JP2007525418A - 先進的糖化最終産物(age)形成の新規阻害剤 - Google Patents
先進的糖化最終産物(age)形成の新規阻害剤 Download PDFInfo
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Abstract
【選択図】なし
Description
[0001]本出願は、1999年4月5日出願の仮出願第60/127,835号に関連し、2000年4月5日出願の出願第09/543,703(現、米国特許第6,337,350号)の一部継続出願である、2001年3月8日出願の出願第09/800,976号(現、米国特許第6,605、642号)の一部継続出願であり、これら全ては参照により本明細書に援用される。
[0002]本発明は、一般的に、グルコース及び他の還元糖、例えばフルクトース又はリボースとの反応を通じてタンパク質の修飾や老化に関し、より具体的には先進的糖化最終産物や架橋の形成にしばしば帰着するタンパク質の非酵素的糖化の阻害に関する。
1.シッフ塩基の可逆的形成、それに続く
2.アマドリ凝縮/脱水産物、例えば、3−デオキシグルカソン(3−DG)、高反応性ジカルボニル化合物(Kato et al.,1990)。
3.不可逆性であり高反応性の先進的糖付加最終産物。初期のアマドリ産物の例は、さらに後期のAGEを形成する凝縮反応を受けるケトアミンである。いくつかのAGE産物は、最近、精製され特徴付けられている。各々はインビボで生じたAGEの主要な断片のみから構成されている。例は、ピラリン、ペントシジン、カルボキシメチル−リジン(CML)、カルボキシエチル−リジン(CEL)、クロスリン、ピロロピリジニウム、メチルグリオキサルリジン二量体(MOLD)、Arg−Lysイミダゾール、アルギニン、ピリジニウム、サイペントジン(cypentodine)、ピペリジンジオンエノール及びアルキル、ホルミル、ジグリコシル−ピロールである(Vlassara,1994)
に導く。
[00021]フェノキシイソブチル酸誘導体及び安息香酸誘導体は、アリール及び複素環式ウレイド誘導体並びにアリール及び複素環式カルボキサミド誘導体を含み、しばしば先進的糖化最終産物及び架橋の形成に帰着するタンパク質の非酵素的糖化を阻害することが見出されている。多くの他のフェノキシイソブチル酸誘導体並びに下記に詳述するようなある種の他の化合物はまた、タンパク質の非酵素的糖化を阻害することが見出されている。タンパク質の非酵素的糖化及び架橋は、年齢とともに増加する長命なタンパク質の糖化最終産物及び架橋を伴う加齢プロセスの一部である。このプロセスは、糖尿病とともに発生するように血中及び細胞内環境における還元糖の上昇した濃度で増加する。影響される分子の構造的及び機能的な完全な状態は、これらの修飾によって妨害され、深刻な結果に至る可能性がある。本発明の化合物は、非酵素的な糖化及び架橋のこのプロセスを阻害し、したがって、糖尿病又は加齢によって引き起こされるいくつかの病的影響を阻害するために使用され得る。化合物はまた、早発の加齢、慢性関節リウマチ、アルツハイマー症、尿毒症、神経毒症、アテローム性動脈硬化症、及び食物中のタンパク質の損傷を妨げるのに有用であり、歯の変色を妨げることができる。
[00038]本出願人は、糖化及びAGE形成の阻害剤として、アリール(及び複素環式)ウレイド及びアリール(及び複素環式)カルボキシアミドフェノキシイソブチル酸、並びに安息香酸誘導体及び関連する化合物である新クラスの化合物を以前に報告している(Rahbar et al.,1999; Rahbar et al.,2000; Rahbar et al.,2002)。先進的糖化最終産物(AGE)への可能な阻害効果の調査に関する有機化合物の異なるクラスをスクリーニングするに際して、本出願人は、試験した大部分のフェニルウレイド置換フェノキシプロピオン酸誘導体が阻害効果を有し、これらのいくつかの化合物は、アミノグアニジンの等しい阻害濃度よりも非常に低い濃度のAGE形成の強力な阻害剤であった。本研究の目的は、糖化、AGE形成及びAGE架橋の新規な阻害剤のクラスを開発することであり、インビトロの化学的及び免疫化学的アッセイを通じてそれらの効果を調査することであった。全115個の化合物を設計し、合成した。最初の102個の化合物は、他の場所で報告されている。本明細書で報告される13個の新規な化合物は、以前に報告された最も強力な阻害剤の1つである以前に報告されたLR23(4−(3,5−ジクロロフェニルウレイド)−フェノキシイソブチル−1−アミノシクロヘキサン−1−カルボン酸)に基づいて設計し、開発した(Rahbar et al.,1999; 米国特許第6,337,350B1号、参照により本明細書に援用される)。これらの化合物は、LR3に基づいており(図20参照)、その合成は、Lalezari and Lalezari(1989)に報告され、本明細書に援用される。特にAGE−タンパク質−架橋の阻害における阻害潜在性のかなりの増加は、プロトタイプのLR23と比較される化合物中に見出され、20−30倍の大きな効果である(Khalifah et al.,1999)。
[00045]本発明の化合物は、LR103−LR115のように図7−19に示され、タンパク質糖化及びAGE形成における阻害効果についてスクリーニングした。開示の目的で、これらの構造に割り当てられた名称は、下記の通りである:
LR103: 1−[(4−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR104: 4−(4−フルオロ−3−クロロフェニルウレイド)フェノキシイソブチリルアミドフェニル−2−カルボン酸、
LR105: 1[(2−フルオロ−6−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR106: 4−(4−クロロベンジルアミノフェノキシイソブチル)酸、
LR107: 2−クロロベンゼン−1,4−ビス(4−ウレイドフェノキシイソブチル酸)、
LR108: 1−[(4−クロロベンジル)−3−(3,5−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR109: 1−[(2−フルオロ−6−クロロベンジル)−3−(2−フルオロ−6−クロロフェニルウレイド)]−4−フェノキシイソブチル酸
LR110: 4−(1,2,3,4−テトラヒドロアクリジン−9−カルボキサミドフェノキシイソブチル)酸、
LR111: 8−キノリノキシ酢酸、
LR112: 4,4’−ビス[(メチレンオキシエチレンアミノ)フェノキシ]イソブチル酸、
LR113: L−8−キノリノリル(アセチルヒスチジン)、
LR114: 4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]−2−ヒドロキシベンゼン−4−カルボン酸、及び
LR115: L,α−4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]フェニルアラニン。
ヘモグロビン−δ−グルコノラクトン(δ−Glu)アッセイ
[00047]δ−Gluアッセイは、糖化の初期段階の阻害剤を調査するための特異的な方法である。ヘモグロビン(HbAlC)上の初期の糖化産物(アマドリ)形成の評価は、阻害化合物の存在及び不存在におけるグルコースの酸化形態とともに赤血球細胞を培養し、試験対対照におけるHbAlCの決定によって実行される(Rahobar and Nadler,1999)。本試験は、Lindsayら(1997)による報告に基づいている。δ−Glu、グルコースの酸化類似体は、赤血球細胞内のヘモグロビンと即座に反応することができ、インキュベーションの数時間以内にHbAlCレベルを有意に増加させる。対照的に、グルコースは生じるために等しい反応について数週間を要する。本出願人は、ヘモグロビンの初期段階の糖化(アマドリ産物)の能力を測定するためのアッセイ、及びHbAlC形成を阻害する阻害剤の能力を評価するためのアッセイを考案するためにこの発見を使用した。簡単には、新鮮な血液をカリウム−EDTA中に吸出し、200μLの血液と40μLのリン酸緩衝液(PBS)、pH7.4単独、50ミリモル/Lのδ−Glu(Sigma)含有PBS、又は50ミリモル/Lのδ−Glu+1ミリモル/Lの阻害剤含有PBSの何れかと混合することにより、回収30分以内にインキュベーション用に調製した。37℃で16時間インキュベーション後、糖化したヘモグロビン存在のパーセントを決定した。糖化したHb(HbAlC)のパーセントは、専用のイオン交換HPLCシステム(BIORAD DIAMAT)を用いて決定した。血液サンプルは3回の試験で分析した。該化合物によるHbAlC形成の阻害%は、下記の式:
((B−C)/(B−A))×100
[ここで、Aは、δ−Gluで未処理の基底の対照試験管におけるHbAlC濃度であり、Bは、δ−Gluでインキュベートした血液のHbAlC濃度であり、Cは、δ−Glu及び阻害化合物の両方で処理した試験管HbAlC内容物である]
により計算した。
BSA−グルコースアッセイ
[00050]本試験は、グルコースを介したBSAの蛍光の発生を阻害する阻害剤の能力を評価するために使用される(Ikeda et al.,1996)。NaN3 0.2g/Lを含有する1.5Mのリン酸緩衝液 pH7.4中のSigma 50mg/mL及び800mM グルコース(144mg/mL)由来のBSA(断片V、基本的には脂肪酸無し、低エンドトキシン)の3重のサンプルを、化合物の各種濃度の存在又は不存在で7日間37℃で無菌状態でインキュベートした。インキュベーションの7日後、各サンプルを特異的な蛍光の発生について調べた(励起、330nm;放射、410nm)。試験サンプル対対照におけるAGE形成の阻害%は、各阻害化合物について計算した。アミノグアニジン(50mM)を正の対照として使用した。結果を表2に示す。
N−アセチル−グリシル−リジンメチルエステル(G.K.ペプチド)−リボースアッセイ
[00052]後期の糖化産物(AGE)、及び新規阻害化合物によるAGE阻害の評価は、試薬の存在又は不存在におけるリボースのG.K.ペプチドのインキュベーションによって試験し、それらの特異的な蛍光の測定を通した糖化及びAGE形成の過程において発生した蛍光団を決定した。リボースの存在下でN−アセチルグリシル−リジンメチルエステルの架橋を阻害する本発明の化合物の能力を評価するために使用したNagarajら(1996)の方法は、下記:
保存液:
NaN3 0.2g/Lを含む0.5M リン酸ナトリウム緩衝液 pH7.4
0.5M リン酸ナトリウム緩衝液 pH7.4中のGKペプチド(Sigma) 80mg/mL
0.5M リン酸緩衝液中のリボース800mM(120mg/mL)
の通りであった。
アマドリ転移後のタンパク質アッセイ
[00055]糖としてのリボースを使用してAGEを含まないアマドリが豊富なタンパク質を調製するための詳細なアプローチは、最近、報告されている(Khalifa et al.,1999)。タンパク質は、はじめに0.5Mのリボースとともに24時間37℃でインキュベートし、続いて、過剰の遊離リボースを除去し、4℃で透析によってシッフ塩基を除く。その後、AGEタンパク質への転換は、候補のアマドリ転移後の阻害剤の存在及び不存在で、37℃まで温めることによって開始する。このアッセイは、推定の化合物に対する阻害効果の評価について使用した。簡単には、タンパク質としてのBSA及び糖化試薬としてのリボースを用いて、AGEを含まない、アマドリが豊富であるタンパク質をKhalifaらに従って調製し、リン酸緩衝液に対して4℃で24時間長期の透析を行った。その後、透析した調製物を希釈し、加温し、候補阻害剤の存在及び不存在下で7日間37℃でインキュベートした。AGE産物のELISA検出は、0.5−1(0.3の代わりに)μgのタンパク質を各ポリスチレンウェルに被覆し、Superblot緩衝液をウェルをブロックするために使用したことを除き、Khalifaらによって記載したように実行した。ウサギのポリクローナル抗RNase−AGEを確立したプロトコール(Makita et al.,1992)を用いて調製し、1:1000に希釈して使用した。化合物LR103−LR115を用いた結果を図1及び2に示す。
アスコルビン酸の銅触媒の自動酸化の阻害
[00056]本アッセイは、Priceら(2001)に従って実行した。265nmの吸光度の減少の割合でアスコルビン酸(AA)の酸化の動力学を測定した。AGE阻害剤の研究について、アスコルビン酸は反応を開始するために添加した。アリコートを0、15、30、45、及び60分で回収し、DPTAを含有する自動注射バイアルに移動した。XterraTM RP18カラム(250×4.6mm、5μm)を用いて自動注入器を備えた逆相HPLC(Waters 2690 Millenium 32 Separator Module)によってサンプルを分析した。溶媒及び勾配はすべて、Priceら(2001)に記載されるように使用した。AA酸化の割合を50%まで阻害した各阻害化合物の濃度は、Prism(Graph Pad−San Diego)を用いて計算した。いくつかの新規化合物の銅をキレートする活性の実施例は、図3及び4に示される。
AGE形成のカルボニル中間体の回収
[00057]実験手法、インキュベーション条件、CML−BSAのELISA検出、反応性カルボニル及びジカルボニル基の決定は全てVoziyanら(2002)に従って行った。図5及び6は、全化合物のジカルボニルの除去性質を示す。図5は、メチルグリオキサル(MGO)捕捉のデータを示す。図6は、全ての化合物について、グリコールアルデヒド捕捉のデータを示す。データは、これらの化合物のクラスが一時的な金属キレート化及びジカルボニル回収の性質の両方を有することを示す。
Claims (6)
- 生物における糖化最終産物又はタンパク質架橋の形成を阻害する方法であって、当該方法が有効量の化合物又はその化合物の薬学的に許容可能な塩を前記生物に投与することを含み、前記化合物が:
LR103: 1−[(4−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR104: 4−(4−フルオロ−3−クロロフェニルウレイド)フェノキシイソブチリルアミドフェニル−2−カルボン酸、
LR105: 1[(2−フルオロ−6−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR106: 4−(4−クロロベンジルアミノフェノキシイソブチル)酸、
LR107: 2−クロロベンゼン−1,4−ビス(4−ウレイドフェノキシイソブチル酸)、
LR108: 1−[(4−クロロベンジル)−3−(3,5−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR109: 1−[(2−フルオロ−6−クロロベンジル)−3−(2−フルオロ−6−クロロフェニルウレイド)]−4−フェノキシイソブチル酸
LR110: 4−(1,2,3,4−テトラヒドロアクリジン−9−カルボキサミドフェノキシイソブチル)酸、
LR111: 8−キノリノキシ酢酸、
LR112: 4,4’−ビス[(メチレンオキシエチレンアミノ)フェノキシ]イソブチル酸、
LR113: L−8−キノリノリル(アセチルヒスチジン)、
LR114: 4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]−2−ヒドロキシベンゼン−4−カルボン酸、及び
LR115: L,α−4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]フェニルアラニン
からなる群から選択される、前記方法。 - 生物における加齢の有害な効果を遅らせる方法であって、前記効果が糖化した最終産物又はタンパク質架橋の形成であり、前記方法が有効量の化合物又はその化合物の薬学的に許容可能な塩を前記生物に投与することを含み、前記化合物が:
LR103: 1−[(4−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR104: 4−(4−フルオロ−3−クロロフェニルウレイド)フェノキシイソブチリルアミドフェニル−2−カルボン酸、
LR105: 1[(2−フルオロ−6−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR106: 4−(4−クロロベンジルアミノフェノキシイソブチル)酸、
LR107: 2−クロロベンゼン−1,4−ビス(4−ウレイドフェノキシイソブチル酸)、
LR108: 1−[(4−クロロベンジル)−3−(3,5−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR109: 1−[(2−フルオロ−6−クロロベンジル)−3−(2−フルオロ−6−クロロフェニルウレイド)]−4−フェノキシイソブチル酸
LR110: 4−(1,2,3,4−テトラヒドロアクリジン−9−カルボキサミドフェノキシイソブチル)酸、
LR111: 8−キノリノキシ酢酸、
LR112: 4,4’−ビス[(メチレンオキシエチレンアミノ)フェノキシ]イソブチル酸、
LR113: L−8−キノリノリル(アセチルヒスチジン)、
LR114: 4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]−2−ヒドロキシベンゼン−4−カルボン酸、及び
LR115: L,α−4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]フェニルアラニン
からなる群から選択される、前記方法。 - 糖尿病に起因する合併症の患者の進行を遅らせる方法であって、前記合併症が糖化最終産物又はタンパク質架橋の形成に起因し、前記方法が有効量の化合物又はその化合物の薬学的に許容可能な塩を前記患者に投与することを含み、前記化合物が:
LR103: 1−[(4−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR104: 4−(4−フルオロ−3−クロロフェニルウレイド)フェノキシイソブチリルアミドフェニル−2−カルボン酸、
LR105: 1[(2−フルオロ−6−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR106: 4−(4−クロロベンジルアミノフェノキシイソブチル)酸、
LR107: 2−クロロベンゼン−1,4−ビス(4−ウレイドフェノキシイソブチル酸)、
LR108: 1−[(4−クロロベンジル)−3−(3,5−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR109: 1−[(2−フルオロ−6−クロロベンジル)−3−(2−フルオロ−6−クロロフェニルウレイド)]−4−フェノキシイソブチル酸
LR110: 4−(1,2,3,4−テトラヒドロアクリジン−9−カルボキサミドフェノキシイソブチル)酸、
LR111: 8−キノリノキシ酢酸、
LR112: 4,4’−ビス[(メチレンオキシエチレンアミノ)フェノキシ]イソブチル酸、
LR113: L−8−キノリノリル(アセチルヒスチジン)、
LR114: 4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]−2−ヒドロキシベンゼン−4−カルボン酸、及び
LR115: L,α−4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]フェニルアラニン
からなる群から選択される、前記方法。 - 慢性関節リウマチ、アルツハイマー症、尿毒症、神経毒症、又はアテローム性動脈硬化症の患者の進行を遅らせる方法であって、前記方法が有効量の化合物又はその化合物の薬学的に許容可能な塩を前記患者に投与することを含み、前記化合物が:
LR103: 1−[(4−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR104: 4−(4−フルオロ−3−クロロフェニルウレイド)フェノキシイソブチリルアミドフェニル−2−カルボン酸、
LR105: 1[(2−フルオロ−6−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR106: 4−(4−クロロベンジルアミノフェノキシイソブチル)酸、
LR107: 2−クロロベンゼン−1,4−ビス(4−ウレイドフェノキシイソブチル酸)、
LR108: 1−[(4−クロロベンジル)−3−(3,5−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR109: 1−[(2−フルオロ−6−クロロベンジル)−3−(2−フルオロ−6−クロロフェニルウレイド)]−4−フェノキシイソブチル酸
LR110: 4−(1,2,3,4−テトラヒドロアクリジン−9−カルボキサミドフェノキシイソブチル)酸、
LR111: 8−キノリノキシ酢酸、
LR112: 4,4’−ビス[(メチレンオキシエチレンアミノ)フェノキシ]イソブチル酸、
LR113: L−8−キノリノリル(アセチルヒスチジン)、
LR114: 4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]−2−ヒドロキシベンゼン−4−カルボン酸、及び
LR115: L,α−4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]フェニルアラニン
からなる群から選択される、前記方法。 - 食料品におけるタンパク質の損傷を防ぐ方法であって、前記方法が有効量の化合物又はその化合物の薬学的に許容可能な塩と前記食料品とを混合することを含み、前記有効量が糖化最終産物又はタンパク質架橋の形成を阻害し、前記化合物が:
LR103: 1−[(4−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR104: 4−(4−フルオロ−3−クロロフェニルウレイド)フェノキシイソブチリルアミドフェニル−2−カルボン酸、
LR105: 1[(2−フルオロ−6−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR106: 4−(4−クロロベンジルアミノフェノキシイソブチル)酸、
LR107: 2−クロロベンゼン−1,4−ビス(4−ウレイドフェノキシイソブチル酸)、
LR108: 1−[(4−クロロベンジル)−3−(3,5−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR109: 1−[(2−フルオロ−6−クロロベンジル)−3−(2−フルオロ−6−クロロフェニルウレイド)]−4−フェノキシイソブチル酸
LR110: 4−(1,2,3,4−テトラヒドロアクリジン−9−カルボキサミドフェノキシイソブチル)酸、
LR111: 8−キノリノキシ酢酸、
LR112: 4,4’−ビス[(メチレンオキシエチレンアミノ)フェノキシ]イソブチル酸、
LR113: L−8−キノリノリル(アセチルヒスチジン)、
LR114: 4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]−2−ヒドロキシベンゼン−4−カルボン酸、及び
LR115: L,α−4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]フェニルアラニン
からなる群から選択される、前記方法。 - LR103: 1−[(4−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR104: 4−(4−フルオロ−3−クロロフェニルウレイド)フェノキシイソブチリルアミドフェニル−2−カルボン酸、
LR105: 1[(2−フルオロ−6−クロロベンジル)−3−(3,4−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR106: 4−(4−クロロベンジルアミノフェノキシイソブチル)酸、
LR107: 2−クロロベンゼン−1,4−ビス(4−ウレイドフェノキシイソブチル酸)、
LR108: 1−[(4−クロロベンジル)−3−(3,5−ジクロロフェニルウレイド)]−4−フェノキシイソブチル酸、
LR109: 1−[(2−フルオロ−6−クロロベンジル)−3−(2−フルオロ−6−クロロフェニルウレイド)]−4−フェノキシイソブチル酸
LR110: 4−(1,2,3,4−テトラヒドロアクリジン−9−カルボキサミドフェノキシイソブチル)酸、
LR111: 8−キノリノキシ酢酸、
LR112: 4,4’−ビス[(メチレンオキシエチレンアミノ)フェノキシ]イソブチル酸、
LR113: L−8−キノリノリル(アセチルヒスチジン)、
LR114: 4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]−2−ヒドロキシベンゼン−4−カルボン酸、及び
LR115: L,α−4−[(3,5−ジクロロフェニルウレイド)フェノキシイソブチリルアミド]フェニルアラニン
からなる群から選択される化合物、又はその化合物の薬学的に許容可能な塩。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US10/358,403 US7030133B2 (en) | 1999-04-05 | 2003-02-05 | Inhibitors of formation of advanced glycation endproducts (AGEs) |
PCT/US2004/003203 WO2004071416A2 (en) | 2003-02-05 | 2004-02-05 | Novel inhibitors of formation of advanced glycation endproducts (ages) |
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JP2007525418A true JP2007525418A (ja) | 2007-09-06 |
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JP2006503321A Pending JP2007525418A (ja) | 2003-02-05 | 2004-02-05 | 先進的糖化最終産物(age)形成の新規阻害剤 |
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US (1) | US7030133B2 (ja) |
EP (1) | EP1594492B1 (ja) |
JP (1) | JP2007525418A (ja) |
AT (1) | ATE415159T1 (ja) |
AU (1) | AU2004211899C1 (ja) |
CA (1) | CA2514356C (ja) |
DE (1) | DE602004017962D1 (ja) |
WO (1) | WO2004071416A2 (ja) |
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JP2014129322A (ja) * | 2012-11-30 | 2014-07-10 | Ueno Fine Chem Ind Ltd | 終末糖化産物生成抑制剤 |
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US7030133B2 (en) | 1999-04-05 | 2006-04-18 | City Of Hope | Inhibitors of formation of advanced glycation endproducts (AGEs) |
EP2269601A1 (en) | 2003-10-27 | 2011-01-05 | City of Hope | LR-9, LR-74 and LR-90 for use in treating complications resulting from diabetes |
WO2005040102A2 (en) * | 2003-10-28 | 2005-05-06 | Dr. Reddy's Laboratories Ltd. | Novel compounds and their use as antidiabetic and hypolipidemic agents, process for their preparation and pharmaceutical compositions containing them |
WO2007044309A2 (en) * | 2005-10-05 | 2007-04-19 | Vasix Corporation | Device and method for inhibiting age complex formation |
DE102007041232A1 (de) | 2007-08-30 | 2009-03-05 | Henkel Ag & Co. Kgaa | Verwendung von Sulfonylharnstoffen zur Spaltung von AGEs |
DE102007054653A1 (de) | 2007-11-14 | 2009-05-20 | Henkel Ag & Co. Kgaa | Verwendung von Thioharnstoff-Derivaten zur Spaltung von AGEs |
US20120071502A1 (en) * | 2010-09-17 | 2012-03-22 | Cell Viable Corporation | Novel phenoxyisobutyric acid compounds and methods for synthesis |
WO2012103523A2 (en) | 2011-01-27 | 2012-08-02 | Samuel Rahbar | Novel modulators of development of adipocyte and cancer cells |
US9808434B2 (en) | 2011-01-27 | 2017-11-07 | City Of Hope | Compound for treating cancer and diabetes |
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- 2004-02-05 AU AU2004211899A patent/AU2004211899C1/en not_active Expired
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- 2004-02-05 EP EP04708575A patent/EP1594492B1/en not_active Expired - Lifetime
- 2004-02-05 AT AT04708575T patent/ATE415159T1/de not_active IP Right Cessation
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AU2004211899A1 (en) | 2004-08-26 |
CA2514356A1 (en) | 2004-08-26 |
US7030133B2 (en) | 2006-04-18 |
ATE415159T1 (de) | 2008-12-15 |
WO2004071416B1 (en) | 2004-11-25 |
CA2514356C (en) | 2012-05-08 |
AU2004211899C1 (en) | 2010-05-20 |
DE602004017962D1 (de) | 2009-01-08 |
EP1594492B1 (en) | 2008-11-26 |
WO2004071416A3 (en) | 2004-10-14 |
US20030220362A1 (en) | 2003-11-27 |
AU2004211899B2 (en) | 2009-09-24 |
EP1594492A4 (en) | 2007-04-18 |
WO2004071416A2 (en) | 2004-08-26 |
EP1594492A2 (en) | 2005-11-16 |
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