JP4782695B2 - Solid preparation with improved solubility and stability and method for producing the same - Google Patents

Description

The present invention relates to a solid preparation having improved solubility and stability and a method for producing the same.
More specifically, a solid preparation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as an active pharmaceutical ingredient,
(1) The poorly water-soluble chemical substance forms a solid dispersion together with the water-soluble polymer substance,
(2) The water-soluble polymer material forming the solid dispersion is in the form of fine pieces, and (3) the fine piece-like water-soluble polymer material is adsorbed on the surface of the inorganic porous material and / or Alternatively, the present invention relates to a solid preparation with improved water solubility, characterized by being held in an adhered state, and a method for producing the same.
The solid preparation of the present invention has excellent solubility, high bioavailability (bioavailability), and can fully exhibit its original activity as an active pharmaceutical ingredient with a very small dose. It is. Therefore, when the solid preparation of the present invention is administered to a patient, the burden on the patient is small and the side effects can be reduced. Furthermore, the present solid preparation has excellent stability, and these solid preparations can be produced very efficiently and easily by the production method of the present invention.
In addition, since the solid preparation of the present invention is rapidly and completely absorbed into the body, if this technique is applied to, for example, a microsome triglyceride transfer protein (MTP) inhibitor, etc., it is simply administered. Superior hyperlipidemia and arteriosclerosis, which are not only effective in reducing the amount and improving bioavailability, but also by reducing side effects such as fatty liver by selectively inhibiting MTP in the target small intestine It can be a therapeutic or prophylactic agent for coronary artery disease, obesity, diabetes or hypertension.

｛式中、Ｒは式（ｉ）

［式中、Ｒ１及びＲ２は同一又は異なっていてもよく、水素原子；炭素数１乃至４個の低級アルキル基；アラルキル基；ベンゾイル基；炭素数３乃至７個のシクロアルキル基；アリール基；又は窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１乃至３個含んでなるヘテロアリール基（ここで、これらシクロアルキル基、アリール基又はヘテロアリール基はハロゲン原子；炭素数１乃至４個の低級アルキル基；炭素数１乃至４個の低級ハロアルキル基；ニトロ基；炭素数１乃至４個の低級アルコキシ基；アミノ基；炭素数１乃至４個の低級アルキル基で置換されたアミノ基；水酸基；フェノキシ基；及びスルホ基から選ばれる１乃至３個の置換基で置換されていてもよい）であり、かつ、Ｒ１又はＲ２の少なくとも一つは水素原子ではない。］、又は式（ｉｉ）

［式中、Ａ及びＢは同一又は異なっていてもよく、芳香族炭化水素環；窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１乃至３個含んでなる芳香族複素環；炭素数３乃至７個のシクロアルカン環；又は炭素数５乃至７個のシクロアルケン環（ここで、これら芳香族炭化水素環、芳香族複素環、シクロアルカン環又はシクロアルケン環はハロゲン原子；炭素数１乃至４個の低級アルキル基；炭素数１乃至４個の低級ハロアルキル基；水酸基；ニトロ基；炭素数１乃至４個の低級アルコキシ基；アミノ基；及び炭素数１乃至４個の低級アルキル基で置換されたアミノ基；及びスルホ基から選ばれる１乃至３個の置換基で置換されていてもよい）であり、Ｘは単結合；直鎖或るいは分枝状の炭素数１乃至４個の低級アルキレン基；直鎖或るいは分枝状の炭素数２乃至４個の低級アルケニレン基（ここで、これら低級アルキレン基又は低級アルケニレン基はハロゲン原子；水酸基；ニトロ基；炭素数１乃至４個の低級アルコキシ基；アミノ基；及びスルホ基から選ばれる基で置換されていてもよい）；酸素原子；硫黄原子；炭素数１乃至４個の低級アルキル基で置換されていてもよいイミノ基；カルボニル基；−Ｏ−Ｚ−；−Ｚ−Ｏ−；−Ｓ−Ｚ−；−Ｚ−Ｓ−；−ＮＨ−Ｚ−；−ＮＲ５−Ｚ−；−Ｚ−ＮＨ−；又は−Ｚ−ＮＲ５−（ここで、Ｚは炭素数１乃至４個の低級アルキレン基；又はカルボニル基であり、Ｒ５は炭素数１乃至４個の低級アルキル基である）であり、Ｙは単結合；直鎖或るいは分枝状の炭素数１乃至４個の低級アルキレン基；又はカルボニル基である］であり、ｎは１乃至４から選ばれる整数であり、Ｒ３及びＲ４は同一又は異なっていてもよく、水素原子；炭素数１乃至４個の低級アルキル基；ハロゲン原子；炭素数１乃至４個の低級ハロアルキル基；水酸基；アミノ基；又はニトロ基である｝
（Ｂ）特表２００４−５１４６７６号公報（ＷＯ２００２／０４２２９１）には下記のごときピペリジン環を有するベンズアミド化合物からなるＭＴＰ阻害物質が記載されている（特許文献１５参照）。

（式中、
Ｚは、２’位、３’位、４’位、５’位および６’位において、トリハロメチルおよびトリハロメトキシから選ばれる１つまたは複数の置換基で場合により置換されたビフェニルを表し、Ｈｅｔは、ハロ、シアノ、ニトロ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_６〜Ｃ_１２）アリール、（Ｃ_１〜Ｃ_６）アルコキシ、ヒドロキシル、（Ｃ_１〜Ｃ_６）チオアルコキシ、カルボキシルおよび（Ｃ_１〜Ｃ_６）アルコキシカルボニルから選ばれる１つまたは複数の置換基で場合により置換されたキノリルまたはキノキサリルまたはピリジルを表す）
（Ｃ）特表２００３−５３５９００号公報（ＷＯ０１／０９７８１０）には、下記式で表されるベンズアミド誘導体からなるＭＴＰ阻害物質が記載されている（特許文献１６参照）。

［式中：Ａは、ＮまたはＣＨであり；
Ｘは、以下の群：（ｉ）１または２個の二重結合を含有していてもよく、かつ１またはそれ以上のヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アシルまたはＣ_１−６アシルオキシ基で置換されていてもよい、−Ｃ_１−６アルキレン−、（ｉｉ）オキソ、スルホニル、チオキソ、（ｉｉｉ）−Ｃ_１−６アルキレンカルボニル−、−Ｃ_１−６アルキレンスルホニル−、−Ｃ_１−６アルキレンチオキソ−、（ｉｖ）−Ｃ_２−６アルキレンオキシ−、−Ｃ_２−６アルキレンチオ−、−Ｃ_２−６アルキレン（Ｎ−ＨまたはＮ−Ｃ_１−６アルキル）アミノ−、（ｖ）−Ｃ_１−６アルキレンカルボキシ−、−Ｃ_１−６アルキレンチオアミド−、−Ｃ_１−６アルキレン（Ｎ−ＨまたはＮ−Ｃ_１−６アルキル）カルボキサミド−、および（ｖｉ）−Ｃ_２−６アルキレンオキシカルボニル−、−Ｃ_２−６アルキレンチオカルボニル−、−Ｃ_２−６アルキレン（Ｎ−ＨまたはＮ−Ｃ_１−６アルキル）アミノカルボニル−からなる群より選択され；
Ｚは、直接結合であるか、または１個の二重結合を含有していてもよく、かつ１またはそれ以上のヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アシルまたはＣ_１−６アシルオキシ基で置換されていてもよい、−Ｃ_１−６アルキレン−であり；
Ｒ^１は、以下の群：（ｉ）水素、Ｃ_１−３ペルフルオロアルキル、（ｉｉ）Ｃ_６−１０アリール、Ｃ_３−８シクロアルキルおよびそれらの縮合ベンズ誘導体、Ｃ_７−１０ポリシクロアルキル、Ｃ４−８シクロアルケニル、Ｃ_７−１０ポリシクロアルケニル、（ｉｉｉ）単環および縮合多環部分より選択されるヘテロサイクリルであり、ここで、該部分は合計５−１４個の環原子を含有し、該部分は酸素、窒素および硫黄から独立して選択される合計１−４個のヘテロ環原子を含有し、該部分の個々の環は、独立して、飽和していても、部分的に不飽和であっても、または芳香族であってもよく、および（ｉｖ）ＸがＣ_１−６アルキレンであり、Ｚが直接結合であるか、またはＺがＣ_１−６アルキレンのいずれかである場合、Ｒ^１は、付加的に、ハロゲン、シアノ、ニトロまたはＣ_１−６アシル基であってもよく、から選択され；
ここで、Ｒ^１が１またはそれ以上の環を含有する場合、該環は、各々独立して、以下の群：（ｉ）ハロゲン、ヒドロキシ、シアノ、ニトロ、ホルミル、Ｃ_１−６アルキルスルホニルアミノ、（ｉｉ）Ｃ_１−６アルキル、Ｃ_３−８シクロアルキル、Ｃ_１−３ペルフルオロアルキル、（ｉｉｉ）Ｃ_１−６アルコキシ、メチレンジオキシ、Ｃ_１−３ペルフルオロアルコキシ、Ｃ_１−６アルキルチオ、（ｉｖ）アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノ、（ｖ）フェニル、フェノキシ、フェニルチオ、ハロフェニルチオ、ベンジル、ベンジルオキシ、（ｖｉ）ヒドロキシカルボニル、Ｃ_１−６アルコキシカルボニル、（ｖｉｉ）アミノカルボニル、Ｃ_１−６アルキルアミノカルボニル、ジ−Ｃ_１−６アルキルアミノカルボニル、ジ−Ｃ_１−６アルキルアミノカルボニルＣ_１−６アルコキシ、Ｃ_１−３ペルフルオロアルキルアミノカルボニル、（ｖｉｉｉ）Ｃ_１−６アシル、Ｃ_１−６アシルオキシ、Ｃ_１−６アシルオキシＣ_１−６アルキル、Ｃ_１−６アシルアミノ、および（ｉｘ）単環部分からなる芳香族ヘテロサイクリルであり、ここで該部分は５−６個の環原子を含有し、該部分は酸素、窒素および硫黄から独立して選択される合計１−４個のヘテロ環原子を含有し、および該ヘテロサイクリル基は、各々、ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４アルコキシ、Ｃ_１−３ペルフルオロアルキルおよびＣ_１−３ペルフルオロアルコキシから独立して選択される１またはそれ以上の基により置換されていてもよく；
から独立して選択される０ないし４個の置換基を有していてもよく、Ｙは、直接またはオキシ結合、−Ｃ_１−６アルキレン−、−オキシＣ_１−６アルキレン−あるいは単環部分からなるヘテロサイクリルであり、ここで、該部分は５個の環原子を含有し、該部分は酸素、窒素および硫黄から独立して選択される合計１−４個のヘテロ環原子を含有し、該環は、独立して、飽和であっても、部分的に不飽和であっても、または芳香族であってもよく；
Ｒ^２は、フェニル、Ｃ_３−８シクロアルキル、あるいは単環部分からなるヘテロサイクリルであり、ここで該部分は５−６個の環原子を含有し、該部分は酸素、窒素および硫黄から独立して選択される合計１−４個のヘテロ環原子を含有し、該環は、独立して、飽和であっても、部分的に不飽和であっても、または芳香族であってもよく、Ｒ^２は、各々、ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４アルコキシ、Ｃ_３−８シクロアルキル、Ｃ_１−３ペルフルオロアルキル、Ｃ_１−３ペルフルオロアルコキシ、ヒドロキシカルボニル、Ｃ_１−６アルコキシカルボニル、シアノ、ニトロ、Ｃ_１−４アルキルアミノスルホニルから独立して選択される１またはそれ以上の基により置換されていてもよく；
Ｒ^３は水素であるか、またはハロゲン、Ｃ_１−４アルキル、Ｃ_１−４アルコキシ、Ｃ_１−３ペルフルオロアルキルまたはＣ_１−３ペルフルオロアルコキシから独立して選択される１またはそれ以上の基を意味する］
（Ｄ）特表２００３−５２１４８４号公報（ＷＯ０１／０４７８９８）には下記式で表される置換ピペラジン誘導体、からなるＭＴＰ阻害物質が記載されている（特許文献１７参照）。

〔式中、ｍは数２又は３を表し、ｎは数１、２、３、４又は５を表し、Ｘは炭素−炭素結合、酸素原子、メチレン基、エチレン基、イミノ基又はＮ−（Ｃ_１−３−アルキル）−イミノ基を表し、Ｒ_ａは二核又は三核芳香族炭化水素（核間メチン基は窒素原子により置換されていてもよい）、炭素原子を介してピペラジノ基に結合された二核又は三核ヘテロ芳香族炭化水素〔これは１個又は２個の窒素原子及びビニレン基を介して縮合されたシクロペンタジエニル環を含む５員ヘテロアリール環（更にメチン基は窒素原子により置換されていてもよく、かつ／又は核間メチン基は窒素原子により置換されていてもよい）、必要によりＣ_１−３−アルキル基、フェニル−Ｃ_１−３−アルキル基、フェニル基、ピリジニル基、ピリダジニル基、ピリミジニル基又はピラジニル基により置換されていてもよいイミノ基、又は酸素原子もしくは硫黄原子、及び１個又は２個の利用できるビニレン基を介して縮合されたフェニル環又は６員ヘテロアリール環（１個、２個又は３個の窒素原子を含み、その縮合環は同じであってもよく、また異なっていてもよい）、又は２個の利用できるビニレン基の一つを介して縮合されたナフチル環を含む５員ヘテロアリール環（更に、こうして形成された二環式基又は三環式基中で、核間炭素原子は窒素原子により置換されていてもよい）、もしくは必要によりＣ_１−３−アルキル基、フェニル−Ｃ_１−３−アルキル基、フェニル基、ピリジニル基、ピリダジニル基、ピリミジニル基又はピラジニル基により置換されていてもよいイミノ基、又は酸素原子もしくは硫黄原子、及び１個又は２個の窒素原子、並びに利用できるビニレン基を介して縮合されたフェニル環、ナフチル環、ピリジン環、ピリダジン環、ピリミジン環又はピラジン環を含む５員ヘテロアリール環（核間炭素原子は窒素原子により置換されていてもよい）、１個、２個又は３個の窒素原子、及びビニレン基を介して縮合されたピリジニル環、ピリダジニル環、ピリミジニル環又はピラジニル環を含むナフチル環又は６員ヘテロアリール環（核間炭素原子は窒素原子により置換されていてもよい）、又はフェニル環及び１個又は２個の利用できるビニレン基を介して縮合された６員ヘテロアリール環（１個、２個又は３個の窒素原子を含む）（これらの縮合環は同じであってもよく、また異なっていてもよく、更にこうして形成された二環式基又は三環式基中で、核間炭素原子は窒素原子により置換されていてもよい）、ピリジン環、ピラジン環又はピリダジン環及び２個の利用できるビニレン基を介して縮合されたフェニル環又は６員ヘテロアリール環（１個、２個又は３個の窒素原子を含む）（これらの縮合環は同じであってもよく、また異なっていてもよく、更にこうして形成された三環式基中で、核間炭素原子は窒素原子により置換されていてもよい）からなる〕を表し、Ｒ_ａに上記された二環式基及び三環式基は更に炭素骨格中でフッ素原子、塩素原子、臭素原子もしくはヨウ素原子、Ｃ_１−３−アルキル基、ヒドロキシ基、Ｃ_１−３−アルコキシ基、カルボキシ基、Ｃ_１−３−アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３−アルキルアミノカルボニル基又はＮ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノカルボニル基により一置換又は二置換されていてもよく、これらの置換基は同じであってもよく、また異なっていてもよく、更に上記アルキル部分及びアルコキシ部分中の水素原子はフッ素原子により全部又は一部置換されていてもよく、Ｒ_ｂ及びＲ_ｃは互いに独立に夫々の場合に水素原子又はＣ_１−３−アルキル基を表し、Ｒ_ｆ及びＲ_ｇ（これらは同じであってもよく、また異なっていてもよい）は水素原子又はＣ_１−６−アルキル基（その水素原子はフッ素原子により全部又は一部置換されていてもよい）、Ｃ_３−７−シクロアルキル基、フェニル基、Ｃ_１−３−アルコキシ−カルボニル−Ｃ_１−２−アルキル基、カルボキシ−Ｃ_１−２−アルキル基、メトキシ−Ｃ_２−３−アルキル基、ヘテロアリール基、フェニル−Ｃ_１−３−アルキル基もしくはヘテロアリール−Ｃ_１−３−アルキル基を表し、上記フェニル基及びヘテロアリール基はその炭素骨格中でフッ素原子、塩素原子もしくは臭素原子、Ｃ_１−３−アルキル基又はＣ_１−３−アルコキシ基（その水素原子はフッ素原子により全部又は一部置換されていてもよい）、ヒドロキシ基、カルボキシ基、Ｃ_１−３−アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３−アルキル−アミノカルボニル基、Ｎ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノカルボニル基、Ｎ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノ基、ニトロ基又はアミノ基により一置換、二置換又は三置換されていてもよく、これらの置換基は同じであってもよく、また異なっていてもよく、かつ／又は上記ヘテロアリール基の窒素原子に結合された水素原子はＣ_１−３−アルキル基（その水素原子はフッ素原子により全部又は一部置換されていてもよい）、Ｃ_１−３−アルキル−カルボニル基又はＣ_１−４−アルコキシ−カルボニル基により置換されていてもよく、又はＲ_ｆ及びＲ_ｇはそれらの間の窒素原子と一緒になって３員〜７員シクロアルキレンイミノ基を表し、６員又は７員シクロアルキレンイミノ基の４位のメチレン基は更に酸素原子もしくは硫黄原子、スルフィニル基、スルホニル基、イミノ基又はＮ−（Ｃ_１−３−アルキル）−イミノ基により置換されていてもよく、上記一般式Ｉ中の三環式基はフッ素原子もしくは塩素原子、メチル基又はメトキシ基により一置換又は二置換されていてもよく、これらの置換基は同じであってもよく、また異なっていてもよい〕
（Ｅ）特表２００３−５２０２７０号公報（ＷＯ０１／０５３２６０）には下記式で表されるベンズアミド誘導体からなるＭＴＰ阻害物質が記載されている（特許文献１８参照）。

〔式中、Ｒ_２−Ｃ、Ｒ_３−Ｃ、Ｒ_４−ＣまたはＲ_５−ＣはＮで置換され得る；
そして、ここでｎは１、２または３；
Ｒ_１はアリール、ヘテロアリールまたは（アリールまたはヘテロアリール）−低級アルコキシ；
Ｒ_２、Ｒ_３、Ｒ_４およびＲ_５は独立して水素、低級アルキル、低級アルコキシ、ハロ、トリフルオロメチルまたはシアノ；
Ｒ_６は

ｍは１、２または３；
Ｒ_７は水素、低級アルキル、（アリールまたはヘテロアリール）−低級アルキル、低級アルコキシ、（アリールまたはヘテロアリール）−低級アルコキシ、ヒドロキシ、オキソ、低級アルキレンジオキシまたは低級アルカノイルオキシ；
ＷはＯ、ＳまたはＮＲ_８；
Ｒ_８は−ＣＯＲ_ａ、

、−ＣＯＯＲ_ｄ、−ＳＯ_２Ｒ_ｅ、水素、所望により置換されていてもよい低級アルキル、アリール、ヘテロアリール（またはアリールまたはヘテロアリール）−低級アルキル；
Ｒ^ａ、Ｒ_ｄおよびＲ_ｅは独立して所望により置換されていてもよい低級アルキル、シクロアルキル、アダマンチル、アリール、ヘテロアリールまたは（アリールまたはヘテロアリール）−低級アルキル；
Ｒ_ｂおよびＲ_ｃは独立して水素、シクロアルキル、所望により置換されていてもよい低級アルキル、アリール、ヘテロアリールまたは（アリールまたはヘテロアリール）−低級アルキル；またはＲ_ｂおよびＲ_ｃは一緒に低級アルキレンを意味する。
（Ｆ）特表２００３−５１９１３１号公報（ＷＯ０１／０４７８９９）には、下記式で表される置換ピペラジン誘導体からなるＭＴＰ阻害物質が記載されている（特許文献１９参照）。

〔式中、ｎは数２、３、４又は５を表し、Ｘは炭素−炭素結合、酸素原子、メチレン基、エチレン基、イミノ基又はＮ−（Ｃ_１−３−アルキル）−イミノ基を表し、Ｙ_ａはカルボニル基又はスルホニル基を表し、Ｙ_ｂは基−（ＣＨ_２）_ｍ−（式中、ｍは数２又は３を表し、水素原子はＣ_１−３−アルキル基により置換されていてもよく、又は窒素原子に結合されたメチレン基はカルボニル基により置換されていてもよい）を表し、Ｒ_ａはＣ_１−６−アルコキシ基、フェニル−Ｃ_１−３−アルコキシ基又はアミノ基（そのアミノ基はＣ_１−３−アルキル基、フェニル−Ｃ_１−４−アルキル基又はフェニル基により一置換又は二置換されていてもよく、置換基は同じであってもよく、また異なっていてもよい）、フェニル基、ナフチル基、テトラヒドロナフチル基、フェノキシ基又はヘテロアリール基、必要によりヒドロキシ基、Ｃ_１−３−アルコキシ基、Ｃ_１−４−アルコキシカルボニル基もしくはＣ_１−４−アルキル−カルボニルオキシ基により置換されていてもよいＣ_１−９−アルキル基（これはそのアルキル部分中でＣ_１−３−アルキル基、１個又は２個のフェニル基、ナフチル基、フルオレニル基、フェノキシ基、ヘテロアリール基又はＣ_３−７−シクロアルキル基により置換されていてもよい）、又はフェニル基により置換されたＣ_３−７−シクロアルキル基、フェニルカルボニル基、ナフチルカルボニル基、テトラヒドロナフチル−カルボニル基、フェノキシカルボニル基又はヘテロアリールカルボニル基、Ｃ_１−９−アルキルカルボニル基（これはそのアルキル部分中で１個又は２個のフェニル基、ナフチル基、フルオレニル基、フェノキシ基、ヘテロアリール基又はＣ_３−７−シクロアルキル基により置換されていてもよい）、又はフェニル基により置換されたＣ_３−７−シクロアルキルカルボニル基を表し、先のＲ_ａに記載された全てのフェニル部分、ナフチル部分及びヘテロアリール部分は基Ｒ^１及びＲ_２により置換されていてもよく、Ｒ_１は水素原子、フッ素原子、塩素原子もしくは臭素原子、シアノ基、Ｃ_１−３−アルキル基、Ｃ_２−４−アルケニル基、フェニル基、ヒドロキシ基、Ｃ_１−４−アルコキシ基、フェニル−Ｃ_１−３−アルコキシ基、カルボキシ基、Ｃ_１−３−アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３−アルキルアミノカルボニル基、Ｎ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノカルボニル基、ニトロ基、アミノ基、Ｃ_１−３−アルキルアミノ基、ジ−（Ｃ_１−３−アルキル）−アミノ基、フェニル−Ｃ_１−３−アルキルアミノ基、Ｎ−（Ｃ_１−３−アルキル）−フェニル−Ｃ_１−３−アルキルアミノ基、Ｃ_１−３−アルキルカルボニルアミノ基、Ｎ−（Ｃ_１−３−アルキル）−Ｃ_１−３−アルキルカルボニルアミノ基、Ｃ_１−３−アルキルスルホニルアミノ基又はＮ−（Ｃ_１−３−アルキル）−Ｃ_１−３−アルキルスルホニルアミノ基を表し、かつＲ_２は水素原子、フッ素原子、塩素原子もしくは臭素原子、Ｃ_１−３−アルキル基、ヒドロキシ基又はＣ_１−４−アルコキシ基を表し、基Ｒ_１及びＲ_２の上記アルキル部分及びアルコキシ部分中で、水素原子はフッ素原子により全部又は一部置換されていてもよく、又はＲ_１及びＲ_２は一緒になってメチレンジオキシ基を表し、又はＲ_ａに上記された全てのフェニル部分は３個の塩素原子もしくは臭素原子又は３〜５個のフッ素原子により置換されていてもよく、Ｒ_ｂはカルボキシ基、Ｃ_１−６−アルコキシカルボニル基、Ｃ_１−６−アルコキシカルボニル−Ｃ_１−３−アルキルカルボニル基、Ｃ_３−７−シクロアルコキシカルボニル基もしくはフェニル−Ｃ_１−３−アルコキシカルボニル基又はＲ_３ＮＲ_４−ＣＯ基を表し、Ｒ_３及びＲ_４（これらは同じであってもよく、また異なっていてもよい）は水素原子、Ｃ_１−６−アルキル基（その水素原子はフッ素原子により全部又は一部置換されていてもよく、またＣ_１−３−アルキルアミノ基のＣ_１−３−アルキル部分はカルボキシ基もしくはＣ_１−３−アルコキシカルボニル基により置換されていてもよく、又はその２位もしくは３位でまたアミノ基、Ｃ_１−３−アルキルアミノ基もしくはジ−（Ｃ_１−３−アルキル）−アミノ基により置換されていてもよい）、Ｃ_３−７−シクロアルキル基、ピリジル基、ピリジニル−Ｃ_１−３−アルキル基、フェニル基、ナフチル基又はフェニル−Ｃ_１−３−アルキル基を表し、上記フェニル基は夫々の場合にフッ素原子、塩素原子もしくは臭素原子、Ｃ_１−３−アルキル基（その水素原子はフッ素原子により全部又は一部置換されていてもよい）、ヒドロキシ基、Ｃ_１−３−アルコキシ基、カルボキシ基、Ｃ_１−３−アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３−アルキルアミノカルボニル基、Ｎ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノカルボニル基又はＮ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノ基により置換されていてもよく、又はＲ_３及びＲ_４はそれらの間の窒素原子と一緒になって３〜７員シクロアルキレンイミノ基を表し、６員又は７員シクロアルキレンイミノ基の４位のメチレン基は更に酸素原子もしくは硫黄原子、スルフィニル基、スルホニル基、イミノ基又はＮ−（Ｃ_１−３−アルキル）−イミノ基により置換されていてもよく、かつＲ_ｃは水素原子又はＣ_１−３−アルキル基を表し、上記一般式Ｉ中の三環式基は更にフッ素原子もしくは塩素原子、メチル基又はメトキシ基により一置換又は二置換されていてもよく、これらの置換基は同じであってもよく、また異なっていてもよく、上記ヘテロアリール基は１個、２個又は３個の窒素原子を含む、６員ヘテロアリール基、又は必要によりＣ_１−３−アルキル基により置換されていてもよいイミノ基、酸素原子もしくは硫黄原子又は必要によりＣ_１−３−アルキル基により置換されていてもよいイミノ基及び１個又は２個の窒素原子或いは酸素原子又は硫黄原子及び窒素原子を含む、５員ヘテロアリール基を意味し、フェニル環がビニレン基を介して上記ヘテロアリール基に縮合されていてもよく、また上記基の定義に記載されたカルボキシ基は生体内でカルボキシ基に変換し得る基又は生理条件下で負に荷電される基により置換されていてもよく、また ２個より多い炭素原子を含むすべての上記飽和アルキル部分及びアルコキシ部分は、特にことわらない限り、直鎖又は分岐であってもよい〕
（Ｇ）特表２００３−５０９５０５、ＷＯ０１／０２１６０４には、下記式で表される置換ピペラジン誘導体からなるＭＴＰ阻害物質が記載されている。（特許文献２０参照）。

（式中、ｎは数１、２、３、４又は５を表し、ｍは数２又は３を表し、Ｘは炭素−炭素結合、酸素原子、メチレン基、エチレン基、イミノ基又はＮ−（Ｃ_１−３−アルキル）−イミノ基を表し、Ｒ_ａは基Ｒ_１及び基Ｒ_２により置換されたフェニル基又はヘテロアリール基を表し、Ｒ_１は水素原子、フッ素原子、塩素原子もしくは臭素原子、Ｃ_１−３−アルキル基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）、ヒドロキシ基、Ｃ_１−４−アルコキシ基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）、フェノキシ基、ヘテロアリールオキシ基、フェニル−Ｃ_１−３−アルコキシ基、カルボキシ基、Ｃ_１−３−アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３−アルキルアミノカルボニル基、Ｎ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノカルボニル基、ニトロ基、アミノ基、Ｃ_１−３−アルキルアミノ基、ジ−（Ｃ_１−３−アルキル）−アミノ基、フェニル−Ｃ_１−３−アルキルアミノ基、Ｎ−（Ｃ_１−３−アルキル）−フェニル−Ｃ_１−３−アルキルアミノ基、Ｃ_１−３−アルキルカルボニルアミノ基、Ｎ−（Ｃ_１−３−アルキル）−Ｃ_１−３−アルキルカルボニルアミノ基、Ｃ_１−３−アルキルスルホニルアミノ基又はＮ−（Ｃ_１−３−アルキル）−Ｃ_１−３−アルキルスルホニルアミノ基を表し、基Ｒ_１の上記フェニル部分又はヘテロアリール部分は１〜５個のフッ素原子、塩素原子もしくは臭素原子、Ｃ_１−３−アルキル基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）、ヒドロキシ基、又はＣ_１−４−アルコキシ基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）により置換されていてもよく、かつＲ_２は水素原子、フッ素原子、塩素原子もしくは臭素原子、Ｃ_１−３−アルキル基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）、又はＣ_１−４−アルコキシ基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）を表し、又はＲ_１及びＲ_２は一緒になってメチレンジオキシ基を表し、又はＲ_ａは単環式ヘテロアリール基又はフェニル基（これは夫々の場合にフェニル基又は単環式ヘテロアリール基により置換されている）を表し、上記フェニル基及びヘテロアリール基は夫々の場合にフッ素原子、塩素原子もしくは臭素原子、Ｃ_１−３−アルキル基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）、ヒドロキシ基、Ｃ_１−３−アルコキシ基、カルボキシ基、Ｃ_１−３−アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３−アルキルアミノカルボニル基又はＮ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノカルボニル基により置換されていてもよく、Ｒ_ｂ及びＲ_ｃは互いに独立に水素原子又はＣ_１−３−アルキル基を表し、かつＲ_ｆ及びＲ_ｇ（これらは同じであってもよく、また異なっていてもよい）は水素原子、Ｃ_１−６−アルキル基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）、Ｃ_３−７−シクロアルキル基、フェニル基、ヘテロアリール基、フェニル−Ｃ_１−３−アルキル基又はヘテロアリール−Ｃ_１−３−アルキル基を表し、上記フェニル基及びヘテロアリール基は夫々の場合に１〜３個のフッ素原子、塩素原子もしくは臭素原子、１〜３個のＣ_１−３−アルキル基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）、１〜３個のヒドロキシ基、１〜３個のＣ_１−３−アルコキシ基（その水素原子はフッ素原子により完全又は部分置換されていてもよい）、又はカルボキシ基、Ｃ_１−３−アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３−アルキルアミノカルボニル基、Ｎ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノカルボニル基、Ｎ，Ｎ−ジ−（Ｃ_１−３−アルキル）−アミノ基、ニトロ基もしくはアミノ基により置換されていてもよく、又はＲ_ｆ及びＲ_ｇはそれらの間の窒素原子と一緒になって３〜７員シクロアルキレンイミノ基を表し、６員又は７員シクロアルキレンイミノ基の４位のメチレン基は更に酸素原子もしくは硫黄原子、スルフィニル基、スルホニル基、イミノ基又はＮ−（Ｃ_１−３−アルキル）−イミノ基により置換されていてもよく、上記一般式Ｉ中の三環式基はフッ素原子もしくは塩素原子、メチル基又はメトキシ基により一置換又は二置換されていてもよく、またこれらの置換基は同じであってもよく、また異なっていてもよく、上記ヘテロアリール基は１個、２個又は３個の窒素原子を含む６員ヘテロアリール基、又は１〜４個のヘテロ原子、例えば、窒素、酸素及び硫黄を含んでもよい５員ヘテロアリール基を意味し、窒素に結合された水素原子は必要によりＣ_１−３−アルキル基により置換されていてもよい）
（Ｈ）特表２００３−５０５３７３号公報（ＷＯ０１／００５７６２）には、下記式で表されるベンズアミド誘導体（ビフェニルアミド誘導体）からなるＭＴＰ阻害物質が記載されている（特許文献２１参照）。

［式中、ｎは１、２、３、４又は５の数であり、Ｒ_ａ及びＲ_ｂは同じでも異なってもよく、各々水素原子、フッ素原子、塩素原子又は臭素原子、Ｃ_１−３アルキル基（ここで、水素原子は全部又は一部がフッ素原子で置換されていてもよい。）、ヒドロキシ基、Ｃ_１−３アルコキシ基、アミノ基、Ｃ_１−３アルキルアミノ基又はジ（Ｃ_１−３アルキル）アミノ基であり、Ｒ_ｃは水素原子、Ｃ_１−１０アルキル、Ｃ_３−７シクロアルキル基又はＣ_３−７シクロアルキル−Ｃ_１−３アルキル基（ここで、それぞれの場合において、水素原子は全部又は一部がフッ素原子で置換されていてもよい。）、フッ素原子、塩素原子又は臭素原子、Ｃ_１−３アルキル基（ここで、水素原子は全部又は一部がフッ素原子で置換されていてもよい。）、ヒドロキシ基、Ｃ_１−３アルコキシ基、Ｃ_１−３アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３アルキルアミノカルボニル基又はＮ，Ｎ−ジ（Ｃ_１−３アルキル）アミノカルボニル基、３〜７員シクロアルキレンイミノ基（ここで、６又は７員シクロアルキレンイミノ基において４位のメチレン基は、酸素原子又はイオウ原子で更に置換されていてもよい。）、スルフィニル基、スルホニル基、イミノ基又はＮ−（Ｃ_１−３アルキル）イミノ基、ニトロ基、アミノ基、Ｃ_１−３アルキルアミノ基、ジ（Ｃ_１−３アルキル）アミノ基、Ｃ_１−３アルキルカルボニルアミノ基、Ｎ−（Ｃ_１−３アルキル）−Ｃ_１−３アルキルカルボニルアミノ基、Ｃ_１−３アルキルスルホニルアミノ基又はＮ−（Ｃ_１−３アルキル）−Ｃ_１−３アルキルスルホニルアミノ基で置換されていてもよいフェニル基、ナフチル基又は単環式５又は６員ヘテロアリール基であり、ここで、６員ヘテロアリール基は窒素原子１個、２個又は３個を有し、５員ヘテロアリール基はＣ_１−３アルキル基、酸素原子又はイオウ原子で置換されていてもよいイミノ基、又はＣ_１−３アルキル基と酸素原子又はイオウ原子又は１個又は２個の窒素原子で置換されていてもよいイミノ基を有し、更に、フェニル環は２つの炭素原子によって上記単環式複素環基と縮合していてもよく、Ｒ_ｄはフッ素原子、塩素原子又は臭素原子、Ｃ_１−３アルキル基（ここで、水素原子は全部又は一部がフッ素原子で置換されていてもよい。）、ヒドロキシ基、Ｃ_１−３アルコキシ基、カルボキシ基、Ｃ_１−３アルコキシカルボニル基、アミノカルボニル基、Ｃ_１−３アルキルアミノカルボニル基又はＮ，Ｎ−ジ（Ｃ_１−３アルキル）アミノカルボニル基、３〜７員シクロアルキレンイミノ基（ここで、６又は７員シクロアルキレンイミノ基において４位のメチレン基は酸素原子又はイオウ原子で更に置換されていてもよい。）、スルフィニル基、スルホニル基、イミノ基又Ｎ−（Ｃ_１−３アルキル）イミノ基、ニトロ基、アミノ基、Ｃ_１−３アルキルアミノ基、ジ（Ｃ_１−３アルキル）アミノ基、Ｃ_１−３アルキルカルボニルアミノ基、Ｎ−（Ｃ_１−３アルキル）Ｃ_１−３アルキルカルボニルアミノ基、Ｃ_１−３アルキルスルホニルアミノ基又はＮ−（Ｃ_１−３アルキル）−Ｃ_１−３アルキルスルホニルアミノ基で置換されていてもよいフェニル基、ナフチル基又は単環式５又は６員ヘテロアリール基であり、ここで、６員ヘテロアリール基は窒素原子１個、２個又は３個を有し、５員ヘテロアリール基はＣ_１−３アルキル基、酸素原子又はイオウ原子で置換されていてもよいイミノ基、又はＣ_１−３アルキル基と酸素原子又はイオウ原子又は１個又は２個の窒素原子で置換されていてもよいイミノ基を有し、更に、フェニル環は２つの隣接した炭素原子によって上記単環式複素環基と縮合していてもよく、Ｒ_ｅはカルボキシ基、Ｃ_１−６アルコキシカルボニル基又はＣ_３−７シクロアルコキシカルボニル基（ここで、それぞれの場合において、酸素原子について２位からのアルキル部分又はシクロアルキル部分はＣ_１−３アルコキシ基、アミノ基、Ｃ_１−３アルキルアミノ基又はジ（Ｃ_１−３アルキル）アミノ基、フェニル−Ｃ_１−３アルコキシカルボニル基又はヘテロアリール−Ｃ_１−３アルコキシカルボニル基で置換されていてもよく、ヘテロアリール部分は上で定義した通りである。）であり、Ｒ_ｆは水素原子、Ｃ_１−３アルキル基又はフェニル−Ｃ_１−３アルキル基であり、Ｒ_ｇは水素原子又はＣ_１−３アルキル基である。］
（Ｉ）特表２０００−５１０４８３、ＷＯ９８／４７８７５には、下記式で表されるベンズアミド誘導体、具体的には４’−トリフルオロメチル−ビフェニル−２−カルボン酸（１，２，３，４−テトラヒドロ−イソキノリン−６−イル）−アミドを有効成分とするＭＴＰ阻害物質が記載されている（特許文献２２参照）。

（Ｊ）特開２００１−１７２１８０号公報には、下記（ｉ）、（ｉｉ）、（ｉｉｉ）、（ｉｖ）で表されるベンズアミド誘導体（ビフェニルアミド誘導体）からなるＭＴＰ阻害物質が記載されている（特許文献２３参照）。
（ｉ）式（１）

上記式中、Ｌは（Ａ）Ｘ−Ｙ−Ｚであり、ここで、Ｘは、ＣＨ_２、ＣＯ、ＣＳまたはＳＯ_２よりなる群から選択される部分であり；Ｙは、直接結合；ヒドロキシ、（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_１０）アシル、（Ｃ_１−Ｃ_１０）アシルオキシ、または（Ｃ_６−Ｃ_１０）アリールでモノ置換されていてもよい２０個以下の炭素原子を有する脂肪族ヒドロカルビレン基；ＮＨ；およびＯよりなる群から選択される部分であり、ただし、ＸがＣＨ_２であるなら、Ｙは直接結合である；そしてＺは、（１）水素、ハロゲン、シアノ、（２）ヒドロキシ、（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_１０）アルキルチオ、（Ｃ_１−Ｃ_１０）アシル、チオフェニルカルボニル、（Ｃ_１−Ｃ_１０）アルコキシカルボニル、（３）（Ｃ_１−Ｃ_１０）アルキルアミノ、ジ（Ｃ_１−Ｃ_１０）アルキルアミノ、（Ｃ_６−Ｃ_１０）アリール（Ｃ_１−Ｃ_１０）アルキルアミノ、ただし、ＹはＯまたはＮＨではない、（４）非置換ビニル、（Ｃ_６−Ｃ_１０）アリール、（Ｃ_３−Ｃ_８）シクロアルキルおよびそれらの縮合ベンズ誘導体、（Ｃ_７−Ｃ_１０）ポリシクロアルキル、（Ｃ_４−Ｃ_８）シクロアルケニル、（Ｃ_７−Ｃ_１０）ポリシクロアルケニル（５）（Ｃ_６−Ｃ_１０）アリールオキシ、（Ｃ_６−Ｃ_１０）アリールチオ、（Ｃ_６−Ｃ_１０）アリール（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_６−Ｃ_１０）アリール（Ｃ_１−Ｃ_１０）アルキルチオ、（Ｃ_３−Ｃ_８）シクロアルキルオキシ、（Ｃ_４−Ｃ_８）シクロアルケニルオキシ、（６）単環式基および縮合多環式基よりなる群から選択される複素環式基、該基は合計５〜１４個の環原子を含み、酸素、窒素および硫黄から独立して選択される合計１〜４個の環複素原子を含み、該基の個々の環は独立して飽和、部分不飽和、または芳香族であってもよく、ただし、ＸがＣＨ_２であるなら、ＺはＨであるかまたは群（４）および（６）から選択される、よりなる群から選択される部分であり、ここで、Ｚが１つ以上の環を含むとき、該環は各々、ハロ、ヒドロキシ、シアノ、ニトロ、オキソ、チオキソ、アミノスルホニル、フェニル、フェノキシ、フェニルチオ、ハロフェニルチオ、ベンジル、ベンジルオキシ、（Ｃ_１−Ｃ_１０）アルキル、（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_１０）アルコキシカルボニル、（Ｃ_１−Ｃ_１０）アルキルチオ、（Ｃ_１−Ｃ_１０）アルキルアミノ、（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、ジ（Ｃ_１−Ｃ_１０）アルキルアミノ、ジ（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、ジ（Ｃ_１−Ｃ_１０）アルキルアミノ（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_３）ペルフルオロアルキル、（Ｃ_１−Ｃ_３）ペルフルオロアルコキシ、（Ｃ_１−Ｃ_１０）アシル、（Ｃ_１−Ｃ_１０）アシルオキシ、（Ｃ_１−Ｃ_１０）アシルオキシ（Ｃ_１−Ｃ_１０）アルキル、およびピロリジニルから独立して選択される０〜４個の置換基を独立して含んでいてもよい；あるいは（Ｂ）Ｇ、ここで、Ｇは下記の基よりなる群から選択される：（ａ）フェニル、または合計３〜１４個の環原子を含む複素環式環、該複素環式環は酸素、窒素および硫黄から独立して選択される合計１〜４個の環複素原子を含み、複素環式環の個々の環は独立して飽和、部分飽和、または芳香族であってもよく、各フェニルまたは複素環式環は、ハロゲン、ヒドロキシ、シアノ、ニトロ、オキソ、チオキソ、アミノスルホニル、フェニル、フェノキシ、フェニルチオ、ベンジル、ベンゾイル、ベンジルオキシ、（Ｃ_１−Ｃ_１０）アルキル、（Ｃ_１−Ｃ_４）ペルフルオロアルキル、（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_４）ペルフルオロアルコキシ、（Ｃ_１−Ｃ_１０）アルコキシカルボニル、（Ｃ_１−Ｃ_１０）アルキルチオ、（Ｃ_１−Ｃ_１０）アルキルアミノ、ジ（Ｃ_１−Ｃ_１０）アルキルアミノ、（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、ジ（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、（Ｃ_１−Ｃ_１０）アシル、（Ｃ_１−Ｃ_４）ペルフルオロアシル、（Ｃ_１−Ｃ_１０）アシルオキシ、（Ｃ_１−Ｃ_６）アシルアミノおよび（Ｃ_１−Ｃ_６）ペルフルオロアシルアミノから独立して選択される１〜４個の置換基を含んでいてもよい；（ｂ）−ＣＨ_２ＣＮ、（ｃ）

（ｄ）下記の置換基から独立して選択される１〜３個の置換基で置換されていてもよい（Ｃ_２−Ｃ_１２）アルキルまたは（Ｃ_２−Ｃ_１２）ペルフルオロアルキル：（１）フェニル、ハロゲン、ニトロ、シアノ、ヒドロキシ、−ＮＲ^１Ｒ^２、−ＯＣＯＲ^３、（Ｃ_１−Ｃ_４）アルコキシ、（Ｃ_１−Ｃ_４）ペルフルオロアルコキシ、（Ｃ_１−Ｃ_４）チオアルコキシまたは（Ｃ_１−Ｃ_４）ペルフルオロチオアルコキシ、ここで、−ＮＲ^１Ｒ^２のＲ^１およびＲ^２は各々、水素、ホルミル、フェニル、ベンジル、ベンゾイル、（Ｃ_３−Ｃ_８）シクロアルキル、（Ｃ_３−Ｃ_８）シクロアルケニル、（Ｃ_１−Ｃ_４）アルキル、（Ｃ_１−Ｃ_４）ペルフルオロアルキル、（Ｃ_１−Ｃ_１０）アルコキシカルボニル、（Ｃ_１−Ｃ_６）アシル、（Ｃ_１−Ｃ_６）ペルフルオロアシル、アミノカルボニル、（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、ジ（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、アミノスルホニル、（Ｃ_１−Ｃ_４）アルキルアミノスルホニル、ジ（Ｃ_１−Ｃ_４）アルキルアミノスルホニル、（Ｃ_１−Ｃ_４）ペルフルオロアルキルアミノスルホニル、ジ（Ｃ_１−Ｃ_４）ペルフルオロアルキルアミノスルホニル、（Ｃ_１−Ｃ_４）アルキルスルホニル、および（Ｃ_１−Ｃ_４）ペルフルオロアルキルスルホニルから独立して選択されるか、あるいはＲ^１およびＲ^２はこれらが結合している窒素原子と一緒になって飽和、部分飽和または芳香族複素環式環を形成し、該複素環式環は合計３〜１４個の環原子を含み、酸素、窒素および硫黄から独立して選択される１〜４個の環複素原子をさらに含んでいてもよく、該複素環式環はハロゲン、ヒドロキシ、シアノ、ニトロ、オキソ、チオキソ、アミノスルホニル、フェニル、フェノキシ、フェニルチオ、ベンジル、ベンゾイル、ベンジルオキシ、（Ｃ_１−Ｃ_１０）アルキル、（Ｃ_１−Ｃ_４）ペルフルオロアルキル、（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_４）ペルフルオロアルコキシ、（Ｃ_１−Ｃ_１０）アルコキシカルボニル、（Ｃ_１−Ｃ_１０）アルキルチオ、（Ｃ_１−Ｃ_１０）アルキルアミノ、ジ（Ｃ_１−Ｃ_１０）アルキルアミノ、（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、ジ（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、（Ｃ_１−Ｃ_１０）アシル、（Ｃ_１−Ｃ_１０）ペルフルオロアシル、（Ｃ_１−Ｃ_１０）アシルアミノ、および（Ｃ_１−Ｃ_１０）アシルオキシから独立して選択される１〜４個の置換基を含んでいてもよく、−ＯＣＯＲ^３のＲ^３は−ＮＲ^１Ｒ^２、フェニル、（Ｃ_１−Ｃ_１０）アルキル、（Ｃ_１−Ｃ_４）ペルフルオロアルキル、（Ｃ_１−Ｃ_６）アルコキシおよび（Ｃ_１−Ｃ_６）ペルフルオロアルコキシから選択される、（２）（Ｃ_３−Ｃ_８）シクロアルキルまたは（Ｃ_３−Ｃ_８）シクロアルケニル、ここで、該（Ｃ_３−Ｃ_８）シクロアルキルまたは（Ｃ_３−Ｃ_８）シクロアルケニルの各々は、ハロゲン、ヒドロキシ、シアノ、ニトロ、オキソ、チオキソ、アミノスルホニル、フェニル、フェノキシ、フェニルチオ、ベンジル、ベンゾイル、ベンジルオキシ、（Ｃ_１−Ｃ_１０）アルキル、（Ｃ_１−Ｃ_４）ペルフルオロアルキル、（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_４）ペルフルオロアルコキシ、（Ｃ_１−Ｃ_１０）アルコキシカルボニル、（Ｃ_１−Ｃ_１０）アルキルチオ、（Ｃ_１−Ｃ_１０）アルキルアミノ、ジ（Ｃ_１−Ｃ_１０）アルキルアミノ、（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、ジ（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、（Ｃ_１−Ｃ_１０）アシル、（Ｃ_１−Ｃ_１０）ペルフルオロアシル、（Ｃ_１−Ｃ_１０）アシルアミノ、（Ｃ_１−Ｃ_１０）ペルフルオロアシルアミノ、および（Ｃ_１−Ｃ_１０）アシルオキシから独立して選択される１〜４個の置換基を含んでいてもよい、
（３）合計３〜１４個の環原子を含む飽和、部分飽和または芳香族複素環式環、ここで、該複素環式環は酸素、窒素および硫黄から独立して選択される合計１〜４個の環複素原子を含み、該複素環式環は、ハロゲン、ヒドロキシ、シアノ、ニトロ、オキソ、チオキソ、アミノスルホニル、フェニル、フェノキシ、フェニルチオ、ベンジル、ベンゾイル、ベンジルオキシ、（Ｃ_１−Ｃ_１０）アルキル、（Ｃ_１−Ｃ_４）ペルフルオロアルキル、（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_４）ペルフルオロアルコキシ、（Ｃ_１−Ｃ_１０）アルコキシカルボニル、（Ｃ_１−Ｃ_１０）アルキルチオ、（Ｃ_１−Ｃ_１０）アルキルアミノ、ジ（Ｃ_１−Ｃ_１０）アルキルアミノ、（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、ジ（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、（Ｃ_１−Ｃ_１０）アシル、（Ｃ_１−Ｃ_１０）ペルフルオロアシル、（Ｃ_１−Ｃ_１０）アシルアミノ、（Ｃ_１−Ｃ_１０）ペルフルオロアシルアミノ、および（Ｃ_１−Ｃ_１０）アシルオキシから独立して選択される１〜４個の置換基を含んでいてもよい、（ｅ）（Ｃ_３−Ｃ_８）シクロアルキルまたは（Ｃ_３−Ｃ_８）シクロアルケニル、ここで、該（Ｃ_３−Ｃ_８）シクロアルキルおよび（Ｃ_３−Ｃ_８）シクロアルケニルの各々は、ハロゲン、ヒドロキシ、シアノ、ニトロ、オキソ、チオキソ、アミノスルホニル、フェニル、フェノキシ、フェニルチオ、ベンジル、ベンゾイル、ベンジルオキシ、（Ｃ_１−Ｃ_１０）アルキル、（Ｃ_１−Ｃ_４）ペルフルオロアルキル、（Ｃ_１−Ｃ_１０）アルコキシ、（Ｃ_１−Ｃ_４）ペルフルオロアルコキシ、（Ｃ_１−Ｃ_１０）アルコキシカルボニル、（Ｃ_１−Ｃ_１０）アルキルチオ、（Ｃ_１−Ｃ_１０）アルキルアミノ、ジ（Ｃ_１−Ｃ_１０）アルキルアミノ、（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、ジ（Ｃ_１−Ｃ_１０）アルキルアミノカルボニル、（Ｃ_１−Ｃ_１０）アシル、（Ｃ_１−Ｃ_１０）ペルフルオロアシル、（Ｃ_１−Ｃ_１０）アシルアミノ、（Ｃ_１−Ｃ_１０）ペルフルオロアシルアミノ、および（Ｃ_１−Ｃ_１０）アシルオキシから独立して選択される１〜４個の置換基を含んでいてもよい、（ｆ）−（ＣＨ_２）_ｎＣＯＲ^４、ここで、−（ＣＨ_２）_ｎＣＯＲ^４のＲ^４は、ヒドロキシ、フェニル、−ＮＲ^１Ｒ^２、（Ｃ_１−Ｃ_４）アルキル、（Ｃ_１−Ｃ_４）ペルフルオロアルキル、（Ｃ_１−Ｃ_４）アルコキシ、（Ｃ_１−Ｃ_４）ペルフルオロアルコキシ、（Ｃ_３−Ｃ_８）シクロアルキル、および（Ｃ_３−Ｃ_８）シクロアルケニルから選択され、ｎは１〜４の整数である。
（ｉｉ）ＢＭＳ−１９７６３６（９−［４−［４−（２，３−ジヒドロ−１−オキソ−１Ｈ−イソインドール−２−イル）−１−ピペリジニル］ブチル］−Ｎ−プロピル−９Ｈ−フルオレン−９−カルボキサミド）およびその薬学的に許容される塩。
（ｉｉｉ）化合物ＢＭＳ−２００１５０（２−［１−（３，３−ジフェニルプロピル）−４−ピペリジニル］−２，３−ジヒドロ−１Ｈ−イソインドール−１−オン）およびその薬学的に許容される塩。
（ｉｖ）化合物ＢＭＳ−２０１０３８（９−［４−（４−［２−（４−トリフルオロメチルフェニル）ベンゾイルアミノ］ピペリジン−１−イル）ブチル］−Ｎ−２，２，２−トリフルオロエチル）−９Ｈ−フルオレン−９−カルボキサミド）およびその薬学的に許容される塩。
また、同特許文献２３には、以下の化合物が具体例として記載されている。
・４’−トリフルオロメチル−ビフェニル−２−カルボン酸−（２−ブチル−１，２，３，４−テトラヒドロイソキノリン−６−イル）−アミド、
・４’−トリフルオロメチル−ビフェニル−２−カルボン酸−［２−（２−アセチルアミノエチル）−１，２，３，４−テトラヒドロイソキノリン−６−イル）−アミド、
・９−［４−［４−（２，３−ジヒドロ−１−オキソ−１Ｈ−イソインドール−２−イル）−１−ピペリジニル］ブチル］−Ｎ−プロピル−９Ｈ−フルオレン−９−カルボキサミド、
・２−［１−（３，３−ジフェニルプロピル）−４−ピペリジニル］−２，３−ジヒドロ−１Ｈ−イソインドール−１−オン、
（Ｋ）特開２０００−１６９３９５号公報には、下記のごときベンズアミド誘導体からなるＭＴＰ阻害物質が記載されている（特許文献２４参照）。
・４’−トリフルオロメチル−ビフェニル−２−カルボン酸−［２−（１Ｈ−［１，２，４］トリアゾール−３−イルメチル）−１，２，３，４−テトラヒドロイソキノリン−６−イル］−アミド、
・４’−トリフルオロメチル−ビフェニル−２−カルボン酸−［２−（２−アセチルアミノエチル）−１，２，３，４−テトラヒドロイソキノリン−６−イル］−アミド、
・９−（４−［４−［４’−トリフルオロメチル−ビフェニル−２−カルボニル）アミノ］−ピペリジン−１−イル｝ブチル）−９Ｈ−フルオレン−９−カルボン酸−（２，２，２−トリフルオロエチル）−アミド、
・９−［４−［４−（２−ベンゾチアゾール−２−イル−ベンゾイルアミノ）ピペリジン−１−イル］ブチル］−９Ｈ−フルオレン−９−カルボン酸−（２，２，２−トリフルオロエチル）アミド、
・［１１ａ−Ｒ］−８−［（４−シアノフェニル）メトキシ］−２−シクロペンチル−７−（プロプ−２−エニル）−２，３，１１，１１ａ−テトラヒドロ−６Ｈ−ピラジノ［１，２ｂ］イソキノリン−１，４−ジオン、
・［１１ａ−Ｒ］−２−シクロペンチル−７−（プロプ−２−エニル）−８−［（ピリジン−２−イル）メトキシ］−２，３，１１，１１ａ−テトラヒドロ−６Ｈ−ピラジノ［１，２ｂ］イソキノリン−１，４−ジオン、
・２−シクロペンチル−２−［４−（２，４−ジメチルピリド［２，３−ｂ］インドール−９−イルメチル）フェニル］−Ｎ−（２−ヒドロキシ−１−フェニルエチル）アセトアミド、
・２−シクロペンチル−Ｎ−（２−ヒドロキシ−１−フェニルエチル）−２−［４−（キノリン−２−イルメトキシ）−フェニル］アセトアミド。
２−３．ＭＴＰ阻害物質における課題
ところで、上記のとおり様々なＭＴＰ阻害物質が知られるようになったが、一方では、ＭＴＰの阻害薬の開発が進められるにつれて、ＭＴＰ阻害物質は血中脂質の低下作用を発揮するものの、肝臓への脂肪蓄積（脂肪肝）を惹起する可能性が指摘され、肝毒性が懸念されるようになった（特許文献２５参照）。
このようなことから、脂肪肝等の副作用のない十分な予防及び治療効果を新規なＭＴＰ阻害薬が強く望まれている。
（Ｌ）最近では小腸のＭＴＰを選択的に阻害する化合物の研究も盛んに行われており、特開２００３−３２１４２４公報には下記一般式（１）で表される小腸選択的なＭＴＰ阻害のための化合物も報告されている（特許文献２６参照）。
一般式（１）

〔式中、Ｒ^１及びＲ^２は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−７シクロアルキル基、Ｃ_１−６アルコキシ基、ハロＣ_１−６アルキル基、ハロＣ_１−６アルキルオキシ基、置換されてもよいＣ_６−１４アリール基、置換されてもよいＣ_７−１６アラルキル基、置換されてもよいＣ_６−１４アリールオキシ基、置換されてもよいＣ_７−１６アラルキルオキシ基、置換されてもよいＣ_７−１５アリールカルボニル基、置換されてもよいヘテロ環基、Ｃ_２−７アルコキシカルボニル基、ハロゲン原子、Ｃ_２−６アルケニル基、−Ｎ（Ｒ^４０）（Ｒ^４１）（ここで、Ｒ^４０及びＲ^４１は、同一又は異なって水素原子または置換されていてもよいＣ_６−１４アリール基である。）であり；環Ａは、Ｃ_６−１４アリール基、ヘテロ環基、又は

であり；Ｘは、−ＣＯＯ−（ＣＨ_２）_ｎ−、−ＣＯＮ（Ｒ^１０）−（ＣＨ_２）_ｎ−又は−Ｎ（Ｒ^１０）−ＣＯ−（ＣＨ_２）_ｎ−（ここで、Ｒ^１０は、水素原子、Ｃ_１−６アルキル基又はＣ_３−７シクロアルキル基であり、ｎは０又は１乃至３の整数である。）であり；Ｒ^３及びＲ^４は、同一又は異なって水素原子、水酸基、ハロゲン原子、置換されていてもよいＣ_１−６アルキル基、Ｃ_１−６アルコキシ基、ハロＣ_１−６アルキル基、Ｃ_７−１６アラルキルオキシ基、Ｃ_１−６アシル基、置換されていてもよいヘテロ環基、−ＣＯＮ（Ｒ^１１）（Ｒ^１２）（ここで、Ｒ^１１及びＲ^１２は、同一又は異なって水素原子、Ｃ_１−６アルキル基、置換されてもよいＣ_６−１４アリール基、置換されてもよいＣ_７−１６アラルキル基、Ｃ_１−６アルコキシ基であり、又は結合する窒素原子と一緒になって

（ここで、ｐは０又は１乃至２の整数である。）を形成してもよい。）、−（ＣＨ_２）_ｑ−Ｎ（Ｒ^１３）（Ｒ^１４）（ここで、Ｒ^１３及びＲ^１４は、同一又は異なって水素原子、Ｃ_１−６アルキル基、Ｃ_２−７アルコキシカルボニル基、Ｃ_１−６アシル基であり、又は結合する窒素原子と一緒になって

（ここで、ｐは前記と同意義。）を形成してもよい。ｑは０又は１乃至３の整数である。）又は−ＣＯ（Ｒ^１５）（ここで、Ｒ^１５は、水酸基、Ｃ_１−６アルコキシ基、置換されてもよいＣ_６−１４アリールオキシ基、置換されてもよいＣ_７−１６アラルキルオキシ基又はＣ_１−６アルキル基である。）であり；環Ｂは、

（ここでＫは０又は１乃至２の整数である。）であり、又はＲ^３とＲ^１０とＲ^１０がけつごうしている窒素原子と環Ｂが一緒になって、

を形成してもよく；Ａｌｋ１^１はアルカンジイル又はアルケンジイルであり；Ａｌｋ１^２はアルカンジイル又はアルケンジイルであり；ｌは０又は１乃至３の整数であり；ｍは０又は１乃至３の整数であり；Ｄは、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−７アルコキシカルボニル基、−Ｎ（Ｒ^４２）−ＣＯ（Ｒ^４３）（ここで、Ｒ^４２は水素原子又はＣ_{１− ６}アルキル基であり、Ｒ^４３はＣ_６−１４アリール基又はＣ_７−１６アラルキル基である。）又は下記式；

（式中、Ｒ^５、Ｒ^６及びＲ^７は、同一又は異なって水素原子、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_２−７アルコキシカルボニル基、カルボキシル基、ハロゲン原子、シアノ基、ニトロ基、ハロＣ_１−６アルキル基、Ｃ_１−６アシル基、水酸基、アミノ基、置換されてもよいＣ_６−１４アリール基又は−（ＣＨ_２）_ｒ−ＣＯＮ（Ｒ^１６）（Ｒ^１７）（ここで、Ｒ^１６及びＲ^１７は、同一又は異なって水素原子、Ｃ_１−６アルキル基又はハロＣ_１−６アルキル基である。ｒは０又は１乃至３の整数である。）であり；環Ｃは、Ｃ_６−１４アリール基、Ｃ_７−１５アリールカルボニルアミノ基、Ｃ_８−１７アラルキルカルボニルアミノ基、ヘテロ環残基、Ｃ_３−７シクロアルキル基、Ｃ_７−１６アラルキル基、又は環ＣとＲ^７とＲ^８が一緒になって、

を形成してもよい。）で示される基であり；Ｒ^８及びＲ^９は、同一又は異なって水素原子、Ｃ_１−６アルキル基、置換されてもよいＣ_６−１４アリール基、ヒドロキシＣ_１−６アルキル基、−ＣＯＮ（Ｒ^１８）（Ｒ^１９）（ここで、Ｒ^１８及びＲ^１９は、同一又は異なって水素原子、Ｃ_１−６アルキル基、Ｃ_３−７シクロアルキル基、ハロＣ_１−６アルキル基、Ｃ_２−１２アルコキシアルキル基又は置換されてもよいＣ_６−１４アリール基である）、−ＣＯＯ（Ｒ^２０）もしくは−（ＣＨ_２）_ｓ−ＯＣＯ（Ｒ^２０）（ここで、Ｒ^２０は、水素原子、Ｃ_１−６アルキル基又はＣ_３−７シクロアルキル基である。ｓは０又は１乃至３の整数である。）、−Ｎ（Ｒ^２１）（Ｒ^２２）（ここで、Ｒ^２１及びＲ^２２は、同一又は異なって水素原子、Ｃ_１−６アルキル基、Ｃ_１−６アシル基、Ｃ_１−６アルキルスルホニル基、又はＲ^２１及びＲ^２２が結合する窒素原子と一緒になって、

を形成してもよい。）であり、又はＲ^８とＲ^９が一緒になってＣ_３−７シクロアルキル基を形成してもよい。〕で示されるエステル化合物若しくはそのプロドラッグ又はそれらの製薬上許容される塩。
そして、同特許文献には具体的な化合物として下記化合物が記載されている。
・２−（２−｛３−メチル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［メチル−（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジイソプロピル エステル、
・２−フェニル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジメチル エステル、
・２−シクロペンチル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジシクロヘキシル エステル、
・２−ベンジル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛２−メチル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−シクロヘキシル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛２−トリフルオロメチル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−ピリジン−２−イル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−ピリジン−３−イル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛３−トリフルオロメチル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛４−［（４’−メチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（４’−メトキシ−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛４−［（３’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛４−［イソプロピル−（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［シクロヘキシル−（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジプロピル エステル、
・２−フェニル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジイソブチル エステル、
・２−（２−｛４−［エチル−（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−エチル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−イソプロピル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−イソブチル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−クロロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ブロモ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジエチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジイソプロピルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−（エチル−メチルカルバモイル）−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・｛３−（エチル−メチルカルバモイル）−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−酢酸２，２−ビス−エチルカルバモイル−２−フェニル−エチル エステル、
・｛３−（ピロリジン−１−カルボニル）−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−酢酸２，２−ビス−エチルカルバモイル−２−フェニル−エチル エステル、
・２−フェニル−２−（２−｛３−（ピロリジン−１−カルボニル）−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛３−（ピペリジン−１−カルボニル）−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−［２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシ）−エチル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−フルオロ−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（４’−ブロモ−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジメチル エステル、
・２−シクロペンチル−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−シクロヘキシル−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛４−［（４’−クロロ−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（４’−アセチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（４’−シアノ−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［３−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシ）−プロピル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−メトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（５−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジ２，２，２−トリフルオロエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（２’−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ブロモ−５−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−クロロ−５−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（３’−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（３’−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（５−ニトロ−ピリジン−２−イル）−マロン酸 ジエチル エステル、
・２−（５−アミノ−ピリジン−２−イル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ピリジン−２−イル−マロン酸 ジエチル エステル、
・２−（２−｛３−クロロ−５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ブロモ−５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｏ−トリル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｍ−トリル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｐ−トリル−マロン酸 ジエチル エステル、
・２−（２−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（３−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（４−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−コハク酸 ジエチルエステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（２−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（３−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（４−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛４−［（５，４’−ビス−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（６−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［２−（２−｛３−ジメチルカルバモイル−４−［（５−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシ）−エチル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−エトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−イソプロポキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［２−（２−｛４−［（５，４’−ビス−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシ）−エチル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−メトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（３−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−［４−（２，４−ビス−トリフルオロメチル−ベンゾイルアミノ）−３−ジメチルカルバモイル−フェニル］−アセトキシメチル｝−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−メチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−｛２−［３−ジメチルカルバモイル−４−（２−エチル−４−トリフルオロメチル−ベンゾイルアミノ）−フェニル］−アセトキシメチル｝−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−エチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−イソプロペニル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−イソプロピル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−チオフェン−２−イル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−チオフェン−３−イル−マロン酸 ジエチル エステル、
・２−（２−｛４−ジメチルカルバモイル−５−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−ピリジン−２−イル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（３−メチル−チオフェン−２−イル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（５−メチル−チオフェン−２−イル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−チアゾール−２−イル−マロン酸 ジエチル エステル、
・２−（２−｛３−エトキシ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−メトキシ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−イソプロポキシ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ベンジルオキシ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ヒドロキシ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛３−ピペリジン−１−イル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛３−ピロリジン−１−イル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルアミノ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−モルホリン−４−イル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジエチルアミノ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛２−クロロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−ベンゾイルオキシ｝−エチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−エトキシカルボニル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（３−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−プロピオニルオキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ベンジルオキシカルボニル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−カルボキシ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−イソプロポキシカルボニル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−メトキシカルボニル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−アセチルアミノ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−メトキシカルボニルアミノ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−（４−メチル−チアゾール−２−イル）−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−フェニル−２−（２−｛６−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−ビフェニル−３−イル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ホルミル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルアミノメチル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−（メトキシ−メチルカルバモイル）−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−イソブチリル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、及び
・２−（２−｛３−（１−ヒドロキシ−２−メチル−プロピル）−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル。
上記化合物群のうち、特に代表的なビフェニルアミド誘導体は次のとおりである。
・２−フェニル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジイソブチル エステル、
・２−（２−｛４−［エチル−（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジメチル エステル、
・２−シクロペンチル−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−シクロヘキシル−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［３−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシ）−プロピル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−メトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（５−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジ２，２，２−トリフルオロエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（２’−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ブロモ−５−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−クロロ−５−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（３’−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（３’−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（５−ニトロ−ピリジン−２−イル）−マロン酸 ジエチル エステル、
・２−（５−アミノ−ピリジン−２−イル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ピリジン−２−イル−マロン酸 ジエチル エステル、
・２−（２−｛３−クロロ−５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ブロモ−５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｏ−トリル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｍ−トリル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｐ−トリル−マロン酸 ジエチル エステル、
・２−（２−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（３−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（４−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−コハク酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（２−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（３−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（４−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛４−［（５，４’−ビス−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（６−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［２−（２−｛３−ジメチルカルバモイル−４−［（５−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシ）−エチル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−エトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−イソプロポキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［２−（２−｛４−［（５，４’−ビス−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシ）−エチル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−メトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（３−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
特開２０００−２８１５６１号公報 特開平９−３０９８３４号公報 特開２００４−１０５７５号公報 特表平１１−５０９２３８号公報 特開２００３−７３２６１号公報 特公平３−１２８８号公報 特公平３−２８４０４号公報 特開平１１−２４６４０４号公報 特表２００３−５３１０９９号公報 ＷＯ００／０５６７２６号公報 特開平０８−２０８４７６号公報 ＷＯ２００２／０５１３８５号公報 特開平９−５９１５９号公報 特開平１１−２２８５６９号公報 特表２００４−５１４６７６号公報（ＷＯ２００２／０４２２９１） 特表２００３−５３５９００号公報（ＷＯ０１／０９７８１０） 特表２００３−５２１４８４号公報（ＷＯ０１／０４７８９８） 特表２００３−５２０２７０号公報（ＷＯ０１／０５３２６０） 特表２００３−５１９１３１号公報（ＷＯ０１／０４７８９９） 特表２００３−５０９５０５号公報（ＷＯ０１／０２１６０４） 特表２００３−５０５３７３号公報（ＷＯ０１／００５７６２） 特表２０００−５１０４８３号公報（ＷＯ９８／４７８７５） 特開２００１−１７２１８０号公報 特開２０００−１６９３９５号公報 特開２００２−２２０３４５号公報 特開２００３−３２１４２４号公報 Ｗ．Ｌ．Ｃｈｉｏｕ ａｎｄ Ｓ．Ｒｉｅｇｅｌｍａｎ：Ｐｈａｒｍａｃｅｕｔｉｃａｌ ａｐｐｌｉｃａｔｉｏｎ ｏｆ ｓｏｌｉｄ ｄｉｓｐｅｒｓｉｏｎ ｓｙｓｔｅｍｓ，「Ｊ．Ｐｈａｒｍ．Ｓｃｉ．」（ｖｏｌ．６０，１２８１−１３０２，１９７１） ［ウェッテラウ・アンド・ジルバースミットの「Ｃｈｅｍ．Ｐｈｙｓ．Ｌｉｐｉｄｓ」（３８、２０５−２２２頁、１９８５年）］   Hereinafter, MTP inhibition as an example of a pharmaceutical that seems to be most suitable for application to the solid preparation of the present invention, and background art relating to formulation for improving the solubility of poorly water-soluble chemical substances as pharmaceutical active ingredients The background art about substances will be explained.
1. Formulation technology
1-1. Drug and solubility and stability
  In designing a pharmaceutical solid preparation, particularly an oral preparation, it is important from the viewpoint of the effectiveness of the drug to design a sufficiently high bioavailability (Bioavailability).
  Many factors influence the bioavailability of oral administration. These factors include water solubility, drug absorption throughout the gastrointestinal tract, dosing strength and first-pass effect, but especially for poorly water-soluble drugs, the dissolution rate is known to be the rate-limiting step of absorption. Therefore, it is said that water solubility is the most important and high priority factor in drug development.
  Unfortunately, however, many medicinal chemicals are poorly soluble in water and, therefore, only a small portion of the dose is transferred or absorbed into the blood even when administered orally. Has the disadvantage of being extremely low.
  The results of the Japanese Pharmacopoeia solubility test for 338 orally-administered pharmaceutical compounds already marketed, excluding protein preparations, etc., and classified as “very soluble” to “almost insoluble”. It has been reported that there are 150 samples with a solubility of 0.1 mg / ml or less, which accounted for about 40% of the total.
  As described above, a drug must have high bioavailability, in other words, high solubility in order to exert its medicinal effect, but on the other hand, since the drug is stored for a long time, its stability is Sex is also a very important requirement.
  In general, a crystal of a chemical substance is inferior in terms of solubility, although it is more stable than its amorphous substance. Thus, the solution of stability and the solution of solubility are in a mutually contradictory relationship, and it is extremely difficult to solve the problems of stability and solubility at the same time.
1-2. Improvement of solubility of poorly soluble drugs
  In order to improve the solubility of these sparingly soluble drugs, various preparations such as conversion to salt compounds, formation of solvates, crystal polymorphism, micronization of drugs, mixed grinding with excipients, etc. Has been made.
  However, a formulation technique that improves the solubility while maintaining stability, particularly a versatile formulation technique that can be applied to any drug has not yet been found.
  Solid dispersion is widely used as a means for improving the solubility of hardly soluble drugs, and many hardly soluble drugs have been put into practical use as solid dispersion preparations. A solid dispersion is defined as “one or more active ingredients dispersed in a solid state inert carrier or matrix thereof prepared by a melt, solvent, or melt-solvent method”. (See Non-Patent Document 1).
  In other words, the solid dispersion is dried after forming a uniform liquid phase by dissolving the drug in an organic solvent together with a carrier composed of an inorganic porous material or a polymer material, or melting both the polymer material and the drug. In the solid mixture obtained by the operation of solidifying after being allowed to form, the drug is uniformly dispersed in the carrier matrix or on the surface thereof in the form of microcrystals or molecular size, that is, a monomolecular state. In general, amorphous is in a high energy state as compared with crystals, so that the dissolution rate is improved and the drug concentration in the aqueous solution is increased, resulting in an increase in absorption rate and an increase in blood concentration. (For example, refer to Patent Documents 1 and 2).
1-3. Production method of solid dispersion
  Several methods have been proposed for the production method of the solid dispersion, and particularly practical methods include a solvent method, a melting method, a spray drying method (spray drying method), a mixed pulverization method, and the like. . Among these, the melting method and the solvent method are described below.
(A) Melting method
  The melting method is a method of obtaining a solid dispersion by heating and melting a carrier made of an inorganic porous material or a polymer material and a drug as an active ingredient. For example, itraconazole, a triazole antifungal agent, calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium metasilicate aluminate, magnesium magnesium silicate, synthetic aluminum silicate, hydrous dioxide Production of a solid dispersion comprising itraconazole and an inorganic porous material, wherein an inorganic porous material selected from the group consisting of silicon is mixed, heated and melted, and the obtained melt is cooled. A method has been reported (for example, see Patent Document 3). Apart from this, a method of melt-extruding a mixture containing itraconazole and a water-soluble polymer and subsequently grinding the melt-extruded mixture has also been reported (see, for example, Patent Document 4).
(B) Solvent method
  The solvent method is a method for producing a solid dispersion by dissolving a drug and a water-soluble polymer as a carrier in a solvent such as an organic solvent and then distilling the solvent. It is considered that by dissolving a poorly water-soluble drug in a solvent, the drug becomes amorphous and is dispersed in the carrier in this state, so that solubility and bioavailability can be improved (for example, Patent Document 5). reference).
  As a specific example, nifedipine, which is a poorly water-soluble drug, and a polymer base such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, and methylcellulose on fine granules obtained by granulating lactose or the like with a water-soluble polymer such as hydroxypropylcellulose. A so-called spray drying method is known in which a liquid dissolved in an organic solvent is sprayed and dried to obtain a solid dispersion (see, for example, Patent Documents 6 and 7).
  Dispersing solids by dissolving poorly water-soluble drugs such as cycloheptazines and water-soluble polymers such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropylcellulose in a water / alcohol system, followed by spray granulation into lactose It has also been reported to prepare a body (for example, see Patent Document 5).
  In addition, regarding a specific poorly water-soluble drug, a method of adsorbing the drug on the inorganic porous material by dissolving the drug in an organic solvent and mixing it with an inorganic porous material or polymer material, and then distilling off the solvent. However, this method is not applicable to all poorly soluble drugs, and the physical properties of poorly soluble drugs are examined in detail to determine the optimal method. It has also been reported that it had to be determined on a trial and error basis (see, for example, Patent Document 8).
  Also, a pharmaceutical composition having improved solubility and absorbability by amorphizing 3-bis (4-methoxyphenyl) methylene-2-indolinone in the presence of a polymer substance and / or an inorganic porous substance And a manufacturing method thereof. Further, as a specific manufacturing method thereof, a method of amorphizing TAS-301 by a heat melting method or a solvent method using an inorganic porous material, and a polymer material There is known a method of making an amorphous film by a solvent method using. However, there is no specific knowledge about the technical significance of simultaneously using both the polymer substance and the inorganic porous substance (see, for example, Patent Document 8).
(C) Carrier in solid dispersion
  There are two types of carriers for solid dispersions, polymeric materials and inorganic porous materials.
  As the polymer substance, a substance that is usually dissolved in water or a weakly basic or strongly basic buffer solution and pharmaceutically acceptable can be used, but the kind thereof is not particularly limited. For example, hydroxypropylmethylcellulose (Shin-Etsu Chemical: trade name TC-5), hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methylcellulose, carboxymethylethylcellulose, polyvinylpyrrolidone (BASF: tradename Kollidon), polyethylene Glycol, ethyl acrylate / methyl methacrylate copolymer, methacrylic acid copolymer, or the like, or a mixture thereof is used (for example, see Patent Document 8).
  On the other hand, the inorganic porous material is fine particles or powder having many fine voids, and is not particularly limited as long as it is stable at the heating and melting temperature of the active ingredient. For example, calcium silicate, light Anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate metasilicate, magnesium aluminum silicate, synthetic aluminum silicate, hydrous silicon dioxide and the like are used. The particle size is from 0.01 μ to 100 μ, and on average from 0.1 to 10 μ.
  The amount of the polymer substance and / or inorganic porous substance used is not particularly limited, but it varies depending on the type of drug or carrier used, but in many cases 0.5 to 5 times the weight (weight) of the drug 1 Ratio) is said to be appropriate. (For example, refer to Patent Document 8).
  Apart from this, a preparation containing a hydrophobic excipient, a stabilizer and a disintegrant is also known.
  For example, (a) a solid solution of an amorphous pharmaceutically active drug and a pharmaceutically acceptable hydrophobic excipient that is normally crystalline and slightly soluble at ambient pressure and temperature, (b) A stabilizer consisting of polyethylene glycol, sugar, sorbitol, mannitol, polyvinylpyrrolidone, or one or more cellulose ethers, and (c) a disintegrant consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, or a crosslinked polyacrylate, There are known granulated particles characterized by containing (for example, see Patent Documents 9 and 10).
(D) Mixing ratio of drug and carrier in solid dispersion
  Regarding the ratio of the drug to the base (carrier) in the solid dispersion, for example, in the case of nifedipine, which is one of the calcium antagonists widely used for the prevention and treatment of angina pectoris and hypertension, the ratio to the drug (nifedipine) is high. It has been reported that the ratio of the molecular substance (hydroxypropylmethylcellulose) is advantageously 1.5 to 3 parts by weight. The reason for the blending ratio is that when the blending amount of the base is 1 part by weight or less with respect to 1 part by weight of nifedipine, a solid dispersion-like composition cannot be obtained. This is because the volume of the product becomes large, and by extension, the preparation produced using this becomes undesirably large (see, for example, Patent Document 11).
  The solid dispersion technology described above is an excellent technology, but this solid dispersion technology is also not absolute and cannot always be obtained in an amorphous state. As a result, the drug dissolution rate is increased. Sometimes you don't. Some parameters, such as, for example, the interaction between the polymer and the active ingredient, their proportions and the production technology employed, influence the chemical-physical characteristics of the resulting solid dispersion. For this reason, for each specific active ingredient, it is necessary to select both the polymer and the operating conditions in order to produce a dispersion that results in a conversion to an amorphous form and to maintain the amorphous form of the product. There is also a report (for example, refer to Patent Document 12).
  In addition, in the case of adopting any of the melting method and the solvent method, the solid dispersion obtained in this way is pulverized and sieved, and mixed with other substances as necessary to prepare granules, tablets (For example, refer patent document 13). In particular, in the solvent method, the dispersion may be film-like depending on the production conditions. In this case, it is necessary to cut the film to make it fine.
1-4. About stability
  Formulation stability is one of the important factors for ensuring the effectiveness and quality of pharmaceutical products.
  In order to obtain the information necessary for setting the storage method and shelf life of pharmaceutical products when applying for manufacturing approval of pharmaceutical products, stability tests such as long-term storage tests, accelerated tests, and severe tests on the drug substance and its preparations are required. ing.
  In general, crystals are more stable than amorphous ones. However, from the viewpoint of solubility, there is a problem that a drug constituting a stable crystal form is difficult to solve.
2. About MTP
  Hereinafter, a lipid absorption inhibitor, particularly an MTP inhibitor will be described as an example of a poorly water-soluble drug.
  MTP is expressed in both liver and small intestine organs and is a transfer protein that catalyzes the migration of triglycerides, cholesteryl esters and phosphatidylcholines between small unilamellar endoplasmic reticulum, producing lipoproteins.
  Thus, MTP can lipidate apo B-100 newly synthesized in the liver, as well as apo B-48 newly synthesized in the intestine.
  Therefore, lipoparticles rich in triglycerides such as VLDL (very low density lipoprotein) and chylomicron, respectively, will be produced. Thus, an MTP inhibitor and / or an Apo B secretion inhibitor can be expected to reduce the plasma concentration of LDL-c and triglycerides, and further reduce the lipid absorption in the intestine.
  Therefore, MTP inhibitors and / or ApoB secretion inhibitors are non-insulin-dependent diabetes mellitus, coronary heart disease, pancreatitis, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, mixed dyslipidemia, postprandial high It can be used to treat lipemia, atherosclerosis and obesity.
2-1. MTP and ApoB and blood lipids
  Conventionally, in arteriosclerosis, hyperlipidemia, diabetes, hypertension and the like are said to be one of the risk factors. Hyperlipidemia is a condition in which lipids such as cholesterol are abnormally increased in the blood, and its origin is genetics of enzymes and proteins involved in the metabolism of low density lipoprotein (LDL), lipoprotein receptors, etc. Examples include primary hyperlipidemia caused by abnormalities, secondary hyperlipidemia caused by various diseases and drug administration, and acquired hyperlipidemia based on overnutrition.
  Lipids ingested by meals are absorbed in the small intestine by the action of bile acids and secreted into the blood as chylomicrons via lymphatic vessels. The secreted chylomicron is broken down into free fatty acids by the action of lipoprotein lipase (LPL) present in capillaries to form chylomicron remnants with a high cholesteryl ester (CE) content. It is taken into the liver through the chylomicron remnant receptor. Furthermore, in the liver, the incorporated chylomicron remnant is converted into CE and TG, and associates with apolipoprotein B synthesized on the rough endoplasmic reticulum to form VLDL. After this VLDL is transported to the Golgi apparatus and modified, it is secreted to the outside of the cell, becomes LDL by intermediate density lipoprotein (IDL), is converted to LDL by hepatic triglyceride lipase (HTGL), and the lipid is Distributed to peripheral tissues.
  During the formation of chylomicron in the small intestine or VLDL in the liver, the presence of a protein having TG and CE transfer activity in the microsome fraction of the small intestine and liver was previously pointed out. The protein, that is, MTP, was purified and separated from the liver and intestine from the microsomal fraction of the liver (see Non-Patent Document 2). However, this MTP came into the limelight from the clinical medicine field after it was reported in 1993 that the cause of abetalipoproteinemia was MTP deficiency. That is, although there is no abnormality in the gene related to apolipoprotein B, apolipoprotein B is hardly detected in serum, serum cholesterol is 50 mg / dL or less, and serum triglyceride is extremely low. It is characterized in that lipoproteins including apolipoprotein B such as chylomicron, VLDL, and LDL are not present in the blood. This indicates that MTP is an essential protein for the association of apolipoprotein B with TG and CE, that is, the formation of VLDL and chylomicron, and plays a fundamental role in their secretion.
  Since lipids are inherently insoluble in water, lipids in blood exist as so-called lipoproteins in association with hydrophilic proteins called apolipoproteins. VLDL, IDL, LDL, chylomicron, and the like related to hyperlipidemia are all lipoproteins. MTP is present in the microsomal fraction of hepatocytes and small intestinal epithelial cells, and is responsible for intracellular TG and CE transfer. In the liver and small intestine, along with the synthesis of apolipoprotein B (apolipoprotein B100 in the liver and apolipoprotein B48 in the small intestine), TG and CE are associated with each apolipoprotein B by the transfer action of MTP. The chylomicron is formed. As a result, these lipoproteins are secreted extracellularly as VLDL in the liver and as chylomicron in the small intestine.
  MTP can be said to be essential for the construction of this lipoprotein. That is, by inhibiting the activity of MTP, transfer of lipids such as TG and CE to apolipoprotein is inhibited, and the formation of lipoprotein can be inhibited.
  On the other hand, it has been clarified that LDL is generally involved in the progression of arteriosclerosis, and LDL permeates the vascular endothelium and deposits in the intercellular matrix of the vascular wall, where oxidative degeneration occurs. Oxidized lipid peroxides and denatured proteins cause a series of inflammatory reactions, leading to macrophage invasion and lipid deposition / foaming into the blood vessel wall, smooth muscle cell migration / proliferation, and increase in intercellular matrix. Forming an arteriosclerotic lesion. Therefore, it is considered that arteriosclerosis, coronary artery disease, and hypertension can be prevented or treated by reducing LDL.
  Thus, MTP can lipidate apo B-100 newly synthesized in the liver as well as apo B-48 newly synthesized in the small intestine.
  Therefore, MTP inhibitors and / or Apo B secretion inhibitors inhibit the formation of lipoproteins such as chylomicron, VLDL, LDL, reduce plasma concentrations of LDL-c and triglycerides, and further lipid absorption in the intestine Prevent or treat new types of hyperlipidemia, arteriosclerosis, coronary artery disease, diabetes, obesity or hypertension, as well as treatment of pancreatitis, hypercholesterolemia, hypertriglyceridemia, etc. It is also expected as a drug or preventive drug.
  On the other hand, as the development of MTP inhibitors progresses, MTP inhibitors exert blood lipid lowering effects, but it has been pointed out that they may cause fat accumulation in the liver (fatty liver), and hepatotoxicity is a concern. It became so. Therefore, if only MTP of the small intestine can be selectively inhibited immediately before reaching the liver, it can significantly reduce blood triglycerides and cholesterol without side effects such as fatty liver. .
  For these reasons, a novel MTP inhibitor and its improved preparation without side effects such as fatty liver are strongly desired.
2-2. MTP inhibitor
  The following compounds are already known as the above MTP inhibitors and / or ApoB secretion inhibitors, particularly MTP inhibitors.
(A) JP-A-11-228569 describes the following 3-piperidyl-4-oxoquinazoline derivative (see Patent Document 14).

  {Wherein R is the formula (i)

  [Wherein R1 and R2 may be the same or different and are a hydrogen atom; a lower alkyl group having 1 to 4 carbon atoms; an aralkyl group; a benzoyl group; a cycloalkyl group having 3 to 7 carbon atoms; an aryl group; Or a heteroaryl group comprising 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (wherein the cycloalkyl group, aryl group or heteroaryl group is a halogen atom; 1 to 4 carbon atoms) A lower alkyl group having 1 to 4 carbon atoms; a nitro group; a lower alkoxy group having 1 to 4 carbon atoms; an amino group; an amino group substituted with a lower alkyl group having 1 to 4 carbon atoms; And optionally substituted by 1 to 3 substituents selected from a hydroxyl group; a phenoxy group; and a sulfo group, and at least one of R 1 or R 2 is a hydrogen atom No. Or formula (ii)

[Wherein, A and B may be the same or different, and are aromatic hydrocarbon rings; aromatic heterocycles containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms; A cycloalkane ring having 3 to 7 carbon atoms; or a cycloalkene ring having 5 to 7 carbon atoms (wherein the aromatic hydrocarbon ring, aromatic heterocyclic ring, cycloalkane ring or cycloalkene ring is a halogen atom; A lower alkyl group having 1 to 4 carbon atoms; a lower haloalkyl group having 1 to 4 carbon atoms; a hydroxyl group; a nitro group; a lower alkoxy group having 1 to 4 carbon atoms; an amino group; and a lower alkyl group having 1 to 4 carbon atoms. A substituted amino group; and optionally substituted with 1 to 3 substituents selected from a sulfo group, and X is a single bond; straight or branched 1 to 4 carbon atoms Lower alkylene group; linear Or a branched lower alkenylene group having 2 to 4 carbon atoms (wherein the lower alkylene group or lower alkenylene group is a halogen atom; a hydroxyl group; a nitro group; a lower alkoxy group having 1 to 4 carbon atoms; an amino group) And optionally substituted with a group selected from a sulfo group); an oxygen atom; a sulfur atom; an imino group optionally substituted with a lower alkyl group having 1 to 4 carbon atoms; a carbonyl group; -; -Z-O-; -S-Z-; -ZS-; -NH-Z-; -NR5-Z-; -Z-NH-; or -Z-NR5- (where Z is A lower alkylene group having 1 to 4 carbon atoms; or a carbonyl group, and R5 is a lower alkyl group having 1 to 4 carbon atoms), Y is a single bond; a straight chain or branched carbon A lower alkylene group of 1 to 4; or a carbonyl group] N is an integer selected from 1 to 4, R3 and R4 may be the same or different, and are a hydrogen atom; a lower alkyl group having 1 to 4 carbon atoms; a halogen atom; A lower haloalkyl group; a hydroxyl group; an amino group; or a nitro group}
(B) Japanese translations of PCT publication No. 2004-514676 (WO2002 / 042291) describes an MTP inhibitor comprising a benzamide compound having a piperidine ring as described below (see Patent Document 15).

(Where
Z represents biphenyl optionally substituted at the 2 ′, 3 ′, 4 ′, 5 ′ and 6 ′ positions with one or more substituents selected from trihalomethyl and trihalomethoxy; Is halo, cyano, nitro, (C₁~ C₆) Alkyl, (C₆~ C₁₂) Aryl, (C₁~ C₆) Alkoxy, hydroxyl, (C₁~ C₆) Thioalkoxy, carboxyl and (C₁~ C₆) Represents quinolyl or quinoxalyl or pyridyl optionally substituted with one or more substituents selected from alkoxycarbonyl)
(C) Japanese translations of PCT publication No. 2003-535900 (WO01 / 097810) describes an MTP inhibitor comprising a benzamide derivative represented by the following formula (see Patent Document 16).

[Wherein A is N or CH;
X can contain the following groups: (i) one or two double bonds and one or more hydroxy, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl or C_1-6-C optionally substituted with an acyloxy group_1-6Alkylene-, (ii) oxo, sulfonyl, thioxo, (iii) -C_1-6Alkylenecarbonyl-, -C_1-6Alkylenesulfonyl-, -C_1-6Alkylenethioxo-, (iv) -C_2-6Alkyleneoxy-, -C_2-6Alkylenethio-, -C_2-6Alkylene (N—H or N—C_1-6Alkyl) amino-, (v) -C_1-6Alkylenecarboxy-, -C_1-6Alkylenethioamide-, -C_1-6Alkylene (N—H or N—C_1-6Alkyl) carboxamide-, and (vi) -C_2-6Alkyleneoxycarbonyl-, -C_2-6Alkylenethiocarbonyl-, -C_2-6Alkylene (N—H or N—C_1-6Selected from the group consisting of (alkyl) aminocarbonyl-;
Z may be a direct bond or may contain one double bond, and one or more hydroxy, C,_1-6Alkyl, C_1-6Alkoxy, C_1-6Acyl or C_1-6-C optionally substituted with an acyloxy group_1-6Is alkylene-;
R¹Are the following groups: (i) hydrogen, C_1-3Perfluoroalkyl, (ii) C_6-10Aryl, C_3-8Cycloalkyl and their condensed benz derivatives, C_7-10Polycycloalkyl, C4-8 cycloalkenyl, C_7-10Polycycloalkenyl, (iii) a heterocyclyl selected from monocyclic and fused polycyclic moieties, wherein the moiety contains a total of 5-14 ring atoms, the moiety comprising oxygen, nitrogen and sulfur Containing a total of 1 to 4 heterocycle atoms independently selected from and each individual ring of the moiety is independently saturated, partially unsaturated, or aromatic And (iv) X is C_1-6Alkylene, Z is a direct bond, or Z is C_1-6If any of alkylene, R¹Is additionally halogen, cyano, nitro or C_1-6May be an acyl group, selected from;
Where R¹Each contain one or more rings, each of which is independently selected from the following group: (i) halogen, hydroxy, cyano, nitro, formyl, C_1-6Alkylsulfonylamino, (ii) C_1-6Alkyl, C_3-8Cycloalkyl, C_1-3Perfluoroalkyl, (iii) C_1-6Alkoxy, methylenedioxy, C_1-3Perfluoroalkoxy, C_1-6Alkylthio, (iv) amino, C_1-6Alkylamino, di-C_1-6Alkylamino, (v) phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (vi) hydroxycarbonyl, C_1-6Alkoxycarbonyl, (vii) aminocarbonyl, C_1-6Alkylaminocarbonyl, di-C_1-6Alkylaminocarbonyl, di-C_1-6Alkylaminocarbonyl C_1-6Alkoxy, C_1-3Perfluoroalkylaminocarbonyl, (viii) C_1-6Acyl, C_1-6Acyloxy, C_1-6Acyloxy C_1-6Alkyl, C_1-6Acylamino, and (ix) an aromatic heterocyclyl consisting of a monocyclic moiety, wherein said moiety contains 5-6 ring atoms, said moiety being independently selected from oxygen, nitrogen and sulfur Contains a total of 1-4 hetero ring atoms, and the heterocyclyl groups are each halogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-3Perfluoroalkyl and C_1-3Optionally substituted by one or more groups independently selected from perfluoroalkoxy;
Optionally having 0 to 4 substituents independently selected from: Y is a direct or oxy bond, -C_1-6Alkylene-,-oxy-C_1-6A heterocyclyl consisting of an alkylene- or monocyclic moiety, wherein said moiety contains 5 ring atoms, said moiety being a total of 1-4 independently selected from oxygen, nitrogen and sulfur Containing a heterocyclic atom, which ring may independently be saturated, partially unsaturated, or aromatic;
R²Is phenyl, C_3-8Cycloalkyl, or heterocyclyl consisting of a monocyclic moiety, wherein the moiety contains 5-6 ring atoms, the moiety being independently selected from oxygen, nitrogen and sulfur Containing heterocyclic atoms, which ring may independently be saturated, partially unsaturated or aromatic, R²Are respectively halogen, C_1-4Alkyl, C_1-4Alkoxy, C_3-8Cycloalkyl, C_1-3Perfluoroalkyl, C_1-3Perfluoroalkoxy, hydroxycarbonyl, C_1-6Alkoxycarbonyl, cyano, nitro, C_1-4Optionally substituted by one or more groups independently selected from alkylaminosulfonyl;
R³Is hydrogen or halogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-3Perfluoroalkyl or C_1-3Means one or more groups independently selected from perfluoroalkoxy]
(D) JP-T-2003-521484 (WO01 / 047898) describes an MTP inhibitor comprising a substituted piperazine derivative represented by the following formula (see Patent Document 17).

[Wherein, m represents the number 2 or 3, n represents the number 1, 2, 3, 4 or 5, and X represents a carbon-carbon bond, an oxygen atom, a methylene group, an ethylene group, an imino group, or N- ( C_1-3-Alkyl) -imino group, R_aIs a dinuclear or trinuclear aromatic hydrocarbon (the internuclear methine group may be replaced by a nitrogen atom), a dinuclear or trinuclear heteroaromatic hydrocarbon bonded to a piperazino group via a carbon atom [this Is a 5-membered heteroaryl ring containing a cyclopentadienyl ring fused via one or two nitrogen atoms and a vinylene group (and the methine group may be substituted by nitrogen atoms and / or internuclear The methine group may be substituted by a nitrogen atom), and optionally C_1-3-Alkyl groups, phenyl-C_1-3-Condensation via an alkyl group, phenyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group or an imino group optionally substituted by a pyrazinyl group, or an oxygen or sulfur atom, and one or two available vinylene groups Phenyl ring or 6-membered heteroaryl ring (containing 1, 2 or 3 nitrogen atoms, the fused rings may be the same or different), or two available A 5-membered heteroaryl ring containing a naphthyl ring fused via one of the vinylene groups (further, in the bicyclic or tricyclic group thus formed, the internuclear carbon atom is replaced by a nitrogen atom) Or C if necessary_1-3-Alkyl groups, phenyl-C_1-3An alkyl group, phenyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group or an imino group optionally substituted by a pyrazinyl group, or an oxygen or sulfur atom, and one or two nitrogen atoms, and an available vinylene group A five-membered heteroaryl ring containing a phenyl ring, a naphthyl ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring condensed via a (internuclear carbon atom may be substituted by a nitrogen atom), 2 or 3 nitrogen atoms and a naphthyl ring or 6-membered heteroaryl ring containing a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl ring fused via a vinylene group (internuclear carbon atoms are replaced by nitrogen atoms) Or fused via a phenyl ring and one or two available vinylene groups. Membered heteroaryl rings (including 1, 2 or 3 nitrogen atoms) (these fused rings may be the same or different, and may be the bicyclic groups or three In a cyclic group, the internuclear carbon atom may be substituted by a nitrogen atom), a pyridine ring, a pyrazine ring or a pyridazine ring and a phenyl ring or a 6-membered heterocycle fused via two available vinylene groups An aryl ring (containing 1, 2 or 3 nitrogen atoms) (these fused rings may be the same or different, and in the tricyclic group thus formed, The interstitial carbon atom may be substituted by a nitrogen atom)_aIn the carbon skeleton, the bicyclic group and tricyclic group described above are further a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, C_1-3-Alkyl group, hydroxy group, C_1-3-Alkoxy group, carboxy group, C_1-3-Alkoxycarbonyl group, aminocarbonyl group, C_1-3An alkylaminocarbonyl group or N, N-di- (C_1-3-Alkyl) -aminocarbonyl groups may be mono- or di-substituted, and these substituents may be the same or different, and the hydrogen atoms in the alkyl and alkoxy moieties are May be wholly or partially substituted by fluorine atoms, R_bAnd R_cAre independently of each other a hydrogen atom or C_1-3-Represents an alkyl group, R_fAnd R_g(These may be the same or different) are hydrogen atoms or C_1-6An alkyl group (the hydrogen atoms may be wholly or partially substituted by fluorine atoms), C_3-7-Cycloalkyl group, phenyl group, C_1-3-Alkoxy-carbonyl-C_1-2-Alkyl group, carboxy-C_1-2-Alkyl group, methoxy-C_2-3-Alkyl group, heteroaryl group, phenyl-C_1-3-Alkyl or heteroaryl-C_1-3-Represents an alkyl group, and the phenyl group and heteroaryl group in the carbon skeleton are a fluorine atom, a chlorine atom or a bromine atom, C_1-3An alkyl group or C_1-3-Alkoxy groups (the hydrogen atoms may be wholly or partially substituted by fluorine atoms), hydroxy groups, carboxy groups, C_1-3-Alkoxycarbonyl group, aminocarbonyl group, C_1-3-Alkyl-aminocarbonyl group, N, N-di- (C_1-3-Alkyl) -aminocarbonyl group, N, N-di- (C_1-3-Alkyl) -amino group, nitro group or amino group may be mono-, di- or tri-substituted, these substituents may be the same or different and / or The hydrogen atom bonded to the nitrogen atom of the heteroaryl group is C_1-3An alkyl group (the hydrogen atoms may be wholly or partially substituted by fluorine atoms), C_1-3-Alkyl-carbonyl group or C_1-4Optionally substituted by an alkoxy-carbonyl group or R_fAnd R_gRepresents a 3- to 7-membered cycloalkyleneimino group together with a nitrogen atom between them, and the 4-position methylene group of the 6-membered or 7-membered cycloalkyleneimino group is further an oxygen atom or a sulfur atom, a sulfinyl group, Sulfonyl group, imino group or N- (C_1-3-Alkyl) -imino group, and the tricyclic group in the above general formula I may be mono- or di-substituted by fluorine atom, chlorine atom, methyl group or methoxy group. The substituents may be the same or different.)
(E) JP-T-2003-520270 (WO01 / 053260) describes an MTP inhibitor comprising a benzamide derivative represented by the following formula (see Patent Document 18).

[In the formula, R₂-C, R₃-C, R₄-C or R₅-C can be substituted with N;
Where n is 1, 2 or 3;
R₁Is aryl, heteroaryl or (aryl or heteroaryl) -lower alkoxy;
R₂, R₃, R₄And R₅Are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano;
R₆Is

m is 1, 2 or 3;
R₇Is hydrogen, lower alkyl, (aryl or heteroaryl) -lower alkyl, lower alkoxy, (aryl or heteroaryl) -lower alkoxy, hydroxy, oxo, lower alkylenedioxy or lower alkanoyloxy;
W is O, S or NR₈;
R₈Is -COR_a,

, -COOR_d, -SO₂R_eHydrogen, optionally substituted lower alkyl, aryl, heteroaryl (or aryl or heteroaryl) -lower alkyl;
R^a, R_dAnd R_eAre independently optionally substituted lower alkyl, cycloalkyl, adamantyl, aryl, heteroaryl or (aryl or heteroaryl) -lower alkyl;
R_bAnd R_cAre independently hydrogen, cycloalkyl, optionally substituted lower alkyl, aryl, heteroaryl or (aryl or heteroaryl) -lower alkyl; or R_bAnd R_cTogether means lower alkylene.
(F) Japanese translations of PCT publication No. 2003-519131 (WO01 / 047899) describes an MTP inhibitor comprising a substituted piperazine derivative represented by the following formula (see Patent Document 19).

[Wherein, n represents the number 2, 3, 4 or 5, and X represents a carbon-carbon bond, an oxygen atom, a methylene group, an ethylene group, an imino group or N- (C_1-3-Alkyl) -imino group, Y_aRepresents a carbonyl group or a sulfonyl group, Y_bIs a group-(CH₂)_m-(Wherein m represents the number 2 or 3, and the hydrogen atom is C_1-3A methylene group optionally substituted by an alkyl group or a methylene group bonded to a nitrogen atom may be substituted by a carbonyl group), R_aIs C_1-6-Alkoxy group, phenyl-C_1-3-Alkoxy group or amino group (the amino group is C_1-3-Alkyl groups, phenyl-C_1-4-May be mono- or di-substituted by alkyl group or phenyl group, the substituents may be the same or different), phenyl group, naphthyl group, tetrahydronaphthyl group, phenoxy group or hetero An aryl group, optionally a hydroxy group, C_1-3-Alkoxy group, C_1-4-Alkoxycarbonyl group or C_1-4-C optionally substituted by an alkyl-carbonyloxy group_1-9An alkyl group (which is a C in its alkyl part)_1-3-Alkyl group, 1 or 2 phenyl group, naphthyl group, fluorenyl group, phenoxy group, heteroaryl group or C_3-7-Optionally substituted by a cycloalkyl group), or C substituted by a phenyl group_3-7-Cycloalkyl group, phenylcarbonyl group, naphthylcarbonyl group, tetrahydronaphthyl-carbonyl group, phenoxycarbonyl group or heteroarylcarbonyl group, C_1-9An alkylcarbonyl group (which has one or two phenyl, naphthyl, fluorenyl, phenoxy, heteroaryl or C_3-7-Optionally substituted by a cycloalkyl group), or C substituted by a phenyl group_3-7-Represents a cycloalkylcarbonyl group, the above R_aAll the phenyl, naphthyl and heteroaryl moieties described in 1¹And R₂Optionally substituted by R₁Is a hydrogen atom, fluorine atom, chlorine atom or bromine atom, cyano group, C_1-3-Alkyl group, C_2-4-Alkenyl group, phenyl group, hydroxy group, C_1-4-Alkoxy group, phenyl-C_1-3-Alkoxy group, carboxy group, C_1-3-Alkoxycarbonyl group, aminocarbonyl group, C_1-3-Alkylaminocarbonyl group, N, N-di- (C_1-3-Alkyl) -aminocarbonyl group, nitro group, amino group, C_1-3-Alkylamino groups, di- (C_1-3-Alkyl) -amino group, phenyl-C_1-3-Alkylamino group, N- (C_1-3-Alkyl) -phenyl-C_1-3-Alkylamino group, C_1-3-Alkylcarbonylamino group, N- (C_1-3-Alkyl) -C_1-3-Alkylcarbonylamino group, C_1-3-Alkylsulfonylamino group or N- (C_1-3-Alkyl) -C_1-3-Represents an alkylsulfonylamino group and R₂Is a hydrogen atom, fluorine atom, chlorine atom or bromine atom, C_1-3-Alkyl group, hydroxy group or C_1-4-Represents an alkoxy group, the group R₁And R₂In the above alkyl and alkoxy moieties, hydrogen atoms may be fully or partially substituted with fluorine atoms, or R₁And R₂Together represent a methylenedioxy group, or R_aAll the phenyl moieties mentioned above may be substituted by 3 chlorine atoms or bromine atoms or 3-5 fluorine atoms;_bIs a carboxy group, C_1-6-Alkoxycarbonyl group, C_1-6-Alkoxycarbonyl-C_1-3-Alkylcarbonyl group, C_3-7-Cycloalkoxycarbonyl group or phenyl-C_1-3An alkoxycarbonyl group or R₃NR₄Represents a -CO group, R₃And R₄(These may be the same or different) are hydrogen atoms, C_1-6-Alkyl groups (the hydrogen atoms may be wholly or partially substituted by fluorine atoms, and C_1-3-C of alkylamino group_1-3The alkyl moiety is a carboxy group or C_1-3-Optionally substituted by an alkoxycarbonyl group, or also in the 2- or 3-position thereof by an amino group, C_1-3-Alkylamino groups or di- (C_1-3-Alkyl) -optionally substituted by an amino group), C_3-7-Cycloalkyl group, pyridyl group, pyridinyl-C_1-3-Alkyl, phenyl, naphthyl or phenyl-C_1-3-Represents an alkyl group, the phenyl group being in each case a fluorine, chlorine or bromine atom, C_1-3An alkyl group (the hydrogen atoms may be wholly or partially substituted by fluorine atoms), a hydroxy group, C_1-3-Alkoxy group, carboxy group, C_1-3-Alkoxycarbonyl group, aminocarbonyl group, C_1-3-Alkylaminocarbonyl group, N, N-di- (C_1-3-Alkyl) -aminocarbonyl group or N, N-di- (C_1-3-Alkyl) -amino group may be substituted or R₃And R₄Represents a 3- to 7-membered cycloalkyleneimino group together with a nitrogen atom between them, and the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is further an oxygen atom or a sulfur atom, a sulfinyl group, a sulfonyl group Group, imino group or N- (C_1-3-Alkyl) -imino groups and R_cIs a hydrogen atom or C_1-3-Represents an alkyl group, and the tricyclic group in the above general formula I may be further mono- or disubstituted by a fluorine atom, a chlorine atom, a methyl group or a methoxy group, and these substituents are the same. The heteroaryl group may be a 6-membered heteroaryl group containing 1, 2 or 3 nitrogen atoms, or optionally C_1-3An imino group optionally substituted by an alkyl group, an oxygen atom or a sulfur atom or optionally C_1-3-Means a 5-membered heteroaryl group containing an imino group optionally substituted by an alkyl group and one or two nitrogen atoms or oxygen or sulfur atoms and a nitrogen atom, the phenyl ring via a vinylene group The heteroaryl group may be condensed, and the carboxy group described in the definition of the group is substituted with a group that can be converted into a carboxy group in vivo or a group that is negatively charged under physiological conditions. And all the above saturated alkyl and alkoxy moieties containing more than two carbon atoms may be straight or branched unless otherwise specified.)
(G) Special Tables 2003-509505 and WO01 / 021604 describe MTP inhibitors consisting of substituted piperazine derivatives represented by the following formula. (See Patent Document 20).

(In the formula, n represents the number 1, 2, 3, 4 or 5, m represents the number 2 or 3, and X represents a carbon-carbon bond, oxygen atom, methylene group, ethylene group, imino group or N- ( C_1-3-Alkyl) -imino group, R_aIs the group R₁And the group R₂Represents a phenyl group or a heteroaryl group substituted by₁Is a hydrogen atom, fluorine atom, chlorine atom or bromine atom, C_1-3-Alkyl group (the hydrogen atom may be completely or partially substituted by a fluorine atom), hydroxy group, C_1-4-Alkoxy group (the hydrogen atom may be completely or partially substituted by fluorine atom), phenoxy group, heteroaryloxy group, phenyl-C_1-3-Alkoxy group, carboxy group, C_1-3-Alkoxycarbonyl group, aminocarbonyl group, C_1-3-Alkylaminocarbonyl group, N, N-di- (C_1-3-Alkyl) -aminocarbonyl group, nitro group, amino group, C_1-3-Alkylamino groups, di- (C_1-3-Alkyl) -amino group, phenyl-C_1-3-Alkylamino group, N- (C_1-3-Alkyl) -phenyl-C_1-3-Alkylamino group, C_1-3-Alkylcarbonylamino group, N- (C_1-3-Alkyl) -C_1-3-Alkylcarbonylamino group, C_1-3-Alkylsulfonylamino group or N- (C_1-3-Alkyl) -C_1-3-Represents an alkylsulfonylamino group, the group R₁The above phenyl moiety or heteroaryl moiety is 1 to 5 fluorine atoms, chlorine atoms or bromine atoms, C_1-3An alkyl group (the hydrogen atom may be fully or partially substituted by a fluorine atom), a hydroxy group, or C_1-4An alkoxy group, the hydrogen atom of which may be fully or partially substituted by a fluorine atom, and R₂Is a hydrogen atom, fluorine atom, chlorine atom or bromine atom, C_1-3An alkyl group (the hydrogen atom may be fully or partially substituted by a fluorine atom) or C_1-4-Represents an alkoxy group (the hydrogen atom may be fully or partially substituted by a fluorine atom) or R₁And R₂Together represent a methylenedioxy group, or R_aRepresents a monocyclic heteroaryl group or a phenyl group (which in each case is substituted by a phenyl group or a monocyclic heteroaryl group), wherein the phenyl group and heteroaryl group are in each case a fluorine atom, Chlorine or bromine atom, C_1-3-Alkyl group (the hydrogen atom may be completely or partially substituted by a fluorine atom), hydroxy group, C_1-3-Alkoxy group, carboxy group, C_1-3-Alkoxycarbonyl group, aminocarbonyl group, C_1-3An alkylaminocarbonyl group or N, N-di- (C_1-3-Alkyl) -aminocarbonyl group optionally substituted by R_bAnd R_cAre independently of each other a hydrogen atom or C_1-3-Represents an alkyl group and R_fAnd R_g(These may be the same or different) are hydrogen atoms, C_1-6An alkyl group (the hydrogen atom may be fully or partially substituted by a fluorine atom), C_3-7-Cycloalkyl group, phenyl group, heteroaryl group, phenyl-C_1-3-Alkyl groups or heteroaryl-C_1-3-Represents an alkyl group, the phenyl group and heteroaryl group in each case having 1 to 3 fluorine, chlorine or bromine atoms, 1 to 3 C_1-3An alkyl group (the hydrogen atom may be fully or partially substituted by a fluorine atom), 1 to 3 hydroxy groups, 1 to 3 C_1-3An alkoxy group (the hydrogen atom may be fully or partially substituted by a fluorine atom), or a carboxy group, C_1-3-Alkoxycarbonyl group, aminocarbonyl group, C_1-3-Alkylaminocarbonyl group, N, N-di- (C_1-3-Alkyl) -aminocarbonyl group, N, N-di- (C_1-3-Alkyl) -amino group, optionally substituted by nitro group or amino group, or R_fAnd R_gRepresents a 3- to 7-membered cycloalkyleneimino group together with a nitrogen atom between them, and the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimino group is further an oxygen atom or a sulfur atom, a sulfinyl group, a sulfonyl group Group, imino group or N- (C_1-3-Alkyl) -imino group, and the tricyclic group in the above general formula I may be mono- or di-substituted by fluorine atom, chlorine atom, methyl group or methoxy group, and these The substituents may be the same or different and the heteroaryl group may be a 6-membered heteroaryl group containing 1, 2 or 3 nitrogen atoms, or 1 to 4 heteroatoms. For example, a 5-membered heteroaryl group which may contain nitrogen, oxygen and sulfur, wherein the hydrogen atom bonded to the nitrogen is optionally C_1-3-May be substituted by an alkyl group)
(H) Japanese translations of PCT publication No. 2003-505373 (WO01 / 005762) describes an MTP inhibitor consisting of a benzamide derivative (biphenylamide derivative) represented by the following formula (see Patent Document 21).

[Wherein n is a number of 1, 2, 3, 4 or 5 and R_aAnd R_bMay be the same or different and each represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, C_1-3An alkyl group (wherein the hydrogen atom may be wholly or partially substituted with a fluorine atom), a hydroxy group, C_1-3Alkoxy group, amino group, C_1-3An alkylamino group or di (C_1-3Alkyl) amino group, R_cIs a hydrogen atom, C_1-10Alkyl, C_3-7A cycloalkyl group or C_3-7Cycloalkyl-C_1-3An alkyl group (wherein, in each case, the hydrogen atom may be wholly or partially substituted with a fluorine atom), a fluorine atom, a chlorine atom or a bromine atom, C_1-3An alkyl group (wherein the hydrogen atom may be wholly or partially substituted with a fluorine atom), a hydroxy group, C_1-3Alkoxy group, C_1-3Alkoxycarbonyl group, aminocarbonyl group, C_1-3An alkylaminocarbonyl group or N, N-di (C_1-3Alkyl) aminocarbonyl group, 3-7 membered cycloalkyleneimino group (wherein the 6- or 7-membered cycloalkyleneimino group, the 4-position methylene group may be further substituted with an oxygen atom or a sulfur atom), Sulfinyl group, sulfonyl group, imino group or N- (C_1-3Alkyl) imino group, nitro group, amino group, C_1-3Alkylamino group, di (C_1-3Alkyl) amino group, C_1-3Alkylcarbonylamino group, N- (C_1-3Alkyl) -C_1-3Alkylcarbonylamino group, C_1-3An alkylsulfonylamino group or N- (C_1-3Alkyl) -C_1-3A phenyl group, a naphthyl group or a monocyclic 5- or 6-membered heteroaryl group which may be substituted with an alkylsulfonylamino group, wherein the 6-membered heteroaryl group has 1, 2 or 3 nitrogen atoms; And the 5-membered heteroaryl group is C_1-3An alkyl group, an imino group optionally substituted with an oxygen atom or a sulfur atom, or C_1-3An alkyl group and an imino group which may be substituted with an oxygen atom or sulfur atom or one or two nitrogen atoms, and the phenyl ring is condensed with the monocyclic heterocyclic group by two carbon atoms. R may be_dIs a fluorine atom, a chlorine atom or a bromine atom, C_1-3An alkyl group (wherein the hydrogen atom may be wholly or partially substituted with a fluorine atom), a hydroxy group, C_1-3Alkoxy group, carboxy group, C_1-3Alkoxycarbonyl group, aminocarbonyl group, C_1-3An alkylaminocarbonyl group or N, N-di (C_1-3Alkyl) aminocarbonyl group, 3- to 7-membered cycloalkyleneimino group (wherein in the 6- or 7-membered cycloalkyleneimino group, the 4-position methylene group may be further substituted with an oxygen atom or a sulfur atom), sulfinyl. Group, sulfonyl group, imino group or N- (C_1-3Alkyl) imino group, nitro group, amino group, C_1-3Alkylamino group, di (C_1-3Alkyl) amino group, C_1-3Alkylcarbonylamino group, N- (C_1-3Alkyl) C_1-3Alkylcarbonylamino group, C_1-3An alkylsulfonylamino group or N- (C_1-3Alkyl) -C_1-3A phenyl group, a naphthyl group or a monocyclic 5- or 6-membered heteroaryl group which may be substituted with an alkylsulfonylamino group, wherein the 6-membered heteroaryl group has 1, 2 or 3 nitrogen atoms; And the 5-membered heteroaryl group is C_1-3An alkyl group, an imino group optionally substituted with an oxygen atom or a sulfur atom, or C_1-3An alkyl group and an imino group which may be substituted with an oxygen atom or sulfur atom or one or two nitrogen atoms, and the phenyl ring is bonded to the monocyclic heterocyclic group by two adjacent carbon atoms. May be condensed, R_eIs a carboxy group, C_1-6An alkoxycarbonyl group or C_3-7A cycloalkoxycarbonyl group, wherein in each case the alkyl or cycloalkyl moiety from the 2-position with respect to the oxygen atom is C_1-3Alkoxy group, amino group, C_1-3An alkylamino group or di (C_1-3Alkyl) amino group, phenyl-C_1-3An alkoxycarbonyl group or heteroaryl-C_1-3It may be substituted with an alkoxycarbonyl group and the heteroaryl moiety is as defined above. ) And R_fIs a hydrogen atom, C_1-3Alkyl group or phenyl-C_1-3An alkyl group, R_gIs a hydrogen atom or C_1-3It is an alkyl group. ]
(I) In Japanese translations 2000-510483 and WO 98/47875, benzamide derivatives represented by the following formula, specifically, 4′-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-carboxylic acid) An MTP inhibitor having tetrahydro-isoquinolin-6-yl) -amide as an active ingredient has been described (see Patent Document 22).

(J) JP-A-2001-172180 describes an MTP inhibitor comprising a benzamide derivative (biphenylamide derivative) represented by the following (i), (ii), (iii), (iv): (See Patent Document 23).
(I) Formula (1)

  In the above formula, L is (A) XYZ, where X is CH₂, CO, CS or SO₂A moiety selected from the group consisting of: Y is a direct bond; hydroxy, (C₁-C₁₀) Alkoxy, (C₁-C₁₀) Acyl, (C₁-C₁₀) Acyloxy or (C₆-C₁₀) An aliphatic hydrocarbylene group having up to 20 carbon atoms which may be monosubstituted with aryl; a moiety selected from the group consisting of NH; and O, wherein X is CH₂Y is a direct bond; and Z is (1) hydrogen, halogen, cyano, (2) hydroxy, (C₁-C₁₀) Alkoxy, (C₁-C₁₀) Alkylthio, (C₁-C₁₀) Acyl, thiophenylcarbonyl, (C₁-C₁₀) Alkoxycarbonyl, (3) (C₁-C₁₀) Alkylamino, di (C₁-C₁₀) Alkylamino, (C₆-C₁₀Aryl (C₁-C₁₀) Alkylamino, wherein Y is not O or NH, (4) unsubstituted vinyl, (C₆-C₁₀) Aryl, (C₃-C₈) Cycloalkyl and their condensed benz derivatives, (C₇-C₁₀) Polycycloalkyl, (C₄-C₈) Cycloalkenyl, (C₇-C₁₀) Polycycloalkenyl (5) (C₆-C₁₀Aryloxy, (C₆-C₁₀) Arylthio, (C₆-C₁₀Aryl (C₁-C₁₀) Alkoxy, (C₆-C₁₀Aryl (C₁-C₁₀) Alkylthio, (C₃-C₈) Cycloalkyloxy, (C₄-C₈) Cycloalkenyloxy, (6) a heterocyclic group selected from the group consisting of monocyclic groups and fused polycyclic groups, the groups comprising a total of 5 to 14 ring atoms, from oxygen, nitrogen and sulfur Containing a total of 1 to 4 ring heteroatoms independently selected, wherein each ring of the group may independently be saturated, partially unsaturated, or aromatic, provided that X is CH₂Z is H or a moiety selected from the group consisting of selected from groups (4) and (6), wherein when Z contains one or more rings, Each ring is halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C₁-C₁₀) Alkyl, (C₁-C₁₀) Alkoxy, (C₁-C₁₀) Alkoxycarbonyl, (C₁-C₁₀) Alkylthio, (C₁-C₁₀) Alkylamino, (C₁-C₁₀) Alkylaminocarbonyl, di (C₁-C₁₀) Alkylamino, di (C₁-C₁₀) Alkylaminocarbonyl, di (C₁-C₁₀) Alkylamino (C₁-C₁₀) Alkoxy, (C₁-C₃) Perfluoroalkyl, (C₁-C₃) Perfluoroalkoxy, (C₁-C₁₀) Acyl, (C₁-C₁₀) Acyloxy, (C₁-C₁₀) Acyloxy (C₁-C₁₀) May optionally contain 0-4 substituents independently selected from alkyl and pyrrolidinyl; or (B) G, wherein G is selected from the group consisting of: (A) phenyl or a heterocyclic ring containing a total of 3 to 14 ring atoms, the heterocyclic ring containing a total of 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur Each ring of the heterocyclic ring may independently be saturated, partially saturated, or aromatic and each phenyl or heterocyclic ring may be halogen, hydroxy, cyano, nitro, oxo, thioxo, amino Sulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C₁-C₁₀) Alkyl, (C₁-C₄) Perfluoroalkyl, (C₁-C₁₀) Alkoxy, (C₁-C₄) Perfluoroalkoxy, (C₁-C₁₀) Alkoxycarbonyl, (C₁-C₁₀) Alkylthio, (C₁-C₁₀) Alkylamino, di (C₁-C₁₀) Alkylamino, (C₁-C₁₀) Alkylaminocarbonyl, di (C₁-C₁₀) Alkylaminocarbonyl, (C₁-C₁₀) Acyl, (C₁-C₄) Perfluoroacyl, (C₁-C₁₀) Acyloxy, (C₁-C₆) Acylamino and (C₁-C₆) May contain 1 to 4 substituents independently selected from perfluoroacylamino; (b) —CH₂CN, (c)

(D) may be substituted with 1 to 3 substituents independently selected from the following substituents (C₂-C₁₂) Alkyl or (C₂-C₁₂) Perfluoroalkyl: (1) phenyl, halogen, nitro, cyano, hydroxy, -NR¹R², -OCOR³, (C₁-C₄) Alkoxy, (C₁-C₄) Perfluoroalkoxy, (C₁-C₄) Thioalkoxy or (C₁-C₄) Perfluorothioalkoxy, where -NR¹R²R¹And R²Are hydrogen, formyl, phenyl, benzyl, benzoyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) Cycloalkenyl, (C₁-C₄) Alkyl, (C₁-C₄) Perfluoroalkyl, (C₁-C₁₀) Alkoxycarbonyl, (C₁-C₆) Acyl, (C₁-C₆) Perfluoroacyl, aminocarbonyl, (C₁-C₁₀) Alkylaminocarbonyl, di (C₁-C₁₀) Alkylaminocarbonyl, aminosulfonyl, (C₁-C₄) Alkylaminosulfonyl, di (C₁-C₄) Alkylaminosulfonyl, (C₁-C₄) Perfluoroalkylaminosulfonyl, di (C₁-C₄) Perfluoroalkylaminosulfonyl, (C₁-C₄) Alkylsulfonyl, and (C₁-C₄) Independently selected from perfluoroalkylsulfonyl or R¹And R²Together with the nitrogen atom to which they are attached form a saturated, partially saturated or aromatic heterocyclic ring, the heterocyclic ring containing a total of 3 to 14 ring atoms, oxygen, nitrogen and It may further contain 1 to 4 ring heteroatoms independently selected from sulfur, which heterocyclic ring is halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio , Benzyl, benzoyl, benzyloxy, (C₁-C₁₀) Alkyl, (C₁-C₄) Perfluoroalkyl, (C₁-C₁₀) Alkoxy, (C₁-C₄) Perfluoroalkoxy, (C₁-C₁₀) Alkoxycarbonyl, (C₁-C₁₀) Alkylthio, (C₁-C₁₀) Alkylamino, di (C₁-C₁₀) Alkylamino, (C₁-C₁₀) Alkylaminocarbonyl, di (C₁-C₁₀) Alkylaminocarbonyl, (C₁-C₁₀) Acyl, (C₁-C₁₀) Perfluoroacyl, (C₁-C₁₀) Acylamino, and (C₁-C₁₀) May contain 1 to 4 substituents independently selected from acyloxy, -OCOR³R³Is -NR¹R², Phenyl, (C₁-C₁₀) Alkyl, (C₁-C₄) Perfluoroalkyl, (C₁-C₆) Alkoxy and (C₁-C₆) Selected from perfluoroalkoxy, (2) (C₃-C₈) Cycloalkyl or (C₃-C₈) Cycloalkenyl, where the (C₃-C₈) Cycloalkyl or (C₃-C₈) Each of cycloalkenyl is halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C₁-C₁₀) Alkyl, (C₁-C₄) Perfluoroalkyl, (C₁-C₁₀) Alkoxy, (C₁-C₄) Perfluoroalkoxy, (C₁-C₁₀) Alkoxycarbonyl, (C₁-C₁₀) Alkylthio, (C₁-C₁₀) Alkylamino, di (C₁-C₁₀) Alkylamino, (C₁-C₁₀) Alkylaminocarbonyl, di (C₁-C₁₀) Alkylaminocarbonyl, (C₁-C₁₀) Acyl, (C₁-C₁₀) Perfluoroacyl, (C₁-C₁₀) Acylamino, (C₁-C₁₀) Perfluoroacylamino, and (C₁-C₁₀) May contain 1 to 4 substituents independently selected from acyloxy,
(3) A saturated, partially saturated or aromatic heterocyclic ring containing a total of 3 to 14 ring atoms, wherein the heterocyclic ring is independently selected from oxygen, nitrogen and sulfur Containing heterocyclic heteroatoms, such as halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C₁-C₁₀) Alkyl, (C₁-C₄) Perfluoroalkyl, (C₁-C₁₀) Alkoxy, (C₁-C₄) Perfluoroalkoxy, (C₁-C₁₀) Alkoxycarbonyl, (C₁-C₁₀) Alkylthio, (C₁-C₁₀) Alkylamino, di (C₁-C₁₀) Alkylamino, (C₁-C₁₀) Alkylaminocarbonyl, di (C₁-C₁₀) Alkylaminocarbonyl, (C₁-C₁₀) Acyl, (C₁-C₁₀) Perfluoroacyl, (C₁-C₁₀) Acylamino, (C₁-C₁₀) Perfluoroacylamino, and (C₁-C₁₀) May contain 1 to 4 substituents independently selected from acyloxy, (e) (C₃-C₈) Cycloalkyl or (C₃-C₈) Cycloalkenyl, where the (C₃-C₈) Cycloalkyl and (C₃-C₈) Each of cycloalkenyl is halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C₁-C₁₀) Alkyl, (C₁-C₄) Perfluoroalkyl, (C₁-C₁₀) Alkoxy, (C₁-C₄) Perfluoroalkoxy, (C₁-C₁₀) Alkoxycarbonyl, (C₁-C₁₀) Alkylthio, (C₁-C₁₀) Alkylamino, di (C₁-C₁₀) Alkylamino, (C₁-C₁₀) Alkylaminocarbonyl, di (C₁-C₁₀) Alkylaminocarbonyl, (C₁-C₁₀) Acyl, (C₁-C₁₀) Perfluoroacyl, (C₁-C₁₀) Acylamino, (C₁-C₁₀) Perfluoroacylamino, and (C₁-C₁₀) May contain 1 to 4 substituents independently selected from acyloxy, (f)-(CH₂)_nCOR⁴Where-(CH₂)_nCOR⁴R⁴Is hydroxy, phenyl, -NR¹R², (C₁-C₄) Alkyl, (C₁-C₄) Perfluoroalkyl, (C₁-C₄) Alkoxy, (C₁-C₄) Perfluoroalkoxy, (C₃-C₈) Cycloalkyl, and (C₃-C₈) Selected from cycloalkenyl and n is an integer from 1 to 4.
(Ii) BMS-197636 (9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl-9H-fluorene -9-carboxamide) and pharmaceutically acceptable salts thereof.
(Iii) Compound BMS-200150 (2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one) and its pharmaceutically acceptable salt.
(Iv) Compound BMS-201038 (9- [4- (4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl) butyl] -N-2,2,2-trifluoroethyl ) -9H-fluorene-9-carboxamide) and pharmaceutically acceptable salts thereof.
  Further, in Patent Document 23, the following compounds are described as specific examples.
4'-trifluoromethyl-biphenyl-2-carboxylic acid- (2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,
4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,
9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl-9H-fluorene-9-carboxamide;
2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one,
(K) Japanese Patent Application Laid-Open No. 2000-169395 describes an MTP inhibitor comprising a benzamide derivative as described below (see Patent Document 24).
4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (1H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] An amide,
4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide,
9- (4- [4- [4′-trifluoromethyl-biphenyl-2-carbonyl) amino] -piperidin-1-yl} butyl) -9H-fluorene-9-carboxylic acid- (2,2,2 -Trifluoroethyl) -amide,
9- [4- [4- (2-Benzothiazol-2-yl-benzoylamino) piperidin-1-yl] butyl] -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoroethyl ) Amide,
[11a-R] -8-[(4-cyanophenyl) methoxy] -2-cyclopentyl-7- (prop-2-enyl) -2,3,11,11a-tetrahydro-6H-pyrazino [1,2b ] Isoquinoline-1,4-dione,
[11a-R] -2-cyclopentyl-7- (prop-2-enyl) -8-[(pyridin-2-yl) methoxy] -2,3,11,11a-tetrahydro-6H-pyrazino [1, 2b] isoquinoline-1,4-dione,
2-cyclopentyl-2- [4- (2,4-dimethylpyrido [2,3-b] indol-9-ylmethyl) phenyl] -N- (2-hydroxy-1-phenylethyl) acetamide,
2-cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) -phenyl] acetamide.
2-3. Issues with MTP inhibitors
  By the way, as described above, various MTP inhibitors have been known. On the other hand, as the development of MTP inhibitors progresses, the MTP inhibitors exert an action to lower blood lipids, but to the liver. The possibility of causing fat accumulation (fatty liver) was pointed out, and hepatotoxicity was a concern (see Patent Document 25).
  For these reasons, a novel MTP inhibitor is strongly desired to have a sufficient preventive and therapeutic effect without side effects such as fatty liver.
(L) Recently, studies on compounds that selectively inhibit MTP in the small intestine have been actively conducted. Has also been reported (see Patent Document 26).
General formula (1)

  [In the formula, R¹And R²Is a hydrogen atom, C_1-6Alkyl group, C_3-7A cycloalkyl group, C_1-6Alkoxy group, halo C_1-6Alkyl group, halo C_1-6Alkyloxy group, C which may be substituted_6-14Aryl group, optionally substituted C_7-16Aralkyl group, C which may be substituted_6-14Aryloxy group, C which may be substituted_7-16Aralkyloxy group, C which may be substituted_7-15An arylcarbonyl group, an optionally substituted heterocyclic group, C_2-7Alkoxycarbonyl group, halogen atom, C_2-6An alkenyl group, -N (R⁴⁰) (R⁴¹) (Where R⁴⁰And R⁴¹Are the same or different and each represents a hydrogen atom or optionally substituted C_6-14An aryl group. Ring A is C_6-14An aryl group, a heterocyclic group, or

X is —COO— (CH₂)_n-, -CON (R¹⁰)-(CH₂)_n-Or -N (R¹⁰) -CO- (CH₂)_n-(Where R¹⁰Is a hydrogen atom, C_1-6Alkyl group or C_3-7A cycloalkyl group, n is 0 or an integer of 1 to 3; ); R³And R⁴Are the same or different and are a hydrogen atom, a hydroxyl group, a halogen atom, or optionally substituted C._1-6Alkyl group, C_1-6Alkoxy group, halo C_1-6Alkyl group, C_7-16Aralkyloxy group, C_1-6An acyl group, an optionally substituted heterocyclic group, -CON (R¹¹) (R¹²) (Where R¹¹And R¹²Are the same or different and are a hydrogen atom, C_1-6Alkyl group, optionally substituted C_6-14Aryl group, optionally substituted C_7-16Aralkyl group, C_1-6An alkoxy group or together with the nitrogen atom to which it is attached

  (Where p is an integer of 0 or 1 to 2). ),-(CH₂)_q-N (R¹³) (R¹⁴) (Where R¹³And R¹⁴Are the same or different and are a hydrogen atom, C_1-6Alkyl group, C_2-7Alkoxycarbonyl group, C_1-6An acyl group or together with the nitrogen atom to which it is attached

  (Wherein p is as defined above). q is 0 or an integer of 1 to 3. ) Or -CO (R¹⁵) (Where R¹⁵Is a hydroxyl group, C_1-6An alkoxy group, optionally substituted C_6-14Aryloxy group, C which may be substituted_7-16Aralkyloxy group or C_1-6It is an alkyl group. Ring B is

  (Where K is 0 or an integer from 1 to 2) or R³And R¹⁰And R¹⁰The ringing nitrogen atom and ring B come together,

  May be formed; Alk1¹Is alkanediyl or alkenediyl; Alk1²Is alkanediyl or alkenediyl; l is 0 or an integer from 1 to 3; m is 0 or an integer from 1 to 3; D is C_1-6Alkyl group, C_2-6Alkenyl group, C_2-7An alkoxycarbonyl group, -N (R⁴²) -CO (R⁴³) (Where R⁴²Is a hydrogen atom or C_{1- 6}An alkyl group, R⁴³Is C_6-14Aryl group or C_7-16Aralkyl group. ) Or the following formula:

(Wherein R⁵, R⁶And R⁷Are the same or different and are a hydrogen atom, C_1-6Alkyl group, C_1-6Alkoxy group, C_2-7Alkoxycarbonyl group, carboxyl group, halogen atom, cyano group, nitro group, haloC_1-6Alkyl group, C_1-6Acyl group, hydroxyl group, amino group, C which may be substituted_6-14An aryl group or-(CH₂)_r-CON (R¹⁶) (R¹⁷) (Where R¹⁶And R¹⁷Are the same or different and are a hydrogen atom, C_1-6Alkyl group or halo C_1-6It is an alkyl group. r is 0 or an integer of 1 to 3. Ring C is C_6-14Aryl group, C_7-15Arylcarbonylamino group, C_8-17Aralkylcarbonylamino group, heterocyclic residue, C_3-7A cycloalkyl group, C_7-16Aralkyl group, or ring C and R⁷And R⁸Together

May be formed. R); and R⁸And R⁹Are the same or different and are a hydrogen atom, C_1-6Alkyl group, optionally substituted C_6-14Aryl group, hydroxy C_1-6An alkyl group, -CON (R¹⁸) (R¹⁹) (Where R¹⁸And R¹⁹Are the same or different and are a hydrogen atom, C_1-6Alkyl group, C_3-7Cycloalkyl group, halo C_1-6Alkyl group, C_2-12An alkoxyalkyl group or an optionally substituted C_6-14An aryl group), —COO (R²⁰) Or-(CH₂)_s-OCO (R²⁰) (Where R²⁰Is a hydrogen atom, C_1-6Alkyl group or C_3-7A cycloalkyl group; s is 0 or an integer of 1 to 3. ), -N (R²¹) (R²²) (Where R²¹And R²²Are the same or different and are a hydrogen atom, C_1-6Alkyl group, C_1-6Acyl group, C_1-6An alkylsulfonyl group, or R²¹And R²²Together with the nitrogen atom to which

May be formed. ) Or R⁸And R⁹Together with C_3-7A cycloalkyl group may be formed. Or a prodrug thereof or a pharmaceutically acceptable salt thereof.
  In the same patent document, the following compounds are described as specific compounds.
2- (2- {3-methyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {4- [methyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisopropyl ester,
2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid dimethyl ester,
2-cyclopentyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid dicyclohexyl ester,
2-benzyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {2-methyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2-cyclohexyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-phenyl-2- (2- {2-trifluoromethyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-Pyridin-2-yl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-Pyridin-3-yl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-phenyl-2- (2- {3-trifluoromethyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {4-[(4'-methyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {4-[(4'-methoxy-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2-phenyl-2- (2- {4-[(3'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {4- [Isopropyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {4- [cyclohexyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid dipropyl ester,
2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,
2- (2- {4- [ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-ethyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-isopropyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-isobutyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-chloro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-bromo-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-diethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-diisopropylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3- (ethyl-methylcarbamoyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
{3- (Ethyl-methylcarbamoyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetic acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,
{3- (Pyrrolidine-1-carbonyl) -4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetic acid 2,2-bis-ethylcarbamoyl-2-phenyl- Ethyl ester,
2-phenyl-2- (2- {3- (pyrrolidine-1-carbonyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malon Acid diethyl ester,
2-phenyl-2- (2- {3- (piperidine-1-carbonyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malon Acid diethyl ester,
2- [2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -ethyl] -2-phenyl-malon Acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-fluoro-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {4-[(4'-bromo-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid dimethyl ester,
2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {4-[(4'-chloro-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {4-[(4'-acetyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {4-[(4'-cyano-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- [3- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] -2-phenyl-malon Acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {4-[(5-Chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di2,2 , 2-trifluoroethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {5-Dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5-nitro-pyridine-2 -Yl) -malonic acid diethyl ester,
2- (5-amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridin-2-yl-malonic acid Diethyl ester,
2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
2- (2- {3-Bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o-tolyl-malonic acid diethyl ester ,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m-tolyl-malonic acid diethyl ester ,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p-tolyl-malonic acid diethyl ester ,
2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (3-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-succinic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {4-[(6-Chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- [2- (2- {3-Dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -ethyl] -2 -Phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- [2- (2- {4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy) -ethyl] -2 -Phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- [4- (2,4-bis-trifluoromethyl-benzoylamino) -3-dimethylcarbamoyl-phenyl] -acetoxymethyl} -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-methyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- {2- [3-dimethylcarbamoyl-4- (2-ethyl-4-trifluoromethyl-benzoylamino) -phenyl] -acetoxymethyl} -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-ethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-isopropenyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-isopropyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-thiophen-2-yl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-thiophen-3-yl-malonic acid Diethyl ester,
2- (2- {4-Dimethylcarbamoyl-5-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -pyridin-2-yl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3-methyl-thiophene-2 -Yl) -malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5-methyl-thiophene-2 -Yl) -malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-thiazol-2-yl-malonic acid Diethyl ester,
2- (2- {3-ethoxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-methoxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-isopropoxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-benzyloxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-hydroxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2-phenyl-2- (2- {3-piperidin-1-yl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-phenyl-2- (2- {3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -diethyl malonate ester,
2- (2- {3-dimethylamino-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-morpholin-4-yl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-diethylamino-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {2-chloro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -benzoyloxy} -ethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-ethoxycarbonyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (3- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -propionyloxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-benzyloxycarbonyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-carboxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-isopropoxycarbonyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-methoxycarbonyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-acetylamino-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-methoxycarbonylamino-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3- (4-Methyl-thiazol-2-yl) -4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2 -Phenyl-malonic acid diethyl ester,
2-phenyl-2- (2- {6-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -biphenyl-3-yl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-formyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylaminomethyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3- (methoxy-methylcarbamoyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-isobutyryl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester, and
2- (2- {3- (1-hydroxy-2-methyl-propyl) -4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2 -Phenyl-malonic acid diethyl ester.
  Among the above compound groups, particularly representative biphenylamide derivatives are as follows.
2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,
2- (2- {4- [ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid dimethyl ester,
2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- [3- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] -2-phenyl-malon Acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {4-[(5-Chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di2,2 , 2-trifluoroethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {5-Dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5-nitro-pyridine-2 -Yl) -malonic acid diethyl ester,
2- (5-amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridin-2-yl-malonic acid Diethyl ester,
2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
2- (2- {3-Bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o-tolyl-malonic acid diethyl ester ,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m-tolyl-malonic acid diethyl ester ,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p-tolyl-malonic acid diethyl ester ,
2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (3-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-succinic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {4-[(6-Chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- [2- (2- {3-Dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -ethyl] -2 -Phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- [2- (2- {4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy) -ethyl] -2 -Phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
JP 2000-281561 A JP-A-9-309834 JP 2004-10575 A Japanese National Patent Publication No. 11-509238 JP 2003-73261 A Japanese Patent Publication No.3-1288 Japanese Patent Publication No. 3-28404 JP 11-246404 A Special table 2003-531099 gazette WO00 / 056726 Japanese Patent Laid-Open No. 08-208476 WO2002 / 051385 publication Japanese Patent Laid-Open No. 9-59159 JP-A-11-228569 Japanese translation of PCT publication No. 2004-514676 (WO2002 / 042291) Japanese translation of PCT publication No. 2003-535900 (WO01 / 097810) Japanese translation of PCT publication No. 2003-521484 (WO01 / 047898) Japanese translation of PCT publication No. 2003-520270 (WO01 / 053260) JP-T-2003-519131 (WO01 / 047899) Japanese translation of PCT publication No. 2003-509505 (WO01 / 021604) Japanese translation of PCT publication No. 2003-505373 (WO01 / 005762) JP 2000-510483 A (WO 98/47875) JP 2001-172180 A JP 2000-169395 A JP 2002-220345 A JP 2003-321424 A W. L. Chiou and S. Riegelman: Pharmaceutical application of solid dispersal systems, “J. Pharm. Sci.” (Vol. 60, 1281-1302, 1971). [Wetterau and Gilbersmit, “Chem. Phys. Lipids” (38, pp. 205-222, 1985)]

〔式中、Ｒ^１及びＲ^２は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−７シクロアルキル基、Ｃ_１−６アルコキシ基、ハロＣ_１−６アルキル基、ハロＣ_１−６アルキルオキシ基、置換されてもよいＣ_６−１４アリール基、置換されてもよいＣ_７−１６アラルキル基、置換されてもよいＣ_６−１４アリールオキシ基、置換されてもよいＣ_７−１６アラルキルオキシ基、置換されてもよいＣ_７−１５アリールカルボニル基、置換されてもよいヘテロ環基、Ｃ_２−７アルコキシカルボニル基、ハロゲン原子、Ｃ_２−６アルケニル基、−Ｎ（Ｒ^４０）（Ｒ^４１）（ここで、Ｒ^４０及びＲ^４１は、同一又は異なって水素原子または置換されていてもよいＣ_６−１４アリール基である。）であり；環Ａは、Ｃ_６−１４アリール基、ヘテロ環基、又は

であり；Ｘは、−ＣＯＮ（Ｒ^１０）−（ＣＨ_２）_ｎ−（ここで、Ｒ^１０は、水素原子、Ｃ_１−６アルキル基又はＣ_３−７シクロアルキル基であり、ｎは０又は１乃至３の整数である。）であり；Ｒ^３及びＲ^４は、同一又は異なって水素原子、水酸基、ハロゲン原子、置換されていてもよいＣ_１−６アルキル基、Ｃ_１−６アルコキシ基、ハロＣ_１−６アルキル基、Ｃ_７−１６アラルキルオキシ基、Ｃ_１−６アシル基、置換されていてもよいヘテロ環基、−ＣＯＮ（Ｒ^１１）（Ｒ^１２）（ここで、Ｒ^１１及びＲ^１２は、同一又は異なって水素原子、Ｃ_１−６アルキル基、置換されてもよいＣ_６−１４アリール基、置換されてもよいＣ_７−１６アラルキル基、Ｃ_１−６アルコキシ基であり、又は結合する窒素原子と一緒になって

（ここで、ｐは０又は１乃至２の整数である。）を形成してもよい。）、−（ＣＨ_２）_ｑ−Ｎ（Ｒ^１３）（Ｒ^１４）（ここで、Ｒ^１３及びＲ^１４は、同一又は異なって水素原子、Ｃ_１−６アルキル基、Ｃ_２−７アルコキシカルボニル基、Ｃ_１−６アシル基であり、又は結合する窒素原子と一緒になって

（ここで、ｐは前記と同意義。）を形成してもよい。ｑは０又は１乃至３の整数である。）又は−ＣＯ（Ｒ^１５）（ここで、Ｒ^１５は、水酸基、Ｃ_１−６アルコキシ基、置換されてもよいＣ_６−１４アリールオキシ基、置換されてもよいＣ_７−１６アラルキルオキシ基又はＣ_１−６アルキル基である。）であり；環Ｂは、

（ここでＫは０又は１乃至２の整数である。）であり、又はＲ^３とＲ^１０とＲ^１０が結合している窒素原子と環Ｂが一緒になって、

を形成してもよく；Ａｌｋ１^１はアルカンジイル又はアルケンジイルであり；Ａｌｋ１^２はアルカンジイル又はアルケンジイルであり；ｌは０又は１乃至３の整数であり；ｍは０又は１乃至３の整数であり；Ｄは、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−７アルコキシカルボニル基、−Ｎ（Ｒ^４２）−ＣＯ（Ｒ^４３）（ここで、Ｒ^４２は水素原子又はＣ_１−６アルキル基であり、Ｒ^４３はＣ_６−１４アリール基又はＣ_７−１６アラルキル基である。）又は下記式；

（式中、Ｒ^５、Ｒ^６及びＲ^７は、同一又は異なって水素原子、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_２−７アルコキシカルボニル基、カルボキシル基、ハロゲン原子、シアノ基、ニトロ基、ハロＣ_１−６アルキル基、Ｃ_１−６アシル基、水酸基、アミノ基、置換されてもよいＣ_６−１４アリール基又は−（ＣＨ_２）_ｒ−ＣＯＮ（Ｒ^１６）（Ｒ^１７）（ここで、Ｒ^１６及びＲ^１７は、同一又は異なって水素原子、Ｃ_１−６アルキル基又はハロＣ_１−６アルキル基である。ｒは０又は１乃至３の整数である。）であり；環Ｃは、Ｃ_６−１４アリール基、Ｃ_７−１５アリールカルボニルアミノ基、Ｃ_８−１７アラルキルカルボニルアミノ基、ヘテロ環残基、Ｃ_３−７シクロアルキル基、Ｃ_７−１６アラルキル基、又は環ＣとＲ^７とＲ^８が一緒になって、

を形成してもよい。）で示される基であり；Ｒ^８及びＲ^９は、同一又は異なって水素原子、Ｃ_１−６アルキル基、置換されてもよいＣ_６−１４アリール基、ヒドロキシＣ_１−６アルキル基、−ＣＯＮ（Ｒ^１８）（Ｒ^１９）（ここで、Ｒ^１８及びＲ^１９は、同一又は異なって水素原子、Ｃ_１−６アルキル基、Ｃ_３−７シクロアルキル基、ハロＣ_１−６アルキル基、Ｃ_２−１２アルコキシアルキル基又は置換されてもよいＣ_６−１４アリール基である）、−ＣＯＯ（Ｒ^２０）もしくは−（ＣＨ_２）_ｓ−ＯＣＯ（Ｒ^２０）（ここで、Ｒ^２０は、水素原子、Ｃ_１−６アルキル基又はＣ_３−７シクロアルキル基である。ｓは０又は１乃至３の整数である。）、−Ｎ（Ｒ^２１）（Ｒ^２２）（ここで、Ｒ^２１及びＲ^２２は、同一又は異なって水素原子、Ｃ_１−６アルキル基、Ｃ_１−６アシル基、Ｃ_１−６アルキルスルホニル基、又はＲ^２１及びＲ^２２が結合する窒素原子と一緒になって、

を形成してもよい。）であり、又はＲ^８とＲ^９が一緒になってＣ_３−７シクロアルキル基を形成してもよい。〕で示されるエステル化合物若しくはそのプロドラッグ又はそれらの製薬上許容される塩。
１８．ベンズアミド誘導体が下記から選ばれる化合物である上記１５に記載の固形製剤。
・２−フェニル−２−（２−｛４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジイソブチル エステル、
・２−（２−｛４−［エチル−（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジメチル エステル、
・２−シクロペンチル−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−シクロヘキシル−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［３−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシ）−プロピル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−メトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（５−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジ２，２，２−トリフルオロエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（２’−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ブロモ−５−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−クロロ−５−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（３’−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（３’−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（５−ニトロ−ピリジン−２−イル）−マロン酸 ジエチル エステル、
・２−（５−アミノ−ピリジン−２−イル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ピリジン−２−イル−マロン酸 ジエチル エステル、
・２−（２−｛３−クロロ−５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ブロモ−５−ジメチルカルバモイル−２−フルオロ−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｏ−トリル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｍ−トリル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−ｐ−トリル−マロン酸 ジエチル エステル、
・２−（２−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（３−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（４−クロロ−フェニル）−２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−コハク酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（２−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（３−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−（４−メトキシ−フェニル）−マロン酸 ジエチル エステル、
・２−（２−｛４−［（５，４’−ビス−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛４−［（６−クロロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−フルオロ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［２−（２−｛３−ジメチルカルバモイル−４−［（５−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシ）−エチル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−エトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（５−イソプロポキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
・２−［２−（２−｛４−［（５，４’−ビス−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−３−ジメチルカルバモイル−フェニル｝−アセトキシ）−エチル］−２−フェニル−マロン酸 ジエチル エステル、
・２−（２−｛３−ジメチルカルバモイル−４−［（６−メトキシ−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、及び
・２−（２−｛３−ジメチルカルバモイル−４−［（３−メチル−４’−トリフルオロメチル−ビフェニル−２−カルボニル）−アミノ］−フェニル｝−アセトキシメチル）−２−フェニル−マロン酸 ジエチル エステル、
１９．医薬有効成分としての水難溶性の化学物質と水溶性高分子物質を有機溶媒に溶解して得られる溶液と無機多孔性物質を攪拌混合した後、造粒し、乾燥することを特徴とする、医薬有効成分としての水難溶性の化学物質、水溶性高分子物質及び無機多孔性物質を含む固形製剤であって、
（１）該水難溶性の化学物質が該水溶性高分子物質とともに固体分散体を形成しており、
（２）該固体分散体を形成する水溶性高分子物質が微細片状であって、かつ
（３）該微細片状の水溶性高分子物質が前記無機多孔性物質表面に吸着された及び／又は接着した状態で保持されていることを特徴とする水溶解性が改善された固形製剤の製造方法。
２０．水溶性高分子物質が、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、コポリビドン、カンテン、デキストリン、ゼラチン又はこれらの混合物である上記１９に記載の固形製剤の製造方法。
２１．水溶性高分子物質が、ポリビニルピロリドン又はヒドロキシプロピルセルロースである上記２０に記載の固形製剤の製造方法。
２２．水溶性高分子物質が、医薬有効成分としての水難溶性の化学物質に対して重量比で３乃至１００倍量である上記１９乃至２１のいずれか１項に記載の固形製剤の製造方法。
２３．水溶性高分子物質がポリビニルピロリドンであり、かつ該ポリビニルピロリドンが医薬有効成分としての水難溶性の化学物質に対して重量比で３乃至５０倍量である上記２２に記載の固形製剤の製造方法。
２４．水溶性高分子物質がヒドロキシプロピルセルロースであり、かつ該ヒドロキシプロピルセルロースが医薬有効成分としての水難溶性の化学物質に対して重量比で６乃至１５倍量である上記２２に記載の固形製剤の製造方法。
２５．無機多孔性物質が、ケイ酸カルシウム、軽質無水ケイ酸、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミニウムマグネシウム、合成ケイ酸アルミニウム、含水二酸化ケイ素、又はこれらの混合物である上記１９乃至２４のいずれか１項に記載の固形製剤の製造方法。
２６．無機多孔性物質が、軽質無水ケイ酸である上記２５に記載の固形製剤の製造方法。
２７．無機多孔性物質が、医薬有効成分としての水難溶性の化学物質に対して重量比で４乃至１４倍量である上記１９乃至２６のいずれか１項に記載の固形製剤の製造方法。
２８．有機溶媒量が水溶性高分子物質の１乃至２重量倍である上記１９乃至２７のいずれか１項に記載の固形製剤の製造方法。
２９．医薬有効成分としての水難溶性の化学物質が、脂質吸収阻害剤である上記１９乃至２８のいずれか１項に記載の固形製剤の製造方法。
３０．脂質吸収阻害剤が、アポリポタンパク質Ｂ（Ａｐｏ Ｂ）分泌の阻害剤、トリグリセリド（ＴＧ）転送淡タンパク阻害剤又はコレステリルエステル転送タンパク（ＣＥＴＰ）阻害剤である上記２９に記載の固形製剤の製造方法。
３１．脂質吸収阻害剤が、ＭＴＰ阻害剤、リパーゼ阻害剤又はＡＣＡＴ阻害剤である上記２９に記載の固形製剤の製造方法。
３２．脂質吸収阻害剤が、ＭＴＰ阻害剤である上記３１に記載の固形製剤の製造方法。
卓越した溶解性を有する本発明の固形製剤は、バイオアベイラビリテイが格段に向上され、極めて少量の投与量でその医薬品が本来有する機能を十分かつ有効に発揮させることができ、しかも安定性にも優れている。また、本発明がもたらす溶解性改善の効果は、薬剤固有の化学的な性質に起因するのではなく、物理学的効果に起因するものと考えられることから、様々な幅広い医薬品への応用が期待できる。
例えば、本発明技術をＭＴＰ阻害物質及び／又はＡｐｏ Ｂ分泌阻害物質に適用した場合には、投与後、体内において速やか、かつ完全に溶解されるので、投与量を低減できるだけでなく、少量の薬剤が小腸に速やかに作用することによって余分なＭＴＰ阻害物質が肝臓に到達して脂肪肝等の副作用や予期せぬ副作用を惹起する恐れを低減することも期待できる。したがって、本発明技術を適用したＭＴＰ阻害剤は、今までにない優れた高脂血症、動脈硬化症、冠動脈疾患、肥満症、糖尿病又は高血圧症の治療薬又は予防薬となり得るだろう。
これら固形製剤は、有効成分としての化学物質が水溶性高分子物質とともに微細片状の固体分散体を形成し、更に該微細片状の水溶性高分子物質が前記無機多孔性物質表面に吸着された及び／又は接着した状態で保持されていることによって溶解性の向上に寄与しているものと推定される。
更に、本発明の製造方法によって得られる固体分散体は微細片状であり、かつ嵩高・重質（高密度）であるので、溶媒法や溶融法のように得られた固体分散体を裁断したり、破砕する必要もなく、また、乾燥作業下でも顆粒が容器に付着したり飛散することもなく取扱い性に優れ、噴霧乾燥法により得られた顆粒に比して含量均一性が確保しやすく、そのままハードカプセル剤への充填や錠剤化が可能である。Drugs are required to have sufficient effectiveness for the original purpose of the drug, and high stability is required from the viewpoint of safety. In terms of effectiveness, that is, medicinal effect, it is important to design bioavailability sufficiently high in designing a solid pharmaceutical preparation, particularly an oral preparation. As described above, factors affecting bioavailability include water solubility, drug absorption throughout the digestive tract, dosage strength, and first-pass effect, but especially for poorly water-soluble drugs, the dissolution rate is the rate-limiting factor for absorption. Since it is known to be a stage, solubility in water is the most important and high priority factor in drug development.
Unfortunately, many medicinal chemicals are sparingly soluble in water, so even if administered orally, only a small portion of the dose is transferred and absorbed into the blood, so its bioavailability is extremely low. Has the disadvantages.
The same is true for MTP inhibitors. In addition, many conventional MTP inhibitors have the disadvantage that they do not act selectively in the small intestine but also act on the liver suspected of causing side effects such as fatty liver.
In addition, regarding the method for producing a solid dispersion, when the solvent method is adopted, the solid dispersion may be in the form of a film depending on the production conditions as described above, and therefore a step for finely cutting this is required. Further, when the melting method is adopted, the solid dispersion obtained is in the form of pellets, and thus further processing such as pulverization is necessary. In addition, when the spray drying method is adopted, a large amount of solvent is required, and the inside of the resulting granule becomes hollow, resulting in high bulkiness and poor handleability. There is a disadvantage that the specific gravity difference occurs in the tablet and the homogeneity at the time of tableting cannot be maintained.
Therefore, the object of the present invention is to improve the solubility and improve the bioavailability by adding a formulation to a poorly water-soluble chemical substance (for example, a lipid absorption inhibitor such as an MTP inhibitor) as an active pharmaceutical ingredient. It is an object of the present invention to provide a novel solid preparation having improved and excellent high stability and an effective production method thereof.
The inventors have intensively studied mainly from the viewpoint of preparation in order to provide pharmaceuticals having excellent dissolution characteristics, that is, high bioavailability, and also excellent stability, such as MTP inhibitors. As a result, a poorly water-soluble chemical substance (for example, an MTP inhibitor) as an active ingredient and a water-soluble polymer substance such as polyvinyl pyrrolidone or hydroxypropyl cellulose are dissolved in an organic solvent. The present invention was completed by discovering that the solid preparation obtained by stirring and mixing, granulating and drying has excellent solubility and excellent stability.
Specifically, the present invention is as follows.
1. A solid preparation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as an active pharmaceutical ingredient,
(1) The poorly water-soluble chemical substance forms a solid dispersion together with the water-soluble polymer substance,
(2) The water-soluble polymer material forming the solid dispersion is in the form of fine pieces, and (3) the fine piece-like water-soluble polymer material is adsorbed on the surface of the inorganic porous material and / or Alternatively, a solid preparation with improved water solubility, characterized by being held in an adhered state.
2. 2. The solid preparation according to 1 above, wherein the water-soluble polymer substance is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin, or a mixture thereof.
3. 3. The solid preparation according to 2 above, wherein the water-soluble polymer substance is polyvinyl pyrrolidone or hydroxypropyl cellulose.
4). 4. The solid preparation according to any one of 1 to 3 above, wherein the water-soluble polymer substance is 3 to 100 times by weight with respect to a poorly water-soluble chemical substance as an active pharmaceutical ingredient.
5. 5. The solid preparation according to 4 above, wherein the water-soluble polymer substance is polyvinyl pyrrolidone, and the polyvinyl pyrrolidone is 3 to 50 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient.
6). 5. The solid preparation according to 4 above, wherein the water-soluble polymer substance is hydroxypropylcellulose, and the hydroxypropylcellulose is 6 to 15 times by weight with respect to a poorly water-soluble chemical substance as an active pharmaceutical ingredient.
7). The inorganic porous material is calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate metasilicate, magnesium magnesium silicate, synthetic aluminum silicate, hydrous silicon dioxide, or a mixture thereof. 7. The solid preparation according to any one of 1 to 6 above.
8). 8. The solid preparation according to 7 above, wherein the inorganic porous substance is light anhydrous silicic acid.
9. 9. The solid preparation according to any one of 1 to 8 above, wherein the inorganic porous substance is 4 to 14 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient.
10. 10. The solid preparation according to any one of 1 to 9 above, wherein the poorly water-soluble chemical substance as a pharmaceutical active ingredient is a lipid absorption inhibitor.
11. 11. The solid preparation according to 10 above, wherein the lipid absorption inhibitor is an inhibitor of apolipoprotein B (Apo B) secretion, a triglyceride (TG) transfer light protein inhibitor or a cholesteryl ester transfer protein (CETP) inhibitor.
12 11. The solid preparation according to 10 above, wherein the lipid absorption inhibitor is an MTP inhibitor, a lipase inhibitor or an ACAT inhibitor.
13. 13. The solid preparation according to 12 above, wherein the lipid absorption inhibitor is an MTP inhibitor.
14 14. The solid preparation according to the above 13, wherein the MTP inhibitor is a substituted piperazine derivative or a salt thereof.
15. 14. The solid preparation according to the above 13, wherein the MTP inhibitor is a benzamide derivative or a salt thereof.
16. 16. The solid preparation according to 15 above, wherein the MTP inhibitor is a benzamide derivative selected from the following or a salt thereof.
4′-trifluoromethyl-biphenyl-2-carboxylic acid- (2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,
4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,
9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl-9H-fluorene-9-carboxamide;
2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one,
9- [4- (4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl) butyl] -N-2,2,2-trifluoroethyl) -9H-fluorene-9 Carboxamide.
4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (1H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] An amide,
4′-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide,
9H- (4- [4- [4'-trifluoromethyl-biphenyl-2-carbonyl) amino] -piperidin-1-yl} butyl) -9H-fluorene-9-carboxylic acid- (2,2,2 -Trifluoroethyl) -amide,
9- [4- [4- (2-Benzothiazol-2-yl-benzoylamino) piperidin-1-yl] butyl] -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoroethyl ) Amide,
[11a-R] -8-[(4-cyanophenyl) methoxy] -2-cyclopentyl-7- (prop-2-enyl) -2,3,11,11a-tetrahydro-6H-pyrazino [1,2b ] Isoquinoline-1,4-dione,
[11a-R] -2-cyclopentyl-7- (prop-2-enyl) -8-[(pyridin-2-yl) methoxy] -2,3,11,11a-tetrahydro-6H-pyrazino [1, 2b] isoquinoline-1,4-dione,
2-cyclopentyl-2- [4- (2,4-dimethylpyrido [2,3-b] indol-9-ylmethyl) phenyl] -N- (2-hydroxy-1-phenylethyl) acetamide, and 2- Cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) -phenyl] acetamide.
17. 16. The solid preparation according to 15 above, wherein the benzamide derivative is a compound represented by the following formula (where X represents —CON (R ¹⁰ ) — (CH ₂ ) _n —).
General formula (1)

[Wherein, R ¹ and R ² are a hydrogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _1-6 alkoxy group, a halo C _1-6 alkyl group, a halo C _1-6 alkyl An oxy group, an _optionally substituted C _6-14 aryl group, an _optionally substituted C _7-16 aralkyl group, an _optionally substituted C _6-14 aryloxy group, an _optionally substituted C _7-16 aralkyl An oxy group, an optionally substituted C _7-15 arylcarbonyl group, an optionally substituted heterocyclic group, a C _2-7 alkoxycarbonyl group, a halogen atom, a C _2-6 alkenyl group, —N (R ⁴⁰ ) ( R ⁴¹ ) (wherein R ⁴⁰ and R ⁴¹ are the same or different and are a hydrogen atom or an optionally substituted C _6-14 aryl group); ring A is a C _6-14 aryl group A heterocyclic group, Or

X is —CON (R ¹⁰ ) — (CH ₂ ) _n — (wherein R ¹⁰ is a hydrogen atom, a C _1-6 alkyl group or a C _3-7 cycloalkyl group, and n is 0 Or R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted C _1-6 alkyl group, or a C _1-6 alkoxy. A group, a halo C _1-6 alkyl group, a C _7-16 aralkyloxy group, a C _1-6 acyl group, an _optionally substituted heterocyclic group, —CON (R ¹¹ ) (R ¹² ) (where R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, an optionally substituted C _6-14 aryl group, an optionally substituted C _7-16 aralkyl group, or a C _1-6 alkoxy group. Or together with the binding nitrogen atom

(Where p is an integer of 0 or 1 to 2). ), — (CH ₂ ) _q —N (R ¹³ ) (R ¹⁴ ) (wherein R ¹³ and R ¹⁴ are the same or different and represent a hydrogen atom, a C _1-6 alkyl group, a C _2-7 alkoxycarbonyl group, A C _1-6 acyl group, or together with the nitrogen atom to which it is attached

(Wherein p is as defined above). q is 0 or an integer of 1 to 3. ) Or —CO (R ¹⁵ ) (where R ¹⁵ is a hydroxyl group, a C _1-6 alkoxy group, an optionally substituted C _6-14 aryloxy group, an optionally substituted C _7-16 aralkyloxy group. Or a C _1-6 alkyl group); ring B is

(Wherein K is 0 or an integer of 1 to 2), or the nitrogen atom to which R ³ , R ¹⁰ and R ¹⁰ are bonded together with ring B,

Alk1 ¹ is alkanediyl or alkenediyl; Alk1 ² is alkanediyl or alkenediyl; l is 0 or an integer from 1 to 3; m is 0 or an integer from 1 to 3 D represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-7 alkoxycarbonyl group, —N (R ⁴² ) —CO (R ⁴³ ) (where R ⁴² represents a hydrogen atom or C _{1; -6} alkyl group, and R ⁴³ is a C _6-14 aryl group or a C _7-16 aralkyl group.) Or the following formula:

(Wherein R ⁵ , R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-7 alkoxycarbonyl group, a carboxyl group, a halogen atom, cyano Group, nitro group, halo C _1-6 alkyl group, C _1-6 acyl group, hydroxyl group, amino group, optionally substituted C _6-14 aryl group or — (CH ₂ ) _r —CON (R ¹⁶ ) ( R ¹⁷ ) (where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a halo C _1-6 alkyl group, and r is 0 or an integer of 1 to 3). Ring C is a C _6-14 aryl group, a C _7-15 arylcarbonylamino group, a C _8-17 aralkylcarbonylamino group, a heterocyclic residue, a C _3-7 cycloalkyl group, a C _7-16 An aralkyl group, or C and ^{R 7} and ^{R 8} together,

May be formed. R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, an _optionally substituted C _6-14 aryl group, a hydroxy C _1-6 alkyl group, — CON (R ¹⁸ ) (R ¹⁹ ) (wherein R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a halo C _1-6 alkyl group, A C _2-12 alkoxyalkyl group or an optionally substituted C _6-14 aryl group), —COO (R ²⁰ ) or — (CH ₂ ) _s —OCO (R ²⁰ ) (where R ²⁰ is A hydrogen atom, a C _1-6 alkyl group or a C _3-7 cycloalkyl group, s is 0 or an integer of 1 to 3, and —N (R ²¹ ) (R ²² ) (where R ²¹ and ^{R 22} are the same or different and each represents a hydrogen atom, _1-6 alkyl _{group, C 1-6} acyl _{group, C 1-6} alkylsulfonyl group, or together with the nitrogen atom ^{to which R 21} and ^{R 22} are bonded,

May be formed. Or R ⁸ and R ⁹ may be taken together to form a C _3-7 cycloalkyl group. Or a prodrug thereof or a pharmaceutically acceptable salt thereof.
18. 16. The solid preparation according to 15 above, wherein the benzamide derivative is a compound selected from the following.
2-phenyl-2- (2- {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,
2- (2- {4- [Ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid dimethyl ester,
2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- [3- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] -2-phenyl-malon Acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {4-[(5-Chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di2,2 , 2-trifluoroethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {5-Dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5-nitro-pyridine-2 -Yl) -malonic acid diethyl ester,
2- (5-amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridin-2-yl-malonic acid Diethyl ester,
2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
2- (2- {3-Bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o-tolyl-malonic acid diethyl ester ,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m-tolyl-malonic acid diethyl ester ,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p-tolyl-malonic acid diethyl ester ,
2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (3-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-succinic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {4-[(6-Chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- [2- (2- {3-Dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -ethyl] -2 -Phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- [2- (2- {4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy) -ethyl] -2 -Phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester, and 2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
19. A pharmaceutical product comprising a solution obtained by dissolving a poorly water-soluble chemical substance as a pharmaceutical active ingredient and a water-soluble polymer substance in an organic solvent and an inorganic porous substance, and then granulating and drying. A solid preparation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as an active ingredient,
(1) The poorly water-soluble chemical substance forms a solid dispersion together with the water-soluble polymer substance,
(2) The water-soluble polymer material forming the solid dispersion is in the form of fine pieces, and (3) the fine piece-like water-soluble polymer material is adsorbed on the surface of the inorganic porous material and / or Or the manufacturing method of the solid formulation with which water solubility was improved characterized by hold | maintaining in the state which adhere | attached.
20. 20. The method for producing a solid preparation according to 19 above, wherein the water-soluble polymer substance is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin, or a mixture thereof.
21. 21. The method for producing a solid preparation according to the above 20, wherein the water-soluble polymer substance is polyvinyl pyrrolidone or hydroxypropyl cellulose.
22. 22. The method for producing a solid preparation according to any one of the above 19 to 21, wherein the water-soluble polymer substance is 3 to 100 times by weight with respect to a poorly water-soluble chemical substance as an active pharmaceutical ingredient.
23. 23. The method for producing a solid preparation according to the above 22, wherein the water-soluble polymer substance is polyvinyl pyrrolidone, and the polyvinyl pyrrolidone is 3 to 50 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient.
24. 23. The production of a solid preparation according to the above 22, wherein the water-soluble polymer substance is hydroxypropylcellulose, and the hydroxypropylcellulose is 6 to 15 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. Method.
25. The inorganic porous material is calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate metasilicate, magnesium magnesium silicate, synthetic aluminum silicate, hydrous silicon dioxide, or a mixture thereof. 25. A method for producing a solid preparation according to any one of 19 to 24 above.
26. 26. The method for producing a solid preparation according to the above 25, wherein the inorganic porous substance is light silicic anhydride.
27. 27. The method for producing a solid preparation according to any one of 19 to 26 above, wherein the inorganic porous substance is 4 to 14 times the weight ratio with respect to the poorly water-soluble chemical substance as a pharmaceutical active ingredient.
28. 28. The method for producing a solid preparation according to any one of 19 to 27 above, wherein the amount of the organic solvent is 1 to 2 times by weight of the water-soluble polymer substance.
29. 29. The method for producing a solid preparation according to any one of 19 to 28 above, wherein the poorly water-soluble chemical substance as a pharmaceutical active ingredient is a lipid absorption inhibitor.
30. 30. The method for producing a solid preparation according to the above 29, wherein the lipid absorption inhibitor is an inhibitor of apolipoprotein B (Apo B) secretion, a triglyceride (TG) transfer light protein inhibitor or a cholesteryl ester transfer protein (CETP) inhibitor.
31. 30. The method for producing a solid preparation according to the above 29, wherein the lipid absorption inhibitor is an MTP inhibitor, a lipase inhibitor or an ACAT inhibitor.
32. 32. The method for producing a solid preparation according to 31 above, wherein the lipid absorption inhibitor is an MTP inhibitor.
The solid preparation of the present invention having excellent solubility has a significantly improved bioavailability, and can sufficiently and effectively exert its original function with an extremely small amount of dosage, while also being stable. Is also excellent. In addition, the effect of improving the solubility brought about by the present invention is not caused by chemical properties inherent to the drug, but is considered to be caused by a physical effect, so that it can be expected to be applied to various medicines. it can.
For example, when the technology of the present invention is applied to an MTP inhibitor and / or an Apo B secretion inhibitor, it is rapidly and completely dissolved in the body after administration. By acting on the small intestine quickly, it can be expected that the excess MTP inhibitor will reach the liver and reduce the risk of causing side effects such as fatty liver and unexpected side effects. Therefore, the MTP inhibitor to which the technology of the present invention is applied may be an excellent therapeutic or preventive agent for hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension which has never been achieved.
In these solid preparations, a chemical substance as an active ingredient forms a fine flaky solid dispersion together with a water-soluble polymer substance, and the fine flaky water-soluble polymer substance is further adsorbed on the surface of the inorganic porous substance. It is presumed that it contributes to the improvement of solubility by being held in a state of being adhered and / or adhered.
Furthermore, since the solid dispersion obtained by the production method of the present invention is in the form of fine pieces and is bulky and heavy (high density), the solid dispersion obtained by the solvent method or the melting method is cut. It does not need to be crushed or crushed, and the granule does not adhere to or scatter in the container even during the drying operation. It is easy to handle, and it is easy to ensure content uniformity compared to the granule obtained by the spray drying method. It can be filled into a hard capsule or tableted as it is.

FIG. 1 is a graph showing the dissolution test results of the solid preparation obtained in Example 1. (Example 2)
FIG. 2 is a graph showing a powder X-ray diffraction pattern of the amorphous solid preparation obtained in Example 3-2. (Example 5)

The meaning of each term in the present invention is as follows.
"Solid dispersion" means a solid mixture in which a chemical substance as an active ingredient is dispersed in a polymer substance in a monomolecular and amorphous state (the presence of some crystals is allowed). .
“Slightly water-soluble” means that the drug is sparingly soluble in water and cannot be used as a pharmaceutical product by a normal formulation method. Specifically, at about 20 ° C. It can be expressed as the amount of water required to dissolve 1 g of drug within 30 minutes.
In general, when the amount of water required to dissolve 1 g of drug is 100 mL or more and less than 1000 mL, it is said to be “not easily soluble”, and when the amount of water required is 1000 mL or more to less than 10000 mL, it is said to be “extremely insoluble”. A case of 10,000 mL or more is called “almost insoluble”. Here, “poorly water-soluble” refers to the above-mentioned “difficult to dissolve”, “extremely insoluble” and “almost insoluble” states, and in a narrow sense, to “very insoluble” and “almost insoluble” states.
“Improved water solubility” means that a poorly soluble drug as described above is in a state where it can be used as a medicine depending on the usual formulation method by improving water solubility. Is. Specifically, it means that the solubility in water at about 20 ° C. is improved about 5 times, preferably about 10 times, more preferably 100 times or more.
“Amorphous” is a term for “crystal”, where a chemical substance, such as an MTP inhibitor, as an active ingredient in a solid dispersion has a molecular size or simple substance in a carrier matrix made of a water-soluble polymer substance. It means a state of being uniformly dispersed in a molecular state (the presence of some crystals is allowed).
Whether it is amorphous or not can be confirmed by powder X-ray diffraction or differential scanning calorimetry (hereinafter referred to as DSC), which is a normal analysis means.
“Solid formulation” is a term for liquids, injections, etc., and means a solid formulation. If it is a solid formulation, there is no restriction | limiting in particular, According to a conventional method, it can convert and use for various dosage forms, such as a powder, a fine granule, a granule, a pill, and a tablet.
The “water-soluble polymer substance” is a polymer substance for forming a solid dispersion together with a chemical substance as an active ingredient, for example, an MTP inhibitor and / or an Apo B secretion inhibitor. The water-soluble polymer substance is not particularly limited as long as it can form a solid dispersion with these chemical substances. Specific examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin, or a mixture thereof. Polyvinyl pyrrolidone or hydroxypropyl cellulose is preferable, and polyvinyl pyrrolidone is particularly preferable. Povidone K30 is preferable in terms of grade.
These water-soluble polymeric substances, especially polyvinylpyrrolidone, are also known as binders and stabilizers, and do not only form solid dispersions, but also stabilize chemical substances that exist as amorphous molecules in solid dispersions. It is thought that it contributes to the conversion.
In order to effectively achieve the object of the present invention, these water-soluble polymer substances are used in an amount of 3 to 100 times by weight with respect to poorly water-soluble chemical substances (for example, MTP inhibitors, Apo B secretion inhibitors), in particular 3 to 50 times by weight is preferable. When polyvinylpyrrolidone is used as the water-soluble polymer substance, it can be used preferably in the range of 3 to 50 times by weight, particularly preferably 3 to 20 times by weight, more preferably 8 to 12 times by weight. If it is out of this range, it is not possible to obtain a sufficient pharmaceutical effect such as an appropriate dose and an appropriate dissolution property.
When hydroxypropyl cellulose is used as the water-soluble polymer substance, it can be used preferably in the range of 6 to 15 times by weight. This is because the stability is somewhat inferior in the case of 6 times by weight or less.
“Organic solvents” for producing solid dispersions are those that can dissolve both chemical substances (for example, MTP inhibitors, Apo B secretion inhibitors) as active ingredients and water-soluble polymer substances such as PVP. Although there is no particular limitation as long as it is present, it is desirable to use a solvent having a relatively low boiling point. For example, alcohol such as methanol, ethanol, propanol, isopropyl alcohol, butanol, monomethoxyethanol, ethylene glycol monomethyl ether; ethers such as diethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran, ethylene glycol; n-hexane, cyclohexane Aliphatic hydrocarbons such as n-heptane: Aromatic hydrocarbons such as benzene, toluene and xylene: Nitriles such as acetonitrile; Organic acids such as acetic acid and propionic acid; Esters such as ethyl acetate; Dichloromethane Aliphatic halogenated hydrocarbons such as dichloroethane and chloroform; Ketones such as acetone and methyl ketone; Amides such as dimethylformamide and dimethylacetamide; Or the like can be used a mixture of these appropriate ratio. Among these, low boiling point solvents such as ketones such as acetone and alcohols such as absolute ethanol are preferable, and acetone and absolute ethanol are particularly preferable.
An “excipient” is generally a pharmaceutical additive that is added as appropriate during the formulation of a powder or a solid preparation such as a granule or a tablet formed from the powder, and the powder formulation or tablet bulk. It is used in the case of expecting an action of increasing or reducing compressibility and solubility.
“Inorganic porous material” is an inorganic material having a large number of fine voids, and is not particularly limited. For example, calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, and aluminate metasilicate. There may be mentioned magnesium, magnesium aluminum silicate, synthetic aluminum silicate, hydrous silicon dioxide, or mixtures thereof. Preferably, calcium silicate or light anhydrous silicic acid, especially light anhydrous silicic acid is desirable. Here, the type of calcium silicate or light anhydrous silicic acid is not particularly limited, but calcium silicate is preferably described in the Pharmaceutical Additives Standard (1998), and light anhydrous silicic acid is the Japanese Pharmacopoeia (No. 14 (Revision) is desirable. As for the particle size, for the purpose of the present invention, 70% or more, preferably 80% or more is preferably in the range of 0.01μ to 100μ, and optimally, 70% or more, preferably 80% or more. Those belonging to the range of 0.1 to 10 μ are preferable.
The weight ratio of these inorganic porous substances and chemical substances as active ingredients (for example, MTP inhibitor, Apo B secretion inhibitor) is not particularly limited, but the mixing ratio of the inorganic porous substance in the solid dispersion of the present invention is In order to obtain a sufficient effect as an excipient, the amount by weight is preferably 4 to 100 times, more preferably 6 to 50 times, particularly 7 to 20 times the chemical substance as the active ingredient. An amount is preferred. When the amount of the inorganic porous material is less than 4 with respect to 1 of the amount of the chemical substance as the active ingredient, it is not desirable because a desired effective solid dispersion cannot be obtained. When the amount of the inorganic porous material is more than 100 with respect to 1 of the amount of the chemical substance as the active ingredient, a solid dispersion can be obtained, but the MTP inhibitory substance required therapeutically and An attempt to obtain an amount of an Apo B secretion inhibitor inevitably increases the amount of the solid dispersion used, which increases the dose per administration when administered to a patient.
“Fine piece” means a substantially flat fine piece, in other words, a fine thin piece. However, spherical or thread-like ones are not excluded, and 70% or more, preferably 80% or more, may correspond to the flaky piece as described above. The size is preferably 0.01 times to 100 times, particularly 0.1 times to 10 times the particle size of the inorganic porous material, and more than 70% of the fine pieces, preferably 80 times. % Or more belongs to the range of 0.01 μ to 100 μ, particularly 0.1 μ to 10 μ.
“Adsorbed and / or held in an adhering state” means that both the fine flaky water-soluble polymer material and the inorganic porous material forming the solid dispersion are simply present in a mixed state. Without being held together and adsorbed and / or adhered.
Formation of the fine pieces and realization of the adsorbed / adhered state are achieved by stirring and mixing a solution in which the active ingredient and the water-soluble polymer substance are dissolved together with the inorganic porous substance, and granulating and drying.
The term “poorly water-soluble” in the term “poorly water-soluble chemical substance as a pharmaceutical active ingredient” is as defined above. A “chemical substance as a pharmaceutical active ingredient” is a chemical substance that constitutes a main ingredient for exerting an action as a pharmaceutical. The chemical substances here include natural substances as well as substances obtained by chemical synthesis.
The definition of the “solid preparation” of the present invention is as described above, but other “excipients”, “lubricants”, “binders”, “disintegrants”, “interfaces” as necessary. Formulation additives such as “active agents”, “preservatives”, “antioxidants”, “coloring agents”, “sweetening agents” and the like can also be used. Preferable examples of other “excipients” include, for example, lactose, sucrose, D-mannitol, starch, crystalline cellulose, starch, mannitol, calcium silicate (trade name: Florite RE), magnesium aluminate metasilicate (Product name: Neusilin), Sucrose / starch spherical granules (Product name: Nonparel), Crystalline cellulose / Carboxymethylcellulose (Product name: Avicel RC), Hydroxypropyl starch, etc. are used. Preferable examples of the “lubricant” include crystalline cellulose, magnesium stearate, calcium stearate, talc, colloidal silica, corn starch, magnesium oxide and the like. Preferable examples of other “binders” include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Suitable examples of the “disintegrant” include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, methylcellulose (trade name: Metrols SM), croscarmellose sodium, carmellose calcium, low Substituted hydroxypropylcellulose, sodium starch glycolate, partially pregelatinized starch and the like are used. Particularly preferred is carboxymethylcellulose calcium. As the “surfactant”, for example, polyoxyethylene polyoxypropylene glycol (trade name: Pluronic), glycerin fatty acid ester, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate 80, cetanol and the like are used. Preferable examples of the “preservative” include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the “antioxidant” include sulfite and ascorbic acid. These additives may be used alone or in admixture of two or more.
The “lipid absorption inhibitor” in the present invention is particularly a drug (a chemical substance as an active ingredient, which may be a natural product) that inhibits or suppresses absorption of lipids regardless of the mechanism of action. There is no limit. Specifically, a lipid absorption inhibitor selected from the group consisting of an inhibitor of apolipoprotein B (Apo B) secretion, a triglyceride (TG) transfer light protein inhibitor and a cholesteryl ester transfer protein (CETP) inhibitor, and MTP inhibition And a lipid absorption inhibitor selected from the group consisting of an agent, a lipase inhibitor, and an ACAT inhibitor.
In the present invention, “MTP inhibitor (MTP inhibitor)” and “Apo B secretion inhibitor (Apo B secretion inhibitor)” are substances having MTP inhibitory activity and Apo B secretion inhibitory activity, respectively, particularly chemically synthesized. Means a hydrated or solvated substance, prodrug, or salt thereof, and is not particularly limited, meaning any MTP inhibitor, Apo B secretion inhibitor is there.
In the present invention, “the MTP inhibitor is a 3-piperidyl-4-oxoquinazoline derivative or a salt thereof” means a compound and a salt thereof defined above and / or below (A).
In the present invention, “the MTP inhibitor is a substituted piperazine derivative or a salt thereof” means a compound or a salt thereof as defined above or below (D), (F) and / or (G).
In the present invention, the “MTP inhibitor is a benzamide derivative or a salt thereof” means the above or the following (B), (C), (E), (H), (I), (J), (K) and And / or a benzamide derivative defined by (L) or a salt thereof.
Specifically, the “MTP inhibitors” of (A) to (L) are as follows.
(A) 3-piperidyl-4-oxoquinazoline derivatives described and defined in JP-A-11-228569 (see (A) above and Patent Document 14).
(B) A compound group having a piperidine skeleton described and defined in JP-T-2004-514676 (WO2002 / 042291) (see (B) above and Patent Document 15).
(C) A benzamide derivative described and defined in JP-T-2003-535900 (WO01 / 097810) (see (C) above and Patent Document 16).
(D) Substituted piperazine derivatives described and defined in JP-T-2003-521484 (WO 01/047898) (see (D) above and Patent Document 17).
(E) A benzamide derivative described and defined in JP-T-2003-520270 (WO01 / 053260) (see (E) above and Patent Document 18).
(F) Substituted piperazine derivatives described and defined in JP-T-2003-519131 (WO01 / 047899) (see (F) above and Patent Document 19).
(G) Substituted piperazine derivatives described and defined in JP-T-2003-509505 and WO01 / 021604 (see (G) above and Patent Document 20).
(H) A benzamide derivative (biphenylamide derivative) described and defined in JP-T-2003-505373 (WO01 / 005762) (see (H) above and Patent Document 21).
(I) Benzamide derivatives described and defined in JP-T-2000-510483, WO 98/47875, such as 4′-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinoline-6 Yl) -amide (see (I) above and Patent Document 22).
(J) Benzamide derivatives (biphenylamide derivatives) described and defined in (i), (ii), (iii), and (iv) of JP-A-2001-172180 (see (J) above and Patent Document 23) .
(K) A benzamide derivative described and defined in JP-A No. 2000-169395 (see (K) above and Patent Document 24).
(L) A benzamide derivative described and defined in JP-A-2003-321424 (see (L) above and Patent Document 26).
In addition, the following specific compounds are also included in the present invention.
The following compounds described in JP 2001-172180 A (see Patent Document 23).
4′-trifluoromethyl-biphenyl-2-carboxylic acid- (2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,
4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,
9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl-9H-fluorene-9-carboxamide;
2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one,
9- [4- (4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl) butyl] -N-2,2,2-trifluoroethyl) -9H-fluorene-9 Carboxamide.
The following compounds described in JP 2001-172180 A (see Patent Document 23).
4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (1H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] An amide,
4′-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide,
9- (4- [4- [4′-trifluoromethyl-biphenyl-2-carbonyl) amino] -piperidin-1-yl} butyl) -9H-fluorene-9-carboxylic acid- (2,2,2 -Trifluoroethyl) -amide,
9- [4- [4- (2-Benzothiazol-2-yl-benzoylamino) piperidin-1-yl] butyl] -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoroethyl ) Amide,
[11a-R] -8-[(4-cyanophenyl) methoxy] -2-cyclopentyl-7- (prop-2-enyl) -2,3,11,11a-tetrahydro-6H-pyrazino [1,2b ] Isoquinoline-1,4-dione,
[11a-R] -2-cyclopentyl-7- (prop-2-enyl) -8-[(pyridin-2-yl) methoxy] -2,3,11,11a-tetrahydro-6H-pyrazino [1, 2b] isoquinoline-1,4-dione,
2-cyclopentyl-2- [4- (2,4-dimethylpyrido [2,3-b] indol-9-ylmethyl) phenyl] -N- (2-hydroxy-1-phenylethyl) acetamide,
2-cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) -phenyl] acetamide.
In addition to the above, BAY 13-9952, CP-10447, R1037570 or WM-1159 are also included in the present invention.
Particularly preferred “MTP inhibitors” include compounds in which X is —CON (R ¹⁰ ) — (CH ₂ ) n— among the compounds described in the above item (L). In addition, when the compounds described in (L) are listed with more specific compound names, the following compounds may be mentioned.
2-phenyl-2- (2- {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,
2- (2- {4- [Ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid dimethyl ester,
2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- [3- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] -2-phenyl-malon Acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {4-[(5-Chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di2,2 , 2-trifluoroethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {5-Dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5-nitro-pyridine-2 -Yl) -malonic acid diethyl ester,
2- (5-amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridin-2-yl-malonic acid Diethyl ester,
2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
2- (2- {3-Bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o-tolyl-malonic acid diethyl ester ,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m-tolyl-malonic acid diethyl ester ,
2- (2- {3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p-tolyl-malonic acid diethyl ester ,
2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (3-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-succinic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4-methoxy-phenyl)- Malonic acid diethyl ester,
2- (2- {4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {4-[(6-Chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- [2- (2- {3-Dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -ethyl] -2 -Phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-Dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon Acid diethyl ester,
2- [2- (2- {4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy) -ethyl] -2 -Phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,
The salt of the compound constituting the MTP inhibitor and Apo B secretion inhibitor is preferably a pharmaceutically acceptable salt. For example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, an organic salt Examples include salts with acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
The production method of the solid preparation of the present invention is as follows.
1. Granulation step (1) An appropriate amount of a poorly water-soluble chemical substance as an active ingredient, for example, an MTP inhibitor, is dissolved in a suitable organic solvent such as acetone or absolute ethanol or a mixed solvent thereof. The amount of the organic solvent is sufficient to dissolve the polymer substance added in the next step. However, when an unnecessarily large amount of solvent is used, not only the subsequent operation becomes complicated, but also the preparation is adversely affected. Therefore, the amount of the solvent used is from 1 to 2 times the amount of the polymer substance. Is appropriate. Stirring and dissolution can be performed by using, for example, a propeller mixer.
(2) A water-soluble polymer substance is added to an organic solvent in which an appropriate amount of chemical substance is dissolved, and further stirred and mixed to sufficiently dissolve both the chemical substance and the water-soluble polymer substance. At this time, in order to promote dissolution, the solvent may be heated as necessary.
(3) Separately, using a mixing stirrer or the like, an inorganic porous material such as light anhydrous silicic acid as an excipient and, if necessary, a disintegrant such as carboxymethylcellulose calcium are stirred and mixed.
(4) Next, the mixture of the inorganic porous material and disintegrant prepared in (3) above is mixed with the solution obtained by dissolving both the chemical substance and polymer material obtained in (2), and according to a conventional method. This is granulated.
From the viewpoint of operability, it is preferable to add and mix the solution of (2) to the mixture obtained in (3), but there is no particular limitation, and (3) )) May be added and mixed.
(5) Next, this is granulated, and then the organic solvent is distilled off under reduced pressure or normal pressure by vacuum drying or the like and dried.
(6) Finally, the dried granulated product is sized using a sieve or the like.
The organic solvent used in the above operation (1) is one that can dissolve poorly water-soluble or insoluble chemical substances (for example, MTP inhibitor and / or Apo B secretion inhibitor) and polymer substances as active ingredients. For example, alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol, monomethoxyethanol, and ethylene glycol monomethyl ether; ketones such as acetone and methyl ketone, or a mixed solution thereof can be used. . Low-boiling solvents such as ketones such as acetone and alcohols such as absolute ethanol are preferred, and acetone, absolute ethanol or a mixture thereof is particularly preferred. Water may be added as necessary.
2. Tableting process When a tablet is desired, a disintegrating agent such as carboxymethylcellulose calcium and crosslinked polyvinylpolydon and a lubricant such as magnesium stearate are further added to the granulated particles obtained in the granulation process. After uniformly mixing, tablets can be obtained by tableting according to a conventional method.
The amount of the chemical substance as an active ingredient to be contained in the solid preparation varies depending on the dosage form, administration method, carrier, age, weight, etc. of the recipient, and may be determined according to each condition and environment. It is not limited. In the case of an MTP inhibitor, it is usually 0.1 to 20% (w / w), preferably 1 to 8% (w / w) based on the total amount of the preparation. If it is 0.1% (w / w) or less, the effect as a drug cannot be expected, and if it is 20% (w / w) or more, a sufficient effect as a solid dispersion cannot be exhibited.
In order to obtain a sufficient effect as a solid dispersion, the compounding amount of the water-soluble polymer substance in the solid preparation of the present invention is not limited to chemical substances as active ingredients (for example, MTP inhibitor, Apo B secretion inhibitor). 3 to 100 times by weight, preferably 3 to 50 times, more preferably 3 to 20 times by weight. In the case of polyvinylpyrrolidone, 3 to 20 times by weight, more preferably by weight. The amount is 8 to 12 times, and in the case of hydroxypropyl cellulose, the amount is particularly preferably 6 to 15 times.
In order to obtain a sufficient effect as a solid preparation of the present invention, the inorganic porous substance is 4 to 14 by weight ratio with respect to a chemical substance (for example, MTP inhibitor, Apo B secretion inhibitor) as an active ingredient. Double amount is preferable, further 6 to 13 times amount is preferable, and 7 to 11 times amount is particularly preferable.
In order to obtain a sufficient effect as a solid preparation of the present invention, the disintegrant is 1 to 10 times by weight with respect to a chemical substance (for example, MTP inhibitor, Apo B secretion inhibitor) as an active ingredient. The amount is particularly preferably 3 to 7 times. A preferred disintegrant is cross-linked polyvinyl pyrrolidone (crospovidone).
The “solid preparation” thus obtained is heavy (high density) and can be used as a pharmaceutical preparation for oral administration in addition to tablets. Moreover, it can also be set as pharmaceutical preparations, such as a fine granule, a fine granule, a granule, a capsule, a liquid agent, according to a conventional method. When a preparation such as a powder, granule, capsule or the like is desired, the sized drug particles obtained by the above method are replaced with appropriate excipients, disintegrants, lubricants, surfactants as necessary. Etc. and can be easily obtained by preparing according to a conventional method. Methods for producing these preparations are well known and commonly used by those skilled in the art, and appropriate methods can be employed depending on the form of the preparation.
If a sugar-coated tablet or the like is desired, the preparation surface may be coated with an appropriate coating composition.
Usually, chemical substances (for example, MTP inhibitors and Apo B secretion inhibitors) as pharmaceutical active ingredients are poorly water-soluble or insoluble, and therefore, when administered orally, the proportion of the dose that is actually absorbed into the blood. Has a disadvantage that bioavailability is low. However, the solid preparation of the present invention has excellent solubility, oral absorbability, and absorbability into blood, and thereby the bioavailability of the poorly water-soluble chemical substance is dramatically improved.
Furthermore, the solid formulation of the present invention maintained excellent stability as long as the solubility was improved.
The solid preparation of the present invention can be used in combination with other pharmaceutical preparations. For example, the solid preparation of the present invention containing an MTP inhibitor or an Apo B secretion inhibitor as an active ingredient can be used in combination with another therapeutic agent for hyperlipidemia. In this case, a solid preparation of an MTP inhibitor or Apo B secretion inhibitor and another therapeutic drug for hyperlipidemia may be taken separately, or both may be integrated and used as a mixture.

上記表１から明らかなとおり、製剤化初期は勿論のこと、８０℃の加温条件下においても本発明製剤は非晶質（アモルファス）状態を保っており、安定性を維持していた。
実施例５
非晶質の確認；
実施例３−２で得られた製剤の非晶質（アモルファス）状態を観察するため、製剤化直後、及び４０℃、１ヶ月、各種湿度の条件下（１１％、３２％、５３％、７５％）で粉末Ｘ線回折法によって測定した。試験は、試料適量を深さ０．２ｍｍのアルミセルに入れ、毎分５°の走査速度で粉末Ｘ線回折パターンを測定することによって行った。結果を第２図に示す。
第２図から明らかなとおり、本発明製剤は、このような条件下でも良好な非晶質状態を維持し、優れた安定性を有する。
実施例６
加湿条件下での安定性試験；
実施例３で得られた各製剤を４０℃、加湿条件下で試験した。結果は下記表２のとおりであった。

上記表２から明らかなとおり、ポリビニルピロリドンとヒドロキシプロピルセルロース、特にポリビニルピロリドンが、各種湿度条件下においても優れた安定性を示した。Example 1
Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
In the following examples, 2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-), which is an MTP inhibitor made of a benzamide derivative, is used as a poorly water-soluble chemical substance as an active ingredient. 2-Carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester (hereinafter simply referred to as “MTP inhibitory compound”) was used.
1. Granulation;
(1) Dissolution of chemical substances as active ingredients;
418.5 g of acetone and 46.5 g of absolute ethanol (weight% ratio: 9 to 1) were injected into a propeller mixer machine and mixed by stirring and mixed in an acetone / anhydrous ethanol mixed solution as a poorly water-soluble chemical substance. 0 g of the MTP inhibitor compound was added and dissolved sufficiently.
(2) Dissolution of polymer substance;
300.0 g of polyvinylpyrrolidone (Povidone K30) as a water-soluble polymer substance was gradually added to the solvent in which the MTP inhibitor compound was dissolved, and the mixture was further stirred and mixed to dissolve.
(3) Preparation of excipients;
Separately, 239.1 g of light anhydrous silicic acid as an excipient and 150.0 g of carboxymethylcellulose calcium as a disintegrant were mixed and stirred uniformly using a mixing stirrer. It was.
(4) Mixing of excipient and polymer substance solution;
The organic mixed solvent prepared by dissolving the MTP-inhibiting compound and polyvinylpyrrolidone prepared in the step (2) is gradually added to the light anhydrous silicic acid mixture prepared in the step (3) and mixed and stirred until homogeneous. did.
(5) coarse granulation;
The mixture obtained in the above (4) was granulated according to a conventional method, and then dried in a vacuum dryer.
(6) sizing;
Furthermore, in order to make the particle size uniform, the sizing operation was performed according to a conventional method using a sieve having an opening of 600 μm.
2. Tableting;
The above granulation process was repeated twice, and 150.0 g of cross-linked polyvinyl pyrrolidone (crospovidone) as a disintegrant and 7.8 g of magnesium stearate as a lubricant were added to 1438.2 g of the resulting granulate, and W After uniformly mixing using a mold mixer, tableting is performed using a rotary tableting machine, whereby about 133 mg of a tablet (about 5 mg / tablet of MTP-inhibiting compound as an active ingredient) per tablet is about 1,200. Tablets were manufactured.
Example 2
Dissolution test;
The dissolution test was conducted using a degassed 0.1 w / v% sodium lauryl sulfate solution (900 mL, 37 ° C.) according to the second method of JP dissolution test method (paddle method, 50 rpm). The tablet produced in Example 1 (133.00 mg / tablet; containing 5 mg of drug substance) was directly added to the test solution. As a comparative control, the drug substance consisting of crystals was directly added to the test solution. The temperature was adjusted to 37 ± 0.1 ° C. The results are as shown in FIG.
As shown in FIG. 1, the comparative compound (crystal) did not dissolve even after 60 minutes, whereas the solid preparation of the present invention dissolved 95.45% after only 15 minutes.
Considering that foods in the mouth are said to reach the small intestine after about 15 to 30 minutes, the preparation of the present invention is completely dissolved when reaching the small intestine and is absorbed into the small intestine very efficiently. In particular, it is ideal as a drug targeting the small intestine.
In addition, because of its excellent solubility, the dose of the drug can be reduced, that is, the minimum necessary dose can be administered, and the transfer of the drug into the blood can be effectively increased by improving the solubility. It becomes possible to make it. This prevents unwanted drugs that have not been degraded in the blood from moving to the liver, resulting in risks from the drugs (eg, fear of liver fat due to MTP inhibitors), and sometimes unexpected risks Can be prevented in advance.
Further, the effect of improving the solubility is not derived from the chemical characteristics of the active ingredient compound, but the chemical substance as the active ingredient forms a fine flaky solid dispersion together with the water-soluble polymer substance, It is presumed that the fine flaky water-soluble polymer substance contributes to the improvement of the solubility by being adsorbed and / or adhered to the surface of the inorganic porous substance.
Therefore, the pharmaceutical technology of the present invention can be applied to a wide range of drug compounds regardless of the chemical properties of the drug as an active ingredient.
Example 3
Formulations for stability testing and amorphous confirmation testing;
In order to confirm the stability and amorphousness of this solid preparation, a preparation for testing was produced according to the following method.
In addition, since it is thought that the main cause which affects stability and crystallinity depends on the combination of a water-soluble polymer substance and a poorly water-soluble chemical substance, a solid dispersion composed of these two substances was used as a test preparation. Moreover, the said MTP inhibitory compound was used as a poorly water-soluble chemical substance.
The test preparation was prepared by adding an appropriate amount of an MTP-inhibiting compound to an appropriate and appropriate amount of solvent as described below, gradually adding the polymer substance to be tested and dissolving it sufficiently, and spray-drying it.
Example 3-1
A powder was obtained by dissolving 5 g of an MTP-inhibiting compound and 15 g of polyvinylpyrrolidone (Collidon 30, manufactured by BASF) in a mixed solvent of 108 g of acetone and 72 g of water and spray drying.
Example 3-2
A powder was obtained by dissolving 5 g of an MTP-inhibiting compound and 50 g of polyvinylpyrrolidone (Kollidon 30, manufactured by BASF) in a mixed solvent of 270 g of acetone and 180 g of water and spray drying.
Example 3-3
A powder was obtained by dissolving 5 g of an MTP-inhibiting compound and 15 g of hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) in 180 g of acetone and spray drying.
Example 3-4
A powder was obtained by dissolving 5 g of an MTP-inhibiting compound and 50 g of hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) in 450 g of acetone and spray drying.
Example 3-5
A powder was obtained by dissolving 5 g of an MTP-inhibiting compound and 15 g of hydroxypropyl methylcellulose (TC-5EW, manufactured by Shin-Etsu Chemical Co., Ltd.) in a mixed solvent of 135 g of acetone and 60 g of water and spray drying.
Example 3-6
A powder was obtained by dissolving 5 g of an MTP-inhibiting compound and 50 g of hydroxypropylmethylcellulose (TC-5EW, manufactured by Shin-Etsu Chemical Co., Ltd.) in a mixed solvent of 375 g of acetone and 150 g of water and spray drying.
Example 4
Stability test under warming conditions;
Each powder obtained in Example 3 was tested under a heating condition of 80 ° C. The purity was measured by high performance liquid chromatography (measurement wavelength: 242 nm). The crystallization state was confirmed by powder X-ray diffraction. The results are shown in Table 1 below.
The term “maximum” in Table 1 means the percentage of one or more impurities that showed the highest peak, and “total” means the total percentage of all impurities.

As is apparent from Table 1 above, the formulation of the present invention maintained an amorphous state and maintained stability even under the heating condition of 80 ° C. as well as the initial stage of formulation.
Example 5
Confirmation of amorphousness;
In order to observe the amorphous state of the preparation obtained in Example 3-2, immediately after preparation and at 40 ° C. for 1 month under various humidity conditions (11%, 32%, 53%, 75 %) By a powder X-ray diffraction method. The test was performed by placing an appropriate amount of sample in an aluminum cell having a depth of 0.2 mm and measuring a powder X-ray diffraction pattern at a scanning speed of 5 ° per minute. The results are shown in FIG.
As apparent from FIG. 2, the preparation of the present invention maintains a good amorphous state even under such conditions and has excellent stability.
Example 6
Stability test under humidified conditions;
Each formulation obtained in Example 3 was tested under humidified conditions at 40 ° C. The results are shown in Table 2 below.

As is clear from Table 2 above, polyvinyl pyrrolidone and hydroxypropyl cellulose, particularly polyvinyl pyrrolidone, showed excellent stability even under various humidity conditions.

As is apparent from the results of the above stability test, the solid preparation of the present invention, particularly polyvinyl pyrrolidone or hydroxypropyl cellulose, particularly preferably polyvinyl pyrrolidone, particularly preferably polyvinyl pyrrolidone, is used as the polymer substance. About 3 to 100 times by weight with respect to a substance (for example, an MTP inhibitor or an Apo B secretion inhibitor), preferably about 3 to 20 times by weight, particularly preferably about 8 to 12 times by weight in the case of PVP, and HPC In this case, the solid preparation applied in the range of 6 to 15 times by weight has excellent water solubility characteristics and excellent stability.
As described above, the solid preparation of the present invention has excellent water-dissolving properties, and therefore it is possible to realize high availability. This fact has three important implications. First, the realization of high availability has enabled the practical application of many poorly soluble chemical substances as active ingredients such as MTP inhibitors and / or Apo B secretion inhibitors as drugs. Because it dissolves quickly, it can be absorbed quickly from the small intestine, which is the site of drug absorption, especially for drugs that use the small intestine as the target site, and it acts selectively on the small intestine. Therefore, the dose is remarkably reduced as compared with the prior art, and the burden on the liver is reduced correspondingly, thereby reducing the risk of side effects such as fatty liver or unexpected side effects.
Further, the manufacturing method itself is very simple and effective.
As described above, the solid preparation of the present invention not only has surprising dissolution characteristics, but also has excellent stability, and is simple and effective in production. Widely applicable to soluble drugs.
Therefore, when the solid preparation technology of the present invention is applied to lipid absorption inhibitors such as MTP inhibitors and Apo B secretion inhibitors, for example, there is no fear of fatty liver or unexpected side effects. It can be an excellent therapeutic or preventive for hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension.

Claims (33)

A solid preparation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as an active pharmaceutical ingredient,
(1) A poorly water-soluble chemical substance as a pharmaceutical active ingredient is 2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy Methyl) -2-phenyl-malonic acid diethyl ester or a salt thereof,
(2) The poorly water-soluble chemical substance forms a solid dispersion with the water-soluble polymer substance, (3) The water-soluble polymer substance forming the solid dispersion is in the form of fine pieces, and
(4) A solid preparation with improved water solubility, characterized in that the fine flaky water-soluble polymer substance is adsorbed and / or adhered to the surface of the inorganic porous substance.   The solid preparation according to claim 1, wherein the water-soluble polymer substance is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin or a mixture thereof.   The solid preparation according to claim 2, wherein the water-soluble polymer substance is polyvinylpyrrolidone or hydroxypropylcellulose. The solid preparation according to claim 3, wherein the water-soluble polymer substance is polyvinylpyrrolidone. The solid preparation according to any one of claims 1 to 4 , wherein the water-soluble polymer substance is 3 to 100 times by weight with respect to a poorly water-soluble chemical substance as an active pharmaceutical ingredient. The solid preparation according to claim 5, wherein the water-soluble polymer substance is 3 to 50 times by weight with respect to the poorly water-soluble chemical substance as an active pharmaceutical ingredient. The solid preparation according to claim 6 , wherein the water-soluble polymer substance is polyvinyl pyrrolidone, and the polyvinyl pyrrolidone is 3 to 50 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. The solid preparation according to claim 7, wherein the water-soluble polymer substance is polyvinyl pyrrolidone, and the polyvinyl pyrrolidone is 3 to 20 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. The solid preparation according to claim 8, wherein the water-soluble polymer substance is polyvinyl pyrrolidone, and the polyvinyl pyrrolidone is 8 to 12 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. 6. The solid preparation according to claim 5 , wherein the water-soluble polymer substance is hydroxypropyl cellulose, and the hydroxypropyl cellulose is 6 to 15 times the weight of the poorly water-soluble chemical substance as an active pharmaceutical ingredient. The inorganic porous material is calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate metasilicate, magnesium magnesium silicate, synthetic aluminum silicate, hydrous silicon dioxide, or a mixture thereof. The solid preparation according to any one of claims 1 to 10 . The solid preparation according to claim 11 , wherein the inorganic porous substance is light anhydrous silicic acid. The solid preparation according to any one of claims 1 to 12 , wherein the inorganic porous substance is 4 to 100 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. 14. The solid preparation according to claim 13, wherein the inorganic porous substance is 6 to 50 times the weight ratio with respect to the poorly water-soluble chemical substance as a pharmaceutical active ingredient. The solid preparation according to claim 14, wherein the inorganic porous substance is 7 to 20 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. A pharmaceutical product comprising a solution obtained by dissolving a poorly water-soluble chemical substance as a pharmaceutical active ingredient and a water-soluble polymer substance in an organic solvent and an inorganic porous substance, and then granulating and drying. A solid preparation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as an active ingredient,
(1) The poorly water-soluble chemical substance is 2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester or a salt thereof,
(1) The poorly water-soluble chemical substance forms a solid dispersion with the water-soluble polymer substance, (2) the water-soluble polymer substance forming the solid dispersion is in the form of fine pieces, and (3) A solid preparation with improved water solubility, characterized in that the fine flaky water-soluble polymer substance is adsorbed on and / or adhered to the surface of the inorganic porous substance. Production method. The method for producing a solid preparation according to claim 16 , wherein the water-soluble polymer substance is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin, or a mixture thereof. The method for producing a solid preparation according to claim 17 , wherein the water-soluble polymer substance is polyvinylpyrrolidone or hydroxypropylcellulose. The method for producing a solid preparation according to claim 18 , wherein the water-soluble polymer substance is polyvinylpyrrolidone. 20. The method for producing a solid preparation according to any one of claims 16 to 19 , wherein the water-soluble polymer substance is 3 to 100 times in weight ratio with respect to a poorly water-soluble chemical substance as an active pharmaceutical ingredient. 21. The method for producing a solid preparation according to claim 20, wherein the water-soluble polymer substance is 3 to 50 times by weight with respect to the poorly water-soluble chemical substance as a pharmaceutical active ingredient. The method for producing a solid preparation according to claim 21 , wherein the water-soluble polymer substance is polyvinyl pyrrolidone, and the polyvinyl pyrrolidone is 3 to 50 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. . 23. The method for producing a solid preparation according to claim 22, wherein the water-soluble polymer substance is polyvinyl pyrrolidone, and the polyvinyl pyrrolidone is 3 to 20 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. . The method for producing a solid preparation according to claim 23, wherein the water-soluble polymer substance is polyvinyl pyrrolidone, and the polyvinyl pyrrolidone is in an amount of 8 to 12 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. . 21. The solid preparation according to claim 20 , wherein the water-soluble polymer substance is hydroxypropylcellulose, and the hydroxypropylcellulose is 6 to 15 times the weight of the poorly water-soluble chemical substance as an active pharmaceutical ingredient. Production method. The inorganic porous material is calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate metasilicate, magnesium magnesium silicate, synthetic aluminum silicate, hydrous silicon dioxide, or a mixture thereof. 26. A method for producing a solid preparation according to any one of claims 16 to 25 . 27. The method for producing a solid preparation according to claim 26 , wherein the inorganic porous substance is light silicic anhydride. 28. The method for producing a solid preparation according to any one of claims 16 to 27 , wherein the inorganic porous substance is 4 to 100 times by weight with respect to a poorly water-soluble chemical substance as a pharmaceutical active ingredient. The solid preparation according to claim 28, wherein the inorganic porous substance is 6 to 50 times in weight ratio with respect to the poorly water-soluble chemical substance as a pharmaceutical active ingredient. 30. The solid preparation according to claim 29, wherein the inorganic porous substance is 7 to 20 times in weight ratio with respect to the poorly water-soluble chemical substance as an active pharmaceutical ingredient. The method for producing a solid preparation according to any one of claims 16 to 30 , wherein the amount of the organic solvent is 1 to 2 times by weight of the water-soluble polymer substance. A tablet comprising a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as an active pharmaceutical ingredient,
The chemical substance as an active pharmaceutical ingredient is 2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl -Malonic acid diethyl ester or a salt thereof, the water-soluble polymer substance is polyvinylpyrrolidone, the inorganic porous substance is light anhydrous silicic acid, and the chemical substance as a pharmaceutical active ingredient is solid-dispersed together with the water-soluble polymer substance. Tablet that formed the body. A solid preparation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as an active pharmaceutical ingredient,
2- (2- {3-Dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- as a poorly water-soluble chemical substance A solution obtained by dissolving malonic acid diethyl ester or a salt thereof and polyvinylpyrrolidone as a water-soluble polymer substance in an organic solvent and light anhydrous silicic acid as an inorganic porous substance are stirred and mixed, and then granulated and dried. 2- (2- {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malon, characterized in that A method for producing a solid preparation, wherein acid diethyl ester or a salt thereof forms a solid dispersion together with polyvinylpyrrolidone.

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