JP5851990B2 - Plk阻害剤の塩 - Google Patents
Plk阻害剤の塩 Download PDFInfo
- Publication number
- JP5851990B2 JP5851990B2 JP2012522114A JP2012522114A JP5851990B2 JP 5851990 B2 JP5851990 B2 JP 5851990B2 JP 2012522114 A JP2012522114 A JP 2012522114A JP 2012522114 A JP2012522114 A JP 2012522114A JP 5851990 B2 JP5851990 B2 JP 5851990B2
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- Prior art keywords
- compound
- salt
- fumarate
- free base
- crystalline
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Description
温度は、摂氏温度(℃)で測定される。
別段の指示がない限り、反応または実験は室温で行われる。
略語:
RT:室温
RH:相対湿度
PXRD:粉末X線回折
DSC:示差走査熱量測定
DVS:動的蒸気収着
TGA:熱重量分析
化合物937の塩の小規模な調製
化合物937の遊離塩基の一定分量(約40÷50mg)を、メタノールとジクロロメタンの2:1混合物4−5mL中でRTにおいて溶解し、約10mg/mLの名目上の濃度を得た。
化合物937のL−酒石酸塩、コハク酸塩、フマル酸塩、クエン酸塩、マレイン酸塩およびL−リンゴ酸塩の2グラムスケールの調製
遊離塩基(500mg、0.939ミリモル)を、ジクロロメタン:メタノールが2:1の混合物(24mL)中に室温で溶解し、次に、メタノール中に溶解した1当量の酸性対イオン、またはフマル酸のケースでは96%のエタノール中に溶解した1当量の酸性対イオンを加えた。溶液を真空中で10mLに減少させ、次に、−20℃まで冷却した。析出した物質を次にろ過し、ジエチルエーテルで洗浄し、最後に真空下において40℃で少なくとも24時間乾燥した。
化合物937のフマル酸塩、形態Iの大規模な調製
かなりの量の化合物937の遊離塩基を、無水エタノール中で撹拌しながら30分間加熱還流して、出発物質(濃度約25g/L)を完全に溶解させた。
化合物937のフマル酸塩、形態IIの大規模な調製
かなりの量の化合物937の遊離塩基を、水中においてRTで撹拌し、30分間後に約1当量のフマル酸を加えた。
化合物937の塩および遊離塩基の溶解度
実施例2に記載されているように調製した化合物937の塩の溶解度の決定を、次の手順により行った。化合物937の塩および遊離塩基の既知の量を、10mg/mlの目標濃度を考慮して過剰な固体がある条件で、水中においてRTで4時間撹拌した。得られた調製物をろ過し、HPLCにより分析した。
粉末X線回折(PXRD)による分析結果
Thermo/ARL XTRA装置を用い、室温で2θを5°から34°の間にし、CuKα源(45kV、40mA、1.8kW−Kα1放射線、波長λ=1.54060オングストローム)を粉末サンプルに照射して行った粉末X線回折(PXRD)で、化合物937の塩を特徴付けた。
示差走査熱量測定(DSC)による分析結果
DSC分析を、Perkin−Elmer DSC−7装置で行った。DSC用アルミニウム製パンに、サンプル約2mgを充填した。分析の温度範囲は、30℃と最大値300℃の間とした。サンプルを窒素フロー下で加熱速度10℃/分において分析した。
熱重量分析(TGA)による分析結果
TGA分析を、Perkin−Elmer TGA−7装置で行った。アルミニウム製パンに5÷10mgのサンプルを充填した。分析の温度範囲は、30℃と最大値約250℃の間であった。サンプルを、窒素フロー下で加熱速度2℃/分において分析した。
動的蒸気収着(DVS)による分析結果
化合物937の塩および遊離塩基の水分吸収を、かかる物質のサンプルをDVS1000(SMS)による吸湿性試験に送ることで調べた。装置は「環境制御型微量てんびん」であり、計量したサンプルを、一定の制御された温度においてプログラムで変化させた相対湿度(RH)に曝露する。測定されたパラメーター(重量、時間およびRH)はExcelワークシートに報告され、試験を行ったRH範囲にわたる吸湿曲線が得られた。RHが0%と90%の間の収着/脱着サイクルを、25℃の制御温度で実施することができる。RHの漸進的な変化は10%であり、これらの変化は、サンプル重量の平衡化においてソウトウェアで操作される。この条件は、重量変化パーセントの一定速度、例えば0.005%/分において規定することができる。実験結果は、DVS等温線レポートおよびDVS等温線プロットとして両方に報告される。
NMRによる同定分析
1H NMR実験を、499.8MHzで作動する分光計Varian Inova 500において、28℃の一定温度で行った。各サンプルの少量を、0.75mLのDMSO−d6に溶解し、引き続く分析のために5mmのNMR管に移した。当該分析により、分子および対イオンの両方の予測される化学構造を確認することが可能になる。
経口使用のための剤形のパーセント組成
粉末かさ密度
化合物937のフマル酸塩、L−リンゴ酸塩およびL−酒石酸塩ならびに遊離塩基の粉末かさ密度の決定を、おおまかに固めた活性成分を硬ゼラチンカプセルに手作業で充填することによって行った。
Claims (5)
- 請求項1に記載の化合物937のフマル酸塩の結晶形態、またはその溶媒和物もしくは水和物。
- 請求項1に記載の化合物937の塩、またはその結晶形態、溶媒和物もしくは水和物;または、
請求項2に記載の化合物937のフマル酸塩の結晶形態、溶媒和物もしくは水和物;
を活性成分として含み、ならびに薬学的に許容し得る賦形剤および/または担体を含む、医薬組成物。 - 医薬品として使用するための、
請求項1に記載の化合物937の塩、またはその結晶形態、溶媒和物もしくは水和物;または、
請求項2に記載の化合物937のフマル酸塩の結晶形態、溶媒和物もしくは水和物。 - PLKの阻害によって治療可能な病態の治療をする医薬品の製造のための、
請求項1に記載の化合物937の塩、またはその結晶形態、溶媒和物もしくは水和物;または、
請求項2に記載の化合物937のフマル酸塩の結晶形態、溶媒和物もしくは水和物;
の使用。
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PCT/EP2010/060659 WO2011012534A1 (en) | 2009-07-29 | 2010-07-22 | Plk inhibitor salts |
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US8598172B2 (en) * | 2007-12-04 | 2013-12-03 | Nerviano Medical Sciences S.R.L. | Substituted dihydropteridin-6-one derivatives, process for their preparation and their use as kinase inhibitors |
CN102382106A (zh) * | 2010-08-30 | 2012-03-21 | 黄振华 | 苯胺取代的喹唑啉衍生物 |
RU2652638C2 (ru) * | 2010-12-17 | 2018-04-28 | НЕРВИАНО МЕДИКАЛ САЙЕНСИЗ С.р.л. | Замещенные пиразолхиназолиновые производные в качестве ингибиторов киназы |
EP2668190B1 (en) * | 2011-01-26 | 2016-08-17 | Nerviano Medical Sciences S.r.l. | Tricyclic pyrrolo derivatives, process for their preparation and their use as kinase inhibitors |
JP5925808B2 (ja) * | 2011-01-26 | 2016-05-25 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | 三環式誘導体、これらの調製方法およびこれらのキナーゼ阻害剤としての使用 |
JP2014507950A (ja) | 2011-02-28 | 2014-04-03 | トランスゲノミック,インク. | 混合個体群における標的dnaを配列決定するためのキットおよび方法 |
US9856258B2 (en) | 2014-04-07 | 2018-01-02 | Netherlands Translational Research Center B.V. | (5,6-dihydro)pyrimido[4,5-E]indolizines |
US9811393B2 (en) | 2014-05-29 | 2017-11-07 | Apple Inc. | Consistent extension points to allow an extension to extend functionality of an application to another application |
CN113056267A (zh) | 2018-08-26 | 2021-06-29 | 凯帝夫肿瘤科技有限公司 | Plk1靶磷酸化状态以及用plk1抑制剂治疗癌症 |
WO2023104178A1 (zh) * | 2021-12-10 | 2023-06-15 | 山东绿叶制药有限公司 | 蛋白激酶抑制剂及其制备方法和应用 |
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CN103626777A (zh) | 2014-03-12 |
HK1166015A1 (en) | 2012-10-19 |
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HK1195773A1 (zh) | 2014-11-21 |
US20120157468A1 (en) | 2012-06-21 |
CN103626777B (zh) | 2015-10-21 |
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AR077422A1 (es) | 2011-08-24 |
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