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RU2018142330A - Способы ингибирования превращения холина в триметиламин (тма) - Google Patents

Способы ингибирования превращения холина в триметиламин (тма) Download PDF

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RU2018142330A
RU2018142330A RU2018142330A RU2018142330A RU2018142330A RU 2018142330 A RU2018142330 A RU 2018142330A RU 2018142330 A RU2018142330 A RU 2018142330A RU 2018142330 A RU2018142330 A RU 2018142330A RU 2018142330 A RU2018142330 A RU 2018142330A
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aminium
prop
dimethylprop
alkyl
dimethyl
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RU2018142330A
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RU2018142330A3 (ru
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Стенли Леон ХЕЙЗЕН
Хосе Карлос ГАРСИЯ-ГАРСИЯ
Джордж Франклин ГЕРБЕРИК
Джон Август ВОС
Сяньдун ГУ
Майкл РЕЙЛЛИ
Марк Роберт СИВИК
Джоди Мишель РИД
Дэвид Блэр КОДИ
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Дзе Проктер Энд Гэмбл Компани
Дзе Кливленд Клиник Фаундейшн
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Claims (38)

1. Композиция, содержащая физиологически приемлемый носитель и соединение формулы (III)
Figure 00000001
где Y+ представляет собой четвертичный атом азота, X- представляет собой фармацевтически приемлемый анион, а n равен 1, 2, 3 или 4,
R12 = 
Figure 00000002
W представляет собой CH2 или O,
R13 и R14 независимо выбраны из C1–C4 алкила или пропаргила,
R15 выбран из C1–C4 алкила, гидроксиэтила или пропаргила,
R5 = H или C1–C4 алкил,
R6 может быть независимо выбран из гидроксила, C1–C4 алкокси или кислорода, когда является частью кольцевой системы,
R16 выбран из H, C1–C4 алкила или имеет отрицательный заряд, когда [O] существует в виде карбоксилат-аниона,
и включая любые их приемлемые соли или сольваты.
2. Композиция по п. 1, в которой соединение выбрано из группы, состоящей из: 2-(метоксикарбонил)-N,N-диметил-N-(проп-2-ин-1-ил)проп-2-ен-1-аминия бромида, 2-карбокси-N,N-диметил-N-(проп-2-ин-1-ил)проп-2-ен-1-аминия бромида, 2-циано-N-(2-гидроксиэтил)-N,N-диметилпроп-2-ен-1-аминия бромида, 2-циано-N,N-диметил-N-(проп-2-ин-1-ил)проп-2-ен-1-аминия бромида или N-(3-метокси-2,3-диоксопропил)-N,N-диметилпроп-2-ин-1-аминия бромида.
3. Композиция по п. 1, в которой
R12 представляет собой акриловую группу, ацеталь, алкокси, амидо, амино, карбоксильную группу, карбоксилат или глиоксил,
R13 и R14 независимо выбраны из C1–C4 алкила; и
R15 представляет собой пропаргил.
4. Способ ингибирования превращения холина в триметиламин (ТМА) и снижения уровня TMAO посредством обеспечения соединения, представленного формулой (I)
Figure 00000003
Формула (I),
где Y+ представляет собой четвертичный атом азота, X- представляет собой фармацевтически приемлемый анион, а n равен 1, 2, 3 или 4,
R1 выбран из
Figure 00000004
,
Z = CH или O,
R2 и R3 независимо выбраны из C1–С4 алкила, аллила, пропаргила или CH2, когда являются частью алифатической, карбоциклической или гетероциклической кольцевой системы,
R4 = H, C1–C4 алкил, аллил, алкилкарбоксил, алкилкарбоксилат, алкиловый эфир, гидроксиалкил, алкоксиалкил, пропаргил, амин или аминоалкил,
R5 = H или C1–C4 алкил,
R6 может быть независимо выбран из гидроксила, C1–C4 алкокси или кислорода, когда является частью кольцевой системы, и;
R7 = H, C1–C4 алкил или отсутствует, когда ион карбоксилата является частью бетаина, внутренней соли или имеет форму Цвиттер-иона;
и включая любые их приемлемые соли или сольваты;
причем соединение вводят в количестве, эффективном для ингибирования образования триметиламина (ТМА) из холина у субъекта.
5. Способ по п. 4, в котором
R1 представляет собой
Figure 00000005
,
R6 может быть независимо выбран из гидроксила, C1–C4 алкокси или кислорода, если является частью кольцевой системы; и
включая любые их приемлемые соли или сольваты.
6. Способ по п. 4, в котором соединение выбрано из группы, состоящей из: 2-(метоксикарбонил)-N,N-диметил-N-(проп-2-ин-1-ил)проп-2-ен-1-аминия, 4-карбокси-N,N-диметил-N-(проп-2-ин-1-ил)бутан-1-аминия, N-(2,2-диметоксиэтил)-N,N-диметилпроп-2-ин-1-аминия, N-(2,2-дигидроксиэтил)-N,N-диметилпроп-2-ин-1-аминия, N-(2-гидроксиэтил)-N,N-диметилбут-3-ин-1-аминия, N-(2,2-диэтоксиэтил)-N,N-диметилпроп-2-ин-1-аминия, 4-гидрокси-1-метил-1-(проп-2-ин-1-ил)пиперидин-1-ия, 2-циано-N,N-диметил-N-(проп-2-ин-1-ил)проп-2-ен-1-аминия, N-(карбоксиметил)-N,N-диметилпроп-2-ин-1-аминия, триметил(проп-2-инил)аммония, аллил-(цианометил)-диметиламмония или N-(2-гидроксиэтил)-N,N-диметилпроп-2-ин-1-аминия и их фармацевтически приемлемой соли.
7. Способ по п. 4, дополнительно включающий обеспечение соединения, выбранного из группы, состоящей 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 и ресвератрола.
8. Композиция, содержащая соединение, выбранное из группы, состоящей из: 2-(метоксикарбонил)-N,N-диметил-N-(проп-2-ин-1-ил)проп-2-ен-1-аминия, 4-карбокси-N,N-диметил-N-(проп-2-ин-1-ил)бутан-1-аминия, N-(2-гидроксиэтил)-2,2-диметокси-N,N-диметилэтан-1-аминия, N-(2,2-диметоксиэтил)-N,N-диметилпроп-2-ин-1-аминия, N-(2,2-дигидроксиэтил)-N,N-диметилпроп-2-ин-1-аминия, 5-карбокси-N,N-диметил-N-(проп-2-ин-1-ил)пентан-1-аминия, 2-карбокси-N,N-диметил-N-(проп-2-ин-1-ил)проп-2-ен-1-аминия, N-(2-амино-2-оксоэтил)-N,N-диметилпроп-2-ин-1-аминия, 2-карбокси-N-(2-гидроксиэтил)-N,N-диметилпроп-2-ен-1-аминия, 2-циано-N-(2-гидроксиэтил)-N,N-диметилпроп-2-ен-1-аминия, 2-циано-N,N-диметил-N-(проп-2-ин-1-ил)проп-2-ен-1-аминия, N-(3-метокси-2,3-диоксопропил)-N,N-диметилпроп-2-ин-1-аминия, 8-(2-цианоаллил)-8-метил-8-азабицикло[3.2.1]октан-8-ия, N-(2-гидроксиэтил)-N,N-диметилбут-3-ин-1-аминия, 4-гидрокси-1-метил-1-(проп-2-ин-1-ил)пиперидин-1-ия, хлорметилдиметилпроп-2-иниламмония, бромметилдиметилпроп-2-иниламмония или йодметилдиметилпроп-2-иниламмония и их фармацевтически приемлемой соли.
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