RU2012103671A - Пептидные эпоксикетоны для ингибирования протеасомы - Google Patents

Пептидные эпоксикетоны для ингибирования протеасомы Download PDF

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RU2012103671A
RU2012103671A RU2012103671/04A RU2012103671A RU2012103671A RU 2012103671 A RU2012103671 A RU 2012103671A RU 2012103671/04 A RU2012103671/04 A RU 2012103671/04A RU 2012103671 A RU2012103671 A RU 2012103671A RU 2012103671 A RU2012103671 A RU 2012103671A
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Russia
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alkyl
compound according
zaz
6alkyl
hydrogen
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RU2012103671/04A
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English (en)
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Кевин Д. Шенк
Франческо Парлати
Хань-Цзе ЧЖОУ
Катрин СИЛЬВЕН
Марк С. СМИТ
Марк К. Беннетт
Гай Дж. Лэйдиг
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Протеоликс, Инк.
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Publication of RU2012103671A publication Critical patent/RU2012103671A/ru

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Abstract

1. Соединение, имеющее структуру формулы (I), или его фармацевтически приемлемая соль,где каждый Ar независимо представляет собой ароматическую группу, необязательно замещенную 1-4 заместителями;каждый A независимо выбран из C=O, C=S и SO; илиА необязательно представляет собой ковалентную связь, когда является смежным по отношению к присутствующему Z;В отсутствует или представляет собой N(R)R;L отсутствует;М отсутствует или представляет собой Салкил;Q отсутствует;Х выбран из О, S, NH и N-Салкила;Y отсутствует или выбран из С=О и SO;каждый Z независимо выбран из О, S, NH и N-Салкила; илиZ необязательно представляет собой ковалентную связь, когда является смежным по отношению к присутствующему А;Rвыбран из Н, -Салкил-В, Сгидроксиалкила, Салкоксиалкила, арила и Сарилалкила;Rи R, каждый независимо, выбран из арила, Сарилалкила, гетероарила и Сгетероарилалкила;Rпредставляет собой N(R)L-Q-R;Rпредставляет собой H;Rвыбран из водорода, Салкила, Салкенила, Салкинила, Ar-Y-, карбоциклила, гетероциклила, N-концевой защитной группы, арила, Сарилалкила, RZAZ-Cалкила-, RZ-Cалкила-, (RO)(RO)P(=O)O-Cалкил-ZAZ-Салкила-, RZAZ-Cалкил-ZAZ-Cалкила-, гетероциклилМZAZ-Cалкила-, (RO)(RO)P(=O)O-Cалкила-, (R)N-Cалкила-, (R)N-Cалкила-, гетероциклилМ-, карбоциклилМ-, RSOCалкила- и RSONH, илиRи R, вместе представляют собой Салкил-Y-Салкил, Салкил-ZAZ-Салкил, ZAZ-Cалкил-ZAZ-Салкил, ZAZ-Салкил-ZAZ или Салкил-А, тем самым образуя кольцо;Rи Rнезависимо выбраны из водорода, Салкила и Сарилалкила;Rвыбран из водорода, ОН и Салкила; иRпредставляет собой N-концевую защитную группу;Rи Rнезависимо выбраны из водорода, катиона металла, Салкила, Салкенила, Салкинила, арила и Сарилалкила;каждый Rнезависимо выбран из водорода и Салкила; иRнезависим�

Claims (30)

1. Соединение, имеющее структуру формулы (I), или его фармацевтически приемлемая соль,
Figure 00000001
где каждый Ar независимо представляет собой ароматическую группу, необязательно замещенную 1-4 заместителями;
каждый A независимо выбран из C=O, C=S и SO2; или
А необязательно представляет собой ковалентную связь, когда является смежным по отношению к присутствующему Z;
В отсутствует или представляет собой N(R9)R10;
L отсутствует;
М отсутствует или представляет собой С1-12алкил;
Q отсутствует;
Х выбран из О, S, NH и N-С1-6алкила;
Y отсутствует или выбран из С=О и SO2;
каждый Z независимо выбран из О, S, NH и N-С1-6алкила; или
Z необязательно представляет собой ковалентную связь, когда является смежным по отношению к присутствующему А;
R1 выбран из Н, -С1-6алкил-В, С1-6гидроксиалкила, С1-6алкоксиалкила, арила и С1-6арилалкила;
R2 и R3, каждый независимо, выбран из арила, С1-6арилалкила, гетероарила и С1-6гетероарилалкила;
R4 представляет собой N(R5)L-Q-R6;
R5 представляет собой H;
R6 выбран из водорода, С1-6алкила, С2-6алкенила, С2-6алкинила, Ar-Y-, карбоциклила, гетероциклила, N-концевой защитной группы, арила, С1-6арилалкила, R11ZAZ-C1-8алкила-, R14Z-C1-8алкила-, (R11O)(R12O)P(=O)O-C1-8алкил-ZAZ-С1-8алкила-, R11ZAZ-C1-8алкил-ZAZ-C1-8алкила-, гетероциклилМZAZ-C1-8алкила-, (R11O)(R12O)P(=O)O-C1-8алкила-, (R13)2N-C1-12алкила-, (R13)3N+-C1-12алкила-, гетероциклилМ-, карбоциклилМ-, R14SO2C1-8алкила- и R14SO2NH, или
R5 и R6, вместе представляют собой С1-6алкил-Y-С1-6алкил, С1-6алкил-ZAZ-С1-6алкил, ZAZ-C1-6алкил-ZAZ-С1-6алкил, ZAZ-С1-6алкил-ZAZ или С1-6алкил-А, тем самым образуя кольцо;
R7 и R8 независимо выбраны из водорода, С1-6алкила и С1-6арилалкила;
R9 выбран из водорода, ОН и С1-6алкила; и
R10 представляет собой N-концевую защитную группу;
R11 и R12 независимо выбраны из водорода, катиона металла, С1-6алкила, С2-6алкенила, С2-6алкинила, арила и С1-6арилалкила;
каждый R13 независимо выбран из водорода и С1-6алкила; и
R14 независимо выбран из водорода, С1-6алкила, С2-6алкенила, С2-6алкинила, карбоциклила, гетероциклила, арила и С1-6арилалкила;
R15 выбран из водорода, С1-6алкила, С1-6гидроксиалкила, С1-6алкокси, -С(О)ОС1-6алкила, -С(О)NHC1-6алкила и С1-6арилалкила;
при условии, что в любом случае присутствия последовательности ZAZ, по меньшей мере один член последовательности должен быть другим, чем ковалентная связь.
2. Соединение по п.1, где R6 представляет собой N-концевую защитную группу.
3. Соединение по п.2, где R6 выбран из трет-бутоксикарбонила, бензилоксикарбонила, бензоила, флуорен-9-илметоксикарбонила, трифенилметила и трихлорэтоксикарбонила.
4. Соединение по п.1, где углерод, имеющий заместитель R1, имеет стереохимическую конфигурацию D.
5. Соединение по п.1, где А представляет собой С=О.
6. Соединение по п.1, где М представляет собой С1-8алкил.
7. Соединение по п.1, где В отсутствует.
8. Соединение по п.1, где Х представляет собой О.
9. Соединение по п.1, где Z представляет собой О.
10. Соединение по п.1, где R7 и R8 представляют собой Н.
11. Соединение по п.1, где R9 представляет собой C1-6алкил.
12. Соединение по п.1, где R11 и R12 независимо выбраны из водорода, катиона металла и C1-6алкила.
13. Соединение по п.1, где R1 выбран из C1-6алкил-B и C1-6аралкила.
14. Соединение по п.13, где R1 замещен одним или несколькими заместителями, выбранными из гидрокси, галогена, амида, аминогруппы, карбоновой кислоты или ее соли, сложного эфира, тиола или простого тиоэфира.
15. Соединение по п.13, где R1 выбран из метила, этила, изопропила, карбоксиметила и бензила.
16. Соединение по п.1, где R2 выбран из C1-6аралкила и C1-6гетероаралкила.
17. Соединение по п.16, где R2 выбран из C1-6алкилфенила, C1-6алкилиндолила, C1-6алкилтиенила, C1-6алкилтиазолила и C1-6алкилизотиазолила.
18. Соединение по п.17, где R2 замещен одним или несколькими заместителями, выбранными из гидрокси, галогена, амида, аминогруппы, карбоновой кислоты или ее соли, сложного эфира, тиола и простого тиоэфира.
19. Соединение по п.17, где R2 замещен одним или несколькими заместителями, выбранными из алкила, тригалогеналкила, алкокси, гидрокси и циано.
20. Соединение по п.17, где R2 выбран из C1-6алкилфенила и C1-6алкилиндолила.
21. Соединение по п.1, где R3 выбран из C1-6аралкила C1-6 гетероаралкила.
22. Соединение по п.21, где R3 амещен одним или несколькими заместителями, выбранными из гидрокси, галогена, амида, аминогруппы, карбоновой кослоты или ее соли, сложного эфира, тиола или простого тиоэфира.
23. Соединение по п.21, где R3 замещен одним или несколькими заместителями, выбранными из алкила, тригалогеналкила, алкокси, гидрокси и циано.
24. Соединение по п.21, где R3 выбран из C1-6алкилфенила и C1-6 алкилиндолила.
25. Соединение по п.1, где R6 выбран из C1-6алкила, C2-6алкенила, C2-6алкинила, C1-6аралкила и C1-6гетероаралкила.
26. Соединение по п.1, где R6 выбран из бутила, аллила, пропаргила, фенилметила, 2-пиридила, 3-пиридила и 4-пиридила.
27. Соединение по п.1, где R7 и R8 независимо выбраны из водорода и C1-6алкила.
28. Соединение по п.1, где углерод, имеющий заместитель R2, имеет стереохимическую конфигурацию D.
29. Соединение по п.1, где углерод, имеющий заместитель R3, имеет стереохимическую конфигурацию D.
30. Фармацевтическая композиция, содержащая соединение по п.1 или его фармацевтически приемлемую соль и фармацевтически приемлемый носитель.
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