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RU2008151690A - Контролируемое высвобождение фенольных опиатов - Google Patents

Контролируемое высвобождение фенольных опиатов Download PDF

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RU2008151690A
RU2008151690A RU2008151690/04A RU2008151690A RU2008151690A RU 2008151690 A RU2008151690 A RU 2008151690A RU 2008151690/04 A RU2008151690/04 A RU 2008151690/04A RU 2008151690 A RU2008151690 A RU 2008151690A RU 2008151690 A RU2008151690 A RU 2008151690A
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Томас Э. ДЖЕНКИНС (US)
Томас Э. ДЖЕНКИНС
Александр КОЛЕСНИКОВ (US)
Александр КОЛЕСНИКОВ
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Фармакофор, Инк. (Us)
Фармакофор, Инк.
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Abstract

1. Соединение структурной формулы (I) ! ! или его фармацевтически приемлемая соль, где ! Х является фенольным опиатом, в котором атом водорода гидроксильной группы фенола замещен ковалентной связью с -C(O)-Y-(C(R1)(R2))n-N(R3)(R4); ! Y является -NR5- и R5 является (1-4С)алкилом, ! n равно 2 или 3, ! R1 и R2 каждый является водородом, ! R3 является водородом или (1-4С)алкилом и ! R4 является остатком L-аминокислоты, выбранной из аланина, аргинина, аспарагина, аспарагиновой кислоты, цистеина, глицина, глутамина, глутаминовой кислоты, гистидина, изолейцина, лейцина, метионина, фенилаланина, пролина, серина, треонина, триптофана, тирозина, лизина и валина, остатком дипептида или трипептида, состоящего из двух или трех L-аминокислотных остатков, независимо выбранных из аланина, аргинина, аспарагина, аспарагиновой кислоты, цистеина, глицина, глутамина, глутаминовой кислоты, гистидина, изолейцина, лейцина, метионина, фенилаланина, пролина, серина, треонина, триптофана, тирозина, лизина и валина или остатком их N-ацильных производных. ! 2. Соединение по п.1, где фенольный опиат является оксиморфоном, гидроморфоном или морфином. ! 3. Соединение по п.1 или 2, где R5 является метилом. ! 4. Соединение по п.3, где R3 является водородом или метилом. ! 5. Соединение по п.4, где R4 является остатком аргинина, N-ацетиларгинина, N-трет-бутаноиларгинина, N-бензоиларгинина, N-пиперониларгинина, N-глициниларгинина, лизина, глутаминовой кислоты, аспарагиновой кислоты, тирозина, пролина и N-глицинилпролина. ! 6. Соединение по п.5, где R4 является остатком аргинина, N-ацетиларгинина, N-трет-бутаноиларгинина, N-бензоиларгинина, N-пиперониларгинина, N-глициниларгинина, лизина, глутаминовой кислот�

Claims (9)

1. Соединение структурной формулы (I)
Figure 00000001
или его фармацевтически приемлемая соль, где
Х является фенольным опиатом, в котором атом водорода гидроксильной группы фенола замещен ковалентной связью с -C(O)-Y-(C(R1)(R2))n-N(R3)(R4);
Y является -NR5- и R5 является (1-4С)алкилом,
n равно 2 или 3,
R1 и R2 каждый является водородом,
R3 является водородом или (1-4С)алкилом и
R4 является остатком L-аминокислоты, выбранной из аланина, аргинина, аспарагина, аспарагиновой кислоты, цистеина, глицина, глутамина, глутаминовой кислоты, гистидина, изолейцина, лейцина, метионина, фенилаланина, пролина, серина, треонина, триптофана, тирозина, лизина и валина, остатком дипептида или трипептида, состоящего из двух или трех L-аминокислотных остатков, независимо выбранных из аланина, аргинина, аспарагина, аспарагиновой кислоты, цистеина, глицина, глутамина, глутаминовой кислоты, гистидина, изолейцина, лейцина, метионина, фенилаланина, пролина, серина, треонина, триптофана, тирозина, лизина и валина или остатком их N-ацильных производных.
2. Соединение по п.1, где фенольный опиат является оксиморфоном, гидроморфоном или морфином.
3. Соединение по п.1 или 2, где R5 является метилом.
4. Соединение по п.3, где R3 является водородом или метилом.
5. Соединение по п.4, где R4 является остатком аргинина, N-ацетиларгинина, N-трет-бутаноиларгинина, N-бензоиларгинина, N-пиперониларгинина, N-глициниларгинина, лизина, глутаминовой кислоты, аспарагиновой кислоты, тирозина, пролина и N-глицинилпролина.
6. Соединение по п.5, где R4 является остатком аргинина, N-ацетиларгинина, N-трет-бутаноиларгинина, N-бензоиларгинина, N-пиперониларгинина, N-глициниларгинина, лизина, глутаминовой кислоты, пролина и N-глицинилпролина.
7. Соединение по п.6, представляющее собой гидроморфон-3-(N-метил-N(2-N'-ацетиларгиниламино)этилкарбаматом или его фармацевтически приемлемой солью.
8. Способ получения соединения формулы (I) или его фармацевтически приемлемой соли, как определено по любому из пп.1-7, который включает реагирование соединения формулы (III)
Figure 00000002
или его производного с защитой с соединением формулы (IV)
Figure 00000003
где M представляет отходящий атом или группу,
с последующим удалением любой защитной группы и при необходимости ацилированием соединения формулы (I) и/или образованием фармацевтически приемлемой соли.
9. Фармацевтическая композиция, включающая соединение по любому из пп.1-7 и фармацевтически приемлемый носитель.
RU2008151690/04A 2006-05-26 2007-05-24 Контролируемое высвобождение фенольных опиатов RU2469038C2 (ru)

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US80908206P 2006-05-26 2006-05-26
US60/809,082 2006-05-26
US90179507P 2007-02-16 2007-02-16
US60/901,795 2007-02-16
PCT/US2007/069683 WO2007140272A2 (en) 2006-05-26 2007-05-24 Controlled release of phenolic opioids

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US20100035826A1 (en) 2010-02-11
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US20150148284A1 (en) 2015-05-28
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US8217005B2 (en) 2012-07-10
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