JP2018521121A - (z)−4−(5−((3−ベンジル−4−オキソ−2−チオキソチアゾリジン−5−イリデン)メチル)フラン−2−イル)安息香酸の固体形状 - Google Patents
(z)−4−(5−((3−ベンジル−4−オキソ−2−チオキソチアゾリジン−5−イリデン)メチル)フラン−2−イル)安息香酸の固体形状 Download PDFInfo
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
Description
本願は、2015年6月12日に出願された米国特許仮出願第62/175,066号及び2016年1月6日に出願された米国特許仮出願第62/275,655号に対して優先権を主張し、そして、それらの出願全体を参照により本明細書に援用する。
本発明は、NIAID Advanced Technology SBIR(NIAID−AT−SBIR[R43/R44])助成金番号1R43 AI100499−01A1の下で提供された基金を用いて成された。合衆国政府は、本発明において特定の権利を有する。
本発明は、ロイカドヘリン1(LA1;(Z)−4−(5−((3−ベンジル−4−オキソ−2−チオキソチアゾリジン−5−イリデン)メチル)フラン−2−イル)安息香酸)の新規の塩及び結晶形を提供する。LA1のこれらの新しい形態は、経口投与された医薬製剤の増強されたバイオアベイラビリティを含めた多くの利点を提供する。従って、本発明は、β2インテグリン媒介性病態を処置するための改善方法を可能にする。
II.定義
III.LA1塩
IV.医薬組成物
V.処置方法
式Iによる化合物:
免疫チェックポイント阻害剤の処置的に有効な量を投与することを含む。
式IVによる化合物:
PD1抗体の処置的に有効な量を投与することを含む。
式Iによる化合物:
骨髄細胞を標的とする作用物質の処置的に有効な量を投与することを含む癌を処置する方法を提供する。
式Iによる化合物:
免疫チェックポイント阻害剤、骨髄細胞を標的とする作用物質、及びその組み合わせ物から成る群から選択される作用物質の有効量を投与することを含む。
式Iによる化合物:
対象の潜在的転移部位におけるCD11b+白血球の浸潤を低減させることを含む。
樹脂結合抗体によるサイトカインの捕獲とフローサイトメトリーによる検出のためのビーズアレイシステムが挙げられる。
対象の、CD11b、CD18、IDO1、IDO2、TDO、CSF1R、CD14、CD16、CD68、VEGFR、SIRPa、ARG1、UPAR、CD114、CD11a、CD11c、CD11d、CD45、CD4、CD8、FOXP3、CD3、ICAM1、CD31、DESMIN、α−平滑筋アクチン、CD64、CD32、CD89から成る群から選択される1若しくは複数のタンパク質の発現レベルを測定し、そして、該対象にLA1又はその塩若しくは結晶形の処置的に有効な量を投与することを含む。いくつかの実施形態において、タンパク質の発現レベルの測定は、患者から生物検体(生検検体など)を得、そして、その生物検体内のタンパク質の発現レベルを測定することを含む。いくつかの斯かる実施形態において、その方法は、免疫チェックポイント阻害剤の処置的に有効な量を対象に投与することを更に含む。いくつかの斯かる実施形態において、その方法は、評価期間の間のタンパク質の発現レベルを測定し、そして、タンパク質の発現レベルが評価期間の間に変化することが観察された場合、処置を調整することを更に含む。
実施例1.ロイカドヘリンLA1のDMSO溶媒和物形態Iの調製
1H NMR (500 MHz, DMSO) δ 8.10 (d, 2H, J = 8.2 Hz), 7.96 (d, 2H, J = 8.4 Hz), 7.74 (s, 1H), 7.50 (d, 1H, J = 3.8 Hz) 7.42 (d, 1H, J = 4 Hz), 7.37-7.26 (m, 5H), 5.25 (s, 1H), 3.31 (bs, 1H).
表1.LA1のDMSO溶媒和物形態Iの結晶データ
表2.100.0(5)KにおけるロイカドヘリンLA1の位置パラメーター
実施例2.LA1遊離酸の特性解析
表3.20℃におけるLA1の大まかな溶解度
実施例3.LA1塩の調製と特性解析
表4.塩の試験に使用した材料と試薬
スラリー状実験から生じ、選択した固形物を、パルスプログラムを使用したCole-Parmer 130W超音波処理装置を使用して70%の強度にて約8分間、超音波処理した。これらの実験が回収したすべての固形物を、XRPDを使用して分析した。
表5.バイアル内での留去からの結果
表6.スラリー実験からの結果
実施例4.結晶性塩の吸湿性及び水溶解度
表7.湿度ストレス付加実験からの結果
表8.水溶解度の概算からの結果
実施例5.コリン及びメグルミンの製塩のスケールアップ
表9.コリン及びメグルミン塩の結晶化からの結果
実施例6.ロイカドヘリンLA1メグルミン塩形態Hの調製
1H NMR (500 MHz, DMSO) δ 8.04 (d, 2H, J = 8.6 Hz), 7.87 (d, 2H, J = 8.6 Hz), 7.74 (s, 1H), 7.41 (ABq, 2H, JAB = 3.9 Hz), 7.27-7.37 (m, 5H), 5.26 (s, 2H), 3.84 (dt, 1H, J = 4.4, 3.9 Hz), 3.68 (dd, 1H, J = 4.9, 1.5 Hz), 3.60 (dd, 1H, J = 10.9, Hz), 3.50 (m, 1H) 3.44 (dd, 1H, J = 8.1, 1.7 Hz), 3.41 (dd, 1H, J = 10.8, 5.8 Hz), 3.31 (bs, 7H), 2.91 (dd, 1H, J = 12.5, 3.8 Hz), 2.84(dd, 1H, J = 11.3, 7.8 Hz), 2.47 (s, 3H).
表10.ロイカドヘリンLA1のメグルミン塩形態Hに関する粉末X線回折ピーク位置及び強度
実施例7.ロイカドヘリンLA1のメグルミン塩形態Tの調製
1H NMR (500 MHz, DMSO) δ 8.04 (d, 2H, J = 8.6 Hz), 7.87 (d, 2H, J = 8.6 Hz), 7.74 (s, 1H), 7.41 (ABq, 2H, JAB = 3.9 Hz), 7.27-7.37 (m, 5H), 5.26 (s, 2H), 3.84 (dt, 1H, J = 4.4, 3.9 Hz), 3.68 (dd, 1H, J = 4.9, 1.5 Hz), 3.60 (dd, 1H, J = 10.9, Hz), 3.50 (m, 1H) 3.44 (dd, 1H, J = 8.1, 1.7 Hz), 3.41 (dd, 1H, J = 10.8, 5.8 Hz), 3.31 (bs, 7H), 2.91 (dd, 1H, J = 12.5, 3.8 Hz), 2.84(dd, 1H, J = 11.3, 7.8 Hz), 2.47 (s, 3H).
表11.ロイカドヘリンLA1のメグルミン塩形態Tに関する粉末X線回折ピーク位置及び強度
実施例8.LA1メグルミン(NMDG)塩の多形体の精製
表12.プロトン性溶媒中のメグルミン塩の多形体スクリーニング
表13.非プロトン性溶媒中のメグルミン塩の多形体スクリーニング
実施例9.ロイカドヘリンLA1のコリン塩形態Gの調製
1H NMR (500 MHz, DMSO) δ 7.95 (d, 2H, J = 6.8 Hz), 7.75 (d, 2H, J = 7.3 Hz), 7.72 (s, 1H), 7.40 (d, 1H, J = 3.8 Hz), 7.37-7.27 (m, 6H), 5.26 (s, 2H), 3.87-3.83 (m, 2H), 3.42-3.39 (m, 2H), 3.11 (s, 9H).
表14.ロイカドヘリンLA1のコリン塩形態Gに関する粉末X線回折ピーク位置及び強度
実施例10.ロイカドヘリンLA1のコリン塩形態Oの調製
1H NMR (500 MHz, DMSO) δ 7.95 (d, 2H, J = 6.8 Hz), 7.75 (d, 2H, J = 7.3 Hz), 7.72 (s, 1H), 7.40 (d, 1H, J = 3.8 Hz), 7.37-7.27 (m, 6H), 5.26 (s, 2H), 3.87-3.83 (m, 2H), 3.42-3.39 (m, 2H), 3.11 (s, 9H).
表15.ロイカドヘリンLA1のコリン塩形態Oに関する粉末X線回折ピーク位置及び強度
実施例11.ロイカドヘリンLA1のコリン塩形態Qの調製
1H NMR (500 MHz, DMSO) δ 7.95 (d, 2H, J = 6.8 Hz), 7.75 (d, 2H, J = 7.3 Hz), 7.72 (s, 1H), 7.40 (d, 1H, J = 3.8 Hz), 7.37-7.27 (m, 6H), 5.26 (s, 2H), 3.87-3.83 (m, 2H), 3.42-3.39 (m, 2H), 3.11 (s, 9H).
表16.ロイカドヘリンLA1のコリン塩形態Qに関する粉末X線回折ピーク位置及び強度
示差走査熱量測定
表17.塩の様々な形態のDSCサーモグラム測定値
実施例12.LA1コリン塩の多形体の精製
表18.プロトン性溶媒中のコリン塩の多形体スクリーニング
表19.非プロトン性溶媒中のコリン塩の多形体スクリーニング
実施例13.ラットにおけるLA1遊離酸の薬物動態学的特性の解析
表20.PO投与に関するLA1遊離酸のPKデータ
表21.PO及びIP投与に関するLA1遊離酸のPKデータ
実施例14.ラットにおける微粉化LA1遊離酸の薬物動態学的特性の解析
表22.微粉化LA1遊離酸のPO投与に関するPKデータ
実施例15.ラットにおけるLA1塩の薬物動態学的特性の特性解析
結果:
表23.PO及びIP投与に関するLA1コリン塩のPKデータ
表24.PO及びIP投与に関するLA1メグルミン塩のPKデータ
表25.様々な塩の経口投与に関するPKデータの比較
表26.様々な塩のIP投与に関するPKパラメーターの比較
表27.様々な塩のIV投与に関するPKパラメーターの比較
実施例16.ラットにおけるLA1製剤の薬物動態学的特性の特性解析
結果:
表28.LA1製剤の経口投与に関するPKデータの比較
表29.LA1製剤のIV投与に関するPKデータの比較
実施例17.イヌにおけるLA1遊離酸の薬物動態学的特性の特性解析
表30.イヌにおけるLA1遊離酸の経口投与に関するPKデータ
結果:
表31.異なった時間間隔でのIV投与に関する微粉化LA1の血漿中濃度
表32.異なった時間間隔での経口投与に関する微粉化LA1の血漿中濃度
表33.ビーグル犬のIV及び経口PKパラメーターの比較
表34.IV投与に関する様々なビーグル犬の間でのPKパラメーターの比較
表35.経口投与に関する様々なビーグル犬の間でのPKパラメーターの比較
実施例18.イヌにおけるLA1コリン塩の薬物動態学的特性の特性解析
表36.雄ビーグル犬におけるLA1コリン塩の投与に関するPKデータ
表37.異なった時間間隔でのIV投与に関するLA1コリン塩の血漿中濃度
表38.異なった時間間隔での経口投与に関するLA1コリン塩の血漿中濃度
表39.ビーグル犬におけるIV及び経口PKパラメーターの比較
実施例19.C57BL/6マウスにおけるマウス黒色腫B16F10同種移植片を処置するためのLA1のインビボにおける有効性の評価
実施例20.C57BL/6マウスにおけるマウス黒色腫B16F10同種移植片を処置するためのLA1のインビボにおける有効性の評価
α−PD1抗体及びLA1コリン塩(3mg/kg及び10mg/kg)の複合療法は、単独のα−PD1抗体と比較して、それぞれ66%及び68%の更なる腫瘍増殖阻害をもたらした。図26を参照。
Claims (58)
- 式I:
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.6、7.9、11.2、13.3、15.0、15.7、16.1、16.2、16.5、16.6、17.8、18.1、18.5、19.1、19.8、20.0、21.1、23.0、24.6、25.0、25.6、26.6、26.8、26.9、29.3、29.7、30.6、30.7、及び34.4°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項2に記載の結晶形G。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.6、11.2、13.3、15.0、15.7、16.1、16.6、19.1、24.6、25.0、25.6、及び26.8°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項2に記載の結晶形G。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.6、11.2、13.3、15.0、15.7、16.1、16.6、19.1、24.6、25.0、25.6、及び26.8°2θ±0.2°2θから成る群から選択される少なくとも10個のピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項2に記載の結晶形G。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図5BによるX線粉末回折(XRPD)パターンを特徴とする、請求項2に記載の結晶形G。
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、8.4、8.8、9.3、13.3、14.3、16.7、17.0、18.1、19.4、19.6、19.9、20.7、20.9、21.4、21.7、22.5、23.4、24.1、及び25.5°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項7に記載の結晶形O。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、8.4、8.8、9.3、16.7、19.9、20.7、21.7、22.5、23.4、及び25.5°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項7に記載の結晶形O。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図6EによるX線粉末回折(XRPD)パターンを特徴とする、請求項7に記載の結晶形O。
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.0、5.2、8.4、9.6、9.9、11.5、12.6、12.8、13.3、14.4、15.8、16.1、16.6、17.5、18.0、19.3、20.6、20.7、21.5、21.7、22.9、23.7、24.8、25.1、25.3、25.3、25.5、26.3、26.9、27.0、28.1、28.8、30.4、31.2、32.0、35.7、及び37.4°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項11に記載の結晶形Q。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.0、8.4、9.6、9.9、11.5、12.8、13.3、14.4、18.0、19.3、23.7、及び25.5°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項11に記載の結晶形Q。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.0、8.4、9.6、9.9、11.5、12.8、13.3、14.4、18.0、19.3、23.7、及び25.5°2θ±0.2°2θから成る群から選択される少なくとも10個のピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項11に記載の結晶形Q。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図10DによるX線粉末回折(XRPD)パターンを特徴とする、請求項11に記載の結晶形Q。
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.1、5.6、8.0、8.2、8.4、9.8、11.2、12.7、13.4、14.6、15.1、15.7、16.1、16.3、16.7、17.1、17.8、18.2、18.5、19.1、19.9、20.1、21.1、22.6、23.0、23.4、24.0、24.5、24.7、25.0、25.6、26.0、26.6、26.8、27.1、27.4、27.7、28.1、29.3、29.7、30.6、31.1、31.7、32.2、32.8、33.2、33.5、34.5、34.8、35.1、35.4、36.5、37.6、38.5、39.5、40.4、41.3、42.7、及び44.4°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項16に記載の結晶形R。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.6、11.2、15.1、16.3、16.7、19.1、20.1、21.1、23.0、24.5、25.0、25.6、26.0、31.1、32.8、及び33.5±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項16に記載の結晶形R。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.6、11.2、15.1、16.3、16.7、19.1、20.1、21.1、23.0、24.5、25.0、25.6、26.0、31.1、32.8、及び33.5±0.2°2θから成る群から選択される少なくとも9つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項16に記載の結晶形R。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、図7によるX線粉末回折(XRPD)パターンを特徴とする、請求項16に記載の結晶形R。
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.1、8.4、9.6、10.0、11.6、12.9、13.3、14.4、14.9、15.8、16.6、17.4、18.0、19.2、19.3、20.6、21.4、21.7、22.7、23.7、24.8、25.4、26.3、26.8、28.1、28.7、29.6、30.3、31.0、31.9、33.0、34.0、35.7、37.4、39.2、40.5、及び41.7°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項21に記載の結晶形S。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.1、8.4、9.6、10.0、12.9、13.3、16.6、17.4、18.0、19.2、20.6、21.4、21.7、23.7、25.4、及び28.1°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項21に記載の結晶形S。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.1、8.4、9.6、10.0、12.9、13.3、16.6、17.4、18.0、19.2、20.6、21.4、21.7、23.7、25.4、及び28.1°2θ±0.2°2θから成る群から選択される少なくとも10個のピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項21に記載の結晶形S。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図8によるX線粉末回折(XRPD)パターンを特徴とする、請求項21に記載の結晶形S。
- 式I:
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.3、7.1、10.7、10.9、16.1、16.5、17.7、18.5、20.3、23.6、24.9、及び27.2°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項27に記載の結晶形H。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.3、7.1、10.7、10.9、16.1、16.5、17.7、18.5、20.3、23.6、24.9、及び27.2°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項27に記載の結晶形H。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.3、7.1、10.7、10.9、16.1、16.5、17.7、18.5、20.3、23.6、24.9、及び27.2°2θ±0.2°2θから成る群から選択される少なくとも10個のピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項27に記載の結晶形H。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図6BによるX線粉末回折(XRPD)パターンを特徴とする、請求項27に記載の結晶形H。
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.3、7.9、8.5、9.0、9.9、10.6、10.9、11.6、12.0、12.6、13.1、14.5、14.8、15.0、15.3、15.9、16.2、16.9、17.4、17.8、18.0、18.4、18.8、19.2、20.2、20.8、21.3、21.7、22.1、23.2、23.8、24.5、25.2、25.5、26.3、26.9、27.3、27.9、28.4、28.9、29.2、29.8、30.3、30.6、31.1、32.1、32.8、34.1、34.5、34.9、35.1、36.0、36.5、37.5、38.0、38.9、39.6、40.7、41.7、42.5、及び42.9°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項32に記載の結晶形L。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、8.5、9.0、10.9、15.0、16.9、20.2、21.7、23.8、24.5、25.2、26.3、29.2、及び29.8°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項32に記載の結晶形L。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、8.5、9.0、10.9、15.0、16.9、20.2、21.7、23.8、24.5、25.2、26.3、29.2、及び29.8°2θ±0.2°2θから成る群から選択される少なくとも10個のピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項32に記載の結晶形L。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図11によるX線粉末回折(XRPD)パターンを特徴とする、請求項32に記載の結晶形L。
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、6.5、8.5、9.0、9.9、10.6、11.6、14.4、14.8、15.0、15.3、15.9、16.1、16.9、17.8、18.0、19.0、20.4、20.8、21.3、21.7、23.6、24.5、25.2、26.3、26.9、27.5、27.9、28.5、28.9、29.8、30.6、32.1、32.8、33.8、34.5、36.0、36.4、37.1、38.0、39.7、40.7、41.7、43.0、及び44.0°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項37に記載の結晶形M。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、8.5、9.0、14.8、15.0、16.9、18.0、21.7、24.5、25.2、26.3、及び29.8°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項37に記載の結晶形M。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、8.5、9.0、14.8、15.0、16.9、18.0、21.7、24.5、25.2、26.3、及び29.8±0.2°2θから成る群から選択される少なくとも9つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項37に記載の結晶形M。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図12によるX線粉末回折(XRPD)パターンを特徴とする、請求項37に記載の結晶形M。
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、4.3、5.0、5.4、6.1、7.5、7.9、8.9、9.5、10.0、10.8、11.4、12.1、12.5、13.8、14.3、14.8、15.6、16.1、16.7、17.4、18.1、19.2、19.5、20.1、20.9、21.4、21.5、22.1、22.5、23.9、24.6、25.3、26.3、26.7、27.1、27.6、28.2、29.0、30.4、30.9、32.0、32.9、33.9、34.7、36.9、38.3、39.1、39.6、40.2、及び41.4°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項42に記載の結晶形N。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、6.1、7.9、8.9、9.5、10.0、12.5、14.3、14.8、15.6、16.1、17.4、18.1、19.5、20.9、21.4、21.5、23.9、24.6、25.3、及び29.0°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項42に記載の結晶形N。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、6.1、7.9、8.9、9.5、10.0、12.5、14.3、14.8、15.6、16.1、17.4、18.1、19.5、20.9、21.4、21.5、23.9、24.6、25.3、及び29.0°2θ±0.2°2θから成る群から選択される少なくとも10個のピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項42に記載の結晶形N。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図13によるX線粉末回折(XRPD)パターンを特徴とする、請求項42に記載の結晶形N。
- 式I:
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、6.9、8.2、8.4、9.4、11.6、15.0、15.1、15.5、17.2、17.8、18.1、20.5、21.3、21.9、22.3、23.5、25.0、及び26.7°2θ±0.2°2θから成る群から選択される少なくとも3つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項47に記載の結晶形T。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、6.9、8.4、9.4、11.6、15.5、17.2、21.3、21.9、22.3、23.5、25.0、及び26.7°2θ±0.2°2θから成る群から選択される少なくとも6つのピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項47に記載の結晶形T。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、5.3、7.1、10.7、10.9、16.1、16.5、17.7、18.5、20.3、23.6、24.9、及び27.2°2θ±0.2°2θから成る群から選択される少なくとも10個のピークを含むX線粉末回折(XRPD)パターンを特徴とする、請求項47に記載の結晶形T。
- Cu−Kα放射線を使用したディフラクトメーターで測定した場合に、実質的に図10EによるX線粉末回折(XRPD)パターンを特徴とする、請求項47に記載の結晶形T。
- 医薬的に許容し得る賦形剤、及び、請求項1に記載の塩、請求項26に記載の塩、請求項2〜25のいずれか1項に記載の結晶形、又は請求項27〜51のいずれか1項に記載の結晶形を含む医薬製剤。
- 医薬的に許容し得る賦形剤、及び、実質的に式I:
を含む、医薬製剤。 - 前記粒子の平均直経が、25μm未満である、請求項53に記載の医薬製剤。
- 前記粒子が、実質的に式(I)の化合物の遊離酸形態から成る、請求項53又は請求項54に記載の医薬製剤。
- β2インテグリン媒介性病態を処置するための方法であって、それを必要としている患者に、請求項1に記載の塩、請求項26に記載の塩、請求項2〜25のいずれか1項に記載の結晶形請求項27〜51のいずれか1項に記載の結晶形、又は請求項52〜55のいずれか1項に記載の医薬製剤を投与することを含む方法。
- 前記β2インテグリン媒介性病態が、急性炎症、慢性炎、慢性の腎臓病、血管障害に関連した新生内膜肥厚、組織傷害、腹膜炎、糖尿病性腎症、自己免疫疾患、癌、緑内障、移植片対宿主病、黄斑変性、及びブドウ膜炎から成る群から選択される、請求項56に記載の方法。
- β2インテグリン媒介性病態が癌である、請求項57に記載の方法。
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