CN1101814C - 新的香豆素羟基和多羟基衍生物,其制备和其抗病毒作用 - Google Patents

新的香豆素羟基和多羟基衍生物,其制备和其抗病毒作用 Download PDF

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CN1101814C
CN1101814C CN98120642A CN98120642A CN1101814C CN 1101814 C CN1101814 C CN 1101814C CN 98120642 A CN98120642 A CN 98120642A CN 98120642 A CN98120642 A CN 98120642A CN 1101814 C CN1101814 C CN 1101814C
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M·特考威尼克
Z·艾维滋克
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Abstract

本发明涉及稠合了二醛或醛酸的通式I、II、III和IV的香豆素的新的羟基和多羟基衍生物：式中R1＝R2＝4-羟基香豆素；R1＝R2＝4，7-二羟基香豆素；R1＝R2＝4，5，7-三羟基香豆素；R1＝4-羟基香豆素，R2＝-CH(OH)CH3。本发明的目的也是提供制备稠合了二醛和醛酸的香豆素的羟基和多羟基衍生物的方法，及其抗病毒作用。本发明的新的香豆素的羟基和多羟基衍生物表现出抗HIV-1病毒的作用。

Description

新的香豆素羟基和多羟基衍生物，其制备和其抗病毒作用
在发现具有抵抗引起AIDS疾病的HIV-1和HIV-2病毒作用的新的化合物的领域的研究中，一些4-羟基香豆素的衍生物，例如phenoprocoumon，有显著疗效(H.I.Skulnick等人，J.Med.Chem.40(1997)1149)。本发明强有力地推动进一步研究新的羟基香豆素衍生物，导致具有活性IC50＝1.5μM的3，3’，3”，3-(1，4-(二亚甲基苯基)四[4-羟基香豆素]的合成，H.Zhao等人，(药物化学杂志40(1997)242)。
特别应该指出的是这些羟基香豆素衍生物可以作为HIV-1蛋白酶和整合酶的口服非肽抑制剂，并且上述一些衍生物已经达到临床试验的第一和第二阶段。
在他们早先经验的基础上，本发明人已经制备出一系列新的香豆素的羟基和多羟基衍生物，以便找出具有抗HIV-1和HIV-2病毒特殊作用的更有疗效的制剂。
本发明涉及稠合了二醛或醛酸的通式I、II、III和IV的香豆素的新的羟基和多羟基衍生物：式中
R1＝R2＝4-羟基香豆素；
R1＝R2＝4，7-二羟基香豆素；
R1＝R2＝4，5，7-三羟基香豆素；
R1＝4-羟基香豆素，R2＝-CH(OH)CH3。
本发明的目的也提供制备稠合了二醛或醛酸的香豆素的羟基和多羟基衍生物的方法，及其抗病毒作用。
本发明的新的稠合了二醛或醛酸的通式I、II、III和IV的香豆素的羟基和多羟基衍生物由是通式V的羟基-和多羟基香豆素起始：式中
R1＝OH，R2＝R3＝H；
R1＝R3＝OH，R2＝H；
R1＝R2＝R3＝OH，
通过在乙醇或冰醋酸中与式VI、VII、VIII和IX的二醛或醛酸进行缩合反应制备的：
本发明的新的香豆素二羟基和多羟基衍生物表现出抗HIV-1病毒的作用。
本发明通过以下的实施例具体说明，这些实施例绝非限制本发明的范围。
实施例1
3，3’，3”，3亚乙基四个[4-羟基香豆素]
将4-羟基香豆素(10.00g；61.7mmol)溶于冰醋酸(70.0ml)中，并往这种溶液里加入30％乙二醛水溶液(2.75ml；17.0mmol)。将反应混合物在沸点温度加热5小时。在冷却时得到黄色沉淀(7.21g；70％)，将它从冰醋酸中再结晶。M.p.298～300℃。
分析：
计算值(C38H22O12)：C＝68.06；H＝3.31。
实际值；           C＝68.33；H＝3.12。
FABMS：m/z：671(M+)
IR(KBr)：v/cm-1：3447(br)；1719；1637；1607；761。
实施例2
3，4’-二(4-羟基香豆素)-己烷-2，5-二醇
将4-羟基香豆素(10.00g；61.7mmol)溶于96％乙醇(50.0ml)中，并往这种溶液里加入30％乙二醛水溶液(2.75ml；17.0mmol)。将反应混合物在沸点温度加热15分钟。得到的白色沉淀真空过滤并用96％热乙醇(6.05g；58％)洗涤几次。M.p.309～310℃。
分析：
计算值(C24H22O8)：C＝65.75；H＝5.06。
实际值；          C＝65.64；H＝5.04。
FABMS：m/z：439(M+)
IR(KBr)：v/cm-1：3389(br)；2981；1721；1669；1640；1236；761。
实施例3
3，3’，3”，3亚乙基四个[4，7-二羟基香豆素]
Figure C9812064200091
将30％乙二醛水溶液(0.65ml；3.85mmol)加入到4，7-二羟基香豆素(2.50g；14.0mmol)在无水乙醇(10.0ml)的溶液中。将反应混合物在沸点温度加热4小时，在反应期间将乙醇排出，当冷却时将它在-13℃放置一晚上，真空过滤得到的浅黄色沉淀(1.20g；47％)。将它从N，N-二甲基甲酰胺/冰醋酸混合物(1∶1)中再结晶。M.p.＞300℃。
分析：
计算值(C38H22O16)：C＝62.13；H＝3.02。
实际值；           C＝62.39；H＝2.65。
FABMS：m/z：735(M+)
IR(KBr)：v/cm-1：3435(br)；1720；1630；1601；760。
实施例4
3，3’，3”，3亚乙基四个[4，5，7-三羟基香豆素]
Figure C9812064200101
将30％乙二醛水溶液(0.50ml；2.48mmol)加入到4，5，7-三羟基香豆素(2.00g；10.3mmol)在无水乙醇(10.0ml)的溶液中。将反应混合物在沸点温度加热30分钟然后蒸发至体积的三分之一。往烧瓶里的剩余物加入一种低熔点石油醚并在室温下搅拌1小时，而胶凝状的溶液转变为一种细的晶状橙棕色沉淀(1.44g；70％)。将它从96％乙醇/冰醋酸混合物(1∶1)中再结晶。M.p.＞300℃。
分析：
计算值(C38H22O20xH2O)：C＝55.89；H＝2.96。
实际值；               C＝55.53；H＝3.32。
FABMS：m/z：799(M+)
IR(KBr)：v/cm-1：3423(br)；2959；1618；1299；1157；761。
实施例5
3，3’，3”，3-(1，4-二亚甲基苯基)四个[4，5，7-三羟基香豆素]
Figure C9812064200111
将对苯二醛(0.57ml；4.26mmol)加入到4，5，7-三羟基香豆素(3.00g；15.5mmol)在96％乙醇(15.0ml)的溶液中。将反应混合物在沸点温度加热30分钟而形成充足的胶凝状沉淀。真空过滤得到的白色沉淀然后移送至一烧瓶中，在室温下再往烧瓶里加入二异丙醚(30.0ml)并搅拌1小时。过滤得到的橙红色沉淀并干燥(2.92g；86％)。M.p.228～230℃。
分析：
计算值(C44H26O20)： C＝60.42；H＝3.00。
实际值；            C＝60.37；H＝2.76。
FABMS：m/z：875(M+)
IR(KBr)：v/cm-1：3380(br)；1648；1622；1601；1260；760。
实施例6
3，3’，3”，3-(1，3-二亚甲基苯基)四个[4，5，7-三羟基香豆素]
将间苯二醛(0.57ml；4.26mmol)加入到4，5，7-三羟基香豆素(3.00g；15.5mmol)在96％乙醇(15.0ml)的溶液中。将反应混合物在沸点温度加热3.5小时而形成充足的胶凝状沉淀。真空过滤得到的沉淀进行然后移送至一烧瓶中，在室温下还再烧瓶里加入二异丙醚(150.0ml)并搅拌30分钟，然后再回流1小时。过滤冷却得到的红棕色沉淀并干燥(3.33g；98％)。M.p.300＞0℃。
分析：
计算值(C44H26O20)：C＝60.42；H＝3.00。
实际值；           C＝60.48；H＝3.04。
FABMS：m/z：875(M+)
IR(KBr)：v/cm-1：3374(br)；1640；1610；1597；1249；761。
实施例7
3，3’-(4-羧基苯亚甲基)双[4，7-二羟基香豆素]
Figure C9812064200131
将对苯二酸(1.86ml；1.24mmol)加入到4，7-二羟基香豆素(4.00g；22.5mmol)在96％乙醇(50.0ml)的溶液中。将反应混合物在沸点温度加热8小时。冷却至室温后将反应混合物蒸发至其体积的二分之一，并在-13℃放置一晚上。真空过滤后得到浅黄色沉淀(2.84g；52％)并从20％乙醇中结晶。M.p.239～242℃。
分析：
计算值(C26H16O10xH2O)：C＝61.66；H＝3.58。
实际值；               C＝61.32；H＝3.56。
FABMS：m/z：489(M+)
IR(KBr)：v/cm-1：3323(br)；1697；1620；1571；1253；760。
实施例8
3，3’-(4-羧基苯亚甲基)双[4，5，7-三羟基香豆素]
Figure C9812064200141
将对苯二酸(0.85ml；5.67mmol)加入到4，5，7-三羟基香豆素(2.00g；10.3mmol)在96％乙醇(10.0ml)的溶液中。将反应混合物在沸点温度加热12小时。冷却至室温后将反应混合物蒸发至其体积的二分之一，在-13℃放置一晚上，然后在搅拌下和在由外部用冰冷却的条件下加入水(20.0ml)。真空过滤得到的沉淀(1.80g；67％)。M.p.278～280℃。
分析：
计算值(C26H16O12)：C＝60.01；H＝3.10。
实际值；           C＝59.73；H＝3.34。
FABMS：m/z：521(M+)
IR(KBr)：v/cm-1：3420(br)；1697；1662；1609；1285；760。

Claims (11)

1、稠合了二醛或醛酸的通式I、II、III和IV的香豆素的新的羟基和多羟基衍生物：
Figure C9812064200021
式中
R1＝R2＝4-羟基香豆素；
R1＝R2＝4，7-二羟基香豆素；
R1＝R2＝4，5，7-三羟基香豆素；
R1＝4-羟基香豆素，R2＝-CH(OH)CH3；
Figure C9812064200022
其中R1＝4，5，7-三羟基香豆素；并且
其中
R1＝4，7-二羟基香豆素；
R1＝4，5，7-三羟基香豆素。
2、根据权利要求1的通式I的化合物，其特征在于R1＝R2＝4-羟基香豆素。
3、根据权利要求1的通式I的化合物，其特征在于R1＝4-羟基香豆素，R2＝-CH(OH)CH3。
4、根据权利要求1的通式I的化合物，其特征在于R1＝R2＝4，7-二羟基香豆素。
5、根据权利要求1的通式I的化合物，其特征在于R1＝R2＝4，5，7-三羟基香豆素。
6、根据权利要求1的通式II的化合物，其特征在于R1＝4，5，7-三羟基香豆素。
7、根据权利要求1的通式III的化合物，其特征在于R1＝4，5，7-三羟基香豆素。
8、根据权利要求1的通式IV的化合物，其特征在于R1＝4，7-二羟基香豆素。
9、根据权利要求1的通式IV的化合物，其特征在于R1＝4，5，7-三羟基香豆素。
10、根据权利要求1的通式I，II，III和IV的化合物的制备方法，其特征在于，它们是用通式V的化合物：式中
R1＝OH，R2＝R3＝H，R1＝R3＝OH，R2＝H，R1＝R2＝R3＝OH，通过在乙醇或冰醋酸中与式VI、VII、和IX的二醛或醛酸进行缩合反应制备的。
Figure C9812064200041
11、新的稠合了二醛或醛酸的通式I、II、III和IV的香豆素的羟基和多羟基衍生物在制备用于抗HIV-1病毒药物中的用途。
CN98120642A 1997-10-02 1998-09-30 新的香豆素羟基和多羟基衍生物,其制备和其抗病毒作用 Expired - Fee Related CN1101814C (zh)

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HRP20030604A2 (en) * 2003-07-25 2005-04-30 Pliva-Istra�iva�ki institut d.o.o. Substituted furochromenes, preparation thereof andtheir antiinflammatory action
HRP20030603A2 (en) 2003-07-25 2005-10-31 Pliva-Istra�iva�ki institut d.o.o. Substituted furochromene compounds of antiinflammatory action
DE102009029050A1 (de) * 2009-08-31 2011-03-03 Evonik Oxeno Gmbh Organophosphorverbindungen basierend auf Tetraphenol(TP)-substituierten Strukturen
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