SU1516011A3 - Способ получени 5-[4-(4-ацетил-3-гидрокси-2-пропилбензилокси)бензил]-тетразола - Google Patents

Способ получени 5-[4-(4-ацетил-3-гидрокси-2-пропилбензилокси)бензил]-тетразола Download PDF

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SU1516011A3
SU1516011A3 SU843775301A SU3775301A SU1516011A3 SU 1516011 A3 SU1516011 A3 SU 1516011A3 SU 843775301 A SU843775301 A SU 843775301A SU 3775301 A SU3775301 A SU 3775301A SU 1516011 A3 SU1516011 A3 SU 1516011A3
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acetyl
hydroxy
tetrazole
propylbenzyloxy
benzyl
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Делейн Диллард Роберт
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Эли Лилли Энд Компани (Фирма)
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    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
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Abstract

Изобретение касаетс  замещенных гетероциклических веществ, в частности получени  5-[4-(4-ацетил-3-гидрокси-2-пропилбензилокси)-бензил]тетразола, используемого дл  лечени  аллергических заболеваний, например астмы. Цель - создание нового более активного вещества указанного класса. Синтез ведут реакцией азида тетраметилгуанидини  с 4-[4-ацетил-3-гидрокси-2-пропилбензилокси]фенилацетонитрилом в среде диметилформамида в атмосфере аргона при 120-123°С. Выход 55,8%, т.пл. 155-157°С, брутто-ф-ла C20H22N4O3. Новое вещество малотоксично и имеет более высокий срок службы (6 ч, против 0,6 мин в известном случае). 1 табл.

Description

Данное изобретение относитс  к . способу получени  нового химического соединени , в частности к (4- ацетил-З-гидрокси-2-пропилбензилок- си)бензил -тетразола формулы
.N-N
сн,Ч
СзН7
Г
Ц
-N
который  вл етс  антагонистом лейко- триена и может быть использован при лечении аллергических заболеваний, например астмы.
Цель изобретени  - изыскание способа получени  нового производного тетразола, который по сравнению с аналогом по структуре того же назна - чени  имеет более высокую активность.
. ого - к-
N
-N
ко- ри ,
поо сть.
П р и м е р 1.6,9г (0,021 моль) 4-(4-ацетил-3-гидрокси-2-пропилбен- зилокси)фенилацетонитрила и 13,2 г (0,084 моль) азида тетраметилгуани- динил раствор ют в 50 мл диметилформамида в атмосфере аргона и смесь нагревают при 120-123 С в течение ночи. Смесь затем вливают в 1 л воды и подкисл ют концентрированной хлористоводородной кислотой.
Продукт экстрагируют этилацетатом, и этилацетатный раствор промывают три раза водой, после чего сушат сульфатом натри . Полученный продукт восстанавливают из этого раствора посредством высокоэффективной жидкостной хроматографии. Выход (А-ацетил-З-гидрокси-2-пропилбензилСП
О5
СМ
окси)бензил}тетразола составл ет 55,8%, Т. пл. 155-157 с,
Найдено, %: С 65,54; Н 6,00j N 15,00,CaoHjaN Oj
Вычислено, %: С 65,56; Н 6,05; N 16,29.
Полученное соединение  вл етс  антагонистом лейкотриенов,
Лейкотриеновый антагонизм был продемонстрирован следующим образом.
Пример 2. Самцов морских свинок Хартли весом 200-450 г убивают . Удал ют часть терминальной подвздошной кости, полость вычищают и ткань дел т на сегменты по 2,5 см.
Подвоздушнуто кость устанавливают в 10 мл тканевых ваннах, содержа- щих бикарбонатный раствор Кребса, имеющий следующий состав, ммол х/л: КС1 4,6; CaCl, 1,2; 1,2; MgS04 7H O 1,2; NaCl 118,2; NaHCOj 24,8, декстроза 10,0.
Жидкость в ванночках поддерживают при 37°С и аэрируют смесью 95% кислорода и 5% СО. Кроме того, такой биффер содержит 1x10 М атропина с целью уменьшени  подвздошной спонтанной активности. Изометрические измерени  провод т с помощью преобразовател  силового перемещени  Грасса ТОЭС и записывают на полиграфе Грасса в виде изменени  в гр.силы
К ткани прикладывают пассивную силу пор дка 0,5 г. После соответствующего периода установлени  равновеси  получают единичные субмаксимальные контрольные отк1шки на чис- тый ITD , Через 5 мин экспонировани  подвздошной кости действию зкспе- риментального медикамента в тканевую ванночку ввод т контрольную концентрацию ITD, Реакцию подвздошной кос- ти на ITD4 в присутствии медикамента сравнивают с реакцией в отсутст- ВИИ лекарства.
Пример 3, Провод т-эксперимент с целью более детального ана- лиза 1TD антагонизма.
В этих экспериментах получают ком . мул тивные кривые в координатах концентра1и1  - отклик на ITD подвздошной кости и трахеи морских свинок. Эти результаты получают после 30 мин инкубировани  в присутствии различных концентраций экспериментальных лекарств. Затем кривую концентраци  - отклик на ITD- повторно получают в присутствии дитд- гониста,,
Дл  одного образца ткани используют лишь одну концентрацию анто- рониета. Рассчитывают величину KB по методу Фюрхготта с использованием следующего уравнени :
L 2I§E22S lJ
дозовое соотношение-1
где антагонист - концентраци  полученного соединени 
Дозовое соотношение относитс  к концентрации антагониста, котора  требуетс  дл  того, чтобы вызвать 50% от максимального отклика в присутствии антагониста, деленной на EDgj в отсутствии антагониста.
Расчеты провод т с помощью компьютера и построени  кривых. Затем рассчитывают рА, как отрицательный log Kg, в том случае, когда наклон кривой шилда незначительно отличаетс  от единицы.
Результаты испытаний представлены в таблице.
Полученное соединение  вл етс  малотоксичиым,
Предлагаемое соединение имеет более высокий срок службы (период полураспада сыворотки морских свинок составл ет 6ч, период полураспада дл  известного 7-(3-(А-ацетил-3-ок- си-2-пропш1фенокси)-2-оксипропоксил- 4-оксо-3-пропил-4с)1-бензопиран-2-кар- боновой кислоты составл ет 0,6 мин,

Claims (1)

  1. Формула изобретени 
    Способ получени  5-СА-(4-ацетил- 3-гидгокси-2-протшбензилокси)бенг зил1-тетразола формулы
    о тличающийс  соединение формулы
    тем, что
    II
    но
    СН2О
    CH2CN
    подвергают взаимодействию с азидом тетраметилгуанидини ,
    51516011
    Концентраци 
    I 1x10 М 3x10 М 1x10 М 1 рА 9А 92 81 31 8,12
    отрицательный логарифм ;
    отрицательный логарифм концентрации, при которой осуществл етс  50%-ное ингибирование.
SU843775301A 1983-07-18 1984-07-16 Способ получени 5-[4-(4-ацетил-3-гидрокси-2-пропилбензилокси)бензил]-тетразола SU1516011A3 (ru)

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US06/514,428 US5105017A (en) 1983-07-18 1983-07-18 Leukotriene antagonist intermediates

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SU1516011A3 true SU1516011A3 (ru) 1989-10-15

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EP0132366B1 (en) 1990-01-03
DK349184D0 (da) 1984-07-17
US5105017A (en) 1992-04-14
EP0132366A2 (en) 1985-01-30
ATE49203T1 (de) 1990-01-15
KR850001179A (ko) 1985-03-16
GB8418172D0 (en) 1984-08-22
GB2143530A (en) 1985-02-13
CA1242196A (en) 1988-09-20
RO89314A (ro) 1986-03-15
PT78921B (en) 1986-10-23
AU569310B2 (en) 1988-01-28
ES8601836A1 (es) 1985-11-01
DE3480924D1 (de) 1990-02-08
AU3075184A (en) 1985-01-24
PT78921A (en) 1984-08-01
NZ208880A (en) 1987-06-30
JPH0350736B2 (ru) 1991-08-02
EP0132366A3 (en) 1986-06-25
FI842844A0 (fi) 1984-07-16
HUT44472A (en) 1988-03-28
FI842844A (fi) 1985-01-19
CS264107B2 (en) 1989-06-13
CS548784A2 (en) 1988-09-16
JPS6048944A (ja) 1985-03-16
DD229116A5 (de) 1985-10-30
DK349184A (da) 1985-01-19
GR81529B (ru) 1984-12-11
ES534268A0 (es) 1985-11-01
ZA845408B (en) 1986-02-26
KR880000688B1 (ko) 1988-04-23
US5393768A (en) 1995-02-28
IL72384A (en) 1987-10-20
GB2143530B (en) 1987-06-10

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