JP7447071B2 - 固体形態 - Google Patents
固体形態 Download PDFInfo
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- JP7447071B2 JP7447071B2 JP2021209048A JP2021209048A JP7447071B2 JP 7447071 B2 JP7447071 B2 JP 7447071B2 JP 2021209048 A JP2021209048 A JP 2021209048A JP 2021209048 A JP2021209048 A JP 2021209048A JP 7447071 B2 JP7447071 B2 JP 7447071B2
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Description
本出願は、2019年5月21日に出願された米国仮出願第62/851,044号の利益を主張しており、この明細書は、その全体が参照により本明細書に組み込まれる。
「化合物1」という用語は、6-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)-1-(4-メチル-2-(2-プロパニル)-3-ピリジニル)-4-((2S)-2-メチル-4-(2-プロペノイル)-1-ピペラジニル)ピリド[2,3-d]ピリミジン-2(1H)-オンを意味する。
1. 一実施形態では、本発明は、6-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)-1-(4-メチル-2-(2-プロパニル)-3-ピリジニル)-4-((2S)-2-メチル-4-(2-プロペノイル)-1-ピペラジニル)ピリド[2,3-d]ピリミジン-2(1H)-オン(化合物1)の結晶無水物形態Iを提供する。
実施形態1として本明細書で提供されるのは、化合物であって、6-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)-1-(4-メチル-2-(2-プロパニル)-3-ピリジニル)-4-((2S)-2-メチル-4-(2-プロペノイル)-1-ピペラジニル)ピリド[2,3-d]ピリミジン-2(1H)-オン(化合物1)又はそのアトロプ異性体の結晶形態である化合物である。
抗溶媒沈殿
本開示の化合物の溶液を様々な溶媒で調製し、次いで抗溶媒を添加した。形成された固体を、単離して分析した。
本開示の化合物の溶液又は懸濁液を様々な溶媒で調製し、90~180分にわたり氷浴中で超音波処理した。固体を単離して分析した。
本開示の化合物の飽和溶液を、周囲温度又は高温にて、様々な溶媒で調製した。高温で調製された試料を、周囲又は2~8℃まで放冷した。形成された固体を、単離して分析した。
本開示の化合物の溶液を、様々な溶媒で調製した。完全な溶解を観察すると、周囲温度又は加熱温度にて、減圧により溶媒を蒸発させた。形成された固体を、単離して分析した。
本開示の化合物の溶液を、様々な溶媒で調製した。完全な溶解を観察すると、この溶液を、窒素ガスのブランケットを使用して、又は使用することなく、部分的にカバーされたバイアル中において、周囲で蒸発させた。形成された固体を、単離して分析した。
本開示の化合物の溶液又は懸濁液を様々な溶媒で調製し、続いて60分にわたり超音波処理した。次いで、試料を24~72時間にわたり30℃まで撹拌し、続いて24時間にわたり50℃で撹拌した。試料を、最後の単離及び分析の前の各段階で、XRPDにより分析した。
本開示の化合物の溶液を、過剰な固体が存在するのに十分な固体を所与の溶媒に添加することにより調製した。下記で説明する全ての形態を、様々な溶媒(例えば、限定されないが、実施例で説明されている具体的な溶媒)から得ることができる。次いで、この混合物を、周囲温度又は高温にて、密封バイアル中で撹拌した。所定の時間の後、減圧又は遠心分離ろ過により固体を単離して分析した。
X線粉末回折(XRPD)
固定スリットとリアルタイムマルチストリップ(RTMS)検出器とを備えたPhillips X線自動粉末回折装置(X’Pert)を使用して、X線粉末回折データを得た。放射線はCuKα(1.54Å)であり、電圧及び電流はそれぞれ、45kV及び40mAであった。データを、3.0~40.0度の2シータで室温にて収集し、ステップサイズは0.0167度であり、カウント時間は15.240秒であった。ステージを、1.0秒の回転時間で回転させた。
熱重量分析を、TGA Discovery Series,TA Instrumentsで実施した。試料を、25℃~325℃の温度範囲にわたり10℃/分の加熱速度にて窒素下で分析した。
標準的なDSCモード(Discovery Series,TA Instruments)を使用して、示差走査熱量測定データを収集した。25℃~350℃の温度範囲わたり、10℃/分の加熱速度を採用した。分析を窒素下で実行し、試料をアルミニウムパンに載せた。較正標準として、インジウムを使用した。
SSNMR充填ツールを使用して、試料約100mgを、4mmのセラミックローターに充填した。SSNMRスペクトルを、Bruker Avance III 500MHz WB分光計で取得した。19Fスペクトルを、500MHzの1H共鳴周波数で動作するBruker二重共鳴MASプローブを使用して収集した。全ての実験に、14kHzのスピニング周波数で動作する4-mm H/F/Xスピニングプローブ(spinning probe)を使用した。19F測定には4us pi/2パルスを使用し、スピナル64シーケンス(spinal 64 sequence)を使用して1Hデカップリングを実行した。最適なS/N/時間のために、1.26*T1のリサイクル遅延を使用した。
医薬品の研究開発分野では、適切な固体形態の調査は重要なステップとなっている。固体形態の調査は、いくつかの決定を含み、主に、非結晶形態、塩形態、又は共結晶形態の調査と、それぞれの非結晶、塩、又は共結晶の多形の調査とを含む。リード最適化プログラム中に、研究対象の化合物のいくつかの特性が最適化され、典型的には、1つ又は数個の候補が探究開発プログラムへと続く。典型的には、リード最適化中での物理化学的パラメータの評価及び最適化では、主に溶解性に焦点が当てられている。本場合には、化合物1は、良好な溶解性の特徴を有する。溶解性の最適化に加えて、塩を調査する場合には、更なる物理化学的パラメータを考慮しなければならず、例えば、(1)融点、(2)熱的挙動、(3)吸湿性、(4)晶癖、(5)多形の挙動、又は物理的安定性、(6)不純物プロファイル、及び(7)無水物形態又は塩形態の化学的安定性を考慮しなければならない。遊離塩基、酸、又は塩の形態のいずれかとしての薬物の融点は、乾燥又は打錠等の処理工程を可能にするために、ある特定の閾値と比べて高いべきである。典型的には熱重量分析(TGA)及び示差走査熱量測定(DSC)により行なわれる熱的挙動の評価はまた、固相-固相転移も含む。これは、エナンチオトロピック又はモノトロピックのいずれであってもよく、且つある多形から別のものへの変換に関連し得るか、又はある疑似多形から別疑似多形(例えば、より低い溶媒和物若しくは水和物)への変換に関連し得るか、又は真の多形に関連し得る。吸湿性は、固体形態の評価で重要な役割を果たしており、なぜならば、この特性は、多くのプロセス工程(ほんの数例を挙げると、乾燥、貯蔵、ブレンド、造粒等)に大きく関与するからである。吸湿性を、動的蒸気吸着(DVS)により調査し得る。簡潔に言うと、この技術により、ある特定の相対湿度レベルで化合物により取り込まれる水分の量の情報が得られる。熱的挙動及び吸湿性の議論は、無水又塩の調査で考慮すべき下記の別のパラメータへのつながりを表す:医薬品開発を継続するために、無水物形態又は塩形態には管理可能な多形挙動が必要である。従って、無水又は塩の調査手順では、典型的には、多型の少なくとも簡単な評価を実行する。この意味では、管理可能な多形挙動は、1種又は2種の多形形態のみの存在と等価ではなく、むしろ等価ではない多形形態の変換の状況を与える。晶癖は、無水又は塩の調査に影響を及ぼし得、最適化は、多くの場合、針状結晶の形態の薬物を、例えば小板又はより良好な流動性を示す立方晶に移行させることを意味する。塩の調査は、薬物の不純物プロファイルを改善するためのツールであり得、なぜならば、医薬品の塩は、対応する遊離塩基又は遊離酸の構造とは全く異なる結晶構造を示すことが多いからである。
従って、化合物1の多形及び塩のスクリーニングを実行した。結晶性の塩化物、リン酸塩、及びメシル酸塩、並びに結晶性の無水物、水和物、及び溶媒和物の形態を同定した。同定された塩はいずれも、DSCデータに基づいて、特に有利な熱的特性を示さないか、又は結晶化度が比較的低いようには見えなかった。いくつかの残りの遊離塩基多形(例えば、水和物及び溶媒和物)の内、結晶無水物形態Iは、驚くべき且つ予想外の利点を示した。
6-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)-1-(4-メチル-2-(2-プロパニル)-3-ピリジニル)-4-((2S)-2-メチル-4-(2-プロペノイル)-1-ピペラジニル)ピリド[2,3-d]ピリミジン-2(1H)-オン(化合物1)のMアトロプ異性体の様々な固体形態を生成するための多形スクリーニングを、下記で説明するように実行した。便宜上、後述する実施例で言及する「化合物1」は、化合物1のMアトロプ異性体であると理解しなければならない。
2018年11月22日に公開された米国特許出願公開第2018/0334454号明細書で開示されている手順に従って、化合物1を製造し得、この明細書は、その全体が参照により本明細書に組み込まれる。
水10mLに化合物1の結晶無水物形態II 1.5gを加えてスラリーを形成することにより、結晶無水物形態Iを調製した。このスラリーを2時間にわたり90℃まで加熱し、次いでRTで一晩撹拌した。固体をろ別し、減圧下で乾燥させ、XRPDにより結晶無水物形態Iと同定した。約292.6℃でのDSC吸熱開始、約25℃から約275℃へと加熱した場合に約0.2%の重量減少を含むTGA。
MeOH 15mLに無水化合物1 0.987gを加えてスラリーを生成することにより、化合物1の結晶無水物形態IIを調製した。単離した固体を、XRPDにより結晶無水物形態IIと同定した。
約65℃~76℃での減圧により化合物1のアセトン溶媒和物形態Iを乾燥させることによって、化合物1の結晶無水物形態IIIを調製した。約194℃でのDSC吸熱開始、約25℃から約250℃へと加熱した場合に重量減少がほぼ無視できるTGA。
RTでMeOHに化合物1を溶解させ、ポリッシュろ過し(polish filtering)、次いで、沈殿が生じるまで抗溶媒として水のアリコートを加えることにより、化合物1の可変水和物形態Iを調製した。13日にわたるRTでの撹拌後、固体を単離した。
開口している小さいバイアルに非結晶化合物1を入れ、次いで、このバイアルを、THFが入ったより大きいバイアル内に置き、蓋をして4日にわたりRTで固体に蒸気ストレスを与えることにより、化合物1の結晶THF溶媒和物形態Iを調製した。
14日にわたるRTでのMeCN中における化合物1のスラリーにより、結晶MeCN溶媒和物形態Iを調製した。
RTでMEKに化合物1を溶解させ、ポリッシュろ過し、次いで、沈殿が生じるまで抗溶媒としてヘプタンのアリコートを加えることにより、結晶MEK溶媒和物形態Iを調製した。13日にわたるRTでの撹拌後、固体を単離した。RTでのMEK中における非結晶化合物1のスラリーによっても調製した。
24時間にわたるRTでの酢酸エチル(EtOAC)中の化合物1のスラリーにより、結晶EtOAc溶媒和物形態Iを調製した。
24時間にわたるRTでのDMF/水中の化合物1のスラリーにより、化合物1の結晶DMF溶媒和物形態Iを調製した。
RTでDCMに化合物1を溶解させ、ポリッシュろ過し、次いで、沈殿が生じるまで抗溶媒としてヘプタンのアリコートを加えることにより、化合物1の結晶DCM溶媒和物形態Iを調製した。1時間にわたるRTでの撹拌後、固体を単離した。
15日にわたるRTでのアセトン/水(50:50)中の非結晶化合物1のスラリー又は2~8℃でのアセトン/水(50:50)中の化合物1のスラリーにより、化合物1の結晶アセトン溶媒和物形態Iを調製した。
15日にわたる2~8℃でのアセトン中の化合物1のスラリーにより、化合物1の結晶アセトン溶媒和物形態IIを調製した。
14日にわたるRTでのp-ジオキサン中の化合物1のスラリーにより、化合物1の結晶p-ジオキサン溶媒和物形態Iを調製した。
開口している小さいバイアルに化合物1を入れ、次いで、このバイアルを、メタノール(MeOH)が入ったより大きいバイアル内に置き、蓋をして4日にわたりRTで固体に蒸気ストレスを与えることにより、化合物1の結晶MeOH溶媒和物形態Iを調製した。
5日にわたるRTでのIPA中の非結晶化合物1のスラリーにより、化合物1の結晶イソプロパノール(IPA)溶媒和物形態Iを調製した。
10日にわたるRTでのエタノール(EtOH)中の非結晶化合物1のスラリーにより、化合物1の結晶EtOH溶媒和物形態Iを調製した。
Claims (9)
- 6-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)-1-(4-メチル-2-(2-プロパニル)-3-ピリジニル)-4-((2S)-2-メチル-4-(2-プロペノイル)-1-ピペラジニル)ピリド[2,3-d]ピリミジン-2(1H)-オン(化合物1)のMアトロプ異性体の結晶であり、-109及び-120ppmでのピークを含む19F固体NMRを特徴とする結晶を含む、KRAS G12C変異癌の処置での使用のための医薬組成物。
- さらに薬学的に許容される添加剤を含む、請求項1に記載の医薬組成物。
- 前記医薬組成物は、経口投与用の剤形である、請求項2に記載の医薬組成物。
- 前記剤形は、固体剤形である、請求項3に記載の医薬組成物。
- 前記固体剤形は、錠剤である、請求項4に記載の医薬組成物。
- 癌が、非小細胞肺癌、小腸癌、虫垂癌、結腸直腸癌、子宮内膜癌、膵臓癌、皮膚癌、胃癌、鼻腔癌、胆管癌又は脳腫瘍である、請求項1~5のいずれか一項に記載の医薬組成物。
- 癌が、非小細胞肺癌である、請求項6に記載の医薬組成物。
- 癌が、結腸直腸癌である、請求項6に記載の医薬組成物。
- 癌が、膵癌である、請求項6に記載の医薬組成物。
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