JP3947627B2

JP3947627B2 - Phthalazine derivatives and therapeutic agents for erectile dysfunction

Info

Publication number: JP3947627B2
Application number: JP03844599A
Authority: JP
Inventors: 信久渡辺; 則夫苅部; 和城宮崎; 文博尾崎; 厚鎌田; 修平宮澤; 吉充直江; 金子敏彦; 格塚田; 廷長倉; 浩樹石原; 耕太郎児玉; 秀之足立
Original assignee: Eisai R&D Management Co Ltd
Current assignee: Eisai R&D Management Co Ltd
Priority date: 1998-02-19
Filing date: 1999-02-17
Publication date: 2007-07-25
Anticipated expiration: 2019-02-17
Also published as: JP2000204080A

Description

【０００１】
【産業上の利用分野】
本発明は、フタラジン誘導体に関する。更に詳しくは男性の***機能不全症予防・治療剤ならびに女性の性的機能不全または月経困難症の予防・治療剤に関する。さらには高血圧症、肺高血圧症、狭心症などの心疾患、糖尿病、または腎炎の予防・治療剤に関する。
【０００２】
【従来技術】
***機能不全症の潜在的患者は、我が国においては約300万人といわれて、米国においては2000万人で50代の男性の15％、60代の男性の約1／3が本疾患に該当すると報告されている。高齢化社会を迎え、セックスが快楽、情動行動と考えられ、より高質な生活が求められる中で、今後***機能不全症は医療上の問題だけでなく、社会的な問題になることが予想される。本疾患は、陰茎そのものの神経、血管、筋肉あるいは性ホルモンなどの障害による器質性と、精神的あるいは心理的原因などによる機能性（心因性）の二つに分類される。***には、陰茎動脈血流の増加、陰茎静脈からの血液漏出の抑制、および海綿体組織の弛緩の三条件が必要とされ、いずれかひとつでも阻害されると***機能不全が起こる。
【０００３】
現在、泌尿器科で実施されている***機能不全症の治療法は、薬物療法と陰茎補綴具による手術的陰茎補綴法である。
薬物療法として、塩酸パパベリンやプロスタグランジンE1の陰茎海綿体内への注射などが可能であるが、日本では患者自身で注射はできず、セックスのたびに医者に行くことができないため、現在ではあまり行われていない。さらに、塩酸パパベリンの注射は稀ではあるが、陰茎持続***症という痛みを伴う症状を起こすことがある。このように、現在ある薬物による治療法は実用的でなく、臨床上、実用性の高い薬物療法が切望されている。
【０００４】
【発明が解決しようとする課題】
1984年、バウマン（Bowman）とドルモンド（Drummond）はウシの陰茎後引筋において、選択的なサイクリック GMP ホスフォジエステラーゼ阻害薬、M&B22948（ザプリナスト）が組織中のサイクリックGMPを増加し、弛緩することを報告した（Cyclic GMP mediates neurogenic relaxation in the bovine retractor penis muscle, Br. J. Pharmacol.，81，665-674, 1984）。その後、他の研究者により、組織中のサイクリックGMPを増加することによる陰茎海綿体の弛緩作用について報告が相次いで行われた（Int. J. Impotence Res., 4，85-93，1992； J. Urol., 147，1650-1655，1992；N. Engl. J. Med., 326，90-94，1992）。しかし、これらの研究で使用されている化合物は、作用が弱いなど、臨床上使用するには満足のいくものではない。
【０００５】
ホスホジエステラーゼタイプ５の阻害剤は女性の性的機能障害にも有効である。
ホスホジエステラーゼタイプ５の阻害作用を有するフタラジン誘導体はＷＯ９６０５１７６（特許公開公報平８−２２５５４１）に開示されているが、窒素原子含有スピロ化合物、ビシクロ環および６員式ヘテロ環誘導体に関する開示はなく、また***機能不全症予防・治療に関する記載は全く無い。
【０００６】
【課題を解決するための手段】
種々検討重ねた結果、一般式（I）に示すフタラジン誘導体がサイクリックGMPの分解酵素であるホスホジエステラーゼタイプ５に対し高い選択性と強力な阻害作用を有し、かつ陰茎海綿体に対し強力な弛緩作用を示すと共に、生体内での利用率は上昇し、また高い安全性を有することを見出し本発明を完成した。
【０００７】
本発明は特開平８−２２５５４１に具体的に開示されていないフタラジン誘導体および全く示唆されていないフタラジン誘導体、さらには一部の誘導体の製造方法に関するものである。
一般式（I）
【０００８】
【化１９】

【０００９】
｛式中、
R¹およびR²は同一または相異なって、ハロゲン原子、ハロゲン原子で置換されていてもよいC1〜C4アルキル基、ハロゲン原子で置換されていてもよいC1〜C4アルコキシ基またはシアノ基を意味する。
Xはシアノ基、ニトロ基、ハロゲン原子、チオカルバモイル基、C1〜C4アルキル基・アリールC1〜C4アルキル基またはカルボキシC1〜C4アルキル基で置換されていてもよいヒドロキシイミノ基、または下記置換基群Aから選ばれる１〜３個の置換基で置換されていてもよいヘテロアリール基を意味する。
【００１０】
Yは
i)式（II）
【００１１】
【化２０】

【００１２】
（式中、環Aはメチル基で置換されていてもよく、二重結合を有していてもよい4〜8員式アミン環を、Dは単結合または酸素原子を、R³は水素原子、C1〜C4アルキル基またはハロゲン原子を、mは０または１〜３の整数を意味する。Wはアミノ基、水酸基、シアノ基、保護基を有していてもよいカルボキシル基またはC1〜C4アルコキシ基を意味する。）で示される基、
ii)式（III）
【００１３】
【化２１】

【００１４】
（式中、環Bは二重結合を有していてもよい4〜8員式アミン環を、nおよびpは同一または相異なって０または１〜３の整数を意味する。）で示される基、
iii)式（IV）
【００１５】
【化２２】

【００１６】
｛式中、環Gは二重結合を有していてもよい4〜8員式アミン環を示し、Eは水酸基、ハロゲン原子、C1〜C4アルキル基またはC1〜C4アルコキシ基を、Jは式-(CHR⁴)q-Q（式中、R⁴は水素原子またはC1〜C4アルキル基を、Qは水酸基、ハロゲン原子、保護基を有していてもよいカルボキシル基、カルバモイル基または窒素原子以外のヘテロ原子を含まないアゾリル基を、qは０または１〜４の整数を意味する。）示す。またはEとJは結合している炭素原子と一緒になって３から６員式の環を形成してもよく、この環はヘテロ原子を有していてよい。またこの環は置換基を有していてもよい。で示｝される基、
iv)式（V）
【００１７】
【化２３】

【００１８】
（式中、Mは単結合、または水酸基・カルボキシル基・C1〜C4アルキル基またはC1〜C4アルコキシ基で置換されていてもよいC1〜C4アルキレン基を意味する。環KはMと一緒になって５ないし８員式アミン環を意味する。環Lは置換基を有していてもよく、酸素原子を有していてもよい、５〜８員式アルキル環を示す。）で示される基、
v）式（VI）
【００１９】
【化２４】

【００２０】
（式中、環Pは５〜７員式アミン環、R⁵は水素原子、またはハロゲン原子・水酸基またはカルボキシル基で置換されていてもよいC1〜C4アルキル基を意味する。）で示される基、
vi)置換基を有していてもよい、アルキニル基、アルケニル基またはアルキル基、
vii)下記置換基群Aから選ばれる１〜３個の置換基で置換されていてもよいフェニル基、または、
viii）下記置換基群Aから選ばれる１〜３個の置換基で置換されていてもよいピリジル基、ピリミジル基、チエニル基、チアゾリル基またはフリール基を意味する。
[置換基群A]ハロゲン原子・シアノ基・ニトロ基または水酸基で置換されていてもよいC1〜C4アルキル基、ハロゲン原子・シアノ基・ニトロ基または水酸基で置換されていてもよいC1〜C4アルコキシ基、シアノ基、ニトロ基、保護基を有していてもよいカルボキシル基、保護基を有していてもよい水酸基、；低級アルキル基で置換されていてもよいカルバモイル基、ハロゲン原子、C1〜C4アシル基・C1〜C4アルキルスルホニル基または置換基を有していてもよいアリールスルホニル基で置換されていてもよいアミノ基。
【００２１】
lは１〜３の整数を意味する。
但し、lが１または２、Xがシアノ基、ニトロ基またはクロロ原子、R¹がクロロ原子、R²がメトキシ基、環Aが５または６員式アミン環、Dが単結合、mが０でWが保護基を有していてもよいカルボキシル基またはC1〜C4アルコキシ基の場合；lが１、R¹がクロロ原子、R²がメトキシ基、環Aが飽和の５または６員式アミン環、Dが単結合でWが水酸基の場合；lが１で環Bが５または６員式アミン環でｎおよびｐが共に０の場合；lが１でEおよびQが水酸基で、qが０の場合；およびlが１でXがクロロ原子でYがメトキシ基で置換されたフェニル基である場合を除く。｝で示されるフタラジン誘導体または薬理学的に許容される塩、またはそれらの水和物。
【００２２】
さらに、以下の一般式（VII）も陰茎海綿体に対し強力な弛緩作用を示すと共に、生体内での利用率は上昇し、また高い安全性を有することを見出して、本発明を完成させた。
一般式（VII）
【００２３】
【化２５】

【００２４】
｛式中、l’は１〜３の整数を意味する。R⁶はハロゲン原子、ハロゲン原子で置換されていてもよいC1〜C4アルキル基またはシアノ基を意味する。
X1はシアノ基、ニトロ基またはハロゲン原子を意味する。
Y1は
i)式（VIII）
【００２５】
【化２６】

【００２６】
（式中、環A1は５または６員式アミン環を、m1は０または１〜３の整数を意味し、Zはアミノ基、保護基を有していてもよい水酸基、保護基を有していてもよいカルボキシル基、C1〜C4アルコキシ基またはシアノ基を意味する。）で示される基、
ii)式（IX）
【００２７】
【化２７】

【００２８】
（式中、環B1は５または６員式アミン環を、n1およびp1は０または１〜３の整数を意味する。）で示される基、
iii)モルホリノ基または硫黄原子が酸化されていてもよいチオモルホリノ基、
iv)下記置換基群Aから選ばれる１〜３個の置換基で置換されていてもよいフェニル基、
v）下記置換基群Aから選ばれる１〜３個の置換基で置換されていてもよいピリジル基、ピリミジル基、チエニル基またはフリール基であるヘテロアリール基、または、
vi)式-N(R⁷)-(CH₂)s-Het
（式中、R⁷は低級アルキル基を、Hetは下記の置換基群A1から選ばれる１から３個の置換基で置換されていてもよいピリジル基またはピリミジル基を意味する。sは０または１〜３の整数を意味する。）
[置換基群A1]ハロゲン原子・シアノ基・ニトロ基または水酸基で置換されていてもよい低級アルキル基、ハロゲン原子・シアノ基・ニトロ基または水酸基で置換されていてもよい低級アルコキシ基、シアノ基、ニトロ基、保護基を有していてもよいカルボキシル基、保護基を有していてもよい水酸基、低級アルキル基で置換されていてもよいカルバモイル基、ハロゲン原子、アルキル基・アルコキシ基・ハロゲン原子またはアミノ基フェニル基。｝
で示されるフタラジン誘導体または薬理学的に許容される塩、またはそれらの水和物を有効成分とする***機能不全症治療剤。
【００２９】
本発明で示される定義において、X、R¹、R²、R³、R⁴、R⁵、E、Q、置換基群AおよびA1等に見られるハロゲン原子とはフッ素原子、塩素原子、臭素原子、ヨウ素原子を意味する。
R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、置換基群AおよびA1等にみられるC1〜C4アルキル基とは、炭素数1-4の直鎖状または分枝状のアルキル基、例えばメチル，エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、1-メチルプロピル、tert-ブチルを意味する。R¹、R²、および置換基群AおよびA1等にみられるC1〜C4アルコキシ基とは、上記C1〜C4アルキル基から誘導される基を意味する。例えば、メトキシ基、エトキシ基、プロポキシ基などを意味する。
【００３０】
Q、W、置換基群AおよびA1等にみられる保護基を有していてもよいカルボキシル基における保護基とは、例えば、メチル基、エチル基、tert-ブチル基等の低級アルキル基やp-メトキシベンジル、p-ニトロベンジル、3,4-ジメトキシベンジル、ジフェニルメチル、トリチル、フェネチル等の置換基を有していてもよいフェニル基で置換された低級アルキル基、2,2,2-トリクロロエチル、2-ヨードエチルなどのハロゲン化低級アルキル基、ピバロイルオキシメチル、アセトキシメチル、プオピオニルオキシメチル、ブチリルオキシメチル、バレリルオキシメチル、1-アセトキシエチル、2-アセトキシエチル、1-ピバロイルオキシエチル、2-ピバロイルオキシエチルなどの低級アルカノイルオキシ低級アルキル基、パルミトイルオキシエチル、ヘプタデカノイルオキシメチル、1-パルミトイルオキシエチルなどの高級アルカノイルオキシ低級アルキル基、メトキシカルボニルオキシメチル、1-ブトキシカルボニルオキシエチル、1-（イソプロポキシカルボニルオキシ）エチル等の低級アルコキシカルボニルオキシ低級アルキル基、カルボキシメチル、2-カルボキシエチルなどのカルボキシ低級アルキル基、3-フタリジル等のヘテロアリール基、4-グリシルオキシベンゾイルオキシメチルなどの置換基を有していてもよいベンゾイルオキシ低級アルキル基、（5-メチル-2-オキソ-1,3-ジオキソレン-4-イル）メチルなどの（置換ジオキソレン）低級アルキル基、1-シクロヘキシルアセチルオキシエチルなどのシクロアルキル置換低級アルカノイルオキシ低級アルキル基、1-シクロヘキシルオキシカルボニルオキシエチルなどのシクロアルキルオキシカルボニルオキシ低級アルキル基などを挙げることができる。要するに生体内で何らかの手段で分解されて、カルボン酸となりうるものであれば、いかなるものもカルボキシル基の保護基となり得る。
【００３１】
また、置換基群AおよびA1等にみられる保護基を有していてもよい水酸基における保護基とは、例えばホルミル基、アセチル基，ベンゾイル基等のアシル基；2-メトキシエトキシメチル基などの低級アルコキシメチル基等を挙げることができる。要するに生体内で何らかの手段で分解されて、水酸基となりうるものであれば、いかなるものも水酸基の保護基となり得る。
【００３２】
Qにおける窒素原子以外のヘテロ原子を含まないアゾリル基とはピロール、ピラゾール、イミダゾール、トリアゾール、テトラゾール、インダゾール、ベンゾイミダゾール、ベンゾトリアゾールから導かれる基を意味する。
【００３３】
式（IV）において、EとJとが結合している炭素原子と一緒になって形成する環と環Gとでできる化合物はスピロ化合物である。EとJとが結合している炭素原子と一緒になって形成する環としては、シクロブタン、シクロペンタン、シクロヘキサン、オキシラン、テトラヒドロフラン、テトラヒドロピラン、ブチロラクトン、ブチロラクタムなどを挙げることができる。また、これらの環上の置換基としては、水酸基、前記の保護基を有していてもよいカルボキシル基、ヒドロキシメチル基・ヒドロキシエチル基等の水酸基で置換されていてもよいC1〜C4アルキル基、カルボニル基、フッ素・クロロ原子等のハロゲン原子などを挙げることができる。
【００３４】
式（V）において、MがC1〜C4アルキレン基である場合に環Kと環Lで形成されビシクロ環は架橋環であることを意味する。環L上の置換基としては、水酸基、前記の保護基を有していてもよいカルボキシル基、ヒドロキシメチル基・ヒドロキシエチル基等の水酸基で置換されていてもよいC1〜C4アルキル基、カルボキシメチル基・カルボキシエチル基等のカルボキシル基で置換されていてもよいC1〜C4アルキル基カルボニル基、フッ素・クロロ原子等のハロゲン原子、ビニル基等を挙げることができる。
【００３５】
Yが置換基を有していてもよい、アルキニル基、アルケニル基またはアルキル基における置換基とは、メチル基・エチル基・プロピル基・イソプロピル基・ブチル基・イソブチル基・sec-ブチル基・tert-ブチル基などのC1〜C4アルキル基、シクロプロパン・シクロブタン・シクロペンタン・シクロヘキサン等のシクロアルカンから導かれる基、メトキシ基・エトキシ基・プロポキシ基などの、前記C1〜C4アルキル基から誘導されるC1〜C4アルコキシ基、水酸基、C1〜C4アルキル基で置換されていてもよいアミノ基、水酸基で置換されていてもよいアジリジン・アゼチジン、ピロリジン・ピペリジンなどの環状アミン、ヒドロキシC1〜C4アルキル基、ヒドロキシC1〜C4アルコキシ基、カルボキシアルコキシ基、フッ素原子・クロロ原子等のハロゲン原子等を意味する。
【００３６】
Xにおけるヘテロアリール基としては、ピロール、ピラゾール、イミダゾール、トリアゾール、テトラゾール、インダゾール、ベンゾイミダゾール、ベンゾトリアゾール、チアゾール、イソチアゾール、チアジアゾール、ベンゾチアジアゾール、ピリジン、ピリミジン、トリアジン、キノリン、イソキノリン、ナフチリジン、フタラジンなどから導かれる基を挙げることができる。
【００３７】
本発明において、薬理学的に許容される塩とは、例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩などの無機酸塩、蟻酸塩、酢酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩などの有機酸塩を挙げることができる。
本発明において不斉原子を有する化合物はその光学活性生体も本発明に包含されることは言うまでもない。
【００３８】
さらに、本発明には生体内で代謝されて生成する本発明化合物および本発明化合物が代謝されて生成する化合物も含まれる。
これらのフタラジン誘導体またはその薬理的に許容される塩、またはそれらの水和物は経口吸収性および持続性にすぐれているので、陰茎海綿体または陰部へ直接注射するなく、経皮、静脈内および経口投与による治療が可能であり、***機能不全症予防・治療剤、および女性の性的機能不全または月経困難症の予防・治療剤として望ましいものである。
PDE5阻害剤が高血圧症、肺高血圧症、狭心症等の心疾患、糖尿病や腎炎の予防・治療に有効であることはＷＯ９６０５１７６やＷＯ９９００３５９に記載されている。
【００３９】
本発明化合物の投与量は、特に限定されないが、通常成人１回あたり、静脈内投与により使用する場合は、５μｇ−１００ｍｇ、好ましくは１０−１０００μｇを、経口投与により使用する場合は、１−１０００ｍｇ、好ましくは５−１００ｍｇを用いる。
【００４０】
【発明の実施の形態】
製造方法１
本発明フタラジン誘導体またはその薬理的に許容される塩の類似の化合物の製造方法はＷＯ９６０５１７６（特許公開公報平８−２２５５４１）に記載されており、本発明フタラジン誘導体も同様にして以下のよう製造される。
【００４１】
【化２８】

【００４２】
式（X）で示される化合物を溶媒中HY²と反応させて式（XII）を得る反応である。反応溶媒はN-メチル-2-ピロリジノンなどが好ましいが、反応に関与しないあらゆる溶媒を用いることができる。HYは化合物（X）に対して過剰量用いるか、あるいは、ジイソプロピルエチルアミンなどの有機塩基、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウムなどの塩を用いることにより、良い結果が得られることがある。反応温度は、室温から溶媒の沸点であるが、好ましくは１００℃以上に加熱する。
【００４３】
ＷＯ９６０５１７６（特許公開公報平８−２２５５４１）に記載のないWがシアノ基である化合物の製造に必要なHY²の合成は次のように行われる。
【００４４】
【化２９】

【００４５】
また、上記公報には具体的な記載のない、前記定義におけるWがアミノ基の場合はアミノ基が保護基されたHY²を下記のように合成し、上記は工程終了後脱保護することにより製造される。
【００４６】
【化３０】

【００４７】
一般式（I）においてYが一般式（IV）および一般式（V）である場合のHY²は、ＷＯ９８０６７２０に開示されている化合物を用いるか、またそこに開示されている方法を利用することにより製造することができる。
１）例えば、一般式（IV）で示される一部の化合物は以下の方法により製造される。
【００４８】
【化３１】

【００４９】
（式中、G1は４〜８員式アミン環を、Q1はピロリル、ピラゾリル、イミダゾリル、トリアゾリル、テトラゾリル、インダゾリル、ベンゾイミダゾリル、ベンゾトリアゾリル基またはフッ素原子を、Proは窒素原子の保護基を意味する。）
トルエン、キシレン、テトラヒドロフラン等の溶媒中、メチルトリフェニルスルホニウムブロミドをカリウムtert-ブトキシド、ブチルリチウム等の塩基で処理し、式（a）で示されるケトン体と反応させると、式（b）で示される化合物を得ることができる。反応温度は−７８℃から室温が好ましい。
【００５０】
化合物（b）にジエチルエーテル、ジメトキシエタン、テトラヒドロフラン等の溶媒中でトリクロロアセチルクロリドと反応させてジクロロシクロブタノン体（f）（またはジアセチルクロリドと反応させるとモノクロロ体が得られる。このモノクロロ体はトリクロロアセチルクロリドと反応後、酢酸で処理しても得られる。）を得た後、亜鉛末等の還元剤で処理することにより式（g）で示されるシクロブタノン体を得ることができる。反応温度は１０から５０℃が好ましい。化合物（g）をジクロロメタン等の溶媒中炭酸水素ナトリウム等の存在下に、3-クロロ過安息香酸等の過酸化物を作用させると、式（h）で示されるラクトン体を得ることができる。反応温度としては室温から４０℃の範囲が好ましい。化合物（b）をジクロロケテンおよびジアゾメタン、あるいは化合物（g）をジアゾメタンで処理すると式（g）においてシクロペンタノン体が得られる。またこのシクロペンタノン体をジアゾメタンで処理するとシクロヘキサノン体が得られる。
【００５１】
化合物（b）を溶媒中フタル酸モノ過酸マグネシウム等の過酸で処理すると式（c）で示されるエポキシド体が得られる。このエポキシド体（c）をジメチルホルムアミド等の溶媒中、ヘテロ原子として窒素原子のみからなるアゾールのナトリウム塩と反応させると、対応する式（d）で示される化合物（Q1が1-イミダゾリル基、1-トリアゾリル基等）が得られる。また、Bu₄N・H₂F₃存在下に１００から１５０℃でフッ化水素カリウムで処理すると式（d）で示される化合物においてQ1がフルオロ原子であるフルオロメチル体が得られる。
【００５２】
一方、化合物（c）を−１０から１０℃で塩化メチレン等の溶媒中フッ化水素ピリジンと処理すると、式（e）で示されるフルオロ体が得られる。
２）一般式（V）で示されるの化合物のうち、Mが水酸基で置換されているメチレンの場合は、例えば以下の方法により製造される。
【００５３】
【化３２】

【００５４】
環Lが酸素原子を含む場合も同様に製造することができる。
製造方法２
一般式（I）において、Yが置換基を有していてもよいアルキニル基、アルケニル基、アルキル基である化合物は以下の方法により製造することができる。
【００５５】
【化３３】

【００５６】
（式中、Halはハロゲン原子を、R⁸は置換基を有していてもよいC1〜C4アルキル基、または置換基を有していてもよいシクロアルキル基またはシクロアルキルアルキル基を意味する。R¹、R²、lおよびXは前記を意味する。）
一般式（X）とアルキン誘導体との反応は、触媒量のジクロロビストリフェニルホスフィンパラジウム(II)とヨウ化第一銅および3級アミン存在下で室温あるいは加熱下で行われる。使用される溶媒としてはジメチルホルムアミドまたは1-メチルピロリジノンなどを挙げることができる。使用する3級アミンとしてはトリエチルアミン、ジイソプロピルエチルアミン、DBU、ジメチルアニリンなどである。反応温度は0〜150℃が好適である。
【００５７】
式（XIII）で示されるアルキン化合物から式（XIV）で示されるアルケン化合物および式（XV）で示されるアルカン化合物への変換はリンドラー触媒やPd-C触媒存在下に接触還元等により行われる。
製造方法３
また、Yが置換基を有していてもよいアリール基またはヘテロアリール基であるY3のフタラジン誘導体は以下のようにして製造される。
【００５８】
【化３４】

【００５９】
反応は０価または２価のパラジウム錯体を用い、式（X）で示される1-ハロゲノキナゾリン誘導体と対応するアリール基またはヘテロアリール基のボロン酸、ジアルコキシボランまたはトリアルキルスズ誘導体をカップリングさせることにより行われる。アリール基またはヘテロアリール基のボロン酸、ジアルコキシボランまたはトリアルキルスズ誘導体とパラジウム錯体を有機溶媒と炭酸ナトリウム水溶液の二相系溶媒に溶解または懸濁し、窒素気流下、室温から溶媒の沸点でおよそ1−24時間反応させる。パラジウム錯体としては反応を進行させるあらゆるパラジウム錯体を用いることができるが、テトラキス（トリフェニルフォスフィン）パラジウムなどが好ましい。有機溶媒としては反応に影響を与えないあらゆるものを用いることができるが、キシレン、トルエン、テトラヒドロフラン、またはそれらの混合溶媒が好ましい。
製造方法４
一般式（Ｉ）において、Xがシアノ基である化合物（XVII）を用いて公知の反応を組み合わせ、下記の反応式中に示される化合物を製造することができる。
【００６０】
【化３５】

【００６１】
（式中、R⁹は水素原子、ハロゲン原子で置換されていてもよいC1〜C4アルキル基、アリールC1〜C4アルキル基またはカルボキシC1〜C4アルキル基を意味し、R¹⁰はC1〜C4アルキル基を意味する。R¹、R²、lおよびYは前記を意味する。）
製造方法５
一般式（Ｉ）において、Xがヘテロアリール基である一部の化合物については、製造方法３と同様の方法で製造することができる。
【００６２】
【化３６】

【００６３】
（式中、Halはハロゲン原子を、Het¹はヘテロアリール基を意味し、R¹、R²、lおよびYは前記を意味する。）
ハロゲン原子としてはブロム原子またはヨウ素原子が好ましい。
また、一般式（Ｉ）において、窒素原子以外のヘテロ原子を有しないアゾリル基である化合物の製造は、あらかじめ対応する一般式（X）で示される化合物を製造した後、前記製造方法１に準じて行われる。対応する一般式（X）で示される化合物は、例えば、4-フルオロフタル酸ジメチルを窒素原子以外のヘテロ原子を含まないアゾールと処理して4-アゾリルフタル酸ジメチルを得、続いてヒドラジンと処理して6-アゾリル-2,3-ジヒドロ-1,4-フタラジンジオンを得た後、ＷＯ９６０５１７６に開示の方法により製造される。
製造方法６
一般式（I）においてYが一般式（VI）で示される化合物は、下記の一般式（XXIV）で示される化合物から公知の方法によるオキシム化により製造される。
【００６４】
【化３７】

【００６５】
（式中、R¹、R²、R⁵、lおよびXは前記を意味する。）
【００６６】
【発明の効果】
以下に実験例により本化合物の効果を示す。
【００６７】
【実験例】
１）ブタ血小板より得た cGMP-PDE を用いた酵素阻害作用
ブタ血小板より調製したcGMP-PDEの酵素活性をトンプソン（Tompson）等の方法に準じて1mM EGTA存在下に1μM cGMPを基質とし,被験化合物をDMSOに溶解して反応液に加えて阻害活性を測定した。尚、反応液中のDMSOの最終濃度は1%以下とした。cGMP-PDEの調製は次のように行った。ブタ血小板をバッファーA（20mM Tris/HCl、2mM 酢酸マグネシウム、10mM 2-メルカプトエタノール、0.1mM EGTA、pH7.4）に加えソニケートした。懸濁液を100000xgで60分間遠心分離し、得られた上清を、DEAE-Toyopearl 650S（Toso, Tokyo, Japan）カラムにかけた。バッファーAでカラムを洗浄した後、バッファーAの0.075-0.25M NaClグラジェントで溶出し、cGMP-PDE画分を得た。得られた画分を透析、濃縮して保存した。
【００６８】
【表１】

【００６９】
２）ウサギ摘出陰茎海綿体標本におけるニトロプルシッドによる弛緩作用に対する PDE5 阻害化合物の増強作用
NZW系ウサギ（約3.0 kg）はペントバルビタール（50 mg/kg）の静脈内投与により致死せしめ、陰茎を摘出した。摘出後、白膜等の周囲組織を除き海綿体を露出し、約10 x 1.5 x 1.5 mmの標本を作成した。この標本を37℃において10mlのKrebs-Henseleit溶液（NaCl:118.4mM, KCl:4.7mM, CaCl₂:2.5mM, MgSO₄:1.3mM, KH₂PO₄:1.2mM, NaHCO₃:25.0mM, glucose:11.0mM, EDTA:0.026mM, indomethacin:0.001mM）を満たしたマグヌス管に懸垂し、混合ガス（95%O₂ + 5%CO₂）を通気し、2gの負荷のもとに収縮張力の変化を等尺性に記録し測定した。収縮を安定させるため、KCl添加（最終濃度100 mM）による収縮と洗浄を２回繰り返し、さらにフェニレフリン添加（最終濃度10 mM）による収縮と洗浄を行った。再度、10mlのKrebs-Henseleit溶液で満たし、L-N^G-ニトロアルギニンメチルエステル（最終濃度100 mM）を添加により内因性の一酸化窒素の生成を阻害した。フェニレフリン添加（最終濃度10 mM）により収縮を惹起させ、3、30または300 nMとなるよう薬物溶液を添加した。この時、媒体としてジメチルスルホキシドを用いた。薬物添加15分後にニトロプルシッド（最終濃度300 mM）を加え、標本を弛緩させた。さらに、パパベリン添加（最終濃度100 mM）により最大弛緩を求めた。実験終了後、パパベリン添加時の発生張力を基線とし、チャート上におけるニトロプルシッド添加による弛緩をデジマチックキャリパを用いて計測し、弛緩率を求めた。
【００７０】
【表２】

【００７１】
表中の数値は3、30及び300 nMの化合物で前処理した標本におけるニトロプルシッド添加後の弛緩率について%で示し、２例の平均値を記載した。また、EC₅₀値はフェニレフリンで惹起した収縮に対する50%弛緩を生じさせる化合物濃度を示し、２例の弛緩曲線から回帰分析により算出した。
ニトロプルッシドから生成した一酸化窒素が、グアニレートサイクラーゼを活性化し、GTPからのcGMPの生成を促進して陰茎海綿体を弛緩した。PDE5阻害剤はcGMPの分解を抑制することによりこの弛緩作用を増強した。
【００７２】
以上のように、本発明化合物はPDE5阻害作用を有し、濃度依存的にウサギ摘出陰茎海綿体標本におけるニトロプルシッドによる弛緩作用を増強することが示された。即ち、本発明化合物は***機能不全症の予防・治療剤として有用である。
本発明の理解を容易にするために製造例および実施例を示すが、本発明がこれらの化合物に限定されるものでないことは言うまでもない。
なお、実施例９，１１，１２，２１〜２５，２８，４０，４１，４５，５１〜５７，６７〜７４，８２，８５，８７，９０，９５，９８，１０１，１０６，１１４，１１５が本発明の実施例であり、他の実施例は参考例である。
製造例１
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-[(3R)-3-ヒドロキシピペリジノ]フタラジン塩酸塩
【００７３】
【化３８】

【００７４】
1-クロロ-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジン1.0g、(R)-(+)-3-ヒドロキシピペリジン塩酸塩1.92g、ジイソプロピルエチルアミン1.80g、1-メチル-2-ピロリドン12mLの混合物を170℃で1時間１５分攪拌した。冷後、反応液に酢酸エチルを加え、水及び飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、残渣をシリカゲルカラムクロマトグラフィーで精製した。得られたフリー体を酢酸エタノール−水に懸濁し、1Ｎ塩酸水溶液を加え加熱溶解した。冷後、析出した結晶をろ取し標記化合物を黄色の粉末として860mg得た。
MASS(ESI):424.1(MH⁺)
¹H-NMR(400MHz, DMSO-d₆)δ;1.39-1.50(1H, m), 1.65-1.78(1H, m), 1.75-1.98(2H, m), 2.82-2.91(1H, m), 2.93-3.02(1H, m), 3.33-3.48(2H, m), 3.79-3.88(1H, m), 3.85(3H, s), 4.72(2H, br), 7.16(1H, d, J=8.4Hz), 7.47(1H, dd, J=8.4, 1.6Hz), 7.62(1H, d, J=1.6Hz), 8.31(1H, d, J=8.4Hz), 8.48(1H, d, J=8.4Hz),9.38-9.46(1H, m), 10.27(1H, br)
製造例２
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-[(3S)-3-ヒドロキシピロリジノ]フタラジン塩酸塩
【００７５】
【化３９】

【００７６】
製造例１の(R)-(+)-3-ヒドロキシピペリジン塩酸塩の代わりに(S)-3-ヒドロキシピロリジンを用いて標記化合物を得た。
MASS(ESI)；410.0(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.94-2.10 (2H, m), 3.50-3.62 (1H, m), 3.42-3.68 (1H, m), 3.83 (3H, s), 3.93-4.10 (2H, m), 4.43-4.50 (1H, m), 4.50-4.64 (2H, m), 5.30 (1H, br), 7.13 (1H, d, J= 8.4 Hz), 7.34-7.44 (1H, m), 7.48-7.56 (1H, m), 8.38-8.46 (1H, m), 8.62-8.74 (1H, m), 9.10-9.32 (1H, m)
.製造例３
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-[(2S)-2-ヒドロキシメチルピロリジノ]フタラジン塩酸塩
【００７７】
【化４０】

【００７８】
製造例１の(R)-(+)-3-ヒドロキシピペリジン塩酸塩の代わりに(S)-2-ヒドロキシメチルピロリジンを用いて標記化合物を得た。
MASS(ESI)；424.1(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.60-2.39 (4H, m), 3.44-3.53 (1H, m), 3.83 (3H, s), 3.89-3.99 (1H, m), 4.34-4.70 (3H, m), 7.12-7.16 (1H, m), 7.38-7.46 (1H, m), 7.52-7.59 (1H, m), 8.40-8.43 (1H, m), 8.43-8.60 (1H, m), 9.23-9.30 (1H, m)
製造例４
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-(3-ヒドロキシメチルピペリジノ)フタラジン塩酸塩
【００７９】
【化４１】

【００８０】
製造例１の(R)-(+)-3-ヒドロキシピペリジン塩酸塩の代わりに3-ヒドロキシメチルピペリジンを用いて標記化合物を得た。
MASS(ESI)；438.2(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.13-1.28 (1H, m), 1.70-1.86 (3H, m), 1.87-1.99 (1H, m), 2.67-2.75 (1H, m), 2.86-2.95 (1H, m), 3.33-3.50 (3H, m), 3.51-3.60 (1H, m), 3.16 (3H, s), 3.85 (3H, s), 4.71 (2H, br s), 7.16 (1H, d, J= 8.4 Hz), 7.44 (1H, dd, J = 8.4, 0.8 Hz), 7.59 (1H, d, J = 0.8 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.45 (1H, dd, J = 8.8, 0.4 Hz), 9.28-9.35 (1H, m), 9.95 (1H, br), 14.00 (1H, br)
製造例５
4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノ-1-(3-ヒドロキシメチルピペリジノ)フタラジン塩酸塩
【００８１】
【化４２】

【００８２】
製造例４の1-クロロ-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジンの代わりに1-クロロ-4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノフタラジンを用いて標記化合物を得た。
MASS(ESI)；452.3(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.70-1.90 (2H, m), 1.90-2.05 (2H, m), 2.70 (1H, br.t), 2.88 (1H,br.t), 2.95-3.08 (2H, m), 3.25-3.63 (2H, m), 3.78 (2H, m), 3.83 (3H, s), 7.09 (1H, d, J= 8.6 Hz), 7.29 (1H, d, J= 8.6 Hz), 7.47 (1H, s), 8.25 (1H, d, J= 8.6 Hz), 8.49 (1H, d, J= 8.6 Hz), 9.48 (1H, s)
製造例６
4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノ-1-(4-ヒドロキシメチルピペリジノ)フタラジン
【００８３】
【化４３】

【００８４】
製造例5の3-ヒドロキシメチルピペリジンの代わりに4-ヒドロキシメチルピペリジンを用いて標記化合物を得た。
MASS(ESI)；452.3(MH⁺)
¹H-NMR(400 MHz, CDCl₃)δ;1.51-1.65 (2H, m), 1.79-1.85 (1H, m), 1.93 (2H, m), 2.99-3.09 (4H, m), 3.56-3.68 (4H, m), 3.90 (3H, s), 3.85-3.99 (2H, m), 4.94 (1H, br t), 6.88 (1H, d, J= 8.4 Hz), 7.13 (1H, dd, J= 2.2, 8.4 Hz), 7.28 (1H,d, J= 2.2 Hz), 7.94 (1H, d, J= 8.4 Hz), 7.98 (1H, s), 8.13 (1H, d, J= 8.4 Hz)
製造例７
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-[メチル(2-ピリジルメチル)アミノ]フタラジン・二塩酸塩
【００８５】
【化４４】

【００８６】
製造例１の(R)-(+)-3-ヒドロキシピペリジン塩酸塩の代わりにN-メチル-[(2-ピリジル)メチル]アミンを用いて同様に処理し標記化合物を得た。
MASS(ESI)；445.3(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;2.95 (3H, s), 3.85 (3H, s), 4.73-4.79 (4H, m), 7.16 (1H, d, J= 8.4 Hz), 7.49 (1H, dd, J = 8.4, 2.0 Hz), 7.64 (1H, d, J = 2.0 Hz), 7.65-7.72 (1H, m), 7.83-7.87 (1H, m), 8.18-8.26 (1H, m), 8.52 (1H, dd, J = 8.4, 1.2 Hz), 8.60 (1H, d, J = 8.4 Hz), 8.74 (1H, d, J = 4.8 Hz), 9.53-9.55 (1H, m), 10.64 (1H, br)
製造例８
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-[N-メチル-[2-(2-ピリジル)エチル]アミノ]フタラジン・二塩酸塩
【００８７】
【化４５】

【００８８】
製造例７のN-メチル-[(2-ピリジル)メチル]アミンの代わりにN-メチル-[2-(2-ピリジル)エチル]アミンを用いて同様に処理し標記化合物を得た。
MASS(ESI)；459.2(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;3.00 (3H, s), 3.35 (2H, t, J = 6.4 Hz), 3.76 (2H, t, J = 6.4 Hz), 3.85 (3H, s), 4.73-4.77 (2H, m), 7.18 (1H, d, J= 8.4 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.53-7.64 (1H, m), 7.65 (1H, s), 7.68-7.77 (1H, m), 8.10-8.30 (1H, m), 8.16 (1H, d, J = 8.6 Hz), 8.44 (1H, d, J = 8.6 Hz), 8.55 -8.61 (1H, m), 9.45-9.51 (1H, m), 10.53 (1H, br)
製造例９
4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノ-1-(4-メトキシピペリジノ)フタラジン塩酸塩
【００８９】
【化４６】

【００９０】
製造例５の3-ヒドロキシピペリジンの代わりに4-メトキシピペリジン塩酸塩を用いて同様に処理し標記化合物を得た。
MASS(ESI)；452.2(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.66-1.76 (2H, m), 2.00-2.08 (2H, m), 2.91-2.97 (2H, m), 2.99-3.07 (2H, m), 3.29 (3H, s), 3.37-3.49 (3H, m), 3.70-3.77 (2H, m), 3.81 (3H, s), 7.07 (1H, d, J = 8.6 Hz), 7.26 (1H, dd, J = 8.6, 2.0 Hz), 7.43 (1H, d, J = 2.0 Hz), 8.24 (1H, d, J = 8.3 Hz), 8.45 (1H, dd, J = 8.3, 1.6 Hz), 9.22 (1H, d, J = 1.6 Hz)
製造例１０
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-(4-メトキシフェニル)フタラジン塩酸塩
【００９１】
【化４７】

【００９２】
1-クロロ-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジン1.0gと4-メトキシフェニルほう酸423mgとトルエン30mL、テトラヒドロフラン30mL、2M炭酸ナトリウム水溶液30mLの混合物に窒素雰囲気下、テトラキス(トリフェニルホスフィン)パラジウム(0)423mgを加え、80℃で２時間さらに、100℃で15.5時間攪拌した。反応液を室温に戻し、塩化アンモニウム水溶液と酢酸エチルを加え、抽出した。有機層をアンモニア水、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製した。得られたカップリング体を酢酸エチル−エタノールに溶解し、4N塩酸−酢酸エチル溶液を加え、析出した結晶をろ取し標記化合物を黄色の粉末として460mg得た。
MASS(ESI)；431.2 (MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ; 3.85 (3H, s), 3.87 (3H, s), 4.82-4.85 (2H, m), 7.16-7.21 (3H, m), 7.49 (1H, dd, J = 8.6, 2.2 Hz), 7.60-7.63 (3H, m), 8.08 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 8.4, 1.4 Hz), 9.45-9.49 (1H, m), 10.39 (1H, br)
製造例１１
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシ-3-メチルピペリジノ)-6-フタラジンカルボニトリル塩酸塩
製造例1の(R)-(+)-3-ヒドロキシピペリジン塩酸塩の代わりに4-ヒドロキシ-3-メチルピペリジンを用いて同様に処理し標記化合物を得た。
¹H NMR (DMSO-d₆) δ 0.94 (3H, t, J = 8.0 Hz), 1.59-2.03 (3H, m), 2.74-3.96 (5H, m), 3.83 (3H, s), 4.68 (2H, d, J = 5.2 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.0 Hz), 7.58 (1H, s), 8.23 (1H, t, J = 8.0 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.29 (1H, s)
製造例１２
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシ-3,3,5,5-テトラメチルピペリジノ)-6-フタラジンカルボニトリル塩酸塩
製造例1の(R)-(+)-3-ヒドロキシピペリジン塩酸塩の代わりに4-ヒドロキシ-3,3,5,5-テトラメチルピペリジンを用いて同様に処理し標記化合物を得た。
¹H NMR (DMSO-d₆) δ; 0.91 (6H, s), 1.15 (6H, s), 2.57 (1H, d, J = 12.4 Hz), 2.95 (1H, s), 3.21 (2H, d, J = 12.0 Hz), 3.83 (3H, s), 4.47 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.8 Hz), 7.63 (1H, s), 8.29 (1H, d, J = 8.4 Hz), 8.55 (1H, d, J = 8.4 Hz), 9.52 (1H, s), 10.63 (1H, brs)
中間体製造例１
1-クロロ-4-[[(4-メトキシ-3-トリフルオロメチル)ベンジル]アミノ]-6-フタラジンカルボニトリル
【００９３】
【化４８】

【００９４】
2-トリフルオロメチルフェノール10 g、炭酸カリウム17 g、アセトン150 mL、ヨードメタン7.7 mLの混合物を２時間加熱還流した。冷後、不溶物を濾去し、濾液を減圧下濃縮した。残渣を酢酸エチルに溶解し、水及び飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮し、2-トリフルオロメチルアニソールを12.15 g得た。
【００９５】
2-トリフルオロメチルアニソール8.5 gとヘキサメチレンテトラミン7.0 gの混合物をトリフルオロ酢酸80 mL中９０℃で１．５時間撹拌した。反応液を減圧下濃縮した。残渣を酢酸エチルに溶解し、氷冷した飽和重曹水に滴下した。酢酸エチル層を分取し、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、3-トリフルオロメチル-p-アニスアルデヒドを5.8 g得た。
【００９６】
3-トリフルオロメチル-p-アニスアルデヒド5.8 g、ホルムアミド8.6 mL、ぎ酸13.6 mLの混合物を１３０℃で９時間撹拌した。冷後、水と酢酸エチルを加えた。酢酸エチル層を分取し、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、N-[4-メトキシ-3-(トリフルオロメチル)ベンジル]ホルムアミドを3.8 g得た。
【００９７】
N-[4-メトキシ-3-(トリフルオロメチル)ベンジル]ホルムアミドを3.8 gをエタノール20 mLに溶解し、濃塩酸2 mLを加え、３時間加熱還流した。冷後、ジエチルエーテルを加え、析出した結晶を濾取し、4-メトキシ-3-(トリフルオロメチル)ベンジルアミン塩酸塩を2.5 g得た。
1,4-ジクロロフタラジン-6-カルボニトリル2.2 g、4-メトキシ-3-(トリフルオロメチル)ベンジルアミン塩酸塩を2.5 g、1-メチル-2-ピロリジノン25 mLの混合物にDBU 3.7 gを加え、室温で１．２５時間撹拌した。反応液に酢酸エチルを加え、水及び飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥、濾過、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、より極性の低い生成物として標記化合物を1.66 g得た。
¹H NMR (DMSO-d₆) δ 3.86 (3H, s), 4.74 (2H, d, J = 5.2 Hz), 7.22 (1H, d, J = 9.6 Hz), 7.67-7.71 (2H, m), 8.20 (1H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 8.4, 1.4 Hz), 8.50 (1H, t, J = 5.2 Hz), 8.99 (1H, d, J = 1.4 Hz)
同様の方法により市販の2-ヨードアニソールより1-クロロ-4-[(3-ヨード-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリルを、3-ブロモ-p-アニスアルデヒドより4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-クロロ-6-フタラジンカルボニトリルを、3-フルオロ-p-アニスアルデヒドより1-クロロ-4-[(3-フルオロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリルを、3-メチル-p-アニスアルデヒドより1-クロロ-4-[(4-メトキシ−３−メチルベンジル)アミノ]-6-フタラジンカルボニトリルを得た。
中間体製造例２
1-クロロ-4-[(3-ヨード-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル
¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.67 (2H, d, J = 5.2 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.42 (1H, dd, J = 8.4, 2.0 Hz), 7.83 (1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 8.4, 1.2 Hz), 8.45 (1H, t, J = 5.2 Hz), 8.99 (1H, d, J = 1.2 Hz)
中間体製造例３
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-クロロ-6-フタラジンカルボニトリル
¹H NMR (DMSO-d₆) δ 3.82 (3H, s), 4.70 (2H, d, J = 5.2 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.41 (1H, dd, J = 8.4, 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 8.4, 1.2 Hz), 8.47 (1H, t, J = 5.2 Hz), 8.99 (1H, d, J = 1.2 Hz)
中間体製造例４
1-クロロ-4-[(3-フルオロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル
¹H NMR (DMSO-d₆) δ; 3.81 (3H, s), 4.70(2H, d, J = 5.4 Hz), 7.11 (1H, t, J = 8.8 Hz), 7.19 (1H, d, J = 8.8 Hz), 7.26 (1H, dd, J = 12.8, 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 8.4, 0.8 Hz), 8.46 (1H, t, J = 5.4 Hz), 9.01 (1H, d, J = 0.8 Hz)
中間体製造例５
1-クロロ-4-[(3-シアノ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル
4-メトキシベンジルクロリド20 g、フタルイミドカリウム26 g、ジメチルホルムアミド100 mLの混合物を５０℃で５時間撹拌した。冷後、反応液を氷水に注ぎ、沈殿物を濾取した。これを水で洗浄し、乾燥しN-(4-メトキシベンジル)フタルイミドを31 g得た。
【００９８】
N-(4-メトキシベンジル)フタルイミド31 gとトリフルオロ酢酸100 mLの混合物にヘキサメチレンテトラミン18 gを少量ずつ加え、室温で１時間撹拌後、４時間加熱還流した。反応液を０℃に冷却し、水を加えた。炭酸カリウムを加え、析出した結晶を濾取した。結晶を乾燥しN-(3-ホルミル-4-トキシベンジル)フタルイミドを20 g得た。
【００９９】
N-(3-ホルミル-4-メトキシベンジル)フタルイミド20 gとテトラヒドロフラン200 mLの混合物にヒドロキシルアミン塩酸塩5.2 g、酢酸ナトリウム12.2 g、水50 mLを加え室温で１時間撹拌した。６０℃で１時間撹拌し、減圧下濃縮した。残渣に水を加え、不溶物を濾取した。ジエチルエーテルで洗浄し、N-(3-ヒドロキシイミノ-4-メトキシベンジル)フタルイミドを20 g得た。
【０１００】
N-(3-ヒドロキシイミノ-4-メトキシベンジル)フタルイミド20 gとキシレン200 mLの混合物に無水酢酸6.7 mLを加え、１０時間加熱還流した。室温に戻し、析出している結晶を濾取し、キシレンで洗浄し、 N-(3-シアノ-4-メトキシベンジル)フタルイミドを15 g得た。
N-(3-シアノ-4-メトキシベンジル)フタルイミド15 gとエタノール200 mLの混合物にヒドラジン一水和物3.9 gを加え、３時間加熱還流した。冷後、不溶物を濾去した。濾液を減圧下濃縮し、残渣に１N水酸化ナトリウム水溶液を加え、ジクロロメタンで抽出した。抽出液を無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、３−シアノ−４−メトキシベンジルアミンを8.0 g得た。
【０１０１】
1,4-ジクロロフタラジン-6-カルボニトリル、3-シアノ-4-メトキシベンジルアミンをDBU存在下1-メチル-2-ピロリジノン中室温で撹拌することにより、より極性の低い生成物として1-クロロ-4-[(3-シアノ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリルを得た。
¹H NMR (DMSO-d₆) δ; 3.87 (3H, s), 4.70 (2H, d, J = 5.6 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.70 (1H, dd, J = 2.4, 8.4 Hz), 7.75 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 1.2, 8.4 Hz), 8.48 (1H, t, J = 5.6 Hz), 8.97 (1H, s)
中間体製造例６
1-クロロ-4-[(3-エチル-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル
メチルトリフェニルホスホニウムブロミド12.7 gのテトラヒドロフラン80 mL溶液に０℃でカリウム−ｔ−ブトキシド3.99 gを加え、N-(3-ホルミル-4-メトキシベンジル)フタルイミド７gを加え、室温で１時間撹拌した。反応液をセライト濾過し、減圧下濃縮した。残渣シリカゲルカラムクロマトグラフィーで精製し、 N-メ(4-メトキシ-3-ビニルベンジル)フタルイミドを2.75 g得た。
【０１０２】
N-(4-メトキシ-3-ビニルベンジル)フタルイミド2.75 gをテトラヒドロフラン50 mLに溶解し、10% Pd-C 0.1 gを加え、水素雰囲気下４０分撹拌した。セライト濾過し、濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、N-(3-エチル-4-メトキシベンジル)フタルイミドを2.55 g得た。
N-(3-エチル-4-メトキシベンジル)フタルイミド2.55 gとエタノール60 mLの混合物にヒドラジン一水和物0.84 mLを加え、１時間加熱還流した。冷後、減圧下濃縮し、残渣に２N水酸化ナトリウム水溶液を加え、ジクロロメタンで抽出した。抽出液を無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、酢酸エチルを加え、不溶物を濾過した。４Ｎ塩酸（酢酸エチル溶液）を加え、析出した結晶を濾取し、3-エチル-4-メトキシベンジルアミン塩酸塩を1.75 g得た。
【０１０３】
1,4-ジクロロフタラジン-6-カルボニトリル、3-エチル-4-メトキシベンジルアミン塩酸塩をDBU存在下1-メチル-2-ピロリジノン中室温で撹拌することにより、より極性の低い生成物として1-クロロ-4-[(3-エチル-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリルを得た。
¹H NMR (CDCl₃) δ; 1.14 (3H, t, J = 7.5 Hz), 2.60 (2H, q, J = 7.5 Hz), 3.81 (3H, s), 4.84 (2H, s), 6.80 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 2.0 Hz), 7.30 (1H, dd, J = 2.0, 8.2 Hz), 8.06 (1H, d, J = 9.0 Hz), 8.27 (1H, d, J = 9.0 Hz), 8.42 (1H, m)
中間体製造例７
1-クロロ-4-[(3-クロロ-4-メチルベンジル)アミノ]-6-フタラジンカルボニトリル水素化リチウムアルミニウム453 mgのテトラヒドロフラン40 mL溶液に窒素雰囲気下３−クロロ−４−メチルベンゾニトリル2.0 gのテトラヒドロフラン15 mL溶液を滴下した。２時間１０分加熱還流した。氷冷し、１０℃以下に保つように水0.45 mL、１５％水酸化ナトリウム水溶液0.45 mL、水1.35 mLを滴下した。セライト濾過し、濾液に無水硫酸ナトリウムを加え乾燥した。NH-formシリカゲルで濾過し、濾液を減圧下濃縮し、３−クロロ−４−メチルベンジルアミンを1.74 g得た。
【０１０４】
1,4-ジクロロフタラジン-6-カルボニトリル、3-クロロ-4-メチルベンジルアミンをDBU存在下1-メチル-2-ピロリジノン中室温で撹拌することにより、より極性の低い生成物として標記化合物を得た。
¹H NMR (DMSO-d₆) δ; 2.29 (3H, s), 4.73 (2H, d, J = 5.2 Hz), 7.28-7.32 (2H, m), 7.45 (1H, d, J = 0.8 Hz), 8.20 (1H, dd, J = 8.4, 0.4 Hz), 8.34 (1H, d, J = 8.4, 1.6 Hz), 8.52 (1H, t, J = 5.2 Hz), 9.00 (1H, m)
中間体製造例８
1-クロロ-4-[(4-クロロ-3-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル
ＷＯ９５１８０９７に記載の方法により合成した4-クロロ-3-メトキシベンジルアミンベンジルアミン塩酸塩、1,4-ジクロロフタラジン-6-カルボニトリルをDBU存在下1-メチル-2-ピロリジノン中室温で撹拌することにより、より極性の低い生成物として1-クロロ-4-[(4-クロロ-3-メトキシベンジル)アミノ]-6-フタラジンカルボニトリルを得た。
¹H NMR (DMSO-d₆) δ; 3.86 (3H, s), 4.76 (2H, d, J = 5.5 Hz), 4.74 (1H, d, J = 4.2 Hz), 6.99 (1H, dd, J = 1.8, 8.1 Hz), 7.22 (1H, d, J = 1.8 Hz), 7.35 (1H, d, J = 8.1 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.36 (1H, d, J = 8.6 Hz), 8.52 (1H, t, J = 5.5 Hz), 9.03(1H, s)
中間体製造例９
1-クロロ-4-[(3,4-ジクロロベンジル)アミノ]-6-フタラジンカルボニトリル
¹H NMR (DMSO-d₆) δ; 4.76 (2H, d, J = 5.4 Hz), 7.40 (1H, dd, J = 8.4, 1.8 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 1.8 Hz), 8.21 (1H, dd, J = 8.4, 0.4 Hz), 8.36 (1H, dd, J = 8.4, 1.6 Hz), 8.57 (1H, t, J = 5.4 Hz), 8.99 (1H, d, J = 1.6 Hz)
中間体製造例１０
4-フルオロ-4-ヒドロキシメチル-1-ピペリジンカルボン酸ベンジル
【０１０５】
【化４９】

【０１０６】
tert-ブトキシカリウム16.1 gとテトラヒドロフラン500 mLの混合物にメチルトルフェニルホスホニウムブロミド51.1 gを加え、１時間２０分室温で撹拌した。4-オキソ-1-ピペリジンカルボン酸ベンジル16.1 gを加え、２時間４０分室温で撹拌した。反応液を減圧下濃縮しジエチルエーテルを加え、セライト濾過した。濾液を水及び飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し4-メチレン-1-ピペリジンカルボン酸ベンジルを25.5 g得た。
【０１０７】
4-メチレン-1-ピペリジンカルボン酸ベンジル14.7 gをメタノール300 mLに溶解し、フタル酸モノ過酸マグネシウム塩20.4 g及び重曹13.3 gを加え、室温で７．５時間撹拌した。反応液を減圧下濃縮した。残渣に酢酸エチルを加え、水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、1-オキサ-6-アザスピロ[2.5]オクタン-6-カルボン酸ベンジルを11.3 g得た。
【０１０８】
ふっ化水素ピリジン5 mLと塩化メチレン20 mLの混合物を冷却し、1-オキサ-6-アザスピロ[2.5]オクタン-6-カルボン酸ベンジル4.95 gの塩化メチレン10 mL溶液を内温が０℃以下になるように２５分で滴下した。氷冷下３５分撹拌した。反応液を飽和重曹水と氷の混合物中に注いだ。有機層を分取し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、標記化合物を2.84 g得た。
中間体製造例１１
4-ヒドロキシ-4-(1H-1-イミダゾリルメチル)-1-ピペリジンカルボン酸tert-ブチル
【０１０９】
【化５０】

【０１１０】
4-メチレン-1-ピペリジンカルボン酸tert-ブチル13.5 gをメタノール300 mLに溶解し、フタル酸モノ過酸マグネシウム塩28.3 g及び重曹8.62 gを加え、室温で１日撹拌した。反応液をセライト濾過し、濾液を減圧下濃縮した。残渣に酢酸エチルを加え、水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、1-オキサ-6-アザスピロ[2.5]オクタン-6-カルボン酸tert-ブチルを12.2 g得た。
【０１１１】
1-オキサ-6-アザスピロ[2.5]オクタン-6-カルボン酸tert-ブチル4.25 gをジメチルホルムアミド30 mLに溶解し、イミダゾールナトリウム5.38 gを加え、６０℃で３時間４０分撹拌した。冷後、反応液に酢酸エチルを加え、水で３回、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、4-ヒドロキシ-4-(1H-1-イミダゾリルメチル)-1-ピペリジンカルボン酸tert-ブチルを4.93 g得た。
中間体製造例１２
4-ヒドロキシ-4-(1H-1,2,4-トリアゾール-1-イルメチル)-1-ピペリジンカルボン酸tert-ブチル
中間体製造例１１のイミダゾールナトリウムの代わりに1,2,4-トリアゾールナトリウムを用いて、標記化合物を得た。
中間体製造例１３
4-フルオロメチル-4-ヒドロキシ-1-ピペリジンカルボン酸ベンジル
1-オキサ-6-アザスピロ[2.5]オクタン-6-カルボン酸ベンジル5 gにふっ化水素カリウム3.2 g、テトラ−n−ブチルアンモニウムジハイドロジェントリフルオリド610 mgを加え、１２０℃で７時間撹拌した。冷後、塩化メチレンを加え、セライト濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し、標記化合物を4.7 g得た。
中間体製造例１４
4-ヒドロキシ-4-ピペリジンカルボキサミド塩酸塩
濃硫酸18 mLと水1.8 mLの混合液を０℃に冷却し、1-ベンジル-4-ヒドロキシ-4-ピペリジンカルボニトリル塩酸塩5 gを少量ずつ加えた。濃硫酸25 mLと水2.5 mLの混合液を加え、室温で２時間撹拌した。フリーザー中に一夜放置した。反応液を氷に注ぎ、水酸化ナトリウム47 gを少量ずつ加えた。テトラヒドロフラン、酢酸エチル（１：１）の混合溶媒で３回抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、1-ベンジル-4-ヒドロキシ-4-ピペリジンカルボキサミドを3.19 g得た。
【０１１２】
1-ベンジル-4-ヒドロキシ-4-ピペリジンカルボキサミド3.19 gをメタノール150mLに溶解し、20%含水水酸化パラジウム 1.5 gを加えた。４気圧水素雰囲気下４時間震とうした。反応液をセライト濾過し、濾液をに4N HCl-ジオキサン5 mLを加え、減圧下濃縮した。結晶性残渣をジイソプロピルエーテルで洗浄濾取し、標記化合物を1.96 g得た。
中間体製造例１５
N-(3-クロロ-4-メトキシベンジル)-N-[4-クロロ-7-(1H-1-ピラゾリル)-1-フタラジニル]アミン
【０１１３】
【化５１】

【０１１４】
4-フルオロフタル酸無水物100ｇとメタノール1500 mLの混合物に塩化チオニル110 mLを３０分で滴下した。８時間加熱還流し、減圧下濃縮した。残渣に氷水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、4-フルオロフタル酸ジメチルを125 g得た。
【０１１５】
ピラゾール44 gの1-メチル-2-ピロリジノン200 mL溶液に油性水素化ナトリウム26 gを４０分で加えた。4-フルオロフタル酸ジメチル125 gを３０分で加え、室温で２時間撹拌した。反応液を０℃に冷却し、氷水に加えた。酢酸エチルで抽出し、飽和重曹水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、得られた結晶性残渣にジエチルエーテルを加え濾取し、4-(1H-1-ピラゾリル）フタル酸ジメチルを77ｇ得た。
【０１１６】
4-(1H-1-ピラゾリル）フタル酸ジメチル77 gとエタノール500ｍＬの混合物にヒドラジン１水和物22 mLを加え、６時間加熱還流した。冷後、沈殿物を濾取し、6-(1H-1-ピラゾリル)-1,4-フタラジンジオンを36 g得た。
6-(1H-1-ピラゾリル)-1,4-フタラジンジオン5.0 gとオキシ塩化リン20 mLの混合物にジイソプロピルエチルアミン15 mLを加え、１１０℃で０．５時間撹拌した。反応液を０℃に冷却し、酢酸エチルを加え、更に氷及び水を少量ずつ加えた。０℃で０．５時間撹拌し、不溶物を濾去した。酢酸エチル層を分取し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、得られた結晶性残渣に酢酸エチルを加え濾取し、1,4-ジクロロ-6-(1H-1-ピラゾリル）フタラジンを3.8 g得た。
【０１１７】
1,4-ジクロロ-6-(1H-1-ピラゾリル）フタラジン8 g、3-クロロ-4-メトキシベンジルアミン塩酸塩を9.5 g、1-メチル-2-ピロリジノン30 mLの混合物にDBU 14 mLを加え、室温で１時間撹拌した。更に６０℃で３時間撹拌した。反応液を０℃に冷却し、酢酸エチルを加え、水及び飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、濾過し濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、より極性の低い生成物として標記化合物を2.6 g得た。
¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.68 (2H, d, J = 6.0 Hz), 6.70 (1H, t, J = 2.0 Hz), 7.09 (1H, d, J = 8.8 Hz), 7.35 (1H, dd, J = 2.0, 8.4 Hz), 7.47 (1H, d, J = 2.0 Hz), 7.91 (1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 9.2 Hz), 8.32 (1H, t , J = 5.6 Hz), 8.50 (1H, dd, J = 2.0, 8.8 Hz), 8.68 (1H, d, J = 2.4 Hz), 8.78 (1H, d, J = 2.0 Hz)
中間体製造例１６
N-(3-クロロ-4-メトキシベンジル)-N-[4-クロロ-7-(1H-1,2,3-トリアゾール-1-イル)-1-フタラジニル]アミン
ピラゾールの代わりに1,2,3-トリアゾールを用い実施例１５と同様にして標記化合物を得た。
¹H NMR (CD₃OD) δ; 3.82 (3H, s), 4.72 (2H, s), 6.97 (1H, d, J = 8.4 Hz), 7.34 (1H, dd, J = 1.6, 8.4 Hz), 7.44 (1H, d, J = 1.6 Hz), 7.99 (1H, d, J = 1.2 Hz), 8.34 (1H, d, J = 8.8 Hz), 8.52 (1H, dd, J = 1.6, 8.8 Hz), 8.72 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 2 Hz)
中間体製造例１７
6-ブロモ-1-クロロ-4-[(3-クロロ-4-メトキシベンジル)アミノ]フタラジン
4-ブロモフタル酸無水物20 g とエタノール400ｍＬの混合物にヒドラジン１水和物96.9 mLを加え、８時間加熱還流した。冷後、沈殿物を濾取し、6-ブロモ-1,4-フタラジンジオンを28 g得た。
【０１１８】
6-ブロモ-1,4-フタラジンジオン6.8 gとオキシ塩化リン15 mLの混合物にジイソプロピルエチルアミン15 mLを加え、１．５時間加熱還流した。冷後、反応液を氷水に注ぎ良く撹拌し、塩化メチレンで抽出した。水層を酢酸エチルで抽出した。合わせた抽出液を無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し、6-ブロモ-1,4-ジクロロフタラジンを4.3 g得た。
【０１１９】
6-ブロモ-1,4-ジクロロフタラジン3.8 g、3-クロロ-4-メトキシベンジルアミン塩酸塩を3.5 g、1-メチル-2-ピロリジノン30 mLの混合物にDBU 5.2 mLを加え、１００℃で３時間撹拌した。冷後、反応液に水を加え酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、濾過し濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、より極性の低い生成物として標記化合物を1.8 g得た。
中間体製造例１８
1-(1,1-ジメチル-2-プロピニル)-4-ピペリジノール
4-ヒドロキシピペリジン7.3 gのジエチルエーテル5 mL、水2.5 mLの混合溶液に、窒素雰囲気下塩化第一銅24 mg、銅粉15 mgを加えた。氷冷し、内温が１７〜２２℃で3-クロロ-3-メチル-1-ブチン2.7 mLのジエチルエーテル2.5 mL溶液を滴下した。室温で一夜撹拌した。水を加え、ジエチルエーテルで５回抽出した。有機層を合わせ炭酸カリウムで次いで水酸化カリウムで乾燥し、濾過した。濾液を常圧で濃縮し、得られた結晶性残渣を酢酸エチル−ヘキサンを加え濾取し、を2.54 g得た。
中間体製造例１９
1-(1,1-ジメチル-2-プロピニル)ピロリジン
ピロリジンと3-クロロ-3-メチル-1-ブチンより中間体製造例１８と同様にして、標記化合物を得た。
中間体製造例２０
(2R)-1-オキサ-8-アザスピロ[4.5]デカ-2-イルメタノール
(5S)-5-(ヒドロキシメチル)テトラヒドロ-2-フラノン105.5gをピリジン1.2lに溶解し、トリチルクロリド380gを室温で加え、80℃で一夜撹拌した。反応終了後、冷却し水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄した。溶媒を除き、クロロホルム300mlに溶かし、シリカゲル600mlを加えてから溶媒を除いた。シリカゲルカラムクロマトグラフィーで精製して(5S)-5-[(トリチルオキシ)メチル]テトラヒドロ-2-フラノン149.3gを得た。
【０１２０】
(5S)-5-[(トリチルオキシ)メチル]テトラヒドロ-2-フラノン26.9gをTHF200mlに溶かし、１ＭビニルマグネシウムブロミドTHF溶液300mlを室温で加え、加熱環流下1.5時間撹拌した。反応終了後、氷冷下で飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、飽和食塩水で２回洗浄した。溶媒を除き、シリカゲルカラムクロマトグラフィーで精製して(2S)-1-(トリチルオキシ)-5-ビニル-6-ヘプテン-2,5-ジオール13.0gを得た。
【０１２１】
(2S)-1-(トリチルオキシ)-5-ビニル-6-ヘプテン-2,5-ジオール体13.0gおよびトルエンスルホニルクロリド57.2gをピリジン200mlに溶かし、80℃で一夜撹拌した。反応終了後、水を加え、室温で10分間撹拌した。酢酸エチルで２回抽出した後、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を除き、トルエンに溶かして再び溶媒を除いた後、シリカゲルカラムクロマトグラフィーで精製して(5R)-5-[(トリチルオキシ)メチル]-2,2-ジビニルテトラヒドロフラン5.88gを得た。
【０１２２】
(5R)-5-[(トリチルオキシ)メチル]-2,2-ジビニルテトラヒドロフラン体4.68g、0.5M 9-BBN100mlおよび9-BBNdimer6.1gをTHF100mlにけんだくさせ、加熱環流下、30時間撹拌した。冷後30%過酸化水素水50mlと3N水酸化ナトリウム50mlを氷冷下で加え、50℃で２０時間撹拌した。反応終了後、室温に戻し酢酸エチルで抽出し、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を除き、シリカゲルカラムクロマトグラフィーで精製した後、シリカゲルカラムクロマトグラフィーで精製して2-(5R)-2-(2-ヒドロキシエチル)-5-[(トリチルオキシ)メチル]テトラヒドロ-2-フラニル-1-エタノール2.68gを得た。
【０１２３】
2-(5R)-2-(2-ヒドロキシエチル)-5-[(トリチルオキシ)メチル]テトラヒドロ-2-フラニル-1-エタノール2.68gおよびピリジン12mlをジクロロメタン30mlに溶かし、トルエンスルホニルクロリド11.82gを氷冷下で加え、2.5時間撹拌した。反応終了後、ピリジン30mlを加え濃縮し、再び氷冷下でピリジンと水を加えて15分間撹拌した。酢酸エチルで抽出し、飽和食塩水で洗浄した後硫酸マグネシウムで乾燥した。溶媒を留去し、トルエンを加えてから再び溶媒を留去した後、シリカゲルカラムクロマトグラフィーで精製して2-(5R)-2-[2-[(4-メチルフェニル)フルホニル]オキシエチル]-5-[(トリチルオキシ)メチル]テトラヒドロ-2-フラニルエチル 4-メチル-1-ベンゼンスルホナート4.17gを得た。
【０１２４】
2-(5R)-2-[2-[(4-メチルフェニル)フルホニル]オキシエチル]-5-[(トリチルオキシ)メチル]テトラヒドロ-2-フラニルエチル 4-メチル-1-ベンゼンスルホナート4.17gおよびベンジルアミン5.36gをDMF80mlに溶かし、110℃で11.5時間撹拌した。反応終了後水を加え、酢酸エチルで抽出し、飽和食塩水と飽和重曹水で２回洗浄した。硫酸マグネシウムで乾燥した後、溶媒を除き、シリカゲルカラムクロマトグラフィーで精製して(2R)-8-ベンジル-2-[(トリチルオキシ)メチル]-1-オキサ-8-アザスピロ[4.5]デカン2.1gを得た。
【０１２５】
(2R)-8-ベンジル-2-[(トリチルオキシ)メチル]-1-オキサ-8-アザスピロ[4.5]デカン2.10gをTHF20mlに溶かし、氷冷下、4N塩酸1,4-ジオキサン溶液8mlを加え、１時間撹拌した。反応終了後、水および飽和重曹水を加え、酢酸エチルで２回抽出し、飽和重曹水および飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を除き、シリカゲルカラムクロマトグラフィーで精製して[(2R)-8-ベンジル-1-オキサ-8-アザスピロ[4.5]デカ-2-イル]メタノール1.03gを得た。
【０１２６】
[(2R)-8-ベンジル-1-オキサ-8-アザスピロ[4.5]デカ-2-イル]メタノール1.03gおよび10%パラジウムカーボン0.45gをエタノール30mlにけんだくさせ、１気圧の水素雰囲気下、室温で18時間撹拌した。不溶物を濾去し、溶媒を除き、乾燥させて標記化合物0.76gを得た。
中間体実施例２１
4-オキソ-1-ピペリジンカルボン酸tert-ブチル25.0 gをジエチルエーテル800 mL溶液を氷−メタノールで冷却し、アリルマグネシウムブロミド（１Ｍinジエチルエーテル）溶液138 mLを滴下した。３時間１０分撹拌した。反応液を飽和塩化アンモニウム水溶液と氷の混合物に注いだ。ジエチルエーテル層を分取し、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、4-アリル-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチルを15.9 g得た。
【０１２７】
4-アリル-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチル9.83g をテトラヒドロフラン-水(9:1) 60ml に溶解し、四酸化オスミウムtert-ブチルアルコール溶液(2.5wt%, 2ml)とN-メチルモルホリン-N-オキシド6.68gを加え、室温にて終夜撹拌した。反応液を減圧下に濃縮し、残渣を酢酸エチルと水に分配し、飽和塩化ナトリウム溶液にて洗浄し、硫酸マグネシウムにて乾燥した。濾過後、溶媒を減圧下で留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル-メタノール）にて精製し、tert-butyl 4-(2,3-ジヒドロキシプロピル)-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチルを9.11g 得た。
【０１２８】
4-(2,3-ジヒドロキシプロピル)-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチル9.11g をピリジン 40ml に溶解し、クロロトリフェニルメタン10.0gを加え室温にて終夜撹拌した。反応液を酢酸エチルと水に分配し、２規定塩酸、水、飽和炭酸水素ナトリウム溶液、飽和塩化ナトリウム溶液にて洗浄し、硫酸マグネシウムにて乾燥した。濾過後、溶媒を減圧下で留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン-酢酸エチル）にて精製し、4-[3-(tert-ブトキシ)-2-ヒドロキシプロピル]-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチルを10.3g得た。
【０１２９】
4-[3-(tert-ブトキシ)-2-ヒドロキシプロピル]-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチル2.59g をジメチルホルムアミド10ml に溶解し、水素化ナトリウム400mgとベンジルクロリド823mgを加え、室温にて20分間撹拌した。反応液を氷水に注ぎ、酢酸エチルで抽出し、水、飽和塩化ナトリウム溶液にて洗浄し、硫酸マグネシウムにて乾燥した。濾過後、溶媒を減圧下で留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン-酢酸エチル）にて精製し、4-[2-(ベンジルオキシ)-3-(tert-ブトキシ)プロピル]-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチルを2.66g 得た。
【０１３０】
4-[2-(ベンジルオキシ)-3-(tert-ブトキシ)プロピル]-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチル2.36g をアセトニトリル40ml に溶解し、セリウムアンモニウムナイトレイト426mgを加え室温にて終夜撹拌した。反応液にシリカゲルを加え、減圧下に濃縮した。吸着シリカゲルを非吸着シリカゲルカラムに充填し、ヘキサン-酢酸エチルにて精製し、4-[2-(ベンジルオキシ)-3-ヒドロキシプロピル]-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチルを 547mg 得た。
【０１３１】
4-[2-(ベンジルオキシ)-3-ヒドロキシプロピル]-4-ヒドロキシ-1-ピペリジンカルボン酸tert-ブチル4.81g をピリジン２0ml に溶解し、トシルクロリド2.76gを加え室温にて2時間撹拌した。さらにトシルクロリド1.00gを加え、室温で30分間、50℃で35分間撹拌した。反応液を酢酸エチルと水に分配し、1規定塩酸、飽和炭酸水素ナトリウム溶液、飽和塩化ナトリウム溶液にて洗浄し、硫酸マグネシウムにて乾燥した。濾過後、溶媒を減圧下で留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン-酢酸エチル）にて精製し、3-(ベンジルオキシ)-1-オキサ-8-アザスピロ[4.5]デカン-8-カルボン酸tert-ブチルを3.72g を得た。
【０１３２】
3-(ベンジルオキシ)-1-オキサ-8-アザスピロ[4.5]デカン-8-カルボン酸tert-ブチル6.47g をテトラヒドロフラン100ml に溶解し、パラジウム炭素1.3gを加え、水素雰囲気下で終夜撹拌した。反応液から触媒を濾取し、パラジウム炭素1.3gを加え、水素雰囲気下にて終夜撹拌した。反応液から触媒を濾取し、パラジウム炭素2.6gを加え水素雰囲気下4.2気圧で終夜撹拌した。反応液から触媒を濾取し、溶媒を減圧下で留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル-メタノール）にて精製し、3-ヒドロキシ-1-オキサ-8-アザスピロ[4.5]デカン-8-カルボン酸tert-ブチルを4.27g 得た。
中間体製造例２２
(anti)-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-オール塩酸塩
水素化アルミニウムリチウム2.0gをテトラヒドロフラン200mlに懸濁し氷冷下、9-メチル-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-オン 14.17gをテトラヒドロフラン20mlに溶解した溶液を滴下した。35分撹拌した後、反応液に水2.0ml、15%水酸化ナトリウム水溶液2.0ml、水6.0mlを順次加え室温で撹拌した。反応液を濾過し、溶媒を減圧下で留去した。残査を酢酸エチルに溶解しアルミナで濾過した。溶媒を減圧下で濃縮し、(anti)- 9-メチル-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-オールを黄色蝋状物として10.00g得た。
【０１３３】
(anti)- 9-メチル-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-オール 10.0gをテトラヒドロフラン100mlに溶解しトリエチルアミン10.7ml、無水酢酸7.2mlおよび4-ジメチルアミノピリジン0.77gを加え50℃で終夜撹拌した。反応液を減圧下で濃縮し、残査を酢酸エチルに溶解しアルミナで濾過した。濾液を濃縮しアルミナカラムクロマトグラフィー（溶媒；n-ヘキサン：酢酸エチル）で精製し、(anti)-9-メチル-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-イルアセタートを淡黄色油状物として8.68g得た。
【０１３４】
(anti)-9-メチル-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-イルアセタート 8.68gを１，２−ジクロロエタン40mlに溶解し、クロロぎ酸ビニル 7.0mlを加え室温で30分撹拌した後、2時間35分加熱還流した。反応液を減圧下で濃縮後、シリカゲルカラムクロマトグラフィー（溶媒；n-ヘキサン：酢酸エチル）で精製し、(anti)-3-オキサ-9-ビニルオキシカルボニル-9-アザビシクロ[3.3.1]ノナン-7-イルアセタートを淡黄色油状物として8.96g得た。
【０１３５】
(anti)-3-オキサ-9-ビニルオキシカルボニル-9-アザビシクロ[3.3.1]ノナン-7-イルアセタート 8.96gをメタノール45mlに溶解し、水30mlおよび炭酸カリウム7.3gを加え室温で1時間30分撹拌し、更に50℃で30分撹拌した。反応液を減圧下で濃縮後、飽和食塩水を加え酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去し、(anti)-3-オキサ-9-ビニルオキシカルボニル-9-アザビシクロ[3.3.1]ノナン-7-オールを淡黄色油状物として7.37g得た。
【０１３６】
(anti)-3-オキサ-9-ビニルオキシカルボニル-9-アザビシクロ[3.3.1]ノナン-7-オール 7.37gに4N-塩化水素-ジオキサン溶液17mlを加え室温で30分撹拌した。反応液にエタノール40mlを加え1時間加熱還流した。溶媒を減圧下で留去し、残査に酢酸エチルを加え析出物を濾取し、標記化合物を白色針状晶として5.55g得た。
中間体製造例２３
(syn)-3-アザビシクロ[3.2.1]オクタン-8-オール塩酸塩
3-メチル-3-アザビシクロ[3.2.1]オクタン-8-オンより中間体製造法２２と同様にして標記化合物を得た。
中間体製造例２４
(anti)-3-オキサ-7-アザビシクロ[3.3.1]ノナン-9-オール塩酸塩
7-メチル-3-オキサ-7-アザビシクロ[3.3.1]ノナン-9-オンより中間体製造法２２と同様にして標記化合物を得た。
中間体製造例２５
(anti)-9-アザビシクロ[3.3.1]ノナン-3-オール塩酸塩
9-メチル-9-アザビシクロ[3.3.1]ノナン-3-オンより中間体製造法２２と同様にして標記化合物を得た。
中間体製造例２６
(exo)-8-アザビシクロ[3.2.1]オクタン-3-オール塩酸塩
(exo)-8-メチル-8-アザビシクロ[3.2.1]オクタン-3-オールよりアセチル化後、中間体製造例２２と同様にして標記化合物を得た。
中間体製造例２７
(endo)-8-アザビシクロ[3.2.1]オクタン-3-オール塩酸塩
(endo)-8-メチル-8-アザビシクロ[3.2.1]オクタン-3-オールよりアセチル化後、中間体製造例２２と同様にして標記化合物を得た。
中間体製造例２８
(anti)-3-アザビシクロ[3.3.1]ノナン-9-オール塩酸塩
水素化アルミニウムリチウム1.0gをテトラヒドロフラン100mlに懸濁し氷冷下、3-メチル-3-アザビシクロ[3.3.1]ノナン-9-オン 7.00gをテトラヒドロフラン20mlに溶解した溶液を滴下した。50分撹拌した後、反応液に水1.0ml、15%水酸化ナトリウム水溶液1.0ml、水3.0mlを順次加え室温で撹拌した。反応液を濾過後、溶媒を減圧下で留去し、淡黄色油状物7.08gを得た。これをテトラヒドロフラン90mlに溶解しトリエチルアミン9.55mlを加え,氷冷下撹拌した。無水酢酸6.46mlおよび4-ジメチルアミノピリジン0.56gを加え室温で14時間撹拌した。メタノール約20mlを加え反応液を減圧下で濃縮し、残査に炭酸カリウム水溶液を加え酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下で留去後、シリカゲルカラムクロマトグラフィー（溶媒；n-ヘキサン：酢酸エチル）で精製し、より極性の低い生成物として(anti)-3-メチル-3-アザビシクロ[3.3.1]ノナン-9-イルアセタート（無色油状物）を3.33g得た。また、より極性の高い生成物として(syn)-3-メチル-3-アザビシクロ[3.3.1]ノナン-9-イルアセタート（淡橙色油状物）を2.06g得た。
【０１３７】
(anti)-3-メチル-3-アザビシクロ[3.3.1]ノナン-9-イルアセタート 2.06gを１，２−ジクロロエタン10mlに溶解し、クロロぎ酸ビニル 2.07mlを加え室温で50分撹拌した後、5時間25分加熱還流した。反応液を減圧下で濃縮し、残査に水を加え酢酸エチルで抽出した。有機層を1N-塩酸、飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下で留去し、(anti)-3-ビニルオキシカルボニル-3-アザビシクロ[3.3.1]ノナン-9-イルアセタートを淡橙色油状物として2.51g得た。
【０１３８】
(anti)-3-ビニルオキシカルボニル-3-アザビシクロ[3.3.1]ノナン-9-イルアセタート 4.02gをエタノール36mlに溶解し、1N-水酸化ナトリウム水溶液18mlを加え室温で1時間50分撹拌した。反応液を減圧下で濃縮し、残査に水を加え酢酸エチルで抽出した。有機層を水、飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下で留去後、シリカゲルカラムクロマトグラフィー（溶媒；n-ヘキサン：酢酸エチル）で精製し、(anti)-3-ビニルオキシカルボニル-3-アザビシクロ[3.3.1]ノナン-9-オールを微黄色油状物として3.09g得た。
【０１３９】
(anti)-3-ビニルオキシカルボニル-3-アザビシクロ[3.3.1]ノナン-9-オール 3.09gに4N-塩化水素-ジオキサン溶液7mlを加え室温で50分撹拌した。反応液を減圧下で濃縮し、残査にエタノール30mlを加え50分加熱還流した。溶媒を減圧下で留去し、残査に酢酸エチルを加え析出物を濾取し、標記化合物を微乳白色粉末として2.41g得た。
中間体製造例２９
(syn)-3-アザビシクロ[3.3.1]ノナン-9-オール酸塩
(syn)-3-メチル-3-アザビシクロ[3.3.1]ノナン-9-イルアセタートより中間体製造例２８と同様にして標記化合物を得た。
中間体製造例３０
(anti)-2-(3-アザビシクロ[3.3.1]ノン-9-イル)-1-エタノール塩酸塩
水素化アルミニウムリチウム1.0gをテトラヒドロフラン30mlに懸濁し氷冷下、(anti)-メチル (3-アザビシクロ[3.3.1]ノン-9-イル)アセタート 3.24gをテトラヒドロフラン25mlに懸濁したものを滴下した。35分撹拌した後、反応液に水1.0ml、15%水酸化ナトリウム水溶液1.0ml、水3.0mlを順次加え室温で撹拌した。セライトおよび無水硫酸ナトリウムを加え濾過し、溶媒を減圧下で留去した。残査を酢酸エチルに溶解し、4N-塩化水素-酢酸エチル溶液5mlを加え析出物を濾取し、標記化合物を白色粉末として2.29g得た。
中間体製造例３１
1-クロロ-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラジンカルボニトリル
¹H NMR (DMSO-d₆) δ; 2.10 (3H, s), 3.73 (3H, s), 4.64 (2H, d, J = 5.4 Hz), 6.85 (1H, d, J = 8.0 Hz), 7.17-7.21 (2H, m), 8.15 (1H, d, J = 8.6 Hz), 8.31 (1H, dd, J = 8.6, 1.2 Hz), 8.35 (1H, t, J = 5.4 Hz), 9.00 (1H, d, J = 1.2 Hz)
実施例１
4-(3-クロロ-4-メトキシベンジル）アミノ-6-シアノ-1-(3-ピリジル)フタラジン・二塩酸塩
【０１４０】
【化５２】

【０１４１】
3-ブロモピリジン2.53gの無水ジエチルエーテル50mL溶液に-70℃以下で、ｎ-ブチルリチウム1.6Mヘキサン溶液10mLを滴下し、30分間攪拌した。この混合物にトリ-ｎ-ブチルすずクロリド5.21gの無水ジエチルエーテル10mL溶液を加えた。反応液を１時間で室温にした。反応液を飽和食塩水に注ぎ、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下濃縮し、3-(1,1,1-トリ-n-ブチルスタニル)ピリジンを黄色油状物として得た。
【０１４２】
1-クロロ-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジン1.80g、テトラキス（トリフェニルホスフィン）パラジウム579mg、キシレン25mLと1-メチル-2-ピロリドン3mLの混合物を激しく攪拌し、加熱還流させ、これに上で得た3-(1,1,1-トリ-n-ブチルスタニル)ピリジンのキシレン25mL溶液を１時間で滴下した。反応液をさらに１５分間加熱還流した。反応液を室温に戻し、水で３回、飽和食塩水で１回洗浄した。シリカゲルカラムクロマトグラフィーで精製し、カップリング体を得た。これをテトラヒドロフランとメタノールの混合溶媒に懸濁し、４Ｎ塩酸−酢酸エチル溶液を加え、減圧下濃縮した。酢酸エチル-メタノールより再結晶し、表記化合物を無色の粉末として1.80g得た。
MASS(ESI)；402.0(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ; 3.85 (3H, s), 4.06 (2H, br), 4.89 (2H, br), 7.18 (1H, d, J= 8.0 Hz), 7.53 (1H, dd, J = 8.0, 1.2 Hz), 7.67 (1H, d, J = 1.2 Hz), 7.81-7.90 (1H, m), 8.07 (1H, dd, J = 8.8, 0.4 Hz), 8.38-8.45 (1H, m), 8.46 (1H, dd, J = 8.8, 1.4 Hz), 8.90-9.00 (2H, m), 9.57 (1H, dd, J = 1.4, 0.4 Hz), 10.76 (1H, br)
実施例２
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-(2-ピリジル)フタラジン・二塩酸塩
【０１４３】
【化５３】

【０１４４】
実施例１の3-ブロモピリジンの代わりに2-ブロモピリジンを用いて同様にして標記化合物を得た。
MASS(ESI)；402.0(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ; 3.83 (3H, s), 4.86-4.90 (2H, m), 7.16 (1H, d, J = 8.6 Hz), 7.52 (1H, dd, J = 8.6, 2.1 Hz), 7.63-7.69 (2H, m), 7.97 (1H, d, J = 8.5 Hz), 8.08-8.13 (1H, m), 8.47 (1H, dd, J = 8.5, 1.4 Hz), 8.72-8.83 (2H, m), 9.56 (1H, d, J = 1.4 Hz), 10.82-10.92 (1H, m).
実施例３
4-(3-クロロ-4-メトキシベンジル）アミノ-6-シアノ-1-(4-シアノピペリジノ)フタラジン塩酸塩
【０１４５】
【化５４】

【０１４６】
4-ピペリジンカルボキサミド15g、塩化ベンジル16.3g、炭酸カリウム32.3gとN,N-ジメチルホルムアミド200mLの混合物を80℃で4時間攪拌した。反応液を室温に戻し、水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。得られた結晶性残渣をヘキサン-酢酸エチルで洗浄し、ろ取した。白色鱗片状結晶として、1-ベンジル-4-ピペリジンカルボキサミド12.7g得た。
【０１４７】
1-ベンジル-4-ピペリジンカルボキサミド12.7gとオキシ塩化リン60mLの混合物に氷冷下、N,N-ジメチルホルムアミド5mLを加え、室温で、1.5時間攪拌した。減圧下濃縮し、残渣を酢酸エチルに溶解し、水酸化ナトリウム水溶液、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下濃縮し、得られた残渣を、シリカゲルカラムクロマトグラフィーで精製し、1-ベンジル-4-ピペリジンカルボニトリルを11.0g得た。
【０１４８】
1-ベンジル-4-ピペリジンカルボニトリル11.0gを1,2-ジクロロエタン100mLに溶解し、氷冷下、クロロ蟻酸1-クロロエチル7.1mLを加え、室温で15分間攪拌後、1時間20分加熱還流した。減圧下濃縮後、メタノール50mLを加え、1時間加熱還流した。減圧下濃縮し、酢酸エチルで結晶性残渣を洗浄ろ取し、4-ピペリジンカルボニトリル塩酸塩を白色結晶として8.0g得た。
【０１４９】
このようにして得た4-ピペリジンカルボニトリル塩酸塩1.2gおよび1-クロロ-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジン1.0g、ジイソプロピルエチルアミン1.8g、1-メチル-2-ピロリドン10mLの混合物を170℃で２時間３０分攪拌した。冷後、反応液に酢酸エチルを加え、水及び飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、残さをシリカゲルカラムクロマトグラフィーで精製した。得られたフリー体を酢酸エチルに溶解し、４Ｎ塩酸−酢酸エチル溶液を加え、析出した結晶をろ取し標記化合物を黄色の粉末として880ｍg得た。
MASS(ESI)；433.2(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ; 1.98-2.17(4H, m), 3.10-3.33 (5H, m), 3.86 (3H, s), 4.70-4.74 (2H, m), 7.17 (1H, d, J= 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.27 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.34-9.38 (1H, m), 10.28 (1H, br)
実施例４
4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノ-1-(4-シアノピペリジノ)フタラジン塩酸塩
【０１５０】
【化５５】

【０１５１】
実施例３の1-クロロ-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジンの代わり1-クロロ-4-(3-クロロ-4-メトキシフェネチル)アミノ-6-シアノフタラジンを用い、標記化合物を得た。
MASS(ESI)；447.1(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.97-2.18 (4H, m), 2.94-3.00 (2H, m), 3.11-3.23 (3H, m), 3.33-3.40 (2H, m), 3.72-3.80 (2H, m), 3.82 (3H, s), 7.09 (1H, d, J= 8.4 Hz), 7.27 (1H, dd, J = 8.4, 2.0 Hz), 7.44 (1H, d, J = 2.0 Hz), 8.28 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.23-9.28 (1H, m), 9.85 (1H, br)
実施例５
1-(4-アミノピペリジノ)-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジン・二塩酸塩
【０１５２】
【化５６】

【０１５３】
1-クロロ-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジン10.0ｇを1-メチル-2-ピロリドン50mLに溶解し、4-ヒドロキシピペリジン43.32g、ジイソプロピルエチルアミン10mLを加え、170℃で8時間加熱した。冷後、酢酸エチルを加え、水で３回、飽和食塩水で1回洗浄した。無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、1-(4-ヒドロキシピペリジノ)-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジンを黄色結晶として10.1g得た。
【０１５４】
次に1-(4-ヒドロキシピペリジノ)-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジン4.2g、フタルイミド2.94g、トリフェニルホスフィン5.24gのテトラヒドロフラン100mL溶液に、氷冷下ジエチルアゾジカルボキシラート3.48gのテトラヒドロフラン30mL溶液を30分で滴下し、４℃で２４時間攪拌した。反応液を減圧下濃縮し、水と酢酸エチルを加え、不溶物をろ去した。有機層を濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-(4-フタルイミドピペリジノ)フタラジンを4.85g得た。
【０１５５】
この4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-(4-フタルイミドピペリジノ)フタラジンを4.85g、ヒドラジン１水和物4mLとエタノール40mLの混合物を１時間加熱還流した。反応液を減圧下濃縮し、酢酸エチルに溶解し、1N塩酸を加え、pH=3とし、不溶物をろ去した。ろ液の水層を1N水酸化ナトリウム水溶液でpH=11とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下濃縮後、シリカゲルカラムクロマトグラフィーで精製し、生成物をエタノール−水に懸濁し、1Ｎ塩酸水溶液を加え加熱溶解した。冷後、析出した結晶をろ取し表記化合物を黄色の粉末として440ｍｇ得た。
MASS(FAB)；423(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.78-1.92 (2H, m), 2.03-2.11 (2H, m), 2.90-3.0 (2H, m), 3.20-3.34 (1H, m), 3.54-3.63 (2H, m), 3.82 (3H, s), 4.70 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J= 8.4 Hz), 7.47 (1H, dd, J = 8.4, 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 8.4 Hz), 8.35-8.45 (2H, m), 8.47 (1H, dd, J = 8.4, 1.0 Hz), 9.54 (1H, d, J = 1.0 Hz), 10.63 (1H, br)実施例６
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-[4-ヒドロキシ-4-(ヒドロキシメチル)ピペリジノ]フタラジン塩酸塩
【０１５６】
【化５７】

【０１５７】
60％水素化ナトリウム7.9gをヘキサンで洗浄後、減圧下乾燥した。ジメチルスルホキシド100mLを加え、窒素雰囲気下、80〜100℃で30分間攪拌した。氷冷し、テトラヒドロフラン180mLを加え、ヨウ化トリメチルスルホニウム43.7gのジメチルスルホキシド150mL溶液を滴下した。氷冷下30分間攪拌後1-ベンジル-4-ピペリドン15gを加え、氷冷下30分間攪拌した後、室温で6時間攪拌した。反応液に、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。シリカゲルカラムクロマトグラフィーで精製し、6-ベンジル-1-オキソ-6-アザスピロ[2.5]オクタンを6.8g得た。
【０１５８】
この6-ベンジル-1-オキソ-6-アザスピロ[2.5]オクタン6.8gのテトラヒドルフラン100mL溶液に、水100mLと過塩素酸10mLを加え、室温で7時間攪拌した。氷冷し、炭酸ナトリウム水溶液を加え、pH=7とし、減圧下濃縮した。残渣に酢酸エチルを加え、不要物をろ去した。ろ液を減圧下濃縮後、シリカゲルカラムクロマトグラフィーで精製し、1-ベンジル-4-(ヒドロキシメチル)-4-ピペリジノールを4g得た。
【０１５９】
次に1-ベンジル-4-(ヒドロキシメチル)-4-ピペリジノール1.46gをメタノール30mLに溶解し、酢酸10mLおよび10%Pd-Cを加え、４気圧で水素添加した。反応液を、セライトでろ過し、ろ液を減圧下濃縮し、メタノールに溶解し、4N塩酸-酢酸エチル溶液を加え、濃縮した。メタノール-酢酸エチルより結晶化させろ取し、4-(ヒドロキシメチル)-4-ピペリジノール塩酸塩を880mg得た。
【０１６０】
実施例３と同様にこの4-(ヒドロキシメチル)-4-ピペリジノール塩酸塩と1-クロロ-4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノフタラジンとを反応させて標記化合物を得た。
MASS(FAB)；454.2(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.46-1.54 (2H, m), 1.82-1.94 (2H, m), 3.16-3.30 (6H, m), 3.84 (3H, s), 4.68-4.72 (2H, m), 7.15 (1H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 8.6, 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.6 Hz), 8.45 (1H, dd, J = 8.6, 1.0 Hz), 9.36 (1H, d, J = 1.0 Hz)
実施例７
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-[(2S)-2-(メトキシメチル)ピロリジノ]フタラジン塩酸塩
【０１６１】
【化５８】

【０１６２】
製造例１の(Ｒ)-(+)-3-ヒドロキシピペリジン塩酸塩の代わりに(S)-2-メトキシメチルピロリジンを用いて標記化合物を得た。
MASS(ESI)；438.1(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;1.81-1.89 (2H, m), 1.95-2.03 (1H, m), 2.15-2.24 (1H, m), 3.16 (3H, s), 3.28-3.37 (1H, m), 3.46-3.58 (2H, m), 3.84 (3H, s), 3.87-3.98 (1H, m), 4.44-4.57 (1H, m), 4.62-4.78 (2H, m), 7.15 (1H, d, J= 8.6 Hz), 7.47 (1H, dd, J = 8.6, 0.4 Hz), 7.61 (1H, d, J = 0.4 Hz), 8.41-8.51 (2H, m), 9.42-9.60 (1H, m), 10.50 (1H, br), 13.79 (1H, br)
実施例８
4-(3-クロロ-4-メトキシベンジル)アミノ-6-シアノ-1-フェニルフタラジン塩酸塩
【０１６３】
【化５９】

【０１６４】
製造例１０のメトキシフェニルホウ酸の代わりにフェニルホウ酸を用いて同様にして標記化合物を得た。
MASS(ESI)；401.1(MH⁺)
¹H-NMR(400 MHz, DMSO-d₆)δ;3.84 (3H, s), 4.81-4.85 (2H, m), 7.15 (1H, d, J = 8.6 Hz), 7.48 (1H, dd, J = 8.6, 2.1 Hz), 7.60-7.66 (6H, m), 8.00 (1H, d, J = 8.6 Hz), 8.41 (1H, dd, J = 8.6, 0.9 Hz), 9.42 (1H, d, J = 0.9 Hz)
実施例９
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリル塩酸塩
【０１６５】
【化６０】

【０１６６】
tert-ブトキシカリウム14.8 gとテトラヒドロフラン300 mLの混合物にメチルトルフェニルホスホニウムブロミド47.2 g、4-オキソ-1-ピペリジンカルボン酸tert-ブチル21.9 gを加え、４０分室温で撹拌した。反応液を減圧下濃縮しジエチルエーテルを加え、セライト濾過した。濾液を水及び飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し4-メチレン-1-ピペリジンカルボン酸tert-ブチルを20.8 g得た。
【０１６７】
亜鉛・銅合金157.2 gとジエチルエーテル500 mLの混合物に4-メチレン-1-ピペリジンカルボン酸tert-ブチル49.3 gを加え、塩化トリクロロアセチル181.8 gのジメトキシエタン900 mL溶液を５．５時間で滴下した。３０分撹拌後、冷却し、０℃以下で、飽和重曹水を加えた。混合液をセライト濾過し、減圧下濃縮した。残渣を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し、1,1-ジクロロ-2-オキソ-7-アザスピロ[3.5]ノナン-7-カルボン酸tert-ブチルを62.5 g得た。
【０１６８】
1,1-ジクロロ-2-オキソ-7-アザスピロ[3.5]ノナン-7-カルボン酸tert-ブチル62.5 gと飽和塩化アンモニウムメタノール溶液500 mLの混合物に亜鉛粉末106.1 gを加えた。１時間２０分室温で撹拌し、セライト濾過した。濾液を減圧下濃縮し、酢酸エチル１Ｎ塩酸を加え、有機層を分取した。抽出液を水、飽和重曹水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し2-オキソ-7-アザスピロノ[3.5]ノナン-7-カルボン酸tert-ブチルを38.9 g得た。
【０１６９】
エタノール 300ml を氷冷し、水素化ホウ素ナトリウム 6.13g を溶解させた。
2-オキソ-7-アザスピロ[3.5]ノナン-7-カルボン酸tert-ブチル38.9gのエタノール 100ml 溶液を２５分間かけて滴下した。反応液を、飽和塩化アンモニウム水溶液にて処理し、減圧下で濃縮した。残渣を酢酸エチルと水に分配し、酢酸エチル層を飽和塩化ナトリウム水溶液にて洗浄し、硫酸マグネシウムにより乾燥した。濾過後、溶媒を減圧下に留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン-酢酸エチル）にて精製し、 2-ヒドロキシ-7-アザスピロ[3.5]ノナン-7-カルボン酸tert-ブチル36.6ｇを得た。
¹H-NMR (CDCl₃)δ; 1.45 (9H, s), 1.43-1.57 (4H, m), 1.65-1.72 (2H, m), 3.27-3.35 (4H, m), 4.32 (1H, quint, J = 7.2 Hz)
2-ヒドロキシ-7-アザスピロ[3.5]ノナン-7-カルボン酸tert-ブチル 6.22g をテトラヒドロフラン 20ml に溶解させ、この溶液に４規定塩化水素-ジオキサン溶液 80ml を加え、室温にて1時間撹拌した。反応液を減圧下に濃縮し、得られた残渣を1-メチル-2-ピロリジノン 20ml に溶解させ、1-クロロ-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル 4.67g 、ジイソプロピルエチルアミン 6.72g を加え、160℃にて9時間撹拌した。反応液を室温に戻し、酢酸エチルと水に分配し、水層を酢酸エチルで抽出した。酢酸エチル層を合わせて、水（5回）、飽和食塩水で順次洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を減圧下に留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル-メタノール）にて精製し、得られた粗結晶をジエチルエーテル中で破砕洗浄し、黄色結晶4.86ｇを得た。このものをエタノール 150ml に溶解し、４規定塩化水素-ジオキサン溶液 15ml を加え、溶媒を減圧下留去した。残渣をエタノール 150ml に溶解し、80℃に加熱し、含水エタノールより別途合成した結晶にて種づけを行い、結晶化が始まった時点で加熱を停止した。室温まで放冷した後、濾取及びエタノール洗浄を行い、標記化合物 4.35g を得た。
【０１７０】
¹H-NMR (DMSO-d₆)δ; 1.58-1.66 (2H, m), 1.68-1.76 (4H, m), 2.14-2.22 (2H, m), 3.05-3.16 (4H, m), 3.83 (3H, s), 4.12 (1H, t, J = 7.2 Hz), 4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 8.4, 1.2 Hz), 9.46 (1H, s)
実施例１０
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ピリジル)-6-フタラジンカルボニトリル
【０１７１】
【化６１】

【０１７２】
実施例１と同様にして標記化合物を得た。
¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.76 (2H, d, J = 5.5 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 8.8, 2.4 Hz), 7.50 (1H, d, J = 2.4 Hz), 7.64 (2H, d, J = 5.6 Hz), 7.94 (1H, d, J = 8.8 Hz), 8.20 (1H, d, J = 8.8 Hz), 8.52 (1H, dd, J =5.5, 5.5 Hz), 8.73 (2H, d, J = 5.6 Hz), 9.02(1H, s)
実施例１１
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-オキソ-2-オキサ-8-アザスピロ[4.5]デセ-8-イル)-6-フタラジンカルボニトリル
【０１７３】
【化６２】

【０１７４】
2-オキソ-7-アザスピロ[3.5]ノナン-7-カルボン酸tert-ブチル37.8 gのメタノール567 mL溶液を氷水で冷却し、３０％過酸化水素水43 gを滴下した。１N水酸化ナトリウム水溶液63 mLを滴下した。室温で２時間撹拌した。反応液に酢酸エチル1000 mL、水600 mL、飽和チオ硫酸ナトリウム、５水和物水溶液100 mLを加え、有機層を分取した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、3-オキソ-2-オキサ-8-アザスピロ[4.5]デカン-8-カルボン酸tert-ブチルを28.4 g得た。
【０１７５】
3-オキソ-2-オキサ-8-アザスピロ[4.5]デカン-8-カルボン酸tert-ブチル1.16 gをメタノール2.3 mLに溶解し、4N塩酸−酢酸エチル4.6 mLを加え、１時間室温で撹拌した。酢酸エチル5 mL加え、析出している結晶を濾取し3-オキソ-2-オキサ-8-アザスピロ[4.5]デカン塩酸塩を700 mg得た。
1-クロロ-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル657 mg、3-オキソ-2-オキサ-8-アザスピロ[4.5]デカン塩酸塩700 mg、ジエチルアニリン0.44 mL、ヨウ化ナトリウム137 mgおよび1-メチル-2-ピロリジノン1.7 mLの混合物を１３０℃で１５時間４０分撹拌した。冷後、反応液にテトラヒドロフラン40 mL、酢酸エチル100 mLおよび1-メチル-2-ピロリジノン15 mLを加え希釈し、飽和重曹水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー精製し4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-オキソ-2-オキサ-8-アザスピロ[4.5]デセ-8-イル)-6-フタラジンカルボニトリルを713 mg得た。
¹H NMR(CDCl₃) δ; 1.88-2.01 (4H, m), 2.53 (2H, s), 3.22-3.40 (4H, m), 3.90 (3H, s), 4.20 (2H, s), 4.77 (2H, d, J = 5.2 Hz), 5.20 (1H, t, J = 5.2 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 8.4, 2.0 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.96 (1H, dd, J = 8.4, 2.0 Hz), 8.11 (1H, d, J = 8.4 Hz), 8.14 (1H, d, J = 0.8 Hz)
実施例１２
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-オキソ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリル
【０１７６】
【化６３】

【０１７７】
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリル500 mgをジクロロメタン20 mLとテトラヒドロフラン10 mL中に懸濁し、1,1,1-トリアセトキシ-1,1-ジヒドロ-1,2-ベンズヨードキソール−３（１Ｈ）−オン690 mg加え、室温で１５分撹拌した。反応液に酢酸エチル、飽和重曹水30 mLと飽和チオ硫酸ナトリウム、５水和物水溶液2 mLを加えた。有機層を分取し、水層を酢酸エチルで抽出した。抽出液を合わせ、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、エタノール中で結晶化させ、ヘキサンを加え濾取し、4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-オキソ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリルを420 mg得た。
¹H NMR(DMSO-d₆) δ; 1.90 (4H, m), 2.86 (4H, m), 3.09 (4H, s), 3.80 (3H, s), 4.62 (2H, d, J = 5.6 Hz), 7.07 (1H, d, J = 8.5 Hz), 7.33 (1H, d, J = 8.5 Hz), 7.44 (1H, s), 7.89 (1H, t, J = 5.6 Hz), 8.09 (1H, d, J = 8.0 Hz), 8.19 (1H, d, J = 8.0 Hz), 8.88 (1H, s)
実施例１３
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-ヒドロキシ-4-(1H-1-イミダゾリルメチル)ピペリジノ]-6-フタラジンカルボニトリル・二塩酸塩
【０１７８】
【化６４】

【０１７９】
¹H NMR (DMSO-d₆) δ; 1.49 (2H, d, J = 12.4 Hz), 1.82-1.93 (2H, m), 3.13 (2H, t, J = 10.8 Hz), 3.37 (2H, d, J = 12.4Hz), 3.82 (3H, s), 4.30 (2H, s), 4.74 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.63 (1H, d, J = 2.0 Hz), 7.66-7.71 (2H, m), 8.18 (1H, d, J = 8.4 Hz), 8.48 (1H, d, J = 8.4 Hz), 9.10 (1H, s), 9.60 (1H, s).
実施例１4
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-ヒドロキシ-4-(1H-1,2,4-トリアゾール-1-イルメチル)ピペリジノ]-6-フタラジンカルボニトリル・二塩酸塩
【０１８０】
【化６５】

【０１８１】
¹H NMR (DMSO-d₆) δ; 1.54 (2H, d, J = 12.8 Hz), 1.82-1.92 (2H, m), 3.15 (2H, t, J = 11.2 Hz), 3.35 (2H, d, J = 12.8Hz), 3.82 (3H, s), 4.29 (2H, s), 4.73 (2H, d, J = 6.0 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.21 (1H, s), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 8.79 (1H, s), 9.56 (1H, s), 10.75 (1H, br.s)
実施例１５
1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-1,2,3,4-テロラアゾール-5-イル)-1-フタラジニル]-4-ピペリジノール
【０１８２】
【化６６】

【０１８３】
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル1.0 g、トリエチルアミン塩酸塩1.2 g、1-メチル-2-ピロリジノン20 mLの混合物にアジ化ナトリウム0.55 gを加え、１００℃で８時間撹拌した。反応液を室温に戻し、水を加え、析出した結晶を濾取し、標記化合物を1.0 g得た。
¹H NMR (DMSO-d₆) δ; 1.58-1.7 (2H, m), 1.8-1.97 (2H, m), 2.8-2.98 (2H, m), 3.3-3.43 (2H, m), 3.6-3.7 (1H, m), 3.79 (3H, s), 4.6 (2H, s), 7.06 (1H, d, J = 8 Hz), 7.34 (1H, d, J = 8 Hz), 7.45 (1H, s), 7.95 (1H, d, J = 8 Hz), 8.45 (1H, d, J = 8 Hz), 8.89 (1H, s)
実施例１６
1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1-メチル-1H-1,2,3,4-テロラアゾール-5-イル)-1-フタラジニル]-4-ピペリジノール
【０１８４】
【化６７】

【０１８５】
1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-1,2,3,4-テロラアゾール-5-イル)-1-フタラジニル]-4-ピペリジノール0.25 g、炭酸カリウム1.2 g及びジメチルホルムアミド5 mLの混合物にヨウ化メチル0.037 mLを加え、室温で３時間撹拌した。反応液に水を加え、析出した不溶物を濾取した。シリカゲルカラムクロマトグラフィーで精製し標記化合物を50 mg得た。
¹H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.25-3.45 (2H, m), 3.6-3.7 (1H, m), 3.80 (3H, s), 4.48 (3H, s), 4.61 (2H, d, J = 5.6 Hz), 4.73 (1H, d, J = 4.0 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.34 (1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0 Hz), 8.07 (1H, t, J = 5.6 Hz), 8.10 (1H, d, J = 8.4 Hz), 8.47 (1H, d, J = 8.8 Hz), 9.00 (1H, s)
実施例１７
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボチアミド
【０１８６】
【化６８】

【０１８７】
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(ヒドロキシピペリジノ)-6-フタラジンカルボニトリル2.0 g、水1 mL、イソプロパノール2 mLの混合物にジチオりん酸ジエチル3.7 mLを加え、１時間加熱還流した。冷後、反応液に水を加え、析出した結晶を濾取した。濾液を酢酸エチルで抽出し、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥、濾過した。濾液を減圧下濃縮し、得られた結晶性残渣を上記で濾取した結晶と合わせ標記化合物を1.5 g得た。
¹H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-2.00 (2H, m), 2.90-3.1 (2H, m), 3.3-3.5 (2H, m), 3.6-3.8 (1H, m), 3.81 (3H, s), 4.68 (2H, d, J = 4 Hz), 7.13 (1H, d, J = 8 Hz), 7.40 (1H, d, J = 8 Hz), 7.54 (1H, s), 8.08 (1H, d, J = 8 Hz), 8.3-8.4 (1H, m), 8.9-9.1 (1H, m), 9.88 (1H, s), 10.33 (1H, s)
実施例１８
1-[4-[(3-ブロモ-4-メトキシベンジル)アミノ]-6-(4-メチル-1,3-チアゾール-2-イル)-1-フタラジニル]-4-ピペリジノール
【０１８８】
【化６９】

【０１８９】
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボチアミド1.5 gをジメチルホルムアミド50 mLに溶解し、クロロアセトン1.1 mLを加え、１００℃で４時間撹拌した。冷後、反応液に水を加え、デカンテーションで水層を除いた。残渣を減圧乾燥後、シリカゲルカラムクロマトグラフィーで精製し標記化合物を200 mg得た。
¹H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-1.95 (2H, m), 2.47 (3H, s), 2.83-2.94 (2H, m), 3.3-3.4 (2H, m), 3.6-3.7 (1H, m), 3.80 (3H, s), 4.63 (2H, d, J = 5.6 Hz), 4.72 (1H, d, J = 4.0 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.34 (1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.48 (1H, s), 7.96-8.04 (1H, m), 8.01 (1H, d, J = 8.4 Hz), 8.36 (1H, dd, J = 1.6, 8.4 Hz), 8.76 (1H, d, J = 1.6Hz)
実施例１９
1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(2-チエニル)-1-フタラジニル]-4-ピペリジノール塩酸塩
【０１９０】
【化７０】

【０１９１】
1-[6-ブロモ-4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-フタラジニル]-4-ピペリジノール200 mgとトルエン2 mLの混合物にテトラキス（トリフェニルホスフィン）パラジウム（０）24 mg、2-(トリブチルスタニル)チオフェン1.4 mLを加えた。２時間加熱還流した。冷後、反応液を氷水に注ぎ酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーにより精製した。４Ｎ塩酸−酢酸エチルにより塩酸塩とすることにより標記化合物を73 mg得た。
¹H NMR (DMSO-d₆) δ; 1.67 (2H, m), 1.92 (2H, m), 3.00 (2H, m), 3.45 (2H, m), 3.74 (1H, m), 3.82 (3H, s), 4.73 (2H, m), 7.13 (1H, d, J = 7.2 Hz), 7.27 (1H, s), 7.46 (1H, d, J = 7.2 Hz), 7.61 (1H, s), 7.79 (1H, d, J = 5.6 Hz), 8.03 (1H, d, J = 5.6 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.34 (1H, d, J = 8.8 Hz), 9.20 (1H, brs)
実施例２０
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルバルデヒドオキシム塩酸塩
【０１９２】
【化７１】

【０１９３】
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル10.0 gおよびｔ−ブチルジメチルクロロシラン5.3 gをジメチルホルムアミド80 mLに溶解し、イミダゾール4.8 gを加えた。室温で一夜撹拌した。反応液に酢酸エチルを加え、水で一回、飽和食塩水で二回洗浄した。無水硫酸マグネシウムで乾燥し、濾過した。濾液を減圧下濃縮し、1-[4-[[1-(tert-ブチル)-1,1-ジメチルシリル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリルを11.7 g得た。
【０１９４】
1-[4-[[1-(tert-ブチル)-1,1-ジメチルシリル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル11.7 gを塩化メチレン150 mLに溶解し、冷却した。−７８℃で１Ｍ水素化ジイソブチルアルミニウムのトルエン溶液44 mLを加えた。室温に戻し、一夜撹拌した。飽和塩化アンモニウム水溶液100 mLを加え、室温で０．５時間撹拌した。10%硫酸40 mLを加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、1-[4-[[1-(tert-ブチル)-1,1-ジメチルシリル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボアルデヒドを5.3 g得た。
【０１９５】
1-[4-[[1-(tert-ブチル)-1,1-ジメチルシリル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボアルデヒド1.5 gとヒドロキシルアミン塩酸塩0.35 gをメタノール50 mLに溶解し、２時間加熱還流した。冷後、水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、1-[4-[[1-(tert-ブチル)-1,1-ジメチルシリル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルバルデヒドオキシムを1.18 g得た。
【０１９６】
1-[4-[[1-(tert-ブチル)-1,1-ジメチルシリル]オキシ]ピペリジノ]-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボアルデヒドオキシム1.18 gのテトラヒドロフラン30 mL溶液にテトラブチルアンモニウムフルオリドのテトラヒドロフラン１Ｍ溶液を加えた。室温で一夜撹拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、濾過した。濾液を減圧下濃縮し、結晶性残渣を酢酸エチルで洗浄し、ろ取し標記化合物を0.34 g得た。常法により塩酸塩とした。
¹H NMR (DMSO-d₆) δ; 1.58-1.70 (2H, m), 1.86-1.95 (2H, m), 2.92-3.02 (2H, m), 3.08-3.22 (2H, m), 3.64-3.73 (1H, m), 3.82 (3H, s), 4.61-4.68 (2H, m), 4.77-4.79 (1H, m), 7.10 (1H, d, J = 8 Hz), 7.38 (1H, d, J = 8 Hz), 7.51 (1H, s), 8.06 (1H, d, J = 8 Hz), 8.23 (1H, d, J = 8 Hz), 8.28 (1H, s), 8.69-8.76 (1H, m)
実施例２１
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[(2R)-2-(ヒドロキシメチル)-1-オキサ-8-アザスピロ[4.5]デカ-8-イル]-6-フタラジンカルボニトリル塩酸塩
【０１９７】
【化７２】

【０１９８】
1-クロロ-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル1.08gおよび(2R)-1-オキサ-8-アザスピロ[4.5]デカ-2-イルメタノール0.76gをN-メチル-2-ピロリドン20mlに溶かし、160℃で５時間撹拌した。反応終了後、室温に戻し水および飽和重曹水を加え、酢酸エチルで抽出し、飽和食塩水で３回洗浄した。硫酸マグネシウムで乾燥後、溶媒を除き、シリカゲルカラムクロマトグラフィーで精製して結晶性化合物0.60gを得た。
【０１９９】
これをエタノール20mlに溶かし、1N塩酸エタノール溶液1.40mlを室温で加え,10分間撹拌した。溶媒を除き、ジイソプロピルエーテルで処理した後、乾燥させて標記化合物555mgを得た。
¹H NMR (DMSO-d₆) δ; 1.67-1.98 (8H, m), 3.15-3.40 (6H, m), 3.82 (3H, s), 3.90-3.98 (1H, m), 4.68-4.77 (2H, m), 7.14(1H, d, J = 9Hz), 7.46 (1H, dd, J = 2, 9Hz), 7.62 (1H, d, J = 2Hz), 8.23 (1H, d, J = 9 Hz), 8.45 (1H, d, J = 9Hz), 9.50 (1H, s)
実施例２２
(anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(7-ヒドロキシ-3-オキサ-9-アザビシクロ[3.3.1]ノン-9-イル)-6-フタラジンカルボニトリル塩酸塩
【０２００】
【化７３】

【０２０１】
1-クロロ-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル 1.5g、(anti)-3-オキサ-9-アザビシクロ[3.3.1]ノナン-7-オール塩酸塩 1.13g、ジイソプロピルエチルアミン2.16mlをN-メチル-2-ピロリドン8mlに加え170℃で9時間15分撹拌した。反応液に水を加え酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧下で留去した。シリカゲルカラムクロマトグラフィー（溶媒；ジクロロメタン：メタノール）で精製し、黄色油状物0.085gを得た。
【０２０２】
これを酢酸エチルに溶解し、4N-塩化水素-酢酸エチル溶液0.05mlを加え室温で撹拌した。析出物を濾取し、標記化合物を0.075g得た。
¹H NMR (DMSO-d₆) δ; 1.69-1.78 (2H, m), 2.46-2.56 (2H, m), 3.77-3.84 (2H, m), 3.86 (3H, s), 3.86-3.95 (3H, m), 4.04-4.12 (2H, m), 4.74 (2H, s), 7.17 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J= 2.2, 8.4 Hz), 7.61 (1H, d, J = 2.2 Hz), 8.13 (1H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.39 (1H,m)実施例２３
(anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(9-ヒドロキシ-3-アザビシクロ[3.3.1]ノン-3-イル)-6-フタラジンカルボニトリル塩酸塩
【０２０３】
【化７４】

【０２０４】
1-クロロ-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル 1.5g、(anti)-3-アザビシクロ[3.3.1]ノナン-9-オール塩酸塩 1.12g、ジイソプロピルエチルアミン2.18mlをN-メチル-2-ピロリドン8mlに加え170℃で9時間撹拌した。反応液に水を加え酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧下で留去した。ジクロロメタンを加え不溶物を濾取し淡黄色粉末1.23gを得た。これを酢酸エチルに懸濁し、4N-塩化水素-酢酸エチル溶液0.7mlを加え室温で撹拌した。析出物を濾取し、標記化合物を淡色粉末として1.28g得た。
¹H NMR (DMSO-d₆) δ; 1.54 (1H, m), 1.66-1.75 (2H, m), 1.86-1.93 (2H, m), 2.11-2.23 (2H, m), 2.38 (1H, m), 3.15-3.24 (2H, m), 3.62-3.70 (2H, m), 3.75 (1H, m), 3.85 (3H, s), 4.74 (2H, s), 7.16 (1H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 1.8, 8.4 Hz), 7.62 (1H, d, J = 1.8 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.56 (1H, dd, J = 1.3, 8.4 Hz), 9.49 (1H, m).
実施例２４
(anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[9-(2-ヒドロキシエチル)-3-アザビシクロ[3.3.1]ノン-3-イル]-6-フタラジンカルボニトリル塩酸塩
【０２０５】
【化７５】

【０２０６】
1-クロロ-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル 1.5g、(anti)-2-(3-アザビシクロ[3.3.1] ノン-9-イル)-1-エタノール塩酸塩 1.29g、ジイソプロピルエチルアミン2.18mlをN-メチル-2-ピロリドン8mlに加え170℃で8時間40分撹拌した。反応液に水を加え酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧下で留去した。シリカゲルカラムクロマトグラフィー（溶媒；ジクロロメタン：メタノール）で精製後、ジクロロメタン-酢酸エチル-エーテルで結晶化させ淡黄色粉末1.12gを得た。これをアセトンに懸濁し、4N-塩化水素-酢酸エチル溶液2ml、酢酸エチルを加え室温で撹拌した。析出物を濾取し、標記化合物を淡黄色粉末として0.98g得た。
¹H NMR (DMSO-d₆) δ; 1.61 (1H, m), 1.66-1.73 (2H, m), 1.73-1.87 (5H, m), 1.88-2.00 (2H, m), 2.42 (1H, m), 3.14-3.23 (2H, m), 3.49 (2H, t, J = 6.4 Hz), 3.67-3.76 (2H, m), 3.85 (3H, s), 4.73 (2H, s), 7.16( 1H, d, J = 8.6 Hz), 7.47 (1H, dd, J = 1.6, 8.6 Hz), 7.62 (1H, d, J = 1.6 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.55 (1H, dd, J = 1.3, 8.4 Hz), 9.46 (1H, m)
実施例２５
1-(3-アミノ-3-メチル-1-ブチニル)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル塩酸塩
【０２０７】
【化７６】

【０２０８】
1-クロロ-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル500 mg、ヨウ化第一銅53 mg、ジクロロビス（トリフェニルホスフィン）パラジウム（II）98 mg、3-アミノ-3-メチル-1-ブチン347 mg、ジメチルホルムアミド10 mLの混合物にトリエチルアミン0.39 mLを加え、窒素雰囲気下８０℃で３時間撹拌した。冷後、反応液に酢酸エチルを加え、水及び濃アンモニア水を加え、有機層を分取した。有機層を、希アンモニア水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過し、濾液を減圧下濃縮した。残渣をNH-formシリカゲルカラムクロマトグラフィーで精製し、標記化合物を446 mg得た。常法により塩酸塩とした。
¹H NMR (DMSO-d₆) δ; 1.75 (6H, s), 3.82 (3H, s), 4.76 (2H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.37 (1H, dd, J = 8.4, 2.2 Hz), 7.50 (1H, d, J = 2.2 Hz), 8.31 (1H, dd, J = 8.4, 1.4 Hz), 8.35 (1H, d, J = 8.4 Hz), 8.83 (1H, t, J = 5.6 Hz), 8.92-9.05 (3H, m), 9.07 (1H, br)
実施例２６
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(メトキシイミノ)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０２０９】
【化７７】

【０２１０】
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-オキソピペリジノ]-6-フタラジンカルボニトリル1.19 g、塩酸メトキシアミン354 mg、炭酸ナトリウム1.2 g及びエタノール10 mLの混合物を２時間加熱還流した。冷後、反応液に食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥し、濾過した。濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(メトキシイミノ)ピペリジノ]-6-フタラジンカルボニトリルを620 mg得た。これをメタノールとエタノールの混合溶媒に溶解し、４Ｎ塩酸−酢酸エチル0.35 mLを加え再結晶し、4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(メトキシイミノ)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩388 mgを得た。
¹H NMR (DMSO-d₆) δ; 2.50-2.55 (2H, m), 2.74-2.80 (2H, m), 3.29-3.35 (4H, m), 3.77 (3H, s), 3.85 (3H, s), 4.72 (2H, br), 7.16 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.33 (1H, d, J = 8.8 Hz), 8.48 (1H, dd, J = 8.8, 0.8 Hz), 9.35 (1H, d, J = 0.8 Hz), 10.19 (1H, br)
対応する原料を用いて、製造例あるいは実施例の方法と同様にして、以下の化合物を合成した。
実施例２７
4-[(3-クロロ-4-メチルベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル塩酸塩
【０２１１】
【化７８】

【０２１２】
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-1.99 (2H, m), 2.32(3H, s), 2.98-3.08 (2H, m), 3.42-3.50 (2H, m), 3.72-3.80 (1H, m), 4.76 (2H, d, J = 5.6 Hz), 7.36 (2H, s), 7.57 (1H, s), 8.23 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.2 Hz), 9.37 (1H, d, J = 1.2 Hz), 10.21 (1H, br)
実施例２８
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(5-ヒドロキシペルヒドロシクロペンタ[c]ピロール-2-イル)-6-フタラジンカルボニトリル
【０２１３】
【化７９】

【０２１４】
¹H NMR (DMSO-d₆) δ; 1.40-1.49 (2H, m), 2.02-2.12 (2H, m), 2.55-2.64 (2H, m), 3.24 (4H, d, J = 4.0 Hz), 3.80 (3H, s), 3.94-4.04 (1H, m), 4.61 (2H, d, J = 5.2 Hz), 4.72 (1H, d, J = 5.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 2.0, 8.4 Hz), 7.77-7.83 (1H, m), 8.14-8.23 (2H, m), 8.66 (1H, d, J = 0.8 Hz)
実施例２９
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(2-ヒドロキシエチル)-1,2,3,6-テトラヒドロ-1-ピリジニル]-6-フタラジンカルボニトリル
【０２１５】
【化８０】

【０２１６】
¹H NMR (DMSO-d₆) δ; 2.15-2.22 (2H, m), 2.27-2.39 (2H,m), 3.20 (2H, t, J = 5.6 Hz), 3.48-3.60 (2H, m), 3.69 (2H, s), 3.80 (3H, s), 4.47 (1H, t, J = 5.6 Hz), 4.61 (2H, d, J = 5.6 Hz), 5.55 (1H, d, J = 0.4 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.83-7.89 (1H, m), 8.04 (1H, d, J = 8.4 Hz), 8.08 (1H, dd, J = 1.2, 8.4 Hz), 8.87 (1H, t, J = 0.4 Hz)
実施例３０
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル
【０２１７】
【化８１】

【０２１８】
¹H NMR (DMSO-d₆) δ; 1.59-1.70 (1H, m), 1.83-2.02 (2H, m), 2.31-2.41 (1H, m), 3.34-3.60 (5H, m), 4.58 (2H, J = 5.6 Hz), 4.67 (1H, t, J = 5.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 2.0, 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.56-7.62 (1H, m), 8.14 (1H, dd, J = 1.6, 8.8 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.82 (1H, d, J = 1.2 Hz)
実施例３１
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(ヒドロキシメチル)-1,2,3,6-テトラヒドロ-1-ピリジニル]-6-フタラジンカルボニトリル
【０２１９】
【化８２】

【０２２０】
¹H NMR (DMSO-d₆) δ; 2.28 (2H, brs), 3.19-3.26 (2H, m), 3.73 (2H, br.s), 3.80 (3H, s), 3.89 (2H, d, J = 4.4 Hz), 4.62 (2H, d, J = 5.6 Hz), 4.78 (1H, t, J = 5.6 Hz), 5.72 (1H, br.s), 7.08 (1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.87 (1H, t, J = 5.6 Hz), 8.05 (1H, d, J = 8.4 Hz), 8.18 (1H, dd, J = 1.2, 8.4 Hz), 8.87 (1H, d, J = 1.2 Hz)
実施例３２
2-[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]-4-ピペリジニル]プロピオン酸塩酸塩
【０２２１】
【化８３】

【０２２２】
¹H NMR (DMSO-d₆) δ; 1.08 (3H, d, J = 6.8 Hz), 1.46-1.64 (2H, m), 1.66-1.83 (3H, m), 2.22-2.32 (1H, m), 2.78-2.90(2H, m), 3.54-3.64 (2H, m), 3.83 (3H, s), 4.72 ( 2H, d, J = 6.0 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61(1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 1.6, 8.4 Hz), 9.49 (1H, s)
実施例３３
2-[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]-1,2,3,6-テトラヒドロ-4-ピリジニル]酢酸塩酸塩
【０２２３】
【化８４】

【０２２４】
¹H NMR (DMSO-d₆) δ; 2.38-2.44 (2H, m), 3.04 (2H, s), 3.79-3.83 (2H, m), 3.83 (3H, s), 4.72 (2H, t, J = 2.8 Hz), 5.63-5.68 (1H, m), 7.15 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 2.4, 8.4 Hz), 7.61 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz), 9.45 (1H, s).実施例３４
2-[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]-4-ピペリジニル]-2-フルオロ酢酸塩酸塩
【０２２５】
【化８５】

【０２２６】
¹H NMR (DMSO-d₆) δ; 1.60-1.90 (4H, m), 2.03-2.20 (1H, m), 2.83-2.98 (2H, m), 3.58-3.65 (2H, m), 3.83 (3H, s), 4.73 (2H, t, J = 2.8 Hz), 4.98 (1H, dd, J = 4.0, 48.4 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.4 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 1.2, 8.4 Hz), 8.46 (1H, s)
実施例３５
2-[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]-4-ピペリジル]酢酸塩酸塩
【０２２７】
【化８６】

【０２２８】
¹H NMR (DMSO-d₆) δ; 1.44-1.57 (2H, m), 1.79-1.84 (2H, m), 1.85-1.96 (1H, m), 2.25 (2H, d, J = 6.8 Hz), 2.89 (2H, t, J = 12.0 Hz), 3.55 (2H, d, J = 12.0 Hz), 3.84 (3H, s), 4.70 (2H, d, J = 6.0 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.44 (1H, dd, J = 2.0, 8.4 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.21 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.6, 8.8 Hz), 9.37 (1H, s).
実施例３６
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(1-フルオロ-2-ヒドロキシエチル)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０２２９】
【化８７】

【０２３０】
¹H NMR (DMSO-d₆) δ; 1.56-1.78 (3H, m), 1.83-1.99 (2H, m), 2.80-2.91 (2H, m), 3.51-3.69 (4H, m), 3.83 (3H, s), 4.25-4.31 (1/2H, m), 4.37-4.43 (1/2H, m), 4.73 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 2.0, 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 9.52 (1H, s), 10.58 (1H, s)
実施例３７
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(2-ヒドロキシエトキシ)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０２３１】
【化８８】

【０２３２】
¹H NMR (DMSO-d₆) δ; 1.68-1.77 (4H, m), 1.98-2.07 (2H, m), 2.98-3.07 (2H, m), 3.44-3.52 (2H, m), 3.56-3.62 (3H, m), 3.83 (3H, s), 4.74 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.627 (1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 1.6, 8.4 Hz), 9.57 (1H, s), 10.68 (1H, brs)
実施例３８
2-[[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]-4-ピペリジル]オキシ]酢酸塩酸塩
【０２３３】
【化８９】

【０２３４】
¹H NMR (DMSO-d₆) δ; 1.69-1.82 (2H, m), 1.99-2.10 (2H, m), 2.98-3.09 (2H, m), 3.60-3.68 (1H, m), 3.83 (3H, s), 4.08 (2H, s), 4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4Hz), 7.46 (1H, dd, J = 2.4, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz), 9.46 (1H, s), 10.46 (1H, brs)
実施例３９
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(2-ヒドロキシ-1-メチルエチル)ピペリジノ]-6-フタラジンカルボニトリル
【０２３５】
【化９０】

【０２３６】
¹H NMR (DMSO-d₆) δ; 0.85 (3H, d, J = 6.4Hz), 1.40-1.59 (4H, m), 1.64-1.73 (2H, m), 2.68-2.79 (2H, m), 3.33-3.47 (4H, m), 3.78 (3H, m), 4.40 (1H, t, J = 5.2 Hz), 4.60 (2H, d, J = 5.6 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 2.0, 8.4 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.85 (1H, t, J = 6.0 Hz), 8.03 (1H, d, J = 8.4 Hz), 8.16 (1H, dd, J = 1.6, 8.4 Hz), 8.85 (1H, d, J = 0.8 Hz)
実施例４０
2-[7-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニリル]-7-アザスピロ[3.5]ノン-2-イル]酢酸塩酸塩
【０２３７】
【化９１】

【０２３８】
¹H NMR (DMSO-d₆) δ; 1.45-1.53 (2H, m), 1.66-1.73 (2H, m), 1.77-1.84 (2H, m), 1.96-2.04 (2H, m), 2.34 (2H, d, J = 7.6 Hz), 3.02 (2H, br.s), 3.11 (2H, br.s), 3.82 (3H, s), 4.67 (2H, s), 7.11 (1H, d, J = 8.4 Hz), 7.40 (1H, dd, J = 2.0, 8.4 Hz), 7.54 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 8.8 Hz), 8.34 (1H, d, J = 8.8 Hz), 9.24 (1H, s)
実施例４１
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[2-(ヒドロキシメチル)ペルヒドロ[1,3]ジオキソロ[4,5-c]ピロール-5-イル]-6-フタラジンカルボニトリル塩酸塩
【０２３９】
【化９２】

【０２４０】
¹H NMR (DMSO-d₆) δ; 3.54-3.67 (2H, m), 3.80-3.92 (2H, m), 4.16 (2/3H, brs), 4.29 (4/3H, brs), 4.54 (1H, t, J = 5.2 Hz), 4.54-4.62 (1H, m), 5.16-5.32 (2H, m), 7.11 (1H, d, J = 8.4 Hz), 7.34-7.40 (1H, m), 7.50 (1H, s), 8.37 (1H, d, J = 8.4 Hz), 8.48-8.58 (1H, m), 9.12-9.21 (1H, m)
実施例４２
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(1-ヒドロキシエチル)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０２４１】
【化９３】

【０２４２】
¹H NMR (DMSO-d₆) δ; 1.07 (3H, d, J = 6.0 Hz), 1.34-1.60 (3H, m), 1.65-1.76 (2H, m), 1.86-1.94 (2H, m), 2.75-2.86 (2H, m), 3.55-3.63 (2H, m), 3.82 (3H, s), 4.73 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 2.0, 8.8 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 9.56 (1H, s), 10.69 (1H, br.s)
実施例４３）
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-フルオロ-4-(ヒドロキシメチル)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０２４３】
【化９４】

【０２４４】
¹H NMR (DMSO-d₆) δ; 1.69-1.77 (2H, m), 1.83-2.08 (2H, m), 3.05-3.16 (2H, m), 3.48 (2H, d, J = 20.0 Hz), 3.82 (3H, s), 4.74 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 2.0, 8.8 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.26 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz), 9.57 (1H, s), 10.73 (1H, br.s)
実施例４４
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(ヒドロキシメチル)-4-メトキシピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０２４５】
【化９５】

【０２４６】
¹H NMR (DMSO-d₆) δ; 1.71-1.86 (4H,m), 3.04-3.16 (2H,m), 3.16 (3H, s), 3.41 (2H, s), 3.83 (3H, s), 4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.44 (1H, dd, J = 1.2, 8.8 Hz), 9.48 (1H, s), 10.46 (1H, brs)
実施例４５
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-ヒドロキシ-6-アザスピロ[3.4]オクト-6-イル)-6-フタラジンカルボニトリル塩酸塩
【０２４７】
【化９６】

【０２４８】
¹H NMR (DMSO-d₆) δ; 1.00-1.08 (2H, m), 1.82-2.04 (4H, m), 2.19-2.35 (2H, m), 3.32-3.45 (2H, m), 3.55-3.60 (2H, m), 3.80 (3H, s), 4.04-4.19 (1H, m), 4.56 (2H, br.s), 7.10 (1H, d, J = 8.4 Hz), 7.37 (1H, br.s), 7.50 (1H, br.s), 8.38 (1H, d, J = 8.4 Hz), 8.45-8.73 (1H, m)
実施例４６
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(ヒドロキシメチル)-2,5-ジヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル塩酸塩
【０２４９】
【化９７】

【０２５０】
¹H NMR (DMSO-d₆) δ; 3.82 (3H, s), 4.12 (2H, s), 4.45-4.83 (6H, m), 5.84 (1H, brs), 7.11 (1H, d, J = 9 Hz,), 7.33-7.56 (2H, m), 8.45 (1H, d, J = 9 Hz), 8.66-9.14 (2H, m)
実施例４７
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[(3R,4S)-3,4-ジ(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル塩酸塩
【０２５１】
【化９８】

【０２５２】
¹H NMR (DMSO-d₆) δ; 2.50-2.57 (2H, m), 3.38-3.49 (2H, m), 3.56-3.60 (2H, m), 3.76-3.87 (4H, m), 3.81 (3H, s), 4.55 (2H, brs), 7.10 (1H, d, J = 8.4 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.49 (1H,s), 8.41 (1H, d, J = 8.4 Hz), 8.68 (1H, d, J = 8.4 Hz), 9.13 (1H, s)
実施例４８
1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]-4-ヒドロキシ-4-ピペリジンカルボキサミド塩酸塩
【０２５３】
【化９９】

【０２５４】
¹H NMR (DMSO-d₆) δ; 1.56-1.64 (2H, m), 2.16-2.28 (2H, m), 3.12-3.24 (2H, m), 3.32-3.48 (2H, m),3.54 (1H, brs), 3.83 (3H, s), 4.10-4.30 (1H, m), 4.74 (2H, s), 7.13 (1H, d, J = 8.4 Hz), 7.15 (1H, brs), 7.31 (1H, brs), 7.48 (1H, d, J = 8.4 Hz), 7.64 (1H, s), 8.26 (1H, d, J = 8.4 Hz), 8.44 (1H, d, J = 8.4 Hz), 9.52-9.60 (1H, m)
実施例４９
[4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(フルオロメチル)-4-ヒドロキシピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０２５５】
【化１００】

【０２５６】
¹H NMR (DMSO-d₆) δ; 1.54-1.64 (2H, m), 1.80-1.92 (2H, m), 3.18-3.26 (2H, m), 3.32-3.44 (4H, m), 3.83 (3H, s), 4.22 (2H, d, J = 7.6 Hz), 4.72 (1H, d, J = 6.0 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4,1.6 Hz), 7.62 (1H, d, J = 1.6 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.45 (1H, brs)
実施例５０
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシイミノピペリジノ)-6-フタラジンカルボニトリル塩酸塩
【０２５７】
【化１０１】

【０２５８】
¹H NMR (DMSO-d₆) δ; 2.50-2.52 (2H, m), 2.74-2.80 (2H, m), 3.26-3.35 (4H, m), 3.85 (3H, s), 4.71 (2H, br), 7.17 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.49 (1H, dd, J = 8.4, 0.4 Hz), 9.34 (1H, d, J = 0.4 Hz), 10.53 (1H, br)
実施例５１
(anti)-2-[3-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]-3-アザビシクロ[3.3.1]ノン-9-イル]酢酸塩酸塩
【０２５９】
【化１０２】

【０２６０】
¹H NMR (DMSO-d₆) δ; 1.62 (1H, m), 1.75-2.00 (4H, m), 2.12 (1H, m), 2.52 (2H, d, J = 8.1 Hz), 3.16-3.24 (2H, m), 3.68-3.76 (2H, m), 3.85 (3H, s), 4.74 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.48 (1H, dd, J = 1.8, 8.6 Hz), 7.62 (1H, d, J = 1.8Hz), 8.23 (1H, d, J = 8.4 Hz), 8.55 (1H, dd, J = 1.3, 8.4 Hz), 9.48 (1H, m).
実施例５２
(endo)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-6-フタラジンカルボニトリル塩酸塩
【０２６１】
【化１０３】

【０２６２】
¹H NMR (DMSO-d₆) δ; 1.81-1.88 (2H, m), 1.90-1.98 (2H, m), 2.19-2.30 (4H, m), 3.85 (3H, s), 4.04 (1H, m), 4.16-4.26 (2H, m), 4.71 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.61 (1H, s), 8.29 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 1.3, 8.4 Hz), 9.44 (1H,m)
実施例５３
(syn)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(9-ヒドロキシ-3-アザビシクロ[3.3.1]ノン-3-イル)-6-フタラジンカルボニトリル塩酸塩
【０２６３】
【化１０４】

【０２６４】
¹H NMR (DMSO-d₆) δ; 1.53 (1H,m), 1.74-1.86 (2H, m), 1.87-1.93 (2H, m), 2.05-2.14 (2H, m), 2.37 (1H, m), 3.28-3.44 (2H, m), 3.41-3.61 (2H, m), 3.68 (1H, m), 3.85 (3H, s), 4.73 (2H, s), 7.15 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.62 (1H, s), 8.22 (1H, d, J = 8.6 Hz), 8.54 (1H, d, J = 8.6 Hz), 9.48 (1H, m)
実施例５４
(syn)-4-[(3-クロロ-4)アミノ]-1-(8-ヒドロキシ-3-アザビシクロ[3.2.1]オクト-3-イル)-6-フタラジンカルボニトリル塩酸塩
【０２６５】
【化１０５】

【０２６６】
¹H NMR (DMSO-d₆) δ; 1.75-1.96 (4H, m), 2.02-2.09 (2H, m), 3.06-3.18 (2H, m), 3.50-3.60 (2H, m), 3.86 (3H, s), 3.91 (1H, t, J = 4.8 Hz), 4.73 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.61 (1H, s), 8.36 (1H, d, J = 8.6 Hz), 8.48 (1H, dd, J = 1.5, 8.6 Hz), 9.43 (1H, m).
実施例５５
(exo)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-6-フタラジンカルボニトリル塩酸塩
【０２６７】
【化１０６】

【０２６８】
¹H NMR (DMSO-d₆) δ; 1.68-1.83 (2H, m), 1.90-2.02 (4H, m), 3.85 (3H, s), 3.97 (1H, m), 4.18-4.28 (2H, m), 4.70 (2H, s), 7.15 (1H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.59 (1H, s), 8.29 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.36 (1H, m)
実施例５６
(anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(9-ヒドロキシ-3-オキサ-7-アザビシクロ[3.3.1]ノン-7-イル)-6-フタラジンカルボニトリル塩酸塩
【０２６９】
【化１０７】

【０２７０】
¹H NMR (DMSO-d₆) δ; 1.69-1.76 (2H, m), 3.24-3.38 (2H, m), 3.73-3.83 (2H, m), 3.85 (3H, s) 3.85-3.93 (2H, m), 4.11-4.20 (2H, m), 4.73 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.62 (1H, s), 8.36 (1H, d, J = 8.4 Hz), 8.52 (1H, d, J = 8.4 Hz), 9.43 (1H, m)
実施例５７
(anti)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-9-アザビシクロ[3.3.1]ノン-9-イル)-6-フタラジンカルボニトリル塩酸塩
【０２７１】
【化１０８】

【０２７２】
¹H NMR (DMSO-d₆) δ; 1.38-1.54 (4H, m), 1.59 (1H, m), 1.90-2.02 (2H, m), 2.22-2.45 (3H, m), 3.86 (3H, s), 3.87 (1H, m), 4.08-4.17 (2H, m), 4.69 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.58 (1H, s), 8.07 (1H, d, J = 8.6 Hz), 8.44 (1H, d, J = 8.6 Hz), 9.29 (1H, m)
実施例５８
N¹-[3-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-６−シアノ-1-フタラジニル]フェニル]アセタミド
【０２７３】
【化１０９】

【０２７４】
¹H NMR (DMSO-d₆) δ; 2.05 (3H, s), 3.81 (3H, s), 4.76 (2H, d, J = 6.0 Hz), 7.09 (1H, d, J = 8.4 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.38 (1H, dd, J = 8.0, 1.6 Hz), 7.45 (1H, dd, J = 8.4, 8.0 Hz), 7.50 (1H, d, J = 1.6 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.86 (1H, m), 7.92 (1H, d, J = 8.4 Hz), 8.17 (1H, dd, J = 8.4, 1.6 Hz), 8.35 (1H, dd, J = 6.0, 6.0 Hz), 9.00 (1H, s), 10.09 (1H, s)
実施例５９
1-(3-アミノフェニル)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-６−フタラジンカルボニトリル・二塩酸塩
【０２７５】
【化１１０】

【０２７６】
¹H NMR (DMSO-d₆) δ; 3.83 (3H, s), 4.89 (2H, brs), 7.16 (1H, d, J = 8.6 Hz), 7.38-7.44 (3H, m), 7.53 (1H, dd, J = 8.6, 2.0 Hz) , 7.58-7.62 (2H, m), 7.68 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.65 (1H, s)
実施例６０
N-[3-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-６-シアノ-1-フタラジニル]フェニル]メタンスルホンアミド塩酸塩
【０２７７】
【化１１１】

【０２７８】
¹H NMR (DMSO-d₆) δ; 3.06 (3H, s), 3.84 (3H, s), 4.86 (2H, d, J = 5.6 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.50 (1H, brs), 7.53 (1H, dd, J = 8.4, 2.0 Hz), 7.55 (1H, dd, J = 7.6, 7.6 Hz), 7.66 (1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.44 (1H, d, J = 8.8 Hz), 9.60 (1H, brs), 10.14 (1H, brs)
実施例６１
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(メチルスルフィニル)フェニル]-6-フタラジンカルボニトリル塩酸塩
【０２７９】
【化１１２】

【０２８０】
¹H NMR (DMSO-d₆) δ; 2.84 (3H, s), 3.83 (3H, s), 4.87 (2H, brs), 7.16 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.66 (1H, brs), 7.83 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.00 (1H, d, J =8.4 Hz), 8.43 (1H, d, J = 8.4 Hz), 9.52-9.60 (1H, m)
実施例６２
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(メチルスルホニル)フェニル]-6-フタラジンカルボニトリル塩酸塩
【０２８１】
【化１１３】

【０２８２】
¹H NMR (DMSO-d₆) δ; 3.31 (3H, s), 3.82 (3H, s), 4.80 (2H, brs), 7.12 (1H, d, J = 8.8 Hz), 7.43 (1H, dd, J = 8.8, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 7.90 (2H, d, J = 8.0 Hz), 7.93 (1H, d, J = 8.4 Hz), 8.11 (2H, d, J = 8.0 Hz), 8.28 (1H, d, J = 8.4 Hz), 9.19-9.22 (1H, m)
実施例６３
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ホルミルフェニル)-6-フタラジンカルボニトリル塩酸塩
【０２８３】
【化１１４】

【０２８４】
¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.86 (2H, brs), 7.16 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.66 (1H, brs), 7.86 (2H, d, J = 8.0 Hz), 7.99 (1H, d, J = 8.8 Hz), 8,13 (2H, d, J = 8.0 Hz), 8.42 (1H, d, J = 8.8 Hz), 9.48-9.53 (1H, m), 10.15 (1H, s)
実施例６４
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[4-(ヒドロキシメチル)フェニル]-6-フタラジンカルボニトリル塩酸塩
【０２８５】
【化１１５】

【０２８６】
¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.62 (2H, s), 4.84 (2H, brs), 7.16 (1H, d, J = 8.4 Hz), 7.49 (1H, dd, J = 8.4, 2.0 Hz), 7.55 (2H, d, J = 8.0 Hz), 7.60 (2H, d, J = 8.0 Hz), 7.65 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 8.4 Hz), 8.43 (1H, d, J = 8.4 Hz), 9.50-9.58 (1H, m)
実施例６５
4-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]安息香酸
【０２８７】
【化１１６】

【０２８８】
¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.76 (2H, d, J = 6.0 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 8.8, 2.0 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.08 (2H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 8.4, 1.6 Hz), 8.44 (1H, dd, J = 6.0, 6.0 Hz), 9.01 (1H, d, J = 1.6 Hz)
実施例６６
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(1,3-チアゾール-2-イル)-6-フタラジンカルボニトリル塩酸塩
【０２８９】
【化１１７】

【０２９０】
¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.82 (2H, s), 7.13 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.57 (1H, s), 7.94 (1H, d, J = 3.6 Hz), 8.11 (1H, d, J = 3.6 Hz), 8.46 (1H, d, J = 8.4 Hz), 9.20-9.26 (1H, m), 9.70 (1H, d, J = 8.4 Hz)
実施例６７
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-3-メチル-1-ブチニル)-6-フタラジンカルボニトリル塩酸塩
【０２９１】
【化１１８】

【０２９２】
¹H NMR (DMSO-d₆) δ; 1.57 (6H, s), 3.84 (3H, s), 4.84 (2H, s), 7.15 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.52 (1H, dd, J = 8.4, 0.4 Hz), 9.04 (1H, d, J = 0.4 Hz), 10.36 (1H, br)
実施例６８
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-1-プロピニル)-6-フタラジンカルボニトリル塩酸塩
【０２９３】
【化１１９】

【０２９４】
¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.49 (2H, s), 4.81 (2H, d, J = 4.0 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.43 (1H, dd, J = 8.4, 2.4 Hz), 7.58 (1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.48 (1H, dd, J = 8.8, 0.8 Hz), 9.28 (1H, d, J = 0.8 Hz), 9.92 (1H, br)
実施例６９
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3,4-ジヒドロキシ-3-(ヒドロキシメチル)-1-ブチニル]-6-フタラジンカルボニトリル
【０２９５】
【化１２０】

【０２９６】
¹H NMR (DMSO-d₆) δ; 3.54-3.66 (4H, m), 3.82 (3H, s), 4.76 (2H, d, J = 5.2 Hz), 4.98 (2H, t, J = 5.2 Hz), 5.62 (1H, s), 7.10 (1H, d, J = 8.8 Hz), 7.36 (1H, dd, J = 8.8, 2.0 Hz), 7.49 (1H, d, J = 2.0 Hz), 8.29-8.34 (1H, m), 8.51 (1H, t, J = 5.2 Hz), 8.96 (1H, s)
実施例７０
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(ジメチルアミノ)-1-プロピニル]-6-フタラジンカルボニトリル・二塩酸塩
【０２９７】
【化１２１】

【０２９８】
¹H NMR (DMSO-d₆) δ; 2.91 (6H, s), 3.83 (3H, s), 4.52 (2H, s), 4.83 (2H, d, J = 4.8 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.8, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 8.40 (1H, dd, J = 8.4, 1.4 Hz), 8.46 (1H, d, J = 8.4 Hz), 9.27 (1H, d, J = 1.4 Hz), 9.76 (1H, br), 11.39 (1H, br)
実施例７１
2-[[3-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-シアノ-1-フタラジニル]-1,1-ジメチル-2-プロピニル]オキシ]酢酸塩酸塩
【０２９９】
【化１２２】

【０３００】
¹H NMR (DMSO-d₆) δ; 1.62 (6H, s), 3.84 (3H, s), 4.21-4.24 (2H, m), 4.77-4.82 (2H, br), 7.11-7.15 (1H, m), 7.38-7.42 (1H, m), 7.51-7.55 (1H, m), 8.19-8.24 (1H, m), 8.38-8.42 (1H, m), 9.12-9.16 (1H, m)
実施例７２
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(2-ヒドロキシエトキシ)-3-メチル-1-ブチニル]-6-フタラジンカルボニトリル塩酸塩
【０３０１】
【化１２３】

【０３０２】
¹H NMR (DMSO-d₆) δ; 1.61 (6H, s), 3.55 (2H, t, J = 5.6 Hz), 3.65 (2H, t, J = 5.6 Hz), 3.84 (3H, s), 4.85 (2H, d, J = 4.8 Hz), 7.14 (1H, d, J = 8.6 Hz), 7.46 (1H, dd, J = 8.6, 2.2 Hz), 7.61 (1H, d, J = 2.2 Hz), 8.30 (1H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 8.4, 1.6 Hz), 9.42 (1H, d, J = 1.6 Hz), 10.41 (1H, br)
実施例７３
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(4-ヒドロキシピペリジノ)-3-メチル-1-ブチニル]-6-フタラジンカルボニトリル・二塩酸塩
【０３０３】
【化１２４】

【０３０４】
¹H NMR (DMSO-d₆) d 1.79-2.04 (10H, m), 2.12-2.23 (1H, m), 3.04-3.19 (1H, m), 3.26-3.37 (2H, m), 3.54-3.77 (1H, m), 3.82 (3H, s), 4.83 (2H, d, J = 5.6 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.43 (1H, dd, J = 8.4, 1.2 Hz), 7.56 (1H, d, J = 1.2 Hz), 8.38 (1H, dd, J = 8.4, 0.8 Hz), 8.43 (1H, d, J = 8.4 Hz), 9.30 (1H, d, J = 0.8 Hz), 9.91 (1H, br), 11.40-11.66 (1H, m)
実施例７４
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-メチル-3-テトラヒドロ-1H-1-ピロリル-1-ブチニル)-6-フタラジンカルボニトリル・二塩酸塩
【０３０５】
【化１２５】

【０３０６】
¹H NMR (DMSO-d₆) δ; 1.85 (6H, s), 1.90-2.08 (4H, m), 3.30-3.42 (2H, m), 3.60-3.72 (2H, m), 3.83 (3H, s), 4.80 (2H, d, J = 5.2 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.39 (1H, dd, J = 8.4, 2.0 Hz), 7.52 (1H, d, J = 2.0 Hz), 8.28 (1H, d, J = 8.4 Hz), 8.36 (1H, dd, J = 8.4, 0.8 Hz), 9.14 (1H, d, J = 0.8 Hz), 9.33 (1H, br), 11.89 (1H, m)
実施例７５
1-(4-ヒドロキシピペリジノ)-4-[[4-メトキシ-3-(トリフルオロメチル)ベンジル]アミノ]-6-フタラジンカルボニトリル塩酸塩
【０３０７】
【化１２６】

【０３０８】
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-1.99 (2H, m), 2.97-3.07 (2H, m), 3.40-3.52 (2H, m), 3.72-3.80 (1H, m), 3.89 (3H, s), 4.80 (2H, d, J = 5.6 Hz), 7.28 (1H, d, J = 8.4 Hz), 7.81-7.85 (2H, m), 8.24 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.2 Hz), 9.53 (1H, d, J = 1.2 Hz), 10.29 (1H, br), 14.02 (1H, br)
実施例７６
1-(4-ヒドロキシピペリジノ)-4-[(3-ヨード-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル塩酸塩
【０３０９】
【化１２７】

【０３１０】
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-2.00 (2H, m), 2.98-3.08 (2H, m), 3.40-3.50 (2H, m), 3.72-3.80 (1H, m), 3.82 (3H, s), 4.68 (2H, d, J = 4.8 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.50 (1H, dd, J = 8.8, 2.2 Hz), 7.93 (1H, d, J = 2.2 Hz), 8.24 (1H, d, J = 8.6 Hz), 8.46 (1H, dd, J = 8.6, 0.8 Hz), 9.32 (1H, d, J = 0.8 Hz), 10.05 (1H, br)
実施例７７
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル塩酸塩
【０３１１】
【化１２８】

【０３１２】
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-1.99 (2H, m), 2.98-3.07 (2H, m), 3.39-3.50 (2H, m), 3.72-3.80 (1H, m), 3.84 (3H, s), 4.71 (2H, d, J = 4.8 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.49 (1H, dd, J = 8.6, 2.2 Hz), 7.75 (1H, d, J = 2.2 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 8.4, 0.8 Hz), 9.34 (1H, d, J = 0.8 Hz), 10.11 (1H, br)
実施例７８
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル塩酸塩
【０３１３】
【化１２９】

【０３１４】
¹H NMR (DMSO-d₆) δ; 1.72-1.86 (1H, m), 1.99-2.12 (1H, m), 2.39-2.51 (1H, m), 3.42 (1H, dd, J = 7.2, 10.8 Hz), 3.48 (1H, dd, J = 6.0, 10.8 Hz), 3.60-3.90 (4H, m), 3.80 (3H, s), 7.06 (1H, d, J = 8.4 Hz), 7.38-7.46 (1H, m), 7.64 (1H, s), 8.40 (1H, dd, J = 1.6, 8.8 Hz), 8.65 (1H, d, J = 8.0 Hz), 9.18 (1H, s)
実施例７９
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[(3S)-3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル塩酸塩
【０３１５】
【化１３０】

【０３１６】
¹H NMR (DMSO-d₆) δ; 1.58-1.76 (3H, m), 1.92-2.02 (2H, m), 2.29-2.42 (2H, m), 3.42-3.60 (2H, m), 3.78 (3H, s), 4.58 (2H, J = 6.0 Hz), 4.69 (1H, t, J = 5.6 Hz), 7.03 (1H, d, J = 8.4 Hz), 7.36 (1H, dd, J = 2.0, 8.4 Hz), 7.57 (1H, d, J = 2.0 Hz), 7.59 (1H, d, J = 6.0 Hz), 8.13 (1H, dd, J = 1.2, 8.8 Hz), 8.22 (1H, d, J = 8.8 Hz), 8.81 (1H, d, J = 0.8 Hz)
実施例８０
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[(3R)-3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル塩酸塩
【０３１７】
【化１３１】

【０３１８】
¹H NMR (DMSO-d₆) δ; 1.72-1.86 (1H, m), 1.99-2.12 (1H, m), 2.39-2.51 (1H, m), 3.42 (1H, dd, J = 7.2, 10.8 Hz), 3.48 (1H, dd, J = 6.0, 10.8 Hz), 3.60-3.90 (4H, m), 3.80 (3H, s), 7.06 (1H, d, J = 8.8 Hz), 7.38-7.46 (1H, m), 7.65 (1H, s), 8.40 (1H, d, J = 8.8 Hz), 8.59-8.68 (1H, m), 9.26 (1H, s)
実施例８１
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[4-(2-ヒドロキシエチル)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０３１９】
【化１３２】

【０３２０】
¹H NMR (DMSO-d₆) δ; 1.68-1.77 (2H, m), 1.96-2.07 (2H, m), 3.02 (2H, t, J = 12.0 Hz), 3.38-3.59 (6H, m), 3.80 (3H, s), 3.81-3.99 (3H, m), 4.72 (2H, d, J = 6.0 Hz), 7.10 (1H, d, J = 8.6 Hz), 7.49 (1H, d, J = 8.6 Hz), 7.76 (1H, s), 8.22 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.50 (1H, s)
実施例８２
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリル塩酸塩
【０３２１】
【化１３３】

【０３２２】
¹H NMR (DMSO-d₆) δ; 1.58-1.66 (2H, m), 1.68-1.76 (4H, m), 2.14-2.23 (2H, m), 3.08 (2H, br.s), 3.13 (2H, br.s), 4.08-4.17 (1H, m), 4.73 (1H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.52 (1H, dd, J = 2.0, 8.4 Hz), 7.70 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 1.6, 8.4 Hz), 9.55 (1H, s)
実施例８３
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[4-フルオロ-4-(ヒドロキシメチル)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０３２３】
【化１３４】

【０３２４】
¹H NMR (DMSO-d₆) δ; 1.87-2.10 (4H, m), 3.08-3.17 (2H, m), 3.40-3.49 (2H, m), 3.55 (2H, d, J = 12 Hz), 3.84 (3H, s), 4.74 (2H, d, J = 5.2 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.52 (1H, dd, J = 8.6, 2.2 Hz), 7.78 (1H, d, J = 2.2 Hz), 8.28 (1H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 8.4, 1.2 Hz), 9.47 (1H, br), 10.43 (1H, br), 14.00 (1H, br)
実施例８４
4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-[4-(ヒドロキシメチル)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０３２５】
【化１３５】

【０３２６】
¹H NMR (DMSO-d₆) δ; 1.41-1.52 (2H, m), 1.58-1.69 (1H, m), 1.79-1.86 (2H, m), 2.85-2.94 (2H, m), 3.35-3.40 (2H, m), 3.59 (2H, d, J = 12.8 Hz), 3.84 (3H, s), 4.71 (2H, d, J = 5.2 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 8.4, 2.0 Hz), 7.76 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.38 (1H, br), 10.21 (1H, br)
実施例８５
(endo)-4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-6-フタラジンカルボニトリル
【０３２７】
【化１３６】

【０３２８】
¹H NMR (DMSO-d₆) δ; 1.70-1.95 (4H, m), 2.14-2.28 (4H, m), 3.82 (3H, s), 4.15 (1H, m), 4.09 (2H, m), 4.49 (1H, d, J = 2.2 Hz), 4.62 (2H, d, J = 5.5 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.38 (1H, dd, J = 2.2, 8.6 Hz), 7.60 (1H, d, J = 2.2 Hz), 7.72 (1H, t, J = 5.5 Hz), 8.11 (1H, d, J = 8.6 Hz), 8.18 (1H, dd, J = 1.5, 8.6 Hz), 8.87 (1H, d, J = 1.5 Hz)
実施例８６
1-(4-ヒドロキシピペリジノ)-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラジンカルボニトリル塩酸塩
【０３２９】
【化１３７】

【０３３０】
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-1.99 (2H, m), 2.15(3H, s), 2.98-3.07 (2H, m), 3.42-3.50 (2H, m), 3.72-3.80 (1H, m), 3.78 (3H, s), 4.67-4.70 (2H, m), 6.94 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.31 (1H, dd, J = 8.2, 2.0 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.2 Hz), 9.45 (1H, d, J = 1.2 Hz), 10.39 (1H, br)
実施例８７
1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラジンカルボニトリル塩酸塩
【０３３１】
【化１３８】

【０３３２】
¹H NMR (DMSO-d₆) δ; 1.57-1.66 (2H, m), 1.67-1.8 (4H, m), 2.11 (3H, s), 2.14-2.23 (2H, m), 3.07 (2H, br.s), 3.12 (2H, br.s), 3.55-3.61 (1H, m), 4.07-4.17 (1H, m), 4.69 (1H, d, J = 5.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.29 (1H, s), 7.31 (1H, dd, J = 2.0, 8.4 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 1.2, 8.4 Hz), 9.56 (1H, s), 10.59 (1H, brs)
実施例８８
1-[4-フルオロ-4-(ヒドロキシメチル)ピペリジノ]-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラジンカルボニトリル塩酸塩
【０３３３】
【化１３９】

【０３３４】
¹H NMR (DMSO-d₆) δ; 1.88-2.10 (4H, m), 2.15 (3H, s), 3.08-3.17 (2H, m), 3.40-3.50 (2H, m), 3.51 (2H, d, J = 19.6 Hz), 3.78 (3H, s), 4.68 (2H, d, J = 5.2 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.28-7.33 (2H, m), 8.28 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.4 Hz), 9.42 (1H, dd, J = 1.4 Hz), 10.26 (1H, br), 13.96 (1H, br)
実施例８９
1-[4-(ヒドロキシメチル)ピペリジノ]-4-[(3-メトキシ-4-メチルベンジル)アミノ]-6-フタラジンカルボニトリル塩酸塩
【０３３５】
【化１４０】

【０３３６】
¹H NMR (DMSO-d₆) δ; 1.41-1.52 (2H, m), 1.58-1.68 (1H, m), 1.79-1.87 (2H, m), 2.15 (3H, s), 2.82-2.93 (2H, m), 3.30-3.40 (2H, m), 3.58 (2H, d, J = 12.8 Hz), 3.78 (3H, s), 4.67 (2H, d, J = 5.2 Hz), 6.94 (1H, d, J = 8.8 Hz), 7.26-7.32 (2H, m), 8.22 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.36 (1H, br), 10.09 (1H, br)
実施例９０
(endo)-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラジンカルボニトリル
【０３３７】
【化１４１】

【０３３８】
¹H NMR (DMSO-d₆) δ; 1.79-1.93 (4H, m), 2.13 (3H, s), 2.13-2.27 (4H, m), 3.75 (3H, s), 4.03 (1H, m), 4.08 (2H, m), 4.49 (1H, d, J = 2.2 Hz), 4.59 (2H, d, J = 5.3 Hz), 6.87 (1H, d, J = 7.9 Hz), 7.16-7.22 (2H, m), 7.61 (1H, t, J = 5.3 Hz), 8.11 (1H, d, J = 8.4 Hz), 8.17 (1H, dd, J = 1.5, 8.4 Hz), 8.90 (1H, d, J = 1.5 Hz)
実施例９１
1-[3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-4-[(4-メトキシ-3-メチルベンジル)アミノ]-6-フタラジンカルボニトリル
【０３３９】
【化１４２】

【０３４０】
¹H NMR (DMSO-d₆) δ; 1.67 (1H, m), 2.00 (1H, m), 2.16 (3H, s), 2.38 (1H, m), 3.36-3.61 (6H, m), 3.75 (3H, s), 4.58 (2H, d, J = 5.5 Hz), 4.68 (1H, t, J = 5.5 Hz), 6.86 (1H, d, J = 8.1 Hz), 7.16-7.22 (2H, m), 7.50 (1H, t, J = 5.3 Hz), 8.15 (1H, dd, J = 1.5, 8.6 Hz), 8.24 (1H, dd, J = 8.6 Hz), 8.88 (1H, d, J = 1.5 Hz)
実施例９２
4-[(3-フルオロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル
【０３４１】
【化１４３】

【０３４２】
¹H NMR (DMSO-d₆) δ; 1.60-1.73 (2H, m), 1.88-1.97 (2H, m), 2.86-2.94 (2H, m), 3.42-3.50 (2H, m), 3.64-3.71 (1H, m), 3.80 (3H, s), 4.62 (2H, d, J = 5.4 Hz), 4.77 (1H, d, J = 2.0 Hz), 7.09 (1H, t, J = 8.2 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.23 (1H, dd, J = 12.0, 2.0 Hz), 7.84 (1H, t, J = 5.4 Hz), 8.04 (1H, d, J = 8.4 Hz), 8.20 (1H, dd, J = 8.4, 1.2 Hz), 8.89 (1H, d, J = 1.2 Hz)
実施例９３
4-[(4-クロロ-3-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル
【０３４３】
【化１４４】

【０３４４】
¹H NMR (DMSO-d₆) δ; 1.60-1.72 (2H, m), 1.87-1.96 (2H, m), 2.86-2.95 (2H, m), 3.31-3.39 (2H, m), 3.68 (1H, m), 3.84 (3H, s), 4.72 (2H, d, J = 5.5 Hz), 4.74 (1H, d, J = 4.2 Hz), 6.98 (1H, dd, J = 1.8, 8.1 Hz), 7.20 (1H, d, J = 1.8 Hz), 7.34 (1H, d, J = 8.1 Hz), 7.92 (1H, t, J = 5.5 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.21 (1H, dd, J = 1.5, 8.6 Hz), 8.92 (1H, d, J = 1.5 Hz)
実施例９４
4-[(3-シアノ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル塩酸塩
【０３４５】
【化１４５】

【０３４６】
¹H NMR (DMSO-d₆) δ; 1.6-1.73 (2H, m), 1.88-2.0 (2H, m), 2.95-3.08 (2H, m), 3.4-3.7 (2H, m), 3.7-3.8 (1H, m), 3.90 (3H, s), 4.74 (2H, d, J = 5.6 Hz), 7.27 (1H, d, J = 9.2 Hz), 7.79 (1H, dd, J = 2.0, 8.8 Hz), 7.87 (1H, d, J = 2.0 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 1.2, 8.4 Hz), 9.38 (1H, s)
実施例９５
(endo)-4-[(3-シアノ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-6-フタラジンカルボニトリル塩酸塩
【０３４７】
【化１４６】

【０３４８】
¹H NMR (DMSO-d₆) δ; 1.9-1.96 (4H, m), 2.17-2.29 (4H, m), 3.91 (3H, s), 4.04 (1H, m), 4.15 (2H, m), 4.68 (2H, s), 7.25 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 8.21 (1H, d, J = 8.6 Hz), 8.34 (1H, m), 9.07 (1H, m)
実施例９６
4-[(3-シアノ-4-メトキシベンジル)アミノ]-1-[3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル塩酸塩
【０３４９】
【化１４７】

【０３５０】
¹H NMR (DMSO-d₆) δ; 1.84 (1H, m), 2.09 (1H, m), 2.48 (1H, m), 3.40-3.55 (2H, m), 3.64-3.90 (4H, m), 3.91 (3H, s), 4.59 (2H, m), 7.24 (1H, d, J = 8.8 Hz), 7.74 (1H, d, J = 8.8 Hz), 7.79 (1H, s), 8.42 (1H, d, J = 9.3 Hz), 8.70 (1H, m), 9.15 (1H, m)
実施例９７
4-[(3-エチル-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル塩酸塩
【０３５１】
【化１４８】

【０３５２】
¹H NMR (DMSO-d₆) δ; 1.14 (3H, t, J = 7.5 Hz), 1.63-1.74 (2H, m), 1.90-2.01 (2H, m), 2.57 (2H, q, J = 7.5 Hz), 2.97-3.08 (2H, m), 3.40-3.54 (2H, m), 3.75 (1H, m), 3.79 (3H, s), 4.69 (2H, s), 6.95 (1H, d, J = 8.2 Hz), 7.26-7.35 (2H, m), 8.25 (1H, d, J = 8.6 Hz), 8.48 (1H, dd, J = 1.3, 8.6 Hz), 9.44 (1H, m)
実施例９８
4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリル塩酸塩
【０３５３】
【化１４９】

【０３５４】
¹H NMR (DMSO-d₆) d 1.58-1.66 (2H, m), 1.67-1.78 (4H, m), 2.14-2.23 (2H, m), 2.92-3.01 (2H, m), 3.07 (2H, s), 3.11 (2H, s), 3.70-3.82 (3H, m), 3.80 (3H, s), 4.08-4.18 (1H, m), 7.06 (1H, d, J = 8.4 Hz), 7.26 (1H, dd, J = 2.0, 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 1.2, 8.4 Hz), 9.55 (1H, s), 10.47 (1H, br.s), 13.9 (1H, brs)
実施例９９
4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-[4-(2-ヒドロキシエトキシ)ピペリジノ]-6-フタラジンカルボニトリル塩酸塩
【０３５５】
【化１５０】

【０３５６】
¹H NMR (DMSO-d₆) δ; 1.68-1.77 (2H, m), 2.00-2.06 (2H, m), 2.76 (2H, t, J = 8.0 Hz), 3.03 (2H, t, J = 12.0 Hz), 3.32 (10H, m), 3.75 (2H, d, J = 8.0 Hz), 3.81 (3H, s), 7.07 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 8.6 Hz), 7.43 (1H, s), 8.24 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.32 (1H, s)
実施例１００
4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-[4-フルオロ-4-(ヒドロキシメチル)ピペリジノ]-6-フタラジンカルボニトリル
【０３５７】
【化１５１】

【０３５８】
¹H NMR (DMSO-d₆) δ; 1.82-2.06 (4H, m), 2.83-2.94 (2H, m), 3.04-3.14 (2H, m), 3.24-3.30 (1H, m), 3.49 (2H, dd, J = 10.2, 6.0 Hz), 3.54-3.60 (1H, m), 3.64-3.70 (2H, m), 3.80 (3H, s), 5.03 (1H, dd, J = 6.0, 6.0 Hz), 7.05 (1H, d, J = 12.6 Hz), 7.19 (1H, dd, J = 12.6, 2.0 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.40-7.45 (1H, m), 8.08 (1H, d, J = 8.4 Hz), 8.18 (1H, d, J = 8.4 Hz), 8.82 (1H, brs)
実施例１０１
(endo)-4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-6-フタラジンカルボニトリル
【０３５９】
【化１５２】

【０３６０】
¹H NMR (DMSO-d₆) δ; 1.78-1.94 (4H, m), 2.14-2.28 (4H, m), 2.92 (2H, t, J = 7.0 Hz), 3.67 (2H, q, J = 7.0 Hz), 3.82 (3H, s), 4.04 (1H, m), 4.09 (2H, m), 4.49 (1H, d, J = 1.8 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 2.2, 8.4 Hz), 7.27 (1H, m), 7.33 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 8.6 Hz), 8.17 (1H, dd, J = 1.5, 8.6 Hz), 8.80 (1H, d, J = 1.5 Hz)
実施例１０２
4-[(3-クロロ-4-メトキシフェネチル)アミノ]-1-[3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル
【０３６１】
【化１５３】

【０３６２】
¹H NMR (DMSO-d₆) δ; 1.68 (1H, m), 2.00 (1H, m), 2.40 (1H, m), 2.92 (2H, t, J = 7.5 Hz), 3.37-3.70 (8H, m), 3.82 (3H, s), 4.69 (1H, d, J = 5.3 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.16 (1H, m), 7.20 (1H, dd, J = 2.0, 8.6Hz), 7.33 (1H, d, J = 2.0 Hz), 8.15 (1H, dd, J = 1.3, 8.6 Hz), 8.25 (1H, d, J = 8.6 Hz), 8.78 (1H,m)
実施例１０３
4-[(3,4-ジクロロベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルボニトリル塩酸塩
【０３６３】
【化１５４】

【０３６４】
¹H NMR (DMSO-d₆) δ; 1.61-1.72 (2H, m), 1.90-2.00 (2H, m), 3.01-3.18 (2H, m), 3.40-3.52 (2H, m), 3.72-3.80 (1H, m), 4.75 (2H, d, J = 5.2 Hz), 7.49 (1H, dd, J = 8.6, 2.0 Hz), 7.66 (1H, d, J = 8.6 Hz), 7.79 (1H, d, J = 2.0 Hz), 8.25 (1H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 8.6, 1.0 Hz), 9.36 (1H, d, J = 1.0 Hz), 10.24 (1H, br)
実施例１０４
1-[6-ブロモ-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-フタラジニル]-4-ピペリジノール塩酸塩
【０３６５】
【化１５５】

【０３６６】
¹H NMR (DMSO-d₆) δ; 1.59-1.68 (2H, m), 1.85-1.94 (2H, m), 2.94-3.08 (2H, m), 3.45-3.55 (2H, m), 3.70-3.76 (1H, m), 3.83 (3H, s), 4.69 (2H, d, J = 4.8 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.59 (1H, s), 8.01 (1H, d, J = 8.8 Hz), 8.26 (1H, d, J = 8.8 Hz), 9.18 (1H, s)
実施例１０５
1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-1-ピラゾリル)-1-フタラジニル]-4-ピペリジノール塩酸塩
【０３６７】
【化１５６】

【０３６８】
¹H NMR (DMSO-d₆) δ; 1.6-1.75 (2H, m), 1.85-2.0 (2H, m), 2.95-3.1 (2H, m), 3.3-3.55 (2H, m), 3.7-3.8 (1H, m), 3.82 (3H, s), 4.68-4.77 (2H, m), 6.72 (1H, m), 7.14 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 7.6 Hz), 7.63 (1H, s), 7.93 (1H, d, J = 1.6Hz), 8.22 (1H, d, J = 8.8 Hz), 8.61 (1H, dd, J = 1.6, 8.8 Hz), 8.97 (1H, s), 9.46 (1H, m)
実施例１０６
7-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-1-ピラゾリル)-1-フタラジニル]-7-アザスピロ[3.5]ノナン-2-オール塩酸塩
【０３６９】
【化１５７】

【０３７０】
¹H NMR (DMSO-d₆) δ; 1.55-1.68 (2H, m), 1.68-1.80 (4H, m), 2.14-2.25 (2H, m), 3.0-3.2 (4H, m), 3.82 (3H, s), 4.14 (1H, hep, J = 7.2 Hz), 4.72 (2H, m), 6.72 (1H, t, J = 2 Hz), 7.14 (1H, d, J = 8.4Hz), 7.47 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 7.93 (1H, d, J = 1.6Hz), 8.20 (1H, d, J = 9.2 Hz), 8.60 (1H, dd, J = 2.0, 9.2 Hz), 8.94 (1H, d, J = 2.4 Hz), 9.43 (1H, s)実施例１０７
[1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-1-ピラゾリル)-1-フタラジニル]-4-フルオロ-4-ピペリジニル]メタノール塩酸塩
【０３７１】
【化１５８】

【０３７２】
¹H NMR (DMSO-d₆) δ; 1.85-2.0 (2H, m), 1.95-2.1 (2H, m), 3.05-3.2 (2H, m), 3.4-3.6 (2H, m), 3.51 (2H, d, J = 20 Hz), 3.83 (3H, s), 4.74 (2H, d, J = 5.2 Hz), 6.72 (1H, t, J = 1.6 Hz), 7.14 (1H, d, J = 8.8Hz), 7.48 (1H, d, J = 8.4 Hz), 7.64 (1H, s), 7.93 (1H, d, J = 1.6Hz), 8.25 (1H, d, J = 9.2 Hz), 8.61 (1H, dd, J = 2.0, 9.2 Hz), 8.95 (1H, s), 9.44 (1H, s)
実施例１０８
1-[4-[(3-ブロモ-4-メトキシベンジル)アミノ]-6-(1H-1-ピラゾリル)-1-フタラジニル]-4-ピペリジノール塩酸塩
【０３７３】
【化１５９】

【０３７４】
¹H NMR (DMSO-d₆) δ; 1.6-1.74 (2H, m), 1.87-2.0 (2H, m), 2.9-3.1 (2H, m), 3.4-3.55 (2H, m), 3.7-3.8 (1H, m), 3.81 (3H, s), 4.65-4.8 (2H, m), 6.72 (1H, m), 7.10 (1H, d, J = 8.8 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.79 (1H, s), 7.93 (1H, d, J = 1.2 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J = 8.8 Hz), 9.00 (1H, d, J = 2.8 Hz), 9.51 (1H, s)
実施例１０９
1-[4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-(1H-1,2,3-トリアゾール-1-イル)-1-フタラジニル]-4-ピペリジノール塩酸塩
【０３７５】
【化１６０】

【０３７６】
¹H NMR (DMSO-d₆) δ; 1.62-1.75 (2H, m), 1.9-2.0 (2H, m), 3.0-3.1 (2H, m), 3.3-3.58 (2H, m), 3.7-3.8 (1H, m), 3.83 (3H, s), 4.73 (2H, d, J = 5.6 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.13 (1H, m), 8.32 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 9.2 Hz), 9.17 (1H, s), 9.56 (1H, s)
実施例１１０
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルバルデヒド O6-メチルオキシム塩酸塩
【０３７７】
【化１６１】

【０３７８】
¹H NMR (DMSO-d₆) δ; 1.60-1.70 (2H, m), 1.87-1.70 (2H, m), 2.96-3.05 (2H, m), 3.30-3.50 (2H, m), 3.68-3.78 (1H, m), 3.83 (3H, s), 3.99 (3H, s), 4.66-4.73 (2H, m), 7.14 (1H, d, J = 8 Hz), 7.42 (1H, dd, J = 2, 8 Hz), 7.57 (1H, d, J = 2 Hz), 8.13 (1H, d, J = 8 Hz), 8.28 (1H, d, J = 8 Hz), 8.39 (1H, s), 8.94 (1H, brs)
実施例１１１
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルバルデヒド O6-エチルオキシム塩酸塩
【０３７９】
【化１６２】

【０３８０】
¹H NMR (DMSO-d₆) δ; 1.28 (3H, t, J = 6 Hz), 1.60-1.73 (2H, m), 1.87-1.98 (2H, m), 2.94-3.06 (2H, m), 3.39-3.52 (2H, m), 3.68-3.78 (1H, m), 3.83 (3H, s), 4.25 (2H, q, J = 6 Hz), 4.67-4.74 (2H, m), 7.13 (1H, d, J = 9 Hz), 7.42 (1H, d, J = 9 Hz), 7.58 (1H, s), 8.13 (1H, d, J = 8 Hz), 8.30 (1H, d, J = 8 Hz), 8.39 (1H, s), 8.97 (1H, s)
実施例１１２
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(4-ヒドロキシピペリジノ)-6-フタラジンカルバルデヒド O6-ベンジルオキシム塩酸塩
【０３８１】
【化１６３】

【０３８２】
¹H NMR (DMSO-d₆) δ; 1.59-1.71 (2H, m), 1.87-1.96 (2H, m), 2.94-3.05 (2H, m), 3.37-3.51 (2H, m), 3.68-3.78 (1H, m), 3.82 (3H, s), 4.67-4.76 (2H, m), 5.27 (2H, s), 7.13 (1H, d, J = 9 Hz), 7.29-7.48 (6H, m), 7.59 (1H, s), 8.12 (1H, d, J = 9 Hz), 8.29 (1H, d, J = 9 Hz), 8.45 (1H, s), 9.04 (1H, brs)
実施例１１３
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-フルオロ-3-(ヒドロキシメチル)テトラヒドロ-1H-1-ピロリル]-6-フタラジンカルボニトリル塩酸塩
【０３８３】
【化１６４】

【０３８４】
¹H NMR (DMSO-d₆) δ; 2.09-2.28 (2H, m), 3.50-4.05 (6H, m), 3.81 (3H, s), 4.66 (2H, s), 7.11 (1H, d, J = 8.0 Hz), 7.43 (1H, d, J = 8.0 Hz), 7.58 (1H, s), 8.43 (1H, d, J = 8.4 Hz), 8.53 (1H, s), 9.45 (1H, s)
実施例１１４
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-1-オキサ-8-アザスピロ[4.5]デカ-8-イル)-6-フタラジンカルボニトリル塩酸塩
【０３８５】
【化１６５】

【０３８６】
¹H NMR (DMSO-d₆) δ; 1.65-1.85 (3H, m), 1.87-2.01(2H, m), 3.16-3.63 (8H, m), 3.82 (3H, s), 4.32 (1H, s), 4.73 (2H, d, J = 4.8 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.62 (1H, s), 8.23 (1H, d, J = 8.0 Hz), 8.44 (1H, d, J = 8.0 Hz), 9.57 (1H, s), 10.78 (1H, s)
実施例１１５
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[2-(1-ヒドロキシシクロペンチル)-1-エチニル]-6-フタラジンカルボニトリル
【０３８７】
【化１６６】

【０３８８】
NMR(DMSO-d₆)δ; 1.69-1.86 (4H, m), 1.97-2.04 (4H, m), 3.82 (3H, s), 4.75 (2H, d, J = 5.4 Hz), 5.60 (1H, s), 7.10 (1H, d, J = 8.8 Hz), 7.36 (1H, dd, J = 8.8, 1.2 Hz), 7.49 (1H, d, J = 1.2 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.31 (1H, dd, J = 8.8, 0.6 Hz), 8.52 (1H, t, J = 5.4 Hz), 8.97 (1H, d, J = 0.6 Hz)
実施例１１６
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[2-(1-ヒドロキシシクロペンチル)エチル]-6-フタラジンカルボニトリル塩酸塩
【０３８９】
【化１６７】

【０３９０】
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[2-(1-ヒドロキシシクロペンチル)-１-エチニル]-6-フタラジンカルボニトリル690 mgをテトラヒドロフラン200 mLに溶解し、１０％Pd-C 50 mgを加え、水素雰囲気下０．５時間撹拌した。セライト濾過し、濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[2-(1-ヒドロキシシクロペンチル)エチル]-6-フタラジンカルボニトリルを400 mg得た。常法により塩酸塩とした。
¹H NMR (DMSO-d₆) δ; 1.47-1.78 (8H, m), 1.89-1.94 (2H, m), 3.24-3.33 (2H, m), 3.84 (3H, s), 4.74 (2H, d, J = 4.4 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.46 (1H, d, J = 8.8 Hz), 8.55 (1H, dd, J = 8.8, 1.2 Hz), 9.40 (1H, br)
同様にして以下の化合物を得た。
実施例１１７
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-3-メチルブチル)-6-フタラジンカルボニトリル塩酸塩
【０３９１】
【化１６８】

【０３９２】
¹H NMR (DMSO-d₆) δ; 1.17 (6H, s), 1.73-1.80 (2H, m), 3.17-3.24 (2H, m), 3.80 (3H, s), 4.78 (2H, d, J = 4.4 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 1.8 Hz), 7.62 (1H, d, J = 1.8 Hz), 8.43 (1H, d, J = 8.6 Hz), 8.51 (1H, dd, J = 8.6, 1.2 Hz), 9.63 (1H, br), 10.30 (1H, br).
実施例１１８
1-(3-アミノ-3-メチルブチル)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル・二塩酸塩
【０３９３】
【化１６９】

【０３９４】
¹H NMR (DMSO-d₆) δ; 1.37 (6H, s), 2.00-2.19 (2H, m), 3.21-3.56 (2H, m), 3.84 (3H, s), 4.78 (2H, d, J = 4.4 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.61 (1H, s), 8.15-8.29 (4H, m), 8.48 (1H, d, J = 8.8 Hz), 8.56 (1H, d, J = 8.8 Hz), 9.38 (1H, br)
実施例１１９
4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-[3-(ジメチルアミノ)プロピル]-6-フタラジンカルボニトリル・二塩酸塩
【０３９５】
【化１７０】

【０３９６】
¹H NMR (DMSO-d₆) d 2.11-2.19 (2H, m), 2.74 (3H, s), 2.75 (3H, s), 3.16-3.29 (4H, m), 3.85 (3H, s), 4.80 (2H, d, J = 5.2 Hz), 7.16 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.49 (1H, d, J = 8.4 Hz), 8.56 (1H, dd, J = 8.4, 1.4 Hz), 9.47 (1H, d, J = 1.4 Hz), 10.56 (2H, br)[0001]
[Industrial application fields]
The present invention relates to phthalazine derivatives. More particularly, the present invention relates to a prophylactic / therapeutic agent for male erectile dysfunction and a prophylactic / therapeutic agent for female sexual dysfunction or dysmenorrhea. Furthermore, the present invention relates to a prophylactic / therapeutic agent for heart diseases such as hypertension, pulmonary hypertension, angina pectoris, diabetes, or nephritis.
[0002]
[Prior art]
There are about 3 million potential patients with erectile dysfunction in Japan. In the United States, 20 million people, 15% of men in their 50s and about 1/3 of men in their 60s fall under this disease It has been reported. With the aging of society, sex is considered to be pleasure and emotional behavior, and a higher quality of life is required. In the future, erectile dysfunction is expected to become a social problem as well as a medical problem. Is done. This disease is classified into two types: organicity due to damage to nerves, blood vessels, muscles or sex hormones of the penis itself, and functionality (psychogenicity) due to mental or psychological causes. The erection requires three conditions: increased penile arterial blood flow, suppression of blood leakage from the penile vein, and relaxation of the cavernous tissue, and if any one of them is inhibited, erectile dysfunction occurs.
[0003]
The treatment for erectile dysfunction currently practiced in the urology department is the surgical penis prosthesis with drug therapy and penile prosthesis.
As drug therapy, papaverine hydrochloride and prostaglandin E1 can be injected into the cavernosal cavity of the penis, but in Japan it is not possible to inject by yourself, and it is not possible to go to the doctor every time you have sex. Not done. In addition, injections of papaverine hydrochloride are rare, but can cause painful symptoms of penile priapism. In this way, the existing drug treatment methods are not practical, and clinically highly practical drug therapies are eagerly desired.
[0004]
[Problems to be solved by the invention]
In 1984, Bowman and Drummond, in the bovine penile retractor, a selective cyclic GMP phosphodiesterase inhibitor, M & B22948 (Zaprinast), increases cyclic GMP in tissues and relaxes. (Cyclic GMP mediates neurogenic relaxation in the bovine retractor penis muscle, Br. J. Pharmacol., 81, 665-674, 1984). Subsequently, other researchers reported on the relaxing action of the corpus cavernosum by increasing cyclic GMP in tissues (Int. J. Impotence Res., 4, 85-93, 1992; J. Urol., 147, 1650-1655, 1992; N. Engl. J. Med., 326, 90-94, 1992). However, the compounds used in these studies are not satisfactory for clinical use due to their weak action.
[0005]
Phosphodiesterase type 5 inhibitors are also effective in female sexual dysfunction.
A phthalazine derivative having an inhibitory action on phosphodiesterase type 5 is disclosed in WO 9605176 (Patent Publication No. 8-225541), but there is no disclosure regarding spiro compounds containing nitrogen atoms, bicyclo rings and 6-membered heterocyclic derivatives, and erection There is no mention of prevention / treatment of dysfunction.
[0006]
[Means for Solving the Problems]
As a result of various investigations, the phthalazine derivative represented by the general formula (I) has high selectivity and strong inhibitory action on phosphodiesterase type 5 which is a cyclic GMP degrading enzyme, and strong relaxation against the cavernous corpus cavernosum. The present invention has been completed by finding that it exhibits an action, increases the utilization rate in vivo, and has high safety.
[0007]
The present invention relates to a method for producing phthalazine derivatives not specifically disclosed in JP-A-8-225541, phthalazine derivatives not suggested at all, and some derivatives.
Formula (I)
[0008]
Embedded image

[0009]
{Where
R¹And R²Are the same or different and represent a halogen atom, a C1-C4 alkyl group optionally substituted with a halogen atom, a C1-C4 alkoxy group optionally substituted with a halogen atom, or a cyano group.
X is a cyano group, nitro group, halogen atom, thiocarbamoyl group, C1-C4 alkyl group / aryl C1-C4 alkyl group or hydroxyimino group optionally substituted with a carboxy C1-C4 alkyl group, or the following substituent group It means a heteroaryl group which may be substituted with 1 to 3 substituents selected from A.
[0010]
Y is
i) Formula (II)
[0011]
Embedded image

[0012]
(Wherein ring A is a 4- to 8-membered amine ring which may be substituted with a methyl group and may have a double bond, D is a single bond or an oxygen atom, R^ThreeRepresents a hydrogen atom, a C1-C4 alkyl group or a halogen atom, and m represents an integer of 0 or 1-3. W means an amino group, a hydroxyl group, a cyano group, a carboxyl group which may have a protecting group, or a C1-C4 alkoxy group. Group represented by
ii) Formula (III)
[0013]
Embedded image

[0014]
Wherein ring B is a 4- to 8-membered amine ring optionally having a double bond, and n and p are the same or different and each represents an integer of 0 or 1-3. Group,
iii) Formula (IV)
[0015]
Embedded image

[0016]
{In the formula, ring G represents a 4- to 8-membered amine ring which may have a double bond; E represents a hydroxyl group, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group; J represents a formula -(CHR^Four) q-Q (where R^FourIs a hydrogen atom or a C1-C4 alkyl group, Q is a hydroxyl group, a halogen atom, an optionally substituted carboxyl group, a carbamoyl group or an azolyl group containing no hetero atom other than a nitrogen atom, q is 0 or An integer of 1 to 4 is meant. ) Or E and J may form a 3- to 6-membered ring together with the carbon atoms to which they are bonded, and this ring may have a hetero atom. Moreover, this ring may have a substituent. A group represented by
iv) Formula (V)
[0017]
Embedded image

[0018]
(In the formula, M means a single bond, or a C1-C4 alkylene group optionally substituted with a hydroxyl group, a carboxyl group, a C1-C4 alkyl group or a C1-C4 alkoxy group. Ring K together with M A 5- to 8-membered amine ring, wherein the ring L represents a 5- to 8-membered alkyl ring which may have a substituent and may have an oxygen atom. ,
v) Formula (VI)
[0019]
Embedded image

[0020]
(Wherein ring P is a 5- to 7-membered amine ring, R^FiveMeans a hydrogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group. Group represented by
vi) an alkynyl group, an alkenyl group or an alkyl group, which may have a substituent,
vii) a phenyl group optionally substituted with 1 to 3 substituents selected from the following substituent group A, or
viii) A pyridyl group, a pyrimidyl group, a thienyl group, a thiazolyl group or a freel group which may be substituted with 1 to 3 substituents selected from the following substituent group A.
[Substituent group A] C1-C4 alkyl group optionally substituted with a halogen atom, cyano group, nitro group or hydroxyl group, C1-C4 alkoxy optionally substituted with a halogen atom, cyano group, nitro group or hydroxyl group Group, cyano group, nitro group, carboxyl group optionally having protective group, hydroxyl group optionally having protective group; carbamoyl group optionally substituted with lower alkyl group, halogen atom, C1 ~ An amino group optionally substituted with a C4 acyl group / C1-C4 alkylsulfonyl group or an arylsulfonyl group which may have a substituent.
[0021]
l means an integer of 1 to 3;
Where l is 1 or 2, X is a cyano group, nitro group or chloro atom, R¹Is a chloro atom, R²Is a methoxy group, ring A is a 5- or 6-membered amine ring, D is a single bond, m is 0 and W is an optionally substituted carboxyl group or C1-C4 alkoxy group; R¹Is a chloro atom, R²Is a methoxy group, ring A is a saturated 5- or 6-membered amine ring, D is a single bond and W is a hydroxyl group; l is 1, ring B is a 5- or 6-membered amine ring, and n and p are both 0 Except when l is 1, E and Q are hydroxyl groups and q is 0; and when l is 1, X is a chloro atom and Y is a phenyl group substituted by a methoxy group. } Or a pharmacologically acceptable salt thereof, or a hydrate thereof.
[0022]
Furthermore, the following general formula (VII) also showed a strong relaxing action on the cavernous corpus cavernosum, increased the utilization rate in vivo, and found it to have high safety, thereby completing the present invention. .
Formula (VII)
[0023]
Embedded image

[0024]
{Wherein, l 'represents an integer of 1 to 3. R⁶Means a halogen atom, a C1-C4 alkyl group which may be substituted with a halogen atom, or a cyano group.
X1 means a cyano group, a nitro group or a halogen atom.
Y1
i) Formula (VIII)
[0025]
Embedded image

[0026]
(In the formula, ring A1 represents a 5- or 6-membered amine ring, m1 represents an integer of 0 or 1 to 3, Z represents an amino group, a hydroxyl group optionally having a protecting group, and a protecting group. A carboxyl group, a C1-C4 alkoxy group or a cyano group, which may be
ii) Formula (IX)
[0027]
Embedded image

[0028]
Wherein ring B1 represents a 5- or 6-membered amine ring, and n1 and p1 represent 0 or an integer of 1 to 3,
iii) a morpholino group or a thiomorpholino group in which the sulfur atom may be oxidized,
iv) a phenyl group which may be substituted with 1 to 3 substituents selected from the following substituent group A;
v) a heteroaryl group that is a pyridyl group, a pyrimidyl group, a thienyl group, or a freel group that may be substituted with 1 to 3 substituents selected from the following substituent group A; or
vi) Formula -N (R⁷)-(CH₂s-Het
(Where R⁷Represents a lower alkyl group, and Het represents a pyridyl group or a pyrimidyl group which may be substituted with 1 to 3 substituents selected from the following substituent group A1. s means 0 or an integer of 1-3. )
[Substituent group A1] Lower alkyl group optionally substituted by halogen atom, cyano group, nitro group or hydroxyl group, Lower alkoxy group optionally substituted by halogen atom, cyano group, nitro group or hydroxyl group, cyano group , A nitro group, a carboxyl group optionally having a protecting group, a hydroxyl group optionally having a protecting group, a carbamoyl group optionally substituted by a lower alkyl group, a halogen atom, an alkyl group / alkoxy group / halogen Atom or amino group phenyl group. }
A therapeutic agent for erectile dysfunction, comprising as an active ingredient a phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof.
[0029]
In the definition shown in the present invention, X, R¹, R², R^Three, R^Four, R^Five, E, Q, substituent groups A and A1, etc., halogen atom means fluorine atom, chlorine atom, bromine atom, iodine atom.
R¹, R², R^Three, R^Four, R^Five, R⁶, R⁷The C1-C4 alkyl group found in the substituent groups A and A1 and the like is a linear or branched alkyl group having 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl. , Isobutyl, 1-methylpropyl, tert-butyl. R¹, R²And the C1-C4 alkoxy group found in the substituent groups A and A1, etc. means a group derived from the C1-C4 alkyl group. For example, methoxy group, ethoxy group, propoxy group and the like are meant.
[0030]
Examples of the protecting group in the carboxyl group which may have a protecting group found in Q, W, substituent groups A and A1, etc. include, for example, lower alkyl groups such as methyl group, ethyl group and tert-butyl group, p Lower alkyl group substituted with a phenyl group which may have a substituent such as -methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl, phenethyl, etc., 2,2,2-trichloro Halogenated lower alkyl groups such as ethyl and 2-iodoethyl, pivaloyloxymethyl, acetoxymethyl, pupionyloxymethyl, butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1- Lower alkanoyloxy lower alkyl groups such as pivaloyloxyethyl and 2-pivaloyloxyethyl, palmitoyloxyethyl, heptadecanoyl Higher alkanoyloxy lower alkyl groups such as oxymethyl, 1-palmitoyloxyethyl, lower alkoxycarbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl, 1- (isopropoxycarbonyloxy) ethyl, carboxymethyl Carboxy lower alkyl group such as 2-carboxyethyl, heteroaryl group such as 3-phthalidyl, benzoyloxy lower alkyl group optionally having substituents such as 4-glycyloxybenzoyloxymethyl, (5-methyl (Substituted dioxolene) lower alkyl groups such as 2-oxo-1,3-dioxolen-4-yl) methyl, cycloalkyl substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl, 1-cyclohexyloxycarbonyloxy D , And the like cycloalkyloxycarbonyl-lower alkyl groups such as Le. In short, as long as it can be decomposed by some means in a living body to be a carboxylic acid, any can be a protecting group for a carboxyl group.
[0031]
In addition, the protecting group in the hydroxyl group which may have a protecting group found in the substituent groups A and A1 and the like is, for example, an acyl group such as a formyl group, an acetyl group or a benzoyl group; a 2-methoxyethoxymethyl group or the like A lower alkoxymethyl group etc. can be mentioned. In short, any substance can be used as a hydroxyl-protecting group as long as it can be decomposed by some means in vivo to form a hydroxyl group.
[0032]
The azolyl group containing no hetero atom other than the nitrogen atom in Q means a group derived from pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, benzimidazole, and benzotriazole.
[0033]
In the formula (IV), a compound formed by the ring formed by combining the carbon atom to which E and J are bonded together with the ring G is a spiro compound. Examples of the ring formed together with the carbon atom to which E and J are bonded include cyclobutane, cyclopentane, cyclohexane, oxirane, tetrahydrofuran, tetrahydropyran, butyrolactone, butyrolactam, and the like. In addition, the substituents on these rings include a hydroxyl group, a C1-C4 alkyl group which may be substituted with a hydroxyl group such as a hydroxyl group, hydroxymethyl group / hydroxyethyl group, etc. , Carbonyl groups, halogen atoms such as fluorine and chloro atoms, and the like.
[0034]
In the formula (V), when M is a C1-C4 alkylene group, it means that the bicyclo ring formed by the ring K and the ring L is a bridged ring. Examples of the substituent on the ring L include a hydroxyl group, a carboxyl group that may have the above-described protecting group, a C1-C4 alkyl group that may be substituted with a hydroxyl group such as a hydroxymethyl group or a hydroxyethyl group, or carboxymethyl. A C1-C4 alkyl group carbonyl group optionally substituted with a carboxyl group such as a group or carboxyethyl group, a halogen atom such as a fluorine or chloro atom, or a vinyl group.
[0035]
The substituent in the alkynyl group, alkenyl group or alkyl group which Y may have a substituent is methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert -C1-C4 alkyl group such as butyl group, groups derived from cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, methoxy group, ethoxy group, propoxy group, etc. C1-C4 alkoxy groups, hydroxyl groups, amino groups optionally substituted with C1-C4 alkyl groups, cyclic amines such as aziridines / azetidines, pyrrolidines / piperidines optionally substituted with hydroxyl groups, hydroxy C1-C4 alkyl groups, Hydroxy C1-C4 alkoxy groups, carboxyalkoxy groups, halogen atoms such as fluorine atoms and chloro atoms, etc. means.
[0036]
Heteroaryl groups in X include pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, benzimidazole, benzotriazole, thiazole, isothiazole, thiadiazole, benzothiadiazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline, naphthyridine, phthalazine, etc. The group derived from can be mentioned.
[0037]
In the present invention, pharmacologically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromide, and phosphate, formate, acetate, maleate, and fumaric acid. Mention may be made of organic acid salts such as salts, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate.
It goes without saying that the compound having an asymmetric atom in the present invention includes its optically active organism.
[0038]
Furthermore, the present invention includes the compound of the present invention produced by metabolism in vivo and the compound produced by metabolism of the compound of the present invention.
These phthalazine derivatives or pharmacologically acceptable salts thereof, or hydrates thereof are excellent in oral absorption and persistence, so that they can be transdermally, intravenously and injected directly into the penile corpus caverno or genital area. It can be treated by oral administration, and is desirable as a prophylactic / therapeutic agent for erectile dysfunction and a prophylactic / therapeutic agent for female sexual dysfunction or dysmenorrhea.
It is described in WO 9605176 and WO 9900359 that a PDE5 inhibitor is effective in the prevention and treatment of heart diseases such as hypertension, pulmonary hypertension and angina, diabetes and nephritis.
[0039]
The dose of the compound of the present invention is not particularly limited, but is usually 5 μg-100 mg, preferably 10-1000 μg when used by intravenous administration per adult, and 1-1000 mg when used by oral administration. Preferably, 5-100 mg is used.
[0040]
DETAILED DESCRIPTION OF THE INVENTION
Manufacturing method 1
A method for producing a similar compound of the phthalazine derivative of the present invention or a pharmacologically acceptable salt thereof is described in WO 9605176 (Patent Publication No. 8-225541), and the phthalazine derivative of the present invention is also produced as follows. The
[0041]
Embedded image

[0042]
HY in a solvent when the compound represented by formula (X)²To obtain formula (XII). The reaction solvent is preferably N-methyl-2-pyrrolidinone or the like, but any solvent that does not participate in the reaction can be used. Good results may be obtained by using an excess amount of HY relative to compound (X), or using an organic base such as diisopropylethylamine, or a salt such as potassium carbonate, sodium carbonate, or sodium bicarbonate. The reaction temperature is from room temperature to the boiling point of the solvent, but is preferably heated to 100 ° C. or higher.
[0043]
HY required for the production of a compound in which W is a cyano group, which is not described in WO 9605176 (Patent Publication No. 8-225541)²Is synthesized as follows.
[0044]
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[0045]
In addition, there is no specific description in the above publication, and when W in the above definition is an amino group, the amino group is protected with HY²Is synthesized as follows, and the above is produced by deprotection after completion of the process.
[0046]
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[0047]
HY when Y in general formula (I) is general formula (IV) or general formula (V)²Can be prepared using the compounds disclosed in WO 9806720 or utilizing the methods disclosed therein.
1) For example, some compounds represented by the general formula (IV) are produced by the following method.
[0048]
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[0049]
(In the formula, G1 represents a 4- to 8-membered amine ring, Q1 represents pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, indazolyl, benzoimidazolyl, benzotriazolyl group or fluorine atom, and Pro represents a protecting group for nitrogen atom. To do.)
When methyltriphenylsulfonium bromide is treated with a base such as potassium tert-butoxide or butyllithium in a solvent such as toluene, xylene, or tetrahydrofuran, and reacted with a ketone body represented by formula (a), it is represented by formula (b). Can be obtained. The reaction temperature is preferably -78 ° C to room temperature.
[0050]
When the compound (b) is reacted with trichloroacetyl chloride in a solvent such as diethyl ether, dimethoxyethane, tetrahydrofuran or the like and reacted with dichlorocyclobutanone (f) (or diacetyl chloride, a monochloro form is obtained. It can also be obtained by treating with chloride and then treating with acetic acid.) And then treating with a reducing agent such as zinc dust to obtain the cyclobutanone compound represented by formula (g). The reaction temperature is preferably 10 to 50 ° C. When the compound (g) is reacted with a peroxide such as 3-chloroperbenzoic acid in the presence of sodium hydrogen carbonate or the like in a solvent such as dichloromethane, a lactone compound represented by the formula (h) can be obtained. The reaction temperature is preferably in the range of room temperature to 40 ° C. When compound (b) is treated with dichloroketene and diazomethane, or compound (g) is treated with diazomethane, a cyclopentanone compound is obtained in formula (g). When this cyclopentanone is treated with diazomethane, a cyclohexanone is obtained.
[0051]
When the compound (b) is treated with a peracid such as magnesium phthalate monoperoxide in a solvent, an epoxide represented by the formula (c) is obtained. When this epoxide (c) is reacted with a sodium salt of an azole consisting only of a nitrogen atom as a hetero atom in a solvent such as dimethylformamide, the corresponding compound represented by the formula (d) (Q1 is a 1-imidazolyl group, 1 -Triazolyl group and the like). Also Bu_FourN ・ H₂F_ThreeTreatment with potassium hydrogen fluoride at 100 to 150 ° C. in the presence provides a fluoromethyl compound in which Q1 is a fluoro atom in the compound represented by formula (d).
[0052]
On the other hand, when the compound (c) is treated with hydrogen fluoride pyridine in a solvent such as methylene chloride at −10 to 10 ° C., a fluoro compound represented by the formula (e) is obtained.
2) Among the compounds represented by the general formula (V), when M is methylene substituted with a hydroxyl group, it is produced, for example, by the following method.
[0053]
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[0054]
It can be similarly produced when the ring L contains an oxygen atom.
Manufacturing method 2
In the general formula (I), a compound in which Y is an alkynyl group, alkenyl group or alkyl group which may have a substituent can be produced by the following method.
[0055]
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[0056]
(In the formula, Hal represents a halogen atom, R⁸Means a C1-C4 alkyl group which may have a substituent, or a cycloalkyl group or a cycloalkylalkyl group which may have a substituent. R¹, R², L and X are as defined above. )
The reaction of the general formula (X) with the alkyne derivative is carried out at room temperature or under heating in the presence of a catalytic amount of dichlorobistriphenylphosphine palladium (II), cuprous iodide and a tertiary amine. Examples of the solvent used include dimethylformamide and 1-methylpyrrolidinone. The tertiary amine used is triethylamine, diisopropylethylamine, DBU, dimethylaniline and the like. The reaction temperature is preferably 0 to 150 ° C.
[0057]
Conversion from the alkyne compound represented by the formula (XIII) to the alkene compound represented by the formula (XIV) and the alkane compound represented by the formula (XV) is performed by catalytic reduction in the presence of Lindlar catalyst or Pd-C catalyst.
Manufacturing method 3
In addition, a phthalazine derivative of Y3 in which Y is an aryl group or heteroaryl group which may have a substituent is produced as follows.
[0058]
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[0059]
In the reaction, a 0-valent or divalent palladium complex is used to couple a 1-halogenoquinazoline derivative represented by the formula (X) with a boronic acid, dialkoxyborane or trialkyltin derivative of the corresponding aryl group or heteroaryl group. Is done. A boronic acid, dialkoxyborane or trialkyltin derivative of an aryl group or a heteroaryl group and a palladium complex are dissolved or suspended in a two-phase solvent of an organic solvent and an aqueous sodium carbonate solution, and the reaction temperature is approximately from room temperature to the boiling point of the solvent under a nitrogen stream. React for 1-24 hours. As the palladium complex, any palladium complex that causes the reaction to proceed can be used, but tetrakis (triphenylphosphine) palladium and the like are preferable. Any organic solvent that does not affect the reaction can be used, but xylene, toluene, tetrahydrofuran, or a mixed solvent thereof is preferable.
Manufacturing method 4
In the general formula (I), a compound represented by the following reaction formula can be produced by combining known reactions using the compound (XVII) in which X is a cyano group.
[0060]
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[0061]
(Where R⁹Represents a hydrogen atom, a C1-C4 alkyl group optionally substituted with a halogen atom, an aryl C1-C4 alkyl group or a carboxy C1-C4 alkyl group, and R^TenMeans a C1-C4 alkyl group. R¹, R², L and Y are as defined above. )
Manufacturing method 5
In the general formula (I), some compounds in which X is a heteroaryl group can be produced by the same method as Production Method 3.
[0062]
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[0063]
(Where Hal is a halogen atom, Het¹Means a heteroaryl group, R¹, R², L and Y are as defined above. )
The halogen atom is preferably a bromine atom or an iodine atom.
In addition, in the general formula (I), the production of the compound which is an azolyl group having no hetero atom other than the nitrogen atom is performed in accordance with the production method 1 after the corresponding compound represented by the general formula (X) is produced in advance. Done. The corresponding compound represented by the general formula (X) is obtained by, for example, treating dimethyl 4-fluorophthalate with an azole containing no hetero atom other than a nitrogen atom to obtain dimethyl 4-azolyl phthalate, followed by treatment with hydrazine. To 6-azolyl-2,3-dihydro-1,4-phthalazinedione, and then produced by the method disclosed in WO 9605176.
Manufacturing method 6
In the general formula (I), a compound in which Y is represented by the general formula (VI) is produced from a compound represented by the following general formula (XXIV) by oximation by a known method.
[0064]
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[0065]
(Where R¹, R², R^Five, L and X are as defined above. )
[0066]
【The invention's effect】
The effects of this compound are shown below by experimental examples.
[0067]
[Experimental example]
1) Obtained from porcine platelets cGMP-PDE Enzyme inhibitory action
Inhibition of enzyme activity of cGMP-PDE prepared from porcine platelets by dissolving 1 μM cGMP in DMSO in the presence of 1 mM EGTA in the presence of 1 mM EGTA according to the method of Tompson etc. and adding it to the reaction solution did. The final concentration of DMSO in the reaction solution was 1% or less. cGMP-PDE was prepared as follows. Porcine platelets were sonicated in buffer A (20 mM Tris / HCl, 2 mM magnesium acetate, 10 mM 2-mercaptoethanol, 0.1 mM EGTA, pH 7.4). The suspension was centrifuged at 100,000 × g for 60 minutes, and the resulting supernatant was applied to a DEAE-Toyopearl 650S (Toso, Tokyo, Japan) column. After washing the column with buffer A, elution was performed with a 0.075-0.25M NaCl gradient of buffer A to obtain a cGMP-PDE fraction. The obtained fraction was dialyzed and concentrated for storage.
[0068]
[Table 1]

[0069]
2) Against the relaxation effect of nitroprusside in rabbit penile cavernous specimens PDE5 Inhibitory compound potentiation
NZW rabbits (approximately 3.0 kg) were killed by intravenous administration of pentobarbital (50 mg / kg), and the penis was removed. After excision, the cavernous body was exposed except for surrounding tissues such as white membrane, and a specimen of about 10 × 1.5 × 1.5 mm was prepared. This sample was washed with 10ml of Krebs-Henseleit solution (NaCl: 118.4mM, KCl: 4.7mM, CaCl₂: 2.5mM, MgSO_Four: 1.3mM, KH₂PO_Four: 1.2 mM, NaHCO_Three: 25.0mM, glucose: 11.0mM, EDTA: 0.026mM, indomethacin: 0.001mM) suspended in a Magnus tube and mixed gas (95% O₂ + 5% CO₂), And the change in shrinkage tension was recorded isometrically under a load of 2 g. In order to stabilize the contraction, the contraction and washing by adding KCl (final concentration 100 mM) were repeated twice, and further the contraction and washing by adding phenylephrine (final concentration 10 mM) were performed. Again, fill with 10 ml of Krebs-Henseleit solution and add L-N^G-Nitroarginine methyl ester (final concentration 100 mM) was added to inhibit endogenous nitric oxide production. Contraction was induced by addition of phenylephrine (final concentration 10 mM), and the drug solution was added to 3, 30, or 300 nM. At this time, dimethyl sulfoxide was used as a medium. Nitroplusside (final concentration 300 mM) was added 15 minutes after drug addition to relax the specimen. Furthermore, maximum relaxation was determined by addition of papaverine (final concentration 100 mM). After the experiment was completed, the tension generated when papaverine was added was taken as the baseline, and the relaxation due to the addition of nitroprusside on the chart was measured using a digimatic caliper to determine the relaxation rate.
[0070]
[Table 2]

[0071]
The numerical values in the table indicate the relaxation rate after addition of nitroprusside in the samples pretreated with the compounds of 3, 30 and 300 nM, and the average value of 2 cases is described. EC₅₀The value indicates the concentration of the compound that causes 50% relaxation against the contraction induced by phenylephrine, and was calculated by regression analysis from the relaxation curves of two cases.
Nitric oxide produced from nitroprusside activated guanylate cyclase and promoted cGMP production from GTP to relax the cavernous corpus cavernosum. PDE5 inhibitors enhanced this relaxation by suppressing the degradation of cGMP.
[0072]
As described above, it was shown that the compound of the present invention has a PDE5 inhibitory action and enhances the relaxing action of nitroprusside in the rabbit isolated penile cavernous specimen in a concentration-dependent manner. That is, the compound of the present invention is useful as a prophylactic / therapeutic agent for erectile dysfunction.
In order to facilitate understanding of the present invention, production examples and examples are shown, but it goes without saying that the present invention is not limited to these compounds.
In addition, Example 9, 11, 12, 21-25, 28, 40, 41, 45, 51-57, 67-74, 82, 85, 87, 90, 95, 98, 101, 106, 114, 115 are It is an example of the present invention, and other examples are reference examples.
Production Example 1
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1-[(3R) -3-hydroxypiperidino] phthalazine hydrochloride
[0073]
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[0074]
1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine 1.0 g, (R)-(+)-3-hydroxypiperidine hydrochloride 1.92 g, diisopropylethylamine 1.80 g, 1-methyl- A mixture of 12 mL of 2-pyrrolidone was stirred at 170 ° C. for 1 hour and 15 minutes. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained free body was suspended in acetic acid ethanol-water, and 1N hydrochloric acid aqueous solution was added and dissolved by heating. After cooling, the precipitated crystals were collected by filtration to obtain 860 mg of the title compound as a yellow powder.
MASS (ESI): 424.1 (MH⁺)
¹H-NMR (400MHz, DMSO-d₆) δ; 1.39-1.50 (1H, m), 1.65-1.78 (1H, m), 1.75-1.98 (2H, m), 2.82-2.91 (1H, m), 2.93-3.02 (1H, m), 3.33- 3.48 (2H, m), 3.79-3.88 (1H, m), 3.85 (3H, s), 4.72 (2H, br), 7.16 (1H, d, J = 8.4Hz), 7.47 (1H, dd, J = 8.4, 1.6Hz), 7.62 (1H, d, J = 1.6Hz), 8.31 (1H, d, J = 8.4Hz), 8.48 (1H, d, J = 8.4Hz), 9.38-9.46 (1H, m) , 10.27 (1H, br)
Production Example 2
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1-[(3S) -3-hydroxypyrrolidino] phthalazine hydrochloride
[0075]
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[0076]
The title compound was obtained by using (S) -3-hydroxypyrrolidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride of Production Example 1.
MASS (ESI); 410.0 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.94-2.10 (2H, m), 3.50-3.62 (1H, m), 3.42-3.68 (1H, m), 3.83 (3H, s), 3.93-4.10 (2H, m), 4.43-4.50 ( 1H, m), 4.50-4.64 (2H, m), 5.30 (1H, br), 7.13 (1H, d, J = 8.4 Hz), 7.34-7.44 (1H, m), 7.48-7.56 (1H, m) , 8.38-8.46 (1H, m), 8.62-8.74 (1H, m), 9.10-9.32 (1H, m)
Production Example 3
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1-[(2S) -2-hydroxymethylpyrrolidino] phthalazine hydrochloride
[0077]
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[0078]
The title compound was obtained by using (S) -2-hydroxymethylpyrrolidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride of Production Example 1.
MASS (ESI); 424.1 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.60-2.39 (4H, m), 3.44-3.53 (1H, m), 3.83 (3H, s), 3.89-3.99 (1H, m), 4.34-4.70 (3H, m), 7.12-7.16 ( 1H, m), 7.38-7.46 (1H, m), 7.52-7.59 (1H, m), 8.40-8.43 (1H, m), 8.43-8.60 (1H, m), 9.23-9.30 (1H, m)
Production Example 4
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (3-hydroxymethylpiperidino) phthalazine hydrochloride
[0079]
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[0080]
The title compound was obtained by using 3-hydroxymethylpiperidine in place of (R)-(+)-3-hydroxypiperidine hydrochloride of Production Example 1.
MASS (ESI); 438.2 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.13-1.28 (1H, m), 1.70-1.86 (3H, m), 1.87-1.99 (1H, m), 2.67-2.75 (1H, m), 2.86-2.95 (1H, m), 3.33- 3.50 (3H, m), 3.51-3.60 (1H, m), 3.16 (3H, s), 3.85 (3H, s), 4.71 (2H, br s), 7.16 (1H, d, J = 8.4 Hz), 7.44 (1H, dd, J = 8.4, 0.8 Hz), 7.59 (1H, d, J = 0.8 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.45 (1H, dd, J = 8.8, 0.4 Hz) ), 9.28-9.35 (1H, m), 9.95 (1H, br), 14.00 (1H, br)
Production Example 5
4- (3-Chloro-4-methoxyphenethyl) amino-6-cyano-1- (3-hydroxymethylpiperidino) phthalazine hydrochloride
[0081]
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[0082]
Instead of 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine in Production Example 4, 1-chloro-4- (3-chloro-4-methoxyphenethyl) amino-6-cyanophthalazine was used. Used to give the title compound.
MASS (ESI) ； 452.3 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.70-1.90 (2H, m), 1.90-2.05 (2H, m), 2.70 (1H, br.t), 2.88 (1H, br.t), 2.95-3.08 (2H, m), 3.25- 3.63 (2H, m), 3.78 (2H, m), 3.83 (3H, s), 7.09 (1H, d, J = 8.6 Hz), 7.29 (1H, d, J = 8.6 Hz), 7.47 (1H, s ), 8.25 (1H, d, J = 8.6 Hz), 8.49 (1H, d, J = 8.6 Hz), 9.48 (1H, s)
Production Example 6
4- (3-Chloro-4-methoxyphenethyl) amino-6-cyano-1- (4-hydroxymethylpiperidino) phthalazine
[0083]
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[0084]
The title compound was obtained by using 4-hydroxymethylpiperidine instead of 3-hydroxymethylpiperidine in Production Example 5.
MASS (ESI) ； 452.3 (MH⁺)
¹H-NMR (400 MHz, CDCl_Three) δ; 1.51-1.65 (2H, m), 1.79-1.85 (1H, m), 1.93 (2H, m), 2.99-3.09 (4H, m), 3.56-3.68 (4H, m), 3.90 (3H, s), 3.85-3.99 (2H, m), 4.94 (1H, br t), 6.88 (1H, d, J = 8.4 Hz), 7.13 (1H, dd, J = 2.2, 8.4 Hz), 7.28 (1H, d, J = 2.2 Hz), 7.94 (1H, d, J = 8.4 Hz), 7.98 (1H, s), 8.13 (1H, d, J = 8.4 Hz)
Production Example 7
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [methyl (2-pyridylmethyl) amino] phthalazine dihydrochloride
[0085]
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[0086]
The title compound was obtained in the same manner as in Production Example 1 except that N-methyl-[(2-pyridyl) methyl] amine was used instead of (R)-(+)-3-hydroxypiperidine hydrochloride.
MASS (ESI); 445.3 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 2.95 (3H, s), 3.85 (3H, s), 4.73-4.79 (4H, m), 7.16 (1H, d, J = 8.4 Hz), 7.49 (1H, dd, J = 8.4, 2.0 Hz) ), 7.64 (1H, d, J = 2.0 Hz), 7.65-7.72 (1H, m), 7.83-7.87 (1H, m), 8.18-8.26 (1H, m), 8.52 (1H, dd, J = 8.4 , 1.2 Hz), 8.60 (1H, d, J = 8.4 Hz), 8.74 (1H, d, J = 4.8 Hz), 9.53-9.55 (1H, m), 10.64 (1H, br)
Production Example 8
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [N-methyl- [2- (2-pyridyl) ethyl] amino] phthalazine dihydrochloride
[0087]
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[0088]
The title compound was obtained in the same manner as in Production Example 7 using N-methyl- [2- (2-pyridyl) ethyl] amine instead of N-methyl-[(2-pyridyl) methyl] amine.
MASS (ESI); 459.2 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 3.00 (3H, s), 3.35 (2H, t, J = 6.4 Hz), 3.76 (2H, t, J = 6.4 Hz), 3.85 (3H, s), 4.73-4.77 (2H, m), 7.18 (1H, d, J = 8.4 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.53-7.64 (1H, m), 7.65 (1H, s), 7.68-7.77 (1H, m), 8.10 -8.30 (1H, m), 8.16 (1H, d, J = 8.6 Hz), 8.44 (1H, d, J = 8.6 Hz), 8.55 -8.61 (1H, m), 9.45-9.51 (1H, m), 10.53 (1H, br)
Production Example 9
4- (3-Chloro-4-methoxyphenethyl) amino-6-cyano-1- (4-methoxypiperidino) phthalazine hydrochloride
[0089]
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[0090]
The title compound was obtained in the same manner as in Production Example 5 using 4-methoxypiperidine hydrochloride instead of 3-hydroxypiperidine.
MASS (ESI) ； 452.2 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.66-1.76 (2H, m), 2.00-2.08 (2H, m), 2.91-2.97 (2H, m), 2.99-3.07 (2H, m), 3.29 (3H, s), 3.37-3.49 ( 3H, m), 3.70-3.77 (2H, m), 3.81 (3H, s), 7.07 (1H, d, J = 8.6 Hz), 7.26 (1H, dd, J = 8.6, 2.0 Hz), 7.43 (1H , d, J = 2.0 Hz), 8.24 (1H, d, J = 8.3 Hz), 8.45 (1H, dd, J = 8.3, 1.6 Hz), 9.22 (1H, d, J = 1.6 Hz)
Production Example 10
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4-methoxyphenyl) phthalazine hydrochloride
[0091]
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[0092]
To a mixture of 1.0 g of 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine, 423 mg of 4-methoxyphenylboric acid, 30 mL of toluene, 30 mL of tetrahydrofuran, and 30 mL of 2M aqueous sodium carbonate solution under a nitrogen atmosphere, tetrakis (Triphenylphosphine) palladium (0) (423 mg) was added, and the mixture was stirred at 80 ° C for 2 hours and further at 100 ° C for 15.5 hours. The reaction solution was returned to room temperature, and extracted with an aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with aqueous ammonia, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained coupled product was dissolved in ethyl acetate-ethanol, 4N hydrochloric acid-ethyl acetate solution was added, and the precipitated crystals were collected by filtration to obtain 460 mg of the title compound as a yellow powder.
MASS (ESI) ； 431.2 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 3.85 (3H, s), 3.87 (3H, s), 4.82-4.85 (2H, m), 7.16-7.21 (3H, m), 7.49 (1H, dd, J = 8.6, 2.2 Hz), 7.60 -7.63 (3H, m), 8.08 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 8.4, 1.4 Hz), 9.45-9.49 (1H, m), 10.39 (1H, br)
Production Example 11
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxy-3-methylpiperidino) -6-phthalazinecarbonitrile hydrochloride
The title compound was obtained in the same manner as in Production Example 1 except that 4-hydroxy-3-methylpiperidine was used instead of (R)-(+)-3-hydroxypiperidine hydrochloride.
¹H NMR (DMSO-d₆) δ 0.94 (3H, t, J = 8.0 Hz), 1.59-2.03 (3H, m), 2.74-3.96 (5H, m), 3.83 (3H, s), 4.68 (2H, d, J = 5.2 Hz) , 7.15 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.0 Hz), 7.58 (1H, s), 8.23 (1H, t, J = 8.0 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.29 (1H, s)
Production Example 12
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxy-3,3,5,5-tetramethylpiperidino) -6-phthalazinecarbonitrile hydrochloride
The title compound was obtained in the same manner as in Production Example 1 except that 4-hydroxy-3,3,5,5-tetramethylpiperidine was used instead of (R)-(+)-3-hydroxypiperidine hydrochloride.
¹H NMR (DMSO-d₆) δ; 0.91 (6H, s), 1.15 (6H, s), 2.57 (1H, d, J = 12.4 Hz), 2.95 (1H, s), 3.21 (2H, d, J = 12.0 Hz), 3.83 ( 3H, s), 4.47 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.8 Hz), 7.63 (1H, s), 8.29 ( 1H, d, J = 8.4 Hz), 8.55 (1H, d, J = 8.4 Hz), 9.52 (1H, s), 10.63 (1H, brs)
Intermediate production example 1
1-chloro-4-[[(4-methoxy-3-trifluoromethyl) benzyl] amino] -6-phthalazinecarbonitrile
[0093]
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[0094]
A mixture of 10 g of 2-trifluoromethylphenol, 17 g of potassium carbonate, 150 mL of acetone and 7.7 mL of iodomethane was heated to reflux for 2 hours. After cooling, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 12.15 g of 2-trifluoromethylanisole.
[0095]
A mixture of 8.5 g of 2-trifluoromethylanisole and 7.0 g of hexamethylenetetramine was stirred in 90 mL of trifluoroacetic acid at 90 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and added dropwise to ice-cooled saturated aqueous sodium bicarbonate. The ethyl acetate layer was separated and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.8 g of 3-trifluoromethyl-p-anisaldehyde.
[0096]
A mixture of 5.8 g of 3-trifluoromethyl-p-anisaldehyde, 8.6 mL of formamide, and 13.6 mL of formic acid was stirred at 130 ° C. for 9 hours. After cooling, water and ethyl acetate were added. The ethyl acetate layer was separated and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.8 g of N- [4-methoxy-3- (trifluoromethyl) benzyl] formamide.
[0097]
N- [4-methoxy-3- (trifluoromethyl) benzyl] formamide (3.8 g) was dissolved in ethanol (20 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was heated to reflux for 3 hours. After cooling, diethyl ether was added, and the precipitated crystals were collected by filtration to obtain 2.5 g of 4-methoxy-3- (trifluoromethyl) benzylamine hydrochloride.
To a mixture of 2.2 g of 1,4-dichlorophthalazine-6-carbonitrile, 2.5 g of 4-methoxy-3- (trifluoromethyl) benzylamine hydrochloride and 25 mL of 1-methyl-2-pyrrolidinone, 3.7 g of DBU was added. The mixture was further stirred at room temperature for 1.25 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.66 g of the title compound as a less polar product.
¹H NMR (DMSO-d₆) δ 3.86 (3H, s), 4.74 (2H, d, J = 5.2 Hz), 7.22 (1H, d, J = 9.6 Hz), 7.67-7.71 (2H, m), 8.20 (1H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 8.4, 1.4 Hz), 8.50 (1H, t, J = 5.2 Hz), 8.99 (1H, d, J = 1.4 Hz)
In a similar manner, 1-chloro-4-[(3-iodo-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile was obtained from commercially available 2-iodoanisole and 4-bromo-p-anisaldehyde from 4- [(3-Bromo-4-methoxybenzyl) amino] -1-chloro-6-phthalazinecarbonitrile is converted from 3-fluoro-p-anisaldehyde to 1-chloro-4-[(3-fluoro-4-methoxy Benzyl) amino] -6-phthalazinecarbonitrile is obtained from 3-methyl-p-anisaldehyde to give 1-chloro-4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile It was.
Intermediate production example 2
1-chloro-4-[(3-iodo-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile
¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.67 (2H, d, J = 5.2 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.42 (1H, dd, J = 8.4, 2.0 Hz), 7.83 ( 1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 8.4, 1.2 Hz), 8.45 (1H, t, J = 5.2 Hz), 8.99 ( (1H, d, J = 1.2 Hz)
Intermediate production example 3
4-[(3-Bromo-4-methoxybenzyl) amino] -1-chloro-6-phthalazinecarbonitrile
¹H NMR (DMSO-d₆) δ 3.82 (3H, s), 4.70 (2H, d, J = 5.2 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.41 (1H, dd, J = 8.4, 2.0 Hz), 7.63 (1H , d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 8.4, 1.2 Hz), 8.47 (1H, t, J = 5.2 Hz), 8.99 (1H , d, J = 1.2 Hz)
Intermediate production example 4
1-Chloro-4-[(3-fluoro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile
¹H NMR (DMSO-d₆) δ; 3.81 (3H, s), 4.70 (2H, d, J = 5.4 Hz), 7.11 (1H, t, J = 8.8 Hz), 7.19 (1H, d, J = 8.8 Hz), 7.26 (1H, dd, J = 12.8, 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 8.4, 0.8 Hz), 8.46 (1H, t, J = 5.4 Hz), 9.01 ( (1H, d, J = 0.8 Hz)
Intermediate production example 5
1-Chloro-4-[(3-cyano-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile
A mixture of 20 g of 4-methoxybenzyl chloride, 26 g of potassium phthalimide, and 100 mL of dimethylformamide was stirred at 50 ° C. for 5 hours. After cooling, the reaction solution was poured into ice water, and the precipitate was collected by filtration. This was washed with water and dried to obtain 31 g of N- (4-methoxybenzyl) phthalimide.
[0098]
To a mixture of 31 g of N- (4-methoxybenzyl) phthalimide and 100 mL of trifluoroacetic acid, 18 g of hexamethylenetetramine was added little by little, and the mixture was stirred at room temperature for 1 hour and then heated to reflux for 4 hours. The reaction was cooled to 0 ° C. and water was added. Potassium carbonate was added and the precipitated crystals were collected by filtration. The crystals were dried to obtain 20 g of N- (3-formyl-4-toxylbenzyl) phthalimide.
[0099]
Hydroxylamine hydrochloride (5.2 g), sodium acetate (12.2 g) and water (50 mL) were added to a mixture of 20 g of N- (3-formyl-4-methoxybenzyl) phthalimide and 200 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. The mixture was stirred at 60 ° C. for 1 hour and concentrated under reduced pressure. Water was added to the residue, and the insoluble material was collected by filtration. Washing with diethyl ether gave 20 g of N- (3-hydroxyimino-4-methoxybenzyl) phthalimide.
[0100]
To a mixture of 20 g of N- (3-hydroxyimino-4-methoxybenzyl) phthalimide and 200 mL of xylene, 6.7 mL of acetic anhydride was added and heated to reflux for 10 hours. The temperature was returned to room temperature, and the precipitated crystals were collected by filtration and washed with xylene to obtain 15 g of N- (3-cyano-4-methoxybenzyl) phthalimide.
To a mixture of 15 g of N- (3-cyano-4-methoxybenzyl) phthalimide and 200 mL of ethanol, 3.9 g of hydrazine monohydrate was added and heated to reflux for 3 hours. After cooling, insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 8.0 g of 3-cyano-4-methoxybenzylamine.
[0101]
By stirring 1,4-dichlorophthalazine-6-carbonitrile, 3-cyano-4-methoxybenzylamine in 1-methyl-2-pyrrolidinone in the presence of DBU at room temperature, Chloro-4-[(3-cyano-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile was obtained.
¹H NMR (DMSO-d₆) δ; 3.87 (3H, s), 4.70 (2H, d, J = 5.6 Hz), 7.20 (1H, d, J = 8.4 Hz), 7.70 (1H, dd, J = 2.4, 8.4 Hz), 7.75 ( 1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.34 (1H, dd, J = 1.2, 8.4 Hz), 8.48 (1H, t, J = 5.6 Hz), 8.97 ( 1H, s)
Intermediate production example 6
1-Chloro-4-[(3-ethyl-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile
To a solution of 12.7 g of methyltriphenylphosphonium bromide in 80 mL of tetrahydrofuran was added 3.99 g of potassium tert-butoxide at 0 ° C., 7 g of N- (3-formyl-4-methoxybenzyl) phthalimide was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.75 g of N-me (4-methoxy-3-vinylbenzyl) phthalimide.
[0102]
N- (4-methoxy-3-vinylbenzyl) phthalimide (2.75 g) was dissolved in tetrahydrofuran (50 mL), 10% Pd-C (0.1 g) was added, and the mixture was stirred under a hydrogen atmosphere for 40 min. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.55 g of N- (3-ethyl-4-methoxybenzyl) phthalimide.
To a mixture of 2.55 g of N- (3-ethyl-4-methoxybenzyl) phthalimide and 60 mL of ethanol was added 0.84 mL of hydrazine monohydrate, and the mixture was heated to reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, 2N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, ethyl acetate was added, and the insoluble material was filtered off. 4N Hydrochloric acid (ethyl acetate solution) was added, and the precipitated crystals were collected by filtration to obtain 1.75 g of 3-ethyl-4-methoxybenzylamine hydrochloride.
[0103]
By stirring 1,4-dichlorophthalazine-6-carbonitrile, 3-ethyl-4-methoxybenzylamine hydrochloride in 1-methyl-2-pyrrolidinone at room temperature in the presence of DBU, a less polar product was obtained. 1-Chloro-4-[(3-ethyl-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile was obtained.
¹H NMR (CDCl_Three) δ; 1.14 (3H, t, J = 7.5 Hz), 2.60 (2H, q, J = 7.5 Hz), 3.81 (3H, s), 4.84 (2H, s), 6.80 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 2.0 Hz), 7.30 (1H, dd, J = 2.0, 8.2 Hz), 8.06 (1H, d, J = 9.0 Hz), 8.27 (1H, d, J = 9.0 Hz), 8.42 (1H, m)
Intermediate production example 7
1-chloro-4-[(3-chloro-4-methylbenzyl) amino] -6-phthalazinecarbonitrile 3-chloro-4-methylbenzonitrile in a solution of 453 mg lithium aluminum hydride in 40 mL tetrahydrofuran under nitrogen atmosphere 2.0 g of a 15 mL solution of tetrahydrofuran was added dropwise. The mixture was heated to reflux for 2 hours and 10 minutes. The mixture was ice-cooled, and water (0.45 mL), 15% aqueous sodium hydroxide solution (0.45 mL), and water (1.35 mL) were added dropwise so as to maintain the temperature at 10 ° C. or lower. The mixture was filtered through Celite, and anhydrous sodium sulfate was added to the filtrate for drying. The mixture was filtered through NH-form silica gel, and the filtrate was concentrated under reduced pressure to obtain 1.74 g of 3-chloro-4-methylbenzylamine.
[0104]
By stirring 1,4-dichlorophthalazine-6-carbonitrile, 3-chloro-4-methylbenzylamine in 1-methyl-2-pyrrolidinone at room temperature in the presence of DBU, the title compound is obtained as a less polar product. Got.
¹H NMR (DMSO-d₆) δ; 2.29 (3H, s), 4.73 (2H, d, J = 5.2 Hz), 7.28-7.32 (2H, m), 7.45 (1H, d, J = 0.8 Hz), 8.20 (1H, dd, J = 8.4, 0.4 Hz), 8.34 (1H, d, J = 8.4, 1.6 Hz), 8.52 (1H, t, J = 5.2 Hz), 9.00 (1H, m)
Intermediate production example 8
1-Chloro-4-[(4-chloro-3-methoxybenzyl) amino] -6-phthalazinecarbonitrile
4-Chloro-3-methoxybenzylamine benzylamine hydrochloride, 1,4-dichlorophthalazine-6-carbonitrile synthesized by the method described in WO9518097 is stirred in 1-methyl-2-pyrrolidinone at room temperature in the presence of DBU. This gave 1-chloro-4-[(4-chloro-3-methoxybenzyl) amino] -6-phthalazinecarbonitrile as a less polar product.
¹H NMR (DMSO-d₆) δ; 3.86 (3H, s), 4.76 (2H, d, J = 5.5 Hz), 4.74 (1H, d, J = 4.2 Hz), 6.99 (1H, dd, J = 1.8, 8.1 Hz), 7.22 ( 1H, d, J = 1.8 Hz), 7.35 (1H, d, J = 8.1 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.36 (1H, d, J = 8.6 Hz), 8.52 (1H, t, J = 5.5 Hz), 9.03 (1H, s)
Intermediate production example 9
1-chloro-4-[(3,4-dichlorobenzyl) amino] -6-phthalazinecarbonitrile
¹H NMR (DMSO-d₆) δ; 4.76 (2H, d, J = 5.4 Hz), 7.40 (1H, dd, J = 8.4, 1.8 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 1.8 Hz), 8.21 (1H, dd, J = 8.4, 0.4 Hz), 8.36 (1H, dd, J = 8.4, 1.6 Hz), 8.57 (1H, t, J = 5.4 Hz), 8.99 (1H, d, J = 1.6 Hz)
Intermediate production example 10
Benzyl 4-fluoro-4-hydroxymethyl-1-piperidinecarboxylate
[0105]
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[0106]
To a mixture of 16.1 g of tert-butoxypotassium and 500 mL of tetrahydrofuran was added 51.1 g of methyltolphenylphosphonium bromide, and the mixture was stirred for 1 hour and 20 minutes at room temperature. 16.1 g of benzyl 4-oxo-1-piperidinecarboxylate was added, and the mixture was stirred for 2 hours and 40 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the mixture was filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 25.5 g of benzyl 4-methylene-1-piperidinecarboxylate.
[0107]
14.7 g of benzyl 4-methylene-1-piperidinecarboxylate was dissolved in 300 mL of methanol, 20.4 g of magnesium phthalate monoperacid salt and 13.3 g of sodium bicarbonate were added, and the mixture was stirred at room temperature for 7.5 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 11.3 g of benzyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate.
[0108]
A mixture of 5 mL of hydrogen fluoride pyridine and 20 mL of methylene chloride is cooled, and a solution of 4.95 g of benzyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate in 10 mL of methylene chloride is brought to an internal temperature of 0 ° C or lower. The solution was added dropwise over 25 minutes. The mixture was stirred for 35 minutes under ice cooling. The reaction solution was poured into a mixture of saturated aqueous sodium hydrogen carbonate and ice. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 2.84 g of the title compound.
Intermediate production example 11
4-hydroxy-4- (1H-1-imidazolylmethyl) -1-piperidinecarboxylate tert-butyl
[0109]
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[0110]
13.5 g of tert-butyl 4-methylene-1-piperidinecarboxylate was dissolved in 300 mL of methanol, 28.3 g of magnesium phthalate monoperacid salt and 8.62 g of sodium bicarbonate were added, and the mixture was stirred at room temperature for 1 day. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 12.2 g of tert-butyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate.
[0111]
4.25 g of tert-butyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate was dissolved in 30 mL of dimethylformamide, 5.38 g of sodium imidazole was added, and the mixture was stirred at 60 ° C. for 3 hours and 40 minutes. After cooling, ethyl acetate was added to the reaction solution, washed three times with water and with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 4.93 g of tert-butyl 4-hydroxy-4- (1H-1-imidazolylmethyl) -1-piperidinecarboxylate.
Intermediate production example 12
4-hydroxy-4- (1H-1,2,4-triazol-1-ylmethyl) -1-piperidinecarboxylate tert-butyl
The title compound was obtained by using 1,2,4-triazole sodium in place of sodium imidazole in Intermediate Production Example 11.
Intermediate production example 13
Benzyl 4-fluoromethyl-4-hydroxy-1-piperidinecarboxylate
3.2 g of potassium hydrogen fluoride and 610 mg of tetra-n-butylammonium dihydrogen fluoride were added to 5 g of benzyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate, and the mixture was stirred at 120 ° C. for 7 hours. . After cooling, methylene chloride was added and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 4.7 g of the title compound.
Intermediate production example 14
4-hydroxy-4-piperidinecarboxamide hydrochloride
A mixed solution of 18 mL of concentrated sulfuric acid and 1.8 mL of water was cooled to 0 ° C., and 5 g of 1-benzyl-4-hydroxy-4-piperidinecarbonitrile hydrochloride was added little by little. A mixed solution of 25 mL of concentrated sulfuric acid and 2.5 mL of water was added, and the mixture was stirred at room temperature for 2 hours. Left in the freezer overnight. The reaction solution was poured into ice and 47 g of sodium hydroxide was added little by little. Extraction was performed three times with a mixed solvent of tetrahydrofuran and ethyl acetate (1: 1). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 3.19 g of 1-benzyl-4-hydroxy-4-piperidinecarboxamide.
[0112]
1.19 g of 1-benzyl-4-hydroxy-4-piperidinecarboxamide was dissolved in 150 mL of methanol, and 1.5 g of 20% aqueous palladium hydroxide was added. Shake for 4 hours under a 4 atmosphere hydrogen atmosphere. The reaction mixture was filtered through celite, 4N HCl-dioxane (5 mL) was added to the filtrate, and the mixture was concentrated under reduced pressure. The crystalline residue was washed with diisopropyl ether and collected by filtration to obtain 1.96 g of the title compound.
Intermediate production example 15
N- (3-Chloro-4-methoxybenzyl) -N- [4-chloro-7- (1H-1-pyrazolyl) -1-phthalazinyl] amine
[0113]
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[0114]
To a mixture of 100 g of 4-fluorophthalic anhydride and 1500 mL of methanol, 110 mL of thionyl chloride was added dropwise over 30 minutes. The mixture was heated to reflux for 8 hours and concentrated under reduced pressure. Ice water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 125 g of dimethyl 4-fluorophthalate.
[0115]
To a solution of 44 g of pyrazole in 200 mL of 1-methyl-2-pyrrolidinone, 26 g of oily sodium hydride was added over 40 minutes. 125 g of dimethyl 4-fluorophthalate was added in 30 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction was cooled to 0 ° C. and added to ice water. The mixture was extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. It was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and diethyl ether was added to the resulting crystalline residue and collected by filtration to obtain 77 g of dimethyl 4- (1H-1-pyrazolyl) phthalate.
[0116]
To a mixture of 77 g of dimethyl 4- (1H-1-pyrazolyl) phthalate and 500 mL of ethanol was added 22 mL of hydrazine monohydrate, and the mixture was heated to reflux for 6 hours. After cooling, the precipitate was collected by filtration to obtain 36 g of 6- (1H-1-pyrazolyl) -1,4-phthalazinedione.
15 mL of diisopropylethylamine was added to a mixture of 5.0 g of 6- (1H-1-pyrazolyl) -1,4-phthalazinedione and 20 mL of phosphorus oxychloride, and the mixture was stirred at 110 ° C. for 0.5 hour. The reaction solution was cooled to 0 ° C., ethyl acetate was added, and ice and water were added little by little. The mixture was stirred at 0 ° C. for 0.5 hour, and insoluble materials were removed by filtration. The ethyl acetate layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and ethyl acetate was added to the resulting crystalline residue and collected by filtration to obtain 3.8 g of 1,4-dichloro-6- (1H-1-pyrazolyl) phthalazine.
[0117]
DBU (14 mL) was added to a mixture of 1,4-dichloro-6- (1H-1-pyrazolyl) phthalazine (8 g), 3-chloro-4-methoxybenzylamine hydrochloride (9.5 g) and 1-methyl-2-pyrrolidinone (30 mL). The mixture was further stirred at room temperature for 1 hour. Furthermore, it stirred at 60 degreeC for 3 hours. The reaction mixture was cooled to 0 ° C., ethyl acetate was added, and the mixture was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.6 g of the title compound as a less polar product.
¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.68 (2H, d, J = 6.0 Hz), 6.70 (1H, t, J = 2.0 Hz), 7.09 (1H, d, J = 8.8 Hz), 7.35 (1H, dd, J = 2.0, 8.4 Hz), 7.47 (1H, d, J = 2.0 Hz), 7.91 (1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 9.2 Hz), 8.32 (1H, t, J = 5.6 Hz), 8.50 (1H, dd, J = 2.0, 8.8 Hz), 8.68 (1H, d, J = 2.4 Hz), 8.78 (1H, d, J = 2.0 Hz)
Intermediate Production Example 16
N- (3-Chloro-4-methoxybenzyl) -N- [4-chloro-7- (1H-1,2,3-triazol-1-yl) -1-phthalazinyl] amine
The title compound was obtained in the same manner as in Example 15 using 1,2,3-triazole instead of pyrazole.
¹H NMR (CD_ThreeOD) δ; 3.82 (3H, s), 4.72 (2H, s), 6.97 (1H, d, J = 8.4 Hz), 7.34 (1H, dd, J = 1.6, 8.4 Hz), 7.44 (1H, d, J = 1.6 Hz), 7.99 (1H, d, J = 1.2 Hz), 8.34 (1H, d, J = 8.8 Hz), 8.52 (1H, dd, J = 1.6, 8.8 Hz), 8.72 (1H, d, J = 1.2 Hz), 8.81 (1H, d, J = 2 Hz)
Intermediate Production Example 17
6-Bromo-1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] phthalazine
96.9 mL of hydrazine monohydrate was added to a mixture of 20 g of 4-bromophthalic anhydride and 400 mL of ethanol, and the mixture was heated to reflux for 8 hours. After cooling, the precipitate was collected by filtration to obtain 28 g of 6-bromo-1,4-phthalazinedione.
[0118]
To a mixture of 6.8 g of 6-bromo-1,4-phthalazinedione and 15 mL of phosphorus oxychloride, 15 mL of diisopropylethylamine was added and heated to reflux for 1.5 hours. After cooling, the reaction mixture was poured into ice water, stirred well, and extracted with methylene chloride. The aqueous layer was extracted with ethyl acetate. The combined extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 4.3 g of 6-bromo-1,4-dichlorophthalazine.
[0119]
DBU (5.2 mL) was added to a mixture of 6-bromo-1,4-dichlorophthalazine (3.8 g), 3-chloro-4-methoxybenzylamine hydrochloride (3.5 g) and 1-methyl-2-pyrrolidinone (30 mL) at 100 ° C. Stir for 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.8 g of the title compound as a less polar product.
Intermediate Production Example 18
1- (1,1-dimethyl-2-propynyl) -4-piperidinol
To a mixed solution of 7.3 g of 4-hydroxypiperidine in 5 mL of diethyl ether and 2.5 mL of water, 24 mg of cuprous chloride and 15 mg of copper powder were added under a nitrogen atmosphere. The mixture was ice-cooled, and a solution of 2.7 mL of 3-chloro-3-methyl-1-butyne in 2.5 mL of diethyl ether was added dropwise at an internal temperature of 17 to 22 ° C. Stir overnight at room temperature. Water was added and extracted five times with diethyl ether. The organic layers were combined, dried over potassium carbonate, then potassium hydroxide and filtered. The filtrate was concentrated at normal pressure, and the resulting crystalline residue was filtered with ethyl acetate-hexane to obtain 2.54 g.
Intermediate Production Example 19
1- (1,1-dimethyl-2-propynyl) pyrrolidine
The title compound was obtained from pyrrolidine and 3-chloro-3-methyl-1-butyne in the same manner as in Intermediate Production Example 18.
Intermediate production example 20
(2R) -1-Oxa-8-azaspiro [4.5] dec-2-ylmethanol
105.5 g of (5S) -5- (hydroxymethyl) tetrahydro-2-furanone was dissolved in 1.2 l of pyridine, 380 g of trityl chloride was added at room temperature, and the mixture was stirred at 80 ° C. overnight. After completion of the reaction, the reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was removed, the residue was dissolved in 300 ml of chloroform, 600 ml of silica gel was added, and then the solvent was removed. Purification by silica gel column chromatography gave 149.3 g of (5S) -5-[(trityloxy) methyl] tetrahydro-2-furanone.
[0120]
26.9 g of (5S) -5-[(trityloxy) methyl] tetrahydro-2-furanone was dissolved in 200 ml of THF, 300 ml of 1M vinylmagnesium bromide THF solution was added at room temperature, and the mixture was stirred for 1.5 hours under heating reflux. After completion of the reaction, a saturated aqueous ammonium chloride solution was added under ice-cooling, extracted with ethyl acetate, and washed twice with saturated brine. The solvent was removed and the residue was purified by silica gel column chromatography to obtain 13.0 g of (2S) -1- (trityloxy) -5-vinyl-6-heptene-2,5-diol.
[0121]
13.0 g of (2S) -1- (trityloxy) -5-vinyl-6-heptene-2,5-diol and 57.2 g of toluenesulfonyl chloride were dissolved in 200 ml of pyridine and stirred at 80 ° C. overnight. After completion of the reaction, water was added and stirred at room temperature for 10 minutes. The mixture was extracted twice with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed, the residue was dissolved in toluene, the solvent was removed again, and purified by silica gel column chromatography to obtain 5.88 g of (5R) -5-[(trityloxy) methyl] -2,2-divinyltetrahydrofuran.
[0122]
(5R) -5-[(trityloxy) methyl] -2,2-divinyltetrahydrofuran 4.68g, 0.5M 9-BBN 100ml and 9-BBNdimer6.1g were poured into THF 100ml and stirred for 30 hours under reflux. . After cooling, 50 ml of 30% hydrogen peroxide and 50 ml of 3N sodium hydroxide were added under ice cooling, and the mixture was stirred at 50 ° C. for 20 hours. After completion of the reaction, the mixture was returned to room temperature, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. Remove the solvent, purify by silica gel column chromatography, then purify by silica gel column chromatography to give 2- (5R) -2- (2-hydroxyethyl) -5-[(trityloxy) methyl] tetrahydro-2-furanyl 1.68 g of ethanol was obtained.
[0123]
2- (5R) -2- (2-hydroxyethyl) -5-[(trityloxy) methyl] tetrahydro-2-furanyl-1-ethanol (2.68 g) and pyridine (12 ml) were dissolved in dichloromethane (30 ml), and toluenesulfonyl chloride (11.82 g) was dissolved. The mixture was added under ice cooling and stirred for 2.5 hours. After completion of the reaction, 30 ml of pyridine was added for concentration, and pyridine and water were added again under ice cooling, followed by stirring for 15 minutes. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, toluene was added and the solvent was distilled off again, followed by purification by silica gel column chromatography to obtain 2- (5R) -2- [2-[(4-methylphenyl) sulfonyl] oxyethyl]- 4.17 g of 5-[(trityloxy) methyl] tetrahydro-2-furanylethyl 4-methyl-1-benzenesulfonate was obtained.
[0124]
2- (5R) -2- [2-[(4-methylphenyl) sulfonyl] oxyethyl] -5-[(trityloxy) methyl] tetrahydro-2-furanylethyl 4-methyl-1-benzenesulfonate 4.17 g and benzyl The amine 5.36g was dissolved in DMF80ml, and it stirred at 110 degreeC for 11.5 hours. After completion of the reaction, water was added, extracted with ethyl acetate, and washed twice with saturated brine and saturated aqueous sodium bicarbonate. After drying with magnesium sulfate, the solvent was removed, and the residue was purified by silica gel column chromatography to obtain (2R) -8-benzyl-2-[(trityloxy) methyl] -1-oxa-8-azaspiro [4.5] decane 2.1 g Got.
[0125]
Dissolve 2.10 g of (2R) -8-benzyl-2-[(trityloxy) methyl] -1-oxa-8-azaspiro [4.5] decane in 20 ml of THF and add 8 ml of 4N hydrochloric acid 1,4-dioxane solution under ice cooling. Added and stirred for 1 hour. After completion of the reaction, water and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted twice with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography to obtain 1.03 g of [(2R) -8-benzyl-1-oxa-8-azaspiro [4.5] dec-2-yl] methanol.
[0126]
[(2R) -8-Benzyl-1-oxa-8-azaspiro [4.5] dec-2-yl] methanol (1.03 g) and 10% palladium carbon (0.45 g) were dissolved in ethanol (30 ml). Stir at room temperature for 18 hours. The insoluble material was removed by filtration, the solvent was removed, and the residue was dried to obtain 0.76 g of the title compound.
Intermediate Example 21
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (25.0 g) in diethyl ether (800 mL) was cooled with ice-methanol, and allylic magnesium bromide (1Min diethyl ether) solution (138 mL) was added dropwise. Stir for 3 hours and 10 minutes. The reaction was poured into a mixture of saturated aqueous ammonium chloride and ice. The diethyl ether layer was separated and washed with saturated brine. Dry over anhydrous magnesium sulfate and filter. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 15.9 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate.
[0127]
Dissolve 9.83 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate in 60 ml of tetrahydrofuran-water (9: 1), add osmium tetroxide tert-butyl alcohol solution (2.5 wt%, 2 ml) and N- 6.68 g of methylmorpholine-N-oxide was added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water, washed with saturated sodium chloride solution, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain tert-butyl 4- (2,3-dihydroxypropyl) -4-hydroxy- 9.11 g of tert-butyl 1-piperidinecarboxylate was obtained.
[0128]
9.11 g of tert-butyl 4- (2,3-dihydroxypropyl) -4-hydroxy-1-piperidinecarboxylate was dissolved in 40 ml of pyridine, 10.0 g of chlorotriphenylmethane was added, and the mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water, washed with 2N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- [3- (tert-butoxy) -2-hydroxypropyl] -4 10.3 g of tert-butyl 1-hydroxy-1-piperidinecarboxylate was obtained.
[0129]
Dissolve 2.59 g of tert-butyl 4- [3- (tert-butoxy) -2-hydroxypropyl] -4-hydroxy-1-piperidinecarboxylate in 10 ml of dimethylformamide, add 400 mg of sodium hydride and 823 mg of benzyl chloride, Stir at room temperature for 20 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- [2- (benzyloxy) -3- (tert-butoxy) propyl. 2.66 g of tert-butyl] -4-hydroxy-1-piperidinecarboxylate was obtained.
[0130]
Dissolve 2.36 g of tert-butyl 4- [2- (benzyloxy) -3- (tert-butoxy) propyl] -4-hydroxy-1-piperidinecarboxylate in 40 ml of acetonitrile and add 426 mg of cerium ammonium nitrate to room temperature. And stirred overnight. Silica gel was added to the reaction mixture and concentrated under reduced pressure. Adsorbed silica gel was packed in a non-adsorbed silica gel column and purified with hexane-ethyl acetate. 547 mg of tert-butyl 4- [2- (benzyloxy) -3-hydroxypropyl] -4-hydroxy-1-piperidinecarboxylate Obtained.
[0131]
4.81 g of tert-butyl 4- [2- (benzyloxy) -3-hydroxypropyl] -4-hydroxy-1-piperidinecarboxylate was dissolved in 20 ml of pyridine, added 2.76 g of tosyl chloride and stirred at room temperature for 2 hours. . Further, 1.00 g of tosyl chloride was added, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C. for 35 minutes. The reaction mixture was partitioned between ethyl acetate and water, washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (benzyloxy) -1-oxa-8-azaspiro [4.5] decane. 3.72 g of tert-butyl-8-carboxylate was obtained.
[0132]
6.47 g of tert-butyl 3- (benzyloxy) -1-oxa-8-azaspiro [4.5] decane-8-carboxylate was dissolved in 100 ml of tetrahydrofuran, 1.3 g of palladium carbon was added, and the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered from the reaction solution, 1.3 g of palladium carbon was added, and the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered from the reaction solution, 2.6 g of palladium carbon was added, and the mixture was stirred overnight at 4.2 atm under a hydrogen atmosphere. The catalyst was filtered off from the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give 3-hydroxy-1-oxa-8-azaspiro [ 4.5] 4.27 g of tert-butyl decane-8-carboxylate was obtained.
Intermediate Production Example 22
(anti) -3-Oxa-9-azabicyclo [3.3.1] nonane-7-ol hydrochloride
Lithium aluminum hydride (2.0 g) was suspended in tetrahydrofuran (200 ml), and a solution of 9-methyl-3-oxa-9-azabicyclo [3.3.1] nonan-7-one (14.17 g) in tetrahydrofuran (20 ml) was added dropwise under ice cooling. After stirring for 35 minutes, 2.0 ml of water, 2.0 ml of a 15% aqueous sodium hydroxide solution and 6.0 ml of water were sequentially added to the reaction solution and stirred at room temperature. The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and filtered through alumina. The solvent was concentrated under reduced pressure to obtain 10.00 g of (anti) -9-methyl-3-oxa-9-azabicyclo [3.3.1] nonane-7-ol as a yellow wax.
[0133]
Dissolve 10.0 g of (anti) -9-methyl-3-oxa-9-azabicyclo [3.3.1] nonane-7-ol in 100 ml of tetrahydrofuran, and add 10.7 ml of triethylamine, 7.2 ml of acetic anhydride and 0.77 g of 4-dimethylaminopyridine. The mixture was further stirred at 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and filtered through alumina. The filtrate was concentrated and purified by alumina column chromatography (solvent; n-hexane: ethyl acetate), and (anti) -9-methyl-3-oxa-9-azabicyclo [3.3.1] nonane-7-yl acetate was diluted lightly. 8.68 g was obtained as a yellow oil.
[0134]
(anti) -9-Methyl-3-oxa-9-azabicyclo [3.3.1] nonane-7-yl acetate 8.68 g is dissolved in 1,2-dichloroethane 40 ml, and 7.0 ml of vinyl chloroformate is added at room temperature. After stirring for 2 minutes, the mixture was heated to reflux for 2 hours and 35 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate) to give (anti) -3-oxa-9-vinyloxycarbonyl-9-azabicyclo [3.3.1] nonane. 8.96 g of 7-yl acetate was obtained as a pale yellow oil.
[0135]
(anti) -3-Oxa-9-vinyloxycarbonyl-9-azabicyclo [3.3.1] nonane-7-yl acetate 8.96 g was dissolved in 45 ml of methanol, and 30 ml of water and 7.3 g of potassium carbonate were added for 1 hour at room temperature. The mixture was stirred for 30 minutes and further stirred at 50 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give (anti) -3-oxa-9-vinyloxycarbonyl-9-azabicyclo [3.3.1] nonan-7-ol as a pale yellow oil. g got.
[0136]
(anti) -3-Oxa-9-vinyloxycarbonyl-9-azabicyclo [3.3.1] nonane-7-ol To 7.37 g, 17 ml of 4N hydrogen chloride-dioxane solution was added and stirred at room temperature for 30 minutes. 40 ml of ethanol was added to the reaction solution, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the precipitate was collected by filtration to obtain 5.55 g of the title compound as white needle crystals.
Intermediate Production Example 23
(syn) -3-Azabicyclo [3.2.1] octane-8-ol hydrochloride
The title compound was obtained from 3-methyl-3-azabicyclo [3.2.1] octane-8-one in the same manner as in Intermediate Production Method 22.
Intermediate Production Example 24
(anti) -3-Oxa-7-azabicyclo [3.3.1] nonane-9-ol hydrochloride
The title compound was obtained from 7-methyl-3-oxa-7-azabicyclo [3.3.1] nonan-9-one in the same manner as in Intermediate Production Method 22.
Intermediate Production Example 25
(anti) -9-Azabicyclo [3.3.1] nonan-3-ol hydrochloride
The title compound was obtained from 9-methyl-9-azabicyclo [3.3.1] nonan-3-one in the same manner as in Intermediate Production Method 22.
Intermediate Production Example 26
(exo) -8-Azabicyclo [3.2.1] octan-3-ol hydrochloride
After acetylation from (exo) -8-methyl-8-azabicyclo [3.2.1] octan-3-ol, the title compound was obtained in the same manner as in Intermediate Production Example 22.
Intermediate Production Example 27
(endo) -8-Azabicyclo [3.2.1] octan-3-ol hydrochloride
After acetylation from (endo) -8-methyl-8-azabicyclo [3.2.1] octan-3-ol, the title compound was obtained in the same manner as in Intermediate Production Example 22.
Intermediate Production Example 28
(anti) -3-Azabicyclo [3.3.1] nonane-9-ol hydrochloride
1.0 g of lithium aluminum hydride was suspended in 100 ml of tetrahydrofuran, and a solution of 7.00 g of 3-methyl-3-azabicyclo [3.3.1] nonan-9-one in 20 ml of tetrahydrofuran was added dropwise under ice cooling. After stirring for 50 minutes, water (1.0 ml), 15% aqueous sodium hydroxide solution (1.0 ml) and water (3.0 ml) were successively added to the reaction solution, and the mixture was stirred at room temperature. After the reaction solution was filtered, the solvent was distilled off under reduced pressure to obtain 7.08 g of a pale yellow oil. This was dissolved in 90 ml of tetrahydrofuran, 9.55 ml of triethylamine was added, and the mixture was stirred under ice cooling. Acetic anhydride (6.46 ml) and 4-dimethylaminopyridine (0.56 g) were added, and the mixture was stirred at room temperature for 14 hours. About 20 ml of methanol was added and the reaction mixture was concentrated under reduced pressure. To the residue was added an aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate) to give (anti) -3-methyl-3-azabicyclo [3.3.1] as a less polar product. 3.33 g of nonan-9-yl acetate (colorless oil) was obtained. In addition, 2.06 g of (syn) -3-methyl-3-azabicyclo [3.3.1] nonane-9-yl acetate (light orange oily product) was obtained as a more polar product.
[0137]
(anti) -3-Methyl-3-azabicyclo [3.3.1] nonane-9-yl acetate 2.06 g is dissolved in 1,2-dichloroethane 10 ml, and then added vinyl chloroformate 2.07 ml and stirred at room temperature for 50 minutes. The mixture was heated to reflux for 5 hours and 25 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.51 g of (anti) -3-vinyloxycarbonyl-3-azabicyclo [3.3.1] nonan-9-yl acetate as a pale orange oil.
[0138]
(anti) -3-Vinyloxycarbonyl-3-azabicyclo [3.3.1] nonan-9-yl acetate 4.02 g was dissolved in ethanol 36 ml, 1N sodium hydroxide aqueous solution 18 ml was added, and the mixture was stirred at room temperature for 1 hour 50 minutes. . The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate), and (anti) -3-vinyloxycarbonyl-3-azabicyclo [3.3.1] nonane-9-ol. Was obtained as a pale yellow oil.
[0139]
7 ml of 4N-hydrogen chloride-dioxane solution was added to 3.09 g of (anti) -3-vinyloxycarbonyl-3-azabicyclo [3.3.1] nonane-9-ol, and the mixture was stirred at room temperature for 50 minutes. The reaction solution was concentrated under reduced pressure, 30 ml of ethanol was added to the residue, and the mixture was heated to reflux for 50 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the precipitate was collected by filtration to obtain 2.41 g of the title compound as a fine milky white powder.
Intermediate Production Example 29
(syn) -3-Azabicyclo [3.3.1] nonane-9-olate
The title compound was obtained from (syn) -3-methyl-3-azabicyclo [3.3.1] nonan-9-yl acetate in the same manner as in Intermediate Production Example 28.
Intermediate Production Example 30
(anti) -2- (3-Azabicyclo [3.3.1] non-9-yl) -1-ethanol hydrochloride
Suspension of lithium aluminum hydride (1.0 g) in 30 ml of tetrahydrofuran and ice-cooling were added dropwise with (anti) -methyl (3-azabicyclo [3.3.1] non-9-yl) acetate (3.24 g) suspended in 25 ml of tetrahydrofuran. . After stirring for 35 minutes, 1.0 ml of water, 1.0 ml of a 15% aqueous sodium hydroxide solution and 3.0 ml of water were sequentially added to the reaction solution and stirred at room temperature. Celite and anhydrous sodium sulfate were added and filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, 5 ml of 4N-hydrogen chloride-ethyl acetate solution was added, and the precipitate was collected by filtration to obtain 2.29 g of the title compound as a white powder.
Intermediate Production Example 31
1-Chloro-4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile
¹H NMR (DMSO-d₆) δ; 2.10 (3H, s), 3.73 (3H, s), 4.64 (2H, d, J = 5.4 Hz), 6.85 (1H, d, J = 8.0 Hz), 7.17-7.21 (2H, m), 8.15 (1H, d, J = 8.6 Hz), 8.31 (1H, dd, J = 8.6, 1.2 Hz), 8.35 (1H, t, J = 5.4 Hz), 9.00 (1H, d, J = 1.2 Hz)
Example 1
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (3-pyridyl) phthalazine dihydrochloride
[0140]
Embedded image

[0141]
To a solution of 2.53 g of 3-bromopyridine in 50 mL of anhydrous diethyl ether was added dropwise 10 mL of n-butyllithium 1.6M hexane solution at −70 ° C. or less, and the mixture was stirred for 30 minutes. To this mixture was added a solution of 5.21 g of tri-n-butyltin chloride in 10 mL of anhydrous diethyl ether. The reaction was brought to room temperature over 1 hour. The reaction solution was poured into saturated brine, and the organic layer was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3- (1,1,1-tri-n-butylstannyl) pyridine as a yellow oil.
[0142]
A mixture of 1.80 g of 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine, 579 mg of tetrakis (triphenylphosphine) palladium, 25 mL of xylene and 3 mL of 1-methyl-2-pyrrolidone was vigorously stirred. The solution was heated to reflux, and 25 mL of xylene in 3- (1,1,1-tri-n-butylstannyl) pyridine obtained above was added dropwise thereto over 1 hour. The reaction was heated to reflux for an additional 15 minutes. The reaction solution was returned to room temperature and washed 3 times with water and once with saturated brine. The product was purified by silica gel column chromatography to obtain a coupled product. This was suspended in a mixed solvent of tetrahydrofuran and methanol, 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. Recrystallization from ethyl acetate-methanol gave 1.80 g of the title compound as a colorless powder.
MASS (ESI); 402.0 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 3.85 (3H, s), 4.06 (2H, br), 4.89 (2H, br), 7.18 (1H, d, J = 8.0 Hz), 7.53 (1H, dd, J = 8.0, 1.2 Hz), 7.67 (1H, d, J = 1.2 Hz), 7.81-7.90 (1H, m), 8.07 (1H, dd, J = 8.8, 0.4 Hz), 8.38-8.45 (1H, m), 8.46 (1H, dd, J = 8.8, 1.4 Hz), 8.90-9.00 (2H, m), 9.57 (1H, dd, J = 1.4, 0.4 Hz), 10.76 (1H, br)
Example 2
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (2-pyridyl) phthalazine dihydrochloride
[0143]
Embedded image

[0144]
The title compound was obtained in the same manner using 2-bromopyridine instead of 3-bromopyridine in Example 1.
MASS (ESI); 402.0 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 3.83 (3H, s), 4.86-4.90 (2H, m), 7.16 (1H, d, J = 8.6 Hz), 7.52 (1H, dd, J = 8.6, 2.1 Hz), 7.63-7.69 (2H , m), 7.97 (1H, d, J = 8.5 Hz), 8.08-8.13 (1H, m), 8.47 (1H, dd, J = 8.5, 1.4 Hz), 8.72-8.83 (2H, m), 9.56 ( 1H, d, J = 1.4 Hz), 10.82-10.92 (1H, m).
Example 3
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4-cyanopiperidino) phthalazine hydrochloride
[0145]
Embedded image

[0146]
A mixture of 15 g of 4-piperidinecarboxamide, 16.3 g of benzyl chloride, 32.3 g of potassium carbonate and 200 mL of N, N-dimethylformamide was stirred at 80 ° C. for 4 hours. The reaction solution was returned to room temperature, an aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystalline residue was washed with hexane-ethyl acetate and collected by filtration. 12.7 g of 1-benzyl-4-piperidinecarboxamide was obtained as white scaly crystals.
[0147]
To a mixture of 12.7 g of 1-benzyl-4-piperidinecarboxamide and 60 mL of phosphorus oxychloride was added 5 mL of N, N-dimethylformamide under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with aqueous sodium hydroxide solution and saturated brine. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 11.0 g of 1-benzyl-4-piperidinecarbonitrile.
[0148]
Dissolve 11.0 g of 1-benzyl-4-piperidinecarbonitrile in 100 mL of 1,2-dichloroethane, add 7.1 mL of 1-chloroethyl chloroformate under ice cooling, stir at room temperature for 15 minutes, and then heat to reflux for 1 hour and 20 minutes . After concentration under reduced pressure, 50 mL of methanol was added, and the mixture was heated to reflux for 1 hour. After concentration under reduced pressure, the crystalline residue was washed with ethyl acetate and collected by filtration to obtain 8.0 g of 4-piperidinecarbonitrile hydrochloride as white crystals.
[0149]
Thus obtained 4-piperidinecarbonitrile hydrochloride 1.2 g and 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine 1.0 g, diisopropylethylamine 1.8 g, 1-methyl-2 -A mixture of 10 mL of pyrrolidone was stirred at 170 ° C for 2 hours and 30 minutes. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained free form was dissolved in ethyl acetate, 4N hydrochloric acid-ethyl acetate solution was added, and the precipitated crystals were collected by filtration to obtain 880 mg of the title compound as a yellow powder.
MASS (ESI); 433.2 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.98-2.17 (4H, m), 3.10-3.33 (5H, m), 3.86 (3H, s), 4.70-4.74 (2H, m), 7.17 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.27 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz) , 9.34-9.38 (1H, m), 10.28 (1H, br)
Example 4
4- (3-Chloro-4-methoxyphenethyl) amino-6-cyano-1- (4-cyanopiperidino) phthalazine hydrochloride
[0150]
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[0151]
Instead of 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine of Example 3, 1-chloro-4- (3-chloro-4-methoxyphenethyl) amino-6-cyanophthalazine was used. To give the title compound.
MASS (ESI); 447.1 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.97-2.18 (4H, m), 2.94-3.00 (2H, m), 3.11-3.23 (3H, m), 3.33-3.40 (2H, m), 3.72-3.80 (2H, m), 3.82 ( 3H, s), 7.09 (1H, d, J = 8.4 Hz), 7.27 (1H, dd, J = 8.4, 2.0 Hz), 7.44 (1H, d, J = 2.0 Hz), 8.28 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.23-9.28 (1H, m), 9.85 (1H, br)
Example 5
1- (4-Aminopiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine dihydrochloride
[0152]
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[0153]
Dissolve 10.0 g of 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine in 50 mL of 1-methyl-2-pyrrolidone, add 43.32 g of 4-hydroxypiperidine and 10 mL of diisopropylethylamine, and add 170 Heated at 0 ° C. for 8 hours. After cooling, ethyl acetate was added, and the mixture was washed 3 times with water and once with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 10.1 g of 1- (4-hydroxypiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine as yellow crystals.
[0154]
Next, in a 100 mL tetrahydrofuran solution of 1- (4-hydroxypiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine 4.2 g, phthalimide 2.94 g, triphenylphosphine 5.24 g, A solution of 3.48 g of diethylazodicarboxylate in 30 mL of tetrahydrofuran was added dropwise over 30 minutes, and the mixture was stirred at 4 ° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain 4.85 g of 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4-phthalimidopiperidino) phthalazine. .
[0155]
4.85 g of this 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4-phthalimidopiperidino) phthalazine, 4 mL of hydrazine monohydrate and 40 mL of ethanol are heated to reflux for 1 hour. did. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, 1N hydrochloric acid was added to adjust to pH = 3, and insoluble materials were removed by filtration. The aqueous layer of the filtrate was adjusted to pH = 11 with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography. The product was suspended in ethanol-water, and 1N aqueous hydrochloric acid solution was added to dissolve it with heating. After cooling, the precipitated crystals were collected by filtration to obtain 440 mg of the title compound as a yellow powder.
MASS (FAB); 423 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.78-1.92 (2H, m), 2.03-2.11 (2H, m), 2.90-3.0 (2H, m), 3.20-3.34 (1H, m), 3.54-3.63 (2H, m), 3.82 ( 3H, s), 4.70 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 8.4, 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 8.4 Hz), 8.35-8.45 (2H, m), 8.47 (1H, dd, J = 8.4, 1.0 Hz), 9.54 (1H, d, J = 1.0 Hz ), 10.63 (1H, br) Example 6
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [4-hydroxy-4- (hydroxymethyl) piperidino] phthalazine hydrochloride
[0156]
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[0157]
7.9 g of 60% sodium hydride was washed with hexane and dried under reduced pressure. Dimethyl sulfoxide (100 mL) was added, and the mixture was stirred at 80 to 100 ° C. for 30 minutes under a nitrogen atmosphere. The mixture was ice-cooled, 180 mL of tetrahydrofuran was added, and a solution of 43.7 g of trimethylsulfonium iodide in 150 mL of dimethyl sulfoxide was added dropwise. After stirring for 30 minutes under ice cooling, 15 g of 1-benzyl-4-piperidone was added, and the mixture was stirred for 30 minutes under ice cooling and then stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography gave 6.8 g of 6-benzyl-1-oxo-6-azaspiro [2.5] octane.
[0158]
To a solution of 6-benzyl-1-oxo-6-azaspiro [2.5] octane (6.8 g) in tetrahidolfuran (100 mL) was added 100 mL of water and 10 mL of perchloric acid, and the mixture was stirred at room temperature for 7 hours. The mixture was ice-cooled, an aqueous sodium carbonate solution was added to adjust to pH = 7, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and unnecessary substances were removed by filtration. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 4 g of 1-benzyl-4- (hydroxymethyl) -4-piperidinol.
[0159]
Next, 1.46 g of 1-benzyl-4- (hydroxymethyl) -4-piperidinol was dissolved in 30 mL of methanol, 10 mL of acetic acid and 10% Pd—C were added, and hydrogenated at 4 atm. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, dissolved in methanol, 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was concentrated. Crystallization from methanol-ethyl acetate and filtration gave 880 mg of 4- (hydroxymethyl) -4-piperidinol hydrochloride.
[0160]
In the same manner as in Example 3, this 4- (hydroxymethyl) -4-piperidinol hydrochloride was reacted with 1-chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine to give the title compound. It was.
MASS (FAB); 454.2 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.46-1.54 (2H, m), 1.82-1.94 (2H, m), 3.16-3.30 (6H, m), 3.84 (3H, s), 4.68-4.72 (2H, m), 7.15 (1H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 8.6, 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.6 Hz), 8.45 (1H, dd, J = 8.6, 1.0 Hz), 9.36 (1H, d, J = 1.0 Hz)
Example 7
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1-[(2S) -2- (methoxymethyl) pyrrolidino] phthalazine hydrochloride
[0161]
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[0162]
The title compound was obtained by using (S) -2-methoxymethylpyrrolidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride of Production Example 1.
MASS (ESI); 438.1 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 1.81-1.89 (2H, m), 1.95-2.03 (1H, m), 2.15-2.24 (1H, m), 3.16 (3H, s), 3.28-3.37 (1H, m), 3.46-3.58 ( 2H, m), 3.84 (3H, s), 3.87-3.98 (1H, m), 4.44-4.57 (1H, m), 4.62-4.78 (2H, m), 7.15 (1H, d, J = 8.6 Hz) , 7.47 (1H, dd, J = 8.6, 0.4 Hz), 7.61 (1H, d, J = 0.4 Hz), 8.41-8.51 (2H, m), 9.42-9.60 (1H, m), 10.50 (1H, br ), 13.79 (1H, br)
Example 8
4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1-phenylphthalazine hydrochloride
[0163]
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[0164]
The title compound was obtained in the same manner using phenylboric acid instead of methoxyphenylboric acid in Production Example 10.
MASS (ESI); 401.1 (MH⁺)
¹H-NMR (400 MHz, DMSO-d₆) δ; 3.84 (3H, s), 4.81-4.85 (2H, m), 7.15 (1H, d, J = 8.6 Hz), 7.48 (1H, dd, J = 8.6, 2.1 Hz), 7.60-7.66 (6H , m), 8.00 (1H, d, J = 8.6 Hz), 8.41 (1H, dd, J = 8.6, 0.9 Hz), 9.42 (1H, d, J = 0.9 Hz)
Example 9
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile hydrochloride
[0165]
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[0166]
To a mixture of 14.8 g of potassium tert-butoxy and 300 mL of tetrahydrofuran were added 47.2 g of methyltolphenylphosphonium bromide and 21.9 g of tert-butyl 4-oxo-1-piperidinecarboxylate, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the mixture was filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 20.8 g of tert-butyl 4-methylene-1-piperidinecarboxylate.
[0167]
To a mixture of 157.2 g of zinc / copper alloy and 500 mL of diethyl ether was added 49.3 g of tert-butyl 4-methylene-1-piperidinecarboxylate, and a solution of trichloroacetyl chloride 181.8 g in dimethoxyethane 900 mL was added dropwise over 5.5 hours. . After stirring for 30 minutes, the mixture was cooled and saturated aqueous sodium hydrogen carbonate was added at 0 ° C. or lower. The mixture was filtered through celite and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 62.5 g of tert-butyl 1,1-dichloro-2-oxo-7-azaspiro [3.5] nonane-7-carboxylate.
[0168]
To a mixture of 62.5 g of tert-butyl 1,1-dichloro-2-oxo-7-azaspiro [3.5] nonane-7-carboxylate and 500 mL of saturated ammonium chloride methanol solution, 106.1 g of zinc powder was added. The mixture was stirred for 1 hour and 20 minutes at room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, ethyl acetate 1N hydrochloric acid was added, and the organic layer was separated. The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 38.9 g of tert-butyl 2-oxo-7-azaspirono [3.5] nonane-7-carboxylate.
[0169]
Ethanol (300 ml) was ice-cooled to dissolve 6.13 g of sodium borohydride.
A solution of 38.9 g of tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate in 100 ml of ethanol was added dropwise over 25 minutes. The reaction was treated with saturated aqueous ammonium chloride and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-hydroxy-7-azaspiro [3.5] nonane-7-carboxylic acid tert- 36.6 g of butyl was obtained.
¹H-NMR (CDCl_Three) δ; 1.45 (9H, s), 1.43-1.57 (4H, m), 1.65-1.72 (2H, m), 3.27-3.35 (4H, m), 4.32 (1H, quint, J = 7.2 Hz)
6.22 g of tert-butyl 2-hydroxy-7-azaspiro [3.5] nonane-7-carboxylate was dissolved in 20 ml of tetrahydrofuran, 80 ml of 4N hydrogen chloride-dioxane solution was added to this solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 20 ml of 1-methyl-2-pyrrolidinone to give 1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazine. 4.67 g of carbonitrile and 6.72 g of diisopropylethylamine were added and stirred at 160 ° C. for 9 hours. The reaction solution was returned to room temperature, partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed successively with water (5 times) and saturated brine, and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol). The resulting crude crystals were crushed and washed in diethyl ether to give 4.86 g of yellow crystals. Got. This was dissolved in 150 ml of ethanol, 15 ml of 4N hydrogen chloride-dioxane solution was added, and the solvent was distilled off under reduced pressure. The residue was dissolved in 150 ml of ethanol, heated to 80 ° C., seeded with crystals separately synthesized from hydrous ethanol, and heating was stopped when crystallization started. After allowing to cool to room temperature, filtration and ethanol washing were performed to obtain 4.35 g of the title compound.
[0170]
¹H-NMR (DMSO-d₆) δ; 1.58-1.66 (2H, m), 1.68-1.76 (4H, m), 2.14-2.22 (2H, m), 3.05-3.16 (4H, m), 3.83 (3H, s), 4.12 (1H, t, J = 7.2 Hz), 4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 8.4, 1.2 Hz), 9.46 (1H, s)
Example 10
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-pyridyl) -6-phthalazinecarbonitrile
[0171]
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[0172]
The title compound was obtained in the same manner as in Example 1.
¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.76 (2H, d, J = 5.5 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 8.8, 2.4 Hz), 7.50 ( 1H, d, J = 2.4 Hz), 7.64 (2H, d, J = 5.6 Hz), 7.94 (1H, d, J = 8.8 Hz), 8.20 (1H, d, J = 8.8 Hz), 8.52 (1H, dd, J = 5.5, 5.5 Hz), 8.73 (2H, d, J = 5.6 Hz), 9.02 (1H, s)
Example 11
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-oxo-2-oxa-8-azaspiro [4.5] dec-8-yl) -6-phthalazinecarbonitrile
[0173]
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[0174]
A solution of 37.8 g of tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate in 567 mL of methanol was cooled with ice water, and 43 g of 30% aqueous hydrogen peroxide was added dropwise. 63 mL of 1N aqueous sodium hydroxide solution was added dropwise. Stir at room temperature for 2 hours. Ethyl acetate 1000 mL, water 600 mL, saturated sodium thiosulfate pentahydrate aqueous solution 100 mL was added to the reaction liquid, and the organic layer was fractionated. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 28.4 g of tert-butyl 3-oxo-2-oxa-8-azaspiro [4.5] decane-8-carboxylate.
[0175]
1.16 g of tert-butyl 3-oxo-2-oxa-8-azaspiro [4.5] decane-8-carboxylate was dissolved in 2.3 mL of methanol, 4.6 mL of 4N hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. 5 mL of ethyl acetate was added, and the precipitated crystals were collected by filtration to obtain 700 mg of 3-oxo-2-oxa-8-azaspiro [4.5] decane hydrochloride.
1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 657 mg, 3-oxo-2-oxa-8-azaspiro [4.5] decane hydrochloride 700 mg, diethyl A mixture of 0.44 mL of aniline, 137 mg of sodium iodide and 1.7 mL of 1-methyl-2-pyrrolidinone was stirred at 130 ° C. for 15 hours and 40 minutes. After cooling, the reaction mixture was diluted with 40 mL of tetrahydrofuran, 100 mL of ethyl acetate and 15 mL of 1-methyl-2-pyrrolidinone, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. It was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-[(3-chloro-4-methoxybenzyl) amino] -1- (3-oxo-2-oxa-8-azaspiro [4.5] dece. 713 mg of -8-yl) -6-phthalazinecarbonitrile was obtained.
¹H NMR (CDCl_Three) δ; 1.88-2.01 (4H, m), 2.53 (2H, s), 3.22-3.40 (4H, m), 3.90 (3H, s), 4.20 (2H, s), 4.77 (2H, d, J = 5.2 Hz), 5.20 (1H, t, J = 5.2 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 8.4, 2.0 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.96 (1H, dd, J = 8.4, 2.0 Hz), 8.11 (1H, d, J = 8.4 Hz), 8.14 (1H, d, J = 0.8 Hz)
Example 12
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (2-oxo-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile
[0176]
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[0177]
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile (500 mg) and dichloromethane (20 mL) and tetrahydrofuran The mixture was suspended in 10 mL, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (690 mg) was added, and the mixture was stirred at room temperature for 15 minutes. To the reaction solution were added ethyl acetate, 30 mL of saturated aqueous sodium hydrogen carbonate, and 2 mL of saturated sodium thiosulfate pentahydrate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, crystallized in ethanol, hexane was added and collected by filtration, and 4-[(3-chloro-4-methoxybenzyl) amino] -1- ( 420 mg of 2-oxo-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile was obtained.
¹H NMR (DMSO-d₆) δ; 1.90 (4H, m), 2.86 (4H, m), 3.09 (4H, s), 3.80 (3H, s), 4.62 (2H, d, J = 5.6 Hz), 7.07 (1H, d, J = 8.5 Hz), 7.33 (1H, d, J = 8.5 Hz), 7.44 (1H, s), 7.89 (1H, t, J = 5.6 Hz), 8.09 (1H, d, J = 8.0 Hz), 8.19 ( 1H, d, J = 8.0 Hz), 8.88 (1H, s)
Example 13
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4-hydroxy-4- (1H-1-imidazolylmethyl) piperidino] -6-phthalazinecarbonitrile dihydrochloride
[0178]
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[0179]
¹H NMR (DMSO-d₆) δ; 1.49 (2H, d, J = 12.4 Hz), 1.82-1.93 (2H, m), 3.13 (2H, t, J = 10.8 Hz), 3.37 (2H, d, J = 12.4 Hz), 3.82 ( 3H, s), 4.30 (2H, s), 4.74 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.63 (1H, d, J = 2.0 Hz), 7.66-7.71 (2H, m), 8.18 (1H, d, J = 8.4 Hz), 8.48 (1H, d, J = 8.4 Hz), 9.10 (1H, s ), 9.60 (1H, s).
Example 14
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4-hydroxy-4- (1H-1,2,4-triazol-1-ylmethyl) piperidino] -6-phthalazinecarbonitrile Dihydrochloride
[0180]
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[0181]
¹H NMR (DMSO-d₆) δ; 1.54 (2H, d, J = 12.8 Hz), 1.82-1.92 (2H, m), 3.15 (2H, t, J = 11.2 Hz), 3.35 (2H, d, J = 12.8 Hz), 3.82 ( 3H, s), 4.29 (2H, s), 4.73 (2H, d, J = 6.0 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.21 (1H, s), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 8.79 (1H, s ), 9.56 (1H, s), 10.75 (1H, br.s)
Example 15
1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6- (1H-1,2,3,4-terolaazol-5-yl) -1-phthalazinyl] -4-piperidinol
[0182]
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[0183]
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile 1.0 g, 1.2 g triethylamine hydrochloride, 1-methyl-2-pyrrolidinone 20 To a mixture of mL, 0.55 g of sodium azide was added and stirred at 100 ° C. for 8 hours. The reaction solution was returned to room temperature, water was added, and the precipitated crystals were collected by filtration to obtain 1.0 g of the title compound.
¹H NMR (DMSO-d₆) δ; 1.58-1.7 (2H, m), 1.8-1.97 (2H, m), 2.8-2.98 (2H, m), 3.3-3.43 (2H, m), 3.6-3.7 (1H, m), 3.79 ( 3H, s), 4.6 (2H, s), 7.06 (1H, d, J = 8 Hz), 7.34 (1H, d, J = 8 Hz), 7.45 (1H, s), 7.95 (1H, d, J = 8 Hz), 8.45 (1H, d, J = 8 Hz), 8.89 (1H, s)
Example 16
1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6- (1-methyl-1H-1,2,3,4-terolaazol-5-yl) -1-phthalazinyl] -4- Piperidinol
[0184]
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[0185]
1- [4-[(3-chloro-4-methoxybenzyl) amino] -6- (1H-1,2,3,4-terolaazol-5-yl) -1-phthalazinyl] -4-piperidinol 0.25 g, To a mixture of 1.2 g of potassium carbonate and 5 mL of dimethylformamide was added 0.037 mL of methyl iodide, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the precipitated insoluble material was collected by filtration. Purification by silica gel column chromatography gave 50 mg of the title compound.
¹H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.25-3.45 (2H, m), 3.6-3.7 (1H, m), 3.80 ( 3H, s), 4.48 (3H, s), 4.61 (2H, d, J = 5.6 Hz), 4.73 (1H, d, J = 4.0 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.34 ( 1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0 Hz), 8.07 (1H, t, J = 5.6 Hz), 8.10 (1H, d, J = 8.4 Hz), 8.47 ( 1H, d, J = 8.8 Hz), 9.00 (1H, s)
Example 17
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbothiamide
[0186]
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[0187]
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (hydroxypiperidino) -6-phthalazinecarbonitrile 2.0 g, water 1 mL, isopropanol 2 mL 3.7 mL diethyl dithiophosphate And heated to reflux for 1 hour. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration. The filtrate was extracted with ethyl acetate and washed with saturated brine. It was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crystalline residue was combined with the crystals collected by filtration above to obtain 1.5 g of the title compound.
¹H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-2.00 (2H, m), 2.90-3.1 (2H, m), 3.3-3.5 (2H, m), 3.6-3.8 (1H, m), 3.81 ( 3H, s), 4.68 (2H, d, J = 4 Hz), 7.13 (1H, d, J = 8 Hz), 7.40 (1H, d, J = 8 Hz), 7.54 (1H, s), 8.08 ( 1H, d, J = 8 Hz), 8.3-8.4 (1H, m), 8.9-9.1 (1H, m), 9.88 (1H, s), 10.33 (1H, s)
Example 18
1- [4-[(3-Bromo-4-methoxybenzyl) amino] -6- (4-methyl-1,3-thiazol-2-yl) -1-phthalazinyl] -4-piperidinol
[0188]
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[0189]
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbothamide 1.5 g is dissolved in dimethylformamide 50 mL, and chloroacetone 1.1 mL is dissolved. In addition, the mixture was stirred at 100 ° C. for 4 hours. After cooling, water was added to the reaction solution, and the aqueous layer was removed by decantation. The residue was dried under reduced pressure and purified by silica gel column chromatography to obtain 200 mg of the title compound.
¹H NMR (DMSO-d₆) δ; 1.6-1.7 (2H, m), 1.85-1.95 (2H, m), 2.47 (3H, s), 2.83-2.94 (2H, m), 3.3-3.4 (2H, m), 3.6-3.7 ( 1H, m), 3.80 (3H, s), 4.63 (2H, d, J = 5.6 Hz), 4.72 (1H, d, J = 4.0 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.34 ( 1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.48 (1H, s), 7.96-8.04 (1H, m), 8.01 (1H, d, J = 8.4 Hz) ), 8.36 (1H, dd, J = 1.6, 8.4 Hz), 8.76 (1H, d, J = 1.6 Hz)
Example 19
1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6- (2-thienyl) -1-phthalazinyl] -4-piperidinol hydrochloride
[0190]
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[0191]
1- [6-Bromo-4-[(3-bromo-4-methoxybenzyl) amino] -1-phthalazinyl] -4-piperidinol in a mixture of 200 mg and toluene 2 mL tetrakis (triphenylphosphine) palladium (0) 24 mg, 1.4 mL of 2- (tributylstannyl) thiophene was added. Heated to reflux for 2 hours. After cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 73 mg of the title compound was obtained by converting to hydrochloride with 4N hydrochloric acid-ethyl acetate.
¹H NMR (DMSO-d₆) δ; 1.67 (2H, m), 1.92 (2H, m), 3.00 (2H, m), 3.45 (2H, m), 3.74 (1H, m), 3.82 (3H, s), 4.73 (2H, m ), 7.13 (1H, d, J = 7.2 Hz), 7.27 (1H, s), 7.46 (1H, d, J = 7.2 Hz), 7.61 (1H, s), 7.79 (1H, d, J = 5.6 Hz) ), 8.03 (1H, d, J = 5.6 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.34 (1H, d, J = 8.8 Hz), 9.20 (1H, brs)
Example 20
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbaldehyde oxime hydrochloride
[0192]
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[0193]
Dissolve 10.0 g of 4-[(3-chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile and 5.3 g of t-butyldimethylchlorosilane in 80 mL of dimethylformamide Then, 4.8 g of imidazole was added. Stir overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed once with water and twice with saturated brine. Dry over anhydrous magnesium sulfate and filter. The filtrate was concentrated under reduced pressure to give 1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3-chloro-4-methoxybenzyl) amino]- 11.7 g of 6-phthalazinecarbonitrile was obtained.
[0194]
1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 11.7 g was dissolved in 150 mL of methylene chloride and cooled. At −78 ° C., 44 mL of a 1M diisobutylaluminum hydride toluene solution was added. It returned to room temperature and stirred overnight. 100 mL of saturated aqueous ammonium chloride solution was added, and the mixture was stirred at room temperature for 0.5 hour. 40 mL of 10% sulfuric acid was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3- 5.3 g of (chloro-4-methoxybenzyl) amino] -6-phthalazinecarbaldehyde was obtained.
[0195]
1- [4-[[1- (tert-Butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbaldehyde 1.5 g and 0.35 g of hydroxylamine hydrochloride were dissolved in 50 mL of methanol and heated to reflux for 2 hours. After cooling, water was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 1- [4-[[1- (tert-butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3- 1.18 g of chloro-4-methoxybenzyl) amino] -6-phthalazinecarbaldehyde oxime was obtained.
[0196]
1- [4-[[1- (tert-Butyl) -1,1-dimethylsilyl] oxy] piperidino] -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbaldehyde oxime Tetrabutylammonium fluoride in 1M tetrahydrofuran was added to 1.18 g in tetrahydrofuran (30 mL). Stir overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crystalline residue was washed with ethyl acetate and collected by filtration to obtain 0.34 g of the title compound. The hydrochloride was obtained by a conventional method.
¹H NMR (DMSO-d₆) δ; 1.58-1.70 (2H, m), 1.86-1.95 (2H, m), 2.92-3.02 (2H, m), 3.08-3.22 (2H, m), 3.64-3.73 (1H, m), 3.82 ( 3H, s), 4.61-4.68 (2H, m), 4.77-4.79 (1H, m), 7.10 (1H, d, J = 8 Hz), 7.38 (1H, d, J = 8 Hz), 7.51 (1H , s), 8.06 (1H, d, J = 8 Hz), 8.23 (1H, d, J = 8 Hz), 8.28 (1H, s), 8.69-8.76 (1H, m)
Example 21
4-[(3-Chloro-4-methoxybenzyl) amino] -1-[(2R) -2- (hydroxymethyl) -1-oxa-8-azaspiro [4.5] dec-8-yl] -6-phthal Razine carbonitrile hydrochloride
[0197]
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[0198]
1.08 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile and 0.72 of (2R) -1-oxa-8-azaspiro [4.5] dec-2-ylmethanol g was dissolved in 20 ml of N-methyl-2-pyrrolidone and stirred at 160 ° C. for 5 hours. After completion of the reaction, the temperature was returned to room temperature, water and saturated aqueous sodium hydrogen carbonate were added, the mixture was extracted with ethyl acetate, and washed 3 times with saturated brine. After drying over magnesium sulfate, the solvent was removed and the residue was purified by silica gel column chromatography to obtain 0.60 g of a crystalline compound.
[0199]
This was dissolved in 20 ml of ethanol, 1.40 ml of 1N hydrochloric acid ethanol solution was added at room temperature, and the mixture was stirred for 10 minutes. The solvent was removed, and the residue was treated with diisopropyl ether and dried to obtain 555 mg of the title compound.
¹H NMR (DMSO-d₆) δ; 1.67-1.98 (8H, m), 3.15-3.40 (6H, m), 3.82 (3H, s), 3.90-3.98 (1H, m), 4.68-4.77 (2H, m), 7.14 (1H, d, J = 9Hz), 7.46 (1H, dd, J = 2, 9Hz), 7.62 (1H, d, J = 2Hz), 8.23 (1H, d, J = 9 Hz), 8.45 (1H, d, J = 9Hz), 9.50 (1H, s)
Example 22
(anti) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (7-hydroxy-3-oxa-9-azabicyclo [3.3.1] non-9-yl) -6-phthalazine Carbonitrile hydrochloride
[0200]
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[0201]
1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 1.5 g, (anti) -3-oxa-9-azabicyclo [3.3.1] nonane-7-ol 1.13 g of hydrochloride and 2.16 ml of diisopropylethylamine were added to 8 ml of N-methyl-2-pyrrolidone and stirred at 170 ° C. for 9 hours and 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (solvent; dichloromethane: methanol) gave 0.085 g of a yellow oil.
[0202]
This was dissolved in ethyl acetate, 0.05 ml of 4N-hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature. The precipitate was collected by filtration to obtain 0.075 g of the title compound.
¹H NMR (DMSO-d₆) δ; 1.69-1.78 (2H, m), 2.46-2.56 (2H, m), 3.77-3.84 (2H, m), 3.86 (3H, s), 3.86-3.95 (3H, m), 4.04-4.12 ( 2H, m), 4.74 (2H, s), 7.17 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.2, 8.4 Hz), 7.61 (1H, d, J = 2.2 Hz), 8.13 (1H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.39 (1H, m) Example 23
(anti) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (9-hydroxy-3-azabicyclo [3.3.1] non-3-yl) -6-phthalazinecarbonitrile hydrochloride
[0203]
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[0204]
1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 1.5 g, (anti) -3-azabicyclo [3.3.1] nonan-9-ol hydrochloride 1.12 g Then, 2.18 ml of diisopropylethylamine was added to 8 ml of N-methyl-2-pyrrolidone and stirred at 170 ° C. for 9 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Dichloromethane was added and insolubles were collected by filtration to obtain 1.23 g of a pale yellow powder. This was suspended in ethyl acetate, 0.7 ml of 4N-hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature. The precipitate was collected by filtration to obtain 1.28 g of the title compound as a pale powder.
¹H NMR (DMSO-d₆) δ; 1.54 (1H, m), 1.66-1.75 (2H, m), 1.86-1.93 (2H, m), 2.11-2.23 (2H, m), 2.38 (1H, m), 3.15-3.24 (2H, m), 3.62-3.70 (2H, m), 3.75 (1H, m), 3.85 (3H, s), 4.74 (2H, s), 7.16 (1H, d, J = 8.4 Hz), 7.47 (1H, dd , J = 1.8, 8.4 Hz), 7.62 (1H, d, J = 1.8 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.56 (1H, dd, J = 1.3, 8.4 Hz), 9.49 (1H , m).
Example 24
(anti) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- [9- (2-hydroxyethyl) -3-azabicyclo [3.3.1] non-3-yl] -6-phthal Razine carbonitrile hydrochloride
[0205]
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[0206]
1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 1.5 g, (anti) -2- (3-azabicyclo [3.3.1] non-9-yl) -1-ethanol Hydrochloride 1.29 g and diisopropylethylamine 2.18 ml were added to N-methyl-2-pyrrolidone 8 ml and stirred at 170 ° C. for 8 hours 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. After purification by silica gel column chromatography (solvent; dichloromethane: methanol), crystallization from dichloromethane-ethyl acetate-ether gave 1.12 g of a pale yellow powder. This was suspended in acetone, 2 ml of 4N-hydrogen chloride-ethyl acetate solution and ethyl acetate were added, and the mixture was stirred at room temperature. The precipitate was collected by filtration to obtain 0.98 g of the title compound as a pale yellow powder.
¹H NMR (DMSO-d₆) δ; 1.61 (1H, m), 1.66-1.73 (2H, m), 1.73-1.87 (5H, m), 1.88-2.00 (2H, m), 2.42 (1H, m), 3.14-3.23 (2H, m), 3.49 (2H, t, J = 6.4 Hz), 3.67-3.76 (2H, m), 3.85 (3H, s), 4.73 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H, dd, J = 1.6, 8.6 Hz), 7.62 (1H, d, J = 1.6 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.55 (1H, dd, J = 1.3, 8.4 Hz) ), 9.46 (1H, m)
Example 25
1- (3-Amino-3-methyl-1-butynyl) -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile hydrochloride
[0207]
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[0208]
1-chloro-4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile 500 mg, cuprous iodide 53 mg, dichlorobis (triphenylphosphine) palladium (II) 98 mg, To a mixture of 347 mg of 3-amino-3-methyl-1-butyne and 10 mL of dimethylformamide was added 0.39 mL of triethylamine, and the mixture was stirred at 80 ° C. for 3 hours under a nitrogen atmosphere. After cooling, ethyl acetate was added to the reaction solution, water and concentrated aqueous ammonia were added, and the organic layer was separated. The organic layer was washed with dilute aqueous ammonia and saturated brine, and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. The residue was purified by NH-form silica gel column chromatography to obtain 446 mg of the title compound. The hydrochloride was obtained by a conventional method.
¹H NMR (DMSO-d₆) δ; 1.75 (6H, s), 3.82 (3H, s), 4.76 (2H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.37 (1H, dd, J = 8.4 , 2.2 Hz), 7.50 (1H, d, J = 2.2 Hz), 8.31 (1H, dd, J = 8.4, 1.4 Hz), 8.35 (1H, d, J = 8.4 Hz), 8.83 (1H, t, J = 5.6 Hz), 8.92-9.05 (3H, m), 9.07 (1H, br)
Example 26
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (methoxyimino) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0209]
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[0210]
A mixture of 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4-oxopiperidino] -6-phthalazinecarbonitrile 1.19 g, methoxyamine hydrochloride 354 mg, sodium carbonate 1.2 g and ethanol 10 mL Heated to reflux for 2 hours. After cooling, brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (methoxyimino) piperidino] -6-phthalazinecarbo 620 mg of nitrile was obtained. This was dissolved in a mixed solvent of methanol and ethanol, recrystallized by adding 0.35 mL of 4N hydrochloric acid-ethyl acetate, and 4-[(3-chloro-4-methoxybenzyl) amino] -1- [4- (methoxyimino) Piperidino] -6-phthalazinecarbonitrile hydrochloride 388 mg was obtained.
¹H NMR (DMSO-d₆) δ; 2.50-2.55 (2H, m), 2.74-2.80 (2H, m), 3.29-3.35 (4H, m), 3.77 (3H, s), 3.85 (3H, s), 4.72 (2H, br) , 7.16 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.33 (1H, d, J = 8.8 Hz) , 8.48 (1H, dd, J = 8.8, 0.8 Hz), 9.35 (1H, d, J = 0.8 Hz), 10.19 (1H, br)
The following compounds were synthesized in the same manner as in the production examples or examples using the corresponding raw materials.
Example 27
4-[(3-Chloro-4-methylbenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride
[0211]
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[0212]
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-1.99 (2H, m), 2.32 (3H, s), 2.98-3.08 (2H, m), 3.42-3.50 (2H, m), 3.72-3.80 ( 1H, m), 4.76 (2H, d, J = 5.6 Hz), 7.36 (2H, s), 7.57 (1H, s), 8.23 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.2 Hz), 9.37 (1H, d, J = 1.2 Hz), 10.21 (1H, br)
Example 28
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (5-hydroxyperhydrocyclopenta [c] pyrrol-2-yl) -6-phthalazinecarbonitrile
[0213]
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[0214]
¹H NMR (DMSO-d₆) δ; 1.40-1.49 (2H, m), 2.02-2.12 (2H, m), 2.55-2.64 (2H, m), 3.24 (4H, d, J = 4.0 Hz), 3.80 (3H, s), 3.94 -4.04 (1H, m), 4.61 (2H, d, J = 5.2 Hz), 4.72 (1H, d, J = 5.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 2.0, 8.4 Hz), 7.77-7.83 (1H, m), 8.14-8.23 (2H, m), 8.66 (1H, d, J = 0.8 Hz)
Example 29
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (2-hydroxyethyl) -1,2,3,6-tetrahydro-1-pyridinyl] -6-phthalazinecarbonitrile
[0215]
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[0216]
¹H NMR (DMSO-d₆) δ; 2.15-2.22 (2H, m), 2.27-2.39 (2H, m), 3.20 (2H, t, J = 5.6 Hz), 3.48-3.60 (2H, m), 3.69 (2H, s), 3.80 (3H, s), 4.47 (1H, t, J = 5.6 Hz), 4.61 (2H, d, J = 5.6 Hz), 5.55 (1H, d, J = 0.4 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.83-7.89 (1H, m), 8.04 (1H, d, J = 8.4 Hz) , 8.08 (1H, dd, J = 1.2, 8.4 Hz), 8.87 (1H, t, J = 0.4 Hz)
Example 30
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile
[0217]
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[0218]
¹H NMR (DMSO-d₆) δ; 1.59-1.70 (1H, m), 1.83-2.02 (2H, m), 2.31-2.41 (1H, m), 3.34-3.60 (5H, m), 4.58 (2H, J = 5.6 Hz), 4.67 (1H, t, J = 5.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 2.0, 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.56 -7.62 (1H, m), 8.14 (1H, dd, J = 1.6, 8.8 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.82 (1H, d, J = 1.2 Hz)
Example 31
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (hydroxymethyl) -1,2,3,6-tetrahydro-1-pyridinyl] -6-phthalazinecarbonitrile
[0219]
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[0220]
¹H NMR (DMSO-d₆) δ; 2.28 (2H, brs), 3.19-3.26 (2H, m), 3.73 (2H, br.s), 3.80 (3H, s), 3.89 (2H, d, J = 4.4 Hz), 4.62 (2H , d, J = 5.6 Hz), 4.78 (1H, t, J = 5.6 Hz), 5.72 (1H, br.s), 7.08 (1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 2.0, 8.4 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.87 (1H, t, J = 5.6 Hz), 8.05 (1H, d, J = 8.4 Hz), 8.18 (1H, dd, J = 1.2, 8.4 Hz), 8.87 (1H, d, J = 1.2 Hz)
Example 32
2- [1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -4-piperidinyl] propionate hydrochloride
[0221]
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[0222]
¹H NMR (DMSO-d₆) δ; 1.08 (3H, d, J = 6.8 Hz), 1.46-1.64 (2H, m), 1.66-1.83 (3H, m), 2.22-2.32 (1H, m), 2.78-2.90 (2H, m) , 3.54-3.64 (2H, m), 3.83 (3H, s), 4.72 (2H, d, J = 6.0 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0 , 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 1.6, 8.4 Hz), 9.49 (1H, s)
Example 33
2- [1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -1,2,3,6-tetrahydro-4-pyridinyl] acetic acid hydrochloride
[0223]
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[0224]
¹H NMR (DMSO-d₆) δ; 2.38-2.44 (2H, m), 3.04 (2H, s), 3.79-3.83 (2H, m), 3.83 (3H, s), 4.72 (2H, t, J = 2.8 Hz), 5.63-5.68 (1H, m), 7.15 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 2.4, 8.4 Hz), 7.61 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz), 9.45 (1H, s) .Example 34
2- [1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -4-piperidinyl] -2-fluoroacetic acid hydrochloride
[0225]
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[0226]
¹H NMR (DMSO-d₆) δ; 1.60-1.90 (4H, m), 2.03-2.20 (1H, m), 2.83-2.98 (2H, m), 3.58-3.65 (2H, m), 3.83 (3H, s), 4.73 (2H, t, J = 2.8 Hz), 4.98 (1H, dd, J = 4.0, 48.4 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61 ( 1H, d, J = 2.4 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 1.2, 8.4 Hz), 8.46 (1H, s)
Example 35
2- [1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -4-piperidyl] acetic acid hydrochloride
[0227]
[Chemical Formula 86]

[0228]
¹H NMR (DMSO-d₆) δ; 1.44-1.57 (2H, m), 1.79-1.84 (2H, m), 1.85-1.96 (1H, m), 2.25 (2H, d, J = 6.8 Hz), 2.89 (2H, t, J = 12.0 Hz), 3.55 (2H, d, J = 12.0 Hz), 3.84 (3H, s), 4.70 (2H, d, J = 6.0 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.44 (1H , dd, J = 2.0, 8.4 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.21 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.6, 8.8 Hz), 9.37 (1H, s).
Example 36
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (1-fluoro-2-hydroxyethyl) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0229]
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[0230]
¹H NMR (DMSO-d₆) δ; 1.56-1.78 (3H, m), 1.83-1.99 (2H, m), 2.80-2.91 (2H, m), 3.51-3.69 (4H, m), 3.83 (3H, s), 4.25-4.31 ( 1 / 2H, m), 4.37-4.43 (1 / 2H, m), 4.73 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 2.0, 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 9.52 (1H, s) , 10.58 (1H, s)
Example 37
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (2-hydroxyethoxy) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0231]
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[0232]
¹H NMR (DMSO-d₆) δ; 1.68-1.77 (4H, m), 1.98-2.07 (2H, m), 2.98-3.07 (2H, m), 3.44-3.52 (2H, m), 3.56-3.62 (3H, m), 3.83 ( 3H, s), 4.74 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.627 (1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 1.6, 8.4 Hz), 9.57 (1H, s), 10.68 (1H, brs)
Example 38
2-[[1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -4-piperidyl] oxy] acetic acid hydrochloride
[0233]
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[0234]
¹H NMR (DMSO-d₆) δ; 1.69-1.82 (2H, m), 1.99-2.10 (2H, m), 2.98-3.09 (2H, m), 3.60-3.68 (1H, m), 3.83 (3H, s), 4.08 (2H, s), 4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.4, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz), 9.46 (1H, s), 10.46 (1H, brs)
Example 39
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (2-hydroxy-1-methylethyl) piperidino] -6-phthalazinecarbonitrile
[0235]
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[0236]
¹H NMR (DMSO-d₆) δ; 0.85 (3H, d, J = 6.4Hz), 1.40-1.59 (4H, m), 1.64-1.73 (2H, m), 2.68-2.79 (2H, m), 3.33-3.47 (4H, m) , 3.78 (3H, m), 4.40 (1H, t, J = 5.2 Hz), 4.60 (2H, d, J = 5.6 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 2.0, 8.4 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.85 (1H, t, J = 6.0 Hz), 8.03 (1H, d, J = 8.4 Hz), 8.16 (1H, dd, J = 1.6, 8.4 Hz), 8.85 (1H, d, J = 0.8 Hz)
Example 40
2- [7- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -7-azaspiro [3.5] non-2-yl] acetic acid hydrochloride
[0237]
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[0238]
¹H NMR (DMSO-d₆) δ; 1.45-1.53 (2H, m), 1.66-1.73 (2H, m), 1.77-1.84 (2H, m), 1.96-2.04 (2H, m), 2.34 (2H, d, J = 7.6 Hz) , 3.02 (2H, br.s), 3.11 (2H, br.s), 3.82 (3H, s), 4.67 (2H, s), 7.11 (1H, d, J = 8.4 Hz), 7.40 (1H, dd , J = 2.0, 8.4 Hz), 7.54 (1H, d, J = 2.0 Hz), 8.15 (1H, d, J = 8.8 Hz), 8.34 (1H, d, J = 8.8 Hz), 9.24 (1H, s )
Example 41
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [2- (hydroxymethyl) perhydro [1,3] dioxolo [4,5-c] pyrrol-5-yl] -6-phthalazine Carbonitrile hydrochloride
[0239]
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[0240]
¹H NMR (DMSO-d₆) δ; 3.54-3.67 (2H, m), 3.80-3.92 (2H, m), 4.16 (2 / 3H, brs), 4.29 (4 / 3H, brs), 4.54 (1H, t, J = 5.2 Hz) , 4.54-4.62 (1H, m), 5.16-5.32 (2H, m), 7.11 (1H, d, J = 8.4 Hz), 7.34-7.40 (1H, m), 7.50 (1H, s), 8.37 (1H , d, J = 8.4 Hz), 8.48-8.58 (1H, m), 9.12-9.21 (1H, m)
Example 42
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (1-hydroxyethyl) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0241]
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[0242]
¹H NMR (DMSO-d₆) δ; 1.07 (3H, d, J = 6.0 Hz), 1.34-1.60 (3H, m), 1.65-1.76 (2H, m), 1.86-1.94 (2H, m), 2.75-2.86 (2H, m) , 3.55-3.63 (2H, m), 3.82 (3H, s), 4.73 (2H, d, J = 5.6 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 2.0 , 8.8 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 1.2, 8.4 Hz), 9.56 (1H, s), 10.69 (1H, br.s)
Example 43)
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4-fluoro-4- (hydroxymethyl) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0243]
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[0244]
¹H NMR (DMSO-d₆) δ; 1.69-1.77 (2H, m), 1.83-2.08 (2H, m), 3.05-3.16 (2H, m), 3.48 (2H, d, J = 20.0 Hz), 3.82 (3H, s), 4.74 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 2.0, 8.8 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.26 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 1.2, 8.4 Hz), 9.57 (1H, s), 10.73 (1H, br.s)
Example 44
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (hydroxymethyl) -4-methoxypiperidino] -6-phthalazinecarbonitrile hydrochloride
[0245]
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[0246]
¹H NMR (DMSO-d₆) δ; 1.71-1.86 (4H, m), 3.04-3.16 (2H, m), 3.16 (3H, s), 3.41 (2H, s), 3.83 (3H, s), 4.72 (2H, d, J = 5.6 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.44 (1H, dd, J = 1.2, 8.8 Hz), 9.48 (1H, s), 10.46 (1H, brs)
Example 45
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (2-hydroxy-6-azaspiro [3.4] oct-6-yl) -6-phthalazinecarbonitrile hydrochloride
[0247]
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[0248]
¹H NMR (DMSO-d₆) δ; 1.00-1.08 (2H, m), 1.82-2.04 (4H, m), 2.19-2.35 (2H, m), 3.32-3.45 (2H, m), 3.55-3.60 (2H, m), 3.80 ( 3H, s), 4.04-4.19 (1H, m), 4.56 (2H, br.s), 7.10 (1H, d, J = 8.4 Hz), 7.37 (1H, br.s), 7.50 (1H, br. s), 8.38 (1H, d, J = 8.4 Hz), 8.45-8.73 (1H, m)
Example 46
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3- (hydroxymethyl) -2,5-dihydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride
[0249]
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[0250]
¹H NMR (DMSO-d₆) δ; 3.82 (3H, s), 4.12 (2H, s), 4.45-4.83 (6H, m), 5.84 (1H, brs), 7.11 (1H, d, J = 9 Hz,), 7.33-7.56 ( 2H, m), 8.45 (1H, d, J = 9 Hz), 8.66-9.14 (2H, m)
Example 47
4-[(3-Chloro-4-methoxybenzyl) amino] -1-[(3R, 4S) -3,4-di (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride salt
[0251]
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[0252]
¹H NMR (DMSO-d₆) δ; 2.50-2.57 (2H, m), 3.38-3.49 (2H, m), 3.56-3.60 (2H, m), 3.76-3.87 (4H, m), 3.81 (3H, s), 4.55 (2H, brs), 7.10 (1H, d, J = 8.4 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.49 (1H, s), 8.41 (1H, d, J = 8.4 Hz), 8.68 (1H, d, J = 8.4 Hz), 9.13 (1H, s)
Example 48
1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -4-hydroxy-4-piperidinecarboxamide hydrochloride
[0253]
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[0254]
¹H NMR (DMSO-d₆) δ; 1.56-1.64 (2H, m), 2.16-2.28 (2H, m), 3.12-3.24 (2H, m), 3.32-3.48 (2H, m), 3.54 (1H, brs), 3.83 (3H, s), 4.10-4.30 (1H, m), 4.74 (2H, s), 7.13 (1H, d, J = 8.4 Hz), 7.15 (1H, brs), 7.31 (1H, brs), 7.48 (1H, d , J = 8.4 Hz), 7.64 (1H, s), 8.26 (1H, d, J = 8.4 Hz), 8.44 (1H, d, J = 8.4 Hz), 9.52-9.60 (1H, m)
Example 49
[4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (fluoromethyl) -4-hydroxypiperidino] -6-phthalazinecarbonitrile hydrochloride
[0255]
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[0256]
¹H NMR (DMSO-d₆) δ; 1.54-1.64 (2H, m), 1.80-1.92 (2H, m), 3.18-3.26 (2H, m), 3.32-3.44 (4H, m), 3.83 (3H, s), 4.22 (2H, d, J = 7.6 Hz), 4.72 (1H, d, J = 6.0 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 1.6 Hz), 7.62 (1H, d, J = 1.6 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.45 (1H, brs)
Example 50
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxyiminopiperidino) -6-phthalazinecarbonitrile hydrochloride
[0257]
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[0258]
¹H NMR (DMSO-d₆) δ; 2.50-2.52 (2H, m), 2.74-2.80 (2H, m), 3.26-3.35 (4H, m), 3.85 (3H, s), 4.71 (2H, br), 7.17 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.49 (1H, dd, J = 8.4, 0.4 Hz), 9.34 (1H, d, J = 0.4 Hz), 10.53 (1H, br)
Example 51
(anti) -2- [3- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -3-azabicyclo [3.3.1] non-9-yl] acetic acid Hydrochloride
[0259]
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[0260]
¹H NMR (DMSO-d₆) δ; 1.62 (1H, m), 1.75-2.00 (4H, m), 2.12 (1H, m), 2.52 (2H, d, J = 8.1 Hz), 3.16-3.24 (2H, m), 3.68-3.76 (2H, m), 3.85 (3H, s), 4.74 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.48 (1H, dd, J = 1.8, 8.6 Hz), 7.62 (1H, d, J = 1.8Hz), 8.23 (1H, d, J = 8.4 Hz), 8.55 (1H, dd, J = 1.3, 8.4 Hz), 9.48 (1H, m).
Example 52
(endo) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -6-phthalazinecarbonitrile hydrochloride
[0261]
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[0262]
¹H NMR (DMSO-d₆) δ; 1.81-1.88 (2H, m), 1.90-1.98 (2H, m), 2.19-2.30 (4H, m), 3.85 (3H, s), 4.04 (1H, m), 4.16-4.26 (2H, m), 4.71 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.61 (1H, s), 8.29 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 1.3, 8.4 Hz), 9.44 (1H, m)
Example 53
(syn) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (9-hydroxy-3-azabicyclo [3.3.1] non-3-yl) -6-phthalazinecarbonitrile hydrochloride
[0263]
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[0264]
¹H NMR (DMSO-d₆) δ; 1.53 (1H, m), 1.74-1.86 (2H, m), 1.87-1.93 (2H, m), 2.05-2.14 (2H, m), 2.37 (1H, m), 3.28-3.44 (2H, m), 3.41-3.61 (2H, m), 3.68 (1H, m), 3.85 (3H, s), 4.73 (2H, s), 7.15 (1H, d, J = 8.6 Hz), 7.47 (1H, d , J = 8.6 Hz), 7.62 (1H, s), 8.22 (1H, d, J = 8.6 Hz), 8.54 (1H, d, J = 8.6 Hz), 9.48 (1H, m)
Example 54
(syn) -4-[(3-Chloro-4) amino] -1- (8-hydroxy-3-azabicyclo [3.2.1] oct-3-yl) -6-phthalazinecarbonitrile hydrochloride
[0265]
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[0266]
¹H NMR (DMSO-d₆) δ; 1.75-1.96 (4H, m), 2.02-2.09 (2H, m), 3.06-3.18 (2H, m), 3.50-3.60 (2H, m), 3.86 (3H, s), 3.91 (1H, t, J = 4.8 Hz), 4.73 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.61 (1H, s), 8.36 (1H, d, J = 8.6 Hz), 8.48 (1H, dd, J = 1.5, 8.6 Hz), 9.43 (1H, m).
Example 55
(exo) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -6-phthalazinecarbonitrile hydrochloride
[0267]
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[0268]
¹H NMR (DMSO-d₆) δ; 1.68-1.83 (2H, m), 1.90-2.02 (4H, m), 3.85 (3H, s), 3.97 (1H, m), 4.18-4.28 (2H, m), 4.70 (2H, s) , 7.15 (1H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.59 (1H, s), 8.29 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.36 (1H, m)
Example 56
(anti) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (9-hydroxy-3-oxa-7-azabicyclo [3.3.1] non-7-yl) -6-phthalazine Carbonitrile hydrochloride
[0269]
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[0270]
¹H NMR (DMSO-d₆) δ; 1.69-1.76 (2H, m), 3.24-3.38 (2H, m), 3.73-3.83 (2H, m), 3.85 (3H, s) 3.85-3.93 (2H, m), 4.11-4.20 (2H , m), 4.73 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 7.62 (1H, s), 8.36 (1H, d, J = 8.4 Hz), 8.52 (1H, d, J = 8.4 Hz), 9.43 (1H, m)
Example 57
(anti) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-9-azabicyclo [3.3.1] non-9-yl) -6-phthalazinecarbonitrile hydrochloride
[0271]
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[0272]
¹H NMR (DMSO-d₆) δ; 1.38-1.54 (4H, m), 1.59 (1H, m), 1.90-2.02 (2H, m), 2.22-2.45 (3H, m), 3.86 (3H, s), 3.87 (1H, m) , 4.08-4.17 (2H, m), 4.69 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.58 (1H, s), 8.07 ( 1H, d, J = 8.6 Hz), 8.44 (1H, d, J = 8.6 Hz), 9.29 (1H, m)
Example 58
N¹-[3- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] phenyl] acetamide
[0273]
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[0274]
¹H NMR (DMSO-d₆) δ; 2.05 (3H, s), 3.81 (3H, s), 4.76 (2H, d, J = 6.0 Hz), 7.09 (1H, d, J = 8.4 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.38 (1H, dd, J = 8.0, 1.6 Hz), 7.45 (1H, dd, J = 8.4, 8.0 Hz), 7.50 (1H, d, J = 1.6 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.86 (1H, m), 7.92 (1H, d, J = 8.4 Hz), 8.17 (1H, dd, J = 8.4, 1.6 Hz), 8.35 (1H, dd, J = 6.0, 6.0 Hz ), 9.00 (1H, s), 10.09 (1H, s)
Example 59
1- (3-aminophenyl) -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile dihydrochloride
[0275]
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[0276]
¹H NMR (DMSO-d₆) δ; 3.83 (3H, s), 4.89 (2H, brs), 7.16 (1H, d, J = 8.6 Hz), 7.38-7.44 (3H, m), 7.53 (1H, dd, J = 8.6, 2.0 Hz) ), 7.58-7.62 (2H, m), 7.68 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 8.4 Hz), 8.45 (1H, d, J = 8.4 Hz), 9.65 (1H , s)
Example 60
N- [3- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] phenyl] methanesulfonamide hydrochloride
[0277]
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[0278]
¹H NMR (DMSO-d₆) δ; 3.06 (3H, s), 3.84 (3H, s), 4.86 (2H, d, J = 5.6 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.50 (1H, brs), 7.53 (1H, dd, J = 8.4, 2.0 Hz), 7.55 (1H, dd, J = 7.6, 7.6 Hz), 7.66 (1H, d, J = 2.0 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.44 (1H, d, J = 8.8 Hz), 9.60 (1H, brs), 10.14 (1H, brs)
Example 61
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (methylsulfinyl) phenyl] -6-phthalazinecarbonitrile hydrochloride
[0279]
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[0280]
¹H NMR (DMSO-d₆) δ; 2.84 (3H, s), 3.83 (3H, s), 4.87 (2H, brs), 7.16 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.66 ( 1H, brs), 7.83 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.00 (1H, d, J = 8.4 Hz), 8.43 (1H, d, J = 8.4 Hz), 9.52-9.60 (1H, m)
Example 62
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (methylsulfonyl) phenyl] -6-phthalazinecarbonitrile hydrochloride
[0281]
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[0282]
¹H NMR (DMSO-d₆) δ; 3.31 (3H, s), 3.82 (3H, s), 4.80 (2H, brs), 7.12 (1H, d, J = 8.8 Hz), 7.43 (1H, dd, J = 8.8, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 7.90 (2H, d, J = 8.0 Hz), 7.93 (1H, d, J = 8.4 Hz), 8.11 (2H, d, J = 8.0 Hz), 8.28 ( 1H, d, J = 8.4 Hz), 9.19-9.22 (1H, m)
Example 63
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-formylphenyl) -6-phthalazinecarbonitrile hydrochloride
[0283]
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[0284]
¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.86 (2H, brs), 7.16 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.66 (1H, brs), 7.86 ( 2H, d, J = 8.0 Hz), 7.99 (1H, d, J = 8.8 Hz), 8,13 (2H, d, J = 8.0 Hz), 8.42 (1H, d, J = 8.8 Hz), 9.48- 9.53 (1H, m), 10.15 (1H, s)
Example 64
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [4- (hydroxymethyl) phenyl] -6-phthalazinecarbonitrile hydrochloride
[0285]
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[0286]
¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.62 (2H, s), 4.84 (2H, brs), 7.16 (1H, d, J = 8.4 Hz), 7.49 (1H, dd, J = 8.4, 2.0 Hz), 7.55 (2H, d, J = 8.0 Hz), 7.60 (2H, d, J = 8.0 Hz), 7.65 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 8.4 Hz), 8.43 ( 1H, d, J = 8.4 Hz), 9.50-9.58 (1H, m)
Example 65
4- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] benzoic acid
[0287]
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[0288]
¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.76 (2H, d, J = 6.0 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 8.8, 2.0 Hz), 7.50 ( 1H, d, J = 2.0 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.08 (2H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 8.4, 1.6 Hz), 8.44 (1H, dd, J = 6.0, 6.0 Hz), 9.01 (1H, d, J = 1.6 Hz)
Example 66
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (1,3-thiazol-2-yl) -6-phthalazinecarbonitrile hydrochloride
[0289]
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[0290]
¹H NMR (DMSO-d₆) δ; 3.80 (3H, s), 4.82 (2H, s), 7.13 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.57 (1H, s), 7.94 ( 1H, d, J = 3.6 Hz), 8.11 (1H, d, J = 3.6 Hz), 8.46 (1H, d, J = 8.4 Hz), 9.20-9.26 (1H, m), 9.70 (1H, d, J = 8.4 Hz)
Example 67
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-3-methyl-1-butynyl) -6-phthalazinecarbonitrile hydrochloride
[0291]
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[0292]
¹H NMR (DMSO-d₆) δ; 1.57 (6H, s), 3.84 (3H, s), 4.84 (2H, s), 7.15 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.34 (1H, d, J = 8.4 Hz), 8.52 (1H, dd, J = 8.4, 0.4 Hz), 9.04 (1H, d, J = 0.4 Hz), 10.36 (1H, br)
Example 68
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-1-propynyl) -6-phthalazinecarbonitrile hydrochloride
[0293]
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[0294]
¹H NMR (DMSO-d₆) δ; 3.84 (3H, s), 4.49 (2H, s), 4.81 (2H, d, J = 4.0 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.43 (1H, dd, J = 8.4 , 2.4 Hz), 7.58 (1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.48 (1H, dd, J = 8.8, 0.8 Hz), 9.28 (1H, d, J = 0.8 Hz), 9.92 (1H, br)
Example 69
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3,4-dihydroxy-3- (hydroxymethyl) -1-butynyl] -6-phthalazinecarbonitrile
[0295]
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[0296]
¹H NMR (DMSO-d₆) δ; 3.54-3.66 (4H, m), 3.82 (3H, s), 4.76 (2H, d, J = 5.2 Hz), 4.98 (2H, t, J = 5.2 Hz), 5.62 (1H, s), 7.10 (1H, d, J = 8.8 Hz), 7.36 (1H, dd, J = 8.8, 2.0 Hz), 7.49 (1H, d, J = 2.0 Hz), 8.29-8.34 (1H, m), 8.51 (1H , t, J = 5.2 Hz), 8.96 (1H, s)
Example 70
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3- (dimethylamino) -1-propynyl] -6-phthalazinecarbonitrile dihydrochloride
[0297]
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[0298]
¹H NMR (DMSO-d₆) δ; 2.91 (6H, s), 3.83 (3H, s), 4.52 (2H, s), 4.83 (2H, d, J = 4.8 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.42 ( 1H, dd, J = 8.8, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 8.40 (1H, dd, J = 8.4, 1.4 Hz), 8.46 (1H, d, J = 8.4 Hz), 9.27 (1H, d, J = 1.4 Hz), 9.76 (1H, br), 11.39 (1H, br)
Example 71
2-[[3- [4-[(3-Chloro-4-methoxybenzyl) amino] -6-cyano-1-phthalazinyl] -1,1-dimethyl-2-propynyl] oxy] acetic acid hydrochloride
[0299]
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[0300]
¹H NMR (DMSO-d₆) δ; 1.62 (6H, s), 3.84 (3H, s), 4.21-4.24 (2H, m), 4.77-4.82 (2H, br), 7.11-7.15 (1H, m), 7.38-7.42 (1H, m), 7.51-7.55 (1H, m), 8.19-8.24 (1H, m), 8.38-8.42 (1H, m), 9.12-9.16 (1H, m)
Example 72
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3- (2-hydroxyethoxy) -3-methyl-1-butynyl] -6-phthalazinecarbonitrile hydrochloride
[0301]
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[0302]
¹H NMR (DMSO-d₆) δ; 1.61 (6H, s), 3.55 (2H, t, J = 5.6 Hz), 3.65 (2H, t, J = 5.6 Hz), 3.84 (3H, s), 4.85 (2H, d, J = 4.8 Hz), 7.14 (1H, d, J = 8.6 Hz), 7.46 (1H, dd, J = 8.6, 2.2 Hz), 7.61 (1H, d, J = 2.2 Hz), 8.30 (1H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 8.4, 1.6 Hz), 9.42 (1H, d, J = 1.6 Hz), 10.41 (1H, br)
Example 73
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3- (4-hydroxypiperidino) -3-methyl-1-butynyl] -6-phthalazinecarbonitrile dihydrochloride
[0303]
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[0304]
¹H NMR (DMSO-d₆) d 1.79-2.04 (10H, m), 2.12-2.23 (1H, m), 3.04-3.19 (1H, m), 3.26-3.37 (2H, m), 3.54-3.77 (1H, m), 3.82 (3H , s), 4.83 (2H, d, J = 5.6 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.43 (1H, dd, J = 8.4, 1.2 Hz), 7.56 (1H, d, J = 1.2 Hz), 8.38 (1H, dd, J = 8.4, 0.8 Hz), 8.43 (1H, d, J = 8.4 Hz), 9.30 (1H, d, J = 0.8 Hz), 9.91 (1H, br), 11.40 -11.66 (1H, m)
Example 74
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-methyl-3-tetrahydro-1H-1-pyrrolyl-1-butynyl) -6-phthalazinecarbonitrile dihydrochloride
[0305]
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[0306]
¹H NMR (DMSO-d₆) δ; 1.85 (6H, s), 1.90-2.08 (4H, m), 3.30-3.42 (2H, m), 3.60-3.72 (2H, m), 3.83 (3H, s), 4.80 (2H, d, J = 5.2 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.39 (1H, dd, J = 8.4, 2.0 Hz), 7.52 (1H, d, J = 2.0 Hz), 8.28 (1H, d, J = 8.4 Hz), 8.36 (1H, dd, J = 8.4, 0.8 Hz), 9.14 (1H, d, J = 0.8 Hz), 9.33 (1H, br), 11.89 (1H, m)
Example 75
1- (4-Hydroxypiperidino) -4-[[4-methoxy-3- (trifluoromethyl) benzyl] amino] -6-phthalazinecarbonitrile hydrochloride
[0307]
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[0308]
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-1.99 (2H, m), 2.97-3.07 (2H, m), 3.40-3.52 (2H, m), 3.72-3.80 (1H, m), 3.89 ( 3H, s), 4.80 (2H, d, J = 5.6 Hz), 7.28 (1H, d, J = 8.4 Hz), 7.81-7.85 (2H, m), 8.24 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.2 Hz), 9.53 (1H, d, J = 1.2 Hz), 10.29 (1H, br), 14.02 (1H, br)
Example 76
1- (4-Hydroxypiperidino) -4-[(3-iodo-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile hydrochloride
[0309]
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[0310]
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-2.00 (2H, m), 2.98-3.08 (2H, m), 3.40-3.50 (2H, m), 3.72-3.80 (1H, m), 3.82 ( 3H, s), 4.68 (2H, d, J = 4.8 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.50 (1H, dd, J = 8.8, 2.2 Hz), 7.93 (1H, d, J = 2.2 Hz), 8.24 (1H, d, J = 8.6 Hz), 8.46 (1H, dd, J = 8.6, 0.8 Hz), 9.32 (1H, d, J = 0.8 Hz), 10.05 (1H, br)
Example 77
4-[(3-Bromo-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride
[0311]
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[0312]
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-1.99 (2H, m), 2.98-3.07 (2H, m), 3.39-3.50 (2H, m), 3.72-3.80 (1H, m), 3.84 ( 3H, s), 4.71 (2H, d, J = 4.8 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.49 (1H, dd, J = 8.6, 2.2 Hz), 7.75 (1H, d, J = 2.2 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 8.4, 0.8 Hz), 9.34 (1H, d, J = 0.8 Hz), 10.11 (1H, br)
Example 78
4-[(3-Bromo-4-methoxybenzyl) amino] -1- [3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride
[0313]
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[0314]
¹H NMR (DMSO-d₆) δ; 1.72-1.86 (1H, m), 1.99-2.12 (1H, m), 2.39-2.51 (1H, m), 3.42 (1H, dd, J = 7.2, 10.8 Hz), 3.48 (1H, dd, J = 6.0, 10.8 Hz), 3.60-3.90 (4H, m), 3.80 (3H, s), 7.06 (1H, d, J = 8.4 Hz), 7.38-7.46 (1H, m), 7.64 (1H, s ), 8.40 (1H, dd, J = 1.6, 8.8 Hz), 8.65 (1H, d, J = 8.0 Hz), 9.18 (1H, s)
Example 79
4-[(3-Bromo-4-methoxybenzyl) amino] -1-[(3S) -3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride
[0315]
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[0316]
¹H NMR (DMSO-d₆) δ; 1.58-1.76 (3H, m), 1.92-2.02 (2H, m), 2.29-2.42 (2H, m), 3.42-3.60 (2H, m), 3.78 (3H, s), 4.58 (2H, J = 6.0 Hz), 4.69 (1H, t, J = 5.6 Hz), 7.03 (1H, d, J = 8.4 Hz), 7.36 (1H, dd, J = 2.0, 8.4 Hz), 7.57 (1H, d, J = 2.0 Hz), 7.59 (1H, d, J = 6.0 Hz), 8.13 (1H, dd, J = 1.2, 8.8 Hz), 8.22 (1H, d, J = 8.8 Hz), 8.81 (1H, d, (J = 0.8 Hz)
Example 80
4-[(3-Bromo-4-methoxybenzyl) amino] -1-[(3R) -3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride
[0317]
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[0318]
¹H NMR (DMSO-d₆) δ; 1.72-1.86 (1H, m), 1.99-2.12 (1H, m), 2.39-2.51 (1H, m), 3.42 (1H, dd, J = 7.2, 10.8 Hz), 3.48 (1H, dd, J = 6.0, 10.8 Hz), 3.60-3.90 (4H, m), 3.80 (3H, s), 7.06 (1H, d, J = 8.8 Hz), 7.38-7.46 (1H, m), 7.65 (1H, s ), 8.40 (1H, d, J = 8.8 Hz), 8.59-8.68 (1H, m), 9.26 (1H, s)
Example 81
4-[(3-Bromo-4-methoxybenzyl) amino] -1- [4- (2-hydroxyethyl) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0319]
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[0320]
¹H NMR (DMSO-d₆) δ; 1.68-1.77 (2H, m), 1.96-2.07 (2H, m), 3.02 (2H, t, J = 12.0 Hz), 3.38-3.59 (6H, m), 3.80 (3H, s), 3.81 -3.99 (3H, m), 4.72 (2H, d, J = 6.0 Hz), 7.10 (1H, d, J = 8.6 Hz), 7.49 (1H, d, J = 8.6 Hz), 7.76 (1H, s) , 8.22 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.50 (1H, s)
Example 82
4-[(3-Bromo-4-methoxybenzyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile hydrochloride
[0321]
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[0322]
¹H NMR (DMSO-d₆) δ; 1.58-1.66 (2H, m), 1.68-1.76 (4H, m), 2.14-2.23 (2H, m), 3.08 (2H, br.s), 3.13 (2H, br.s), 4.08- 4.17 (1H, m), 4.73 (1H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.52 (1H, dd, J = 2.0, 8.4 Hz), 7.70 (1H, d , J = 2.0 Hz), 8.20 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 1.6, 8.4 Hz), 9.55 (1H, s)
Example 83
4-[(3-Bromo-4-methoxybenzyl) amino] -1- [4-fluoro-4- (hydroxymethyl) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0323]
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[0324]
¹H NMR (DMSO-d₆) δ; 1.87-2.10 (4H, m), 3.08-3.17 (2H, m), 3.40-3.49 (2H, m), 3.55 (2H, d, J = 12 Hz), 3.84 (3H, s), 4.74 (2H, d, J = 5.2 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.52 (1H, dd, J = 8.6, 2.2 Hz), 7.78 (1H, d, J = 2.2 Hz), 8.28 (1H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 8.4, 1.2 Hz), 9.47 (1H, br), 10.43 (1H, br), 14.00 (1H, br)
Example 84
4-[(3-Bromo-4-methoxybenzyl) amino] -1- [4- (hydroxymethyl) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0325]
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[0326]
¹H NMR (DMSO-d₆) δ; 1.41-1.52 (2H, m), 1.58-1.69 (1H, m), 1.79-1.86 (2H, m), 2.85-2.94 (2H, m), 3.35-3.40 (2H, m), 3.59 ( 2H, d, J = 12.8 Hz), 3.84 (3H, s), 4.71 (2H, d, J = 5.2 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 8.4 , 2.0 Hz), 7.76 (1H, d, J = 2.0 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.38 (1H, br), 10.21 (1H, br)
Example 85
(endo) -4-[(3-Bromo-4-methoxybenzyl) amino] -1- (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -6-phthalazinecarbonitrile
[0327]
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[0328]
¹H NMR (DMSO-d₆) δ; 1.70-1.95 (4H, m), 2.14-2.28 (4H, m), 3.82 (3H, s), 4.15 (1H, m), 4.09 (2H, m), 4.49 (1H, d, J = 2.2 Hz), 4.62 (2H, d, J = 5.5 Hz), 7.05 (1H, d, J = 8.6 Hz), 7.38 (1H, dd, J = 2.2, 8.6 Hz), 7.60 (1H, d, J = 2.2 Hz), 7.72 (1H, t, J = 5.5 Hz), 8.11 (1H, d, J = 8.6 Hz), 8.18 (1H, dd, J = 1.5, 8.6 Hz), 8.87 (1H, d, J = 1.5 Hz)
Example 86
1- (4-Hydroxypiperidino) -4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile hydrochloride
[0329]
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[0330]
¹H NMR (DMSO-d₆) δ; 1.62-1.73 (2H, m), 1.90-1.99 (2H, m), 2.15 (3H, s), 2.98-3.07 (2H, m), 3.42-3.50 (2H, m), 3.72-3.80 ( 1H, m), 3.78 (3H, s), 4.67-4.70 (2H, m), 6.94 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.31 (1H, dd , J = 8.2, 2.0 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 1.2 Hz), 9.45 (1H, d, J = 1.2 Hz), 10.39 (1H , br)
Example 87
1- (2-Hydroxy-7-azaspiro [3.5] non-7-yl) -4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile hydrochloride
[0331]
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[0332]
¹H NMR (DMSO-d₆) δ; 1.57-1.66 (2H, m), 1.67-1.8 (4H, m), 2.11 (3H, s), 2.14-2.23 (2H, m), 3.07 (2H, br.s), 3.12 (2H, br.s), 3.55-3.61 (1H, m), 4.07-4.17 (1H, m), 4.69 (1H, d, J = 5.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.29 (1H , s), 7.31 (1H, dd, J = 2.0, 8.4 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 1.2, 8.4 Hz), 9.56 (1H, s) , 10.59 (1H, brs)
Example 88
1- [4-Fluoro-4- (hydroxymethyl) piperidino] -4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile hydrochloride
[0333]
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[0334]
¹H NMR (DMSO-d₆) δ; 1.88-2.10 (4H, m), 2.15 (3H, s), 3.08-3.17 (2H, m), 3.40-3.50 (2H, m), 3.51 (2H, d, J = 19.6 Hz), 3.78 (3H, s), 4.68 (2H, d, J = 5.2 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.28-7.33 (2H, m), 8.28 (1H, d, J = 8.4 Hz) , 8.47 (1H, dd, J = 8.4, 1.4 Hz), 9.42 (1H, dd, J = 1.4 Hz), 10.26 (1H, br), 13.96 (1H, br)
Example 89
1- [4- (Hydroxymethyl) piperidino] -4-[(3-methoxy-4-methylbenzyl) amino] -6-phthalazinecarbonitrile hydrochloride
[0335]
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[0336]
¹H NMR (DMSO-d₆) δ; 1.41-1.52 (2H, m), 1.58-1.68 (1H, m), 1.79-1.87 (2H, m), 2.15 (3H, s), 2.82-2.93 (2H, m), 3.30-3.40 ( 2H, m), 3.58 (2H, d, J = 12.8 Hz), 3.78 (3H, s), 4.67 (2H, d, J = 5.2 Hz), 6.94 (1H, d, J = 8.8 Hz), 7.26- 7.32 (2H, m), 8.22 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 8.4, 0.8 Hz), 9.36 (1H, br), 10.09 (1H, br)
Example 90
(endo) -1- (3-Hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile
[0337]
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[0338]
¹H NMR (DMSO-d₆) δ; 1.79-1.93 (4H, m), 2.13 (3H, s), 2.13-2.27 (4H, m), 3.75 (3H, s), 4.03 (1H, m), 4.08 (2H, m), 4.49 (1H, d, J = 2.2 Hz), 4.59 (2H, d, J = 5.3 Hz), 6.87 (1H, d, J = 7.9 Hz), 7.16-7.22 (2H, m), 7.61 (1H, t, J = 5.3 Hz), 8.11 (1H, d, J = 8.4 Hz), 8.17 (1H, dd, J = 1.5, 8.4 Hz), 8.90 (1H, d, J = 1.5 Hz)
Example 91
1- [3- (Hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -4-[(4-methoxy-3-methylbenzyl) amino] -6-phthalazinecarbonitrile
[0339]
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[0340]
¹H NMR (DMSO-d₆) δ; 1.67 (1H, m), 2.00 (1H, m), 2.16 (3H, s), 2.38 (1H, m), 3.36-3.61 (6H, m), 3.75 (3H, s), 4.58 (2H) , d, J = 5.5 Hz), 4.68 (1H, t, J = 5.5 Hz), 6.86 (1H, d, J = 8.1 Hz), 7.16-7.22 (2H, m), 7.50 (1H, t, J = 5.3 Hz), 8.15 (1H, dd, J = 1.5, 8.6 Hz), 8.24 (1H, dd, J = 8.6 Hz), 8.88 (1H, d, J = 1.5 Hz)
Example 92
4-[(3-Fluoro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile
[0341]
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[0342]
¹H NMR (DMSO-d₆) δ; 1.60-1.73 (2H, m), 1.88-1.97 (2H, m), 2.86-2.94 (2H, m), 3.42-3.50 (2H, m), 3.64-3.71 (1H, m), 3.80 ( 3H, s), 4.62 (2H, d, J = 5.4 Hz), 4.77 (1H, d, J = 2.0 Hz), 7.09 (1H, t, J = 8.2 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.23 (1H, dd, J = 12.0, 2.0 Hz), 7.84 (1H, t, J = 5.4 Hz), 8.04 (1H, d, J = 8.4 Hz), 8.20 (1H, dd, J = 8.4 , 1.2 Hz), 8.89 (1H, d, J = 1.2 Hz)
Example 93
4-[(4-Chloro-3-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile
[0343]
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[0344]
¹H NMR (DMSO-d₆) δ; 1.60-1.72 (2H, m), 1.87-1.96 (2H, m), 2.86-2.95 (2H, m), 3.31-3.39 (2H, m), 3.68 (1H, m), 3.84 (3H, s), 4.72 (2H, d, J = 5.5 Hz), 4.74 (1H, d, J = 4.2 Hz), 6.98 (1H, dd, J = 1.8, 8.1 Hz), 7.20 (1H, d, J = 1.8 Hz), 7.34 (1H, d, J = 8.1 Hz), 7.92 (1H, t, J = 5.5 Hz), 8.07 (1H, d, J = 8.6 Hz), 8.21 (1H, dd, J = 1.5, 8.6 Hz), 8.92 (1H, d, J = 1.5 Hz)
Example 94
4-[(3-Cyano-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride
[0345]
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[0346]
¹H NMR (DMSO-d₆) δ; 1.6-1.73 (2H, m), 1.88-2.0 (2H, m), 2.95-3.08 (2H, m), 3.4-3.7 (2H, m), 3.7-3.8 (1H, m), 3.90 ( 3H, s), 4.74 (2H, d, J = 5.6 Hz), 7.27 (1H, d, J = 9.2 Hz), 7.79 (1H, dd, J = 2.0, 8.8 Hz), 7.87 (1H, d, J = 2.0 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.47 (1H, dd, J = 1.2, 8.4 Hz), 9.38 (1H, s)
Example 95
(endo) -4-[(3-Cyano-4-methoxybenzyl) amino] -1- (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -6-phthalazinecarbonitrile hydrochloride
[0347]
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[0348]
¹H NMR (DMSO-d₆) δ; 1.9-1.96 (4H, m), 2.17-2.29 (4H, m), 3.91 (3H, s), 4.04 (1H, m), 4.15 (2H, m), 4.68 (2H, s), 7.25 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz), 7.80 (1H, s), 8.21 (1H, d, J = 8.6 Hz), 8.34 (1H, m), 9.07 (1H, m)
Example 96
4-[(3-Cyano-4-methoxybenzyl) amino] -1- [3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride
[0349]
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[0350]
¹H NMR (DMSO-d₆) δ; 1.84 (1H, m), 2.09 (1H, m), 2.48 (1H, m), 3.40-3.55 (2H, m), 3.64-3.90 (4H, m), 3.91 (3H, s), 4.59 (2H, m), 7.24 (1H, d, J = 8.8 Hz), 7.74 (1H, d, J = 8.8 Hz), 7.79 (1H, s), 8.42 (1H, d, J = 9.3 Hz), 8.70 (1H, m), 9.15 (1H, m)
Example 97
4-[(3-Ethyl-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride
[0351]
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[0352]
¹H NMR (DMSO-d₆) δ; 1.14 (3H, t, J = 7.5 Hz), 1.63-1.74 (2H, m), 1.90-2.01 (2H, m), 2.57 (2H, q, J = 7.5 Hz), 2.97-3.08 (2H , m), 3.40-3.54 (2H, m), 3.75 (1H, m), 3.79 (3H, s), 4.69 (2H, s), 6.95 (1H, d, J = 8.2 Hz), 7.26-7.35 ( 2H, m), 8.25 (1H, d, J = 8.6 Hz), 8.48 (1H, dd, J = 1.3, 8.6 Hz), 9.44 (1H, m)
Example 98
4-[(3-Chloro-4-methoxyphenethyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile hydrochloride
[0353]
Embedded image

[0354]
¹H NMR (DMSO-d₆) d 1.58-1.66 (2H, m), 1.67-1.78 (4H, m), 2.14-2.23 (2H, m), 2.92-3.01 (2H, m), 3.07 (2H, s), 3.11 (2H, s ), 3.70-3.82 (3H, m), 3.80 (3H, s), 4.08-4.18 (1H, m), 7.06 (1H, d, J = 8.4 Hz), 7.26 (1H, dd, J = 2.0, 8.4 Hz), 7.43 (1H, d, J = 2.0 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.44 (1H, dd, J = 1.2, 8.4 Hz), 9.55 (1H, s), 10.47 ( 1H, br.s), 13.9 (1H, brs)
Example 99
4-[(3-Chloro-4-methoxyphenethyl) amino] -1- [4- (2-hydroxyethoxy) piperidino] -6-phthalazinecarbonitrile hydrochloride
[0355]
Embedded image

[0356]
¹H NMR (DMSO-d₆) δ; 1.68-1.77 (2H, m), 2.00-2.06 (2H, m), 2.76 (2H, t, J = 8.0 Hz), 3.03 (2H, t, J = 12.0 Hz), 3.32 (10H, m ), 3.75 (2H, d, J = 8.0 Hz), 3.81 (3H, s), 7.07 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 8.6 Hz), 7.43 (1H, s ), 8.24 (1H, d, J = 8.6 Hz), 8.45 (1H, d, J = 8.6 Hz), 9.32 (1H, s)
Example 100
4-[(3-Chloro-4-methoxyphenethyl) amino] -1- [4-fluoro-4- (hydroxymethyl) piperidino] -6-phthalazinecarbonitrile
[0357]
Embedded image

[0358]
¹H NMR (DMSO-d₆) δ; 1.82-2.06 (4H, m), 2.83-2.94 (2H, m), 3.04-3.14 (2H, m), 3.24-3.30 (1H, m), 3.49 (2H, dd, J = 10.2, 6.0 Hz), 3.54-3.60 (1H, m), 3.64-3.70 (2H, m), 3.80 (3H, s), 5.03 (1H, dd, J = 6.0, 6.0 Hz), 7.05 (1H, d, J = 12.6 Hz), 7.19 (1H, dd, J = 12.6, 2.0 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.40-7.45 (1H, m), 8.08 (1H, d, J = 8.4 Hz) , 8.18 (1H, d, J = 8.4 Hz), 8.82 (1H, brs)
Example 101
(endo) -4-[(3-Chloro-4-methoxyphenethyl) amino] -1- (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -6-phthalazinecarbonitrile
[0359]
Embedded image

[0360]
¹H NMR (DMSO-d₆) δ; 1.78-1.94 (4H, m), 2.14-2.28 (4H, m), 2.92 (2H, t, J = 7.0 Hz), 3.67 (2H, q, J = 7.0 Hz), 3.82 (3H, s ), 4.04 (1H, m), 4.09 (2H, m), 4.49 (1H, d, J = 1.8 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 2.2, 8.4 Hz), 7.27 (1H, m), 7.33 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 8.6 Hz), 8.17 (1H, dd, J = 1.5, 8.6 Hz), 8.80 (1H, d, J = 1.5 Hz)
Example 102
4-[(3-Chloro-4-methoxyphenethyl) amino] -1- [3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile
[0361]
Embedded image

[0362]
¹H NMR (DMSO-d₆) δ; 1.68 (1H, m), 2.00 (1H, m), 2.40 (1H, m), 2.92 (2H, t, J = 7.5 Hz), 3.37-3.70 (8H, m), 3.82 (3H, s ), 4.69 (1H, d, J = 5.3 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.16 (1H, m), 7.20 (1H, dd, J = 2.0, 8.6 Hz), 7.33 (1H , d, J = 2.0 Hz), 8.15 (1H, dd, J = 1.3, 8.6 Hz), 8.25 (1H, d, J = 8.6 Hz), 8.78 (1H, m)
Example 103
4-[(3,4-Dichlorobenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbonitrile hydrochloride
[0363]
Embedded image

[0364]
¹H NMR (DMSO-d₆) δ; 1.61-1.72 (2H, m), 1.90-2.00 (2H, m), 3.01-3.18 (2H, m), 3.40-3.52 (2H, m), 3.72-3.80 (1H, m), 4.75 ( 2H, d, J = 5.2 Hz), 7.49 (1H, dd, J = 8.6, 2.0 Hz), 7.66 (1H, d, J = 8.6 Hz), 7.79 (1H, d, J = 2.0 Hz), 8.25 ( 1H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 8.6, 1.0 Hz), 9.36 (1H, d, J = 1.0 Hz), 10.24 (1H, br)
Example 104
1- [6-Bromo-4-[(3-chloro-4-methoxybenzyl) amino] -1-phthalazinyl] -4-piperidinol hydrochloride
[0365]
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[0366]
¹H NMR (DMSO-d₆) δ; 1.59-1.68 (2H, m), 1.85-1.94 (2H, m), 2.94-3.08 (2H, m), 3.45-3.55 (2H, m), 3.70-3.76 (1H, m), 3.83 ( 3H, s), 4.69 (2H, d, J = 4.8 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.59 (1H, s), 8.01 ( 1H, d, J = 8.8 Hz), 8.26 (1H, d, J = 8.8 Hz), 9.18 (1H, s)
Example 105
1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6- (1H-1-pyrazolyl) -1-phthalazinyl] -4-piperidinol hydrochloride
[0367]
Embedded image

[0368]
¹H NMR (DMSO-d₆) δ; 1.6-1.75 (2H, m), 1.85-2.0 (2H, m), 2.95-3.1 (2H, m), 3.3-3.55 (2H, m), 3.7-3.8 (1H, m), 3.82 ( 3H, s), 4.68-4.77 (2H, m), 6.72 (1H, m), 7.14 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 7.6 Hz), 7.63 (1H, s ), 7.93 (1H, d, J = 1.6Hz), 8.22 (1H, d, J = 8.8 Hz), 8.61 (1H, dd, J = 1.6, 8.8 Hz), 8.97 (1H, s), 9.46 (1H , m)
Example 106
7- [4-[(3-Chloro-4-methoxybenzyl) amino] -6- (1H-1-pyrazolyl) -1-phthalazinyl] -7-azaspiro [3.5] nonan-2-ol hydrochloride
[0369]
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[0370]
¹H NMR (DMSO-d₆) δ; 1.55-1.68 (2H, m), 1.68-1.80 (4H, m), 2.14-2.25 (2H, m), 3.0-3.2 (4H, m), 3.82 (3H, s), 4.14 (1H, hep, J = 7.2 Hz), 4.72 (2H, m), 6.72 (1H, t, J = 2 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.4 Hz) , 7.62 (1H, s), 7.93 (1H, d, J = 1.6Hz), 8.20 (1H, d, J = 9.2 Hz), 8.60 (1H, dd, J = 2.0, 9.2 Hz), 8.94 (1H, d, J = 2.4 Hz), 9.43 (1H, s) Example 107
[1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6- (1H-1-pyrazolyl) -1-phthalazinyl] -4-fluoro-4-piperidinyl] methanol hydrochloride
[0371]
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[0372]
¹H NMR (DMSO-d₆) δ; 1.85-2.0 (2H, m), 1.95-2.1 (2H, m), 3.05-3.2 (2H, m), 3.4-3.6 (2H, m), 3.51 (2H, d, J = 20 Hz) , 3.83 (3H, s), 4.74 (2H, d, J = 5.2 Hz), 6.72 (1H, t, J = 1.6 Hz), 7.14 (1H, d, J = 8.8Hz), 7.48 (1H, d, J = 8.4 Hz), 7.64 (1H, s), 7.93 (1H, d, J = 1.6Hz), 8.25 (1H, d, J = 9.2 Hz), 8.61 (1H, dd, J = 2.0, 9.2 Hz) , 8.95 (1H, s), 9.44 (1H, s)
Example 108
1- [4-[(3-Bromo-4-methoxybenzyl) amino] -6- (1H-1-pyrazolyl) -1-phthalazinyl] -4-piperidinol hydrochloride
[0373]
Embedded image

[0374]
¹H NMR (DMSO-d₆) δ; 1.6-1.74 (2H, m), 1.87-2.0 (2H, m), 2.9-3.1 (2H, m), 3.4-3.55 (2H, m), 3.7-3.8 (1H, m), 3.81 ( 3H, s), 4.65-4.8 (2H, m), 6.72 (1H, m), 7.10 (1H, d, J = 8.8 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.79 (1H, s ), 7.93 (1H, d, J = 1.2 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J = 8.8 Hz), 9.00 (1H, d, J = 2.8 Hz), 9.51 (1H, s)
Example 109
1- [4-[(3-Chloro-4-methoxybenzyl) amino] -6- (1H-1,2,3-triazol-1-yl) -1-phthalazinyl] -4-piperidinol hydrochloride
[0375]
Embedded image

[0376]
¹H NMR (DMSO-d₆) δ; 1.62-1.75 (2H, m), 1.9-2.0 (2H, m), 3.0-3.1 (2H, m), 3.3-3.58 (2H, m), 3.7-3.8 (1H, m), 3.83 ( 3H, s), 4.73 (2H, d, J = 5.6 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.13 ( 1H, m), 8.32 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 9.2 Hz), 9.17 (1H, s), 9.56 (1H, s)
Example 110
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbaldehyde O6-methyloxime hydrochloride
[0377]
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[0378]
¹H NMR (DMSO-d₆) δ; 1.60-1.70 (2H, m), 1.87-1.70 (2H, m), 2.96-3.05 (2H, m), 3.30-3.50 (2H, m), 3.68-3.78 (1H, m), 3.83 ( 3H, s), 3.99 (3H, s), 4.66-4.73 (2H, m), 7.14 (1H, d, J = 8 Hz), 7.42 (1H, dd, J = 2, 8 Hz), 7.57 (1H , d, J = 2 Hz), 8.13 (1H, d, J = 8 Hz), 8.28 (1H, d, J = 8 Hz), 8.39 (1H, s), 8.94 (1H, brs)
Example 111
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbaldehyde O6-ethyloxime hydrochloride
[0379]
Embedded image

[0380]
¹H NMR (DMSO-d₆) δ; 1.28 (3H, t, J = 6 Hz), 1.60-1.73 (2H, m), 1.87-1.98 (2H, m), 2.94-3.06 (2H, m), 3.39-3.52 (2H, m) , 3.68-3.78 (1H, m), 3.83 (3H, s), 4.25 (2H, q, J = 6 Hz), 4.67-4.74 (2H, m), 7.13 (1H, d, J = 9 Hz), 7.42 (1H, d, J = 9 Hz), 7.58 (1H, s), 8.13 (1H, d, J = 8 Hz), 8.30 (1H, d, J = 8 Hz), 8.39 (1H, s), 8.97 (1H, s)
Example 112
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (4-hydroxypiperidino) -6-phthalazinecarbaldehyde O6-benzyloxime hydrochloride
[0381]
Embedded image

[0382]
¹H NMR (DMSO-d₆) δ; 1.59-1.71 (2H, m), 1.87-1.96 (2H, m), 2.94-3.05 (2H, m), 3.37-3.51 (2H, m), 3.68-3.78 (1H, m), 3.82 ( 3H, s), 4.67-4.76 (2H, m), 5.27 (2H, s), 7.13 (1H, d, J = 9 Hz), 7.29-7.48 (6H, m), 7.59 (1H, s), 8.12 (1H, d, J = 9 Hz), 8.29 (1H, d, J = 9 Hz), 8.45 (1H, s), 9.04 (1H, brs)
Example 113
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3-fluoro-3- (hydroxymethyl) tetrahydro-1H-1-pyrrolyl] -6-phthalazinecarbonitrile hydrochloride
[0383]
Embedded image

[0384]
¹H NMR (DMSO-d₆) δ; 2.09-2.28 (2H, m), 3.50-4.05 (6H, m), 3.81 (3H, s), 4.66 (2H, s), 7.11 (1H, d, J = 8.0 Hz), 7.43 (1H , d, J = 8.0 Hz), 7.58 (1H, s), 8.43 (1H, d, J = 8.4 Hz), 8.53 (1H, s), 9.45 (1H, s)
Example 114
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-1-oxa-8-azaspiro [4.5] dec-8-yl) -6-phthalazinecarbonitrile hydrochloride
[0385]
Embedded image

[0386]
¹H NMR (DMSO-d₆) δ; 1.65-1.85 (3H, m), 1.87-2.01 (2H, m), 3.16-3.63 (8H, m), 3.82 (3H, s), 4.32 (1H, s), 4.73 (2H, d, J = 4.8 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.62 (1H, s), 8.23 (1H, d, J = 8.0 Hz), 8.44 (1H, d, J = 8.0 Hz), 9.57 (1H, s), 10.78 (1H, s)
Example 115
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [2- (1-hydroxycyclopentyl) -1-ethynyl] -6-phthalazinecarbonitrile
[0387]
Embedded image

[0388]
NMR (DMSO-d₆) δ; 1.69-1.86 (4H, m), 1.97-2.04 (4H, m), 3.82 (3H, s), 4.75 (2H, d, J = 5.4 Hz), 5.60 (1H, s), 7.10 (1H , d, J = 8.8 Hz), 7.36 (1H, dd, J = 8.8, 1.2 Hz), 7.49 (1H, d, J = 1.2 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.31 (1H , dd, J = 8.8, 0.6 Hz), 8.52 (1H, t, J = 5.4 Hz), 8.97 (1H, d, J = 0.6 Hz)
Example 116
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [2- (1-hydroxycyclopentyl) ethyl] -6-phthalazinecarbonitrile hydrochloride
[0389]
Embedded image

[0390]
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [2- (1-hydroxycyclopentyl) -1-ethynyl] -6-phthalazinecarbonitrile (690 mg) is dissolved in tetrahydrofuran (200 mL). % Pd-C (50 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 0.5 hr. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 400 mg of 4-[(3-chloro-4-methoxybenzyl) amino] -1- [2- (1-hydroxycyclopentyl) ethyl] -6-phthalazinecarbonitrile. It was. The hydrochloride was obtained by a conventional method.
¹H NMR (DMSO-d₆) δ; 1.47-1.78 (8H, m), 1.89-1.94 (2H, m), 3.24-3.33 (2H, m), 3.84 (3H, s), 4.74 (2H, d, J = 4.4 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.46 (1H, d, J = 8.8 Hz), 8.55 (1H, dd, J = 8.8, 1.2 Hz), 9.40 (1H, br)
Similarly, the following compounds were obtained.
Example 117
4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-3-methylbutyl) -6-phthalazinecarbonitrile hydrochloride
[0390]
Embedded image

[0392]
¹H NMR (DMSO-d₆) δ; 1.17 (6H, s), 1.73-1.80 (2H, m), 3.17-3.24 (2H, m), 3.80 (3H, s), 4.78 (2H, d, J = 4.4 Hz), 7.10 (1H , d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 1.8 Hz), 7.62 (1H, d, J = 1.8 Hz), 8.43 (1H, d, J = 8.6 Hz), 8.51 (1H , dd, J = 8.6, 1.2 Hz), 9.63 (1H, br), 10.30 (1H, br).
Example 118
1- (3-Amino-3-methylbutyl) -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile dihydrochloride
[0393]
Embedded image

[0394]
¹H NMR (DMSO-d₆) δ; 1.37 (6H, s), 2.00-2.19 (2H, m), 3.21-3.56 (2H, m), 3.84 (3H, s), 4.78 (2H, d, J = 4.4 Hz), 7.15 (1H , d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.61 (1H, s), 8.15-8.29 (4H, m), 8.48 (1H, d, J = 8.8 Hz), 8.56 (1H, d, J = 8.8 Hz), 9.38 (1H, br)
Example 119
4-[(3-Chloro-4-methoxybenzyl) amino] -1- [3- (dimethylamino) propyl] -6-phthalazinecarbonitrile dihydrochloride
[0395]
Embedded image

[0396]
¹H NMR (DMSO-d₆) d 2.11-2.19 (2H, m), 2.74 (3H, s), 2.75 (3H, s), 3.16-3.29 (4H, m), 3.85 (3H, s), 4.80 (2H, d, J = 5.2 Hz), 7.16 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.49 (1H, d, J = 8.4 Hz), 8.56 (1H, dd, J = 8.4, 1.4 Hz), 9.47 (1H, d, J = 1.4 Hz), 10.56 (2H, br)

Claims

一般式（I）

｛式中、
R¹およびR²は同一または相異なって、ハロゲン原子、ハロゲン原子で置換されていてもよいC1〜C4アルキル基、ハロゲン原子で置換されていてもよいC1〜C4アルコキシ基またはシアノ基を意味する。Xはシアノ基、ニトロ基、ハロゲン原子、チオカルバモイル基、C1〜C4アルキル基・アリールC1〜C4アルキル基またはカルボキシC1〜C4アルキル基で置換されていてもよいヒドロキシイミノメチン基、または下記置換基群Aから選ばれる１〜３個の置換基で置換されていてもよいヘテロアリール基を意味する。Yは
i) 式（ IV ）

｛式中、環Gは二重結合を有していてもよい４〜８員式アミン環を示し、E と J は結合している炭素原子と一緒になって３から６員式の環を形成する基を示し、この環はヘテロ原子を有していてよい。またこの環は置換基を有していてもよい。｝で示される基、
ii)式（V）

（式中、Mは単結合、または水酸基・カルボキシル基・C1〜C4アルキル基またはC1〜C4アルコキシ基で置換されていてもよいC1〜C4アルキレン基を意味する。環KはMと一緒になって５ないし８員式アミン環を意味する。環Lは置換基を有していてもよく、酸素原子を有していてもよい、５〜８員式アルキル環を示す。）で示される基、または
iii) 置換基を有していてもよい、アルキニル基
を意味する。
[置換基群A]ハロゲン原子・シアノ基・ニトロ基または水酸基で置換されていてもよいC1〜C4アルキル基、ハロゲン原子・シアノ基・ニトロ基または水酸基で置換されていてもよいC1〜C4アルコキシ基、シアノ基、ニトロ基、保護基を有していてもよいカルボキシル基、保護基を有していてもよい水酸基、低級アルキル基で置換されていてもよいカルバモイル基、ハロゲン原子、C1〜C4アシル基・C1〜C4アルキルスルホニル基または置換基を有していてもよいアリールスルホニル基で置換されていてもよいアミノ基。
lは１〜３の整数を意味する。
但し、 lが１でEとJが結合している炭素原子と一緒になってジオキソラン環を形成している場合を除く。｝
で示されるフタラジン誘導体または薬理学的に許容される塩、またはそれらの水和物。Formula (I)

{Where,
R ¹ and R ² are the same or different and represent a halogen atom, a C1-C4 alkyl group optionally substituted with a halogen atom, a C1-C4 alkoxy group optionally substituted with a halogen atom, or a cyano group. . X is a cyano group, a nitro group, a halogen atom, a thiocarbamoyl group, a C1-C4 alkyl group, an aryl C1-C4 alkyl group or a hydroxyiminomethine group optionally substituted with a carboxy C1-C4 alkyl group, or the following substituents It means a heteroaryl group which may be substituted with 1 to 3 substituents selected from group A. Y is
i) Formula ( IV )

{Wherein ring G represents a 4- to 8-membered amine ring which may have a double bond, E and J from 3 together with the carbon atom bonded to the 6-membered equation ring The group to be formed is shown , and this ring may have a hetero atom. Moreover, this ring may have a substituent. } Group represented by
ii) Formula (V)

(In the formula, M means a single bond, or a C1-C4 alkylene group optionally substituted with a hydroxyl group, a carboxyl group, a C1-C4 alkyl group or a C1-C4 alkoxy group. Ring K together with M A 5- to 8-membered amine ring, wherein the ring L represents a 5- to 8-membered alkyl ring which may have a substituent and may have an oxygen atom. Or
iii) An alkynyl group which may have a substituent.
[Substituent group A] C1-C4 alkyl group optionally substituted with a halogen atom, cyano group, nitro group or hydroxyl group, C1-C4 alkoxy optionally substituted with a halogen atom, cyano group, nitro group or hydroxyl group Group, cyano group, nitro group, carboxyl group which may have a protecting group, hydroxyl group which may have a protecting group, carbamoyl group which may be substituted with a lower alkyl group, halogen atom, C1-C4 An amino group which may be substituted with an acyl group, a C1-C4 alkylsulfonyl group or an arylsulfonyl group which may have a substituent.
l means an integer of 1 to 3;
However , the case where l is 1 and the carbon atom to which E and J are bonded together forms a dioxolane ring is excluded. }
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

R¹がハロゲン原子、ハロゲン原子で置換されていてもよいC1〜C4アルキル基またはシアノ基で、R²がハロゲン原子またはC1〜C4アルコキシ基である請求項１記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物。The phthalazine derivative according to claim 1, wherein R ¹ is a halogen atom, a C1-C4 alkyl group which may be substituted with a halogen atom or a cyano group, and R ² is a halogen atom or a C1-C4 alkoxy group. Acceptable salts or hydrates thereof.

Yが式（IV）

（式中、環G、EおよびJは前記を意味する。）である請求項１または２に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物。Y is the formula (IV)

(Wherein rings G, E and J mean the same as above). The phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof according to claim 1 or 2.

Yが式（V）

（式中、M、環Kおよび環Lは前記を意味する。）である請求項１または２に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物。Y is the formula (V)

(Wherein, M, ring K and ring L are as defined above). The phthalazine derivative or a pharmaceutically acceptable salt thereof, or a hydrate thereof according to claim 1 or 2.

Yが置換基を有していてもよい、アルキニル基である請求項１または２に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物。 The phthalazine derivative or a pharmaceutically acceptable salt thereof, or a hydrate thereof according to claim 1 or 2, wherein Y is an alkynyl group which may have a substituent.

Yが式（IV）で示される基であって、EとJは結合している炭素原子と一緒になって、ヘテロ原子を有していてもよく、置換基を有していてもよい３から６員式環を形成し、環Gが二重結合を有していてもよい４から８員式アミン環である請求項１〜３のいずれか一項に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物。Y is a group represented by the formula (IV), and E and J together with the carbon atom to which they are bonded may have a hetero atom or may have a substituent. A phthalazine derivative or a pharmacology thereof according to any one of claims 1 to 3 , wherein the phthalazine derivative is a 4- to 8-membered amine ring which forms a 6-membered ring from 1 to 4 and ring G may have a double bond. Acceptable salts or hydrates thereof.

Yが式（V）で示される基であって、環Kおよび環Lは前記を意味し、Mが水酸基・カルボキシル基・ヒドロキシC1〜C4アルキレン基またはカルボキシC1〜C4アルキレン基で置換されたC1〜C4アルキレン基である請求項１、２または４のいずれか一項に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物。Y is a group represented by formula (V), ring K and ring L mean the above, and M is a C1 substituted with a hydroxyl group, a carboxyl group, a hydroxy C1-C4 alkylene group or a carboxy C1-C4 alkylene group A phthalazine derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof according to any one of claims 1, 2 and 4 , which is a -C4 alkylene group.

Yが置換基を有していてもよいアルキニル基であって、三重結合が１個である請求項１、２または５のいずれか一項に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物。The phthalazine derivative according to any one of claims 1, 2, and 5 , or a pharmacologically acceptable group thereof, wherein Y is an alkynyl group which may have a substituent and has one triple bond. Salts, or hydrates thereof.

化合物が以下に示す化合物群から選ばれる請求項１〜８のいずれか一項に記載の縮合フタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物。
１３）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリル
１４）4-[(3-クロロ-4-メトキフェネチル)アミノ]-1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリル
１５）4-[(3-ブロモ-4-メトキシベンジル)アミノ]-1-(2-ヒドロキシ-7-アザスピロ[3.5]ノン-7-イル)-6-フタラジンカルボニトリル
１６）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(2-ヒドロキシ-6-アザスピロ[3.4]オクト-6-イル)-6-フタラジンカルボニトリル
２１）4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-3-メチル-1-ブチニル)-6-フタラジンカルボニトリル
２２）1-(3-アミノ-3-メチル-1-ブチニル)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-6-フタラジンカルボニトリル
３５）(endo)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(3-ヒドロキシ-8-アザビシクロ[3.2.1]オクト-8-イル)-6-フタラジンカルボニトリル
３６）(syn)-4-[(3-クロロ-4-メトキシベンジル)アミノ]-1-(9-ヒドロキシ-3-アザビシクロ[3.3.1]ノン-3-イル)-6-フタラジンカルボニトリルThe condensed phthalazine derivative according to any one of claims 1 to 8 , or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the compound is selected from the group of compounds shown below.
13) 4-[(3-Chloro-4-methoxybenzyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 14) 4-[( 3-chloro-4-methoxyphenethyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 15) 4-[(3-bromo-4- Methoxybenzyl) amino] -1- (2-hydroxy-7-azaspiro [3.5] non-7-yl) -6-phthalazinecarbonitrile 16) 4-[(3-chloro-4-methoxybenzyl) amino]- 1- (2-Hydroxy-6-azaspiro [3.4] oct-6-yl) -6-phthalazinecarbonitrile
21) 4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-3-methyl-1-butynyl) -6-phthalazinecarbonitrile 22) 1- (3-amino-3 -Methyl-1-butynyl) -4-[(3-chloro-4-methoxybenzyl) amino] -6-phthalazinecarbonitrile
35) (endo) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) -6-phthalazinecarbonitrile 36) (syn) -4-[(3-Chloro-4-methoxybenzyl) amino] -1- (9-hydroxy-3-azabicyclo [3.3.1] non-3-yl) -6-phthalazinecarbonitrile

請求項１〜９のいずれか一項に記載のフタラジン誘導体または薬理学的に許容される塩、またはそれらの水和物を有効成分とする***機能不全予防・治療剤。An agent for preventing or treating erectile dysfunction comprising the phthalazine derivative according to any one of claims 1 to 9, a pharmacologically acceptable salt, or a hydrate thereof as an active ingredient.

請求項１〜９のいずれか一項に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物を有効成分とする女性の性的機能不全または月経困難症の予防・治療剤。Prevention or prevention of sexual dysfunction or dysmenorrhea in women comprising the phthalazine derivative according to any one of claims 1 to 9 , or a pharmacologically acceptable salt thereof, or a hydrate thereof as an active ingredient. Therapeutic agent.

***機能不全症治療剤を製造するための請求項１〜９のいずれか一項に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物の使用。Use of the phthalazine derivative according to any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, or a hydrate thereof for producing a therapeutic agent for erectile dysfunction.

請求項１〜９のいずれか一項に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物からなるPDE5阻害剤を有効成分とする高血圧症、肺高血圧症、狭心症、糖尿病、または腎炎の予防・治療剤。The phthalazine derivative according to any one of claims 1 to 9 , or a pharmacologically acceptable salt thereof, or a PDE5 inhibitor comprising the hydrate thereof as an active ingredient, hypertension, pulmonary hypertension, narrow A preventive or therapeutic agent for heart disease, diabetes, or nephritis.

請求項１〜９のいずれか一項に記載のフタラジン誘導体またはその薬理学的に許容される塩、またはそれらの水和物が有効な疾患の予防・治療剤。A prophylactic / therapeutic agent for a disease for which the phthalazine derivative according to any one of claims 1 to 9 , or a pharmacologically acceptable salt thereof, or a hydrate thereof is effective.