JP6981983B2 - 3−(5−フルオロインドリル)−4−アリールマレイミド化合物および腫瘍処理におけるその使用 - Google Patents
3−(5−フルオロインドリル)−4−アリールマレイミド化合物および腫瘍処理におけるその使用 Download PDFInfo
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- JP6981983B2 JP6981983B2 JP2018534580A JP2018534580A JP6981983B2 JP 6981983 B2 JP6981983 B2 JP 6981983B2 JP 2018534580 A JP2018534580 A JP 2018534580A JP 2018534580 A JP2018534580 A JP 2018534580A JP 6981983 B2 JP6981983 B2 JP 6981983B2
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D403/02—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
- 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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- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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Description
および、式(Ia),(Ib),(Ic),(Id),(Ie),(If)および(Ig)の化合物の生理学的に許容される塩、溶媒和物および塩の溶媒和物である。
rt 室温
DMF ジメチルホルムアミド
DMAP ジメチルアミノピリジン
DCM ジクロロメタン
THF テトラヒドロフラン
DMSO ジメチルスルホキシド
PE/EE 石油エーテル/酢酸エチル
Mp 融点
2−(3−(2,5−ジオキソ−4−(3,4,5−トリメトキシフェニル)−2,5−ジヒドロ−1H−ピロール−3−イル)−5−フルオロ−1H−インドール−1−イル)−エチル−2−アミノ−4−メチルペンタンノエート
Galka et al., J. Lab. Comp. Rad. 2005, 48, 11, 797−809に記載の方法を変形して用いて標記化合物を調製した。2−ブロモエタノール(40mmol)、tert−ブチルジメチルシリルクロライド(40mmol)およびイミダゾール(44mmol)の混合物を室温で3時間不活性雰囲気下で撹拌した。反応物を水でクエンチし、ジエチルエーテルで抽出した。有機層をMgSO4で乾燥させ、濾過し、減圧濃縮した。精製は、カラムクロマトグラフィー(PE/EE)によって達成され、標記化合物(36.4mmol;91%)を得た。1H NMR(300MHz、CDCl3)δ[ppm]=3.91(t;3J=6.5Hz;2H;OCH2);3.41(t;3J=6.5Hz;2H;CH2Br);0.93(s;9H;C(CH3)3);0.11(s;6H;2xCH3)。
ジエチルエーテル中の5−フルオロインドール(16.28mmol)の溶液に、0℃でピリジン(170ml)およびエチルクロロオキソアセテート(19.8mmol)を不活性ガス下でゆっくりと添加した。反応混合物を0℃で1時間、次いで室温で4時間撹拌した。沈殿物を濾過し、水およびエタノール(0℃)で洗浄して、標題化合物を無色結晶(11mmol;66%)として得た。1H NMR(300MHz、CDCl3)δ[ppm]=9.22(bs,1H;NH);8.53(d;J=3.3Hz;1H;インドール−H);8.11(dd;J=2.5Hz;J=9.0Hz;1H;インドール−H);7.41(dd;J=4.3Hz;J=9.0Hz;1H;インドール−H);7.06(dt;J=2.5Hz;J=9.0Hz;1H;インドール−H);4.41(q;3J=7.1Hz;2H;OCH 2CH3);1.43(t;3J=7.1Hz;3H;OCH2 CH 3)。
Faul et al., J. of Org. Chem, 1998, 63, 6, 1961−1973およびZhang et al., Bioorg. Med. Chem. Lett., 2004, 14, 12, 3245−3250の方法を変形して用いた。エチル−2−(5−フルオロ−1H−インドール)−2−オキソアセテート(2)(4.3mmol)、CsCO3(5.6mmol)および2−ブロモエトキシ−tert−ブチルジメチルシラン(1)(4.7mmol)の無水DMF中の撹拌懸濁液を窒素下で8時間75〜80℃に加熱した。反応物を室温に冷却し、酢酸エチル(40ml)で希釈し、濾過した。混合物を水で洗浄し、MgSO4で乾燥させ、濾過し、濃縮し、カラムクロマトグラフィーにより精製して、橙色油状物として標記化合物を得た(12.5mmol;78%)。1H NMR(300MHz、CDCl3)δ[ppm]=8.44(s,1H,インドール−H),8.12(m,1H,インドール−H),7.30(m,インドール−H),7.06(インドール−H),4.40(q,J=7.1Hz,2H,CH 2 −CH3)、4.27(t,J=5.0Hz,2H,N−CH 2 −CH2−O),3.95(t,J=5.0Hz,2H,N−CH2−CH 2 −O),1.44(t,J=7.1Hz,3H,CH2−CH 3 ),0.80(s,9H,C(CH3)3),−0.16(s,6H,Si(CH3)2)。
無水DCM中の3,4,5−トリメトキシフェニル酢酸(10mmol)および五塩化リン(10mmol)の混合物を不活性ガス下で撹拌した。2時間後、シリンジを介してアンモニア(25%)10mlを加え、さらに1時間後、混合物を氷(100ml)でクエンチし、酸性化し(10%HCl)、DCMで抽出した。有機画分を乾燥させ(MgSO4)、濃縮し、次いで粗生成物をエタノール中で再結晶化させて、標題化合物を無色粉末として得た(8.5mmol;85%)。1H NMR(300MHz,DMSO)δ[ppm]=7.39(bs;1H;NH);6.87(bs;1H;NH);6.55(s;2H;Ar−H);3.73(s;6H;2xOCH3);3.61(s;3H;OCH3);3.28(s;2H;CH2)。
Peifer et al., WO 2006/061212およびJ. Med. Chem., 2006, 49, 4, 1271−1281の方法を変形して用いて3−フェニル−4−インドリル−マレインイミドを調製した。エチル2−(1−(3−(tert−ブチルジメチルシリルオキシ)−エチル)−5−フルオロ−1H−インドール−3−イル)−2−オキソアセテート(3)(3.2mmol)と、THF(不活性ガス、活性化モレキュラーシーブ4Å)中の3,4,5−トリメトキシフェニルアセトアミド(4)(3.2mmol)の溶液に、THF中のカリウムtert−ブトキシド(14mmol)をシリンジでゆっくり加えた。混合物を室温で2時間撹拌し、次いで酢酸エチルで希釈し、濾過した。水で洗浄した後、有機層をMgSO4で乾燥させ、濃縮し、カラムクロマトグラフィー(PE/EE)で精製して橙色の固体(1.3mmol;41%)として標記化合物を得た。1H NMR(300MHz,CDCl3)δ[ppm]=8.09(s,1H,インドール−H),7.34(s,1H,イミド−H),7.29(m,1H,インドール−H),6.90(m,1H,インドール−H),6.74(s,2H,Ar‐H),5.99(m,1H,インドール−H),4.29(t,J=5.0Hz,2H,N−CH 2 −CH2−O−),3.97(t,J=5.1Hz,2H N−CH2−CH 2 −O−),3.88(s,3H,OCH3),3.56(s,6H,2xOCH3),0.80(s,9H,C(CH3)3),−0.14(s,6H,Si(CH3)2)。
無水DCM中の1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI;1.3mmol)およびジメチルアミノピリジン(DMAP;0.22mmol)の撹拌溶液に、無水DCM中の3−(5−フルオロ−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(6)(0.45mmol)をシリンジを介してゆっくり加えた。反応混合物を周囲温度で24時間撹拌した。水でクエンチし、酢酸エチルで抽出した後、合わせた有機層をMgSO4で乾燥させ、濾過し、濃縮し、カラムクロマトグラフィー(PE/EE)により精製して橙色の固体(0.4mmol;89%)として標題化合物を得た。1H NMR(300MHz,CDCl3)δ[ppm]=8.05(s,1H,インドール−H),7.47(s,1H,イミド−H),7.29(m,1H,インドール−H),6.96(m,1H,インドール−H),6.75(s,2H,Ar−H),6.08(d,J=12,67Hz,1H,インドール−H),5.00(d,J=8.75Hz,1H,−NH−CH−CO),4.48(m,4H,−CH 2 −CH 2 −O−),3.87(s,3H,OCH3),3.56(s,6H,2xOCH3),1.68(m,4H,−NH−CH−COおよび−CH 2 −CH(CH3)2,1.42(s,9H,C(CH 3 )3),0.87(m,6H,−CH2−CH(CH 3 )2。
3−(5−フルオロ−1−(2−ヒドロキシエチル)−1H−インドール−3−イル)−4−(4−ヒドロキシ−3,5−ジメトキシフェニル)−マレイミド
(1)3−(5−フルオロ−1H−インドール−3−イル)−4−(4−ヒドロキシ−3,5−ジメトキシフェニル)−マレイミド
DCM中の塩化アルミニウム(35mmol)に、DCM中の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(10)(1.2mmol)をゆっくり加えた。混合物を周囲温度で4時間撹拌した。 完了後、20mlの水を加え(0〜3℃)、混合物を酢酸エチルで抽出した。有機相を水および塩水で洗浄し、MgSO4で乾燥させ、濃縮し、カラムクロマトグラフィー(PE/EE)によって精製して、生成物を得た(0.8mmol;67%)。1H NMR(300MHz,DMSO)δ[ppm]=11.92(bs,1H,インドール−NH),10.98(bs,1H,イミド−NH),8.85(s,1H,インドール−H),7.98(s,1H,インドール−H),7.44(dd,J=4.56Hz,J=9.03Hz,1H,インドール−H),6.88(m,1H,インドール−H);6.74(s,2H,Ar−H),6.08(d,J=8.20Hz,1H,インドール−H),3.43(s,6H,2xOCH3)。C22H19FN2O6x0,5H2Oの分析計算値:C,61.38;H,4.12;N,7.16。実測値:C,61.07;H,4.40;N,6.84。
1.塩化マグネシウム六水和物 50μl
2.グルコース−6−リン酸 50μl
3.NADP+ 50μl
4.グルコース−6−リン酸−デヒドロゲナーゼ:10μl
5.ミクロソーム:50μl
6.化合物:40μl(エタノール中の4mM溶液10μl)
全量:0.1M Trizma緩衝液(37℃でpH7.4)で1000μl
Acquity UPLC(登録商標)−Waters社のQuattro Premier XE(MS)システム
カラム:BEH C18,2.1×50mm、1.2μm細孔径、Waters社製
注入量:10μl
溶媒A:H2O、NH4−蟻酸塩2mM+0.1%蟻酸
溶媒B:メタノール、NH4−蟻酸塩2mM+0.1%蟻酸
流動様式:70%溶媒A/30%溶媒Bから2.4分で100%溶媒A、次いで70%溶媒A/30%溶媒Bで0.8分。
Claims (22)
- R1がメトキシであり、R2が2−アミノ−4−メチルブタノイルオキシエチル、ヒドロキシエチルである、式(I)を有する請求項1に記載の化合物、または、式(I)の化合物の生理学的に許容し得る塩、溶媒和物、または、前記塩の溶媒和物。
- R1がヒドロキシであり、R2がヒドロキシエチルまたはHである、式(I)を有する請求項1に記載の化合物、または、式(I)の化合物の生理学的に許容し得る塩、溶媒和物、または、前記塩の溶媒和物。
- R1がメトキシまたはヒドロキシルであり、R2がヒドロキシエチルである、式(I)を有する請求項1に記載の化合物、または、式(I)の化合物の生理学的に許容し得る塩、溶媒和物、または、前記塩の溶媒和物。
- 請求項1から請求項11までのいずれか1項に記載の1つ以上の化合物および薬学的に許容される賦形剤を含む医薬組成物。
- 1つ以上の追加の化学療法剤をさらに含む、請求項12に記載の組成物。
- 前記追加の化学療法剤が、抗腫瘍剤、多剤耐性逆転剤、および、生物学的再補体改変剤、およびそれらの組み合わせから選択される、請求項13に記載の組成物。
- 前記追加の化学療法剤が少なくとも1つのトポイソメラーゼI阻害剤である、請求項13に記載の組成物。
- 前記トポイソメラーゼI阻害剤が、イリノテカンまたはトポテカンまたはそれらの混合物である、請求項15に記載の組成物。
- 腫瘍の治療または予防における使用のための、請求項1から請求項11までのいずれか1項に記載の化合物。
- 1つ以上の追加の化学療法剤の使用をさらに含む、請求項17に記載の使用のための化合物。
- 前記追加の化学療法剤が、抗腫瘍剤、多剤耐性逆転剤、および、生物学的応答調節剤、およびそれらの組み合わせから選択される、請求項18に記載の使用のための化合物。
- 前記追加の化学療法剤が少なくとも1つのトポイソメラーゼI阻害剤である、請求項18に記載の使用のための化合物。
- 前記トポイソメラーゼI阻害剤が、イリノテカンまたはトポテカンまたはそれらの混合物である、請求項20に記載の使用のための化合物。
- 前記追加の化学療法剤および請求項1から請求項8までのいずれか1項に記載の化合物が、連続的に、断続的に、または、同時に投与される、請求項18から請求項21、までのいずれか1項に記載の使用のための化合物。
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EP15203072.2A EP3187495A1 (en) | 2015-12-30 | 2015-12-30 | 3-(5-fluoroindolyl)-4-arylmaleimide compounds and their use in tumor treatment |
PCT/EP2016/082777 WO2017114863A1 (en) | 2015-12-30 | 2016-12-28 | 3-(5-fluoroindolyl)-4-arylmaleimide compounds and their use in tumor treatment |
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NZ227850A (en) | 1988-02-10 | 1991-11-26 | Hoffmann La Roche | Indole substituted pyrrole derivatives; preparatory process and medicaments for use against inflammatory immunological, bronchopulmonary or vascular disorders |
GB8904161D0 (en) | 1989-02-23 | 1989-04-05 | Hoffmann La Roche | Substituted pyrroles |
MC2096A1 (fr) | 1989-02-23 | 1991-02-15 | Hoffmann La Roche | Pyrroles substitues |
DE4005969A1 (de) | 1990-02-26 | 1991-08-29 | Boehringer Mannheim Gmbh | Neue trisubstituierte pyrrole, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten |
GB9123396D0 (en) | 1991-11-04 | 1991-12-18 | Hoffmann La Roche | A process for the manufacture of substituted maleimides |
GB9319297D0 (en) | 1993-09-17 | 1993-11-03 | Wellcome Found | Indole derivatives |
EP0888339A4 (en) | 1996-03-20 | 2001-02-28 | Lilly Co Eli | SYNTHESIS OF INDOLYLMALEINIMIDES |
JP2002527419A (ja) | 1998-10-08 | 2002-08-27 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Gsk−3阻害物質としてのピロール−2,5−ジオン類 |
GB9828640D0 (en) | 1998-12-23 | 1999-02-17 | Smithkline Beecham Plc | Novel method and compounds |
WO2001013916A1 (fr) | 1999-08-20 | 2001-03-01 | Sagami Chemical Research Center | Medicaments inhibant la mort cellulaire |
DE60107857T2 (de) | 2000-07-27 | 2005-12-08 | F. Hoffmann-La Roche Ag | 3-Indolyl-4-Phenyl-1H-Pyrrol-2,5-Dion-Derivate als Glycogen Synthase-Kinase 3Beta Inhibitoren |
KR100916613B1 (ko) | 2000-11-07 | 2009-09-14 | 노파르티스 아게 | 단백질 키나제 c 억제제로서의 인돌릴말레이미드 유도체 |
JP4237066B2 (ja) | 2002-01-10 | 2009-03-11 | エフ.ホフマン−ラ ロシュ アーゲー | 骨形成を増加させるための薬物の製造におけるGSK−3β阻害剤の使用 |
DE60319364T2 (de) | 2002-05-08 | 2009-02-19 | Janssen Pharmaceutica N.V. | Substituierte pyrroline als kinase inhibitoren |
ES2312785T3 (es) | 2002-06-05 | 2009-03-01 | Janssen Pharmaceutica Nv | Pirrolinas sustituidas utiles como inhibidores de quinasa. |
US20110293746A1 (en) | 2004-07-09 | 2011-12-01 | Agency For Science, Technology And Research | Modulation of Gsk-3Beta and Method of Treating Proliferative Disorders |
EP1819697B1 (en) | 2004-12-08 | 2012-08-01 | Johannes Gutenberg-Universität Mainz | 3-(indolyl)-4-arylmaleimide derivatives and their use as angiogenesis inhibitors |
WO2006073202A1 (ja) | 2005-01-04 | 2006-07-13 | National University Corporation Kanazawa University | GSK3β阻害効果に基づくがんの抑制および抗がん剤の評価方法 |
ATE535241T1 (de) | 2007-12-05 | 2011-12-15 | Univ Mainz Johannes Gutenberg | Verwendung von 3-(indolyl)- oder 3-(azaindolyl)-4-arylmaleimid-derivaten bei der behandlung von leukämie |
EP2343291A1 (en) | 2009-12-18 | 2011-07-13 | Johannes Gutenberg-Universität Mainz | 3-(Indolyl)- or 3-(Azaindolyl)-4-arylmaleimide compounds and their use in tumor treatment |
EP2338486A1 (en) | 2009-12-18 | 2011-06-29 | Johannes Gutenberg-Universität Mainz | 3-(indolyl)- or 3-(azaindolyl)-4-arylmaleimide derivatives for use in the treatment of colon and gastric adenocarcinoma |
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 |
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CA3004007C (en) | 2023-12-05 |
US20200253930A1 (en) | 2020-08-13 |
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CA3004007A1 (en) | 2017-07-06 |
US11045449B2 (en) | 2021-06-29 |
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