RU2001904C1 - Способ получени хиноновых производных - Google Patents

Способ получени хиноновых производных

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RU2001904C1
RU2001904C1 SU904831237A SU4831237A RU2001904C1 RU 2001904 C1 RU2001904 C1 RU 2001904C1 SU 904831237 A SU904831237 A SU 904831237A SU 4831237 A SU4831237 A SU 4831237A RU 2001904 C1 RU2001904 C1 RU 2001904C1
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Russia
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group
formula
lower alkyl
group represented
represented
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SU904831237A
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English (en)
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Абе Синйа
Окамото Ясуси
Тагами Катсу
Хиби Сигеки
Нагакава Дзунити
Хирота Казуо
Хисинума Иехару
Ми мото Канаме
Яманака Такаси
Екохама Хиромитсу
Есимура Тсутомо
Хорие Тохру
Акита Ясунори
Ката ма Коити
Яматсу Исао
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Эйсай Ко., Лтд. (JP)
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Publication of RU2001904C1 publication Critical patent/RU2001904C1/ru

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  • Organic Chemistry (AREA)
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  • Pyridine Compounds (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

Использование: хими  Сущность изобретени : продукт - производные хинона общей формулы I. где R1-C Н .С Нциклогексилметип, СН2СН8ЩСНЗСН ftH54CM(CH2)3SCH3 группа формулы И, foiR3 может быть идентичными или отличатьс  друг от друга и каждый представл ет СН О или С Н О. Реагент 1: гидрохиноновое про13 изводное общей формулы III. где R -R имеют указанные значени  X и Y - одинаковые или различные и означают ОН. СН О или С Н О- группу. Реагент 2 окисл ющий агент. Услови  реакции, при 20°С в среде растворител  3 табл. ф-пы I, II, III соответственно йфз с-соон Н R э :Н С-СООН III

Description

Изобретение относитс  к области производных бенэохинона. которые про вл ют активность как лекарства.
Более конкретно изобретение касаетс  новых производных бензохинона, пригодных в качестве терапевтических агентов дл  лечени  болезней печени.
Поскольку причина, внешнее про вление и патофизиологи  каждой из гепатиче- ских болезней различны и включают немало неизвестных факторов, очень трудно разработать терапевтический агент против этих болезней.
В насто щее врем  характерные представители этих лекарств, широко использующиес  дл  лечени  и предупреждени  гепатических болезней и оцененных клинически , включают глицирризиновые препараты
Хот  они считаютс  эффективными против гепатических расстройств, циррозов или гепатитов и дл  постоперационной защиты печени, и т.д.. их действенность не так сильна и они про вл ют побочные стероидные эффекты. Кроме того, они примен ютс  в форме внутривенных инъекций и неактивны при оральном употреблении.
, и; бретени  в результате исследований по поиску терапевтических аген- тос претив статических болезней установили, что производные бензохинона удовлетвор ют поставленной цели изобретени .
Примеры бензохиноновых производных , которые про вл ют фармацевтическую активность, включают также и известные соединени  1. 2.
Бснзохиноноаое производное патента Японии № 223150 отличаетс  от соединени  0) изобретени  по химической структуре и и моет антиастматическую активность, таким образом  вл етс  отличным от соединени , представленного в изобретении, по фармацевтической активности
Патент Японии № 177934 раскрывает бензохиноновое производное, которое, отличаетс  от соединени  изобретени  как по эффективности, так и по структуре
Изобретение относитс  к получению бензохиноновых производных следующей общей формулы ()
СН3 R(1)
.сн с-соон
R
где R1 представл ет СбНп. CgHig, циклогек- симетил. СН2СН2СН(СНз)СНз. (
(СН2)з5СН3.сн х/3 - 2 о
R и R могут быть идентичны, либо отличаютс  друг от друга и представл ют собой СНзО- или C2Hs-0-rpynny.
Способ получени  соединений по изобретению может быть представлен следующей схемой:
-СН3 R1,
СН-С-СООН
сн,
R1 I
I
сн с-соон
5
0
5
0
5
0
5
0
В описанных формулах (I) и (II) X и Y могут быть одинаковыми или различными и каждый представл ет ОН, СНзО или C2HsO группу; R . R и R имеют значени , опреде- ,. ленные ранее:
Как видно из приведенной схемы, бензохиноновое производное (I) может быть получено обработкой гидрохинонового производного (II) окисл ющим агентом.
В качестве окисл ющего агента используют гексагидрат хлорида двухвалентного железа или окись свинца. Окисл ющий агент используетс  в количестве от 3 до 10 моль на моль гидрохинонового производного , предпочтительные примеры растворителей включает бензол, этилацетат, диоксан, этанол и 1.2-диметоксиэтан, необ зательно содержащие воду. Реакцию провод т обыч но при температуре от 0 до 80°С. предпочтительно от 20 до 40°С.
Врем  реакции обычно от 1 до 12 ч.
Эффект изобретени  описан более подробно с помощью примеров фармакологических испытаний с использованием соединений, полученных по изобретению
Фармакологические испытани .
Тест 1. Действие на крыс, модели с острым гепатитом, индуцированным а-галакто- замином (GaIN).
(1) Методика.
300 мг/кг GAIN инъецировали подкожно самцам крыс (примерно 180 г) Фишера (F 344), чтобы индуцировать острый гепатит. В каждом опыте соединение суспедировалось в 0,5%-ном водном растворе метилцеллюло- зы и давалось в дозе 100 мг/кг спуст  час после инъекции GaIN.
Брали пробу крови из хвоста крысы через 48 ч после иньекции GaIN. Врем  свертывани  крови измер ли с помощью Гепапластинового теста (НРТ) и в то же врем  НРТ-активность в плазме измер ли энзи- матически.
Процент ингибировани  GalN-индуци- рованного гепатита при каждом испытании соединени  показан в табл. 1.
(2) Результаты
Результаты показаны в табл. 1. Соединени  описаны в табл.3.
Тест 2. Действие на мышей с Propionlbactrium acnes (P acnes) - липопо- лисахарид (LPS) - индуцированным скоротечным гепатитом
(1)Методика
Убитые теплом P. acnes в количестве 1 мг/мышь инъецировались внутривенно п тинедельным самцам BaLb /с мышей, и дополнительно внутривенно инъецировалс  LPS в дом 1 миг/мышь через 7 дне после инъекции P. acnes дл  провоцировани  скоротечного гепатита. Каждое исследуемое соединение суспендировалось в 0.5% -ном растворе метилцеллюлозы и давалось орально в доэе 100 мг/кг эа 30 мин до внутривенной инъекции LPS.
Процент выживани  и GPT-активность в плазме выживших животных определ лись через 24 ч после внутривенной инъекции LPS Показатели дл  мышей, обработанных каждым исследуемым соединением в цел х предотвращени  летательного исхода и повреждени  печени индуцируемого P acnes - LPS. показаны в табл 2
(2)Результаты
Результаты приведены в табл 2
Номера соединений во всех таблицах соответствуют
Экспериментальный пример 3.
Тест на токсичность
Соединени  по изобретению давались орально 7-недельным самцам sic SO крыс в течение недели (доза 300 мг/миг). В результате было установлено, ни одно из соединений не привело к смерти
Из экспериментальных примеров 1 и 2 видно, что соединени , представленные изобретением, высокоэффективны как терапевтические агенты против болезней печени .
Таким образом соединени  по изобретению  вл ютс  полезными в качестве терапевтических и профилактических агентов дл  различных типов гепатитов животных, включа  человека и могут в частности использоватьс  дл  лечени  или предотвращени  например, хронического гепатита, острого гепатита, токсической гепэтопатии, алкогольного гепатита, желтухи и цирроза как последней стадии болезни
Кроме того как отмечалось, соединени  изобретени   вл ютс  очень низко токсичными , т.е. высоко безопасными Во многих
случа х соединени  должны будут приниматьс  в длительнсго периода времени з зависимости от природы заболевани , в данном отношении изобре- тение представл ет большую ценность.
Представленные примеры иллюстрируют изобретение, хот  следует отметить, что изобретение не ограничиваетс  ими.
Поскольку соединени  изобретени  o имеют двойную св зь, они могут существовать в форме цис- и транс-изомеров. В примерах соединени  наход тс  в форме транс-изомеров, если ие оговорено иначе.
Сокращен химических структурны 5 формулах имеют следующие значени :
Me: метилъна  группа: Et : атильна 
группа; л-Рг и - пропмльиа группа; MOM О:
мето смметило си ьна  группа: - Рг
изолропильна  группа. Oct октильиа 
0 группа.
Пример 1. (Е)-3-/5-(2.Э-Димето«си-6- метил 1,4-бенэот иоил)/-2-иоиил-2-пропе- мова  кислота
Ие°-°- -.
U
,CHj
weoV- С|Н О «нн
3.4 г (Е) -3-/5-0-падрокси-6-метил-2.Э.4-тримвтокси )фвни /-2-пропеноеой кислоты раствор ли в 100 мл атил ацетата и туда же добавл ли 3,4 г гексагидрата двухвалентного железа. Смесь перемешивали при комнатной температуре в течение 2 ч. мтем
добавл ли 200 мл воды. Получающуюс  в результате смесь раздел ли на две жидкие фазы, органическую фазу промывали еодо и суыжли над безводным сульфатом маг нив. Растворитель отгон ли, остаток очищали на
хроматогрвфичежков силикагельной колонке (элювнт: днхлорметан: этанол - 95 : 5) и перекриста лиэовывали из п-гексана с пол- учетов 2.9 г целевого соединени  в виде оранжевого твердого вещества Точка плавлени : 68аС.
Н-ЯМР ®: 0.86 (Т. J - б Гц ЗН). 1.02- 1.60
(м 14Н). 1.96 (д.. J - 2 Гц. ЗН). 2.01-2.22
(м.. 2Н). 3.99 (с., ЗН). 4,01 (с ЗН) 720 (шир с.. 1Н)
Аналогичным образом получали соединени , представленные в табл 3
(56) Выложенна  за вка Японии
№ 62-223150, кл С 07 С 103/76. 1987
Выложенна  за вка Японии N- 58- 177934. кл. С 07 С 103/737 1983
Таблица 1
Исследуемое Соединение
(compound N б)
Е1(пА О СООН
(compound N 8)
ИеО
МеО
хх
(compound № 12)
о
о соон
(compound № 13)
МеО
МеО EtO
fco
соон
(compound N 14)
EtOvA.Me
Т Т
ЕЮО соон
(compound N; 20)
MeOvJLOMe
о соон
(Пример Ne 1)
МеО МеО
и ) A Me
ИГ/ -V4
С9Н19
& Лсоон
Процент ингибировани . %
НРТ
ОРТ
51
52
73
72
98
too
67
76
79
78
95
93
87
91
Исследуемое соединение
(compound № 47)
О МеОууме
О СООН
(compound № 54)
MeOsJLMe
меоЛг Ч4 5 О СООН
(compound Г 88)
МеО.
меОО соон
Таблица 2
Вли ние испытываемых соединений на смертность и гепатопатию. индуцированные введением P. acnes - LPS
Продолжение табл. 1
Процент ингибироаани , %
НРТ
GPT
CN
97
96
80
86
99
97
Табл и ц а 3
u
52
MeO
53
54
Me С
55
56
MeO
1.08-1.80 (m. 12H). 1,97(d, J 2 Hz, 3H). 2,00-2.43 (m. 4H), 2,98 (s, 3H),
4.01 (s. 3H), 7,23 (bs. 1H)
1,07-1,80 (m. 12H), 1.38 (t, J - 7 Hz.
3H). l,39(t. J 7 Hz, 3H), 1.96(d, J
-2 hz. 3H). 1,96- 2,42 f.n, 4H), 4,23 (q.
J 7 H7, 2H). 4,28 (q. J Hz, 2H),
7.22 (DS. 1H)
1.50-1.90 (m, 2H), 1.96(ti, J -2 Sz
3H), 2.00 (s, 3H). 2.15-2.50 (m.4H),
3,98 (s, 3H), 4,00 (s, ЗН), 7.30 (d J
2 Hz. 1H)
1 40 (t, J 7 Hz, 3H), 1 63-1,89 (m, 2H),
1.97 (d, J 2 Hz, 3H). 2.00 (s, 3H).2.192 ,49 (m, 4H), 4,03 (s, 3H), 4,25 (q, J
7 Hz, 2H), 7.34 (bs, 1H)
1,61-1,93 (m, 2H). 2.00 (s, 3H). 2.142 .47 (m, 4H), 3,97 (s, 3H), 4,01 (s, 3H),
,4-°3 (s. 3H), 729(s. 1H)
MeO
EtO
iVleO
EtO
MeO
Me
4CH2)8-CN
Me -fCH2)8-CN
Mt- i -(CH2)3-8.Me
Me КСНуз-S-Mel
MeO Kc;-i-e)rS-tV e
OH
OH
OH
OH
OH
XX
57°C
86°C
78-8C°C
x 74-76°C
61-62°C
NJ C.
О CO
o
Ю
т
О)
| о
§ а
С
8
«о
о
- Оранжевое твердое вещество. - желтовато-оранжевое твердо вещество:
коричневое масло;
желтое твердое вещество:
оранжевое твердо вещество:
коричневое твердое вещество.
коасиое масло:
оранжевое масло;
красновато-оранжевое вещество.
л
(«

Claims (1)

  1. Формула изобретени 
    СПОСОБ ПОЛУЧЕНИЯ ХИНОНОВЫХ ПРОИЗВОДНЫХ общей формулы
    -соон.
    - CcHi
    где - v sriii; bonig, циклогексилметил СН2СН2СНГСНз)СН3; (СН2)„СМ; (СНг);
    ЧУ
    R2 и Нз, идентичные или различные, и представл ют каждый СНзО или C2HsO-rpynny,
    отличающийс  тем. что соединение общей
    формулы
    .
    где RI - РЭ имеют указанные значени , X и Y, одинаковые или различные, - ОН.
    СНзО или C2HsO-rpynn8. подвергают обработке окисл ющим агентом .
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KR910006200A (ko) 1991-04-27
NO174292B (no) 1994-01-03
ES2082811T3 (es) 1996-04-01
AU6225890A (en) 1991-03-14
EP0419905A3 (en) 1992-06-24
PT95266A (pt) 1991-05-22
US5210239A (en) 1993-05-11
DD299637A5 (de) 1992-04-30
JP2919030B2 (ja) 1999-07-12
CA2024479A1 (en) 1991-03-12
ATE133156T1 (de) 1996-02-15
GR3019614T3 (en) 1996-07-31
CN1031992C (zh) 1996-06-12
CN1050182A (zh) 1991-03-27
FI904206A0 (fi) 1990-08-24
US5385942A (en) 1995-01-31
RU2049771C1 (ru) 1995-12-10
JPH03188042A (ja) 1991-08-16
NZ235193A (en) 1992-04-28
DE69024896T2 (de) 1996-06-13
AU637138B2 (en) 1993-05-20
NO903909L (no) 1991-03-12
HU208105B (en) 1993-08-30
DE69024896D1 (de) 1996-02-29
EP0419905A2 (en) 1991-04-03
NO903909D0 (no) 1990-09-07
FI102273B1 (fi) 1998-11-13
EP0419905B1 (en) 1996-01-17
FI102273B (fi) 1998-11-13
IE903241A1 (en) 1991-03-27

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