JP4334476B2

JP4334476B2 - 1,3-azole derivative and pharmaceutical composition for treating thrombosis comprising the derivative

Info

Publication number: JP4334476B2
Application number: JP2004524089A
Authority: JP
Inventors: 清中戸川; 正道高木; 真赤嶋; 徳明大石; 明子大嶋
Original assignee: 株式会社静岡カフェイン工業所
Priority date: 2002-07-29
Filing date: 2002-07-29
Publication date: 2009-09-30
Anticipated expiration: 2022-07-29
Also published as: WO2004010996A1; AU2002368133A1; JPWO2004010996A1

Description

本発明は、プラスミノーゲンアクチベータ（ＰＡ）活性促進作用及びプラスミノーゲンアクチベーターインヒビター（ＰＡＩ−１）阻害活性作用を有し、血栓溶解剤、抗血栓剤として有用な１，３−アゾール誘導体に関する。 The present invention relates to a 1,3-azole derivative that has a plasminogen activator (PA) activity promoting action and a plasminogen activator inhibitor (PAI-1) inhibitory action action and is useful as a thrombolytic agent or antithrombotic agent. .

血栓を溶解させるためには、ＰＡ類を投与する療法、すなわち血栓溶解療法（線溶療法）が、現在広く実施されている。線溶系の活性化は、血液線溶系調節因子の前駆体であるプラスミノーゲンをＰＡがプラスミンに活性化することによって開始され、生じたプラスミンが酵素作用を発現して血栓の構成成分であるフィブリンを分解することによって血栓溶解が進行する。現在、この線溶療法に使用される血栓溶解剤として、ウロキナーゼ（ＵＫ）、組織プラスミノーゲンアクチベータ（ｔ−ＰＡ）などの生体内物質、ストレプトキナーゼ（ＳＫ）、スタフィロキナーゼ（ＳＡＫ）などの菌体産生物質およびそれらの遺伝子組換え体等が知られている。しかし、これら既存の血栓溶解薬はすべて蛋白製剤であるため、血中半減期が短く、速やかに肝臓で代謝され、また、生体内に阻害因子が存在するため、血栓の生じている局所に於いて血栓溶解作用を発現させるためには大量投与を必要とする。臨床に於いて、投与量が多いほど再潅流率が高いことが報告されているが、このような血栓溶解剤の一過性の大量投与は、全身的に血栓溶解活性を著しく高め、血栓塞栓部位を開通させることが期待される一方、副作用として重篤な出血症状が認められるという問題を抱えている。又、これらの血栓溶解剤の投与により一時的に塞栓部位を開通させても、再閉塞を生じ易いことが大きな問題となっている。
本発明の目的は、上記した欠点をもたない血栓溶解作用及び抗血栓作用を有する医薬組成物を提供することである。In order to dissolve the thrombus, a therapy for administering PAs, that is, a thrombolytic therapy (fibrinolytic therapy) is currently widely performed. Activation of the fibrinolytic system is initiated by the activation of plasminogen, which is a precursor of the blood fibrinolytic regulator, by plasmin, and the resulting plasmin develops an enzymatic action to produce fibrin, a constituent of thrombus. The thrombolysis proceeds by decomposing. Currently, thrombolytic agents used in this fibrinolytic therapy include in vivo substances such as urokinase (UK), tissue plasminogen activator (t-PA), streptokinase (SK), staphylokinase (SAK) and the like. Fungus-producing substances and their gene recombinants are known. However, since all these existing thrombolytic drugs are protein preparations, their blood half-life is short, they are rapidly metabolized in the liver, and there are inhibitors in the living body, so there is a local thrombus. In order to develop a thrombolytic action, a large dose is required. In clinical practice, it has been reported that the higher the dose, the higher the reperfusion rate. However, the transient large-scale administration of such a thrombolytic agent significantly increases the thrombolytic activity systemically, and the thromboembolism While it is expected to open the site, it has a problem that severe bleeding symptoms are observed as a side effect. Moreover, even if the embolization site is temporarily opened by administration of these thrombolytic agents, it is a big problem that re-occlusion is likely to occur.
An object of the present invention is to provide a pharmaceutical composition having a thrombolytic action and an antithrombotic action that does not have the above-mentioned drawbacks.

本発明者らは、ＰＡの強力なインヒビターであるプラスミノーゲンアクチベーターインヒビター（ＰＡＩ−１）を阻害することにより、ＰＡの活性を維持し、血栓症または再閉塞の発生率を減少させることができるという点に着目し、鋭意研究した結果、下記１，３−アゾール誘導体又はその医薬的に許容しうる塩化合物若しくは溶媒和物が上記目的に適合することを見出した。
本発明は、かかる知見に基づきなされたもので、優れたＰＡ活性促進作用とＰＡＩ−１阻害活性を有し、経口投与が可能な、線溶促進作用、血栓溶解作用及び抗血栓作用を有する医薬組成物を提供するものである。
すなわち、本発明は、以下の発明に関する。
［１］有効成分として、一般式（１）

［式中、
（１）Ｚは、
（ｉ）酸素
（ｉｉ）硫黄

（ここでＺ_１は、
＜１＞水素
＜２＞−低級アルキレン基−Ｚ_２ …（３）
（ここでＺ_２は、１． −ＣＯＯＲ_１ …（４）
（ここでＲ_１は水素、低級アシルオキシ基で
置換されて良い低級アルキル基）

（ここでＲ_２，Ｒ_３は互いに独立して水素、低
級アシルオキシ基で置換されて良い低級アル
キル基）
３．ハロゲンで置換されて良いフェニル基
４．シクロヘキシル基））
（２）Ａは、
（ｉ）−アリーレン基−Ｏ−低級アルキレン基−ａ_１…（６）
（ここで
＜１＞ａ_１は、
１．−ＣＯＯＲ_４ …（７）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて良い
低級アルキル基、ベンジル基）

（ここでＲ_５，Ｒ_６は互いに独立して水素、低級アシルオキ
シ基で置換されて良い低級アルキル基、ベンジル基）

（ここでＲ_７は水素、低級アシルオキシ基で置換されて良い
低級アルキル基、ベンジル基）

（ここでＲ_８，Ｒ_９は互いに独立して水素、低級アシルオキ
シ基で置換されて良い低級アルキル基、ベンジル基）
５．ハロゲン
６．フェニル基
７．４−モルホリニル基
８．１−ピロリジニル基
９．１−ピペリジニル基
１０．４−ピリジニル基
１１．４−メチル−１−ピペラジニル基

（ここでｙ_１，ｙ_２は互いに独立して
▲１▼水素
▲２▼低級アルキル基
▲３▼低級アルコキシカルボニル基）
＜２＞アリーレン基は、１，４−及び１，２−フェニレン基、［１，１’−ビフェ
ニル］−４，４’−ジイル基、２，６−、２，３−及び式（６）の酸素が６
位に結合した６，１−ナフタレンジイル基）
（ｉｉ）−アリーレン基−ａ_２ …（１２）
（ここで
＜１＞ａ_２は、
１．水酸基
２．低級アルコキシ基
３．−ＣＯＯＲ_１０ …（１３）
（ここでＲ_１０は水素、低級アシルオキシ基で置換されて良
い低級アルキル基、ベンジル基）

（ここでＲ_１１，Ｒ_１２は互いに独立して水素、低級アシル
オキシ基で置換されて良い低級アルキル基、ベンジル基、
Ｒ_１３は水素、低級アルキル基）

（ここでＲ_１４，Ｒ_１５は互いに独立して水素、低級アシル
オキシ基で置換されて良い低級アルキル基、ベンジル基）

（ここでＲ_１６は水素、低級アシルオキシ基で置換されて良
い低級アルキル基、ベンジル基）
＜２＞アリーレン基は、１，４−フェニレン基、［１，１’−ビフェニル］−
４，４’−ジイル基、２，６−、２，３−及び式（１２）に於いてａ_２が
６位に結合した６，１−ナフタレンジイル基）
（ｉｉｉ） −低級アルキレン基−ＣＯＯＲ_１７ …（１７）
（ここでＲ_１７は水素、低級アシルオキシ基で置換されて良い低
級アルキル基、ベンジル基）
（３）Ｂ_１，Ｂ_２は、
（ｉ）Ｚが酸素の時、それぞれ単独に、
１．Ｂ_１は、
▲１▼２−ナフチル基
▲２▼フェニル基
２．Ｂ_２は、
▲１▼水素
▲２▼フェニル基
（ｉｉ）それぞれに隣接する炭素と共に、一緒になってベンゼン環を
形成し、全体として、前記式（１）が、下記一般式（１８）

（ここで
▲１▼Ａ，Ｚは前記の通りである
▲２▼ｂ_１は、
１．水素
２．低級アルキル基
▲３▼ｂ_２は、
１．水素
２．低級アルキル基
３．フェニル基
４．ハロゲン
▲４▼ｂ_３は、
１．水素
２．ニトロ基
３．アミノ基
（ここでアミノ基は低級アルキル基、ベンジル基で
置換されて良い）
４．低級アルキル基
５． −Ｏ−ｂ_３１ …（１９）
（ここでｂ_３１は、
１．水素
２．低級アルキル基
３．低級アシル基
４．シクロヘキシル基
５．−低級アルキレン基−ｂ_３２ …（２０）
（ここでｂ_３２は、
−１．フェニル基
−２．シクロヘキシル基
−３． −ＣＯＯＲ_１８ …（２１）
（ここでＲ_１８は水素、低級アシルオ
キシ基で置換されて良い低級アルキ
ル基、ベンジル基）

（ここでＲ_１９，Ｒ_２０は互いに独立
して水素、低級アシルオキシ基で置
換されて良い低級アルキル基、ベン
ジル基））））
である］
で表される化合物又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物からなる血栓症を治療するための医薬組成物。
［２］血栓溶解剤である、前記［１］の医薬組成物。
［３］抗血栓剤である、前記［１］の医薬組成物。
［４］医薬組成物として使用するための前記［１］の式（１）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［５］血栓症を治療するための医薬組成物を製造するための前記［１］の式（１）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物の使用。
［６］前記［１］の式（１）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物の有効量を対象に投与することからなる血栓症を治療する方法。
［７］下記式（２３）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。

［式中、
（１）Ａは、
（ｉ） −アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（６）
（ここで
＜１＞ａ_１は、
１． −ＣＯＯＲ_４ …（７）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて良
い低級アルキル基、ベンジル基）

（ここでＲ_５，Ｒ_６は互いに独立して水素、低級アシルオ
キシ基で置換されて良い低級アルキル基、ベンジル基）

（ここでＲ_７は水素、低級アシルオキシ基で置換されて良
い低級アルキル基、ベンジル基）

（ここでＲ_８，Ｒ_９は互いに独立して水素、低級アシルオ
キシ基で置換されて良い低級アルキル基、ベンジル基）
５．ハロゲン
６．フェニル基
７．４−モルホリニル基
８．１−ピロリジニル基
９．１−ピペリジニル基
１０．４−ピリジニル基
１１．４−メチル−１−ピペラジニル基

（ここでｙ_１，ｙ_２は互いに独立して
▲１▼水素
▲２▼低級アルキル基
▲３▼低級アルコキシカルボニル基）
＜２＞アリーレン基は、１，４−及び１，２−フェニレン基、［１，１’−
ビフェニル］−４，４’−ジイル基、２，６−、２，３−及び式（６
）の酸素が６位に結合した６，１−ナフタレンジイル基を意味する。
但し、
▲１▼同時にａ_１がカルボキシル基、低級アルコキシカルボニル
基、アリーレン基が１，４−フェニレン基、下記するｂ_１，
ｂ_２，ｂ_３が共に水素である場合は、低級アルキレン基と
してメチレン基を除く。
▲２▼ａ_１が式（１１）の場合は、１，４−フェニレン基を除く。）
（ｉｉ） −アリーレン基−ａ_２ …（１２）
（ここで
＜１＞ａ_２は、
１．水酸基
２．低級アルコキシ基

（ここでＲ_１６は水素、低級アシルオキシ基で置換されて良
い低級アルキル基、ベンジル基）
＜２＞アリーレン基は［１，１’−ビフェニル］−４，４’−ジイル基、２，６
−、２，３−及び式（１２）に於いてａ_２が６位に結合した６，１−ナフ
タレンジイル基）
（２）ｂ_１は、
１．水素
２．低級アルキル基
（３）ｂ_２は、
１．水素
２．低級アルキル基
３．フェニル基
４．ハロゲン
（４）ｂ_３は、
１．水素
２．ニトロ基
３．アミノ基
（ここでアミノ基は低級アルキル基、ベンジル基で置換されて
良い）
４．低級アルキル基
５．−Ｏ−ｂ_３１ …（１９）
（ここでｂ_３１は、
１．水素
２．低級アルキル基
３．低級アシル基
４．シクロヘキシル基
５．−低級アルキレン基−ｂ_３２ …（２０）
（ここでｂ_３２は、
−１．フェニル基
−２．シクロヘキシル基
−３．−ＣＯＯＲ_１８ …（２１）
（ここでＲ_１８は水素、低級アシルオキシ
基で置換されて良い低級アルキル基、ベ
ンジル基）

（ここでＲ_１９，Ｒ_２０は互いに独立して
水素、低級アシルオキシ基で置換されて
良い低級アルキル基、ベンジル基）））
である］
［８］下記式（２４）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。

［式中、
（１）Ａは、
（ｉ）−アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（６）
（ここで
＜１＞ａ_１は、
１．−ＣＯＯＲ_４ …（７）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて良い
低級アルキル基、ベンジル基）

（ここでＲ_５，Ｒ_６は互いに独立して水素、低級アシルオキシ
基で置換されて良い低級アルキル基、ベンジル基）
３．フェニル基
＜２＞アリーレン基は、１，４−フェニレン基、２，６−ナフタレンジイル
基である。（但し、同時にａ_１がカルボキシル基、低級アルコキ
シカルボニル基、低級アルキレン基がメチレン基、下記する
Ｚ_１が水素である場合は１，４−フェニレン基を除く））
（ｉｉ）−アリーレン基−ａ_２ …（１２）
（ここで
＜１＞ａ_２は水酸基
＜２＞アリーレン基は１，４−フェニレン基、２，６−ナフタレンジイル
基（但し、同時にａ_２が水酸基、下記するＺ_１が水素の時、
１，４−フェニレン基を除く））
（２）Ｚ_１は、
＜１＞水素
＜２＞−低級アルキレン基−Ｚ_２ …（３）
（ここでＺ_２は、
１．−ＣＯＯＲ_１ …（４）
（ここでＲ_１は水素、低級アシルオキシ基で
置換されて良い低級アルキル基）

（ここでＲ_２，Ｒ_３は互いに独立して水素、低
級アシルオキシ基で置換されて良い低級アル
キル基）
３．ハロゲンで置換されて良いフェニル基
４．シクロヘキシル基）
（３）ｂ_２は、
１．水素
２．塩素
（４）ｂ_１，ｂ_３は水素
である］
［９］下記式（２５）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。

［ここで
（１）Ａは、
（ｉ）−アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（６）
（ここで
＜１＞ａ_１は、
１．−ＣＯＯＲ_４ …（７）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて
良い低級アルキル基、ベンジル基）

（ここでＲ_５，Ｒ_６は互いに独立して水素、低級アシルオ
キシ基で置換されて良い低級アルキル基、ベンジル基）
３．フェニル基
＜２＞アリーレン基は２，６−ナフタレンジイル基）
（ｉｉ）−アリーレン基−ａ_２ …（１２）
（ここで
＜１＞ａ_２は水酸基
＜２＞アリーレン基は、２，６−ナフタレンジイル基）
（２）ｂ_１，ｂ_２，ｂ_３は水素
である］
［１０］下記式（２６）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。

［ここで
（１）Ａは、
（ｉ）−アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（６）
（ここで
＜１＞ａ_１は、
１．−ＣＯＯＲ_４ …（７）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて
良い低級アルキル基、ベンジル基）
２．フェニル基
＜２＞アリーレン基は２，６−ナフタレンジイル基）
（ｉｉ）−アリーレン基−ａ_２ …（１２）
（ここで
＜１＞ａ_２は、
１．水酸基
２．−ＣＯＯＲ_１０ …（１３）
（ここでＲ_１０は水素、低級アシルオキシ基で置換され
て良い低級アルキル基、ベンジル基）
＜２＞アリーレン基は、２，６−ナフタレンジイル基）
（ｉｉｉ）−低級アルキレン基−ＣＯＯＲ_１７ …（１７）
（ここでＲ_１７は水素、低級アシルオキシ基で置換されて良い
低級アルキル基、ベンジル基）
（２）Ｂ_１は、
１．２−ナフチル基
２．フェニル基
（３）Ｂ_２は、
１．水素
２．フェニル基
である］
［１１］以下の化合物群から選ばれる化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
４−（２−ナフタレニル）−２−オキサゾールプロパン酸メチルエステル、４−（２−ナフタレニル）−２−オキサゾールプロパン酸、６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレンカルボン酸メチルエステル、６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレンカルボン酸、４，５−ジフェニル−２−［６−（フェニルメトキシ）−２−ナフタレニル］オキサゾール、６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレノール、［［６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレニル］オキシ］酢酸メチルエステル、［［６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレニル］オキシ］酢酸、４−［４−（２−ベンゾオキサゾリル）フェノキシ］ブタン酸、４−［４−（２−ベンゾオキサゾリル）フェノキシ］ブタン酸（２，２−ジメチル−１−オキソプロポキシ）メチルエステル、６−［４−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸、６−［４−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸（２，２−ジメチル−１−オキソプロポキシ）メチルエステル、［５−［４−（２−ベンゾオキサゾリル）フェノキシ］ペンチル］プロパン二酸、［４−（６−ニトロ−２−ベンゾオキサゾリル）フェノキシ］酢酸メチルエステル、［４−（６−ニトロ−２−ベンゾオキサゾリル）フェノキシ］酢酸、６−［２−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸、［５−［２−（２−ベンゾオキサゾリル）フェノキシ］ペンチル］プロパン二酸、２−［４’−（フェニルメトキシ）［１，１’−ビフェニル］−４−イル］ベンゾオキサゾール、４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−オール、４−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ブタン酸エチルエステル、４−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ブタン酸、６−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ヘキサン酸エチルエステル、６−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ヘキサン酸、［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］メチルプロパン二酸ジエチルエステル、［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］メチルプロパン二酸、［３−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］プロピル］プロパン二酸、［５−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ペンチル］プロパン二酸ジエチルエステル、２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール、６−（２−ベンゾオキサゾリル）−２−ナフタレノール、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸メチルエステル、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸、４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、Ｎ−［４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソブチル］グリシンエチルエステル、２−［［４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソブチル］アミノ］ペンタン二酸ジエチルエステル、２−［［４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソブチル］アミノ］ペンタン二酸、６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（２，２−ジメチル−１−オキソプロポキシ）メチルエステル、２−［［６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソヘキシル］アミノ］ペンタン二酸ジエチルエステル、２−［［６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソヘキシル］アミノ］ペンタン二酸、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸ジエチルエステル、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸、［３−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸、２−［６−［２−（１−ピロリジニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩、２−［６−［２−（１−ピペリジニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩、２−［６−［（４−ピリジニル）メトキシ］−２−ナフタレニル］ベンゾオキサゾール、２−［６−［（５−クロロペンチル）オキシ］−２−ナフタレニル］ベンゾオキサゾール、２−［６−［［５−（１−ピロリジニル）ペンチル］オキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩、２−［６−［［５−（４−メチル−１−ピペラジニル）ペンチル］オキシ］−２−ナフタレニル］ベンゾオキサゾール二塩酸塩、６−メチル−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール、６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール、［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸、４−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンタン酸、５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンタン酸（２，２−ジメチル−１−オキソプロポキシ）メチルエステル、６−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、７−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘプタン酸、［５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、６−メチル−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール、［３−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］カルバミン酸１，１−ジメチルエチルエステル、３−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミンメタンスルホン酸塩、Ｎ，Ｎ−ジメチル−３−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩、６−［６−（１−メチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレノール、６−［［６−［６−（１−メチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、２−［６−（フェニルメトキシ）−２−ナフタレニル］−６−ベンゾオキサゾロール、２−［６−（フェニルメトキシ）−２−ナフタレニル］−６−ベンゾオキサゾロール酢酸エステル、２−（６−ヒドロキシ−２−ナフタレニル）−６−ベンゾオキサゾロール酢酸エステル、６−［［６−（６−ヒドロキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、６−［［６−［６−（フェニルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、６−メトキシ−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール、６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレノール、［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸、４−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、６−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］メチルプロパン二酸、［５−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル、［５−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、６−エトキシ−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール、６−（６−エトキシ−２−ベンゾオキサゾリル）−２−ナフタレノール、６−［［６−（６−エトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［６−（６−エトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、６−［［２−［６−（フェニルメトキシ）−２−ナフタレニル］−６−ベンゾオキサゾリル］オキシ］ヘキサン酸エチルエステル、６−［［２−（６−ヒドロキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸、６−［［２−（６−ヒドロキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸エチルエステル、６−［［６−［６−［（６−エトキシ−６−オキソヘキシル）オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［６−［６−［（５−カルボキシペンチル）オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、６−［［２−（６−エトキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸エチルエステル、６−［［２−（６−エトキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸、［５−［［６−［６−［［７−エトキシ−６−（エトキシカルボニル）−７−オキソヘプチル］オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル、［５−［［６−［６−［（６，６−ジカルボキシヘキシル）オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、［５−［［６−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、［５−［［６−［６−（フェニルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸塩酸塩、４−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、４−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、６−［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、６−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸ジエチルエステル、［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸、［５−［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル、［５−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩、６−ニトロ−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール、２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩、Ｎ，Ｎ−ジエチル−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩、６−［６−（シクロヘキシルオキシ）−２−ベンゾオキサゾリル］−２−ナフタレノール、６−［［６−［６−（シクロヘキシルオキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、６−（５−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール、６−［［６−（５−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレノール、６−［［６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレノール、６−［［６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［３−［［６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル、［３−［［６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸、５−クロロ−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール、６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、６−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［３−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸、［５−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、５−クロロ−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩、６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール、６−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［３−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸、［５−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、６−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、６−メチル−２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩、Ｎ，Ｎ−ジメチル−３−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩、６−ニトロ−２−［３−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール、３−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［３−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［３−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、４−［［３−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、６−［［３−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［３−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、６−［［３−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［３−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル、２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−ニトロベンゾオキサゾール、２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩、３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレノール、４−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、６−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、５−（１，１−ジメチルエチル）−２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩、３−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩、３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、６−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−５−フェニルベンゾオキサゾール塩酸塩、Ｎ，Ｎ−ジメチル−３−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩、５−クロロ−２−［３−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール、３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、６−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［３−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸、［５−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、５−クロロ−２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩、３−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩、５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール、６−［［５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、６−ニトロ−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール、５−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［５−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、４−［［５−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［５−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、６−［［５−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［５−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸塩酸塩、６−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、６−［［５−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［５−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル、［５−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］−６−ニトロベンゾオキサゾール、２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩、Ｎ，Ｎ−ジエチル−２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩、２−［６−（フェニルメトキシ）−１−ナフタレニル］−６−ベンゾオキサゾロール、６−（シクロヘキシルメトキシ）−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール、５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレノール、４−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、６−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル、６−（シクロヘキシルメトキシ）−２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］ベンゾオキサゾール塩酸塩、３−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩、５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレノール、４−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸、６−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸、［３−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］プロピル］プロパン二酸、［５−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、５−（１，１−ジメチルエチル）−２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］ベンゾオキサゾール塩酸塩、３−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩、５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、６−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］−５−フェニルベンゾオキサゾール塩酸塩、Ｎ，Ｎ−ジメチル−３−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩、５−クロロ−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール、５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレノール、４−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸、６−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸、［３−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル、［５−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル、５−クロロ−２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］ベンゾオキサゾール塩酸塩、３−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩、２−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］ペンタン二酸ジエチルエステル、２−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］ペンタン二酸、２−アミノ−６−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］ヘキサン酸塩酸塩、２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール、２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル、２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸、２−（４−ヒドロキシフェニル）−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル、２−（４−ヒドロキシフェニル）−１Ｈ−ベンゾイミダゾール−１−酢酸、２−［４−（２−メトキシ−２−オキソエトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル、２−［４−（カルボキシメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸、５−クロロ−２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール、５−クロロ−２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル、５−クロロ−２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸、５−クロロ−２−（４−ヒドロキシフェニル）−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル、５−クロロ−２−（４−ヒドロキシフェニル）−１Ｈ−ベンゾイミダゾール−１−酢酸、２−［４−（カルボキシメトキシ）フェニル］−５−クロロ−１Ｈ−ベンゾイミダゾール−１−酢酸、２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール、６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレノール、［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］酢酸メチルエステル、［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］酢酸、２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル、２−［６−（カルボキシメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸、２−［６−（３−カルボキシプロポキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ブタン酸、２−［６−［（５−カルボキシペンチル）オキシ］−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ヘキサン酸、［５−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル、［５−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、４−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ブタン酸、４−［［６−［１−（フェニルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸、４−［［６−［１−［（２−クロロフェニル）メチル］−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸、１−（シクロヘキシルメチル）−２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール、６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレノール、４−［［６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸、６−［［６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ヘキサン酸、２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル、２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸、２−（６−ヒドロキシ−２−ナフタレニル）−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル、２−（６−ヒドロキシ−２−ナフタレニル）−１Ｈ−ベンゾイミダゾール−１−酢酸、２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ブタン酸、２−（６−ヒドロキシ−２−ナフタレニル）−１Ｈ−ベンゾイミダゾール−１−ブタン酸、［５−［２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−イル］ペンチル］プロパン二酸、２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾチアゾール、６−（２−ベンゾチアゾリル）−２−ナフタレノール、［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］酢酸メチルエステル、［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］酢酸、６−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、［３−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸、［５−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル
［１２］医薬組成物として使用するための前記［７］〜［１１］のいずれかに記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［１３］血栓溶解剤又は抗血栓剤として使用するための前記［７］〜［１１］のいずれかに記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［１４］血栓症を治療するための医薬組成物を製造するための前記［７］〜［１１］のいずれかに記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［１５］前記［７］〜［１１］のいずれかに記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物の有効量を対象に投与することからなる血栓症を治療する方法。
［１６］血栓溶解剤又は抗血栓剤として使用するための以下の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［４−（２−ベンゾオキサゾリル）フェノキシ］酢酸、［４−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル）フェノキシ］酢酸By inhibiting plasminogen activator inhibitor (PAI-1), which is a potent inhibitor of PA, we can maintain the activity of PA and reduce the incidence of thrombosis or reocclusion. As a result of diligent research focusing on the point that it can be performed, it was found that the following 1,3-azole derivative or a pharmaceutically acceptable salt compound or solvate thereof meets the above purpose.
The present invention has been made based on such findings, and has excellent PA activity promoting action and PAI-1 inhibitory activity, and can be administered orally, and has a fibrinolysis promoting action, a thrombolytic action and an antithrombotic action. A composition is provided.
That is, the present invention relates to the following inventions.
[1] As an active ingredient, the general formula (1)

[Where:
(1) Z is
(I) oxygen
(Ii) sulfur

(Where Z ₁ Is
<1> Hydrogen
<2> -Lower alkylene group-Z ₂ ... (3)
(Where Z ₂ 1. -COOR ₁ ... (4)
(Where R ₁ Is hydrogen, lower acyloxy group
Lower alkyl group which may be substituted)

(Where R ₂ , R ₃ Are independent of each other, hydrogen, low
Lower alkyl which may be substituted with a secondary acyloxy group
Kill group)
3. Phenyl group which may be substituted with halogen
4). Cyclohexyl group))
(2) A is
(I) -arylene group-O-lower alkylene group-a ₁ ... (6)
(here
<1> a ₁ Is
1. -COOR ₄ ... (7)
(Where R ₄ May be substituted with hydrogen or a lower acyloxy group
Lower alkyl group, benzyl group)

(Where R ₅ , R ₆ Are independently of each other hydrogen, lower acyloxy
A lower alkyl group or a benzyl group which may be substituted with

(Where R ₇ May be substituted with hydrogen or a lower acyloxy group
Lower alkyl group, benzyl group)

(Where R ₈ , R ₉ Are independently of each other hydrogen, lower acyloxy
A lower alkyl group or a benzyl group which may be substituted with
5. halogen
6). Phenyl group
7. 4-morpholinyl group
8.1-Pyrrolidinyl group
9.1-Piperidinyl group
10.4-pyridinyl group
11.4-methyl-1-piperazinyl group

(Where y ₁ , Y ₂ Are independent of each other
▲ 1 ▼ Hydrogen
(2) Lower alkyl group
(3) Lower alkoxycarbonyl group)
<2> The arylene group includes 1,4- and 1,2-phenylene groups, [1,1′-biphenyl,
Nyl] -4,4′-diyl group, 2,6-, 2,3- and oxygen of formula (6) are 6
6,1-naphthalenediyl group bonded to the position)
(Ii) -arylene group-a ₂ (12)
(here
<1> a ₂ Is
1. Hydroxyl group
2. Lower alkoxy group
3. -COOR ₁₀ ... (13)
(Where R ₁₀ May be substituted with hydrogen or a lower acyloxy group
Lower alkyl group, benzyl group)

(Where R ₁₁ , R ₁₂ Are independently of each other hydrogen, lower acyl
A lower alkyl group which may be substituted with an oxy group, a benzyl group,
R ₁₃ Is hydrogen, lower alkyl group)

(Where R ₁₄ , R ₁₅ Are independently of each other hydrogen, lower acyl
A lower alkyl group which may be substituted with an oxy group, a benzyl group)

(Where R ₁₆ May be substituted with hydrogen or a lower acyloxy group
Lower alkyl group, benzyl group)
<2> The arylene group is a 1,4-phenylene group, [1,1′-biphenyl]-
4,4′-diyl group, 2,6-, 2,3- and in formula (12) a ₂ But
6,1-naphthalenediyl group bonded to the 6-position)
(Iii) -Lower alkylene group -COOR ₁₇ ... (17)
(Where R ₁₇ May be substituted with hydrogen, lower acyloxy groups
Secondary alkyl group, benzyl group)
(3) B ₁ , B ₂ Is
(I) when Z is oxygen,
1. B ₁ Is
(1) 2-naphthyl group
(2) Phenyl group
2. B ₂ Is
▲ 1 ▼ Hydrogen
(2) Phenyl group
(Ii) together with adjacent carbons, together form a benzene ring
As a whole, the formula (1) is represented by the following general formula (18)

(here
(1) A and Z are as described above.
▲ 2 ▼ b ₁ Is
1. hydrogen
2. Lower alkyl group
▲ 3 ▼ b ₂ Is
1. hydrogen
2. Lower alkyl group
3. Phenyl group
4). halogen
▲ 4 ▼ b ₃ Is
1. hydrogen
2. Nitro group
3. Amino group
(Here amino group is lower alkyl group, benzyl group
May be replaced)
4). Lower alkyl group
5. -Ob ₃₁ ... (19)
(Where b ₃₁ Is
1. hydrogen
2. Lower alkyl group
3. Lower acyl group
4). Cyclohexyl group
5. -Lower alkylene group -b ₃₂ ... (20)
(Where b ₃₂ Is
-1. Phenyl group
-2. Cyclohexyl group
-3. -COOR ₁₈ ... (21)
(Where R ₁₈ Is hydrogen, lower acylo
Lower alkyl which may be substituted with a xy group
Group, benzyl group)

(Where R ₁₉ , R ₂₀ Are independent of each other
Hydrogen and lower acyloxy group
Lower alkyl group which may be substituted,
Gyl group))))
Is]
Or a pharmaceutically acceptable salt compound thereof or a solvate thereof. A pharmaceutical composition for treating thrombosis comprising:
[2] The pharmaceutical composition according to the above [1], which is a thrombolytic agent.
[3] The pharmaceutical composition of the above [1], which is an antithrombotic agent.
[4] A compound represented by the formula (1) of the above [1] for use as a pharmaceutical composition, or a pharmaceutically acceptable salt compound thereof or a solvate thereof.
[5] A compound represented by the formula (1) of [1], or a pharmaceutically acceptable salt compound or a solvate thereof for producing a pharmaceutical composition for treating thrombosis use.
[6] Treating thrombosis comprising administering to a subject an effective amount of the compound represented by formula (1) of [1] above, or a pharmaceutically acceptable salt compound thereof, or a solvate thereof. Method.
[7] A compound represented by the following formula (23), or a pharmaceutically acceptable salt compound or a solvate thereof.

[Where:
(1) A is
(I) -arylene group-O-lower alkylene group-a ₁ ... (6)
(here
<1> a ₁ Is
1. -COOR ₄ ... (7)
(Where R ₄ May be substituted with hydrogen or a lower acyloxy group
Lower alkyl group, benzyl group)

(Where R ₅ , R ₆ Are independently of each other hydrogen, lower acylo
A lower alkyl group which may be substituted with a xy group, a benzyl group)

(Where R ₈ , R ₉ Are independently of each other hydrogen, lower acylo
A lower alkyl group which may be substituted with a xy group, a benzyl group)
5. halogen
6). Phenyl group
7. 4-morpholinyl group
8.1-Pyrrolidinyl group
9.1-Piperidinyl group
10.4-pyridinyl group
11.4-methyl-1-piperazinyl group

(Where y ₁ , Y ₂ Are independent of each other
▲ 1 ▼ Hydrogen
(2) Lower alkyl group
(3) Lower alkoxycarbonyl group)
<2> arylene groups are 1,4- and 1,2-phenylene groups, [1,1′-
Biphenyl] -4,4′-diyl group, 2,6-, 2,3- and formula (6
) Means a 6,1-naphthalenediyl group in which oxygen is bonded to the 6-position.
However,
▲ 1 ▼ a at the same time ₁ Is a carboxyl group, lower alkoxycarbonyl
Group, arylene group is 1,4-phenylene group, b described below ₁ ,
b ₂ , B ₃ When both are hydrogen, a lower alkylene group and
To remove the methylene group.
▲ 2 ▼ a ₁ Is a formula (11), the 1,4-phenylene group is excluded. )
(Ii) -arylene group-a ₂ (12)
(here
<1> a ₂ Is
1. Hydroxyl group
2. Lower alkoxy group

(Where R ₁₆ May be substituted with hydrogen or a lower acyloxy group
Lower alkyl group, benzyl group)
<2> The arylene group is [1,1′-biphenyl] -4,4′-diyl group, 2,6
-, 2, 3- and in formula (12) a ₂ 6,1-naphtho bonded to the 6th position
Talendyl group)
(2) b ₁ Is
1. hydrogen
2. Lower alkyl group
(3) b ₂ Is
1. hydrogen
2. Lower alkyl group
3. Phenyl group
4). halogen
(4) b ₃ Is
1. hydrogen
2. Nitro group
3. Amino group
(Where the amino group is substituted with a lower alkyl group, a benzyl group,
good)
4). Lower alkyl group
5. -Ob ₃₁ ... (19)
(Where b ₃₁ Is
1. hydrogen
2. Lower alkyl group
3. Lower acyl group
4). Cyclohexyl group
5. -Lower alkylene group -b ₃₂ ... (20)
(Where b ₃₂ Is
-1. Phenyl group
-2. Cyclohexyl group
-3. -COOR ₁₈ ... (21)
(Where R ₁₈ Is hydrogen, lower acyloxy
A lower alkyl group which may be substituted with
Nyl group)

(Where R ₁₉ , R ₂₀ Are independent of each other
Substituted with hydrogen, lower acyloxy groups
Good lower alkyl group, benzyl group)))
Is]
[8] A compound represented by the following formula (24), or a pharmaceutically acceptable salt compound or a solvate thereof.

(Where R ₅ , R ₆ Are independently of each other hydrogen, lower acyloxy
A lower alkyl group which may be substituted with a group, a benzyl group)
3. Phenyl group
<2> The arylene group is a 1,4-phenylene group or 2,6-naphthalenediyl
It is a group. (However, at the same time a ₁ Is carboxyl group, lower alkoxy
Sicarbonyl group, lower alkylene group is methylene group,
Z ₁ When is hydrogen, except 1,4-phenylene group))
(Ii) -arylene group-a ₂ (12)
(here
<1> a ₂ Is a hydroxyl group
<2> The arylene group is 1,4-phenylene group and 2,6-naphthalenediyl
Group (however, a ₂ Is a hydroxyl group, Z described below ₁ When is hydrogen
Excluding 1,4-phenylene groups))
(2) Z ₁ Is
<1> Hydrogen
<2> -Lower alkylene group-Z ₂ ... (3)
(Where Z ₂ Is
1. -COOR ₁ ... (4)
(Where R ₁ Is hydrogen, lower acyloxy group
Lower alkyl group which may be substituted)

(Where R ₂ , R ₃ Are independent of each other, hydrogen, low
Lower alkyl which may be substituted with a secondary acyloxy group
Kill group)
3. Phenyl group which may be substituted with halogen
4). (Cyclohexyl group)
(3) b ₂ Is
1. hydrogen
2. chlorine
(4) b ₁ , B ₃ Is hydrogen
Is]
[9] A compound represented by the following formula (25), or a pharmaceutically acceptable salt compound or a solvate thereof.

[here
(1) A is
(I) -arylene group-O-lower alkylene group-a ₁ ... (6)
(here
<1> a ₁ Is
1. -COOR ₄ ... (7)
(Where R ₄ Is substituted with hydrogen, lower acyloxy group
Good lower alkyl group, benzyl group)

(Where R ₅ , R ₆ Are independently of each other hydrogen, lower acylo
A lower alkyl group which may be substituted with a xy group, a benzyl group)
3. Phenyl group
<2> The arylene group is a 2,6-naphthalenediyl group)
(Ii) -arylene group-a ₂ (12)
(here
<1> a ₂ Is a hydroxyl group
<2> arylene group is 2,6-naphthalenediyl group)
(2) b ₁ , B ₂ , B ₃ Is hydrogen
Is]
[10] A compound represented by the following formula (26), or a pharmaceutically acceptable salt compound or a solvate thereof.

[here
(1) A is
(I) -arylene group-O-lower alkylene group-a ₁ ... (6)
(here
<1> a ₁ Is
1. -COOR ₄ ... (7)
(Where R ₄ Is substituted with hydrogen, lower acyloxy group
Good lower alkyl group, benzyl group)
2. Phenyl group
<2> The arylene group is a 2,6-naphthalenediyl group)
(Ii) -arylene group-a ₂ (12)
(here
<1> a ₂ Is
1. Hydroxyl group
2. -COOR ₁₀ ... (13)
(Where R ₁₀ Is substituted with hydrogen or a lower acyloxy group
Lower alkyl group, benzyl group)
<2> arylene group is 2,6-naphthalenediyl group)
(Iii) -Lower alkylene group -COOR ₁₇ ... (17)
(Where R ₁₇ May be substituted with hydrogen or a lower acyloxy group
Lower alkyl group, benzyl group)
(2) B ₁ Is
1.2-Naphthyl group
2. Phenyl group
(3) B ₂ Is
1. hydrogen
2. Phenyl group
Is]
[11] A compound selected from the following group of compounds, or a pharmaceutically acceptable salt compound thereof or a solvate thereof.
4- (2-naphthalenyl) -2-oxazolepropanoic acid methyl ester, 4- (2-naphthalenyl) -2-oxazolepropanoic acid, 6- (4 5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid methyl ester, 6- (4 5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid, 4, 5-diphenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] oxazole, 6- (4 5-diphenyl-2-oxazolyl) -2-naphthalenol, [[6- (4 5-diphenyl-2-oxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- (4 5-diphenyl-2-oxazolyl) -2-naphthalenyl] oxy] acetic acid, 4- [4- (2-benzoxazolyl) phenoxy] butanoic acid, 4- [4- (2-Benzoxazolyl) phenoxy] butanoic acid (2, 2-dimethyl-1-oxopropoxy) methyl ester, 6- [4- (2-benzoxazolyl) phenoxy] hexanoic acid, 6- [4- (2-Benzoxazolyl) phenoxy] hexanoic acid (2, 2-dimethyl-1-oxopropoxy) methyl ester, [5- [4- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid, [4- (6-nitro-2-benzoxazolyl) phenoxy] acetic acid methyl ester, [4- (6-nitro-2-benzoxazolyl) phenoxy] acetic acid, 6- [2- (2-benzoxazolyl) phenoxy] hexanoic acid, [5- [2- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid, 2- [4 ′-(phenylmethoxy) [1, 1′-biphenyl] -4-yl] benzoxazole, 4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-ol, 4-[[4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-yl] oxy] butanoic acid ethyl ester, 4-[[4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-yl] oxy] butanoic acid, 6-[[4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-yl] oxy] hexanoic acid ethyl ester, 6-[[4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-yl] oxy] hexanoic acid, [[4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-yl] oxy] methylpropanedioic acid diethyl ester, [[4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-yl] oxy] methylpropanedioic acid, [3-[[4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-yl] oxy] propyl] propanedioic acid, [5-[[4 ′-(2-Benzoxazolyl) [1, 1′-biphenyl] -4-yl] oxy] pentyl] propanedioic acid diethyl ester, 2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 6- (2-benzoxazolyl) -2-naphthalenol, [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] acetic acid, 4-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, N- [4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] glycine ethyl ester, 2-[[4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid diethyl ester, 2-[[4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid, 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid (2, 2-dimethyl-1-oxopropoxy) methyl ester, 2-[[6-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid diethyl ester, 2-[[6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid, [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid diethyl ester, [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid, [3-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, 2- [6- [2- (1-pyrrolidinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, 2- [6- [2- (1-piperidinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, 2- [6-[(4-pyridinyl) methoxy] -2-naphthalenyl] benzoxazole, 2- [6-[(5-chloropentyl) oxy] -2-naphthalenyl] benzoxazole, 2- [6-[[5- (1-pyrrolidinyl) pentyl] oxy] -2-naphthalenyl] benzoxazole hydrochloride, 2- [6-[[5- (4-Methyl-1-piperazinyl) pentyl] oxy] -2-naphthalenyl] benzoxazole dihydrochloride, 6-methyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 6- (6-methyl-2-benzoxazolyl) -2-naphthalenol, [[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid, 4-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid, 5-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid (2, 2-dimethyl-1-oxopropoxy) methyl ester, 6-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 7-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] heptanoic acid, [5-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-methyl-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole, [3-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] carbamic acid 1, 1-dimethylethyl ester, 3-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine methanesulfonate, N, N-dimethyl-3-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride, 6- [6- (1-methylethyl) -2-benzoxazolyl] -2-naphthalenol, 6-[[6- [6- (1-methylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 2- [6- (phenylmethoxy) -2-naphthalenyl] -6-benzoxazolol, 2- [6- (phenylmethoxy) -2-naphthalenyl] -6-benzoxazolol acetate, 2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolol acetate, 6-[[6- (6-Hydroxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- [6- (phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-methoxy-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 6- (6-methoxy-2-benzoxazolyl) -2-naphthalenol, [[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid, 4-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] methylpropanedioic acid, [5-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-ethoxy-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 6- (6-Ethoxy-2-benzoxazolyl) -2-naphthalenol, 6-[[6- (6-Ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- (6-Ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[2- [6- (phenylmethoxy) -2-naphthalenyl] -6-benzoxazolyl] oxy] hexanoic acid ethyl ester, 6-[[2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid, 6-[[2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6-[(6-Ethoxy-6-oxohexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6-[(5-carboxypentyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[2- (6-Ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester, 6-[[2- (6-Ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid, [5-[[6- [6-[[7-Ethoxy-6- (ethoxycarbonyl) -7-oxoheptyl] oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid Diethyl ester, [5-[[6- [6-[(6, 6-dicarboxyhexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, [5-[[6- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, [5-[[6- [6- (phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6- (6-nitro-2-benzoxazolyl) -2-naphthalenol, 4-[[6- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (6-amino-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid hydrochloride, 4-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid diethyl ester, [[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid, [5-[[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt, 6-nitro-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole, 2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-benzoxazolamine dihydrochloride, N, N-diethyl-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-benzoxazolamine dihydrochloride, 6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenol, 6-[[6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6- (5-methyl-2-benzoxazolyl) -2-naphthalenol, 6-[[6- (5-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenol, 6-[[6- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[6- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6- (5-phenyl-2-benzoxazolyl) -2-naphthalenol, 6-[[6- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[6- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester, [3-[[6- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, 5-chloro-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 6- (5-chloro-2-benzoxazolyl) -2-naphthalenol, 4-[[6- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 5-chloro-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, 6- (4-methyl-2-benzoxazolyl) -2-naphthalenol, 6-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 3- (6-methyl-2-benzoxazolyl) -2-naphthalenol, 4-[[3- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-methyl-2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, N, N-dimethyl-3-[[3- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride, 6-nitro-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 3- (6-nitro-2-benzoxazolyl) -2-naphthalenol, 4-[[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[3- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[3- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[3- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, 2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-nitrobenzoxazole, 2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-benzoxazolamine dihydrochloride, 3- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenol, 4-[[3- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[3- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 5- (1, 1-dimethylethyl) -2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, 3-[[3- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 3- (5-phenyl-2-benzoxazolyl) -2-naphthalenol, 4-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -5-phenylbenzoxazole hydrochloride, N, N-dimethyl-3-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride, 5-chloro-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 3- (5-chloro-2-benzoxazolyl) -2-naphthalenol, 4-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 5-chloro-2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, 3-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 5- (6-methyl-2-benzoxazolyl) -2-naphthalenol, 6-[[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-nitro-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole, 5- (6-nitro-2-benzoxazolyl) -2-naphthalenol, 4-[[5- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[5- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- (6-Amino-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid hydrochloride, 6-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[5- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-nitrobenzoxazole, 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-benzoxazolamine dihydrochloride, N, N-diethyl-2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-benzoxazolamine dihydrochloride, 2- [6- (phenylmethoxy) -1-naphthalenyl] -6-benzoxazolol, 6- (cyclohexylmethoxy) -2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole, 5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenol, 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, 6- (cyclohexylmethoxy) -2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride, 3-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 5- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenol, 4-[[5- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[5- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [3-[[5- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[5- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 5- (1, 1-dimethylethyl) -2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride, 3-[[5- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 5- (5-phenyl-2-benzoxazolyl) -2-naphthalenol, 4-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -5-phenylbenzoxazole hydrochloride, N, N-dimethyl-3-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride, 5-chloro-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole, 5- (5-chloro-2-benzoxazolyl) -2-naphthalenol, 4-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester, [5-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, 5-chloro-2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride, 3-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 2-[[[6- (2-Benzoxazolyl) -2-naphthalenyl] carbonyl] amino] pentanedioic acid diethyl ester, 2-[[[6- (2-Benzoxazolyl) -2-naphthalenyl] carbonyl] amino] pentanedioic acid, 2-amino-6-[[[6- (2-benzoxazolyl) -2-naphthalenyl] carbonyl] amino] hexanoic acid hydrochloride, 2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole, 2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester, 2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid, 2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid methyl ester, 2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid, 2- [4- (2-methoxy-2-oxoethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester, 2- [4- (carboxymethoxy) phenyl] -1H-benzimidazole-1-acetic acid, 5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole, 5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester, 5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid, 5-chloro-2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid methyl ester, 5-chloro-2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid, 2- [4- (carboxymethoxy) phenyl] -5-chloro-1H-benzimidazol-1-acetic acid, 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole, 6- (1H-benzoimidazol-2-yl) -2-naphthalenol, [[6- (1H-benzoimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- (1H-benzoimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid, 2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -1H-benzimidazol-1-acetic acid methyl ester, 2- [6- (carboxymethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid, 2- [6- (3-carboxypropoxy) -2-naphthalenyl] -1H-benzimidazol-1-butanoic acid, 2- [6-[(5-carboxypentyl) oxy] -2-naphthalenyl] -1H-benzimidazole-1-hexanoic acid, [5-[[6- (1H-benzimidazol-2-yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[6- (1H-benzoimidazol-2-yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 4-[[6- (1H-benzoimidazol-2-yl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (1H-benzoimidazol-2-yl) -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [1- (phenylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [1-[(2-chlorophenyl) methyl] -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid, 1- (cyclohexylmethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole, 6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenol, 4-[[6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid, 6-[[6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] hexanoic acid, 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid methyl ester, 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid, 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazole-1-acetic acid methyl ester, 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazole-1-acetic acid, 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazol-1-butanoic acid, 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazole-1-butanoic acid, [5- [2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazol-1-yl] pentyl] propanedioic acid, 2- [6- (phenylmethoxy) -2-naphthalenyl] benzothiazole, 6- (2-benzothiazolyl) -2-naphthalenol, [[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid, 6-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, [3-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester
[12] The compound according to any one of [7] to [11], or a pharmaceutically acceptable salt compound or a solvate thereof, for use as a pharmaceutical composition.
[13] The compound according to any one of [7] to [11], or a pharmaceutically acceptable salt compound or solvate thereof for use as a thrombolytic agent or antithrombotic agent.
[14] The compound according to any one of the above [7] to [11] for producing a pharmaceutical composition for treating thrombosis, or a pharmaceutically acceptable salt compound thereof or a solvate thereof object.
[15] Thrombosis comprising administering to a subject an effective amount of the compound according to any of [7] to [11] above, or a pharmaceutically acceptable salt compound thereof, or a solvate thereof How to treat.
[16] The following compounds for use as thrombolytic agents or antithrombotic agents, or pharmaceutically acceptable salt compounds or solvates thereof:
[4- (2-Benzoxazolyl) phenoxy] acetic acid, [4- (5-chloro-1H-benzoimidazol-2-yl) phenoxy] acetic acid

本明細書に於いて、「低級アルキル基」とは、炭素数１乃至４の直鎖又は分岐状のアルキル基を意味し、具体的には、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−ブチル基及びｔｅｒｔ−ブチル基等を挙げることが出来る。「低級アルキレン基」とは、炭素数１乃至７の直鎖又は分岐状のアルキレン基を意味し、メチレン基、エタンジイル基、プロパンジイル基、ブタンジイル基、ペンタンジイル基、ヘキサンジイル基、ヘプタンジイル基等がこれらに該当する。「低級アルコキシ基」とは、炭素数１乃至４の直鎖又は分岐状のアルコキシ基を意味し、具体的には、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｓｅｃ−ブトキシ基及びｔｅｒｔ−ブトキシ基等を挙げることが出来る。「低級アルコキシカルボニル基」とは、前記の如き炭素数１乃至４の低級アルコキシ基を有するアルコキシカルボニル基であり、例えばメトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、ブトキシカルボニル基等を挙げることが出来る。「低級アシルオキシ基」とは、炭素数１乃至７の直鎖又は分岐状の１−オキソアルキルオキシ基であり、アセチルオキシ基、１−オキソプロポキシ基、２，２−ジメチル−１−オキソプロポキシ基、１−オキソブトキシ基、１−オキソペンチルオキシ基、１−オキソヘキシルオキシ基、１−オキソヘプチルオキシ基等が挙げられる。本発明の前記式（１）で表わされる化合物は、必要に応じて薬理学的に許容し得る塩に変換することも、あるいは生成した塩から遊離酸、エステルに変換することもできる。さらにそれらの化合物を溶媒和物とすることもできる。塩としては、薬理学的に許容し得る酸付加塩、金属塩、アンモニウム塩、有機アミン塩、アミノ酸付加塩が挙げられる。具体的には酸付加塩としては塩酸塩、リン酸塩、硫酸塩等の無機酸塩、酢酸塩、クエン酸塩、メタンスルホン酸塩等の有機酸塩が挙げられ、金属塩としてはナトリウム塩、カリウム塩等のアルカリ金属、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩等が挙げられ、アンモニウム塩としてはアンモニウム等の塩が挙げられ、有機アミン付加塩としてはモルホリン、ピペリジン等の付加塩が挙げられ、アミノ酸付加塩としては、グリシン、リジン等の付加塩が挙げられる。溶媒和物としては、水和物等が挙げられる。エステルとしては、低級アルキルエステル等が挙げられる。
本発明化合物中、［４−（２−ベンゾオキサゾリル）フェノキシ］酢酸、［４−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル）フェノキシ］酢酸は既知の化合物であるが、いずれもその血栓溶解作用、抗血栓作用については何も知られていない。
本発明の前記式（１）で表わされる化合物はいずれも公知の方法により製造することができる。以下に、これらの化合物の代表的製造方法を示す。
単環式オキサゾール誘導体は下記スキームＡに従って得られる。

［ここでＰ，Ｔ１，Ｔ２は一般式（１）に於けるＡ，Ｂ１，Ｂ２自体
又はこれに変換しうる基を、Ｘはハロゲンをそれぞれ意味する。］
炭酸ナトリウム等の炭酸アルカリを含む水性アルコール中で、式（Ａ１）で示されるカルボン酸と式（Ａ２）で示されるα−ハロケトン体を、例えば還流下で、反応させ、得られる式（Ａ３）で示されるエステル体を、酢酸中、窒素供給源、例えば尿素、酢酸アンモニウム等と加熱する事により式（Ａ４）で示されるオキサゾールが得られる（参考文献：ＨｅｔｅｒｏｃｙｃｌｉｃＣｏｍｐｏｕｎｄｓ，Ｗｉｌｅｙ＆Ｓｏｎｓ，Ｉｎｃ．，５，３０２−３２３）。
式（Ａ３）で示されるエステル体は、式（Ａ５）で示される酸ハロゲン化体を、ピリジンやトリアルキルアミン等の存在下で、式（Ａ６）で示されるα−ヒドロキシケトン体と室温〜１００℃で反応させる事によっても得られる。上記置換基Ｐ中に水酸基が存在する場合、常法に従い、例えば、ベンジル基等で予め保護しておき、式（Ａ４）で示されるオキサゾール自体、或いはその置換基Ｔ１，Ｔ２等をそれぞれ別の基に変換した後のオキサゾール体の処で保護基脱離に処することも出来る。
上記の方法は例であり、その他同様の既知の方法を用いることも出来る。
ベンゾオキサゾール誘導体は下記スキームＢに従って得られる。

［ここでＰ，ｔ１，ｔ２，ｔ３は一般式（２３）に於けるＡ，ｂ１，ｂ２，
ｂ３自体又はこれに変換しうる基を、又、Ｒ１は低級アルキル基、
Ｘはハロゲンをそれぞれ意味する。］
ルート１（参考文献：Ｇｕｎｔｅｒ等，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，４６（１３），２８２４−２８２６（１９８１））に従い、トリメチルアルミニウムのトルエン溶液中、式（Ｂ１）で示される２−アミノフェノール体を０℃〜還流温度下で反応せしめた後、式（Ｂ２）で示されるカルボン酸エステル体を加えて数時間還流反応に処するか、或いは、ルート２に従い、式（Ｂ３）で示されるカルボン酸ハロゲン化物と式（Ｂ１）で示される２−アミノフェノール体を、トリエチルアミン等の塩基存在下、ベンゼン、トルエン、キシレン、ジオキサン、１，３−ジメチル−２−イミダゾリジノン等の不活性溶媒中で室温下或いは加熱還流下で反応させる事により、式（Ｂ４）で示されるアミド体を得、このアミド体を、ベンゼン、トルエン、キシレン、１，３−ジメチル−２−イミダゾリジノン等の溶媒中でパラトルエンスルホン酸一水和物（ＰＴＳ）と共に加熱環流しながら生成する水を除去するか、或いはハロゲン化チオニルと共に加熱する事により、式（Ｂ５）で示されるベンゾオキサゾールが得られる。上記置換基Ｐ中に水酸基が存在する場合、常法に従い、例えば、ベンジル基等で予め保護しておき、式（Ｂ５）で示されるベンゾオキサゾール自体、或いはその置換基ｔ１，ｔ２，ｔ３等をそれぞれ別の基、例えば、水酸基をアシルオキシ基等に変換した後のベンゾオキサゾール体の処で保護基脱離に処することが好ましい。
上記の方法は例であり、その他同様の既知の方法を用いることも出来る。
ベンゾイミダゾール誘導体はスキームＣに従って得られる。

［ここでＰ，ｔ１，ｔ２，ｔ３は一般式（２４）に於けるＡ，ｂ１，ｂ２，
ｂ３自体又はこれに変換しうる基を、又、Ｒ１は低級アルキル基
をそれぞれ意味する。］
ルート１（参考文献：Ｇｕｎｔｅｒ等，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，４６，（１３），２８２４−２８２６（１９８１））に従い、トリメチルアルミニウムのトルエン溶液中、式（Ｃ１）で示される１，２−フェニレンジアミン体を０℃〜還流温度下で反応せしめた後、式（Ｃ２）で示されるカルボン酸エステル体を加えて数時間還流反応に処するか、又は、ルート２（参考文献：黄等，ＮａｔｕｒａｌｓｃｉｅｎｃｅＥｄｉｔｉｏｎ，Ｊ．ＷｕｈａｎＵｎｉｖ．，４１，（２），１４２−１４８（１９９５））に従い、式（Ｃ１）で示される１，２−フェニレンジアミン体のアルコール溶液中に式（Ｃ３）で示されるアルデヒドのアルコール溶液と過剰のフェリシアン化カリウム水溶液を同時に滴下し、更に数時間還流させるか、或いはルート３（参考文献：Ｎ．Ｌａｔｉｆ等，ＩｎｄｉａｎＪｏｕｒｎａｌｏｆＣｈｅｍｉｓｔｒｙ，２１Ｂ，８７２−８７４（１９８２））に従い、式（Ｃ４）で示される１−アリール−２−ニトロエテン体と式（Ｃ１）で示される当量の１，２−フェニレンジアミン体をアルコール中で数時間還流反応に処することにより、何れも直接、式（Ｃ５）で示されるベンゾイミダゾールが得られる。上記置換基Ｐ中に水酸基が存在する場合、常法に従い、例えば、ベンジル基等で予め保護しておく事が出来る。式（Ｃ４）で示される化合物は、Ｐ−ＣＨＯで示されるアルデヒドとニトロメタンを触媒量のｎ−ブチルアミンと共に酢酸中で加熱還流反応する事により容易に得られる（参考文献：ＯｒｇａｎｉｃＲｅａｃｔｉｏｎｓ，ＪｏｈｎＷｉｌｅｙ＆Ｓｏｎｓ，Ｉｎｃ．，１５，Ｃｈａｐｔｅｒ２）。
上記の方法は例であり、その他同様の既知の方法を用いることも出来る。
ベンゾチアゾール誘導体は下記スキームＤに従って得られる。

［ここでＰ，ｔ１，ｔ２，ｔ３は一般式（２５）に於けるＡ，ｂ１，ｂ２，
ｂ３自体又はこれに変換しうる基を、又、Ｒ１は低級アルキル基
をそれぞれ意味する。］
前記したＧｕｎｔｅｒ等，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，４６，（１３），２８２４−２８２６（１９８１）に従い、トリメチルアルミニウムのトルエン溶液中、式（Ｄ１）で示される２−アミノチオフェノール体を０℃〜還流温度下で反応せしめた後、式（Ｄ２）で示されるカルボン酸エステル体を加えて数時間還流反応に処する事により、式（Ｄ３）で示されるベンゾチアゾールが得られる。上記置換基Ｐ中に水酸基が存在する場合、常法に従い、例えば、ベンジル基等で予め保護しておき、式（Ｄ３）で示されるベンゾチアゾール自体、或いはその置換基ｔ１，ｔ２，ｔ３等をそれぞれ別の基に変換した後のベンゾチアゾール体の処で保護基脱離に処することも出来る。
上記の方法は例であり、その他同様の既知の方法を用いることも出来る。
上記スキームＡ〜Ｄに於いて表示した各官能基Ｐ，Ｔ１，Ｔ２，ｔ１，ｔ２，ｔ３中の水酸基を他の官能基へ変換する場合、及びスキームＣで示したベンゾイミダゾール誘導体の１位の窒素に他の官能基を導入する場合は、下記スキームＥに従って行われる。

［ここで、Ｚは酸素，硫黄、Ａｒはアリーレン基、ａｌｋは低級アルキ
レン基、Ｘはハロゲンであり、ａ１，ｂ３１，Ｚ２，Ｐは前記の通り
である。］
反応は、ＤＭＦ等の非プロトン性極性溶媒中で、炭酸アルカリ等の塩基の存在下、ａ１−ａｌｋ−Ｘで示されるハロゲン化体と、室温下或いは加温下で反応させる事により行われる。他に無置換アミノ基が存在している場合は予めこのアミノ基にｔ−ブトキシカルボニル基等の保護基を導入しておくことが望ましい。これら保護基の導入及び脱離は、例えば、Ｔ．Ｗ．Ｇｒｅｅｎ，ＰｒｏｔｅｃｔｉｖｅＧｒｏｕｐｓｉｎＯｒｇａｎｉｃＳｙｎｔｈｅｓｉｓ，２ｎｄＥｄ．，ＪｏｈｎＷｉｌｌｅｙ＆Ｓｏｎｓ，Ｉｎｃ．，（１９９１）に方法が記載されており、これらの常法に従って行われる。この変換に位置特異性を必要とする場合は、当量のハロゲン化体を用いて得られた反応混合物をカラムクロマト分離に処して所望の目的物を得たり、或いは下記スキームＦに従って官能基の変換を行う事もできる。

［ここで、Ｚは酸素，硫黄、Ａｒはアリーレン基、ａｌｋは低級アルキ
レン基、ａ１，ｂ３１，Ｚ２は前記の通りである、Ｐｒ１，Ｐｒ２はそ
れぞれ異なった種類の保護基を意味する。］
式（Ｆ１），（Ｆ９）で示される化合物は、スキームＡ〜Ｄに於いて、閉環反応に処する前に、例えば、ＤＭＦやアセトン中、炭酸アルカリ等の存在下で、ベンジルハライド等と反応させる事により得られる。
上記の方法は例であり、その他同様の既知の方法を用いることも出来る。
前記一般式（１）で示される化合物中に存在するエステル基、即ち、低級アルコキシカルボニル基等のカルボン酸への変換は、常法に従い、例えば、アルコール中、水酸化ナトリウム水溶液等と共に、室温下或いは還流下、数時間処理した後、酸析する事により達成される。得られた遊離カルボン酸を当量の水酸化ナトリウム等で溶解し、凍結乾燥する事によって、ナトリウム塩等のアルカリ金属塩として得ることも出来る。前記一般式（１）で示される化合物中に、低級アルコキシカルボニル基が存在する場合、それ自体、本発明の医薬組成物を構成するひとつの形態を成すものであるが、この様にして、本発明のもう一つの形態である対応するカルボキシル基及びその塩に変換する事が出来る。
一般式（１）で示される化合物の塩酸等による酸付加塩も本発明の医薬組成物を構成する一つの形態であり、これらは常法に従い、例えば、対応する遊離体を水或いは水性アルコール、水性アセトンの如き溶媒中で当量の塩酸と処理し、必要なら減圧濃縮する事によって得られる。
上記の方法は例であり、これに限定したものではない。
このようにして製造される一般式（１）で表わされる１，３−アゾール誘導体若しくはそれらの塩化合物あるいはそれらの溶媒和物を有効成分とする医薬は、通常、哺乳類（ヒト患者を含む）に対し、錠剤、カプセル剤、散剤、細粒剤、シロップ剤等の経口投与剤、直腸投与剤、あるいは注射剤として投与することができる。また、本発明化合物は１個の治療剤として、あるいは他の治療剤との混合物として投与することができる。それらは単体で投与しても良いが、一般的には医薬組成物の形態で投与する。それらの製剤は薬理学的、製剤学的に許容し得る添加物を加え、常法により製造することができる。すなわち、経口剤には、通常の賦形剤、滑沢剤、結合剤、崩壊剤、湿潤剤、コーティング剤等の添加剤を用いることができる。経口用液剤は、水性または油性懸濁液、溶液、乳濁液、シロップ、エリキシル等の形態であっても良く、あるいは使用前水または他の適当な溶媒で調製するドライシロップとして供されても良い。前記の液剤は、懸濁化剤、香料、希釈剤あるいは乳化剤のような通常の添加剤を含有できる。直腸内投与する場合は、坐剤として投与することができる。坐剤は、カカオ脂、ラウリン脂、マクロゴール、グリセロゼラチン、ウィテップゾール、ステアリン酸ナトリウムまたはそれらの混合物など、適当な物質を基剤とし、必要に応じて乳化剤、懸濁化剤、保存剤等を加えることができる。注射剤は、水性あるいは用時溶解型剤形を構成し得る注射用蒸留水、生理食塩水、５％ブドウ糖溶液、プロピレングリコール等の溶解剤ないし溶解補助剤、ｐＨ調節剤、等張化剤、安定化剤等の製剤成分が使用される。上記組成物で用いられる賦形剤等の具体例を以下に挙げる。
賦形剤：リン酸水素カルシウム、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、水酸化アルミニウム・マグネシウム、ケイ酸マグネシウム、炭酸カルシウム、炭酸マグネシウム、リン酸水素カルシウム、軽質無水ケイ酸、無水ケイ酸、アビセル、各種デンプン、デキストリン、カルボキシメチルスターチ（ＣＭＳ）、乳糖等。
結合剤：エチルセルロース（ＥＣ）、カルボキシメチルセルロースＮａ（ＣＭＣ−Ｎａ）、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、メチルセルロース（ＭＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、各種デンプン、デキストリン、アルギン酸ナトリウム、ゼラチン、ポリビニルアルコール（ＰＶＡ）、ポリビニルピロリドン（ＰＶＰ）等。
崩壊剤：合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、ＣＭＣ−Ｃａ、ＣＭＣ、アビセル、Ｌ−ＨＰＣ、ＨＰＭＣ、ＭＣ、各種デンプン、ＣＭＳ、ヒドロキシプロピルスターチ（ＣＰＳ）等。
固化防止剤：軽質無水ケイ酸、合成ケイ酸アルミニウム等。
滑沢剤：合成ケイ酸アルミニウム、無水ケイ酸、タルク、アビセル等。
矯味剤：マンニトール、クエン酸、クエン酸Ｎａ、砂糖等。
乳化剤：ゼラチン、クエン酸、クエン酸Ｎａ、ポリオキシエチレン硬化ヒマシ油、マクロゴール（ＰＥＧ）、プロピレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、プロピレングリコール、ラウリル硫酸Ｎａ、リン脂質等。
安定化剤：亜硫酸水素ナトリウム、ポリオキシエチレン硬化ヒマシ油、ＰＥＧ、プロピレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、プロピレングリコール、ラウリル硫酸Ｎａ、各種天然・合成シクロデキストリン、リン脂質等。
吸収促進剤：ポリオキシエチレン硬化ヒマシ油、ＰＥＧ、プロピレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、プロピレングリコール、ラウリル硫酸Ｎａ、各種天然・合成シクロデキストリン、中鎖脂肪酸トリグリセリド等。
溶解補助剤：エタノール、ポリオキシエチレン硬化ヒマシ油、ＰＥＧ、プロピレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、プロピレングリコール、ラウリル硫酸Ｎａ、各種天然・合成シクロデキストリン等。
懸濁化剤：ＣＭＣ−Ｎａ、ＨＰＭＣ、ＭＣ、ＨＰＣ、アルギン酸ナトリウム、ゼラチン、プロピレングリコール、ラウリル硫酸Ｎａ等。
被覆剤：ＥＣ、ケイ酸マグネシウム、タルク、酸化チタン、炭酸カルシウム、トリアセチン、カルボキシメチルエチルセルロース（ＣＭＥＣ）、酢酸フタル酸セルロース（ＣＡＰ）、ＨＰＭＣ、ヒドロキシプロピルメチルセルロースフタレート（ＨＰＭＣＰ）、ＭＣ、ＨＰＣ、アルギン酸ナトリウム、ポリビニルアセタールジエチルアミノアセテート、ポリアクリル酸Ｎａ、各種アクリル酸メタクリル酸誘導体のコポリマー、ポリグリコール酸Ｎａ等。
着色剤：酸化チタン、タール色素、カラメル等。
本発明化合物をヒトに投与する場合の投与量は、患者の年齢、症状等により異なるが、通常成人の場合、経口剤あるいは直腸内投与剤で１ｍｇ〜１０００ｍｇ／人／日程度、注射剤で０．１〜５００ｍｇ／人／日程度である。しかし、これらの数値はあくまでも例示であり、投与量は患者の症状等種々の条件によって適宜増減される。In the present specification, the “lower alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms, and specifically includes a methyl group, an ethyl group, a propyl group, an isopropyl group, A butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, etc. can be mentioned. “Lower alkylene group” means a linear or branched alkylene group having 1 to 7 carbon atoms, such as methylene group, ethanediyl group, propanediyl group, butanediyl group, pentanediyl group, hexanediyl group, heptanediyl group, etc. It corresponds to these. The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, Examples thereof include a sec-butoxy group and a tert-butoxy group. The “lower alkoxycarbonyl group” is an alkoxycarbonyl group having a lower alkoxy group having 1 to 4 carbon atoms as described above, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group. I can do it. The “lower acyloxy group” is a linear or branched 1-oxoalkyloxy group having 1 to 7 carbon atoms, and includes an acetyloxy group, a 1-oxopropoxy group, and a 2,2-dimethyl-1-oxopropoxy group. 1-oxobutoxy group, 1-oxopentyloxy group, 1-oxohexyloxy group, 1-oxoheptyloxy group and the like. The compound represented by the above formula (1) of the present invention can be converted into a pharmacologically acceptable salt as necessary, or the formed salt can be converted into a free acid or an ester. Further, these compounds can be solvated. Examples of the salt include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine salts, and amino acid addition salts. Specific examples of acid addition salts include inorganic acid salts such as hydrochloride, phosphate, and sulfate, and organic acid salts such as acetate, citrate, and methanesulfonate, and metal salts include sodium salt. Alkali metals such as potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and the like. Examples of ammonium salts include salts such as ammonium. Examples of organic amine addition salts include morpholine and piperidine. And amino acid addition salts include addition salts such as glycine and lysine. Examples of solvates include hydrates. Examples of esters include lower alkyl esters.
Among the compounds of the present invention, [4- (2-benzoxazolyl) phenoxy] acetic acid and [4- (5-chloro-1H-benzoimidazol-2-yl) phenoxy] acetic acid are known compounds. Nothing is known about its thrombolytic and antithrombotic effects.
Any of the compounds represented by the formula (1) of the present invention can be produced by a known method. Below, the typical manufacturing method of these compounds is shown.
Monocyclic oxazole derivatives are obtained according to Scheme A below.

[Wherein P, T1 and T2 represent A, B1 and B2 themselves in the general formula (1) or groups which can be converted to this, and X represents halogen, respectively. ]
In an aqueous alcohol containing an alkali carbonate such as sodium carbonate, the carboxylic acid represented by the formula (A1) and the α-haloketone body represented by the formula (A2) are reacted, for example, under reflux to obtain the formula (A3) The oxazole represented by the formula (A4) is obtained by heating the ester represented by formula (A4) in acetic acid with a nitrogen source such as urea or ammonium acetate (reference: Heterocyclic Compounds, Wiley & Sons, Inc.,). 5 , 302-323).
The ester form represented by the formula (A3) is obtained by reacting the acid halide represented by the formula (A5) with the α-hydroxyketone form represented by the formula (A6) in the presence of pyridine, trialkylamine, etc. It can also be obtained by reacting at 100 ° C. When a hydroxyl group is present in the substituent P, the oxazole itself represented by the formula (A4), or the substituents T1, T2, etc., are separately protected according to a conventional method, for example, with a benzyl group. It can also be subjected to elimination of the protecting group at the oxazole form after conversion to a group.
The above method is an example, and other similar known methods can also be used.
The benzoxazole derivative is obtained according to Scheme B below.

[Where P, t1, t2, t3 are A, b1, b2,
b3 itself or a group that can be converted to this, R1 is a lower alkyl group,
X means halogen. ]
According to route 1 (reference: Gunter et al., J. Org. Chem., 46 (13), 2824-2826 (1981)), a 2-aminophenol compound represented by the formula (B1) in a toluene solution of trimethylaluminum is obtained. After reacting at 0 ° C. to reflux temperature, the carboxylic acid ester represented by formula (B2) is added and subjected to reflux reaction for several hours, or according to route 2, the carboxylic acid halogen represented by formula (B3) And the 2-aminophenol compound represented by formula (B1) in the presence of a base such as triethylamine in an inert solvent such as benzene, toluene, xylene, dioxane, 1,3-dimethyl-2-imidazolidinone at room temperature Or by heating under reflux to obtain an amide compound represented by the formula (B4), which is converted to benzene, toluene, Remove water generated by heating and refluxing with paratoluenesulfonic acid monohydrate (PTS) in a solvent such as silene or 1,3-dimethyl-2-imidazolidinone, or heating with thionyl halide. Thus, a benzoxazole represented by the formula (B5) is obtained. When a hydroxyl group is present in the substituent P, the benzoxazole itself represented by the formula (B5), or the substituents t1, t2, t3, etc., is protected in advance according to a conventional method, for example, with a benzyl group. It is preferable to remove the protecting group at the position of the benzoxazole after each different group, for example, a hydroxyl group is converted to an acyloxy group or the like.
The above method is an example, and other similar known methods can also be used.
The benzimidazole derivative is obtained according to Scheme C.

[Where P, t1, t2, t3 are A, b1, b2,
b3 itself or a group that can be converted to this, and R1 means a lower alkyl group. ]
According to Route 1 (reference: Gunter et al., J. Org. Chem., 46 , (13), 2824-2826 (1981)), 1,2-phenylene represented by the formula (C1) in a toluene solution of trimethylaluminum. After reacting the diamine compound at 0 ° C. to reflux temperature, the carboxylic acid ester compound represented by the formula (C2) is added and subjected to reflux reaction for several hours, or route 2 (reference: Yellow et al., Natural science). In accordance with Edition, J. Wuhan Univ., 41 , (2), 142-148 (1995)), an aldehyde represented by formula (C3) in an alcohol solution of a 1,2-phenylenediamine compound represented by formula (C1) Of alcohol and excess potassium ferricyanide solution at the same time and reflux for several hours, or Route 3 (Reference: N.Latif like, Indian Journal of Chemistry, 21B, 872-874 (1982)) in accordance with, represented by 1-aryl-2-nitroethene body represented by the formula formula (C4) (C1) By subjecting an equivalent 1,2-phenylenediamine compound to a reflux reaction in alcohol for several hours, any of the benzimidazoles represented by the formula (C5) can be obtained directly. When a hydroxyl group is present in the substituent P, it can be protected in advance by, for example, a benzyl group according to a conventional method. The compound represented by the formula (C4) can be easily obtained by heating and refluxing an aldehyde represented by P-CHO and nitromethane together with a catalytic amount of n-butylamine in acetic acid (reference: Organic Reactions, John Wiley & Sons, Inc., 15 , Chapter 2).
The above method is an example, and other similar known methods can also be used.
The benzothiazole derivative is obtained according to Scheme D below.

[Where P, t1, t2, t3 are A, b1, b2,
b3 itself or a group that can be converted to this, and R1 means a lower alkyl group. ]
Gunter et al. Org. Chem. , 46 , (13), 2824-2826 (1981), the 2-aminothiophenol compound represented by the formula (D1) is reacted in a toluene solution of trimethylaluminum at 0 ° C. to reflux temperature, and then the formula ( A benzothiazole represented by the formula (D3) is obtained by adding a carboxylic acid ester represented by D2) and subjecting it to a reflux reaction for several hours. When a hydroxyl group is present in the substituent P, the benzothiazole itself represented by the formula (D3) or the substituents t1, t2, t3, etc. is protected according to a conventional method, for example, with a benzyl group. It can also be subjected to elimination of the protecting group at the benzothiazole form after conversion to a different group.
The above method is an example, and other similar known methods can also be used.
When the hydroxyl group in each of the functional groups P, T1, T2, t1, t2, and t3 displayed in the above schemes A to D is converted to another functional group, and at the 1-position of the benzimidazole derivative shown in the scheme C When introducing another functional group into nitrogen, it is carried out according to the following scheme E.

[Wherein Z is oxygen, sulfur, Ar is an arylene group, alk is a lower alkylene group, X is a halogen, and a1, b31, Z2, and P are as described above. ]
The reaction is carried out by reacting with a halide represented by a1-alk-X at room temperature or under heating in an aprotic polar solvent such as DMF in the presence of a base such as alkali carbonate. In addition, when an unsubstituted amino group is present, it is desirable to introduce a protective group such as a t-butoxycarbonyl group into this amino group in advance. The introduction and removal of these protecting groups are described in, for example, T.W. W. Green, Protective Groups in Organic Synthesis, 2nd Ed. , John Willy & Sons, Inc. , (1991), and is carried out according to these conventional methods. When regiospecificity is required for this conversion, the reaction mixture obtained using an equivalent amount of the halogenated product is subjected to column chromatography separation to obtain a desired target, or functional group conversion is performed according to Scheme F below. Can also be done.

[Wherein Z is oxygen, sulfur, Ar is an arylene group, alk is a lower alkylene group, a1, b31, and Z2 are as described above, and Pr1 and Pr2 are different types of protecting groups, respectively. To do. ]
In the schemes A to D, the compounds represented by the formulas (F1) and (F9) are reacted with benzyl halide or the like in the presence of an alkali carbonate or the like, for example, in DMF or acetone in the schemes A to D. It is obtained by things.
The above method is an example, and other similar known methods can also be used.
Conversion to an ester group present in the compound represented by the general formula (1), that is, a carboxylic acid such as a lower alkoxycarbonyl group, is carried out according to a conventional method, for example, in an alcohol, an aqueous sodium hydroxide solution or the like at room temperature. Alternatively, it can be achieved by treating for several hours under reflux, followed by acid precipitation. The obtained free carboxylic acid can be dissolved in an equivalent amount of sodium hydroxide and freeze-dried to obtain an alkali metal salt such as a sodium salt. When a lower alkoxycarbonyl group is present in the compound represented by the general formula (1), the compound itself constitutes one form constituting the pharmaceutical composition of the present invention. It can be converted to the corresponding carboxyl group and its salt which is another form of the invention.
Acid addition salts of the compound represented by the general formula (1) with hydrochloric acid or the like are also one form constituting the pharmaceutical composition of the present invention, and these are prepared according to a conventional method, for example, the corresponding free form is water or aqueous alcohol, It can be obtained by treating with an equivalent amount of hydrochloric acid in a solvent such as aqueous acetone and concentrating under reduced pressure if necessary.
The above method is an example, and the present invention is not limited to this.
A medicament containing the 1,3-azole derivative represented by the general formula (1) or a salt compound thereof or a solvate thereof thus produced as an active ingredient is usually used in mammals (including human patients). On the other hand, it can be administered as oral preparations such as tablets, capsules, powders, fine granules, syrups, rectal preparations, or injections. The compound of the present invention can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by a conventional method with addition of pharmacologically and pharmaceutically acceptable additives. That is, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, and coating agents can be used for the oral preparations. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be provided as dry syrups prepared in water or other suitable solvent prior to use. . The liquid preparation can contain conventional additives such as suspending agents, perfumes, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. The suppository is based on a suitable substance such as cacao butter, lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or a mixture thereof, and if necessary an emulsifier, suspending agent, preservative. Etc. can be added. Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used. Specific examples of excipients used in the above composition are listed below.
Excipients: calcium hydrogen phosphate, synthetic aluminum silicate, magnesium metasilicate aluminate, aluminum hydroxide / magnesium, magnesium silicate, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, light anhydrous silicic acid, anhydrous silicic acid, Avicel, various starches, dextrin, carboxymethyl starch (CMS), lactose, etc.
Binder: Ethylcellulose (EC), carboxymethylcellulose Na (CMC-Na), low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxypropylcellulose (HPC), various starches , Dextrin, sodium alginate, gelatin, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and the like.
Disintegrants: synthetic aluminum silicate, magnesium aluminate metasilicate, CMC-Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CMS, hydroxypropyl starch (CPS) and the like.
Anti-caking agent: light anhydrous silicic acid, synthetic aluminum silicate, etc.
Lubricant: Synthetic aluminum silicate, silicic anhydride, talc, Avicel, etc.
Flavoring agents: mannitol, citric acid, sodium citrate, sugar and the like.
Emulsifiers: gelatin, citric acid, sodium citrate, polyoxyethylene hydrogenated castor oil, macrogol (PEG), propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, phospholipid and the like.
Stabilizer: Sodium bisulfite, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, phospholipids, and the like.
Absorption accelerators: polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, medium chain fatty acid triglycerides, and the like.
Solubilizing agents: ethanol, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, and the like.
Suspending agent: CMC-Na, HPMC, MC, HPC, sodium alginate, gelatin, propylene glycol, sodium lauryl sulfate and the like.
Coating agent: EC, magnesium silicate, talc, titanium oxide, calcium carbonate, triacetin, carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), HPMC, hydroxypropyl methylcellulose phthalate (HPMCP), MC, HPC, sodium alginate , Polyvinyl acetal diethylaminoacetate, polyacrylic acid Na, copolymers of various acrylic acid methacrylic acid derivatives, polyglycolic acid Na and the like.
Colorant: Titanium oxide, tar pigment, caramel, etc.
The dosage when the compound of the present invention is administered to humans varies depending on the age, symptoms, etc. of the patient, but in the case of an adult, it is usually about 1 mg to 1000 mg / person / day for oral or rectal administration, and 0 for injection. About 1 to 500 mg / person / day. However, these numerical values are merely examples, and the dosage is appropriately increased or decreased depending on various conditions such as patient symptoms.

次に本発明の化合物の製造、および試験例を挙げて本発明を具体的に説明するが、本発明はこれらの例によって限定されるものではない。 Next, although manufacture of the compound of this invention and a test example are given and this invention is demonstrated concretely, this invention is not limited by these examples.

４−（２−ナフタレニル）−２−オキサゾールプロパン酸メチルエステル（化合物１）、４−（２−ナフタレニル）−２−オキサゾールプロパン酸（化合物２）、４−（２−ナフタレニル）−２−オキサゾールプロパン酸ナトリウム塩（化合物３）の製造：
エタノール（３０ｍＬ）中、コハク酸モノメチル（１．３２ｇ）に水（１０ｍＬ）、炭酸ナトリウム（０．５３ｇ）を加え、還流下で２−ブロモアセチルナフタレン（２．４９ｇ）のエタノール（２０ｍＬ）溶液を滴下し、同温で４時間反応した後、冷却し、析出物をろ取した。得られた結晶に酢酸（１５ｍＬ）、尿素（５．４０ｇ）を加え、還流下で５時間反応した。反応液に水（３００ｍＬ）を加え、晶析した後、ろ取し粗生成物を得た。粗生成物をシリカゲルカラム（クロロホルム）に付し化合物１（１５８ｍｇ，Ｙ＝５．６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．８８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．１０（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．６４（３Ｈ，ｓ）７．４４−７．５９（２Ｈ，ｍ）７．９２−８．００（４Ｈ，ｍ）８．２９（１Ｈ，ｓ）８．６１（１Ｈ，ｓ）
メタノール（２５ｍＬ）中、化合物１（１２７ｍｇ）に、１Ｎ水酸化ナトリウム水溶液（１．３５ｍＬ）を加え、還流下で２時間反応した。反応液を減圧濃縮し、残渣を水（１５ｍＬ）に溶解した後、活性炭（２０ｍｇ）を加えろ過した。ろ液に１Ｎ塩酸（１．３５ｍＬ）を加え酸析した。析出した結晶をろ取した後、乾燥し化合物２（８８ｍｇ，Ｙ＝７３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．７９（２Ｈ，ｔ，Ｊ＝５Ｈｚ）３．０６（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．４３−７．５９（２Ｈ，ｍ）７．９２（４Ｈ，ｓ）８．０３（１Ｈ，ｓ）８．６０（１Ｈ，ｓ）１１．４１−１３．４６（１Ｈ，ｂｒ）
化合物２（５３．５ｍｇ）、０．１Ｎ水酸化ナトリウム水溶液（３ｍＬ）を水（２５ｍＬ）に溶解し、ろ過した後、ろ液を凍結乾燥し化合物３を得た。4- (2-Naphthalenyl) -2-oxazolepropanoic acid methyl ester (Compound 1), 4- (2-Naphthalenyl) -2-oxazolepropanoic acid (Compound 2), 4- (2-Naphthalenyl) -2-oxazolepropane Preparation of acid sodium salt (compound 3):
Water (10 mL) and sodium carbonate (0.53 g) were added to monomethyl succinate (1.32 g) in ethanol (30 mL), and a solution of 2-bromoacetylnaphthalene (2.49 g) in ethanol (20 mL) was added under reflux. The solution was added dropwise, reacted at the same temperature for 4 hours, cooled, and the precipitate was collected by filtration. Acetic acid (15 mL) and urea (5.40 g) were added to the obtained crystals and reacted under reflux for 5 hours. Water (300 mL) was added to the reaction solution and crystallized, followed by filtration to obtain a crude product. The crude product was applied to a silica gel column (chloroform) to obtain Compound 1 (158 mg, Y = 5.6%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.88 (2H, t, J = 6 Hz) 3.10 (2H, t, J = 6 Hz) 3.64 (3H, s) 7.44-7.59 (2H, m) 7.92- 8.00 (4H, m) 8.29 (1H, s) 8.61 (1H, s)
1N sodium hydroxide aqueous solution (1.35 mL) was added to compound 1 (127 mg) in methanol (25 mL), and reacted under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (15 mL), and then activated carbon (20 mg) was added and filtered. 1N hydrochloric acid (1.35 mL) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 2 (88 mg, Y = 73%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.79 (2H, t, J = 5 Hz) 3.06 (2H, t, J = 5 Hz) 7.43-7.59 (2H, m) 7.92 (4H, s) 8.03 ( 1H, s) 8.60 (1H, s) 11.41-13.46 (1H, br)
Compound 2 (53.5 mg) and 0.1N aqueous sodium hydroxide solution (3 mL) were dissolved in water (25 mL) and filtered, and then the filtrate was lyophilized to obtain compound 3.

６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレンカルボン酸メチルエステル（化合物４）、６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレンカルボン酸（化合物５）、６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレンカルボン酸ナトリウム塩（化合物６）の製造：
トルエン（１５ｍ）中、ナフタレン−２，６−ジカルボン酸モノメチルエステル（２．５３ｇ）に塩化チオニル（１．５５ｇ）、ＤＭＦ（１滴）を加え、還流下で２時間反応した後、減圧濃縮し酸クロリド体を得た。酸クロリド体にピリジン（１５ｍＬ）、ベンゾイン（２．１２ｇ）を加え、室温下２０時間反応した後、メタノール（７５ｍＬ）を投入し、晶析した。析出物をろ取した後、乾燥し中間体（３．６７ｇ）を得た。
中間体（３．２７ｇ）に酢酸（６０ｍＬ）、酢酸アンモニウム（５．９４ｇ）を加え、還流下で１時間反応した。反応液に水（６０ｍＬ）を加え晶析した後、ろ取し粗生成物を得た。粗生成物をトルエン（１５ｍＬ）に加熱溶解した後、メタノール（１５０ｍＬ）を加え晶析した。析出した結晶をろ取した後、乾燥し化合物４（２．６２ｇ，Ｙ＝７３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．９５（３Ｈ，ｓ）７．４８−７．６８（１０Ｈ，ｍ）８．１３−８．３０（４Ｈ，ｍ）８．７１（１Ｈ，ｓ）８．７８（１Ｈ，ｓ）
メタノール（５０ｍＬ）中、化合物４（１．０１ｇ）に、１Ｎ水酸化ナトリウム水溶液（７．５ｍＬ）を加え、還流下で６時間反応した。反応液を減圧濃縮し、残渣を水（７５ｍＬ）に溶解した後、活性炭（０．１ｇ）を加えろ過した。ろ液に１Ｎ塩酸（７．５ｍＬ）を加え酸析した。析出した結晶をろ取した後、乾燥し化合物５（０．８７ｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．５３−７．６８（１０Ｈ，ｍ）７．９６−８．２８（４Ｈ，ｍ）８．６８（１Ｈ，ｓ）８．７７（１Ｈ，ｓ）１２．４３−１３．８７（１Ｈ，ｂｒ）
化合物５（３９１ｍｇ）、０．１Ｎ水酸化ナトリウム水溶液（１．５ｍＬ）を水（１００ｍＬ）に加温溶解し、ろ過した後、ろ液を凍結乾燥し化合物６を得た。6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid methyl ester (compound 4), 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid (compound 5), Preparation of 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid sodium salt (Compound 6):
Thionyl chloride (1.55 g) and DMF (1 drop) were added to naphthalene-2,6-dicarboxylic acid monomethyl ester (2.53 g) in toluene (15 m), reacted for 2 hours under reflux, and then concentrated under reduced pressure. An acid chloride form was obtained. After adding pyridine (15 mL) and benzoin (2.12 g) to the acid chloride form and reacting at room temperature for 20 hours, methanol (75 mL) was added and crystallized. The precipitate was collected by filtration and dried to obtain an intermediate (3.67 g).
Acetic acid (60 mL) and ammonium acetate (5.94 g) were added to the intermediate (3.27 g), and reacted under reflux for 1 hour. Water (60 mL) was added to the reaction solution for crystallization, followed by filtration to obtain a crude product. The crude product was dissolved in toluene (15 mL) with heating, and methanol (150 mL) was added for crystallization. The precipitated crystals were collected by filtration and dried to obtain Compound 4 (2.62 g, Y = 73%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.95 (3H, s) 7.48-7.68 (10H, m) 8.13-8.30 (4H, m) 8.71 (1H, s) 8.78 (1H, s)
A 1N aqueous sodium hydroxide solution (7.5 mL) was added to compound 4 (1.01 g) in methanol (50 mL), and reacted under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (75 mL), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (7.5 mL) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain compound 5 (0.87 g, Y = 89%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.53-7.68 (10H, m) 7.96-8.28 (4H, m) 8.68 (1H, s) 8.77 (1H, s) 12.43-13.87 ( 1H, br)
Compound 5 (391 mg) and 0.1N aqueous sodium hydroxide solution (1.5 mL) were dissolved in water (100 mL) by heating and filtered, and then the filtrate was lyophilized to obtain compound 6.

４，５−ジフェニル−２−［６−（フェニルメトキシ）−２−ナフタレニル］オキサゾール（化合物７）、６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレノール（化合物８）、６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレノールナトリウム塩（化合物９）、［［６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレニル］オキシ］酢酸メチルエステル（化合物１０）、［［６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレニル］オキシ］酢酸（化合物１１）、［［６−（４，５−ジフェニル−２−オキサゾリル）−２−ナフタレニル］オキシ］酢酸ナトリウム塩（化合物１２）の製造：
トルエン（１５ｍ）中、６−ベンジルオキシ−２−ナフトエ酸（３．０６ｇ）に塩化チオニル（１．５５ｇ）、ＤＭＦ（１滴）を加え、還流下で３時間反応した後、減圧濃縮し酸クロリド体を得た。酸クロリド体にピリジン（１５ｍＬ）、ベンゾイン（２．１２ｇ）を加え、室温下２０時間反応した後、メタノール（７５ｍＬ）を投入した。析出物をろ取した後、乾燥し中間体（３．９８ｇ）を得た。
中間体（３．６４ｇ）に酢酸（６０ｍＬ）、酢酸アンモニウム（５．９４ｇ）を加え還流下で１時間反応した後、反応液を冷却した。析出した結晶をろ取し、水洗した後、乾燥し化合物７（３．１ｇ，Ｙ＝７５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２８（２Ｈ，ｓ）７．３０−７．８８（１７Ｈ，ｍ）８．０２−８．１２（３Ｈ，ｍ）８．６４（１Ｈ，ｓ）
トルエン（１５０ｍＬ）に化合物７（２．９５ｇ）を加温溶解した後、エタノール（１５０ｍＬ）、５％パラジウム炭素（１．５ｇ）を加え、水素雰囲気下、室温で４日間反応した。反応液をろ過し、ろ液を減圧濃縮し粗生成物を得た。粗生成物をトルエン（３０ｍＬ）で再結晶し化合物８（１．８３ｇ，Ｙ＝７８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．１３−７．２５（２Ｈ，ｍ）７．４６−８．１６（１３Ｈ，ｍ）８．５８（１Ｈ，ｓ）１０．０６（１Ｈ，ｂｒｓ）
化合物８（３６３ｍｇ）、１Ｎ水酸化ナトリウム水溶液（１ｍＬ）、水（５０ｍＬ）をメタノール（２５０ｍＬ）に加温溶解した後、減圧濃縮し化合物９を得た。
ＤＭＦ（１０ｍＬ）中、化合物８（１．０９ｇ）に炭酸カリウム（８２９ｍｇ）、ブロモ酢酸メチル（５２７ｍｇ）を加え、室温下２０時間反応した。反応液に水（１００ｍＬ）を加え晶析した後、ろ取し粗生成物を得た。粗生成物をメタノール（４００ｍＬ）で再結晶し化合物１０（０．８ｇ，Ｙ＝６１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．７６（３Ｈ，ｓ）４．９８（２Ｈ，ｓ）７．２７−７．４５（１２Ｈ，ｍ）８．０２−８．１２（３Ｈ，ｍ）８．６５（１Ｈ，ｓ）
メタノール（５０ｍＬ）中、化合物１０（４３５ｍｇ）に１Ｎ水酸化ナトリウム水溶液（３ｍＬ）を加え、還流下で１時間反応した。反応液を減圧濃縮し、残渣を水（１００ｍＬ）に加温溶解した後、活性炭（０．１ｇ）を加えろ過した。ろ液に１Ｎ塩酸（３ｍＬ）を加え酸析した。析出した結晶をろ取した後、乾燥し化合物１１（３３８ｍｇ，Ｙ＝８０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８５（２Ｈ，ｓ）７．２５−７．７４（１２Ｈ，ｍ）８．０２−８．１０（３Ｈ，ｍ）８．６４（１Ｈ，ｓ）
化合物１１（８４．３ｍｇ）、０．１Ｎ水酸化ナトリウム水溶液（３ｍＬ）を水（５０ｍＬ）に溶解し、ろ過した後、ろ液を凍結乾燥し化合物１２を得た。4,5-diphenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] oxazole (Compound 7), 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenol (Compound 8), 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenol sodium salt (compound 9), [[6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester (compound 10), [[6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenyl] oxy] acetic acid (compound 11), [[6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenyl Preparation of oxy] acetic acid sodium salt (compound 12):
Thionyl chloride (1.55 g) and DMF (1 drop) were added to 6-benzyloxy-2-naphthoic acid (3.06 g) in toluene (15 m), reacted under reflux for 3 hours, and concentrated under reduced pressure. A chloride body was obtained. After adding pyridine (15 mL) and benzoin (2.12 g) to the acid chloride form and reacting at room temperature for 20 hours, methanol (75 mL) was added. The precipitate was collected by filtration and dried to obtain an intermediate (3.98 g).
Acetic acid (60 mL) and ammonium acetate (5.94 g) were added to the intermediate (3.64 g) and reacted under reflux for 1 hour, and then the reaction solution was cooled. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 7 (3.1 g, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 7.30-7.88 (17H, m) 8.02-8.12 (3H, m) 8.64 (1H, s)
Compound 7 (2.95 g) was dissolved by heating in toluene (150 mL), ethanol (150 mL) and 5% palladium carbon (1.5 g) were added, and the mixture was reacted at room temperature in a hydrogen atmosphere for 4 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from toluene (30 mL) to obtain Compound 8 (1.83 g, Y = 78%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.13-7.25 (2H, m) 7.46-8.16 (13H, m) 8.58 (1H, s) 10.06 (1H, brs)
Compound 8 (363 mg), 1N aqueous sodium hydroxide solution (1 mL), and water (50 mL) were dissolved in methanol (250 mL) by heating, and then concentrated under reduced pressure to obtain compound 9.
In DMF (10 mL), potassium carbonate (829 mg) and methyl bromoacetate (527 mg) were added to compound 8 (1.09 g) and reacted at room temperature for 20 hours. Water (100 mL) was added to the reaction solution for crystallization, followed by filtration to obtain a crude product. The crude product was recrystallized from methanol (400 mL) to obtain Compound 10 (0.8 g, Y = 61%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.76 (3H, s) 4.98 (2H, s) 7.27-7.45 (12H, m) 8.02-8.12 (3H, m) 8.65 (1H, s)
A 1N aqueous sodium hydroxide solution (3 mL) was added to compound 10 (435 mg) in methanol (50 mL) and reacted under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (100 mL) with heating, and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (3 mL) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to give compound 11 (338 mg, Y = 80%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.85 (2H, s) 7.25-7.74 (12H, m) 8.02-8.10 (3H, m) 8.64 (1H, s)
Compound 11 (84.3 mg) and 0.1N aqueous sodium hydroxide solution (3 mL) were dissolved in water (50 mL) and filtered, and then the filtrate was lyophilized to obtain Compound 12.

［４−（２−ベンゾオキサゾリル）フェノキシ］酢酸メチルエステル（化合物１３）、［４−（２−ベンゾオキサゾリル）フェノキシ］酢酸（化合物１４）、［４−（２−ベンゾオキサゾリル）フェノキシ］酢酸ナトリウム塩（化合物１５）の製造：
窒素気流中、氷水冷却下でトルエン（１００ｍＬ）に１５％トリメチルアルミニウム・トルエン溶液（１１ｍＬ）、２−アミノフェノール（２．２ｇ）を加え、還流下で２０分間反応した後、４−ベンジルオキシ安息香酸エチル（３．０ｇ）を加えて還流下で４時間反応した。反応液にメタノール（３０ｍＬ）を加えて一夜撹拌後濃縮した。残渣に水（４０ｍＬ）、トルエン（３０ｍＬ）を加えて３０分還流後、結晶をろ取した。得られた結晶から酢酸エチルで目的化合物を抽出し、５％塩酸水溶液、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をトルエンから再結晶して中間体のアミド化合物（３．０ｇ，Ｙ＝８０％）を得た。
トルエン（１３０ｍＬ）にアミド化合物（２．６ｇ）、塩化チオニル（６ｍＬ）、ＤＭＦ（１滴）を加えて還流下で６時間反応した。反応液を減圧濃縮し、残渣をシリカゲルカラム（クロロホルム）で精製して２−［４−（フェニルメトキシ）フェニル］ベンゾオキサゾール（１．７ｇ，Ｙ＝６９％）を得た。
２−［４−（フェニルメトキシ）フェニル］ベンゾオキサゾール（１．４ｇ）にメタノール（１４０ｍＬ）、５％パラジウム炭素（１ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して４−（２−ベンゾオキサゾリル）フェノール（８２０ｍｇ，Ｙ＝８４％）を得た。
４−（２−ベンゾオキサゾリル）フェノール（０．５ｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（１．０ｇ）、ブロモ酢酸メチル（０．５２ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物１３（７５０ｍｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．７５（３Ｈ，ｓ）４．９６（２Ｈ，ｓ）７．１０−８．２４（８Ｈ，ｍ）
化合物１３（４４０ｍｇ）をメタノール（５０ｍＬ）に懸濁し、２％水酸化ナトリウム水溶液（５ｍＬ）を加えて約５０℃で３０分間反応した。反応液を減圧濃縮し、残渣に水（８０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１４（４１０ｍｇ，Ｙ＝９８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８４（２Ｈ，ｓ）７．０８−８．２４（８Ｈ，ｍ）
化合物１４（１０１ｍｇ）を水（５０ｍＬ）に懸濁し、１％水酸化ナトリウム（１．６ｍＬ）を加えて加熱溶解した後、ろ過し、ろ液を凍結乾燥して化合物１５（１１１ｍｇ，Ｙ＝１０２％）を得た。[4- (2-Benzoxazolyl) phenoxy] acetic acid methyl ester (Compound 13), [4- (2-Benzoxazolyl) phenoxy] acetic acid (Compound 14), [4- (2-Benzoxazolyl) ) Preparation of phenoxy] acetic acid sodium salt (compound 15):
In a nitrogen stream, 15% trimethylaluminum / toluene solution (11 mL) and 2-aminophenol (2.2 g) were added to toluene (100 mL) under cooling with ice water, reacted for 20 minutes under reflux, and then 4-benzyloxybenzoate. Ethyl acid (3.0 g) was added and reacted under reflux for 4 hours. Methanol (30 mL) was added to the reaction mixture, and the mixture was stirred overnight and concentrated. Water (40 mL) and toluene (30 mL) were added to the residue, and after refluxing for 30 minutes, the crystals were collected by filtration. The target compound was extracted from the obtained crystals with ethyl acetate, and washed successively with 5% aqueous hydrochloric acid and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from toluene to obtain an intermediate amide compound (3.0 g, Y = 80%).
An amide compound (2.6 g), thionyl chloride (6 mL), and DMF (1 drop) were added to toluene (130 mL), and reacted under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain 2- [4- (phenylmethoxy) phenyl] benzoxazole (1.7 g, Y = 69%).
Methanol (140 mL) and 5% palladium carbon (1 g) were added to 2- [4- (phenylmethoxy) phenyl] benzoxazole (1.4 g) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to give 4- (2-benzoxazolyl) phenol (820 mg, Y = 84%).
4- (2-Benzoxazolyl) phenol (0.5 g) was dissolved in DMF (10 mL), potassium carbonate (1.0 g) and methyl bromoacetate (0.52 g) were added, and the mixture was reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 13 (750 mg, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.75 (3H, s) 4.96 (2H, s) 7.10-8.24 (8H, m)
Compound 13 (440 mg) was suspended in methanol (50 mL), 2% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. for 30 min. The reaction solution was concentrated under reduced pressure, and water (80 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 14 (410 mg, Y = 98%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.84 (2H, s) 7.08-8.24 (8H, m)
Compound 14 (101 mg) is suspended in water (50 mL), 1% sodium hydroxide (1.6 mL) is added and dissolved by heating, and the mixture is filtered. The filtrate is lyophilized to give compound 15 (111 mg, Y = 102). %).

４−［４−（２−ベンゾオキサゾリル）フェノキシ］ブタン酸エチルエステル（化合物１６）、４−［４−（２−ベンゾオキサゾリル）フェノキシ］ブタン酸（化合物１７）、４−［４−（２−ベンゾオキサゾリル）フェノキシ］ブタン酸カリウム塩（化合物１８）の製造：
ＤＭＦ（１５ｍＬ）中、４−（２−ベンゾオキサゾリル）フェノール（１．００ｇ）に炭酸カリウム（１．３１ｇ），４−ブロモ−ｎ−酪酸エチル（１．１１ｇ）を加え、室温で１８時間反応した。反応液を水（１５０ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して化合物１６（１．４６ｇ，Ｙ＝９５％）を得た。
メタノール（４０ｍＬ）中、化合物１６（１．３１ｇ）に１４％水酸化カリウム水溶液（１０ｍＬ）を加え、室温で１７時間反応した後、活性炭を加えろ過し、ろ液を減圧濃縮した。残渣に水（１００ｍＬ）を加えて溶解した後、３５％塩酸で酸析した。析出結晶をろ取、水洗後、乾燥して化合物１７（１．１２ｇ，Ｙ＝９４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．７７−２．５４（４Ｈ，ｍ）４．１２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．０９−８．２２（８Ｈ，ｍ）１２．２０（１Ｈ，ｂｒｓ）
化合物１７（２００ｍｇ）に０．１％水酸化カリウム水溶液（５０ｍＬ）を加え加温溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物１８（２３１ｍｇ，Ｙ＝１００％）を得た。4- [4- (2-Benzoxazolyl) phenoxy] butanoic acid ethyl ester (Compound 16), 4- [4- (2-Benzoxazolyl) phenoxy] butanoic acid (Compound 17), 4- [4 -(2-Benzoxazolyl) phenoxy] butanoic acid potassium salt (compound 18):
Potassium carbonate (1.31 g) and ethyl 4-bromo-n-butyrate (1.11 g) were added to 4- (2-benzoxazolyl) phenol (1.00 g) in DMF (15 mL) at room temperature. Reacted for hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 16 (1.46 g, Y = 95%).
A 14% aqueous potassium hydroxide solution (10 mL) was added to compound 16 (1.31 g) in methanol (40 mL), reacted at room temperature for 17 hours, activated carbon was added and filtered, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue for dissolution, and then acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 17 (1.12 g, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.77−2.54 (4H, m) 4.12 (2H, t, J = 6 Hz) 7.09−8.22 (8H, m) 12.20 (1H, brs)
A 0.1% aqueous potassium hydroxide solution (50 mL) was added to compound 17 (200 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 18 (231 mg, Y = 100%).

４−［４−（２−ベンゾオキサゾリル）フェノキシ］ブタン酸（２，２−ジメチル−１−オキソプロポキシ）メチルエステル（化合物１９）の製造：
ＤＭＦ（１０ｍＬ）中、化合物１７（１５０ｍｇ）に炭酸カリウム（２５６ｍｇ），ピバリン酸クロロメチル（１４２ｍｇ）を加え、８０〜９０℃で２時間反応した。反応液を水（１００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶を５０％エタノール水溶液（６．４ｍＬ）から再結晶して化合物１９（１１５ｍｇ，Ｙ＝５５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２０（９Ｈ，ｓ）２．０６−２．７６（４Ｈ，ｍ）４．１０（２Ｈ，ｔ，Ｊ＝６Ｈｚ）５．７９（２Ｈ，ｓ）７．００（２Ｈ，ｄ，Ｊ＝８Ｈｚ）７．１８−７．８２（４Ｈ，ｍ）８．１９（２Ｈ，ｄ，Ｊ＝９Ｈｚ）Preparation of 4- [4- (2-benzoxazolyl) phenoxy] butanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester (Compound 19):
In DMF (10 mL), potassium carbonate (256 mg) and chloromethyl pivalate (142 mg) were added to compound 17 (150 mg) and reacted at 80 to 90 ° C. for 2 hours. The reaction solution was added to water (100 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from 50% aqueous ethanol (6.4 mL) to give compound 19 (115 mg, Y = 55%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.20 (9H, s) 2.06-2.76 (4H, m) 4.10 (2H, t, J = 6 Hz) 5.79 (2H, s) 7.00 (2H, d, J = 8 Hz) 7.18-7.82 (4H, m) 8.19 (2H, d, J = 9 Hz)

６−［４−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸エチルエステル（化合物２０）、６−［４−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸（化合物２１）、６−［４−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸カリウム塩（化合物２２）の製造：
ＤＭＦ（１５ｍＬ）中、４−（２−ベンゾオキサゾリル）フェノール（１．００ｇ）に炭酸カリウム（１．３１ｇ），６−ブロモヘキサン酸エチル（１．２８ｇ）を加え室温で２１時間反応した。反応液を水（１５０ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して化合物２０（Ｗｅｔ１．８３ｇ）を得た。
メタノール（４０ｍＬ）中、化合物２０（Ｗｅｔ１．６３ｇ）に１４％水酸化カリウム水溶液（１０ｍＬ）を加え、６０〜７０℃で１時間反応した。反応液をろ過後、ろ液を減圧濃縮した。残渣を水（１００ｍＬ）に加熱溶解後、３５％塩酸を加えて酸析した。析出結晶をろ取、水洗後、乾燥して化合物２１（１．２２ｇ，Ｙ＝７９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．５６−２．５４（８Ｈ，ｍ）４．０８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．０７−８．２２（８Ｈ，ｍ）１２．０５（１Ｈ，ｂｒｓ）
化合物２１（２００ｍｇ）に０．１％水酸化カリウム水溶液（５０ｍＬ）を加え加温溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物２２（２２８ｍｇ，Ｙ＝１００％）を得た。6- [4- (2-Benzoxazolyl) phenoxy] hexanoic acid ethyl ester (Compound 20), 6- [4- (2-Benzoxazolyl) phenoxy] hexanoic acid (Compound 21), 6- [4 -(2-Benzoxazolyl) phenoxy] hexanoic acid potassium salt (Compound 22):
In DMF (15 mL), potassium carbonate (1.31 g) and ethyl 6-bromohexanoate (1.28 g) were added to 4- (2-benzoxazolyl) phenol (1.00 g) and reacted at room temperature for 21 hours. . The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 20 (Wet 1.83 g).
A 14% aqueous potassium hydroxide solution (10 mL) was added to compound 20 (Wet 1.63 g) in methanol (40 mL), and reacted at 60 to 70 ° C. for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL) with heating, and acidified with 35% hydrochloric acid. Precipitated crystals were collected by filtration, washed with water, and dried to give compound 21 (1.22 g, Y = 79%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.56-2.54 (8H, m) 4.08 (2H, t, J = 6 Hz) 7.07-8.22 (8H, m) 12.05 (1H, brs)
To compound 21 (200 mg), 0.1% aqueous potassium hydroxide solution (50 mL) was added and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 22 (228 mg, Y = 100%).

６−［４−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸（２，２−ジメチル−１−オキソプロポキシ）メチルエステル（化合物２３）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２１（２００ｍｇ）に炭酸カリウム（２８０ｍｇ），ピバリン酸クロロメチル（１５５ｍｇ）を加え、８０〜９０℃で２．５時間反応した。反応液を水（１００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶を８０％エタノール水溶液（４ｍＬ）から再結晶して化合物２３（２０５ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２１（９Ｈ，ｓ）１．４８−２．００（６Ｈ，ｍ）２．４１（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．０４（２Ｈ，ｔ，Ｊ＝６Ｈｚ）５．７７（２Ｈ，ｓ）７．００（２Ｈ，ｄ，Ｊ＝９Ｈｚ）７．２３−７．８３（４Ｈ，ｍ）８．１９（２Ｈ，ｄ，Ｊ＝９Ｈｚ）Preparation of 6- [4- (2-benzoxazolyl) phenoxy] hexanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester (Compound 23):
In DMF (10 mL), potassium carbonate (280 mg) and chloromethyl pivalate (155 mg) were added to compound 21 (200 mg), and reacted at 80 to 90 ° C. for 2.5 hours. The reaction solution was added to water (100 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (4 mL) to give compound 23 (205 mg, Y = 76%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.21 (9H, s) 1.48-2.00 (6H, m) 2.41 (2H, t, J = 6 Hz) 4.04 (2H, t, J = 6 Hz) 5.77 ( 2H, s) 7.00 (2H, d, J = 9 Hz) 7.23-7.83 (4H, m) 8.19 (2H, d, J = 9 Hz)

［５−［４−（２−ベンゾオキサゾリル）フェノキシ］ペンチル］プロパン二酸ジエチルエステル（化合物２４）、［５−［４−（２−ベンゾオキサゾリル）フェノキシ］ペンチル］プロパン二酸（化合物２５）、［５−［４−（２−ベンゾオキサゾリル）フェノキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物２６）の製造：
ＤＭＦ（１０ｍＬ）中、４−（２−ベンゾオキサゾリル）フェノール（５００ｍｇ）に炭酸カリウム（１．０ｇ），（５−ブロモペンチル）マロン酸ジエチル（８８９ｍｇ）を加え、室温で２３時間反応した。反応液を水（１５０ｍＬ）中に加え、生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し粗製オイル（１．６９ｇ）を得た。粗製オイル（１．６９ｇ）をシリカゲルカラム（トルエン／酢酸エチル）で精製して化合物２４（１．０９ｇ）を得た。
メタノール（２０ｍＬ）中、化合物２４（１．０９ｇ）に３０％水酸化カリウム水溶液（５ｍＬ）を加え、室温で一夜反応した。反応液に活性炭を加えろ過し、ろ液を減圧濃縮した。残渣に水（５０ｍＬ）を加え溶解後、３５％塩酸で酸析し、分離したオイルを酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗後、硫酸マグネシウムで脱水し、減圧濃縮、乾燥して化合物２５（７５４ｍｇ，Ｙ＝８３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１８−１．９９（８Ｈ，ｍ）３．２４（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．０８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．０７−７．８５（６Ｈ，ｍ）８．１４（２Ｈ，ｄ，Ｊ＝９Ｈｚ）１２．１２−１３．３０（２Ｈ，ｂｒ）
化合物２５（１５０ｍｇ）に０．１６％水酸化ナトリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物２６（１５９ｍｇ，Ｙ＝９５％）を得た。[5- [4- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid diethyl ester (Compound 24), [5- [4- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid ( Compound 25), Preparation of [5- [4- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid disodium salt (Compound 26):
Potassium carbonate (1.0 g) and diethyl (5-bromopentyl) malonate (889 mg) were added to 4- (2-benzoxazolyl) phenol (500 mg) in DMF (10 mL) and reacted at room temperature for 23 hours. . The reaction was added into water (150 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (1.69 g). Crude oil (1.69 g) was purified by silica gel column (toluene / ethyl acetate) to give compound 24 (1.09 g).
A 30% aqueous potassium hydroxide solution (5 mL) was added to compound 24 (1.09 g) in methanol (20 mL), and the mixture was reacted at room temperature overnight. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The separated oil was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and dried to obtain compound 25 (754 mg, Y = 83%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-1.99 (8H, m) 3.24 (1H, t, J = 7 Hz) 4.08 (2H, t, J = 6 Hz) 7.07-7.85 (6H, m) 8.14 (2H, d, J = 9 Hz) 12.12-13.30 (2H, br)
To the compound 25 (150 mg), 0.16% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 26 (159 mg, Y = 95%).

［４−（６−ニトロ−２−ベンゾオキサゾリル）フェノキシ］酢酸メチルエステル（化合物２７）、［４−（６−ニトロ−２−ベンゾオキサゾリル）フェノキシ］酢酸（化合物２８）、［４−（６−ニトロ−２−ベンゾオキサゾリル）フェノキシ］酢酸ナトリウム塩（化合物２９）の製造：
４−ベンジルオキシ安息香酸（３ｇ）にトルエン（５０ｍＬ）、塩化チオニル（１．１５ｍＬ）、ＤＭＦ（１滴）を加えて還流下で１．５時間反応した後、２−アミノ−５−ニトロフェノール（４．２ｇ）の１，４−ジオキサン（１００ｍＬ）溶液を加えて室温で一夜、還流下で１時間反応した。反応液に塩化チオニル（６ｍＬ）を加えて還流下で９時間反応した。反応液を減圧濃縮後、水（１５０ｍＬ）を加えて晶析した。析出結晶をろ取し、メタノール洗浄後乾燥して６−ニトロ−２−［４−（フェニルメトキシ）フェニル］ベンゾオキサゾール（４．１４５ｇ，Ｙ＝９１％）を得た。
６−ニトロ−２−［４−（フェニルメトキシ）フェニル］ベンゾオキサゾール（１．０ｇ）に飽和塩酸・酢酸溶液（２５ｍＬ）を加えて約１００℃で一夜反応した。反応液を減圧濃縮し、残渣にクロロホルム（１５０ｍＬ）、水（１５０ｍＬ）を加え２％水酸化ナトリウム水溶液を加えて強塩基性とした後、分液した。水層に希塩酸を加えて酸析し、析出した結晶をろ取、乾燥して４−（６−ニトロ−２−ベンゾオキサゾリル）フェノール（４３５ｍｇ，Ｙ＝５９％）を得た。
４−（６−ニトロ−２−ベンゾオキサゾリル）フェノール（３５０ｍｇ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（５００ｍｇ）、ブロモ酢酸メチル（３００ｍｇ）を加えて一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物２７（３７５ｍｇ，Ｙ＝８４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．７５（３Ｈ，ｓ）４．９８（２Ｈ，ｓ）７．１４−８．６９（７Ｈ，ｍ）
化合物２７（３４５ｍｇ）を１，４−ジオキサン（２０ｍＬ）、メタノール（５０ｍＬ）の混液に溶解し、２％水酸化ナトリウム水溶液（５ｍＬ）を加えて約６０℃で１．５時間反応した。反応液を減圧濃縮し、残渣に１Ｎ塩酸を加え、析出した結晶をろ取した。得られた結晶をメタノール、トルエンの混液から再結晶して化合物２８（１４３ｍｇ，Ｙ＝４３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８５（２Ｈ，ｓ）７．１１−８．６９（７Ｈ，ｍ）
化合物２８（１０８ｍｇ）を水（３０ｍＬ）に懸濁し、１．６％水酸化ナトリウム水溶液（０．９ｍＬ）を加えて溶解後、ろ過した。ろ液を凍結乾燥して化合物２９（９８ｍｇ，Ｙ＝８５％）を得た。[4- (6-Nitro-2-benzoxazolyl) phenoxy] acetic acid methyl ester (Compound 27), [4- (6-Nitro-2-benzoxazolyl) phenoxy] acetic acid (Compound 28), [4 Preparation of-(6-nitro-2-benzoxazolyl) phenoxy] acetic acid sodium salt (compound 29):
Toluene (50 mL), thionyl chloride (1.15 mL) and DMF (1 drop) were added to 4-benzyloxybenzoic acid (3 g) and reacted under reflux for 1.5 hours, and then 2-amino-5-nitrophenol. A solution of (4.2 g) in 1,4-dioxane (100 mL) was added and reacted at room temperature overnight and under reflux for 1 hour. Thionyl chloride (6 mL) was added to the reaction solution and reacted for 9 hours under reflux. The reaction solution was concentrated under reduced pressure, and then water (150 mL) was added for crystallization. The precipitated crystals were collected by filtration, washed with methanol and dried to give 6-nitro-2- [4- (phenylmethoxy) phenyl] benzoxazole (4.145 g, Y = 91%).
A saturated hydrochloric acid / acetic acid solution (25 mL) was added to 6-nitro-2- [4- (phenylmethoxy) phenyl] benzoxazole (1.0 g), and the mixture was reacted at about 100 ° C. overnight. The reaction mixture was concentrated under reduced pressure, chloroform (150 mL) and water (150 mL) were added to the residue, and a 2% aqueous sodium hydroxide solution was added to make it strongly basic, followed by liquid separation. Dilute hydrochloric acid was added to the aqueous layer for acid precipitation, and the precipitated crystals were collected by filtration and dried to obtain 4- (6-nitro-2-benzoxazolyl) phenol (435 mg, Y = 59%).
4- (6-Nitro-2-benzoxazolyl) phenol (350 mg) was dissolved in DMF (20 mL), and potassium carbonate (500 mg) and methyl bromoacetate (300 mg) were added and reacted overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 27 (375 mg, Y = 84%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.75 (3H, s) 4.98 (2H, s) 7.14-8.69 (7H, m)
Compound 27 (345 mg) was dissolved in a mixture of 1,4-dioxane (20 mL) and methanol (50 mL), 2% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 60 ° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from a mixed solution of methanol and toluene to obtain Compound 28 (143 mg, Y = 43%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.85 (2H, s) 7.11-8.69 (7H, m)
Compound 28 (108 mg) was suspended in water (30 mL), dissolved by adding 1.6% aqueous sodium hydroxide solution (0.9 mL), and then filtered. The filtrate was lyophilized to give compound 29 (98 mg, Y = 85%).

６−［２−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸エチルエステル（化合物３０）、６−［２−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸（化合物３１）、６−［２−（２−ベンゾオキサゾリル）フェノキシ］ヘキサン酸カリウム塩（化合物３２）の製造：
ＤＭＦ（１０ｍＬ）中、２−（２−ヒドロキシフェニル）ベンゾオキサゾール（４００ｍｇ）に炭酸カリウム（７９１ｍｇ），６−ブロモヘキサン酸エチル（５２１ｍｇ）を加え室温で１７時間反応した。反応液を水（１５０ｍＬ）中に加え撹拌した後、生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し化合物３０（８５６ｍｇ）を得た。
エタノール（２０ｍＬ）中、化合物３０（８５６ｍｇ）に２３％水酸化カリウム水溶液（５ｍＬ）を加え、室温で１時間反応した。反応液を減圧濃縮し、残渣を水（３０ｍＬ）に溶解後、３５％塩酸で酸析した。析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶をトルエン（３ｍＬ）から再結晶し、化合物３１（３７３ｍｇ，Ｙ＝６１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６１−２．２４（８Ｈ，ｍ）４．１５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．０１−８．１０（８Ｈ，ｍ）１０．６３−１３．３５（１Ｈ，ｂｒ）
化合物３１（１５０ｍｇ）に０．０６％水酸化カリウム水溶液（５０ｍＬ）を加え加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物３２（１１４ｍｇ，Ｙ＝６８％）を得た。6- [2- (2-Benzoxazolyl) phenoxy] hexanoic acid ethyl ester (Compound 30), 6- [2- (2-Benzoxazolyl) phenoxy] hexanoic acid (Compound 31), 6- [2 Production of-(2-benzoxazolyl) phenoxy] hexanoic acid potassium salt (compound 32):
Potassium carbonate (791 mg) and ethyl 6-bromohexanoate (521 mg) were added to 2- (2-hydroxyphenyl) benzoxazole (400 mg) in DMF (10 mL) and reacted at room temperature for 17 hours. The reaction mixture was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 30 (856 mg).
A 23% aqueous potassium hydroxide solution (5 mL) was added to compound 30 (856 mg) in ethanol (20 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (30 mL), and then acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from toluene (3 mL) to obtain compound 31 (373 mg, Y = 61%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.6-2.24 (8H, m) 4.15 (2H, t, J = 6 Hz) 7.01-8.10 (8H, m) 10.63-13.35 (1H, br)
0.06% aqueous potassium hydroxide solution (50 mL) was added to compound 31 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 32 (114 mg, Y = 68%).

［５−［２−（２−ベンゾオキサゾリル）フェノキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３３）、［５−［２−（２−ベンゾオキサゾリル）フェノキシ］ペンチル］プロパン二酸（化合物３４）、［５−［２−（２−ベンゾオキサゾリル）フェノキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物３５）の製造：
ＤＭＦ（１２ｍＬ）中、２−（２−ヒドロキシフェニル）ベンゾオキサゾール（４００ｍｇ）に炭酸カリウム（１．１１ｇ），（５−ブロモペンチル）マロン酸ジエチル（９３２ｍｇ）を加え、室温で２９時間反応した。反応液を水（１５０ｍＬ）中に加え撹拌した後、生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し粗製オイル（１．０９ｇ）を得た。粗製オイル（１．０９ｇ）をシリカゲルカラム（トルエン／酢酸エチル）で精製し、化合物３３（０．９２ｇ）を得た。
エタノール（２０ｍＬ）中、化合物３３（０．９２ｇ）に２６％水酸化カリウム水溶液（５ｍＬ）を加え、室温で２時間反応した。反応液を減圧濃縮し、残渣を水（３０ｍＬ）に溶解した後、３５％塩酸で酸析し、生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し、残渣を乾燥して化合物３４（５８８ｍｇ，Ｙ＝８１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．０６−１．９９（８Ｈ，ｍ）３．２３（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１５（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．０１−８．１２（８Ｈ，ｍ）１２．６０（２Ｈ，ｂｒｓ）
化合物３４（１５０ｍｇ）に０．１６％水酸化ナトリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物３５（１５６ｍｇ，Ｙ＝９３％）を得た。[5- [2- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid diethyl ester (compound 33), [5- [2- (2-benzoxazolyl) phenoxy] pentyl] propanedioic acid ( Preparation of Compound 34), [5- [2- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid disodium salt (Compound 35):
In DMF (12 mL), potassium carbonate (1.11 g) and diethyl (5-bromopentyl) malonate (932 mg) were added to 2- (2-hydroxyphenyl) benzoxazole (400 mg) and reacted at room temperature for 29 hours. The reaction mixture was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (1.09 g). Crude oil (1.09 g) was purified by silica gel column (toluene / ethyl acetate) to obtain compound 33 (0.92 g).
A 26% aqueous potassium hydroxide solution (5 mL) was added to compound 33 (0.92 g) in ethanol (20 mL) and reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (30 mL), acidified with 35% hydrochloric acid, and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, concentrated under reduced pressure, and the residue was dried to obtain Compound 34 (588 mg, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.6-1.99 (8H, m) 3.23 (1H, t, J = 7 Hz) 4.15 (2H, t, J = 5 Hz) 7.01-8.12 (8H, m) 12.60 (2H, brs)
To the compound 34 (150 mg), 0.16% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 35 (156 mg, Y = 93%).

２−［４’−（フェニルメトキシ）［１，１’−ビフェニル］−４−イル］ベンゾオキサゾール（化合物３６）、４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−オール（化合物３７）、４−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ブタン酸エチルエステル（化合物３８）、４−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ブタン酸（化合物３９）、４−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ブタン酸ナトリウム塩（化合物４０）の製造：
４’−ベンジルオキシ−４−ビフェニルカルボン酸（７．０ｇ）にトルエン（５０ｍＬ）、塩化チオニル（３．０ｇ）、ＤＭＦ（１滴）を加えて還流下で３時間反応した後、２−アミノフェノール（５．１ｇ）の１，４−ジオキサン（１００ｍＬ）溶液を加えて還流下で３時間反応した。冷却後、析出した結晶をろ取した。得られた結晶を５％塩酸水溶液、メタノールで順次洗浄後、乾燥して中間体のアミド化合物（７．５７ｇ，Ｙ＝８３％）を得た。
アミド化合物（７．５ｇ）を１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）に溶解し、ｐ−トルエンスルホン酸一水和物（１０ｇ）及びトルエン（１００ｍＬ）を加え、還流下で生成する水を除去しながら一夜反応した。冷却後、析出した結晶をろ取し、得られた結晶をメタノール（３０ｍＬ）、０．３％水酸化ナトリウム水溶液（３００ｍＬ）と共に還流下で懸濁した。結晶をろ取し、メタノールで洗浄後乾燥して化合物３６（６．１ｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝５．１３（２Ｈ，ｓ）７．００−８．３８（１７Ｈ，ｍ）
化合物３６（６．０５ｇ）にメタノール（３００ｍＬ）、トルエン（１５０ｍＬ）、５％パラジウム炭素（２．５ｇ）を加えて水素雰囲気下約４５℃で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物３７（３．６２ｇ，Ｙ＝７９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝６．９１（２Ｈ，ｄ，Ｊ＝８Ｈｚ）７．３４−７．９１（８Ｈ，ｍ）８．２５（２Ｈ，ｄ，Ｊ＝８Ｈｚ）９．５０（１Ｈ，ｂｒ）
化合物３７（０．６３ｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、４−ブロモ−ｎ−酪酸エチル（０．５４ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を２０％メタノール水溶液で洗浄後、エタノールから再結晶して化合物３８（７７５ｍｇ，Ｙ＝８８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．０３−２．７０（４Ｈ，ｍ）３．９８−４．３５（４Ｈ，ｍ）６．９１−８．３８（１２Ｈ，ｍ）
化合物３８（６９５ｍｇ）にメタノール（１５０ｍＬ）、１，４−ジオキサン（２０ｍＬ）、４％水酸化ナトリウム水溶液（１０ｍＬ）を加えて還流下で１時間反応した。反応液を減圧濃縮し、残渣に５０％アセトン水溶液（４００ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３９（６４２ｍｇ，Ｙ＝９９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８３−２．５７（４Ｈ，ｍ）４．０６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９９−８．３３（１２Ｈ，ｍ）１２．１６（１Ｈ，ｂｒ）
化合物３９（１１０ｍｇ）に水（２００ｍＬ）、１％水酸化ナトリウム水溶液（１．３ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物４０（１２２．８ｍｇ，Ｙ＝１０５％）を得た。2- [4 ′-(Phenylmethoxy) [1,1′-biphenyl] -4-yl] benzoxazole (Compound 36), 4 ′-(2-Benzoxazolyl) [1,1′-biphenyl]- 4-ol (compound 37), 4-[[4 ′-(2-benzoxazolyl) [1,1′-biphenyl] -4-yl] oxy] butanoic acid ethyl ester (compound 38), 4- [ [4 ′-(2-Benzoxazolyl) [1,1′-biphenyl] -4-yl] oxy] butanoic acid (Compound 39), 4-[[4 ′-(2-Benzoxazolyl) [ Preparation of 1,1′-biphenyl] -4-yl] oxy] butanoic acid sodium salt (compound 40):
Toluene (50 mL), thionyl chloride (3.0 g), and DMF (1 drop) were added to 4′-benzyloxy-4-biphenylcarboxylic acid (7.0 g) and reacted under reflux for 3 hours. A solution of phenol (5.1 g) in 1,4-dioxane (100 mL) was added and reacted under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration. The obtained crystals were washed successively with 5% aqueous hydrochloric acid and methanol and dried to obtain an intermediate amide compound (7.57 g, Y = 83%).
The amide compound (7.5 g) was dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), p-toluenesulfonic acid monohydrate (10 g) and toluene (100 mL) were added, and the product was produced under reflux. The reaction was carried out overnight while removing water. After cooling, the precipitated crystals were collected by filtration, and the obtained crystals were suspended under reflux with methanol (30 mL) and 0.3% aqueous sodium hydroxide solution (300 mL). The crystals were collected by filtration, washed with methanol and dried to give compound 36 (6.1 g, Y = 85%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.13 (2H, s) 7.00-8.38 (17H, m)
Methanol (300 mL), toluene (150 mL), and 5% palladium carbon (2.5 g) were added to compound 36 (6.05 g), and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 37 (3.62 g, Y = 79%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 6.91 (2H, d, J = 8 Hz) 7.34-7.91 (8H, m) 8.25 (2H, d, J = 8 Hz) 9.50 (1H, br)
Compound 37 (0.63 g) was dissolved in DMF (15 mL), and potassium carbonate (1.5 g) and ethyl 4-bromo-n-butyrate (0.54 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with 20% aqueous methanol solution and recrystallized from ethanol to obtain Compound 38 (775 mg, Y = 88%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.03-2.70 (4H, m) 3.98-4.35 (4H, m) 6.91-8.38 (12H, m)
Methanol (150 mL), 1,4-dioxane (20 mL), and 4% aqueous sodium hydroxide solution (10 mL) were added to compound 38 (695 mg) and reacted under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, 50% acetone aqueous solution (400 mL) was added to the residue and dissolved by heating, and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 39 (642 mg, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.83-2.57 (4H, m) 4.06 (2H, t, J = 6 Hz) 6.99-8.33 (12H, m) 12.16 (1H, br)
To compound 39 (110 mg), water (200 mL) and 1% aqueous sodium hydroxide solution (1.3 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 40 (122.8 mg, Y = 105%).

６−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ヘキサン酸
エチルエステル（化合物４１）、６−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ヘキサン酸（化合物４２）、６−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ヘキサン酸ナトリウム塩（化合物４３）の製造：
化合物３７（０．６ｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、６−ブロモヘキサン酸エチル（０．６１ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を１７％メタノール水溶液で洗浄後、エタノールから再結晶して化合物４１（７７４ｍｇ，Ｙ＝８６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２６（３Ｈ，ｔ，Ｊ＝７Ｈ）１．３７−１．９５（６Ｈ，ｍ）２．３５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９３−４．３３（４Ｈ，ｍ）６．９１−８．３８（１２Ｈ，ｍ）
化合物４１（７００ｍｇ）にメタノール（７０ｍＬ）、１，４−ジオキサン（３０ｍＬ）を加えて溶解し、５％水酸化ナトリウム水溶液（１０ｍＬ）を加えて還流下で３時間反応した。反応液を減圧濃縮後、残渣に３３％アセトン水溶液（４５０ｍＬ）を加えて加熱溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４２（６５１ｍｇ，Ｙ＝１００％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２８−１．９０（６Ｈ，ｍ）２．２６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．０１（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９７−８．３２（１２Ｈ，ｍ）１２．０１（１Ｈ，ｂｒ）
化合物４２（９７ｍｇ）に水（２００ｍＬ）、１％水酸化ナトリウム水溶液（１．１ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物４３（１０４．４ｍｇ，Ｙ＝１０２％）を得た。6-[[4 ′-(2-Benzoxazolyl) [1,1′-biphenyl] -4-yl] oxy] hexanoic acid ethyl ester (Compound 41), 6-[[4 ′-(2-Benzo) Oxazolyl) [1,1′-biphenyl] -4-yl] oxy] hexanoic acid (Compound 42), 6-[[4 ′-(2-Benzoxazolyl) [1,1′-biphenyl]- Preparation of 4-yl] oxy] hexanoic acid sodium salt (compound 43):
Compound 37 (0.6 g) was dissolved in DMF (15 mL), and potassium carbonate (1.5 g) and ethyl 6-bromohexanoate (0.61 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with a 17% aqueous methanol solution and recrystallized from ethanol to obtain Compound 41 (774 mg, Y = 86%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7H) 1.37-1.95 (6H, m) 2.35 (2H, t, J = 6 Hz) 3.93-4.33 (4H, m) 6.91-8.38 (12H, m)
Methanol (70 mL) and 1,4-dioxane (30 mL) were added to and dissolved in compound 41 (700 mg), 5% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted under reflux for 3 hours. After concentrating the reaction solution under reduced pressure, 33% acetone aqueous solution (450 mL) was added to the residue and dissolved by heating, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 42 (651 mg, Y = 100%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.28-1.90 (6H, m) 2.26 (2H, t, J = 6 Hz) 4.01 (2H, t, J = 6 Hz) 6.97-8.32 (12H, m) 12.01 (1H, br)
To compound 42 (97 mg), water (200 mL) and a 1% aqueous sodium hydroxide solution (1.1 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 43 (104.4 mg, Y = 102%).

［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］メチルプロパン二酸ジエチルエステル（化合物４４）、［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］メチルプロパン二酸（化合物４５）、［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］メチルプロパン二酸二ナトリウム塩（化合物４６）の製造：
化合物３７（０．６０ｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、２−ブロモ−２−メチルマロン酸ジエチル（０．７０ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を２０％メタノール水溶液で洗浄後、エタノールから再結晶して化合物４４（６３６ｍｇ，Ｙ＝６６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２８（６Ｈ，ｔ，Ｊ＝７Ｈｚ）１．８２（３Ｈ，ｓ）４．１４−４．４９（４Ｈ，ｍ）７．０１−８．３９（１２Ｈ，ｍ）
化合物４４（５６０ｍｇ）をメタノール（８０ｍＬ）に溶解し、４．５％水酸化ナトリウム水溶液（１０ｍＬ）を加えて還流下で１時間反応した。反応液を減圧濃縮し、残渣に３３％アセトン水溶液（４５０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取し、トルエン、酢酸エチルの混液から再結晶して化合物４５（２６３ｍｇ，Ｙ＝５４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．７１（３Ｈ，ｓ）６．９７−８．３５（１２Ｈ，ｍ）９．５０（２Ｈ，ｂｒ）
化合物４５（９６．５ｍｇ）に水（４０ｍＬ）、１％水酸化ナトリウム水溶液（２ｍＬ）を加えて加温溶解し、ろ過した。ろ液を凍結乾燥して化合物４６（１０５．８ｍｇ，Ｙ＝９９％）を得た。[[4 ′-(2-Benzoxazolyl) [1,1′-biphenyl] -4-yl] oxy] methylpropanedioic acid diethyl ester (Compound 44), [[4 ′-(2-Benzoxazolyl ) [1,1′-biphenyl] -4-yl] oxy] methylpropanedioic acid (compound 45), [[4 ′-(2-benzoxazolyl) [1,1′-biphenyl] -4- Preparation of [Ill] oxy] methylpropanedioic acid disodium salt (compound 46):
Compound 37 (0.60 g) was dissolved in DMF (15 mL), and potassium carbonate (1.5 g) and diethyl 2-bromo-2-methylmalonate (0.70 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with 20% aqueous methanol solution and recrystallized from ethanol to obtain Compound 44 (636 mg, Y = 66%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.28 (6H, t, J = 7 Hz) 1.82 (3H, s) 4.14-4.49 (4H, m) 7.01-8.39 (12H, m)
Compound 44 (560 mg) was dissolved in methanol (80 mL), a 4.5% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and 33% acetone aqueous solution (450 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and recrystallized from a mixed solution of toluene and ethyl acetate to obtain Compound 45 (263 mg, Y = 54%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.71 (3H, s) 6.97-8.35 (12H, m) 9.50 (2H, br)
To compound 45 (96.5 mg), water (40 mL) and 1% aqueous sodium hydroxide solution (2 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 46 (105.8 mg, Y = 99%).

［３−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物４７）、［３−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］プロピル］プロパン二酸（化合物４８）、［３−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物４９）の製造：
化合物３７（５００ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（２．０ｇ）、（３−クロロプロピル）マロン酸ジエチル（５７０ｍｇ）を加えて約５５℃で一夜反応した。反応液に酢酸エチル（１５０ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水後、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物４７（３０２ｍｇ，Ｙ＝３６％）を得た。
化合物４７（３０２ｍｇ）にメタノール（８０ｍＬ）、１，４−ジオキサン（２０ｍＬ）、１０％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で一夜反応した。冷却後、析出した結晶をろ取、乾燥して化合物４９（８５ｍｇ，Ｙ＝２９％）を得た。
化合物４９のろ液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加温溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４８（１５０ｍｇ，Ｙ＝５６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６４−２．１１（４Ｈ，ｍ）３．３５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．０６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９９−８．３４（１２Ｈ，ｍ）１２．６９（２Ｈ，ｂｒ）[3-[[4 ′-(2-Benzoxazolyl) [1,1′-biphenyl] -4-yl] oxy] propyl] propanedioic acid diethyl ester (Compound 47), [3-[[4 ′ -(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] propyl] propanedioic acid (Compound 48), [3-[[4 '-(2-Benzoxazolyl) Preparation of [1,1′-biphenyl] -4-yl] oxy] propyl] propanedioic acid disodium salt (compound 49):
Compound 37 (500 mg) was dissolved in DMF (15 mL), potassium carbonate (2.0 g) and diethyl (3-chloropropyl) malonate (570 mg) were added, and the mixture was reacted at about 55 ° C. overnight. Ethyl acetate (150 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 47 (302 mg, Y = 36%).
Methanol (80 mL), 1,4-dioxane (20 mL), and 10% aqueous sodium hydroxide (3 mL) were added to compound 47 (302 mg), and the mixture was reacted at about 50 ° C. overnight. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 49 (85 mg, Y = 29%).
The filtrate of compound 49 was concentrated under reduced pressure, and water (50 mL) was added to the residue and dissolved by heating. Then, dilute hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 48 (150 mg, Y = 56%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.64-2.11 (4H, m) 3.35 (1H, t, J = 7 Hz) 4.06 (2H, t, J = 6 Hz) 6.99-8.34 (12H, m) 12.69 (2H, br)

［５−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物５０）、［５−［［４’−（２−ベンゾオキサゾリル）［１，１’−ビフェニル］−４−イル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物５１）の製造：
化合物３７（３００ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（１．２ｇ）、（５−ブロモペンチル）マロン酸ジエチル（４４０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加え水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水後、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物５０（４１１ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１４−２．１５（１４Ｈ，ｍ）３．３５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）３．９１−４．３９（６Ｈ，ｍ）６．９１−８．３８（１２Ｈ，ｍ）
化合物５０（４１１ｍｇ）をメタノール（１００ｍＬ）に溶解し、１０％水酸化ナトリウム水溶液（６ｍＬ）を加えて約６０℃で一夜、還流下で６時間反応した。冷却後、析出した結晶をろ取、乾燥して化合物５１（３６２ｍｇ，Ｙ＝９０％）を得た。[5-[[4 ′-(2-Benzoxazolyl) [1,1′-biphenyl] -4-yl] oxy] pentyl] propanedioic acid diethyl ester (compound 50), [5-[[4 ′ Preparation of-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] pentyl] propanedioic acid disodium salt (Compound 51):
Compound 37 (300 mg) was dissolved in DMF (10 mL), and potassium carbonate (1.2 g) and diethyl (5-bromopentyl) malonate (440 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 50 (411 mg, Y = 76%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.4-2.15 (14H, m) 3.35 (1H, t, J = 7 Hz) 3.91-4.39 (6H, m) 6.91-8.38 (12H, m)
Compound 50 (411 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (6 mL) was added, and the mixture was reacted at about 60 ° C. overnight and under reflux for 6 hours. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 51 (362 mg, Y = 90%).

２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物５２）、６−（２−ベンゾオキサゾリル）−２−ナフタレノール（化合物５３）、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸メチルエステル（化合物５４）、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸（化合物５５）、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸ナトリウム塩（化合物５６）の製造：
窒素気流中、氷水冷却下でトルエン（１２０ｍＬ）に１５％トリメチルアルミニウム・トルエン溶液（１２．５ｍＬ）、２−アミノフェノール（２．５ｇ）を加え、還流下で３０分間反応した後、６−ベンジルオキシ−２−ナフトエ酸エチル（４．０ｇ）のトルエン（４０ｍＬ）溶液を加えて還流下で６時間反応した。反応液に７０％メタノール水溶液（１００ｍＬ）を加えて１時間還流後、結晶をろ取した。得られた結晶に含まれる目的化合物を酢酸エチルで熱時抽出した後、減圧濃縮した。残渣を酢酸エチルから再結晶して中間体のアミド化合物（３．３２ｇ，Ｙ＝６９％）を得た。
アミド化合物（２．９ｇ）にトルエン（１６０ｍＬ）、塩化チオニル（４ｍＬ）、ＤＭＦ（１滴）を加えて３時間還流下で反応した。反応液を減圧濃縮し、残渣をシリカゲルカラム（クロロホルム）で精製して化合物５２（１．０５ｇ，Ｙ＝３８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２９（２Ｈ，ｓ）７．２７−８．７７（１５Ｈ，ｍ）
化合物５２（０．８８ｇ）をトルエン（４０ｍＬ）に懸濁し、エタノール（８０ｍＬ）、５％パラジウム炭素（１ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物５３（４８０ｍｇ，Ｙ＝７３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．１２−８．２７（９Ｈ，ｍ）８．７１（１Ｈ，ｓ）
化合物５３（３３０ｍｇ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（０．５ｇ）、ブロモ酢酸メチル（０．２５ｇ）を加えて室温で一夜反応した。反応液にトルエン（１５０ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した。トルエン層を硫酸マグネシウムで脱水し、減圧濃縮、乾燥して化合物５４（４２０ｍｇ，Ｙ＝１００％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．７６（３Ｈ，ｓ）５．００（２Ｈ，ｓ）７．２９−８．７７（１０Ｈ，ｍ）
化合物５４（２１５ｍｇ）にメタノール（１５０ｍＬ）を加えて溶解し、３．３％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で１．５時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）、酢酸エチル（２００ｍＬ）を加え、希塩酸を加えて強酸性として分液した。酢酸エチル層を飽和食塩水で洗浄後、硫酸マグネシウムで脱水し、減圧濃縮、乾燥して化合物５５（１９０ｍｇ，Ｙ＝９２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８８（２Ｈ，ｓ）７．２４−８．７７（１０Ｈ，ｍ）
化合物５５（１０１ｍｇ）にメタノール（５０ｍＬ）、１％水酸化ナトリウム水溶液（１．３ｍＬ）を加えて加熱溶解し、減圧濃縮、乾燥して化合物５６（１０９ｍｇ，Ｙ＝１０１％）を得た。2- [6- (Phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 52), 6- (2-Benzoxazolyl) -2-naphthalenol (Compound 53), [[6- (2-Benzoxazolid L) -2-Naphthalenyl] oxy] acetic acid methyl ester (Compound 54), [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] acetic acid (Compound 55), [[6- (2-Benzo) Preparation of Oxazolyl) -2-naphthalenyl] oxy] acetic acid sodium salt (Compound 56):
In a nitrogen stream, 15% trimethylaluminum / toluene solution (12.5 mL) and 2-aminophenol (2.5 g) were added to toluene (120 mL) under cooling with ice water, reacted for 30 minutes under reflux, and then 6-benzyl. A solution of ethyl oxy-2-naphthoate (4.0 g) in toluene (40 mL) was added and reacted under reflux for 6 hours. A 70% aqueous methanol solution (100 mL) was added to the reaction mixture, and the mixture was refluxed for 1 hour, and the crystals were collected by filtration. The target compound contained in the obtained crystals was extracted with ethyl acetate while hot, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain an intermediate amide compound (3.32 g, Y = 69%).
Toluene (160 mL), thionyl chloride (4 mL) and DMF (1 drop) were added to the amide compound (2.9 g), and reacted under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain Compound 52 (1.05 g, Y = 38%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.29 (2H, s) 7.27-8.77 (15H, m)
Compound 52 (0.88 g) was suspended in toluene (40 mL), ethanol (80 mL), 5% palladium carbon (1 g) was added, and the mixture was reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 53 (480 mg, Y = 73%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.12−8.27 (9H, m) 8.71 (1H, s)
Compound 53 (330 mg) was dissolved in DMF (20 mL), potassium carbonate (0.5 g) and methyl bromoacetate (0.25 g) were added, and the mixture was reacted overnight at room temperature. Toluene (150 mL) was added to the reaction solution, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The toluene layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 54 (420 mg, Y = 100%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.76 (3H, s) 5.00 (2H, s) 7.29-8.77 (10H, m)
Methanol (150 mL) was added to compound 54 (215 mg) to dissolve, and 3.3% aqueous sodium hydroxide solution (3 mL) was added to react at about 50 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, water (50 mL) and ethyl acetate (200 mL) were added to the residue, and dilute hydrochloric acid was added to make the solution strongly acidic. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give compound 55 (190 mg, Y = 92%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.88 (2H, s) 7.24-8.77 (10H, m)
Methanol (50 mL) and 1% aqueous sodium hydroxide solution (1.3 mL) were added to compound 55 (101 mg), dissolved by heating, concentrated under reduced pressure, and dried to obtain compound 56 (109 mg, Y = 101%).

４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物５７）、４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物５８）、４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物５９）の製造：
化合物５３（３．５ｇ）をＤＭＦ（４０ｍＬ）に溶解し、炭酸カリウム（８．０ｇ）、４−ブロモ−ｎ−酪酸エチル（３．４ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を２０％メタノール水溶液で洗浄後、エタノールから再結晶して化合物５７（４．４ｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．００−２．６８（４Ｈ，ｍ）４．００−４．３５（４Ｈ，ｍ）７．１４−８．６９（１０Ｈ，ｍ）
化合物５７（４．３５ｇ）をメタノール（１５０ｍＬ）に溶解し、２０％水酸化ナトリウム水溶液（１０ｍＬ）を加えて還流下で３時間反応した。反応液を減圧濃縮し、残渣に４０％メタノール水溶液（７００ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物５８（３．９９ｇ，Ｙ＝９９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８３−２．６０（４Ｈ，ｍ）４．１７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１８−８．７３（１０Ｈ，ｍ）１２．２１（１Ｈ，ｂｒ）
化合物５８（１１０ｍｇ）に水（１００ｍＬ）、１％水酸化ナトリウム水溶液（１．５ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物５９（１２１ｍｇ，Ｙ＝１０３％）を得た。4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 57), 4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy Preparation of butanoic acid (Compound 58), 4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 59):
Compound 53 (3.5 g) was dissolved in DMF (40 mL), potassium carbonate (8.0 g) and ethyl 4-bromo-n-butyrate (3.4 g) were added, and the mixture was reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with a 20% aqueous methanol solution and recrystallized from ethanol to obtain Compound 57 (4.4 g, Y = 87%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.00-2.68 (4H, m) 4.00-4.35 (4H, m) 7.14-8.69 (10H, m)
Compound 57 (4.35 g) was dissolved in methanol (150 mL), 20% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted under reflux for 3 hr. The reaction solution was concentrated under reduced pressure, and 40% methanol aqueous solution (700 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 58 (3.99 g, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.83-2.60 (4H, m) 4.17 (2H, t, J = 6 Hz) 7.18-8.73 (10H, m) 12.21 (1H, br)
To compound 58 (110 mg), water (100 mL) and 1% aqueous sodium hydroxide solution (1.5 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give Compound 59 (121 mg, Y = 103%).

Ｎ−［４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソブチル］グリシンエチルエステル（化合物６０）、Ｎ−［４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソブチル］グリシンカリウム塩（化合物６１）の製造：
トルエン（３０ｍＬ）中、化合物５８（０．８０ｇ）を塩化チオニル（０．４ｇ）と還流下で２時間反応した。冷却後、グリシンエチルエステル塩酸塩（０．４２ｇ）、トリエチルアミン（０．９ｇ）の１，３−ジメチル−２−イミダゾリジノン（４０ｍＬ）溶液を加え、水冷下１６時間反応した。反応液を減圧濃縮し、残渣に水（５００ｍＬ）を加え晶析した。析出した結晶をろ取、水洗し粗製結晶を得た。粗製結晶をアセトン（２５０ｍＬ）から再結晶して化合物６０（７０９ｍｇ，Ｙ＝７１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１９（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．９５−２．６６（４Ｈ，ｍ）３．８０−４．３８（６Ｈ，ｍ）７．２３−８．４７（１０Ｈ，ｍ）８．７６（１Ｈ，ｓ）
メタノール（４０ｍＬ）中、化合物６０（５００ｍｇ）に５％水酸化カリウム水溶液（１０ｍＬ）を加え、室温で一夜反応した。析出結晶をろ取し、８０％メタノール水溶液で洗浄後、乾燥して化合物６１（３６５ｍｇ，Ｙ＝７１％）を得た。N- [4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] glycine ethyl ester (compound 60), N- [4-[[6- (2-benzo Preparation of Oxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] glycine potassium salt (Compound 61):
Compound 58 (0.80 g) was reacted with thionyl chloride (0.4 g) in toluene (30 mL) for 2 hours under reflux. After cooling, a solution of glycine ethyl ester hydrochloride (0.42 g) and triethylamine (0.9 g) in 1,3-dimethyl-2-imidazolidinone (40 mL) was added and reacted for 16 hours under water cooling. The reaction solution was concentrated under reduced pressure, and water (500 mL) was added to the residue for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from acetone (250 mL) to give compound 60 (709 mg, Y = 71%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.19 (3H, t, J = 7 Hz) 1.95-2.66 (4H, m) 3.80-4.38 (6H, m) 7.23-8.47 (10H, m) 8.76 (1H, s)
A 5% aqueous potassium hydroxide solution (10 mL) was added to compound 60 (500 mg) in methanol (40 mL), and the mixture was reacted overnight at room temperature. The precipitated crystals were collected by filtration, washed with an 80% aqueous methanol solution, and dried to obtain Compound 61 (365 mg, Y = 71%).

２−［［４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソブチル］アミノ］ペンタン二酸ジエチルエステル（化合物６２）、２−［［４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソブチル］アミノ］ペンタン二酸（化合物６３）、２−［［４−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソブチル］アミノ］ペンタン二酸二ナトリウム塩（化合物６４）の製造：
化合物５８（６５０ｍｇ）にトルエン（２０ｍＬ）、塩化チオニル（０．１７ｍＬ）、ＤＭＦ（１滴）を加えて還流下で２．５時間反応した後、Ｌ−グルタミン酸ジエチル塩酸塩（６００ｍｇ）の１，３−ジメチル−２−イミダゾリジノン（２０ｍＬ）溶液、トリエチルアミン（０．８５ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残液に２％塩酸水溶液（８０ｍＬ）を加え、析出した結晶をろ取した。得られた結晶をエタノールから再結晶して化合物６２（５３４ｍｇ，Ｙ＝５４％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１５−１．３９（６Ｈ，ｍ）１．８８−２．６６（８Ｈ，ｍ）３．９３−４．８１（７Ｈ，ｍ）７．１６−８．７０（１０Ｈ，ｍ）
化合物６２（５００ｍｇ）をメタノール（２００ｍＬ）に溶解し、２％水酸化ナトリウム水溶液（１５ｍＬ）を加えて約４５℃で一夜反応した。析出した結晶をろ取、乾燥して化合物６４（９９ｍｇ，Ｙ＝２０％）を得た。
化合物６４のろ液を減圧濃縮し、残渣に水（３０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物６３（１２５ｍｇ，Ｙ＝２８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６６−２．６４（８Ｈ，ｍ）４．００−４．５０（３Ｈ，ｍ）７．２３−８．７５（１０Ｈ，ｍ）１２．３（２Ｈ，ｂｒ）2-[[4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid diethyl ester (Compound 62), 2-[[4-[[ 6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid (Compound 63), 2-[[4-[[6- (2-Benzoxazolyl)] Preparation of 2-Naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid disodium salt (Compound 64):
Toluene (20 mL), thionyl chloride (0.17 mL) and DMF (1 drop) were added to compound 58 (650 mg) and reacted under reflux for 2.5 hours. 3-Dimethyl-2-imidazolidinone (20 mL) solution and triethylamine (0.85 mL) were added and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, 2% aqueous hydrochloric acid solution (80 mL) was added to the remaining solution, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 62 (534 mg, Y = 54%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.5-1.39 (6H, m) 1.88-2.66 (8H, m) 3.93-4.81 (7H, m) 7.16-8.70 (10H, m)
Compound 62 (500 mg) was dissolved in methanol (200 mL), 2% aqueous sodium hydroxide solution (15 mL) was added, and the mixture was reacted at about 45 ° C. overnight. The precipitated crystals were collected by filtration and dried to obtain Compound 64 (99 mg, Y = 20%).
The filtrate of Compound 64 was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution, and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 63 (125 mg, Y = 28%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.6-2.64 (8H, m) 4.00-4.50 (3H, m) 7.23-8.75 (10H, m) 12.3 (2H, br)

６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物６５）、６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物６６）、６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物６７）の製造：
ＤＭＦ（１５ｍＬ）中、化合物５３（１．００ｇ）に炭酸カリウム（０．９２ｇ），６−ブロモヘキサン酸エチル（０．９１ｇ）を加え、室温で１８時間，８０〜９０℃で１．５時間反応した。反応液を水（１５０ｍＬ）に加え晶析し、析出結晶をろ取、水洗して化合物６５（１．３９ｇ，Ｙ＝１００％）を得た。
メタノール（４０ｍＬ）中、化合物６５（０．９８ｇ）に１０％水酸化カリウム水溶液（１０ｍＬ）を加え、室温で一夜、還流下で１時間反応した。反応液を減圧濃縮後、残渣に水（２００ｍＬ），３５％塩酸を加え酸析した。結晶をろ取、水洗後、乾燥して化合物６６（０．９０ｇ，Ｙ＝９９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２８−２．５１（８Ｈ，ｍ）４．１３（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．１７−８．２６（９Ｈ，ｍ）８．７２（１Ｈ，ｓ）
化合物６６（２００ｍｇ）に０．０３％水酸化カリウム水溶液（１５０ｍＬ）を加え加温溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物６７（２１６ｍｇ，Ｙ＝９８％）を得た。6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 65), 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy Preparation of hexanoic acid (Compound 66), 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 67):
Potassium carbonate (0.92 g) and ethyl 6-bromohexanoate (0.91 g) were added to compound 53 (1.00 g) in DMF (15 mL), and the mixture was added at room temperature for 18 hours and at 80 to 90 ° C. for 1.5 hours. Reacted. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 65 (1.39 g, Y = 100%).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 65 (0.98 g) in methanol (40 mL), and reacted at room temperature overnight and under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and water (200 mL) and 35% hydrochloric acid were added to the residue for acid precipitation. The crystals were collected by filtration, washed with water, and dried to obtain Compound 66 (0.90 g, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.28−2.51 (8H, m) 4.13 (2H, t, J = 4 Hz) 7.17-8.26 (9H, m) 8.72 (1H, s)
0.066% aqueous potassium hydroxide solution (150 mL) was added to compound 66 (200 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 67 (216 mg, Y = 98%).

６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（２，２−ジメチル−１−オキソプロポキシ）メチルエステル（化合物６８）の製造：
ＤＭＦ（１０ｍＬ）中、化合物６６（１５０ｍｇ）に炭酸カリウム（３２０ｍｇ），ピバリン酸クロロメチル（１８０ｍｇ）を加え、８０〜９０℃で２０時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して粗製結晶を得た。粗製結晶を８０％エタノール水溶液（１０ｍＬ）から再結晶して化合物６８（１４７ｍｇ，Ｙ＝７５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２２（９Ｈ，ｓ）１．６１−２．００（６Ｈ，ｍ）２．４３（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１１（２Ｈ，ｔ，Ｊ＝６Ｈｚ）５．７７（２Ｈ，ｓ）７．１４−７．９６（８Ｈ，ｍ）８．２２−８．３６（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，９Ｈｚ）８．７０（１Ｈ，ｓ）Preparation of 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester (Compound 68):
In DMF (10 mL), potassium carbonate (320 mg) and chloromethyl pivalate (180 mg) were added to compound 66 (150 mg) and reacted at 80 to 90 ° C. for 20 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (10 mL) to give compound 68 (147 mg, Y = 75%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.22 (9H, s) 1.61-2.00 (6H, m) 2.43 (2H, t, J = 6 Hz) 4.11 (2H, t, J = 6 Hz) 5.77 ( 2H, s) 7.14-7.96 (8H, m) 8.22-8.36 (1H, dd, J = 1 Hz, 9 Hz) 8.70 (1H, s)

２−［［６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソヘキシル］アミノ］ペンタン二酸ジエチルエステル（化合物６９）、２−［［６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソヘキシル］アミノ］ペンタン二酸（化合物７０）、２−［［６−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−オキソヘキシル］アミノ］ペンタン二酸二ナトリウム塩（化合物７１）の製造：
化合物６６（７００ｍｇ）にトルエン（２０ｍＬ）、塩化チオニル（０．１６ｍＬ）、ＤＭＦ（１滴）を加え、還流下で３時間反応した後、Ｌ−グルタミン酸ジエチル塩酸塩（０．５５ｇ）の１，３−ジメチル−２−イミダゾリジノン（２０ｍＬ）溶液、トリエチルアミン（０．８ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残液に２％塩酸水溶液（８０ｍＬ）を加え、析出した結晶をろ取した。得られた結晶をエタノールから再結晶して化合物６９（４２５ｍｇ，Ｙ＝４４％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１１−２．５７（１８Ｈ，ｍ）３．９６−４．８３（７Ｈ，ｍ）７．１４−８．７７（１１Ｈ，ｍ）
化合物６９（４００ｍｇ）にメタノール（１００ｍＬ）を加えて溶解し、１％水酸化ナトリウム水溶液（２０ｍＬ）を加えて約４５℃で一夜反応した。反応液を減圧濃縮後、残渣を水（６０ｍＬ）に溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物７０（１１４ｍｇ，Ｙ＝３２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３０−２．４１（１２Ｈ，ｍ）４．０５−４．２８（３Ｈ，ｍ）７．１８−８．７５（１０Ｈ，ｍ）１２．３（２Ｈ，ｂｒ）
化合物７０（９０．５ｍｇ）に水（４０ｍＬ）、０．５％水酸化ナトリウム水溶液（２．９ｍＬ）を加えて溶解し、ろ過した。ろ液を凍結乾燥して化合物７１（１００．６ｍｇ，Ｙ：１０２％）を得た。2-[[6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid diethyl ester (Compound 69), 2-[[6- [ [6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid (Compound 70), 2-[[6-[[6- (2-Benzoxazolyl] (L) -2-Naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid disodium salt (Compound 71):
Toluene (20 mL), thionyl chloride (0.16 mL) and DMF (1 drop) were added to compound 66 (700 mg), reacted for 3 hours under reflux, and then 1, L-glutamic acid diethyl hydrochloride (0.55 g) 1, 3-Dimethyl-2-imidazolidinone (20 mL) solution and triethylamine (0.8 mL) were added and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, 2% aqueous hydrochloric acid solution (80 mL) was added to the remaining solution, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 69 (425 mg, Y = 44%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.1-12.57 (18H, m) 3.96-4.83 (7H, m) 7.14-8.77 (11H, m)
Methanol (100 mL) was added to Compound 69 (400 mg) to dissolve, 1% aqueous sodium hydroxide solution (20 mL) was added, and the mixture was reacted at about 45 ° C. overnight. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water (60 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 70 (114 mg, Y = 32%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.30-2.41 (12H, m) 4.05-4.28 (3H, m) 7.18-8.75 (10H, m) 12.3 (2H, br)
To compound 70 (90.5 mg), water (40 mL) and 0.5% aqueous sodium hydroxide solution (2.9 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to obtain Compound 71 (100.6 mg, Y: 102%).

［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸ジエチルエステル（化合物７２）、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸（化合物７３）、［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸二ナトリウム塩（化合物７４）の製造：
化合物５３（６００ｍｇ）をＤＭＦ（１８ｍＬ）に溶解し、炭酸カリウム（０．９ｇ）、ブロモマロン酸ジエチル（６５０ｍｇ）を加えて室温で一夜反応した。反応液をろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラム（酢酸エチル／ｎ−ヘキサン）で精製して化合物７２（１５６ｍｇ，Ｙ＝１９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．３２（６Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１８−４．５４（４Ｈ，ｍ）５．３９（１Ｈ，ｓ）７．１５−８．６９（１０Ｈ，ｍ）
化合物７２（１００ｍｇ）にメタノール（５０ｍＬ）、５％水酸化ナトリウム水溶液（２ｍＬ）を加えて約５０℃で３時間反応した。反応液を減圧濃縮し、残渣を水（５０ｍＬ）に溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物７３（９７ｍｇ，Ｙ＝９０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．６５（１Ｈ，ｓ）７．３３−８．７８（１０Ｈ，ｍ）
化合物７３（６０ｍｇ）を水（４０ｍＬ）に懸濁し、１．６％水酸化ナトリウム水溶液（０．８ｍＬ）を加えて溶解後、ろ過した。ろ液を凍結乾燥して化合物７４（６５ｍｇ，Ｙ＝９７％）を得た。[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid diethyl ester (Compound 72), [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propane Preparation of acid (compound 73), [[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid disodium salt (compound 74):
Compound 53 (600 mg) was dissolved in DMF (18 mL), potassium carbonate (0.9 g) and diethyl bromomalonate (650 mg) were added, and the mixture was reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate / n-hexane) to obtain Compound 72 (156 mg, Y = 19%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.32 (6H, t, J = 7 Hz) 4.18-4.54 (4H, m) 5.39 (1H, s) 7.15-8.69 (10H, m)
Methanol (50 mL) and 5% aqueous sodium hydroxide solution (2 mL) were added to compound 72 (100 mg) and reacted at about 50 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL), and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 73 (97 mg, Y = 90%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.65 (1H, s) 7.33-8.78 (10H, m)
Compound 73 (60 mg) was suspended in water (40 mL), dissolved by adding 1.6% aqueous sodium hydroxide solution (0.8 mL), and then filtered. The filtrate was lyophilized to give compound 74 (65 mg, Y = 97%).

［３−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物７５）、［３−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸（化合物７６）、［３−［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物７７）の製造：
化合物５３（３７２ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（１．０ｇ）、（３−クロロプロピル）マロン酸ジエチル（３５０ｍｇ）を加えて約６０℃で一夜反応した。反応液に酢酸エチル（３００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水後、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物７５（２９９ｍｇ，Ｙ＝５２％）を得た。
化合物７５（２９９ｍｇ）にメタノール（５０ｍＬ）、３０％水酸化ナトリウム水溶液（１ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物７６（１７４ｍｇ，Ｙ＝６６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６６−２．０９（４Ｈ，ｍ）３．３８（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１０−４．３０（２Ｈ，ｍ）７．２３−８．７５（１０Ｈ，ｍ）１２．８２（２Ｈ，ｂｒ）
化合物７６（１３３ｍｇ）に水（４０ｍＬ）、０．５％水酸化ナトリウム水溶液（５．２ｍＬ）を加えて溶解し、ろ過した。ろ液を凍結乾燥して化合物７７（１２５ｍｇ，Ｙ＝８５％）を得た。[3-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 75), [3-[[6- (2-Benzoxazolyl)- 2-Naphthalenyl] oxy] propyl] propanedioic acid (Compound 76), [3-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (Compound 77) Manufacturing of:
Compound 53 (372 mg) was dissolved in DMF (15 mL), potassium carbonate (1.0 g) and diethyl (3-chloropropyl) malonate (350 mg) were added, and the mixture was reacted at about 60 ° C. overnight. Ethyl acetate (300 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 75 (299 mg, Y = 52%).
Methanol (50 mL) and 30% aqueous sodium hydroxide solution (1 mL) were added to compound 75 (299 mg), and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 76 (174 mg, Y = 66%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.66-2.09 (4H, m) 3.38 (1H, t, J = 6 Hz) 4.10-4.30 (2H, m) 7.23-8.75 (10H, m) 12.82 (2H, br)
To compound 76 (133 mg), water (40 mL) and a 0.5% aqueous sodium hydroxide solution (5.2 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to give compound 77 (125 mg, Y = 85%).

２−［６−［２−（１−ピロリジニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物７８）の製造：
ＤＭＦ（１０ｍＬ）中、化合物５３（３００ｍｇ）に炭酸カリウム（６９０ｍｇ），１−（２−クロロエチル）ピロリジン塩酸塩（２６６ｍｇ）を加え、７０〜８０℃で１７時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム／メタノール）で精製後、３５％塩酸で塩酸塩として化合物７８（１９５ｍｇ，Ｙ＝４９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８７−２．０９（４Ｈ，ｍ）３．０８−３．７３（６Ｈ，ｍ）４．５８（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３２−８．３４（９Ｈ，ｍ）８．７８（１Ｈ，ｓ）１０．５５−１２．０７（１Ｈ，ｂｒ）Preparation of 2- [6- [2- (1-pyrrolidinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 78):
Potassium carbonate (690 mg) and 1- (2-chloroethyl) pyrrolidine hydrochloride (266 mg) were added to compound 53 (300 mg) in DMF (10 mL) and reacted at 70-80 ° C. for 17 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform / methanol), and then compound 78 (195 mg, Y = 49%) was obtained as a hydrochloride with 35% hydrochloric acid.
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.87-2.09 (4H, m) 3.08-3.73 (6H, m) 4.58 (2H, t, J = 5 Hz) 7.32-8.34 (9H, m) 8.78 (1H, s) 10.55-12.07 (1H, br)

２−［６−［２−（１−ピペリジニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物７９）の製造：
ＤＭＦ（８ｍＬ）中、化合物５３（３００ｍｇ）に炭酸カリウム（６９４ｍｇ），１−（２−クロロエチル）ピペリジン塩酸塩（２８４ｍｇ）を加え、７０〜８０℃で３時間反応した。反応液を水（１００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗した。得られた結晶をアセトン（２０ｍＬ）に溶解後、３５％塩酸を加え、析出した結晶をろ取、乾燥して化合物７９（３３１ｍｇ，Ｙ＝８１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３８−２．１４（６Ｈ，ｍ）２．７７−３．６１（６Ｈ，ｍ）４．６４（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３０−８．３６（９Ｈ，ｍ）８．７８（１Ｈ，ｓ）１０．２０−１１．６９（１Ｈ，ｂｒ）Preparation of 2- [6- [2- (1-piperidinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 79):
Potassium carbonate (694 mg) and 1- (2-chloroethyl) piperidine hydrochloride (284 mg) were added to compound 53 (300 mg) in DMF (8 mL) and reacted at 70-80 ° C. for 3 hours. The reaction solution was added to water (100 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were dissolved in acetone (20 mL), 35% hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 79 (331 mg, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38-2.14 (6H, m) 2.77-3.61 (6H, m) 4.64 (2H, t, J = 5 Hz) 7.30-8.36 (9H, m) 8.78 (1H, s) 10.20-11.69 (1H, br)

２−［６−［（４−ピリジニル）メトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物８０）、２−［６−［（４−ピリジニル）メトキシ］−２−ナフタレニル］ベンゾオキサゾール（化合物８１）の製造：
ＤＭＦ（１０ｍＬ）中、化合物５３（３００ｍｇ）に炭酸カリウム（６９６ｍｇ），４−クロロメチルピリジン塩酸塩（２４７ｍｇ）を加え、７０〜８０℃で２時間，１２０℃で３時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム／メタノール）で精製した後、３５％塩酸で塩酸塩として化合物８０（１１２ｍｇ，Ｙ＝２９％）を得た。
水（３ｍＬ）中、化合物８０（５０ｍｇ）に２５％アンモニア水溶液を加え撹拌懸濁後、結晶をろ取、乾燥して化合物８１（３５ｍｇ，Ｙ＝７７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２３（２Ｈ，ｓ）７．１０−８．７１（１４Ｈ，ｍ）2- [6-[(4-pyridinyl) methoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 80), 2- [6-[(4-pyridinyl) methoxy] -2-naphthalenyl] benzoxazole (Compound 81) )Manufacturing of:
Potassium carbonate (696 mg) and 4-chloromethylpyridine hydrochloride (247 mg) were added to compound 53 (300 mg) in DMF (10 mL) and reacted at 70-80 ° C. for 2 hours and 120 ° C. for 3 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform / methanol), and then compound 80 (112 mg, Y = 29%) was obtained as a hydrochloride with 35% hydrochloric acid.
A 25% aqueous ammonia solution was added to compound 80 (50 mg) in water (3 mL) and suspended with stirring. The crystals were collected by filtration and dried to obtain compound 81 (35 mg, Y = 77%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.23 (2H, s) 7.10-8.71 (14H, m)

２−［６−［（５−クロロペンチル）オキシ］−２−ナフタレニル］ベンゾオキサゾール（化合物８２）の製造：
化合物５３（０．９ｇ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（３．５ｇ）、１−ブロモ−５−クロロペンタン（０．８０ｇ）を加えて室温で一夜反応した。反応液に水（８０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノール洗浄後乾燥して化合物８２（１．１５ｇ，Ｙ＝１０５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．３−２．１（６Ｈ，ｍ）３．５９（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１１（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１３−８．６９（１０Ｈ，ｍ）Preparation of 2- [6-[(5-chloropentyl) oxy] -2-naphthalenyl] benzoxazole (Compound 82):
Compound 53 (0.9 g) was dissolved in DMF (20 mL), and potassium carbonate (3.5 g) and 1-bromo-5-chloropentane (0.80 g) were added and reacted overnight at room temperature. Water (80 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 82 (1.15 g, Y = 105%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.3−2.1 (6H, m) 3.59 (2H, t, J = 6 Hz) 4.11 (2H, t, J = 6 Hz) 7.13-8.69 (10H, m)

２−［６−［［５−（１−ピロリジニル）ペンチル］オキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物８３）の製造：
化合物８２（３７０ｍｇ）にキシレン（６０ｍＬ）、ピロリジン（３ｍＬ）を加えて還流下で３日間反応した。反応液を減圧濃縮後、残渣に０．５％水酸化ナトリウム水溶液（５０ｍＬ）を加え、析出した結晶をろ取した。得られた結晶をアセトン（８０ｍＬ）に溶解後、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物８３（３３８ｍｇ，Ｙ＝７７％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝１．５０−２．３０（１０Ｈ，ｍ）３．０２−３．５４（６Ｈ，ｍ）４．１７（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．１６−８．６４（１０Ｈ，ｍ）Preparation of 2- [6-[[5- (1-pyrrolidinyl) pentyl] oxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 83):
Xylene (60 mL) and pyrrolidine (3 mL) were added to compound 82 (370 mg), and reacted under reflux for 3 days. The reaction mixture was concentrated under reduced pressure, 0.5% aqueous sodium hydroxide solution (50 mL) was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (80 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 83 (338 mg, Y = 77%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.50-2.30 (10H, m) 3.02-3.54 (6H, m) 4.17 (2H, t, J = 4 Hz) 7.16-8.64 (10H, m)

２−［６−［［５−（４−メチル−１−ピペラジニル）ペンチル］オキシ］−２−ナフタレニル］ベンゾオキサゾール二塩酸塩（化合物８４）の製造：
化合物８２（３００ｍｇ）にキシレン（５０ｍＬ）、Ｎ−メチルピペラジン（１．５ｍＬ）を加えて還流下で二夜反応した。反応液を減圧濃縮し、残渣に０．５％水酸化ナトリウム水溶液（５０ｍＬ）を加え、析出した結晶をろ取した。得られた結晶をアセトン（５０ｍＬ）に溶解後、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物８４（３７０ｍｇ，Ｙ＝９０％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４，Ｄ_２Ｏ／ＴＭＳ）：
δ＝１．６０−２．１０（６Ｈ，ｍ）２．９２−３．６６（１３Ｈ，ｍ）４．１９（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．１６−８．６７（１０Ｈ，ｍ）Preparation of 2- [6-[[5- (4-Methyl-1-piperazinyl) pentyl] oxy] -2-naphthalenyl] benzoxazole dihydrochloride (Compound 84):
To compound 82 (300 mg), xylene (50 mL) and N-methylpiperazine (1.5 mL) were added and reacted under reflux overnight. The reaction mixture was concentrated under reduced pressure, 0.5% aqueous sodium hydroxide solution (50 mL) was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (50 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 84 (370 mg, Y = 90%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 1.60-2.10 (6H, m) 2.92-3.66 (13H, m) 4.19 (2H, t, J = 5 Hz) 7.16-8.67 (10H, m)

６−メチル−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物８５）、６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物８６）、［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸メチルエステル（化合物８７）、［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸（化合物８８）、［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸カリウム塩（化合物８９）の製造：
トルエン（５０ｍＬ）中、６−ベンジルオキシ−２−ナフトエ酸（５．０ｇ）に塩化チオニル（２．４ｇ）を加え、２時間還流下で反応した。反応液を減圧濃縮後、残渣にｎ−ヘキサン（２００ｍＬ）を加え撹拌した。結晶をろ取、乾燥して６−ベンジルオキシ−２−ナフトエ酸クロライド（４．９ｇ，Ｙ＝９２％）を得た。
６−ベンジルオキシ−２−ナフトエ酸クロライド（２．０ｇ）を６−アミノ−ｍ−クレゾール（１．０ｇ）、トリエチルアミン（０．８ｇ）の１，３−ジメチル−２−イミダゾリジノン（４０ｍＬ）溶液に加え、室温で一夜反応した。反応液を飽和炭酸水素カリウム水溶液（４００ｍＬ）中に加え晶析し、結晶をろ取、水洗し粗製結晶を得た。粗製結晶をメタノールと共に還流下で撹拌懸濁後、結晶をろ取して中間体のアミド化合物（０．４６ｇ）を得た。
１，３−ジメチル−２−イミダゾリジノン（１５０ｍＬ）、トルエン（４５０ｍＬ）の混液中、アミド化合物（１０．０ｇ）にｐ−トルエンスルホン酸一水和物（９．９３ｇ）を加え、還流下で生成する水を除去しながら２７時間反応した。反応液を減圧濃縮し、残液を１％水酸化カリウム水溶液（１５００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗し、得られた粗製結晶にメタノール（６００ｍＬ），水酸化カリウム（６ｇ）を加え、５時間還流下で撹拌懸濁した後、結晶をろ取、乾燥して化合物８５（６．９１ｇ，Ｙ＝７２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．４９（３Ｈ，ｓ）５．２８（２Ｈ，ｓ）７．１７−８．２８（１３Ｈ，ｍ）８．７２（１Ｈ，ｓ）
１，３−ジメチル−２−イミダゾリジノン（９００ｍＬ）に化合物８５（１８．０ｇ）を加え溶解後、５％パラジウム炭素（２．０ｇ）を加え水素雰囲気下で２３時間反応した。反応液をろ過し、ろ液を水（１０Ｌ）中に加え晶析した。析出結晶をろ取、水洗後、乾燥して化合物８６（１３．２ｇ，Ｙ＝９７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．４９（３Ｈ，ｓ）７．１６−８．２３（８Ｈ，ｍ）８．６７（１Ｈ，ｓ）１０．１４（１Ｈ，ｓ）
ＤＭＦ（１２ｍＬ）中、化合物８６（０．６ｇ）に炭酸カリウム（０．６ｇ），ブロモ酢酸メチル（０．４ｇ）を加え、室温で８時間反応した。反応液を水（１２０ｍＬ）中に加え晶析し、析出結晶をろ取、水洗し化合物８７（Ｗｅｔ２．５５ｇ）を得た。
メタノール（２０ｍＬ）中、化合物８７（Ｗｅｔ２．５５ｇ）に４％水酸化ナトリウム水溶液（５ｍＬ）を加え、室温で３．５時間、５０℃で１時間反応した。反応液を減圧濃縮後、残渣に水（１００ｍＬ）を加え、３５％塩酸で酸析した。析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶をメタノール（２０ｍＬ）と共に還流下で１時間撹拌した後、結晶をろ取、乾燥して化合物８８（０．５１ｇ，Ｙ＝７０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．４９（３Ｈ，ｓ）４．８７（２Ｈ，ｓ）７．１７−８．２９（８Ｈ，ｍ）８．７２（１Ｈ，ｓ）
化合物８８（１００ｍｇ）に０．１％水酸化カリウム水溶液（２０ｍＬ），エタノール（１０ｍＬ）を加え加温溶解した。活性炭（０．１ｇ）を加え熱時ろ過後、ろ液を減圧濃縮し、化合物８９（５６ｍｇ，Ｙ＝５０％）を得た。6-methyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 85), 6- (6-methyl-2-benzoxazolyl) -2-naphthalenol (compound 86), [[ 6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester (Compound 87), [[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] Production of [oxy] acetic acid (compound 88), [[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid potassium salt (compound 89):
Thionyl chloride (2.4 g) was added to 6-benzyloxy-2-naphthoic acid (5.0 g) in toluene (50 mL) and reacted under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and n-hexane (200 mL) was added to the residue and stirred. The crystals were collected by filtration and dried to obtain 6-benzyloxy-2-naphthoic acid chloride (4.9 g, Y = 92%).
6-Benzyloxy-2-naphthoic acid chloride (2.0 g) was replaced with 6-amino-m-cresol (1.0 g) and triethylamine (0.8 g) of 1,3-dimethyl-2-imidazolidinone (40 mL). Added to the solution and reacted overnight at room temperature. The reaction solution was added to a saturated aqueous potassium hydrogen carbonate solution (400 mL) for crystallization, and the crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were stirred and suspended with methanol under reflux, and the crystals were collected by filtration to obtain an intermediate amide compound (0.46 g).
In a mixed liquid of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL), p-toluenesulfonic acid monohydrate (9.93 g) was added to the amide compound (10.0 g), and the mixture was refluxed. The reaction was carried out for 27 hours while removing the water produced in step (b). The reaction solution was concentrated under reduced pressure, and the residue was added to a 1% aqueous potassium hydroxide solution (1500 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, methanol (600 mL) and potassium hydroxide (6 g) were added to the resulting crude crystals, and the mixture was suspended under stirring for 5 hours under reflux. The crystals were collected by filtration and dried to give compound 85. (6.91 g, Y = 72%) was obtained.
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.49 (3H, s) 5.28 (2H, s) 7.17-8.28 (13H, m) 8.72 (1H, s)
Compound 85 (18.0 g) was added to 1,3-dimethyl-2-imidazolidinone (900 mL) and dissolved, 5% palladium carbon (2.0 g) was added, and the reaction was carried out in a hydrogen atmosphere for 23 hours. The reaction solution was filtered, and the filtrate was added to water (10 L) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 86 (13.2 g, Y = 97%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.49 (3H, s) 7.16-8.23 (8H, m) 8.67 (1H, s) 10.14 (1H, s)
In DMF (12 mL), potassium carbonate (0.6 g) and methyl bromoacetate (0.4 g) were added to compound 86 (0.6 g) and reacted at room temperature for 8 hours. The reaction solution was added to water (120 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 87 (Wet 2.55 g).
A 4% aqueous sodium hydroxide solution (5 mL) was added to compound 87 (Wet 2.55 g) in methanol (20 mL), and reacted at room temperature for 3.5 hours and at 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were stirred with methanol (20 mL) under reflux for 1 hour, and then the crystals were collected by filtration and dried to obtain Compound 88 (0.51 g, Y = 70%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.49 (3H, s) 4.87 (2H, s) 7.17-8.29 (8H, m) 8.72 (1H, s)
To compound 88 (100 mg), 0.1% aqueous potassium hydroxide solution (20 mL) and ethanol (10 mL) were added and dissolved by heating. Activated carbon (0.1 g) was added and filtered while hot, and then the filtrate was concentrated under reduced pressure to obtain Compound 89 (56 mg, Y = 50%).

４−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物９０）、４−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物９１）、４−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸カリウム塩（化合物９２）の製造：
ＤＭＦ（１５ｍＬ）中、化合物８６（１．０ｇ）に炭酸カリウム（１．０ｇ），４−ブロモ−ｎ−酪酸エチル（０．８５ｇ）を加え、室温で２２時間，４５℃で４．５時間反応した。反応液を水（１５０ｍＬ）中に加え晶析し、析出結晶をろ取、水洗し化合物９０（Ｗｅｔ３．９ｇ）を得た。
メタノール（４０ｍＬ）中、化合物９０（Ｗｅｔ３．９ｇ）に１０％水酸化カリウム水溶液（１０ｍＬ）を加え、室温で３日間，６０〜７０℃で４時間反応した。反応液を減圧濃縮し、残渣に水（３００ｍＬ）を加えて加温溶解後、活性炭（０．５ｇ）を加え熱時ろ過した。ろ液に３５％塩酸を加え酸析し、結晶をろ取、水洗後、乾燥して化合物９１（０．９５ｇ，Ｙ＝７２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８２−２．４９（７Ｈ，ｍ）４．１７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１７−８．２９（８Ｈ，ｍ）８．７０（１Ｈ，ｓ）１１．４８−１２．９７（１Ｈ，ｂｒ）
化合物９１（２００ｍｇ）に０．０２％水酸化カリウム水溶液（１７０ｍＬ）を加え加温溶解した後、活性炭（０．２ｇ）を加え熱時ろ過した。ろ液を凍結乾燥して化合物９２（１１２ｍｇ，Ｙ＝５１％）を得た。4-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 90), 4-[[6- (6-Methyl-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] butanoic acid (Compound 91), 4-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 92) Manufacturing:
Potassium carbonate (1.0 g) and ethyl 4-bromo-n-butyrate (0.85 g) were added to compound 86 (1.0 g) in DMF (15 mL), and the mixture was stirred at room temperature for 22 hours and at 45 ° C. for 4.5 hours. Reacted. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 90 (Wet 3.9 g).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 90 (Wet 3.9 g) in methanol (40 mL), and the mixture was reacted at room temperature for 3 days at 60 to 70 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and water (300 mL) was added to the residue and dissolved by heating. Then, activated carbon (0.5 g) was added and filtered while hot. 35% hydrochloric acid was added to the filtrate for acid precipitation, and the crystals were collected by filtration, washed with water, and dried to obtain Compound 91 (0.95 g, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.82-2.49 (7H, m) 4.17 (2H, t, J = 6 Hz) 7.17-8.29 (8H, m) 8.70 (1H, s) 11.48- 12.97 (1H, br)
To compound 91 (200 mg), 0.02% aqueous potassium hydroxide solution (170 mL) was added and dissolved by heating, and then activated carbon (0.2 g) was added and filtered while hot. The filtrate was lyophilized to give compound 92 (112 mg, Y = 51%).

５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンタン酸エチルエステル（化合物９３）、５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンタン酸（化合物９４）、５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンタン酸カリウム塩（化合物９５）の製造：
ＤＭＦ（１５ｍＬ）中、化合物８６（１．０ｇ）に炭酸カリウム（２．０ｇ），５−ブロモ吉草酸エチル（１．６８ｇ）を加え室温で２２時間，４５℃で６時間反応した。反応液を水（１５０ｍＬ）中に加え晶析し、析出結晶をろ取、水洗し化合物９３（１．５９ｇ，Ｙ＝１００％）を得た。
メタノール（４０ｍＬ）中、化合物９３（１．１６ｇ）に１０％水酸化カリウム水溶液（１０ｍＬ）を加え、４５℃で３時間反応した。反応液に活性炭（０．２ｇ）を加えろ過し、ろ液を減圧濃縮した。残渣に水（１００ｍＬ）を加え溶解した後、３５％塩酸で酸析した。結晶をろ取、水洗後、乾燥して化合物９４（０．８０ｇ，Ｙ＝７４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．７７−１．８３（４Ｈ，ｍ）２．２５−２．６６（５Ｈ，ｍ）４．１５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１７−８．２８（８Ｈ，ｍ）８．６９（１Ｈ，ｓ）１１．０６−１２．７６（１Ｈ，ｂｒ）
化合物９４（２００ｍｇ）に０．０２％水酸化カリウム水溶液（１７０ｍｌ）を加え加温溶解した後、活性炭（０．２ｇ）を加え熱時ろ過した。ろ液を凍結乾燥して化合物９５（１４２ｍｇ，Ｙ＝６５％）を得た。5-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid ethyl ester (Compound 93), 5-[[6- (6-Methyl-2-benzoxazolyl) ) -2-naphthalenyl] oxy] pentanoic acid (compound 94), 5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid potassium salt (compound 95) Manufacturing:
Potassium carbonate (2.0 g) and ethyl 5-bromovalerate (1.68 g) were added to compound 86 (1.0 g) in DMF (15 mL) and reacted at room temperature for 22 hours and at 45 ° C. for 6 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 93 (1.59 g, Y = 100%).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 93 (1.16 g) in methanol (40 mL) and reacted at 45 ° C. for 3 hours. Activated carbon (0.2 g) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue for dissolution, and then acidified with 35% hydrochloric acid. The crystals were collected by filtration, washed with water, and dried to obtain Compound 94 (0.80 g, Y = 74%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.77-1.83 (4H, m) 2.25-2.66 (5H, m) 4.15 (2H, t, J = 6 Hz) 7.17-8.28 (8H, m) 8.69 (1H, s) 11.06-12.76 (1H, br)
0.04% aqueous potassium hydroxide solution (170 ml) was added to compound 94 (200 mg) and dissolved by heating, and then activated carbon (0.2 g) was added and filtered while hot. The filtrate was lyophilized to give compound 95 (142 mg, Y = 65%).

５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンタン酸（２，２−ジメチル−１−オキソプロポキシ）メチルエステル（化合物９６）の製造：
ＤＭＦ（１０ｍＬ）中、化合物９４（１５０ｍｇ）に炭酸カリウム（１７７ｍｇ），ピバリン酸クロロメチル（１０４ｍｇ）を加え、８０〜９０℃で２時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して粗製結晶を得た。粗製結晶を８０％エタノール水溶液（１０ｍＬ）から再結晶して化合物９６（１５４ｍｇ，Ｙ＝７９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２２（９Ｈ，ｓ）１．６０−１．９０（４Ｈ，ｍ）２．２８−２．５２（５Ｈ，ｍ）４．１２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）５．７８（２Ｈ，ｓ）７．１３−７．９４（７Ｈ，ｍ）８．２８（１Ｈ，ｄ，Ｊ＝９Ｈｚ）８．６７（１Ｈ，ｓ）Preparation of 5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester (Compound 96):
Potassium carbonate (177 mg) and chloromethyl pivalate (104 mg) were added to compound 94 (150 mg) in DMF (10 mL), and reacted at 80 to 90 ° C. for 2 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (10 mL) to obtain Compound 96 (154 mg, Y = 79%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.22 (9H, s) 1.60-1.90 (4H, m) 2.28-2.52 (5H, m) 4.12 (2H, t, J = 6 Hz) 5.78 ( 2H, s) 7.13-7.94 (7H, m) 8.28 (1H, d, J = 9 Hz) 8.67 (1H, s)

６−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物９７）、６−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物９８）、６−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物９９）の製造：
ＤＭＦ（１５ｍＬ）中、化合物８６（１．０ｇ）に炭酸カリウム（２．０ｇ），６−ブロモヘキサン酸エチル（１．７９ｇ）を加え、室温で２１時間，４５℃で６時間反応した。反応液を水（１５０ｍＬ）中に加え晶析し、結晶をろ取、水洗して化合物９７（１．５４ｇ，Ｙ＝１００％）を得た。
メタノール（４０ｍＬ）中、化合物９７（１．２１ｇ）に１０％水酸化カリウム水溶液（１０ｍＬ）を加え、４５℃で３時間、還流下で１７時間反応した。反応液を減圧濃縮し、残渣に水（１００ｍＬ）を加え加温溶解後、活性炭（０．２ｇ）を加え熱時ろ過した。ろ液に３５％塩酸を加え酸析し、結晶をろ取、水洗後、乾燥して粗製結晶を得た。粗製結晶を酢酸エチルから再結晶して化合物９８（０．７４ｇ，Ｙ＝６６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．５９−２．０５（６Ｈ，ｍ）２．１８−２．６８（５Ｈ，ｍ）４．１３（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１６−８．２８（８Ｈ，ｍ）８．６９（１Ｈ，ｓ）１１．９７（１Ｈ，ｂｒｓ）
化合物９８（２００ｍｇ）に０．０３％水酸化カリウム水溶液（１２０ｍＬ）を加え加温溶解した後、活性炭（０．２ｇ）を加え熱時ろ過した。ろ液を凍結乾燥して化合物９９（１０５ｍｇ，Ｙ＝４８％）を得た。6-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 97), 6-[[6- (6-Methyl-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid (Compound 98), 6-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 99) Manufacturing:
Potassium carbonate (2.0 g) and ethyl 6-bromohexanoate (1.79 g) were added to compound 86 (1.0 g) in DMF (15 mL), and reacted at room temperature for 21 hours and at 45 ° C. for 6 hours. The reaction solution was added to water (150 mL) for crystallization, and the crystals were collected by filtration and washed with water to obtain Compound 97 (1.54 g, Y = 100%).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 97 (1.21 g) in methanol (40 mL) and reacted at 45 ° C. for 3 hours and under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was dissolved by heating. After that, activated carbon (0.2 g) was added and filtered while hot. 35% hydrochloric acid was added to the filtrate for acid precipitation, and the crystals were collected by filtration, washed with water, and dried to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate to give Compound 98 (0.74 g, Y = 66%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.59-2.05 (6H, m) 2.18-2.68 (5H, m) 4.13 (2H, t, J = 6 Hz) 7.16-8.28 (8H, m) 8.69 (1H, s) 11.97 (1H, brs)
0.098% aqueous potassium hydroxide solution (120 mL) was added to compound 98 (200 mg) and dissolved by heating, and then activated carbon (0.2 g) was added and filtered while hot. The filtrate was lyophilized to give Compound 99 (105 mg, Y = 48%).

７−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘプタン酸エチルエステル（化合物１００）、７−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘプタン酸（化合物１０１）、７−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘプタン酸カリウム塩（化合物１０２）の製造：
ＤＭＦ（２０ｍＬ）中、化合物８６（１．０ｇ）に炭酸カリウム（２．０ｇ），７−ブロモヘプタン酸エチル（１．１ｇ）を加え、室温で１９時間，８０℃で６時間反応した。反応液を水（２００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して化合物１００（１．４４ｇ，Ｙ＝９２％）を得た。
メタノール（４０ｍＬ）中、化合物１００（１．１９ｇ）に１０％水酸化カリウム水溶液（１０ｍＬ）を加え、７０℃で１時間反応した。反応液に活性炭（０．１ｇ）を加えろ過し、ろ液を減圧濃縮した。残渣を水（１００ｍＬ）に溶解し、３５％塩酸を加え酸析した。析出結晶をろ取、水洗後、乾燥して化合物１０１（１．０５ｇ，Ｙ＝９４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１３−２．４９（１３Ｈ，ｍ）４．１２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１７−８．２４（８Ｈ，ｍ）８．６９（１Ｈ，ｓ）１２．００（１Ｈ，ｂｒｓ）
化合物１０１（２００ｍｇ）に０．０５％水酸化カリウム水溶液（７０ｍＬ）を加え加温溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物１０２（２１０ｍｇ，Ｙ＝９６％）を得た。7-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] heptanoic acid ethyl ester (Compound 100), 7-[[6- (6-Methyl-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] heptanoic acid (Compound 101), 7-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] heptanoic acid potassium salt (Compound 102) Manufacturing:
In DMF (20 mL), potassium carbonate (2.0 g) and ethyl 7-bromoheptanoate (1.1 g) were added to compound 86 (1.0 g), and reacted at room temperature for 19 hours and at 80 ° C. for 6 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 100 (1.44 g, Y = 92%).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 100 (1.19 g) in methanol (40 mL) and reacted at 70 ° C. for 1 hour. Activated carbon (0.1 g) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL), and acidified by adding 35% hydrochloric acid. Precipitated crystals were collected by filtration, washed with water, and dried to give compound 101 (1.05 g, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.13-2.49 (13H, m) 4.12 (2H, t, J = 6 Hz) 7.17-8.24 (8H, m) 8.69 (1H, s) 12.00 ( 1H, brs)
To compound 101 (200 mg), 0.05% aqueous potassium hydroxide solution (70 mL) was added and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 102 (210 mg, Y = 96%).

［５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１０３）、［５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物１０４）、［５−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物１０５）の製造：
ＤＭＦ（１２ｍＬ）中、化合物８６（４００ｍｇ）に炭酸カリウム（９１０ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（７５７ｍｇ）を加え、室温で３０時間反応した。反応液を水（１５０ｍＬ）中に加え晶析し、析出結晶をろ取、水洗し化合物１０３（５６９ｍｇ，Ｙ＝７８％）を得た。
メタノール（２０ｍＬ）中、化合物１０３（４９６ｍｇ）に２２％水酸化カリウム水溶液（５ｍＬ）を加え、室温で１７時間反応した。反応液に活性炭を加えろ過し、ろ液を減圧濃縮した。残渣に水（５０ｍＬ）を加え、３５％塩酸で酸析した。分離したオイルを酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水した後、減圧濃縮した。残渣にエタノール（５ｍＬ）を加え撹拌懸濁した後、結晶をろ取、乾燥して化合物１０４（２７９ｍｇ，Ｙ＝６３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１８−１．９９（８Ｈ，ｍ）２．４９（３Ｈ，ｓ）３．２５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１７−８．２９（８Ｈ，ｍ）８．７０（１Ｈ，ｓ）１２．１５−１３．１９（２Ｈ，ｂｒ）
化合物１０４（１５０ｍｇ）に０．１４％水酸化ナトリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物１０５（１５８ｍｇ，Ｙ＝９６％）を得た。[5-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 103), [5-[[6- (6-methyl- 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 104), [5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid disodium salt (compound 105):
In DMF (12 mL), potassium carbonate (910 mg) and diethyl (5-bromopentyl) malonate (757 mg) were added to compound 86 (400 mg) and reacted at room temperature for 30 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 103 (569 mg, Y = 78%).
A 22% aqueous potassium hydroxide solution (5 mL) was added to compound 103 (496 mg) in methanol (20 mL), and reacted at room temperature for 17 hours. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and acidified with 35% hydrochloric acid. The separated oil was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. Ethanol (5 mL) was added to the residue and suspended with stirring, and the crystals were collected by filtration and dried to obtain Compound 104 (279 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-1.99 (8H, m) 2.49 (3H, s) 3.25 (1H, t, J = 7 Hz) 4.12 (2H, t, J = 6 Hz) 7.17− 8.29 (8H, m) 8.70 (1H, s) 12.15-13.19 (2H, br)
To the compound 104 (150 mg), 0.14% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 105 (158 mg, Y = 96%).

６−メチル−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物１０６）、６−メチル−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール（化合物１０７）の製造：
ＤＭＦ（２０ｍＬ）中、化合物８６（１．０ｇ）に炭酸カリウム（２．０ｇ），Ｎ−（２−クロロエチル）モルホリン塩酸塩（０．８１ｇ）を加え、室温で３時間，８０〜９０℃で３時間反応した。反応液を水（２００ｍＬ）中に加え晶析し、結晶をろ取、水洗し粗製結晶を得た。粗製結晶をアセトン（４０ｍＬ）に懸濁し、３５％塩酸を加えｐＨ≒１〜２とした後、結晶をろ取、乾燥して化合物１０６（１．３７ｇ，Ｙ＝８９％）を得た。
水（５ｍＬ）中、化合物１０６（１０３ｍｇ）に２５％アンモニア水溶液を加え撹拌懸濁後、結晶をろ取、乾燥して化合物１０７（７０ｍｇ，Ｙ＝７４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．４９−２．５９（７Ｈ，ｍ）２．７８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．６１（４Ｈ，ｔ，Ｊ＝５Ｈｚ）４．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１８−８．３０（８Ｈ，ｍ）８．７１（１Ｈ，ｓ）6-methyl-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 106), 6-methyl-2- [6- [2- (4-morpholinyl) Preparation of [Ethoxy] -2-naphthalenyl] benzoxazole (Compound 107):
Potassium carbonate (2.0 g) and N- (2-chloroethyl) morpholine hydrochloride (0.81 g) were added to compound 86 (1.0 g) in DMF (20 mL), and the mixture was heated at room temperature for 3 hours at 80 to 90 ° C. Reacted for 3 hours. The reaction solution was added to water (200 mL) for crystallization, and the crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were suspended in acetone (40 mL), and 35% hydrochloric acid was added to adjust the pH to about 1 to 2. Then, the crystals were collected by filtration and dried to obtain Compound 106 (1.37 g, Y = 89%).
A 25% aqueous ammonia solution was added to compound 106 (103 mg) in water (5 mL) and suspended with stirring. The crystals were collected by filtration and dried to obtain compound 107 (70 mg, Y = 74%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.49-2.59 (7H, m) 2.78 (2H, t, J = 6 Hz) 3.61 (4H, t, J = 5 Hz) 4.27 (2H, t, J = 6 Hz) 7.18-8.30 (8H, m) 8.71 (1H, s)

［３−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］カルバミン酸１，１−ジメチルエチルエステル（化合物１０８）、３−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩（化合物１０９）、３−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミンメタンスルホン酸塩（化合物１１０）の製造：
クロロホルム（３０ｍＬ）中、３−クロロプロピルアミン塩酸塩（２．６０ｇ）にトリエチルアミン（４．１０ｇ），二炭酸ジ−ｔ−ブチル（５．３０ｇ）を加え、３０℃で２時間反応した。反応液を１Ｎクエン酸水溶液（２５ｍＬ）及び飽和食塩水（２５ｍＬ）で洗浄した後、クロロホルム層を硫酸マグネシウムで脱水した。減圧下に濃縮してＮ−Ｂｏｃ−３−クロロプロピルアミン（４．２２ｇ）を得た。
ＤＭＦ（２０ｍＬ）中、化合物８６（１．０ｇ）に炭酸カリウム（１．０ｇ），Ｎ−Ｂｏｃ−３−クロロプロピルアミン（１．０ｇ）を加え、８０〜９０℃で１２時間反応した。反応液を水（２００ｍＬ）に加え晶析し、析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶をアセトン（２０ｍＬ）から再結晶して化合物１０８（０．９１ｇ，Ｙ＝５８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３９（９Ｈ，ｓ）１．８２−２．１５（２Ｈ，ｍ）２．４９（３Ｈ，ｓ）３．１６（２Ｈ，ｑ，Ｊ＝６Ｈｚ）４．１６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９０（１Ｈ，ｂｒｓ）７．１７−８．２７（８Ｈ，ｍ）８．７０（１Ｈ，ｓ）
化合物１０８（０．９０ｇ）に、氷水冷下で飽和塩酸・酢酸溶液（１０ｍＬ）を加え２時間反応した。反応液をジエチルエーテル（２００ｍＬ）に加え、室温で２時間撹拌後、結晶をろ取し、ジエチルエーテルで洗浄後、乾燥して化合物１０９（０．７１ｇ，Ｙ＝９２％）を得た。
７７％メタノール水溶液（１３ｍＬ）中、化合物１０９（１０６ｍｇ）にメタンスルホン酸（約０．８ｇ）を加え加温溶解した。冷却後、析出した結晶をろ取、乾燥して化合物１１０（９３ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８１−２．４９（８Ｈ，ｍ）３．０６（２Ｈ，ｔ，Ｊ＝７Ｈｚ）４．２６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１９−８．３１（１０Ｈ，ｍ）８．７３（１Ｈ，ｓ）[3-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] carbamic acid 1,1-dimethylethyl ester (Compound 108), 3-[[6- (6 -Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 109), 3-[[6- (6-Methyl-2-benzoxazolyl) -2- Preparation of naphthalenyl] oxy] -1-propanamine methanesulfonate (compound 110):
Triethylamine (4.10 g) and di-t-butyl dicarbonate (5.30 g) were added to 3-chloropropylamine hydrochloride (2.60 g) in chloroform (30 mL) and reacted at 30 ° C. for 2 hours. The reaction solution was washed with 1N aqueous citric acid solution (25 mL) and saturated brine (25 mL), and then the chloroform layer was dehydrated with magnesium sulfate. Concentration under reduced pressure gave N-Boc-3-chloropropylamine (4.22 g).
Potassium carbonate (1.0 g) and N-Boc-3-chloropropylamine (1.0 g) were added to compound 86 (1.0 g) in DMF (20 mL), and reacted at 80 to 90 ° C. for 12 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from acetone (20 mL) to give compound 108 (0.91 g, Y = 58%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39 (9H, s) 1.82-2.15 (2H, m) 2.49 (3H, s) 3.16 (2H, q, J = 6 Hz) 4.16 (2H, t, J = 6 Hz) 6.90 (1H, brs) 7.17-8.27 (8H, m) 8.70 (1H, s)
To compound 108 (0.90 g), a saturated hydrochloric acid / acetic acid solution (10 mL) was added under ice-water cooling and reacted for 2 hours. The reaction mixture was added to diethyl ether (200 mL) and stirred at room temperature for 2 hours. The crystals were collected by filtration, washed with diethyl ether and dried to give compound 109 (0.71 g, Y = 92%).
In 77% aqueous methanol solution (13 mL), methanesulfonic acid (about 0.8 g) was added to compound 109 (106 mg) and dissolved by heating. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 110 (93 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.8-1.2.49 (8H, m) 3.06 (2H, t, J = 7 Hz) 4.26 (2H, t, J = 6 Hz) 7.19-8.31 (10H, m) 8.73 (1H, s)

Ｎ，Ｎ−ジメチル−３−［［６−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩（化合物１１１）の製造：
ＤＭＦ（１０ｍＬ）中、化合物８６（０．５０ｇ）に炭酸カリウム（１．５０ｇ），３−ジメチルアミノプロピルクロリド塩酸塩（０．５０ｇ）を加え、室温で４時間，８０〜９０℃で１５時間反応した。反応液を水（３００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗した。得られた結晶をアセトン（６０ｍＬ）に加熱溶解後、３５％塩酸を加え酸性とした。析出結晶をろ取、乾燥して粗製結晶（０．３９ｇ）を得た。粗製結晶をメタノールから再結晶し化合物１１１（０．２２ｇ，Ｙ＝３１％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝２．１８−２．６３（５Ｈ，ｍ）２．９８（６Ｈ，ｓ）３．４３（２Ｈ，ｔ，Ｊ＝７Ｈｚ）４．２６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１４−８．２５（８Ｈ，ｍ）８．５６（１Ｈ，ｓ）Production of N, N-dimethyl-3-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 111):
Potassium carbonate (1.50 g) and 3-dimethylaminopropyl chloride hydrochloride (0.50 g) were added to compound 86 (0.50 g) in DMF (10 mL), 4 hours at room temperature, and 15 hours at 80 to 90 ° C. Reacted. The reaction solution was added to water (300 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were dissolved in acetone (60 mL) with heating, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain crude crystals (0.39 g). The crude crystal was recrystallized from methanol to obtain Compound 111 (0.22 g, Y = 31%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 2.18-2.63 (5H, m) 2.98 (6H, s) 3.43 (2H, t, J = 7 Hz) 4.26 (2H, t, J = 6 Hz) 7.14− 8.25 (8H, m) 8.56 (1H, s)

６−（１−メチルエチル）−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物１１２）、６−［６−（１−メチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレノール（化合物１１３）、６−［［６−［６−（１−メチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１１４）、６−［［６−［６−（１−メチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物１１５）、６−［［６−［６−（１−メチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物１１６）の製造：
３−イソプロピルフェノール（１０ｇ）をプロピオン酸（２０ｍＬ）に溶解後、０〜７℃で発煙硝酸（６．１ｍＬ）とプロピオン酸（３０ｍＬ）の混液を滴下し反応した。反応液を撹拌下の氷水（１５０ｇ）中に加え、５０％水酸化ナトリウム水溶液で中和した後、水蒸気蒸留にて２−ニトロ−５−イソプロピルフェノールのオイル（３．７９ｇ，Ｙ＝２９％）を得た。
２−ニトロ−５−イソプロピルフェノール（３．５５ｇ）をメタノール（４０ｍＬ）に溶解し、５％パラジウム炭素（０．２ｇ）を加え、水素雰囲気下で一夜反応した。反応液をろ過し、ろ液に３５％塩酸（５ｇ）を加え、減圧濃縮した。残渣をメタノール（１０ｍＬ）に溶解後、ジエチルエーテル（５００ｍＬ）を加えて晶析した。析出結晶をろ取、乾燥して２−アミノ−５−イソプロピルフェノール塩酸塩（２．５９ｇ，Ｙ＝７０％）を得た。
６−ベンジルオキシ−２−ナフトエ酸クロライド（２．５ｇ）を２−アミノ−５−イソプロピルフェノール塩酸塩（２．４ｇ），トリエチルアミン（２．４ｇ）の１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）溶液に加え、室温で５時間反応した。反応液を水（５００ｍＬ）中に加え晶析し、結晶をろ取、水洗後、乾燥して中間体のアミド化合物（３．９ｇ，Ｙ＝１００％）を得た。
１，３−ジメチル−２−イミダゾリジノン（５７ｍＬ）、トルエン（１７１ｍＬ）の混液中、アミド化合物（３．８ｇ）にｐ−トルエンスルホン酸一水和物（３．６ｇ）を加え、還流下で生成する水を除去しながら２２時間反応した。反応液を減圧濃縮し、残液を水（１０００ｍＬ）に加え撹拌後、目的物を酢酸エチルで抽出した。有機層を減圧濃縮し、粗製結晶を得た。粗製結晶にメタノール（３０ｍＬ），水酸化カリウム（０．６ｇ）を加え、還流下２時間懸濁した後、結晶をろ取、乾燥して化合物１１２（１．６１ｇ，Ｙ＝４４％）を得た。
１，３−ジメチル−２−イミダゾリジノン（２０ｍＬ）に化合物１１２（１．５０ｇ）を加え溶解後、５％パラジウム炭素（０．１ｇ）を加え水素雰囲気下で三日間反応した。反応液をろ過し、ろ液を水（５００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶をエタノール（３５ｍＬ）から再結晶して化合物１１３（０．７５ｇ，Ｙ＝６５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２３−１．３４（６Ｈ，ｄ，Ｊ＝７Ｈｚ）２．８４−３．３０（１Ｈ，ｍ）７．２６−８．２２（８Ｈ，ｍ）８．６６（１Ｈ，ｓ）１０．１５（１Ｈ，ｓ）
ＤＭＦ（１５ｍＬ）中、化合物１１３（０．６０ｇ）に炭酸カリウム（０．５５ｇ），６−ブロモヘキサン酸エチル（０．５４ｇ）を加え、室温で２４時間，８０〜９０℃で１時間反応した。反応液を水（４００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して化合物１１４（０．６２ｇ，Ｙ＝７０％）を得た。
メタノール（４０ｍＬ）中、化合物１１４（０．５３ｇ）に６％水酸化カリウム水溶液（１０ｍＬ）を加え還流下で１時間反応した。反応液に活性炭を加え熱時ろ過し、ろ液を減圧濃縮した。残渣を水（１００ｍＬ）に加熱溶解後、３５％塩酸を加え酸析した。析出結晶をろ取、水洗後、乾燥して化合物１１５（４３０ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２４−２．６５（１４Ｈ，ｍ）２．８３−３．２９（１Ｈ，ｍ）４．１４（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．２２−８．２７（８Ｈ，ｍ）８．７０（１Ｈ，ｓ）１１．９９（１Ｈ，ｂｒｓ）
化合物１１５（１５０ｍｇ）に０．０５％水酸化カリウム水溶液（５０ｍＬ）を加え加温溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物１１６（１５５ｍｇ，Ｙ＝９５％）を得た。6- (1-methylethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 112), 6- [6- (1-methylethyl) -2-benzoxazolyl]- 2-Naphthalenol (Compound 113), 6-[[6- [6- (1-Methylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 114), 6- [ [6- [6- (1-Methylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 115), 6-[[6- [6- (1-Methylethyl)- Preparation of 2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 116):
After 3-isopropylphenol (10 g) was dissolved in propionic acid (20 mL), a mixture of fuming nitric acid (6.1 mL) and propionic acid (30 mL) was added dropwise at 0-7 ° C. to react. The reaction solution was added to ice water (150 g) with stirring, neutralized with 50% aqueous sodium hydroxide solution, and then steam distilled to give 2-nitro-5-isopropylphenol oil (3.79 g, Y = 29%). Got.
2-Nitro-5-isopropylphenol (3.55 g) was dissolved in methanol (40 mL), 5% palladium carbon (0.2 g) was added, and the reaction was carried out overnight under a hydrogen atmosphere. The reaction mixture was filtered, 35% hydrochloric acid (5 g) was added to the filtrate, and the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), and diethyl ether (500 mL) was added for crystallization. The precipitated crystals were collected by filtration and dried to obtain 2-amino-5-isopropylphenol hydrochloride (2.59 g, Y = 70%).
1,3-Dimethyl-2-imidazolidinone of 6-benzyloxy-2-naphthoic acid chloride (2.5 g) in 2-amino-5-isopropylphenol hydrochloride (2.4 g) and triethylamine (2.4 g) (50 mL) The solution was added and reacted at room temperature for 5 hours. The reaction solution was added to water (500 mL) for crystallization, and the crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (3.9 g, Y = 100%).
In a mixed solution of 1,3-dimethyl-2-imidazolidinone (57 mL) and toluene (171 mL), p-toluenesulfonic acid monohydrate (3.6 g) was added to the amide compound (3.8 g) and refluxed. The reaction was carried out for 22 hours while removing the water produced in step (b). The reaction solution was concentrated under reduced pressure, and the residue was added to water (1000 mL) and stirred. The organic layer was concentrated under reduced pressure to obtain crude crystals. Methanol (30 mL) and potassium hydroxide (0.6 g) were added to the crude crystals, and suspended for 2 hours under reflux. The crystals were collected by filtration and dried to obtain compound 112 (1.61 g, Y = 44%). It was.
Compound 112 (1.50 g) was added to 1,3-dimethyl-2-imidazolidinone (20 mL) and dissolved, 5% palladium carbon (0.1 g) was added, and the reaction was carried out in a hydrogen atmosphere for 3 days. The reaction solution was filtered, and the filtrate was added to water (500 mL) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from ethanol (35 mL) to give compound 113 (0.75 g, Y = 65%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.3-1.34 (6H, d, J = 7 Hz) 2.84-3.30 (1H, m) 7.26-8.22 (8H, m) 8.66 (1H, s) 10.15 (1H, s)
Potassium carbonate (0.55 g) and ethyl 6-bromohexanoate (0.54 g) were added to compound 113 (0.60 g) in DMF (15 mL), and reacted at room temperature for 24 hours and at 80 to 90 ° C. for 1 hour. . The reaction solution was added to water (400 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 114 (0.62 g, Y = 70%).
A 6% aqueous potassium hydroxide solution (10 mL) was added to compound 114 (0.53 g) in methanol (40 mL) and reacted under reflux for 1 hour. Activated charcoal was added to the reaction solution and filtered while hot, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL) with heating, and 35% hydrochloric acid was added for acid precipitation. Precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 115 (430 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.4-2.65 (14H, m) 2.83-3.29 (1H, m) 4.14 (2H, t, J = 5 Hz) 7.22-8.27 (8H, m) 8.70 (1H, s) 11.99 (1H, brs)
0.05% aqueous potassium hydroxide solution (50 mL) was added to compound 115 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 116 (155 mg, Y = 95%).

２−［６−（フェニルメトキシ）−２−ナフタレニル］−６−ベンゾオキサゾロール（化合物１１７）、２−［６−（フェニルメトキシ）−２−ナフタレニル］−６−ベンゾオキサゾロール酢酸エステル（化合物１１８）、２−（６−ヒドロキシ−２−ナフタレニル）−６−ベンゾオキサゾロール酢酸エステル（化合物１１９）、６−［［６−［６−（アセチルオキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１２０）、６−［［６−（６−ヒドロキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物１２１）、６−［［６−（６−ヒドロキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物１２２）の製造：
４−アミノレゾルシノール塩酸塩（１０．３ｇ）を１，３−ジメチル−２−イミダゾリジノン（２００ｍＬ）に溶解し、トリエチルアミン（１２．５ｇ）を加え、次いで６−ベンジルオキシ−２−ナフトエ酸クロライド（１６．２ｇ）の１，３−ジメチル−２−イミダゾリジノン（１６０ｍＬ）溶液を加えて室温で一夜反応した。反応液を水（４Ｌ）中に加えて晶析し、析出結晶をろ取、乾燥して中間体のアミド化合物（２０．７ｇ，Ｙ＝９８．４％）を得た。
１，３−ジメチル−２−イミダゾリジノン（１５０ｍＬ）、トルエン（３００ｍＬ）の混合溶媒にアミド化合物（２０．７ｇ）、ｐ−トルエンスルホン酸一水和物（１７．０ｇ）を加え、還流下で生成する水を除去しながら一夜反応した。反応液を減圧濃縮し、残液に水を加えて晶析した。析出結晶をろ取し、メタノール洗浄後乾燥して化合物１１７（１４．７５ｇ，Ｙ＝７５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２８（２Ｈ，ｓ）６．７９−８．６５（１４Ｈ，ｍ）９．８６（１Ｈ，ｂｒ）
化合物１１７（２．３ｇ）に無水酢酸（２３ｍＬ）を加えて１０５〜１１０℃で一夜反応した。冷却後、析出した結晶をろ取し、ｎ−ヘキサンで洗浄後乾燥して化合物１１８（２．３４ｇ，Ｙ＝９１％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝２．３５（３Ｈ，ｓ）５．２２（２Ｈ，ｓ）７．００−８．６８（１４Ｈ，ｍ）
化合物１１８（２．３ｇ）にトルエン（４６ｍＬ）、メタノール（９２ｍＬ）、５％パラジウム炭素（０．５ｇ）を加えて水素雰囲気下約４５℃で反応した。反応液をろ過後、得られた結晶を１，４−ジオキサンから再結晶して化合物１１９（１．５９ｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．３３（３Ｈ，ｓ）７．１４−８．６９（９Ｈ，ｍ）１０．２（１Ｈ，ｂｒ）
化合物１１９（１．５５ｇ）をＤＭＦ（５０ｍＬ）に溶解し、炭酸カリウム（３．０ｇ）、６−ブロモヘキサン酸エチル（２．１ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗後、乾燥して化合物１２０を得た。
化合物１２０をメタノール（５０ｍＬ）に溶解し、１０％水酸化ナトリウム水溶液（１０ｍＬ）を加えて約５０℃で一夜反応した。反応液を減圧濃縮し、残渣を水（１００ｍＬ）に溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１２１（９０２ｍｇ，Ｙ＝４７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４９−１．９６（６Ｈ，ｍ）２．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１４（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．７９−８．６４（９Ｈ，ｍ）
化合物１２１（１４５．４ｍｇ）を水（７０ｍＬ）に懸濁し、２％水酸化カリウム水溶液（１ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物１２２（１７１ｍｇ，Ｙ＝１０７％）を得た。2- [6- (phenylmethoxy) -2-naphthalenyl] -6-benzoxazolol (compound 117), 2- [6- (phenylmethoxy) -2-naphthalenyl] -6-benzoxazolol acetate ( Compound 118), 2- (6-Hydroxy-2-naphthalenyl) -6-benzoxazolol acetate (Compound 119), 6-[[6- [6- (acetyloxy) -2-benzoxazolyl] 2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 120), 6-[[6- (6-hydroxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid (compound 121), 6- Production of [[6- (6-hydroxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 122):
4-Aminoresorcinol hydrochloride (10.3 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (200 mL), triethylamine (12.5 g) is added, then 6-benzyloxy-2-naphthoic acid chloride. A solution of (16.2 g) in 1,3-dimethyl-2-imidazolidinone (160 mL) was added and reacted overnight at room temperature. The reaction solution was added to water (4 L) for crystallization, and the precipitated crystals were collected by filtration and dried to obtain an intermediate amide compound (20.7 g, Y = 98.4%).
An amide compound (20.7 g) and p-toluenesulfonic acid monohydrate (17.0 g) were added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (300 mL), and the mixture was refluxed. The reaction was carried out overnight while removing the water produced in step 1. The reaction solution was concentrated under reduced pressure, and water was added to the residue to crystallize. Precipitated crystals were collected by filtration, washed with methanol and dried to obtain Compound 117 (14.75 g, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 6.79-8.65 (14H, m) 9.86 (1H, br)
Acetic anhydride (23 mL) was added to Compound 117 (2.3 g) and reacted at 105 to 110 ° C. overnight. After cooling, the precipitated crystals were collected by filtration, washed with n-hexane and dried to obtain Compound 118 (2.34 g, Y = 91%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.35 (3H, s) 5.22 (2H, s) 7.00-8.68 (14H, m)
Toluene (46 mL), methanol (92 mL), and 5% palladium carbon (0.5 g) were added to compound 118 (2.3 g), and reacted at about 45 ° C. in a hydrogen atmosphere. After filtering the reaction solution, the obtained crystals were recrystallized from 1,4-dioxane to obtain Compound 119 (1.59 g, Y = 89%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.33 (3H, s) 7.14-8.69 (9H, m) 10.2 (1H, br)
Compound 119 (1.55 g) was dissolved in DMF (50 mL), potassium carbonate (3.0 g) and ethyl 6-bromohexanoate (2.1 g) were added, and the mixture was reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to obtain Compound 120.
Compound 120 was dissolved in methanol (50 mL), 10% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (100 mL), and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 121 (902 mg, Y = 47%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.49-1.96 (6H, m) 2.27 (2H, t, J = 6 Hz) 4.14 (2H, t, J = 6 Hz) 6.79-8.64 (9H, m)
Compound 121 (145.4 mg) was suspended in water (70 mL), 2% aqueous potassium hydroxide solution (1 mL) was added, and the mixture was heated and dissolved, followed by filtration. The filtrate was lyophilized to give Compound 122 (171 mg, Y = 107%).

６−［［６−［６−（フェニルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸フェニルメチルエステル（化合物１２３）、６−［［６−［６−（フェニルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物１２４）、６−［［６−［６−（フェニルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物１２５）の製造：
化合物１２１（５００ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、ベンジルブロミド（７６０ｍｇ）を加えて室温で二夜反応した。反応液をろ過後、ろ液を減圧濃縮した。残渣を水洗し、乾燥して化合物１２３を得た。
化合物１２３に７０％メタノール水溶液（５００ｍＬ）、１，４−ジオキサン（５０ｍＬ）を加えた後、水酸化ナトリウム（０．５ｇ）を加えて約６０℃で一夜反応した。反応液を減圧濃縮し、残渣に水（０．５Ｌ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１２４（４７４ｍｇ，Ｙ＝７７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０−１．９４（６Ｈ，ｍ）２．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１４（２Ｈ，ｔ，Ｊ＝７Ｈｚ）５．２２（２Ｈ，ｓ）６．９９−８．６５（１４Ｈ，ｍ）１０．１（１Ｈ，ｂｒ）
化合物１２４（１４０ｍｇ）を水（３００ｍＬ）に懸濁し、２％水酸化カリウム（１．１ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物１２５（１７５ｍｇ，Ｙ＝１１６％）を得た。6-[[6- [6- (Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid phenylmethyl ester (compound 123), 6-[[6- [6- (phenylmethoxy) ) -2-Benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 124), 6-[[6- [6- (Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy Production of potassium hexanoate (Compound 125):
Compound 121 (500 mg) was dissolved in DMF (10 mL), and potassium carbonate (1.5 g) and benzyl bromide (760 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to obtain Compound 123.
70% aqueous methanol solution (500 mL) and 1,4-dioxane (50 mL) were added to compound 123, and then sodium hydroxide (0.5 g) was added and reacted at about 60 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (0.5 L) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 124 (474 mg, Y = 77%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-1.94 (6H, m) 2.27 (2H, t, J = 6 Hz) 4.14 (2H, t, J = 7 Hz) 5.22 (2H, s) 6.99- 8.65 (14H, m) 10.1 (1H, br)
Compound 124 (140 mg) was suspended in water (300 mL), 2% potassium hydroxide (1.1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 125 (175 mg, Y = 116%).

６−メトキシ−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物１２６）、６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物１２７）、［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸
メチルエステル（化合物１２８）、［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸（化合物１２９）、［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］酢酸ナトリウム塩（化合物１３０）の製造：
５−メトキシ−２−アミノフェノール塩酸塩（３．１ｇ）を１．４−ジオキサン（１００ｍＬ）に懸濁し、トリエチルアミン（４．６ｍＬ）を加え、６−ベンジルオキシ−２−ナフトエ酸クロライド（４．５ｇ）の１，４−ジオキサン（５０ｍＬ）溶液を加えて還流下で３．５時間反応した。反応液を減圧下で約１／３量に濃縮した後、２％塩酸（８００ｍＬ）中に加え、析出した結晶をろ取した。得られた結晶を１，４−ジオキサンから再結晶して中間体のアミド化合物（４．７９ｇ，Ｙ＝７９％）を得た。
１，３−ジメチル−２−イミダゾリジノン（４５ｍＬ）、トルエン（９０ｍＬ）の混液にアミド化合物（４．４３ｇ）及びｐ−トルエンスルホン酸一水和物（３．３ｇ）を加えて還流下で生成する水を除去しながら一夜反応した。反応液を減圧濃縮し、残液に水（２００ｍＬ）を加えて晶析した。析出結晶をろ取し、メタノール（１００ｍＬ）、１２％水酸化ナトリウム水溶液（５ｍＬ）を加えて還流下で４０分懸濁した。結晶をろ取、乾燥して化合物１２６（３．０３ｇ，Ｙ＝７２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．８７（３Ｈ，ｓ）５．２７（２Ｈ，ｓ）６．９２−８．６６（１４Ｈ，ｍ）
化合物１２６（３．６３ｇ）にトルエン（１００ｍＬ）、メタノール（１５０ｍＬ）を加えて溶解し、５％パラジウム炭素（１ｇ）を加えて水素雰囲気下約４５℃で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物１２７（２．５ｇ，Ｙ＝９０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．８７（３Ｈ，ｓ）６．９２−８．６２（９Ｈ，ｍ）１０．１５（１Ｈ，ｂｒ）
化合物１２７（２００ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（３８０ｍｇ）、ブロモ酢酸メチル（１５０ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗後、乾燥して化合物１２８を得た。
化合物１２８に１，４−ジオキサン（７０ｍＬ）、２％水酸化ナトリウム水溶液（１０ｍＬ）を加えて約５０℃で３０分間反応した。反応液を減圧濃縮し、残渣に酢酸エチル（３００ｍＬ）、水（１００ｍＬ）を加え、希塩酸を加えて強酸性とした後、分液した。酢酸エチル層を飽和食塩水で洗浄後、硫酸マグネシウムで脱水し、減圧濃縮、乾燥して化合物１２９（２１４ｍｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．８７（３Ｈ，ｓ）４．８７（２Ｈ，ｓ）６．９２−８．６７（９Ｈ，ｍ）１３．１（１Ｈ，ｂｒ）
化合物１２９（７８ｍｇ）にメタノール（３０ｍＬ）、１％水酸化ナトリウム水溶液（０．９ｍＬ）を加えて加温溶解し、減圧濃縮、乾燥して化合物１３０（８２ｍｇ，Ｙ＝９９％）を得た。6-methoxy-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 126), 6- (6-methoxy-2-benzoxazolyl) -2-naphthalenol (compound 127), [[ 6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester (Compound 128), [[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] Preparation of [oxy] acetic acid (compound 129), [[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid sodium salt (compound 130):
5-Methoxy-2-aminophenol hydrochloride (3.1 g) was suspended in 1.4-dioxane (100 mL), triethylamine (4.6 mL) was added, and 6-benzyloxy-2-naphthoic acid chloride (4. 5 g) of 1,4-dioxane (50 mL) was added and reacted under reflux for 3.5 hours. The reaction mixture was concentrated to about 1/3 volume under reduced pressure, added to 2% hydrochloric acid (800 mL), and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from 1,4-dioxane to obtain an intermediate amide compound (4.79 g, Y = 79%).
An amide compound (4.43 g) and p-toluenesulfonic acid monohydrate (3.3 g) were added to a mixed liquid of 1,3-dimethyl-2-imidazolidinone (45 mL) and toluene (90 mL) under reflux. The reaction was carried out overnight while removing the produced water. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the remaining solution for crystallization. Precipitated crystals were collected by filtration, methanol (100 mL) and 12% aqueous sodium hydroxide solution (5 mL) were added, and the mixture was suspended under reflux for 40 minutes. The crystals were collected by filtration and dried to obtain Compound 126 (3.03 g, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.87 (3H, s) 5.27 (2H, s) 6.92-8.66 (14H, m)
Toluene (100 mL) and methanol (150 mL) were added and dissolved in Compound 126 (3.63 g), and 5% palladium carbon (1 g) was added and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 127 (2.5 g, Y = 90%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.87 (3H, s) 6.92-8.62 (9H, m) 10.15 (1H, br)
Compound 127 (200 mg) was dissolved in DMF (10 mL), potassium carbonate (380 mg) and methyl bromoacetate (150 mg) were added, and the mixture was reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to give compound 128.
1,4-Dioxane (70 mL) and 2% aqueous sodium hydroxide solution (10 mL) were added to Compound 128 and reacted at about 50 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate (300 mL) and water (100 mL) were added to the residue, and the mixture was made strongly acidic by adding dilute hydrochloric acid, followed by liquid separation. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give compound 129 (214 mg, Y = 89%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.87 (3H, s) 4.87 (2H, s) 6.92-8.67 (9H, m) 13.1 (1H, br)
Methanol (30 mL) and 1% aqueous sodium hydroxide solution (0.9 mL) were added to compound 129 (78 mg), dissolved by heating, concentrated under reduced pressure, and dried to obtain compound 130 (82 mg, Y = 99%).

４−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物１３１）、４−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物１３２）、４−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物１３３）の製造：
化合物１２７（６５０ｍｇ）をＤＭＦ（１８ｍＬ）に溶解し、炭酸カリウム（１．１ｇ）、４−ブロモ−ｎ−酪酸エチル（７６０ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗後、メタノールから再結晶して化合物１３１（８２５ｍｇ，Ｙ＝９１％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．０９−２．６９（４Ｈ，ｍ）３．８９−４．３６（７Ｈ，ｍ）６．９０−８．６２（９Ｈ，ｍ）
化合物１３１（７５９ｍｇ）に１，４−ジオキサン（４０ｍＬ）、３％水酸化ナトリウム水溶液（１０ｍＬ）を加えて約５０℃で２時間反応した。反応液を減圧濃縮し、残渣に水（２００ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１３２（６１３ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．９３−２．６１（４Ｈ，ｍ）３．８７（３Ｈ，ｓ）４．１７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９２−８．６６（９Ｈ，ｍ）
化合物１３２（１９１ｍｇ）を水（１００ｍＬ）に懸濁し、２．７％水酸化ナトリウム水溶液（０．８ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物１３３（１９９ｍｇ，Ｙ＝９８％）を得た。4-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 131), 4-[[6- (6-Methoxy-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] butanoic acid (Compound 132), 4-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 133) Manufacturing:
Compound 127 (650 mg) was dissolved in DMF (18 mL), and potassium carbonate (1.1 g) and ethyl 4-bromo-n-butyrate (760 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from methanol to obtain Compound 131 (825 mg, Y = 91%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.09-2.69 (4H, m) 3.89-4.36 (7H, m) 6.90-8.62 (9H, m)
To compound 131 (759 mg), 1,4-dioxane (40 mL) and 3% aqueous sodium hydroxide solution (10 mL) were added and reacted at about 50 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 132 (613 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.93-2.61 (4H, m) 3.87 (3H, s) 4.17 (2H, t, J = 6 Hz) 6.92-8.66 (9H, m)
Compound 132 (191 mg) was suspended in water (100 mL), and a 2.7% aqueous sodium hydroxide solution (0.8 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give Compound 133 (199 mg, Y = 98%).

６−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１３４）、６−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物１３５）、６−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物１３６）の製造：
化合物１２７（３５０ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（８００ｍｇ）、６−ブロモヘキサン酸エチル（５２０ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水、エタノールで順次洗浄後、エタノールから再結晶して化合物１３４（３．７２ｇ，Ｙ＝９８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．４９−２．０２（６Ｈ，ｍ）２．３７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９０−４．３３（７Ｈ，ｍ）６．９０−８．６３（９Ｈ，ｍ）
化合物１３４（３８０ｍｇ）をメタノール（８０ｍＬ）に溶解し、５％水酸化ナトリウム水溶液（４ｍＬ）を加えて還流下で２時間反応した。反応液を減圧濃縮し、残渣に水（２００ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１３５（３５３ｍｇ，Ｙ＝１００％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３４−１．９６（６Ｈ，ｍ）２．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．８７（３Ｈ，ｓ）４．１２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９５−８．６３（９Ｈ，ｍ）１２．０１（１Ｈ，ｂｒ）
化合物１３５（１１５ｍｇ）に水（１００ｍＬ）、０．４％水酸化カリウム水溶液（４ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物１３６（１３３ｍｇ，Ｙ＝１０６％）を得た。6-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 134), 6-[[6- (6-Methoxy-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] hexanoic acid (Compound 135), 6-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 136) Manufacturing:
Compound 127 (350 mg) was dissolved in DMF (15 mL), and potassium carbonate (800 mg) and ethyl 6-bromohexanoate (520 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed successively with water and ethanol, and recrystallized from ethanol to obtain Compound 134 (3.72 g, Y = 98%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7 Hz) 1.49-2.02 (6H, m) 2.37 (2H, t, J = 6 Hz) 3.90-4.33 (7H, m) 6.90-8.63 (9H, m)
Compound 134 (380 mg) was dissolved in methanol (80 mL), 5% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 135 (353 mg, Y = 100%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.34-1.96 (6H, m) 2.28 (2H, t, J = 6 Hz) 3.87 (3H, s) 4.12 (2H, t, J = 6 Hz) 6.95− 8.63 (9H, m) 12.01 (1H, br)
Water (100 mL) and 0.4% aqueous potassium hydroxide solution (4 mL) were added to compound 135 (115 mg), dissolved by heating, and filtered. The filtrate was lyophilized to give Compound 136 (133 mg, Y = 106%).

［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］メチルプロパン二酸ジエチルエステル（化合物１３７）、［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］メチルプロパン二酸（化合物１３８）、［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］メチルプロパン二酸二ナトリウム塩（化合物１３９）の製造：
化合物１２７（０．６ｇ）をＤＭＦ（１８ｍＬ）に溶解し、炭酸カリウム（１．０ｇ）、２−ブロモ−２−メチルマロン酸ジエチル（０．６７ｇ）を加えて室温で一夜反応した。反応液にクロロホルム（２００ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、クロロホルム層を硫酸マグネシウムで脱水し、減圧濃縮して化合物１３７を得た。
化合物１３７をメタノール（４０ｍＬ）に溶解し、６％水酸化ナトリウム水溶液（７ｍＬ）を加えて約５０℃で一夜反応した。反応液を減圧濃縮し、残渣に水（２００ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１３８（７３０ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８０（３Ｈ，ｓ）３．８７（３Ｈ，ｓ）６．９４−８．６９（９Ｈ，ｍ）
化合物１３８（１９２ｍｇ）を水（３０ｍＬ）に懸濁し、２．７％水酸化ナトリウム水溶液（１．４ｍＬ）を加えて溶解後、ろ過した。ろ液を凍結乾燥して化合物１３９（２０５ｍｇ，Ｙ＝９６％）を得た。[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] methylpropanedioic acid diethyl ester (Compound 137), [[6- (6-Methoxy-2-benzoxazolyl) -2-Naphthalenyl] oxy] methylpropanedioic acid (Compound 138), [[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] methylpropanedioic acid disodium salt (Compound 139) Manufacturing of:
Compound 127 (0.6 g) was dissolved in DMF (18 mL), and potassium carbonate (1.0 g) and diethyl 2-bromo-2-methylmalonate (0.67 g) were added and reacted at room temperature overnight. Chloroform (200 mL) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure to give compound 137.
Compound 137 was dissolved in methanol (40 mL), 6% aqueous sodium hydroxide solution (7 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue for dissolution, and then dilute hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 138 (730 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80 (3H, s) 3.87 (3H, s) 6.94-8.69 (9H, m)
Compound 138 (192 mg) was suspended in water (30 mL), dissolved by adding 2.7% aqueous sodium hydroxide solution (1.4 mL), and then filtered. The filtrate was lyophilized to give compound 139 (205 mg, Y = 96%).

［５−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１４０）、［５−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物１４１）、［５−［［６−（６−メトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物１４２）の製造：
化合物１２７（５５０ｍｇ）をＤＭＦ（１８ｍＬ）に溶解し、炭酸カリウム（０．９ｇ）、（５−ブロモペンチル）マロン酸ジエチル（１．０ｇ）を加え、室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗後、エタノールから再結晶して化合物１４０（７５０ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．０８−２．２０（１４Ｈ，ｍ）３．３６（１Ｈ，ｔ，Ｊ＝７Ｈｚ）３．７４−４．５５（９Ｈ，ｍ）６．８７−８．６２（９Ｈ，ｍ）
化合物１４０（６８０ｍｇ）を１，４−ジオキサン（４０ｍＬ）に溶解後、６％水酸化ナトリウム水溶液（５ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣を水（１５０ｍＬ）に溶解した後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１４１（５３１ｍｇ，Ｙ＝９０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２０−１．９４（８Ｈ，ｍ）３．２５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）３．８７（３Ｈ，ｓ）４．１３（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９５−８．６４（９Ｈ，ｍ）
化合物１４１（１９２ｍｇ）を水（３０ｍＬ）に懸濁し、２．７％水酸化ナトリウム水溶液（１．２５ｍＬ）を加えて溶解後、ろ過した。ろ液を凍結乾燥して化合物１４２（２０２ｍｇ，Ｙ＝９３％）を得た。[5-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 140), [5-[[6- (6-methoxy- 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 141), [5-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid disodium salt (compound 142):
Compound 127 (550 mg) was dissolved in DMF (18 mL), potassium carbonate (0.9 g) and diethyl (5-bromopentyl) malonate (1.0 g) were added, and the mixture was reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 140 (750 mg, Y = 76%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.08-2.20 (14H, m) 3.36 (1H, t, J = 7 Hz) 3.74-4.55 (9H, m) 6.87-8.62 (9H, m)
Compound 140 (680 mg) was dissolved in 1,4-dioxane (40 mL), 6% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (150 mL), and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 141 (531 mg, Y = 90%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.20-1.94 (8H, m) 3.25 (1H, t, J = 7 Hz) 3.87 (3H, s) 4.13 (2H, t, J = 6 Hz) 6.95− 8.64 (9H, m)
Compound 141 (192 mg) was suspended in water (30 mL), dissolved in 2.7% aqueous sodium hydroxide solution (1.25 mL), and then filtered. The filtrate was lyophilized to give Compound 142 (202 mg, Y = 93%).

６−エトキシ−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物１４３）、６−（６−エトキシ−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物１４４）、６−［［６−（６−エトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１４５）、６−［［６−（６−エトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物１４６）、６−［［６−（６−エトキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物１４７）の製造：
エタノール（１００ｍＬ）に化合物１１７（２．０ｇ）、ナトリウムメトキシド（０．４６ｇ）を加えて溶解し、ジエチル硫酸（１．３８ｇ）を加え、約６０℃で一夜反応した。冷却後、析出した結晶をろ取し、エタノールで洗浄後乾燥して化合物１４３（１．６６ｇ，Ｙ＝７７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．４７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）３．９４−４．３０（２Ｈ，ｍ）５．２２（２Ｈ，ｓ）６．８６−８．６５（１４Ｈ，ｍ）
化合物１４３（１．６１５ｇ）にトルエン（３２ｍＬ）、メタノール（６４ｍＬ）、５％パラジウム炭素（０．５ｍｇ）を加えて水素雰囲気下約４０℃で反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をメタノールで洗浄後乾燥して化合物１４４（１．０６ｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３８（３Ｈ，ｔ，Ｊ＝７Ｈｚ）３．９５−４．３０（２Ｈ，ｍ）６．９０−８．６１（９Ｈ，ｍ）１０．１３（１Ｈ，ｂｒ）
化合物１４４（５００ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（１．０ｇ）、６−ブロモヘキサン酸エチル（０．６３ｇ）を加えて室温で二夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗後、エタノールから再結晶して化合物１４５（６５１ｍｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．０８−２．２０（１２Ｈ，ｍ）２．３６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９５−４．３３（６Ｈ，ｍ）６．８６−８．６２（９Ｈ，ｍ）
化合物１４５（６００ｍｇ）を１，４−ジオキサン（４０ｍＬ）に溶解し、メタノール（１０ｍＬ）、６％水酸化ナトリウム水溶液（５ｍＬ）を加えて約５０℃で３時間反応した。反応液を減圧濃縮し、残渣に水（１００ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１４６（４５６ｍｇ，Ｙ＝８１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２６−２．０２（９Ｈ，ｍ）２．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９５−４．２９（４Ｈ，ｍ）６．９０−８．６３（９Ｈ，ｍ）１２．０（１Ｈ，ｍ）
化合物１４６（１５７ｍｇ）に水（１００ｍＬ）、２．７％水酸化ナトリウム水溶液（１．８ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物１４７（１５０ｍｇ，Ｙ＝９１％）を得た。6-ethoxy-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 143), 6- (6-ethoxy-2-benzoxazolyl) -2-naphthalenol (compound 144), 6- [[6- (6-Ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 145), 6-[[6- (6-Ethoxy-2-benzoxazolyl) Preparation of 2-naphthalenyl] oxy] hexanoic acid (Compound 146), 6-[[6- (6-Ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 147):
Compound 117 (2.0 g) and sodium methoxide (0.46 g) were added and dissolved in ethanol (100 mL), diethyl sulfate (1.38 g) was added, and the mixture was reacted at about 60 ° C. overnight. After cooling, the precipitated crystals were collected by filtration, washed with ethanol and dried to obtain Compound 143 (1.66 g, Y = 77%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.47 (3H, t, J = 7 Hz) 3.94-4.30 (2H, m) 5.22 (2H, s) 6.86-8.65 (14H, m)
Toluene (32 mL), methanol (64 mL), and 5% palladium carbon (0.5 mg) were added to compound 143 (1.615 g), and reacted at about 40 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with methanol and dried to obtain Compound 144 (1.06 g, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38 (3H, t, J = 7 Hz) 3.95-4.30 (2H, m) 6.90-8.61 (9H, m) 10.13 (1H, br)
Compound 144 (500 mg) was dissolved in DMF (15 mL), potassium carbonate (1.0 g) and ethyl 6-bromohexanoate (0.63 g) were added, and the mixture was reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 145 (651 mg, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.08-2.20 (12H, m) 2.36 (2H, t, J = 6 Hz) 3.95-4.33 (6H, m) 6.86-8.62 (9H, m)
Compound 145 (600 mg) was dissolved in 1,4-dioxane (40 mL), methanol (10 mL) and 6% aqueous sodium hydroxide solution (5 mL) were added, and the mixture was reacted at about 50 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 146 (456 mg, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.6-2.02 (9H, m) 2.27 (2H, t, J = 6 Hz) 3.95-4.29 (4H, m) 6.90-8.63 (9H, m) 12.0 (1H, m)
To compound 146 (157 mg), water (100 mL) and a 2.7% aqueous sodium hydroxide solution (1.8 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 147 (150 mg, Y = 91%).

６−［［２−［６−（フェニルメトキシ）−２−ナフタレニル］−６−ベンゾオキサゾリル］オキシ］ヘキサン酸エチルエステル（化合物１４８）、６−［［２−［６−（フェニルメトキシ）−２−ナフタレニル］−６−ベンゾオキサゾリル］オキシ］ヘキサン酸（化合物１４９）、６−［［２−（６−ヒドロキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸（化合物１５０）、６−［［２−（６−ヒドロキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸カリウム塩（化合物１５１）の製造：
化合物１１７（３．０ｇ）をＤＭＦ（４０ｍＬ）に溶解し、炭酸カリウム（５．０ｇ）、６−ブロモヘキサン酸エチル（２．８ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗後、エタノールから再結晶して化合物１４８（３．７２ｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．４８−１．９７（６Ｈ，ｍ）２．３６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９７−４．３３（４Ｈ，ｍ）５．２１（２Ｈ，ｓ）６．８９−８．６４（１４Ｈ，ｍ）
化合物１４８（１．２５ｇ）を１，４−ジオキサン（３０ｍＬ）に溶解し、メタノール（３０ｍＬ）、１０％水酸化ナトリウム水溶液（５ｍＬ）を加えて還流下で３時間反応した。反応液を減圧濃縮後、残渣を水（１００ｍＬ）に懸濁し、希塩酸を加えて酸析した。結晶をろ取して化合物１４９を得た。
化合物１４９にメタノール（３００ｍＬ）、５％パラジウム炭素（０．６ｇ）を加えて水素雰囲気下約４０℃で反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をアセトンから再結晶して化合物１５０（６０４ｍｇ，Ｙ＝６３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３５−１．９０（６Ｈ，ｍ）２．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．０６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．８９−８．６１（９Ｈ，ｍ）１０．３（１Ｈ，ｂｒ）１１．７（１Ｈ，ｂｒ）
化合物１５０（１１６ｍｇ）に水（８０ｍＬ）、０．４％水酸化カリウム水溶液（４．２ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物１５１（１２９ｍｇ，Ｙ＝１０１％）を得た。6-[[2- [6- (Phenylmethoxy) -2-naphthalenyl] -6-benzoxazolyl] oxy] hexanoic acid ethyl ester (Compound 148), 6-[[2- [6- (Phenylmethoxy) 2-naphthalenyl] -6-benzoxazolyl] oxy] hexanoic acid (compound 149), 6-[[2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ( Compound 150), 6-[[2- (6-Hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid potassium salt (Compound 151):
Compound 117 (3.0 g) was dissolved in DMF (40 mL), potassium carbonate (5.0 g) and ethyl 6-bromohexanoate (2.8 g) were added, and the mixture was reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 148 (3.72 g, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7 Hz) 1.48-1.97 (6H, m) 2.36 (2H, t, J = 6 Hz) 3.97-4.33 (4H, m) 5.21 (2H, s) 6.89-8.64 (14H, m)
Compound 148 (1.25 g) was dissolved in 1,4-dioxane (30 mL), methanol (30 mL), 10% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was suspended in water (100 mL), and diluted hydrochloric acid was added for acid precipitation. The crystals were collected by filtration to give compound 149.
Methanol (300 mL) and 5% palladium carbon (0.6 g) were added to compound 149 and reacted at about 40 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from acetone to obtain Compound 150 (604 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.35-1.90 (6H, m) 2.27 (2H, t, J = 6 Hz) 4.06 (2H, t, J = 6 Hz) 6.89-8.61 (9H, m) 10.3 (1H, br) 11.7 (1H, br)
Water (80 mL) and 0.4% aqueous potassium hydroxide solution (4.2 mL) were added to compound 150 (116 mg), dissolved by heating, and filtered. The filtrate was lyophilized to give compound 151 (129 mg, Y = 101%).

６−［［２−（６−ヒドロキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸エチルエステル（化合物１５２）、６−［［６−［６−［（６−エトキシ−６−オキソヘキシル）オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１５３）、６−［［６−［６−［（５−カルボキシペンチル）オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物１５４）、６−［［６−［６−［（５−カルボキシペンチル）オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸二カリウム塩（化合物１５５）の製造：
化合物１４８（２．３ｇ）にトルエン（４０ｍＬ）、エタノール（８０ｍＬ）、５％パラジウム炭素（０．５ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物１５２（１．９ｇ，Ｙ＝１００％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．４８−２．０７（６Ｈ，ｍ）２．３７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９０−４．３７（４Ｈ，ｍ）６．８２−８．５９（９Ｈ，ｍ）
化合物１５２（５００ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（８００ｍｇ）、６−ブロモヘキサン酸エチル（４００ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗後、エタノールから再結晶して化合物１５３（５４０ｍｇ，Ｙ＝８１％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．０８−２．４３（２２Ｈ，ｍ）３．９７−４．３３（８Ｈ，ｍ）６．８８−８．６１（９Ｈ，ｍ）
化合物１５３（５１０ｍｇ）をメタノール（５０ｍＬ）に溶解し、８％水酸化ナトリウム水溶液（５ｍＬ）を加えて約５０℃で一夜反応した。反応液を減圧濃縮し、残渣に水（８０ｍＬ）を加えて加温溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１５４（４６０ｍｇ，Ｙ＝１００％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２３−２．４５（１６Ｈ，ｍ）３．９５−４．３０（４Ｈ，ｍ）６．９０−８．６４（９Ｈ，ｍ）１２．０１（２Ｈ，ｂｒ）
化合物１５４（１１９ｍｇ）に水（５０ｍＬ）、０．４％水酸化カリウム水溶液（６．６ｍＬ）を加え加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物１５５（１３８ｍｇ，Ｙ＝１０１％）を得た。6-[[2- (6-Hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester (Compound 152), 6-[[6- [6-[(6-Ethoxy-6] -Oxohexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 153), 6-[[6- [6-[(5-carboxypentyl) oxy] -2 -Benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (compound 154), 6-[[6- [6-[(5-carboxypentyl) oxy] -2-benzoxazolyl] -2-naphthalenyl Production of dipotassium oxy] hexanoate (Compound 155):
Toluene (40 mL), ethanol (80 mL), and 5% palladium carbon (0.5 g) were added to compound 148 (2.3 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 152 (1.9 g, Y = 100%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 1.48-2.07 (6H, m) 2.37 (2H, t, J = 6 Hz) 3.90-4.37 (4H, m) 6.82-8.59 (9H, m)
Compound 152 (500 mg) was dissolved in DMF (15 mL), potassium carbonate (800 mg) and ethyl 6-bromohexanoate (400 mg) were added, and the mixture was reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 153 (540 mg, Y = 81%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.08-2.43 (22H, m) 3.97-4.33 (8H, m) 6.88-8.61 (9H, m)
Compound 153 (510 mg) was dissolved in methanol (50 mL), 8% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (80 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 154 (460 mg, Y = 100%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.2-2.45 (16H, m) 3.95-4.30 (4H, m) 6.90-8.64 (9H, m) 12.01 (2H, br)
To compound 154 (119 mg), water (50 mL) and 0.4% aqueous potassium hydroxide solution (6.6 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 155 (138 mg, Y = 101%).

６−［［２−（６−エトキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸エチルエステル（化合物１５６）、６−［［２−（６−エトキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸（化合物１５７）、６−［［２−（６−エトキシ−２−ナフタレニル）−６−ベンゾオキサゾリル］オキシ］ヘキサン酸ナトリウム塩（化合物１５８）の製造：
化合物１５２（０．５０ｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（０．８０ｇ）、ヨウ化エチル（０．３０ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗し、エタノール洗浄後乾燥して化合物１５６（４６６ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１３−１．９７（１２Ｈ，ｍ）２．３６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９３−４．３３（６Ｈ，ｍ）６．８８−８．６１（９Ｈ，ｍ）
化合物１５６（４０３ｍｇ）をメタノール（１００ｍＬ）に溶解し、１０％水酸化ナトリウム水溶液（３ｍＬ）を加えて約６０℃で反応した。反応液を減圧濃縮し、残渣に水（２００ｍＬ）、酢酸エチル（３００ｍＬ）を加え、希塩酸を加えて強酸性とした後、分液した。酢酸エチル層を飽和食塩水で洗浄後、硫酸マグネシウムで脱水し、減圧濃縮、乾燥して化合物１５７（３５０ｍｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１８−２．０９（９Ｈ，ｍ）２．２６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９５−４．３７（４Ｈ，ｍ）６．９０−８．６３（９Ｈ，ｍ）１２．０（１Ｈ，ｂｒ）
化合物１５７（７８．３ｍｇ）を水（６０ｍＬ）に懸濁し、０．７％水酸化ナトリウム水溶液（１．１ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物１５８（８３ｍｇ，Ｙ＝１０１％）を得た。6-[[2- (6-Ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester (Compound 156), 6-[[2- (6-Ethoxy-2-naphthalenyl)- 6-benzoxazolyl] oxy] hexanoic acid (compound 157), 6-[[2- (6-ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid sodium salt (compound 158) Manufacturing:
Compound 152 (0.50 g) was dissolved in DMF (10 mL), and potassium carbonate (0.80 g) and ethyl iodide (0.30 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water, washed with ethanol and dried to give compound 156 (466 mg, Y = 87%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.13-1.97 (12H, m) 2.36 (2H, t, J = 6 Hz) 3.93-4.33 (6H, m) 6.88-8.61 (9H, m)
Compound 156 (403 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. The reaction solution was concentrated under reduced pressure, water (200 mL) and ethyl acetate (300 mL) were added to the residue, and the mixture was made strongly acidic by adding dilute hydrochloric acid, followed by liquid separation. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give compound 157 (350 mg, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-2.09 (9H, m) 2.26 (2H, t, J = 6 Hz) 3.95-4.37 (4H, m) 6.90-8.63 (9H, m) 12.0 (1H, br)
Compound 157 (78.3 mg) was suspended in water (60 mL), 0.7% aqueous sodium hydroxide solution (1.1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 158 (83 mg, Y = 101%).

２−（６−ヒドロキシ−２−ナフタレニル）−６−ベンゾオキサゾロール（化合物１５９）、［５−［［６−［６−［［７−エトキシ−６−（エトキシカルボニル）−７−オキソヘプチル］オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１６０）、［５−［［６−（６−ヒドロキシ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１６１）の製造：
化合物１１７（２．１ｇ）をメタノール（４０ｍＬ）に懸濁し、５％パラジウム炭素（０．５ｇ）を加えて水素雰囲気下約４５℃で反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をトルエン、メタノールの混液から再結晶して化合物１５９（１．４１ｇ，Ｙ＝８９％）を得た。
化合物１５９（１．３５ｇ）をＤＭＦ（４５ｍＬ）に溶解し、炭酸カリウム（５．０ｇ）、（５−ブロモペンチル）マロン酸ジエチル（１．８ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣からシリカゲルカラム（クロロホルム）で分取して化合物１６０（０．６１ｇ，Ｙ＝１７％）、化合物１６１（０．６７ｇ，Ｙ＝２７％）を得た。
＜化合物１６０＞^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１４−２．２２（２８Ｈ，ｍ）３．２３−３．５０（２Ｈ，ｍ）３．９６−６．８９（１２Ｈ，ｍ）７．０１−８．６２（９Ｈ，ｍ）2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolol (compound 159), [5-[[6- [6-[[7-ethoxy-6- (ethoxycarbonyl) -7-oxoheptyl] ] Oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 160), [5-[[6- (6-hydroxy-2-benzoxazolyl)- Preparation of 2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 161):
Compound 117 (2.1 g) was suspended in methanol (40 mL), 5% palladium carbon (0.5 g) was added, and the reaction was performed at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixed solution of toluene and methanol to obtain Compound 159 (1.41 g, Y = 89%).
Compound 159 (1.35 g) was dissolved in DMF (45 mL), and potassium carbonate (5.0 g) and diethyl (5-bromopentyl) malonate (1.8 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was fractionated on a silica gel column (chloroform) to obtain Compound 160 (0.61 g, Y = 17%) and Compound 161 (0.67 g, Y = 27%).
<Compound 160> ¹ H-NMR (CDCl ₃ / TMS):
δ = 1.14-2.22 (28H, m) 3.23-3.50 (2H, m) 3.96-6.89 (12H, m) 7.01-8.62 (9H, m)

［５−［［６−［６−［（６，６−ジカルボキシヘキシル）オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物１６２）、［５［［６−［６［（６，６−ジカルボキシヘキシル）オキシ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸四ナトリウム塩（化合物１６３）の製造：
化合物１６０（６００ｍｇ）をメタノール（１００ｍＬ）に溶解し、１％水酸化ナトリウム水溶液（３０ｍＬ）を加えて約５０℃で一夜反応した。反応液を減圧濃縮後、残渣に水（５０ｍＬ）を加えて溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１６２（４３４．５ｍｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２３−２．０２（１６Ｈ，ｍ）３．１２−３．４１（２Ｈ，ｍ）３．９５−４．２６（４Ｈ，ｍ）６．９４−８．６５（９Ｈ，ｍ）１２．６４（４Ｈ，ｂｒ）
化合物１６２（１０４．５ｍｇ）に水（４０ｍＬ）、０．５％水酸化ナトリウム水溶液（５．４ｍＬ）を加えて溶解し、ろ過した。ろ液を凍結乾燥して化合物１６３（１１６ｍｇ，Ｙ＝９７％）を得た。[5-[[6- [6-[(6,6-dicarboxyhexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 162), [5 [ Preparation of [6- [6 [(6,6-dicarboxyhexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid tetrasodium salt (Compound 163):
Compound 160 (600 mg) was dissolved in methanol (100 mL), 1% aqueous sodium hydroxide solution (30 mL) was added, and the mixture was reacted at about 50 ° C. overnight. After the reaction solution was concentrated under reduced pressure, water (50 mL) was added to the residue for dissolution, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 162 (434.5 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.23-2.02 (16H, m) 3.12-3.41 (2H, m) 3.95-4.26 (4H, m) 6.94-8.65 (9H, m) 12.64 (4H, br)
Water (40 mL) and 0.5% aqueous sodium hydroxide solution (5.4 mL) were added to Compound 162 (104.5 mg) to dissolve it, followed by filtration. The filtrate was lyophilized to give compound 163 (116 mg, Y = 97%).

［５−［［６−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１６４）、［５−［［６−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物１６５）、［５−［［６−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物１６６）の製造：
化合物１６１（３３５ｍｇ）をＤＭＦ（６ｍＬ）に溶解し、炭酸カリウム（４５０ｍｇ）、ブロモメチルシクロヘキサン（１５３ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮して化合物１６４を得た。
化合物１６４にメタノール（１００ｍＬ）、６％水酸化ナトリウム水溶液（５ｍＬ）を加えて還流下で一夜反応した。冷却後、析出した結晶をろ取、乾燥して化合物１６５（２４２．８ｍｇ，Ｙ＝６２％）を得た。
化合物１６５（２６ｍｇ）を水（５ｍＬ）に溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１６６（１０ｍｇ，Ｙ＝４１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．００−２．０２（１９Ｈ，ｍ）３．０５−４．３０（５Ｈ，ｍ）６．９０−８．６４（９Ｈ，ｍ）１２．６（２Ｈ，ｂｒ）[5-[[6- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 164), [5-[[6- [6 -(Cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 165), [5-[[6- [6- (cyclohexylmethoxy) -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 166):
Compound 161 (335 mg) was dissolved in DMF (6 mL), and potassium carbonate (450 mg) and bromomethylcyclohexane (153 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain Compound 164.
Methanol (100 mL) and 6% aqueous sodium hydroxide solution (5 mL) were added to compound 164 and reacted overnight under reflux. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 165 (242.8 mg, Y = 62%).
Compound 165 (26 mg) was dissolved in water (5 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 166 (10 mg, Y = 41%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.00-2.02 (19H, m) 3.05-4.30 (5H, m) 6.90-8.64 (9H, m) 12.6 (2H, br)

［５−［［６−［６−（フェニルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１６７）、［５−［［６−［６−（フェニルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物１６８）、［５−［［６−［６−（フェニルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物１６９）の製造：
化合物１６１（３３５ｍｇ）をＤＭＦ（６ｍＬ）に溶解し、炭酸カリウム（４５０ｍｇ）、ベンジルブロミド（１５０ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮し化合物１６７を得た。
化合物１６７にメタノール（１００ｍＬ）、６％水酸化ナトリウム水溶液（５ｍＬ）を加えて還流下で一夜反応した。冷却後、析出した結晶をろ取、乾燥して化合物１６８（３１６．５ｍｇ，Ｙ＝８２％）を得た。
化合物１６８（２６ｍｇ）を水（５ｍＬ）に溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１６９（２３ｍｇ，Ｙ＝９６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２５−２．０（８Ｈ，ｍ）４．１８（２Ｈ，ｔ，Ｊ＝７Ｈｚ）５．２２（２Ｈ，ｓ）７．１８−８．６５（１４Ｈ，ｍ）[5-[[6- [6- (Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 167), [5-[[6- [6 -(Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (compound 168), [5-[[6- [6- (phenylmethoxy) -2- Preparation of Benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 169):
Compound 161 (335 mg) was dissolved in DMF (6 mL), and potassium carbonate (450 mg) and benzyl bromide (150 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain Compound 167.
Methanol (100 mL) and 6% aqueous sodium hydroxide solution (5 mL) were added to compound 167 and reacted overnight under reflux. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 168 (316.5 mg, Y = 82%).
Compound 168 (26 mg) was dissolved in water (5 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 169 (23 mg, Y = 96%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.25-2.0 (8H, m) 4.18 (2H, t, J = 7 Hz) 5.22 (2H, s) 7.18-8.65 (14H, m)

６−ニトロ−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物１７０）、６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物１７１）、４−［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物１７２）、４−［［６−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物１７３）、４−［［６−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸塩酸塩（化合物１７４）の製造：
６−ベンジルオキシ−２−ナフトエ酸（６．２ｇ）をトルエン（１００ｍＬ）に懸濁し、塩化チオニル（１．９ｍＬ）、ＤＭＦ（１滴）を加えて還流下で２時間反応した後、２−アミノ−５−ニトロフェノール（７．０ｇ）の１，４−ジオキサン（２００ｍＬ）溶液を加えて還流下で３時間反応した。冷却後、析出した結晶をろ取し、水、メタノールで順次洗浄後乾燥して中間体のアミド化合物（８．７ｇ，Ｙ＝９４％）を得た。
アミド化合物（８．６９ｇ）を１，３−ジメチル−２−イミダゾリジノン（８７ｍＬ）に溶解し、ｐ−トルエンスルホン酸一水和物（６．５ｇ）、トルエン（１７４ｍＬ）を加えて還流下で生成する水を除去しながら一夜反応した。冷却後、析出した結晶をろ取し、メタノール洗浄後乾燥して化合物１７０（７．４６ｇ，Ｙ＝９０％）を得た。
化合物１７０（６．０ｇ）に３０％臭化水素・酢酸溶液（１００ｍＬ）を加えて約１００℃で６時間反応した。反応液を水に加えて晶析し、析出結晶をろ取した。得られた結晶をトルエン、メタノールの混液から再結晶して化合物１７１（４．０５ｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．１４−８．６８（９Ｈ，ｍ）１０．２５（１Ｈ，ｓ）
化合物１７１（１．９６ｇ）にＤＭＦ（３０ｍＬ）、炭酸カリウム（３．０ｇ）、４−ブロモ−ｎ−酪酸エチル（９１０ｍｇ）を加えて室温で一夜反応した。反応液に水（３００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物１７２（１．４ｇ，Ｙ＝９４％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．１０−２．７３（４Ｈ，ｍ）４．０１−４．３６（４Ｈ，ｍ）７．１４−８．６８（９Ｈ，ｍ）
化合物１７２（１．１ｇ）にエタノール（１００ｍＬ）、５％パラジウム炭素（０．５ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物１７３（９１５ｍｇ，Ｙ＝９０％）を得た。
化合物１７３（２４２ｍｇ）をメタノール（１００ｍＬ）に溶解し、６％水酸化ナトリウム水溶液（５ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣を水（５０ｍＬ）に加温溶解後、希塩酸を加えて中和し、析出した結晶をろ取した。得られた結晶をアセトン（５０ｍＬ）に懸濁し、３５％塩酸（０．５ｍＬ）を加えた後、結晶をろ取、乾燥して化合物１７４（１５１ｍｇ，Ｙ＝６１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，Ｄ_２Ｏ／ＴＭＳ）：
δ＝１．８０−２．５８（４Ｈ，ｍ）４．１９（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２３−８．７２（９Ｈ，ｍ）6-nitro-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 170), 6- (6-nitro-2-benzoxazolyl) -2-naphthalenol (compound 171), 4- [[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 172), 4-[[6- (6-Amino-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid ethyl ester (Compound 173), 4-[[6- (6-Amino-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid hydrochloride (Compound 174) Manufacturing:
6-Benzyloxy-2-naphthoic acid (6.2 g) was suspended in toluene (100 mL), thionyl chloride (1.9 mL) and DMF (1 drop) were added and reacted under reflux for 2 hours. A solution of amino-5-nitrophenol (7.0 g) in 1,4-dioxane (200 mL) was added and reacted under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration, washed successively with water and methanol and dried to obtain an intermediate amide compound (8.7 g, Y = 94%).
The amide compound (8.69 g) was dissolved in 1,3-dimethyl-2-imidazolidinone (87 mL), and p-toluenesulfonic acid monohydrate (6.5 g) and toluene (174 mL) were added under reflux. The reaction was carried out overnight while removing the water produced in step 1. After cooling, the precipitated crystals were collected by filtration, washed with methanol and dried to obtain Compound 170 (7.46 g, Y = 90%).
A 30% hydrogen bromide / acetic acid solution (100 mL) was added to compound 170 (6.0 g) and reacted at about 100 ° C. for 6 hours. The reaction solution was added to water for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from a mixed solution of toluene and methanol to obtain Compound 171 (4.05 g, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.14−8.68 (9H, m) 10.25 (1H, s)
To compound 171 (1.96 g), DMF (30 mL), potassium carbonate (3.0 g), and ethyl 4-bromo-n-butyrate (910 mg) were added and reacted overnight at room temperature. Water (300 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 172 (1.4 g, Y = 94%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.10-2.73 (4H, m) 4.01-4.36 (4H, m) 7.14-8.68 (9H, m)
Ethanol (100 mL) and 5% palladium carbon (0.5 g) were added to compound 172 (1.1 g) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 173 (915 mg, Y = 90%).
Compound 173 (242 mg) was dissolved in methanol (100 mL), 6% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) by heating, neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were suspended in acetone (50 mL), 35% hydrochloric acid (0.5 mL) was added, and the crystals were collected by filtration and dried to obtain Compound 174 (151 mg, Y = 61%).
¹ H-NMR (DMSO-d6, D ₂ O / TMS):
δ = 1.80-2.58 (4H, m) 4.19 (2H, t, J = 6 Hz) 7.23-8.72 (9H, m)

４−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物１７５）、４−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物１７６）、４−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物１７７）の製造：
化合物１７３（３６５ｍｇ）をＤＭＦ（１３ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ヨウ化エチル（２．０ｇ）を加えて約７０℃で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加え、水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮後、残渣をシリカゲルカラム（クロロホルム）で精製して化合物１７５（２６６ｍｇ，Ｙ＝６４％）を得た。
化合物１７５（２６６ｍｇ）をメタノール（４０ｍＬ）に溶解し、７％水酸化ナトリウム水溶液（３ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣を水（５０ｍＬ）に加温溶解後、希塩酸を加えて中和した。析出した結晶をろ取、乾燥して化合物１７６（２２０ｍｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１４（６Ｈ，ｔ，Ｊ＝７Ｈｚ）１．９０−２．５１（４Ｈ，ｍ）３．１５−３．６０（４Ｈ，ｍ）４．１６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．６８−８．５９（９Ｈ，ｍ）１２．１６（１Ｈ，ｂｒ）
化合物１７６（８０．５ｍｇ）に水（３０ｍＬ）、０．４％水酸化ナトリウム水溶液（２ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物１７７（７７ｍｇ，Ｙ＝９１％）を得た。4-[[6- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 175), 4-[[6- [6- (Diethylamino) -2 -Benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (compound 176), sodium 4-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoate Production of the salt (compound 177):
Compound 173 (365 mg) was dissolved in DMF (13 mL), potassium carbonate (2.5 g) and ethyl iodide (2.0 g) were added, and the mixture was reacted at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain Compound 175 (266 mg, Y = 64%).
Compound 175 (266 mg) was dissolved in methanol (40 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) with heating, and then neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 176 (220 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.14 (6H, t, J = 7 Hz) 1.90-2.51 (4H, m) 3.15-3.60 (4H, m) 4.16 (2H, t, J = 6 Hz) 6.68-8.59 (9H, m) 12.16 (1H, br)
To compound 176 (80.5 mg), water (30 mL) and a 0.4% aqueous sodium hydroxide solution (2 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 177 (77 mg, Y = 91%).

４−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物１７８）、４−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物１７９）、４−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物１８０）の製造：
化合物１７３（３１７ｍｇ）をＤＭＦ（１３ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ベンジルブロミド（５５０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をエタノールから再結晶して化合物１７８（１．０５ｇ，Ｙ＝４７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．００−２．７０（４Ｈ，ｍ）３．９８−４．３５（４Ｈ，ｍ）４．７４（４Ｈ，ｓ）６．７５−８．５５（１９Ｈ，ｍ）
化合物１７８（３１７ｍｇ）をメタノール（８０ｍＬ）に溶解し、７％水酸化ナトリウム水溶液（４ｍＬ）を加えて室温で一夜、約５０℃で１時間反応した。反応液を減圧濃縮し、残渣に酢酸エチル（１５０ｍＬ）、水（１５０ｍＬ）を加え、希塩酸を加えて強酸性とした後、分液した。酢酸エチル層を水洗後、硫酸マグネシウムで脱水し、減圧濃縮、乾燥して化合物１７９（２６５ｍｇ，Ｙ＝８８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝２．０４−２．７５（４Ｈ，ｍ）４．１７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．７４（４Ｈ，ｓ）６．７５−８．５４（１９Ｈ，ｍ）
化合物１７９（９３．５ｍｇ）を水（１００ｍＬ）に懸濁し、０．４％水酸化ナトリウム水溶液（１．８ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物１８０（９５ｍｇ，Ｙ＝９８％）を得た。4-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 178), 4-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 179), 4-[[6- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 180):
Compound 173 (317 mg) was dissolved in DMF (13 mL), potassium carbonate (2.5 g) and benzyl bromide (550 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain Compound 178 (1.05 g, Y = 47%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7 Hz) 2.00-2.70 (4H, m) 3.98-4.35 (4H, m) 4.74 (4H, s) 6.75- 8.55 (19H, m)
Compound 178 (317 mg) was dissolved in methanol (80 mL), 7% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at room temperature overnight at about 50 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (150 mL) and water (150 mL) were added to the residue, and the mixture was made strongly acidic by adding dilute hydrochloric acid, followed by liquid separation. The ethyl acetate layer was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 179 (265 mg, Y = 88%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.4-2.75 (4H, m) 4.17 (2H, t, J = 6 Hz) 4.74 (4H, s) 6.75-8.54 (19H, m)
Compound 179 (93.5 mg) was suspended in water (100 mL), 0.4% aqueous sodium hydroxide solution (1.8 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 180 (95 mg, Y = 98%).

６−［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１８１）、６−［［６−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１８２）、６−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１８３）、６−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物１８４）、６−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物１８５）の製造：
化合物１７１（１．２ｇ）をＤＭＦ（３６ｍＬ）に溶解し、炭酸カリウム（３．０ｇ）、６−ブロモヘキサン酸エチル（１．１５ｇ）を加え、室温で一夜反応した。反応液に酢酸エチル（３００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をエタノールで洗浄後乾燥して化合物１８１（１．５３７ｇ，Ｙ＝８８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．４５−２．０３（６Ｈ，ｍ）２．３７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．０１−４．３４（４Ｈ，ｍ）７．１４−８．６８（９Ｈ，ｍ）
化合物１８１（１．３ｇ）にエタノール（８０ｍＬ）、トルエン（２０ｍＬ）、５％パラジウム炭素（０．６ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物１８２（１．０４ｇ，Ｙ＝８６％）を得た。
化合物１８２（０．５２ｇ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（３．０ｇ）、ヨウ化エチル（３．０ｇ）を加えて約７０℃で２４時間反応した。反応液に酢酸エチル（３００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物１８３（５００ｍｇ，Ｙ＝８５％）を得た。
化合物１８３（５００ｍｇ）に１，４−ジオキサン（５ｍＬ）、メタノール（４５ｍＬ）を加えて溶解し、１５％水酸化ナトリウム水溶液（２ｍＬ）を加えて室温で一夜、約５０℃で７時間反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水（１００ｍＬ）に溶解し、希塩酸を加えて中和した。析出した結晶をろ取、乾燥して化合物１８４（３８８ｍｇ，Ｙ＝８３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１４（６Ｈ，ｔ，Ｊ＝７Ｈｚ）１．３６−１．９７（６Ｈ，ｍ）２．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．１４−３．６１（４Ｈ，ｍ）４．１２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．８３−８．５８（９Ｈ，ｍ）１２．０（１Ｈ，ｂｒ）
化合物１８４（８７ｍｇ）に水（２５ｍＬ）、０．５％水酸化ナトリウム水溶液（１．５５ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物１８５（８７ｍｇ，Ｙ＝９５％）を得た。6-[[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 181), 6-[[6- (6-Amino-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 182), 6-[[6- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester ( Compound 183), 6-[[6- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 184), 6-[[6- [6- (Diethylamino) Preparation of 2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 185):
Compound 171 (1.2 g) was dissolved in DMF (36 mL), potassium carbonate (3.0 g) and ethyl 6-bromohexanoate (1.15 g) were added, and the mixture was reacted at room temperature overnight. Ethyl acetate (300 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol and dried to obtain Compound 181 (1.537 g, Y = 88%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 1.45-2.03 (6H, m) 2.37 (2H, t, J = 6 Hz) 4.01-4.34 (4H, m) 7.14-8.68 (9H, m)
Ethanol (80 mL), toluene (20 mL), and 5% palladium carbon (0.6 g) were added to compound 181 (1.3 g) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 182 (1.04 g, Y = 86%).
Compound 182 (0.52 g) was dissolved in DMF (20 mL), potassium carbonate (3.0 g) and ethyl iodide (3.0 g) were added, and the mixture was reacted at about 70 ° C. for 24 hours. Ethyl acetate (300 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 183 (500 mg, Y = 85%).
To compound 183 (500 mg), 1,4-dioxane (5 mL) and methanol (45 mL) were added and dissolved, 15% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at room temperature overnight at about 50 ° C. for 7 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL) and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 184 (388 mg, Y = 83%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.14 (6H, t, J = 7 Hz) 1.36-1.97 (6H, m) 2.27 (2H, t, J = 6 Hz) 3.14-3.61 (4H, m) 4.12 (2H, t, J = 6 Hz) 6.83-8.58 (9H, m) 12.0 (1H, br)
To compound 184 (87 mg), water (25 mL) and a 0.5% aqueous sodium hydroxide solution (1.55 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 185 (87 mg, Y = 95%).

６−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物１８６）、６−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物１８７）、６−［［６−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物１８８）の製造：
化合物１８２（０．５２ｇ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（２．０ｇ）、ベンジルブロミド（０．８ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をエタノールで洗浄後乾燥して化合物１８６（６２９．３ｍｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．５３−２．０５（６Ｈ，ｍ）２．３６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９５−４．３２（４Ｈ，ｍ）４．７４（４Ｈ，ｓ）６．７２−８．５５（１９Ｈ，ｍ）
化合物１８６（５８０ｍｇ）に１，４−ジオキサン（１０ｍＬ）、メタノール（３０ｍＬ）を加えて溶解し、１５％水酸化ナトリウム水溶液（２ｍＬ）を加えて室温で一夜、還流下で２時間反応した。反応液をろ過後、ろ液を減圧濃縮した。残渣に水（１００ｍＬ）を加えて加温溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１８７（５３１ｍｇ，Ｙ＝９６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．５０−２．２０（６Ｈ，ｍ）２．４４（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１０（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．７４（４Ｈ，ｍ）６．７６−８．５５（１９Ｈ，ｍ）
化合物１８７（１００ｍｇ）に水（２５ｍＬ）、０．５％水酸化ナトリウム水溶液（１．４ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物１８８（９８ｍｇ，Ｙ＝９４％）を得た。6-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 186), 6-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 187), 6-[[6- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 188):
Compound 182 (0.52 g) was dissolved in DMF (20 mL), and potassium carbonate (2.0 g) and benzyl bromide (0.8 g) were added and reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (100 mL) was added to the residue, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol and dried to obtain Compound 186 (629.3 mg, Y = 85%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.25 (3H, t, J = 7 Hz) 1.53-2.05 (6H, m) 2.36 (2H, t, J = 6 Hz) 3.95-4.32 (4H, m) 4.74 (4H, s) 6.72-8.55 (19H, m)
To compound 186 (580 mg), 1,4-dioxane (10 mL) and methanol (30 mL) were added and dissolved, and 15% aqueous sodium hydroxide solution (2 mL) was added and reacted at room temperature overnight and under reflux for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue and dissolved by heating, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 187 (531 mg, Y = 96%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.50-2.20 (6H, m) 2.44 (2H, t, J = 6 Hz) 4.10 (2H, t, J = 6 Hz) 4.74 (4H, m) 6.76− 8.55 (19H, m)
To compound 187 (100 mg), water (25 mL) and a 0.5% aqueous sodium hydroxide solution (1.4 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 188 (98 mg, Y = 94%).

［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸ジエチルエステル（化合物１８９）、［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸（化合物１９０）、［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロパン二酸二ナトリウム塩（化合物１９１）の製造：
化合物１７１（２．０ｇ）をＤＭＦ（８０ｍＬ）に溶解し、炭酸カリウム（３ｇ）、ブロモマロン酸ジエチル（２．１ｇ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣に水（２００ｍＬ）を加えて晶析した。析出結晶をろ取し、エタノール洗浄後、シリカゲルカラム（クロロホルム）で精製して化合物１８９（１．０８ｇ，Ｙ＝３６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．３３（６Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１９−４．５５（４Ｈ，ｍ）５．４０（１Ｈ，ｓ）７．２０−８．７２（９Ｈ，ｍ）
化合物１８９（６００ｍｇ）に１，４−ジオキサン（２０ｍＬ）、メタノール（８０ｍＬ）を加えて溶解し、１０％水酸化ナトリウム水溶液（４ｍＬ）を加え、約５０℃で２時間反応した。反応液を減圧濃縮し、残渣に水（４０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物１９０（４８０ｍｇ，Ｙ＝９１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８７（１Ｈ，ｓ）７．２８−８．７８（９Ｈ，ｍ）
化合物１９０（８０ｍｇ）を水（４０ｍＬ）に懸濁し、１．６％水酸化ナトリウム水溶液（１ｍＬ）を加えて溶解後、ろ過した。ろ液を凍結乾燥して化合物１９１（８５ｍｇ，Ｙ＝９６％）を得た。[[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid diethyl ester (Compound 189), [[6- (6-Nitro-2-benzoxazolyl)- Preparation of 2-Naphthalenyl] oxy] propanedioic acid (Compound 190), [[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid disodium salt (Compound 191):
Compound 171 (2.0 g) was dissolved in DMF (80 mL), and potassium carbonate (3 g) and diethyl bromomalonate (2.1 g) were added and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue for crystallization. Precipitated crystals were collected by filtration, washed with ethanol, and purified by silica gel column (chloroform) to obtain Compound 189 (1.08 g, Y = 36%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.33 (6H, t, J = 7 Hz) 4.19-4.55 (4H, m) 5.40 (1H, s) 7.20-8.72 (9H, m)
To compound 189 (600 mg), 1,4-dioxane (20 mL) and methanol (80 mL) were added and dissolved, 10% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at about 50 ° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and water (40 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 190 (480 mg, Y = 91%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.87 (1H, s) 7.28-8.78 (9H, m)
Compound 190 (80 mg) was suspended in water (40 mL), dissolved by adding 1.6% aqueous sodium hydroxide solution (1 mL), and then filtered. The filtrate was lyophilized to give compound 191 (85 mg, Y = 96%).

［５−［［６−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１９２）、［５−［［６−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１９３）、［５−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物１９４）、［５−［［６−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物１９５）の製造：
化合物１７１（８２５ｍｇ）をＤＭＦ（２５ｍＬ）に溶解し、炭酸カリウム（３．２ｇ）、（５−ブロモペンチル）マロン酸ジエチル（１．１６ｇ）を加えて室温で一夜、約７０℃で一夜反応した。反応液を水（２５０ｍＬ）中に加えて晶析し、析出結晶をろ取した。得られた結晶をメタノール洗浄後乾燥して化合物１９２（１．２８ｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１５−２．２０（１４Ｈ，ｍ）３．３６（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．０４−４．４４（６Ｈ，ｍ）７．１４−８．７０（９Ｈ，ｍ）
化合物１９２（９７０ｍｇ）にエタノール（１００ｍＬ）、トルエン（２０ｍＬ）、５％パラジウム炭素（０．３ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物１９３（８６６ｍｇ，Ｙ＝９５％）を得た。
化合物１９３（４４６ｍｇ）をＤＭＦ（８ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、ヨウ化エチル（１．０ｇ）を加えて約７０℃で一夜反応した。反応液を酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物１９４（３０５ｍｇ，Ｙ＝６２％）を得た。
化合物１９４（３０５ｍｇ）をメタノール（５０ｍＬ）に溶解し、６％水酸化ナトリウム水溶液（５ｍＬ）を加えて室温で４日間反応した。析出した結晶をろ取、乾燥して化合物１９５（２０４ｍｇ，Ｙ＝６８％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４，Ｄ_２Ｏ／ＴＭＳ）：
δ＝１．０１−１．９９（１４Ｈ，ｍ）３．００−３．５９（５Ｈ，ｍ）４．１１（２Ｈ，ｔ，Ｊ＝５Ｈｚ）６．９０−８．４２（９Ｈ，ｍ）[5-[[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 192), [5-[[6- (6-amino- 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 193), [5-[[6- [6- (diethylamino) -2-benzoxazolyl] -2- Naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 194), [5-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diacid Preparation of sodium salt (compound 195):
Compound 171 (825 mg) was dissolved in DMF (25 mL), potassium carbonate (3.2 g) and diethyl (5-bromopentyl) malonate (1.16 g) were added, and the mixture was reacted at room temperature overnight and at about 70 ° C. overnight. . The reaction solution was added to water (250 mL) for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 192 (1.28 g, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.5-2.20 (14H, m) 3.36 (1H, t, J = 7 Hz) 4.04-4.44 (6H, m) 7.14-8.70 (9H, m)
Ethanol (100 mL), toluene (20 mL), and 5% palladium carbon (0.3 g) were added to compound 192 (970 mg) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 193 (866 mg, Y = 95%).
Compound 193 (446 mg) was dissolved in DMF (8 mL), potassium carbonate (1.5 g) and ethyl iodide (1.0 g) were added, and the mixture was reacted at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 194 (305 mg, Y = 62%).
Compound 194 (305 mg) was dissolved in methanol (50 mL), 6% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature for 4 days. The precipitated crystals were collected by filtration and dried to obtain Compound 195 (204 mg, Y = 68%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 1.01-1.99 (14H, m) 3.00-3.59 (5H, m) 4.11 (2H, t, J = 5Hz) 6.90-8.42 (9H, m)

６−ニトロ−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール（化合物１９６）、２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩（化合物１９７）、Ｎ，Ｎ−ジエチル−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩（化合物１９８）の製造：
化合物１７１（４９８ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、Ｎ−（２−クロロエチル）モルホリン塩酸塩（４７０ｍｇ）を加えて７０℃で一夜反応した。反応液に水（５０ｍＬ）を加えて晶析し、析出結晶をろ取、乾燥して化合物１９６（６４８ｍｇ，Ｙ＝９５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝２．５５−２．９９（６Ｈ，ｍ）３．７７（４Ｈ，ｔ，Ｊ＝５Ｈｚ）４．２９（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１８−８．７３（９Ｈ，ｍ）
化合物１９６（５５０ｍｇ）にメタノール（５０ｍＬ）、５％パラジウム炭素（０．４ｇ）を加えて水素雰囲気下室温で反応した。反応液に３５％塩酸（１ｍＬ）を加えてろ過し、ろ液を減圧濃縮した。残渣にアセトン（５０ｍＬ）、３５％塩酸（０．５ｍＬ）を加えて懸濁後、結晶をろ取、乾燥して化合物１９７（５０５ｍｇ，Ｙ＝８３％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４，Ｄ_２Ｏ／ＴＭＳ）：
δ＝３．３３−４．１９（１０Ｈ，ｍ）４．６６（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．４９−８．７５（９Ｈ，ｍ）
化合物１９７（２２０ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、ヨウ化エチル（１．０ｇ）を加えて約７０℃で一夜反応した。反応液に水（４０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をシリカゲルカラム（クロロホルム）で精製後、アセトン（５０ｍＬ）に溶解し、３５％塩酸（０．３ｍＬ）を加えて析出した結晶をろ取、乾燥して化合物１９８（６７ｍｇ，Ｙ＝２７％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝１．２３（６Ｈ，ｔ，Ｊ＝７Ｈｚ）３．１７−４．０９（１４Ｈ，ｍ）４．６５（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３１−８．７７（９Ｈ，ｍ）6-nitro-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole (Compound 196), 2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl ] -6-benzoxazolamine dihydrochloride (Compound 197), N, N-diethyl-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-benzoxazolamine dihydrochloride Production of (Compound 198):
Compound 171 (498 mg) was dissolved in DMF (10 mL), potassium carbonate (1.5 g) and N- (2-chloroethyl) morpholine hydrochloride (470 mg) were added, and the mixture was reacted at 70 ° C. overnight. Water (50 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and dried to obtain Compound 196 (648 mg, Y = 95%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.5-2.99 (6H, m) 3.77 (4H, t, J = 5 Hz) 4.29 (2H, t, J = 6 Hz) 7.18-8.73 (9H, m)
Methanol (50 mL) and 5% palladium carbon (0.4 g) were added to compound 196 (550 mg), and reacted at room temperature in a hydrogen atmosphere. To the reaction solution, 35% hydrochloric acid (1 mL) was added and filtered, and the filtrate was concentrated under reduced pressure. Acetone (50 mL) and 35% hydrochloric acid (0.5 mL) were added to the residue for suspension, and the crystals were collected by filtration and dried to obtain Compound 197 (505 mg, Y = 83%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 3.33-4.19 (10H, m) 4.66 (2H, t, J = 5 Hz) 7.49-8.75 (9H, m)
Compound 197 (220 mg) was dissolved in DMF (10 mL), potassium carbonate (1.5 g) and ethyl iodide (1.0 g) were added, and the mixture was reacted at about 70 ° C. overnight. Water (40 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were purified with a silica gel column (chloroform), dissolved in acetone (50 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 198 (67 mg, Y = 27%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.23 (6H, t, J = 7 Hz) 3.17-4.09 (14H, m) 4.65 (2H, t, J = 5 Hz) 7.31-8.77 (9H, m)

６−（シクロヘキシルオキシ）−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物１９９）、６−［６−（シクロヘキシルオキシ）−２−ベンゾオキサゾリル］−２−ナフタレノール（化合物２００）、６−［［６−［６−（シクロヘキシルオキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２０１）、６−［［６−［６−（シクロヘキシルオキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物２０２）、６−［［６−［６−（シクロヘキシルオキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物２０３）の製造：
化合物１１７（１．５ｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（２．０ｇ）、ブロモシクロヘキサン（１．５ｇ）を加えて約６５℃で４日間反応した。反応液をろ過後、ろ液を減圧濃縮した。残渣を１５％メタノール水溶液で洗浄し、次いで０．５％水酸化ナトリウム・メタノール溶液で洗浄後乾燥して化合物１９９（９１７ｍｇ，Ｙ＝５０％）を得た。
化合物１９９（９１０ｍｇ）にトルエン（２０ｍＬ）、メタノール（４０ｍＬ）、５％パラジウム炭素（４５０ｍｇ）を加えて水素雰囲気下約４５℃で反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をトルエン、メタノールの混液から再結晶して化合物２００（４３０ｍｇ，Ｙ＝６６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２５−２．３６（１１Ｈ，ｍ）５．８５（１Ｈ，ｓ）７．０５−８．６５（９Ｈ，ｍ）
化合物２００（４３０ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（１．２ｇ）、６−ブロモヘキサン酸エチル（０．８０ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を水洗後、エタノールから再結晶して化合物２０１（１９７ｍｇ，Ｙ＝３３％）を得た。
化合物２０１（１９７ｍｇ）をメタノール（１００ｍＬ）に溶解し、４％水酸化ナトリウム水溶液（５ｍＬ）を加えて約６０℃で１時間反応した。反応液を減圧濃縮し、残渣に水（１００ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物２０２（１７９ｍｇ，Ｙ＝９６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１６−２．４２（１８Ｈ，ｍ）４．０３−４．６０（３Ｈ，ｍ）６．９１−８．６４（９Ｈ，ｍ）１２．０（１Ｈ，ｂｒ）
化合物２０２（８９ｍｇ）に水（２００ｍＬ）、０．４％水酸化カリウム水溶液（２．７ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物２０３（１１０ｍｇ，Ｙ＝１１４％）を得た。6- (cyclohexyloxy) -2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 199), 6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenol ( Compound 200), 6-[[6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 201), 6-[[6- [6- (Cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 202), 6-[[6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2- Preparation of Naphthalenyl] oxy] hexanoic acid potassium salt (Compound 203):
Compound 117 (1.5 g) was dissolved in DMF (15 mL), potassium carbonate (2.0 g) and bromocyclohexane (1.5 g) were added, and the mixture was reacted at about 65 ° C. for 4 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with 15% aqueous methanol solution, then washed with 0.5% sodium hydroxide / methanol solution and dried to obtain Compound 199 (917 mg, Y = 50%).
Toluene (20 mL), methanol (40 mL), and 5% palladium carbon (450 mg) were added to compound 199 (910 mg), and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixed solution of toluene and methanol to obtain Compound 200 (430 mg, Y = 66%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.25-2.36 (11H, m) 5.85 (1H, s) 7.05-8.65 (9H, m)
Compound 200 (430 mg) was dissolved in DMF (15 mL), and potassium carbonate (1.2 g) and ethyl 6-bromohexanoate (0.80 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 201 (197 mg, Y = 33%).
Compound 201 (197 mg) was dissolved in methanol (100 mL), 4% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 60 ° C. for 1 hr. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 202 (179 mg, Y = 96%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.16-2.42 (18H, m) 4.03-4.60 (3H, m) 6.91-8.64 (9H, m) 12.0 (1H, br)
Water (200 mL) and 0.4% aqueous potassium hydroxide solution (2.7 mL) were added to compound 202 (89 mg), and the mixture was heated and dissolved, followed by filtration. The filtrate was lyophilized to give compound 203 (110 mg, Y = 114%).

５−メチル−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２０４）、６−（５−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物２０５）、６−［［６−（５−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２０６）、６−［［６−（５−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物２０７）、６−［［６−（５−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物２０８）の製造：
１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）に２−アミノ−ｐ−クレゾール（１．５ｇ），トリエチルアミン（１．２ｇ）を加え溶解した後、６−ベンジルオキシ−２−ナフトエ酸クロライド（３．０ｇ）を加え室温で２時間反応した。反応液を水（８００ｍＬ）中に加えて晶析し、析出結晶をろ取、水洗後、乾燥して中間体のアミド化合物（３．５ｇ，Ｙ＝９０％）を得た。
１，３−ジメチル−２−イミダゾリジノン（３４ｍＬ）、トルエン（１０２ｍＬ）の混液中、アミド化合物（３．４ｇ）にｐ−トルエンスルホン酸一水和物（３．４ｇ）を加え、還流下で生成する水を除去しながら２２時間反応した。反応液を減圧濃縮した後、残渣を水（５００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（１２０ｍＬ），水酸化カリウム（２．０ｇ）を加え、還流下２時間懸濁した後、結晶をろ取、乾燥して化合物２０４（２．１４ｇ，Ｙ＝６６％）を得た。
化合物２０４（１．８ｇ）に１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）を加え溶解後、５％パラジウム炭素（０．２ｇ）を加え水素雰囲気下で２３時間反応した。反応液をろ過し、ろ液を水（８００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗後、乾燥して化合物２０５（１．３４ｇ，Ｙ＝９９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．４６（３Ｈ，ｓ）７．１５−８．２２（８Ｈ，ｍ）８．６７（１Ｈ，ｓ）１０．１３（１Ｈ，ｓ）
ＤＭＦ（１５ｍＬ）中、化合物２０５（５００ｍｇ）に炭酸カリウム（５１０ｍｇ），６−ブロモヘキサン酸エチル（４９０ｍｇ）を加え室温で２０時間反応した。反応液を水（２００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して化合物２０６（７００ｍｇ，Ｙ＝９２％）を得た。
メタノール（４０ｍＬ）中、化合物２０６（６４６ｍｇ）に５％水酸化カリウム水溶液（１０ｍＬ）を加え、室温で２０時間，６０〜７０℃で４時間反応した。反応液を減圧濃縮し、残渣に水（１００ｍＬ）を加え撹拌下に３５％塩酸で酸析後、ろ過して粗製結晶を得た。粗製結晶にメタノール（３０ｍＬ）を加え、６０〜７０℃で懸濁した後、結晶をろ取、乾燥して化合物２０７（５００ｍｇ，Ｙ＝８３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．５８−２．６７（１１Ｈ，ｍ）４．１２（２Ｈ，ｔ，Ｊ＝３Ｈｚ）７．１７−８．２４（８Ｈ，ｍ）８．６８（１Ｈ，ｓ）１１．９６（１Ｈ，ｓ）
化合物２０７（１５０ｍｇ）に０．０５％水酸化カリウム水溶液（５０ｍＬ）を加え加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥し化合物２０８（１６７ｍｇ，Ｙ＝１００％）を得た。5-methyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 204), 6- (5-methyl-2-benzoxazolyl) -2-naphthalenol (compound 205), 6- [[6- (5-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 206), 6-[[6- (5-Methyl-2-benzoxazolyl) Preparation of 2-naphthalenyl] oxy] hexanoic acid (Compound 207), 6-[[6- (5-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 208):
2-Amino-p-cresol (1.5 g) and triethylamine (1.2 g) were added to and dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), and then 6-benzyloxy-2-naphthoic acid chloride. (3.0 g) was added and reacted at room temperature for 2 hours. The reaction solution was added to water (800 mL) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (3.5 g, Y = 90%).
In a mixture of 1,3-dimethyl-2-imidazolidinone (34 mL) and toluene (102 mL), p-toluenesulfonic acid monohydrate (3.4 g) was added to the amide compound (3.4 g), and the mixture was refluxed. The reaction was carried out for 22 hours while removing the water produced in step (b). The reaction mixture was concentrated under reduced pressure, and the residue was added to water (500 mL) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (120 mL) and potassium hydroxide (2.0 g) were added to the crude crystals and suspended under reflux for 2 hours. The crystals were collected by filtration and dried to obtain compound 204 (2.14 g, Y = 66%). It was.
1,3-Dimethyl-2-imidazolidinone (50 mL) was added to Compound 204 (1.8 g) and dissolved, 5% palladium carbon (0.2 g) was added, and the mixture was reacted under a hydrogen atmosphere for 23 hours. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 205 (1.34 g, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.46 (3H, s) 7.15-8.22 (8H, m) 8.67 (1H, s) 10.13 (1H, s)
Potassium carbonate (510 mg) and ethyl 6-bromohexanoate (490 mg) were added to compound 205 (500 mg) in DMF (15 mL) and reacted at room temperature for 20 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 206 (700 mg, Y = 92%).
5% aqueous potassium hydroxide solution (10 mL) was added to compound 206 (646 mg) in methanol (40 mL), and the mixture was reacted at room temperature for 20 hours and at 60 to 70 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) was added to the residue, acidified with 35% hydrochloric acid with stirring, and then filtered to obtain crude crystals. Methanol (30 mL) was added to the crude crystals and suspended at 60 to 70 ° C., and then the crystals were collected by filtration and dried to obtain Compound 207 (500 mg, Y = 83%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.58-2.67 (11H, m) 4.12 (2H, t, J = 3 Hz) 7.17-8.24 (8H, m) 8.68 (1H, s) 11.96 ( 1H, s)
0.05% aqueous potassium hydroxide solution (50 mL) was added to compound 207 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to obtain Compound 208 (167 mg, Y = 100%).

５−（１，１−ジメチルエチル）−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２０９）、６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレノール（化合物２１０）、６−［［６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２１１）、６−［［６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物２１２）、６−［［６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物２１３）の製造：
６−ベンジルオキシ−２−ナフトエ酸クロライド（７．０ｇ）を２−アミノ−４−ｔｅｒｔ−ブチルフェノール（４．７ｇ）、トリエチルアミン（２．９ｇ）の１，３−ジメチル−２−イミダゾリジノン（８０ｍＬ）溶液中に加え、室温で３．５時間反応した。反応液を水（１．５Ｌ）中に加え晶析し、析出結晶をろ取、水洗後、乾燥して中間体のアミド化合物（９．３ｇ，Ｙ＝９３％）を得た。
１，３−ジメチル−２−イミダゾリジノン（１３２ｍＬ）、トルエン（３９６ｍＬ）の混液中、アミド化合物（８．８ｇ）にｐ−トルエンスルホン酸一水和物（７．９ｇ）を加え、還流下で生成する水を除去しながら２１時間反応した。反応液を減圧濃縮した後、残液を水（１５００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（８８ｍＬ），水酸化カリウム（２．４ｇ）を加え、還流下２時間懸濁した後、結晶をろ取、乾燥して化合物２０９（３．５２ｇ，Ｙ＝４２％）を得た。
１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）に化合物２０９（３．３０ｇ）を加え溶解後、５％パラジウム炭素（０．４ｇ）を加え水素雰囲気下で２３時間反応した。反応液をろ過し、ろ液を水（１．５Ｌ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶をエタノール（５２ｍＬ）から再結晶し、化合物２１０（１．３２ｇ，Ｙ＝５１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３８（９Ｈ，ｓ）７．１６−８．２５（８Ｈ，ｍ）８．６９（１Ｈ，ｓ）１０．１５（１Ｈ，ｓ）
ＤＭＦ（１２ｍＬ）中、化合物２１０（０．８０ｇ）に炭酸カリウム（０．７ｇ），６−ブロモヘキサン酸エチル（０．６９ｇ）を加え、室温で３時間，８０〜９０℃で８．５時間反応した。反応液を水（２００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗し化合物２１１（１．０６ｇ，Ｙ＝９２％）を得た。
メタノール（４０ｍＬ）中、化合物２１１（０．８２ｇ）に７％水酸化カリウム水溶液（１０ｍＬ）を加え、還流下で１．５時間反応した。活性炭を加え熱時ろ過し、ろ液を減圧濃縮した。残渣に水（１００ｍＬ）を加えた後、３５％塩酸で酸析し、結晶をろ取、水洗して粗製結晶を得た。粗製結晶をメタノール（４５ｍＬ）から再結晶し、化合物２１２（０．５８ｇ，Ｙ＝６７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３８−２．５２（１７Ｈ，ｍ）４．１５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２０−８．３０（８Ｈ，ｍ）８．７２（１Ｈ，ｓ）１１．９９（１Ｈ，ｂｒｓ）
化合物２１２（２００ｍｇ）に０．０３％水酸化カリウム水溶液（１２０ｍＬ）を加え加温溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物２１３（２０５ｍｇ，Ｙ＝９４％）を得た。5- (1,1-dimethylethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 209), 6- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenol (compound 210), 6-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 211), 6-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 212), 6-[[6- [5 Preparation of-(1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 213):
6-Benzyloxy-2-naphthoic acid chloride (7.0 g) was replaced with 2-amino-4-tert-butylphenol (4.7 g) and triethylamine (2.9 g) in 1,3-dimethyl-2-imidazolidinone ( 80 mL) was added to the solution and reacted at room temperature for 3.5 hours. The reaction solution was added to water (1.5 L) for crystallization, and the precipitated crystals were collected by filtration, washed with water and dried to obtain an intermediate amide compound (9.3 g, Y = 93%).
In a mixture of 1,3-dimethyl-2-imidazolidinone (132 mL) and toluene (396 mL), p-toluenesulfonic acid monohydrate (7.9 g) was added to the amide compound (8.8 g), and the mixture was refluxed. The reaction was carried out for 21 hours while removing the water produced in step (b). After the reaction solution was concentrated under reduced pressure, the remaining solution was added to water (1500 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (88 mL) and potassium hydroxide (2.4 g) were added to the crude crystals and suspended under reflux for 2 hours. The crystals were collected by filtration and dried to obtain compound 209 (3.52 g, Y = 42%). It was.
Compound 209 (3.30 g) was dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL) and dissolved, 5% palladium carbon (0.4 g) was added, and the reaction was carried out in a hydrogen atmosphere for 23 hours. The reaction solution was filtered, and the filtrate was added to water (1.5 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from ethanol (52 mL) to obtain compound 210 (1.32 g, Y = 51%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38 (9H, s) 7.16-8.25 (8H, m) 8.69 (1H, s) 10.15 (1H, s)
Potassium carbonate (0.7 g) and ethyl 6-bromohexanoate (0.69 g) were added to compound 210 (0.80 g) in DMF (12 mL), and the mixture was added at room temperature for 3 hours and at 80 to 90 ° C. for 8.5 hours. Reacted. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 211 (1.06 g, Y = 92%).
A 7% aqueous potassium hydroxide solution (10 mL) was added to compound 211 (0.82 g) in methanol (40 mL), and reacted under reflux for 1.5 hours. Activated carbon was added and filtered while hot, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue, and then acidified with 35% hydrochloric acid. The crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from methanol (45 mL) to give compound 212 (0.58 g, Y = 67%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38−2.52 (17H, m) 4.15 (2H, t, J = 6 Hz) 7.20-8.30 (8H, m) 8.72 (1H, s) 11.99 ( 1H, brs)
A 0.03% aqueous potassium hydroxide solution (120 mL) was added to Compound 212 (200 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 213 (205 mg, Y = 94%).

［５−［［６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物２１４）、［５−［［６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物２１５）、［５−［［６−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物２１６）の製造：
ＤＭＦ（１２ｍＬ）中、化合物２１０（３００ｍｇ）に炭酸カリウム（６１０ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（６２３ｍｇ）を加え室温で２６時間反応した。反応液を水（１５０ｍＬ）中に加え、生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し粗製オイル（１．０４ｇ）を得た。粗製オイル（１．０４ｇ）をシリカゲルカラム（トルエン／酢酸エチル）で精製し、化合物２１４（０．６９ｇ）を得た。
エタノール（２０ｍＬ）中、化合物２１４（０．６９ｇ）に１３％水酸化カリウム水溶液（５ｍＬ）を加え、室温で１７時間反応した。反応液に水（１０ｍＬ）を加え、析出した結晶を溶解後、活性炭を加えろ過し、ろ液を減圧濃縮した。残渣に水（５０ｍＬ）を加え溶解後、３５％塩酸で酸析した。分離したオイルを酢酸エチル（１００ｍＬ）で抽出し、有機層を水洗後、硫酸マグネシウムで脱水した後、減圧濃縮して化合物２１５（３５７ｍｇ，Ｙ＝７７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３８−１．９８（１７Ｈ，ｍ）３．２５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１４（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．２１−８．３０（８Ｈ，ｍ）８．７２（１Ｈ，ｓ）１１．４８−１４．０４（２Ｈ，ｂｒ）
化合物２１５（１５０ｍｇ）に０．１３％水酸化ナトリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物２１６（１５８ｍｇ，Ｙ＝９７％）を得た。[5-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 214), [5-[[ 6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 215), [5-[[6- [5- (1 , 1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 216):
In DMF (12 mL), potassium carbonate (610 mg) and diethyl (5-bromopentyl) malonate (623 mg) were added to compound 210 (300 mg) and reacted at room temperature for 26 hours. The reaction was added into water (150 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (1.04 g). Crude oil (1.04 g) was purified by silica gel column (toluene / ethyl acetate) to obtain compound 214 (0.69 g).
A 13% aqueous potassium hydroxide solution (5 mL) was added to compound 214 (0.69 g) in ethanol (20 mL) and reacted at room temperature for 17 hours. Water (10 mL) was added to the reaction solution, the precipitated crystals were dissolved, activated carbon was added and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The separated oil was extracted with ethyl acetate (100 mL), and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give compound 215 (357 mg, Y = 77%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38-1.98 (17 H, m) 3.25 (1 H, t, J = 7 Hz) 4.14 (2 H, t, J = 5 Hz) 7.21-8.30 (8 H, m) 8.72 (1H, s) 11.48-14.04 (2H, br)
To the compound 215 (150 mg), 0.13% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 216 (158 mg, Y = 97%).

５−フェニル−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２１７）、６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物２１８）、６−［［６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２１９）、６−［［６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物２２０）の製造：
１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）に２−アミノ−４−フェニルフェノール（２．３ｇ），トリエチルアミン（１．２ｇ）を加え溶解後、６−ベンジルオキシ−２−ナフトエ酸クロライド（３．０ｇ）を加え室温で５時間反応した。反応液を水（８００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗後、乾燥して中間体のアミド化合物（４．５ｇ，Ｙ＝１００％）を得た。
１，３−ジメチル−２−イミダゾリジノン（４４ｍＬ）、トルエン（１３２ｍＬ）の混液中、アミド化合物（４．４ｇ）にｐ−トルエンスルホン酸一水和物（３．８ｇ）を加え、還流下で生成する水を除去しながら２３時間反応した。反応液を減圧濃縮し、残渣を水（６００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（１５０ｍＬ），水酸化カリウム（２．２ｇ）を加え、還流下２時間懸濁した後、結晶をろ取、乾燥して化合物２１７（１．７３ｇ，Ｙ＝４１％）を得た。
化合物２１７（１．５ｇ）に１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）、５％パラジウム炭素（０．２ｇ）を加え、水素雰囲気下５０℃で２３時間反応した。反応液をろ過し、ろ液を水（８００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗後、乾燥して化合物２１８（１．０９ｇ，Ｙ＝９２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．１７−８．２８（１３Ｈ，ｍ）８．７３（１Ｈ，ｓ）１０．１７（１Ｈ，ｓ）
ＤＭＦ（１５ｍＬ）中、化合物２１８（５００ｍｇ）に炭酸カリウム（６１５ｍｇ），６−ブロモヘキサン酸エチル（６０６ｍｇ）を加え室温で２４時間、８０〜９０℃で１．５時間反応した。反応液を水（２００ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して化合物２１９（６２１ｍｇ，Ｙ＝８７％）を得た。
メタノール（４０ｍＬ）中、化合物２１９（５７１ｍｇ）に５．７％水酸化カリウム水溶液（１０ｍＬ）を加え、６０〜７０℃で１７時間，室温で一夜反応した。反応液を減圧濃縮し、残渣に水（１００ｍＬ）を加え撹拌し、３５％塩酸で酸析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（３０ｍＬ）を加え、６０〜７０℃で撹拌懸濁後、結晶をろ取、乾燥して化合物２２０（４６６ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．５９−２．５２（８Ｈ，ｍ）４．１３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．１３−８．３２（１３Ｈ，ｍ）８．７４（１Ｈ，ｓ）１２．００（１Ｈ，ｓ）5-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 217), 6- (5-phenyl-2-benzoxazolyl) -2-naphthalenol (compound 218), 6- [[6- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 219), 6-[[6- (5-Phenyl-2-benzoxazolyl) Preparation of -2-naphthalenyl] oxy] hexanoic acid (Compound 220):
After dissolving 2-amino-4-phenylphenol (2.3 g) and triethylamine (1.2 g) in 1,3-dimethyl-2-imidazolidinone (50 mL), 6-benzyloxy-2-naphthoic acid chloride is dissolved. (3.0 g) was added and reacted at room temperature for 5 hours. The reaction solution was added to water (800 mL) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (4.5 g, Y = 100%).
In a mixed solution of 1,3-dimethyl-2-imidazolidinone (44 mL) and toluene (132 mL), p-toluenesulfonic acid monohydrate (3.8 g) was added to the amide compound (4.4 g), and the mixture was refluxed. The reaction was carried out for 23 hours while removing the water produced in step (b). The reaction mixture was concentrated under reduced pressure, and the residue was added to water (600 mL) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (150 mL) and potassium hydroxide (2.2 g) were added to the crude crystals and suspended for 2 hours under reflux. The crystals were collected by filtration and dried to obtain compound 217 (1.73 g, Y = 41%). It was.
1,3-Dimethyl-2-imidazolidinone (50 mL) and 5% palladium on carbon (0.2 g) were added to Compound 217 (1.5 g), and reacted at 50 ° C. for 23 hours in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 218 (1.09 g, Y = 92%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.17-8.28 (13H, m) 8.73 (1H, s) 10.17 (1H, s)
In DMF (15 mL), potassium carbonate (615 mg) and ethyl 6-bromohexanoate (606 mg) were added to compound 218 (500 mg) and reacted at room temperature for 24 hours and at 80 to 90 ° C. for 1.5 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 219 (621 mg, Y = 87%).
A 5.7% aqueous potassium hydroxide solution (10 mL) was added to compound 219 (571 mg) in methanol (40 mL), and the mixture was reacted at 60 to 70 ° C. for 17 hours and at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was stirred and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (30 mL) was added to the crude crystals, and after stirring and suspending at 60 to 70 ° C., the crystals were collected by filtration and dried to obtain Compound 220 (466 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.59-2.52 (8H, m) 4.13 (2H, t, J = 5 Hz) 7.13-8.32 (13H, m) 8.74 (1H, s) 12.00 ( 1H, s)

［３−［［６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物２２１）、［３−［［６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸（化合物２２２）、［３−［［６−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物２２３）の製造：
ＤＭＦ（１４ｍＬ）中、化合物２１８（４００ｍｇ）に炭酸カリウム（６７４ｍｇ），（３−クロロプロピル）マロン酸ジエチル（５５２ｍｇ）を加え、８０〜９０℃で三日間反応した。反応液を水（１００ｍＬ）中に加え撹拌した後、酢酸エチル（２００ｍＬ）で生成物を抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して粗製オイル（０．８ｇ）を得た。粗製オイル（０．８ｇ）をシリカゲルカラム（トルエン／酢酸エチル）で精製して化合物２２１（２１１ｍｇ，Ｙ＝３３％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２８（６Ｈ，ｔ，Ｊ＝７Ｈｚ）１．７２−２．３４（４Ｈ，ｍ）３．４７（１Ｈ，ｔ，Ｊ＝７Ｈｚ）３．９７−４．４０（６Ｈ，ｍ）７．１５−８．３８（１３Ｈ，ｍ）８．７１（１Ｈ，ｓ）
エタノール（２０ｍＬ）中、化合物２２１（１９０ｍｇ）に４．５％水酸化カリウム水溶液（２０ｍＬ）を加え室温で２３時間反応した。反応液に活性炭（０．１ｇ）を加えろ過し、ろ液を減圧濃縮した後、残渣に水（５０ｍＬ）を加え溶解後、３５％塩酸で酸析した。生成物を酢酸エチル（１００ｍＬ）で抽出し、有機層を水洗後、硫酸マグネシウムで脱水し、減圧濃縮した。残渣を乾燥して化合物２２２（１４４ｍｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８９−１．９９（４Ｈ，ｍ）３．３８（１Ｈ，ｔ，Ｊ＝４Ｈｚ）４．１９（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．２３−８．３４（１３Ｈ，ｍ）８．７７（１Ｈ，ｓ）１２．２８−１３．１９（２Ｈ，ｂｒ）
化合物２２２（８０ｍｇ）に０．０３％水酸化ナトリウム水溶液（５０ｍＬ）を加え溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物２２３（８７ｍｇ，Ｙ＝１００％）を得た。[3-[[6- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 221), [3-[[6- (5-Phenyl- 2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid (compound 222), [3-[[6- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid disodium salt (compound 223):
In DMF (14 mL), potassium carbonate (674 mg) and diethyl (3-chloropropyl) malonate (552 mg) were added to compound 218 (400 mg), and reacted at 80 to 90 ° C. for 3 days. The reaction solution was added to water (100 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (0.8 g). The crude oil (0.8 g) was purified with a silica gel column (toluene / ethyl acetate) to give compound 221 (211 mg, Y = 33%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.28 (6H, t, J = 7 Hz) 1.72-2.34 (4H, m) 3.47 (1H, t, J = 7 Hz) 3.97-4.40 (6H, m) 7.15-8.38 (13H, m) 8.71 (1H, s)
A 4.5% aqueous potassium hydroxide solution (20 mL) was added to compound 221 (190 mg) in ethanol (20 mL) and reacted at room temperature for 23 hours. Activated carbon (0.1 g) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The product was extracted with ethyl acetate (100 mL), and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dried to obtain Compound 222 (144 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.89-1.99 (4H, m) 3.38 (1H, t, J = 4 Hz) 4.19 (2H, t, J = 5 Hz) 7.23-8.34 (13H, m) 8.77 (1H, s) 12.28-13.19 (2H, br)
0.022% aqueous sodium hydroxide solution (50 mL) was added to and dissolved in compound 222 (80 mg), and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 223 (87 mg, Y = 100%).

５−クロロ−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２２４）、６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物２２５）、４−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物２２６）、４−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物２２７）、４−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物２２８）の製造：
２−アミノ−４−クロロフェノール（５．１ｇ）を１，４−ジオキサン（７０ｍＬ）に溶解し、６−ベンジルオキシ−２−ナフトエ酸クロライド（３．５ｇ）を加えて還流下で２時間反応した。反応液を減圧濃縮し、残渣を希塩酸、メタノールで順次洗浄後乾燥して中間体のアミド化合物（４．１９ｇ，Ｙ＝８８％）を得た。
アミド化合物（４．１９ｇ）に１，３−ジメチル−２−イミダゾリジノン（２５ｍＬ）、トルエン（５０ｍＬ）、ｐ−トルエンスルホン酸一水和物（３．０ｇ）を加えて一夜還流下で生成する水を除去しながら反応した。反応液を減圧濃縮し、残液に水（２００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物２２４（３．７３ｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝５．２１（２Ｈ，ｓ）７．２３−８．６７（１４Ｈ，ｍ）
化合物２２４（２．８ｇ）に３０％臭化水素・酢酸溶液（２８ｍＬ）を加えて約１００℃で２時間反応した。反応液に水（２００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物２２５（１．９９ｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．１６−８．２５（８Ｈ，ｍ）８．７０（１Ｈ，ｓ）１０．２１（１Ｈ，ｓ）
化合物２２５（４５３ｍｇ）をＤＭＦ（１２ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、４−ブロモ−ｎ−酪酸エチル（４１０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をエタノールで洗浄後乾燥して化合物２２６（６０２ｍｇ，Ｙ＝９６％）を得た。
化合物２２６（６０２ｍｇ）にメタノール（５０ｍＬ）、１，４−ジオキサン（１０ｍＬ）を加えて溶解し、１５％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で一夜反応した。反応液を冷却後、析出した結晶をろ取、乾燥して化合物２２８（４７６ｍｇ，Ｙ＝８０％）を得た。
化合物２２８のろ液を減圧濃縮後、残渣に水（５０ｍＬ）を加えて加熱溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物２２７（５８ｍｇ，Ｙ＝１０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．９０−２．５２（４Ｈ，ｍ）４．１７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２１−８．７２（９Ｈ，ｍ）１２．２（１Ｈ，ｂｒ）5-chloro-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 224), 6- (5-Chloro-2-benzoxazolyl) -2-naphthalenol (Compound 225), 4- [[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 226), 4-[[6- (5-Chloro-2-benzoxazolyl) Preparation of 2-naphthalenyl] oxy] butanoic acid (Compound 227), 4-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 228):
2-Amino-4-chlorophenol (5.1 g) was dissolved in 1,4-dioxane (70 mL), 6-benzyloxy-2-naphthoic acid chloride (3.5 g) was added, and the mixture was reacted under reflux for 2 hours. did. The reaction solution was concentrated under reduced pressure, and the residue was washed successively with dilute hydrochloric acid and methanol and dried to obtain an intermediate amide compound (4.19 g, Y = 88%).
1,3-dimethyl-2-imidazolidinone (25 mL), toluene (50 mL), p-toluenesulfonic acid monohydrate (3.0 g) was added to the amide compound (4.19 g), and the mixture was refluxed overnight. The reaction was carried out while removing water. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 224 (3.73 g, Y = 93%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.21 (2H, s) 7.23-8.67 (14H, m)
A 30% hydrogen bromide / acetic acid solution (28 mL) was added to compound 224 (2.8 g) and reacted at about 100 ° C. for 2 hours. Water (200 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 225 (1.99 g, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.16-8.25 (8H, m) 8.70 (1H, s) 10.21 (1H, s)
Compound 225 (453 mg) was dissolved in DMF (12 mL), potassium carbonate (1.5 g) and ethyl 4-bromo-n-butyrate (410 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol and dried to obtain Compound 226 (602 mg, Y = 96%).
Methanol (50 mL) and 1,4-dioxane (10 mL) were added to compound 226 (602 mg) and dissolved, and 15% aqueous sodium hydroxide solution (3 mL) was added and reacted overnight at about 50 ° C. After cooling the reaction solution, the precipitated crystals were collected by filtration and dried to obtain Compound 228 (476 mg, Y = 80%).
The filtrate of compound 228 was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 227 (58 mg, Y = 10%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.90-2.52 (4H, m) 4.17 (2H, t, J = 6 Hz) 7.21-8.72 (9H, m) 12.2 (1H, br)

６−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２２９）、６−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物２３０）、６−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物２３１）の製造：
化合物２２５（４５３ｍｇ）をＤＭＦ（１２ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、６−ブロモヘキサン酸エチル（４４０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をエタノールで洗浄後乾燥して化合物２２９（５４０ｍｇ，Ｙ＝８１％）を得た。
化合物２２９（５４０ｍｇ）にメタノール（５０ｍＬ）、１，４−ジオキサン（１０ｍＬ）を加えて溶解した後、１５％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で一夜反応した。冷却後、析出した結晶をろ取、乾燥して化合物２３１（４７８ｍｇ，Ｙ＝９０％）を得た。
化合物２３１のろ液を減圧濃縮後、残渣に水（５０ｍＬ）を加えて加熱溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物２３０（４８ｍｇ，Ｙ＝１０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２０−２．００（６Ｈ，ｍ）２．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１１（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１５−８．６９（９Ｈ，ｍ）6-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 229), 6-[[6- (5-Chloro-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid (Compound 230), 6-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 231) Manufacturing:
Compound 225 (453 mg) was dissolved in DMF (12 mL), potassium carbonate (1.5 g) and ethyl 6-bromohexanoate (440 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol and dried to obtain Compound 229 (540 mg, Y = 81%).
Methanol (50 mL) and 1,4-dioxane (10 mL) were added to compound 229 (540 mg) and dissolved, and then 15% aqueous sodium hydroxide solution (3 mL) was added and reacted at about 50 ° C. overnight. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 231 (478 mg, Y = 90%).
The filtrate of compound 231 was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 230 (48 mg, Y = 10%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.20-2.00 (6H, m) 2.27 (2H, t, J = 6 Hz) 4.11 (2H, t, J = 6 Hz) 7.15-8.69 (9H, m)

［３−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物２３２）、［３−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物２３３）、［３−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸（化合物２３４）の製造：
化合物２２５（４００ｍｇ）をＤＭＦ（７ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、（３−クロロプロピル）マロン酸ジエチル（４６０ｍｇ）を加えて約５０℃で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物２３２（３０９ｍｇ，Ｙ＝４６％）を得た。
化合物２３２（３０９ｍｇ）をメタノール（４０ｍＬ）、１，４−ジオキサン（１０ｍＬ）に溶解し、１５％水酸化ナトリウム水溶液（３ｍＬ）を加えて、室温で一夜反応した。析出した結晶をろ取、乾燥して化合物２３３（２７３ｍｇ，Ｙ＝９１％）を得た。
化合物２３３（２８ｍｇ）を水（５ｍＬ）に加温溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物２３４（１９ｍｇ，Ｙ＝７５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．７５−２．１０（４Ｈ，ｍ）３．３７（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１７（２Ｈ，ｔ，Ｊ＝７Ｈｚ）７．２１−８．７２（９Ｈ，ｍ）１２．７５（２Ｈ，ｂｒ）[3-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 232), [3-[[6- (5-Chloro- 2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (compound 233), [3-[[6- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] Production of] oxy] propyl] propanedioic acid (compound 234):
Compound 225 (400 mg) was dissolved in DMF (7 mL), and potassium carbonate (1.5 g) and diethyl (3-chloropropyl) malonate (460 mg) were added and reacted at about 50 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 232 (309 mg, Y = 46%).
Compound 232 (309 mg) was dissolved in methanol (40 mL) and 1,4-dioxane (10 mL), 15% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at room temperature overnight. The precipitated crystals were collected by filtration and dried to obtain Compound 233 (273 mg, Y = 91%).
Compound 233 (28 mg) was dissolved in water (5 mL) by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 234 (19 mg, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.75-2.10 (4H, m) 3.37 (1H, t, J = 6 Hz) 4.17 (2H, t, J = 7 Hz) 7.21-8.72 (9H, m) 12.75 (2H, br)

［５−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物２３５）、［５−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物２３６）、［５−［［６−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物２３７）の製造：
化合物２２５（１６３ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（０．６ｇ）、（５−ブロモペンチル）マロン酸ジエチル（２６０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物２３５（２０６ｍｇ，Ｙ＝７１％）を得た。
化合物２３５（２０６ｍｇ）にメタノール（８０ｍＬ）を加えて溶解した後、６％水酸化ナトリウム水溶液（５ｍＬ）を加えて室温で７日間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加温溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物２３６（１３８ｍｇ，Ｙ＝７５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．２１−１．９５（８Ｈ，ｍ）３．２５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２０−８．７１（９Ｈ，ｍ）１２．７（２Ｈ，ｂｒ）
化合物２３６（７５．６ｍｇ）を水（３０ｍＬ）に懸濁し、０．４％水酸化ナトリウム水溶液（３．３ｍＬ）を加えて加温溶解後、ろ過した。ろ液を凍結乾燥して化合物２３７（７７ｍｇ，Ｙ＝９９％）を得た。[5-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 235), [5-[[6- (5-chloro- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 236), [5-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 237):
Compound 225 (163 mg) was dissolved in DMF (5 mL), potassium carbonate (0.6 g) and diethyl (5-bromopentyl) malonate (260 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 235 (206 mg, Y = 71%).
Methanol (80 mL) was added to and dissolved in compound 235 (206 mg), 6% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature for 7 days. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 236 (138 mg, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.2-1-1.95 (8H, m) 3.25 (1H, t, J = 7 Hz) 4.12 (2H, t, J = 6 Hz) 7.20-8.71 (9H, m) 12.7 (2H, br)
Compound 236 (75.6 mg) was suspended in water (30 mL), 0.4% aqueous sodium hydroxide solution (3.3 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 237 (77 mg, Y = 99%).

５−クロロ−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物２３８）の製造
化合物２２５（１２７ｍｇ）をＤＭＦ（２．５ｍＬ）に溶解し、炭酸カリウム（０．５２ｇ）、Ｎ−（２−クロロエチル）モルホリン塩酸塩（１２２ｍｇ）を加えて約７０℃で一夜反応した。反応液に水（２５ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をアセトン（５０ｍＬ）に溶解し、３５％塩酸（０．５ｍＬ）を加えて析出した結晶をろ取、乾燥して化合物２３８（１７７ｍｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．１８−４．１０（１０Ｈ，ｍ）４．６８（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３０−８．７７（９Ｈ，ｍ）１２．０（１Ｈ，ｂｒ）Preparation of 5-chloro-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 238) Compound 225 (127 mg) was dissolved in DMF (2.5 mL), Potassium carbonate (0.52 g) and N- (2-chloroethyl) morpholine hydrochloride (122 mg) were added and reacted at about 70 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (50 mL), 35% hydrochloric acid (0.5 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 238 (177 mg, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.18-4.10 (10H, m) 4.68 (2H, t, J = 5 Hz) 7.30-8.77 (9H, m) 12.0 (1H, br)

４−メチル−２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２３９）、６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物２４０）、６−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２４１）、６−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物２４２）、６−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物２４３）の製造：
１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）に２−アミノ−ｍ−クレゾール（１．５ｇ），トリエチルアミン（１．２ｇ）を加え溶解した後、６−ベンジルオキシ−２−ナフトエ酸クロライド（３．０ｇ）を加え室温で２時間反応した。反応液を水（８００ｍＬ）に加え晶析し、析出結晶をろ取、水洗後、乾燥して中間体のアミド化合物（３．５ｇ，Ｙ＝９０％）を得た。
１，３−ジメチル−２−イミダゾリジノン（３４ｍＬ）、トルエン（１０２ｍＬ）の混液中、アミド化合物（３．４ｇ）にｐ−トルエンスルホン酸一水和物（３．４ｇ）を加え、還流下で生成する水を除去しながら２３時間反応した。反応液を減圧濃縮し、残液を水（８００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（１００ｍＬ），水酸化カリウム（２．０ｇ）を加え、還流下２時間懸濁した後、結晶をろ取、乾燥して化合物２３９（２．６４ｇ，Ｙ＝８１％）を得た。
化合物２３９（２．４０ｇ）に１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）を加え溶解した後、５％パラジウム炭素（０．２ｇ）を加え水素雰囲気下で２３時間反応した。反応液をろ過し、ろ液を水（８００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗後、乾燥して化合物２４０（１．７７ｇ，Ｙ＝９８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．６２（３Ｈ，ｓ）７．１６−８．２６（８Ｈ，ｍ）８．７０（１Ｈ，ｓ）１０．１４（１Ｈ，ｓ）
ＤＭＦ（１５ｍＬ）中、化合物２４０（５００ｍｇ）に炭酸カリウム（５１０ｍｇ），６−ブロモヘキサン酸エチル（５００ｍｇ）を加え、室温で２１時間反応した。反応液を水（２００ｍＬ）中に加え撹拌した後、酢酸エチル（６００ｍＬ）で目的物を抽出した。有機層を水洗後、減圧濃縮して化合物２４１（１．０ｇ）を得た。
メタノール（４０ｍＬ）中、化合物２４１（１．０ｇ）に５％水酸化カリウム水溶液（１０ｍＬ）を加え４５℃で１５時間反応した。反応液を減圧濃縮後、残渣に水（１５０ｍＬ）を加え溶解し、３５％塩酸で酸析した。析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶をトルエン（３０ｍＬ）から再結晶して化合物２４２（５９６ｍｇ，Ｙ＝８４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６０−２．６２（１１Ｈ，ｍ）４．１４（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．２３−８．３１（８Ｈ，ｍ）８．７３（１Ｈ，ｓ）１２．０１（１Ｈ，ｓ）
化合物２４２（１５０ｍｇ）に０．０５％水酸化カリウム水溶液（５０ｍＬ）を加え、加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物２４３（１５３ｍｇ，Ｙ＝９３％）を得た。4-methyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 239), 6- (4-methyl-2-benzoxazolyl) -2-naphthalenol (compound 240), 6- [[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 241), 6-[[6- (4-Methyl-2-benzoxazolyl) Preparation of 2-naphthalenyl] oxy] hexanoic acid (Compound 242), 6-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 243):
After 2-amino-m-cresol (1.5 g) and triethylamine (1.2 g) are added to 1,3-dimethyl-2-imidazolidinone (50 mL) and dissolved, 6-benzyloxy-2-naphthoic acid chloride is dissolved. (3.0 g) was added and reacted at room temperature for 2 hours. The reaction solution was added to water (800 mL) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (3.5 g, Y = 90%).
In a mixed liquid of 1,3-dimethyl-2-imidazolidinone (34 mL) and toluene (102 mL), p-toluenesulfonic acid monohydrate (3.4 g) was added to the amide compound (3.4 g), and the mixture was refluxed. The reaction was carried out for 23 hours while removing the water produced in step (b). The reaction solution was concentrated under reduced pressure, and the remaining solution was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (100 mL) and potassium hydroxide (2.0 g) were added to the crude crystals and suspended for 2 hours under reflux. The crystals were collected by filtration and dried to obtain compound 239 (2.64 g, Y = 81%). It was.
1,3-Dimethyl-2-imidazolidinone (50 mL) was added to and dissolved in Compound 239 (2.40 g), 5% palladium on carbon (0.2 g) was added, and the mixture was reacted under a hydrogen atmosphere for 23 hours. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 240 (1.77 g, Y = 98%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.62 (3H, s) 7.16-8.26 (8H, m) 8.70 (1H, s) 10.14 (1H, s)
Potassium carbonate (510 mg) and ethyl 6-bromohexanoate (500 mg) were added to compound 240 (500 mg) in DMF (15 mL), and reacted at room temperature for 21 hours. The reaction mixture was added to water (200 mL) and stirred, and the target product was extracted with ethyl acetate (600 mL). The organic layer was washed with water and concentrated under reduced pressure to obtain Compound 241 (1.0 g).
A 5% aqueous potassium hydroxide solution (10 mL) was added to compound 241 (1.0 g) in methanol (40 mL) and reacted at 45 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, water (150 mL) was added to the residue to dissolve it, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from toluene (30 mL) to give compound 242 (596 mg, Y = 84%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.60-2.62 (11H, m) 4.14 (2H, t, J = 5 Hz) 7.23-8.31 (8H, m) 8.73 (1H, s) 12.01 ( 1H, s)
A 0.05% aqueous potassium hydroxide solution (50 mL) was added to compound 242 (150 mg), dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 243 (153 mg, Y = 93%).

［３−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物２４４）、［３−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸（化合物２４５）、［３−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物２４６）の製造：
ＤＭＦ（１２ｍＬ）中、化合物２４０（３００ｍｇ）に炭酸カリウム（４６０ｍｇ），（３−クロロプロピル）マロン酸ジエチル（４２６ｍｇ）を加え、８０℃で２４時間反応した。
反応液を水（１５０ｍＬ）中に加え撹拌した後、酢酸エチル（５００ｍＬ）で生成物を抽出した。有機層を水洗後、硫酸マグネシウムで脱水し、減圧濃縮して粗製オイル（０．６２ｇ）を得た。粗製オイル（０．６２ｇ）をシリカゲルカラム（トルエン／酢酸エチル）で精製し、化合物２４４（０．４１ｇ）を得た。
エタノール（２０ｍＬ）中、化合物２４４（０．４１ｇ）に１８％水酸化カリウム水溶液（５ｍＬ）を加え室温で２時間，５０℃で１時間２０分反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加えて溶解した後、３５％塩酸で酸析した。析出結晶をろ取、水洗し、乾燥して粗製結晶（２１７ｍｇ）を得た。粗製結晶を５０％エタノール水溶液から再結晶して化合物２４５（１７８ｍｇ，Ｙ＝３９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６９−２．１９（４Ｈ，ｍ）２．６２（３Ｈ，ｓ）３．３７（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．０７−８．３３（８Ｈ，ｍ）８．７４（１Ｈ，ｓ）１２．１２−１３．２２（２Ｈ，ｂｒ）
化合物２４５（８０ｍｇ）に０．０８％水酸化ナトリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物２４６（８７ｍｇ，Ｙ＝９８％）を得た。[3-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 244), [3-[[6- (4-methyl- 2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid (compound 245), [3-[[6- (4-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid disodium salt (compound 246):
Potassium carbonate (460 mg) and diethyl (3-chloropropyl) malonate (426 mg) were added to compound 240 (300 mg) in DMF (12 mL) and reacted at 80 ° C. for 24 hours.
The reaction mixture was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (500 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (0.62 g). Crude oil (0.62 g) was purified by silica gel column (toluene / ethyl acetate) to obtain compound 244 (0.41 g).
18% aqueous potassium hydroxide solution (5 mL) was added to compound 244 (0.41 g) in ethanol (20 mL) and reacted at room temperature for 2 hours and at 50 ° C. for 1 hour and 20 minutes. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the residue to dissolve it, followed by acid precipitation with 35% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to obtain crude crystals (217 mg). The crude crystals were recrystallized from 50% aqueous ethanol to give compound 245 (178 mg, Y = 39%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.69-2.19 (4H, m) 2.62 (3H, s) 3.37 (1H, t, J = 7 Hz) 4.18 (2H, t, J = 6 Hz) 7.07− 8.33 (8H, m) 8.74 (1H, s) 12.12-13.22 (2H, br)
To the compound 245 (80 mg), 0.08% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 246 (87 mg, Y = 98%).

［５−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物２４７）、［５−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物２４８）、［５−［［６−（４−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物２４９）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２４０（３００ｍｇ）に炭酸カリウム（６０７ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（６２９ｍｇ）を加え、室温で２５時間反応した。反応液を水（１００ｍＬ）中に加え撹拌した後、酢酸エチル（２００ｍＬ）で生成物を抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し化合物２４７（７９４ｍｇ）を得た。
エタノール（２０ｍＬ）中、化合物２４７（７６５ｍｇ）に６％水酸化カリウム水溶液（１５ｍＬ）を加え室温で６時間反応した。反応液に活性炭を加えろ過し、ろ液を減圧濃縮した。残渣に水（５０ｍＬ）を加え溶解後、３５％塩酸で酸析した。分離したオイルを酢酸エチル（２００ｍＬ）で抽出した後、有機層を水洗し、硫酸マグネシウムで脱水した後、減圧濃縮して粗製結晶（５１２ｍｇ）を得た。粗製結晶（５１２ｍｇ）にメタノール（２０ｍＬ）を加え撹拌懸濁後、結晶をろ取、乾燥して化合物２４８（３６２ｍｇ，Ｙ＝７４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．０５−２．１７（８Ｈ，ｍ）２．６２（３Ｈ，ｓ）３．２６（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１３（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２４−８．３６（８Ｈ，ｍ）８．７３（１Ｈ，ｓ）１１．９１−１３．２４（２Ｈ，ｂｒ）
化合物２４８（１００ｍｇ）に０．０４％水酸化ナトリウム水溶液（５０ｍＬ）を加え、ほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥し化合物２４９（１１０ｍｇ，Ｙ＝１００％）を得た。[5-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 247), [5-[[6- (4-Methyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 248), [5-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 249):
In DMF (10 mL), potassium carbonate (607 mg) and (5-bromopentyl) diethyl malonate (629 mg) were added to compound 240 (300 mg) and reacted at room temperature for 25 hours. The reaction solution was added to water (100 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 247 (794 mg).
A 6% aqueous potassium hydroxide solution (15 mL) was added to compound 247 (765 mg) in ethanol (20 mL) and reacted at room temperature for 6 hours. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The separated oil was extracted with ethyl acetate (200 mL), and then the organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals (512 mg). Methanol (20 mL) was added to the crude crystals (512 mg) and suspended with stirring, and the crystals were collected by filtration and dried to obtain Compound 248 (362 mg, Y = 74%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.5-2.17 (8H, m) 2.62 (3H, s) 3.26 (1H, t, J = 6 Hz) 4.13 (2H, t, J = 6 Hz) 7.24− 8.36 (8H, m) 8.73 (1H, s) 11.91-13.24 (2H, br)
0.04% aqueous sodium hydroxide solution (50 mL) was added to compound 248 (100 mg), and the mixture was almost dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to obtain Compound 249 (110 mg, Y = 100%).

６−メチル−２−［３−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２５０）、３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物２５１）、４−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物２５２）、４−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物２５３）、４−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸カリウム塩（化合物２５４）の製造：
トルエン（１００ｍＬ）中、３−ベンジルオキシ−２−ナフトエ酸（７．０ｇ）を塩化チオニル（３．６ｇ）と還流下で１時間２０分反応した。反応液を減圧濃縮し、３−ベンジルオキシ−２−ナフトエ酸クロライド（７．９ｇ）を得た。
３−ベンジルオキシ−２−ナフトエ酸クロライドのオイル（７．９ｇ）を６−アミノ−ｍ−クレゾール（３．８ｇ），トリエチルアミン（３．１ｇ）の１，３−ジメチル−２−イミダゾリジノン（１００ｍＬ）溶液に加え、室温で２．５時間反応した。反応液を水（１Ｌ）に加えて晶析し、析出結晶をろ取、水洗後、乾燥して中間体のアミド化合物（９．２ｇ，Ｙ＝９５％）を得た。
１，３−ジメチル−２−イミダゾリジノン（９０ｍＬ）、トルエン（２７０ｍＬ）の混液中、アミド化合物（９．０ｇ）にｐ−トルエンスルホン酸一水和物（９．０ｇ）を加え、還流下で生成する水を除去しながら反応した。反応液を減圧濃縮し、残液を水（１．５Ｌ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（３００ｍＬ），水酸化カリウム（１０．０ｇ）を加え、還流下２時間懸濁した後、結晶をろ取、乾燥して化合物２５０（１．９３ｇ，Ｙ＝２３％）を得た。
１，３−ジメチル−２−イミダゾリジノン（４０ｍＬ）に化合物２５０（２．７０ｇ）を溶解し、５％パラジウム炭素（０．２ｇ）を加え水素雰囲気下で三日間反応した。反応液をろ過し、ろ液を水（８００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗後、乾燥して化合物２５１（１．９１ｇ，Ｙ＝９４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．５０（３Ｈ，ｓ）７．２７−８．１１（８Ｈ，ｍ）８．６７（１Ｈ，ｓ）１１．０１（１Ｈ，ｓ）
ＤＭＦ（１２ｍＬ）中、化合物２５１（３００ｍｇ）に炭酸カリウム（４５２ｍｇ），４−ブロモ−ｎ−酪酸エチル（２７１ｍｇ）を加え、室温で１６．５時間反応した。反応液を水（１５０ｍＬ）中に加えて晶析し、析出結晶をろ取、水洗して化合物２５２（３８２ｍｇ，Ｙ＝９０％）を得た。
エタノール（２０ｍＬ）中、化合物２５２（３２１ｍｇ）に１３％水酸化カリウム水溶液（５ｍＬ）を加え、室温で１．５時間反応した。反応液に活性炭を加えろ過し、ろ液を減圧濃縮した。残渣に水（５０ｍＬ）を加え溶解し、３５％塩酸で酸析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶を酢酸エチル（６ｍＬ）から再結晶し化合物２５３（１９８ｍｇ，Ｙ＝６７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８４−２．７３（７Ｈ，ｍ）４．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１９−８．１２（８Ｈ，ｍ）８．６４（１Ｈ，ｓ）１２．１２（１Ｈ，ｂｒｓ）
化合物２５３（１００ｍｇ）に０．１％水酸化カリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物２５４（８５ｍｇ，Ｙ＝７７％）を得た。6-methyl-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 250), 3- (6-methyl-2-benzoxazolyl) -2-naphthalenol (compound 251), 4- [[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 252), 4-[[3- (6-Methyl-2-benzoxazolyl) Preparation of 2-naphthalenyl] oxy] butanoic acid (Compound 253), 4-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 254):
3-Benzyloxy-2-naphthoic acid (7.0 g) was reacted with thionyl chloride (3.6 g) in toluene (100 mL) for 1 hour and 20 minutes under reflux. The reaction solution was concentrated under reduced pressure to obtain 3-benzyloxy-2-naphthoic acid chloride (7.9 g).
3-Benzyloxy-2-naphthoic acid chloride oil (7.9 g) was replaced with 6-amino-m-cresol (3.8 g), triethylamine (3.1 g) 1,3-dimethyl-2-imidazolidinone ( 100 mL) solution and reacted at room temperature for 2.5 hours. The reaction solution was added to water (1 L) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (9.2 g, Y = 95%).
In a mixed solution of 1,3-dimethyl-2-imidazolidinone (90 mL) and toluene (270 mL), p-toluenesulfonic acid monohydrate (9.0 g) was added to the amide compound (9.0 g), and the mixture was refluxed. The reaction was carried out while removing the water produced in step 1. The reaction solution was concentrated under reduced pressure, and the residue was added to water (1.5 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (300 mL) and potassium hydroxide (10.0 g) were added to the crude crystals, suspended for 2 hours under reflux, and the crystals were collected by filtration and dried to obtain compound 250 (1.93 g, Y = 23%). It was.
Compound 250 (2.70 g) was dissolved in 1,3-dimethyl-2-imidazolidinone (40 mL), 5% palladium carbon (0.2 g) was added, and the mixture was reacted under a hydrogen atmosphere for 3 days. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. Precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 251 (1.91 g, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.50 (3H, s) 7.27-8.11 (8H, m) 8.67 (1H, s) 11.01 (1H, s)
In DMF (12 mL), potassium carbonate (452 mg) and ethyl 4-bromo-n-butyrate (271 mg) were added to compound 251 (300 mg), and reacted at room temperature for 16.5 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 252 (382 mg, Y = 90%).
A 13% aqueous potassium hydroxide solution (5 mL) was added to compound 252 (321 mg) in ethanol (20 mL) and reacted at room temperature for 1.5 hours. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue for dissolution, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate (6 mL) to obtain Compound 253 (198 mg, Y = 67%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.84-2.73 (7H, m) 4.28 (2H, t, J = 6 Hz) 7.19-8.12 (8H, m) 8.64 (1H, s) 12.12 ( 1H, brs)
A 0.1% aqueous potassium hydroxide solution (20 mL) was added to compound 253 (100 mg) and dissolved substantially, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 254 (85 mg, Y = 77%).

６−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２５５）、６−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物２５６）、６−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物２５７）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２５１（３００ｍｇ）に炭酸カリウム（３０７ｍｇ），６−ブロモヘキサン酸エチル（３１４ｍｇ）を加え、室温で２２時間反応した。反応液を水（１５０ｍＬ）中に加え撹拌し、生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して化合物２５５（０．６６ｇ）を得た。
メタノール（２０ｍＬ）中、化合物２５５（０．６６ｇ）に１３％水酸化カリウム水溶液（５ｍＬ）を加え、室温で１７時間反応した。反応液を減圧濃縮後、残渣に水（２０ｍＬ）を加え、３５％塩酸で酸析した。析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶にエタノール（２ｍＬ）を加え、撹拌懸濁後、結晶をろ取、乾燥して化合物２５６（３０４ｍｇ，Ｙ＝７２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６７−２．５１（１１Ｈ，ｍ）４．２３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．１９−８．１２（８Ｈ，ｍ）８．６３（１Ｈ，ｓ）１１．９８（１Ｈ，ｓ）
化合物２５６（１５０ｍｇ）に０．０６％水酸化カリウム水溶液（５０ｍＬ）を加え加熱溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物２５７（１３５ｍｇ，Ｙ＝８２％）を得た。6-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 255), 6-[[3- (6-Methyl-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] hexanoic acid (Compound 256), 6-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 257) Manufacturing:
In DMF (10 mL), potassium carbonate (307 mg) and ethyl 6-bromohexanoate (314 mg) were added to compound 251 (300 mg) and reacted at room temperature for 22 hours. The reaction mixture was added to water (150 mL) and stirred, and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 255 (0.66 g).
A 13% aqueous potassium hydroxide solution (5 mL) was added to compound 255 (0.66 g) in methanol (20 mL) and reacted at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Ethanol (2 mL) was added to the crude crystals and suspended with stirring. The crystals were collected by filtration and dried to obtain Compound 256 (304 mg, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.67−2.51 (11H, m) 4.23 (2H, t, J = 5 Hz) 7.19-8.12 (8H, m) 8.63 (1H, s) 11.98 ( 1H, s)
0.06% aqueous potassium hydroxide solution (50 mL) was added to compound 256 (150 mg) and dissolved by heating, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 257 (135 mg, Y = 82%).

［５−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物２５８）、［５−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物２５９）、［５−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物２６０）、の製造：
ＤＭＦ（１４ｍＬ）中、化合物２５１（３００ｍｇ）に炭酸カリウム（６１１ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（８２６ｍｇ）を加え室温で一夜反応した。反応液を水（１５０ｍＬ）中に加え、生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して化合物２５８（１．０７ｇ）を得た。
メタノール（２０ｍＬ）中、化合物２５８（１．０７ｇ）に、２０％水酸化カリウム水溶液（５ｍＬ）を加え、室温で２０時間反応した。反応液を減圧濃縮後、残渣に水（３０ｍＬ）を加え溶解した後、３５％塩酸で酸析した。析出した結晶をろ取し、エタノール（６ｍＬ）と共に撹拌懸濁後、結晶をろ取、乾燥して化合物２５９（３０９ｍｇ，Ｙ＝６３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１９−１．７８（８Ｈ，ｍ）２．５１（３Ｈ，ｓ）３．２２（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．２３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．１９−８．１０（８Ｈ，ｍ）８．６３（１Ｈ，ｓ）
化合物２５９（１５０ｍｇ）に１３％水酸化ナトリウム水溶液（２０ｍＬ）を加え、ほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物２６０（１６０ｍｇ，Ｙ＝９７％）を得た。[5-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 258), [5-[[3- (6-methyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 259), [5-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 260):
In DMF (14 mL), potassium carbonate (611 mg) and diethyl (5-bromopentyl) malonate (826 mg) were added to compound 251 (300 mg) and reacted overnight at room temperature. The reaction was added into water (150 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 258 (1.07 g).
A 20% aqueous potassium hydroxide solution (5 mL) was added to compound 258 (1.07 g) in methanol (20 mL) and reacted at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and water (30 mL) was added to the residue to dissolve it. The precipitated crystals were collected by filtration and stirred and suspended with ethanol (6 mL), and then the crystals were collected by filtration and dried to obtain Compound 259 (309 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.19-1.78 (8H, m) 2.51 (3H, s) 3.22 (1H, t, J = 6 Hz) 4.23 (2H, t, J = 5 Hz) 7.19- 8.10 (8H, m) 8.63 (1H, s)
A 13% aqueous sodium hydroxide solution (20 mL) was added to compound 259 (150 mg), and the mixture was almost dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 260 (160 mg, Y = 97%).

６−メチル−２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物２６１）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２５１（２００ｍｇ）に炭酸カリウム（５１１ｍｇ），２−クロロエチルモルホリン塩酸塩（２０４ｍｇ）を加え、７０〜８０℃で２０時間反応した。反応液を水（１００ｍＬ）中に加え撹拌した後、生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られたオイル（３１５ｍｇ）をアセトン（１０ｍＬ）に溶解した後、３５％塩酸を加えｐＨ≒１〜２に調整した。析出した結晶をろ取、乾燥して化合物２６１（２２８ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．５１（３Ｈ，ｓ）３．２２−４．００（１０Ｈ，ｍ）４．７８（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．２０−８．１５（８Ｈ，ｍ）８．７０（１Ｈ，ｓ）１１．２２−１２．５５（１Ｈ，ｂｒ）Preparation of 6-methyl-2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 261):
In DMF (10 mL), potassium carbonate (511 mg) and 2-chloroethylmorpholine hydrochloride (204 mg) were added to compound 251 (200 mg) and reacted at 70-80 ° C. for 20 hours. The reaction mixture was added to water (100 mL) and stirred, and then the product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained oil (315 mg) was dissolved in acetone (10 mL), and 35% hydrochloric acid was added to adjust the pH to about 1 to 2. The precipitated crystals were collected by filtration and dried to obtain Compound 261 (228 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.51 (3H, s) 3.22-4.00 (10H, m) 4.78 (2H, t, J = 4 Hz) 7.20-8.15 (8H, m) 8.70 ( 1H, s) 11.2-12.55 (1H, br)

Ｎ，Ｎ−ジメチル−３−［［３−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩（化合物２６２）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２５１（２００ｍｇ）に炭酸カリウム（４０５ｍｇ），３−ジメチルアミノプロピルクロライド塩酸塩（１３８ｍｇ）を加え、８０〜９０℃で１６時間反応した。反応液を水（１５０ｍＬ）中に加え撹拌した後、生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して得られたオイル（２６３ｍｇ）をアセトン（１０ｍＬ）に溶解し、３５％塩酸を加えｐＨ≒１〜２に調整した。析出した結晶をろ取、乾燥して化合物２６２（２１１ｍｇ，Ｙ＝７３％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝２．３０−２．５３（５Ｈ，ｍ）３．０８（６Ｈ，ｓ）３．５８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．４４（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２３−８．０１（８Ｈ，ｍ）８．６９（１Ｈ，ｓ）Preparation of N, N-dimethyl-3-[[3- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 262):
In DMF (10 mL), potassium carbonate (405 mg) and 3-dimethylaminopropyl chloride hydrochloride (138 mg) were added to compound 251 (200 mg) and reacted at 80 to 90 ° C. for 16 hours. The reaction mixture was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate and concentrated under reduced pressure. An oil (263 mg) obtained by dissolving in acetone was dissolved in acetone (10 mL), and 35% hydrochloric acid was added to adjust the pH to approximately 1-2. The precipitated crystals were collected by filtration and dried to obtain Compound 262 (211 mg, Y = 73%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 2.30−2.53 (5H, m) 3.08 (6H, s) 3.58 (2H, t, J = 6 Hz) 4.44 (2H, t, J = 6 Hz) 7.23- 8.01 (8H, m) 8.69 (1H, s)

６−ニトロ−２−［３−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２６３）、３−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物２６４）、４−［［３−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物２６５）、４−［［３−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物２６６）、４−［［３−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物２６７）、４−［［３−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物２６８）、４−［［３−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物２６９）の製造：
３−ベンジルオキシ−２−ナフトエ酸（１０．８ｇ）にトルエン（１００ｍＬ）、塩化チオニル（３．３５ｍＬ）、ＤＭＦ（１滴）を加えて還流下で３．５時間反応した後、２−アミノ−５ニトロフェノール（１２．５ｇ）の１，４−ジオキサン（１５０ｍＬ）溶液を加え、還流下で６時間反応した。反応液を冷却し、析出した結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して中間体のアミド化合物（１４．９ｇ，Ｙ＝９３％）を得た。
アミド化合物（１４．９ｇ）を１，３−ジメチル−２−イミダゾリジノン（８０ｍＬ）に溶解し、ｐ−トルエンスルホン酸一水和物（１９ｇ）及びトルエン（１８０ｍＬ）を加え、還流下で生成する水を除去しながら一夜反応した。冷却後、析出した結晶をろ取し、トルエン洗浄後、メタノール洗浄した。得られた結晶にメタノール（４００ｍＬ）、４０％水酸化ナトリウム水溶液（１０ｍＬ）を加え、還流下で３０分間懸濁後、結晶をろ取、乾燥して化合物２６３（６．８５ｇ，Ｙ＝４８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝５．４２（２Ｈ，ｓ）７．２８−８．７５（１４Ｈ，ｍ）
化合物２６３（６．８ｇ）に３０％臭化水素・酢酸溶液（７０ｍＬ）を加えて約１００℃で２．５時間反応した。反応液に水（４３０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶を５０％メタノール水溶液で洗浄後乾燥して化合物２６４（５．２ｇ，Ｙ＝９１％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝７．２６−８．６９（９Ｈ，ｍ）１０．７６（１Ｈ，ｓ）
化合物２６４（７４０ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（３．５ｇ）、４−ブロモ−ｎ−酪酸エチル（６１０ｍｇ）を加え、室温で一夜反応した。反応液に水（９０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールで洗浄後乾燥して化合物２６５（８８４ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．１８−２．９２（４Ｈ，ｍ）４．０１−４．４２（４Ｈ，ｍ）７．３１−８．７４（９Ｈ，ｍ）
化合物２６５（８５０ｍｇ）にトルエン（２０ｍＬ）、エタノール（８０ｍＬ）、５％パラジウム炭素（０．３ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物２６６（７８０ｍｇ，Ｙ＝９９％）を得た。
化合物２６６（３９０ｍｇ）をＤＭＦ（７ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ヨウ化エチル（３．０ｇ）を加え約６５℃で一夜反応した。反応液にクロロホルム（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。クロロホルム層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物２６７（１５０ｍｇ，Ｙ＝３４％）を得た。
化合物２６７（１５０ｍｇ）をメタノール（１００ｍＬ）に溶解し、１０％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で一夜反応した。反応液を減圧濃縮し、残渣を水（５０ｍＬ）に加熱溶解後、希塩酸を加えて中和した。析出した結晶をろ取、乾燥して化合物２６８（８０ｍｇ，Ｙ＝５７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１４（６Ｈ，ｔ，Ｊ＝６Ｈｚ）１．８０−２．８５（４Ｈ，ｍ）３．２０−３．６５（４Ｈ，ｍ）４．２７（２Ｈ，ｔ，Ｊ＝７Ｈｚ）６．６９−８．１５（８Ｈ，ｍ）８．５７（１Ｈ，ｓ）１２．１６（１Ｈ，ｂｒ）
化合物２６８（２５ｍｇ）を水（５０ｍＬ）に懸濁し、０．５％水酸化ナトリウム水溶液（０．９５ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物２６９（２８ｍｇ，Ｙ＝１０６％）を得た。6-nitro-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 263), 3- (6-nitro-2-benzoxazolyl) -2-naphthalenol (compound 264), 4- [[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 265), 4-[[3- (6-Amino-2-benzoxazolyl) 2-Naphthalenyl] oxy] butanoic acid ethyl ester (Compound 266), 4-[[3- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 267) ), 4-[[3- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 268), 4 [[3- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 269) Preparation:
Toluene (100 mL), thionyl chloride (3.35 mL) and DMF (1 drop) were added to 3-benzyloxy-2-naphthoic acid (10.8 g) and reacted under reflux for 3.5 hours. A solution of -5 nitrophenol (12.5 g) in 1,4-dioxane (150 mL) was added and reacted under reflux for 6 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain an intermediate amide compound (14.9 g, Y = 93%).
The amide compound (14.9 g) was dissolved in 1,3-dimethyl-2-imidazolidinone (80 mL), p-toluenesulfonic acid monohydrate (19 g) and toluene (180 mL) were added, and the product was produced under reflux. The reaction was carried out overnight while removing water. After cooling, the precipitated crystals were collected by filtration, washed with toluene, and then washed with methanol. Methanol (400 mL) and 40% aqueous sodium hydroxide solution (10 mL) were added to the obtained crystals, suspended for 30 minutes under reflux, the crystals were collected by filtration and dried to give compound 263 (6.85 g, Y = 48%). )
¹ H-NMR (CDCl ₃ , Methanol-d4 / TMS):
δ = 5.42 (2H, s) 7.28-8.75 (14H, m)
A 30% hydrogen bromide / acetic acid solution (70 mL) was added to compound 263 (6.8 g) and reacted at about 100 ° C. for 2.5 hours. Water (430 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with 50% aqueous methanol solution and dried to obtain compound 264 (5.2 g, Y = 91%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 7.26-8.69 (9H, m) 10.76 (1H, s)
Compound 264 (740 mg) was dissolved in DMF (15 mL), potassium carbonate (3.5 g) and ethyl 4-bromo-n-butyrate (610 mg) were added, and the mixture was reacted overnight at room temperature. Water (90 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 265 (884 mg, Y = 87%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.18-2.92 (4H, m) 4.01-4.42 (4H, m) 7.31-8.74 (9H, m)
Toluene (20 mL), ethanol (80 mL), and 5% palladium carbon (0.3 g) were added to compound 265 (850 mg), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 266 (780 mg, Y = 99%).
Compound 266 (390 mg) was dissolved in DMF (7 mL), potassium carbonate (2.5 g) and ethyl iodide (3.0 g) were added, and the mixture was reacted at about 65 ° C. overnight. Chloroform (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 267 (150 mg, Y = 34%).
Compound 267 (150 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) by heating, and then neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 268 (80 mg, Y = 57%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.14 (6H, t, J = 6 Hz) 1.80-2.85 (4H, m) 3.20-3.65 (4H, m) 4.27 (2H, t, J = 7 Hz) 6.69-8.15 (8H, m) 8.57 (1H, s) 12.16 (1H, br)
Compound 268 (25 mg) was suspended in water (50 mL), 0.5% aqueous sodium hydroxide solution (0.95 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 269 (28 mg, Y = 106%).

４−［［３−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物２７０）、４−［［３−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物２７１）、４−［［３−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物２７２）の製造：
化合物２６６（３９０ｍｇ）をＤＭＦ（６ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ベンジルブロミド（１．２ｇ）を加えて室温で一夜反応した。反応液にクロロホルム（１００ｍＬ）を加え水、飽和食塩水で順次洗浄した。クロロホルム層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物２７０（３４５ｍｇ，Ｙ＝６１％）を得た。
化合物２７０（３４５ｍｇ）をメタノール（１００ｍＬ）に溶解し、１０％水酸化ナトリウム水溶液（５ｍＬ）を加えて約５０℃で３日間反応した。反応液を減圧濃縮し、残渣を水（１００ｍＬ）に加熱懸濁後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物２７１（２６６ｍｇ，Ｙ＝８１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８０−２．７３（４Ｈ，ｍ）４．２３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）４．８２（４Ｈ，ｓ）６．７６−８．１０（１８Ｈ，ｍ）８．５４（１Ｈ，ｓ）１２．１２（１Ｈ，ｂｒ）
化合物２７１（７４ｍｇ）を水（１００ｍＬ）に懸濁し、０．５％水酸化ナトリウム水溶液（１．１ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物２７２（６６ｍｇ，Ｙ＝８６％）を得た。4-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 270), 4-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 271), 4-[[3- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 272):
Compound 266 (390 mg) was dissolved in DMF (6 mL), potassium carbonate (2.5 g) and benzyl bromide (1.2 g) were added, and the mixture was reacted overnight at room temperature. Chloroform (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 270 (345 mg, Y = 61%).
Compound 270 (345 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was suspended in water (100 mL) by heating, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 271 (266 mg, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.73 (4H, m) 4.23 (2H, t, J = 5 Hz) 4.82 (4H, s) 6.76-8.10 (18H, m) 8.54 ( 1H, s) 12.12 (1H, br)
Compound 271 (74 mg) was suspended in water (100 mL), 0.5% aqueous sodium hydroxide solution (1.1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 272 (66 mg, Y = 86%).

６−［［３−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２７３）、６−［［３−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２７４）、６−［［３−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２７５）、６−［［３−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物２７６）、６−［［３−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物２７７）の製造：
化合物２６４（７４０ｍｇ）をＤＭＦ（１４ｍＬ）に溶解し、炭酸カリウム（３．５ｇ）、６−ブロモヘキサン酸エチル（６９０ｍｇ）を加え、室温で一夜反応した。反応液に水（１００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールから再結晶して化合物２７３（７４７ｍｇ，Ｙ＝７１％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２４（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．５７−２．０９（６Ｈ，ｍ）２．３８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９５−４．３５（４Ｈ，ｍ）７．２７−８．７３（９Ｈ，ｍ）
化合物２７３（７００ｍｇ）にトルエン（２０ｍＬ）、エタノール（８０ｍＬ）、５％パラジウム炭素（０．３ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物２７４（６５０ｍｇ，Ｙ＝１００％）を得た。
化合物２７４（３２５ｍｇ）をＤＭＦ（６ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ヨウ化エチル（２．５ｇ）を加えて約６５℃で一夜反応した。反応液にクロロホルム（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。クロロホルム層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物２７５（１８０ｍｇ，Ｙ＝４９％）を得た。
化合物２７５（１８０ｍｇ）をメタノール（１００ｍＬ）に溶解し、１０％水酸化ナトリウム水溶液（３ｍＬ）を加え約５０℃で一夜反応した。反応液を減圧濃縮し、残渣を水（５０ｍＬ）に加熱溶解後、希塩酸を加えて中和した。析出した結晶をろ取、乾燥して化合物２７６（１４０ｍｇ，Ｙ＝８３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１４（６Ｈ，ｔ，Ｊ＝７Ｈｚ）１．５０−２．００（６Ｈ，ｍ）２．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．２５−３．６１（４Ｈ，ｍ）４．２２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．７３−８．０８（８Ｈ，ｍ）８．５６（１Ｈ，ｍ）１２．０１（１Ｈ，ｂｒ）
化合物２７６（５８ｍｇ）を水（５０ｍＬ）に懸濁し、０．５％水酸化ナトリウム水溶液（１．１ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物２７７（７０ｍｇ，Ｙ＝１１５％）を得た。6-[[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 273), 6-[[3- (6-Amino-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 274), 6-[[3- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester ( Compound 275), 6-[[3- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 276), 6-[[3- [6- (Diethylamino) Preparation of 2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 277):
Compound 264 (740 mg) was dissolved in DMF (14 mL), potassium carbonate (3.5 g) and ethyl 6-bromohexanoate (690 mg) were added, and the mixture was reacted overnight at room temperature. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 273 (747 mg, Y = 71%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.24 (3H, t, J = 7 Hz) 1.57-2.09 (6H, m) 2.38 (2H, t, J = 6 Hz) 3.95-4.35 (4H, m) 7.27-8.73 (9H, m)
Toluene (20 mL), ethanol (80 mL), and 5% palladium carbon (0.3 g) were added to compound 273 (700 mg), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 274 (650 mg, Y = 100%).
Compound 274 (325 mg) was dissolved in DMF (6 mL), potassium carbonate (2.5 g) and ethyl iodide (2.5 g) were added, and the mixture was reacted at about 65 ° C. overnight. Chloroform (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 275 (180 mg, Y = 49%).
Compound 275 (180 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) by heating, and then neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 276 (140 mg, Y = 83%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.14 (6H, t, J = 7 Hz) 1.50-2.00 (6H, m) 2.28 (2H, t, J = 6 Hz) 3.25-3.61 (4H, m) 4.22 (2H, t, J = 6 Hz) 6.73-8.08 (8H, m) 8.56 (1H, m) 12.01 (1H, br)
Compound 276 (58 mg) was suspended in water (50 mL), 0.5% aqueous sodium hydroxide solution (1.1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 277 (70 mg, Y = 115%).

６−［［３−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２７８）、６−［［３−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物２７９）、６−［［３−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物２８０）の製造：
化合物２７４（３２５ｍｇ）をＤＭＦ（６ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ベンジルブロミド（１．０ｇ）を加え、室温で一夜反応した。反応液にクロロホルム（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。クロロホルム層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物２７８（２６７ｍｇ，Ｙ＝６２％）を得た。
化合物２７８（２６７ｍｇ）をメタノール（１００ｍＬ）に溶解し、１０％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で一夜反応した。反応液を減圧濃縮し、残渣を水（１００ｍＬ）に加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物２７９（９０ｍｇ，Ｙ＝３５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３９−２．３９（８Ｈ，ｍ）４．１７（２Ｈ，ｔ，Ｊ＝４Ｈｚ）４．８３（４Ｈ，ｓ）６．７０−８．５２（１９Ｈ，ｍ）１２．０（１Ｈ，ｂｒ）
化合物２７９（３６ｍｇ）を水（８０ｍＬ）に懸濁し、０．５％水酸化ナトリウム水溶液（０．５１ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物２８０（３０ｍｇ，Ｙ＝８０％）を得た。6-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 278), 6-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 279), 6-[[3- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 280):
Compound 274 (325 mg) was dissolved in DMF (6 mL), potassium carbonate (2.5 g) and benzyl bromide (1.0 g) were added, and the mixture was reacted overnight at room temperature. Chloroform (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 278 (267 mg, Y = 62%).
Compound 278 (267 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (100 mL) with heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 279 (90 mg, Y = 35%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39-2.39 (8H, m) 4.17 (2H, t, J = 4 Hz) 4.83 (4H, s) 6.70-8.52 (19H, m) 12.0 ( 1H, br)
Compound 279 (36 mg) was suspended in water (80 mL), 0.5% aqueous sodium hydroxide solution (0.51 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 280 (30 mg, Y = 80%).

［５−［［３−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物２８１）の製造：
化合物２６４（７００ｍｇ）をＤＭＦ（１４ｍＬ）に溶解し、炭酸カリウム（３．５ｇ）、（５−ブロモペンチル）マロン酸ジエチル（９２０ｍｇ）を加えて室温で二夜反応した。反応液に水（１００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールから再結晶して化合物２８１（９９８ｍｇ，Ｙ＝８２％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１３−２．２０（１４Ｈ，ｍ）３．３５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．０２−４．３７（６Ｈ，ｍ）７．４２−８．７２（９Ｈ，ｍ）Preparation of [5-[[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 281):
Compound 264 (700 mg) was dissolved in DMF (14 mL), and potassium carbonate (3.5 g) and diethyl (5-bromopentyl) malonate (920 mg) were added and reacted at room temperature overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 281 (998 mg, Y = 82%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.13-2.20 (14H, m) 3.35 (1H, t, J = 7 Hz) 4.02-4.37 (6H, m) 7.42-8.72 (9H, m)

２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−ニトロベンゾオキサゾール（化合物２８２）、２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩（化合物２８３）の製造：
化合物２６４（７４０ｍｇ）をＤＭＦ（１４ｍＬ）に溶解し、炭酸カリウム（３．５ｇ）、Ｎ−（２−クロロエチル）モルホリン塩酸塩（６３０ｍｇ）を加えて約６５℃で一夜反応した。反応液に水（１００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物２８２（６４７ｍｇ，Ｙ＝６４％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝２．６０−３．０９（６Ｈ，ｍ）３．７３（４Ｈ，ｔ，Ｊ＝５Ｈｚ）４．１４（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２６−８．７２（９Ｈ，ｍ）
化合物２８２（５８０ｍｇ）にトルエン（２０ｍＬ）、メタノール（８０ｍＬ）、５％パラジウム炭素（０．３ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣にアセトン（５０ｍＬ）を加えて溶解し、３５％塩酸（０．３ｍＬ）を加えて析出した結晶をろ取、乾燥して化合物２８３（５０１ｍｇ，Ｙ＝７８％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝３．２８−４．０４（１０Ｈ，ｍ）４．６０−４．８５（２Ｈ，ｍ）７．４３−８．７４（９Ｈ，ｍ）2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-nitrobenzoxazole (Compound 282), 2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl Preparation of -6-benzoxazolamine dihydrochloride (Compound 283):
Compound 264 (740 mg) was dissolved in DMF (14 mL), potassium carbonate (3.5 g) and N- (2-chloroethyl) morpholine hydrochloride (630 mg) were added, and the mixture was reacted at about 65 ° C. overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to give compound 282 (647 mg, Y = 64%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.60-3.09 (6H, m) 3.73 (4H, t, J = 5 Hz) 4.14 (2H, t, J = 6 Hz) 7.26-8.72 (9H, m)
Toluene (20 mL), methanol (80 mL), and 5% palladium carbon (0.3 g) were added to compound 282 (580 mg), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Acetone (50 mL) was added to the residue for dissolution, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 283 (501 mg, Y = 78%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 3.28-4.04 (10H, m) 4.60-4.85 (2H, m) 7.43-8.74 (9H, m)

５−（１，１−ジメチルエチル）−２−［３−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２８４）、３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレノール（化合物２８５）、４−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物２８６）、４−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物２８７）、４−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸カリウム塩（化合物２８８）の製造：
トルエン（２００ｍＬ）中、３−ベンジルオキシ−２−ナフトエ酸（２０．０ｇ）を塩化チオニル（１０．３ｇ）と還流下で２時間反応した。反応液を減圧濃縮し、３−ベンジルオキシ−２−ナフトエ酸クロライド（２４．２ｇ）を得た。
３−ベンジルオキシ−２−ナフトエ酸クロライドのオイル（２４．２ｇ）を２−アミノ−４−ｔｅｒｔ−ブチルフェノール（１４．３ｇ），トリエチルアミン（８．８ｇ）の１，３−ジメチル−２−イミダゾリジノン（１５０ｍＬ）溶液に加え、室温で２時間反応した。反応液を水（２Ｌ）に加え晶析し、析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（２００ｍＬ）を加え、撹拌懸濁後、結晶をろ取、乾燥して中間体のアミド化合物（２９．６ｇ，Ｙ＝９７％）を得た。
アミド化合物（２５．０ｇ）とｐ−トルエンスルホン酸一水和物（２２．４ｇ）を１，３−ジメチル−２−イミダゾリジノン（１５０ｍＬ）、トルエン（４５０ｍＬ）の混合溶媒に加え、還流下で生成する水を除去しながら二夜反応した。反応液を減圧濃縮し、残液を水（３Ｌ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（３００ｍＬ），水酸化カリウム（１０ｇ）を加え、還流下２．５時間懸濁した後、結晶をろ取、乾燥して化合物２８４（７．６７ｇ，Ｙ＝３２％）を得た。
化合物２８４（７．４０ｇ）にメタノール（２００ｍＬ）及び５％パラジウム炭素（０．５ｇ）を加え、水素雰囲気下５０℃で２２時間反応した。反応液をろ過し、ろ液を減圧濃縮し粗製結晶を得た。粗製結晶をメタノールで洗浄後、酢酸エチル（９５ｍＬ）から再結晶して化合物２８５（４．２７ｇ，Ｙ＝７４％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．４２（９Ｈ，ｓ）７．２５−７．９４（８Ｈ，ｍ）８．５９（１Ｈ，ｓ）１１．３１（１Ｈ，ｓ）
ＤＭＦ（１０ｍＬ）中、化合物２８５（３００ｍｇ）に炭酸カリウム（５２４ｍｇ），４−ブロモ−ｎ−酪酸エチル（２２９ｍｇ）を加え、室温で２２時間反応した。反応液を水（１５０ｍＬ）中に加えて晶析し、析出結晶をろ取、水洗し化合物２８６（Ｗｅｔ０．６６ｇ）を得た。
エタノール（２０ｍＬ）中、化合物２８６（Ｗｅｔ０．６６ｇ）に１１％水酸化カリウム水溶液（５ｍＬ）を加え、４５℃で１８時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加え、３５％塩酸で酸析した。結晶をろ取、水洗し粗製結晶を得た。粗製結晶を８０％エタノール水溶液（１０ｍＬ）から再結晶して化合物２８７（２２６ｍｇ，Ｙ＝５９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３９（９Ｈ，ｓ）１．９６−２．２９（２Ｈ，ｍ）２．５１−２．７５（２Ｈ，ｍ）４．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．４５−８．１１（８Ｈ，ｍ）８．６４（１Ｈ，ｓ）
化合物２８７（１００ｍｇ）に０．０５％水酸化カリウム水溶液（４０ｍＬ）を加え加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物２８８（１００ｍｇ，Ｙ＝９１％）を得た。5- (1,1-dimethylethyl) -2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 284), 3- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenol (compound 285), 4-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 286), 4-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 287), 4-[[3- [5 Preparation of-(1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 288):
3-Benzyloxy-2-naphthoic acid (20.0 g) was reacted with thionyl chloride (10.3 g) in toluene (200 mL) for 2 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain 3-benzyloxy-2-naphthoic acid chloride (24.2 g).
3-Benzyloxy-2-naphthoic acid chloride oil (24.2 g) was converted to 1,3-dimethyl-2-imidazolide of 2-amino-4-tert-butylphenol (14.3 g) and triethylamine (8.8 g). It added to the non (150 mL) solution and reacted at room temperature for 2 hours. The reaction solution was added to water (2 L) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (200 mL) was added to the crude crystals and suspended by stirring. The crystals were collected by filtration and dried to obtain an intermediate amide compound (29.6 g, Y = 97%).
The amide compound (25.0 g) and p-toluenesulfonic acid monohydrate (22.4 g) were added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL), and the mixture was refluxed. The reaction was carried out for two nights while removing the water produced in step 1. The reaction solution was concentrated under reduced pressure, and the residue was added to water (3 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (300 mL) and potassium hydroxide (10 g) were added to the crude crystals and suspended under reflux for 2.5 hours. The crystals were collected by filtration and dried to obtain compound 284 (7.67 g, Y = 32%). It was.
Methanol (200 mL) and 5% palladium carbon (0.5 g) were added to compound 284 (7.40 g), and the mixture was reacted at 50 ° C. for 22 hours in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude crystals. The crude crystals were washed with methanol and recrystallized from ethyl acetate (95 mL) to obtain Compound 285 (4.27 g, Y = 74%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.42 (9H, s) 7.25-7.94 (8H, m) 8.59 (1H, s) 11.31 (1H, s)
In DMF (10 mL), potassium carbonate (524 mg) and ethyl 4-bromo-n-butyrate (229 mg) were added to compound 285 (300 mg) and reacted at room temperature for 22 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 286 (Wet 0.66 g).
11% aqueous potassium hydroxide solution (5 mL) was added to compound 286 (Wet 0.66 g) in ethanol (20 mL), and reacted at 45 ° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and acidified with 35% hydrochloric acid. The crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (10 mL) to give compound 287 (226 mg, Y = 59%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39 (9H, s) 1.96-2.29 (2H, m) 2.51-2.75 (2H, m) 4.28 (2H, t, J = 6 Hz) 7.45- 8.11 (8H, m) 8.64 (1H, s)
0.05% aqueous potassium hydroxide solution (40 mL) was added to compound 287 (100 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 288 (100 mg, Y = 91%).

６−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物２８９）、６−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物２９０）、６−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物２９１）の製造：
ＤＭＦ（１２ｍＬ）中、化合物２８５（３００ｍｇ）に炭酸カリウム（６５３ｍｇ），６−ブロモヘキサン酸エチル（３３８ｍｇ）を加え、室温で２８時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸ナトリウムで脱水した後、減圧濃縮して化合物２８９（０．６５ｇ）を得た。
エタノール（２０ｍＬ）中、化合物２８９（０．６５ｇ）に１１％水酸化カリウム水溶液（５ｍＬ）を加え、室温で１９時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加え加熱溶解した後、３５％塩酸で酸析した。分離した生成物を酢酸エチル（５０ｍＬ）で抽出した後、有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られたオイルをアセトン（２ｍＬ）に溶解後、水（０．５ｍＬ）を加え晶析した。結晶をろ取、乾燥して化合物２９０（３１９ｍｇ，Ｙ＝７８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３９−２．４０（１７Ｈ，ｍ）４．２３（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．４０−８．１１（８Ｈ，ｍ）８．６２（１Ｈ，ｓ）１１．４８−１２．５５（１Ｈ，ｂｒ）
化合物２９０（１００ｍｇ）に０．０４％水酸化カリウム水溶液（４０ｍＬ）を加え加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物２９１（９５ｍｇ，Ｙ＝８７％）を得た。6-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 289), 6-[[3- [5- (1,1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 290), 6-[[3- [5- (1,1-dimethylethyl) -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 291):
In DMF (12 mL), potassium carbonate (653 mg) and ethyl 6-bromohexanoate (338 mg) were added to compound 285 (300 mg), and reacted at room temperature for 28 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain Compound 289 (0.65 g).
11% aqueous potassium hydroxide solution (5 mL) was added to compound 289 (0.65 g) in ethanol (20 mL), and the mixture was reacted at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was dissolved by heating. The separated product was extracted with ethyl acetate (50 mL), and then the organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in acetone (2 mL), and water (0.5 mL) was added for crystallization. The crystals were collected by filtration and dried to obtain Compound 290 (319 mg, Y = 78%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39-2.40 (17H, m) 4.23 (2H, t, J = 6 Hz) 7.40-8.11 (8H, m) 8.62 (1H, s) 11.48- 12.55 (1H, br)
0.04% aqueous potassium hydroxide solution (40 mL) was added to compound 290 (100 mg) and dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 291 (95 mg, Y = 87%).

［５−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物２９２）、［５−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物２９３）、［５−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物２９４）の製造：
ＤＭＦ（１２ｍＬ）中、化合物２８５（３００ｍｇ）に炭酸カリウム（６５４ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（４４９ｍｇ）を加え、室温で２８時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して化合物２９２（０．７５ｇ）を得た。
エタノール（２０ｍＬ）中、化合物２９２（０．７５ｇ）に２０％水酸化カリウム水溶液（５ｍＬ）を加え、室温で２０時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加え加熱溶解した後、３５％塩酸で酸析した。分離した生成物を酢酸エチル（５０ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し粗製オイルを得た。粗製オイルをシリカゲルカラム（トルエン／酢酸エチル）で精製し、化合物２９３（２２０ｍｇ，Ｙ＝４８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３９−２．０９（１７Ｈ，ｍ）３．２５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．２３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．４０−８．１１（８Ｈ，ｍ）８．６３（１Ｈ，ｓ）１２．０２−１３．４０（２Ｈ，ｂｒ）
化合物２９３（１００ｍｇ）に０．１％水酸化ナトリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物２９４（１０４ｍｇ，Ｙ＝９５％）を得た。[5-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 292), [5-[[ 3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 293), [5-[[3- [5- (1 , 1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 294):
In DMF (12 mL), potassium carbonate (654 mg) and diethyl (5-bromopentyl) malonate (449 mg) were added to compound 285 (300 mg), and reacted at room temperature for 28 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 292 (0.75 g).
A 20% aqueous potassium hydroxide solution (5 mL) was added to compound 292 (0.75 g) in ethanol (20 mL) and reacted at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was dissolved by heating. The separated product was extracted with ethyl acetate (50 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified by a silica gel column (toluene / ethyl acetate) to obtain Compound 293 (220 mg, Y = 48%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39-2.09 (17H, m) 3.25 (1H, t, J = 7 Hz) 4.23 (2H, t, J = 5 Hz) 7.40-8.11 (8H, m) 8.63 (1H, s) 12.02-13.40 (2H, br)
A 0.1% aqueous sodium hydroxide solution (20 mL) was added to compound 293 (100 mg) to dissolve it, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 294 (104 mg, Y = 95%).

５−（１，１−ジメチルエチル）−２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物２９５）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２８５（３００ｍｇ）に炭酸カリウム（５２７ｍｇ），Ｎ−（２−クロロエチル）モルホリン塩酸塩（２１１ｍｇ）を加え、７０〜８０℃で４．５時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られた残渣をアセトン（２０ｍＬ）に溶解後、３５％塩酸を加え、析出した結晶をろ取、乾燥して化合物２９５（３８６ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３９（９Ｈ，ｓ）３．１９−４．００（１０Ｈ，ｍ）４．７７（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．４５−８．１４（８Ｈ，ｍ）８．７０（１Ｈ，ｓ）１１．２７−１２．４７（１Ｈ，ｂｒ）Preparation of 5- (1,1-dimethylethyl) -2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 295):
In DMF (10 mL), potassium carbonate (527 mg) and N- (2-chloroethyl) morpholine hydrochloride (211 mg) were added to compound 285 (300 mg) and reacted at 70-80 ° C. for 4.5 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetone (20 mL), 35% hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 295 (386 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39 (9H, s) 3.19-4.00 (10H, m) 4.77 (2H, t, J = 4 Hz) 7.45-8.14 (8H, m) 8.70 ( 1H, s) 11.27-12.47 (1H, br)

３−［［３−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩（化合物２９６）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２８５（３００ｍｇ）に炭酸カリウム（５２５ｍｇ），３−ジメチルアミノプロピルクロライド塩酸塩（１８０ｍｇ）を加え、７０〜８０℃で４．５時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（３００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られた残渣をアセトン（３０ｍＬ）に溶解後、３５％塩酸を加え、析出した結晶をろ取、乾燥し化合物２９６（３０４ｍｇ，Ｙ＝７３％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝１．４６（９Ｈ，ｓ）２．２４−２．６６（２Ｈ，ｍ）３．０３（６Ｈ，ｓ）３．５５（２Ｈ，ｔ，Ｊ＝７Ｈｚ）４．５５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．４８−８．０５（８Ｈ，ｍ）８．７８（１Ｈ，ｓ）3-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 296) Manufacturing:
In DMF (10 mL), potassium carbonate (525 mg) and 3-dimethylaminopropyl chloride hydrochloride (180 mg) were added to compound 285 (300 mg) and reacted at 70-80 ° C. for 4.5 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (300 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetone (30 mL), 35% hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 296 (304 mg, Y = 73%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.46 (9H, s) 2.24-2.66 (2H, m) 3.03 (6H, s) 3.55 (2H, t, J = 7 Hz) 4.55 (2H, t, J = 6 Hz) 7.48-8.05 (8H, m) 8.78 (1H, s)

５−フェニル−２−［３−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物２９７）、３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物２９８）、４−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物２９９）、４−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物３００）の製造：
トルエン（１２０ｍＬ）中、３−ベンジルオキシ−２−ナフトエ酸（１２．０ｇ）を塩化チオニル（６．２ｇ）と還流下で３時間反応した。反応液を減圧濃縮し、３−ベンジルオキシ−２−ナフトエ酸クロライド（１３．２ｇ）を得た。
３−ベンジルオキシ−２−ナフトエ酸クロライドのオイル（１３．２ｇ）を２−アミノ−４−フェニルフェノール（９．６ｇ），トリエチルアミン（５．３ｇ）の１，３−ジメチル−２−イミダゾリジノン（１００ｍＬ）溶液に加え、室温で３．５時間反応した。反応液を水（２Ｌ）に加え晶析し、析出結晶をろ取、水洗後、メタノール（１５０ｍＬ）と共に５０〜６０℃で撹拌懸濁後、結晶をろ取、乾燥して中間体のアミド化合物（１８．７ｇ，Ｙ＝９７％）を得た。
アミド化合物（１５．０ｇ）とｐ−トルエンスルホン酸一水和物（１２．８ｇ）を１，３−ジメチル−２−イミダゾリジノン（１５０ｍＬ）、トルエン（４５０ｍＬ）の混合溶媒に加え、還流下で生成する水を除去しながら二夜反応した。反応液を減圧濃縮し、残液を水（２Ｌ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（３００ｍＬ），水酸化カリウム（６．０ｇ）を加え、還流下１．５時間懸濁後、結晶をろ取し、酢酸エチルから再結晶して化合物２９７（３．４６ｇ，Ｙ＝２４％）を得た。
化合物２９７（３．３０ｇ）にメタノール（１００ｍＬ）及び５％パラジウム炭素（０．２ｇ）を加え、水素雰囲気下４５℃で２３時間反応した。反応液を減圧濃縮し、残渣に１，３−ジメチル−２−イミダゾリジノン（８０ｍＬ）を加え加熱溶解した。不溶物をろ去後、ろ液を水（２Ｌ）に加え晶析し、析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶をアセトン（８０ｍＬ）と共に２時間還流した後、ろ過、乾燥して化合物２９８（２．２８ｇ，Ｙ＝８８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝７．２５−７．９３（１３Ｈ，ｍ）８．６０（１Ｈ，ｓ）１１．２３（１Ｈ，ｓ）
ＤＭＦ（１２ｍＬ）中、化合物２９８（３００ｍｇ）に炭酸カリウム（６３４ｍｇ），４−ブロモ−ｎ−酪酸エチル（２８４ｍｇ）を加え、室温で２６時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して化合物２９９（５４５ｍｇ）を得た。
エタノール（２０ｍＬ）中、化合物２９９（５４５ｍｇ）に１３％水酸化カリウム水溶液（５ｍＬ）を加え、４５℃で１５時間反応した。反応液を減圧濃縮後、残渣に水（５０ｍＬ）を加え、３５％塩酸で酸析した。析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶にアセトン（４ｍＬ）を加え加熱溶解後、水（１ｍＬ）を加え晶析した。析出結晶をろ取、乾燥して化合物３００（２３６ｍｇ，Ｙ＝６３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．００−２．３１（２Ｈ，ｍ）２．４９−２．７８（２Ｈ，ｍ）４．３１（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．３５−８．０９（１３Ｈ，ｍ）８．７１（１Ｈ，ｓ）１１．２７−１３．２４（１Ｈ，ｂｒ）5-phenyl-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 297), 3- (5-phenyl-2-benzoxazolyl) -2-naphthalenol (compound 298), 4- [[3- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 299), 4-[[3- (5-Phenyl-2-benzoxazolyl) Preparation of -2-naphthalenyl] oxy] butanoic acid (Compound 300):
3-Benzyloxy-2-naphthoic acid (12.0 g) was reacted with thionyl chloride (6.2 g) in toluene (120 mL) for 3 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain 3-benzyloxy-2-naphthoic acid chloride (13.2 g).
3-Benzyloxy-2-naphthoic acid chloride oil (13.2 g) was converted to 1,3-dimethyl-2-imidazolidinone of 2-amino-4-phenylphenol (9.6 g) and triethylamine (5.3 g). (100 mL) The solution was added and reacted at room temperature for 3.5 hours. The reaction solution is added to water (2 L) for crystallization, and the precipitated crystals are collected by filtration, washed with water, stirred and suspended with methanol (150 mL) at 50-60 ° C., and then the crystals are collected by filtration and dried to obtain an intermediate amide compound. (18.7 g, Y = 97%) was obtained.
The amide compound (15.0 g) and p-toluenesulfonic acid monohydrate (12.8 g) were added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL), and the mixture was refluxed. The reaction was carried out for two nights while removing the water produced in step 1. The reaction solution was concentrated under reduced pressure, and the residue was added to water (2 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (300 mL) and potassium hydroxide (6.0 g) were added to the crude crystals. After suspension for 1.5 hours under reflux, the crystals were collected by filtration and recrystallized from ethyl acetate to give compound 297 (3.46 g, Y = 24%).
Methanol (100 mL) and 5% palladium carbon (0.2 g) were added to compound 297 (3.30 g), and the mixture was reacted at 45 ° C. for 23 hours in a hydrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and 1,3-dimethyl-2-imidazolidinone (80 mL) was added to the residue and dissolved by heating. The insoluble material was removed by filtration, and the filtrate was added to water (2 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were refluxed with acetone (80 mL) for 2 hours, then filtered and dried to obtain Compound 298 (2.28 g, Y = 88%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 7.25-7.93 (13H, m) 8.60 (1H, s) 11.23 (1H, s)
In DMF (12 mL), potassium carbonate (634 mg) and ethyl 4-bromo-n-butyrate (284 mg) were added to compound 298 (300 mg) and reacted at room temperature for 26 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 299 (545 mg).
A 13% aqueous potassium hydroxide solution (5 mL) was added to compound 299 (545 mg) in ethanol (20 mL) and reacted at 45 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Acetone (4 mL) was added to the crude crystals and dissolved by heating, and then water (1 mL) was added for crystallization. Precipitated crystals were collected by filtration and dried to obtain Compound 300 (236 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.00-2.31 (2H, m) 2.49-2.78 (2H, m) 4.31 (2H, t, J = 6 Hz) 7.35-8.09 (13H, m) 8.71 (1H, s) 11.27-13.24 (1H, br)

６−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３０１）、６−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物３０２）の製造：
ＤＭＦ（１２ｍＬ）中、化合物２９８（３００ｍｇ）に炭酸カリウム（６２９ｍｇ），６−ブロモヘキサン酸エチル（３２６ｍｇ）を加え、室温で２６時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し化合物３０１（６７６ｍｇ）を得た。
エタノール（２０ｍＬ）中、化合物３０１（６７６ｍｇ）に１５％水酸化カリウム水溶液（５ｍＬ）を加え、１５時間反応した。反応液を減圧濃縮後、残渣に水（５０ｍＬ）を加え、３５％塩酸で酸析し、分離した生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られた残渣をトルエン（４ｍＬ）から再結晶して化合物３０２（２２６ｍｇ，Ｙ＝５６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６７−２．３８（８Ｈ，ｍ）４．２５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２１−８．３５（１３Ｈ，ｍ）８．６９（１Ｈ，ｓ）１１．９８（１Ｈ，ｂｒｓ）6-[[3- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 301), 6-[[3- (5-Phenyl-2-benzoxazolyl) (L) -2-Naphthalenyl] oxy] hexanoic acid (Compound 302):
In DMF (12 mL), potassium carbonate (629 mg) and ethyl 6-bromohexanoate (326 mg) were added to compound 298 (300 mg) and reacted at room temperature for 26 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 301 (676 mg).
A 15% aqueous potassium hydroxide solution (5 mL) was added to compound 301 (676 mg) in ethanol (20 mL) and reacted for 15 hours. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue, acidified with 35% hydrochloric acid, and the separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from toluene (4 mL) to obtain Compound 302 (226 mg, Y = 56%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.67-2.38 (8H, m) 4.25 (2H, t, J = 6 Hz) 7.21-8.35 (13H, m) 8.69 (1H, s) 11.98 ( 1H, brs)

［５−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３０３）、［５−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物３０４）、［５−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物３０５）の製造：
ＤＭＦ（１２ｍＬ）中、化合物２９８（３００ｍｇ）に炭酸カリウム（６３０ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（４９７ｍｇ）を加え、室温で３７時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し化合物３０３（７８９ｍｇ）を得た。
エタノール（２０ｍＬ）中、化合物３０３（７８９ｍｇ）に３２％水酸化カリウム水溶液（５ｍＬ）を加え、４５℃で１時間反応した。反応液を減圧濃縮し、残渣に水（３０ｍＬ）を加え加温溶解した後、３５％塩酸で酸析した。分離した生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られた残渣を酢酸エチル（１０ｍＬ）と共に６０〜７０℃で撹拌懸濁した後、ろ過して粗製結晶を得た。粗製結晶をシリカゲルカラム（クロロホルム／メタノール）で精製し、化合物３０４（１１４ｍｇ，Ｙ＝２５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１８−２．０８（８Ｈ，ｍ）３．１６（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．２５（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．４２−８．１０（１３Ｈ，ｍ）８．７０（１Ｈ，ｓ）
化合物３０４（７０ｍｇ）に０．０６％水酸化ナトリウム水溶液（２０ｍＬ）を加え加温溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物３０５（７２ｍｇ，Ｙ＝９５％）を得た。[5-[[3- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 303), [5-[[3- (5-Phenyl- 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 304), [5-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid disodium salt (compound 305):
In DMF (12 mL), potassium carbonate (630 mg) and diethyl (5-bromopentyl) malonate (497 mg) were added to compound 298 (300 mg) and reacted at room temperature for 37 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 303 (789 mg).
A 32% aqueous potassium hydroxide solution (5 mL) was added to compound 303 (789 mg) in ethanol (20 mL) and reacted at 45 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, water (30 mL) was added to the residue, and the mixture was dissolved by heating, and then acidified with 35% hydrochloric acid. The separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was suspended with stirring at 60 to 70 ° C. with ethyl acetate (10 mL), and then filtered to obtain crude crystals. The crude crystals were purified with a silica gel column (chloroform / methanol) to obtain Compound 304 (114 mg, Y = 25%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-2.08 (8H, m) 3.16 (1H, t, J = 6 Hz) 4.25 (2H, t, J = 5 Hz) 7.42-8.10 (13H, m) 8.70 (1H, s)
0.06% aqueous sodium hydroxide solution (20 mL) was added to compound 304 (70 mg) and dissolved by heating, then activated carbon was added and filtered. The filtrate was lyophilized to give compound 305 (72 mg, Y = 95%).

２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−５−フェニルベンゾオキサゾール塩酸塩（化合物３０６）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２９８（３００ｍｇ）に炭酸カリウム（４９５ｍｇ），（２−クロロエチル）モルホリン塩酸塩（２０４ｍｇ）を加え、７０〜８０℃で５時間反応した。反応液を水（１００ｍＬ）中に加え晶析し、析出した結晶をろ取した。得られた結晶をアセトン（２０ｍＬ）に溶解し、３５％塩酸を加え酸性とし、析出した結晶をろ取、乾燥して化合物３０６（３８３ｍｇ，Ｙ＝８８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．１７−４．０１（１０Ｈ，ｍ）４．７６（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．４２−８．１６（１３Ｈ，ｍ）８．７６（１Ｈ，ｓ）１１．２２−１２．７６（１Ｈ，ｂｒ）Preparation of 2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -5-phenylbenzoxazole hydrochloride (Compound 306):
In DMF (10 mL), potassium carbonate (495 mg) and (2-chloroethyl) morpholine hydrochloride (204 mg) were added to compound 298 (300 mg), and reacted at 70-80 ° C. for 5 hours. The reaction solution was added to water (100 mL) for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (20 mL), acidified with 35% hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain Compound 306 (383 mg, Y = 88%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.17-4.01 (10H, m) 4.76 (2H, t, J = 4 Hz) 7.42-8.16 (13H, m) 8.76 (1H, s) 11.22- 12.76 (1H, br)

Ｎ，Ｎ−ジメチル−３−［［３−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩（化合物３０７）の製造：
ＤＭＦ（１０ｍＬ）中、化合物２９８（３００ｍｇ）に炭酸カリウム（４９４ｍｇ），３−ジメチルアミノプロピルクロリド塩酸塩（１６５ｍｇ）を加え、７０〜８０℃で５時間反応した。反応液を水（１００ｍＬ）中に加え、酢酸エチル（３００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して得られた残渣をアセトン（２０ｍＬ）に溶解した後、３５％塩酸を加え酸性とし、析出した結晶をろ取、乾燥して化合物３０７（２１８ｍｇ，Ｙ＝５３％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝２．２３−２．６１（２Ｈ，ｍ）３．０４（６Ｈ，ｓ）３．５６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．４５（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．４１−７．９３（１３Ｈ，ｍ）８．６８（１Ｈ，ｓ）Preparation of N, N-dimethyl-3-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 307):
In DMF (10 mL), potassium carbonate (494 mg) and 3-dimethylaminopropyl chloride hydrochloride (165 mg) were added to compound 298 (300 mg), and reacted at 70-80 ° C. for 5 hours. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer is washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The residue obtained is dissolved in acetone (20 mL), acidified with 35% hydrochloric acid, and the precipitated crystals are collected by filtration and dried to give compound 307. (218 mg, Y = 53%) was obtained.
¹ H-NMR (Methanol-d4 / TMS):
δ = 2.23-2.61 (2H, m) 3.04 (6H, s) 3.56 (2H, t, J = 6 Hz) 4.45 (2H, t, J = 5 Hz) 7.41− 7.93 (13H, m) 8.68 (1H, s)

５−クロロ−２−［３−（フェニルメトキシ）−２−ナフタレニル］ベンゾオキサゾール（化合物３０８）、３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物３０９）、４−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３１０）、４−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物３１１）の製造：
３−ベンジルオキシ−２−ナフトエ酸（７．５ｇ）にトルエン（７５ｍＬ）、塩化チオニル（２．３６ｍＬ）、ＤＭＦ（１滴）を加えて還流下で２時間反応した後、２−アミノ−４−クロロフェノール（８ｇ）の１，４−ジオキサン（１５０ｍＬ）溶液を加えて還流下で２．５時間反応した。反応液を減圧濃縮し、残渣に５％塩酸水溶液（５００ｍＬ）を加えて懸濁後、結晶をろ取し、メタノールで洗浄後乾燥して中間体のアミド化合物（９．６４ｇ，Ｙ＝８９％）を得た。
１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）にアミド化合物（９．６ｇ）を溶解し、ｐ−トルエンスルホン酸一水和物（７．０ｇ）及びトルエン（１００ｍＬ）を加えて還流下で生成する水を除去しながら一夜反応した。反応液を減圧濃縮後、残液に水（２００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶にメタノール（４００ｍＬ）、５０％水酸化ナトリウム水溶液（１０ｍＬ）を加えて還流下で１時間懸濁後、結晶をろ取、乾燥して化合物３０８（３．８５ｇ，Ｙ＝４２％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝５．３９（２Ｈ，ｓ）７．２６−７．９８（１３Ｈ，ｍ）８．７０（１Ｈ，ｓ）
化合物３０８（３．８ｇ）に３０％臭化水素・酢酸溶液（４０ｍＬ）を加えて約１００℃で２時間反応した。反応液に水（２６０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物３０９（２．８ｇ，Ｙ＝９６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝７．２７−７．９７（８Ｈ，ｍ）８．５６（１Ｈ，ｓ）１０．９６（１Ｈ，ｂｒ）
化合物３０９（３１５ｍｇ）をＤＭＦ（７ｍＬ）に溶解し、炭酸カリウム（１．８ｇ）、４−ブロモ−ｎ−酪酸エチル（２６０ｍｇ）を加え、室温で一夜反応した。反応液に水（３０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールから再結晶して化合物３１０（２４５ｍｇ，Ｙ＝５６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．１０−２．８５（４Ｈ，ｍ）３．９７−４．４０（４Ｈ，ｍ）７．２９−７．９７（８Ｈ，ｍ）８．６５（１Ｈ，ｓ）
化合物３１０（２２５ｍｇ）をメタノール（５０ｍＬ）に溶解後、４％水酸化ナトリウム水溶液（５ｍＬ）を加えて約５０℃で一夜反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３１１（１８０ｍｇ，Ｙ＝８６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８０−２．３０（２Ｈ，ｍ）２．６１（２Ｈ，ｔ，Ｊ＝７Ｈｚ）４．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．４０−８．２０（８Ｈ，ｍ）８．６９（１Ｈ，ｓ）１２．１０（１Ｈ，ｂｒ）5-chloro-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 308), 3- (5-Chloro-2-benzoxazolyl) -2-naphthalenol (Compound 309), 4- [[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 310), 4-[[3- (5-Chloro-2-benzoxazolyl) Preparation of -2-naphthalenyl] oxy] butanoic acid (Compound 311):
Toluene (75 mL), thionyl chloride (2.36 mL) and DMF (1 drop) were added to 3-benzyloxy-2-naphthoic acid (7.5 g) and reacted under reflux for 2 hours, and then 2-amino-4 -A solution of chlorophenol (8 g) in 1,4-dioxane (150 mL) was added and reacted under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and 5% aqueous hydrochloric acid (500 mL) was added to the residue for suspension. The crystals were collected by filtration, washed with methanol and dried to give an intermediate amide compound (9.64 g, Y = 89%). )
An amide compound (9.6 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), p-toluenesulfonic acid monohydrate (7.0 g) and toluene (100 mL) are added, and the mixture is refluxed. The reaction was carried out overnight while removing the water produced in step 1. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. Methanol (400 mL) and 50% aqueous sodium hydroxide solution (10 mL) were added to the obtained crystals and suspended under reflux for 1 hour, and the crystals were collected by filtration and dried to give compound 308 (3.85 g, Y = 42%). )
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.39 (2H, s) 7.26-7.98 (13H, m) 8.70 (1H, s)
A 30% hydrogen bromide / acetic acid solution (40 mL) was added to compound 308 (3.8 g) and reacted at about 100 ° C. for 2 hours. Water (260 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 309 (2.8 g, Y = 96%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 7.27-7.97 (8H, m) 8.56 (1H, s) 10.96 (1H, br)
Compound 309 (315 mg) was dissolved in DMF (7 mL), potassium carbonate (1.8 g) and ethyl 4-bromo-n-butyrate (260 mg) were added, and the mixture was reacted overnight at room temperature. Water (30 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 310 (245 mg, Y = 56%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.25 (3H, t, J = 7 Hz) 2.10-2.85 (4H, m) 3.97-4.40 (4H, m) 7.29-7.97 (8H, m) 8.65 (1H, s)
Compound 310 (225 mg) was dissolved in methanol (50 mL), 4% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 311 (180 mg, Y = 86%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.30 (2H, m) 2.61 (2H, t, J = 7 Hz) 4.28 (2H, t, J = 6 Hz) 7.40-8.20 (8H, m) 8.69 (1H, s) 12.10 (1H, br)

６−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３１２）、６−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物３１３）の製造：
化合物３０９（３０４ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（１．８ｇ）、６−ブロモヘキサン酸エチル（２８５ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（５０ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物３１２を得た。
得られた化合物３１２をメタノール（５０ｍＬ）に溶解後、７％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で二夜反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３１３（２２２ｍｇ，Ｙ＝５３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０−２．００（６Ｈ，ｍ）２．２６（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．２３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３９−８．１１（８Ｈ，ｍ）８．６７（１Ｈ，ｓ）１２．０（１Ｈ，ｂｒ）6-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 312), 6-[[3- (5-Chloro-2-benzoxazoli) (L) -2-Naphthalenyl] oxy] hexanoic acid (Compound 313):
Compound 309 (304 mg) was dissolved in DMF (5 mL), potassium carbonate (1.8 g) and ethyl 6-bromohexanoate (285 mg) were added, and the mixture was reacted at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain compound 312.
The obtained compound 312 was dissolved in methanol (50 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 313 (222 mg, Y = 53%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-2.00 (6H, m) 2.26 (2H, t, J = 6 Hz) 4.23 (2H, t, J = 5 Hz) 7.39-8.11 (8H, m) 8.67 (1H, s) 12.0 (1H, br)

［３−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物３１４）、［３−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸（化合物３１５）、［３−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物３１６）の製造：
化合物３０９（２５０ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（１．２ｇ）、（３−クロロプロピル）マロン酸ジエチル（２６０ｍｇ）を加えて約６５℃で一夜反応した。反応液に酢酸エチル（５０ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物３１４（１７０ｍｇ，Ｙ＝４１％）を得た。
化合物３１４（１７０ｍｇ）をメタノール（５０ｍＬ）に溶解後、７％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で一夜反応した。析出した結晶をろ取、乾燥して化合物３１６（６３ｍｇ，Ｙ＝３８％）を得た。
化合物３１６のろ液を減圧濃縮後、水（３０ｍＬ）に溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３１５（５２ｍｇ，Ｙ＝３５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．７３−２．２９（４Ｈ，ｍ）３．４５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．４２−８．１４（８Ｈ，ｍ）８．７３（１Ｈ，ｓ）１２．６８（２Ｈ，ｂｒ）[3-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 314), [3-[[3- (5-Chloro- 2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid (compound 315), [3-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid disodium salt (compound 316):
Compound 309 (250 mg) was dissolved in DMF (5 mL), and potassium carbonate (1.2 g) and diethyl (3-chloropropyl) malonate (260 mg) were added and reacted at about 65 ° C. overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 314 (170 mg, Y = 41%).
Compound 314 (170 mg) was dissolved in methanol (50 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The precipitated crystals were collected by filtration and dried to obtain Compound 316 (63 mg, Y = 38%).
The filtrate of compound 316 was concentrated under reduced pressure, dissolved in water (30 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 315 (52 mg, Y = 35%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.73-2.29 (4H, m) 3.45 (1H, t, J = 7 Hz) 4.28 (2H, t, J = 6 Hz) 7.42-8.14 (8H, m) 8.73 (1H, s) 12.68 (2H, br)

［５−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３１７）、［５−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物３１８）、［５−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物３１９）の製造：
化合物３０９（２９０ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（１．８ｇ）、（５−ブロモペンチル）マロン酸ジエチル（３７５ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（５０ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物３１７を得た。
化合物３１７をメタノール（８０ｍＬ）に溶解後、８％水酸化ナトリウム水溶液（５ｍＬ）を加えて室温で一夜反応した。析出した結晶をろ取、乾燥して化合物３１８（２９４ｍｇ，Ｙ＝５９％）を得た。
化合物３１８（４８．６ｍｇ）を水（５ｍＬ）に溶解し、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３１９（３１ｍｇ，Ｙ＝７０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−Ｄ６／ＴＭＳ）：
δ＝１．２９−２．１０（８Ｈ，ｍ）３．１９（１Ｈ，ｔ，Ｊ＝３Ｈｚ）４．２３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３８−８．１１（８Ｈ，ｍ）８．６８（１Ｈ，ｓ）[5-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 317), [5-[[3- (5-Chloro- 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (compound 318), [5-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] Preparation of Oxy] pentyl] propanedioic acid (Compound 319):
Compound 309 (290 mg) was dissolved in DMF (5 mL), potassium carbonate (1.8 g) and diethyl (5-bromopentyl) malonate (375 mg) were added, and the mixture was reacted at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 317.
Compound 317 was dissolved in methanol (80 mL), 8% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature overnight. The precipitated crystals were collected by filtration and dried to obtain Compound 318 (294 mg, Y = 59%).
Compound 318 (48.6 mg) was dissolved in water (5 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 319 (31 mg, Y = 70%).
¹ H-NMR (DMSO-D6 / TMS):
δ = 1.29-2.10 (8H, m) 3.19 (1H, t, J = 3 Hz) 4.23 (2H, t, J = 5 Hz) 7.38-8.11 (8H, m) 8.68 (1H, s)

５−クロロ−２−［３−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物３２０）の製造：
化合物３０９（２１５ｍｇ）にＤＭＦ（４ｍＬ）、炭酸カリウム（１．３ｇ）、Ｎ−（２−クロロエチル）モルホリン塩酸塩（２００ｍｇ）を加えて約６５℃で一夜反応した。反応液に水（２５ｍＬ）を加えて晶析し、析出結晶をろ取し、５０％メタノール水溶液（３０ｍＬ）で洗浄した。得られた結晶をアセトン（４０ｍＬ）に溶解し、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物３２０（２４６ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．１０−４．１０（１０Ｈ，ｍ）４．８０（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．４５−８．１７（８Ｈ，ｍ）８．７５（１Ｈ，ｓ）１２．０（１Ｈ，ｂｒ）Preparation of 5-chloro-2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 320):
To compound 309 (215 mg), DMF (4 mL), potassium carbonate (1.3 g), and N- (2-chloroethyl) morpholine hydrochloride (200 mg) were added and reacted at about 65 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and washed with a 50% aqueous methanol solution (30 mL). The obtained crystals were dissolved in acetone (40 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 320 (246 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.10-4.10 (10H, m) 4.80 (2H, t, J = 4Hz) 7.45-8.17 (8H, m) 8.75 (1H, s) 12.0 ( 1H, br)

３−［［３−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩（化合物３２１）の製造：
化合物３０９（３０３ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、３−ジメチルアミノプロピルクロリド塩酸塩（３２０ｍｇ）を加え、６５℃で一夜反応した。反応液に酢酸エチル（５０ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム／メタノール）で精製して得た結晶をアセトン（３０ｍＬ）に溶解し、３５％塩酸（０．３ｍＬ）を加えて析出した結晶をろ取、乾燥して化合物３２１（１３３ｍｇ，Ｙ＝３１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，Ｄ_２Ｏ／ＴＭＳ）：
δ＝２．２０−２．５２（２Ｈ，ｍ）２．８６（６Ｈ，ｓ）３．４５（２Ｈ，ｔ，Ｊ＝７Ｈｚ）４．３８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．４５−８．１５（８Ｈ，ｍ）８．７３（１Ｈ，ｓ）Preparation of 3-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 321):
Compound 309 (303 mg) was dissolved in DMF (5 mL), potassium carbonate (2.5 g) and 3-dimethylaminopropyl chloride hydrochloride (320 mg) were added, and the mixture was reacted at 65 ° C. overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. Crystals obtained by purifying the residue with a silica gel column (chloroform / methanol) were dissolved in acetone (30 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 321 (133 mg). , Y = 31%).
¹ H-NMR (DMSO-d6, D ₂ O / TMS):
δ = 2.20−2.52 (2H, m) 2.86 (6H, s) 3.45 (2H, t, J = 7 Hz) 4.38 (2H, t, J = 6 Hz) 7.45− 8.15 (8H, m) 8.73 (1H, s)

６−メチル−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール（化合物３２２）、５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物３２３）、６−［［５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３２４）、６−［［５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物３２５）、６−［［５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物３２６）の製造：
トルエン（１００ｍＬ）中、６−ベンジルオキシ−１−ナフトエ酸（７．０ｇ）を塩化チオニル（３．６ｇ）と還流下で２時間反応した。反応液を減圧濃縮し、６−ベンジルオキシ−１−ナフトエ酸クロライドのオイルを得た。
６−ベンジルオキシ−１−ナフトエ酸クロライドを６−アミノ−ｍ−クレゾール（３．８ｇ），トリエチルアミン（３．１ｇ）の１，３−ジメチル−２−イミダゾリジノン（１００ｍＬ）溶液に加え、室温で２．５時間反応した。反応液を水（１．５Ｌ）に加え晶析し、析出結晶をろ取、水洗後、乾燥して中間体のアミド化合物（９．０ｇ，Ｙ＝９３％）を得た。
１，３−ジメチル−２−イミダゾリジノン（９０ｍＬ）、トルエン（２７０ｍＬ）の混液中、アミド化合物（８．５ｇ）にｐ−トルエンスルホン酸一水和物（８．５ｇ）を加え、還流下で生成する水を除去しながら２０時間反応した。反応液を減圧濃縮し、残渣を水（１．５Ｌ）中に加え晶析した。析出結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（１５０ｍＬ），水酸化カリウム（６．０ｇ）を加え、還流下１４時間懸濁した後、結晶をろ取、乾燥して化合物３２２（３．２７ｇ，Ｙ＝４０％）を得た。
１，３−ジメチル−２−イミダゾリジノン（４０ｍＬ）に化合物３２２（３．００ｇ）を加え溶解した後、５％パラジウム炭素（０．２ｇ）を加え水素雰囲気下で４７時間反応した。反応液をろ過し、ろ液を水（８００ｍＬ）中に加え晶析した。析出結晶をろ取、水洗後、乾燥して化合物３２３（２．１０ｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．５０（３Ｈ，ｓ）７．１１−８．２３（８Ｈ，ｍ）９．３１（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）９．９７（１Ｈ，ｓ）
ＤＭＦ（１０ｍＬ）中、化合物３２３（３００ｍｇ）に炭酸カリウム（４１０ｍｇ），６−ブロモヘキサン酸エチル（４４５ｍｇ）を加え室温で２５時間反応した。反応液を水（１５０ｍＬ）中に加え撹拌した後、酢酸エチル（２００ｍＬ）で生成物を抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し化合物３２４（Ｗｅｔ０．７５ｇ）を得た。
メタノール（４０ｍＬ）中、化合物３２４（Ｗｅｔ０．７５ｇ）に１２％水酸化カリウム水溶液（１０ｍＬ）を加え、室温で一夜反応した。反応液に活性炭を加えろ過し、ろ液を減圧濃縮した。残渣に水（５０ｍＬ）を加え、３５％塩酸で酸析した後、結晶をろ取、水洗し粗製結晶を得た。粗製結晶にメタノール（１０ｍＬ）を加え、撹拌懸濁した後、結晶をろ取、乾燥して化合物３２５（３２６ｍｇ，Ｙ＝７７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３１−２．６９（１１Ｈ，ｍ）４．１４（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２１−８．３０（８Ｈ，ｍ）９．３６（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．９７（１Ｈ，ｓ）
化合物３２５（１５０ｍｇ）に０．０５％水酸化カリウム水溶液（５０ｍＬ）を加え、加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物３２６（１４２ｍｇ，Ｙ＝８６％）を得た。6-methyl-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (compound 322), 5- (6-methyl-2-benzoxazolyl) -2-naphthalenol (compound 323), 6- [[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 324), 6-[[5- (6-Methyl-2-benzoxazolyl) Preparation of 2-Naphthalenyl] oxy] hexanoic acid (Compound 325), 6-[[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 326):
6-Benzyloxy-1-naphthoic acid (7.0 g) was reacted with thionyl chloride (3.6 g) in toluene (100 mL) for 2 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain 6-benzyloxy-1-naphthoic acid chloride oil.
6-Benzyloxy-1-naphthoic acid chloride was added to a solution of 6-amino-m-cresol (3.8 g) and triethylamine (3.1 g) in 1,3-dimethyl-2-imidazolidinone (100 mL) at room temperature. For 2.5 hours. The reaction solution was added to water (1.5 L) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (9.0 g, Y = 93%).
In a mixture of 1,3-dimethyl-2-imidazolidinone (90 mL) and toluene (270 mL), p-toluenesulfonic acid monohydrate (8.5 g) was added to the amide compound (8.5 g), and the mixture was refluxed. The reaction was carried out for 20 hours while removing the water produced in step (b). The reaction solution was concentrated under reduced pressure, and the residue was added to water (1.5 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (150 mL) and potassium hydroxide (6.0 g) were added to the crude crystals and suspended under reflux for 14 hours. The crystals were collected by filtration and dried to obtain compound 322 (3.27 g, Y = 40%). It was.
Compound 322 (3.00 g) was added to and dissolved in 1,3-dimethyl-2-imidazolidinone (40 mL), 5% palladium carbon (0.2 g) was added, and the reaction was carried out in a hydrogen atmosphere for 47 hours. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 323 (2.10 g, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.50 (3H, s) 7.11-8.23 (8H, m) 9.31 (1H, d, J = 10 Hz) 9.97 (1H, s)
In DMF (10 mL), potassium carbonate (410 mg) and ethyl 6-bromohexanoate (445 mg) were added to compound 323 (300 mg) and reacted at room temperature for 25 hours. The reaction solution was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 324 (Wet 0.75 g).
A 12% aqueous potassium hydroxide solution (10 mL) was added to compound 324 (Wet 0.75 g) in methanol (40 mL), and the mixture was reacted at room temperature overnight. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and after acidifying with 35% hydrochloric acid, the crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (10 mL) was added to the crude crystals and suspended by stirring, and then the crystals were collected by filtration and dried to obtain Compound 325 (326 mg, Y = 77%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.31-2.69 (11H, m) 4.14 (2H, t, J = 6 Hz) 7.21-8.30 (8 H, m) 9.36 (1 H, d, J = 9 Hz) 11.97 (1H, s)
A 0.05% aqueous potassium hydroxide solution (50 mL) was added to compound 325 (150 mg), dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 326 (142 mg, Y = 86%).

［５−［［５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３２７）、［５−［［５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物３２８）、［５−［［５−（６−メチル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物３２９）の製造：
ＤＭＦ（１０ｍＬ）中、化合物３２３（３００ｍｇ）に炭酸カリウム（６７０ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（６４２ｍｇ）を加え室温で２７時間反応した。反応液を水（１５０ｍＬ）中に加え、生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し化合物３２７（０．９５ｇ）を得た。
メタノール（４０ｍＬ）中、化合物３２７（０．９５ｇ）に１１％水酸化カリウム水溶液（１０ｍＬ）を加え、室温で一夜反応した。反応液に活性炭を加えろ過し、ろ液を減圧濃縮した。残渣に水（５０ｍＬ）を加え、３５％塩酸で酸析し、分離した生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し粗製オイル（０．７２ｇ）を得た。粗製オイル（０．７２ｇ）をシリカゲルカラム（クロロホルム／メタノール）で精製し、化合物３２８（３２０ｍｇ，Ｙ＝６６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１５−１．８０（８Ｈ，ｍ）２．５１（３Ｈ，ｓ）３．２５（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．２１−８．３０（８Ｈ，ｍ）９．３６（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．４８−１３．８３（２Ｈ，ｂｒ）
化合物３２８（２６８ｍｇ）に０．２５％水酸化ナトリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物３２９（２６８ｍｇ，Ｙ＝９１％）を得た。[5-[[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 327), [5-[[5- (6-methyl- 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 328), [5-[[5- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid disodium salt (compound 329):
In DMF (10 mL), potassium carbonate (670 mg) and diethyl (5-bromopentyl) malonate (642 mg) were added to compound 323 (300 mg) and reacted at room temperature for 27 hours. The reaction was added into water (150 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 327 (0.95 g).
11% aqueous potassium hydroxide solution (10 mL) was added to compound 327 (0.95 g) in methanol (40 mL), and the mixture was reacted at room temperature overnight. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, acidified with 35% hydrochloric acid, and the separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (0.72 g). Crude oil (0.72 g) was purified by silica gel column (chloroform / methanol) to obtain compound 328 (320 mg, Y = 66%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.5-1.80 (8H, m) 2.51 (3H, s) 3.25 (1H, t, J = 6 Hz) 4.13 (2H, t, J = 5 Hz) 7.21- 8.30 (8H, m) 9.36 (1H, d, J = 9 Hz) 11.48-13.83 (2H, br)
0.25% aqueous sodium hydroxide solution (20 mL) was added to compound 328 (268 mg) and almost dissolved, then activated carbon was added and filtered. The filtrate was lyophilized to give compound 329 (268 mg, Y = 91%).

６−ニトロ−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール（化合物３３０）、５−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物３３１）、４−［［５−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３３２）、４−［［５−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３３３）、４−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３３４）、４−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物３３５）の製造：
６−ベンジルオキシ−１−ナフトエ酸（１０．８ｇ）にトルエン（１００ｍＬ）、塩化チオニル（３．３５ｍＬ）、ＤＭＦ（１滴）を加えて還流下で２時間反応した後、２−アミノ−５−ニトロフェノール（１２．５ｇ）の１，４−ジオキサン（１５０ｍＬ）溶液を加えて還流下で３時間反応した。冷却後、析出した結晶をろ取した。得られた結晶を希塩酸で洗浄し、メタノールで洗浄後乾燥して中間体のアミド化合物（１３．４ｇ，Ｙ＝８９％）を得た。
１，３−ジメチル−２−イミダゾリジノン（７０ｍＬ）にアミド化合物（１３．４ｇ）を溶解し、ｐ−トルエンスルホン酸一水和物（１０ｇ）及びトルエン（１４０ｍＬ）を加えて還流下で生成する水を除去しながら一夜反応した。反応液を減圧濃縮し、残液に水（２５０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶にメタノール（２５０ｍＬ）、２％水酸化ナトリウム水溶液（５ｍＬ）を加えて還流下で１時間懸濁後、結晶をろ取し、メタノールで洗浄後乾燥して化合物３３０（１０．９６ｇ，Ｙ＝８６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２９（２Ｈ，ｓ）７．３４−８．７５（１３Ｈ，ｍ）９．３３（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３３０（１０．９ｇ）に３０％臭化水素・酢酸溶液（１００ｍＬ）を加え、約１００℃で２時間反応した。反応液に水（８００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶を６０％メタノール水溶液で洗浄し、トルエンで洗浄後乾燥して化合物３３１（７．７ｇ，Ｙ＝９１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．２１−８．７４（８Ｈ，ｍ）９．２６（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）１０．０５（１Ｈ，ｓ）
化合物３３１（１．１ｇ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（５．５ｇ）、４−ブロモ−ｎ−酪酸エチル（９２０ｍｇ）を加えて室温で一夜反応した。反応液に水（１００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールで洗浄後乾燥して化合物３３２（１．４ｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．０９−２．７０（４Ｈ，ｍ）４．０１−４．３６（４Ｈ，ｍ）７．２６−８．５１（８Ｈ，ｍ）９．３９（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３３２（１．３ｇ）にエタノール（８０ｍＬ）、トルエン（２０ｍＬ）、５％パラジウム炭素（０．６ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物３３３（１．０９ｇ，Ｙ＝９０％）を得た。
化合物３３３（５５０ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ヨウ化エチル（２．５ｇ）を加え、約６５℃で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をエタノールから再結晶して化合物３３４（４５０ｍｇ，Ｙ＝７２％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１０−１．３８（９Ｈ，ｍ）２．０４−２．７３（４Ｈ，ｍ）３．２７−３．６２（４Ｈ，ｍ）３．９９−４．３５（４Ｈ，ｍ）６．６８−８．２８（８Ｈ，ｍ）９．４０（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３３４（３８０ｍｇ）をメタノール（５０ｍＬ）に溶解し、７％水酸化ナトリウム水溶液（３ｍＬ）を加えて約６０℃で４時間反応した。反応液を減圧濃縮し、残渣を水（５０ｍＬ）に加熱溶解後、希塩酸を加えて中和した。析出した結晶をろ取、乾燥して化合物３３５（３１２ｍｇ，Ｙ＝８８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１５（６Ｈ，ｔ，Ｊ＝７Ｈｚ）１．８５−２．５１（４Ｈ，ｍ）３．２５−３．６１（４Ｈ，ｍ）４．１７（２Ｈ，ｔ，Ｊ＝７Ｈｚ）６．７４−８．２４（８Ｈ，ｍ）９．４１（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１２．１７（１Ｈ，ｂｒ）6-nitro-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (compound 330), 5- (6-nitro-2-benzoxazolyl) -2-naphthalenol (compound 331), 4- [[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 332), 4-[[5- (6-Amino-2-benzoxazolyl) 2-Naphthalenyl] oxy] butanoic acid ethyl ester (Compound 333), 4-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 334) ), 4-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 335) :
Toluene (100 mL), thionyl chloride (3.35 mL) and DMF (1 drop) were added to 6-benzyloxy-1-naphthoic acid (10.8 g) and reacted for 2 hours under reflux, and then 2-amino-5 A solution of nitrophenol (12.5 g) in 1,4-dioxane (150 mL) was added and reacted under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration. The obtained crystals were washed with dilute hydrochloric acid, washed with methanol and dried to obtain an intermediate amide compound (13.4 g, Y = 89%).
An amide compound (13.4 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (70 mL), and p-toluenesulfonic acid monohydrate (10 g) and toluene (140 mL) are added to produce it under reflux. The reaction was carried out overnight while removing water. The reaction solution was concentrated under reduced pressure, and water (250 mL) was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. Methanol (250 mL) and 2% aqueous sodium hydroxide solution (5 mL) were added to the obtained crystals and suspended under reflux for 1 hour. The crystals were collected by filtration, washed with methanol and dried to give compound 330 (10.96 g). , Y = 86%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.29 (2H, s) 7.34-8.75 (13H, m) 9.33 (1H, d, J = 9 Hz)
A 30% hydrogen bromide / acetic acid solution (100 mL) was added to compound 330 (10.9 g), and the mixture was reacted at about 100 ° C. for 2 hours. Water (800 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with a 60% aqueous methanol solution, washed with toluene and then dried to obtain Compound 331 (7.7 g, Y = 91%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.21−8.74 (8H, m) 9.26 (1H, d, J = 10 Hz) 10.05 (1H, s)
Compound 331 (1.1 g) was dissolved in DMF (20 mL), potassium carbonate (5.5 g) and ethyl 4-bromo-n-butyrate (920 mg) were added, and the mixture was reacted at room temperature overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 332 (1.4 g, Y = 93%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.09-2.70 (4H, m) 4.01-4.36 (4H, m) 7.26-8.51 (8H, m) 9.39 (1H, d, J = 9Hz)
Ethanol (80 mL), toluene (20 mL), and 5% palladium carbon (0.6 g) were added to compound 332 (1.3 g) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 333 (1.09 g, Y = 90%).
Compound 333 (550 mg) was dissolved in DMF (15 mL), potassium carbonate (2.5 g) and ethyl iodide (2.5 g) were added, and the mixture was reacted at about 65 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain Compound 334 (450 mg, Y = 72%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.10-1.38 (9H, m) 2.04-2.73 (4H, m) 3.27-3.62 (4H, m) 3.99-4.35 (4H, m) 6.68-8.28 (8H, m) 9.40 (1H, d, J = 9 Hz)
Compound 334 (380 mg) was dissolved in methanol (50 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) by heating, and then neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 335 (312 mg, Y = 88%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.15 (6H, t, J = 7 Hz) 1.85-2.51 (4H, m) 3.25-3.61 (4H, m) 4.17 (2H, t, J = 7 Hz) 6.74-8.24 (8H, m) 9.41 (1H, d, J = 9 Hz) 12.17 (1H, br)

４−［［５−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３３６）、４−［［５−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物３３７）の製造：
化合物３３３（５４０ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、臭化ベンジル（８００ｍｇ）を加えて室温で一夜反応した。反応液に水（１００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールから再結晶して化合物３３６（６７９ｍｇ，Ｙ＝８６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．００−２．８０（４Ｈ，ｍ）３．９８−４．３５（４Ｈ，ｍ）４．８６（４Ｈ，ｓ）６．６４−８．２２（１８Ｈ，ｍ）９．３６（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３３６（５５０ｍｇ）をメタノール（６０ｍＬ）に溶解して４％水酸化ナトリウム水溶液（５ｍＬ）を加えて約５０℃で６時間反応した。反応液を減圧濃縮し、残渣を水（８０ｍＬ）に加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３３７（４８３ｍｇ，Ｙ＝９２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８０−２．５３（４Ｈ，ｍ）４．１５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．８３（４Ｈ，ｓ）６．７７−８．１８（１８Ｈ，ｍ）９．３５（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）4-[[5- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 336), 4-[[5- [6- Preparation of [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 337):
Compound 333 (540 mg) was dissolved in DMF (15 mL), potassium carbonate (2.5 g) and benzyl bromide (800 mg) were added, and the mixture was reacted at room temperature overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 336 (679 mg, Y = 86%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7 Hz) 2.00-2.80 (4H, m) 3.98-4.35 (4H, m) 4.86 (4H, s) 6.64- 8.22 (18H, m) 9.36 (1H, d, J = 9 Hz)
Compound 336 (550 mg) was dissolved in methanol (60 mL), 4% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. for 6 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (80 mL) with heating, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 337 (483 mg, Y = 92%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.53 (4H, m) 4.15 (2H, t, J = 6 Hz) 4.83 (4H, s) 6.77-8.18 (18H, m) 9.35 ( 1H, d, J = 10Hz)

６−［［５−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３３８）、６−［［５−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３３９）、６−［［５−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸塩酸塩（化合物３４０）の製造：
化合物３３１（１．０ｇ）をＤＭＦ（２０ｍＬ）に溶解し、炭酸カリウム（５．０ｇ）、６−ブロモヘキサン酸エチル（９３０ｍｇ）を加えて室温で一夜反応した。反応液に水（８０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールで洗浄後乾燥して化合物３３８（１．４ｇ，Ｙ＝９５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．５４−２．１０（６Ｈ，ｍ）２．３７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９８−４．３３（４Ｈ，ｍ）７．１９−８．５１（８Ｈ，ｍ）９．３８（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３３８（１．２ｇ）にトルエン（３０ｍＬ）、エタノール（１５０ｍＬ）、５％パラジウム炭素（０．４ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物３３９（１．０３ｇ，Ｙ＝９２％）を得た。
化合物３３９（２２０ｍｇ）をメタノール（１００ｍＬ）に溶解後、７％水酸化ナトリウム水溶液（６ｍＬ）を加えて約５０℃で８時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加温溶解後、希塩酸を加えて中和し、析出した結晶をろ取した。得られた結晶をアセトン（５０ｍＬ）に溶解後、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物３４０（１１２ｍｇ，Ｙ＝５０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，Ｄ_２Ｏ／ＴＭＳ）：
δ＝１．４０−２．００（６Ｈ，ｍ）２．３０（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１５（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３３−８．３５（８Ｈ，ｍ）９．３１（１Ｈ，ｄ，Ｊ＝９Ｈｚ）6-[[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 338), 6-[[5- (6-Amino-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 339), 6-[[5- (6-Amino-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid hydrochloride (Compound 340) )Manufacturing of:
Compound 331 (1.0 g) was dissolved in DMF (20 mL), and potassium carbonate (5.0 g) and ethyl 6-bromohexanoate (930 mg) were added and reacted overnight at room temperature. Water (80 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 338 (1.4 g, Y = 95%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 1.54-2.10 (6H, m) 2.37 (2H, t, J = 6 Hz) 3.98-4.33 (4H, m) 7.19-8.51 (8H, m) 9.38 (1H, d, J = 9 Hz)
Toluene (30 mL), ethanol (150 mL), and 5% palladium carbon (0.4 g) were added to compound 338 (1.2 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 339 (1.03 g, Y = 92%).
Compound 339 (220 mg) was dissolved in methanol (100 mL), 7% aqueous sodium hydroxide solution (6 mL) was added, and the mixture was reacted at about 50 ° C. for 8 hr. The reaction solution was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, neutralized by adding dilute hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (50 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 340 (112 mg, Y = 50%).
¹ H-NMR (DMSO-d6, D ₂ O / TMS):
δ = 1.40-2.00 (6H, m) 2.30 (2H, t, J = 6 Hz) 4.15 (2H, t, J = 5 Hz) 7.33-8.35 (8H, m) 9.31 (1H, d, J = 9Hz)

６−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３４１）、６−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物３４２）、６−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物３４３）の製造：
化合物３３９（４５０ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（４．０ｇ）、ヨウ化エチル（２．５ｇ）を加え、約７０℃で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物３４１（３８５ｍｇ，Ｙ＝７５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１１−２．４６（１７Ｈ，ｍ）３．２７−３．６２（４Ｈ，ｍ）３．９７−４．３３（４Ｈ，ｍ）６．６８−８．２５（８Ｈ，ｍ）９．３９（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３４１（３５０ｍｇ）をメタノール（５０ｍＬ）に溶解し、７％水酸化ナトリウム水溶液（３ｍＬ）を加えて約６０℃で４時間反応した。反応液を減圧濃縮し、残渣に水（４０ｍＬ）を加えて加熱溶解後、希塩酸を加えて中和した。析出した結晶をろ取、乾燥して化合物３４２（２５０ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１５（６Ｈ，ｔ，Ｊ＝７Ｈｚ）１．３９−２．００（６Ｈ，ｍ）２．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．１９−３．６５（４Ｈ，ｍ）４．１３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）６．７５−８．２４（８Ｈ，ｍ）９．４２（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１２．０１（１Ｈ，ｂｒ）
化合物３４２（６８ｍｇ）を水（５０ｍＬ）に懸濁し、０．５％水酸化ナトリウム水溶液（１．３ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物３４３（６３ｍｇ，Ｙ＝８８％）を得た。6-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 341), 6-[[5- [6- (Diethylamino) -2 -Benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (compound 342), 6-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] sodium hexanoate Production of salt (compound 343):
Compound 339 (450 mg) was dissolved in DMF (10 mL), potassium carbonate (4.0 g) and ethyl iodide (2.5 g) were added, and the mixture was reacted at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 341 (385 mg, Y = 75%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.11-2.46 (17H, m) 3.27-3.62 (4H, m) 3.97-4.33 (4H, m) 6.68-8.25 (8H, m) 9.39 (1H, d, J = 9Hz)
Compound 341 (350 mg) was dissolved in methanol (50 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, water (40 mL) was added to the residue and dissolved by heating, and then diluted hydrochloric acid was added to neutralize. The precipitated crystals were collected by filtration and dried to obtain Compound 342 (250 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.15 (6H, t, J = 7 Hz) 1.39-2.00 (6H, m) 2.28 (2H, t, J = 6 Hz) 3.19-3.65 (4H, m) 4.13 (2H, t, J = 5 Hz) 6.75-8.24 (8H, m) 9.42 (1H, d, J = 9 Hz) 12.01 (1H, br)
Compound 342 (68 mg) was suspended in water (50 mL), 0.5% aqueous sodium hydroxide solution (1.3 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 343 (63 mg, Y = 88%).

６−［［５−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３４４）、６−［［５−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物３４５）、６−［［５−［６−［ビス（フェニルメチル）アミノ］−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物３４６）の製造：
化合物３３９（３６０ｍｇ）をＤＭＦ（８ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ベンジルブロミド（０．５ｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（５０ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物３４４（４７５ｍｇ，Ｙ＝９２％）を得た。
化合物３４４（４７５ｍｇ）をメタノール（１００ｍＬ）に溶解し、７％水酸化ナトリウム水溶液（３ｍＬ）を加えて約６０℃で一夜反応した。反応液を減圧濃縮し、残渣を水（１００ｍＬ）に加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３４５（３３２ｍｇ，Ｙ＝７３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０−１．９０（６Ｈ，ｍ）２．１８（２Ｈ，ｔ，Ｊ＝４Ｈｚ）４．１２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．８３（４Ｈ，ｓ）６．７５−８．１９（１８Ｈ，ｍ）９．３５（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３４５（７１ｍｇ）を水（１００ｍＬ）に懸濁し、０．５％水酸化ナトリウム水溶液（１ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物３４６（４２ｍｇ，Ｙ＝５７％）を得た。6-[[5- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 344), 6-[[5- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 345), 6-[[5- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 346):
Compound 339 (360 mg) was dissolved in DMF (8 mL), and potassium carbonate (2.5 g) and benzyl bromide (0.5 g) were added and reacted at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 344 (475 mg, Y = 92%).
Compound 344 (475 mg) was dissolved in methanol (100 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (100 mL) with heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 345 (332 mg, Y = 73%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-1.90 (6H, m) 2.18 (2H, t, J = 4 Hz) 4.12 (2H, t, J = 6 Hz) 4.83 (4H, s) 6.75− 8.19 (18H, m) 9.35 (1H, d, J = 9 Hz)
Compound 345 (71 mg) was suspended in water (100 mL), 0.5% aqueous sodium hydroxide solution (1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 346 (42 mg, Y = 57%).

［５−［［５−（６−ニトロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３４７）、［５−［［５−（６−アミノ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３４８）、［５−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３４９）、［５−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物３５０）、［５−［［５−［６−（ジエチルアミノ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物３５１）の製造：
化合物３３１（９００ｍｇ）をＤＭＦ（１８ｍＬ）に溶解し、炭酸カリウム（４．５ｇ）、（５−ブロモペンチル）マロン酸ジエチル（１．２ｍｇ）を加えて室温で一夜反応した。反応液に水（１００ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールで洗浄後乾燥して化合物３４７（１．４ｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１５−２．１８（１４Ｈ，ｍ）３．３６（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．０３−４．４０（６Ｈ，ｍ）７．２３−８．５２（８Ｈ，ｍ）９．３９（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３４７（１．２ｇ）にトルエン（３０ｍＬ）、エタノール（１２０ｍＬ）、５％パラジウム炭素（０．３ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物３４８（１．０９ｇ，Ｙ＝９７％）を得た。
化合物３４８（５５０ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、ヨウ化エチル（２．５ｇ）を加えて約７０℃で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物３４９（４４０ｍｇ，Ｙ＝７２％）を得た。
化合物３４９（４４０ｍｇ）をメタノール（１００ｍＬ）に溶解し、１５％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で４日間反応した。冷却後、析出した結晶をろ取、乾燥して化合物３５１（２６１ｍｇ，Ｙ＝６１％）を得た。
化合物３５１のろ液を減圧濃縮し、残渣を水（４０ｍＬ）に溶解後、希塩酸を加えて中和した。析出した結晶をろ取、乾燥して化合物３５０（７２ｍｇ，Ｙ＝１８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．０３−２．４１（１４Ｈ，ｍ）３．１４−３．６５（５Ｈ，ｍ）４．１４（２Ｈ，ｔ，Ｊ＝５Ｈｚ）６．７９−８．２５（８Ｈ，ｍ）９．４０（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１２．５（２Ｈ，ｂｒ）[5-[[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 347), [5-[[5- (6-amino- 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 348), [5-[[5- [6- (diethylamino) -2-benzoxazolyl] -2- Naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 349), [5-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid ( Compound 350), [5-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propane Preparation of disodium salt (Compound 351):
Compound 331 (900 mg) was dissolved in DMF (18 mL), potassium carbonate (4.5 g) and diethyl (5-bromopentyl) malonate (1.2 mg) were added, and the mixture was reacted overnight at room temperature. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to obtain Compound 347 (1.4 g, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.15-2.18 (14H, m) 3.36 (1H, t, J = 6 Hz) 4.03-4.40 (6H, m) 7.23-8.52 (8H, m) 9.39 (1H, d, J = 9Hz)
Toluene (30 mL), ethanol (120 mL), and 5% palladium carbon (0.3 g) were added to compound 347 (1.2 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 348 (1.09 g, Y = 97%).
Compound 348 (550 mg) was dissolved in DMF (10 mL), potassium carbonate (2.5 g) and ethyl iodide (2.5 g) were added, and the mixture was reacted at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform) to obtain Compound 349 (440 mg, Y = 72%).
Compound 349 (440 mg) was dissolved in methanol (100 mL), 15% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. for 4 days. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 351 (261 mg, Y = 61%).
The filtrate of compound 351 was concentrated under reduced pressure, and the residue was dissolved in water (40 mL), and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 350 (72 mg, Y = 18%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.03-2.41 (14H, m) 3.14-3.65 (5H, m) 4.14 (2H, t, J = 5 Hz) 6.79-8.25 (8H, m) 9.40 (1H, d, J = 9 Hz) 12.5 (2H, br)

２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］−６−ニトロベンゾオキサゾール（化合物３５２）、２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩（化合物３５３）、Ｎ，Ｎ−ジエチル−２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］−６−ベンゾオキサゾールアミン二塩酸塩（化合物３５４）の製造：
化合物３３１（１．０ｇ）をＤＭＦ（１６ｍＬ）に溶解し、炭酸カリウム（６．０ｇ）、Ｎ−（２−クロロエチル）モルホリン塩酸塩（８５０ｍｇ）を加えて約６５℃で一夜反応した。反応液に水（９０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物３５２（１．２ｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝２．５５−３．００（６Ｈ，ｍ）３．７７（４Ｈ，ｔ，Ｊ＝５Ｈｚ）４．２９（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２２−８．５１（８Ｈ，ｍ）９．４０（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３５２（１．０５ｇ）にトルエン（３０ｍＬ）、メタノール（８０ｍＬ）、５％パラジウム炭素（０．３ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣にアセトン（１００ｍＬ）を加えて溶解し、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物３５３（１．０１ｇ，Ｙ＝８６％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４，Ｄ_２Ｏ／ＴＭＳ）：
δ＝３．３６−４．１２（１０Ｈ，ｍ）４．６３（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．１４−８．３３（８Ｈ，ｍ）９．２３（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）
化合物３５３（４５０ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し炭酸カリウム（２．４ｇ）、ヨウ化エチル（１．５ｇ）を加えて６５℃で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をアセトン（５０ｍＬ）に溶解し、３５％塩酸（０．２ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物３５４（１２０ｍｇ，Ｙ＝２４％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝１．２４（６Ｈ，ｔ，Ｊ＝７Ｈｚ）３．３２−４．０９（１４Ｈ，ｍ）４．６５（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．４３−８．４４（８Ｈ，ｍ）９．４２（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-nitrobenzoxazole (Compound 352), 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl ] -6-benzoxazolamine dihydrochloride (compound 353), N, N-diethyl-2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-benzoxazolamine dihydrochloride Production of (Compound 354):
Compound 331 (1.0 g) was dissolved in DMF (16 mL), potassium carbonate (6.0 g) and N- (2-chloroethyl) morpholine hydrochloride (850 mg) were added, and the mixture was reacted at about 65 ° C. overnight. Water (90 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 352 (1.2 g, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.55-3.00 (6H, m) 3.77 (4H, t, J = 5 Hz) 4.29 (2H, t, J = 6 Hz) 7.22-8.51 (8H, m) 9.40 (1H, d, J = 9Hz)
Toluene (30 mL), methanol (80 mL), and 5% palladium carbon (0.3 g) were added to compound 352 (1.05 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Acetone (100 mL) was added to the residue for dissolution, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 353 (1.01 g, Y = 86%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 3.36-4.12 (10H, m) 4.63 (2H, t, J = 5 Hz) 7.14-8.33 (8H, m) 9.23 (1H, d, J = 10 Hz)
Compound 353 (450 mg) was dissolved in DMF (10 mL), potassium carbonate (2.4 g) and ethyl iodide (1.5 g) were added, and the mixture was reacted at 65 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (50 mL), 35% hydrochloric acid (0.2 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 354 (120 mg, Y = 24%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.24 (6H, t, J = 7 Hz) 3.32-4.09 (14H, m) 4.65 (2H, t, J = 5 Hz) 7.43-8.44 (8H, m) 9.42 (1H, d, J = 10Hz)

２−［６−（フェニルメトキシ）−１−ナフタレニル］−６−ベンゾオキサゾロール（化合物３５５）、６−（シクロヘキシルメトキシ）−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール（化合物３５６）、５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレノール（化合物３５７）、４−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３５８）、４−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物３５９）の製造：
６−ベンジルオキシ−１−ナフトエ酸（１２．８ｇ）にトルエン（８０ｍＬ）、塩化チオニル（４ｍＬ）、ＤＭＦ（１滴）を加えて２．５時間還流下で反応した後、減圧濃縮した。残渣を１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）に溶解後、４−アミノレゾルシノール塩酸塩（７．５ｇ）及びトリエチルアミン（９．４ｇ）の１，３−ジメチル−２−イミダゾリジノン（２５０ｍＬ）溶液に加え、室温で一夜反応した。反応液に酢酸エチル（１．２Ｌ）を加えて水、希塩酸水溶液、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮、乾燥して中間体のアミド化合物（１７．６８ｇ，Ｙ＝１００％）を得た。
アミド化合物（１７．６５ｇ）を１，３−ジメチル−２−イミダゾリジノン（８０ｍＬ）に溶解し、ｐ−トルエンスルホン酸一水和物（１３．１ｇ）、トルエン（１６０ｍＬ）を加えて還流下で生成する水を除去しながら一夜反応した。反応液を減圧濃縮し、残液に水（２００ｍＬ）を加えて懸濁後、上澄液をデカントした。残渣を２０％メタノール水溶液（２５０ｍＬ）で洗浄後、乾燥した。取得物をシリカゲルカラム（クロロホルム）で精製して化合物３５５（６．５ｇ，Ｙ＝３９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２８（２Ｈ，ｓ）６．８２−８．２８（１３Ｈ，ｍ）９．４０（１Ｈ，ｄ，Ｊ＝９Ｈｚ）９．９２（１Ｈ，ｓ）
化合物３５５（３．５ｇ）をＤＭＦ（３５ｍＬ）に溶解し、炭酸カリウム（１５ｇ）、ブロモメチルシクロヘキサン（３．０ｇ）を加えて約６５℃で４日間反応した。反応液に水（２５０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物３５６（４．１１ｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．００−２．１０（１１Ｈ，ｍ）３．８５（２Ｈ，ｄ，Ｊ＝６Ｈｚ）５．２３（２Ｈ，ｓ）６．８９−８．３１（１３Ｈ，ｍ）９．４２（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３５６（４．１１ｇ）にメタノール（３００ｍＬ）、トルエン（１００ｍＬ）、５％パラジウム炭素（１ｇ）を加えて水素雰囲気下約４０℃で反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をトルエンで洗浄後乾燥して化合物３５７（２．５２ｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝０．９４−２．１０（１１Ｈ，ｍ）３．８５（２Ｈ，ｄ，Ｊ＝６Ｈｚ）５．５６（１Ｈ，ｓ）６．８９−８．２５（８Ｈ，ｍ）９．３５（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）
化合物３５７（３５０ｍｇ）をＤＭＦ（４ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、４−ブロモ−ｎ−酪酸エチル（２４０ｍｇ）を加えて室温で一夜反応した。反応液に水（３６ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物３５８（３２０ｍｇ，Ｙ＝７０％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝０．９７−２．７０（１８Ｈ，ｍ）３．７４−４．３６（６Ｈ，ｍ）６．８９−８．３０（８Ｈ，ｍ）９．３９（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３５８（３００ｍｇ）をメタノール（６０ｍＬ）に溶解後、７％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で一夜反応した。反応液を減圧濃縮し、残渣に水（３０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３５９（２６７ｍｇ，Ｙ＝９４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝０．９５−２．５７（１５Ｈ，ｍ）３．８８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９７−８．２７（８Ｈ，ｍ）９．３６（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）2- [6- (phenylmethoxy) -1-naphthalenyl] -6-benzoxazolol (compound 355), 6- (cyclohexylmethoxy) -2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole ( Compound 356), 5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenol (Compound 357), 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] ] -2-Naphthalenyl] oxy] butanoic acid ethyl ester (Compound 358), 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 359) )Manufacturing of:
Toluene (80 mL), thionyl chloride (4 mL), and DMF (1 drop) were added to 6-benzyloxy-1-naphthoic acid (12.8 g), reacted for 2.5 hours under reflux, and then concentrated under reduced pressure. After the residue was dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), 4-aminoresorcinol hydrochloride (7.5 g) and triethylamine (9.4 g) in 1,3-dimethyl-2-imidazolidinone (250 mL) added to the solution and reacted overnight at room temperature. Ethyl acetate (1.2 L) was added to the reaction mixture, and the mixture was washed successively with water, dilute hydrochloric acid aqueous solution and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain an intermediate amide compound (17.68 g, Y = 100%).
The amide compound (17.65 g) was dissolved in 1,3-dimethyl-2-imidazolidinone (80 mL), and p-toluenesulfonic acid monohydrate (13.1 g) and toluene (160 mL) were added under reflux. The reaction was carried out overnight while removing the water produced in step 1. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the remaining solution to suspend it, and then the supernatant was decanted. The residue was washed with 20% aqueous methanol (250 mL) and dried. The obtained product was purified by silica gel column (chloroform) to obtain Compound 355 (6.5 g, Y = 39%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 6.82-8.28 (13H, m) 9.40 (1H, d, J = 9 Hz) 9.92 (1H, s)
Compound 355 (3.5 g) was dissolved in DMF (35 mL), potassium carbonate (15 g) and bromomethylcyclohexane (3.0 g) were added, and the mixture was reacted at about 65 ° C. for 4 days. Water (250 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 356 (4.11 g, Y = 93%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.00-2.10 (11H, m) 3.85 (2H, d, J = 6 Hz) 5.23 (2H, s) 6.89-8.31 (13H, m) 9.42 ( 1H, d, J = 9Hz)
Methanol (300 mL), toluene (100 mL), and 5% palladium carbon (1 g) were added to compound 356 (4.11 g), and reacted at about 40 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with toluene and dried to obtain Compound 357 (2.52 g, Y = 76%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 0.94-2.10 (11H, m) 3.85 (2H, d, J = 6 Hz) 5.56 (1H, s) 6.89-8.25 (8H, m) 9.35 ( 1H, d, J = 10Hz)
Compound 357 (350 mg) was dissolved in DMF (4 mL), potassium carbonate (1.5 g) and ethyl 4-bromo-n-butyrate (240 mg) were added, and the mixture was reacted overnight at room temperature. Water (36 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 358 (320 mg, Y = 70%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 0.97-2.70 (18H, m) 3.74-4.36 (6H, m) 6.89-8.30 (8H, m) 9.39 (1H, d, J = 9 Hz)
Compound 358 (300 mg) was dissolved in methanol (60 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 359 (267 mg, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.95-2.57 (15H, m) 3.88 (2H, t, J = 6 Hz) 4.17 (2H, t, J = 6 Hz) 6.97-8.27 (8H, m) 9.36 (1H, d, J = 10Hz)

６−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３６０）、６−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物３６１）の製造：
化合物３５７（３４０ｍｇ）をＤＭＦ（４ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、６−ブロモヘキサン酸エチル（２７０ｍｇ）を加え、室温で一夜反応した。反応液に水（２６ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物３６０（４４３ｍｇ，Ｙ＝９４％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．０２−２．５０（２２Ｈ，ｍ）３．７９−４．３３（６Ｈ，ｍ）６．９２−８．３０（８Ｈ，ｍ）９．３８（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３６０（４１３ｍｇ）をメタノール（５０ｍＬ）に溶解後、４％水酸化ナトリウム水溶液（５ｍＬ）を加えて約６０℃で３時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３６１（３３８ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝０．８１−２．００（１７Ｈ，ｍ）２．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．７４−４．２１（４Ｈ，ｍ）６．９２−８．２７（８Ｈ，ｍ）９．３５（１Ｈ，ｄ，Ｊ＝９Ｈｚ）6-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 360), 6-[[5- [6- (cyclohexylmethoxy) Preparation of -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 361):
Compound 357 (340 mg) was dissolved in DMF (4 mL), potassium carbonate (1.5 g) and ethyl 6-bromohexanoate (270 mg) were added, and the mixture was reacted overnight at room temperature. Water (26 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 360 (443 mg, Y = 94%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.2-2.50 (22H, m) 3.79-4.33 (6H, m) 6.92-8.30 (8H, m) 9.38 (1H, d, J = 9 Hz)
Compound 360 (413 mg) was dissolved in methanol (50 mL), 4% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 60 ° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 361 (338 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.81-2.00 (17H, m) 2.27 (2H, t, J = 6 Hz) 3.74-4.21 (4H, m) 6.92-8.27 (8H, m) 9.35 (1H, d, J = 9Hz)

［５−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３６２）、［５−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物３６３）の製造：
化合物３５７（３２０ｍｇ）をＤＭＦ（４ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、（５−ブロモペンチル）マロン酸ジエチル（３５０ｍｇ）を加え、室温で一夜反応した。反応液に水（２５ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールから再結晶して化合物３６２（４６２ｍｇ，Ｙ＝９０％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１４−２．１５（２５Ｈ，ｍ）３．３５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）３．７９−４．３９（８Ｈ，ｍ）６．８８−８．２９（８Ｈ，ｍ）９．３７（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３６２（４３４ｍｇ）をメタノール（１００ｍＬ）に溶解後、８％水酸化ナトリウム水溶液（５ｍＬ）を加えて約５０℃で３日間反応した。冷却後、析出した結晶をろ取して化合物３６３（３８４ｍｇ，Ｙ＝９０％）を得た。[5-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 362), [5-[[5- [6 Preparation of-(cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (compound 363):
Compound 357 (320 mg) was dissolved in DMF (4 mL), potassium carbonate (1.5 g) and diethyl (5-bromopentyl) malonate (350 mg) were added, and the mixture was reacted at room temperature overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 362 (462 mg, Y = 90%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.4-2.15 (25H, m) 3.35 (1H, t, J = 7 Hz) 3.79-4.39 (8H, m) 6.88-8.29 (8H, m) 9.37 (1H, d, J = 9Hz)
Compound 362 (434 mg) was dissolved in methanol (100 mL), 8% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. for 3 days. After cooling, the precipitated crystals were collected by filtration to obtain Compound 363 (384 mg, Y = 90%).

６−（シクロヘキシルメトキシ）−２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物３６４）の製造：
化合物３５７（２０３ｍｇ）をＤＭＦ（４ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、Ｎ−（２−クロロエチル）モルホリン塩酸塩（１５５ｍｇ）を加えて約６５℃で一夜反応した。反応液に水（２５ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールから再結晶した。得られた結晶をアセトン（３０ｍＬ）に溶解し、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物３６４（１８０ｍｇ，Ｙ＝６３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝０．９８−１．９２（１１Ｈ，ｍ）３．１０−４．０２（１２Ｈ，ｍ）４．６８（２Ｈ，ｔ，Ｊ＝５Ｈｚ）６．９４−８．３１（８Ｈ，ｍ）９．４０（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１２．０（１Ｈ，ｂｒ）Preparation of 6- (cyclohexylmethoxy) -2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride (Compound 364):
Compound 357 (203 mg) was dissolved in DMF (4 mL), potassium carbonate (1.5 g) and N- (2-chloroethyl) morpholine hydrochloride (155 mg) were added, and the mixture was reacted at about 65 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystal was recrystallized from methanol. The obtained crystals were dissolved in acetone (30 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 364 (180 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.98-1.92 (11H, m) 3.10-4.02 (12H, m) 4.68 (2H, t, J = 5 Hz) 6.94-8.31 (8H, m) 9.40 (1H, d, J = 9 Hz) 12.0 (1H, br)

３−［［５−［６−（シクロヘキシルメトキシ）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩（化合物３６５）の製造：
化合物３５７（２９８ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（２．２ｇ）、３−ジメチルアミノプロピルクロリド塩酸塩（２５０ｍｇ）を加えて約６５℃で一夜反応した。反応液に酢酸エチル（５０ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣にアセトン（２５ｍＬ）を加えて溶解し、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物３６５（１７２ｍｇ，Ｙ＝４４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝０．８８−２．５２（１３Ｈ，ｍ）２．８１（６Ｈ，ｓ）３．３２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．８９（２Ｈ，ｄ，Ｊ＝６Ｈｚ）４．２７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）６．９４−８．２９（８Ｈ，ｍ）９．３９（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．０（１Ｈ，ｂｒ）Preparation of 3-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 365):
Compound 357 (298 mg) was dissolved in DMF (5 mL), potassium carbonate (2.2 g) and 3-dimethylaminopropyl chloride hydrochloride (250 mg) were added, and the mixture was reacted at about 65 ° C. overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. Acetone (25 mL) was added to the residue for dissolution, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 365 (172 mg, Y = 44%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.88−2.52 (13H, m) 2.81 (6H, s) 3.32 (2H, t, J = 6 Hz) 3.89 (2H, d, J = 6 Hz) 4.27 ( 2H, t, J = 6 Hz) 6.94-8.29 (8H, m) 9.39 (1H, d, J = 9 Hz) 11.0 (1H, br)

５−（１，１−ジメチルエチル）−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール（化合物３６６）、５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレノール（化合物３６７）、４−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３６８）、４−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸（化合物３６９）、４−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ブタン酸カリウム塩（化合物３７０）の製造：
トルエン（１００ｍＬ）中、６−ベンジルオキシ−１−ナフトエ酸（１０．０ｇ）を塩化チオニル（５．２ｇ）と還流下で１．５時間反応した。反応液を減圧濃縮して６−ベンジルオキシ−１−ナフトエ酸クロライド（１１．０ｇ）を得た。
６−ベンジルオキシ−１−ナフトエ酸クロライド（１１．０ｇ）を２−アミノ−４−ｔｅｒｔ−ブチルフェノール（７．２ｇ），トリエチルアミン（４．４ｇ）の１，３−ジメチル−２−イミダゾリジノン（１２０ｍＬ）溶液に加え、室温で２．５時間反応した。反応液を水（２Ｌ）に加え晶析し、析出結晶をろ取、水洗後、乾燥し中間体のアミド化合物（１５．３ｇ，Ｙ＝１００％）を得た。
アミド化合物（１５．０ｇ）とｐ−トルエンスルホン酸一水和物（１３．４ｇ）を１，３−ジメチル−２−イミダゾリジノン（１５０ｍＬ）、トルエン（４５０ｍＬ）の混合溶媒に加え、還流下で生成する水を除去しながら２１時間反応した。反応液を減圧濃縮し、残液を水（１．５Ｌ）中に加え撹拌した後、クロロホルム（１．５Ｌ）で生成物を抽出した。クロロホルム層を水洗後、濃縮して得られた残渣にメタノール（２００ｍＬ），水酸化カリウム（６．０ｇ）を加え、還流下３．５時間懸濁した後、結晶をろ取、乾燥して化合物３６６（６．５５ｇ，Ｙ＝４６％）を得た。
１，３−ジメチル−２−イミダゾリジノン（１００ｍＬ）に化合物３６６（６．３０ｇ）を加え加温溶解した後、５％パラジウム炭素（０．３ｇ）を加え水素雰囲気下で２４時間反応した。反応液をろ過し、ろ液を水（２Ｌ）中に加え撹拌した後、反応生成物を酢酸エチル（１Ｌ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し粗製オイル（４．７ｇ）を得た。粗製オイルをシリカゲルカラム（トルエン／酢酸エチル）で精製して化合物３６７（２．６８ｇ，Ｙ＝５５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０（９Ｈ，ｓ）７．２８−８．２５（８Ｈ，ｍ）９．３２（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）９．９８（１Ｈ，ｓ）
ＤＭＦ（１２ｍＬ）中、化合物３６７（３００ｍｇ）に炭酸カリウム（６００ｍｇ），４−ブロモ−ｎ−酪酸エチル（３４３ｍｇ）を加え、室温で２８時間反応した。反応液を水（１５０ｍＬ）中に加え晶析し、析出結晶をろ取、水洗して粗製結晶を得た。粗製結晶を８０％エタノール水溶液（４ｍＬ）から再結晶して化合物３６８（３３４ｍｇ，Ｙ＝８２％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．４３（９Ｈ，ｓ）２．１０−２．６９（４Ｈ，ｍ）４．００−４．３５（４Ｈ，ｍ）７．２４−７．９１（７Ｈ，ｍ）８．２１−８．３３（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，７Ｈｚ）９．４０（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
エタノール（２０ｍＬ）中、化合物３６８（２７０ｍｇ）に８％水酸化カリウム水溶液（５ｍＬ）を加え、４５℃で３時間反応した。反応液を減圧濃縮して得られたオイルに水（２０ｍＬ）を加え、撹拌下に３５％塩酸で酸析した。析出結晶をろ取、水洗後、乾燥して化合物３６９（２１４ｍｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０（９Ｈ，ｓ）１．９０−２．５４（４Ｈ，ｍ）４．１９（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．３１−８．３４（８Ｈ，ｍ）９．３８（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．４８−１２．７６（１Ｈ，ｂｒ）
化合物３６９（１００ｍｇ）に０．０４％水酸化カリウム水溶液（４０ｍＬ）を加え、加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物３７０（９７ｍｇ，Ｙ＝８９％）を得た。5- (1,1-dimethylethyl) -2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (Compound 366), 5- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenol (compound 367), 4-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 368), 4-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 369), 4-[[5- [5 Preparation of-(1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 370):
6-Benzyloxy-1-naphthoic acid (10.0 g) was reacted with thionyl chloride (5.2 g) in toluene (100 mL) for 1.5 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain 6-benzyloxy-1-naphthoic acid chloride (11.0 g).
6-Benzyloxy-1-naphthoic acid chloride (11.0 g) was converted to 2-amino-4-tert-butylphenol (7.2 g) and triethylamine (4.4 g) in 1,3-dimethyl-2-imidazolidinone ( 120 mL) solution and reacted at room temperature for 2.5 hours. The reaction solution was added to water (2 L) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (15.3 g, Y = 100%).
The amide compound (15.0 g) and p-toluenesulfonic acid monohydrate (13.4 g) were added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL), and the mixture was refluxed. The reaction was carried out for 21 hours while removing the water produced in step (b). The reaction solution was concentrated under reduced pressure, the residue was added to water (1.5 L) and stirred, and then the product was extracted with chloroform (1.5 L). Methanol (200 mL) and potassium hydroxide (6.0 g) were added to the residue obtained by washing the chloroform layer with water and concentrated, and suspended under reflux for 3.5 hours. The crystals were collected by filtration and dried to give a compound. 366 (6.55 g, Y = 46%) was obtained.
Compound 366 (6.30 g) was added to 1,3-dimethyl-2-imidazolidinone (100 mL), dissolved by heating, 5% palladium carbon (0.3 g) was added, and the reaction was carried out in a hydrogen atmosphere for 24 hours. The reaction solution was filtered, the filtrate was added to water (2 L) and stirred, and then the reaction product was extracted with ethyl acetate (1 L). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (4.7 g). The crude oil was purified on a silica gel column (toluene / ethyl acetate) to give compound 367 (2.68 g, Y = 55%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40 (9H, s) 7.28-8.25 (8H, m) 9.32 (1H, d, J = 10 Hz) 9.98 (1H, s)
In DMF (12 mL), potassium carbonate (600 mg) and ethyl 4-bromo-n-butyrate (343 mg) were added to compound 367 (300 mg) and reacted at room temperature for 28 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (4 mL) to give compound 368 (334 mg, Y = 82%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 1.43 (9H, s) 2.10-2.69 (4H, m) 4.00-4.35 (4H, m) 7.24- 7.91 (7H, m) 8.21-8.33 (1H, dd, J = 1 Hz, 7 Hz) 9.40 (1H, d, J = 9 Hz)
An 8% aqueous potassium hydroxide solution (5 mL) was added to compound 368 (270 mg) in ethanol (20 mL) and reacted at 45 ° C. for 3 hours. Water (20 mL) was added to the oil obtained by concentrating the reaction solution under reduced pressure, and acidified with 35% hydrochloric acid with stirring. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 369 (214 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40 (9H, s) 1.90-2.54 (4H, m) 4.19 (2H, t, J = 6 Hz) 7.31-8.34 (8H, m) 9.38 ( 1H, d, J = 9 Hz) 11.48-12.76 (1H, br)
0.04% aqueous potassium hydroxide solution (40 mL) was added to compound 369 (100 mg), dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 370 (97 mg, Y = 89%).

６−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３７１）、６−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物３７２）、６−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物３７３）の製造：
ＤＭＦ（１２ｍＬ）中、化合物３６７（３００ｍｇ）に炭酸カリウム（８１０ｍｇ），６−ブロモヘキサン酸エチル（５３９ｍｇ）を加え、室温で４２時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し化合物３７１（７８０ｍｇ）を得た。
エタノール（２０ｍＬ）中、化合物３７１（７８０ｍｇ）に８％水酸化カリウム水溶液（５ｍＬ）を加え、４５℃で１７時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加え溶解後、３５％塩酸で酸析し、分離した生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して約４分の１量とし、析出した結晶をろ取、乾燥して化合物３７２（３０５ｍｇ，Ｙ＝７５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１８−２．４１（１７Ｈ，ｍ）４．１５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．３０−８．３３（８Ｈ，ｍ）９．３７（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．０３−１２．９７（１Ｈ，ｂｒ）
化合物３７２（１５０ｍｇ）に０．０３５％水酸化カリウム水溶液（７０ｍＬ）を加え加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物３７３（１４２ｍｇ，Ｙ＝８７％）を得た。6-[[5- [5- (1,1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 371), 6-[[5- [5- (1,1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 372), 6-[[5- [5- (1,1-dimethylethyl) -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 373):
In DMF (12 mL), potassium carbonate (810 mg) and ethyl 6-bromohexanoate (539 mg) were added to compound 367 (300 mg) and reacted at room temperature for 42 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 371 (780 mg).
An 8% aqueous potassium hydroxide solution (5 mL) was added to compound 371 (780 mg) in ethanol (20 mL) and reacted at 45 ° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to about a quarter volume. The precipitated crystals were collected by filtration and dried to obtain Compound 372 (305 mg, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-2.41 (17H, m) 4.15 (2H, t, J = 6 Hz) 7.30-8.33 (8H, m) 9.37 (1H, d, J = 9 Hz) 11.03-12.97 (1H, br)
0.035% aqueous potassium hydroxide solution (70 mL) was added to compound 372 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 373 (142 mg, Y = 87%).

［３−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物３７４）、［３−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］プロピル］プロパン二酸（化合物３７５）、［３−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物３７６）の製造：
ＤＭＦ（１０ｍＬ）中、化合物３６７（３００ｍｇ）に炭酸カリウム（６５６ｍｇ），（３−クロロプロピル）マロン酸ジエチル（４００ｍｇ）を加え、７０〜８０℃で２２時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（４００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して粗製オイルを得た。粗製オイルをシリカゲルカラム（トルエン／酢酸エチル）で精製し、化合物３７４（０．８１ｇ）を得た。
エタノール（２０ｍＬ）中、化合物３７４（０．８１ｇ）に１８％水酸化カリウム水溶液（５ｍＬ）を加え、室温で１９時間反応した。反応液を減圧濃縮し、得られたオイルに水（５０ｍＬ）を加え溶解した後、３５％塩酸で酸析した。析出結晶をろ取、水洗後、乾燥して化合物３７５（１０９ｍｇ，Ｙ＝２５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０（９Ｈ，ｓ）１．７４−２．１４（４Ｈ，ｍ）３．３７（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１９（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３１−８．３４（８Ｈ，ｍ）９．３７（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３７５（７０ｍｇ）に０．０８％水酸化ナトリウム水溶液（１５ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物３７６（７２ｍｇ，Ｙ＝９４％）を得た。[3-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 374), [3-[[ 5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propanedioic acid (Compound 375), [3-[[5- [5- (1 , 1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (Compound 376):
In DMF (10 mL), potassium carbonate (656 mg) and diethyl (3-chloropropyl) malonate (400 mg) were added to compound 367 (300 mg) and reacted at 70-80 ° C. for 22 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (400 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified on a silica gel column (toluene / ethyl acetate) to give compound 374 (0.81 g).
18% aqueous potassium hydroxide solution (5 mL) was added to compound 374 (0.81 g) in ethanol (20 mL), and reacted at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the obtained oil for dissolution, followed by acid precipitation with 35% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 375 (109 mg, Y = 25%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40 (9H, s) 1.74-2.14 (4H, m) 3.37 (1H, t, J = 6 Hz) 4.19 (2H, t, J = 5 Hz) 7.31− 8.34 (8H, m) 9.37 (1H, d, J = 9 Hz)
0.08% aqueous sodium hydroxide solution (15 mL) was added to compound 375 (70 mg) and dissolved substantially, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 376 (72 mg, Y = 94%).

［５−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３７７）、［５−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物３７８）、［５−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物３７９）の製造：
ＤＭＦ（１２ｍＬ）中、化合物３６７（３００ｍｇ）に炭酸カリウム（６００ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（５２０ｍｇ）を加え、室温で２８時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（２００ｍＬ）で抽出した。有機層を水洗後、硫酸マグネシウムで脱水した後、減圧濃縮して化合物３７７（７００ｍｇ）を得た。
エタノール（２０ｍＬ）中、化合物３７７（７００ｍｇ）に８％水酸化カリウム水溶液（５ｍＬ）を加え、室温で３時間，４５℃で１８時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加え溶解した。３５％塩酸で酸析し、分離した生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し粗製オイルを得た。粗製オイルをシリカゲルカラム（トルエン／酢酸エチル）で精製して化合物３７８（２６３ｍｇ，Ｙ＝５７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０−２．０８（１７Ｈ，ｍ）３．２４（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１５（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．２１−８．３２（８Ｈ，ｍ）９．３７（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３７８（１００ｍｇ）に０．０８％水酸化ナトリウム水溶液（２０ｍＬ）を加え溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物３７９（９２ｍｇ，Ｙ＝８４％）を得た。[5-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 377), [5-[[ 5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 378), [5-[[5- [5- (1 , 1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 379):
In DMF (12 mL), potassium carbonate (600 mg) and diethyl (5-bromopentyl) malonate (520 mg) were added to compound 367 (300 mg) and reacted at room temperature for 28 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 377 (700 mg).
An 8% aqueous potassium hydroxide solution (5 mL) was added to compound 377 (700 mg) in ethanol (20 mL) and reacted at room temperature for 3 hours and at 45 ° C. for 18 hours. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the residue to dissolve it. Acidified with 35% hydrochloric acid, and the separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified on a silica gel column (toluene / ethyl acetate) to give compound 378 (263 mg, Y = 57%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-2.08 (17H, m) 3.24 (1H, t, J = 7 Hz) 4.15 (2H, t, J = 5 Hz) 7.21-8.32 (8H, m) 9.37 (1H, d, J = 9Hz)
0.08% aqueous sodium hydroxide solution (20 mL) was added to and dissolved in compound 378 (100 mg), and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 379 (92 mg, Y = 84%).

５−（１，１−ジメチルエチル）−２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物３８０）の製造：
ＤＭＦ（１０ｍＬ）中、化合物３６７（２００ｍｇ）に炭酸カリウム（３５０ｍｇ），Ｎ−（２−クロロエチル）モルホリン塩酸塩（１４１ｍｇ）を加え、７０〜８０℃で１６時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られた残渣をアセトン（２０ｍＬ）に溶解し、３５％塩酸を加え、析出した結晶をろ取、乾燥して化合物３８０（２１２ｍｇ，Ｙ＝７２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０（９Ｈ，ｓ）３．１５−４．０２（１０Ｈ，ｍ）４．６９（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．３８−８．３５（８Ｈ，ｍ）９．４１（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．０６−１２．７６（１Ｈ，ｂｒ）Preparation of 5- (1,1-dimethylethyl) -2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride (Compound 380):
Potassium carbonate (350 mg) and N- (2-chloroethyl) morpholine hydrochloride (141 mg) were added to compound 367 (200 mg) in DMF (10 mL), and reacted at 70-80 ° C. for 16 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetone (20 mL), 35% hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 380 (212 mg, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40 (9H, s) 3.15-4.02 (10H, m) 4.69 (2H, t, J = 4 Hz) 7.38-8.35 (8H, m) 9.41 ( 1H, d, J = 9 Hz) 11.06-12.76 (1H, br)

３−［［５−［５−（１，１−ジメチルエチル）−２−ベンゾオキサゾリル］−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩（化合物３８１）の製造：
ＤＭＦ（１０ｍＬ）中、化合物３６７（２００ｍｇ）に炭酸カリウム（３５０ｍｇ），３−ジメチルアミノプロピルクロライド塩酸塩（１２０ｍｇ）を加え、７０〜８０℃で１６時間反応した。反応液を水（１５０ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られた残渣をアセトン（２０ｍＬ）に溶解後、３５％塩酸を加え酸性とした後、減圧濃縮、乾燥して化合物３８１（１７１ｍｇ，Ｙ＝６２％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝１．４２（９Ｈ，ｓ）２．０１−２．５４（２Ｈ，ｍ）２．９８（６Ｈ，ｓ）３．５６（２Ｈ，ｔ，Ｊ＝４Ｈｚ）４．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２９−８．２７（８Ｈ，ｍ）９．２５（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）3-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 381) Manufacturing:
In DMF (10 mL), potassium carbonate (350 mg) and 3-dimethylaminopropyl chloride hydrochloride (120 mg) were added to compound 367 (200 mg) and reacted at 70-80 ° C. for 16 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetone (20 mL), acidified with 35% hydrochloric acid, concentrated under reduced pressure and dried to give compound 381 (171 mg, Y = 62%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.42 (9H, s) 2.01-2.54 (2H, m) 2.98 (6H, s) 3.56 (2H, t, J = 4 Hz) 4.28 (2H, t, J = 6 Hz) 7.29-8.27 (8H, m) 9.25 (1H, d, J = 10 Hz)

５−フェニル−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール（化合物３８２）、５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物３８３）、４−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３８４）、４−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物３８５）、４−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸カリウム塩（化合物３８６）の製造：
トルエン（１２０ｍＬ）中、６−ベンジルオキシ−１−ナフトエ酸（１２．０ｇ）を塩化チオニル（６．２ｇ）と還流下で２．５時間反応した。反応液を減圧濃縮し、６−ベンジルオキシ−１−ナフトエ酸クロライド（１３．２ｇ）を得た。
６−ベンジルオキシ−１−ナフトエ酸クロライド（１３．２ｇ）を２−アミノ−４−フェニルフェノール（９．６ｇ），トリエチルアミン（５．３ｇ）の１，３−ジメチル−２−イミダゾリジノン（１００ｍＬ）溶液に加え、室温で３時間反応した。反応液を水（１．５Ｌ）に加え晶析し、析出結晶をろ取、水洗した。得られた結晶をメタノール（２００ｍＬ）と共に５０〜６０℃で撹拌懸濁した後、結晶をろ取、乾燥して中間体のアミド化合物（１６．６ｇ，Ｙ＝８６％）を得た。
アミド化合物（１５．０ｇ）とｐ−トルエンスルホン酸一水和物（１２．８ｇ）を１，３−ジメチル−２−イミダゾリジノン（１５０ｍＬ）、トルエン（４５０ｍＬ）の混合溶媒に加え、還流下で生成する水を除去しながら１７時間反応した。反応液を減圧濃縮し、残液を水洗してタール状物を得た。
得られたタール状物にメタノール（３００ｍＬ），水酸化カリウム（１０．０ｇ）を加え、室温で一夜撹拌した。結晶をろ取、乾燥して化合物３８２（４．２６ｇ，Ｙ＝３０％）を得た。
化合物３８２（４．００ｇ）にメタノール（３００ｍＬ）及び５％パラジウム炭素（１．０ｇ）を加え、水素雰囲気下４５℃で三日間反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣にメタノール（５０ｍＬ）を加え懸濁後、結晶をろ取した。得られた結晶にアセトン（２０ｍＬ）を加え、還流下で懸濁後、結晶をろ取、乾燥して化合物３８３（２．５７ｇ，Ｙ＝８１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．３１−８．４０（１３Ｈ，ｍ）９．３５（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）１０．０２（１Ｈ，ｓ）
ＤＭＦ（１２ｍＬ）中、化合物３８３（３００ｍｇ）に炭酸カリウム（６２７ｍｇ），４−ブロモ−ｎ−酪酸エチル（７３５ｍｇ）を加え、室温で２６時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。残渣にエタノール（２０ｍＬ）を加え撹拌懸濁後、結晶をろ取、乾燥して化合物３８４（２７７ｍｇ，Ｙ＝６９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．０６−２．７３（４Ｈ，ｍ）４．００−４．３５（４Ｈ，ｍ）７．２５−８．３５（１３Ｈ，ｍ）９．４３（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
エタノール（１０ｍＬ）中、化合物３８４（２５０ｍｇ）に１０％水酸化カリウム水溶液（２ｍＬ）を加え、４５℃で４時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加え加温溶解した後、３５％塩酸で酸析した。析出結晶をろ取、水洗後、乾燥して化合物３８５（１８６ｍｇ，Ｙ＝７９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．９５−２．６４（４Ｈ，ｍ）４．１９（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．３８−８．３６（１３Ｈ，ｍ）９．４０（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．４８−１２．７６（１Ｈ，ｂｒ）
化合物３８５（１００ｍｇ）に０．０４％水酸化カリウム水溶液（４０ｍＬ）を加え加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物３８６（１０５ｍｇ，Ｙ＝９６％）を得た。5-phenyl-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (Compound 382), 5- (5-phenyl-2-benzoxazolyl) -2-naphthalenol (Compound 383), 4- [[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 384), 4-[[5- (5-Phenyl-2-benzoxazolyl) Preparation of 2-naphthalenyl] oxy] butanoic acid (Compound 385), 4-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 386):
6-Benzyloxy-1-naphthoic acid (12.0 g) was reacted with thionyl chloride (6.2 g) under reflux in toluene (120 mL) for 2.5 hours. The reaction solution was concentrated under reduced pressure to obtain 6-benzyloxy-1-naphthoic acid chloride (13.2 g).
6-Benzyloxy-1-naphthoic acid chloride (13.2 g) was added to 1,3-dimethyl-2-imidazolidinone (100 mL) of 2-amino-4-phenylphenol (9.6 g) and triethylamine (5.3 g). ) Added to the solution and reacted at room temperature for 3 hours. The reaction solution was added to water (1.5 L) for crystallization, and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were suspended in methanol (200 mL) with stirring at 50 to 60 ° C., and the crystals were collected by filtration and dried to obtain an intermediate amide compound (16.6 g, Y = 86%).
The amide compound (15.0 g) and p-toluenesulfonic acid monohydrate (12.8 g) were added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL), and the mixture was refluxed. The reaction was carried out for 17 hours while removing the water produced in step (b). The reaction solution was concentrated under reduced pressure, and the remaining solution was washed with water to obtain a tar-like product.
Methanol (300 mL) and potassium hydroxide (10.0 g) were added to the obtained tar-like material, and the mixture was stirred overnight at room temperature. The crystals were collected by filtration and dried to obtain Compound 382 (4.26 g, Y = 30%).
Methanol (300 mL) and 5% palladium carbon (1.0 g) were added to compound 382 (4.00 g), and reacted at 45 ° C. for 3 days in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Methanol (50 mL) was added to the residue for suspension, and the crystals were collected by filtration. Acetone (20 mL) was added to the obtained crystals and suspended under reflux, and the crystals were collected by filtration and dried to obtain Compound 383 (2.57 g, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.31-8.40 (13H, m) 9.35 (1H, d, J = 10 Hz) 10.02 (1H, s)
In DMF (12 mL), potassium carbonate (627 mg) and ethyl 4-bromo-n-butyrate (735 mg) were added to compound 383 (300 mg) and reacted at room temperature for 26 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. Ethanol (20 mL) was added to the residue and suspended by stirring, and the crystals were collected by filtration and dried to obtain Compound 384 (277 mg, Y = 69%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.06-2.73 (4H, m) 4.00-4.35 (4H, m) 7.25-8.35 (13H, m) 9.43 (1H, d, J = 9Hz)
A 10% aqueous potassium hydroxide solution (2 mL) was added to compound 384 (250 mg) in ethanol (10 mL) and reacted at 45 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was dissolved by heating. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 385 (186 mg, Y = 79%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.95-2.64 (4H, m) 4.19 (2H, t, J = 6 Hz) 7.38-8.36 (13H, m) 9.40 (1H, d, J = 9 Hz) 11.48-12.76 (1H, br)
0.04% aqueous potassium hydroxide solution (40 mL) was added to compound 385 (100 mg) and dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 386 (105 mg, Y = 96%).

６−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物３８７）、６−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物３８８）、６−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸カリウム塩（化合物３８９）の製造：
ＤＭＦ（１２ｍＬ）中、化合物３８３（３００ｍｇ）に炭酸カリウム（６３０ｍｇ），６−ブロモヘキサン酸エチル（３２５ｍｇ）を加え、室温で４８時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮した。得られた残渣をエタノール（１０ｍＬ）と共に撹拌懸濁後、結晶をろ取、乾燥して化合物３８７（３４３ｍｇ，Ｙ＝８０％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．４５−２．４７（８Ｈ，ｍ）３．９７−４．３３（４Ｈ，ｍ）７．２３−８．３５（１３Ｈ，ｍ）９．４２（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
エタノール（１０ｍＬ）中、化合物３８７（３２０ｍｇ）に１２％水酸化カリウム水溶液（２ｍＬ）を加え、４５℃で４時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加え加温溶解した後、３５％塩酸で酸析した。析出結晶をろ取、水洗後、乾燥して化合物３８８（２２８ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．６０−２．２８（８Ｈ，ｍ）４．１４（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３６−８．３５（１３Ｈ，ｍ）９．４０（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）１１．０６−１３．６１（１Ｈ，ｂｒ）
化合物３８８（１００ｍｇ）に０．０４％水酸化カリウム水溶液（５０ｍＬ）を加え加熱溶解した後、活性炭を加え熱時ろ過した。ろ液を凍結乾燥して化合物３８９（１００ｍｇ，Ｙ＝９２％）を得た。6-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 387), 6-[[5- (5-Phenyl-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid (Compound 388), 6-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 389) Manufacturing:
In DMF (12 mL), potassium carbonate (630 mg) and ethyl 6-bromohexanoate (325 mg) were added to compound 383 (300 mg) and reacted at room temperature for 48 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was stirred and suspended with ethanol (10 mL), and the crystals were collected by filtration and dried to obtain Compound 387 (343 mg, Y = 80%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7 Hz) 1.45-2.47 (8H, m) 3.97-4.33 (4H, m) 7.23-8.35 (13H, m) 9.42 (1H, d, J = 9Hz)
A 12% aqueous potassium hydroxide solution (2 mL) was added to compound 387 (320 mg) in ethanol (10 mL) and reacted at 45 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was dissolved by heating. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 388 (228 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.60-2.28 (8H, m) 4.14 (2H, t, J = 5 Hz) 7.36-8.35 (13H, m) 9.40 (1H, d, J = 10 Hz) 11.06-13.61 (1H, br)
0.04% aqueous potassium hydroxide solution (50 mL) was added to compound 388 (100 mg) and dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 389 (100 mg, Y = 92%).

［５−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物３９０）、［５−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物３９１）、［５−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物３９２）の製造：
ＤＭＦ（１２ｍＬ）中、化合物３８３（３００ｍｇ）に炭酸カリウム（６２３ｍｇ），（５−ブロモペンチル）マロン酸ジエチル（４５１ｍｇ）を加え、室温で２７時間反応した。反応液を水（１００ｍＬ）中に加え、分離した反応生成物を酢酸エチル（１００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮し化合物３９０（０．７６ｇ）を得た。
エタノール（２０ｍＬ）中、化合物３９０（０．７６ｇ）に２３％水酸化カリウム水溶液（５ｍＬ）を加え、４５℃で５時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加え加温溶解後、３５％塩酸で酸析し、分離した反応生成物を酢酸エチル（５０ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して得られたオイルをシリカゲルカラム（トルエン／酢酸エチル）で精製し、化合物３９１（１５５ｍｇ，Ｙ＝３４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４３−１．８３（８Ｈ，ｍ）３．２５（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１４（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．２１−８．３６（１３Ｈ，ｍ）９．４０（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）１２．６５（２Ｈ，ｂｒｓ）
化合物３９１（７０ｍｇ）に０．０６％水酸化ナトリウム水溶液（２０ｍＬ）を加えほぼ溶解した後、活性炭を加えろ過した。ろ液を凍結乾燥して化合物３９２（５８ｍｇ，Ｙ＝７６％）を得た。[5-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 390), [5-[[5- (5-phenyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 391), [5-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid disodium salt (compound 392):
In DMF (12 mL), potassium carbonate (623 mg) and (5-bromopentyl) diethyl malonate (451 mg) were added to compound 383 (300 mg), and reacted at room temperature for 27 hours. The reaction mixture was added to water (100 mL), and the separated reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 390 (0.76 g).
A 23% aqueous potassium hydroxide solution (5 mL) was added to compound 390 (0.76 g) in ethanol (20 mL) and reacted at 45 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was dissolved by heating. After acidifying with 35% hydrochloric acid, the separated reaction product was extracted with ethyl acetate (50 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The oil obtained was purified with a silica gel column (toluene / ethyl acetate) to obtain Compound 391 (155 mg, Y = 34%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.4-1.83 (8H, m) 3.25 (1H, t, J = 6 Hz) 4.14 (2H, t, J = 4 Hz) 7.21-8.36 (13H, m) 9.40 (1H, d, J = 10 Hz) 12.65 (2H, brs)
To the compound 391 (70 mg), 0.06% aqueous sodium hydroxide solution (20 mL) was added and dissolved substantially, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 392 (58 mg, Y = 76%).

２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］−５−フェニルベンゾオキサゾール塩酸塩（化合物３９３）の製造：
ＤＭＦ（１０ｍＬ）中、化合物３８３（３００ｍｇ）に炭酸カリウム（４９６ｍｇ），（２−クロロエチル）モルホリン塩酸塩（２０７ｍｇ）を加え、７０〜８０℃で１９時間撹拌した。反応液を水（１００ｍＬ）中に入れ晶析し、析出結晶をろ取、水洗した後、得られた結晶をアセトン（２０ｍＬ）に溶解後、３５％塩酸を加え酸性とした。析出した結晶をろ取、乾燥して化合物３９３（３３９ｍｇ，Ｙ＝７８．３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．０９−４．１６（１０Ｈ，ｍ）４．６７（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．４３−８．４０（１３Ｈ，ｍ）９．４４（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．０６−１２．５５（１Ｈ，ｂｒ）Preparation of 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -5-phenylbenzoxazole hydrochloride (Compound 393):
In DMF (10 mL), potassium carbonate (496 mg) and (2-chloroethyl) morpholine hydrochloride (207 mg) were added to compound 383 (300 mg), and the mixture was stirred at 70 to 80 ° C. for 19 hours. The reaction solution was crystallized in water (100 mL), and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were dissolved in acetone (20 mL) and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 393 (339 mg, Y = 78.3%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.09-4.16 (10H, m) 4.67 (2H, t, J = 4 Hz) 7.43-8.40 (13H, m) 9.44 (1H, d, J = 9 Hz) 11.06-12.55 (1H, br)

Ｎ，Ｎ−ジメチル−３−［［５−（５−フェニル−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩（化合物３９４）の製造：
ＤＭＦ（１０ｍＬ）中、化合物３８３（３００ｍｇ）に炭酸カリウム（４９３ｍｇ），３−ジメチルアミノプロピルクロリド塩酸塩（１７１ｍｇ）を加え、７０〜８０℃で１９時間反応した。反応液を水（１００ｍＬ）中に加え、反応生成物を酢酸エチル（３００ｍＬ）で抽出した。有機層を水洗し、硫酸マグネシウムで脱水後、減圧濃縮して得られた残渣をアセトン（２０ｍＬ）に溶解し、３５％塩酸を加え酸性とした。析出した結晶をろ取、乾燥して化合物３９４（２２５ｍｇ，Ｙ＝５５％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝２．１５−２．４８（２Ｈ，ｍ）２．９５（６Ｈ，ｓ）３．４１（２Ｈ，ｔ，Ｊ＝７Ｈｚ）４．２２（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２５−８．３０（１３Ｈ，ｍ）９．２７（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）Preparation of N, N-dimethyl-3-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 394):
In DMF (10 mL), potassium carbonate (493 mg) and 3-dimethylaminopropyl chloride hydrochloride (171 mg) were added to compound 383 (300 mg) and reacted at 70-80 ° C. for 19 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (300 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The residue obtained was dissolved in acetone (20 mL) and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 394 (225 mg, Y = 55%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 2.15−2.48 (2H, m) 2.95 (6H, s) 3.41 (2H, t, J = 7 Hz) 4.22 (2H, t, J = 6 Hz) 7.25− 8.30 (13H, m) 9.27 (1H, d, J = 10 Hz)

５−クロロ−２−［６−（フェニルメトキシ）−１−ナフタレニル］ベンゾオキサゾール（化合物３９５）、５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレノール（化合物３９６）、４−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物３９７）、４−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸（化合物３９８）、４−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物３９９）の製造：
６−ベンジルオキシ−１−ナフトエ酸（７．５ｇ）にトルエン（７５ｍＬ）、塩化チオニル（２．３６ｍＬ）、ＤＭＦ（１滴）を加え、還流下で２時間反応した後、２−アミノ−４−クロロフェノール（９．８ｇ）の１，４−ジオキサン（１５０ｍＬ）溶液を加えて還流下で３時間反応した。反応液を減圧濃縮し、残渣に２％塩酸水溶液（５００ｍＬ）を加えて懸濁後、結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して中間体のアミド化合物（９．７ｇ，Ｙ＝８９％）を得た。
１，３−ジメチル−２−イミダゾリジノン（５０ｍＬ）にアミド化合物（９．７ｇ）を溶解し、ｐ−トルエンスルホン酸一水和物（７．０ｇ）及びトルエン（１００ｍＬ）を加えて還流下で生成する水を除去しながら一夜反応した。反応液を減圧濃縮し、残液に水（２５０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物３９５（６．４６ｇ，Ｙ＝７０％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝５．２３（２Ｈ，ｓ）７．２５−８．３５（１３Ｈ，ｍ）９．３８（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３９５（６．４ｇ）に３０％臭化水素・酢酸溶液（７０ｍＬ）を加え、約１００℃で２時間反応した。反応液に水（４３０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後、トルエンから再結晶して化合物３９６（３．５７ｇ，Ｙ＝７３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．２９−８．２７（８Ｈ，ｍ）９．２６（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）１０．０２（１Ｈ，ｓ）
化合物３９６（３７０ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（１．８ｇ）、４−ブロモ−ｎ−酪酸エチル（３１５ｍｇ）を加え、室温で一夜反応した。反応液に水（４５ｍＬ）を加えて晶析し、析出結晶をろ取、乾燥して化合物３９７（４８６ｍｇ，Ｙ＝９５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（３Ｈ，ｔ，Ｊ＝７Ｈｚ）２．０５−２．６９（４Ｈ，ｍ）４．００−４．３５（４Ｈ，ｍ）７．２４−８．３２（８Ｈ，ｍ）９．３５（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物３９７（４５０ｍｇ）にメタノール（５０ｍＬ）、０．４％水酸化ナトリウム水溶液（２．２ｍＬ）を加えて約５０℃で４時間反応した。反応液を減圧濃縮し、残渣を水（５０ｍＬ）に加熱溶解した後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物３９８（３８３ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．９１−２．６３（４Ｈ，ｍ）４．１８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．３２−８．３３（８Ｈ，ｍ）９．３１（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１２．２（１Ｈ，ｂｒ）
化合物３９８（７８．８ｍｇ）を水（４０ｍＬ）に懸濁し、０．４％水酸化ナトリウム水溶液（２．２ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物３９９（７５ｍｇ，Ｙ＝９０％）を得た。5-chloro-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (compound 395), 5- (5-chloro-2-benzoxazolyl) -2-naphthalenol (compound 396), 4- [[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 397), 4-[[5- (5-Chloro-2-benzoxazolyl) Preparation of 2-Naphthalenyl] oxy] butanoic acid (Compound 398), 4-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 399):
Toluene (75 mL), thionyl chloride (2.36 mL), and DMF (1 drop) were added to 6-benzyloxy-1-naphthoic acid (7.5 g), reacted for 2 hours under reflux, and then 2-amino-4 -A solution of chlorophenol (9.8 g) in 1,4-dioxane (150 mL) was added and reacted under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, 2% aqueous hydrochloric acid (500 mL) was added to the residue to suspend it, and the crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain an intermediate amide compound (9.7 g, Y = 89%).
An amide compound (9.7 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), p-toluenesulfonic acid monohydrate (7.0 g) and toluene (100 mL) are added, and the mixture is refluxed. The reaction was carried out overnight while removing the water produced in step 1. The reaction solution was concentrated under reduced pressure, and water (250 mL) was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 395 (6.46 g, Y = 70%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.23 (2H, s) 7.25-8.35 (13 H, m) 9.38 (1 H, d, J = 9 Hz)
30% hydrogen bromide / acetic acid solution (70 mL) was added to compound 395 (6.4 g), and the mixture was reacted at about 100 ° C. for 2 hours. Water (430 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and recrystallized from toluene to obtain Compound 396 (3.57 g, Y = 73%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.29-8.27 (8H, m) 9.26 (1H, d, J = 10 Hz) 10.02 (1H, s)
Compound 396 (370 mg) was dissolved in DMF (5 mL), potassium carbonate (1.8 g) and ethyl 4-bromo-n-butyrate (315 mg) were added, and the mixture was reacted at room temperature overnight. Water (45 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and dried to obtain Compound 397 (486 mg, Y = 95%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.05-2.69 (4H, m) 4.00-4.35 (4H, m) 7.24-8.32 (8H, m) 9.35 (1H, d, J = 9Hz)
Methanol (50 mL) and 0.4% aqueous sodium hydroxide solution (2.2 mL) were added to compound 397 (450 mg) and reacted at about 50 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) with heating, and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 398 (383 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.9-12.63 (4H, m) 4.18 (2H, t, J = 6 Hz) 7.32-8.33 (8H, m) 9.31 (1H, d, J = 9 Hz) 12.2 (1H, br)
Compound 398 (78.8 mg) was suspended in water (40 mL), 0.4% aqueous sodium hydroxide solution (2.2 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 399 (75 mg, Y = 90%).

６−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物４００）、６−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸（化合物４０１）、６−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物４０２）の製造：
化合物３９６（３６０ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（１．８ｇ）、６−ブロモヘキサン酸エチル（３４０ｍｇ）を加え、室温で一夜反応した。反応液に水（４５ｍＬ）を加えて晶析し、析出結晶をろ取、乾燥して化合物４００（４６０ｍｇ，Ｙ＝８６％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．５５−２．０１（６Ｈ，ｍ）２．３７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９７−４．３３（４Ｈ，ｍ）７．１８−８．３４（８Ｈ，ｍ）９．３５（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物４００（４２０ｍｇ）にメタノール（５０ｍＬ）、４％水酸化ナトリウム水溶液（５ｍＬ）を加えて約５０℃で４時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４０１（３５２ｍｇ，Ｙ＝７１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．４０−２．００（６Ｈ，ｍ）２．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１３（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２９−８．３２（８Ｈ，ｍ）９．２９（１Ｈ，ｔ，Ｊ＝９Ｈｚ）１２．０４（１Ｈ，ｂｒ）
化合物４０１（８７ｍｇ）を水（４０ｍＬ）に懸濁し、０．４％水酸化ナトリウム水溶液（２．２ｍＬ）を加えて加熱溶解後、ろ過した。ろ液を凍結乾燥して化合物４０２（８０ｍｇ，Ｙ＝８７％）を得た。6-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 400), 6-[[5- (5-Chloro-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid (Compound 401), 6-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 402) Manufacturing:
Compound 396 (360 mg) was dissolved in DMF (5 mL), potassium carbonate (1.8 g) and ethyl 6-bromohexanoate (340 mg) were added, and the mixture was reacted overnight at room temperature. Water (45 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and dried to obtain Compound 400 (460 mg, Y = 86%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7 Hz) 1.55-2.01 (6H, m) 2.37 (2H, t, J = 6 Hz) 3.97-4.33 (4H, m) 7.18-8.34 (8H, m) 9.35 (1H, d, J = 9 Hz)
Methanol (50 mL) and 4% aqueous sodium hydroxide solution (5 mL) were added to compound 400 (420 mg) and reacted at about 50 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 401 (352 mg, Y = 71%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-2.00 (6H, m) 2.28 (2H, t, J = 6 Hz) 4.13 (2H, t, J = 6 Hz) 7.29-8.32 (8H, m) 9.29 (1H, t, J = 9 Hz) 12.04 (1H, br)
Compound 401 (87 mg) was suspended in water (40 mL), 0.4% aqueous sodium hydroxide solution (2.2 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 402 (80 mg, Y = 87%).

［３−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物４０３）、［３−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物４０４）の製造：
化合物３９６（２５０ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（１．２ｇ）、（３−クロロプロピル）マロン酸ジエチル（２６０ｍｇ）を加えて約６５℃で一夜反応した。反応液に水（４５ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をシリカゲルカラム（クロロホルム）で精製して化合物４０３（２１０ｍｇ，Ｙ＝５０％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２７（６Ｈ，ｔ，Ｊ＝７Ｈｚ）１．７９−２．２８（１Ｈ，ｍ）３．４７（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．０５−４．４０（６Ｈ，ｍ）７．１８−８．３５（８Ｈ，ｍ）９．３６（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物４０３（１９４ｍｇ）をメタノール（６０ｍＬ）に溶解後、７％水酸化ナトリウム水溶液（３ｍＬ）を加えて約６０℃で一夜反応した。析出した結晶をろ取、乾燥して化合物４０４（１６３ｍｇ，Ｙ＝８６．１％）を得た。[3-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 403), [3-[[5- (5-Chloro- Preparation of 2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (compound 404):
Compound 396 (250 mg) was dissolved in DMF (5 mL), and potassium carbonate (1.2 g) and diethyl (3-chloropropyl) malonate (260 mg) were added and reacted at about 65 ° C. overnight. Water (45 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were purified with a silica gel column (chloroform) to obtain Compound 403 (210 mg, Y = 50%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (6H, t, J = 7 Hz) 1.79-2.28 (1H, m) 3.47 (1H, t, J = 7 Hz) 4.05-4.40 (6H, m) 7.18-8.35 (8H, m) 9.36 (1H, d, J = 9Hz)
Compound 403 (194 mg) was dissolved in methanol (60 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. overnight. The precipitated crystals were collected by filtration and dried to obtain Compound 404 (163 mg, Y = 86.1%).

［５−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物４０５）、［５−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物４０６）の製造：
化合物３９６（３４０ｍｇ）をＤＭＦ（４ｍＬ）に溶解し、炭酸カリウム（１．８ｇ）、（５−ブロモペンチル）マロン酸ジエチル（４５０ｍｇ）を加え、室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物４０５（５００ｍｇ，Ｙ＝８３％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１５−２．２０（１４Ｈ，ｍ）３．３６（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．０３−４．４３（６Ｈ，ｍ）７．１８−８．３４（８Ｈ，ｍ）８．８５（１Ｈ，ｄ，Ｊ＝９Ｈｚ）
化合物４０５（４７０ｍｇ）にメタノール（５０ｍＬ）、５％水酸化ナトリウム水溶液（４ｍＬ）を加えて約５０℃で一夜反応した。冷却後、析出した結晶をろ取、乾燥して化合物４０６（３５２ｍｇ，Ｙ＝９１％）を得た。[5-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 405), [5-[[5- (5-chloro- Preparation of 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (compound 406):
Compound 396 (340 mg) was dissolved in DMF (4 mL), potassium carbonate (1.8 g) and (5-bromopentyl) diethyl malonate (450 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 405 (500 mg, Y = 83%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.5-2.20 (14H, m) 3.36 (1H, t, J = 7 Hz) 4.03-4.43 (6H, m) 7.18-8.34 (8H, m) 8.85 (1H, d, J = 9Hz)
Methanol (50 mL) and 5% aqueous sodium hydroxide solution (4 mL) were added to compound 405 (470 mg) and reacted at about 50 ° C. overnight. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 406 (352 mg, Y = 91%).

５−クロロ−２−［６−［２−（４−モルホリニル）エトキシ］−１−ナフタレニル］ベンゾオキサゾール塩酸塩（化合物４０７）の製造：
化合物３９６（２０３ｍｇ）にＤＭＦ（４ｍＬ）、炭酸カリウム（１．２ｇ）、Ｎ−（２−クロロエチル）モルホリン塩酸塩（２００ｍｇ）を加え、約６５℃で一夜反応した。反応液に水（２５ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶にアセトン（４０ｍＬ）を加えて溶解後、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物４０７（２３３ｍｇ，Ｙ＝７６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．１７−４．００（１０Ｈ，ｍ）４．６７（２Ｈ，ｔ，Ｊ＝４Ｈｚ）７．３９−８．７４（８Ｈ，ｍ）９．３４（１Ｈ，ｄ，Ｊ＝９Ｈｚ）１１．９０（１Ｈ，ｂｒ）Preparation of 5-chloro-2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride (Compound 407):
DMF (4 mL), potassium carbonate (1.2 g), and N- (2-chloroethyl) morpholine hydrochloride (200 mg) were added to compound 396 (203 mg), and reacted at about 65 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. Acetone (40 mL) was added and dissolved in the obtained crystals, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 407 (233 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.17-4.00 (10H, m) 4.67 (2H, t, J = 4 Hz) 7.39-8.74 (8H, m) 9.34 (1H, d, J = 9 Hz) 11.90 (1H, br)

３−［［５−（５−クロロ−２−ベンゾオキサゾリル）−２−ナフタレニル］オキシ］−Ｎ，Ｎ−ジメチル−１−プロパンアミン塩酸塩（化合物４０８）の製造：
化合物３９６（２１８ｍｇ）にＤＭＦ（４ｍＬ）、炭酸カリウム（１．２ｇ）、３−ジメチルアミノプロピルクロリド塩酸塩（１８５ｍｇ）を加えて約６５℃で一夜反応した。反応液に水（２５ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶にアセトン（５０ｍＬ）を加えて溶解し、３５％塩酸（０．３ｍＬ）を加え、析出した結晶をろ取、乾燥して化合物４０８（１４３ｍｇ，Ｙ＝４７％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４，Ｄ_２Ｏ／ＴＭＳ）：
δ＝２．１９−２．５７（２Ｈ，ｍ）３．０２（６Ｈ，ｓ）３．５０（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．２８（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．２１−８．２８（８Ｈ，ｍ）９．１９（１Ｈ，ｄ，Ｊ＝１０Ｈｚ）Preparation of 3-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 408):
DMF (4 mL), potassium carbonate (1.2 g), and 3-dimethylaminopropyl chloride hydrochloride (185 mg) were added to compound 396 (218 mg), and reacted at about 65 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. Acetone (50 mL) was added and dissolved in the obtained crystals, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 408 (143 mg, Y = 47%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 2.19-2.57 (2H, m) 3.02 (6H, s) 3.50 (2H, t, J = 6 Hz) 4.28 (2H, t, J = 6 Hz) 7.21- 8.28 (8H, m) 9.19 (1H, d, J = 10 Hz)

２−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］ペンタン二酸ジエチルエステル（化合物４０９）、２−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］ペンタン二酸（化合物４１０）、２−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］ペンタン二酸二ナトリウム塩（化合物４１１）の製造：
２，６−ナフタレンジカルボン酸モノメチルエステル（１０ｇ）にトルエン（６０ｍＬ）、塩化チオニル（６．２ｇ）、ＤＭＦ（１滴）を加えて４時間還流下で反応した後、２−アミノフェノール（９．６ｇ）の１，４−ジオキサン（１００ｍＬ）溶液を加え、室温で一夜、還流下で１時間反応した。冷却後、析出した結晶をろ取した。得られた結晶にメタノール・１Ｎ塩酸（１：１）溶液（４００ｍＬ）を加えて懸濁後、結晶をろ取、乾燥して中間体のアミド化合物（１１．２ｇ，Ｙ＝８０％）を得た。
アミド化合物（１１．１ｇ）に１，３−ジメチル−２−イミダゾリジノン（７０ｍＬ）、トルエン（１４０ｍＬ）、ｐ−トルエンスルホン酸一水和物（１０ｇ）を加え、還流下で生成する水を除去しながら一夜反応した。反応液を減圧濃縮し、残液に水を加えて晶析し、析出結晶をろ取した。得られた結晶をメタノールで洗浄後、トルエンから再結晶して６−（２−ベンゾオキサゾリル）−２−ナフタレンカルボン酸メチルエステル（９．７ｇ，Ｙ＝９３％）を得た。
６−（２−ベンゾオキサゾリル）−２−ナフタレンカルボン酸メチルエステル（９．６ｇ）にトルエン（３００ｍＬ）を加えて加熱溶解し、９％水酸化カリウム・メタノール溶液（２０ｍＬ）を加えて還流下で３時間反応した。冷却後、析出した結晶をろ取した。得られた結晶を３０％アセトン水溶液（１Ｌ）に加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して６−（２−ベンゾオキサゾリル）−２−ナフタレンカルボン酸（８．７８ｇ，Ｙ＝９６％）を得た。
６−（２−ベンゾオキサゾリル）−２−ナフタレンカルボン酸（０．８１ｇ）にトルエン（２０ｍＬ）、塩化チオニル（０．２６ｍＬ）、ＤＭＦ（１滴）を加えて還流下で３．５時間反応した後、Ｌ−グルタミン酸ジエチル塩酸塩（０．９ｇ）の１，３−ジメチル−２−イミダゾリジノン（３０ｍＬ）溶液、トリエチルアミン（１．３ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残液に２％塩酸水溶液（１００ｍＬ）を加え、析出した結晶をろ取した。得られた結晶をメタノールで洗浄後乾燥して化合物４０９（９５９ｍｇ，Ｙ＝６８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１１−１．４５（６Ｈ，ｍ）２．１４−２．６３（４Ｈ，ｍ）３．９６−４．４７（４Ｈ，ｍ）４．７０−５．０５（１Ｈ，ｍ）７．１６−８．７９（１０Ｈ，ｍ）
化合物４０９（８４５ｍｇ）をメタノール（２００ｍＬ）に溶解し、３％水酸化ナトリウム水溶液（１０ｍＬ）を加えて約４５℃で一夜反応した。反応液を減圧濃縮し、残渣に水（１００ｍＬ）を加え溶解した後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４１０（７０２ｍｇ，Ｙ＝９４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝２．００−２．４９（４Ｈ，ｍ）４．３５−４．７５（１Ｈ，ｍ）７．３９−８．９１（１１Ｈ，ｍ）１２．４５（２Ｈ，ｂｒ）
化合物４１０（１１１．４ｍｇ）に水（４０ｍＬ）、０．５％水酸化ナトリウム水溶液（４ｍＬ）を加えて溶解後、ろ過した。ろ液を凍結乾燥して化合物４１１（１２５．８ｍｇ，Ｙ＝１０３％）を得た。2-[[[6- (2-Benzoxazolyl) -2-naphthalenyl] carbonyl] amino] pentanedioic acid diethyl ester (Compound 409), 2-[[[6- (2-Benzoxazolyl)- 2-Naphthalenyl] carbonyl] amino] pentanedioic acid (Compound 410), 2-[[[6- (2-Benzoxazolyl) -2-naphthalenyl] carbonyl] amino] pentanedioic acid disodium salt (Compound 411) Manufacturing of:
Toluene (60 mL), thionyl chloride (6.2 g) and DMF (1 drop) were added to 2,6-naphthalenedicarboxylic acid monomethyl ester (10 g) and reacted under reflux for 4 hours, and then 2-aminophenol (9. 6 g) in 1,4-dioxane (100 mL) was added and reacted at room temperature overnight and under reflux for 1 hour. After cooling, the precipitated crystals were collected by filtration. A suspension of methanol and 1N hydrochloric acid (1: 1) (400 mL) was added to the obtained crystals, and the crystals were collected by filtration and dried to obtain an intermediate amide compound (11.2 g, Y = 80%). It was.
1,3-Dimethyl-2-imidazolidinone (70 mL), toluene (140 mL) and p-toluenesulfonic acid monohydrate (10 g) are added to the amide compound (11.1 g), and water generated under reflux is added. It reacted overnight while removing. The reaction solution was concentrated under reduced pressure, and water was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and recrystallized from toluene to obtain 6- (2-benzoxazolyl) -2-naphthalenecarboxylic acid methyl ester (9.7 g, Y = 93%).
Toluene (300 mL) is added to 6- (2-benzoxazolyl) -2-naphthalenecarboxylic acid methyl ester (9.6 g) and heated to dissolve, and 9% potassium hydroxide / methanol solution (20 mL) is added to reflux. Reacted for 3 hours under. After cooling, the precipitated crystals were collected by filtration. The obtained crystals were dissolved in a 30% aqueous acetone solution (1 L) by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain 6- (2-benzoxazolyl) -2-naphthalenecarboxylic acid (8.78 g, Y = 96%).
Toluene (20 mL), thionyl chloride (0.26 mL) and DMF (1 drop) were added to 6- (2-benzoxazolyl) -2-naphthalenecarboxylic acid (0.81 g) and refluxed for 3.5 hours. After the reaction, a solution of diethyl L-glutamate hydrochloride (0.9 g) in 1,3-dimethyl-2-imidazolidinone (30 mL) and triethylamine (1.3 mL) were added and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, a 2% aqueous hydrochloric acid solution (100 mL) was added to the remaining solution, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 409 (959 mg, Y = 68%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.1-1.45 (6H, m) 2.14-2.63 (4H, m) 3.96-4.47 (4H, m) 4.70-5.05 (1H, m) 7.16-8.79 (10H, m)
Compound 409 (845 mg) was dissolved in methanol (200 mL), 3% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted at about 45 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the residue for dissolution, and then dilute hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 410 (702 mg, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.00-2.49 (4H, m) 4.35-4.75 (1H, m) 7.39-8.91 (11H, m) 12.45 (2H, br)
Water (40 mL) and a 0.5% aqueous sodium hydroxide solution (4 mL) were added to compound 410 (111.4 mg) and dissolved, followed by filtration. The filtrate was lyophilized to give compound 411 (125.8 mg, Y = 103%).

２−アミノ−６−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］ヘキサン酸塩酸塩（化合物４１２）の製造：
トルエン（４０ｍＬ）中、６−（２−ベンゾオキサゾリル）−２−ナフタレンカルボン酸（１．０ｇ）を塩化チオニル（０．７ｇ）と還流下で３．５時間反応した。冷却後反応液にＮ^α（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−リジン（１．１ｇ）、トリエチルアミン（１．０ｇ）の１，３−ジメチル−２−イミダゾリジノン（２０ｍＬ）溶液を加え、水冷下１９時間反応した。反応液を減圧濃縮し、濃縮液を水（４００ｍＬ）に加え晶析した。析出結晶をろ取、水洗後、アセトン（２０ｍＬ）と共に撹拌懸濁し、ろ過して粗製結晶（１．３３ｇ）を得た。粗製結晶（１．３３ｇ）をシリカゲルカラム（トルエン／酢酸エチル）で精製し、６−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ヘキサン酸（３８４ｍｇ，Ｙ＝２１％）を得た。
６−［［［６−（２−ベンゾオキサゾリル）−２−ナフタレニル］カルボニル］アミノ］−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ヘキサン酸（２００ｍｇ）に飽和塩酸・酢酸溶液（５ｍＬ）を加え、氷水冷下２時間反応した。反応液をジエチルエーテル（５０ｍＬ）中に加え晶析した。析出結晶をろ取、乾燥して化合物４１２（１４７ｍｇ，Ｙ＝８４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．３７−２．０６（６Ｈ，ｍ）３．１６−３．６３（２Ｈ，ｍ）３．９２（１Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３９−８．８９（１２Ｈ，ｍ）Preparation of 2-amino-6-[[[6- (2-benzoxazolyl) -2-naphthalenyl] carbonyl] amino] hexanoic acid hydrochloride (Compound 412):
6- (2-Benzoxazolyl) -2-naphthalenecarboxylic acid (1.0 g) was reacted with thionyl chloride (0.7 g) in toluene (40 mL) for 3.5 hours under reflux. After cooling, a solution of N ^α (tert-butoxycarbonyl) -L-lysine (1.1 g) and triethylamine (1.0 g) in 1,3-dimethyl-2-imidazolidinone (20 mL) was added to the reaction mixture, and the mixture was cooled with water. It reacted for 19 hours. The reaction solution was concentrated under reduced pressure, and the concentrated solution was added to water (400 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, suspended with stirring with acetone (20 mL), and filtered to obtain crude crystals (1.33 g). The crude crystals (1.33 g) were purified on a silica gel column (toluene / ethyl acetate) to give 6-[[[6- (2-benzoxazolyl) -2-naphthalenyl] carbonyl] amino] -2-[(tert -Butoxycarbonyl) amino] hexanoic acid (384 mg, Y = 21%) was obtained.
6-[[[6- (2-Benzoxazolyl) -2-naphthalenyl] carbonyl] amino] -2-[(tert-butoxycarbonyl) amino] hexanoic acid (200 mg) in saturated hydrochloric acid / acetic acid solution (5 mL) And reacted for 2 hours under cooling with ice water. The reaction solution was added to diethyl ether (50 mL) for crystallization. Precipitated crystals were collected by filtration and dried to obtain Compound 412 (147 mg, Y = 84%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.37-2.06 (6H, m) 3.16-3.63 (2H, m) 3.92 (1H, t, J = 5 Hz) 7.39-8.89 (12H, m)

２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール（化合物４１３）、２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４１４）、２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４１５）、２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸ナトリウム塩（化合物４１６）の製造：
窒素気流中、氷水冷却下でトルエン（１２０ｍＬ）に１５％トリメチルアルミニウム・トルエン溶液（１１ｍＬ）、ｏ−フェニレンジアミン（２．２ｇ）を加えて還流下で３０分間反応した後、ｏ−ベンジルオキシ安息香酸エチル（３．０ｇ）のトルエン（２０ｍＬ）溶液を加えて還流下で６時間反応した。反応液に７３％メタノール水溶液（５５ｍＬ）を加えて３０分間還流した後、メタノール（３００ｍＬ）を加えて熱時ろ過した。ろ液を減圧濃縮し、残渣を酢酸エチルから再結晶して化合物４１３（２．２ｇ，Ｙ＝６３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２１（２Ｈ，ｓ）７．０９−８．２０（１３Ｈ，ｍ）１２．７５（１Ｈ，ｂｒ）
化合物４１３（７６０ｍｇ）をＤＭＦ（３０ｍＬ）に溶解し、炭酸カリウム（１．０ｇ）、ブロモ酢酸メチル（０．５０ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をトルエン（１５０ｍＬ）に溶解して飽和炭酸水素ナトリウム、水、飽和食塩水で順次洗浄した。トルエン層を硫酸マグネシウムで脱水し、減圧濃縮、乾燥して化合物４１４（８９０ｍｇ，Ｙ＝９４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．６７（３Ｈ，ｓ）５．２１（４Ｈ，ｓ）７．１１−７．７３（１３Ｈ，ｍ）
化合物４１４（１９０ｍｇ）をメタノール（２５ｍＬ）に溶解し、４％水酸化ナトリウム水溶液（２ｍＬ）を加えて室温で１時間反応した。反応液を減圧濃縮し、残渣に水（２５ｍＬ）を加えて加熱溶解した後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４１５（１６５ｍｇ，Ｙ＝９０％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．０７（２Ｈ，ｓ）５．２１（２Ｈ，ｓ）７．１２−７．７６（１３Ｈ，ｍ）
化合物４１５（８２ｍｇ）をメタノール（５０ｍＬ）に懸濁し、０．８１％水酸化ナトリウム水溶液（１．２ｍＬ）を加えて溶解後、減圧濃縮し乾燥して化合物４１６（７４ｍｇ，Ｙ＝８５％）を得た。2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole (compound 413), 2- [4- (phenylmethoxy) phenyl] -1H-benzimidazol-1-acetic acid methyl ester (compound 414), 2- [4- (Phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid (Compound 415), 2- [4- (Phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid sodium salt (Compound 416) Manufacturing:
In a nitrogen stream, 15% trimethylaluminum / toluene solution (11 mL) and o-phenylenediamine (2.2 g) were added to toluene (120 mL) under cooling with ice water and reacted under reflux for 30 minutes, and then o-benzyloxybenzoate. A solution of ethyl acid (3.0 g) in toluene (20 mL) was added and reacted under reflux for 6 hours. A 73% aqueous methanol solution (55 mL) was added to the reaction mixture, and the mixture was refluxed for 30 minutes. Methanol (300 mL) was added, followed by hot filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain Compound 413 (2.2 g, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.21 (2H, s) 7.09-8.20 (13H, m) 12.75 (1H, br)
Compound 413 (760 mg) was dissolved in DMF (30 mL), potassium carbonate (1.0 g) and methyl bromoacetate (0.50 g) were added, and the mixture was reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (150 mL) and washed successively with saturated sodium bicarbonate, water, and saturated brine. The toluene layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 414 (890 mg, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.67 (3H, s) 5.21 (4H, s) 7.11-7.73 (13H, m)
Compound 414 (190 mg) was dissolved in methanol (25 mL), 4% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and water (25 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 415 (165 mg, Y = 90%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.07 (2H, s) 5.21 (2H, s) 7.12-7.76 (13H, m)
Compound 415 (82 mg) was suspended in methanol (50 mL), dissolved by adding 0.81% aqueous sodium hydroxide solution (1.2 mL), concentrated under reduced pressure and dried to give compound 416 (74 mg, Y = 85%). Obtained.

２−（４−ヒドロキシフェニル）−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４１７）、２−（４−ヒドロキシフェニル）−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４１８）の製造：
化合物４１４（５２０ｍｇ）をメタノール（１００ｍＬ）に溶解し、５％パラジウム炭素（０．５ｇ）を加え水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物４１７（２１５ｍｇ，Ｙ＝５５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．６８（３Ｈ，ｓ）５．１７（２Ｈ，ｓ）６．８５−７．６１（８Ｈ，ｍ）
化合物４１７（１０５ｍｇ）をメタノール（１００ｍＬ）に溶解し、５％水酸化ナトリウム水溶液（３ｍＬ）を加え約４０℃で１．５時間反応した。反応液を減圧濃縮し、残渣に水（３０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４１８（８５ｍｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．０４（２Ｈ，ｓ）６．８６−７．７５（８Ｈ，ｍ）Production of 2- (4-hydroxyphenyl) -1H-benzimidazol-1-acetic acid methyl ester (Compound 417), 2- (4-hydroxyphenyl) -1H-benzimidazol-1-acetic acid (Compound 418):
Compound 414 (520 mg) was dissolved in methanol (100 mL), 5% palladium carbon (0.5 g) was added, and the mixture was reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 417 (215 mg, Y = 55%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.68 (3H, s) 5.17 (2H, s) 6.85-7.61 (8H, m)
Compound 417 (105 mg) was dissolved in methanol (100 mL), 5% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 40 ° C. for 1.5 hr. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 418 (85 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.04 (2H, s) 6.86-7.75 (8H, m)

２−［４−（２−メトキシ−２−オキソエトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４１９）、２−［４−（カルボキシメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４２０）、２−［４−（カルボキシメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸二ナトリウム塩（化合物４２１）
氷酢酸（１００ｍＬ）中、ｐ−ヒドロキシベンズアルデヒド（６．１ｇ）とニトロメタン（７．６ｇ）をｎ−ブチルアミン（５ｍＬ）の存在下に還流下で４．５時間反応した。反応液を氷水（１Ｌ）中に滴下し、析出した結晶をろ取した。得られた結晶をトルエンから再結晶して中間体の４−ヒドロキシ−β−ニトロスチレン（４．４ｇ，Ｙ＝５３％）を得た。
エタノール（２４ｍＬ）中、中間体（２．０ｇ）とｏ−フェニレンジアミン（１．３１ｇ）を還流下で４．５時間反応した。反応液を減圧濃縮し、残渣にトルエン（１５０ｍＬ）を加えて還流下で懸濁した後、ろ過して粗製結晶（１．５ｇ）を得た。粗製結晶（１．５ｇ）をトルエン、エタノールの混液から再結晶して４−（１Ｈ−ベンゾイミダゾール−２−イル）フェノール（８８０ｍｇ，Ｙ＝３５％）を得た。
４−（１Ｈ−ベンゾイミダゾール−２−イル）フェノール（２００ｍｇ）をＤＭＦ（５０ｍＬ）に溶解し、炭酸カリウム（１．５ｇ）、ブロモ酢酸メチル（５５０ｍｇ）を加えて室温で２日間反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣からシリカゲルカラム（クロロホルム）で化合物４１９（６８０ｍｇ，Ｙ＝５８％）を分取した。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．６８（３Ｈ，ｓ）３．７３（３Ｈ，ｓ）４．９１（２Ｈ，ｓ）５．２０（２Ｈ，ｓ）７．０３−７．７３（８Ｈ，ｍ）
化合物４１９（４００ｍｇ）をメタノール（３０ｍＬ）に溶解し、３％水酸化ナトリウム水溶液（６ｍＬ）を加えて室温で２０分間反応した。反応液を減圧濃縮し、残渣に水（４０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４２０（３７０ｍｇ，Ｙ＝１０１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．７９（２Ｈ，ｓ）５．０７（２Ｈ，ｓ）７．０２−７．７５（８Ｈ，ｍ）
化合物４２０（１２４ｍｇ）を水（４０ｍＬ）に懸濁し、１％水酸化ナトリウム水溶液（３ｍＬ）を加えて溶解後、ろ過した。ろ液を凍結乾燥して化合物４２１（１４８ｍｇ，Ｙ＝１０５％）を得た。2- [4- (2-methoxy-2-oxoethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester (Compound 419), 2- [4- (carboxymethoxy) phenyl] -1H-benzimidazole- 1-acetic acid (compound 420), 2- [4- (carboxymethoxy) phenyl] -1H-benzimidazole-1-acetic acid disodium salt (compound 421)
In glacial acetic acid (100 mL), p-hydroxybenzaldehyde (6.1 g) and nitromethane (7.6 g) were reacted under reflux in the presence of n-butylamine (5 mL) for 4.5 hours. The reaction solution was dropped into ice water (1 L), and the precipitated crystals were collected by filtration. The obtained crystal was recrystallized from toluene to obtain an intermediate 4-hydroxy-β-nitrostyrene (4.4 g, Y = 53%).
The intermediate (2.0 g) and o-phenylenediamine (1.31 g) were reacted in ethanol (24 mL) for 4.5 hours under reflux. The reaction solution was concentrated under reduced pressure, toluene (150 mL) was added to the residue and suspended under reflux, followed by filtration to obtain crude crystals (1.5 g). Crude crystals (1.5 g) were recrystallized from a mixture of toluene and ethanol to give 4- (1H-benzoimidazol-2-yl) phenol (880 mg, Y = 35%).
4- (1H-benzoimidazol-2-yl) phenol (200 mg) was dissolved in DMF (50 mL), potassium carbonate (1.5 g) and methyl bromoacetate (550 mg) were added, and the mixture was reacted at room temperature for 2 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Compound 419 (680 mg, Y = 58%) was fractionated from the residue using a silica gel column (chloroform).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.68 (3H, s) 3.73 (3H, s) 4.91 (2H, s) 5.20 (2H, s) 7.03-7.73 (8H, m)
Compound 419 (400 mg) was dissolved in methanol (30 mL), 3% aqueous sodium hydroxide solution (6 mL) was added, and the mixture was reacted at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and water (40 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 420 (370 mg, Y = 101%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.79 (2H, s) 5.07 (2H, s) 7.02-7.75 (8H, m)
Compound 420 (124 mg) was suspended in water (40 mL), dissolved by adding a 1% aqueous sodium hydroxide solution (3 mL), and then filtered. The filtrate was lyophilized to give compound 421 (148 mg, Y = 105%).

５−クロロ−２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール（化合物４２２）、５−クロロ−２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４２３）、５−クロロ−２−［４−（フェニルメトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４２４）の製造：
氷酢酸（２００ｍＬ）中、４−ベンジルオキシベンズアルデヒド（２４ｇ）とニトロメタン（１４．５ｇ）をｎ−ブチルアミン（１１．５ｍＬ）の存在下に還流下で１０時間反応した。反応液を氷水（２Ｌ）中に滴下し、析出した結晶をろ取した。得られた結晶をメタノールから再結晶して中間体の４−ベンジルオキシ−β−ニトロスチレン（１６．６ｇ，Ｙ＝５８％）を得た。
中間体（５ｇ）に、４−クロロ−１，２−フェニレンジアミン（２．８ｇ）、エタノール（７５ｍＬ）を加えて２日間還流下で反応した。反応液を減圧濃縮し、残渣をシリカゲルカラム（クロロホルム）で精製して化合物４２２（２．６７ｇ，Ｙ＝４１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２２（２Ｈ，ｓ）７．１３−８．２０（１２Ｈ，ｍ）１２．９５（１Ｈ，ｂｒ）
化合物４２２（１．２ｇ）をＤＭＦ（３０ｍＬ）に溶解し、炭酸カリウム（１ｇ）、ブロモ酢酸メチル（０．７ｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣を酢酸エチル（１５０ｍＬ）に溶解し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水後、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物４２３（６２０ｍｇ，Ｙ＝４３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．６７（３Ｈ，ｓ）５．２１（４Ｈ，ｓ）７．１１−７．７７（１２Ｈ，ｍ）
化合物４２３（１００ｍｇ）をメタノール（３０ｍＬ）に溶解し２％水酸化ナトリウム水溶液（１ｍＬ）を加えて約５０℃で３０分間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４２４（９０ｍｇ，Ｙ＝４３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．１０（２Ｈ，ｓ）５．２０（２Ｈ，ｓ）７．１２−７．７５（１２Ｈ，ｍ）5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole (Compound 422), methyl 5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetate Preparation of ester (compound 423), 5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazol-1-acetic acid (compound 424):
In glacial acetic acid (200 mL), 4-benzyloxybenzaldehyde (24 g) and nitromethane (14.5 g) were reacted under reflux in the presence of n-butylamine (11.5 mL) for 10 hours. The reaction solution was dropped into ice water (2 L), and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from methanol to obtain the intermediate 4-benzyloxy-β-nitrostyrene (16.6 g, Y = 58%).
4-Chloro-1,2-phenylenediamine (2.8 g) and ethanol (75 mL) were added to the intermediate (5 g) and reacted under reflux for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain Compound 422 (2.67 g, Y = 41%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.22 (2H, s) 7.13-8.20 (12H, m) 12.95 (1H, br)
Compound 422 (1.2 g) was dissolved in DMF (30 mL), and potassium carbonate (1 g) and methyl bromoacetate (0.7 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 423 (620 mg, Y = 43%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.67 (3H, s) 5.21 (4H, s) 7.11-7.77 (12H, m)
Compound 423 (100 mg) was dissolved in methanol (30 mL), 2% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at about 50 ° C. for 30 min. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 424 (90 mg, Y = 43%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.10 (2H, s) 5.20 (2H, s) 7.12-7.75 (12H, m)

５−クロロ−２−（４−ヒドロキシフェニル）−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４２５）、５−クロロ−２−（４−ヒドロキシフェニル）−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４２６）の製造：
化合物４２３（４４０ｍｇ）に飽和塩酸・酢酸溶液（１０ｍＬ）を加えて約１００℃で８時間反応した。反応液を減圧濃縮後、水（５０ｍＬ）を加えて晶析し、析出結晶をろ取した。得られた結晶をシリカゲルカラム（クロロホルム／メタノール）で精製して化合物４２５（１７５ｍｇ，Ｙ＝５１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．６８（３Ｈ，ｓ）５．１９（２Ｈ，ｓ）６．８５−７．７４（７Ｈ，ｍ）
化合物４２５（１００ｍｇ）をメタノール（４０ｍＬ）に溶解し５．２％水酸化ナトリウム水溶液（２ｍＬ）を加えて約５０℃で１．５時間反応した。反応液を減圧濃縮し、残渣に水（３０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４２６（８４ｍｇ，Ｙ＝８８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．０７（２Ｈ，ｓ）６．８６−７．７３（７Ｈ，ｍ）１０．０（１Ｈ，ｂｒ）5-chloro-2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid methyl ester (compound 425), 5-chloro-2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid ( Preparation of compound 426):
Saturated hydrochloric acid / acetic acid solution (10 mL) was added to compound 423 (440 mg) and reacted at about 100 ° C. for 8 hours. After the reaction liquid was concentrated under reduced pressure, water (50 mL) was added for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were purified by silica gel column (chloroform / methanol) to obtain compound 425 (175 mg, Y = 51%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.68 (3H, s) 5.19 (2H, s) 6.85-7.74 (7H, m)
Compound 425 (100 mg) was dissolved in methanol (40 mL), 5.2% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at about 50 ° C. for 1.5 hr. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 426 (84 mg, Y = 88%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.07 (2H, s) 6.86-7.73 (7H, m) 10.0 (1H, br)

［４−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル）フェノキシ］酢酸メチルエステル（化合物４２７）、［４−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル）フェノキシ］酢酸（化合物４２８）、［４−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル）フェノキシ］酢酸ナトリウム塩（化合物４２９）、５−クロロ−２−［４−（２−メトキシ−２−オキソエトキシ）フェニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４３０）、２−［４−（カルボキシメトキシ）フェニル］−５−クロロ−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４３１）、２−［４−（カルボキシメトキシ）フェニル］−５−クロロ−１Ｈ−ベンゾイミダゾール−１−酢酸二ナトリウム塩（化合物４３２）の製造：
化合物４２２（６００ｍｇ）に飽和塩酸・酢酸溶液（１０ｍＬ）を加えて約１００℃で８時間反応した。冷却後、析出した結晶をろ取した。得られた結晶をトルエン、メタノールの混液から再結晶して４−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル）フェノール（３４６ｍｇ，Ｙ＝７９％）を得た。
４−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル）フェノール（２９０ｍｇ）をＤＭＦ（９ｍＬ）に溶解し、炭酸カリウム（５００ｍｇ）、ブロモ酢酸メチル（２８０ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣からシリカゲルカラム（クロロホルム／メタノール）で化合物４２７（５０ｍｇ，Ｙ＝１３％）、化合物４３０（２６０ｍｇ，Ｙ＝５６％）を分取した。
化合物４２７（５０ｍｇ）をメタノール（４０ｍＬ）に溶解し、３％水酸化ナトリウム水溶液（１ｍＬ）を加えて約５０℃で１時間反応した。反応液を減圧濃縮し、残渣に水（２０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４２８（４７．８ｍｇ，Ｙ＝１００％）を得た。
化合物４２８（４８ｍｇ）をメタノール（４０ｍＬ）に溶解し、０．６３％水酸化ナトリウム水溶液（１ｍＬ）を加えた後、減圧濃縮し乾燥して化合物４２９（４６ｍｇ，Ｙ＝９０％）を得た。
^１Ｈ−ＮＭＲ（Ｍｅｔｈａｎｏｌ−ｄ４／ＴＭＳ）：
δ＝４．４８（２Ｈ，ｓ）７．０２−８．０９（７Ｈ，ｍ）
化合物４３０（１９５ｍｇ）をメタノール（５０ｍＬ）に溶解し５％水酸化ナトリウム水溶液（２ｍＬ）を加えて約５０℃で１．５時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４３１（１７９ｍｇ，Ｙ＝９９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８０（２Ｈ，ｓ）５．１１（２Ｈ，ｓ）７．０３−７．７６（７Ｈ，ｍ）
化合物４３１（６６ｍｇ）を水（４０ｍＬ）に懸濁し１％水酸化ナトリウム水溶液（１．５ｍＬ）を加えて溶解後、ろ過した。ろ液を凍結乾燥して化合物４３２（７８ｍｇ，Ｙ＝１０６％）を得た。[4- (5-Chloro-1H-benzimidazol-2-yl) phenoxy] acetic acid methyl ester (Compound 427), [4- (5-Chloro-1H-benzimidazol-2-yl) phenoxy] acetic acid (Compound 428) ), [4- (5-chloro-1H-benzimidazol-2-yl) phenoxy] acetic acid sodium salt (Compound 429), 5-chloro-2- [4- (2-methoxy-2-oxoethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester (compound 430), 2- [4- (carboxymethoxy) phenyl] -5-chloro-1H-benzimidazole-1-acetic acid (compound 431), 2- [4- Preparation of (carboxymethoxy) phenyl] -5-chloro-1H-benzimidazol-1-acetic acid disodium salt (compound 432) Structure:
Saturated hydrochloric acid / acetic acid solution (10 mL) was added to compound 422 (600 mg) and reacted at about 100 ° C. for 8 hours. After cooling, the precipitated crystals were collected by filtration. The obtained crystal was recrystallized from a mixed solution of toluene and methanol to obtain 4- (5-chloro-1H-benzoimidazol-2-yl) phenol (346 mg, Y = 79%).
4- (5-Chloro-1H-benzoimidazol-2-yl) phenol (290 mg) was dissolved in DMF (9 mL), and potassium carbonate (500 mg) and methyl bromoacetate (280 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. From the residue, Compound 427 (50 mg, Y = 13%) and Compound 430 (260 mg, Y = 56%) were separated by silica gel column (chloroform / methanol).
Compound 427 (50 mg) was dissolved in methanol (40 mL), 3% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at about 50 ° C. for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding water (20 mL), and then acidified by adding diluted hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 428 (47.8 mg, Y = 100%).
Compound 428 (48 mg) was dissolved in methanol (40 mL), 0.63% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was concentrated under reduced pressure and dried to give compound 429 (46 mg, Y = 90%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 4.48 (2H, s) 7.02−8.09 (7H, m)
Compound 430 (195 mg) was dissolved in methanol (50 mL), 5% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at about 50 ° C. for 1.5 hr. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 431 (179 mg, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.80 (2H, s) 5.11 (2H, s) 7.03-7.76 (7H, m)
Compound 431 (66 mg) was suspended in water (40 mL), dissolved by adding a 1% aqueous sodium hydroxide solution (1.5 mL), and then filtered. The filtrate was lyophilized to give compound 432 (78 mg, Y = 106%).

２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール（化合物４３３）、６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレノール（化合物４３４）、［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］酢酸メチルエステル（化合物４３５）、［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］酢酸（化合物４３６）、［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］酢酸ナトリウム塩（化合物４３７）、２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４３８）、２−［６−（カルボキシメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４３９）、２−［６−（カルボキシメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸二ナトリウム塩（化合物４４０）の製造：
窒素気流中、氷水冷却下でトルエン（８０ｍＬ）に１５％トリメチルアルミニウム・トルエン溶液（１２ｍＬ）、ｏ−フェニレンジアミン（２．４ｇ）を加え、還流下で４０分間反応した後、６−ベンジルオキシ−２−ナフトエ酸エチル（４．０ｇ）のトルエン（３５ｍＬ）溶液を加えて還流下で６時間反応した。反応液に８６％メタノール水溶液（１４０ｍＬ）を加えて１時間還流した後、熱時ろ過し、ろ液を減圧濃縮した。残渣からシリカゲルカラム（酢酸エチル／ｎ−ヘキサン）で粗製物を分取した。得られた粗製物（２．１ｇ）をトルエンから再結晶して化合物４３３（１．３１ｇ，Ｙ＝２９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２８（２Ｈ，ｓ）７．１３−８．６８（１５Ｈ，ｍ）１３．０（１Ｈ，ｂｒ）
化合物４３３（０．９ｇ）にトルエン（１００ｍＬ）、メタノール（２００ｍＬ）を加えて溶解し、５％パラジウム炭素（０．６ｇ）を加えて水素雰囲気下約４５℃で反応した。反応液をろ過し、ろ液を減圧濃縮、乾燥して化合物４３４（６９０ｍｇ，Ｙ＝１０３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．２４−８．９５（１０Ｈ，ｍ）１０．５０（１Ｈ，ｂｒ）
化合物４３４（６６０ｍｇ）をＤＭＦ（４０ｍＬ）に溶解し、炭酸カリウム（１．１ｇ）、ブロモ酢酸メチル（４４０ｍｇ）を加えて室温で６時間反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣からシリカゲルカラム（クロロホルム）で化合物４３８の粗製物（２７０ｍｇ）、化合物４３５の粗製物（３２５ｍｇ）を分取した。得られた粗製物をそれぞれシリカゲルカラム（酢酸エチル／ｎ−ヘキサン）で精製して化合物４３５（２７８ｍｇ，Ｙ＝３３％）、化合物４３８（１９６ｍｇ，Ｙ＝１９％）を得た。
＜化合物４３５＞^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．７６（３Ｈ，ｓ）４．９８（２Ｈ，ｓ）７．１３−８．６７（１０Ｈ，ｍ）１２．９８（１Ｈ，ｂｒ）
＜化合物４３８＞^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．６６（３Ｈ，ｓ）３．７５（３Ｈ，ｓ）４．９８（２Ｈ，ｓ）５．３１（２Ｈ，ｓ）７．２１−８．２１（１０Ｈ，ｍ）
化合物４３５（２１０ｍｇ）に１，４−ジオキサン（３０ｍＬ）、メタノール（１０ｍＬ）を加えて溶解し、２％水酸化ナトリウム水溶液（７ｍＬ）を加えて約５０℃で２０分反応した。反応液を減圧濃縮し、残渣に水（４０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４３６（１９７ｍｇ，Ｙ＝９８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８６（２Ｈ，ｓ）７．１４−８．６８（１０Ｈ，ｍ）
化合物４３６（３１ｍｇ）を水（４０ｍＬ）に懸濁し、１％水酸化ナトリウム水溶液（０．７８ｍＬ）を加えて加温溶解後、ろ過した。ろ液を凍結乾燥して化合物４３７（３４．７ｍｇ，Ｙ＝１０５％）を得た。
化合物４３８（１４４ｍｇ）にメタノール（５０ｍＬ）を加えて溶解後、４％水酸化ナトリウム水溶液（４ｍＬ）を加えて約５０℃で４０分間反応した。反応液を減圧濃縮し、残渣に水（３０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４３９（１２７ｍｇ，Ｙ＝９５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８９（２Ｈ，ｓ）５．３５（２Ｈ，ｓ）７．３０−８．３６（１０Ｈ，ｓ）
化合物４３９（７４．７ｍｇ）を水（３０ｍＬ）に懸濁し、１％水酸化ナトリウム水溶液（１．６ｍＬ）を加えて加温溶解後、ろ過した。ろ液を凍結乾燥して化合物４４０（７９．１ｍｇ，Ｙ＝９５％）を得た。2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole (Compound 433), 6- (1H-Benzimidazol-2-yl) -2-naphthalenol (Compound 434), [[6- ( 1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid methyl ester (Compound 435), [[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid (Compound 436) , [[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid sodium salt (Compound 437), 2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid methyl ester (compound 438), 2- [6- (carboxymethoxy) -2-naphth Preparation of Tarenyl] -1H-Benzimidazol-1-acetic acid (Compound 439), 2- [6- (Carboxymethoxy) -2-naphthalenyl] -1H-Benzimidazol-1-acetic acid disodium salt (Compound 440):
In a nitrogen stream, 15% trimethylaluminum / toluene solution (12 mL) and o-phenylenediamine (2.4 g) were added to toluene (80 mL) under cooling with ice water and reacted for 40 minutes under reflux, and then 6-benzyloxy- A solution of ethyl 2-naphthoate (4.0 g) in toluene (35 mL) was added and reacted under reflux for 6 hours. 86% aqueous methanol solution (140 mL) was added to the reaction mixture, and the mixture was refluxed for 1 hour, filtered while hot, and the filtrate was concentrated under reduced pressure. The crude product was separated from the residue by a silica gel column (ethyl acetate / n-hexane). The obtained crude product (2.1 g) was recrystallized from toluene to obtain Compound 433 (1.31 g, Y = 29%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 7.13-8.68 (15H, m) 13.0 (1H, br)
Toluene (100 mL) and methanol (200 mL) were added and dissolved in compound 433 (0.9 g), and 5% palladium carbon (0.6 g) was added and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 434 (690 mg, Y = 103%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.24-8.95 (10H, m) 10.50 (1H, br)
Compound 434 (660 mg) was dissolved in DMF (40 mL), potassium carbonate (1.1 g) and methyl bromoacetate (440 mg) were added, and the mixture was reacted at room temperature for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. A crude product of compound 438 (270 mg) and a crude product of compound 435 (325 mg) were separated from the residue by a silica gel column (chloroform). The obtained crude product was purified with a silica gel column (ethyl acetate / n-hexane) to obtain Compound 435 (278 mg, Y = 33%) and Compound 438 (196 mg, Y = 19%).
<Compound 435> ¹ H-NMR (DMSO-d6 / TMS):
δ = 3.76 (3H, s) 4.98 (2H, s) 7.13-8.67 (10H, m) 12.98 (1H, br)
<Compound 438> ¹ H-NMR (DMSO-d6 / TMS):
δ = 3.66 (3H, s) 3.75 (3H, s) 4.98 (2H, s) 5.31 (2H, s) 7.21-8.21 (10H, m)
To compound 435 (210 mg), 1,4-dioxane (30 mL) and methanol (10 mL) were added and dissolved, and 2% aqueous sodium hydroxide solution (7 mL) was added and reacted at about 50 ° C. for 20 minutes. The reaction solution was concentrated under reduced pressure, and water (40 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 436 (197 mg, Y = 98%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.86 (2H, s) 7.14-8.68 (10H, m)
Compound 436 (31 mg) was suspended in water (40 mL), 1% aqueous sodium hydroxide solution (0.78 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 437 (34.7 mg, Y = 105%).
After dissolving methanol (50 mL) in compound 438 (144 mg), 4% aqueous sodium hydroxide solution (4 mL) was added and reacted at about 50 ° C. for 40 minutes. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 439 (127 mg, Y = 95%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.89 (2H, s) 5.35 (2H, s) 7.30-8.36 (10H, s)
Compound 439 (74.7 mg) was suspended in water (30 mL), 1% aqueous sodium hydroxide solution (1.6 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 440 (79.1 mg, Y = 95%).

２−［６−（４−エトキシ−４−オキソブトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ブタン酸エチルエステル（化合物４４１）、２−［６−（３−カルボキシプロポキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ブタン酸（化合物４４２）、２−［６−（３−カルボキシプロポキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ブタン酸二ナトリウム塩（化合物４４３）の製造：
化合物４３４（３５０ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、４−ブロモ−ｎ−酪酸エチル（６８０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮して化合物４４１を得た。
化合物４４１をメタノール（５０ｍＬ）に溶解し、１６％水酸化ナトリウム水溶液（３ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣に水（３０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４４２（２２０ｍｇ，Ｙ＝３８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８４−２．５０（８Ｈ，ｍ）４．２１（２Ｈ，ｔ，Ｊ＝６Ｈｚ）４．５７（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．３−８．５２（１０Ｈ，ｍ）
化合物４４２（９９．２ｍｇ）に水（３０ｍＬ）、０．５％水酸化ナトリウム水溶液（３．８ｍＬ）を加えて溶解し、ろ過した。ろ液を凍結乾燥して化合物４４３（１１４ｍｇ，Ｙ＝１０４％）を得た。2- [6- (4-Ethoxy-4-oxobutoxy) -2-naphthalenyl] -1H-benzimidazole-1-butanoic acid ethyl ester (Compound 441), 2- [6- (3-carboxypropoxy) -2 -Naphthalenyl] -1H-benzimidazol-1-butanoic acid (Compound 442), 2- [6- (3-Carboxypropoxy) -2-naphthalenyl] -1H-benzimidazol-1-butanoic acid disodium salt (Compound 443) )Manufacturing of:
Compound 434 (350 mg) was dissolved in DMF (15 mL), potassium carbonate (2.5 g) and ethyl 4-bromo-n-butyrate (680 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure to obtain Compound 441.
Compound 441 was dissolved in methanol (50 mL), 16% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 442 (220 mg, Y = 38%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.84-2.50 (8H, m) 4.21 (2H, t, J = 6 Hz) 4.57 (2H, t, J = 5 Hz) 7.3-8.52 (10H, m)
To compound 442 (99.2 mg), water (30 mL) and 0.5% aqueous sodium hydroxide solution (3.8 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to give compound 443 (114 mg, Y = 104%).

２−［６−［（６−エトキシ−６−オキソヘキシル）オキシ］−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ヘキサン酸エチルエステル（化合物４４４）、２−［６−［（５−カルボキシペンチル）オキシ］−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ヘキサン酸（化合物４４５）、２−［６−［（５−カルボキシペンチル）オキシ］−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ヘキサン酸二ナトリウム塩（化合物４４６）の製造：
化合物４３４（３５０ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（２．５ｇ）、６−ブロモヘキサン酸エチル（８００ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮して化合物４４４を得た。
化合物４４４をメタノール（５０ｍＬ）に溶解後、１６％水酸化ナトリウム水溶液（３ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣に水（３０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４４５（１７７ｍｇ，Ｙ＝２７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．０９−２．３９（１６Ｈ，ｍ）４．０６−４．５９（４Ｈ，ｍ）７．２３−８．３８（１０Ｈ，ｍ）
化合物４４５（９５．３ｍｇ）に水（３０ｍＬ）、０．５％水酸化ナトリウム水溶液（３．３ｍＬ）を加えて溶解し、ろ過した。ろ液を凍結乾燥して化合物４４６（１１０ｍｇ，Ｙ＝１０６％）を得た。2- [6-[(6-Ethoxy-6-oxohexyl) oxy] -2-naphthalenyl] -1H-benzimidazole-1-hexanoic acid ethyl ester (Compound 444), 2- [6-[(5-carboxyl Pentyl) oxy] -2-naphthalenyl] -1H-benzimidazol-1-hexanoic acid (Compound 445), 2- [6-[(5-carboxypentyl) oxy] -2-naphthalenyl] -1H-benzimidazole-1 -Production of disodium hexanoate (compound 446):
Compound 434 (350 mg) was dissolved in DMF (15 mL), potassium carbonate (2.5 g) and ethyl 6-bromohexanoate (800 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure to obtain Compound 444.
Compound 444 was dissolved in methanol (50 mL), 16% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 445 (177 mg, Y = 27%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.09-2.39 (16H, m) 4.06-4.59 (4H, m) 7.23-8.38 (10H, m)
To compound 445 (95.3 mg), water (30 mL) and 0.5% aqueous sodium hydroxide solution (3.3 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to give compound 446 (110 mg, Y = 106%).

［５−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物４４７）、［５−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸（化合物４４８）、［５−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物４４９）の製造：
化合物４３４（１．２ｇ）をＤＭＦ（５０ｍＬ）に懸濁し、炭酸カリウム（６ｇ）、（５−ブロモペンチル）マロン酸ジエチル（１．５ｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（４００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣からシリカゲルカラム（クロロホルム）で粗製物を分取した。粗製物をトルエン、ｎ−ヘキサンの混液から再結晶して化合物４４７（１．０５ｇ，Ｙ＝４７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１３−２．１５（１４Ｈ，ｍ）３．３５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）３．９４−４．３８（６Ｈ，ｍ）７．０６−８．４５（１０Ｈ，ｍ）
化合物４４７（１６０ｍｇ）をメタノール（５０ｍＬ）に溶解後、８％水酸化ナトリウム水溶液（３ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣を水（３０ｍＬ）に溶解した後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４４８（１３８ｍｇ，Ｙ＝９８％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．１９−２．０（８Ｈ，ｍ）３．２４（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．１２（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．１４−８．６６（１０Ｈ，ｍ）
化合物４４８（９９．５ｍｇ）に水（４０ｍＬ）、０．４５％水酸化ナトリウム水溶液（４．２ｍＬ）を加えて溶解し、ろ過した。ろ液を凍結乾燥して化合物４４９（１１１ｍｇ，Ｙ＝１０１％）を得た。[5-[[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 447), [5-[[6- (1H-Benzimidazole-2] -Yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 448), [5-[[6- (1H-benzimidazol-2-yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diacid Preparation of sodium salt (compound 449):
Compound 434 (1.2 g) was suspended in DMF (50 mL), and potassium carbonate (6 g) and diethyl (5-bromopentyl) malonate (1.5 g) were added and reacted at room temperature overnight. Ethyl acetate (400 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was separated from the residue with a silica gel column (chloroform). The crude product was recrystallized from a mixed solution of toluene and n-hexane to obtain Compound 447 (1.05 g, Y = 47%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.13-2.15 (14H, m) 3.35 (1H, t, J = 7 Hz) 3.94-4.38 (6H, m) 7.06-8.45 (10H, m)
Compound 447 (160 mg) was dissolved in methanol (50 mL), 8% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (30 mL). The precipitated crystals were collected by filtration and dried to obtain Compound 448 (138 mg, Y = 98%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.19-2.0 (8H, m) 3.24 (1H, t, J = 7 Hz) 4.12 (2H, t, J = 5 Hz) 7.14-8.66 (10H, m)
To compound 448 (99.5 mg), water (40 mL) and a 0.45% aqueous sodium hydroxide solution (4.2 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to give compound 449 (111 mg, Y = 101%).

４−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物４５０）、４−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ブタン酸（化合物４５１）、４−［［６−（１Ｈ−ベンゾイミダゾール−２−イル）−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物４５２）の製造：
化合物４３４（１．２ｇ）をＤＭＦ（６０ｍＬ）に懸濁し、炭酸カリウム（５．０ｇ）、４−ブロモ−ｎ−酪酸エチル（０．９ｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（６００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣からシリカゲルカラム（クロロホルム）により粗製物を分取した。得られた粗製物をクロロホルム、トルエンの混液から再結晶して化合物４５０（１．０６ｇ，Ｙ＝６１％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．９０−２．７０（４Ｈ，ｍ）３．９８−４．３４（４Ｈ，ｍ）７．０１−８．４７（１０Ｈ，ｍ）
化合物４５０（２２５ｍｇ）をメタノール（５０ｍＬ）に溶解し、９％水酸化ナトリウム水溶液（３ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加温溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４５１（２１０ｍｇ，Ｙ＝１０１％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．９０−２．４８（４Ｈ，ｍ）４．１８（２Ｈ，ｔ，Ｊ＝７Ｈｚ）７．２１−８．２３（１０Ｈ，ｍ）
化合物４５１（１２５ｍｇ）に水（３０ｍＬ）、０．５％水酸化ナトリウム水溶液（５．９ｍＬ）を加えて加温溶解し、ろ過した。ろ液を凍結乾燥して化合物４５２（１３９ｍｇ，Ｙ＝９９％）を得た。4-[[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 450), 4-[[6- (1H-Benzimidazol-2-yl) -2 Preparation of -Naphthalenyl] oxy] butanoic acid (Compound 451), 4-[[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 452):
Compound 434 (1.2 g) was suspended in DMF (60 mL), and potassium carbonate (5.0 g) and ethyl 4-bromo-n-butyrate (0.9 g) were added and reacted at room temperature overnight. Ethyl acetate (600 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was separated from the residue by a silica gel column (chloroform). The obtained crude product was recrystallized from a mixed solution of chloroform and toluene to obtain Compound 450 (1.06 g, Y = 61%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.25 (3H, t, J = 7 Hz) 1.90-2.70 (4H, m) 3.98-4.34 (4H, m) 7.01-8.47 (10H, m)
Compound 450 (225 mg) was dissolved in methanol (50 mL), 9% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 451 (210 mg, Y = 101%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.90-2.48 (4H, m) 4.18 (2H, t, J = 7 Hz) 7.21-8.23 (10H, m)
To compound 451 (125 mg), water (30 mL) and a 0.5% aqueous sodium hydroxide solution (5.9 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 452 (139 mg, Y = 99%).

４−［［６−［１−（フェニルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物４５３）、４−［［６−［１−（フェニルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸（化合物４５４）、４−［［６−［１−（フェニルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物４５５）の製造：
化合物４５０（２５０ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（０．６ｇ）、ベンジルブロミド（１５０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮後、乾燥して化合物４５３（３０３ｍｇ，Ｙ＝９８％）を得た。
化合物４５３（３０３ｍｇ）をメタノール（５０ｍＬ）に溶解し、８％水酸化ナトリウム水溶液（３ｍＬ）を加え、約５０℃で２．５時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４５４（１９２ｍｇ，Ｙ＝６７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８０−２．５０（４Ｈ，ｍ）４．１５（２Ｈ，ｔ，Ｊ＝６Ｈｚ）５．６８（２Ｈ，ｓ）６．９８−８．２２（１５Ｈ，ｍ）
化合物４５４（１０２ｍｇ）に水（５０ｍＬ）、０．４５％水酸化ナトリウム水溶液（２．１ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物４５５（１０６ｍｇ，Ｙ＝９９％）を得た。4-[[6- [1- (Phenylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 453), 4-[[6- [1- (phenyl) Methyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid (compound 454), 4-[[6- [1- (phenylmethyl) -1H-benzimidazol-2-yl]- Preparation of 2-Naphthalenyl] oxy] butanoic acid sodium salt (Compound 455):
Compound 450 (250 mg) was dissolved in DMF (5 mL), and potassium carbonate (0.6 g) and benzyl bromide (150 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 453 (303 mg, Y = 98%).
Compound 453 (303 mg) was dissolved in methanol (50 mL), 8% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. for 2.5 hr. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 454 (192 mg, Y = 67%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.50 (4H, m) 4.15 (2H, t, J = 6 Hz) 5.68 (2H, s) 6.98-8.22 (15H, m)
To compound 454 (102 mg), water (50 mL) and 0.45% aqueous sodium hydroxide solution (2.1 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 455 (106 mg, Y = 99%).

４−［［６−［１−［（２−クロロフェニル）メチル］−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物４５６）、４−［［６−［１−［（２−クロロフェニル）メチル］−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸（化合物４５７）、４−［［６−［１−［（２−クロロフェニル）メチル］−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物４５８）の製造：
化合物４５０（２５０ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（０．６ｇ）、２−クロロベンジルブロミド（１８０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮後、乾燥して化合物４５６（３２５ｍｇ，Ｙ＝９８％）を得た。
化合物４５６（３２５ｍｇ）にメタノール（５０ｍＬ）を加えて溶解後、８％水酸化ナトリウム水溶液（３ｍＬ）を加えて約５０℃で３時間反応した。反応液を減圧下で濃縮し、残渣に水（５０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４５７（１８５ｍｇ，Ｙ＝６０％）を得た。
^１Ｈ−ＮＭＲ（ＰＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８０−２．５０（４Ｈ，ｍ）４．１４（２Ｈ，ｔ，Ｊ＝６Ｈｚ）５．７０（２Ｈ，ｓ）６．６１−８．１３（１４Ｈ，ｍ）１２．１７（１Ｈ，ｂｒ）
化合物４５７（１００ｍｇ）に水（５０ｍＬ）、０．４５％水酸化ナトリウム水溶液（１．９ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物４５８を得た。4-[[6- [1-[(2-chlorophenyl) methyl] -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 456), 4-[[6- [ 1-[(2-chlorophenyl) methyl] -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid (compound 457), 4-[[6- [1-[(2-chlorophenyl) methyl] ] -1H-Benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 458):
Compound 450 (250 mg) was dissolved in DMF (5 mL), and potassium carbonate (0.6 g) and 2-chlorobenzyl bromide (180 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 456 (325 mg, Y = 98%).
Methanol (50 mL) was added to Compound 456 (325 mg) and dissolved, 8% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. for 3 hr. The reaction solution was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 457 (185 mg, Y = 60%).
¹ H-NMR (PMSO-d6 / TMS):
δ = 1.80-2.50 (4H, m) 4.14 (2H, t, J = 6 Hz) 5.70 (2H, s) 6.61-8.13 (14H, m) 12.17 ( 1H, br)
To compound 457 (100 mg), water (50 mL) and a 0.45% aqueous sodium hydroxide solution (1.9 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 458.

１−（シクロヘキシルメチル）−２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール（化合物４５９）、６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレノール（化合物４６０）、４−［［６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル（化合物４６１）、４−［［６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸（化合物４６２）、４−［［６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩（化合物４６３）の製造：
化合物４３３（１．５ｇ）をＤＭＦ（４０ｍＬ）に溶解し、炭酸カリウム（７．０ｇ）、ブロモメチルシクロヘキサン（１．５ｇ）を加えて室温で一夜、約７０℃で１７時間反応した。反応液に水（４００ｍＬ）を加えて晶析し、析出結晶をろ取、乾燥して化合物４５９（１．０ｇ，Ｙ＝５２％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝０．５０−１．８０（１１Ｈ，ｍ）４．１９（２Ｈ，ｄ，Ｊ＝７Ｈｚ）５．２３（２Ｈ，ｓ）７．２１−８．１５（１５Ｈ，ｍ）
化合物４５９（１．０ｇ）をトルエン（４０ｍＬ）に溶解し、メタノール（８０ｍＬ）、５％パラジウム炭素（０．６ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮後、乾燥して化合物４６０（６９５ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝０．６９−２．００（１１Ｈ，ｍ）４．５３（２Ｈ，ｄ，Ｊ＝６Ｈｚ）７．２７−８．５０（１０Ｈ，ｍ）
化合物４６０（１７０ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（０．５ｇ）、４−ブロモ−ｎ−酪酸エチル（１４０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮後、乾燥して化合物４６１（２００ｍｇ，Ｙ＝８９％）を得た。
化合物４６１（２００ｍｇ）にメタノール（８０ｍＬ）を加えて溶解し、１４％水酸化ナトリウム水溶液（２ｍＬ）を加えて５０℃で一夜反応した後、還流下で３時間反応した。反応液を減圧濃縮し、残渣に水（４０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４６２（１６３ｍｇ，Ｙ＝８７％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝０．６９−２．５０（１５Ｈ，ｍ）４．０８−４．４２（４Ｈ，ｍ）７．２−８．３４（１０Ｈ，ｍ）１２．３（１Ｈ，ｂｒ）
化合物４６２（７９ｍｇ）に水（２５ｍＬ）、０．５％水酸化ナトリウム水溶液（１．４ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物４６３（８０ｍｇ，Ｙ＝９７％）を得た。1- (cyclohexylmethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole (compound 459), 6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] 2-naphthalenol (compound 460), 4-[[6- [1- (cyclohexylmethyl) -1H-benzoimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 461), 4- [[6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid (Compound 462), 4-[[6- [1- (cyclohexylmethyl) -1H -Benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 463) :
Compound 433 (1.5 g) was dissolved in DMF (40 mL), potassium carbonate (7.0 g) and bromomethylcyclohexane (1.5 g) were added, and the mixture was reacted at room temperature overnight at about 70 ° C. for 17 hours. Water (400 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and dried to obtain Compound 459 (1.0 g, Y = 52%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 0.50-1.80 (11H, m) 4.19 (2H, d, J = 7 Hz) 5.23 (2H, s) 7.21-8.15 (15H, m)
Compound 459 (1.0 g) was dissolved in toluene (40 mL), methanol (80 mL), 5% palladium carbon (0.6 g) was added, and the mixture was reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 460 (695 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.69-2.00 (11 H, m) 4.53 (2 H, d, J = 6 Hz) 7.27-8.50 (10 H, m)
Compound 460 (170 mg) was dissolved in DMF (10 mL), potassium carbonate (0.5 g) and ethyl 4-bromo-n-butyrate (140 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 461 (200 mg, Y = 89%).
Methanol (80 mL) was added to compound 461 (200 mg) to dissolve, 14% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at 50 ° C. overnight, and then reacted under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, water (40 mL) was added to the residue and dissolved by heating, and then dilute hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 462 (163 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.69-2.50 (15H, m) 4.08-4.42 (4H, m) 7.2-8.34 (10H, m) 12.3 (1H, br)
To compound 462 (79 mg), water (25 mL) and a 0.5% aqueous sodium hydroxide solution (1.4 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 463 (80 mg, Y = 97%).

６−［［６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物４６４）、６−［［６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ヘキサン酸（化合物４６５）、６−［［６−［１−（シクロヘキシルメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物４６６）の製造：
化合物４６０（１６０ｍｇ）をＤＭＦ（１５ｍＬ）に溶解し、炭酸カリウム（０．５ｇ）、６−ブロモヘキサン酸エチル（１５０ｍｇ）を加えて室温で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮後、乾燥して化合物４６４（１９４ｍｇ，Ｙ＝８７％）を得た。
化合物４６４（１９４ｍｇ）にメタノール（８０ｍＬ）を加えて溶解した後、１５％水酸化ナトリウム水溶液（２ｍＬ）を加えて約５０℃で一夜、還流下で３時間反応した。反応液を減圧濃縮し、残渣に水（６０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４６５（１３２ｍｇ，Ｙ＝７２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝０．７０−２．５１（１９Ｈ，ｍ）４．０４−４．３７（４Ｈ，ｍ）７．１９−８．２９（１０Ｈ，ｍ）
化合物４６５（７５．５ｍｇ）に水（２５ｍＬ）、０．５％水酸化ナトリウム水溶液（１．３ｍＬ）を加え、加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物４６６（７６ｍｇ，Ｙ＝９６％）を得た。6-[[6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 464), 6-[[6- [1- (cyclohexyl) Methyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] hexanoic acid (Compound 465), 6-[[6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl]- 2-Naphthalenyl] oxy] hexanoic acid sodium salt (Compound 466):
Compound 460 (160 mg) was dissolved in DMF (15 mL), potassium carbonate (0.5 g) and ethyl 6-bromohexanoate (150 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 464 (194 mg, Y = 87%).
Methanol (80 mL) was added to and dissolved in compound 464 (194 mg), 15% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at about 50 ° C. overnight and under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and water (60 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 465 (132 mg, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.70-2.51 (19H, m) 4.04-4.37 (4H, m) 7.19-8.29 (10H, m)
To compound 465 (75.5 mg), water (25 mL) and a 0.5% aqueous sodium hydroxide solution (1.3 mL) were added, dissolved by heating and filtered. The filtrate was lyophilized to give compound 466 (76 mg, Y = 96%).

２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４６７）、２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４６８）、２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−酢酸ナトリウム塩（化合物４６９）の製造：
化合物４３３（４５８ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（４００ｍｇ）、ブロモ酢酸メチル（２４０ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣に酢酸エチル（２００ｍＬ）を加えて飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（酢酸エチル／ｎ−ヘキサン）で精製して化合物４６７（４４８ｍｇ，Ｙ＝８１％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝３．８０（３Ｈ，ｓ）４．９７（２Ｈ，ｓ）５．２２（２Ｈ，ｓ）７．２６−８．１４（１５Ｈ，ｍ）
化合物４６７（１２０ｍｇ）に１，４−ジオキサン（４０ｍＬ）、メタノール（２０ｍＬ）を加えて溶解し、４．５％水酸化ナトリウム水溶液（４ｍＬ）を加えて約５０℃で２時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加温溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４６８（１０３．７ｍｇ，Ｙ＝８９％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．２１（２Ｈ，ｓ）５．２９（２Ｈ，ｓ）７．２０−８．２５（１５Ｈ，ｍ）
化合物４６８（７０ｍｇ）にメタノール（３０ｍＬ）、０．７％水酸化ナトリウム水溶液（１ｍＬ）を加えて加熱溶解後、減圧濃縮し乾燥して化合物４６９（６６．４ｍｇ，Ｙ＝９０％）を得た。2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid methyl ester (Compound 467), 2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole- Production of 1-acetic acid (compound 468), 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid sodium salt (compound 469):
Compound 433 (458 mg) was dissolved in DMF (10 mL), and potassium carbonate (400 mg) and methyl bromoacetate (240 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (200 mL) was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate / n-hexane) to obtain Compound 467 (448 mg, Y = 81%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 3.80 (3H, s) 4.97 (2H, s) 5.22 (2H, s) 7.26-8.14 (15H, m)
To compound 467 (120 mg), 1,4-dioxane (40 mL) and methanol (20 mL) were added and dissolved, and 4.5% aqueous sodium hydroxide solution (4 mL) was added and reacted at about 50 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 468 (103.7 mg, Y = 89%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.21 (2H, s) 5.29 (2H, s) 7.20-8.25 (15H, m)
Methanol (30 mL) and 0.7% aqueous sodium hydroxide solution (1 mL) were added to compound 468 (70 mg), dissolved by heating, then concentrated under reduced pressure and dried to obtain compound 469 (66.4 mg, Y = 90%). .

２−（６−ヒドロキシ−２−ナフタレニル）−１Ｈ−ベンゾイミダゾール−１−酢酸メチルエステル（化合物４７０）、２−（６−ヒドロキシ−２−ナフタレニル）−１Ｈ−ベンゾイミダゾール−１−酢酸（化合物４７１）、２−（６−ヒドロキシ−２−ナフタレニル）−１Ｈ−ベンゾイミダゾール−１−酢酸二ナトリウム塩（化合物４７２）の製造：
化合物４６７（３００ｍｇ）にトルエン（５０ｍＬ）、メタノール（１００ｍＬ）を加えて溶解し、５％パラジウム炭素（０．３ｇ）を加えて水素雰囲気下約４５℃で反応した。反応液をろ過し、ろ液を減圧濃縮後、乾燥して化合物４７０（２２９ｍｇ，Ｙ＝９６％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝３．６７（３Ｈ，ｓ）５．２９（２Ｈ，ｓ）７．１０−８．１３（１０Ｈ，ｍ）１０．０２（１Ｈ，ｓ）
化合物４７０（１９４ｍｇ）に１，４−ジオキサン（３０ｍＬ）、メタノール（３０ｍＬ）を加えて溶解し、４％水酸化ナトリウム水溶液（４ｍＬ）を加えて約５０℃で１時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加温溶解した後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４７１（１６７ｍｇ，Ｙ＝８５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝５．１７（２Ｈ，ｓ）７．１３−８．１７（１０Ｈ，ｍ）
化合物４７１（９６．７ｍｇ）にメタノール（４０ｍＬ）、２．２７％水酸化ナトリウム水溶液（１ｍＬ）を加えて加温溶解し、減圧濃縮して化合物４７２（１００ｍｇ，Ｙ＝９１％）を得た。2- (6-Hydroxy-2-naphthalenyl) -1H-benzimidazole-1-acetic acid methyl ester (Compound 470), 2- (6-Hydroxy-2-naphthalenyl) -1H-benzimidazole-1-acetic acid (Compound 471) ), 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazol-1-acetic acid disodium salt (Compound 472):
Toluene (50 mL) and methanol (100 mL) were added to compound 467 (300 mg) to dissolve, and 5% palladium on carbon (0.3 g) was added and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 470 (229 mg, Y = 96%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.67 (3H, s) 5.29 (2H, s) 7.10-8.13 (10H, m) 10.02 (1H, s)
To compound 470 (194 mg), 1,4-dioxane (30 mL) and methanol (30 mL) were added and dissolved, 4% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at about 50 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, and then dilute hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 471 (167 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.17 (2H, s) 7.13-8.17 (10H, m)
Methanol (40 mL) and 2.27% aqueous sodium hydroxide solution (1 mL) were added to compound 471 (96.7 mg), dissolved by heating, and concentrated under reduced pressure to obtain compound 472 (100 mg, Y = 91%).

２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ブタン酸エチルエステル（化合物４７３）、２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ブタン酸（化合物４７４）、２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−ブタン酸ナトリウム塩（化合物４７５）の製造：
化合物４３３（２９０ｍｇ）をＤＭＦ（６ｍＬ）に溶解し、炭酸カリウム（０．８ｇ）、４−ブロモ−ｎ−酪酸エチル（２１０ｍｇ）を加えて室温で一夜、約４５℃で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮して化合物４７３を得た。
化合物４７３をメタノール（５０ｍＬ）に溶解し、１２％水酸化ナトリウム水溶液（４ｍＬ）を加えて約６０℃で３時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて加熱溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４７４（２６１ｍｇ，Ｙ＝７２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，Ｄ_２Ｏ／ＴＭＳ）：
δ＝１．８０−２．４０（４Ｈ，ｍ）４．４８（２Ｈ，ｔ，Ｊ＝５Ｈｚ）５．３１（２Ｈ，ｓ）７．３３−８．４０（１５Ｈ，ｍ）
化合物４７４（６２ｍｇ）に水（５０ｍＬ）、０．４５％水酸化ナトリウム水溶液（１．３ｍＬ）を加えて加熱溶解し、ろ過した。ろ液を凍結乾燥して化合物４７５（６７ｍｇ，Ｙ＝１０３％）を得た。2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-butanoic acid ethyl ester (Compound 473), 2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole Preparation of -1-butanoic acid (compound 474), 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-butanoic acid sodium salt (compound 475):
Compound 433 (290 mg) was dissolved in DMF (6 mL), potassium carbonate (0.8 g) and ethyl 4-bromo-n-butyrate (210 mg) were added, and the mixture was reacted at room temperature overnight and at about 45 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure to obtain Compound 473.
Compound 473 was dissolved in methanol (50 mL), 12% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at about 60 ° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 474 (261 mg, Y = 72%).
¹ H-NMR (DMSO-d6, D ₂ O / TMS):
δ = 1.80-2.40 (4H, m) 4.48 (2H, t, J = 5 Hz) 5.31 (2H, s) 7.33-8.40 (15H, m)
To compound 474 (62 mg), water (50 mL) and a 0.45% aqueous sodium hydroxide solution (1.3 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 475 (67 mg, Y = 103%).

２−（６−ヒドロキシ−２−ナフタレニル）−１Ｈ−ベンゾイミダゾール−１−ブタン酸（化合物４７６）、２−（６−ヒドロキシ−２−ナフタレニル）−１Ｈ−ベンゾイミダゾール−１−ブタン酸ナトリウム塩（化合物４７７）の製造：
化合物４７４（１７０ｍｇ）にメタノール（８０ｍＬ）、５％パラジウム炭素（０．２ｇ）を加えて水素雰囲気下室温で反応した。反応液をろ過し、ろ液を減圧濃縮後、乾燥して化合物４７６（１００ｍｇ，Ｙ＝７４％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．８０−２．２７（４Ｈ，ｍ）４．４１（２Ｈ，ｔ，Ｊ＝６Ｈｚ）７．１０−８．２８（１０Ｈ，ｍ）１０．０４（１Ｈ，ｂｒ）１２．２（１Ｈ，ｂｒ）
化合物４７６（８０ｍｇ）に水（４０ｍＬ）、０．４５％水酸化ナトリウム水溶液（２．１ｍＬ）を加えて加温溶解し、ろ過した。ろ液を凍結乾燥して化合物４７７（８６ｍｇ，Ｙ＝１０１％）を得た。2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazol-1-butanoic acid (compound 476), 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazol-1-butanoic acid sodium salt ( Preparation of compound 477):
Methanol (80 mL) and 5% palladium on carbon (0.2 g) were added to compound 474 (170 mg) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 476 (100 mg, Y = 74%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.27 (4H, m) 4.41 (2H, t, J = 6 Hz) 7.10-8.28 (10 H, m) 10.04 (1 H, br) 12.2 ( 1H, br)
To compound 476 (80 mg), water (40 mL) and a 0.45% aqueous sodium hydroxide solution (2.1 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 477 (86 mg, Y = 101%).

［５−［２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−イル］ペンチル］プロパン二酸ジエチルエステル（化合物４７８）、［５−［２−［６−（フェニルメトキシ）−２−ナフタレニル］−１Ｈ−ベンゾイミダゾール−１−イル］ペンチル］プロパン二酸（化合物４７９）の製造：
化合物４３３（２８５ｍｇ）をＤＭＦ（１２ｍＬ）に溶解し、炭酸カリウム（１２ｇ）、（５−ブロモペンチル）マロン酸ジエチル（６６０ｍｇ）を加えて室温で一夜、約７０℃で一夜反応した。反応液に酢酸エチル（１００ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物４７８（８０ｍｇ，Ｙ＝１８％）を得た。
化合物４７８（８０ｍｇ）にメタノール（５０ｍＬ）、１２％水酸化ナトリウム水溶液（２ｍＬ）を加えて室温で一夜反応した。反応液を減圧濃縮し、残渣を水（２０ｍｌ）に溶解して酢酸エチルで洗浄後、水層に希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４７９（３１ｍｇ，Ｙ＝４３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．００−１．９２（８Ｈ，ｍ）３．０８（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．４４（２Ｈ，ｔ，Ｊ＝７Ｈｚ）５．３１（２Ｈ，ｓ）７．２６−８．３７（１５Ｈ，ｍ）[5- [2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazol-1-yl] pentyl] propanedioic acid diethyl ester (Compound 478), [5- [2- [6- ( Preparation of (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazol-1-yl] pentyl] propanedioic acid (Compound 479):
Compound 433 (285 mg) was dissolved in DMF (12 mL), potassium carbonate (12 g) and diethyl (5-bromopentyl) malonate (660 mg) were added, and the mixture was reacted at room temperature overnight and at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 478 (80 mg, Y = 18%).
Methanol (50 mL) and 12% aqueous sodium hydroxide solution (2 mL) were added to compound 478 (80 mg) and reacted overnight at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (20 ml), washed with ethyl acetate, and diluted hydrochloric acid was added to the aqueous layer for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 479 (31 mg, Y = 43%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.00-1.92 (8H, m) 3.08 (1H, t, J = 7 Hz) 4.44 (2H, t, J = 7 Hz) 5.31 (2H, s) 7.26− 8.37 (15H, m)

２−［６−（フェニルメトキシ）−２−ナフタレニル］ベンゾチアゾール（化合物４８０）、６−（２−ベンゾチアゾリル）−２−ナフタレノール（化合物４８１）、［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］酢酸メチルエステル（化合物４８２）、［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］酢酸（化合物４８３）、［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］酢酸ナトリウム塩（化合物４８４）の製造：
窒素気流中、氷水冷却下でトルエン（５０ｍＬ）に１５％トリメチルアルミニウム・トルエン溶液（５ｍＬ）、２−アミノベンゼンチオール（１．２ｇ）を加え、還流下で１時間反応した後、６−ベンジルオキシ−２−ナフトエ酸メチル（１．８ｇ）のトルエン（５０ｍＬ）溶液を加えて還流下で一夜反応した。反応液に９５％メタノール水溶液（８４ｍＬ）を加えて１時間還流した後、熱時ろ過した。ろ液を減圧濃縮し、残渣をシリカゲルカラム（クロロホルム）で精製して化合物４８０（９２８ｍｇ，Ｙ＝３９％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝５．２１（２Ｈ，ｓ）７．２５−８．４９（１５Ｈ，ｍ）
化合物４８０（６００ｍｇ）に飽和塩酸・酢酸溶液（４０ｍＬ）を加え、約９５℃で３日間反応した。反応液を減圧濃縮し、残渣をシリカゲルカラム（クロロホルム／メタノール）で精製して化合物４８１（２１４ｍｇ，Ｙ＝３３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝７．１４−８．２２（９Ｈ，ｍ）８．５６（１Ｈ，ｓ）１０．１０（１Ｈ，ｓ）、
化合物４８１（１９０ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（３００ｍｇ）、ブロモ酢酸メチル（１３０ｍｇ）を加えて室温で一夜反応した。反応液をろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物４８２（１５５ｍｇ，Ｙ＝６５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝３．８５（３Ｈ，ｓ）４．７９（２Ｈ，ｓ）７．１３−８．５０（１０Ｈ，ｍ）
化合物４８２（１２０ｍｇ）にメタノール（２０ｍＬ）、１，４−ジオキサン（５０ｍＬ）を加え、８％水酸化ナトリウム水溶液（１ｍＬ）を加えて約５０℃で３０分間反応した。反応液を減圧濃縮し、残渣に水（１０ｍＬ）、酢酸エチル（６０ｍＬ）を加え、希塩酸を加えて強酸性とした後、分液した。酢酸エチル層を水、飽和食塩水で順次洗浄した後、硫酸マグネシウムで脱水し、減圧濃縮、乾燥して化合物４８３（１１４ｍｇ，Ｙ＝９３％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝４．８７（２Ｈ，ｓ）７．２３−８．６４（１０Ｈ，ｍ）１３．０（１Ｈ，ｂｒ）
化合物４８３（７０．３ｍｇ）をメタノール（３０ｍＬ）に加熱溶解後１．６％水酸化ナトリウム水溶液（０．５ｍＬ）を加えて撹拌し、析出した固体をろ過し乾燥して化合物４８４（５４ｍｇ，Ｙ＝７６％）を得た。2- [6- (phenylmethoxy) -2-naphthalenyl] benzothiazole (Compound 480), 6- (2-Benzothiazolyl) -2-naphthalenol (Compound 481), [[6- (2-Benzothiazolyl) -2-naphthalenyl ] Oxy] acetic acid methyl ester (compound 482), [[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid (compound 483), [[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid Preparation of sodium salt (compound 484):
In a nitrogen stream, 15% trimethylaluminum / toluene solution (5 mL) and 2-aminobenzenethiol (1.2 g) were added to toluene (50 mL) under cooling with ice water and reacted for 1 hour under reflux, then 6-benzyloxy A solution of methyl 2-naphthoate (1.8 g) in toluene (50 mL) was added, and the mixture was reacted overnight under reflux. A 95% aqueous methanol solution (84 mL) was added to the reaction mixture, and the mixture was refluxed for 1 hour, and then filtered while hot. The filtrate was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain Compound 480 (928 mg, Y = 39%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.21 (2H, s) 7.25-8.49 (15H, m)
A saturated hydrochloric acid / acetic acid solution (40 mL) was added to compound 480 (600 mg), and the mixture was reacted at about 95 ° C. for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform / methanol) to obtain Compound 481 (214 mg, Y = 33%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.14-8.22 (9H, m) 8.56 (1H, s) 10.10 (1H, s),
Compound 481 (190 mg) was dissolved in DMF (10 mL), potassium carbonate (300 mg) and methyl bromoacetate (130 mg) were added, and the mixture was reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 482 (155 mg, Y = 65%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 3.85 (3H, s) 4.79 (2H, s) 7.13-8.50 (10H, m)
Methanol (20 mL) and 1,4-dioxane (50 mL) were added to compound 482 (120 mg), 8% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at about 50 ° C. for 30 min. The reaction solution was concentrated under reduced pressure, water (10 mL) and ethyl acetate (60 mL) were added to the residue, and the mixture was made strongly acidic by adding dilute hydrochloric acid, followed by liquid separation. The ethyl acetate layer was washed successively with water and saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give compound 483 (114 mg, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.87 (2H, s) 7.23-8.64 (10H, m) 13.0 (1H, br)
Compound 483 (70.3 mg) was dissolved in methanol (30 mL) with heating, 1.6% aqueous sodium hydroxide solution (0.5 mL) was added and stirred, and the precipitated solid was filtered and dried to give compound 484 (54 mg, Y = 76%).

６−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル（化合物４８５）、６−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩（化合物４８６）の製造：
化合物４８１（２５０ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（５．０ｇ）、６−ブロモヘキサン酸エチル（２５０ｍｇ）を加えて室温で一夜反応した。反応液に水（２０ｍｇ）を加えて晶析し、析出結晶をろ取した。得られた結晶をエタノールで洗浄後乾燥して化合物４８５（３０３ｍｇ，Ｙ＝８０％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ）１．４７−２．１０（６Ｈ，ｍ）２．３７（２Ｈ，ｔ，Ｊ＝６Ｈｚ）３．９７−４．３３（４Ｈ，ｍ）７．１３−８．４９（１０Ｈ，ｍ）
化合物４８５（２９０ｍｇ）にメタノール（５０ｍＬ）を加え加温溶解した後、３０％水酸化ナトリウム水溶液（１ｍＬ）を加えて還流下で１８時間反応した。冷却後、析出した結晶をろ取し乾燥して化合物４８６（２４０ｍｇ，Ｙ＝８４％）を得た。6-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 485), 6-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] hexanoic acid sodium salt ( Preparation of compound 486):
Compound 481 (250 mg) was dissolved in DMF (5 mL), and potassium carbonate (5.0 g) and ethyl 6-bromohexanoate (250 mg) were added and reacted at room temperature overnight. Water (20 mg) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 485 (303 mg, Y = 80%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7 Hz) 1.47-2.10 (6H, m) 2.37 (2H, t, J = 6 Hz) 3.97-4.33 (4H, m) 7.13-8.49 (10H, m)
Methanol (50 mL) was added to compound 485 (290 mg) and dissolved by heating, and then 30% aqueous sodium hydroxide solution (1 mL) was added and reacted under reflux for 18 hours. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 486 (240 mg, Y = 84%).

［３−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸ジエチルエステル（化合物４８７）、［３−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸（化合物４８８）、［３−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］プロピル］プロパン二酸二ナトリウム塩（化合物４８９）の製造：
化合物４８１（２５０ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（１．２ｇ）、（３−クロロプロピル）マロン酸ジエチル（２６０ｍｇ）を加えて約５５℃で一夜反応した。反応液に酢酸エチル（１５０ｍＬ）を加え、水洗した。酢酸エチル層を硫酸マグネシウムで脱水後、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物４８７（１９４ｍｇ，Ｙ＝４５％）を得た。
化合物４８７（１９４ｍｇ）をメタノール（５０ｍＬ）に溶解し、３０％水酸化ナトリウム水溶液（１ｍＬ）を加えて室温で１８時間反応した。反応液を減圧濃縮し、残渣に水（５０ｍＬ）を加えて溶解後、希塩酸を加えて酸析した。析出した結晶をろ取、乾燥して化合物４８８（１２８ｍｇ，Ｙ＝７５％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６／ＴＭＳ）：
δ＝１．７０−２．００（４Ｈ，ｍ）３．３８（１Ｈ，ｔ，Ｊ＝６Ｈｚ）４．１８（２Ｈ，ｔ，Ｊ＝５Ｈｚ）７．１８−８．６１（１０Ｈ，ｍ）１２．７（２Ｈ，ｂｒ）
化合物４８８（１０９．７ｍｇ）に０．０５％水酸化ナトリウム水溶液（４０ｍＬ）を加えて溶解した。ろ過後、ろ液を凍結乾燥して化合物４８９（１０８ｍｇ，Ｙ＝８９％）を得た。[3-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 487), [3-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid (compound 488), [3-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (compound 489):
Compound 481 (250 mg) was dissolved in DMF (10 mL), potassium carbonate (1.2 g) and diethyl (3-chloropropyl) malonate (260 mg) were added, and the mixture was reacted at about 55 ° C. overnight. Ethyl acetate (150 mL) was added to the reaction solution and washed with water. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 487 (194 mg, Y = 45%).
Compound 487 (194 mg) was dissolved in methanol (50 mL), 30% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 488 (128 mg, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.70-2.00 (4H, m) 3.38 (1H, t, J = 6 Hz) 4.18 (2H, t, J = 5 Hz) 7.18-8.61 (10H, m) 12.7 (2H, br)
Compound 488 (109.7 mg) was dissolved by adding 0.05% aqueous sodium hydroxide solution (40 mL). After filtration, the filtrate was lyophilized to obtain Compound 489 (108 mg, Y = 89%).

［５−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸ジエチルエステル（化合物４９０）、［５−［［６−（２−ベンゾチアゾリル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸二ナトリウム塩（化合物４９１）の製造：
化合物４８１（２５２ｍｇ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（１．２ｇ）、（５−ブロモペンチル）マロン酸ジエチル（３４０ｍｇ）を加えて室温で一夜撹拌した。反応液に酢酸エチル（８０ｍＬ）を加えて水、飽和食塩水で順次洗浄した。酢酸エチル層を硫酸マグネシウムで脱水し、減圧濃縮した。残渣をシリカゲルカラム（クロロホルム）で精製して化合物４９０（３６０ｍｇ，Ｙ＝７８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３／ＴＭＳ）：
δ＝１．１４−２．１５（１４Ｈ，ｍ）３．３５（１Ｈ，ｔ，Ｊ＝７Ｈｚ）４．０２−４．３９（６Ｈ，ｍ）７．１３−８．４８（１０Ｈ，ｍ）
化合物４９０（３４０ｍｇ）をメタノール（１００ｍＬ）に溶解後、９％水酸化ナトリウム水溶液（６ｍＬ）を加えて約５０℃で１８時間、還流下で８時間反応した。冷却後、析出した結晶をろ取、乾燥して化合物４９１（２９０ｍｇ，Ｙ＝８７％）を得た。
以上の実施例で得られた化合物を表１に示す。化合物番号は各実施例で化合物に付与した番号に対応する。

製剤処方例１（錠剤）：
本発明化合物１０．０ｇ
乳糖９．０ｇ
ヒドロキシプロピルセルロース２．０ｇ
結晶セルロース７．７ｇ
ステアリン酸マグネシウム０．３ｇ
タルク１．０ｇ
以上を常法により、本発明化合物１００ｍｇを含有する錠剤とする。
製剤処方例２（注射剤）：
本発明化合物１ｍｇ
５％ブドウ糖注射液２ｍＬ
以上を常法により注射剤とする。
製剤処方例３（坐剤）：
本発明化合物１０ｍｇ
カカオ脂適量
以上を常法により坐剤とする。
次に本発明化合物のプラスミン形成促進試験、ｔ−ＰＡ賦活活性試験及びＰＡＩ−１阻害活性試験を示す。
プラスミン形成促進試験：
本発明化合物を注射用水とＤＭＳＯにより１×１０^−３Ｍに調製し、本発明化合物溶液とした。９６穴マイクロプレートを氷上に置き、本発明化合物溶液を２５μＬ（終濃度１．２５×１０^−４Ｍ）、１５０ｍＭ塩化ナトリウムを含む２０ｍＭ燐酸緩衝液（ｐＨ７．４）で希釈したｒｔ−ＰＡを５０μＬ（終濃度４０００ＩＵ／ｍＬ）、グルタミン酸タイプ−ヒトプラスミノーゲンを２５μＬ（終濃度８．７５μｇ／ｍＬ）、合成基質Ｓ−２２５１を１００μＬ（終濃度０．５ｍＭ）をそれぞれ添加して混合した。コントロールとして本発明化合物溶液の代わりに、ＤＭＳＯ溶液２５μＬ（終濃度１．２５％）を添加した。３７℃でインキュベートしながら、マイクロプレートリーダーで４０５ｎｍの吸光度を２時間測定した。吸光度１．４に達するのに要する時間を算出し、コントロールに対する比から、プラスミン形成促進活性を求めた。その結果、本発明化合物が優れたプラスミン形成促進作用を有する事が明らかとなった。結果を表２に示した。

ｔ−ＰＡ賦活活性試験及びＰＡＩ−１阻害活性試験：
本発明化合物、ＰＡＩ−１、ｒｔ−ＰＡを下記表３に示すＡ〜Ｄの四種類の組み合わせで下記の試験を実施した。

本発明化合物を注射用水とＤＭＳＯにより１．８７５×１０^−３Ｍに調製し、さらにこれを注射用水で段階希釈して、本発明化合物溶液とした。本発明化合物溶液と注射用水で調製したＰＡＩ−１を室温に於いて、９６穴マイクロプレート上で１０分インキュベートした後、トリス塩酸緩衝液で調製したｒｔ−ＰＡをそれぞれのウェルに添加・混合し、更に室温で１０分インキュベートした。次に、トリス塩酸緩衝液で調製した合成基質Ｓ−２２８８（終濃度０．５ｍＭ）５０μＬをそれぞれのウェルに添加・混合し、室温で１０分インキュベートした。その後、３７℃でインキュベートしながら、マイクロプレートリーダーで４０５ｎｍの吸光度を測定し、Ａ，Ｂ，Ｃ，Ｄの吸光度をａ，ｂ，ｃ，ｄとして、下記の要領で各活性を求めた。
ｔ−ＰＡ賦活活性：
ａ／ｂを、本発明化合物のｔ−ＰＡ賦活活性値とした。
ＰＡＩ−１阻害活性：
先ず、本発明化合物のＰＡＩ−１阻害率を、ａ＝ｃの時１００％、ｃ／ｄ＝ａ／ｂの時０％とした直線関係から求め、得られたＰＡＩ−１阻害率（％）を縦軸に、その時の本発明化合物の終濃度（１．２５×１０^−４Ｍ，１．２５×１０^−５Ｍ）の対数値を横軸に採り、ＩＣ５０を求めた。その結果、本発明化合物が優れたｔ−ＰＡ賦活活性及びＰＡＩ−１阻害活性を有する事が明らかとなった。結果を表４、表５に示した。

[5-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 490), [5-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid disodium salt (Compound 491):
Compound 481 (252 mg) was dissolved in DMF (10 mL), potassium carbonate (1.2 g) and (5-bromopentyl) malonate (340 mg) were added, and the mixture was stirred overnight at room temperature. Ethyl acetate (80 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 490 (360 mg, Y = 78%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.14-2.15 (14H, m) 3.35 (1H, t, J = 7 Hz) 4.02-4.39 (6H, m) 7.13-8.48 (10H, m)
Compound 490 (340 mg) was dissolved in methanol (100 mL), 9% aqueous sodium hydroxide solution (6 mL) was added, and the mixture was reacted at about 50 ° C. for 18 hr and under reflux for 8 hr. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 491 (290 mg, Y = 87%).
The compounds obtained in the above examples are shown in Table 1. The compound number corresponds to the number assigned to the compound in each example.

Formulation example 1 (tablet):
Present compound 10.0 g
Lactose 9.0g
Hydroxypropylcellulose 2.0g
7.7 g of crystalline cellulose
Magnesium stearate 0.3g
Talc 1.0g
The above is made into a tablet containing 100 mg of the compound of the present invention by a conventional method.
Formulation example 2 (injection):
1 mg of the present compound
5% glucose injection solution 2mL
The above is made into an injection by a conventional method.
Formulation example 3 (suppository):
10 mg of the present compound
Cocoa butter
The above is made into a suppository by a conventional method.
Next, a plasmin formation promotion test, a t-PA activation activity test, and a PAI-1 inhibitory activity test of the compound of the present invention are shown.
Plasmin formation promotion test:
The compound of the present invention was prepared to 1 × 10 ⁻³ M with water for injection and DMSO to obtain a compound solution of the present invention. Place a 96-well microplate on ice, 25 μL of the compound solution of the present invention (final concentration 1.25 × 10 ⁻⁴ M), 50 μL of rt-PA diluted with 20 mM phosphate buffer (pH 7.4) containing 150 mM sodium chloride. (Final concentration 4000 IU / mL), glutamic acid type-human plasminogen 25 μL (final concentration 8.75 μg / mL), and synthetic substrate S-2251 100 μL (final concentration 0.5 mM) were added and mixed. As a control, 25 μL of DMSO solution (final concentration 1.25%) was added instead of the compound solution of the present invention. While incubating at 37 ° C., the absorbance at 405 nm was measured with a microplate reader for 2 hours. The time required to reach an absorbance of 1.4 was calculated, and the plasmin formation promoting activity was determined from the ratio to the control. As a result, it was revealed that the compound of the present invention has an excellent plasmin formation promoting action. The results are shown in Table 2.

t-PA activation activity test and PAI-1 inhibitory activity test:
The following tests were carried out on the compounds of the present invention, PAI-1, and rt-PA using the four combinations A to D shown in Table 3 below.

The compound of the present invention was prepared to 1.875 × 10 ⁻³ M with water for injection and DMSO, and this was serially diluted with water for injection to obtain a compound solution of the present invention. After incubating PAI-1 prepared with the compound solution of the present invention and water for injection on a 96-well microplate at room temperature for 10 minutes, rt-PA prepared with Tris-HCl buffer was added to each well and mixed. The mixture was further incubated at room temperature for 10 minutes. Next, 50 μL of synthetic substrate S-2288 (final concentration 0.5 mM) prepared in Tris-HCl buffer was added to and mixed with each well, and incubated at room temperature for 10 minutes. Thereafter, the absorbance at 405 nm was measured with a microplate reader while incubating at 37 ° C., and the activities of A, B, C and D were determined as a, b, c and d, and the respective activities were determined in the following manner.
t-PA activation activity:
a / b was defined as the t-PA activation activity value of the compound of the present invention.
PAI-1 inhibitory activity:
First, the PAI-1 inhibition rate of the compound of the present invention was determined from a linear relationship with 100% when a = c and 0% when c / d = a / b, and the obtained PAI-1 inhibition rate (%) Is the vertical axis, and the logarithmic value of the final concentration (1.25 × 10 ⁻⁴ M, 1.25 × 10 ⁻⁵ M) of the compound of the present invention is plotted on the horizontal axis to obtain IC50. As a result, it was revealed that the compound of the present invention has excellent t-PA activation activity and PAI-1 inhibitory activity. The results are shown in Tables 4 and 5.

本発明化合物は優れたＰＡ活性促進作用及びＰＡＩ−１阻害活性作用を有し、優れた血栓溶解作用を発現するため、血栓に関連して起こる疾患に有効である。すなわち、静脈血栓症、心筋梗塞症、肺塞栓症、脳梗塞症、緩徐に進行する脳血栓症、血管手術および血液体外循環に伴う血栓・塞栓の治療並びに血流障害の改善、慢性動脈閉塞症に伴う諸症状の改善、虚血性脳血管障害に伴う血栓・塞栓の治療等、血栓・塞栓症全般の治療薬として、単独で血栓溶解剤、抗血栓剤として、あるいは他の血栓溶解剤等の血栓症治療剤と併用することができる。 The compound of the present invention has an excellent PA activity promoting action and PAI-1 inhibitory activity action, and expresses an excellent thrombolytic action, and is therefore effective for diseases caused by thrombus. In other words, venous thrombosis, myocardial infarction, pulmonary embolism, cerebral infarction, slowly progressing cerebral thrombosis, treatment of thrombosis / embolism associated with vascular surgery and extracorporeal blood circulation, improvement of blood flow disorder, chronic arterial occlusion Thrombus such as thrombolytic agent, antithrombotic agent alone or other thrombolytic agent as a therapeutic agent for all thrombosis / embolism such as improvement of various symptoms, treatment of thrombus / embolism associated with ischemic cerebrovascular disorder It can be used in combination with a symptom treatment agent.

Claims

下記式（25）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。

［ここで
（１）Ａは、
（ｉ）−アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（6）
（ここで、低級アルキレン基とは、炭素数１乃至７の直鎖又は分岐状のアルキレ
ン基を意味し、
<1>ａ_１は、
１．−ＣＯＯＲ_４ …（7）
（ここでＲ_４は水素原子、炭素数１乃至７の直鎖又は分岐状のアシルオキ
シ基で置換されてよい炭素数１乃至４の直鎖又は分岐状のアルキル基又
はベンジル基を意味する。）
２．

（ここでＲ_５，Ｒ_６は互いに独立して水素原子、炭素数１乃至７の直鎖又
は分岐状のアシルオキシ基で置換されてよい炭素数１乃至４の直鎖又は
分岐状のアルキル基又はベンジル基を意味する。）
又は
３．フェニル基
を意味し、
<2>アリーレン基は2,6-ナフタレンジイル基を意味する。）
又は
（ii）−アリーレン基−ａ_２ …（12）
（ここで、ａ_２は水酸基を意味し、アリーレン基は、2,6-ナフタレンジイ
ル基を意味する。）
を意味し、
（２）ｂ_１，ｂ_２及びｂ_３は水素原子
を意味する。］A compound represented by the following formula (25), or a pharmaceutically acceptable salt compound thereof or a solvate thereof.

[Where (1) A is
(I) -arylene group-O-lower alkylene group-a ₁ (6)
(Here, the lower alkylene group is a linear or branched alkyl group having 1 to 7 carbon atoms.
Meaning
<1> a ₁ is
1. -COOR ₄ (7)
(Wherein R ₄ is a hydrogen atom, a linear or branched acyloxy group having 1 to 7 carbon atoms)
A linear or branched alkyl group having 1 to 4 carbon atoms which may be substituted with
Means a benzyl group. )
2.

(Where R ₅ and R ₆ are each independently a hydrogen atom, a straight chain or
Is a straight chain having 1 to 4 carbon atoms which may be substituted with a branched acyloxy group or
A branched alkyl group or benzyl group is meant. )
Or
3. Phenyl group
Means
<2> Arylene group means 2,6-naphthalenediyl group. )
Or (ii) -arylene group-a ₂ (12)
(Wherein a ₂ represents a hydroxyl group, and an arylene group represents 2,6-naphthalenedi
Means a ru group. )
Means
(2) b ₁ , b ₂ and b ₃ are hydrogen atoms
Means. ]

以下の化合物群から選ばれる化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
2-[6-(フェニルメトキシ)-2-ナフタレニル]ベンゾチアゾール、
6-(2-ベンゾチアゾリル)-2-ナフタレノール、
[[6-(2-ベンゾチアゾリル)-2-ナフタレニル]オキシ]酢酸メチルエステル、
[[6-(2-ベンゾチアゾリル)-2-ナフタレニル]オキシ]酢酸、
6-[[6-(2-ベンゾチアゾリル)-2-ナフタレニル]オキシ]ヘキサン酸エチルエステル、
[3-[[6-(2-ベンゾチアゾリル)-2-ナフタレニル]オキシ]プロピル]プロパン二酸、
[5-[[6-(2-ベンゾチアゾリル)-2-ナフタレニル]オキシ]ペンチル]プロパン二酸ジエチルエステルThe compound chosen from the following compound groups, or those pharmaceutically acceptable salt compounds, or those solvates.
2- [6- (phenylmethoxy) -2-naphthalenyl] benzothiazole,
6- (2-benzothiazolyl) -2-naphthalenol,
[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester,
[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid,
6-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester,
[3-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid,
[5-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester

請求項１または２に記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物を有効成分として含む医薬組成物。 A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt compound or a solvate thereof as an active ingredient .

請求項１または２に記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物を有効成分として含む、血栓溶解剤又は抗血栓剤。 A thrombolytic agent or antithrombotic agent comprising the compound according to claim 1 or 2, or a pharmaceutically acceptable salt compound thereof or a solvate thereof as an active ingredient.

血栓症を治療するための医薬組成物を製造するための請求項１または２に記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物の使用。A compound according to claim 1 or 2 for preparing a pharmaceutical composition for the treatment of thrombosis, or the use of a pharmaceutically acceptable salt thereof the compounds or a solvate thereof.