JP2005533851A - 高コレステロール血症処置用物質および方法 - Google Patents
高コレステロール血症処置用物質および方法 Download PDFInfo
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Abstract
Description
本出願は、2002年7月19日付けで出願された米国仮出願第60/397,076号に優先権を主張するものである。
上昇したレベルの低密度リポタンパク質(LDL)−コレステロールは冠状動脈疾病(CAD)に関連する最も重要な危険因子として認識されている。LDL−コレステロールの最も効果的な低下方法は、コレステロール合成経路の律速キイ酵素であるHMG−CoAレダクターゼの阻害薬(スタチン化合物)の投与である。コムパクチン(compactin)およびロバスタチン(lovastatin)(これらの化合物は両方ともに、微生物起源の化合物である)が発見されて以来、一次および二次予防的測定法が数種のスタチン化合物試験で確立されており、LDL−コレステロールレベルの低下によるCADの将来的事象を予防する助けになっている。現時点まで、プラバスタチン(pravastatin)、ロバスタチン(lovastatin)、シムバスタチン(simvastatin)、フルバスタチン(fluvastatin)、セリバスタチン(cerivastatin)およびアトルバスタチン(atorvastatin)が臨床試験に用いられている。
本発明は、高コレステロール血症処置用の新規で有利な物質および方法を提供することにある。本発明による組成物および治療方法は、コレステロールレベルの効果的で安全な減少に使用することができる。本明細書で特別に例示されるものは、HMG−CoAレダクターゼの新規阻害剤である。これらの化合物の使用は、LDLコレステロールレベルの低下による冠状動脈疾病(CAD)の防止を助ける。
本発明はまた、有効量の本発明による化合物を、該当処置を要する患者に投与することを包含する処置方法を提供する。
本発明は新規HMG−CoA−レダクターゼ阻害剤を提供する。好適態様において、本発明によるHMG−CoA−レダクターゼ阻害剤は加水分解酵素によって一次不活性代謝物に不活性化させることができる。本発明による化合物は高コレステロール血症を患う個体の処置に有利に使用することができる。本発明による化合物は、これらの化合物がさらに予測可能な薬物動態性および医薬に対する減少された全身的露呈性を有することから、特に有利である。
本明細書で使用されているものとして、「個体」(individual(s))の用語は、本発明による化合物または組成物が投与される哺乳動物を意味する。この哺乳動物は、例えばマウス、ラット、ブタ、ウマ、ウサギ、ヤギ、ブタ、ウシ、ネコ、イヌ、またはヒトであることができる。好適態様において、個体はヒトである。
1.本発明による化合物は、CYP450および非酸化性代謝酵素または酵素系の両方によって代謝される;
2.本発明による化合物は、短い(四(4)時間まで)非酸化性代謝半減期間を有する;
3.当該化合物の経口生体利用性は、標準的経口医薬組成物を用いる経口投与と一致する;しかしながら、当該化合物およびその組成物はまた、経過時間にわたり一定の、また制御可能な血中レベルを生じるいずれかの放出系を用いて投与することもできる;
4.本発明による化合物は、加水分解性酵素によって非酸化的に分解させることができる加水分解可能な結合を含有する;
5.本発明による化合物は、小規模および大規模化学合成の標準的技術を用いて製造することができる;
7.元の医薬の可溶性物性に関係なく、一次代謝物は生理学的pHで水溶性であり、また親の化合物に比較し、格別に減少された薬理学的活性を有する;
8.元の医薬の電気生理学的性質に関係なく、一次代謝物は元の医薬の正常な血中治療濃度において、IKR(HERG)チャンネルで無視できる抑制活性を有する(例えば、この代謝物の濃度は、IKRチャンネルで活性が見出される以前の元の化合物の正常な治療濃度に比較し、少なくとも5倍高くなければならない);
9.本発明による化合物、ならびにその代謝物は、別種の医薬と一緒に投与された場合、代謝性DDIを生じさせない;
10.本発明による化合物、ならびにその代謝物は、単独で投与された場合、LFT値を高めない。
本発明による化合物は、未修飾の元の化合物と同様の治療物性を有する。従って、開示化合物の投与率および投与経路は、当業界ですでに使用されており、当業者にとって公知であるものと同様である(例えば、Physicians´Desk Refernce,54版,Medical Economics Company,Montvale,NJ,2000年参照)。
本発明に従い、活性成分として、有効量の1種または2種以上の化合物および1種または2種以上の無毒性の医薬上で許容される担体または稀釈剤を含有する医薬組成物が提供される。
さらに、本発明による化合物はまた、リポソームなどの形態で投与することもできる。非制限的であるが、小型単層状小胞、大型単層状小胞および多層小胞などの放出系には、崩壊剤を包含させる。リポソームはリン脂質、例えばコレステロール、ステアリルアミンまたはホスファチジルコリンから形成することができる。
一般に、動物における満足な結果は、約0.1〜約200mg/動物の体重kg、好ましくは約0.1〜約5mg/動物の体重kgの一日薬用量で得られることを示す。大型哺乳動物において、例えばヒトにおいて、指示一日薬用量は約0.5〜約100mg、好ましくは約1〜約50mgの範囲であり、本発明による薬剤は適当に、例えば4回までの分割用量で投与することができ、または持続放出形態であることができる。
本明細書に記載されている例および態様は説明の目的のみのものであること、およびその観点での種々の修正または変更は当業者に示唆されており、また本出願の精神および範囲内に包含されることは理解されるべきである。
図5:(a):NaBH4;(b):RCOCl/トリエチルアミン;(c):H2、Pd/C、次いでH+。
図6:(a):PDC/DMF;(b):ROH/DCC;(c):H2、Pd/C、次いでH+。
Claims (14)
- HMG−CoAレダクターゼを阻害し、および下記群から選択される少なくとも1種の特性を有するスタチン類縁化合物:
a.当該化合物は、CYP450および非酸化性代謝酵素または酵素系の両方によって代謝される;
b.当該化合物は、短い(四(4)時間まで)非酸化性代謝半減期間を有する;
c.当該化合物は、加水分解性酵素によって非酸化的に分解させることができる加水分解可能な結合を有する:
d.当該化合物の一次代謝物は、当該化合物の非酸化性代謝から生じる;
e.当該一次代謝物は、生理学的pHにおいて水溶性である;
f.当該一次代謝物は、血漿中における元の医薬の正常治療濃度において、IKR(HERG)チャンネルで無視できる抑制活性を有する:
g.当該化合物ならびにその代謝物は、別種の医薬を一緒に投与した場合、代謝性DDIを生じさせない;および
h.当該化合物ならびにその代謝物は、単独で投与した場合、LFT値を高めない。 - HMG−CoAレダクターゼを阻害し、および下記群から選択される少なくとも1種の特性を有するスタチン類縁化合物を含有し、さらに医薬用担体を含有する医薬組成物:
a.当該化合物は、CYP450および非酸化性代謝酵素または酵素系の両方によって代謝される;
b.当該化合物は、短い(四(4)時間まで)非酸化性代謝半減期間を有する;
c.当該化合物は、加水分解性酵素によって非酸化的に分解させることができる加水分解可能な結合を有する:
d.当該化合物の一次代謝物は、当該化合物の非酸化性代謝から生じる;
e.当該一次代謝物は、生理学的pHにおいて水溶性である;
f.当該一次代謝物は、血漿中における元の医薬の正常治療濃度において、IKR(HERG)チャンネルで無視できる抑制活性を有する:
g.当該化合物ならびにその代謝物は、別種の医薬を一緒に投与した場合、代謝性DDIを生じさせない;および
h.当該化合物ならびにその代謝物は、単独で投与した場合、LFT値を高めない。 - HMG−CoAレダクターゼを阻害する処置を必要とする個体におけるHMG−CoAレダクターゼの阻害方法であって、HMG−CoAレダクターゼを阻害し、および下記群から選択される少なくとも1種の特性を有するスタチン類縁化合物を含有する医薬組成物を上記個体に投与することを包含する、上記阻害方法:
a.当該化合物は、CYP450および非酸化性代謝酵素または酵素系の両方によって代謝される;
b.当該化合物は、短い(四(4)時間まで)非酸化性代謝半減期間を有する;
c.当該化合物は、加水分解性酵素によって非酸化的に分解させることができる加水分解可能な結合を有する:
d.当該化合物の一次代謝物は、当該化合物の非酸化性代謝から生じる;
e.当該一次代謝物は、生理学的pHにおいて水溶性である;
f.当該一次代謝物は、血漿中における元の医薬の正常治療濃度において、IKR(HERG)チャンネルで無視できる抑制活性を有する:
g.当該化合物ならびにその代謝物は、別種の医薬を一緒に投与した場合、代謝性DDIを生じさせない;および
h.当該化合物ならびにその代謝物は、単独で投与した場合、LFT値を高めない。 - 個体がヒトである、請求項9に記載の方法。
- 上記方法をコレステロールレベルの低下に使用する、請求項9に記載の方法。
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US39707602P | 2002-07-19 | 2002-07-19 | |
PCT/US2003/022756 WO2004009527A1 (en) | 2002-07-19 | 2003-07-21 | Materials and methods for treating hypercholesterolemia |
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EP (1) | EP1537068A1 (ja) |
JP (1) | JP2005533851A (ja) |
AU (1) | AU2003259188B2 (ja) |
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CA2492906A1 (en) * | 2002-07-19 | 2004-01-29 | Pascal Druzgala | Materials and methods for treating hypercholesterolemia |
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US5214197A (en) | 1990-07-06 | 1993-05-25 | Kanegafuchi Chemical Industry Co., Ltd. | 2,4-dihydroxyadipic acid derivative |
DE19627420A1 (de) * | 1996-07-08 | 1998-01-15 | Bayer Ag | 6-(Hydroxymethyl-ethyl)pyridine |
US6080778A (en) * | 1998-03-23 | 2000-06-27 | Children's Medical Center Corporation | Methods for decreasing beta amyloid protein |
KR20020028876A (ko) * | 1999-04-30 | 2002-04-17 | 추후제출 | 스테로이드 유도체 |
CA2402123A1 (en) * | 2000-04-24 | 2001-11-01 | Aryx Therapeutics | Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis |
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US6743926B2 (en) * | 2000-05-26 | 2004-06-01 | Ciba Specialty Chemicals Corporation | Process for the preparation of indole derivatives and intermediates of the process |
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- 2003-07-21 AU AU2003259188A patent/AU2003259188B2/en not_active Ceased
- 2003-07-21 WO PCT/US2003/022756 patent/WO2004009527A1/en active Application Filing
- 2003-07-21 JP JP2004523222A patent/JP2005533851A/ja active Pending
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US20040068001A1 (en) | 2004-04-08 |
US7384973B2 (en) | 2008-06-10 |
US20060116418A1 (en) | 2006-06-01 |
AU2003259188A1 (en) | 2004-02-09 |
CA2492906A1 (en) | 2004-01-29 |
US20080132561A1 (en) | 2008-06-05 |
EP1537068A1 (en) | 2005-06-08 |
WO2004009527A1 (en) | 2004-01-29 |
AU2003259188B2 (en) | 2008-03-06 |
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