RU2014127753A - Ингибиторы пути передачи сигнала notch и их применение при лечении рака - Google Patents
Ингибиторы пути передачи сигнала notch и их применение при лечении рака Download PDFInfo
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- RU2014127753A RU2014127753A RU2014127753A RU2014127753A RU2014127753A RU 2014127753 A RU2014127753 A RU 2014127753A RU 2014127753 A RU2014127753 A RU 2014127753A RU 2014127753 A RU2014127753 A RU 2014127753A RU 2014127753 A RU2014127753 A RU 2014127753A
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Abstract
1. Соединение для применения в лечении и/или предотвращении зависимого от Notch рака, при этом указанное соединение, обладающее ингибирующими свойствами в отношении пути передачи сигнала Notch, имеет формулугде m представляет собой целое число, выбранное из 1-4;W выбран из Η и галогенов; указанный галоген выбран из F-, Cl-, Br- или Ι-;R, R, R, Rкаждый независимо выбран из группы, состоящей из H, изопропила, трет-бутила, (CH)CH; нижний индекс n представляет собой целое число, независимо выбранное из 1-15;X представляет собой O, NR, где Rпредставляет собой H;Υ представляет собой N или CH;Ζ представляет собой NRR, где Rи Rпредставляют собой H,илигде m представляет собой целое число, выбранное из 1-4;W выбран из Η и галогенов; указанный галоген выбран из F-, Cl-, Br- или Ι-;Rи Rкаждый независимо выбран из группы, состоящей из Н, трет-бутила, (CH)CH; нижний индекс n представляет собой целое число, независимо выбранное из 1-15;X представляет собой O, NR, где Rпредставляет собой H;Υ представляет собой N или CH;Ζ представляет собой NRR, где Rи Rпредставляют собой H,илигде m представляет собой целое число, выбранное из 1-4;W выбран из Η и галогенов; указанный галоген выбран из F-, Cl-, Br- или Ι-;Rнезависимо выбран из группы, состоящей из H, изопропила, трет-бутила, (CH)CH; нижний индекс n представляет собой целое число, независимо выбранное из 1-15;X представляет собой O, NR, где Rпредставляет собой H;Υ представляет собой N или CH;Ζ представляет собой NRNR, где Rи Rпредставляют собой H.2. Соединение по п. 1, выбранное из группы, состоящей из следующих соединений:6-(4-Трет-бутилфенокси)пиридин-3-амин (13) формулы I4-(4-циклогексилфенокси)анилина формулы IIIa6-(4-((3r,5r,7r)-адамантан-1-ил)фенокси)пиридин-3-амина формулы IVa6-(3-(трет-бутил)фенокси)пиридин-3-амина формулы IIe4-(4-(трет-бутил)фенокси)-3-фторанилина формулы IIf6-(4-(трет-пентил)фенокси)пиридин-3-амина формулы IIg6-(4-бутил
Claims (17)
1. Соединение для применения в лечении и/или предотвращении зависимого от Notch рака, при этом указанное соединение, обладающее ингибирующими свойствами в отношении пути передачи сигнала Notch, имеет формулу
где m представляет собой целое число, выбранное из 1-4;
W выбран из Η и галогенов; указанный галоген выбран из F-, Cl-, Br- или Ι-;
R1, R2, R3, R4 каждый независимо выбран из группы, состоящей из H, изопропила, трет-бутила, (CH2)nCH3; нижний индекс n представляет собой целое число, независимо выбранное из 1-15;
X представляет собой O, NR7, где R7 представляет собой H;
Υ представляет собой N или CH;
Ζ представляет собой NR10R11, где R10 и R11 представляют собой H,
или
где m представляет собой целое число, выбранное из 1-4;
W выбран из Η и галогенов; указанный галоген выбран из F-, Cl-, Br- или Ι-;
R4 и R15 каждый независимо выбран из группы, состоящей из Н, трет-бутила, (CH2)nCH3; нижний индекс n представляет собой целое число, независимо выбранное из 1-15;
X представляет собой O, NR7, где R7 представляет собой H;
Υ представляет собой N или CH;
Ζ представляет собой NR10R11, где R10 и R11 представляют собой H,
или
где m представляет собой целое число, выбранное из 1-4;
W выбран из Η и галогенов; указанный галоген выбран из F-, Cl-, Br- или Ι-;
R4 независимо выбран из группы, состоящей из H, изопропила, трет-бутила, (CH2)nCH3; нижний индекс n представляет собой целое число, независимо выбранное из 1-15;
X представляет собой O, NR7, где R7 представляет собой H;
Υ представляет собой N или CH;
Ζ представляет собой NR10NR11, где R10 и R11 представляют собой H.
2. Соединение по п. 1, выбранное из группы, состоящей из следующих соединений:
6-(4-Трет-бутилфенокси)пиридин-3-амин (13) формулы I
4-(4-циклогексилфенокси)анилина формулы IIIa
6-(4-((3r,5r,7r)-адамантан-1-ил)фенокси)пиридин-3-амина формулы IVa
6-(3-(трет-бутил)фенокси)пиридин-3-амина формулы IIe
4-(4-(трет-бутил)фенокси)-3-фторанилина формулы IIf
6-(4-(трет-пентил)фенокси)пиридин-3-амина формулы IIg
6-(4-бутилфенокси)пиридин-3-амина формулы IIh
3-фтор-4-(4-(трет-пентил)фенокси)анилина формулы IIi
4-(4-циклогексилфенокси)-3-фторанилина формулы IIIb
4-(4-((3r,5r,7r)-адамантан-1-ил)фенокси)анилина формулы IVb
6-(4-циклогексилфенокси)пиридин-3-амина формулы IIIc
или одного из их солей, сольватов, таутомеров или изомеров.
3. Соединение по п. 1 или 2, отличающееся тем, что зависимый от Notch рак выбран из группы, включающей T-клеточный острый лимфобластный лейкоз (T-ALL), хронический миелоидный лейкоз (CML), хронический лимфоцитарный лейкоз (CLL), лимфому из клеток мантийной зоны, рак молочной железы, рак поджелудочной железы, рак предстательной железы, меланому, опухоли головного мозга, ангиогенез опухоли и рак толстой и прямой кишки.
4. Соединение по любому из пп. 1-3, отличающееся тем, что зависимый от Notch рак резистентен к лечению ингибиторами γ-секретазы.
5. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-4 или его фармацевтически приемлемые соли, сольваты, таутомеры, изомеры и фармацевтически приемлемый носитель.
6. Набор, содержащий одну или более доз соединения по любому из пп. 1-4, возможно совместно с реагентами и/или инструкциями по применению.
7. Набор по п. 6, дополнительно содержащий одну или более доз химиотерапевтического агента.
8. Применение соединения по любому из пп. 1-4 для ингибирования пути передачи сигнала Notch в клетках in vitro.
9. Применение по п. 8, отличающееся тем, что указанные клетки представляют собой раковые клетки.
10. Применение соединения по любому из пп. 1-4 для ингибирования пути передачи сигнала Notch в клетках in vivo.
11. Применение по п. 10, отличающееся тем, что указанные клетки представляют собой раковые клетки.
12. Способ лечения субъекта от зависимого от Notch рака, включающий
i) определение в раковых клетках, полученных из биологического образца от указанного субъекта, является ли рак зависимым от пути передачи сигнала Notch,
ii) и лечение указанного субъекта исходя из того, является ли указанный рак зависимым от Notch раком, путем введения терапевтически эффективного количества соединения по любому из пп. 1-4 или фармацевтической композиции по п. 5.
13. Способ лечения по п. 12, отличающийся тем, что зависимость от пути передачи сигнала Notch в раковых клетках определяют путем анализа активности комплекса γ-секретазы in vitro.
14. Способ лечения по п. 12 или 13, дополнительно включающий применение по меньшей мере одного традиционного лечения рака.
15. Способ лечения по п. 13, отличающийся тем, что указанное традиционное лечение рака применяют перед, одновременно или после введения терапевтически эффективного количества соединения по любому из пп. 1-4 или фармацевтической композиции по п. 5.
16. Способ лечения по п. 14 или 15, отличающийся тем, что указанное традиционное лечение рака заключается в лучевой терапии и/или химиотерапии.
17. Способ лечения заболевания, связанного с повышенной активностью пути передачи сигнала Notch, включающий введение соединения по любому из пп. 1-4 или фармацевтической композиции по п. 5 нуждающемуся в этом субъекту.
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2021
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