JP2015517551A - N−[5−(3,5−ジフルオロ−ベンジル)−1h−インダゾール−3−イル]−4−(4−メチル−ピペラジン−1−イル)−2−(テトラヒドロ−ピラン−4−イルアミノ)−ベンズアミドの調製方法 - Google Patents
N−[5−(3,5−ジフルオロ−ベンジル)−1h−インダゾール−3−イル]−4−(4−メチル−ピペラジン−1−イル)−2−(テトラヒドロ−ピラン−4−イルアミノ)−ベンズアミドの調製方法 Download PDFInfo
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Abstract
Description
a)式(II)
c1)結果として得られた式(I)の非晶質化合物を、シードの存在下、エタノールと水との混合物を用いて処理して、所望の式(I)の化合物を結晶形態1で得るステップ
または
c2)結果として得られた式(I)の非晶質化合物を、エタノールと水との混合物を用いて処理して、所望の式(I)の化合物を結晶形態2で得るステップ
によって得、
場合によって、
d)ステップb)において、ステップc1)においてもしくはステップc2)において得られる、結果として得られた化合物を、医薬として許容される塩に変換するステップ
を含む方法である。
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:動的水蒸気収着
TGA:熱重量分析
ACN(アセトニトリル)
EtOAc(酢酸エチル)
DCM(ジクロロメタン)
DMA(N,N−ジメチルアセトアミド)
DMF(N,N−ジメチルホルムアミド)
DMSO(ジメチルスルホキシド)
MTBE(メチルtert−ブチルエーテル)
THF(テトラヒドロフラン)
TFA(トリフルオロ酢酸)
下記スキーム1は、式(I)の化合物の結晶形態1および結晶形態2の調製を示す。
化合物(I)の結晶形態3、非晶質形態、結晶形態1および結晶形態2を、粉末X線回折(PXRD)によって特性決定した。粉末X線回折は、Thermo/ARL XTRA装置を使用し、CuKα源(45kV、40mA 1.8kW−Kα1放射線、波長λ=1.54060オングストローム)、2°から40°の間の2θを用いて、室温にて粉末サンプルを照射して行った。
DSC分析は、Mettler Toledo Starシステム装置を用いて実施した。アルミニウム製DSCパンに、2−4mgのサンプルを入れた。分析の温度範囲は、25℃から最大値の300℃の間であった。サンプルを窒素静的条件下にて、10℃/分の加熱速度で分析した。
観測された水の取り込みは、そのような物質のサンプルを、DVS1000(SMS)を用いた吸湿性試験に供することによって検討した。装置は、秤量されたサンプルを、一定温度および制御温度で、相対湿度(RH)のプログラムされた変化に曝す「制御雰囲気微量天秤(controlled atmosphere microbalance)」である。測定されたパラメータ(重量、時間およびRH)は、Excelワークシートに報告され、試験されるRH範囲にわたって吸湿曲線を得ることができる。例えば、0%から90%RHの間の収着/脱着サイクルを、25℃の制御温度で行うことができる。RHの連続的な変化は、例えば、10%および3%のものである可能性があり、サンプル重量の平衡時に、ソフトウェアによって操作される。この条件は、例えば、0.005%/分などの定速のパーセント重量変化で明確に示すことができる。
TGA分析は、Perkin−Elmer TGA−7装置を用いて実施した。アルミニウム製DSCパンに、5÷10mgのサンプルを入れた。分析の温度範囲は、30°から最大値の約250℃の間であった。サンプルを窒素気流下にて(酸化および熱分解の影響を取り除くため)、2℃/分の加熱速度で分析した。
1H NMR実験は、結晶形態3サンプルについて、28℃の一定温度で、Varian Inova500分光計を用いて行い(図8を参照のこと)、結晶形態1サンプルについて、28℃の一定温度で、Varian Inova400分光計を用いて行った(図7を参照のこと)。少量の各サンプルを、0.75mLのDMSO−d6中に溶かし、5mm NMR管に移して、その後の分析を行った。
Claims (16)
- 式(I)
a)式(II)
b)得られた式(IV)
c1)結果として得られた式(I)の非晶質化合物を、シードの存在下、エタノールと水との混合物を用いて処理して、所望の式(I)の化合物を結晶形態1で得るステップ
または
c2)結果として得られた式(I)の非晶質化合物を、エタノールと水との混合物を用いて処理して、所望の式(I)の化合物を結晶形態2で得るステップ、
および場合によって、
d)ステップb)、ステップc1)もしくはステップc2)において結果として得られた化合物を、医薬として許容される塩に変換するステップ
を含む方法。 - 約4.8、7.5、15.2、16.2、17.4、17.8、18.7、19.5、20.1、20.5、22.3、23.0、23.3、24.4および25.0°の反射角2θにおいて主要なピークを含むX線粉末回折パターンを特徴とする、請求項1に記載の式(I)の化合物の結晶形態1。
- 約4.1、4.8、7.3、7.5、8.1、8.9、9.2、9.8、11.1、13.0、13.5、13.8、14.6、15.2、16.2、17.4、17.8、18.2、18.7、19.5、20.1、20.5、21.1、21.8、22.3、23.0、23.3、23.9、24.4、24.7、25.0、25.5、26.2、27.2、27.3、29.1、29.5、30.1、30.6、31.5および36.6°の反射角2θにおいて特有のピークを有するX線粉末回折パターンを特徴とする、請求項2に記載の結晶形態1。
- 188℃−196℃の範囲においての融解に関連する吸熱ピークを含むDSCサーモグラムを特徴とする、請求項2または3に記載の結晶形態1。
- 約10.5、11.1、14.3、15.3、17.8、18.4、19.0、19.9、21.3、21.8、22.3、22.5、23.6、26.4および30.0°の反射角2θにおいて主要なピークを含むX線粉末回折パターンを特徴とする、請求項1に記載の式(I)の化合物の結晶形態2。
- 約6.6、9.8、10.5、11.1、12.4、14.3、15.3、15.9、16.9、17.8、18.4、19.0、19.9、20.2、21.0、21.3、21.8、22.3、22.5、23.2、23.6、24.9、25.1、25.5、25.9、26.4、27.6、28.1、28.7、29.0、29.3、29.5、30.0、30.4、30.8、31.5、31.9、32.2、32.4、33.0、33.6、34.7、34.9、38.1および38.4°の反射角2θにおいて特有のピークを有するX線粉末回折パターンを特徴とする、請求項5に記載の結晶形態2。
- 197℃−198.5℃の範囲においての融解に関連する吸熱ピークを含むDSCサーモグラムを特徴とする、請求項5または6に記載の結晶形態2。
- 活性成分として、治療有効量の、請求項2に記載の結晶形態1もしくは請求項5に記載の結晶形態2またはこれらの医薬として許容される塩および医薬として許容される賦形剤、担体または希釈剤を含む医薬組成物。
- 医薬として使用するための、請求項2に記載の結晶形態1もしくは請求項5に記載の結晶形態2またはこれらの医薬として許容される塩。
- がんおよび細胞増殖性障害などの、ALK阻害によって治療可能な病状の治療に使用するための、単独のまたは他の治療剤もしくは放射線療法と併せた、請求項2に記載の結晶形態1もしくは請求項5に記載の結晶形態2またはこれらの医薬として許容される塩。
- がんおよび細胞増殖性障害などの、ALK阻害によって治療可能な病状の治療のための医薬を製造するための、単独のまたは他の治療剤もしくは放射線療法と併せた、請求項2に記載の結晶形態1もしくは請求項5に記載の結晶形態2またはこれらの医薬として許容される塩の使用。
- ALK阻害を必要としている、ヒトを含む哺乳動物を治療するための方法であって、哺乳動物に、治療有効量の、請求項2に記載の結晶形態1もしくは請求項5に記載の結晶形態2またはこれらの医薬として許容される塩を投与することを含む方法。
- 式(II)の化合物をジクロロメタン中に懸濁させ、式(III)の化合物をピリジン中に懸濁させる、請求項1に記載の方法。
- 式(IV)の化合物の脱保護を、K2CO3の水/メタノール溶液の中で行う、請求項1に記載の方法。
- 式(I)の非晶質化合物を、最初にエタノールを用いて、加熱還流し溶媒の一部を蒸留して処理し、次いで、20℃から25℃の間の温度で水および結晶形態1のシードを用いて処理する、請求項1に記載の方法。
- 式(I)の非晶質化合物を、エタノールを用いて20℃から25℃の間の温度で処理し、次いで、水を用いて20℃から25℃の間の温度で順次処理する、請求項1に記載の方法。
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