RU2015146957A - Производные доластатина 10 и ауристатинов - Google Patents

Производные доластатина 10 и ауристатинов Download PDF

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RU2015146957A
RU2015146957A RU2015146957A RU2015146957A RU2015146957A RU 2015146957 A RU2015146957 A RU 2015146957A RU 2015146957 A RU2015146957 A RU 2015146957A RU 2015146957 A RU2015146957 A RU 2015146957A RU 2015146957 A RU2015146957 A RU 2015146957A
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Мишель ПЕРЕС
Айан РИЛАТТ
Мари ЛАМОТ
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Пьер Фабр Медикамент
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Claims (78)

1. Соединение приведенной ниже формулы (I):
Figure 00000001
где:
- R1 представляет собой Н или ОН,
- R2 представляет собой (С1-С6)алкильную, СООН, СОО-((С1-С6)алкил) или тиазолильную группу,
- R3 представляет собой Н или (С1-С6)алкильную группу, и
- R4 представляет собой:
арил-(C1-С8)алкильную группу, замещенную одной или более группой, выбранной из групп ОН и NR9R10, где R9 и R10, каждый независимо от другого, представляет собой Н или (С1-С6)алкильную группу, или
гетероцикл-(С1-С8)алкильную группу, необязательно замещенную одной или более группой, выбранной из (С1-С6)алкильной, ОН и NR12R13 групп, где R12 и R13, 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 ОН, и R2 представляет собой (С1-С6)алкильную группу, или
- R1 представляет собой Н, и R2 представляет собой СООН, СОО-(С1-С6)алкильную или тиазольную группу.
3. Соединение по п. 1, отличающееся тем, что R1 представляет собой Н, и R2 представляет собой СООН или COOMe.
4. Соединение по п. 1, отличающееся тем, что R3 представляет собой Н или метильную группу.
5. Соединение по п. 1, отличающееся тем, что R4 представляет собой одну из следующих групп:
- арил-(С1-С2)алкильную, замещенную одной группой, выбранной из ОН и NR9R10, или
- гетероцикл-(С1-С2)алкильную, замещенную одной группой, выбранной из NR12R13, ОН и (С1-С6)алкила.
6. Соединение по п. 1, отличающееся тем, что R4 представляет собой арил-(С1-С2)алкильную группу, замещенную на арильной группировке одной группой NR9R10.
7. Соединение по п. 1, отличающееся тем, что арильная группа представляет собой фенильную группу и гетероцикл представляет собой насыщенное, ненасыщенное или ароматическое кольцо с 5 или 6 членами, содержащее 1 или 2 атома азота, выбранное, в частности, из пиридина, пиперидина и имидазола.
8. Соединение по п. 1, выбранное из:
Figure 00000002
,
Figure 00000003
,
Figure 00000004
,
Figure 00000005
,
Figure 00000006
,
Figure 00000007
,
Figure 00000008
,
Figure 00000009
,
Figure 00000010
,
Figure 00000011
,
Figure 00000012
,
Figure 00000013
,
Figure 00000014
,
Figure 00000015
,
Figure 00000016
,
Figure 00000017
,
Figure 00000018
,
Figure 00000019
,
Figure 00000020
,
Figure 00000021
,
Figure 00000022
,
Figure 00000023
,
Figure 00000024
,
Figure 00000025
,
Figure 00000026
,
Figure 00000027
,
Figure 00000028
,
Figure 00000029
,
Figure 00000030
,
Figure 00000031
,
Figure 00000032
,
и их фармацевтически приемлемых солей, таких как соли, образованные с трифторуксусной кислотой.
9. Соединение по любому из пп. 1-8, применяемое в качестве лекарственного препарата.
10. Соединение по любому из пп. 1-8, применяемое в качестве лекарственного препарата, предназначенного для лечения рака или доброкачественных пролиферативных расстройств.
11. Фармацевтическая композиция, содержащая соединение формулы (I) по любому из пп. 1-8 и по меньшей мере один фармацевтически приемлемый эксципиент.
12. Фармацевтическая композиция по п. 11, 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.
13. Способ получения соединения формулы (I) по любому из пп. 1-8, включающий реакцию конденсации между соединением приведенной ниже формулы (VI):
Figure 00000033
,
где R1 и R2 являются такими, как определено в п. 1, и
соединением приведенной ниже формулы (VII):
Figure 00000034
,
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 OH или Cl.
14. Способ получения соединения формулы (I) по любому из пп. 1-8, включающий реакцию замещения между соединением приведенной ниже формулы (VIII):
Figure 00000035
,
где R1, R2 и R3 являются такими, как определено в п. 1, и
соединением приведенной ниже формулы (X):
Figure 00000036
,
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.
15. Способ получения соединения формулы (I) по любому из пп. 1-8, где R4 представляет собой группу -CH2R4b, где R4b представляет собой:
арильную группу или арил-(С1-С7)алкильную группу, замещенную одной или более группой, выбранной из групп ОН и NR9R10, или
гетероциклическую или гетероцикл-(С1-С7)алкильную группу, необязательно замещенную одной или более группой, выбранной из (С1-С6)алкильной, ОН и NR12R13 групп,
включающий реакцию восстановительного аминирования между соединением приведенной ниже формулы (VIII):
Figure 00000037
,
где R1, R2 и R3 являются такими, как определено в п.1, и
соединением приведенной ниже формулы (XI):
Figure 00000038
,
где R4b является таким, как определено выше.
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