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RU2015148010A - Высокоактивное производное нуклеозида для лечения hcv - Google Patents

Высокоактивное производное нуклеозида для лечения hcv Download PDF

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RU2015148010A
RU2015148010A RU2015148010A RU2015148010A RU2015148010A RU 2015148010 A RU2015148010 A RU 2015148010A RU 2015148010 A RU2015148010 A RU 2015148010A RU 2015148010 A RU2015148010 A RU 2015148010A RU 2015148010 A RU2015148010 A RU 2015148010A
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salt
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Милинд ДИШПАНДЕ
Джесон Аллан ВАЙЛС
Акихиро Хашимото
Авинаш Фадке
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Ачиллион Фармасютикалз, Инк.
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    • C07F9/02—Phosphorus compounds
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    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Claims (41)

1. Соединение формулы I или его фармацевтически приемлемая соль, причем формула I представляет собой
Figure 00000001
,
где R1 и R2 каждый представляют собой водород или D; и каждое положение, представленное в виде D, характеризуется дейтериевым обогащением, составляющим по меньшей мере 50%.
2. Соединение или соль по п. 1 формулы
Figure 00000002
3. Соединение или соль по п. 2 формулы
Figure 00000003
4. Соединение или соль по п. 2 формулы
Figure 00000004
5. Соединение или соль по п. 2, в котором каждое положение, представленное в виде D, характеризуется дейтериевым обогащением, составляющим по меньшей мере 90%.
6. Соединение или соль по п. 2, в котором каждое положение, представленное в виде D, характеризуется дейтериевым обогащением, составляющим по меньшей мере 95%.
7. Смесь 50/50 стереоизомеров соединения по п. 2, причем смесь содержит
Figure 00000005
8. Фармацевтическая композиция, содержащая активный агент, в которой активный агент представляет собой соединение или соль по п. 2, а также содержащая фармацевтически приемлемый носитель.
9. Фармацевтическая композиция по п. 8, содержащая один или несколько дополнительных активных агентов.
10. Фармацевтическая композиция по п. 9, в которой один или несколько дополнительных активных агентов представляют собой ингибитор протеазы NS3 HCV, ингибитор NS5A HCV, ингибитор NS5B HCV или комбинацию вышеперечисленного.
11. Фармацевтическая композиция по п. 9, в которой один или несколько дополнительных активных агентов представляют собой ингибитор NS5A и по меньшей мере одно из совапревира и АСН-2684.
12. Способ лечения инфекции HCV у пациента, предусматривающий введение терапевтически эффективного количества соединения или соли по п. 2 пациенту.
13. Способ лечения инфекции HCV у пациента, предусматривающий введение терапевтически эффективного количества фармацевтической композиции по п. 8 пациенту.
14. Способ лечения инфекции HCV у пациента, предусматривающий введение терапевтически эффективного количества первого активного агента и терапевтически эффективного количества одного или нескольких дополнительных активных агентов пациенту, причем первый активный агент представляет собой соединение или соль по п. 1 и один или несколько дополнительных активных агентов выбирают из ингибитора NS3 и ингибитора NS5A.
15. Способ лечения вирусной инфекции Flaviviridae у пациента, предусматривающий введение терапевтически эффективного количества соединения или соли по п. 2 пациенту, причем вирусная инфекция Flaviviridae представляет собой лихорадку денге, вирусную инфекцию Западного Нила, желтую лихорадку или вирусную инфекцию диареи крупного рогатого скота.
16. Способ получения соединения формулы
Figure 00000006
,
предусматривающий
(I) взаимодействие сложного аминоэфира (100), в котором сложный аминоэфир представляет собой изопропиловый эфир аланина L, с дихлорфосфатом (200) с образованием реакционной смеси
Figure 00000007
;
(II) добавление к реакционной смеси (I) R-LH, где L представляет собой S или О и R представляет собой необязательно замещенный арильную, гетероарильную или гетероциклоалкильную группу, или R-LH, где R-LH представляет собой N-гидроксиимид; с образованием промежуточного соединения (300)
Figure 00000008
; и
(III) взаимодействие промежуточного соединения (300) с нуклеозидом (400)
Figure 00000009
с образованием
Figure 00000010
в котором каждое положение D, представленное в виде D, характеризуется дейтериевым обогащением, составляющим по меньшей мере 50%.
17. Способ по п. 16 для получения соединения формулы
Figure 00000011
, в котором промежуточное соединение 300 характеризуется структурой
Figure 00000012
18. Способ по п. 16, при котором сложный аминоэфир (100) и дихлорфосфат (200) объединяют при температуре менее чем -20°C и R-LH выбирают из
Figure 00000013
Figure 00000014
и
Figure 00000015
.
19. Способ по п. 16, при котором сложный аминоэфир (100) и дихлорфосфат (200) объединяют при температуре от -40°C до приблизительно -60°C.
20. Способ по п. 18, при котором основание добавляют к смеси аминоэфира (100) и дихлорфосфата (200).
21. Способ по п. 20, при котором основание представляет собой триэтиламин, и добавление основания к смеси происходит в органическом растворителе, выбранном из дихлорметана, 2-метилтетрагидрофурана или тетрагидрофурана.
RU2015148010A 2013-04-12 2014-04-14 Высокоактивное производное нуклеозида для лечения hcv RU2015148010A (ru)

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PCT/US2014/034018 WO2014169278A1 (en) 2013-04-12 2014-04-14 Highly active nucleoside derivative for the treatment of hcv

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