SU1646488A3 - Способ получени 5-[3-(бицикло[2.2.1]-гепт-2-илокси)-4-метоксифенил]гексагидро-2-пиримидинона - Google Patents

Способ получени 5-[3-(бицикло[2.2.1]-гепт-2-илокси)-4-метоксифенил]гексагидро-2-пиримидинона Download PDF

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SU1646488A3
SU1646488A3 SU884613064A SU4613064A SU1646488A3 SU 1646488 A3 SU1646488 A3 SU 1646488A3 SU 884613064 A SU884613064 A SU 884613064A SU 4613064 A SU4613064 A SU 4613064A SU 1646488 A3 SU1646488 A3 SU 1646488A3
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Алекс Саккомано Николас
Джеймс Виник Фредерик
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Abstract

Изобретение относитс  к гетероциклическим соединени м, в частности к получению (бицикло 2.2„ ij-гепт- 2-илокси) -4-метоксиФенилТгексагидро- 2-пиримидинона, который может найти применение в медицине. Дель изобретени  - разработка способа получени  указанных соединений. Получение ведут циклизацией соответственно замещенного глутарамида в реакционно- инертном растворителе при комнатной температуре в присутствии тетрааце- тата свинца. I IB

Description

Изобретение относится к способу получения нового химического соединения формулы
которое может быть применено в медицине.
Цель изобретения - поиск способа получения нового соединения в ряду гексагидропиримидин-2-она, обладающего высокой антидепрессантной активностью.
П р и м е р 1, 5~[3-(экзо~Бицикло[2.2.1] -гепт-2-илокси)-4-метоксифенил^гексагидро-2-пиримидинон.
А. 3-[(3-Бицикло[2.2.1]“гепт-2илокси) -4-метоксифенил[| глутаронитрил.
Пианоуксусную кислоту (18,1 г, 0,213 ммоль) и экзо-норборнилизованилиновый эфир (17,5 г, 71,1 ммоль) растворяют в смеси 80 мп пиридина и 2 мл пиперидина и выдерживают при 1006С в течение 40 ч. Реакционную смесь охлаждают до комнатной температуры, выливают в 200 мл воды и экстрагируют 2 к 100. мп этилацетата.
Объединенные экстракты промывают Водой, 1 н. раствором НС1, насыщенным раствором NaHC03, снова водой и высушивают над сульфатом магния, затем фильтруют и концентрируют под ваку > см умом.
Получают коричневый кристаллический осадок, который перекристаллизовывают из эфира и получают 15,1 г
1646488 (68,5%) дицианида в виде кристаллического твердого вещества, т.пл. 122123°С.
(300 МГц, CDClg): 6,82-6,65 (м, 38); 4,14 (м, 1Н); 3,8 (с, ЗН);
3,3 (м, 18); 2,77 (м, 18); 2,45 (м, 1Н); 2,3 (м, 18); 1,8-1,0 (м, 88).
Б 3-£( 3-Бицикло[2„2.1J -гепт-2-илокси)-4-метоксифенил2глутарамид.
Глутаронитрил со стадии А (14,8 г,
47,7 ммоль) растворяют в 200 мл ацетона и обрабатывают при 0°С 100 мл воды, 33,8 мл 30%-ного раствора Вг02 и 21,2 мл 10%-ного раствора Na2C03, затем медленно нагревают и перемешивают при комнатной температуре в течение 14 ч. Реакционную смесь концентрируют до 150 мл и остаток разделяют в смеси 100 мл воды и 200 мл этилацетата. Органическую фазу промывают водой, высушивают над сульфатом магния, Фильтруют и концентрируют под вакуумом. Сырой диамин растирают с эФиром и получают Г3,8 г (84%) диамина в виде кристаллического вещества, т.пл. 175-177°С.
•1Н-ЯМР (300 МГц, CDC1.): 6,8-6,6 (м, ЗН); 4,15 (м, 18); 3,75 (с, 38); 3,6 (м, 18); 2,6-1,0 (м, 14 8).
С. 5-£3-(экзо-Бицикло[2.2. lj-гепт2-илокси)-4-метоксиФенил^-гексагидро2-пиримидинон.
Глутарамид со стадии В (1г,
2,89 ммоль) растворяют в пиридине, в раствор добавляют (2,72 г, 6,13 ммоль) тетраацетата свинца и перемешивают в течение 20 ч при комнатной температуре. Реакционную смесь разбавляют водой и экстрагируют 2 X 100 мп этилацетата. Органические вытяжки промывают раствором НС1, высушивают над сульфатом магния, фильтруют и концентрируют под вакуумом. Неочищенный продукт кристаллизуют из этилацётата и получают 0,60 г (65,7%) циклической мочевины в виде кристаллического твердого вещества, т.пл.' 191-192°С, 1Н-ЯМР (300 МГц, CDCl3)s 6,8-6,6 (м, ЗН); 5,35 (шир. с, 2Н); 4,15 (м, 1Н); 3,8 (с, 38); 3,4 (м, 48); 3,1 (м, ГН); 2,5-1,0 (м, 108) .
Активность предлагаемого соединения в качестве антидепрессанта определяли на примере отчаяния в поведении. Б соответствии с этой процедурой состояние депрессии вызывали у мышей, заставляя их плавать в узком, содержащем воду, цилиндре, из которого нет выхода. Эта процедура включает введение мышам через рот предлагаемого соединения, а затем (через 30 мин после инъекции) мышей помещали в стандартный стеклянный стакан емкостью 1л, содержащий 800 мл воды при 25°С. Наблюдатель оценивает способность к движению (0 - подвижная, 1 - неподвижная) каждые 30 с в течение 5 мин, начиная после 2 мин пребывания мыши в воде. В качестве животных использовали самцов мыши массой 20-25 г (Чарлз Ривер) по 10 мышей в каждом эксперименте. Сравнивали с ролипрамом. Соединения применяли в растворе (носителе), содержащем Физиологический раствор (90%), диметилсульФоксид (5%) и эмул. 4 (5%). вводили в объеме 10 мл/кг» Мыши, обработанные-носителем, в типичном случае имели оценку по плаванию 9, в то время как применение антидепрессанта снижало степень неподвижности, что приводило к уменьшению оценки по плаванию.
Сравнение антидепрессантной активности предлагаемого соединения и ролипрама на модели отчаяния в поведении приведено ниже:
.
Соединение Минимально
эффективная доза, мг/кг
Предлагаемое
экзо-изомер 0,10
эндо—изомер 3,20
Смесь эндо- и экзо-
изомеров (7:3) 0,32
^Ролипрам 1,78
С точки зрения биологической активности экзо-изомер предлагаемого соединения более эффективен по сравнению с эндо-изомером, однако в реальной практике смесь изомеров предпочтительнее вследствие относительной простоты получения по сравнению с чистым изомером.
Как видно из данных, приведенных выше, экзо-изомер предлагаемого соединения или его смесь с эндо-изомером эффективнее ролипрама, кроме того, предлагаемое соединение является менее р.вотным, чем ролипрам.
По противодействию гипотермии, вызванной резерпином у мышей, предлагаемое соединение находится на уровне известного антидепрессанта дезипрамина.
Таким образом, реализация предлагаемого способа позволяет получать соединение, экзо-изомер которого превосходит по антидепрессантной активности ролипрам в 17,8 раз.

Claims (1)

  1. Формула изобретения
    Способ получения 5-£з-(бицикло 2, 2,1J-гепт-2-илокси)-4-метоксифенил гексагидро-2-пиримидинона формулы отличающийся тем, что проводят циклизацию соединения формулы в реакционно-инертном растворителе при комнатной температуре в присутствии тетраацетата свинца.
SU884613064A 1986-04-29 1988-12-12 Способ получени 5-[3-(бицикло[2.2.1]-гепт-2-илокси)-4-метоксифенил]гексагидро-2-пиримидинона SU1646488A3 (ru)

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PCT/US1986/000958 WO1987006576A1 (en) 1986-04-29 1986-04-29 Calcium independent camp phosphodiesterase inhibitor antidepressant

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SU884613064A SU1646488A3 (ru) 1986-04-29 1988-12-12 Способ получени 5-[3-(бицикло[2.2.1]-гепт-2-илокси)-4-метоксифенил]гексагидро-2-пиримидинона
SU884613133A SU1653542A3 (ru) 1986-04-29 1988-12-22 Способ получени производных 2-имидазолидинона

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YU115588A (en) 1988-10-31
DK172033B1 (da) 1997-09-22
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YU77387A (en) 1988-10-31
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WO1987006576A1 (en) 1987-11-05
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