JP2022518601A - 抗体薬物複合体用薬物リンカーmc-mmafの調製方法及びその中間体 - Google Patents
抗体薬物複合体用薬物リンカーmc-mmafの調製方法及びその中間体 Download PDFInfo
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- JP2022518601A JP2022518601A JP2021544579A JP2021544579A JP2022518601A JP 2022518601 A JP2022518601 A JP 2022518601A JP 2021544579 A JP2021544579 A JP 2021544579A JP 2021544579 A JP2021544579 A JP 2021544579A JP 2022518601 A JP2022518601 A JP 2022518601A
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- AZHFODCZUFTUNZ-KBPBESRZSA-N CC(C)[C@@H](C(NC)=O)NC([C@H](C(C)C)N(C)N(C(C=C1)=O)C1=O)=O Chemical compound CC(C)[C@@H](C(NC)=O)NC([C@H](C(C)C)N(C)N(C(C=C1)=O)C1=O)=O AZHFODCZUFTUNZ-KBPBESRZSA-N 0.000 description 1
- VULIACPNYYTAOH-ZBCVKJESSA-N CC[C@H](C)[C@@H]([C@@H](CC(OC(C)(C)C)=O)OC)N(C)C([C@H](C(C)C)NC([C@H](C(C)C)N(C)N(C(C=C1)=O)C1=O)=O)=O Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(OC(C)(C)C)=O)OC)N(C)C([C@H](C(C)C)NC([C@H](C(C)C)N(C)N(C(C=C1)=O)C1=O)=O)=O VULIACPNYYTAOH-ZBCVKJESSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
- C07K1/062—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha- or omega-carboxy functions
-
- 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
- A61K47/51—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 the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- 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
- A61K47/51—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 the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/113—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure
- C07K1/1136—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure by reversible modification of the secondary, tertiary or quarternary structure, e.g. using denaturating or stabilising agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
Rは、水素、スクシンイミド、ペンタフルオロフェニル、p-ニトロフェニル、フタルアミドから選ばれる一種類であるMC-MMAFを合成する中間体化合物がさらに提供される。表1に示すように、以下の化合物であることが好ましい。
酸濃度範囲が30%~50%である酸性条件を提供するためにトリフルオロ酢酸を選択可能である、
Claims (10)
- 構造式が
Rは水素であり、反応時に試薬Mにより、試薬Nを添加し、前記試薬Mは、DCC、DCEP、EDC、DIC、HATU、HBTU、HBPIPU、HBPyU、HSPyU、HCTU、HOTU、HOTT、HSTU、HDMA、TATU、TBTU、TCTU、TCFH、TDBTU、TOTU、TOTT、TPTU、TFFH、BTFFH、TNTU、TSTU、COMU、T3P、BOP、PyBOP、PyBrOP、PyClOP、BrOP、PyAOP、PyCIU、CDI、TPSI、TSTU、DEPBT、DMTMM、EEDQ、CIP、CIB、DMC、HOAt、HOBt及びEDCIから選ばれる一種類又は複数種類であり、前記試薬Nは、トリエチルアミン、ジイソプロピルエチルアミン(DIEA)、ピリジン、N,N-ジメチル-4-ピリジンから選ばれる一種類又は複数種類であり、
前記溶媒は、ジクロロメタン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、テトラヒドロフラン、1,4-ジオキシヘキサシクロ及び2-メチルテトラヒドロフランから選ばれる一種類又は複数種類であり、
反応温度は-20℃~40℃である、
ことを特徴とするMC-MMAFを合成する方法。 - 前記試薬Mは、EDCIとHOBtとの混合物であり、
前記試薬Nは、ジイソプロピルエチルアミン(DIEA)である、
ことを特徴とする請求項2に記載の方法。 - 反応温度は-10℃~25℃である、
ことを特徴とする請求項2に記載の方法。 - 構造式が
Rは、スクシンイミド、ペンタフルオロフェニル、p-ニトロフェニル、フタルアミドから選ばれる一種類又は複数種類であり、トリエチルアミン、ジイソプロピルエチルアミン(DIEA)、ピリジン、N,N-ジメチル-4-ピリジン、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸リチウム及び炭酸水素リチウムから選ばれる一種類又は複数種類である試薬Pにより反応させ、
前記溶媒は、ジクロロメタン、ジメチルスルホキシド、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、テトラヒドロフラン、1,4-ジオキサン及び2-メチルテトラヒドロフランから選ばれる一種類又は複数種類であり、
反応温度は0℃~100℃である、
ことを特徴とするMC-MMAFを合成する方法。 - 試薬Pは、炭酸ナトリウム又はジイソプロピルエチルアミン(DIEA)である、
ことを特徴とする請求項5に記載の方法。 - 反応温度は15℃~50℃である、
ことを特徴とする請求項5に記載の方法。 - 前記反応が完了した後に、MC-MMAFを反応液から分離する、
ことを特徴とする請求項2から7のいずれか1項に記載の方法。 - 前記分離操作は、減圧により溶媒を蒸発乾燥させ、それから、中圧クロマトグラフィーで精製又は再結晶することを含む、
ことを特徴とする請求項8に記載の方法。
Applications Claiming Priority (3)
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CN201910178142.X | 2019-03-08 | ||
CN201910178142.XA CN109912684A (zh) | 2019-03-08 | 2019-03-08 | 一种用于抗体药物偶联物的药物-连接子mc-mmaf的制备方法及其中间体 |
PCT/CN2019/092950 WO2020181687A1 (zh) | 2019-03-08 | 2019-06-26 | 一种用于抗体药物偶联物的药物-连接子mc-mmaf的制备方法及其中间体 |
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EP (1) | EP3907234A4 (ja) |
JP (1) | JP7292751B2 (ja) |
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CN (1) | CN109912684A (ja) |
AU (1) | AU2019433421B2 (ja) |
CA (1) | CA3127391A1 (ja) |
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CN109912684A (zh) * | 2019-03-08 | 2019-06-21 | 联宁(苏州)生物制药有限公司 | 一种用于抗体药物偶联物的药物-连接子mc-mmaf的制备方法及其中间体 |
CN111328333B (zh) * | 2019-09-29 | 2023-10-03 | 烟台迈百瑞国际生物医药股份有限公司 | 一种酸法制备抗体药物偶联物中间体的方法及其应用 |
WO2024044709A2 (en) * | 2022-08-24 | 2024-02-29 | The Research Foundation For The State University Of New York | Anti-monomethyl auristatin antibodies and antibody fragments |
Citations (4)
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JP2009500424A (ja) * | 2005-07-07 | 2009-01-08 | シアトル ジェネティックス, インコーポレイテッド | フェニルアラニン側鎖修飾をc末端に有するモノメチルバリン化合物 |
WO2017170637A1 (ja) * | 2016-03-29 | 2017-10-05 | 東レ株式会社 | ペプチド誘導体及びその用途 |
WO2018140275A2 (en) * | 2017-01-26 | 2018-08-02 | Seattle Genetics, Inc. | Novel auristatin derivatives and related antibody-drug conjugates (adcs) and methods of preparation thereof |
WO2019042447A1 (zh) * | 2017-09-04 | 2019-03-07 | 江苏恒瑞医药股份有限公司 | 一种新毒素及其中间体的制备方法 |
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- 2019-06-26 EP EP19918805.3A patent/EP3907234A4/en active Pending
- 2019-06-26 WO PCT/CN2019/092950 patent/WO2020181687A1/zh unknown
- 2019-06-26 KR KR1020217023605A patent/KR102590042B1/ko active IP Right Grant
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Patent Citations (4)
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JP2009500424A (ja) * | 2005-07-07 | 2009-01-08 | シアトル ジェネティックス, インコーポレイテッド | フェニルアラニン側鎖修飾をc末端に有するモノメチルバリン化合物 |
WO2017170637A1 (ja) * | 2016-03-29 | 2017-10-05 | 東レ株式会社 | ペプチド誘導体及びその用途 |
WO2018140275A2 (en) * | 2017-01-26 | 2018-08-02 | Seattle Genetics, Inc. | Novel auristatin derivatives and related antibody-drug conjugates (adcs) and methods of preparation thereof |
WO2019042447A1 (zh) * | 2017-09-04 | 2019-03-07 | 江苏恒瑞医药股份有限公司 | 一种新毒素及其中间体的制备方法 |
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US20220119441A1 (en) | 2022-04-21 |
AU2019433421A1 (en) | 2021-08-26 |
EP3907234A1 (en) | 2021-11-10 |
WO2020181687A1 (zh) | 2020-09-17 |
CN109912684A (zh) | 2019-06-21 |
EP3907234A4 (en) | 2022-10-19 |
AU2019433421B2 (en) | 2022-08-18 |
JP7292751B2 (ja) | 2023-06-19 |
CA3127391A1 (en) | 2020-09-17 |
KR20210125484A (ko) | 2021-10-18 |
KR102590042B1 (ko) | 2023-10-17 |
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