JP2013514295A - 3−(インドリル)−または3−(アザインドリル)−4−アリールマレイミド化合物および腫瘍処置におけるそれらの使用 - Google Patents
3−(インドリル)−または3−(アザインドリル)−4−アリールマレイミド化合物および腫瘍処置におけるそれらの使用 Download PDFInfo
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- JP2013514295A JP2013514295A JP2012543626A JP2012543626A JP2013514295A JP 2013514295 A JP2013514295 A JP 2013514295A JP 2012543626 A JP2012543626 A JP 2012543626A JP 2012543626 A JP2012543626 A JP 2012543626A JP 2013514295 A JP2013514295 A JP 2013514295A
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- indole
- mmol
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 79
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 22
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- 125000001041 indolyl group Chemical group 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 239000012453 solvate Substances 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 46
- -1 ruletocan Chemical compound 0.000 claims description 36
- 239000002246 antineoplastic agent Substances 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 229940127089 cytotoxic agent Drugs 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 229960004768 irinotecan Drugs 0.000 claims description 13
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- 239000000365 Topoisomerase I Inhibitor Substances 0.000 claims description 11
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- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
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- 125000006413 ring segment Chemical group 0.000 claims description 6
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Description
式中、
R1は、H,C1−C6−アルキル、フェニル−C1−C4−アルキルまたはフェニルであり;
R2は、2個または3個のC1−C6−アルコキシ基で置換されたフェニル基であり;
R3は、C1−C6アルキル、C1−C6−アルコキシ、フェニル、OH、ハロゲン、NH2、C1−C6−アルキルアミノ、ジ−C1−C6−アルキルアミノ、O,N,およびSから独立に選ばれた1個または2個のヘテロ原子を含んでいる5または6環原子を有するヘテロアリール、そして、O,N,およびSから独立に選ばれた1個または2個のヘテロ原子を含んでいる5または6環原子を有するヘテロサイクリルから独立に選ばれた1個または2個の置換基を持つことができるインドリルまたはアザインドリルおよびこれらの生理学的に許容し得る塩と、式Iの化合物の溶媒和物と、その生理学的に許容し得る塩である。これら化合物は脈管形成阻害剤として有用である。J.Med.Chem.2006,49,1271−1281およびJ.Med.Chem.2006,49,7549−7553は、脈管形成阻害剤としての、3,4−ジアリールマレイミドのデザイン、合成および評価に関する。
R1は、H、C1−C6−アルキル、フェニル−C1−C6−アルキルまたはフェニル;
R2は3個のC1−C6−アルコキシ基で置換されたフェニル基、および
R3は、
R7はHまたはC1−C6−アルキル、
R8はC1−C6−アルキル−R10であって、R10は、
a)アミノ、
b)C1−C6−アルキルアミノ、
c)ジ−C1−C6−アルキルアミノ、
d)ヒドロキシ、
e)C1−C6−アルコキシ、
f)1個の窒素ヘテロ原子と、任意にO,NおよびSから独立に選ばれた1個または2個の追加のヘテロ原子を含んでいる5または6個の環原子を有する飽和ヘテロサイクリルであって、窒素原子を介してC1−C6−アルキル基と結合し、そして1,2,3または4個のC1−C6−アルキル置換基を担持し得る飽和ヘテロサイクリル;
g)フェノキシ、
h)ベンジルオキシ、
i)R11CONR12−、
j)NR12R12CO―、
k)C1−C6−アルキル−NHCONH−、
l)C1−C6−アルキル−NHCOO−、
m)C1−C6−アルキル−OCONH−、
n)R12−OSO2O−、
o)R11SO2O−、
p)R12−OSO2−、
q)R11SO2−、
r)(R12O)2P(O)O−、
s)(R12O)2P(O)−、および
t)(R12O)R11P(O)O−、
であり、
R9は、H、C1−C6−アルキル、C1−C6−アルコキシ、OH,またはハロゲン;
R11は、C1−C6−アルキル;
R12は、HまたはC1−C6―アルキルである。
a)アミノ、
b)C1−C6−アルキルアミノ、
c)ジ−C1−C6―アルキルアミノ、
d)ヒドロキシ、
e)C1−C6−アルコキシ、および
f)1個の窒素ヘテロ原子と、任意にO,NおよびSから独立に選ばれた1個または2個の追加のヘテロ原子を含んでいる環原子5個または6個の飽和ヘテロサイクリルであって、窒素原子を介してC1−C6−アルキル基へ結合し、そして炭素原子または窒素原子上に追加のC1−C6−アルキル置換基を持つことができるヘテロサイクリル、
から選ばれる。
a)アミノ、
b)C1−C6−アルキルアミノ、
c)ジ−C1−C6−アルキルアミノ、
d)ヒドロキシ、および
e)C1−C6−アルコキシ
から選ばれる。
a)アミノ、
b)C1−C6−アルキルアミノ、および
c)ジ−C1−C6−アルキルアミノ
から選ばれる。
d)ヒドロキシ、および
e)C1−C6−アルコキシ
から選ばれる。
f)1個の窒素ヘテロ原子と、任意にO,NおよびSから独立に選ばれた1個または2個の追加のヘテロ原子を含んでいる環原子5個または6個の飽和ヘテロサイクリルであって、窒素原子を介してC1−C6−アルキル基へ結合し、そして炭素原子または窒素原子において追加のC1−C6−アルキル置換基を持つことができるヘテロサイクリル、
である。
g)フェノキシ、および
h)ベンジルオキシ
から選ばれる。
i)R11CONR12−、および
j)NR12R12CO−
から選ばれる。
k)C1−C6−アルキル−NHCONH−、
l)C1−C6−アルキル−NHCOO−、および
m)C1−C6−アルキル−OCONH−
から選ばれる。
n)R12−OSO2O−、
o)R11SO2O−、
p)R12−OSO2−、および
q)R11SO2−
から選ばれる。
r)(R12O)2P(O)O−、
s)(R12O)2P(O)−、および
t)(R12O)R11P(O)O−
から選ばれる。
テスト化合物の抗増殖活性は、以前記載されたように(Mosmann,T.et al.(1983)J.Immunol.Methods65,55−63),3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフェニルテトラゾリウムブロマイド(MTT)アッセイによって決定された。指数増殖期にある細胞が96ウェル平底プレートへ移された。10,000個の生存細胞を含んでいる細胞懸濁液(200μl)が各ウェルへプレートされ、異なる濃度の化合物の100μlと共に37℃において5%CO2と共に3日インキュベートされた。時点(3日)の終りに,MTTストック溶液(5mg/ml)(Biomol,ドイツ)の10μl/ウェルが加えられた。細胞は次に37℃において5%CO2と共に4時間インキュベートされた。可溶化溶液(0.01M HCl中10%SDS)100μlが加えられ、そして細胞は37℃において5%CO2と共に一夜インキュベートされた。プレートがELISA−リーダーELX800(BIO−TEKソフトウェアKC4)上で562nm吸光度において読まれた。各実験は3回実施された。
癌細胞が12ウェル平底プレートへ移された。1.5×105個生存細胞を含んでいる細胞懸濁液(1ml)が各ウェルへプレートされ、そして種々濃度の剤へ暴露前に一夜インキュベートされた。細胞は次に単独で適用された剤、イリノテカン単独、または剤とイリノテカンまたはトポテカンとの組合わせの種々の濃度を有する媒体中で37℃において5%CO2と共にインキュベートされた。インキュベーション後、細胞はPBSで洗浄され、トリプシン化およびペレット化され、そしてヨウ化プロピジウムバッファー(0.1%クエン酸ナトリウム、0.1%トリトンX−100,50mg/mlヨウ化プロピジウムを含有)と混合され、4℃で1時間インキュベートされた。細胞サイクルサブ−G1−分画分析は、FACSサイトメーター(BD FACS CaliburTM,BD Bioscience,Heidelberg,ドイツ)を用いて以前記載されたとおりに実施された。各実験は3回実施された。
IC50値はMillipore UK Ltd.,Gemini Crescent;Dundee Technology Park;Dendee DD2 1SW;UK(IC50Profiler)において実施された。
http:www.millipore.com/drugdiscovery/svp3/kpservices
各アッセイプロトロールの詳細はMilliporeのウェブサイト上で見ることができる。
www.millipore.com/drugdiscovery/dd3/assayprotocols.
他のキナーゼアッセイデータは、ProQinase GmbH,Freiburg,ドイツによって実施された、Peiferet al.J.Med.Chem.2006,49,7549−7553からのものである。
DMSO中テスト化合物の26mmol/l作業溶液が調製され、そして部分標本で−20℃において貯蔵された。イリノテカンおよびトポテカンはマインツ大学病院の薬局から得た。ストック溶液はイリノテカンについては29.6mmol/lに、トロテカンについては、4.75mmol/lに調製され、部分標本として4℃において貯蔵された。薬物は使用直前所望の濃度を得るため培養培地中に希釈された。
ヒト結腸癌細胞ラインHCT−116,HT−29,Caco−2,SW480,および胃癌細胞ラインMKN−45は、DSMZ,ドイツから得た。HCT−116,HT−29およびSW480細胞は10%FCSを補給したRPMI 1640中で、MKN−45は20%FCSを補給したRPMI 1640中で、そしてCaco−2細胞は80%MEM(Erle’s塩添加)+20%FCS+非必須アミノ酸中で日常的に培養された。すべての細胞は5%CO2を含む雰囲気のもとインキュベーター中37℃に保たれた。インキュベーション後、細胞はPBSで洗浄され、トリプシン化され、ペレット化され、そしてPIバッファー(0.1%クエン酸ナトリウム、0.1%トリトンX−100,50mg/mlヨウ化プロピジウム含有)と混合され、4℃で1時間インキュベートされた。細胞サイクルサブ−Gl分画分析はフローサイトメーター(BD FACS Calibu TM,BD Bioscience,Heiderberg ドイツ)を用いて以前記載されたように(Nicoletti,I.et al.,(1991)J.Immunol.Methods 139,271−279)実施された。各実験は3回実施された。
同じ分析はHUVEC細胞を使って実施された。1.5×104細胞が各ウェルへプレートされ、そしてテスト化合物で4日間処理された。
本発明の化合物の抗腫瘍有効性はHT−29ヒト結腸腺癌細胞に対して調べられた。テストした化合物は、低いマイクロモル範囲までの濃度で使用される時、初期投与量依存性細胞毒性を示した(表1)。WO2006/061212の実施例1の化合物が比較化合物として使用された。
Faulet al.,J.of Organic Chemistry 1998,63,6,1961−1973およびZhang et al.,Bioorg.Med.Chem.Lett.,2004,14,12,3245−3250の修飾操作が使用された。インドール−3−グリオキシル酸エチルと、CsCO3またはKCO3(1.3当量)と、そして対応する脂肪族ブロモーまたはクロモー置換剤のDMF中の撹拌懸濁液を窒素下75〜80℃へ8時間加熱した。反応物を室温へ冷却し、酢酸エチル(40ml)で希釈し、セライト(登録商標)上で濾過した。混合物を水(4×40ml)で洗った。有機相をNa2SO4上で乾燥し、濃縮し、カラムフロマトグラフィーにより精製した。
Peifer et al.,WO2006/061212およびJ.Med.Chem.2006,49,4,1271−1281の操作を3−フェニル−4−インドリルマレイミドを製造するために用いた。
3−(1−[2−アンモニオエチル]−1H−インドール−3−イル)−4−(3,4,5−トリメトキシフェニル)−マレイミドクロライド
3−(1−[3−アンモニオプロピル]−1H−インドール−3−イル)−4−(3,4,5−トリメトキシフェニル)−マレイミドクロライド
1H−NMR(300MHz,CDCl3)8.45(m,2H,インドール−H);7.35(m,3H,インドール−H);4.63(bs,1H,NH);4.41(q,3J=7.1Hz,2H,OCH 2 CH3);4.24(t,3J=7.1Hz,2H,インドール−CH3);3.18(q,3J=6.1Hz,2H,CH2N);2.09(m,2H,CH2 CH 2CH),1.44(s,9H,C(CH3));1,43(t,3J=7.1Hz,3H,OCH2 CH 3)
3−(1−[2−ヒドロキシエチル]−1H−インドール−3−イル)−4−(3,4,5−トリメトキシフェニル)−マレイミド
3−(1−[3−ヒドロキシプロピル]−1H−インドール−3−イル)−4−(3,4,5−トリメトキシフェニル)−マレイミド
3−{1−[2−(ジメチルアミノ)エチル]−1H−インドール−3−イル}−4−(3,4,5−トリメトキシフェニル)−マレイミド
3−{1−[3−(ジメチルアミノ)プロピル]−1H−インドール−3−イル}−4−(3,4,5)トリメトキシフェニル)−マレイミド
3−{1−[2−(ピペリジン−1−イル)エチル]−1H−インドール−3−イル}−4−(3,4,5−トリメトキシフェニル)−マレイミド
3−{1−(2−モリホリノエチル)−1H−インドール−3−イル}−4−(3,4,5−トリメトキシフェニル)−マレイミド
3−{1−[3−(4−メチルヘキサヒドロ−1−ピラジンジイウム)プロピル]−1H−インドール−3−イル}−4−(3,4,5−トリメトキシフェニル)−マレイミドジクロライド
3−(5−フルオロ−1H−インドール−3−イル)−4−(3,4,5−トリメトキシフェニル)−マレイミド
3−(5−ブロモ−1H−インドール−3−イル)−4−(3,4,5−トリメトキシフェニル)−マレイミド
エチルオキザリルクロライド(7.5mmol,1.02g=0.83ml);ピリジン(0.7ml);ジエチルエーテル(30ml)
2−(5−ブロモ−1H−インドール−3−イル)−2−オキソ酢酸エチル(3.5mmol,53%)が淡黄色結晶として得られた。mp182−183℃;IR[cm−1]=3224,1720,1618;EI−MSm/z(相対強度)=297(100%,M+);1H−NMR(300MHz,CDCl3+DMSO)11.79(bs,1H,NH);8.09(d,J=1.1Hz,1H,インドール−H);8.01(d,J=3.3Hz,1H,インドール−H);7.01(m,2H,インドール−H);4.04(q,3J=7.1Hz,2H,OCH 2CH3);1.07(t,3J=7.1Hz,3H,OCH2 CH 3)
2−{1−(t−ブトキシカルボニル)−5−ブロモ−1H−インドール−3−イル}−2−オキソ酢酸エチルが白色結晶(2.6mmol,74,3%)として得られた。mp159−160℃;IR[cm−1]=2962,1751,1732,1663;EI−MSm/z(相対強度)=397(12.17%,M+);1H−NMR(300MHz,CDCl3)8.78(s,1H,インドール−H);8.56(d,5J=2.0Hz,インドール−H);8.05(d,3J=8.9Hz,1H,インドール−H);7.52(dd,5J=2.0Hz,3J=8.9Hz,1H,インドール−H);4.44(q,3J=7.1Hz,2H,OCH 2CH3);1.70(s,9H,C(CH3)3);1.45(t,3J=7.1Hz,3H,OCH2 CH 3)
分子ふるい(4オングストローム)15gを含有する乾燥THF中の3,4,5−トリメトキシフェニルアセタミド(0.38g,1.7mmol)と、2−[1−(t−ブトキシカルボニル)−4−アザインドール−3−イル]−2−オキソ酢酸エチル(0.54g,1.7mmol)の撹拌溶液を窒素下0℃へ冷却した。この温度において10M t−BuOK(3.7ml,3.62mmol)を隔膜を通って添加し、混合物が室温へ昇温するのを許容した。一夜撹拌後、反応物を再び0℃へ冷却し、飽和NH4Cl溶液で反応停止した。残渣を濾過し、酢酸エチルで抽出し、合併した有機層をNa2SO4上で乾燥し、濃縮し、カラムクロマトグラフィー(酢酸エチル:エタノール=9:1)によって精製した。3−(4−アザインドール−3−イル)−4−(3,4,5−トリメトキシフェニル)−マレイミドが黄色結晶(0.17g,0.45mmol,26%)として得られた。mp274−275℃;IR[cm−1]=3338,2946,1716;EI−MS m/z(相対強度)=380.75(1.37%,M+);379.79(25.54%),378.79(71.14%);1H−NMR(300MHz,DMSO)11.98(bs,1H,アザインドール−NH);11.14(bs,1H イミド−NH);8.12(ppd,4J=1.0Hz,3J=4.6Hz,1H,H−5);8.04(pd,3J=2.7Hz,1H,H−2);7.83(pdd,4J=1.0Hz,3J=8.2Hz,1H,H−7);7.09(pdd,3J=4.6Hz,3J=8.2Hz,1H,H−6);6.87(s,2H,Ar−H);3.62(s,3H,OCH3);3.32(s,6H,OCH3)
Claims (20)
- 式Iの3−(インドリル)−および3−(アザインドリル)−4−フェニルマレイミド化合物、その生理学的に許容し得る塩、並びに式Iの化合物の溶媒和物およびその塩:
R1は、H、C1−C6アルキル、フェニル−C1−C4アルキルまたはフェニル;
R2は3個のC1−C6アルコキシ基で置換されたフェニル基;および
R3は、
R7はHまたはC1−C6アルキル、
R8はC1−C6アルキル−R10であって、R10は、
a)アミノ、
b)C1−C6アルキルアミノ、
c)ジ−C1−C6アルキルアミノ、
d)ヒドロキシ、
e)C1−C6アルコキシ、
f)1個の窒素ヘテロ原子と、任意にO,NおよびSから独立に選ばれた1個または2個の追加のヘテロ原子を含んでいる5または6個の環原子を有する飽和ヘテロサイクリルであって、窒素原子を介してC1−C6−アルキル基へ結合し、そして追加のC1−C6アルキル基を炭素原子または窒素原子上に担持し得;
g)フェノキシ、
h)ベンジルオキシ、
i)R11CONR12−、
j)NR12R12CO−、
k)C1−C6−アルキル−NHCONH−、
l)C1−C6−アルキル−NHCOO−、
m)C1−C6−アルキル−OCONH−、
n)R12−OSO2O−、
o)R11SO2O−、
p)R12−OSO2−、
q)R11SO2−、
r)(R12O)2P(O)O−、
s)(R12O)2P(O)−、および
t)(R12O)R11P(O)O−、
であり、
R9はH、C1−C6−アルキル,C1−C6−アルコキシ,OH,またはハロゲン;
R11はC1−C6−アルキル;
R12はHまたはC1−C6−アルキルである。 - R1,R7およびR9はHである請求項1ないし3のいずれかの化合物。
- R10は、
a)アミノ、
b)C1−C6−アルキルアミノ、
c)ジ−C1−C6−アルキルアミノ、
d)ヒドロキシ、
e)C1−C6−アルコキシ、および
f)1個の窒素ヘテロ原子と、任意にO,NおよびSから独立に選ばれた1個または2個の追加のヘテロ原子を含んでいる環原子5個または6個の飽和ヘテロサイクリルであって、窒素原子を介してC1−C6−アルキル基へ結合し、そして炭素原子または窒素原子上に追加のC1−C6−アルキル置換基を持つことができるヘテロサイクリルから選ばれる、請求項1ないし4のいずれかの化合物。 - 請求項1ないし5のいずれかに従った少なくとも1つの式Iの化合物と薬学的に許容し得る補助剤を含み、任意に化学療法剤をさらに含んでいる医薬品組成物。
- 化学療法剤は抗腫瘍剤、多剤抵抗逆転剤、生物学的応答修飾剤、およびそれらの組合わせから選ばれる請求項6の組成物。
- 化学療法剤は、イリノテカン、トポテカン、ルビテカン、エクサテカン、ルールトテカン、ギマテカン、プロセカン、カレニテシン、ベロテカン、シラテカン、ジフロモテカンおよびそれらの塩から選ばれたトポイソメラーゼI阻害剤である請求項6の組成物。
- トポイソメラーゼI阻害剤は、イリノテカンまたはトポテカンである請求項8の組成物。
- 任意に追加化学療法剤の使用を含む、腫瘍処置に使用するための請求項1ないし5のいずれかに従った式Iの化合物。
- 追加の化学療法剤は、抗腫瘍剤、多剤抵抗逆転剤、生物学的応答修飾剤およびそれらの組合わせから選ばれる請求項10に従った使用のための化合物。
- 追加の化学療法剤は、トポイソメラーゼI阻害剤である請求項10に従った使用のための化合物。
- トポイソメラーゼI阻害剤は、イリノテカン、トポテカン、ルビテカン、エキサテカン、ルールトテカン、ギマテカン、プロセカン、カルニテシン、ベロテカン、シラテカン、ジフロモテカンおよびそれらの塩から選ばれる請求項12に従った使用のための化合物。
- トポイソメラーゼI阻害剤は、イリノテカンまたはトポテカンである請求項12に従った使用のための化合物。
- 腫瘍処置を必要とする哺乳類へ請求項1ないし5のいずれかの式Iの化合物の有効量を投与することを含む、哺乳類の腫瘍処置方法。
- さらなる化学療法剤の投与を含む請求項15の方法。
- 化学療法剤は、抗腫瘍剤、多剤抵抗逆転剤、生物学的応答修飾剤およびそれらの組合わせから選ばれる請求項16の方法。
- さらなる化学療法剤は、トポイソメラーゼI阻害剤である請求項15の方法。
- トポイソメラーゼI阻害剤は、イリノテカン、トポテカン、ルビテカン、エキサテカン、ルールトテカン、ギマテカン、プロセカン、カルニテシン、ベロテカン、シラテカン、ジフロモテカンおよびそれらの塩から選ばれる請求項18の方法。
- トポイソメラーゼI阻害剤は、イリノテカンまたはトポテカンである請求項18の方法。
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EP20090179986 EP2343291A1 (en) | 2009-12-18 | 2009-12-18 | 3-(Indolyl)- or 3-(Azaindolyl)-4-arylmaleimide compounds and their use in tumor treatment |
PCT/EP2010/069352 WO2011073092A1 (en) | 2009-12-18 | 2010-12-10 | 3-(indolyl)- or 3-(azaindolyl)-4-arylmaleimide compounds and their use in tumor treatment |
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US (1) | US9012659B2 (ja) |
EP (2) | EP2343291A1 (ja) |
JP (1) | JP5980684B2 (ja) |
AU (1) | AU2010333083B2 (ja) |
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JP2013514294A (ja) * | 2009-12-18 | 2013-04-25 | ヨハネス、グーテンベルク−ウニフェルジテート、マインツ | 結腸および胃の腺癌の処置に使用のための3−(インドリル)−または3−(アザインドリル)−4−アリールマレイミド誘導体 |
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EP2474541A1 (en) * | 2010-12-23 | 2012-07-11 | Johannes- Gutenberg-Universität Mainz | Conjugated 3-(indolyl)- and 3-(azaindolyl)-4-arylmaleimide compounds and their use in tumor treatment |
US9724331B2 (en) * | 2012-12-10 | 2017-08-08 | Centogene Ag | Use of maleimide derivatives for preventing and treating leukemia |
ES2851208T3 (es) | 2012-12-10 | 2021-09-03 | Centogene Gmbh | Uso de derivados de maleimida para prevenir y tratar el cáncer |
CN104370903A (zh) * | 2013-08-14 | 2015-02-25 | 苏州科捷生物医药有限公司 | 3-乙酰基-4-氮杂吲哚的实用合成方法 |
EP3187495A1 (en) | 2015-12-30 | 2017-07-05 | Johannes Gutenberg-Universität Mainz | 3-(5-fluoroindolyl)-4-arylmaleimide compounds and their use in tumor treatment |
US20220133740A1 (en) | 2019-02-08 | 2022-05-05 | Frequency Therapeutics, Inc. | Valproic acid compounds and wnt agonists for treating ear disorders |
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AU2010333083B2 (en) | 2016-02-25 |
CA2782574A1 (en) | 2011-06-23 |
JP5980684B2 (ja) | 2016-08-31 |
WO2011073092A1 (en) | 2011-06-23 |
EP2343291A1 (en) | 2011-07-13 |
EP2513089B1 (en) | 2015-09-09 |
US20130131060A1 (en) | 2013-05-23 |
AU2010333083A1 (en) | 2012-06-21 |
EP2513089A1 (en) | 2012-10-24 |
US9012659B2 (en) | 2015-04-21 |
CA2782574C (en) | 2017-05-16 |
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