JP2020533398A - 抗体薬物複合体中間体の製造方法 - Google Patents
抗体薬物複合体中間体の製造方法 Download PDFInfo
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- JP2020533398A JP2020533398A JP2020515844A JP2020515844A JP2020533398A JP 2020533398 A JP2020533398 A JP 2020533398A JP 2020515844 A JP2020515844 A JP 2020515844A JP 2020515844 A JP2020515844 A JP 2020515844A JP 2020533398 A JP2020533398 A JP 2020533398A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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Abstract
Description
反応A:Py−MAA−Val−Cit−PAB−OHを溶媒に溶解させ、ジ(p−ニトロベンゼン)カーボネートを加え、溶解するか、わずかに濁るまで撹拌した後、有機塩基を加え;
反応B:反応Aが終了した後に、トリアゾール類触媒、薬物部分D、有機塩基を加え、反応終了後、精製し、Py−MAA−Val−Cit−PAB−Dを得る方法であるのが好ましく、この際の精製は、pre−HPLCを使用して実施されることがより好ましい。
反応A:Py−MAA−Val−Cit−PABをDMFに溶解させ、ジ(p−ニトロベンゼン)カーボネートを加え、溶解するか、わずかに濁るまで撹拌した後、N,N−ジイソプロピルエチルアミンを滴下し、分離・精製してPy−MAA−Val−Cit−PAB−PNPを得;
反応B:Py−MAA−Val−Cit−PAB−PNPをDMFに溶解させ、1−ヒドロキシベンゾトリアゾール、MMAE、N,N−ジイソプロピルエチルアミン及びピリジンを加え、反応終了後、pre−HPLCによる精製を行い、構造式(1)で表される化合物Py−MAA−Val−Cit−PAB−MMAEを得る、ことを含む。
ここで、前記Py−MAA−Val−Cit−PAB−PNPの構造は、以下の通りである。
(1)反応Aの反応液を遠心し、上清液を取得し、
(2)上清液に溶媒1を加え、均一に撹拌し、
(3)0〜10℃の条件下で溶媒2を滴下し、均一に撹拌し、
(4)吸引ろ過し、ケーキを取得し、
(5)ケーキを溶媒3と溶媒4の混合溶液に再溶解させ、
(6)0〜10℃の条件下で溶媒5に滴下し、撹拌し、
(7)吸引ろ過して類白色粉末として精製後のPy−MAA−Val−Cit−PAB−PNPを得る。
ここで、溶媒1は、中極性溶媒であり、好ましくは、酢酸エチル、ジクロロメタン、メタノール、メチルtert−ブチルエーテルなどであり、最も好ましくは、酢酸エチルであり、
溶媒2は、低極性溶媒であり、好ましくは、石油エーテル、n−ヘキサン、n−ペンタン、シクロヘキサンなどであり、最も好ましくは、石油エーテルであり、
溶媒3及び4は、Py−MAA−Val−Cit−PAB−PNPが溶解しやすい溶媒であり、好ましくは、酢酸、トリフルオロ酢酸、ギ酸、メタノール、エタノールなどであり、最も好ましくは、酢酸及びメタノールであり、
溶媒5は、Py−MAA−Val−Cit−PAB−PNPが溶解しにくい溶媒であり、好ましくは、アセトニトリル、酢酸エチル、ジクロロメタン、水などであり、最も好ましくは、水である。
前記溶媒1と溶媒2と溶媒3と溶媒4とPy−MAA−Val−Cit−PABの体積重量比は、40〜100:80〜200:5〜15:1〜3:15〜30:1である。
(1)中間生成物Aを遠心し、上清液を取得し、
(2)上清液に酢酸エチルを加え、均一に撹拌し、
(3)0〜10℃の条件下で石油エーテルを滴下し、均一に撹拌し、
(4)吸引ろ過し、ケーキを取得し、
(5)ケーキを酢酸とメタノールの混合溶液に再溶解させ、
(6)0〜10℃の条件下で精製水を滴下し、撹拌し、
(7)吸引ろ過して類白色粉末として精製後のPy−MAA−Val−Cit−PAB−PNPを得る。
他に特に定義されない限り、本明細書で使用される全ての技術用語及び科学用語は、当業者によって理解されるものと同じ意味を有する。
Claims (15)
- リンカー部分と薬物部分とを含む抗体薬物複合体中間体において、前記抗体薬物複合体中間体は、Py−MAA−Val−Cit−PAB−Dであり、前記中間体中のPy−MAA−Val−Cit−PABは、リンカー部分であり、前記中間体の前記Dは、遊離アミノ基を含む連結される薬物部分を示す、抗体薬物複合体中間体の製造方法であって、前記製造方法は、以下の反応経路を含むことを特徴とする抗体薬物複合体中間体の製造方法。
- 反応A:Py−MAA−Val−Cit−PAB−OHを溶媒に溶解させ、ジ(p−ニトロベンゼン)カーボネートを加え、溶解するかわずかに濁るまで撹拌した後、有機塩基を加え、
反応B:反応A終了後、トリアゾール類触媒、薬物部分D、有機塩基を加え、反応終了後、精製し、Py−MAA−Val−Cit−PAB−Dを得る、ことを特徴とする請求項1に記載の製造方法。 - 前記薬物部分Dは、アウリスタチン(auristatin)類細胞毒性剤、アントラマイシン(Anthramycin)類細胞毒性剤、アントラサイクリン(anthracycline)類細胞毒性剤又はピューロマイシン(puromycin)細胞毒性剤であることを特徴とする請求項1又は2に記載の製造方法。
- 前記アウリスタチン(auristatin)類細胞毒性剤は、MMAE、MMAF、MMAD又はその誘導体であり、前記アントラマイシン(Anthramycin)類細胞毒性剤は、アントラマイシン又はその誘導体であり、前記アントラサイクリン(anthracycline)類細胞毒性剤は、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、バルルビシン、ミトキサントロン又はその誘導体であり、前記ピューロマイシン(puromycin)細胞毒性剤は、ピューロマイシン又はその誘導体であることを特徴とする請求項3に記載の製造方法。
- 前記Py−MAA−Val−Cit−PAB−Dの構造が、式(1)−(11)で表されることを特徴とする請求項4に記載の製造方法。
- 前記溶媒は、極性溶媒及び/又は非極性溶媒であり、前記極性溶媒はDMF、DMA、NMPの1種又は複数種であり、前記非極性溶媒はジクロロメタン、四塩化炭素の1種又は複数種である、ことを特徴とする請求項1〜5のいずれか1項に記載の製造方法。
- 前記有機塩基はN,N−ジイソプロピルエチルアミン、トリエチルアミン、ピリジンの1種又は複数種であり、好ましくは、N,N−ジイソプロピルエチルアミン、ピリジンの1種又は2種である、ことを特徴とする請求項1〜6のいずれか1項に記載の製造方法。
- 前記トリアゾール類触媒は1−ヒドロキシベンゾトリアゾール、1−ヒドロキシ−7−アザベンゾトリアゾール、1−ヒドロキシ−1H−1,2,3−トリアゾール−4−カルボン酸エチルの1種又は複数種であり、好ましくは、1−ヒドロキシベンゾトリアゾールである、ことを特徴とする請求項1〜7のいずれか1項に記載の製造方法。
- 前記反応Aにおいて、ジ(p−ニトロベンゼン)カーボネートの添加前、反応系の温度を5〜15℃、さらに好ましくは10℃に制御し、さらに好ましくは、前記反応Aにおいて、有機塩基の添加後、系の温度を20〜35℃、好ましくは30℃に制御する、ことを特徴とする請求項1〜8のいずれか1項に記載の製造方法。
- 前記反応Bにおいて、トリアゾール類触媒の添加前、反応系の温度を5〜15℃、好ましくは10℃に制御し、さらに好ましくは、前記反応Bにおいて、有機塩基の添加後、系の温度を15〜30℃、好ましくは20℃に制御する、ことを特徴とする請求項1〜9のいずれか1項に記載の製造方法。
- 前記反応Aにおいて、Py−MAA−Val−Cit−PAB−OHとジ(p−ニトロベンゼン)カーボネートと有機塩基とのモル比が1:1〜5:1〜3である、ことを特徴とする請求項1〜10のいずれか1項に記載の製造方法。
- 前記反応Bにおいて、トリアゾール類触媒とMMAEと有機塩基とPy−MAA−Val−Cit−PAB−OHとのモル比が1〜3:1〜3:1.5〜30:1である、ことを特徴とする請求項1〜11のいずれか1項に記載の製造方法。
- 前記反応B終了後、pre−HPLCにより精製し、Py−MAA−Val−Cit−PAB−Dを得る、ことを特徴とする請求項1〜12のいずれか1項に記載の製造方法。
- 反応Aは、通常、以下の方法により精製してPy−MAA−Val−Cit−PAB−PNPを得ることを特徴とする請求項1〜13のいずれか1項に記載の製造方法。
(1)反応Aの反応液を遠心し、上清液を得、
(2)上清液に溶媒1を加え、均一に撹拌し、
(3)0〜10℃条件下で溶媒2滴下し、均一に撹拌し、
(4)吸引ろ過し、ケーキを得、
(5)ケーキを溶媒3と溶媒4の混合溶液に再溶解させ、
(6)0〜10℃条件下で溶媒5に滴下し、撹拌し、
(7)吸引ろ過して類白色粉末として精製後のPy−MAA−Val−Cit−PAB−PNPを得る(ここで、溶媒1は、中極性溶媒であり、好ましくは、酢酸エチル、ジクロロメタン、メタノール、メチルtert−ブチルエーテルなどであり、最も好ましくは、酢酸エチルであり、溶媒2は、低極性溶媒であり、好ましくは、石油エーテル、n−ヘキサン、n−ペンタン、シクロヘキサンなどであり、最も好ましくは、石油エーテルであり、溶媒3及び4は、Py−MAA−Val−Cit−PAB−PNPが溶解しやすい溶媒であり、好ましくは、酢酸、トリフルオロ酢酸、ギ酸、メタノール、エタノールなどであり、最も好ましくは、酢酸及びメタノールであり、溶媒5はアセトニトリル、酢酸エチル、ジクロロメタン、水などであることが好ましく、水であることが最も好ましい)。 - 前記反応はいずれも窒素ガス保護下で行われる、ことを特徴とする請求項1〜14のいずれか1項に記載の製造方法。
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