JP2018503649A - C21H22Cl2N4O2の結晶形態 - Google Patents
C21H22Cl2N4O2の結晶形態 Download PDFInfo
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- JP2018503649A JP2018503649A JP2017539596A JP2017539596A JP2018503649A JP 2018503649 A JP2018503649 A JP 2018503649A JP 2017539596 A JP2017539596 A JP 2017539596A JP 2017539596 A JP2017539596 A JP 2017539596A JP 2018503649 A JP2018503649 A JP 2018503649A
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- crystalline
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- pyrrole
- chlorophenyl
- chloro
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Description
本特許出願は、2015年1月30日に出願された米国仮特許出願第62/110,449号に対する利益を主張し、これはその全体が本明細書において参考として援用される。
本発明は、ERKタンパク質キナーゼの阻害剤として有用な、4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの結晶形態に関する。
医薬組成物の製剤のための特性の改善を呈する4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの結晶形態に対する必要は満たされていない。本出願は、この必要および他の必要を満たすことを対象とする。
実験方法
粉末X線回折(XRPD)
透過モードによるXRPDパターンは、微小焦点線源を使用して発生させた、Cu放射の入射ビームを使用して収集した。楕円傾斜多層ミラーを使用して、標本を通り検出器に向かうCu KαX線放射の焦点を絞った。解析の前に、ケイ素標本(NIST SRM 640d)について解析して、観察されたSi 111ピークの位置が、NISTにより認定された位置と符合することを検証した。試料の標本を、3μmの厚さの薄膜の間に挟み、透過型配置により解析した。ビームストップ、短型散乱防止エクステンション、および散乱防止ナイフエッジを使用して、空気により生じるバックグラウンドを最小化した。入射ビームおよび回折ビームのためのソラースリットを使用して、軸発散に由来するブロードニングを最小化した。回折パターンは、標本から240mmに配置された走査位置感受性検出器を使用して収集した。好ましい配向および静的粒子効果については、評価しなかった。
FT−IRスペクトルは、中/遠IR線源、範囲拡張型臭化カリウム(KBr)ビームスプリッター、および重水素化硫酸トリグリシン(DTGS)検出器を装備したフーリエ変換赤外分光光度計を使用して得た。波長の検証は、NIST SRM 1921b(ポリスチレン)を使用して実施した。ゲルマニウム(Ge)結晶を伴う減衰全反射(ATR)アクセサリーを、データを得るために使用した。重ね合わせた256の走査を2cm−1のスペクトル解像度で収集した。バックグラウンドデータセットは、不純物を含まないGe結晶で得た。これらの2つのデータセットの、互いに対する比を取ることにより、log 1/R(R=反射率)スペクトルを得た。ピークの選択は、ベースライン近傍の絶対閾値および75の感度を使用して実施した。
DSC解析は、示差走査熱量測定計を使用して実施した。温度較正は、NISTトレーサブルのインジウム金属を使用して実施した。試料を、アルミニウム製のDSCパンに入れ、蓋で覆い、重量を正確に記録した。試料パンとして構成された、秤量されたアルミニウム製のT0HSMPパンを、セルの基準側に置いた。そうでないことが指定されない限り、報告される温度は、1の度数へと丸めた。
ラマン分光分析を、in situにおける反応モニタリングのために分散RamanRXN3(Kaiser Optical Systems Inc.、Ann Arbor、MI)を使用して実施した。RamanRXN3システムは、外付けの共振器安定化ダイオードレーザーによる、785nmの励起波長を使用する。全てのスペクトルは、プローブの先端におけるレーザー出力を約103mWとする、1/4インチの水浸光プローブを使用して得た。スペクトルは、5〜15秒間の曝露時間を使用して収集し、5つのスペクトルを集積した。波長較正およびレーザー波長較正は、それぞれ、内部ネオン標準物質、およびダイアモンドラマンシフト標準物質を使用して実施した。強度較正は、Kaiser Raman較正アクセサリー(Kaiser Optical Systems Inc.、Ann Arbor、MI)を使用して実施した。
結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの調製
4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの遊離塩基は、以下の合成スキームに従い調製した。
表2: 4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの遊離塩基について観察されたXRPDピーク
表4: 4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの遊離塩基について観察されたFT−IRピーク
4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Cの調製
4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Cの代替的調製
表5: 4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Cについて観察されたXRPDピーク
表7: 4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Cについての観察されたFT−IRピーク
4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Aの調製
4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Cを、60℃でメタノールに溶解させ、その結果、透明な溶液が得られた。試料を、60℃から周囲温度へとゆっくりと冷却し、続いて、急速に蒸発させた。4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Aが、白色の固体/針状結晶として形成された。
表8: 4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Aについて観察されたXRPDピーク
表10: 4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Aについての観察されたFT−IRピーク
4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Dの調製
4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Aを含有する容器を、乾燥窒素でパージし、相対湿度をモニタリングした。約73分後、相対湿度は、36.9%から1.0%へと減少した。結果として得られた材料について解析し、新たな形態であることを決定し、形態Dと名付けた。
表11: 4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Dについて観察されたXRPDピーク
表13: 4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Dについての観察されたFT−IRピーク
ラマン分光分析による、4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Aと形態Cとの比較
4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドの形態Aおよび形態Cの各々の試料を、24℃のエタノール:メタノール:イソプロパノール(90:5:5)混合物中、60mg/mlで調製した。ラマン分光分析を、実施例1で記載した通りに、各試料および溶媒単独に対して実施した。
参考文献
(項目1)
結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミド。
(項目2)
結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミド。
(項目3)
約19.5°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、式:
(項目4)
約9.1および19.5°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
(項目5)
約9.1、15.4、19.5および21.4°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
(項目6)
約9.1、12.5、15.2、15.4、19.2、19.5、20.3、20.5、21.4、21.7、21.9、23.1、23.3、23.6および24.3からなる群から選択される、1または複数のXRPD 2θ反射(°)を有する、式:
(項目7)
実質的に図1に示される通りのXRPDパターンを有する、式:
(項目8)
約1603、1533、1487、1080、857および681cm−1における1または複数のピークを含むフーリエ変換赤外分光分析(FT−IR)スペクトルを有する、項目2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目9)
実質的に図2に示される通りのFT−IRスペクトルを有する、項目2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目10)
(i)約9.1、15.4、19.5および21.4°の2θにおける1または複数のピークを含むXRPDパターン;ならびに(ii)約1603、1533、1487、1080、857および681cm−1における1または複数のピークを含むFT−IRスペクトルを有する、項目2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目11)
約184℃の開始温度を有する吸熱を伴うDSCサーモグラムを有する、項目2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目12)
実質的に図3に示される通りのDSCサーモグラムを有する、項目2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目13)
項目1から12に記載の結晶性化合物を含む医薬組成物。
(項目14)
がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の項目1から12のいずれか一項に記載の結晶性化合物を投与するステップを含む方法。
(項目15)
前記対象が、哺乳動物である、項目14に記載の方法。
(項目16)
前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、項目15に記載の方法。
(項目17)
前記哺乳動物が、ヒトである、項目15に記載の方法。
(項目18)
前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、項目14に記載の方法。
(項目19)
がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の項目13に記載の医薬組成物を投与するステップを含む方法。
(項目20)
前記対象が、哺乳動物である、項目19に記載の方法。
(項目21)
前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、項目20に記載の方法。
(項目22)
前記哺乳動物が、ヒトである、項目20に記載の方法。
(項目23)
前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、項目19に記載の方法。
(項目24)
結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目25)
約6.7°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、式:
(項目26)
約6.7および11.0°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
(項目27)
約6.7、11.0、17.6および19.9°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
(項目28)
約6.1、6.7、11.0、12.1、13.7、15.2、16.5、17.6、17.9、18.4、18.7、19.6、19.9および20.4からなる群から選択される、1または複数のXRPD 2θ反射(°)を有する、式:
(項目29)
実質的に図4に示される通りのXRPDパターンを有する、式:
(項目30)
約1610、1523、1219、1141、1076および845cm−1における1または複数のピークを含むフーリエ変換赤外分光分析(FT−IR)スペクトルを有する、形態Cの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目31)
実質的に図5に示される通りのFT−IRスペクトルを有する、形態Cの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目32)
(i)約6.7、11.0、17.6および19.9°の2θにおける1または複数のピークを含むXRPDパターン;ならびに(ii)約1610、1523、1219、1141、1076および845cm−1における1または複数のピークを含むFT−IRスペクトルを有する、形態Cの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目33)
約239℃の開始温度を有する吸熱を伴うDSCサーモグラムを有する、形態Cの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目34)
実質的に図6に示される通りのDSCサーモグラムを有する、形態Cの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
(項目35)
項目24から34のいずれか一項に記載の結晶性化合物を含む医薬組成物。
(項目36)
がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の項目24から34のいずれか一項に記載の結晶性化合物を投与するステップを含む方法。
(項目37)
前記対象が、哺乳動物である、項目36に記載の方法。
(項目38)
前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、項目37に記載の方法。
(項目39)
前記哺乳動物が、ヒトである、項目37に記載の方法。
(項目40)
前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、項目36に記載の方法。
(項目41)
がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の項目35に記載の医薬組成物を投与するステップを含む方法。
(項目42)
前記対象が、哺乳動物である、項目41に記載の方法。
(項目43)
前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、項目42に記載の方法。
(項目44)
前記哺乳動物が、ヒトである、項目42に記載の方法。
(項目45)
前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、項目41に記載の方法。
(項目46)
結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
(項目47)
約10.5°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、式:
(項目48)
約6.2および10.5°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
(項目49)
約6.2、10.5、22.4および28.5°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
(項目50)
約5.8、5.9、6.2、10.5、11.8、12.4、15.9、17.6、17.8、20.0、20.4、21.1、21.4、21.9、22.4、23.1、24.0、24.2、24.9および25.3からなる群から選択される、1または複数のXRPD 2θ反射(°)を有する、式:
(項目51)
実質的に図7に示される通りのXRPDパターンを有する、式:
(項目52)
約1573、1237、1163、946および790cm−1における1または複数のピークを含むフーリエ変換赤外分光分析(FT−IR)スペクトルを有する、形態Aの項目46に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
(項目53)
実質的に図8に示される通りのFT−IRスペクトルを有する、形態Aの項目46に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
(項目54)
(i)約6.2、10.5、22.4および28.5°の2θにおける1または複数のピークを含むXRPDパターン;ならびに(ii)約1573、1237、1163、946および790cm−1における1または複数のピークを含むFT−IRスペクトルを有する、形態Aの項目46に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
(項目55)
実質的に図9に示される通りのDSCサーモグラムを有する、形態Aの項目46に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
(項目56)
項目46から55のいずれか一項に記載の結晶性化合物を含む医薬組成物。
(項目57)
がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の項目46から55のいずれか一項に記載の結晶性化合物を投与するステップを含む方法。
(項目58)
前記対象が、哺乳動物である、項目57に記載の方法。
(項目59)
前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、項目58に記載の方法。
(項目60)
前記哺乳動物が、ヒトである、項目58に記載の方法。
(項目61)
前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、項目57に記載の方法。
(項目62)
がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の項目56に記載の医薬組成物を投与するステップを含む方法。
(項目63)
前記対象が、哺乳動物である、項目62に記載の方法。
(項目64)
前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、項目63に記載の方法。
(項目65)
前記哺乳動物が、ヒトである、項目63に記載の方法。
(項目66)
前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、項目62に記載の方法。
(項目67)
約10.7°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、式:
(項目68)
約10.7および18.1°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
(項目69)
約6.0、10.7、12.7および18.1°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
(項目70)
約6.0、6.3、10.7、12.0、12.7、15.6、16.2、16.3、16.7、17.9、18.1および21.4からなる群から選択される、1または複数のXRPD 2θ反射(°)を有する、式:
(項目71)
実質的に図10に示される通りのXRPDパターンを有する、式:
(項目72)
約1537、1471、1239、1163、1067および946cm−1における1または複数のピークを含むフーリエ変換赤外分光分析(FT−IR)スペクトルを有する、形態Dの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl。
(項目73)
実質的に図11に示される通りのFT−IRスペクトルを有する、形態Dの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl。
(項目74)
(i)約6.0、12.7および18.1°の2θにおける1または複数のピークを含むXRPDパターン;ならびに(ii)約1537、1471、1239、1163、1067および946cm−1における1または複数のピークを含むFT−IRスペクトルを有する、形態Dの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl。
(項目75)
実質的に図12に示される通りのDSCサーモグラムを有する、形態Dの項目24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl。
(項目76)
項目67から75のいずれか一項に記載の結晶性化合物を含む医薬組成物。
(項目77)
がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の項目67から75のいずれか一項に記載の結晶性化合物を投与するステップを含む方法。
(項目78)
前記対象が、哺乳動物である、項目77に記載の方法。
(項目79)
前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、項目78に記載の方法。
(項目80)
前記哺乳動物が、ヒトである、項目78に記載の方法。
(項目81)
前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、項目77に記載の方法。
(項目82)
がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の項目76に記載の医薬組成物を投与するステップを含む方法。
(項目83)
前記対象が、哺乳動物である、項目82に記載の方法。
(項目84)
前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、項目83に記載の方法。
(項目85)
前記哺乳動物が、ヒトである、項目83に記載の方法。
(項目86)
前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、項目82に記載の方法。
Claims (86)
- 約19.5°の2θ、6.7°の2θ、10.5°の2θまたは10.7°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミド。
- 結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミド。
- 約19.5°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、式:
- 約9.1および19.5°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
- 約9.1、15.4、19.5および21.4°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
- 約9.1、12.5、15.2、15.4、19.2、19.5、20.3、20.5、21.4、21.7、21.9、23.1、23.3、23.6および24.3からなる群から選択される、1または複数のXRPD 2θ反射(°)を有する、式:
- 実質的に図1に示される通りのXRPDパターンを有する、式:
- 約1603、1533、1487、1080、857および681cm−1における1または複数のピークを含むフーリエ変換赤外分光分析(FT−IR)スペクトルを有する、請求項2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 実質的に図2に示される通りのFT−IRスペクトルを有する、請求項2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- (i)約9.1、15.4、19.5および21.4°の2θにおける1または複数のピークを含むXRPDパターン;ならびに(ii)約1603、1533、1487、1080、857および681cm−1における1または複数のピークを含むFT−IRスペクトルを有する、請求項2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 約184℃の開始温度を有する吸熱を伴うDSCサーモグラムを有する、請求項2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 実質的に図3に示される通りのDSCサーモグラムを有する、請求項2に記載の結晶性遊離塩基4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 請求項1から12のいずれか一項に記載の結晶性化合物を含む医薬組成物。
- がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の請求項1から12のいずれか一項に記載の結晶性化合物を投与するステップを含む方法。
- 前記対象が、哺乳動物である、請求項14に記載の方法。
- 前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、請求項15に記載の方法。
- 前記哺乳動物が、ヒトである、請求項15に記載の方法。
- 前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、請求項14に記載の方法。
- がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の請求項13に記載の医薬組成物を投与するステップを含む方法。
- 前記対象が、哺乳動物である、請求項19に記載の方法。
- 前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、請求項20に記載の方法。
- 前記哺乳動物が、ヒトである、請求項20に記載の方法。
- 前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、請求項19に記載の方法。
- 約6.7°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 約6.7°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、式:
- 約6.7および11.0°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
- 約6.7、11.0、17.6および19.9°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
- 約6.1、6.7、11.0、12.1、13.7、15.2、16.5、17.6、17.9、18.4、18.7、19.6、19.9および20.4からなる群から選択される、1または複数のXRPD 2θ反射(°)を有する、式:
- 実質的に図4に示される通りのXRPDパターンを有する、式:
- 約1610、1523、1219、1141、1076および845cm−1における1または複数のピークを含むフーリエ変換赤外分光分析(FT−IR)スペクトルを有する、形態Cの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 実質的に図5に示される通りのFT−IRスペクトルを有する、形態Cの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- (i)約6.7、11.0、17.6および19.9°の2θにおける1または複数のピークを含むXRPDパターン;ならびに(ii)約1610、1523、1219、1141、1076および845cm−1における1または複数のピークを含むFT−IRスペクトルを有する、形態Cの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 約239℃の開始温度を有する吸熱を伴うDSCサーモグラムを有する、形態Cの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 実質的に図6に示される通りのDSCサーモグラムを有する、形態Cの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドモノHCl。
- 請求項24から34のいずれか一項に記載の結晶性化合物を含む医薬組成物。
- がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の請求項24から34のいずれか一項に記載の結晶性化合物を投与するステップを含む方法。
- 前記対象が、哺乳動物である、請求項36に記載の方法。
- 前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、請求項37に記載の方法。
- 前記哺乳動物が、ヒトである、請求項37に記載の方法。
- 前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、請求項36に記載の方法。
- がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の請求項35に記載の医薬組成物を投与するステップを含む方法。
- 前記対象が、哺乳動物である、請求項41に記載の方法。
- 前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、請求項42に記載の方法。
- 前記哺乳動物が、ヒトである、請求項42に記載の方法。
- 前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、請求項41に記載の方法。
- 結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
- 約10.5°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、式:
- 約6.2および10.5°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
- 約6.2、10.5、22.4および28.5°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
- 約5.8、5.9、6.2、10.5、11.8、12.4、15.9、17.6、17.8、20.0、20.4、21.1、21.4、21.9、22.4、23.1、24.0、24.2、24.9および25.3からなる群から選択される、1または複数のXRPD 2θ反射(°)を有する、式:
- 実質的に図7に示される通りのXRPDパターンを有する、式:
- 約1573、1237、1163、946および790cm−1における1または複数のピークを含むフーリエ変換赤外分光分析(FT−IR)スペクトルを有する、形態Aの請求項46に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
- 実質的に図8に示される通りのFT−IRスペクトルを有する、形態Aの請求項46に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
- (i)約6.2、10.5、22.4および28.5°の2θにおける1または複数のピークを含むXRPDパターン;ならびに(ii)約1573、1237、1163、946および790cm−1における1または複数のピークを含むFT−IRスペクトルを有する、形態Aの請求項46に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
- 実質的に図9に示される通りのDSCサーモグラムを有する、形態Aの請求項46に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl水和物。
- 請求項46から55のいずれか一項に記載の結晶性化合物を含む医薬組成物。
- がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の請求項46から55のいずれか一項に記載の結晶性化合物を投与するステップを含む方法。
- 前記対象が、哺乳動物である、請求項57に記載の方法。
- 前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、請求項58に記載の方法。
- 前記哺乳動物が、ヒトである、請求項58に記載の方法。
- 前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、請求項57に記載の方法。
- がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の請求項56に記載の医薬組成物を投与するステップを含む方法。
- 前記対象が、哺乳動物である、請求項62に記載の方法。
- 前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、請求項63に記載の方法。
- 前記哺乳動物が、ヒトである、請求項63に記載の方法。
- 前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、請求項62に記載の方法。
- 約10.7°の2θにおいて特徴的ピークを含む粉末X線回折(XRPD)パターンを有する、式:
- 約10.7および18.1°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
- 約6.0、10.7、12.7および18.1°の2θにおいて特徴的ピークを含むXRPDパターンを有する、式:
- 約6.0、6.3、10.7、12.0、12.7、15.6、16.2、16.3、16.7、17.9、18.1および21.4からなる群から選択される、1または複数のXRPD 2θ反射(°)を有する、式:
- 実質的に図10に示される通りのXRPDパターンを有する、式:
- 約1537、1471、1239、1163、1067および946cm−1における1または複数のピークを含むフーリエ変換赤外分光分析(FT−IR)スペクトルを有する、形態Dの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl。
- 実質的に図11に示される通りのFT−IRスペクトルを有する、形態Dの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl。
- (i)約6.0、12.7および18.1°の2θにおける1または複数のピークを含むXRPDパターン;ならびに(ii)約1537、1471、1239、1163、1067および946cm−1における1または複数のピークを含むFT−IRスペクトルを有する、形態Dの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl。
- 実質的に図12に示される通りのDSCサーモグラムを有する、形態Dの請求項24に記載の結晶性4−(5−クロロ−2−イソプロピルアミノピリジン−4−イル)−1H−ピロール−2−カルボン酸[1−(3−クロロフェニル)−2−ヒドロキシエチル]アミドHCl。
- 請求項67から75のいずれか一項に記載の結晶性化合物を含む医薬組成物。
- がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の請求項67から75のいずれか一項に記載の結晶性化合物を投与するステップを含む方法。
- 前記対象が、哺乳動物である、請求項77に記載の方法。
- 前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、請求項78に記載の方法。
- 前記哺乳動物が、ヒトである、請求項78に記載の方法。
- 前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、請求項77に記載の方法。
- がんの処置を必要とする対象においてがんを処置する方法であって、前記対象に有効量の請求項76に記載の医薬組成物を投与するステップを含む方法。
- 前記対象が、哺乳動物である、請求項82に記載の方法。
- 前記哺乳動物が、ヒト、霊長動物、農場動物および家畜からなる群から選択される、請求項83に記載の方法。
- 前記哺乳動物が、ヒトである、請求項83に記載の方法。
- 前記対象に少なくとも1つの追加の抗がん剤を投与することをさらに含む、請求項82に記載の方法。
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