JP6126613B2 - アミノキナゾリン誘導体及びそれらの塩並びに使用方法 - Google Patents
アミノキナゾリン誘導体及びそれらの塩並びに使用方法 Download PDFInfo
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- JP6126613B2 JP6126613B2 JP2014540291A JP2014540291A JP6126613B2 JP 6126613 B2 JP6126613 B2 JP 6126613B2 JP 2014540291 A JP2014540291 A JP 2014540291A JP 2014540291 A JP2014540291 A JP 2014540291A JP 6126613 B2 JP6126613 B2 JP 6126613B2
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- 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
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Description
本出願は、2011年11月14日に出願された、中国特許出願第201110359739.8号の利益を主張するものであり、この出願はその全体が引用により本明細書中に組み込まれている。
哺乳動物において、癌などの過増殖性疾患の治療に有用である、新規アミノキナゾリン誘導体及びそれらの塩が、本明細書において提供される。特に本発明は、タンパク質チロシンキナーゼの活性を阻害し、その結果細胞内又は細胞間のシグナル伝達の阻害を生じる化合物に関する。哺乳動物における過増殖性疾患、特にヒトの過増殖性疾患の治療において、化合物、又は該化合物を含有する医薬組成物を使用する方法も、本明細書において提供される。
プロテインキナーゼは、細胞機能に対する制御を維持する、多種多様な細胞プロセスの調節において重要な役割を果たすタンパク質の大きなファミリーを表している。タンパク質チロシンキナーゼは、成長因子受容体型キナーゼ(例えば、VEGFR、EGFR、PDGFR、FGFR及びerbB2)又は非受容体型キナーゼ(例えば、c-src及びbcr-abl)として分類することができる。受容体型チロシンキナーゼは、約20種の異なるサブファミリーを作製する。非受容体型チロシンキナーゼは、非常に多くのサブファミリーを作製する。受容体型チロシンキナーゼは、細胞膜にまたがる大きい酵素であり、且つ成長因子のための細胞外結合ドメイン、膜貫通ドメイン、及びタンパク質内の特異的チロシン残基をリン酸化するキナーゼとして機能し、結果的に細胞増殖に影響を及ぼす細胞内領域を持つ。異常な又は不適切なプロテインキナーゼ活性は、そのような異常なキナーゼ活性に関連した病態の発生の原因となり得る。
新規アミノキナゾリン化合物及び細胞増殖性疾患の治療方法が、本明細書において提供される。本明細書に開示された化合物は、タンパク質チロシンキナーゼ活性の阻害において有用である。要求を満たすように、本明細書に開示された化合物は、例えばEGFRシグナル伝達などを阻害することが可能である、複数の機能阻害剤である。
Rbは、アルキル又はHであり;
Rcは、H、アルキル、ハロアルキル、エーテルアルキル(ether alkyl)、ヘテロアルキル、シクロアルキル、ヘテロシクリルアルキル、アリール、アラルキル、ヘテロアリール又はヘテロアリールアルキルであり;
X1及びX2の各々は、独立して、S、O、CH2又はNHであり;
Aは、-(CH2)q-X4-(CH2)k-又は-(CH2)q-であり;
B及びEの各々は、独立して、結合又はCH2であり;
X3は、N、C、CH又はCRxであり;
X4は、O、S又はNHであり;
Rdは、同じ又は異なることができ、且つRdの各々は、独立して、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、オキソ、エーテルアルキル、H、F、Cl、Br、I、ヒドロキシ、メルカプト、アミノ、ニトロ、カルボキシ、シアノ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アミノスルホニル、カルバモイル、アリールアミノ、ヘテロアリールアミノ、アリールアルキルアミノ、ヘテロアリールアルキルアミノ、ヘテロシクリルアミノ、ヘテロシクリルアルキルアミノ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシであり;
Rxは、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、エーテルアルキル、F、Cl、Br、I、ヒドロキシ、メルカプト、アミノ、ニトロ、カルボキシ、シアノ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アミノスルホニル、カルバモイル、アリールアミノ、ヘテロアリールアミノ、アリールアルキルアミノ、ヘテロアリールアルキルアミノ、ヘテロシクリルアミノ、ヘテロシクリルアルキルアミノ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシであり;
n、m、i、j、k、p及びqの各々は、独立して、1、2、3、4又は5であり;
gの各々は、独立して、0、1又は2であり;
R1及びR2の各々は、独立して、H、アルキル、シクロアルキル、アラルキル、ヘテロアリールアルキル又はハロアルキルであり;並びに
ここで、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、エーテルアルキル、不飽和ヘテロシクリル、アミノ、カルボキシ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アミノスルホニル、カルバモイル、アリールアミノ、ヘテロアリールアミノ、アリールアルキルアミノ、ヘテロアリールアルキルアミノ、ヘテロシクリルアミノ、ヘテロシクリルアルキルアミノ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシの各々は、置換又は非置換であり、ここでその置換基は、ヒドロキシ、ヒドロキシアルキル、アミノ、ハロ、シアノ、オキソ、アリール、ヘテロアリール、アルコキシ、アルキル、ハロアルキル、アミノアルキル、アルケニル、アルキニル、ヘテロシクリル、メルカプト、ニトロ、アリールオキシ又はアラルキルである。
X8及びX9の各々は、独立して、N又はCHであり;
n、m、p、r及びsの各々は、独立して、1、2、3、4又は5であり;
Rd’は、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、エーテルアルキル、H、F、Cl、Br、I、ヒドロキシ、メルカプト、アミノ、ニトロ、カルボキシ、シアノ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アミノスルホニル、カルバモイル、アリールアミノ、ヘテロアリールアミノ、アリールアルキルアミノ、ヘテロアリールアルキルアミノ、ヘテロシクリルアミノ、ヘテロシクリルアルキルアミノ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシであり;
Ryは、CH=CHC(=O)NR1R2、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、エーテルアルキル、H、F、Cl、Br、I、ヒドロキシ、メルカプト、ニトロ、カルボキシ、シアノ、アルキル、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシであり;
Rdは、同じ又は異なることができ、且つRdの各々は、独立して、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、オキソ、エーテルアルキル、H、F、Cl、Br、I、ヒドロキシ、メルカプト、アミノ、ニトロ、カルボキシ、シアノ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル又はヘテロアリールアルキルであり;並びに
R1及びR2の各々は、独立して、H、アルキル、シクロアルキル、アラルキル、ヘテロアリールアルキル又はハロアルキルである。
i及びjの各々は、独立して、1、2、3、4又は5であり;並びに
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
i及びjの各々は、独立して、1、2、3、4又は5であり;
gの各々は、独立して、0、1又は2であり;並びに
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
R1は、H、メチル、エチル、プロピル、イソプロピル、ブチル又はペンチルである。
i及びjの各々は、独立して、1、2、3、4又は5であり;並びに
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
Dは、結合、メチレン又はエチレンであり;
Re及びRfの各々は、独立して、H、C1-6アルキル、C1-6アルキルアシル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルであり;並びに、
nは、1又は2である。
(定義及び一般的技術用語)
ここで、本明細書に開示されたある実施態様を詳細に説明し、その例は、付随する構造及び式に例示している。本発明は、請求項により規定されるような、本明細書に開示された範囲内に含まれ得る、全ての代替物、修飾物、及び同等物を対象とすることを意図している。当業者は、本明細書に開示された実践において使用することができる、本明細書に記載されたものと類似の又は同等の多くの方法及び材料を認識するであろう。本明細書に説明されたものは、方法及び材料をいかなる意味においても限定しない。組み込まれた文献、特許及び類似の材料の1種以上が、非限定的に、定義された用語、用語の利用、説明された技術などを含む本出願と異なるか又は矛盾する場合には、本出願が支配する。
プロテインキナーゼ、特にEGFRにより調節された、疾患、状態及び/又は障害の治療において有用な可能性がある、アミノキナゾリン化合物、及びそれらの医薬製剤が、本明細書において開示される。一態様において、式(I)の化合物、又はラセミ混合物、ジアステレオマー、エナンチオマー、幾何異性体、互変異性体、N-オキシド、水和物、溶媒和物、代謝産物、もしくはそれらの医薬として許容し得る塩が、本明細書において提供される:
一部の実施態様において、Raは、アリール、ヘテロアリール又は不飽和ヘテロシクリルであり;
Rbは、アルキル又はHであり;
Rcは、H、アルキル、ハロアルキル、エーテルアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクリルアルキル、アリール、アラルキル、ヘテロアリール又はヘテロアリールアルキルであり;
X1及びX2の各々は、独立して、S、O、CH2又はNHであり;
Aは、-(CH2)q-X4-(CH2)k-又は-(CH2)q-であり;
B及びEの各々は、独立して、結合又はCH2であり;
X3は、N、C、CH又はCRxであり;
X4は、O、S又はNHであり;
Rdは、同じ又は異なることができ、且つRdの各々は、独立して、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、オキソ、エーテルアルキル、H、F、Cl、Br、I、ヒドロキシ、メルカプト、アミノ、ニトロ、カルボキシ、シアノ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アミノスルホニル、カルバモイル、アリールアミノ、ヘテロアリールアミノ、アリールアルキルアミノ、ヘテロアリールアルキルアミノ、ヘテロシクリルアミノ、ヘテロシクリルアルキルアミノ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシであり;
Rxは、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、エーテルアルキル、F、Cl、Br、I、ヒドロキシ、メルカプト、アミノ、ニトロ、カルボキシ、シアノ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アミノスルホニル、カルバモイル、アリールアミノ、ヘテロアリールアミノ、アリールアルキルアミノ、ヘテロアリールアルキルアミノ、ヘテロシクリルアミノ、ヘテロシクリルアルキルアミノ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシであり;
n、m、i、j、k、p及びqの各々は、独立して、1、2、3、4又は5であり;
gの各々は、独立して、0、1又は2であり;並びに
R1及びR2の各々は、独立して、H、アルキル、シクロアルキル、アラルキル、ヘテロアリールアルキル又はハロアルキルであり;
ここで、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、エーテルアルキル、不飽和ヘテロシクリル、アミノ、カルボキシ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アミノスルホニル、カルバモイル、アリールアミノ、ヘテロアリールアミノ、アリールアルキルアミノ、ヘテロアリールアルキルアミノ、ヘテロシクリルアミノ、ヘテロシクリルアルキルアミノ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシの各々は、置換又は非置換であり、ここでその置換基は、ヒドロキシ、ヒドロキシアルキル、アミノ、ハロ、シアノ、オキソ、アリール、ヘテロアリール、アルコキシ、アルキル、ハロアルキル、アミノアルキル、アルケニル、アルキニル、ヘテロシクリル、メルカプト、ニトロ、アリールオキシ又はアラルキルである。
X8及びX9の各々は、独立して、N又はCHであり;
n、m、p、r及びsの各々は、独立して、1、2、3、4又は5であり;
Rd’は、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、エーテルアルキル、H、F、Cl、Br、I、ヒドロキシ、メルカプト、アミノ、ニトロ、カルボキシ、シアノ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アミノスルホニル、カルバモイル、アリールアミノ、ヘテロアリールアミノ、アリールアルキルアミノ、ヘテロアリールアルキルアミノ、ヘテロシクリルアミノ、ヘテロシクリルアルキルアミノ、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシであり;
Ryは、CH=CHC(=O)NR1R2、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、エーテルアルキル、H、F、Cl、Br、I、ヒドロキシ、メルカプト、ニトロ、カルボキシ、シアノ、アルキル、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル、ヘテロアリールアルキル、アリールオキシ、ヘテロアリールオキシ、アリールアルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルオキシ又はヘテロシクリルアルコキシであり;
Rdは、同じ又は異なることができ、且つRdの各々は、独立して、-CH=CHC(=O)NR1R2、R1-S(=O)g-、R1-S(=O)gO-、R1-OS(=O)g-、R1-C(=O)-、R1-C(=S)-、R1O(CH2)i-O-(CH2)j-、-(CH2)i-NR1R2、オキソ、エーテルアルキル、H、F、Cl、Br、I、ヒドロキシ、メルカプト、アミノ、ニトロ、カルボキシ、シアノ、アルキル、アルキルアミノ、ヒドロキシ-置換されたアルキル、ハロアルキル、ヘテロアルキル、アルコキシ、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、アラルキル又はヘテロアリールアルキルであり;並びに
R1及びR2の各々は、独立して、H、アルキル、シクロアルキル、アラルキル、ヘテロアリールアルキル又はハロアルキルである。
i及びjの各々は、独立して、1、2、3、4又は5であり;並びに
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
i及びjの各々は、独立して、1、2、3、4又は5であり;
gの各々は、独立して、0、1又は2であり;並びに
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
R1は、H、メチル、エチル、プロピル、イソプロピル、ブチル又はペンチルである。
i及びjの各々は、独立して、1、2、3、4又は5であり;並びに
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
R1及びR2の各々は、独立して、H、C1-6アルキル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルである。
Dは、結合、メチレン又はエチレンであり;
Re及びRfの各々は、独立して、H、C1-6アルキル、C1-6アルキルアシル、C3-8シクロアルキル、C6-10アリール-C1-6-アルキル、C1-9ヘテロアリール-C1-6-アルキル又はC1-6ハロアルキルであり;並びに、
nは、1又は2である。
別の態様に従い、本発明は、式(I)の化合物、本明細書に列記された化合物、又は実施例1-53に挙げられた化合物、並びに医薬として許容し得る担体、補助剤、又はビヒクルを含む、医薬組成物を特徴としている。本明細書に開示された組成物中の該化合物の量は、生物学的試料中又は患者におけるプロテインキナーゼを検出可能に阻害するのに有効な量である。
本発明は、式(I)の化合物又は本明細書に列記された化合物、及び医薬として許容し得る担体、補助剤、又はビヒクルを含有する医薬組成物を特徴としている。本明細書に開示された組成物中の該化合物の量は、EGFR阻害活性などの、プロテインキナーゼを検出可能に阻害するのに有効なものである。本明細書に開示された化合物は、抗新生物薬として療法において、又はEGFRの有害作用を最小化するのに、有用である。
一般に本明細書に開示された化合物は、本明細書に記載の方法により調製することができ、ここで置換基は、更に注記した場合を除き、先の式(I)について規定されたものである。下記の非限定的スキーム及び実施例は、本発明の更なる例示のために提示される。
HCOONH4 ギ酸アンモニウム
CH(OMe)3 トリメトキシメタン
MeOH、CH3OH メタノール
CH3SO3H メタンスルホン酸
Ac2O 無水酢酸
SOCl2 塩化チオニル
i-PrOH イソプロパノール
NaOH 水酸化ナトリウム
K2CO3 炭酸カリウム
KI ヨウ化カリウム
DMF N,N-ジメチルホルムアミド
H2NNH2-H2O ヒドラジン水和物
PPA ポリリン酸
H2 水素
Pd/C 炭素に担持されたパラジウム
EtOH エタノール
PhCHO ベンズアルデヒド
DCM、CH2Cl2 塩化メチレン
NaBH4 水素化ホウ素ナトリウム
KOH 水酸化カリウム
c-C5H11MgCl シクロペンチル塩化マグネシウム
ClTi(OiPr)3 クロロチタントリイソプロポキシド
Pd(OH)2 水酸化パラジウム
OsO4 四酸化オスミウム
NMO N-メチルモルホリン-N-オキシド
ClCH2CH2Cl 1,2-ジクロロエタン
TBAB テトラブチルアンモニウムブロミド
HCO2H メタン酸
TFA トリフルオロ酢酸
(CF3CO)2O 無水トリフルオロ酢酸
LiAlH4 水素化リチウムアルミニウム
THF テトラヒドロフラン
(Boc)2O 二炭酸ジ-tert-ブチル
Et3N、TEA、NEt3 トリエチルアミン
NBS N-ブロモスクシンイミド
TsCl 塩化トシル
DMAP 4-ジメチルアミノピリジン
HCHO ホルムアルデヒド
NaB(OCOCH3)3H トリアセトキシ水素化ホウ素ナトリウム
HCl 塩酸
i-PrMgBr イソプロピルマグネシウムブロミド
Me3Al トリメチルアルミニウム
NHMe2 ジメチルアミン
Ag2CO3 炭酸銀
CH3CN、MeCN アセトニトリル
PtO2 二酸化白金
AcOH、CH3COOH 酢酸
MsCl メチルスルホニルクロリド
PCC クロロクロム酸ピリジニウム
DBU 1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン
Ac アセチル
Boc tert-ブトキシカルボニル
Ts トシル
Bn ベンジル
Et エチル
TMS トリメチルシリル
Ms メチルスルホニル
toluene メチルベンゼン
LiBH4 水素化ホウ素リチウム
Na2CO3 炭酸ナトリウム
Dess-Martin デス-マーチン酸化剤
LDA リチウムジイソプロピルアミド
NH2OH.HCl ヒドロキシルアミン塩酸塩
Glycol monomethyl ether エチレングリコールモノメチルエーテル
r.t、RT 室温
BnBr 臭化ベンジル
MnO2 二酸化マンガン
CHCl3 クロロホルム、トリクロロメタン
LiBr 臭化リチウム
HBr 臭化水素
Na2SO4 硫酸ナトリウム
H2O 水
N2 窒素
CDCl3 重水素化クロロホルム
PE 石油エーテル
DMSO ジメチルスルホキシド
mL、ml ミリリットル
g グラム
mg ミリグラム
h 時
eq 電気化学当量
mmol ミリモル
NH3H2O 水酸化アンモニウム
EA、EtOAc 酢酸エチル
HPLC 高速液体クロマトグラフィー
Mpa メガパスカル
ATP アデノシン三リン酸
NADPH 還元型補酵素ΙΙ
PBS リン酸緩衝液
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)プロポキシ)キナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-6-(3-(3-エチル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-6-(3-(5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
((1R,5S)-3-(3-((4-((3-クロロ-4-フルオロフェニル)アミノ)-7-メトキシキナゾリン-6-イル)オキシ)プロピル)-3-アザビシクロ[3.1.0]ヘキサン-1-オール)
無水MeOH(200mL)中のグリシン(15.00g, 1.0当量)の溶液へ、SOCl2 (17.4mL, 1.2当量)を0℃で滴加した。この混合物を、0℃で15分間攪拌し、次に65℃で4時間加熱し、真空において濃縮し、表題化合物を白色固形物(17.80g, 100%)として生じた。
(N-(3-クロロ-4-フルオロフェニル)-6-(3-((1R,5S)-1-(ジメチルアミノ)-3-アザビシクロ[3.1.0]ヘキサン-3-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(テトラヒドロ-2H-[1,4]ジオキシノ[2,3-c]ピロール-6(3H)-イル)プロポキシ)キナゾリン-4-アミン)
(N-(3-エチニル-4-フルオロフェニル)-7-メトキシ-6-(3-(テトラヒドロ-2H-[1,4]ジオキシノ[2,3-c]ピロール-6(3H)-イル)プロポキシ)キナゾリン-4-アミン)
(N-(4-ブロモ-2-フルオロフェニル)-7-メトキシ-6-(3-(テトラヒドロ-2H-[1,4]ジオキシノ[2,3-c]ピロール-6(3H)-イル)プロポキシ)キナゾリン-4-アミン)
CH2Cl2(50mL)中の3-ベンジル-3,7-ジアザビシクロ[3.3.0]オクタン(3.41g)の溶液へ、0℃で、(Boc)2O (5.15g)を滴加した。この反応混合物を、室温で一晩攪拌し、水で洗浄した。水層を、CH2Cl2により抽出した。一緒にした有機相を、無水Na2SO4上で1時間乾燥し、濾過した。濾液を真空において濃縮し、残渣を、シリカゲルカラム(溶離剤:50:1 (v/v) EA/MeOH)によりクロマトグラフィーにかけ、該化合物を油状物(2.50g, 49.00%)として生じた。
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(5-メチルヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル)プロポキシ)キナゾリン-4-アミン)
(1-(1-(3-((4-((3-クロロ-4-フルオロフェニル)アミノ)-7-メトキシキナゾリン-6-イル)オキシ)プロピル)ヘキサヒドロピロロ[3,4-b]ピロール-5(1H)-イル)エタノン)
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(4-メチルヘキサヒドロピロロ[3,4-b][1,4]オキサジン-6(2H)-イル)プロポキシ)キナゾリン-4-アミン)
(6-(3-(4-ベンジルヘキサヒドロピロロ[3,4-b][1,4]オキサジン-6(2H)-イル)プロポキシ)-N-(3-クロロ-4-フルオロフェニル)-7-メトキシキナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(1-メチルヘキサヒドロ-1H-ピロロ[2,3-c]ピリジン-6(2H)-イル)プロポキシ)キナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(3-メチル-6,7-ジヒドロイソオキサゾロ[4,3-c]ピリジン-5(4H)-イル)プロポキシ)キナゾリン-4-アミン)
THF(300mL)中の4-ヒドロキシピペリジン(30.00g)の溶液へ、水(300mL)中のNa2CO3 (60.60g)の溶液、次に(Boc)2O (85mL)を、0℃で滴加した。この反応混合物を室温で一晩攪拌し、CH2Cl2 (200mL×3)により抽出した。一緒にした有機相を、無水Na2SO4上で乾燥し、濾過した。濾液を真空において濃縮し、残渣を、シリカゲルカラム(溶離剤:2:1(v/v) PE/EA)によりクロマトグラフィーにかけ、表題化合物を白色固形物(53.10g, 90.00%)、HPLC:95.00%として生じた。この化合物は、下記の分光学的データにより特徴付けられる:MS (ESI, 正イオン) m/z: 202.2 (M+1);
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(6-メチルオクタヒドロ-1H-ピロロ[3,4-b]ピリジン-1-イル)プロポキシ)キナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(1-メチルヘキサヒドロ-1H-ピロロ[3,4-b]ピリジン-6(2H)-イル)プロポキシ)キナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-6-(3-(1-エチルヘキサヒドロ-1H-ピロロ[3,4-b]ピリジン-6(2H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-(オクタヒドロイソキノリン-2(1H)-イル)プロポキシ)キナゾリン-4-アミン
(N-(3-クロロ-4-フルオロフェニル)-6-(3-(1,3-ジメチル-6,7-ジヒドロ-1H-ピラゾロ[4,3-c]ピリジン-5(4H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-6-(3-(2,3-ジメチル-6,7-ジヒドロ-2H-ピラゾロ[4,3-c]ピリジン-5(4H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(N-(3-クロロ-4-フルオロフェニル)-7-メトキシ-6-(3-((4aS,7aS)-テトラヒドロ-2H-[1,4]ジオキシノ[2,3-c]ピロール-6(3H)-イル)プロポキシ)キナゾリン-4-アミン)
(6-(3-(5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)プロポキシ)-N-(4-フルオロフェニル)-7-メトキシキナゾリン-4-アミン)
(N-(4-フルオロフェニル)-6-(3-(ヘキサヒドロフロ[3,4-c]ピリジン-5(3H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(6-(3-(5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)プロポキシ)-N-(3-エチニル-4-フルオロフェニル)-7-メトキシキナゾリン-4-アミン)
(N-(3-エチニル-4-フルオロフェニル)-6-(3-(ヘキサヒドロフロ[3,4-c]ピリジン-5(3H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(6-(3-(5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)プロポキシ)-N-(3-エチニルフェニル)-7-メトキシキナゾリン-4-アミン)
(N-(3-エチニルフェニル)-6-(3-(ヘキサヒドロフロ[3,4-c]ピリジン-5(3H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(N-(4-ブロモ-2-フルオロフェニル)-6-(3-(5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(N-(4-ブロモ-2-フルオロフェニル)-6-(3-(ヘキサヒドロフロ[3,4-c]ピリジン-5(3H)-イル)プロポキシ)-7-メトキシキナゾリン-4-アミン)
(2-(3-((4-((4-フルオロフェニル)アミノ)-7-メトキシキナゾリン-6-イル)オキシ)プロピル)ヘキサヒドロピラノ[3,4-c]ピロール-4(2H)-オン)
(ヒト肝ミクロソーム安定性試験)
(全般的LC/MS/MS分析法)
(前臨床薬物動態評価)
化合物を、マウス、ラット、イヌ又はサルにおける薬物動態試験において評価した。本化合物は、水溶液中の5%DMSO+5%ソルトール-15として投与した。静脈内投与に関して、ラット、イヌ及びサルには投与量2mg/kgで与え、マウスには投与量10mg/kgで与えた。経口(p.o.)投与に関して、マウスには投与量10mg/kgで与え、ラット、イヌ及びサルには投与量5mg/kgで与えた。血液試料(0.3mL)を、0.083、0.25、0.5、1.0、2.0、4.0、6.0、8.0及び24時の時点で採取し、3,000rpmで10分間遠心分離し、血漿溶液を収集し、前述のLC/MS/MSによる分析まで、-20℃で貯蔵した。
以下の代表的アッセイを、本明細書に開示された化合物の生物学的活性の評価において行った。これらは、本発明を例証するために、非限定的様式で行った。
(EGFR阻害活性試験)
パイロット試験において、本明細書に開示された化合物を、それらのEGFR阻害活性についてスクリーニングした。Cisbio Research Product HTRF kinEASE STK S1キナーゼアッセイ/インヒビタースクリーニングキットは、リン酸化された基質の生成を検出することができる。キナーゼ、ビオチニル化された基質及びATPを、緩衝溶液へ最初に添加し、リン酸化されビオチニル化された基質が、酵素反応により形成された。次に、先の溶液へ、ユーロピウム-標識した抗-ホスホ-部位特異的抗体及びXL665-標識したアビジンを添加した。抗体の抗原との、及びビオチンのアビジンとの特異的結合は、ユーロピウムとXL665を互いに近接させ、共鳴エネルギーを転移させた。620nm及び665nmでのシグナルを検出し、これら2つのシグナル値の比により、キナーゼの活性を評価した。具体的手順を、図1に示した。
(ヒト異種移植片腫瘍モデルアッセイ)
(ヒトA549非小細胞肺癌異種移植片腫瘍モデル)
腫瘍成長の進行を、腫瘍容積により評価し、且つ時間の関数として記録した。皮下腫瘍の長軸(L)及び短軸(S)を、キャリパーにより週2回測定し、腫瘍容積(TV)を、(L×W2)/2として算出した。TGIを、ビヒクル-処理マウスと薬物-処理マウスの間の腫瘍容積中央値の差から計算し、下記の関係により、ビヒクル-処理対照群の腫瘍容積中央値の割合として表した:
Claims (10)
- 請求項1又は2記載の化合物、及び医薬として許容し得る担体、賦形剤、希釈剤、補助剤、ビヒクル又はそれらの組合せを含有する、医薬組成物。
- 治療薬を更に含有し、該治療薬が、化学療法薬、抗増殖薬、非小細胞肺癌もしくは類表皮癌を治療する薬剤、又はそれらの組合せから選択され;又は該治療薬が、アドリアマイシン、ラパマイシン、テムシロリムス、エベロリムス、イクサベピロン、ゲムシタビン、シクロホスファミド、デキサメタゾン、エトポシド、フルオロウラシル、イマチニブメシラート、ダサチニブ、ニロチニブ、エルロチニブ、ラパチニブ、ゲフィチニブ、ソラフェニブ、スニチニブ、インターフェロン、カルボプラチン、トポテカン、タキソール、ビンブラスチン、ビンクリスチン、テモゾロミド、トシツモマブ、トラベデクチン、ベバシズマブ、トラスツズマブ、セツキシマブ、パニツムマブ又はそれらの組合せである、請求項3記載の医薬組成物。
- 増殖性障害を予防、管理もしくは治療するか、又は患者における増殖性障害の重症度を軽減する際に使用するための、請求項1又は2記載の化合物であって、該増殖性障害が、転移性癌、類表皮癌、結腸癌、胃腺癌、膀胱癌、乳癌、腎臓癌、肝癌、肺癌、甲状腺癌、脳腫瘍、頸部癌、前立腺癌、膵臓癌、CNS癌、膠芽細胞腫、骨髄増殖性疾患、アテローム性動脈硬化症又は肺線維症である、前記化合物。
- 生物学的試料を、請求項1又は2記載の化合物と接触させることを含んで、インビボ及びインビトロにおいて、プロテインキナーゼ活性を阻害又は調節する際に使用するための該化合物であって、該プロテインキナーゼが、受容体型チロシンキナーゼである、前記化合物。
- 前記受容体型チロシンキナーゼが、EGFRである、請求項6記載の化合物。
- 増殖性障害を予防、管理もしくは治療するか、又は患者における増殖性障害の重症度を軽減する際に使用するための、請求項3又は4記載の医薬組成物であって、該増殖性障害が、転移性癌、類表皮癌、結腸癌、胃腺癌、膀胱癌、乳癌、腎臓癌、肝癌、肺癌、甲状腺癌、脳腫瘍、頸部癌、前立腺癌、膵臓癌、CNS癌、膠芽細胞腫、骨髄増殖性疾患、アテローム性動脈硬化症又は肺線維症である、前記医薬組成物。
- 生物学的試料を、請求項3又は4記載の医薬組成物と接触させることを含んで、インビボ及びインビトロにおいて、プロテインキナーゼ活性を阻害又は調節する際に使用するための該医薬組成物であって、該プロテインキナーゼが、受容体型チロシンキナーゼである、前記医薬組成物。
- 前記受容体型チロシンキナーゼが、EGFRである、請求項9記載の医薬組成物。
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AU2012339499A1 (en) | 2014-06-05 |
HK1196609A1 (zh) | 2014-12-19 |
CA2851151C (en) | 2017-09-12 |
AR092289A1 (es) | 2015-04-15 |
TW201319055A (zh) | 2013-05-16 |
CN103102344A (zh) | 2013-05-15 |
ES2580481T3 (es) | 2016-08-24 |
CA2851151A1 (en) | 2013-05-23 |
EP2780342A4 (en) | 2015-04-08 |
WO2013071697A1 (en) | 2013-05-23 |
US9181277B2 (en) | 2015-11-10 |
CN103102344B (zh) | 2015-10-14 |
KR20140093271A (ko) | 2014-07-25 |
US20140228361A1 (en) | 2014-08-14 |
AU2012339499B2 (en) | 2015-09-10 |
EP2780342A1 (en) | 2014-09-24 |
KR101965271B1 (ko) | 2019-04-03 |
JP2014534975A (ja) | 2014-12-25 |
EP2780342B1 (en) | 2016-06-01 |
TWI577671B (zh) | 2017-04-11 |
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