CN101405291B - 选择性抑制电压门控Kv1.3钾通道的5-苯氧基烷氧基补骨脂及方法 - Google Patents
选择性抑制电压门控Kv1.3钾通道的5-苯氧基烷氧基补骨脂及方法 Download PDFInfo
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- CN101405291B CN101405291B CN2005800412104A CN200580041210A CN101405291B CN 101405291 B CN101405291 B CN 101405291B CN 2005800412104 A CN2005800412104 A CN 2005800412104A CN 200580041210 A CN200580041210 A CN 200580041210A CN 101405291 B CN101405291 B CN 101405291B
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Abstract
包括5-苯氧基烷氧基补骨脂化合物的物质组合物及其合成和使用方法。这些化合物可用于治疗人类或动物受试者的疾病或病症,包括自身免疫性疾病。这些化合物抑制钾通道,包括Kv1.3通道,并且,至少这些化合物的某些疗效应至少部分归于钾通道抑制作用。在一些实施方案中,这些化合物对某些钾通道(例如,Kv1.3通道)的选择性比对其它钾通道(例如,Kv1.5通道)的选择性强。
Description
发明领域
本发明提供了a)包括或由5-苯氧基烷氧基补骨脂组成的新的物质组合物,b)治疗和/或预防人类或动物受试者的疾病或病症的方法,c)在体内和/或体外抑制选定类型的钾通道的方法和试剂盒,以及d)5-苯氧基烷氧基补骨脂组合物在用于人类或动物受试者的疾病或病症的治疗和/或预防的药物制剂的生产中的应用。
发明背景
T细胞及其功能:
T细胞是淋巴细胞,其具有能识别蛋白片段(抗原)的受体,该蛋白片段来自于外源可能有害的蛋白或有机体,如细菌和病毒,或者来自于宿主体内存在的蛋白。每个T细胞受体识别不同的氨基酸链,包括抗原。在总的T细胞中,必需始终至少有一种识别体内任何特定抗原的T细胞受体。
T细胞有两种主要类型,即CD4+辅助T细胞和CD8+杀伤T细胞。辅助T细胞(Th)携带的载体使抗原呈递在抗原呈递细胞(APC)如树突状细胞表面,有时呈递到巨噬细胞表面。只有通过与呈递在APC上的抗原接合,随后发生被称为共刺激的过程,Th细胞才能被活化,从而能攻击特异性抗原。在Th细胞活化之前,其被称为“原初(naive)”T细胞。在Th细胞活化之后,其变成“效应(effector)”T细胞,并对特定抗原发动免疫攻击。在含有抗原的细胞被毁坏后,大多数效应T细胞死亡。然而,仍有一些效应T细胞保持在休眠或静止状态,因而被称为“记忆T细胞”。记忆T细胞至少存在两种类型,每一种类型均具有不同的迁移特性和效应功能。第一种类型的记忆T细胞被称为“效应记忆T细胞”(TEM),当其遇到抗原时产生IFN-γ,TNF-α和IL-2或预存穿孔素(在CD8s的情况下)。第二种类型的记忆T细胞被称为“中枢记忆T细胞”(TCM),其表达与原初T细胞相似的趋化因子受体CCR7,并且没有直接效应功能。当TEM细胞遇到最初导致其活化的相同抗原时,其无需共刺激即迅速回转为效应T细胞。这种无需共刺激的对效应T细胞的迅速遣调使免疫系统可以非常有效的方式攻击抗原。
离子通道:药理干预的分子靶点
离子通道是镶嵌在细胞膜内的蛋白质,其控制选择性的离子流通过细胞膜,从而使离子可以在电信号过程中快速运动。由于离子浓度直接参与可兴奋细胞(例如,神经元细胞)的电活性,因此离子通道的正常运行(或运行障碍)大体上可以控制这类细胞的电特性和行为。实际上,多种被广泛地称为“离子通道病”的病症,被认为与离子通道机能不全或机能障碍有关。
能开或关的离子通道被称为是“门控”的。门控离子通道的基本类型包括:a)配体门控通道,b)机械门控通道,和c)电压门控通道。电压门控通道主要发现于神经元细胞和肌细胞中。其对质膜两侧的电压差的变化应答以开或者关。
近年来,药物开发方面的尝试包括这样的工作,其目标是鉴定和表征各种离子通道,并设计能增加或减少通过这些离子通道的离子流从而产生预期疗效的药剂。
Kv1.3通道及其在T细胞生理中的作用
人类T淋巴细胞中主要的门控钾离子通道由Shaker相关基因Kv1.3编码。Kv1.3通道的特征已在分子和生理水平上广泛描述,并且已知其主要通过维持休眠T淋巴细胞的膜电位,在控制T淋巴细胞增殖中起着至关重要的作用。例如,现已证实,已被髓鞘抗原慢性活化(chronically activated)的致脑炎和致关节炎大鼠T细胞表达独特的通道显型(高Kv1.3通道和低IKCa1通道),该显型与在静止和急性活化(acutely activated)的T细胞中发现的截然不同(Beeton et al.,2001,Selective blockade of T lymphocyte K(+)channels amelioratesexperimental autoimmune encephalomyelitis,a model for multiplesclerosis.Proc.Natl.Acad.Sci.USA 98:13942),并且这种发现已经在人类多发性硬化症(MS)患者的髓鞘抗原特异性T细胞中得到证实。与来自健康对照的髓鞘反应性T细胞和来自MS患者的丝裂原或控制抗原活化的T细胞相反,来自MS患者的髓鞘反应性T细胞主要表达终末分化(terminally differentiated)的效应记忆T细胞(CCR7-CD45RA-)的表面标记,并且表现出Kv1.3高IKCa1低显型(Wulff et al.,Thevoltage-gated Kv 1.3K(+)channel in effector memory T cells as new targetfor MS.2003,J.Clin.Invest.111:1703)。同一研究还显示,该特殊K+通道显型导致效应记忆T细胞增殖对Kv1.3阻断剂的抑制作用高度敏感。原初和中枢记忆T细胞仅在10倍高浓度Kv1.3阻断剂下受到影响,并且可以在随后的刺激过程中通过上调钙活化的钾通道IKCa1而避开Kv1.3抑制作用。因此,开发以致病效应T细胞群为靶点而不影响正常免疫反应的选择性钾通道阻断剂是可能的。
Kv1.3和IKCa1在原初T细胞和记忆T细胞中的表达和功能作用
原初T细胞,中枢记忆T(TCM)细胞和效应记忆T(TEM)细胞根据趋化因子受体CCR7和磷酸酶CD45RA的表达进行分类。原初(CCR7+CD45RA+)细胞和TCM(CCR7+CD45RA-)细胞在迁移至炎症部位之前,先以CCR7为入口码迁移至淋巴结。相反地,TEM细胞则能直接到达炎症部位,在那里,TEM细胞可以分泌大量干扰素(IFN-γ)和肿瘤坏死因子-α(TNF-α),并表现出直接效应功能。当原初细胞变成记忆细胞时,Kv1.3和IKCa1的表达模式发生显著变化。休眠时,所有三种亚群的CD4+和CD8+T细胞均表现约200至400个Kv1.3通道,和0至30个IKCa1通道(Wulff et al.,The voltage-gated Kv1.3K(+)channel ineffector memory T cells as new target for MS.2003,J.Clin.Invest.111:1703)。活化作用对通道的表达有着完全相反的作用;当原初和TCM细胞从休眠细胞移入增殖母细胞时,其转录性上调IKCa1至约500个通道/细胞。相反地,TEM细胞的活化增强了Kv1.3表达,而IKCa1水平无任何变化(Wulff et al.,2003,J.Clin.Invest.111:1703)。功能性Kv1.3的表达在活化的15h内显著增加至1500个Kv1.3通道/细胞的水平,并在之后的48至72h内保持提高的水平,然后在接下来的5天内回落至基线(Beeton et al.,A novel fluorescent toxin to detect andinvestigate Kv1.3 channel up-regulation in chronically activated Tlymphocytes.2003,J.Biol.Chem.278:9928)。
由于Kv1.3和IKCa1通过与电压门控Ca2+通道相比表现出“倒转”(upside-down)电压依赖性的Ca2+释放活化的Ca2+通道调节进入T细胞的Ca2+,因此亚群特异性通道表达具有重要的功能性结果。负膜电位驱使Ca2+进入这些通道。支持Ca2+进入的电化学梯度起初很大,从而导致了大量的Ca2+流入。然而,Ca2+的进入导致了质膜的去极化,从而限制了进一步的流入。为了在基因转录所需时间段内维持Ca2+的进入,就必需平衡阳离子的流出;K+离子通过Kv1.3和/或IKCa1通道流出,经膜的超极化为Ca2+的进入提供了电化学驱动力。
由Kv1.3和IKCa1阻断导致的去极化抑制Ca2+流入,发信号和淋巴细胞活化。当Kv1.3通道在三种亚群的休眠T细胞中占优势时,Kv1.3阻断剂ShK可抑制抗原或丝裂原驱动的活化作用,但IKCa1阻断剂TRAM-34则不能。然而,ShK对TEM细胞的作用是对原初和TCM细胞的作用的10倍(IC50值分别为400pM和4nM),这是因为后者细胞在刺激作用后迅速上调IKCa1,从而变得对Kv1.3抑制剂的敏感性降低(Wulff et al.,The voltage-gated Kv1.3K(+)channel in effector memory Tcells as new target for MS.2003,J.Clin.Invest.111:1703)。一旦原初和TCM细胞中的IKCa1上调,则这些细胞的再活化对IKCa1的阻断敏感,而对Kv1.3的阻断不敏感。即使其最初的活化由Kv1.3阻断抑制,原初和TCM细胞仍可以在丝裂原或抗原刺激之后上调IKCa1;并且可以因此避开Kv1.3抑制剂的进一步抑制(Wulff et al.,2003,J.Clin.Invest.111:1703)。早期的体内研究支持了这些体外发现。Kv1.3阻断剂MgTX(Koo et al.,Blockade of the voltage-gated potassium channel Kv1.3inhibits immune responses in vivo.1997,J.Immunol.158:1520)和科雷内酯(correolide)(Koo et al.,Correolide and derivatives are novelimmunosuppressants blocking the lymphocyte Kv1.3 potassium channels.1999,Cell Immunol.197:99)可以强效抑制小型猪的初次(primary)迟发型超敏(DTH)反应,但其抑制二次DTH反应的效果则大大减弱,这可能是由于活化的相关原初或TCM细胞上调了IKCa1表达。相反地,TEM细胞专门上调Kv1.3通道,并且可以被Kv1.3抑制剂持续抑制。
Kv1.3和IKCa1在原初和记忆B细胞中的表达和功能作用
类似的钾通道表达的变化发生在原初B细胞分化为类别转换(class-switched)记忆B细胞的过程中。原初B细胞(lgD+CD27-)和“早期”记忆B细胞(lgD+CD27+)的增殖依赖于IKCa1,而类别转换(IgD-CD27+)记忆B细胞的增殖依赖于Kv1.3,并且其增殖因此可以被Kv1.3阻断剂ShK和Psora-4有效抑制(Wulff et al.K+channel expressionduring B cell differentiation:implications for immunomodulation andautoimmunity.2004.J.Immunol.173:776-86)。因此,Kv1.3阻断剂选择性地以T和B细胞系的“后期”记忆反应为靶点,应该对治疗自身免疫性病症有效。
Kv1.5通道和心律的调节/反调节
通过电压门控钾通道的离子流也在心律的调节中起作用。心房纤颤(AF)是一种常见的心律失常。AF可以通过延长心房动作电位时程和不应性的药剂来治疗或预防。的确,药物如多非利特(dofetilide),阿莫兰特(almokalant),胺碘酮(amiodarone)和右旋索他洛尔(d-sotalol)都可以有效抑制AF。然而,这类药物也能延长心室动作电位时程,从而导致生命危险或者致命性室性心律失常。这种抗心律失常药物在抑制其它类型心律失常的同时,竟然能引发某些类型心律失常的潜能有时被称为药物的“潜在致心律失常作用(proarrhythmic potential)”。潜在致心律失常作用是使用抗心律失常药物时重要的剂量限制因素。事实上,报道的由使用传统抗心律失常药物引起的常见致心律失常事件是一种被称为扭转性室速的疾病,它是一种快速多形性室性心动过速,所述传统抗心律失常药物延长心室复极化。
由于电压门控Kv1.5钾通道主要位于心房组织,因此正在开发抑制Kv1.5通道的药物用于治疗AF(Brendel,J.and Peukert,S.;Blockers ofthe Kv1.5 Channel for the Treatment of Atrial Arrhythmias;CurrentMedicinal Chemistry-Cardiovascular & Hematological Agents,Volume1,No.3,273-287(2003))。选择性抑制Kv1.5通道的药物可能证实为治疗AF而具有最小或者没有潜在致心律失常作用的可行新方法。然而,同样有可能的是,对心律正常患者的Kv1.5通道的不良抑制作用可以导致电失衡,并事实上导致这类患者心律失常。因此,当开发预期抑制Kv1.5之外的钾通道的药物时(例如,预期抑制Kv1.3通道以治疗T细胞介导疾病的药物),值得努力的是,将这些药物设计成相对于影响心脏的Kv1.5通道,对靶钾通道(例如,Kv1.3通道)更具有选择性。
综上所述,对合成和开发特异性抑制某些钾通道超过其它钾通道,从而提供副作用较小的独特疗效的新型钾通道抑制剂的需求仍然存在。
发明概述
本发明提供了5-苯氧基烷氧基补骨脂,即一种在低纳摩尔范围内阻断Kv1.3通道的新型小分子,其优先抑制效应记忆T细胞的增殖,并且仅在非常高的浓度下影响原初和中枢记忆T细胞。假设已知Kv1.3通道的肽类和非肽类抑制剂的体外和体内效应,本发明进一步包括这些5-苯氧基烷氧基补骨脂在任何由阻断或抑制Kv1.3通道引起或推动的诊断或治疗方面的治疗性和/或诊断性用途,包括但不限于以5-苯氧基烷氧基补骨脂作为免疫抑制剂和/或用5-苯氧基烷氧基补骨脂治疗多发性硬化症,类风湿性关节炎,移植排斥反应和/或所有自身免疫性病症。
根据本发明,提供了包括或由如下通式I的5-苯氧基烷氧基补骨脂组成的物质组合物:
通式I
其中:
n是1至10,环状或无环并且被任选取代或未取代的;
X是O,S,N,C Si或P;以及
R1是芳基,杂环基或环烷基,并且其被一个或多个选自烷基,烷氧基,氨基及其烷基衍生物,酰氨基,羧基及其烷基酯,氰基,卤素,羟基,硝基和亚磺酰氨基的取代基任选取代。
进一步根据本发明,提供了施用于人类或动物患者的药物制剂,所述制剂包括上述通式I的5-苯氧基烷氧基补骨脂或其药学上可接受的盐,其单独存在于所述制剂中,或者与常用于口服给药,直肠给药,静脉内给药,动脉内给药,皮内给药,皮下给药,肌内给药,鞘内给药,舌下给药,经颊给药,鼻内给药,透粘膜给药,透皮给药,局部给药,其它肠给药,其它胃肠外给药和/或其它可能的给药途径的药物制剂的药学上可接受的载体,赋形剂及其它成分结合。
更进一步根据本发明,提供了通过给予受试者治疗或预防量的上述通式I或其药学上可接受的盐或衍生物的组合物,治疗或预防人类或动物受试者的疾病或病症的方法。多种疾病或病症可以通过抑制选定类型的钾通道而治疗或预防。例如,抑制人类T细胞Kv1.3通道的本发明的组合物可以用于治疗或预防T细胞介导的疾病或病症,如各种自身免疫性疾病和病症。下面是一些可以通过本发明的方法治疗或预防的某些T细胞介导自身免疫性疾病或病症的非限制性实例,其根据各种疾病主要侵袭的靶器官进行分类:
与受侵袭的特定器官无关,T淋巴细胞被认为促进了自身免疫疾病的发展。目前对这些疾病可用的治疗方法在很大程度上令人不满意,其通常包括糖皮质激素(例如,甲基强的松龙,强的松),非甾体抗炎剂,金盐,氨甲喋呤,抗疟药,以及其它免疫抑制剂如环孢菌素和FK-506的使用。同样,另一类可以通过本发明的方法预防或治疗的T细胞介导病症是移植物抗宿主病和/或移植器官排斥反应。T淋巴细胞在免疫应答中起主要作用,其在很大程度上对多数移植器官的排斥反应负责。T淋巴细胞还对移植的骨髓细胞识别和破坏MHC错配宿主组织的所谓移植物抗宿主病负责。因此,药物如抑制T细胞免疫性的环孢菌素和FK506被用于预防移植排斥反应和移植物抗宿主病。然而,环孢菌素A的免疫抑制疗法因为严重的副作用如肝肾损伤而受到限制。Kv1.3钾通道的选择性抑制剂,如上述通式I的5-苯氧基烷氧基补骨脂导致这类副作用的可能性较小,因此,可以单独使用或者与其它药剂(例如,环孢菌素和/或FK506)结合使用以治疗或预防移植组织或器官的排斥反应和/或移植物抗宿主病。同样,电压门控Kv1.3钾通道抑制剂已证实对抑制效应记忆T细胞尤其有效,并且,因此,本发明的方法可能对预防或治疗与效应记忆T细胞相关的疾病,如骨吸收和牙周病,银屑病,类风湿性关节炎,1型糖尿病以及多发性硬化症特别有效。除了T细胞介导疾病之外,已确认Kv1.3通道还调控能量平衡,体重和外周胰岛素敏感性。因此,本发明的方法可以通过抑制细胞膜上的Kv1.3通道用于治疗包括异常动态平衡,异常体重和异常外周胰岛素敏感性在内的其它疾病和病症,这类其它疾病和病症包括但不限于牙周病中的骨吸收,2型糖尿病,代谢综合征和肥胖。另外,尤其是对于多发性硬化症,目前使用干扰素-β和克帕松(Copaxone)的疗法仅对约60%的患者有用。接受干扰素-β治疗的患者中约40%出现中和抗体,导致干扰素-β治疗对响应患者(responsive patients)的长时间疗效较差。因此,本文公开的5-苯氧基烷氧基补骨脂可以在MS的治疗方面提供显著的改良。
更进一步根据本发明,这里提供了在人类或动物受试者中引发对第一种类型钾通道(例如,Kv1.3通道)的预期抑制作用,同时却不引发对第二种类型钾通道(例如,Kv1.5通道)的非预期抑制作用的方法。这类方法通常包括以可以引发对第一种类型钾通道的预期抑制作用,但不引发对第二种类型钾通道的非预期抑制作用的量和形式,给予人类或动物受试者通式I的化合物的步骤。“对第一种类型钾通道的预期抑制作用”可以是,例如,导致预期治疗或预防效果的任何类型钾通道的任何抑制作用,如抑制Kv1.3钾通道以治疗或预防人类或动物受试者的T细胞介导病症。“对第二种类型钾通道的非预期抑制作用”可以是,例如,导致副作用,不良反应或者除了预期治疗或预防效果之外的任何作用的任何类型钾通道的任何抑制作用,如以这样的方式抑制Kv1.5钾通道,其引发人类或动物受试者的致心律失常作用或增加心律失常的可能性。
更进一步根据本发明,这里提供了通过使细胞与一种或多种通式I的化合物接触而在体外抑制钾通道的方法。这类方法可以用于药理学研究和/或筛选候选药物。用于这些方法的特异性的通式I的化合物可以根据其对特定类型钾通道与其它类型钾通道的相对抑制选择性进行选择。
另一方面,对本领域技术人员而言,在阅读和理解下文所述优选实施方案的详细说明之后,本发明的目标和优点将显而易见。
详细说明和实施例
下列详细说明和附图意欲描述一些,但未必是全部的本发明的实施例或实施方案,并且不以任何方式限制本发明的范围。
以下所述为本发明的取代5-苯氧基烷氧基补骨脂的一些实施例,其在低纳摩尔浓度下抑制Kv1.3通道,并且抑制效应记忆T细胞的增殖。
实施例1
5-(4-苯氧基丁氧基)补骨脂(PAP 1)
4-(4-苯氧基丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-羟基补骨脂(结晶)700mg(3.462mmol)和4-苯氧基丁基溴600mg(3.462mmol)在30ml 2-丁酮中,在过量(2g)无水碳酸钾和催化量碘化钾存在下回流24小时。反应进程通过薄层色谱法监测。24小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH1。将所得浆液搅拌15-20min,并用3×100ml二氯甲烷萃取。将二氯甲烷层用25ml 1%氢氧化钠萃取,以分离未反应的5-羟基补骨脂。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。将固体残留物溶解在甲醇-丙酮混合物中,用活性炭处理,并在甲醇-丙酮(80∶20)混合物中重结晶。
收率:733.6mg(60.48%)
熔点:104℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.13(d,1H,3J=9.7Hz,3-H),7.59(d,1H,3J=2.0Hz,2’-H),7.30(m,5H,5-OCH2CH2CH2CH2OC6 H 5),7.15(s,1H,8-H),6.91(d,1H,3J=2.0Hz,3′-H),6.25(d,1H,3J=9.8Hz,4-H),4.56(t,2H,3J=6.14Hz,5-OCH 2CH2CH2CH2OC6H5),4.09(t,2H,3J=5.80Hz,5-OCH2CH2CH2CH 2OC6H5),2.09(m,4H,3J=4.21Hz,5-OCH2CH 2CH 2CH2OC6H5).
13C-NMR(DMSO-d6,75MHz):δ[ppm]=25.26和26.18(5-O-CH2(CH2)2CH2-O-C6H5);66.91和72.29(5-O-CH2(CH2)2 CH2-O-C6H5);93.18(C-8);105.62(C-4’);105.98(C-4a);112.29(C-3);112.92(C-6);114.39(C-3″和C-5″);120.39(C-4″);129.41(C-2″和C-6″);139.44(C-4);145.89(C-5’);148.72(C-5);152.11(C-8a);157.63(C-1″);158.48(C-7);160.07(C-2).
MS(70eV)m/z:350(20%,M+),202(9%,[M-C10H12O]+),201(5%),174(13%,[202-CO]+),173(4%),150(11%),149(100%),145(8%),107(100%,[149-C3H6]+),94(9%,C6H6O),89(4%),77(37%,C6H5),65(6%,C5H5).
燃烧分析:(FW:350.37)%C71.92,%H 5.08.
(计算值%C 71.99,%H 5.18)
实施例2
5-(3-苯氧基丙氧基)补骨脂(PAP 3)
4-(3-苯氧基丙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-羟基补骨脂700mg(3.5mmol)和3-苯氧基丙基溴750mg(3.5mmol)在30ml 2-丁酮中,在过量无水碳酸钾(3.0g)和催化量碘化钾存在下回流36小时。反应进程通过薄层色谱法监测。36小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH1。将所得浆液搅拌15-20min,并用3×30ml二氯甲烷萃取。将二氯甲烷层用25ml 1%氢氧化钠萃取,以分离未反应的5-羟基补骨脂。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。将所得油状残留物溶解于甲醇中,用活性炭处理,并在甲醇-乙酸乙酯(10∶90)混合物中重结晶。
收率:390mg(33.48%).
熔点:108.4℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.13(d,1H,3J=9.8Hz,3-H),7.59(d,1H,3J=2.3Hz,2′-H),7.31(t,3H,3″-H,4″-H,5″-H),7.16(s,1H,8-H),6.99(d,1H,3J=2.4Hz,3′-H),6.93(d,2H,2″-H,6″-H),6.24(d,1H,3J=9.5Hz,4-H),4.66(t,2H,3J=5.9Hz,5-OCH 2CH2CH2OC6H5),4.26(t,2H,3J=6.0Hz,5-OCH2CH2CH 2OC6H5),2.38(p,2H,3J=6.0Hz,5-OCH2CH 2CH2OC6H5).
MS(70eV)m/z:336(91%,M+),203(7%),202(57%,[M-C9H10O]+),201(11%),174(16%,[202-CO]+),173(11%),145(14%),135(90%),134(9%),108(8%),107(100%),95(8%),89(9%),77(62%,C6H5),65(9%,C5H5).
燃烧分析:(FW:336.35)%C 71.09,%H 4.74
(计算值%C 71.42,%H 4.79)
实施例3
5-(2-苄氧基乙氧基)补骨脂(PAP 5)
4-(2-苄氧基乙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-羟基补骨脂600mg(2.967mmol)和2-溴乙基苄基醚1.0g(4.649mmol)在30ml 2-丁酮中,在过量无水碳酸钾(2.0g)和催化量碘化钾存在下回流16小时。反应进程通过薄层色谱法监测。16小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用25ml 1%氢氧化钠萃取,以分离未反应的5-羟基补骨脂。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。所得油状残留物溶解于甲醇中,用活性炭处理,并用70%甲醇重结晶。
收率:123mg(12.33%)
熔点:90.9℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.19(d,1H,3J=9.7Hz,3-H),7.59(d,1H,3J=2.2Hz,2′-H),7.37(m,5H,5-OCH2CH2OCH2C6 H 5),7.19(s,1H,8-H),6.95(d,1H,3J=2.0Hz,3′-H),6.25(d,1H,3J=9.7Hz,4-H),4.64(s,2H,5-OCH2CH2OCH 2C6H5),4.58(t,2H,3J=4.62Hz,5-OCH 2CH2OCH2C6H5),3.88(t,2H,3J=4.56Hz,5-OCH2CH 2OCH2C6H5).
MS(70eV)m/z:336(35%,M+),105(5%),91(100%,[C7H7]+).
燃烧分析:(FW:336.35)%C 70.65,%H 4.73
(计算值%C 71.42,%H 4.79)
实施例4
5-(4-苄氧基丁氧基)补骨脂(PAP 6)
4-(4-苄氧基丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-羟基补骨脂700mg(3.5mmol)和4-溴丁基苄基醚850.5mg(3.5mmol)在30ml 2-丁酮中,在过量无水碳酸钾(2.0g)和催化量碘化钾存在下回流24小时。反应进程通过薄层色谱法监测。24小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用25ml 1%氢氧化钠萃取,以分离未反应的5-羟基补骨脂。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。将油状残留物溶解于甲醇中,用活性炭处理,并用80%甲醇重结晶。
收率:171mg(13.41%)
熔点:78.4℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.14(d,1H,3J=9.8Hz,3-H),7.55(d,1H,3J=2.5Hz,2′-H),7.34(m,5H,5-OCH2CH2CH2CH2OCH2C6 H 5),7.13(s,1H,8-H),6.91(d,1H,3J=2.4Hz,3′-H),6.25(d,1H,3J=9.8Hz,4-H),4.54(s,2H,5-OCH2CH2CH2CH2OCH 2C6H5),4.49(t,2H,3J=6.5Hz,5-OCH 2CH2CH2CH2OCH2C6H5),3.59(t,2H,3J=6.1Hz,5-OCH2CH2CH2CH 2OCH2C6H5),2.00(p,2H,3J=6.9Hz,5-OCH2CH 2CH2CH2OCH2C6H5),1.87(p,2H,3J=6.8Hz,5-OCH2CH2CH 2CH2OCH2C6H5).
MS(70eV)m/z:364(37%,M+),292(10%),202(7%,[M-C11H14O]+),174(6%,[202-CO]+),163(12%),91(100%,C7H7),71(8%).
燃烧分析:(FW:364.40)%C 72.36,%H 5.46
(计算值%C 72.51,%H 5.53)
实施例5
5-(3-苄氧基丙氧基)补骨脂(PAP 7)
4-(3-苄氧基丙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-羟基补骨脂1.0g(4.946mmol)和3-溴丙基苄基醚1.36g(5.936mmol)在30ml 2-丁酮中,在过量无水碳酸钾(3.4g)和催化量碘化钾存在下回流24小时。反应进程通过薄层色谱法监测。24小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用25ml 1%氢氧化钠萃取,以分离未反应的5-羟基补骨脂。二氯甲烷层用30ml 2%盐酸溶液洗涤,在无水硫酸钠上干燥,浓缩。所得油状残留物溶解于甲醇中,用活性炭处理,并用70%甲醇-水混合物重结晶。
收率:700mg(40.39%)
熔点:75.2℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.06(d,1H,3J=9.7Hz,3-H),7.57(d,1H,3J=2.2Hz,2′-H),7.29(m,5H,3J=6.3Hz,5-OCH2CH2CH2OCH2C6 H 5),7.15(s,1H,8-H),6.98(d,1H,3J=2.2Hz,3′-H),6.21(d,1H,3J=9.8Hz,4-H),4.58(t,2H,3J=6.1Hz,5-OCH 2CH2CH2OCH2C6H5),4.55(s,2H,5-OCH2CH2CH2OCH 2C6H5),3.73(t,2H,3J=5.7Hz,5-OCH2CH2CH 2OCH2C6H5),2.18(p,2H,3J=6.1Hz,5-OCH2CH 2CH2OCH2C6H5).
MS(70eV)m/z:350(25%,M+),202(9%,[M-C10H12O]+),174(5%,[202-CO]+),91(100%,[C7H7]+).
燃烧分析:(FW:350.37)%C 71.64,%H 5.34
(计算值%C 71.99,%H 5.18)
实施例6
5-(4-氯丁氧基)补骨脂(I1)
4-(4-氯丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-羟基补骨脂817mg(4.041mmol)和4-氯丁基碘1.413g(6.47mmol)在80ml丙酮中,在过量(3.0g)无水碳酸钾存在下回流30小时。反应进程通过薄层色谱法监测。30小时后,将反应混合物减压浓缩,并蒸馏除去几乎全部的溶剂。油状残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用3×100ml二氯甲烷萃取。将二氯甲烷层用1×25ml 1%氢氧化钠萃取,以分离痕量的未反应的5-羟基补骨脂。二氯甲烷层先用30ml 2%盐酸洗涤,再用水洗涤至pH中性。二氯甲烷层在无水硫酸钠上干燥,浓缩至干。所得残留物然后悬浮于石油醚中,过滤,以除去过量的4-氯丁基碘。所得5-(4-氯丁氧基)补骨脂未经进一步纯化,直接用于合成各种衍生物。
收率:1.10g(92.98%)
熔点:115.4-115.6℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.15(d,1H,3J=9.75Hz,3-H),7.60(d,1H,3J=2.62Hz,2′-H),7.17(s,1H,8-H),6.95(d,1H,3J=2.15Hz,3′-H),6.29(d,1H,3J=9.79Hz,4-H),4.52(t,2H,3J=5.44Hz,5-OCH 2CH2CH2CH2Cl),3.68(t,2H,3J=5.89Hz,5-OCH2CH2CH2CH 2Cl),2.08(p,4H,3J=3.06Hz,5-OCH2CH 2CH 2CH2Cl).
实施例7
5-(4-{2″-甲氧基-4″-硝基苯氧基}丁氧基)补骨脂(PAP 10)
4-(4-{2″-甲氧基-4″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-(4-氯丁氧基)补骨脂500mg(1.708mmol)和碘化钠741.41mg(4.946mmol)在15ml无水乙腈中回流60min,以获得碘衍生物。向该溶液中加入4-硝基愈创木酚(4-nitroguaicol)837mg(4.946mmol),过量(3.0g)无水碳酸钾和10ml无水乙腈,所得混合物回流72小时。反应进程通过薄层色谱法监测。72小时后,将反应混合物减压浓缩。残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用2×35ml 1%氢氧化钠萃取,以分离过量的4-硝基愈创木酚。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。所得固体溶解于甲醇-丙酮混合物中,用活性炭处理,并在甲醇-丙酮(80∶20)混合物中重结晶。
收率:381.9mg(52.56%)
熔点:170.5℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.15(d,1H,3J=9.8Hz,3-H),7.91(d,1H,4J=2.6Hz,3″-H),7.75(dd,1H,3J=2.65Hz,5″-H),7.60(d,1H,3J=2.2Hz,2′-H),7.16(s,1H,8-H),6.98(d,1H,3J=2.4Hz,3′-H),6.93(d,1H,3J=2.2Hz,6″-H),6.26(d,1H,3J=9.7Hz,4-H),4.59(t,2H,3J=6.0Hz,5-OCH 2CH2CH2CH2OC6H3[4-NO2-2-CH3O]),4.23(t,2H,3J=5.7Hz,5-OCH2CH2CH2CH 2OC6H3[4-NO2-2-CH3O]),3.915(s,3H,2″-OCH3),2.14(m,4H,5-OCH2CH 2CH 2CH2OC6H3[4-NO2-2-CH3O]).
实施例8
5-(4-{4″-甲基-2″-硝基苯氧基}丁氧基)补骨脂(PAP 11)
4-(4-{4″-甲基-2″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-(4-氯丁氧基)补骨脂500mg(1.708mmol)和碘化钠741mg(4.946mmol)在15ml无水乙腈中回流60min,以获得碘衍生物。向该溶液中加入2-硝基对甲苯酚523.2mg(3.416mmol),过量无水碳酸钾(4.0g)和10ml无水乙腈,所得混合物回流69小时。反应进程通过薄层色谱法监测。69小时后,将反应混合物减压浓缩。残留物冷却,并用水稀释。水溶液然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用2×30ml 1%氢氧化钠萃取,以分离过量的2-硝基对甲苯酚。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。所得残留物溶解于甲醇-丙酮混合物中,用活性炭处理,并在甲醇-丙酮(80∶20)混合物中重结晶。
收率:447.2mg(63.95%)
熔点:124.5℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.14(d,1H,3J=9.7Hz,3-H),7.63(d,1H,4J=1.8Hz,3″-H),7.59(d,1H,3J=2.4Hz,2′-H),7.31(d,1H,3J=8.2Hz,5″-H),7.14(s,1H,8-H),6.98(d,1H,3J=2.5Hz,3′-H),6.96(d,1H,3J=8.76Hz,6″-H),6.26(d,1H,3J=9.8Hz,4-H),4.56(t,2H,3J=5.7Hz,5-OCH 2CH2CH2CH2OC6H3[4-CH3-2-NO2]),4.17(t,2H,3J=6.0Hz,5-OCH2CH2CH2CH 2OC6H3[4-CH3-2-NO2]),2.34(s,3H,4″-CH3),2.05(m,4H,3J=4.216Hz,5-OCH2CH 2CH 2CH2OC6H3[4-CH3-2-NO2]).
实施例9
5-(4-{2″-硝基苯氧基}丁氧基)补骨脂(PAP 12)
4-(4-{2″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-(4-氯丁氧基)补骨脂500mg(1.708mmol)和碘化钠512mg(3.416mmol)在15ml无水乙腈中回流60min,以获得碘衍生物。向该溶液中加入2-硝基苯酚475mg(3.416mmol),过量(4.0g)无水碳酸钾和15ml无水乙腈,所得混合物回流29小时。反应进程通过薄层色谱法监测。29小时后,将反应混合物减压浓缩。残留物冷却,并用水稀释。水溶液然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用2×20ml 1%氢氧化钠溶液萃取,以分离过量的2-硝基苯酚。二氯甲烷层用30ml 2%盐酸溶液洗涤,在无水硫酸钠上干燥,浓缩。所得固体残留物溶解于甲醇-丙酮混合物中,用活性炭处理,并在甲醇-丙酮(80∶20)混合物中重结晶。
收率:380.3mg(56.32%)
熔点:121.6-121.8℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.14(d,1H,3J=9.7Hz,3-H),7.82-7.86(重叠dd,2H,4J=1.6Hz,3J=8.3Hz,3J=7.91Hz,3″-H,6″-H),7.60(d,1H,3J=2.5Hz,2′-H),7.52-7.55(t,2H,3J=7.57Hz,4J=1.0Hz,3″-H,4″-H),7.15(S,1H,8-H),6.99(d,1H,3J=2.35Hz,3′-H),6.26(d,1H,3J=9.7Hz,4-H),4.57(t,2H,3J=5.8Hz,5-OCH 2CH2CH2CH2OC6H4[2-NO2]),4.23(t,2H,3J=2.74Hz,5-OCH2CH2CH2CH 2OC6H4[2-NO2]),2.09-2.16(m,4H,5-OCH2CH 2CH 2CH2OC6H4[2-NO2]).
实施例10
5-(4-{3″-硝基苯氧基}丁氧基)补骨脂(PAP 13)
4-(4-{3″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-(4-氯丁氧基)补骨脂500mg(1.708mmol)和碘化钠512mg(3.416mmol)在15ml无水乙腈中回流60min,以获得碘衍生物。向该溶液中加入3-硝基苯酚475mg(3.416mmol),过量(4.0g)无水碳酸钾和15ml无水乙腈,所得混合物回流29小时。反应进程通过薄层色谱法监测。29小时后,将反应混合物减压浓缩。残留物冷却,并用水稀释。水溶液然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用2×20ml 1%氢氧化钠萃取,以分离过量的3-硝基苯酚。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。所得残留物溶解于甲醇-丙酮混合物中,用活性炭处理,并在甲醇-丙酮(80∶20)混合物中重结晶。
收率:286.4mg(42.41%)
熔点:140.3℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.15(d,1H,3J=9.7Hz,3-H),7.84(dd,1H,3J=8.1Hz,4J=1.6Hz,4″-H),7.61(d,1H,3J=2.3Hz,2′-H),7.42(t,1H,3J=8.3Hz,5″-H),7.41(t,1H,4J=2.2Hz,2″-H),7.22(dd,1H,3J=8.1Hz,4J=2.3Hz,6″-H)7.16(s,1H,8-H),6.97(d,1H,3J=2.2Hz,3′-H),6.27(d,1H,3J=9.8Hz,4-H),4.56(t,2H,3J=5.8Hz,5-OCH 2CH2CH2CH2OC6H4[3-NO2]),4.16(t,2H,3J=5.6Hz,5-OCH2CH2CH2CH 2OC6H4[3-NO2]),2.12(m,4H,5-OCH2CH 2CH 2CH2OC6H4[3-NO2]).
实施例11
5-(4-{2″,4″-二硝基苯氧基}丁氧基)补骨脂(PAP 14)
4-(4-{2″,4″-二硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-(4-氯丁氧基)补骨脂500mg(1.708mmol),碘化钠512mg(3.416mmol)和2,4-二硝基苯酚629mg(3.416mmol)在30ml无水乙腈中,在过量(3g)无水碳酸钾存在下回流50小时。反应进程通过薄层色谱法监测。50小时后,将反应混合物减压浓缩。残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用2×35ml 1%氢氧化钠萃取,以分离过量的2,4-二硝基苯酚。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。所得固体残留物溶解于甲醇-丙酮混合物中,用活性炭处理,并在甲醇-丙酮(80∶20)混合物中重结晶。
收率:82.4mg(10.96%)
熔点:134.2℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.78(d,1H,4J=2.8Hz,3″-H),8.45(dd,1H,3J=9.0Hz,4J=2.8Hz,5″-H),8.15(d,1H,3J=9.7Hz,3-H),7.61(d,1H,3J=2.0Hz,2′-H),7.22(d,1H,3J=9.5Hz,6″-H),7.17(s,1H,8-H),6.98(d,1H,3J=2.1Hz,3′-H),6.29(d,1H,3J=9.8Hz,4-H),4.57(t,2H,3J=5.3Hz,5-OCH 2CH2CH2CH2OC6H3[2,4-(NO2)2]),4.36(t,2H,3J=5.1Hz,5-OCH2CH2CH2CH 2OC6H3[2,4-(NO2)2]),2.2(m,4H,5-OCH2CH 2CH 2CH2OC6H3[2,4-(NO2)2]).
下列实施例12-47描述的化合物可以通过与上述有关实施例1-11相似的方法合成,因此,实施例12-47的化合物仅提供了物理数据。
实施例12
5-(4-[4-甲氧基苯氧基]丁氧基)补骨脂(AS67)
4-(4-[4-甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:111.5℃
燃烧分析:C22H20O6(380.4)
计算值:C 69.46,H 5.30
测定值:C 69.52,H 5.39
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.91-1.99(m,4H,5-O-CH2(CH 2)2CH2-O-C6H4-OCH3);3.69(s,3H,-OCH 3);4.00(t,2H,3J=5.8Hz,5-O-CH2(CH2)2CH 2-O-C6H4-OCH3);4.57(t,2H,3J=5.7Hz,5-O-CH 2(CH2)2CH2-O-C6H4-OCH3);6.30(d,1H,3J=9.8Hz,H-3);6.81-6.87(m,4H,5-O-CH2(CH2)2CH2-O-C6 H 4-OCH3);7.32-734(m,2H,H-8和H-4’);8.03(d,1H,3J=2.3Hz,H-5’);8.18(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.30和26.18(5-O-CH2(CH2)2CH2-O-C6H5);55.3(-OCH3);67.49和72.29(5-O-CH2(CH2)2 CH2-O-C6H5);93.17(C-8);105.61(C-4’);105.97(C-4a);112.27(C-3);112.91(C-6);114.54和115.29(C-2″,C-3″,C-5″和C-6″);139.42(C-4);145.88(C-5’);148.71(C-5);152.10(C-8a);152.47和153.25(C-1″和C-4″);157.62(C-7);160.06(C-2).
IR(KBr):v/cm-1=3126,2958,1722,1626,1508,1233,1130.
MS(EI):m/z(%)=380M+(14),257(8),215(7),202[M-C11H14O2]+(5),179[C11H15O2]+(69),145(6),137[CH3-O-C6H4O-CH2]+(100),109(29),107[C6H5O-CH2]+(18),77[C6H5]+(23),55[C4H7]+(61),41(15).
实施例13
5-(4-[3-甲氧基苯氧基]丁氧基)补骨脂(AS68)
4-(4-[3-甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:102.5℃
燃烧分析:C22H20O6(380.4)
计算值:C 69.46,H 5.30
测定值:C 68.89,H 5.38
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.91-1.99(m,4H,5-O-CH2(CH 2)2CH2-O-C6H4-OCH3);3.71(s,3H,-OCH 3);4.05(t,2H,3J=5.4Hz,5-O-CH2(CH2)2CH 2-O-C6H4-OCH3);4.58(t,2H,3J=5.4Hz,5-O-CH 2(CH2)2CH2-O-C6H4-OCH3);6.29(d,1H,3J=9.8Hz,H-3);6.45-6.51(m,3H,H-2″,H-4″和H-6″);7.15(t,1H,3J=8.14Hz,H-5″);7.33(s,2H,H-8和H-4’);8.02(d,1H,3J=1.9Hz,H-5″);8.18(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.21和26.17(5-O-CH2(CH2)2CH2-O-C6H4-OCH3);54.98(-OCH3);67.04和72.24(5-O-CH2(CH2)2 CH2-O-C6H4-OCH3);93.15(C-8);100.62(C-5″);105.61(C-4’);105.95(C-4a);106.14和106.57(C-4″和C-6″);112.25(C-3);112.89(C-6);129.86(C-2″);139.42(C-4);145.86(C-5’);148.69(C-5);152.09(C-8a);157.61(C-7);159.73和160.44(C-1″和C-3″);160.05(C-2).
IR(KBr):v/cm-1=3128,2948,1728,1626,1604,1454,1348,1154.
MS(EI):m/z(%)=380M+(14),257(8),202[M-C11H14O2]+(5),179[C11H15O2]+(84),145(6),137[CH3-O-C6H4O-CH2]+(100),109(14),107[C6H5O-CH2]+(32),77[C6H5]+(27),55[C4H7]+(63),41(12).
实施例14
5-(4-[3,5-二甲氧基苯氧基]丁氧基)补骨脂(AS69)
4-(4-[3,5-二甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:139℃
燃烧分析:C23H22O7(410.43)
计算值:C 67.31,H 5.40
测定值:C 66.92,H 5.60
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.93-1.97(m,4H,5-O-CH2(CH 2)2CH2-O-C6H3-(OCH3)2);3.69(s,3H,-(OCH 3)2);4.05(t,2H,3J=5.4Hz,5-O-CH2(CH2)2CH 2-O-C6H3-(OCH3)2);4.58(t,2H,3J=5.4Hz,5-O-CH 2(CH2)2CH2-O-C6H3-(OCH3)2);6.07(s,3H,H-2″,H-4″和H-6″);6.31(d,1H,3J=9.8Hz,H-3);7.34(s,2H,H-8和H-4′);8.03(d,1H,3J=2.1Hz,H-5′);8.19(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.15和26.18(5-O-CH2(CH2)2CH2-O-C6H3-(OCH3)2);55.05(-(OCH3)2);67.10和72.20(5-O-CH2(CH2)2 CH2-O-C6H3-(OCH3)2);92.79(C-4″);93.12(C-8);93.21(C-2″和C-6″);105.61(C-4’);105.94(C-4a);112.22(C-3);112.86(C-6);139.40(C-4);145.84(C-5’);148.68(C-5);152.09(C-8a);157.61(C-7);160.05(C-2);160.34(C-1″);161.09(C-3″和C-5″).
IR(KBr):v/cm-1=3158,2954,1716,1600,1456,1354,1152.
MS(EI):m/z(%)=410M+(12),209[C12H17O3]+(100),202[M-[C12H17O3]+(5),167[(CH3-O)2-C6H3O-CH2]+(75),137[CH3-O-C6H4O-CH2]+(34),122(15),107[C6H5O-CH2]+(10),77[C6H5]+(11),55[C4H7]+(46),41(6).
实施例15
5-(4-[4-硝基苯氧基]丁氧基)补骨脂(AS78)
4-(4-[4-硝基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:132℃
燃烧分析:C21H17O7(395.34)
计算值:C 63.80,H 4.33,N 3.54
测定值:C 63.79,H 4.46,N 3.60
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.99(s,4H,5-O-CH2(CH 2)2CH2-O-C6H4-NO2);4.05(s,2H,5-O-CH2(CH2)2CH 2-O-C6H4-NO2);4.56(s,2H,5-O-CH 2(CH2)2CH2-O-C6H4-NO2);6.27(d,1H,3J=9.8Hz,H-3);7.10(d,2H,3J=9.2Hz,H-2″和H-6″);7.28(s,1H,H-8);7.30(d,1H,3J=1.9Hz,H-4’);8.00(d,1H,3J=2.1Hz,H-5’);8.15(d,1H,3J=9.6Hz,H-4);8.16(d,2H,3J=9.1Hz,H-3″和H-5″).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=24.95和25.96(5-O-CH2(CH2)2CH2-O-C6H4-NO2);68.25和72.04(5-O-CH2(CH2)2 CH2-O-C6H4-NO2);93.07(C-8);105.56(C-4″);105.84(C-4a);112.17(C-3);112.78(C-6);114.87和125.74(C-2″,C-3″,C-5″和C-6″);139.28(C-4);140.65(C-4″);145.80(C-5’);148.58(C-5);152.03(C-8a);157.57(C-7);159.99(C-2);163.80(C-1″).
IR(KBr):v/cm-1=2960,2881,1728,1593,1498,1455,1327,1270.
MS(EI):m/z(%)=395M+(25),202[M-C10H14O3N]+(30),194[C10H12O3N]+(100),174[202-CO]+(26),152[O2N-C6H4O-CH2]+(82),133(17),106(17),89(13),75(12),55[C4H7]+(84),41(11).
实施例16
5-(4-[4-氯苯氧基]丁氧基)补骨脂(AS 84)
4-(4-[4-氯苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:142.5℃
燃烧分析:C21H17ClO5(384.82)
计算值:C 65.55,H 4.45
测定值:C 65.23,H 4.57
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.95-1.96(m,4H,5-O-CH2(CH 2)2CH2-O-C6H4-Cl);4.05(m,2H,5-O-CH2(CH2)2CH 2-O-C6H4-Cl);4.55(m,2H,5-O-CH 2(CH2)2CH2-O-C6H4-Cl);6.28(d,1H,3J=9.8Hz,H-3);6.93(d,2H,3J=8.9Hz,H-2″和H-6″);7.29(d,2H,3J=8.9Hz,H-3″和H-5″);7.31(s,2H,H-8和H-4′);8.01(d,1H,3J=2.0Hz,H-5′);8.15(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.12和26.08(5-O-CH2(CH2)2CH2-O-C6H4-Cl);67.44和72.17(5-O-CH2(CH2)2 CH2-O-C6H4-Cl);93.10(C-8);105.59(C-4’);105.89(C-4a);112.21(C-3);112.83(C-6);116.14(C-2″和C-6″);124.08(C-4″);129.13(C-3″和C-5″);139.34(C-4);145.83(C-5′);148.65(C-5);152.07(C-8a);157.32(C-7);157.60(C-1″);160.03(C-2).
IR(KBr):v/cm-1=3090,2929,2882,1718,1618,1577,1491,1346,1246.
MS(EI):m/z(%)=384M+(10),202[M-C10H14ClO]+(14),183[C10H12OCl]+(80),174[202-CO]+(11),141[Cl-C6H4O-CH2]+(100),113(18),111(23),89(7),77[C6H5]+(9),55[C4H7]+(72),41(5).
实施例17
5-(4-[4-苯氧基苯氧基]丁氧基)补骨脂(AS85)
4-(4-[4-苯氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:137℃
燃烧分析:C27H22O6(442.47)
计算值:C 73.29,H 5.01
测定值:C 73.24,H 5.09
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.97(s,4H,5-O-CH2(CH 2)2CH2-O-C6H4-O-C6H5);4.05(s,2H,5-O-CH2(CH2)2CH 2-O-C6H4-O-C6H5);4.57(S,2H,5-O-CH 2(CH2)2CH2-O-C6H4-O-C6H5);6.29(d,1H,3J=9.7Hz,H-3);6.89-6.96(m,6H,-O-C6 H 4-O-C6 H 5);7.06(t,1H,H-4′″);7.31-7.35(m,4H,H-8,H-4’和-O-C6 H 4-O-C6 H 5);8.02(s,1H,H-5’);8.17(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.28和26.14(5-O-CH2(CH2)2CH2-O-C6H4-O-C6H5);67.46和72.23(5-O-CH2(CH2)2 CH2-O-C6H4-O-C6H5);93.11(C-8);105.59(C-4’);105.91(C-4a);112.22(C-3);112.85(C-6);139.36(C-4);145.83(C-5’);148.67(C-5);152.07(C-8a);157.60(C-7);160.03(C-2);115.60,117.23,120.57,122.49,129.78,149.32,154.85和157.92(-O-C 6H4-O-C 6H5).
IR(KBr):v/cm-1=3119,2930,1724,1626,1578,1506,1456,1349,1221.
MS(EI):m/z(%)=442M+(25),257(16),241[C6H5-OC10H12O]+(100),215(12),199[C6H5-OC8H8O]+(100),186[C6H5-OC7H5O]+(100),171(12),148(38),129(13),115(17),93(10),77[C6H5]+(49),55[C4H7]+(70),41(7).
实施例18
5-(4-[4-甲基苯氧基]丁氧基)补骨脂(AS96)
4-(4-[4-甲基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:128℃
燃烧分析:C22H20O5(364.40)
计算值:C 72.51,H 5.53
测定值:C 72.59,H 5.65
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.92-2.01(m,4H,5-O-CH2(CH 2)2CH2-O-C6H4-CH3);2.22(s,3H,-CH3);4.02(t,2H,3J=5.7Hz,5-O-CH2(CH2)2CH 2-O-C6H4-CH3);4.56(t,2H,3J=5.6Hz,5-O-CH 2(CH2)2CH2-O-C6H4-CH3);6.28(d,1H,3J=9.8Hz,H-3);6.80(d,2H,3J=8.5Hz,H-3″和H-5″);7.06(d,2H,3J=8.4Hz,H-2″和H-6″);7.31(s,2H,H-8和H-4’);8.02(d,1H1 3J=2.1Hz,H-5′);8.15(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=19.97(-CH3);25.25和26.16(5-O-CH2(CH2)2CH2-O-C6H4-CH3);66.96和72.21(5-O-CH2(CH2)2 CH2-O-C6H4-CH3);93.06(C-8);105.56(C-4′);105.87(C-4a);112.16(C-3);112.79(C-6);114.19(C-3″和C-5″);128.95(C-4″);129.69(C-2″和C-6″);139.32(C-4);145.78(C-5′);148.63(C-5);152.05(C-8a);156.33(C-1″);157.57(C-7);160.01(C-2).
IR(KBr):v/cm-1=3091,2915,1717,1619,1576,1509,1456,1346,1244.
MS(EI):m/z(%)=364M+(10),202[M-C11H13O]+(5),163[C11H15O]+(87),121[CH3-C6H4O-CH2]+(100),91[C7H7]+(33),65(9),55[C4H7]+(35),41(4).
实施例19
5-(4-[4-乙基苯氧基]丁氧基)补骨脂(AS106)
4-(4-[4-乙基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:104℃
燃烧分析:C23H22O5(378.43)
计算值:C 73.00,H 5.86
测定值:C 71.74,H 5.89
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.14(t,3H,3J=7.6Hz,-CH2CH 3);1.95-1.99(m,4H,5-O-CH2(CH 2)2CH2-O-C6H4-CH2CH3);2.52(q,2H,3J=7.6Hz-CH 2CH3);4.03(t,2H,3J=5.7Hz,5-O-CH2(CH2)2CH 2-O-C6H4-CH2CH3);4.57(t,2H,3J=5.7Hz,5-O-CH 2(CH2)2CH2-O-C6H4-CH2CH3);6.28(d,1H,3J=9.8Hz,H-3);6.82(d,2H,3J=8.6Hz,H-3″和H-5″);7.09(d,2H,3J=8.5Hz,H-2″和H-6″);7.33(s,2H,H-8和H-4′);8.02(d,1H,3J=2.3Hz,H-5′);8.18(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=15.82(-CH3);25.27和26.17(5-O-CH2(CH2)2CH2-O-C6H4-C2H5);27.20(-CH2CH3);66.98和72.26(5-O-CH2(CH2)2 CH2-O-C6H4-C2H5);93.13(C-8);105.59(C-4′);105.93(C-4a);112.22(C-3);112.87(C-6);114.22(C-3″和C-5″);128.51(C-4″);135.55(C-2″和C-6″);139.38(C-4);145.84(C-5′);148.68(C-5);152.08(C-8a);156.51(C-1″);157.60(C-7);160.03(C-2).
IR(KBr):v/cm-1=3088,2928,1720,1618,1576,1512,1456,1346,1250.
MS(EI):m/z(%)=378M+(9),202[M-C12H15O]+(5),177[C12H17O]+(92),135[CH3-CH2C6H4O-CH2]+(100),107[C8H11]+(26),79(22),55[C4H7]+(44).
实施例20
5-(4-[4-氟苯氧基]丁氧基)补骨脂(AS111)
4-(4-[4-氟苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:121℃
燃烧分析:C21H17FO5(368.37)
计算值:C 68.47,H 4.65
测定值:C 68.15,H 4.65
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.94-1.96(m,4H,5-O-CH2(CH 2)2CH2-O-C6H4-F);4.01-4.05(m,2H,5-O-CH2(CH2)2CH 2-O-C6H4-F);4.53-4.55(m,2H,5-O-CH 2(CH2)2CH2-O-C6H4-F);6.27(d,1H,3J=9.8Hz,H-3);6.89-6.94(m,2H,5-O-CH2(CH2)2CH2-O-C6 H 4-F);7.30(s,2H,H-4’和H-8);8.01(d,1H,3J=2.0Hz,H-5’);8.14(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.20和26.10(5-O-CH2(CH2)2CH2-O-C6H4-F);67.60和72.17(5-O-CH2(CH2)2 CH2-O-C6H4-F);93.07(C-8);105.56(C-4’);105.87(C-4a);112.18(C-3);112.80(C-6);115.53,115.63和115.83(C-2″,C-3″,C-5″和C-6″);139.32(C-4);145.80(C-5’);148.63(C-5);152.05(C-8a);154.79(C-5″);157.58(C-7);157.91(C-1″);160.02(C-2).
IR(KBr):v/cm-1=2947,1722,1625,1503,1457,1346,1203.
MS(EI):m/z(%)=368M+(11),202[M-C10H14FO]+(11),174[202-CO]+(11),167[C10H12OF]+(83),125[F-C6H4O-CH2]+(100),95(23),89(5),55[C4H7]+(46),41(3).
实施例21
5-(4-[3-三氟甲基苯氧基]丁氧基)补骨脂(AS118)
4-(4-[3-三氟甲基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:118℃
燃烧分析:C22H17F3O5(418.37)
计算值:C 63.16,H 4.10
测定值:C 63.19,H 4.09
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.98(s,4H,5-O-CH2(CH 2)2CH2-O-C6H4-CF3);4.15(s,2H,5-O-CH2(CH2)2CH 2-O-C6H4-CF3);4.57(s,2H,5-O-CH 2(CH2)2CH2-O-C6H4-CF3);6.26(d,1H,3J=9.8Hz,H-3);7.18-7.32(m,5H,H-2″,H-4″,H-6″,H-8和H-4’);7.49(t,1H,3J=7.93Hz,H-5″);8.01(d,1H,3J=2.3Hz,H-5’);8.15(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.05和26.04(5-O-CH2(CH2)2CH2-O-C6H4-CF3);67.56和72.10(5-O-CH2(CH2)2 CH2-O-C6H4-CF3);93.06(C-8);105.58(C-4’);105.84(C-4a);110.78,110.84,116.86,116.91和130.58(5-O-CH2(CH2)2CH2-O-C 6H4-CF3);112.16(C-3);112.78(C-6);118.64(-CF3);139.30(C-4);145.78(C-5’);148.63(C-5);152.06(C-8a);157.59(C-7);158.76(C-1″);160.00(C-2).
IR(KBr):v/cm-1=2960,1724,1626,1590,1456,1348,1328,1130.
MS(EI):m/z(%)=418M+(14),217(79),202[M-C11H14O2]+(19),175[C12H15O]+(100),145(37),127(7),109(14),89(6),55[C4H7]+(75),41(4).
实施例22
5-(4-[1-萘氧基]丁氧基)补骨脂(AS119)
4-(4-[1-萘氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:119℃
燃烧分析:C25H20O5(400.44)
计算值:C 74.99,H 5.30
测定值:C 74.91,H 5.16
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.10(s,4H,5-O-CH2(CH 2)2CH2-O-C10H7);4.25(s,2H,5-O-CH2(CH2)2CH 2-O-C10H7);4.63(s,2H,5-O-CH 2(CH2)2CH2-O-C10H7);6.22(d,1H,3J=9.8Hz,H-3);6.95(d,1H,3J=7.2Hz,5-O-CH2(CH2)2CH2-O-C10 H 7);7.30-7.52(m,6H,H-8,H-4’和5-O-CH2(CH2)2CH2-O-C10 H 7);7.84(d,1H,3J=8.1Hz,5-O-CH2(CH2)2CH2-O-C10 H 7);8.00(d,1H,3J=2.2Hz,H-5’);8.08(d,1H,3J=8.3,5-O-CH2(CH2)2CH2-O-C10 H 7);Hz 8.16(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.28和26.39(5-O-CH2(CH2)2CH2-O-C10H7);67.37和72.20(5-O-CH2(CH2)2 CH2-O-C10H7);93.06(C-8);105.07,119.73,121.28,124.86,125.03,126.13,126.29,127.36和133.95(5-O-CH2(CH2)2CH2-O-C 10H7);105.61(C-4’);105.87(C-4a);112.14(C-3);112.78(C-6);139.34(C-4);145.79(C-5″);148.61(C-5);152.06(C-8a);157.60(C-7);153.88(C-1″);160.02(C-2).
IR(KBr):v/cm-1=2956,1728,1624,1578,1456,1344,1268,1128.
MS(EI):m/z(%)=400M+(35),257(42),215(26),199[C14H15O]+(100),157[C11H9O]+(96),127(40),89(12),55[C4H7]+(97).
实施例23
5-(4-[2-萘氧基]丁氧基)补骨脂(AS120)
4-(4-[2-萘氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:122℃
燃烧分析:C25H20O5(400.44)
计算值:C 74.99,H 5.30
测定值:C 75.28,H 5.22
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.04(s,4H,5-O-CH2(CH 2)2CH2-O-C10H7);4.21(s,2H,5-O-CH2(CH2)2CH 2-O-C10H7);4.60(s,2H,5-O-CH 2(CH2)2CH2-O-C10H7);6.22(d,1H,3J=9.8Hz,H-3);7.14(dd,1H,3J=8.9Hz,5J=2.4Hz,H-3″);7.27-7.36(m,4H,H-8,H-4’和5-O-CH2(CH2)2CH2-O-C10 H 7);7.45(t,1H,3J=7.5Hz,5-O-CH2(CH2)2CH2-O-C10 H 7);7.76-7.83(m,3H,5-O-CH2(CH2)2CH2-O-C10 H 7);8.00(d,1H,3J=2.3Hz,H-5’);Hz 8.17(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=25.21和26.22(5-O-CH2(CH2)2CH2-O-C10H7);67.16和72.26(5-O-CH2(CH2)2 CH2-O-C10H7);93.13(C-8);105.65(C-4’);105.92(C-4a);106.74,118.64,123.47,126.32,126.58,127.45,128.41,129.22和134.27(5-O-CH2(CH2)2CH2-O-C 10H7);112.21(C-3);112.86(C-6);139.38(C-4);145.86(C-5’);148.71(C-5);152.11(C-8a);156.38(C-1″);157.64(C-7);160.04(C-2).
IR(KBr):v/cm-1=1732,1626,1600,1460,1354,1260.
MS(EI):m/z(%)=400M+(20),257(5),215(5),199[C14H15O]+(97),157[C11H9O]+(100),127(49),89(8),55[C4H7]+(72).
实施例24
5-[3-(4-甲氧基苯氧基)丙氧基]补骨脂(AS79)
4-[3-(4-甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:139.5℃
燃烧分析:C21H18O6(366.37)
计算值:C 68.85 H 4.95
测定值:C 68.56 H 5.07
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.24(t,2H,3J=6.0Hz,5-O-CH2CH 2CH2-O-C6H4-OCH3);3.68(s,3H,-OCH 3);4.15(t,2H,3J=6.0Hz,5-O-CH2CH2CH 2-O-C6H4-OCH3);4.63(t,2H,3J=5.9Hz,5-O-CH 2CH2CH2-O-C6H4-OCH3);6.28(d,1H,3J=9.8Hz,H-3);6.82-6.90(m,4H,5-O-CH2CH2CH2-O-C6 H 4-OCH3);7.31-7.32(m,2H,H-8和H-4′);8.02(s,1H,H-5′);8.20(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.30(5-O-CH2 CH2CH2-O-C6H4OCH3);55.29(-OCH3);64.55和69.52(5-O-CH2CH2 CH2-O-C6H4OCH3);93.33(C-8);105.38(C-4′);106.08(C-4a);112.30(C-3);113.02(C-6);114.56和115.35(C-2″,C-3″,C-5″和C-6″);139.42(C-4);145.96(C-5′);148.54(C-5);152.05(C-8a);152.40和153.37(C-1″和C-4″);157.55(C-7);160.02(C-2).
IR(KBr):v/cm-1=3125,2952,2828,1721,1622,1508,1456,1352,1233,1129.
MS(EI):m/z(%)=366M+(32),243(18),215(17),202[C11H6O4]+(18),165[C10H13O2]+(100),145(10),137[CH3-O-C6H4O-CH2]+(94),109(30),92(17),77[C6H5]+(35),51(14),44(40).
实施例25
5-[3-(3-甲氧基苯氧基)丙氧基]补骨脂(AS64)
4-[3-(3-甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:154.5℃
燃烧分析:C21H18O6(366.37)
计算值:C 68.85 H 4.95
测定值:C 68.57 H 5.05
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.27(五重峰,2H,3J=6.1Hz,5-O-CH2CH 2CH2-O-C6H4-OCH3);3.72(s,6H,-OCH 3);4.22(t,2H,3J=6.2Hz,5-O-CH2CH2CH 2-O-C6H4-OCH3);4.66(t,2H,3J=6.0Hz,5-O-CH 2CH2CH2-O-C6H4-OCH3);6.30(d,1H,3J=9.8Hz,H-3);6.50-6.55(m,3H,H-2″,H-4″和H-6″);7.17(t,1H,3J=8.5Hz,H-5″);7.33(d,1H,3J=2.2Hz,H-4′);7.36(s,1H,H-8);8.04(d,1H,3J=2.2Hz,H-5″);8.24(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.20(5-O-CH2 CH2CH2-O-C6H4-OCH3);55.01(-OCH3);64.10和69.49(5-O-CH2CH2 CH2-O-C6H4-OCH3);93.35(C-8);100.70(C-5″);105.41(C-4′);106.09(C-4a);106.30和106.61(C-4″和C-6″);112.31(C-3);113.01(C-6);129.91(C-2″);139.49(C-4);145.99(C-5′);148.55(C-5);152.06(C-8a);157.56(C-7);159.65和160.46(C-1″和C-3″);160.02(C-2).
IR(KBr):v/cm-1=3125,2956,1724,1618,1455,1352,1270,1175.
MS(EI):m/z(%)=366M+(16),202[C11H6O4]+(7),165[C10H13O2]+(100),137[CH3-O-C6H4O-CH2]+(80),124(8),107[C6H5O-CH2]+(30),92(16),77[C6H5]+(32),64(8),51(10),41[C3H5]+(24).
实施例26
5-[3-(3,5-二甲氧基苯氧基)丙氧基]补骨脂(AS104)
4-[3-(3,5-二甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:154.5℃
燃烧分析:C22H20O7(396.40)
计算值:C 66.66 H 5.09
测定值:C 66.43 H 5.06
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.97(t,2H,3J=5.7Hz,5-O-CH2CH 2CH2-O-C6H3-(OCH3)2);3.70(s,3H,-(OCH 3)2);4.20(t,2H,3J=5.8Hz,5-O-CH2CH2CH 2-O-C6H3-(OCH3)2);4.65(t,2H,3J=5.6Hz,5-O-CH 2CH2CH2-O-C6H3-(OCH3)2);6.09-6.12(m,3H,H-2″,H-4″和H-6″);6.29(d,1H,3J=9.8Hz,H-3);7.33(s,2H,H-8和H-4′);8.03(s,1H,H-5′);8.24(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.17(5-O-CH2 CH2CH2-O-C6H3-(OCH3)2);55.07(-(OCH3)2);64.16和69.44(5-O-CH2CH2 CH2-O-C6H3-(OCH3)2);92.92(C-8);93.29(C-2″,C-4″和C-6″);105.40(C-4′);106.05(C-4a);112.26(C-3);112.96(C-6);139.48(C-4);145.95(C-5′);148.53(C-5);152.05(C-8a);157.56(C-7);160.01(C-2);160.27(C-1″);161.11(C-3″和C-5″).
IR(KBr):v/cm-1=3082,2939,1727,1605,1456,1387,1156.
MS(EI):m/z(%)=396M+(12),202[C11H6O4]+(3),195[C11H15O3]+(100),167[(CH3-O)2-C6H3O-CH2]+(53),154(11),137[CH3-O-C6H4O-CH2]+(19),122(13),107[C6H5O-CH2]+(7),77[C6H5]+(9),51(6),41[C3H5]+(6).
实施例27
5-[3-(4-硝基苯氧基)丙氧基]补骨脂(AS92)
4-[3-(4-硝基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:179℃
燃烧分析:C20H15NO7(381.35)
计算值:C 62.99 H 3.96 N 3.67
测定值:
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.32-2.36(m,2H,5-O-CH2CH 2CH2-O-C6H4-NO2);4.40(t,2H,3J=6.1Hz,5-O-CH2CH2CH 2-O-C6H4-NO2);4.68(t,2H,3J=5.7Hz,5-O-CH 2CH2CH2-O-C6H4-NO2);6.31(d,1H,3J=9.8Hz,H-3);7.18(d,2H,3J=9.0Hz,5-O-CH2CH2CH2-O-C6 H 4-NO2);7.34(s,2H,H-8和H-4′);8.04(s,1H,H-5′);8.19-8.27(m,3H,H-4和5-O-CH2CH2CH2-O-C6 H 4-NO2).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=28.93(5-O-CH2 CH2CH2-O-C6H4-NO2);65.44和69.29(5-O-CH2CH2 CH2-O-C6H4-NO2);93.36(C-8);105.40(C-4′);106.05(C-4a);112.33(C-3);112.96(C-6);114.99(C-2″和C-6″);125.82(C-3″和C-5″);139.48(C-4);140.80(C-4″);146.00(C-5′);148.46(C-5);152.04(C-8a);157.55(C-7);160.01(C-2);163.72(C-1″).
IR(KBr):v/cm-1=3153,2945,2358,1716,1520,1352,1266,1132.
MS(EI):m/z(%)=381M+(49),202[C11H6O4]+(100),174[202-CO]+(31),152[O2N-C6H4O-CH2]+(52),119(35),106(16),75(23),51(26),41[C3H5]+(55).
实施例28
5-[3-(4-氯苯氧基)丙氧基]补骨脂(AS132)
4-[3-(4-氯苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:137.5℃
燃烧分析:C20H15ClO5(370.79)
计算值:C 64.79 H 4.08
测定值:C 64.47 H 4.18
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.28(五重峰,2H,3J=6.1Hz,5-O-CH2CH 2CH2-O-C6H4-Cl);4.23(t,2H,3J=6.2Hz,5-O-CH2CH2CH 2-O-C6H4-Cl);4.65(t,2H,3J=6.1Hz,5-O-CH2CH2CH2-O-C6 H 4-Cl);6.30(d,1H,3J=9.8Hz,H-3);6.96-7.02(m,2H,5-O-CH2CH2CH2-O-C6 H 4-Cl);7.29-7.34(m,4H,H-8,H-4′和5-O-CH2CH2CH2-O-C6 H 4-Cl);8.03(d,1H,3J=2.4Hz,H-5′);8.23(d,1H,3J=9.7Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.09(5-O-CH2 CH2CH2-O-C6H4-Cl);64.54和69.40(5-O-CH2CH2 CH2-O-C6H4-Cl);93.33(C-8);105.37(C-4′);106.05(C-4a);112.30(C-3);112.98(C-6);116.17(C-2″和C-6″);124.23(C-4″);129.16(C-3″和C-5″);139.44(C-4);145.96(C-5′);148.49(C-5);152.03(C-8a);157.24(C-7);157.54(C-1″);159.99(C-2).
IR(KBr):v/cm-1=3129,2953,1716,1621,1578,1492,1353,1251.
MS(EI):m/z(%)=370M+(38),202[C11H6O4]+(88),169[C9H10OCl]+(69),141[Cl-C6H4O-CH2]+(100),111(39),75(23),41[C3H5]+(88).
实施例29
5-[3-(4-苯氧基苯氧基)丙氧基]补骨脂(AS122)
4-[3-(4-苯氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:133.5℃
燃烧分析:C26H20O6(428.45)
计算值:C 72.89 H 4.71
测定值:C 73.23 H 4.81
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.29(五重峰,2H,3J=6.0Hz,5-O-CH2CH 2CH2-O-C6H4-O-C6H5);4.23(t,2H,3J=6.1Hz,5-O-CH2CH2CH 2-O-C6H4-O-C6H5);4.67(t,2H,3J=6.0Hz,5-O-CH 2CH2CH2-O-C6H4-O-C6H5);6.30(d,1H,3J=9.7Hz,H-3);6.91(d,2H,3J=8.1Hz,-O-C6 H 4-O-C6 H 5);6.96-7.02(m,4H,5-O-CH 2CH2CH2-O-C6H4-O-C6H5);7.07(t,1H,3J=7.3Hz,H-4′″);7.32-7.37(m,4H,H-8,H-4′和-O-C6 H 4-O-C6 H 5);8.04(d,1H,3J=1.9Hz,H-5′);8.24(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.24(5-O-CH2 CH2CH2-O-C6H4-O-C6H5);64.52和69.47(5-O-CH2CH2 CH2-O-C6H4-O-C6H5);93.33(C-8);105.42(C-4′);106.06(C-4a);112.31(C-3);112.98(C-6);139.47(C-4);145.97(C-5′);148.54(C-5);152.06(C-8a);157.57(C-7);160.02(C-2);115.68,117.23,120.62,122.52,129.80,149.45,154.76和157.91(-O-C 6H4-O-C 6H5).
IR(KBr):v/cm-1=3124,2954,1716,1578,1506,1456,1348,1222.
MS(EI):m/z(%)=428M+(50),227(19),199(57),171(6),134(100),77[C6H5]+(43),51(15)
实施例30
5-[3-(4-甲基苯氧基)丙氧基]补骨脂(AS127)
4-[3-(4-甲基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:126.5℃
燃烧分析:C21H18O5(350.37)
计算值:C 71.99 H 5.18
测定值:C 72.27 H 5.24
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.22-2.30(m,5H,5-O-CH2CH 2CH2-O-C6H4-CH3和-CH3);4.18(t,2H,3J=6.2Hz,5-O-CH2CH2CH 2-O-C6H4-CH3);4.63(t,2H,3J=6.1Hz,5-O-CH 2CH2CH2-O-C6H4-CH3);6.28(d,1H,3J=9.8Hz,H-3);6.80(d,2H,3J=8.5Hz,H-3″和H-5″);7.07(d,2H,3J=8.3Hz,H-2″和H-6″);7.31(d,1H,3J=2.3Hz,H-4′);7.33(s,1H,H-8);8.02(d,1H,3J=2.4Hz,H-5′);8.15(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=20.01(-CH3);29.27(5-O-CH2 CH2CH2-O-C6H4-CH3);64.06和69.54(5-O-CH2CH2 CH2-O-C6H4-CH3);93.35(C-8);105.39(C-4′);106.11(C-4a);112.33(C-3);113.04(C-6);114.29(C-3″和C-5″);129.20(C-4″);129.78(C-2″和C-6″);139.45(C-4);145.98(C-5′);148.55(C-5);152.07(C-8a);156.30(C-1″);157.57(C-7);160.04(C-2).
IR(KBr):v/cm-1=3126,2954,1720,1622,1511,1454,1351,1240,1129.
MS(EI):m/z(%)=350M+(37),215(5),202[C11H6O4]+(38),174(6),149[C10H13O]+(87),121[CH3-C6H4O-CH2]+(100),91[C7H7]+(58),41[C3H5]+(22).
实施例31
5-[3-(4-乙基苯氧基)丙氧基]补骨脂(AS123)
4-[3-(4-乙基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:122℃
燃烧分析:C22H20O5(364.40)
计算值:C 72.51 H 5.53
测定值:C 72.50 H 5.62
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.14(t,3H,3J=7.6Hz,-CH2CH 3);2.27(五重峰,3J=7.6Hz,2H,5-O-CH2CH 2CH2-O-C6H4-CH2CH3);2.53(q,2H,3J=7.7Hz,-CH 2CH3);4.20(t,2H,3J=6.2Hz,5-O-CH2CH2CH 2-O-C6H4-CH2CH3);4.65(t,2H,3J=6.0Hz,5-O-CH 2CH2CH2-O-C6H4-CH2CH3);6.30(d,1H,3J=9.8Hz,H-3);6.87(d,2H,3J=8.4Hz,H-3″和H-5″);7.10(d,2H,3J=8.4Hz,H-2″和H-6″);7.33(d,1H,3J=1.4Hz,H-4′);7.35(s,1H,H-8);8.04(d,1H,3J=2.2Hz,H-5′);8.23(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=15.80(-CH3);27.17(-CH2CH3);29.21(5-O-CH2 CH2CH2-O-C6H4-C2H5);64.00和69.49(5-O-CH2CH2 CH2-O-C6H4-C2H5);93.31(C-8);105.36(C-4′);106.06(C-4a);112.28(C-3);112.98(C-6);114.26(C-3″和C-5″);128.53(C-2″和C-6″);135.73(C-4″);139.42(C-4);145.94(C-5′);148.51(C-5);152.02(C-8a);156.41(C-1″);157.52(C-7);159.98(C-2).
IR(KBr):v/cm-1=3124,2952,1724,1622,1512,1454,1350,1238.
MS(EI):m/z(%)=364M+(28),243(3),202[C11H6O4]+(32),163[C11H15O]+(68),135[CH3-CH2C6H4O-CH2]+(100),107[C8H11]+(43),79(34),41[C3H5]+(19).
实施例32
5-[3-(4-氟苯氧基)丙氧基]补骨脂(AS133)
4-[3-(4-氟苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:123℃
燃烧分析:C20H15FO5(354.34)
计算值:C 67.79 H 4.27
测定值:C 68.04 H 4.42
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.28(五重峰,2H,3J=6.1Hz,5-O-CH2CH 2CH2-O-C6H4-F);4.21(t,2H,3J=6.2Hz,5-O-CH2CH2CH 2-O-C6H4-F);4.65(t,2H,3J=6.0Hz,5-O-CH 2CH2CH2-O-C6H4-F);6.30(d,1H,3J=9.8Hz,H-3);6.95-7.00(m,2H,5-O-CH2CH2CH2-O-C6 H 4-F);7.07-7.14(m,2H,5-O-CH2CH2CH2-O-C6 H 4-F);7.33(d,1H,3J=2.1Hz,H-4′);7.35(s,1H,H-8);8.04(d,1H,3J=2.3Hz,H-5′);8.23(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.18(5-O-CH2 CH2CH2-O-C6H4-F);64.71和69.45(5-O-CH2CH2 CH2-O-C6H4-F);93.34(C-8);105.38(C-4′);106.07(C-4a);112.31(C-3);113.00(C-6);115.60,115.72和115.90(C-2″,C-3″,C-5″和C-6″);139.45(C-4);145.97(C-5′);148.51(C-5);152.04(C-8a);154.72(C-4″);157.55(C-7);158.01(C-1″);160.01(C-2).
IR(KBr):v/cm-1=3128,2954,1717,1620,1508,1455,1353,1213.
MS(EI):m/z(%)=354M+(26),202[C11H6O4]+(46),153[C10H12OF]+(48),125[F-C6H4O-CH2]+(100),95(36),83(13),41[C3H5]+(64).
实施例33
5-[3-(3-三氟甲基苯氧基)丙氧基]补骨脂(AS124)
4-[3-(3-三氟甲基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:137℃
燃烧分析:C21H15F3O5(404.35)
计算值:C 62.38 H 3.47
测定值:C 62.13 H 3.78
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.30(t,2H,3J=5.5Hz,5-O-CH2CH 2CH2-O-C6H4-CF3);4.32(s,2H,5-O-CH2CH2CH 2-O-C6H4-CF3);4.67(s,2H,5-O-CH 2CH2CH2-O-C6H4-CF3);6.27(d,1H,3J=9.6Hz1H-3);7.23-7.33(m,5H,H-2″,H-4″,H-6″,H-8和H-4″);7.51(t,1H,3J=7.7Hz,H-5″);8.03(s,1H,H-5′);8.23(d,1H,3J=10.0Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.08(5-O-CH2 CH2CH2-O-C6H4-CF3);64.75和69.36(5-O-CH2CH2 CH2-O-C6H4-CF3);93.31(C-8);105.44(C-4′);106.02(C-4a);110.93,110.98,117.06,117.06,130.48和130.67(5-O-CH2(CH2)2CH2-O-C 6H4-CF3);112.26(C-3);112.94(C-6);118.73(-CF3);139.51(C-4);145.97(C-5′);148.53(C-5);152.06(C-8a);157.58(C-7);158.72(C-1″);160.01(C-2).
IR(KBr):v/cm-1=3126,2924,1724,1622,1454,1342,1242,1130.
MS(EI):m/z(%)=404M+(56),216(2),175[C12H15O]+(100),145(56),127(12),89(14),41[C3H5]+(84).
实施例34
5-[3-(1-萘氧基)丙氧基]补骨脂(AS135)
4-[3-(1-萘氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:140℃
燃烧分析:C24H18O5(386.41)
计算值:C 74.60 H 4.70
测定值:C 75.33 H 4.81
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.43(五重峰,2H,3J=6.1Hz,5-O-CH2CH 2CH2-O-C10H7);4.43(t,2H,3J=6.0Hz,5-O-CH2CH2CH 2-O-C10H7);4.79(t,2H,3J=6.0Hz,5-O-CH 2CH2CH2-O-C10H7);6.21(d,1H,3J=9.8Hz,H-3);7.03(d,1H,3J=7.3Hz,H-2″);7.34(s,1H,H-8);7.36(d,1H,3J=2.2Hz,H-4′);7.39-7.53(m,4H,5-O-CH2CH2CH2-O-C10 H 7);7.86(d,1H,3J=7.9Hz,H-5″);8.03(d,1H,3J=2.3Hz,H-5′);8.14(d,1H,3J=8.1Hz,H-8″);8.24(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.25(5-O-CH2 CH2CH2-O-C10H7);64.45和69.66(5-O-CH2CH2 CH2-O-C10H7);93.32(C-8);105.07(C-2″);105.39(C-4′);106.06(C-4a);112.20(C-3);113.01(C-6);119.73(C-4″);121.28(C-8″);124.86,125.03,126.13,126.29和127.36(C-3″,C-5″,C-6″,C-7″和C-8a″);133.95(C-4a″);139.39(C-4);145.94(C-5″);148.55(C-5);152.03(C-8a);153.84(C-1″);157.54(C-7);159.97(C-2).
IR(KBr):v/cm-1=3126,2949,1721,1622,1580,1454,1351,1129.
MS(EI):m/z(%)=386M+(63),243(25),215(24),185[C13H13O]+(100),157[C11H9O]+(65),115(36),89(12),41[C3H5]+(13).
实施例35
5-[3-(2-萘氧基)丙氧基]补骨脂(AS137)
4-[3-(2-萘氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:151℃
燃烧分析:C25H20O5(400.44)
计算值:C 74.60 H 4.70
测定值:C 75.11 H 4.81
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=2.35(五重峰,2H,3J=6.1Hz,5-O-CH2CH 2CH2-O-C10H7);4.35(t,2H,3J=6.2Hz,5-O-CH2CH2CH 2-O-C10H7);4.68(t,2H,3J=6.0Hz,5-O-CH 2CH2CH2-O-C10H7);6.25(d,1H,3J=9.8Hz,H-3);7.17(dd,1H,3J=9.0Hz,4J=2.4Hz,H-3″);7.30-7.35(m,4H,H-8,H-4′和5-O-CH2CH2CH2-O-C10 H 7);7.44(t,1H,3J=7.0Hz,H-7″);7.76-7.82(m,3H,5-O-CH2CH2CH2-O-C10 H 7);8.01(d,1H,3J=2.2Hz,H-5′);8.22(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=29.22(5-O-CH2 CH2CH2-O-C10H7);64.26和69.52(5-O-CH2CH2 CH2-O-C10H7);93.31(C-8);105.42(C-4′);106.05(C-4a);106.80(C-1″);112.28(C-3);112.96(C-6);118.60(C-3″);123.53(C-6″);126.33,126.60,127.44,128.46和129.27(C-4″,C-4a″,C-5″,C-7″和C-8″);134.23(C-8a″);139.45(C-4);145.96(C-5′);148.52(C-5);152.06(C-8a);156.32(C-2″);157.57(C-7);160.02(C-2).
IR(KBr):v/cm-1=3133,3046,1720,1452,1349,1130.
MS(EI):m/z(%)=386M+(59),215(6),185[C13H13O]+(100),157[C11H9O]+(59),127(41),89(8),41[C3H5]+(8).
实施例36
5-(5-苯氧基戊氧基)补骨脂(AS121)
4-(5-苯氧基戊氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:91℃
燃烧分析:C22H20O5(364.40)
计算值:C 72.51 H 5.53
测定值:C 72.74 H 5.68
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.63-1.71(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C6H5);1.77-1.93(m,4H,5-O-CH2CH 2CH2CH 2CH2-O-C6H5);4.00(t,2H,3J=6.2Hz,5-O-CH2CH2CH2CH2CH 2-O-C6H5);4.52(t,2H,3J=6.0Hz,5-O-CH 2CH2CH2CH2CH2-O-C6H5);6.30(d,1H,3J=9.7Hz,H-3);6.90-6.93(m,3H,5-O-CH2CH2CH2CH2CH2-O-C6 H 5);7.25-7.33(m,4H,H-8,H-4′和5-O-CH2CH2CH2CH2CH2-O-C6 H 5);8.02(s,1H,H-5′);8.19(d,1H,3J=9.7Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=22.02(5-O-CH2CH2 CH2CH2CH2-O-C6H5);28.31和29.01(5-O-CH2 CH2CH2 CH2CH2-O-C6H5);67.06和72.49(5-O-CH2CH2CH2CH2 CH2-O-C6H5);93.20(C-8);105.55(C-4′);106.04(C-4a);112.30(C-3);113.01(C-6);114.34(C-3″和C-5″);120.32(C-4″);129.39(C-2″和C-6″);139.38(C-4);145.88(C-5′);148.74(C-5);152.08(C-8a);157.59(C-1″);158.58(C-7);160.05(C-2).
IR(KBr):v/cm-1=3130,2946,2872,1716,1602,1496,1350,1242,1134.
MS(EI):m/z(%)=364M+(9),202[C11H6O4]+(22),163[C11H15O]+(44),107[C6H5O-CH2]+(40),69[C5H9]+(100),41[C3H5]+(52).
实施例37
5-[5-(4-甲氧基苯氧基)戊氧基]补骨脂(AS125)
4-[5-(4-甲氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:87.5℃
燃烧分析:C23H22O6(394.43)
计算值:C 70.04 H 5.62
测定值:C 69.32 H 5.63
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.61-1.93(m,6H,5-O-CH2CH 2CH 2CH 2CH2-O-C6H4-OCH3);3.68(s,3H,-OCH 3);3.93(t,2H,3J=6.1Hz,5-O-CH2CH2CH2CH2CH 2-O-C6H4-OCH3);4.52(t,2H,3J=6.2Hz,5-O-CH 2CH2CH2CH2CH2-O-C6H4-OCH3);6.31(d,1H,3J=9.8Hz,H-3);6.84(s,4H,5-O-CH2CH2CH2CH2CH2-O-C6 H 4-OCH3);7.32(d,1H,3J=2.3Hz,H-4′);7.35(s,1H,H-8);8.03(d,1H,3J=2.4Hz,H-5′);8.20(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=22.03(5-O-CH2CH2 CH2CH2CH2-O-C6H4-OCH3);28.39和29.03(5-O-CH2 CH2CH2 CH2CH2-O-C6H4-OCH3);55.31(-OCH3);64.55和69.52(5-O-CH2CH2CH2CH2 CH2-O-C6H4-OCH3);93.24(C-8);105.57(C-4′);106.08(C-4a);112.34(C-3);113.05(C-6);114.54和115.26(C-2″,C-3″,C-5″和C-6″);139.42(C-4);145.91(C-5′);148.77(C-5);152.10(C-8a);152.61和153.22(C-1″和C-4″);157.61(C-7);160.08(C-2).
IR(KBr):v/cm-1=3123,2932,2866,1725,1628,1508,1457,1343,1232,1130.
实施例38
5-[5-(3,5-二甲氧基苯氧基)戊氧基]补骨脂(AS126)
4-[5-(3,5-二甲氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:134.5℃
燃烧分析:C24H24O7(424.45)
计算值:C 67.92 H 5.66
测定值:C 68.30 H 5.85
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.64-1.86(m,6H,5-O-CH2CH 2CH 2CH 2CH2-O-C6H3-(OCH3)2);3.69(s,6H,-(OCH 3)2);3.96(s,2H,5-O-CH2CH2CH2CH2CH 2-O-C6H3-(OCH3)2);4.51(t,2H,5-O-CH 2CH2CH2CH2CH2-O-C6H3-(OCH3)2);6.07(s,3H,H-2″,H-4″和H-6″);6.30(d,1H,3J=9.3Hz,H-3);7.33(s,2H,H-8和H-4′);8.02(s,1H,H-5′);8.19(d,1H,3J=9.2Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=22.01(5-O-CH2CH2 CH2CH2CH2-O-C6H3-(OCH3)2);28.26和29.00(5-O-CH2 CH2CH2 CH2CH2-O-C6H3-(OCH3)2);55.06(-(OCH3)2);67.24和72.48(5-O-CH2CH2CH2CH2 CH2-O-C6H3-(OCH3)2);92.76(C-8);93.20(C-2″,C-4″和C-6″);105.56(C-4′);106.04(C-4a);112.30(C-3);113.01(C-6);139.39(C-4);145.88(C-5′);148.75(C-5);152.09(C-8a);157.60(C-7);160.05(C-2);160.48(C-1″);161.10(C-3″和C-5″).
IR(KBr):v/cm-1=3120,2956,1720,1602,1456,1354,1208.
MS(EI):m/z(%)=424M+(27),270(6),223[C13H19O3]+(100),202[C11H6O4]+(19),155(81),137[CH3-O-C6H4O-CH2]+(28),69(82),41[C3H5]+(70).
实施例39
5-[5-(4-硝基苯氧基)戊氧基]补骨脂(AS139)
4-[5-(4-硝基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:126.5℃
燃烧分析:C22H19NO7(409.40)
计算值:C 64.54 H 4.86 N 3.42
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.52-1.57(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C6H4-NO2);1.66-1.68(m,4H,5-O-CH2CH 2CH2CH 2CH2-O-C6H4-NO2);4.17(s,2H,5-O-CH2CH2CH2CH2CH 2-O-C6H4-NO2);4.52(s,2H,5-O-CH 2CH2CH2CH2CH2-O-C6H4-NO2);6.32(d,1H,3J=9.9Hz,H-3);7.14(d,2H,3J=7.7Hz,5-O-CH2CH2CH2CH2CH2-O-C6 H 4-NO2);7.32(s,2H,H-8和H-4′);8.02(s,1H,H-5′);8.17-8.20(m,3H,H-4和5-O-CH2CH2CH2CH2CH2-O-C6 H 4-NO2).
13C-NMR(CDCl3,75MHz):δ/ppm(TMS)=22.66(5-O-CH2CH2 CH2CH2CH2-O-C6H4-NO2);28.78和29.76(5-O-CH2 CH2CH2 CH2CH2-O-C6H4-NO2);68.47和72.66(5-O-CH2CH2CH2CH2 CH2-O-C6H4-NO2);94.02(C-8);105.06(C-4′);106.80(C-4a);112.68(C-3);113.35(C-6);114.39(C-2″和C-6″);125.95(C-3″和C-5″);139.18(C-4);141.54(C-4″);144.89(C-5′);148.91(C-5);152.75(C-8a);158.29(C-7);161.13(C-2);164.00(C-1″).
IR(KBr):v/cm-1=3126,2959,1729,1594,1507,1339,1264.
MS(EI):m/z(%)=409M+(19),202[C11H6O4]+(58),174[202-CO]+(21),152[O2N-C6H4O-CH2]+(17),69(100),41[C3H5]+(79).
实施例40
5-[5-(4-氯苯氧基)戊氧基]补骨脂(AS131)
4-[5-(4-氯苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:126.5℃
燃烧分析:C22H19ClO5(398.85)
计算值:C 66.25 H 4.80
测定值:C 66.62 H 4.91
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.58-1.68(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C6H4-Cl);1.75-1.92(m,4H,5-O-CH2CH 2CH2CH 2CH2-O-C6H4-Cl);3.99(t,2H,3J=6.3Hz,5-O-CH2CH2CH2CH2CH 2-O-C6H4-Cl);4.50(t,2H,3J=6.2Hz,5-O-CH 2CH2CH2CH2CH2-O-C6H4-Cl);6.30(d,1H,3J=9.8Hz,H-3);6.92-6.95(m,2H,5-O-CH2CH2CH2CH2CH2-O-C6H4-Cl);7.28-7.32(m,4H,H-8,H-4′和5-O-CH2CH2CH2CH2CH2-O-C6 H 4-Cl);8.01(d,1H,3J=2.3Hz,H-5′);8.17(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=21.93(5-O-CH2CH2 CH2CH2CH2-O-C6H4-Cl);28.17和28.96(5-O-CH2 CH2CH2 CH2CH2-O-C6H4-Cl);67.59和72.43(5-O-CH2CH2CH2CH2 CH2-O-C6H4-Cl);93.16(C-8);105.53(C-4′);106.00(C-4a);112.27(C-3);112.97(C-6);116.09(C-2″和C-6″);123.99(C-4″);129.11(C-3″和C-5″);139.34(C-4);145.84(C-5′);148.70(C-5);152.06(C-8a);157.42(C-7);157.57(C-1″);160.03(C-2).
IR(KBr):v/cm-1=3155,2940,1719,1622,1579,1451,1350,1246.
MS(EI):m/z(%)=398M+(10),197[C11H14OCl]+(30),174(11),141[Cl-C6H4O-CH2]+(22),111(10),69[C5H9]+(100),41[C3H5]+(50).
实施例41
5-[5-(4-苯氧基苯氧基)戊氧基]补骨脂(AS138)
4-[5-(4-苯氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:100℃
燃烧分析:C28H24O6(456.50)
计算值:C 73.67 H 5.30
测定值:C 73.49 H 5.36
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.61-1.68(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C6H4-O-C6H5);1.77-1.94(m,4H,5-O-CH2CH 2CH2CH 2CH2-O-C6H4-O-C6H5);4.00(t,2H,3J=6.2Hz,5-O-CH2CH2CH2CH2CH 2-O-C6H4-O-C6H5);4.52(t,2H,3J=6.2Hz,5-O-CH 2CH2CH2CH2CH2-O-C6H4-O-C6H5);631(d,1H,3J=9.8Hz,H-3);6.91-7.00(m,6H,-O-C6 H 4-O-C6 H 5);7.07(t,1H,3J=7.4Hz,H-4′″);7.31-7.37(m,4H,H-8,H-4′和-O-C6 H 4-O-C6 H 5);8.02(d,1H,3J=2.2Hz,H-5′);8.18(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=22.01(5-O-CH2CH2 CH2CH2CH2-O-C6H4-O-C6H5);28.34和29.01(5-O-CH2 CH2CH2 CH2CH2-O-C6H4-O-C6H5);67.63和72.46(5-O-CH2CH2CH2CH2 CH2-O-C6H4-O-C6H5);93.16(C-8);105.54(C-4′);106.01(C-4a);112.27(C-3);112.97(C-6);139.33(C-4);145.84(C-5′);148.71(C-5);152.07(C-8a);157.58(C-7);160.04(C-2);115.57,117.23,120.58,122.48,129.79,149.28,154.97和157.95(-O-C6H4-O-C6H5).
IR(KBr):v/cm-1=2949,1725,1626,1580,1340,1223.
MS(EI):m/z(%)=456M+(39),255(28),199(27),186(32),141(13),69[C5H9]+(100),41[C3H5]+(65).
实施例42
5-[5-(4-甲基苯氧基)戊氧基]补骨脂(AS129)
4-[5-(4-甲基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:83℃
燃烧分析:C23H22O5(378.43)
计算值:C 73.01 H 5.86
测定值:C 73.41 H 6.09
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.64-1.69(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C6H4-CH3);1.75-1.90(m,4H,5-O-CH2CH 2CH2CH 2CH2-O-C6H4-CH3);2.51(s,3H,-CH3);3.95(t,2H,3J=6.2Hz,5-O-CH2CH2CH2CH2CH 2-O-C6H4-CH3);4.51(t,2H,3J=6.1Hz,5-O-CH 2CH2CH2CH2CH2-O-C6H4-CH3);6.30(d,1H,3J=9.8Hz,H-3);6.80(d,2H,3J=8.4Hz,H-3″和H-5″);7.06(d,2H,3J=8.2Hz,H-2″和H-6″);7.31(d,1H,3J=1.6Hz,H-4′);7.33(s,1H,H-8);8.02(d,1H,3J=2.2Hz,H-5′);8.18(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=19.98(-CH3);22.00(5-O-CH2CH2 CH2CH2CH2-O-C6H4-CH3);28.32和29.00(5-O-CH2 CH2CH2CH2CH2-O-C6H4-CH3);67.12和72.47(5-O-CH2CH2CH2CH2 CH2-O-C6H4-CH3);93.17(C-8);105.54(C-4′);106.02(C-4a);112.28(C-3);112.99(C-6);114.18(C-3″和C-5″);128.90(C-4″);129.69(C-2″和C-6″);139.36(C-4);145.85(C-5′);148.72(C-5);152.07(C-8a);156.45(C-1″);157.58(C-7);160.03(C-2).
IR(KBr):v/cm-1=3154,2939,1722,1625,1511,1457,1345,1243,1131.
MS(EI):m/z(%)=378M+(12),202[C11H6O4]+(14),177[C12H17O]+(53),121[CH3-C6H4O-CH2]+(49),69[C5H9]+(100),41[C3H5]+(45).
实施例43
5-[5-(4-乙基苯氧基)戊氧基]补骨脂(AS93)
4-[5-(4-乙基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:88℃
燃烧分析:C24H24O5(392.46)
计算值:C 73.45 H 6.16
测定值:C 73.36 H 6.28
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.14(t,3H,3J=7.6Hz,-CH2CH 3);1.61-1.69(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C6H4-CH2CH3);1.75-1.93(m,4H,5-O-CH2CH 2CH2CH 2CH2-O-C6H4-CH2CH3);2.54(q,2H,3J=7.5Hz,-CH 2CH3);3.96(t,2H,3J=6.3Hz,5-O-CH2CH2CH2CH2CH 2-O-C6H4-CH2CH3);4.52(t,2H,3J=6.2Hz,5-O-CH2CH2CH2CH2CH 2-O-C6H4-CH2CH3);6.30(d,1H,3J=9.8Hz,H-3);6.82(d,2H,3J=8.6Hz,H-3″和H-5″);7.10(d,2H,3J=8.5Hz,H-2″和H-6″);7.32(d,1H,3J=1.5Hz,H-4′);7.34(s,1H,H-8);8.01(d,1H,3J=2.3Hz,H-5′);8.20(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=15.82(-CH3);22.01(5-O-CH2CH2 CH2CH2CH2-O-C6H4-C2H5);27.21(-CH2CH3);28.33和29.00(5-O-CH2 CH2CH2 CH2CH2-O-C6H4-C2H5);67.12和72.46(5-O-CH2CH2CH2CH2 CH2-O-C6H4-C2H5);93.15(C-8);105.53(C-4′);106.00(C-4a);112.26(C-3);112.97(C-6);114.19(C-3″和C-5″);128.50(C-2″和C-6″);135.49(C-4″);139.34(C-4);145.84(C-5′);148.71(C-5);152.07(C-8a);156.63(C-1″);157.58(C-7);160.03(C-2).
IR(KBr):v/cm-1=3150,2933,2866,1721,1626,1511,1458,1344,1241.
MS(EI):m/z(%)=392M+(13),191[C13H19O]+(52),135[CH3-CH2C6H4O-CH2]+(45),107[C8H11]+(24),69[C5H9]+(100),41[C3H5]+(48).
实施例44
5-[5-(4-氟苯氧基)戊氧基]补骨脂(AS128)
4-[5-(4-氟苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:109℃
燃烧分析:C22H19FO5(382.39)
计算值:C 69.10 H 5.01
测定值:C 69.47 H 5.14
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.60-1.66(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C6H4-F);1.76-1.91(m,4H,5-O-CH2CH 2CH2CH 2CH2-O-C6H4-F);3.96(t,2H,3J=6.2Hz,5-O-CH2CH2CH2CH2CH 2-O-C6H4-F);4.50(t,2H,3J=6.2Hz,5-O-CH 2CH2CH2CH2CH2-O-C6H4-F);6.29(d,1H,3J=9.8Hz,H-3);6.89-6.95(m,2H,5-O-CH2CH2CH2CH2CH2-O-C6 H 4-F);7.04-7.12(m,2H,5-O-CH2CH2CH2CH2CH2-O-C6 H 4-F);7.29(d,1H,3J=2.3Hz,H-4′);7.31(s,1H,H-8);8.01(d,1H,3J=2.3Hz,H-5′);8.17(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=21.97(5-O-CH2CH2 CH2CH2CH2-O-C6H4-F);28.27和28.99(5-O-CH2 CH2CH2 CH2CH2-O-C6H4-F);67.78和72.44(5-O-CH2CH2CH2CH2 CH2-O-C6H4-F);93.15(C-8);105.53(C-4′);105.99(C-4a);112.27(C-3);112.96(C-6);115.49,115.52,115.59和115.83(C-2″,C-3″,C-5″和C-6″);139.33(C-4);145.84(C-5′);148.70(C-5);152.06(C-8a);154.77(C-4″);157.58(C-7);157.89(C-1″);160.03(C-2).
IR(KBr):v/cm-1=3136,2944,2872,1720,1626,1504,1452,1351,1134.
MS(EI):m/z(%)=382M+(8),202[C11H6O4]+(21),181[C12H16OF]+(37),125[F-C6H4O-CH2]+(30),69[C5H9]+(100),41[C3H5]+(42).
实施例45
5-[5-(1-萘氧基)戊氧基]补骨脂(AS136)
4-[5-(1-萘氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:103℃
燃烧分析:C26H22O5(414.46)
计算值:C 75.35 H 5.35
测定值:C 75.56 H 5.43
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.71-1.81(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C10H7);1.89-2.00(m,1H,5-O-CH2CH 2CH2CH 2CH2-O-C10H7);4.18(t,2H,3J=6.1Hz,5-O-CH2CH2CH2CH2CH 2-O-C10H7);4.54(t,2H,3J=6.0Hz,5-O-CH 2CH2CH2CH2CH2-O-C10H7);6.21(d,1H,3J=9.8Hz,H-3);6.94(d,1H,3J=7.2Hz,H-2″);7.30(s,2H,H-8和H-4′);7.36-7.53(m,4H,5-O-CH2CH2CH2CH2CH2-O-C10 H 7);7.84(d,1H,3J=7.7Hz,H-5″);8.00(d,1H,3J=2.2Hz,H-5′);8.14(d,1H,3J=8.0Hz,H-8″);8.16(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=22.23(5-O-CH2CH2 CH2CH2CH2-O-C10H7);28.33和29.05(5-O-CH2 CH2CH2 CH2CH2-O-C10H7);67.48和72.43(5-O-CH2CH2CH2CH2 CH2-O-C10H7);93.12(C-8);105.01(C-2″);105.57(C-4′);105.93(C-4a);112.20(C-3);112.89(C-6);119.69(C-4″);121.35(C-8″);124.91,125.08,126.17,126.30和127.39(C-3″,C-5″,C-6″,C-7″和C-8a″);133.97(C-4a″);139.30(C-4);145.82(C-5′);148.73(C-5);152.07(C-8a);154.02(C-1″);157.60(C-7);160.02(C-2).
IR(KBr):v/cm-1=2946,2870,1733,1591,1458,1345.
MS(EI):m/z(%)=414M+(82),271(28),213[C15Hi7O]+(54),144(58),115(36),69[C5H9]+(100),41[C3H5]+(85).
实施例46
5-[5-(2-萘氧基)戊氧基]补骨脂(AS134)
4-[5-(2-萘氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
熔点:118℃
燃烧分析:C26H22O5(414.46)
计算值:C 75.35 H 5.35
测定值:C 75.00 H 5.52
1H-NMR(DMSO-d6,300MHz):δ/ppm(TMS)=1.66-1.75(m,2H,5-O-CH2CH2CH 2CH2CH2-O-C10H7);1.84-1.96(m,1H,5-O-CH2CH 2CH2CH 2CH2-O-C10H7);4.14(t,2H,3J=6.3Hz,5-O-CH2CH2CH2CH2CH 2-O-C10H7);4.53(t,2H,3J=6.1Hz,5-O-CH 2CH2CH2CH2CH2-O-C10H7);6.31(d,1H,3J=9.8Hz,H-3);7.15(dd,1H,3J=8.9Hz,4J=2.4Hz,H-3″);7.31-7.36(m,4H,H-8,H-4′和5-O-CH2CH2CH2CH2CH2-O-C10 H 7);7.45(t,1H,3J=7.2Hz,H-7″);7.77-7-82(m,3H,5-O-CH2CH2CH2CH2CH2-O-C10 H 7);8.02(d,1H,3J=2.3Hz,H-5′);8.20(d,1H,3J=9.8Hz,H-4).
13C-NMR(DMSO-d6,75MHz):δ/ppm(TMS)=22.05(5-O-CH2CH2 CH2CH2CH2-O-C10H7);28.26和29.02(5-O-CH2 CH2CH2 CH2CH2-O-C10H7);67.29和72.47(5-O-CH2CH2CH2CH2 CH2-O-C10H7);93.17(C-8);105.54(C-4′);106.02(C-4a);106.60(C-1″);112.28(C-3);112.99(C-6);118.62(C-3″);123.39(C-6″);126.26,126.55,127.41,128.35和129.16(C-4″,C-4a″,C-5″,C-7″和C-8″);134.25(C-8a″);139.35(C-4);145.85(C-5′);148.72(C-5);152.07(C-8a);156.48(C-2″);157.58(C-7);160.03(C-2).
IR(KBr):v/cm-1=3155,3087,2949,2864,1716,1626,1546,1342,1259.
MS(EI):m/z(%)=414M+(20),271(3),213[C15H17O]+(45),202[C11H6O4]+(13),157(45),127(31),69[C5H9]+(100),41[C3H5]+(62)
实施例47
5-{4-(1-N-吡唑基)丁氧基}补骨脂(PH 1)
4-{4-(1-N-吡唑基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-羟基补骨脂500mg(2.473mmol)和4-碘-1-氯丁烷893mg(4.088mmol)在30ml无水丙酮中,在过量(2.0g)无水碳酸钾存在下于25℃搅拌28小时。反应进程通过薄层色谱法监测。28小时后,将反应混合物减压浓缩,并蒸馏除去几乎所有的溶剂。油状残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,过滤。固体用水洗涤至pH中性,干燥。将干燥的固体悬浮于石油醚中,过滤,并真空干燥。向该固体中加入400mg(5.875mmol)吡唑,2.0g无水碳酸钾,催化量的碘化钾和30ml 2-丁酮,所得反应混合物回流50小时。50小时后,反应混合物真空浓缩。残留物用水稀释,并用浓盐酸酸化至pH 1。分离出的油状有机层用3×50ml二氯甲烷萃取。然后将二氯甲烷层用0.75%氢氧化钠水溶液洗涤,以分离未反应的5-羟基补骨脂,随后用酸水洗涤。二氯甲烷层在无水硫酸钠上干燥,浓缩。残留物溶解于丙酮-甲醇混合物中,用活性炭处理,并用乙酸乙酯-石油醚(20∶80)混合物重结晶。
收率:108.6mg(13.54%)
熔点:145.6℃
1H-NMR(500MHz,DMSO-d6):δ[ppm]=8.17(d,1H,3J=9.1Hz,3-H),8.02(s,1H,2′-H),7.74(s,1H,5-OCH2CH2CH2CH2C3 H 3N2),7.43(s,1H,5-OCH2CH2CH2CH2-C3 H 3N2),7.34(s,1H,8-H),7.29(s,1H,3′-H),6.32(d,1H,3J=9.1Hz,4-H),4.47(s,2H,5-OCH 2CH2CH2CH2C3H3N2),4.20(s,2H,5-OCH2CH2CH2CH 2C3H3N2),2.0(s,2H,5-OCH2CH 2CH 2CH2C3H3N2),1.75(s,2H,5-OCH2CH2CH 2CH2C3H3N2).
MS(70eV)m/z:324(29%,M+),202(6%,[M-C10H12O]+),174(6%,[202-CO]+),123(99%),81(26%),69(13%).
燃烧分析:(FW:324.34)%C 65.83,%H 4.96,%N 7.36
(计算值%C 66.66,%H 4.97,%N 8.64)
实施例48
5-{4-N-(4-吡啶基)氨基丁氧基}补骨脂(PH 3)
4-{4-N-(4-吡啶基)氨基丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
390mg(1.334mmol)5-(4-氯丁氧基)补骨脂和628mg(6.67mmol)4-氨基吡啶在20ml无水乙腈中,在催化量碘化钾存在下回流45小时。反应进程通过薄层色谱法监测。45小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释,并用10%盐酸水溶液酸化至pH7-7.5。将所得浆液搅拌15-20min,过滤。将固体溶解于甲醇中,用活性炭处理,并在2%酸性丙酮中重结晶。
收率:171.5mg(30.37%)
熔点:133.9℃
1H-NMR(500MHz,DMSO-d6):δ[ppm]=8.272(s,1H,5-OCH2CH2CH2CH2NHC5H4N),8.25(d,2H,3J=7.41Hz,5-OCH2CH2CH2CH2NHC5 H 4N),8.18(d,1H,3J=9.8Hz,3-H),8.05(d,1H,3J=2.6Hz,2′-H),7.36(s,1H,8-H),7.33(d,1H,3J=2.3Hz,3′-H),6.85(d,2H,3J=7.32Hz,5-OCH2CH2CH2CH2NHC5 H 4N),6.32(d,1H,3J=9.8Hz,4-H),4.514(t,2H,3J=6.06Hz,5-OCH 2CH2CH2CH2NHC5H4N),4.22(t,2H,3J=6.98Hz,5-OCH2CH2CH2CH 2NHC5H4N),1.99(p,2H,5-OCH2CH 2CH2CH2NHC5H4N),1.77(p,2H,5-OCH2CH2CH 2CH2NHC5H4N).
MS(70eV)m/z:350(12%,M+),202(99%,[M-C9H12N2]+,174(60%,[202-CO]+),184(20%),145(11%),123(15%),107(46%),94(7%,C5H6N2).
燃烧分析:(FW:423.38)%C 56.69,%H 4.94,%N 6.38
(计算值%C 56.68,%H 4.72,%N 6.61)
实施例49
5-{4-(5″-甲基-1″,3″,4″-噻二唑-2″-硫基)丁氧基}补骨脂(PH 4)
4-{4-(5″-甲基-1″,3″,4″-噻二唑-2″-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
500mg(1.708mmol)5-(4-氯丁氧基)补骨脂和361mg(2.733mmol)2-巯基-1,3,4-噻二唑在30ml 2-丁酮中,在过量无水碳酸钾(2.0gm)和催化量碘化钾存在下回流66小时。反应进程通过薄层色谱法监测。66小时后,将反应混合物减压浓缩,并蒸馏除去几乎全部溶剂。油状残留物冷却,用水稀释,并用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用100ml二氯甲烷萃取。将二氯甲烷层用30ml 2%盐酸溶液洗涤,在无水硫酸钠上干燥,浓缩。将所得油状残留物溶解于甲醇中,用活性炭处理,并在石油醚-乙酸乙酯(80∶20)混合物中重结晶。
收率:107mg(16.13%)
熔点:92.1℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.15(d,1H,3J=9.79Hz,3-H),7.59(d,1H,3J=2.48Hz,2′-H),7.16(S,1H,8-H),6.95(d,1H,3J=2.45Hz,3′-H),6.29(d,1H,3J=9.76Hz,4-H),4.51(t,2H,3J=5.81Hz,5-OCH 2CH2CH2CH2S-),3.43(t,2H,3J=6.88Hz,5-OCH2CH2CH2CH 2S-),2.74(s,3H,5″-CH3),2.09(m,4H,3J=3.00Hz,5-OCH2CH 2CH 2CH2S-).
MS(70eV)m/z:388(62%,M+),202(14%,[M-C7H10N2S2]+),187(96%,C7H11N2S2),174(12%,[202-CO]+),145(10%),133(32%),99(34%,C3H3N2S),87(8%,C4H7S),55(28%,C4H7).
燃烧分析:(FW:388.47)%C 53.44,%H 4.45,%N 7.59,%S 16.77
(计算值%C 55.65,%H 4.15,%N 7.21,%S 16.51)
实施例50
5-{4-(7-香豆素基氧基)丁氧基}补骨脂(PH 5)
4-{4-(7-香豆素基氧基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
5-(4-氯丁氧基)补骨脂500mg(1.708mmol)和7-羟基香豆素443mg(2.733mmol)在30ml 2-丁酮中,在过量无水碳酸钾(2.0g)和催化量碘化钾存在下回流48小时。反应进程通过薄层色谱法监测。68小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释,并用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用3×50ml二氯甲烷萃取。将二氯甲烷层用3×25ml 1%氢氧化钠萃取,以分离未反应的7-羟基香豆素。二氯甲烷层用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。所得油状残留物溶解于甲醇中,用活性炭处理,并用甲醇-丙酮(70∶30)混合物重结晶。
收率:134.0mg(18.75%)
熔点:147℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.15(d,1H,3J=9.80Hz,3-H),7.64(d,1H,3J=9.5Hz,5-OCH2CH2CH2CH2OC9 H 5O2),7.61(d,1H,3J=2.1Hz,2′-H),7.36(dd,1H,3J=8.6Hz,5J=2.5Hz,5-OCH2CH2CH2CH2OC9 H 5O2),7.16(s,1H,8-H),6.99(d,1H,3J=2.1Hz,3′-H),6.83(m,2H,5-OCH2CH2CH2CH2OC9 H 5O2),6.26(d,1H,3J=9.50Hz,4-H),6.20(d,1H,3J=9.8Hz,5-OCH2CH2CH2CH2OC9 H 5O2),4.57(t,2H,3J=5.4Hz,5-OCH 2CH2CH2CH2OC9H5O2),4.15(t,2H,3J=5.0Hz,5-OCH2CH2CH2CH 2OC9H5O2),2.11(m,4H,3J=2.6Hz,5-OCH2CH 2CH 2CH2OC9H5O2).
MS(70eV)m/z:418(34%,M+),378(68%),217(89%),202(20%,[M-C13H12O3]+),175(100%),174(14%,[202-CO]+),187(16%),145(32%),134(26%),89(30%),55(48%,C4H7).
燃烧分析:(FW:418.41)%C 69.08,%H 4.46.
(计算值%C 68.90,%H 4.34)
实施例51
5-{4-(5-甲氧基-1,3-苯并噻唑-2-硫基)丁氧基}补骨脂(PH 8)
4-{4-(5-甲氧基-1,3-苯并噻唑-2-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
539mg(2.733mmol)2-巯基-5-甲氧基-1,3-苯并噻唑和161mg(2.869mmol)氢氧化钾在25ml甲醇中回流,直至得到澄清溶液。将该溶液真空浓缩至干。向所得固体钾盐中加入20ml无水乙腈,500mg(1.708mmol)5-(4-氯丁氧基)补骨脂和333mg(2.221mmol)碘化钠,所得混合物回流69小时。反应进程通过薄层色谱法监测。69小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释,并用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用100ml二氯甲烷萃取。将二氯甲烷层用30ml 1%氢氧化钠洗涤,以分离未反应的2-巯基苯并噻唑,然后用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。所得油状残留物溶解于甲醇中,用活性炭处理,并在石油醚-丙酮(80∶20)混合物中重结晶。
收率:599.8mg(77.09%)
熔点:134.8℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.09(d,1H,3J=9.76Hz,3-H),7.61(d,1H,3J=8.9Hz苯并噻唑),7.58(d,1H,3J=2.24Hz,2′-H),7.35(d,1H,4J=2.2Hz,苯并噻唑),7.14(s,1H,8-H),6.97(dd,1H,3J=8.9Hz,4J=2.1Hz,苯并噻唑),6.95(d,1H,3J=2.76Hz,3′-H),6.18(d,1H,3J=9.78Hz,4-H),4.53(t,2H,3J=5.78Hz,5-OCH 2CH2CH2CH2S-),3.87(s,3H,O-CH 3),3.48(t,2H,3J=6.61Hz,5-OCH2CH2CH2CH 2S-),2.11(m,4H,5-OCH2CH 2CH 2CH2S-).
MS(70eV)m/z:455(6%,M+),453(44%),328(28%),252(100%,C12H14NOS2),201(6%),196(12%,C8H6NOS2),174(14%,[202-CO]+),145(8%),89(6%),55(28%,C4H7).
燃烧分析:(FW:455.56)%C 60.70,%H 4.49,%N 3.09,%S 13.94
(计算值%C 60.70,%H 4.65,%N 3.07,%S 14.08)
实施例52
5-{4-(嘧啶-2-硫基)丁氧基}补骨脂(PH 9)
4-{4-(嘧啶-2-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
306mg(2.733mmol)2-巯基嘧啶和氢氧化钾163mg(2.87mmol)在50ml甲醇中回流,直至得到澄清溶液。将该溶液减压浓缩至干。然后向该固体钾盐中加入30ml无水乙腈,500mg(1.708mmol)5-(4-氯丁氧基)补骨脂和333mg(2.220mmol)碘化钠,所得混合物回流67小时。反应进程通过薄层色谱法监测。67小时后,将反应混合物减压浓缩,并蒸馏除去几乎全部溶剂。油状残留物冷却,用水稀释,然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,并用100ml二氯甲烷萃取。将二氯甲烷层用30ml 1%氢氧化钠洗涤,以分离未反应的2-巯基嘧啶,然后用30ml 2%盐酸洗涤,在无水硫酸钠上干燥,浓缩。将油状残留物溶解于甲醇中,用活性炭处理,并用甲醇重结晶。
收率:244mg(38.78%)
熔点:107-107.1℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.51(d,2H,嘧啶),8.14(d,1H,3J=10.1Hz,3-H),7.59(d,1H,3J=2.4Hz,2′-H),7.16(s,1H,8-H),7.0(t,1H,3J=4.89Hz,嘧啶),6.96(d,1H,3J=1.5Hz,3′-H),6.25(d,1H,3J=9.8Hz,4-H),4.52(t,2H,3J=5.8Hz,5-OCH 2CH2CH2CH2S-),3.29(t,2H,3J=6.8Hz,5-OCH2CH2CH2CH 2S-),2.01(m,4H,5-OCH2CH 2CH 2CH2S-).
MS(70eV)m/z:368(27%,M+),202(8%,M-C8H10N2S),167(100%,C8H11N2S),125(34%),113(37%),55(26%,C4H7).
燃烧分析:(FW:368.41)%C 61.55,%H 4.24,%N 7.41,%S 8.46
(计算值%C 61.94,%H 4.38,%N 7.60,%S 8.70)
实施例53
5-(3-氰基丙氧基)补骨脂[ACP 1]
4-(3-氰基丙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
800mg(3.956mmol)5-羟基补骨脂和0.7ml(655.5mg,6.33mmol)4-氯丁腈在50ml 2-丁酮中,在过量(2.6g)无水碳酸钾和催化量碘化钾存在下回流48小时。反应进程通过薄层色谱法监测。48小时后,将反应混合物减压浓缩。残留的油层冷却,用水稀释,并用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,然后过滤。固体用水洗涤至pH中性,抽干,然后用石油醚进一步洗涤。干燥后的固体溶解于回流的甲醇中,用活性炭处理,并用甲醇重结晶。
收率:710.2mg(66.67%)
熔点:155.2℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.13(d,1H,3J=9.8Hz,3-H),7.63(d,1H,3J=2.0Hz,2′-H),7.21(s,1H,8-H),6.98(d,1H,3J=2.0Hz,3′-H),6.32(d,1H,3J=9.5Hz,4-H),4.58(t,2H,3J=5.8Hz,5-OCH 2CH2CH2CN),2.72(t,2H,3J=5.7Hz,5-OCH2CH2CH 2CN),2.26(p,2H,3J=6.3Hz,5-OCH2CH 2CH2CN).
MS(70eV)m/z:269(100%,M+),202(74%,[M-C4H5N]+),174(63%,[202-CO]+),145(26%),118(7%),89(14%).
燃烧分析:(FW:269.26)%C 66.52,%H 4.03,%N 5.01
(计算值%C 66.91,%H 4.12,%N 5.01)
实施例54
5-(4-苯基-3-氧丁氧基)补骨脂(KP 1)
4-(4-苯基-3-氧丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
497mg(2.720mmol)4-氯丁酰苯和445mg(2.968mmol)碘化钠在30ml丙酮中回流1.5小时,以获得碘衍生物。反应通过TLC,同时观察氯化钠的沉淀来监测。向该浆液中加入500mg(2.473mmol)5-羟基补骨脂和过量(2g)无水碳酸钾,回流140小时。反应进程通过薄层色谱法监测。140小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释。水溶液然后用浓盐酸酸化至pH 1。将所得浆液搅拌15-20min,过滤,用水洗涤,并真空干燥。使固体悬浮于50ml乙酸乙酯中,回流,以分离未反应的5-羟基补骨脂。乙酸乙酯层浓缩,所得残留物溶解于100ml二氯甲烷中,用25ml 1%氢氧化钠萃取,以分离剩余痕量的未反应的5-羟基补骨脂。二氯甲烷层用30ml 2%盐酸溶液洗涤,在无水硫酸钠上干燥,浓缩。所得固体残留物溶解于甲醇-丙酮混合物中,用活性炭处理,并在石油醚-丙酮(90∶10)混合物中重结晶。
收率:295.2mg(34.27%)
熔点:129.1℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.13(d,1H,3J=9.9Hz,3-H),8.01(d,2H,3J=7.9Hz,4J=0.95Hz,2″-H,6″-H),7.62(t,1H,3J=7.4Hz,3″-H,5″-H),7.60(d,1H,3J=2.4Hz,2′-H),7.50(t,2H,3J=7.7Hz,4″-H),7.15(s,1H,8-H),6.99(d,1H,3J=2.5Hz,3′-H),6.26(d,1H,3J=9.8Hz,4-H)4.59(t,2H,3J=6.2Hz,5-OCH 2CH2CH2COC6H5),3.28(t,2H,3J=6.8Hz,5-OCH2CH2CH 2COC6H5),2.38(p,2H,3J=6.5Hz,5-OCH2CH 2CH2COC6H5).
MS(70eV)m/z:348(34%,M+),202(5%,M+-C10H10O),147(99%,C10H10O),174,(5%,[202-CO]+),105(71%,C3H6),77(33%,C6H5).
燃烧分析:(FW:348.36)%C 71.68,%H 5.25
(计算值%C 72.41,%H 4.63)
实施例55
5-(4-戊烯氧基)补骨脂(AP1)
4-(4-戊烯氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
500mg(2.473mmol)5-羟基补骨脂和405.85mg(3.957mmol)5-氯-1-戊炔在30ml乙腈中,在过量无水碳酸钾(2.0gm)和催化量碘化钾存在下回流24小时。反应进程通过薄层色谱法监测。24小时后,将反应混合物减压浓缩。油状残留物冷却,用水稀释,并用浓盐酸酸化至pH1。水相用二氯甲烷萃取。将二氯甲烷相用25ml 1%氢氧化钠萃取,以分离未反应的5-羟基补骨脂。将二氯甲烷相用酸水洗涤,然后用水洗涤至pH约6-7。有机相随后在无水硫酸钠上干燥,浓缩至干。残留物溶解于甲醇中,用活性炭脱色,并用甲醇重结晶。
收率:55mg(8.29%)
熔点:144.9-145.1℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.16(d,1H,3J=9.77Hz,3-H),7.60(d,1H,3J=2.32Hz,2′-H),7.17(s,1H,8-H),7.01(d,1H,3J=1.53Hz,3′-H),6.29(d,1H,3J=9.78Hz,4-H),4.56(t,2H,3J=6.06Hz,5-OCH 2CH2CH2CCH),2.51(q,2H,3J=2.55Hz,5-OCH2CH2CH 2CCH),2.09(p,2H,3J=6.44Hz,5-OCH2CH 2CH2CCH),2.03(t,1H,4J=2.59Hz,5-OCH2CH2CH2CCH)
MS(70eV)m/z:268(88%,M+),203(15%),202(100%,[M-C5H6]+),175(8%),174(11%,[202-CO]+),173(14%),146(7%),145(21%),118(8%),89(10%),67(5%,C5H7)
燃烧分析:(FW:268.27)%C 71.25,%H 4.38
(计算值%C 71.64,%H 4.51)
实施例56
5-[4-(N-苯二甲酰亚氨基)丁氧基]补骨脂(PP1)
4-[4-(N-苯二甲酰亚氨基)丁氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
500mg(2.473mmol)5-羟基补骨脂和1.12g(3.959mmol)N-(4-溴丁基)苯邻二甲酰亚胺在50ml乙腈中,在过量(2.2g)无水碳酸钾和催化量碘化钾存在下回流72小时。反应进程通过薄层色谱法监测。72小时后,将反应混合物减压浓缩。残留物冷却,用甲醇萃取。将浆液过滤,固体用甲醇洗涤。然后固体用10%盐酸水溶液酸化至pH约为1,过滤,用水洗涤至pH中性,并真空干燥。将固体溶解于丙酮,用活性炭处理,并用甲醇重结晶。
收率:260mg(26.06%)
熔点:177.9℃
1H-NMR(500MHz,CDCl3):δ[ppm]=8.14(d,1H,3J=9.8Hz,3-H),7.8(dd,4H,3J=5.4Hz,4J=3.0Hz,5-OCH2CH2CH2CH2NC8 H 4O2),7.6(d,1H,3J=2.4Hz,2′-H),7.13(s,1H,8-H),6.95(d,1H,3J=1.6Hz,3′-H),6.30(d,1H,3J=9.8Hz,4-H),4.5(t,2H,3J=5.7Hz,5-OCH 2CH2CH2CH2NC8H4O2),3.82(t,2H,3J=6.6Hz,5-OCH2CH2CH2CH 2NC8H4O2),1.98(p,4H,3J=3.2Hz,5-OCH2CH 2CH 2CH2NC8H4O2).
MS(70eV)m/z:403(13%,M+),202(72%,[M-C12H11NO2]+),202(72%,C12H11NO2),174(8%,[202-CO]+),160(99%),148(6%),130(14%),55(5%,C4H7).
燃烧分析:(FW:403.40)%C 68.17%,%H 4.32,%N 3.36
(计算值%C 68.48,%H 4.25,%N 3.47)
B.比较对不同钾通道的抑制活性的数据
附件A列出了本发明的某些5-苯氧基烷氧基补骨脂化合物对各种钾通道的抑制作用的例子。这些数据表明,相对Kv1.5通道,本发明的化合物中的某些(尤其是附件A中命名为PAP-1,AS78和AS85的化合物)对Kv1.3通道具有选择性。如上文说明的那样,抑制Kv1.5钾通道在临床上可能导致严重心律失常。因此,这些化合物对Kv1.3通道相对于Kv1.5通道的选择性可能使这些化合物可以在很少或者不发生由Kv1.5通道抑制作用引起的心律失常的情况下,用于治疗或预防广泛的T细胞介导的病症和/或其它能通过抑制Kv1.3通道治疗或预防的病症。
C.治疗或预防疾病或病症的方法
如上所述本发明的组合物,和/或其药学上可接受的盐或衍生物,可以按照给药方案的量,通过有效治疗或预防疾病或病症的给药途径,施用于人类或动物受试者,该有效治疗或预防是通过抑制一种或多种类型钾通道实现的。如附件A所示,不同的本发明的化合物对不同类型钾通道表现出不同的选择度,因此,可以根据化合物的钾通道选择性选择特定的化合物用于治疗特定疾病或病症。尽管任何适宜的剂量都可以使用,但是目前可得到的信息表明,一次或多次剂量为约0.1mg/kg至约10.0mg/kg的通式I的化合物可以施用于人类,以治疗或预防疾病或病症,如T细胞介导疾病或病症。给药途径可以根据给定的特定化合物和/或要治疗或预防的特定疾病或病症的变化而变化。
实施例57
施用5-(4-苯氧基丁氧基)7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
(PAP-1)系统治疗T细胞介导疾病
例如,5-(4-苯氧基丁氧基)7H-呋喃并[3,2-g][1]苯并吡喃-7-酮(即,实施例1中命名为PAP-1的化合物),或其药学上可接受的盐或衍生物,可以经口服或者注射(皮下注射,肌内注射,静脉注射等),以日剂量约0.1mg/kg至约10.0mg/kg一次或多次施用于人类,以系统治疗T细胞介导的自身免疫性病症。这种系统治疗尤其适用于治疗疾病和病症如1型糖尿病,MS,移植物抗宿主病或移植排斥反应等。
实施例58
施用5-(4-苯氧基丁氧基)7H-呋喃并[3,2-g][1]苯并吡喃-7-酮
(PAP-1)局部治疗T细胞介导的疾病
例如,5-(4-苯氧基丁氧基)7H-呋喃并[3,2-g][1]苯并吡喃-7-酮(即,实施例1中命名为PAP-1的化合物),或其药学上可接受的盐或衍生物,可以经局部或者局部注射(例如,皮内注射,皮下注射,肌内注射等),以日剂量约0.1mg/kg至约10.0mg/kg一次或多次施用于人类,以局部治疗T细胞介导的自身免疫性病症。这种局部治疗尤其适用于导致皮肤损伤的T细胞介导疾病,如银屑病,疱疹样皮炎,寻常天疱疮,蕈样霉菌病,变应性接触性皮炎,异位性皮炎,扁平苔藓和急性苔藓状痘疮样糠疹(PLEAV)。当5-(4-苯氧基丁氧基)7H-呋喃并[3,2-g][1]苯并吡喃-7-酮局部给药时,其可以与药学上可接受的载体结合组成局部制剂,如软膏剂,乳膏剂,乳剂,凝胶剂,香波,液体制剂,贴剂,poltus等。尽管任何适宜的浓度都可以使用,但局部制剂中5-(4-苯氧基丁氧基)7H-呋喃并[3,2-g][1]苯并吡喃-7-酮的浓度以重量计应该在约0.0001%至约1%的范围内。
应该认识到的是,虽然已在上文中描述了本发明的某些实施例或实施方案,但是,在不超出本发明所包含的精神和范围的条件下,可以对这些实施例和实施方案进行各种添加,删除,变更和修改。例如,一个实施方案或实施例的任何要素或特征可以并入另一个实施方案或实施例,或者与另一个实施方案或实施例一起使用,除非这样做可以使该实施方案或实施例不适合于其目标用途。所有合理的添加,删除,变更和修改都将被视为所述实施例和实施方案的等同体,并且都包含在下列权利要求的范围内。
附件A
示例性化合物及其对K+通道的EC50s
Claims (112)
2.根据权利要求1所述的组合物,其中的化合物包括4-(4-苯氧基丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
3.根据权利要求1所述的组合物,其中的化合物包括4-(3-苯氧基丙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
4.根据权利要求1所述的组合物,其中的化合物包括4-(2-苄氧基乙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
5.根据权利要求1所述的组合物,其中的化合物包括4-(4-苄氧基丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
6.根据权利要求1所述的组合物,其中的化合物包括4-(3-苄氧基丙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
7.根据权利要求1所述的组合物,其中的化合物包括4-(4-氯丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
8.根据权利要求1所述的组合物,其中的化合物包括4-(4-{2″-甲氧基-4″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
9.根据权利要求1所述的组合物,其中的化合物包括4-(4-{4″-甲基-2″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
10.根据权利要求1所述的组合物,其中的化合物包括4-(4-{2″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
11.根据权利要求1所述的组合物,其中的化合物包括4-(4-{3″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
12.根据权利要求1所述的组合物,其中的化合物包括4-(4-{2″,4″-二硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
13.根据权利要求1所述的组合物,其中的化合物包括4-(4-[4-甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
14.根据权利要求1所述的组合物,其中的化合物包括4-(4-[3-甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
15.根据权利要求1所述的组合物,其中的化合物包括4-(4-[3,5-二甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
16.根据权利要求1所述的组合物,其中的化合物包括4-(4-[4-硝基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
17.根据权利要求1所述的组合物,其中的化合物包括4-(4-[4-氯苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
18.根据权利要求1所述的组合物,其中的化合物包括4-(4-[4-苯氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
19.根据权利要求1所述的组合物,其中的化合物包括4-(4-[4-甲基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
20.根据权利要求1所述的组合物,其中的化合物包括4-(4-[4-乙基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
21.根据权利要求1所述的组合物,其中的化合物包括4-(4-[4-氟苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
22.根据权利要求1所述的组合物,其中的化合物包括4-(4-[3-三氟甲基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
23.根据权利要求1所述的组合物,其中的化合物包括4-(4-[1-萘氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
24.根据权利要求1所述的组合物,其中的化合物包括4-(4-[2-萘氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
25.根据权利要求1所述的组合物,其中的化合物包括4-[3-(4-甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
26.根据权利要求1所述的组合物,其中的化合物包括4-[3-(3-甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
27.根据权利要求1所述的组合物,其中的化合物包括4-[3-(3,5-二甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
28.根据权利要求1所述的组合物,其中的化合物包括4-[3-(4-硝基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
29.根据权利要求1所述的组合物,其中的化合物包括4-[3-(4-氯苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
30.根据权利要求1所述的组合物,其中的化合物包括4-[3-(4-苯氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
31.根据权利要求1所述的组合物,其中的化合物包括4-[3-(4-甲基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
32.根据权利要求1所述的组合物,其中的化合物包括4-[3-(4-乙基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
33.根据权利要求1所述的组合物,其中的化合物包括4-[3-(4-氟苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
34.根据权利要求1所述的组合物,其中的化合物包括4-[3-(3-三氟甲基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
35.根据权利要求1所述的组合物,其中的化合物包括4-[3-(1-萘氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
36.根据权利要求1所述的组合物,其中的化合物包括4-[3-(2-萘氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
37.根据权利要求1所述的组合物,其中的化合物包括4-(5-苯氧基戊氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
38.根据权利要求1所述的组合物,其中的化合物包括4-[5-(4-甲氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
39.根据权利要求1所述的组合物,其中的化合物包括4-[5-(3,5-二甲氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
40.根据权利要求1所述的组合物,其中的化合物包括4-[5-(4-硝基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
41.根据权利要求1所述的组合物,其中的化合物包括4-[5-(4-氯苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
42.根据权利要求1所述的组合物,其中的化合物包括4-[5-(4-苯氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
43.根据权利要求1所述的组合物,其中的化合物包括4-[5-(4-甲基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
44.根据权利要求1所述的组合物,其中的化合物包括4-[5-(4-乙基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
45.根据权利要求1所述的组合物,其中的化合物包括4-[5-(4-氟苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
46.根据权利要求1所述的组合物,其中的化合物包括4-[5-(1-萘氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
47.根据权利要求1所述的组合物,其中的化合物包括4-[5-(2-萘氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
48.根据权利要求1所述的组合物,其中的化合物包括4-{4-(5″-甲基-1″,3″,4″-噻二唑-2″-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
49.根据权利要求1所述的组合物,其中的化合物包括4-{4-(7-香豆素基氧基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
50.根据权利要求1所述的组合物,其中的化合物包括4-{4-(5-甲氧基-1,3-苯并噻唑-2-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
51.根据权利要求1所述的组合物,其中的化合物包括4-{4-(嘧啶-2-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
52.根据权利要求1所述的组合物,其中的化合物包括4-(4-苯基-3-氧丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
54.根据权利要求53所述的应用,其中的疾病或病症是T细胞介导的自身免疫性疾病或病症。
55.根据权利要求54所述的应用,其中的化合物抑制Kv1.3通道。
56.根据权利要求55所述的应用,其中的化合物抑制Kv1.3通道的倾向性大大于抑制Kv1.5通道。
57.根据权利要求55所述的应用,其中的受试者未患有心房纤颤,并且其中的化合物抑制Kv1.3通道的作用足以治疗或预防疾病或病症,但其抑制Kv1.5通道的作用不足以引发心律失常。
58.根据权利要求56所述的应用,其中的化合物抑制Kv1.3通道的倾向性是其抑制Kv1.5通道的倾向性的至少10倍。
59.根据权利要求55所述的应用,其中的化合物为口服给药。
60.根据权利要求55所述的应用,其中的化合物为注射给药。
61.根据权利要求55所述的应用,其中的化合物为局部给药。
62.根据权利要求53所述的应用,其中的化合物包括4-(4-苯氧基丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
63.根据权利要求53所述的应用,其中的化合物包括4-(3-苯氧基丙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
64.根据权利要求53所述的应用,其中的化合物包括4-(2-苄氧基乙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
65.根据权利要求53所述的应用,其中的化合物包括4-(4-苄氧基丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
66.根据权利要求53所述的应用,其中的化合物包括4-(3-苄氧基丙氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
67.根据权利要求53所述的应用,其中的化合物包括4-(4-氯丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
68.根据权利要求53所述的应用,其中的化合物包括4-(4-{2″-甲氧基-4″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
69.根据权利要求53所述的应用,其中的化合物包括4-(4-{4″-甲基-2″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
70.根据权利要求53所述的应用,其中的化合物包括4-(4-{2″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
71.根据权利要求53所述的应用,其中的化合物包括4-(4-{3″-硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
72.根据权利要求53所述的应用,其中的化合物包括4-(4-{2″,4″-二硝基苯氧基}丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
73.根据权利要求53所述的应用,其中的化合物包括4-(4-[4-甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
74.根据权利要求53所述的应用,其中的化合物包括4-(4-[3-甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
75.根据权利要求53所述的应用,其中的化合物包括4-(4-[3,5-二甲氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
76.根据权利要求53所述的应用,其中的化合物包括4-(4-[4-硝基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
77.根据权利要求53所述的应用,其中的化合物包括4-(4-[4-氯苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
78.根据权利要求53所述的应用,其中的化合物包括4-(4-[4-苯氧基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
79.根据权利要求53所述的应用,其中的化合物包括4-(4-[4-甲基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
80.根据权利要求53所述的应用,其中的化合物包括4-(4-[4-乙基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
81.根据权利要求53所述的应用,其中的化合物包括4-(4-[4-氟苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
82.根据权利要求53所述的应用,其中的化合物包括4-(4-[3-三氟甲基苯氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
83.根据权利要求53所述的应用,其中的化合物包括4-(4-[1-萘氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
84.根据权利要求53所述的应用,其中的化合物包括4-(4-[2-萘氧基]丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
85.根据权利要求53所述的应用,其中的化合物包括4-[3-(4-甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
86.根据权利要求53所述的应用,其中的化合物包括4-[3-(3-甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
87.根据权利要求53所述的应用,其中的化合物包括4-[3-(3,5-二甲氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
88.根据权利要求53所述的应用,其中的化合物包括4-[3-(4-硝基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
89.根据权利要求53所述的应用,其中的化合物包括4-[3-(4-氯苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
90.根据权利要求53所述的应用,其中的化合物包括4-[3-(4-苯氧基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
91.根据权利要求53所述的应用,其中的化合物包括4-[3-(4-甲基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
92.根据权利要求53所述的应用,其中的化合物包括4-[3-(4-乙基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
93.根据权利要求53所述的应用,其中的化合物包括4-[3-(4-氟苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
94.根据权利要求53所述的应用,其中的化合物包括4-[3-(3-三氟甲基苯氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
95.根据权利要求53所述的应用,其中的化合物包括4-[3-(1-萘氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
96.根据权利要求53所述的应用,其中的化合物包括4-[3-(2-萘氧基)丙氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
97.根据权利要求53所述的应用,其中的化合物包括4-(5-苯氧基戊氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
98.根据权利要求53所述的应用,其中的化合物包括4-[5-(4-甲氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
99.根据权利要求53所述的应用,其中的化合物包括4-[5-(3,5-二甲氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
100.根据权利要求53所述的应用,其中的化合物包括4-[5-(4-硝基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
101.根据权利要求53所述的应用,其中的化合物包括4-[5-(4-氯苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
102.根据权利要求53所述的应用,其中的化合物包括4-[5-(4-苯氧基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
103.根据权利要求53所述的应用,其中的化合物包括4-[5-(4-甲基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
104.根据权利要求53所述的应用,其中的化合物包括4-[5-(4-乙基苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
105.根据权利要求53所述的应用,其中的化合物包括4-[5-(4-氟苯氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
106.根据权利要求53所述的应用,其中的化合物包括4-[5-(1-萘氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
107.根据权利要求53所述的应用,其中的化合物包括4-[5-(2-萘氧基)戊氧基]-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
108.根据权利要求53所述的应用,其中的化合物包括4-{4-(5″-甲基-1″,3″,4″-噻二唑-2″-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
109.根据权利要求53所述的应用,其中的化合物包括4-{4-(7-香豆素基氧基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
110.根据权利要求53所述的应用,其中的化合物包括4-{4-(5-甲氧基-1,3-苯并噻唑-2-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
111.根据权利要求53所述的应用,其中的化合物包括4-{4-(嘧啶-2-硫基)丁氧基}-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
112.根据权利要求53所述的应用,其中的化合物包括4-(4-苯基-3-氧丁氧基)-7H-呋喃并[3,2-g][1]苯并吡喃-7-酮。
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US10/958,997 US7557138B2 (en) | 2004-10-04 | 2004-10-04 | 5-phenoxyalkoxypsoralens and methods for selective inhibition of the voltage gated Kv1.3 potassium channel |
PCT/US2005/035572 WO2006041800A2 (en) | 2004-10-04 | 2005-10-04 | 5-phenoxyalkoxypsoralens and methods for selective inhibition of the voltage gated kv1.3 potassium channel |
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US20100239562A1 (en) * | 2006-05-22 | 2010-09-23 | The Johns Hopkins University | Kv CHANNELS IN NEURODEGENERATION AND NEUROPROTECTION |
NZ575686A (en) | 2006-10-04 | 2012-02-24 | Bionomics Ltd | Novel chromenone potassium channel blockers and uses thereof |
US8309545B2 (en) * | 2006-10-04 | 2012-11-13 | Bionomics Limited | Benzofuran potassium channel blockers and uses thereof |
WO2009042114A2 (en) * | 2007-09-21 | 2009-04-02 | The Johns Hopkins University | Phenazine derivatives and uses thereof |
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Irene Drizin et al.《Structure–Activity Studies for a Novel Series of Tricyclic Dihydropyrimidines as KATP Channel Openers (KCOs)》.《Bioorganic & Medicinal Chemistry Letters》.2002,(第12期),1481-1484. |
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US20100121059A1 (en) | 2010-05-13 |
IL182126A (en) | 2017-06-29 |
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