JP2010530883A - ピロリジノン、ピロリジン−2,5−ジオン、ピロリジンおよびチオスクシンイミド誘導体、癌の治療のための組成物および方法 - Google Patents
ピロリジノン、ピロリジン−2,5−ジオン、ピロリジンおよびチオスクシンイミド誘導体、癌の治療のための組成物および方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
- C07D403/14—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 three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Description
本願は、2007年6月22日に出願された米国仮特許出願第60/945,834号の利益を主張し、この米国仮特許出願の全体の内容は、本明細書中に参考として援用される。
癌は、米国における第2の主要死亡原因であり、これを上回るのは心臓疾患だけである(Cancer Facts and Figures 2004年、American Cancer Society、Inc.)。癌の診断および治療における最近の進歩にもかかわらず、癌が早期に発見された場合、外科処置や放射線治療が治療に有効であるが、転移性疾患のための現在の薬物治療は概して一時的に抑えるに過ぎず、めったに長期的な治癒をもたらすものではない。新規な化学療法が市場に参入してきているが、耐性腫瘍の治療における、第1治療としての、そして、第2および第3治療としての、単剤治療かまたは既存の薬剤との併用治療に有効な新規な薬物が依然として求められている。
本発明は、式I、II、IIIもしくはIVの化合物または薬学的に許容されるその塩を提供する
R1、R2およびR3は、H、F、Cl、Br、I、−NR7R8、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、−O−(C1〜C6)アルキル、−O−(C3〜C9)シクロアルキルおよび−O−(C3〜C9)置換シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立に選択され、
R4は、H、−(C1〜C4)アルキルおよび−(C1〜C4)置換アルキルからなる群から選択され、
R5は、H、−(C1〜C6)アルキル、−CH2R6、−CONHR9、−COR10および−SO2R11からなる群から選択され、
R6は、−O−P(=O)(OH)2、−O−P(=O)(−OH)(−O−(C1〜C6)アルキル)、−O−P(=O)(−O−(C1〜C6)アルキル)2、−O−P(=O)(−OH)(−O−(CH2)−フェニル)、−O−P(=O)(−O−(CH2)−フェニル)2、カルボン酸基、アミノカルボン酸基およびペプチドからなる群から独立に選択され、
R7およびR8は、Hおよび−(C1〜C6)アルキルからなる群から独立に選択され、
R9、R10およびR11は、H、NHR12、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立に選択され、
Qは、インドリル、置換インドリル、アリール、ヘテロアリール、ヘテロシクリルおよびアルキルからなる群から独立に選択され、
VおよびZは、O、S、H2からなる群から独立に選択され、VとZがどちらもOである場合、R4は、−(C1〜C4)アルキルまたは−(C1〜C4)置換アルキルであり、ZとVがどちらもH2でない場合、R5は、H、−(C1〜C6)アルキルまたは−CH2R6であり、
Xは、−CH2−、−NR12、S、O、および結合からなる群から選択され、
R12は、H、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、−O−(C1〜C6)アルキル、−C(=O)−O−(C1〜C6)アルキルおよび−C(=O)−O−(C1〜C6)置換アルキルからなる群から選択され、
Wは、−CH2−、CO、および結合からなる群から選択され、
mは0、1または2である)。
1.ピロリジン−2−オン、ピロリジン−2,5−ジオン、ピロリジンおよびチオスクシンイミド
本発明は、式I、II、IIIまたはIVのピロリジン−2−オン、ピロリジン−2,5−ジオン、ピロリジンおよびチオスクシンイミド化合物、ならびに式I、II、IIIまたはIVの化合物の調製方法を提供する。
R1、R2およびR3は、H、F、Cl、Br、I、−NR7R8、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、−O−(C1〜C6)アルキル、−O−(C3〜C9)シクロアルキルおよび−O−(C3〜C9)置換シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立に選択され、
R4は、H、−(C1〜C4)アルキルおよび−(C1〜C4)置換アルキルからなる群から選択され、
R5は、H、−(C1〜C6)アルキル、−CH2R6、−CONHR9、−COR10および−SO2R11からなる群から選択され、
R6は、−O−P(=O)(OH)2、−O−P(=O)(−OH)(−O−(C1〜C6)アルキル)、−O−P(=O)(−O−(C1〜C6)アルキル)2、−O−P(=O)(−OH)(−O−(CH2)−フェニル)、−O−P(=O)(−O−(CH2)−フェニル)2、カルボン酸基、アミノカルボン酸基およびペプチドからなる群から独立に選択され、
R7およびR8は、Hおよび−(C1〜C6)アルキルからなる群から独立に選択され、
R9、R10およびR11は、H、NHR12、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立に選択され、
Qは、インドリル、置換インドリル、アリール、ヘテロアリール、ヘテロシクリルおよびアルキルからなる群から独立に選択され、
VおよびZは、O、S、H2からなる群から独立に選択され、VとZがどちらもOである場合、R4は、−(C1〜C4)アルキルまたは−(C1〜C4)置換アルキルであり、ZとVがどちらもH2でない場合、R5は、H、−(C1〜C6)アルキルまたは−CH2R6であり、
Xは、−CH2−、−NR12、S、O、および結合からなる群から選択され、
R12は、H、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、−O−(C1〜C6)アルキル、−C(=O)−O−(C1〜C6)アルキルおよび−C(=O)−O−(C1〜C6)置換アルキルからなる群から選択され、
Wは、−CH2−、CO、および結合からなる群から選択され、
mは0、1または2である)。
有機分子の調製のための標準的な合成方法または手順、ならびに保護基の使用を含む官能基の転換および操作法は、この分野の関連する科学文献または標準的参考書から得ることができる。1つまたは複数のいずれかの情報源に限定するわけではないが、広く認められている有機合成の参考書には、Smith、M.B.;March、J.March’s Advanced Organic Chemistry:Reactions、Mechanisms、and Structure、第5版;John Wiley & Sons:New York、2001年;およびGreene、T.W.;Wuts、P.G.M.Protective Groups in Organic Synthesis、3rd;John Wiley & Sons:New York、1999年が含まれる。合成方法の以下の記述は、限定するわけではないが、本発明の化合物の調製のための基本手順を示すものである。
式I、II、IIIまたはIVの化合物(ZとVの両方がOまたはH2であることはない)の調製は、式VまたはXの化合物の還元、スキーム1および2によって達成することができる。
式Vの化合物の式VI、VII、VIIIおよびIXの化合物への還元は、これらに限定されないが、アルコール中の金属(還元手順A)、触媒的水素化(還元手順B)または触媒的水素化(還元手順B)を用いた還元、続く、基本スキーム1による異性化などの様々な手順を用いて実施することができる。
式Vの化合物は、これらに限定されないが、メタノール、エタノール、n−プロパノールおよびイソプロパノールなどの適切な無水溶媒中で、不活性雰囲気下、50℃〜混合物の沸点の範囲の温度で、これらに限定されないが、ナトリウム、カルシウムまたはマグネシウム等適切な還元性金属と0.5〜12時間反応させることによって、式VIIIおよびIXの化合物に還元することができる。時間と温度はどちらも、使用する化合物の具体的な置換基に応じて変えることができる。特定の実施形態では、反応は、実施例1のステップ10に記載するように、メタノール中、還流下で約6時間、金属マグネシウムを使用する。
式Vの化合物は、これらに限定されないが、エタノール、メタノール、テトラヒドロフラン(THF)またはN,N−ジメチルホルムアミド(DMF)などの適切な溶媒中、20〜100℃の温度範囲で、酸化白金、パラジウム炭素、ロジウムまたはルテニウムなどの貴金属触媒を用いて、少なくとも1気圧の水素ガス下で1〜48時間触媒的水素化することによって、式VIおよびVIIの化合物に還元することができる。時間と温度はどちらも、使用する化合物の具体的な置換基に応じて変えることができる。
式Xの化合物からの式XI、XII、XIIIおよびXIVの化合物の調製、スキーム2は、節2.1.1に記載の基本手順を用いて実施することができる。
式Vの化合物は、式XVの化合物から、式XVIまたはXVIIの酸または酸クロリドとカップリングし、続く保護、塩基による環化、脱保護するスキーム3(Pは保護基である)によって調製することができる。
式Vの化合物は、式XXIの化合物から、式XXIIのオキソエステル(R13は(C1〜C4)アルキル基である)と縮合して式XXIIIの化合物を生成し、続いて、チオカルボニル基を除去することによって得ることもできる(スキーム4)。
式Xの化合物は、節2.1.3.スキーム5に記載の基本手順によって式XXVの化合物から調製することができる。
式Xの化合物は、節2.1.4.スキーム6に記載の基本手順によって式XXXの化合物から調製することができる。
式I、II、IIIまたはIV(ZとVの両方がOまたはSであることはない)の化合物は、WO2006086484に記載のようにして、カルボニル基をチオカルボニル基に転換させることができる試薬で処理することによって式XXXII〜XXXVの化合物から調製することができ、式I、II、IIIまたはIV(ZとVの両方がOまたはH2であることはない)の化合物は、チオカルボニル基を除去することによって式XXXVI〜XLIIIの化合物から得ることができる(スキーム7)。
式XXXVI〜XLIIIの化合物は、式XXXII〜XXXVの化合物から、これらに限定されないが、THF、1,4−ジオキサンまたはトルエンなどの適切な溶媒中、25℃から反応混合物の沸点の温度範囲で0.5〜24時間、これらに限定されないが、ローソン試薬または五硫化リンなどの、カルボニル基をチオカルボニル基に転換させることができる試薬で処理することによって調製することができる。時間と温度はどちらも、使用する化合物の具体的な置換基に応じて変えることができる。
式XXXVI〜XLIIIの化合物からの式VI〜IXおよびXI〜XIVの化合物の調製は、25℃から反応混合物の沸点の温度範囲で0.5〜24時間、これらに限定されないが、エタノールまたはメタノールなどの適切な溶媒中、これらに限定されないが、チオカルボニル基を除去することができるラネーニッケルなどの還元剤と反応させることによって実施することができる。時間と温度はどちらも、使用する化合物の具体的な置換基に応じて変えることができる。
式I、II、IIIまたはIV(ZとVはどちらもH2である)の化合物は、式XXXII、XXXIII、XXXIVまたはXXXVの化合物から、これを還元し、続いてイソシアネート、酸もしくは酸クロリド、スルホニルクロリドまたはアルキル化試薬と反応させることによって調製することができる(スキーム8)。
式XLIVの化合物は、式XXXII〜XXXVの化合物から、これらに限定されないが、THFまたは1,4−ジオキサンなどの適切な溶媒中、25℃から反応混合物の沸点の温度範囲で0.5〜24時間、これらに限定されないが、水素化アルミニウムリチウムなどの適切な還元剤と反応させることによって調製することができる。時間と温度はどちらも、使用する化合物の具体的な置換基に応じて変えることができる。
式XLVIIの化合物は、式XLVIの化合物から、これらに限定されないが、THF、1,4−ジオキサン、DCM、メタノールまたはDMFなどの適切な溶媒中で、これらに限定されないが、エチルイソシアネート、シクロプロピルイソシアネート、フェニルイソシアネート、ベンゾイルイソシアネートなどの適切なイソシアネートを用い、必要なら、これらに限定されないが、トリエチルアミン、DIPEAまたはピリジン等適切な塩基を用いて、0℃〜60℃の温度範囲で0.5〜24時間反応することによって調製することができる。時間と温度はどちらも、使用する化合物の具体的な置換基に応じて変えることができる。
式XV、XXI、XXIVおよびXXIXの化合物は、式Aの化合物から、市販されているか、またはWO2006086484および文献Tetrahedron Letter 1997年、第38巻(30号)、5379〜5382頁;Journal of Heterocyclic Chemistry 1988年、第25巻(3号)、937〜942頁;Bioorganic & Medicinal Chemistry Letter 2004年、第24巻(12号)、3217〜3220頁(スキーム9)に記載されている様々な合成経路によって得ることができる。
式XXIXの化合物は、式Aの化合物から、これらに限定されないが、THF、1,4−ジオキサンまたはDCMなどの適切な無水溶媒中、0℃〜25℃の温度範囲で0.5〜24時間塩化オキサリルと反応させ、続いて、これらに限定されないが、エタノール、メタノールまたはイソプロパノールなどの適切なアルコールを加えて0℃〜25℃の温度範囲で0.5〜24時間反応させることによって得ることができる。時間と温度はどちらも、使用する化合物の具体的な置換基に応じて変えることができる。
式XXIの化合物は、式Aの化合物から、様々な合成経路、スキーム9によって得ることができる。
式XVの化合物は、4段階の一連のスキーム9により式Aの化合物から得ることができる。
式I、II、IIIおよびIVの構造を有する個々の生成物の単離が望ましい場合、その生成物は、1つまたは複数のクロマトグラフィー媒体を用いたクロマトグラフィーにより分離することができる。試料中に存在する生成物のアイデンティティおよび純度を判定するために、クロマトグラフィーは、分取スケールまたは分析的スケールで実施することができる。これらに限定されないが、シリカ、C18逆相シリカ、イオン交換、キラルクロマトグラフィー媒体またはその組合せを含む適切な任意のクロマトグラフィー媒体を分離に有利に使用することができるが、式I、II、IIIおよびIVを有する生成物の分離のための具体的なクロマトグラフィー媒体の適合性および条件は、その化合物上に存在する置換基に依存することになる。好ましい実施形態では、クロマトグラフィー分離はHPLCを用いて実施する。他の好ましい実施形態では、分離は超臨界流体クロマトグラフィーを用いて実施する。超臨界流体クロマトグラフィーを用いる場合、CO2、またはCO2とアセトニトリル(ACN)、メタノール、エタノール、イソプロパノールもしくはヘキサンを含む他の溶媒の混合物が好ましい移動相であり、CO2とメタノールの混合物が最も好ましい。これらに限定されないが、ChiralCel OA、OB、ODまたはOJ;ChiralPak ADまたはAS;Cyclobond I、IIまたはIII;およびChirobiotic T、VおよびR媒体を含む様々なクロマトグラフィー媒体(固定相)を、超臨界流体クロマトグラフィーで使用することができる。
本明細書で用いるように、「対象」は任意の哺乳動物、例えば、ヒト、霊長類、マウス、ラット、イヌ、ネコ、ウシ、ウマ、ブタ、ヒツジ、ヤギ、ラクダであってよい。好ましい態様では、対象はヒトである。
本発明の活性化合物を含む医薬組成物は、公知である方法で、例えば、従来の混合、溶解、造粒、糖衣錠化、摩砕、乳状化、封入、混入または凍結乾燥工程によって製造することができる。医薬組成物は、薬学的に用いることができる調製物への活性化合物の加工を促進する、賦形剤および/または補助剤を含む1つまたは複数の薬学的に許容される担体を用いて、従来の方法で製剤化することができる。当然、適当な製剤は、選択される投与経路によって決まる。
4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−3−(1H−インドール−3−イル)−ピロリジン−2−オンの調製
ステップ1
(3R,4R)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−3−(1H−インドール−3−イル)−5−チオキソ−ピロリジン−2−オンおよび(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−5−チオキソ−ピロリジン−2−オン(1/1混合物)の調製
(3R,4R)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−3−(1H−インドール−3−イル)−ピロリジン−2−オンおよび(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−2−オン(1/1混合物)の調製
(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−2−オンの調製
ステップ1
(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(3−トリフルオロメチル−フェニル)−ピロリジン−2−オンの調製
(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(3−メトキシ−フェニル)−ピロリジン−2−オンの調製
1−[(3R,4R)−4−(1H−インドール−3−イル)−ピロリジン−3−イル]−5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリンの調製
ステップ1
(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−1−カルボン酸エチルアミドの調製
1−[(3R,4R)−1−ベンゼンスルホニル−4−(1H−インドール−3−イル)−ピロリジン−3−イル]−5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリンの調製
1−[(3R,4R)−4−(1H−インドール−3−イル)−1−(プロパン−2−スルホニル)−ピロリジン−3−イル]−5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリンの調製
シクロブチル[(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−1−イル]−メタノンの調製
1−[(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−1−イル]−3,3−ジメチルブタン−1−オンの調製
指数的に増殖するHT29細胞を、黒色96ウェルプレートの10%FBS含有培地に、5,000細胞数/ウェルで一晩平板培養した。その翌日、DharmaFECT 4試薬を用いて、細胞を4つのmet特異21−ヌクレオチドRNAオリゴヌクレオチドのプールで2日間一時的にトランスフェクトし、組み合わされた2−ヌクレオチド3’オーバーハングを有する19−bp二重鎖コアを形成した(Dharmacon,Inc.、Lafayette、CO)。対照として、同じ条件下でのgapdh siRNA(Dharmacon,Inc.)および非標的siRNAのトランスフェクションを並行して行った(Dharmacon,Inc.)。次に、濃度を次第に高めた不可逆的カスパーゼ阻害剤ZvAD−FMKの非存在下または存在下で、細胞をさらに1日インキュベートした。2μg/ml Hoescht 33342(青色チャネル、Molecular Probes/Invitrogen Corp.、Natick、MA)、500倍希釈のAnnexin V−Fluos(緑色チャネル、Roche Applied Science、Indianapolis、IN)および1μg/mlヨウ化プロピジウム(赤色チャネル、Roche Applied Science)を含む標識化溶液(10mM HEPES、140mM NaClおよび6mM CaCl2)で、少なくとも10分間細胞をインキュベートした。高含量画像獲得および分析を、Beckman Coulter IC100血球計算器を用いて実施した。プログラムは、1ウェルにつき4画像をとるように設定した。曝露時間は、DAPI、FITCおよびローダミンチャネルのために、それぞれ16.7ms/10%増、500ms/35%増および300ms/30%増に設定した。画像を処理し、各チャネルおよび各条件に陽性の細胞数を、Cytoshop 2.1ソフトウェア(Beckman Coulter,Inc.)を用いて判定した。対照(gapdhおよび非標的siRNAによってトランスフェクトされた細胞)と比較して、Annexin V−Fluosによって陽性に染色された細胞の割合によって判定された細胞死の増加量が、met siRNAでトランスフェクトされたHT29細胞で観察された。さらに、濃度を増加させたZvAD−FMKの存在は細胞死のレベルを低下させ、それは、c−MetノックダウンがHT29細胞でカスパーゼ依存性アポトーシスを誘導することを示す。さらに、これらのデータは、HT29細胞が、それらの生存のためにc−Met経路に少なくとも部分的に依存し、したがって、c−Met阻害化合物について試験するための良好なモデルであることを示す。例えば図1Aを参照。
c−Met 33Pアッセイ
Origen Technologiesから購入した完全長c−MetのcDNAを、PCR増幅のための鋳型として用いた。キナーゼドメイン(1038〜1346)をコードするDNA断片を、Novagenベクターpet28aのNcoIおよびSalIの部位の間に挿入した。プライマーは、N末端に6−ヒスチジンタグを含むように設計した。脱リン酸化c−Metキナーゼタンパク質を発現させるために、チロシンホスファターゼPTP1B(1−283)を、作製した構築物のSalIおよびNotIの部位の間に逐次的に連結した。第2のリボソーム結合部位を、SalI部位の後のPTP1Bプライマーに組み込んだ。N末端His標識タンパク質を、Circlegrow培養液(Q−Biogen)中に発現させた。形質転換E. Coli細胞系BL21(DE3)RIL(Stratagene)を、37℃でOD=0.8まで培養し、12℃で一晩、0.3mMのIPTGで誘導した。同時発現したタンパク質を金属キレート化クロマトグラフィーで、続いてアニオンおよびカチオンカラムで精製した。簡潔には、20mM MOPS pH=6.5、200mM NaCl、7.5%グリセロール、0.1%Igepalを含み、1mM PMSFを補給した140mlの緩衝液での超音波処理によって、4リットルの細胞を溶解した。50,000gで30分間の遠心分離によって上清を得、それを、4℃で1時間、8mLのNi−NTA His結合樹脂(Novagen)とインキュベートした。溶解緩衝液による最初の洗浄の後、第2段階の50mL洗浄緩衝液(100mM NaClおよび5mMイミダゾールで)を加えた。200mMイミダゾールpH=8.5、100mM NaClおよび7.5%グリセロールによってタンパク質を溶出させ、10mL QFFカラムを通させることによって直ちに清澄化した。希釈によってタンパク質フロースルーの塩濃度およびpH値を50mMおよび7.5に調節し、次に、1mL SP FFカラムに加えた。20mMトリスHCl pH=8.5、150mM NaCl、7.5%グリセロールおよび2mM DTTの平衡緩衝液で、タンパク質をさらにゲルろ過した。−80℃での保存のために、単量体非リン酸化c−Metタンパク質を30mg/mLまで濃縮した。
MTSアッセイ
HT29細胞を、96ウェルプレートの10%FBS含有培地に、1,800細胞数/ウェルで一晩播種した。その翌日、37℃で24時間、濃度を次第に高めた化合物で細胞を処理した。処理の後、化合物含有培地を除去し、細胞をPBSで2回洗浄し、10%FBSを含有する無薬剤培地でさらなる48時間インキュベートした。それぞれ2mg/mLおよび0.92mg/mLの濃度のMTSおよびPMSの4時間の添加の後、結果をλ=490nmでの分光測光によって数量化し、各化合物のIC50値を判定した。
Claims (33)
- 式I、II、IIIもしくはIVの化合物または薬学的に許容されるその塩
R1、R2およびR3は、H、F、Cl、Br、I、−NR7R8、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、−O−(C1〜C6)アルキル、−O−(C3〜C9)シクロアルキルおよび−O−(C3〜C9)置換シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立に選択され、
R4は、H、−(C1〜C4)アルキルおよび−(C1〜C4)置換アルキルからなる群から選択され、
R5は、H、−(C1〜C6)アルキル、−CH2R6、−CONHR9、−COR10および−SO2R11からなる群から選択され、
R6は、−O−P(=O)(OH)2、−O−P(=O)(−OH)(−O−(C1〜C6)アルキル)、−O−P(=O)(−O−(C1〜C6)アルキル)2、−O−P(=O)(−OH)(−O−(CH2)−フェニル)、−O−P(=O)(−O−(CH2)−フェニル)2、カルボン酸基、アミノカルボン酸基およびペプチドからなる群から選択され、
R7およびR8は、Hおよび−(C1〜C6)アルキルからなる群から独立に選択され、
R9、R10およびR11は、H、NHR12、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、アリール、ヘテロアリールおよびヘテロシクリルからなる群から独立に選択され、
Qは、インドリル、置換インドリル、アリール、ヘテロアリール、ヘテロシクリルおよびアルキルからなる群から独立に選択され、
VおよびZは、O、S、H2からなる群から独立に選択され、VとZがどちらもOである場合、R4は、−(C1〜C4)アルキルまたは−(C1〜C4)置換アルキルであり、ZとVがどちらもH2でない場合、R5は、H、−(C1〜C6)アルキルまたは−CH2R6であり、
Xは、−CH2−、−NR12、S、O、および結合からなる群から選択され、
R12は、H、−(C1〜C6)アルキル、−(C1〜C6)置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)置換シクロアルキル、−O−(C1〜C6)アルキル、−C(=O)−O−(C1〜C6)アルキルおよび−C(=O)−O−(C1〜C6)置換アルキルからなる群から選択され、
Wは、−CH2−、CO、および結合からなる群から選択され、
mは0、1または2である)。 - Qが、インドリル基、あるいは、F、Cl、Br、I、−(C1〜C6)アルキル、−(C1〜C6)フルオロ−置換アルキル、−(C3〜C9)シクロアルキル、−(C3〜C9)フルオロ−置換シクロアルキル、−O−(C1〜C6)アルキル、−O−(C1〜C6)フルオロ−置換アルキル、−O−(C3〜C9)シクロアルキルおよび−O−(C3〜C9)フルオロ−置換シクロアルキル、−アリール、−O−アリール、−O−(C1〜C4)アルキル−アリール、−O−(C1〜C4)アルキル−複素環ならびに−S(=O)2−(C1〜C6)アルキルからなる群から独立に選択される1つまたは複数の置換基で置換されたインドリル基である、請求項1に記載の化合物。
- VがOである、請求項1に記載の化合物。
- ZがOであり、そしてR4が−(C1〜C4)アルキルまたは−(C1〜C4)置換アルキルである、請求項3に記載の化合物。
- ZがSまたはH2である、請求項3に記載の化合物。
- VがSである、請求項1に記載の化合物。
- ZがOまたはH2である、請求項6に記載の化合物。
- VがH2である、請求項1に記載の化合物。
- ZがO、SまたはH2である、請求項8に記載の化合物。
- Wが−CH2−である、請求項1に記載の化合物。
- mが1である、請求項10に記載の化合物。
- Xが結合である、請求項11に記載の化合物。
- R5はHである、請求項1に記載の化合物。
- 4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−3−(1H−インドール−3−イル)−ピロリジン−2−オン、(3R,4R)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−3−(1H−インドール−3−イル)−ピロリジン−2−オン、(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−2−オン、(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−2−オン、(3R,4R)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−3−(1H−インドール−3−イル)−5−チオキソ−ピロリジン−2−オン、(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−5−チオキソ−ピロリジン−2−オン、1−[(3R,4R)−4−(1H−インドール−3−イル)−ピロリジン−3−イル]−5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン、(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−1−カルボン酸エチルアミド、1−[(3R,4R)−4−(1H−インドール−3−イル)−1−(プロパン−2−スルホニル)−ピロリジン−3−イル]−5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン、およびシクロブチル−[(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−1−イル]−メタノン、(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(3−トリフルオロメチル−フェニル)−ピロリジン−2−オン、(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(3−メトキシ−フェニル)−ピロリジン−2−オン、1−[(3R,4R)−1−ベンゼンスルホニル−4−(1H−インドール−3−イル)−ピロリジン−3−イル]−5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン、および1−[(3R,4R)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−1−イル]−3,3−ジメチル−ブタン−1−オンからなる群から独立に選択される、請求項1に記載の化合物。
- 請求項1に記載の式I、II、IIIもしくはIVの化合物、または薬学的に許容されるその塩を、1つもしくは複数の薬学的に許容される担体または賦形剤と合わせて含む、医薬組成物。
- 第2の化学療法剤をさらに含む、請求項15に記載の医薬組成物。
- 前記第2の化学療法剤が、タモキシフェン、ラロキシフェン、アナストロゾール、エキセメスタン、レトロゾール、トラスツズマブ、イマチニブ、パクリタキセル、シクロホスファミド、ロバスタチン、ミノシン、ゲムシタビン、araC、5−フルオロウラシル、メトトレキサート、ドセタキセル、ゴセレリン、ビンクリスチン、ビンブラスチン、ノコダゾール、テニポシド、エトポシド、ゲムシタビン、エポチロン、ナベルビン、カンプトテシン、ダウノルビシン、ダクチノマイシン、ミトキサントロン、アムサクリン、ドキソルビシン、エピルビシンおよびイダルビシンからなる群から選択される、請求項16に記載の医薬組成物。
- 細胞増殖性障害を治療する方法であって、該治療を必要とする対象に、治療有効量の請求項1に記載の式I、II、III、IVの化合物、あるいは薬学的に許容されるその塩、またはそのプロドラッグもしくは代謝産物を、薬学的に許容される担体と組み合わせて投与することを含み、該細胞増殖性障害が治療される方法。
- 前記細胞増殖性障害が前癌状態である、請求項18に記載の方法。
- 前記細胞増殖性障害が癌である、請求項18に記載の方法。
- 前記癌が、肺癌、結腸癌、乳癌、膵臓癌、前立腺癌、慢性骨髄性白血病、黒色腫または卵巣癌である、請求項20に記載の方法。
- 前記細胞増殖性障害が乳房の細胞増殖性障害である、請求項18に記載の方法。
- 前記乳房の細胞増殖性障害が乳房の前癌状態である、請求項22に記載の方法。
- 前記乳房の前癌状態が、乳房の非定型過形成、腺管上皮内癌および上皮内小葉癌からなる群から選択される、請求項23に記載の方法。
- 前記乳房の細胞増殖性障害が乳癌である、請求項22に記載の方法。
- 前記乳癌がエストロゲン受容体陰性乳癌である、請求項25に記載の方法。
- 前記式I、II、III、IVの化合物、あるいは薬学的に許容されるその塩、またはそのプロドラッグもしくは代謝産物を、第2の化学療法剤と組み合わせて投与する、請求項18に記載の方法。
- 前記第2の化学療法剤が、タモキシフェン、ラロキシフェン、アナストロゾール、エキセメスタン、レトロゾール、トラスツズマブ、イマチニブ、パクリタキセル、シクロホスファミド、ロバスタチン、ミノシン、ゲムシタビン、araC、5−フルオロウラシル、メトトレキサート、ドセタキセル、ゴセレリン、ビンクリスチン、ビンブラスチン、ノコダゾール、テニポシド、エトポシド、ゲムシタビン、エポチロン、ナベルビン、カンプトテシン、ダウノルビシン、ダクチノマイシン、ミトキサントロン、アムサクリン、ドキソルビシン、エピルビシンまたはイダルビシンからなる群から選択される、請求項27に記載の方法。
- 前記癌治療が腫瘍サイズの縮小を含む、請求項18に記載の方法。
- 前記癌が転移性癌である、請求項20に記載の方法。
- 前記癌治療が転移性癌細胞浸潤の阻害を含む、請求項30に記載の方法。
- 増殖性障害を有する細胞がc−MetをコードするDNAを含む、請求項18に記載の方法。
- 前記細胞が構成的に高められたc−Met活性を有する、請求項32に記載の方法。
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US20100178291A1 (en) | 2010-07-15 |
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EP2170870A1 (en) | 2010-04-07 |
US8304425B2 (en) | 2012-11-06 |
WO2009002806A1 (en) | 2008-12-31 |
TWI409069B (zh) | 2013-09-21 |
CA2690799A1 (en) | 2008-12-31 |
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