JPWO2002044129A1 - Substituted carboxylic acid derivatives - Google Patents

Abstract

A novel substituted carboxylic acid derivative that binds to and activates human peroxisome proliferator-activated receptor alpha (PPARα) as a ligand and has lipid-lowering, arteriosclerosis-inhibiting, anti-obesity, and hypoglycemic effects And methods for their production. In the general formula (1), wherein n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and n represents 1 A lower alkyl group having 1 to 10 carbon atoms], an ester thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a method for producing the same.

Description

（式中、Ｗは（置換）ラクタム環を表し、Ａはアルキレン基又はアルキレンオキシ基を表し、ＸはＯ、Ｓ、ＮＨ、ＣＨ_２を表し、Ｙ^１はアミノ基、水酸基又はアルコキシ基を表し、Ｒ^１はＨ又はアルキル基等を表し、Ｒ^２はアルキル基又はフェニル基等を表し、Ｒ^３はＨ、アルキル基又はアルコキシ基等を表す）で表される化合物が報告されている。
しかしながらこれらの化合物は連結部分のＡにカルボニル基やアミド基を含まない点及び末端置換基であるＷにラクタム環を含む点で本発明の化合物とは構造が異なり、またこれらの化合物がヒトＰＰＡＲα結合活性、転写活性化作用を有する事は記述されていない。
国際公開番号　ＷＯ９８／２８２５４号（日本ケミファ株式会社）に血糖降下作用を有する化合物として
一般式（Ｂ）

（式中、Ａ^１は置換基を有していても良いアリール基又は複素環基を表し、Ｙ^２は炭素数１から５のアルキレン鎖を表し、Ｘ^４は結合手、酸素原子又は硫黄原子を表し、Ｗ^１は置換基を有していても良いナフタレン環、キノリン環、インドール環、ベンズイソキサゾール環又はベンゾ［ｂ］チオフェン環を表し、Ｒ^４は水素原子又は炭素数１から８のアルキル基を表し、Ｘ^５は酸素原子又は硫黄原子を表し、そしてＲ^５は置換基を有していても良い炭素数１から８のアルキル基、アラルキル基又はアリール基を表す）で表される化合物が報告されている。
しかしながらこれらの化合物は連結部分のＹ^２及びＸ^４にカルボニル基やアミド基を含まない点及びプロピオン酸の３位に結合するＷ^１は複素環である点で本発明の化合物とは構造が異なり、またこれらの化合物がヒトＰＰＡＲα結合活性、転写活性化作用を有する事は記述されていない。
国際公開番号　ＷＯ９８／０７６９９号（日本たばこ産業株式会社）に血糖降下作用及び脂質低下作用を有するプロピオン酸誘導体として
一般式（Ｃ）

（式中、ＲはＤ_１及びＤ_２で示される置換基を表し、Ｒ^１は芳香族環、シクロアルキル基及び複素芳香族環を表し、Ｒ^５はアルキル基を表し、Ｒ^４は水素原子又はアルキル基を表し、Ｒ^６は水素原子又はＲ^９と連結して二重結合を形成していても良く、Ｒ^７はカルボキシル基、アシル基、置換基を有していても良いアルコキシカルボニル基、アルキル基、アリールオキシカルボニル基、アラルキルオキシカルボニル基、カルバモイル基、ＮＨＲ^８基及びＯＲ^８基を表し、Ｒ^８は置換基を有していても良いアシル基及びアルコキシカルボニル基を表し、Ｒ^９は水素原子、アルキル基、アルコキシカルボニル基を表し、Ｒ^１０は水素原子、アミノ基、アルコキシ基、アルキル基、アリールオキシ基及びアラルキルオキシ基を表す）で表される化合物が報告されている。
しかしながらこれらの化合物もベンゼン環上の置換基が１位と４位の二置換体である点で本発明の化合物とは構造が異なり、またこれらの化合物がヒトＰＰＡＲα結合活性、転写活性化作用を有する事は記述されていない。
公開特許公報　昭６３−９１３５４号（山之内製薬株式会社）にロイコトリエン受容体作動作用を有するカルボン酸誘導体として
一般式（Ｅ）

（式中、Ａは水素原子またはフェニル基を表し、ｍは３から１０の整数を表し、ｎは１から６の整数を表し、ＸはＣＯＮＨ基或いはＮＨＣＯ基を表し、Ｒはカルボキシ低級アルキル基又はカルボキシ低級アルキルカルバモイル基（但し、Ａがフェニル基の時はＲはカルボキシ低級アルキルカルバモイル低級アルキル基である）を表す）で表される化合物が報告されている。
しかしながらこれらの化合物はプロピオン酸の２位に置換基を有さず、又Ｒ基部分には全てにカルボニル基が存在するので本発明の化合物とは構造が異なり、またこれらの化合物がヒトＰＰＡＲα結合活性、転写活性化作用を有する事は記述されていない。
ＵＳ５２２７４９０号（メルク株式会社）にフィブリノーゲン受容体拮抗作用を有するカルボン酸誘導体として
一般式（Ｆ）

（式中、Ｒ^１は水素原子、Ｃ_１−６アルキル基、アリールＣ_４−１０アルキル基、アリール基、カルボキシル基、Ｃ_１−６アルコキシ基、カルボキシＣ_０−６アルキル基、カルボキシＣ_０−６アルコキシ基、ヒドロキシＣ_１−６アルキル基、Ｃ_１−４アルキルスルホニルＣ_０−６アルキル基、Ｃ_０−４アルキルアミノＣ_０−６アルキル基、アリールＣ_０−１０アルキルアミノＣ_０−６アルキル基、Ｃ_２−１０アシルアミノＣ_０−６アルキル基、Ｃ_１−４カルボアルコキシＣ_０−６アルキル基又はハロゲン原子を表し、Ｒ^２は同一又は相異なって水素原子、ハロゲン原子、ヒドロキシル基、Ｃ_１−６アルコキシ基、アリールＣ_０−４アルキル基、アリールＣ_０−６アルコキシ基、置換基を有していても良いＣ_１−６アルキル基を表し、Ｒ^３は水素原子、Ｃ_１−６アルキル基又はアリールＣ_１−１０アルキル基を表し、Ｘは酸素原子、硫黄原子、ＳＯ基、ＳＯ_２基、ＣＯ基、ＮＲ^４ＣＯ基、ＣＯＮＲ^４基、ＣＨ_２基、ＣＨ＝ＣＨ基、ＮＲ^４ＣＳ基を表し、Ｙは無置換又は置換基を有していても良いＣ_１−１０アルキル基、Ｃ_４−８シクロアルキル基、アリール基、Ｃ_０−３アルキルアリールＣ_０−３アルキル基、Ｃ_０−３アルキルアリールＣ_０−３アルキルカルボニル基、Ｃ_０−３アルキルアリールＣ_{０− ３}アルキルカルボキシアミド基、Ｃ_０−３アルキルアリールオキシＣ_０−３アルキル基、ＣＯＮＨ基、ＮＨＣＯ基又は（ＣＨ_２）ｍ−Ｑ−（ＣＨ_２）ｎ基（但し、Ｑは酸素又は硫黄から選ばれる１から３種類のヘテロ原子を含むＣ_３−８員環複素環を表し、ｍとｎは０から４である）を表し、ＺはＮＲ^４Ｒ^５基（但し、Ｒ^４とＲ^５は同一又は相異なって水素原子、Ｃ_１−６アルキル基、アリールＣ_１−１０アルキル基でアルキル基は無置換又はＣ_１−４アルコキシ基、カルボキシＣ_０−６アルキル基、ヒドロキシル基、ハロゲン原子又は窒素、酸素及び硫黄より選択される１−３のヘテロ原子を含む４−９員環の単環又はビシクロ環で置換されていても良い）又は置換基を有していても良いグアニジノ基を表す）で表される化合物が報告されている。
しかしながらこれらの化合物はＺ基部分に全て置換基を有していても良いアミノ基を必ず含むアミノ酸誘導体である事から本発明の化合物とは構造が異なり、またこれらの化合物がヒトＰＰＡＲα結合活性、転写活性化作用を有する事は記述されていない。
ＰＰＡＲα作動作用を報告している特許に関しては、国際公開番号　ＷＯ９７／２５０４２号（スミスクラインビーチャム株式会社）にＰＰＡＲα及びＰＰＡＲγ作動作用を有する化合物として
一般式（Ｇ）

（式中、Ｒ^ａは２−ベンズオキサゾリル基又は２−ピリジル基を表し、Ｒ^ｂはメトキシメチル基又はトリフルオロメチル基を表す）で表される化合物が報告されている。しかしながらこれらの化合物はベンゼン環上の置換基は１位及び４位の二置換誘導体である点で本発明の化合物とは構造が異なり、更にヒトＰＰＡＲα結合活性、転写活性化作用を有する事は記述されていない。
国際公開番号　ＷＯ９７／３６５７９（グラクソウェルカム株式会社）にＰＰＡＲα作動作用を有する化合物として
一般式（Ｈ）

（式中、Ｘは水素原子又はフッ素原子を表す）で表される化合物が報告されている。
しかしながらこれらの化合物はフェノキシ酢酸誘導体であり、またベンゼン環上の置換基の位置関係は１位及び４位の二置換体である点で本発明の化合物とは構造が異なる。又ＰＰＡＲαの転写活性化作用も決して満足のいく強さではない。
食生活やライフスタイルの急激な変化に伴い虚血性心疾患などの動脈硬化性疾患の頻度が増加し問題となっている。この動脈硬化性疾患の主たる危険因子として高脂血症、糖尿病、高血圧が考えられており、その病態にはインスリン抵抗性の存在が重要であるとされているが、その成因基盤として内臓脂肪の蓄積による肥満が深く関与している事が明らかとなっている。そこでこれらの疾患に対し総合的に有効でかつ安全性の高い代謝性疾患治療薬の開発が臨床上望まれている。
発明の開示
本発明者らは、代謝性疾患治療薬として有効性及び安全性の高い構造上新規な薬物の創製を目的としてかかるヒトＰＰＡＲαの特異的な役割に着目し、鋭意研究を重ねた結果下記一般式（１）で表される新規置換カルボン酸誘導体が優れたヒトＰＰＡＲα結合活性並びに転写活性化作用を有する事を見出し本発明を完成した。
即ち本発明は一般式（１）

［式中、ｎは０、１又は２を表し、Ｒはｎが０あるいは２の場合は水素原子又は炭素数１から１０の低級アルキル基を表し、ｎが１の場合は炭素数１から１０の低級アルキル基を表す］で表される置換カルボン酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその水和物に関する。
本発明における一般式（１）で表される化合物の塩類は慣用のものであって、金属塩例えばアルカリ金属塩（例えばナトリウム塩、カリウム塩、リチウム塩など）、アルカリ土類金属塩（例えばカルシウム塩、マグネシウム塩など）、アルミニウム塩等薬理学的に許容しうる塩が挙げられる。
また、本発明における一般式（１）で表される化合物には、置換カルボン酸部分に基づく光学異性体が含まれる事がある。また一般式（１）で表される化合物の合成の過程で得られる化合物の中には幾何異性体の混合物が含まれる場合がある。そのような異性体及びそれらの混合物はすべてこの発明の範囲内に含まれるものである。
各光学異性体は立体選択的な合成法により製造する事ができる。またそれらは光学活性なアルコール誘導体や光学活性なオキサゾリジノン誘導体と反応させて得られるジアステレオマリックなエステル誘導体やオキサゾリジノン誘導体を分別結晶又はクロマトグラフィーの手法により分離した後加水分解する事により製造する事もできる。さらにそれらはキラル支持体を使用するクロマトグラフィーの手法により製造する事もできる。
本発明の一般式（１）において、「炭素数１から１０の低級アルキル基」とは、メチル、エチル、プロピル、イソプロピル、ブチル等の直鎖もしくは分岐した炭素数１から１０のものが挙げられる。
上記一般式（１）である化合物は例えば以下の方法により製造することができる（スキーム１）。

すなわち、一般式（１）

［式中、ｎは０、１又は２を表し、Ｒはｎが０あるいは２の場合は水素原子又は炭素数１から１０の低級アルキル基を表し、ｎが１の場合は炭素数１から１０の低級アルキル基を表す］で表される置換カルボン酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその水和物は２−メトキシ−５−ホルミル安息香酸ベンジルエステル（２）

と一般式（６）

［式中、Ｒ^１は炭素数１から４の低級アルキル基であり、ＸはＰＰｈ_３基またはＰＯ（ＯＣ_２Ｈ_５）_２基を表す］で表される化合物を塩基存在下作用させる（Ｗｉｔｔｉｇ反応又はＨｏｒｎｅｒ−Ｅｍｍｏｎｓ反応；第一工程）事により合成される一般式（３）

［式中、Ｒ^１は前述の通り］で表される化合物を還元及び水素化分解する（第二工程）事により得られる一般式（４）

［式中、Ｒ^１は前述の通り］で表される化合物に一般式（７）

［式中、ｎ及びＲは前述の通り］で表される化合物を反応させ（第三工程）、得られた一般式（５）

［式中、Ｒ，Ｒ^１及びｎは前述の通り］で表される化合物のＣＯＯＲ^１部位を加水分解する（第四工程）事により製造する事ができる。
第一工程のＷｉｔｔｉｇ反応又はＨｏｒｎｅｒ−Ｅｍｍｏｎｓ反応はテトラヒドロフラン、トルエン、ジオキサン、Ｎ，Ｎ−ジメチルホルムアミド等の溶媒中、塩基としては例えば水素化ナトリウムのようなアルカリ金属水素化物、ブチルリチウムのような有機金属化合物、リチウムジイソプロピルアミドのような金属アミド、ナトリウムメトキシドやカリウム　ｔ−ブトキシドのような金属アルコキシドを用いる事ができる。反応温度としては−２０℃から１５０℃にて、好適には０℃から５０℃にて実施する事ができる。
第二工程の還元反応はパラジウム担持活性炭、白金担持活性炭、酸化白金、ロジウム担持アルミナ等の金属触媒存在下、エタノール、メタノール、テトラヒドロフラン、酢酸エチル、Ｎ，Ｎ−ジメチルホルムアミド等の溶媒中９８．１ｋＰａから４９１ｋＰａで実施する事ができる。反応温度としては０℃から１００℃にて、好適には室温から８０℃にて実施する事ができる。
第三工程の縮合反応はカルボキシル基をそのままで、または反応性の誘導体に変換して実施する事ができる。
「カルボキシル基の反応性誘導基」としては酸塩化物、酸臭化物、酸無水物、カルボニルイミダゾール等が挙げられる。反応性誘導体を用いた反応の場合には、ジオキサン、Ｎ，Ｎ−ジメチルホルムアミド等の溶媒中、塩基として例えば水素化ナトリウムのようなアルカリ金属水素化物、水酸化ナトリウムのようなアルカリ金属水酸化物、炭酸カリウム等のアルカリ金属炭酸塩、又はピリジン、トリエチルアミンのような有機塩基の存在下または非存在下に実施する事ができる。
カルボン酸体のままで反応を行う場合には塩化メチレン、クロロホルム、ジオキサン、Ｎ，Ｎ−ジメチルホルムアミド等の溶媒中縮合剤の存在下塩基の存在下又は非存在下で更には添加剤の存在下又は非存在下実施する事ができる。
縮合剤としては例えばジシクロヘキシルカルボジイミド、１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド塩酸塩、シアノリン酸ジエチル、ジフェニルリン酸アジド、カルボニルジイミダゾール等が挙げられる。塩基としては例えば水酸化ナトリウムのようなアルカリ金属水酸化物、炭酸カリウム等のアルカリ金属炭酸塩、又はピリジン、トリエチルアミンのような有機塩基が挙げられる。添加剤としてはＮ−ヒドロキシベンゾトリアゾール、Ｎ−ヒドロキシスクシンイミドや３，４−ジヒドロ−３−ヒドロキシ−４−オキソ−１，２，３−ベンゾトリアジン等が挙げられる。反応温度としては−２０℃から１００℃にて、好適には０℃から５０℃にて実施する事ができる。
第四工程の加水分解反応はアルカリ性条件下で行う事ができる。アルカリ性条件としては水酸化リチウム、水酸化ナトリウム、水酸化カリウム等が用いられる。反応温度としては０℃から８０℃にて、好適には室温から６０℃にて実施する事ができる。
本発明の新規化合物の投与形態としては、経口投与のための固体組成物、液体組成物及びその他の組成物及び非経口投与のための注射剤、外用剤、坐剤等を挙げる事ができる。経口投与のための固体組成物には、錠剤、丸剤、カプセル剤、散剤、顆粒剤等が含まれる。経口投与のための液体組成物は薬剤的に許容される乳濁剤、シロップ剤等が含まれる。経口投与のためのその他の組成物としてはスプレー剤が含まれる。また非経口投与のための注射剤としては、無菌の水性または非水性の溶液剤、懸濁剤、乳濁剤等が含まれる。
発明を実施するための最良の形態
次に本発明を具体例によって説明するがこれらの例によって本発明が限定されるものではない。
（実施例１）
２−［［３−［Ｎ−［２−［４−（トリフルオロメチル）フェニル］エチル］カルバモイル］−４−メトキシフェニル］メチル］酪酸エチル

３−（３−カルボキシ−４−メトキシフェニル）−２−エチルプロピオン酸エチル（特願　２０００−１５７６００；５６０ｍｇ，２．００ｍｍｏｌ）、トリエチルアミン（９７７μＬ，７．００ｍｍｏｌ）と脱水ジクロロメタン８０ｍＬを混合し、氷冷攪拌下クロロ炭酸エチル（２２８ｍｇ，２．１０ｍｍｏｌ）を脱水ジクロロメタン５ｍＬに溶かし滴下した。氷冷下１０分攪拌後４−（トリフルオロメチル）フェネチルアミン塩酸塩（５６６ｍｇ，２．５１ｍｍｏｌ）を脱水ジクロロメタン１５ｍＬに懸濁させ滴下した。次に氷冷下３０分、室温にて６時間攪拌後反応液を１０％クエン酸水溶液、０．５ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後無水硫酸ナトリウムで乾燥し濃縮した。残留物をシリカゲルクロマトグラフィー（溶出液　ｎ−ヘキサン：酢酸エチル＝２：３ｖ／ｖ）にて精製し、７７０ｍｇ（８５％）の表題化合物を無色油状物として得た。
質量分析値　ｍ／ｚ　４５１（Ｍ^＋）
（実施例２−５）
実施例１と同様にして表１に示す化合物を合成した。

（実施例６）
２−［［３−［Ｎ−［２−［４−（トリフルオロメチル）フェニル］エチル］カルバモイル］−４−メトキシフェニル］メチル］酪酸

２−［［３−［Ｎ−［２−［４−（トリフルオロメチル）フェニル］エチル］カルバモイル］−４−メトキシフェニル］メチル］酪酸エチル（７７０ｍｇ，１．７１ｍｍｏｌ；実施例１）とメタノール３０ｍＬ、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液５ｍＬを混合し、６０℃で４時間撹拌後反応液を減圧下濃縮した。残留物を氷冷下２ｍｏｌ／Ｌ塩酸で酸性とした。生じた沈殿を濾過、乾燥した後ｎ−ヘキサンと酢酸エチルの混合溶媒にて再結晶し、無色粉末の表題化合物を５８０ｍｇ（８０％）得た。
融点１４６−１４７℃；質量分析値　ｍ／ｚ　４２３（Ｍ^＋）；
元素分析値　Ｃ_２２Ｈ_２４Ｆ_３ＮＯ_４（４２３．４３）：
計算値　Ｃ，６２．４０；Ｈ，５．７１；Ｎ，３．３１．
実測値　Ｃ，６２．２０；Ｈ，５．６２；Ｎ，３．３２．；
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．９５（３Ｈ，ｔ，Ｊ＝７．８Ｈｚ），１．５４−１．７０（２Ｈ，ｍ），２．５８−２．６５（１Ｈ，ｍ），２．７６（１Ｈ，ｄｄ，Ｊ＝１３．７，８．３Ｈｚ），２．９４（１Ｈ，ｄｄ，Ｊ＝１３．７，８．３Ｈｚ），２．９９（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．７２（３Ｈ，ｓ），３．７３（２Ｈ，ｍ），６．８３（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２４（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．３７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８９（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），８．０４（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
（実施例７−１０）
実施例６と同様にして表２の化合物を得た。

（実施例１１）
２−［［３−［Ｎ−［４−（トリフルオロメチル）フェニル］カルバモイル］−４−メトキシフェニル］メチル］酪酸

３−（３−カルボキシ−４−メトキシフェニル）−２−エチルプロピオン酸エチル（特願２０００−１５７６００；５３０ｍｇ，１．８９ｍｍｏｌ）、４−トリフルオロメチルアニリン（３８２ｍｇ，２．３７ｍｍｏｌ）、トリエチルアミン（６５７μＬ，４．７１ｍｍｏｌ）と脱水ジクロロメタン３０ｍＬを混合し、氷冷攪拌下２−クロロ−１，３−ジメチルイミダゾリウムクロライド（４６７ｍｇ，２．７６ｍｍｏｌ）を脱水ジクロロメタン２０ｍＬに溶かし滴下した。次に室温にて６時間攪拌後反応液を１０％クエン酸水溶液、０．５ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後無水硫酸ナトリウムで乾燥し濃縮して８００ｍｇの縮合体を定量的に得た。
得られた縮合体（５５０ｍｇ，１．３０ｍｍｏｌ）を２ｍｏｌ／Ｌ水酸化ナトリウム水溶液５ｍＬ及びメタノール３０ｍＬと混合し、６０℃で４時間撹拌した。反応液を減圧下濃縮し、残留物を水に溶解させ希塩酸で酸性とした。生じた沈殿を濾過しシリカゲルクロマトグラフィー（溶出液　塩化メチレン：メタノール＝１５：１ｖ／ｖ）にて精製し、２００ｍｇ（３９％）の表題化合物を無色粉末として得た。
融点１４１−１４２℃；　質量分析値　ｍ／ｚ３９５（Ｍ^＋）；
元素分析値　Ｃ_２０Ｈ_２０Ｆ_３ＮＯ_４（３９５．３７）：
計算値　Ｃ，６０．７６；Ｈ，５．１０；Ｎ，３．５４．
実測値　Ｃ，６０．７２；Ｈ，５．２５；Ｎ，３．５３．；
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．９７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．５６−１．７２（２Ｈ，ｍ），２．６０−２．６７（１Ｈ，ｍ），２．８０（１Ｈ，ｄｄ，Ｊ＝１４．２，８．３Ｈｚ），２．９８（１Ｈ，ｄｄ，Ｊ＝１４．２，８．３Ｈｚ），４．０５（３Ｈ，ｓ），６．９６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３４（１Ｈ，ｄｄ，Ｊ＝８．３，２．４Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．１０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），１０．００（１Ｈ，ｓ）．
（実施例１２）
Ｎ−［［４−（トリフルオロメチル）フェニル］メチル］ペンタナミド

４−（トリフルオロメチル）ベンジルアミン（１．０６ｇ，６．０５ｍｍｏｌ）、トリエチルアミン（１．００ｍＬ，７．１７ｍｍｏｌ）及びジクロロメタン３０ｍＬを混合し、氷冷撹拌下ｎ−吉草酸クロライド（７１６μＬ，６．００ｍｍｏｌ）を加えた。
氷冷下３０分撹拌後室温にて２時間撹拌した。反応液を１ｍｏｌ／Ｌ塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後無水硫酸ナトリウムで乾燥し濃縮した。残留物をシリカゲルクロマトグラフィー（溶出液　ｎ−ヘキサン：酢酸エチル＝２：１ｖ／ｖ）にて精製し、１．４１ｇ（９０％）の表題化合物を無色結晶として得た。
質量分析値　ｍ／ｚ　２５９（Ｍ^＋）．
（実施例１３−１４）
実施例１２と同様にして表３の化合物を得た。

（実施例１５）
Ｎ−［［４−（トリフルオロメチル）フェニル］メチル］−ｎ−ペンチルアミン塩酸塩

水素化アルミニウムリチウム（２１０ｍｇ，５．５３ｍｍｏｌ）と脱水テトラヒドロフラン１０ｍＬの懸濁液中に、アルゴン雰囲気、氷冷攪拌下Ｎ−［［４−（トリフルオロメチル）フェニル］メチル］ペンタナミド（１．４１ｇ，５．４４ｍｍｏｌ）を脱水テトラヒドロフラン２０ｍＬに溶かし滴下した。８時間還流後放冷し、５ｍｏｌ／Ｌ水酸化ナトリウム水溶液０．５ｍＬを加えた。３０分還流後冷却し、セライトを通して濾過した。テトラヒドロフランでセライトを洗浄し、濾液及び洗浄液を合わせ濃縮した。残留物をエタノール５０ｍｌに溶かし水、飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥し濃縮した。残留物を酢酸エチル２０ｍｌに溶かし氷冷撹拌下メタノール性塩酸を加え濃縮した。残留物に酢酸エチル１０ｍｌを加え不溶性の結晶を濾取し酢酸エチルで洗浄後乾燥して１．０５ｇ（６９％）の表題化合物を黄色結晶として得た。
質量分析値　ｍ／ｚ　２４５（Ｍ^＋；遊離塩基として）．
（実施例１６−１７）
実施例１５と同様にして表４の化合物を得た。

（実施例１８）
Ｎ−メチル−４−（トリフルオロメチル）ベンズアミド

４−（トリフルオロメチル）安息香酸（１．１４ｇ，６．００ｍｍｏｌ）の脱水ベンゼン１５ｍＬ懸濁液に塩化チオニル（６６０μＬ，９．０５ｍｍｏｌ）及びＮ，Ｎ−ジメチルホルムアミド一滴を加え２時間加熱還流した。放冷後反応液を濃縮し、残留物に脱水ベンゼン３０ｍＬを加え濃縮した（この操作を再度繰り返した）。残留物を脱水塩化メチレン３０ｍＬに溶かし氷冷攪拌下トリエチルアミン（４．２０ｍＬ，３０．１ｍｍｏｌ）、硫酸メチルアミン（１．１５ｇ，７．１８ｍｍｏｌ）を加えた。氷冷下３０分、室温にて２時間攪拌後反応液を塩化メチレン５０ｍＬで希釈し、１ｍｏｌ／Ｌ塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後無水硫酸ナトリウムで乾燥し濃縮した。残留物をシリカゲルクロマトグラフィー（溶出液　ｎ−ヘキサン：酢酸エチル＝２：１ｖ／ｖ）にて精製し、６８３ｍｇ（５６％）の表題化合物を無色結晶として得た。
質量分析値　ｍ／ｚ　２０３（Ｍ^＋）．
（実施例１９）
Ｎ−メチル−Ｎ−［４−（トリフルオロメチル）フェニルメチル］アミン　塩酸塩

実施例１５と同様にして、Ｎ−メチル−４−（トリフルオロメチル）ベンズアミド（６８０ｍｇ，３．３５ｍｍｏｌ）より４８３ｍｇ（６４％）の表題化合物を淡黄色結晶として得た。
質量分析値　ｍ／ｚ　１８８（遊離塩基として；（Ｍ−１）^＋）．
＜生物活性＞
（試験例１）
ペルオキシゾーム増殖薬活性化受容体αに対する転写活性化試験
１０％脱脂牛血清を含むダルベッコ変法イーグル培地（ＦＣＳ／ＤＭＥＭ）にて培養したＣＨＯ細胞に、酵母の転写因子のＤＮＡ結合領域とヒト型ＰＰＡＲαのリガンド結合領域（Ｂｉｏｃｈｅｍｉｓｔｒｙ，１９９３，３２，５５９８）との融合蛋白質を発現する受容体プラスミド及びそのレポータープラスミド（ＳＴＲＡＴＡＧＥＮＥ社）、及び内部標準用のウミシイタケルシフェラーゼプラスミド（ＰＲＯＭＥＧＡ社）をリポフェクトアミンにて無血清状態にてコトランスフェクションした。その後１０％ＳＦＣＳ／ＤＭＥＭ中で被検化合物を添加して２４時間後に両ルシフェラーゼ活性を測定し、内部標準により補正した。
結果を表５に示す。これらの結果より、本発明化合物はヒトペルオキシゾーム増殖薬活性化受容体αに対して強力な転写活性化作用を有することが示された。

産業上利用可能性
上述の結果から、本発明の置換カルボン酸誘導体は優れたＰＰＡＲα転写活性化作用を有する新規な化合物群である。
これら本発明の化合物では、ＰＰＡＲαに対する強い作動活性を有する事から前述した脂質低下薬、特に肝臓における脂質の低下薬、動脈硬化の進展に対する抑制薬、抗肥満薬、糖尿病治療薬等の代謝性疾患治療薬として有効な化合物と言える。Technical field
The present invention relates to a human peroxisome proliferator-activated receptor (abbreviated as PPAR) agonist, particularly a lipid-lowering drug as an agonist for human PPARα isoform, particularly a lipid-lowering drug in the liver, an inhibitor for the development of arteriosclerosis, an anti-obesity drug The present invention relates to a substituted carboxylic acid derivative effective as a therapeutic drug for metabolic diseases such as a therapeutic drug for diabetes, an addition salt thereof, a production method thereof, and a pharmaceutical composition containing these compounds.
Background art
Peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily like steroid receptor, retinoid receptor, thyroid receptor, etc., and has a different tissue distribution. (Α type, δ (or β) type, and γ type) have been identified in various animal species including humans (Proc. Natl. Acad. Sci., 1992,89, 4653). Among them, PPARα is distributed in the liver, kidney and the like having high catabolic ability of fatty acids, and high expression is particularly observed in the liver (Endocrinology, 1995,137354), genes related to fatty acid metabolism and intracellular transport (eg, acyl-CoA synthetase, fatty acid binding protein and lipoprotein lipase) and apolipoproteins (AI, AII, CIII) related to cholesterol and neutral lipid metabolism It controls gene expression to be positive or negative. PPARδ is ubiquitously expressed in various tissues in a living body, mainly in nerve cells. At this time, the physiological significance of PPARδ is unknown. PPARγ is highly expressed in adipocytes and is involved in adipocyte differentiation (J. Lipid. Res., 1996,37, 907). Thus, each PPAR isoform plays a specific function in a specific organ or tissue.
In addition, it has been reported that PPARα knockout mice exhibit hypertriglyceridemia and hypoglycemia with aging, and become obese mainly due to an increase in white adipocytes (J. Biol. Chem., 1998,273, 29577, J. Mol. clin. Invest. , 1998,102, 1083, Proc. Natl. Acad. Sci. , 1999,96, 7473), and strongly suggest that PPARα plays an important role in regulating blood lipid (cholesterol and neutral lipid) and blood glucose homeostasis and energy balance.
By the way, a fibrate-based drug has been widely used as a therapeutic drug for hyperlipidemia, in particular, a drug for hypertriglyceridemia, and PPARα activation has been reported as a mechanism of action of this fibrate-based drug (J Lipid Res., 1996,37, 907). In addition, it has been reported that fibrate-based drugs suppress the increase in body weight and adipose tissue weight and normalize decreased glucose tolerance in insulin-resistant model animals (J. Biol. Chem., 2000,275, 16638, Biochem. Biophys. Res. Commn. , 2000,271445) that PPARα is also involved in improving insulin resistance.
However, the fibrates have a weak PPARα activating effect and are not satisfactory in efficacy. In addition, various side effects such as gastrointestinal disorders, rash, headache, hepatic dysfunction, renal dysfunction and gallstones have been reported for fibrate drugs, due to various non-specific effects of fibrate drugs. Therefore, development of a therapeutic drug for metabolic diseases by a specific mechanism is desired.
Considering the role of the nuclear transcription factor PPARα in regulating lipid metabolism and its relationship to hyperlipidemia, obesity, and diabetes, it is believed that PPARα, specifically, directly binds to human PPARα ligand to activate human PPARα If a compound that can be converted into a compound can be created, its use as a therapeutic drug for metabolic diseases by a very specific mechanism is expected.
Compounds having an affinity for PPARα as ligands for PPARα include LTB, a metabolite of arachidonic acid.₄In addition, eicosanoids of the HETE (hydroxyeicosatetraenoic acid) group generated through oxidation by cytochrome P-450, particularly 8-HETE, 8-HEPE, and the like have been reported (Proc. Natl. Acad. Sci., 1997,94, 312). However, these endogenous unsaturated fatty acid derivatives are metabolically and chemically unstable and cannot be used as medicines.
On the other hand, the following compound groups and the like have been reported as similar structural compounds of the substituted carboxylic acid derivative of the present invention.
Published Japanese Patent Application No. JP-A-11-158144 (SSP) as an α-substituted phenylpropionic acid derivative having a blood glucose lowering action and a lipid lowering action
General formula (A)

(Wherein, W represents a (substituted) lactam ring, A represents an alkylene group or an alkyleneoxy group, and X represents O, S, NH, CH₂And Y¹Represents an amino group, a hydroxyl group or an alkoxy group;¹Represents H or an alkyl group;²Represents an alkyl group or a phenyl group;³Represents H, an alkyl group or an alkoxy group, etc.).
However, these compounds differ in structure from the compounds of the present invention in that they do not contain a carbonyl group or an amide group in A of the linking moiety, and they contain a lactam ring in W which is a terminal substituent, and these compounds are human PPARα. It is not described that it has a binding activity and a transcription activating effect.
International Publication No. WO98 / 28254 (Nippon Chemiphar Corporation) as a compound having hypoglycemic action
General formula (B)

(Where A¹Represents an aryl group or a heterocyclic group which may have a substituent;²Represents an alkylene chain having 1 to 5 carbon atoms;⁴Represents a bond, an oxygen atom or a sulfur atom;¹Represents a naphthalene ring, a quinoline ring, an indole ring, a benzisoxazole ring or a benzo [b] thiophene ring which may have a substituent;⁴Represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms;⁵Represents an oxygen atom or a sulfur atom;⁵Represents an alkyl group having 1 to 8 carbon atoms, which may have a substituent, an aralkyl group or an aryl group).
However, these compounds have the linking moiety Y²And X⁴Does not contain a carbonyl group or an amide group, and W binds to the 3-position of propionic acid.¹Is different from the compounds of the present invention in that it is a heterocycle, and it is not described that these compounds have human PPARα binding activity and transcription activating activity.
International Publication No. WO98 / 07699 (Nippon Tobacco Inc.) as a propionic acid derivative having hypoglycemic and lipid-lowering effects
General formula (C)

(Where R is D₁And D₂Represents a substituent represented by the formula:¹Represents an aromatic ring, a cycloalkyl group and a heteroaromatic ring;⁵Represents an alkyl group;⁴Represents a hydrogen atom or an alkyl group;⁶Is a hydrogen atom or R⁹To form a double bond;⁷Is a carboxyl group, an acyl group, an optionally substituted alkoxycarbonyl group, an alkyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, an NHR⁸Group and OR⁸R represents a group⁸Represents an acyl group or an alkoxycarbonyl group which may have a substituent;⁹Represents a hydrogen atom, an alkyl group or an alkoxycarbonyl group;¹⁰Represents a hydrogen atom, an amino group, an alkoxy group, an alkyl group, an aryloxy group and an aralkyloxy group).
However, these compounds also differ in structure from the compounds of the present invention in that the substituents on the benzene ring are disubstituted at the 1- and 4-positions, and these compounds exhibit human PPARα binding activity and transcription activation activity. Nothing is stated.
Published Patent Publication No. 63-91354 (Yamanouchi Pharmaceutical Co., Ltd.) as a carboxylic acid derivative having a leukotriene receptor agonizing action
General formula (E)

(Wherein A represents a hydrogen atom or a phenyl group, m represents an integer of 3 to 10, n represents an integer of 1 to 6, X represents a CONH group or an NHCO group, and R represents a carboxy lower alkyl group. Alternatively, a compound represented by a carboxy lower alkylcarbamoyl group (however, when A is a phenyl group, R represents a carboxy lower alkylcarbamoyl lower alkyl group) has been reported.
However, these compounds do not have a substituent at the 2-position of propionic acid, and have a structure different from the compounds of the present invention since all R groups have a carbonyl group. No activity or transcriptional activation is described.
US Pat. No. 5,227,490 (Merck) as a carboxylic acid derivative having fibrinogen receptor antagonistic activity
General formula (F)

(Where R¹Is a hydrogen atom, C_1-6Alkyl group, aryl C_4-10Alkyl group, aryl group, carboxyl group, C_1-6Alkoxy group, carboxy C_0-6Alkyl group, carboxy C_0-6Alkoxy group, hydroxy C_1-6Alkyl group, C_1-4Alkylsulfonyl C_0-6Alkyl group, C_0-4Alkylamino C_0-6Alkyl group, aryl C_0-10Alkylamino C_0-6Alkyl group, C_2-10Acylamino C_0-6Alkyl group, C_1-4Carboalkoxy C_0-6Represents an alkyl group or a halogen atom,²May be the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group,_1-6Alkoxy group, aryl C_0-4Alkyl group, aryl C_0-6An alkoxy group, an optionally substituted C_1-6Represents an alkyl group;³Is a hydrogen atom, C_1-6Alkyl group or aryl C_1-10X represents an oxygen atom, a sulfur atom, an SO group, SO₂Group, CO group, NR⁴CO group, CONR⁴Group, CH₂Group, CH = CH group, NR⁴Represents a CS group, and Y represents unsubstituted or optionally substituted C_1-10Alkyl group, C_4-8Cycloalkyl group, aryl group, C_0-3Alkylaryl C_0-3Alkyl group, C_0-3Alkylaryl C_0-3Alkylcarbonyl group, C_0-3Alkylaryl C_{0- 3}Alkyl carboxamide group, C_0-3Alkylaryloxy C_0-3Alkyl group, CONH group, NHCO group or (CH₂) MQ- (CH₂) N group (where Q is C containing 1 to 3 types of heteroatoms selected from oxygen or sulfur)_3-8And m and n are from 0 to 4), and Z is NR⁴R⁵Group (however, R⁴And R⁵Are the same or different and are each a hydrogen atom, C_1-6Alkyl group, aryl C_1-10The alkyl group is unsubstituted or C_1-4Alkoxy group, carboxy C_0-6An alkyl group, a hydroxyl group, a halogen atom or a 4- to 9-membered monocyclic or bicyclo ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur) or a substituent. Which represents a guanidino group which may be substituted).
However, these compounds are structurally different from the compounds of the present invention because they are amino acid derivatives that always contain an amino group which may have a substituent in the Z group, and these compounds have human PPARα binding activity, It has not been described that it has a transcription activating effect.
Regarding patents reporting PPARα agonism, International Publication No. WO97 / 25042 (SmithKline Beecham Co., Ltd.) discloses compounds having PPARα and PPARγ agonism.
General formula (G)

(Where R^aRepresents a 2-benzoxazolyl group or a 2-pyridyl group;^bRepresents a methoxymethyl group or a trifluoromethyl group). However, it is described that these compounds are different from the compounds of the present invention in that the substituent on the benzene ring is a disubstituted derivative at the 1-position and 4-position, and further, have a human PPARα binding activity and a transcription activating activity. It has not been.
International Publication No. WO97 / 36579 (GlaxoWelcome Co., Ltd.) as a compound having a PPARα agonistic action
General formula (H)

(Wherein, X represents a hydrogen atom or a fluorine atom).
However, these compounds are phenoxyacetic acid derivatives, and have a different structure from the compound of the present invention in that the substituents on the benzene ring are di-substituted at the 1- and 4-positions. Moreover, the transcription activating effect of PPARα is by no means satisfactory.
The frequency of arteriosclerotic diseases, such as ischemic heart disease, is increasing due to rapid changes in eating habits and lifestyle. Hyperlipidemia, diabetes, and hypertension are considered as the main risk factors for this arteriosclerotic disease, and the presence of insulin resistance is considered to be important in the pathology. It is clear that obesity due to accumulation is deeply involved. Therefore, there is a clinical need for the development of a therapeutic drug for metabolic diseases which is comprehensively effective and highly safe for these diseases.
Disclosure of the invention
The present inventors have focused on the specific role of human PPARα for the purpose of creating a structurally novel drug having high efficacy and safety as a therapeutic drug for metabolic diseases, and as a result of intensive studies, the following general formula The present inventors have found that the novel substituted carboxylic acid derivative represented by (1) has excellent human PPARα binding activity and transcription activating effect, and completed the present invention.
That is, the present invention relates to the general formula (1)

[In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. And a pharmaceutically acceptable salt thereof, and a hydrate thereof.
The salts of the compound represented by the general formula (1) in the present invention are conventional ones, and include metal salts such as alkali metal salts (eg, sodium salt, potassium salt, lithium salt, etc.) and alkaline earth metal salts (eg, calcium salt). Pharmacologically acceptable salts such as aluminum salts and the like.
Further, the compound represented by the general formula (1) in the present invention may include an optical isomer based on a substituted carboxylic acid moiety. In some cases, compounds obtained in the course of synthesis of the compound represented by the general formula (1) include a mixture of geometric isomers. All such isomers and mixtures thereof are included within the scope of the present invention.
Each optical isomer can be produced by a stereoselective synthesis method. They can also be produced by separating diastereomeric ester derivatives or oxazolidinone derivatives obtained by reacting with optically active alcohol derivatives or optically active oxazolidinone derivatives by fractional crystallization or chromatographic techniques and then hydrolyzing them. it can. Further, they can be produced by a chromatography technique using a chiral support.
In the general formula (1) of the present invention, the “lower alkyl group having 1 to 10 carbon atoms” includes straight or branched ones having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl. .
The compound represented by the general formula (1) can be produced, for example, by the following method (Scheme 1).

That is, the general formula (1)

[In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. And a pharmaceutically acceptable salt thereof and a hydrate thereof are benzyl 2-methoxy-5-formylbenzoate (2)

And general formula (6)

[Wherein, R¹Is a lower alkyl group having 1 to 4 carbon atoms, and X is PPh₃Group or PO (OC₂H₅)₂(Wittig reaction or Horner-Emmons reaction; first step), a compound represented by the formula (3):

[Wherein, R¹Is as described above], and the compound represented by the general formula (4) obtained by reduction and hydrogenolysis (second step)

[Wherein, R¹Is as described above] to the compound represented by the general formula (7)

Wherein n and R are as described above (third step), and the resulting compound represented by the general formula (5)

[Where R, R¹And n are as described above].¹It can be produced by hydrolyzing the site (fourth step).
The Wittig reaction or Horner-Emmons reaction in the first step is carried out in a solvent such as tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide or the like. As a base, for example, an alkali metal hydride such as sodium hydride or an organic compound such as butyllithium is used. Metal compounds, metal amides such as lithium diisopropylamide, and metal alkoxides such as sodium methoxide and potassium @ t-butoxide can be used. The reaction can be carried out at a reaction temperature of -20 ° C to 150 ° C, preferably 0 ° C to 50 ° C.
The reduction reaction in the second step is performed in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, or N, N-dimethylformamide in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, or rhodium-alumina in a solvent such as 98.1 kPa. To 491 kPa. The reaction can be carried out at a temperature of 0 ° C to 100 ° C, preferably at room temperature to 80 ° C.
The condensation reaction in the third step can be carried out with the carboxyl group as it is or after converting it into a reactive derivative.
Examples of the “reactivity-inducing group of carboxyl group” include acid chloride, acid bromide, acid anhydride, carbonylimidazole and the like. In the case of a reaction using a reactive derivative, a base such as an alkali metal hydride such as sodium hydride or an alkali metal hydroxide such as sodium hydroxide is used as a base in a solvent such as dioxane or N, N-dimethylformamide. The reaction can be carried out in the presence or absence of an alkali metal carbonate such as potassium carbonate and the like, or an organic base such as pyridine and triethylamine.
When the reaction is carried out in the form of a carboxylic acid, the reaction is carried out in a solvent such as methylene chloride, chloroform, dioxane, N, N-dimethylformamide in the presence of a condensing agent, in the presence or absence of a base, and further in the presence of an additive. Or it can be implemented in the absence.
Examples of the condensing agent include dicyclohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphate azide, carbonyldiimidazole and the like. Examples of the base include alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium carbonate, and organic bases such as pyridine and triethylamine. Examples of the additive include N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, and the like. The reaction can be carried out at a reaction temperature of -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
The hydrolysis reaction in the fourth step can be performed under alkaline conditions. As the alkaline condition, lithium hydroxide, sodium hydroxide, potassium hydroxide or the like is used. The reaction can be carried out at a temperature of 0 ° C to 80 ° C, preferably at room temperature to 60 ° C.
Examples of the dosage form of the novel compound of the present invention include solid compositions, liquid compositions and other compositions for oral administration, and injections, external preparations and suppositories for parenteral administration. Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, syrups and the like. Other compositions for oral administration include sprays. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, emulsions and the like.
BEST MODE FOR CARRYING OUT THE INVENTION
Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
(Example 1)
Ethyl 2-[[3- [N- [2- [4- (trifluoromethyl) phenyl] ethyl] carbamoyl] -4-methoxyphenyl] methyl] butyrate

Ethyl 3- (3-carboxy-4-methoxyphenyl) -2-ethylpropionate (Japanese Patent Application No. 2000-157600; 560 mg, 2.00 mmol), triethylamine (977 μL, 7.00 mmol) and 80 mL of dehydrated dichloromethane were mixed, and the mixture was mixed with ice. Under cold stirring, ethyl chlorocarbonate (228 mg, 2.10 mmol) was dissolved in 5 mL of dehydrated dichloromethane and added dropwise. After stirring for 10 minutes under ice cooling, 4- (trifluoromethyl) phenethylamine hydrochloride (566 mg, 2.51 mmol) was suspended in 15 mL of dehydrated dichloromethane and added dropwise. Next, the reaction solution was stirred for 30 minutes under ice-cooling and at room temperature for 6 hours, washed successively with a 10% aqueous citric acid solution, a 0.5 mol / L aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: n-hexane: ethyl acetate = 2: 3 v / v) to give 770 mg (85%) of the title compound as a colorless oil.
Mass spectrometry value {m / z} 451 (M⁺)
(Example 2-5)
The compounds shown in Table 1 were synthesized in the same manner as in Example 1.

(Example 6)
2-[[3- [N- [2- [4- (trifluoromethyl) phenyl] ethyl] carbamoyl] -4-methoxyphenyl] methyl] butyric acid

Ethyl 2-[[3- [N- [2- [4- (trifluoromethyl) phenyl] ethyl] carbamoyl] -4-methoxyphenyl] methyl] butyrate (770 mg, 1.71 mmol; Example 1) and 30 mL of methanol Then, 5 mL of a 2 mol / L aqueous sodium hydroxide solution was mixed, and the mixture was stirred at 60 ° C. for 4 hours, and then concentrated under reduced pressure. The residue was acidified with 2 mol / L hydrochloric acid under ice cooling. The resulting precipitate was filtered and dried, and then recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 580 mg (80%) of the title compound as a colorless powder.
Melting point 146-147 ° C; mass spectrometry value {m / z} 423 (M⁺);
Elemental analysis value C₂₂H₂₄F₃NO₄(423.43):
Calculated value {C, 62.40; H, 5.71; N, 3.31.
Found, ΔC, 62.20; H, 5.62; N, 3.32. ;
¹H-NMR (400 MHz, CDCl₃) Δ 0.95 (3H, t, J = 7.8 Hz), 1.54-1.70 (2H, m), 2.58-2.65 (1H, m), 2.76 (1H, dd, J = 13.7, 8.3 Hz), 2.94 (1H, dd, J = 13.7, 8.3 Hz), 2.99 (2H, t, J = 6.8 Hz), 3.72 (3H) , S), 3.73 (2H, m), 6.83 (1H, d, J = 8.3 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.37 (2H, d) , J = 7.8 Hz), 7.58 (2H, d, J = 7.8 Hz), 7.89 (1H, t, J = 4.9 Hz), 8.04 (1H, d, J = 2.0 Hz). 4 Hz).
(Example 7-10)
The compounds in Table 2 were obtained in the same manner as in Example 6.

(Example 11)
2-[[3- [N- [4- (trifluoromethyl) phenyl] carbamoyl] -4-methoxyphenyl] methyl] butyric acid

Ethyl 3- (3-carboxy-4-methoxyphenyl) -2-ethylpropionate (Japanese Patent Application No. 2000-157600; 530 mg, 1.89 mmol), 4-trifluoromethylaniline (382 mg, 2.37 mmol), triethylamine (657 μL) , 4.71 mmol) and 30 mL of dehydrated dichloromethane were mixed, and 2-chloro-1,3-dimethylimidazolium chloride (467 mg, 2.76 mmol) was dissolved in 20 mL of dehydrated dichloromethane under ice cooling and stirring, and added dropwise. Next, after stirring at room temperature for 6 hours, the reaction solution was washed successively with a 10% aqueous citric acid solution, a 0.5 mol / L aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to determine 800 mg of a condensate. I got it.
The obtained condensate (550 mg, 1.30 mmol) was mixed with 5 mL of a 2 mol / L aqueous sodium hydroxide solution and 30 mL of methanol, and stirred at 60 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and acidified with diluted hydrochloric acid. The resulting precipitate was filtered and purified by silica gel chromatography (eluent: methylene chloride: methanol = 15: 1 v / v) to give 200 mg (39%) of the title compound as a colorless powder.
Melting point 141-142 ° C; mass spectrometry m / z 395 (M⁺);
Elemental analysis value C₂₀H₂₀F₃NO₄(395.37):
Calculated value {C, 60.76; H, 5.10; N, 3.54.
Found, C, 60.72; H, 5.25; N, 3.53. ;
¹H-NMR (400 MHz, CDCl₃) Δ 0.97 (3H, t, J = 7.3 Hz), 1.56-1.72 (2H, m), 2.60-2.67 (1H, m), 2.80 (1H, dd, J = 14.2, 8.3 Hz), 2.98 (1H, dd, J = 14.2, 8.3 Hz), 4.05 (3H, s), 6.96 (1H, d, J = 8) 0.33), 7.34 (1H, dd, J = 8.3, 2.4 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.79 (2H, d, J = 8.3 Hz). 8 Hz), 8.10 (1H, d, J = 2.0 Hz), 10.00 (1H, s).
(Example 12)
N-[[4- (trifluoromethyl) phenyl] methyl] pentanamide

4- (Trifluoromethyl) benzylamine (1.06 g, 6.05 mmol), triethylamine (1.00 mL, 7.17 mmol) and 30 mL of dichloromethane are mixed, and n-valeric acid chloride (716 µL, 6. 00 mmol) was added.
After stirring for 30 minutes under ice cooling, the mixture was stirred at room temperature for 2 hours. The reaction solution was washed successively with 1 mol / L hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: n-hexane: ethyl acetate = 2: 1 v / v) to give 1.41 g (90%) of the title compound as colorless crystals.
Mass spectrometry value {m / z} 259 (M⁺).
(Examples 13-14)
In the same manner as in Example 12, the compounds in Table 3 were obtained.

(Example 15)
N-[[4- (trifluoromethyl) phenyl] methyl] -n-pentylamine hydrochloride

In a suspension of lithium aluminum hydride (210 mg, 5.53 mmol) and 10 mL of dehydrated tetrahydrofuran, N-[[4- (trifluoromethyl) phenyl] methyl] pentanamide (1.41 g, (5.44 mmol) was dissolved in 20 mL of dehydrated tetrahydrofuran and added dropwise. After refluxing for 8 hours, the mixture was allowed to cool, and 0.5 mL of a 5 mol / L aqueous sodium hydroxide solution was added. After refluxing for 30 minutes, the mixture was cooled and filtered through celite. Celite was washed with tetrahydrofuran, and the filtrate and the washing solution were combined and concentrated. The residue was dissolved in 50 ml of ethanol, washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in 20 ml of ethyl acetate, and methanolic hydrochloric acid was added thereto while stirring under ice-cooling, followed by concentration. 10 ml of ethyl acetate was added to the residue, insoluble crystals were collected by filtration, washed with ethyl acetate, and dried to obtain 1.05 g (69%) of the title compound as yellow crystals.
Mass spectrometry value {m / z} 245 (M⁺As a free base).
(Examples 16-17)
In the same manner as in Example 15, the compounds in Table 4 were obtained.

(Example 18)
N-methyl-4- (trifluoromethyl) benzamide

To a suspension of 4- (trifluoromethyl) benzoic acid (1.14 g, 6.00 mmol) in 15 mL of dehydrated benzene was added thionyl chloride (660 μL, 9.05 mmol) and one drop of N, N-dimethylformamide, and the mixture was heated under reflux for 2 hours. . After allowing to cool, the reaction solution was concentrated, and 30 mL of dehydrated benzene was added to the residue, followed by concentration (this operation was repeated again). The residue was dissolved in 30 mL of dehydrated methylene chloride, and triethylamine (4.20 mL, 30.1 mmol) and methylamine sulfate (1.15 g, 7.18 mmol) were added under ice-cooling and stirring. After stirring under ice-cooling for 30 minutes and at room temperature for 2 hours, the reaction solution was diluted with methylene chloride (50 mL), washed with 1 mol / L hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in that order, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: n-hexane: ethyl acetate = 2: 1 v / v) to give 683 mg (56%) of the title compound as colorless crystals.
Mass spectrometry value {m / z} 203 (M⁺).
(Example 19)
N-methyl-N- [4- (trifluoromethyl) phenylmethyl] amine hydrochloride

In the same manner as in Example 15, 483 mg (64%) of the title compound was obtained as pale yellow crystals from N-methyl-4- (trifluoromethyl) benzamide (680 mg, 3.35 mmol).
Mass spectrometry value {m / z} 188 (as free base; (M-1)⁺).
<Biological activity>
(Test Example 1)
Transcriptional activation test for peroxisome proliferator-activated receptor α
CHO cells cultured in Dulbecco's modified Eagle's medium (FCS / DMEM) containing 10% defatted bovine serum were added to the DNA-binding domain of yeast transcription factor and the ligand-binding domain of human PPARα (Biochemistry, 1993,32, 5598) and a reporter plasmid (STRATAGENE) and a Renilla luciferase plasmid (PROMEGA) for internal standard were cotransfected with lipofectamine in serum-free state. . Thereafter, the test compound was added in 10% SFCS / DMEM, and 24 hours later, both luciferase activities were measured and corrected by an internal standard.
Table 5 shows the results. These results indicate that the compound of the present invention has a strong transcriptional activating effect on human peroxisome proliferator-activated receptor α.

Industrial applicability
From the above results, the substituted carboxylic acid derivatives of the present invention are a group of novel compounds having an excellent PPARα transcription activating action.
Since these compounds of the present invention have a strong agonistic activity against PPARα, the above-mentioned lipid-lowering drugs, in particular, lipid-lowering drugs in the liver, inhibitors for progression of arteriosclerosis, anti-obesity drugs, metabolic diseases such as antidiabetic drugs, etc. It can be said that the compound is effective as a therapeutic agent.

Claims (10)

General formula (1)

[In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. A substituted carboxylic acid derivative or an ester thereof, a pharmaceutically acceptable salt thereof, and a hydrate thereof. 2. The substituted carboxylic acid derivative according to claim 1, wherein n is 0, an ester thereof, a pharmaceutically acceptable salt thereof, and a hydrate thereof. 2. The substituted carboxylic acid derivative according to claim 1, wherein n is 2, an ester thereof, a pharmaceutically acceptable salt thereof, and a hydrate thereof. The substituted carboxylic acid derivative according to claim 1, which is 2-ethyl-3- [4-methoxy-3- [N- [4- (trifluoromethyl) phenyl] carbamoyl] phenyl] propionic acid or an ester thereof, and a drug thereof. Acceptable salts and hydrates thereof. The substituted carboxylic acid according to claim 1, which is 2-ethyl-3- [4-methoxy-3- [N- [2- [4- (trifluoromethyl) phenyl] ethyl] carbamoyl] phenyl] propionic acid or an ester thereof. Derivatives and pharmaceutically acceptable salts thereof and hydrates thereof. General formula (1)

[In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. And a pharmaceutically acceptable salt thereof, and a hydrate thereof, a lipid-lowering drug comprising as an active ingredient at least one of the substituted carboxylic acid derivatives represented by the formula: General formula (1)

[In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. And a pharmaceutically acceptable salt thereof, and a human peroxisome proliferator-activated receptor comprising at least one of the hydrates thereof as an active ingredient. (PPAR) alpha agonist. General formula (1)

[In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. And a pharmaceutically acceptable salt thereof and a hydrate thereof as an active ingredient. General formula (1)

[In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. And a pharmaceutically acceptable salt thereof, and a hydrate thereof, as an active ingredient. General formula (1)

[In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. And a pharmaceutically acceptable salt thereof and a hydrate thereof as an active ingredient.