JPWO2002046176A1 - Activator of peroxisome proliferator-activated receptor - Google Patents

Abstract

（式中、Ｒ^６及びＲ^７は水素原子、ニトロ基、炭素原子数１〜８のアルキル基、若しくは炭素原子数６〜１０のアリール基等を表すか、又はＲ^６とＲ^７が一緒になってＲ^６及びＲ^７が結合している炭素原子と共にベンゼン環を形成しても良く、Ｇ^１は単結合又はカルボニル基を表し、
Ｒ^８は炭素原子数１〜８のアルキル基、炭素原子数６〜１０のアリール基、又はアリールアルキル基（アリール部分の炭素原子数６〜１０で、アルキル部分の炭素原子数１〜８）等を表し、
ｍは０〜５の整数を表し、
Ｙ^１は−ＣＨ_２−、カルボニル基等を表し、
Ｚ^１は酸素原子又は硫黄原子を表し、
Ｒ^９及びＲ^１０は水素原子又は炭素原子数１〜８のアルキル基を表し、
そしてＲは水素原子又は炭素原子数１〜６のアルキル基を表す。）
で表されるチアゾール誘導体、又はその塩をＰＰＡＲの活性化剤として使用する。The following general formula (II):

(Wherein, R ⁶ and R ⁷ represent a hydrogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or R ⁶ and R ⁷ together May form a benzene ring with the carbon atom to which R ⁶ and R ⁷ are attached, G ¹ represents a single bond or a carbonyl group,
R ⁸ is an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an arylalkyl group (6 to 10 carbon atoms in the aryl portion and 1 to 8 carbon atoms in the alkyl portion), etc. Represents
m represents an integer of 0 to 5,
Y ¹ represents —CH ₂ —, a carbonyl group, or the like;
Z ¹ represents an oxygen atom or a sulfur atom,
R ⁹ and R ¹⁰ represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. )
Is used as a PPAR activator.

Description

で表されるＧＷ−２４３３（Ｇｌａｘｏ　Ｗｅｌｌｃｏｍｅ）、次式、

で表されるＬ−１６５０４１（Ｍｅｒｃｋ）或いは次式、

で表されるＹＭ−１６６３８（山之内製薬）等が知られている。
ＧＷ−２４３３はアテローム硬化症の予防及び治療薬としての使用がＷＯ９２／１０４６８に記載され、Ｌ−１６５０４１は糖尿病治療剤や抗肥満薬としての使用がＷＯ９７／２８１１５に記載され、そしてＹＭ−１６６３８についてはＷＯ９９／０４８１５に血清コレステロール低下作用、ＬＤＬ−コレステロール低下作用を有する旨の記載がなされている。
更に最近、ＰＰＡＲδのリガンドは抗ガン剤や抗炎症剤としての応用を促す報告（ＪＢＣ，２７２（６）、ｐ３４０６−３４１０，１９９７；Ｃｅｌｌ、９９，ｐ３３５−３４５，１９９９）がなされている。
一方、後記一般式（ＩＩ）で表される本発明化合物（チアゾール誘導体）と類似した構造を有する化合物として血清脂質改善作用を有するベザフィブラート（Ｂｅｚａｆｉｂｒａｔｅ）が挙げられる。

ベザフィブラートと本発明化合物とは共にベンゼン環にアミノ基で置換されたアルキル基とカルボキシル基で置換されたアルコキシ基が結合した化学構造を有するが、このアミノ基で置換されたアルキル基が、ベザフィブラートではＮ−（ｐ−クロロベンゾイル）アミノアルキル基であり、本発明化合物ではＮ−（窒素含有複素環、又は窒素含有複素環カルボニル）アミノアルキル基であり、両者は構造上明確に相違する。
また、上記のＧＷ−２４３３（ＷＯ　９２／１０４６８）もベンゼン環にアミノ基で置換されたアルキル基とカルボキシル基で置換されたアルコキシ基が結合した化学構造を有するが、ＧＷ−２４３３ではかかるアミノ基で置換されたアルキル基がＮ−（フェニルカルバモイル）アミノアルキル基であるので、本発明化合物とは構造上明確に相違する。
その他、米国特許第６０２８０８７号、中国特許第１１１４３２１号、ＷＯ　９７／３６８８７、ＷＯ　９４／２１５９９、ＷＯ　９４／１４７７５、ＷＯ　９８／１７６４６、米国特許第５３６４８６９号及び特開平６−２５２５０には本発明化合物と構造の一部を共通とする化合物の記載があるが、これら文献記載の化合物も本発明化合物とは明確に構造上の相違がある。
本発明の目的はペルオキシソーム増殖剤応答性受容体の活性化作用を有する下記一般式（Ｉ）で表される化合物、下記一般式（ＩＩ）で表されるチアゾール誘導体及びその塩を提供することにある。
発明の開示
即ち、本発明は、次の一般式（Ｉ）、

（式中、Ｒ^１及びＲ^２はそれぞれ水素原子、ハロゲン原子、ニトロ基、炭素原子数１〜８のアルキル基、炭素原子数１〜８のアルコキシ基、若しくは炭素原子数６〜１０のアリール基を表すか、又はＲ^１とＲ^２が一緒になってＲ^１及びＲ^２が結合している炭素原子と共にベンゼン環を形成しても良く、
Ｘは酸素原子、硫黄原子、−ＮＲ^０−（Ｒ^０は水素原子又は炭素原子数１〜８のアルキル基）、又は−ＣＨ＝ＣＨ−を表し、
Ｇは単結合又はカルボニル基を表し、
Ｒ^３は炭素原子数１〜８のアルキル基、炭素原子数２〜８のアルケニル基、炭素原子数２〜８のアルキニル基、炭素原子数３〜７のシクロアルキル基、炭素原子数３〜７のシクロアルキル基で置換された炭素原子数１〜８のアルキル基、炭素原子数６〜１０のアリール基、アリールアルキル基（アリール部分の炭素原子数６〜１０で、アルキル部分の炭素原子数１〜８）、複素環基、又は複素環アルキル基（アルキル部分の炭素原子数１〜８）を表し、
ｎは０〜５の整数を表し、
Ｙは−ＣＨ_２−、カルボニル基、又は−ＣＨ＝ＣＨ−を表し、
Ｚは酸素原子又は硫黄原子を表し、
ｐは０〜５の整数を表し、
Ｒ^４及びＲ^５はそれぞれ水素原子又は炭素原子数１〜８のアルキル基を表し、
そしてＷはカルボキシル基、炭素原子数２〜８のアルコキシカルボニル基、スルホン酸基、ホスホン酸基、シアノ基、又はテトラゾリル基を表す。
上記Ｒ^１及びＲ^２のアリール基、Ｒ^３のアリール基、アリールアルキル基、複素環基、複素環アルキル基、並びにＲ^１とＲ^２が一緒になってＲ^１及びＲ^２が結合している炭素原子と共に形成されるベンゼン環は炭素原子数１〜８のアルキル基、炭素原子数１〜８のアルコキシ基、炭素原子数２〜８のアルコキシカルボニル基、炭素原子数２〜８のアシル基、ホルミル基、水酸基、ハロゲン原子、ニトロ基、アミノ基、アルキルアミノ基（アルキル基の炭素原子数は１〜８）、又はジアルキルアミノ基（アルキル基の炭素原子数は１〜８）から選ばれる置換基を有していても良い。）
で表される化合物又はその塩に関する。
また、本発明は次の一般式（ＩＩ）、

（式中、Ｒ^６及びＲ^７はそれぞれ水素原子、ハロゲン原子、ニトロ基、炭素原子数１〜８のアルキル基、炭素原子数１〜８のアルコキシ基、若しくは炭素原子数６〜１０のアリール基を表すか、又はＲ^６とＲ^７が一緒になってＲ^６及びＲ^７が結合している炭素原子と共にベンゼン環を形成しても良く、
Ｇ^１は単結合又はカルボニル基を表し、
Ｒ^８は炭素原子数１〜８のアルキル基、炭素原子数２〜８のアルケニル基、炭素原子数２〜８のアルキニル基、炭素原子数３〜７のシクロアルキル基、炭素原子数３〜７のシクロアルキル基で置換された炭素原子数１〜８のアルキル基、炭素原子数６〜１０のアリール基、アリールアルキル基（アリール部分の炭素原子数６〜１０で、アルキル部分の炭素原子数１〜８）、複素環基、又は複素環アルキル基（アルキル部分の炭素原子数１〜８）を表し、
ｍは０〜５の整数を表し、
Ｙ^１は−ＣＨ_２−、カルボニル基、又は−ＣＨ＝ＣＨ−を表し、
Ｚ^１は酸素原子又は硫黄原子を表し、
Ｒ^９及びＲ^１０はそれぞれ水素原子又は炭素原子数１〜８のアルキル基を表し、そしてＲは水素原子又は炭素原子数１〜６のアルキル基を表す。
上記Ｒ^６及びＲ^７のアリール基、Ｒ^８のアリール基、アリールアルキル基、複素環基、複素環アルキル基、並びにＲ^６とＲ^７が一緒になってＲ^６及びＲ^７が結合している炭素原子と共に形成されるベンゼン環は炭素原子数１〜８のアルキル基、炭素原子数１〜８のアルコキシ基、炭素原子数２〜８のアルコキシカルボニル基、炭素原子数２〜８のアシル基、ホルミル基、水酸基、ハロゲン原子、ニトロ基、アミノ基、アルキルアミノ基（アルキル基の炭素原子数は１〜８）、又はジアルキルアミノ基（アルキル基の炭素原子数は１〜８）から選ばれる置換基を有していても良い。）
で表されるチアゾール誘導体又はその塩に関する。
さらにまた本発明は上記一般式（Ｉ）で表される化合物若しくは上記一般式（ＩＩ）で表される化合物又はこれらの塩を有効成分として含有するＰＰＡＲの活性化剤に関する。
次に本発明を詳細に説明する。
上記一般式（Ｉ）における記号の説明をする。
上記一般式（Ｉ）のＲ^１、Ｒ^２のハロゲン原子としては、フッ素原子、塩素原子又は臭素原子が挙げられる。Ｒ^１、Ｒ^２、Ｒ^０、Ｒ^３、Ｒ^４及びＲ^５の炭素原子数１〜８のアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｉ−ブチル基、ｔ−ブチル基、又はペンチル基等が挙げられる。Ｒ^１及びＲ^２の炭素原子数１〜８のアルコキシ基としてはメトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、ブチルオキシ基、ｉ−ブチルオキシ基、ｔ−ブチルオキシ基、又はペンチルオキシ基等が挙げられる。
Ｒ^３の炭素原子数２〜８のアルケニル基としては、ビニル基、アリル基等が挙げられる。
Ｒ^３の炭素原子数２〜８のアルキニル基としては、プロパルギル基等が挙げられる。
Ｒ^３の炭素原子数３〜７のシクロアルキル基としては、シクロヘキシル基、シクロペンチル基等が挙げられる。
Ｒ^３の炭素原子数３〜７のシクロアルキル基で置換された炭素原子数１〜８のアルキル基としては、シクロヘキシルメチル基、シクロペンチルメチル基等が挙げられる。
Ｒ^１、Ｒ^２及びＲ^３のアリール基としては、フェニル基、ナフチル基等が挙げられる。
Ｒ^３のアリールアルキル基（アリール部分の炭素原子数６〜１０で、アルキル部分の炭素原子数１〜８）としては、ベンジル基、フェネチル基等が挙げられる。
Ｒ^３の複素環としては、チエニル基、フリル基、チアゾリル基、オキサゾリル基、ピリジル基、イミダゾリル基、キノリル基、インドリル基、又はベンゾフラニル基等が挙げられる。
Ｒ^３の複素環アルキル基（アルキル部分の炭素原子数１〜８）としては、前記Ｒ^３の複素環基の例としてあげた複素環基がメチル基、エチル基、プロピル基に置換したものが挙げられる。
また上記一般式（Ｉ）のＲ^１及びＲ^２のアリール基、Ｒ^３のアリール基、アリールアルキル基、複素環基、複素環アルキル基、並びにＲ^１とＲ^２が一緒になってＲ^１及びＲ^２が結合している炭素原子と共に形成されるベンゼン環の置換基として挙げられる基又は原子のうち、炭素原子数１〜８のアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｉ−ブチル基、ｔ−ブチル基、又はペンチル基等が挙げられ、炭素原子数１〜８のアルコキシ基としてはメトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、ブチルオキシ基、ｉ−ブチルオキシ基、ｔ−ブチルオキシ基、又はペンチルオキシ基等が挙げられ、炭素原子数２〜８のアルコキシカルボニル基としては、メトキシカルボニル基、エトキシカルボニル基等が挙げられ、炭素原子数２〜８のアシル基としては、アセチル基、プロピオニル基等が挙げられ、ハロゲン原子としては、フッ素原子、塩素原子又は臭素原子が挙げられ、アルキルアミノ基（アルキル基の炭素原子数は１〜８）としては、メチルアミノ基、エチルアミノ基が挙げられ、そしてジアルキルアミノ基（アルキル基の炭素原子数は１〜８）としてはジメチルアミノ基、ジエチルアミノ基等が挙げられる。
次に上記一般式（ＩＩ）における記号の説明をする。
上記一般式（ＩＩ）において、Ｒ^６及びＲ^７のハロゲン原子としては、上記一般式（Ｉ）のＲ^１及びＲ^２で例示したハロゲン原子と同じものが、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９及びＲ^１０の炭素原子数１〜８のアルキル基としては、同じくＲ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５で例示したアルキル基と同じものが、Ｒ^６、Ｒ^７の炭素原子数１〜８のアルコキシ基としては、Ｒ^１及びＲ^２で例示をしたアルコキシ基が挙げられる。
上記一般式（ＩＩ）において、Ｒ^８の炭素原子数２〜８のアルケニル基、炭素原子数２〜８のアルキニル基、炭素原子数３〜７のシクロアルキル基、炭素原子数３〜７のシクロアルキル基で置換された炭素原子数１〜８のアルキル基、アリールアルキル基（アリール部分の炭素原子数６〜１０で、アルキル部分の炭素原子数１〜８）、複素環及び複素環アルキル基（アルキル部分の炭素原子数１〜８）としては同じく上記一般式（Ｉ）のＲ^３で例示したものが挙げられる。
Ｒ^６、Ｒ^７及びＲ^８のアリール基としては同じく上記一般式（Ｉ）のＲ^１、Ｒ^２及びＲ^３のアリール基として例示したものが挙げられる。
また上記一般式（ＩＩ）でＲ^６及びＲ^７のアリール基、Ｒ^８のアリール基、アリールアルキル基、複素環基、複素環アルキル基、並びにＲ^６とＲ^７が一緒になってＲ^６及びＲ^７が結合している炭素原子と共に形成されるベンゼン環が有していても良い置換基として挙げられる炭素原子数１〜８のアルキル基、炭素原子数１〜８のアルコキシ基、炭素原子数２〜８のアルコキシカルボニル基、炭素原子数２〜８のアシル基、ハロゲン原子、アルキルアミノ基（アルキル基の炭素原子数は１〜８）、又はジアルキルアミノ基（アルキル基の炭素原子数は１〜８）としては、同じく上記一般式（Ｉ）のＲ^１及びＲ^２のアリール基、Ｒ^３のアリール基、アリールアルキル基、複素環基、複素環アルキル基、並びにＲ^１とＲ^２が一緒になってＲ^１及びＲ^２が結合している炭素原子と共に形成されるベンゼン環の置換基として挙げられる基又は原子ので例示したものが挙げられ、さらにこれらの置換基の数は１〜３が好ましい。
（１）本発明化合物としては、上記一般式（ＩＩ）で表されるチアゾール誘導体のうち、Ｒ^８が炭素原子数１〜８のアルキル基、又は置換基として炭素原子数１〜８のアルキル基、炭素原子数１〜８のアルコキシ基、炭素原子数２〜８のアシル基、水酸基、ハロゲン原子、ニトロ基、又はアミノ基から選ばれる基又は原子を有していても良いフェニルアルキル基（アルキル部分の炭素原子数は１〜８）であるチアゾール誘導体又はその塩が好ましい。
（２）また、本発明化合物としては、上記一般式（ＩＩ）で表されるチアゾール誘導体のうち、Ｙ^１が−ＣＨ_２−である上記一般式（ＩＩ）で表されるチアゾール誘導体若しくはその塩、又はＲ^８が上記（１）で記載のもので、Ｙ^１が−ＣＨ_２−である上記一般式（ＩＩ）で表されるチアゾール誘導体若しくはその塩が好ましい。
（３）さらにまた、上記一般式（ＩＩ）で、Ｒ^６及びＲ^７はそれぞれ水素原子、ニトロ基、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｉ−ブチル基、ｔ−ブチル基若しくはペンチル基等の炭素原子数１〜６のアルキル基、メトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、ブチルオキシ基、ｉ−ブチルオキシ基、ｔ−ブチルオキシ基若しくはペンチルオキシ基等の炭素原子数１〜６のアルコキシ基を表すか、又はＲ^６とＲ^７が一緒になってＲ^６及びＲ^７が結合している炭素原子と共にベンゼン環を形成することが好ましい。
Ｇ^１は単結合又はカルボニル基である。
Ｒ^８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、ｉ−ブチル基、ｔ−ブチル基若しくはペンチル基等の炭素原子数１〜６のアルキル基、フェニルアルキル基（アルキル部分の炭素原子数は１〜６）が好ましく、更に好ましくはベンジル基、フェネチル基若しくは３−フェニルプロピル基等のフェニルアルキル基（アルキル部分の炭素原子数は１〜６）が挙げられる。
ｍは１〜４の整数が好ましい。
Ｙ^１は−ＣＨ_２−が好ましい。
Ｚ^１は酸素原子が好ましい。
Ｒ^９及びＲ^１０は同一又は異なりメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｉ−ブチル基、ｔ−ブチル基若しくはペンチル基等の炭素原子数１〜６のアルキル基が好ましいく、されに好ましくはＲ^９及びＲ^１０は共にメチル基、エチル基又はプロピル基が挙げられる。
そしてＲは水素原子が好ましい。
上記Ｒ^８のフェニルアルキル基（アルキル部分の炭素原子数は１〜６）、並びにＲ^６とＲ^７が一緒になってＲ^６及びＲ^７が結合している炭素原子と共にベンゼン環を形成する場合にベンゼン環が有していても良い置換基としてはメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｉ−ブチル基、ｔ−ブチル基若しくはペンチル基等の炭素原子数１〜６のアルキル基、メトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、ブチルオキシ基、ｉ−ブチルオキシ基、ｔ−ブチルオキシ基若しくはペンチルオキシ基等の炭素原子数１〜６のアルコキシ基、メトキシカルボニル基若しくはエトキシカルボニル基等の炭素原子数２〜６のアルコキシカルボニル基、アセチル基若しくはプロピオニル基等の炭素数２〜６のアシル基、水酸基、ハロゲン原子、ニトロ基又はアミノ基が好ましい。
尚、フェニル基に結合している

に対して

は、３又は４位に結合することが好ましく、更に好ましくは４位が挙げられる。
本発明化合物である上記一般式（Ｉ）で表される化合物及びその塩、並びに上記一般式（ＩＩ）で表されるチアゾール誘導体及びその塩は、シス、トランスの幾何異性体や光学異性体等も存在する場合もあるが、これらの異性体も本発明に含まれる。
更にまた、本発明化合物としては、ナトリウム塩、カリウム塩等のアルカリ金属塩等の製薬学的に許容される塩も含まれる。
次に本発明化合物である一般式（Ｉ）の製造方法を記載する。
合成方法１

（式中、Ｑ^１は臭素原子、塩素原子等の脱離基を表し、そしてＲ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｘ、Ｇ、ｎ、Ｙ、Ｚ、ｐ及びＷは前記と同じ。）
上記反応は一般式（ａ）で表されるフェノール（又はチオフェノール）誘導体と一般式（ｂ）で表される化合物を炭酸カリウム等の塩基の存在下、アセトン、エチルメチルケトン等の溶媒中で行うことができる。
原料である一般式（ａ）で表されるフェノール（又はチオフェノール）誘導体は例えば以下の方法により得ることができる。
（ｉ）Ｇ＝単結合で、Ｙ＝−ＣＨ_２−又は−ＣＨ＝ＣＨ−の場合

（式中、Ｑ^２は臭素原子、塩素原子等の脱離基を表し、Ｔは水素原子又は水酸基（又はメルカプト基）の保護基を表し、そしてＲ^１、Ｒ^２、Ｒ^３、Ｘ、ｎ及びＺは前記と同じ。）
一般式（ｅ）の化合物は一般式（ｃ）の複素環化合物と一般式（ｄ）のアミンを水素化ナトリウム等の塩基の存在下、ＤＭＳＯ等の溶媒中で反応させ得ることができる。ここでＴが水酸基（又はメルカプト基）の保護基の場合、更に得られた一般式（ｅ）の化合物を脱保護することにより一般式（ｆ）で表される化合物を得ることができる。
（ｉｉ）Ｇ＝カルボニル基で、Ｙ＝−ＣＨ_２−又は−ＣＨ＝ＣＨ−の場合

（式中、Ｑ^３は水酸基、ｐ−トシル基、臭素原子若しくは塩素原子のハロゲン原子、又はメトキシ、エトキシ、プロポキシ若しくはブトキシ等の炭素原子数１〜６のアルコキシ基を表し、そしてＲ^１、Ｒ^２、Ｒ^３、Ｘ、ｎ、Ｚ及びＴは前記と同じ。）
一般式（ｈ）の化合物は一般式（ｇ）のカルボン酸誘導体と一般式（ｄ）のアミンをソジウム　メトキサイド等の塩基の存在下、ベンゼン等の溶媒中で反応させることで得ることができる（アミド化反応）。ここでＴが保護基の場合、さらに得られた一般式（ｈ）の化合物を脱保護することにより一般式（ｉ）で表される化合物を得ることができる。
合成方法２
Ｗ＝カルボキシル基の場合

（式中、Ｒ^２０はアルキル基を表し、そしてＲ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｘ、Ｇ、ｎ、Ｙ及びｐ前記と同じ。）
一般式（ｋ）で表される化合物は、一般式（ｊ）で表されるエステル体を水酸化ナトリウム、水酸化カリウム又は水酸化リチウム等の塩基の存在下、エタノール等の溶媒中で加水分解反応に付すことにより得ることができる。
合成方法３
（ｉ）Ｇ＝単結合で、Ｙ＝カルボニル基の場合

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｘ、Ｑ^２、ｎ、Ｚ、ｐ及びＷは前記と同じ。）
（ｉｉ）Ｇ＝カルボニル基で、Ｙ＝カルボニル基の場合

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｘ、Ｑ^３、ｎ、Ｚ、ｐ及びＷは前記と同じ。）
上記（ｉ），（ｉｉ）の反応は無溶媒、又はＤＭＳＯ、ＤＭＦ、ベンゼン若しくはトルエン等の溶媒中、場合によっては炭酸カリウム等の塩基の存在下行うことができる。
また、上記一般式（ｌ）で表されるアミンは例えば以下の合成ルートで得ることができる。

（式中、Ｍは窒素原子の保護基を、Ｑ^４はｐ−トシル基、又は臭素原子若しくは塩素原子等のハロゲン原子を表し、そしてＲ^３、Ｒ^４、Ｒ^５、Ｒ、ｎ及びｐは前記と同じ。）
かくして得られた本発明化合物の代表化合物例を次に示す。
（１）上記一般式（Ｉ）で表される化合物で、Ｘ＝Ｓ、Ｚ＝Ｏ、ｐ＝０、Ｗ＝ＣＯ_２Ｈの化合物例：

【表１】

【表２】

【表３】

（２）上記一般式（Ｉ）で表される化合物で、Ｘ＝Ｓ、Ｚ＝Ｓ、ｐ＝０、Ｗ＝ＣＯ_２Ｈの化合物例：

【表４】

【表５】

（３）上記一般式（Ｉ）で表される化合物で、Ｚ＝Ｏ、ｐ＝０、Ｒ^４＝Ｒ^５＝メチル基、Ｗ＝ＣＯ_２Ｈの化合物例：

【表６】

【表７】

（４）上記一般式（Ｉ）で表される化合物で、Ｚ＝Ｏ、ｐ＝０、Ｒ^４＝Ｒ^５＝メチル基、Ｗ＝ＣＯ_２Ｈの化合物例：

【表８】

【表９】

次に本発明の薬理効果について述べる。
本発明化合物のＰＰＡＲδ活性化作用は、ＣＶ−１細胞にキメラ受容体発現プラスミド（ＧＡＬ４−ｈＰＰＡＲδ　ＬＢＤ）、レポータープラスミド（ＵＡＳｘ４−ＴＫ−ＬＵＣ）及びβ−ガラクトシダーゼ（β−ＧＡＬ）発現プラスミドをリポフェクション試薬ＤＭＲＩＥ−Ｃ（Ｌｉｆｅ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）によりトランスフェクト後、本発明化合物又は比較化合物であるＧＷ−２４３３の存在下、４０時間培養後、可溶化細胞をルシフェラーゼ活性及びβ−ＧＡＬ活性を測定することにより求めた。
尚、ルシフェラーゼ活性はβ−ＧＡＬ活性で補正した。
同様な方法によりＰＰＡＲα及びγ活性化作用に関する相対的なリガンド活性を算出した。（後記実施例８）
表１０記載の様に、本発明化合物は優れたＰＰＡＲ活性化作用（ＰＰＡＲα、γ又はδ活性化作用）を示した。
従って、本発明の一般式（Ｉ）で表される化合物は、優れたＰＰＡＲ活性化作用を有することから、血糖降下剤、脂質低下剤、肥満、シンドロームＸ，高コレステロール血症、高リポ蛋白血症等の代謝異常疾患、高脂血症、動脈硬化症、循環器系疾患、過食症、虚血性疾患、肺ガン、乳がん、結腸ガン、大腸ガン、卵巣ガン等の悪性腫瘍、アルツハイマー病、炎症性疾患、骨粗鬆症（Ｍａｎｏ　Ｈ．ｅｔ．Ａｌ．，（２０００）Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，２７５：８１２６−８１３２）、バセドウ病眼症，副腎白質ジストロフィー等の予防、あるいは治療剤として期待される。
本発明化合物は、ヒトに対して一般的な経口投与又は非経口投与のような適当な投与方法によって投与することができる。
製剤化するためには、製剤の技術分野における通常の方法で錠剤、顆粒剤、散剤、カプセル剤、懸濁剤、注射剤、坐薬等の剤型に製造することができる。
これらの調製には、通常の賦形剤、崩壊剤、結合剤、滑沢剤、色素、希釈剤などが用いられる。ここで、賦形剤としては、乳糖、Ｄ−マンニトール、結晶セルロース、ブドウ糖などが、崩壊剤としては、デンプン、カルボキシメチルセルロースカルシウム（ＣＭＣ−Ｃａ）などが、滑沢剤としては、ステアリン酸マグネシウム、タルクなどが、結合剤としては、ヒドロキシプロピルセルロース（ＨＰＣ）、ゼラチン、ポリビニルピロリドン（ＰＶＰ）などが挙げられる。
投与量は通常成人においては、注射剤で有効成分である本発明化合物を１日約０．１ｍｇ〜１００ｍｇ，経口投与で１日１ｍｇ〜２０００ｍｇであるが、年齢、症状等により増減することができる。
次に、実施例を挙げ本発明を更に詳細に説明するが本発明はこれらに限定されるものではない。
【実施例】
実施例１
（１）４−ヒドロキシケイ皮酸メチル
４−ヒドロキシケイ皮酸（２０．０ｇ，１２１．５ｍｍｏｌ）をメタノール（１２０ｍＬ）に溶解し、濃硫酸（０．２ｍＬ）を加えて、２３時間加熱還流した。減圧下溶媒を留去し、残渣を酢酸エチルに溶解後、飽和炭酸水素ナトリウム水溶液および水の混合溶液、ならびに飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して２１．７６ｇ（純度９９．５％，定量的収率）の標題化合物（茶色味を帯びた白色結晶）を得た。
ｍｐ：１３０−１３２℃
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
３．８１（３Ｈ，ｓ），
６．３０（１Ｈ，ｄ，Ｊ＝１６Ｈｚ），
６．８６（２Ｈ，ｄｄ，Ｊ＝２Ｈｚ，７Ｈｚ），
７．４２（２Ｈ，ｄｄ，Ｊ＝２Ｈｚ，７Ｈｚ），
７．６４（１Ｈ，ｄ，Ｊ＝１６Ｈｚ）
（２）４−メトキシメトキシケイ皮酸メチル
４−ヒドロキシケイ皮酸メチル（２１．７６ｇ，純度９９．５％，１２１．５ｍｍｏｌ）を乾燥ＤＭＦ（１００ｍＬ）に溶解し、氷冷下、水素化ナトリウム（６０％，５．３５ｇ，１３３．８ｍｍｏｌ）を少しずつ加え、３０分間撹拌した。次いでクロロメチル　メチルエーテル（１０．０ｍＬ，１３２．９ｍｍｏｌ）を加え、室温で２時間３０分撹拌後、氷水および酢酸エチルの混合溶液の中に注いだ。５分間撹拌し、有機層を分液後、水層を酢酸エチルで抽出した。有機層を合わせ、水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して２７．１４ｇ（純度９９．５％，定量的収率）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
３．４８（３Ｈ，ｓ），
３．８０（３Ｈ，ｓ），
５．２０（２Ｈ，ｓ），
６．３３（１Ｈ，ｄ，Ｊ＝１６Ｈｚ），
７．０４（２Ｈ，ｄｄ，Ｊ＝２Ｈｚ，７Ｈｚ），
７．４７（２Ｈ，ｄｄ，Ｊ＝２Ｈｚ，７Ｈｚ），
７．６５（１Ｈ，ｄ，Ｊ＝１６Ｈｚ）
（３）４−メトキシメトキシケイ皮酸
４−メトキシメトキシケイ皮酸メチル（２７．１４ｇ，純度９９．５％，１２１．５ｍｍｏｌ）をメタノール（１５０ｍＬ）およびＴＨＦ（２０ｍＬ）の混合溶液に溶解し、４Ｍ水酸化ナトリウム水溶液（４５ｍＬ）を加え、室温で２時間撹拌後、メタノール（５０ｍＬ）を加えて３時間撹拌した。減圧下溶媒を留去し、残渣に酢酸エチルおよび水を加え、濃塩酸をｐＨ４になるまで加えた。有機層を分液し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、残渣を酢酸エチルおよびヘキサンの混合溶媒に懸濁し、室温で１時間撹拌した。結晶を濾取し、ヘキサンで洗浄後、風乾して２２．７７ｇ（収率９０．０％）の標題化合物を白色結晶として得た。
ｍｐ：１４７−１４９℃
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
３．４９（３Ｈ，ｓ），
５．２１（２Ｈ，ｓ），
６．３６（１Ｈ，ｄ，Ｊ＝１６Ｈｚ），
７．０４（２Ｈ，ｄ，Ｊ＝９Ｈｚ），
７．５０（２Ｈ，ｄ，Ｊ＝９Ｈｚ），
７．７５（１Ｈ，ｄ，Ｊ＝１６Ｈｚ）
（４）３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）プロパンアミド
４−メトキシメトキシケイ皮酸（２０．９ｇ，１００ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１９．２ｇ，１００ｍｍｏｌ）および乾燥ジクロロメタン（１００ｍＬ）を混合し、室温で１５分間撹拌後、氷冷下、フェネチルアミン（１２．７ｍＬ，１０１ｍｍｏｌ）を加えて室温で１９時間撹拌した。反応溶液を水、０．１Ｍ塩酸水溶液、水、飽和炭酸水素ナトリウム水溶液、水、および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して、２６．６ｇの３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）−２−プロペンアミドの粗体を黄色味がかった白色結晶として得た。この粗体２０．０ｇをエタノール（５０ｍＬ）およびメタノール（５０ｍＬ）の混合溶媒に溶解し、パラジウム−活性炭（１０％，３．４ｇ，３．１９ｍｍｏｌ）を加え、水素雰囲気下、室温で１８時間撹拌した。不溶物を濾過により除去し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１−１／２）にて精製して１２．８９ｇ（純度９７．７％，収率５３．４％）の標題化合物を白色結晶として得た。
ｍｐ：８５−８７℃
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
２．３８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．７４（２Ｈ，ｔ，Ｊ＝７Ｈｚ），
２．８８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４６（３Ｈ，ｓ），
３．４９（２Ｈ，ｔ，Ｊ＝７Ｈｚ），
５．１４（２Ｈ，ｓ），
５．３０（ｂｒｓ，１Ｈ），
６．９３−６．９７（２Ｈ，ｍ），
７．０７−７．１１（４Ｈ，ｍ），
７．１８−７．３１（３Ｈ，ｍ）
（５）３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）プロピルアミン
水素化リチウムアルミニウム（１．２２ｇ，３２．１ｍｍｏｌ）を乾燥ＴＨＦ（１０ｍＬ）に懸濁し、氷冷下、上記４（１０．３ｇ，純度９７．７％，３２．１ｍｍｏｌ）の乾燥ＴＨＦ（２０ｍＬ）溶液を滴下した。室温で２時間撹拌後、２時間加熱還流し、氷冷下、飽和硫酸ナトリウム水溶液を少しずつ加えた。不溶物を濾過により除去し、ＴＨＦで洗浄した洗浄液と合わせ、減圧下溶媒を留去した後、残渣を酢酸エチルに溶解した。水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して９．５１ｇ（純度９３．０％，収率９２．０％）の標題化合物を黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．７６（２Ｈ，ｄｔ，Ｊ＝７Ｈｚ，１５Ｈｚ），
２．５６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６４（２Ｈ，ｔ，Ｊ＝７Ｈｚ），
２．７６−２．９０（４Ｈ，ｍ），
３．４７（３Ｈ，ｓ），
５．１４（２Ｈ，ｓ），
６．９１−６．９７（２Ｈ，ｍ），
７．０３−７．０９（２Ｈ，ｍ），
７．１６−７．３２（５Ｈ，ｍ）
（６）４−イソプロピル−１，３−チアゾール−２−カルボン酸エチル
３−メチル−２−ブタノン（１０．０ｍＬ，９２．９ｍｍｏｌ）を乾燥メタノール（５０ｍＬ）に溶解し、氷冷下、臭素（４．８ｍＬ，９３．２ｍｍｏｌ）を一気に加え、５０分間激しく撹拌した。反応溶液に水（３０ｍＬ）を加え、室温で１５分間撹拌し、水を加えた後、エーテルで抽出した。１０％炭酸カリウム水溶液および水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して１−ブロモ−３−メチル−２−ブタノンの粗体１０．６４ｇを淡黄色油状物として得た。この粗体（１．７７ｇ）およびエチル　チオオキサメート（ｅｔｈｙｌ　ｔｈｉｏｏｘａｍａｔｅ）（１．００ｇ，７．５１ｍｍｏｌ）をエタノール（３５ｍＬ）に溶解し、１９時間加熱還流後、減圧下溶媒を留去した。残渣に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出し、水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／クロロホルム＝１／１０）にて精製して１．０９ｇ（純度７６．０％，収率２６．７％）の標題化合物を淡褐色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．３５（６Ｈ，ｄ，Ｊ＝７Ｈｚ），
１．４３（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
３．２５（１Ｈ，ｄｑ，Ｊ＝７Ｈｚ，７Ｈｚ），
４．４８（２Ｈ，ｑ，Ｊ＝７Ｈｚ）
７．２０（１Ｈ，ｓ）
（７）４−イソプロピル−Ｎ−［３−（４−メトキシメトキシフェニル）プロピル）］−Ｎ−（フェネチル）−１，３−チアゾール−２−カルボキサミド
３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）プロピルアミン（純度９３．０％，１．００ｇ，３．１１ｍｍｏｌ）および４−イソプロピル−１，３−チアゾール−２−カルボン酸エチル（０．５８ｇ，純度７６．０％，２．２１ｍｍｏｌ）を混合し、５０℃で６日間撹拌した後、室温まで冷却した。ここに乾燥ベンゼン（２ｍＬ）およびソジウム　メトキサイド（１６８ｍｇ，３．１１ｍｍｏｌ）を加え、４時間加熱還流し、室温まで冷却後、氷水および酢酸エチルを加えた。さらに、２Ｍ塩酸水溶液をｐＨ４になるまで加え、有機層を分液し、水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／５）にて精製して０．８３ｇ（純度９５．７％，収率７９．４％）の標題化合物をオレンジ色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．３３（６Ｈ，ｄｄ，Ｊ＝３Ｈｚ，７Ｈｚ），
１．９７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．０３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．５７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９３−３．０１（２Ｈ，ｍ），
３．０５−３．１９（１Ｈ，ｍ），
３．４８（３Ｈ，ｓ），
３．５１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
５．１５（２Ｈ，ｓ），
６．９２−６．９８（２Ｈ，ｍ），
７．０３−７．１４（３Ｈ，ｍ），
７．１６−７．３３（５Ｈ，ｍ）
（８）Ｎ−［３−（４−ヒドロキシフェニル）プロピル）］−４−イソプロピル−Ｎ−（フェネチル）−１，３−チアゾール−２−カルボキサミド
４−イソプロピル−Ｎ−［３−（４−メトキシメトキシフェニル］プロピル）］−Ｎ−（フェネチル）−１，３−チアゾール−２−カルボキサミド（５００ｍｇ，純度９５．７％，１．０６ｍｍｏｌ）をＴＨＦ（３ｍＬ）およびイソプロパノール（０．５ｍＬ）の混合溶媒に溶解し、２Ｍ塩酸水溶液（０．５ｍＬ）を加え、室温で１６時間３０分撹拌後、２Ｍ塩酸水溶液（１ｍＬ）およびイソプロパノール（１ｍＬ）を加えて室温で９時間、次いで５０℃で１４時間撹拌した。減圧下溶媒を留去し、残渣を酢酸エチルに溶解後、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して５３０ｍｇ（純度８１．８％，定量的収率）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．３３（６Ｈ，ｄｄ，Ｊ＝３Ｈｚ，７Ｈｚ），
１．９６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．００（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．５６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９２−３．０１（２Ｈ，ｍ），
３．０４−３．１９（１Ｈ，ｍ），
３．５０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６２−３．６９（１Ｈ，ｍ），
３．９７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．７２−４．８２（１Ｈ，ｍ），
６．７２−６．７７（２Ｈ，ｍ），
６．９８−７．０８（３Ｈ，ｍ），
７．１６−７．３３（５Ｈ，ｍ）
（９）２−［４−［３−［Ｎ−［（４−イソプロピル−１，３−チアゾール−２−イル）カルボニル］−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸エチル
Ｎ−［３−（４−ヒドロキシフェニル）プロピル）］−４−イソプロピル−Ｎ−（フェネチル）−１，３−チアゾール−２−カルボキサミド（５３０ｍｇ，純度８１．８％，１．０６ｍｍｏｌ）、２−ブロモ−２−メチルプロピオン酸エチル（２３０ｍｇ，１．１８ｍｍｏｌ）および炭酸カリウム（１７０ｍｇ，１．２３ｍｍｏｌ）を乾燥アセトン（３ｍＬ）に加え、１９時間３０分加熱還流した。減圧下溶媒を留去し、残渣に酢酸エチルを加え、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／５−１／３）にて精製して１３４ｍｇ（純度９６．６％，収率２３．４％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
１．３２（３Ｈ，ｓ），
１．３４（３Ｈ，ｓ），
１．５６（６Ｈ，ｄ，Ｊ＝８Ｈｚ），
１．９６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．００（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．５５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９２−３．０１（２Ｈ，ｍ），
３．０５−３．２０（１Ｈ，ｍ），
３．５０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．７３−６．７９（２Ｈ，ｍ），
６．９７−７．０９（３Ｈ，ｍ），
７．１６−７．３３（５Ｈ，ｍ）
（１０）２−［４−［３−［Ｎ−［（４−イソプロピル−１，３−チアゾール−２−イル）カルボニル］−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸
２−［４−［３−［Ｎ−［（４−イソプロピル−１，３−チアゾール−２−イル）カルボニル］−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸エチル（１３４ｍｇ，純度９６．６％，０．２５ｍｍｏｌ）をエタノール（１．３ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（０．３ｍＬ）を加え、室温で２３間撹拌後、減圧下溶媒を留去した。残渣に酢酸エチルおよび１Ｍ塩酸水溶液を加え、有機層を分液し、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して１３１ｍｇ（純度９２．６％，収率９８．１％）の標題化合物を黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．３３（６Ｈ，ｄ，Ｊ＝７Ｈｚ），
１．５６（６Ｈ，ｓ），
１．９７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．０１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．５９（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．０５−３．１９（１Ｈ，ｍ），
３．５１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６１−３．６９（１Ｈ，ｍ），
３．９８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．８４−６．９０（２Ｈ，ｍ），
７．０３−７．１５（３Ｈ，ｍ），
７．１７−７．３３（５Ｈ，ｍ），
ＩＲ（ｃｍ^−１，ＫＢｒ）：
３０２８，２９６４，２９３７，１７３８，１６１８，１５０８，１４７９，
１４５４，１３７９，１３７３，１２４０，１１４６，１０４７，７０２
実施例２
（１）１，３−チアゾール−２−カルボン酸エチル
２−トリメチルシリル−１，３−チアゾール（２．０ｍＬ，１２．６ｍｍｏｌ）を乾燥ベンゼン（６ｍＬ）に溶解し、氷冷下、クロロギ酸エチル（２．４ｍＬ，２５．２ｍｍｏｌ）を滴下後、水浴中で３０分間、次いで室温で１９時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液（２４ｍＬ）を滴下し、１０分間撹拌した後、有機層を分液した。水（６ｍＬ）および飽和食塩水（６ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム）にて精製して０．９９ｇ（収率５０．０％）の標題化合物を白色結晶として得た。
ｍｐ：４４−４５℃
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．４５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
４．４９（２Ｈ，ｑ，Ｊ＝７Ｈｚ），
７．６４（１Ｈ，ｄ，Ｊ＝３Ｈｚ），
８．０３（１Ｈ，ｄ，Ｊ＝３Ｈｚ）
（２）Ｎ−［３−（４−ヒドロキシフェニル）プロピル）］−Ｎ−（フェネチル）−１，３−チアゾール−２−カルボキサミド
３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）プロピルアミン（純度９３．０％，９７０ｍｇ，３．０１ｍｍｏｌ）および１，３−チアゾール−２−カルボン酸エチル（３１５ｍｇ，２．００ｍｍｏｌ）を乾燥ベンゼン（４ｍＬ）に溶解し、ソジウム　メトキサイド（１６２ｍｇ，３．００ｍｍｏｌ）を加え、４時間加熱還流後、室温まで冷却した。氷水および酢酸エチルを加え、さらに、３Ｍ塩酸水溶液をｐＨ４になるまで加えた後、不溶物を濾過により除去した。濾液と不溶物の酢酸エチル洗浄液を合わせ、有機層を分液し、水および飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／５−１／３）に付してＮ−［３−（４−メトキシメトキシフェニル）プロピル）］−Ｎ−（２−フェネチル）−１，３−チアゾール−２−カルボキサミドの粗体を５００ｍｇ得た。この粗体（３００ｍｇ）をＴＨＦ（１．８ｍＬ）およびイソプロパノール（１．１ｍＬ）の混合溶媒に溶解し、２Ｍ塩酸水溶液（１．１ｍＬ）を加え、５０℃で２０時間撹拌した。減圧下溶媒を留去し、残渣を酢酸エチルに溶解後、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／２）にて精製して２６８ｍｇ（純度９２．４％，収率５６．３％）の標題化合物を無色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．９１−２．０２（２Ｈ，ｍ），
２．５５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９６（２Ｈ，ｄ，Ｊ＝８Ｈｚ），
３．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．７２−４．８２（１Ｈ，ｍ），
６．７４（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
６．７６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１７−７．３２（５Ｈ，ｍ），
７．５１，７．５１（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ），
７．８８，７．９２（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ）
（３）２−メチル−２−［４−［３−［Ｎ−フェネチル−Ｎ−［（１，３−チアゾール−２−イル）カルボニル］］アミノプロピル］フェノキシ］プロピオン酸エチル
Ｎ−［３−（４−ヒドロキシフェニル）プロピル）］−Ｎ−（フェネチル）−１，３−チアゾール−２−カルボキサミド（５３０ｍｇ，純度９２．４％，０．６８ｍｍｏｌ）、２−ブロモ−２−メチルプロピオン酸エチル（４００ｍｇ，２．０５ｍｍｏｌ）および炭酸カリウム（２８０ｍｇ，２．０３ｍｍｏｌ）を乾燥アセトン（５ｍＬ）に加え、４３時間加熱還流した。減圧下溶媒を留去し、残渣に酢酸エチルを加え、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）にて精製して１７３ｍｇ（純度９７．９％，収率５１．８％）の標題化合物を無色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
１．５７（６Ｈ，ｓ），
１．９０−２．００（２Ｈ，ｍ），
２．５４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．５１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．１８−４．２６（３Ｈ，ｍ），
６．７６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
６．７７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１８−７．３２（５Ｈ，ｍ），
７．５１，７．５１（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ），
７．８８，７．９２（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ）
（４）２−メチル−２−［４−［３−［Ｎ−フェネチル−Ｎ−［（１，３−チアゾール−２−イル）カルボニル］］アミノプロピル］フェノキシ］プロピオン酸
２−メチル−２−［４−［３−［Ｎ−フェネチル−Ｎ−［（１，３−チアゾール−２−イル）カルボニル］］アミノプロピル］フェノキシ］プロピオン酸エチル（１７３ｍｇ，純度９７．９％，０．３５ｍｍｏｌ）をエタノール（１．７ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（０．４ｍＬ）を加え、室温で１７時間撹拌後、減圧下溶媒を留去した。残渣に酢酸エチルおよび１Ｍ塩酸水溶液を加え、有機層を分液し、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して１６１ｍｇ（純度９４．０％，収率９５．５％）の標題化合物を黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．５７（６Ｈ，ｓ），
１．９５−２．０４（２Ｈ，ｍ），
２．５７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．５３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．８６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
６．８８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０５（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１７−７．３２（５Ｈ，ｍ），
７．５２，７．５２（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ），
７．８４，７．９２（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ），
ＩＲ（ｃｍ^−１，ＫＢｒ）：
３０８６，３０２８，２９８９，２９３９，１７３８，１７３２，１６１４，
１５０６，１４７０，１４６６，１４５２，１４３５，１３７３，１２３８，
１１４６，１１０１，７５０，７００
実施例３
（１）カルボエトキシフォルムイミデェート（Ｃａｒｂｏｅｔｈｏｘｙｆｏｒｍｉｍｉｄａｔｅ）
エチル　シアノフォルメート（５．００ｇ，５０．５ｍｍｏｌ）および乾燥エタノール（２．９１ｍＬ，４９．８ｍｍｏｌ）を石油エーテル（６ｍＬ）に溶解し、−１５℃に冷却して反応溶液の重さが１．９７〜２．１２ｇになるまで塩酸ガスを通した。同温度で４時間撹拌し、徐々に０℃まで昇温後、同温度で一晩撹拌した。反応溶液を−５〜０℃に保ちながら炭酸カリウム（７．６７ｇ，５５．５ｍｍｏｌ）の水（１５．５ｍＬ）溶液を加え、さらに同温度を保ちながらエーテル（６ｍＬ）を加えて、有機層を分液後、水層をエーテル（１０ｍＬ）で抽出した溶液と合わせ、０〜３℃にて無水炭酸カリウムで乾燥した。減圧下溶媒を留去し、残渣を蒸留（７７〜７８℃／１６ｍｍＨｇ）精製して４．９３ｇ（収率６８．３％）の標題化合物を無色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．３５−１．４２（６Ｈ，ｍ），
４．２８−４．３６（４Ｈ，ｍ）
（２）１，３−ベンゾチアゾール−２−カルボン酸エチル
カルボエトキシフォルムイミデェート（１．００ｇ，６．８９ｍｍｏｌ）および２−アミノチオフェノール（０．８６ｇ，６．８７ｍｍｏｌ）を乾燥エタノール（１７ｍＬ）に溶解し、３時間３０分加熱還流後、室温まで冷却した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／５）にて精製して０．７９ｇ（収率５５．５％）の標題化合物を微黄色結晶として得た。
ｍｐ：６１−６２℃
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．４９（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
４．５６（２Ｈ，ｑ，Ｊ＝７Ｈｚ），
７．５２−７．６１（２Ｈ，ｍ），
７．９８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
８．２６（１Ｈ，ｄ，Ｊ＝８Ｈｚ）
（３）Ｎ−［３−（４−ヒドロキシフェニル）プロピル）］−Ｎ−フェネチル−１，３−ベンゾチアゾール−２−カルボキサミド
３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）プロピルアミン（純度９３．０％，５６０ｍｇ，１．７４ｍｍｏｌ）および１，３−チアゾール−２−カルボン酸エチル（３００ｍｇ，１．４５ｍｍｏｌ）を乾燥ベンゼン（３ｍＬ）に溶解し、ソジウム　メトキサイド（９４ｍｇ，１．７４ｍｍｏｌ）を加え、６時間加熱還流後、室温まで冷却した。氷水および酢酸エチルを加え、さらに、２Ｍ塩酸水溶液をｐＨ４になるまで加えた後、不溶物を濾過により除去した。濾液と不溶物の酢酸エチル洗浄液を合わせ、有機層を分液し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）に付してＮ−［３−（４−メトキシメトキシフェニル）プロピル）−Ｎ−フェネチル−１，３−ベンゾチアゾール−２−カルボキサミドの粗体を３５４ｍｇ得た。この粗体（３５４ｍｇ）をＴＨＦ（２．１ｍＬ）およびイソプロパノール（１．２ｍＬ）の混合溶媒に溶解し、２Ｍ塩酸水溶液（１．２ｍＬ）を加え、５０℃で１７時間３０分撹拌した。減圧下溶媒を留去し、残渣を酢酸エチルに溶解後、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）にて精製して３１２ｍｇ（純度８９．１％，収率４６．０％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
２．００−２．０６（２Ｈ，ｍ），
２．５８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９７−３．０６（２Ｈ，ｍ），
３．５８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６９−３．７４（１Ｈ，ｍ），
３．９８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２３−４．２８（１Ｈ，ｍ），
６．６９−６．７２（１Ｈ，ｍ），
６．７５−６．７９（１Ｈ，ｍ），
７．００（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１８−７．３３（５Ｈ，ｍ），
７．４６−７．５８（２Ｈ，ｍ），
７．９６，７．９６（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝８Ｈｚ），
８．０３，８．１３（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝８Ｈｚ）
（４）２−［４−［３−［Ｎ−［（１，３−ベンゾチアゾール−２−イル）カルボニル］−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸エチル
Ｎ−［３−（４−ヒドロキシフェニル）プロピル）］−Ｎ−フェネチル−１，３−ベンゾチアゾール−２−カルボキサミド（３１２ｍｇ，純度８９．１％，０．６７ｍｍｏｌ）、２−ブロモ−２−メチルプロピオン酸エチル（３５０ｍｇ，１．７９ｍｍｏｌ）および炭酸カリウム（２５０ｍｇ，１．８１ｍｍｏｌ）を乾燥アセトン（５ｍＬ）に加え、４３時間加熱還流した。減圧下溶媒を留去し、残渣に酢酸エチルを加え、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）にて精製して２０８ｍｇ（純度９６．５％，収率５６．５％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
１．５７（６Ｈ，ｓ），
１．９８−２．０７（２Ｈ，ｍ），
２．５９（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９７−３．０６（２Ｈ，ｍ），
３．５７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６９−３．７４（１Ｈ，ｍ），
３．９９（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．１９−４．２７（３Ｈ，ｍ），
６．７３−６．８０（２Ｈ，ｍ），
７．０２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１８−７．３３（５Ｈ，ｍ），
７．４６−７．５８（２Ｈ，ｍ），
７．９６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
８．０４，８．１２（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝８Ｈｚ）
（５）２−［４−［３−［Ｎ−［（１，３−ベンゾチアゾール−２−イル）カルボニル］−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸
２−［４−［３−［Ｎ−［（１，３−ベンゾチアゾール−２−イル）カルボニル］−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸エチル（２０８ｍｇ，純度９６．５％，０．３８ｍｍｏｌ）をエタノール（２．１ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（０．５ｍＬ）を加え、室温で１９時間３０分撹拌後、減圧下溶媒を留去した。残渣に酢酸エチルおよび１Ｍ塩酸水溶液を加え、有機層を分液し、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して１８３ｍｇ（純度９５．８％，収率９１．８％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．５４（３Ｈ，ｓ），
１．５６（３Ｈ，ｓ），
１．９８−２．０８（２Ｈ，ｍ），
２．６２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９６−３．３２（２Ｈ，　ｍ），
３．５９（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．７２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．００（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．８３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
６．８９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１５（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１７−７．３４（５Ｈ，ｍ），
７．４６−７．５８（２Ｈ，ｄｄ，Ｊ＝２Ｈｚ，３Ｈｚ），
７．９７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
８．０８（１Ｈ，ｄｄ，Ｊ＝８Ｈｚ，３７Ｈｚ），
ＩＲ（ｃｍ^−１，ＫＢｒ）：
３１４９，２９３１，２８６４，１７３８，１７３２，１６２２，１６１５，
１５１４，１５０４，１４６４，１４５６，１４２９，１３７３，１３１７，
１２３６，１１８０，１１４２
実施例４
（１）Ｎ−イソブチル−３−（４−メトキシメトキシフェニル）プロパンアミド
４−メトキシメトキシケイ皮酸（１．００ｇ，４．８０ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．９２ｇ，４．８０ｍｍｏｌ）および乾燥ジクロロメタン（６ｍＬ）を混合し、室温で１０分間撹拌後、氷冷下、イソブチルアミン（０．４７ｍＬ，４．８２ｍｍｏｌ）を加えて室温で２３時間撹拌した。反応溶液を水と１Ｍ塩酸水溶液の混合溶液、飽和炭酸水素ナトリウム水溶液、および水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して、１．４４ｇのＮ−イソブチル−３−（４−メトキシメトキシフェニル）−２−プロペンアミドの粗体を白色結晶として得た。この粗体１．４４ｇをエタノール（４ｍＬ）およびメタノール（６ｍＬ）の混合溶媒に溶解し、パラジウム−活性炭（１０％，２９０ｍｇ，０．２７ｍｍｏｌ）を加え、水素雰囲気下、室温で１７時間撹拌した。不溶物を濾過により除去し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）にて精製して０．７２ｇ（収率５６．５％）の標題化合物を白色結晶として得た。
ｍｐ：７５−７７℃
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
０．８３（６Ｈ，ｄ，Ｊ＝６Ｈｚ），
１．６３−１．７４（１Ｈ，ｍ），
２．４４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９２（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．０４（２Ｈ，ｄｄ，Ｊ＝７Ｈｚ），
３．４７（３Ｈ，ｓ），
５．１４（２Ｈ，ｓ），
５．３０（ｂｒｓ，１Ｈ），
６．９３−７．００（２Ｈ，ｍ），
７．１０−７．１３（２Ｈ，ｍ）
（２）Ｎ−イソブチル−Ｎ−［３−（４−メトキシメトキシフェニル）プロピル）］−１，３−チアゾール−２−カルボキサミド
水素化リチウムアルミニウム（８６ｍｇ，２．２７ｍｍｏｌ）を乾燥ＴＨＦ（２ｍＬ）に懸濁し、氷冷下、上記Ｎ−イソブチル−３−（４−メトキシメトキシフェニル）プロパンアミド（６００ｍｇ，２．２６ｍｍｏｌ）の乾燥ＴＨＦ（４ｍＬ）溶液を滴下した。４時間加熱還流し、氷冷下、飽和硫酸ナトリウム水溶液を固形物が析出しなくなるまで少しずつ加えた。不溶物を濾過により除去し、ＴＨＦで洗浄した洗浄液と合わせ、減圧下溶媒を留去した後、残渣を酢酸エチルに、溶解した。水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去してＮ−イソブチル−３−（４−メトキシメトキシフェニル）プロピルアミンの粗体を５５５ｍｇ黄色油状物として得た。この粗体（５５５ｍｇ）および１，３−チアゾール−２−カルボン酸エチル（３７０ｍｇ，２．３５ｍｍｏｌ）を乾燥ベンゼン（５ｍＬ）に溶解し、ソジウム　メトキサイド（１４０ｍｇ，２．５９ｍｍｏｌ）を加え、７時間加熱還流後、室温まで冷却した。氷水を加え、さらに、３Ｍ塩酸水溶液をｐＨ４になるまで加えた後、有機層を分液し、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）にて精製して４１６ｍｇ（収率５０．７％）の標題化合物を黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
０．８６（３Ｈ，ｄ，Ｊ＝７Ｈｚ），
０．９４（３Ｈ，ｄ，Ｊ＝７Ｈｚ），
１．９０−２．１２（３Ｈ，ｍ），
２．５６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．３４（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
３．４７（３Ｈ，ｓ），
３．５４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９６（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
４．０４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．７２−４．８２（１Ｈ，ｍ），
５．１５（２Ｈ，ｓ），
６．９２−６．９８（２Ｈ，ｍ），
７．０５−７．２６（２Ｈ，ｍ），
７．４９（１Ｈ，ｄ，Ｊ＝３Ｈｚ），
７．８２，７．８５（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ）
（３）Ｎ−「３−（４−ハイドロキシフェニル）プロピル）］−Ｎ−イソブチル−１，３−チアゾール−２−カルボキサミド
Ｎ−イソブチル−Ｎ−［３−（４−メトキシメトキシフェニル）プロピル）］−１，３−チアゾール−２−カルボキサミド（４１６ｍｇ）をＴＨＦ（２．５ｍＬ）およびイソプロパノール（１．７ｍＬ）の混合溶媒に溶解し、２Ｍ塩酸水溶液（１．７ｍＬ）を加え、５０℃で１８時間撹拌した。減圧下溶媒を留去し、残渣を酢酸エチルに溶解後、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）にて精製して３５９ｍｇ（純度９２．６％，収率９０．８％）の標題化合物を黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
０．９０（６Ｈ，ｅａｃｈ　ｄ，Ｊ＝７Ｈｚ），
１．９０−２．１４（３Ｈ，ｍ），
２．５５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．３４（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
３．５４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９５（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
４．０４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．７０−４．７８（１Ｈ，ｍ），
６．７５（２Ｈ，ｄｄ，Ｊ＝５Ｈｚ，８Ｈｚ），
７．０１（１Ｈ，ｄ，Ｊ＝８Ｈｚ，
７．０７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．４９（１Ｈ，ｄ，Ｊ＝３Ｈｚ），
７．８３，７．８６（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ）
（４）２−［４−［３−［Ｎ−イソブチル−Ｎ−［（１，３−チアゾール−２−イル）カルボニル］］アミノプロピル］フェノキシ］−２−メチルプロピオン酸エチル
Ｎ−［３−（４−ハイドロキシフェニル）プロピル）］−Ｎ−イソブチル−１，３−チアゾール−２−カルボキサミド（５３０ｍｇ，純度９２．６％，１．０４ｍｍｏｌ）、２−ブロモ−２−メチルプロピオン酸エチル（０．４７ｍＬ，３．１６ｍｍｏｌ）および炭酸カリウム（４３０ｍｇ，３．１１ｍｍｏｌ）を２−ブタノン（ＭＥＫ）（６ｍＬ）に加え、４６時間加熱還流した。減圧下溶媒を留去し、残渣に酢酸エチルを加え、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／５−１／３）にて精製して３２３ｍｇ（収率７１．８％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
０．８５（３Ｈ，ｄ，Ｊ＝７Ｈｚ），
０．９３（３Ｈ，ｄ，Ｊ＝７Ｈｚ），
１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
１．５４（３Ｈ，ｓ），
１．５７（３Ｈ，ｓ），
１．９０−２．１４（３Ｈ，ｍ），
２．５４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．３３（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
３．５３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９４（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
４．０３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２３（２Ｈ，ｑ，Ｊ＝７Ｈｚ），
６．７７（２Ｈ，ｄｄ，Ｊ＝５Ｈｚ，８Ｈｚ），
７．０１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．４９（１Ｈ，ｄ，Ｊ＝３Ｈｚ），
７．８３，７．８６（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ）
（５）２−［４−［３−［Ｎ−イソブチル−Ｎ−［（１，３−チアゾール−２−イル）カルボニル］］アミノプロピル］フェノキシ］−２−メチルプロピオン酸
２−［４−［３−［Ｎ−イソブチル−Ｎ−［（１，３−チアゾール−２−イル）カルボニル］］アミノプロピル］フェノキシ］−２−メチルプロピオン酸エチル（３２３ｍｇ，０．７５ｍｍｏｌ）をエタノール（３ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（１ｍＬ）を加え、室温で２３時間撹拌後、減圧下溶媒を留去した。残渣に酢酸エチルおよび１Ｍ塩酸水溶液をｐＨ３になるまで加え、有機層を分液し、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して３１７ｍｇ（純度９３．１％，収率９７．３％）の標題化合物を黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
０．８６（３Ｈ，ｄ，Ｊ＝７Ｈｚ），
０．９４（３Ｈ，ｄ，Ｊ＝７Ｈｚ），
１．５４（３Ｈ，ｓ），
１．５７（３Ｈ，ｓ），
１．９０−２．１４（３Ｈ，ｍ），
２．５８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．３４（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
３．５４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．９５（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
４．０４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．８７（２Ｈ，ｄｄ，Ｊ＝６Ｈｚ，８Ｈｚ），
７．０７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．５０（１Ｈ，ｄ，Ｊ＝３Ｈｚ），
７．８３，７．８６（１Ｈ，ｅａｃｈ　ｄ，Ｊ＝３Ｈｚ），
ＩＲ（ｃｍ^−１，ＫＢｒ）：
２９６０，２８７２，１７３８，１６１２，１５０８，１４６８，１４３９，
１３９２，１３８９，１３７３，１３６９，１２４０，１１４７，１０９０，
１０４７，７５２
実施例５
（１）２−［Ｎ−３−（４−メトキシメトキシフェニル）プロピル−Ｎ−フェネチル］アミノ−１，３−ベンゾチアゾール
３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）プロピルアミン（２．６５ｇ，純度９３．０％，８．２３ｍｍｏｌ）および２−クロロ−１，３−ベンゾチアゾール（１．００ｇ，５．９０ｍｍｏｌ）をＤＭＳＯ（２．６ｍＬ）に溶解し、室温で４６時間撹拌した後、５０℃で１６時間撹拌した。反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水、および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／７−１／５）にて精製して１．４０ｇ（純度９７．４％，収率５３．４％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．９６（２Ｈ，ｄｔ，Ｊ＝８Ｈｚ，１６Ｈｚ），
２．６０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４２（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４８（３Ｈ，ｓ），
３．７１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
５．１５（２Ｈ，ｓ），
６．９３−６．９８（２Ｈ，ｍ），
７．０２−７．１１（３Ｈ，ｍ），
７．１９−７．３２（６Ｈ，ｍ），
７．５４−７．６０（２Ｈ，ｍ）
（２）２−［Ｎ−３−（４−ハイドロキシフェニル）プロピル−Ｎ−フェネチル］アミノ−１，３−ベンゾチアゾール
２−［Ｎ−３−（４−メトキシメトキシフェニル）プロピル−Ｎ−フェネチル］アミノ−１，３−ベンゾチアゾール（７００ｍｇ，純度９７．４％，１．５８ｍｍｏｌ）をＴＨＦ（３ｍＬ）およびイソプロパノール（１．５ｍＬ）の混合溶媒に溶解し、２Ｍ塩酸水溶液（１．５ｍＬ）を加え、５０℃で２３時間撹拌した。減圧下溶媒を留去し、残渣に酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分液後、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して６２３ｍｇ（純度９６．８％，収率９８．１％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．９３（２Ｈ，ｄｔ，Ｊ＝８Ｈｚ，１５Ｈｚ），
２．５５（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４２（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．７０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．７０−６．７４（２Ｈ，ｍ），
６．９５−７．０１（２Ｈ，ｍ），
７．０６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
７．１８−７．３２（６Ｈ，ｍ），
７．５８（２Ｈ，ｔ，Ｊ＝８Ｈｚ）
（３）２−［４−［３−［Ｎ−（１，３−ベンゾチアゾール−２−イル）−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸エチル
２−［Ｎ−３−（４−ハイドロキシフェニル）プロピル−Ｎ−フェネチル］アミノ−１，３−ベンゾチアゾール（６２３ｍｇ，純度９６．８％，１．５５ｍｍｏｌ）、２−ブロモ−２−メチルプロピオン酸エチル（９００ｍｇ，４．６１ｍｍｏｌ）および炭酸カリウム（２６０ｍｇ，３．１１ｍｍｏｌ）をアセトン（５ｍＬ）に加え、１８時間加熱還流した。減圧下溶媒を留去し、残渣に酢酸エチル（５ｍＬ）を加え、水（５ｍＬ）および飽和食塩水（５ｍＬ）で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／５−１／３）にて精製して２２８ｍｇ（純度９２．８％，収率２７．２％）の標題化合物を無色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
１．５７（６Ｈ，ｓ），
１．９５（２Ｈ，ｄｔ，Ｊ＝８Ｈｚ，１６Ｈｚ），
２．５８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．７０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２３（２Ｈ，ｑ），
６．７５−６．８０（２Ｈ，ｍ），
７．００−７．１７（３Ｈ，ｍ），
７．１９−７．３３（６Ｈ，ｍ），
７．５４−７．６０（２Ｈ，ｍ）
（４）２−［４−［３−［Ｎ−（１，３−ベンゾチアゾール−２−イル）−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸
２−［４−［３−［Ｎ−（１，３−ベンゾチアゾール−２−イル）−Ｎ−フェネチル］アミノプロピル］フェノキシ］−２−メチルプロピオン酸エチル（２２８ｍｇ，純度９２．８％，０．４２ｍｍｏｌ）をエタノール（３ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（０．５ｍＬ）を加え、室温で２７時間撹拌後、減圧下溶媒を留去した。残渣に１Ｍ塩酸水溶液をｐＨ７になるまで加え、酢酸エチルで抽出し、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して１９９ｍｇ（純度９７．８％，収率９７．６％）の標題化合物を白色アモルファスとして得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．５３（６Ｈ，ｓ），
１．９３（２Ｈ，ｄｔ，Ｊ＝８Ｈｚ，１５Ｈｚ），
２．５７（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９７（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．６７（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．８２（２Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０２（２Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１８−７．３２（６Ｈ，ｍ），
７．５７（２Ｈ，ｄｄ，Ｊ＝４Ｈｚ，８Ｈｚ）
ＩＲ（ｃｍ^−１，ＫＢｒ）：
２９３３，１７２０，１５９５，１５４３，１５０８，１４５８，１４５４，
１４４４，１３７１，１２３４，１１４７，７５０，７００
実施例６
（１）２−［Ｎ−３−（４−メトキシメトキシフェニル）プロピル−Ｎ−フェネチル］アミノ−１，３−チアゾール
３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）プロピルアミン（８００ｍｇ，純度９３．０％，２．４８ｍｍｏｌ）を乾燥ＤＭＦ（６ｍＬ）に溶解し、６０％−水素化ナトリウム（１２０ｍｇ，３．００ｍｍｏｌ）を加えて室温で１時間撹拌後、２−ブロモ−１，３−チアゾール（０．２７ｍＬ，３．０５ｍｍｏｌ）を加え、室温で４４時間３０分撹拌した。反応溶液に酢酸エチルを加え、水、および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）にて精製して２６６ｍｇ（純度９８．６％，収率２７．６％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．８６（２Ｈ，ｄｔ，Ｊ＝８Ｈｚ，１５Ｈｚ），
２．５６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．８６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．１４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４８（３Ｈ，ｓ），
５．１５（２Ｈ，ｓ），
６．８７（１Ｈ，ｓ），
６．９４−６．９８（２Ｈ，ｍ），
７．０３−７．０８（２Ｈ，ｍ），
７．１４−７．３２（５Ｈ，ｍ），
８．０７（１Ｈ，ｓ）
（２）２−［Ｎ−３−（４−ハイドロキシフェニル）プロピル−Ｎ−フェネチル］アミノ−１，３−チアゾール
２−［Ｎ−３−（４−メトキシメトキシフェニル）プロピル−Ｎ−フェネチル］アミノ−１，３−チアゾール（２６６ｍｇ，純度９８．６％，０．６９ｍｍｏｌ）をＴＨＦ（１．２ｍＬ）およびイソプロパノール（０．６ｍＬ）の混合溶媒に溶解し、２Ｍ塩酸水溶液（０．６ｍＬ）を加え、５０℃で３時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液（１．５ｍＬ）を加え、減圧下溶媒を留去し、残渣に酢酸エチルを加えた。有機層を分液後、水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／２）にて精製して７７ｍｇ（純度９４．０％，収率３１．０％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．８５（２Ｈ，ｄｔ，Ｊ＝８Ｈｚ，１５Ｈｚ），
２．５４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．８６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．１４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．７４−６．７８（２Ｈ，ｍ），
６．８４（１Ｈ，ｓ），
６．９２−７．０２（２Ｈ，ｍ），
７．１５−７．３２（５Ｈ，ｍ），
８．０７（１Ｈ，ｓ）
（３）２−メチル−２−［４−［３−［Ｎ−フェネチル−Ｎ−（１，３−チアゾール−２−イル）］アミノプロピル］フェノキシ］プロピオン酸エチル
２−［Ｎ−３−（４−ハイドロキシフェニル）プロピル−Ｎ−フェネチル］アミノ−１，３−チアゾール（６７７ｍｇ，純度９４．０％，，１．５５ｍｍｏｌ）、２−ブロモ−２−メチルプロピオン酸エチル（０．１ｍＬ，０．６７ｍｍｏｌ）および炭酸カリウム（９０ｍｇ，０．６５ｍｍｏｌ）をメチルエチルケトン（ＭＥＫ）（２ｍＬ）に加え、４７時間加熱還流した。減圧下溶媒を留去し、残渣に酢酸エチルを加え、水および飽和食塩水で順次洗浄した。
無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／２）にて精製して６９ｍｇ（純度９９．９％収率７２．５％）の標題化合物を黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ＝１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
１．５７（６Ｈ，ｓ），
１．８５（２Ｈ，ｄｔ，Ｊ＝８Ｈｚ，１５Ｈｚ），
２．５４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．８５（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．１３（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２４（２Ｈ，ｑ，Ｊ＝７Ｈｚ），
６．７５−６．８０（２Ｈ，ｍ），
６．８６（１Ｈ，ｓ），
６．９８−７．０３（２Ｈ，ｍ），
７．１５−７．３２（５Ｈ，ｍ），
８．０６（１Ｈ，ｓ）
（４）２−メチル−２−［４−［３−［Ｎ−フェネチル−Ｎ−（１，３−チアゾール−２−イル）］アミノプロピル］フェノキシ］プロピオン酸
２−メチル−２−［４−［３−［Ｎ−フェネチル−Ｎ−（１，３−チアゾール−２−イル）］アミノプロピル］フェノキシ］プロピオン酸エチル（６９ｍｇ，純度９９．９％，０．１５ｍｍｏｌ）をエタノール（０．７ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（０．２ｍＬ）を加え、室温で２６時間撹拌後、減圧下溶媒を留去した。残渣に１Ｍ塩酸水溶液をｐＨ７になるまで加え、酢酸エチルで抽出し、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して６１ｍｇ（収率９５．８％）の標題化合物を黄色結晶として得た。
ｍｐ：９１−９２℃
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．６４（６Ｈ，ｓ），
１．８２（２Ｈ，ｄｔ，Ｊ＝８Ｈｚ，１５Ｈｚ），
２．５４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．８５（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．１０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．３９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．１９，６．２１（１Ｈ，ｅａｃｈ　ｓ），
６．９０−６．９４（２Ｈ，ｍ），
７．０４−７．０７（２Ｈ，ｍ），
７．１５−７．１８（２Ｈ，ｍ），
７．２０−７．３３（４Ｈ，ｍ），
８．０１（１Ｈ，ｓ）
ＩＲ（ｃｍ^−１，ＫＢｒ）：
３０８９，１７１８，１５３３，１５１０，１４５６，１４３１，１３８１，
１３７９，１３６５，１２８８，１２３０，１１８０，１１４９，１１１１
実施例７
（１）２−［Ｎ−３−（４−メトキシメトキシフェニル）プロピル−Ｎ−フェネチル］アミノ−５−ニトロ−１，３−チアゾール
３−（４−メトキシメトキシフェニル）−Ｎ−（フェネチル）プロピルアミン（６８０ｍｇ，純度９３．０％，２．１１ｍｍｏｌ）を乾燥ＤＭＦ（５ｍＬ）に溶解し、６０％−水素化ナトリウム（１１０ｍｇ，２．７５ｍｍｏｌ）を加えて室温で１時間撹拌後、２−ブロモ−５−ニトロ−１，３−チアゾール（５６０ｍｇ，２．６８ｍｍｏｌ）を加え、室温で４３時間３０分撹拌した。反応溶液に酢酸エチルを加え、水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３−１／２）にて精製して６０５ｍｇ（純度９３．１％，　収率６２．４％）の標題化合物を橙色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．９５−２．０５（２Ｈ，ｍ），
２．６０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．６６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．９７（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．２８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４８（３Ｈ，ｓ），
３．６２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．７２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．０１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
５．１６（２Ｈ，ｓ），
６．９７−７．０１（２Ｈ，ｍ），
７．０４−７．１４（３Ｈ，ｍ），
７．１９（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
７．２５−７．３６（３Ｈ，ｍ），
８．３９，８．６５（１Ｈ，ｅａｃｈ　ｓ）
（２）２−［Ｎ−３−（４−ヒドロキシフェニル）プロピル−Ｎ−フェネチル］アミノ−５−ニトロ−１，３−チアゾール
２−［Ｎ−３−（４−メトキシメトキシフェニル）プロピル−Ｎ−フェネチル］アミノ−５−ニトロ−１，３−チアゾール（６０５ｍｇ，純度９３．１％，１．３２ｍｍｏｌ）をＴＨＦ（２．４ｍＬ）およびイソプロパノール（１．２ｍＬ）の混合溶媒に溶解し、２Ｍ塩酸水溶液（１．２ｍＬ）を加え、５０℃で５時間撹拌した。減圧下溶媒を留去し、残渣に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加えた。有機層を分液後、水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／２−１／１）にて精製して３０６ｍｇ（純度９０．４％，収率５４．６％）の標題化合物を褐色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．７６−１．９０（２Ｈ，ｍ），
２．６５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．５６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．７９（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．８５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．１０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．３６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．５３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．７７（２Ｈ，ｄ，Ｊ＝８Ｈｚ），
６．９９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０４（１Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．１１（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
７．１９−７．３２（４Ｈ，ｍ），
７．８３，７．９９（１Ｈ，ｅａｃｈ　ｓ）
（３）２−メチル−２−［４−［３−［Ｎ−（５−ニトロ−１，３−チアゾール−２−イル）−Ｎ−フェネチル］アミノプロピル］フェノキシ］プロピオン酸エチル
２−［Ｎ−３−（４−ヒドロキシフェニル）プロピル−Ｎ−フェネチル］アミノ−５−ニトロ−１，３−チアゾール（３０６ｍｇ，純度９０．４％，０．７２ｍｍｏｌ）、２−ブロモ−２−メチルプロピオン酸エチル（０．３２ｍＬ，２．１５ｍｍｏｌ）および炭酸カリウム（２９０ｍｇ，２．１０ｍｍｏｌ）をメチルエチルケトン（ＭＥＫ）（２ｍＬ）に加え、４７時間加熱還流した。減圧下溶媒を留去し、残渣に酢酸エチルを加え、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／２−１／１）にて精製して２４２ｍｇ（純度９９．７％　収率６７．３％）の標題化合物を淡黄色油状物として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．２５（３Ｈ，ｔ，Ｊ＝７Ｈｚ），
１．５７（６Ｈ，ｓ），
１．７６−２．０５（２Ｈ，ｍ），
２．５０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．５６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．７８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．８４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．１０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．３５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
４．２４（２Ｈ，ｑ，Ｊ＝７Ｈｚ），
６．７６−６．８０（２Ｈ，ｍ），
６．９９（１Ｈ，ｄ，Ｊ＝９Ｈｚ），
７．０５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），
７．１１（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
７．１９−７．３２（４Ｈ，ｍ），
７．８３，８．００（１Ｈ，ｅａｃｈ　ｓ）
（４）２−メチル−２−［４−［３−［Ｎ−（５−ニトロ−１，３−チアゾール−２−イル）−Ｎ−フェネチル］アミノプロピル］フェノキシ］プロピオン酸
２−メチル−２−［４−［３−［Ｎ−（５−ニトロ−１，３−チアゾール−２−イル）−Ｎ−フェネチル］アミノプロピル］フェノキシ］プロピオン酸エチル（２４２ｍｇ，純度９９．７％，０．４８ｍｍｏｌ）をエタノール（２．４ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（０．６３ｍＬ）を加え、室温で２６時間撹拌後、減圧下溶媒を留去した。残渣に１Ｍ塩酸水溶液をｐＨ７になるまで加え、酢酸エチルで抽出し、水および飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去して１７９ｍｇ（収率７６．６％）の標題化合物を淡黄色結晶として得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）
δ：
１．５７（６Ｈ，ｓ），
１．７６−１．８９（２Ｈ，ｍ），
２．５１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．５６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．７９（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
２．８３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．０９（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．３５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．４２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
３．５１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），
６．８６（２Ｈ，ｄ，Ｊ＝８Ｈｚ），
７．０１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），
７．０７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），
７．１１（１Ｈ，ｄ，Ｊ＝７Ｈｚ），
７．１８−７．３２（４Ｈ，ｍ），
７．９２（１Ｈ，ｄ，Ｊ＝５４Ｈｚ）
ＩＲ（ｃｍ^−１，ＫＢｒ）：
２９８７，２９３７，２８６６，１７３６，１６７０，１６３５，１５０８，
１４５４，１４５０，１３９６，１３７３，１２４０，１１５１，７０２
実施例８
（薬理実験）
Ｉ．測定方法
（１）ＰＰＡＲα、γ、δ活性化作用の測定
試験化合物〔実施例１〜３，５及び既知のＰＰＡＲδアゴニストのＧＷ−２４３３（Ｂｅｒｇｅｒ，Ｊ．他，（１９９９）Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，２７４：６７１８−６７２５）〕のＰＰＡＲα、γ及びδ活性化作用を以下のように測定した。
１）材料
アフリカミドリザル腎線維芽細胞（ＣＶ−１細胞）は，東北大学加齢医学研究所　医用細胞資源センターより入手した。すべての試験化合物は，ジメチルスルホキシド（ＤＭＳＯ）に溶解し，最終ＤＭＳＯ濃度０．１％で試験に用いた。
２）プラスミド
受容体発現プラスミド（ＧＡＬ４−ｈＰＰＡＲα　ＬＢＤ、ＧＡＬ４−ｈＰＰＡＲγ　ＬＢＤ、ＧＡＬ４−ｈＰＰＡＲδ　ＬＢＤ），ルシフェラーゼ発現プラスミド（ＵＡＳｘ４−ＴＫ−ＬＵＣ），β−ガラクトシダーゼ発現プラスミド（βＧＡＬ）はＫｌｉｅｗｅｒ，Ｓ．Ａ．他，（（１９９２）Ｎａｔｕｒｅ，３５８：７７１−７７４）と同様のものを使用した。
３）トランスフェクション
ＣＶ−１細胞を１ウェル当たり２×１０^５個の細胞濃度で，２４ウェル培養プレートに播き，２４時間，４％胎児ウシ血清（ＦＣＳ）添加ＯＰＴＩ−ＭＥＭ　Ｉ　Ｒｅｄｕｃｅｄ　Ｓｅｒｕｍ　Ｍｅｄｉｕｍ（Ｌｉｆｅ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）５００μｌ／ｗｅｌｌで培養した。その後，血清無添加のＯＰＴＩ−ＭＥＭで細胞を洗い，ＤＮＡ含有溶液〔１ウェル（２５０μｌ添加溶液）当たり，以下の成分を含有するもの；０．０３μｇのＧＡＬ４−ｈＰＰＡＲδ　ＬＢＤ，０．２５μｇのＵＡＳｘ４−ＴＫ−ＬＵＣ，０．３５μｇのβＧＡＬおよび２μｌのリポフェクション試薬ＤＭＲＩＥ−Ｃ（Ｌｉｆｅ　Ｔｅｃｈｎｏｌｏｇｉｅｓ），これらをＯＰＴＩ−ＭＥＭに溶解し，室温で３０分間静置したもの〕を添加して，３７℃で５時間培養した。
４）試験化合物添加による細胞処理
ＤＮＡ含有溶液を除き，試験化合物（終濃度：１０^−４Ｍあるいは１０^−５Ｍになるように１００％ＤＭＳＯに溶解したもの）を含む４％ＦＣＳ−ＯＰＴＩ−ＭＥＭ　５００μｌに新たに交換してさらに４０時間，３７℃で培養した。
５）レポーター遺伝子発現レベルの測定
培地を除き，ＰＢＳで２回洗った後，凍結融解を１回行い，１ウェル当たり，ルシフェラーゼ活性測定用可溶化緩衝液（２５ｍＭ　Ｔｒｉｓ−ＰＯ_４（ｐＨ　７．８），１５％ｖ／ｖ　Ｇｌｙｓｅｒｏｌ，２％ＣＨＡＰＳ，１％Ｌｅｃｉｔｈｉｎ，１％ＢＳＡ，４ｍＭ　ＥＧＴＡ（ｐＨ　８．０），８ｍＭ　ＭｇＣｌ_２，１ｍＭ　ＤＴＴ）１００μｌを添加して，室温で１０分間放置した。そのうちの２０μｌを９６ウェル測定用プレートに分取して，ルシフェラーゼ基質溶液１００μｌ（ピッカジーン；ニッポンジーン社製）を添加し，ＭＬＲ−１００型マイクロルミノリーダ（コロナ電気社製）を用いて，１秒間の発光量（ルシフェラーゼ活性）を求めた。ルシフェラーゼ遺伝子の添加と同時に加えておいたβＧＡＬの細胞内導入による活性発現量を測定し，化合物添加によるルシフェラーゼ活性の変動を導入遺伝子のトランスフェクション効率で補正した。β−ガラクトシダーゼ活性の測定方法は，５０μｌの可溶化試料を別な９６ウェルプレートに分取し，ＯＮＰＧ（２−ニトロフェニル−β−Ｄ−ガラクトピラノシド）溶液１００μｌを添加して，室温で５分間インキュベートした。反応停止液（１Ｍ炭酸ナトリウム溶液）５０μｌを加え，４１４ｎｍの吸光度を測定した。溶媒として用いたＤＭＳＯ（０．１％濃度）のみで処理した細胞のルシフェラーゼ活性値（コントロール値）を０％に，対照薬（ＰＰＡＲα：１０^−４Ｍ　ＷＹ−１４６４３（４−クロロ−６−［（２，３−ジメチルフェニル）アミノ］−２−ピリミジニル）チオ）酢酸　ドイツ特許２３１４１６０），ＰＰＡＲγ：１０^−５Ｍ　Ｒｏｓｉｇｌｉｔａｚｏｎｅ、ＰＰＡＲδ　１０^−４ＭにおけるＬ−１６５０４１）で処理した細胞のルシフェラーゼ活性値を１００％として，相対的なリガンド活性を算出した。
ＩＩ．試験結果
ＰＰＡＲの活性化作用（ＥＣ５０μＭ）を示す試験結果表１０に示す。
【表１０】

表中、実施例１，２，３，及び５は以下の化合物である。
実施例１：２−［４−［３−［Ｎ−［（４−イソプロピル−１，３−チアゾー
ル−２−イル）カルボニル］−Ｎ−フェネチル］アミノプロピル］
フェノキシ］−２−メチルプロピオン酸
実施例２：２−メチル−２−［４−［３−［Ｎ−フェネチル−Ｎ−［（１，３
−チアゾール−２−イル）カルボニル］］アミノプロピル］フェノ
キシ］プロピオン酸
実施例３：２−［４−［３−［Ｎ−［（１，３−ベンゾチアゾール−２−イル
）カルボニル］−Ｎ−フェネチル］アミノプロピル］フェノキシ］
−２−メチルプロピオン酸
実施例５：２−メチル−２−［４−［３−［Ｎ−（１，３−ベンゾチアゾール
−２−イル）−Ｎ−フェネチル］アミノプロピル］フェノキシ］プ
ロピオン酸
表１０から明らかなように、本発明化合物は優れたＰＰＡＲ活性化作用（ＰＰＡＲα、γ又はδ活性作用）を有することが明らかになったTechnical field
The present invention relates to an activator of a peroxisome proliferator-activated receptor.
Background art
Peroxisomes are organelles found in the cells of animals and plants, and their matrices contain various enzymes such as catalase. Peroxisome proliferators are substances that induce the proliferation of peroxisomes, and various compound groups such as antilipidemic drugs (fibrates), herbicides, and phthalate plasticizers are known.
A nuclear receptor activated by this peroxisome proliferator was identified by Isseman et al. And named peroxisome proliferator-activated receptor (PPAR). (Nature, 347, p645-650, 1990)
PPAR has so far been confirmed to have three subtypes of PPARα, PPARγ and PPARδ. (Proc. Natl. Acad. Sci. USA, 91, p7335-7359, 1994).
The above-mentioned fibrate drugs have a ligand effect on PPARα among them, and a strong serum TG (triglyceride) lowering action has been recognized in clinical practice.
Also, a thiazolidinedione compound (Troglitazone, Rosiglitazone, Pioglitazone) which is a therapeutic agent for diabetes is known as a ligand of PPARγ.
Examples of the drug having a PPARδ activation effect include the following formula:

GW-2433 (Glaxo @ Wellcome) represented by the following formula:

L-165041 (Merck) represented by the following formula or

YM-16638 (Yamanouchi Pharmaceutical) and the like are known.
GW-2433 is described in WO92 / 10468 for use as a prophylactic and therapeutic agent for atherosclerosis, L-165041 is described in WO97 / 28115 for use as a diabetic or antiobesity agent, and YM-16638 is described. WO 99/04815 describes that it has a serum cholesterol lowering effect and an LDL-cholesterol lowering effect.
More recently, PPARδ ligands have been reported to promote their application as anticancer and anti-inflammatory agents (JBC, 272 (6), p3406-3410, 1997; Cell, 99, p335-345, 1999).
On the other hand, as a compound having a structure similar to the compound of the present invention (thiazole derivative) represented by the following general formula (II), bezafibrate having a serum lipid improving effect is exemplified.

Both bezafibrate and the compound of the present invention have a chemical structure in which an alkyl group substituted with an amino group and an alkoxy group substituted with a carboxyl group are bonded to a benzene ring, and the alkyl group substituted with the amino group is a bezafibrate. It is an N- (p-chlorobenzoyl) aminoalkyl group, and in the compound of the present invention, it is an N- (nitrogen-containing heterocyclic ring or nitrogen-containing heterocyclic carbonyl) aminoalkyl group, and both are clearly different in structure.
The above GW-2433 (WO ／ 92/10468) also has a chemical structure in which an alkyl group substituted with an amino group and an alkoxy group substituted with a carboxyl group are bonded to a benzene ring. Is an N- (phenylcarbamoyl) aminoalkyl group, which is structurally distinct from the compound of the present invention.
In addition, the compounds of the present invention are described in U.S. Pat. No. 6,028,087, Chinese Patent No. 1,114,321, WO 97/36887, WO 94/21599, WO 94/14775, WO 98/17646, U.S. Pat. And compounds having a part of the structure in common. However, the compounds described in these documents also have a clear structural difference from the compounds of the present invention.
An object of the present invention is to provide a compound represented by the following general formula (I), a thiazole derivative represented by the following general formula (II) and a salt thereof, which have an activating effect on a peroxisome proliferator-activated receptor. is there.
Disclosure of the invention
That is, the present invention provides the following general formula (I):

(Where R¹And R²Represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an aryl group having 6 to 10 carbon atoms, or R¹And R²But together R¹And R²May form a benzene ring with the carbon atom to which it is attached,
X is an oxygen atom, a sulfur atom, -NR⁰− (R⁰Represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms), or -CH = CH-,
G represents a single bond or a carbonyl group,
R³Is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and a cycloalkyl having 3 to 7 carbon atoms. An alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an arylalkyl group (having 6 to 10 carbon atoms in the aryl portion, and 1 to 8 carbon atoms in the alkyl portion substituted with an alkyl group) ), A heterocyclic group, or a heterocyclic alkyl group (1 to 8 carbon atoms in the alkyl portion);
n represents an integer of 0 to 5,
Y is -CH₂-, A carbonyl group, or -CH = CH-,
Z represents an oxygen atom or a sulfur atom,
p represents an integer of 0 to 5,
R⁴And R⁵Represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
W represents a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonic acid group, a phosphonic acid group, a cyano group, or a tetrazolyl group.
R above¹And R²An aryl group of R³An aryl group, an arylalkyl group, a heterocyclic group, a heterocyclic alkyl group, and R¹And R²But together R¹And R²The benzene ring formed together with the carbon atom to which is bonded is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, 8 acyl groups, formyl groups, hydroxyl groups, halogen atoms, nitro groups, amino groups, alkylamino groups (the alkyl group has 1 to 8 carbon atoms), or dialkylamino groups (the alkyl group has 1 to 8 carbon atoms) ) May be substituted. )
Or a salt thereof.
Further, the present invention provides the following general formula (II):

(Where R⁶And R⁷Represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an aryl group having 6 to 10 carbon atoms, or R⁶And R⁷But together R⁶And R⁷May form a benzene ring with the carbon atom to which it is attached,
G¹Represents a single bond or a carbonyl group,
R⁸Is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and a cycloalkyl having 3 to 7 carbon atoms. An alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an arylalkyl group (having 6 to 10 carbon atoms in the aryl portion, and 1 to 8 carbon atoms in the alkyl portion substituted with an alkyl group) ), A heterocyclic group, or a heterocyclic alkyl group (1 to 8 carbon atoms in the alkyl portion);
m represents an integer of 0 to 5,
Y¹Is -CH₂-, A carbonyl group, or -CH = CH-,
Z¹Represents an oxygen atom or a sulfur atom,
R⁹And R¹⁰Represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, respectively, and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R above⁶And R⁷An aryl group of R⁸An aryl group, an arylalkyl group, a heterocyclic group, a heterocyclic alkyl group, and R⁶And R⁷But together R⁶And R⁷The benzene ring formed together with the carbon atom to which is bonded is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, 8 acyl groups, formyl groups, hydroxyl groups, halogen atoms, nitro groups, amino groups, alkylamino groups (the alkyl group has 1 to 8 carbon atoms), or dialkylamino groups (the alkyl group has 1 to 8 carbon atoms) ) May be substituted. )
Or a salt thereof.
Furthermore, the present invention relates to a PPAR activator containing a compound represented by the above general formula (I), a compound represented by the above general formula (II) or a salt thereof as an active ingredient.
Next, the present invention will be described in detail.
The symbols in the general formula (I) will be described.
R of the above general formula (I)¹, R²Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom. R¹, R², R⁰, R³, R⁴And R⁵Examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, and a pentyl group. R¹And R²Examples of the alkoxy group having 1 to 8 carbon atoms include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an i-butyloxy group, a t-butyloxy group, and a pentyloxy group.
R³Examples of the alkenyl group having 2 to 8 carbon atoms include a vinyl group and an allyl group.
R³Examples of the alkynyl group having 2 to 8 carbon atoms include a propargyl group.
R³Examples of the cycloalkyl group having 3 to 7 carbon atoms include a cyclohexyl group and a cyclopentyl group.
R³Examples of the alkyl group having 1 to 8 carbon atoms substituted with a cycloalkyl group having 3 to 7 carbon atoms include a cyclohexylmethyl group and a cyclopentylmethyl group.
R¹, R²And R³Examples of the aryl group include a phenyl group and a naphthyl group.
R³Examples of the arylalkyl group (wherein the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 8 carbon atoms) include a benzyl group and a phenethyl group.
R³Examples of the heterocyclic ring include a thienyl group, a furyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, an imidazolyl group, a quinolyl group, an indolyl group, and a benzofuranyl group.
R³As the heterocyclic alkyl group (having 1 to 8 carbon atoms in the alkyl portion),³Examples of the heterocyclic group include those in which the heterocyclic group exemplified above is substituted with a methyl group, an ethyl group, or a propyl group.
In addition, R in the above general formula (I)¹And R²An aryl group of R³An aryl group, an arylalkyl group, a heterocyclic group, a heterocyclic alkyl group, and R¹And R²But together R¹And R²Among the groups or atoms listed as substituents on the benzene ring formed with the carbon atom to which they are bonded, alkyl groups having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, and butyl Group, i-butyl group, t-butyl group, pentyl group and the like. Examples of the alkoxy group having 1 to 8 carbon atoms include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, i- A butyloxy group, a t-butyloxy group, a pentyloxy group, and the like, and examples of the alkoxycarbonyl group having 2 to 8 carbon atoms include a methoxycarbonyl group and an ethoxycarbonyl group, and an acyl group having 2 to 8 carbon atoms. Examples of the group include an acetyl group and a propionyl group, and examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine. And the alkylamino group (the alkyl group has 1 to 8 carbon atoms) includes a methylamino group and an ethylamino group, and the dialkylamino group (the alkyl group has 1 to 8 carbon atoms) Examples thereof include a dimethylamino group and a diethylamino group.
Next, the symbols in the general formula (II) will be described.
In the general formula (II), R⁶And R⁷Is a halogen atom represented by the general formula (I)¹And R²The same as the halogen atom exemplified in⁶, R⁷, R⁸, R⁹And R¹⁰As the alkyl group having 1 to 8 carbon atoms, R¹, R², R³, R⁴And R⁵The same as the alkyl group exemplified in⁶, R⁷Is an alkoxy group having 1 to 8 carbon atoms,¹And R²And the alkoxy groups exemplified above.
In the general formula (II), R⁸Having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and 1 carbon atom substituted by a cycloalkyl group having 3 to 7 carbon atoms To 8 alkyl groups, arylalkyl groups (6 to 10 carbon atoms in the aryl portion, 1 to 8 carbon atoms in the alkyl portion), heterocyclic and heterocyclic alkyl groups (1 to 8 carbon atoms in the alkyl portion) Is also the same as R in the above general formula (I)³And the like.
R⁶, R⁷And R⁸As the aryl group of the formula (I),¹, R²And R³Examples of the aryl group include:
In the general formula (II), R⁶And R⁷An aryl group of R⁸An aryl group, an arylalkyl group, a heterocyclic group, a heterocyclic alkyl group, and R⁶And R⁷But together R⁶And R⁷Are alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, and 2 to 2 carbon atoms which are mentioned as a substituent which the benzene ring formed with the carbon atom to which is bonded may have 8 alkoxycarbonyl groups, 2 to 8 carbon atom acyl groups, halogen atoms, alkylamino groups (alkyl groups have 1 to 8 carbon atoms), or dialkylamino groups (alkyl groups have 1 to 8 carbon atoms) ) Is the same as defined above for the general formula (I).¹And R²An aryl group of R³An aryl group, an arylalkyl group, a heterocyclic group, a heterocyclic alkyl group, and R¹And R²But together R¹And R²And the groups or atoms exemplified as the substituents of the benzene ring formed together with the carbon atom to which is bonded, and the number of these substituents is preferably 1 to 3.
(1) As the compound of the present invention, among the thiazole derivatives represented by the above general formula (II), R⁸Is an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms as a substituent, an alkoxy group having 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a hydroxyl group, a halogen atom, A thiazole derivative or a salt thereof which is a phenylalkyl group (the alkyl portion has 1 to 8 carbon atoms) which may have a group or atom selected from a nitro group or an amino group is preferable.
(2) Further, as the compound of the present invention, among the thiazole derivatives represented by the general formula (II), Y¹Is -CH₂A thiazole derivative represented by the above general formula (II) or a salt thereof, or R⁸Is the one described in the above (1), and Y¹Is -CH₂The thiazole derivative represented by the above general formula (II) or a salt thereof is preferable.
(3) Furthermore, in the general formula (II), R⁶And R⁷Is a hydrogen atom, a nitro group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, an alkyl group having 1 to 6 carbon atoms such as a t-butyl group or a pentyl group, a methoxy group, Represents an alkoxy group having 1 to 6 carbon atoms such as an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an i-butyloxy group, a t-butyloxy group, a pentyloxy group, or R⁶And R⁷But together R⁶And R⁷Preferably forms a benzene ring with the carbon atom to which it is attached.
G¹Is a single bond or a carbonyl group.
R⁸Represents an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group or a pentyl group; Is preferably 1 to 6), and more preferably a phenylalkyl group (the alkyl portion has 1 to 6 carbon atoms) such as a benzyl group, a phenethyl group or a 3-phenylpropyl group.
m is preferably an integer of 1 to 4.
Y¹Is -CH₂-Is preferred.
Z¹Is preferably an oxygen atom.
R⁹And R¹⁰Are the same or different, preferably an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group or a pentyl group, and more preferably R⁹And R¹⁰Each represents a methyl group, an ethyl group or a propyl group.
R is preferably a hydrogen atom.
R above⁸A phenylalkyl group (the alkyl moiety has 1 to 6 carbon atoms);⁶And R⁷But together R⁶And R⁷When a benzene ring is formed together with the carbon atom to which it is bonded, the substituent that the benzene ring may have is methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t- A carbon atom such as an alkyl group having 1 to 6 carbon atoms such as a butyl group or a pentyl group, a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an i-butyloxy group, a t-butyloxy group or a pentyloxy group; An alkoxy group having 1 to 6 atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms such as a methoxycarbonyl group or an ethoxycarbonyl group, an acyl group having 2 to 6 carbon atoms such as an acetyl group or a propionyl group, a hydroxyl group, a halogen atom, Nitro or amino groups are preferred.
In addition, it is bonded to the phenyl group

Against

Preferably binds to the 3- or 4-position, more preferably the 4-position.
The compound of the present invention represented by the above general formula (I) and its salt, and the thiazole derivative represented by the above general formula (II) and its salt include cis and trans geometric isomers and optical isomers. However, these isomers are also included in the present invention.
Furthermore, the compound of the present invention also includes pharmaceutically acceptable salts such as alkali metal salts such as sodium salt and potassium salt.
Next, the method for producing the compound of the present invention of the general formula (I) will be described.
Synthesis method 1

(Where Q¹Represents a leaving group such as a bromine atom and a chlorine atom;¹, R², R³, R⁴, R⁵, X, G, n, Y, Z, p and W are the same as above. )
In the above reaction, a phenol (or thiophenol) derivative represented by the general formula (a) and a compound represented by the general formula (b) are mixed in a solvent such as acetone or ethyl methyl ketone in the presence of a base such as potassium carbonate. It can be carried out.
The phenol (or thiophenol) derivative represented by the general formula (a) as a raw material can be obtained, for example, by the following method.
(I) G = single bond, Y = —CH₂-Or -CH = CH-

(Where Q²Represents a leaving group such as a bromine atom or a chlorine atom, T represents a hydrogen atom or a protecting group for a hydroxyl group (or a mercapto group), and R¹, R², R³, X, n and Z are the same as above. )
The compound of the general formula (e) can be reacted with a heterocyclic compound of the general formula (c) and an amine of the general formula (d) in a solvent such as DMSO in the presence of a base such as sodium hydride. Here, when T is a protecting group for a hydroxyl group (or a mercapto group), the compound represented by the general formula (f) can be obtained by deprotecting the obtained compound of the general formula (e).
(Ii) G = carbonyl group and Y = —CH₂-Or -CH = CH-

(Where Q³Represents a hydroxyl group, a p-tosyl group, a halogen atom such as a bromine atom or a chlorine atom, or an alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy or butoxy;¹, R², R³, X, n, Z and T are the same as above. )
The compound of the general formula (h) can be obtained by reacting the carboxylic acid derivative of the general formula (g) with the amine of the general formula (d) in a solvent such as benzene in the presence of a base such as sodium methoxide ( Amidation reaction). Here, when T is a protecting group, the compound represented by the general formula (i) can be obtained by further deprotecting the obtained compound of the general formula (h).
Synthesis method 2
When W = carboxyl group

(Where R²⁰Represents an alkyl group, and R¹, R², R³, R⁴, R⁵, X, G, n, Y and p Same as above. )
The compound represented by the general formula (k) is obtained by hydrolyzing an ester represented by the general formula (j) in a solvent such as ethanol in the presence of a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide. It can be obtained by subjecting it to a reaction.
Synthesis method 3
(I) When G = single bond and Y = carbonyl group

(Where R¹, R², R³, R⁴, R⁵, X, Q², N, Z, p and W are the same as above. )
(Ii) G = carbonyl group and Y = carbonyl group

(Where R¹, R², R³, R⁴, R⁵, X, Q³, N, Z, p and W are the same as above. )
The reactions (i) and (ii) can be carried out without a solvent or in a solvent such as DMSO, DMF, benzene or toluene, and in some cases in the presence of a base such as potassium carbonate.
The amine represented by the general formula (1) can be obtained, for example, by the following synthesis route.

(Wherein M represents a protecting group for a nitrogen atom, Q⁴Represents a p-tosyl group or a halogen atom such as a bromine atom or a chlorine atom;³, R⁴, R⁵, R, n and p are the same as above. )
Representative examples of the compound of the present invention thus obtained are shown below.
(1) A compound represented by the above general formula (I), wherein X = S, Z = O, p = 0, W = CO₂Examples of compounds of H:

[Table 1]

[Table 2]

[Table 3]

(2) a compound represented by the above general formula (I), wherein X = S, Z = S, p = 0, W = CO₂Examples of compounds of H:

[Table 4]

[Table 5]

(3) A compound represented by the above general formula (I), wherein Z = O, p = 0, R⁴= R⁵= Methyl group, W = CO₂Examples of compounds of H:

[Table 6]

[Table 7]

(4) a compound represented by the above general formula (I), wherein Z = O, p = 0, R⁴= R⁵= Methyl group, W = CO₂Examples of compounds of H:

[Table 8]

[Table 9]

Next, the pharmacological effects of the present invention will be described.
The PPARδ-activating effect of the compound of the present invention can be determined by using a chimeric receptor expression plasmid (GAL4-hPPARδ LBD), a reporter plasmid (UASx4-TK-LUC) and a β-galactosidase (β-GAL) expression plasmid in a CV-1 cell. After transfection with DMRIE-C (Life @ Technologies), and culturing for 40 hours in the presence of the compound of the present invention or GW-2433 as a comparative compound, the solubilized cells were determined by measuring luciferase activity and β-GAL activity. .
The luciferase activity was corrected by the β-GAL activity.
In a similar manner, relative ligand activities relating to PPARα and γ activation were calculated. (Example 8 described later)
As shown in Table 10, the compound of the present invention exhibited an excellent PPAR activating action (PPARα, γ or δ activating action).
Therefore, since the compound represented by the general formula (I) of the present invention has an excellent PPAR activating action, it is used as a hypoglycemic agent, a hypolipidemic agent, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia. Metabolic disorders such as sickness, hyperlipidemia, arteriosclerosis, cardiovascular disease, bulimia, ischemic disease, lung cancer, malignant tumors such as breast cancer, colon cancer, colon cancer, ovarian cancer, Alzheimer's disease, inflammation It is expected as a preventive or therapeutic agent for sexual diseases, osteoporosis (Mano @ H. Et. Al., (2000) J. Biol. Chem., 275: 8126-8132), Basedow's disease ophthalmopathy, adrenoleukodystrophy, and the like.
The compound of the present invention can be administered to humans by a suitable administration method such as general oral administration or parenteral administration.
For formulation, it can be produced in the form of tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by a usual method in the technical field of formulation.
For these preparations, ordinary excipients, disintegrants, binders, lubricants, pigments, diluents and the like are used. Here, lactose, D-mannitol, crystalline cellulose, glucose and the like are used as excipients, starch and calcium carboxymethylcellulose (CMC-Ca) are used as disintegrants, magnesium stearate is used as a lubricant, Examples of the binder include talc and the like, and examples of the binder include hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP).
The dosage is usually about 0.1 mg to 100 mg per day of the compound of the present invention, which is an active ingredient in an injection, and 1 mg to 2000 mg per day in oral administration, but can be increased or decreased depending on age, symptoms and the like. .
Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.
【Example】
Example 1
(1) Methyl 4-hydroxycinnamate
4-Hydroxycinnamic acid (20.0 g, 121.5 mmol) was dissolved in methanol (120 mL), concentrated sulfuric acid (0.2 mL) was added, and the mixture was heated under reflux for 23 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 21.76 g (purity: 99.5%, quantitative yield) of the title compound (brownish white crystals).
mp: 130-132 ° C
¹H NMR (CDCl₃, 400MHz)
δ:
3.81 (3H, s),
6.30 (1H, d, J = 16 Hz),
6.86 (2H, dd, J = 2 Hz, 7 Hz),
7.42 (2H, dd, J = 2 Hz, 7 Hz),
7.64 (1H, d, J = 16Hz)
(2) Methyl 4-methoxymethoxycinnamate
Methyl 4-hydroxycinnamate (21.76 g, purity 99.5%, 121.5 mmol) was dissolved in dry DMF (100 mL), and sodium hydride (60%, 5.35 g, 133.8 mmol) was added under ice-cooling. ) Was added little by little and stirred for 30 minutes. Then, chloromethyl-methyl ether (10.0 mL, 132.9 mmol) was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes, and then poured into a mixed solution of ice water and ethyl acetate. After stirring for 5 minutes, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 27.14 g (purity 99.5%, quantitative yield) of the title compound. Obtained as a yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
3.48 (3H, s),
3.80 (3H, s),
5.20 (2H, s),
6.33 (1H, d, J = 16 Hz),
7.04 (2H, dd, J = 2 Hz, 7 Hz),
7.47 (2H, dd, J = 2 Hz, 7 Hz),
7.65 (1H, d, J = 16Hz)
(3) 4-methoxymethoxycinnamic acid
Methyl 4-methoxymethoxycinnamate (27.14 g, purity 99.5%, 121.5 mmol) was dissolved in a mixed solution of methanol (150 mL) and THF (20 mL), and a 4 M aqueous sodium hydroxide solution (45 mL) was added. After stirring at room temperature for 2 hours, methanol (50 mL) was added and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the residue, and concentrated hydrochloric acid was added until pH 4 was reached. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was suspended in a mixed solvent of ethyl acetate and hexane and stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with hexane, and air-dried to obtain 22.77 g (yield 90.0%) of the title compound as white crystals.
mp: 147-149 ° C
¹H NMR (CDCl₃, 400MHz)
δ:
3.49 (3H, s),
5.21 (2H, s),
6.36 (1H, d, J = 16 Hz),
7.04 (2H, d, J = 9 Hz),
7.50 (2H, d, J = 9 Hz),
7.75 (1H, d, J = 16Hz)
(4) 3- (4-methoxymethoxyphenyl) -N- (phenethyl) propanamide
A mixture of 4-methoxymethoxycinnamic acid (20.9 g, 100 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (19.2 g, 100 mmol) and dry dichloromethane (100 mL) are mixed at room temperature. After stirring for 15 minutes, phenethylamine (12.7 mL, 101 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 19 hours. The reaction solution was washed successively with water, 0.1 M aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 26.6 g. A crude product of 3- (4-methoxymethoxyphenyl) -N- (phenethyl) -2-propenamide was obtained as yellowish white crystals. 20.0 g of this crude product was dissolved in a mixed solvent of ethanol (50 mL) and methanol (50 mL), palladium-activated carbon (10%, 3.4 g, 3.19 mmol) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. did. After removing the insoluble matter by filtration and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 1-1 / 2) to obtain 12.89 g (purity: 97.7%). , Yield 53.4%) of the title compound as white crystals.
mp: 85-87 ° C
¹H NMR (CDCl₃, 400MHz)
δ:
2.38 (2H, t, J = 8 Hz),
2.74 (2H, t, J = 7 Hz),
2.88 (2H, t, J = 8 Hz),
3.46 (3H, s),
3.49 (2H, t, J = 7 Hz),
5.14 (2H, s),
5.30 (brs, 1H),
6.93-6.97 (2H, m),
7.07-7.11 (4H, m),
7.18-7.31 (3H, m)
(5) 3- (4-methoxymethoxyphenyl) -N- (phenethyl) propylamine
Lithium aluminum hydride (1.22 g, 32.1 mmol) was suspended in dry THF (10 mL), and the above 4 (10.3 g, purity 97.7%, 32.1 mmol) in dry THF (20 mL) was suspended under ice-cooling. The solution was added dropwise. After stirring at room temperature for 2 hours, the mixture was heated under reflux for 2 hours, and a saturated aqueous sodium sulfate solution was added little by little under ice cooling. The insolubles were removed by filtration, combined with a washing solution washed with THF, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 9.51 g (purity: 93.0%, yield: 92.0%) of the title compound as a yellow oil. Obtained.
¹H NMR (CDCl₃, 400MHz)
δ:
1.76 (2H, dt, J = 7 Hz, 15 Hz),
2.56 (2H, t, J = 8 Hz),
2.64 (2H, t, J = 7 Hz),
2.76-2.90 (4H, m),
3.47 (3H, s),
5.14 (2H, s),
6.91-6.97 (2H, m),
7.03-7.09 (2H, m),
7.16-7.32 (5H, m)
(6) Ethyl 4-isopropyl-1,3-thiazole-2-carboxylate
3-Methyl-2-butanone (10.0 mL, 92.9 mmol) was dissolved in dry methanol (50 mL), and bromine (4.8 mL, 93.2 mmol) was added at a stretch under ice-cooling, followed by vigorous stirring for 50 minutes. Water (30 mL) was added to the reaction solution, the mixture was stirred at room temperature for 15 minutes, water was added, and the mixture was extracted with ether. After washing with a 10% aqueous potassium carbonate solution and water successively and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 10.64 g of a crude product of 1-bromo-3-methyl-2-butanone as a pale yellow oil. Obtained. This crude product (1.77 g) and ethyl thiooxamate (1.00 g, 7.51 mmol) were dissolved in ethanol (35 mL), and after heating under reflux for 19 hours, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / chloroform = 1/10) to give 1.09 g (purity: 76.0%, yield: 26.7%) of the title compound. Obtained as a brown oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.35 (6H, d, J = 7 Hz),
1.43 (3H, t, J = 7 Hz),
3.25 (1H, dq, J = 7 Hz, 7 Hz),
4.48 (2H, q, J = 7Hz)
7.20 (1H, s)
(7) 4-isopropyl-N- [3- (4-methoxymethoxyphenyl) propyl)]-N- (phenethyl) -1,3-thiazole-2-carboxamide
3- (4-methoxymethoxyphenyl) -N- (phenethyl) propylamine (purity 93.0%, 1.00 g, 3.11 mmol) and ethyl 4-isopropyl-1,3-thiazole-2-carboxylate (0 .58 g, purity 76.0%, 2.21 mmol), and the mixture was stirred at 50 ° C. for 6 days, and then cooled to room temperature. Dry benzene (2 mL) and sodium methoxide (168 mg, 3.11 mmol) were added thereto, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, ice water and ethyl acetate were added. Further, a 2M aqueous hydrochloric acid solution was added until the pH became 4, the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/5) to give 0.83 g (purity: 95.7%, yield: 79.4%) of the title compound. Obtained as an orange oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.33 (6H, dd, J = 3 Hz, 7 Hz),
1.97 (1H, t, J = 8Hz),
2.03 (1H, t, J = 8Hz),
2.57 (1H, t, J = 8Hz),
2.63 (1H, t, J = 8 Hz),
2.93-3.01 (2H, m),
3.05-3.19 (1H, m),
3.48 (3H, s),
3.51 (1H, t, J = 8 Hz),
3.66 (1H, t, J = 8 Hz),
3.97 (1H, t, J = 8Hz),
4.23 (1H, t, J = 8Hz),
5.15 (2H, s),
6.92-6.98 (2H, m),
7.03-7.14 (3H, m),
7.16-7.33 (5H, m)
(8) N- [3- (4-hydroxyphenyl) propyl)]-4-isopropyl-N- (phenethyl) -1,3-thiazole-2-carboxamide
4-isopropyl-N- [3- (4-methoxymethoxyphenyl] propyl)]-N- (phenethyl) -1,3-thiazole-2-carboxamide (500 mg, purity 95.7%, 1.06 mmol) was added to THF. Dissolve in a mixed solvent of (3 mL) and isopropanol (0.5 mL), add 2M aqueous hydrochloric acid (0.5 mL), stir at room temperature for 16 hours 30 minutes, then add 2M aqueous hydrochloric acid (1 mL) and isopropanol (1 mL). And stirred at room temperature for 9 hours, then at 50 ° C. for 14 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 530 mg (purity: 81.8%, quantitative yield) of the title compound as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.33 (6H, dd, J = 3 Hz, 7 Hz),
1.96 (1H, t, J = 8Hz),
2.00 (1H, t, J = 8Hz),
2.56 (1H, t, J = 8Hz),
2.61 (1H, t, J = 8 Hz),
2.92-3.01 (2H, m),
3.04-3.19 (1H, m),
3.50 (1H, t, J = 8 Hz),
3.62-3.69 (1H, m),
3.97 (1H, t, J = 8Hz),
4.23 (1H, t, J = 8Hz),
4.72-4.82 (1H, m),
6.72-6.77 (2H, m),
6.98-7.08 (3H, m),
7.16-7.33 (5H, m)
(9) Ethyl 2- [4- [3- [N-[(4-isopropyl-1,3-thiazol-2-yl) carbonyl] -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionate
N- [3- (4-Hydroxyphenyl) propyl)]-4-isopropyl-N- (phenethyl) -1,3-thiazole-2-carboxamide (530 mg, purity 81.8%, 1.06 mmol), 2- Ethyl bromo-2-methylpropionate (230 mg, 1.18 mmol) and potassium carbonate (170 mg, 1.23 mmol) were added to dry acetone (3 mL), and the mixture was heated under reflux for 19 hours and 30 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 5-1 / 3) to obtain 134 mg (purity: 96.6%, yield). 23.4%) of the title compound as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.25 (3H, t, J = 7 Hz),
1.32 (3H, s),
1.34 (3H, s),
1.56 (6H, d, J = 8 Hz),
1.96 (1H, t, J = 8Hz),
2.00 (1H, t, J = 8Hz),
2.55 (1H, t, J = 8Hz),
2.61 (1H, t, J = 8 Hz),
2.92-3.01 (2H, m),
3.05-3.20 (1H, m),
3.50 (1H, t, J = 8 Hz),
3.65 (1H, t, J = 8 Hz),
3.97 (1H, t, J = 8Hz),
4.23 (1H, t, J = 8Hz),
6.73-6.79 (2H, m),
6.97-7.09 (3H, m),
7.16-7.33 (5H, m)
(10) 2- [4- [3- [N-[(4-isopropyl-1,3-thiazol-2-yl) carbonyl] -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionic acid
Ethyl 2- [4- [3- [N-[(4-isopropyl-1,3-thiazol-2-yl) carbonyl] -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionate (134 mg, purity 96.6%, 0.25 mmol) was dissolved in ethanol (1.3 mL), a 1 M aqueous sodium hydroxide solution (0.3 mL) was added, and the mixture was stirred at room temperature for 23 hours, and then the solvent was distilled off under reduced pressure. Ethyl acetate and a 1M aqueous hydrochloric acid solution were added to the residue, the organic layer was separated, and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 131 mg (purity: 92.6%, yield: 98.1%) of the title compound as a yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.33 (6H, d, J = 7 Hz),
1.56 (6H, s),
1.97 (1H, t, J = 8Hz),
2.01 (1H, t, J = 8Hz),
2.59 (1H, t, J = 8Hz),
2.65 (1H, t, J = 8Hz),
2.97 (1H, t, J = 8Hz),
2.98 (1H, t, J = 8 Hz),
3.05-3.19 (1H, m),
3.51 (1H, t, J = 8 Hz),
3.61-3.69 (1H, m),
3.98 (1H, t, J = 8 Hz),
4.24 (1H, t, J = 8 Hz),
6.84-6.90 (2H, m),
7.03-7.15 (3H, m),
7.17-7.33 (5H, m),
IR (cm^-1, KBr):
3028, 2964, 2937, 1738, 1618, 1508, 1479,
1454, 1379, 1373, 1240, 1146, 1047, 702
Example 2
(1) Ethyl 1,3-thiazole-2-carboxylate
2-Trimethylsilyl-1,3-thiazole (2.0 mL, 12.6 mmol) was dissolved in dry benzene (6 mL), and ethyl chloroformate (2.4 mL, 25.2 mmol) was added dropwise under ice-cooling, followed by water bathing. For 30 minutes and then at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution (24 mL) was added dropwise to the reaction solution, and the mixture was stirred for 10 minutes, and then the organic layer was separated. The extract was washed with water (6 mL) and saturated saline (6 mL) sequentially, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 0.99 g (yield 50.0%) of the title compound as white crystals.
mp: 44-45 ° C
¹H NMR (CDCl₃, 400MHz)
δ:
1.45 (3H, t, J = 7 Hz),
4.49 (2H, q, J = 7 Hz),
7.64 (1H, d, J = 3 Hz),
8.03 (1H, d, J = 3Hz)
(2) N- [3- (4-hydroxyphenyl) propyl)]-N- (phenethyl) -1,3-thiazole-2-carboxamide
3- (4-methoxymethoxyphenyl) -N- (phenethyl) propylamine (purity 93.0%, 970 mg, 3.01 mmol) and ethyl 1,3-thiazole-2-carboxylate (315 mg, 2.00 mmol) The residue was dissolved in dry benzene (4 mL), sodium methoxide (162 mg, 3.00 mmol) was added, and the mixture was refluxed for 4 hours and then cooled to room temperature. Ice water and ethyl acetate were added, and further a 3M aqueous hydrochloric acid solution was added until pH 4, and then insolubles were removed by filtration. The filtrate and the insoluble ethyl acetate washing solution were combined, the organic layer was separated, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1 / 5-1 / 3) to give N- [3- (4-methoxymethoxyphenyl) propyl)]-N- 500 mg of a crude product of (2-phenethyl) -1,3-thiazole-2-carboxamide was obtained. This crude product (300 mg) was dissolved in a mixed solvent of THF (1.8 mL) and isopropanol (1.1 mL), a 2 M aqueous hydrochloric acid solution (1.1 mL) was added, and the mixture was stirred at 50 ° C for 20 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2) to obtain 268 mg (purity: 92.4%, yield: 56.3%). ) Was obtained as a colorless oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.91-2.02 (2H, m),
2.55 (1H, t, J = 8Hz),
2.62 (1H, t, J = 8 Hz),
2.96 (2H, d, J = 8 Hz),
3.52 (1H, t, J = 8 Hz),
3.67 (1H, t, J = 8 Hz),
3.95 (1H, t, J = 8Hz),
4.21 (1H, t, J = 8 Hz),
4.72-4.82 (1H, m),
6.74 (1H, d, J = 8 Hz),
6.76 (1H, d, J = 8 Hz),
7.01 (1H, d, J = 8 Hz),
7.06 (1H, d, J = 8 Hz),
7.17-7.32 (5H, m),
7.51, 7.51 (1H, each d, J = 3 Hz),
7.88, 7.92 (1H, each d, J = 3Hz)
(3) Ethyl 2-methyl-2- [4- [3- [N-phenethyl-N-[(1,3-thiazol-2-yl) carbonyl]] aminopropyl] phenoxy] propionate
N- [3- (4-hydroxyphenyl) propyl)]-N- (phenethyl) -1,3-thiazole-2-carboxamide (530 mg, purity 92.4%, 0.68 mmol), 2-bromo-2- Ethyl methyl propionate (400 mg, 2.05 mmol) and potassium carbonate (280 mg, 2.03 mmol) were added to dry acetone (5 mL), and the mixture was heated under reflux for 43 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to obtain 173 mg (purity 97.9%, yield 51.8%). ) Was obtained as a colorless oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.25 (3H, t, J = 7 Hz),
1.57 (6H, s),
1.90-2.00 (2H, m),
2.54 (1H, t, J = 8Hz),
2.62 (1H, t, J = 8 Hz),
2.96 (2H, t, J = 8 Hz),
3.51 (1H, t, J = 8 Hz),
3.67 (1H, t, J = 8 Hz),
3.95 (1H, t, J = 8Hz),
4.18-4.26 (3H, m),
6.76 (1H, d, J = 8 Hz),
6.77 (1H, d, J = 8 Hz),
7.01 (1H, d, J = 8 Hz),
7.06 (1H, d, J = 8 Hz),
7.18-7.32 (5H, m),
7.51, 7.51 (1H, each d, J = 3 Hz),
7.88, 7.92 (1H, each d, J = 3Hz)
(4) 2-methyl-2- [4- [3- [N-phenethyl-N-[(1,3-thiazol-2-yl) carbonyl]] aminopropyl] phenoxy] propionic acid
Ethyl 2-methyl-2- [4- [3- [N-phenethyl-N-[(1,3-thiazol-2-yl) carbonyl]] aminopropyl] phenoxy] propionate (173 mg, purity 97.9%) , 0.35 mmol) was dissolved in ethanol (1.7 mL), 1 M aqueous sodium hydroxide solution (0.4 mL) was added, and the mixture was stirred at room temperature for 17 hours, and the solvent was distilled off under reduced pressure. Ethyl acetate and a 1M aqueous hydrochloric acid solution were added to the residue, the organic layer was separated, and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 161 mg (purity: 94.0%, yield: 95.5%) of the title compound as a yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.57 (6H, s),
1.95-2.04 (2H, m),
2.57 (1H, t, J = 8Hz),
2.65 (1H, t, J = 8Hz),
2.96 (2H, t, J = 8 Hz),
3.53 (1H, t, J = 8 Hz),
3.67 (1H, t, J = 8 Hz),
3.96 (1H, t, J = 8Hz),
4.21 (1H, t, J = 8 Hz),
6.86 (1H, d, J = 8 Hz),
6.88 (1H, d, J = 8 Hz),
7.05 (1H, d, J = 8 Hz),
7.12 (1H, d, J = 8 Hz),
7.17-7.32 (5H, m),
7.52, 7.52 (1H, each d, J = 3 Hz),
7.84, 7.92 (1H, each d, J = 3 Hz),
IR (cm^-1, KBr):
3086, 3028, 2989, 2939, 1738, 1732, 1614,
1506, 1470, 1466, 1452, 1435, 1373, 1238,
1146,1101,750,700
Example 3
(1) Carboethoxyformimidate
Ethyl dicyanoformate (5.00 g, 50.5 mmol) and dry ethanol (2.91 mL, 49.8 mmol) were dissolved in petroleum ether (6 mL), cooled to -15 ° C and the reaction solution weighed 1. Hydrochloric acid gas was passed until the amount became 97 to 2.12 g. The mixture was stirred at the same temperature for 4 hours, gradually heated to 0 ° C., and stirred at the same temperature overnight. While maintaining the reaction solution at −5 to 0 ° C., a solution of potassium carbonate (7.67 g, 55.5 mmol) in water (15.5 mL) was added, and while maintaining the same temperature, ether (6 mL) was added. After liquid separation, the aqueous layer was combined with a solution extracted with ether (10 mL), and dried over anhydrous potassium carbonate at 0 to 3 ° C. The solvent was distilled off under reduced pressure, and the residue was purified by distillation (77-78 ° C./16 mmHg) to obtain 4.93 g (yield 68.3%) of the title compound as a colorless oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.35-1.42 (6H, m),
4.28-4.36 (4H, m)
(2) Ethyl 1,3-benzothiazole-2-carboxylate
Carboethoxyformimidate (1.00 g, 6.89 mmol) and 2-aminothiophenol (0.86 g, 6.87 mmol) are dissolved in dry ethanol (17 mL), and the mixture is refluxed for 3 hours and 30 minutes, and then cooled to room temperature. Cool. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/5) to obtain 0.79 g (yield: 55.5%) of the title compound as pale yellow crystals. .
mp: 61-62 ° C
¹H NMR (CDCl₃, 400MHz)
δ:
1.49 (3H, t, J = 7 Hz),
4.56 (2H, q, J = 7 Hz),
7.52-7.61 (2H, m),
7.98 (1H, d, J = 8 Hz),
8.26 (1H, d, J = 8Hz)
(3) N- [3- (4-hydroxyphenyl) propyl)]-N-phenethyl-1,3-benzothiazole-2-carboxamide
3- (4-methoxymethoxyphenyl) -N- (phenethyl) propylamine (purity 93.0%, 560 mg, 1.74 mmol) and ethyl 1,3-thiazole-2-carboxylate (300 mg, 1.45 mmol) The residue was dissolved in dry benzene (3 mL), sodium methoxide (94 mg, 1.74 mmol) was added, and the mixture was refluxed for 6 hours and then cooled to room temperature. Ice water and ethyl acetate were added, and further a 2M aqueous hydrochloric acid solution was added until pH 4, and then insolubles were removed by filtration. The filtrate and the insoluble ethyl acetate wash were combined, the organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/3) to give N- [3- (4-methoxymethoxyphenyl) propyl) -N-phenethyl-1,3. 354 mg of a crude product of -benzothiazole-2-carboxamide was obtained. This crude product (354 mg) was dissolved in a mixed solvent of THF (2.1 mL) and isopropanol (1.2 mL), a 2M aqueous hydrochloric acid solution (1.2 mL) was added, and the mixture was stirred at 50 ° C for 17 hours and 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to obtain 312 mg (purity: 89.1%, yield: 46.0%). )) Was obtained as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
2.00-2.06 (2H, m),
2.58 (1H, t, J = 8Hz),
2.64 (1H, t, J = 8 Hz),
2.97-3.06 (2H, m),
3.58 (1H, t, J = 8 Hz),
3.69-3.74 (1H, m),
3.98 (1H, t, J = 8 Hz),
4.23-4.28 (1H, m),
6.69-6.72 (1H, m),
6.75-6.79 (1H, m),
7.00 (1H, d, J = 8 Hz),
7.07 (1H, d, J = 8 Hz),
7.18-7.33 (5H, m),
7.46-7.58 (2H, m),
7.96, 7.96 (1H, each d, J = 8Hz),
8.03, 8.13 (1H, each d, J = 8 Hz)
(4) Ethyl 2- [4- [3- [N-[(1,3-benzothiazol-2-yl) carbonyl] -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionate
N- [3- (4-hydroxyphenyl) propyl)]-N-phenethyl-1,3-benzothiazole-2-carboxamide (312 mg, purity 89.1%, 0.67 mmol), 2-bromo-2-methyl Ethyl propionate (350 mg, 1.79 mmol) and potassium carbonate (250 mg, 1.81 mmol) were added to dry acetone (5 mL), and the mixture was heated under reflux for 43 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to obtain 208 mg (purity: 96.5%, yield: 56.5%). )) Was obtained as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.25 (3H, t, J = 7 Hz),
1.57 (6H, s),
1.98-2.07 (2H, m),
2.59 (1H, t, J = 8Hz),
2.65 (1H, t, J = 8Hz),
2.97-3.06 (2H, m),
3.57 (1H, t, J = 8 Hz),
3.69-3.74 (1H, m),
3.99 (1H, t, J = 8 Hz),
4.19-4.27 (3H, m),
6.73-6.80 (2H, m),
7.02 (1H, d, J = 8 Hz),
7.08 (1H, d, J = 8 Hz),
7.18-7.33 (5H, m),
7.46-7.58 (2H, m),
7.96 (1H, d, J = 8 Hz),
8.04, 8.12 (1H, each d, J = 8Hz)
(5) 2- [4- [3- [N-[(1,3-benzothiazol-2-yl) carbonyl] -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionic acid
Ethyl 2- [4- [3- [N-[(1,3-benzothiazol-2-yl) carbonyl] -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionate (208 mg, purity 96.5) %, 0.38 mmol) was dissolved in ethanol (2.1 mL), a 1 M aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 19 hours and 30 minutes, and then the solvent was distilled off under reduced pressure. Ethyl acetate and a 1M aqueous hydrochloric acid solution were added to the residue, the organic layer was separated, and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 183 mg (purity: 95.8%, yield: 91.8%) of the title compound as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.54 (3H, s),
1.56 (3H, s),
1.98-2.08 (2H, m),
2.62 (1H, t, J = 8 Hz),
2.68 (1H, t, J = 8 Hz),
2.96-3.32 (2H, @m),
3.59 (1H, t, J = 8 Hz),
3.72 (1H, t, J = 8 Hz),
4.00 (1H, t, J = 8 Hz),
4.26 (1H, t, J = 8Hz),
6.83 (1H, d, J = 8 Hz),
6.89 (1H, d, J = 8 Hz),
7.07 (1H, d, J = 8 Hz),
7.15 (1H, d, J = 8 Hz),
7.17-7.34 (5H, m),
7.46-7.58 (2H, dd, J = 2 Hz, 3 Hz),
7.97 (1H, d, J = 8 Hz),
8.08 (1H, dd, J = 8Hz, 37Hz),
IR (cm^-1, KBr):
3149, 2931, 2864, 1738, 1732, 1622, 1615,
1514, 1504, 1464, 1456, 1429, 1373, 1317,
1236, 1180, 1142
Example 4
(1) N-isobutyl-3- (4-methoxymethoxyphenyl) propanamide
A mixture of 4-methoxymethoxycinnamic acid (1.00 g, 4.80 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.92 g, 4.80 mmol) and dry dichloromethane (6 mL) After stirring at room temperature for 10 minutes, isobutylamine (0.47 mL, 4.82 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 23 hours. The reaction solution was washed successively with a mixed solution of water and a 1M aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove 1.44 g of N-isobutyl-3 A crude product of-(4-methoxymethoxyphenyl) -2-propenamide was obtained as white crystals. 1.44 g of this crude product was dissolved in a mixed solvent of ethanol (4 mL) and methanol (6 mL), palladium-activated carbon (10%, 290 mg, 0.27 mmol) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. After removing the insoluble matter by filtration and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 0.72 g (yield: 56.5%) of the title. The compound was obtained as white crystals.
mp: 75-77 ° C
¹H NMR (CDCl₃, 400MHz)
δ:
0.83 (6H, d, J = 6 Hz),
1.63-1.74 (1H, m),
2.44 (2H, t, J = 8 Hz),
2.92 (2H, t, J = 8 Hz),
3.04 (2H, dd, J = 7 Hz),
3.47 (3H, s),
5.14 (2H, s),
5.30 (brs, 1H),
6.93-7.00 (2H, m),
7.10-7.13 (2H, m)
(2) N-isobutyl-N- [3- (4-methoxymethoxyphenyl) propyl)]-1,3-thiazole-2-carboxamide
Lithium aluminum hydride (86 mg, 2.27 mmol) was suspended in dry THF (2 mL), and the above N-isobutyl-3- (4-methoxymethoxyphenyl) propanamide (600 mg, 2.26 mmol) was dried under ice cooling. A solution of THF (4 mL) was added dropwise. The mixture was heated under reflux for 4 hours, and a saturated aqueous solution of sodium sulfate was added little by little under ice-cooling until no solid was precipitated. The insolubles were removed by filtration, combined with a washing solution washed with THF, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. After washing with water and saturated saline in this order and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 555 mg of a crude product of N-isobutyl-3- (4-methoxymethoxyphenyl) propylamine as a yellow oily substance. Was. This crude product (555 mg) and ethyl 1,3-thiazole-2-carboxylate (370 mg, 2.35 mmol) were dissolved in dry benzene (5 mL), sodium methoxide (140 mg, 2.59 mmol) was added, and the mixture was heated for 7 hours. After reflux, the mixture was cooled to room temperature. After adding ice water and further adding a 3M hydrochloric acid aqueous solution until pH 4, the organic layer was separated and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to give 416 mg (yield 50.7%) of the title compound as a yellow solid. Obtained as an oil.
¹H NMR (CDCl₃, 400MHz)
δ:
0.86 (3H, d, J = 7 Hz),
0.94 (3H, d, J = 7 Hz),
1.90-2.12 (3H, m),
2.56 (1H, t, J = 8Hz),
2.63 (1H, t, J = 8 Hz),
3.34 (1H, d, J = 7 Hz),
3.47 (3H, s),
3.54 (1H, t, J = 8 Hz),
3.96 (1H, d, J = 7Hz),
4.04 (1H, t, J = 8 Hz),
4.21 (1H, t, J = 8 Hz),
4.72-4.82 (1H, m),
5.15 (2H, s),
6.92-6.98 (2H, m),
7.05-7.26 (2H, m),
7.49 (1H, d, J = 3 Hz),
7.82, 7.85 (1H, each d, J = 3Hz)
(3) N- "3- (4-hydroxyphenyl) propyl)]-N-isobutyl-1,3-thiazole-2-carboxamide
N-isobutyl-N- [3- (4-methoxymethoxyphenyl) propyl)]-1,3-thiazole-2-carboxamide (416 mg) was added to a mixed solvent of THF (2.5 mL) and isopropanol (1.7 mL). After dissolution, a 2M aqueous hydrochloric acid solution (1.7 mL) was added, and the mixture was stirred at 50 ° C for 18 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to obtain 359 mg (purity: 92.6%, yield: 90.8%). ) Was obtained as a yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
0.90 (6H, each d, J = 7Hz),
1.90-2.14 (3H, m),
2.55 (1H, t, J = 8Hz),
2.61 (1H, t, J = 8 Hz),
3.34 (1H, d, J = 7 Hz),
3.54 (1H, t, J = 8 Hz),
3.95 (1H, d, J = 7Hz),
4.04 (1H, t, J = 8 Hz),
4.70-4.78 (1H, m),
6.75 (2H, dd, J = 5Hz, 8Hz),
7.01 (1H, d, J = 8 Hz,
7.07 (1H, d, J = 8 Hz),
7.49 (1H, d, J = 3 Hz),
7.83, 7.86 (1H, each d, J = 3 Hz)
(4) Ethyl 2- [4- [3- [N-isobutyl-N-[(1,3-thiazol-2-yl) carbonyl]] aminopropyl] phenoxy] -2-methylpropionate
N- [3- (4-hydroxyphenyl) propyl)]-N-isobutyl-1,3-thiazole-2-carboxamide (530 mg, purity 92.6%, 1.04 mmol), 2-bromo-2-methylpropion Ethyl acid (0.47 mL, 3.16 mmol) and potassium carbonate (430 mg, 3.11 mmol) were added to 2-butanone (MEK) (6 mL), and the mixture was heated under reflux for 46 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 5-1 / 3) to obtain 323 mg (yield: 71.8%). The title compound was obtained as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
0.85 (3H, d, J = 7 Hz),
0.93 (3H, d, J = 7 Hz),
1.25 (3H, t, J = 7 Hz),
1.54 (3H, s),
1.57 (3H, s),
1.90-2.14 (3H, m),
2.54 (1H, t, J = 8Hz),
2.61 (1H, t, J = 8 Hz),
3.33 (1H, d, J = 7 Hz),
3.53 (1H, t, J = 8 Hz),
3.94 (1H, d, J = 7 Hz),
4.03 (1H, t, J = 8 Hz),
4.23 (2H, q, J = 7 Hz),
6.77 (2H, dd, J = 5 Hz, 8 Hz),
7.01 (1H, d, J = 8 Hz),
7.07 (1H, d, J = 8 Hz),
7.49 (1H, d, J = 3 Hz),
7.83, 7.86 (1H, each d, J = 3 Hz)
(5) 2- [4- [3- [N-isobutyl-N-[(1,3-thiazol-2-yl) carbonyl]] aminopropyl] phenoxy] -2-methylpropionic acid
Ethyl 2- [4- [3- [N-isobutyl-N-[(1,3-thiazol-2-yl) carbonyl]] aminopropyl] phenoxy] -2-methylpropionate (323 mg, 0.75 mmol) After dissolving in ethanol (3 mL), a 1 M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 23 hours, and the solvent was distilled off under reduced pressure. Ethyl acetate and a 1M aqueous solution of hydrochloric acid were added to the residue until the pH reached 3, and the organic layer was separated and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 317 mg (purity: 93.1%, yield: 97.3%) of the title compound as a yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
0.86 (3H, d, J = 7 Hz),
0.94 (3H, d, J = 7 Hz),
1.54 (3H, s),
1.57 (3H, s),
1.90-2.14 (3H, m),
2.58 (1H, t, J = 8Hz),
2.65 (1H, t, J = 8Hz),
3.34 (1H, d, J = 7 Hz),
3.54 (1H, t, J = 8 Hz),
3.95 (1H, d, J = 7Hz),
4.04 (1H, t, J = 8 Hz),
6.87 (2H, dd, J = 6 Hz, 8 Hz),
7.07 (1H, d, J = 8 Hz),
7.13 (1H, d, J = 8 Hz),
7.50 (1H, d, J = 3Hz),
7.83, 7.86 (1H, each d, J = 3 Hz),
IR (cm^-1, KBr):
2960,2872,1738,1612,1508,1468,1439,
1392, 1389, 1373, 1369, 1240, 1147, 1090,
1047,752
Example 5
(1) 2- [N-3- (4-methoxymethoxyphenyl) propyl-N-phenethyl] amino-1,3-benzothiazole
3- (4-methoxymethoxyphenyl) -N- (phenethyl) propylamine (2.65 g, purity 93.0%, 8.23 mmol) and 2-chloro-1,3-benzothiazole (1.00 g, 5. 90 mmol) was dissolved in DMSO (2.6 mL), stirred at room temperature for 46 hours, and then at 50 ° C. for 16 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 7-1 / 5) to obtain 1.40 g (purity: 97.4%, yield: 53.4%). The title compound was obtained as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.96 (2H, dt, J = 8 Hz, 16 Hz),
2.60 (2H, t, J = 8 Hz),
2.99 (2H, t, J = 8 Hz),
3.42 (2H, t, J = 8 Hz),
3.48 (3H, s),
3.71 (2H, t, J = 8 Hz),
5.15 (2H, s),
6.93-6.98 (2H, m),
7.02-7.11 (3H, m),
7.19-7.32 (6H, m),
7.54-7.60 (2H, m)
(2) 2- [N-3- (4-hydroxyphenyl) propyl-N-phenethyl] amino-1,3-benzothiazole
2- [N-3- (4-methoxymethoxyphenyl) propyl-N-phenethyl] amino-1,3-benzothiazole (700 mg, purity 97.4%, 1.58 mmol) was added to THF (3 mL) and isopropanol (1 (2.5 mL), mixed with 2M aqueous hydrochloric acid (1.5 mL), and stirred at 50 ° C. for 23 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue. The organic layer was separated, and washed sequentially with water and saturated saline. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 623 mg (purity: 96.8%, yield: 98.1%) of the title compound as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.93 (2H, dt, J = 8 Hz, 15 Hz),
2.55 (2H, t, J = 8 Hz),
2.99 (2H, t, J = 8 Hz),
3.42 (2H, t, J = 8 Hz),
3.70 (2H, t, J = 8 Hz),
6.70-6.74 (2H, m),
6.95-7.01 (2H, m),
7.06 (1H, t, J = 8 Hz),
7.18-7.32 (6H, m),
7.58 (2H, t, J = 8Hz)
(3) Ethyl 2- [4- [3- [N- (1,3-benzothiazol-2-yl) -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionate
2- [N-3- (4-hydroxyphenyl) propyl-N-phenethyl] amino-1,3-benzothiazole (623 mg, purity 96.8%, 1.55 mmol), 2-bromo-2-methylpropionic acid Ethyl (900 mg, 4.61 mmol) and potassium carbonate (260 mg, 3.11 mmol) were added to acetone (5 mL), and the mixture was heated under reflux for 18 hours. The solvent was distilled off under reduced pressure, ethyl acetate (5 mL) was added to the residue, and the mixture was washed sequentially with water (5 mL) and saturated saline (5 mL). After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 / 5-1 / 3) to obtain 228 mg (purity: 92.8%, yield). (27.2%) of the title compound as a colorless oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.25 (3H, t, J = 7 Hz),
1.57 (6H, s),
1.95 (2H, dt, J = 8 Hz, 16 Hz),
2.58 (2H, t, J = 8 Hz),
2.99 (2H, t, J = 8 Hz),
3.40 (2H, t, J = 8 Hz),
3.70 (2H, t, J = 8 Hz),
4.23 (2H, q),
6.75-6.80 (2H, m),
7.00-7.17 (3H, m),
7.19-7.33 (6H, m),
7.54-7.60 (2H, m)
(4) 2- [4- [3- [N- (1,3-benzothiazol-2-yl) -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionic acid
Ethyl 2- [4- [3- [N- (1,3-benzothiazol-2-yl) -N-phenethyl] aminopropyl] phenoxy] -2-methylpropionate (228 mg, purity 92.8%, 0 .42 mmol) was dissolved in ethanol (3 mL), a 1 M aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 27 hours, and the solvent was distilled off under reduced pressure. A 1 M aqueous hydrochloric acid solution was added to the residue until the pH reached 7, and the mixture was extracted with ethyl acetate and washed sequentially with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 199 mg (purity: 97.8%, yield: 97.6%) of the title compound as a white amorphous substance.
¹H NMR (CDCl₃, 400MHz)
δ:
1.53 (6H, s),
1.93 (2H, dt, J = 8 Hz, 15 Hz),
2.57 (2H, t, J = 8 Hz),
2.97 (2H, t, J = 8 Hz),
3.40 (2H, t, J = 8 Hz),
3.67 (2H, t, J = 8 Hz),
6.82 (2H, d, J = 8 Hz),
7.02 (2H, d, J = 8 Hz),
7.06 (1H, d, J = 8 Hz),
7.18-7.32 (6H, m),
7.57 (2H, dd, J = 4Hz, 8Hz)
IR (cm^-1, KBr):
2933, 1720, 1595, 1543, 1508, 1458, 1454,
1444, 1371, 1234, 1147, 750, 700
Example 6
(1) 2- [N-3- (4-methoxymethoxyphenyl) propyl-N-phenethyl] amino-1,3-thiazole
3- (4-Methoxymethoxyphenyl) -N- (phenethyl) propylamine (800 mg, purity 93.0%, 2.48 mmol) was dissolved in dry DMF (6 mL), and 60% sodium hydride (120 mg, 3 mg). 0.000 mmol), and the mixture was stirred at room temperature for 1 hour. Then, 2-bromo-1,3-thiazole (0.27 mL, 3.05 mmol) was added, and the mixture was stirred at room temperature for 44 hours and 30 minutes. Ethyl acetate was added to the reaction solution, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/3). 266 mg (purity 98.6%, yield 27.6%) of the title compound was obtained as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.86 (2H, dt, J = 8 Hz, 15 Hz),
2.56 (2H, t, J = 8 Hz),
2.86 (2H, t, J = 8 Hz),
3.14 (2H, t, J = 8 Hz),
3.40 (2H, t, J = 8 Hz),
3.48 (3H, s),
5.15 (2H, s),
6.87 (1H, s),
6.94-6.98 (2H, m),
7.03-7.08 (2H, m),
7.14-7.32 (5H, m),
8.07 (1H, s)
(2) 2- [N-3- (4-hydroxyphenyl) propyl-N-phenethyl] amino-1,3-thiazole
2- [N-3- (4-methoxymethoxyphenyl) propyl-N-phenethyl] amino-1,3-thiazole (266 mg, purity 98.6%, 0.69 mmol) was added to THF (1.2 mL) and isopropanol ( (0.6 mL), a 2M aqueous hydrochloric acid solution (0.6 mL) was added, and the mixture was stirred at 50 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution (1.5 mL) was added to the reaction solution, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The organic layer was separated, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2) to give 77 mg (purity 94.0%, yield 31.0%) of the title compound as a pale yellow substance. Obtained as an oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.85 (2H, dt, J = 8 Hz, 15 Hz),
2.54 (2H, t, J = 8 Hz),
2.86 (2H, t, J = 8 Hz),
3.14 (2H, t, J = 8 Hz),
3.41 (2H, t, J = 8 Hz),
6.74-6.78 (2H, m),
6.84 (1H, s),
6.92-7.02 (2H, m),
7.15-7.32 (5H, m),
8.07 (1H, s)
(3) Ethyl 2-methyl-2- [4- [3- [N-phenethyl-N- (1,3-thiazol-2-yl)] aminopropyl] phenoxy] propionate
2- [N-3- (4-hydroxyphenyl) propyl-N-phenethyl] amino-1,3-thiazole (677 mg, purity 94.0%, 1.55 mmol), 2-bromo-2-methylpropionic acid Ethyl (0.1 mL, 0.67 mmol) and potassium carbonate (90 mg, 0.65 mmol) were added to methyl ethyl ketone (MEK) (2 mL), and the mixture was heated under reflux for 47 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline.
After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2) to obtain 69 mg (purity: 99.9%, yield: 72.5%). The title compound was obtained as a yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ = 1.25 (3H, t, J = 7 Hz),
1.57 (6H, s),
1.85 (2H, dt, J = 8 Hz, 15 Hz),
2.54 (2H, t, J = 8 Hz),
2.85 (2H, t, J = 8 Hz),
3.13 (2H, t, J = 8 Hz),
3.40 (2H, t, J = 8 Hz),
4.24 (2H, q, J = 7 Hz),
6.75-6.80 (2H, m),
6.86 (1H, s),
6.98-7.03 (2H, m),
7.15-7.32 (5H, m),
8.06 (1H, s)
(4) 2-methyl-2- [4- [3- [N-phenethyl-N- (1,3-thiazol-2-yl)] aminopropyl] phenoxy] propionic acid
Ethyl 2-methyl-2- [4- [3- [N-phenethyl-N- (1,3-thiazol-2-yl)] aminopropyl] phenoxy] propionate (69 mg, purity 99.9%, 0.1%). 15 mmol) was dissolved in ethanol (0.7 mL), a 1 M aqueous sodium hydroxide solution (0.2 mL) was added, and the mixture was stirred at room temperature for 26 hours, and the solvent was distilled off under reduced pressure. A 1M aqueous hydrochloric acid solution was added to the residue until the pH reached 7, and the mixture was extracted with ethyl acetate and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 61 mg (yield 95.8%) of the title compound as yellow crystals.
mp: 91-92 ° C
¹H NMR (CDCl₃, 400MHz)
δ:
1.64 (6H, s),
1.82 (2H, dt, J = 8 Hz, 15 Hz),
2.54 (2H, t, J = 8 Hz),
2.85 (2H, t, J = 8 Hz),
3.10 (2H, t, J = 8 Hz),
3.39 (2H, t, J = 8 Hz),
6.19, 6.21 (1H, each s),
6.90-6.94 (2H, m),
7.04-7.07 (2H, m),
7.15-7.18 (2H, m),
7.20-7.33 (4H, m),
8.01 (1H, s)
IR (cm^-1, KBr):
3089, 1718, 1533, 1510, 1456, 1431, 1381,
1379, 1365, 1288, 1230, 1180, 1149, 1111
Example 7
(1) 2- [N-3- (4-methoxymethoxyphenyl) propyl-N-phenethyl] amino-5-nitro-1,3-thiazole
3- (4-methoxymethoxyphenyl) -N- (phenethyl) propylamine (680 mg, purity 93.0%, 2.11 mmol) was dissolved in dry DMF (5 mL), and 60% sodium hydride (110 mg, 2 .75 mmol) and stirred at room temperature for 1 hour, and then 2-bromo-5-nitro-1,3-thiazole (560 mg, 2.68 mmol) was added and the mixture was stirred at room temperature for 43 hours and 30 minutes. Ethyl acetate was added to the reaction solution, washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1 / 3-1). / 2) to give 605 mg (purity 93.1%, yield 62.4%) of the title compound as an orange oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.95-2.05 (2H, m),
2.60 (1H, t, J = 8Hz),
2.66 (1H, t, J = 8 Hz),
2.95 (1H, t, J = 8Hz),
2.97 (1H, t, J = 8Hz),
3.28 (1H, t, J = 8 Hz),
3.48 (3H, s),
3.62 (1H, t, J = 8 Hz),
3.72 (1H, t, J = 8 Hz),
4.01 (1H, t, J = 8 Hz),
5.16 (2H, s),
6.97-7.01 (2H, m),
7.04-7.14 (3H, m),
7.19 (1H, d, J = 7 Hz),
7.25-7.36 (3H, m),
8.39, 8.65 (1H, each s)
(2) 2- [N-3- (4-hydroxyphenyl) propyl-N-phenethyl] amino-5-nitro-1,3-thiazole
2- [N-3- (4-methoxymethoxyphenyl) propyl-N-phenethyl] amino-5-nitro-1,3-thiazole (605 mg, purity 93.1%, 1.32 mmol) was added to THF (2.4 mL). ) And isopropanol (1.2 mL), and a 2M aqueous hydrochloric acid solution (1.2 mL) was added, followed by stirring at 50 ° C. for 5 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the residue. The organic layer was separated, washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2/1) to give 306 mg (purity: 90.4%, yield: 54.6%) of the title. The compound was obtained as a brown oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.76-1.90 (2H, m),
2.65 (1H, t, J = 8Hz),
2.56 (1H, t, J = 8Hz),
2.79 (1H, t, J = 8 Hz),
2.85 (1H, t, J = 8Hz),
3.10 (1H, t, J = 8Hz),
3.36 (1H, t, J = 8 Hz),
3.43 (1H, t, J = 8 Hz),
3.53 (1H, t, J = 8 Hz),
6.77 (2H, d, J = 8 Hz),
6.99 (1H, d, J = 8 Hz),
7.04 (1H, d, J = 8 Hz),
7.11 (1H, d, J = 7 Hz),
7.19-7.32 (4H, m),
7.83, 7.99 (1H, each s)
(3) Ethyl 2-methyl-2- [4- [3- [N- (5-nitro-1,3-thiazol-2-yl) -N-phenethyl] aminopropyl] phenoxy] propionate
2- [N-3- (4-hydroxyphenyl) propyl-N-phenethyl] amino-5-nitro-1,3-thiazole (306 mg, purity 90.4%, 0.72 mmol), 2-bromo-2- Ethyl methyl propionate (0.32 mL, 2.15 mmol) and potassium carbonate (290 mg, 2.10 mmol) were added to methyl ethyl ketone (MEK) (2 mL), and the mixture was heated under reflux for 47 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2/1/1) to obtain 242 mg (purity 99.7% yield 67). 0.3%) of the title compound as a pale yellow oil.
¹H NMR (CDCl₃, 400MHz)
δ:
1.25 (3H, t, J = 7 Hz),
1.57 (6H, s),
1.76-2.05 (2H, m),
2.50 (1H, t, J = 8Hz),
2.56 (1H, t, J = 8Hz),
2.78 (1H, t, J = 8 Hz),
2.84 (1H, t, J = 8 Hz),
3.10 (1H, t, J = 8Hz),
3.35 (1H, t, J = 8 Hz),
3.42 (1H, t, J = 8 Hz),
3.52 (1H, t, J = 8 Hz),
4.24 (2H, q, J = 7 Hz),
6.76-6.80 (2H, m),
6.99 (1H, d, J = 9 Hz),
7.05 (1H, d, J = 9 Hz),
7.11 (1H, d, J = 7 Hz),
7.19-7.32 (4H, m),
7.83, 8.00 (1H, each s)
(4) 2-methyl-2- [4- [3- [N- (5-nitro-1,3-thiazol-2-yl) -N-phenethyl] aminopropyl] phenoxy] propionic acid
Ethyl 2-methyl-2- [4- [3- [N- (5-nitro-1,3-thiazol-2-yl) -N-phenethyl] aminopropyl] phenoxy] propionate (242 mg, purity 99.7) %, 0.48 mmol) in ethanol (2.4 mL), 1M aqueous sodium hydroxide solution (0.63 mL) was added, and the mixture was stirred at room temperature for 26 hours, and the solvent was distilled off under reduced pressure. A 1M aqueous hydrochloric acid solution was added to the residue until the pH reached 7, and the mixture was extracted with ethyl acetate and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 179 mg (yield: 76.6%) of the title compound as pale yellow crystals.
¹H NMR (CDCl₃, 400MHz)
δ:
1.57 (6H, s),
1.76-1.89 (2H, m),
2.51 (1H, t, J = 8Hz),
2.56 (1H, t, J = 8Hz),
2.79 (1H, t, J = 8 Hz),
2.83 (1H, t, J = 8 Hz),
3.09 (1H, t, J = 8 Hz),
3.35 (1H, t, J = 8 Hz),
3.42 (1H, t, J = 8 Hz),
3.51 (1H, t, J = 8 Hz),
6.86 (2H, d, J = 8 Hz),
7.01 (1H, d, J = 9 Hz),
7.07 (1H, d, J = 9 Hz),
7.11 (1H, d, J = 7 Hz),
7.18-7.32 (4H, m),
7.92 (1H, d, J = 54Hz)
IR (cm^-1, KBr):
2987, 2937, 2866, 1736, 1670, 1635, 1508,
1454, 1450, 1396, 1373, 1240, 1151, 702
Example 8
(Pharmacological experiment)
I. Measuring method
(1) Measurement of PPARα, γ, δ activating action
PPARα, γ and δ activity of test compounds [Examples 1-3, 5 and GW-2433, a known PPARδ agonist (Berger, J. et al., (1999) J. Biol. Chem., 274: 6718-6725)] The chemical action was measured as follows.
1) Materials
African green monkey kidney fibroblasts (CV-1 cells) were obtained from Tohoku University Institute for Aging and Medicine @ Medical Cell Resources Center. All test compounds were dissolved in dimethyl sulfoxide (DMSO) and used for the test at a final DMSO concentration of 0.1%.
2) Plasmid
Receptor expression plasmids (GAL4-hPPARα LBD, GAL4-hPPARγ LBD, GAL4-hPPARδ LBD), luciferase expression plasmid (UASx4-TK-LUC), and β-galactosidase expression plasmid (βGAL) are available from Kliewer, S.L. A. Others, ((1992) Nature, 358: 771-774) were used.
3) Transfection
CV-1 cells at 2 × 10 per well⁵The cells were seeded in a 24-well culture plate at a cell concentration of 24 cells and cultured for 24 hours at 500 μl / well of OPTI-MEM I Reduced Serum Medium (Life Technologies) supplemented with 4% fetal calf serum (FCS). Thereafter, the cells were washed with serum-free OPTI-MEM, and a DNA-containing solution [containing one of the following components per well (250 µl added solution): 0.03 µg of GAL4-hPPARδ LBD, 0.25 µg of UASx4- TK-LUC, 0.35 μg βGAL, and 2 μl of lipofection reagent DMRIE-C (Life @ Technologies), which were dissolved in OPTI-MEM and allowed to stand at room temperature for 30 minutes], and were added at 37 ° C. for 5 hours. Cultured.
4) Cell treatment by adding test compound
Excluding the DNA-containing solution, the test compound (final concentration: 10^-4M or 10^-5M was dissolved in 100% DMSO) and replaced with 4% FCS-OPTI-MEM (500 µl), followed by further culturing at 37 ° C for 40 hours.
5) Measurement of reporter gene expression level
After removing the medium and washing twice with PBS, the cells were freeze-thawed once, and the lysis buffer for measuring luciferase activity (25 mM @ Tris-PO₄(PH 7.8), 15% v / v Glyserol, 2% CHAPS, 1% Lecithin, 1% BSA, 4 mM EGTA (pH 8.0), 8 mM MgCl₂, 1 mM @ DTT) and left at room temperature for 10 minutes. Twenty μl of the solution was dispensed into a 96-well measurement plate, 100 μl of luciferase substrate solution (Picka Gene; manufactured by Nippon Gene) was added, and the solution was used for 1 second using an MLR-100 microlumino reader (manufactured by Corona Electric Co., Ltd.). The amount of luminescence (luciferase activity) was determined. The expression level of the activity due to intracellular transfection of βGAL added at the same time as the addition of the luciferase gene was measured, and the change in luciferase activity due to the addition of the compound was corrected by the transfection efficiency of the transgene. To measure β-galactosidase activity, 50 μl of a solubilized sample was dispensed into another 96-well plate, and 100 μl of ONPG (2-nitrophenyl-β-D-galactopyranoside) solution was added. Incubated for 5 minutes. 50 μl of a reaction stop solution (1 M sodium carbonate solution) was added, and the absorbance at 414 nm was measured. The luciferase activity value (control value) of cells treated only with DMSO (0.1% concentration) used as a solvent was set to 0%, and the control drug (PPARα: 10^-4M {WY-14643 (4-chloro-6-[(2,3-dimethylphenyl) amino] -2-pyrimidinyl) thio) acetic acid {German Patent 2314160), PPARγ: 10^-5M Rosiglitazone, PPARδ 10^-4The relative luciferase activity of cells treated with L-165041) was determined as 100%, and the relative ligand activity was calculated.
II. Test results
Test results showing the PPAR activating effect (EC 50 μM) are shown in Table 10.
[Table 10]

In the table, Examples 1, 2, 3, and 5 are the following compounds.
Example 1: 2- [4- [3- [N-[(4-isopropyl-1,3-thiazolate)]
Ru-2-yl) carbonyl] -N-phenethyl] aminopropyl]
Phenoxy] -2-methylpropionic acid
Example 2: 2-methyl-2- [4- [3- [N-phenethyl-N-[(1,3
-Thiazol-2-yl) carbonyl]] aminopropyl] pheno
Xy] propionic acid
Example 3: 2- [4- [3- [N-[(1,3-benzothiazol-2-yl)
) Carbonyl] -N-phenethyl] aminopropyl] phenoxy]
-2-methylpropionic acid
Example 5: 2-methyl-2- [4- [3- [N- (1,3-benzothiazole)
-2-yl) -N-phenethyl] aminopropyl] phenoxy] p
Ropionic acid
As is clear from Table 10, the compound of the present invention has an excellent PPAR activating action (PPARα, γ or δ activity).

Claims (5)

The following general formula (I):

(Wherein, R ¹ and R ² each represent a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an aryl group having 6 to 10 carbon atoms) Or R ¹ and R ² may together form a benzene ring with the carbon atom to which R ¹ and R ² are attached,
X represents an oxygen atom, a sulfur atom, —NR ⁰ — (R ⁰ is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms), or —CH ＝ CH—,
G represents a single bond or a carbonyl group,
R ³ is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and 3 to 7 carbon atoms. An alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an arylalkyl group (having 6 to 10 carbon atoms in the aryl portion and 1 carbon atom in the alkyl portion) To 8), a heterocyclic group, or a heterocyclic alkyl group (1 to 8 carbon atoms in the alkyl portion);
n represents an integer of 0 to 5,
Y is -CH ₂ -, represents a carbonyl group, or -CH = CH-,
Z represents an oxygen atom or a sulfur atom,
p represents an integer of 0 to 5,
R ⁴ and R ⁵ each represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
W represents a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonic acid group, a phosphonic acid group, a cyano group, or a tetrazolyl group.
The aryl group of R ¹ and R ^2, the aryl group of R ³ , the arylalkyl group, the heterocyclic group, the heterocyclic alkyl group, and R ¹ and R ² are combined to form R ¹ and R ² . A benzene ring formed with carbon atoms is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, Substitution selected from a formyl group, a hydroxyl group, a halogen atom, a nitro group, an amino group, an alkylamino group (the alkyl group has 1 to 8 carbon atoms), or a dialkylamino group (the alkyl group has 1 to 8 carbon atoms) It may have a group. )
Or a salt thereof. The following general formula (II):

(Wherein, R ⁶ and R ⁷ are a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an aryl group having 6 to 10 carbon atoms, respectively) Or R ⁶ and R ⁷ may together form a benzene ring with the carbon atom to which R ⁶ and R ⁷ are attached,
G ¹ represents a single bond or a carbonyl group,
R ⁸ is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and 3 to 7 carbon atoms. An alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an arylalkyl group (having 6 to 10 carbon atoms in the aryl portion and 1 carbon atom in the alkyl portion) To 8), a heterocyclic group, or a heterocyclic alkyl group (1 to 8 carbon atoms in the alkyl portion);
m represents an integer of 0 to 5,
Y ¹ represents —CH ₂ —, a carbonyl group, or —CH ＝ CH—;
Z ¹ represents an oxygen atom or a sulfur atom,
R ⁹ and R ¹⁰ each represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
The aryl groups of R ⁶ and R ^7, the aryl group of R ⁸ , the arylalkyl group, the heterocyclic group, the heterocyclic alkyl group, and R ⁶ and R ⁷ are combined to form R ⁶ and R ⁷ . A benzene ring formed with carbon atoms is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, Substitution selected from a formyl group, a hydroxyl group, a halogen atom, a nitro group, an amino group, an alkylamino group (the alkyl group has 1 to 8 carbon atoms), or a dialkylamino group (the alkyl group has 1 to 8 carbon atoms) It may have a group. )
Or a salt thereof. R ⁸ is an alkyl group having 1 to ⁸ carbon atoms, or an alkyl group having 1 to 8 carbon atoms as a substituent, an alkoxy group having 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a hydroxyl group, and halogen. The thiazole derivative or its salt according to claim 2, which is a phenylalkyl group (the alkyl portion has 1 to 8 carbon atoms) which may have a group or an atom selected from an atom, a nitro group, and an amino group. 4. The thiazole derivative or a salt thereof according to claim _{2, wherein} Y ¹ is —CH ₂ —. An activator of a peroxisome proliferator-activated receptor, comprising the compound according to any one of claims 1 to 4 or a salt thereof as an active ingredient.