RU2018116864A - Соединения и способы ингибирования продукции триметиламина - Google Patents

Соединения и способы ингибирования продукции триметиламина Download PDF

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RU2018116864A
RU2018116864A RU2018116864A RU2018116864A RU2018116864A RU 2018116864 A RU2018116864 A RU 2018116864A RU 2018116864 A RU2018116864 A RU 2018116864A RU 2018116864 A RU2018116864 A RU 2018116864A RU 2018116864 A RU2018116864 A RU 2018116864A
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compound
alkyl
isothiocyanato
aminium
pharmaceutically acceptable
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Хосе Карлос ГАРСИЯ-ГАРСИЯ
Стэнли Леон Др. ХАЗЕН
Джон Аугуст УОС
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Дзе Проктер Энд Гэмбл Компани
Дзе Кливленд Клиник Фоундатион
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Claims (36)

1. Способ ингибирования превращения холина или карнитина в триметиламин (ТМА) бактерией, включающий приведение бактерии в контакт с соединением, представленным формулой (I)
Figure 00000001
где Y+ выбирают из четвертичного атома азота; X- представляет собой любую фармацевтически приемлемую соль; n выбирают из 1, 2 или 3; R2 и R3 независимо выбраны из С1-4 алкила или связаны вместе с образованием алифатической, ароматической или гетероциклической кольцевой системы;
R4 выбирают из С1-4 алкила, алкенила, алкинила, алкоксикарбонила, алкоксидикарбонила, акрила, алкокси, алкоксиалкила, арилоксиалкила, алкилкарбоксилата в составе бетаина, внутренней соли или цвиттерионной формы, галогеналкила, гидроксиалкила, нитрила или пропаргила;
R6 выбирают из С1-4 алкила, алкокси, гидрокси, алкоксиалкила, гидроксиалкила или эпокси; и
включая любые их приемлемые соли или сольваты.
2. Способ по п. 1, в котором соединение представляет собой по меньшей мере одно из трифлата N-(2-феноксиэтил)-2-изотиоцианато-N,N-диметилэтан-1-аминия, бромида N-(2-изотиоцианатоэтил)-N,N-диметилпроп-2-ин-1-аминия, йодида 3-изотиоцианато-N,N-диэтил-N-метилпропанаминия и бромида N-(2-изотиоцианатоэтил)-2-(метоксикарбонил)-N,N-диметилпроп-2-ен-1-аминия или их фармацевтически приемлемых солей.
3. Способ по п. 1, в котором соединение представляет собой по меньшей мере одно из йодида N,N-диэтил-2-изотиоцианато-N-метилпропанаминия, трифлата N-(2-бромэтил)-3-изотиоцианато-N,N-диэтилпропан-1-аминия, бромида N-(этоксипропил-2,3-дион)-3-изотиоцианато-N,N-диэтилпропан-1-аминия или их фармацевтически приемлемых солей.
4. Способ по любому из пп. 1-3, дополнительно включающий приведение бактерии в контакт со вторым агентом, который представляет собой по меньшей мере одно из масла омега-3, салициловой кислоты, диметилбутанола, чесночного масла, оливкового масла, масла криля, кофермента Q-10, пробиотика, пребиотика, пищевых волокон, шелухи семян подорожника, солей висмута, фитостеролов, масла виноградных косточек, экстракта зеленого чая, витамина D, антиоксиданта, куркумы, куркумина, ресвератрола, активированного угля или хлорофиллина меди.
5. Способ по любому из пп. 1-4, в котором превращение холина или карнитина в триметиламин (ТМА) ингибируется на от приблизительно 1% до приблизительно 100%.
6. Способ по п. 5, в котором превращение холина или карнитина в триметиламин (ТМА) ингибируется по меньшей мере на 50%.
7. Способ по любому из пп. 1-6, в котором бактерия представляет собой по меньшей мере одну из Proteus mirabilis, Desulfovibrio alaskensis, Clostridium Ijungdahlii, C. scindens, C. aldenense, C. aminobutyricum, Collinsella tanakaei, Anaerococcus vaginalis, Streptococcus dysgalactiae, Desultitobacterium hafniense, Klebsiella variicola, K. pneumonia, Proteus penneri, Eggerthella lenta, Edwardsiella tarda, Escherichia coli или E. fergusonii.
8. Соединение, содержащее
Figure 00000002
где R1 представляет собой Н, С1-С4 алкокси, Br, Cl, F, I или выбран из
Figure 00000003
Y+ выбирают из четвертичного атома азота; X- представляет собой любую фармацевтически приемлемую соль; n выбирают из 1, 2 или 3; R2 и R3 независимо выбраны из С1-4 алкила или связаны вместе с образованием алифатической, ароматической или гетероциклической кольцевой системы;
Z представляет собой О, СН2 или Н, Н;
m равно 0, 1 или 2;
R5 представляет собой гидроксил или гидроксиалкил; и
R7 представляет собой Н или С1-С4 алкил; и включая любые их приемлемые соли или сольваты.
9. Соединение по п. 8, которое представляет собой по меньшей мере одно соединение, выбранное из соединений ТАБЛИЦЫ 1 с идентификационными номерами 3-45.
10. Способ получения соединения, представленного ФОРМУЛОЙ (II), включающий
Figure 00000004
где R1 представляет собой Н, С1-С4 алкокси, Br, Cl, F, I или выбран из
Figure 00000005
Y+ выбирают из четвертичного атома азота; X- представляет собой любую фармацевтически приемлемую соль; n выбирают из 1, 2 или 3; R2 и R3 независимо выбраны из С1-4 алкила или связаны вместе с образованием алифатической, ароматической или гетероциклической кольцевой системы;
Z представляет собой О, СН2 или Н, Н;
m равно 0, 1 или 2;
R5 представляет собой гидроксил или гидроксиалкил; и
R7 представляет собой Н или С1-С4 алкил; и включая любые их приемлемые соли или сольваты;
взаимодействие соединения А
Figure 00000006
с соединением со структурой В
Figure 00000007
где LG представляет собой подходящую уходящую группу, известную специалисту в данной области.
11. Способ по п. 10, в котором уходящая группа LG представляет собой по меньшей мере одно из хлорида, бромида, йодида, трифлата, мезилата или тозилата.
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