JP5161774B2 - Ampk活性化物質としてのチエノピリドン誘導体の使用およびこれを含む医薬組成物 - Google Patents
Ampk活性化物質としてのチエノピリドン誘導体の使用およびこれを含む医薬組成物 Download PDFInfo
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- JP5161774B2 JP5161774B2 JP2008526387A JP2008526387A JP5161774B2 JP 5161774 B2 JP5161774 B2 JP 5161774B2 JP 2008526387 A JP2008526387 A JP 2008526387A JP 2008526387 A JP2008526387 A JP 2008526387A JP 5161774 B2 JP5161774 B2 JP 5161774B2
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- Prior art keywords
- alkyl
- formula
- pyridin
- hydroxy
- phenyl
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Description
本発明は、AMP−活性化プロテインキナーゼ(AMPK)の活性化物質であるチエノピリドン誘導体に関する。本発明はまた、これらのチエノピリドンの糖尿病、代謝症候群および肥満症などの障害の治療における調製および使用に関する。
AMPKは、細胞エネルギー恒常性のセンサーおよび調節剤として確立されている(Hardie,D.G.およびHawley,S.A.、「AMP−activated protein kinase:the energy charge hypothesis revisited」、Bioassays、23、1112頁、(2001年)、Kemp,B.E.ら、「AMP−activated protein kinase,super metabolic regulator」、Biochem.Soc.Transactions、31、162頁(2003年))。AMPレベル上昇によるこのキナーゼのアロステリック活性化は、細胞エネルギー枯渇状態において生じる。結果として生じる標的酵素のセリン/スレオニンリン酸化は、細胞代謝を低エネルギー状態に適応させる。AMPK活性化で誘導される変化の正味効果は、ATP消費プロセスの抑制およびATP生成経路の活性化であり、したがって、ATP貯蔵の再生である。AMPK基質の例としては、アセチル−CoA−カルボキシラーゼ(ACC)およびHMG−CoA−レダクターゼ(Carling D.ら、「A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis」、FEBS Letters、223、217頁(1987年))などがある。リン酸化、したがってACCの阻害は、脂肪酸合成(ATP消費)の減少および脂肪酸酸化(ATP生成)の増加を同時にもたらす。リン酸化およびその結果生じるHMG−CoAレダクターゼの阻害により、コレステロール合成は減少する。AMPKの他の基質としては、ホルモン感受性リパーゼ(Garton,A.J.ら、「Phosphorylation of bovine hormone−sensitive lipase by the AMP−activated protein kinase.A possible antilipolytic mechanism」、Eur.J.Biochem.、179、249頁、(1989年))、グリセロール−3−ホスフェートアシルトランスフェラーゼ(Muoio D.M.ら、「AMP−activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle:evidence that sn−glycerol−3−phosphate acyltransferase is a novel target」、Biochem.J.、338、783頁、(1999年))、マロニル−CoAデカルボキシラーゼ(Saha A.K.ら、「Activation of malonyl−CoA decarboxylase in rat skeletal muscle by contraction and the AMP−activated protein kinase activator 5−aminoimidazole−4−carboxamide−1−β−D−ribofuranoside」、J.Biol.Chem.、275、24279頁、(2000年))、および肝細胞核因子−4α(Leclerc I.ら、「Hepatocyte nuclear factor−4α involved in type−1 maturity−onset diabetes of the young is a novel target of AMP−activated protein kinase」、Diabetes、50、1515頁、(2001年))などがあり、これらの一部は、代謝症候群の成分に対する潜在的な薬剤標的である。正確なAMPK基質は同定されていないが、AMPK活性化を介して調節されていると考えられるさらなるプロセスとしては、骨格筋におけるグルコース輸送の刺激や、肝臓における脂肪酸およびグルコース代謝の鍵となる遺伝子の発現調節(Hardie D.G.およびHawley S.A.、「AMP−activated protein kinase:the energy charge hypothesis revisited」、Bioassays、23、1112頁、(2001年)、Kemp B.E.ら、「AMP−activated protein kinase,super metabolic regulator」、Biochem.Soc.Transactions、31、162頁、(2003年)、Musi N.およびGoodyear L.J.、「Targeting the AMP−activated protein kinase for the treatment of type 2 diabetes」、Current Drug Targets−Immune,Endocrine and Metabolic Disorders、2、119頁、(2002年))などがある。例えば、肝臓でのグルコース産生の鍵となる酵素であるグルコース−6−ホスファターゼ(Lochhead P.A.ら、「5−aminoimidazole−4−carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose−6−phosphatase」、Diabetes、49、896頁、(2000年))、および主要な脂肪形成転写因子であるSREBP−1c(Zhou G.ら、「Role of AMP−activated protein kinase in mechanism of metformin action」、The J.of Clin.Invest.、108、1167頁、(2001年))の発現低下がAMPK刺激後に見出された。
米国特許第5602144号には、神経変性疾患の治療に有用な化合物として新規なチエノピリドン誘導体が記載および請求されている。これらの化合物および一部の新規なアナログは、AMP活性化プロテインキナーゼ(AMPK)の活性化物質であり、したがって糖尿病、代謝症候群および肥満症などの障害の治療に有用であることが現在発見されている。本発明は、糖尿病、代謝症候群、関連障害および肥満症の治療に有用である医薬組成物の調製のための、本明細書に組み込まれる米国特許第5602144号に記載された化合物、および特定の新規なチエノピリドン誘導体、ならびにこれらの医薬的に許容される塩の使用であって、該既知および新規な化合物が、式(I):
Bは、CHまたはNであり、
Rは、H、
R1およびR2は、互いに独立して、H、直鎖もしくは分岐の(C1〜C4)アルキル、(C1〜C4)シクロアルキル、(C1〜C4)シクロアルキル(C1〜C4)アルキル、ハロゲンを表し、または
一緒に、基−(CH2)n−(nは、1から4)を形成し、
R3およびR4は、互いに独立して、H、直鎖もしくは分岐の(C1〜C4)アルキル、OH、直鎖もしくは分岐の(C1〜C4)アルコキシ、ハロゲン、CF3、NO2、NH2、NHR’[ここで、R’は、直鎖または分岐の(C1〜C6)アシル、NHR”、N(R”)2、(ここで、R”は、直鎖もしくは分岐の(C1〜C4)アルキル、場合によって置換されたアニリノ、場合によって置換されたフェノキシ、場合によって置換されたベンジル、または場合によって置換されたベンゾイルである)である]を表し、
R5は、H、直鎖もしくは分岐の(C1〜C4)アルキル、またはハロゲンであり、
R6は、Hまたはハロゲン、直鎖もしくは分岐の(C1〜C4)アルキル、(C1〜C4)シクロアルキル、(C1〜C4)シクロアルキル(C1〜C4)アルキルであり、
Xは、−CH2−、−CO−、−O−、−S−、−NH−、または−NR’’’−(ここで、R’’’は、直鎖または分岐の(C1〜C4)アルキルである)である]
である、使用に関する。
一緒に、基−(CH2)n−(nは1から4)を形成し、
B、R、R3、R4、R5、R6およびXは、式(I)において上記に定義したとおりである)
の化合物およびその医薬的に許容される塩に関する。
B、−Y−Z−、R1、R2、R5、R6およびXは、式(I)において上記に定義したとおりである)
の新規な化合物およびその医薬的に許容される塩を包含する。
R6は、直鎖もしくは分岐の(C1〜C4)アルキル、(C1〜C4)シクロアルキル、または(C1〜C4)シクロアルキル(C1〜C4)アルキルであり、
B、−Y−Z−、R、R1、R2、R3、R4、R5およびXは、式(I)において上記に定義したとおりである)
の化合物およびその医薬的に許容される塩に関する。
1)式(II)
の化合物を環化剤で処理するステップと、
2)必要に応じて、式(I)の化合物中の基Rを別の基Rに変換し、それにより式(I)の別の化合物を形成し、および/または式(I)の化合物を酸もしくは塩基で処理することによってその医薬的に許容される塩の1つに転換するステップと、
を含む方法に関する。
(Ia)において、BはCHであり;
(Ib)において、BはNであり;
(Ic)において、−Y−Z−は、
R1は、HまたはCH3であり、
R2は、H、CH3、C2H5、ClまたはBrであり、
R3は、H、CH3、OH、OCH3、F、Cl、CF3、NO2、NH2、N(CH3)2またはNHCOCH3であり、
R4は、Hであり、
R5は、Hであり、
Xは、−CH2−、−CO−、−O−または−NH−である)であり;
(Id)において、−Y−Z−は、
Rは、Hまたは
R1はHまたはCH3であり、
R2は、H、CH3、C2H5、ClまたはBrであり、
R3は、H、CH3、OCH3、F、ClまたはCF3であり、
R4は、Hであり、
Xは、−CH2−、−CO−、−O−または−NH−である)であり;
(Ie)において、Bは、CHであり、
−Y−Z−は、
Rは、Hであり、
R1は、HまたはCH3であり、
R2は、H、CH3、C2H5、ClまたはBrである)
である。
Bは、CHであり、
RおよびR6は、各々Hであり、
−Y−Z−は、
R1は、H、メチル、エチル、イソプロピル、イソブチル、シクロプロピルであり、
R2は、H、Cl、Brまたはメチルであり、
あるいは、
R1およびR2は、一緒に、基−(CH2)4−を形成する)
である。
4−ヒドロキシ−2,3−ジメチル−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
2−エチル−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
2−ブロモ−4−ヒドロキシ−3−メチル−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
2−ブロモ−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
2−クロロ−4−ヒドロキシ−3−イソプロピル−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
3−sec−ブチル−2−クロロ−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
4−ヒドロキシ−3−イソプロピル−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
3−sec−ブチル−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;および
2−クロロ−3−シクロプロピル−4−ヒドロキシ−5−(3−フェノキシ−フェニル)−7H−チエノ[2,3−b]ピリジン−6−オン。
Bは、CHであり、
RおよびR6は、各々Hであり、
−Y−Z−は、
R1は、シクロプロピルであり、
R2は、Hであり、または
R1およびR2は、一緒に、−(CH2)4−を形成する)
である。
4−ヒドロキシ−3−フェニル−5,6,7,8−テトラヒドロ−1H−ベンゾ[4,5]チエノ[2,3−b]ピリジン−2−オン、および
3−シクロプロピル−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン
である。
THF20mL中、メチル5−クロロ−4−メチル−2−(フェニルアセトアミド)チオフェン−3−カルボキシラート(m.p.:105〜107℃;対応する塩素を含まない化合物をN−クロロスクシンイミドで塩素化することによって得られる)0.6gの溶液を−70℃に冷却する。次いで、トルエン中KN(Si(CH3)3)2の0.5モル溶液8.16mLを滴下して加える。反応溶液をゆっくり室温にし、次いで蒸発させる。残渣を水に溶かし、この溶液をジエチルエーテルで数回抽出する。次いで、水相を2N HClで酸性化し、沈殿物をろ別し、水で洗浄し、ジエチルエーテルで分解した後、再度ろ別し、乾燥する。2−クロロ−3−メチル−4−ヒドロキシ−5−フェニル−6,7−ジヒドロ−チエノ[2,3−b]ピリジン−6−オンを得る。
以下の2−R2−3−R1−4−ヒドロキシ−5−フェニル−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン:
以下の2−クロロ−3−メチル−4−ヒドロキシ−5−(3−R−フェニル)−6,7−ジヒドロ−チエノ[2,3−b]ピリジン−6−オン:
以下の2−クロロ−3−メチル−4−ヒドロキシ−5−(4−R−2−ピリジル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン:
以下の2−R2−3−R1−4−ヒドロキシ−5−(2−ピリジル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン:
以下の2−クロロ−3−メチル−4−ヒドロキシ−5−(3−R−フェニル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン:
以下の2−クロロ−3−メチル−4−ヒドロキシ−5−(3−R−フェニル)−6,7−ジヒドロ−チエノ[2,3−b]ピリジン−6−オン:
7−ヒドロキシ−6−フェニル−4,5−ジヒドロチエノ−[3,2−b]−ピリジン−5−オン(Rf 0.31、ジクロロメタン/メタノール 10:1)を、実施例1と同様に、メチル3−フェニルアセトアミドチオフェン−2−カルボキシラートから環化によって得る。
化合物4−ヒドロキシ−3フェニル−1,2−ジヒドロチエノ[3,4−b]ピリジン−2−オン(Rf 0.37、ジクロロメタン/メタノール 10:1)を、実施例1と同様に、メチル4−フェニルアセトアミドチオフェン−3−カルボキシラートから得る。
95%エタノール50mL中2−クロロ−3−メチル−4−ヒドロキシ−5−(3−m−ニトロフェノキシフェニル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン4.28gの溶液に、酸化白金20mgを加える。3モル等量が吸収されるまでこの溶液に水素を通す。白金をろ別し、アルコールを蒸留除去する。2−クロロ−3−メチル−4−ヒドロキシ−5−(3−m−アミノフェノキシフェニル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オンを得る。
10%メタノール性KOH溶液80mL中2−クロロ−3−メチル−4−ヒドロキシ−5−(3−o−アセトアミドフェノキシフェニル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン4.4gの溶液を48時間煮沸する。通常の処理後、2−クロロ−3−メチル−4−ヒドロキシ−5−(3−o−アミノフェノキシフェニル)−6,7−ジヒドロ−チエノ[2,3−b]ピリジン−6−オンを得る。
2−クロロ−3−メチル−4−ヒドロキシ−5−(3−p−メトキシベンゾイルフェニル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン4.25gとピリジン塩酸塩3.5gの混合物を160℃で3時間攪拌する。通常の処理後、2−クロロ−3−メチル−4−ヒドロキシ−5−(3−p−ヒドロキシベンゾイルフェニル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オンを得る。
以下の2−R2−3−R1−4−ヒドロキシ−5−(3−R−4−R6−フェニル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン:
以下の2−R2−3−R1−4−ヒドロキシ−5−(3−R−4−R6−フェニル)−6,7−ジヒドロチエノ[2,3−b]ピリジン−6−オン:
4−ヒドロキシ−3−フェニル−5,6,7,8−テトラヒドロ−1−ベンゾチエノ[2,3−b]ピリジン−2(1H)−オンを、実施例1と同様に、エチル2−(フェニルアセチル)アミノ−4,5,6,7−テトラヒドロ−1−ベンゾチオフェン−3−カルボキシラートから、環化によって得る。
スクリーニングアッセイ
ヒト組換えAMPK酵素をE.Coliで発現させ、酵素活性測定前にLKB1によってin vitroで再活性化した。
必要に応じて、蔗糖基剤に通常の被覆表面をコーティングした以下の組成の錠剤を、通常の方法でプレスする:
式(I)の活性化合物 100mg
微結晶セルロース 278.8mg
乳糖 110mg
コーンスターチ 11mg
ステアリン酸マグネシウム 5mg
微粉化二酸化ケイ素 0.2mg
通常の2部式ハードゼラチンカプセルを、それぞれ、以下で充填する:
式(I)の活性化合物 100mg
乳糖 150mg
セルロース 50mg
ステアリン酸マグネシウム 6mg
通常のソフトゼラチンカプセルに、それぞれ、活性化合物50mgおよびオリーブオイル250mgを含む混合物を充填する。
1,2−プロパンジオール2kg中に活性化合物200gを含む溶液を、水で10Lにし、これを用いて各アンプルが活性化合物20mgを含むようにアンプルに充填する。
活性化合物の水性懸濁液を通常の方法で調製する。この単回用量(5mL)は、活性化合物100mg、カルボキシメチルセルロースNa100mg、安息香酸Na5mgおよびソルビトール100mgを含む。
Claims (9)
- 糖尿病、代謝症候群、関連障害および肥満症の治療のために有用である医薬組成物の調製のための、式(I):
R1およびR2は、互いに独立して、H、直鎖もしくは分岐の(C1〜C4)アルキル、(C1〜C4)シクロアルキル、(C1〜C4)シクロアルキル(C1〜C4)アルキル、ハロゲンを表し、または
一緒に、基−(CH2)n−(nは、1から4)を形成し、
R3およびR4は、互いに独立して、H、直鎖もしくは分岐の(C1〜C4)アルキル、OH、直鎖もしくは分岐の(C1〜C4)アルコキシ、ハロゲン、CF3、NO2、NH2、NHR’(ここで、R’は、直鎖または分岐の(C1〜C6)アシル、NHR”、N(R”)2(ここで、R”は、直鎖または分岐の(C1〜C4)アルキル、場合によって置換されたアニリノ、場合によって置換されたフェノキシ、場合によって置換されたベンジル、または場合によって置換されたベンゾイルである)である)を表し、
R5は、H、直鎖もしくは分岐の(C1〜C4)アルキル、またはハロゲンであり、
R6は、Hまたはハロゲン、直鎖または分岐の(C1〜C4)アルキル、(C1〜C4)シクロアルキル、(C1〜C4)シクロアルキル(C1〜C4)アルキルであり、
Xは、−CH2−、−CO−、−O−、−S−、−NH−、または−NR’’’−(ここで、R’’’は、直鎖または分岐の(C1〜C4アルキル)である)である]
の化合物および/またはその医薬的に許容される塩の使用。 - 式(I)の化合物および/またはその医薬的に許容される塩が、
4−ヒドロキシ−2,3−ジメチル−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
2−エチル−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
2−ブロモ−4−ヒドロキシ−3−メチル−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
2−ブロモ−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
2−クロロ−4−ヒドロキシ−3−イソプロピル−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
3−sec−ブチル−2−クロロ−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン;
4−ヒドロキシ−3−フェニル−5,6,7,8−テトラヒドロ−1H−ベンゾ[4,5]チエノ[2,3−b]ピリジン−2−オン;および
3−シクロプロピル−4−ヒドロキシ−5−フェニル−7H−チエノ[2,3−b]ピリジン−6−オン。
から選択される、請求項1または2に記載の使用。 - 請求項1から3のいずれかに記載の少なくとも1つの化合物、および/またはその生理学的に無害な塩の1つ、を含む製剤。
- 少なくとも前記1つの化合物、および/または生理学的に無害な塩が、用量単位当たり1mgから500mgの範囲の量で存在する、請求項4に記載の医薬組成物。
- 薬剤の調製のための、請求項1から3のいずれかに記載の式(I)の化合物、および/またはその医薬的に許容される塩の1つ、の使用。
- 請求項1から3のいずれかに記載の式(I)の少なくとも1つの化合物、および/またはその医薬的に許容される塩の1つを、少なくとも1つの固体、液体もしくは半固体の担体および/または補助剤と一緒に剤形にする、製剤を製造するための方法。
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EP05291753A EP1754483A1 (en) | 2005-08-18 | 2005-08-18 | Use of thienopyridone derivatives as AMPK activators and pharmaceutical compositions containing them |
EP05291753.1 | 2005-08-18 | ||
PCT/EP2006/006446 WO2007019914A1 (en) | 2005-08-18 | 2006-07-03 | Use of thienopyridone derivatives as ampk activators and pharmaceutical compositions containing them |
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KR101062670B1 (ko) * | 2009-06-01 | 2011-09-06 | (주)아모레퍼시픽 | 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난을 유효성분으로 포함하는 에이엠피케이의 활성화에 의해 매개되는 비만 관련 질환의 예방 또는 치료용 조성물 |
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EP1915150A1 (en) | 2008-04-30 |
US20090105293A1 (en) | 2009-04-23 |
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SI1915150T1 (sl) | 2011-04-29 |
CA2619505C (en) | 2015-04-28 |
DE602006019880D1 (de) | 2011-03-10 |
CA2619505A1 (en) | 2007-02-22 |
ZA200802454B (en) | 2009-01-28 |
EP1915150B1 (en) | 2011-01-26 |
ES2359860T3 (es) | 2011-05-27 |
ATE496622T1 (de) | 2011-02-15 |
JP2009504693A (ja) | 2009-02-05 |
KR20080034491A (ko) | 2008-04-21 |
CY1111660T1 (el) | 2015-10-07 |
BRPI0614828A2 (pt) | 2011-04-19 |
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CN101232883A (zh) | 2008-07-30 |
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DK1915150T3 (da) | 2011-02-21 |
EP1754483A1 (en) | 2007-02-21 |
MX2008002062A (es) | 2008-04-16 |
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