JP2012511549A - Ampk活性に関連する疾患を処置するためのテトラヒドロトリアジン化合物 - Google Patents
Ampk活性に関連する疾患を処置するためのテトラヒドロトリアジン化合物 Download PDFInfo
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- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/10—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
Description
[式中、ラジカル:R1〜R6は、後述の意味を有する]で示される化合物、及び/又は生理学的に許容しうるその塩に関する。本発明の別の目的は、グルコース恒常性の強化、ポドサイト病(podocytopathy)の改善及び/又は活性酸素種(ROS)の産生の低下のための該化合物の使用に関する。本発明はまた、糖尿病性腎症のインビトロ診断方法及びポドサイト病を軽減する化合物のスクリーニング方法に関するものであり、いずれもバイオマーカーとしてシナプトポディン(synaptopodin)を適用することによるものである。
[式中、
R1、R2は、それぞれ相互に独立に、H又はAを意味し、
R3、R4は、それぞれ相互に独立に、H、A、2〜6個のC原子を有するアルケニル、2〜6個のC原子を有するアルキニル、Ar又はHetを意味し、
R5及びR6はまた、一緒になって2、3、4又は5個のC原子を有するアルキレンを意味し、
R5、R6は、それぞれ相互に独立に、H、A、(CH2)nAr、(CH2)mOAr、(CH2)mOA又は(CH2)mOHを意味し、
R5及びR6はまた、一緒になって2、3、4又は5個のC原子を有するアルキレン(ここで、1個のCH2基は、O、NH若しくはNAにより置き換えられていてもよいか、かつ/又は1個のH原子は、OHにより置き換えられていてもよい)を意味し、
Arは、フェニル、ナフチル又はビフェニル(ここで、これらそれぞれは、非置換であるか、あるいはHal、A、OA、OH、COOH、COOA、CN、NH2、NHA、NA2、SO2A及び/又はCOAにより、単置換、二置換又は三置換されている)を意味し、
Hetは、1〜4個のN、O及び/又はS原子を有する、単環、二環又は三環式の飽和、不飽和又は芳香族複素環(非置換であるか、あるいはHal、A、OH、OA、NH2、(CH2)nAr、NHA、NA2、COOH、COOA及び/又は=O(カルボニル酸素)により単置換、二置換又は三置換されていてもよい)を意味し、
Aは、1〜10個のC原子を有する非分岐若しくは分岐のアルキル(ここで、1〜7個のH原子は、Fにより置き換えられていてもよい)、又は3〜7個のC原子を有する環状アルキルを意味し、
Halは、F、Cl、Br又はIを意味し、
mは、1、2、3、4、5又は6を意味し、そして
nは、0、1又は2を意味する]で示される化合物及び/又は生理学的に許容しうるその塩を提供することにより、この問題を解決している。
[式中、
R1、R2、R3、R4は、上記の意味を有する]で示される化合物を、式(III)、(IV)又は(V):
[式中、
R5、R6は、上記の意味を有し、そして
R7は、メチル又はエチル基である]で示される化合物と反応させる(ここで、本反応は、極性溶媒(例えば、エタノール又はジメチルホルムアミド)中で、かつ有機酸(例えば、カンファースルホン酸)又は無機酸(例えば、塩酸)の存在下で実行される)ことにより、調製することができる。
[式中、
R1、R2、R3、R4は、上記の意味を有する]で示される化合物と、式(VI):
[式中、
R5、R6は、上記の意味を有する]で示される化合物との反応を含む製造法によって調製されるのが好ましい。
− そのポドサイトがシナプトポディンを発現できる、細胞系又はその試料を準備する工程(ここで、この系は、単一細胞、培養細胞、組織、臓器及び哺乳動物の群から選択される)、
− 少なくとも系の一部をスクリーニングすべき化合物と共にインキュベートする工程、
− シグナル又はシグナルの変化の量を系中のシナプトポディン濃度と相互に関連付ける工程、
− シナプトポディン濃度を、非アポトーシス及び/又はアポトーシスのポドサイトの対照細胞系の別のシナプトポディン濃度と比較することにより、ポドサイト病のレベルを検出する工程、並びに場合により
− ポドサイト病を軽減する化合物の、ampk遺伝子若しくはそのレギュレーター遺伝子との、又は該遺伝子のいずれかの産物との、又は該遺伝子若しくはその遺伝子産物のいずれかを含むシグナル伝達経路の成分との特異的相互作用を検出する工程
を含む方法を教示している。
− 哺乳動物から採取したポドサイトの試料をシナプトポディンに特異的な物質と共にインキュベートする工程、
− 特異的インキュベーション生成物を測定する工程、
− シグナル又はシグナルの変化の量を試料中のシナプトポディン濃度と相互に関連付ける工程、並びに
− シナプトポディン濃度を、非アポトーシス及び/又はアポトーシスのポドサイトの試料中の別のシナプトポディン濃度と比較することにより、糖尿病性腎症を検出する工程(ここで、糖尿病性腎症の病期とシナプトポディン濃度とは反比例する)
を含む方法に関する。
上記及び下記において、全ての温度は℃で与えられる。以下の実施例において、「従来の処理」は、必要ならば水を加え、必要ならば最終生成物の構成に応じてpHを2〜10の間の値に調整し、混合物を酢酸エチル又はジクロロメタンで抽出し、相を分離し、有機相を硫酸ナトリウムで乾燥して溶媒を留去し、そして生成物をシリカゲルのクロマトグラフィーにより、及び/又は結晶化により精製することを意味する。
5,6−ジヒドロ−4−ジメチルアミノ−2−イミノ−6−メチル−1,3,5−トリアジンは、AMPKの有意な活性化を示した。この活性化は、肝細胞(図1)及び筋細胞において観測した。メトホルミン及び5,6−ジヒドロ−4−ジメチルアミノ−2−イミノ−6−メチル−1,3,5−トリアジンは、肝細胞ではAMPKの類似のAMPK活性化を示した。筋細胞では、5,6−ジヒドロ−4−ジメチルアミノ−2−イミノ−6−メチル−1,3,5−トリアジンはAMPK活性を有意に上昇させた(図2)。この作用はまた用量依存的であり、メトホルミンの作用よりも更に強かった。
シナプトポディン(G1D4)は、モノクローナルマウスIgG抗体(#61094、Progen(商標))で検出した。各ラットについて、2つの連続した切片から40個の糸球体を無作為に選択した。メサンギウム細胞内のシナプトポディン(G1D4)陽性面積は、×20(x/yスケール:1ピクセル=0.36×0.36μm2)で切片を走査し、そして糸球体の中心部に2400μm2の円形測定野をセットする、Ariol SL-50自動顕微鏡(Applied Imaging Int. Ltd.)で測定した。シナプトポディン(G1D4)の陽性標識面積は、測定野中の組織面積の百分率として算出した。各動物について、40個の糸球体からの平均値を算出した。対応のないMann-Whitney検定により統計的な比較を実施した。データは、平均値±SEMである。
5,6−ジヒドロ−4−ジメチルアミノ−2−イミノ−6−メチル−1,3,5−トリアジンの効果は、絶食Wistarラットの飲料水に一旦投与(50mg/kg/日)すると少なくとも10日間試験した。このアプローチは、高用量の皮下注射よりも生理的である。5,6−ジヒドロ−4−ジメチルアミノ−2−イミノ−6−メチル−1,3,5−トリアジンは、複合体Iを通る逆電子束に結び付いたROS産生を時間依存的に阻害した(即ち、コハク酸単独又はグルタミン酸/リンゴ酸との組合せの存在下)。この作用は、ラット肝臓(図4)及びヒト微小血管内皮細胞(HMEC;表2)の両方において観測された。
A) 注射バイアル: 再蒸留水3l中の本発明の活性成分100g及びリン酸水素二ナトリウム5gの溶液を2N塩酸を用いてpH6.5に調整し、無菌濾過し、注射バイアルに移し、無菌条件下で凍結乾燥して、無菌条件下で密封した。各注射バイアルは活性成分5mgを含有する。
Claims (15)
- AMP活性化プロテインキナーゼの活性に起因するか、これが介在するか、かつ/又はこれにより広められる疾患の予防若しくは治療処置及び/又はモニターのための、式(I):
[式中、
R1、R2は、それぞれ相互に独立に、H又はAを意味し、
R3、R4は、それぞれ相互に独立に、H、A、2〜6個のC原子を有するアルケニル、2〜6個のC原子を有するアルキニル、Ar又はHetを意味し、
R5及びR6はまた、一緒になって2、3、4又は5個のC原子を有するアルキレンを意味し、
R5、R6は、それぞれ相互に独立に、H、A、(CH2)nAr、(CH2)mOAr、(CH2)mOA又は(CH2)mOHを意味し、
R5及びR6はまた、一緒になって2、3、4又は5個のC原子を有するアルキレン(ここで、1個のCH2基は、O、NH若しくはNAにより置き換えられていてもよいか、かつ/又は1個のH原子は、OHにより置き換えられていてもよい)を意味し、
Arは、フェニル、ナフチル又はビフェニル(ここで、これらそれぞれは、非置換であるか、あるいはHal、A、OA、OH、COOH、COOA、CN、NH2、NHA、NA2、SO2A及び/又はCOAにより、単置換、二置換又は三置換されている)を意味し、
Hetは、1〜4個のN、O及び/又はS原子を有する、単環、二環又は三環式の飽和、不飽和又は芳香族複素環(非置換であるか、あるいはHal、A、OH、OA、NH2、(CH2)nAr、NHA、NA2、COOH、COOA及び/又は=O(カルボニル酸素)により単置換、二置換又は三置換されていてもよい)を意味し、
Aは、1〜10個のC原子を有する非分岐若しくは分岐のアルキル(ここで、1〜7個のH原子は、Fにより置き換えられていてもよい)、又は3〜7個のC原子を有する環状アルキルを意味し、
Halは、F、Cl、Br又はIを意味し、
mは、1、2、3、4、5又は6を意味し、そして
nは、0、1又は2を意味する]で示される化合物及び/又は生理学的に許容しうるその塩。 - 式(I)の化合物が、5,6−ジヒドロ−4−ジメチルアミノ−2−イミノ−6−メチル−1,3,5−トリアジン及び/又は生理学的に許容しうるその塩酸塩である、請求項1に記載の化合物。
- 疾患が、糖尿病、前糖尿病、高血糖症、インスリン抵抗性、メタボリック症候群、肥満症、腎臓肥大、腎不全、糖尿病性腎症、神経障害、糖尿病性網膜症、癌、炎症、心血管疾患、アルツハイマー病及び加齢の群から選択され、好ましくは腎臓肥大及び糖尿病性腎症である、請求項1又は2に記載の化合物。
- AMP活性化プロテインキナーゼの活性に起因するか、これが介在するか、かつ/又はこれにより広まる疾患の予防若しくは治療処置及び/又はモニター用の、活性成分として有効量の少なくとも1種の請求項1に記載の式(I)の化合物及び/又は生理学的に許容しうるその塩を、1種以上の薬学的に許容しうる補助剤と共に含む医薬組成物。
- 活性成分が、少なくとももう1種の活性成分、好ましくはACE阻害薬、AT1アンタゴニスト、利尿薬、HMG−CoAレダクターゼ阻害薬及び/又はサリチル酸薬と組合せられる、請求項4に記載の組成物。
- AMP活性化プロテインキナーゼを活性化するための、少なくとも1種の請求項1に記載の式(I)の化合物及び/又は生理学的に許容しうるその塩の使用。
- AMP活性化プロテインキナーゼの活性が、少なくとも30%、好ましくは少なくとも2倍増強される、請求項6に記載の使用。
- グルコース恒常性を強化するための、請求項6に記載の使用。
- ポドサイト病を軽減するための、請求項6に記載の使用。
- シナプトポディンの糸球体発現が、増加、好ましくは回復し、かつ/又はラミニンの糸球体発現が、低下する、請求項9に記載の使用。
- 活性酸素種の産生を低下させるための、請求項6に記載の使用。
- AMP活性化プロテインキナーゼの活性に起因するか、これが介在するか、かつ/又はこれにより広められる疾患を処置する方法であって、有効量の少なくとも1種の請求項1に記載の式(I)の化合物及び/又は生理学的に許容しうるその塩が、このような処置を必要としている哺乳動物に投与される方法。
- 糖尿病性腎症のインビトロ診断方法であって、
− 哺乳動物から採取したポドサイトの試料をシナプトポディンに特異的な物質と共にインキュベートする工程、
− 特異的インキュベーション生成物を測定する工程、
− シグナル又はシグナルの変化の量を試料中のシナプトポディン濃度と相互に関連付ける工程、並びに
− シナプトポディン濃度を、非アポトーシス及び/又はアポトーシスのポドサイトの試料中の別のシナプトポディン濃度と比較することにより、糖尿病性腎症を検出する工程(ここで、糖尿病性腎症の病期とシナプトポディン濃度とは反比例する)
を含む方法。 - ポドサイト病のバイオマーカーとしてのシナプトポディンの使用。
- ポドサイト病を軽減する化合物のスクリーニング方法であって、
− そのポドサイトがシナプトポディンを発現できる、細胞系又はその試料を準備する工程(ここで、この系は、単一細胞、培養細胞、組織、臓器及び哺乳動物の群から選択される)、
− 少なくとも系の一部をスクリーニングすべき化合物と共にインキュベートする工程、
− シグナル又はシグナルの変化の量を系中のシナプトポディン濃度と相互に関連付ける工程、
− シナプトポディン濃度を、非アポトーシス及び/又はアポトーシスのポドサイトの対照細胞系の別のシナプトポディン濃度と比較することにより、ポドサイト病のレベルを検出する工程、並びに場合により
− ポドサイト病を軽減する化合物の、AMP活性化プロテインキナーゼ遺伝子若しくはそのレギュレーター遺伝子との、又は該遺伝子のいずれかの産物との、又は該遺伝子若しくはその遺伝子産物のいずれかを含むシグナル伝達経路の成分との特異的相互作用を検出する工程
を含む方法。
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JP2021529728A (ja) * | 2018-06-06 | 2021-11-04 | メタヴァント サイエンシズ ゲーエムベーハー | 慢性腎疾患を持つ糖尿病対象を治療する方法 |
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JP5485292B2 (ja) | 2014-05-07 |
CN102245581A (zh) | 2011-11-16 |
EP2367802A2 (en) | 2011-09-28 |
WO2010066901A3 (en) | 2010-08-05 |
CA2745854A1 (en) | 2010-06-17 |
MX2011005644A (es) | 2011-06-16 |
IL212901A0 (en) | 2011-07-31 |
BRPI0922650A2 (pt) | 2017-07-11 |
US20110236317A1 (en) | 2011-09-29 |
WO2010066901A2 (en) | 2010-06-17 |
US9035048B2 (en) | 2015-05-19 |
AU2009326965A1 (en) | 2011-06-23 |
ES2573266T3 (es) | 2016-06-06 |
EP2367802B1 (en) | 2016-04-20 |
TW201033182A (en) | 2010-09-16 |
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