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RU2012112461A - Конъюгаты жирных кислот и ниацина и их применение - Google Patents

Конъюгаты жирных кислот и ниацина и их применение Download PDF

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RU2012112461A
RU2012112461A RU2012112461/04A RU2012112461A RU2012112461A RU 2012112461 A RU2012112461 A RU 2012112461A RU 2012112461/04 A RU2012112461/04 A RU 2012112461/04A RU 2012112461 A RU2012112461 A RU 2012112461A RU 2012112461 A RU2012112461 A RU 2012112461A
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Джилл К. МИЛН
Майкл Р. Джироусек
Джин Э. БЕМИС
Чи Б. Ву
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Катабэйсис Фармасьютикалз, Инк.
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Abstract

1. Молекулярный конъюгат, содержащий ниацин и жирную кислоту, выбранную из омега-3 жирных кислот или жирных кислот, которые метаболизируются in vivo до омега-3 жирных кислот, где конъюгат содержит по меньшей мере один амид.2. Соединение Формулы Iили его фармацевтически приемлемая соль, гидрат, сольват, пролекарство, энантиомер или стереоизомер;где каждый из R, Rи Rнезависимо выбран из группы, состоящей из -Н, -D, -Cl, -F, -CN, -NH, -NH(C-Салкил), -N(C-Салкил), -NH(C(O)C-Cалкил), -N(C(O)C-Cалкил), -С(O)Н, -С(O)С-Салкила, -С(O)ОС-Салкила, -C(O)NH, -C(O)NH(C-Cалкил), -C(O)N(C-Cалкил), -C-Салкила, -O-C-Салкила, -S(O)С-Салкила и -S(O)С-Салкила;каждый из Wи Wнезависимо представляет собой ноль, О, S, NH, NR или Wи Wвместе могут образовывать имидазолидиновую или пиперазиновую группу при условии, что Wи Wне могут одновременно представлять собой О;каждый а, b, с и d независимо представляет собой -Н, -D, -СН, -ОСН, -ОСНСНили -C(O)OR, -O-Z или бензил или два из а, b, с и d, вместе с одинарным атомом углерода, к которому они присоединены, могут образовывать циклоалкил или гетероцикл;каждый n, о, р и q независимо равно 0 или 1;каждый L независимо представляет собой -O-, -S-, -S(O) -, -S(O)-, -S-S-,иликаждый g независимо равен 2, 3 или 4;каждый h независимо равен 1, 2, 3 или 4;каждый Rнезависимо представляет собой Н или C-Салкил или обе группы Rвместе с атомом азота, к которому они присоединены, могут образовывать гетероцикл;каждый Rнезависимо представляет собой е, В или неразветвленный или разветвленный C-Салкил, который может быть необязательно замещен ОН, NH, COR, CONH, фенилом, CHOH, имидазолом или аргинином;каждый е независимо представляет собой Н или любую из боковых цепей природных аминокислот;каждый Z независимо представляет собой -Н илиилипри усл

Claims (35)

1. Молекулярный конъюгат, содержащий ниацин и жирную кислоту, выбранную из омега-3 жирных кислот или жирных кислот, которые метаболизируются in vivo до омега-3 жирных кислот, где конъюгат содержит по меньшей мере один амид.
2. Соединение Формулы I
Figure 00000001
или его фармацевтически приемлемая соль, гидрат, сольват, пролекарство, энантиомер или стереоизомер;
где каждый из R1, R2 и R3 независимо выбран из группы, состоящей из -Н, -D, -Cl, -F, -CN, -NH2, -NH(C1-С3 алкил), -N(C1-С3 алкил)2, -NH(C(O)C1-C3 алкил), -N(C(O)C1-C3 алкил)2, -С(O)Н, -С(O)С1-С3 алкила, -С(O)ОС1-С3 алкила, -C(O)NH2, -C(O)NH(C1-C3 алкил), -C(O)N(C1-C3 алкил)2, -C1-С3 алкила, -O-C1-С3 алкила, -S(O)С1-С3 алкила и -S(O)2С1-С3 алкила;
каждый из W1 и W2 независимо представляет собой ноль, О, S, NH, NR или W1 и W2 вместе могут образовывать имидазолидиновую или пиперазиновую группу при условии, что W1 и W2 не могут одновременно представлять собой О;
каждый а, b, с и d независимо представляет собой -Н, -D, -СН3, -ОСН3, -ОСН2СН3 или -C(O)OR, -O-Z или бензил или два из а, b, с и d, вместе с одинарным атомом углерода, к которому они присоединены, могут образовывать циклоалкил или гетероцикл;
каждый n, о, р и q независимо равно 0 или 1;
каждый L независимо представляет собой -O-, -S-, -S(O) -, -S(O)2-, -S-S-,
Figure 00000002
Figure 00000003
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
или
Figure 00000020
каждый g независимо равен 2, 3 или 4;
каждый h независимо равен 1, 2, 3 или 4;
каждый R6 независимо представляет собой Н или C1-С6 алкил или обе группы R6 вместе с атомом азота, к которому они присоединены, могут образовывать гетероцикл;
каждый R7 независимо представляет собой е, В или неразветвленный или разветвленный C1-С10 алкил, который может быть необязательно замещен ОН, NH2, CO2R, CONH2, фенилом, C6H4OH, имидазолом или аргинином;
каждый е независимо представляет собой Н или любую из боковых цепей природных аминокислот;
каждый Z независимо представляет собой -Н или
Figure 00000021
или
Figure 00000022
при условии, что в соединении присутствует по меньшей мере один из
Figure 00000023
или
Figure 00000024
каждый r независимо равен 2, 3 или 7;
каждый s независимо равен 3, 5 или 6;
каждый t независимо равен 0 или 1;
каждый v независимо равен 1, 2 или 6;
каждый из R4 и R5 независимо представляет собой водород, дейтерий, -C1-C4 алкил, -галоген, -ОН, -С(O)С1-С4 алкил, -O-арил, -O-бензил, -OC(O)C1-C4 алкил, -C1-С3 алкен, -C1-С3 алкин, -С(O)С1-С4 алкил, -NH2, -NH(C1-C3 алкил), -N(C1-C3 алкил)2, -NH(С(O)С1-С3 алкил), -N(С(O)С1-С3 алкил)2, -SH, -S(C1-С3 алкил), -S(O)С1-С3 алкил, -S(O)2C1-C3 алкил; и
каждый R независимо представляет собой -Н или -С1-С3 алкил;
при условии, что
если каждый из m, n, о, p и q равен 0, каждый из W1 и W2 равен нулю и Z представляет собой
Figure 00000023
то t должен равняться 0; и
если каждый из m, n, о, p и q равен 0 и каждый из W1 и W2 равен нулю, то Z не может представлять собой
Figure 00000024
3. Соединение по п.2, отличающееся тем, что Z представляет собой
Figure 00000023
4. Соединение по п.3, отличающееся тем, что t равно 1.
5. Соединение по п.4, отличающееся тем, что r равно 2, и s равно 6.
6. Соединение по п.4, отличающееся тем, что r равно 3, и s равно 5.
7. Соединение по п.4, отличающееся тем, что r равно 7, и s равно 3.
8. Соединение по п.5, отличающееся тем, что L представляет собой -S-S-
9. Соединение по п.5, отличающееся тем, что L представляет собой -O-.
10. Соединение по п.5, отличающееся тем, что L представляет собой
Figure 00000020
11. Соединение по п.5, отличающееся тем, что L представляет собой
Figure 00000025
12. Соединение по п.5, отличающееся тем, что L представляет собой
Figure 00000007
Figure 00000009
или
Figure 00000011
13. Соединение по п.5, отличающееся тем, что L представляет собой
Figure 00000006
,
Figure 00000008
или
Figure 00000010
14. Соединение по п.5, отличающееся тем, что каждый из n, о, p и q равен 1.
15. Соединение по п.5, отличающееся тем, что два из n, о, p и q равны 1.
16. Соединение по п.5, отличающееся тем, что каждый из Wi и Wz представляет собой NH.
17. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n, о, р и q равен 1 и L представляет собой О.
18. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n, о, р и q равен 1 и L представляет собой -S-S-.
19. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n и о равен 0, каждый из р и q равен 1 и L представляет собой
Figure 00000011
20. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n, о, р и q равен 0 и L представляет собой
Figure 00000011
21. Соединение по п.5, отличающееся тем, что каждый из m, n и о равен 0 и каждый из р и q равен 1.
22. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n и о равен 0, каждый из р и q равен 1 и L представляет собой
Figure 00000010
23. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n и о равен 1, каждый из р и q равен 0 и L представляет собой
Figure 00000010
24. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n, о, р и q равен 1 и L представляет собой
Figure 00000006
25. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n, о, р и q равен 1 и L представляет собой NR6.
26. Соединение по п.5, отличающееся тем, что каждый из m, n и о равен 0 и каждый из р и q равен 1, а один из с представляет собой -СН3 и второй из с представляет собой -СН3.
27. Соединение по п.5, отличающееся тем, что m равно 1, каждый из n и о равен 1, каждый из р и q равен 0 и L представляет собой
Figure 00000020
28. Соединение по п.2, отличающееся тем, что соединение выбрано из группы, состоящей из N-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидоэтокси)этил)никотинамида; N-(2-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидоэтил)дисульфанил)этил)никотинамида; и N-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидоэтиламино)этил)никотинамида.
29. Соединение по п.2, отличающееся тем, что соединение выбрано из группы, состоящей из 1,3-дигидроксипропан-2-ил-6-(4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидо-2-(никотинамидо)гексаноата; и 1,3-дигидроксипропан-2-ил-4-(4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидо-2-(никотинамидо)бутаноата.
30. Соединение по п.2, отличающееся тем, что соединение выбрано из группы, состоящей из N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидоэтил)никотинамида; N-(2-(5Z,8Z,11Z,14Z,17Z)-эйкоза-5,8,11,14,17-пентаенамидоэтил)никотинамида; и N-(1-(4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидо-2-метилпропан-2-ил)никотинамида.
31. Соединение по п.2, отличающееся тем, что соединение выбрано из группы, состоящей из (S)-6-((4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидо)-2-(никотинамидо)гексановой кислоты; (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидо)-6-(никотинамидо)гексановой кислоты; (S)-6-((5Z,8Z,11Z,14Z,17Z)-эйкоза-5,8,11,14,17-пентаенамидо)-2-(никотинамидо)гексановой кислоты; (S)-2-((5Z,8Z,11Z,14Z,17Z)-эйкоза-5,8,11,14,17-пентаенамидо)-6-(никотинамидо)гексановой кислоты; и 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-докоза-4,7,10,13,16,19-гексаенамидоэтил)-4-(никотинамидо)бутановой кислоты.
32. Соединение по п.2, отличающееся тем, что соединение выбрано из группы, состоящей из (S)-((R)-1-(никотинамидо)пропан-2-ил)-2-((5Z,8Z,11Z,14Z,17Z)-эйкоза-5,8,11,14,17-пентаенамидо)пропаноата; и (S)-((R)-1-(никотинамид)пропан-2-ил)-2-((5Z,8Z,11Z,14Z,17Z)-эйкоза-5,8,11,14,17-пентаенамидо)-3-мэтилбутаноата.
33. Фармацевтическая композиция, содержащая соединение по п.2 и фармацевтически приемлемый носитель.
34. Способ лечения метаболического расстройства, включающий введение пациенту, который нуждается в таком лечении, эффективного количества соединения по п.2.
35. Способ по п.34, отличающийся тем, что метаболическое расстройство выбрано из гипертриглицеридемии, гиперхолестеринемии, жирового заболевания печенки, атеросклероза, заболевания коронарных сосудов сердца, диабета 2 типа, диабетической нефропатии, диабетической невропатии, диабетической ретинопатии, метаболического синдрома или сердечнососудистого заболевания.
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