JP5490688B2 - 癌の治療のためのインドリルピロリジン - Google Patents
癌の治療のためのインドリルピロリジン Download PDFInfo
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- JP5490688B2 JP5490688B2 JP2010513422A JP2010513422A JP5490688B2 JP 5490688 B2 JP5490688 B2 JP 5490688B2 JP 2010513422 A JP2010513422 A JP 2010513422A JP 2010513422 A JP2010513422 A JP 2010513422A JP 5490688 B2 JP5490688 B2 JP 5490688B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
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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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
本願は、2007年6月22日に出願された米国仮特許出願第60/945,820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。
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、R7およびR8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独立に選択され、
R5は、H、−(C1〜C6)アルキルおよび−CH2R6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、
R9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、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選択され、
Qは、アリール、ヘテロアリール、ヘテロシクリル、アルキル、置換アリール、置換ヘテロアリール、置換ヘテロシクリルおよび置換アルキルからなる群から選択され、
Tは−CH2−、−C(O)−または結合であり、Tが結合であり、Yが結合であり、Wが結合であり、Xが−CH2−であり、m=1である場合、n=1であり、
VおよびZは、O、SおよびH2からなる群から独立に選択され、
Xは、−CH2−、−NR8、S、O、および結合からなる群から独立に選択され、
YおよびWは独立に−CH2−または結合であり、
mは1または2であり、
nは1または2であり、
ただし、XとYとWがすべて結合であることはない。
本発明は、例えば以下の項目を提供する。
(項目1)
式Ia、Ib、IIaまたはIIbの化合物もしくは薬学的に許容されるその塩:
(式中、Uは、
から独立に選択され、
R1、R2およびR3は、H、F、Cl、Br、I、−NR7R8、−(C 1 〜C 6 )アルキル、−(C 1 〜C 6 )置換アルキル、−(C 3 〜C 9 )シクロアルキル、−(C 3 〜C 9 )置換シクロアルキル、−O−(C 1 〜C 6 )アルキル、−O−(C 3 〜C 9 )シクロアルキルおよび−O−(C 3 〜C 9 )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、R7およびR8は、H、−(C 1 〜C 4 )アルキルおよび−(C 1 〜C 4 )置換アルキルからなる群から独立に選択され、
R5は、H、−(C 1 〜C 6 )アルキルおよび−CH 2 R6からなる群から選択され、
R6は、−O−P(=O)(OH) 2 、−O−P(=O)(−OH)(−O−(C 1 〜C 6 )アルキル)、−O−P(=O)(−O−(C 1 〜C 6 )アルキル) 2 、−O−P(=O)(−OH)(−O−(CH 2 )−フェニル)、−O−P(=O)(−O−(CH 2 )−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、
R9は、H、−(C 1 〜C 6 )アルキル、−(C 1 〜C 6 )置換アルキル、−(C 3 〜C 9 )シクロアルキル、−(C 3 〜C 9 )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選択され、
Qは、アリール、ヘテロアリール、ヘテロシクリル、アルキル、置換アリール、置換ヘテロアリール、置換ヘテロシクリルおよび置換アルキルからなる群から選択され、
Tは−CH 2 −、−C(O)−または結合であり、Tが結合であり、Yが結合であり、Wが結合であり、Xが−CH 2 −であり、m=1である場合、n=1であり、
VおよびZは、O、SおよびH 2 からなる群から独立に選択され、
Xは、−CH 2 −、−NR8、S、O、および結合からなる群から独立に選択され、
YおよびWは独立に−CH 2 −または結合であり、
mは1または2であり、
nは1または2であり、
ただし、XとYとWがすべて結合であることはない)。
(項目2)
Qはインドリル基、あるいはF、Cl、Br、I、−(C 1 〜C 6 )アルキル、−(C 1 〜C 6 )フルオロ−置換アルキル、−(C 3 〜C 9 )シクロアルキル、−(C 3 〜C 9 )フルオロ−置換シクロアルキル、−O−(C 1 〜C 6 )アルキル、−O−(C 1 〜C 6 )フルオロ−置換アルキル、−O−(C 3 〜C 9 )シクロアルキルおよび−O−(C 3 〜C 9 )フルオロ−置換シクロアルキル、−アリール、−O−アリール、−O−(C 1 〜C 4 )アルキル−アリール、−O−(C 1 〜C 4 )アルキル−複素環および−S(=O) 2 −(C 1 〜C 6 )アルキルからなる群から独立に選択される一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、項目1に記載の化合物。
(項目3)
Qが、2−クロロフェニルまたは3−メトキシフェニルである、項目1に記載の化合物。
(項目4)
VおよびZがOである、項目1に記載の化合物。
(項目5)
R5がHである、項目1に記載の化合物。
(項目6)
Xが、−(NR8)−、S、およびOから選択される、項目1に記載の化合物。
(項目7)
Xが−CH 2 −である、項目1に記載の化合物。
(項目8)
Yが結合である、項目7に記載の化合物。
(項目9)
mが2である、項目8に記載の化合物。
(項目10)
Wが−CH 2 −である、項目9に記載の化合物。
(項目11)
nが1である、項目10に記載の化合物。
(項目12)
Uが、
である、項目1に記載の化合物。
(項目13)
Tが−CH 2 −である、項目6に記載の化合物。
(項目14)
Tが−C(O)−である、項目6に記載の化合物。
(項目15)
Uが、
である、項目6に記載の化合物。
(項目16)
Uが、
である、項目1に記載の化合物。
(項目17)
(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イルメチル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオン、(±)−シス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−カルボニル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオン、(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオン、(±)−トランス−3−(5−ブロモ−1H−インドール−3−イル)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロリジン−2,5−ジオン、(±)−トランス−3−(2−クロロ−フェニル)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロリジン−2,5−ジオン、(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−4−(3−メトキシ−フェニル)−ピロリジン−2,5−ジオンおよび(±)−トランス−3−(4,5−ジヒドロ−ピロロ[3,2,1−hi]インドール−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオンからなる群から選択される、項目1に記載の化合物。
(項目18)
項目1に記載の式Ia、Ib、IIaまたはIIbの化合物または薬学的に許容されるその塩を、一つまたは複数の薬学的に許容される担体または賦形剤と組み合わせて含む、医薬組成物。
(項目19)
第2の化学療法剤をさらに含む、項目18に記載の医薬組成物。
(項目20)
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、項目19に記載の医薬組成物。
(項目21)
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、治療有効量の項目1に記載の式Ia、Ib、IIaまたはIIb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。
(項目22)
前記細胞増殖性障害が前癌状態である、項目21に記載の方法。
(項目23)
前記細胞増殖性障害が癌である、項目21に記載の方法。
(項目24)
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、項目21に記載の方法。
(項目25)
前記式Ia、Ib、IIaまたはIIb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の化学療法剤と合わせて投与する、項目21に記載の方法。
(項目26)
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、項目25に記載の方法。
(項目27)
前記癌治療が腫瘍サイズの縮小を含む、項目21に記載の方法。
(項目28)
前記癌が転移性癌である、項目21に記載の方法。
(項目29)
前記癌の治療が転移性癌細胞浸潤の阻害を含む、項目28に記載の方法。
(項目30)
前記増殖性障害を有する細胞がc−MetをコードするDNAを含む、項目21に記載の方法。
(項目31)
前記細胞が構成的に高められたc−Met活性を有する、項目30に記載の方法。
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、R7およびR8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独立に選択され、
R5は、H、−(C1〜C6)アルキルおよび−CH2R6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、
R9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、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選択され、
Qは、アリール、ヘテロアリール、ヘテロシクリル、アルキル、置換アリール、置換ヘテロアリール、置換ヘテロシクリルおよび置換アルキルからなる群から選択され、
Tは−CH2−、−C(O)−または結合であり、Tが結合であり、Yが結合であり、Wが結合であり、Xが−CH2−であり、m=1である場合、n=1であり、
VおよびZは、O、SおよびH2からなる群から独立に選択され、
Xは、−CH2−、−NR8、S、O、および結合からなる群から独立に選択され、
YおよびWは独立に−CH2−または結合であり、
mは1または2であり、
nは1または2であり、
ただし、XとYとWがすべて結合であることはない。
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。
本発明は、式IAa、IBb、IIAaまたはIIBbのピロリジン−2,5−ジオン化合物を提供する。式IAa、IBb、IIAaおよびIIBbの化合物の調製は、スキーム1〜5に示すように、式IV、VII、IXまたはXIIIのオキソ酢酸エステルと、式III、VIまたはXIのアミドを反応させて式V、VIII、X、XIIまたはXIVのピロール−2,5−ジオンを生成させ、続いて、式IAa、IBb、IIAaまたはIIBbのピロリジン−2,5−ジオン化合物へと還元する一連の反応で実施することができる。
式V、VIII、X、XIIおよびXIVの化合物を生成するための式IV、VII、IXまたはXIIIのオキソ酢酸エステルと式III、VIまたはXIの化合物の縮合は、これらに限定されないが、テトラヒドロフラン(THF)、テトラヒドロピラン、ジエチルエーテルなどの適切な任意の無水溶媒中、塩基の存在下で実施する。この反応のための適切な式IV、VII、IXまたはXIIIのオキソ酢酸エステルには、これらに限定されないが、R10が(C1〜C4)アルキル基であるアルキルエステルで含まれ、好ましいエステルには、メチルおよびエチルエステルが含まれる。この反応のための適切な塩基には、これらに限定されないが、メタノール、エタノール、プロパノール、イソプロパノール、n−ブタノール、イソブタノールおよびtert−ブタノールのアルカリ金属塩を含む低分子量アルキルアルコールのアルカリ金属塩が含まれる。低分子量アルキルアルコールの好ましいアルカリ金属塩には、ナトリウムおよびカリウム塩が含まれ、カリウムtert−ブトキシド(t−BuOK)が好ましい塩基である。一般的には反応は0℃で2時間実施するが、時間と温度はどちらも、式III、IV、VI、VII、IX、XIおよびVIIIの化合物の具体的な置換基、ならびに使用する溶媒に応じて変えることができる。反応温度は−78℃〜37℃、好ましくは−35℃〜25℃、より好ましくは−15℃〜10℃で変えることができる。反応時間は一般に、使用する温度に逆比例して変えることになり、約15分間〜24時間、より好ましくは30分間〜12時間、より好ましくは1〜6時間の適切な時間を用いることができる。
式IAa、IBb、IIAaまたはIIBbを有する対応するピロリジン−2,5−ジオンを得るための式V、VIII、X、XIIおよびXIVの化合物の還元は、これらに限定されないが、触媒的水素化を用いた還元(手順B)、およびメタノール中のマグネシウムを用いた還元(手順A)を含む様々な手順で実施することができる。スキーム1に示すように、選択した還元反応および条件に応じて、反応は、主に式IAaおよびIBbの化合物、または主に式IIAaおよびIIBbの化合物を生成する。
式IAa、IBb、IIAaおよびIIBb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IAa、IBb、IIAaおよびIIBb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。
式V、VIII、X、XIIおよびXIVのピロール−2,5−ジオンの合成で使用する式VIおよびVIIの化合物は購入するか、または、以下に示すものなどの様々な合成経路によって得ることができる。
式VIIの化合物は、式Aの対応化合物(ただし、Xは、−(CH2)−、−(NR6)−、SおよびOからなる群から選択され、R8は、水素、−(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および−O−(C1〜C6)アルキルからなる群から選択され、mは1または2である)から調製することができる。式Aの化合物の例には、1,2,3,4−テトラヒドロキノリン、1,2,3,4−テトラヒドロ−キノキサリン、3,4−ジヒドロ−2H−ベンゾ[1,4]オキサジン、3,4−ジヒドロ−2H−ベンゾ[1,4]チアジン、2,3,4,5−テトラヒドロ−1H−ベンゾ[b]アゼピン、2,3,4,5−テトラヒドロ−1H−ベンゾ[b][1,4]ジアゼピン、6,7,8,9−テトラヒドロ−5−オキサ−9−アザ−ベンゾシクロヘプテンまたは2,3,4,5−テトラヒドロ−ベンゾ[b][1,4]チアゼピン)が含まれる。その調製は、式Aの化合物を式Bの対応する3−置換−2−オキソプロピオン酸エチルエステルに転換させることから始まる。式Bのエチルエステルを環化して式Cの化合物を生成させ、これを遊離酸Dに転換させ、次いで脱炭酸して所望の三環型の生成物Eを得る。続いて三環型の生成物Eを塩化オキサリルと反応させ、アルコール性塩基で後処理して対応する式VIIの化合物を得る。スキーム6に、式Aの化合物から出発する一連の反応を示す。
スキーム6
置換アセトアミドである式VIの化合物は購入するか、または、市販されている出発原料から調製することができる。2−(1H−インドール−3−イル)−アセトアミド、2−(5−メチル−1H−インドール−3−イル)アセトアミド、2−(5−メトキシ−1H−インドール−3−イル)アセトアミド、2−(4−ヒドロキシ−1H−インドール−3−イル)アセトアミド、2−フェニルアセトアミド、2−(4−メチルフェニル)アセトアミド、4−ヒドロキシフェニルアセトアミド、4−ヒドロキシフェニルアセトアミド、N−シクロペンチル−2−(4−ヒドロキシ−2−オキソ−1,2−ジヒドロ−3−キノリニル)アセトアミド、2−フェノキシアセトアミド、2−(2−メチルフェノキシ)アセトアミド、2−(4−フルオロフェノキシ)アセトアミド、2−(4−ピリジニル)アセトアミドおよび2−[(4−クロロフェニル)スルファニル]アセトアミドを含む市販のアセトアミドは、Sigma Aldrich Chemical Co.、St.Louis Moを含む様々な供給業者から入手することができる。式VIの化合物は、対応する遊離酸から、遊離酸をその酸クロリドに転換し、続いて、アンモニアと反応させることによって調製することもできる。
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。
3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−3−オキソ−プロピオニトリルの調製
(E)−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−アクリロニトリルの調製
3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−プロピオニトリルの調製
3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−プロピオンアミドの調製
3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イルメチル)−4−(1H−インドール−3−イル)−ピロール−2,5−ジオンの調製
手順A:メタノール中でのマグネシウムによる3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イルメチル)−4−(1H−インドール−3−イル)−ピロール−2,5−ジオンの還元
3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イル)−3−オキソ−プロピオンアミドの調製
3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−カルボニル)−4−(1H−インドール−3−イル)−ピロール−2,5−ジオンの調製
手順B:パラジウム炭素の存在下での水素による3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−カルボニル)−4−(1H−インドール−3−イル)−ピロール−2,5−ジオンの還元
1,2,5,6−テトラヒドロ−4H−ピロロ[3,2,1−ij]キノリンの調製
8−ブロモ−1,2,5,6−テトラヒドロ−4H−ピロロ[3,2,1−ij]キノリンの調製
オキソ−(1,2,5,6−テトラヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−酢酸メチルエステルの調製
3−(1H−インドール−3−イル)−4−(1,2,5,6−テトラヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロール−2,5−ジオンの調製
3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−4−(1H−インドール−3−イル)−ピロール−2,5−ジオンの調製
(±)−シス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオンの調製
(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオンの調製
3−(5−ブロモ−1H−インドール−3−イル)−4−(1,2,5,6−テトラヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロール−2,5−ジオンの調製
3−(5−ブロモ−1H−インドール−3−イル)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロール−2,5−ジオンの調製
(±)−トランス−3−(5−ブロモ−1H−インドール−3−イル)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロリジン−2,5−ジオンの調製
3−(2−クロロ−フェニル)−4−(1,2,5,6−テトラヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロール−2,5−ジオンの調製
3−(2−クロロ−フェニル)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロール−2,5−ジオンの調製
(±)−トランス−3−(2−クロロ−フェニル)−4−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロリジン−2,5−ジオンの調製
3−(3−メトキシ−フェニル)−4−(1,2,5,6−テトラヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−ピロール−2,5−ジオンの調製
3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−4−(3−メトキシ−フェニル)−ピロール−2,5−ジオンの調製
(±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−8−イル)−4−(3−メトキシ−フェニル)−ピロリジン−2,5−ジオンの調製
1−ニトロソ−2,3−ジヒドロ−1H−インドールの調製
2,3−ジヒドロ−インドール−1−イルアミンの調製
4,5−ジヒドロ−ピロロ[3,2,1−hi]インドール−2−カルボン酸エチルエステルの調製
4,5−ジヒドロ−ピロロ[3,2,1−hi]インドール−2−カルボン酸の調製
1,2−ジヒドロ−ピロロ[3,2,1−hi]インドールの調製
(4,5−ジヒドロ−ピロロ[3,2,1−hi]インドール−1−イル)−オキソ−酢酸メチルエステルの調製
3−(4,5−ジヒドロ−ピロロ[3,2,1−hi]インドール−1−イル)−4−(1H−インドール−3−イル)−ピロール−2,5−ジオンの調製
(±)−トランス−3−(4,5−ジヒドロ−ピロロ[3,2,1−hi]インドール−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオンの調製
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 Hoechst 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。
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 (27)
- 式Ia、Ib、IIaまたはIIbの化合物もしく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、R7およびR8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独立に選択され、
R5は、H、−(C1〜C6)アルキルおよび−CH2R6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、
Qは、アリール、ヘテロアリール、ヘテロシクリル、アルキル、置換アリール、置換ヘテロアリール、置換ヘテロシクリルおよび置換アルキルからなる群から選択され、
Tは−CH2−、−C(O)−または結合であり、ただしTが結合である場合、Yが結合であり、Wが結合であり、Xが−CH2−であり、m=1であり、かつn=1であり、
VおよびZは、O、SおよびH2からなる群から独立に選択され、
Xは、−CH2−または結合であり、
YおよびWは独立に−CH2−または結合であり、
mは1または2であり、
nは1または2であり、
ただし、XとYとWがすべて結合であることはない)。 - Qはインドリル基、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−複素環および−S(=O)2−(C1〜C6)アルキルからなる群から独立に選択される一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に記載の化合物または薬学的に許容されるその塩。
- Qが、2−クロロフェニルおよび3−メトキシフェニルからなる群から選択される、請求項1に記載の化合物または薬学的に許容されるその塩。
- VおよびZの両方がOである、請求項1に記載の化合物または薬学的に許容されるその塩。
- R5がHである、請求項1に記載の化合物または薬学的に許容されるその塩。
- Xが−CH2−である、請求項1に記載の化合物または薬学的に許容されるその塩。
- Yが結合である、請求項6に記載の化合物または薬学的に許容されるその塩。
- mが2である、請求項7に記載の化合物または薬学的に許容されるその塩。
- Wが−CH2−である、請求項8に記載の化合物または薬学的に許容されるその塩。
- nが1である、請求項9に記載の化合物または薬学的に許容されるその塩。
- Tが−C(O)−である、請求項1に記載の化合物または薬学的に許容されるその塩。
- Uが、
- (±)−トランス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−イルメチル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオン、(±)−シス−3−(5,6−ジヒドロ−4H−ピロロ[3,2,1−ij]キノリン−1−カルボニル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオン、および(±)−トランス−3−(4,5−ジヒドロ−ピロロ[3,2,1−hi]インドール−1−イル)−4−(1H−インドール−3−イル)−ピロリジン−2,5−ジオンからなる群から選択される、請求項1に記載の化合物または薬学的に許容されるその塩。
- 請求項13に記載の化合物または薬学的に許容されるその塩を、一つまたは複数の薬学的に許容される担体または賦形剤と組み合わせて含む、医薬組成物。
- 第2の化学療法剤をさらに含む、請求項14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、エピルビシンまたはイダルビシンからなる群から選択される、請求項15に記載の医薬組成物。
- 細胞増殖性障害を治療するための組成物であって、治療有効量の請求項13に記載の化合物、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含む、組成物。
- 前記細胞増殖性障害が前癌状態である、請求項17に記載の組成物。
- 前記細胞増殖性障害が癌である、請求項17に記載の組成物。
- 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17に記載の組成物。
- 第2の化学療法剤と組み合わせて投与されることを特徴とする、請求項17に記載の組成物。
- 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、エピルビシンまたはイダルビシンからなる群から選択される、請求項21に記載の組成物。 - 前記癌治療が腫瘍サイズの縮小を含む、請求項17に記載の組成物。
- 前記癌が転移性癌である、請求項17に記載の組成物。
- 前記癌の治療が転移性癌細胞浸潤の阻害を含む、請求項24に記載の組成物。
- 前記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17に記載の組成物。
- 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26に記載の組成物。
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