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RU2015147447A - Производные доластатина 10 и ауристатинов - Google Patents

Производные доластатина 10 и ауристатинов Download PDF

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RU2015147447A
RU2015147447A RU2015147447A RU2015147447A RU2015147447A RU 2015147447 A RU2015147447 A RU 2015147447A RU 2015147447 A RU2015147447 A RU 2015147447A RU 2015147447 A RU2015147447 A RU 2015147447A RU 2015147447 A RU2015147447 A RU 2015147447A
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Мишель ПЕРЕС
Айан РИЛАТТ
Мари ЛАМОТ
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Пьер Фабр Медикамент
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Claims (60)

1. Соединение формулы (I)
Figure 00000001
где
- R1 представляет собой Н или ОН,
- R2 представляет собой (C1-C6)алкильную, COOH, COO-((C1-C6)алкил) или тиазолильную группу,
- R3 представляет собой Н или (C1-C6)алкильную группу и
- R4 представляет собой:
- прямоцепочечную или разветвленную, насыщенную или ненасыщенную углеводородную цепь, имеющую от 1 до 8 атомов углерода, такую как (C1-С8)алкильная группа, причем цепь замещена одной или несколькими группами, выбранными из ОН и NR5R6, где R5 и R6, каждый независимо , представляет собой H или (C1-C6)алкильную группу,
- группу -(CH2CH2X1)(CH2CH2X2)a2(CH2CH2X3)a3(CH2CH2X4)a4(CH2CH2X5)a5R7, где X1, X2, X3, X4 и X5, каждый независимо , представляет собой О или NR8, a2, a3, a4 и a5, каждый независимо , представляет собой 0 или 1, R7 представляет собой H, и R8 представляет собой H или (C1-C6)алкильную группу,
- арил-(C1-C8)алкильную группу, замещенную одной или несколькими группами, выбранными из групп ОН и NR9R10, где R9 и R10, каждый независимо , представляет собой Н или (C1-C6)алкильную группу, или
- гетероцикл-(С1-С8)алкильную группу, необязательно замещенную одной или несколькими группами, выбранными из (C1-C6)алкильной, ОН и NR12R13 групп, где R12 и R13, каждый независимо , представляет собой Н или (C1-С6)алкильную группу,
или его фармацевтически приемлемая соль, гидрат или сольват.
2. Соединение по п. 1, отличающееся тем, что:
-R1=ОН и R2 представляет собой (С1-С6)алкильную группу или
-R1=H, 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 СООМе.
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:
- (С1-С6)алкил, замещенный группой, выбранной из OH и NR5R6,
- -(CH2CH2X1)(CH2CH2X2)a2(CH2CH2X3)a3R7,
- арил-(C1-C2)алкил, замещенный одной группой, выбранной из OH и NR9R10,
или
- гетероцикл-(С1-С2)алкил, замещенный 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 в 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
и его фармацевтически приемлемые соли, такие как соли, образованные с трифторуксусной кислотой.
9. Соединение по любому из п.п. 1-8 для применения в качестве лекарственного средства.
10. Соединение по любому из п.п. 1-8 для применения в качестве лекарственного средства, предназначенного для лечения рака или доброкачественных пролиферативных расстройств.
11. Фармацевтическая композиция, содержащая соединение формулы (I) по любому из п.п. 1-8 и по меньшей мере один фармацевтически приемлемый эксципиент.
12. Фармацевтическая композиция по п. 11, дополнительно содержащая еще один активный ингредиент, преимущественно выбранный из противораковых средств, в частности, включающих 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 п.п. 1-8, включающий реакцию конденсации между соединением формулы (VI):
Figure 00000008
где R1 и R2 являются такими, как определено в п. 1, и
соединением формулы (VII):
Figure 00000009
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.
14. Способ получения соединения формулы (I) по любому из п.п. 1-8, включающий реакцию замещения между соединением формулы (VIII):
Figure 00000010
где R1, R2 и R3 являются такими, как определено в п. 1, и
соединением формулы (X):
Figure 00000011
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 O-тозил.
15. Способ получения соединения формулы (I) по любому из п.п. 1-8, где R4 представляет собой группу -CH2R4b, где R4b представляет собой:
- ОН, NR5R6, прямоцепочечную или разветвленную, насыщенную или ненасыщенную углеводородную группу, содержащую от 1 до 7 атомов углерода, замещенную одной или несколькими группами, выбранными из ОН и NR5R6,
- -CH2X1(CH2CH2X2)a2(CH2CH2X3)a3(CH2CH2X4)a4(CH2CH2X5)a5R7,
- арильную группу или арил-(С1-С7)алкильную группу, замещенную одной или несколькими группами, выбранными из групп ОН и NR9R10, или
- гетероциклическую или гетероцикл-(С1-С7)алкильную группу, необязательно замещенную одной или несколькими группами, выбранными из (C1-С6)алкильной, ОН и NR12R13 групп,
включающий реакцию восстановительного аминирования между соединением формулы (VIII):
Figure 00000012
где R1, R2 и R3 являются такими, как определено в п. 1, и
соединением формулы (XI):
Figure 00000013
где R4b является таким, как определено выше.
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