JP3992306B2 - Fused polycyclic heterocyclic derivatives - Google Patents

Description

部分を有する縮合多環式ヘテロ環系抗腫瘍性物質としては三環系化合物のアモナフィド［５−アミノ−２−［２−（ジメチルアミノ）エチル］−１Ｈ−ベンズ［ｄｅ］イソキノリン−１，３（２Ｈ）−ジオン］が最もよく知られているが、これまでに行われた臨床試験において骨髄毒性が強く、有効率が低いことが報告されている［Drugs Fut., 17, 832 （1992）］。また、四環系化合物としては、アモナフィドのアミノナフタレン部分をアントラセンに変換することにより前臨床試験での抗腫瘍活性を上昇させたアゾナフィド［２−［２′−（ジメチルアミノ）エチル］−１，２−ジヒドロ−３Ｈ−ジベンズ（ｄｅｈ）−イソキノリン−１，３−ジオン］が報告されている（ＷＯ９２００２８１）。
また環状イミドに窒素原子をひとつ導入したウラシル構造を分子内に有する縮合四環式ヘテロ環系抗腫瘍性物質としては、２−［２−（ジメチルアミノ）エチル］ピリミド［５，６，１−ｄｅ］アクリジン−１，３，７−トリオン［ファルマコ（Farmaco), 47, 1035（1992）］および２，３−ジヒドロ−２−［２−（ジメチルアミノ）エチル］−１Ｈ，７Ｈ−ナフチリジノ［３，２，１−ｉｊ］キナゾリン−１，３，７（２Ｈ）−トリオン［ジャーナル・オブ・メディシナルケミストリー（J. Med. Chem.), 37, 593 （1994）］が報告されているが、いずれも前臨床試験で弱い抗腫瘍活性しか示していない。そしてこのタイプの縮合五および六環式ヘテロ環系抗腫瘍性物質についての報告はない。
【０００３】
【発明が解決しようとする課題】
本発明は、低毒性で優れた抗腫瘍活性を有する新規化合物の提供を目的とする。さらに、該化合物の製造法および該化合物を有効成分とする医薬組成物をも提供することを目的とする。
【０００４】
【課題を解決するための手段】
本発明者らは、上記趣旨に鑑み、優れた抗腫瘍性物質を求めて鋭意研究を行ってきた結果、分子内にウラシル構造を有する新規縮合五および六環式ヘテロ環化合物が優れた抗腫瘍活性を有し、かつ低毒性であることを見出し、本発明を完成した。
【０００５】
すなわち、本発明は一般式（Ｉ）
【化５】

【０００６】
［式中、Ａ環は、置換基を有していてもよい、単環式芳香環または少なくとも一方の環が芳香環である二環式縮合環を意味する。Ｂ環は、ピロール、４Ｈ−１，４−オキサジン、４Ｈ−１，４−チアジンまたは４（１Ｈ）−ピリドンを意味する。Ｃ環は置換基を有していてもよい、単環式または縮合二環式芳香環を意味する。Ｙは式−ｅ−ｆ（式中、ｅは低級アルキレン基を、ｆはアミジノ基、グアニジノ基、または水酸化もしくは低級アルキルアミノ化されたあるいはされていない低級アルキル基で置換されていてもよいアミノ基を意味する）で示される基を意味する。
但し、Ａ環およびＣ環のいずれもが置換基を有していてもよい単環式芳香環である組合せを除く］で表わされる化合物またはその薬理学的に許容される塩に関する。
【０００７】
上記一般式（Ｉ）のＡ環の定義において、「単環式芳香環」とは、窒素原子、酸素原子および硫黄原子のうち少なくとも１個を含んでいてもよい芳香族５または６員環であり、「少なくとも一方の環が芳香環である二環式縮合環」とは、各々の環が窒素原子、酸素原子および硫黄原子のうち少なくとも１個を含んでいてもよい５〜８員環であり、かつ少なくともそのうちの一方が芳香環である二環式縮合環である。当該環上には１〜３個の置換基があってもよい。
Ａ環に含まれる環としては、例えばベンゼン、ピリジン、ピラジン、ピリミジン、ピリダジン、フラン、チオフェン、ピロール、チアゾール、および一部水素化されていてもよく、かつ硫黄原子がある場合にはそれが酸化されていてもよい以下の二環式縮合環などを挙げることができ、これらの環は化学的に可能な任意の位置でＢ環と縮合することがでる。
【０００８】
【化６】

【０００９】
【化７】

【００１０】
【化８】

【００１１】
上記環は置換基１〜３個を有していてもよく、置換基が複数個ある場合には、同一または異なっていてもよい。置換基としては、例えば水酸基、オキソ基、シアノ基、ハロゲン基、ニトロ基、水酸化または低級アルキルアミノ化されていてもよい低級アルキル基、低級アルコキシ基、低級アシル基、低級アルキル化されていてもよいカルバモイル基、低級アルキル化、低級アシル化、アリールスルホニル化あるいは低級アルキルスルホニル化されていてもよいアミノ基などを挙げることができる。
Ｃ環の意味する「単環式または縮合二環式芳香環」とは、単環式または二環式の芳香族炭化水素あるいは窒素原子を１ないし２個含む芳香族へテロ環であり、当該環上には１〜３個の置換基があってもよい。
Ｃ環に含まれる環としては、例えば、ベンゼン、ピリジン、ピリミジン、ナフタレン、キノリン、イソキノリン、インドール、キナゾリンなどを挙げることができ、これらの環は化学的に可能な任意の位置でＢ環と縮合することがでる。
【００１２】
上記環は置換基１〜３個を有していてもよく、置換基が複数個ある場合には同一または異なっていてもよい。置換基としては、例えばハロゲン基、水酸基、低級アルキル基、低級アルコキシ基、ニトロ基、低級アルキル化あるいは低級アシル化されていてもよいアミノ基などを挙げることができる。
【００１３】
上記一般式（Ｉ）において、Ａ環およびＣ環が有していてもよい置換基ならびにＹの定義中の低級アルキル基としては、炭素数１〜６の直鎖もしくは分枝状のアルキル基、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、sec −ブチル基、tert−ブチル基、ｎ−ペンチル基（アミル基）、イソペンチル基、ネオペンチル基、tert−ペンチル基、１−メチルブチル基、２−メチルブチル基、１，２−ジメチルプロピル基、ｎ−ヘキシル基、イソヘキシル基、１−メチルペンチル基、２−メチルペンチル基、３−メチルペンチル基、１，１ジメチルブチル基、１，２−ジメチルブチル基、２，２−ジメチルブチル基、１，３−ジメチルブチル基、２，３−ジメチルブチル基、３，３−ジメチルブチル基、１−エチルブチル基、２−エチルブチル基、１，１，２−トリメチルプロピル基、１，２，２−トリメチルプロピル基、１−エチル−１−メチルプロピル基、１−エチル−２−メチルプロピル基などを挙げることができる。これらのうち好ましい基としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基などを挙げることができ、これらのうち、最も好ましい基としてはメチル基、エチル基を挙げることができる。
また、Ｙ中のｅの定義において低級アルキレン基とは、上記低級アルキル基から水素１原子を除いた残基を意味する。Ａ環およびＣ環が有していてもよい置換基ならびにＹ中のｆの定義において、アミノ基が２個の低級アルキル基で置換されている場合には、これらのアルキル基が結合して５または６員環を形成してもよい。
Ａ環およびＣ環が有していてもよい置換基の定義中の低級アルコキシ基とは、メトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、イソブトキシ基、tert−ブトキシ基など上記の低級アルキル基から誘導される低級アルコキシ基を意味するが、これらのうち最も好ましい基としてはメトキシ基、エトキシ基を挙げることができる。またハロゲン原子としてはフッ素原子、塩素原子、臭素原子などが挙げられる。
低級アシル基としては、炭素数１〜６のホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基などが挙げられる。
Ａ環が有していてもよい置換基の定義中のアリールスルホニル化あるいは低級アルキルスルホニル化されていてもよいアミノ基としては、例えばｐ−トルエンスルホニル化、メチルスルホニル化、エチルスルホニル化されていてもよいアミノ基などを意味する。
【００１４】
上記一般式（Ｉ）で示される縮合多環式へテロ環誘導体は酸と塩を形成する場合もある。本発明は化合物（Ｉ）の塩をも包含する。酸との塩としては、たとえば塩酸、臭化水素酸、硫酸等との無機酸塩や酢酸、乳酸、コハク酸、フマル酸、マレイン酸、クエン酸、安息香酸、メタンスルホン酸、ｐ−トルエンスルホン酸などとの有機酸塩を挙げることができる。
また、これら化合物の水和物はもちろんのこと光学異性体が存在する場合はそれらすべてが含まれることはいうまでもない。また、本発明化合物は強い抗腫瘍活性を示すが、生体内で酸化、還元、加水分解、抱合などの代謝を受けて抗腫瘍活性を示す化合物をも包含する。またさらに、本発明は生体内で酸化、還元、加水分解などの代謝を受けて本発明化合物を生成する化合物をも包含する。
【００１５】
本発明化合物（Ｉ）は種々の方法によって製造することができるが、それらのうち代表的な方法を示せば以下の通りである。
【００１６】
１）一般式（II）
【化９】

【００１７】
（式中、Ａａ環およびＣａ環は各々保護されていてもよいＡ環およびＣ環を意味し、Ｂａ環は４Ｈ−１，４−オキサジン，４Ｈ−１，４−チアジン，４（１Ｈ）−ピリドンまたはピロールを意味する。ｆａは保護されていてもよいｆを意味する。ｅは前記と同じ意味を示す）で表わされる化合物と一般式（III ）
【化１０】

【００１８】
（式中、ＤおよびＥは同一または異なって脱離基を意味する）で表わされる化合物を反応させることにより製造することができる。
【００１９】
本反応は一般に、例えばジメチルホルムアミド、テトラヒドロフラン、ジオキサンなどの非プロトン性の溶媒に化合物（II）を溶解し、次に２〜３当量の水素化ナトリウムを加えた後、化合物（III ）を加えることにより行われる。
化合物（III ）としては、例えば、ホスゲン、クロロ炭酸エチル、Ｎ，Ｎ′−カルボニルジイミダゾールなどを挙げることができる。反応は通常−50〜150 ℃の温度範囲で行われる。
得られた生成物において、アミノ基、水酸基などが保護されている場合には、酸処理、アルカリ処理、接触還元など通常の脱保護法を行うことにより、目的とする化合物（Ｉ）を得ることが可能である。
【００２０】
２）一般式（IV）
【化１１】

【００２１】
（式中、Ａｂ環は、低級アシル基またはオキソ基を有し、他に保護されたまたは保護されていない置換基を有していてもよい、少なくとも一方の環が芳香環である二環式縮合環を意味する。Ｂｂ環はピロール，４Ｈ−１，４−オキサジンまたは４Ｈ−１，４−チアジンを意味する。Ｃｂ環は保護されたまたは保護されていない置換基を有していてもよい単環式芳香環を意味する。Ｙは前記と同じ意味を示す）で表わされる化合物をカルボニル基の還元剤と反応させることにより製造することができる。
還元には、一般に用いられるカルボニル基の還元法を使用することができるが、好ましい例としては、パラジウム−炭素などを触媒とした接触還元やボラン−ピリジンコンプレックス、シアノ水素化ほう素ナトリウムなどによる還元を挙げることができる。
【００２２】
次に、本発明に用いられる原料化合物（II）を製造する方法について説明する。原料化合物（II）には公知化合物および新規化合物が含まれる。新規化合物の場合、既に報告されている公知化合物の合成法を応用することにより、または、それらを組み合わせることにより製造することが可能である。
【００２３】
製造法１
【化１２】

【００２４】
（式中、Ａｃ環は、置換基を有していてもよい、芳香環ではない単環または一方あるいは両方の環が芳香環ではない二環式縮合環を意味する。Ａｄ環はＡｃ環中の一部または全部が脱水素された環を意味する。Ｃａ環、ｅおよびｆａは前記と同じ意味を示す。）
一般式（IX）で表わされる化合物はフィシャー（Fischer) のインドール合成法、ボルシェ（Borsche)のテトラヒドロカルバゾール合成法［オーガニック・シンセシス（Org . Syn.）IV, 884 （1963）］などを応用することにより製造することができる。即ち、一般式（VII ）で表わされる環式ケトンと一般式（VIII）で表わされるｏ−ヒドラジノ芳香族カルボン酸を例えば酢酸中またはギ酸中あるいは塩酸、硫酸、塩化亜鉛などの酸触媒存在下エタノールなどの中性溶媒中加熱することにより製造することができる。化合物（IX）において、Ａｃ環が、置換基を有していてもよい、一方の環のみが芳香環である二環式縮合環である場合には、そのまま一般式（VI）で表わされる化合物と縮合させることにより、目的とする化合物（IIａ）を製造することが可能である。化合物（Ｘ）は、化合物（IX）中の芳香環ではない環を脱水素剤により一部または全部脱水素することにより製造することができる。脱水素剤としては、例えば２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン，クロラニル，パラジウム−炭素などを挙げることができる。反応は通常室温または加熱下で行われる。Ａｃ環が、両方の環とも芳香環ではない二環式縮合環の場合には、試薬の種類、量、反応条件等を適切に選ぶことにより一方の環のみを選択的に脱水素することも可能である。目的とする化合物（IIａ）はこのようにして得られた化合物（Ｘ）と化合物（VI）を縮合させることにより製造することができる。縮合法としては、例えば酸クロリド法、活性エステル法、混合酸無水物法や縮合剤として１，３−ジシクロヘキシルカルボジイミド、Ｎ，Ｎ′−カルボニルジイミダゾール、ジフェニルホスホリルアジドを用いる方法などがある。
【００２５】
製造法２
【化１３】

【００２６】
（式中、Ａｅ環は、置換基を有していてもよい、単環式芳香環または少なくとも置換基−Ｇ−Ｈを有する環が芳香環である二環式縮合環を意味する。Ｇは酸素原子または硫黄原子を意味する。ＫおよびＬは脱離基を意味し、Ｒは低級アルキル基を意味する。Ｃａ環、ｅおよびｆａは前記と同じ意味を示す。）
一般式（XIII）で表わされる化合物は一般式（XI）の化合物と一般式（XII ）の化合物を反応させることにより製造することができる。化合物（XII ）中の脱離基Ｋの好ましい例としてはニトロ基を、Ｌの好ましい例としてはハロゲン原子を挙げることができる。反応はトリエチルアミン、酢酸ナトリウム、水酸化ナトリウムなどの塩基存在下または非存在下加熱することにより行うことができる。目的とする化合物（IIｂ）は、化合物（XIII）のエステルをアルカリ加水分解により化合物（XIV ）に導き、これを製造法（Ｉ）と同様にして化合物（VI）と縮合させることにより製造することができる。
【００２７】
本発明化合物を医薬として使用する場合は、経口もしくは非経口的に投与される。投与量は、症状の程度、患者の年齢、性別、体重、感受性差、投与方法、投与時期、投与間隔、医薬製剤の性質、調剤、種類、有効成分の種類等によって異なり特に限定されないが、通常成人１日あたり１〜3000mg、好ましくは約10〜2000mg、さらに好ましくは20〜1000mgでありこれを通常１日１〜３回に分けて投与する。
【００２８】
経口用固形製剤を調製する場合は、主薬に賦形剤さらに必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤などを加えた後、常法により錠剤、被覆錠剤、顆粒剤、細粒剤、散剤、カプセル剤等とする。
賦形剤としては、例えば乳糖、コーンスターチ、白糖、ぶどう糖、ソルビット、結晶セルロース、二酸化ケイ素などが、結合剤としては、例えばポリビニルアルコール、エチルセルロース、メチルセルロース、アラビアゴム、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等が、滑沢剤としては、例えばステアリン酸マグネシウム、タルク、シリカ等が、着色剤としては医薬品に添加することが許可されているものが、矯味矯臭剤としては、ココア末、ハッカ脳、芳香酸、ハッカ油、龍脳、桂皮末等が用いられる。これらの錠剤、顆粒剤には糖衣、ゼラチン衣、その他必要により適宜コーティングすることは勿論差し支えない。
注射剤を調製する場合には、必要により主薬にpH調整剤、緩衝剤、懸濁化剤、溶解補助剤、安定化剤、等張化剤、保存剤などを添加し、常法により静脈、皮下、筋肉内注射剤とする。その際必要により、常法により凍結乾燥物とすることもある。
懸濁化剤としては、例えばメチルセルロース、ポリソルベート80、ヒドロキシエチルセルロース、アラビアゴム、トラガント末、カルボキシメチルセルロースナトリウム、ポリオキシエチレンソルビタンモノラウレートなどを挙げることができる。
【００２９】
溶解補助剤としては、例えばポリオキシエチレン硬化ヒマシ油、ポリソルベート80、ニコチン酸アミド、ポリオキシエチレンソルビタンモノラウレート、マクロゴール、ヒマシ油脂肪酸エチルエステルなどを挙げることができる。
また安定化剤としては、例えば亜硫酸ナトリウム、メタ亜硫酸ナトリウム等を、保存剤としては、例えばパラオキシ安息香酸メチル、パラオキシ安息香酸エチル、ソルビン酸、フェノール、クレゾール、クロロクレゾールなどを挙げることができる。
【００３０】
【発明の実施の形態】
【発明の効果】
次に本発明化合物の効果を記述するための薬理実験例を示す。
【００３１】
実験例１ Ｐ 388 細胞（マウス白血病細胞）に対する in vitro 抗腫瘍試験
10％牛胎児血清、ペニシリン（100 単位／ml）、ストレプトマイシン（100 μg ／ml）、メルカプトエタノール（５×10^-5Ｍ）およびピルビン酸ナトリウム（１mM）を含むRPMI1640培地（三光純薬）に浮遊させたＰ388 細胞を96穴Ｕ底マイクロプレートの各穴に1.25×10³ 個（0.1ml)ずつ播種し、５％炭酸ガス含有の培養器中37℃で１日培養した。
【００３２】
本発明化合物をジメチルスルホキシドにて10^-2Ｍの濃度に溶解し、10％牛胎児血清−RPMI1640培養液で10^-4Ｍあるいは10^-5Ｍの濃度まで希釈した。これを最高濃度として10％牛胎児血清−RPMI1640培養液にて３倍系列希釈を行った。これを先に述べたＰ388 細胞の培養プレートの各穴に 0.1mlずつ加え、５％炭酸ガス含有培養器中37℃で３日間培養した。
【００３３】
培養後、ＭＴＴ［３−（４，５−ジメチルチアゾール−２−イル）−２，５−ジフェニルテトラゾリウムブロミド］溶液（3.3 mg／ml）を0.05mlずつ各穴に加え、さらに２時間培養した。マイクロプレートを遠心し、各穴から上清を吸引除去後、生成したホルマザンをジメチルスルホキシド 0.1mlで溶解し、マイクロプレートリーダーで540nm における吸光度を測定し、生細胞数の指標とした。以下の式より抑制率を算出し、50％抑制する被検化合物の濃度（ＩＣ₅₀）を求めた。
【００３４】
【数１】

【００３５】
Ｔ：被検化合物を添加した穴の吸光度
Ｃ：被検化合物を添加しなかった穴の吸光度
得られたＩＣ₅₀値を表１に示す。
【００３６】
【表１】

【００３７】
実験例２ Ｍ 5076 （マウス細網肉腫）に対する in vivo 抗腫瘍試験
BDF1マウス（６〜７週齢、雌）の体側皮下に1x10⁶ 個のＭ5076を移植した。本発明化合物を5%ブドウ糖液に溶解し、移植した翌日以降に各スケジュールにより１日１回腹腔内投与した。対照群には5%ブドウ糖液を投与した。対照群は一群１０匹、薬剤投与群は一群５匹で実験を行った。
移植後２１日目に腫瘍を摘出し、腫瘍重量を測定した。対照群に対する薬剤投与群の腫瘍増加抑制率を下記式より求めた。
【００３８】
【数２】

【００３９】
Ｔ：被検化合物投与群の平均腫瘍重量
Ｃ：対照群の平均腫瘍重量
実験結果を表２に示す。
【００４０】
【表２】

【００４１】
実験例３ ＭＸ -1 （ヒト乳癌）に対する in vivo 抗腫瘍試験
ヌードマウス（ＢＡＬＢ／Ｃ・ nu/nu 、６〜７週齢、雌）の体側皮下に1mm³程度のＭＸ-1腫瘍片を移植した。移植後50mm³ の腫瘍体積になる約１０日後より本発明化合物を5%ブドウ糖液に溶解し、各スケジュールにより１日１回腹腔内投与した。対照群には5%ブドウ糖液を投与した。対照群は一群１０匹、薬剤投与群は一群５匹で実験を行った。
薬剤投与開始後２２日目に腫瘍を摘出し、腫瘍重量を測定した。対照群に対する薬剤投与群の腫瘍増加抑制率を下記式より求めた。
【００４２】
【数３】

【００４３】
Ｔ：被検化合物投与群の平均腫瘍重量
Ｃ：対照群の平均腫瘍重量
実験結果を表３に示す。
【００４４】
【表３】

【００４５】
以上の実験結果から明らかなように本発明化合物は優れた抗腫瘍効果を有し、抗腫瘍剤として有用である。
【００４６】
【実施例】
次に本発明化合物の原料化合物の製造を示す製造例および発明化合物の代表的化合物についての実施例を挙げるが、本発明がこれらのみに限定されるものではない。
【００４７】
製造例１
５，６−ジヒドロ−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボン酸
【化１４】

【００４８】
２−ヒドラジノ安息香酸塩酸塩 7.05g（37.4ミリモル）の酢酸40ml懸濁液に80℃でβ−テトラロン5.00g （34.2ミリモル）の酢酸10ml溶液を滴下し、３時間45分加熱還流した。室温にもどして水を加え、生じた沈澱を濾取、水洗、乾燥後、エタノールから再結晶し、表題化合物5.2gを得た。
¹H-NMR(DMSO-d₆) δ(ppm);2.91-3.06(m,4H),7.03(t,J=7.6Hz,1H),7.17(t,J=7.6Hz,1H),7.20-7.27(m,2H),7.72(d,J=7.6Hz,1H),7.76(d,J=7.6Hz,1H),8.19(d,J=7.6Hz,1H),11.29(s,1H)
【００４９】
製造例２
７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボン酸
【化１５】

【００５０】
製造例１の化合物2.97g （11.3ミリモル）のベンゼン 200ml懸濁液に室温で２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン3.29g （14.3ミリモル）を加え、50分間攪拌した。さらに３時間20分加熱還流後、室温にもどして析出物を濾取、エタノールから再結晶し、表題化合物 2.76gを得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；7.39(t,J=7.3Hz,1H),7.48(t,J=7.3Hz,1H),7.70(t,J=7.3Hz,1H),7.93(d,J=8.7Hz,1H),8.00-8.07(m,3H),8.79(d,J=7.3Hz,1H),8.87(d,J=7.3Hz,1H),11.82(s,1H),13.22(br-s,1H ）
【００５１】
製造例３
Ｎ−［２− (ジメチルアミノ）エチル］−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボキサミド
【化１６】

【００５２】
製造例２の化合物1.89g (7.25 ミリモル）のジメチルホルムアミド60ml溶液に室温でＮ，Ｎ′−カルボニルジイミダゾール2.52g (15.5 ミリモル）を加えた。45分間攪拌後、Ｎ，Ｎ−ジメチルエチレンジアミン5.0ml (45.5 ミリモル）を加え、２時間40分攪拌した。濃縮後、水と酢酸エチルを加えて抽出、有機層を分取、水洗した。硫酸ナトリウムで乾燥後、濃縮乾固し、表題化合物2.47g 得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.33(s,6H),2.60(t,J=5.7Hz,2H),3.63(q,J=5.7Hz,2H),7.16(br-s,1H),7.38(t,J=7.5Hz,1H),7.46-7.50(m,1H),7.65-7.73(m,3H),7.89(d,J=9.0Hz,1H),8.01(d,J=8.2Hz,1H),8.69(d,J=7.5Hz,1H),8.74(d,J=8.2Hz,1H),10.94(br-s,1H)
【００５３】
製造例４
３−アセチル−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボン酸
【化１７】

【００５４】
塩化アルミニウム5.1g (38ミリモル）のジクロロメタン 300ml懸濁液に０℃で無水酢酸1.17ml（12.4ミリモル）を加え20分間攪拌した。この液に０℃で製造例２の化合物2.16g ( 8.28ミリモル）を加え、同温度で４時間30分攪拌した。反応混合物を氷水に注ぎ、クロロホルムとエタノールの混液で抽出した。有機層を分取、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物1.45g を得た。
¹H-NMR(DMSO-d₆) δ(ppm) ；2.72(s,3H),7.44(t,J=7.6Hz,1H),8.07(d,J=7.6Hz,1H),8.11(d,J=9.1Hz,1H),8.14(d,J=9.1Hz,1H),8.18(dd,J=1.9,8.8Hz,1H),8.79(d,J=1.9Hz,1H),8.87(d,J=8.8Hz,1H),8.91(d,J=7.6Hz,1H),12.01(s,1H）
【００５５】
製造例５
３−アセチル−Ｎ−［２− (ジメチルアミノ）エチル］−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボキサミド
【化１８】

【００５６】
製造例４の化合物 247mg (0.815 ミリモル）のジメチルホルムアミド７ml溶液にＮ，Ｎ′−カルボニルジイミダゾール 291mg (1.80ミリモル）を氷冷下加え、室温にもどして約２時間攪拌した。これに氷冷下Ｎ，Ｎ−ジメチルエチレンジアミン0.45ml (4.1 ミリモル）を加え、室温にもどして約12時間攪拌した。水とクロロホルムを加えて抽出、有機層を分取、硫酸ナトリウムで乾燥、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 140mgを得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.29(s,6H),2.53-2.61(m,2H),2.74(s,3H),3.52(q, J=5.9Hz,2H),7.43(t,J=7.1Hz,1H),7.97(d,J=7.1Hz,1H),8.10(d,J=8.7Hz,1H),8.14(d,J=8.7Hz,1H),8.20(dd,J=1.8,8.5Hz,1H),8.72(t,J=5.9Hz,1H),8.79-8.83(m,2H),8.88(d,J=8.5Hz,1H),12.17(s,1H）
【００５７】
製造例６
３，４，５，８−テトラヒドロナフタレン−１，６ (２Ｈ，７Ｈ）−ジオン
【化１９】

【００５８】
１，２，３，４，５，８−ヘキサヒドロ−１−オキソ−６−メトキシナフタレン6.8g (38.2ミリモル）をテトラヒドロフラン50mlに溶解し、１Ｎ塩酸５mlを加えた。室温で１時間攪拌後、酢酸エチルを加え、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。濃縮後、ｎ−ヘキサンと酢酸エチルの混液（１：１）少量を加え、ドライアイス−エーテル浴で冷却した。生じた沈澱を濾取、ｎ−ヘキサン少量で洗浄し、表題化合物4.8gを得た。
¹H-NMR(CDCl₃) δ(ppm) ；2.01-2.11(m,2H),2.30-2.37(m,2H),2.45-2.51(m,4H),2.68-2.76(m,2H),3.05(s,2H)
【００５９】
製造例７
４−オキソ−１，２，３，４−テトラヒドロ−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボン酸
【化２０】

【００６０】
２−ヒドラジノ安息香酸塩酸塩5.4g（28.6ミリモル）と塩化亜鉛4.7g（34.3ミリモル）を氷酢酸 300ml中に加えた。約85℃で攪拌下、製造例６の化合物4.7g（28.6ミリモル）を約５分かけて加えた。同温度で約２時間攪拌後、室温にもどして沈澱を濾取した。濾液を濃縮後、水を加えて生じた沈澱を濾取した。これらの沈澱を合わせて乾燥後、ジメチルホルムアミド約 500mlに溶解した。室温攪拌下、２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン6.5g（28.6ミリモル）のテトラヒドロフラン20ml溶液を加え、約30分間攪拌した。濃縮後、エタノール約50mlを加え、生じた沈澱を濾取し、表題化合物3.4gを得た。
¹H-NMR(DMSO-d₆) δ(ppm) ；2.17-2.29(m,2H),2.63-2.70(m,2H),3.55(t,J=6.0Hz,2H),7.36(t,J=7.6Hz,1H),7.73(d,J=8.8Hz,1H),8.03(d,J=8.8Hz,1H),8.06(dd,J=0.8,7.6Hz,1H),8.48(dd,J=0.8,7.6Hz,1H),11.83(s,1H),13.33(br-s,1H)
【００６１】
製造例８
Ｎ−［２−（ジメチルアミノ）エチル］−４−オキソ−１，２，３，４−テトラヒドロ−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボキサミド
【化２１】

【００６２】
製造例７の化合物3.4g (12.2ミリモル）をジメチルホルムアミド 120mlに加えて攪拌後、Ｎ，Ｎ′−カルボニルジイミダゾール3.0g（18.5ミリモル）のジメチルホルムアミド30ml溶液を加えた。室温で１時間攪拌後、Ｎ，Ｎ−ジメチルエチレンジアミン3.2g（36.3ミリモル）を加えた。同温度で更に１時間攪拌後、濃縮し、酢酸エチルを加えた。希アンモニア水、食塩水で順次洗浄、硫酸マグネシウムで乾燥後、濃縮乾固し、表題化合物4.3gを得た。
ＦＡＢ質量分析ｍ／ｚ；350 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(CDCl₃) δ(ppm) ；2.30-2.40(m+s,2H+6H),2.62(t,J=6.0Hz,2H),2.74-2.79(m,2H),3.56-3.66(m,4H),7.21(br-s,1H),7.32(t,J=8.0Hz,1H),7.41(d,J=8.4Hz,1H),7.70(dd,J=0.8,8.0Hz,1H),8.25(d,J=8.4Hz,1H),8.33(dd,J=0.8,8.0Hz,1H),10.91(br-s,1H）
【００６３】
製造例９
２，３−ジヒドロ−３−オキソ−１Ｈ，６Ｈ−シクロペンタ［ｃ］カルバゾール−７−カルボン酸
【化２２】

【００６４】
２，３，４，７−テトラヒドロ−５−メトキシ−１Ｈ−インデン−１−オンから製造例６と同様にして合成した２，３，４，７−テトラヒドロ−１Ｈ−インデン−１，５（６Ｈ）−ジオンを製造例７と同様に反応させ、表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ；266 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆) δ(ppm) ；2.70-2.82(m,2H),3.52-3.62(m,2H),7.41(t,J=7.6Hz,1H),7.70(d,J=8.4Hz,1H),7.81(d,J=8.4Hz,1H),8.09(dd,J=0.8,7.6Hz,1H),8.39(d,J=7.6Hz,1H),11.95(s,1H),13.37(br-s,1H)
【００６５】
製造例１０
２，３−ジヒドロ−Ｎ−［２−（ジメチルアミノ）エチル］−３−オキソ−１Ｈ，６Ｈ−シクロペンタ［ｃ］カルバゾール−７−カルボキサミド
【化２３】

【００６６】
製造例９の化合物から製造例８と同様の方法で表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ；336 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(CDCl₃) δ(ppm) ；2.34(s,6H),2.61(t,J=6.0Hz,2H),2.85-2.91(m,2H),3.58-3.66(m,4H),7.18(br-s,1H),7.36(t,J=7.6Hz,1H),7.49(d,J=8.4Hz,1H),7.71(d,J=7.6Hz,1H),7.88(d,J=8.4Hz,1H),8.22(d,J=7.6Hz,1H),10.95(br-s,1H)
【００６７】
製造例１１
メチル ５，６，７，８−テトラヒドロ−９Ｈ−カルバゾール−１−カルボキシラート
【化２４】

【００６８】
２−ヒドラジノ安息香酸塩酸塩52g （0.276 モル）の酢酸 500ml懸濁液に約 100℃で攪拌下、シクロヘキサノン28ml（0.270 モル）の酢酸 100ml溶液を滴下した。６時間加熱還流後、室温にもどして水１ｌを加えた。生じた沈澱を濾取、水洗、乾燥し、粉末43g を得た。これをアセトン 500mlに溶解し、ヨウ化メチル37.5ml（0.602 モル）と無水炭酸カリウム41.4g （0.300 モル）を加え、２時間加熱還流した。室温にもどして不溶物を濾去、濃縮後、水を加えて沈澱を濾取し、表題化合物45.7g を得た。
¹H-NMR(CDCl₃) δ(ppm) ；1.85-1.97(m,4H),2.70-2.74(m,2H),2.76-2.80(m,2H),3.97(s,3H),7.09(t,J=7.6Hz,1H),7.65-7.68(m,1H),7.79(dd,J=1.1,7.6Hz,1H),9.39(br-s,1H)
【００６９】
製造例１２
メチル ５−オキソ−５，６，７，８−テトラヒドロ−９Ｈ−カルバゾール−１−カルボキシラート
【化２５】

【００７０】
製造例１１の化合物45.7g （0.199 モル）をテトラヒドロフラン 500mlと水50mlの混液に溶解し、窒素雰囲気、氷冷攪拌下２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン90.8g （0.400 モル）のテトラヒドロフラン 200ml溶液を滴下した。室温で３時間攪拌後、炭酸カリウム水溶液１ｌを加え、酢酸エチルで抽出した。有機層を分取、水洗、硫酸マグネシウムで乾燥、濃縮後、残渣をエタノールから再結晶し、表題化合物 39.7gを得た。
¹H-NMR(DMSO-d₆) δ(ppm) ；2.10-2.17(m,2H),2.44-2.48(m,2H),3.07(t,J=6.2Hz,2H),3.96(s,3H),7.28(t,J=7.7Hz,1H),7.81(dd,J=1.3,7.7Hz,1H),8.25(dd,J=1.3,7.7Hz,1H),11.79(br-s,1H)
【００７１】
製造例１３
メチル ５−ヒドロキシ−９Ｈ−カルバゾール−１−カルボキシラート
【化２６】

【００７２】
製造例１２の化合物39.1g （0.161 モル）をジフェニルエーテル 150mlに懸濁し、10％パラジウム炭素10g を加え、窒素雰囲気下３時間加熱還流した。放冷後、析出した結晶およびパラジウム炭素を濾取し、ヘキサンで洗浄した。濾取した混合物を熱テトラヒドロフランに溶解し、パラジウム炭素を濾去した。濃縮後、残渣をエタノールから再結晶し、表題化合物 34.7gを得た。
¹H-NMR(CDCl₃) δ(ppm) ；4.03(s,3H),5.54(s,1H),6.62(dd,J=0.6,7.9Hz,1H),7.10(dd,J=0.6,7.9Hz,1H),7.27(t,J=7.9Hz,1H),7.30(t,J=7.9Hz,1H),8.05(dd,J=1.2,7.9Hz,1H),8.46-8.50(m,1H),9.93(br-s,1H)
【００７３】
製造例１４
［１−メトキシカルボニル−９Ｈ−カルバゾール−５−イル］オキシ酢酸
【化２７】

【００７４】
製造例１３の化合物 34.8g（0.144 モル）をアセトン 550mlに溶解し、ベンジルブロモアセタート68.5ml（0.432 モル）、ヨウ化ナトリウム 64.8g（0.432 モル）および無水炭酸カリウム 29.8g（0.216 モル）を加え60時間加熱還流した。放冷後沈澱を濾去し、濃縮した。酢酸エチルと水を加え抽出し、有機層を分取、水洗、硫酸マグネシウムで乾燥後濃縮した。残渣にｎ−ヘキサンを加えて固化させた後、濾取、エタノールから再結晶して表題化合物のベンジルエステル 40.7gを得た。これをテトラヒドロフラン 600mlとメタノール 500mlの混液に懸濁し、10％パラジウム炭素 12gを加えて常温常圧で水素添加し、表題化合物 29.4gを得た。
¹H-NMR(CD₃OD）δ(ppm) ；4.02(s,3H),4.90(s,2H),6.67(dd,J=0.6,8.0Hz,1H),7.23(t,J=7.7Hz,1H),7.26(dd,J=0.6,8.0Hz,1H),7.35(t,J=8.0Hz,1H),8.02(dd,J=1.1,7.7Hz,1H),8.63(dd,J=1.1,7.7Hz,1H),10.87(br-s,1H)
【００７５】
製造例１５
２，３−ジヒドロ−３−オキソ−６Ｈ−フロ[ ３，２−ｃ] カルバゾール−７−カルボン酸
【化２８】

【００７６】
製造例１４の化合物 29.4g（0.098 モル）をトルエン 500mlに懸濁し、塩化チオニル36ml（0.494 モル）を加え、均一になるまで加熱還流した。濃縮後、ジクロロメタン 500mlを加えて溶解し、氷冷攪拌下、塩化アルミニウム 32.1g（0.240 モル）を少量ずつ加えた。室温にもどして一晩攪拌後、氷冷下氷水を加えた。室温で攪拌後、濃縮し、希塩酸を加えた。沈澱を濾取、水、エタノールで順次洗浄、乾燥し、粉末26.5g を得た。この粉末全量をテトラヒドロフラン 350mlとメタノール 250mlの混液に溶解し、窒素雰囲気下、脱気した 0.2Ｎ水酸化ナトリウム水溶液 750mlを加えた。50℃にてエステルを加水分解後、濃塩酸20mlを加えた。酢酸エチルとテトラヒドロフランの混液で抽出し、有機層を分取、水洗、硫酸マグネシウムで乾燥、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 11.4gを得た。
¹H-NMR(DMSO-d₆) δ(ppm) ；5.00(s,2H),7.41(t,J=7.7Hz,1H),7.56(d,J=8.5Hz,1H),7.63(d,J=8.5Hz,1H),8.07(dd,J=1.3,7.7Hz,1H),8.29-8.32(m,1H),12.10(br-s,1H)
【００７７】
製造例１６
Ｎ−［２−（アリルメチルアミノ）エチル］−４−オキソ−１，２，３，４−テトラヒドロ−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボキサミド
【化２９】

【００７８】
製造例７の化合物0.5g（1.79ミリモル）とＮ−メチルエチレンジアミン 0.53g（7.15ミリモル）から製造例８と同様の方法でＮ−［２−（メチルアミノ）エチル］−４−オキソ−１，２，３，４−テトラヒドロ−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボキサミド 0.49gを得た。このもの 0.49g（1.46ミリモル）、臭化アリル0.25g （1.74ミリモル）およびＮ，Ｎ−ジイソプロピルエチルアミン 0.23g（1.78ミリモル）をテトラヒドロフラン30mlに溶解し、55℃で約５時間攪拌した。放冷後、酢酸エチルを加えて希釈し、希アンモニア水、食塩水で順次洗浄、硫酸マグネシウムで乾燥した。濃縮後、残渣をプレパラティブ薄層クロマトグラフィーで精製し、表題化合物 0.24gを得た。
¹H-NMR(CDCl₃) δ(ppm) ；2.28-2.40(m+s,2H+3H),2.70(t,J=6.0Hz,2H),2.73-2.80(m,2H),3.11-3.17(m,2H),3.56-3.68(m,4H),5.17-5.29(m,2H),5.82-5.97(m,1H),7.24(br-s,1H),7.33(t,J=7.6Hz,1H),7.42(d,J=8.4Hz,1H),7.67(dd,0.8,7.6Hz,1H),8.25(d,J=8.4Hz,1H),8.33(dd,J=0.8,7.6Hz,1H),10.88(br-s,1H)
【００７９】
製造例１７
５−［２−（アリルメチルアミノ）エチル］−１２，１３−ジヒドロ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６，１０（５Ｈ，１１Ｈ）−トリオン
【化３０】

【００８０】
製造例１６の化合物 0.24g（0.64ミリモル）から実施例２と同様の方法（塩酸塩にする操作を除く）で表題化合物0.23g を得た。
¹1H-NMR(CDCl₃)δ(ppm) ；2.32-2.42(m+s,2H+3H),2.73-2.84(m,4H),3.10-3.15(m,2H),3.53(t,J=6.4Hz,2H),4.35(t,J=7.2Hz,2H),5.08-5.22(m,2H),5.74-5.90(m,1H),7.63(t,J=7.6Hz,1H),8.19(dd,J=0.8,7.6Hz,1H),8.32(dd,J=0.8,7.6Hz,1H),8.35(d,J=8.4Hz,1H),8.51(d,J=8.4Hz,1H)
【００８１】
製造例１８
メチル ６−メチル−９Ｈ−カルバゾール−１−カルボキシラート
【化３１】

【００８２】
２−ヒドラジノ安息香酸塩酸塩2.0g（10.6ミリモル）の酢酸20ml懸濁液を攪拌下緩和に沸騰させ、４−メチルシクロヘキサノン 1.2ml（9.8 ミリモル）を滴下した。８時間加熱還流、放冷後、水を加えて沈澱を濾取、水洗、乾燥し、６−メチル−５，６，７，８−テトラヒドロ−９Ｈ−カルバゾール−１−カルボン酸 1.96gを得た。これをアセトン50mlに溶解し、ヨウ化メチル 2.1ml（34ミリモル）と無水炭酸カリウム 2.35g（17ミリモル）を加え、攪拌下２時間加熱還流した。放冷後、水と酢酸エチルを加えて抽出し、有機層を分取、水洗、硫酸マグネシウムで乾燥、濃縮乾固し、メチル ６−メチル−５，６，７，８−テトラヒドロ−９Ｈ−カルバゾール−１−カルボキシラート 1.49gを得た。これをジフェニルエーテル10mlに懸濁し、10％パラジウム炭素 890mgを加え、窒素雰囲気下攪拌しながら１時間加熱還流した。放冷後熱テトラヒドロフランを加えて溶解し、触媒を濾去、濃縮した。ｎ−ヘキサンを加え、結晶を濾取し、表題化合物1.26g を得た。¹H-NMR(CDCl₃) δ(ppm) ；2.54(s,3H),4.02(s,3H),7.22(t,J=7.8Hz,1H),7.27-7.31(m,1H),7.41(d,J=8.2Hz,1H),7.87-7.90(m,1H),8.05(dd,J=1.1,7.8Hz,1H),8.21-8.25(m,1H),9.82(br-s,1H)
【００８３】
製造例１９
メチル ６−ホルミル−９Ｈ−カルバゾール−１−カルボキシラート
【化３２】

【００８４】
製造例１８の化合物1.2g（５ミリモル）の四塩化炭素 100ml溶液にＮ−ブロモスクシンイミド1.8g（10ミリモル）とα, α′−アゾビスイソブチロニトリル 220mg（1.3 ミリモル）を加え、攪拌下１時間加熱還流した。放冷後、濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物1.13g を得た。
¹H-NMR(CDCl₃) δ(ppm) ；4.05(s,3H),7.36(t,J=7.8Hz,1H),7.62(d,J=8.4Hz,1H),8.03(dd,J=1.6,8.4Hz,1H),8.14(dd,J=1.2,7.8Hz,1H),8.32-8.36(m,1H),8.62-8.64(m,1H),10.12(s,1H),10.23(br-s,1H)
【００８５】
製造例２０
メチル １，２−ジヒドロ−１−オキソ−７Ｈ−ピリド［４，３−ｃ］カルバゾール−８−カルボキシラート
【化３３】

【００８６】
製造例１９の化合物2.0g（7.9 ミリモル）のピリジン80ml溶液にマロン酸 2.6g （25ミリモル）とピペリジン 0.3mlを加え、浴温80℃で１時間攪拌した。マロン酸2.6g（25ミリモル）を加熱攪拌下１時間かけて加えた後、さらに１時間加熱還流した。放冷後、濃塩酸−氷に反応混合物を注ぎ、生じた沈澱を濾取、水洗、乾燥し、３−（１−メトキシカルボニル−９Ｈ−カルバゾール−６−イル）アクリル酸1.8gを得た。これをアセトン70mlに溶解し、トリエチルアミン２mlを加えた。氷冷攪拌下クロロギ酸エチル0.64ml（6.7 ミリモル）を滴下した。同温度で１時間攪拌後、アジ化ナトリウム（90％）870mg （12ミリモル）を水20mlに溶かした溶液を氷冷攪拌下滴下した。同温度で１時間攪拌後、反応混合物を氷に注ぎ、生じた沈澱を濾取した。この沈澱とトリブチルアミン３mlをジフェニルエーテル20mlに加え、260 ℃に加熱した。放冷後、ヘキサンを加え、生じた沈澱を濾取、ｎ−ヘキサンおよびエタノールで洗浄し、表題化合物 1.39gを得た。
¹H-NMR(DMSO-d₆）δ(ppm);4.01(s,3H),6.73(d,J=7.0Hz,1H),7.18-7.24(m,1H),7.31(t,J=7.9Hz,1H),7.77(d,J=8.5Hz,1H),8.08(dd,J=1.3,7.9Hz,1H),8.22(d,J=8.5Hz,1H),10.13(dd,J=1.3,7.9Hz,1H),11.36-11.42(m,1H),11.93(br-s,1H)
【００８７】
製造例２１
メチル ７Ｈ−ピリド［４，３−ｃ］カルバゾール−８−カルボキシラート
【化３４】

【００８８】
製造例２０の化合物 1.19g（４ミリモル）にオキシ塩化リン10mlを加え加熱還流した。３時間後、反応混合物を氷に注ぎ、重曹を加えて中和した。ジクロロメタンで抽出し、有機層を分取、水洗、硫酸マグネシウムで乾燥、濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、メチル １−クロロ−７Ｈ−ピリド［４，３−ｃ］カルバゾール−８−カルボキシラート 390mgを得た。これをテトラヒドロフランとメタノールの混合液に溶解し、トリエチルアミン１mlを加え、パラジウム炭素存在下常温常圧で水素添加し、表題化合物 300mgを得た。
¹H-NMR(DMSO-d₆）δ(ppm);4.04(s,3H),7.48(t,J=7.7Hz,1H),8.00(d,J=5.4Hz,1H),8.02(d,J=8.8Hz,1H),8.14(d,J=7.7Hz,1H),8.28(d,J=8.8Hz,1H),8.58(d,J=5.4Hz,1H),9.06(d,J=7.7Hz,1H),10.22(s,1H),12.11(br-s,1H)
【００８９】
製造例２２
１０−ニトロ−７Ｈ−ベンゾ［ｃ］フェノチアジン−８−カルボン酸
【化３５】

【００９０】
２−アミノ−１−ナフタレンチオール1.7g（9.73ミリモル）のエタノール30ml溶液に２Ｎ水酸化ナトリウム水溶液５mlを加え、加熱還流した。この混合物に２−クロロ−３，５−ジニトロ安息香酸メチルエステル2.54g （9.76ミリモル）を加え、１時間加熱還流した。この混合物に２Ｎ水酸化ナトリウム水溶液10ml、エタノール40mlを加え、更に10時間加熱還流を続けた。室温にもどし、濃縮後、水を加え攪拌下、１Ｎ塩酸を徐々に加えて、pHを約１にした。沈澱物を濾取し、エタノール、メタノールで順次洗浄して、表題化合物 1.14gを得た。
¹H-NMR(DMSO-d₆) δ(ppm) ；7.04(d,J=8.4Hz,1H),7.40(t,J=8.4Hz,1H),7.55(t,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),7.82(d,J=8.4Hz,1H),7.90(s,1H),8.35(s,1H),11.37(br-s,1H)
【００９１】
製造例２３
Ｎ−［２− (ジメチルアミノ）エチル］−１０−ニトロ−７Ｈ−ベンゾ［ｃ］フェノチアジン−８−カルボキサミド
【化３６】

【００９２】
製造例２２の化合物1.82g （5.39ミリモル）のクロロホルム60ml懸濁液に０℃で三塩化リン10ml、ジメチルホルムアムド２mlを順次加えた後、徐々に室温にもどし、一晩攪拌した。この混合物から減圧下、溶媒を完全に留去した後、得られた残渣にジクロロメタン30mlを加え、０℃で攪拌しながら、Ｎ，Ｎ−ジメチルエチレンジアミン５mlをジクロロメタン30mlに溶解したものを滴下した。反応混合物を徐々に室温にもどし、室温で７時間攪拌した。水、飽和炭酸水素ナトリウム水溶液を加え攪拌した後、セライト濾過により、不溶物を取り除き、有機層を分取した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、濃縮乾固し、エタノールから再結晶することにより、表題化合物 956mgを得た。
¹H-NMR(DMSO-d₆) δ(ppm) ；2.20(s,6H),2.45(t,J=6.0Hz,2H),3.37(t,J=6.0Hz,2H),7.06(d,J=8.4Hz,1H),7.41(t,J=8.4Hz,1H),7.56(t,J=8.4Hz,1H),7.66(t,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.83(d,J=8.4Hz,1H),7.93(br-s,1H),8.39(d,J=2.9Hz,1H),9.50(br-s,1H)
【００９３】
製造例２４
３− (４−メチルベンゼンスルホンアミド）−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボン酸
【化３７】

【００９４】
６− (４−メチルベンゼンスルホンアミド）−２−テトラロンと２−ヒドラジノ安息香酸塩酸塩をキシレン中で加熱還流することにより得られた５，６−ジヒドロ−３−（４−メチルベンゼンスルホンアミド）−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボン酸を製造例２と同様にして反応させ、表題化合物を得た。
¹H-NMR(DMSO-d₆) δ(ppm) ；2.26(s,3H),7.29(d,J=8.0Hz,2H),7.35(dt,J=2.0,7.6Hz,1H),7.46(d,J=8.8Hz,1H),7.66(d,J=6.8Hz,2H),7.71(s,1H),7.79(d,J=9.2Hz,1H),7.96(dd,J=2.0,9.2Hz,1H),8.01(d,J=8.8Hz,1H),8.66(d,J=8.8Hz,1H),8.79(d,J=8.0Hz,1H),10.33(s,1H),11.76(s,1H)
【００９５】
製造例２５
エチル １３Ｈ−ベンズ［６，７］インドロ［２，３−ｃ］キノリン−１２−カルボキシラート
【化３８】

【００９６】
１−ナフチルヒドラジン塩酸塩 4.24g(22.5mmol)の酢酸（35ml) 懸濁液を緩和に沸騰させ、攪拌下に２−ニトロフェニルアセトアルデヒド 3.4g(20.6ミリモル) の酢酸(15ml)溶液を滴下した。滴下後１時間加熱還流し、更に１Ｎ塩酸−酢酸20mlを加え１時間加熱還流した。溶媒を留去し、残渣に酢酸エチルを加えて溶解し、有機層を炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、７-(２- ニトロフェニル）ベンゾ[g] インドールを1.91g(収率32%)得た。 次いで、これを酢酸エチル 60ml に溶解し、酸化白金(IV)200mg を加え、常圧水素雰囲気下、室温で接触還元を行い、７−（２- アミノフェニル）ベンゾ[g] インドールを1.7g（収率99%)得た。
続いて７-(２- アミノフェニル) ベンゾ[g ]インドール 540mg(2.1mmol) 及びグリオキシル酸エチルエステル（ポリマ−型）260mg(2.5mmol)にエタノール20mlを加え８時間加熱還流した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物 380mg (収率53%)を得た。
¹H-NMR(CDCl₃) δ(ppm);1.64(t,J=7.1Hz,3H),4.74(q,J=7.1Hz,2H),7.63-7.77(m,3H),7.79(d,J=8.6Hz,1H),7.79-7.85(m,1H),8.06(dd,J=1.3,7.7Hz,1H),8.35(dd,J=0.7,8.1Hz,1H),8.45(dd,J=1.3,8.4Hz,1H),8.54(d,J=8.6Hz,1H),8.79(dd,J=1.1,8.2Hz,1H),10.98(br-s,1H)
【００９７】
実施例１
５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化３９】

【００９８】
製造例３の化合物 1.44gのジメチルホルムアミド50ml溶液に室温で水素化ナトリウム（油性55％）457mg （10.5ミリモル）を加え、50分間攪拌した。０℃でクロロギ酸エチル１ml（10.5ミリモル）を加え、同温度で２時間、さらに室温で６時間攪拌した。水を加え、沈澱を濾取、水洗、乾燥後、ジクロロメタンとメタノールの混液に溶解し、不溶物を濾去した。濃縮後、エタノール、濃塩酸を順次加えて生成した塩酸塩を濾取、エタノールから再結晶し、表題化合物 1.24gを得た。
融点；254 〜255 ℃（エタノールから再結晶）
ＦＡＢ質量分析ｍ／ｚ：358 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆) δ(ppm) ；2.90(d,J=5.5Hz,6H),3.49(q,J=5.5Hz,2H),4.42(t,J=5.5Hz,2H),7.67(t,J=8.0Hz,1H),7.78(t,J=8.0Hz,1H),7.83(t,J=8.0Hz,1H),8.14(d,J=8.0Hz,1H),8.19(d,J=8.0Hz,1H),8.23(d,J=8.8Hz,1H),8.62(d,J=8.0Hz,1H),8.86(d,J=8.0Hz,1H),9.02(d,J=8.0Hz,1H),9.70(br-s,1H)
元素分析値：C₂₂H₁₉N₃O₂・HCl・H₂Oとして

【００９９】
実施例２
１１−アセチル−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化４０】

【０１００】
製造例５の化合物 105mg（ 0.282ミリモル）のジメチルホルムアミド 2.5ml溶液に０℃で水素化ナトリウム13.2mg（ 0.549ミリモル）を加え、同温度で１時間10分、ついで室温で１時間撹拌した。これに０℃でクロロギ酸エチル53.6μl （ 0.564ミリモル）を加え、同温度で１時間20分撹拌した。水とクロロホルムを加えて抽出後、有機層を分取、硫酸ナトリウムで乾燥、濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製後、１Ｎ塩酸（エタノール）を用いて塩酸塩にし、表題化合物 106mgを得た。
融点；240 ℃付近から着色し始め、250-254 ℃で分解（エタノールから再結晶）ＦＡＢ質量分析ｍ／ｚ：400 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆) δ(ppm) ；2.78(s,3H),2.92(s,6H),3.48-3.54(m,2H),4.44(t,J=5.6Hz,2H),7.80(t,J=7.5Hz,1H),8.16(d,J=7.5Hz,1H),8.24(dd,J=2.3,9.4Hz,1H),8.40(d,J=8.9Hz,1H),8.68(d,J=8.9Hz,1H),8.87-8.91(m,2H),9.01(d,J=7.5Hz,1H),9.88(br-s,1H)
元素分析値：C₂₄H₂₁N₃O₃・HCl・H₂Oとして

【０１０１】
実施例３
５−［２−（ジメチルアミノ）エチル］−１１−（１−ヒドロキシエチル）−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化４１】

【０１０２】
実施例２の化合物を遊離塩基にしたもの84mg（ 0.211ミリモル）の酢酸 1.5ml懸濁液にボラン・ピリジンコンプレックス（約８Ｍ）21μl （ 0.168ミリモル）を加え、70℃で３時間撹拌した。室温で１Ｎ塩酸を加えて酸性にし、１分間撹拌した後、飽和重曹水を加えて中和した。ジクロロメタンとエタノールの混液を加えて抽出、有機層を分取、水洗、硫酸ナトリウムで乾燥、濃縮した。残渣をプレパラティブ薄層クロマトグラフィーで精製後、１Ｎ塩酸を用いて塩酸塩にし、表題化合物44mgを得た。
融点；247 〜248 ℃（分解）（エタノール−エーテルから再結晶）
ＦＡＢ質量分析ｍ／ｚ：402 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆) δ(ppm) ；1.50(d,J=5.0Hz,3H),2.92(s,6H),3.49(t,J=5.7Hz,2H),4.43(t,J=5.7Hz,2H),4.95-5.05(m,1H),5.45(d,J=4.2Hz,1H),7.77(t,J=8.4Hz,1H),7.84(d,J=8.4Hz,1H),8.08-8.15(m,2H),8.21(d,J=8.4Hz,1H),8.59(dd,J=1.4,8.4Hz,1H),8.81(d,J=8.4Hz,1H),8.99(d,J=7.6Hz,1H),9.90(br-s,1H)
元素分析値：C₂₄H₂₄N₃O₃Clとして

【０１０３】
実施例４
１２，１３−ジヒドロ−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６，１０（５Ｈ，１１Ｈ）−トリオン 塩酸塩
【化４２】

【０１０４】
水素化ナトリウム0.9g（37.5ミリモル）のジメチルホルムアミド30ml懸濁液に製造例８の化合物 4.9g （14ミリモル）のジメチルホルムアミド70ml溶液を室温で滴下し、同温度で２時間撹拌した。これに氷冷撹拌下クロロギ酸エチル2.5g（23ミリモル）を加えた。15分後、酢酸エチルを加え、希アンモニア水、食塩水で順次洗浄、硫酸マグネシウムで乾燥した。濃縮後、メタノールを加えて結晶を濾取した。これをメタノールに懸濁し、撹拌下、１Ｎ塩酸を加えて酸性にした。室温で撹拌、濃縮後、エタノールを加えて沈澱を濾取し、表題化合物4.3gを得た。融点；250 ℃付近から着色し始め、260 ℃付近から徐々に分解が起こり、273 −275 ℃付近で速やかに分解。
ＦＡＢ質量分析ｍ／ｚ：376 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆) δ(ppm) ；2.22-2.36(m,2H),2.72-2.80(m,2H),2.92(s,6H),3.44-3.54(m,2H),3.54-3.60(m,2H),4.38-4.46(m,2H),7.75(t,J=7.6Hz,1H),8.17(dd,J=0.8,7.6Hz,1H),8.25(d,J=8.8Hz,1H),8.41(d,J=8.8Hz,1H),8.61(dd,J=0.8,7.6Hz,1H),9.52(br-s,1H)
元素分析値：C₂₂H₂₁N₃O₃・HCl・1H₂O として

【０１０５】
実施例５
５−［２−（ジメチルアミノ）エチル］−１０−ヒドロキシ−１０，１１，１２，１３−テトラヒドロ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン
【化４３】

【０１０６】
実施例４の化合物 0.5g （ 1.2ミリモル）を水50mlとメタノール25mlの混液に溶解し、１Ｎ塩酸 1.2mlを加えた。パラジウム−炭素の存在下、約 4.5kg／cm² の圧で水素添加を行った。反応の終了を薄層クロマトグラフィーで確認後、触媒を濾去し、約2/3 量になるまで濃縮した。水50mlと濃アンモニア水５mlを加え、酢酸エチルで抽出した。有機層を分取、食塩水で洗浄、硫酸マグネシウムで乾燥、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 0.35gを得た。
ＦＡＢ質量分析ｍ／ｚ：378 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(CDCl₃) δ(ppm) ；1.92-2.30(m,4H),2.37(s,6H),2.70(t,J=6.8Hz,2H),3.06-3.32(m,2H),4.32(t,J=6.8Hz,2H),4.95(br-t,J=4.8Hz,1H),7.52(t,J=7.6Hz,1H),7.67(d,J=8.4Hz,1H),8.09(dd,J=0.8,7.6Hz,1H),8.15(dd,J=0.8,7.6Hz,1H),8.33(d,J=8.4Hz,1H)
元素分析値：C₂₂H₂₃N₃O₃・1H₂O として

【０１０７】
実施例６
（＋）- ５−［２−（ジメチルアミノ）エチル］−１０−ヒドロキシ−１０，１１，１２，１３−テトラヒドロ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン
【化４４】

【０１０８】
実施例５の化合物を光学分割カラム〔ダイセル、キラルセルＯＤ，ｎ−ヘキサン−２−プロパノール（７：３〜６：４）で溶出〕で分割し、先に溶出されたフラクションを濃縮乾固し、表題化合物を得た。
融点；160 〜162 ℃
ＦＡＢ質量分析ｍ／ｚ：378 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(CDCl₃) δ(ppm) ；1.90-2.30(m,4H),2.43(s,6H),2.77(t,J=6.4Hz,2H),3.04-3.31(m,2H),4.34(t,J=6.8Hz,2H),4.95(br-t,J=4.8Hz,1H),7.51(t,J=7.6Hz,1H),7.68(d,J=8.4Hz,1H),8.08(d,J=7.6Hz,1H),8.13(d,J=7.6Hz,1H),8.32(d,J=8.4Hz,1H)
元素分析値：C₂₂H₂₃N₃O₃・0.75H₂Oとして

【０１０９】
実施例７
１１，１２−ジヒドロ−５−［２−（ジメチルアミノ）エチル］−４Ｈ，１０Ｈ−シクロペンタ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６，１０（５Ｈ）−トリオン 塩酸塩
【化４５】

【０１１０】
製造例１０の化合物から実施例２と同様の方法で表題化合物を得た。
融点；255 ℃付近より着色し始め、265 ℃付近より徐々に分解。
ＦＡＢ質量分析ｍ／ｚ：362 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆) δ(ppm) ；2.83-2.94(m,8H),3.45(br-s,2H),3.64(br-t,J=6.0Hz,2H),4.42(br-t,J=6.0Hz,2H),7.79(t,J=7.6Hz,1H),7.97(d,J=8.4Hz,1H),8.19(dd,J=0.8,7.6Hz,1H),8.49(d,J=8.4Hz,1H),8.55(dd,J=0.8,7.6Hz,1H),9.44(br-s,1H)
元素分析値：C₂₁H₁₉N₃O₃・HCl・0.75H₂Oとして

【０１１１】
実施例８
８−［２−（ジメチルアミノ）エチル］−７Ｈ−フロ［３，２−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−３，７，９（２Ｈ，８Ｈ）−トリオン 塩酸塩
【化４６】

【０１１２】
製造例１５の化合物 590mg（ 2.2ミリモル）をジメチルホルムアミド20mlに溶解し、Ｎ，Ｎ′−カルボニルジイミダゾール 720mg（ 4.4ミリモル）を加え室温で30分間撹拌した。Ｎ，Ｎ−ジメチルエチレンジアミン0.97ml（ 8.8ミリモル）を加えて一晩撹拌後、濃縮した。残渣に水を加え、酢酸エチルとテトラヒドロフランの混液で抽出した。有機層を分取、飽和重曹水、水で順次洗浄、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、２，３−ジヒドロ−Ｎ−［２−（ジメチルアミノ）エチル］−３−オキソ−６Ｈ−フロ［３，２−ｃ］カルバゾール−７−カルボキサミド 250mgを得た。これをジメチルホルムアミド10mlに溶解し、水素化ナトリウム（油性60％）60mg（ 1.5ミリモル）を加え、窒素雰囲気下30分間撹拌した。氷冷下クロロギ酸エチル 0.145ml（ 1.5ミリモル）を加え、30分間撹拌した後、１Ｎ塩酸を加えて酸性にした。濃縮後、飽和重曹水を加え、酢酸エチルとテトラヒドロフランの混液で抽出した。有機層を分取、水洗、硫酸マグネシウムで乾燥、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製した。これをエタノ−ル20mlに懸濁し、１Ｎ塩酸１mlを加え撹拌後、結晶を濾取し、表題化合物 175mgを得た。
融点；240 ℃付近から着色が始まり、270 〜273 ℃で分解。
ＦＡＢ質量分析ｍ／ｚ：364 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆) δ(ppm) ；2.89(br-s,6H),3.42-3.50(m,2H),4.39-4.45(m,2H),5.14(s,2H),7.78(t,J=7.7Hz,1H),7.95(d,J=8.4Hz,1H),8.17(dd,J=0.8,7.7Hz,1H),8.22(d,J=8.4Hz,1H),8.43(dd,J=0.8,7.7Hz,1H),9.62(br-s,1H)
元素分析値：C₂₀H₁₇N₃O₄・HCl・0.15H₂Oとして

【０１１３】
実施例９
２，３−ジヒドロ−８−［２−（ジメチルアミノ）エチル］−３−ヒドロキシ−７Ｈ−フロ［３，２−c ］ピリミド［５，６，１−ｊｋ］カルバゾール−７，９（８Ｈ）−ジオン
【化４７】

【０１１４】
実施例８の化合物 105.5mg（0.29ミリモル）を酢酸１mlに溶解し室温撹拌下、８Ｍボラン・ピリジンコンプレックス36μl を加え、4.5 時間撹拌した。８Ｍボラン・ピリジンコンプレックス30μl を加え、さらに、一晩撹拌し、濃縮後、水、飽和炭酸水素ナトリウム水溶液、クロロホルムを加え抽出し、有機層を無水硫酸ナトリウムで乾燥し、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製した。得られた生成物をエタノール−ジイソプロピルエーテルから再結晶して、表題化合物22.6mgを得た。
¹H-NMR(DMSO-d₆) δ(ppm) ；2.24(s,6H),2.56(t,J=6.8Hz,2H),4.15(t,J=6.8Hz,2H),4.56(dd,J=2.8,10.0Hz,1H),4.84(dd,J=6.8,10.0Hz,1H),5.43-5.49(m,1H),5.80(d,J=5.6Hz,1H),7.61-7.67(m,2H),7.97(d,J=8.4Hz,1H),8.02(dd,J=0.8,7.6Hz,1H),8.22(dd,J=0.8,7.6Hz,1H)
【０１１５】
実施例１０
１２，１３−ジヒドロ−５−［２−（メチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６，１０（５Ｈ，１１Ｈ）−トリオン 塩酸塩
【化４８】

【０１１６】
製造例１７の化合物 0.23g（0.57ミリモル）とトリス（トリフェニルホスフィン）ロジウムクロリド95mg（ 0.1ミリモル）をアセトニトリルと水の混液（84：16）20mlに溶解した。窒素雰囲気下加熱して溶媒を留去しながら、液量を一定に保つため、アセトニトリルと水の混液（84：16）を滴下した。約３時間この操作を続けた後、薄層クロマトグラフィーで原料の消失を確認した。反応混合物を約1/4 量になるまで濃縮後、酢酸エチルを加えて抽出した。有機層を分取、希アンモニア水、食塩水で順次洗浄、硫酸マグネシウムで乾燥後濃縮した。残渣をプレパラティブ薄層クロマトグラフィーで精製後、実施例４と同様の方法で塩酸塩とし、表題化合物0.1gを得た。
融点；250 ℃付近から着色し始め、260 ℃付近から徐々に分解し始め、267 − 269 ℃で速やかに分解
ＦＡＢ質量分析ｍ／ｚ：362 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆・D₂O 混液）δ(ppm) ；2.24-2.34(m,2H),2.59(s,3H),2.76(br-t,J=6.0Hz,2H),3.31(br-t,J=5.2Hz,2H),3.56(br-t,J=6.0Hz,2H),4.36(br-t,J=5.2Hz,2H),7.75(t,J=8.0Hz,1H),8.16(d,J=8.0Hz,1H),8.24(d,J=8.8Hz,1H),8.39(d,J=8.8Hz,1H),8.59(d,J=8.0Hz,1H)
元素分析値：C₂₁H₁₉N₃O₃・HCl・0.2H₂O として

【０１１７】
実施例１１
１２，１３−ジヒドロ−５−［２−（１−ピロリジニル）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６，１０（５Ｈ，１１Ｈ）−トリオン 塩酸塩
【化４９】

【０１１８】
製造例７の化合物と１−（２−アミノエチル）ピロリジンを製造例８、実施例４と同様にして反応させ、表題化合物を得た。
融点；235 ℃付近より着色し始め、260 ℃付近より徐々に分解。
ＦＡＢ質量分析ｍ／ｚ：402 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；1.86(br-s,2H),2.01(br-s,2H),2.23-2.32(m,2H),2.71-2.79(m,2H),3.15(br-s,2H),3.46-3.74(br-t+m,J=6.0Hz,4H+2H),4.40(br-t,J=5.2Hz,2H),7.73(t,J=8.0Hz,1H),8.15(d,J=8.0Hz,1H),8.23(d,J=8.8Hz,1H),8.39(d,J=8.8Hz,1H),8.57(d,J=8.0Hz,1H),10.10(br-s,1H)
元素分析値：C₂₄H₂₃N₃O₃・HCl・1.5H₂O として

【０１１９】
実施例１２
５−［２−（１−ピロリジニル）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化５０】

【０１２０】
製造例２の化合物と１−（２−アミノエチル）ピロリジンを製造例３、実施例１と同様にして反応させ、表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ：384 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；1.78-1.92(m,2H),1.94-2.06(m,2H),3.08-3.22(m,2H),3.56(t,J=5.6Hz,2H),3.60-3.70(m,2H),4.41(t,J=5.6Hz,2H),7.66(t,J=7.6Hz,1H),7.75(t,J=8.0Hz,1H),7.81(t,J=8.0Hz,1H),8.11(d,J=7.6Hz,1H),8.18(d,J=8.0Hz,1H),8.21(d,J=9.2Hz,1H),8.60(d,J=9.2Hz,1H),8.83(d,J=8.0Hz,1H),8.98(d,J=7.6Hz,1H),10.29(br-s,1H)
元素分析値：C₂₄H₂₁N₃O₃・HCl・H₂Oとして

【０１２１】
実施例１３
２−［２−（ジメチルアミノ）エチル］−５−ニトロ−１Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｋｌ］フェノチアジン−１，３（２Ｈ）−ジオン 塩酸塩
【化５１】

【０１２２】
製造例２３の化合物 200mg（0.49ミリモル）のテトラヒドロフラン15ml溶液に室温撹拌下、トリエチルアミン 0.5ml、クロロギ酸エチル 200μl （2.09ミリモル）を順次加えた。室温で一晩撹拌した後、濃縮し、水、飽和炭酸水素ナトリウム水溶液、ジクロロメタンを加え抽出した。有機層を水、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、濃縮乾固した。残渣をエタノールから再結晶することにより表題化合物の遊離塩基 104mgを得た。これをメタノールに懸濁し、撹拌下、濃塩酸を加えた後、濃縮乾固させることにより表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.90(s,6H),3.49(br-s,2H),4.38(t,J=5.6Hz,2H),7.66(t,J=7.6Hz,1H),7.73(t,J=7.6Hz,1H),7.82(d,J=9.2Hz,1H),7.96(d,J=8.8Hz,1H),8.03(d,J=8.0Hz,1H),8.09(d,J=8.4Hz,1H),8.49-8.52(m,1H),8.59-8.62(m,1H),9.72(br-s,1H)
【０１２３】
実施例１４
２−［２−（ジメチルアミノ）エチル］−１Ｈ−ピリミド［５，６，１−ｊｋ］チエノ［３，２−ａ］カルバゾール−１，３（２Ｈ）−ジオン 塩酸塩
【化５２】

【０１２４】
４−オキソ−４，５，６，７−テトラヒドロ−ベンゾ［ｂ］チオフェンと２−ヒドラジノ安息香酸塩酸塩から製造例１、２、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.92(br-s,6H),3.44-3.57(m,2H),4.44-4.51(m,2H),7.74(t,J=7.6Hz,1H),7.98(d,J=5.6Hz,1H),8.13(dd,J=0.8,7.6Hz,1H),8.26(d,J=8.4Hz,1H),8.36(d,J=8.4Hz,1H),8.65(dd,J=0.8,7.6Hz,1H),8.84(d,J=5.6Hz,1H),9.53(br-s,1H)
【０１２５】
実施例１５
２，３−ジヒドロ−９−［２−（ジメチルアミノ）エチル］−４Ｈ，８Ｈ−ピラノ［３，２−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，８，１０（９Ｈ）−トリオン 塩酸塩
【化５３】

【０１２６】
実施例２と同様にして表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ：378 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；2.88(s,6H),2.99(t,J=6.4Hz,2H),3.46(br-s,2H),4.40(br-t,J=5.6Hz,2H),4.89(t,J=6.4Hz,2H),7.73(t,J=7.6Hz,1H),8.06(d,J=8.4Hz,1H),8.09(d,J=8.4Hz,1H),8.12(d,J=7.6Hz,1H)),8.42(d,J=7.6Hz,1H),9.68(br-s,1H)
元素分析値：C₂₁H₁₉N₃O₄・HCl・1.25H₂O

【０１２７】
実施例１６
９−［２−（ジメチルアミノ）エチル］−４Ｈ，８Ｈ−ピラノ［３，２−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，８，１０（９Ｈ）−トリオン塩酸塩
【化５４】

【０１２８】
実施例２と同様の方法で表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ：376 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(s,6H),3.46(br-s,2H),4.43(br-t,J=5.6Hz,2H),6.55(d,J=6.0Hz,1H),7.83(t,J=7.6Hz,1H),8.23(dd,J=0.8,7.6Hz,1H),8.34(d,J=8.8Hz,1H),8.48(d,J=8.8Hz,1H),8.54(d,J=6.0Hz,1H)),8.65(dd,J=0.8,7.6Hz,1H),9.52(br-s,1H)
【０１２９】
実施例１７
２−［２−（ジメチルアミノ）エチル］−１Ｈ−フロ［３，２−ａ］ピリミド［５，６，１−ｊｋ］カルバゾール−１，３（２Ｈ）−ジオン 塩酸塩
【化５５】

【０１３０】
４−オキソ−４，５，６，７−テトラヒドロ−ベンゾ［ｂ］フランと２−ヒドラジノ安息香酸塩酸塩から製造例１，２，３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.91(br-s,6H),3.40-3.55(m,2H),4.41-4.51(m,2H),7.72(t,J=7.6Hz,1H),7.83(d,J=2.0Hz,1H),7.88(d,J=8.4Hz,1H),8.09(d,J=7.6Hz,1H),8.20(d,J=2.0Hz,1H),8.32(d,J=8.4Hz,1H)),8.61(d,J=7.6Hz,1H),9.46(br-s,1H)
【０１３１】
実施例１８
２−［２−（ジメチルアミノ）エチル］−１Ｈ−ベンゾ［ａ］ピリミド［５，６，１−ｊｋ］カルバゾール−１，３（２Ｈ）−ジオン 塩酸塩
【化５６】

【０１３２】
α−テトラロンと２−ヒドラジノ安息香酸塩酸塩から製造例１，２，３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(s,6H),3.49(br-s,2H),4.49(t,J=5.5Hz,2H),7.64-7.71(m,2H),7.74(t,J=8.0Hz,1H),8.11-8.18(m,3H),8.44(d,J=8.3Hz,1H),8.66(d,J=8.0Hz,1H),9.59(br-s,1H),9.76(d,J=8.3Hz,1H)
元素分析値：C₂₂H₁₉N₃O₂・HCl・0.2H₂O として

【０１３３】
実施例１９
５−［３−（ジメチルアミノ）プロピル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化５７】

【０１３４】
製造例２の化合物とＮ，Ｎ−ジメチル−１，３−プロパンジアミンを製造例３、実施例１と同様にして反応させ、表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ：372 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；2.03-2.13(m,2H),2.74(s,6H),3.19(t,J=8.0Hz,2H),4.12(t,J=6.0Hz,2H),7.65(t,J=7.2Hz,1H),7.75(t,J=8.0Hz,1H),7.81(t,J=7.6Hz,1H),8.10(d,J=7.6Hz,1H),8.16(d,J=8.0Hz,1H),8.19(d,J=9.6Hz,1H),8.58(d,J=9.6Hz,1H),8.80(t,J=8.4Hz,1H),8.94(d,J=8.0Hz,1H),9.69(br-s,1H)
元素分析値：C₂₃H₂₁N₃O₂・HCl・0.3H₂O として

【０１３５】
実施例２０
２−［２−（ジメチルアミノ）エチル］−１Ｈ、１１Ｈ−インデノ［１′，２′：４，５］ピロロ［３，２，１−ｉｊ］キナゾリン−１，３（２Ｈ）−ジオン塩酸塩
【化５８】

【０１３６】
２−インダノンと２−ヒドラジノ安息香酸塩酸塩から製造例１、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(CD₃OD）δ(ppm) ；3.02(s,6H),3.53(t,J=5.8Hz,2H),4.10(s,2H),4.50(t,J=5.8Hz,2H),7.28(dt,J=1.2,7.6Hz,1H),7.41(dt,J=1.0,7.6Hz,1H),7.56-7.59(m,1H),7.62(t,J=7.7Hz,1H),7.76-7.79(m,1H),8.02(dd,J=0.8,7.7Hz,1H),8.25(dd,J=0.8,7.7Hz,1H)
【０１３７】
実施例２１
７−［２−（ジメチルアミノ）エチル］−６Ｈ，１４Ｈ−ベンゾ［ａ］ピリミド［５，６，１−ｄｅ］アクリジン−６，８，１４（７Ｈ）−トリオン 塩酸塩
【化５９】

【０１３８】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.91(br-s,6H),3.50-3.56(m,2H),4.49(t,J=5.7Hz,2H),7.64-7.69(m,1H),7.77-7.82(m,1H),7.87-7.92(m,1H),7.98-8.03(m,1H),8.37-8.40(m,1H),8.43-8.46(m,1H),8.63(dd,J=0.5,8.8Hz,1H),9.26(s,1H),9.81(dd,J=0.7,8.6Hz,1H),10.04(br-s,1H)
【０１３９】
実施例２２
５−［２−（ジメチルアミノ）エチル］−１１−メトキシ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化６０】

【０１４０】
６−メトキシ−β−テトラロンと２−ヒドラジノ安息香酸塩酸塩から製造例２４、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.93(d,J=4.6Hz,6H),3.47-3.54(m,2H),3.94(s,3H),4.39-4.45(m,2H),7.46(dd,J=2.2,9.0Hz,1H),7.62(d,J=2.2Hz,1H),7.78(t,J=8.4Hz,1H),8.14(d,J=8.4Hz,1H),8.16(d,J=9.0Hz,1H),8.59(d,J=9.0Hz,1H),8.78(d,J=9.0Hz,1H),9.01(d,J=8.4Hz,1H),9.16(br-s,1H)
元素分析値：C₂₃H₂₁N₃O₃・HCl・1.5H₂O として

【０１４１】
実施例２３
５−［２−（ジメチルアミノ）エチル］−１０−メトキシ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化６１】

【０１４２】
５−メトキシ−β−テトラロンと２−ヒドラジノ安息香酸塩酸塩から製造例１、２、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(s,6H),3.44-3.51(m,2H),4.04(s,3H),4.40(t,J=6.2Hz,2H),7.12(d,J=8.2Hz,1H),7.72(t,J=8.5Hz,1H),7.73(dt,J=3.4,8.2Hz,1H),8.09(d,J=8.5Hz,1H),8.32(d,J=8.5Hz,1H),8.41(d,J=8.5Hz,1H),8.52(dd,J=1.0,8.5Hz,1H),8.88(d,J=8.5Hz,1H),9.93(br-s,1H)
元素分析値：C₂₃H₂₁N₃O₃・HCl・1.3H₂O として

【０１４３】
実施例２４
２−［２−（ジメチルアミノ）エチル］−１Ｈ−ベンゾ［ｂ］ピリミド［１，６，５−ｌｍ］−４−アザカルバゾール−１，３（２Ｈ）−ジオン 二塩酸塩
【化６２】

【０１４４】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.90(s,6H),3.47-3.55(m,2H),4.48(t,J=6.3Hz,2H),7.67(t,J=7.8Hz,1H),7.86-7.95(m,3H),8.36-8.44(m,3H),9.24-9.29(m,1H),10.41(br-s,1H)
【０１４５】
実施例２５
１，２−ジヒドロ−９−［２−（ジメチルアミノ）エチル］−４Ｈ，８Ｈ−ピラノ［３，４−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，８，１０（９Ｈ）−トリオン 塩酸塩
【化６３】

【０１４６】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(s,6H),3.47(t,J=6.0Hz,2H),3.64(t,J=6.0Hz,2H),4.38(t,J=6.0Hz,2H),4.68(t,J=6.0Hz,2H),7.73(t,J=7.6Hz,1H),8.15(t,J=7.6Hz,1H),8.27(d,J=8.8Hz,1H),8.44(d,J=8.8Hz,1H),8.55(d,J=7.6Hz,1H),9.82(br-s,1H)
【０１４７】
実施例２６
５−［２−（ジメチルアミノ）エチル］−１２−メトキシ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化６４】

【０１４８】
７−メトキシ−β−テトラロンと２−ヒドラジノ安息香酸塩酸塩から製造例１、２、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.85(br-s,6H),3.35-3.46(m,2H),4.08(s,3H),4.39(br-s,2H),7.32(dd,J=2.2,8.8Hz,1H),7.79(t,J=7.8Hz,1H),7.99(d,J=1.7Hz,1H),8.09-8.19(m,3H),8.48(d,J=8.8Hz,1H),8.97(d,J=7.8Hz,1H),9.25(br-s,1H)
【０１４９】
実施例２７
２−［２−（ジメチルアミノ）エチル］−５−ニトロ−１Ｈ−ベンゾ［ｂ］ピリミド［５，６，１−ｋｌ］フェノキサジン−１，３（２Ｈ）−ジオン 塩酸塩
【化６５】

【０１５０】
３−アミノ−２−ナフトール 304mg（1.91ミリモル）、２−クロロ−３，５−ジニトロ安息香酸メチルエステル 477mg（1.81ミリモル）、酢酸ナトリウム 178mg（2.17ミリモル）を水５ml−エタノール10ml混液に懸濁し、７時間加熱還流した。２Ｎ水酸化ナトリウム水溶液３mlを加え、更に 2.5時間加熱還流し、室温にもどした後、１Ｎ塩酸10mlを加えると沈澱物が生じた。沈澱物を濾取し、水、１Ｎ塩酸、エタノールで順次洗浄することにより、３−ニトロ−１２Ｈ−ベンゾ［ｂ］フェノキサジン−１−カルボン酸 430mgを得た。これを製造例２３、実施例１３と同様にして、表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(s,6H),3.45(t,J=5.2Hz,2H),4.40(t,J=5.2Hz,2H),7.47(t,J=8.0Hz,1H),7.52(t,J=8.0Hz,1H),7.69(s,1H),7.86(d,J=6.8Hz,1H),7.88(d,J=8.0Hz,1H),8.19(d,J=2.4Hz,1H),8.34(d,J=2.4Hz,1H),9.05(s,1H),9.82(br-s,1H)
【０１５１】
実施例２８
２−クロロ−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化６６】

【０１５２】
β−テトラロンと５−クロロ−２−ヒドラジノ安息香酸塩酸塩から製造例１、２、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(br-s,6H),3.39-3.53(m,2H),4.38-4.48(m,2H),7.68-7.75(m,1H),7.81-7.89(m,1H),8.13(d,J=1.6Hz,1H),8.22(d,J=8.4Hz,1H),8.31(d,J=8.8Hz,1H),8.63(d,J=8.8Hz,1H),8.94(d,J=8.4Hz,1H),9.14(d,J=1.6Hz,1H),9.46(br-s,1H)
元素分析値：C₂₂H₁₈N₃O₂Cl・HCl・1.75H₂Oとして

【０１５３】
実施例２９
９−［２−（ジメチルアミノ）エチル］−８Ｈ−ピリド［４，３−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−１，８，１０（２Ｈ，９Ｈ）−トリオン塩酸塩
【化６７】

【０１５４】
製造例２０の化合物のエステルをケン化後、製造例３、実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.90(br-s,6H),3.43-3.53(m,2H),4.40-4.46(m,2H),6.80-6.83(m,1H),7.34-7.38(m,1H),7.73(t,J=7.9Hz,1H),8.01(d,J=8.9Hz,1H),8.18(dd,J=0.9,7.9Hz,1H),8.89(d,J=8.9Hz,1H),9.52(br-s,1H),9.91(dd,J=0.9,7.9Hz,1H),11.67-11.71(m,1H)
元素分析値：C₂₁H₁₈N₄O₃・HCl・1.3H₂O として

実施例３０
５−［２−（ジメチルアミノ）エチル］−４Ｈ−キノ［４′，３′−４，５］ピロロ［３，２，１−ｉｊ］キナゾリン−４，６（５Ｈ）−ジオン 二塩酸塩
【化６８】

【０１５５】
製造例２と同様にして表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ；359 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆+D₂O）δ(ppm) ；2.94(s,6H),3.54(br-t,J=5.6Hz,2H),4.47(br-t,J=5.6Hz,2H),7.89(t,J=7.6Hz,1H),7.91-7.99(m,2H),8.30-8.37(m,2H),8.89-8.95(m,1H),9.16(d,J=7.6Hz,1H),9.97(s,1H)
元素分析値：C₂₁H₁₈N₄O₂・2HCl・0.5H₂Oとして

【０１５６】
実施例３１
５−アミノ−２−［２−（ジメチルアミノ）エチル］−１Ｈ−ベンゾ［ｂ］ピリミド［５，６，１−ｋｌ］フェノキサジン−１，３（２Ｈ）−ジオン 二塩酸塩
【化６９】

【０１５７】
実施例２７の化合物の遊離塩基 268mg（ 0.641ミリモル）を酢酸10mlに溶解し、10％パラジウム炭素を加え、室温、水素雰囲気下で、接触還元を行った。セライトにて、パラジウム炭素を濾去後、濾液を濃縮し、水、飽和炭酸水素ナトリウム水溶液を加え、室温にて撹拌した。沈澱物を濾過し、水で洗浄後、メタノールに懸濁して、濃塩酸を加えた。室温で撹拌すると、均一溶液になった後、沈澱物が生成し、これを濾取して表題化合物 179mgを得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(s,6H),3.43(t,J=5.6Hz,2H),4.34(t,J=5.6Hz,2H),6.76(s,1H),6.96(s,1H),7.38-7.48(m,2H),7.59(s,1H),7.79(d,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),9.15(s,1H),9.65(br-s,1H)
【０１５８】
実施例３２
５−［２−（ジメチルアミノ）エチル］−１３−メトキシ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化７０】

【０１５９】
８−メトキシ−β−テトラロンと２−ヒドラジノ安息香酸塩酸塩から製造例１、２、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.91(br-s,6H),3.40-3.53(m,2H),4.23(s,3H),4.40-4.49(m,2H),7.33(d,J=7.6Hz,1H),7.61(t,J=8.0Hz,1H),7.72-7.79(m,2H),8.15(d,J=8.0Hz,1H),8.23(d,J=8.8Hz,1H),8.82(d,J=8.8Hz,1H),9.09(d,J=8.0Hz,1H),9.35(br-s,1H)
元素分析値：C₂₃H₂₁N₃O₃・HCl・0.65H₂Oとして

【０１６０】
実施例３３
９−［２−（ジメチルアミノ）エチル］−８Ｈ−ピリド［４，３−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−８，１０（９Ｈ）−ジオン 二塩酸塩
【化７１】

【０１６１】
製造例２１の化合物 300mg（ 1.1ミリモル）をテトラヒドロフラン10mlとメタノール10mlの混液に溶解し、１Ｎ水酸化ナトリウム５mlを加え、１時間加熱還流後、常法に従い単離した７Ｈ−ピリド［４，３−ｃ］カルバゾール−８−カルボン酸をジメチルホルムアミド40mlに溶解し、Ｎ，Ｎ′−カルボニルジイミダゾール 360mg（ 2.2ミリモル）を加えた。室温で30分間撹拌後、Ｎ，Ｎ−ジメチルエチレンジアミン0.48ml（ 4.4ミリモル）を加え、一晩撹拌した。濃縮後、水と酢酸エチルを加えて抽出し、有機層を分取、飽和重曹水、水で順次洗浄、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、Ｎ−［２−（ジメチルアミノ）エチル］−７Ｈ−ピリド［４，３−ｃ］カルバゾール−８−カルボキサミド 250mgを得た。これを実施例２と同様の方法で反応させ、処理し、表題化合物 110mgを得た。
融点；270 ℃付近から着色し始め、279 ℃で分解。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89-2.93(m,6H),3.49-3.54(m,2H),4.46(t,J=6.0Hz,2H),7.85(t,J=7.6Hz,1H),8.25(d,J=7.6Hz,1H),8.40-8.44(m,2H),8.79(d,J=6.4Hz,1H),9.04(d,J=9.2Hz,1H),9.23(d,J=7.6Hz,1H),10.10(br-s,1H),10.44(s,1H)
元素分析値：C₂₁H₁₈N₄O₂・2HCl・2H₂Oとして

【０１６２】
実施例３４
５−［４−（ジメチルアミノ）ブチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化７２】

【０１６３】
製造例２の化合物とＮ，Ｎ−ジメチル−１，４−ブタンジアミンを製造例３、実施例１と同様にして反応させ、表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ；386 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；1.68-1.85(m,4H),2.74(s,6H),3.09(br-t,J=6.4Hz,2H),4.10(br-t,J=6.4Hz,2H),7.64-7.70(m,1H),7.75(t,J=7.6Hz,1H),7.79-7.85(m,1H),8.11(d,J=7.6Hz,1H),8.16-8.24(m,2H),8.62(d,J=8.8Hz,1H),8.83(d,J=8.4Hz,1H),8.97(d,J=7.6Hz,1H),9.99(br-s,1H)
元素分析値：C₂₄H₂₃N₃O₂・HCl・0.5H₂O として

【０１６４】
実施例３５
１１−シアノ−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化７３】

【０１６５】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.93(s,6H),3.48-3.55(m,2H),4.46(t,J=5.6Hz,2H),7.83(t,J=8.2Hz,1H),8.10(dd,J=1.3,8.9Hz,1H),8.21(d,J=8.2Hz,1H),8.38(d,J=8.9Hz,1H),8.79(d,J=8.9Hz,1H),8.88(d,J=1.3Hz,1H),9.04(d,J=8.9Hz,1H),9.10(d,J=8.2Hz,1H)
【０１６６】
実施例３６
９−［２−（ジメチルアミノ）エチル］−８Ｈ−ピリド［２，３−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−８，１０（９Ｈ）−ジオン 二塩酸塩
【化７４】

【０１６７】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.92(s,3H),2.93(s,3H),3.46-3.58(m,2H),4.41-4.51(m,2H),7.82(t,J=8.0Hz,1H),7.92(dd,J=4.8,8.4Hz,1H),8.21(d,J=8.0Hz,1H),8.40(d,J=9.2Hz,1H),8.92(d,J=9.2Hz,1H),9.10(d,J=8.0Hz,1H),9.14(dd,J=0.8,4.8Hz,1H),9.47(dd,J=0.8,8.4Hz,1H),9.86(br-s,1H)
元素分析値：C₂₁H₁₈N₄O₂・2HCl・0.75H₂O として

【０１６８】
実施例３７
５−［２−（ジメチルアミノ）エチル］−２−ニトロ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化７５】

【０１６９】
β−テトラロンと５−ニトロ−２−ヒドラジノ安息香酸から製造例１、２、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(s,6H),3.44-3.52(m,2H),4.45(t,J=5.2Hz,2H),7.73(t,J=8.1Hz,1H),7.90(t,J=8.1Hz,1H),8.23(d,J=8.1Hz,1H),8.35(d,J=9.2Hz,1H),8.63(d,J=9.2Hz,1H),8.80(d,J=1.8Hz,1H),8.94(d,J=8.1Hz,1H),9.64(d,J=1.8Hz,1H),9.75(br-s,1H)
【０１７０】
実施例３８
５−［２−（ジメチルアミノ）エチル］−２−メチル−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化７６】

【０１７１】
β−テトラロンと２−ヒドラジノ−５−メチル−安息香酸塩酸塩から製造例１、２、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.71(s,3H),2.90(br-s,6H),3.38-3.55(m,2H),4.39-4.46(m,2H),7.66-7.72(m,1H),7.81-7.88(m,1H),7.97-8.00(m,1H),8.18-8.23(m,1H),8.22-8.27(m,1H),8.63(d,J=9.2Hz,1H),8.88-8.95(m,2H)
元素分析値：C₂₃H₂₁N₃O₂・HCl・1.5H₂O として

【０１７２】
実施例３９
１，２−ジヒドロ−９−［２−（ジメチルアミノ）エチル］−８Ｈ−ピリド［３，４−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，８，１０（３Ｈ，９Ｈ）−トリオン 塩酸塩
【化７７】

【０１７３】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.88(br-s,6H),3.37-3.52(m,2H),3.50-3.64(m,4H),4.36-4.44(m,2H),7.73(t,J=7.6Hz,1H),8.11(br-s,1H),8.15(dd,J=0.8,7.6Hz,1H),8.22(d,J=8.4Hz,1H),8.40(d,J=8.4Hz,1H),8.57(dd,J=0.8,7.6Hz,1H)
元素分析値：C₂₁H₂₀N₄O₃・HCl・H₂Oとして

【０１７４】
実施例４０
８−［２−（ジメチルアミノ）エチル］−７Ｈ−１，３−ジオキソロ［４，５−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−７，９（８Ｈ）−ジオン 塩酸塩
【化７８】

【０１７５】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.90(br-s,6H),3.42-3.49(m,2H),4.36-4.42(m,2H),6.35(s,2H),7.29(d,J=8.4Hz,1H),7.68(t,J=7.7Hz,1H),7.89(d,J=8.4Hz,1H),8.10(dd,J=0.8,7.7Hz,1H),8.27(dd,J=0.8,7.7Hz,1H),9.35(br-s,1H)
【０１７６】
実施例４１
１１−ブロモ−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化７９】

【０１７７】
６−ブロモ−β−テトラロンと２−ヒドラジノ安息香酸塩酸塩から製造例１、２、３および実施例２と同様にして表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ；436 （［Ｍ＋Ｈ］⁺ ），438 （［Ｍ＋２＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；2.90(s,6H),3.48(br-s,2H),4.42(t,J=5.6Hz,2H),7.77(t,J=7.6Hz,1H),7.89(dd,J=2.0,8.8Hz,1H),8.14(d,J=7.2Hz,1H),8.20(d,J=8.8Hz,1H),8.47(d,J=2.0Hz,1H),8.63(d,J=8.8Hz,1H),8.79(d,J=9.2Hz,1H),8.97(d,J=8.0Hz,1H),9.74(br-s,1H)
元素分析値：C₂₂H₁₈N₃O₂Br・HCl・0.6H₂O として

【０１７８】
実施例４２
２−［２−（ジメチルアミノ）エチル］−１Ｈ−ベンゾ［ｂ］ピリミド［５，６，１−ｊｋ］カルバゾール−１，３（２Ｈ）−ジオン 塩酸塩
【化８０】

【０１７９】
実施例２と同様にして表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ；358 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；2.90(br-s,6H),3.39-3.53(m,2H),4.37-4.48(m,2H),7.60-7.70(m,2H),7.73(t,J=7.6Hz,1H),8.13(dd,J=0.8,7.6Hz,1H),8.16-8.20(m,1H),8.21-8.26(m,1H),8.66(dd,J=0.8,7.6Hz,1H),8.86(s,1H),8.93(s,1H)
元素分析値：C₂₂H₁₉N₃O₂・HClとして

【０１８０】
実施例４３
５−［２−（ジメチルアミノ）エチル］−１０，１１，１２，１３−テトラヒドロ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化８１】

【０１８１】
実施例４の化合物から実施例５と同様の方法で表題化合物を得た。
ＦＡＢ質量分析ｍ／ｚ；362 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；1,79-2.01(m,4H),2.89(s,6H),2.90(br-t,J=6.0Hz,2H),3.24(br-t,J=6.0Hz,2H),3.46(br-t,J=5.6Hz,2H),4.39(br-t,J=6.0Hz,2H),7.38(d,J=8.8Hz,1H),7.65(t,J=8.0Hz,1H),8.06(d,J=8.0Hz,1H),8.13(d,J=8.8Hz,1H),8.41(dd,J=0.8,8.0Hz,1H),9.74(br-s,1H)
元素分析値：C₂₂H₂₃N₃O₂・HCl・0.75H₂Oとして

【０１８２】
実施例４４
１２，１３−ジヒドロ−１１，１１−ジメチル−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６，１０（５Ｈ，１１Ｈ）−トリオン 塩酸塩
【化８２】

【０１８３】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；1.20(s,6H),2.13(t,J=6.1Hz,2H),2.88(s,6H),3.43(br-s,2H),3.52(t,J=6.1Hz,2H),4.38(t,J=5.7Hz,2H),7.71(t,J=7.4Hz,1H),8.11(d,J=7.4Hz,1H),8.20(d,J=8.8Hz,1H),8.35(d,J=8.8Hz,1H),8.54(d,J=7.4Hz,1H),10.08(br-s,1H)
元素分析値：C₂₄H₂₅N₃O₃・HCl・H₂Oとして

【０１８４】
実施例４５
５−［２−（ジメチルアミノ）エチル］−２−メトキシ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化８３】

【０１８５】
β−テトラロンと２−ヒドラジノ−５−メトキシ安息香酸塩酸塩から製造例１、２、３および実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(br-s,6H),3.40-3.52(m,2H),4.03(s,3H),4.40(t,J=6.0Hz,2H),7.60(d,J=2.4Hz,1H),7.63-7.70(m,1H),7.76-7.85(m,1H),8.17(dd,J=0.4,8.4Hz,1H),8.21(d,J=8.8Hz,1H),8.49(d,J=2.4Hz,1H),8.57(d,J=8.8Hz,1H),8.84(dd,J=0.4,8.4Hz,1H),9.57(br-s,1H)
元素分析値：C₂₃H₂₁N₃O₃・HCl・H₂Oとして

【０１８６】
実施例４６
５−［２−（ジメチルアミノ）エチル］−１１−ヒドロキシ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化８４】

【０１８７】
実施例２２の化合物を47％臭化水素酸中で加熱還流後、反応混合物をメタノール中、パラジウム炭素を触媒として、室温で接触還元を行った。生成物を常法により塩酸塩にすることにより表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.92(d,J=5.5Hz,6H),3.48(q,J=5.5Hz,2H),4.41(t,J=5.5Hz,2H),7.36-7.42(m,2H),7.73(t,J=8.1Hz,1H),8.00(d,J=9.4Hz,1H),8.11(d,J=8.1Hz,1H),8.49(d,J=8.1Hz,1H),8.71(d,J=9.4Hz,1H),8.94(d,J=8.1Hz,1H),9.60(br-s,1H),10.01(br-s,1H)
【０１８８】
実施例４７
２−アミノ−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 二塩酸塩
【化８５】

【０１８９】
実施例３７の化合物をパラジウム炭素触媒存在下常温常圧で水素添加し、表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(d,J=4.1Hz,6H),3.44-3.51(m,2H),4.40(t,J=5.8Hz,2H),7.67(t,J=8.2Hz,1H),7.77(s,1H),7.84(t,J=8.2Hz,1H),8.19(d,J=8.2Hz,1H),8.22(d,J=9.3Hz,1H),8.57(d,J=9.3Hz,1H),8.61(d,J=8.2Hz,1H),8.63(s,1H),9.94(br-s,1H)
【０１９０】
実施例４８
５−［２−（ジメチルアミノ）エチル］−１１−（４−メチルベンゼンスルホンアミド）−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化８６】

【０１９１】
製造例２４の化合物を製造例３と同様にして得られたＮ−［２−（ジメチルアミノ）エチル］−３−（４−メチルベンゼンスルホンアミド）−７Ｈ−ベンゾ［ｃ］カルバゾール−８−カルボキサミドをジメチルホルムアミド中、氷冷下で、水素化ナトリウム、クロロギ酸エチルと反応させることにより、５−［２−（ジメチルアミノ）エチル］−１１−（Ｎ−エトキシカルボニル−４−メチルベンゼンスルホンアミド）−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオンを得た。これをメタノール−テトラヒドロフラン（１：１）混液中、１Ｎ水酸化ナトリウム水溶液で処理した後、常法により塩酸塩とし、エタノールより再結晶することで、表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.28(s,3H),2.90(s,6H),3.48(br-s,2H),4.41(t,J=5.6Hz,2H),7.33(d,J=9.2Hz,2H),7.60(d,J=8.8Hz,1H),7.70-7.78(m,3H),7.82(s,1H),8.09(d,J=9.2Hz,1H),8.12(d,J=8.0Hz,1H),8.54(d,J=8.4Hz,1H),8.76(d,J=8.4Hz,1H),8.94(d,J=8.4Hz,1H),9.56(br-s,1H),10.68(s,1H)
【０１９２】
実施例４９
１１−アミノ−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 二塩酸塩
【化８７】

【０１９３】
実施例４８の化合物の遊離塩基 341mg（ 0.648ミリモル）とフェノール 419mg（4.45ミリモル）を47％臭化水素酸15ml中で、９時間30分加熱還流した後、室温にもどし、飽和炭酸水素ナトリウム水溶液を加え、塩基性にした。これに酢酸エチル、テトラヒドロフランを加え抽出し、有機層を水、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。有機層を濃縮し、得られた残渣をエタノールから再結晶することにより表題化合物の遊離塩基 141mgを得た。これを常法により塩酸塩にして、表題化合物を得た。
（遊離塩基）¹H-NMR(DMSO-d₆）δ(ppm) ；2.22(s,6H),2.55(t,J=6.8Hz,2H),4.14(t,J=6.8Hz,2H),5.50-5.53(m,2H),7.06(d,J=2.0Hz,1H),7.22(dd,J=2.4,9.2Hz,1H),7.67(t,J=8.0Hz,1H),7.79(d,J=9.2Hz,1H),8.03(d,J=8.0Hz,1H),8.38(d,J=8.8Hz,1H),8.52(d,J=9.2Hz,1H),8.84(d,J=7.6Hz,1H)
【０１９４】
実施例５０
１１−アセトアミド−５−［２−（ジメチルアミノ）エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化８８】

【０１９５】
実施例４９の化合物の遊離塩基 141mg（ 0.379ミリモル）のジクロロメタン20ml懸濁液に室温撹拌下、トリエチルアミン４ml、無水酢酸２mlを順次加え、16時間撹拌を続けた。濃縮後、残渣にメタノール30mlを加え、撹拌下、飽和炭酸水素ナトリウム水溶液を加えて塩基性にした後、沈澱物を濾取し、水洗した。得られた固形物をエタノールに懸濁し、室温撹拌下、濃塩酸を加え、さらにメタノール、ジクロロメタンを加え、撹拌を続けた。濃縮後エタノールを加え、加熱還流後、室温にもどし沈澱物を濾取し、表題化合物 148mgを得た。
ＦＡＢ質量分析ｍ／ｚ；415 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(DMSO-d₆）δ(ppm) ；2.13(s,3H),2.90(s,3H),2.91(s,3H),3.44-3.52(m,2H),4.42(t,J=5.6Hz,2H),7.76(t,J=8.0Hz,1H),7.89(dd,J=1.6,9.2Hz,1H),8.06-8.14(m,2H),8.52(d,J=1.6Hz,1H),8.54(d,J=9.2Hz,1H),8.79(d,J=8.8Hz,1H),8.98(d,J=8.0Hz,1H),9.60(br-s,1H),10.35(s,1H)
元素分析値：C₂₄H₂₂N₄O₃・HCl・0.6H₂O として

【０１９６】
実施例５１
５−［２−［Ｎ−［２−（ジメチルアミノ）エチル］−Ｎ−メチルアミノ］エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 二塩酸塩
【化８９】

【０１９７】
実施例２と同様にして表題化合物を得た。
（遊離塩基）¹H-NMR(CDCl₃）δ(ppm) ；2.20(s,6H),2.42(t,J=7.2Hz,2H),2.45(s,3H),2.63(t,J=7.2Hz,2H),2.81(t,J=7.2Hz,2H),4.35(t,J=7.2Hz,2H),7.59(t,J=7.8Hz,1H),7.64(t,J=7.8Hz,1H),7.74(t,J=7.8Hz,1H),8.01(d,J=9.2Hz,1H),8.03(d,J=7.8Hz,1H),8.14(d,J=7.8Hz,1H),8.56-8.61(m,2H),8.66(d,J=9.2Hz,1H)
元素分析値：C₂₅H₂₆N₄O₂・2HCl・0.8H₂Oとして

【０１９８】
実施例５２
５−［２−［Ｎ−（２−ヒドロキシエチル）−Ｎ−メチルアミノ］エチル］−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化９０】

【０１９９】
実施例２と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.93(s,3H),3.14-3.67(m,4H),3.71-3.80(m,2H),4.40-4.49(m,2H),5.33-5.39(m,1H),7.64-7.70(m,1H),7.73-7.86(m,2H),8.10-8.26(m,3H),8.59-8.65(m,1H),8.83-8.89(m,1H),9.00-9.04(m,1H),9.60(br-s,1H)
元素分析値：C₂₃H₂₁N₃O₃・HCl・1.1H₂O として

【０２００】
実施例５３
５−［２−（ジメチルアミノ）エチル］−２−ヒドロキシ−４Ｈ−ベンゾ［ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−４，６（５Ｈ）−ジオン 塩酸塩
【化９１】

【０２０１】
実施例４５の化合物を実施例４６と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.89(br-s,6H),3.39-3.54(m,2H),4.32-4.46(m,2H),7.53-7.56(m,1H),7.65-7.71(m,1H),7.81-7.87(m,1H),8.19(d,J=8.0Hz,1H),8.23(d,J=8.8Hz,1H),8.35-8.39(m,1H),8.60(d,J=8.8Hz,1H),8.73(d,J=8.0Hz,1H),9.29-9.39(br,1H),10.25(s,1H)
元素分析値：C₂₂H₁₉N₃O₃・HCl・H₂Oとして

【０２０２】
実施例５４
２−［２−（ジメチルアミノ）エチル］−９−メトキシ−１Ｈ−ベンゾ［ａ］ピリミド［５，６，１−ｊｋ］カルバゾール−１，３（２Ｈ）−ジオン 塩酸塩
【化９２】

【０２０３】
５−メトキシ−１−テトラロンと２−ヒドラジノ安息香酸塩酸塩から実施例１８と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.92(s,6H),3.46-3.55(m,2H),4.02(s,3H),4.42-4.46(m,2H),7.16(d,J=7.1Hz,1H),7.60(t,J=7.1Hz,1H),7.73(t,J=7.1Hz,1H),8.12(d,J=7.1Hz,1H),8.34-8.44(m,2H),8.63(d,J=7.1Hz,1H),9.28(d,J=9.2Hz,1H),9.78(br-s,1H)
【０２０４】
実施例５５
９−［２−（１−ピロリジニル）エチル］−８Ｈ−ピリド［２，３−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−８，１０（９Ｈ）−ジオン 二塩酸塩
【化９３】

【０２０５】
実施例３６と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆+D₂O）δ(ppm) ；1.84-1.94(m,2H),2.01-2.13(m,2H),3.13-3.25(m,2H),3.57-3.64(m,2H),3.65-3.74(m,2H),4.43-4.49(m,2H),7.85(t,J=7.6Hz,1H),7.94(dd,J=4.4,8.4Hz,1H),8.23(d,J=7.6Hz,1H),8.37(d,J=9.2Hz,1H),8.92(d,J=9.2Hz,1H),9.05(d,J=7.6Hz,1H),9.12(dd,J=1.6,4.4Hz,1H),9.40-9.45(m,1H)
【０２０６】
実施例５６
９−［２−（ジメチルアミノ）エチル］−１３−フルオロ−８Ｈ−ピリド［２，３−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−８，１０（９Ｈ）−ジオン 二塩酸塩
【化９４】

【０２０７】
実施例３６と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆）δ(ppm) ；2.92(s,3H),2.93(s,3H),3.47-3.55(m,2H),4.41-4.47(m,2H),7.69(dd,J=8.4,12.0Hz,1H),7.93(dd,J=4.4,8.4Hz,1H),8.29(dd,J=4.4,8.4Hz,1H),8.45(d,J=9.2Hz,1H),8.97(d,J=9.2Hz,1H),9.10-9.14(m,1H),9.25-9.31(m,1H)
【０２０８】
実施例５７
９−［２−（ジメチルアミノ）エチル］−３−メチル−８Ｈ−ピリド［２，３−ｃ］ピリミド［５，６，１−ｊｋ］カルバゾール−８，１０（９Ｈ）−ジオン二塩酸塩
【化９５】

【０２０９】
実施例３６と同様にして表題化合物を得た。
¹H-NMR(DMSO-d₆+D₂O) δ(ppm) ；2.93(s,3H),2.95(s,6H),3.51-3.57(m,2H),4.44-4.50(m,2H),7.86(t,J=8.0Hz,1H),7.98(d,J=8.8Hz,1H),8.25(d,J=8.0Hz,1H),8.39(d,J=9.2Hz,1H),8.98(d,J=9.2Hz,1H),9.09(d,J=8.0Hz,1H),9.55(d,J=8.8Hz,1H)
【０２１０】
実施例５８
７−［２−（ジメチルアミノ）エチル］−６Ｈ−ジベンゾ［c,i]ピリミド［１，６，５−lm]-β- カルボリン−６，８（７Ｈ）−ジオン
【化９６】

【０２１１】
製造例２５の化合物1.06g(3.1mmol)をメタノール(20ml)及びテトラヒドロフラン(20ml)に溶解し、１Ｎ水酸化ナトリウム水溶液(10ml)を加え１時間加熱還流した。放冷後、１Ｎ塩酸水溶液(10ml)を加え溶媒を留去した。残渣にN,N - ジメチルホルムアミド(50ml)を加え、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩770mg(4mmol)及び１−ヒドロキシベンゾトリアゾール１水和物540mg(4mmol)、N,N-ジメチルエチレンジアミン0.4ml(3.7mmol)を加え室温にて終夜攪拌した。炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後濃縮した。析出した沈殿をエタノールで洗浄後濾取し中間体660mg(収率55%)を得た。
この中間体100mg(0.26mmol) をN,N-ジメチルホルムアミド(20ml)に溶解し、窒素気流下、水素化ナトリウム（油性60%)22mg(0.55mmol)を加え、１時間撹拌後、室温にてクロロぎ酸メチル0.046ml(0.6mmol)を加えた。直ちに１Ｎ塩酸を加え酸性とし、飽和炭酸水素ナトリウム水溶液を加え弱アルカリ性として、酢酸エチルを用いて抽出した。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後濃縮した。残渣をシリカゲルクロマトグラフィーで精製し表題化合物を25mg( 収率24%)得た。
ＦＡＢ質量分析m/z;409 （［Ｍ＋Ｈ］⁺ ）
¹H-NMR(CDCl₃) δ(ppm) ；2.39(s,6H),2.80(t,J=6.7Hz,2H),4.51(t,J=6.7Hz,2H),7.66-7.78(m,2H),7.85-7.93(m,2H),8.01-8.07(m,2H),8.51(d,J=8.6Hz,1H),8.57-8.63(m,1H),8.73-8.79(m,1H),9.74(dd,J=0.7,8.6Hz,1H)[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel fused polycyclic heterocyclic derivative, a process for producing the same, and a pharmaceutical composition containing the compound as an active ingredient.
[0002]
[Prior art]
Cyclic imide in the molecule
[Formula 4]

As the condensed polycyclic heterocycle antitumor substance having a moiety, the tricyclic compound amonafide [5-amino-2- [2- (dimethylamino) ethyl] -1H-benz [de] isoquinoline-1,3 (2H) -dione] is the best known, but in clinical trials conducted so far, it has been reported that myelotoxicity is strong and the efficacy rate is low [Drugs Fut.,17, 832 (1992)]. In addition, as a tetracyclic compound, azonaphthide [2- [2 ′-(dimethylamino) ethyl] -1, which has increased antitumor activity in a preclinical study by converting the aminonaphthalene moiety of amonafide to anthracene, 2-dihydro-3H-dibenz (deh) -isoquinoline-1,3-dione] has been reported (WO9200281).
Further, as a condensed tetracyclic heterocyclic antitumor substance having a uracil structure in which one nitrogen atom is introduced into a cyclic imide in its molecule, 2- [2- (dimethylamino) ethyl] pyrimido [5,6,1- de] acridine-1,3,7-trione [Farmaco,47, 1035 (1992)] and 2,3-dihydro-2- [2- (dimethylamino) ethyl] -1H, 7H-naphthyridino [3,2,1-ij] quinazoline-1,3,7 (2H)- Trion [Journal of Medicinal Chemistry (J. Med. Chem.),37, 593 (1994)], all of which show weak antitumor activity in preclinical studies. There are no reports of this type of fused penta- and hexacyclic heterocyclic antitumor substances.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel compound having low toxicity and excellent antitumor activity. Furthermore, it aims at providing the manufacturing method of this compound, and the pharmaceutical composition which uses this compound as an active ingredient.
[0004]
[Means for Solving the Problems]
In light of the above, the present inventors have conducted intensive research for an excellent antitumor substance. As a result, the novel condensed penta- and hexacyclic heterocyclic compounds having a uracil structure in the molecule are excellent anti-tumors. The present invention was completed by finding that it has activity and low toxicity.
[0005]
That is, the present invention relates to the general formula (I)
[Chemical formula 5]

[0006]
[Wherein, A ring means a monocyclic aromatic ring which may have a substituent or a bicyclic condensed ring in which at least one ring is an aromatic ring. Ring B means pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4 (1H) -pyridone. Ring C means a monocyclic or fused bicyclic aromatic ring which may have a substituent. Y may be substituted by the formula -ef (wherein e is a lower alkylene group, f is an amidino group, a guanidino group, or a lower alkyl group that is hydroxylated or lower alkylaminated or not. Means an amino group).
However, it is related with the compound or its pharmacologically acceptable salt represented by these except the combination whose both A ring and C ring are monocyclic aromatic rings which may have a substituent.
[0007]
In the definition of the A ring in the general formula (I), the “monocyclic aromatic ring” is an aromatic 5- or 6-membered ring which may contain at least one of a nitrogen atom, an oxygen atom and a sulfur atom. And “a bicyclic fused ring in which at least one ring is an aromatic ring” means a 5- to 8-membered ring in which each ring may contain at least one of a nitrogen atom, an oxygen atom and a sulfur atom. And at least one of them is a bicyclic fused ring which is an aromatic ring. There may be 1 to 3 substituents on the ring.
Examples of the ring included in the A ring include benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, pyrrole, thiazole, and a partially hydrogenated group. The following bicyclic fused rings may be mentioned, and these rings can be condensed with the B ring at any chemically possible position.
[0008]
[Chemical 6]

[0009]
[Chemical 7]

[0010]
[Chemical 8]

[0011]
The ring may have 1 to 3 substituents, and when there are a plurality of substituents, they may be the same or different. Examples of the substituent include a hydroxyl group, an oxo group, a cyano group, a halogen group, a nitro group, a hydroxyl group, a lower alkyl group which may be aminated with a lower alkyl group, a lower alkoxy group, a lower acyl group or a lower alkyl group. Examples thereof may include a carbamoyl group, a lower alkylated group, a lower acylated group, an arylsulfonylated group or an amino group which may be a lower alkylsulfonylated group.
The “monocyclic or condensed bicyclic aromatic ring” in the meaning of the C ring is a monocyclic or bicyclic aromatic hydrocarbon or an aromatic heterocycle containing 1 to 2 nitrogen atoms, There may be 1 to 3 substituents on the ring.
Examples of the ring included in the C ring include benzene, pyridine, pyrimidine, naphthalene, quinoline, isoquinoline, indole, quinazoline and the like, and these rings are condensed with the B ring at any chemically possible position. You can do it.
[0012]
The ring may have 1 to 3 substituents, and when there are a plurality of substituents, they may be the same or different. Examples of the substituent include a halogen group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a lower alkylated or lower acylated amino group, and the like.
[0013]
In the general formula (I), the substituent that the A ring and the C ring may have and the lower alkyl group in the definition of Y include a linear or branched alkyl group having 1 to 6 carbon atoms, For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group (amyl group), isopentyl group, neopentyl group, tert- Pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1 Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, -Ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc. Can be mentioned. Among these, preferred groups include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and among these, the most preferred groups include a methyl group and an ethyl group.
In the definition of e in Y, the lower alkylene group means a residue obtained by removing one hydrogen atom from the lower alkyl group. When the amino group is substituted with two lower alkyl groups in the definition of f in Y and the ring which may be possessed by the A ring and the C ring, these alkyl groups are bonded together to form 5 Alternatively, a 6-membered ring may be formed.
The lower alkoxy group in the definition of the substituent which A ring and C ring may have is methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy It means a lower alkoxy group derived from the above lower alkyl group such as a group, and among these, the most preferred group includes a methoxy group and an ethoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom.
Examples of the lower acyl group include a formyl group having 1 to 6 carbon atoms, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, and a valeryl group.
The amino group which may be arylsulfonylated or lower alkylsulfonylated in the definition of the substituent which the ring A may have is, for example, p-toluenesulfonylated, methylsulfonylated, ethylsulfonylated, Or a good amino group.
[0014]
The condensed polycyclic heterocyclic derivative represented by the general formula (I) may form a salt with an acid. The present invention also includes a salt of compound (I). Examples of the salts with acids include inorganic acid salts with hydrochloric acid, hydrobromic acid, sulfuric acid, etc., acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulfone. The organic acid salt with an acid etc. can be mentioned.
Needless to say, not only hydrates of these compounds but also optical isomers are present when they are present. In addition, the compound of the present invention exhibits strong antitumor activity, but also includes compounds exhibiting antitumor activity by undergoing metabolism such as oxidation, reduction, hydrolysis, and conjugation in vivo. Furthermore, the present invention also includes a compound that produces a compound of the present invention upon metabolism such as oxidation, reduction, hydrolysis, etc. in vivo.
[0015]
The compound (I) of the present invention can be produced by various methods. Among them, typical methods are as follows.
[0016]
1) General formula (II)
[Chemical 9]

[0017]
(In the formula, Aa ring and Ca ring mean A and C rings which may be protected, respectively, and Ba ring is 4H-1,4-oxazine, 4H-1,4-thiazine, 4 (1H)- Pyridone or pyrrole, fa means f which may be protected, e means the same as above, and a compound represented by the general formula (III)
[Chemical Formula 10]

[0018]
(Wherein D and E are the same or different and represent a leaving group).
[0019]
This reaction generally involves dissolving compound (II) in an aprotic solvent such as dimethylformamide, tetrahydrofuran, dioxane, etc., and then adding 2-3 equivalents of sodium hydride, followed by addition of compound (III). Is done.
Examples of the compound (III) include phosgene, ethyl chlorocarbonate, N, N′-carbonyldiimidazole and the like. The reaction is usually carried out in the temperature range of −50 to 150 ° C.
In the obtained product, when the amino group, hydroxyl group, etc. are protected, the desired compound (I) can be obtained by carrying out usual deprotection methods such as acid treatment, alkali treatment, catalytic reduction. Is possible.
[0020]
2) General formula (IV)
Embedded image

[0021]
(In the formula, the Ab ring has a lower acyl group or an oxo group and may have another protected or unprotected substituent, and at least one ring is an aromatic ring. Bb ring means pyrrole, 4H-1,4-oxazine or 4H-1,4-thiazine Cb ring may have a protected or unprotected substituent (Y represents the same meaning as described above) and can be produced by reacting with a carbonyl group reducing agent.
For the reduction, a commonly used carbonyl group reduction method can be used. Preferred examples include catalytic reduction using palladium-carbon as a catalyst, reduction with borane-pyridine complex, sodium cyanoborohydride, and the like. Can be mentioned.
[0022]
Next, a method for producing the raw material compound (II) used in the present invention will be described. The starting compound (II) includes known compounds and novel compounds. In the case of a novel compound, it can be produced by applying a known method for synthesizing a known compound or by combining them.
[0023]
Manufacturing method 1
Embedded image

[0024]
(In the formula, the Ac ring means a monocyclic ring that is not an aromatic ring or a bicyclic condensed ring in which one or both of the rings are not aromatic rings, which may have a substituent. The Ad ring is a ring in the Ac ring. A part or all of is dehydrogenated.Ca ring, e and fa have the same meaning as described above.)
The compound represented by the general formula (IX) is Fischer's indole synthesis method, Borsche's tetrahydrocarbazole synthesis method [Org. Syn.IV, 884 (1963)] and the like. That is, the cyclic ketone represented by the general formula (VII) and the o-hydrazino aromatic carboxylic acid represented by the general formula (VIII) are ethanol in acetic acid or formic acid, or in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, zinc chloride or the like. It can manufacture by heating in neutral solvents. In the compound (IX), when the Ac ring may have a substituent, and only one of the rings is a bicyclic condensed ring which is an aromatic ring, the compound represented by the general formula (VI) as it is It is possible to produce the target compound (IIa) by condensation with. Compound (X) can be produced by partially or fully dehydrogenating a ring that is not an aromatic ring in compound (IX) with a dehydrogenating agent. Examples of the dehydrogenating agent include 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, chloranil, palladium-carbon, and the like. The reaction is usually performed at room temperature or under heating. When the Ac ring is a bicyclic fused ring in which neither ring is an aromatic ring, only one of the rings may be selectively dehydrogenated by appropriately selecting the type, amount, reaction conditions, etc. of the reagent. Is possible. The target compound (IIa) can be produced by condensing the compound (X) and the compound (VI) thus obtained. Examples of the condensation method include an acid chloride method, an active ester method, a mixed acid anhydride method, and a method using 1,3-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, diphenylphosphoryl azide as a condensing agent.
[0025]
Manufacturing method 2
Embedded image

[0026]
(In the formula, the Ae ring means a monocyclic aromatic ring which may have a substituent, or a bicyclic condensed ring in which at least the ring having the substituent —G—H is an aromatic ring. (Refers to an oxygen atom or a sulfur atom, K and L represent a leaving group, R represents a lower alkyl group, and the Ca ring, e and fa have the same meaning as described above.)
The compound represented by the general formula (XIII) can be produced by reacting the compound of the general formula (XI) with the compound of the general formula (XII). A preferred example of the leaving group K in the compound (XII) is a nitro group, and a preferred example of L is a halogen atom. The reaction can be carried out by heating in the presence or absence of a base such as triethylamine, sodium acetate or sodium hydroxide. The target compound (IIb) is produced by deriving the ester of compound (XIII) into compound (XIV) by alkaline hydrolysis and condensing it with compound (VI) in the same manner as in production method (I). Can do.
[0027]
When the compound of the present invention is used as a medicine, it is administered orally or parenterally. The dose varies depending on the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc. The daily dose for adults is 1 to 3000 mg, preferably about 10 to 2000 mg, more preferably 20 to 1000 mg.
[0028]
When preparing an oral solid preparation, after adding a binder, a disintegrating agent, a lubricant, a coloring agent, a corrigent, etc. to the main drug as necessary, tablets, coated tablets, Granules, fine granules, powders, capsules, etc.
Examples of excipients include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, and silicon dioxide.Examples of binders include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. As the lubricant, for example, magnesium stearate, talc, silica and the like are permitted to be added to the pharmaceutical as the coloring agent, and as the flavoring agent, cocoa powder, mint brain, aromatic acid, Mentha oil, Borneolum, cinnamon powder, etc. are used. Of course, these tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. as required.
When preparing injections, add pH adjusters, buffers, suspending agents, solubilizing agents, solubilizers, tonicity agents, preservatives, etc. to the main drug as necessary. Subcutaneous and intramuscular injection. At that time, if necessary, it may be lyophilized by a conventional method.
Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
[0029]
Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
Examples of the stabilizer include sodium sulfite and sodium metasulfite, and examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
[0030]
DETAILED DESCRIPTION OF THE INVENTION
【The invention's effect】
Next, pharmacological experimental examples for describing the effects of the compound of the present invention are shown.
[0031]
Experimental example 1P 388 Against cells (mouse leukemia cells) in vitro Anti-tumor test
10% fetal bovine serum, penicillin (100 units / ml), streptomycin (100 μg / ml), mercaptoethanol (5 × 10^-FiveM) and P388 cells suspended in RPMI1640 medium (Sanko Junyaku) containing sodium pyruvate (1 mM) were added to each well of a 96-well U-bottom microplate at 1.25 × 10^Three Each seed (0.1 ml) was inoculated and cultured at 37 ° C. for 1 day in an incubator containing 5% carbon dioxide gas.
[0032]
The compound of the present invention was added with dimethyl sulfoxide to 10^-210% with 10% fetal bovine serum-RPMI1640 medium^-FourM or 10^-FiveDilute to M concentration. This was used as a maximum concentration, and 3-fold serial dilution was performed with 10% fetal bovine serum-RPMI1640 culture solution. 0.1 ml of this was added to each well of the P388 cell culture plate described above and cultured at 37 ° C. for 3 days in a 5% carbon dioxide incubator.
[0033]
After culturing, 0.05 ml each of MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] solution (3.3 mg / ml) was added to each well and further cultured for 2 hours. After centrifuging the microplate and removing the supernatant from each hole by suction, the produced formazan was dissolved in 0.1 ml of dimethyl sulfoxide, and the absorbance at 540 nm was measured with a microplate reader to give an index of the number of living cells. The inhibition rate is calculated from the following formula, and the concentration of the test compound that inhibits 50% (IC₅₀)
[0034]
[Expression 1]

[0035]
T: Absorbance of the hole to which the test compound was added
C: Absorbance of the hole where the test compound was not added
IC obtained₅₀Values are shown in Table 1.
[0036]
[Table 1]

[0037]
Experimental example 2M 5076 Against (mouse reticulosarcoma) in vivo Anti-tumor test
1x10 subcutaneously on the body side of BDF1 mice (6-7 weeks old, female)⁶ Pieces of M5076 were transplanted. The compound of the present invention was dissolved in 5% glucose solution and administered intraperitoneally once a day according to each schedule after the day after transplantation. A 5% glucose solution was administered to the control group. The experiment was conducted with 10 mice per control group and 5 mice per drug administration group.
On day 21 after transplantation, the tumor was excised and the tumor weight was measured. The tumor growth inhibition rate of the drug administration group relative to the control group was determined from the following formula.
[0038]
[Expression 2]

[0039]
T: Average tumor weight of test compound administration group
C: Average tumor weight of the control group
The experimental results are shown in Table 2.
[0040]
[Table 2]

[0041]
Experimental example 3MX -1 Against (human breast cancer) in vivo Anti-tumor test
1mm subcutaneously on the body side of nude mice (BALB / C · nu / nu, 6-7 weeks old, female)^ThreeAbout MX-1 tumor pieces were transplanted. 50mm after transplant^Three The compound of the present invention was dissolved in a 5% glucose solution from about 10 days after the tumor volume was reached and administered intraperitoneally once a day according to each schedule. A 5% glucose solution was administered to the control group. The experiment was conducted with 10 mice per control group and 5 mice per drug administration group.
On day 22 after the start of drug administration, the tumor was excised and the tumor weight was measured. The tumor growth inhibition rate of the drug administration group relative to the control group was determined from the following formula.
[0042]
[Equation 3]

[0043]
T: Average tumor weight of test compound administration group
C: Average tumor weight of the control group
The experimental results are shown in Table 3.
[0044]
[Table 3]

[0045]
As is clear from the above experimental results, the compound of the present invention has an excellent antitumor effect and is useful as an antitumor agent.
[0046]
【Example】
Next, although the manufacture example which shows manufacture of the raw material compound of this invention compound and the Example about the typical compound of an invention compound are given, this invention is not limited only to these.
[0047]
Production Example 1
5,6-Dihydro-7H-benzo [c] carbazole-8-carboxylic acid
Embedded image

[0048]
To a suspension of 7.05 g (37.4 mmol) of 2-hydrazinobenzoic acid hydrochloride in 40 ml of acetic acid, a solution of β-tetralone 5.00 g (34.2 mmol) in 10 ml of acetic acid was added dropwise at 80 ° C. and heated under reflux for 3 hours and 45 minutes. The mixture was returned to room temperature, water was added, and the resulting precipitate was collected by filtration, washed with water, dried and recrystallized from ethanol to obtain 5.2 g of the title compound.
¹H-NMR (DMSO-d₆) δ (ppm); 2.91-3.06 (m, 4H), 7.03 (t, J = 7.6Hz, 1H), 7.17 (t, J = 7.6Hz, 1H), 7.20-7.27 (m, 2H), 7.72 ( d, J = 7.6Hz, 1H), 7.76 (d, J = 7.6Hz, 1H), 8.19 (d, J = 7.6Hz, 1H), 11.29 (s, 1H)
[0049]
Production Example 2
7H-benzo [c] carbazole-8-carboxylic acid
Embedded image

[0050]
To a suspension of 2.97 g (11.3 mmol) of the compound of Production Example 1 in 200 ml of benzene, 3.29 g (14.3 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added at room temperature and stirred for 50 minutes. . The mixture was further heated under reflux for 3 hours and 20 minutes, and then returned to room temperature. The precipitate was collected by filtration and recrystallized from ethanol to obtain 2.76 g of the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 7.39 (t, J = 7.3Hz, 1H), 7.48 (t, J = 7.3Hz, 1H), 7.70 (t, J = 7.3Hz, 1H), 7.93 (d, J = 8.7Hz) , 1H), 8.00-8.07 (m, 3H), 8.79 (d, J = 7.3Hz, 1H), 8.87 (d, J = 7.3Hz, 1H), 11.82 (s, 1H), 13.22 (br-s, 1H)
[0051]
Production Example 3
N- [2- (dimethylamino) ethyl] -7H-benzo [c] carbazole-8-carboxamide
Embedded image

[0052]
To a solution of 1.89 g (7.25 mmol) of the compound of Preparation Example 2 in 60 ml of dimethylformamide was added 2.52 g (15.5 mmol) of N, N'-carbonyldiimidazole at room temperature. After stirring for 45 minutes, 5.0 ml (45.5 mmol) of N, N-dimethylethylenediamine was added and stirred for 2 hours and 40 minutes. After concentration, water and ethyl acetate were added for extraction, and the organic layer was separated and washed with water. The extract was dried over sodium sulfate and concentrated to dryness to give 2.47 g of the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.33 (s, 6H), 2.60 (t, J = 5.7Hz, 2H), 3.63 (q, J = 5.7Hz, 2H), 7.16 (br-s, 1H), 7.38 (t, J = 7.5Hz, 1H), 7.46-7.50 (m, 1H), 7.65-7.73 (m, 3H), 7.89 (d, J = 9.0Hz, 1H), 8.01 (d, J = 8.2Hz, 1H), 8.69 (d, J = 7.5Hz, 1H), 8.74 (d, J = 8.2Hz, 1H), 10.94 (br-s, 1H)
[0053]
Production Example 4
3-acetyl-7H-benzo [c] carbazole-8-carboxylic acid
Embedded image

[0054]
To a suspension of 5.1 g (38 mmol) of aluminum chloride in 300 ml of dichloromethane was added 1.17 ml (12.4 mmol) of acetic anhydride at 0 ° C. and stirred for 20 minutes. To this solution was added 2.16 g (8.28 mmol) of the compound of Production Example 2 at 0 ° C., and the mixture was stirred at the same temperature for 4 hours 30 minutes. The reaction mixture was poured into ice water and extracted with a mixture of chloroform and ethanol. The organic layer was separated and concentrated, and the residue was purified by silica gel column chromatography to obtain 1.45 g of the title compound.
¹H-NMR (DMSO-d₆) δ (ppm); 2.72 (s, 3H), 7.44 (t, J = 7.6Hz, 1H), 8.07 (d, J = 7.6Hz, 1H), 8.11 (d, J = 9.1Hz, 1H), 8.14 (d, J = 9.1Hz, 1H), 8.18 (dd, J = 1.9,8.8Hz, 1H), 8.79 (d, J = 1.9Hz, 1H), 8.87 (d, J = 8.8Hz, 1H), 8.91 (d, J = 7.6Hz, 1H), 12.01 (s, 1H)
[0055]
Production Example 5
3-acetyl-N- [2- (dimethylamino) ethyl] -7H-benzo [c] carbazole-8-carboxamide
Embedded image

[0056]
291 mg (1.80 mmol) of N, N′-carbonyldiimidazole was added to a solution of 247 mg (0.815 mmol) of the compound of Production Example 4 in 7 ml of dimethylformamide, and the mixture was returned to room temperature and stirred for about 2 hours. To this was added 0.45 ml (4.1 mmol) of N, N-dimethylethylenediamine under ice cooling, and the mixture was returned to room temperature and stirred for about 12 hours. Extraction was performed by adding water and chloroform, and the organic layer was separated, dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give 140 mg of the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.29 (s, 6H), 2.53-2.61 (m, 2H), 2.74 (s, 3H), 3.52 (q, J = 5.9Hz, 2H), 7.43 (t, J = 7.1Hz, 1H), 7.97 (d, J = 7.1Hz, 1H), 8.10 (d, J = 8.7Hz, 1H), 8.14 (d, J = 8.7Hz, 1H), 8.20 (dd, J = 1.8, 8.5Hz, 1H), 8.72 (t, J = 5.9Hz, 1H), 8.79-8.83 (m, 2H), 8.88 (d, J = 8.5Hz, 1H), 12.17 (s, 1H)
[0057]
Production Example 6
3,4,5,8-tetrahydronaphthalene-1,6 (2H, 7H) -dione
Embedded image

[0058]
6.8 g (38.2 mmol) of 1,2,3,4,5,8-hexahydro-1-oxo-6-methoxynaphthalene was dissolved in 50 ml of tetrahydrofuran, and 5 ml of 1N hydrochloric acid was added. After stirring at room temperature for 1 hour, ethyl acetate was added, washed with saturated brine, and dried over magnesium sulfate. After concentration, a small amount of a mixed solution (1: 1) of n-hexane and ethyl acetate was added, and the mixture was cooled in a dry ice-ether bath. The resulting precipitate was collected by filtration and washed with a small amount of n-hexane to obtain 4.8 g of the title compound.
¹H-NMR (CDCl_Three) δ (ppm); 2.01-2.11 (m, 2H), 2.30-2.37 (m, 2H), 2.45-2.51 (m, 4H), 2.68-2.76 (m, 2H), 3.05 (s, 2H)
[0059]
Production Example 7
4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazole-8-carboxylic acid
Embedded image

[0060]
5.4 g (28.6 mmol) of 2-hydrazinobenzoic acid hydrochloride and 4.7 g (34.3 mmol) of zinc chloride were added to 300 ml of glacial acetic acid. While stirring at about 85 ° C., 4.7 g (28.6 mmol) of the compound of Production Example 6 was added over about 5 minutes. After stirring at the same temperature for about 2 hours, the mixture was returned to room temperature and the precipitate was collected by filtration. After the filtrate was concentrated, water was added and the resulting precipitate was collected by filtration. These precipitates were combined, dried, and dissolved in about 500 ml of dimethylformamide. While stirring at room temperature, a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 6.5 g (28.6 mmol) in tetrahydrofuran 20 ml was added and stirred for about 30 minutes. After concentration, about 50 ml of ethanol was added, and the resulting precipitate was collected by filtration to give 3.4 g of the title compound.
¹H-NMR (DMSO-d₆) δ (ppm); 2.17-2.29 (m, 2H), 2.63-2.70 (m, 2H), 3.55 (t, J = 6.0Hz, 2H), 7.36 (t, J = 7.6Hz, 1H), 7.73 ( d, J = 8.8Hz, 1H), 8.03 (d, J = 8.8Hz, 1H), 8.06 (dd, J = 0.8,7.6Hz, 1H), 8.48 (dd, J = 0.8,7.6Hz, 1H), 11.83 (s, 1H), 13.33 (br-s, 1H)
[0061]
Production Example 8
N- [2- (dimethylamino) ethyl] -4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazole-8-carboxamide
Embedded image

[0062]
After adding 3.4 g (12.2 mmol) of the compound of Production Example 7 to 120 ml of dimethylformamide and stirring, a solution of 3.0 g (18.5 mmol) of N, N'-carbonyldiimidazole in 30 ml of dimethylformamide was added. After stirring at room temperature for 1 hour, 3.2 g (36.3 mmol) of N, N-dimethylethylenediamine was added. The mixture was further stirred at the same temperature for 1 hour, concentrated, and ethyl acetate was added. The extract was washed successively with dilute aqueous ammonia and brine, dried over magnesium sulfate, and concentrated to dryness to give 4.3 g of the title compound.
FAB mass spectrometry m / z; 350 ([M + H]⁺ )
¹H-NMR (CDCl_Three) δ (ppm); 2.30-2.40 (m + s, 2H + 6H), 2.62 (t, J = 6.0Hz, 2H), 2.74-2.79 (m, 2H), 3.56-3.66 (m, 4H), 7.21 (br-s, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.41 (d, J = 8.4Hz, 1H), 7.70 (dd, J = 0.8,8.0Hz, 1H), 8.25 (d, J = 8.4Hz, 1H), 8.33 (dd, J = 0.8,8.0Hz, 1H), 10.91 (br-s, 1H)
[0063]
Production Example 9
2,3-Dihydro-3-oxo-1H, 6H-cyclopenta [c] carbazole-7-carboxylic acid
Embedded image

[0064]
2,3,4,7-tetrahydro-1H-indene-1,5 (6H) synthesized from 2,3,4,7-tetrahydro-5-methoxy-1H-inden-1-one in the same manner as in Production Example 6. ) -Dione was reacted in the same manner as in Production Example 7 to obtain the title compound.
FAB mass spectrometry m / z; 266 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) δ (ppm): 2.70-2.82 (m, 2H), 3.52-3.62 (m, 2H), 7.41 (t, J = 7.6Hz, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.81 ( d, J = 8.4Hz, 1H), 8.09 (dd, J = 0.8,7.6Hz, 1H), 8.39 (d, J = 7.6Hz, 1H), 11.95 (s, 1H), 13.37 (br-s, 1H )
[0065]
Production Example 10
2,3-dihydro-N- [2- (dimethylamino) ethyl] -3-oxo-1H, 6H-cyclopenta [c] carbazole-7-carboxamide
Embedded image

[0066]
The title compound was obtained from the compound of Production Example 9 in the same manner as in Production Example 8.
FAB mass spectrometry m / z; 336 ([M + H]⁺ )
¹H-NMR (CDCl_Three) δ (ppm); 2.34 (s, 6H), 2.61 (t, J = 6.0Hz, 2H), 2.85-2.91 (m, 2H), 3.58-3.66 (m, 4H), 7.18 (br-s, 1H) ), 7.36 (t, J = 7.6Hz, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.71 (d, J = 7.6Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 8.22 (d, J = 7.6Hz, 1H), 10.95 (br-s, 1H)
[0067]
Production Example 11
Methyl 5,6,7,8-tetrahydro-9H-carbazole-1-carboxylate
Embedded image

[0068]
To a suspension of 2-hydrazinobenzoic acid hydrochloride 52 g (0.276 mol) in acetic acid 500 ml, a solution of cyclohexanone 28 ml (0.270 mol) in acetic acid 100 ml was added dropwise with stirring at about 100 ° C. After heating at reflux for 6 hours, the temperature was returned to room temperature and 1 l of water was added. The resulting precipitate was collected by filtration, washed with water and dried to obtain 43 g of powder. This was dissolved in 500 ml of acetone, 37.5 ml (0.602 mol) of methyl iodide and 41.4 g (0.300 mol) of anhydrous potassium carbonate were added, and the mixture was heated to reflux for 2 hours. The mixture was returned to room temperature, insolubles were removed by filtration, concentrated, water was added, and the precipitate was collected by filtration to give 45.7 g of the title compound.
¹H-NMR (CDCl_Three) δ (ppm); 1.85-1.97 (m, 4H), 2.70-2.74 (m, 2H), 2.76-2.80 (m, 2H), 3.97 (s, 3H), 7.09 (t, J = 7.6Hz, 1H) ), 7.65-7.68 (m, 1H), 7.79 (dd, J = 1.1, 7.6Hz, 1H), 9.39 (br-s, 1H)
[0069]
Production Example 12
Methyl 5-oxo-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylate
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[0070]
45.7 g (0.199 mol) of the compound of Production Example 11 was dissolved in a mixed solution of 500 ml of tetrahydrofuran and 50 ml of water, and 90.8 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (under nitrogen atmosphere and ice-cooling stirring) 0.400 mol) in 200 ml of tetrahydrofuran was added dropwise. After stirring at room temperature for 3 hours, 1 l of an aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to obtain 39.7 g of the title compound.
¹H-NMR (DMSO-d₆) δ (ppm); 2.10-2.17 (m, 2H), 2.44-2.48 (m, 2H), 3.07 (t, J = 6.2Hz, 2H), 3.96 (s, 3H), 7.28 (t, J = 7.7) Hz, 1H), 7.81 (dd, J = 1.3, 7.7Hz, 1H), 8.25 (dd, J = 1.3, 7.7Hz, 1H), 11.79 (br-s, 1H)
[0071]
Production Example 13
Methyl 5-hydroxy-9H-carbazole-1-carboxylate
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[0072]
39.1 g (0.161 mol) of the compound of Production Example 12 was suspended in 150 ml of diphenyl ether, 10 g of 10% palladium carbon was added, and the mixture was heated to reflux for 3 hours in a nitrogen atmosphere. After allowing to cool, the precipitated crystals and palladium on carbon were collected by filtration and washed with hexane. The mixture collected by filtration was dissolved in hot tetrahydrofuran, and palladium on carbon was removed by filtration. After concentration, the residue was recrystallized from ethanol to obtain 34.7 g of the title compound.
¹H-NMR (CDCl_Three) δ (ppm); 4.03 (s, 3H), 5.54 (s, 1H), 6.62 (dd, J = 0.6, 7.9Hz, 1H), 7.10 (dd, J = 0.6, 7.9Hz, 1H), 7.27 ( t, J = 7.9Hz, 1H), 7.30 (t, J = 7.9Hz, 1H), 8.05 (dd, J = 1.2,7.9Hz, 1H), 8.46-8.50 (m, 1H), 9.93 (br-s , 1H)
[0073]
Production Example 14
[1-Methoxycarbonyl-9H-carbazol-5-yl] oxyacetic acid
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[0074]
34.8 g (0.144 mol) of the compound of Production Example 13 was dissolved in 550 ml of acetone, and 68.5 ml (0.432 mol) of benzyl bromoacetate, 64.8 g (0.432 mol) of sodium iodide and 29.8 g (0.216 mol) of anhydrous potassium carbonate were added. Heated to reflux for 60 hours. After allowing to cool, the precipitate was filtered off and concentrated. Ethyl acetate and water were added for extraction, and the organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The residue was solidified by adding n-hexane, then collected by filtration and recrystallized from ethanol to obtain 40.7 g of the benzyl ester of the title compound. This was suspended in a mixed solution of 600 ml of tetrahydrofuran and 500 ml of methanol, 12 g of 10% palladium carbon was added, and hydrogenated at room temperature and normal pressure to obtain 29.4 g of the title compound.
¹H-NMR (CD_ThreeOD) δ (ppm); 4.02 (s, 3H), 4.90 (s, 2H), 6.67 (dd, J = 0.6, 8.0Hz, 1H), 7.23 (t, J = 7.7Hz, 1H), 7.26 (dd , J = 0.6,8.0Hz, 1H), 7.35 (t, J = 8.0Hz, 1H), 8.02 (dd, J = 1.1,7.7Hz, 1H), 8.63 (dd, J = 1.1,7.7Hz, 1H) , 10.87 (br-s, 1H)
[0075]
Production Example 15
2,3-Dihydro-3-oxo-6H-furo [3,2-c] carbazole-7-carboxylic acid
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[0076]
The compound of Production Example 14 (29.4 g, 0.098 mol) was suspended in toluene (500 ml), thionyl chloride (36 ml, 0.494 mol) was added, and the mixture was heated to reflux until uniform. After concentration, 500 ml of dichloromethane was added to dissolve, and 32.1 g (0.240 mol) of aluminum chloride was added little by little with stirring with ice cooling. After returning to room temperature and stirring overnight, ice water was added under ice cooling. After stirring at room temperature, the mixture was concentrated and diluted hydrochloric acid was added. The precipitate was collected by filtration, washed successively with water and ethanol and dried to obtain 26.5 g of powder. The total amount of this powder was dissolved in a mixed solution of 350 ml of tetrahydrofuran and 250 ml of methanol, and 750 ml of 0.2N sodium hydroxide aqueous solution degassed under a nitrogen atmosphere. After hydrolysis of the ester at 50 ° C., 20 ml of concentrated hydrochloric acid was added. Extraction was performed with a mixture of ethyl acetate and tetrahydrofuran, and the organic layer was separated, washed with water, dried over magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain 11.4 g of the title compound.
¹H-NMR (DMSO-d₆) δ (ppm) 5.00 (s, 2H), 7.41 (t, J = 7.7Hz, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.63 (d, J = 8.5Hz, 1H), 8.07 (dd, J = 1.3,7.7Hz, 1H), 8.29-8.32 (m, 1H), 12.10 (br-s, 1H)
[0077]
Production Example 16
N- [2- (allylmethylamino) ethyl] -4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazole-8-carboxamide
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[0078]
N- [2- (methylamino) ethyl] -4-oxo-1,2 was prepared in the same manner as in Production Example 8 from 0.5 g (1.79 mmol) of the compound of Production Example 7 and 0.53 g (7.15 mmol) of N-methylethylenediamine. , 3,4-tetrahydro-7H-benzo [c] carbazole-8-carboxamide 0.49 g was obtained. 0.49 g (1.46 mmol) of this product, 0.25 g (1.74 mmol) of allyl bromide and 0.23 g (1.78 mmol) of N, N-diisopropylethylamine were dissolved in 30 ml of tetrahydrofuran and stirred at 55 ° C. for about 5 hours. After allowing to cool, the reaction mixture was diluted with ethyl acetate, washed successively with dilute aqueous ammonia and brine, and dried over magnesium sulfate. After concentration, the residue was purified by preparative thin layer chromatography to give 0.24 g of the title compound.
¹H-NMR (CDCl_Three) δ (ppm); 2.28-2.40 (m + s, 2H + 3H), 2.70 (t, J = 6.0Hz, 2H), 2.73-2.80 (m, 2H), 3.11-3.17 (m, 2H), 3.56 -3.68 (m, 4H), 5.17-5.29 (m, 2H), 5.82-5.97 (m, 1H), 7.24 (br-s, 1H), 7.33 (t, J = 7.6Hz, 1H), 7.42 (d , J = 8.4Hz, 1H), 7.67 (dd, 0.8,7.6Hz, 1H), 8.25 (d, J = 8.4Hz, 1H), 8.33 (dd, J = 0.8,7.6Hz, 1H), 10.88 (br -s, 1H)
[0079]
Production Example 17
5- [2- (Allylmethylamino) ethyl] -12,13-dihydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione
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[0080]
From 0.24 g (0.64 mmol) of the compound of Production Example 16, 0.23 g of the title compound was obtained in the same manner as in Example 2 (except for the operation of converting to hydrochloride).
¹1H-NMR (CDCl_Three) δ (ppm); 2.32-2.42 (m + s, 2H + 3H), 2.73-2.84 (m, 4H), 3.10-3.15 (m, 2H), 3.53 (t, J = 6.4Hz, 2H), 4.35 (t, J = 7.2Hz, 2H), 5.08-5.22 (m, 2H), 5.74-5.90 (m, 1H), 7.63 (t, J = 7.6Hz, 1H), 8.19 (dd, J = 0.8,7.6 Hz, 1H), 8.32 (dd, J = 0.8, 7.6Hz, 1H), 8.35 (d, J = 8.4Hz, 1H), 8.51 (d, J = 8.4Hz, 1H)
[0081]
Production Example 18
Methyl 6-methyl-9H-carbazole-1-carboxylate
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[0082]
A suspension of 2.0 g (10.6 mmol) of 2-hydrazinobenzoic acid hydrochloride in 20 ml of acetic acid was boiled gently with stirring, and 1.2 ml (9.8 mmol) of 4-methylcyclohexanone was added dropwise. After heating under reflux for 8 hours and allowing to cool, water was added and the precipitate was collected by filtration, washed with water and dried to obtain 1.96 g of 6-methyl-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylic acid. . This was dissolved in 50 ml of acetone, 2.1 ml (34 mmol) of methyl iodide and 2.35 g (17 mmol) of anhydrous potassium carbonate were added, and the mixture was heated to reflux for 2 hours with stirring. After cooling, water and ethyl acetate are added for extraction, the organic layer is separated, washed with water, dried over magnesium sulfate, concentrated to dryness, and methyl 6-methyl-5,6,7,8-tetrahydro-9H-carbazole -1.49 g of -1-carboxylate was obtained. This was suspended in 10 ml of diphenyl ether, 890 mg of 10% palladium carbon was added, and the mixture was heated to reflux for 1 hour with stirring under a nitrogen atmosphere. After allowing to cool, hot tetrahydrofuran was added for dissolution, and the catalyst was filtered off and concentrated. n-Hexane was added, and the crystals were collected by filtration to obtain 1.26 g of the title compound.¹H-NMR (CDCl_Three) δ (ppm); 2.54 (s, 3H), 4.02 (s, 3H), 7.22 (t, J = 7.8Hz, 1H), 7.27-7.31 (m, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.87-7.90 (m, 1H), 8.05 (dd, J = 1.1, 7.8Hz, 1H), 8.21-8.25 (m, 1H), 9.82 (br-s, 1H)
[0083]
Production Example 19
Methyl 6-formyl-9H-carbazole-1-carboxylate
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[0084]
To a solution of 1.2 g (5 mmol) of the compound of Production Example 18 in 100 ml of carbon tetrachloride, 1.8 g (10 mmol) of N-bromosuccinimide and 220 mg (1.3 mmol) of α, α'-azobisisobutyronitrile were added and stirred. Heated to reflux for 1 hour. The mixture was allowed to cool and then concentrated, and the residue was purified by silica gel column chromatography to obtain 1.13 g of the title compound.
¹H-NMR (CDCl_Three) δ (ppm); 4.05 (s, 3H), 7.36 (t, J = 7.8Hz, 1H), 7.62 (d, J = 8.4Hz, 1H), 8.03 (dd, J = 1.6, 8.4Hz, 1H) , 8.14 (dd, J = 1.2, 7.8Hz, 1H), 8.32-8.36 (m, 1H), 8.62-8.64 (m, 1H), 10.12 (s, 1H), 10.23 (br-s, 1H)
[0085]
Production Example 20
Methyl 1,2-dihydro-1-oxo-7H-pyrido [4,3-c] carbazole-8-carboxylate
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[0086]
To a solution of 2.0 g (7.9 mmol) of the compound of Production Example 19 in 80 ml of pyridine were added 2.6 g (25 mmol) of malonic acid and 0.3 ml of piperidine, and the mixture was stirred at a bath temperature of 80 ° C. for 1 hour. After adding 2.6 g (25 mmol) of malonic acid over 1 hour under heating and stirring, the mixture was further heated under reflux for 1 hour. After allowing to cool, the reaction mixture was poured into concentrated hydrochloric acid-ice, and the resulting precipitate was collected by filtration, washed with water and dried to obtain 1.8 g of 3- (1-methoxycarbonyl-9H-carbazol-6-yl) acrylic acid. This was dissolved in 70 ml of acetone and 2 ml of triethylamine was added. While cooling with ice, 0.64 ml (6.7 mmol) of ethyl chloroformate was added dropwise. After stirring at the same temperature for 1 hour, a solution of 870 mg (12 mmol) of sodium azide (90%) in 20 ml of water was added dropwise with ice-cooling and stirring. After stirring at the same temperature for 1 hour, the reaction mixture was poured onto ice and the resulting precipitate was collected by filtration. This precipitate and 3 ml of tributylamine were added to 20 ml of diphenyl ether and heated to 260 ° C. After allowing to cool, hexane was added, and the resulting precipitate was collected by filtration and washed with n-hexane and ethanol to obtain 1.39 g of the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 4.01 (s, 3H), 6.73 (d, J = 7.0Hz, 1H), 7.18-7.24 (m, 1H), 7.31 (t, J = 7.9Hz, 1H), 7.77 (d, J = 8.5Hz, 1H), 8.08 (dd, J = 1.3, 7.9Hz, 1H), 8.22 (d, J = 8.5Hz, 1H), 10.13 (dd, J = 1.3, 7.9Hz, 1H), 11.36- 11.42 (m, 1H), 11.93 (br-s, 1H)
[0087]
Production Example 21
Methyl 7H-pyrido [4,3-c] carbazole-8-carboxylate
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[0088]
To 1.19 g (4 mmol) of the compound of Production Example 20, 10 ml of phosphorus oxychloride was added and heated to reflux. After 3 hours, the reaction mixture was poured onto ice and neutralized with sodium bicarbonate. Extraction was performed with dichloromethane, and the organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 390 mg of methyl 1-chloro-7H-pyrido [4,3-c] carbazole-8-carboxylate. This was dissolved in a mixed solution of tetrahydrofuran and methanol, 1 ml of triethylamine was added, and hydrogenated at room temperature and normal pressure in the presence of palladium carbon to obtain 300 mg of the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 4.04 (s, 3H), 7.48 (t, J = 7.7Hz, 1H), 8.00 (d, J = 5.4Hz, 1H), 8.02 (d, J = 8.8Hz, 1H), 8.14 (d, J = 7.7Hz, 1H), 8.28 (d, J = 8.8Hz, 1H), 8.58 (d, J = 5.4Hz, 1H), 9.06 (d, J = 7.7Hz, 1H), 10.22 (s , 1H), 12.11 (br-s, 1H)
[0089]
Production Example 22
10-Nitro-7H-benzo [c] phenothiazine-8-carboxylic acid
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[0090]
To a solution of 1.7 g (9.73 mmol) of 2-amino-1-naphthalenethiol in 30 ml of ethanol was added 5 ml of a 2N aqueous sodium hydroxide solution, and the mixture was heated to reflux. To this mixture, 2.54 g (9.76 mmol) of 2-chloro-3,5-dinitrobenzoic acid methyl ester was added and heated to reflux for 1 hour. To this mixture were added 10 ml of 2N aqueous sodium hydroxide and 40 ml of ethanol, and the mixture was further heated to reflux for 10 hours. After returning to room temperature and concentrating, water was added and 1N hydrochloric acid was gradually added under stirring to bring the pH to about 1. The precipitate was collected by filtration and washed successively with ethanol and methanol to give 1.14 g of the title compound.
¹H-NMR (DMSO-d₆) δ (ppm) 7.04 (d, J = 8.4Hz, 1H), 7.40 (t, J = 8.4Hz, 1H), 7.55 (t, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz) , 1H), 7.68 (d, J = 8.4Hz, 1H), 7.82 (d, J = 8.4Hz, 1H), 7.90 (s, 1H), 8.35 (s, 1H), 11.37 (br-s, 1H)
[0091]
Production Example 23
N- [2- (Dimethylamino) ethyl] -10-nitro-7H-benzo [c] phenothiazine-8-carboxamide
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[0092]
To a suspension of 1.82 g (5.39 mmol) of the compound of Production Example 22 in 60 ml of chloroform were sequentially added 10 ml of phosphorus trichloride and 2 ml of dimethylformam at 0 ° C., and then gradually returned to room temperature and stirred overnight. After the solvent was completely distilled off from this mixture under reduced pressure, 30 ml of dichloromethane was added to the resulting residue, and 5 ml of N, N-dimethylethylenediamine dissolved in 30 ml of dichloromethane was added dropwise with stirring at 0 ° C. The reaction mixture was gradually returned to room temperature and stirred at room temperature for 7 hours. Water and a saturated aqueous sodium hydrogen carbonate solution were added and stirred, and then insolubles were removed by Celite filtration, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated to dryness, and recrystallized from ethanol to give 956 mg of the title compound.
¹H-NMR (DMSO-d₆) δ (ppm); 2.20 (s, 6H), 2.45 (t, J = 6.0Hz, 2H), 3.37 (t, J = 6.0Hz, 2H), 7.06 (d, J = 8.4Hz, 1H), 7.41 (t, J = 8.4Hz, 1H), 7.56 (t, J = 8.4Hz, 1H), 7.66 (t, J = 8.4Hz, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.83 (d , J = 8.4Hz, 1H), 7.93 (br-s, 1H), 8.39 (d, J = 2.9Hz, 1H), 9.50 (br-s, 1H)
[0093]
Production Example 24
3- (4-Methylbenzenesulfonamide) -7H-benzo [c] carbazole-8-carboxylic acid
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[0094]
5,6-dihydro-3- (4-methylbenzenesulfonamide) obtained by heating 6- (4-methylbenzenesulfonamido) -2-tetralone and 2-hydrazinobenzoic acid hydrochloride under reflux in xylene -7H-benzo [c] carbazole-8-carboxylic acid was reacted in the same manner as in Production Example 2 to obtain the title compound.
¹H-NMR (DMSO-d₆) δ (ppm); 2.26 (s, 3H), 7.29 (d, J = 8.0Hz, 2H), 7.35 (dt, J = 2.0, 7.6Hz, 1H), 7.46 (d, J = 8.8Hz, 1H) , 7.66 (d, J = 6.8Hz, 2H), 7.71 (s, 1H), 7.79 (d, J = 9.2Hz, 1H), 7.96 (dd, J = 2.0,9.2Hz, 1H), 8.01 (d, J = 8.8Hz, 1H), 8.66 (d, J = 8.8Hz, 1H), 8.79 (d, J = 8.0Hz, 1H), 10.33 (s, 1H), 11.76 (s, 1H)
[0095]
Production Example 25
Ethyl 13H-benz [6,7] indolo [2,3-c] quinoline-12-carboxylate
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[0096]
A suspension of 4.24 g (22.5 mmol) of 1-naphthylhydrazine hydrochloride in acetic acid (35 ml) was boiled gently and a solution of 3.4 g (20.6 mmol) of 2-nitrophenylacetaldehyde in acetic acid (15 ml) was added dropwise with stirring. After the dropwise addition, the mixture was heated to reflux for 1 hour, further added with 20 ml of 1N hydrochloric acid-acetic acid and heated to reflux for 1 hour. The solvent was distilled off, and the residue was dissolved by adding ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 1.91 g (yield 32%) of 7- (2-nitrophenyl) benzo [g] indole. Next, this was dissolved in 60 ml of ethyl acetate, 200 mg of platinum (IV) oxide was added, and catalytic reduction was carried out at room temperature in an atmospheric hydrogen atmosphere to obtain 1.7 g (7- (2-aminophenyl) benzo [g] indole ( Yield 99%).
Subsequently, 20 ml of ethanol was added to 540 mg (2.1 mmol) of 7- (2-aminophenyl) benzo [g] indole and 260 mg (2.5 mmol) of glyoxylic acid ethyl ester (polymer type), and the mixture was heated to reflux for 8 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound (380 mg, yield 53%).
¹H-NMR (CDCl_Three) δ (ppm); 1.64 (t, J = 7.1Hz, 3H), 4.74 (q, J = 7.1Hz, 2H), 7.63-7.77 (m, 3H), 7.79 (d, J = 8.6Hz, 1H) , 7.79-7.85 (m, 1H), 8.06 (dd, J = 1.3,7.7Hz, 1H), 8.35 (dd, J = 0.7,8.1Hz, 1H), 8.45 (dd, J = 1.3,8.4Hz, 1H ), 8.54 (d, J = 8.6Hz, 1H), 8.79 (dd, J = 1.1,8.2Hz, 1H), 10.98 (br-s, 1H)
[0097]
Example 1
5- [2- (Dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
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[0098]
To a solution of 1.44 g of the compound of Production Example 3 in 50 ml of dimethylformamide was added 457 mg (10.5 mmol) of sodium hydride (oil 55%) at room temperature, and the mixture was stirred for 50 minutes. 1 ml (10.5 mmol) of ethyl chloroformate was added at 0 ° C., and the mixture was stirred at the same temperature for 2 hours and further at room temperature for 6 hours. Water was added, the precipitate was collected by filtration, washed with water and dried, then dissolved in a mixed solution of dichloromethane and methanol, and the insoluble material was removed by filtration. After concentration, ethanol and concentrated hydrochloric acid were added in turn, and the resulting hydrochloride was collected by filtration and recrystallized from ethanol to give 1.24 g of the title compound.
Melting point: 254 to 255 ° C (recrystallized from ethanol)
FAB mass spectrometry m / z: 358 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) δ (ppm) ； 2.90 (d, J = 5.5Hz, 6H), 3.49 (q, J = 5.5Hz, 2H), 4.42 (t, J = 5.5Hz, 2H), 7.67 (t, J = 8.0Hz) , 1H), 7.78 (t, J = 8.0Hz, 1H), 7.83 (t, J = 8.0Hz, 1H), 8.14 (d, J = 8.0Hz, 1H), 8.19 (d, J = 8.0Hz, 1H ), 8.23 (d, J = 8.8Hz, 1H), 8.62 (d, J = 8.0Hz, 1H), 8.86 (d, J = 8.0Hz, 1H), 9.02 (d, J = 8.0Hz, 1H), 9.70 (br-s, 1H)
Elemental analysis value: C_{twenty two}H₁₉N_ThreeO₂・ HCl ・ H₂As O

[0099]
Example 2
11-acetyl-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
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[0100]
To a solution of 105 mg (0.282 mmol) of Preparation Example 5 in 2.5 ml of dimethylformamide was added 13.2 mg (0.549 mmol) of sodium hydride at 0 ° C., and the mixture was stirred at the same temperature for 1 hour and 10 minutes and then at room temperature for 1 hour. To this was added 53.6 μl (0.564 mmol) of ethyl chloroformate at 0 ° C., and the mixture was stirred at the same temperature for 1 hour and 20 minutes. After extraction with water and chloroform, the organic layer was separated, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography and converted to hydrochloride using 1N hydrochloric acid (ethanol) to obtain 106 mg of the title compound.
Melting point: Coloring started at around 240 ° C. and decomposed at 250-254 ° C. (recrystallized from ethanol) FAB mass spectrometry m / z: 400 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) δ (ppm) 2.78 (s, 3H), 2.92 (s, 6H), 3.48-3.54 (m, 2H), 4.44 (t, J = 5.6Hz, 2H), 7.80 (t, J = 7.5Hz, 1H), 8.16 (d, J = 7.5Hz, 1H), 8.24 (dd, J = 2.3,9.4Hz, 1H), 8.40 (d, J = 8.9Hz, 1H), 8.68 (d, J = 8.9Hz, 1H), 8.87-8.91 (m, 2H), 9.01 (d, J = 7.5Hz, 1H), 9.88 (br-s, 1H)
Elemental analysis value: C_{twenty four}H_{twenty one}N_ThreeO_Three・ HCl ・ H₂As O

[0101]
Example 3
5- [2- (Dimethylamino) ethyl] -11- (1-hydroxyethyl) -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
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[0102]
Borane-pyridine complex (about 8M) (21 μl, 0.168 mmol) was added to a suspension of 84 mg (0.211 mmol) of acetic acid in 1.5 mg of the compound of Example 2 and stirred at 70 ° C. for 3 hours. The mixture was acidified with 1N hydrochloric acid at room temperature, stirred for 1 minute, and then neutralized with saturated aqueous sodium hydrogen carbonate. A mixture of dichloromethane and ethanol was added for extraction, the organic layer was separated, washed with water, dried over sodium sulfate, and concentrated. The residue was purified by preparative thin layer chromatography and then converted into hydrochloride using 1N hydrochloric acid to obtain 44 mg of the title compound.
Melting point: 247-248 ° C (decomposition) (recrystallization from ethanol-ether)
FAB mass spectrometry m / z: 402 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) δ (ppm): 1.50 (d, J = 5.0 Hz, 3H), 2.92 (s, 6H), 3.49 (t, J = 5.7 Hz, 2H), 4.43 (t, J = 5.7 Hz, 2H), 4.95 -5.05 (m, 1H), 5.45 (d, J = 4.2Hz, 1H), 7.77 (t, J = 8.4Hz, 1H), 7.84 (d, J = 8.4Hz, 1H), 8.08-8.15 (m, 2H), 8.21 (d, J = 8.4Hz, 1H), 8.59 (dd, J = 1.4,8.4Hz, 1H), 8.81 (d, J = 8.4Hz, 1H), 8.99 (d, J = 7.6Hz, 1H), 9.90 (br-s, 1H)
Elemental analysis value: C_{twenty four}H_{twenty four}N_ThreeO_ThreeAs Cl

[0103]
Example 4
12,13-dihydro-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione hydrochloride
Embedded image

[0104]
To a suspension of 0.9 g (37.5 mmol) of sodium hydride in 30 ml of dimethylformamide, a solution of 4.9 g (14 mmol) of the compound of Preparation Example 8 in 70 ml of dimethylformamide was added dropwise at room temperature and stirred at the same temperature for 2 hours. To this was added 2.5 g (23 mmol) of ethyl chloroformate with stirring under ice cooling. After 15 minutes, ethyl acetate was added, washed successively with dilute aqueous ammonia and brine, and dried over magnesium sulfate. After concentration, methanol was added and the crystals were collected by filtration. This was suspended in methanol and acidified with 1N hydrochloric acid with stirring. After stirring and concentrating at room temperature, ethanol was added and the precipitate was collected by filtration to give 4.3 g of the title compound. Melting point: Coloring starts at around 250 ° C, gradually decomposes around 260 ° C, and rapidly decomposes around 273–275 ° C.
FAB mass spectrometry m / z: 376 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) δ (ppm); 2.22-2.36 (m, 2H), 2.72-2.80 (m, 2H), 2.92 (s, 6H), 3.44-3.54 (m, 2H), 3.54-3.60 (m, 2H), 4.38 -4.46 (m, 2H), 7.75 (t, J = 7.6Hz, 1H), 8.17 (dd, J = 0.8,7.6Hz, 1H), 8.25 (d, J = 8.8Hz, 1H), 8.41 (d, J = 8.8Hz, 1H), 8.61 (dd, J = 0.8,7.6Hz, 1H), 9.52 (br-s, 1H)
Elemental analysis value: C_{twenty two}H_{twenty one}N_ThreeO_Three・ HCl ・ 1H₂As O

[0105]
Example 5
5- [2- (Dimethylamino) ethyl] -10-hydroxy-10,11,12,13-tetrahydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -Dione
Embedded image

[0106]
0.5 g (1.2 mmol) of the compound of Example 4 was dissolved in a mixture of 50 ml of water and 25 ml of methanol, and 1.2 ml of 1N hydrochloric acid was added. About 4.5 kg / cm in the presence of palladium-carbon² Hydrogenation was performed at a pressure of. After confirming the end of the reaction by thin layer chromatography, the catalyst was filtered off and concentrated to about 2/3 volume. 50 ml of water and 5 ml of concentrated aqueous ammonia were added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (0.35 g).
FAB mass spectrometry m / z: 378 ([M + H]⁺ )
¹H-NMR (CDCl_Three) δ (ppm); 1.92-2.30 (m, 4H), 2.37 (s, 6H), 2.70 (t, J = 6.8Hz, 2H), 3.06-3.32 (m, 2H), 4.32 (t, J = 6.8) Hz, 2H), 4.95 (br-t, J = 4.8Hz, 1H), 7.52 (t, J = 7.6Hz, 1H), 7.67 (d, J = 8.4Hz, 1H), 8.09 (dd, J = 0.8 , 7.6Hz, 1H), 8.15 (dd, J = 0.8,7.6Hz, 1H), 8.33 (d, J = 8.4Hz, 1H)
Elemental analysis value: C_{twenty two}H_{twenty three}N_ThreeO_Three・ 1H₂As O

[0107]
Example 6
(+)-5- [2- (Dimethylamino) ethyl] -10-hydroxy-10,11,12,13-tetrahydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4, 6 (5H) -dione
Embedded image

[0108]
The compound of Example 5 was separated with an optical resolution column (Daicel, Chiralcel OD, eluted with n-hexane-2-propanol (7: 3 to 6: 4)), and the fraction eluted earlier was concentrated and dried. The title compound was obtained.
Melting point: 160-162 ° C
FAB mass spectrometry m / z: 378 ([M + H]⁺ )
¹H-NMR (CDCl_Three) δ (ppm); 1.90-2.30 (m, 4H), 2.43 (s, 6H), 2.77 (t, J = 6.4Hz, 2H), 3.04-3.31 (m, 2H), 4.34 (t, J = 6.8) Hz, 2H), 4.95 (br-t, J = 4.8Hz, 1H), 7.51 (t, J = 7.6Hz, 1H), 7.68 (d, J = 8.4Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 8.13 (d, J = 7.6Hz, 1H), 8.32 (d, J = 8.4Hz, 1H)
Elemental analysis value: C_{twenty two}H_{twenty three}N_ThreeO_Three・ 0.75H₂As O

[0109]
Example 7
11,12-dihydro-5- [2- (dimethylamino) ethyl] -4H, 10H-cyclopenta [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H) -trione hydrochloride
Embedded image

[0110]
The title compound was obtained from the compound of Production Example 10 by the same method as in Example 2.
Melting point: Coloring starts at around 255 ° C and gradually decomposes around 265 ° C.
FAB mass spectrometry m / z: 362 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) δ (ppm); 2.83-2.94 (m, 8H), 3.45 (br-s, 2H), 3.64 (br-t, J = 6.0Hz, 2H), 4.42 (br-t, J = 6.0Hz, 2H) ), 7.79 (t, J = 7.6Hz, 1H), 7.97 (d, J = 8.4Hz, 1H), 8.19 (dd, J = 0.8, 7.6Hz, 1H), 8.49 (d, J = 8.4Hz, 1H) ), 8.55 (dd, J = 0.8, 7.6Hz, 1H), 9.44 (br-s, 1H)
Elemental analysis value: C_{twenty one}H₁₉N_ThreeO_Three・ HCl ・ 0.75H₂As O

[0111]
Example 8
8- [2- (Dimethylamino) ethyl] -7H-furo [3,2-c] pyrimido [5,6,1-jk] carbazole-3,7,9 (2H, 8H) -trione hydrochloride
Embedded image

[0112]
590 mg (2.2 mmol) of the compound of Production Example 15 was dissolved in 20 ml of dimethylformamide, 720 mg (4.4 mmol) of N, N′-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 30 minutes. N, N-dimethylethylenediamine (0.97 ml, 8.8 mmol) was added, and the mixture was stirred overnight and concentrated. Water was added to the residue, and the mixture was extracted with a mixed solution of ethyl acetate and tetrahydrofuran. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and water, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 2,3-dihydro-N- [2- (dimethylamino) ethyl] -3-oxo-6H-furo [3,2-c] carbazole-7-carboxamide. 250 mg was obtained. This was dissolved in 10 ml of dimethylformamide, 60 mg (1.5 mmol) of sodium hydride (60% oily) was added, and the mixture was stirred for 30 minutes in a nitrogen atmosphere. Under ice-cooling, 0.145 ml (1.5 mmol) of ethyl chloroformate was added and stirred for 30 minutes, and then acidified with 1N hydrochloric acid. After concentration, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated, and the residue was purified by silica gel column chromatography. This was suspended in 20 ml of ethanol, 1 ml of 1N hydrochloric acid was added and stirred, and the crystals were collected by filtration to obtain 175 mg of the title compound.
Melting point: Coloring starts at around 240 ° C and decomposes at 270-273 ° C.
FAB mass spectrometry m / z: 364 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) δ (ppm); 2.89 (br-s, 6H), 3.42-3.50 (m, 2H), 4.39-4.45 (m, 2H), 5.14 (s, 2H), 7.78 (t, J = 7.7Hz, 1H ), 7.95 (d, J = 8.4Hz, 1H), 8.17 (dd, J = 0.8, 7.7Hz, 1H), 8.22 (d, J = 8.4Hz, 1H), 8.43 (dd, J = 0.8, 7.7Hz) , 1H), 9.62 (br-s, 1H)
Elemental analysis value: C₂₀H₁₇N_ThreeO_Four・ HCl ・ 0.15H₂As O

[0113]
Example 9
2,3-dihydro-8- [2- (dimethylamino) ethyl] -3-hydroxy-7H-furo [3,2-c] pyrimido [5,6,1-jk] carbazole-7,9 (8H) -Dione
Embedded image

[0114]
105.5 mg (0.29 mmol) of the compound of Example 8 was dissolved in 1 ml of acetic acid, and 36 μl of 8M borane / pyridine complex was added with stirring at room temperature, followed by stirring for 4.5 hours. Add 30 μl of 8M borane / pyridine complex, and stir overnight. Concentrate, extract with water, saturated aqueous sodium bicarbonate and chloroform, dry the organic layer with anhydrous sodium sulfate, concentrate, and concentrate the residue on a silica gel column. Purified by chromatography. The obtained product was recrystallized from ethanol-diisopropyl ether to obtain 22.6 mg of the title compound.
¹H-NMR (DMSO-d₆) δ (ppm); 2.24 (s, 6H), 2.56 (t, J = 6.8Hz, 2H), 4.15 (t, J = 6.8Hz, 2H), 4.56 (dd, J = 2.8, 10.0Hz, 1H) , 4.84 (dd, J = 6.8,10.0Hz, 1H), 5.43-5.49 (m, 1H), 5.80 (d, J = 5.6Hz, 1H), 7.61-7.67 (m, 2H), 7.97 (d, J = 8.4Hz, 1H), 8.02 (dd, J = 0.8,7.6Hz, 1H), 8.22 (dd, J = 0.8,7.6Hz, 1H)
[0115]
Example 10
12,13-Dihydro-5- [2- (methylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione hydrochloride
Embedded image

[0116]
0.23 g (0.57 mmol) of the compound of Production Example 17 and 95 mg (0.1 mmol) of tris (triphenylphosphine) rhodium chloride were dissolved in 20 ml of a mixture of acetonitrile and water (84:16). A mixture of acetonitrile and water (84:16) was added dropwise to keep the liquid volume constant while heating in a nitrogen atmosphere and distilling off the solvent. After this operation was continued for about 3 hours, disappearance of the raw materials was confirmed by thin layer chromatography. The reaction mixture was concentrated to about 1/4 volume, and extracted with ethyl acetate. The organic layer was separated, washed successively with dilute aqueous ammonia and brine, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin layer chromatography and then converted into a hydrochloride by the same method as in Example 4 to obtain the title compound (0.1 g).
Melting point: Coloring starts at around 250 ° C, gradually begins to decompose at around 260 ° C, and rapidly decomposes at 267-269 ° C
FAB mass spectrometry m / z: 362 ([M + H]⁺ )
¹H-NMR (DMSO-d₆・ D₂O mixture) δ (ppm); 2.24-2.34 (m, 2H), 2.59 (s, 3H), 2.76 (br-t, J = 6.0Hz, 2H), 3.31 (br-t, J = 5.2Hz, 2H) ), 3.56 (br-t, J = 6.0Hz, 2H), 4.36 (br-t, J = 5.2Hz, 2H), 7.75 (t, J = 8.0Hz, 1H), 8.16 (d, J = 8.0Hz , 1H), 8.24 (d, J = 8.8Hz, 1H), 8.39 (d, J = 8.8Hz, 1H), 8.59 (d, J = 8.0Hz, 1H)
Elemental analysis value: C_{twenty one}H₁₉N_ThreeO_Three・ HCl ・ 0.2H₂As O

[0117]
Example 11
12,13-dihydro-5- [2- (1-pyrrolidinyl) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione hydrochloric acid salt
Embedded image

[0118]
The title compound was obtained by reacting the compound of Production Example 7 and 1- (2-aminoethyl) pyrrolidine in the same manner as in Production Example 8 and Example 4.
Melting point: Coloring starts at around 235 ° C and gradually decomposes around 260 ° C.
FAB mass spectrometry m / z: 402 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 1.86 (br-s, 2H), 2.01 (br-s, 2H), 2.23-2.32 (m, 2H), 2.71-2.79 (m, 2H), 3.15 (br-s, 2H) , 3.46-3.74 (br-t + m, J = 6.0Hz, 4H + 2H), 4.40 (br-t, J = 5.2Hz, 2H), 7.73 (t, J = 8.0Hz, 1H), 8.15 (d , J = 8.0Hz, 1H), 8.23 (d, J = 8.8Hz, 1H), 8.39 (d, J = 8.8Hz, 1H), 8.57 (d, J = 8.0Hz, 1H), 10.10 (br-s , 1H)
Elemental analysis value: C_{twenty four}H_{twenty three}N_ThreeO_Three・ HCl ・ 1.5H₂As O

[0119]
Example 12
5- [2- (1-Pyrrolidinyl) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0120]
The title compound was obtained by reacting the compound of Production Example 2 and 1- (2-aminoethyl) pyrrolidine in the same manner as in Production Example 3 and Example 1.
FAB mass spectrometry m / z: 384 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm): 1.78-1.92 (m, 2H), 1.94-2.06 (m, 2H), 3.08-3.22 (m, 2H), 3.56 (t, J = 5.6Hz, 2H), 3.60-3.70 (m , 2H), 4.41 (t, J = 5.6Hz, 2H), 7.66 (t, J = 7.6Hz, 1H), 7.75 (t, J = 8.0Hz, 1H), 7.81 (t, J = 8.0Hz, 1H ), 8.11 (d, J = 7.6Hz, 1H), 8.18 (d, J = 8.0Hz, 1H), 8.21 (d, J = 9.2Hz, 1H), 8.60 (d, J = 9.2Hz, 1H), 8.83 (d, J = 8.0Hz, 1H), 8.98 (d, J = 7.6Hz, 1H), 10.29 (br-s, 1H)
Elemental analysis value: C_{twenty four}H_{twenty one}N_ThreeO_Three・ HCl ・ H₂As O

[0121]
Example 13
2- [2- (Dimethylamino) ethyl] -5-nitro-1H-benzo [c] pyrimido [5,6,1-kl] phenothiazine-1,3 (2H) -dione hydrochloride
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[0122]
To a solution of 200 mg (0.49 mmol) of Production Example 23 in 15 ml of tetrahydrofuran, 0.5 ml of triethylamine and 200 μl (2.09 mmol) of ethyl chloroformate were sequentially added with stirring at room temperature. After stirring overnight at room temperature, the mixture was concentrated and extracted by adding water, a saturated aqueous sodium hydrogen carbonate solution, and dichloromethane. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was recrystallized from ethanol to give 104 mg of the free base of the title compound. This was suspended in methanol, concentrated hydrochloric acid was added with stirring, and the mixture was concentrated to dryness to give the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.90 (s, 6H), 3.49 (br-s, 2H), 4.38 (t, J = 5.6Hz, 2H), 7.66 (t, J = 7.6Hz, 1H), 7.73 (t, J = 7.6Hz, 1H), 7.82 (d, J = 9.2Hz, 1H), 7.96 (d, J = 8.8Hz, 1H), 8.03 (d, J = 8.0Hz, 1H), 8.09 (d, J = 8.4Hz, 1H), 8.49-8.52 (m, 1H), 8.59-8.62 (m, 1H), 9.72 (br-s, 1H)
[0123]
Example 14
2- [2- (Dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] thieno [3,2-a] carbazole-1,3 (2H) -dione hydrochloride
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[0124]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from 4-oxo-4,5,6,7-tetrahydro-benzo [b] thiophene and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.92 (br-s, 6H), 3.44-3.57 (m, 2H), 4.44-4.51 (m, 2H), 7.74 (t, J = 7.6Hz, 1H), 7.98 (d, J = 5.6Hz, 1H), 8.13 (dd, J = 0.8,7.6Hz, 1H), 8.26 (d, J = 8.4Hz, 1H), 8.36 (d, J = 8.4Hz, 1H), 8.65 (dd, J = 0.8,7.6Hz, 1H), 8.84 (d, J = 5.6Hz, 1H), 9.53 (br-s, 1H)
[0125]
Example 15
2,3-dihydro-9- [2- (dimethylamino) ethyl] -4H, 8H-pyrano [3,2-c] pyrimido [5,6,1-jk] carbazole-4,8,10 (9H) -Trione hydrochloride
Embedded image

[0126]
The title compound was obtained in the same manner as in Example 2.
FAB mass spectrometry m / z: 378 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 2.88 (s, 6H), 2.99 (t, J = 6.4Hz, 2H), 3.46 (br-s, 2H), 4.40 (br-t, J = 5.6Hz, 2H), 4.89 ( t, J = 6.4Hz, 2H), 7.73 (t, J = 7.6Hz, 1H), 8.06 (d, J = 8.4Hz, 1H), 8.09 (d, J = 8.4Hz, 1H), 8.12 (d, J = 7.6Hz, 1H)), 8.42 (d, J = 7.6Hz, 1H), 9.68 (br-s, 1H)
Elemental analysis value: C_{twenty one}H₁₉N_ThreeO_Four・ HCl ・ 1.25H₂O

[0127]
Example 16
9- [2- (Dimethylamino) ethyl] -4H, 8H-pyrano [3,2-c] pyrimido [5,6,1-jk] carbazole-4,8,10 (9H) -trione hydrochloride
Embedded image

[0128]
The title compound was obtained in the same manner as in Example 2.
FAB mass spectrometry m / z: 376 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (s, 6H), 3.46 (br-s, 2H), 4.43 (br-t, J = 5.6Hz, 2H), 6.55 (d, J = 6.0Hz, 1H), 7.83 ( t, J = 7.6Hz, 1H), 8.23 (dd, J = 0.8,7.6Hz, 1H), 8.34 (d, J = 8.8Hz, 1H), 8.48 (d, J = 8.8Hz, 1H), 8.54 ( d, J = 6.0Hz, 1H)), 8.65 (dd, J = 0.8,7.6Hz, 1H), 9.52 (br-s, 1H)
[0129]
Example 17
2- [2- (Dimethylamino) ethyl] -1H-furo [3,2-a] pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride
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[0130]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from 4-oxo-4,5,6,7-tetrahydro-benzo [b] furan and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.91 (br-s, 6H), 3.40-3.55 (m, 2H), 4.41-4.51 (m, 2H), 7.72 (t, J = 7.6Hz, 1H), 7.83 (d, J = 2.0Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 8.09 (d, J = 7.6Hz, 1H), 8.20 (d, J = 2.0Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H)), 8.61 (d, J = 7.6Hz, 1H), 9.46 (br-s, 1H)
[0131]
Example 18
2- [2- (Dimethylamino) ethyl] -1H-benzo [a] pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride
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[0132]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from α-tetralone and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (s, 6H), 3.49 (br-s, 2H), 4.49 (t, J = 5.5Hz, 2H), 7.64-7.71 (m, 2H), 7.74 (t, J = 8.0 Hz, 1H), 8.11-8.18 (m, 3H), 8.44 (d, J = 8.3Hz, 1H), 8.66 (d, J = 8.0Hz, 1H), 9.59 (br-s, 1H), 9.76 (d , J = 8.3Hz, 1H)
Elemental analysis value: C_{twenty two}H₁₉N_ThreeO₂・ HCl ・ 0.2H₂As O

[0133]
Example 19
5- [3- (Dimethylamino) propyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0134]
The compound of Production Example 2 and N, N-dimethyl-1,3-propanediamine were reacted in the same manner as in Production Example 3 and Example 1 to obtain the title compound.
FAB mass spectrometry m / z: 372 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 2.03-2.13 (m, 2H), 2.74 (s, 6H), 3.19 (t, J = 8.0Hz, 2H), 4.12 (t, J = 6.0Hz, 2H), 7.65 (t, J = 7.2Hz, 1H), 7.75 (t, J = 8.0Hz, 1H), 7.81 (t, J = 7.6Hz, 1H), 8.10 (d, J = 7.6Hz, 1H), 8.16 (d, J = 8.0Hz, 1H), 8.19 (d, J = 9.6Hz, 1H), 8.58 (d, J = 9.6Hz, 1H), 8.80 (t, J = 8.4Hz, 1H), 8.94 (d, J = 8.0Hz , 1H), 9.69 (br-s, 1H)
Elemental analysis value: C_{twenty three}H_{twenty one}N_ThreeO₂・ HCl ・ 0.3H₂As O

[0135]
Example 20
2- [2- (Dimethylamino) ethyl] -1H, 11H-indeno [1 ′, 2 ′: 4,5] pyrrolo [3,2,1-ij] quinazoline-1,3 (2H) -dione hydrochloride
Embedded image

[0136]
The title compound was obtained in the same manner as in Production Examples 1, 3 and Example 2 from 2-indanone and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (CD_ThreeOD) δ (ppm); 3.02 (s, 6H), 3.53 (t, J = 5.8Hz, 2H), 4.10 (s, 2H), 4.50 (t, J = 5.8Hz, 2H), 7.28 (dt, J = 1.2,7.6Hz, 1H), 7.41 (dt, J = 1.0,7.6Hz, 1H), 7.56-7.59 (m, 1H), 7.62 (t, J = 7.7Hz, 1H), 7.76-7.79 (m, 1H), 8.02 (dd, J = 0.8, 7.7Hz, 1H), 8.25 (dd, J = 0.8, 7.7Hz, 1H)
[0137]
Example 21
7- [2- (Dimethylamino) ethyl] -6H, 14H-benzo [a] pyrimido [5,6,1-de] acridine-6,8,14 (7H) -trione hydrochloride
Embedded image

[0138]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.91 (br-s, 6H), 3.50-3.56 (m, 2H), 4.49 (t, J = 5.7Hz, 2H), 7.64-7.69 (m, 1H), 7.77-7.82 (m , 1H), 7.87-7.92 (m, 1H), 7.98-8.03 (m, 1H), 8.37-8.40 (m, 1H), 8.43-8.46 (m, 1H), 8.63 (dd, J = 0.5,8.8Hz , 1H), 9.26 (s, 1H), 9.81 (dd, J = 0.7,8.6Hz, 1H), 10.04 (br-s, 1H)
[0139]
Example 22
5- [2- (Dimethylamino) ethyl] -11-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0140]
The title compound was obtained in the same manner as in Production Examples 24, 3 and Example 2 from 6-methoxy-β-tetralone and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.93 (d, J = 4.6 Hz, 6H), 3.47-3.54 (m, 2H), 3.94 (s, 3H), 4.39-4.45 (m, 2H), 7.46 (dd, J = 2.2) , 9.0Hz, 1H), 7.62 (d, J = 2.2Hz, 1H), 7.78 (t, J = 8.4Hz, 1H), 8.14 (d, J = 8.4Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.59 (d, J = 9.0Hz, 1H), 8.78 (d, J = 9.0Hz, 1H), 9.01 (d, J = 8.4Hz, 1H), 9.16 (br-s, 1H)
Elemental analysis value: C_{twenty three}H_{twenty one}N_ThreeO_Three・ HCl ・ 1.5H₂As O

[0141]
Example 23
5- [2- (Dimethylamino) ethyl] -10-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0142]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from 5-methoxy-β-tetralone and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (s, 6H), 3.44-3.51 (m, 2H), 4.04 (s, 3H), 4.40 (t, J = 6.2Hz, 2H), 7.12 (d, J = 8.2Hz, 1H), 7.72 (t, J = 8.5Hz, 1H), 7.73 (dt, J = 3.4,8.2Hz, 1H), 8.09 (d, J = 8.5Hz, 1H), 8.32 (d, J = 8.5Hz, 1H), 8.41 (d, J = 8.5Hz, 1H), 8.52 (dd, J = 1.0,8.5Hz, 1H), 8.88 (d, J = 8.5Hz, 1H), 9.93 (br-s, 1H)
Elemental analysis value: C_{twenty three}H_{twenty one}N_ThreeO_Three・ HCl ・ 1.3H₂As O

[0143]
Example 24
2- [2- (Dimethylamino) ethyl] -1H-benzo [b] pyrimido [1,6,5-lm] -4-azacarbazole-1,3 (2H) -dione dihydrochloride
Embedded image

[0144]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.90 (s, 6H), 3.47-3.55 (m, 2H), 4.48 (t, J = 6.3Hz, 2H), 7.67 (t, J = 7.8Hz, 1H), 7.86-7.95 ( m, 3H), 8.36-8.44 (m, 3H), 9.24-9.29 (m, 1H), 10.41 (br-s, 1H)
[0145]
Example 25
1,2-dihydro-9- [2- (dimethylamino) ethyl] -4H, 8H-pyrano [3,4-c] pyrimido [5,6,1-jk] carbazole-4,8,10 (9H) -Trione hydrochloride
Embedded image

[0146]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (s, 6H), 3.47 (t, J = 6.0Hz, 2H), 3.64 (t, J = 6.0Hz, 2H), 4.38 (t, J = 6.0Hz, 2H), 4.68 (t, J = 6.0Hz, 2H), 7.73 (t, J = 7.6Hz, 1H), 8.15 (t, J = 7.6Hz, 1H), 8.27 (d, J = 8.8Hz, 1H), 8.44 (d , J = 8.8Hz, 1H), 8.55 (d, J = 7.6Hz, 1H), 9.82 (br-s, 1H)
[0147]
Example 26
5- [2- (Dimethylamino) ethyl] -12-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0148]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from 7-methoxy-β-tetralone and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.85 (br-s, 6H), 3.35-3.46 (m, 2H), 4.08 (s, 3H), 4.39 (br-s, 2H), 7.32 (dd, J = 2.2, 8.8Hz , 1H), 7.79 (t, J = 7.8Hz, 1H), 7.99 (d, J = 1.7Hz, 1H), 8.09-8.19 (m, 3H), 8.48 (d, J = 8.8Hz, 1H), 8.97 (d, J = 7.8Hz, 1H), 9.25 (br-s, 1H)
[0149]
Example 27
2- [2- (Dimethylamino) ethyl] -5-nitro-1H-benzo [b] pyrimido [5,6,1-kl] phenoxazine-1,3 (2H) -dione hydrochloride
Embedded image

[0150]
304 mg (1.91 mmol) of 3-amino-2-naphthol, 477 mg (1.81 mmol) of 2-chloro-3,5-dinitrobenzoic acid methyl ester and 178 mg (2.17 mmol) of sodium acetate were suspended in a mixture of 5 ml of water and 10 ml of ethanol, The mixture was heated to reflux for 7 hours. 3 ml of 2N sodium hydroxide aqueous solution was added, and the mixture was further heated under reflux for 2.5 hours, returned to room temperature, and then 10 ml of 1N hydrochloric acid was added to form a precipitate. The precipitate was collected by filtration and washed successively with water, 1N hydrochloric acid and ethanol to obtain 430 mg of 3-nitro-12H-benzo [b] phenoxazine-1-carboxylic acid. The title compound was obtained in the same manner as in Production Example 23 and Example 13.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (s, 6H), 3.45 (t, J = 5.2Hz, 2H), 4.40 (t, J = 5.2Hz, 2H), 7.47 (t, J = 8.0Hz, 1H), 7.52 (t, J = 8.0Hz, 1H), 7.69 (s, 1H), 7.86 (d, J = 6.8Hz, 1H), 7.88 (d, J = 8.0Hz, 1H), 8.19 (d, J = 2.4Hz , 1H), 8.34 (d, J = 2.4Hz, 1H), 9.05 (s, 1H), 9.82 (br-s, 1H)
[0151]
Example 28
2-Chloro-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0152]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from β-tetralone and 5-chloro-2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (br-s, 6H), 3.39-3.53 (m, 2H), 4.38-4.48 (m, 2H), 7.68-7.75 (m, 1H), 7.81-7.89 (m, 1H) , 8.13 (d, J = 1.6Hz, 1H), 8.22 (d, J = 8.4Hz, 1H), 8.31 (d, J = 8.8Hz, 1H), 8.63 (d, J = 8.8Hz, 1H), 8.94 (d, J = 8.4Hz, 1H), 9.14 (d, J = 1.6Hz, 1H), 9.46 (br-s, 1H)
Elemental analysis value: C_{twenty two}H₁₈N_ThreeO₂Cl ・ HCl ・ 1.75H₂As O

[0153]
Example 29
9- [2- (Dimethylamino) ethyl] -8H-pyrido [4,3-c] pyrimido [5,6,1-jk] carbazole-1,8,10 (2H, 9H) -trione hydrochloride
Embedded image

[0154]
After saponifying the ester of the compound of Production Example 20, the title compound was obtained in the same manner as in Production Example 3 and Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.90 (br-s, 6H), 3.43-3.53 (m, 2H), 4.40-4.46 (m, 2H), 6.80-6.83 (m, 1H), 7.34-7.38 (m, 1H) , 7.73 (t, J = 7.9Hz, 1H), 8.01 (d, J = 8.9Hz, 1H), 8.18 (dd, J = 0.9,7.9Hz, 1H), 8.89 (d, J = 8.9Hz, 1H) , 9.52 (br-s, 1H), 9.91 (dd, J = 0.9,7.9Hz, 1H), 11.67-11.71 (m, 1H)
Elemental analysis value: C_{twenty one}H₁₈N_FourO_Three・ HCl ・ 1.3H₂As O

Example 30
5- [2- (Dimethylamino) ethyl] -4H-quino [4 ′, 3′-4,5] pyrrolo [3,2,1-ij] quinazoline-4,6 (5H) -dione dihydrochloride
Embedded image

[0155]
The title compound was obtained in the same manner as in Production Example 2.
FAB mass spectrometry m / z; 359 ([M + H]⁺ )
¹H-NMR (DMSO-d₆+ D₂O) δ (ppm); 2.94 (s, 6H), 3.54 (br-t, J = 5.6Hz, 2H), 4.47 (br-t, J = 5.6Hz, 2H), 7.89 (t, J = 7.6Hz) , 1H), 7.91-7.99 (m, 2H), 8.30-8.37 (m, 2H), 8.89-8.95 (m, 1H), 9.16 (d, J = 7.6Hz, 1H), 9.97 (s, 1H)
Elemental analysis value: C_{twenty one}H₁₈N_FourO₂・ 2HCl ・ 0.5H₂As O

[0156]
Example 31
5-amino-2- [2- (dimethylamino) ethyl] -1H-benzo [b] pyrimido [5,6,1-kl] phenoxazine-1,3 (2H) -dione dihydrochloride
Embedded image

[0157]
268 mg (0.641 mmol) of the free base of the compound of Example 27 was dissolved in 10 ml of acetic acid, 10% palladium carbon was added, and catalytic reduction was performed at room temperature in a hydrogen atmosphere. The palladium carbon was removed by filtration through Celite, the filtrate was concentrated, water and a saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was stirred at room temperature. The precipitate was filtered, washed with water, suspended in methanol, and concentrated hydrochloric acid was added. Upon stirring at room temperature, a homogeneous solution was formed, and a precipitate was formed, which was collected by filtration to give 179 mg of the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (s, 6H), 3.43 (t, J = 5.6Hz, 2H), 4.34 (t, J = 5.6Hz, 2H), 6.76 (s, 1H), 6.96 (s, 1H) , 7.38-7.48 (m, 2H), 7.59 (s, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 9.15 (s, 1H), 9.65 ( br-s, 1H)
[0158]
Example 32
5- [2- (Dimethylamino) ethyl] -13-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0159]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from 8-methoxy-β-tetralone and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.91 (br-s, 6H), 3.40-3.53 (m, 2H), 4.23 (s, 3H), 4.40-4.49 (m, 2H), 7.33 (d, J = 7.6Hz, 1H ), 7.61 (t, J = 8.0Hz, 1H), 7.72-7.79 (m, 2H), 8.15 (d, J = 8.0Hz, 1H), 8.23 (d, J = 8.8Hz, 1H), 8.82 (d , J = 8.8Hz, 1H), 9.09 (d, J = 8.0Hz, 1H), 9.35 (br-s, 1H)
Elemental analysis value: C_{twenty three}H_{twenty one}N_ThreeO_Three・ HCl ・ 0.65H₂As O

[0160]
Example 33
9- [2- (Dimethylamino) ethyl] -8H-pyrido [4,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) -dione dihydrochloride
Embedded image

[0161]
300 mg (1.1 mmol) of the compound of Production Example 21 was dissolved in a mixed solution of 10 ml of tetrahydrofuran and 10 ml of methanol, 5 ml of 1N sodium hydroxide was added, and the mixture was heated under reflux for 1 hour, and then 7H-pyrido [4,3- c] Carbazole-8-carboxylic acid was dissolved in 40 ml of dimethylformamide, and 360 mg (2.2 mmol) of N, N'-carbonyldiimidazole was added. After stirring at room temperature for 30 minutes, 0.48 ml (4.4 mmol) of N, N-dimethylethylenediamine was added and stirred overnight. After concentration, water and ethyl acetate were added for extraction, and the organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and water, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 250 mg of N- [2- (dimethylamino) ethyl] -7H-pyrido [4,3-c] carbazole-8-carboxamide. This was reacted and processed in the same manner as Example 2 to give 110 mg of the title compound.
Melting point: Coloring starts at around 270 ° C and decomposes at 279 ° C.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89-2.93 (m, 6H), 3.49-3.54 (m, 2H), 4.46 (t, J = 6.0Hz, 2H), 7.85 (t, J = 7.6Hz, 1H), 8.25 ( d, J = 7.6Hz, 1H), 8.40-8.44 (m, 2H), 8.79 (d, J = 6.4Hz, 1H), 9.04 (d, J = 9.2Hz, 1H), 9.23 (d, J = 7.6 Hz, 1H), 10.10 (br-s, 1H), 10.44 (s, 1H)
Elemental analysis value: C_{twenty one}H₁₈N_FourO₂・ 2HCl ・ 2H₂As O

[0162]
Example 34
5- [4- (Dimethylamino) butyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0163]
The title compound was obtained by reacting the compound of Production Example 2 with N, N-dimethyl-1,4-butanediamine in the same manner as in Production Example 3 and Example 1.
FAB mass spectrometry m / z; 386 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 1.68-1.85 (m, 4H), 2.74 (s, 6H), 3.09 (br-t, J = 6.4Hz, 2H), 4.10 (br-t, J = 6.4Hz, 2H), 7.64-7.70 (m, 1H), 7.75 (t, J = 7.6Hz, 1H), 7.79-7.85 (m, 1H), 8.11 (d, J = 7.6Hz, 1H), 8.16-8.24 (m, 2H) , 8.62 (d, J = 8.8Hz, 1H), 8.83 (d, J = 8.4Hz, 1H), 8.97 (d, J = 7.6Hz, 1H), 9.99 (br-s, 1H)
Elemental analysis value: C_{twenty four}H_{twenty three}N_ThreeO₂・ HCl ・ 0.5H₂As O

[0164]
Example 35
11-cyano-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0165]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.93 (s, 6H), 3.48-3.55 (m, 2H), 4.46 (t, J = 5.6Hz, 2H), 7.83 (t, J = 8.2Hz, 1H), 8.10 (dd, J = 1.3,8.9Hz, 1H), 8.21 (d, J = 8.2Hz, 1H), 8.38 (d, J = 8.9Hz, 1H), 8.79 (d, J = 8.9Hz, 1H), 8.88 (d, J = 1.3Hz, 1H), 9.04 (d, J = 8.9Hz, 1H), 9.10 (d, J = 8.2Hz, 1H)
[0166]
Example 36
9- [2- (Dimethylamino) ethyl] -8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) -dione dihydrochloride
Embedded image

[0167]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.92 (s, 3H), 2.93 (s, 3H), 3.46-3.58 (m, 2H), 4.41-4.51 (m, 2H), 7.82 (t, J = 8.0Hz, 1H), 7.92 (dd, J = 4.8,8.4Hz, 1H), 8.21 (d, J = 8.0Hz, 1H), 8.40 (d, J = 9.2Hz, 1H), 8.92 (d, J = 9.2Hz, 1H), 9.10 (d, J = 8.0Hz, 1H), 9.14 (dd, J = 0.8,4.8Hz, 1H), 9.47 (dd, J = 0.8,8.4Hz, 1H), 9.86 (br-s, 1H)
Elemental analysis value: C_{twenty one}H₁₈N_FourO₂・ 2HCl ・ 0.75H₂As O

[0168]
Example 37
5- [2- (Dimethylamino) ethyl] -2-nitro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0169]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from β-tetralone and 5-nitro-2-hydrazinobenzoic acid.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (s, 6H), 3.44-3.52 (m, 2H), 4.45 (t, J = 5.2Hz, 2H), 7.73 (t, J = 8.1Hz, 1H), 7.90 (t, J = 8.1Hz, 1H), 8.23 (d, J = 8.1Hz, 1H), 8.35 (d, J = 9.2Hz, 1H), 8.63 (d, J = 9.2Hz, 1H), 8.80 (d, J = 1.8Hz, 1H), 8.94 (d, J = 8.1Hz, 1H), 9.64 (d, J = 1.8Hz, 1H), 9.75 (br-s, 1H)
[0170]
Example 38
5- [2- (Dimethylamino) ethyl] -2-methyl-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0171]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from β-tetralone and 2-hydrazino-5-methyl-benzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.71 (s, 3H), 2.90 (br-s, 6H), 3.38-3.55 (m, 2H), 4.39-4.46 (m, 2H), 7.66-7.72 (m, 1H), 7.81 -7.88 (m, 1H), 7.97-8.00 (m, 1H), 8.18-8.23 (m, 1H), 8.22-8.27 (m, 1H), 8.63 (d, J = 9.2Hz, 1H), 8.88-8.95 (m, 2H)
Elemental analysis value: C_{twenty three}H_{twenty one}N_ThreeO₂・ HCl ・ 1.5H₂As O

[0172]
Example 39
1,2-dihydro-9- [2- (dimethylamino) ethyl] -8H-pyrido [3,4-c] pyrimido [5,6,1-jk] carbazole-4,8,10 (3H, 9H) -Trione hydrochloride
Embedded image

[0173]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.88 (br-s, 6H), 3.37-3.52 (m, 2H), 3.50-3.64 (m, 4H), 4.36-4.44 (m, 2H), 7.73 (t, J = 7.6Hz , 1H), 8.11 (br-s, 1H), 8.15 (dd, J = 0.8,7.6Hz, 1H), 8.22 (d, J = 8.4Hz, 1H), 8.40 (d, J = 8.4Hz, 1H) , 8.57 (dd, J = 0.8,7.6Hz, 1H)
Elemental analysis value: C_{twenty one}H₂₀N_FourO_Three・ HCl ・ H₂As O

[0174]
Example 40
8- [2- (Dimethylamino) ethyl] -7H-1,3-dioxolo [4,5-c] pyrimido [5,6,1-jk] carbazole-7,9 (8H) -dione hydrochloride
Embedded image

[0175]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.90 (br-s, 6H), 3.42-3.49 (m, 2H), 4.36-4.42 (m, 2H), 6.35 (s, 2H), 7.29 (d, J = 8.4Hz, 1H ), 7.68 (t, J = 7.7Hz, 1H), 7.89 (d, J = 8.4Hz, 1H), 8.10 (dd, J = 0.8, 7.7Hz, 1H), 8.27 (dd, J = 0.8, 7.7Hz) , 1H), 9.35 (br-s, 1H)
[0176]
Example 41
11-Bromo-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0177]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from 6-bromo-β-tetralone and 2-hydrazinobenzoic acid hydrochloride.
FAB mass spectrometry m / z; 436 ([M + H]⁺ ), 438 ([M + 2 + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 2.90 (s, 6H), 3.48 (br-s, 2H), 4.42 (t, J = 5.6Hz, 2H), 7.77 (t, J = 7.6Hz, 1H), 7.89 (dd, J = 2.0,8.8Hz, 1H), 8.14 (d, J = 7.2Hz, 1H), 8.20 (d, J = 8.8Hz, 1H), 8.47 (d, J = 2.0Hz, 1H), 8.63 (d, J = 8.8Hz, 1H), 8.79 (d, J = 9.2Hz, 1H), 8.97 (d, J = 8.0Hz, 1H), 9.74 (br-s, 1H)
Elemental analysis value: C_{twenty two}H₁₈N_ThreeO₂Br ・ HCl ・ 0.6H₂As O

[0178]
Example 42
2- [2- (Dimethylamino) ethyl] -1H-benzo [b] pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride
Embedded image

[0179]
The title compound was obtained in the same manner as in Example 2.
FAB mass spectrometry m / z; 358 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 2.90 (br-s, 6H), 3.39-3.53 (m, 2H), 4.37-4.48 (m, 2H), 7.60-7.70 (m, 2H), 7.73 (t, J = 7.6Hz , 1H), 8.13 (dd, J = 0.8,7.6Hz, 1H), 8.16-8.20 (m, 1H), 8.21-8.26 (m, 1H), 8.66 (dd, J = 0.8,7.6Hz, 1H), 8.86 (s, 1H), 8.93 (s, 1H)
Elemental analysis value: C_{twenty two}H₁₉N_ThreeO₂・ As HCl

[0180]
Example 43
5- [2- (Dimethylamino) ethyl] -10,11,12,13-tetrahydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0181]
The title compound was obtained from the compound of Example 4 by a method similar to that in Example 5.
FAB mass spectrometry m / z; 362 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 1,79-2.01 (m, 4H), 2.89 (s, 6H), 2.90 (br-t, J = 6.0Hz, 2H), 3.24 (br-t, J = 6.0Hz, 2H) ), 3.46 (br-t, J = 5.6Hz, 2H), 4.39 (br-t, J = 6.0Hz, 2H), 7.38 (d, J = 8.8Hz, 1H), 7.65 (t, J = 8.0Hz) , 1H), 8.06 (d, J = 8.0Hz, 1H), 8.13 (d, J = 8.8Hz, 1H), 8.41 (dd, J = 0.8,8.0Hz, 1H), 9.74 (br-s, 1H)
Elemental analysis value: C_{twenty two}H_{twenty three}N_ThreeO₂・ HCl ・ 0.75H₂As O

[0182]
Example 44
12,13-dihydro-11,11-dimethyl-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione hydrochloride
Embedded image

[0183]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 1.20 (s, 6H), 2.13 (t, J = 6.1Hz, 2H), 2.88 (s, 6H), 3.43 (br-s, 2H), 3.52 (t, J = 6.1Hz, 2H), 4.38 (t, J = 5.7Hz, 2H), 7.71 (t, J = 7.4Hz, 1H), 8.11 (d, J = 7.4Hz, 1H), 8.20 (d, J = 8.8Hz, 1H) , 8.35 (d, J = 8.8Hz, 1H), 8.54 (d, J = 7.4Hz, 1H), 10.08 (br-s, 1H)
Elemental analysis value: C_{twenty four}H_{twenty five}N_ThreeO_Three・ HCl ・ H₂As O

[0184]
Example 45
5- [2- (Dimethylamino) ethyl] -2-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0185]
The title compound was obtained in the same manner as in Production Examples 1, 2, 3 and Example 2 from β-tetralone and 2-hydrazino-5-methoxybenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (br-s, 6H), 3.40-3.52 (m, 2H), 4.03 (s, 3H), 4.40 (t, J = 6.0Hz, 2H), 7.60 (d, J = 2.4) Hz, 1H), 7.63-7.70 (m, 1H), 7.76-7.85 (m, 1H), 8.17 (dd, J = 0.4,8.4Hz, 1H), 8.21 (d, J = 8.8Hz, 1H), 8.49 (d, J = 2.4Hz, 1H), 8.57 (d, J = 8.8Hz, 1H), 8.84 (dd, J = 0.4,8.4Hz, 1H), 9.57 (br-s, 1H)
Elemental analysis value: C_{twenty three}H_{twenty one}N_ThreeO_Three・ HCl ・ H₂As O

[0186]
Example 46
5- [2- (Dimethylamino) ethyl] -11-hydroxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
Embedded image

[0187]
The compound of Example 22 was heated to reflux in 47% hydrobromic acid, and then the reaction mixture was subjected to catalytic reduction at room temperature using palladium on carbon as a catalyst in methanol. The title compound was obtained by converting the product to hydrochloride by a conventional method.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.92 (d, J = 5.5Hz, 6H), 3.48 (q, J = 5.5Hz, 2H), 4.41 (t, J = 5.5Hz, 2H), 7.36-7.42 (m, 2H) , 7.73 (t, J = 8.1Hz, 1H), 8.00 (d, J = 9.4Hz, 1H), 8.11 (d, J = 8.1Hz, 1H), 8.49 (d, J = 8.1Hz, 1H), 8.71 (d, J = 9.4Hz, 1H), 8.94 (d, J = 8.1Hz, 1H), 9.60 (br-s, 1H), 10.01 (br-s, 1H)
[0188]
Example 47
2-Amino-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione dihydrochloride
Embedded image

[0189]
The compound of Example 37 was hydrogenated at normal temperature and pressure in the presence of a palladium carbon catalyst to give the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (d, J = 4.1Hz, 6H), 3.44-3.51 (m, 2H), 4.40 (t, J = 5.8Hz, 2H), 7.67 (t, J = 8.2Hz, 1H) , 7.77 (s, 1H), 7.84 (t, J = 8.2Hz, 1H), 8.19 (d, J = 8.2Hz, 1H), 8.22 (d, J = 9.3Hz, 1H), 8.57 (d, J = 9.3Hz, 1H), 8.61 (d, J = 8.2Hz, 1H), 8.63 (s, 1H), 9.94 (br-s, 1H)
[0190]
Example 48
5- [2- (Dimethylamino) ethyl] -11- (4-methylbenzenesulfonamido) -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloric acid salt
[Chemical Formula 86]

[0191]
N- [2- (dimethylamino) ethyl] -3- (4-methylbenzenesulfonamido) -7H-benzo [c] carbazole-8-carboxamide obtained by preparing the compound of Production Example 24 in the same manner as in Production Example 3. Is reacted with sodium hydride and ethyl chloroformate in dimethylformamide under ice-cooling to give 5- [2- (dimethylamino) ethyl] -11- (N-ethoxycarbonyl-4-methylbenzenesulfonamide) -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione was obtained. This was treated with 1N aqueous sodium hydroxide solution in a methanol-tetrahydrofuran (1: 1) mixed solution, then converted into hydrochloride by a conventional method, and recrystallized from ethanol to obtain the title compound.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.28 (s, 3H), 2.90 (s, 6H), 3.48 (br-s, 2H), 4.41 (t, J = 5.6Hz, 2H), 7.33 (d, J = 9.2Hz, 2H), 7.60 (d, J = 8.8Hz, 1H), 7.70-7.78 (m, 3H), 7.82 (s, 1H), 8.09 (d, J = 9.2Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 8.4Hz, 1H), 8.76 (d, J = 8.4Hz, 1H), 8.94 (d, J = 8.4Hz, 1H), 9.56 (br-s, 1H), 10.68 (s, 1H)
[0192]
Example 49
11-amino-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione dihydrochloride
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[0193]
341 mg (0.648 mmol) of the free base of the compound of Example 48 and 419 mg (4.45 mmol) of phenol were refluxed for 9 hours and 30 minutes in 15 ml of 47% hydrobromic acid, then returned to room temperature, and saturated aqueous sodium hydrogen carbonate solution was added. In addition, it was made basic. Ethyl acetate and tetrahydrofuran were added thereto for extraction, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated, and the resulting residue was recrystallized from ethanol to obtain 141 mg of the free base of the title compound. This was converted to a hydrochloride by a conventional method to obtain the title compound.
(Free base)¹H-NMR (DMSO-d₆) Δ (ppm); 2.22 (s, 6H), 2.55 (t, J = 6.8Hz, 2H), 4.14 (t, J = 6.8Hz, 2H), 5.50-5.53 (m, 2H), 7.06 (d, J = 2.0Hz, 1H), 7.22 (dd, J = 2.4,9.2Hz, 1H), 7.67 (t, J = 8.0Hz, 1H), 7.79 (d, J = 9.2Hz, 1H), 8.03 (d, J = 8.0Hz, 1H), 8.38 (d, J = 8.8Hz, 1H), 8.52 (d, J = 9.2Hz, 1H), 8.84 (d, J = 7.6Hz, 1H)
[0194]
Example 50
11-acetamido-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
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[0195]
4 ml of triethylamine and 2 ml of acetic anhydride were successively added to a suspension of 141 mg (0.379 mmol) of the free base of Example 49 in 20 ml of dichloromethane at room temperature, and stirring was continued for 16 hours. After concentration, 30 ml of methanol was added to the residue, and the mixture was made basic by adding a saturated aqueous sodium hydrogen carbonate solution with stirring. The precipitate was collected by filtration and washed with water. The obtained solid was suspended in ethanol, concentrated hydrochloric acid was added with stirring at room temperature, methanol and dichloromethane were further added, and stirring was continued. After concentration, ethanol was added, and the mixture was heated to reflux, and then returned to room temperature.
FAB mass spectrometry m / z; 415 ([M + H]⁺ )
¹H-NMR (DMSO-d₆) Δ (ppm); 2.13 (s, 3H), 2.90 (s, 3H), 2.91 (s, 3H), 3.44-3.52 (m, 2H), 4.42 (t, J = 5.6Hz, 2H), 7.76 ( t, J = 8.0Hz, 1H), 7.89 (dd, J = 1.6,9.2Hz, 1H), 8.06-8.14 (m, 2H), 8.52 (d, J = 1.6Hz, 1H), 8.54 (d, J = 9.2Hz, 1H), 8.79 (d, J = 8.8Hz, 1H), 8.98 (d, J = 8.0Hz, 1H), 9.60 (br-s, 1H), 10.35 (s, 1H)
Elemental analysis value: C_{twenty four}H_{twenty two}N_FourO_Three・ HCl ・ 0.6H₂As O

[0196]
Example 51
5- [2- [N- [2- (Dimethylamino) ethyl] -N-methylamino] ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -Dione dihydrochloride
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[0197]
The title compound was obtained in the same manner as in Example 2.
(Free base)¹H-NMR (CDCl_Three) Δ (ppm); 2.20 (s, 6H), 2.42 (t, J = 7.2Hz, 2H), 2.45 (s, 3H), 2.63 (t, J = 7.2Hz, 2H), 2.81 (t, J = 7.2Hz, 2H), 4.35 (t, J = 7.2Hz, 2H), 7.59 (t, J = 7.8Hz, 1H), 7.64 (t, J = 7.8Hz, 1H), 7.74 (t, J = 7.8Hz , 1H), 8.01 (d, J = 9.2Hz, 1H), 8.03 (d, J = 7.8Hz, 1H), 8.14 (d, J = 7.8Hz, 1H), 8.56-8.61 (m, 2H), 8.66 (d, J = 9.2Hz, 1H)
Elemental analysis value: C_{twenty five}H₂₆N_FourO₂・ 2HCl ・ 0.8H₂As O

[0198]
Example 52
5- [2- [N- (2-hydroxyethyl) -N-methylamino] ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloric acid salt
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[0199]
The title compound was obtained in the same manner as in Example 2.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.93 (s, 3H), 3.14-3.67 (m, 4H), 3.71-3.80 (m, 2H), 4.40-4.49 (m, 2H), 5.33-5.39 (m, 1H), 7.64 -7.70 (m, 1H), 7.73-7.86 (m, 2H), 8.10-8.26 (m, 3H), 8.59-8.65 (m, 1H), 8.83-8.89 (m, 1H), 9.00-9.04 (m, 1H), 9.60 (br-s, 1H)
Elemental analysis value: C_{twenty three}H_{twenty one}N_ThreeO_Three・ HCl ・ 1.1H₂As O

[0200]
Example 53
5- [2- (Dimethylamino) ethyl] -2-hydroxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione hydrochloride
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[0201]
The title compound was obtained by treating the compound of Example 45 in the same manner as in Example 46.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.89 (br-s, 6H), 3.39-3.54 (m, 2H), 4.32-4.46 (m, 2H), 7.53-7.56 (m, 1H), 7.65-7.71 (m, 1H) , 7.81-7.87 (m, 1H), 8.19 (d, J = 8.0Hz, 1H), 8.23 (d, J = 8.8Hz, 1H), 8.35-8.39 (m, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.73 (d, J = 8.0Hz, 1H), 9.29-9.39 (br, 1H), 10.25 (s, 1H)
Elemental analysis value: C_{twenty two}H₁₉N_ThreeO_Three・ HCl ・ H₂As O

[0202]
Example 54
2- [2- (Dimethylamino) ethyl] -9-methoxy-1H-benzo [a] pyrimido [5,6,1-jk] carbazole-1,3 (2H) -dione hydrochloride
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[0203]
The title compound was obtained in the same manner as in Example 18 from 5-methoxy-1-tetralone and 2-hydrazinobenzoic acid hydrochloride.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.92 (s, 6H), 3.46-3.55 (m, 2H), 4.02 (s, 3H), 4.42-4.46 (m, 2H), 7.16 (d, J = 7.1Hz, 1H), 7.60 (t, J = 7.1Hz, 1H), 7.73 (t, J = 7.1Hz, 1H), 8.12 (d, J = 7.1Hz, 1H), 8.34-8.44 (m, 2H), 8.63 (d, J = 7.1Hz, 1H), 9.28 (d, J = 9.2Hz, 1H), 9.78 (br-s, 1H)
[0204]
Example 55
9- [2- (1-Pyrrolidinyl) ethyl] -8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) -dione dihydrochloride
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[0205]
The title compound was obtained in the same manner as in Example 36.
¹H-NMR (DMSO-d₆+ D₂O) δ (ppm); 1.84-1.94 (m, 2H), 2.01-2.13 (m, 2H), 3.13-3.25 (m, 2H), 3.57-3.64 (m, 2H), 3.65-3.74 (m, 2H) ), 4.43-4.49 (m, 2H), 7.85 (t, J = 7.6Hz, 1H), 7.94 (dd, J = 4.4, 8.4Hz, 1H), 8.23 (d, J = 7.6Hz, 1H), 8.37 (d, J = 9.2Hz, 1H), 8.92 (d, J = 9.2Hz, 1H), 9.05 (d, J = 7.6Hz, 1H), 9.12 (dd, J = 1.6,4.4Hz, 1H), 9.40 -9.45 (m, 1H)
[0206]
Example 56
9- [2- (Dimethylamino) ethyl] -13-fluoro-8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) -dione dihydrochloride
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[0207]
The title compound was obtained in the same manner as in Example 36.
¹H-NMR (DMSO-d₆) Δ (ppm); 2.92 (s, 3H), 2.93 (s, 3H), 3.47-3.55 (m, 2H), 4.41-4.47 (m, 2H), 7.69 (dd, J = 8.4, 12.0Hz, 1H ), 7.93 (dd, J = 4.4, 8.4Hz, 1H), 8.29 (dd, J = 4.4, 8.4Hz, 1H), 8.45 (d, J = 9.2Hz, 1H), 8.97 (d, J = 9.2Hz) , 1H), 9.10-9.14 (m, 1H), 9.25-9.31 (m, 1H)
[0208]
Example 57
9- [2- (Dimethylamino) ethyl] -3-methyl-8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) -dione dihydrochloride
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[0209]
The title compound was obtained in the same manner as in Example 36.
¹H-NMR (DMSO-d₆+ D₂O) δ (ppm); 2.93 (s, 3H), 2.95 (s, 6H), 3.51-3.57 (m, 2H), 4.44-4.50 (m, 2H), 7.86 (t, J = 8.0Hz, 1H) , 7.98 (d, J = 8.8Hz, 1H), 8.25 (d, J = 8.0Hz, 1H), 8.39 (d, J = 9.2Hz, 1H), 8.98 (d, J = 9.2Hz, 1H), 9.09 (d, J = 8.0Hz, 1H), 9.55 (d, J = 8.8Hz, 1H)
[0210]
Example 58
7- [2- (Dimethylamino) ethyl] -6H-dibenzo [c, i] pyrimido [1,6,5-lm] -β-carboline-6,8 (7H) -dione
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[0211]
1.06 g (3.1 mmol) of the compound of Production Example 25 was dissolved in methanol (20 ml) and tetrahydrofuran (20 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was heated to reflux for 1 hour. After allowing to cool, 1N aqueous hydrochloric acid solution (10 ml) was added and the solvent was distilled off. N, N-dimethylformamide (50 ml) was added to the residue, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 770 mg (4 mmol) and 1-hydroxybenzotriazole monohydrate 540 mg (4 mmol), N Then, 0.4 ml (3.7 mmol) of N-dimethylethylenediamine was added and stirred overnight at room temperature. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The deposited precipitate was washed with ethanol and collected by filtration to obtain 660 mg of intermediate (yield 55%).
100 mg (0.26 mmol) of this intermediate was dissolved in N, N-dimethylformamide (20 ml), 22 mg (0.55 mmol) of sodium hydride (60% oily) was added under a nitrogen stream, and the mixture was stirred for 1 hour and then at room temperature. 0.046 ml (0.6 mmol) of methyl chloroformate was added. Immediately after adding 1N hydrochloric acid, the mixture was acidified, saturated aqueous sodium hydrogen carbonate solution was added to make it weakly alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 25 mg (yield 24%) of the title compound.
FAB mass spectrometry m / z; 409 ([M + H]⁺ )
¹H-NMR (CDCl_Three) δ (ppm); 2.39 (s, 6H), 2.80 (t, J = 6.7Hz, 2H), 4.51 (t, J = 6.7Hz, 2H), 7.66-7.78 (m, 2H), 7.85-7.93 ( m, 2H), 8.01-8.07 (m, 2H), 8.51 (d, J = 8.6Hz, 1H), 8.57-8.63 (m, 1H), 8.73-8.79 (m, 1H), 9.74 (dd, J = (0.7, 8.6Hz, 1H)

Claims (10)

Formula (I)
[Chemical 1-1]

[In the formula, A ring is represented by the following (1) and (2)
(1) hydroxyl group, an oxo group, a cyano group, a halogen group, a nitro group, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms which may be substituted by an alkylamino group having 1 to 6 carbon atoms, 1 to carbon atoms An alkoxy group having 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, a carbamoyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, It may have a substituent selected from an arylsulfonyl group or an amino group optionally substituted with an alkylsulfonyl group having 1 to 6 carbon atoms (hereinafter referred to as substituent 1), and one ring is hydrogenated. Naphthalene or indene ring which may be substituted (2) may have a substituent 1, and the heterocyclic moiety may be hydrogenated, quinoline, isoquinoline, 4H-1-benzopyran, 1H-2- Benzopyra Means 1,3-benzodioxole, benzofuran, the bicyclic fused ring selected from the group consisting of isobenzofuran or benzothiophene ring.
Ring B means pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4 (1H) -pyridone.
The C ring is substituted with a halogen group, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 1 to 6 carbon atoms. It means a benzene ring optionally having a substituent selected from amino groups that may be present.
In addition, one ring portion of the bicyclic condensed ring of the A ring, the B ring, and the benzene ring of the C ring are condensed to form any of the following rings.
[Chemical 1-2]

Y is wherein -e-f (wherein, e is 1 to carbon atoms not an alkylene group having 1 to 6 carbon atoms, and f is or substituted with hydroxyl group or an alkylamino group having 1 to 6 carbon atoms It means an amino group which may be substituted with an alkyl group of 6. When the amino group is substituted with two alkyl groups, these alkyl groups are bonded to form a 5- or 6-membered ring. Or a group represented by ]
Or a pharmacologically acceptable salt thereof. The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein A ring is tetralin or indane optionally having substituent 1 and is condensed with B ring at the benzene ring portion.   The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the A ring is tetralin or indane substituted with an oxo group, and the benzene ring portion is condensed with the B ring. The compound or pharmacology thereof according to claim 1 , wherein the ring A is a chroman, isochroman, tetrahydrobenzofuran or tetrahydroisobenzofuran which may have a substituent 1 , and the benzene ring part is condensed with the ring B. Acceptable salt. The ring B is pyrrole, The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4 . F in the definition of Y is an amino group substituted by a C1-C6 alkyl group, The compound or its pharmacologically acceptable salt as described in any one of Claims 1-5 . The fused polycyclic heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the condensed polycyclic heterocyclic derivatives listed below.
1) 5- [2- (Dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione 2) 11-acetyl-5- [2 -(Dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione 3) 12,13-dihydro-5- [2- (dimethylamino) ) Ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione 4) (+)-5- [2- (dimethylamino) ethyl ] -10-hydroxy-10,11,12,13-tetrahydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione 5) 8- [2- ( Dimethylamino) ethyl] -7H-furo 3,2-c] pyrimido [5,6,1-jk] carbazole-3,7,9 (2H, 8H) -trione 6) 11,12-dihydro-5- [2- (dimethylamino) ethyl]- 4H, 10H-cyclopenta [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H) -trione 7) 12,13-dihydro-5- [2- (methylamino) ethyl]- 4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione 8) 12,13-dihydro-5- [2- (1-pyrrolidinyl) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione 9) 9- [2- (dimethylamino) ethyl] -8H-pyrido [4 , 3-c] pyrimido [5,6 1-jk] carbazole -8,10 (9H) - dione The compound is 12,13-dihydro-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione The condensed polycyclic heterocyclic derivative or a pharmacologically acceptable salt thereof according to claim 1. Formula (II)

(In the formula, Aa ring and Ca ring mean A ring and C ring according to claim 1, respectively , and Ba ring is pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4 (1H). - .Fa meaning pyridone means f the 請 Motomeko 1 wherein .e has the same meaning as in claim 1 wherein)
A method for producing a compound or a pharmacologically acceptable salt thereof according to claim 1, characterized in that phosgene, ethyl chlorocarbonate or N, N'-carbonyldiimidazole is reacted . The antitumor agent which uses the condensed polycyclic heterocyclic derivative as described in any one of Claims 1-8 , or its pharmacologically acceptable salt as an active ingredient.