_7-14Aralkyl, Formyl, C_1-6Alkyl-carbonyl, C_6-10Aryl-carbonyl, C_1-6Alkoxy-carbonyl, C_1-6The compound according to (46), which is a piperidino, piperazino or morpholino group optionally substituted by 1 to 3 substituents selected from acyloxy, aromatic heterocycle and aromatic heterocyclethio,
(48) W is a bond, -(CH₂)_1-3- or -O-(CH₂)_1-3The compound according to (46),
(49) A is the formula
[C27]
The compound described in (46) above, which is a ring represented by the formula: [wherein the symbols have the same meanings as those described in (14) above.]
(50) Z is a divalent C group which may contain -O- or -S-_1-6The compound according to (46), which is an aliphatic hydrocarbon group.
(51) Ar³is the formula
[C28]
The compound according to (46) above,
(52) General formula
D-Alk-E-Ar¹—CO—Ar²
[Wherein D is an optionally substituted quinazolin-5-one, pyrido[1,2-a]pyrimidin-4-one, imidazo[1,2-a]pyrimidin-5-one, thiazolo[3,2-a]pyrimidin-5-one, oxazolo[3,2-a]pyrimidin-5-one, or pyrido[1,2-a]pyrimidin-4-one (which may be partially reduced); Alk is C_1-3Alkylene group; E is a bond, —NR—, —O—, —S—, or —NR—CH₂—, —O—CH₂-or-S-CH₂- (R is hydrogen, C_1-6Alkyl group or C_2-6the other symbols are as defined above.],
(53) 1-[4-(4-chlorobenzoyl)benzyl]-6,7,8,9-tetrahydroimidazo[2,1-b]quinazolin-5(1H)-one or a salt thereof,
(54) 3-methyl-2-[4-(4-trifluoromethylbenzoyl)benzyloxy]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one or a salt thereof,
(55) 7-[4-(4-methoxybenzoyl)benzyloxy]-6-methyl-2,3-dihydro-5H-thiazolo[1,2-a]pyrimidin-5-one or a salt thereof,
【0010】
(56) a) A-Y^aor a salt thereof and Y-Ar¹—CO—Ar²or a salt thereof,
b) A or a salt thereof and X-Z-Ar¹—CO—Ar²or a salt thereof,
c) A-X or its salt and HZ-Ar¹—CO—Ar²or a salt thereof,
d) A^aor its salt and A^b-Z-Ar¹—CO—Ar²or a salt thereof, or
e) A-Z-Ar¹or a salt thereof and X—CO—Ar²or its salts
[Where Y and Y^aare taken together to form a divalent group represented by Z; A^aand A^ba fused pyrimidinone or fused pyridazinone ring represented by A, which may be substituted, when taken together; X is a reactive group; and the other symbols are as defined above.
(57) A medicine containing the compound described in (1) above.
(58) A pharmaceutical composition according to (57) for the treatment of cancer, and
(59) This relates to a pharmaceutical agent described in (57) above intended for eradicating Helicobacter pylori.
【0011】
In the above formula [I], A represents an optionally substituted fused pyrimidinone or fused pyridazinone ring.
The "fused pyrimidinone ring" represented by A is, for example, a fused pyrimidinone ring formed by the fusion of (i) one or two cyclic hydrocarbon and/or heterocyclic rings with (ii) a pyrimidinone ring, and a fused pyrimidinone ring composed of 9 to 14 atoms selected from carbon, nitrogen, oxygen, and sulfur as ring-constituting atoms is preferred.
The "cyclic hydrocarbon" refers to, for example, a 5- to 10-membered monocyclic hydrocarbon or a fused bicyclic hydrocarbon formed by condensing these with each other. Preferred "cyclic hydrocarbons" include, for example, C_6-14Aromatic hydrocarbons (e.g., benzene, naphthalene, etc.), C_5-10Examples include cycloalkanes (for example, cyclopentane, cyclohexane, cycloheptane, indane, tetralin, etc.).
The "heterocycle" refers to, for example, a 5- to 10-membered monocyclic heterocycle containing, in addition to carbon, one or two, preferably one to four, heteroatoms selected from nitrogen, oxygen, and sulfur, or a fused bicyclic heterocycle formed by condensing such a heterocycle with another ring (e.g., the above-mentioned cyclic hydrocarbon or monocyclic heterocycle). Preferred "heterocycles" include, for example, imidazole, thiazole, oxazole, pyrrole, isoxazole, isothiazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, thiophene, furan, thiazine, indole, isoindole, purine, quinoline, and isoquinoline, which may be partially reduced.
【0012】
Specific examples of the "fused pyrimidinone ring" include, for example, pyrrolo[2,3-d]pyrimidin-4-one, pyrrolo[3,2-d]pyrimidin-4-one, pyrrolo[3,4-d]pyrimidin-4-one, pyrazolo[3,4-d]pyrimidin-4-one, pyrazolo[4,3-d]pyrimidin-7-one, 6-oxopurine, imidazo[1,2-a]pyrimidin-5-one, imidazo[1,2-a]pyrimidin-7-one, thieno[2,3-d]pyrimidin-4-one, thieno[3,4-d]pyrimidin-4-one, thieno[3,2-d]pyrimidin-4-one, furo[2,3-d]pyrimidin-4-one, furo[3,4-d]pyrimidin-4-one, furo[3,2 -d]pyrimidin-4-one, isoxazolo[5,4-d]pyrimidin-4-one, isoxazolo[4,5-d]pyrimidin-7-one, oxazolo[5,4-d]pyrimidin-4-one, oxazolo[4,5-d]pyrimidin-7-one, thiazolo[5,4-d]pyrimidin-4-one, thiazolo[4,5-d]pyrimidin-7-one, isothiazolo[5,4-d]pyrimidin-4-one, isothiazolo[4,5-d]pyrimidin-7-one, triazolo[4,5-d]pyrimidin-4-one, 1,2,4-triazolo[1,5-a]pyrimidin-7-one, dihydrocyclopenta[d]pyrimidin-4-one, 5H or 7H-cyclopenta[d]pyrimidin-4-one Pyrimidin-4-one, pyrido[2,3-d]pyrimidin-4-one, pyrido[3,2-d]pyrimidin-4-one, pyrido[4,3-d]pyrimidin-4-one, pyrido[3,4-d]pyrimidin-4-one, pteridin-4-one, quinazolin-4-one, pyrido[1,2-a]pyrimidin-4-one, pyrimido[1,2-a]pyrimidin-4-one, thiazolo[3,2-a]pyrimidin-5-one, oxazolo[3,2-a]pyrimidin-5-one, pyrrolo[1,2-a]pyrimidin-4-one, pyrimido[3,4-a]pyrimidin-4-one, pyrimido[4,5-d]pyrimidin-4-one, pyrimido[5,4-d]pyrimidin-4-one, pyrimido Examples include ridazino[2,3-a]pyrimidin-4-one, pyridazino[4,3-d]pyrimidin-4-one, pyridazino[3,4-d]pyrimidin-4-one, xanthine, uric acid, pyrrolo[3,2-d]pyrimidine-2,4-dione, pyrrolo[2,3-d]pyrimidine-2,4-dione, pyrrolo[3,4-d]pyrimidine-2,4-dione, pyrimido[2,1-b][1,3]thiazin-6-one, pyrimido[2,1-b][1,3]oxazin-6-one, imidazo[2,1-b]quinazolin-5-one, cyclopento[d]imidazo[1,2-a]pyrimidin-5-one, and cyclopento[d]imidazo[1,2-a]pyrimidin-5-one.
【0013】
The "fused pyridazinone ring" represented by A refers to, for example, a fused pyridazinone ring formed by condensing (i) one or two cyclic hydrocarbon and/or heterocyclic rings with (ii) a pyridazinone ring, and a fused pyridazinone ring composed of 9 to 14 atoms selected from carbon, nitrogen, oxygen, and sulfur as ring-constituting atoms is preferred.
The "cyclic hydrocarbons" and "heterocycles" used may be, for example, the same as those described above.
Specific examples of the "fused pyridazinone ring" include pyridazino[4,5-b]-1,5-oxazepin-9(8H)-one, pyridazino[4,5-b]-1,4-oxazin-8(7H)-one, pyrrolo[3,4-d]pyridazin-4(5H)-one, pyrrolo[2,3-d]pyridazin-7(6H)-one, pyrrolo[2,3-d]pyridazin-4(5H)-one, and imidazo[4,5-d]pyridazinone. pyridazine-4(5H)-one, imidazo[4,5-c]pyridazine-6(5H)-one, pyrazolo[4,3-d]pyridazine-4(5H)-one, pyrazolo[3,4-d]pyridazine-4(5H)-one, triazolo[4,5-d]pyridazine-4(5H)-one, pyrido[2,3-d]pyridazine-5(6H)-one, thiazolo[4,5-d]pyridazine-7(6H)-one, and the like.
The "fused pyrimidinone and fused pyridazinone rings" may be partially reduced.
【0014】
Examples of the substituent (referred to as -L) that the "fused pyrimidinone and fused pyridazinone ring" may have include, for example, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkyl-alkyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, an arylthio group, an aralkylthio group, an alkylsulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, an arylsulfonyl group, a carbamoyloxy group, a mono- or di-alkylcarbamoyloxy group, a phosphonooxy group, a mono- or di-alkylphosphonooxy group, a Examples of the alkyl group include a silyl group, an oxo group, a nitro group, a cyano group, a sulfo group, a hydroxyl group, an amino group, a mono- or di-alkylamino group, a mono- or di-aralkylamino group, a cyclic amino group, a carboxyl group, a mercapto group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a mono- or di-arylcarbamoyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group, an alkylsulfonylamino group, an aralkyl group, an aryl group, a styryl group, an arylimino group, an aromatic heterocyclic group, a formyl group, an alkylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an arylcarbonyl group, an acylamino group, -CO-Q (Q is a substituted amino group), and an acyloxy group. These substituents are substituted at substitutable positions on the "fused pyrimidinone ring and fused pyridazinone ring", and the number of the substituents is 1 to 5, preferably 1 to 3. However, when the number of the substituents is 2 or more, the substituents may be the same or different. Specific examples of the substituents on these "fused pyrimidinone and fused pyridazinone rings" are described below.
【0015】
The term "halogen atom" refers to, for example, fluorine, chlorine, bromine, iodine, etc.
The "alkyl group" includes, for example, C groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 1,1-dimethylbutyl, and 2,2-dimethylbutyl._1-10This indicates an alkyl group, etc.
The "alkenyl group" refers to, for example, a C alkyl group such as vinyl, allyl, 2-butenyl, isopropenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl._2-10It represents an alkenyl group, etc.
The "alkynyl group" refers to, for example, C alkynyl groups such as ethynyl, 1-propynyl, propargyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and 4-hexynyl._2-10It represents an alkynyl group, etc.
The "cycloalkyl group" is, for example, a C group such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl._3-10This indicates a cycloalkyl group, etc.
The "cycloalkyl-alkyl group" is, for example, a C group such as cyclopropylmethyl._3-6Cycloalkyl-C_1-6This indicates an alkyl group, etc.
The "alkoxy group" refers to, for example, C alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy._1-10This indicates an alkoxy group, etc.
【0016】
The "alkenyloxy group" refers to a C group such as allyloxy or isopropenyloxy._2-10It represents an alkenyloxy group, etc.
The "alkynyloxy group" is, for example, a C group such as propargyloxy._2-10It represents an alkynyloxy group, etc.
The "aryloxy group" is, for example, a C group such as phenoxy._6-14An aryloxy group, etc.
The "aralkyloxy group" is, for example, a C group such as benzyloxy._7-16This represents an aralkyloxy group, etc.
The "alkylthio group" is, for example, a C alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, or hexylthio._1-10This represents an alkylthio group, etc.
The "alkenylthio group" is, for example, a C group such as allylthio or isopropenylthio._2-10It represents an alkenylthio group, etc.
The "alkynylthio group" is, for example, a C group such as propargylthio._2-10It represents an alkynylthio group, etc.
The "arylthio group" is, for example, a C such as phenylthio._6-14An arylthio group or the like.
The "aralkylthio group" is, for example, a C group such as benzylthio._7-16It represents an aralkylthio group, etc.
【0017】
The "alkylsulfinyl group" includes, for example, C groups such as methylsulfinyl and ethylsulfinyl._1-10It represents an alkylsulfinyl group, etc.
The "alkenylsulfinyl group" refers to a C group such as allylsulfinyl or isopropenylsulfinyl._2-10It represents an alkenylsulfinyl group, etc.
The "alkynylsulfinyl group" is, for example, a C group such as propargylsulfinyl._2-10It represents an alkynylsulfinyl group, etc.
The "arylsulfinyl group" is, for example, a C group such as benzenesulfinyl._6-14An arylsulfinyl group, etc.
The "alkylsulfonyl group" refers to a C group such as methylsulfonyl, ethylsulfonyl, or propylsulfonyl._1-10It represents an alkylsulfonyl group, etc.
The "alkenylsulfonyl group" refers to a C group such as allylsulfonyl or isopropenylsulfonyl._2-10It represents an alkenylsulfonyl group, etc.
The "alkynylsulfonyl group" is, for example, a C group such as propargylsulfonyl._2-10It represents an alkynylsulfonyl group, etc.
The "arylsulfonyl group" is, for example, a C group such as benzenesulfonyl._6-14An arylsulfonyl group, etc.
The "mono- or di-alkylcarbamoyloxy group" refers to a mono- or di-C alkylcarbamoyloxy group, such as methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, or diethylcarbamoyloxy._1-6An alkylcarbamoyloxy group or the like is shown.
The "mono- or di-alkylphosphonooxy group" refers to a mono- or di-C alkylphosphonooxy group, such as methylphosphonooxy, dimethylphosphonooxy, or diethylphosphonooxy._1-6An alkylphosphonooxy group, etc.
The "mono- or di-alkylamino group" refers to a mono- or di-C alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, or diethylamino._1-10It represents an alkylamino group, etc.
【0018】
The "mono- or di-aralkylamino group" refers to a mono- or di-C, such as benzylamino._7-16This represents an aralkylamino group, etc.
The "cyclic amino group" refers to a 5- or 6-membered cyclic amino group such as pyrrolidino, piperidino, piperazino, morpholino, etc.
The "mono- or di-alkylcarbamoyl group" refers to a mono- or di-C alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, or diethylcarbamoyl._1-10It represents an alkylcarbamoyl group, etc.
The "mono- or di-arylcarbamoyl group" refers to a mono- or di-C, such as phenylcarbamoyl._6-14An arylcarbamoyl group or the like.
The "alkoxy-carbonyl group" refers to a C group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and butoxycarbonyl._1-10It represents an alkoxy-carbonyl group, etc.
The "alkenyloxy-carbonyl group" refers to, for example, C groups such as allyloxycarbonyl and isopropenyloxycarbonyl._2-10It represents an alkenyloxy-carbonyl group, etc.
The "alkynyloxy-carbonyl group" refers to, for example, C such as propargyloxycarbonyl._2-10An alkynyloxy-carbonyl group is shown.
The "aryloxy-carbonyl group" is, for example, a C group such as phenoxycarbonyl._6-14An aryloxy-carbonyl group, etc.
The "alkylsulfonylamino group" is, for example, a C group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, or butylsulfonylamino._1-10An alkylsulfonylamino group or the like.
The "aralkyl group" is, for example, a C alkyl group such as benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, or 5-phenylpentyl._7-16This indicates an aralkyl group, etc.
The "aryl group" is, for example, a C-substituted aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenyl, or 2-anthryl._6-14This indicates an aryl group, etc.
The "arylimino group" is, for example, a C such as phenylimino._6-14An aryl imino group, etc.
【0019】
The term "aromatic heterocyclic group" refers to, for example, a 5- to 10-membered aromatic heterocyclic group or a fused bicyclic aromatic heterocyclic group containing, in addition to carbon, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Specific examples include 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-quinolyl, 4-quinolyl, 8-quinolyl, 3-isoquinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 1-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 3-isoxazolyl, 3-pyridazinyl, 2-pyridon-1-yl, 3-pyridon-1-yl, and 1-isoindolinyl. , 2-isoindolyl, 1-indolyl, 3-indolyl, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-purinyl, 6-purinyl, 7-purinyl, 8-purinyl, 9-purinyl, 1-xanthinyl, 3-xanthinyl, 7-xanthinyl, 8-xanthinyl, 2-quinazolinyl , 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 4(3H)-quinazolinon-2-yl, 4(3H)-quinazolinon-3-yl, 4(3H)-quinazolinon-5-yl, 4(3H)-quinazolinon-6-yl, 4(3H)-quinazolinon-7-yl, 4(3H)-quinazolinon-8-yl, and the like are used.
The "alkyl-carbonyl group" refers to a C group such as acetyl, propionyl, butyryl, and valeryl._1-10It represents an alkyl-carbonyl group, etc.
The "alkenyl-carbonyl group" refers to, for example, C such as acryloyl._2-10It represents an alkenyl-carbonyl group, etc.
The "alkynyl-carbonyl group" refers to, for example, C such as propioloyl._2-10It represents an alkynyl-carbonyl group, etc.
The "aryl-carbonyl group" refers to, for example, C such as benzoyl._6-14An arylcarbonyl group or the like.
The "acylamino group" refers to a C group such as formylamino, acetylamino, propionylamino, butyrylamino, or benzoylamino._1-10It represents an acylamino group, etc.
The "substituted amino group" represented by "Q" in "-CO-Q" is, for example, a mono- or di-C_1-6It represents an alkylamino group (for example, methylamino, ethylamino, dimethylamino, diethylamino, etc.), a cyclic amino group (for example, a 5- to 8-membered cyclic amino group such as pyrrolidino, piperidino, piperazino, morpholino, etc.), etc.
The "acyloxy group" refers to a C group such as formyloxy, acetoxy, or propionyloxy._1-10It represents an acyloxy group, etc.
【0020】
The substituent "-L" may further include a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.) at a substitutable position of the substituent, C_1-6Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, etc.), C_2-6Alkenyl groups (e.g., vinyl, allyl, etc.), C_2-6Alkynyl groups (e.g., ethynyl, propargyl, etc.), C_3-6Cycloalkyl groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, etc.), carboxyl groups, hydroxyl groups, cyano groups, nitro groups, sulfo groups, phosphono groups, oxo groups, C_1-6Alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, etc.), C_6-10Aryloxy groups (e.g., phenoxy, etc.), C_7-14Aralkyloxy group (e.g., benzyloxy, etc.), mercapto group, C_1-6Alkylthio groups (e.g., methylthio, ethylthio, propylthio, isopropylthio, etc.), C_6-10arylthio groups (e.g., phenylthio, etc.), C_7-14Aralkylthio group (e.g., benzylthio, etc.), carbamoyl group, mono- or di-C_1-6Alkylcarbamoyl group (e.g., methylcarbamoyl, dimethylcarbamoyl, etc.), amino group, mono- or di-C_1-6Alkylamino groups (e.g., methylamino, ethylamino, dimethylamino, diethylamino, etc.), cyclic amino groups (e.g., pyrrolidino, piperidino, piperazino, morpholino, etc.), mono- or di-C_7-14Aralkylamino group (e.g., benzylamino, etc.), C_6-10Aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.), C_7-14Aralkyl groups (e.g., benzyl, etc.), formyl groups, C_1-6Alkyl-carbonyl groups (e.g., acetyl, propionyl, butyryl, valeryl, etc.), C_6-10Aryl-carbonyl groups (e.g., benzoyl, etc.), C_1-6Alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, etc.), acyloxy groups (e.g., formyloxy, acetoxy, etc.), and aromatic heterocyclic or aromatic heterocyclic thio groups ("aromatic heterocyclic group" refers to, for example, a 5- to 10-membered aromatic heterocyclic group or a fused bicyclic aromatic hydrocarbon group containing, in addition to carbon, 1 to 4 heteroatoms selected from nitrogen atoms, oxygen, and sulfur, and specifically is 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-quinolyl, 4-quinolyl, 8-quinolyl, 3-isoquinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 1-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 3-isoxazolyl, 3-pyridazinyl, 2-pyridon-1-yl, 3-pyridyl don-1-yl, 1-isoindolyl, 2-isoindolyl, 1-indolyl, 3-indolyl, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-purinyl, 6-purinyl, 7-purinyl, 8-purinyl, 9-purinyl, 1-xanthinyl, 3-xanthinyl, 7-xanthinyl, 8-xanthinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8 4(3H)-quinazolinyl, 4(3H)-quinazolinon-2-yl, 4(3H)-quinazolinon-3-yl, 4(3H)-quinazolinon-5-yl, 4(3H)-quinazolinon-6-yl, 4(3H)-quinazolinon-7-yl, 4(3H)-quinazolinon-8-yl, etc.) and the like. The substituent (-M) may further have a substituent "-M" as described above on the substituent to form a substituent (-M-M). In other words, "A" may have a substituent: -L-M-M.
When A has a hydroxyl group or a mercapto group, their tautomers, such as keto and thione forms, are also included in the compounds of the present invention.
【0021】
In the formula [I], Ar¹and Ar²represents an optionally substituted ring.
The "ring" in the term "optionally substituted ring" refers to, for example, a cyclic hydrocarbon, a heterocycle, etc.
The "cyclic hydrocarbon" may be, for example, a monocyclic or fused polycyclic hydrocarbon having 6 to 14 carbon atoms, specifically C_6-10Aromatic hydrocarbons (e.g., benzene, naphthalene, etc.), C_6-10Cycloalkanes (for example, cyclohexane) are commonly used, with benzene being particularly preferred.
Examples of such "heterocycles" include monocyclic heterocycles containing one or two, preferably one to four, heteroatoms selected from nitrogen, oxygen, and sulfur in addition to carbon, as well as those fused with other rings (e.g., the aforementioned cyclic hydrocarbons or monocyclic heterocycles) to form fused bicyclic or tricyclic heterocycles. Examples of such "monocyclic heterocycles" include six-membered monocyclic heterocycles (e.g., furan, thiophene, pyrrole, pyridine, pyrazole, imidazole, oxazole, thiazole, pyrazine, pyrimidine, pyridazine, isoxazole, isothiazole, triazole, etc.) and five- or six-membered cyclic aminos (e.g., pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, etc.). Examples of the "fused bicyclic or tricyclic heterocycle" include benzofuran, indole, indazole, quinoline, benzothiazole, coumarin, isoquinoline, and the like, and preferably pyridine, piperidine, piperazine, pyrimidine, and morpholine.¹and Ar²may be the same or different.
【0022】
The substituents that the "ring" of the "optionally substituted ring" may have include, for example, the same as the substituents that the "fused pyrimidinone ring or fused pyridazinone ring" represented by A above may have. These substituents are substituted at substitutable positions on the ring, and the number of substituents is 1 to 5, preferably 1 to 3. However, when the number of substituents is 2 or more, they may be the same or different. Ar¹and Ar²The total number of the substituents in Ar is preferably 5 or less.²is, for example, a halogen atom, C_1-10Alkyl group, C_2-10Alkenyl group, C_1-10Alkoxy group, C_6-14Aryloxy group, C_7-16Aralkyloxy group, C_1-10Alkylthio group, carbamoyloxy group, mono- or di-C_1-10Alkylcarbamoyloxy group, phosphonooxy group, mono- or di-C_1-10Alkylphosphonooxy group, nitro group, cyano group, hydroxyl group, amino group, mono- or di-C_1-10Alkylamino group, cyclic amino group, carboxyl group, mercapto group, carbamoyl group, mono- or di-C_1-10Alkylcarbamoyl group, C_1-10Alkoxy-carbonyl group, C_6-14Allyloxy-carbonyl group, C_7-16Aralkyl group, C_6-14Aryl group, formyl group, C_1-10Alkyl-carbonyl group, C_6-14Aryl-carbonyl group, C_1-10Acylamino group and C_1-10It is preferred that the alkyl group has 1 to 5 substituents selected from the group consisting of 1 to 3 halogen atoms, C_1-6Alkyl group, carboxyl group, hydroxyl group, oxo group, C_1-6Alkoxy group, C_1-3Alkylenedioxy group, C_6-10Aryloxy group, C_7-14Aralkyloxy group, mercapto group, C_1-6Alkylthio group, carbamoyl group, mono- or di-C_1-6Alkylcarbamoyl group, amino group, mono- or di-C_1-6Alkylamino group, cyclic amino group, C_6-10Aryl group, C_7-14Aralkyl group, formyl group, C_1-6Alkyl-carbonyl group, C_6-10Aryl-carbonyl group, C_1-6Alkoxy-carbonyl group, C_1-6an acyloxy group, an aromatic heterocyclic group, or an aromatic heterocyclic thio group, these substituents further containing 1 to 3 halogen atoms, C_1-6Alkyl group, oxo group, C_1-6Alkoxy group, amino group or mono- or di-C_1-6It may have an alkylamino group.
In the formula [I], Z represents a divalent group. The "divalent group" refers to, for example, a fused pyrimidinone or fused pyridazinone ring and a ring (Ar¹) are bonded by 1 to 5 (preferably 1 to 3) atoms selected from carbon, nitrogen, oxygen, sulfur, etc., such as -NH-, -O-, -S-, or a divalent aliphatic group (for example, a linear or branched aliphatic group having 1 to 6 carbon atoms) which may contain these groups at any position, and specifically, for example, -CH₂-, -NH-, -O-, -S-, -CH₂CH₂-, -CH₂—NH—, —CH₂—O—, —CH₂—S—, —CH₂CH₂CH₂-, -NH-CH₂CH₂-, -CH₂—NH—CH₂—, —O—CH₂CH₂-, -CH₂—O—CH₂-, -S-CH₂CH₂-, -CH₂-S-CH₂- (these bonds may be oriented in any direction).
【0023】
The "divalent group" is, for example, C_1-6Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), C_2-6Alkenyl groups (e.g., vinyl, allyl, isopropenyl, etc.), C_2-6Alkynyl groups (e.g., propargyl, ethynyl, etc.), C_1-6Alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, etc.), C_1-6Alkylthio groups (e.g., methylthio, ethylthio, propylthio, isopropylthio, etc.), C_1-6It may have 1 to 3 substituents selected from an acyl group (e.g., formyl, acetyl, etc.), an amino group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, a mercapto group, an oxo group, etc.
When the "divalent group" represented by Z contains consecutive carbon atoms, the carbon-carbon bonds may be unsaturated bonds (e.g., double bonds). For example, -CH=CH-, -CH₂-CH=CH- and the like.
【0024】
A and Ar in the formula [I]¹, Ar²Preferred examples of Z are shown below.
(1) A:
(A-1) "Optionally substituted pyrimidinone ring"; the term "optionally substituted pyrimidinone ring" has the same meaning as defined above.
(A-2) "Optionally substituted pyrrolo[2,3-d]pyrimidin-4-one, quinazolin-4-one, pyrido[1,2-a]pyrimidin-4-one, thiazolo[3,2-a]pyrimidin-5-one, pyrimido[2,1-b][1,3]thiazin-6-one or imidazo[2,1-b]quinazolin-5-one"; the term "optionally substituted" refers to the same substituents as the "fused pyrimidinone ring" may have.
【0025】
(A-3) formula
[C29]
[In the formula, A¹and A²each represents an optionally substituted 5- to 8-membered homocyclic or heterocyclic ring; R¹and R²are hydrogen, halogen, and C, respectively._1-6Alkyl group, halo-C_1-6Alkyl group, hydroxyl group, C_1-6Alkoxy group, halo-C_1-6Alkoxy group, C_1-6Alkylthio group or halo-C_1-6an alkylthio group, preferably hydrogen or C_1-6The term "5- to 8-membered homo- or heterocyclic ring" refers to a ring which may contain, in addition to carbon, 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and specifically includes cyclopentane, cyclohexane, cycloheptane, benzene, imidazole, pyridine, thiazine, thiazole, oxazole, thiophene, pyrrole, pyrazole, pyrazine, pyrimidine (which may be partially reduced), and these are also examples of the ring represented by the above R¹and R²The term "halogen" refers to, for example, fluorine, chlorine, bromine, iodine, etc., and the term "C_1-6The term "alkyl group" refers to, for example, methyl, ethyl, propyl, isopropyl, etc., and the term "halo-C_1-6The term "alkyl group" refers to, for example, trifluoromethyl, and the term "C_1-6The term "alkoxy group" refers to, for example, methoxy, ethoxy, propoxy, isopropoxy, etc., and the term "halo-C_1-6The term "alkoxy group" refers to, for example, trifluoromethoxy, and the like._1-6The term "alkythio group" refers to, for example, methylthio, ethylthio, propylthio, isopropylthio, etc., and the term "halo-C_1-6The "alkylthio group" means, for example, trifluoromethylthio.
【0026】
(A-4) Formula
[C30]
[The symbols in the formula have the same meanings as in (A-3) above.] A ring represented by the formula:
【0027】
(A-5) formula
[Chemical formula 31]
[The symbols in the formula have the same meanings as in (A-3) above.] A ring represented by the formula:
【0028】
(A-6) formula
[C32]
[Where n is an integer from 0 to 3, and the other symbols have the same meanings as in (A-3) above.] A ring represented by the formula:
【0029】
(A-7) formula
[Chemical formula 33]
[Where n is an integer from 0 to 3, and the other symbols have the same meanings as in (A-3) above.] A ring represented by the formula:
【0030】
(A-8) Formula
[C34]
[In the formula, R¹has the same meaning as that of the above (A-3).
【0031】
(2) Z:
(B-1) A divalent C group which may contain -NH-, -O-, or -S-_1-6Aliphatic hydrocarbon group (Z^aThe term "divalent C_1-6Examples of the "aliphatic hydrocarbon group" include C_1-6Alkylene group (e.g., methylene, ethylene, trimethylene, tetramethylene, etc.) or C_2-6Alkenylene groups (for example, vinylene, propenylene, etc.) are used.
(B-2) Divalent C which may contain -O- or -S-_1-6Aliphatic hydrocarbon group; the term "divalent C_1-6The "aliphatic hydrocarbon group" may be, for example, the same as those described above.
(B-3) C optionally containing -O- or -S-_1-6Alkylene group; the term "C_1-6As the "alkylene group", for example, methylene, ethylene, trimethylene, tetramethylene, etc. are used, with methylene being the most commonly used.
(B-4) C which may contain -O-_1-6Alkylene group; the term "C_1-6As the "alkylene group", for example, methylene, ethylene, trimethylene, tetramethylene, etc. are used, with methylene being the most commonly used.
(B-5) C_2-6Alkenylene group; the term "C_2-6The "alkenylene group" includes, for example, vinylene.
(B-6)-S-CH₂—, —O—CH₂—or —CH₂−.
(B-7)-O-CH₂—or —CH₂−.
【0032】
(3) Ar¹:
(C-1) An optionally substituted aromatic ring; the term "aromatic ring" refers to, for example, C_6-10Aromatic hydrocarbons (e.g., benzene, naphthalene, etc.) or pyridine are used. The term "optionally substituted" refers to the same substituents as those that A may have.
(C-2) Para-substituted benzene.
(4) Ar²:
(D-1) An optionally substituted aromatic ring; the term "aromatic ring" refers to, for example, C_6-10Examples of suitable substituents include aromatic hydrocarbons (e.g., benzene, naphthalene, etc.), pyridine, indole, pyrrole, imidazole, thiophene, pyrazine, pyrimidine, purine, quinoline, isoquinoline, etc. The term "optionally substituted" refers to, for example, the same substituents as those that A may have.
(D-2) An optionally substituted phenyl, pyridyl, indolyl, pyrrolyl, thienyl, piperidino, piperazino or morpholino group; the term "optionally substituted" refers to, for example, the same substituents as those that A may have.
(D-3) An optionally substituted phenyl group; the term "optionally substituted" refers to, for example, the same substituents as those that A may have.
(D-4) An optionally substituted piperidino, piperazino or morpholino group; the term "optionally substituted" refers to, for example, the same substituents as those that A may have.
(D-5) An optionally substituted piperidino or piperazino group; the term "optionally substituted" refers to, for example, the same substituents as those that A may have.
【0033】
(D-6) C_1-6Alkyl, halo-C_1-6Alkyl, C_1-6Alkoxy, halo-C_1-6Alkoxy, C_1-6Alkylthio, halo-C_1-6Alkylthio, halogen, amino, mono- or di-C_1-6Alkylamino, C_1-6Acylamino, C_1-6Alkyl-carbonyl, C_6-10Aryl-carbonyl, C_7-14Aralkyl-carbonyl, C_1-6Alkoxy-carbonyl, C_1-6Acyloxy, carbamoyloxy, mono- or di-C_1-6Alkylcarbamoyloxy, cyano, nitro, carbamoyl and mono- or di-C_1-6a phenyl group optionally substituted by 1 to 5 substituents selected from alkylcarbamoyl;_1-6The term "alkyl" refers to, for example, methyl, ethyl, propyl, isopropyl, etc., and the term "halo-C_1-6The term "C alkyl" refers to, for example, trifluoromethyl, etc._1-6"Alkoxy" refers to, for example, methoxy, ethoxy, propoxy, isopropoxy, etc., and the term "halo-C_1-6"Alkoxy" refers to, for example, trifluoromethoxy, and the term "C_1-6The term "alkythio" refers to, for example, methylthio, ethylthio, propylthio, isopropylthio, etc., and the term "halo-C_1-6The term "alkylthio" refers to, for example, trifluoromethylthio, the term "halogen" refers to, for example, fluorine, chlorine, bromine, iodine, and the term "mono- or di-C_1-6The term "alkylamino" refers to, for example, methylamino, ethylamino, dimethylamino, diethylamino, etc._1-6"Acylamino" refers to, for example, formylamino, acetylamino, etc., and the term "C_1-6"Alkyl-carbonyl" refers to, for example, acetyl, propionyl, etc._6-10"Aryl-carbonyl" refers to, for example, benzoyl, and the term "C_7-14"Aralkyl-carbonyl" refers to, for example, benzylcarbonyl, and the term "C_1-6"Alkoxy-carbonyl" refers to, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc., and the term "C_1-6The term "acyloxy" refers to, for example, formyloxy, acetoxy, etc., and the term "mono- or di-C_1-6The term "alkylcarbamoyloxy" refers to, for example, methylcarbamoyloxy, dimethylcarbamoyloxy, etc., and the term "mono- or di-C_1-6The term "alkylcarbamoyl" refers to, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and the like.
【0034】
(D-7) Formula
[C35]
[In the formula, R^arepresents the same meaning as the substituent that A may have;^aPreferred examples of the halogen atom include halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), C_1-6Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, etc.), halo-C_1-6Alkyl groups (e.g., trifluoromethyl, etc.), C_1-6an alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, etc.) or a halo-C_1-6Alkoxy groups (for example, trifluoromethoxy) and the like are included.
【0035】
(D-8) Formula
[C36]
[In the formula, R^ahas the same meaning as defined above.
【0036】
(D-9) formula
[C37]
[In the formula, Ar³is a ring; W is a bond, carbonyl or -NR³Divalent C which may contain -, -O- or -S-_1-6aliphatic hydrocarbon group, R³is hydrogen or C_1-6an alkyl group; T represents an optionally substituted primary, secondary, or tertiary amino group;³The term "ring" represented by the formula¹and Ar²The same as Ar is used.³Preferred examples of the formula include piperidino, piperazino, phenyl, and pyridyl, and more preferred examples of the formula include
[C38]
The term "divalent C_1-6The "aliphatic hydrocarbon group" is one described in (B-1) above, and is preferably -CH₂-, -CH₂CH₂—, —O—CH₂CH₂The term "primary to tertiary amino group" refers to, for example, mono- or di-C_1-6Alkylamino (e.g., methylamino, ethylamino, dimethylamino, diethylamino, etc.), mono- or di-C_6-10It refers to arylamino (e.g., phenylamino, diphenylamino, etc.), cyclic amino (e.g., piperidino, piperazino, morpholino, etc.), etc., and preferably cyclic amino (e.g., piperidino, piperazino, etc.), etc. The "primary to tertiary amino group" may have 1 to 3 substituents such as the above-mentioned -M.
【0037】
Preferred combinations are shown below (/ indicates the separation between combinations):
(A-1), (B-1), (C-1), (D-1)/(A-2), (B-1), (C-2), (D-1)/(A-3), (B-1), (C-2), (D -1)/(A-4), (B-1), (C-2), (D-1)/(A-5), (B-1), (C-2), (D-1)/(A-6), (B-1), (C-2) , (D-1)/(A-7), (B-1), (C-2), (D-1)/(A-2), (B-2), (C-2), (D-1)/(A-3), (B-2), ( C-2), (D-1)/(A-4), (B-2), (C-2), (D-1)/(A-5), (B-2), (C-2), (D-1)/(A-6), (B-2 ), (C-2), (D-1)/(A-7), (B-2), (C-2), (D-1)/(A-2), (B-3), (C-2), (D-1)/(A-3), (B-3), (C-2), (D-1)/(A-4), (B-3), (C-2), (D-1)/(A-5), (B-3), (C-2), (D-1)/(A- 6), (B-3), (C-2), (D-1)/(A-7), (B-3), (C-2), (D-1)/(A-2), (B-4), (C-2), (D-1) /(A-3), (B-4), (C-2), (D-1)/(A-4), (B-4), (C-2), (D-1)/(A-5), (B-4), (C-2), (D -1)/(A-6), (B-4), (C-2), (D-1)/(A-7), (B-4), (C-2), (D-1)/(A-2), (B-5), (C-2 ), (D-1)/(A-3), (B-5), (C-2), (D-1)/(A-4), (B-5), (C-2), (D-1)/(A-5), (B-5), ( C-2), (D-1)/(A-6), (B-5), (C-2), (D-1)/(A-7), (B-5), (C-2), (D-1)/(A-3), (B- 3), (C-2), (D-2)/(A-4), (B-3), (C-2), (D-2)/(A-4), (B-3), (C-2), (D-2)/(A-5), (B-3), (C-2), (D-2)/(A-6), (B-3), (C-2), (D-2)/(A-7), (B-3), (C-2), (D-2)/(A -3), (B-5), (C-2), (D-2)/(A-4), (B-5), (C-2), (D-2)/(A-5), (B-5), (C-2), (D-2) /(A-6), (B-5), (C-2), (D-2)/(A-7), (B-5), (C-2), (D-2)/(A-3), (B-3), (C-2), ( D-3)/(A-3), (B-3), (C-2), (D-4)/(A-4), (B-3), (C-2), (D-3)/(A-4), (B-3), (C-2 ), (D-4)/(A-5), (B-3), (C-2), (D-3)/(A-6), (B-3), (C-2), (D-6)/(A-7), (B-3), (C-2), (D-6)/(A-6), (B-4), (C-2), (D-6)/(A-7), (B-4), (C-2), (D-6)/(A-6), (B- 6), (C-2), (D-5)/(A-7), (B-6), (C-2), (D-5)/(A-6), (B-7), (C-2), (D-6)/(A-7) , (B-7), (C-2), (D-6)/(A-6), (B-7), (C-2), (D-7)/(A-7), (B-7), (C-2), (D-7)/(A -6), (B-7), (C-2), (D-8)/(A-7), (B-7), (C-2), (D-8)/(A-1), (B-1), (C-1), (D-9 )/(A-2), (B-1), (C-2), (D-9)/(A-3), (B-1), (C-2), (D-9)/(A-4), (B-1), (C-2), ( D-9)/(A-5), (B-1), (C-2), (D-9)/(A-6), (B-1), (C-2), (D-9)/(A-7), (B-1), (C- 2), (D-9)/(A-8), (B-1), (C-2), (D-9)/(A-3), (B-2), (C-2), (D-9)/(A-4), (B-2), (C-2), (D-9)/(A-5), (B-2), (C-2), (D-9)/(A-6), (B-2), (C-2), (D-9)/(A-7), (B -2), (C-2), (D-9)/(A-8), (B-2), (C-2), (D-9)/(A-3), (B-4), (C-2), (D-9)/(A-4) , (B-4), (C-2), (D-9)/(A-5), (B-4), (C-2), (D-9)/(A-6), (B-4), (C-2), (D-9)/( A-7), (B-4), (C-2), (D-9)/(A-8), (B-4), (C-2), (D-9)/(A-3), (B-6), (C-2), (D-9 )/(A-4), (B-6), (C-2), (D-9)/(A-5), (B-6), (C-2), (D-9)/(A-6), (B-6), (C-2), (D-9)/(A-7), (B-6), (C-2), (D-9)/(A-8), (B-6), (C-2), (D-9)/(A-3), (B-7), (C- 2), (D-9)/(A-4), (B-7), (C-2), (D-9)/(A-5), (B-7), (C-2), (D-9)/(A-6), (B-7), (C-2), (D-9)/(A-7), (B-7), (C-2), (D-9)/(A-8), (B-7), (C-2), (D-9), etc.
More preferred compounds among compound [I] or its salts include the following compounds.
【0038】
(1) General formula: B-Z-Ar¹—CO—Ar²[I-a]
[Wherein B is an optionally substituted (1) pyrrolo[2,3-d]pyrimidin-4-one, (2) pyrrolo[3,2-d]pyrimidin-4-one, (3) pyrrolo[3,4-d]pyrimidin-4-one, (4) pyrazolo[3,4-d]pyrimidin-4-one, (5) pyrazolo[4,3-d]pyrimidin-7-one, (6) 6-oxopurine, (7) thieno[2,3-d]pyrimidin-4-one, (8) Thieno[3,4-d]pyrimidin-4-one, (9) thieno[3,2-d]pyrimidin-7-one, (10) furo[2,3-d]pyrimidin-4-one, (11) furo[3,4-d]pyrimidin-4-one, (12) furo[3,2-d]pyrimidin-7-one, (13) isoxazolo[5,4-d]pyrimidin-4-one, (14) isoxazolo[4,5-d]pyrimidin-7-one, (15) o (16) oxazolo[5,4-d]pyrimidin-4-one, (17) thiazolo[5,4-d]pyrimidin-4-one, (18) thiazolo[4,5-d]pyrimidin-7-one, (19) isothiazolo[5,4-d]pyrimidin-4-one, (20) isothiazolo[4,5-d]pyrimidin-7-one, (21) triazolo[4,5-d]pyrimidin (22) 1,2,4-triazolo[1,5-a]pyrimidin-7-one, (23) dihydrocyclopenta[d]pyrimidin-4-one, (24) 5H or 7H-cyclopenta[d]pyrimidin-4-one, (25) pyrido[2,3-d]pyrimidin-4-one, (26) pyrido[3,2-d]pyrimidin-4-one, (27) pyrido[4,3-d]pyrimidin-4-one, (28) ) pyrido[3,4-d]pyrimidin-4-one, (29) pteridin-4-one, (30) pyrrolo[1,2-a]pyrimidin-4-one, (31) pyrimido[3,4-a]pyrimidin-4-one, (32) pyrimido[4,5-d]pyrimidin-4-one, (33) pyrimido[5,4-d]pyrimidin-4-one, (34) pyridazino[2,3-a]pyrimidin-4-one, (35) pyridazino[ 4,3-d]pyrimidin-4-one, (36) pyridazino[3,4-d]pyrimidin-4-one, (37) xanthine, (38) uric acid, (39) pyrrolo[3,2-d]pyrimidine-2,4-dione, (40) pyrrolo[2,3-d]pyrimidine-2,4-dione, (41) pyrrolo[3,4-d]pyrimidine-2,4-dione, (42) pyridazino[4,5-b]-1,5-oxazepine-9(8H) -one, (43) pyridazino[4,5-b]-1,4-oxazin-8(7H)-one, (44) pyrrolo[3,4-d]pyridazin-4(5H)-one, (45) pyrrolo[2,3-d]pyridazin-7(6H)-one, (46) pyrrolo[2,3-d]pyridazin-4(5H)-one, (47) imidazo[4,5-d]pyridazin-4(5H)-one, (48) imidazo[4,5-c]pyridazin- the other symbols are as defined above.] or a salt thereof.
The substituents that B may have include, for example, those similar to the substituents that A may have.
【0039】
(2) General formula: D-Alk-E-Ar¹—CO—Ar²[I-b]
[Wherein D is an optionally substituted (1) quinazolin-5-one, (2) pyrido[1,2-a]pyrimidin-4-one, (3) imidazo[1,2-a]pyrimidin-5-one, (4) thiazolo[3,2-a]pyrimidin-5-one, (5) oxazolo[3,2-a]pyrimidin-5-one, or (6) pyrido[1,2-a]pyrimidin-4-one;
Alk is C_1-3Alkylene groups (e.g., —CH₂-, -CH₂CH₂− etc.);
E is a bond, -S-, -O-, -NR-, -S-CH₂—, —O—CH₂-or -NR-CH₂- [R is a hydrogen atom, C_1-6Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, etc.) or C_2-6represents an alkenyl group (for example, vinyl, aryl, etc.); other symbols are as defined above; or a salt thereof.
The substituents that D may have include, for example, those similar to the substituents that A may have.
(3) -Z-Ar at the 1-position of an optionally substituted imidazo[1,2-a]pyrimidin-5-one¹—CO—Ar²or a salt thereof.
The substituents that imidazo[1,2-a]pyrimidin-5-one may have include the same substituents that A may have. Z, Ar¹, Ar²has the same meaning as above.
Compound [I] or its salt can be prepared, for example, by the method shown below.
【0040】
[Reaction scheme]
(1 set)
HZ-Ar¹+ X-CO-Ar²→ HZ-Ar¹-CO-Ar²
HZ-Ar¹−CO−X + Ar²→ HZ-Ar¹-CO-Ar²
(2 sets)
Y-Ar¹+ X-CO-Ar²→ Y-Ar¹-CO-Ar²
Y-Ar¹−CO−X + Ar²→ Y-Ar¹-CO-Ar²
(3 types)
A-Y^a+ Y-Ar¹-CO-Ar²→ A-Z-Ar¹-CO-Ar²
(4 types)
A + X-Z-Ar¹-CO-Ar → A-Z-Ar¹-CO-Ar²
A-X + HZ-Ar¹-CO-Ar²→ A-Z-Ar¹-CO-Ar²
(Type 5)
A^a+ A^b-Z-Ar¹-CO-Ar²→ A-Z-Ar¹-CO-Ar²
(6 types)
A-Z-Ar¹+ XCO-Ar²→ A-Z-Ar¹-CO-Ar²
[In the reaction scheme, -CO-X is a reactive derivative of a carboxyl group, Y and Y^arepresents a divalent group represented by Z when both react, X-Z- represents a reactive derivative of Z, A^aand A^brepresents a fused pyrimidinone or fused pyridazinone ring represented by A upon reaction of the two.
【0041】
In the formula (1), reactive derivatives of the carboxyl group represented by -CO-X include, for example, acid halides (e.g., acid chlorides, acid bromides, etc.), acid anhydrides (Ar²Examples of suitable solvents include anhydrides of COOH and mixed acid anhydrides with formic acid. The reaction is usually carried out in the presence of a Lewis acid (e.g., aluminum chloride, aluminum bromide, tin chloride, antimony chloride, titanium chloride, boron trifluoride, etc.). The solvent used in this reaction is not particularly limited as long as it is inert to the reaction, but carbon disulfide and halogenated hydrocarbons are commonly used.¹and Ar²When is liquid, HZ-Ar¹or Ar²The reaction temperature ranges from 0°C to the boiling point of the solvent, but is generally 20 to 80°C. The reaction time is about 1 to 12 hours. The amount of catalyst used varies depending on the reaction substrate, but is 1 to 5 times the amount of the reactive derivative of the carboxyl group used. The above formula (2) also proceeds under the same conditions as formula (1). In the above formulas (2) and (3), Y and Y^ais a group that generates a divalent group represented by Z in a carbon-carbon bond forming reaction, a nitrogen-carbon bond forming reaction, an oxygen-carbon bond forming reaction, a sulfur-carbon bond forming reaction, or the like.^aExamples of reactions that produce a divalent group represented by Z from include the Wittig reaction, the Grignard reaction, the aldol reaction, the Claisen reaction, carbon-carbon bond formation reactions using transition metals, nitrogen-carbon bond formation reactions by alkylation or arylation of amino groups, oxygen-carbon bond formation reactions by O-alkylation of alcohols, and sulfur-carbon bond formation reactions by S-alkylation of mercaptans. The alkylation of amino groups, alcohols, and mercaptans usually proceeds favorably in the presence of a base. Examples of bases that can be used include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, and sodium ethoxide. For the alkylation of amino groups and mercaptans, typical solvents include alcohols (e.g., methanol, ethanol, propanol, etc.), amides (e.g., dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone, etc.), and dimethyl sulfoxide. For the alkylation of alcohols, amides and dimethyl sulfoxide are commonly used. These reactions proceed in the range of 0° C. to the boiling point of the solvent, preferably room temperature to the boiling point of the solvent, and are completed in 1 to 10 hours, usually about 5 hours.^aWhen one of the groups is an amino group and the other is a carboxylic acid or its derivative, Z may be formed by the formation of an amide bond. The method used in this case is a conventional amide bond formation reaction. When the fused pyrimidinone or fused pyridazinone ring represented by A has an amino group, the process of bonding Z to the amino group is shown in (4). Examples of reactive derivatives of Z represented by X-Z- include those where X is a halogen (e.g., chlorine, bromine, iodine, etc.) or an alkyl or arylsulfonyloxy group (e.g., methanesulfonyloxy, paratoluenesulfonyloxy, etc.). The reaction is usually carried out in the presence of a base. Examples of bases that can be used include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, and sodium ethoxide. Any solvent inert to the reaction can be used, and commonly used solvents include methanol, ethanol, dimethyl sulfoxide, dimethylformamide, and dimethylacetamide. The reaction temperature is between 0°C and the boiling point of the solvent, and the reaction is completed in 1 to 10 hours, usually about 5 hours. In the step of forming the fused pyrimidinone and fused pyridazinone rings represented by A in the formula (5), a precursor A of these rings is^aor A^bis already -Z-Ar¹-CO-Ar²As shown in the above formula (6), A-Z-Ar¹After synthesizing the part, -CO-Ar²A moiety represented by the following formula may be introduced.
【0042】
The raw material compounds and manufacturing intermediates of the present invention may form salts, and the manufacturing process is not particularly limited, but examples of acids that can be used include inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.), organic acids (e.g., acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, etc.), alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, magnesium, etc.), and organic bases (e.g., triethylamine, piperidine, etc.).
Furthermore, in each of the reactions of the present invention and each reaction for synthesizing raw material compounds, if the raw material compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, these groups may be introduced with protecting groups such as those commonly used in peptide chemistry, and the target compound can be obtained by removing the protecting groups as necessary after the reaction.
Protecting groups for amino groups include, for example, C_1-6Alkyl-carbonyl group (e.g., formyl, acetyl, ethylcarbonyl, etc.), benzyl group, tert-butyloxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, allyloxycarbonyl group, phenylcarbonyl group, C_1-6Alkyloxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), C_7-10Examples of the group that can be used include an aralkyl-carbonyl group (e.g., benzylcarbonyl), a trityl group, a phthaloyl group, and an N,N-dimethylaminomethylene group. These groups may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), a nitro group, or the like.
【0043】
Protecting groups for carboxyl groups include, for example, C_1-6Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, butyl, and tert-butyl, as well as phenyl, silyl, benzyl, and allyl groups. These groups may be substituted with one to three halogen atoms (e.g., fluorine, chlorine, bromine, and iodine), a nitro group, or the like.
Protecting groups for hydroxyl groups include, for example, methoxymethyl, allyl, tert-butyl, and C_7-10Aralkyl groups (e.g., benzyl, etc.), C_1-6Alkyl-carbonyl group (e.g., formyl, acetyl, ethylcarbonyl, etc.), benzoyl group, C_7-10Aralkyl-carbonyl groups (e.g., benzylcarbonyl, etc.), pyranyl groups, furanyl groups, trialkylsilyl groups, etc. are used. These groups contain 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), C_1-6Alkyl groups (e.g., methyl, ethyl, n-propyl, etc.), phenyl groups, C_7-10It may be substituted with an aralkyl group (for example, benzyl), a nitro group, or the like.
These protecting groups can be removed by known methods or methods similar thereto, such as methods using acids, bases, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
【0044】
If the desired product is obtained in a free form by the above reaction, it may be converted into a salt by a conventional method. If the desired product is obtained as a salt, it may also be converted into the free form or another salt by a conventional method. The compound [I] or a salt thereof thus obtained can be isolated and purified from the reaction solution by known means, such as transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc.
When compound [I] or a salt thereof exists as diastereomers, conformers, etc., they can be isolated by the above-mentioned separation and purification means, if desired. Furthermore, when compound [I] or a salt thereof is a racemate, it can be separated into the d- and l-isomers by conventional optical resolution means.
When compound [I] contains a basic group, it can be prepared as an acid addition salt, particularly a pharmacologically acceptable acid addition salt, by a method known per se. Examples of such acids include inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (e.g., acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, etc.). When compound [I] contains an acidic group, it can be prepared as a salt with a base, particularly a salt with a pharmacologically acceptable base. Examples of such bases include alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, magnesium, etc.), and organic bases (e.g., triethylamine, piperidine, etc.).
【0045】
Compound [I] or its salts have excellent antitumor activity, low toxicity, and few side effects, and can therefore be used as an antitumor agent for primary solid cancers such as prostate cancer, pancreatic cancer, and lung cancer in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, rats, etc.). In addition, they have high clinical utility as they have effects to inhibit metastasis, prevent recurrence after surgical operation, and improve various symptoms associated with cancer (e.g., pain, cachexia, etc.). Furthermore, the therapy by administering compound [I] or a salt thereof is effective in combination with various chemotherapeutic agents (e.g., alkylating agents such as ifosfamide, estramustine phosphate, nimustine hydrochloride, etc.; metabolic antimetabolites such as fluorouracil and tegafur; antibiotics such as mitomycin, doxorubicin hydrochloride, bleomycin, peplomycin sulfate, aclarubicin hydrochloride, neocarzinostatin, etc.; and cisplatin, carboplatin, etc.), BRMs (IL-2, IFN-α, IFN-β, IFN-γ, TNF-α, etc.), angiogenesis inhibitors, etc., thermotherapy, and in the case of prostate cancer, hormone therapy (orchiectomy, administration of estrogen, diethylstilbestrol phosphate, LHRH agonist, LHRH antagonist, etc.). Furthermore, compound [I] or a salt thereof has an excellent eradicating effect against Helicobacter pylori, and can therefore be used as a preventive and therapeutic agent for infectious diseases caused by Helicobacter pylori. Examples of such "infectious diseases" include duodenal ulcer, gastric ulcer, esophagitis, gastritis, and gastric cancer. Furthermore, the combined use of compound [I] or a salt thereof with one to three drugs selected from antiulcer agents and antibacterial agents is an excellent treatment for digestive diseases caused by Helicobacter pylori. Examples of such "antiulcer agents" include proton pump inhibitors (e.g., lansoprazole, omeprazole, pantoprazole, pariprazole, leminoprazole, etc.), H₂-receptor antagonists (e.g., cimetidine, ranitidine, famotidine, etc.). Examples of the "antibacterial agents" include amoxicillin, clarithromycin, tetracycline, metronidazole, tinidazole, etc. Examples of the "gastrointestinal diseases" include duodenal ulcer, gastric ulcer, esophagitis, gastritis, gastric cancer, etc.
Compound [I] or a salt thereof can be safely administered orally or parenterally, either as is or in the form of a pharmaceutical composition mixed with a medically acceptable carrier according to a method known per se (e.g., as described in the 12th edition of the Japanese Pharmacopoeia), such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, caucasse, capsules (including soft capsules), solutions, infusions, injections, topical preparations (e.g., intranasal preparations, transdermal preparations, etc.), suppositories (e.g., rectal suppositories, cavity suppositories, etc.), sustained-release preparations, etc. The dosage varies depending on the recipient, administration route, disease, etc., but for example, when administered orally to an adult patient with prostate cancer, the active ingredient (compound [I] or a salt thereof) is 0.1 to 20 mg/kg, preferably 0.2 to 10 mg/kg, administered once or several times a day in divided doses.
【0046】
Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials. These are formulated as excipients, lubricants, binders, disintegrants, and thickeners in solid formulations; and as solvents, dispersants, solubilizers, suspending agents, isotonicity agents, buffers, and soothing agents in liquid formulations. Additives such as preservatives, antioxidants, colorants, and sweeteners can also be used as needed. Suitable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid. Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica. Suitable examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, and carboxymethylstarch sodium. Suitable examples of thickeners include natural gums, cellulose derivatives, and acrylic acid polymers. Suitable examples of solvents include water for injection, alcohol, propylene glycol, marcgol, sesame oil, and corn oil. Suitable examples of dispersants include Tween 80, HCO 60, polyethylene glycol, carboxymethylcellulose, and sodium alginate. Suitable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate. Suitable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of isotonicity agents include sodium chloride, glycerin, and D-mannitol. Suitable examples of buffering agents include buffer solutions such as phosphates, acetates, carbonates, and citrates. Suitable examples of soothing agents include benzyl alcohol. Suitable examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of antioxidants include sulfites and ascorbic acid.
【0047】
Specific examples of pharmaceutical formulations of the present invention are shown below.
(1) Tablets, powders, granules, and caucel:
The compound [I] or its salt can be produced by adding, for example, an excipient, disintegrant, binder, or lubricant, compressing the mixture, and then, if necessary, applying a coating for taste masking, enteric coating, or sustained release.
(2) Injection:
Compound [I] or its salt can be prepared as an aqueous injection together with, for example, a dispersant, a preservative, an isotonic agent, etc., or by dissolving, suspending, or emulsifying it in vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, etc., or in propylene glycol, etc., and molding it into an oily injection.
(3) Topical agents:
The composition is prepared by converting compound [I] or a salt thereof into a solid, semi-solid, or liquid composition. For example, the solid composition is prepared by converting compound [I] or a salt thereof directly, or by adding and mixing excipients, thickeners, etc., to form a powder. The liquid composition is prepared by converting it into an oily or aqueous suspension, much like an injection. The semi-solid composition is preferably an aqueous or oily gel, or an ointment. Furthermore, all of these compositions may contain buffers, preservatives, etc.
(4) Suppositories:
The composition is produced by converting compound [I] or its salt into an oily or aqueous solid, semi-solid, or liquid composition. Examples of oily bases used in such compositions include glycerides of higher fatty acids (e.g., cocoa butter, witepsols, etc.), medium-chain fatty acids (e.g., miglyols, etc.), and vegetable oils (e.g., sesame oil, soybean oil, cottonseed oil, etc.). Examples of aqueous gel bases include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
【0048】
[Embodiment of the invention]
[Example]
The present invention is further explained in detail in the following Reference Examples, Examples, Formulation Examples, and Test Examples, but these examples are merely illustrative and do not limit the present invention, and may be modified within the scope of the present invention. The abbreviations in the Reference Examples and Examples have the following meanings.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, m: multiplet, br: broad, J: coupling constant, room temperature: 0-30°C.
Reference example 1
2-mercapto-3-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-one
Five drops of concentrated sulfuric acid were added to a mixed solution of 2-ethoxycarbonylcyclopentanone (31.2 g) and methylthiourea (18.0 g) and heated at 100°C for two days. The resulting precipitate was collected by filtration, washed with ethanol, and dried to yield the title compound (10.2 g) as a colorless powder.
¹H-NMR (DMSO-d₆)δ: 1.98(2H,m), 2.55(2H,t,J=7.2Hz), 2.74(2H,t,J=7.8Hz), 3.52(3H,s).
【0049】
Reference example 2
1,7-dimethyl-2-mercapto-6-oxopurine
A mixture of 1,7-dimethylxanthine (500 mg) and phosphorus oxychloride (10 ml) was heated under reflux for 5 hours and then concentrated. The residue was dissolved in ethanol (15 ml), and thiourea (1.06 g) was added and refluxed for 15 hours. After cooling, the resulting precipitate was collected by filtration, washed with ethanol, and dried to give the title compound (290 mg) as a yellow solid.
¹H-NMR (DMSO-d₆)δ: 3.60(3H,s), 3.89(3H,s), 8.07(1H,s), 13.54(1H,brs).
Reference example 3
9-Hydroxy-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
A mixture of 2-amino-3-hydroxypyridine (11 g), ethyl 2-methylacetoacetate (14.4 g), polyphosphoric acid (20 ml), and acetic acid (40 ml) was heated and stirred at 100°C for 4 hours. The reaction mixture was poured into ice water, and the pH was adjusted to 4 with aqueous sodium hydroxide, followed by potassium carbonate to pH 7. The resulting precipitate was extracted with chloroform, washed with water, dried, and concentrated to give the title compound (3.63 g) as a brown solid.
¹H-NMR (DMSO-d₆)δ: 2.25(3H,s), 2.49(3H,s), 6.97(1H,dd,J=7.4,6.8Hz), 7.05(1H,dd,J=7.4,1.6Hz), 8.47(1H,dd,J=6.8,1.6Hz).
【0050】
Reference example 4
7-[4-(4-chlorobenzoyl)benzyl〕-2,6-dichloropurine
2,6-Dichloropurine (3.25 g) in dimethylformamide (34 ml) was added with potassium carbonate (2.85 g) and 4-(4-chlorobenzoyl)benzyl bromide (5.32 g) and stirred at room temperature for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1 to 1:3) to give the title compound (1.37 g, 19%) as an anhydrous powder.
¹H-NMR (CDCl₃)δ: 5.76(2H,s), 7.21-7.85(8H,m), 8.33(1H,s).
IR(KBr)：1655, 1600, 1580, 1530, 1400, 1270, 1230, 1170, 1090, 990, 925,750cm^-1.
Reference example 5
7-[4-(4-chlorobenzoyl)benzyl〕-2,6-diethoxypurine
7-[4-(4-chlorobenzoyl)benzyl〕To a solution of 1.12 g of 2,6-dichloropurine in 30 ml of ethanol was added sodium ethoxide (1.83 g) and the mixture was stirred at room temperature for 96 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ether and hexane to give the title compound (0.78 g, 67%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 1.34(3H,t,J=7.0Hz), 1.50(3H,t,J=7.0Hz), 4.50(2H,q,J=7.0Hz), 4.55(2H,q,J=7.0Hz), 5.53(2H,s), 7.25-7.80(8H,m), 7.98(1H,s).
IR(KBr): 2980, 1660, 1620, 1570, 1490, 1450, 1380, 1345, 1300, 1190, 1140, 1120, 1090, 1065, 930 cm^-1.
【0051】
Reference example 6
1-[4-(4-chlorobenzoyl)benzyl]-4,5-dimethoxycarbonyl-imidazole
Under an argon atmosphere, sodium hydride (816 mg) was washed with hexane (10 ml) and dissolved in DMF (30 ml). The reaction solution was then cooled to 0°C, and dimethyl 1H-imidazole-4,5-dicarboxylate (3.17 g) was added. The mixture was stirred at 0°C for 15 minutes and at room temperature for 1.5 hours, after which it was cooled to 0°C again. 4-(4-chlorobenzoyl)benzyl bromide (5.14 g) was added to the reaction solution and stirred at room temperature for 1 hour. Ice was added and the mixture was diluted with ethyl acetate (150 ml). The organic layer was washed four times with water (100 ml) and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (100 g carrier; dichloromethane:ether = 10:2-2:1) to obtain 4.06 g (yield 59%) of the title compound.
¹H-NMR (CDCl₃)δ: 3.86(3H,s), 3.94(3H,s), 5.52(2H,s), 7.26(2H,d,J=7.2Hz),7.47(2H,d,J=8.6Hz), 7.64-7.80(5H,m).
【0052】
Reference example 7
1-[4-(4-chlorobenzoyl)benzyl]imidazo[4,5-d]pyridazine-4(5H),7(6H)-dione
1-[4-(4-chlorobenzoyl)benzyl]-4,5-dimethoxycarbonylimidazole (3.31 g) was dissolved in methanol (20 ml), and then hydrazine hydrate (1.68 g) was added and the mixture was heated to reflux for 5 hours. The resulting crystals were filtered off and then suspended in water (100 ml). Concentrated hydrochloric acid (10 ml) was added and the mixture was stirred at 80°C for 30 minutes. The crystals were filtered off and dried under reduced pressure to give 2.67 g of the title compound (yield 88%).
¹H-NMR (DMSO-d₆)δ: 5.78(2H,s), 7.45-7.77(8H,m), 8.49(1H,s).
Reference example 8
1-[4-(4-chlorobenzoyl)benzyl]-4,7-dichloroimidazo[4,5-d]pyridazine
1-[4-(4-chlorobenzoyl)benzyl]imidazo[4,5-d]pyridazine-4(5H),7(6H)-dione (2.57 g) was dissolved in phosphorus oxychloride (33.2 g) and heated to reflux for 2 hours. The phosphorus oxychloride was removed by distillation under reduced pressure, and saturated aqueous sodium bicarbonate solution was added. The precipitated crystals were filtered off. The resulting crystals were washed with water, dried under reduced pressure, and then purified by silica gel column chromatography (carrier 30 g; dichloromethane:ethyl acetate = 1:0-4:1) to give 2.17 g (yield 77%) of the title compound.
¹H-NMR (CDCl₃)δ: 5.85(2H,s), 7.26(2H,d,J=8.6Hz), 7.46(2H,d,J=8.4Hz), 7.72(2H,d,J=8.6Hz), 7.80(2H,d,J=8.4Hz), 8.24(1H,s).
IR (KBr): 1654, 754 cm^-1.
【0053】
Reference example 9
3-[4-(4-chlorobenzoyl)benzylamino]-1-propanol
4-(4-chlorobenzoyl)benzyl bromide (3.10 g) was added to a solution of 3-amino-1-propanol (3.00 g) in ethanol (40 ml) and heated to reflux for 4.5 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: chloroform/methanol = 9/1] to obtain the title compound as a white powder (1.36 g, yield 45%).
¹H-NMR (CDCl₃)δ: 1.76(2H,quintet,J=5.6Hz), 2.29(2H,m), 2.93(2H,t,J=5.6Hz), 3.83(2H,t,J=5.6Hz), 3.90(2H,s), 7.41-7.50(4H,m), 7.71-7.78(4H,m).
IR (KBr): 3255, 3140, 2840, 1660, 1600 cm^-1.
Reference example 10
2-tert-butyl-4-chloro-5-[N-(3-hydroxypropyl)-(4-(4-chlorobenzoyl)benzyl)amino]-3(2H)-pyridazinone
2-tert-Butyl-4,5-dichloro-3(2H)-pyridazinone (473 mg) and 3-[4-(4-chlorobenzoyl)benzylamino]-1-propanol (1.30 g) were dissolved in a mixed solvent of dioxane (5 mL) and water (5 mL) and stirred at 100°C for 64 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography [developing solvent: n-hexane/ethyl acetate = 4/1 → 2/1] to obtain the title compound as a white powder (120 mg, yield 12%).
¹H-NMR (CDCl₃)δ: 1.63(9H,s), 1.83-1.98(3H,m), 3.51(2H,t,J=7.2Hz), 3.70(2H,m), 4.71(2H,m), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.60(1H,s), 7.75(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
【0054】
Reference example 11
2,3-Dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of methylhydrazine (4.72 g) and 3-carbethoxy-4,5-dichloro-2-formylpyrrole (4.72 g) in ethanol (50 ml) was heated to reflux for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.5 ml) was added and the mixture was heated to reflux for an additional 21 hours. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with ethanol and ether, and dried under reduced pressure to obtain the title compound as a brown powder (3.29 g, 81% yield).
¹H-NMR (DMSO-d₆) δ: 3.66 (3H, s), 8.11 (1H, s),
IR (KBr): 3080, 2980, 1630, 1570 cm^-1.
【0055】
Reference example 12
Ethyl 1-[4-(4-chlorobenzoyl)benzyl]-5-(diethoxymethyl)imidazole-4-carboxylate (A) and ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-(diethoxymethyl)imidazole-5-carboxylate (B)
To a suspension of 60% sodium hydride in oil (363 mg) in DMF (15 mL) cooled in an ice bath, a solution of ethyl 5-(diethoxymethyl)imidazole-4-carboxylate (2.00 g) in DMF (25 mL) was added dropwise. After stirring at room temperature for 45 minutes, a solution of 4-(4-chlorobenzoyl)benzyl bromide (2.81 g) in DMF (15 mL) was added and the mixture was stirred at 60°C for an additional 3 hours. The reaction was terminated by the addition of saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/2) to give the title compound (A) as a white powder (2.18 g, yield 56%) and the title compound (B) as a brown oil (1.13 g, yield 29%).
(A):¹H-NMR (CDCl₃)δ: 1.13(6H,t,J=7.0Hz), 1.42(3H,t,J=7.0Hz), 3.43-3.59(2H,m), 3.70-3.87(2H,m), 4.39(2H,q,J=7.0Hz), 5.53(2H,s), 6.41(1H,s), 7.28(2H,d,J=8.4Hz), 7.41(1H,s), 7.46(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.74(2H,d,J=8.6Hz).
IR(KBr)：3120, 3050, 2980, 2950, 2900, 1700, 1660cm^-1.
(B):¹H-NMR (CDCl₃)δ: 1.25(6H,t,J=7.2Hz), 1.32(3H,t,J=7.0Hz), 3.61-3.85(4H,m), 4.30(2H,q,J=7.2Hz), 5.57(2H,s), 6.08(1H,s), 7.24(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.68-7.77(5H,m).
【0056】
Reference example 13
Ethyl 1-[4-(4-chlorobenzoyl)benzyl]-5-formylimidazole-4-carboxylate
Ethyl 1-[4-(4-chlorobenzoyl)benzyl]-5-(diethoxymethyl)imidazole-4-carboxylate (1.70 g) was dissolved in 20% aqueous acetic acid (15 ml) and stirred at room temperature for 23 hours. After dilution with water, the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium bicarbonate, and water, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound as a white powder (1.37 g, 95% yield).
¹H-NMR (CDCl₃)δ: 1.45(3H,t,J=7.2Hz), 4.47(2H,q,J=7.2Hz), 5.65(2H,s), 7.28(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.69-7.77(5H,m), 10.51(1H,s).
IR (KBr): 3100, 2980, 1740, 1710, 1675, 1610, 1590 cm^-1.
【0057】
Reference example 14
Ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-formylimidazole-5-carboxylate
Ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-(diethoxymethyl)imidazole-5-carboxylate (1.20 g) was dissolved in 20% aqueous acetic acid (10 ml) and stirred at room temperature for 8 hours. After dilution with water, the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium bicarbonate, and water, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography [developing solvent: n-hexane/ethyl acetate = 1/1] to obtain the title compound as a white powder (671 mg, yield 67%).
¹H-NMR (CDCl₃)δ: 1.38(3H,t,J=7.0Hz), 4.41(2H,q,J=7.0Hz), 5.66(2H,s), 7.26(2H,d,J=8.8Hz), 7.46(2H,d,J=8.8Hz), 7.70-7.79(5H,m), 10.42(1H,s).
IR (KBr): 3000, 1720, 1685, 1655, 1610, 1580 cm^-1.
【0058】
Reference example 15
2-Hydroxy-3-methylpyrido[1,2-a]pyrimidin-4-one
Concentrated hydrochloric acid (10 drops) was added to a mixture of 2-aminopyridine (9.71 g) and dimethyl 2-methylmalonate (19.70 g), and the mixture was stirred at 150°C for 1 hour and then allowed to cool to room temperature. Hexane and ethyl acetate were added to the reaction mixture, and the precipitated pale yellow solid was collected by filtration. Yield: 0.403 g (2.2%)
¹H-NMR (CDCl₃-CD₃OD)δ: 2.09(3H,s), 7.31-7.50(2H,m), 9.12(1H,m).
IR(KBr)ν: 3358, 3167, 1666, 1622, 1126, 769, 621 cm^-1.
Reference example 16
2-mercapto-6,7-dimethoxy-3-methylquinazolin-4-one
An ethanol solution of 2-amino-4,5-dimethoxybenzoic acid (20.0 g) and methyl isothiocyanate (7.23 g) was refluxed for 30 minutes. The title compound precipitated as colorless needles and was collected by filtration. Yield: 11.77 g (47%)
¹H-NMR (CDCl₃)δ: 3.67(3H,s), 3.85(3H,s), 3.89(3H,s), 6.93(1H,s), 7.31(1H,s).
IR(KBr)ν: 1648, 1622, 1402, 1273, 1209, 1092, 1028 cm^-1.
【0059】
Reference example 17
2-amino-6-methylbenzoic acid
Palladium-carbon (1.40 g) was added to a methanol solution (150 ml) of 6-methyl-2-nitrobenzoic acid (14.25 g), followed by the addition of hydrogen (5.3 L) at room temperature and atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (15.12 g; yield 100%) as a pale yellow solid.
¹H-NMR (CDCl₃)δ: 2.47(3H,s), 6.50(2H,t,J=8.1Hz), 7.00-7.07(4H,m).
IR(KBr)ν: 2927, 2645, 1645, 1599, 1545, 1470, 1394, 1334, 1288, 1236, 813, 775, 580, 419 cm^-1.
Reference example 18
2-mercapto-3,5-dimethylquinazolin-4-one
An ethanol solution of 2-amino-6-methylbenzoic acid (14.12 g) obtained in Reference Example 17 and methyl isothiocyanate (7.22 g) was refluxed for 1 hour. The title compound precipitated as colorless needles and was collected by filtration. Yield: 7.72 g (40.0%)
¹H-NMR (CDCl₃)δ: 2.47(3H,s), 6.50(2H,t,J=8.1Hz), 7.00-7.07(4H,m).
IR(KBr)ν: 3286, 1660, 1614, 1537, 1474, 1431, 1385, 1271, 1109, 1049, 991, 795, 691, 665, 420 cm^-1.
【0060】
Reference example 19
N,N-dimethylphenylacetamide
Phenylacetyl chloride (25 ml) was added dropwise to a 50% aqueous dimethylamine solution under ice cooling. After removing the solvent under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate water and then with MgSO₄The mixture was dried over 100 ml of ethyl acetate and concentrated under reduced pressure to give the title compound as a colorless oil.
Yield: 28.90g (95%)
¹H-NMR (CDCl₃)δ: 2.95(3H,s), 2.98(3H,s), 3.71(2H,s), 7.26-7.30(5H,m).
IR(Neat)ν: 3466, 2937, 1643, 1495, 1450, 1398, 1266, 1132, 1068, 733, 700, 598 cm^-1.
Reference example 20
7-[4-(4-chlorobenzoyl)benzyl]-4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine
Under an argon atmosphere, 60% oil-based sodium hydride (220 mg) was suspended in dry dimethylformamide (5 mL). With stirring and ice-cooling, powdered 4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (1.05 g) was added in small portions. After the entire amount was added, the mixture was stirred for 30 minutes, and then a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.63 g) in dimethylformamide (5 mL) was added. The mixture was returned to room temperature and stirred for 2 hours. Water (50 mL) was added to the reaction mixture, and the precipitate was collected by filtration, washed with water, and dried. This was purified by flash column chromatography (silica gel; hexane-ethyl acetate; 9:1) to yield the title compound (1.19 g).
¹H-NMR (CDCl₃)δ: 2.33(3H,d,J=1.2Hz), 2.60(3H,s), 4.08(3H,s), 5.36(2H,s),6.57(1H,d,J=1.2Hz), 7.28(2H,d,J=8.6Hz), 7.44(2H,d,J=8.6Hz), 7.70(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz).
IR(KBr)：3430, 3100, 2920, 1650, 1600, 1590, 1560, 1530, 1480, 1455, 1430, 1395, 1335, 1300, 1280, 1240, 1190, 1170, 1145, 1100, 1090cm^-1.
【0061】
Reference example 21
7-[4-(4-chlorobenzoyl)benzyl]-4-methoxy-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine
Under an argon atmosphere, 4-methoxy-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (0.54 g) was dissolved in dry 1,2-dimethoxyethane (DME) (10 mL). With stirring and ice-cooling, 60% sodium hydride in oil (132 mg) was added in two portions. After the entire amount was added, the mixture was stirred for 30 minutes, and then a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.11 g) in DME (5 mL) was added. The mixture was returned to room temperature and stirred overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; hexane-ethyl acetate=9:1) to yield the title compound (0.941 g).
¹H-NMR (CDCl₃)δ: 2.61(3H,s), 4.10(3H,s), 5.44(2H,s), 6.49(1H,d,J=3.6Hz),6.87(1H,d,J=3.6Hz), 7.29(2H,d,J=8.6Hz), 7.44(2H,d,J=8.6Hz), 7.72(4H,d,J=8.6Hz).
IR(KBr)：3450, 3120, 3000, 2960, 2930, 1660, 1610, 1590, 1560, 1510, 1460, 1390, 1380, 1335, 1280, 1260, 1240, 1170, 1155, 1090, 1065cm^-1.
【0062】
Reference example 22
6-t-Butyl-pyrido[2,3-d]pyridazin-5(6H)-one
Ethyl 2-formyl-3-pyridinecarboxylate (1.3 g) was dissolved in acetic acid-water (1:1) (5 ml), t-butylhydrazine hydrochloride (1.8 g) was added, and the mixture was refluxed and stirred for 1 hour. The reaction mixture was cooled to room temperature, adjusted to pH 5.0 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by concentrating this mixture was dissolved in acetic acid (2 ml) and refluxed and stirred for 1 hour. The reaction mixture was cooled, adjusted to pH 5.0 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was concentrated, and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate (1:1)). 1.2 g of white powder
¹H-NMR (CDCl₃)δ: 1.73(9H,s), 7.64(1H,dd,J=8.2 and 4.4Hz), 8.38(1H,s), 8.69(1H,d,J=8.2Hz), 9.03(1H,d,J=4.4Hz).
Reference example 23
6-t-butyl-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5(6H)-one
6-t-Butylpyrido[2,3-d]pyridazin-5(6H)-one (955 mg) was dissolved in acetic acid (20 ml), platinum oxide (94 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was washed with diethyl ether and dried. 911 mg of white powder was obtained.
¹H-NMR (CDCl₃)δ: 1.63(9H,s), 1.8-2.0(2H,m), 2.54(2H,t,J=6.2Hz), 3.28(2H,t,J=5.4Hz), 4.24(1H,br s), 7.19(1H,s).
【0063】
Reference example 24
6-Methylpyrido[2,3-d]pyridazin-5(6H)-one
Ethyl 2-formyl-3-pyridinecarboxylate (519 mg) was dissolved in ethanol (3 ml), methylhydrazine (267 mg) was added, and the mixture was refluxed and stirred for 2 hours. The reaction mixture was concentrated to dryness, and the residue was washed with diethyl ether and acetone and dried. 391 mg of yellow powder
¹H-NMR (DMSO-d₆)δ: 3.75(3H,s), 7.86(1H,dd,J=8.4 and 4.4Hz), 8.48(1H,s),8.62(1H,d,J=8.4Hz), 9.14(1H,d,J=4.4Hz).
Reference example 25
6-Methyl-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5(6H)-one
6-Methylpyrido[2,3-d]pyridazin-5(6H)-one (402 mg) was dissolved in acetic acid (15 ml), platinum oxide (50 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was washed with acetone and dried. 250 mg of white powder was obtained.
¹H-NMR (CDCl₃)δ: 1.8-2.0(2H,m), 2.58(2H,t,J=6.4Hz), 3.29(2H,t,J=5.6Hz),3.69(3H,s). 4.30(1H,br s), 7.23(1H,s).
【0064】
Reference example 26
2-t-butyl-4-chloro-5-dimethylamino-3(2H)-pyridazinone
2-t-Butyl-4,5-dichloro-3(2H)-pyridazinone (4.4 g) was dissolved in ethanol-water (2:1) (45 ml), and 50% dimethylamine (7.2 g) was added and stirred at room temperature for 15 hours. After evaporating the ethanol, the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentrating it to dryness, the residue was washed with n-hexane and dried. 4.4 g of white powder
¹H-NMR (CDCl₃)δ: 1.63(9H,s), 3.10(6H,s), 7.57(1H,s).
Reference example 27
2-t-butyl-5-dimethylamino-3(2H)-pyridazinone
2-t-Butyl-4-chloro-5-dimethylamino-3(2H)-pyridazinone (4.3 g) was dissolved in methanol (40 ml), 10% palladium carbon (50% water content) (430 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 48 hours. The catalyst was removed by filtration, and the filtrate was concentrated. After that, saturated aqueous sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentrating this to dryness, the residue was washed with n-hexane and dried. 3.4 g of white powder
¹H-NMR (CDCl₃)δ: 1.63(9H,s), 2.98(6H,s), 5.65(1H,d,J=3.0Hz), 7.55(1H,d,J=3.0Hz).
【0065】
Reference example 28
2-t-butyl-5-dimethylamino-4-formyl-3(2H)-pyridazinone
Phosphorus oxychloride (6.5 g) was added dropwise to DMF (15 ml) under ice cooling and stirred at room temperature for 30 minutes. Subsequently, 2-t-butyl-5-dimethylamino-3(2H)-pyridazinone (3.3 g) in DMF (40 ml) was added dropwise under ice cooling and stirred at 70°C for 1 hour. The reaction mixture was gradually added to ice-water sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. This was concentrated to dryness, and the residue was washed with n-hexane and dried. 3.7 g of yellow powder
¹H-NMR (CDCl₃)δ: 1.63(9H,s), 3.10(6H,s), 7.71(1H,s), 10.27(1H,s).
Reference example 29
5-t-Butyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one
2-t-Butyl-5-dimethylamino-4-formyl-3(2H)-pyridazinone (3.5 g) was added to hydrazine (5.1 g)/ethanol (30 ml) and stirred under reflux for 40 hours. After distilling off the ethanol and hydrazine, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentrating it to dryness, the residue was washed with n-hexane-diethyl ether and dried. 1.9 g of white powder
¹H-NMR (CDCl₃)δ: 1.71(9H,s), 8.19(1H,s), 8.32(1H,s).
【0066】
Reference example 30
5-methyl-1H-triazolo[4,5-d]pyridazin-4(5H)-one
4,5-Diamino-2-methyl-3(2H)-pyridazinone (280 mg) was dissolved in water (10 ml), concentrated hydrochloric acid (0.5 ml) was added under ice cooling, and then sodium nitrite (290 mg) in water (5 ml) was added dropwise at below 10°C. The mixture was stirred at below 10°C for 1 hour and then at 100°C for 1 hour. The reaction mixture was left in the refrigerator for 16 hours, after which the precipitate was collected by filtration, washed with water, and dried. 262 mg of white powder
¹H-NMR (DMSO-d₆)δ: 3.76(3H,s), 8.71(1H,s).
Reference example 31
5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of methylhydrazine (4.84 g) and 3-ethoxycarbonyl-2-formylpyrrole (3.34 g) in ethanol (30 ml) was heated to reflux for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.7 ml) was added and the mixture was heated to reflux for an additional 19 hours. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: dichloromethane/methanol = 19/1] to obtain the title compound as a white powder (1.81 g, yield 61%).
¹H-NMR (DMSO-d₆) δ :3.68(3H,s), 6.65(1H,d,J=2.8Hz), 7.42(1H,t,J=2.8Hz),8.17(1H,s), 12.02(1H,m).
IR(KBr): 3200, 3100, 1640.
【0067】
Reference example 32
2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of methylhydrazine (1.82 g) and 3-ethoxycarbonyl-4,5-dimethyl-2-formylpyrrole (3.85 g) in ethanol (40 ml) was heated to reflux for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.7 ml) was added and the mixture was heated to reflux for an additional 13 hours. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with ethanol and ether, and dried under reduced pressure to obtain the title compound as a pale yellow powder (3.64 g, 100% yield).
¹H-NMR (DMSO-d₆) δ :2.26(6H,s), 3.62(3H,s), 7.98(1H,s), 11.6-11.7(1H,m).
Reference example 33
2-t-butyl-5-dimethylamino-4-(1-hydroxy)ethyl-3(2H)-pyridazinone
2-t-Butyl-5-dimethylamino-4-formyl-3(2H)-pyridazinone (3.2 g) was dissolved in THF (45 ml), and 3.0 M methylmagnesium bromide/diethyl ether (7.1 ml) was added dropwise under ice cooling, followed by stirring at 50°C for 30 minutes. 1 N hydrochloric acid (22 ml) was added to the reaction solution under ice cooling, followed by saturated sodium bicarbonate water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. This was then concentrated and dried. 3.5 g of yellow oil was obtained.
¹H-NMR (CDCl₃)δ: 1.63(9H,s), 1.63(3H,d,J=6.6Hz), 2.91(6H,s), 4.93(1H,dq,J=6.6Hz and 11.0Hz), 5.55(1H,d,J=11.0Hz), 7.65(1H,s)
【0068】
Reference example 34
4-acetyl-2-t-butyl-5-dimethylamino-3(2H)-pyridazinone
2-t-Butyl-5-dimethylamino-4-(1-hydroxy)ethyl-3(2H)-pyridazinone (3.4 g) was dissolved in toluene, activated manganese dioxide (17.0 g) was added, and the mixture was stirred at 80°C for 24 hours. The oxidizing agent was removed by filtration, and the filtrate was concentrated. The residue was washed with n-hexane-diethyl ether and dried. 2.5 g of yellow powder was obtained.
¹H-NMR (CDCl₃)δ: 1.62(9H,s), 2.63(3H,s), 2.92(6H,s), 7.62(1H,s)
Reference example 35
5-t-Butyl-3-methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one
4-Acetyl-2-t-butyl-5-dimethylamino-3(2H)-pyridazinone (2.5 g) was added to hydrazine (3.2 g)/ethanol (30 ml) and stirred under reflux for 6 hours. After distilling off the ethanol and hydrazine, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentrating to dryness, the residue was washed with n-hexane-diethyl ether and dried. 1.7 g of white powder
¹H-NMR (CDCl₃)δ: 1.70(9H,s), 2.74(3H,s), 8.10(1H,s)
【0069】
Reference example 36
5-dimethylamino-4-(1-hydroxy)ethyl-2-methyl-3(2H)-pyridazinone
5-Dimethylamino-4-formyl-2-methyl-3(2H)-pyridazinone (362 mg) was dissolved in THF (10 ml), and 3.0 M methylmagnesium bromide/diethyl ether (1.0 ml) was added dropwise under ice-cooling, followed by stirring at 50°C for 30 minutes. 1N hydrochloric acid (3 ml) was added to the reaction solution under ice-cooling, followed by saturated sodium bicarbonate water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. This was then concentrated and dried. 371 mg of yellow oil
¹H-NMR (CDCl₃)δ: 1.64(3H,d,J=6.6Hz), 2.94(6H,s), 3.72(3H,s), 4.93(1H,dq,J=6.6Hz and 11.4Hz), 5.31(1H,d,J=11.4Hz), 7.66(1H,s)
Reference example 37
4-acetyl-5-dimethylamino-2-methyl-3(2H)-pyridazinone
5-Dimethylamino-4-(1-hydroxy)ethyl-2-methyl-3(2H)-pyridazinone (355 mg) was dissolved in chloroform, activated manganese dioxide (2.0 g) was added, and the mixture was stirred at 50°C for 24 hours. The oxidizing agent was removed by filtration, and the filtrate was concentrated. The residue was washed with n-hexane-diethyl ether and dried. 178 mg of yellow powder was obtained.
¹H-NMR (CDCl₃)δ: 2.67(3H,s), 2.94(6H,s), 3.69(3H,s), 7.66(1H,s)
【0070】
Reference example 38
3,5-dimethyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one
4-Acetyl-5-dimethylamino-2-methyl-3(2H)-pyridazinone (137 mg) was added to hydrazine (224 mg) and ethanol (5 ml) and stirred under reflux for 6 hours. After distilling off the ethanol and hydrazine, the residue was washed with diethyl ether and dried. 114 g of white powder was obtained.
¹H-NMR (CDCl₃)δ: 2.57(3H,s), 3.64(3H,s), 8.30(1H,s)
Reference example 39
1-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4-one
Metallic sodium (1.21 g) was dissolved in absolute ethanol (50 ml), and N-methylthiourea (4.96 g) was added. The mixture was stirred at 50°C for 30 minutes to dissolve. Next, a solution of ethyl 2-cyano-4,4-diethoxybutyrate (11.47 g) in ethanol (10 ml) was added, and the mixture was refluxed at 100°C for 5 hours. After distilling off the solvent under reduced pressure, water (20 ml) was added to dissolve the mixture. 10% hydrochloric acid (75 ml) was then added and the mixture was left stirring overnight. The precipitate was collected by filtration, washed with water, ethanol, and ether, and then dried to obtain the title compound (6.8 g).
¹H-NMR (DMSO-d₆)δ: 3.82(3H,s), 6.41-6.44(1H,m), 6.92-6.95(1H,s), 12.02(1H,s), 12.06(1H,s)
【0071】
Reference example 40
1-[4-(4-chlorobenzoyl)benzyl]-2,3-diethoxycarbonyl-pyrrole
Under an argon atmosphere, diethyl 1H-pyrrole-2,3-dicarboxylate (4.79 g) was dissolved in DME (100 ml), and the reaction solution was cooled to 0°C. Sodium hydride (990 mg) was added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was then cooled to 0°C again. 4-(4-chlorobenzoyl)benzyl bromide (8.53 g) was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. Water was added and the mixture was diluted with ethyl acetate (500 ml). The organic layer was washed twice with aqueous sodium bicarbonate (300 ml), washed with saturated brine (100 ml), and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (250 g carrier: hexane: ethyl acetate = 6:1-1:1) to obtain 9.56 g of the title compound (yield 96%).
¹H-NMR (CDCl₃)δ: 1.26(3H,t,J=7.1Hz), 1.35(3H,t,J=7.0Hz), 4.26(2H,q,J=7.1Hz), 4.30(2H,q,J=7.1Hz), 5.49(2H,s), 6.57(1H,d,J=3.0Hz), 6.88(1H,d,J=3.2Hz), 7.19(2H,d,J=8.4Hz), 7.45(2H,d,J=8.6Hz), 7.72(4H,d,J=8.8Hz)
Reference example 41
3-ethyl-5-methyl-2-mercaptoquinazolin-4-one
A solution of 6-methylanthranilic acid (14.97 g, 0.099 mol) and ethyl isothiocyanate (15.00 ml, 0.171 mol) in ethanol (200 ml) was stirred and refluxed for 5 hours, allowed to cool, and the precipitated colorless needles were filtered. 9.63 g (43.0%)
¹H-NMR (CDCl₃)δ: 1.37(3H,t,J=7.0Hz), 2.80(3H,s), 4.57(2H,q,J=7.0Hz), 6.96(1H,d,J=8.0Hz), 7.08(1H,d,J=8.0Hz), 7.49(1H,t,J=8.0Hz)
IR(KBr)：3188, 3130, 2981, 1693, 1618, 1549, 1468, 1338, 1232, 1117, 775cm^-1
【0072】
Reference example 42
7-[4-(4-fluorobenzoyl)benzyl]-4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine
Under an argon atmosphere, 4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (4.18 g) was dissolved in dry DME (120 ml), and 60% sodium hydride in oil (0.88 g) was added in three portions while stirring and ice-cooling. After the entire amount was added, the mixture was stirred for 30 minutes, and then a solution of 4-(4-fluorobenzoyl)benzyl bromide (6.74 g) in dry DME (20 ml) was added, returned to room temperature, and stirred for 2 hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, resulting in the precipitation of colorless needles. This material was collected by filtration, washed with ethyl acetate, and dried to obtain the title compound (7.07 g).
¹H-NMR (CDCl₃)δ: 2.33(3H,d,J=1.2Hz), 2.61(3H,s), 4.09(3H,s), 5.37(2H,s),6.58(1H,d,J=1.2Hz), 7.15(2H,t,J=8.6Hz), 7.29(2H,d,J=8.4Hz), 7.71(2H,d,J=8.4Hz), 7.82(2H,dd,J=5.4Hz,8.8Hz)
Reference example 43
7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
2-Mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (15.06 g) was suspended in methanol (714 ml) and dissolved in 28% sodium methylate/methanol solution (18.4 ml). Raney nickel was added while stirring at 50°C. The catalyst was removed by filtration, and the filtrate was neutralized with 1N hydrochloric acid (90 ml). The solvent was concentrated under reduced pressure, and the resulting precipitate was collected by filtration, washed with water, methanol, and ether, and then dried to yield the title compound (8.1 g).
¹H-NMR (DMSO-d₆)δ: 6.44(1H,d,J=3.0Hz), 7.03(1H,d,J=3.0Hz), 7.83(1H,s), 11.80(1H,brs).
【0073】
Reference example 44
5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
2-Mercapto-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (15.06 g) was suspended in methanol (714 ml) and dissolved in 28% sodium methylate/methanol solution (18.4 ml). Raney nickel was added with stirring at 50°C. The catalyst was removed by filtration, and the filtrate was neutralized with 1N hydrochloric acid (90 ml). The solvent was concentrated under reduced pressure, and the resulting precipitate was collected by filtration, washed with water, methanol, and ether, and then dried to yield the title compound (8.1 g).
¹H-NMR (DMSO-d₆)δ: 6.44(1H,d,J=3.0Hz), 7.03(1H,d,J=3.0Hz), 7.83(1H,s), 11.80(1H,brs).
Reference example 45
3-Isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.0 g) was dissolved in DMF (35 ml) with heating. Anhydrous potassium carbonate (1.02 g) and isopropyl iodide (1.1 ml) were then added, and the mixture was stirred at 55°C for 13 hours. Insoluble materials were removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; hexane:ethyl acetate 4:1 → 1:1) to yield the title compound (110 mg).
¹H-NMR (CDCl₃)δ: 1.48(6H,d,J=7.0Hz), 5.31(1H,m), 6.74(1H,dd,J=2.2Hz,3.4Hz), 6.96(1H,dd,J=2.2Hz,3.4Hz), 7.95(1H,s), 9.20(1H,brs).
【0074】
Reference example 46
3-Propyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.0 g) was dissolved in DMF (35 ml) with heating. Anhydrous potassium carbonate (1.02 g) and propyl iodide (1.08 ml) were then added and the mixture was stirred at 55°C for 20 hours. Insoluble materials were removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; hexane:ethyl acetate 4:1 → 1:1) to yield the title compound (521 mg).
¹H-NMR (CDCl₃)δ: 0.96(3H,t,J=7.4Hz), 1.73-1.92(2H,m), 4.01(2H,t,J=7.4Hz), 6.71(1H,dd,J=2.2Hz,3.4Hz), 7.01(1H,dd,J=2.2Hz,3.4Hz), 7.94(1H,s).
Reference example 47
N-tert-butoxycarbonyl-4-piperidone
4-Piperidone hydrochloride (5.22 g) was suspended in tetrahydrofuran (100 ml), N,N-dimethylaminopyridine (208 mg) was added, and triethylamine (18.9 ml) was added under ice cooling. After stirring at room temperature for 1.5 hours, di-tert-butyl dicarbonate (14.84 g) was added. After stirring at room temperature for 20 hours, triethylamine (9.4 ml) and di-tert-butyl dicarbonate (14.84 g) were added. After stirring for 4 days, the THF was removed by evaporation, the mixture was diluted with ethyl acetate, washed with 10% citric acid, water, sodium bicarbonate, water, and brine, and then dried over magnesium sulfate. The mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1) to give the title compound (4.24 g) as a yellow powder.
¹H-NMR (CDCl₃)δ: 1.50(9H,s), 2.45(4H,t,J=6.2Hz), 3.73(4H,t,J=6.2Hz).
【0075】
Reference example 48
Ethyl N-tert-butoxycarbonyl-4-piperidideneacetate
Sodium hydride (412 mg) was suspended in tetrahydrofuran (5 ml) and ethyl diethylphosphonoacetate (2.18 ml) was added dropwise under ice-cooling. After stirring at room temperature for 30 minutes, a solution of N-tert-butoxycarbonyl-4-piperidone (1.00 g) in THF (5 ml) was added. After stirring at room temperature for 1 hour, water was added under ice-cooling. The mixture was diluted with ethyl acetate, washed with sodium bicarbonate water and brine, and then dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1) to give the title compound (1.40 g) as a white powder.
IR(KBr)ν（cm^-1): 2924, 1709, 1680, 1429, 1166.
¹H-NMR (CDCl₃)δ: 1.28(3H,t,J=7.0Hz), 1.47(9H,s), 2.28(2H,t,J=5.6Hz), 3.48(2H,t,J=5.8Hz), 3.51(2H,t,J=5.6Hz), 4.15(2H,q,J=7.0Hz), 5.71(1H,s).
Reference example 49
Ethyl N-tert-butoxycarbonyl-4-piperidyl acetate
Ethyl N-tert-butoxycarbonyl-4-piperidideneacetate (1.20 g) was dissolved in ethanol (10 ml) and Pd/C (180 mg) was added. After replacing the atmosphere with nitrogen, hydrogen gas was introduced. After stirring at room temperature for 2 hours, the catalyst was removed by filtration. Concentration gave the title compound (1.18 g) as a white powder.
IR(Neat)ν（cm^-1): 1736, 1695, 1421, 1286, 1159.
¹H-NMR (CDCl₃)δ: 1.1-1.3(2H,m), 1.26(3H,t,J=7.2Hz), 1.45(9H,s), 1.6-2.0(3H,m), 2.23(2H,d,J=7.0Hz), 2.72(2H,t,J=12.0Hz), 4.0-4.1(2H,m), 4.13(2H,q,J=7.2Hz).
【0076】
Reference example 50
N-tert-butoxycarbonyl-4-(2(-hydroxyethyl)piperidine
Ethyl N-tert-butoxycarbonyl-4-piperidyl acetate (1.18 g) was dissolved in diethyl ether (20 ml) and methanol (0.19 ml) was added. Lithium borohydride (123 mg) was added under ice cooling. After stirring at room temperature for 15 hours, water was added under ice cooling. The mixture was diluted with ethyl acetate, washed with brine, and dried over magnesium sulfate. Concentration afforded the title compound (0.96 g) as a colorless oil.
IR(Neat)ν（cm^-1): 3350, 2927, 1697, 1672, 1429, 1169.
¹H-NMR (CDCl₃)δ: 1.0-1.4(4H,m), 1.45(9H,s), 1.5-1.8(4H,m), 2.69(2H,t,J=13.3Hz), 3.6-3.8(2H,brm), 4.0-4.2(2H,brm).
Reference example 51
N-tert-butoxycarbonyl-4-(2-bromoethyl)piperidine
N-tert-butoxycarbonyl-4-(2(-hydroxyethyl)piperidine (0.92 g) was dissolved in dichloromethane (20 ml) and carbon tetrabromide (1.62 g) was added. Under ice-cooling, triphenylphosphine (1.58 g) was slowly added. After stirring at room temperature for 2 hours, the mixture was evaporated with dichloromethane and diluted with ethyl acetate. Aqueous sodium bicarbonate was added, and insoluble materials were removed by filtration. The mixture was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 8/1) to give the title compound (1.34 g) as a colorless oil.
IR(Neat)ν（cm^-1): 2926, 1691, 1425, 1242, 1167.
¹H-NMR (CDCl₃)δ: 1.0-1.3(3H,m), 1.45(9H,s), 1.6-1.9(4H,m), 2.6-2.8(2H,brm), 3.45(2H,t,J=6.8Hz), 4.0-4.2(2H,brm).
【0077】
Example 1
2-[4-(4-chlorobenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone
4-(4-Chlorobenzoyl)benzyl bromide (1.8 g) was added to a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g), synthesized by the method described in Chem. Pharm. Bull., Vol. 17, p. 2357, 1969, and sodium hydroxide (250 mg) in 50% ethanol (15 ml)-dimethylformamide (15 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from ethyl acetate-methanol to yield the title compound (1.29 g) as a colorless solid.
¹H-NMR (CDCl₃)δ: 3.61(3H,s), 4.62(2H,s), 7.35-7.50(3H,m), 7.55-7.80(8H,m), 8.24(1H,d,J=8.0Hz).
IR(KBr): 1670, 1645, 1550cm^-1.
【0078】
Example 2
2-[4-(4-fluorobenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone
4-(4-Fluorobenzoyl)benzyl bromide (1.55 g) was added to a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) and sodium hydroxide (250 mg) in 50% ethanol (15 mL)-dimethylformamide (15 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to yield the title compound (1.85 g) as a colorless solid.
¹H-NMR (CDCl₃)δ: 3.61(3H,s), 4.62(2H,s), 7.15(2H,t,J=8.6Hz), 7.40(1H,dt,J=8.2,1.4Hz), 7.58-7.90(8H,m), 8.23(1H,dd,J=8.0,1.4Hz).
IR(KBr): 1670, 1645, 1550cm^-1.
Example 3
2-[3-(4-chlorobenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone
3-(4-Chlorobenzoyl)benzyl bromide (1.8 g) was added to a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) and sodium hydroxide (250 mg) in 50% ethanol (15 mL)-dimethylformamide (15 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to yield the title compound (2.22 g) as a colorless solid.
¹H-NMR (CDCl₃)δ: 3.59(3H,s), 4.59(2H,s), 7.34-7.52(5H,m), 7.61-7.80(5H,m), 7.96(1H,d,J=2.0Hz), 8.22(1H,dd,J=8.0,1.4Hz).
IR(KBr): 1660, 1650, 1525 cm^-1.
【0079】
Example 4
2-[4-(2,4-dichlorobenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone
4-(2,4-Dichlorobenzoyl)benzyl bromide (1.88 g) was added to a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) and sodium hydroxide (250 mg) in 50% ethanol (15 mL)-dimethylformamide (15 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to yield the title compound (2.16 g) as a colorless solid.
¹H-NMR (CDCl₃)δ: 3.59(3H,s), 4.59(2H,s), 7.25-7.80(10H,m), 8.22(1H,dd,J=8.2,1.4Hz).
IR(KBr): 1670, 1650, 1550cm^-1.
【0080】
Example 5
2-[4-(4-chlorobenzoyl)benzyl]thio-3-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4(3H)-one
4-(4-chlorobenzoyl)benzyl bromide (1.75 g) was added to a solution of 2-mercapto-3-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4(3H)-one (1.0 g) obtained in Reference Example 1 and sodium hydroxide (220 mg) in 50% ethanol (15 ml)-dimethylformamide (8 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to yield the title compound (1.15 g) as a colorless solid.
¹H-NMR (CDCl₃)δ: 2.06(2H,quint,J=7.4Hz), 2.79(2H,t,J=7.4Hz), 2.84(2H,t,J=7.4Hz), 3.49(3H,s), 4.50(2H,s), 7.46(2H,d,J=8.6Hz), 7.54(2H,d,J=8.6Hz),7.74(4H,d,J=8.6Hz).
IR(KBr): 1670, 1645, 1495 cm-1.
【0081】
Example 6
2-[4-(4-chlorobenzoyl)benzyl]thio-1,7-dimethyl-6-oxopurine
4-(4-chlorobenzoyl)benzyl bromide (480 mg) was added to a solution of 1,7-dimethyl-2-mercapto-6-oxopurine (286 mg) obtained in Reference Example 2 and sodium hydroxide (60 mg) in 50% ethanol (10 ml)-dimethylformamide (15 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to yield the title compound (535 mg) as a colorless solid.
¹H-NMR (CDCl₃)δ: 3.57(3H,s), 4.05(3H,s), 4.63(2H,s), 7.45(2H,d,J=8.4Hz),7.61(2H,d,J=8.4Hz), 7.73(1H,s), 7.74(4H,d,J=8.4Hz).
IR(KBr)：1680, 1650, 1490cm^-1.
【0082】
Example 7
2-[4-(4-chlorobenzoyl)benzyl]thio-3-methylthio[3,2-d]pyrimidin-4(3H)-one
4-(4-Chlorobenzoyl)benzyl bromide (1.56 g) was added to a solution of 2-mercapto-3-methyltheno[3,2-d]pyrimidin-4(3H)-one (1.0 g) and sodium hydroxide (205 mg) in 50% ethanol (12 ml)-dimethylformamide (20 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to give the title compound (1.497 g) as a colorless solid.
¹H-NMR (CDCl₃)δ: 3.61(3H,s), 4.58(2H,s), 7.23(1H,d,J=5.2Hz), 7.45(2H,d,J=8.6Hz), 7.59(2H,d,J=8.2Hz), 7.70-7.80(5H,m).
IR(KBr): 1665, 1645, 1510 cm^-1.
【0083】
Example 8
2-[4-(4-chlorobenzoyl)benzyl]thio-3-methyl-5,6,7,8-tetrahydro-benz[b]cheno[2,3-d]pyrimidin-4(3H)-one
4-(4-Chlorobenzoyl)benzyl bromide (565 mg) was added to a solution of 2-mercapto-3-methyl-5,6,7,8-tetrahydro-benz[b]cheno[2,3-d]pyrimidin-4(3H)-one (500 mg) and sodium hydroxide (75 mg) in 50% ethanol (5 mL)-dimethylformamide (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to yield the title compound (497 mg) as a colorless solid.
¹H-NMR (CDCl₃)δ: 1.72-1.94(4H,m), 2.75(2H,m), 2.98(2H,m), 3.53(3H,s), 4.53(2H,s), 7.45(2H,d,J=8.6Hz), 7.56(2H,d,J=8.4Hz), 7.74(4H,d,J=8.6Hz).
IR(KBr): 1670, 1660, 1510cm^-1.
【0084】
Example 9
6-[4-(4-chlorobenzoyl)benzyl]thio-5-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
4-(4-chlorobenzoyl)benzyl bromide (1.393 g) was added to a solution of 6-mercapto-5-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium salt (1.0 g) in dimethylformamide (10 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to give the title compound (1.647 g) as a colorless solid.
¹H-NMR (DMSO-d₆)δ: 3.53(3H,s), 4.58(2H,s), 7.50(2H,t,J=8.6Hz), 7.65(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 7.79(1H,s).
IR(KBr)：3200, 1660, 1640, 1575, 1280cm^-1.
【0085】
Example 10
6-[4-(4-chlorobenzoyl)benzyl]thio-1,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 6-[4-(4-chlorobenzoyl)benzyl]thio-2,5-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
To a suspension of 6-[4-(4-chlorobenzoyl)benzyl]thio-5-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (1.0 g) in dimethylformamide (20 ml), 60% sodium hydride (197 mg) was added and stirred at room temperature for 10 minutes to form a clear solution. After this, methyl iodide (515 mg) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/2) to give colorless solid 6-[4-(4-chlorobenzoyl)benzyl]thio-1,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (120 mg) and colorless solid 6-[4-(4-chlorobenzoyl)benzyl]thio-2,5-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (570 mg).
6-[4-(4-chlorobenzoyl)benzyl]thio-1,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
¹H-NMR (CDCl₃)δ: 3.54(3H,s), 4.06(3H,s), 4.60(2H,s), 7.46(2H,d,J=8.6Hz),7.61(2H,d,J=8.4Hz), 7.75(4H,d,J=8.6Hz), 7.99(1H,s).
IR(KBr)：1680, 1645, 1570cm^-1.
6-[4-(4-chlorobenzoyl)benzyl]thio-2,5-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
¹H-NMR (CDCl₃)δ:3.57(3H,s), 3.97(3H,s), 4.57(2H,s), 7.47(2H,d,J=8.6Hz),7.59(2H,d,J=8.4Hz), 7.75(2H,d,J=8.6Hz), 7.78(2H,d,J=8.4Hz), 8.00(1H,s).
IR(KBr): 1700, 1660, 1550 cm^-1.
【0086】
Example 11
6-[4-(4-chlorobenzoyl)benzyl]thio-3,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
4-(4-chlorobenzoyl)benzyl bromide (1.05 g) was added to a solution of 6-mercapto-3,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium salt (800 mg) in dimethylformamide (12 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to give the title compound (1.086 g) as a colorless solid.
¹H-NMR (DMSO-d₆)δ: 2.44(3H,s), 3.42(3H,s), 4.60(2H,s), 7.63(2H,d,J=8.6Hz), 7.71(4H,s), 7.75(2H,d,J=8.6Hz), 13.29(1H,brs).
IR(KBr)：3210, 1660, 1575, 1550, 1280cm^-1.
【0087】
Example 12
6-[4-(4-chlorobenzoyl)benzyl]thio-1,3,5-trimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 6-[4-(4-chlorobenzoyl)benzyl]thio-2,3,5-trimethyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
To a suspension of 6-[4-(4-chlorobenzoyl)benzyl]thio-3,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (500 mg) in dimethylformamide (15 ml), 60% sodium hydride (55 mg) was added and stirred at room temperature for 10 minutes to form a clear solution. After this, methyl iodide (235 mg) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/2) to give a colorless solid 6-[4-(4-chlorobenzoyl)benzyl]thio-1,3,5-trimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (90 mg) and a colorless solid 6-[4-(4-chlorobenzoyl)benzyl]thio-2,3,5-trimethyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (170 mg).
6-[4-(4-chlorobenzoyl)benzyl]thio-1,3,5-trimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
¹H-NMR (CDCl₃)δ: 2.66(3H,s), 3.51(3H,s), 3.91(3H,s), 4.59(2H,s), 7.46(2H,d,J=8.8Hz), 7.60(2H,d,J=8.4Hz), 7.70-7.80(4H,m).
IR(KBr)：1680, 1645, 1585, 1520cm^-1.
6-[4-(4-chlorobenzoyl)benzyl]thio-2,3,5-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
¹H-NMR (CDCl₃)δ:2.55(3H,s), 3.54(3H,s), 3.88(3H,s), 4.55(2H,s), 7.47(2H,d,J=8.6Hz), 7.58(2H,d,J=8.2Hz), 7.75(2H,d,J=8.6Hz), 7.77(2H,d,J=8.2Hz).
IR (KBr): 1695, 1660, 1550 cm^-1.
【0088】
Example 13
6-[4-(4-chlorobenzoyl)benzyl]thio-3,5-dimethyl-isoxazolo[5,4-d]pyrimidin-4(5H)-one
4-(4-Chlorobenzoyl)benzyl bromide (1.25 g) was added to a solution of 6-mercapto-3,5-dimethyl-isoxazolo[5,4-d]pyrimidin-4(5H)-one (800 mg) and sodium hydroxide (165 mg) in 50% ethanol (10 mL)-dimethylformamide (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1) to yield the title compound (470 mg) as a colorless solid.
¹H-NMR (CDCl₃)δ: 2.57(3H,s), 3.55(3H,s), 4.59(2H,s), 7.46(2H,d,J=8.6Hz),7.58(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.76(2H,d,J=8.6Hz).
IR(KBr)：1715, 1690, 1650, 1590, 1525cm^-1.
【0089】
Example 14
9-[4-(4-chlorobenzoyl)benzyloxy]-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
4-(4-chlorobenzoyl)benzyl bromide (896 mg) was added to a solution of 9-hydroxy-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (500 mg) obtained in Reference Example 3 and potassium carbonate (375 mg) in acetone (15 ml), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was washed with water and ethyl acetate and recrystallized from methanol to give the title compound (415 mg) as a colorless solid.
¹H-NMR (DMSO-d₆)δ: 2.14(3H,s), 2.43(3H,s), 7.16(1H,t,J=7.2Hz), 7.31(1H,d,J=7.4Hz), 7.63(2H,d,J=8.0Hz), 7.68(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz), 8.50(1H,d,J=7.0Hz).
IR(KBr): 1630, 1480, 1280cm^-1.
【0090】
Example 15
7-[4-(4-chlorobenzoyl)benzyl〕-1,3-dimethylxanthine
To a solution of theophylline (1.80 g) in dimethylformamide (20 ml), potassium carbonate (1.66 g) and 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) were added and stirred at room temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:4) to yield the title compound (2.79 g, 68%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 3.41(3H,s), 3.63(3H,s), 5.59(2H,s), 7.38-7.50(4H,m), 7.65(1H,s), 7.68-7.81(4H,m).
IR(KBr)：3110, 1690, 1650, 1400, 1280, 1230cm^-1.
Example 16
7-[4-(4-chlorobenzoyl)benzyl〕-1,3-Dimethylxanthine Hydrochloride
7-[4-(4-chlorobenzoyl)benzyl〕To a solution of 1,3-dimethylxanthine (100 mg) in methanol (4 ml) was added 4N hydrochloric acid (1 ml) and the mixture was stirred at room temperature for 10 minutes. Ether was added to the reaction mixture, and the precipitate was filtered to give the title compound (84 mg, 77%) as a white powder.
¹H-NMR (CDCl₃)δ: 3.45(3H,s), 3.70(3H,s), 5.70(2H,s), 7.42-7.83(8H,m), 8.47(1H,s).
IR(KBr)：3010, 2950, 1710, 1675, 1660cm^-1.
【0091】
Example 17
7-[4-(4-chlorobenzoyl)benzyl〕3-methylxanthine
To a solution of 3-methylxanthine (1.06 g) in dimethylformamide (26 ml), potassium carbonate (1.06 g) and 4-(4-chlorobenzoyl)benzyl bromide (1.98 g) were added and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction mixture, the resulting precipitate was filtered, and 1N aqueous hydrochloric acid was added to the resulting aqueous solution. The mixture was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ethyl acetate to give the title compound (239 mg, 10%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 3.54(3H,s), 3.57(3H,s), 7.41-7.52(4H,m), 7.68-7.81(5H,m).
IR(KBr): 3450, 3160, 3040, 2820, 1685, 1585, 1540, 1375, 1280, 1230, 1190, 925, 750 cm^-1.
Example 18
1-[4-(4-chlorobenzoyl)benzyl〕-3,7-dimethylxanthine
To theobromine (0.90 g) in dimethylformamide (20 ml) were added sodium hydride (240 ml) and 4-(4-chlorobenzoyl)benzyl bromide (1.55 g), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ether to give the title compound (1.37 g, 67%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 3.60(3H,s), 4.00(3H,s), 5.27(2H,s), 7.38-7.79(8H,m).
IR(KBr):3310, 2940, 1710, 1655, 1645, 1600, 1580, 1545, 1280, 930cm^-1.
【0092】
Example 19
8-chloro-7-[4-(4-chlorobenzoyl)benzyl〕-1,3-dimethylxanthine
To a solution of 8-chlorotheophylline (2.15 g) in dimethylformamide (20 ml), potassium carbonate (1.66 g) and 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) were added and stirred at room temperature for 20 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ether to give the title compound (3.34 g, 75%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 3.41(3H,s), 3.57(3H,s), 5.64(2H,s), 7.41-7.52(4H,m), 7.68-7.80(4H,m).
IR(KBr):2940, 1710, 1660, 1580, 1530, 1445, 1400, 1370, 1280, 740cm^-1.
Example 20
7-[4-(4-chlorobenzoyl)benzyl〕1,3-dimethyl-8-methoxyxanthine
8-chloro-7-[4-(4-chlorobenzylZoil) BenJillTo a solution of 1,3-dimethylxanthine (866 mg) in dimethylformamide (40 mL) was added sodium methoxide (10 mL, 28% methanol solution), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate and saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ether to give the title compound (470 mg, 54%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 3.40(3H,s), 3.54(3H,s), 4.17(3H,s), 5.36(2H,s), 7.38-7.78(8H,m).
IR(KBr)：2950, 1705, 1670, 1655, 1610, 1525, 1460, 1410, 1285 cm^-1.
【0093】
Example 21
7-[4-(4-chlorobenzylZoil) BenJill-1,3-dimethyluric acid
7-[4-(4-chlorobenzylZoil) BenJillTo 1,3-dimethyl-8-methoxyxanthine (400 mg) was added concentrated hydrochloric acid (8 ml) at room temperature, and the mixture was stirred for 1 hour at 130° C. After cooling, the precipitate was collected by filtration and washed with water and ether to give the title compound (333 mg, 86%) as a colorless powder.
¹H-NMR (CDCl₃+5%CD₃OD)δ: 3.36(3H,s), 3.45(3H,s), 5.23(2H,s), 7.40-7.80(8H,m).
IR(KBr)：3450, 2950, 2710, 1680, 1550, 1280, 1185, 740 cm^-1.
Example 22
1-[4-(4-chlorobenzoyl)benzyl〕-4,6-dimethyl-triazolo[4,5-d]pyrimidine-5,7-dione
4-Amino-1,3-dimethyluracil (1.55 g) was added to a solution of N,N-dimethylazidophosgeniminium chloride (1.70 g) in methylene chloride (40 ml) and heated to reflux for 3 hours. The reaction mixture was concentrated. Potassium carbonate (6.91 g) and 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) were added to a solution of the residue in dimethylformamide (30 ml) and stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1 to 1:1) to give the title compound (0.92 g, 22%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 3.41(3H,s), 3.66(3H,s), 5.93(2H,s), 7.39-7.80(8H,m).
IR(KBr)：1710, 1680, 1560, 1270, 925, 745cm^-1.
【0094】
Example 23
7-[3-(4-chlorobenzoyl)benzyl〕-1,3-dimethylxanthine
To a solution of theophylline (1.80 g) in dimethylformamide (50 ml), potassium carbonate (1.66 g) and 3-(4-chlorobenzoyl)benzyl bromide (3.10 g) were added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized (acetone-hexane) to give the title compound (1.64 g, 40%) as a white powder.
¹H-NMR (CDCl₃)δ: 3.40(3H,s), 3.60(3H,s), 5.57(2H,s), 7.42-7.79(9H,m).
IR(KBr)：1700, 1660, 1550, 1290, 750 cm^-1.
Example 24
7-[4-(2,4-dichlorobenzoyl)benzyl〕-1,3-dimethylxanthine
To a solution of theophylline (1.80 g) in dimethylformamide (20 ml), potassium carbonate (1.66 g) and 4-(2,4-dichlorobenzoyl)benzyl bromide (3.33 g) were added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized (ethyl acetate) to give the title compound (3.38 g, 76%) as a white powder.
¹H-NMR (CDCl₃)δ: 3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.25-7.84(8H,m).
IR(KBr)：1700, 1660, 1290, 930, 745cm^-1.
【0095】
Example 25
7-[4-(4-fluorobenzoyl)benzyl〕-1,3-dimethylxanthine
To a solution of theophylline (1.80 g) in dimethylformamide (20 ml), potassium carbonate (1.66 g) and 4-(4-fluorobenzoyl)benzyl bromide (2.93 g) were added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ether to give the title compound (2.79 g, 74%) as a white powder.
¹H-NMR (CDCl₃)δ: 3.41(3H,s), 3.60(3H,s), 5.59(2H,s), 7.08-7.86(9H,m).
IR(KBr)：1700, 1660, 1640, 1590, 1545, 1270, 1230cm^-1.
Example 26
7-[4-(2-chlorobenzoyl)benzyl〕-1,3-dimethylxanthine
To a solution of theophylline (0.90 g) in dimethylformamide (20 ml), potassium carbonate (0.83 g) and 4-(2-chlorobenzoyl)benzyl bromide (1.55 g) were added and stirred at room temperature for 13 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ether to give the title compound (1.70 g, 83%) as needle-like crystals.
¹H-NMR (CDCl₃)δ: 3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.30-7.48(6H,m), 7.63(1H,s), 7.76-7.85(2H,m).
IR(KBr)：3100, 1700, 1660, 1540, 1430, 1285, 740cm^-1.
【0096】
Example 27
7-[4-(4-chlorobenzoyl)benzyl〕Xanthine Hydrochloride
1,3-diethoxy-7-[4-(4-chlorobenzoyl)benzyl〕Concentrated hydrochloric acid (10 ml) was added to purine (100 mg) at room temperature, and the mixture was stirred for 2 hours at 130° C. After cooling, the precipitate was filtered and washed with water and ether to obtain the title compound (73 mg, 73%) as a colorless powder.
¹H-NMR (CDCl₃+5%CD₃OD)δ: 5.59(2H,s), 7.45-7.55(4H,m), 7.70-7.90(4H,m), 8.05(1H,s).
IR(KBr)：2950, 2760, 1710, 1650, 1575, 1270cm^-1.
Example 28
7-[4-(4-chlorobenzoyl)benzyl〕-1,3,8-trimethylxanthine
To a solution of 1,3,8-trimethylxanthine (0.97 g) in dimethylformamide (20 ml), potassium carbonate (0.83 g) and 4-(4-chlorobenzoyl)benzyl bromide (1.55 g) were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with acetone to give the title compound (1.34 g, 61%) as a white powder.
¹H-NMR (CDCl₃)δ: 2.46(3H,s), 3.41(3H,s), 3.60(3H,s), 5.63(2H,s), 7.25-7.80(8H,m).
IR(KBr): 2950, 1705, 1660, 1610, 1590, 1545, 1490, 1410, 1395, 1290, 1270, 1090, 925, 755, 745 cm^-1.
【0097】
Example 29
7-[4-(4-chlorobenzoyl)benzyl〕1,3-dimethyl-8-ethylxanthine
To a solution of 1,3-dimethyl-8-ethylxanthine (416 mg) in dimethylformamide (10 ml), potassium carbonate (332 mg) and 4-(4-chlorobenzoyl)benzyl bromide (619 mg) were added and stirred at room temperature for 21 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized (ethyl acetate-ether) to give the title compound (584 mg, 67%) as a white powder.
¹H-NMR (CDCl₃)δ: 1.30(3H,t,J=7.6Hz), 2.72(2H,q,J=7.6Hz), 3.40(3H,s), 3.61(3H,s), 5.64(2H,s), 7.21-7.80(8H,m).
IR(KBr)：1700, 1600, 1650, 1410, 1280cm^-1.
Example 30
2-[4-(4-chlorobenzoyl)benzylthio〕-3-methylpyrido[2,3-d]pyrimidin-4-one
To a solution of 3-methylpyrido[2,3-d]pyrimidin-4-one-2-thione (193 mg) in dimethylformamide (5 mL) was added sodium hydride (60 mg) and 4-(4-chlorobenzoyl)benzyl bromide (310 mg), and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized (ethyl acetate-ether-hexane) to give the title compound (162 mg, 38%) as a white powder.
¹H-NMR (CDCl₃)δ: 3.62(3H,s), 4.73(2H,s), 7.26-7.79(9H,m), 8.54-8.61(1H,m), 8.90-8.95(1H,m).
IR (KBr): 1680, 1645, 1580, 1550, 1425, 1285, 1270, 1080, 725 cm^-1.
【0098】
Example 31
1-[4-(4-chlorobenzoyl)benzyl]-4-chloro-imidazo[4,5-d]pyridazin-7(6H)-one and 1-[4-(4-chlorobenzoyl)benzyl]-7-chloro-imidazo[4,5-d]pyridazin-4(5H)-one
1-[4-(4-chlorobenzoyl)benzyl]-4,7-dichloroimidazo[4,5-d]pyridazine (2.006 g) was dissolved in dioxane (20 ml), and an aqueous solution of sodium hydroxide (3.78 g sodium hydroxide/30 ml water) was added. The mixture was heated under reflux for 15 hours. Water (100 ml) and acetic acid (5 ml) were then added, and the precipitated crystals were collected by filtration. The obtained crystals were purified by silica gel column chromatography (carrier 50 g; dichloromethane:ethyl acetate - 10:1-1:1) to obtain 1.32 g (yield 69%) of the title compound 1-[4-(4-chlorobenzoyl)benzyl]-4-chloro-imidazo[4,5-d]pyridazin-7(6H)-one and 441 mg (yield 23%) of the title compound 1-[4-(4-chlorobenzoyl)benzyl]-7-chloro-imidazo[4,5-d]pyridazin-4(5H)-one.
1-[4-(4-chlorobenzoyl)benzyl]-4-chloroimidazo[4,5-d]pyridazin-7(6H)-one
¹H-NMR (CDCl₃)δ: 5.80(2H,s), 7.51(2H,d,J=8.4Hz), 7.60(2H,d,J=8.8Hz), 7.73(4H,d,J=8.8Hz), 8.69(1H,s).
IR(KBr)：3101, 2933, 1672, 1533, 742cm^-1.
1-[4-(4-chlorobenzoyl)benzyl]-7-chloro-imidazo[4,5-d]pyridazin-4(5H)-one
¹H-NMR (CDCl₃)δ: 5.86(2H,s), 7.31(2H,d,J=8.4Hz), 7.61(2H,d,J=8.8Hz), 7.74(4H,d,J=8.6Hz), 8.62(1H,s).
IR(KBr)：3116, 2926, 1676, 1533, 739cm^-1.
【0099】
Example 32
1-[4-(4-chlorobenzoyl)benzyl]-4-chloro-6-methyl-imidazo[4,5-d]pyridazin-7(6H)-one
1-[4-(4-chlorobenzoyl)benzyl]-4-chloro-imidazo[4,5-d]pyridazin-7(6H)-one (963 mg) was dissolved in DMF (15 ml), and potassium carbonate (985 mg) and then methyl iodide (0.45 ml) were added. The mixture was stirred at room temperature for 65 hours. Water (50 ml) was added, and the precipitated crystals were collected by filtration. The resulting crystals were purified by silica gel column chromatography (carrier 30 g; dichloromethane:ether = 1:0-3:1) to give 655 mg (yield 66%) of the title compound.
¹H-NMR (CDCl₃)δ: 3.86(3H,s), 5.81(2H,s), 7.45(2H,d,J=7.8Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.01(1H,s).
IR(neat): 2949, 1666, 1537, 741 cm^-1．
Example 33
1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7-chloro-imidazo[4,5-d]pyridazin-4(5H)-one
As in Example 32, 1-[4-(4-chlorobenzoyl)benzyl]-7-chloro-imidazo[4,5-d]pyridazin-4(5H)-one (424 mg) was dissolved in DMF (7 ml), potassium carbonate (465 mg) was added, followed by methyl iodide (0.2 ml), and the mixture was stirred at room temperature for 65 hours. Water (50 ml) was added, and the precipitated crystals were collected by filtration. The resulting crystals were purified by silica gel column chromatography (30 g carrier; ethyl acetate:methanol = 1:0-20:1) to give 218 mg (50% yield) of the title compound.
¹H-NMR (CDCl₃)δ: 3.87(3H,s), 5.74(2H,s), 7.23(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.72(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.01(1H,s).
IR(neat): 2951, 1672, 1529, 739 cm^-1.
【0100】
Example 34
1-[4-(4-chlorobenzoyl)benzyl]-4-methoxy-6-methyl-imidazo[4,5-d]pyridazin-7(6H)-one
1-[4-(4-chlorobenzoyl)benzyl]-4-chloro-6-methyl-imidazo[4,5-d]pyridazin-7(6H)-one (72 mg) was dissolved in methanol (5 mL), and 28% sodium methoxide/methanol solution (1.0 mL) was added. The mixture was then heated under reflux for 5 hours. A large amount of water was added to precipitate crystals, which were washed with water and dried under reduced pressure to give 50 mg of the title compound (70% yield).
¹H-NMR (CD₃OD)δ:3.71(3H,s), 4.00(3H,s), 5.85(2H,s), 7.50(2H,d,J=8.6Hz),7.52(2H,d,J=8.8Hz), 7.74(2H,d,J=8.8Hz), 7.75(2H,d,J=8.6Hz), 8.42(1H,s).
IR(neat)：2945, 1660, 1561, 1269, 1234, 739 cm^-1.
Example 35
1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7-methoxy-imidazo[4,5-d]pyridazin-4(5H)-one
As in Example 7, 1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7-chloro-imidazo[4,5-d]pyridazin-4(5H)-one (52 mg) was dissolved in methanol (5 mL), and 28% sodium methoxide/methanol solution (0.5 mL) was added. The mixture was then heated under reflux for 3 hours. A large amount of water was added to precipitate crystals, which were washed with water and dried under reduced pressure to give 20 mg of the title compound (yield 39%).
¹H-NMR (CD₃OD)δ：3.73(3H,s), 3.97(3H,s), 5.70(2H,s), 7.41(2H,d,J=8.4), 7.51(2H,d,J=8.8Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 8.36(1H,s).
IR(neat): 2947, 1660, 1568, 1272, 737 cm^-1.
【0101】
Example 36
8-tert-butyl-5-[4-(4-chlorobenzoyl)benzyl]-2,3,4,5-tetrahydropyridazino[4,5-b]-1,4-oxazepin-9(8H)-one
A solution of 2-tert-butyl-4-chloro-5-[4-(4-chlorobenzoyl)benzyl-N-(3-hydroxypropyl)amino]-3(2H)-pyridazinone (91 mg) in ethanol (5 mL) was added to a solution of sodium ethoxide in ethanol (1 mL) and heated under reflux for 46 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1 → 1/2) to give the title compound as a white powder (120 mg, yield 12%).
¹H-NMR (CDCl₃)δ: 1.62(9H,s), 2.06(2H,quintet,J=6.2Hz), 3.55(2H,t,J=6.2Hz), 4.42(2H,t,J=6.2Hz), 4.55(2H,m), 7.32(1H,s), 7.41(2H,d,J=8.4Hz), 7.48(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz).
【0102】
Example 37
1-[4-(4-chlorobenzoyl)benzyl]-2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
To a suspension of 60% sodium hydride in oil (96 mg) in DMF (10 mL) cooled in an ice bath, a solution of 2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 mL) was added dropwise. After stirring at room temperature for 3 hours, a solution of 4-(4-chlorobenzoyl)benzyl bromide (681 mg) in DMF (15 mL) was added and the mixture was stirred at room temperature for an additional 18 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: n-hexane/ethyl acetate = 2/1 → 1/1] to obtain the title compound as a white powder (351 mg, yield 39%).
¹H-NMR (DMSO-d₆)δ: 3.68(3H,s), 5.73(2H,s), 7.30(2H,d,J=8.6Hz), 7.61(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 8.71(1H,s).
IR(KBr)：3055, 3040, 2990, 2960, 1660, 1640, 1605cm^-1.
【0103】
Example 38
1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-1H-imidazo[4,5-d]pyridazin-4(5H)-one
A solution of methylhydrazine (472 mg) and ethyl 1-[4-(4-chlorobenzoyl)benzyl]-5-formylimidazole-4-carboxylate (1.03 g) in ethanol (20 ml) was heated to reflux for 3 hours. After cooling to room temperature, concentrated sulfuric acid (0.2 ml) was added and the mixture was heated to reflux for an additional 21 hours. After dilution with water, the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: chloroform/methanol = 19/1] to obtain the title compound as a white powder (66 mg, yield 7%).
¹H-NMR (CDCl₃)δ:3.90(3H,s), 5.47(2H,s), 7.31(2H,d,J=8.4Hz), 7.48(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 7.92(1H,s), 8.00(1H,s).
【0104】
Example 39
3-[4-(4-chlorobenzoyl)benzyl]-5-methyl-3H-imidazo[4,5-d]pyridazin-4(5H)-one
A solution of methylhydrazine (209 mg) and ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-formylimidazole-5-carboxylate (601 g) in ethanol (10 ml) was heated to reflux for 2.5 hours. After cooling to room temperature, concentrated sulfuric acid (0.1 ml) was added and the mixture was heated to reflux for an additional 15 hours. After dilution with water, the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: n-hexane/ethyl acetate = 2/1] to obtain the title compound as a white powder (115 mg, yield 20%).
¹H-NMR (CDCl₃)δ: 3.88(3H,s), 5.81(2H,s), 7.46(4H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz), 7.97(1H,s), 8.33(1H,s).
IR(KBr)：3100, 2950, 1650, 1600, 1580, 1540cm^-1.
【0105】
Example 40
2-[4-(4-chlorobenzoyl)-benzyloxy]-3-methylpyrido[1,2-a]pyrimidin-4-one
Potassium carbonate (0.25 g) was added to a solution of 2-hydroxy-3-methylpyrido[1,2-a]pyrimidin-4-one (0.31 g) obtained in Reference Example 15 and 4-(4-chlorobenzoyl)benzyl bromide (0.56 g) in dimethylformamide (10.0 ml), and the mixture was stirred at 80°C for 30 minutes. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from methanol to give the title compound (0.224 g; yield 31%) as colorless needles.
¹H-NMR (CDCl₃)δ: 2.23(3H,s), 5.62(2H,s), 7.10(1H,t,J=7.4Hz), 7.45-7.82(10H,m), 9.08(1H,d,J=7.4Hz).
IR(KBr)ν: 1689, 1657, 1581, 1431, 1284, 1174, 1088, 930, 748 cm^-1.
【0106】
Example 41
2-[4-(4-chlorobenzoyl)benzylthio]-6,7-dimethoxy-3-methylquinazolin-4-one
1N sodium hydroxide (3.90 ml) was added to a solution of 2-mercapto-6,7-dimethoxy-3-methylquinazolin-4-one (0.998 g) obtained in Reference Example 16 and 4-(4-chlorobenzoyl)benzyl bromide (1.26 g) in ethanol (15.0 ml) and THF (5.0 ml) and stirred overnight at 70°C. Ethyl acetate was added to the reaction solution and washed with saturated brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (1.06 g; yield 56%) as colorless needles.
¹H-NMR (CDCl₃)δ:3.60(3H,s), 3.99(3H,s), 4.02(3H,s), 4.61(2H,s), 7.00(1H,s), 7.46(2H,d,J=8.6Hz), 7.56(1H,s), 7.60(2H,d,J=8.0Hz), 7.73-7.78(4H,m).
IR(KBr): 1660, 1610, 1549, 1497, 1271, 1076, 1022, 928, 781, 743 cm^-1.
【0107】
Example 42
2-[4-(4-chlorobenzoyl)benzylthio]-3,5-dimethylquinazolin-4-one
1N sodium hydroxide (5.10 ml) was added to a solution of 2-mercapto-3,5-dimethylquinazolin-4-one (1.05 g) obtained in Reference Example 18 and 4-(4-chlorobenzoyl)benzyl bromide (1.60 g) in a mixture of ethanol (15.0 ml), THF (15.0 ml), and DMF (5.0 ml), and the mixture was stirred at 70°C for 30 minutes. Ethyl acetate was added to the reaction solution, which was washed with saturated brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (1.54 g; yield 70%) as colorless needles.
¹H-NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.16(1H,d,J=7.0Hz),7.42-7.47(2H,m), 7.53(2H,d,J=8.2Hz), 7.61(2H,d,J=8.6Hz), 7.72-7.77(4H,m).
IR(KBr)：1666, 1554, 1466, 1408, 1306, 1277, 1090, 928cm^-1.
【0108】
Example 43
2-[4-(2,4-dichlorobenzoyl)benzylthio]-3,5-dimethylquinazolin-4-one
To a solution of 2-mercapto-3,5-dimethylquinazolin-4-one (0.511 g) obtained in Reference Example 18 in a mixture of ethanol (10.0 ml) and THF (10.0 ml) was added 1N sodium hydroxide (2.60 ml), followed by 4-(2,4-dichlorobenzoyl)benzyl bromide (0.872 g) and stirring at 60°C for 3.5 hours. Ethyl acetate was added to the reaction solution, which was washed with saturated brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.825 g; yield 69%) as colorless needles.
¹H-NMR (CDCl₃)δ: 2.84(3H,s), 3.53(3H,s), 4.57(2H,s), 7.15(1H,d,J=6.8Hz),7.32-7.54(5H,m), 7.59(2H,d,J=8.2Hz), 7.75(2H,d,J=8.2Hz).
IR(KBr): 1672, 1581, 1554, 1464, 1417, 1306, 1282, 1092, 930 cm^-1.
【0109】
Example 44
2-[3-(4-chlorobenzoyl)benzylthio]-3,5-dimethylquinazolin-4-one
1N sodium hydroxide (2.50 ml) was added to a solution of 2-mercapto-3,5-dimethylquinazolin-4-one (0.522 g) obtained in Reference Example 18 in a mixture of ethanol (10.0 ml) and THF (10.0 ml), followed by 3-(4-chlorobenzoyl)benzyl bromide (0.770 g) and stirring at 60°C for 3.5 hours. Ethyl acetate was added to the reaction solution, which was washed with saturated brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.877 g; yield 81%) as colorless needles.
¹H-NMR (CDCl₃)δ: 2.84(3H,s), 3.53(3H,s), 4.57(2H,s), 7.15(1H,d,J=7.2Hz), 7.30-7.55(5H,m), 7.65-7.74(4H,m), 7.96(1H,bs).
IR(KBr)：1666, 1581, 1554, 1466, 1306, 1090, 733cm^-1.
【0110】
Example 45
2-[4-(4-fluorobenzoyl)benzylthio]-3,5-dimethylquinazolin-4-one
To a solution of 2-mercapto-3,5-dimethylquinazolin-4-one (0.492 g) obtained in Reference Example 18 in a mixture of ethanol (10.0 ml) and THF (10.0 ml) was added 1N sodium hydroxide (2.50 ml), followed by 4-(4-fluorobenzoyl)benzyl bromide (0.700 g) and stirring at 60°C for 3.5 hours. Ethyl acetate was added to the reaction solution, which was washed with saturated brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.717 g; yield 72%) as colorless needles.
¹H-NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.10-7.20(3H,m), 7.46-7.63(4H,m), 7.72-7.87(4H,m).
IR(KBr):1666, 1601, 1554, 1464, 1414, 1304, 1277, 1234, 1153, 1092cm^-1.
【0111】
Example 46
7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7-[4-(4-chlorobenzoyl)benzyl]-4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (0.671 g) was dissolved in dioxane (8 ml), and 4,4'-thiobis(6-t-butyl-m-cresol) (7.2 mg) was added. Then, 0.5 N hydrochloric acid (1.12 ml) was added and the mixture was stirred at 105°C for 36 hours. Another 0.5 N hydrochloric acid (1.12 ml) was added, and the mixture was stirred at the same temperature for 24 hours. Water (30 ml) was added, and the precipitate was collected by filtration and dried. This was purified by flash column chromatography (chloroform) to give the title compound (0.312 g).
¹H-NMR (DMSO-d₆)δ: 2.24(3H,s), 2.51(3H,d,J=1.0Hz), 5.33(2H,s), 6.83(1H,d,J=1.0Hz), 7.43(2H,d,J=8.2Hz), 7.60(2H,d,J=8.6Hz), 7.71(2H,d,J=8.2Hz), 7.73(2H,d,J=8.6Hz), 12.01(1H,s).
IR(KBr)：3430, 3220, 3030, 2920, 2830, 1660, 1605, 1570, 1545, 1520, 1460, 1410, 1305, 1280, 1205, 1180, 1170, 1135, 1035, 1085, 1010 cm^-1.
【0112】
Example 47
7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7-[4-(4-chlorobenzoyl)benzyl]-4-methoxy-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (0.615 g) was dissolved in dioxane (6 ml), and 4,4'-thiobis(6-t-butyl-m-cresol) (7 mg) was added. Then, 0.5 N hydrochloric acid (1.2 ml) was added and the mixture was stirred at 105°C for 36 hours. Another 0.5 N hydrochloric acid (1.2 ml) was added, and the mixture was stirred at the same temperature for 24 hours, then allowed to return to room temperature. The precipitate was collected by filtration, washed with methanol and ether, and dried to obtain the title compound (0.405 g).
¹H-NMR (DMSO-d₆)δ: 2.53(3H,s), 5.42(2H,s), 6.44(1H,d,J=3.4Hz), 7.15(1H,d,J=3.4Hz), 7.45(2H,d,J=8.0Hz), 7.60(2H,d,J=8.4Hz), 7.72(2H,d,J=8.0Hz), 7.73(2H,d,J=8.4Hz), 12.18(1H,s).
IR(KBr)：3450, 2920, 2840, 1670, 1640, 1605, 1550, 1405, 1310, 1280, 1230, 1205, 1140, 1085 cm^-1.
【0113】
Example 48
7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (254 mg) was dissolved in dry DME (10 ml) and dry dimethylformamide (6 ml), and 60% sodium hydride in oil (26.4 mg) was added under ice-cooling. After stirring for 30 minutes, methyl iodide (98 mg) was added, the mixture was returned to room temperature, and stirred for 2.5 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (chloroform) to yield the title compound (176 mg).
¹H-NMR (CDCl₃)δ:2.39(3H,s), 2.56(3H,s), 3.56(3H,s), 5.29(2H,s), 6.47(1H,d,J=1.0Hz), 7.29(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.73(4H,d,J=8.4Hz).
IR(KBr): 3450, 3050, 3030, 1665, 1650, 1605, 1590, 1570, 1535, 1515, 1485, 1410, 1340, 1310, 1280, 1270, 1230, 1180, 1150, 1080 cm^-1．
【0114】
Example 49
7-[4-(4-chlorobenzoyl)benzyl]-3-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (82 mg) was dissolved in dry DME (10 mL) and dry dimethylformamide (4 mL), and 60% sodium hydride in oil (9.6 mg) was added under ice-cooling. After stirring for 30 minutes, methyl iodide (34 mg) was added, the mixture was returned to room temperature, and stirred for 2.5 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (hexane-ethyl acetate; 4:1) to yield the title compound (30 mg).
¹H-NMR (CDCl₃)δ: 2.58(3H,s), 3.60(3H,s), 5.37(2H,s), 6.67(1H,d,J=3.4Hz),6.75(1H,d,J=3.4Hz), 7.30(2H,d,J=8.0Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.0Hz).
IR(KBr)：3430, 3100, 3050, 3000, 2920, 1670, 1650, 1606, 1580, 1540, 1495, 1465, 1410, 1350, 1295, 1275, 1215, 1170, 1085cm^-1.
【0115】
Example 50
2-[4-(4-chlorobenzoyl)benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
5-Methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) was dissolved in dimethylformamide (30 ml), 1N sodium hydroxide (7.5 ml) was added, and a solution of 4-(4-chlorobenzoyl)benzyl bromide (2.48 g) in dimethylformamide (10 ml) was added dropwise under ice cooling. After returning to room temperature and stirring for 4 hours, the reaction mixture was added to ice water (250 ml), and the resulting precipitate was collected by filtration, washed with water, and dried. This material was purified by flash column chromatography (3-5% ethanol in chloroform) to give the title compound (1.57 g).
¹H-NMR (DMSO-d₆)δ: 2.23(3H,s), 4.50(2H,s), 6.65(1H,s), 7.60(2H,d,J=8.6Hz), 7.64(2H,d,J=8.6Hz), 7.69(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 11.42(1H,s), 11.95(1H,s).
IR(KBr)：3420, 3180, 3100, 3020, 2920, 2830, 1660, 1600, 1580, 1545, 1515, 1480, 1430, 1400, 1360, 1300, 1280, 1235, 1170, 1085, 1065, 1010cm^-1.
【0116】
Example 51
2-[4-(4-chlorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
2-Mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (836 ml) was dissolved in dimethylformamide (20 ml), 1N sodium hydroxide (5 ml) was added, and a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.63 g) in dimethylformamide (5 ml) was added dropwise under ice cooling. After returning to room temperature and stirring for 4 hours, the reaction mixture was added to ice water (200 ml), and the resulting precipitate was collected by filtration, washed with water, and dried. This material was purified by flash column chromatography (chloroform containing 3-5% ethanol) to give the title compound (1.33 g).
¹H-NMR (DMSO-d₆)δ: 4.52(2H,s), 6.34-6.37(1H,m), 6.91-6.95(1H,m), 7.61(2H,d,J=8.4Hz), 7.65(2H,d,J=8.4Hz), 7.70(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz),11.42(1H,s), 11.95(1H,s).
IR(KBr)：3430, 3220, 3100, 3030, 2960, 2900, 2840, 1650, 1605, 1565, 1410, 1350, 1300, 1280, 1270, 1215, 1170, 1140, 1090, 1015cm^-1.
【0117】
Example 52
2-[4-(4-fluorobenzoyl)benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
5-Methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.82 g) was suspended in methanol (25 ml) and dissolved by adding 1 N sodium hydroxide (10.5 ml). Under ice cooling, a solution of 4-(4-fluorobenzoyl)benzyl bromide (3.51 g) in DME (10 ml) was added dropwise. After returning to room temperature and stirring for 4 hours, the crystalline precipitate was collected by filtration, washed with water, 50% aqueous ethanol, methanol, and ether, and then dried. This material was recrystallized using DME (1,2-dimethoxyethane) to give the title compound (2.71 g).
¹H-NMR (DMSO-d₆)δ: 2.24(3H,s), 4.51(2H,s), 6.65(1H,s), 7.37(2H,t,J=8.8Hz), 7.64(2H,d,J=8.8Hz), 7.70(2H,d,J=8.8Hz), 7.81(2H,dd,J=5.6Hz,8.8Hz), 11.43(1H,s), 11.97(1H,s).
IR(KBr)：3430, 3180, 3120, 3060, 2980, 2920, 2830, 1650, 1600, 1580, 1545, 1500, 1455, 1435, 1410, 1300, 1280, 1235, 1180, 1155, 1120, 1065cm^-1.
【0118】
Example 53
2-[4-(2,4-dichlorobenzoyl)benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
5-Methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) was suspended in methanol (18.7 ml) and dissolved by adding 1N sodium hydroxide (7.88 ml). Under ice cooling, a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (3.09 g) in DME (8 ml) was added dropwise. After returning to room temperature and stirring for 4 hours, the crystalline precipitate was collected by filtration, washed with water, 50% aqueous ethanol, methanol, and ether, and then dried. This material was recrystallized from DME (1,2-dimethoxyethane) to give the title compound (2.03 g).
¹H-NMR (DMSO-d₆)δ: 2.23(3H,s), 4.48(2H,s), 6.65(1H,s), 7.53(1H,d,J=8.2Hz), 7.59(1H,dd,J=1.6Hz,8.8Hz), 7.64(2H,d,J=8.4Hz), 7.69(2H,d,J=8.4Hz), 7.80(1H,d,J=1.6Hz), 11.40(1H,s), 11.96(1H,s).
IR(KBr)：3430, 3270, 3130, 3080, 2920, 2820 1670, 1650, 1600, 1580, 1550, 1515, 1455, 1430, 1410, 1370, 1280, 1240, 1190, 1180, 1150, 1100, 1085, 1050 cm^-1.
【0119】
Example 54
2-[3-(4-chlorobenzoyl)benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
5-Methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) was suspended in methanol (18.7 ml) and dissolved in 1N sodium hydroxide (7.88 ml). Under ice-cooling, a solution of 3-(4-chlorobenzoyl)benzyl bromide (2.79 g) in DME-DMF (6:5; 22 ml) was added dropwise. After returning to room temperature and stirring for 20 hours, the reaction mixture was added to ice water (200 ml). The resulting precipitate was collected by filtration, washed with water, 50% aqueous ethanol, methanol, and ether, and then dried. This material was purified by flash column chromatography (chloroform containing 1% methanol) to yield the title compound (1.94 g).
¹H-NMR (DMSO-d₆)δ: 2.25(3H,s), 4.50(2H,s), 6.65(1H,s), 7.50(2H,d,J=8.0Hz), 7.69(2H,d,J=8.6Hz), 7.51-7.82(4H,m), 11.38(1H,s), 11.95(1H,s).
IR(KBr)：3430, 3180, 3120, 3060, 2920, 2830, 1650, 1580, 1545, 1515, 1480, 1455, 1430, 1400, 1360, 1300, 1280, 1235, 1200, 1190, 1170, 1120, 1090, 1065, 1010cm^-1.
【0120】
Example 55
2-[4-(4-chlorobenzoyl)benzyl]thio-3,5,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 2-[4-(4-chlorobenzoyl)benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (640 mg) was suspended in dry DME (15.6 ml), and 60% sodium hydride in oil (144 mg) was added in two portions with stirring and ice cooling. Methyl iodide (509 mg) was then added, and the mixture was allowed to return to room temperature and then allowed to stir overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (hexane-ethyl acetate; 4:1) to yield the title compound (542 mg).
¹H-NMR (CDCl₃)δ:2.38(3H,s), 3.55(3H,s), 3.66(3H,s), 4.54(2H,s), 6.44(1H,d,J=1.0Hz), 7.46(2H,d,J=8.4Hz), 7.59(2H,d,J=8.4Hz), 7.75(4H,d,J=8.4Hz).
IR(KBr)：3430, 3110, 3060, 2920, 1680, 1660, 1605, 1580, 1540, 1515, 1460, 1400, 1300, 1275, 1225, 1200, 1170, 1090, 1050, 1010cm^-1.
【0121】
Example 56
2-[4-(4-chlorobenzoyl)benzyl]thio-3,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (A)
2-[1-[4-(4-chlorobenzoyl)phenyl]ethyl]thio-3,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (B)
Under an argon atmosphere, 2-[4-(4-chlorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.2 g) was dissolved in dry DME (15 ml), and 60% sodium hydride in oil (288 mg) was added in two portions with stirring and ice cooling. Methyl iodide (1.11 g) was then added, and the mixture was allowed to return to room temperature and allowed to stir overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (hexane-ethyl acetate; 6:1 → 4:1 → 2.5:1) to yield the title compounds (A; 470 mg, B; 92 mg).
Compound (A)
¹H-NMR (CDCl₃)δ: 3.59(3H,s), 3.74(3H,s), 4.56(2H,s), 6.60(1H,d,J=3.4Hz),6.71(1H,d,J=3.4Hz), 7.46(2H,d,J=8.6Hz), 7.59(2H,d,J=8.4Hz), 7.75(2H,d,J=8.6Hz), 7.76(2H,d,J=8.4Hz).
IR(KBr)：3450, 3120, 2980, 2930, 1700, 1660, 1605, 1585, 1540, 1510, 1460, 1400, 1300, 1270, 1220, 1170, 1105, 1090, 1050, 1010 cm^-1.
Compound (B)
¹H-NMR (CDCl₃)δ: 1.83(3H,d,J=7.2Hz), 3.55(3H,s), 3.71(3H,s), 5.20(1H,q,J=7.2Hz), 6.57(1H,d,J=3.4Hz), 6.68(1H,d,J=3.4Hz), 7.45(2H,d,J=8.4Hz), 7.62(2H,d,J=8.4Hz), 7.74(2H,d,J=8.6Hz), 7.76(2H,d,J=8.6Hz).
IR(KBr): 3430, 2970, 2930, 1680, 1660, 1600, 1580, 1540, 1505, 1460, 1400, 1300, 1280, 1210, 1170, 1100, 1085, 1040, 1010 cm^-1．
【0122】
Example 57
2-[4-(4-fluorobenzoyl)benzyl]thio-3,5,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (A)
2-[1-[4-(4-fluorobenzoyl)phenyl]ethyl]thio-3,5,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (B)
Under an argon atmosphere, 2-[4-(4-fluorobenzoyl)benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.97 g) was suspended in dry DME (50 ml), and 60% sodium hydride in oil (420 mg) was added in two portions with ice-cooling and stirring. After stirring at room temperature for 15 minutes, methyl iodide (1.85 g) was added, and the mixture was allowed to warm to room temperature and then left to stir overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (hexane-ethyl acetate; 4:1 → 2.5:1) to yield the title compound (A; 1.29 g, B; 7 mg).
Compound (A)
¹H-NMR (CDCl₃)δ: 2.38(3H,d,J=1.2Hz), 3.54(3H,s), 3.66(3H,s), 4.54(2H,s),6.43(1H,d,J=1.2Hz), 7.15(2H,t,J=8.8Hz), 7.58(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.83(1H,dd,J=5.4Hz,8.8Hz).
IR(KBr)：3450, 3110, 3060, 2920, 1680, 1660, 1600, 1575, 1540, 1520, 1500, 1455, 1405, 1300, 1280, 1225, 1195, 1150, 1090, 1050cm^-1.
Compound (B)
¹H-NMR (CDCl₃)δ: 1.82(3H,d,J=7.2Hz), 2.37(3H,d,J=1.2Hz), 3.51(3H,s), 3.65(3H,s), 5.19(2H,q,J=7.2Hz), 6.42(1H,d,J=1.2Hz), 7.16(2H,t,J=8.8Hz), 7.62(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.84(2H,dd,J=5.6Hz,8.8Hz).
IR(KBr): 3430, 3100, 3060, 2920, 1680, 1650, 1595, 1570, 1540, 1510, 1445, 1405, 1305, 1275, 1225, 1195, 1150, 1090, 1045 cm^-1．
【0123】
Example 58
2-[4-(2,4-dichlorobenzoyl)benzyl]thio-3,5,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (A)
2-[1-[4-(2,4-dichlorobenzoyl)phenyl]ethyl]thio-3,5,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (B)
Under an argon atmosphere, 2-[4-(2,4-dichlorobenzoyl)benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.78 g) was suspended in dry DME (50 ml), and 60% sodium hydride in oil (336 mg) was added in two portions. The mixture was stirred at room temperature for 15 minutes, followed by the addition of methyl iodide (1.48 g). The mixture was allowed to warm to room temperature and then allowed to stir overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (hexane-ethyl acetate; 4:1 → 2.5:1) to yield the title compound (A; 1.28 g, B; 24 mg).
Compound (A)
¹H-NMR (CDCl₃)δ: 2.37(3H,d,J=1.2Hz), 3.53(3H,s), 3.63(3H,s), 4.52(2H,s),6.43(1H,d,J=1.2Hz), 7.31(1H,d,J=8.2Hz), 7.37(1H,dd,J=1.8Hz,8.2Hz), 7.49(1H,d,J=1.8Hz), 7.57(2H,d,J=8.6Hz), 7.75(2H,d,J=8.6Hz).
IR(KBr)：3430, 3100, 3050, 2920, 1680, 1670, 1605, 1580, 1540, 1515, 1460, 1400, 1365, 1285, 1255, 1225, 1220, 1180, 1150, 1095, 1055cm^-1.
Compound (B)
¹H-NMR (CDCl₃)δ: 1.79(3H,d,J=7.2Hz), 2.35(3H,d,J=1.0Hz), 3.50(3H,s), 3.61(3H,s), 5.16(2H,q,J=7.2Hz), 6.41(1H,d,J=1.0Hz), 7.30(1H,d,J=8.2Hz), 7.36(1H,dd,J=1.8Hz,8.2Hz), 7.49(1H,d,J=1.8Hz), 7.60(2H,d,J=8.6Hz), 7.76(2H,d,J=8.6Hz).
IR(KBr): 3430, 2920, 1675, 1600, 1580, 1570, 1540, 1520, 1450, 1405, 1370, 1310, 1280, 1240, 1220, 1195, 1150, 1100, 1090, 1050 cm^-1．
【0124】
Example 59
2-[3-(4-chlorobenzoyl)benzyl]thio-3,5,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 2-[3-(4-chlorobenzoyl)benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.31 g) was suspended in dry DME (32 ml), and 60% sodium hydride in oil (269 mg) was added in two portions with ice-cooling and stirring. After stirring for 15 minutes, methyl iodide (1.18 g) was added, and the mixture was allowed to return to room temperature and then allowed to stir overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (hexane-ethyl acetate; 4:1 → 2.5:1) to yield the title compound (950 mg).
¹H-NMR (CDCl₃)δ: 2.39(3H,d,J=1.0Hz), 3.53(3H,s), 3.54(3H,s), 4.52(2H,s),6.42(1H,d,J=1.0Hz), 7.36(2H,d,J=8.6Hz), 7.35-7.50(1H,m), 7.65-7.72(2H,m), 7.69(2H,d,J=8.6Hz), 7.97(1H,d,J=1.6Hz).
IR(KBr)：3450, 3100, 2920, 1680, 1640, 1600, 1580, 1540, 1515, 1455, 1430, 1405, 1290, 1280, 1245, 1225, 1200, 1170, 1130, 1105, 1090, 1040, 1010 cm^-1.
【0125】
Example 60
6-t-butyl-1-[4-(4-chlorobenzoyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5(6H)-one
6-t-Butyl-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5(6H)-one (207 mg) was dissolved in DMF (5 ml), sodium hydride (60%) (80 mg) was added, and the mixture was stirred at room temperature for 30 minutes. 4-(4-chlorobenzoyl)benzyl bromide (464 mg) was then added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated, and the residue was purified by silica gel chromatography (dichloromethane-ethyl acetate (4:1)). 139 mg of white powder
¹H-NMR (CDCl₃)δ: 1.63(9H,s), 1.9-2.1(2H,m), 2.64(2H,t,J=6.2Hz), 3.35(2H,t,J=5.6Hz), 4.61(2H,s), 7.34(2H,d,J=8.6Hz), 7.39(1H,s), 7.47(2H,d,J=8.6Hz), 7.76(2H,d,J=8.6Hz), 7.79(2H,d,J=8.6Hz).
IR(KBr): 1605, 1655 cm^-1.
【0126】
Example 61
1-[4-(4-chlorobenzoyl)benzyl]-6-methyl-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5(6H)-one
6-Methyl-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5(6H)-one (116 mg) was dissolved in DMF (5 ml), sodium hydride (60%) (56 mg) was added, and the mixture was stirred at room temperature for 30 minutes. 4-(4-chlorobenzoyl)benzyl bromide (341 mg) was then added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate-THF. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated, and the residue was purified by silica gel chromatography (ethyl acetate). Yellow amorphous, 165 mg
¹H-NMR (CDCl₃)δ: 1.9-2.1(2H,m), 2.67(2H,t,J=6.4Hz), 3.37(2H,t,J=5.6Hz),3.70(3H,s), 4.63(2H,s), 7.32(2H,d,J=8.4Hz), 7.43(2H,d,J=8.4Hz), 7.49(1H,s), 7.75(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【0127】
Example 62
5-t-Butyl-1-[4-(4-chlorobenzoyl)benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (A)
5-t-Butyl-2-[4-(4-chlorobenzoyl)benzyl]-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one (B)
5-t-Butyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (288 mg) was dissolved in DMF (5 ml), and 4-(4-chlorobenzoyl)benzyl bromide (7121 mg) and potassium carbonate (318 mg) were added, followed by stirring at room temperature for 15 hours. The reaction mixture was extracted with diethyl ether, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated, and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate (1:1)). 5-t-butyl-1-[4-(4-chlorobenzoyl)benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with n-hexane-diethyl ether, and 5-t-butyl-2-[4-(4-chlorobenzoyl)benzyl]-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with diethyl ether, and then dried.
Compound (A): 159 mg of white powder
¹H-NMR (CDCl₃)δ:1.69(9H,s), 5.61(2H,s), 7.33(2H,d,J=8.0Hz), 7.46(2H,d,J=8.4Hz), 7.73(2H,d,J=8.0Hz), 7.77(2H,d,J=8.4Hz), 7.95(1H,s), 8.23(1H,s).
IR(KBr): 1650, 1660 cm^-1.
Anal. Calcd: C 65.63%, H 5.03%, N 13.31%
Found: C 65.61%, H 5.03%, N 12.99%
Compound (B): 245 mg of white powder
¹H-NMR (CDCl₃)δ:1.68(9H,s), 5.59(2H,s), 7.38(2H,d,J=8.0Hz), 7.46(2H,d,J=8.4Hz), 7.73(2H,d,J=8.0Hz), 7.78(2H,d,J=8.4Hz), 8.20(1H,s), 8.22(1H,s).
IR(KBr)：1585, 1650, 1660 cm^-1.
【0128】
Example 63
5-t-Butyl-1-[4-(4-fluorobenzoyl)benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (A)
5-t-Butyl-2-[4-(4-fluorobenzoyl)benzyl]-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one (B)
5-t-Butyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (288 mg) was dissolved in DMF (5 ml), and 4-(4-fluorobenzoyl)benzyl bromide (674 mg) and potassium carbonate (318 mg) were added, followed by stirring at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated, and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate (1:1)). 5-t-butyl-1-[4-(4-fluorobenzoyl)benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with n-hexane-diethyl ether, and 5-t-butyl-2-[4-(4-fluorobenzoyl)benzyl]-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with diethyl ether, and then dried.
Compound (A): 115 mg of white powder
¹H-NMR (DMSO-d₆)δ: 1.63(9H,s), 5.81(2H,s), 7.3-7.5(4H,m), 7.7-7.9(4H,m),8.27(1H,s), 8.66(1H,s).
IR(KBr): 1650, 1665 cm^-1.
Compound (B): 235 mg of white powder
¹H-NMR (DMSO-d₆)δ: 1.61(9H,s), 5.74(2H,s), 7.3-7.5(4H,m), 7.7-7.8(4H,m),8.33(1H,s), 8.89(1H,s).
IR(KBr): 1600, 1650, 1655 cm^-1.
【0129】
Example 64
1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (A)
2-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one (B)
5-Methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (101 mg) was dissolved in DMF (2 mL), and 4-(4-chlorobenzoyl)benzyl bromide (310 mg) and potassium carbonate (138 mg) were added. The mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate-THF, and the organic layer was dried over anhydrous magnesium sulfate. The mixture was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:4)). The 1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with diethyl ether-ethyl acetate, and the 2-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with ethyl acetate and then dried.
Compound (A): white powder 20mg
¹H-NMR (DMSO-d₆)δ: 3.70(3H,s), 5.84(2H,s), 7.42(2H,d,J=8.4Hz), 7.60(2H,d,J=8.6Hz), 7.72(2H,d,J=8.4Hz), 7.73(2H,d,J=8.6Hz), 8.33(1H,s), 8.73(1H,s).
IR(KBr): 1655 cm^-1.
Compound (B): 137 mg of white powder
¹H-NMR (DMSO-d₆)δ: 3.64(3H,s), 5.75(2H,s), 7.49(2H,d,J=7.6Hz), 7.61(2H,d,J=8.4Hz), 7.74(4H,br d), 8.38(1H,s), 8.94(1H,s).
IR(KBr): 1585, 1650 cm^-1.
【0130】
Example 65
1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-1H-triazolo[4,5-d]pyridazin-4(5H)-one
5-Methyl-1H-triazolo[4,5-d]pyridazin-4(5H)-one (227 mg) was dissolved in DMF (5 ml), and 4-(4-chlorobenzoyl)benzyl bromide (712 mg) and potassium carbonate (318 mg) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:1)), then washed with diethyl ether and dried. 110 mg of white powder
¹H-NMR (CDCl₃)δ: 3.89(3H,s), 5.90(2H,s), 7.42(2H,d,J=8.4Hz), 7.47(2H,d,J=8.8Hz), 7.73(2H,d,J=8.8Hz), 7.81(2H,d,J=8.4Hz), 7.96(1H,s).
IR(KBr): 1655, 1670 cm^-1.
【0131】
Example 66
1-[4-(4-fluorobenzoyl)benzyl]-2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (10 ml) cooled in an ice bath. After stirring at room temperature for 2 hours, a solution of 4-(4-fluorobenzoyl)benzyl bromide (645 mg) in DMF (15 ml) was added and stirred at room temperature for an additional 16 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate = 1/1) to obtain the title compound as a white powder (371 mg, yield 43%).
¹H-NMR (DMSO-d₆) δ :3.35(3H,s), 5.74(2H,s), 7.30(2H,t,J=8.0Hz), 7.38(2H,d,J=8.8Hz), 7.73(2H,d,J=8.0Hz), 7.81(2H,dd,J=5.4,8.8Hz), 8.59(1H,s).
IR(KBr): 3050, 2950, 1650, 1640, 1600.
【0132】
Example 67
2,3-Dichloro-1-[4-(2,4-dichlorobenzoyl)benzyl]-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (10 ml) cooled in an ice bath. After stirring at room temperature for 2 hours, a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and stirred at room temperature for an additional 16 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ether to obtain the title compound as a yellow-brown powder (471 mg, 49% yield).
¹H-NMR (DMSO-d₆) δ :3.67(3H,s), 5.73(2H,s), 7.27(2H,d,J=8.4Hz), 7.54(1H,d,J=8.2Hz), 7.60(1H,dd,J=2.2,8.2Hz), 7.73(2H,d,J=8.4Hz), 7.82(1H,d,J=2.2Hz), 8.55(1H,s).
IR(KBr): 3050, 2950, 1665, 1600, 1580.
【0133】
Example 68
1-[3-(4-chlorobenzoyl)benzyl]-2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (303 mg) in DMF (50 ml) was added dropwise to a suspension of 60% sodium hydride in oil (72 mg) in DMF (10 ml) cooled in an ice bath. After stirring at room temperature for 2.5 hours, a solution of 3-(4-chlorobenzoyl)benzyl bromide (511 mg) in DMF (10 ml) was added and the mixture was stirred at room temperature for an additional 17 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain the title compound as a white powder (104 mg, yield 16%).
¹H-NMR (DMSO-d₆) δ :3.68(3H,s), 5.71(2H,s), 7.42(1H,dm,J=7.8Hz), 7.56(1H,t,J=7.8Hz), 7.61(2H,d,J=8.6Hz), 7.55-7.65(1H,m), 7.65-7.77(1H,m), 7.71(2H,d,J=8.6Hz), 8.59(1H,s).
IR(KBr): 3050, 2950, 1660, 1630, 1580.
【0134】
Example 69
2,3-Dichloro-5-methyl-1-[4-(4-trifluoromethylbenzoyl)benzyl]-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (10 ml) cooled in an ice bath. After stirring at room temperature for 2 hours, a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (754 mg) in DMF (15 ml) was added and stirred at room temperature for an additional 15 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate = 1/1) to obtain the title compound as a white powder (448 mg, yield 47%).
¹H-NMR (DMSO-d₆) δ: 3.68(3H,s), 5.75(2H,s), 7.31(2H,d,J=8.2Hz), 7.78(2H,d,J=8.2Hz), 7.91(4H,s), 8.58(1H,s).
IR(KBr): 3040, 2930, 1660, 1650, 1605.
【0135】
Example 70
1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (8 ml) cooled in an ice bath. After stirring at room temperature for 30 minutes, a solution of 4-(4-chlorobenzoyl)benzyl bromide (712 mg) in DMF (15 ml) was added and the mixture was stirred at room temperature for an additional 1.5 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/2) to obtain the title compound as a white powder (505 mg, yield 57%).
¹H-NMR (DMSO-d₆) δ :3.68(3H,s), 5.65(2H,s), 6.74(1H,d,J=3.0Hz), 7.39(2H,d,J=8.4Hz), 7.61(2H,d,J=8.4Hz), 7.63(1H,d,J=3.0Hz), 7.73(4H,d,J=8.4Hz),8.45(1H,s).
IR(KBr): 3050, 2940, 1650, 1600, 1580, 1540.
【0136】
Example 71
1-[4-(4-fluorobenzoyl)benzyl]-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (373 mg) in DMF (10 ml) was added dropwise to a suspension of 60% sodium hydride in oil (120 mg) in DMF (10 ml) cooled in an ice bath. After stirring at room temperature for 1 hour, a solution of 4-(4-fluorobenzoyl)benzyl bromide (806 mg) in DMF (20 ml) was added and stirred at room temperature for an additional 13 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 99/1) to obtain the title compound as a white powder (615 mg, yield 68%).
¹H-NMR (DMSO-d₆) δ :3.68(3H,s), 5.64(2H,s), 6.74(1H,d,J=3.0Hz), 7.37(2H,t,J=9.0Hz), 7.39(2H,d,J=8.0Hz), 7.62(1H,d,J=3.0Hz), 7.72(2H,d,J=8.0Hz),7.80(2H,dd,J=5.4,9.0Hz), 8.45(1H,s).
IR(KBr): 3040, 2990, 2940, 1650, 1600, 1540.
【0137】
Example 72
1-[4-(2,4-dichlorobenzoyl)benzyl]-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
To a suspension of 60% sodium hydride in oil (96 mg) in DMF (8 ml) cooled in an ice bath, a solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was added dropwise. After stirring at room temperature for 1 hour, a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and stirred at room temperature for an additional 1.5 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/3) to obtain the title compound as a white powder (511 mg, yield 62%).
¹H-NMR (DMSO-d₆) δ :3.67(3H,s), 5.64(2H,s), 6.73(1H,d,J=3.0Hz), 7.36(2H,d,J=8.2Hz), 7.53(1H,d,J=8.2Hz), 7.60(1H,d,J=3.0Hz), 7.60(1H,dd,J=7.8,8.2Hz), 7.72(2H,d,J=8.2Hz), 7.81(2H,d,J=1.8Hz), 8.40(1H,s).
IR(KBr): 3050, 2940, 1660, 1640, 1600, 1540.
【0138】
Example 73
1-[3-(4-chlorobenzoyl)benzyl]-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (8 ml) cooled in an ice bath. After stirring at room temperature for 1 hour, a solution of 3-(4-chlorobenzoyl)benzyl bromide (681 mg) in DMF (15 ml) was added and the mixture was stirred at room temperature for an additional 2 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate = 1/3) to obtain the title compound as a white powder (630 mg, yield 83%).
¹H-NMR (DMSO-d₆) δ :3.68(3H,s), 5.62(2H,s), 6.71(1H,d,J=3.0Hz), 7.53-7,73(9H,m), 8.47(1H,s).
IR(KBr): 3100, 3040, 2960, 2850, 1650, 1580, 1540.
【0139】
Example 74
5-methyl-1-[4-(4-trifluoromethylbenzoyl)benzyl]-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (8 ml) cooled in an ice bath. After stirring at room temperature for 1 hour, a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (755 mg) in DMF (15 ml) was added and stirred at room temperature for an additional 3 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/2) to obtain the title compound as a pale brown powder (436 mg, yield 53%).
¹H-NMR (CDCl₃) δ :3.86(3H,s), 5.43(2H,s), 6.95(1H,d,J=3.0Hz), 7.13(1H,d,J=3.0Hz), 7.22(2H,d,J=8.8Hz), 7.76(2H,d,J=8.8Hz), 7.80(2H,d,J=8.2Hz), 7.87(2H,d,J=8.2Hz), 7.93(1H,s).
IR(KBr): 3100, 3050, 2950, 1660, 1640, 1605.
【0140】
Example 75
1-[4-(4-chlorobenzoyl)benzyl]-2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (532 mg) in DMF (45 ml) was added dropwise to a suspension of 60% sodium hydride in oil (144 mg) in DMF (12 ml) cooled in an ice bath. After stirring at room temperature for 30 minutes, a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.02 g) in DMF (15 ml) was added and the mixture was stirred at room temperature for an additional 1.5 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/2) to obtain the title compound as a pale yellow powder (711 mg, yield 58%).
¹H-NMR (CDCl₃) δ :2.23(3H,s), 2.48(3H,s), 3.83(3H,s), 5.35(2H,s), 7.04(2H,d,J=8.2Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.2Hz), 7.85(1H,s).
IR(KBr): 3050, 2930, 1660, 1630, 1605, 1520.
【0141】
Example 76
1-[4-(4-fluorobenzoyl)benzyl]-2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (354 mg) in DMF (30 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (8 ml) cooled in an ice bath. After stirring at room temperature for 1 hour, a solution of 4-(4-fluorobenzoyl)benzyl bromide (645 mg) in DMF (15 ml) was added and stirred at room temperature for an additional 2 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate = 1/1) to obtain the title compound as a white powder (628 mg, yield 81%).
¹H-NMR (CDCl₃) δ :2.23(3H,s), 2.48(3H,s), 3.83(3H,s), 5.35(2H,s), 7.04(2H,d,J=8.4Hz), 7.16(2H,t,J=8.6Hz), 7.74(2H,d,J=8.4Hz), 7.78(2H,dd,J=3.0,8.6Hz), 7.86(1H,s).
IR(KBr): 3055, 2940, 1650, 1610, 1595, 1510.
【0142】
Example 77
1-[4-(2,4-dichlorobenzoyl)benzyl]-2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (354 mg) in DMF (30 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (8 ml) cooled in an ice bath. After stirring at room temperature for 1 hour, a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was stirred at room temperature for an additional 1.5 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain the title compound as a pale yellow powder (612 mg, yield 70%).
¹H-NMR (CDCl₃) δ :2.20(3H,s), 2.46(3H,s), 3.82(3H,s), 5.33(2H,s), 7.01(2H,d,J=8.6Hz), 7.30(1H,d,J=8.0Hz), 7.36(1H,dd,J=1.8,8.0Hz), 7.48(1H,d,J=1.8Hz), 7.75(2H,d,J=8.6Hz), 7.82(1H,s).
IR(KBr): 3100, 2910, 1660, 1600, 1580, 1520.
【0143】
Example 78
1-[4-(4-trifluoromethylbenzoyl)benzyl]-2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (354 mg) in DMF (30 ml) was added dropwise to a suspension of 60% sodium hydride in oil (96 mg) in DMF (8 ml) cooled in an ice bath. After stirring at room temperature for 1 hour, a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (755 mg) in DMF (15 ml) was added and stirred at room temperature for an additional 1.5 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain the title compound as a pale yellow powder (566 mg, yield 64%).
¹H-NMR (CDCl₃) δ:2.23(3H,s), 2.48(3H,s), 3.82(3H,s), 5.36(2H,s), 7.05(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.77(2H,d,J=8.0Hz), 7.84(1H,s), 7.86(2H,d,J=8.0Hz).
IR(KBr): 3050, 2910, 1660, 1600, 1570, 1520.
【0144】
Example 79
1-[4-(4-methoxybenzoyl)benzyl]-2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (1.06 g) in DMF (90 ml) was added dropwise to a suspension of 60% sodium hydride in oil (288 mg) in DMF (24 ml) cooled in an ice bath. After stirring at room temperature for 1 hour, a solution of 4-(4-methoxybenzoyl)benzyl bromide (2.40 g) in DMF (30 ml) was added and stirred at room temperature for an additional 2 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1 → 1/2) to obtain the title compound as a pale yellow powder (1.70 g, yield 71%).
¹H-NMR (CDCl₃) δ :2.23(3H,s), 2.48(3H,s), 3.83(3H,s), 3.89(3H,s), 5.34(2H,s), 6.96(2H,d,J=8.6Hz), 7.03(2H,d,J=8.0Hz), 7.72(2H,d,J=8.0Hz), 7.80(2H,d,J=8.6Hz), 7.83(1H,s).
IR(KBr): 3050, 2910, 1660, 1635, 1600, 1570, 1520.
【0145】
Example 80
5-t-Butyl-1-[3-(4-chlorobenzoyl)benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (A)
5-t-Butyl-2-[3-(4-chlorobenzoyl)benzyl]-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one (B)
5-t-Butyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (288 mg) was dissolved in DMF (5 ml), and 3-(4-chlorobenzoyl)benzyl bromide (712 mg) and potassium carbonate (318 mg) were added, followed by stirring at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:1)). 5-t-butyl-1-[3-(4-chlorobenzoyl)benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with diethyl ether, and 5-t-butyl-2-[3-(4-chlorobenzoyl)benzyl]-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with n-hexane-diethyl ether, and then dried.
Compound A: white powder 172mg
¹H-NMR (DMSO-d₆) δ: 1.62(9H,s), 5.78(2H,s), 7.5-7.7(8H,m), 8.25(1H,s), 8.66(1H,s)
Anal.Calcd.: C 65.63%, H 5.03%, N 13.31%
Found: C 65.88%, H 4.97%, N 13.47%
Compound B: white powder 42mg
¹H-NMR (DMSO-d₆)δ: 1.61(9H,s), 5.72(2H,s), 7.5-7.8(8H,m), 8.33(1H,s), 8.88(1H,s)
Anal.Calcd.: C 65.63%, H 5.03%, N 13.31%
Found: C 65.75%, H 4.90%, N 13.41%
【0146】
Example 81
5-t-Butyl-1-[4-(2,4-dichlorobenzoyl)benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (A)
5-t-Butyl-2-[4-(2,4-dichlorobenzoyl)benzyl]-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one (B)
5-t-Butyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (288 mg) was dissolved in DMF (5 ml), and 4-(2,4-dichlorobenzoyl)benzyl bromide (791 mg) and potassium carbonate (318 mg) were added. The mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The mixture was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:1)). The 5-t-butyl-2-[4-(2,4-dichlorobenzoyl)benzyl]-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one was further washed with n-hexane-diethyl ether and dried.
Compound A: white powder 208mg
¹H-NMR (DMSO-d₆)δ: 1.62(9H,s), 5.81(2H,s), 7.44(2H,d,J=8.4Hz), 7.53(1H,d,J=8.2Hz), 7.60(1H,d,J=8.2Hz), 7.73(2H,d,J=8.4Hz), 7.81(1H,s), 8.26(1H,s), 8.63(1H,s)
Compound B: white powder 220mg
¹H-NMR (DMSO-d₆)δ: 1.60(9H,s), 5.73(2H,s), 7.47(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.53(1H,d,J=8.2Hz), 7.60(1H,d,J=8.2Hz), 7.81(1H,s), 8.32(1H,s), 8.88(1H,s)
【0147】
Example 82
5-t-butyl-1-[4-(4-chlorobenzoyl)benzyl]-3-methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one
5-t-Butyl-3-methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (516 mg) was dissolved in DMF (10 ml), and 4-(4-chlorobenzoyl)benzyl bromide (1.2 g) and potassium carbonate (525 mg) were added. The mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate-THF, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:1)), then further washed with n-hexane-diethyl ether and dried. 527 mg of white powder
¹H-NMR (DMSO-d₆)δ: 1.62(9H,s), 2.52(3H,s), 5.70(2H,s), 7.44(2H,d,J=8.4Hz), 7.61(2H,d,J=8.4Hz), 7.73,(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 8.56(1H,s)
【0148】
Example 83
5-t-butyl-1-[4-(4-fluorobenzoyl)benzyl]-3-methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (A)
5-t-butyl-2-[4-(4-fluorobenzoyl)benzyl]-3-methyl-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one (B)
5-t-Butyl-3-methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (516 mg) was dissolved in DMF (10 ml), and 4-(4-fluorobenzoyl)benzyl bromide (1.1 g) and potassium carbonate (525 mg) were added, followed by stirring at room temperature for 15 hours. The reaction mixture was extracted with diethyl ether, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:1)). 5-t-butyl-1-[4-(4-fluorobenzoyl)benzyl]-3-methyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with n-hexane-diethyl ether, and 5-t-butyl-2-[4-(4-fluorobenzoyl)benzyl]-3-methyl-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with diethyl ether-ethyl acetate, and then dried.
Compound A: white powder 513mg
¹H-NMR (DMSO-d₆)δ: 1.62(9H,s), 2.52(3H,s), 5.70(2H,s), 7.36(2H,dd,J=8.8Hz and 8.4Hz), 7.44(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.81(2H,dd,J=5.8Hz and 8.8Hz), 8.55(1H,s)
Anal.Calcd.: C 68.89%, H 5.54%, N 13.39%
Found: C 68.82%, H 5.52%, N 13.37%
Compound B: white powder 262mg
¹H-NMR (DMSO-d₆)δ: 1.61(9H,s), 2.68(3H,s), 5.70(2H,s), 7.35(2H,d,J=8.4Hz), 7.37(2H,dd,J=8.8Hz and 9.2Hz), 7.71(2H,d,J=8.4Hz), 7.81(2H,dd,J=5.4Hz and 9.2Hz), 8.27(1H,S)
Anal.Calcd.: C 68.89%, H 5.54%, N 13.39%
Found: C 68.99%, H 5.41%, N 13.42%
【0149】
Example 84
1-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (A)
2-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one (B)
3,5-Dimethyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one (94 mg) was dissolved in DMF (2 ml), and 4-(4-chlorobenzoyl)benzyl bromide (279 mg) and potassium carbonate (124 mg) were added, followed by stirring at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:4)). 1-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with n-hexane-diethyl ether, and 2-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2H-pyrazolo[3,4-d]pyridazin-4(5H)-one was washed with diethyl ether, and then dried.
Compound A: white powder 92mg
¹H-NMR (DMSO-d₆) δ: 2.52(3H,s), 3.67(3H,s), 5.73(2H,s), 7.41(2H,d,J=8.2Hz), 7.61(2H,d,J=8.8Hz), 7.72,(2H,d,J=8.2Hz), 7.73(2H,d,J=8.8Hz), 8.65(1H,s)
Compound B: white powder 54mg
¹H-NMR (DMSO-d₆) δ: 2.69(3H,s), 3.62(3H,s), 5.72(2H,s), 7.35(2H,d,J=8.2Hz), 7.61(2H,d,J=8.8Hz), 7.73(2H,d,J=8.2Hz), 7.74(2H,d,J=8.8Hz), 8.33(1H,s)
【0150】
Example 85
2-[4-(4-chlorobenzoyl)benzylthio〕-3-methylpteridin-4-one
To a solution of 3-methylpteridin-4-one-2-thione (194 mg) in ethanol (5 ml), 1N aqueous sodium hydroxide (1.2 ml) and 4-(4-chlorobenzoyl)benzyl bromide (310 mg) were added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate) to yield the title compound (118 mg, 28%) as a white powder.
¹H-NMR (CDCl₃)δ: 3.69 (3H, s), 4.73 (2H, s), 7.42-7.82 (8H, m), 8.77 (1H, d, J=2.2Hz), 8.91 (1H, d, J=2.2Hz).
IR(KBr)cm^-1: 1700, 1650, 1545, 1530, 1410, 1400, 1280, 1170.
【0151】
Example 86
7-[4-(4-ToTrifluoromethyRubeBenzyl〕-1,3-dimethylxanthine
A solution of theophylline (1.80 g) in dimethylformamide (20 ml) was added to potassium carbonate (1.66 g) and 4-bromide (4-ToTrifluoromethyRubeTo the reaction mixture was added (3.43 g of benzoylbenzyl benzoyl)benzyl benzoate and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. A 4N hydrochloric acid-ethyl acetate solution was added to the residue, and the precipitate was collected by filtration. A saturated aqueous solution of sodium bicarbonate was added to the collected compound, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (1.57 g, 36%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 3.41 (3H, s), 3.61 (3H, s), 5.61 (2H, s), 7.40-7.90 (9H, m).
IR(KBr)cm^-1： 1705, 1660, 1605, 1550, 1410, 1325, 1275, 1130, 1060.
【0152】
Example 87
7-[4-(1-indolylcarbonyl)benzyl〕-1,3-dimethylxanthine
A solution of theophylline (1.80 g) in dimethylformamide (20 ml) was added to potassium carbonate (1.66 g) and 4-chloro-−(1-IndriLukeTo the reaction mixture was added (2.70 g of carboxybenzylcarbonyl) and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (2.25 g, 54%) as a colorless powder.
¹H-NMR (CDCl₃)δ: 3.42 (3H, s), 3.62 (3H, s), 5.17 (2H, s), 6.62 (1H, d, J=3.0Hz), 7.22-7.80 (9H, m), 8.36-8.45 (1H, m).
IR(KBr)cm^-1: 1700, 1650, 1540, 1450, 1380, 1340.
【0153】
Example 88
6-chloro-2-[3-(4-chlorobenzoyl)benzyl]thio-3,5,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
2-[3-(4-chlorobenzoyl)benzyl]thio-3,5,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (0.351 g) was dissolved in dry dichloromethane (8 ml), and N-chlorosuccinimide (0.113 g) was added under ice-cooling and stirring. After stirring for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; chloroform) to give the title compound (0.104 g).
¹H-NMR (CDCl₃) δ :2.36(3H,s), 3.53(3H,s), 3.56(3H,s), 4.51(2H,s), 7.40(2H,d,J=8.4Hz), 7.40-7.50(1H,m), 7.62-7.73(2H,m), 7.71(2H,d,J=8.4Hz), 7.97(1H,s)
【0154】
Example 89
6-chloro-7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (88 mg) was dissolved in dry dichloromethane (3 ml), and N-chlorosuccinimide (28 mg) was added under ice-cooling and stirring. After stirring for 2 hours, the solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; chloroform) to give the title compound (55 mg).
¹H-NMR (CDCl₃) δ :2.38(3H,s), 2.56(3H,s), 3.56(3H,s), 5.39(2H,s), 7.33(2H,d,J=8.2Hz), 7.45(2H,d,J=8.2Hz), 7.73(4H,d,J=8.6Hz)
【0155】
Example 90
7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (2.46 g) was dissolved in dry DME (72.5 ml) and dry dimethylformamide (72.5 ml). Under ice-cooling, 60% sodium hydride in oil (255 mg) was added in two portions. After stirring for 30 minutes, ethyl iodide (1.09 g) was added, the mixture was returned to room temperature, and allowed to stir overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; dichloromethane → methanol:dichloromethane; 1:49) to yield the title compound (1.04 g).
¹H-NMR (CDCl₃) δ :1.36(3H,t,J=7.0Hz), 2.39(3H,s), 2.56(3H,s), 4.19(2H,q,J=7.0Hz), 5.28(2H,s), 6.46(1H,s), 7.31(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.74(4H,d,J=8.6Hz)
【0156】
Example 91
7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7-[4-(4-fluorobenzoyl)benzyl]-4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (6.75 g) was dissolved in dioxane (45 ml), and 4,4'-thiobis(6-t-butyl-m-cresol) (75 mg) was added. Then, 0.5 N hydrochloric acid (12 ml) was added and the mixture was stirred at 105°C for 23 hours. Another 0.5 N hydrochloric acid (12 ml) was added, and the mixture was stirred at the same temperature for 22 hours. Then, 1 N hydrochloric acid (3 ml) and dioxane (6 ml) were added, and the mixture was stirred at the same temperature for 24 hours. After standing at room temperature, the precipitated crystals were filtered, washed with methanol, DME, and ether, and dried to obtain the title compound (5.35 g).
¹H-NMR (DMSO-d₆) δ: 2.24(3H,S), 2.52(3H,s), 5.34(2H,s), 6.84(1H,s), 7.37(2H,t,J=8.2Hz), 7.43(2H,d,J=8.2Hz), 7.71(2H,d,J=8.2Hz), 7.81(2H,dd,J=5.6Hz,8.6Hz), 12.06(1H,s)
【0157】
Example 92
3,5-dimethyl-7-[4-(4-fluorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.85 g) was dissolved in dry DME (50 ml) and dry dimethylformamide (50 ml). 60% sodium hydride in oil (176 mg) was added in two portions under ice-cooling. After stirring for 30 minutes, methyl iodide (681 mg) was added, the mixture was returned to room temperature, and stirred overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; ethyl acetate:hexane; 1:5.6 → 1:2.3) to yield the title compound (1.31 g).
¹H-NMR (CDCl₃) δ :2.40(3H,d,J=1.0Hz), 2.57(3H,s), 3.57(3H,s), 5.29(2H,s), 6.47(1H,d,J=1.0Hz), 7.16(2H,t,J=8.8Hz), 7.30(2H,d,J=8.2Hz), 7.74(2H,d,J=8.2Hz), 7.83(2H,dd,J=5.4Hz,8.8Hz)
【0158】
Example 93
3-ethyl-7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.85 g) was dissolved in dry DME (50 ml) and dry dimethylformamide (50 ml). Under ice cooling, 60% sodium hydride in oil (176 mg) was added in two portions. After stirring for 30 minutes, ethyl iodide (749 mg) was added, the mixture was returned to room temperature, and allowed to stir overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; ethyl acetate:hexane; 1:5.6 → 1:2.3) to yield the title compound (867 mg).
¹H-NMR (CDCl₃) δ :1.36(3H,t,J=7.2Hz), 2.40(3H,d,J=1.0Hz), 2.56(3H,s), 4.19(2H,q,J=7.2Hz), 5.29(2H,s), 6.47(1H,d,J=1.0Hz), 7.16(2H,t,J=8.6Hz), 7.31(2H,d,J=8.2Hz), 7.74(2H,d,J=8.2Hz), 7.83(2H,dd,J=5.4Hz,8.6Hz)
【0159】
Example 94
7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (800 mg) was dissolved in DME (120 ml) and ethanol (12 ml), and acetic acid (672 mg) was added. The mixture was then heated to 40°C. Raney nickel was added until the starting material disappeared as determined by TLC (thin layer chromatography). The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the mixture was allowed to stand, allowing crystals to precipitate. This material was filtered, washed with ethanol and hexane, and then dried to yield the title compound (608 mg).
¹H-NMR (CDCl₃) δ :2.43(3H,d,J=1.0Hz), 3.57(3H,s), 5.34(2H,s), 6.60(1H,d,J=1.0Hz), 7.26(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.73(4H,d,J=8.4Hz), 7.84(1H,s)
【0160】
Example 95
3,5-dimethyl-7-[4-(4-fluorobenzoyl)benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
3,5-Dimethyl-7-[4-(4-fluorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (755 mg) was dissolved in DME (100 ml) and ethanol (10 ml), and acetic acid (560 mg) was added. The mixture was then heated to 40°C. Raney nickel was added until the starting material disappeared as determined by TLC (thin layer chromatography). The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the mixture was allowed to stand, allowing crystals to precipitate. This material was filtered, washed with ethanol and hexane, and then dried to yield the title compound (512 mg).
¹H-NMR (CDCl₃) δ :2.43(3H,d,J=1.0Hz), 3.57(3H,s), 5.34(2H,s), 6.60(1H,d,J=1.0Hz), 7.15(2H,d,J=8.8Hz), 7.26(2H,d,J=8.0Hz), 7.73(2H,d,J=8.0Hz), 7.82(2H,dd,J=5.6Hz,8.8Hz), 7.84(1H,s)
【0161】
Example 96
7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (500 mg) was dissolved in DME (65 ml) and ethanol (6 ml), and acetic acid (336 mg) was added. The mixture was then heated to 40°C. Raney nickel was added until the starting material disappeared as determined by TLC (thin layer chromatography). The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the mixture was allowed to stand, allowing crystals to precipitate. This material was filtered, washed with ethanol and hexane, and dried to yield the title compound (370 mg).
¹H-NMR (CDCl₃) δ :1.41(3H,t,J=7.2Hz), 2.43(3H,d,J=1.0Hz), 4.06(2H,q,J=7.2Hz), 5.34(2H,s), 6.59(1H,d,J=1.0Hz), 7.27(2H,d,J=8.6Hz), 7.45(2H,d,J=8.6Hz), 7.73(4H,d,J=8.6Hz)
【0162】
Example 97
3-ethyl-7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
3-Ethyl-7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (344 mg) was dissolved in DME (50 ml) and ethanol (2 ml), and acetic acid (224 mg) was added. The mixture was then heated to 40°C. Raney nickel was added until the starting material disappeared as determined by TLC (thin layer chromatography). The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the mixture was allowed to stand, allowing crystals to precipitate. This material was filtered, washed with ethanol and hexane, and dried to yield the title compound (230 mg).
¹H-NMR (CDCl₃) δ :1.41(3H,t,J=7.2Hz), 2.44(3H,d,J=1.2Hz), 4.06(2H,q,J=7.2Hz), 5.34(2H,s), 6.59(1H,d,J=1.2Hz), 7.15(2H,t,J=8.8Hz), 7.27(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.82(2H,dd,J=5.6Hz,8.8Hz), 7.84(1H,s)
【0163】
Example 98
2-[4-(4-fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
2-Mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (2.51 g) was suspended in methanol (67.5 ml) and dissolved in 1N sodium hydroxide (15.75 ml). A solution of 4-(4-fluorobenzoyl)benzyl bromide (5.06 g) in DME (15 ml) was added dropwise under ice cooling. After returning to room temperature, the mixture was left stirring overnight. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; ethyl acetate:hexane; 1:4 → 1:1 → ethyl acetate) to yield the title compound (2.43 g).
¹H-NMR (DMSO-d₆) δ :4.53(2H,s), 6.38(1H,brs), 6.94(1H,brs), 7.42(2H,t,J=8.8Hz), 7.68(4H,s), 7.82(2H,dd,J=5.6Hz,8.8Hz), 11.81(1H,s), 12.13(1H,s)
【0164】
Example 99
3,7-dimethyl-2-[4-(4-fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
Under an argon atmosphere, 2-[4-(4-fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (818 mg) was dissolved in dry DME (21.5 ml), and 60% sodium hydride in oil (181 mg) was added in two portions while stirring and ice-cooling. Methyl iodide (794 mg) was then added, and the mixture was allowed to warm to room temperature and then left to stir overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (hexane-ethyl acetate; 4:1 → 3:2) to yield the title compound (640 mg).
¹H-NMR (CDCl₃) δ :3.59(3H,s), 3.74(3H,s), 4.56(2H,s), 6.61(1H,d,J=3.4Hz), 6.72(1H,d,J=3.4HZ), 7.17(2H,t,J=8.9Hz), 7.60(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.84(2H,dd,J=5.4Hz,8.9Hz)
【0165】
Example 100
5,6-Dichloro-3,7-dimethyl-2-[4-(4-fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
3,7-Dimethyl-2-[4-(4-fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (204 mg) was dissolved in dry dichloromethane (7.5 ml), and N-chlorosuccinimide (141 mg) was added under ice-cooling and stirring. After stirring for 2 hours, the solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; dichloromethane) to yield the title compound (125 mg).
¹H-NMR (CDCl₃) δ :3.56(3H,s), 3.69(3H,s), 4.53(2H,s), 7.17(2H,t,J=8.6Hz), 7.57(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.84(2H,dd,J=5.4Hz,8.6Hz)
【0166】
Example 101
5-Dimethylaminomethyl-2-[4-(4-fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (A)
6-Dimethylaminomethyl-2-[4-(4-fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (B)
2-[4-(4-Fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (570 mg) was dissolved in 80% aqueous acetic acid (15 ml), and 37% aqueous formalin (244 mg) and then 50% aqueous dimethylamine (270 mg) were added. The mixture was stirred at 60°C for 13 hours. After evaporation of the solvent under reduced pressure, the residue was dissolved in water (15 ml), made alkaline with concentrated aqueous ammonia, and extracted with chloroform. After washing with saturated brine, the residue was dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the mixture was purified by flash column chromatography (silica gel; ethanol:chloroform; 1:49 → 7% ammonia-containing ethanol:chloroform; 1:19 → 1:9) to give the title compounds (36 mg; Compound A) and (233 mg; Compound B).
Compound A
¹H-NMR (DMSO-d₆) δ :2.36(6H,brs), 3.76(2H,s), 4.47(2H,s), 6.84(1H,s), 7.37(2H,t,J=8.8Hz), 7.65(4H,s), 7.81(2H,dd,J=5.6Hz,8.8Hz), 11.47(1H,s)
Compound B
¹H-NMR (DMSO-d₆) δ :2.14(6H,brs), 3.39(2H,s), 4.50(2H,s), 6.19(1H,s), 7.37(2H,t,J=8.8Hz), 7.68(4H,s), 7.81(2H,dd,J=5.6Hz,8.8Hz), 11.77(1H,s), 12.06(1H,s)
【0167】
Example 102
2-[4-(4-chlorobenzoyl)benzyl]thio-1,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
Under an argon atmosphere, 2-[4-(4-chlorobenzoyl)benzyl]thio-1-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one (103 mg) was dissolved in dry DMSO (20 ml) with heating. After returning to room temperature, 60% sodium hydride in oil (11 mg) was added and stirred for 20 minutes. Methyl iodide (42.6 mg) was then added and the mixture was left stirring overnight. The reaction mixture was poured into water (200 ml). The precipitate was filtered, dried, and purified by flash column chromatography (silica gel; chloroform → ethanol:chloroform; 1:49) to yield the title compound (47 mg).
¹H-NMR (CDCl₃) δ :3.94(6H,s), 4.65(2H,s), 6.48(1H,d,J=3.4Hz), 6.62(1H,d,J=3.4HZ), 7.46(2H,d,J=8.8Hz), 7.58(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.8Hz)
【0168】
Example 103
1-[4-(4-chlorobenzoyl)benzyl]-pyrrolo[2,3-d]pyridazine-4(5H),7(6H)-dione
1-[4-(4-chlorobenzoyl)benzyl]-2,3-diethoxycarbonyl-pyrrole (3.31 g) was dissolved in ethanol (70 ml), and then anhydrous hydrazine (10.54 g) was added and the mixture was heated to reflux for 3 hours. The solvent was removed under reduced pressure, and the resulting crystals were suspended in water (150 ml). Concentrated hydrochloric acid (30 ml) was added and the mixture was stirred at 85°C for 30 minutes. The crystals were washed with water, methanol, and ether and dried under reduced pressure to obtain 1.46 g of the title compound (yield 81%).
¹H-NMR (DMSO-d₆) δ :5.83(2H,s), 6.54(1H,d,J=3.0Hz), 7.20-7.75(9H,m), 11.2(2H,brs)
【0169】
Example 104
1-[4-(4-chlorobenzoyl)benzyl]-4,7-dichloropyrrolo[2,3-d]pyridazine
1-[4-(4-chlorobenzoyl)benzyl]-pyrrolo[2,3-d]pyridazine-4(5H),7(6H)-dione (1.46 g) was dissolved in phosphorus oxychloride (44.7 g) and heated to reflux for 2 hours. The phosphorus oxychloride was removed by distillation under reduced pressure, and the precipitated crystals were washed with saturated aqueous sodium bicarbonate. The resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was then purified by silica gel column chromatography (40 g collateral: dichloromethane: ether = 1:0-9:1) and recrystallized from ethyl acetate-ether to give 1.23 g (76% yield) of the title compound.
¹H-NMR (CDCl₃) δ :5.89(2H,s), 6.87(1H,d,J=3.0Hz), 7.15(2H,d,J=8.0Hz), 7.45(1H,d,J=3.0Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz)
【0170】
Example 105
1-[4-(4-chlorobenzoyl)benzyl]-4-chloropyrrolo[2,3-d]pyridazin-7(6H)-one (A)
1-[4-(4-chlorobenzoyl)benzyl]-7-chloro-pyrrolo[2,3-d]pyridazin-4(5H)-one (B)
1-[4-(4-chlorobenzoyl)benzyl]-4,7-dichloropyrrolo[2,3-d]pyridazine (1.08 g) was dissolved in dioxane (15 ml), sodium hydroxide (4.42 g) and water (5 ml) were added, and the mixture was heated to reflux for 69 hours. After adding water (120 ml), the precipitated crystals were collected by filtration. The obtained crystals were purified by silica gel column chromatography (carrier 50 g: dichloromethane: ether = 1:0-9:1, ethyl acetate: methanol = 1:9) to obtain 416 mg (yield 40%) of the title compound 1-[4-(4-chlorobenzoyl)benzyl]-4-chloro-pyrrolo[2,3-d]pyridazin-7(6H)-one and 196 mg (yield 19%) of the title compound 1-[4-(4-chlorobenzoyl)benzyl]-7-chloro-pyrrolo[2,3-d]pyridazin-4(5H)-one.
Compound A
¹H-NMR (CDCl₃) δ :5.87(2H,s), 6.59(1H,d,J=2.9Hz), 7.23(1H,d,J=3.0Hz), 7.37(2H,d,J=8.3Hz), 7.45(2H,d,J=8.7Hz), 7.73(2H,d,J=8.7Hz), 7.75(2H,d,J=8.3Hz), 10.02(1H,brs)
Compound B
¹H-NMR (CDCl₃) δ :5.80(2H,s), 7.04(1H,d,J=3.0Hz), 7.13(2H,d,J=8.6Hz), 7.19(1H,d,J=3.0Hz), 7.46(2H,d,J=8.8Hz), 7.73(2H,d,J=8.8Hz), 7.77(2H,d,J=8.4Hz), 10.18(1H,brs)
【0171】
Example 106
1-[4-(4-chlorobenzoyl)benzyl]-4-chloro-6-methyl-pyrrolo[2,3-d]pyridazin-7(6H)-one
1-[4-(4-chlorobenzoyl)benzyl]-4-chloro-pyrrolo[2,3-d]pyridazin-7(6H)-one (830 mg) was dissolved in DMF (20 ml), potassium carbonate (2.11 g) was added, followed by methyl iodide (0.13 ml), and the mixture was stirred at room temperature for 95 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed three times with water (100 ml), washed with saturated brine (100 ml), and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting crystals were washed with ethyl acetate to give 742 mg (84% yield) of the title compound.
¹H-NMR (CDCl₃) δ :3.82(3H,s), 5.89(2H,s), 6.54(1H,d,J=3.0Hz), 7.19(1H,d,J=3.0Hz), 7.34(2H,d,J=8.2Hz), 7.45(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.2Hz)
【0172】
Example 107
1-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7-chloro-pyrrolo[2,3-d]pyridazin-4(5H)-one
1-[4-(4-chlorobenzoyl)benzyl]-7-chloro-pyrrolo[2,3-d]pyridazin-4(5H)-one (352 mg) was dissolved in DMF (15 ml), potassium carbonate (858 mg) was added, followed by methyl iodide (0.06 ml), and the mixture was stirred at room temperature for 16 hours. Water (30 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed three times with water (100 ml), washed with saturated brine (100 ml), and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting crystals were washed with hexane to give 290 mg (80% yield) of the title compound.
¹H-NMR (CDCl₃) δ :3.83(3H,s), 5.77(2H,s), 7.01(1H,d,J=3.0Hz), 7.13(2H,d,J=8.2Hz), 7.16(1H,d,J=3.0Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz)
【0173】
Example 108
1,3-dimethyl-7-[4-(4-methoxybenzoyl)benzyl]xanthine
Theophylline (1.84 g) was dissolved in DMF (20 ml), potassium carbonate (1.42 g) was added, and p-methoxybenzoylbenzyl bromide (3.78 g) was added. The mixture was stirred at room temperature for 14 hours. Water was added and the mixture was diluted with ethyl acetate (1200 ml). The organic layer was washed twice with water (500 ml), washed with saturated brine (500 ml), and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was evaporated under reduced pressure. The resulting crystals were washed with ethyl acetate to give 2.83 g (69% yield) of the title compound.
¹H-NMR (CDCl₃) δ :2.44(3H,s), 3.89(3H,s), 6.96(2H,d,J=9.0Hz), 7.28(2H,d,J=8.0Hz), 7.68(2H,d,J=8.2Hz), 7.82(2H,d,J=8.8Hz)
【0174】
Example 109
7-[4-(4-chlorobenzoyl)benzyloxy]-6-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(4-Chlorobenzoyl)benzyl bromide (664 mg) was added to a solution of 6-methyl-2-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (365 mg) and potassium carbonate (526 mg) in dimethylformamide (10 mL), and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and water/ethyl acetate was added to the residue. The mixture was extracted with ethyl acetate, purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 2:1:1), and recrystallized from ethyl acetate to give the title compound (400 mg) as a colorless solid.
IR(KBr)ν: 1670, 1640, 1565, 1490 cm^-1.
NMR (CDCl₃)δ: 2.11(3H,s), 5.53(2H,s), 6.92(1H,d,J=4.9Hz), 7.47(2H,d,J=8.5Hz), 7.55(2H,d,J=8.2Hz), 7.76(2H,d,J=8.2Hz), 7.80(2H,d,J=8.5Hz), 7.98(1H,d,J=4.9Hz).
【0175】
Example 110
7-[4-(4-chlorobenzoyl)benzyloxy]-2,3,6-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(4-Chlorobenzoyl)benzyl bromide (581 mg) was added to a solution of 2,3,6-trimethyl-2-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (382 mg) and potassium carbonate (357 mg) in dimethylformamide (10 ml), and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and water/ethyl acetate was added to the residue. The mixture was extracted with ethyl acetate and recrystallized from ethyl acetate to give the title compound (266 mg) as a colorless solid.
IR(KBr)ν: 1665, 1580, 1500 cm^-1.
NMR (CDCl₃)δ: 2.04(3H,s), 2.27(3H,s), 2.73(3H,s), 5.48(2H,s), 7.46(2H,d,J=8.4Hz), 7.53(2H,d,J=8.2Hz), 7.76(2H,d,J=8.4Hz), 7.79(2H,d,J=8.2Hz).
【0176】
Example 111
5-[4-(4-chlorobenzoyl)benzyl]-1,3-dimethyl-pyrrolo[3,2-d]pyrimidine-2,4-dione
To a solution of 1,3-dimethyl-pyrrolo[3,2-d]pyrimidine-2,4-dione (0.402 g, 2.24 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (1.20 g, 3.88 mmol) in DMF (5 mL), potassium carbonate (0.73 g, 5.28 mmol) was added and the mixture was stirred at 60°C for 2 hours. After removing the solvent under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the organic layer was diluted with MgSO₄The residue was purified on a silica gel column (developing solvent: isopropyl ether:ethyl acetate:methylene chloride=2:1:1) and then recrystallized from ethyl acetate to give colorless needles.
0.360g (39%)
IR(KBr)ν: 1693, 1653, 1549, 1466, 1434, 1406, 1267, 1065, 1016, 962, 922, 856, 744, 669, 503 cm^-1.
NMR (CDCl₃)δ: 3.40(3H,s), 3.49(3H,s), 5.66(2H,s), 6.00(1H,d,J=3.0Hz), 7.01(1H,d,J=3.0Hz), 7.29(2H,d,J=8.6Hz), 7.45(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz).
【0177】
Example 112
1,3-dimethyl-5-[4-(4-trifluoromethylbenzoyl)benzyl]-pyrrolo[3,2-d]pyrimidine-2,4-dione
To a solution of 1,3-dimethyl-pyrrolo[3,2-d]pyrimidine-2,4-dione (0.405 g, 2.26 mmol) and 4-(4-trifluoromethylbenzoyl)benzyl bromide (2.01 g) in DMF (5 mL), potassium carbonate (0.82 g, 5.93 mmol) was added and the mixture was stirred at 60°C for 2 hours. After removing the solvent under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the organic layer was diluted with MgSO₄The residue was purified on a silica gel column (developing solvent: isopropyl ether:ethyl acetate:methylene chloride=2:1:1) and then recrystallized from ethyl acetate to give colorless needles.
0.398g (40%)
IR(KBr)ν: 1695, 1651, 1468, 1408, 1319, 1277, 1164, 1063, 10146, 926, 759 cm^-1.
【0178】
Example 113
3,5-dimethyl-2-[4-(3-indolylcarbonyl)benzylthio]-quinazolin-4-one
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (0.497 g, 2.41 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.5 mL) was added, followed by 4-(3-indolylcarbonyl)benzyl bromide (0.650 g, 2.41 mmol), and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was purified by silica gel column chromatography (eluent: ethyl acetate:THF=1:1) to give a pale red solid (0.178 g, 17%).
¹H-NMR (CDCl₃) δ :2.76(3H,s), 4.65(2H,s), 7.18-7.28(4H,m), 7.48(2H,d,J=7.6Hz), 7.58-7.83(4H,m), 7.93(1H,dd,J=6.2,3.0Hz), 8.27(1H,m)
IR(KBr): 3149, 1670, 1602, 1556, 1431, 1309, 1213, 1092, 750 cm^-1
【0179】
Example 114
3,5-dimethyl-2-[4-(3,4,5-trimethoxybenzoyl)benzylthio]-quinazolin-4-one
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (0.497 g, 2.41 mmol) in a mixture of EtOH (10.0 ml) and THF (10.0 ml), 1N aqueous sodium hydroxide (2.5 ml) was added, followed by 4-(3,4,5-t-trimethoxybenzoyl)benzyl bromide (0.970 g, 2.52 mmol), and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.983 g, 83%).
¹H-NMR (CDCl₃) δ :2.85(3H,s), 3.55(3H,s), 3.86(6H,s), 3.94(3H,s), 4.60(2H,s), 7.04(2H,s), 7.15(1H,d,J=7.2Hz), 7.44(1H,d,J=7.2Hz), 7.51(1H,t,J=7.2Hz), 7.61(2H,d,J=8.0Hz), 7.78(2H,d,J=8.0Hz)
IR(KBr): 1672, 1581, 1556, 1500, 1462, 1414, 1333, 1234, 1126, 1093, 1001, 806, 773, 696 cm^-1
【0180】
Example 115
3,5-dimethyl-2-[4-(4-methoxybenzoyl)benzylthio]quinazolin-4-one
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (0.495 g, 2.41 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.5 mL) was added, followed by 4-(4-methoxybenzoyl)benzyl bromide (84% purity, 0.960 g, 2.52 mmol) and stirring at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.736 g, 71%).
¹H-NMR (CDCl₃) δ :2.85(3H,s), 3.55(3H,s), 3.89(3H,s), 4.60(2H,s), 6.95(2H,d,J=6.8Hz), 7.15(1H,d,J=6.2Hz), 7.44(1H,d,J=6.2Hz), 7.55(1H,t,J=6.2Hz), 7.59(2H,d,J=6.8Hz), 7.72(2H,d,J=8.0Hz), 7.82(2H,d,J=8.0Hz)
IR(KBr): 1672, 1601, 1554, 1462, 1417, 1308, 1255, 1173, 1090, 1030, 928 cm^-1
【0181】
Example 116
3,5-dimethyl-2-[4-(4-trifluoromethylbenzoyl)benzylthio]-quinazolin-4-one
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (0.495 g, 2.41 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.5 mL) was added, followed by the addition of 4-(4-trifluoromethylbenzoyl)benzyl bromide (purity 63.4%, 1.37 g, 2.52 mmol) and stirring at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO 4₄The residue was recrystallized from methanol to give colorless needles.
¹H-NMR (CDCl₃) δ :2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.16(1H,d,J=7.2Hz), 7.32(2H,d,J=8.2Hz), 7.43(1H,d,J=7.2Hz), 7.55(1H,t,J=7.2Hz), 7.63(2H,d,J=8.0Hz), 7.88(2H,d,J=8.0Hz)
IR(KBr): 1671, 1556, 1410, 1325, 1297, 1171, 1130, 1066, 930, 860, 690 cm^-1
【0182】
Example 117
2-[4-(4-chlorobenzoyl)benzylthio]-3-ethyl-5-methylquinazolin-4-one
To a solution of 3-ethyl-5-methyl-2-mercaptoquinazolin-4-one (0.506 g, 2.30 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.7 mL) was added, followed by 4-(4-chlorobenzoyl)benzyl bromide (0.720 g, 2.33 mmol), and the mixture was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.695 g, 67%).
¹H-NMR (CDCl₃) δ :1.35(3H,t,J=7.2Hz), 2.84(3H,s), 4.13(2H,q,J=7.2Hz), 4.59(2H,s), 7.14(1H,d,J=8.0Hz), 7.41-7.54(4H,m), 7.60(2H,d,J=8.0Hz), 7.73(2H,d,J=6.8Hz), 7.74(2H,d,J=8.0Hz)
IR(KBr): 1668, 1551, 1276, 1221, 1097, 926, 731 cm^-1
【0183】
Example 118
2-[4-(4-fluorobenzoyl)benzylthio]-3-ethyl-5-methylquinazolin-4-one
To a solution of 3-ethyl-5-methyl-2-mercaptoquinazolin-4-one (0.506 g, 2.30 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.7 mL) was added, followed by 4-(4-fluorobenzoyl)benzyl bromide (0.715 g, 2.44 mmol) and stirring at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from methanol to give colorless needles (0.803 g, 81%).
¹H-NMR (CDCl₃) δ :1.35(3H,t,J=7.2Hz), 2.85(3H,s), 4.13(2H,q,J=7.2Hz), 4.59(2H,s), 7.10-7.20(3H,m), 7.42(1H,d,J=7.0Hz), 7.54(1H,t,J=7.0Hz), 7.74(2H,d,J=8.4Hz), 7.76-7.87(2H,m)
IR(KBr): 1666, 1599, 1552, 1450, 1412, 1371, 1277, 1225, 1153, 1103, 856, 808, 777, 734, 698 cm-¹
【0184】
Example 119
3-ethyl-5-methyl-2-[4-(4-trifluoromethylbenzoyl)benzylthio]-quinazolin-4-one
To a solution of 3-ethyl-5-methyl-2-mercaptoquinazolin-4-one (0.507 g, 2.30 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.7 mL) was added, followed by the addition of 4-(4-trifluoromethylbenzoyl)benzyl bromide (purity: 63%, 1.28 g, 2.35 mmol) and stirring at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from methanol to give colorless needles (0.811 g, 73%).
¹H-NMR (CDCl₃) δ :1.35(3H,t,J=7.2Hz), 2.85(3H,s), 4.12(2H,q,J=7.2Hz), 4.60(2H,s), 7.14(1H,d,J=7.0Hz), 7.42(1H,t,J=7.0Hz), 7.54(1H,t,J=7.0Hz), 7.63(2H,d,J=8.0Hz), 7.74(2H,d,J=8.0Hz), 7.78(2H,d,J=8.0Hz), 7.88(2H,d,J=8.0Hz)
IR(KBr): 1670, 1552, 1321, 1171, 1130, 1065, 930cm^-1
【0185】
Example 120
3-ethyl-2-[4-(4-methoxybenzoyl)benzylthio]-5-methylquinazolin-4-one
To a solution of 3-ethyl-5-methyl-2-mercaptoquinazolin-4-one (0.507 g, 2.30 mmol) in EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide solution (2.7 mL) was added, followed by 4-(4-methoxybenzoyl)benzyl bromide (purity: 84%, 0.840 g, 2.31 mmol) and stirring at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from methanol to give colorless needles (0.826 g, 81%).
¹H-NMR (CDCl₃) δ :1.35(3H,t,J=7.0Hz), 2.85(3H,s), 3.89(3H,s), 4.14(2H,q,J=7.0Hz), 4.59(2H,s), 6.96(2H,d,J=8.8Hz), 7.15(1H,d,J=7.2Hz), 7.43(1H,d,J=7.2Hz), 7.54(1H,t,J=7.2Hz), 7.58(2H,d,J=8.1Hz), 7.73(2H,d,J=8.1Hz), 7.82(2H,d,J=8.8Hz)
IR(KBr): 1674, 1601, 1552, 1257, 1173, 1103, 1028, 930, 851, 811, 781 cm^-1
【0186】
Example 121
2-[4-(4-fluorobenzoyl)benzyloxy]-3-methylpyrido[1,2-a]pyrimidin-4-one
To a solution of 2-hydroxy-3-methylpyrido[1,2-a]pyrimidin-4-one (0.480 g, 2.72 mmol) and 4-(4-fluorobenzoyl)benzyl bromide (0.900 g, 3.07 mmol) in a DMF (10.0 ml)-DMSO (10.0 ml) mixture, potassium carbonate (0.800 g, 5.78 mmol) was added and stirred at room temperature for 2.5 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated brine. Then, MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.425 g, 40.2%).
¹H-NMR (CDCl₃) δ :2.23(3H,s), 5.63(2H,s), 7.11-7.21(2H,m), 7.45-7.61(4H,m), 7.64-7.89(5H,m), 9.09(1H,d,J=7.2Hz)
IR(KBr): 1670, 1578, 1531, 1477, 1279, 1165, 926, 854, 762 cm^-1
【0187】
Example 122
2-[4-(2-ethoxycarbonylbenzoyl)benzyloxy]-3-methylpyrido[1,2-a]pyrimidin-4-one
To a solution of 2-hydroxy-3-methylpyrido[1,2-a]pyrimidin-4-one (0.277 g, 1.57 mmol) and 4-(2-ethoxycarbonylbenzoyl)benzyl bromide (0.565 g, 1.63 mmol) in a DMF (10.0 ml)-DMSO (10.0 ml) mixture, potassium carbonate (0.360 g, 2.60 mmol) was added and stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was purified by silica gel column chromatography (eluent: ethyl acetate:hexane = 2:1) to give a colorless amorphous solid (0.345 g, 54.0%).
¹H-NMR (CDCl₃) δ :1.05(3H,t,J=7.2Hz), 2.20(3H,s), 4.08(2H,q,J=7.2Hz), 5.59(2H,s), 7.10(1H,dt,J=7.2,1.4Hz), 7.41(1H,dt,J=6.6,2.0Hz), 7.51-7.81(8H,m), 8.07(1H,dd,J=6.8,1.6Hz), 9.07(1H,dd,J=6.8,1.6Hz)
IR(KBr): 1716, 1674, 1635, 1576, 1531, 1479, 1281, 1165, 769 cm^-1
【0188】
Example 123
2-[4-(1-indolylcarbonyl)benzyloxy]-3-methylpyrido[1,2-a]pyrimidin-4-one
To a solution of 2-hydroxy-3-methylpyrido[1,2-a]pyrimidin-4-one (0.258 g, 1.46 mmol) and 4-(1-indolylcarbonyl)benzyl chloride (0.430 g, 1.59 mmol) in DMF (10.0 ml) and DMSO (5.0 ml) was added potassium carbonate (0.330 g, 2.39 mmol) and stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.19 g, 33.0%).
¹H-NMR (CDCl₃-DMSO-d₆) δ :2.24(3H,s), 5.64(2H,s), 6.62(1H,m), 7.12(1H,t,J=7.7Hz), 7.27-7.40(4H,m), 7.49-7.80(6H,m), 8.42(1H,d,J=7.7Hz), 9.09(2H,d,J=7.7Hz)
IR(KBr): 1676, 1578, 1533, 1450, 1336, 1282, 1169, 754 cm^-1
【0189】
Example 124
3-methyl-2-[4-(4-trifluoromethylbenzoyl)benzyloxy]-pyrido[1,2-a]pyrimidin-4-one
To a solution of 2-hydroxy-3-methylpyrido[1,2-a]pyrimidin-4-one (0.250 g, 1.42 mmol) and 4-(4-trifluoromethylbenzoyl)benzyl bromide (purity: 63.4%, 0.852 g, 2.48 mmol) in DMF (10.0 ml) and DMSO (5.0 ml) was added potassium carbonate (0.360 g, 2.60 mmol) and stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.21 g, 34.0%).
¹H-NMR (CDCl₃) δ :2.23(3H,s), 5.63(2H,s), 7.12(1H,t,J=6.8Hz), 7.50(1H,d,J=8.8Hz), 7.61(2H,d,J=8.3Hz), 7.68(1H,m), 7.76(2H,d,J=8.1Hz), 7.84(2H,d,J=8.1Hz), 7.91(2H,d,J=8.3Hz), 9.09(1H,d,J=7.2Hz)
IR(KBr): 1672, 1578, 1531, 1479, 1325, 1279, 1167, 1128, 1065, 914, 744cm^-1
【0190】
Example 125
2-[4-(4-fluorobenzoyl)benzyl]thio-3-methylthieno[3,2-d]pyrimidin-4(3H)-one
4-(4-Fluorobenzoyl)benzyl bromide (1.48 g) was added to a solution of 2-mercapto-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.0 g) and sodium hydroxide (205 mg) in 50% ethanol (12 mL)-dimethylformamide (20 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to yield the title compound (1.44 g) as a colorless solid.
¹H-NMR (CDCl₃) δ :3.62(3H,s), 4.58(2H,s), 7.16(2H,t,J=8.6Hz), 7.24(1H,d,J=5.2Hz), 7.59(2H,d,J=8.4Hz), 7.70-7.90(5H,m)
IR(KBr): 1670, 1640, 1500cm^-1
【0191】
Example 126
2-[4-(4-fluorobenzoyl)benzyl]thio-3-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4(3H)-one
4-(4-Fluorobenzoyl)benzyl bromide (2.11 g) was added to a solution of 2-mercapto-3-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4(3H)-one (1.0 g) obtained in Reference Example 1 and sodium hydroxide (220 mg) in 50% ethanol (15 ml)-dimethylformamide (8 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and methanol, and recrystallized from methanol to yield the title compound (1.235 g) as a colorless solid.
¹H-NMR (CDCl₃) δ :2.07(2H,quint,J=7.4Hz), 2.80(2H,t,J=7.8Hz), 2.84(2H,t,J=7.8Hz), 3.50(3H,s), 4.50(2H,s), 7.17(2H,t,J=8.4Hz), 7.54(2H,d,J=8.0Hz), 7.74(2H,d,J=8.0Hz), 7.85(2H,dd,J=8.4,5.6Hz)
IR(KBr): 1660, 1650, 1595, 1495 cm^-1
【0192】
Example 127
6-[4-(4-fluorobenzoyl)benzyl]thio-5-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
4-(4-Fluorobenzoyl)benzyl bromide (1.745 g) was added to a solution of 6-mercapto-5-methyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium salt (1.0 g) in dimethylformamide (20 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration and washed with water and methanol to yield the title compound (1.467 g) as a colorless solid.
¹H-NMR (DMSO-d₆) δ :3.45(3H,s), 4.63(2H,s), 7.39(2H,t,J=8.8Hz), 7.72(4H,s), 7.83(2H,dd,J=8.8,5.4Hz), 8.03(1H,s), 13.67(1H,brs)
IR(KBr): 3200, 1670, 1640, 1575cm^-1
【0193】
Example 128
6-[4-(4-chlorobenzoyl)benzyl]thio-5-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
To a solution of 6-mercapto-5-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium salt (1.0 g) in dimethylformamide (25 ml),ChloroTo the reaction mixture was added benzoylbenzyl bromide (1.31 g), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration and washed with water and methanol to give the title compound (1.714 g) as a colorless solid.
¹H-NMR (DMSO-d₆) δ :1.24(3H,t,J=7.0Hz), 4.07(2H,q,J=7.0Hz), 4.62(2H,s), 7.60(2H,d,J=8.0Hz), 7.70-7.80(7H,m)
IR(KBr): 3100, 1660, 1580, 1540cm^-1
【0194】
Example 129
1-[4-(4-chlorobenzoyl)benzyl〕−5-ethyl-6-methylthio-1H-pyrazolo [3,4-d〕Pyrimidin-4(5H)-one (A)
2-[4-(4-chlorobenzoyl)benzyl〕−5-ethyl-6-methylthio-2H-pyrazolo [3,4-d〕Pyrimidin-4(5H)-one (B)
5-ethyl-6-mercapto-1H-pyrazolo [3,4-d〕To a solution of pyrimidin-4(5H)-one potassium salt (5.0 g) in dimethylformamide (40 ml) was added methyl iodide (3.65 g), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and water was added to the resulting residue. The resulting crystals were filtered and washed with water to give 5-ethyl-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (2.908 g) as a colorless solid.
¹H-NMR (DMSO-d₆) δ :1.24(3H,t,J=7.0Hz), 2.61(3H,s), 4.08(2H,q,J=7.0Hz), 8.09(1H,brs)
To a solution of 5-ethyl-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (1.0 g) in dimethylformamide (20 ml), 60% sodium hydride (230 mg) was added and stirred at room temperature for 10 minutes. 4-(4-chlorobenzoyl)benzyl bromide (1.46 g) was then added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting residue was dissolved in ethyl acetate, washed with water and saturated brine, dried, and the solvent was evaporated. A solution of hexane:ethyl acetate = 3:1 was added to the resulting residue, and the resulting crystals were collected by filtration to give a colorless solid, 2-[4-(4-chlorobenzoyl)benzyl〕−530 mg of 5-ethyl-6-methylthio-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (B) were obtained.
¹H-NMR (CDCl₃) δ :1.34(3H,t,J=7.0Hz), 2.65(3H,s), 4.17(2H,q,J=7.0Hz), 5.48(2H,s), 7.41(2H,d,J=8.4Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.76(2H,d,J=8.4Hz), 8.06(1H,s)
IR(KBr): 1695, 1650, 1570cm^-1
The filtrate was concentrated, purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 3/2/1), and crystallized from methanol to give a colorless solid, 1-[4-(4-chlorobenzoyl)benzyl〕−160 mg of 5-ethyl-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (A) were obtained.
¹H-NMR (CDCl₃) δ :1.35(3H,t,J=7.0Hz), 2.63(3H,s), 4.20(2H,q,J=7.0Hz), 5.54(2H,s), 7.43(2H,d,J=8.0Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.75(2H,d,J=8.0Hz), 8.05(1H,s)
IR(KBr): 1695, 1645, 1540 cm^-1
【0195】
Example 130
7-[4-(4-chlorobenzoyl)benzyloxy]-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(4-Chlorobenzoyl)benzyl bromide (2.0 g) was added to a solution of 7-hydroxy-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]-5-one (1.0 g) and potassium carbonate (750 mg) in dimethylformamide (15 ml), and the reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) and recrystallized from isopropyl ether to give the title compound (200 mg) as a colorless solid.
¹H-NMR (CDCl₃) δ :1.97(3H,s), 3.47(2H,t,J=7.8Hz), 4.46(2H,t,J=7.8Hz), 5.43(2H,s), 7.46(2H,d,J=8.0Hz), 7.50(2H,d,J=8.0Hz), 7.76(2H,d,J=8.0Hz), 7.78(2H,d,J=8.0Hz)
IR(KBr): 1650, 1515, 1390cm^-1
【0196】
Example 131
1-[4-(4-chlorobenzoyl)benzyl]-6-(3-dimethylaminopropylthio)-5-ethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one hydrochloride (A)
2-[4-(4-chlorobenzoyl)benzyl]-6-(3-dimethylaminopropylthio)-5-ethyl-2,3-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one hydrochloride (B)
To a solution of 5-ethyl-6-mercapto-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one potassium salt (2.0 g) in dimethylformamide (25 ml) was added 28% sodium methylate (1.75 ml), followed by 3-dimethylaminopropyl chloride hydrochloride (1.62 g) and stirring at 60°C for 1 day. 60% sodium hydride (232 mg) was added to the reaction mixture and stirred at room temperature for 10 minutes. 4-(4-chlorobenzoyl)benzyl bromide (1.778 g) was then added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol/concentrated aqueous ammonia=50/1/0.1) and then converted into hydrochlorides with a solution of hydrochloric acid in ethyl acetate to give the title compounds (A) (518 mg) and (B) (262 mg) as colorless solids.
Compound (A)
IR(KBr)ν: 1710, 1650, 1545 cm^-1.
NMR (CDCl₃)δ: 1.34(3H,t,J=7.0Hz), 2.31(2H,m), 2.73(6H,d,J=4.6Hz), 3.03(2H,m), 3.41(2H,t,J=7.0Hz), 4.17(2H,q,J=7.0Hz), 5.61(2H,s), 7.35(2H,d,J=8.2Hz), 7.46(2H,d,J=8.6Hz), 7.73(4H,d,J=8.6Hz), 8.07(1H,s).
Compound (B)
IR(KBr)ν: 1695, 1655, 1580 cm^-1.
NMR (CDCl₃)δ: 1.33(3H,t,J=7.0Hz), 2.30-2.50(2H,m), 2.83(6H,d,J=4.4Hz), 3.19(2H,m), 3.41(2H,t,J=7.0Hz), 4.15(2H,q,J=7.0Hz), 5.48(2H,s), 7.40(2H,d,J=8.2Hz), 7.47(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.07(1H,s).
【0197】
Example 132
5-ethyl-1-[4-(4-methoxybenzoyl)benzyl]-6-methylthio-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (A)
5-ethyl-2-[4-(4-methoxybenzoyl)benzyl]-6-methylthio-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (B)
To a solution of 5-ethyl-6-methylthio-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (900 mg) in dimethylformamide (20 mL) was added 60% sodium hydride (207 mg) and stirred at room temperature for 10 minutes. Next, 4-(4-methoxybenzoyl)benzyl bromide (1.31 g) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 3/2/1) to yield the title compounds (A) (400 mg) and (B) (366 mg) as colorless solids.
Compound (A)
IR(KBr)ν: 1695, 1645, 1595, 1550, 1495, 1315, 1260, 1170 cm^-1.
NMR (CDCl₃)δ: 1.35(3H,t,J=7.2Hz), 2.63(3H,s), 3.89(3H,s), 4.19(2H,q,J=7.2Hz), 5.54(2H,s), 6.95(2H,d,J=8.8Hz), 7.41(2H,d,J=8.0Hz), 7.73(2H,d,J=8.0Hz), 7.80(2H,d,J=8.8Hz), 8.05(1H,s).
Compound (B)
IR(KBr)ν: 1695, 1650, 1600, 1575, 1515, 1315, 1280, 1170 cm^-1.
NMR (CDCl₃)δ: 1.34(3H,t,J=7.0Hz), 2.65(3H,s), 3.89(3H,s), 4.17(2H,q,J=7.0Hz), 5.47(2H,s), 6.96(2H,d,J=8.8Hz), 7.40(2H,d,J=8.0Hz), 7.75(2H,d,J=8.0Hz), 7.81(2H,d,J=8.8Hz), 8.06(1H,s).
【0198】
Example 133
7-[4-(4-chlorobenzoyl)benzyl〕1-ethyl-3-methylxanthine
Journal of the American Chemical Society (J. Am. Chem. Soc.,75To a solution of 1-ethyl-3-methylxanthine (385 mg) in dimethylformamide (10 mL), potassium carbonate (415 mg) and 4-(4-chlorobenzoyl)benzyl bromide (619 mg) were added and stirred at room temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) and further recrystallized (ethyl acetate-ether-hexane) to give the title compound (207 mg, 25%) as a colorless powder.
IR(KBr): 1695, 1660, 1650, 1600, 1580, 1545, 1455, 1380, 1270, 1230, 1090, 930, 740 cm^-1.
¹H-NMR (CDCl₃)δ: 1.25(3H,t,J=7.0Hz), 3.60(3H,s), 4.08(2H,q,H=7.0Hz), 5.60(2H,s), 7.40-7.53(4H,m), 7.64(1H,s), 7.70-7.85(4H,m).
【0199】
Example 134
2-[4-(4-chlorobenzoyl)benzyloxy]-3,5-dimethyl-4(3H)-quinazolinone
To a solution of 4-(4-chlorobenzoyl)benzyl alcohol (1.0 g) in dimethylformamide (20 ml), 60% sodium hydride (210 mg) was added and stirred at room temperature for 10 minutes. 2-Chloro-3,5-dimethyl-4(3H)-quinazolinone (850 mg) was then added, and the reaction mixture was stirred at room temperature for 1 hour and then at 80°C for 10 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 4/1/1) to yield the title compound (350 mg) as a colorless solid.
IR(KBr)ν: 1680, 1665, 1630, 1600 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.53(3H,s), 5.61(2H,s), 7.09(1H,d,J=8.0Hz), 7.34(1H,d,J=8.0Hz), 7.42-7.53(3H,m), 7.60(2H,d,J=8.2Hz), 7.76(2H,d,J=8.6Hz), 7.82(2H,d,J=8.2Hz).
【0200】
Example 135
3,5-dimethyl-2-[4-(4-fluorobenzoyl)benzyloxy]-4(3H)-quinazolinone
60% sodium hydride (210 mg) was added to a solution of 4-(4-fluorobenzoyl)benzyl alcohol (1.0 g) in dimethylformamide (20 ml) and stirred at room temperature for 10 minutes. 2-Chloro-3,5-dimethyl-4(3H)-quinazolinone (907 mg) was then added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to yield the title compound (560 mg) as a colorless solid.
IR(KBr)ν: 1675, 1660, 1630, 1595 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.53(3H,s), 5.61(2H,s), 7.09(1H,d,J=8.2Hz), 7.17(2H,t,J=8.6Hz), 7.35(1H,d,J=8.2Hz), 7.50(1H,t,J=8.2Hz), 7.61(2H,d,J=8.2Hz), 7.82(2H,d,J=8.2Hz), 7.86(2H,dd,J=8.6,5.4Hz).
【0201】
Example 136
2-[4-(4-chlorobenzoyl)benzyl]thio-3,5,6-trimethylthieno[2,3-d]pyrimidin-4(3H)-one
4-(4-chlorobenzoyl)benzyl bromide (1.69 g) was added to a solution of 2-mercapto-3,5,6-trimethylthieno[2,3-d]pyrimidin-4(3H)-one (1.13 g) and sodium hydroxide (205 mg) in 50% methanol (16 ml)-dimethylformamide (4 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate to yield the title compound (1.425 g) as a colorless solid.
IR(KBr)ν: 1680, 1655, 1525, 1275, 1090 cm^-1.
NMR (CDCl₃)δ: 2.37(3H,s), 2.45(3H,s), 3.54(3H,s), 4.53(2H,s), 7.46(2H,d,J=8.2Hz), 7.56(2H,d,J=8.2Hz), 7.74(4H,d,J=8.2Hz).
【0202】
Example 137
2-[4-(4-chlorobenzoyl)benzyl]thio-3,5-dimethylthieno[2,3-d]pyrimidin-4(3H)-one
4-(4-chlorobenzoyl)benzyl bromide (1.69 g) was added to a solution of 3,5-dimethyl-2-mercapto-thieno[2,3-d]pyrimidin-4(3H)-one (1.06 g) and sodium hydroxide (205 mg) in 50% methanol (16 mL)-dimethylformamide (4 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate to yield the title compound (878 mg) as a colorless solid.
IR(KBr)ν: 1680, 1645, 1515, 1285, 1090 cm^-1.
NMR (CDCl₃)δ: 2.55(3H,s), 3.55(3H,s), 4.55(2H,s), 6.67(1H,s), 7.46(2H,d,J=7.8Hz), 7.57(2H,d,J=8.2Hz), 7.74(4H,d,J=8.2Hz).
【0203】
Example 138
3,5-dimethyl-2-[4-[4-[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl]benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis(bromomethyl)benzophenone (1.75 g), 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole (865 mg), and 1 N aqueous sodium hydroxide (11 ml) in dimethylformamide (20 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia = 50/1/0.1) and crystallized from methanol to yield the title compound (337 mg) as a colorless solid.
IR(KBr)ν: 1670, 1650, 1605, 1580, 1555, 1305, 1280 cm^-1.
NMR (CDCl₃)δ: 2.22(6H,s), 2.69(2H,t,J=6.4Hz), 2.84(3H,s), 3.54(3H,s), 4.24(2H,t,J=6.4Hz), 4.58(2H,s), 4.59(2H,s), 7.15(1H,d,J=7.2Hz), 7.40-7.63(6H,m), 7.70-7.80(4H,m).
【0204】
Example 139
3,5-dimethyl-2-[4-[4-[(3,5,6-trimethyl-3H-pyrimidin-4-one-2-yl)thiomethyl]benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis(bromomethyl)benzophenone (1.75 g), 3,5,6-trimethyl-2-mercapto-3H-pyrimidin-4-one (960 mg), and 1 N aqueous sodium hydroxide (11 ml) in dimethylformamide (20 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 3/1/1) and crystallized from methanol to yield the title compound (662 mg) as a colorless solid.
IR(KBr)ν: 1660, 1555, 1520 cm^-1.
NMR (CDCl₃)δ: 2.03(3H,s), 2.28(3H,s), 2.85(3H,s), 3.47(3H,s), 3.54(3H,s), 4.47(2H,s), 4.59(2H,s), 7.15(1H,d,J=7.2Hz), 7.40-7.63(6H,m), 7.75(2H,d,J=8.0Hz), 7.76(2H,d,J=8.2Hz).
【0205】
Example 140
3,5-dimethyl-2-[4-(4-toluoyl)benzylthio]-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (197 mg), 4-(4-toluoyl)benzyl bromide (336 mg), and 1 N aqueous sodium hydroxide (1 mL) in dimethylformamide (10 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 5/1/1) and crystallized from methanol to yield the title compound (140 mg) as a colorless solid.
IR(KBr)ν: 1665, 1650, 1605, 1580, 1555, 1310, 1280 cm^-1.
NMR (CDCl₃)δ: 2.44(3H,s), 2.85(3H,s), 3.55(3H,s), 4.59(2H,s), 7.15(1H,d,J=8.2Hz), 7.27(2H,d,J=8.0Hz), 7.40-7.63(4H,m), 7.70(2H,d,J=8.2Hz), 7.75(2H,d,J,=8.2Hz).
【0206】
Example 141
3,5-dimethyl-2-[4-[4-[(thiazolidin-2-yl)thiomethyl]benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis(bromomethyl)benzophenone (1.75 g), 2-mercaptothiazoline (600 mg), and 1 N aqueous sodium hydroxide (11 ml) in dimethylformamide (20 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 3/1/1) and crystallized from methanol to yield the title compound (489 mg) as a colorless solid.
IR(KBr)ν: 1660, 1605, 1580, 1555, 1305, 1280 cm^-1.
NMR (CDCl₃)δ: 2.84(3H,s), 3.43(2H,t,J=8.2Hz), 3.55(3H,s), 4.23(2H,t,J=8.2Hz), 4.41(2H,s), 4.59(2H,s), 7.15(1H,d,J=7.0Hz), 7.40-7.63(6H,m), 7.74(2H,d,J=8.0Hz), 7.76(2H,d,J=8.2Hz).
【0207】
Example 142
3,5-dimethyl-2-[4-[4-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis(bromomethyl)benzophenone (1.75 g), 1-methyl-5-mercapto-1H-tetrazole (700 mg), and 1 N aqueous sodium hydroxide (5.5 ml) in dimethylformamide (20 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia = 50/1/0.1) and crystallized from methanol to yield the title compound (603 mg) as a colorless solid.
IR(KBr)ν: 1665, 1605, 1580, 1555, 1305, 1280 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 3.86(3H,s), 4.60(2H,s), 4.61(2H,s), 7.16(1H,d,J=6.6Hz), 7.40-7.63(6H,m), 7.75(4H,d,J=8.0Hz).
【0208】
Example 143
2-[4-(4-chlorobenzoyl)benzylthio]-4(3H)-quinazolinone
A solution of 2-mercapto-4(3H)-quinazolinone (1.78 g), 4-(4-chlorobenzoyl)benzyl bromide (3.07 g), and 1N aqueous sodium hydroxide solution (10.5 ml) in ethanol (20 ml) was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the resulting precipitate was collected by filtration, washed with water, methanol, and ethyl acetate, dried, and recrystallized from ethyl acetate to yield the title compound (3.24 g) as a colorless solid.
IR(KBr)ν: 1690, 1660, 1580, 1560 cm^-1.
NMR (CDCl₃)δ: 4.58(2H,s), 7.33-7.80(11H,m), 8.14(1H,d,J=8.0Hz), 12.30(1H,brs).
【0209】
Example 144
3,5-dimethyl-2-[4-[4-(4-methylpiperazinylmethyl)benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis(bromomethyl)benzophenone (1.75 g), N-methylpiperazine (500 mg), and 1 N aqueous sodium hydroxide (5.5 ml) in dimethylformamide (35 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia = 40/1/0.1) to yield the title compound (180 mg) as a colorless amorphous substance.
IR(KBr)ν: 1670, 1605, 1580, 1555, 1305, 1280 cm^-1.
NMR (CDCl₃)δ: 2.31(3H,s), 2.35-2.60(8H,m), 2.85(3H,s), 3.55(3H,s), 3.58(2H,s), 4.60(2H,s), 7.16(1H,d,J=7.0Hz), 7.40-7.63(6H,m), 7.75(2H,d,J=8.0Hz), 7.77(2H,d,J=8.2Hz).
【0210】
Example 145
3,5-dimethyl-2-[4-[4-(4-phenylpiperazinylmethyl)benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis(bromomethyl)benzophenone (1.75 g), phenylpiperazine (810 mg), and 1 N aqueous sodium hydroxide solution (5.5 ml) in dimethylformamide (35 ml) was stirred at 60°C for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 4/1/1) and crystallized from isopropyl ether to yield the title compound (372 mg) as a colorless solid.
IR(KBr)ν: 1685, 1655, 1600, 1550, 1305, 1260, 1190 cm^-1.
NMR (CDCl₃)δ: 2.64(4H,t,J=5.0Hz), 2.85(3H,s), 3.22(4H,t,J=5.0Hz), 3.55(3H,s), 3.64(2H,s), 4.60(2H,s), 6.80-7.00(3H,m), 7.15(1H,d,J=7.0Hz), 7.20-7.32(2H,m), 7.40-7.65(6H,m), 7.76(2H,d,J=8.2Hz), 7.78(2H,d,J=8.2Hz).
【0211】
Example 146
2-[4-(4-acetoxybenzoyl)benzylthio]-3,5-dimethylthieno[2,3-d]pyrimidin-4(3H)-one
4-(4-acetoxybenzoyl)benzyl bromide (2.68 g) was added to a solution of 3,5-dimethyl-2-mercapto-thieno[2,3-d]pyrimidin-4(3H)-one (1.40 g) and 1N aqueous sodium hydroxide (6.7 ml) in ethanol (13 ml)-dimethylformamide (25 ml), and the reaction mixture was stirred at room temperature to 60°C for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, concentrated, and recrystallized from methanol to give the title compound (887 mg) as a colorless solid.
IR(KBr)ν: 1750, 1680, 1650, 1600, 1520, 1195 cm^-1.
NMR (CDCl₃)δ: 2.44(3H,s), 2.55(3H,s), 3.55(3H,s), 4.54(2H,s), 6.67(1H,s), 7.21(2H,d,J=8.6Hz), 7.56(2H,d,J=8.2Hz), 7.77(2H,d,J=8.2Hz), 7.84(2H,d,J=8.6Hz).
【0212】
Example 147
3,5-dimethyl-2-[4-(4-hydroxybenzoyl)benzylthio]thieno[2,3-d]pyrimidin-4(3H)-one
A solution of 2-[4-(4-acetoxybenzoyl)benzylthio]-3,5-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (1.40 g) and 1N aqueous sodium hydroxide solution (6.7 mL) in tetrahydrofuran (20 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated, dissolved in water, and acidified with 1N hydrochloric acid. The resulting precipitate was extracted with ethyl acetate, washed with water, dried, concentrated, and recrystallized from methanol/ethyl acetate to give the title compound (775 mg) as a colorless solid.
IR(KBr)ν: 3320, 1645, 1600, 1580, 1520, 1310, 1280 cm^-1.
NMR (CDCl₃)δ: 2.55(3H,d,J=1.2Hz), 3.55(3H,s), 4.55(2H,s), 5.59(1H,s), 6.67(1H,d,J=1.2Hz), 6.91(2H,d,J=8.6Hz), 7.55(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.78(2H,d,J=8.6Hz).
【0213】
Example 148
3,5-dimethyl-2-[4-[4-(2-morpholinoethoxy)benzoyl]benzylthio]thieno[2,3-d]pyrimidin-4(3H)-one
A solution of 3,5-dimethyl-2-[4-(4-hydroxybenzoyl)benzylthio]thieno[2,3-d]pyrimidin-4(3H)-one (422 mg), 1-(2-chloroethyl)morpholine hydrochloride (205 mg), and potassium carbonate (414 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 24 hours. The reaction mixture was concentrated, dissolved in water, extracted with ethyl acetate, washed with water, dried, concentrated, and crystallized from hexane/isopropyl ether to give the title compound (495 mg) as a pale yellow solid.
IR(KBr)ν: 1680, 1650, 1600, 1530, 1310, 1265, 1170, 1120 cm^-1.
NMR (CDCl₃)δ: 2.55(3H,d,J=1.2Hz), 2.59(4H,t,J=4.6Hz), 2.84(2H,t,J=5.8Hz), 3.55(3H,s), 3.75(4H,t,J=4.6Hz), 4.19(2H,t,J=5.8Hz), 4.55(2H,s), 6.67(1H,d,J=1.2Hz), 6.96(2H,d,J=9.0Hz), 7.55(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.81(2H,d,J=9.0Hz).
【0214】
Example 149
2-[4-(4-chlorobenzoyl)benzylthio]-3-methyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone
A solution of 2-mercapto-3-methyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone (980 mg), 4-(4-chlorobenzoyl)benzyl bromide (1.53 g), and 1N aqueous sodium hydroxide solution (5.5 ml) in ethanol (10 ml) and dimethylformamide (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and recrystallized from methanol/ethyl acetate to give the title compound (1.27 g) as a colorless solid.
IR(KBr)ν: 1655, 1520, 1410, 1280, 1270 cm^-1.
NMR (CDCl₃)δ: 1.65-1.85(4H,m), 2.40-2.65(4H,m), 3.47(3H,s), 4.47(2H,s), 7.46(2H,d,J=8.2Hz), 7.55(2H,d,J=8.2Hz), 7.74(2H,d,J=8.2Hz), 7.75(2H,d,J=8.2Hz).
【0215】
Example 150
2-[4-(4-chlorobenzoyl)benzylthio]-3-fluoromethyl-4(3H)quinazolinone
To a suspension of 2-[4-(4-chlorobenzoyl)benzylthio]-4(3H)-quinazolinone (1.0 g) in dimethylformamide (30 ml) was added 60% sodium hydride (100 mg). After the solution became clear, fluoromethyl bromide (500 mg) was added and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and purified by silica gel column chromatography (hexane/ethyl acetate/chloroform = 5/1/1). Recrystallization from methanol afforded the title compound (500 mg) as a colorless solid.
IR(KBr)ν: 1695, 1650, 1605, 1580, 1555 cm^-1.
NMR (CDCl₃)δ: 4.63(2H,s), 6.21(2H,d,J=51.2Hz), 7.38-7.80(11H,m), 8.24(1H,d,J=7.8Hz).
【0216】
Example 151
3,5-dimethyl-2-[4-[4-[(1,3-dimethylxanthin-7-yl)methyl]benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 4,4'-bis(bromomethyl)benzophenone (1.75 g), theophylline (900 mg), and potassium carbonate (828 mg) in dimethylformamide (40 ml) was stirred at 40°C for 1 hour, and then 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g) was added and stirred at 60°C for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and purified by silica gel column chromatography (ethyl acetate) to yield the title compound (787 mg) as a colorless solid.
IR(KBr)ν: 1700, 1660, 1605, 1555 cm^-1.
NMR (CDCl₃)δ: 2.84(3H,s), 3.40(3H,s), 3.54(3H,s), 3.60(3H,s), 4.58(2H,s), 5.58(2H,s), 7.15(1H,d,J=7.2Hz), 7.35-7.80(11H,m).
【0217】
Example 152
3-methyl-2-[4-(4-trifluoromethylbenzoyl)benzylthio]-thieno[3,2-d]pyrimidin-4(3H)-one
4-(4-Trifluoromethylbenzoyl)benzyl bromide (1.73 g) was added to a solution of 2-mercapto-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.0 g) and 1 N aqueous sodium hydroxide (5.1 mg) in ethanol (10 ml), and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate/hexane to give the title compound (1.11 g) as a colorless solid.
IR(KBr)ν: 1670, 1655, 1510, 1330, 1120 cm^-1.
NMR (CDCl₃)δ: 3.61(3H,s), 4.58(2H,s), 7.23(1H,d,J=5.2Hz), 7.61(2H,d,J=8.0Hz), 7.70-7.81(5H,m), 7.88(2H,d,J=8.0Hz).
【0218】
Example 153
2-[4-(4-acetoxybenzoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one
4-(4-acetoxybenzoyl)benzyl bromide (3.95 g) was added to a solution of 2-mercapto-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.98 g) and 1N aqueous sodium hydroxide solution (10 ml) in ethanol (30 ml), and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate to give the title compound (3.87 g) as a colorless solid.
IR(KBr)ν: 1760, 1670, 1655, 1505, 1225 cm^-1.
NMR (CDCl₃)δ: 2.35(3H,s), 3.62(3H,s), 4.58(2H,s), 7.21(2H,d,J=8.6Hz), 7.25(1H,d,J=5.2Hz), 7.59(2H,d,J=8.2Hz), 7.72-7.90(5H,m).
【0219】
Example 154
2-[4-(4-hydroxybenzoyl]benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one
To a solution of 2-[4-(4-acetoxybenzoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (3.51 g) in THF (20 ml) was added 1N aqueous sodium hydroxide solution (10 ml), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in water. 1N hydrochloric acid was added, and the resulting precipitate was collected by filtration, washed with water, and dried to yield the title compound (3.22 g) as a colorless solid.
IR(KBr)ν: 3200(br), 1660, 1630, 1605, 1505, 1280 cm^-1.
NMR (CDCl₃)δ: 3.61(3H,s), 4.58(2H,s), 6.91(2H,d,J=8.6Hz), 7.25(1H,d,J=5.6Hz), 7.56(2H,d,J=8.2Hz), 7.68-7.80(5H,m).
【0220】
Example 155
3-methyl-2-[4-[4-(4-phenylpiperazinylmethyl)benzoyl]benzylthio]-thieno[3,2-d]pyrimidin-4(3H)-one
A solution of 2-mercapto-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (990 mg), 4,4'-bis(bromomethyl)benzophenone (1.75 g), phenylpiperazine (810 mg), and potassium carbonate (828 mg) in dimethylformamide (30 ml) was stirred at 60°C for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia = 250/1/0.1) to yield the title compound (428 mg) as a pale yellow syrup.
IR(Neat)ν: 1670, 1600, 1535, 1505, 1275 cm^-1.
NMR (CDCl₃)δ: 2.64(4H,t,J=4.8Hz), 3.22(4H,t,J=4.8Hz), 3.61(3H,s), 3.64(2H,s), 4.58(2H,s), 6.80-6.96(3H,m), 7.20-7.31(3H,m), 7.48(2H,d,J=8.2Hz), 7.58(2H,d,J=8.4Hz), 7.70-7.82(5H,m).
【0221】
Example 156
3-methyl-2-[4-[4-(2-morpholinoethoxy)benzoyl]benzylthio]-thieno[3,2-d]pyrimidin-4(3H)-one
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (408 mg), 1-(2-chloroethyl)morpholine hydrochloride (205 mg), and potassium carbonate (414 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 15 hours. The reaction mixture was concentrated and then poured into water/ethyl acetate. The resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (410 mg) as a colorless solid.
IR(KBr)ν: 1670, 1645, 1595, 1505, 1260 cm^-1.
NMR (CDCl₃)δ: 2.59(4H,t,J=4.6Hz), 2.84(2H,t,J=5.7Hz), 3.61(3H,s), 3.74(4H,t,J=4.6Hz), 4.19(2H,t,J=5.7Hz), 4.58(2H,s), 6.96(2H,d,J=8.8Hz), 7.24(1H,d,J=5.2Hz), 7.56(2H,d,J=8.4Hz), 7.69-7.85(5H,m).
【0222】
Example 157
2-[4-(6-chloronicotinoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one
4-(6-chloronicotinoyl)benzyl bromide (3.35 g) was added to a solution of 2-mercapto-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.98 g) and 1N aqueous sodium hydroxide solution (10.5 ml) in ethanol (30 ml), and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate to give the title compound (3.194 g) as a pale yellow solid.
IR(KBr)ν: 1670, 1655, 1510, 1290 cm^-1.
NMR (CDCl₃)δ: 3.62(3H,s), 4.59(2H,s), 7.24(1H,d,J=5.2Hz), 7.48(1H,d,J=8.0Hz), 7.63(2H,d,J=8.4Hz), 7.75(1H,d,J=5.2Hz), 7.77(2H,d,J=8.4Hz), 8.09(1H,dd,J=2.6, 8.4Hz), 8.76(1H,d,J=2.6Hz).
【0223】
Example 158
3-methyl-2-[4-[6-(4-piperidinopiperidinyl)nicotinoyl]benzylthio]-thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride
A solution of 2-[4-(6-chloronicotinoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (427 mg) and 4-piperidinopiperidine (202 mg) in pyridine (10 ml) was stirred at 80° C. for 10 hours. The reaction mixture was concentrated, and the residue was dissolved in chloroform, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia = 50/1/0.1) and converted to the hydrochloride salt with a solution of hydrochloric acid and ethyl acetate to give the title compound (373 mg) as a colorless solid.
IR(KBr)ν: 1660, 1640, 1600, 1535, 1505 cm^-1.
NMR (CDCl₃)δ: 1.80-2.41(6H,m), 2.50-2.92(4H,m), 3.30-3.60(7H,m), 3.62(3H,s), 4.59(2H,s), 4.88(2H,m), 7.20-7.30(2H,m), 7.60-7.80(5H,m), 8.38(1H,brd,J=8.8Hz), 8.47(1H,brs).
【0224】
Example 159
2-[4-(2,4-dichlorobenzoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one
4-(2,4-Dichlorobenzoyl)benzyl bromide (1.91 g) was added to a solution of 2-mercapto-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.0 g) and 1N aqueous sodium hydroxide (5.5 ml) in ethanol (20 ml), and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate to yield the title compound (1.69 g) as a colorless solid.
IR(KBr)ν: 1665, 1650, 1600, 1535, 1510, 1290 cm^-1.
NMR (CDCl₃)δ: 3.60(3H,s), 4.56(2H,s), 7.22(1H,d,J=5.4Hz), 7.27-7.40(2H,m), 7.49(1H,d,J=2.0Hz), 7.57(2H,d,J=8.2Hz), 7.74(1H,d,J=5.4Hz), 7.76(2H,d,J=8.2Hz).
【0225】
Example 160
2-[4-(1-indolylcarbonyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one
4-(1-indolylcarbonyl)benzyl chloride (1.5 g) was added to a solution of 2-mercapto-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.0 g) and 1N aqueous sodium hydroxide (5.5 ml) in ethanol (20 ml), and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate to yield the title compound (808 mg) as a colorless solid.
IR(KBr)ν: 1680, 1665, 1530, 1510, 1450, 1335 cm^-1.
NMR (CDCl₃)δ: 3.62(3H,s), 4.60(2H,s), 6.61(1H,d,J=3.8Hz), 7.20-7.42(4H,m), 7.56-7.80(6H,m), 8.39(1H,d,J=8.4Hz).
【0226】
Example 161
3,5-dimethyl-2-[4-[4-(2-piperidinoethoxy)benzoyl]benzylthio]thieno[2,3-d]pyrimidin-4(3H)-one hydrochloride
A solution of 3,5-dimethyl-2-[4-(4-hydroxybenzoyl)benzylthio]thieno[2,3-d]pyrimidin-4(3H)-one (255 mg), 1-(2-chloroethyl)piperidine hydrochloride (122 mg), and potassium carbonate (250 mg) in dimethylformamide (8 ml) was stirred at 60° C. for 15 hours. After concentrating the reaction mixture, the residue was dissolved in ethyl acetate, washed with water, and dried. After adding a solution of hydrochloric acid and ethyl acetate, the hydrochloride salt was precipitated, collected by filtration, and dried to give the title compound (268 mg) as a colorless solid.
IR(KBr)ν: 1680, 1640, 1595, 1515, 1310, 1250 cm^-1.
NMR (CDCl₃)δ: 1.35-2.00(6H,m), 2.15-2.40(2H,m), 2.55(3H,d,J=1.2Hz), 2.82(2H,m), 3.43(2H,m), 3.55(3H,s), 3.67(2H,m), 4.55(2H,s), 4.69(2H,t,J=4.4Hz), 6.67(1H,d,J=1.2Hz), 6.97(2H,d,J=8.8Hz), 7.56(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.81(2H,d,J=8.8Hz), 12.64(1H,brs).
【0227】
Example 162
3-methyl-2-[4-[4-(2-piperidinoethoxy)benzoyl]benzylthio]-thieno[3,2-d]pyrimidin-4(3H)-one
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (408 mg), 1-(2-chloroethyl)piperidine hydrochloride (202 mg), and potassium carbonate (414 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 15 hours. After concentrating the reaction mixture, the residue was dissolved in ethyl acetate, washed with water, and dried. After adding a solution of hydrochloric acid and ethyl acetate, the hydrochloride salt was precipitated, collected by filtration, and dried to give the title compound (471 mg) as a colorless solid.
IR(KBr)ν: 1680, 1635, 1600, 1535, 1505, 1300, 1280, 1250 cm^-1.
NMR (CDCl₃)δ: 1.35-2.00(6H,m), 2.15-2.40(2H,m), 2.81(2H,m), 3.42(2H,m), 3.62(3H,s), 3.67(2H,m), 4.58(2H,s), 4.69(2H,t,J=4.4Hz), 6.97(2H,d,J=8.8Hz), 7.24(1H,d,J=5.2Hz), 7.58(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.75(1H,d,J=5.2Hz), 7.81(2H,d,J=8.8Hz), 12.65(1H,brs).
【0228】
Example 163
1-[4-(4-chlorobenzoyl)benzyl]-6,7-dimethylimidazo[1,2-a]pyrimidin-5(1H)-one
To a solution of 6,7-dimethylimidazo[1,2-a]pyrimidin-5-one (1.10 g, 6.75 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (1.60 g, 5.20 mmol) in DMSO (20.0 ml), potassium carbonate (1.16 g, 8.39 mmol) was added and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then extracted with MgSO₄The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give a colorless amorphous solid, which was then recrystallized from ethyl acetate to give colorless needles (1.16 g, 57%).
IR(KBr)ν: 1655, 1583, 1522, 1279, 1223, 1090, 926, 733 cm^-1.
NMR (CDCl₃)δ: 2.15(3H,s), 2.41(3H,s), 5.33(2H,s), 6.86(1H,d,J=2.8Hz), 7.48-7.41(4H,m), 7.54(1H,d,J=2.8Hz), 7.72(2H,d,J=7.8Hz), 7.77(2H,d,J=7.8Hz).
【0229】
Example 164
1-[4-(2,4-dichlorobenzoyl)benzyl]-6,7-dimethylimidazo[1,2-a]pyrimidin-5(1H)-one
To a solution of 6,7-dimethylimidazo[1,2-a]pyrimidin-5-one (0.401 g, 2.46 mmol) and 4-(2,4-dichlorobenzoyl)benzyl bromide (0.86 g, 2.50 mmol) in DMSO (10.0 mL), potassium carbonate (0.376 g, 2.72 mmol) was added and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then extracted with MgSO₄The residue was recrystallized from methanol to obtain colorless needles (0.578 g, 55%).
IR(KBr)ν: 1659, 1581, 1521, 1284, 1223, 930, 733 cm^-1.
NMR (CDCl₃)δ: 2.14(3H,s), 2.88(3H,s), 5.32(2H,s), 6.83(1H,d,J=2.8Hz), 7.32-7.39(4H,m), 7.48-7.54(2H,m), 7.78(2H,d,J=8.4Hz).
【0230】
Example 165
1-[3-(4-chlorobenzoyl)benzyl]-6,7-dimethylimidazo[1,2-a]pyrimidin-5(1H)-one
To a solution of 6,7-dimethylimidazo[1,2-a]pyrimidin-5-one (0.402 g, 2.47 mmol) and 3-(4-chlorobenzoyl)benzyl bromide (0.76 g, 2.45 mmol) in DMSO (10.0 ml), potassium carbonate (0.360 g, 2.60 mmol) was added and stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was washed with saturated brine. The organic layer was then extracted with MgSO₄The residue was recrystallized from ethyl acetate to obtain colorless needles (0.373 g, 39%).
IR(KBr)ν: 1657, 1583, 1522, 1281, 1221, 727 cm^-1.
NMR (CDCl₃)δ: 2.15(3H,s), 2.38(3H,s), 5.31(2H,s), 6.85(1H,d,J=2.6Hz), 7.43-7.55(4H,m), 7.69-7.79(4H,m).
【0231】
Example 166
7-[4-(4-chlorobenzoyl)benzyl〕-1,3-diethylxanthine
Journal of the American Chemical Society (J. Am. Chem. Soc.,75To a solution of 1,3-diethylxanthine (190 mg) in dimethylformamide (5 mL), the synthesis of which is described in [J. Chem. Soc., 114 (1953)], potassium carbonate (189 mg) and 4-(4-chlorobenzoyl)benzyl bromide (282 mg) were added and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and further recrystallized (ether-hexane) to give the title compound (217 mg, 54%) as a colorless powder.
IR(KBr)：1700, 1660, 1650, 1455, 1270cm^-1.
¹H-NMR (CDCl₃)δ: 1,25(3H,t,J=7.0Hz), 1.36(3H,t,J=7.0Hz), 4.07(2H,q,J=7.0Hz), 4.18(2H,q,J=7.0Hz), 5.59(1H,s), 7.41-7.52(4H,m), 7.63(1H,s), 7.69-7.83(4H,m).
【0232】
Example 167
6-chloro-2-[4-(4-chlorobenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone
To a solution of 6-chloro-3-methyl-2-mercaptoquinazolin-4-one (0.500 g, 2.21 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide solution (2.50 mL) was added, followed by 4-(4-chlorobenzoyl)benzyl bromide (0.261 g, 0.843 mmol) and stirring at room temperature overnight. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then purified by evaporation with MgSO₄The residue was recrystallized from ethyl acetate-methanol to give colorless needles (0.230 g, 68%).
IR(KBr)ν: 1741, 1672, 1549, 1470, 1410, 1308, 1297, 1082, 930, 832, 733cm^-1.
NMR (CDCl₃)δ: 3.60(3H,s), 4.59(2H,s), 7.45(2H,d,J=8.4Hz), 7.53(1H,d,J=8.6Hz), 7.59(2H,d,J=8.4Hz), 7.63(1H,dd,J=8.6,2.2Hz), 7.75(2H,d,J=8.4Hz), 8.19(1H,d,J=2.2Hz).
【0233】
Example 168
2-[4-(4-chlorobenzoyl)benzyl]thio-3,6-dimethyl-4(3H)-quinazolinone
To a solution of 3,6-dimethyl-2-mercaptoquinazolin-4-one (0.160 g, 0.776 mmol) in EtOH (5.0 mL) and THF (5.0 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added, followed by 4-(4-chlorobenzoyl)benzyl bromide (0.261 g, 0.843 mmol) and stirring at room temperature for 2 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then purified by evaporation of MgSO₄The residue was recrystallized from ethyl acetate to obtain colorless needles (0.230 g, 68%).
IR(KBr)ν: 1678, 1549, 1489, 1406, 1311, 1286, 1136, 1072, 928, 829, 771, 730, 629, 534, 470 cm^-1.
NMR (CDCl₃)δ: 2.47(3H,s), 3.60(3H,s), 4.60(2H,s), 7.43-7.52(4H,m), 7.60-7.63(2H,m), 7.72-7.77(4H,m), 8.03(1H,bs).
【0234】
Example 169
1-[4-(4-chlorobenzoyl)benzyl]-6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one
Potassium carbonate (0.600 g, 4.3 mmol) was added to a solution of 6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5-one (0.710 g, 4.00 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (1.12 g, 3.6 mmol) in DMF (15.0 ml), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: methylene chloride:acetone = 5:1). The resulting colorless solid was recrystallized from ethyl acetate-hexane to obtain needles. 0.243 g (16%)
IR(KBr)ν: 2968, 1659, 1585, 1522, 1417, 1367, 1279, 1213, 1173, 1088, 928, 689 cm^-1.
NMR (CDCl₃)δ: 1.45(3H,t,J=7.4Hz), 2.43(3H,s), 2.66(2H,q,J=7.4Hz), 5.33(2H,s), 6.85(1H,d,J=2.7Hz), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.54(1H,d,J=2.7Hz), 7.75(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【0235】
Example 170
4,4'-bis[[3,5-dimethyl-4(3H)-quinazolinon-2-yl]thiomethyl]benzophenone
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (1.98 g, 9.60 mmol) in EtOH (15.0 ml) and THF (15.0 ml) was added 1N aqueous sodium hydroxide (10.0 ml), followed by the addition of a solution of 4,4'-bis(bromomethyl)benzophenone (3.50 g) in THF (20 ml) over 1 hour. The mixture was stirred at room temperature for 20 minutes. The solvent was removed, and ethyl acetate was added to the residue. The precipitated colorless solid was collected by filtration. The crystals were washed with water and ethanol and then dried under reduced pressure to obtain a colorless solid. 1.10 g (40%)
IR(KBr)ν: 1670, 1554, 1462, 1415, 1306, 1277, 1090, 930, 808, 694 cm^-1.
NMR (CDCl₃)δ: 2.58(6H,s), 3.54(6H,s), 4.58(4H,s), 7.15(2H,d,J=7.2Hz), 7.44(2H,d,J=7.2Hz), 7.54(2H,t,J=7.2Hz), 7.59(4H,d,J=8.4Hz), 7.75(4H,d,J=8.4Hz).
【0236】
Example 171
2-[4-[4-(dimethylaminomethyl)benzoyl]benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone hydrochloride
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (1.98 g, 9.60 mmol) in EtOH (15.0 ml) and THF (15.0 ml) was added 1N aqueous sodium hydroxide (10.0 ml), followed by a THF (20 ml) solution of 4,4'-bis(bromomethyl)benzophenone (3.50 g) over 1 hour. After stirring at room temperature for 20 minutes, 50% aqueous dimethylamine was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed, and ethyl acetate was added to the residue. The precipitated colorless solid was filtered off. Hydrochloric acid was added to the filtrate, and the precipitated colorless solid was collected by filtration. This solid was washed with water and ethanol and then dried under reduced pressure. 0.789 g (17%)
IR(KBr)ν: 3413, 2931, 2551, 2470, 1695, 1554, 1466, 1416, 1306, 1279, 1089, 927, 864, 804, 773, 696 cm^-1.
NMR (CDCl₃)δ: 2.82(6H,d,J=4.8Hz), 2.84(3H,s), 3.60(3H,s), 4.26(2H,d,J=5.4Hz), 4.91(2H,s), 7.22(1H,d,J=7.4Hz), 7.59(1H,d,J=8.0Hz), 7.64(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz), 7.81(1H,dd,J=8.0,7.4Hz), 7.82(2H,d,J=8.1Hz), 7.86(2H,d,J=8.1Hz).
【0237】
Example 172
2-[4-(4-chlorobenzoyl)benzyloxy]-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
Potassium carbonate (0.31 g, 2.24 mmol) was added to a solution of 3,7-dimethylpyrido[1,2-a]pyrimidine-2,4-dione (0.308 g, 1.62 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (0.511 g, 1.65 mmol) in a DMF (10.0 mL)-DMSO (10.0 mL) mixture and stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles. Yield: 0.246 (36%)
IR(KBr)ν: 1726, 1657, 1604, 1554, 1464, 1409, 1308, 1279, 1184, 1089, 931, 864, 789, 694 cm^-1.
NMR (CDCl₃)δ: 2.23(3H,s), 2.42(3H,s), 5.61(2H,s), 7.42(1H,d,J=8.8Hz), 7.47(2H,d,J=7.3Hz), 7.54-7.61(3H,m), 7.76(2H,d,J=7.3Hz), 7.80(2H,d,J=7.3Hz), 8.88(1H,s).
【0238】
Example 173
2-[4-(4-chlorobenzoyl)benzyl]thio-6-hydroxy-3-methyl-4(3H)-quinazolinone
To a solution of 6-hydroxy-3-methyl-2-mercaptoquinazolin-4-one (0.518 g, 2.49 mmol) in EtOH (5.0 mL) and THF (5.0 mL) was added 1N aqueous sodium hydroxide solution (2.50 mL), followed by the addition of 4-(4-chlorobenzoyl)benzyl bromide (0.261 g, 0.843 mmol) and stirring at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water and ethanol, and dried under reduced pressure to obtain a pale yellow solid. 0.88 g (81%)
IR(KBr)ν: 3383, 1663, 1560, 1495, 1408, 1363, 1309, 1282, 1234, 1089, 1064, 930, 833 cm^-1.
NMR (CDCl₃)δ: 3.48(3H,s), 4.62(2H,s), 7.24(1H,dd,J=8.8,2.8Hz), 7.37(1H,d,J=2.8Hz), 7.52(1H,d,J=8.8Hz), 7.60(2H,d,J=8.6Hz), 7.71(4H,s), 7.74(2H,d,J=8.6Hz).
【0239】
Example 174
2-[4-(4-chlorobenzoyl)benzyl]thio-6-methoxy-3-methyl-4(3H)-quinazolinone
To a solution of 2-[4-(4-chlorobenzoyl)benzyl]thio-6-hydroxy-3-methyl-4(3H)-quinazolinone (0.306 g, 0.700 mmol) in DMF (5.0 mL), potassium carbonate (0.25 g, 1.45 mmol) and methyl iodide (0.100 mL, 1.61 mmol) were added and stirred at room temperature for 3 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was filtered and purified by evaporation with MgSO₄The residue was recrystallized from ethyl acetate-methanol to give colorless needles, 0.202 g (64%).
IR(KBr)ν: 1672, 1643, 1578, 1535, 1481, 1392, 1282, 1165, 1088, 928, 830 cm^-1.
NMR (CDCl₃)δ: 3.61(3H,s), 3.91(3H,s), 4.59(2H,s), 7.31(1H,dd,J=8.8,2.8Hz), 7.44(1H,d,J=8.5Hz), 7.53(1H,d,J=8.8Hz), 7.59(1H,d,J=2.8Hz), 7.60(2H,d,J=8.5Hz), 7.33(2H,d,J=8.5Hz), 7.74(2H,d,J=8.5Hz).
【0240】
Example 175
2-[4-(4-chlorobenzoyl)benzyl]thio-6-isopropoxy-3-methyl-4(3H)-quinazolinone
To a solution of 2-[4-(4-chlorobenzoyl)benzyl]thio-6-hydroxy-3-methyl-4(3H)-quinazolinone (0.300 g, 0.687 mmol) in DMF (5.0 ml), potassium carbonate (0.200 g, 1.45 mmol) and isopropyl iodide (0.200 ml, 2.00 mmol) were added and stirred at 50°C for 1 hour. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate-methanol to give colorless needles (0.232 g, 71%).
IR(KBr)ν: 1674, 1581, 1557, 1485, 1365, 1313, 1281, 1226, 1112, 1066, 928, 833 cm^-1.
NMR (CDCl₃)δ: 1.38(6H,d,J=6.0Hz), 3.60(3H,s), 4.59(2H,s), 4.69(1H,m), 7.27(1H,dd,J=9.0,3.0Hz), 7.43-7.50(3H,m), 7.55-7.62(3H,m), 7.73(2H,d,J=8.0Hz), 7.74(2H,d,J=8.0Hz).
【0241】
Example 176
6-hydroxy-2-[4-(4-methoxybenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone
To a solution of 6-hydroxy-3-methyl-2-mercaptoquinazolin-4-one (1.52 g, 7.30 mmol) in EtOH (15.0 ml) and THF (15.0 ml) was added 1N aqueous sodium hydroxide solution (7.50 ml), followed by 4-(4-methoxybenzoyl)benzyl bromide (2.30 g, 7.50 mmol) and stirring at room temperature for 4 hours. The precipitated crystals were collected by filtration, washed with water and ethanol, and dried under reduced pressure to obtain a pale yellow solid. 1.830 g (58%)
IR(KBr)ν: 3400, 1660, 1603, 1556, 1496, 1464, 1416, 1362, 1311, 1254, 1176, 1147, 1066, 1030, 930, 839, 775 cm^-1.
NMR (CDCl₃)δ: 3.61(3H,s), 3.88(3H,s), 4.58(2H,s), 6.95(2H,d,J=9.0Hz), 7.29(1H,dd,J=8.9,2.8Hz), 7.54(1H,d,J=8.9Hz), 7.58(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.78(1H,d,J=2.8Hz), 7.81(2H,d,J=9.0Hz).
【0242】
Example 177
2-[4-(4-methoxybenzoyl)benzyl]thio-6-methoxy-3-methyl-4(3H)-quinazolinone
To a solution of 6-hydroxy-2-[4-(4-methoxybenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone (0.400 g, 0.925 mmol) in DMF (10.0 mL), potassium carbonate (0.260 g, 1.88 mmol) and methyl iodide (0.200 mL, 3.21 mmol) were added and stirred at room temperature for 2 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then diluted with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.338 g, 82%).
IR(KBr)ν: 2931, 1682, 1649, 1606, 1551, 1489, 1412, 1360, 1319, 1266, 1173, 1066, 1022, 931, 833, 779, 750 cm^-1.
NMR (CDCl₃)δ: 3.61(3H,s), 3.88(3H,s), 3.91(3H,s), 4.59(2H,s), 6.95(2H,d,J=8.8Hz), 7.31(1H,dd,J=8.8,3.2Hz), 7.54(1H,d,J=8.8Hz), 7.58(2H,d,J=8.0Hz), 7.59(1H,d,J=3.2Hz), 7.73(2H,d,J=8.0Hz), 7.81(2H,d,J=8.8Hz).
【0243】
Example 178
6-Isopropoxy-2-[4-(4-methoxybenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone
To a solution of 6-hydroxy-2-[4-(4-methoxybenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone (0.400 g, 0.925 mmol) in DMF (10.0 mL), potassium carbonate (0.260 g, 1.88 mmol) and isopropyl iodide (0.300 mL, 3.00 mmol) were added and the mixture was stirred at 50°C for 8 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.348 g, 79%).
IR(KBr)ν: 1673, 1674, 1605, 1554, 1487, 1311, 1254, 1174, 145, 1113, 1086, 841 cm^-1.
NMR (CDCl₃)δ: 1.37(6H,d,J=6.4Hz), 3.60(3H,s), 3.88(3H,s), 4.59(2H,s), 6.59(2H,d,J=9.0Hz), 7.27(1H,dd,J=7.8,3.0Hz), 7.53(1H,d,J=7.8Hz), 7.58(2H,d,J=8.1Hz), 7.59(1H,d,J=3.0Hz), 7.72(2H,d,J=8.1Hz), 7.80(2H,d,J=9.0Hz).
【0244】
Example 179
2-[4-(4-methoxybenzoyl)benzyl]thio-3,8-dimethyl-4(3H)-quinazolinone
To a solution of 3,8-dimethyl-2-mercaptoquinazolin-4-one (0.503 g, 2.44 mmol) in a mixture of EtOH (5.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.80 mL) was added, followed by 4-(4-methoxybenzoyl)benzyl bromide (0.744 g, 2.44 mmol) and stirring at room temperature overnight. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.696 g, 66%).
IR(KBr)ν:1682, 1585, 1558, 1458, 1404, 1327, 1275, 1084, 930, 764 cm^-1.
NMR (CDCl₃)δ: 2.60(3H,s), 3.62(3H,s), 3.89(3H,s), 4.65(2H,s), 6.96(2H,d,J=8.8Hz), 7.28(1H,t,J=8.0Hz), 7.56(1H,d,J=8.0Hz), 7.59(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.82(2H,d,J=8.8Hz), 8.09(1H,d,J=8.0Hz).
【0245】
Example 180
2-[4-(4-chlorobenzoyl)benzyl]thio-3,8-dimethyl-4(3H)-quinazolinone
To a solution of 3,8-dimethyl-2-mercaptoquinazolin-4-one (0.504 g, 2.44 mmol) in EtOH (5.0 mL) and THF (10.0 mL) was added 1N aqueous sodium hydroxide solution (2.80 mL), followed by 4-(4-chlorobenzoyl)benzyl bromide (0.763 g, 2.46 mmol) and stirring at room temperature overnight. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from ethyl acetate to give colorless needles (0.768 g, 72%).
IR(KBr)ν: 1682, 1663, 1585, 1458, 1404, 1327, 1275, 1084, 930, 764 cm^-1.
NMR (CDCl₃)δ: 2.59(3H,s), 3.62(3H,s), 4.66(2H,s), 7.29(1H,t,J=7.6Hz), 7.45(2H,d,J=8.4Hz), 7.56(1H,d,J=7.6Hz), 7.61(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.75(2H,d,J=8.4Hz), 8.08(1H,d,J=7.6Hz).
【0246】
Example 181
1-[4-(4-chlorobenzoyl)benzyl]-6-isopropyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one
Potassium carbonate (0.600 g, 4.50 mmol) was added to a solution of 6-isopropyl-7-methylimidazo[1,2-a]pyrimidin-5-one (0.400 g, 2.23 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (0.762 g, 2.46 mmol) in DMF (15.0 mL) and stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:acetone = 20:1) to obtain a colorless amorphous product. 0.48 g (51%)
IR(KBr)ν: 1659, 1585, 1512, 1408, 1367, 1279, 1088, 928, 735, 692 cm^-1.
NMR (CDCl₃)δ: 1.39(6H,d,J=7.0Hz), 2.45(3H,s), 3.17(1H,m), 5.31(2H,s), 6.83(1H,d,J=2.6Hz), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.53(1H,d,J=2.6Hz), 7.73(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【0247】
Example 182
2-[4-(4-chlorobenzoyl)benzyl]thio-5-methoxycarbonyl-3-methyl-4(3H)-quinazolinone
To a solution of 5-carboxy-3-methyl-2-mercaptoquinazolin-4-one (0.520 g, 2.20 mmol) in EtOH (10.0 mL) and THF (10.0 mL) was added 1N aqueous sodium hydroxide (4.40 mL), followed by the addition of 4-(4-chlorobenzoyl)benzyl bromide (0.638 g, 2.21 mmol) and stirring at room temperature for 1 hour. Hydrochloric acid was added to the reaction solution to make it acidic, and the precipitated solid was collected by filtration and washed with water. This solid was dissolved in DMF (20 mL) and water (5.0 mL), and cesium carbonate (1.40 g, 4.30 mmol) and methyl iodide (1.00 mL) were added, followed by stirring at room temperature overnight. After removing the solvent, ethyl acetate was added to the residue and washed with saturated brine. The organic layer was then washed with MgSO₄The residue was purified with a silica gel column (methylene chloride) and then recrystallized from ethyl acetate-ethanol to give colorless needles.
IR(KBr)ν: 1734, 1674, 1593, 1554, 1441, 1408, 1323, 1282, 1203, 1082, 926, 818, 762 cm^-1.
NMR (CDCl₃)δ: 3.58(3H,s), 4.01(3H,s), 4.61(2H,s), 7.34(1H,dd,J=6.6,1.8Hz), 7.46(2H,d,J=8.6Hz), 7.60(2H,d,J=8.2Hz), 7.68-7.77(6H,m).
【0248】
Example 183
2-[4-(4-methoxycarbonylbenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (5.00 g, 24.2 mmol) in EtOH (100.0 mL) and THF (100.0 mL) was added 1N aqueous sodium hydroxide solution (25.0 mL), followed by the addition of 4-(4-methoxycarbonylbenzoyl)benzyl bromide (8.06 g, 24.2 mmol) and stirring overnight at room temperature. The precipitated colorless solid was collected by filtration, washed with water, and dried under reduced pressure. This was recrystallized from ethyl acetate to yield colorless needles. 10.89 g (98%)
IR(KBr)ν: 1722, 1658, 1554, 1431, 1275, 1093, 1020, 966, 928, 962, 715cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 3.95(3H,s), 4.60(2H,s), 7.15(1H,d,J=7.4Hz), 7.43(1H,d,J=7.4Hz), 7.62(2H,d,J=8.5Hz), 7.77(2H,d,J=8.6Hz), 7.79(1H,t,J=7.4Hz), 7.82(2H,d,J=8.5Hz), 8.14(2H,d,J=8.6Hz).
【0249】
Example 184
3,5-dimethyl-2-[4-(4-(4-methylpiperazinocarbonyl)benzoyl)benzyl]thio-4(3H)-quinazolinone
DEPC (0.37 g, 2.27 mmol) and 1-methylpiperazine (0.200 ml, 1.80 mmol) were added to a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone (0.320 g, 0.720 mmol) in DMF (5.0 ml) and stirred overnight at room temperature. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then filtered with MgSO₄The mixture was dried over hexane and then concentrated under reduced pressure. The residue was purified using a silica gel column (methylene chloride:methanol:ammonia=20:1:0.1). The resulting solid was recrystallized from ethanol to give colorless needles. 0.201 g (18%)
IR(KBr)ν: 1674, 1628, 1552, 1462, 1433, 1299, 1276, 1144, 1092, 931 cm^-1.
NMR (CDCl₃)δ: 2.33(3H,s), 3.55(3H,s), 2.36(2H,m), 2.60(2H,m), 2.85(3H,s), 3.41(2H,m), 3.55(3H,s), 3.82(2H,m), 4.59(2H,s), 7.15(1H,d,J=6.6Hz), 7.40(1H,d,J=6.6Hz), 7.50(2H,d,J=8.0Hz), 7.51(1H,t,J=6.6Hz), 7.61(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz).
【0250】
Example 185
2-[4-(2-chlorobenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (0.513 g, 2.49 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.70 mL) was added, followed by 4-(2-chlorobenzoyl)benzyl bromide (0.800 g, 2.58 mmol) and stirring at room temperature overnight. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then filtered with MgSO₄The residue was recrystallized from methanol to give colorless needles, 0.704 g (65%).
IR(KBr)ν: 1678, 1659, 1599, 1552, 1286, 1240, 1089, 926, 860, 769, 692cm^-1.
NMR (CDCl₃)δ: 2.84(3H,s), 3.53(3H,s), 4.57(2H,s), 7.14(1H,d,J=7.0Hz), 7.26-7.46(5H,m), 7.49(1H,t,J=7.0Hz), 7.58(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz).
【0251】
Example 186
3,5-dimethyl-2-[4-(4-nitrobenzoyl)benzyl]thio-4(3H)-quinazolinone
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (2.03 g, 9.74 mmol) in a mixture of EtOH (30.0 mL) and THF (30.0 mL), 1N aqueous sodium hydroxide (10.0 mL) was added, followed by 4-(4-nitrobenzoyl)benzyl bromide (3.50 g, 10.9 mmol) and stirring at room temperature overnight. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then purified by evaporation with MgSO₄The residue was recrystallized from methanol to give pale yellow needles (0.307 g, 70%).
IR(KBr)ν: 1678, 1660, 1558, 1522, 1414, 1346, 1307, 1277, 1249, 1088, 929, 858, 810, 708 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.15(1H,d,J=7.4Hz), 7.43(1H,d,J=7.4Hz), 7.54(1H,t,J=7.4Hz), 7.64(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 7.91(2H,d,J=8.4Hz), 8.33(2H,d,J=8.4Hz).
【0252】
Example 187
7-[4-(4-chlorobenzoyl)benzyl〕1-ethyl-3,8-dimethylxanthine
Journal of the American Chemical Society (J. Am. Chem. Soc.,75To a solution of 1-ethyl-3,8-dimethylxanthine (170 mg) in dimethylformamide (8 mL), the synthesis of which is described in [J. Chem. Soc., 114 (1953)], potassium carbonate (169 mg) and 4-(4-chlorobenzoyl)benzyl bromide (278 mg) were added and stirred at room temperature for 20 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized (ethyl acetate-hexane) to give the title compound (87 mg, 24%) as a colorless powder.
IR(KBr)：1700, 1660, 1610, 1400, 1280, 1270cm^-1.
¹H-NMR (CDCl₃)δ: 1.25(3H,t,J=7.0Hz), 2.45(3H,s), 3.59(3H,s), 4.08(2H,q,J=7.0Hz), 5.63(2H,s), 7.25-7.81(8H,m).
【0253】
Example 188
2-[4-(4-aminobenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone
Iron (2.00 g) was added to a solution of 3,5-dimethyl-2-[4-(4-nitrobenzoyl)benzyl]thio-4(3H)-quinazolinone (1.00 g, 2.24 mmol) in acetic acid (30.0 ml) and THF (15.0 ml) and stirred overnight at room temperature. After removing the solvent, 1N sodium hydroxide (20 ml) was added to the residue and extracted with chloroform. The organic layer was then washed with MgSO₄The residue was crystallized from ethyl acetate to give a pale yellow solid, 0.380 g (41%).
IR(KBr)ν: 352, 1650, 1583, 1552, 1469, 1430, 1311, 1282, 1172, 1147, 1089, 928, 844 cm^-1.
NMR (DMSO-d₆)δ: 2.76(3H,s), 3.46(3H,s), 4.63(2H,s), 6.12(2H,s), 6.59(2H,d,J=8.8Hz), 7.20(1H,d,J=7.4Hz), 7.44-7.67(8H,m).
【0254】
Example 189
1-[4-(4-chlorobenzoyl)benzyl]-6,7,8,9-tetrahydroimidazo[2,1-b]quinazolin-5(1H)-one
Potassium carbonate (0.250 g, 1.81 mmol) was added to a solution of 6,7,8,9-tetrahydroimidazo[2,1-b]quinazolin-5(1H)-one (0.235 g, 1.24 mmol) and 4-(4-chlorobenzoyl)-benzyl bromide (0.410 g, 1.32 mmol) in DMF (15.0 mL) and DMSO (5 mL) and stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (methylene chloride:methanol = 20:1) to obtain a colorless amorphous solid. 0.085 g (16%)
IR(KBr)ν: 2933, 1659, 1585, 1528, 1419, 1306, 1277, 1209, 1170, 1088, 928, 733 cm^-1.
NMR (CDCl₃)δ: 1.82(4H,m), 2.64(2H,t,J=5.4Hz), 2.73(2H,t,J=5.4Hz), 5.32(2H,s), 6.84(1H,d,J=2.6Hz), 7.40(2H,d,J=8.1Hz), 7.46(2H,d,J=8.1Hz), 7.54(1H,d,J=2.6Hz), 7.73(2H,d,J=8.1Hz), 7.77(2H,d,J=8.1Hz).
【0255】
Example 190
1-[4-(4-chlorobenzoyl)benzyl]-1,6,7,8-tetrahydro-5H-cyclopenta[d〕stomachMidazo[1,2-a]pyrimidin-5-one
1,6,7,8-tetrahydro-5H-cyclopenta[d〕stomachPotassium carbonate (0.300 g, 2.17 mmol) was added to a solution of midazo[1,2-a]pyrimidin-5-one (0.345 g, 1.967 mmol) and 4-(4-chlorobenzoyl)-benzyl bromide (0.0650 g, 2.10 mmol) in DMF (15.0 mL) and DMSO (5 mL) and stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (methylene chloride:methanol = 20:1) to obtain a colorless amorphous solid (0.260 g, 33%).
IR(Neat)ν: 2954, 1675, 1660, 1579, 1522, 1417, 1279, 1240, 1173, 1089, 928, 849, 733 cm^-1.
NMR (CDCl₃)δ: 2.13(2H,quint,J=7.2Hz), 2.89(4H,t,J=7.2Hz), 5.36(2H,s), 6.89(1H,d,J=2.6Hz), 7.39(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.61(1H,d,J=2.6Hz), 7.73(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
【0256】
Example 191
3,5-dimethyl-2-[4-(4-(t-butoxycarbonylmethyl)carbamoylbenzoyl)benzyl]thio-4(3H)-quinazolinone
DEPC (0.364 g, 2.23 mmol) and triethylamine (0.60 ml) were added to a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)quinazolinone (0.495 g, 1.11 mmol) and glycine t-butyl ester hydrochloride (0.236 g, 1.41 mmol) in DMF (10.0 ml), and the mixture was stirred at room temperature for 3.5 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then evaporated under reduced pressure.₄The residue was recrystallized from ethyl acetate to obtain colorless needles (0.351 g, 55%).
IR(KBr)ν: 3259, 2978, 1741, 1673, 1658, 1605, 1554, 1371, 1306, 1230, 1157, 1092, 931, 869, 808, 754 cm^-1.
NMR (CDCl₃)δ: 1.52(9H,s), 2.85(3H,s), 3.55(3H,s), 4.17(2H,d,J=5.0Hz), 4.60(2H,s), 6.75(1H,t,J=5.0Hz), 7.15(1H,d,J=7.2Hz), 7.44(1H,d,J=7.2Hz), 7.55(1H,t,J=7.2Hz), 7.62(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 7.83(2H,d,J=8.6Hz), 7.92(2H,d,J=8.6Hz).
【0257】
Example 192
3,5-dimethyl-2-[4-(4-(N-methoxycarbonylmethyl-N-methylcarbamoyl)benzoyl)benzyl]thio-4(3H)-quinazolinone
DEPC (0.374 g, 2.29 mmol) and triethylamine (0.60 ml) were added to a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)quinazolinone (0.500 g, 1.12 mmol) and N-methylglycine methyl ester hydrochloride (0.199 g, 1.43 mmol) in DMF (10.0 ml), and the mixture was stirred at room temperature for 3 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then purified by evaporation of MgSO₄The residue was purified with a silica gel column (hexane:ethyl acetate=1:3) and then crystallized from ethanol to give a colorless solid (0.250 g, 38%).
IR(KBr)ν: 2935, 1668, 1597, 1554, 1462, 1412, 1315, 1259, 1171, 1080, 1020, 930, 841, 769 cm^-1.
NMR (CDCl₃)δ: 2.84(3H,s), 3.05(2/3×3H,s), 3.15(1/3×3H,s), 3.55(3H,s), 3.74(1/3×3H,s), 3.81(2/3×3H,s), 3.99(1/3×2H,s), 4.31(2/3×2H,s), 4.59(2H,s), 7.15(1H,d,J=7.6Hz), 7.40-7.66(6H,m), 7.67(2H,d,J=8.6Hz), 7.82(2H,d,J=8.4Hz).
【0258】
Example 193
3,5-dimethyl-2-[4-(4-(4-piperidinopiperidinocarbonyl)benzoyl)benzyl]thio-4(3H)-quinazolinone
DEPC (0.370 g, 2.27 mmol) was added to a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)quinazolinone (0.495 g, 1.11 mmol) in DMF (10.0 mL) and stirred at room temperature for 1 hour. 4-Piperidinopiperidine (0.277 g, 1.65 mmol) was then added and stirred overnight. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then extracted with MgSO₄The residue was purified with a silica gel column (isopropyl ether:methylene chloride:methanol:ammonia=5:5:1:0.1) to give a colorless amorphous substance (0.270 g, 40%).
IR(KBr)ν: 2931, 1664, 1631, 1608, 1554, 1508, 1448, 1306, 1277, 1092, 1016, 931, 864 cm^-1.
NMR (CDCl₃)δ: 1.40-2.56(15H,m), 2.75-2.80(1H,m), 2.85(3H,s), 2.90-3.10(1H,m), 3.55(3H,s), 3.70-3.85(1H,m), 4.59(2H,s), 7.45-4.82(1H,m), 7.15(1H,d,J=7.8Hz), 7.46(1H,t,J=7.8Hz), 7.48(2H,d,J=8.0Hz), 7.49(1H,d,J=7.8Hz), 7.61(2H,d,J=8.0Hz), 7.65(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz).
【0259】
Example 194
1-[4-(6-chloronicotinoyl)benzyl]-6,7-dimethylimidazo[1,2-a]pyrimidin-5(1H)-one hydrochloride
6,7-dimethylimidazo[1,2-a]pyrimidin-5-one (0.900 g, 5.5 mmol) and 4-(6-chloroNicotinoyl)Potassium carbonate (2.10 g, 15.20 mmol) was added to a solution of benzyl bromide (1.92 g, 3.6 mmol) in a DMF (20.0 mL)-DMSO (10.0 mL) mixture and stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain a pale yellow oil. 4N hydrochloric acid-ethyl acetate was added to this ethyl acetate solution, and the precipitated crystals were collected by filtration and dried under reduced pressure. 1.45 g (70%)
IR(KBr)ν: 2366, 1680, 1659, 1578, 1365, 1281, 1099, 926 cm^-1.
NMR (DMSO-d₆)δ: 2.02(3H,s), 2.39(3H,s), 5.59(2H,s), 7.41(1H,t,J=8.4Hz), 7.56(2H,d,J=8.0Hz), 7.67-7.73(2H,m), 7.79(2H,d,J=8.0Hz), 8.16(1H,dd,J=8.4,2.6Hz), 8.69(1H,d,J=2.6Hz).
【0260】
Example 195
3,5-dimethyl-2-[4-(4-bis(t-butoxycarbonylmethyl)carbamoyl)benzoyl)benzyl]thio-4(3H)-quinazolinone
60% sodium hydride (0.040 g, 1.00 mmol) and t-butyl bromoacetate (0.210 g, 1.08 mmol) were added to a solution of 3,5-dimethyl-2-[4-(4-(t-butoxycarbonylmethyl)carbamoylbenzoyl)benzyl]thio-4(3H)quinazolinone (0.511 g, 0.894 mmol) in DMF (15.0 mL), and the mixture was stirred at room temperature overnight. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then purified by evaporation of MgSO₄The residue was purified with a silica gel column (hexane:ethyl acetate=2:1) to obtain a colorless amorphous product (0.270 g, 40%).
IR(KBr)ν: 1741, 1662, 1556, 1153 cm^-1.
NMR (CDCl₃)δ: 1.44(9H,s), 1.51(9H,s), 2.85(3H,s), 3.55(3H,s), 3.94(2H,s), 4.22(2H,s), 4.59(2H,s), 7.15(1H,d,J=7.0Hz), 7.43(1H,d,J=8.6Hz), 7.48-7.66(5H,m), 7.77(2H,d,J=8.6Hz), 7.79(2H,d,J=8.0Hz).
【0261】
Example 196
2-[4-(6-chloronicotinoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
3-Methylpyrido[1,2-a]pyrimidine-2,4-dione (1.520 g, 8.62 mmol) and 4-(6-chloroNicotinoyl)Potassium carbonate (3.50 g, 25.3 mmol) was added to a solution of benzyl bromide (3.00 g, 9.66 mmol) in a DMF (25.0 mL)-DMSO (10.0 mL) mixture and stirred overnight at room temperature. Water was added to the reaction mixture, and the precipitated crystals were washed with ethanol and then dried under reduced pressure to obtain a pale yellow solid (2.44 g, 70%).
IR(KBr)ν: 1670, 1576, 1477, 1280, 1165, 1103, 924, 764 cm^-1.
NMR (CDCl₃)δ: 2.28(3H,s), 5.63(2H,s), 7.12(1H,t,J=7.5Hz), 7.49(2H,d,J=8.4Hz), 7.62(2H,d,J=8.4Hz), 7.71(1H,t,J=8.4Hz), 7.82(2H,d,J=8.4Hz), 8.00(1H,dd,J=8.4,2.4Hz), 8.77(1H,d,J=2.4Hz), 9.08(1H,d,J=7.5Hz).
【0262】
Example 197
3-methyl-2-[4-[6-(4-piperidinopiperidino)nicotinoyl]benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
A solution of 2-[4-(6-chloronicotinoyl)benzyloxy]-3-methyl-pyrido[1,2-a]pyrimidin-4-one (0.49 g, 1.21 mmol) and 4-piperidinopiperidine (0.402 g, 2.39 mmol) in pyridine (15 ml) was stirred at 90°C overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (isopropyl ether: methylene chloride: methanol: ammonia = 5:5:1:0.1) to give a pale yellow oil. 0.38 g (59%)
IR(Neat)ν: 2929, 2852, 1676, 1637, 1589, 1533, 1477, 1423, 1281, 1246, 1164, 1012, 922, 768 cm^-1.
NMR (CDCl₃)δ: 1.42-1.76(8H,m), 1.92-1.99(2H,m), 2.23(3H,s), 2.48-2.58(5H,m), 2.87-3.01(2H,m), 4.49-4.60(2H,m), 5.61(2H,s), 6.68(1H,d,J=7.5Hz), 7.10(1H,t,J=7.5Hz), 7.49(1H,d,J=8.9Hz), 7.56(2H,d,J=8.1Hz), 7.68(1H,d,J=8.1Hz), 8.01(1H,dd,J=8.9,2.2Hz), 8.59(1H,d,J=2.2Hz), 9.08 (1H, d, J = 7.1 Hz).
【0263】
Example 198
2-[4-(2-chloronicotinoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (0.516 g, 2.50 mmol) in a mixture of EtOH (10.0 mL) and THF (10.0 mL), 1N aqueous sodium hydroxide (2.60 mL) was added, followed by 4-(2-chloronicotinoyl)benzyl bromide (0.807 g, 2.60 mmol) and stirring at room temperature for 30 minutes. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then purified by evaporation with MgSO₄The residue was recrystallized from ethyl acetate to give pale yellow needles (0.810 g, 74%).
IR(KBr)ν: 1670, 1549, 1460, 1402, 1304, 1280, 1284, 1161, 1086, 1036, 924, 864, 746, 694, 656 cm^-1.
NMR (CDCl₃)δ: 2.84(3H,s), 3.54(3H,s), 4.58(2H,s), 7.14(1H,d,J=7.6Hz), 7.37(1H,dd,J=7.9,4.8Hz), 7.41(1H,d,J=7.6Hz), 7.51(1H,t,J=7.6Hz), 7.61(2H,d,J=8.4Hz), 7.71(1H,dd,J=7.9,2.0Hz), 7.76(2H,d,J=8.4Hz), 8.54(1H,dd,J=4.8,2.0Hz).
【0264】
Example 199
1-[4-(6-chloronicotinoyl)benzyl]-6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one
To a solution of 6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5-one (4.19 g, 23.60 mmol) and 4-(6-chloronicotinoyl)benzyl bromide (7.36 g, 23.70 mmol) in DMF (100.0 mL) and DMSO (20.0 mL), potassium carbonate (7.10 g, 50.70 mmol) was added and stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). The resulting colorless oil was crystallized from ethyl acetate to yield colorless needles. 4.59 g (48%)
IR(KBr)ν: 1655, 1581, 1520, 1414, 1282, 1217, 1103, 923 cm^-1.
NMR (CDCl₃)δ: 1.15(3H,t,J=7.4Hz), 2.43(3H,s), 2.66(2H,q,J=7.4Hz), 5.35(2H,s), 6.86(1H,d,J=2.6Hz), 7.44(2H,d,J=8.0Hz), 7.53(1H,d,J=8.0Hz), 7.56(1H,d,J=2.6Hz), 7.81(2H,d,J=8.0Hz), 8.09(1H,dd,J=8.0,2.4Hz), 8.75(1H,d,J=2.4Hz).
【0265】
Example 200
6-ethyl-1-[4-(4-methoxycarbonylbenzoyl)benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one
Potassium carbonate (7.14 g, 51.7 mmol) was added to a solution of 6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5-one (4.00 g, 22.6 mmol) and 4-(4-methoxycarbonylbenzoyl)benzyl bromide (11.00 g, 33.02 mmol) in a DMF (100.0 ml)-DMSO (20.0 ml) mixture, and the mixture was stirred overnight at room temperature. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate). The resulting colorless oil was crystallized from ethyl acetate to yield colorless needles. 4.59 g (48%)
IR(KBr)ν: 1724, 1657, 1581, 1520, 1277, 1109, 928, 721 cm^-1.
NMR (CDCl₃)δ: 1.15(3H,t,J=6.6Hz), 2.44(3H,s), 2.66(2H,q,J=6.6Hz), 3.97(3H,s), 5.34(2H,s), 6.86(1H,d,J=2.6Hz), 7.42(2H,d,J=8.0Hz), 7.56(1H,d,J=2.6Hz), 7.81(2H,d,J=8.0Hz), 7.82(2H,d,J=8.0Hz), 8.16(2H,d,J=8.0Hz).
【0266】
Example 201
2-[4-(4-methoxycarbonylbenzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
Potassium carbonate (3.92 g, 28.4 mmol) was added to a solution of 3-methylpyrido[1,2-a]pyrimidine-2,4-dione (2.20 g, 12.5 mmol) and 4-(4-methoxycarbonylbenzoyl)benzyl bromide (7.04 g, 12.7 mmol) in a DMF (40.0 ml)-DMSO (20.0 ml) mixture and stirred overnight at room temperature. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. These were dissolved in ethyl acetate and then added with MgSO₄The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain colorless needles (2.67 g, 50%).
IR(KBr)ν: 1722, 1672, 1576, 1530, 1477, 1277, 1167, 1108 cm^-1.
NMR (CDCl₃)δ: 2.23(3H,s), 3.97(3H,s), 5.63(2H,s), 7.11(1H,dt,J=6.7,1.5Hz), 7.49(1H,dd,J=8.7,1.5Hz), 7.60(2H,d,J=8.4Hz), 7.71(1H,ddd,J=8.7,6.7,1.5Hz), 7.84(2H,d,J=8.4Hz), 7.86(2H,d,J=8.4Hz), 8.17(2H,d,J=8.4Hz), 9.08(1H,dd,J=6.7,1.5Hz).
【0267】
Example 202
6-Ethyl-1-[4-(6-(4-piperidinopiperidino)nicotinoyl)benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one trihydrochloride
A solution of 1-[4-(6-chloronicotinoyl)benzyl]-6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (0.810 g, 1.99 mmol) and 4-piperidinopiperidine (0.372 g, 2.21 mmol) in pyridine (10.0 ml) was stirred at 90°C overnight. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (THF:methanol:ammonia = 60:1:0.1) to give a pale yellow oil. This was dissolved in ethyl acetate, and 4N hydrochloric acid-ethyl acetate was added. The precipitated crystals were collected by filtration and dried under reduced pressure. 0.596 g (49%)
IR(KBr)ν: 3383, 2937, 2615, 2519, 1643, 1595, 1554, 1444, 1321, 1273, 1240, 1178, 1008, 762, 723 cm^-1.
NMR (DMSO-d₆)δ: 1.04(3H,t,J=7.4Hz), 1.72(2H,m), 1.82(2H,m), 2.23(2H,m), 2.38(3H,s), 2.51(2H,q,J=7.4Hz), 2.94(2H,m), 3.02(2H,m), 3.40(2H,m), 4.20(3H,m), 4.65(4H,m), 5.49(2H,s), 7.07(1H,m), 7.49-7.54(2H,m), 7.63-7.95(4H,m), 7.98(1H,m), 8.42(1H,m).
【0268】
Example 203
6-ethyl-7-methyl-1-[4-(6-(4-phenylpiperazino)nicotinoyl)benzyl]-imidazo[1,2-a]pyrimidin-5(1H)-one trihydrochloride
6-Ethyl-7-methyl-1-[4-(6-(4-phenylpiperazino)nicotinoyl)benzyl]imidazo[1,2-a]pyrimidin-5(1H)-one (696 mg) was dissolved in ethyl acetate (10.0 ml), and 4N hydrochloric acid-ethyl acetate was added to the solution. The resulting crystals were collected by filtration and dried under reduced pressure to obtain a pale yellow solid.
0.667g (84%)
IR(KBr)ν:3412, 2681, 1703, 1647, 1595, 1446, 1284, 1257, 756, 692 cm^-1.
NMR (DMSO-d₆)δ: 1.04(3H,t,J=7.4Hz), 2.39(3H,s), 2.51(2H,q,J=7.4Hz), 3.41(4H,bs), 4.00(4H,bs), 5.50(2H,s), 7.00(1H,m), 7.11(1H,d,J=9.0Hz), 7.22-7.38(4H,m), 7.51(2H,d,J=8.0Hz), 7.62-7.73(4H,m), 8.00(1H,dd,J=9.0,2.2Hz),8.46(1H,d,J=2.2Hz).
【0269】
Example 204
6-ethyl-7-methyl-1-[4-(6-(4-phenylpiperazino)nicotinoyl)benzyl]-imidazo[1,2-a]pyrimidin-5(1H)-one
A solution of 1-[4-(6-chloronicotinoylbenzyl]-6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (0.810 g, 1.99 mmol) and 4-phenylpiperazine (0.350 g, 2.16 mmol) in pyridine (10.0 ml) was stirred at 90°C overnight. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain a pale yellow amorphous product. 0.907 g (85%)
IR(KBr)ν: 1657, 1589, 1518, 1417, 1282, 1225, 951, 824, 760 cm^-1.
NMR (CDCl₃)δ: 1.15(3H,t,J=7.6Hz), 2.44(3H,s), 2.66(2H,q,J=7.6Hz), 3.31(4H,t,J=4.8Hz), 3.90(4H,t,J=4.8Hz), 5.32(2H,s), 6.72(1H,d,J=9.0Hz), 6.83(1H,d,J=2.6Hz), 6.91(1H,t,J=8.4Hz), 6.97(2H,d,J=8.4Hz), 7.30(2H,t,J=8.4Hz), 7.39(2H,d,J=8.2Hz), 7.54(1H,d,J=2.6Hz), 7.75(1H,d,
【0270】
Example 205
3-methyl-2-[4-(6-(4-phenylpiperazino)nicotinoyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
A solution of 2-[4-(6-chloronicotinoyl)benzyloxy]-3-methyl-pyrido[1,2-a]pyrimidin-4-one (0.805 g, 1.98 mmol) and 4-phenylpiperazine (0.478 g, 2.95 mmol) in pyridine (10 ml) was stirred at 90°C overnight. The solvent was removed under reduced pressure, and water was added to the residue. The resulting crystals were dried under reduced pressure to give a pale yellow solid. 0.38 g (59%)
IR(KBr)ν: 1674, 1637, 1589, 1479, 1282, 1164 cm^-1.
NMR (CDCl₃)δ: 2.22(3H,s), 3.32(4H,t,J=7.2Hz), 3.90(4H,t,J=7.2Hz), 5.62(2H,s), 6.73(1H,d,J=9.2Hz), 6.86-7.02(3H,m), 7.10(1H,dt,J=7.0,1.2Hz), 7.24-7.36(2H,m), 7.45-7.82(6H,m), 8.08(1H,dd,J=9.2,2.6Hz), 8.64(1H,d,J=2.2Hz), 9.08(1H,d,J=8.0Hz).
【0271】
Example 206
3,5-dimethyl-2-[4-(4-(4-phenylpiperazinocarbonyl)benzoyl)benzyl]thio-4(3H)-quinazolinone
DEPC (0.356 g, 2.18 mmol) was added to a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone (0.472 g, 1.06 mmol) in DMF (10.0 mL) and stirred at room temperature for 15 minutes. 4-phenylpiperazine (0.35 mL, 2.29 mmol) was then added and stirred at room temperature for 3 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then extracted with MgSO₄The residue was recrystallized from THF to obtain colorless needles (0.366 g, 59%).
IR(KBr)ν: 1666, 1635, 1554, 1432, 1277, 1090, 729 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.05-3.35(2H,m), 3.55(3H,s), 3.59(1H,m), 3.95(1H,m), 4.60(2H,s), 6.88-6.98(3H,m), 7.15(1H,d,J=7.6Hz), 7.25-7.35(2H,m), 7.43(1H,d,J=7.4Hz), 7.50-7.65(5H,m), 7.78(2H,d,J=8.4Hz), 7.83(2H,d,J=8.2Hz).
【0272】
Example 207
3,5-dimethyl-2-[4-(4-(4-hydroxypiperidinocarbonyl)benzoyl)benzyl]thio-4(3H)-quinazolinone
DEPC (0.755 g, 4.63 mmol) was added to a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone (1.00 g, 2.26 mmol) in DMF (10.0 mL) and stirred at room temperature for 10 minutes. 4-Hydroxypiperidine (0.522 g, 5.16 mmol) was then added and stirred at room temperature for 4 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then extracted with MgSO₄The residue was recrystallized from THF to obtain colorless needles (0.735 g, 62%).
IR(KBr)ν: 3425, 1664, 1608, 1554, 1448, 1305, 1277, 1088, 729 cm^-1.
NMR (CDCl₃)δ: 1.40-2.10(4H,m), 2.81(3H,s), 3.10-3.80(3H,m), 3.55(3H,s), 4.01(1H,m), 4.10-4.30(1H,m), 4.59(2H,s), 7.15(1H,d,J=6.6Hz), 7.40-7.68(6H,m), 7.75-7.86(4H,m).
【0273】
Example 208
2-[4-(4-carboxybenzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
A solution of 2-[4-(4-methoxycarbonylbenzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.48 g, 3.47 mmol) in DMF (30.0 ml) was heated to 90°C, 1N sodium hydroxide (4.00 ml) was added, and the mixture was stirred for 2 hours. Hydrochloric acid was added to adjust the pH to 6, resulting in the precipitation of colorless needles, which were collected by filtration and dried under reduced pressure. 1.40 g (97%)
IR(KBr)ν: 3421, 3050, 1716, 1691, 1579, 1527, 1408, 1282, 1257, 1178, 931, 788, 735 cm^-1.
NMR (DMSO-d₆)δ: 2.09(3H,s), 5.63(2H,s), 7.32(1H,t,J=7.2Hz), 7.57(1H,d,J=8.8Hz), 7.67(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz), 7.83(2H,d,J=8.0Hz), 7.94(1H,dd,J=8.8,7.2Hz), 8.96(1H,d,J=7.2Hz).
【0274】
Example 209
1-[4-(4-carboxybenzoyl)benzyl]-6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one
To a solution of 6-ethyl-1-[4-(4-methoxycarbonylbenzoyl)benzyl]-7-methylimidazole[1,2-a]pyrimidin-5(1H)-one (1.91 g, 4.45 mmol) in a mixture of THF (30.0 ml) and methanol (10 ml), 1N sodium hydroxide (5.00 ml) was added and the mixture was stirred at room temperature for 3 hours. Hydrochloric acid was added to adjust the pH to 4, resulting in the precipitation of colorless needles, which were collected by filtration and dried under reduced pressure. 0.900 g (49%)
IR(KBr)ν: 3396, 3134, 2968, 1713, 1645, 1562, 1523, 1414, 1275, 1225, 931, 787, 717 cm^-1.
NMR (DMSO-d₆)δ: 1.03(3H,t,J=7.4Hz), 2.33(3H,s), 3.33(2H,q,J=7.4Hz), 5.40(2H,s), 7.49(2H,d,J=8.4Hz), 7.58(1H,d,J=2.6Hz), 7.64(1H,d,J=2.6Hz), 7.76(2H,d,J=8.4Hz), 7.80(2H,d,J=8.4Hz), 8.09(2H,d,J=8.4Hz).
【0275】
Example 210
3-methyl-2-[4-(4-(4-phenylpiperazinocarbonyl)benzoyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
DEPC (0.75 mml, 4.91 mmol) was added to a solution of 2-[4-(4-carboxy)benzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.495 g, 1.20 mmol) in DMF (15 mL) and stirred at room temperature for 30 minutes. 4-phenylpiperazine (0.437 g, 2.68 mmol) was then added and stirred overnight. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then purified with MgSO₄The residue was recrystallized from ethyl acetate to obtain colorless needles (0.394 g, 59%).
IR(KBr)ν: 1668, 1635, 1529, 1477, 1281, 1165, 1012, 928, 731 cm^-1.
NMR (CDCl₃)δ:2.23(3H,s), 3.13(2H,bs), 3.24(2H,bs), 3.59(2H,bs), 3.97(2H,bs), 5.63(2H,s), 6.93(1H,t,J=7.8Hz), 6.95(2H,d,J=7.8Hz), 7.11(1H,t,J=7.0Hz), 7.31(2H,d,J=7.8Hz), 7.50(1H,d,J=7.0Hz), 7.56(2H,d,J=8.4Hz), 7.60(2H,d,J=8.4Hz), 7.71(1H,t,J=7.0Hz), 7.85(2H,d,J=8.4Hz), 7.87(2H,d,J=8.4Hz), 9.07(1H,d,J=7.0Hz).
【0276】
Example 211
6-ethyl-7-methyl-1-[4-(4-(4-phenylpiperazinocarbonyl)benzoyl)benzyl]-imidazo[1,2-a]pyrimidin-5(1H)-one
DEPC (0.44 mml, 2.88 mmol) was added to a solution of 1-[4-(4-carboxybenzoyl)benzyl]-6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (0.303 g, 0.729 mmol) in DMF (15 mL) and stirred at room temperature for 30 minutes. 4-phenylpiperazine (0.407 g, 2.49 mmol) was then added and stirred overnight. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then purified with MgSO₄The residue was recrystallized from THF to obtain colorless needles (0.329 g, 81%).
IR(KBr)ν: 1653, 1587, 1520, 1435, 1277, 1221, 1011, 926, 729 cm^-1.
NMR (CDCl₃)δ: 1.15(3H,t,J=7.2Hz), 2.43(3H,s), 2.66(2H,q,5.33(2H,s), 6.85(1H,d,J=2.6Hz), 6.92(1H,t,J=7.0Hz), 6.94(2H,d,J=7.0Hz), 7.30(2H,t,J=7.0Hz), 7.42(2H,d,J=8.4Hz), 7.55(2H,d,J=8.4Hz), 7.55(1H,d,J=2.6Hz), 7.82(2H,d,J=8.4Hz), 7.84(2H,d,J=8.4Hz).
【0277】
Example 212
3-methyl-2-[4-(4-(4-piperidinopiperidinocarbonyl)benzoyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one dihydrochloride
2-[4-(4-carboxylateShibeTo a solution of [(benzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.333 g, 0.804 mmol) in DMF (10 mL), DEPC (0.424 mml, 2.52 mmol) was added and stirred at room temperature for 30 minutes, followed by addition of 4-piperidinopiperidine (0.348 g, 2.13 mmol) and stirring for 2.5 hours. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine, and the organic layer was then diluted with MgSO₄The residue was purified by silica gel column chromatography (THF:methanol:ammonia=50:1:0.1) to give a colorless oil, which was converted into a hydrochloride salt with 4N hydrochloric acid-ethyl acetate and then freeze-dried from water to give a colorless powder.
IR(KBr)ν: 3423, 2945, 1633, 1529, 1475, 1448, 1281, 1167, 1003, 930, 773 cm^-1.
NMR (DMSO-d₆)δ: 1.30-1.60(2H,m), 1.60-2.00(6H,m), 2.00-2.30(2H,m), 2.80-3.10(4H,m), 3.60-3.80(4H,m), 4.50-4.70(1H,m), 7.33(1H,t,J=8.2Hz), 7.58(2H,d,J=8.0Hz), 7.68(2H,d,J=8.0Hz), 7.73(1H,d,J=8.2Hz), 7.79(2H,d,J=8.0Hz), 7.80(2H,d,J=8.0Hz), 7.95(1H,t,J=8.2Hz), 8.96(1H,d,J=8.2Hz).
【0278】
Example 213
6-ethyl-7-methyl-1-[4-(4-(4-piperidinopiperidinocarbonyl)benzoyl)benzyl]-imidazo[1,2-a]pyrimidin-5(1H)-one hydrochloride
DEPC (0.318 mg, 1.95 mmol) was added to a solution of 1-[4-(4-carboxybenzoyl)benzyl]-6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (0.302 g, 0.727 mmol) in DMF (10 mL) and stirred at room temperature for 30 minutes. Then, 4-piperidinopiperidine (0.336 g, 2.00 mmol) was added and stirred for 2.5 hours. Ethyl acetate was added to the reaction mixture, which was then washed with saturated brine. The organic layer was then purified with MgSO₄The residue was purified by silica gel column chromatography (THF:methanol:ammonia=50:1:0.1) to give a colorless oil, which was converted into a hydrochloride salt with 4N hydrochloric acid-ethyl acetate and then lyophilized from water to give a colorless powder.
IR(KBr)ν: 3456, 2960, 2690, 1703, 1657, 1601, 1510, 1452, 1278, 1225, 1171, 1034, 1003 cm^-1.
NMR (DMSO-d₆)δ: 1.19(3H,t,J=7.0Hz), 1.35-1.55(2H,m), 1.60-2.00(6H,m), 2.05-2.30(2H,m), 2.38(3H,s), 2.47(2H,q,J=7.0Hz), 2.60-3.00(4H,m), 3.30-3.50(4H,m), 4.50-4.70(1H,m), 5.49(2H,s), 7.53(2H,d,J=8.2Hz), 7.57(2H,d,J=8.2Hz), 7.64(1H,d,J=2.8Hz), 7.68(1H,d,J=2.8Hz), 7.77(2H,d,J=8.2Hz), 7.78(2H,d,J=8.2Hz).
【0279】
Example 214
2-[4-(4-chlorobenzoyl)benzyl]thio-5-ethyl-3-methyl-4(3H)-quinazolinone
To a solution of 5-ethyl-3-methyl-2-mercaptoquinazolin-4-one (0.307 g, 1.39 mmol) in EtOH (5.0 mL) and THF (5.0 mL), 1N aqueous sodium hydroxide solution (1.50 mL) was added, followed by 4-(4-chlorobenzoyl)benzyl bromide (0.434 g, 1.40 mmol), and the mixture was stirred at room temperature for 1.5 hours. Water (100 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. This solid was recrystallized from ethyl acetate to yield pale yellow needles. 0.398 g (64%)
IR(KBr)ν: 1666, 1583, 1554, 1441, 1311, 1277, 1090, 928, 822 cm^-1.
NMR (CDCl₃)δ: 1.27(3H,t,J=7.2Hz), 2.29(2H,q,J=7.2Hz), 4.59(2H,s), 7.18(1H,d,J=8.0Hz), 7.44(1H,d,J=8.0Hz), 7.45(2H,d,J=7.2Hz), 7.58(1H,t,J=8.0Hz), 7.60(2H,d,J=7.2Hz), 7.72(2H,d,J=7.2Hz), 7.73(2H,d,J=7.2Hz).
【0280】
Example 215
5-ethyl-2-[4-(4-methoxybenzoyl)benzyl]thio-3-methyl-4(3H)-quinazolinone
To a solution of 5-ethyl-3-methyl-2-mercaptoquinazolin-4-one (0.298 g, 1.35 mmol) in EtOH (5.0 mL) and THF (5.0 mL), 1N aqueous sodium hydroxide solution (1.50 mL) was added, followed by 4-(4-methoxybenzoyl)benzyl bromide (0.430 g, 1.41 mmol), and the mixture was stirred at room temperature for 40 minutes. Water (100 mL) was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. This solid was recrystallized from ethyl acetate to obtain colorless needles. 0.572 g (95%)
IR(KBr)ν: 1668, 1601, 1552, 1464, 1435, 1414, 1311, 1171, 1091, 1026, 928, 820 cm^-1.
NMR (CDCl₃)δ: 1.27(3H,t,J=8.0Hz), 3.34(2H,q,J=8.0Hz), 3.56(3H,s), 3.88(3H,s), 4.59(2H,s), 6.95(2H,d,J=9.0Hz), 7.18(1H,d,J=8.8Hz), 7.54(1H,d,J=8.8Hz), 7.58(2H,d,J=8.4Hz), 7.59(1H,t,J=8.8Hz), 7.72(2H,d,J=8.4Hz), 7.81(2H,d,J=9.0Hz).
【0281】
Example 216
5-ethyl-3-methyl-2-[4-(4-nitrobenzoyl)benzyl]thio-4(3H)-quinazolinone
To a solution of 5-ethyl-3-methyl-2-mercaptoquinazolin-4-one (0.295 g, 1.34 mmol) in EtOH (5.0 mL) and THF (5.0 mL), 1N aqueous sodium hydroxide solution (1.50 mL) was added, followed by 4-(4-nitrobenzoyl)benzyl bromide (0.434 g, 1.36 mmol), and the mixture was stirred at room temperature for 40 minutes. Water (100 mL) was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. This solid was recrystallized from ethyl acetate to obtain colorless needles. 0.408 g (70%)
IR(KBr)ν: 1666, 1601, 1552, 1524, 1466, 1437, 1412, 1346, 1311, 1092, 929 cm^-1.
NMR (CDCl₃)δ:1.27(3H,t,J=7.6Hz), 3.29(2H,q,J=7.6Hz), 3.56(3H,s), 4.60(2H,s), 7.19(1H,d,J=8.4Hz), 7.44(1H,d,J=8.4Hz), 7.58(1H,t,J=8.4Hz), 7.64(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 7.91(2H,d,J=8.8Hz), 8.32(2H,d,J=8.8Hz).
【0282】
Example 217
2-[4-(4-diethylphosphonooxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (268 mg), diethylphosphonochloridate (0.16 mL), and triethylamine (0.28 mL) in tetrahydrofuran (8 mL) was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and crystallized from hexane to give the title compound (270 mg) as a colorless solid.
IR(KBr)ν: 1683, 1556, 1471, 1270, 1031 cm^-1.
NMR (CDCl₃)δ: 1.37(3H,t,J=7.1Hz), 1.38(3H,t,J=7.0Hz), 2.85(3H,s), 3.55(3H,s), 4.23(2H,q,J=7.1Hz), 4.27(2H,q,J=7.0Hz), 4.60(2H,s), 7.16(1H,d,J=7.6Hz), 7.32(2H,d,J=8.0Hz), 7.44(1H,d,J=7.8Hz), 7.53(1H,d,J=7.2Hz), 7.61(2H,d,J=8.2Hz), 7.75(2H,d,J=8.4Hz), 7.81(7H,d,J=8.4Hz).
【0283】
Example 218
3,5-dimethyl-2-[4-[4-(2-dimethylaminoethoxy)benzoyl]benzylthio]-4(3H)-quinazolinone hydrochloride
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (306 mg), dimethylaminoethyl chloride hydrochloride (218 mg), and potassium carbonate (316 mg) in dimethylformamide (5 ml) was stirred at 80° C. for 20 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. After washing with water and drying, a solution of hydrochloric acid and ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration to yield the title compound (193 mg) as a colorless solid.
IR(KBr)ν: 1641, 1600, 1473, 1303, 1170, 808 cm^-1.
NMR (DMSO-d₆)δ: 2.76(3H,s), 2.87(6H,s), 3.46(3H,s), 3.56(2H,m), 4.47(2H,m), 4.65(2H,s), 7.14(2H,d,J=8.8Hz), 7.21(1H,d,J=7.6Hz), 7.47(1H,d,J=8.2Hz), 7.58-7.82(7H,m).
【0284】
Example 219
2-[4-(4-acetoxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (917 mg), 4-(4-acetoxybenzoyl)benzyl bromide (1.785 g), and 1N aqueous sodium hydroxide solution (4.5 mL) in methanol (20 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated, extracted with chloroform, washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 6/1) to yield the title compound (4.26 mg) as a colorless solid.
IR(KBr)ν: 1754, 1670, 1652, 1558, 1471, 1303, 1193 cm^-1.
NMR (CDCl₃)δ: 2.34(3H,s), 2.85(3H,s), 3.55(3H,s), 4.59(2H,s), 7.15(1H,d,J=7.6Hz), 7.21(2H,d,J=8.4Hz), 7.44(1H,d,J=7.4Hz), 7.50-7.64(3H,m), 7.77(2H,d,J=8.2Hz), 7.83(2H,d,J=8.8Hz).
【0285】
Example 220
3,5-dimethyl-2-[4-(4-hydroxybenzoyl)benzylthio]-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (952 mg), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (2.90 g), and 1N aqueous sodium hydroxide (4.6 mL) in methanol (20 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated, extracted with chloroform, washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 19/1). The resulting 2-[4-(4-t-butyldimethylsilyloxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone was dissolved in tetrahydrofuran (15 mL), and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.8 mL) was added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the resulting precipitate was collected by filtration, washed with water, and dried to yield the title compound (1.332 g) as a colorless solid.
IR(KBr)ν: 1652, 1604, 1556, 1471, 1309, 1039 cm^-1.
NMR (DMSO-d₆)δ: 2.75(3H,s), 3.45(3H,s), 4.63(2H,s), 6.87(2H,d,J=8.7Hz), 7.21(1H,d,J=7.3Hz), 7.46(1H,d,J=7.3Hz), 7.57-7.72(7H,m).
【0286】
Example 221
2-[4-(4-benzyloxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (395 mg), benzyl bromide (0.13 ml), and potassium carbonate (408 mg) in dimethylformamide (5 ml) was stirred at 60° C. for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and recrystallized from ethyl acetate to give the title compound (346 mg) as a colorless solid.
IR(KBr)ν: 1683, 1598, 1560, 1469, 1172, 1093 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 5.15(2H,s), 7.03(2H,d,J=8.9Hz), 7.16(1H,d,J=7.2Hz), 7.34-7.64(9H,m), 7.73(2H,d,J=8.4Hz), 7.81(2H,d,J=8.9Hz).
【0287】
Example 222
3,5-dimethyl-2-[4-[4-(2-pyrrolidinoethoxy)benzoyl]benzylthio]-4(3H)-quinazolinone hydrochloride
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (384 mg), 1-(2-chloroethyl)pyrrolidine hydrochloride (181 mg), and potassium carbonate (414 mg) in dimethylformamide (5 ml) was stirred at 60° C. for 62 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. After washing with water and drying, a solution of hydrochloric acid in ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration to yield the title compound (227 mg) as a colorless solid.
IR(KBr)ν: 1675, 1600, 1554, 1471, 1307, 1172, 1093 cm^-1.
NMR (DMSO-d₆)δ: 1.78-2.12(4H,m), 2.75(3H,s), 3.02-3.24(2H,m), 3.46(3H,s), 3.50-3.68(4H,m), 4.43(2H,t,J=5.0Hz), 4.65(2H,s), 7.15(2H,d,J=8.8Hz), 7.22(1H,d,J=8.0Hz), 7.47(1H,d,J=7.8Hz), 7.58-7.82(7H,m).
【0288】
Example 223
3,5-dimethyl-2-[4-[4-(2-piperidinoethoxy)benzoyl]benzylthio]-4(3H)-quinazolinone hydrochloride
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (399 mg), 1-(2-chloroethyl)piperidine hydrochloride (185 mg), and potassium carbonate (392 mg) in dimethylformamide (5 ml) was stirred at 60° C. for 62 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. After washing with water and drying, a solution of hydrochloric acid in ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration to yield the title compound (368 mg) as a colorless solid.
IR(KBr)ν: 1675, 1598, 1554, 1309, 1147, 1093 cm^-1.
NMR (DMSO-d₆)δ: 1.76-1.96(6H,m), 2.75(3H,s), 2.90-3.16(2H,m), 3.64(3H,s), 3.20-3.70(4H,m), 4.49(2H,t,J=4.4Hz), 4.65(2H,s), 7.14(2H,d,J=8.8Hz), 7.21(1H,d,J=6.8Hz), 7.47(1H,d,J=7.4Hz), 7.58-7.80(7H,m).
【0289】
Example 224
3,5-dimethyl-2-[4-[4-(2-morpholinoethoxy)benzoyl]benzylthio]-4(3H)-quinazolinone hydrochloride
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (366 mg), 4-(2-chloroethyl)morpholine hydrochloride (192 mg), and potassium carbonate (356 mg) in dimethylformamide (5 ml) was stirred at 60° C. for 62 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. After washing with water and drying, a solution of hydrochloric acid in ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration to yield the title compound (337 mg) as a colorless solid.
IR(KBr)ν: 1683, 1600, 1558, 1471, 1305, 1172, 1095 cm^-1.
NMR (DMSO-d₆)δ: 2.75(3H,s), 3.08-3.68(9H,m), 3.70-4.08(4H,m), 4.53(2H,t,J=4.5Hz), 4.65(2H,s), 7.15(2H,d,J=9.0Hz), 7.21(1H,d,J=7.2Hz), 7.47(1H,d,J=8.0Hz), 7.58-7.81(7H,m).
【0290】
Example 225
3,5-dimethyl-2-[4-[4-(3-dimethylaminopropoxy)benzoyl]benzylthio]-4(3H)-quinazolinone hydrochloride
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (311 mg), 3-dimethylaminopropyl chloride hydrochloride (249 mg), and potassium carbonate (322 mg) in dimethylformamide (5 ml) was stirred at 60° C. for 18 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. After washing with water and drying, a solution of hydrochloric acid in ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration to yield the title compound (185 mg) as a colorless solid.
IR(KBr)ν: 1675, 1558, 1471, 1305, 1172 cm^-1.
NMR (DMSO-d₆)δ: 2.18(2H,m), 2.76(3H,s), 2.81(6H,s), 3.24(2H,m), 3.46(3H,s), 4.17(2H,m), 4.65(2H,s), 7.08(2H,d,J=8.2Hz), 7.23(1H,d,J=8.2Hz), 7.48(1H,d,J=7.8Hz), 7.58-7.82(7H,m).
【0291】
Example 226
2-[4-[4-(2-acetoxyethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.888 g), 4-[4-(acetoxyethoxy)benzoyl]benzyl bromide (3.895 g), and 1N aqueous sodium hydroxide solution (14.3 ml) in methanol (30 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, extracted with chloroform, washed with water, dried, and concentrated. The resulting residue was recrystallized from ethyl acetate to give the title compound (2.597 g) as a colorless solid.
IR(KBr)ν: 1737, 1668, 1600, 1554, 1174, 1085 cm^-1.
NMR (CDCl₃)δ: 2.13(3H,s), 2.85(3H,s), 3.55(3H,s), 4.25(2H,m), 4.46(2H,m), 4.60(2H,s), 6.97(2H,d,J=9.0Hz), 7.15(1H,d,J=6.6Hz), 7.45(1H,d,J=6.8Hz), 7.50-7.64(3H,m), 7.73(2H,d,J=8.2Hz), 7.82(2H,d,J=8.8Hz).
【0292】
Example 227
3,5-dimethyl-2-[4-[4-(2-hydroxyethoxy)benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 2-[4-[4-(2-acetoxyethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (1.75 g) and 1 N aqueous sodium hydroxide (15 ml) in methanol (50 ml) and dichloromethane (25 ml) was stirred at room temperature for 3 hours. The reaction mixture was extracted with dichloromethane, dried, and concentrated. The resulting residue was recrystallized from ethyl acetate to give the title compound (1.278 g) as a colorless solid.
IR(KBr)ν: 1683, 1600, 1553, 1471, 1305, 1093 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.02(2H,m), 4.17(2H,t,J=4.4Hz), 4.60(2H,s), 6.98(2H,d,J=8.8Hz), 7.15(1H,d,J=6.6Hz), 7.45(1H,d,J=6.6Hz), 7.52-7.63(3H,m), 7.73(2H,d,J=8.4Hz), 7.82(2H,d,J=8.8Hz).
【0293】
Example 228
3,5-dimethyl-2-[4-[4-(N,N-dimethylcarbamoyloxy)benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (478 mg), dimethylcarbamoyl chloride (0.15 ml), and potassium carbonate (315 mg) in dimethylformamide (7 ml) was stirred at 50° C. for 48 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and recrystallized from ethyl acetate to give the title compound (346 mg) as a colorless solid.
IR(KBr)ν: 1733, 1670, 1602, 1562, 1471, 1160, 1091 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.04(3H,s), 3.13(3H,s), 3.55(3H,s), 4.59(2H,s), 7.15(1H,d,J=7.0Hz), 7.23(2H,d,J=8.8Hz), 7.44(1H,d,J=8.2Hz), 7.50-7.64(3H,m), 7.77(2H,d,J=8.2Hz), 7.81(2H,d,J=8.8Hz).
【0294】
Example 229
3,5-dimethyl-2-[4-[4-[4-(4-formylpiperazinylcarbonyl)benzyloxy]benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (402 mg), 1-(4-chloromethylbenzoyl)-4-formylpiperazine (354 mg), and potassium carbonate (261 mg) in dimethylformamide (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and purified by silica gel column chromatography (ethyl acetate) to yield the title compound (310 mg) as a colorless solid.
IR(KBr)ν: 1670, 1600, 1558, 1456, 1307, 1172 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.35-3.80(8H,m), 3.55(3H,s), 4.60(2H,s), 5.19(2H,s), 7.02(2H,d,J=8.9Hz), 7.15(1H,d,J=7.2Hz), 7.42-7.61(8H,m), 7.73(2H,d,J=8.3Hz), 7.82(2H,d,J=8.9Hz), 8.12(1H,s).
【0295】
Example 230
2-[4-[4-(4-benzyloxybenzyloxy)[Benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (309 mg), 4-benzyloxybenzyl chloride (224 mg), and potassium carbonate (295 mg) in dimethylformamide (5 mL) was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and the residue was dissolved in chloroform, washed with water, dried, concentrated, and recrystallized from chloroform/ethyl acetate to give the title compound (355 mg) as a colorless solid.
IR(KBr)ν: 1683, 160, 1552, 1456, 1305, 1172, 1093 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.59(2H,s), 5.07(2H,s), 5.09(2H,s), 7.00(2H,d,J=8.6Hz), 7.01(2H,d,J=8.8Hz), 7.15(1H,d,J=7.2Hz), 7.32-7.62(11H,m), 7.73(2H,d,J=8.3Hz), 7.81(2H,d,J=8.8Hz).
【0296】
Example 231
3,5-dimethyl-2-[4-[4-(4-picolyloxy)[Benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (369 mg), 4-picolyl chloride hydrochloride (144 mg), and potassium carbonate (350 mg) in dimethylformamide (5 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and recrystallized from ethyl acetate/chloroform to give the title compound (99 mg) as a colorless solid.
IR(KBr)ν: 1670, 1600, 1554, 1471, 1305, 1170, 1093 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 5.18(2H,s), 7.01(2H,d,J=8.9Hz), 7.15(1H,d,J=6.8Hz), 7.37(2H,d,J=5.4Hz), 7.44(1H,d,J=8.0Hz), 7.50-7.64(3H,m), 7.73(2H,d,J=8.2Hz), 7.82(2H,d,J=8.9Hz), 8.65(2H,d,J=5.4Hz).
【0297】
Example 232
3,5-dimethyl-2-[4-[4-[2-(4-methylpiperazinyl)ethoxy]benzoyl]benzylthio]-4(3H)-quinazolinone dihydrochloride
2-[4-[4-(2-chloroethoxy)A solution of [benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (173 mg) and methylpiperazine (0.12 ml) in dimethylformamide (5 ml) was stirred for 15 hours at 100° C. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, and then dried. A solution of hydrochloric acid in ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration and dried to give the title compound (122 mg) as a colorless solid.
IR(KBr)ν: 1670, 1600, 1558, 1471, 1307, 1172, 1093, 929 cm^-1.
NMR (DMSO-d₆)δ: 2.76(3H,s), 3.46(3H,s), 2.80-3.70(13H,m), 4.16-4.40(2H,m), 4.65(2H,s), 7.10(2H,d,J=8.4Hz), 7.22(1H,d,J=7.4Hz), 7.47(1H,d,J=7.8Hz), 7.58-7.80(7H,m).
【0298】
Example 233
2-[4-[4-(2-chloroethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone
To a suspension of 3,5-dimethyl-2-[4-[4-(2-hydroxyethoxy)benzoyl]benzylthio]-4(3H)-quinazolinone (651 mg) in carbon tetrachloride (15 ml) was added triphenylphosphine (476 mg) and refluxed for 40 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane) and recrystallized from ethyl acetate to give the title compound (391 mg) as a colorless solid.
IR(KBr)ν: 1670, 1600, 1554, 1307, 1174, 1093, 696 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 3.85(2H,t,J=5.9Hz), 4.31(2H,t,J=5.9Hz), 4.60(2H,s), 6.97(2H,d,J=8.9Hz), 7.15(1H,d,J=7.0Hz), 7.44(1H,d,J=8.2Hz), 7.50-7.64(3H,m), 7.73(2H,d,J=8.4Hz), 7.82(2H,d,J=8.9Hz).
【0299】
Example 234
3,5-dimethyl-2-[4-(4-phenacyloxybenzoyl)benzylthio]-4(3H)-quinazolinone
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (413 mg), phenacyl bromide (315 mg), and potassium carbonate (436 mg) in dimethylformamide (7 ml) was stirred at room temperature for 15 hours. The reaction mixture was concentrated, and the residue was dissolved in chloroform, washed with water, dried, concentrated, and recrystallized from chloroform/ethyl acetate to give the title compound (313 mg) as a colorless solid.
IR(KBr)ν: 1708, 1675, 1594, 1560, 1471, 1176, 1093 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.54(3H,s), 4.59(2H,s), 5.38(2H,s), 6.98(2H,d,J=8.8Hz), 7.14(1H,d,J=7.0Hz), 7.40-7.67(7H,m), 7.72(2H,d,J=8.4Hz), 7.80(2H,d,J=8.8Hz), 8.01(2H,m).
【0300】
Example 235
3,5-dimethyl-2-[4-[4-[2-(4-piperidinopiperidino)ethoxy]benzoyl]benzylthio]-4(3H)-quinazolinone dihydrochloride
A solution of 2-[4-[4-(2-chloroethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (375 mg) and 4-piperidinopiperidine (434 mg) in dimethylformamide (5 ml) was stirred at 100°C for 7 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, and then dried and concentrated. A solution of hydrochloric acid in ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration and dried to give the title compound (368 mg) as a colorless solid.
IR(KBr)ν: 1670, 1598, 1558, 1457, 1307, 1172, 1093 cm^-1.
NMR (DMSO-d₆)δ: 2.76(3H,s), 3.46(3H,s), 1.80-3.80(21H,m), 4.50(2H,brs), 4.66(2H,s), 7.15(2H,d,J=8.8Hz), 7.22(1H,d,J=7.4Hz), 7.48(1H,d,J=7.6Hz), 7.58-7.83(7H,m).
【0301】
Example 236
3,5-dimethyl-2-[4-[4-[2-(2-dimethylaminoethylamino)ethoxy]benzoyl]benzylthio]-4(3H)-quinazolinone dihydrochloride
A solution of 2-[4-[4-(2-chloroethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (237 mg) and 2-dimethylaminoethylamine (1.1 mL) in dimethylformamide (5 mL) was stirred at 100° C. for 7 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol/aqueous ammonia = 9/1/0.1) to obtain the title compound (104 mg) as a colorless solid as the hydrochloride salt with a solution of hydrochloric acid in ethyl acetate.
IR(KBr)ν: 1652, 1600, 1558, 1457, 1305, 1172 cm^-1.
NMR (DMSO-d₆)δ: 2.75(3H,s), 2.85(6H,brs), 3.30-3.60(9H,m), 4.36-4.46(2H,brs), 4.65(2H,s), 7.10-7.25(3H,m), 7.46(1H,d,J=8.0Hz), 7.56-7.84(7H,m), 9.58-9.82(1H,br).
【0302】
Example 237
3,5-dimethyl-2-[4-[4-(4-phenylphenacyloxy)benzoyl]benzylthio]-4(3H)-quinazolinone
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (398 mg), 4-phenylphenacyl bromide (290 mg), and potassium carbonate (440 mg) in dimethylformamide (7 ml) was stirred at room temperature for 72 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/ether = 10/1) and recrystallized from chloroform/ethyl acetate to give the title compound (217 mg) as a colorless solid.
IR(KBr)ν: 1675, 1600, 1558, 1471, 1305, 1093 cm^-1.
NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.59(2H,s), 5.41(2H,s), 7.01(2H,d,J=9.0Hz), 7.15(1H,d,J=7.0Hz), 7.41-7.78(13H,m), 7.81(2H,d,J=9.0Hz), 8.09(2H,d,J=8.6Hz).
【0303】
Example 238
3,5-dimethyl-2-[4-[4-[2-(2-morpholinoethylamino)ethoxy]benzoyl]benzylthio]-4(3H)-quinazolinone dihydrochloride
A solution of 2-[4-[4-(2-chloroethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (165 mg) and 4-(2-aminoethyl)morpholine (543 mg) in dimethylformamide (7 ml) was stirred at 100° C. for 7 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol/aqueous ammonia = 9/1/0.1) to obtain the title compound (101 mg) as a colorless solid as the hydrochloride salt with a solution of hydrochloric acid in ethyl acetate.
IR(KBr)ν: 1646, 1602, 1558, 1307, 1174, 1147, 1108 cm^-1.
NMR (DMSO-d₆)δ: 2.75(3H,s), 3.45(3H,s), 3.00-4.80(16H,m), 7.10-7.26(3H,m), 7.47(1H,d,J=8.0Hz), 7.58-7.82(7H,m).
【0304】
Example 239
3,5-dimethyl-2-[4-[4-[2-[N-[2-(2-pyridyl)ethyl〕-N-methylamino]ethoxy]benzoyl]benzylthio]-4(3H)-quinazolinone dihydrochloride
A solution of 2-[4-[4-(2-chloroethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (381 mg), 2-(2-methylaminoethyl)pyridine (0.17 ml), and triethylamine (0.33 ml) in dimethylformamide (7 ml) was stirred at 100° C. for 21 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol/aqueous ammonia = 9/1/0.1) to obtain the title compound (256 mg) as a colorless solid as the hydrochloride salt with a solution of hydrochloric acid in ethyl acetate.
IR(KBr)ν: 1662, 1600, 1556, 1307, 1174, 1110 cm^-1.
NMR (DMSO-d₆)δ: 2.75(3H,s), 2.97(3H,s), 3.45(3H,s), 3.46-4.20(6H,m), 4.56(2H,brs), 4.64(2H,s), 7.08-7.24(3H,m), 7.46(1H,d,J=8.4Hz), 7.56-7.80(7H,m), 7.87(1H,t,J=6.6Hz), 7.99(1H,d,J=7.8Hz), 8.45(1H,t,J=7.8Hz), 8.82(1H,d,J=5.4Hz).
【0305】
Example 240
3,5-dimethyl-2-[4-[4-[4-(4-methylpiperazinylcarbonyl)benzyloxy]benzoyl]benzylthio]-4(3H)-quinazolinone hydrochloride
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (406 mg), 1-(4-chloromethylbenzoyl)-4-methylpiperazine hydrochloride (1.119 g), and potassium carbonate (739 mg) in dimethylformamide (10 ml) was stirred at room temperature for 40 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 9/1). The title compound (86 mg) was converted into the hydrochloride salt with a solution of hydrochloric acid and ethyl acetate to give a colorless solid.
IR(KBr)ν: 1652, 1600, 1558, 1471, 1307, 1172, 1093 cm^-1.
NMR (CDCl₃)δ: 2.28-2.58(4H,m), 2.33(3H,s), 2.85(3H,s), 3.38-3.60(2H,m), 3.54(3H,s), 3.64-3.90(2H,m), 4.59(2H,s), 5.17(2H,s), 7.01(2H,d,J=8.8Hz),7.14(1H,d,J=7.0Hz), 7.40-7.62(8H,m), 7.72(2H,d,J=8.0Hz), 7.81(1H,d,J=8.8Hz).
【0306】
Example 241
6-ethyl-7-methyl-1-[4-[4-(2-morpholinoethoxy)benzoyl]benzyl]imidazo[1,2-a]pyrimidin-5(1H)-one hydrochloride
A solution of 6-ethyl-1-[4-(4-hydroxybenzoyl)benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (136 mg), 4-(2-chloroethyl)morpholine hydrochloride (154 mg), and potassium carbonate (205 mg) in dimethylformamide (7 ml) was stirred at 100° C. for 6 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, and dried. A solution of hydrochloric acid and ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration and dried to yield the title compound (132 mg) as a colorless solid.
IR(KBr)ν: 1699, 1652, 1598, 1176 cm^-1.
NMR (CDCl₃)δ: 1.15(3H,t,J=7.4Hz), 2.63(2H,q,J=7.4Hz), 2.80(3H,s), 2.96-3.21(2H,m), 3.44-3.70(4H,m), 4.01(2H,d,J=12.0Hz), 4.30(2H,t,J=12.4Hz), 4.72(2H,m), 6.20(2H,s), 6.98(2H,d,J=8.8Hz), 7.10(1H,d,J=2.2Hz), 7.58-7.84(7H,m).
【0307】
Example 242
6-ethyl-1-[4-(4-hydroxybenzoyl)benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one
A solution of 6-ethyl-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (3.93 g), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (14.79 g), and potassium carbonate (5.97 g) in dimethylformamide (25 ml) and dimethyl sulfoxide (25 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated, extracted with ethyl acetate, washed with water, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol = 9/1) and recrystallized from ethanol/ethyl acetate to yield the title compound (909 mg) as a colorless solid.
IR(KBr)ν: 150, 1596, 1456, 1168 cm^-1.
NMR (DMSO-d₆)δ: 1.03(3H,t,J=7.2Hz), 2.34(3H,s), 2.52(2H,q,J=7.2Hz), 5.38(2H,s), 6.88(2H,d,J=8.6Hz), 7.45(2H,d,J=8.2Hz), 7.58-7.71(6H,m), 10.44(1H,s).
【0308】
Example 243
6-ethyl-7-methyl-1-[4-[4-(4-picolyloxy)benzoyl]benzyl]imidazo[1,2-a]pyrimidin-5(1H)-one hydrochloride
A solution of 6-ethyl-1-[4-(4-hydroxybenzoyl)benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one (126 mg), 4-picolyl chloride hydrochloride (154 mg), and potassium carbonate (274 mg) in dimethylformamide (7 mL) was stirred at room temperature for 17 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (chloroform/methanol = 19/1) and converted to the hydrochloride salt with a solution of hydrochloric acid and ethyl acetate to give the title compound (140 mg) as a colorless solid.
IR(KBr)ν: 1704, 1652, 1598, 1457, 1174, 929 cm^-1.
NMR (DMSO-d₆)δ: 1.04(3H,t,J=7.2Hz), 2.46-2.62(5H,m), 5.46(2H,s), 5.61(2H,s), 7.21(2H,d,J=8.6Hz), 7.50(2H,d,J=8.0Hz), 7.62-7.88(6H,m), 8.11(2H,d,J=6.6Hz), 8.96(2H,d,J=6.6Hz).
【0309】
Example 244
3-methyl-2-[4-[4-(2-morpholinoethoxy)benzoyl]benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride
A solution of 2-[4-(4-hydroxybenzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (104 mg), 4-(2-chloroethyl)morpholine hydrochloride (90 mg), and potassium carbonate (179 mg) in dimethylformamide (7 ml) was stirred at 100° C. for 20 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, and then dried and concentrated. A solution of hydrochloric acid and ethyl acetate was added, and the resulting hydrochloride was collected by filtration and dried to give the title compound (24 mg) as a colorless solid.
IR(KBr)ν: 1670, 1600, 1481, 1170, 927 cm^-1.
NMR (DMSO-d₆)δ: 2.09(3H,s), 3.10-4.08(10H,m), 4.52(2H,m), 5.64(2H,s), 7.16(2H,d,J=8.6Hz), 7.34(1H,dt,J=7.0,1.4Hz), 7.56-7.84(7H,m), 7.95(1H,m), 8.97(1H,d,J=7.2Hz).
【0310】
Example 245
3-methyl-2-[4-[4-(4-picolyloxy)benzoyl]benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride
A solution of 2-[4-(4-hydroxybenzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (96 mg), 4-picolyl chloride hydrochloride (89 mg), and potassium carbonate (178 mg) in dimethylformamide (7 ml) was stirred at room temperature for 13 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) and converted to the hydrochloride salt with a solution of hydrochloric acid and ethyl acetate to give the title compound (87 mg) as a colorless solid.
IR(KBr)ν: 1666, 1598, 1461, 1172, 929 cm^-1.
NMR (DMSO-d₆)δ: 2.09(3H,s), 5.60(2H,s), 5.63(2H,s), 7.22(2H,d,J=8.8Hz), 7.33(1H,t,J=6.9Hz), 7.56-7.86(7H,m), 7.93(1H,t,J=7.4Hz), 8.09(2H,t,J=5.8Hz), 8.95(3H,m).
【0311】
Example 246
2-[4-(6-chloronicotinoyl)]benzylthio]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
A solution of 2-mercapto-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (599 mg), 4-(6-chloronicotinoyl)benzyl bromide (1.179 g), and potassium carbonate (1.148 g) in dimethylformamide (40 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and recrystallized from tetrahydrofuran/ethyl acetate to give the title compound (367 mg) as a colorless solid.
IR(KBr)ν: 1672, 1577, 1461, 1103, 925, 765 cm^-1.
NMR (CDCl₃)δ: 2.09(3H,s), 4.65(2H,s), 7.31(1H,td,J=7.0,1.4Hz), 7.65-7.80(6H,m), 7.93(1H,m), 8.14(1H,dd,J=8.2,2.4Hz), 8.69(1H,d,J=3.4Hz), 8.89(1H,d,J=7.0Hz).
【0312】
Example 247
3-methyl-2-[4-[6-(4-piperidinopiperidino)nicotinoyl]benzylthio]-4H-pyrido[1,2-a]pyrimidin-4-one trihydrochloride
A solution of 2-[4-(6-chloronicotinoyl)benzylthio]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (287 mg), 4-piperidinopiperidine (137 mg), and potassium carbonate (194 mg) in dimethylformamide (10 ml) was stirred at 80° C. for 24 hours. The reaction mixture was concentrated, and the residue was dissolved in chloroform, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (chloroform/methanol = 9/1) and converted to the hydrochloride salt with ethyl acetate to give the title compound (28 mg) as a colorless solid.
IR(KBr)ν: 1693, 1639, 1006, 765 cm^-1.
NMR (CDCl₃)δ: 1.40-2.14(8H,m), 2.19(3H,s), 2.32-2.46(2H,m), 2.96-3.16(2H,m), 3.26-3.76(5H,m), 4.44-4.60(2H,m), 4.68(2H,s), 7.32(1H,td,J=6.3,1.6Hz), 7.54(1H,d,J=9.7Hz), 7.66-7.80(5H,m), 7.94(1H,m), 8.27(1H,d,J=2.2Hz),8.36(1H,dd,J=7.0,2.2Hz), 8.97(1H,d,J=6.3Hz).
【0313】
Example 248
3-methyl-2-[4-[4-(4-phenylpiperazinylmethyl)benzoyl]benzylthio]-4H-pyrido[1,2-a]pyrimidin-4-one
A solution of 2-mercapto-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (298 mg), 4,4'-bis(bromomethyl)benzophenone (934 mg), phenylpiperazine hydrochloride (402 mg), and potassium carbonate (850 mg) in dimethylformamide (30 ml) was stirred at room temperature for 10 hours. The reaction mixture was concentrated, and the residue was dissolved in chloroform, washed with water, dried, concentrated, and purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to yield the title compound (146 mg) as a colorless solid.
IR(KBr)ν: 1695, 1602, 1465, 1141, 763 cm^-1.
NMR (CDCl₃)δ: 2.24(3H,s), 2.64(4H,m), 3.22(4H,m), 3.64(2H,s), 4.61(2H,s), 6.80-6.97(3H,m), 7.08(1H,td,J=8.8,1.8Hz), 7.21-7.32(2H,m), 7.43-7.62(5H,m), 7.66(1H,m), 7.76(4H,d,J=8.4Hz), 9.00(1H,d,J=7.0Hz).
【0314】
Example 249
2-[4-(4-hydroxybenzoyl)benzylthio]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
A solution of 2-mercapto-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (292 mg), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (843 mg), and potassium carbonate (443 mg) in methanol (10 ml), tetrahydrofuran (10 ml), and water (2 ml) was stirred at room temperature for 48 hours. The reaction mixture was concentrated, and the resulting residue was washed with ethyl acetate and water. The residue was then recrystallized from methanol/tetrahydrofuran/ethyl acetate to give the title compound (276 mg) as a pale yellow solid.
IR(KBr)ν: 1660, 1600, 1556, 1452, 765 cm^-1.
NMR (DMSO-d₆)δ: 2.10(3H,s), 4.63(2H,s), 6.46(2H,d,J=8.8Hz), 7.31(1H,td,J=6.9,1.6Hz), 7.44-7.62(6H,m), 7.70(1H,m), 7.94(1H,m), 8.90(1H,m).
【0315】
Example 250
3-methyl-2-[4-[4-(2-morpholinoethoxy)benzoyl]benzylthio]-4H-pyrido[1,2-a]pyrimidin-4-one
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (214 mg), 4-(2-chloroethyl)morpholine hydrochloride (157 mg), and potassium carbonate (247 mg) in dimethylformamide (7 ml) was stirred at 80° C. for 4 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water, and dried. A solution of hydrochloric acid and ethyl acetate was added, and the resulting hydrochloride precipitate was collected by filtration and dried to give the title compound (182 mg) as a colorless solid.
IR(KBr)ν: 1658, 1600, 1463, 1172, 1143 cm^-1.
NMR (CDCl₃)δ: 2.10(3H,s), 3.10-4.07(10H,m), 4.51(2H,s), 4.65(2H,s), 7.14(2H,d,J=7.0Hz), 7.32(1H,m), 7.58-7.82(7H,m), 7.94(1H,m), 8.89(1H,d,J=7.0Hz).
【0316】
Example 251
3-methyl-2-[4-(4-hydroxybenzoyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
A solution of 2-hydroxy-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.158 g), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (12.24 g), and potassium carbonate (5.07 g) in dimethylformamide (50 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate = 1/2) and recrystallized from chloroform/methanol/ethyl acetate to yield the title compound (325 mg) as a colorless solid.
IR(KBr)ν: 1646, 1604, 1575, 1475, 1170, 929 cm^-1.
NMR (DMSO-d₆)δ: 2.09(3H,s), 5.62(2H,s), 6.89(2H,d,J=8.8Hz), 7.33(1H,dt,J=7.0,1.6Hz), 7.54-7.80(7H,m), 7.94(1H,m), 8.96(1H,d,J=6.8Hz).
【0317】
Example 252
7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one
Under an argon atmosphere, 2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.82 g) was dissolved in DMF (60 ml) with heating. Anhydrous potassium carbonate (1.38 g) and ethyl iodide (1.2 ml) were then added and the mixture was stirred at 55°C for 3.5 hours. Insoluble materials were removed by filtration, and the solvent was evaporated under reduced pressure. Methanol was added to the resulting residue, which was then micronized using ultrasound. This material was collected by filtration, washed with water, methanol, and ether, and dried to yield a mixture of 3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one and 4-ethoxy-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (55:45; 1.34 g). This material was used in the subsequent reaction without further purification.
Under an argon atmosphere, the above mixture (1.14 g) was dissolved in dry DMF (10 ml), followed by the addition of dry DME (1,2-dimethoxyethane; 40 ml) and 60% sodium hydride in oil (250 mg). After stirring for 30 minutes, a solution of 4-(4-chlorobenzoyl)benzyl bromide (2.19 g) in DME (10 ml) was added dropwise. After stirring at room temperature for 15 hours, ethyl acetate and saturated brine were added, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; ethyl acetate:hexane; 1:4) to yield 7-[4-(4-chlorobenzoyl)benzyl]-4-ethoxy-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (725 mg) and the title compound (994 mg).
¹H-NMR (CDCl₃)δ: 1.46(3H,t,J=7.0Hz), 2.60(3H,s), 4.59(2H,q,J=7.0Hz), 5.45(2H,s), 6.50(1H,d,J=3.4Hz), 6.87(1H,d,J=3.4Hz), 7.30(2H,d,J=8.2Hz), 7.45(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.73(2H,d,J=8.2Hz).
【0318】
Example 253
7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-3-propyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
Under an argon atmosphere, 2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (0.91 g) was dissolved in DMF (30 ml) with heating. Anhydrous potassium carbonate (0.691 g) and propyl iodide (0.729 ml) were then added and the mixture was stirred at 60°C for 4 hours. Insoluble materials were removed by filtration, and the solvent was evaporated under reduced pressure. Methanol was added to the resulting residue, which was then micronized using ultrasound. This material was collected by filtration, washed with water, methanol, and ether, and dried to yield a mixture of 2-methylthio-3-propyl-7H-pyrrolo[2,3-d]pyrimidin-4-one and 2-methylthio-4-propoxy-7H-pyrrolo[2,3-d]pyrimidine (45:55; 603 mg). This material was used in the subsequent reaction without further purification.
Under an argon atmosphere, the above mixture (538 mg) was dissolved in dry DME (10 mL), followed by the addition of 60% sodium hydride in oil (106 mg). After stirring for 30 minutes, a solution of 4-(4-chlorobenzoyl)benzyl bromide (966 mg) in DME (2 mL) was added dropwise. After stirring at room temperature for 13 hours, ethyl acetate and saturated brine were added, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; ethyl acetate:hexane; 1:4) to yield 7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-4-propoxy-7H-pyrrolo[2,3-d]pyrimidine (353 mg) and the title compound (360 mg).
¹H-NMR (CDCl₃)δ: 1.01(3H,t,J=7.2Hz), 1.70-1.89(2H,m), 2.57(3H,s), 4.11(2H,t,J=7.2Hz), 5.36(2H,s), 6.65(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 7.32(2H,d,J=8.4Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.4Hz).
【0319】
Example 254
3-(2-Acetoxyethyl)-7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one
Under an argon atmosphere, 2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.82 g) was dissolved in DMF (60 ml) with heating. Anhydrous potassium carbonate (2.07 g) and bromoethyl acetate (3.34 g) were then added and stirred at 70°C for 7 hours. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. Methanol was added to the resulting residue, which was then micronized using ultrasound. This material was collected by filtration, washed with water, methanol, and ether, and then dried to give 3-(2-Acetoxyethyl)-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one and 4-(2-Acetoxyethoxy)A mixture of 1.71 g of 1H-2-methylthio-7H-pyrrolo[2,3-d]pyrimidines (1:2) was obtained, which was used in the next reaction without further purification.
Under an argon atmosphere, the above mixture (1.34 g) was dissolved in dry DME (30 ml), and then 60% sodium hydride in oil (220 mg) was added. After stirring for 30 minutes, a solution of 4-(4-chlorobenzoyl)benzyl bromide (2.02 g) in DME (2 ml) was added dropwise. After stirring at room temperature for 15 hours, ethyl acetate and saturated brine were added, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography (silica gel; ethyl acetate:hexane; 1:4 → 3:7) to give 4-(2-Acetoxyethoxy)From this, 900 mg of 7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine and 460 mg of the title compound were obtained.
¹H-NMR (CDCl₃)δ: 2.06(3H,s), 2.58(3H,s), 4.43(4H,s), 5.37(2H,s), 6.66(1H,d,J=3.6Hz), 6.77(1H,d,J=3.6Hz), 7.32(2H,d,J=8.4Hz), 7.46(2H,d,J=8.6Hz),7.73(2H,d,J=8.6Hz), 7.75(2H,d,J=8.4Hz).
【0320】
Example 255
7-[4-(4-chlorobenzoyl)benzyl]-3-(2-Hydroxyethyl)-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one
3-(2-Acetoxyethyl)7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (410 mg) was dissolved in methanol (8 mL) and DME (4 mL), and 1N aqueous sodium hydroxide solution (1.64 mL) was added and stirred for 2 hours. After neutralization with 1N hydrochloric acid (1.64 mL), the precipitate was collected by filtration and washed with water, methanol, and ether. The product was dried to give the title compound (295 mg).
¹H-NMR (CDCl₃)δ: 2.59(3H,s), 2.98(1H,t,J=5.4Hz), 3.99(2H,q,J=5.4Hz), 4.43(2H,t,J=5.4Hz), 5.38(2H,s), 6.67(1H,d,J=3.4Hz), 6.79(1H,d,J=3.4Hz), 7.32(2H,d,J=7.8Hz), 7.46(2H,d,J=8.2Hz), 7.74(2H,d,J=8.6Hz), 7.75(2H,d,J=8.4Hz).
【0321】
Example 256
7-[4-(4-chlorobenzoyl)benzyl]-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
7-[4-(4-chlorobenzoyl)benzyl]-3-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (221 mg) was dissolved in DME (15 ml) and ethanol (1.5 ml), and acetic acid (185 mg) was added. The mixture was then heated to 40°C. Raney Ni was added until the starting material disappeared as determined by TLC (microcrystalline cellulose). The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the mixture was allowed to stand, resulting in the precipitation of crystals. This material was collected by filtration, washed with ethanol and hexane, and then dried to yield the title compound (149 mg).
¹H-NMR (CDCl₃)δ: 3.61(3H,s), 5.42(2H,s), 6.76(1H,d,J=3.4Hz), 6.88(1H,d,J=3.4Hz), 7.27(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.90(1H,s).
【0322】
Example 257
7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (221 mg) was dissolved in DME (15 ml) and ethanol (1.5 ml), and acetic acid (185 mg) was added. The mixture was then heated to 40°C. Raney Ni was added until the starting material disappeared as determined by TLC (microcrystalline cellulose). The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the mixture was allowed to stand, resulting in the precipitation of crystals. This material was collected by filtration, washed with ethanol and hexane, and then dried to yield the title compound (141 mg).
¹H-NMR (CDCl₃)δ: 1.41(3H,t,J=7.2Hz), 4.09(2H,q,J=7.2Hz), 5.42(2H,s), 6.76(1H,d,J=3.4Hz), 6.87(1H,d,J=3.4Hz), 7.28(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.89(1H,s).
【0323】
Example 258
7-[4-(4-chlorobenzoyl)benzyl]-3-propyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
Under an argon atmosphere, 3-propyl-7H-pyrrolo[2,3-d]pyrimidin-4-one (249 mg) was dissolved in dry DME (6 mL), and 60% sodium hydride in oil (62 mg) was added while stirring and ice-cooling. After stirring for 30 minutes, a solution of 4-(4-chlorobenzoyl)benzyl bromide (564 mg) in dry DME (2 mL) was added, and the mixture was allowed to return to room temperature and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the mixture was purified by flash column chromatography (silica gel; 21 g; hexane:ethyl acetate; 4:1 → 3:2) to give the title compound (507 mg) as a colorless powder.
¹H-NMR (CDCl₃)δ: 0.99(3H,t,J=7.4Hz), 1.74-1.93(2H,m), 3.99(2H,t,J=7.4Hz), 5.42(2H,s), 6.76(1H,d,J=3.4Hz), 6.87(1H,d,J=3.4Hz), 7.28(2H,d,J=8.6Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.87(1H,s).
【0324】
Example 259
7-[4-(4-chlorobenzoyl)benzyl]-3-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
Under an argon atmosphere, 3-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-one (89 mg) was dissolved in dry DME (2 mL), and 60% sodium hydride in oil (22 mg) was added while stirring and ice-cooling. After stirring for 30 minutes, a solution of 4-(4-chlorobenzoyl)benzyl bromide (201 mg) in dry DME (1 mL) was added, and the mixture was allowed to return to room temperature and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the mixture was purified by flash column chromatography (silica gel; 12 g; hexane:ethyl acetate; 4:1 → 3:2) to yield the title compound (181 mg) as a colorless powder.
¹H-NMR (CDCl₃)δ: 1.47(6H,d,J=7.0Hz), 5.30(1H,q,J=7.0Hz), 5.42(2H,s), 6.76(1H,d,J=3.4Hz), 6.88(1H,d,J=3.4Hz), 7.29(2H,d,J=8.8Hz), 7.45(2H,d,J=8.8Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.95(1H,s).
【0325】
Example 260
2-[4-(4-fluorobenzoyl)benzyl]thio-6-methyl-thiazolo[4,5-d]pyridazin-7(6H)one
5-Amino-4-chloro-2-methyl-3(2H)-pyridazinone (638 mg) was dissolved in DMF (10 ml), 60% sodium hydride (384 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Carbon disulfide (365 mg) was then added, and the mixture was stirred at 80°C for 1 hour. 4-(4-fluorobenzoyl)benzyl bromide (1.4 g) was then added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate-THF, and the organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel chromatography (hexane-ethyl acetate (1:1)) to obtain 1.2 g of a white powder.
¹H-NMR (CDCl₃)δ: 3.88(3H,s), 4.66(2H,s), 7.17(2H,dd,J=8.8 and 8.8Hz), 7.57(2H,d,J=8.2Hz), 7.76(2H,d,J=8.2Hz), 7.84(2H,dd,J=8.8 and 5.6Hz), 8.34(1H,s).
【0326】
Example 261
2-[2-[4-(4-chlorobenzoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (376 mg) and 4-(4-chlorobenzoyl)benzaldehyde (1.1 g), acetic anhydride (0.5 ml) was added and stirred at 140°C for 2 hours. After concentrating the reaction mixture, the residue was washed with diethyl ether and dried to obtain 504 ml of a yellow powder.
¹H-NMR (DMSO-d₆)δ: 2.81(3H,s), 3.68(3H,s), 7.27(1H,d,J=7.8Hz), 7.54(1H,d,J=7.8Hz), 7.63(1H,d,J=15.2Hz), 7.66(1H,dd,J=7.8 and 7.8Hz), 7.66(2H,d,J=8.4Hz), 7.80(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 7.97(1H,d,J=15.2Hz), 8.02(2H,d,J=8.4Hz).
【0327】
Example 262
2-[2-[4-(4-chlorobenzoyl)phenyl]ethyl]-3,5-dimethyl-4(3H)-quinazolinone
2-[2-[4-(4-chlorobenzoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (104 mg) was dissolved in THF-ethyl acetate-methanol (2:1:1) (20 ml), and 10% Pd/C (50% aqueous) (10 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was washed with ethyl acetate-methanol and dried to give 53 mg of a white powder.
¹H-NMR (CDCl₃)δ : 2.88(3H,s), 3.05-3.18(2H,m), 3.25-3.38(2H,m), 3.56(3H,s), 7.18-7.30(2H,m), 7.43(2H,d,J=8.6Hz), 7.46(2H,d,J=8.6Hz), 7.54(1H,dd,J=7.6 and 7.6Hz), 7.74(4H,d,J=8.6Hz).
【0328】
Example 263
3,5-dimethyl-2-[2-[4-(4-trifluoromethylbenzoyl)phenyl]vinyl]-4(3H)-quinazolinone
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (508 mg) and 4-(4-trifluoromethylbenzoyl)benzaldehyde (751 mg), acetic anhydride (1.0 ml) was added and stirred at 140°C for 2 hours. After concentrating the reaction mixture, the residue was washed with n-hexane-diethyl ether and dried to obtain 898 mg of a yellow powder.
¹H-NMR (DMSO-d₆)δ: 2.81(3H,s), 3.69(3H,s), 7.26(1H,d,J=7.6Hz), 7.53(1H,d,J=7.6Hz), 7.63(1H,d,J=15.8Hz), 7.65(1H,dd,J=7.6 and 7.6Hz), 7.84(2H,d,J=8.4Hz), 7.96(4H,s), 7.97(1H,d,J=15.8Hz), 8.02(2H,d,J=8.4Hz).
【0329】
Example 264
3,5-dimethyl-2-[2-[4-(4-trifluoromethylbenzoyl)phenyl]ethyl]-4(3H)-quinazolinone
3,5-Dimethyl-2-[2-[4-(4-trifluoromethylbenzoyl)phenyl]vinyl]-4(3H)-quinazolinone (897 mg) was dissolved in THF-ethyl acetate-methanol (1:1:1) (60 mL), and 10% Pd/C (50% water) (179 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (2:1)) and further recrystallized from ethyl acetate-methanol to give 307 mg of a white powder.
¹H-NMR (CDCl₃)δ：2.88(3H,s), 3.06-3.19(2H,m), 3.24-3.38(2H,m), 3.56(3H,s), 7.19-7.30(2H,m), 7.45(2H,d,J=8.4Hz), 7.54(1H,dd,J=7.4 and 7.4Hz), 7.75(2H,d,J=8.2Hz), 7.77(2H,d,J=8.4Hz), 7.88(2H,d,J=8.2Hz).
【0330】
Example 265
2-[2-[4-(4-acetoxybenzoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone
Acetic anhydride (0.5 ml) was added to a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (376 mg) and 4-(4-acetoxybenzoyl)benzaldehyde (537 mg), and the mixture was stirred at 140°C for 2 hours. After concentrating the reaction mixture, the residue was washed with n-hexane-diethyl ether and dried to obtain 653 mg of a yellow powder.
¹H-NMR (DMSO-d₆)δ: 2.33(3H,s), 2.80(3H,s), 3.68(3H,s), 7.25(1H,d,J=7.6Hz), 7.35(2H,d,J=8.6Hz), 7.52(1H,d,J=7.6Hz), 7.60(1H,d,J=15.0Hz), 7.64(1H,dd,J=7.6 and 7.6Hz), 7.81(2H,d,J=8.2Hz), 7.84(2H,d,J=8.6Hz), 7.96(1H,d,J=15.0Hz), 8.00(2H,d,J=8.2Hz).
【0331】
Example 266
3,5-dimethyl-2-[2-[4-(4-hydroxybenzoyl)phenyl]ethyl]-4(3H)-quinazolinone
2-[2-[4-(4-acetoxybenzoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (631 mg) was dissolved in THF-ethyl acetate-methanol (1:1:1) (50 ml), and 10% Pd/C (50% aqueous) (126 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was suspended in ethanol (10 ml), and 1N aqueous sodium hydroxide solution (2.9 ml) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was suspended in water (20 ml) and neutralized with 1N hydrochloric acid (2.9 ml). The precipitate was collected by filtration, washed with water, and dried to yield 538 mg of a white powder.
¹H-NMR (CDCl₃)δ: 2.88(3H,s), 3.05-3.19(2H,m), 3.23-3.36(2H,m), 3.58(3H,s), 6.91(2H,d,J=8.4Hz), 7.18-7.32(2H,m), 7.38(2H,d,J=8.4Hz), 7.58(1H,dd,J=7.6 and 7.6Hz), 7.72(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【0332】
Example 267
3,5-dimethyl-2-[2-[4-[4-(2-dimethylaminoethoxy)benzoyl]phenyl]ethyl]-4(3H)-quinazolinone hydrochloride
3,5-Dimethyl-2-[2-[4-(4-hydroxybenzoyl)phenyl]ethyl]-4(3H)-quinazolinone (534 mg) was dissolved in DMF (10 ml), and 2-dimethylaminoethyl chloride (695 mg) and potassium carbonate (677 mg) were added. The mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. 1N hydrochloric acid (2 ml) was added to the organic layer concentrated to 20 ml, and the mixture was extracted with water. A saturated aqueous solution of sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was concentrated to 10 ml, and 4N hydrogen chloride/ethyl acetate (0.5 ml) was added. The precipitate was collected by filtration, washed with water, and dried to obtain 240 mg of a white powder.
¹H-NMR (DMSO-d₆)δ: 2.79(3H,s), 2.85(3H,s), 2.88(3H,s), 3.16-3.37(4H,m), 3.55(3H,s), 3.51-3.61(2H,m), 4.44-4.44(2H,m), 7.16(2H,d,J=8.8Hz), 7.31(1H,d,J=7.2Hz), 7.52-7.62(2H,m), 7.62(2H,d,J=8.8Hz), 7.66(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
【0333】
Example 268
2-[2-[4-(6-chloronicotinoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (1.1 g) and 4-(6-chloronicotinoyl)benzaldehyde (1.5 g), acetic anhydride (2 ml) was added and stirred at 140°C for 2 hours. After concentrating the reaction mixture, the residue was washed with toluene-diethyl ether and dried to obtain 1.4 g of a yellow powder.
¹H-NMR (CDCl₃)δ: 2.90(3H,s), 3.74(3H,s), 7.20-7.30(1H,m), 7.24(1H,d,J=15.6Hz), 7.51(1H,d,J=8.4Hz), 7.58-7.61(2H,m), 7.76(2H,d,J=8.4Hz), 7.87(2H,d,J=8.4Hz), 8.02(1H,d,J=15.6Hz), 8.12(1H,dd,J=2.6 and 8.4Hz), 8.79(1H,d,J=2.6Hz).
【0334】
Example 269
3,5-dimethyl-2-[2-[4-[6-(2-dimethylaminoethoxy)nicotinoyl]phenyl]vinyl]-4(3H)-quinazolinone
2-Dimethylaminoethanol (53 mg) was dissolved in DMF (3 ml), 60% sodium hydride (29 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 2-[2-[4-(6-chloronicotinoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (208 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated to 10 ml, and 1N hydrochloric acid (2 ml) was added, and the aqueous layer was extracted. A saturated aqueous solution of sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was concentrated to dryness, yielding 169 mg of a yellow powder.
¹H-NMR (CDCl₃)δ: 2.35(6H,s), 2.75(2H,t,J=5.7Hz), 2.90(3H,s), 3.73(3H,s),4.52(2H,t,J=5.7Hz), 6.91(1H,d,J=8.7Hz), 7.18-7.28(1H,m), 7.23(1H,d,J=15.3Hz), 7.57-7.60(2H,m), 7.73(2H,d,J=8.3Hz), 7.84(2H,d,J=8.3Hz), 8.01(1H,d,J=15.3Hz), 8.11(1H,dd,J=2.4 and 8.7Hz), 8.62(1H,d,J=2.4Hz).
【0335】
Example 270
3,5-dimethyl-2-[2-[4-[6-(2-dimethylaminoethoxy)nicotinoyl]phenyl]ethyl]-4(3H)-quinazolinone dihydrochloride
3,5-Dimethyl-2-[2-[4-[6-(2-dimethylaminoethoxy)nicotinoyl]phenyl]vinyl]-4(3H)-quinazolinone (167 mg) was dissolved in ethyl acetate-methanol-acetic acid (10:10:1) (10.5 mL), 10% Pd/C (50% aqueous) (34 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated. A saturated aqueous solution of sodium bicarbonate was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. This mixture was concentrated to 10 mL, and 4N hydrogen chloride/ethyl acetate (0.1 mL) was added. The precipitate was collected by filtration, washed with ethyl acetate/ethanol, and dried to yield 85 mg of a white powder.
¹H-NMR (DMSO-d₆)δ: 2.79(3H,s), 2.86(6H,s), 3.13-3.40(4H,m), 3.56(3H,s), 3.51-3.61(2H,m), 4.73(2H,t,J=5.4Hz), 7.05(1H,d,J=8.6Hz), 7.33(1H,d,J=7.5Hz), 7.55-7.66(2H,m), 7.60(2H,d,J=8.7Hz), 7.72(2H,d,J=8.7Hz), 8.12(1H,dd,J=2.2 and 8.6Hz), 8.55(1H,d,J=2.2Hz).
【0336】
Example 271
3,5-dimethyl-2-[2-[4-[6-(4-phenyl-1-piperazinyl)nicotinoyl]phenyl]vinyl]-4(3H)-quinazolinone
2-[2-[4-(6-chloronicotinoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (333 mg) was dissolved in pyridine (5 ml), phenylpiperazine (156 ml) was added, and the mixture was stirred at 90°C for 4 hours. The reaction mixture was concentrated and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:1)) to yield a yellow powder (162 mg).
¹H-NMR (CDCl₃)δ: 2.90(3H,s), 3.33(4H,t,J=5.2Hz), 3.74(3H,s), 3.92(4H,t,J=5.2Hz), 6.75(1H,d,J=9.1Hz), 6.92(1H,t,J=8.3Hz), 6.98(2H,d,J=8.3Hz), 7.18-7.26(1H,m), 7.21(1H,d,J=15.5Hz), 7.33(2H,d,J=8.3Hz), 7.57-7.60(2H,m), 7.72(2H,d,J=8.2Hz), 7.82(2H,d,J=8.2Hz), 8.01(1H,d,J=15.5Hz), 8.09(1H,dd,J=2.5 and 9.1Hz), 8.65(1H,d,J=2.5Hz).
【0337】
Example 272
3,5-dimethyl-2-[2-[4-[6-(4-phenyl-1-piperazinyl)nicotinoyl]phenyl]ethyl]-4(3H)-quinazolinone dihydrochloride
3,5-Dimethyl-2-[2-[4-[6-(4-phenyl-1-piperazinyl)nicotinoyl]phenyl]vinyl]-4(3H)-quinazolinone (160 mg) was dissolved in THF-ethyl acetate-methanol-acetic acid (10:5:5:1) (21 mL), and 10% Pd/C (50% aqueous) (64 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The catalyst was removed by filtration, and the filtrate was concentrated. A saturated aqueous solution of sodium bicarbonate was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate (1:1)). The desired elution fraction was concentrated to 10 mL, and 4N hydrogen chloride/ethyl acetate (0.15 mL) was added. The precipitate was collected by filtration, washed with ethyl acetate-ethanol, and dried to yield 129 mg of a white powder.
¹H-NMR (DMSO-d₆)δ: 2.80(3H,s), 3.16-3.54(8H,m), 3.60(3H,s), 3.91-4.08(4H,m), 6.99(1H,t,J=8.3Hz), 7.10-7.42(6H,m), 7.59-7.77(6H,m), 8.01(1H,dd,J=2.2 and 8.0Hz), 8.48(1H,d,J=2.2Hz).
【0338】
Example 273
7-[4-(4-chlorobenzoyl)benzyl]-3-methyl-1-propylxanthine
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)benzyl]xanthine (657 mg), potassium carbonate (242 mg), and propyl iodide (427 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) and recrystallized from ethyl acetate to give the title compound (352 mg) as a colorless solid.
IR(KBr)ν: 1700, 1665, 1650 cm^-1.
NMR (CDCl₃)δ: 0.95(3H,t,J=7Hz), 1.66(2H,q,J=8Hz), 3.60(3H,s), 3.96(2H,t,J=7Hz), 5.59(2H,s), 7.42(2H,d,J=7Hz), 7.46(2H,d,J=8Hz), 7.75(5H,m).
【0339】
Example 274
1,7-bis[4-(4-chlorobenzoyl)benzyl]-3-methylxanthine
A solution of 3-methylxanthine (204 mg), potassium carbonate (340 mg), and 4-(4-chlorobenzoyl)benzyl bromide (754 mg) in dimethylformamide (10 ml) was stirred at 60°C for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The extract was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) and recrystallized from ethyl acetate/hexane to give the title compound (184 mg) as a colorless solid.
IR(KBr)ν: 1700, 1660, 1645 cm^-1.
NMR (CDCl₃)δ: 3.61(3H,s), 5.27(2H,s), 5.61(2H,s), 7.46(7H,m), 7.67(1H,s), 7.71(9H,m).
【0340】
Example 275
7-[4-(4-chlorobenzoyl)benzyl]-1-isopropyl-3-methylxanthine
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)benzyl]xanthine (544 mg), potassium carbonate (202 mg), and isopropyl iodide (356 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) and recrystallized from acetone/hexane to give the title compound (38 mg) as a colorless solid.
IR(KBr)ν: 1700, 1665, 1650 cm^-1.
NMR (CDCl₃)δ: 1.50(6H,d,J=6Hz), 3.56(3H,s), 5.29(1H,spt,J=6Hz), 5.60(2H,s), 7.49(4H,m), 7.72(1H,s), 7.76(4H,m).
【0341】
Example 276
7-[4-(4-chlorobenzoyl)benzyl]-1-butyl-3-methylxanthine
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)benzyl]xanthine (612 mg), potassium carbonate (228 mg), and butyl iodide (430 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) and recrystallized from ethyl acetate to give the title compound (147 mg) as a colorless solid.
IR(KBr)ν: 1700, 1680, 1655 cm^-1.
NMR (CDCl₃)δ: 0.95(3H,t,J=7Hz), 1.39(2H,sec,J=7Hz), 1.63(2H,pent,J=7Hz),3.63(3H,s), 4.01(2H,t,J=7Hz), 5.64(2H,s), 7.46(4H,d,J=9Hz), 7.74(5H,d,J=9Hz).
【0342】
Example 277
7-[4-(4-chlorobenzoyl)benzyl]-1-fluoromethyl-3-methylxanthine
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)benzyl]xanthine (975 mg), sodium hydride (61 mg), and fluorobromomethane (121 mg) in dimethylformamide (10 ml) was stirred at 10°C for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The extract was purified by silica gel column chromatography (hexane/ethyl acetate = 1/2) and recrystallized from ethyl acetate to give the title compound (121 mg) as a colorless solid.
IR(KBr)ν: 1715, 1665, 1650 cm^-1.
NMR (CDCl₃)δ: 3.61(3H,s), 5.58(2H,s), 6.14(2H,d,J=50Hz), 7.43(2H,d,J=8.2Hz), 7.47(2H,d,J=8.0Hz), 7.68-7.81(5H,m).
【0343】
Example 278
7-[4-(4-hydroxybenzoyl)benzyl]-1,3-dimethylxanthine
A solution of 1,3-dimethylxanthine (742 mg), potassium carbonate (569 mg), and 4-(4-t-butyldimethylsiloxybenzoyl)benzyl bromide (2292 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The extract was purified by silica gel column chromatography (hexane/ethyl acetate = 1/3) and recrystallized from chloroform/isopropyl ether to yield the title compound (1763 mg) as a colorless solid.
IR(KBr)ν: 1700, 1655, 1645 cm^-1.
NMR (CDCl₃)δ: 3.42(3H,s), 3.62(3H,s), 5.59(2H,s), 6.90(2H,d,J=8.8Hz), 7.40(2H,d,J=8.3Hz), 7.68(1H,s), 7.74(2H,d,J=8.4Hz).
【0344】
Example 279
7-[4-(6-chloronicotinoyl)benzyl]-1,3-dimethylxanthine
A solution of 1,3-dimethylxanthine (712 mg), potassium carbonate (578 mg), and 4-(6-chloronicotinoyl)benzyl bromide (1515 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The extract was purified by silica gel column chromatography (hexane/ethyl acetate = 1/3) and recrystallized from chloroform/isopropyl ether to yield the title compound (1562 mg) as a colorless solid.
IR(KBr)ν: 1700, 1650 cm^-1.
NMR (CDCl₃)δ: 3.40(3H,s), 3.61(3H,s), 5.61(2H,s), 7.45(1H,d,J=8.1Hz), 7.48(2H,d,J=8.1Hz), 7.67(1H,s), 7.80(2H,d,J=8.1Hz), 8.08(1H,dd,J=2.4,8.1Hz), 8.74(1H,d,J=2.3Hz).
【0345】
Example 280
7-[4-(4-bromomethylbenzoyl)benzyl]-1,3-dimethylxanthine
A solution of 1,3-dimethylxanthine (990 mg), potassium carbonate (1348 mg), and 4-(4-bromomethylbenzoyl)benzyl bromide (2007 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The extract was purified by silica gel column chromatography (hexane/ethyl acetate = 1/5) and recrystallized from ethyl acetate/isopropyl ether to yield the title compound (1021 mg) as a colorless solid.
IR(KBr)ν: 1700, 1650 cm^-1.
NMR (CDCl₃)δ: 3.41(3H,s), 3.61(3H,s), 4.53(2H,s), 5.60(2H,s), 7.44(4H,m), 7.66(1H,s), 7.78(4H,m).
【0346】
Example 281
1,3-dimethyl-7-[4-(4-(2-morpholinoethoxy)benzoyl)benzyl]xanthine
A solution of 7-[4-(4-hydroxybenzoyl)benzyl]-1,3-dimethylxanthine (170 mg), potassium carbonate (200 mg), and 1-chloro-2-morpholinoethane hydrochloride (87 mg) in dimethylformamide (10 ml) was stirred at 60°C for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, concentrated, and purified by silica gel column chromatography (chloroform/ethyl acetate/acetone = 1/1/1) to yield the title compound (93 mg).
IR(KBr)ν: 1695, 1650 cm^-1.
NMR (CDCl₃)δ: 2.59(4H,dd,J=4.7, Hz), 2.84(2H,t,J=7.0Hz), 3.41(3H,s), 3.61(3H,s), 3.75(4H,dd,J=4.7, Hz,), 4.19(2H,t,J=7.0Hz), 5.59(2H,s), 6.96(2H,d,J=9.0Hz), 7.43(2H,d,J=8.0Hz), 7.66(1H,s), 7.75(2H,d,J=8.0Hz), 7.79(2H,d,J=9.0Hz).
【0347】
Example 282
1,3-dimethyl-7-[4-(6-(4-piperidinopiperidino)nicotinoyl)benzyl]xanthine
A solution of 7-[4-(6-chloronicotinoyl)benzyl]-1,3-dimethylxanthine (196 mg) and 4-piperidinopiperidine (102 mg) in pyridine (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, concentrated, and purified by silica gel column chromatography (ethyl acetate/acetone/triethylamine = 1/1/0.1) to yield the title compound (108 mg).
IR(KBr)ν: 1695, 1660, 1590 cm^-1.
NMR (CDCl₃)δ: 1.4-1.6(7H,m,br), 1.8-2.0(6H,m,br), 2.56(4H,m,br), 2.95(2H,m), 3.42(3H,s), 3.61(3H,s), 4.56(2H,m), 5.58(2H,s), 6.68(1H,d,J=9.1Hz),7.41(2H,d,J=8.1Hz), 7.65(1H,s), 7.74(2H,d,J=8.1Hz), 8.00(1H,dd,J=2.4,9.1Hz), 8.54(1H,d,J=2.4Hz).
【0348】
Example 283
1,3-dimethyl-7-[4-(4-phenylpiperazinylmethylbenzoyl)benzyl]xanthine
A solution of 7-[4-(4-bromomethylbenzoyl)benzyl]-1,3-dimethylxanthine (232 mg), potassium carbonate (109 mg), and 1-phenylpiperazine (92 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The extract was purified by silica gel column chromatography (ethyl acetate/hexane/triethylamine=3/1/0.1) and recrystallized from chloroform/isopropyl ether to give the title compound (20 mg) as a colorless solid.
IR(KBr)ν: 1695, 1650 cm^-1.
NMR (CDCl₃)δ: 2.64(4H,t,J=5.0Hz), 3.22(4H,t,J=5.0Hz), 3.41(3H,s), 3.61(3H,s), 3.65(2H,s), 5.60(2H,s), 6.91(3H,m), 7.27(2H,m), 7.42(2H,d,J=8.2Hz), 7.48(2H,d,J=8.2Hz), 7.66(1H,s), 7.76(2H,d,J=8.2Hz), 7.81(2H,d,J=8.2Hz).
【0349】
Example 284
7-[4-(4-methylbenzoyl)benzyl]-1,3-dimethylxanthine
A solution of 1,3-dimethylxanthine (99 mg), potassium carbonate (135 mg), and 4-(4-methylbenzoyl)benzyl bromide (201 mg) in dimethylformamide (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried, and concentrated. The extract was purified by silica gel column chromatography (hexane/ethyl acetate = 1/5) and recrystallized from ethyl acetate/isopropyl ether to give the title compound (98 mg) as a colorless solid.
IR(KBr)ν: 1700, 1655 cm^-1.
NMR (CDCl₃)δ: 2.44(3H,s), 3.41(3H,s), 3.60(3H,s), 5.59(2H,s), 7.27(2H,d,J=8.2Hz), 7.41(2H,d,J=8.2Hz), 7.68(1H,s), 7.69(2H,d,J=8.2Hz), 7.77(2H,d,J=8.2Hz).
【0350】
Example 285
7-[4-(4-fluorobenzoyl)benzyloxy]-3,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(4-Fluorobenzoyl)benzyl bromide (782 mg) was added to a solution of 3,6-dimethyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (514 mg) and potassium carbonate (741 mg) in dimethylformamide (10 ml), and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and water/ethyl acetate was added to the residue. The mixture was extracted with ethyl acetate, purified by silica gel column chromatography (hexane/ethyl acetate = 2:1), and recrystallized from ethyl acetate to give the title compound (76 mg) as a colorless solid.
IR(KBr)ν: 1640, 1590, 1385, 1340, 1300, 1270, 1245, 1145 cm^-1.
NMR (CDCl₃)δ: 2.05(3H,s), 2.82(3H,d,J=1.2Hz), 5.50(2H,s), 6.35(1H,d,J=1.2Hz), 7.17(2H,t,J=8.6Hz), 7.45(2H,d,J=8.1Hz), 7.79(2H,d,J=8.1Hz), 7.86(2H,dd,J=5.5,8.6Hz).
[0351]
Example 286
7-[4-(4-methoxybenzoyl)benzyloxy]-3,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(4-Methoxybenzoyl)benzyl bromide (970 mg) was added to a solution of 3,6-dimethyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (537 mg) and potassium carbonate (745 mg) in dimethylformamide (10 mL), and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and water/ethyl acetate was added to the residue. Extraction with ethyl acetate was performed, followed by purification by silica gel column chromatography (hexane/ethyl acetate = 2:1) and recrystallization from ethyl acetate to yield the title compound (106 mg) as a colorless solid.
IR(KBr)ν: 1660, 1645, 1595, 1570, 1490 cm^-1.
NMR (CDCl₃)δ : 2.05(3H,s), 2.82(3H,s), 3.90(3H,s), 5.49(2H,s), 6.35(1H,s), 6.97(2H,d,J=8.5Hz), 7.52(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz), 7.84(2H,d,J=8.5Hz).
【0352】
Example 287
7-[4-(4-nitrobenzoyl)benzyloxy]-3,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(4-Nitrobenzoyl)benzyl bromide (909 mg) was added to a solution of 3,6-dimethyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (537 mg) and potassium carbonate (618 mg) in dimethylformamide (10 mL), and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and water/ethyl acetate was added to the residue. The mixture was extracted with ethyl acetate, purified by silica gel column chromatography (hexane/ethyl acetate = 2:1), and recrystallized from ethyl acetate to give the title compound (105 mg) as a colorless solid.
IR(KBr)ν: 1665, 1515, 1500 cm^-1.
NMR (CDCl₃)δ: 2.05(3H,s), 2.82(3H,s), 5.51(2H,s), 6.36(1H,s), 7.57(2H,d,J=8.1Hz), 7.83(2H,d,J=8.1Hz), 7.94(2H,d,J=8.2Hz), 8.35(2H,d,J=8.2Hz).
【0353】
Example 288
7-[4-(6-chloronicotinoyl)benzyloxy]-3,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(6-chloronicotinoyl)benzyl bromide (852 mg) was added to a solution of 3,6-dimethyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (526 mg) and potassium carbonate (574 mg) in dimethylformamide (10 ml), and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and water/ethyl acetate was added to the residue. Extraction with ethyl acetate was performed, followed by purification by silica gel column chromatography (hexane/ethyl acetate = 2:1) and recrystallization from ethyl acetate to yield the title compound (300 mg) as a colorless solid.
IR(KBr)ν: 1665, 1640, 1570, 1490 cm^-1.
NMR (CDCl₃)δ: 2.05(3H,s), 2.82(3H,s), 5.51(2H,s), 6.35(1H,s), 7.49(1H,d,J=8.4Hz), 7.57(2H,d,J=8.1Hz), 7.82(2H,d,J=8.1Hz), 8.10(1H,dd,J=2.2,8.4Hz), 8.78(1H,d,J=2.2Hz).
【0354】
Example 289
7-[4-(4-chlorobenzoyl)benzyloxy]-3-ethyl-6-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(4-chlorobenzoyl)benzyl bromide (450 mg) was added to a solution of 3-ethyl-6-methyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (298 mg) and potassium carbonate (363 mg) in dimethylformamide (10 ml), and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and water/ethyl acetate was added to the residue. The mixture was extracted with ethyl acetate and recrystallized from ethyl acetate to give the title compound (205 mg) as a colorless solid.
IR(KBr)ν: 1670, 1640, 1570, 1490 cm^-1.
NMR (CDCl₃)δ: 1.31(3H,t,J=7.2Hz), 2.06(3H,s), 3.34(2H,q,J=7.2Hz), 5.50(2H,s), 6.39(1H,s), 7.47(2H,d,J=8.1Hz), 7.54(2H,d,J=8.1Hz), 7.77(2H,d,J=8.1Hz), 7.80(2H,d,J=8.1Hz).
【0355】
Example 290
2-[4-(6-chloronicotinoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone
3,5-Dimethyl-2-mercapto-4(3H)-quinazolinone (2.1 g) was suspended in methanol-THF-water (3:3:1) (70 ml), 1N aqueous sodium hydroxide solution (11 ml) was added, and the mixture was stirred until homogeneous. Next, 4-(6-chloronicotinoyl)benzyl bromide (3.1 g) was added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the residue was washed successively with water, methanol, and diisopropyl ether, and then dried to obtain 3.2 g of a white powder.
IR(KBr): 1660, 1580, 1555 cm^-1.
NMR (CDCl₃)：δ 2.84(3H,s), 3.54(3H,s), 4.60(2H,s), 7.15(1H,d,J=7.8Hz), 7.43(1H,d,J=7.8Hz), 7.47(1H,d,J=8.2Hz), 7.54(1H,dd,J=7.8 and 7.8Hz), 7.64(2H,d,J=8.2Hz), 7.76(2H,d,J=8.2Hz), 8.07(1H,dd,J=2.2 and 8.2Hz), 8.75(1H,d,J=2.2Hz).
[0356]
Example 291
3,5-dimethyl-2-[4-[6-(4-methyl-1-piperazinyl)nicotinoyl]benzylthio]-4(3H)-quinazolinone dihydrochloride
2-[4-(6-chloronicotinoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (218 mg) was dissolved in pyridine (3 mL), 1-methylpiperazine (75 mg) was added, and the mixture was stirred at 90°C for 3 hours. The reaction mixture was concentrated and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. 1N hydrochloric acid (1.2 mL) was added to the organic layer concentrated to 10 mL, and the mixture was extracted with water. The aqueous layer was made basic with saturated aqueous sodium bicarbonate and extracted again with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. This mixture was concentrated to 5 mL, and 4N hydrogen chloride/ethyl acetate (0.4 mL) was added. The precipitate was collected by filtration, washed with ethyl acetate, and dried to obtain 185 mg of a white powder.
mp 187-189℃
IR(KBr)：3450, 1660, 1640, 1600, 1550cm^-1.
¹H-NMR (DMSO): δ 2.75(3H,s), 2.85(3H,s), 2.96-3.20(2H,m), 3.45(3H,s), 3.30-3.59(4H,m), 4.51-4.63(2H,m), 4.64(2H,s), 7.06(1H,d,J=9.3Hz), 7.21(1H,d,J=7.7Hz), 7.47(1H,d,J=7.7Hz), 7.63(1H,dd,J=7.7 and 7.7Hz), 7.65(2H,d,J=8.6Hz), 7.71(2H,d,J=8.6Hz), 7.97(1H,dd,J=2.2 and 9.3Hz), 8.50 (1H, d, J = 2.2 Hz).
【0357】
Example 292
3,5-dimethyl-2-[4-[6-(4-piperidino-1-piperidinyl)nicotinoyl]benzylthio]-4(3H)-quinazolinone dihydrochloride
2-[4-(6-chloronicotinoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (436 mg) was dissolved in pyridine (5 mL), 4-piperidinopiperidine (252 mg) was added, and the mixture was stirred at 90°C for 3 hours. The reaction mixture was concentrated and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel chromatography (dichloromethane-methanol (9:1)). This was dissolved in ethyl acetate (5 mL), and 4N hydrogen chloride/ethyl acetate (0.8 mL) was added. The precipitate was collected by filtration, washed with ethyl acetate-ethanol, and dried to obtain 392 mg of a white powder.
mp 140-142℃
IR(KBr)：3400, 1710, 1660, 1640, 1600, 1550cm^-1.
¹H-NMR (DMSO): δ 1.28-2.03(8H,m), 2.13-2.30(2H,m), 2.75(3H,s), 2.79-3.13(4H,m), 3.29-3.56(3H,m), 3.45(3H,s), 4.65-4.75(2H,m), 4.65(2H,s), 7.10(1H,d,J=9.0Hz), 7.21(1H,d,J=7.9Hz), 7.47(1H,d,J=7.9Hz), 7.63(1H,dd,J=7.9 and 7.9Hz), 7.66(2H,d,J=8.4Hz), 7.71(2H,d,J=8.4Hz), 7.96(1H,dd,J=1.8 and 9.0Hz), 8.42(1H,d,J=1.8Hz).
【0358】
Example 293
3,5-dimethyl-2-[4-[6-(2-pyrimidinylthio)nicotinoyl]benzylthio]-4(3H)-quinazolinone
2-[4-(6-chloronicotinoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (214 mg) was dissolved in DMF (3 mL), and 2-mercaptopyrimidine (66 mg) and N,N-diisopropylethylamine (96 mg) were added. The mixture was stirred at 100°C for 8 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel chromatography (n-hexane-ethyl acetate (1:1)), washed with diethyl ether, and dried to obtain 87 mg of a white powder.
IR(KBr): 1660, 1580, 1550 cm-¹.
¹H-NMR (CDCl₃): δ 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.11(1H,d,J=4.8Hz), 7.15(1H,d,J=7.7Hz), 7.43(1H,d,J=7.7Hz), 7.55(1H,dd,J=7.7 and 7.7Hz), 7.64(2H,d,J=8.3Hz), 7.81(2H,d,J-8.3Hz), 8.02(1H,d,J=8.3Hz), 8.12(1H,dd,J=2.2 and 8.3Hz), 8.60(2H,d,J=4.8Hz), 8.93(1H,d,J=2.2Hz).
【0359】
Example 294
5-[4-(4-chlorobenzoyl)benzyl]-1,3,6-trimethyl-pyrrolo[3,2-d]pyrimidine-2,4-dione
To a solution of 1,3,6-trimethyl-pyrrolo[3,2-d]pyrimidine-2,4-dione (0.120 g, 0.622 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (0.153 g, 0.494 mmol) in DMF (10 ml), potassium carbonate (0.121 g, 0.875 mmol) was added and the mixture was stirred at room temperature overnight. After removing the solvent under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the organic layer was diluted with MgSO₄The residue was recrystallized from ethyl acetate to give colorless prisms (0.080 g, 38%).
IR(KBr)ν: 1691, 1648, 1547, 1506, 1406, 1281, 1086, 928, 748 cm^-1.
NMR (CDCl₃)δ: 2.25(3H,s), 3.39(3H,s), 3.47(3H,s), 5.72(2H,s), 5.83(1H,s), 7.12(2H,d,J=8.3Hz), 7.44(2H,d,J=8.6Hz), 7.71(2H,d,J=8.3Hz), 7.72(2H,d,J=8.6Hz).
【0360】
Example 295
3,5-dimethyl-2-[4-[6-[1-(2-dimethylaminoethyl)-5-tetrazolylthio]nicotinoyl]benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 293.
mp 134-135℃
IR(KBr): 1660, 1575, 1550cm^-1.
¹H-NMR (CDCl₃): δ 2.21(6H,s), 2.80(2H,t,J=6.2Hz), 2.84(3H,s), 3.54(3H,s), 4.51(2H,t,J=6.2Hz), 4.59(2H,s), 7.15(1H,d,J=7.8Hz), 7.42(1H,d,J=7.8Hz), 7.49(1H,d,J=8.4Hz), 7.54(1H,dd,J=7.8 and 7.8Hz), 7.63(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 8.02(1H,dd,J=2.2 and 8.4Hz), 8.71(1H,d,J=2.2Hz).
[0361]
Example 296
2-[4-(4-chlorobenzoyl)phenylthiomethyl]-3,5-dimethyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
mp 131.5-132.5℃
IR(KBr)：1670, 1650, 1585, 1560 cm^-1.
¹H-NMR (CDCl₃): δ 2.87(3H,s), 3.70(3H,s), 4.32(2H,s), 7.22(1H,d,J=7.8Hz), 7.43(1H,d,J=7.8Hz), 7.44(2H,d,J=8.8Hz), 7.55(1H,dd,J=7.8Hz and 7.8Hz), 7.59(2H,d,J=8.5Hz), 7.68(2H,d,J=8.8Hz), 7.69(2H,.d,J=8.5Hz).
【0362】
Example 297
3,5-dimethyl-2-[4-[4-[2-[1-(2-dimethylaminoethyl)-5-tetrazolyl〕Thioethoxy]benzoyl]benzylthio]-4(3H)-quinazolinone
2-[4-[4-(2-chloroethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (240 mg) was dissolved in DMF (3 ml), sodium iodide (75 mg) was added, and the mixture was stirred at 90°C for 30 minutes. Subsequently, 1-(2-dimethylaminoethyl)-5-mercaptotetrazole (104 mg) and N,N-diisopropylethylamine (97 mg) were added, and the mixture was stirred at 90°C for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was washed with diethyl ether and ethyl acetate and dried to obtain 100 mg of a white powder.
IR(KBr)：1670, 1600, 1550 cm^-1.
¹H-NMR (CDCl₃): δ 2.26(6H,s), 2.77(2H,t,J=6.4Hz), 2.85(3H,s), 3.55(3H,s), 3.73(2H,t,J=6.0Hz), 4.32(2H,t,J=6.4Hz), 4.44(2H,t,J=6.0Hz), 4.60(2H,s), 6.97(2H,d,J=8.9Hz), 7.16(1H,d,J=7.7Hz), 7.45(1H,d,J=7.7Hz), 7.55(1H,dd,J=7.7 and 7.7Hz), 7.59(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.81 (2H, d, J = 8.9 Hz).
【0363】
Example 298
2-[4-(4-chlorobenzoyl)benzylthio]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 1.
IR(KBr): 1660, 1630, 1510 cm^-1.
¹H-NMR (CDCl₃): δ 2.24(3H,s), 4.60(2H,s), 7.08(1H,dd,J=7.1 and 7.1Hz), 7.45(1H,d,J=8.6Hz), 7.53(1H,d,J=7.1Hz), 7.57(2H,d,J=8.0Hz), 7.68(1H,dd,J=7.1 and 7.1Hz), 7.73(2H,d,J=8.0Hz), 7.73(2H,d,J=8.6Hz), 9.00(1H,d,J=7.1Hz).
fruitExample 299
3,5-dimethyl-2-[4-(4-(2,2,2-trifluoroethylcarbonyl)benzoyl)benzyl]thio-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 206.
IR:(KBr)ν:3207, 1660, 1554, 1495, 1360, 1282, 1236, 1070, 930, 835, 746 cm^-1.
NMR (CDCl₃)δ(ppm): 2.84(3H,s), 3.55(3H,s), 4.16(2H,dq,J=9.0, 6.8Hz), 6.46(1H,t,J=6.8Hz), 7.15(1H,d,J=7.0Hz), 7.43(1H,d,J=7.0Hz), 7.54(1H,t,J=7.0Hz), 7.62(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.84(2H,d,J=8.4Hz), 7.90(2H,d,J=8.4Hz).
【0364】
Example 300
6-ethyl-7-methyl-1-[4-(4-trifluoromethylbenzoyl)benzyl]-imidazo[1,2-a]pyrimidin-5(1H)-one
The title compound was synthesized in the same manner as in Example 163.
IR:(KBr)ν:3097, 2971, 2489, 1695, 1658, 1596, 1450, 1410, 1331, 1279,1180, 1132, 1066, 860, 773, 687 cm^-1.
NMR: (DMSO-d₆)δ: 1.04(3H,t,J=7.4Hz), 2.35(3H,s), 3.69(2H,q,J=7.4Hz), 5.43(2H,s), 7.50(1H,d,J=2.8Hz), 7.60(1H,d,J=2.8Hz), 7.65(1H,d,J=2.8Hz), 7.77(2H,d,J=7.6Hz), 7.90(4H,s).
Example 301
2-[4-(4-chlorobenzoyl)benzyloxy]-3,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 121.
IR: (KBr)ν: 1672, 1589, 1547, 1484, 1331, 1279, 1163 cm^-1.
NMR: (CDCL₃)δ(ppm): 2.21(3H,s), 3.10(3H,s), 5.57(2H,s), 6.63(1H,d,J=7.0Hz), 7.24(1H,d,J=9.0Hz), 7.39(1H,dd,J=9.0, 7.0Hz), 7.47(2H,d,J=8.3Hz), 7.57(2H,d,J=8.1Hz), 7.76(2H,d,J=8.3Hz), 7.47(2H,d,J=8.1Hz).
【0365】
Example 302
3,6-dimethyl-2-[4-(4-fluorobenzoyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 121.
IR: (KBr)ν: 1672, 1593, 1547, 1485, 1331, 1279, 1279, 1230, 1161, 928, 854, 797, 760 cm^-1.
NMR: (CDCl₃)δ(ppm): 2.12(3H,s), 3.10(3H,s), 5.57(2H,s), 6.63(1H,d,J=6.7Hz), 7.14(1H,d,J=8,5Hz), 7.23(2H,d,J=9.5Hz), 7.39(1H,dd,J=8.5, 6.7Hz), 7.57(2H,d,J=8.0Hz), 7.79(2H,d,J=8.0Hz), 7.85(2H,dd,J=9.5, 5.7Hz).
Example 303
2-[4-(6-chloronicotinoyl)benzyloxy]-3,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 121.
IR: (KBr)ν: 1666, 1585, 1485, 1331, 1282, 1163 cm^-1.
NMR: (CDCl₃)δ(ppm): 2.12(3H,s), 3.10(3H,s), 5.58(2H,s), 6.62(1H,d,J=7.4Hz), 7.23(1H,d,J=8,6Hz), 7.39(1H,dd,J=8.6, 7.4Hz), 7.48(1H,d,J=8.4Hz), 7.60(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 8.09(1H,dd,J=8.4, 2.6Hz), 8.77(1H,d,J=2.6Hz).
[0366]
Example 304
3,6-dimethyl-2-[4-(4-hydroxybenzoyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 121.
IR:(KBr)ν:3410, 2921, 1645, 1591, 1481, 1282, 1165, 926, 731 cm^-1.
NMR: (CDCl₃)δ(ppm): 2.13(3H,s), 3.11(3H,s), 5.25(2H,s), 6.65(1H,d,J=6.6Hz), 7.04(2H,d,J=8,7Hz), 7.27(1H,d,J=8.8Hz), 7.41(1H,dd,J=8.8, 6.6Hz), 7.54(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.77(2H,d,J=8.7Hz).
Example 305
2-[4-(6-chloronicotinoyl)benzylthio]-5-ethyl-3-methyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR: (KBr)ν: 1666, 1552, 1462, 1281, 1159, 1099, 926 cm^-1.
NMR: (CDCl₃)δ(ppm): 1.27(3H,t,J=7.4Hz), 3.30(2H,q,J=7.4Hz), 3.56(3H,s), 4.60(2H,s), 7.19(1H,d,J=7.4Hz), 7.46(1H,t,J=7.4Hz), 7.47(1H,d,J=8.2Hz), 7.57(1H,d,J=7.4Hz), 7.65(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 8.08(1H,dd,J=8.4, 2.4Hz), 8.75(1H,d,J=2.4Hz).
【0367】
Example 306
3,6-dimethyl-2-[4-[6-(4-piperidinopiperidino)Nicotinoyl]benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 197.
IR:(KBr)ν:3423, 2937, 1643, 1549, 1483, 1446, 1331, 1282, 1238, 1177,1003 cm^-1.
NMR: (DMSO)δ(ppm): 1.60-1.97(5H,m), 1.98(3H,s), 2.10-2.30(2H,m), 2.80-3.10(4H,m), 2.98(3H,s), 3.30-3.50(2H,m), 3.60-3.70(4H,m), 5.60(2H,s), 6.87(1H,d,J=7.2Hz), 7.00-7.09(2H,m), 7.30(1H,d,J=9.0Hz), 7.62(2H,d,J=7.6Hz), 7.71(2H,d,J=7.6Hz), 7.95(1H,dd,J=7.6, 2.2Hz), 8.46 (1H, d, J = 2.2 Hz).
Example 307
3,6-dimethyl-2-[4-[6-(4-phenylpiperazinyl)nicotinoyl〕benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one trihydrochloride
The title compound was synthesized in the same manner as in Example 197.
IR:(KBr)ν:3456, 1664, 1637, 1599, 1487, 1439, 1288, 1261, 1187 cm^-1.
NMR: (DMSO)δ(ppm): 1.19(3H,s), 2.99(3H,s), 3.39(4H,m), 3.89(4H,m), 5.58(2H,s), 6.88(1H,d,J=8.0Hz), 6.95(1H,m), 7.07-7.20(3H,m), 7.28-7.35(3H,m), 7.60(1H,m), 7.62(2H,d,J=8.4Hz), 7.73(1H,d,J=8.4Hz), 8.00(1H,dd,J=8.8,2.2Hz), 8.49(1H,d,J=2.2Hz).
【0368】
Example 308
3,6-dimethyl-2-[4-[4-(2-morpholinoethoxy)benzoyl]benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride
The title compound was synthesized in the same manner as in Example 156.
IR: (KBr)ν: 1649, 1599, 1483, 1282, 1255, 1167, 928 cm^-1.
NMR: (CDCl₃)δ(ppm): 2.12(3H,s), 2.60(4H,t,J=4.8Hz), 2.85(2H,t,J=6.0Hz), 3.75(4H,t,J=8.4Hz), 4.20(2H,t,J=6.0Hz), 5.56(2H,s), 6.63(1H,d,J=6.8Hz), 6.97(2H,d,J=8.8Hz), 7.25(1H,d,J=8.7Hz), 7.39(1H,dd,J=8.7, 6.8Hz), 7.55(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz), 7.82(2H,d,J=8.8Hz).
Example 309
5-ethyl-3-methylLu2-[4-[6-(4-piperidinopiperidino)Nicotinoyl]benzylthio]-4(3H)-quinazolinone trihydrochloride
The title compound was synthesized in the same manner as in Example 197.
IR:(KBr)ν:3377, 2933, 2646, 2519, 1647, 1551, 1442, 1317, 1279, 1241,1180, 1093, 1003, 926, 822, 748 cm^-1.
NMR: (DMSO)δ(ppm): 1.18(3H,t,J=7.2Hz), 1.50-1.90(7H,m), 2.10-2.30(2H,m), 2.80-3.10(4H,m), 3.22(2H,q,J=7.2Hz), 3.30-3.50(4H,m), 3.48(3H,s), 4.65(2H,s), 4.70(1H,m), 7.02(1H,d,J=8.4Hz), 7.22(1H,d,J=8.6Hz), 7.48(1H,d,J=9.0Hz), 7.64(1H,d,J=8.7Hz), 7.66(1H,dd,J=8.6, 8.4Hz), 7.71(2H,d,J=8.7Hz), 8.13(1H,dd,J=9.0, 2.6Hz), 8.45(1H,d,J=2.6Hz).
[0369]
Example 310
5-ethyl-3-methyl-2-[4-[6-(4-phenylpiperazinyl)nicotinoyl]benzylthio]-4(3H)-quinazolinone trihydrochloride
The title compound was synthesized in the same manner as in Example 197.
IR:(KBr)ν:3406, 1968, 1637, 1605, 1552, 1435, 1313, 1255, 1182, 1091,760, 696 cm^-1.
NMR: (DMSO)δ(ppm): 1.18(3H,t,J=7.2Hz), 3.22(2H,q,J=7.2Hz), 3.40(4H,m),3.48(3H,s), 3.89(4H,m), 4.65(2H,s), 6.90-7.40(6H,m), 7.48(2H,d,J=8.0Hz), 7.64(2H,d,J=8.0Hz), 7.62-7.80(3H,m), 8.00(1H,m), 8.46(1H,m).
Example 311
3-(2-Acetoxyethyl)-7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 49.
¹H-NMR (CDCl₃)δ: 2.06(3H,s), 2.42(3H,s), 4.22-4.28(2H,m), 4.37-4.43(2H,m), 5.34(2H,s), 6.59(1H,s), 7.27(2H,d,J=8.2Hz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.2Hz), 7.80(1H,s).
【0370】
Example 312
7-[4-(4-chlorobenzoyl)benzyl]-3-(2-Hydroxyethyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
3-(2-Acetoxyethyl)7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one (464 mg) was dissolved in methanol (12 mL), 1N sodium hydroxide (2 mL) was added, and DME (6 mL) was added to obtain a homogeneous solution. After stirring for 4 hours, 1N hydrochloric acid (2 mL) was added, and the solvent was evaporated under reduced pressure. Water was added to finely divide the crystals, which were then collected by filtration, washed with water and methanol, and dried to obtain the title compound (402 mg) as a crystalline powder.
¹H-NMR (CDCl₃)δ: 2.42(3H,d,J=1.0Hz), 2.86(1H,t,J=4.4Hz), 3.97(2H,q,J=4.4Hz), 4.18(2H,t,J=4.4Hz), 5.34(2H,s), 6.60(1H,d,J=1.0Hz), 7.27(2H,d,J=8.2Hz), 7.45(2H,d,J=8.6Hz), 7.73(4H,d,J=8.4Hz), 7.80(1H,s).
[0371]
Example 313
5-[4-(6-chloronicotinoyl)benzyl]-1,3-dimethyl-pyrrolo[3,2-d]pyrimidine-2,4-dione
The title compound was synthesized in the same manner as in Example 163.
IR: (KBr)ν: 1695, 1655, 1551, 1467, 1275, 1099, 922, 758 cm^-1.
¹H-NMR: (CDCl₃)δ: 3.39(3H,s), 3.49(3H,s), 5.67(2H,s), 5.67(2H,s), 6.01(1H,d,J=3.0Hz), 7.02(1H,d,J=3.0Hz), 7.32(2H,d,J=8.4Hz), 7.46(1H,d,J=8.1Hz), 7.75(1H,d,J=8.4Hz), 8.06(1H,dd,J=8.1, 2.2Hz), 8.74(1H,d,J=2.2Hz).
Example 314
1,3-dimethyl-5-[4-(4-fluorobenzoyl)benzyl]-pyrrolo[3,2-d]pyrimidine-2,4-dione
The title compound was synthesized in the same manner as in Example 163.
IR: (KBr)ν: 1686, 1647, 1601, 1551, 1468, 1412, 1275, 1244, 1153, 1061,
928, 856, 746 cm^-1.
¹H-NMR: (CDCl₃): δ3.40(3H,s), 3.49(3H,s), 5.66(2H,s), 6.01(1H,d,J=2.9Hz), 7.02(1H,d,J=2.9Hz), 7.15(2H,t,J=8.6Hz), 7.30(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.82(2H,dd,J=8.6, 5.4Hz).
[0372]
Example 315
1,3-dimethyl-5-[4-[6-(4-piperidinopiperidino)nicotinoyl〕benzyl]-pyrrolo[3,2-d]pyrimidine-2,4-dione dihydrochloride
The title compound was synthesized in the same manner as in Example 197.
IR:(KBr)ν:3417, 1689, 1641, 1551, 1464, 1269, 746 cm^-1.
¹H-NMR (DMSO-d₆)δ: 1.40(2H,m), 1.68-1.82(8H,m), 2.20-2.26(2H,m), 2.80-3.00(5H,m), 3.22(3H,s), 3.39(3H,s), 4.64-4.69(2H,m), 4.64(2H,s), 6.24(1H,d,J=2.4Hz), 7.10(1H,d,J=9.1Hz), 7.34(2H,d,J=8.4Hz), 7.52(1H,d,J=2.4Hz), 7.65(2H,d,J=8.4Hz), 7.96(1H,dd,J=9.1, 2.2Hz), 8.40(1H,d,J=2.4Hz).
Example 316
1,3-Dimethyl-5-[4-[6-(4-phenylpiperazino)nicotinoyl]benzyl]-pyrrolo[3,2-d]pyrimidine-2,4-dione dihydrochloride
The title compound was synthesized in the same manner as in Example 197.
IR:(KBr)ν:3413, 1691, 1641, 1549, 1464, 1255, 750 cm^-1.
¹H-NMR (DMSO-d₆)δ: 3.22(3H,s), 3.39(4H,m), 3.57(3H,s), 5.65(2H,s), 6.24(1H,d,J=3.0Hz), 6.90-7.30(6H,m), 7.34(2H,d,J=8.0Hz), 7.52(1H,d,J=3.0Hz), 7.66(2H,d,J=8.0Hz), 7.98(1H,dd,J=9.0, 2.2Hz), 8.44(1H,d,J=2.2Hz).
[0373]
Example 317
2-[4-(6-chloronicotinoyl)benzylthio]-6-hydroxy-3-methyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR:(KBr)ν:3209, 1660, 1554, 1495, 1360, 1281, 1236, 1105, 1070, 928, 835, 748 cm^-1.
¹H-NMR (DMSO-d₆)δ(ppm): 3.48(3H,s), 4.63(2H,s), 7.27(1H,dd,J=8.8, 2.6Hz), 7.38(1H,d,J=2.7Hz), 7.52(1H,d,J=8.8Hz), 7.69(1H,d,J=8.2Hz), 7.75(4H,s), 8.13(1H,dd,J=8.2, 2.4Hz), 8.69(1H,d,J=2.4Hz).
Example 318
2-[4-(4-fluorobenzoyl)benzylthio]-6-hydroxy-3-methyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR:(KBr)ν:3200, 1654, 1602, 1552, 1494, 1363, 1277, 1232, 1147, 1666,833 cm^-1.
¹H-NMR: (CDCl₃)δ: 3.61(3H,s), 4.59(2H,s), 5.46(1H,brs), 6.51(1H,brs), 7.15(2H,t,J=8.8Hz), 7.30(1H,dd,J=8.8, 2.6Hz), 7.54(2H,d,J=8.8Hz), 7.60(2H,d,J=8.0Hz), 7.74(2H,d,J=8.0Hz), 7.78(1H,m), 7.82(1H,dd,J=5.4, 2.6Hz).
[0374]
Example 319
6-hydroxy-2-[4-(4-trifluoromethylbenzoyl)benzylthio]-3-methyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR:(KBr)ν:3346, 1678, 1610, 1556, 1493, 1323, 1143, 1063, 928, 833 cm^-1.
¹H-NMR (CDCl₃)δ: 3.61(3H,s), 4.59(2H,s), 7.29(1H,dd,J=8.9, 3.0Hz), 7.53(1H,d,J=8.9Hz), 7.62(1H,d,J=8.2Hz), 7.72-7.79(6H,m), 7.87(2H,d,J=8.0Hz).
Example 320
3-methyl-6-(2,2,2-trifluoroethylaminocarbonyloxy)-2-[4-(4-trifluoromethylbenzoyl)benzylthio]-4(3H)-quinazolinone
To a solution of 6-hydroxy-3-methyl-2-[4-(4-trifluoromethylbenzoyl)benzyl]thio-4(3H)-quinazolinone (0.300 g, 0.638 mmol) in DMF (5.0 mL), 4-nitrophenol chlorocarbonate (0.196 g, 0.973 mmol) and triethylamine (0.25 mL) were added and stirred at room temperature for 1 hour. 2,2,2-Trifluoroethylamine (0.148 g, 0.989 mmol) was added and stirred for an additional 14 hours. After removing the solvent, the residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was then filtered with MgSO 4₄The residue was purified on a silica gel column (isopropyl ether:acetone=10:1) and then recrystallized from hexane-isopropyl ether to give colorless needles (0.080 g, 21%).
IR:(KBr)ν:3305, 1726, 1674, 1552, 1483, 1412, 1333, 1284, 1246, 1159,1111, 1068, 1016, 933, 837, 773, 686 cm^-1.
¹H-NMR (CDCl₃)δ: 3.60(3H,s), 3.92(2H,m), 4.60(2H,s), 5.46(1H,brs), 7.51(1H,dd,J=8.5, 2.5Hz), 7.61(1H,d,J=8.8Hz), 7.62(2H,d,J=8.0Hz), 7.74(2H,d,J=8.4Hz), 7.77(2H,d,J=8.0Hz), 7.87(2H,d,J=8.4Hz), 7.94(1H,d,J=2.5Hz).
【0375】
Example 321
2-(4-benzoylbenzylthio)-3,5-dimethyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR: (KBr)ν: 1659, 1552, 1308, 1277, 1088, 931, 858, 802, 702 cm^-1.
¹H-NMR (CDCl₃)δ: 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.15(1H,d,J=7.2Hz),7.44-7.62(7H,m), 7.76-7.81(4H,m).
Example 322
2-[4-(4-chlorobenzoyl)benzylthio]-5-methoxymethyl-3-methyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR: (KBr)ν: 1660, 1552, 1435, 1404, 1308, 1281, 1086, 924, 804, 741, 687 cm^-1.
¹H-NMR (CDCl₃)δ:3.55(3H,s), 3.56(3H,s), 4.60(2H,s), 5.14(2H,s), 7.45(2H,d,J=8.6Hz), 7.52(1H,dd,J=7.4, 1.8Hz), 7.59-7.66(3H,m), 7.70-7.77(5H,m).
[0376]
Example 323
2-[4-(4-fluorobenzoyl)benzylthio]-5-methoxymethyl-3-methyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR: (KBr)ν: 1663, 1589, 1555, 1439, 1408, 1308, 1279, 1234, 1084, 924, 852, 746, 687, 575 cm^-1.
¹H-NMR (CDCl₃)δ: 3.55(3H,s), 3.56(3H,s), 4.60(2H,s), 5.14(2H,s), 7.15(2H,t,J=9.0Hz), 7.52(1H,dd,J=7.6, 2.0Hz), 7.60(2H,d,J=8.4Hz), 7.64(1H,m), 7.68(1H,t,J=7.6Hz), 7.74(2H,d,J=8.4Hz), 7.83(2H,dd,J=9.0, 5.4Hz).
Example 324
2-[4-(4-chlorobenzoyl)benzylthio]-3-methyl-5-(2,2,2-trifluoroethoxymethyl)-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1676, 1645, 1558, 1443, 1409, 1309, 1157, 1088, 806, 693 cm^-1.
¹H-NMR (CDCl₃)δ: 3.55(3H,s), 4.05(2H,q,J=8.4Hz), 4.60(2H,s), 5.36(2H,s),7.45(2H,d,J=8.4Hz), 7.54(1H,d,J=6.6Hz), 7.60(2H,d,J=8.4Hz), 7.61(1H,d,J=6.6Hz), 7.68(1H,t,J=6.6Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz).
[0377]
Example 325
2-[4-(4-fluorobenzoyl)benzylthio]-3-methyl-5-(2,2,2-trifluoroethoxymethyl)-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1662, 1603, 1558, 1443, 1412, 1279, 1161, 1088, 964, 928, 851, 690 cm^-1.
¹H-NMR (CDCl₃)δ: 3.55(3H,s), 4.04(2H,q,J=8.6Hz), 4.60(2H,s), 5.36(2H,s),7.15(2H,t,J=8.8Hz), 7.53-7.67(5H,m), 7.73(2H,d,J=8.4Hz), 7.84(2H,dd,J=8.8, 5.4Hz).
Example 326
5-Methoxymethyl-3-methyl-2-[4-(4-trifluoromethylbenzoyl)benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1660, 1560, 1408, 1315, 1279, 1161, 1134, 1086, 1063 cm^-1.
¹H-NMR (CDCl₃)δ: 3.55(3H,s), 4.60(2H,s), 5.14(2H,s), 7.50(1H,d,J=8.4Hz),7.62(2H,d,J=8.0Hz), 7.68(1H,d,J=8.4Hz), 7.72-7.79(5H,m), 7.87(2H,d,J=8.0Hz).
【0378】
Example 327
3-methyl-5-(2,2,2-trifluoroethoxymethyl)-2-[4-(4-trifluoromethylbenzoyl)benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1678, 1659, 1554, 1331, 1282, 1169, 1128, 1090 cm^-1.
¹H-NMR (CDCl₃)δ: 3.55(3H,s), 4.05(2H,q,J=8.8Hz), 4.61(2H,s), 5.36(2H,s),7.55(1H,d,J=7.8Hz), 7.62(2H,d,J=8.0Hz), 7.66(1H,d,J=7.8Hz), 7.72-7.79(5H,m).
Example 328
1-[4-(4-fluorobenzoyl)benzyl]-6,7,8,9-tetrahydroimidazo[2,1-b]quinazolinon-5(1H)-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1657, 1589, 1527, 1418, 1277, 1213, 1159, 928 cm^-1.
¹H-NMR (CDCl₃)δ: 1.82(4H,m), 2.65(2H,t,J=5.6Hz), 2.74(2H,t,J=5.6Hz), 5.33(2H,s), 6.85(1H,d,J=2.6Hz), 7.17(2H,d,J=8.2Hz), 7.40(2H,d,J=8.0Hz), 7.55(1H,d,J=2.6Hz), 7.78(2H,d,J=8.0Hz), 7.83(2H,dd,J=8.2, 4.8Hz).
[0379]
Example 329
1-[4-(4-trifluoroMethyl[benzoyl]benzyl]-6,7,8,9-tetrahydroimidazo[2,1-b]quinazolinon-5(1H)-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1659, 1583, 1527, 1417, 1321, 1277, 1168, 1128, 1064, 928 cm^-1.
¹H-NMR (CDCl₃)δ: 1.79-1.83(4H,m), 2.65(2H,t,J=5.8Hz), 2.73(2H,t,J=5.8Hz), 5.34(2H,s), 6.84(1H,d,J=2.6Hz), 7.42(2H,d,J=8.2Hz), 7.55(1H,d,J=2.6Hz), 7.76(2H,d,J=8.2Hz), 7.81(2H,d,J=8.4Hz), 7.88(2H,d,J=8.2Hz).
Example 330
3,6-dimethyl-2-[4-(4-trifluoromethylbenzoyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1672, 1599, 1549, 1487, 1331, 1276, 1167, 1113, 1063, 928, 802, 766 cm^-1.
¹H-NMR (CDCl₃)δ: 2.12(3H,s), 3.10(3H,s), 5.58(2H,s), 6.62(1H,d,J=6.4Hz),7.24(1H,d,J=9.0Hz), 7.38(1H,dd,J=9.0, 6.4Hz), 7.58(2H,d,J=8.4Hz), 7.75(2H,d,J=8.4Hz), 7.82(2H,d,J=8.4Hz), 7.89(2H,d,J=8.4Hz).
【0380】
Example 331
3,6-dimethyl-2-[4-(4-(4-fluorophenyl)piperazinocarbonyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1678, 1632, 1595, 1487, 1444, 1331, 1282, 1234, 1163, 1012, 808 cm^-1.
¹H-NMR (CDCl₃)δ：2.10(3H,s), 3.10(3H,s), 3.11(4H,brs), 3.63(2H,brs), 3.87(2H,brs), 5.51(2H,s), 6.62(1H,d,J=7.2Hz), 6.88(2H,dd,J=8.7, 4.8Hz), 6.96(2H,d,J=8.0Hz), 7.24(1H,d,J=7.0Hz), 7.39(1H,dd,J=7.2, 6.6Hz), 7.44(2H,d,J=8.0Hz), 7.49(2H,d,J=8.7Hz).
Example 332
3,6-dimethyl-2-[4-(4-(2-pyridyl)piperazinocarbonyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1674, 1632, 1595, 1551, 1485, 1435, 1375, 1332, 1279, 1238, 1163, 1010, 764 cm^-1.
¹H-NMR (CDCl₃)δ: 2.10(3H,s), 3.10(3H,s), 3.59(6H,brs), 3.85(2H,brs), 5.52(2H,s), 6.61-6.71(3H,m), 7.24(1H,d,J=9.0Hz), 7.35-7.59(6H,m), 8.20(1H,d,J=5.4Hz), 7.39(1H,dd,J=7.2, 6.6Hz), 7.44(2H,d,J=8.0Hz), 7.49(2H,d,J=8.7Hz).
[0381]
Example 333
1-[4-(4-chlorobenzoyl)benzyl]-1,6,7,8,9,10-hexahydrocyclopent[d]imidazo[1,2-a]-pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 2918, 1655, 1584, 1520, 1308, 1277, 1190, 1090, 928, 696 cm^-1.
¹H-NMR (CDCl₃)δ: 1.50-1.80(5H,m), 1.84(1H,m), 2.80-2.91(4H,m), 5.34(2H,s), 6.85(1H,d,J=2.6Hz), 7.40(2H,d,J=8.0Hz), 7.46(2H,d,J=8.4Hz), 7.56(1H,d,J=2.6Hz), 7.74(2H,d,J=8.4Hz), 7.77(2H,d,J=8.0Hz).
Example 334
1-[4-(4-trifluoromethylbenzoyl)benzyl]-1,6,7,8-tetrahydro-5H-cyclopenta[d〕stomachMidazo[1,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1657, 1570, 1520, 1475, 1327, 1277, 1167, 1128, 1063, 700 cm^-1.
¹H-NMR (CDCl₃)δ: 2.15(2H,m), 2.90(2H,t,J=6.4Hz), 2.94(2H,t,J=7.4Hz), 5.37(2H,s), 6.89(1H,d,J=2.6Hz), 7.41(2H,d,J=8.2Hz), 7.63(1H,d,J=2.6Hz), 7.76(2H,d,J=8.2Hz), 7.82(2H,d,J=8.2Hz), 7.88(2H,d,J=8.2Hz).
【0382】
Example 335
1-[4-(4-fluorobenzoyl)benzyl]-1,6,7,8-tetrahydro-5H-cyclopenta[d〕stomachMidazo[1,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν:1664, 1581, 1525, 1410, 1279, 1225, 1151, 928, 852, 736 cm^-1.
¹H-NMR (CDCl₃)δ: 2.13(2H,m), 2.90(2H,t,J=7.1Hz), 2.94(2H,t,J=7.1Hz), 5.36(2H,s), 6.88(1H,d,J=2.6Hz), 7.17(2H,d,J=8.7Hz), 7.39(1H,d,J=7.8Hz), 7.62(1H,d,J=2.6Hz), 7.65(2H,d,J=7.8Hz), 7.83(2H,dd,J=8.7, 5.4Hz).
Example 336
1-[4-(4-fluorobenzoyl)benzyl]-1,6,7,8,9,10-hexahydrocyclopenta[d〕stomachMidazo[1,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1655, 1587, 1522, 1277, 1227, 930, 860, 739, 704 cm^-1.
¹H-NMR (CDCl₃)δ: 1.50-1.72(4H,m), 1.80-2.00(2H,m), 2.86-2.91(4H,m), 5.34(2H,s), 6.86(1H,d,J=2.6Hz), 7.16(2H,d,J=8.8Hz), 7.41(2H,d,J=7.8Hz), 7.56(1H,d,J=2.6Hz), 7.78(2H,d,J=7.8Hz), 7.83(2H,dd,J=8.8, 5.6Hz).
【0383】
Example 337
1-[4-(4-chlorobenzoyl)benzyl]-7-methylimidazo[1,2-a]pyrimidin-5(1H)-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1676, 1657, 1580, 1533, 1423, 1277, 1165, 1088, 926, 835, 746, 685 cm^-1.
¹H-NMR (CDCl₃)δ: 2.93(3H,s), 5.36(2H,s), 5.97(1H,s), 6.88(1H,d,J=2.8Hz),7.41(2H,d,J=8.2Hz), 7.46(2H,d,J=9.0Hz), 7.59(1H,d,J=2.8Hz), 7.71(2H,d,J=9.0Hz), 7.78(2H,d,J=8.2Hz).
Example 338
1-[4-(4-chlorobenzoyl)benzyl]-6,7-diethylimidazo[1,2-a]pyrimidin-5(1H)-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1655, 1576, 1460, 1412, 1360, 1275, 1207, 1169, 1084, 933, 734, 698 cm^-1.
¹H-NMR (CDCl₃)δ: 1.16(3H,t,J=7.4Hz), 1.28(3H,t,J=7.4Hz), 2.66(2H,q,J=7.4Hz), 2.71(2H,q,J=7.4Hz), 5.33(2H,s), 6.87(1H,d,J=2.6Hz), 7.44(2H,d,J=8.0Hz), 7.46(2H,d,J=8.4Hz), 7.54(1H,d,J=2.6Hz), 7.73(2H,d,J=8.0Hz), 7.77(2H,d,J=8.4Hz).
[0384]
Example 339
6,7-diethyl-1-[4-(4-trifluoromethylbenzoyl)benzyl]-imidazo[1,2-a]pyrimidin-5(1H)-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1668, 1585, 1514, 1410, 1331, 1115, 1066, 931, 847, 769, 706cm^-1.
¹H-NMR (CDCl₃)δ: 1.16(3H,t,J=7.4Hz), 1.28(3H,t,J=7.4Hz), 2.66(2H,q,J=7.4Hz), 2.71(2H,q,J=7.4Hz), 5.33(2H,s), 6.87(1H,d,J=2.6Hz), 7.46(2H,d,J=8.4Hz), 7.54(1H,d,J=2.6Hz), 7.75(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 7.88(2H,d,J=8.4Hz).
Example 340
1-[4-(4-chlorobenzoyl)benzyl]-7-methyl-6-propyl-imidazo[1,2-a]pyrimidin-5(1H)-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν:1655, 1585, 1518, 1412, 1273, 1213, 1086, 924, 733, 698 cm^-1.
¹H-NMR (CDCl₃)δ: 1.00(3H,t,J=7.4Hz), 1.58(2H,m), 2.43(3H,s), 2.60(2H,t,J=7.0Hz), 5.33(2H,s), 6.84(1H,d,J=2.6Hz), 7.41(2H,d,J=8.0Hz), 7.46(2H,d,J=8.8Hz), 7.54(1H,d,J=2.6Hz), 7.74(2H,d,J=8.8Hz), 7.78(2H,d,J=8.0Hz).
[0385]
Example 341
7-methyl-6-propyl-1-[4-(4-trifluoromethylbenzoyl)benzyl]-imidazo[1,2-a]pyrimidin-5(1H)-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1655, 1578, 1520, 1414, 1321, 1279, 1221, 1176, 1140, 1065, 931, 708 cm^-1.
¹H-NMR (CDCl₃)δ: 1.00(3H,t,J=7.8Hz), 1.55(2H,m), 2.43(3H,s), 2.60(2H,t,J=7.6Hz), 5.34(2H,s), 6.85(1H,d,J=2.6Hz), 7.42(2H,d,J=8.4Hz), 7.54(1H,d,J=2.6Hz), 7.75(2H,d,J=8.4Hz), 7.81(2H,d,J=8.0Hz), 7.88(2H,d,J=8.0Hz).
Example 342
3,5-dimethyl-2-[4-(4-formylpiperazinylcarbonyl)benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1670, 1558, 1458, 1095, 1004 cm^-1.
¹H-NMR (CDCl₃)δ: 2.85(3H,s), 3.27-3.82(8H,m), 3.54(3H,s), 4.56(2H,s), 7.16(1H,d,J=6.7Hz), 7.34-7.60(6H,m), 8.11(1H,s).
[0386]
Example 343
3,5-dimethyl-2-[4-(4-methylpiperazinylcarbonyl)benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1683, 1473, 1307, 1093 cm^-1.
¹H-NMR (CDCl₃)δ: 2.82(3H,s), 2.85(3H,s), 3.53(3H,s), 2.60-4.21(8H,m), 4.55(2H,s), 7.16(1H,d,J=7.4Hz), 7.35-7.47(3H,m), 7.50-7.63(3H,m).
Example 344
3,5-dimethyl-2-[4-[4-(2-hydroxyethyl)piperazinylcarbonyl]benzylthio]-4(3H)-quinazolinone hydrochloride
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1668, 1558, 1471, 1093, 989, 806 cm^-1.
¹H-NMR (CDCl₃)δ: 2.75(3H,s), 3.00-3.86(15H,m), 4.60(2H,s), 7.21(1H,d,J=7.2Hz), 7.38-7.68(6H,m).
【0387】
Example 345
3,5-dimethyl-2-[4-[4-(2-pyridyl)piperazinylcarbonyl]benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1677, 1625, 1592, 1305, 1095, 1012 cm^-1.
¹H-NMR (CDCl₃)δ: 2.85(3H,s), 3.30-4.06(8H,m), 3.54(3H,s), 4.56(2H,s), 6.68(2H,m), 7.15(1H,d,J=6.6Hz), 7.36-7.60(7H,m), 8.20(1H,m).
Example 346
3,5-dimethyl-2-[4-(4-piperonylpiperazinylcarbonyl)benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1675, 1556, 1307, 1093, 1039 cm^-1.
¹H-NMR (CDCl₃)δ: 2.26-2.58(4H,m), 2.84(3H,s), 3.30-3.56(2H,brs), 3.43(2H,s), 3.53(3H,s), 3.62-3.84(2H,brs), 4.54(2H,s), 5.94(2H,s), 6.73(2H,s), 6.84(1H,s), 7.14(1H,d,J=7.6Hz), 7.35(2H,d,J=8.2Hz), 7.39-7.58(4H,m).
【0388】
Example 347
2-[4-(4-benzylpiperazinylcarbonyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1675, 1616, 1456, 1305, 1095, 933 cm^-1.
¹H-NMR (CDCl₃)δ: 2.30-2.58(4H,m), 2.84(3H,s), 3.30-3.60(2H,m), 3.53(5H,s), 3.66-3.86(2H,m), 4.53(2H,s), 7.14(1H,d,J=7.0Hz), 7.24-7.58(11H,m).
Example 348
3,5-dimethyl-2-[4-[4-(4-fluorophenyl)piperazinylcarbonyl]benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1683, 1629, 1095, 1014 cm^-1.
¹H-NMR (CDCl₃)δ: 2.85(3H,s), 2.80-3.24(4H,m), 3.54(3H,s), 3.30-4.04(4H,m), 4.55(2H,s), 6.83-7.04(4H,m), 7.15(1H,d,J=6.6Hz), 7.36-7.60(6H,m).
【0389】
Example 349
3,5-dimethyl-2-[4-[4-(2-pyrimidyl)piperazinylcarbonyl]benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1675, 1627, 1585, 1510, 1307, 1089 cm^-1.
¹H-NMR (CDCl₃)δ: 2.85(3H,s), 3.38-4.02(8H,m), 3.54(3H,s), 4.56(2H,s), 6.55(1H,t,J=4.7H), 7.15(1H,d,J=6.6Hz), 7.41(2H,d,J=8.2Hz), 7.44(1H,d,J=8.2Hz), 7.50-7.59(3H,m), 8.33(2H,d,J=4.7Hz).
Example 350
3,5-dimethyl-2-(4-morpholinocarbonylbenzylthio)-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1670, 1629, 1550, 1427, 1112, 894 cm^-1.
¹H-NMR (CDCl₃)δ: 2.85(3H,s), 3.30-3.89(8H,m), 3.53(3H,s), 4.54(2H,s), 7.15(1H,d,J=6.6Hz), 7.37(2H,d,J=8.4Hz), 7.43(1H,d,J=8.0Hz), 7.49-7.59(3H,m).
【0390】
Example 351
3,5-dimethyl-2-[3-(4-methylpiperazinylcarbonyl)benzylthio]-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1685, 1579, 1560, 1461, 1423, 1089 cm^-1.
¹H-NMR (CDCl₃)δ: 2.28(3H,s), 2.10-2.58(4H,m), 2.84(3H,s), 3.26-3.55(2H,m), 3.53(3H,s), 3.86-3.60(2H,m), 4.54(2H,s), 7.14(1H,d,J=7.2Hz), 7.26-7.58(6H,m).
Example 352
2-[4-(4-hydroxymethylpiperidylcarbonyl)benzylthio〕-3,5-dimethyl-4(3H)-quinazolinone
2-[4-(4-ethoxycarbonylpiperidylcarbonyl)benzylthio〕3.593 g of 3,5-dimethyl-4(3H)-quinazolinone was dissolved in 25 ml of THF and treated with LiBH₄(254 mg) was added and the mixture was stirred for 30 minutes, washed with 1N hydrochloric acid and saturated brine, dried and concentrated, and the resulting residue was washed with ethyl acetate to give the title compound (1.871 g) as a colorless solid.
IR(KBr)ν: 1668, 1601, 1558, 1471, 1450, 1307, 1097 cm^-1.
¹H-NMR (CDCl₃)δ: 1.04-1.90(6H,m), 2.85(3H,s), 2.66-3.20(2H,m), 3.53(5H,s), 3.56-3.96(1H,s), 4.54(2H,s), 4.55-5.00(1H,m), 7.15(1H,d,J=7.0Hz), 7.35(2H,d,J=8.2Hz), 7.43(2H,d,J=7.2Hz), 7.46-7.58(6H,m).
[0391]
Example 353
2-[4-(4-bromomethylpiperidylcarbonyl)benzylthio〕-3,5-dimethyl-4(3H)-quinazolinone
2-[4-(4-hydroxymethylpiperidylcarbonyl)benzylthio〕3,5-Dimethyl-4(3H)-quinazolinone (1.081 g) was dissolved in dichloromethane (25 ml), carbon tetrabromide (1.050 g) was added, and triphenylphosphine (982 mg) was added over 10 minutes. The mixture was stirred at room temperature for 2 hours. The salt was removed by filtration and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) and washed with ether to give the title compound (496 mg) as a colorless solid.
IR(KBr)ν: 1666, 1550, 1435, 1305, 1095, 964 cm^-1.
¹H-NMR (CDCl₃)δ: 1.08-1.50(2H,m), 1.75-2.06(3H,m), 2.85(3H,s), 2.50-3.14(2H,m), 3.32(2H,d,J=5.8Hz), 3.53(3H,s), 3.64-3.96(1H,m), 4.55(2H,s), 4.60-4.90(1H,m), 7.15(1H,d,J=7.0Hz), 7.34-7.60(6H,m).
【0392】
Example 354
3,5-dimethyl-2-[4-(4-isonicotinoyloxymethylpiperidylcarbonyl)benzylthio〕-4(3H)-quinazolinone
2-[4-(4-hydroxymethylpiperidylcarbonyl)benzylthio〕3,5-Dimethyl-4(3H)-quinazolinone (415 mg) was dissolved in DMF (15 mL), isonicotinic acid chloride hydrochloride (270 mg) was added, and triethylamine (0.40 mL) was added over 5 minutes. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine, dried, and concentrated. Recrystallization from hexane/ethyl acetate gave the title compound (241 mg) as a colorless solid.
IR(KBr)ν: 1718, 1668, 1560, 1295, 1099 cm^-1.
¹H-NMR (CDCl₃)δ: 1.16-2.22(5H,m), 2.85(3H,s), 2.56-3.20(2H,m), 3.53(3H,s), 3.55-4.04(1H,m), 4.26(2H,d,J=6.4Hz), 4.55(2H,s), 4.40-5.00(1H,m), 7.15(1H,d,J=7.2Hz), 7.31-7.60(6H,m), 7.83(2H,d,J=5.8Hz), 8.80(2H,d,J=5.8Hz).
【0393】
Example 355
3,5-dimethyl-2-[4-[4-[4-(4-fluorophenyl)piperazinylcarbonyl〕piperidyl carbonyl〕benzylthio〕-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1672, 1550, 1434, 1307, 1226 cm^-1.
¹H-NMR (CDCl₃)δ: 1.54-1.92(6H,m), 2.85(3H,s), 2.70-3.16(7H,m), 3.53(3H,s), 3.60-3.82(4H,m), 4.54(2H,s), 6.84-7.04(4H,m), 7.14(1H,d,J=8.8Hz), 7.33-7.59(6H,m).
Example 356
3,5-dimethyl-2-[4-(4-morpholinocarbonylpiperidylcarbonyl)benzylthio〕-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 184.
IR(KBr)ν: 1731, 1681, 1556, 1411, 1272, 1085 cm^-1.
¹H-NMR (CDCl₃)δ: 1.54-1.94(6H,m), 2.85(3H,s), 2.60-3.12(3H,m), 3.53(3H,s), 3.67(9H,m), 4.54(2H,m), 7.15(1H,d,J=7.2Hz), 7.33-7.59(6H,m).
[0394]
Example 357
2-[5-[2-[4-(4-(trifluoromethylphenyl)piperazinylcarbonyl〕Pyradil〕Methylthio〕-3,5-dimethylRu4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 184.
IR(KBr)ν: 1675, 1558, 1448, 1307, 1116 cm^-1.
¹H-NMR (CDCl₃)δ: 2.84(3H,s), 3.22(2H,m), 3.34(2H,m), 3.81(2H,m), 3.97(2H,m), 4.67(2H,s), 7.00-7.20(4H,m), 7.30-7.48(2H,m), 7.55(1H,t,J=7.6Hz), 8.87(1H,s), 8.96(1H,s).
Example 358
8-[4-(4-chlorobenzoyl)benzyloxy〕-3,4-dihydro-7-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1649, 1589, 1500, 1390, 1274 cm^-1.
¹H-NMR (CDCl₃)δ: 1.99(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.9Hz), 4.10(2H,t,J=5.9Hz), 5.42(2H,s), 7.49(4H,m), 7.77(4H,m).
[0395]
Example 359
3,4-dihydro-8-[4-(4-fluorobenzoyl)benzyloxy〕-7-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1625, 1580, 1500, 1266, 1118 cm^-1.
¹H-NMR (CDCl₃)δ: 1.99(3H,s), 2.59(2H,m), 3.17(2H,t,J=5.9Hz), 4.10(2H,t,J=5.9Hz), 5.42(2H,s), 7.17(2H,m), 7.52(2H,d,J=8.6Hz), 7.82(4H,m).
Example 360
3,4-dihydro-7-methyl-8-[4-(4-trifluoromethylbenzoyl)benzyloxy〕-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1654, 1591, 1498, 1326, 1187, 1122 cm^-1.
¹H-NMR (CDCl₃)δ: 1.99(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 4.10(2H,t,J=5.8Hz), 5.43(2H,s), 7.54(2H,d,J=8.4Hz), 7.84(6H,m).
[0396]
Example 361
3-methyl-2-[4-[4-(4-fluorophenyl)piperazinylcarbonyl]benzylthio]-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1673, 1633, 1510, 1284, 1236, 1170 cm^-1.
¹H-NMR (CDCl₃)δ: 2.21(3H,s), 2.90-3.26(4H,m), 3.42-4.04(4H,m), 5.57(2H,s), 6.82-7.16(5H,m), 7.50(5H,m), 7.70(1H,m), 9.08(1H,m).
Example 362
3-methyl-2-[4-[4-(2-pyridyl)piperazinylcarbonyl]benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1679, 1627, 1484, 1284, 1170 cm^-1.
¹H-NMR (CDCl₃)δ: 2.22(3H,s), 3.44-4.06(8H,m), 5.57(2H,s), 6.69(2H,m), 7.11(1H,m), 7.48(6H,m), 7.71(1H,m), 8.21(1H,m), 9.08(1H,d,J=6.4Hz).
[0397]
Example 363
3-methyl-2-[4-[4-(2-pyridyl)piperazinylcarbonyl]benzyloxy]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1660, 1527, 1479, 1241, 1155 cm^-1.
¹H-NMR (CDCl₃)δ: 1.80-2.08(4H,m), 2.01(3H,s), 2.84(2H,t,J=6.1Hz), 3.40-4.04(8H,m), 3.95(2H,t,J=6.1Hz), 5.40(2H,s), 6.69(2H,m), 7.40-7.58(5H,m), 8.21(1H,dd,J=1.8, 5.6Hz).
Example 364
8-[4-(4-chlorobenzoyl)benzylthio〕-3,4-dihydro-7-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1647, 1496, 1398, 1286 cm^-1.
¹H-NMR (CDCl₃)δ: 2.00(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 4.07(2H,t,J=5.8Hz), 4.40(2H,s), 7.40-7.56(4H,m), 7.68-7.80(4H,m).
[0398]
Example 365
3,4-dihydro-7-methyl-8-[4-(4-trifluoromethylbenzoyl)benzylthio〕-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1641, 1546, 1494, 1326, 1166, 1130 cm^-1.
¹H-NMR (CDCl₃)δ: 2.00(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 4.07(2H,t,J=5.8Hz), 4.40(2H,s), 7.53(2H,d,J=8.2Hz), 7.76(4H,d,J=8.2Hz), 7.89(2H,d,J=8.2Hz).
Example 366
3,4-dihydro-8-[4-(4-fluorobenzoyl)benzylthio〕-7-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1646, 1596, 1498, 1396, 1155 cm^-1.
¹H-NMR (CDCl₃)δ: 2.00(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 4.07(2H,t,J=5.8Hz), 4.40(2H,s), 7.08-7.23(2H,m), 7.51(2H,d,J=8.3Hz), 7.72(2H,d,J=8.3Hz), 7.76-7.96(2H,m).
[0399]
Example 367
3,5-dimethyl-2-[4-[4-[N-[2-(2-pyridyl)ethyl〕-N-methylaminocarbonyl〕piperidyl carbonyl〕benzylthio〕-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 184.
IR(KBr)ν: 1675, 1556, 1434, 1307 cm^-1.
¹H-NMR (CDCl₃)δ: 1.48-1.84(7H,m), 2.85(3H,s), 2.97(3H,s), 2.46-3.10(4H,m), 3.53(3H,s), 3.77(2H,m), 4.54(2H,s), 7.06-7.25(2H,m), 7.30-7.66(8H,m),8.54(1H,m).
Example 368
1-[4-(4-trifluoroMethylBenzoyl)benzyl〕-1,6,7,8,9,10-hexahydrocyclopent[d]imidazo[1,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 1654, 1581, 1326, 1278 cm^-1.
¹H-NMR (CDCl₃)δ: 1.50-1.95(6H,m), 2.88(4H,m), 5.35(2H,s), 6.87(1H,d,J=2.7Hz), 7.43(2H,d,J=8.4Hz), 7.57(1H,d,J=2.7Hz), 7.72-7.92(6H,m).
【0400】
Example 369
3,4-dihydro-8-[4-(4-methoxybenzoyl)benzyloxy〕-7-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1654, 1504, 1257, 1170, 1128 cm^-1.
¹H-NMR (CDCl₃)δ: 1.99(3H,s), 2.26(2H,m), 3.17(2H,t,J=5.8Hz), 3.89(3H,s),4.10(2H,t,J=5.8Hz), 5.42(2H,s), 6.97(2H,d,J=8.3Hz), 7.51(2H,d,J=8.3Hz), 7.73-7.84(4H,m).
Example 370
3-methyl-2-[4-(4-cyanobenzoyl)benzyloxy〕-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 163.
IR(KBr)ν: 2227, 1658, 1535, 1276, 1149 cm^-1.
¹H-NMR (CDCl₃)δ: 1.78-2.03(4H,m), 2.02(3H,s), 2.83(2H,t,J=6.4Hz), 3.95(2H,t,J=6.2Hz), 5.46(2H,s), 7.55(2H,d,J=8.4Hz), 7.75-7.93(6H,m).
【0401】
Example 371
6-methyl-7-[4-(4-cyanobenzoyl)benzyloxy]-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 2231, 1600, 1523, 1392, 1278, 1143 cm^-1.
¹H-NMR (CDCl₃)δ: 1.97(3H,s), 3.47(2H,t,J=7.7Hz), 4.47(2H,t,J=7.7Hz), 5.44(2H,s), 7.53(2H,d,J=8.0Hz), 7.75-7.92(6H,m).
Example 372
3,4-dihydro-8-[4-(4-hydroxybenzoyl)benzyloxy〕-7-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1645, 1585, 1498, 1278 cm^-1.
¹H-NMR (CDCl₃)δ: 1.85(3H,s), 2.14(2H,m), 3.21(2H,m), 3.95(2H,m), 5.40(2H,s), 6.89(2H,d,J=8.6Hz), 7.54(2H,d,J=8.4Hz), 7.64-7.72(4H,m).
【0402】
Example 373
3,4-dihydro-8-[4-[4-(N,N-dimethylcarbonyl)L(bamoyloxy)benzoyl]benzyloxy]-7-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1718, 1654, 1502, 1390, 1270 cm^-1.
¹H-NMR (CDCl₃)δ: 1.99(3H,s), 2.26(2H,m), 3.05(3H,s), 3.13(3H,s), 3.17(2H,m), 4.10(2H,t,J=5.6Hz), 5.42(2H,s), 7.25(2H,d,J=9.0Hz), 7.52(2H,d,J=8.4Hz), 7.82(4H,m).
Example 374
3-methyl-2-[4-(4-acetoxybenzoyl)benzyloxy〕-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1758, 1646, 1527, 1199 cm^-1.
¹H-NMR (CDCl₃)δ: 1.89(4H,m), 2.02(3H,s), 2.35(3H,s), 2.84(2H,t,J=6.2Hz),3.94(2H,t,J=6.2Hz), 5.45(2H,s), 5.42(2H,s), 7.22(2H,d,J=8.8Hz), 7.52(2H,d,J=8.4Hz), 7.76-7.90(4H,m).
【0403】
Example 375
3-methyl-2-[4-(4-hydroxybenzoyl)benzyloxy〕-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound is used in the following examples.147was synthesized in the same manner as
IR(KBr)ν: 1735, 1635, 1510, 1280, 1149 cm^-1.
¹H-NMR (CDCl₃)δ: 1.81(4H,m), 1.87(3H,s), 2.81(2H,t,J=6.3Hz), 3.79(2H,t,J=5.9Hz), 5.46(2H,s), 6.90(2H,d,J=8.6Hz), 7.56(2H,d,J=8.2Hz), 7.62-7.73(4H,m).
Example 376
3-methyl-2-[4-[4-(N,N-dimethylcarbonyl)L(bamoyloxy)benzoyl]benzyloxy]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 228.
IR(KBr)ν: 1716, 1658, 1602, 1527, 1396 cm^-1.
¹H-NMR (CDCl₃)δ: 1.92(4H,m), 2.03(3H,s), 2.84(2H,t,J=6.3Hz), 3.05(3H,s),3.14(3H,s), 3.95(2H,t,J=6.3Hz), 5.45(2H,s), 7.25(2H,d,J=8.5Hz), 7.52(2H,d,J=8.5Hz), 7.82(4H,m).
【0404】
Example 377
3-methyl-2-[4-(4-methylpiperazinylcarbonyl)benzylthio]-thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1665, 1640, 1530, 1500, 1410, 1280, 1260 cm^-1.
¹H-NMR (DMSO-d₆)δ: 2.80(3H,brs), 3.00-3.90(8H,m), 3.51(3H,s), 4.59(2H,s), 7.37(1H,d,J=5.2Hz), 7.43(2H,d,J=8.2Hz), 7.62(2H,d,J=8.2Hz), 8.16(1H,d,J=5.2Hz).
Example 378
3,6-dimethyl-7-[4-(4-methylpiperazinylcarbonyl)benzyloxy]-5H-thiazolo[3,2-a]pyrimidin-5-one hydrochloride
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1680, 1650, 1630, 1565, 1500 cm^-1.
¹H-NMR (DMSO-d₆)δ: 1.90(3H,s), 2.69(3H,d,J=1.2Hz), 3.78(3H,s), 3.00-3.90(8H,m), 5.44(2H,s), 6.98(1H,d,J=1.2Hz), 7.48(2H,d,J=8.2Hz), 7.54(2H,d,J=8.2Hz).
【0405】
Example 379
3-methyl-2-[4-(4-methylpiperazinylcarbonyl)benzyloxy]-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1670, 1630, 1470, 1420 cm^-1.
¹H-NMR (DMSO-d₆)δ: 2.07(3H,s), 2.80(3H,s), 3.00-3.85(8H,m), 5.57(2H,s), 7.15-7.70(6H,m), 8.00(1H,m), 5.97(1H,d,J=7.4Hz).
Example 380
3,5-dimethyl-2-[4-[4-(2-piperidinoethyl)piperazinylcarbonyl]benzylthio]-4(3H)-quinazolinone dihydrochloride
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1675, 1640, 1550, 1450, 1420 cm^-1.
¹H-NMR (DMSO-d₆+D₂O) δ: 1.50-1.85(6H,m), 2.75(3H,s), 2.95-4.15(16H,m), 3.59(3H,s), 4.59(2H,s), 7.22(1H,d,J=7.0Hz), 7.37-7.70(6H,m).
【0406】
Example 381
3,5-dimethyl-2-[4-(4-cinnamylpiperazinylcarbonyl)benzylthio]-4(3H)-quinazolinone hydrochloride
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1675, 1630, 1550, 1420 cm^-1.
¹H-NMR (DMSO-d₆)δ: 2.75(3H,s), 2.90-3.55(8H,m), 3.44(3H,s), 3.90(2H,m), 4.60(2H,s), 6.39(1H,dt,J=15.8, 7.0Hz), 6.83(1H,d,J=15.8Hz), 7.21(1H,d,J=7.4Hz), 7.30-7.70(11H,m).
Example 382
2-[4-(4-chlorobenzoyl)benzylthio]-5-methyl-4(3H)-quinazolinone
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1670, 1585, 1560 cm^-1.
¹H-NMR (DMSO-d₆)δ: 2.73(3H,s), 4.57(2H,s), 7.18(1H,d,J=7.2Hz), 7.44(1H,d,J=7.2Hz), 7.55-7.80(5H,m), 12.40(1H,brs).
【0407】
Example 383
2-[4-(4-chlorobenzoyl)benzyloxy]-3-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1650, 1640, 1595, 1520, 1135 cm^-1.
¹H-NMR (CDCl₃)δ: 1.75-2.05(4H,m), 2.02(3H,s), 2.83(2H,t,J=6.8Hz), 3.95(2H,t,J=6.0Hz), 5.46(2H,s), 7.47(2H,d,J=8.6Hz), 7.52(2H,d,J=8.4Hz), 7.76(2H,d,J=8.6Hz), 7.78(2H,d,J=8.4Hz).
Example 384
2-[4-(4-fluorobenzoyl)benzyloxy]-3-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1650, 1640, 1590, 1525, 1270, 1130 cm^-1.
¹H-NMR (CDCl₃)δ: 1.80-2.05(4H,m), 2.02(3H,s), 2.84(2H,t,J=6.4Hz), 3.95(2H,t,J=6.0Hz), 5.46(2H,s), 7.17(2H,t,J=8.6Hz), 7.52(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz), 7.86(2H,dd,J=8.6, 5.6Hz).
【0408】
Example 385
3-methyl-2-[4-(4-trifluoromethylbenzoyl)benzyloxy]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1655, 1605, 1325, 1145 cm^-1.
¹H-NMR (CDCl₃)δ: 1.80-2.00(4H,m), 2.02(3H,s), 2.83(2H,t,J=6.6Hz), 3.95(2H,t,J=6.0Hz), 5.47(2H,s), 7.54(2H,d,J=8.0Hz), 7.76(2H,d,J=8.6Hz), 7.82(2H,d,J=8.6Hz), 7.90(2H,d,J=8.0Hz).
Example 386
2-[4-(4-chlorobenzoyl)benzyloxy]-3,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1650, 1640, 1600, 1520, 1135 cm^-1.
¹H-NMR (CDCl₃)δ: 1.34(3H,d,J=6.6Hz), 1.80-2.05(4H,m), 2.02(3H,s), 2.86(2H,m), 4.95(1H,m), 5.44(2H,s), 7.47(2H,d,J=8.6Hz), 7.52(2H,d,J=8.6Hz), 7.76(2H,d,J=8.6Hz), 7.78(2H,d,J=8.6Hz).
【0409】
Example 387
3,6-dimethyl-2-[4-(4-fluorobenzoyl)benzyloxy]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1650, 1595, 1520, 1270, 1135 cm^-1.
¹H-NMR (CDCl₃)δ: 1.34(3H,d,J=6.6Hz), 1.80-2.05(4H,m), 2.02(3H,s), 2.65-3.00(2H,m), 4.96(1H,m), 5.44(2H,s), 7.16(2H,t,J=8.6Hz), 7.52(2H,d,J=8.4Hz), 7.77(2H,d,J-8.4Hz), 7.85(2H,dd,J=8.6, 5.4Hz).
Example 388
3,6-dimethyl-2-[4-(4-trifluoromethylbenzoyl)benzyloxy]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1655, 1645, 1605, 1525, 1325, 1130 cm^-1.
¹H-NMR (CDCl₃)δ: 1.34(3H,d,J=6.6Hz), 1.80-2.05(4H,m), 2.02(3H,s), 2.65-3.00(2H,m), 4.96(1H,m), 5.45(2H,s), 7.54(2H,d,J=8.0Hz), 7.76(2H,d,J=8.6Hz), 7.82(2H,d,J=8.6Hz), 7.90(2H,d,J=8.0Hz).
【0410】
Example 389
7-[4-(4-fluorobenzoyl)benzyloxy]-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1650, 1640, 1590, 1510, 1390, 1345, 1285, 1220, 1145 cm^-1.
¹H-NMR (CDCl₃)δ: 1.98(3H,s), 3.47(2H,t,J=7.8Hz), 4.47(2H,t,J=7.8Hz), 5.44(2H,s), 7.17(2H,t,J=8.6Hz), 7.51(2H,d,J=8.2Hz), 7.78(2H,d,J=8.2Hz), 7.86(2H,dd,J=8.6, 5.4Hz).
Example 390
7-[4-(4-methoxybenzoyl)benzyloxy]-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1650, 1640, 1595, 1515, 1390, 1255 cm^-1.
¹H-NMR (CDCl₃)δ: 1.98(3H,s), 3.47(2H,t,J=7.8Hz), 3.90(3H,s), 4.47(2H,t,J=7.8Hz), 5.43(2H,s), 6.97(2H,t,J=8.8Hz), 7.49(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz), 7.84(2H,d,J=8.8Hz).
【0411】
Example 391
6-methyl-7-[4-(3,4,5-trimethoxybenzoyl)benzyloxy]-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1645, 1595, 1580, 120, 1390, 1330, 1230, 1125 cm^-1.
¹H-NMR (CDCl₃)δ: 1.98(3H,s), 3.47(2H,t,J=7.8Hz), 3.88(6H,s), 3.94(3H,s),4.47(2H,t,J=7.8Hz), 5.44(2H,s), 7.07(2H,s), 7.51(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz).
【0412】
Example 392
7-[4-(4-chlorobenzoyl)benzylthio]-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1645, 1545, 1500 cm^-1.
¹H-NMR (CDCl₃)δ(ppm): 1.99(3H,s), 3.45(2H,t,J=7.6Hz), 4.41(2H,s), 4.45(2H,t,J=7.6Hz), 7.45(2H,d,J=8.2Hz), 7.49(2H,d,J=8.0Hz), 7.72(2H,d,J=8.0Hz), 7.74(2H,d,J=8.2Hz).
Example 393
7-[4-(4-fluorobenzoyl)benzylthio]-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1645, 1600, 1595, 1550, 1500 cm^-1.
¹H-NMR (CDCl₃)δ(ppm): 1.99(3H,s), 3.45(2H,t,J=7.6Hz), 4.42(2H,s), 4.45(2H,t,J=7.6Hz), 7.16(2H,t,J=8.6Hz), 7.48(2H,d,J=8.2Hz), 7.72(2H,d,J=8.2Hz), 7.84(2H,dd,J=8.6, 5.4Hz),
【0413】
Example 394
2-[4-(4-chlorobenzoyl)benzylthio]-3-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1645, 1605, 1560, 1520 cm^-1.
¹H-NMR (CDCl₃)δ: 1.72-2.10(4H,m), 2.03(3H,s), 2.89(2H,t,J=6.2Hz), 3.92(2H,t,J=6.0Hz), 4.44(2H,s), 7.45(2H,d,J=8.6Hz), 7.50(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.74(2H,d,J=8.6Hz).
Example 395
3-methyl-2-[4-(4-trifluoromethylbenzoyl)benzylthio]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1645, 1560, 1520, 1320, 1160, 1120 cm^-1.
¹H-NMR (CDCl₃)δ: 1.75-2.10(4H,m), 2.04(3H,s), 2.89(2H,t,J=6.3Hz), 3.92(2H,t,J=6.0Hz), 4.45(2H,s), 7.53(2H,d,J=8.2Hz), 7.75(4H,d,J=8.2Hz), 7.88(2H,d,J=8.2Hz).
【0414】
Example 396
2-[4-(4-fluorobenzoyl)benzylthio]-3-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1640, 1595, 1560, 1520, 1270, 1225 cm^-1.
¹H-NMR (CDCl₃)δ: 1.80-2.10(4H,m), 2.04(3H,s), 2.90(2H,t,J=6.4Hz), 3.93(2H,t,J=5.9Hz), 4.45(2H,s), 7.16(2H,t,J=8.6Hz), 7.51(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.94(2H,dd,J=8.6, 5.4Hz).
Example 397
6-methyl-7-[4-(4-trifluoromethylbenzoyl)benzylthio]-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1655, 1600, 1555, 1505, 1385, 1325, 1275, 1120, 1060 cm^-1.
¹H-NMR (CDCl₃)δ: 1.99(3H,s), 3.46(2H,t,J=7.7Hz), 4.43(2H,s), 4.45(2H,t,J=7.7Hz), 7.51(2H,d,J=8.4Hz), 7.75(2H,d,J=8.2Hz), 7.76(2H,d,J=8.4Hz), 7.89(2H,d,J=8.2Hz).
【0415】
Example 398
3,6-dimethyl-7-[4-(4-trifluoromethylbenzoyl)benzylthio]-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 1.
IR(KBr)ν: 1660, 1650, 1530, 1485, 1320, 1170, 1110 cm^-1.
¹H-NMR (CDCl₃)δ: 2.06(3H,s), 2.80(3H,d,J=1.2Hz), 4.49(2H,s), 6.35(1H,q,J=1.2Hz), 7.54(2H,d,J=8.2Hz), 7.75(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 7.88(2H,d,J=8.6Hz).
Example 399
2-[2-[4-(4-chlorobenzoyl)phenyl]ethyl]-3-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
To a solution of 2-(2-phenylethyl)-3-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (1.0 g) in methylene chloride (15 mL) was added aluminum chloride (1.51 g), followed by a solution of 4-chlorobenzoyl chloride (980 mg) in methylene chloride (5 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 1N hydrochloric acid, extracted with ethyl acetate, washed with water, aqueous sodium bicarbonate, and brine, dried, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) and crystallized from hexane/ethyl acetate to yield the title compound (495 mg) as a colorless solid.
IR(KBr)ν: 1650, 1600, 1530 cm^-1.
¹H-NMR (CDCl₃)δ: 1.75-2.00(4H,m), 1.99(3H,s), 2.80-3.08(6H,m), 3.95(2H,t,J=6.0Hz), 7.33(2H,d,J=8.2Hz), 7.46(2H,d,J=8.6Hz), 7.71(2H,d,J=8.2Hz), 7.74(2H,d,J=8.6Hz).
【0416】
Example 400
7-[2-[4-(4-chlorobenzoyl)phenyl]ethyl]-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 399.
IR(KBr)ν: 1650, 1510 cm^-1.
¹H-NMR (CDCl₃)δ: 2.06(3H,s), 2.80(3H,d,J=1.2Hz), 4.49(2H,s), 6.35(1H,q,J=1.2Hz), 7.54(2H,d,J=8.2Hz), 7.75(2H,d,J=8.6Hz), 7.76(2H,d,J=8.2Hz), 7.88(2H,d,J=8.6Hz).
Example 401
8-[2-[4-(4-chlorobenzoyl)phenyl]ethyl]-7-methyl-3,4-dihydro-2H,6H-pyriMDo[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 399.
IR(KBr)ν: 1645, 1500 cm^-1.
¹H-NMR (CDCl₃)δ: 1.96(3H,s), 2.28(2H,m), 2.85(2H,m), 3.01(2H,m), 3.18(2H,t,J=6.0Hz), 4.10(2H,t,J=5.6Hz), 7.33(2H,d,J=8.2Hz), 7.47(2H,d,J=8.2Hz),7.71(2H,d,J=8.2Hz), 7.74(2H,d,J=8.2Hz).
【0417】
Example 402
6-methyl-7-[4-(4-trifluoromethylbenzoyl)benzyloxy]-2,3-dihydro-5H-thiazolo[3,2-a] pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1655, 1590, 1510, 1325, 1140 cm^-1.
¹H-NMR (CDCl₃)δ: 1.98(3H,s), 3.48(2H,t,J=7.8Hz), 4.47(2H,t,J=7.8Hz), 5.45(2H,s), 7.53(2H,d,J=8.6Hz), 7.60-7.93(6H,m).
Example 403
2-[4-(4-methoxybenzoyl)benzyloxy]-3-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1660, 1645, 1600, 1530, 1280, 1255, 1150 cm^-1.
¹H-NMR (CDCl₃)δ: 1.80-2.12(4H,m), 2.02(3H,s), 2.84(2H,t,J=6.4Hz), 3.90(3H,s), 3.95(2H,t,J=6.0Hz), 5.45(2H,s), 6.97(2H,d,J=8.8Hz), 7.51(2H,d,J=8.2Hz), 7.77(2H,d,J=8.2Hz), 7.84(2H,d,J=8.8Hz).
【0418】
Example 404
3-methyl-2-[4-(4-methylbenzoyl)benzyloxy]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1650, 1600, 1530, 1270, 1145 cm^-1.
¹H-NMR (CDCl₃)δ: 1.80-2.05(4H,m), 2.02(3H,s), 2.45(3H,s), 2.84(2H,t,J=6.5Hz), 3.94(2H,t,J=6.0Hz), 5.45(2H,s), 7.28(2H,d,J=8.4Hz), 7.50(2H,d,J=8.0Hz), 7.72(2H,d,J=8.0Hz), 7.79(2H,d,J=8.4Hz).
Example 405
6-methyl-7-[4-(4-methylbenzoyl)benzyloxy]-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1655, 1600, 1590, 1515, 1390, 1270 cm^-1.
¹H-NMR (CDCl₃)δ: 1.98(3H,s), 2.45(3H,s), 3.47(2H,t,J=7.7Hz), 4.47(2H,t,J=7.7Hz), 5.43(2H,s), 7.29(2H,d,J=8.4Hz), 7.49(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.79(2H,d,J=8.4Hz).
【0419】
Example 406
7-methyl-8-[4-(4-methylbenzoyl)benzyloxy]-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
The title compound was synthesized in the same manner as in Example 40.
IR(KBr)ν: 1645, 1585, 1495 cm^-1.
¹H-NMR (CDCl₃)δ: 1.99(3H,s), 2.20-2.38(2H,m), 2.45(3H,s), 3.17(2H,t,J=6.0Hz), 4.10(2H,t,J=5.6Hz), 5.42(2H,s), 7.29(2H,d,J=8.2Hz), 7.51(2H,d,J=8.2Hz), 7.73(2H,d,J=8.2Hz), 7.79(2H,d,J=8.2Hz).
Example 407
3-ethyl-2-methylthio-7-[4-(3,4,5-trimethoxybenzoyl)benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 49.
¹H-NMR (CDCl₃)δ: 1.36(3H,t,J=7.2Hz), 2.58(3H,s), 3.87(6H,s), 3.94(3H,s),4.22(2H,q,J=7.2Hz), 5.37(2H,s), 6.65(1H,d,J=3.4Hz), 6.77(1H,d,J=3.4Hz), 7.04(2H,s), 7.34(2H,d,J=8.4Hz), 7.78(2H,d,J=8.4Hz).
【0420】
Example 408
7-[4-(4-t-butyldimethylsilyloxybenzoyl)benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 49.
¹H-NMR (CDCl₃)δ: 0.24(6H,s), 0.99(9H,s), 1.36(3H,t,J=7.2Hz), 2.57(3H,s),4.22(2H,q,J=7.2Hz), 5.35(2H,s), 6.65(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 6.89(2H,d,J=8.6Hz), 7.30(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.74(2H,d,J=8.6Hz).
Example 409
3-ethyl-7-[4-(4-hydroxybenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one
7-[4-(4-t-butyldimethylsilyloxybenzoyl)benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (4.10 g) was dissolved in THF (76.8 ml), and a 1 M THF solution (7.68 ml) was added and stirred for 30 minutes. After adding water, the THF was evaporated, and ethyl acetate was added and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with ether, collected by filtration, washed with ether, methanol, and hexane, and then dried to obtain the title compound (3.0 g) as a crystalline powder.
¹H-NMR (Me₂SO-d₆)δ: 1.24(3H,t,J=7.2Hz), 2.60(3H,s), 4.08(2H,q,J=7.2Hz), 5.41(2H,s), 6.47(1H,d,J=3.4Hz), 6.87(2H,d,J=8.6Hz), 7.19(1H,d,J=3.4Hz), 7.44(2H,d,J=8.0Hz), 7.63(2H,d,J=8.6Hz), 7.65(2H,d,J=8.0Hz).
【0421】
Example 410
7-[4-[4-(2-Dimethylaminoethoxy)Benzoyl〕benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one hydrochloride
The title compound was synthesized in a similar manner to Example 156.
¹H-NMR (CDCl₃) δ: 1.36(3H,t,J=7.2Hz), 2.35(6H,s), 2.58(3H,s), 2.76(2H,t,J=5.6Hz), 4.14(2H,t,J=5.6Hz), 4.22(2H,q,J=7.2Hz), 5.35(2H,s), 6.65(1H,d,H=3.4Hz), 6.75(1H,d,J=3.4Hz), 6.97(2H,d,J=8.8Hz), 7.30(2H,d,J=8.2Hz), 7.72(2H,d,J=8.2Hz), 7.79(2H,d,J=8.8Hz).
Example 411
3-ethyl-2-methylthio-7-[4-(4-nicotinoylmethoxybenzoyl)benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was synthesized in a similar manner to Example 237.
¹H-NMR (CDCl₃) δ: 1.23(3H,t,J=7.2Hz), 2.60(3H,s), 4.08(2H,q,J=7.2Hz), 5.42(2H,s), 5.78(2H,s), 6.47(1H,d,J=3.4Hz), 7.14(2H,d,J=8.8Hz), 7.20(1H,d,J=3.4Hz), 7.46(2H,d,J=8.2Hz), 7.59-7.64(1H,m), 7.69(2H,d,J=8.2Hz), 7.72(2H,d,J=8.8Hz), 8.32-8.39(1H,m), 8.88(1H,dd,J=1.6, 4.8Hz), 9.20 (1H, d, J = 1.6 Hz).
【0422】
Example 412
3-ethyl-2-methylthio-7-[4-[4-(2-Morpholinoethoxy)Benzoyl〕benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one hydrochloride
The title compound was synthesized in the same manner as in Example 156.
¹H-NMR (CDCl₃) δ: 1.36(3H,t,J=7.0Hz), 2.58(3H,s), 2.59(4H,t,J=4.7Hz), 2.84(2H,t,J=5.6Hz), 3.74(4H,t,J=4.7Hz), 4.19(2H,t,J=5.6Hz), 4.22(2H,q,J=7.0Hz), 5.35(2H,s), 6.66(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 6.96(2H,d,J=8.8Hz), 7.30(2H,d,J=8.2Hz), 7.72(2H,d,J=8.2Hz), 7.80(2H,d,J=8.8Hz).
Example 413
3-ethyl-2-methylthio-7-[4-[4-(2-Piperidinoethoxy)Benzoyl〕benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one hydrochloride
The title compound was synthesized in the same manner as in Example 156.
¹H-NMR (CDCl₃) δ: 1.36(3H,t,J=7.2Hz), 1.37-1.52(2H,m), 1.54-1.68(4H,m),2.51(4H,t,J=5.6Hz), 2.58(3H,s), 2.80(2H,t,J=6.2Hz), 4.18(2H,t,J=6.2Hz), 4.12(2H,q,J=7.2Hz), 5.35(2H,s), 6.65(1H,d,J=3.4Hz), 6.76(1H,d,J=3.4Hz), 6.96(2H,d,J=9.0Hz), 7.31(2H,d,J=8.4Hz), 7.72(2H,d,J=8.4Hz), 7.79 (2H, d, J = 9.0 Hz).
【0423】
Example 414
7-[4-(4-fluorobenzoyl)benzyl]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
7-[4-(4-Fluorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (775 mg) was dissolved in DME (100 ml), ethyl acetate (100 ml), and methanol (80 ml). Acetic acid (2.5 ml) was added, followed by Raney nickel. After confirming the disappearance of the raw materials, the catalyst was removed by filtration. The solvent was distilled off under reduced pressure, and the crystalline powder was pulverized with ether. It was collected by filtration, washed with ether, and dried to obtain the title compound (529 mg).
¹H-NMR (DMSO-d₆+D₂O)δ：2.29(3H,s), 5.39(2H,s), 6.96(1H,s), 7.33(2H,d,J=8.1Hz), 7.37(2H,d,J=8.8Hz), 7.69(2H,d,J=8.1Hz), 7.80(2H,dd,J=5.6, 8.8Hz), 7.86(1H,s).
Example 415
3-ethyl-7-[4-(4-hydroxybenzoyl)benzyl]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 49.
¹H-NMR (DMSO-d₆) δ: 1.25(3H,t,J=7.2Hz), 2.30(3H,s), 3.96(2H,q,J=7.2Hz),5.366(2H,s), 6.87(2H,d,J=8.6Hz), 6.97(1H,s), 7.33(2H,d,J=8.2Hz), 7.63(4H,d,J=8.6Hz), 8.19(1H,s), 10.34(1H,s).
【0424】
Example 416
7-[4-(6-chloronicotinoyl)benzyl]-3-ethyl−5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 49.
¹H-NMR (CDCl₃)δ: 1.41(3H,t,J=7.2Hz), 2.44(3H,d,J=1.0Hz), 4.05(2H,q,J=7.2Hz), 5.36(2H,s), 6.60(1H,d,J=1.0Hz), 7.30(2H,d,J=8.2Hz), 7.47(1H,d,J=8.4Hz), 7.75(2H,d,J=8.2Hz), 7.84(1H,s), 8.07(1H,dd,J=2.4, 8.4Hz), 8.74(1H,d,J=2.4Hz).
Example 417
3-ethyl-5-methyl-7-[4-(4-trifluoromethylbenzoyl)benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 49.
¹H-NMR (CDCl₃)δ: 1.41(3H,t,J=7.2Hz), 2.43(3H,s), 4.05(2H,q,J=7.2Hz), 5.35(2H,s), 6.59(1H,s), 7.28(2H,d,J=8.6Hz), 7.74(2H,d,J=8.0Hz), 7.76(2H,d,J=8.0Hz), 7.83(1H,s), 7.87(2H,d,J=8.6Hz).
【0425】
Example 418
3-ethyl-5-methyl-7-[4-(4-(4-phenylpiperazinomethyl)benzoyl)benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was synthesized in the same manner as in Example 49.
¹H-NMR (CDCl₃)δ: 1.41(3H,t,J=7.2Hz), 2.44(3H,d,J=1.0Hz), 2.64(4H,t,J=5.1Hz), 3.22(4H,t,J=5.1Hz), 3.64(2H,s), 4.06(2H,q,J=7.2Hz), 5.34(2H,s), 6.60(1H,d,J=1.0Hz), 6.86(1H,t,J=8.0Hz), 6.93(2H,d,J=8.0Hz), 7.26(2H,d,J=8.4Hz), 7.27(2H,d,J=8.0Hz), 7.47(2H,d,J=8.2Hz), 7.76(2H,d,J=8.4Hz), 7.77(2H,d,J=8.2Hz), 7.83(1H,s).
Example 419
3-ethyl-5-methyl-7-[4-[4-(2-Morpholinoethoxy)Benzoyl〕benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one hydrochloride
The title compound was synthesized in a similar manner to Example 156.
¹H-NMR (CDCl₃)δ: 1.40(3H,t,J=7.2Hz), 2.43(2H,d,J=1.2Hz), 2.59(4H,t,J=4.7Hz), 2.84(2H,t,J=5.7Hz), 3.74(4H,t,J=4.7Hz), 4.05(2H,q,J=7.2Hz), 4.19(2H,t,J=5.7Hz), 5.33(2H,s), 6.60(1H,d,J=1.2Hz), 6.95(2H,d,J=8.8Hz), 7.26(2H,d,J=8.2Hz), 7.71(2H,d,J=8.2Hz), 7.79(2H,d,J=8.8Hz), 7.84(1H,s).
【0426】
Example 420
3-ethyl-5-methyl-7-[4-[6-(4-Piperidinopiperidineof)Nicotinoyl〕benzyl]-7H-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride
The title compound was synthesized in a similar manner to Example 158.
¹H-NMR (CDCl₃)δ: 1.41(3H,t,J=7.2Hz), 1.46-2.02(10H,m), 2.43(3H,s), 2.54(4H,t,J=5.1Hz), 2.55-2.67(1H,m), 2.93(2H,dt,J=2.6, 13.0Hz), 4.06(2H,q,J=7.2Hz), 4.54(2H,d,J=13.0Hz), 5.33(2H,s), 6.58(1H,s), 6.67(1H,d,J=9.0Hz), 7.25(2H,d,J=8.2Hz), 7.69(2H,d,J=8.2Hz), 7.83(1H,s), 8.00(1H,dd,J=2.2, 8.2Hz), 8.55(1H,d,J=2.2Hz).
Example 421
7-[4-[4-(4-N-tert-butoxycarbonylpiperidylmethoxy)benzoyl]benzyl]-1,3-dimethyl-xanthine
The title compound was synthesized in a similar manner to Example 156.
IR(KBr)ν: 1699, 1664, 1655, 1599, 1257 cm^-1.
¹H-NMR (CDCl₃)δ: 1.2-1.4(2H,m), 1.47(9H,s), 1.7-2.1(3H,m), 2.76(2H,t,J=12.7Hz), 3.41(3H,s), 3.61(3H,s), 4.1-4.3(2H,brm), 5.59(2H,s), 6.93(2H,ABq,J=8.6Hz), 7.40(2H,ABq,J=7.9Hz), 7.65(1H,s), 7.74(2H,ABq,J=7.9Hz), 7.78(2H,ABq,J=8.6Hz).
【0427】
Example 422
1,3-dimethyl-7-[4-[4-(4-piperidylmethoxy)benzoyl]benzyl]xanthine hydrochloride
7-[4-[4-(4-N-tert-butoxycarbonylpiperidylmethoxy)benzoyl]benzyl]-1,3-dimethyl-xanthine (366 mg) was dissolved in tetrahydrofuran (5 ml), and 4 N hydrochloric acid/ethyl acetate (0.78 ml) was added dropwise under ice cooling. After stirring overnight at 50°C, the mixture was refluxed for an additional 8 hours. The reaction mixture was concentrated, and the precipitate was collected by filtration and washed with ethyl acetate to yield the title compound (227 mg) as a white powder.
IR(KBr)ν: 1707, 1662, 1599, 1259, 1171 cm^-1.
¹H-NMR (DMSO-d₆)δ: 1.3-1.7(2H,m), 1.8-2.2(3H,m), 2.8-3.0(2H,m), 3.2-3.5(2H,m), 3.22(3H,s), 3.45(3H,s), 3.98(2H,d,J=6.0Hz), 5.61(2H,s), 7.08(2H,ABq,J=8.8Hz), 7.46(2H,ABq,J=8.2Hz), 7.66(2H,ABq,J=8.2Hz), 7.72(2H,ABq,J=8.8Hz), 8.35(1H,s).
【0428】
Example 423
1,3-dimethyl-7-[4-[4-(4-N-methylpiperidylmethoxy)benzoyl]benzyl]xanthine
1,3-Dimethyl-7-[4-[4-(4-piperidylmethoxy)benzoyl]benzyl]xanthine hydrochloride (82 mg) was dissolved in acetonitrile/methanol (2 mL/1 mL), 37% aqueous formaldehyde solution (0.02 mL) was added, and sodium cyanoborohydride (16 mg) was added under ice cooling. After stirring at room temperature for 1 hour, acetic acid was added to adjust the pH to 5. The reaction mixture was concentrated, and ethyl acetate and aqueous sodium bicarbonate were added to the residue, and the ethyl acetate layer was extracted. After washing with brine, it was dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/ethanol/triethylamine = 20/2/1) to give the title compound (36 mg) as a white powder.
IR(KBr)ν: 1713, 1664, 1597, 1252, 1173, 758 cm^-1.
¹H-NMR (CDCl₃)δ: 1.2-2.2(7H,m), 2.35(3H,s), 2.9-3.1(2H,m), 3.41(3H,s), 3.61(3H,s), 3.89(2H,d,J=5.4Hz), 5.59(2H,s), 6.92(2H,ABq,J=8.8Hz), 7.40(2H,ABq,J=8.2Hz), 7.65(1H,s), 7.7-7.9(4H,m).
【0429】
Example 424
7-[4-[4-[1-(4-N-tert-butoxycarbonylpiperidyl)ethoxy]benzoyl]benzyl]-1,3-xanthine
The title compound was synthesized in the same manner as in Example 156.
IR(KBr)ν: 1705, 1664, 1254, 1176 cm^-1.
¹H-NMR (CDCl₃)δ: 1.1-1.3(3H,brm), 1.6-1.8(4H,brm), 1.46(9H,s), 2.71(2H,t,J=13.7Hz), 3.42(3H,s), 3.61(3H,s), 4.0-4.2(4H,brm), 5.59(2H,s), 6.93(2H,ABq,J=8.8Hz), 7.40(2H,ABq,J=8.0Hz), 7.65(1H,s), 7.74(2H,ABq,J=8.0Hz), 7.78(2H,ABq,J=8.8Hz).
【0430】
Example 425
1,3-dimethyl-7-[4-[4-[1-(4-piperidyl)ethoxy]benzoyl]benzyl]xanthine hydrochloride
7-[4-[4-[1-(4-N-tert-butoxycarbonylpiperidyl)ethoxy]benzoyl]benzyl]-1,3-xanthine (454 mg) was dissolved in tetrahydrofuran (10 ml), and 4 N hydrochloric acid/ethyl acetate (0.94 ml) was added dropwise under ice cooling. After stirring overnight at 50°C, the mixture was refluxed for an additional two days. After concentrating the reaction solution, the precipitate was collected by filtration and washed with ethyl acetate/ether to give the title compound (403 mg) as a white powder.
IR(KBr)ν: 1684, 1653, 1601, 1257 cm^-1.
¹H-NMR (DMSO-d₆)δ: 1.2-2.0(7H,brm), 2.7-3.0(2H,brm), 3.21(3H,s), 3.2-3.3(2H,m), 3.44(3H,s), 4.1-4.2(2H,brm), 5.61(2H,s), 7.06(2H,ABq,J=9.0Hz), 7.45(2H,ABq,J=8.1Hz), 7.66(2H,ABq,J=8.1Hz), 7.71(2H,ABq,J=9.0Hz), 8.33(1H,s), 8.4-8.8(2H,brm).
【0431】
Example 426
1,3-dimethyl-7-[4-[4-[1-(4-N-methylpiperidyl)ethoxy]benzoyl]benzyl]xanthine
1,3-Dimethyl-7-[4-[4-[1-(4-piperidyl)ethoxy]benzoyl]benzyl]xanthine hydrochloride (202 ml) was dissolved in acetonitrile/methanol (4 ml/2 ml), 37% aqueous formaldehyde solution (0.045 ml) was added, and sodium cyanoborohydride (38 mg) was added under ice cooling. After stirring at room temperature for 1.5 hours, acetic acid was added to adjust the pH. The reaction mixture was concentrated, and ethyl acetate and aqueous sodium bicarbonate were added to the residue, and the ethyl acetate layer was extracted. After washing with brine, it was dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to give the title compound (34 mg, 18%) as a white powder.
IR(KBr)ν: 1716, 1662, 1525, 1255 cm^-1.
¹H-NMR (CDCl₃)δ:1.2-2.1(9H,m), 2.29(3H,s), 2.8-3.0(2H,brm), 3.42(3H,s), 3.61(3H,s), 4.08(2H,t,J=6.3Hz), 5.59(2H,s), 6.93(2H,ABq,J=8.8Hz), 7.40(2H,ABq,J=7.6Hz), 7.65(1H,s), 7.75(2H,ABq,J=7.6Hz), 7.79(2H,ABq,J=8.8Hz).
【0432】
Example 427
7-[4-(4-chlorobenzoyl)benzyloxy]-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one
4-(4-Chlorobenzoyl)benzyl bromide (2.0 g) was added to a solution of 7-hydroxy-6-methyl-2,3-dihydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (1.0 g) and potassium carbonate (750 mg) in dimethylformamide (15 ml), and the reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) and recrystallized from isopropyl ether to give the title compound (200 mg) as a colorless solid.
IR(KBr)ν: 1650, 1515, 1390 cm^-1.
¹H-NMR (CDCl₃)δ: 1.97(3H,s), 3.47(2H,t,J=7.8Hz), 4.46(2H,t,J=7.8Hz), 5.43(2H,s), 7.46(2H,d,J=8.0Hz), 7.50(2H,d,J=8.0Hz), 7.76(2H,d,J=8.0Hz), 7.78(2H,d,J=8.0Hz).
【0433】
[Formulation example]
Formulation Example 1 (dosage per tablet)
(1) Compound of Example 15 10.0 mg
(2) Lactose 60.0mg
(3) Cornstarch 35.0 mg
(4) Gelatin 3.0 mg
(5) Magnesium stearate 2.0 mg
A mixture of 10.0 mg of the compound of Example 15, 60.0 mg of lactose, and 35.0 mg of cornstarch was passed through a 1 mm mesh sieve using 0.03 ml of a 10% by weight aqueous gelatin solution (3.0 mg as gelatin).ThroughAfter granulation, the mixture was dried at 40°C and sieved again. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting core tablets were coated with a sugar coating of a suspension of sucrose, titanium dioxide, talc, and gum arabic, and the resulting coated tablets were polished with beeswax to obtain coated tablets.
Formulation Example 2 (dosage per tablet)
(1) Compound of Example 15 10.0 mg
(2) Lactose 70.0mg
(3) Cornstarch 50.0 mg
(4) Soluble starch 7.0 mg
(5) Magnesium stearate 3.0 mg
10.0 mg of the compound of Example 15 and 3.0 mg of magnesium stearate were granulated with 0.07 ml of an aqueous solution of soluble starch (7.0 mg as soluble starch), then dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was compressed to obtain tablets.
【0434】
[Test example]
Experimental Example 1
Inhibitory effect on prostate cancer cell proliferation in vitro
Prostate cancer cell line PC-3 cells were suspended in F-12K medium (Flow Laboratories or Dainippon Pharmaceutical) containing 10% fetal bovine serum, and the resulting cell suspension was seeded into a 96-well microplate (5,000 cells/50 or 75 μl/well) and cultured at 37°C in a 5% CO incubator. The following day, a 3-fold serial dilution of each compound solution (50 or 25 μl/well) dissolved in dimethylformamide was added (final volume: 100 μl), and the cells were cultured for an additional 3 days. Viable cell numbers were quantified by adding MTT dye solution [Tada et al., J. Immunol. Methods, Vol. 93, p. 157 (1986)]. The cell volume in the control group without compound solution was set at 100%, and the percentage of cell volume in each compound-treated group was calculated. The compound concentration required to suppress viable cell volume by 50% of the control group (IC ) was calculated.₅₀These are shown in Table 1.
[Table 1]
From Table 1, it can be seen that the compounds of the present invention have excellent inhibitory effects on the proliferation of prostate cancer cell line (PC-3).
【0435】
Experimental Example 2
Tumor growth inhibitory effect on subcutaneously transplanted tumors
Human prostate cancer PC-3 cell line (hereafter referred to as PC-3 cells) subcultured in vitro in a tissue culture dish was detached from the wall of the dish with 0.05% trypsin, washed with Ham's F12K medium containing 10% serum, and then cultured at 3 x 10⁷The cells were suspended in PBS (phosphate buffered saline) to a concentration of 100 μl/ml, and 100 μl of the suspension was transplanted into the center of the right flank of BALB/c nu/nu mice (7-week-old, male) using a syringe (25G). The tumor size was measured 25 days after transplantation, and the average tumor size was 16-179 mm.³The tumor size was measured using a caliper to determine the long diameter (a) and short diameter (b), and the calculated value was 0.5 x a x b²was calculated from
The compound of the present invention was suspended in 0.5% methylcellulose/physiological saline, adjusted to a dosage volume of 10 μl/g mouse body weight, and administered subcutaneously to the back. Dosing was performed three times a week, Monday, Wednesday, and Friday, for a total of three weeks, and tumor growth inhibitory activity was evaluated 46 days after implantation using the following method. The tumor volume ratio (T/C%) between the drug-treated group (T) and the control group (C) was calculated using the tumor size value obtained by subtracting the tumor size before dosing. The results are shown in Table 2. The drug dosage was expressed as the drug weight per administration (mg/kg body weight).
[Table 2]
From Table 2, it was observed that the compounds of the present invention have excellent tumor growth inhibitory effects.
【0436】
Experimental Example 3
Tumor growth inhibitory effect on subcutaneously transplanted tumors
PC-3 cells subcultured in vitro in a tissue culture dish were detached from the wall of the dish with 0.05% trypsin, washed with Ham's F12K medium containing 10% serum, and then 3x10⁷The cells were suspended in PBS to a concentration of 100 μl/ml, and 100 μl of the suspension was transplanted into the center of the right flank of BALB/c nu/nu mice (7-week-old, male) using a syringe (25G). 32 days after transplantation, the tumor size was measured, and the average tumor size was 273-293 mm.³The tumor size was measured using a caliper to determine the long diameter (a) and short diameter (b), and the calculated value was 0.5 x a x b²was calculated from
The compound of the present invention was suspended in 0.5% methylcellulose/physiological saline, adjusted to a dosage volume of 10 μl/g mouse body weight, and orally administered for 21 consecutive days. The tumor growth inhibitory effect was evaluated the day after the final administration, 53 days after transplantation, using the following method. The tumor volume ratio (T/C%) between the drug-treated group (T) and the control group (C) was calculated using the tumor size value obtained by subtracting the tumor size before administration. The results are shown in Table 3. The drug dose was expressed as the drug weight per administration (mg/kg body weight).
[Table 3]
From Table 3, it was observed that the compounds of the present invention have excellent tumor growth inhibitory effects.
【0437】
Experimental Example 4
Tumor growth inhibitory effect on subcutaneously transplanted tumors
PC-3 cells subcultured in vitro in a tissue culture dish were detached from the wall of the dish with 0.05% trypsin, washed with Ham's F12K medium containing 10% serum, and then 3x10⁷The cells were suspended in PBS to a concentration of 100 μl/ml, and 100 μl of the suspension was transplanted into the center of the right flank of BALB/c nu/nu mice (7 weeks old, male) using a syringe (25G). 31 days after transplantation, the tumor size was measured, and the average tumor size was 273-293 mm.³The tumor size was measured using a caliper to determine the long diameter (a) and short diameter (b), and the calculated value was 0.5 x a x b²was calculated from
The compound of the present invention was suspended in 0.5% methylcellulose/physiological saline, the dosage volume adjusted to 10 μl/g mouse body weight, and orally administered for 21 consecutive days. The day after the final administration, 52 days after transplantation, the tumor growth inhibitory effect was evaluated using the following method. The tumor volume ratio (T/C%) between the drug-treated group (T) and the control group (C) was calculated using the tumor size value obtained by subtracting the tumor size before the start of administration. The results are shown in Table 1.4The dose of the drug was expressed as the weight of the drug per administration (mg/kg body weight).
[Table 4]
Table 4 shows that the compounds of the present invention exhibited excellent tumor growth inhibitory effects in a dose-dependent manner.
【0438】
[Effects of the invention]
The compounds of the present invention exhibit excellent antitumor activity and are highly effective in treating refractory solid tumors and preventing distant metastasis to other organs.

JP8059508A 1995-03-16 1996-03-15 Heterocyclic compound, its production and agent containing the same Withdrawn JPH0995485A (en)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
JP8059508A JPH0995485A (en)	1995-03-16	1996-03-15	Heterocyclic compound, its production and agent containing the same

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Application Number	Priority Date	Filing Date	Title
JP5686995		1995-03-16
JP7-56869		1995-07-27
JP19177095		1995-07-27
JP7-191770		1995-07-27
JP8059508A JPH0995485A (en)	1995-03-16	1996-03-15	Heterocyclic compound, its production and agent containing the same

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EP1254907B1 (en) *	2000-02-10	2007-05-09	Sankyo Company, Limited	Pyrrolopyridazine compound
CN101605797A (en) *	2006-11-13	2009-12-16	伊莱利利公司	Thienopyrimidinones for the treatment of inflammatory diseases and cancer
US8809346B2 (en) *	2008-05-30	2014-08-19	Universite De Versailles-Saint-Quentin-En-Yvelines	ANT-ligands molecules and biological applications
JP2012131708A (en) *	2009-04-28	2012-07-12	Nissan Chem Ind Ltd	4-substituted pyridazinone compound and p2x7 receptor inhibitor
CA2824925A1 (en) *	2011-01-20	2012-07-26	The Board Of Trustees Of The Leland Stanford Junior University	Quinazolinone inhibitors of dynein

1996
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