JP2019516749A - 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)−ベンズアミドの新規結晶形 - 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)−ベンズアミドの新規結晶形 Download PDFInfo
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Abstract
Description
a)式(II)
c)得られた式(I)の化合物をエタノール中に懸濁する工程;
d)工程c)の懸濁液を約50℃〜約70℃の温度に加熱し、室温に冷却する工程;及び
e)水を添加し、濾過し、乾燥させて、上記で定義した式(I)の化合物の結晶形4を得る工程
を含む方法を開示する。
f)エタノール中で上記で定義した式(I)の化合物の結晶形2のスラリーを還流温度(約78℃)で加熱し、混合物を約50℃〜約65℃の温度に冷却する工程;
g)工程a)〜e)で定義したようにして得られた一定量の結晶形4のシードを工程f)の混合物に添加し、続いて水を添加する工程;
h)工程g)の混合物を還流温度で30〜90分間加熱し、続いて混合物を室温に冷却し、約12時間撹拌する工程;及び
i)工程h)の混合物を濾過し、約40℃で乾燥させて、上記で定義した式(I)の化合物の結晶形4を得る工程
を含む方法が本明細書で提供される。
以下の実施例は、本開示の実施形態を例示するために含まれるものであり、本開示の範囲を限定することを意図しない。
式(I)の化合物の結晶形4の調製。
工程a)及びb)は、国際公開第2013/174876号の4ページ、15〜28行に記載されている。
国際公開第2013/174876号に記載された手順(3〜4ページの工程a及びb)によって得られた乾燥非晶質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(式(I)の化合物)2.88Kgを約10倍容量のエタノールに懸濁する(懸濁液A)。
工程c)で得られた懸濁液A 20mLを約60℃に加熱して溶液を得、次いでこの溶液を室温に冷却する。
工程d)から得られた懸濁液に水20mLを添加し、沈殿物を濾過する。生成物を減圧下で乾燥して、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)−ベンズアミドを結晶形4として得る(DSC分析を図2に報告する)。
播種による結晶形4の調製。
工程f)
エタノール110mLを、国際公開第2013/174876号(工程c2、4及び11〜12ページ)に記載されているようにして得られた、2N−[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)−ベンズアミドの結晶形2 11.3gに添加し、溶液が得られるまで混合物を加熱還流する。次いで、混合物を約58℃に冷却する。
実施例1に記載したように調製した結晶形4のシード20mgを工程f)の混合物に添加する;次いで、水220mLを約15分以内に混合物に滴下し、完全な沈殿を得る。
このようにして得られた混合物を再び約60分間加熱還流し、室温まで緩やかに冷却する;次いで、この混合物を室温で12時間撹拌する。
沈殿物を濾過し、減圧下に約40℃で乾燥させて、9.5gの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)−ベンズアミドの結晶形4を得る。
X線粉末回折(XRPD)による分析結果
化合物(I)の結晶形4を、Thermo/ARL XTRA装置を用いて実施したX線粉末回折(XRPD)によって特徴付け、室温で2°〜40°の2θにてCuKα線源(45kV、40mA、1.8kW−Kα1放射線、波長λ=1.54060オングストローム)を用いて粉末試料を照射した。
示差走査熱量測定(DSC)による分析結果
DSC分析は、Mettler Toledo Starシステム装置を用いて実施した。アルミニウム製のDSCパンに試料2〜4mgを充填した。分析の温度範囲は、25℃から最大値の300℃までであった。試料を窒素静的条件下に10℃/分の加熱速度で分析した。
Claims (18)
- X線粉末回折パターンが、約15.6、17.9及び39.0±0.2度の反射角2θに特有のピークをさらに含む、請求項1に記載の結晶形4。
- X線粉末回折パターンが、約8.6、10.3、11.0、11.9、14.3、14.6、15.1、15.3、15.6、16.1、17.1、17.9、19.0、19.2、19.6、19.7、20.1、20.7、21.3、22.1、22.7、24.3、24.6、25.3、25.5、25.9、26.7、26.9、27.3、27.7、28.1、28.6、29.0、29.5、29.9、30.5、31.0、31.6、32.2、33.3、34.0、35.4、36.4、36.8及び39.0度±0.2度の反射角2θ値に有意なピークを含む、請求項1又は2に記載の結晶形4。
- 結晶形が、約200℃〜約205℃の示差走査熱量測定スキャンにおけるピークを示すことをさらに特徴とする、請求項1、2又は3に記載の結晶形4。
- 活性成分としての請求項1に記載の式(I)の化合物の結晶形4と、薬学的に許容される賦形剤、担体又は希釈剤とを含む医薬組成物。
- 組成物が、錠剤、カプセル、懸濁液、エマルジョン、分散性粉末又は顆粒の形態である、請求項5に記載の医薬組成物。
- 組成物が、1用量当たり約10mg〜約1gの式(I)の化合物の結晶形4を含む、請求項5又は6に記載の医薬組成物。
- 医薬として使用するための、請求項1に記載の結晶形4。
- 単独の又は他の治療薬若しくは放射線療法と組み合わせた、がん及び細胞増殖性障害などの、ALK阻害によって治療可能な疾患状態の治療における使用のための、請求項1に記載の結晶形4。
- がん及び細胞増殖性障害などの、ALK阻害によって治療可能な疾患状態の治療のための医薬を製造するための、単独での又は他の治療薬若しくは放射線療法と組み合わせた、請求項1に記載の結晶形4の使用。
- ALK阻害を必要とする、ヒトを含む哺乳動物におけるがんを治療する方法であって、治療有効量の請求項1に記載の結晶形4を前記哺乳動物に投与することを含む、方法。
- 単独の又は他の治療薬若しくは放射線療法と組み合わせた、ROS1、NTRK1、NTRK2及びNTRK3からなる群より選択される少なくとも1つの標的遺伝子に少なくとも1つの遺伝子変化を有する患者におけるがんの治療に使用するための、請求項1に記載の結晶形4。
- ROS1、NTRK1、NTRK2及びNTRK3からなる群より選択される少なくとも1つの標的遺伝子に少なくとも1つの遺伝子変化を有する患者におけるがんの治療のための医薬を製造するための、単独での又は他の治療薬若しくは放射線療法と組み合わせた、請求項1に記載の結晶形4の使用。
- ROS1、NTRK1、NTRK2及びNTRK3からなる群より選択される少なくとも1つの標的遺伝子に少なくとも1つの遺伝子変化を有する、ヒトを含む哺乳動物におけるがんを治療する方法であって、治療有効量の請求項に記載の結晶形4を前記哺乳動物に投与することを含む、方法。
- がんが、非小細胞肺がん、乳頭状甲状腺がん、神経芽腫、膵臓がん及び結腸直腸がんからなる群から選択される、請求項11又は14に記載の治療方法。
- 以下の工程:
a)式(II)
b)得られた式(IV):
c)得られた式(I)の化合物をエタノール中に懸濁する工程;
d)工程c)の懸濁液を約50℃〜約70℃の温度に加熱し、室温に冷却する工程;及び
e)水を添加し、濾過し、乾燥させて、請求項1に記載の式(I)の化合物の結晶形4を得る工程;
あるいは、
f)エタノール中で式(I)の化合物の結晶形A2のスラリーを還流温度で加熱して溶液を得、前記溶液を約50℃〜約65℃の温度に冷却する工程;
g)工程a)〜e)に記載のようにして得られた一定量の結晶形4のシードを工程f)の溶液に添加し、続いて水を添加する工程;
h)工程g)の混合物を還流温度で30〜90分間加熱し、続いて前記混合物を室温に冷却し、約12時間撹拌する工程;及び
i)工程h)の混合物を濾過し、約40℃で乾燥させて、請求項1に記載の式(I)の化合物の結晶形4を得る工程
を含む、請求項1〜4に記載の結晶形4を調製する方法。 - 工程f)の溶液を55℃〜60℃の温度に冷却する、請求項16に記載の方法。
- 工程g)の混合物を還流温度で60分間加熱する、請求項16又は17に記載の方法。
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