JP2015514741A - 結晶形態の(S)−4−アミノ−N−(1−(4−クロロフェニル)−3−ヒドロキシプロピル)−1−(7H−ピロロ[2,3−d]−ピリミジン−4−イル)ピペリジン−4−カルボキサミド - Google Patents
結晶形態の(S)−4−アミノ−N−(1−(4−クロロフェニル)−3−ヒドロキシプロピル)−1−(7H−ピロロ[2,3−d]−ピリミジン−4−イル)ピペリジン−4−カルボキサミド Download PDFInfo
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Abstract
Description
形態Bの化合物(I)を後記の‘実施例1’に記載する方法により製造し、Bruker D8 X線粉末回折計を用いて分析すると、図3.1のX線粉末回折パターンが得られた(1.54ÅのX線、すなわちCuKα線を使用)。
・MDV−3100(4−{3−[4−シアノ−3−(トリフルオロメチル)−フェニル]−5,5−ジメチル−4−オキソ−2−チオキソイミダゾリジン−1−イル}−2−フルオロ−N−メチルベンズアミド);
・AZD3514(1−{4−[2−(4−{1−[3−(トリフルオロメチル)−7,8−ジヒドロ[1,2,4]トリアゾロ[4,3−b]ピリダジン−6−イル]ピペリジン−4−イル}フェノキシ)エチル]ピペラジン−1−イル}エタノン);
・アビラテロン(abiraterone)、もしくはそのエステルプロドラッグ((3β)−17−(ピリジン−3−イル)アンドロスタ−5,16−ジエン−3−オール “アビラテロン”、または“酢酸アビラテロン”);および
・ビカルタミド(bicalutamide)(N−[4−シアノ−3−(トリフルオロメチル)−フェニル]−3−[(4−フルオロフェニル)−スルホニル]−2−ヒドロキシ−2−メチルプロパンアミド);
またはその医薬的に許容できる塩。
・MDV−3100(4−{3−[4−シアノ−3−(トリフルオロメチル)−フェニル]−5,5−ジメチル−4−オキソ−2−チオキソイミダゾリジン−1−イル}−2−フルオロ−N−メチルベンズアミド);
・AZD3514(1−{4−[2−(4−{1−[3−(トリフルオロメチル)−7,8−ジヒドロ[1,2,4]トリアゾロ[4,3−b]ピリダジン−6−イル]ピペリジン−4−イル}フェノキシ)エチル]ピペラジン−1−イル}エタノン);
・アビラテロン、もしくはそのエステルプロドラッグ((3β)−17−(ピリジン−3−イル)アンドロスタ−5,16−ジエン−3−オール “アビラテロン”、または“酢酸アビラテロン”);および
・ビカルタミド(N−[4−シアノ−3−(トリフルオロメチル)−フェニル]−3−[(4−フルオロフェニル)−スルホニル]−2−ヒドロキシ−2−メチルプロパンアミド);
またはその医薬的に許容できる塩。
・MDV−3100(4−{3−[4−シアノ−3−(トリフルオロメチル)−フェニル]−5,5−ジメチル−4−オキソ−2−チオキソイミダゾリジン−1−イル}−2−フルオロ−N−メチルベンズアミド);
・AZD3514(1−{4−[2−(4−{1−[3−(トリフルオロメチル)−7,8−ジヒドロ[1,2,4]トリアゾロ[4,3−b]ピリダジン−6−イル]ピペリジン−4−イル}フェノキシ)エチル]ピペラジン−1−イル}エタノン);
・アビラテロン、もしくはそのエステルプロドラッグ((3β)−17−(ピリジン−3−イル)アンドロスタ−5,16−ジエン−3−オール “アビラテロン”、または“酢酸アビラテロン”);および
・ビカルタミド(N−[4−シアノ−3−(トリフルオロメチル)−フェニル]−3−[(4−フルオロフェニル)−スルホニル]−2−ヒドロキシ−2−メチルプロパンアミド);
またはその医薬的に許容できる塩。
・MDV−3100(4−{3−[4−シアノ−3−(トリフルオロメチル)−フェニル]−5,5−ジメチル−4−オキソ−2−チオキソイミダゾリジン−1−イル}−2−フルオロ−N−メチルベンズアミド);
・AZD3514(1−{4−[2−(4−{1−[3−(トリフルオロメチル)−7,8−ジヒドロ[1,2,4]トリアゾロ[4,3−b]ピリダジン−6−イル]ピペリジン−4−イル}フェノキシ)エチル]ピペラジン−1−イル}エタノン);
・アビラテロン、もしくはそのエステルプロドラッグ((3β)−17−(ピリジン−3−イル)アンドロスタ−5,16−ジエン−3−オール “アビラテロン”、または“酢酸アビラテロン”);および
・ビカルタミド(N−[4−シアノ−3−(トリフルオロメチル)−フェニル]−3−[(4−フルオロフェニル)−スルホニル]−2−ヒドロキシ−2−メチルプロパンアミド);
またはその医薬的に許容できる塩。
Siemens D5000 X線粉末回折計を用いて形態Aの化合物(I)についてのX線回折データを得た。結晶性物質の試料をSiemensシリコン単結晶(SSC)ウェーハーマウントに載せ、顕微鏡スライドを用いて試料を薄層状に広げることにより、X線粉末回折スペクトルを測定した。試料を30回転/分で旋回させ(計数統計値を改善するために)、40kVおよび40mAで作動する銅ロングファインフォーカス管(long-fine focus tobe)により発生する波長1.54ÅのX線(すなわち、CuKα線)で照射した。コリメーター処理したX線源を、V20に設定した自動可変拡散スリットに通し、反射光線を2mmの散乱防止スリットおよび0.2mmの検出スリットにより方向づけた。試料を1秒/0.02°の2−シータ増分(連続スキャンモード)で2°〜40°の2−シータ範囲にわたってシータ−シータモードで照射した。走行時間は31分41秒であった。この計測器は検出器としてシンチレーション計数器を備えていた。制御およびデータ取得を、Diffract+ソフトウェアで作動するDell Optiplex 686 NT 4.0 Workstationにより行なった。
WO 2009/047563に化合物(I)を製造するための3つの方法が開示されている−例9ならびに代替経路1および2。“例9の代替経路1”には酢酸エチル中の化合物(I)のスラリーが含まれ、他の2方法はカラムの画分を蒸発させることにより化合物(I)を固体として単離している。これら3つの方法のひとつと同一かまたは実質的に類似する操作を用いて合成した我々の化合物コレクションからの化合物(I)の3つの史的バッチをXRDにより分析し、これらの3つすべてを155.2℃(開始点)の融点をもつ形態Aと表示される半結晶形態と同定した。
約20mgの化合物(I)、形態Aを、マグネチックスターラーバーと共にバイアルに入れ、約2mLのアセトニトリルを添加した。バイアルを次いでキャップで密閉し、マグネチックスターラーのプレート上で撹拌しておいた。3日後、試料をプレートから取り出し、キャップをはずし、スラリーを周囲条件下に放置して乾燥させた後、それをXRPDおよびDSCにより分析した。この形態(形態B)は結晶性であるとXRPDにより判定された。この物質は162.3℃(開始点)の融点をもっていた。この方法により製造した形態BのX線粉末回折図を図3.1に示す。
約20mgの化合物(I)、形態Aを、マグネチックフレア(magnetic flea)と共にバイアルに入れ、約2mLのメタノールを添加し、バイアルを次いでキャップで密閉し、マグネチックスターラーのプレート上で撹拌しておいた。3日後、試料をプレートから取り出し、キャップをはずし、スラリーを周囲条件下に放置して乾燥させた後、それをXRPDおよびDSCにより分析した。この形態(形態C)は半結晶性であるとXRPDにより判定された。この物質は142.7℃(開始点)および約149.2℃にピークをもつ融点をもち、続いて161.6℃の開始点および164.5℃にピークをもつさらなる融解吸熱が起きた。
最初に生成した形態Aの化合物(I)を、下記の方法により形態Bに変換できる:化合物(I)を7〜8相対体積の無水エタノールと混合し、この混合物を次いで還流下で70〜75℃に加熱する。混合物を次いで濾過して不溶性粒状物を除去し、濾液を60〜65℃に冷却する。少量の予め調製した種結晶(たとえば、0.重量%の形態Bの化合物(I))を次いで混合物に添加する。反応器を囲む流体を次いで0.3℃/分の冷却速度で−10℃に冷却し、次いで混合物をさらに8〜12時間撹拌した後、生じた固体を濾過により単離する。この湿った固体を次いで減圧下に60〜65℃の温度で乾燥させると、形態Bの化合物(I)が得られる。この方法により製造した形態BのX線粉末回折図を図3.2に示す。この方法により製造した形態Bの化合物(I)のDSC分析は、168.5℃の開始点および171.0℃にピークをもつ融解吸熱を示す(図7)。誤解を避けるために、1“相対体積”は化合物1g当たり1mLの液体を使用することを意味する。
Claims (13)
- 結晶形態の(S)−4−アミノ−N−(1−(4−クロロフェニル)−3−ヒドロキシプロピル)−1−(7H−ピロロ[2,3−d]−ピリミジン−4−イル)ピペリジン−4−カルボキサミド(すなわち、化合物(I))。
- 形態Bの形態である、請求項1に記載の結晶形態の化合物(I)。
- 形態Bの形態であり、その形態Bが、ほぼ2−シータ=12.3°、15.0°および19.2°に少なくとも3つの特異的ピークをもつX線粉末回折パターンを有する、請求項2に記載の結晶形態の化合物(I)。
- 形態Bの形態であり、その形態Bが、ほぼ2−シータ=10.0、12.3、15.0、17.1、19.2および24.4°に特異的ピークをもつX線粉末回折パターンを有する、請求項2に記載の結晶形態の化合物(I)。
- 形態Bの形態であり、その形態Bが、図3.1に示すものと実質的に同じX線粉末回折パターンを有する、請求項2に記載の結晶形態の化合物(I)。
- 形態Bの形態であり、その形態Bが、図3.2に示すものと実質的に同じX線粉末回折パターンを有する、請求項2に記載の結晶形態の化合物(I)。
- 請求項1〜6のいずれか1項に記載の結晶形態の化合物(I)を医薬的に許容できる希釈剤またはキャリヤーと共に含む、医薬組成物。
- 医薬として使用するための、請求項1〜6のいずれか1項に記載の結晶形態の化合物(I)。
- 癌の処置のための医薬を調製するための、請求項1〜6のいずれか1項に記載の結晶形態の化合物(I)の使用。
- 乳癌、前立腺癌または胃癌を処置する方法であって、その必要がある者に医薬有効量の請求項1〜6のいずれか1項に記載の結晶形態の化合物(I)を投与する段階を含む方法。
- 請求項1〜6のいずれか1項に記載の結晶形態の化合物(I)を、微結晶性セルロース、マンニトール、クロスカルメロースナトリウムおよびステアリン酸マグネシウムと共に含む、医薬組成物。
- 50mgから500mgまでの請求項1〜6のいずれか1項に記載の結晶形態の化合物(I)を、1種類以上の医薬的に許容できる賦形剤と共に含む、医薬錠剤。
- 0.5重量%から2重量%までのステアリン酸マグネシウム、2重量%から5重量%までのクロスカルメロースナトリウム、15重量%から60重量%までの請求項1〜6のいずれか1項に記載の結晶形態の化合物(I)、微結晶性セルロースおよびマンニトールを含む医薬錠剤であって、錠剤中の微結晶性セルロースとマンニトールの相対重量が3:1から1:1までであり、錠剤中の結晶形態の化合物(I)の量が50mgから500mgまでである医薬錠剤。
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US20150087661A1 (en) | 2015-03-26 |
AU2013204533A1 (en) | 2013-10-31 |
KR20150002767A (ko) | 2015-01-07 |
RU2652377C2 (ru) | 2018-04-26 |
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EP2847194B1 (en) | 2017-10-04 |
EP2847194A1 (en) | 2015-03-18 |
IL234966A0 (en) | 2014-12-31 |
TW201345913A (zh) | 2013-11-16 |
RU2014143529A (ru) | 2016-06-10 |
CA2869936A1 (en) | 2013-10-24 |
US20170027943A1 (en) | 2017-02-02 |
BR112014025586A2 (ja) | 2017-06-20 |
US9487525B2 (en) | 2016-11-08 |
MY175052A (en) | 2020-06-03 |
SG11201405963YA (en) | 2014-11-27 |
TWI605046B (zh) | 2017-11-11 |
US10039766B2 (en) | 2018-08-07 |
CN104203953B (zh) | 2016-11-16 |
CA2869936C (en) | 2020-07-28 |
JP2018039807A (ja) | 2018-03-15 |
MX2014012642A (es) | 2014-11-25 |
WO2013156772A1 (en) | 2013-10-24 |
ES2650797T3 (es) | 2018-01-22 |
BR112014025586B1 (pt) | 2022-02-22 |
CN104203953A (zh) | 2014-12-10 |
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