RU2015149527A - Производные доластатина 10 и ауристатинов - Google Patents

Производные доластатина 10 и ауристатинов Download PDF

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RU2015149527A
RU2015149527A RU2015149527A RU2015149527A RU2015149527A RU 2015149527 A RU2015149527 A RU 2015149527A RU 2015149527 A RU2015149527 A RU 2015149527A RU 2015149527 A RU2015149527 A RU 2015149527A RU 2015149527 A RU2015149527 A RU 2015149527A
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compound
group
following formula
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phenyl
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Мишель ПЕРЕС
Айан РИЛАТТ
Мари ЛАМОТ
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Пьер Фабр Медикамент
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Claims (49)

1. Соединение приведенной ниже формулы (I):
Figure 00000001
где
- R1=ОН, и R2= метил, или
R1=Н, и R2=СООН, СООМе или тиазол-2-ил,
- R3 представляет собой (С1-С6)алкильную группу, и
- R4 представляет собой фенил-(С1-С2)алкильную группу, замещенную одной группой, выбранной из групп ОН и NR9R10, где R9 и R10, каждый независимо от другого, представляет собой Н или (С1-С6)алкильную группу,
или его фармацевтически приемлемая соль, гидрат или сольват.
2. Соединение по п. 1, отличающееся тем, что R1 представляет собой Н, и R2 представляет собой СООН или СООМе.
3. Соединение по п. 1, отличающееся тем, что R3 представляет собой метильную группу.
4. Соединение по п. 1, отличающееся тем, что R4 представляет собой фенил-(С1-С2)алкильную группу, замещенную одной группой на фенильной группировке, выбранной из ОН и NR9R10.
5. Соединение по п. 4, отличающееся тем, что R4 представляет собой фенил-(С1-С2)алкильную группу, замещенную одной группой NR9R10 на фенильной группировке.
6. Соединение по п. 1, отличающееся тем, что R4 имеет следующую формулу:
Figure 00000002
где Х0 представляет собой ОН или NR9R10, и m представляет собой 1 или 2.
7. Соединение по п. 6, отличающееся тем, что Х0 представляет собой NR9R10.
8. Соединение по п. 1, отличающееся тем, что R4 имеет следующую формулу:
Figure 00000003
где Х0 представляет собой NR9R10, и m представляет собой 1 или 2.
9. Соединение по п. 1, выбранное из:
Figure 00000004
Figure 00000005
Figure 00000006
Figure 00000007
Figure 00000008
и их фармацевтически приемлемых солей, таких как соли, образованные с трифторуксусной кислотой.
10. Соединение по любому из пп. 1-9 для применения в качестве лекарственного препарата.
11. Соединение по любому из пп. 1-9 для применения в качестве лекарственного препарата, предназначенного для лечения рака или доброкачественных пролиферативных расстройств.
12. Фармацевтическая композиция, содержащая соединение формулы (I) по любому из пп. 1-9 и по меньшей мере один фармацевтически приемлемый эксципиент.
13. Фармацевтическая композиция по п. 12, дополнительно содержащая другой активный ингредиент, преимущественно выбранный из противораковых средств, в частности, включающих в себя цитотоксические противораковые средства, такие как навельбин, винфлунин, таксол, таксотер, 5-фторурацил, метотрексат, доксорубицин, камптотецин, гемцитабин, этопозид, цисплатин или кармустин; и гормональные противораковые средства, такие как тамоксифен или медроксипрогестерон.
14. Способ получения соединения формулы (I) по любому из пп. 1-9, включающий реакцию конденсации между соединением приведенной ниже формулы (VI):
Figure 00000009
где R1 и R2 являются такими, как определено в п. 1, и
соединением приведенной ниже формулы (VII):
Figure 00000010
где R3 является таким, как определено в п. 1, R4a представляет собой группу R4, как определено в п. 1, необязательно в защищенной форме, и X представляет собой ОН или Cl.
15. Способ получения соединения формулы (I) по любому из пп. 1-9, включающий реакцию замещения между соединением приведенной ниже формулы (VIII):
Figure 00000011
где R1, R2 и R3 являются такими, как определено в п. 1, и
соединением приведенной ниже формулы (X):
Figure 00000012
где R4a представляет собой группу R4, как определено в п. 1, необязательно в защищенной форме, и Y представляет собой уходящую группу, такую как Cl, Br, I, OSO2CH3, OSO2CF3 или О-тозил.
16. Способ получения соединения формулы (I) по любому из пп. 1-9, где R4 представляет собой группу -CH2R4b, где R4b представляет собой группу фенил или фенил-метил, замещенную одной группой, выбранных из групп ОН и NR9R10,
включающий реакцию восстановительного аминирования между соединением приведенной ниже формулы (VIII):
Figure 00000013
где R1, R2 и R3 являются такими, как определено в п. 1, и
соединением приведенной ниже формулы (XI):
Figure 00000014
где R4b является таким, как определено выше.
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Families Citing this family (13)

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Publication number Priority date Publication date Assignee Title
FR3005051A1 (fr) * 2013-04-25 2014-10-31 Pf Medicament Derives de la dolastatine 10 et d'auristatines
RU2685259C2 (ru) * 2014-04-25 2019-04-17 Пьер Фабр Медикамент Конъюгат антитела и лекарственного средства и его применение для лечения рака
MA47811A (fr) 2014-04-25 2019-06-19 Pf Medicament Kit comprenant un conjugué anticorps-médicament igf-1r et son utilisation pour le traitement du cancer
ES2785551T3 (es) 2014-06-30 2020-10-07 Glykos Finland Oy Derivado de sacárido de una carga útil tóxica y sus conjugados con anticuerpos
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US11377473B2 (en) * 2017-11-30 2022-07-05 Centurion Biopharma Corporation Albumin-binding prodrugs of auristatin E derivatives
CN113453724A (zh) 2018-09-27 2021-09-28 皮埃尔法布雷医药公司 基于磺酰基马来酰亚胺的连接子和相应的偶联物
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Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0731106B1 (en) * 1993-10-01 2004-11-17 Teikoku Hormone Mfg. Co., Ltd. Dolastatin derivatives
US6884869B2 (en) * 2001-04-30 2005-04-26 Seattle Genetics, Inc. Pentapeptide compounds and uses related thereto
EP2722051B1 (en) * 2005-07-07 2018-11-07 Seattle Genetics, Inc. Monomethylvaline compounds having phenylalanine side-chain modifications at the C-terminus
EP2276509B1 (en) * 2008-04-11 2016-06-15 Seattle Genetics, Inc. Detection and tratment of pancreatic, ovarian and other cancers
EP2403524A4 (en) * 2009-03-06 2012-09-26 Agensys Inc CONJUGATES ANTIBODY-DRUG (ADC) BINDING PROTEINS 24P4C12
EP2579887B1 (de) * 2010-06-10 2014-11-12 Seattle Genetics, Inc. Neue auristatin-derivate und ihre verwendung
ES2553874T3 (es) * 2010-09-29 2015-12-14 Seattle Genetics, Inc. N-Carboxialquil-auristatinas y su uso
EP2635310A2 (en) * 2010-11-05 2013-09-11 Rinat Neuroscience Corp. Engineered polypeptide conjugates and methods for making thereof using transglutaminase
CN103764667B (zh) * 2011-03-16 2017-06-20 西雅图基因公司 N‑羧烷基耳他汀类及其应用
CN103826661B (zh) * 2011-04-21 2019-03-05 西雅图基因公司 新的结合剂-药物缀合物(adc)及其用途
JP6581774B2 (ja) * 2011-05-27 2019-09-25 アンブルックス, インコーポレイテッドAmbrx, Inc. 非天然アミノ酸結合ドラスタチン誘導体を含有する化合物またはその化合物の溶媒和物、およびドラスタチンアナログを誘導体化するための方法
EP3170821B1 (en) * 2011-05-27 2021-09-15 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acid linked dolastatin derivatives
AU2013270686B2 (en) * 2012-06-07 2016-11-10 Ambrx, Inc. Prostate-specific membrane antigen antibody drug conjugates
EP2861262B1 (en) * 2012-06-19 2018-11-28 Ambrx, Inc. Anti-cd70 antibody drug conjugates
EP2934596A1 (en) * 2012-12-21 2015-10-28 Glykos Finland Oy Linker-payload molecule conjugates
FR3005051A1 (fr) * 2013-04-25 2014-10-31 Pf Medicament Derives de la dolastatine 10 et d'auristatines
RU2685259C2 (ru) * 2014-04-25 2019-04-17 Пьер Фабр Медикамент Конъюгат антитела и лекарственного средства и его применение для лечения рака

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