JP2005170790A - N-alkylsulfonyl-substituted amide derivative - Google Patents

N-alkylsulfonyl-substituted amide derivative Download PDF

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JP2005170790A
JP2005170790A JP2002002178A JP2002002178A JP2005170790A JP 2005170790 A JP2005170790 A JP 2005170790A JP 2002002178 A JP2002002178 A JP 2002002178A JP 2002002178 A JP2002002178 A JP 2002002178A JP 2005170790 A JP2005170790 A JP 2005170790A
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substituted
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unsubstituted
alkylsulfonyl
acceptable salt
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Nobuyasu Suzuki
伸育 鈴木
Yukio Nihei
幸夫 二瓶
Hidehiro Ichinose
英弘 一ノ瀬
Toshihiro Hatanaka
敏宏 畑中
Katsumi Maezono
克己 前園
Koji Osumi
幸治 大角
Nobuo Kondo
信雄 近藤
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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Priority to JP2002002178A priority Critical patent/JP2005170790A/en
Priority to AU2003201850A priority patent/AU2003201850A1/en
Priority to PCT/JP2003/000098 priority patent/WO2003059871A1/en
Publication of JP2005170790A publication Critical patent/JP2005170790A/en
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Abstract

<P>PROBLEM TO BE SOLVED: To provide an ACC activity inhibitor which is effective for treating obesity, hyperlipemia induced by obesity, abnormal glucose tolerance thought to be based on fatty liver and insulin resistance, diabetes, diabetic complications (diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy and the like), hypertension, and arteriosclerosis. <P>SOLUTION: An N-alkylsulfonyl-substituted amide derivative of formula (1), its analog or its pharmaceutically acceptable salt has effective action of inhibiting the ACC (acetyl coenzyme A carboxylase) activity. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【０００１】
【発明の属する技術分野】
本発明は、Ｎ−アルキルスルフォニル置換アミド誘導体に係わり、詳細には、acetyl CoA carboxylase（以下、ACC略記する場合もある）阻害活性を有する新規なＮ−アルキルスルフォニル置換アミド誘導体に関する。
【従来の技術】
近年、肥満は、動脈硬化性疾患、特に冠動脈疾患の主要なリスクファクターであることが明らかとなってきた。すなわち、肥満個体では、蓄積された内臓脂肪から、脂肪酸やTNF-α等の種々の因子が放出され、これらが骨格筋、肝臓および脂肪組織におけるインスリン抵抗性を惹起するとともに、肝臓における中性脂肪の合成を促進し、高脂血症をもたらすことが報告されている。更に、インスリン抵抗性によって代償的に上昇した血中のインスリンは、耐糖能異常、更には糖尿病を引き起こすだけではなく、腎臓におけるNaイオンの再吸収亢進や交感神経の活性化を介して、末梢血管抵抗を上昇させ、最終的に高血圧状態を形成する。肥満によってもたらされた高脂血症、糖尿病および高血圧は、脳血管障害や冠動脈疾患などの動脈硬化症に基づく血管障害を惹起し、生命予後に深刻な影響を与えるものと考えられている。
肥満治療の基本は運動療法と食事療法であるが、人間の根源的な欲求との対立、労働時間との兼ね合い、ストレスの増加など様々な要因から、設定した目標を達成することには多大の困難が伴う。極度の肥満患者には胃縮小術、胃バイパス術などの外科治療が適応されることがあるが、肥満者は開腹手術をすると感染、脂肪融解などの創合併症をしばしば起こし、多大な時間の喪失、苦痛を伴うのが現状である。従って、安全かつ簡便に食事・運動療法を補完することのできる医薬品の併用が必要とされている。現在、抗肥満薬として使用されている医薬品として、マジンドール、シブトラミンなどの中枢性食欲抑制剤と、膵リパーゼ阻害剤であるオルリスタットが挙げられる。中枢作働性の薬剤では、口渇、便秘、胃不快感、時には幻聴・幻視など重篤な副作用が出現することがあり、また、オルリスタットでは、下痢、失禁、放屁などの消化管における副作用が認められている。概ね、これらの抗肥満薬については、副作用の出現しない投与量では効果は緩やかであり、長期にわたる使用の安全性は未だ確立されておらず、肥満に深く関わるインスリン抵抗性などに対する有益な作用はほとんど認められていないのが現状である。
【０００２】
インスリン抵抗性に関しては、ビグアナイド剤やペルオキシゾーム増殖関連レセプター（以下、ＰＰＡＲと略する）ガンマのアゴニストを使用した治療が広く行われている。ビグアナイド剤に関しては、主に非インスリン依存性糖尿病患者に対して、インスリン抵抗性の改善に加え、血糖降下作用や高脂血症改善作用を示すことが報告されている。しかしながら、その単独での治療効果は不十分であり、また、上腹部不快感、嘔気、下痢などの消化器症状に加え、乳酸アシドーシス等の生命の危険を伴う副作用を示すことが明らかとなっている。ＰＰＡＲガンマアゴニストに関しては、ビグアナイド剤と同じく、非インスリン依存性糖尿病患者のインスリン抵抗性、高血糖、高脂血症および高血圧を改善するが、副作用（肥満、劇症肝炎）の点で、未だ満足できるものとは言い難い。
ACCは、Acetyl CoAより、Malonyl CoAの合成を触媒する酵素であり、長鎖脂肪酸の合成における律速酵素である。また、ACCにより、Acetyl CoAから合成されたMalonyl CoA自体は、遊離長鎖脂肪酸のエネルギー源としての消費に関与するCarnitine acyltransferaseを負に制御していることが知られている。更に、内臓脂肪組織における脂肪酸合成の活性化には、ACCの活性化が関与しているものと考えられている。従って、ACCを阻害する薬剤は、生体内における長鎖脂肪酸および中性脂肪の新たな合成を抑制するだけではなく、既存の脂肪組織を減少させることにより、肥満症および肥満によって誘発される高脂血症ならびにインスリン抵抗性に基づく様々な疾患の治療薬および予防薬としての可能性を有する。
【０００３】
【発明が解決しようとする課題】
本発明の目的は、肥満症および肥満によって誘発される高脂血症、脂肪肝ならびにインスリン抵抗性に基づく様々な疾患（耐糖能異常、糖尿病、糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症、高血圧、動脈硬化症）の治療に有効なACC活性阻害を有する新規化合物を提供することである。本発明のさらなる目的は、該化合物を含有する医薬組成物を提供することである。
【課題を解決するための手段】
本発明者らは、はかかる課題を解決するために、鋭意検討した結果、下記一般式（Ｉ）で表される新規骨格を有するＮ−アルキルスルフォニル置換アミド誘導体に優れたACC阻害活性が認められることを見出し、本発明を完成するに至った。従って、本発明は、新規なＮ−アルキルスルフォニル置換アミド誘導体を有効成分とする医薬組成物、特にACC活性阻害剤およびそれを用いた治療用医薬組成物を提供する。
【０００４】
【化６】

Figure 2005170790
【０００５】
（式中、Ｒ１は、
置換もしくは無置換のC1〜C20のアルキル基、置換もしくは無置換のC2〜C20のアルケニル基、置換もしくは無置換のC2〜C20のアルキニル基、置換もしくは無置換の芳香族炭化水素基、置換もしくは無置換の芳香族複素環基、置換アミノ基、置換もしくは無置換のC1〜C20のアルコキシル基、置換もしくは無置換のC2〜C20のアルケニルオキシ基、置換もしくは無置換のC2〜C20のアルキニルオキシ基またはＲ２−O−で表される基（式中、Ｒ２は置換もしくは無置換の芳香族炭化水素基または置換もしくは無置換の芳香族複素環基であり）、
Yは、-CR3=CR4-、-N=CR3-もしくは-CR3=N-で表される基または硫黄原子もしくは酸素原子であり、
一般式（１）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６はそれぞれ同じでも異なってもよく、
Ｒ３、Ｒ４、Ｒ５、Ｒ６は、
それぞれ置換もしくは無置換の芳香族炭化水素基、置換もしくは無置換のC1〜C12のアルキル基、置換もしくは無置換のC2〜C12のアルケニル基、置換もしくは無置換のC2〜C12のアルキニル基、または置換もしくは無置換のC1〜C12のアルコキシル基、水素原子、水酸基、メルカプト基、置換もしくは無置換のC1〜C12の置換アミノ基、置換もしくは無置換のC1〜C6のアルキルチオ基、ニトロ基、ハロゲン原子またはシアノ基であり、
環Aは、置換もしくは無置換の芳香族炭化水素基、置換もしくは無置換の芳香族複素環基、置換もしくは無置換の環状アルキル基、無置換もしくは置換の環状アルケ二ル基であり、
Ｘは、一般式（２）、（３）、（４）、（５）、R２０のいずれかで表され、
【０００６】
【化７】
Figure 2005170790
【０００７】
【化８】
Figure 2005170790
【０００８】
【化９】
Figure 2005170790
【０００９】
【化１０】
Figure 2005170790
【００１０】
一般式（２）、（３）、（４）、（５）中のＲ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、Ｒ１５、Ｒ１６、Ｒ１７、Ｒ１８、Ｒ１９は、
それぞれ同じでも異なってもよく、置換もしくは無置換の芳香族炭化水素基、置換もしくは無置換のC1〜C12のアルキル基、置換もしくは無置換のC2〜C12のアルケニル基、置換もしくは無置換のC2〜C12のアルキニル基、または置換もしくは無置換のC1〜C12のアルコキシル基、水素原子、水酸基、メルカプト基、置換もしくは無置換のC1〜C12の置換アミノ基、置換もしくは無置換のC1〜C6のアルキルチオ基、ニトロ基、ハロゲン原子、またはシアノ基であり、
Ｚは-CR9=CR10-、-N=CR9-もしくは-CR9=N-で表される基または硫黄原子もしくは酸素原子であり、
Ｑは-CR9=N-で表される基または硫黄原子もしくは酸素原子であり、
環Ｂは、
置換もしくは無置換の芳香族炭化水素基、環の員数が４から９の置換もしくは無置換である複素環、無置換または置換の環状アルキル基、無置換または置換の環状アルケニル基を含み、
環Ｃは、
ピリジン環、フラン環、チオフェン環をのぞいた置換もしくは無置換の芳香族複素環基、置換もしくは無置換の環状アルキル基、無置換または置換の環状アルケニル基であり、
Ｒ２０は、
置換もしくは無置換のC1〜C12のアルキル基、置換もしくは無置換のC2〜C12のアルケニル基、置換もしくは無置換のC2〜C12のアルキニル基、または置換もしくは無置換のC1〜C12のアルコキシル基、水素原子、水酸基、メルカプト基、置換もしくは無置換のC1〜C12の置換アミノ基、置換もしくは無置換のC1〜C6のアルキルチオ基、ニトロ基、ハロゲン原子、またはシアノ基であり、
また、Ｒ７とＲ８は、一般式（１）中のＲ３、Ｒ４、Ｒ５、Ｒ６あるいは一般式（２）、（３）、（４）、（５）中のＲ９、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、Ｒ１５、Ｒ１６、Ｒ１７、Ｒ１８、Ｒ１９のいずれかと共有結合して、環構造をとるものも含む。）
【００１１】
本発明は、上記Ｎ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とするACC活性阻害剤及び医薬組成物を提供する。
本発明は、又、上記Ｎ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする肥満症、高脂血症、脂肪肝、耐糖能異常、糖尿病、糖尿病性合併症、高血圧、動脈硬化症の予防および/または治療薬又は血糖降下剤を提供する。
本発明は、又、上記Ｎ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩と、下記A群の薬剤のいずれか一つまたは二つとを有効成分とする肥満症、高脂血症、脂肪肝、耐糖能異常、糖尿病、糖尿病性合併症、高血圧、動脈硬化症の予防および/または治療薬又は血糖降下剤を提供する。
A：インスリン、スルホニルウレア剤、アルファ-グリコシダ−ゼ阻害剤、ビグアナイド剤、PPAR-ガンマアゴニスト、PPAR-ガンマアンタゴニスト、PPAR-アルファアゴニスト、SGLT阻害剤、GLP-1受容体アンタゴニスト、DPP-IV阻害剤、アルドース還元酵素阻害剤、糖尿病性神経障害治療薬、HMG-CoA還元酵素阻害剤、抗酸化剤、カルシウム拮抗薬、アンジオテンシン変換酵素阻害薬、アンジオテンシンII受容体拮抗剤、ベータ遮断薬、α１遮断薬、利尿剤、抗肥満薬、低エネルギー食。
【００１２】
【発明の実施の形態】
本発明のＮ−アルキルスルフォニル置換アミド誘導体について更に詳細に説明する。
本明細書中にいては、「Ｃ１〜Ｃ１２のアルキル基」としては、直鎖状、分岐鎖または環状のいずれでもよく、メチル、エチル、n−プロピル、n−ブチル、２−メチルプロピル、１−メチルプロピル、１，１−ジメチルエチル、シクロブチル、n−ペンチル、１−メチルブチル、２−メチルブチル、３−メチルブチル、シクロペンチル、２，２−ジメチルプロピル、n−ヘキシル、１−メチルペンチル、４−メチルペンチル、１−エチルブチル、２−エチルブチル、３，３−ジメチルブチル、シクロヘキシル、n−ヘプチル、１−メチルヘキシル、２−メチルヘキシル、５−メチルヘキシル、４，４−ジメチルペンチル、１−プロピルブチル、２−エチルペンチル、シクロヘキシルメチル、１，１−ジエチルプロピル、シクロヘプチル、n−オクチル、１−メチルオクチル、６−メチルヘプチル、１−エチルヘキシル、２−エチルヘキシル、２−ヘキシルエチル、５，５−ジメチルヘキシル、シクロオクチル、n−ノニル、１−メチルオクチル、７−メチルオクチル、６，６−ジメチルヘプチル、n−デシル、１−メチルノニル、８−メチルノニル、７，７−ジメチルオクチル、n−ウンデカシル、１−メチルデシル、１−メチルデシル、９−メチルデシル、８，８−ジメチルノニル、n−ドデシル、１−メチルウンデシル、１０−メチルウンデシル、５−メチルウンデシル、９，９−ジメチルデシル等を例示することができる。これらのうち炭素数１〜９のアルキル基が好ましい。また、これらのアルキル基には更に種々の置換基が置換されていてもよい。そのような置換基としては、塩素、臭素、ヨウ素、フッ素等のハロゲン原子、シリル基、ニトロ基、アミノ基、シアノ基、水酸基、アルコキシ基、チオール基、トリクロロメチル基、トリフルオロメチル基、フェニル、ナフチル基、の等の芳香族炭化水素基、チエニル、フリル、ピリジル基等の芳香族複素環基を例示することができる。また、これらの芳香族炭化水素および芳香族複素環基には、さらに前記ハロゲン原子、ハロゲン化アルキル基、ハロゲン化アルコキシ基、アルキル基、アルコキシ基、チオール基、ニトロ基、アルキルアミノ基、アミノ基、シアノ基、水酸基等の置換基を有することもできる。
また、「Ｃ１〜Ｃ２０のアルキル基」としては、直鎖状、分岐鎖または環状のいずれでもよく、上記したような例示に加え、ドデシル、テトラデシル、ペンタデシル、ヘキサデシル、ペンタデシル、オクタデシル、ノナデシル、イコシル等を例示することができ、これらのアルキル基には、更に種々の置換基が置換されていてもよい。この置換基としては、前記の「Ｃ１〜Ｃ１２のアルキル基」への置換基と同一の置換基を挙げることができる。
【００１３】
また、「Ｃ２〜Ｃ２０、Ｃ２〜Ｃ１２等のアルケニル基、アルキニル基、アルコシキル基、アルキルチオ基」としては、直鎖状環状、分岐鎖状のいずれでもよく、アルキル基の場合と同様に例示でき、これらアルケニル基、アルキニル基、アルコキシル基には、更に種々の置換基が置換されていてもよい。この置換基としては、前記のＣ１からＣ１２へのアルキル基置換基と同一の置換基を挙げることができる。
アルケニル基、アルキニル基、アルコキシル基、アルキルチオ基の例としては、次のものがあげられる。
アルケニル基の例：１−メチルー１−プロペニル、１−ヘキセニル、エテニル、４，４−ジメチル−１−ペンテニル、デセニル、イコセニル等があげられる。
アルキニル基の例：１−プロピニル、２−プロピニル、１，３−ヘキサニルジイニル、２−ヘキシニル、イコサトリイニル等。
アルコキシ基の例：メトキシ、エトキシ、n−ヘキシルオキシ、３−メチルブトキシ、イコシルオキシ、ノナデシオキシ等。
アルキルチオ基の例：メチルチオ、エチルチオ、２−メチル２−プロピルチオ、３−メチルブチルチオ、n−ヘキシルチオ等。
【００１４】
また、「置換アミノ基」としては、窒素原子に本明細書において示す置換あるいは無置換のアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアルキニル基、置換もしくは無置換の芳香族炭化水素基、または置換もしくは無置換の芳香族複素環基が１ないし２置換した基であり、さらにこれらアルキル、アルケニル基は結合する窒素原子と一体となり、５，６，７員の窒素原子、酸素原子または硫黄原子を含んでもよい複素環を形成することもできる。この置換アミノ基としては、例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジエチルアミノ、２−プロペニルアニノ、１−ピペラジニル、モルホリノ、チオモルホリノ、パーヒドロアゼピニル、フェンニルアミノ、ナフチルアミノ、ピリジルアミノ、フリルアミノ、チエニルアミノ、ピペリジノ、１−ピロリジニル、３−ブテニルアミノ等をあげることができる。
また、「置換もしくは無置換の芳香族炭化水素基」とは、単環式または多環式であり、さらに環状に１個以上の種々の置換基を有していてもよい芳香族炭化水素基をいい、たとえばフェニル、メチルフェニル、ジメチルフェニル、メトキシフェニル、ジメトキシフェニル、フルオロフェニル、ジニトロフェニル、トリフルオロメチルフェニル、ジメチルアミノフェニル、メルカプトフェニル、α−ナフチル、β−ナフチル基等を挙げることができる。
また、「置換もしくは無置換の芳香族複素環基」とは、構成原子として窒素原子、硫黄原子、酸素原子、リン原子等のヘテロ原子を少なくとも１個以上含む、４員環、５員環、６員環、７員環、８員環または９員環の基であり、これらは、ベンゼン環と縮合していてもよく、さらに環上に１個以上の種々の置換基を有していてもいい、例えば、ピリジル、フリル、チエニル、インドリル、キノリル、イソキノリル、ベンゾフラニル、ベンゾチエニル、イミダゾリル、ベンズイミダゾリル、チアゾリル、オキサゾリル、ピラゾリル、ピリミジル、ピラジニル、ホモピペラジニル、イソオキサゾリル、イソインドリル、ピロリル等を挙げることができる。
【００１５】
本発明が提供する前記一般式（１）で表されるＮ−アルキルスルフォニル置換アミド誘導体において、
環Ａは、１，２位を置換位置とする芳香族炭化水素基、１，２位を置換位置とする芳香族複素環基、１，２位を置換位置とするアルケニル基、または１，１位を置換基とする環状アルキル基のいずれかが好ましい。
また、環Aが置換または無置換のフェニル基であるＮ−アルキルスルフォニル置換アミド誘導体も好ましい。
Ｘは、一般式（２）、（３）、（４）、（５）、Ｒ２０のいずれかで示される基が好ましく、特に一般式（２）またはＲ２０で示される基が好ましい。更に一般式（２）の場合は、Ｚが-CR9=CR10-で示される基が好ましい。ここで特にR9及びR10が水素原子であるのが好ましい。Ｒ２０の場合には、アリール基が置換したエチニル基が好ましい。そのエチニル基に結合しているアリール基には、フッ素原子あるいはフッ素原子を含む置換基が結合しているものが好ましい。
R９〜R1８が、ハロゲン原子置換C1〜C12のアルキル基又はアルコキシル基であるのが好ましく、特にフッ素原子置換C1〜C12のアルキル基又はアルコキシル基であるのが好ましい。
また、（１）式中のＹは、-CR3=CR4-、硫黄原子または酸素原子で示されるいずれかの基が好ましく、特に-CR3=CR4-が好ましい。ここで特にR３及びR４が水素原子であるのが好ましい。
環Ｂは、
置換もしくは無置換の芳香族炭化水素基、環の員数が４から９の置換もしくは無置換である複素環、無置換または置換の環状アルキル基、無置換または置換の環状アルケ二ル基を含む。例えば、環Ｂは、以下の（6）に示すような環があげられる。
【００１６】
【化１１】
Figure 2005170790
【００１７】
これらのうち、環Ｂは、環の員数が４から９の置換もしくは無置換である複素環で示される基が好ましく、特に環の員数が５の複素環で示される基、更にはチアゾール環もしくはオキサジアゾール環で示される基が好ましい。
環Ｃは、ピリジン環、フラン環、チオフェン環を除いた置換もしくは無置換の芳香族複素環基、置換もしくは無置換の環状アルキル基、無置換または置換の環状アルケ二ル基である。これらのち、５〜６員である芳香族複素環基が好ましい。
上記一般式（１）で示される化合物として好ましい化合物として例えば、以下の化合物を例示することができる。
【００１８】
【化１２】
Figure 2005170790
【００１９】
【化１３】
Figure 2005170790
前記一般式（１）のＮ−アルキルスルフォニル置換アミド誘導体は、例えば下記に化学式で示す製造方法によって合成することができる。
【００２０】
【化１４】
Figure 2005170790
【００２１】
（式中のＲ１、Ｒ５、Ｒ６、ＡおよびＸは、前記定義のとおりであり、Ｊは、合成反応に用いる通常のエステル保護基であり、例えば、メチル基、エチル基、ベンジル基、アリル基等であり、Ｄは、フッ素、塩素、臭素、水酸基、Ｎ−ヒドロキシスクシンイミド基。４−ニトロフェノキシ基またはペンタフルオロフェノキシ基等である。）
工程１（Step１）では、アミン（７）とカルボニル化合物（８）を縮合させて、エステル化合物（９）を製造する行程である。例えば（８）が、酸クロリドの場合は、適当な塩基を存在させアミン（７）と縮合する方法、或いは（８）がカルボン酸である場合は、ｐ−トルエンスルホン酸クロリド、クロロ炭酸エチル、ピバロイルクロリド等で酸無水物とし、適当な塩基を存在させアミン（７）と縮合する方法等が挙げられる。
また反応には、アミン（７）と、カルボニル化合物（８）をほぼ当モル量用いることが好ましい。反応温度並びに反応時間は化合物の種類等により一概に限定されないが、ほぼ０℃乃至使用する溶媒の沸点程度の温度条件下に、０．１ないし２５時間程度反応させることにより収率良く目的とする化合物を得ることができる。また、縮合剤の使用量は、カルボニル化合物（８）に対してほぼ１．２倍当量添加させるのが好ましい。
使用する塩基としては、例えば、水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物；水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物；炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸化物；炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属炭酸水素化物；ナトリウムメトキシド、ナトリウムエトキシド、カリウムメトキシド、カリウム第三ブトキシド等のアルカリ金属アルコキシド；トリメチルアミン、トリエチルアミン等のトリアルキルアミン；ピリジン、ジメチルアミノピリジン、ピコリン、ルチジン等のピリジン類のような有機塩基又は無機塩基をあげることができる。その塩基の使用量は、カルボン酸化合物に対して１〜１０倍当量使用することが好ましい。
【００２２】
工程2（Step2）は、エステル化合物（９）中のカルボキシル基の保護基を脱保護する行程である。通常は、エステル化合物（９）をメタノール,THFに溶解し、水酸化リチウム１水和物を加え室温で十数時間攪拌し、反応終了後、減圧下溶媒を留去、残留物に１N塩酸水溶液を適当量加え、酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去し、目的のカルボン酸を得る。得られたカルボン酸を工程３（ＳＴＥＰ３）の原料として用い、アルゴン雰囲気下、1.4-ジオキサンに溶解させ、適当なカルボジイミド系縮合剤を加え100℃程度で30分攪拌後、Ｒ１−スルホンアミド誘導体と適当な塩基を加え、さらに100℃程度で20時間程度攪拌し、反応終了後、減圧下溶媒を留去、残留物を酢酸エチルで希釈、2N-塩酸水溶液及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、溶媒を減圧下留去し、残留物から再結晶により一般式（１）化合物を得ることができる。
上に述べた工程１，２，３は、不活性溶媒中で反応を行うことができる、そのような溶媒とは、例えばジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン等のエーテル類；ベンゼン、トルエン、キシレン等の芳香族炭化水素；シクロペンタン、シクロヘキサン等の炭化水素；ジクロルメタン、ジクロルエタン、トリクロロエタン、クロロホルム等のハロゲン化炭化水素；アセトニトリル、プロピオニトリル等のニトリル類；酢酸エチル等のエステル類；Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド等、或いはこれらと水との混合物を挙げることができる。
【００２３】
前記したすべての工程において、必要に応じて、通常行われている精製手段、例えば濾過、デカンテーション、抽出、洗浄、溶媒留去、カラム又は薄層クロマトグラフィー、再結晶、蒸留等に付すことにより単離精製することができる。
一般式（Ｉ）で示されるＮ−アルキルスルフォニル置換アミド誘導体には、これらの各種の塩、水和物や溶媒和物の形態にあるもの、特に医薬的に許容される形態にあるものを含む。
本発明は、一般式（Ｉ）で示される化合物を含むことを特徴とする肥満症および肥満によって誘発される高脂血症ならびにインスリン抵抗性に基づく様々な疾患（耐糖能異常、糖尿病、糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症、高血圧、動脈硬化症）の治療薬、或いはその治療法である。更に、本発明は、肥満症および肥満によって誘発される高脂血症ならびにインスリン抵抗性に基づく様々な疾患（耐糖能異常、糖尿病、糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症、高血圧、動脈硬化症）の予防、治療、進展防止を目的とする薬剤及び治療法である。
また、一般式（Ｉ）で示される化合物と他の医薬、例えば抗糖尿病薬や血糖降下剤が、混合された製剤として、或いはそれぞれの成分を別個に含む２種の製剤として組み合わされた形態にあるものも本発明に含まれる。
【００２４】
一般式（Ｉ）で示される化合物と組み合わせて用いることのできる薬剤しては、例えばインスリン、例えばリスプロ、glargineなどのインスリンアナログ、例えばグリベンクラミド、トルブタミド、グリピザイド、グリメピリドなどのインスリン分泌促進剤、例えばナテグリニド、レパグリニドなどの速効性インスリン分泌促進剤、例えばアカルボース、ボグリボース、ミグリトールなどのアルファ-グリコシダ−ゼ阻害剤、例えばメトォルミン、フェンフォルミンなどのビグアナイド剤、例えばロジグリタゾン、ピオグリタゾン、トログリタゾンなどのチアゾリジン骨格あるいはGI-262570、JTT-501、YM-440などの非チアゾリジン骨格のPPAR-ガンマアゴニストおよびPPAR-ガンマアンタゴニストなどのインスリン抵抗性改善剤、例えばクロフィブラートなどのPPAR-アルファアゴニスト、例えばT-1095などのSGLT阻害剤、GLP-1受容体アンタゴニスト、DPP-IV阻害剤などの血糖降下剤、例えばエパルレスタット、フィダレスタット、ゼネレスタットなどのアルドース還元酵素阻害剤、例えばメコバラミン、メキシチレンなどの糖尿病性神経障害治療薬、例えばプラバスタチン、シンバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、イタバスタチンなどのHMG-CoA還元酵素阻害剤、例えばリポ酸、プロブコールなどの抗酸化剤、例えばカルシウム拮抗薬、アンジオテンシン変換酵素阻害薬、アンジオテンシンII受容体拮抗剤、ベータ遮断薬、α１遮断薬、利尿剤などの降圧剤、例えばオルリスタット、シブトラミンなどの抗肥満薬、例えばオプティファーストなどの低エネルギー食などがある。食事療法、運動療法も含め、例示していない既存の医薬及び開発・基礎研究中の医薬なども、上記の医薬品と同様に肥満症および肥満によって誘発される高脂血症ならびにインスリン抵抗性に基づく様々な疾患（耐糖能異常、糖尿病、糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症、高脂血症、高血圧、動脈硬化症）の治療を目的として一般式（Ｉ）で示される化合物と併用される場合は本発明に含まれる。
【００２５】
一般式（Ｉ）で示される化合物を含有する医薬をヒトに投与する場合、年齢および対象疾患の症状等により異なるが、１製剤あたりでは、好ましくは一般式（Ｉ）の化合物0.01〜1000 mg程度を含有することができる。実際に好ましい投与方法、順序及び間隔は、使用される個々の薬剤の製剤、薬効発現時間、処置される個々の患者の状態（体重、体脂肪率、ボディマスインデックス、血液生化学指標など）によって、慣用技術を駆使して、及び本明細書に記載の情報を考慮して適宜選択され得る。すなわち、より好ましくは、一般式（Ｉ）で表される化合物は、その有効量、例えば、通常１日に１〜１００mgを１〜３回に分け、経口投与するのが好ましい。
一般式（Ｉ）と他剤の併用にあたっては、両者を同時に投与することもでき、また時を異にして投与することもできる。それぞれの薬剤について１日３回までの投与が好ましく、連続投与に伴う禁忌症が認められない限り、また個々の患者において設定される目標が得られるまで治療を繰り返すことができる。
【００２６】
一般式（Ｉ）を含有する医薬は、種々の剤型、例えば錠剤、カプセル剤、顆粒剤、散剤、トローチ剤、液剤等の経口投与製剤とすることができる。これらの製剤化は、それ自体公知の方法によって行い得る。例えば、本発明の前記一般式（Ｉ）の化合物をデンプン、マンニトール、乳糖等の賦形剤；カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース等の結合剤；結晶セルロース、カルボキシメチルセルロース等の崩壊剤；タルク、ステアリン酸マグネシウム等の潤滑剤；軽質無水ケイ酸等の流動性向上剤等を適宜組み合わせて処方することにより、錠剤、カプセル剤、顆粒剤、散剤、トローチ剤等を製造することができる。また、本発明の医薬は、注射剤とすることもできる。この製剤化は、例えば、界面活性剤や分散剤等によりあらかじめ生理食塩水等の水担体に分散または可溶化しておいてもよいし、あるいはまた、必要時にその都度分散または可溶化し得るように注射用結晶製剤または凍結乾燥製剤としておいてもよい。上記の水担体には、pH調整剤や安定化剤を任意成分として添加してもよい。かかる注射剤の投与量および投与経路は特に限定されず、病状や患者の特性に合わせて、静脈内、動脈内、皮下または腹腔内に安全かつ必要な量を、一気にまたは点滴等により投与することができる。
【００２７】
一般式（Ｉ）と他剤の併用にあたっては、有効成分を全て同一製剤に含める必要はなく、各成分について、或いは複数成分について、適切な一又は複数の製剤中に含めることができる。その場合、公知の又は将来開発される様々な医薬製剤の形態、例えば、経口投与製剤、注射剤などに調製することができるが、調製にあたっては、公知の又は将来開発される方法を適宜採用することができる。
【実施例】
次に、実施例により本発明を更に詳細に説明するが、本発明はこれらの実施例により何ら限定されるものではない。以下に、合成実施例と薬理試験実施例を記す。
【００２８】
合成実施例１（構造を下記に示す化合物の合成例）
【化１５】
Figure 2005170790
【００２９】
4-ヨード安息香酸エチル(1.11g, 4.03mmol)をジエチルアミン(10ml)に溶解し、アルゴン雰囲気下3-エチニル-α,α,α-トリフルオトルエン(1.03g, 6.05mmol)、ジクロロビストリフェニルフォスフィンパラジウム(28.3mg, 0.0403mmol)及びヨウ化銅(15.4ｍｇ、0.0806mmol)を加え50℃で1時間攪拌した。反応終了後、減圧下ジエチルアミンを留去、残留物に１N-塩酸を加え、酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下除去した。残留物をシリカゲルカラムクロマトグラフィーにより精製し、実施例１の合成中間体であるエチルエステル1.28ｇ（収率＞99％）を得た。
1H-NMR（ CDCl3 ） : 1.42 ( 3H, t, J=7.2Hz ), 4.40( 2H, q, J=7.2 ), 7.50( 1H, dd, J=7.5 ), 7.58-7.61( 3H, m ), 7.60( 2H, d, J=8.7 ), 7.71( 1H, d, J=7.5 ), 7.81( 1H, S ), 8.05( 2H, d, J=8.7 )
続いて、
得られたエチルエステル (1.28g, 4.03mmol)をメタノール（10ml）,THF(15ml)に溶解し、２N-NaOH(3.0ml, 6.05mmol)を加え室温で1.5ｈ攪拌した。反応終了後、反応溶液に１N-HCｌを加え酸性にし、減圧下溶媒を留去、残留物に多量のH2Oを加え一晩放置した。析出した結晶を濾過し、実施例１の合成中間体であるカルボン酸1.06ｇ（収率91％）を得た。
1H-NMR（ DMSO ） : 7.70-7.73( 1H, m ), 7.72( 2H, d, J=8.4 ), 7.82( 1H,ｄｄ, J=8.7 ), 7.91( 1H, dd, J=7.5 ), 7.97( 1H, S ), 7.99( 2H, d, J=8.4 )続いて、アルゴン雰囲気下、得られたカルボン酸517mg(1.78mmol)に対しチオニルクロライド3mlを加え60℃で2時間攪拌後、チオニルクロライドを減圧下留去した。残留物を塩化メチレン6mlに溶解し、これをAnthranilic acid methylester0.230ml(1.78mmol)の10mlピリジン溶液に0℃で滴下、室温で20時間攪拌後、ピリジンを減圧下留去した。残留物を酢酸エチルに溶解し、2N-HCｌ水溶液及び飽和食塩水で順次洗浄、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。引き続き、残留物をメタノール（10ml）,THF(15ml)に溶解し、大過剰量のLiOH・H2Oを加え室温で4ｈ攪拌した。反応終了後、減圧下溶媒を留去、残留物に１N-塩酸を加え、酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残留物を再結晶により精製し対応するカルボン酸556mg（収率76％）を得た。
【００３０】
続いて、アルゴン雰囲気下、得られたカルボン酸502mg(1.23mmol)を1.4-Dioxane20mlに溶解し、WSC・HCl 280mg(1.47mmol)を加え94℃で30分攪拌後、Butane-1-sulfonic acid amide202mg(1.47mmol)及びDBU0.368ml(2.46mmol)を加え94℃で20時間攪拌した。反応終了後、減圧下溶媒を留去、残留物を酢酸エチル25mlで希釈、2N-HCl水溶液及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、溶媒を減圧下留去した。残留物をPTLCにより精製し、目的の実施例１化合物479mg(収率74％)を得た。
1H-NMR（ DMSO ） : 0.88（ 3H, t, J=7.2Hz ）, 1.34-1.40( 2H, m ), 1.60-1.65( 2H, m ), 2.93( 2H, t, J=7.5 ), 6.69-3.70 ( 1H, ｍ ), 7.18-7.23( 1H, ｍ ), 7.44-7.96( 6H, ｍ ), 8.04-8.26( 2H, m ), 8.61-8.64( 1H, ｍ ), 8.88-8.89( 1H, m ), 12.73( 1H, s )
MS(ESI) m/z : 529.31( MH+ )
【００３１】
合成実施例２（構造を下記に示す化合物の合成例）
【化１６】
Figure 2005170790
合成実施例２の合成中間体であるチアゾール環を持つ下記に示す安息香酸の合成
【００３２】
【化１７】
Figure 2005170790
【００３３】
Wangレジン（０．９１mmol/g）２．０ｇをＮＭＰに懸濁させ室温で３時間放置した。余分な溶媒を除き、そこに、ＮＭＰ３０ｍｌ、４−シアノ安息香酸 １．６ｇ、ピリジン１．４５ｍｌ、２，６−ジクロロベンゾイルクロリド１．５６ｍｌを加え、室温で２０時間撹拌した。溶媒を除きさらに樹脂をＮＭＰ３０ｍｌで２回洗浄した。溶媒を除いた後、ジクロロメタン、ＮＭＰ、ジクロロメタンの順で、それぞれ３０ｍｌずつ用いて、３回ずつ洗浄し、さらにレジンを乾燥させた。
続いて、得られた樹脂に、ＴＨＦ：水＝４：１液を５０ｍｌ加え、さらに、ジチオホスフォリックアシッド Ｏ，Ｏ−ジエチルエステル１０ｍｌを加え、８０℃で１２時間撹拌した。溶媒を除き、樹脂をＮＭＰ３０ｍｌで２回洗浄した。溶媒を除いた後、ジクロロメタン、ＮＭＰ、ジクロロメタンの順で、それぞれ３０ｍｌずつ用いて、３回ずつ洗浄しさらにレジンを乾燥させた。
続いて、
得られたチオアミドレジンに、ＮＭＰを５０ｍｌ加え、さらに、４−（トリフルオロメトキシ）フェナンシルブロマイド２．５ｇを加え、８０℃で１２時間撹拌した。溶媒を除きさらに樹脂をＮＭＰ３０ｍｌで２回洗浄した。溶媒を除いた後、ジクロロメタン、ＮＭＰ、ジクロロメタンの順で、それぞれ３０ｍｌずつ用いて、３回ずつ洗浄し、さらにレジンを乾燥させた。得られたレジンに、１００％トリフルオロ酢酸５０ｍｌを加え、１時間放置後、反応液とレジンをろ別し、反応液を、減圧下濃縮して合成実施例２の合成中間体であるチアゾール環を持つ安息香酸０．９３ｇを得た。
【００３４】
続いて、アルゴン雰囲気下で、得られた安息香酸679mg(1.86mmol)に対しチオニルクロライド3mlを加え60℃で3時間攪拌後、チオニルクロライドを減圧下留去した。残留物を塩化メチレン6mlに溶解し、これをAnthranilic acid methylester 0.240ml(1.86mmol)の10mlピリジン溶液に0℃で滴下、室温で15時間攪拌後、ピリジンを減圧下留去した。残留物を酢酸エチルに溶解し、2N-HCｌ水溶液及び飽和食塩水で順次洗浄、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。残留物を再結晶により精製しエステル化合物568mg(収率61％)を得た。
続いて、アルゴン雰囲気下で、得られたエステル568mg(1.14mmol)をメタノール（20ml）,THF(20ml)に溶解し、LiOH・H2O 239mg(5.70mmol)を加え室温で16時間攪拌した。反応終了後、減圧下溶媒を留去、残留物に１N--HCl水溶液を加え、酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残留物を再結晶により精製しカルボン酸549mg（収率99％）を得た。
続いて、アルゴン雰囲気下、得られたカルボン酸395mg(0.816mmol)を1.4-Dioxane20mlに溶解し、WSC・HCl 187mg(0.979mmol)を加え100℃で30分攪拌後、Butane-1-sulfonic acid amide134mg(0.979mmol)、DBU0.182ml(1.22mmol)及び、触媒量の2-t-Butylimino-2-diethylamino-1.3-dimethylperhydro-1.3.2-
diazaphosphorine を加え100℃で20時間攪拌した。反応終了後、減圧下溶媒を留去、残留物を酢酸エチル25mlで希釈、2N-HCl水溶液及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、溶媒を減圧下留去した。残留物を再結晶により精製し、目的の実施例２化合物380mg(収率77％)を得た。
1H-NMR（ DMSO ） : 0.84（ 3H, t, J=7.2Hz ）, 1.33-1.43( 2H, m ), 1.61-1.76( 2H, m ), 2.92-2.97( 2H, m ), 6.70-6.74( 1H, ｍ ), 7.25-7.30( 1H, ｍ ), 7.48-7.52( 2H, ｍ ), 7.58-7.64( 1H, m ), 7.77-7.82( 1H, ｍ ), 8.08-8.28( 7H, m ), 8.37( 1H, s )
MS(ESI) m/z : 604( MH+ )
【００３５】
合成実施例３（構造を下記に示す化合物の合成例）
【化１８】
Figure 2005170790
【００３６】
アルゴン雰囲気下で、実施例２と同様にして対応する原料を用いて合成したカルボン酸703mg(2.35mmol)に対しチオニルクロライド3mlを加え60℃で2時間攪拌後、チオニルクロライドを減圧下留去した。残留物を塩化メチレン6mlに溶解し、これをAnthranilic acid methylester 0.304ml(2.35mmol)の10mlピリジン溶液に0℃で滴下、室温で2時間攪拌後、ピリジンを減圧下留去した。残留物を酢酸エチルに溶解し、2N-HCｌ水溶液及び飽和食塩水で順次洗浄、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。残留物をメタノール（50ml）,THF(50ml)に溶解し、大過剰量の4N-NaOHを加え室温で16ｈ攪拌した。反応終了後、１N-塩酸を加え、減圧下有機溶媒を留去、酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残留物を再結晶により精製しカルボン酸713mg（収率73％）を得た。
続いて、アルゴン雰囲気下、得られたカルボン酸713mg(1.70mmol)を1.4-Dioxane20mlに溶解し、WSC・HCl 421mg(2.21mmol)を加え100℃で30分攪拌後、Butane-1-sulfonic acid amide280mg(2.04mmol)、DBU0.432ml(2.89mmol)及び、触媒量の2-t-Butylimino-2-diethylamino-1.3-dimethylperhydro-1.3.2-diazaphosphorine を加え100℃で14時間攪拌した。反応終了後、減圧下溶媒を留去、残留物を酢酸エチル25mlで溶解、2N-HCl水溶液及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、溶媒を減圧下留去した。残留物を再結晶により精製し、目的の実施例２化合物659mg(収率72％)を得た。
1H-NMR（ DMSO ） : 0.82（ 3H, t, J=7.2Hz ）, 1.31-1.38( 2H, m ), 1.66-1.74( 2H, m ), 2.80-2.97( 2H, m ), 6.69-6.72( 1H, ｍ ), 7.25-7.35( 3H, ｍ ), 7.55-7.62( 1H, ｍ ), 7.75-7.77( 1H, m ), 8.09-8.35( 9H, ｍ )MS(ESI) m/z : 538.22( MH+ )
【００３７】
合成実施例４（構造を下記に示す化合物の合成例）
【化１９】
Figure 2005170790
【００３８】
合成実施例１で合成した４−（３−トリフルオロメチルフェニルエテニル）安息香酸872mg (3.00mmol)、１−アミノシクロペンタンカルボン酸メチルエステル塩酸塩851mg (4.74mmol)、２−クロロ−１−メチルピリジニウムヨージド1160mg (4.54mmol)、トリエチルアミン1.3mlを乾燥したジクロロメタンに5ml溶解し、室温で一晩撹拌した。1M塩酸20ml、酢酸エチル30mlを加えて抽出した有機層を無水硫酸ナトリウムで乾燥して減圧濃縮した。酢酸エチル5ml、ヘキサン25mlを加えて析出した固体を濾取して955mg (2.30mmol)のエステル化合物を白色粉末として得た（収率77%）。
続いて、エステル化合物955mg (2.30mmol)を、エタノール10ml、１，４−ジオキサン10mlに溶解し、４Ｍ水酸化ナトリウム水溶液10mlを加えて室温で８時間撹拌した。１Ｍ塩酸50mlと酢酸エチル150mlを加え抽出した有機層を無水硫酸ナトリウムで乾燥し減圧濃縮乾固して、920mg (2.29mmol)のカルボン酸を白色粉末として得た（収率99％）。
続いて、得られたカルボン酸598mg (1.49mmol)、ｎ−ペンタンスルホンアミド309mg (2.04mmol)、１，８−ジアザビシクロ［５．４．０］ウンデック−７−エン0.50ml (3.34mmol)、ＷＳＣ塩酸塩469mg (2.45mmol)を乾燥した１，４−ジオキサン5mlに溶解し、８０℃で１晩撹拌した。放冷後、１Ｍ塩酸5mlと酢酸エチル5mlを加え撹拌後に分層し、有機層を１Ｍ塩酸2mlで洗浄後、無水硫酸ナトリウムで乾燥して減圧濃縮した。カラムクロマトグラフィー（シリカゲル、ジクロロメタン：ＴＨＦ＝30：1）で精製後、減圧濃縮乾固し、酢酸エチル：ヘキサン（1：10）で懸濁後濾取して、486mg ( 0.909mmol)の合成実施例４化合物を白色粉末として得た（収率61％）。MS(ESI) m/z : 535( MH+ )
合成実施例5〜８（構造を下記に示す化合物の合成例）
【００３９】
【化２０】
Figure 2005170790
Figure 2005170790
実施例４と同様にして対応する原料を用いて合成した。
【００４０】
合成実施例9（構造を下記に示す化合物の合成例）
【化２１】
Figure 2005170790
実施例４と同様にして対応する原料を用いて合成した。MS(ESI) m/z : 509( MH+ )
【００４１】
合成実施例10（構造を下記に示す化合物の合成例）
【化２２】
Figure 2005170790
実施例４と同様にして対応する原料を用いて合成した。MS(ESI) m/z : 507( MH+ )
【００４２】
合成実施例１１（構造を下記に示す化合物の合成例）
【化２３】
Figure 2005170790
実施例４と同様にして対応する原料を用いて合成した。MS(ESI) m/z : 650( MH+ )
【００４３】
合成実施例１２（構造を下記に示す化合物の合成例）
【化２４】
Figure 2005170790
実施例４と同様にして、合成実施例２の合成中間体であるチアゾール環を持つ下記に示す安息香酸を用いて合成した。MS(ESI) m/z : ６２４( MH+ )
【００４４】
薬理試験例１：ACC阻害活性の測定
１．ACCの精製
雄性SD系ラットを２日間絶食後、高ショ糖食（成分）を２日間与え、エーテル麻酔下に下大静脈を切開し、放血した後、速やかに肝臓を取り出した。氷冷した緩衝液A（225 mM mannitol、75 mM sucrose、10 mM Tris-HCl (pH 7.5)、0.05 mM EDTA、5 mM potassium citrate、2.5 mM MgCl2、10 mg/L pepstatin A、10 mg/L leupeptin、1 mM PMSF）中で、ポリトロンホモジナイザーでホモジナイズした。肝重量に対して、９倍量の緩衝液Aを加え、1000 gで１０分間遠心分離した後、上清を採取し、更に、17000 gにて１０分間遠心分離した。
得られた上清に、35%飽和となるよう硫酸アンモニウムを加え、４５分間撹拌した後、17000 gにて１０分間遠心分離した。得られた沈殿に緩衝液B（100 mM Tris-HCl (pH 7.5)、500 mM NaCl、1 mM EDTA、0.1 mM DTT、10% glycerol、10 mg/L pepstatin A、10 mg/L leupeptin、0.5 mM PMSF）を加え、溶解した後、40000 gにて２０分間遠心分離した。上清を緩衝液C（100 mM Tris-HCl (pH 7.5)、500 mM NaCl、1 mM EDTA、0.1 mM DTT、5% glycerol）に対して一晩透析した。透析した上清を5 μMのフィルターで濾過した後、monomeric avidin sepharoseカラムにアプライし、緩衝液Bで洗浄した後、2 mM d-biotinを含む緩衝液BでACCを溶出した。
【００４５】
２．ACC阻害活性の測定
前記実施例で製造した化合物をそれぞれDMSOに溶解し、ガラスバイアルに入れ、ACCを含む250 μlの反応液１（40 mM Tris-HCl (pH 7.5)、40 mM MgCl2、40 mM sodium citrate、2 mM DTT）を加え、恒温槽にて３７℃で３０分間加温した後、氷冷した。反応液１に、[14C]-NaHCO3を含む250 μlの反応液２（40 mM Tris-HCl (pH 7.5)、２ mM DTT、8 mM ATP、0.5 mM acetyl CoA）を加え、３７℃で１０分間加温した後、1N HClを100 μl添加し、反応を停止させた。遠心エバポレーターにて反応液中の水分を除去した後、シンチレーターを加え、固体成分を溶解し、液体シンチレーションカウンターにて14Cの放射能を測定した。各化合物のACC阻害活性を、以下の式より算出し、50%阻害が得られる濃度（IC50）を求めた。その結果を表１に示す。
ACC阻害率（％） ＝ {1 (a-c)/(b-c)} x 100
a：被験薬添加時の放射能
b：被験薬非添加時の放射能
c：ブランク＊
＊反応液１と反応液２を混合する前に、あらかじめ反応液１に1N HCl 100 μlを加えたもの
【００４６】
薬理試験例２：糖尿病モデルKK-Ayマウスにおける抗肥満作用、高脂血症改善効果、血糖降下作用および耐糖能改善効果
雄性KK-Ayマウスを血糖値および血漿中トリグリセライド値について、群間で差がでないように群分けを行い、前記実施例で製造した化合物58.3〜175 mg/kgを１日に２回４日間強制経口投与した。対照としてKK-Ayマウスに賦形剤のみを投与した。投与最終日に摂食下にて血漿中トリグリセライド、血糖および体重を測定した。更に、投与終了後に一晩絶食した後、経口糖負荷試験（2 g/kgのグルコースを強制経口投与し、投与180分後まで、経時的に血糖を測定）を行い、耐糖能を評価した。抗肥満作用については、投与初日の体重を100%として、投与終了日の相対体重を百分率で求め、評価した（表２）。また、高脂血症改善効果および血糖降下作用については、以下の式に従い、投与終了後の低下率を求め、評価した（表３：高脂血症改善効果、表４：血糖降下作用）。
血漿中トリグリセライド（または血糖）低下率（％） ＝ ｛1-a/b｝x 100
a：化合物投与群の血漿中トリグリセライド濃度（または全血中グルコース濃度）
b：対照群の血漿中トリグリセライド濃度（または全血中グルコース濃度）
体重耐糖能改善効果については、グルコース投与180分後までの血糖推移曲線から血糖のAUCを算出した後、ΔAUCを指標に評価した。尚、ΔAUCは、以下の式より算出した。その結果を表５に示す。
ΔAUC ＝ （対照群のAUCの平均値） - （化合物投与群のAUCの平均値）
【００４７】
【表１】 表１ ACC阻害活性
Figure 2005170790
【００４８】
【表２】 表２ 抗肥満作用
Figure 2005170790
【００４９】
【表３】 表３ 高脂血症改善効果
Figure 2005170790
【００５０】
【表４】 表４ 血糖降下作用
Figure 2005170790
【００５１】
【表５】 表５ 耐糖能改善効果
Figure 2005170790
【００５２】
【発明の効果】
本発明のＮ−アルキルスルフォニル置換アミド誘導体は、従来の抗肥満薬およびインスリン抵抗性改善薬とは異なるメカニズムで、肥満症および肥満によって誘発される高脂血症、脂肪肝ならびにインスリン抵抗性に基づくと考えられる耐糖能異常、糖尿病、糖尿病性合併症（糖尿病性末梢神経障害、糖尿病性腎症、糖尿病性網膜症、糖尿病性大血管症）、高血圧および動脈硬化症の治療が可能であり、これら疾患の治療薬として極めて有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an N-alkylsulfonyl substituted amide derivative, and in particular, relates to a novel N-alkylsulfonyl substituted amide derivative having acetyl CoA carboxylase (hereinafter sometimes abbreviated as ACC) inhibitory activity.
[Prior art]
In recent years, obesity has been shown to be a major risk factor for arteriosclerotic diseases, particularly coronary artery disease. That is, in obese individuals, various factors such as fatty acids and TNF-α are released from the accumulated visceral fat, which causes insulin resistance in skeletal muscle, liver and adipose tissue, and neutral fat in the liver. It has been reported to promote the synthesis of and cause hyperlipidemia. In addition, insulin in the blood that has been compensated for by insulin resistance not only causes impaired glucose tolerance, but also diabetes, but also through peripheral vascularization through increased Na ion reabsorption and sympathetic nerve activation in the kidney. Increases resistance and eventually forms a hypertensive state. Hyperlipidemia, diabetes and hypertension brought about by obesity are thought to cause vascular disorders based on arteriosclerosis such as cerebrovascular disorder and coronary artery disease, and to have a serious impact on life prognosis.
The basics of obesity treatment are exercise therapy and diet therapy, but there are a lot of factors to achieve the set goals due to various factors such as conflict with human fundamental desires, balance with working hours, and increased stress. There are difficulties. Surgical treatments such as gastric reduction and gastric bypass may be applied to extremely obese patients, but obesity often results in wound complications such as infection and lipolysis when laparotomy is performed. The current situation involves loss and pain. Therefore, there is a need for a combination of pharmaceuticals that can supplement diet / exercise therapy safely and simply. Currently, pharmaceuticals used as anti-obesity drugs include central appetite suppressants such as mazindol and sibutramine, and orlistat, which is a pancreatic lipase inhibitor. Centrally acting drugs may cause serious side effects such as dry mouth, constipation, stomach discomfort, and sometimes hallucinations / visual hallucinations.Orlistat has side effects in the digestive tract such as diarrhea, incontinence, and prodigation. It recognized. In general, the effects of these anti-obesity drugs are moderate at doses that do not cause side effects, and the safety of long-term use has not yet been established. The current situation is that almost no recognition has been made.
[0002]
With respect to insulin resistance, treatment using a biguanide agent or a peroxisome proliferation-related receptor (hereinafter abbreviated as PPAR) gamma agonist is widely performed. Regarding biguanides, it has been reported that non-insulin-dependent diabetic patients exhibit hypoglycemic and hyperlipidemic effects in addition to improving insulin resistance. However, the therapeutic effect by itself is inadequate, and in addition to gastrointestinal symptoms such as upper abdominal discomfort, nausea, and diarrhea, it has become clear that life-threatening side effects such as lactic acidosis are exhibited. Yes. As for PPAR gamma agonists, as with biguanides, it improves insulin resistance, hyperglycemia, hyperlipidemia and hypertension in non-insulin dependent diabetics, but is still satisfactory in terms of side effects (obesity, fulminant hepatitis) It's hard to say what you can do.
ACC is an enzyme that catalyzes the synthesis of Malonyl CoA from Acetyl CoA, and is a rate-limiting enzyme in the synthesis of long-chain fatty acids. Moreover, it is known that Malonyl CoA itself synthesized from Acetyl CoA by ACC negatively controls Carnitine acyltransferase involved in consumption of free long chain fatty acid as an energy source. Furthermore, activation of fatty acid synthesis in visceral adipose tissue is considered to involve activation of ACC. Therefore, drugs that inhibit ACC not only suppress the new synthesis of long-chain fatty acids and neutral fats in vivo, but also reduce the pre-existing adipose tissue, thereby causing high fat induced by obesity and obesity. It has potential as a therapeutic and prophylactic agent for various diseases based on blood glucose and insulin resistance.
[0003]
[Problems to be solved by the invention]
The object of the present invention is to obesity and obesity-induced hyperlipidemia, fatty liver and various diseases based on insulin resistance (glucose tolerance, diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic It is to provide a novel compound having ACC activity inhibition effective for the treatment of retinopathy, diabetic macroangiopathy, hypertension, arteriosclerosis). A further object of the present invention is to provide a pharmaceutical composition containing the compound.
[Means for Solving the Problems]
As a result of intensive studies in order to solve such problems, the present inventors have found that an excellent ACC inhibitory activity is found in an N-alkylsulfonyl-substituted amide derivative having a novel skeleton represented by the following general formula (I). As a result, the present invention has been completed. Accordingly, the present invention provides a pharmaceutical composition comprising a novel N-alkylsulfonyl-substituted amide derivative as an active ingredient, particularly an ACC activity inhibitor and a therapeutic pharmaceutical composition using the same.
[0004]
[Chemical 6]
Figure 2005170790
[0005]
(Where R1 is
Substituted or unsubstituted C1-C20 alkyl group, substituted or unsubstituted C2-C20 alkenyl group, substituted or unsubstituted C2-C20 alkynyl group, substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted A substituted aromatic heterocyclic group, a substituted amino group, a substituted or unsubstituted C1-C20 alkoxyl group, a substituted or unsubstituted C2-C20 alkenyloxy group, a substituted or unsubstituted C2-C20 alkynyloxy group, or A group represented by R2-O- (wherein R2 is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group),
Y is a group represented by -CR3 = CR4-, -N = CR3- or -CR3 = N-, or a sulfur atom or an oxygen atom,
In general formula (1), R1, R2, R3, R4, R5, and R6 may be the same or different,
R3, R4, R5, R6 are
Substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted C1-C12 alkyl group, substituted or unsubstituted C2-C12 alkenyl group, substituted or unsubstituted C2-C12 alkynyl group, or substituted, respectively Or an unsubstituted C1-C12 alkoxyl group, a hydrogen atom, a hydroxyl group, a mercapto group, a substituted or unsubstituted C1-C12 substituted amino group, a substituted or unsubstituted C1-C6 alkylthio group, a nitro group, a halogen atom, or A cyano group,
Ring A is a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted cyclic alkyl group, an unsubstituted or substituted cyclic alkenyl group,
X is represented by any one of the general formulas (2), (3), (4), (5), R20,
[0006]
[Chemical 7]
Figure 2005170790
[0007]
[Chemical 8]
Figure 2005170790
[0008]
[Chemical 9]
Figure 2005170790
[0009]
[Chemical Formula 10]
Figure 2005170790
[0010]
R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 in the general formulas (2), (3), (4), (5)
Each may be the same or different, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C2-C12 alkenyl group, a substituted or unsubstituted C2- alkynyl group C12 or a substituted or unsubstituted alkoxyl group having Cl -C 12,, a hydrogen atom, a hydroxyl group, a mercapto group, a substituted or unsubstituted Cl -C 12 substituted amino group, a substituted or unsubstituted C 1 -C 6 An alkylthio group, a nitro group, a halogen atom, or a cyano group,
Z is a group represented by -CR9 = CR10-, -N = CR9- or -CR9 = N-, a sulfur atom or an oxygen atom,
Q is a group represented by -CR9 = N-, a sulfur atom or an oxygen atom,
Ring B is
A substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic ring having 4 to 9 ring members, an unsubstituted or substituted cyclic alkyl group, an unsubstituted or substituted cyclic alkenyl group,
Ring C is
A substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted cyclic alkyl group, an unsubstituted or substituted cyclic alkenyl group except for a pyridine ring, a furan ring, and a thiophene ring,
R20 is
A substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C2-C12 alkenyl group, a substituted or unsubstituted C2-C12 alkynyl group, or a substituted or unsubstituted C1-C12 alkoxyl group, hydrogen An atom, a hydroxyl group, a mercapto group, a substituted or unsubstituted C1-C12 substituted amino group, a substituted or unsubstituted C1-C6 alkylthio group, a nitro group, a halogen atom, or a cyano group,
R7 and R8 are R3, R4, R5, R6 in the general formula (1) or R9, R10, R11, R12, R13 in the general formulas (2), (3), (4), (5). , R14, R15, R16, R17, R18, and R19 are also covalently bonded to form a ring structure. )
[0011]
The present invention provides an ACC activity inhibitor and a pharmaceutical composition containing the N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides obesity, hyperlipidemia, fatty liver, impaired glucose tolerance, diabetes, diabetic complications, comprising the above N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Provided is a prophylactic and / or therapeutic agent or hypoglycemic agent for hypertension and arteriosclerosis.
The present invention also provides obesity and hyperlipidemia comprising the above N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof and any one or two of the following group A drugs as active ingredients. Provided is a preventive and / or therapeutic agent or hypoglycemic agent for fatty liver, impaired glucose tolerance, diabetes, diabetic complications, hypertension, arteriosclerosis.
A: insulin, sulfonylurea, alpha-glycosidase inhibitor, biguanide, PPAR-gamma agonist, PPAR-gamma antagonist, PPAR-alpha agonist, SGLT inhibitor, GLP-1 receptor antagonist, DPP-IV inhibitor, Aldose reductase inhibitor, diabetic neuropathy treatment, HMG-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, beta blocker, α1 blocker, Diuretics, anti-obesity drugs, low-energy diet.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
The N-alkylsulfonyl-substituted amide derivative of the present invention will be described in further detail.
In the present specification, the “C1 to C12 alkyl group” may be linear, branched or cyclic, and may be methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 1 -Methylpropyl, 1,1-dimethylethyl, cyclobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, cyclopentyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 4-methyl Pentyl, 1-ethylbutyl, 2-ethylbutyl, 3,3-dimethylbutyl, cyclohexyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 5-methylhexyl, 4,4-dimethylpentyl, 1-propylbutyl, 2-ethylpentyl, cyclohexylmethyl, 1,1-diethylpropyl, cycloheptyl, n-octyl 1-methyloctyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 2-hexylethyl, 5,5-dimethylhexyl, cyclooctyl, n-nonyl, 1-methyloctyl, 7-methyloctyl, 6, 6-dimethylheptyl, n-decyl, 1-methylnonyl, 8-methylnonyl, 7,7-dimethyloctyl, n-undecacyl, 1-methyldecyl, 1-methyldecyl, 9-methyldecyl, 8,8-dimethylnonyl, n-dodecyl 1-methylundecyl, 10-methylundecyl, 5-methylundecyl, 9,9-dimethyldecyl and the like. Among these, a C1-C9 alkyl group is preferable. These alkyl groups may be further substituted with various substituents. Such substituents include halogen atoms such as chlorine, bromine, iodine, fluorine, silyl groups, nitro groups, amino groups, cyano groups, hydroxyl groups, alkoxy groups, thiol groups, trichloromethyl groups, trifluoromethyl groups, phenyls. And aromatic hydrocarbon groups such as naphthyl group, and aromatic heterocyclic groups such as thienyl, furyl, and pyridyl groups. These aromatic hydrocarbon and aromatic heterocyclic groups further include the halogen atom, halogenated alkyl group, halogenated alkoxy group, alkyl group, alkoxy group, thiol group, nitro group, alkylamino group, amino group. Further, it may have a substituent such as a cyano group or a hydroxyl group.
The “C1-C20 alkyl group” may be linear, branched or cyclic, and in addition to the above examples, dodecyl, tetradecyl, pentadecyl, hexadecyl, pentadecyl, octadecyl, nonadecyl, icosyl and the like These alkyl groups may be further substituted with various substituents. Examples of the substituent include the same substituents as those described above for the “C1-C12 alkyl group”.
[0013]
The “alkenyl group such as C2 to C20, C2 to C12, alkynyl group, alkoxyl group, and alkylthio group” may be either linear cyclic or branched, and can be exemplified as in the case of an alkyl group. These alkenyl group, alkynyl group and alkoxyl group may be further substituted with various substituents. Examples of the substituent include the same substituent as the above-described alkyl group substituent from C1 to C12.
Examples of the alkenyl group, alkynyl group, alkoxyl group and alkylthio group include the following.
Examples of alkenyl groups: 1-methyl-1-propenyl, 1-hexenyl, ethenyl, 4,4-dimethyl-1-pentenyl, decenyl, icocenyl and the like.
Examples of alkynyl groups: 1-propynyl, 2-propynyl, 1,3-hexanyldiynyl, 2-hexynyl, icosatriinyl and the like.
Examples of alkoxy groups: methoxy, ethoxy, n-hexyloxy, 3-methylbutoxy, icosyloxy, nonadecoxy and the like.
Examples of alkylthio groups: methylthio, ethylthio, 2-methyl-2-propylthio, 3-methylbutylthio, n-hexylthio and the like.
[0014]
Further, as the “substituted amino group”, a nitrogen atom substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, A substituted or unsubstituted aromatic hydrocarbon group, or a group obtained by substituting a substituted or unsubstituted aromatic heterocyclic group with 1 or 2 substituents, and these alkyl and alkenyl groups are united with the nitrogen atom to be bonded; , A heterocyclic ring which may contain a 7-membered nitrogen atom, oxygen atom or sulfur atom can also be formed. Examples of the substituted amino group include methylamino, ethylamino, propylamino, diethylamino, 2-propenylanino, 1-piperazinyl, morpholino, thiomorpholino, perhydroazepinyl, phennylamino, naphthylamino, pyridylamino, furyl Amino, thienylamino, piperidino, 1-pyrrolidinyl, 3-butenylamino and the like can be mentioned.
Further, the “substituted or unsubstituted aromatic hydrocarbon group” is monocyclic or polycyclic, and may further have one or more various substituents in the ring. For example, phenyl, methylphenyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl, fluorophenyl, dinitrophenyl, trifluoromethylphenyl, dimethylaminophenyl, mercaptophenyl, α-naphthyl, β-naphthyl group and the like can be mentioned. .
In addition, the “substituted or unsubstituted aromatic heterocyclic group” means a 4-membered ring, 5-membered ring containing at least one hetero atom such as a nitrogen atom, a sulfur atom, an oxygen atom, or a phosphorus atom as a constituent atom, 6-membered ring, 7-membered ring, 8-membered ring or 9-membered ring group, which may be condensed with a benzene ring and further have one or more various substituents on the ring. Examples thereof include pyridyl, furyl, thienyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, imidazolyl, benzimidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrimidyl, pyrazinyl, homopiperazinyl, isoxazolyl, isoindolyl, pyrrolyl and the like. .
[0015]
In the N-alkylsulfonyl-substituted amide derivative represented by the general formula (1) provided by the present invention,
Ring A is an aromatic hydrocarbon group having a substitution position at the 1,2-position, an aromatic heterocyclic group having a substitution position at the 1,2-position, an alkenyl group having a substitution position at the 1,2-position, or 1,1 Any cyclic alkyl group having a substituent at the position is preferred.
Also preferred are N-alkylsulfonyl substituted amide derivatives in which ring A is a substituted or unsubstituted phenyl group.
X is preferably a group represented by any one of the general formulas (2), (3), (4), (5) and R20, and particularly preferably a group represented by the general formula (2) or R20. Further, in the case of the general formula (2), a group in which Z is represented by -CR9 = CR10- is preferable. Here, R9 and R10 are particularly preferably hydrogen atoms. In the case of R20, an ethynyl group substituted with an aryl group is preferred. The aryl group bonded to the ethynyl group preferably has a fluorine atom or a substituent containing a fluorine atom bonded thereto.
R9 to R18 are preferably a halogen atom-substituted C1 to C12 alkyl group or alkoxyl group, particularly preferably a fluorine atom-substituted C1 to C12 alkyl group or alkoxyl group.
Y in the formula (1) is preferably —CR 3 ═CR 4 —, a sulfur atom or an oxygen atom, and particularly preferably —CR 3 ═CR 4 —. In particular, R3 and R4 are preferably hydrogen atoms.
Ring B is
A substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic ring having 4 to 9 members, an unsubstituted or substituted cyclic alkyl group, and an unsubstituted or substituted cyclic alkenyl group. For example, ring B includes the ring shown in the following (6).
[0016]
Embedded image
Figure 2005170790
[0017]
Among these, the ring B is preferably a group represented by a substituted or unsubstituted heterocyclic ring having 4 to 9 ring members, particularly a group represented by a heterocyclic ring having 5 ring members, further a thiazole ring or A group represented by an oxadiazole ring is preferred.
Ring C is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted cyclic alkyl group, or an unsubstituted or substituted cyclic alkenyl group excluding the pyridine ring, furan ring, and thiophene ring. Of these, 5- to 6-membered aromatic heterocyclic groups are preferred.
As preferable compounds as the compound represented by the general formula (1), for example, the following compounds can be exemplified.
[0018]
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Figure 2005170790
[0019]
Embedded image
Figure 2005170790
The N-alkylsulfonyl-substituted amide derivative of the general formula (1) can be synthesized by, for example, a production method represented by the following chemical formula.
[0020]
Embedded image
Figure 2005170790
[0021]
(In the formula, R1, R5, R6, A and X are as defined above, and J is an ordinary ester protecting group used in the synthesis reaction, for example, methyl group, ethyl group, benzyl group, allyl group. D is fluorine, chlorine, bromine, hydroxyl group, N-hydroxysuccinimide group, 4-nitrophenoxy group, pentafluorophenoxy group, etc.)
In step 1 (Step 1), the ester (9) is produced by condensing the amine (7) and the carbonyl compound (8). For example, when (8) is an acid chloride, a method of condensing with an amine (7) in the presence of an appropriate base, or when (8) is a carboxylic acid, p-toluenesulfonic acid chloride, ethyl chlorocarbonate, Examples thereof include a method of condensing with an amine (7) in the presence of a suitable base by forming an acid anhydride with pivaloyl chloride or the like.
In the reaction, it is preferable to use approximately equimolar amounts of amine (7) and carbonyl compound (8). The reaction temperature and reaction time are not limited in general depending on the type of the compound, but the target is obtained in a high yield by reacting for about 0.1 to 25 hours under a temperature condition of about 0 ° C. to the boiling point of the solvent used. A compound can be obtained. The amount of the condensing agent used is preferably about 1.2 times equivalent to the carbonyl compound (8).
Examples of the base used include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen and potassium hydrogen carbonate; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide and potassium tert-butoxide; Trialkylamines such as trimethylamine and triethylamine; Pyridine and dimethylaminopyridine And organic bases or inorganic bases such as pyridines such as picoline and lutidine. The amount of the base used is preferably 1 to 10 times equivalent to the carboxylic acid compound.
[0022]
Step 2 (Step 2) is a step of deprotecting the protecting group of the carboxyl group in the ester compound (9). Usually, the ester compound (9) is dissolved in methanol and THF, lithium hydroxide monohydrate is added and stirred at room temperature for more than 10 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, and 1N hydrochloric acid aqueous solution is added to the residue. Is extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain the desired carboxylic acid. The obtained carboxylic acid was used as a raw material in Step 3 (STEP 3), dissolved in 1.4-dioxane under an argon atmosphere, added with an appropriate carbodiimide-based condensing agent, stirred at about 100 ° C. for 30 minutes, and R1-sulfonamide derivative and An appropriate base was added, and the mixture was further stirred at about 100 ° C. for about 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, washed successively with 2N aqueous hydrochloric acid and saturated brine, and anhydrous After drying with sodium sulfate, the solvent is distilled off under reduced pressure, and the compound of general formula (1) can be obtained from the residue by recrystallization.
Steps 1, 2, and 3 described above can be performed in an inert solvent. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, and the like; benzene, toluene, Aromatic hydrocarbons such as xylene; Hydrocarbons such as cyclopentane and cyclohexane; Halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloroethane and chloroform; Nitriles such as acetonitrile and propionitrile; Esters such as ethyl acetate; N, N-dimethylformamide, dimethyl sulfoxide, etc., or a mixture of these with water can be mentioned.
[0023]
In all the steps described above, if necessary, by subjecting to usual purification means such as filtration, decantation, extraction, washing, solvent distillation, column or thin layer chromatography, recrystallization, distillation, etc. It can be isolated and purified.
The N-alkylsulfonyl substituted amide derivatives represented by the general formula (I) include those in the form of various salts, hydrates and solvates thereof, particularly those in a pharmaceutically acceptable form. .
The present invention includes obesity and obesity-induced hyperlipidemia and various diseases based on insulin resistance (glucose intolerance, diabetes, diabetic), characterized by comprising a compound represented by the general formula (I) Peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, arteriosclerosis) or therapeutic method thereof. Furthermore, the present invention relates to various diseases based on obesity and obesity-induced hyperlipidemia and insulin resistance (glucose tolerance, diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, (Diabetic macroangiopathy, hypertension, arteriosclerosis) is a drug and treatment for the purpose of prevention, treatment, and prevention of progression.
In addition, the compound represented by the general formula (I) and other pharmaceuticals such as antidiabetic drugs and hypoglycemic agents are combined as a mixed preparation or combined into two forms containing each component separately. Some are also included in the present invention.
[0024]
Examples of the drug that can be used in combination with the compound represented by the general formula (I) include insulin, for example, insulin analogs such as lispro and glargine, for example, insulin secretagogues such as glibenclamide, tolbutamide, glipizide and glimepiride, such as nateglinide , Rapid-acting insulin secretagogues such as repaglinide, alpha-glycosidase inhibitors such as acarbose, voglibose, miglitol, biguanides such as metholmin, phenformin, thiazolidine skeletons such as rosiglitazone, pioglitazone, troglitazone, etc. Non-thiazolidine skeleton PPAR-gamma agonists and PPAR-gamma antagonists such as GI-262570, JTT-501 and YM-440, such as clofibrate PPAR-alpha agonists such as SGLT inhibitors such as T-1095, GLP-1 receptor antagonists, hypoglycemic agents such as DPP-IV inhibitors, aldose reductase inhibitors such as epalrestat, fidarestat, generestat, Antidiabetic agents such as mecobalamin, mexitylene, etc., HMG-CoA reductase inhibitors such as pravastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, itavastatin, eg, lipoic acid, probucol, etc. Antihypertensives such as antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, beta blockers, α1 blockers, diuretics, anti-obesity drugs such as orlistat and sibutramine, low-energy foods such as OptiFirst, etc. There is. The existing medicines not illustrated, including diet therapy and exercise therapy, and medicines under development / basic research, etc. are based on obesity and obesity-induced hyperlipidemia and insulin resistance as well as the above-mentioned medicines General formula for the treatment of various diseases (glucose intolerance, diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hyperlipidemia, hypertension, arteriosclerosis) When used in combination with the compound represented by (I), it is included in the present invention.
[0025]
When a medicine containing a compound represented by the general formula (I) is administered to humans, it varies depending on the age, symptoms of the target disease, etc., but is preferably about 0.01 to 1000 mg of the compound of the general formula (I) per preparation. Can be contained. Actually preferred administration method, order and interval depend on the formulation of the individual drug used, the onset of drug effect, the condition of the individual patient being treated (weight, body fat percentage, body mass index, blood biochemical index, etc.) It can be selected as appropriate using conventional techniques and in view of the information described herein. That is, more preferably, the compound represented by the general formula (I) is preferably administered orally in an effective amount, for example, usually 1 to 100 mg per day divided into 1 to 3 times.
In the combined use of the general formula (I) and other agents, both can be administered simultaneously, or can be administered at different times. For each drug, administration up to 3 times a day is preferred, and treatment can be repeated as long as no contraindications associated with continuous administration are observed and until a goal set in an individual patient is achieved.
[0026]
The medicament containing the general formula (I) can be made into various dosage forms such as tablets, capsules, granules, powders, troches, liquids and the like for oral administration. These preparations can be carried out by a method known per se. For example, the compound of the above general formula (I) of the present invention is mixed with an excipient such as starch, mannitol or lactose; a binder such as sodium carboxymethyl cellulose or hydroxypropyl cellulose; a disintegrant such as crystalline cellulose or carboxymethyl cellulose; Tablets, capsules, granules, powders, lozenges, and the like can be produced by appropriately combining a lubricant such as magnesium acid; and a fluidity improver such as light anhydrous silicic acid. Moreover, the pharmaceutical of this invention can also be used as an injection. This preparation may be preliminarily dispersed or solubilized in a water carrier such as physiological saline with a surfactant or a dispersing agent, or may be dispersed or solubilized whenever necessary. Alternatively, it may be a crystal preparation for injection or a lyophilized preparation. A pH adjuster or a stabilizer may be added as an optional component to the water carrier. The dose and route of administration of such an injection are not particularly limited, and a safe and necessary amount administered intravenously, intraarterially, subcutaneously or intraperitoneally according to the medical condition or patient characteristics, at once or by infusion. Can do.
[0027]
In the combined use of general formula (I) and other agents, it is not necessary to include all active ingredients in the same preparation, and each ingredient or a plurality of ingredients can be contained in one or more appropriate preparations. In that case, it can be prepared in various forms of pharmaceutical preparations known or developed in the future, for example, oral administration preparations, injections, etc., but known or future-developed methods are appropriately employed for the preparation. be able to.
【Example】
EXAMPLES Next, although an Example demonstrates this invention further in detail, this invention is not limited at all by these Examples. Hereinafter, synthesis examples and pharmacological test examples are described.
[0028]
Synthesis Example 1 (Synthesis example of a compound whose structure is shown below)
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Figure 2005170790
[0029]
Dissolve ethyl 4-iodobenzoate (1.11 g, 4.03 mmol) in diethylamine (10 ml) and add 3-ethynyl-α, α, α-trifluorotoluene (1.03 g, 6.05 mmol), dichlorobistriphenylphosphine under argon atmosphere. Palladium (28.3 mg, 0.0403 mmol) and copper iodide (15.4 mg, 0.0806 mmol) were added and stirred at 50 ° C. for 1 hour. After completion of the reaction, diethylamine was distilled off under reduced pressure, 1N-hydrochloric acid was added to the residue, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.28 g (yield> 99%) of ethyl ester which is a synthetic intermediate of Example 1.
1H-NMR (CDCl3): 1.42 (3H, t, J = 7.2Hz), 4.40 (2H, q, J = 7.2), 7.50 (1H, dd, J = 7.5), 7.58-7.61 (3H, m), 7.60 (2H, d, J = 8.7), 7.71 (1H, d, J = 7.5), 7.81 (1H, S), 8.05 (2H, d, J = 8.7)
continue,
The obtained ethyl ester (1.28 g, 4.03 mmol) was dissolved in methanol (10 ml) and THF (15 ml), 2N-NaOH (3.0 ml, 6.05 mmol) was added, and the mixture was stirred at room temperature for 1.5 h. After completion of the reaction, the reaction solution was acidified by adding 1N-HCl, the solvent was distilled off under reduced pressure, and a large amount of H2O was added to the residue and left overnight. The precipitated crystals were filtered to obtain 1.06 g (yield 91%) of carboxylic acid, which is a synthetic intermediate of Example 1.
1H-NMR (DMSO): 7.70-7.73 (1H, m), 7.72 (2H, d, J = 8.4), 7.82 (1H, dd, J = 8.7), 7.91 (1H, dd, J = 7.5), 7.97 (1H, S), 7.99 (2H, d, J = 8.4) Subsequently, 3 ml of thionyl chloride was added to 517 mg (1.78 mmol) of the obtained carboxylic acid under an argon atmosphere, and the mixture was stirred at 60 ° C. for 2 hours, and then thionyl chloride. Was distilled off under reduced pressure. The residue was dissolved in 6 ml of methylene chloride, and this was added dropwise to a 10 ml pyridine solution of 0.230 ml (1.78 mmol) of Anthranilic acid methylester at 0 ° C. After stirring at room temperature for 20 hours, pyridine was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 2N-HCl aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Subsequently, the residue was dissolved in methanol (10 ml) and THF (15 ml), a large excess of LiOH.H2O was added, and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the solvent was evaporated under reduced pressure, 1N-hydrochloric acid was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization to give 556 mg (76% yield) of the corresponding carboxylic acid.
[0030]
Subsequently, under an argon atmosphere, the obtained carboxylic acid 502 mg (1.23 mmol) was dissolved in 1.4-Dioxane 20 ml, WSC / HCl 280 mg (1.47 mmol) was added and stirred at 94 ° C. for 30 minutes, butane-1-sulfonic acid amide 202 mg (1.47 mmol) and DBU 0.368 ml (2.46 mmol) were added and stirred at 94 ° C. for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was diluted with 25 ml of ethyl acetate, washed successively with 2N-HCl aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by PTLC to obtain 479 mg (yield 74%) of the desired Example 1 compound.
1H-NMR (DMSO): 0.88 (3H, t, J = 7.2Hz), 1.34-1.40 (2H, m), 1.60-1.65 (2H, m), 2.93 (2H, t, J = 7.5), 6.69- 3.70 (1H, m), 7.18-7.23 (1H, m), 7.44-7.96 (6H, m), 8.04-8.26 (2H, m), 8.61-8.64 (1H, m), 8.88-8.89 (1H, m ), 12.73 (1H, s)
MS (ESI) m / z: 529.31 (MH +)
[0031]
Synthesis Example 2 (Synthesis example of a compound whose structure is shown below)
Embedded image
Figure 2005170790
Synthesis of benzoic acid shown below having a thiazole ring, which is a synthetic intermediate of Synthesis Example 2.
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Figure 2005170790
[0033]
2.0 g of Wang resin (0.91 mmol / g) was suspended in NMP and left at room temperature for 3 hours. Excess solvent was removed, 30 ml of NMP, 1.6 g of 4-cyanobenzoic acid, 1.45 ml of pyridine, 1.56 ml of 2,6-dichlorobenzoyl chloride were added thereto, and the mixture was stirred at room temperature for 20 hours. The solvent was removed and the resin was further washed twice with 30 ml of NMP. After removing the solvent, 30 ml each of dichloromethane, NMP, and dichloromethane was used in this order, and the mixture was washed 3 times, and the resin was further dried.
Subsequently, 50 ml of THF: water = 4: 1 solution was added to the obtained resin, and further 10 ml of dithiophosphoric acid O, O-diethyl ester was added, followed by stirring at 80 ° C. for 12 hours. The solvent was removed and the resin was washed twice with 30 ml NMP. After removing the solvent, 30 ml each of dichloromethane, NMP, and dichloromethane were used in this order, and the mixture was washed 3 times, and the resin was further dried.
continue,
To the obtained thioamide resin, 50 ml of NMP was added, and 2.5 g of 4- (trifluoromethoxy) phenanthyl bromide was further added, followed by stirring at 80 ° C. for 12 hours. The solvent was removed and the resin was further washed twice with 30 ml of NMP. After removing the solvent, 30 ml each of dichloromethane, NMP, and dichloromethane was used in this order, and the mixture was washed 3 times, and the resin was further dried. To the obtained resin, 50 ml of 100% trifluoroacetic acid was added and allowed to stand for 1 hour. The reaction solution and the resin were filtered off, and the reaction solution was concentrated under reduced pressure to obtain a thiazole ring, which is a synthetic intermediate of Synthesis Example 2. 0.93 g of benzoic acid having
[0034]
Subsequently, 3 ml of thionyl chloride was added to 679 mg (1.86 mmol) of the obtained benzoic acid in an argon atmosphere, and the mixture was stirred at 60 ° C. for 3 hours, and then thionyl chloride was distilled off under reduced pressure. The residue was dissolved in 6 ml of methylene chloride, which was added dropwise to a 10 ml pyridine solution of 0.240 ml (1.86 mmol) of Anthranilic acid methylester at 0 ° C. and stirred at room temperature for 15 hours, and then pyridine was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 2N-HCl aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization to obtain 568 mg (yield 61%) of the ester compound.
Subsequently, 568 mg (1.14 mmol) of the obtained ester was dissolved in methanol (20 ml) and THF (20 ml) under an argon atmosphere, 239 mg (5.70 mmol) of LiOH.H2O was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. To the residue was added 1N-HCl aqueous solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain 549 mg (99% yield) of carboxylic acid.
Subsequently, 395 mg (0.816 mmol) of the obtained carboxylic acid was dissolved in 20 ml of 1.4-dioxane under an argon atmosphere, WSC / HCl 187 mg (0.979 mmol) was added, and the mixture was stirred at 100 ° C. for 30 minutes, butane-1-sulfonic acid amide 134 mg (0.979 mmol), DBU 0.182 ml (1.22 mmol) and a catalytic amount of 2-t-Butylimino-2-diethylamino-1.3-dimethylperhydro-1.3.2-
Diazaphosphorine was added and stirred at 100 ° C. for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was diluted with 25 ml of ethyl acetate, washed successively with 2N-HCl aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain 380 mg (yield 77%) of the desired Example 2 compound.
1H-NMR (DMSO): 0.84 (3H, t, J = 7.2Hz), 1.33-1.43 (2H, m), 1.61-1.76 (2H, m), 2.92-2.97 (2H, m), 6.70-6.74 ( 1H, m), 7.25-7.30 (1H, m), 7.48-7.52 (2H, m), 7.58-7.64 (1H, m), 7.77-7.82 (1H, m), 8.08-8.28 (7H, m), 8.37 (1H, s)
MS (ESI) m / z: 604 (MH +)
[0035]
Synthesis Example 3 (Synthesis example of a compound whose structure is shown below)
Embedded image
Figure 2005170790
[0036]
Under an argon atmosphere, 3 ml of thionyl chloride was added to 703 mg (2.35 mmol) of carboxylic acid synthesized using the corresponding raw material in the same manner as in Example 2, and the mixture was stirred at 60 ° C. for 2 hours, and then thionyl chloride was distilled off under reduced pressure. . The residue was dissolved in 6 ml of methylene chloride, which was added dropwise to a 10 ml pyridine solution of 0.304 ml (2.35 mmol) of Anthranilic acid methylester at 0 ° C. and stirred at room temperature for 2 hours, and then pyridine was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 2N-HCl aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50 ml) and THF (50 ml), a large excess of 4N-NaOH was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, 1N-hydrochloric acid was added, the organic solvent was distilled off under reduced pressure, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain 713 mg (73% yield) of carboxylic acid.
Subsequently, 713 mg (1.70 mmol) of the obtained carboxylic acid was dissolved in 20 ml of 1.4-dioxane under an argon atmosphere, and 421 mg (2.21 mmol) of WSC / HCl was added and stirred at 100 ° C. for 30 minutes, butane-1-sulfonic acid amide 280 mg (2.04 mmol), DBU 0.432 ml (2.89 mmol) and a catalytic amount of 2-t-Butylimino-2-diethylamino-1.3-dimethylperhydro-1.3.2-diazaphosphorine were added and stirred at 100 ° C. for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 25 ml of ethyl acetate, washed successively with 2N-HCl aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain 659 mg (yield 72%) of the target compound of Example 2.
1H-NMR (DMSO): 0.82 (3H, t, J = 7.2Hz), 1.31-1.38 (2H, m), 1.66-1.74 (2H, m), 2.80-2.97 (2H, m), 6.69-6.72 ( 1H, m), 7.25-7.35 (3H, m), 7.55-7.62 (1H, m), 7.75-7.77 (1H, m), 8.09-8.35 (9H, m) MS (ESI) m / z: 538.22 ( MH +)
[0037]
Synthesis Example 4 (Synthesis example of a compound having a structure shown below)
Embedded image
Figure 2005170790
[0038]
4- (3-trifluoromethylphenylethenyl) benzoic acid synthesized in Synthesis Example 1 872 mg (3.00 mmol), 1-aminocyclopentanecarboxylic acid methyl ester hydrochloride 851 mg (4.74 mmol), 2-chloro-1- 5 ml of methylpyridinium iodide 1160 mg (4.54 mmol) and triethylamine 1.3 ml were dissolved in dry dichloromethane and stirred overnight at room temperature. The organic layer extracted by adding 20 ml of 1M hydrochloric acid and 30 ml of ethyl acetate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 5 ml of ethyl acetate and 25 ml of hexane were added and the precipitated solid was collected by filtration to obtain 955 mg (2.30 mmol) of the ester compound as a white powder (yield 77%).
Subsequently, 955 mg (2.30 mmol) of the ester compound was dissolved in 10 ml of ethanol and 10 ml of 1,4-dioxane, 10 ml of 4M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 8 hours. The organic layer extracted by adding 50 ml of 1M hydrochloric acid and 150 ml of ethyl acetate was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 920 mg (2.29 mmol) of carboxylic acid as a white powder (99% yield).
Subsequently, the obtained carboxylic acid 598 mg (1.49 mmol), n-pentanesulfonamide 309 mg (2.04 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene 0.50 ml (3.34 mmol), WSC 469 mg (2.45 mmol) of hydrochloride was dissolved in 5 ml of dry 1,4-dioxane and stirred at 80 ° C. overnight. After allowing to cool, 5 ml of 1M hydrochloric acid and 5 ml of ethyl acetate were added and the layers were separated after stirring. The organic layer was washed with 2 ml of 1M hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification by column chromatography (silica gel, dichloromethane: THF = 30: 1), concentration to dryness under reduced pressure, suspension in ethyl acetate: hexane (1:10) and filtration, synthesis of 486 mg (0.909 mmol) Example 4 The compound was obtained as a white powder (yield 61%). MS (ESI) m / z: 535 (MH +)
Synthesis Examples 5 to 8 (Synthesis examples of compounds whose structures are shown below)
[0039]
Embedded image
Figure 2005170790
Figure 2005170790
In the same manner as in Example 4, synthesis was performed using the corresponding raw materials.
[0040]
Synthesis Example 9 (Synthesis example of compound having structure shown below)
Embedded image
Figure 2005170790
In the same manner as in Example 4, synthesis was performed using the corresponding raw materials. MS (ESI) m / z: 509 (MH +)
[0041]
Synthesis Example 10 (Synthesis example of a compound whose structure is shown below)
Embedded image
Figure 2005170790
In the same manner as in Example 4, synthesis was performed using the corresponding raw materials. MS (ESI) m / z: 507 (MH +)
[0042]
Synthesis Example 11 (Synthesis example of a compound whose structure is shown below)
Embedded image
Figure 2005170790
In the same manner as in Example 4, synthesis was performed using the corresponding raw materials. MS (ESI) m / z: 650 (MH +)
[0043]
Synthesis Example 12 (Synthesis example of compound having structure shown below)
Embedded image
Figure 2005170790
In the same manner as in Example 4, synthesis was performed using benzoic acid shown below having a thiazole ring which is a synthetic intermediate of Synthesis Example 2. MS (ESI) m / z: 624 (MH +)
[0044]
Pharmacological Test Example 1: Measurement of ACC inhibitory activity Purified male SD rats of ACC were fasted for 2 days, then fed with a high sucrose diet (component) for 2 days, the inferior vena cava was incised under ether anesthesia, and exsanguinated, and the liver was immediately removed. Ice-cold buffer A (225 mM mannitol, 75 mM sucrose, 10 mM Tris-HCl (pH 7.5), 0.05 mM EDTA, 5 mM potassium citrate, 2.5 mM MgCl2, 10 mg / L pepstatin A, 10 mg / L leupeptin , 1 mM PMSF) with a Polytron homogenizer. After adding 9 times the amount of buffer A to the liver weight and centrifuging at 1000 g for 10 minutes, the supernatant was collected and further centrifuged at 17000 g for 10 minutes.
Ammonium sulfate was added to the resulting supernatant to 35% saturation and stirred for 45 minutes, followed by centrifugation at 17000 g for 10 minutes. Buffer B (100 mM Tris-HCl (pH 7.5), 500 mM NaCl, 1 mM EDTA, 0.1 mM DTT, 10% glycerol, 10 mg / L pepstatin A, 10 mg / L leupeptin, 0.5 mM) (PMSF) was added and dissolved, followed by centrifugation at 40000 g for 20 minutes. The supernatant was dialyzed overnight against buffer C (100 mM Tris-HCl (pH 7.5), 500 mM NaCl, 1 mM EDTA, 0.1 mM DTT, 5% glycerol). The dialyzed supernatant was filtered with a 5 μM filter, applied to a monomeric avidin sepharose column, washed with buffer B, and ACC was eluted with buffer B containing 2 mM d-biotin.
[0045]
2. Measurement of ACC inhibitory activity Each of the compounds prepared in the above examples was dissolved in DMSO, placed in a glass vial, and 250 μl of reaction solution 1 (40 mM Tris-HCl (pH 7.5), 40 mM MgCl2, 40 mM) containing ACC. sodium citrate, 2 mM DTT) was added, and the mixture was heated in a thermostatic bath at 37 ° C. for 30 minutes, and then cooled on ice. To reaction solution 1, 250 μl of reaction solution 2 (40 mM Tris-HCl (pH 7.5), 2 mM DTT, 8 mM ATP, 0.5 mM acetyl CoA) containing [14C] -NaHCO 3 was added and incubated at 37 ° C. for 10 minutes. After warming, 100 μl of 1N HCl was added to stop the reaction. After removing water in the reaction solution with a centrifugal evaporator, a scintillator was added to dissolve the solid components, and the 14C radioactivity was measured with a liquid scintillation counter. The ACC inhibitory activity of each compound was calculated from the following formula, and the concentration at which 50% inhibition was obtained (IC50) was determined. The results are shown in Table 1.
ACC inhibition rate (%) = {1 (ac) / (bc)} x 100
a: Radioactivity when the test drug is added
b: Radioactivity when no test drug is added
c: Blank *
* Before mixing reaction solution 1 and reaction solution 2, 100 μl of 1N HCl is added to reaction solution 1 beforehand.
Pharmacological test example 2: Anti-obesity action, hyperlipidemia improvement effect, hypoglycemic action and glucose tolerance improvement effect in diabetic model KK-Ay mice Male KK-Ay mice differ in blood glucose level and plasma triglyceride level between groups The compounds were divided into groups so that they were not, and 58.3 to 175 mg / kg of the compound prepared in the above Example was orally administered by gavage twice a day for 4 days. As a control, KK-Ay mice received only the vehicle. On the last day of administration, plasma triglyceride, blood glucose and body weight were measured under food intake. Furthermore, after fasting overnight after completion of administration, oral glucose tolerance test (2 g / kg glucose was forcibly administered orally and blood glucose was measured over time until 180 minutes after administration) was performed to evaluate glucose tolerance. The anti-obesity action was evaluated by determining the relative body weight as a percentage with the body weight on the first day of administration as 100% (Table 2). Further, the hyperlipidemia improving effect and the hypoglycemic effect were evaluated by obtaining the reduction rate after the end of administration according to the following formula (Table 3: Hyperlipidemic improving effect, Table 4: Hypoglycemic effect).
Plasma triglyceride (or blood glucose) reduction rate (%) = {1-a / b} x 100
a: Plasma triglyceride concentration (or whole blood glucose concentration) in the compound administration group
b: Plasma triglyceride concentration (or whole blood glucose concentration) in the control group
About the body weight glucose tolerance improvement effect, after calculating AUC of blood glucose from the blood glucose transition curve up to 180 minutes after glucose administration, ΔAUC was evaluated as an index. ΔAUC was calculated from the following equation. The results are shown in Table 5.
ΔAUC = (mean AUC of control group)-(mean AUC of compound administration group)
[0047]
[Table 1] Table 1 ACC inhibitory activity
Figure 2005170790
[0048]
[Table 2] Table 2 Anti-obesity activity
Figure 2005170790
[0049]
[Table 3] Table 3 Hyperlipidemia improvement effect
Figure 2005170790
[0050]
[Table 4] Table 4 Hypoglycemic action
Figure 2005170790
[0051]
[Table 5] Table 5 Glucose tolerance improvement effect
Figure 2005170790
[0052]
【The invention's effect】
The N-alkylsulfonyl-substituted amide derivatives of the present invention are based on obesity and obesity-induced hyperlipidemia, fatty liver, and insulin resistance by a mechanism different from conventional anti-obesity drugs and insulin resistance improving drugs. Possible treatment of impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), hypertension and arteriosclerosis It is extremely useful as a therapeutic agent for diseases.

Claims (26)

下記一般式（１）で示されるＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。
Figure 2005170790
（式中、Ｒ１は、
置換もしくは無置換のC1〜C20のアルキル基、置換もしくは無置換のC2〜C20のアルケニル基、置換もしくは無置換のC2〜C20のアルキニル基、置換もしくは無置換の芳香族炭化水素基、置換もしくは無置換の芳香族複素環基、置換アミノ基、置換もしくは無置換のC1〜C20のアルコキシル基、置換もしくは無置換のC2〜C20のアルケニルオキシ基、置換もしくは無置換のC2〜C20のアルキニルオキシ基またはＲ２−O−で表される基（式中、Ｒ２は置換もしくは無置換の芳香族炭化水素基または置換もしくは無置換の芳香族複素環基であり）、
Yは、-CR3=CR4-、-N=CR3-もしくは-CR3=N-で表される基または硫黄原子もしくは酸素原子であり、
一般式（１）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６はそれぞれ同じでも異なってもよく、
Ｒ３、Ｒ４、Ｒ５、Ｒ６は、
それぞれ置換もしくは無置換の芳香族炭化水素基、置換もしくは無置換のC1〜C12のアルキル基、置換もしくは無置換のC2〜C12のアルケニル基、置換もしくは無置換のC2〜C12のアルキニル基、または置換もしくは無置換のC1〜C12のアルコキシル基、水素原子、水酸基、メルカプト基、置換もしくは無置換のC1〜C12の置換アミノ基、置換もしくは無置換のC1〜C6のアルキルチオ基、ニトロ基、ハロゲン原子またはシアノ基であり、
環Aは、置換もしくは無置換の芳香族炭化水素基、置換もしくは無置換の芳香族複素環基、置換もしくは無置換の環状アルキル基、無置換もしくは置換の環状アルケ二ル基であり、
Ｘは、一般式（２）、（３）、（４）、（５）、R２０のいずれかで表され、
Figure 2005170790
Figure 2005170790
Figure 2005170790
Figure 2005170790
一般式（２）、（３）、（４）、（５）中のＲ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、Ｒ１５、Ｒ１６、Ｒ１７、Ｒ１８、Ｒ１９は、
それぞれ同じでも異なってもよく、置換もしくは無置換の芳香族炭化水素基、置換もしくは無置換のC1〜C12のアルキル基、置換もしくは無置換のC2〜C12のアルケニル基、置換もしくは無置換のC2〜C12のアルキニル基、または置換もしくは無置換のC1〜C12のアルコキシル基、水素原子、水酸基、メルカプト基、置換もしくは無置換のC1〜C12の置換アミノ基、置換もしくは無置換のC1〜C6のアルキルチオ基、ニトロ基、ハロゲン原子、またはシアノ基であり、
Ｚは-CR9=CR10-、-N=CR9-もしくは-CR9=N-で表される基または硫黄原子もしくは酸素原子であり、
Ｑは-CR9=N-で表される基または硫黄原子もしくは酸素原子であり、
環Ｂは、
置換もしくは無置換の芳香族炭化水素基、環の員数が４から９の置換もしくは無置換である複素環、無置換または置換の環状アルキル基、無置換または置換の環状アルケニル基を含み、
環Ｃは、
ピリジン環、フラン環、チオフェン環をのぞいた置換もしくは無置換の芳香族複素環基、置換もしくは無置換の環状アルキル基、無置換または置換の環状アルケニル基であり、
Ｒ２０は、
置換もしくは無置換のC1〜C12のアルキル基、置換もしくは無置換のC2〜C12のアルケニル基、置換もしくは無置換のC2〜C12のアルキニル基、または置換もしくは無置換のC1〜C12のアルコキシル基、水素原子、水酸基、メルカプト基、置換もしくは無置換のC1〜C12の置換アミノ基、置換もしくは無置換のC1〜C6のアルキルチオ基、ニトロ基、ハロゲン原子、またはシアノ基であり、
また、Ｒ７とＲ８は、一般式（１）中のＲ３、Ｒ４、Ｒ５、Ｒ６あるいは一般式（２）、（３）、（４）、（５）中のＲ９、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、Ｒ１５、Ｒ１６、Ｒ１７、Ｒ１８、Ｒ１９のいずれかと共有結合して、環構造をとるものも含む。）An N-alkylsulfonyl-substituted amide derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
Figure 2005170790
 (Where R1 is
Substituted or unsubstituted C1-C20 alkyl group, substituted or unsubstituted C2-C20 alkenyl group, substituted or unsubstituted C2-C20 alkynyl group, substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted A substituted aromatic heterocyclic group, a substituted amino group, a substituted or unsubstituted C1-C20 alkoxyl group, a substituted or unsubstituted C2-C20 alkenyloxy group, a substituted or unsubstituted C2-C20 alkynyloxy group, or A group represented by R2-O- (wherein R2 is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group),
Y is a group represented by -CR3 = CR4-, -N = CR3- or -CR3 = N-, or a sulfur atom or an oxygen atom,
In general formula (1), R1, R2, R3, R4, R5 and R6 may be the same or different,
R3, R4, R5, R6 are
Substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted C1-C12 alkyl group, substituted or unsubstituted C2-C12 alkenyl group, substituted or unsubstituted C2-C12 alkynyl group, or substituted, respectively Or an unsubstituted C1-C12 alkoxyl group, a hydrogen atom, a hydroxyl group, a mercapto group, a substituted or unsubstituted C1-C12 substituted amino group, a substituted or unsubstituted C1-C6 alkylthio group, a nitro group, a halogen atom, or A cyano group,
Ring A is a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted cyclic alkyl group, an unsubstituted or substituted cyclic alkenyl group,
X is represented by any one of the general formulas (2), (3), (4), (5), R20,
Figure 2005170790
Figure 2005170790
Figure 2005170790
Figure 2005170790
 R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 in the general formulas (2), (3), (4), (5)
Each may be the same or different, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C2-C12 alkenyl group, a substituted or unsubstituted C2- alkynyl group C12 or a substituted or unsubstituted alkoxyl group having Cl -C 12,, a hydrogen atom, a hydroxyl group, a mercapto group, a substituted or unsubstituted Cl -C 12 substituted amino group, a substituted or unsubstituted C 1 -C 6 An alkylthio group, a nitro group, a halogen atom, or a cyano group,
Z is a group represented by -CR9 = CR10-, -N = CR9- or -CR9 = N-, a sulfur atom or an oxygen atom,
Q is a group represented by -CR9 = N-, a sulfur atom or an oxygen atom,
Ring B is
A substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic ring having 4 to 9 ring members, an unsubstituted or substituted cyclic alkyl group, an unsubstituted or substituted cyclic alkenyl group,
Ring C is
A substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted cyclic alkyl group, an unsubstituted or substituted cyclic alkenyl group except for a pyridine ring, a furan ring, and a thiophene ring,
R20 is
A substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C2-C12 alkenyl group, a substituted or unsubstituted C2-C12 alkynyl group, or a substituted or unsubstituted C1-C12 alkoxyl group, hydrogen An atom, a hydroxyl group, a mercapto group, a substituted or unsubstituted C1-C12 substituted amino group, a substituted or unsubstituted C1-C6 alkylthio group, a nitro group, a halogen atom, or a cyano group,
R7 and R8 are R3, R4, R5, R6 in the general formula (1) or R9, R10, R11, R12, R13 in the general formulas (2), (3), (4), (5). , R14, R15, R16, R17, R18, and R19, and those having a ring structure. ) 環Ａが、１，２位を置換位置とする芳香族炭化水素基、１，２位を置換位置とする芳香族複素環基、１，２位を置換位置とする環状アルケニル基、または１，１位を置換基とする環状アルキル基で示される請求項１記載のＮ−アルキルスルフォニル置換アミド誘導体または医薬的に許容しうる塩。  Ring A is an aromatic hydrocarbon group having a substitution position at the 1,2-position, an aromatic heterocyclic group having a substitution position at the 1,2-position, a cyclic alkenyl group having a substitution position at the 1,2-position, or 1, The N-alkylsulfonyl-substituted amide derivative or pharmaceutically acceptable salt according to claim 1, which is represented by a cyclic alkyl group substituted at the 1-position. 環Aが置換または無置換のフェニル基である請求項１記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。  The N-alkylsulfonyl substituted amide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ring A is a substituted or unsubstituted phenyl group. Ｘが、一般式（２）、（３）、（４）、（５）のいずれかで示される請求項２又は３記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。  The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein X is represented by any one of the general formulas (2), (3), (4) and (5). Ｘが、Ｒ２０で示される請求項２又は３記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。The N-alkylsulfonyl-substituted amide derivative according to claim 2 or 3, wherein X is R20, or a pharmaceutically acceptable salt thereof. Ｘが、Ｒ２０で示され、そのＲ２０が、アリール基が置換したエチニル基である請求項５記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。  6. The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to claim 5, wherein X is represented by R20, and R20 is an ethynyl group substituted with an aryl group. Ｘが、Ｒ２０で示され、そのＲ２０が、フッ素原子またはフッ素原子を含む置換基が結合したアリール基が置換したエチニル基である請求項５記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。  6. The N-alkylsulfonyl substituted amide derivative according to claim 5, wherein X is represented by R20, and R20 is an ethynyl group substituted with a fluorine atom or an aryl group to which a substituent containing a fluorine atom is bonded, or a pharmaceutically acceptable salt thereof. Acceptable salt. Ｘが、一般式（２）で示される請求項２又は３記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。  The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein X is represented by the general formula (2). Ｘが一般式（２）で示され、（２）式中のＺが-CR9=CR10-で示される請求項３記載のＮ−アルキルスルフォニル置換アミド誘導体または医薬的に許容しうる塩。  The N-alkylsulfonyl-substituted amide derivative or pharmaceutically acceptable salt according to claim 3, wherein X is represented by the general formula (2), and Z in the formula (2) is represented by -CR9 = CR10-. Ｘが一般式（２）で示され、（２）式中のＺが-CR9=CR10-で示さ、（１）式中のＹが-CR3=CR4-または硫黄原子もしくは酸素原子で示される請求項３記載のＮ−アルキルスルフォニル置換アミド誘導体または医薬的に許容しうる塩。  Claims in which X is represented by the general formula (2), Z in the formula (2) is represented by -CR9 = CR10-, and Y in the formula (1) is represented by -CR3 = CR4- or a sulfur atom or an oxygen atom. Item 4. An N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt according to Item 3. 一般式（２）の中の環Ｂが、置換もしくは無置換である環の員数が４から９の複素環で示される請求項８記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。  The N-alkylsulfonyl-substituted amide derivative according to claim 8 or a pharmaceutically acceptable salt thereof, wherein ring B in formula (2) is a substituted or unsubstituted heterocyclic ring having 4 to 9 members. Uru salt. 一般式（２）の中の環Ｂが、置換もしくは無置換である環の員数が５の複素環で示される請求項８記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容しうる塩。  The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to claim 8, wherein ring B in general formula (2) is a substituted or unsubstituted heterocyclic ring having 5 members. . 一般式（２）の中の環Ｂが、チアゾール環もしくはオキサジアゾール環で示される請求項８記載のＮ−アルキルスルフォニル置換アミド誘導体または医薬的に許容しうる塩。  The N-alkylsulfonyl substituted amide derivative or pharmaceutically acceptable salt according to claim 8, wherein ring B in formula (2) is a thiazole ring or an oxadiazole ring. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とするACC活性阻害剤。  An ACC activity inhibitor comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする肥満症の予防および/または治療薬。  A prophylactic and / or therapeutic agent for obesity comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする高脂血症の予防および/または治療薬。  A prophylactic and / or therapeutic drug for hyperlipidemia comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする脂肪肝の予防および/または治療薬。  A prophylactic and / or therapeutic drug for fatty liver comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする血糖降下剤。  A hypoglycemic agent comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする耐糖能異常、糖尿病の予防および/または治療薬。  A drug for preventing and / or treating impaired glucose tolerance and diabetes, comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする糖尿病性合併症の予防および/または治療薬。  A prophylactic and / or therapeutic drug for diabetic complications comprising the N-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 as an active ingredient. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする高血圧および動脈硬化症の予防および/または治療薬。  A prophylactic and / or therapeutic drug for hypertension and arteriosclerosis, comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩と、下記A群の薬剤のいずれか一つまたは二つとを有効成分とする肥満症、高脂血症、脂肪肝の予防および/または治療薬。
A：インスリン、スルホニルウレア剤、アルファ-グリコシダ−ゼ阻害剤、ビグアナイド剤、PPAR-ガンマアゴニスト、PPAR-ガンマアンタゴニスト、PPAR-アルファアゴニスト、SGLT阻害剤、GLP-1受容体アンタゴニスト、DPP-IV阻害剤、アルドース還元酵素阻害剤、糖尿病性神経障害治療薬、HMG-CoA還元酵素阻害剤、抗酸化剤、カルシウム拮抗薬、アンジオテンシン変換酵素阻害薬、アンジオテンシンII受容体拮抗剤、ベータ遮断薬、α１遮断薬、利尿剤、抗肥満薬、低エネルギー食。An obesity comprising as an active ingredient the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and one or two of the following group A drugs: , Prevention and / or treatment of hyperlipidemia, fatty liver.
A: insulin, sulfonylurea, alpha-glycosidase inhibitor, biguanide, PPAR-gamma agonist, PPAR-gamma antagonist, PPAR-alpha agonist, SGLT inhibitor, GLP-1 receptor antagonist, DPP-IV inhibitor, Aldose reductase inhibitor, diabetic neuropathy treatment, HMG-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, beta blocker, α1 blocker, Diuretics, anti-obesity drugs, low-energy diet. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩と、下記A群の薬剤のいずれか一つまたは二つとを有効成分とする耐糖能異常、糖尿病、糖尿病性合併症の予防および/または治療薬。
A：インスリン、スルホニルウレア剤、アルファ-グリコシダ−ゼ阻害剤、ビグアナイド剤、PPAR-ガンマアゴニスト、PPAR-ガンマアンタゴニスト、PPAR-アルファアゴニスト、SGLT阻害剤、GLP-1受容体アンタゴニスト、DPP-IV阻害剤、アルドース還元酵素阻害剤、糖尿病性神経障害治療薬、HMG-CoA還元酵素阻害剤、抗酸化剤、カルシウム拮抗薬、アンジオテンシン変換酵素阻害薬、アンジオテンシンII受容体拮抗剤、ベータ遮断薬、α１遮断薬、利尿剤、抗肥満薬、低エネルギー食。Glucose tolerance comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and any one or two of the following group A drugs as active ingredients: Preventive and / or therapeutic drug for abnormalities, diabetes, diabetic complications.
A: insulin, sulfonylurea, alpha-glycosidase inhibitor, biguanide, PPAR-gamma agonist, PPAR-gamma antagonist, PPAR-alpha agonist, SGLT inhibitor, GLP-1 receptor antagonist, DPP-IV inhibitor, Aldose reductase inhibitor, diabetic neuropathy treatment, HMG-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, beta blocker, α1 blocker, Diuretics, anti-obesity drugs, low-energy diet. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩と、下記A群の薬剤のいずれか一つまたは二つとを有効成分とする高血圧、動脈硬化症の予防および/または治療薬。
A：インスリン、スルホニルウレア剤、アルファ-グリコシダ−ゼ阻害剤、ビグアナイド剤、PPAR-ガンマアゴニスト、PPAR-ガンマアンタゴニスト、PPAR-アルファアゴニスト、SGLT阻害剤、GLP-1受容体アンタゴニスト、DPP-IV阻害剤、アルドース還元酵素阻害剤、糖尿病性神経障害治療薬、HMG-CoA還元酵素阻害剤、抗酸化剤、カルシウム拮抗薬、アンジオテンシン変換酵素阻害薬、アンジオテンシンII受容体拮抗剤、ベータ遮断薬、α１遮断薬、利尿剤、抗肥満薬、低エネルギー食。Hypertension comprising as an active ingredient the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and one or two of the following group A drugs: A prophylactic and / or therapeutic drug for arteriosclerosis.
A: insulin, sulfonylurea, alpha-glycosidase inhibitor, biguanide, PPAR-gamma agonist, PPAR-gamma antagonist, PPAR-alpha agonist, SGLT inhibitor, GLP-1 receptor antagonist, DPP-IV inhibitor, Aldose reductase inhibitor, diabetic neuropathy treatment, HMG-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, beta blocker, α1 blocker, Diuretics, anti-obesity drugs, low-energy diet. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩と、下記A群の薬剤のいずれか一つまたは二つとを有効成分とする血糖降下剤。
A：インスリン、スルホニルウレア剤、アルファ-グリコシダ−ゼ阻害剤、ビグアナイド剤、PPAR-ガンマアゴニスト、PPAR-ガンマアンタゴニスト、PPAR-アルファアゴニスト、SGLT阻害剤、GLP-1受容体アンタゴニスト、DPP-IV阻害剤、アルドース還元酵素阻害剤、糖尿病性神経障害治療薬、HMG-CoA還元酵素阻害剤、抗酸化剤、カルシウム拮抗薬、アンジオテンシン変換酵素阻害薬、アンジオテンシンII受容体拮抗剤、ベータ遮断薬、α１遮断薬、利尿剤、抗肥満薬、低エネルギー食。The hypoglycemia which uses the N-alkyl sulfonyl substituted amide derivative of any one of Claims 1-13, or its pharmaceutically acceptable salt, and the any one or two of the following group A chemical | medical agents as an active ingredient. Agent.
A: insulin, sulfonylurea, alpha-glycosidase inhibitor, biguanide, PPAR-gamma agonist, PPAR-gamma antagonist, PPAR-alpha agonist, SGLT inhibitor, GLP-1 receptor antagonist, DPP-IV inhibitor, Aldose reductase inhibitor, diabetic neuropathy treatment, HMG-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, beta blocker, α1 blocker, Diuretics, anti-obesity drugs, low-energy diet. 請求項１〜１３のいずれか１項記載のＮ−アルキルスルフォニル置換アミド誘導体またはその医薬的に許容される塩を有効成分とする医薬組成物。  A pharmaceutical composition comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.
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