JP2017043640A - (e)−n−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドのマレイン酸塩およびその結晶形態 - Google Patents
(e)−n−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドのマレイン酸塩およびその結晶形態 Download PDFInfo
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- JP2017043640A JP2017043640A JP2016238151A JP2016238151A JP2017043640A JP 2017043640 A JP2017043640 A JP 2017043640A JP 2016238151 A JP2016238151 A JP 2016238151A JP 2016238151 A JP2016238151 A JP 2016238151A JP 2017043640 A JP2017043640 A JP 2017043640A
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- Prior art keywords
- anilino
- ethoxy
- chloro
- cyano
- quinolinyl
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Abstract
【解決手段】本発明は、(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドのマレイン酸塩形態、結晶マレイン酸塩形態を調製する方法、関連する化合物、およびそのマレイン酸塩形態を含有する医薬組成物に関する。このマレイン酸塩は、癌、特に上皮増殖因子受容体ファミリーのキナーゼの影響を受ける癌の治療に有用である。
【選択図】図1
Description
2−({4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}アミノ)−2−オキソ酢酸;
N1−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−エタンジアミド;
6−アミノ−4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−7−エトキシ−3−キノリンカルボニトリル;
4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−7−エトキシ−6−(2−ヒドロキシ−5−オキソピロリジニル)−3−キノリンカルボニトリル;
N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−3,4−ビス(ジメチルアミノ)ブタンアミド;
N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−1−メチル−2,3−ジオキソ−4−ピペリジンカルボキサミド;
N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}アセトアミド;
(E)−4−({4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}アミノ)−N,N,N−トリメチル−4−オキソ−2−ブテン−1−アミニウム
N1−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−N2,N2−ジメチルエタンジアミド;
4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニルホルムアミド;および、
4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−7−エトキシ−6−[(1−メチル−2−ピロリジニリデン)アミノ]−3−キノリンカルボニトリル。
(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩、形態IIの調製
粗(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミド遊離塩基(0.100kg、0.159モル)を、USP精製水のn−プロパノール中10%溶液(0.082kg、0.10L)で洗い流し、続いて水:n−プロパノール溶液(0.74kg、0.90L)を添加する。マレイン酸(0.0191kg、0.164モル)を添加し、混合物を10%水:n−プロパノール(0.082kg、0.10L)で洗い流す。混合物を急速に50〜60℃に加熱し、溶液が得られるまで最低限15分間保持する。50〜60℃に予め加熱した0.2Mmフィルタカートリッジを通して、熱溶液を透明にし、45〜55℃に予め加熱した2L多口フラスコに濾液を集める。45〜55℃に予め加熱した10%水:n−プロパノール(0.082kg、0.10L)を通してフィルタカートリッジを洗い流す。溶液を少なくとも1時間かけて40℃に冷却し、その温度で12時間保持し、その後、最低限4時間かけて室温(25℃)に冷却し、その温度で少なくとも2時間保持する。混合物を直径12.5cmのブフナー漏斗で5分間濾過し、その後、予め濾過した10%水:n−プロパノール溶液(2×0.12kg、2×0.15L)で洗い流し、洗浄する。ケークをせき止め、滴下が本質的に停止するまで、約1時間、吸引を持続する。
(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩、形態Iの調製
実施例1の生成物(形態II)を乾燥して(50℃、10mmHg、24時間)、強度80.8%(遊離塩基)、17.4%(マレイン酸)、総不純物1.06%、最大単一不純物0.38%で、94.4g(収率88%)の結晶無水(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩(形態I)(収率88%)を得る。
Claims (9)
- 無水(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドをマレイン酸塩として調製する方法であって、該方法は:
i)(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドおよびマレイン酸を水:n−プロパノール溶液中で、50℃〜60℃に加熱し、混合物を最低限15分にわたって50〜60℃で維持する工程;
ii)該溶液を少なくとも1時間にわたり40℃に冷却し、冷却された該溶液を40℃で12時間維持する工程;
iii)冷却された該溶液を、最低限4時間にわたり室温(25℃)にさらに冷却し、さらに冷却された該溶液を室温(25℃)で少なくとも2時間にわたって維持する工程;
iv)工程iii)において得られた該混合物を濾過して、結晶性の(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩を得る工程であって、該結晶性の(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩が、(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩一水和物である、工程;ならびに
v)工程iv)からの該(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩一水和物を、真空下で30℃を超える温度で12から48時間にわたって乾燥させて、結晶性の無水(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩を得る工程
を含む、方法。 - 前記乾燥工程が、前記(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩一水和物を50℃、10mmHgで24時間にわたって乾燥させて、前記結晶性の無水(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩を得る工程を含む、請求項1に記載の方法。
- 前記結晶性の(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩一水和物が、そのX線回折パターンにおいて以下の2θ角(±0.20°):6.53、8.43、13.01、15.17、16.76におけるX線回折ピークを特徴とするか;
そのX線回折パターンにおいて以下の2θ角(±0.20°):6.53、8.43、10.16、12.19、12.47、13.01、15.17、16.76、17.95、19.86、21.11、21.88、23.22、23.78、25.69、26.17、27.06、27.58、28.26、28.73、および29.77におけるX線回折ピークを特徴とするか;または
図7の上方スペクトルに示されるX線回折パターンを実質的に有することを特徴とする、
請求項1または2に記載の方法。 - 前記X線回折パターンは、Vantec−1検出器およびNiフィルタを使用して、0.01°の走査幅および総走査時間30分を有するBruker D8 Advance装置において40kVの電圧および40.0mAの電流を用いて、5.00〜30.00°の走査範囲で収集された、請求項3に記載の方法。
- 前記結晶性の無水(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩がそのX線回折パターンにおいて以下の2θ角(±0.20°):6.16、7.38、8.75、12.61、14.65、15,75におけるX線回折ピークを特徴とするか;
そのX線回折パターンにおいて以下の2θ角(±0.20°):6.16、7.38、8.75、10.20、12.24、12.61、14.65、15.75、17.33、18.64、19.99、20.66、21.32、22.30、23.18、24.10、24.69、25.49、26.09、26.54、27.52、28.62、および29.43におけるX線回折ピークを特徴とするか;または
図6の上方スペクトルに示される、X線回折パターンを実質的に有することを特徴とする、
請求項1〜4のいずれか一項に記載の方法。 - 前記X線回折パターンは、Rigaku Miniflexベンチトップ型X線回折装置において30kVの電圧、15mAの電流を用いて、3〜40°の走査範囲で、2.00°/分で収集された、請求項5に記載の方法。
- 前記結晶性の無水(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩が示差走査熱量測定によって測定されたとき、196〜204℃の開始温度を特徴とする、請求項1〜6のいずれか一項に記載の方法。
- 部分水和(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドをマレイン酸塩として調製する方法であって、
i)(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドおよびマレイン酸を水:n−プロパノール溶液中で、50℃〜60℃に加熱し、混合物を最低限15分にわたって50〜60℃で維持する工程;
ii)該溶液を少なくとも1時間にわたり40℃に冷却し、冷却された該溶液を40℃で12時間維持する工程;
iii)冷却された該溶液を、最低限4時間にわたり室温(25℃)にさらに冷却し、さらに冷却された該溶液を室温(25℃)で少なくとも2時間にわたって維持する工程;
iv)工程iii)において得られた該混合物を濾過して、結晶性の(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩を得る工程であって、該結晶性の(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩が、(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩一水和物である、工程;
v)工程iv)からの該(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩一水和物を、真空下で30℃を超える温度で12から48時間にわたって乾燥させて、結晶性の無水(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩を得る工程;ならびに
vi)周囲温度(20〜25℃)で、該結晶性の無水(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩を75%の相対湿度に22日にわたって曝露し、結晶性の部分水和(E)−N−{4−[3−クロロ−4−(2−ピリジニルメトキシ)アニリノ]−3−シアノ−7−エトキシ−6−キノリニル}−4−(ジメチルアミノ)−2−ブテンアミドマレイン酸塩を形成する工程
を含む、方法。 - 前記乾燥工程が50℃、10mmHgで24時間にわたって乾燥させる工程を含む、請求項8に記載の方法。
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