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RU2018100098A - Полициклические соединения и способы их применения - Google Patents

Полициклические соединения и способы их применения Download PDF

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RU2018100098A
RU2018100098A RU2018100098A RU2018100098A RU2018100098A RU 2018100098 A RU2018100098 A RU 2018100098A RU 2018100098 A RU2018100098 A RU 2018100098A RU 2018100098 A RU2018100098 A RU 2018100098A RU 2018100098 A RU2018100098 A RU 2018100098A
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iva
pharmaceutically acceptable
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acceptable salt
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RU2018100098A
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RU2707067C2 (ru
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Лимин ШАО
Джон Эммерсон КЭМПБЕЛЛ
Майкл Чарльз ХЬЮИТТ
Уна КЭМПБЕЛЛ
Талин Дж. ХАНАНИЯ
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Суновион Фармасьютикалз, Инк.
ПиДжиАй Драг Дискавери ЭлЭлСи
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Claims (54)

1. Способ получения соединения формулы (IVa):
Figure 00000001
или его фармацевтически приемлемой соли или стереоизомера, включающий:
обработку гидроксиалкилтиофена формулы (i):
Figure 00000002
(i),
аминоальдегид ацеталем и кислотой с получением соединения формулы (IVa), где:
m равно 0;
n равно 1;
R1 и R2 являются, каждый независимо, водородом или С1-4алкилом;
R3 и R4 являются, каждый независимо, водородом или С1-4алкилом;
R5 представляет собой водород; и
R6 и R7 являются, каждый независимо, водородом, галогеном или С1-4алкилом.
2. Способ по п.1, где указанный аминоальдегид ацетал представляет собой аминоальдегид диметилацеталь формулы (ii):
Figure 00000003
(ii),
где R1 - R5 и m определены в п.1.
3. Способ по п.1, где указанный аминоальдегид ацетал включает аминоальдегид диэтилацеталь.
4. Способ по любому из пп.1-3, где указанная кислота включает трифторметилсульфоновую кислоту.
5. Способ по любому из пп.1-4, где указанную обработку гидроксиалкилтиофена аминоальдегид ацеталем и кислотой проводят в эфирном растворителе.
6. Способ по п.5, где указанный эфирный растворитель представляет собой 1,4-диоксан.
7. Способ по любому из пп.1-6, дополнительно включающий стадию (b) обработки продукта со стадии (a) основанием.
8. Способ по п.7, где указанное основание включает гидроксид калия.
9. Способ по п.8, где указанное основание представляет собой водный гидроксид калия.
10. Способ по любому из пп.1-9, где при осуществлении способа получают по меньшей мере один стереоизомер соединения формулы (IVa) или его фармацевтически приемлемой соли.
11. Способ по п.10, где при осуществлении способа получают смесь, включающую более чем один стереоизомер соединения формулы (IVa) или его фармацевтически приемлемой соли.
12. Способ по п.11, где способ дополнительно включает стадию (c) выделения одного стереоизомера соединения формулы (IVa) или его фармацевтически приемлемой соли путем разделения смеси.
13. Способ по п.12, где указанное разделение включает по меньшей мере одно из хиральной хроматографии, перекристаллизации, образования диастереомерной соли или дериватизации более чем одного стереоизомера соединения формулы (IVa) в диастереомерные аддукты с последующим разделением.
14. Способ по п.13, где указанное разделение включает образование диастереомерной соли.
15. Способ по любому из пп.1-14, где указанное соединение формулы (IVa) или его фармацевтически приемлемая соль включает фармацевтически приемлемую соль.
16. Способ по п.15, где указанное соединение формулы (IVa) или его фармацевтически приемлемая соль или стереоизомер включает гидрохлоридную (HCl) соль.
17. Способ по любому из пп.1-16, где R3 и R4 являются, каждый, водородом, и R6 и R7 являются, каждый независимо, водородом или C1-C4алкилом.
18. Способ по любому из пп.1-17, где указанное соединение формулы (IVa) или его фармацевтически приемлемая соль или стереоизомер выбрано из следующих соединений или фармацевтически приемлемых солей или стереоизомеров:
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
,
Figure 00000033
,
Figure 00000034
,
Figure 00000035
,
Figure 00000036
,
Figure 00000037
,
Figure 00000038
,
Figure 00000039
,
Figure 00000040
,
Figure 00000041
, или
Figure 00000042
.
19. Способ по любому одному из пп.1-17, где R2, R3, R4, R5, R6 и R7 являются, каждый, водородом.
20. Способ по п.19, где R1 представляет собой метил.
21. Способ по любому одному из пп.1-20, где указанное соединение формулы (IVa) представляет собой
Figure 00000043
.
22. Способ по любому одному из пп.1-21, где указанное соединение формулы (IVa) представляет собой
Figure 00000044
.
23. Способ получения соединения формулы
Figure 00000045
,
или его фармацевтически приемлемой соли или стереоизомера, включающий объединение 2-(тиофен-3-ил)этанола, N-метил-2,2-диметоксиэтанамина и трифторметансульфоновой кислоты, и выделения указанного соединения.
24. Способ по п.23, дополнительно включающий разделение
Figure 00000046
на
Figure 00000047
и
Figure 00000048
.
25. Способ по п.24, дополнительно включающий выделение
Figure 00000049
.
26. Способ по п.25, где указанное разделение осуществляют, используя хиральную хроматографию.
27. Способ получения соединения формулы
Figure 00000050
,
или его фармацевтически приемлемой соли или стереоизомера, включающий:
объединение 2-(тиофен-3-ил)этанола, N-метил-2,2-диметоксиэтанамина и трифторметансульфоновой кислоты; выделение
Figure 00000051
; и
отделение
Figure 00000052
от
Figure 00000053
.
28. Способ по п.27, где указанное отделение осуществляют, используя хиральную хроматографию.
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