JP2011509252A - 2−{4−[(3s)−ピペリジン−3−イル]フェニル}−2h−インダゾール−7−カルボキサミドの薬学的に許容される塩 - Google Patents
2−{4−[(3s)−ピペリジン−3−イル]フェニル}−2h−インダゾール−7−カルボキサミドの薬学的に許容される塩 Download PDFInfo
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Abstract
Description
、「モレキュラー・ファーマコロジー(Mol Pharmacol)」、1997年、第52巻、p.249−258、「リューケミア(Leukemia)」、1999年、第13巻、p.901−909、「グリア(Glia)」、2002年、第40巻、p.44−54、及び「クリニカル・キャンサー・リサーチ」、2000年、第6巻、p.2860−2867、及び2004年、第10巻、p.881−889)及びインビボモデル(「ブラッド(Blood)」、2002年、第99巻、p.2241−2244、「クリニカル・キャンサー・リサーチ」、2003年、第9巻、p.5370−5379、「ジャーナル・オブ・ザ・ナショナル・キャンサー・インスティテュート」、2004年、第96巻、p.56−67)において示されてきた。PARP阻害剤はまた、MeOSO2(CH2)−レキシトロプシン(lexitropsin)(Me−Lex)のような選択的N3−アデニンメチル化剤により誘導される壊死の出現を防止することも示されてきた(「ファーマコロジカル・リサーチ」、2005年、第52巻、p.25−33
)。
の化合物の、薬学的に許容される塩を提供する。
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウム4−メチルベンゼンスルホナート;
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムスルファート;
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムベンゼンスルファート;
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムフマラート;
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムスクシナート;
及び、その立体異性体及び互変異性体である。
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウム4−メチルベンゼンスルホナート;
又はその立体異性体若しくは互変異性体である。
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムスルファート;
又はその立体異性体若しくは互変異性体である。
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムベンゼンスルファート;
又はその立体異性体若しくは互変異性体である。
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムフマラート;
又はその立体異性体若しくは互変異性体である。
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムスクシナート;
又はその立体異性体若しくは互変異性体である。
本明細書に記載された代表的な化合物を、このアッセイにおいて試験し、5μM未満、特に50nM未満のIC50値をもつことを見出した。
アッセイ緩衝液: 100mM トリスpH8、4mM MgCl2、4mM スペルミン、200mM KCl、0.04% ノニデットP−40。
酵素混合物: アッセイ緩衝液(12.5ul)、100mM DTT(0.5ul)、PARP−1(5nM、トレビゲン(Trevigen)4668−500−01)、H2O(35ulまで)。
ニコチンアミド−アデニンジヌクレオチド(NAD)/DNA混合物:[3H−NAD](250uCi/ml、0.4ul、パーキンエルマー(Perkin−Elmer)NET−443H)、NAD(1.5mM、0.05ul、シグマ(SIGMA)N−1511)、ビオチニル化−NAD(250uM、0.03ul、トレビゲン 4670−500−01)、活性化仔ウシ胸腺(1mg/ml、0.05ul、アマシャム・バイオサイエンシズ(Amersham Biosciences) 27−4575)、H2O(10ulまで)。
展開混合物: 500mM EDTA中に溶解された、ストレプトアビジンSPAビーズ(5mg/ml、アマシャム・バイオサイエンシズ RPNQ0007)。
反応は、96穴マイクロプレート中で、最終体積50uL/ウェルで行う。5ulの
5%DMSO/化合物溶液を添加し、酵素混合物(35ul)を添加し、NAD/DNA混合物(10uL)の添加により反応を開始し、そして室温で2時間インキュベートする。展開混合物(25ul)の添加により反応を停止し、そして室温で15分間インキュベートする。パッカード・トップ・カウント(Packard TOP COUNT)装置を用いて測定する。
略号:
IMDM(イスコブ(Iscove)改変ダルベッコ培地);RPMI(ロズウェル・パーク記念研究所培地(Roswell Park Memorial Institute Media);MOI(感染多重度);GFP(緑色蛍光タンパク質);PBS(リン酸緩衝食塩水);FCS(ウシ胎児血清);及びDMEM(ダルベッコ改変イーグル培地)。
ヒーラshBRCA1−GFP− これらは、BRCA−1に対するshRNAと、GFP用の発現カセットとを含有するレンチウイルスにより、MOI 100で形質導入されたヒーラ細胞である。BRCA−1のサイレンシングは、Taqman分析により評価される通り80%を超えており、該細胞は安定にGFPを発現する。
−96穴ビュープレート・ブラックにおいて、ウェル当たり300個の細胞を、90μlの培地中に播種*:
− 37℃、5%CO2において、4時間インキュベート
− 10ul/ウェルの、10倍の化合物を添加(H2O中、5%DMSO)
− 37℃、5%CO2において、168時間インキュベート
− 予め1倍のPBSで1:1に希釈した、10μlのセルタイター・ブルー(Celltiter Blue)溶液(プロメガ(Promega)、G8081)を添加
− この混合物を、37℃、5%CO2において、45分間インキュベート
− 暗中で、室温で15分間インキュベート
− ex(励起波長):550nm;em(蛍光波長):590nmで、蛍光測定器においてプレートを読む
本発明化合物はまた、5マイクロモル未満のCC50をもつ、天然のBRCA−1(MDA−MB−436)及びBRCA−2(CAPAN−1)欠損細胞系の増殖を阻害することが示された。
細胞を、96穴プレートにおいて、ウェル当たり100ulの適当な培地中に*、700細胞/ウェルで播種する。
翌日、当該化合物の連続希釈物を、200μl/ウェルの最終体積で添加する。
各希釈物を、三重にアッセイする。
6日後、セルタイター−ブルー・セル・バイアビリティ・アッセイ(CellTiter−Blue Cell Viability Assay)を、製造業者(プロメガ)の指示に従って使用し、細胞生存度を評価する。プレートを、フュージョン・アルファ(Fusion Alpha)マイクロプレートリーダー(パッカード・バイオサイエンス(Packard Bioscience))で読み取る。
MDA−MB−436:RPMI(ギブコ)、10%FBS(5%CO2)
CAPAN−1:IMDM(ギブコ)、20%FBS(5%CO2)
実施例A
2−フェニル−2H−インダゾール−7−カルボキサミド(A6)
工程1:メチル3−メチル−2−ニトロベンゾアート(A1)
MeOH(0.4M)中の3−メチル−2−ニトロ安息香酸(1.0当量)の懸濁液に、0℃で、AcCl(3.0当量)を滴下添加した。反応混合物を、還流下で20時間攪拌した。溶媒を真空中で減量し、残渣をEtOAc中に溶解し、飽和NaHCO3水溶液、食塩水で数回洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させて、(A1)を白色固体として得て、これをさらに精製することなく次の工程に使用した。
1HNMR(400MHz,CDCl3,300K)δ7.86(1H,d,J=7.5Hz),7.53−7.42(2H,m),3.89(3H,s),2.36(3H,s).
MS(ES)C9H9NO4要求値:195,実測値:218(M+Na)+.
(A1)(1.0当量)、(BzO)2(0.06当量)、及びNBS(1.18当量)の、CCl4中(0.2M、A1について)の混合物を、N2雰囲気下で、12時間加熱還流した。混合物を室温に冷却し、DCMで希釈し、減圧下で濃縮し、そしてSiO2にドライローディングした。残渣を、SiO2上でのフラッシュカラムクロマトグラフィーにより、10:90EtOAc/石油エーテルを用いて精製し、所望の(A2)を白色固体として得た。
1HNMR(400MHz,CDCl3,300K)δ7.93(1H,d,J=7.7Hz),7.72(1H,d,J=7.7Hz),7.57(1H,t,J=7.7Hz),4.43(2H,s),3.88(3H,s).
MS(ES)C9H8BrNO4要求値:273:275,実測値:242:244(M−MeO)+,227:229(M−NO2)+.
MeCN(0.2M)中の、(A2)(1.0当量)及び4Åモレキュラーシーブの混合物に、室温で、NMMO(2.0当量)を添加し、そして反応混合物をN2雰囲気下で1.5時間攪拌した。次に、混合物をEtOAcで希釈し、濾過し、そして濾液をH2O、1N HCl、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させて、(A3)を白色固体として得て、これをさらに精製することなく次の工程に使用した。
1HNMR(400MHz,CDCl3,300K)δ9.96(1H,s),8.26(1H,d,J=7.9Hz),8.18(1H,d,J=7.9Hz),7.77(1H,t,J=7.9Hz),3.93(3H,s).
MS(ES)C9H7NO5要求値:209,実測値:208(M−H)−.
EtOH(0.2M)中の、(A3)(1.0当量)及びアニリン(1.05当量)の混合物を、N2雰囲気下で、TLCが反応の完了を示すまで(ヘキサン/EtOAc=75:25)、2時間にわたり還流下で攪拌した。溶媒を蒸発させて、(A4)を白色固体として得て、これをさらに精製することなく次の工程に使用した。
1HNMR(400MHz,CDCl3,300K)δ8.51(1H,d,J=7.3Hz),8.41(1H,s),8.11(1H,d,J=7.8Hz),7.67(1H,t,J=7.8Hz),7.43(2H,t,J=7.8Hz),7.31(1H,t,J=7.3Hz),7.16(2H,d,J=7.8Hz),3.94(3H,s).
無水DMF(0.3M)中の、(A4)(1.0当量)及びNaN3(1.05当量)の混合物を、N2雰囲気下で90℃で一晩攪拌した。粗生成物を真空中で減量し、そして残渣を、シリカ上でのフラッシュカラムクロマトグラフィーにより、10:90から40:60までのEtOAc/石油エーテルの勾配を用いて精製し、所望の(A5)を褐色の油として得た。
1HNMR(400MHz,CDCl3,300K)δ8.50(1H,s),8.12(1H,d,J=7.0Hz),7.96−7.90(3H,m),7.49(2H,t,J=7.6Hz),7.38(1H,t,J=7.4Hz),7.15(1H,t,J=7.4Hz),4.03(3H,s).
MS(ES)C15H12N2O2要求値:252,実測値:253(M+H)+.
封管内で、エステル(A5)を、THF及び32%NH3水溶液の混合物中で、70℃で一晩加熱した。溶媒を真空中で減量し、そしてその残渣を、シリカ上でのフラッシュカラムクロマトグラフィーにより、30:70から50:50までのEtOAc/石油エーテルの勾配を用いて精製し、所望の(A6)を白色固体として得た。
1HNMR(400MHz,DMSO,300K)δ9.33(1H,s),8.56(1H,bs),8.16(2H,d,J=7.9Hz),8.08−8.00(2H,m),7.88(1H,bs),7.63(2H,t,J=7.7Hz),7.50(1H,t,7.4Hz),7.27(1H,t,J=7.9Hz).
MS(ES)C14H11N3O要求値:237,実測値:238(M+H)+.
3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムクロリド(B4)
工程1:tert−ブチル3−[4−({−[3−(メトキシカルボニル)−2−ニトロフェニル]メチレン}アミノ)フェニル]ピペリジン−1−カルボキシラート(B1)
(B1)は、実施例A、工程4に報告した一般的な方法に従い、A3及びtert−ブチル3−(4−アミノフェニル)ピペリジン−1−カルボキシラートを、TLCが反応の完了を示すまで(石油エーテル:EtOAc=4:1)使用して調製し、さらに精製することなく次の工程に使用した。
(B2)を、実施例A、工程5に報告した一般的な方法に従って調製し、そして粗生成物をシリカゲル上でのフラッシュカラムクロマトグラフィーにより、20−40%EtOAc/石油エーテルの勾配を使用して精製し、所望の(B2)を黄色の固体として得た。
1HNMR(400MHz,CDCl3,300K)δ8.51(1H,s),8.13(1H,d,J=7.1Hz),7.95(1H,d,J=8.3Hz),7.91(2H,d,J=8.4Hz),7.39(2H,d,J=8.4Hz),7.18(1H,t,J=7.2Hz),4.30−4.10(2H,m),4.00(3H,s),2.85−2.70(3H,m),2.11−2.03(1H,m),1.83−1.75(1H,m),1.73−1.53(2H,m H2Oシグナルにオーバーラップ),1.48(9H,s).
MS(ES)C25H29N3O4要求値:435,実測値:436(M+H)+.
封管内で、(B2)を、MeOH(0.1M)中の7N NH3中で、60℃で2日間加熱した。溶媒を真空中で減量し、そして粗生成物をEt2Oで粉砕することにより精製し、所望の(B3)を黄色の固体として得た。
1HNMR(400MHz,CDCl3,300K)δ9.04(1H,br.s),8.51(1H,s),8.31(1H,d,J=6.8Hz),7.91(1H,d,J=8.3Hz),7.84(2H,d,J=8.2Hz),7.42(2H,d,J=8.2Hz),7.31−7.22(1H,m CDCl3シグナルにオーバーラップ),5.95(1H,br.s),4.40−4.05(2H,m),2.90−2.70(3H,m),2.15−2.00(1H,m),1.85−1.75(1H,m),1.75−1.50(2H,m H2Oシグナルにオーバーラップ),1.48(9H,s).
MS(ES)C24H28N4O3要求値:420,実測値:421(M+H)+.
EtOAc(0.2M)中の(B3)(1.0当量)の攪拌溶液に、4N HCl/1,4−ジオキサン溶液(10.0当量)を添加し、そして反応混合物を室温で3時間攪拌した。溶媒を減圧下で蒸発させ、そして粗生成物をEt2Oで粉砕することにより精製して、所望の(B4)を黄色の固体として得た。
1HNMR(400MHz,DMSO−d6,300K)δ9.32(1H,s),9.12(1H,br.s),8.87(1H,br.s),8.55(1H,br.s),8.13(2H,d,J=8.6Hz),8.06(1H,J=7.0Hz),8.02(1H,d,J=8.4Hz),7.89(1H,br.s),7.55(2H,d,J=8.6Hz),7.27(1H,dd,J=8.4,7.0Hz),3.43−3.27(2H,m),3.17−3.03(2H,m),3.00−2.85(1H,m),2.00−1.70(4H,m).
MS(ES)C19H21ClN4O要求値:320,実測値:321(M+H)+.
2−{4−[(3R)−ピペリジン−3−イル]フェニル}−2H−インダゾール−7−カルボキサミド(C1)及び2−{4−[(3S)−ピペリジン−3−イル]フェニル}−2H−インダゾール−7−カルボキサミド(C2)
実施例B、B4をキラルSFC(カラム:キラルパック(Chiralpak)AS−H、1x25mm、流量:10ml/分、Tcol:35℃、Pcol:100バール、モディファイア:55%(iPrOH+4%Et2NH))により、CO2を超臨界溶離剤として使用して分離し、双方の純粋なエナンチオマーを得た。
1HNMR(400MHz,DMSO−d6,300K)δ9.28(s,1H),8.57(br.s,1H),8.06(d,2H,J=7.2Hz),8.04(d,2H,J=8.4Hz),7.88(br.s,1H),7.49(d,2H,J=8.4Hz),7.27(dd,1H,J=8.4,7.2Hz),3.08−2.94(m,2H),2.77−2.67(m,1H),2.64−2.52(m,1H),1.98−1.90(m,1H),1.75−1.47(m,4H).MS(ES)C19H20N4O要求値:320,実測値:321(M+H)+.
遊離塩基を、(3R)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムクロリドに変換し、旋光を測定した:[α]20 D=+133.3(c0.15,MeOH).
1HNMR(400MHz,DMSO−d6,300K)δ9.28(s,1H),8.57(br.s,1H),8.06(d,2H,J=7.2Hz),8.04(d,2H,J=8.4Hz),7.88(br.s,1H),7.49(d,2H,J=8.4Hz),7.27(dd,1H,J=8.4,7.2Hz),3.08−2.94(m,2H),2.77−2.67(m,1H),2.64−2.52(m,1H),1.98−1.90(m,1H),1.75−1.47(m,4H).MS(ES)C19H20N4O要求値:320,実測値:321(M+H)+.
遊離塩基を、(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムクロリドに変換し、旋光を測定した:
[α]20 D=−137.9(c0.145,MeOH).
実施例1
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウム4−メチルベンゼンスルホナート(D4)
工程1:tert−ブチル(3S)−3−[4−({(1E)−[3−(メトキシカルボニル)−2−ニトロフェニル]メチレン}アミノ)フェニル]ピペリジン−1−カルボキシラート(D1)
(D1)は、実施例A、A3及びtert−ブチル(3S)−3−(4−アミノフェニル)ピペリジン−1−カルボキシラート(これは、3−(4−アミノフェニル)−ピペリジンを、MeOH中の2当量のL−ジベンゾイル酒石酸で分割し、続いてBoc保護することにより調製した)から、実施例B、B1に記載のように調製した。
(D1)(1当量)及びアジ化ナトリウム(1当量)を、DMF(0.25M)中でスラリー化し、不活性化し、そして2,6−ルチジン(1.0当量)を添加した。混合物を内部温度110℃で20時間加熱した。得られた褐色の溶液を、20℃に冷却し、そしてTHF及び25wt%LiCl水溶液を添加した。相を分離し、そして有機物質を、25wt%LiCl水溶液でさらに3回洗浄した。2.0N NaOH(10当量)を上記の有機溶液に添加し、そして混合物を35℃で20時間加熱した後、20℃に冷却し、そして相を分離した。有機層を、2.0N HCl及び食塩水の混合物で洗浄し、その層を分離し、有機層を食塩水でさらに洗浄し、そして濃縮して(D2)とし、これはさらに精製することはなかった。
(D2)を、DCM(0.35M)中に溶解し、そしてジtert−ブチルカルボナート(1.3当量)及びピリジン(1.0当量)を室温で添加した。30分後、炭酸水素アンモニウム(1.3当量)を添加し、そして攪拌を20時間継続した。1N HCl(5mL/g)を添加し、相を分離し、有機層を水で2回洗浄し、そして少量に濃縮した。粗化合物(D3)を、シリカのパッドを通して濾過し、そして次にメチルtert−ブチルエーテルから結晶化した。
(D3)を、THF(0.15M)中に溶解し、そして水(THFに比較して5%)を添加した。パラ−トルエンスルホン酸一水和物(2.2当量)を添加し、混合物を66℃に加熱し、そして一晩攪拌した。冷却後、所望の固体塩を濾過により単離し、そして一水和物(D4)であることを確認した。
1HNMR(400MHz,DMSO,300K)δ9.34(1H,s);9.20(1H,ブロード s),8.58(1H,s),8.14(2H,d,J=8.8Hz),8.05(2H,ddd,J=1.2,7.2,16.8Hz),7.93(1H,s),7.52(4H,dd,J=8.8,16.8Hz),7.27(1H,dd,J=6.8,8.0Hz),7.13(2H,d,J=8Hz),3.48(3H,m),3.10(2H,m),2.90(1H,m);2.30(3H,s),1.89(2H,m),1.75(2H,m).
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウム4−メチルベンゼンスルホナート
化合物ストック溶液としての、tert−ブチル(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジン−1−カルボキシラート(実施例1、D3)50mgを、エタノール中の1.0モル溶液として添加したp−トルエンスルホン酸1モル当量と反応させた。過剰の溶媒を遠心蒸発下で除去し、そしてエタノール1mLを室温(〜25℃)で添加した。得られた溶液を40℃で24時間攪拌し、ここで無色の固体が溶液から沈殿し、これを濾過により収集した。この固体をX線粉末回折、プロトンNMR、DSC、及びTGAを使用して分析し、標題の塩の生成を確認した。
((3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムベンゼンスルファート
化合物ストック溶液としての、tert−ブチル(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジン−1−カルボキシラート(実施例1、D3)50mgを、THF中の1.0モル溶液として添加したベンゼンスルホン酸1モル当量と反応させた。過剰の溶媒を遠心蒸発下で除去し、そしてTHF1mLを室温(〜25℃)で添加した。得られた溶液を40℃で24時間攪拌し、ここで無色の固体が溶液から沈殿し、これを濾過により収集した。この固体をX線粉末回折、プロトンNMR、DSC、及びTGAを使用して分析し、標題の塩の生成を確認した。
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムフマラート
化合物ストック溶液としての、tert−ブチル(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジン−1−カルボキシラート(実施例1、D3)50mgを、エタノール中の0.405モル溶液として添加したフマル酸1モル当量と反応させた。過剰の溶媒を遠心蒸発下で除去し、そしてエタノール1mLを室温(〜25℃)で添加した。得られた溶液を40℃で24時間攪拌した。実験を放置して大気条件下で穏やかに蒸発させ、ここで無色の固体が見られた。この固体をX線粉末回折、プロトンNMR、DSC、及びTGAを使用して分析し、標題の塩の生成を確認した。
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムスルファート
化合物ストック溶液としての、tert−ブチル(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジン−1−カルボキシラート(実施例1、D3)50mgを、1:1(v/v)メタノール:水の溶液中の1モル溶液として添加した硫酸1モル当量と反応させた。過剰の溶媒を遠心蒸発下で除去し、そしてメタノール:水の溶液1mLを室温(〜25℃)で添加した。得られた溶液を40℃で24時間攪拌した。実験を放置して大気条件下で穏やかに蒸発させ、ここで無色の固体が見られた。
Claims (9)
- (3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウム4−メチルベンゼンスルホナート;
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムスルファート;
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムベンゼンスルファート;
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムフマラート;
(3S)−3−{4−[7−(アミノカルボニル)−2H−インダゾール−2−イル]フェニル}ピペリジニウムスクシナート;
及び、その立体異性体及び互変異性体。 - 請求項1に記載の化合物、又はその立体異性体若しくは互変異性体を、薬学的に許容される担体と共に含んでなる医薬組成物。
- 同時の、別々の、又は連続した投与のための、請求項1に記載の化合物又はその立体異性体若しくは互変異性体、及び抗癌剤。
- 療法において使用するための、請求項1に記載の化合物、又はその立体異性体若しくは互変異性体。
- ポリ(ADP−リボース)ポリメラーゼ(PARP)の阻害により改善し得る症状の、治療又は予防用医薬の製造のための、請求項1に記載の化合物、又はその立体異性体若しくは互変異性体の使用。
- 癌、炎症性疾患、再灌流損傷、虚血症状、卒中、腎不全、心臓血管疾患、心臓血管疾患以外の血管疾患、糖尿病、神経変性疾患、レトロウイルス感染症、網膜損傷、又は皮膚老化、及びUV誘導性皮膚損傷の、治療又は予防用医薬の製造のための、請求項1に記載の化合物、又はその立体異性体若しくは互変異性体の使用。
- 請求項5又は6のいずれか1項に記載の症状の、治療又は予防における使用のための、請求項1に記載の化合物、又はその立体異性体若しくは互変異性体。
- 癌治療のための、化学的増感剤及び/又は放射線増感剤としての、請求項1に記載の化合物、又はその立体異性体若しくは互変異性体の使用。
- 癌、炎症性疾患、再灌流損傷、虚血症状、卒中、腎不全、心臓血管疾患、心臓血管疾患以外の血管疾患、糖尿病、神経変性疾患、レトロウイルス感染症、網膜損傷、又は皮膚老化、及びUV誘導性皮膚損傷を、治療又は予防する方法であって、請求項1に記載の化合物、又は請求項1に記載の化合物を含んでなる組成物の有効量を、それを必要とする患者に投与することを含んでなる該方法。
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JP5989965B2 (ja) | 2016-09-07 |
US8436185B2 (en) | 2013-05-07 |
FR18C1020I1 (ja) | 2018-07-13 |
BRPI0906020A2 (pt) | 2015-06-30 |
MX337421B (es) | 2016-03-04 |
MX2010006593A (es) | 2010-12-21 |
ZA201003902B (en) | 2011-02-23 |
IL206201A (en) | 2014-07-31 |
KR101653548B1 (ko) | 2016-09-02 |
ES2548131T3 (es) | 2015-10-14 |
CN106008460B (zh) | 2022-08-12 |
AU2009203598B2 (en) | 2013-09-26 |
CA2711491A1 (en) | 2009-07-16 |
EP2240466A1 (en) | 2010-10-20 |
US20100286203A1 (en) | 2010-11-11 |
IL206201A0 (en) | 2010-12-30 |
CN101932572A (zh) | 2010-12-29 |
CN106008460A (zh) | 2016-10-12 |
RU2010133241A (ru) | 2012-02-20 |
WO2009087381A1 (en) | 2009-07-16 |
NZ586675A (en) | 2012-04-27 |
CA2711491C (en) | 2016-03-08 |
NL300938I2 (nl) | 2019-01-08 |
KR20100114021A (ko) | 2010-10-22 |
EP2240466B1 (en) | 2015-07-29 |
RU2495035C2 (ru) | 2013-10-10 |
FR18C1020I2 (fr) | 2019-06-07 |
AU2009203598A1 (en) | 2009-07-16 |
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