CN1020096C - 制备咪唑啉衍生物的制备方法 - Google Patents
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Abstract
一种咪唑啉衍生物(Ⅰ)或其药学上可接受的盐,其中R是卤代苯基或吡啶基,X1和X2是氢原子或低级烷氧基,该衍生物可有效地用作免疫调节剂并且对类风湿性关节炎、多发性硬化、系统性红斑狼疮、风湿(性)热等等的治疗和/或预防是有用的。本发明还涉及该衍生物的制备方法以及含有所述化合物作为活性组分的药物组合物。
Description
本发明涉及新颖的咪唑啉衍生物及其制备方法。
咪唑啉的2,4,5-三苯基衍生物、咪唑啉的2,4,5-三(氯代苯基)衍生物以及咪唑啉的2,4,5-三-(4-甲基苯基)衍生物已是众所周知的[Merck Index 9 51,Chroachica Chemica Acta,45,519(1973)和Canadian Journal of Chem-istry 50 669(1972)]。在这之中,已知2,4,5-三苯基衍生物显示出对心脏病的抑制作用,但另外两种衍生物已知是不具有药理作用的。
经过广泛的研究,现已发现,尽管上述已知化合物在咪唑啉环上的2-、4-和5-位具有相同的取代基,但是在咪唑啉环上的2-位和4-与5-位之间具有不同取代基的一组咪唑啉衍生物作为一种免疫调节剂还是有效的。
因此,本发明的目的在于提供新颖的咪唑啉衍生物以及包含该类衍生物的药物组合物。本发明的另一个目的在于提供所述化合物的制备方法。以下列阐述中,这些目的和其它目的以及本发明的优越性对熟悉该技术领域的人员来说是显而易见的。
本发明涉及下式的咪唑啉衍生物或其药学上可接受的盐:
(Ⅰ)
其中R是卤代苯基或吡啶基,X1和X2是氢原子或低级烷氧基。
本发明的式(Ⅰ)化合物或它的盐作为免疫调节剂具有种种优良的特征。例如,式(Ⅰ)化合物或它的盐在巨噬细胞移行测定中表现出强大的巨噬细胞移行增强活性,巨噬细胞移行的测定可用来测定细胞参与的免疫活性。本发明的咪唑啉衍生物(Ⅰ)也显示出如此强大的免疫调节作用结果被抑制的免疫活性得到回升,增加了的免疫活性被降低回复至正常水平。进一步地,咪唑啉衍生物(Ⅰ)其或药学上可接受的盐具有低的毒性,并显示出高的安全性。
本发明的咪唑啉衍生物在药学上优选的例子是这些式(Ⅰ)的衍生物,其中R是一卤代苯基,X1和X2是氢原子。
由于在式中所存的两个不对称碳原子和两种互变结构的同分异构体,本发明的咪唑啉衍生物(Ⅰ)可以以立体异构体的形式存在:
其中R,X1和X2与上述的定义相同,并且本发明还包括这些异构体及其混合物。在本发明的咪唑啉衍生物(Ⅰ)的顺式异构体和反式异构体中,顺式异构体可较好地作为药用。
根据本发明,通过将式(Ⅱ)化合物或它的盐和式(Ⅲ)化合物或它的盐缩合可制得咪唑啉衍生物(Ⅰ)
(其中X1和X2与上述定义相同)
R-C-OR1(Ⅲ)
NH
(其中R与上述定义相同,R1是低级烷基)
缩合反应是在碱存在下或不存在下在溶剂中进行。碱包括碱金属醇盐、碱金属氢氧化物、碱金属碳酸盐、碱金属碳酸氢盐、三(低级烷基)胺等等。起始化合物(Ⅱ)和(Ⅲ)盐的例子为常规的无机酸添加盐和有机酸添加盐。低级链烷醇、二噁烷、四氢呋喃、二甲基甲酰胺、二甲亚砜等可用作溶剂。此反应较好是在0至100℃间进行。
在本发明中,当起始物质(Ⅱ)是赤型化合物时可得到顺式咪唑啉化合物(Ⅰ)。另一方面,分别地从赤型的起始物质(Ⅱ)中可得到反式咪唑啉化合物(Ⅰ),从光学活性的起始物质(Ⅱ)中可得到光学活性的化合物(Ⅰ)。
如前所述,本发明的化合物(Ⅰ)或它的盐显示出强大的免疫调节作用。特别是,化合物(Ⅰ)可激活巨噬细胞(即处在慢性炎症部位的巨噬细胞)的移行以使其离开炎症部位。同时,化合物(Ⅰ)可使抑制性的T-细胞水平得到回复。因此,化合物(Ⅰ)对于类风湿性关节炎、多发性硬化、系统性红斑狼疮、风湿(性)热等等的治疗和/或预防是有用的。
本发明的咪唑啉衍生物(Ⅰ)可以游离碱形式或盐的形式作为药用。化合物(Ⅰ)的药学上可接受的盐包括,例如,诸如盐酸化物、磷酸盐和硫酸盐的无机酸加成盐,以及诸如草酸盐、乙酸盐、乳酸盐、构椽酸盐、酒石酸盐、富马酸盐、马来酸盐、天冬氨酸盐、甲磺酸盐和苯甲酸盐的有机酸加成盐。
咪唑啉衍生物(Ⅰ)或它的盐对于恒温动物(包括人)可口服给药或非肠胃道给药,也可以将含有该化合物的药物制剂与适合于口服或非肠胃道给药的药物赋形剂相混合的形式使用。药剂可呈诸如片剂、颗粒剂、胶囊剂和粉末剂的固体形式或呈诸如溶液剂、悬浮剂或乳剂的液体形式。此外,当非肠胃道给药时,可使用注射剂。
根据用药的途径、病人的年龄、体重及病情以及疾病的种类,咪唑啉衍生物(Ⅰ)或其盐的剂量可以是不同的,较好的剂量是一天0.01至50毫克/公斤,最好的剂量是一天0.1至10毫克/公斤。
实验1
对肺泡巨噬细胞(alveolar macrophage)移行的影响
取重3至4公斤间的雌性日本大白兔在麻醉下宰杀。通过用盐水灌洗肺部得到肺泡的巨噬细胞。在“试验组”中,让巨噬细胞在含有5%兔血清和10-7M或10-9M试验化合物的RPMI-1640培养基中移行,根据Journal of Leukocyte Biology 42∶197-203(1987)中所述的方法,在37℃下让所述的移行试验进行24小时。将所得的移行放大15倍并画出其轮廓。然后,用面积仪测出移行面积。
通过使用含有5%兔血清和5mM1-岩藻糖的RPMI-1640培养基来代替含有试验化合物的培养基来测量“阳性对照组”中巨噬细胞的移行。另一方面,在“对照组”中,只用含5%的兔血清的培养基进行该实验。移动指数可通过下式算出:
移行指数= ((试验组的移行面积)-(对照组的移行面积))/((阳性对照组的移行面积)-(对照组的移行面积))
其结果如表1所示。(表1见文后)
实验2
对免疫增强动物的空斑形成细胞的正常化的影响
给雌性BALB/C小鼠(10周龄,5只小鼠一组)腹腔注射秋水仙素(1毫克/公斤),然后马上给小鼠腹腔内注射蛋白质抗原[吸附在2,4,5-三硝基苯(TNP)-Keyhole Limpet Hemocyanin(KLH)的膨润土颗粒](0.1毫克蛋白质/小鼠)。注射抗原5天后,在麻醉条件下将小鼠宰杀,收集其脾细胞。根据Drug under Exper-imental and Clinical Research,8(1),5-10(1982)中所述的方法计算空斑形成脾细胞的数目,与未使用秋水仙素的一组小鼠相比,该组小鼠的所述脾细胞数增长了129%。另一方面,在使用抗原的两天前、一天前、当天、一天后、二天后、三天后和四天后给小鼠口服本发明的顺-2-(4-氯代苯基)-4,5-二苯基咪唑啉氢氯化物(剂量:2毫克/公斤),与未使用秋水仙素的组相比,所述的用药组小鼠空斑形成脾细胞数只增加18%。
实验3
对免疫抑制动物的空斑形成细胞数的正常化的影响
给雌性BALB/C小鼠[红细胞数约为5×107](10周龄,8个一组)腹腔内注射飘浮有羊红细胞(抗原)的溶液。使用抗原后马上每隔四小时后、一天后、二天后、三天后和四天后将小鼠浸在水中并给一定的压力,水中使用抗原5天后,麻醉条件下杀死小鼠并收集其脾细胞。与未浸在水中的一组小鼠相比,该组小鼠的空斑形成的脾细胞减少47%。另一方面,在使用抗原的两天前、一天前、当天、一天后、两天后、三天后和四天后给小鼠口服本发明的顺-2-(4-氯代苯基)-4,5-二苯基咪唑啉氢氯化物(剂量:2毫克/公斤),与未浸在水中的一组小鼠相比,所述的给药组小鼠其空斑形成的脾细胞仅减少6%。
实施例1
将14.8毫升三乙胺加至16.1克赤-1,2-二氨基-1,2-二苯基乙烷二乙酸盐、13.7克4-氯代苯基亚氨基乙醚,氢氯化物和260毫升乙醇的混合物中,混合物回流4小时。反应后蒸去溶剂,向残留物中加入77毫升1N氢氧化钠水溶液,用氯仿提取溶液,用水洗涤提取液,干燥并蒸去溶剂,残留物用甲醇重结晶得到12.0克顺-2-(4-氯代苯基)-4,5-二苯基咪唑啉。
得率:75%
熔点:152至153℃
液体石蜡
IRν(cm-1):3200,1619,1595
最大值
氢氯化物:熔点>280℃
马来酸盐:溶点199至200℃(分解)
富马酸盐:熔点233至235℃(分解)
D,L-乳酸盐:熔点143至144℃(分解)
L-酒石酸盐:熔点92至95℃(分解)
甲基磺酸盐:熔点>280℃
实施例2
将2.8毫升三乙胺加至2.9克赤-1,2-二氨基-1,2-二苯基乙烷二氢氯化物、1.8克4-吡啶基亚氨基乙醚和60毫升乙醇的混合物中,将混合物回流2小时。反应后,蒸去溶剂。向残留物中加入20毫升10%的氢氧化钠水溶液,用氯仿提取溶液,用水洗涤提取液,干燥并蒸去溶剂。残留物用硅胶柱色谱层析纯化(溶剂∶氯仿∶甲醇=7∶1)。上述所得的产物溶于乙醇中,用10%盐酸-二噁烷溶液使溶液酸化,过滤收集所得的晶体为1.9克顺-2-(4-吡啶基)-4,5-二苯基咪唑啉·氢氯化物。
熔点:>280℃
IRν液体石腊(cm-1):1600,1580
最大值
实施例3至7
用实施例2所述的相同方法相应的赤型起始化合物(Ⅱ)进行处理给出如表2所示的顺式的咪唑啉衍生物。(表2见文后)
实施例8至10
用实施例2所述的方法对相应的苏型起始化合物(Ⅱ)进行处理可得到列于表3中反式的咪唑啉衍生物。(表3见文后)
表1
对肺泡巨噬细胞移行的影响
移行指数
试验化合物 10-9(M) 10-7(M)
(本发明的化合物)
顺-2-(4-氯代苯
基)-4,5-二苯基 113.9 142.5
咪唑啉氢氯化物
(已知化合物)
顺-2,4,5-三(4-
氯代苯基)咪唑 0 40.2
啉氢氯化合物
(注解1)
(已知化合物)
顺-2,4,5-三苯
基咪唑啉氢氯化 0 34.2
物(注解2)
注解1:Canadian Journal of Chemistry 50 669(1972)
注解2:Merek Index 9 51
表2
咪唑衍生物(Ⅰ)(氢氯化物)
实施例号
R X1和X2物理性质
IR*1620,1608
IR*1615,15988
IR*1620,1600,1580
IR*1610,16588
7
4-OCH3- M.P.280℃至283℃
IR*1612,1598
液体石蜡
IR*表示 IRν (cm-1)(下表的含义相同)
最大值
表3
实施例号 咪唑衍生物(Ⅰ) (氢氯化物)
R X1和X2物理性质
IR*:1610
IR*:1612
IR*:2650,1615,1595
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JP63253391A JPH02101065A (ja) | 1988-10-06 | 1988-10-06 | イミダゾリン誘導体及びその製法 |
JP253391/88 | 1988-10-06 | ||
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CN104710408A (zh) | 2007-10-09 | 2015-06-17 | 霍夫曼-拉罗奇有限公司 | 手性顺式-咪唑啉类 |
US8252942B2 (en) * | 2007-10-09 | 2012-08-28 | Board Of Trustees Of Michigan State University | Substituted imidazoline compounds |
CA2933018C (en) * | 2014-01-29 | 2021-10-26 | Toray Industries, Inc. | Therapeutic or prophylactic agent for multiple sclerosis |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH44279A (fr) * | 1908-03-09 | 1909-07-16 | Anonima Per Frigorigeni E Moto | Appareil pour l'échange de chaleur entre des fluides sous pression |
NL296772A (zh) * | 1962-03-21 | |||
GB1047569A (en) * | 1962-10-31 | 1966-11-09 | Du Pont | Light-sensitive compositions |
US3707475A (en) * | 1970-11-16 | 1972-12-26 | Pfizer | Antiinflammatory imidazoles |
EP0005219B1 (en) * | 1978-04-24 | 1981-07-22 | A/S Dumex (Dumex Ltd.) | Arylimidazoles, their synthesis and pharmaceutical or veterinary preparations containing them |
US4424229A (en) * | 1979-04-23 | 1984-01-03 | A/S Dumex (Dumex Ltd.) | Fluorine containing 2,4,5-triphenylimidazoles |
US4252887A (en) * | 1979-08-14 | 1981-02-24 | E. I. Du Pont De Nemours And Company | Dimers derived from unsymmetrical 2,4,5-triphenylimidazole compounds as photoinitiators |
DE3141063A1 (de) * | 1981-10-13 | 1983-04-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue imidazol-derivate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
GB8906198D0 (en) * | 1989-03-17 | 1989-05-04 | Ciba Geigy Ag | Compounds |
-
1988
- 1988-10-06 JP JP63253391A patent/JPH02101065A/ja active Granted
-
1989
- 1989-09-18 CA CA000611765A patent/CA1330997C/en not_active Expired - Fee Related
- 1989-09-18 IE IE297789A patent/IE61924B1/en not_active IP Right Cessation
- 1989-09-20 IL IL91704A patent/IL91704A0/xx unknown
- 1989-09-26 EP EP89309768A patent/EP0363061B1/en not_active Expired - Lifetime
- 1989-09-26 ES ES89309768T patent/ES2052015T3/es not_active Expired - Lifetime
- 1989-09-26 AT AT89309768T patent/ATE78470T1/de not_active IP Right Cessation
- 1989-09-26 DE DE8989309768T patent/DE68902209T2/de not_active Expired - Lifetime
- 1989-09-27 CN CN89107616A patent/CN1020096C/zh not_active Expired - Fee Related
- 1989-09-27 KR KR1019890013908A patent/KR960009570B1/ko not_active IP Right Cessation
- 1989-09-29 AU AU42368/89A patent/AU611827B2/en not_active Ceased
- 1989-10-04 US US07/417,199 patent/US5051441A/en not_active Expired - Fee Related
- 1989-10-04 FI FI894693A patent/FI94632C/fi not_active IP Right Cessation
- 1989-10-05 DK DK491489A patent/DK491489A/da not_active Application Discontinuation
- 1989-10-05 HU HU895226A patent/HU202211B/hu not_active IP Right Cessation
-
1992
- 1992-09-24 GR GR920402101T patent/GR3005779T3/el unknown
-
1995
- 1995-09-07 HK HK143095A patent/HK143095A/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
JPH02101065A (ja) | 1990-04-12 |
HK143095A (en) | 1995-09-15 |
IE61924B1 (en) | 1994-11-30 |
HU202211B (en) | 1991-02-28 |
FI894693A0 (fi) | 1989-10-04 |
JPH0581592B2 (zh) | 1993-11-15 |
DK491489D0 (da) | 1989-10-05 |
HU895226D0 (en) | 1990-01-28 |
IL91704A0 (en) | 1990-06-10 |
AU4236889A (en) | 1990-04-12 |
IE892977L (en) | 1990-04-06 |
FI94632C (fi) | 1995-10-10 |
CN1041760A (zh) | 1990-05-02 |
HUT51601A (en) | 1990-05-28 |
GR3005779T3 (zh) | 1993-06-07 |
DK491489A (da) | 1990-04-07 |
EP0363061B1 (en) | 1992-07-22 |
KR900006296A (ko) | 1990-05-07 |
US5051441A (en) | 1991-09-24 |
EP0363061A1 (en) | 1990-04-11 |
DE68902209D1 (de) | 1992-08-27 |
FI894693A (fi) | 1990-04-07 |
FI94632B (fi) | 1995-06-30 |
DE68902209T2 (de) | 1992-12-10 |
ATE78470T1 (de) | 1992-08-15 |
KR960009570B1 (ko) | 1996-07-20 |
ES2052015T3 (es) | 1994-07-01 |
AU611827B2 (en) | 1991-06-20 |
CA1330997C (en) | 1994-07-26 |
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