CN103764621B - 环氧化二十碳三烯酸类似物、其制备方法及其应用 - Google Patents
环氧化二十碳三烯酸类似物、其制备方法及其应用 Download PDFInfo
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- 229940038773 trisodium citrate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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Abstract
包含环氧化二十碳三烯酸(EET)类似物的化合物和组合物,所述EET类似物用作EET激动剂,并且用作治疗药物诱导的肾脏毒性、高血压和其他相关病症的药物。还描述了制备和使用所述化合物和组合物的方法。
Description
相关申请的交叉参考
本申请要求2011年4月6日提交的美国临时专利申请号61/472,410和2012年3月8日提交的美国临时专利申请号61/608,361的优先权,这两份申请的内容通过引用纳入本文以用于所有目的。
关于联邦资助研究的声明
本发明是在国立卫生研究院(National Institutes of Health)授予的DK38226、HL59699、GM31278和HL51055下由政府资助完成。政府对本发明拥有某些权利。
技术领域
本发明通常涉及环氧化二十碳三烯酸(epoxyeicososatrienoic acid)(EET)类似物。更具体地,本发明关于EET类似物,所述EET类似物用作EET激动剂,并且用作治疗药物诱导的肾脏毒性、高血压和其他相关病症的药剂(medication)。
发明背景
环氧化二十碳三烯酸(EET)是信号分子,能作为心血管系统和肾的短期(short-range)激素(即其是自分泌和旁分泌的调节剂)。其产生血管舒张以及抗炎性和促纤维蛋白溶解(pro-fibrinolytic)的效果。
高血压和相关病症。在3亿美国人中,心血管疾病折磨着8千1百万人,并且其中7千5百万人有高血压。CYP环氧化酶(epoxygenase)代谢物有生物学作用,所述作用表明其是心血管功能和血压控制的重要的参与者。
环氧化二十碳三烯酸(EET)的第一生物学活性之一是抑制肾小管钠的重吸收。然后,确定EET能扩张血管,并且鉴定其是内皮超级化因子(EDHF)。这些生物学作用与EET可以是类二十烷酸的观点相一致,所述类二十烷酸用于降低血压和防止盐敏感型高血压。
EET水平的变化可以对人高血压起作用。CYP环氧化酶基因中的单核苷酸多态性与高血压相关联。啮齿动物中的实验研究也显示了在肾CYP环氧化酶和/或EET水平降低的病症中有高血压。有11,12-EET-SI(11,12-EET类似物)的EET水平增加促进体外肾传入小动脉的功能。
目前,通过体内使用可溶的环氧化物水解酶抑制剂(sEHI)来增加EET水平,并且造成11,12-EET和14,15-EET以及在较小程度上8,9-EET的普遍增加。近期体内研究显示了EET类似物在高血压鼠中降低血压,并且也在血红素加氧酶2缺陷型小鼠中缓解代谢综合症表型,以及防止肥胖相关的血管损伤和肾脏损伤。这确实看起来像是一些EET激动剂如NUDSA也可以抑制sEH和增加CYP2C环氧化酶表达。NUDSA的这种结合活性类型可以提供增加的有益效果。整体而言,这些发现使得人们对靶定CYP环氧化酶通路和EET以治疗高血压产生兴趣。
尽管EET对血压调节重要的肾小管传输和血管功能起作用,显然,EET的其他生物作用使其成为其他心血管疾病的极好的治疗靶标。EET的其他活性包含抑制血小板聚集和抗炎症。EET也发现了对血管迁移和增殖起作用,包含促进血管新生。因此,EET成为与心血管疾病、心脏缺血损伤、动脉粥样硬化和中风相关联的终端器官损伤的治疗靶标。
EET激动剂和sEHI的治疗潜能可以不限于高血压和心血管疾病。缺血损伤的神经保护归结于sEHI对血管和神经元的作用。越来越多的证据表明sEHI通过对凋亡信号级联作用对大脑和心脏中的缺血损害提供保护。EET激动剂和sEHI也显示了在多种实验动物模型中调节疼痛。当这些试剂在其他疾病模型中测试时,必然能发现EET激动剂还有其他可能的治疗应用。
因此,本领域需要新的EET激动剂,所述EET激动剂活性是作为针对高血压和相关心血管疾病和神经疾病的治疗剂。
药物诱导的肾脏毒性。很多用于治疗多种病症的药物的常见副作用是肾脏毒性。例如顺铂(一种铂基无机化合物)是最有效和应用最广的化疗剂之一,用于治疗多种恶性肿瘤,包括卵巢癌、肺癌、睾丸癌和膀胱癌。尽管顺铂是临床中重要的化疗药物,其有潜在的致死性副作用。最常见的这种副作用是肾脏毒性(25-40%的顺铂治疗的患者患有急性肾衰竭),这限制了这种广泛使用的化疗剂的安全和有效使用。顺铂诱导的肾脏毒性的病理生理涉及增加的氧化应激、炎症、增加的内质网应激(ER)应激和肾细胞凋亡。
EET是作用于很多生物学活性的重要的脂质调节剂,所述生物学活性包含抗炎性、抗氧化和抗凋亡活性。很多研究显示了由于有抗炎性、抗凋亡和抗氧化活性,EET有较强的器官保护潜能。例如,通过可溶的环氧化物水解酶(sEH)抑制剂降低EET向其较低活性形式转化,从而造成EET生物可用性的增加,这提供了人疾病的很多临床前模型中的肾保护。这些研究显示了EET肾保护效果与EET的抗炎性和抗氧化效果有关。确实,较强的证据显示EET有针对急性和慢性炎症的抗炎性作用。除了炎症以外,EET也保护细胞免于细胞凋亡。因此,有较强证据显示EET能通过涉及其抗炎性、抗凋亡和抗氧化活性的机制来保护器官。
然而,已知内源生成的EET在化学和代谢上不稳定。同样,快速代谢、低溶解性和储存问题(issue)限制了EET的治疗前景。同样,人们在开发增强EET的生物可利用性的策略上有相当大的兴趣。在这种努力下,试图开发具有EET模拟活性和对稳定性和生物可利用性重要的数种关键特性的EET类似物。许多这种EET类似物显示了包含器官保护的很多生物学活性。
本研究中探索了两种新开发的口服活性EET类似物在顺铂诱导的肾脏毒性中的肾保护作用。显示了EET类似物在顺铂给药中有显著的肾脏保护效果,并且这种效果与其抗氧化、抗炎性、抗ER应激和抗凋亡活性有关。还显示了尽管这些EET类似物保护肾免于顺铂的有害肾脏毒性的影响,但是这些EET类似物不损害顺铂的化疗效果。
因此,本领域需要新的EET类似物,所述EET类似物活性作为针对顺铂的有害肾脏毒性作用的治疗剂。
发明内容
本发明人显示了环氧化二十碳三烯酸(EET)类似物的新的组合物及其用于治疗心血管疾病的方法,特别是把这种组合物用作抗高血压试剂。
因此,第一方面,本发明包含某些化合物,其是14,15-EET类似物。在某些实施方式中,所述化合物有下述任意一种化合物的结构。
在一个实施方式中,本发明包含化合物7和30。
在另一方面,本发明提供了制备本文所述和要求权利的化合物1-33中任一的方法。
在某些实施方式中,本发明所述化合物以组合物形式提供,所述组合物包含本文所述和权利要求的化合物与药物可接受运载体的结合。
本发明还包含提供治疗对象高血压、造成对象血压降低的方法。这种方法包含单独或结合给予对象治疗有效量的本文所述和要求权利的化合物1-33中任一,因而降低对象的血压。在一个实施方式中,所述方法包含给予化合物7。在另一个实施方式中,所述方法包含给予化合物30。
在另一个实施方式中,本发明提供有选自下组的结构的EET类似物:
(EET-A)或(EET-B)。
在另一个实施方式中,本发明包含使用任意上述14,15-EET类似物以制备治疗对象高血压的药剂(medicament)。同样,本发明还考虑到本发明所述化合物在治疗对象高血压中的应用。
本发明还包含治疗对象中药物诱导的肾脏毒性的方法。在一个实施方式中,本发明包含提供对对象中顺铂有害肾脏毒性影响的治疗。这种方法包含给予对象治疗有效量的本文所述和要求权利的化合物,从而降低药物对对象的有害的肾脏毒性影响。
根据以下详细说明、权利要求和图片之后,本发明的其他目的、特征和优点将显而易见。
附图简要说明
图1A显示了对应表1中EET类似化合物26的化学结构SRD-I-71-9。图1B显示了平均测量血压是治疗自发性高血压大鼠天数的函数,所述大鼠给予包含载剂或化合物26的组合物。图1C显示了在自发性高血压大鼠中第0天、第7天和第14天的平均测量血压,所述大鼠给予包含载剂或化合物26的组合物。
图2A显示了对应表1中EET类似化合物20的化学结构LGK-I-119-15。图2B显示了平均测量血压是治疗自发性高血压大鼠天数的函数,所述大鼠给予包含载剂或化合物20的组合物。图2C显示了在自发性高血压大鼠中第0天、第7天和第14天的平均测量血压,所述大鼠给予包含载剂或化合物20的组合物。
图3A显示了对应表1中EET类似化合物7的化学结构JLJ-I-94-6。图3B显示了平均测量血压是治疗自发性高血压大鼠天数的函数,所述大鼠给予包含载剂或化合物7的组合物。所述数据以12小时均值绘图。化合物通过i.p.递送14天。图3C显示了在自发性高血压大鼠中第0天、第7天和第14天中相对于起始治疗的平均测量血压,所述大鼠给予包含载剂或化合物7的组合物。
图4A显示了对应表1中EET类似化合物30的化学结构MV-IV-110-20。图4B显示了平均测量血压作为治疗自发性高血压大鼠天数的函数,所述大鼠给予包含载剂或化合物30的组合物。所述数据以12小时均值绘图。图3C显示了在自发性高血压大鼠中第0天、第7天和第14天的平均测量血压,所述大鼠给予包含载剂或化合物30的组合物。
图5A显示了平均测量血压是治疗血管紧张素II诱导的高血压大鼠天数的函数,所述大鼠给予包含载剂或化合物7的组合物。所述数据以12小时均值绘图。图5B显示了在血管紧张素II诱导的高血压大鼠中第0天、第7天和第14天的平均测量血压,所述大鼠给予包含载剂或化合物7的组合物。
图6A显示了平均测量血压是治疗血管紧张素II诱导的高血压大鼠天数的函数,所述大鼠给予包含载剂或化合物30的组合物。所述数据以12小时均值绘图。图6B显示了在血管紧张素II诱导的高血压大鼠中第0天、第7天和第14天的平均测量血压,所述大鼠给予包含载剂或化合物30的组合物。
图7:在用EET类似物、EET-A和EET-B或者载剂预处理的、给予顺铂的大鼠中(a)血浆肌酸酐,(b)血液尿素氮(BUN),(c)肾损伤分子(kidney injury molecule)-1,和(d)尿NA G。*p<0.05对比正常Wistar Kyoto大鼠;#p<0.05对比载剂处理的、给予顺铂的大鼠。数据表达为平均值±SEM,n=5-7。
图8A:高碘酸-席夫(Schiff)(PAS)染色(200x)的代表性显微照片显示了不同实验组肾皮质切片中管型(tubular cast)形成和所计算的形状(cast)面积分数。*p<0.05对比正常Wistar Kyoto大鼠;#p<0.05对比载剂处理的大鼠。数据表达为平均值±SEM,n=5-7。
图8B:高碘酸-席夫(PAS)染色(200x)的代表性显微照片显示了不同实验组的肾髓质切片中管型形成和所计算的形状面积分数。*p<0.05对比正常Wistar Kyoto大鼠;#p<0.05对比载剂处理的大鼠。数据表达为平均值±SEM,n=5-7。
图9:RT-PCR分析获得在用EET类似物A、B或载剂处理的、给予顺铂的大鼠中的(a)NOX1,(b)gp91Phox,(d)SOD1,(e)SOD2,(f)SOD3的RNA表达和(c)肾硫代巴比妥酸活性物质(TBARS)的测量。*p<0.05对比正常Wistar Kyoto大鼠;#p<0.05对比载剂预处理的、给予顺铂的大鼠。数据表达为平均值±SEM,n=5-7。
图10:用EET类似物EET-A和EET-B或载剂预处理的、给予顺铂的大鼠中,炎性标记基因TNF-α(a)、IL-6(b)和IL-1β(c)的肾表达。*p<0.05对比正常Wistar Kyoto大鼠;#p<0.05对比载剂预处理的、给予顺铂的大鼠。数据表达为平均值±SEM,n=5-7。
图11:EET类似物EET-A和EET-B或载剂处理的、给予顺铂的大鼠中,内质网应激标记基因GRP78/BiP(a)和胱冬酶12(b)的肾表达。*p<0.05对比正常WistarKyoto大鼠;#p<0.05对比载剂处理给予的大鼠。数据表达为平均值±SEM,n=5-7。
图12:不同实验组中,肾皮质胱冬酶3活性(a)和抗-凋亡基因Bcl2的肾表达(b)。不同实验组中,抗-凋亡基因Bcl2与凋亡基因Bak(c)和Bax(d)的肾表达的比例。*p<0.05对比正常Wistar Kyoto大鼠;#p<0.05对比载剂处理的、给予顺铂的大鼠。数据表达为平均值±SEM,n=5-7。
图13A:正常肾细胞(HEK293)和肿瘤细胞(Hela、U87、NCCIT)中顺铂的细胞毒性影响。
图13B:EET类似物EET-A对HEK293、Hela、U87、NCCIT的细胞生长的影响。EET-A不影响NCCIT癌细胞中顺铂的化疗效果。数据表达为平均值±SEM,n=5-7。
图14:EET类似物EET-A和EET-B的结构。
图15:合成EET-B。
图16A:合成EET-A。
图16B:替代合成EET-A。
发明详述
I.概述
描述本发明材料和方法之前,应理解,本发明不限于所述具体方法、方案、材料和试剂,这些可发生变化。还应理解,本文所用术语的目的仅是描述具体实施方式,不应用来限制本发明的范围,所述范围仅受任何随后提交的非临时申请的限制。
必须注意到,本文和所附权利要求书所用的单数形式“一个”、“一种”和“所述”包括复数含义,除非文中另有明确说明。同样,术语“一个”(或“一种”)、“一种或多种”和“至少一种”在本文中可以互换使用。还应当注意,术语“包括”、“包含”、和“具有”可以互换使用。
除非另有说明,否则本文所用的所有科技术语与本发明所属领域普通技术人员通常理解的含义相同。虽然与本文所述类似或等同的任何方法和材料也能用于实施或测试本发明,但描述了优选的方法和材料。本文具体提及的所有出版物和专利都通过引用全文纳入本文用于所有目的,包括描述和公开所述出版物报道的可与本发明关联使用的化学物质、设备、统计分析和方法。本说明书引用的所有参考文献都应看作对本领域技术水平的指示。本文中所有内容均不应解释为承认本发明不能凭借在先发明而先于这些公开内容。
II.发明内容
本发明人公开了新的EET类似物、EET激动剂、和其他相关的脂质化合物、和包含这种化合物的组合物,与合成这种化合物的方法,以及这种组合物在治疗高血压和相关病症、治疗顺铂肾脏毒性和相关病症的有害影响中的应用。本发明人显示了数种化合物展现有抗高血压的效果,并且在相关大鼠模型中耐受良好。可选择很多不同的递送方式,包含腹膜内注射、血液注射、或口服递送。脂质体、胶囊(mycelle)和乳化剂能用于提高这些制剂的可溶性。
本为所用"对象"指的是哺乳动物和非哺乳动物。“哺乳动物”指的是任意的哺乳动物纲成员,包括但不限于人类、非人灵长类,例如大猩猩和其他猿类和猴类;农场动物,例如牛、马、山羊、绵羊和猪;家养动物,例如兔、狗和猫;实验室动物,包含啮齿动物,例如大鼠、小鼠和豚鼠;等等。非哺乳动物的示例包括但不限于鸟类等。所述“术语”不表示特定年龄或性别。
本为所用“给予”或“给药”包含把本发明化合物引入到身体中的任何方式,所述方式优选通过系统循环。示例包括但不限于口服、口颊、舌下、肺部、透皮、经粘膜,以及皮下、腹膜内、静脉内和肌肉内注射。
“治疗有效量”指给予对象用于治疗疾病或病征时,足以实现治疗疾病的化合物的用量。根据所述化合物、治疗的疾病状态、治疗的疾病严重程度、所述对象的年龄和相对健康状态、给药路径和方式、主治医生或兽医从业者的判断、和其他因素,所述“治疗有效量”可以改变。
就本发明目的而言,“治疗”或“处理”描述了管理和护理患者以用于对抗疾病、病症、或紊乱的目的。所述术语包括预防性治疗(即预防)和缓解性治疗。治疗包括给予本发明的化合物以防止所述症状或并发症的发作、缓解所述症状或并发症、或消除所述疾病、病症、或紊乱。
给予患者治疗有效量的化合物。能单独给予化合物,或者作为药学可接受组合物的一部分给予化合物。另外,化合物或组合物能立即全部给药(例如通过推注),多次给药(例如通过一系列片剂),或一段时间内基本均匀(substantially uniformly)递送(例如使用透皮递送)。再者,所述化合物的剂量能随着时间而改变。化合物能使用速释制剂、控释制剂或其组合给药。术语"控释"包含缓释、延迟释放和其组合。
本发明的药物组合物能大量、或作为单个单位剂量、或作为多种单个单位剂量来制备、包装或出售。本文所用"单位剂量"是不连续数量的药物组合物,所述药物组合物包含预定量的活性成分。活性成分的量通常等于能给予患者的活性成分的剂量,或者是这种剂量的合适的部分,例如这种剂量的一半或三分之一。
本发明药物组合物中活性成分、药学可接受运载体和任意其他成分的相对数量会根据要治疗患者本身(identity)、大小和病情而变化,并且也根据所述组合物的给药途径而变化。例如,所述组合物能包含0.1%-100%(w/w)的活性成分。本发明药物组合物的单位剂量通常包含约100毫克-约2克的活性成分,并且优选包含约200毫克-约1.0克的活性成分。
人的优选剂量可以是每天一次口服给药的低的mg/kg范围。也可以接受每天两次。
为了提高水溶性,所述优选化合物能与环糊精或环糊精衍生产物制备,用例如聚乙二醇或其他极性官能团的取代基衍生,或者包含在脂质体中。就口服递送而言,所述化合物可以用亲脂性官能团修饰,或与活性吸附分子偶联。其他方法在"提高口服药物生物可利用性的方案(Strategies to improve oral drug bioavailability)"(Isabel Gomez-Orellana,Expert Opinion on Drug Delivery,2005年5月,卷2,No.3:第419-433页)中讨论,所述文献通过引用纳入本文。
本发明另一方面涉及包含本发明药物组合物的药盒和说明材料。说明材料包含发表物、记录、图表、或任何其他表达媒介,其用于向人传递针对本文所述目的之一的本发明药物组合物的实用性。说明材料也能描述例如本发明药物组合物的合适的剂量。例如,本发明药盒的说明材料可固定在包含本发明药物组合物的容器上,或可与包含本发明药物组合物的容器一起运送。或者,所述说明材料能与本发明的容器分开运送,从而所述说明材料和所述药物组合物能由受体协调使用。
本发明也包含含有本发明药物组合物的药盒和将所述组合物递送给人的递送装置。例如,所述递送装置能是可压挤的喷雾瓶、计量剂量喷雾瓶、气雾剂喷雾装置、雾化器、干燥粉末递送装置、自身推进溶剂/粉末-分配装置、注射器、针头、棉塞、或剂量测量容器。所述药盒还能包含本文所述的说明材料。所述药盒也包含分离组合物的容器,例如分装瓶(divided bottle)或分装箔片包装。容器的其他示例包含注射器、盒、袋等。通常,药盒包括分离组分的给药说明书。当分离组分优选以不同剂型(如口服和胃肠外)给药、以不同的剂量间隔给药时,或者当处方医生需要对结合的个体成分滴定时,所述药盒形式特别有优势。
药盒上可能需要提供记忆辅助工具(memory aid),例如以临近药片或胶囊的数字的形式,从而所述数字对应应该摄取特定药片或胶囊的方案的天数。这种记忆辅助工具的另一个示例是印在卡片上的日历,例如如下"第一周,星期一、星期二...等,第二周,星期一、星期二"等。其他记忆辅助工具的变化形式是显而易见的。"每天剂量"能是给定天使用的单个片剂或胶囊,或者数种丸剂或胶囊。
在本发明的另一个实施方式中,提供了分配器,所述分配器设计为以其所需应用顺序一次一个(one at a time)地分配每天剂量。优选,所述分配器配有记忆辅助工具,从而进一步辅助与剂量方案的适应性。这种记忆辅助工具的示例是机械计数器,所述计数器指示已经分配的每天剂量的数字。这种记忆辅助工具的另一个示例是与液晶读出器或可听声的提示信号偶联的电池供电的微芯片存储器,例如其读出已经使用最后一天剂量的天数和/或提醒何时使用下一个剂量。
可选包含其他药学活性化合物的本发明所述化合物,能通过口服、直肠、经胃肠道外(例如静脉内、肌肉内或皮下)、脑池内、阴道内、腹膜内、膀胱内、局部(例如粉末、油膏剂或液滴)、或者作为口颊或鼻喷雾以向患者给药。其他可考虑的制剂包含突出(projected)纳米颗粒、脂质体制品、包含活性成分的再密封的红血球,和免疫制剂。
药物组合物的胃肠道外给药包含任意给药途径,如人组织物理切口,和通过所述组织切口给予药物组合物的。因此胃肠道外给药包含下列方式给予药物组合物:通过注射所述组合物、通过外科切口应用所述组合物、通过组织穿透性非手术伤口应用所述组合物等等。具体而言,胃肠道外给药包含皮下、腹膜内、静脉内、动脉内、肌内或胸骨内注射,和静脉内、动脉内或肾脏透析输注技术。例如,本发明组合物能通过脑(通过vPAG)注射、鞘内注射、腹膜内注射或血液注射向对象给药。
适合胃肠道外给药的组合物可以包含与药学可接受的运载体结合的活性成分,或可以包含用于重建成无菌注射溶液或分散体的无菌粉末,所述运载体例如生理学可接受的水性或非水性无菌溶液剂、分散剂、悬浮液(suspension)或乳液。合适的水性或非水性运载体、稀释剂、溶剂或载剂的例子包括水、等渗盐、乙醇、多元醇(丙二醇、聚乙二醇、甘油等),其合适混合物,甘油三羧酸酯,包含植物油如橄榄油或可注射的有机酯如油酸乙酯。例如可通过使用如卵磷脂的涂层、通过保持所需粒度(在分散液的情况中)和/或通过使用表面活性剂,来维持合适的流动性。这种制剂能以合适推注给药或连续给药的形式制备、组装或出售。可注射的制剂能以单位剂型制备、组装或出售,所述单位剂型例如在安瓿中、在包含防腐剂的多剂量容器中或者对于自动注射或通过医师注射的单个使用的装置中。
胃肠道外给药的制剂包含悬浮液、溶液、油性或水性载剂中的乳液、糊料和可植入的缓释或可生物降解的制剂。这种制剂还能包含一种或多种其他成分,包含悬浮剂、稳定剂或分散剂。在胃肠道外给药制剂的一个实施方式中,所述活性制剂以干燥(如粉末或颗粒)形式提供,从而在胃肠道外给予重建组合物前,所述制剂与合适的载剂(如无菌无热原的水)重建。
所述药物组合物能以无菌可注射的水性或油性悬浮液或溶液的形式制备、组装或出售。这种悬浮液或溶液能根据现有技术制备,并且能包含除了活性成分以外的其他成分,例如本文所述分散剂、润湿剂或悬浮剂。这种无菌可注射制剂能使用胃肠道外可接受的无毒稀释剂或溶剂(例如水或1,3-丁二醇)中制备。其他可接受的稀释剂或溶剂包含林格氏(Ringer)溶液、等渗氯化钠溶液、和不挥发油如合成的甘油一酯和甘油二酯。其他可用的胃肠道外给药制剂包含含有微晶形式活性成分、脂质体制品中活性成分、或作为可生物降解的聚合物体系组分的活性成分的那些。缓释或植入的组合物能包含药学可接受的聚合材料或疏水性材料,例如乳液、离子交换树脂、难溶性聚合物、或者难溶性盐。
本发明所述化合物也可以包含佐剂,例如防腐剂、润湿剂、乳化剂、和/或分散剂,包含例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等。也可能需要包含等渗剂,如糖、氯化钠等。可通过使用能延迟吸收的试剂,例如单硬脂酸铝和/或明胶来延长可注射药物组合物的吸收。特别地,脂质体、mysomes和乳化剂能用于增加本化合物对递送而言的可溶性。
剂型能包含固体或可注射的植入物(implant)或存储物(depot)。在优选实施方式中,所述植入物包含有效量的活性剂和可生物降解聚合物。在优选实施方式中,合适的可生物降解聚合物能选自聚天冬氨酸酯、聚谷氨酸盐/酯、聚(L-丙交酯)、聚(D,L-丙交酯)、聚(丙交酯-共-乙交酯)、聚(ε-己内酯)、聚酐、聚(β-羟基丁酸酯)、聚(原酸酯)和聚膦腈。在其他实施方式中,所述植入物包含有效量的活性剂和硅橡胶聚合物。所述植入物在约1周到数年的延长时期内,提供释放有效量的活性剂。
用于口服给予的固体剂型包括胶囊、片剂、粉剂和颗粒剂。在这类固体剂型中,活性化合物与至少一种常规惰性赋形剂(或运载体)混合,所述赋形剂包含例如,柠檬酸钠或磷酸氢钙或(a)填料或补充剂,例如,淀粉、乳糖、蔗糖、甘露醇或硅酸,(b)粘合剂,例如,羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖或阿拉伯胶,(c)保湿剂,例如,甘油,(d)崩解剂,例如,琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些复合硅酸盐或碳酸钠,(e)溶液阻滞剂,如石蜡,(f)吸收加速剂,例如,季铵化合物,(g)湿润剂,例如,十六烷醇或甘油一硬脂酸酯,(h)吸附剂,例如,高岭土或膨润土,和/或(i)润滑剂,例如,滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠或其混合物。在胶囊和片剂的情况下,剂型中也可含有缓冲剂。
能例如通过将所述活性成分(优选伴有一种或多种其他成分)压缩或压模(mold)来制成包含活性成分的片剂。压缩片剂可以通过在合适的装置中将活性成份压缩来制备,所述活性成份是可选与一种或多种粘结剂、润滑剂、赋形剂、表面活性剂和分散剂混合的诸如粉末或颗粒制剂的自由流动形式。压模片剂能通过在合适的装置中将混合物压模来制成,所述混合物是活性成分、药学可接受运载体和至少足以使混合物潮湿的液体。
用于生产片剂的药学可接受赋形剂包含惰性稀释剂、成粒剂和崩解剂、粘合剂和润滑剂。已知的分散剂包含土豆淀粉和淀粉乙醇酸钠。已知的表面活性剂包含月桂基硫酸钠。已知的稀释剂包含碳酸钙、碳酸钠、乳糖、微晶纤维素、磷酸钙、磷酸氢钙和磷酸钠。已知的成粒剂和崩解剂包含玉米淀粉和海藻酸。已知的粘合剂包含明胶、阿拉伯胶、预糊化玉米淀粉、聚乙烯基吡咯烷酮和羟丙基甲基纤维素。已知的润滑剂包含硬脂酸镁、硬脂酸、硅石(silica)和滑石。
片剂能没有包衣,或者片剂能使用已知方法包衣以实现在人胃肠道中的延迟崩解,因而提供活性成分的缓释和吸收。例如,如单硬脂酸甘油酯或二硬脂酸甘油酯的材料能用于包衣片剂。再例如,片剂能使用描述于美国专利号4,256,108;4,160,452;和4,265,874的方法包衣以形成渗透控释片剂。片剂还能包含甜味剂、调味剂、着色剂、防腐剂或其组合以提供药学上精良的和可口的制剂。
可用包衣或外壳(如肠溶衣)或本领域熟知的其它材料来制备固体剂型,例如片剂、糖衣丸、胶囊和颗粒。其也可以包含遮光剂(opacifying agent),并且也能是以延迟方式释放一种或多种活性化合物的组合物。能使用的包埋组合物的示例是聚合物和蜡。所述活性化合物也能是微囊密封形式,如果合适,可伴有一种或多种上述赋形剂。
相似类型的固体组合物也可用作软或硬明胶胶囊的填料,所述胶囊中使用如乳糖或高分子量聚乙二醇等赋形剂。包含活性成分的硬胶囊能使用生理可降解组合物(如明胶)来生成。这种硬胶囊包含所述活性成分,并且还能包含其他成分,例如包含惰性固体稀释剂如碳酸钙、磷酸钙或高岭土。包含活性成分的软明胶胶囊能使用生理可降解组合物(如明胶)来生成。这种软胶囊包含能与水或油介质(如花生油、液状石蜡或橄榄油)混合的活性成分。
口服组合物能使用已知技术生成,所述技术在人患者的小肠或大肠内特异性释放口服给药的试剂。例如,递送到胃肠系统(包含结肠)的制剂含有基于例如甲基丙烯酸酯共聚物如聚(甲基丙烯酸,甲基丙烯酸甲酯)的肠衣系统,所述肠衣系统仅在pH6或更高pH下溶解,从而所述聚合物仅在进入小肠后开始溶解。这种聚合物制剂崩解的位点取决于肠道运输率和存在的聚合物的量。例如,使用相对厚的聚合物包衣以递送到近侧结肠(Hardy等,Aliment.Pharmacol.Therap.(1987)1:273-280)。也能使用能提供位点特异性结肠递送的聚合物,其中所述聚合物依赖于大肠的细菌集落以提供聚合物包衣的酶降解和因此释放药物。例如,能在这种制剂中使用偶氮类聚合物(美国专利号4,663,308)、糖苷(Friend等,J.Med.Chem.(1984)27:261-268)和多种天然可用和修饰的多糖(参见PCT申请PCT/GB89/00581)。
例如描述于美国专利号4,777,049中的脉冲释放技术也能用于给予活性试剂到胃肠道内的特异位置。这种系统使得在预定时间递送药物,并且能用于递送所述活性剂,可选与可改变局部微环境的其他添加剂一起来促进试剂稳定性和直接摄入到结肠,而不依赖于外部情况,除了需要水以提供体内释放以外。
口服给药的液体剂型包括药学上可接受的乳剂、溶液剂、悬浮液、糖浆剂和酏剂。除活性化合物外,液体剂型还可含有本领域常用的惰性稀释剂,如水和其它溶剂、等渗盐;增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺,油,具体是杏仁油、花生油、椰子油、棉花籽油、花生油、玉米胚芽油、橄榄油、蓖麻油和芝麻籽油、MIGLYOLTM、甘油、分馏植物油、矿物油如液状石蜡、四氢糠醇、聚乙二醇、山梨聚糖的脂肪酸酯或这些物质的混合物等。
除了这种惰性稀释剂,本发明化合物也能包含佐剂,如润湿剂、乳化剂和悬浮剂、缓和剂、防腐剂、缓冲液、盐、甜味剂、调味剂、着色剂和芳香剂。除活性化合物外,悬浮液还可含有助悬剂,如乙氧基化异硬脂酰醇、聚氧乙烯山梨糖醇或去水山梨糖酯、微晶纤维素、氢化食用脂肪、藻酸钠、聚乙烯基吡咯烷酮、黄蓍胶、阿拉伯树胶、琼脂-琼脂、和纤维素衍生物如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、偏氢氧化铝、膨润土、或这些物质的混合物等。合适口服给药的本发明药物组合物的液体制剂能以液体形式或干燥产物形式制备、包装和出售,所述干燥产物形式打算在使用前与水或另一种合适的载剂重建。
已知的分散剂或湿润剂包含天然产生的磷脂如卵磷脂,氧化烯与脂肪酸、长链脂族醇、脂肪酸和己糖醇衍生的偏酯、或脂肪酸和己糖醇酐衍生的偏酯的缩合产物(如分别是聚氧乙烯硬脂酸酯、十七-氧乙烯十六烷醇(heptadecaethyleneoxycetanol)、聚氧乙烯山梨糖醇单油酸酯和聚氧乙烯脱水山梨糖醇单油酸酯)。已知的乳化剂包含卵磷脂和阿拉伯胶。已知防腐剂包含对羟基苯甲酸甲酯、对羟基苯甲酸乙酯或对羟基苯甲酸正丙基酯、抗坏血酸和山梨酸。已知的甜味剂包含例如甘油、丙二醇、山梨糖醇、蔗糖和糖精。对油性悬浮液而言,已知增稠剂包含例如蜂蜡、硬石蜡和鲸蜡醇。
水性或油性溶剂中活性成分的液体溶液能以与液体悬浮液基本相同的方式制备,主要区别是活性成分是溶解的,而不是悬浮在溶剂中。本发明药物组合物的液体溶液能包含关于液体悬浮液所述的任意成分,应理解悬浮剂并不必然地促进所述活性成分在溶解中的溶解。水性溶剂包含例如水和等渗盐。油性溶剂包含例如杏仁油、油性酯(oily ester)、乙醇、植物油如花生油、橄榄油、芝麻油或椰子油、分馏植物油和矿物油如液状石蜡。
用于直肠或阴道给药的组合物通过混合本发明化合物和任意其他化合物与诸如可可脂、聚乙二醇或栓剂蜡(它们在正常室温下为固态但在体温下为液态,因此在直肠或阴道腔内融化并释放活性成分)等合适的无刺激赋形剂或运载体而制备。这种组合物能是例如栓剂、保留灌肠制剂和直肠或结肠灌注溶液的形式。栓剂制剂还能包含多种其他成分,所述其他成分包含抗氧化剂和防腐剂。保留灌肠制剂或直肠或结肠灌注溶液能通过将活性成分与药物可接受的液体运载体结合来生成。如本领域已知,灌肠制剂能使用适合于人直肠解剖的递送装置来给药和包装在所述递送装置中。灌肠制剂还能包含多种其他成分,所述其他成分包含抗氧化剂和防腐剂。
本发明的药物组合物能作为合适阴道给药的制剂来制备、包装或出售。这种组合物能是例如栓剂、浸渍或包衣的阴道可插入材料(如棉塞、灌注制剂、或阴道灌注溶液)的形式。
用于局部给予本发明化合物的剂型包括软膏剂、粉末剂、喷雾剂和吸入剂。在无菌条件下将化合物与生理上可接受的运载体和任何可能需要的防腐剂、缓冲剂和/或推进剂混合在一起。合适局部给药的制剂包含液体或半液体制剂,例如搽剂、洗剂、水包油或油包水乳液如乳膏剂、油膏剂或糊料,和溶液或悬浮液。可局部给药的制剂能包含例如约0.1%-约10%(w/w)活性成分,尽管所述活性成分的浓度能高至活性成分在溶剂中的溶解度。局部给药的制剂还能包含一种或多种本文所述的其他成分。
眼科制剂、眼膏、粉末剂和溶液也视作本发明范围内。这种制剂能是例如滴眼液形式,例如在水性或油性液体运载体中包含0.1-1.0%(w/w)活性成分的溶液或悬浮液。这种滴液还能包含缓冲剂、盐、或一种或多种本文所述的其他成分。在其他实施方式中,可眼部(ophthalmalmical)给药的制剂包含微结晶形式或脂质体制剂中的活性成分。
本发明为肺部递送制备的药物组合物能提供在溶液或悬浮液的液滴形式中的活性成分。这种制剂能作为包含所述活性成分(可选无菌)的水性或稀释的醇性溶液或悬浮液制备、包装或出售,并且能方便地使用任意喷雾或雾化装置给药。这种制剂还能含有一种或多种其他成分,包含调味剂如糖精钠、挥发油、缓冲剂、表面活性剂、或防腐剂如羟基苯甲酸甲酯。这种给药途径提供的液滴优选平均直径范围是约0.1-约200纳米。
本发明的药物组合物能作为合适于口腔给药的制剂来制备、包装或出售。这种制剂能是例如通过传统方法制成的片剂或锭剂形式,并且包含例如0.1-20%(w/w)活性成分,剩余物(balance)包含口服可溶解的或可降解的组合物,和可选包含一种或多种本文所述的其他成分。或者,合适空腔给药的制剂能包含含有所述活性成分的粉末或者雾化的或微粒化(atomized)的溶液或悬浮液。当分散时,这种粉末化的、雾化的或微粒化制剂的优选平均颗粒或液滴大小的范围约0.1-约200纳米,并且还能包含一种或多种本文所述的其他成分。
就非人动物中胃肠道外给药而言,本发明所述化合物可以以糊料或球团的形式制备,并且通常作为动物头部皮肤或耳朵下面的植入物给予。糊料制剂能通过在药学可接受油中分散一种或多种化合物来制备,所述药学可接受油例如花生油、芝麻油、玉米油等。包含治疗有效量的一种或多种化合物的球团能通过将所述化合物与稀释剂混合来制备,并且能加入润滑剂例如硬脂酸镁或硬脂酸钙以改善生成球团的工艺,所述稀释剂例如碳蜡(carbowax)、巴西棕榈蜡等。当然,应认识到可以给予动物多于一种球团以达到所需的剂量水平。另外,已经发现了这种植入物也可以在动物治疗期间内周期性给药,从而在动物体内维持合适的活性剂水平。
可以每天约0.01-约1,000mg范围的剂量水平向患者给予本发明化合物和其药学上可接受的盐。对体重约70kg的正常的成年人而言,通常剂量范围约0.01-约300mg就足够了,优选剂量是1-10mg/kg。但是,常见剂量范围可以根据要治疗对象的年龄和体重、给药途径、要给药的特定化合物等因素产生一些变化。确定特定患者的剂量范围和最优剂量对本领域普通技术人员来说是显而易见的。也注意到本发明化合物能用于缓释制剂、控释制剂和延迟释放制剂,这对于本领域普通技术人员也是熟知的。
本发明化合物是否直接给予到细胞、包含细胞的组织、与细胞接触的体液、或所述化合物能扩散到或转运到细胞的身体位点,这些并不是关键因素。所述化合物以某个剂量和通过某个途径给药就足够了,所述途径将足以释放(mobilize)细胞中脂质的化合物剂量直接或间接递送到所述细胞。最小剂量随着化合物的性质而变化。
能使用的特定剂量和剂量范围可取决于众多因素,包括患者需求、待治疗的病症严重程度以及所给药的化合物的药理学活性。确定特定患者的剂量范围和最优剂量对本领域普通技术人员是显而易见的。应理解普通技术的医生或兽医易于确定和处方有效量的化合物以在患者中释放(mobilize)脂质存储、诱导减少体重或抑制食欲。在这种过程中,医生或兽医能例如首先处方相对较低的剂量,然后增加剂量,直到获得合适的反应。然而,还应当理解,针对任何特定人的具体剂量水平取决于各种因素,包括所采用的具体化合物的活性、年龄、体重、一般健康情况、性别、和人的饮食、给药时间、给药途径、排泄速度、任意药物组合、以及要治疗的任意疾病的严重程度。
本发明组合物和方法的各种示例性实施方式在下面实施例中描述。在这些实施方式中,阿拉伯数字(如1、2、3等)标明的特定产物指在下列描述中(特别是下面表1和所附权利要求书中)鉴定的特定结构。
III.实施例
提供以下实施例仅用于说明目的,并非旨在以任何方式限制本发明的范围。实际上,本发明所示和描述以外的各种变化通过以上描述以及以下的实施例对本领域技术人员显而易见,所述变化也包括在所附权利要求书的范围之内。
实施例1:合成33种EET类似物
在这个实施例中,本发明人报导了合成EET类似物的文库。指定为化合物1-33的化合物的化学结构示于下面表1。
通用步骤。除非另有表述,产量指纯化的产物,并且没有优化。使用乙腈/水的结合作为溶剂,连接到安捷伦公司(Agilent)1200API/LC-MS的Zorbax Eclipse C18(250×4.6mm;安捷伦公司)的HPLC以评价最终产物的纯度为≥95%。在氩气条件下,使用烘箱干燥的玻璃器皿和无水溶剂来进行所有的氧气敏感反应和/或湿气敏感反应除了从CaH2蒸馏CH2Cl2以外,从二苯甲酮钠羰游离基中新鲜蒸馏无水溶剂。提取物用无水Na2SO4干燥,并且过滤,然后减压条件下除去所有挥发物。除非另有说明,不用纯化而使用市售可得的材料。使用伊默克公司(E.Merck)硅胶60(240–400网)进行快速色谱(FC)。使用购自伊默克公司(E.Merck)(硅胶60PF254,0.25mm)的预涂层的板进行薄层色谱(TLC)。除非另有说明,在CDCl3中300/400/500MHz(1H)或75/100/125MHz(13C)工作频率下,在Varian300、400或500光谱仪上记录核磁共振(NMR)谱。核磁共振(NMR)分裂图案描述为单峰(s)、双峰(d)、三峰(t)、四峰(q)和宽峰(br);以相对于残余溶剂的ppm(对1H NMR,氯仿δ=7.27,或者对质子去耦(decoupled)的13C NMR,δ=77.23)来生成化学位移值(δ),并且偶合常数(J)以赫兹(Hz)表示。熔点使用OptiMelt(斯坦福研究系统(Stanford ResearchSystems))测定,并且未经校正。圣母大学质谱中心或Kasem Nithipatikom教授(威斯康星医学院)友情提供了高分辨率质谱分析。
表1:33种EET类似物、测量的血管舒张和sEH抑制活性。
如下提供表1中EET化合物的合成:
合成类似物25。
叔丁基二苯基-[12-(四氢-2H-吡喃-2-基氧基)十二碳-7-炔基氧基)]硅烷。在–78℃、氩气下,向搅拌的2-(己-5-炔基氧基)四氢-2H-吡喃(5.0g,27.43mmol,GFS化学公司(G.F.Smith Chem.Co.))的THF/HMPA(4:1,150mL)溶液中逐滴加入正丁基锂(12.0mL的2.5M己烷溶液,30.0mmol)。30分钟后,反应混合物加温到0℃,并且在0℃维持2小时(h)。重新冷却到–78℃后,加入1-叔丁基二苯基甲硅烷氧基-6-溴己烷1(11.50g,27.43mmol)的THF(55mL)溶液,并且温度在3小时内升高到23℃。再过12小时后,反应混合物用饱和NH4Cl水溶液(25mL)淬灭。混合物用EtOAc(2×100mL)萃取,并且合并的萃取物用水(2×150mL)、盐水(50mL)洗涤,干燥,并且减压下浓缩。残留物用SiO2柱色谱纯化以生成无色油状物的标题化合物(11.14g,78%),其光谱数据符合文献值。TLC:15%EtOAc/己烷,Rf~0.60;1H NMR(400MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),4.57(t,J=4.3Hz,1H),3.78-3.86(m,2H),3.65(t,J=6.3Hz,2H),3.32-3.54(m,2H),2.10-2.22(m,4H),1.24-1.84(m,18H),1.04(s,9H);13C NMR(100MHz)δ130.61,129.17,124.54,122.62,93.82,75.48,74.89,72.41,72.10,71.78,62.11,58.93,57.32,27.51,25.79,24.18,23.99,23.68,21.96,21.87,21.0,20.55,20.40,14.26,13.77,13.67。
12-(叔丁基二苯基甲硅烷氧基)十二碳-5-炔-1-醇。叔丁基二苯基-[12-(四氢-2H-吡喃-2-基氧基)十二碳-7-炔基氧基)]硅烷(11.0g,21.14mmol)和对甲苯磺酸(165mg)的MeOH(110mL)混合物在室温下搅拌10小时。反应混合物用饱和NaHCO3水溶液(10mL)淬灭。蒸发甲醇,然后蒸发更多的水(50mL),并且混合物用EtOAc(3×75mL)萃取。合并的有机萃取物用水(2×50mL)、盐水(40mL)洗涤,干燥并且减压浓缩。残留物用SiO2色谱纯化以生成所得无色油状物的标题化合物(7.93g,86%),其光谱数据符合文献值。1TLC:EtOAc/己烷(3:7),Rf~0.44;1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),3.62(t,J=6.3Hz,4H),2.06-2.22(m,4H),1.50-1.64(m,12H),1.04(s,9H);13C NMR(100MHz)δ135.81,134.36,129.74,127.82,80.89,80.01,64.14,62.71,32.71,32.10,29.34,28.86,27.11,25.59,25.57,19.46,18.93,18.77。
12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯-1-醇。氢气(1atm)下,NaBH4(82mg,2.28mmol)逐份加入到室温下剧烈搅拌的Ni(OAc)2·4H2O(567mg,2.28mmol)的无水(absolute)乙醇(20mL)溶液中。15分钟后,新鲜蒸馏的乙二胺(0.30mL,4.56mmol)加入到黑色悬浮液,再过15分钟后,加入12-(叔丁基二苯基甲硅烷氧基)十二碳-5-炔-1-醇(4.0g,9.16mmol)的无水EtOH(10mL)溶液。1小时后,反应混合物用Et2O(20mL)淬灭,并且通过小床硅胶。小床再用一份Et2O(5mL)清洗。减压下浓缩合并的醚(ethereal)滤液以生成无色油状物的标题化合物(3.85g,96%),所述化合物足够纯,可以直接用于下一步骤。TLC:EtOAc/己烷(3:7),Rf~0.46。1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),5.42-5.28(m,2H),3.65-3.60(t,J=6.4Hz,4H),2.08-1.96(m,4H),1.50-1.60(m,4H),1.40-1.24(m,10H),1.04(s,9H);13C NMR(100MHz)δ135.81,134.40,130.61,129.71,129.60,127.80,64.21,63.14,32.78,32.60,29.98,29.27,27.42,27.14,27.10,26.08,25.92,19.48。HRMS的计算值为C28H43O2Si[M+1]+439.3032,测定值为439.3027。
1-叔丁基二苯基甲硅烷氧基-12-叠氮基十二碳-7(Z)-烯。氩气下,偶氮二羧酸二异丙酯(DIAD;1.46mL,7.35mmol)逐滴加入到–20℃下PPh3(2.10g,8.0mmol)的干(dry)THF(45mL)溶液中。10分钟后,逐滴加入上述12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯-1-醇(3.20g,7.35mmol)的干THF(10mL)溶液。30分钟后,混合物加温到0℃,并且逐滴加入二苯基磷酰基叠氮化物(1.58mL,7.35mmol)。室温(rt)搅拌4小时后,反应混合物用水(150mL)淬灭,并用EtOAc(2×100mL)萃取。合并的有机萃取物用盐水(100mL)洗涤,(Na2SO4)干燥,并且减压下浓缩。所述残留物通过SiO2柱色谱纯化,用4%EtOAc/己烷洗脱以提供所述标题化合物(2.45g,72%)。TLC:EtOAc/己烷(1:9),Rf~0.55;1H NMR(400MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),5.28-5.42(m,2H),3.70(t,J=5.8Hz,2H),3.27(t,J=6.3Hz,2H),1.96-2.10(m,4H),1.24-1.64(m,12H),1.04(s,9H);13C NMR(100MHz)δ135.84,134.41,130.93,129.75,129.12,127.83,64.22,51.62,32.81,29.93,29.30,28.68,27.46,27.14,27.02,269025961949;IR(纯样)29302783233120971106cm-1。HRMS的计算值为C28H42N3OSi[M+1]+464.3097,测定值为464,3099。
1-叔丁基二苯基甲硅烷氧基-12-氨基十二碳-7(Z)-烯。三苯膦(1.18g,4.50mmol)加入到搅拌的、包含4滴去离子水的叠氮1-叔丁基二苯基甲硅烷氧基-12-叠氮基十二碳-7(Z)-烯(1.90g,4.10mmol)的THF(12mL)溶液中。12小时后,反应混合物用CH2Cl2(10mL)稀释,干燥,并真空浓缩以生成粘稠、无色油状物的标题化合物(1.36g,76%),所述化合物不需要进一步纯化,可以直接用于下一反应。TLC:MeOH/CH2Cl2(1:4),Rf~0.25;1H NMR(400MHz)δ7.62-7.68(m,4H),7.32-7.40(m,6H),5.30-5.40(m,2H),3.63(t,J=5.2Hz,2H),2.62(t,J=4.8Hz,2H),1.92-2.06(m,4H),1.40-1.58(m,4H),1.20-1.40(m,8H),1.03(s,9H);13C NMR(100MHz)δ135.79,134.37,130.42,129.70,127.78,64.19,42.28,33.44,32.77,29.93,29.28,27.40,27.21,27.10,25.92,19.44。HRMS的计算值为C28H44NOSi[M+1]+438.3192,测定值为438.3186。
1-(12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯基)-3-正戊基脲。1-叔丁基二苯基甲硅烷氧基-12-氨基十二碳-7(Z)-烯(1.32g,3.0mmol)的THF(5mL)溶液逐滴加入到搅拌的正戊基异氰酸酯(0.386mL,3.0mmol)的THF(10mL)溶液中。室温搅拌3小时后,减压除去挥发物,并且残留物通过SiO2柱色谱纯化,用20%EtOAc/己烷洗脱以提供粘性油状物的标题化合物(1.26g,76%)。TLC:EtOAc/己烷(2:3),Rf~0.40;1H NMR(300MHz)δ7.60-7.70(m,4H),7.35-7.42(m,6H),5.28-5.42(m,2H),5.16(br s,-NH,2H),3.65(t,J=6.5Hz,2H),3.08-3.20(m,4H),1.96-2.08(m,4H),1.22-1.60(m,18H),1.02(s,9H),0.89(t,J=7.3Hz,3H);13C NMR(100MHz)δ159.23,135.80,134.24,130.52,129.74,129.49,127.82,64.22,40.62,40.54,32.80,30.33,29.95,29.37,29.32,27.46,27.34,27.18,27.11,25.97,22.71,19.46,14.29。HRMS的计算值为C34H55N2O2Si[M+1]+551.4033,测定值为551.4032。
1-(12-羟基十二碳-5(Z)-烯基)-3-正戊基脲。1-(12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯基)-3-正戊基脲(1.12g,2.0mmol)和四正丁基氟化铵(2.20mL的1M THF溶液,2.2mmol)的混合物的干THF(10mL)在氩气下室温搅拌12小时,然后真空蒸发至干。残留物溶解在EtOAc(50mL)中,并用水(30mL)、盐水(30mL)洗涤,干燥,并且真空蒸发。残留物通过SiO2柱色谱纯化以生成无色固体的标题化合物(0.56g,89%),mp63.7-63.8℃。TLC:EtOAc/己烷(7:3),Rf~0.30;1H NMR(300MHz)δ5.25-5.42(m,2H),4.40-4.56(br s,-NH,2H),3.60-3.68(d,J=6.5Hz,2H),3.08-3.20(m,4H),1.96-2.14(m,4H),1.22-1.60(m,18H),0.88(t,J=7.0Hz,3H);13C NMR(125MHz)δ159.26,130.23,129.62,63.72,40.33,40.29,32.92,30.30,30.26,29.74,29.35,29.13,27.26,27.20,27.13,25.82,22.69,14.27。HRMS的计算值为C18H37N2O2[M+1]+313.2855,测定值为313.2857。
1-(12-溴十二碳-5(Z)-烯基)-3-正戊基脲。CBr4(0.55g,1.66mmol)和PPh3(0.43g,1.66mmol)加入到1-(12-羟基十二碳-5(Z)-烯基)-3-正戊基脲(0.43g,1.38mmol)的CH2Cl2(20mL)的0℃溶液中。室温下2小时后,反应混合物在真空下浓缩,并且残留物通过SiO2柱色谱纯化以生成粘性油状物的1-(12-溴十二碳-5(Z)-烯基)-3-正戊基脲(0.43g,83%),mp46.7-46.8℃。TLC:EtOAc/己烷(2:3),Rf~0.60;1H NMR(300MHz)δ5.22-5.42(m,2H),4.40(br s,2H),3.42(t,J=9.3Hz,2H),3.10-3.20(m,4H),1.98-2.10(m,4H),1.80-1.90(m,2H),1.25-1.55(m,16H),0.92(t,J=7.2Hz,3H);13CNMR(100MHz)δ159.51,130.14,129.69,40.48,40.39,34.20,32.96,30.34,29.67,29.36,28.58,28.25,27.31,27.27,27.17,22.68,14.26。HRMS的计算值为C18H36BrN2O[M+1]+375.2011,测定值为375.2014。
1-(12-氰基十二碳-5(Z)-烯基)-3-正戊基脲。氰化钾(0.23g,3.54mmol)和1-(12-溴十二碳-5(Z)-烯基)-3-正戊基脲(0.90g,2.40mmol)的混合物在室温下DMSO(5mL)中搅拌。12小时后,反应混合物用水(20mL)稀释,并用乙酸乙酯(2×50mL)萃取。合并的有机萃取物用水(2×25mL)、盐水(25mL)洗涤,(Na2SO4)干燥,并且通过硅胶柱以生成无色固体的标题化合物(0.62g,81%),mp56-57℃。TLC:EtOAc/己烷(2:3),Rf~0.45.1H NMR(300MHz)δ5.29-5.40(m,2H),4.27(br s,-NH,2H),3.10-3.20(m,4H),2.34(t,J=7.0Hz,2H),1.98-2.08(m,4H)1.24-1.70(m,18H),0.89(t,J=7.0Hz,3H);13C NMR(125MHz)δ159.41,129.94,129.86,120.14,40.45,40.35,30.30,29.50,29.33,28.70,28.51,27.26,27.16,25.47,22.66,17.28,14.24;IR(纯样)2930,2281,2184,2042,1936,1613,1197,1042cm-1。HRMS的计算值为C19H36N3O[M+1]+322.2858,测定值为322.2867。
N'-羟基-13-(3-正戊基脲基)十三碳-8(Z)-烯亚氨逐酰胺(imidamide)。向1-(12-氰基十二碳-5(Z)-烯基)-3-正戊基脲(350mg,1.09mmol)的MeOH/H2O(4:1;12mL)悬浮液中加入H2NOH·HCl(228mg,3.28mmol)和Na2CO3(344mg,3.25mmol)。反应混合物在60℃加热18小时,然后冷却到室温,并且真空除去所有挥发物。残留物用水(30mL)稀释,并萃取到乙酸乙酯中(2×25mL)。合并的有机萃取物用水(2×10mL)、盐水(10mL)洗涤,干燥,并且通过快速硅胶柱色谱、使用5%MeOH/CH2Cl2纯化以生成无色固体的标题化合物(239mg,62%),mp94.6-94.7℃。TLC:MeOH/CH2Cl2(1:4),Rf~0.20;1H NMR(CD3OD,300MHz)δ5.34-5.42(m,2H),3.33(s,2H),3.08-3.16(m,3H),2.02-2.10(m,6H),1.52-1.60(m,2H),1.44-1.52(m,5H),1.30-1.44(m,10H),0.92(t,J=7.2Hz,3H);13C NMR(CD3OD,125MHz)δ160.14,155.23,129.95,129.42,39.86,39.76,30.70,29.95,29.89,29.59,29.06,28.91,27.18,26.97,26.95,26.78,22.39,13.34。HRMS的计算值为C19H39N4O2[M+1]+355.3073,测定值为355.3078。
类似物25。向冰冷的N'-羟基-13-(3-正戊基脲基)十三碳-8(Z)-烯亚氨逐酰胺(imidamide)(100mg,0.28mmol)和吡啶(45μL,0.56mmol)的THF(100mL)溶液中逐滴加入亚硫酰氯(20μL,0.28mmol)的CH2Cl2(2mL)溶液。1小时后,反应混合物真空下浓缩,用水(25mL)稀释,并用CH2Cl2(2×10mL)萃取。合并的有机萃取物用水洗涤,并且干燥。所述溶剂真空下蒸发,并且残留物通过SiO2柱色谱使用10%MeOH/CH2Cl2纯化以生成粘性固体25(80mg,72%)。TLC:MeOH/CH2Cl2(1:9),Rf~0.60;1H NMR(CD3OD,300MHz)δ5.33-5.36(m,2H),3.04-3.13(m,4H),2.57(t,J=7.4Hz,2H),2.00-2.10(m,4H),1.62-1.74(m,2H),1.25-1.54(m,16H),0.92(t,J=7.2Hz,3H);13C NMR(CD3OD,125MHz)δ160.16,153.94,129.83,129.47,39.83,39.71,29.89,29.82,29.40,29.01,28.59,28.52,26.87,26.85,26.71,26.30,23.37,22.33,13.25。HRMS的计算值为C20H38N4O2S[M+1]+398.2716,测定值为398.2720。
合成类似物20。
类似物20。在密封管中剧烈搅拌下,1-(12-氰基十二碳-5(Z)-烯基)-3-正戊基脲(500mg,1.55mmol)、叠氮化钠(100mg,1.55mmol)和溴化锌(335mg,1.48mmol)的混合物在异丙醇/H2O(1:3,8mL)中加热到110℃。18小时后,混合物冷却到室温,并且使用水性HCl(3N,4mL)将pH调节到1。加入乙酸乙酯(10mL),持续搅拌直到没有固体存在。分离有机层,并且用EtOAc(2×25mL)萃取水层。合并的有机组分用水(3×25mL)洗涤,干燥并真空浓缩。所述残留物通过快速硅胶柱色谱纯化以生成无色固体的类似物20(431mg,76%),mp205.6-205.8℃。TLC:10%MeOH/CH2Cl2,Rf~0.30;1H NMR(CD3OD,300MHz)δ5.40-5.30(m,2H),3.06-3.11(m,4H),2.93(t,J=8.0Hz,2H),1.98-2.10(m,4H),1.70-1.82(m,2H),1.24-1.50(m,16H),0.90(t,J=7.6Hz,3H);13C NMR(CD3OD,75MHz)δ160.16,156.81,129.77,129.47,39.81,39.68,29.88,29.80,29.35,28.99,28.69,28.55,27.48,26.85,26.81,26.68,22.96,22.31,13.22。HRMS的计算值为C19H37N6O[M+1]+365.3029,测定值为365.3030。
合成类似物29。
类似物29。在室温下搅拌N'-羟基-13-(3-正戊基脲基)十三碳-8(Z)-烯亚氨逐酰胺(imidamide)(150mg0.42mmol)和1,1'-硫羰基二咪唑(90%;91mg,0.51mmol)混合物的THF(5mL)。45分钟后,混合物用水(10mL)稀释,并用乙酸乙酯(3×5mL)萃取。合并的萃取物用水洗涤,干燥并真空浓缩。残留物溶解在干THF(5mL)中,并且加入二乙醚合三氟化硼(boron trifluoride diethyl etherate)(103μL,0.84mmol)。再待1小时后,反应混合物用水(20mL)稀释,并用乙酸乙酯(2×10mL)萃取。合并的萃取物用水洗涤,(Na2SO4)干燥,并且真空蒸发溶剂。残留物通过柱色谱纯化以生成无色固体29(104mg,63%),mp124.2-125.1℃。TLC:MeOH/CH2Cl2(1:9),Rf~0.60;1H NMR(CD3OD,300MHz)δ5.30-5.40(m,2H),3.02-3.12(m,4H),2.54(t,J=8.0Hz,2H),1.98-2.10(m,4H),1.62-1.74(m,2H),1.24-1.52(m,16H),0.90(t,J=7.0Hz,3H);13C NMR(CD3OD,75MHz)δ181.12,160.13,159.12,129.48,128.84,39.85,39.73,30.90,29.91,29.83,29.41,29.03,28.69,28.65,26.89,26.86,26.73,26.23,22.35,13.29;IR(纯样)2924,1724,1603,1464,1375cm-1。HRMS的计算值为C20H37N4O2S[M+1]+397.2637,测定值为397.2638。
合成类似物28。
类似物28。N'-羟基-13-(3-正戊基脲基)十三碳-8(Z)-烯亚氨逐酰胺(imidamide)(150mg0.42mmol)和1,1'-硫羰基二咪唑(90%;91mg,0.51mmol)混合物的THF(5mL)在室温下搅拌45分钟。混合物用水(20mL)稀释,并用乙酸乙酯(3×10mL)萃取。合并的有机萃取物用水洗涤,干燥,并且真空蒸发溶剂。残留物在乙腈(5mL)中溶解,然后加入DBU(147mg,0.96mmol)。室温下搅拌1小时,混合物用水(10mL)稀释,用1N HCl调节pH~4,并且用乙酸乙酯(3×10mL)萃取。合并的萃取物用水洗涤,通过(Na2SO4)干燥,并且真空蒸发溶剂。所述残留物通过硅胶柱色谱纯化以生成无色糖浆28(101mg,61%)。TLC:MeOH/CH2Cl2(1:9),Rf~0.55;1H NMR(CD3OD,300MHz)δ5.30-5.40(m,2H),3.04-3.14(m,4H),2.62(t,J=7.7Hz,2H),2.00-2.10(m,4H),1.62-1.74(m,2H),1.22-1.54(m,16H),0.91(t,J=6.7Hz,3H);13C NMR(CD3OD,125MHz)δ188.49,161.91,160.15,129.82,129.53,39.88,39.75,29.92,29.85,29.37,29.05,28.63,28.55,26.90,26.86,26.75,25.91,23.67,22.37,13.31。HRMS的计算值为C20H37N4O2S[M+1]+397.2637,测定值为397.2645。
合成类似物11。
类似物11。1-(12-溴十二碳-5(Z)-烯基)-3-正戊基脲(300mg,0.79mmol)、亚硫酸钠(352mg,2.8mmol)和环己烯(649mg,7.9mmol)的乙醇(5mL)溶液回流过夜。减压除去挥发物,并且在去离子水中溶解残留物。加入伯乐(BioRad)SM-2Bio珠(5g;用0.1N NH4OH和H2O洗涤),温和搅拌30分钟,然后在烧结玻璃漏斗中收集所述珠。所述珠用去离子水(2×10mL)洗涤,然后用EtOH(3×10mL)洗涤。浓缩乙醇洗涤液以提供无色固体11(235mg,75%),mp133.6-133.8℃。1H NMR(CD3OD,300MHz)δ5.30-5.40(m,2H),3.02-3.14(m,4H),2.78(t,J=8.0Hz,2H),1.98-2.12(m,4H),1.72-1.84(m,2H),1.22-1.50(m,16H),0.91(t,J=7.0Hz,3H);13C NMR(CD3OD,75MHz)δ160.12,129.86,129.49,51.46,39.01,38.92,29.92,29.32,29.02,28.69,28.42,26.93,26.62,25.78,24.78,22.34,12.02。HRMS的计算值为C18H35N2NaO4S[M]+398.2215,测定值为398.2220。
合成类似物10。
(12-(3-正戊基脲基)十二碳-7(Z)-烯-1-基)膦酸二甲基酯。回流下加热1-(12-溴十二碳-5(Z)-烯基)-3-正戊基脲(250mg,0.67mmol)和三甲基亚磷酸酯(10mL)的THF(10mL)溶液。48小时后,真空除去所有挥发物,并且残留物通过硅胶柱色谱、使用60%EtOAc/CH2Cl2纯化以生成粘性油状物的(12-(3-正戊基脲基)十二碳-7(Z)-烯-1-基)膦酸二甲基酯(160mg,59%)。TLC:EtOAc,Rf~0.55;1H NMR(400MHz)δ5.30-5.40(m,2H),5.10(br s,-NH,1H),5.02(br s,-NH,1H),3.70(s,3H),3.68(s,3H),3.06-3.14(m,4H),1.97-2.20(m,4H),1.63-1.78(m,2H),1.20-1.60(m,18H),0.88(t,J=7.2Hz,3H);13C NMR(100MHz)δ159.11,130.17,129.93,52.59,52.56,40.49,30.49,30.32,30.28,29.34,29.33,28.58,27.21,27.15,27.11,25.32,23.93,22.66,22.35,22.30,14.24。HRMS的计算值为C20H42N2O4P[M+1]+405.2882,测定值为405.2883。
类似物10。溴化三甲基甲硅烷(37μL)加入到上述膦酸二酯(phosphonate diester)(100mg,0.25mmol)的干CHCl3(4mL)溶液中。室温下2小时后,浓缩溶液,并且残留物在乙酸乙酯(5mL)中悬浮。收集所得沉淀,并且在去离子水中溶解。加入伯乐(BioRad)SM-2Bio珠(5g;用0.1N NH4OH和H2O洗涤),温和搅拌1小时,然后在烧结玻璃漏斗中收集所述珠。所述珠用去离子水(2×10mL)洗涤,然后用EtOH(3×10mL)洗涤。浓缩乙醇洗涤液以提供膦酸二钠10(68mg,65%)。1H NMR(CD3OD,300MHz)δ5.30-5.42(m,2H),3.18-3.24(m,4H),1.97-2.20(m,4H),1.50-1.78(m,8H),1.20-1.60(m,12H),0.92(t,J=7.2Hz,3H);13C NMR(CD3OD,75MHz)δ159.48,130.10,129.25,40.85,40.76,30.48,30.25,29.38,29.13,29.06,28.81,28.67,27.62,26.92,26.70,26.64,25.80,22.65,22.58,22.25,13.02。HRMS的计算值为C18H35N2Na2O4P[M]+420.2130,测定值为420.2122。
合成类似物16。
类似物16。甲醇钠(180μL,30%甲醇)加入到1,2,4-三唑-3-硫醇(101mg,0.99mmol)的干DMF(5mL)溶液中。搅拌10分钟后,加入1-(12-溴十二碳-5(Z)-烯基)-3-正戊基脲(250mg,0.66mmol)。搅拌过夜后,反应混合物倒入冰水(100mL)中,并且所得沉底通过过滤收集,以及真空干燥。粗固体在二氯甲烷(100mL)中悬浮,搅拌1小时,并且过滤以生成无色固体16(222mg,85%),mp76.1-76.2℃。TLC:EtOAc,Rf~0.30;1H NMR(CD3OD,300MHz)δ8.26(br s,1H),5.29-5.40(m,2H),3.04-3.14(m,6H),1.98-2.10(m,4H),1.62-1.72(m,2H),1.22-1.50(m,16H),0.90(t,J=7.2Hz,3H);13C NMR(CD3OD,75MHz)δ160.15,157.16,146.90,129.86,129.44,39.84,39.73,32.10,29.91,29.84,29.65,29.49,29.02,28.60,28.30,26.88,26.73,22.34,13.28。HRMS的计算值为C20H38N5OS[M+1]+396.2797,测定值为396.2805。
合成类似物17。
类似物17。钼酸铵(160mg,0.13mmol)和过氧化氢(0.6mL,30%水溶液)在0℃混合,并且搅拌15分钟。所得的淡黄色溶液的等分样品(0.15mL)逐滴加入到搅拌的硫化物16(77mg,0.2mmol)的乙醇(1.0mL)的0℃溶液中,生成浅黄色沉淀。随后15分钟内,每隔5分钟加入氧化溶液的等分样品(0.15mL)。再过10分钟,反应混合物在H2O和二氯甲烷(10mL)之间分配。水相用二氯甲烷(10mL)萃取,并且合并的有机萃取物用盐水洗涤,并用(Na2SO4)干燥。残留物通过快速SiO2色谱(70%EtOAc/己烷)纯化以提供无色固体17(43mg,52%),mp88.2-88.4℃。TLC:MeOH/EtOAc(1:9),Rf~0.30;1H NMR(CD3OD,300MHz)δ8.38(br s,1H),5.26-5.36(m,2H),5.18(br s,2H),3.04-3.26(m,6H),1.92-2.08(m,2H),1.70-1.84(m,2H),1.20-1.50(m,18H),0.86(t,J=7.2Hz,3H);13C NMR(CD3OD,75MHz)δ163.82,160.15,146.98,129.73,129.54,52.62,39.81,39.71,29.90,29.84,29.25,29.01,28.57,28.22,26.88,26.77,26.73,22.33,21.92,13.24。HRMS的计算值为C20H38N5O2S[M+1]+412.2746,测定值为412.2741。
合成类似物18。
类似物18。钼酸铵(960mg,0.77mmol)和过氧化氢(3.6mL,30%水溶液)在0℃混合,并且搅拌15分钟。淡黄色溶液的等分样品(0.45mL)逐滴加入到硫化物16(154mg,0.39mmol)的乙醇(3.6mL)的0℃溶液中,生成浅黄色沉淀。随后90分钟内,每隔15分钟加入氧化溶液的等分样品(0.5mL)。再过15分钟,反应混合物在H2O和二氯甲烷(10mL)之间分配。水相用二氯甲烷(10mL)萃取,并且合并的有机相用盐水洗涤,并用(Na2SO4)干燥。残留物通过快速SiO2色谱(70%EtOAc/己烷)纯化以提供白色固体的砜(sulfone)18(129mg,78%),mp90.6-90.8℃。TLC:MeOH/EtOAc(1:9),Rf~0.50;1H NMR(CD3OD,300MHz)δ8.44(br s,1H),5.25-5.30(m,2H),5.02(br s,1H),4.90(br s,1H),3.35(t,J=7.9Hz,2H),3.22-3.10(m,4H),1.90-2.60(m,4H),1.66-1.80(m,2H),1.20-1.54(m,16H),0.87(t,J=7.3Hz,3H);13C NMR(CD3OD,75MHz)δ161.15,160.13,145.87,129.73,129.56,54.26,39.85,39.74,29.90,29.83,29.21,29.02,28.46,27.80,26.89,26.79,26.73,22.34,22.19,13.30。HRMS的计算值为C20H38N5O3S[M+1]+428.2695,测定值为428.2701。
合成类似物23。
类似物23。向N'-羟基-13-(3-正戊基脲基)十三碳-8(Z)-烯亚氨逐酰胺(imidamide)(50mg,0.14mmol)的干二噁烷(3mL)溶液中加入1,1-羰基二咪唑(CDI;27mg,0.16mmol),然后加入1,8-二氮杂双环十一碳-7-烯(DBU;23mg,0.15mmol)。搅拌15分钟后,反应混合物加温到110℃15分钟,然后回到室温。反应混合物用水(20mL)稀释,并用乙酸乙酯(3×5mL)萃取。合并的有机萃取物用水、盐水洗涤,用(Na2SO4)干燥,并且真空浓缩。所述残留物通过SiO2柱色谱纯化以生成粘性固体23(36mg,67%)。TLC:EtOAc/己烷(4:1),Rf~0.40;1H NMR(CD3OD,300MHz)δ5.30-5.40(m,2H),3.02-3.14(m,4H),2.52(t,J=7.7Hz,2H),2.00-2.10(m,4H),1.60-1.70(m,2H),1.24-1.50(m,16H),0.90(t,J=6.7Hz,3H);13C NMR(CD3OD,75MHz)δ158.30,157.33,126.98,126.68,37.02,36.90,26.97,26.53,26.19,25.76,25.72,24.02,23.89,22.68,21.84,19.52,10.43;IR(纯样)2929,2854,1809,1776,1738,1620,1580,1467,1257,981cm-1。HRMS(ESI-阴性(neg))的计算值为C20H35N4O3[M-1]-379.2715,测定值为379.2731。
合成类似物27。
N1-正丁基-N2-(12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯基)草酰胺(oxalamide)。2-(正丁基氨基)-2-草酰乙酸2(0.40g,2.70mmol)、上述1-叔丁基二苯基甲硅烷氧基-12-氨基十二碳-7(Z)-烯(1.20g,2.70mmol)、1-羟基苯并三唑(HOBt;0.44g,3.30mmol)和[1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐](0.63g,3.30mmol)混合物的干DMF(5mL)在室温下搅拌过夜。反应混合物用水(30mL)淬灭,并萃取到乙酸乙酯中(3×20mL)。合并的有机萃取物用水(2×10mL)、盐水(10mL)洗涤,干燥并且真空浓缩。残留物通过SiO2柱色谱纯化以生成N1-正丁基-N2-(12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯基)草酰胺(1.10g,73%)。TLC:EtOAc/己烷(2:3),Rf~0.55;1H NMR(400MHz)δ8.05(br s,-NH,2H),7.66-7.74(m,4H),7.32-7.42(m,6H),5.30-5.42(m,2H),3.67(t,J=3.9Hz,2H),3.31(q,J=5.2Hz,4H),1.96-2.10(m,4H),1.50-1.64(m,6H),1.22-1.44(m,10H),1.06(s,9H),0.92(t,J=7.8Hz,3H);13C NMR(100MHz)δ160.33,135.80,134.35,130.73,129.74,129.20,127.83,64.17,39.89,39.69,32.79,31.48,29.94,29.29,29.07,27.46,27.23,27.14,27.0,25.96,20.29,19.46,13.96。HRMS的计算值为C34H53N2O3Si[M+1]+565.3826,测定值为565.3824。
N1-正丁基-N2-(12-羟基十二碳-5(Z)-烯基)草酰胺(oxalamide)。将N1-正丁基-N2-(12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯基)草酰胺(1.20g,2.12mmol)如上述去甲硅烷化(de-silylate)以生成无色固体N1-正丁基-N2-(12-羟基十二碳-5(Z)-烯基)草酰胺(0.568g,82%),mp102.8-102.9℃。TLC:EtOAc/己烷(7:3),Rf~0.55;1HNMR(400MHz)δ7.69(br s,2H),5.20-5.35(m,2H),3.56(t,J=4.2Hz,2H),3.26(q,J=5.6Hz,4H),2.17(br s,–OH),1.95-2.02(m,4H),1.44-1.56(m,6H),1.20-1.40(m,10H),0.87(t,J=7.2Hz,3H);13C NMR(100MHz)δ160.15,130.66,129.21,62.98,39.80,39.63,32.93,31.39,29.77,29.18,28.95,27.26,27.0,26.88,25.80,20.18,13.85。HRMS的计算值为C18H35N2O3[M+1]+327.2648,测定值为327.2648。
N1-(12-溴十二碳-5(Z)-烯基)-N2-正丁基草酰胺。将上述N1-正丁基-N2-(12-羟基十二碳-5(Z)-烯基)草酰胺(330mg,1.0mmol)溴化以生成白色固体N1-(12-溴十二碳-5(Z)-烯基)-N2-正丁基草酰胺(330mg,84%),mp46.0-46.3℃。TLC:EtOAc/己烷(3:2),Rf~0.55;1H NMR(400MHz)δ7.79(br s,-NH,1H),7.77(br s,-NH,1H),5.20-5.32(m,2H),3.32(t,J=6.4Hz,2H),3.22(q,J=7.2Hz,4H),1.90-2.00(m,4H),1.72-1.82(m,2H),1.42-1.56(m,4H),1.20-1.40(m,10H),0.85(t,J=7.3Hz,3H);13C NMR(100MHz)δ160.17,160.15,130.40,129.34,39.77,39.59,34.12,32.93,31.40,29.62,29.0,28.54,27.25,27.24,27.0,26.91,20.18,13.85。HRMS的计算值为C18H34BrN2O2[M+1]+389.1804,测定值为389.1809。
N1-正丁基-N2-(12-氰基十二碳-5(Z)-烯基)草酰胺。用上述氰化钾处理N1-(12-溴十二碳-5(Z)-烯基)-N2-正丁基草酰胺(250mg,0.642mmol)以生成无色固体N1-正丁基-N2-(12-氰基十二碳-5(Z)-烯基)草酰胺(168mg,78%),mp83.0-83.3℃。TLC:EtOAc/己烷(3:2),Rf~035;1H NMR(400MHz)δ7.45(br s,-NH,2H),5.30-5.40(m,2H),3.34(q,J=8.6Hz,4H),2.32(t,J=7.6Hz,2H),1.98-2.08(m,4H),1.30-1.68(m,16H),0.92(t,J=7.2Hz,3H);13C NMR(100MHz)δ160.03(2C),130.03,129.08,120.10,39.88,39.42,31.22,29.40,28.82,28.60,28.42,27.07,27.06,26.82,25.54,20.06,17.01,13.80。HRMS的计算值为C19H34N3O2[M+1]+336.2651,测定值为336.2650。
N1-(13-氨基-13-(羟基亚氨基)十三碳-5(Z)-烯基)-N2-正丁基草酰胺。上述步骤之后,N1-正丁基-N2-(12-氰基十二碳-5(Z)-烯基)草酰胺、H2NOH·HCl和Na2CO3的混合物转化成无色固体N1-(13-氨基-13-(羟基亚氨基)十三碳-5(Z)-烯基)-N2-正丁基草酰胺(102mg,62%),116.3-116.4℃。TLC:MeOH/CH2Cl2(1:4),Rf~0.20;1H NMR(CD3OD,400MHz)δ5.28-5.40(m,2H),3.24(t,J=6.4Hz,4H),1.98-2.00(m,6H),1.50-1.60(m,6H),1.26-1.40(m,10H),0.92(t,J=7.3Hz,3H);13C NMR(CD3OD,100MHz)δ160.55(2C),156.31,130.05,129.18,39.23,39.09,31.18,30.63,29.51,28.83,28.69,27.10,26.87,26.59,19.88,12.88。HRMS的计算值为C19H37N4O3[M+1]+369.2866,测定值为369.2864。
类似物27。用1,1'-硫羰基二咪唑处理N1-(13-氨基-13-(羟基亚氨基)十三碳-5(Z)-烯基)-N2-正丁基草酰胺(100mg,0.27mmol)以生成白色固体27(71mg,63%),mp110.6-110.8℃。TLC:MeOH/CH2Cl2(1:9),Rf~0.55;1H NMR(400MHz)δ8.90(br s,NH,1H),7.52(br s,NH,2H),5.28-5.40(m,2H),3.20-3.40(m,4H),2.59(t,J=7.5Hz,2H),1.98-2.10(m,4H),1.21-1.70(m,16H),0.92(t,J=7.3Hz,3H);13C NMR(100MHz)δ160.12,160.08,153.31,130.62,129.46,39.93,39.85,31.35,29.33,28.94,28.89,28.68,27.02,26.84,26.69,23.96,20.23,13.90。HRMS的计算值为C19H35N4O4S[M+1]+415.2379,测定值为415.2372。
合成类似物21。
类似物21。用于制备22的步骤之后,N1-正丁基-N2-(12-氰基十二碳-5(Z)-烯基)草酰胺(30mg,0.10mmol)、叠氮化钠(11mg,0.20mmol)和溴化锌(40mg,0.20mmol)的混合物在异丙醇/甲醇/H2O(1:1:3,4mL)中加热以生成无色固体的四唑21(25mg,74%),mp113-114℃。TLC:10%MeOH/CH2Cl2,Rf~0.26;1H NMR(CD3OD,400MHz)δ5.40-5.35(m,2H),3.26(t,J=7.0Hz,4H),2.44(t,J=7.0Hz,2H),2.05-2.15(m,4H),1.65-1.60(m,6H),1.40-1.30(m,10H),0.94(t,J=7.3Hz,3H);13C NMR(CD3OD,100MHz)δ160.12,160.05,156.80,130.35,129.50,39.20,39.08,31.15,29.33,28.66,28.65,28.53,27.38,26.83,26.79,26.55,22.86,19.85,12.84。HRMS的计算值为C19H35N6O2[M+1]+379.2822,测定值为379.2814。
合成类似物26。
1-叔丁基二苯基甲硅烷氧基-12-碘十二碳-7(Z)-烯。氩气下,三苯膦(504mg,1.14mmol)和咪唑(156mg,2.30mmol)加入到上面12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯-1-醇(500mg,1.14mmol)的干THF(25mL)的0℃溶液中。10分钟后,逐份加入固体碘(252mg,1.2当量(equiv))。室温下搅拌3小时,反应混合物用饱和亚硫酸氢钠水溶液(10mL)猝灭。再过1小时后,溶液用水(2×30mL)洗涤,并且减压下浓缩。残留物通过快速SiO2柱色谱使用10%EtOAc/己烷作为洗脱液纯化,以生成无色油状物的标题化合物(474mg,76%)。TLC:20%EtOAc/己烷,Rf~0.65;1H NMR(300MHz)δ7.65-7.70(m,4H),7.35-7.45(m,6H),5.30-5.40(m,2H),3.64(t,J=6.4Hz,2H),3.18(t,J=5.5Hz,2H),1.95-2.10(m,4H),1.85-1.90(m,2H),1.22-1.50(m,10H),1.20(s,9H);13C NMR(75MHz)δ135.87,130.42,130.22,130.20,129.95,127.89,64.15,38.35,36.20,32.50,29.90,28.62,28.32,27.25,27.20,27.18,26.22,19.12。HRMS的计算值为C28H42IOSi[M+1]+549.2050,测定值为549.2044。
1-(叔丁基二苯基甲硅烷氧基-12-N-异丙基氨基-十二碳-7(Z)-烯。异丙胺(464μL,5.45mmol)和K2CO3(373mg,2.73mmol)顺序加入到1-(叔丁基二苯基甲硅烷氧基-12-碘十二碳-7(Z)-烯(500mg,0.91mmol)的干四氢呋喃(8mL)的室温溶液中。混合物在密封管中90℃加热12小时,然后冷却到室温,用水(5mL)稀释,过滤,并且滤液用乙酸乙酯(3×10mL)萃取。合并的有机萃取物干燥,减压浓缩,并且残留物通过SiO2柱色谱使用2%-5%梯度的MeOH/CH2Cl2作为洗脱液纯化以生成无色油状物的标题胺(335mg,77%)。TLC:5%MeOH/CH2Cl2,Rf~0.3;1H NMR(300MHz)δ7.62-7.70(m,4H),7.34-7.44(m,6H),5.30-5.40(m,2H),3.64(t,J=6.4Hz,2H),2.72-2.84(m,1H),2.58(t,J=7.0Hz,2H),1.94-2.08(m,4H),1.20-1.60(m,12H),1.05(d,J=7.2Hz,6H),1.04(s,9H);13C NMR(75MHz)δ135.81,134.40,132.0,129.72,127.81,64.21,48.96,47.75,32.80,30.33,29.97,29.31,27.85,27.44,27.33,27.11,25.95,23.27,19.46。HRMS的计算值为C31H50NOSi[M+1]+480.3662,测定值为480.3666。
N-(12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯基)-N-异丙基正庚烷酰胺。固体[1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐](EDCI;131mg,0.69mmol)逐份加入到1-(叔丁基二苯基甲硅烷氧基-12-N-异丙基氨基-十二碳-7(Z)-烯(300mg,0.63mmol)、DMAP(84mg,0.69mmol)、N-羟基苯并三唑(HOBt;93mg,0.69mmol)和正庚酸(90mg,0.68mmol)的干DMF(5mL)的室温溶液中。待12小时后,反应混合物用水(10mL)稀释,并用醚(3×5mL)萃取。合并的醚(ethereal)萃取物用盐水洗涤、干燥、并且真空蒸发。残留物通过SiO2柱色谱纯化以生成无色油状物的标题化合物(281mg,76%)。TLC:EtOAc/己烷(1:4),Rf~0.65;1H NMR(300MHz,1:1旋转异构体(rotamer)的混合物)δ7.62-7.70(m,4H),7.34-7.44(m,6H),5.30-5.40(m,2H),4.60-4.70和4.00-4.05(m,对两种旋转异构体是1H),3.05(t,J=5.2Hz,2H),3.02-3.19(m,2H),2.20-2.40(m,2H),1.95-2.10(m,4H),1.20-1.60(m,20H),1.18和1.08(d,J=7.0Hz,对两种旋转异构体是6H),1.02(s,9H),0.88(t,J=7.2Hz,3H);13C NMR(75MHz)δ177.24,173.35,172.25,136.16,135.80,135.14,134.37,134.34,130.97,130.31,129.74,129.73,129.54,129.04,127.82,127.75,64.21,64.18,48.42,45.68,43.62,41.19,34.46,34.02,32.81,32.79,31.95,31.94,31.75,31.28,30.0,29.92,29.55,29.46,29.31,29.09,27.87,27.52,27.49,27.45,27.21,27.13,26.94,26.88,25.97,25.95,25.79,25.15,22.81,22.75,21.63,20.77,19.46,19.33,14.34,14.30。HRMS的计算值为C38H62NO2Si[M+1]+592.4550,测定值为592.4552。
N-(12-羟基十二碳-5(Z)-烯基)-N-异丙基正庚烷酰胺。上述去甲硅烷化步骤之后,N-(12-(叔丁基二苯基甲硅烷氧基)十二碳-5(Z)-烯基)-N-异丙基正庚烷酰胺(275mg,0.464mmol)转化成糖浆状的标题醇(155mg,94%)。TLC:40%EtOAc/己烷,Rf~0.45;1H NMR(300MHz,旋转异构体的混合物45/55)δ5.30-5.46(m,2H),4.62-4.72和4.00-4.08(m,对两种旋转异构体是1H),3.63(t,J=5.4Hz,2H),3.06-3.14(m,2H),2.22-2.36(m,2H),1.98-2.10(m,4H),1.24-1.70(m,20H),1.17和1.10(d,J=6.8Hz,对两种旋转异构体是6H),0.88(t,J=7.2Hz,3H);13C NMR(75MHz)δ173.23,172.67,130.83,130.12,129.71,128.96,62.69,62.64,48.34,45.56,43.52,41.07,34.0,33.91,32.91,32.88,31.84,31.81,31.18,29.82,29.74,29.46,29.33,29.11,27.78,27.37,27.35,27.16,27.13,26.84,25.89,25.81,25.66,22.69,21.51,20.65,14.21。HRMS的计算值为C22H44NO2[M+1]+354.3372,测定值为354.3380。
N-(12-溴十二碳-5(Z)-烯基)-N-异丙基正己烷酰胺。上述步骤之后,将N-(12-羟基十二碳-5(Z)-烯基)-N-异丙基正庚烷酰胺(150mg,0.43mmol)如上述转化成糖浆状的对应的溴化铵(144mg,82%)。TLC:30%EtOAc/己烷,Rf~0.65;1H NMR(300MHz,旋转异构体比率45/55)δ5.30-5.42(m,2H),4.60-4.70和4.00-4.10(m,对两种旋转异构体是1H),3.42(t,J=5.3Hz,2H),3.02-3.20(m,2H),2.20-2.38(m,2H),1.80-2.10(m,4H),1.20-1.70(m,20H),1.16和1.12(d,J=7.2Hz,对两种旋转异构体是6H),0.87(t,J=7.2Hz,3H);13C NMR(75MHz)δ173.20,172.64,130.61,130.46,129.96,129.94,129.24,48.34,45.56,43.54,41.09,34.20,34.16,34.05,33.97,32.98,32.93,32.60,31.90,31.88,31.26,29.78,29.68,29.62,29.51,29.40,28.94,28.55,28.25,28.20,27.81,27.69,27.45,27.30,27.25,27.18,26.92,25.87,25.20,22.75,21.59,20.72,14.72。HRMS的计算值为C22H43BrNO[M+1]+416.2528,测定值为416.2523。
N-(12-氰基十二碳-5(Z)-烯基)-N-异丙基正己烷酰胺。上述氰化物置换步骤之后,N-(12-溴十二碳-5(Z)-烯基)-N-异丙基正己烷酰胺(500mg,1.20mmol)转化成糖浆状的标题腈(339mg,78%)。TLC:EtOAc/己烷(3:7),Rf~0.40;1H NMR(500MHz,旋转异构体比率45/55)δ5.20-5.34(m,2H),4.52-4.62和3.90-4.02(m,对两种旋转异构体是1H),3.00-3.10(m,2H),2.16-2.30(m,4H),1.90-2.05(m,4H),1.60-1.70(m,8H),1.22-1.50(m,12H),1.18和1.11,(d,J=6.8Hz,对两种旋转异构体是6H),0.88(t,J=7.2Hz,3H);13C NMR(75MHz)δ173.22,172.66,130.42,130.04,129.78,129.35,120.04,119.99,48.34,45.58,43.54,41.07,34.02,33.95,31.89,31.86,31.22,29.53,29.49,29.37,28.73,28.70,28.57,28.53,27.78,27.39,27.26,27.18,27.17,26.91,25.85,25.70,25.52,25.49,22.73,21.56,20.70,17.26,14.27。HRMS的计算值为C23H43N2O[M+1]+363.3375,测定值为363.3375。
N-(13-氨基-13-(羟基亚氨基)十三碳-5(Z)-烯基)-N-异丙基正庚烷酰胺。上述步骤之后,N-(12-氰基十二碳-5(Z)-烯基)-N-异丙基正己烷酰胺、H2NOH·HCl和Na2CO3混合物转化成标题化合物(64%)。TLC:MeOH/CH2Cl2(3:7),Rf~0.30;1H NMR(500MHz,旋转异构体比率1:1)δ5.24-5.40(m,2H),4.62-4.68(m,0.5H),4.50-4.60(-NH,2H),3.96-4.40(m,0.5H),3.02-3.14(m,2H),2.18-2.28(m,2H),1.90-2.16(m,6H),1.46-1.64(m,8H),1.20-1.36(m,12H),1.15和1.08(d,J=7.3Hz,对两种旋转异构体是6H),0.85(t,J=7.2Hz,3H);13C NMR(75MHz)δ173.22,172.58,154.26,154.21,130.82,130.13,129.79,129.08,48.32,45.50,43.52,41.09,36.03,34.05,33.97,31.89,31.86,31.459,31.25,29.72,29.67,29.53,29.39,29.21,29.19,29.11,29.03,27.83,27.41,27.24,27.17,26.90,26.84,25.87,25.70,22.74,21.58,20.73,14.26。HRMS的计算值为C23H46N3O2[M+1]+396.3590,测定值为396.3698。
类似物26。如上述,在0℃用亚硫酰氯处理N-(13-氨基-13-(羟基亚氨基)十三碳-5(Z)-烯基)-N-异丙基正庚烷酰胺(150mg,0.38mmol)以生成糖浆26(133mg,68%)。TLC:EtOAc/己烷(1:1),Rf~0.30;1H NMR(400MHz,旋转异构体比率35/65)δ5.22-5.40(m,2H),4.48-4.70和4.00-4.12(m,对两种旋转异构体是1H),3.04-3.20(m,2H),2.50和2.64(t,J=6.9Hz,对两种旋转异构体是2H),2.22,2.38(t,J=8.0Hz,对两种旋转异构体是2H),1.90-2.10(m,4H),1.50-1.78(m,8H),1.20-1.40(m,12H),1.22和1.12(d,J=6.7Hz对两种旋转异构体是6H),0.88(t,J=7.2Hz,3H);13CNMR(100MHz)δ173.82,173.40,153.39,153.26,131.03,130.02,129.97,129.10,48.85,46.04,43.82,41.50,34.13,34.02,31.85,31.80,31.23,29.58,29.32,29.11,29.09,29.02,28.80,28.17,27.96,27.32,27.24,27.19,26.03,26.75,26.64,26.10,24.02,29.96,22.75,21.56,21.53,20.74,20.72,14.27,14.25。HRMS的计算值为C24H44N3O3S[M+1]+442.3103,测定值为442.3106。
合成类似物19。
类似物19。用上述叠氮化钠处理N-(12-氰基十二碳-5(Z)-烯基)-N-异丙基正己烷酰胺(350mg,0.97mmol)以生成粘性固体的四唑19(250mg,64%)。TLC:EtOAc,Rf~0.40;1H NMR(300MHz,旋转异构体比率35/65)δ5.22-5.40(m,2H),4.58-4.68和4.02-4.18(m,对两种旋转异构体是1H),3.10-3.24(m,2H),2.98(t,J=7.6Hz,2H),2.44和2.30(t,J=7.3Hz,对两种旋转异构体是2H),1.94-2.10(m,4H),1.72-1.84(m,2H),1.50-1.70(m,4H),1.18-1.40(m,14H),1.21和1.10(d,J=7.2Hz,对两种旋转异构体是6H),0.82-0.87(m,3H);13C NMR(75MHz)δ174.06,173.80,130.85,130.04,129.79,129.08,48.94,46.32,43.97,41.55,34.11,34.05,31.79,31.72,31.12,29.61,29.61,29.51,29.25,29.05,28.85,28.22,27.98,27.89,27.32,27.19,26.92,25.97,23.70,22.67,21.51,20.67,14.02。HRMS的计算值为C23H44N5O[M+1]+406.3546,测定值为406.3547。
合成类似物22。
1-叔丁基二苯基甲硅烷氧基-13-(四氢-2H-吡喃-2-基氧基)十三碳-8-炔。在用于合成类似物25的步骤之后,将2-(己-5-炔基氧基)四氢-2H-吡喃1(5.0g,27.40mmol)与1-叔丁基二苯基甲硅烷氧基-7-溴庚烷(11.90g,27.40mmol)偶联以生成无色糖浆1-叔丁基二苯基甲硅烷氧基-13-(四氢-2H-吡喃-2-基氧基)十三碳-8-炔3(10.50g,72%),其光谱数据与文献值匹配。3TLC:EtOAc/己烷(1:4),Rf~0.60;1H NMR(400MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),4.57(t,J=4.3Hz,1H),3.78-3.86(m,2H),3.65(t,J=6.3Hz,2H),3.32-3.54(m,2H),2.10-2.22(m,4H),1.24-1.84(m,20H),1.04(s,9H);13CNMR(100MHz)δ135.80,134.38,129.72,127.81,99.0,80.72,80.10,67.30,64.17,62.49,32.77,30.99,29.34,29.18,29.13,29.0,27.11,26.19,25.91,25.74,19.87,19.45,19.0,18.86。
13-(叔丁基二苯基甲硅烷氧基)十三碳-5-炔-1-醇。在用于合成类似物25的步骤之后,1-叔丁基二苯基甲硅烷氧基-13-(四氢-2H-吡喃-2-基氧基)十三碳-8-炔(10.0g,18.70mmol)用PPTS去保护以生成无色糖浆13-(叔丁基二苯基甲硅烷氧基)十三碳-5-炔-1-醇(7.70g,91%)。TLC:EtOAc/己烷(3:7),Rf~0.43;1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),3.62(t,J=5.6Hz,4H),2.06-2.22(m,4H),1.50-1.64(m,14H),1.04(s,9H);13C NMR(100MHz)δ135.82,134.37,129.76,127.85,80.93,80.04,64.21,62.63,32.77,32.09,29.33,29.13,29.10,27.14,25.92,25.63,19.47,19.0,18.81。HRMS的计算值为C29H43O2Si[M+1]+451.3032,测定值为451.3032。
(Z)-13-(叔丁基二苯基甲硅烷氧基)十三碳-5-烯-1-醇。在用于合成类似物25的步骤之后,将13-(叔丁基二苯基甲硅烷氧基)十三碳-5-炔-1-醇(7.50g,16.60mmol)进行半氢化反应(semi-hydrogenation)以生成糖浆13-(叔丁基二苯基甲硅烷氧基)十三碳-5(Z)-炔-1-醇(6.90g,92%),其光谱值与文献数据匹配。2TLC:EtOAc/己烷(3:7),Rf~0.45;1H NMR(400MHz)δ7.64-7.68(m,4H),7.42-7.34(m,6H),5.28-5.42(m,2H),3.68-3.67(t,J=6.4Hz,4H),1.98-2.12(m,4H),1.50-1.60(m,4H),1.40-1.24(m,10H),1.04(s,9H);13C NMR(100MHz)δ135.83,134.40,130.61,129.74,129.60,127.83,64.21,63.08,32.83,32.60,29.94,29.54,27.50,27.18,27.14,26.12,26.01,19.48。
1-叔丁基二苯基甲硅烷氧基-13-叠氮基十三碳-8(Z)-烯。在用于合成类似物25的步骤之后,13-(叔丁基二苯基甲硅烷氧基)十三碳-5(Z)-烯-1-醇(7.0g,15.48mmol)转化成所得的糖浆1-叔丁基二苯基甲硅烷氧基-13-叠氮基十三碳-8(Z)-烯(5.30g,72%)。TLC:EtOAc/己烷(1:9),Rf~0.55;1H NMR(400MHz)δ7.68-7.64(m,4H),7.42-7.34(m,6H),5.28-5.42(m,2H),3.64(t,J=6.4Hz,2H),3.26(t,J=5.6Hz,2H),1.96-2.10(m,4H),1.64-1.24(m,14H),1.04(s,9H);13C NMR(100MHz)δ135.86,134.44,131.0,129.77,129.12,127.85,64.27,51.63,32.87,29.95,29.56,28.70,27.54,27.17,27.05,26.93,26.05,19.51.IR(纯样)2930,2783,2361,2331,2094,1109cm-1。HRMS的计算值为C29H44N3OSi[M+1]+478.3254,测定值为478.3250。
1-叔丁基二苯基甲硅烷氧基-13-氨基十三碳-8(Z)-烯。在用于合成类似物25的步骤之后,用三苯膦还原1-叔丁基二苯基甲硅烷氧基-13-叠氮基十三碳-8(Z)-烯(3.50g,7.32mmol)以生成无色油状物1-叔丁基二苯基甲硅烷氧基-13-氨基十三碳-8(Z)-烯(2.44g,74%)。TLC:MeOH/CH2Cl2(1:4),Rf~0.25;1H NMR(400MHz)δ7.62-7.68(m,4H),7.32-7.40(m,6H),5.30-5.40(m,2H),3.63(t,J=5.2Hz,2H),2.62(br s,2H),1.92-2.06(m,4H),1.40-1.58(m,4H),1.20-1.40(m,10H),1.03(s,9H);13C NMR(100MHz)δ135.79,134.39,130.46,129.70,127.78,64.22,42.02,32.80,29.92,29.52,27.46,27.23,27.10,25.98,19.44。HRMS的计算值为C29H46NOSi[M+1]+452.3349,测定值为452.3357。
1-(13-(叔丁基二苯基甲硅烷氧基)十三碳-5(Z)-烯基)-3-正戊基脲。在用于合成类似物25的步骤之后,将1-叔丁基二苯基甲硅烷氧基-13-氨基十三碳-8(Z)-烯(2.35g,5.20mmol)与异氰酸正戊基酯反应以生成糖浆1-(13-(叔丁基二苯基甲硅烷氧基)十三碳-5(Z)-烯基)-3-正戊基脲(2.23g,76%)。TLC:EtOAc/己烷(1:4),Rf~0.65;1HNMR(500MHz)δ7.62-7.70(m,4H),7.32-7.44(m,6H),5.28-5.44(m,2H),4.37(br s,2H),3.66(t,J=4.2Hz,2H),3.08-3.20(m,4H),1.98-2.08(m,4H),1.20-1.60(m,20H),1.05(s,9H),0.90(t,J=7.2Hz,3H);13C NMR(125MHz)δ159.22,135.80,134.12,130.24,129.88,129.76,127.81,64.21,40.62,40.54,32.82,30.31,29.95,29.56,29.39,27.51,27.35,27.20,27.13,26.01,22.72,19.43,14.30。HRMS的计算值为C35H57N2O2Si[M+1]+565.4189,测定值为565.4186。
1-(13-羟基十三碳-5(Z)-烯基)-3-正戊基脲。在用于合成类似物25的步骤之后,使用TBAF将1-(13-(叔丁基二苯基甲硅烷氧基)十三碳-5(Z)-烯基)-3-正戊基脲(2.30g,4.07mmol)去甲硅烷化以生成白色固体1-(13-羟基十三碳-5(Z)-烯基)-3-正戊基脲(1.22g,92%),mp63.1-63.3℃。TLC:EtOAc/己烷(7:3),Rf~0.55;1H NMR(400MHz)δ5.24-5.38(m,2H),4.74(br s,-NH,2H),3.62(t,J=5.6Hz,2H),3.06-3.18(m,4H),1.98-2.06(m,4H),1.20-1.60(m,20H),0.86(t,J=7.3Hz,3H);13C NMR(100MHz)δ159.31,130.38,129.63,62.90,40.51,40.46,32.93,30.30,30.29,29.79,29.41,29.34,29.23,27.30,27.24,27.15,25.98,22.67,14.25。HRMS的计算值为C19H39N2O2[M+1]+327.3012,测定值为327.3011。
1-(13-溴十三碳-5(Z)-烯基)-3-正戊基脲。在用于合成类似物25的步骤之后,1-(13-羟基十三碳-5(Z)-烯基)-3-正戊基脲(1.20g,3.68mmol)转化成所得粘性固体1-(13-溴十三碳-5(Z)-烯基)-3-正戊基脲(1.17g,82%)。TLC:EtOAc/己烷(2:3),Rf~0.60;1HNMR(500MHz)δ5.28-5.40(m,2H),4.71(br s,-NH,2H),3.40(t,J=4.2Hz,2H),3.10-3.20(m,4H),1.98-2.06(m,4H),1.82-1.88(m,2H),1.26-1.50(m,18H),0.87(t,J=7.2Hz,3H);13C NMR(125MHz)δ159.38,130.34,129.59,40.55,40.46,34.29,33.02,30.34,29.81,29.38,29.30,28.89,28.35,27.39,27.33,27.18,22.71,14.29。HRMS的计算值为C19H37BrN2O[M]+388.2089,测定值为388.2090。
1-(13-氰基十三碳-5(Z)-烯基)-3-正戊基脲。如上述合成类似物25,将1-(13-溴十三碳-5(Z)-烯基)-3-正戊基脲(1.10g,2.82mmol)与氰化钾反应以生成无色固体1-(13-氰基十三碳-5(Z)-烯基)-3-正戊基脲(0.69g,73%),mp44.3-44.4℃。TLC:EtOAc/己烷(1:1),Rf~0.32;1H NMR(500MHz)δ5.30-5.42(m,2H),4.35(br s,2H),3.04-3.20(m,4H),2.34(t,J=7.6Hz,2H),1.98-2.10(m,4H),1.60-1.72(m,2H),1.24-1.56(m,18H),0.89(t,J=7.2Hz,3H);13C NMR(125MHz)δ159.24,130.23,129.68,120.02,40.24,40.13,30.27,29.69,29.32,29.07,28.82,28.78,27.29,27.26,27.13,25.49,22.64,17.30,14.24。HRMS的计算值为C20H38N3O[M+1]+336.3015,测定值为336.3019。
1-(13-(1H-四唑-5-基)十三碳-5(Z)-烯基)-3-正戊基脲(22)。在上述用于合成类似物20的步骤之后,1-(13-氰基十三碳-5(Z)-烯基)-3-正戊基脲、叠氮化钠和溴化锌的混合物加热到110℃以生成无色固体的类似物22(66%),mp86.0-86.2℃。TLC:MeOH/CH2Cl2(1:9),Rf~0.30;1H NMR(CD3OD,300MHz)δ5.30-5.40(m,2H),3.06-3.11(m,4H),2.93(t,J=8.0Hz,2H),1.98-2.10(m,4H),1.70-1.82(m,2H),1.24-1.50(m,18H),0.90(t,J=7.6Hz,3H);13C NMR(CD3OD,100MHz)δ160.15,156.21,129.89,129.39,39.84,39.71,29.89,29.82,29.53,29.01,29.00,28.81,27.45,26.90,26.70,22.89,22.33,13.25。HRMS的计算值为C20H38N6O[M]+378.3107,测定值为378.3111。
合成类似物13。
1-(叔丁基二苯基甲硅烷氧基)-11-(四氢-2H-吡喃-2-基氧基)十一碳-6-炔。在用于合成类似物25的步骤之后,用n-BuLi和1-(叔丁基二苯基甲硅烷氧基-5-溴戊烷4处理2-(己-5-炔基氧基)四氢-2H-吡喃1以生成无色液体的标题化合物(73%)。TLC:EtOAc/己烷(1:4),Rf~0.60;1H NMR(400MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),4.57(t,J=4.3Hz,1H),3.78-3.86(m,2H),3.65(t,J=6.3Hz,2H),3.32-3.54(m,2H),2.10-2.22(m,4H),1.24-1.84(m,16H),1.04(s,9H);13C NMR(125MHz)δ135.80,134.32,129.74,127.84,99.01,80.54,80.16,67.30,64.02,62.50,32.34,30.98,29.18,29.12,27.32,27.10,26.17,25.73,25.32,19.87,18.99,18.86。HRMS的计算值为C31H45O3Si[M+1]+493.3138,测定值为493.3144。
11-(叔丁基二苯基甲硅烷氧基)十一碳-5-炔-1-醇。在报导的制备类似物25的步骤之后,用催化量的PPTS切割1-(叔丁基二苯基甲硅烷氧基)-11-(四氢-2H-吡喃-2-基氧基)十一碳-6-炔以生成无色液体的标题化合物(72%)。TLC:EtOAc/己烷(3:7),Rf~0.43;1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),3.62(t,J=5.6Hz,4H),2.06-2.22(m,4H),1.64-1.50(m,10H),1.04(s,9H);13C NMR(100MHz)δ135.82,134.33,129.77,127.84,80.77,80.11,64.06,62.69,32.35,32.10,29.10,27.12,25.60,25.33,18.97,18.78。HRMS的计算值为C27H39O2Si[M+1]+423.2719,测定值为423.2718。
11-(叔丁基二苯基甲硅烷氧基)十一碳-5(Z)-烯-1-醇。将11-(叔丁基二苯基甲硅烷氧基)十一碳-5-炔-1-醇(6.50g,15.40mmol)进行上述半氢化反应以生成无色油状物的标题烯烃(6.07g,93%)。TLC:EtOAc/己烷(3:7),Rf~0.45;1H NMR(300MHz)δ7.68-7.64(m,4H),7.34-7.32(m,6H),5.28-5.42(m,2H),3.68-3.60(t,J=6.4Hz,4H),2.08-1.96(m,4H),1.60-1.50(m,4H),1.40-1.24(m,6H),1.04(s,9H);13C NMR(100MHz)δ135.79,134.36,130.45,129.71,129.63,127.79,64.16,63.15,32.69,32.59,29.94,29.67,27.43,27.13,27.08,26.06,25.68,19.45。HRMS的计算值为C27H41O2Si[M+1]+425.2876,测定值为425.2874。
1-叔丁基二苯基甲硅烷氧基-11-叠氮基十一碳-6(Z)-烯。上述方案之后,11-(叔丁基二苯基甲硅烷氧基)十一碳-5(Z)-烯-1-醇(6.0g,14.24mmol)转化成无色液体的标题叠氮化物(4.60g,72%)。TLC:EtOAc/己烷(1:9),Rf~0.55;1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),5.28-5.42(m,2H),3.65(t,J=6.4Hz,2H),3.25(t,J=7.1Hz,2H),1.96-2.10(m,4H),1.24-1.64(m,10H),1.04(s,9H);13C NMR(100MHz)δ136.63,135.85,134.41,130.83,129.79,129.22,127.88,64.20,51.62,32.77,29.73,28.70,27.53,27.18,27.05,26.94,25.77,19.52;IR(纯样)2931,2857,2094,1589,1110cm-1。HRMS的计算值为C27H40N3OSi[M+1]+450.2940,测定值为450.2941。
1-氨基-11-(叔丁基二苯基甲硅烷氧基)十一碳-5(Z)-烯。用上述三苯膦将1-(叔丁基二苯基甲硅烷氧基-11-叠氮基十一碳-6(Z)-烯(4.30g,9.57mmol)还原以生成无色油状物的标题胺(2.96g,74%)。TLC:MeOH/CH2Cl2(1:4),Rf~0.25;1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),5.28-5.42(m,2H),3.64(t,J=6.4Hz,2H),2.82(t,J=4.8Hz,2H),1.96-2.10(m,4H),1.52-1.64(m,4H),1.30-1.42(m,6H),1.04(s,9H);13CNMR(100MHz)δ135.82,134.37,132.37,132.27,130.70,129.78,129.21,128.93,128.81,127.86,64.19,40.88,32.77,29.89,29.73,27.52,27.37,27.17,27.12,27.03,25.76,19.47。HRMS的计算值为C27H42NOSi[M+1]+420.3046,测定值为420.3050。
1-(11-(叔丁基二苯基甲硅烷氧基)十一碳-5(Z)-烯基)-3-正戊基脲。76%是无色油状物。TLC:EtOAc/己烷(2:3),Rf~0.45;1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),5.28-5.42(m,2H),4.13(br s,2H),3.65(t,J=6.4Hz,2H),3.02-3.20(m,4H),1.96-2.08(m,4H),1.20-1.60(m,16H),1.04(s,9H),0.89(t,J=7.2Hz,3H);13CNMR(100MHz)δ158.02,135.79,134.36,130.06,129.74,127.90,127.82,64.17,40.42,40.32,32.52,30.28,29.71,29.35,27.62,27.54,27.16,27.11,25.71,22.69,19.45,14.28。HRMS的计算值为C33H53N2O2Si[M+1]+537.3876,测定值为537.3876。
1-(11-羟基十一碳-5(Z)-烯基)-3-正戊基脲。94%,mp62.2-62.5℃。TLC:EtOAc/己烷(7:3),Rf~0.55;1H NMR(300MHz)δ5.28-5.42(m,2H),4.37(br s,2H),3.64(t,J=6.4Hz,2H),3.02-3.20(m,4H),1.96-2.10(m,4H),1.20-1.60(m,16H),0.89(t,J=7.2Hz,3H);13C NMR(75MHz)δ159.41,130.30,129.73,62.77,40.50,40.34,32.75,30.27,30.10,29.56,29.33,27.23,27.15,27.04,25.56,22.66,14.24。HRMS的计算值为C17H35N2O2[M+1]+299.2699,测定值为299.2705。
1-(11-溴十一碳-5(Z)-烯基)-3-正戊基脲。84%是无色油状物。TLC:EtOAc/己烷(2:3),Rf~0.60;1H NMR(300MHz)δ5.28-5.42(m,2H),4.36(br s,2H),3.32(t,J=6.4Hz,2H),3.02-3.20(m,4H),1.96-2.10(m,4H),1.20-1.60(m,16H),0.89(t,J=7.2Hz,3H);13C NMR(75MHz)δ159.20,129.94,40.60,40.49,34.19,32.91,30.29,29.35,29.02,28.01,27.26,27.16,22.67,14.26。HRMS的计算值为C17H33BrN2O[M]+360.1776,测定值为360.1773。
1-(11-(2-羟基苯硫基)十一碳-5(Z)-烯基)-3-正戊基脲(13)。向2-巯基苯酚(100mg,0.79mmol)的DMF(3mL)溶液中,加入K2CO3(161mg,1.18mmol)和1-(11-溴十一碳-5(Z)-烯基)-3-正戊基脲(0.29g,0.79mmol)。室温12小时后,溶液用水(10mL)稀释,并用乙酸乙酯(3×5mL)萃取。合并的有机萃取物用水、盐水洗涤,并且(Na2SO4)干燥。残留物通过SiO2柱色谱纯化以生成粘性固体的类似物23(230mg,69%)。TLC:EtOAc/己烷(1:1),Rf~0.32;1H NMR(300MHz)δ7.45(dd,J=1.9,7.6Hz,1H),7.22-7.28(m,1H),6.99(dd,J=1.2,8.2Hz,1H),6.88(dt,J=1.2,7.6Hz,1H),5.28-5.42(m,2H),4.26(br s,2H),3.02-3.20(m,4H),2.69(t,J=7.7Hz,2H),1.94-2.08(m,4H),1.20-1.60(m,16H),0.89(t,J=7.2Hz,3H);13C NMR(75MHz)δ159.05,157.10,135.60,130.76,130.11,129.82,120.78,119.74,115.02,40.70,40.60,36.50,30.23,29.68,29.32,28.38,27.21,27.11,22.66,14.27。HRMS(ESI-阴性)的计算值为C23H37N2O2S[M-1]-405.2576,测定值为405.2575。
合成类似物14。
1-(11-(2-羟基苯磺酰基)十一碳-5(Z)-烯基)-3-正戊基脲(14)。在用于制备类似物18的步骤之后,将类似物13氧化以生成无色液体14(60mg,75%)。TLC:EtOAc/己烷(2:3),Rf~0.32;1H NMR(300MHz)δ9.08(br s,-OH),7.72(dd,J=1.9,7.4Hz,1H),7.44(dt,J=1.2,7.3Hz,1H),7.10(d,J=7.9Hz,1H),7.12(t,J=6.4Hz,1H),5.28-5.42(m,2H),4.70-4.85(m,2H),3.40-3.60(t,J=6.2Hz,2H),3.20-3.40(m,4H),1.90-2.10(m,4H),1.70-1.80(m,2H),1.20-1.50(m,14H),0.85(t,J=7.2Hz,3H);13C NMR(75MHz)δ159.25,156.66,136.23,130.22,129.78,129.52,122.78,120.22,118.55,55.97,40.08,40.62,30.07,30.02,29.25,28.82,27.62,27.15,27.05,26.62,22.61,22.20,14.24。HRMS(ESI-阴性)的计算值为C23H37N2O4S[M-1]-437.2474,测定值为437.2454。
合成类似物15。
1-正戊基-3-(11-硫氰酸基十一碳-5(Z)-烯基)脲。在室温下搅拌1-(11-溴十一碳-5(Z)-烯基)-3-正戊基脲(191mg,0.53mmol)和硫氰酸钾(154mg,1.58mmol)的干DMSO(4mL)。24小时后,反应混合物用水(10mL)稀释,并用乙酸乙酯(3×5mL)萃取。合并的有机萃取物用水、盐水洗涤,和(Na2SO4)干燥,并且真空浓缩。残留物通过SiO2柱色谱纯化以生成无色糖浆状的标题脲(116mg,65%)。TLC:EtOAc/己烷(2:3),Rf~0.32;1H NMR(300MHz)δ5.28-5.42(m,2H),4.42(br s,2H),3.10-3.20(m,4H),2.94(t,J=7.0Hz,2H),2.00-2.10(m,4H),1.70-1.80(m,2H),1.20-1.56(m,14H),0.88(t,J=7.2Hz,3H);13C NMR(75MHz)δ158.92,130.20,129.68,112.84,40.67,40.54,34.23,30.22,30.03,29.31,29.08,27.66,27.19,27.15,27.04,22.66,14.27;IR(纯样)2929,2856,2153,1630,1573,1456,1256cm-1。HRMS的计算值为C18H34N3OS[M+1]+340.2423,测定值为340.2421。
1-(11-(1H-四唑-5-基硫基)十一碳-5(Z)-烯基)-3-戊基脲(15)。在用于制备类似物19的步骤之后,用叠氮化钠处理1-正戊基-3-(11-硫氰酸基十一碳-5(Z)-烯基)脲(150mg,0.44mmol)以生成粘性固体的类似物15(104mg,62%)。TLC:5%MeOH/CH2Cl2,Rf~0.40;1H NMR(300MHz)δ5.28-5.42(m,2H),4.63(br s,2H),3.30(t,J=6.7Hz,2H),3.17-3.23(m,4H),1.95-2.04(m,4H),1.44-1.80(m,6H),1.24-1.42(m,10H),0.89(t,J=7.2Hz,3H);13C NMR(CD3OD,75MHz)δ160.17,155.38,129.65,129.58,39.81,39.69,32.38,29.87,29.79,29.36,28.99,28.96,27.84,26.84,26.72,26.69,22.31,13.21。HRMS(ESI-阴性)的计算值为C18H33N6OS[M-1]-381.2442,测定值为381.2348。
合成类似物12。
N-(11-(3-正戊基脲基)十一碳-6(Z)-烯基)苯磺酰胺(12)。在氩气、-78℃下,向苯磺酰胺(50mg,0.31mmol)的THF/HMPA(4:1;5mL)溶液中加入正丁基锂(2.5M的己烷溶液,125μL,0.31mmol)。逐滴加入1-(11-溴十一碳-5(Z)-烯基)-3-正戊基脲(115mg,0.32mmol)的THF(2mL)溶液。室温2小时后,反应用饱和水性NH4Cl(5mL)淬灭。混合物用EtOAc(3×5mL)萃取,并且合并的萃取物用水、盐水洗涤,干燥,并且减压下浓缩。残留物通过SiO2柱色谱纯化以生成无色固体的类似物12(44mg,32%),mp73.5-73.6℃。TLC:5%MeOH/CH2Cl2,Rf~0.40;1H NMR(300MHz)δ7.84-7.90(m,2H),7.46-7.60(m,3H),5.48(br s,-NH,1H),5.24-5.38(m,2H),4.70(br s,-NH,1H),4.60(br s,-NH,1H),3.08-3.20(m,4H),2.88-2.94(q,J=6.4Hz,2H),1.94-2.40(m,4H),1.20-1.58(m,16H),0.88(t,J=6.8Hz,3H);13C NMR(75MHz)δ159.90,140.06,132.69,130.03,129.98,129.27,127.19,43.26,40.80,40.52,30.09,29.99,29.61,29.28,29.16,27.02,26.99,26.96,26.13,22.63,14.25。HRMS的计算值为C23H40N3O3S[M+1]+438.2790,测定值为438.2782。
合成类似物24。
1-(11-(2,4-二氧代噻唑烷-5-基)十一碳-5(Z)-烯基)-3-正戊基脲(24)。氩气下,正丁基锂(1.10mL,2.76mmol,2.5M的己烷溶液)逐滴加入到噻唑烷-2,4-二酮(0.16g,1.38mmol)的干THF/HMPA(50mL,4:1)的-78℃溶液中。30分钟后,反应混合物在1小时内加热到0℃,在0℃保持2小时,然后再冷却到-78℃。再加入1-(11-溴十一碳-5(Z)-烯基)-3-正戊基脲(0.50g,1.38mmol)的THF(15mL)溶液之后,3小时内反应温度缓慢升高到室温,并且再搅拌12小时。反应混合物用饱和水性NH4Cl(5mL)淬灭,使用1M草酸把pH调节到4,并且反应混合物用EtOAc(3×125mL)萃取。合并的萃取物用水(2×100mL)、盐水(100mL)洗涤,(Na2SO4)干燥并且真空浓缩。残留物通过SiO2柱色谱、使用5%的MeOH/CH2Cl2纯化以提供无色固体的类似物24(169mg,31%),mp92.8-93℃。TLC:10%MeOH/CH2Cl2,Rf~0.20;1H NMR(CD3OD,300MHz)δ5.30-5.40(m,2H),4.42(dd,J=3.4,4.2Hz,1H),3.04-3.13(m,4H),2.00-2.16(m,4H),1.80-1.96(m,2H),1.24-1.58(m,16H),0.91(t,J=6.7Hz,3H);13CNMR(75MHz)δ177.09,172.56,160.15,129.68,129.60,51.89,39.69,32.57,29.90,29.83,29.23,29.02,28.43,26.88,26.73,26.47,22.35,13.27。HRMS的计算值为C20H36N3O3S[M+1]+398.2477,测定值为398.2477。
合成类似物7。
(S)-2-(13-(3-正戊基脲基)十三碳-8(Z)-烯酰氨基)琥珀酸二甲基酯。氩气下,盐酸L-天冬氨酸二甲酯(38mg,0.19mmol)和HATU(67mg,0.18mmol)加入到搅拌的13-(3-正戊基脲基)十三碳-8(Z)-烯酸2(50mg,0.15mmol)的无水DMF(20mL)溶液中。5分钟后,加入1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI;33mg,0.17mmol),然后加入二异丙基乙胺(33μL,0.19mmol)。12小时后,反应混合物用EtOAc(30mL)稀释,用水(30mL)和盐水(20mL)洗涤。合并的水层用EtOAc(3×30mL)反萃取。合并的有机萃取物用Na2SO4干燥,减压浓缩,并且残留物通过SiO2柱色谱、使用50%的EtOAc/己烷作为洗脱液纯化以生成粘性油状物的标题二酯(60mg,84%)。TLC:EtOAc/己烷(3:2),Rf~0.30;1H NMR(300MHz)δ6.62(d,J=7.0Hz,1H),5.22-5.40(m,2H),4.85-5.04(m,1H),4.80-4.88(m,2H),3.75(s,3H),3.66(s,3H),3.10-3.20(m,4H),3.01(dd,J=4.3,10Hz,1H),2.82(dd,J=4.6,10Hz,1H),2.25(t,J=8.3Hz,2H),1.98-2.07(m,4H),1.60-1.68(m,4H),1.20-1.50(m,14H),0.88(t,J=6.7Hz,3H);13C NMR(75MHz)δ173.51,171.81,171.52,159.02,130.33,129.76,53.05,52.30,48.57,40.61,40.55,36.61,36.28,30.24,30.20,29.51,29.31,29.10,28.88,27.20,27.12,25.7222.6614.26。
(S)-2-(13-(3-正戊基脲基)十三碳-8(Z)-烯酰氨基)琥珀酸(7)。LiOH(2mL,2M水溶液)加入到0℃上述(S)-2-(13-(3-正戊基脲基)十三碳-8(Z)-烯酰氨基)琥珀酸二甲基酯(60mg,0.12mmol)的THF(25mL)溶液和去离子H2O(4mL)中。室温下搅拌过夜后,反应混合物冷却到0℃,用1M水性草酸把pH调节到4,并且混合物用EtOAc(3×15mL)萃取。合并的萃取物用水(30mL)、盐水(25mL)洗涤,用无水Na2SO4干燥,并且真空浓缩。残留物通过SiO2柱色谱、使用25%EtOAc/己烷作为洗脱液纯化,以生成无色油状物的类似物7(48mg,85%)。TLC:5%MeOH/EtOAc(3:2),Rf~0.30;1H NMR(CD3OD,300MHz)δ5.30-5.38(m,2H),4.72(t,J=4.2Hz,1H),3.26-3.32(m,4H),2.86(dd,J=4.3,10Hz,1H),2.77(dd,J=4.6,10Hz,1H),2.22(t,J=7.7Hz,2H),1.98-2.10(m,4H),1.54-1.64(m,4H),1.20-1.52(m,14H),0.89(t,J=6.7Hz,3H);13C NMR(CD3OD,75MHz)δ174.93,173.01,172.83,160.17,129.94,129.39,49.0,39.81,39.73,35.78,35.60,29.90,29.82,29.49,29.02,28.87,26.90,26.73,25.70,22.35,13.29。HRMS的计算值为C23H42N3O6[M+1]+456.3074,测定值为456.3071。
合成类似物3。
2-(2-(2-羟基乙氧基)乙氧基)乙基13-(2-(正丁基氨基)-2-氧代乙酰胺基)十三碳-8(Z)-烯酸酯(3)。在氩气、室温下,三甘醇(0.12g,0.8mmol;通过分子筛干燥)加入到13-(2-(正丁基氨基)-2-氧代乙酰胺基)十三碳-8(Z)-烯酸2(30mg,0.08mmol)和N,N-二甲基氨基吡啶(DMAP,11mg,0.09mmol)的无水二氯甲烷(10mL)溶液中。3分钟后,加入固体EDCI(18mg,0.09mmol)。12小时后,反应混合物用EtOAc(10mL)稀释,用水(5mL)洗涤,并真空浓缩。残留物通过SiO2柱色谱、使用EtOAc纯化以生成无色固体的类似物3(33mg,82%),mp71.7-71.9℃。TLC:EtOAc/己烷(4:1),Rf~0.30;1H NMR(300MHz)δ7.46(br s,2H),5.24-5.40(m,2H),4.23(t,J=4.6Hz,2H),3.58-3.78(m,10H),3.27(表观(apparent)q,J=6.7Hz,4H),2.32(t,J=7.6Hz,2H),1.50-1.66(m,6H),1.24-1.44(m,14H),0.92(t,J=6.7Hz,3H);13C NMR(100MHz)δ174.10,160.09,130.66,129.24,72.70,70.76,70.55,69.42,39.80,39.61,34.35,31.45,29.69,29.21,29.12,29.02,27.36,27.07,26.92,25.04,20.21,13.90。HRMS的计算值为C25H47N2O7[M+1]+487.3383,测定值为487.3379。
合成类似物2。
2-(2-(2-羟基乙氧基)乙氧基)乙基13-(3-正戊基脲基)十三碳-8(Z)-烯酸酯(2)。用上述三甘醇将13-(3-正戊基脲基)十三碳-8(Z)-烯酸2(80mg,0.20mmol)浓缩以生成无色固体的类似物2(86mg,78%),mp42.4-42.6℃。TLC:EtOAc,Rf~0.20;1H NMR(300MHz)δ5.24-5.40(m,2H),4.28(br s,2H),4.23(dd,J=4.9,1.0Hz,2H),3.58-3.68(m,10H),3.10-3.20(m,4H),2.52(br s,-OH,1H),2.33(t,J=7.6Hz,2H),1.90-2.10(m,4H),1.44-1.64(m,4H),1.22-1.40(m,14),0.88(t,J=7.3Hz,3H);13C NMR(75MHz)δ174.22,158.50,130.41,129.62,72.76,70.75,70.51,69.38,63.47,61.94,40.78,40.71,34.33,30.13,30.08,29.57,29.25,29.09,28.94,27.23,27.15,27.06,25.03,22.61,14.24。HRMS的计算值为C25H49N2O6[M+1]+473.3591,测定值为473.3588。
合成类似物1。
2-(2-(2-羟基乙氧基)乙氧基)乙基13-(N-异丙基庚酰氨基)十三碳-8(Z)-烯酸酯(1)。用上述三甘醇将13-(N-异丙基庚酰氨基)十三碳-8(Z)-烯酸2(60mg,0.16mmol)浓缩以生成粘稠无色油状的类似物1(58mg,73%)。TLC:EtOAc(4:1),Rf~0.40;1HNMR(300MHz,旋转异构体的混合物65/35)δ5.26-5.40(m,2H),4.62-4.70(m,0.5H),4.20-4.26(m,2H),3.98-4.08(m,0.5H),3.58-3.76(m,10H),3.04-3.16(m,2H),2.20-2.36(m,对两种旋转异构体是4H),1.98-2.10(m,4H),1.46-1.66(m,6H),1.24-1.38(m,14H),1.18和1.10(d,J=7.3Hz,对两种旋转异构体是6H),0.87(t,J=7.2Hz,3H);13CNMR(75MHz)δ174.05,174.01,173.10,172.55,130.75,130.11,129.85,129.15,72.70,70.76,70.55,69.40,63.43,61.94,48.30,45.52,43.53,41.09,34.36,34.32,34.10,34.0,31.93,31.89,31.28,29.90,29.75,29.69,29.56,29.43,29.23,29.12,27.84,27.48,27.42,27.35,27.18,26.93,25.88,25.70,25.05,25.02,22.76,21.60,20.75,14.28。HRMS的计算值为C29H56NO6[M+1]+514.4108,测定值为514.4111。
合成类似物8。
N-羟基琥珀酰亚胺基13-(3-正戊基脲基)十三碳-8(Z)-烯酸酯。13-(3-正戊基脲基)十三碳-8(Z)-烯酸2(100mg,0.29mmol)和N-羟基琥珀酰亚胺(37mg,0.31mmol)的混合物使用无水苯(2×5mL)共沸干燥,然后在干CH2Cl2(5mL)中溶解。氩气下向其加入EDCI(67mg,0.35mmol)和DMAP(38mg,0.31mmol)。室温下12小时后,反应混合物用更多CH2Cl2(20mL)稀释,用水、盐水洗涤,(Na2SO4)干燥,并真空浓缩。残留物通过SiO2柱色谱纯化以生成粘性固体的标题NHS酯(110mg,86%),所述酯不需进一步纯化,可立即使用。TLC:EtOAc/己烷(7:3),Rf~0.40;1H NMR(400MHz)δ5.27-5.36(m,2H),4.48(br s,2H),3.09-3.15(m,4H),2.81(br s,4H),2.58(t,J=7.8Hz,2H),1.94-2.06(m,4H),1.68-1.74(m,2H),1.20-1.50(m,16H),0.86(t,J=7.2Hz,3H);13C NMR(100MHz)δ169.40,168.96,158.62,130.29,129.71,40.75,40.68,31.12,30.18,30.14,29.51,29.28,28.80,27.21,27.19,27.10,25.81,24.72,22.62,14.24。
13-(3-正戊基脲基)-N-(苯磺酰基)十三碳-8(Z)-烯酰胺(enamide)(8)。上述N-羟基琥珀酰亚胺基13-(3-正戊基脲基)十三碳-8(Z)-烯酸酯(150mg,0.34mmol)、苯磺酰胺(78mg,0.49mmol)和4-二甲基氨基吡啶(DMAP;50mg,0.40mmol)的混合物在干六甲基磷酰胺(HMPA;3mL)中80℃下加热24小时。冷却到室温后,反应混合物用水稀释,并用EtOAc(3×10mL)萃取。合并的萃取物用水、盐水洗涤,用(Na2SO4)干燥,并且真空浓缩。残留物通过SiO2柱色谱纯化以生成无色固体的类似物8(105mg,65%),mp91.4-91.6℃。TLC:EtOAc/己烷(3:2),Rf~0.30;1H NMR(300MHz)δ8.00-8.10(dd,J=0.9,7.3Hz,2H),7.44-7.60(m,3H),5.28-5.42(m,2H),5.03(br s,-NH,1H),4.57(br s,-NH,1H),3.21(t,J=6.8Hz,2H),3.12(t,J=6.5Hz,2H),2.29(t,J=7.9Hz,2H),1.98-2.10(m,4H),1.18-1.60(m,18H),0.90(t,J=7.2Hz,3H);13C NMR(75MHz)δ172.66,159.28,139.67,133.57,130.69,129.65,128.93,128.40,41.41,40.53,36.22,29.89,29.61,29.24,28.87,28.33,27.69,26.91,26.69,26.47,24.70,22.588,14.22。HRMS的计算值为C25H42N3O4S[M+1]+480.2896,测定值为480.2899。
合成类似物9。
N-(甲磺酰基)-13-(3-正戊基脲基)十三碳-8(Z)-烯酰胺(enamide)(9)。上述N-羟基琥珀酰亚胺基13-(3-正戊基脲基)十三碳-8(Z)-烯酸酯(150mg,0.34mmol)与上述甲磺酰胺(48mg,0.50mmol)反应以生成无色固体的类似物8(102mg,72%),mp113.5-113.6℃。TLC:EtOAc/己烷(1:1),Rf~0.30;1H NMR(300MHz)δ5.30-5.40(m,2H),3.21(s,3H),3.04-3.12(m,4H),2.29(t,J=7.3Hz,2H),2.00-2.10(m,4H),1.22-1.66(m,18H),0.90(t,J=7.0Hz,3H);13C NMR(75MHz)δ175.14,161.50,131.17,130.78,41.44,41.10,41.02,37.13,31.22,31.15,30.73,30.34,30.07,30.05,28.19,28.17,28.03,25.80,23.66,14.56。HRMS的计算值为C20H40N3O4S[M+1]+418.2740,测定值为418.2739。
合成类似物6。
2-(13-(1,3-二甲基-3-正戊基脲基)十三碳-8(Z)-烯酰氨基)乙酸甲酯。氩气下,甘氨酸盐酸盐(32mg,0.29mmol)和1-羟基苯并三唑(32mg,0.23mmol;HOBt)加入到13-(1,3-二甲基-3-正戊基脲基)十三碳-8(Z)-烯酸2(70mg,0.19mmol)和二异丙基乙胺(50μL,0.29mmol)的无水DMF(20mL)溶液中。5分钟后,加入固体的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(45mg,0.23mmol;EDCI)。室温搅拌12小时后,反应混合物用水(30mL)稀释,并用EtOAc(3×30mL)萃取。合并的有机萃取物用Na2SO4干燥,减压浓缩,并且残留物通过SiO2柱色谱、使用30%的EtOAc/己烷作为洗脱液纯化以生成粘性油状物的标题甲酯(65mg,79%)。TLC:EtOAc/己烷(7:3),Rf~0.40;1H NMR(300MHz)δ6.18(br s,-NH,1H),5.26-5.40(m,2H),4.04(d,J=5.2Hz,2H),3.75(s,3H),3.11(表观q,J=7.6Hz,4H),2.77(s,3H),2.76(s,3H),2.24(t,J=7.6Hz,2H),1.96-2.08(m,4H),1.46-1.70(m,6H),1.20-1.38(m,12H),0.88(t,J=7.2Hz,3H);13C NMR(100MHz)δ170.69,170.07,165.65,130.36,129.38,52.45,50.43,50.42,41.23,35.86,30.09,29.62,29.26,29.22,29.05,27.32,27.15,26.67,25.74,25.38,21.65,14.48。HRMS的计算值为C24H46N3O4[M+1]+440.3488,测定值为440.3485。
2-(13-(1,3-二甲基-3-正戊基脲基)十三碳-8(Z)-烯酰氨基)乙酸(6)。在上述酯水解条件后,将2-(13-(1,3-二甲基-3-正戊基脲基)十三碳-8(Z)-烯酰氨基)乙酸甲酯转化成所得的无色液体的类似物6(87%)。TLC:EtOAc/己烷(4:1),Rf~0.40;1H NMR(300MHz)δ6.39(br s,-NH,1H),5.24-5.40(m,2H),4.03(d,J=4.5Hz,2H),3.16(表观q,J=5.8Hz,4H),2.79(s,3H),2.77(s,3H),2.25(t,J=7.0Hz,2H),1.90-2.10(m,4H),1.48-1.70(m,6H),1.20-1.40(m,12H),0.88(t,J=7.2Hz,3H);13C NMR(100MHz)δ174.31,171.97,166.01,130.44,129.51,50.79,50.61,41.72,36.86,36.72,36.42,29.64,29.18,29.05,27.36,27.26,27.09,27.04,25.76,22.63,14.24。HRMS的计算值为C23H44N3O4[M+1]+426.3332,测定值为426.3315。
合成类似物5。
2-(13-(N-异丙基庚酰氨基)十三碳-8(Z)-烯酰氨基)乙酸甲酯。用上述甘氨酸甲酯将13-(N-异丙基庚酰氨基)十三碳-8(Z)-烯酸2(100mg,0.26mmol)浓缩以生成无色油状物的对应的酰胺(97mg,82%),所述酰胺可以直接用于下一步。TLC:EtOAc(2:1),Rf~0.45;1H NMR(300MHz,旋转异构体的混合物1:1)δ6.25(br s,-NH,0.5H),6.08(br s,-NH,0.5H),5.24-5.42(m,2H),4.60-4.72(m,1H),4.05(d,J=2.4Hz,2H),3.76(s,1.5H),3.75(s,1.5H),3.06-3.15(m,2H),2.20-2.38(m,4H),1.90-2.10(m,4H),1.40-1.68(m,6H),1.24-1.38(m,14H),1.19(d,J=6.7Hz,3H),1.10(d,J=6.7Hz,3H),0.88(t,J=7.1Hz,3H);13C NMR(100MHz)δ173.60,173.46,173.16,172.60,170.82,130.84,130.12,129.88,129.16,53.66,52.58,52.53,48.35,45.52,43.55,41.38,41.15,36.57,34.11,34.02,31.95,31.92,31.32,29.92,29.72,29.63,29.60,29.45,29.40,29.26,29.21,28.97,27.94,27.45,27.41,27.26,27.16,26.96,25.91,25.80,25.75,22.79,21.62,20.7814.31。
2-(13-(N-异丙基庚酰氨基)十三碳-8(Z)-烯酰氨基)乙酸(5)。在上述酯水解条件后,将2-(13-(N-异丙基庚酰氨基)十三碳-8(Z)-烯酰氨基)乙酸甲酯(50mg,0.10mmol)水解以生成所得的无色液体的类似物5(44mg,91%)。TLC:EtOAc(4:1),Rf~0.20;1HNMR(300MHz,旋转异构体的混合物65/35)δ6.47和6.35(br s,-NH,对两种旋转异构体是1H),5.24-5.42(m,2H),4.60-4.70(m,1H),4.05和4.06(d,J=2.8Hz,对两种旋转异构体是2H),3.06-3.18(m,2H),2.20-2.38(m,4H),1.90-2.10(m,4H),1.50-1.68(m,6H),1.24-1.38(m,14H),1.20和1.10(d,J=7.3Hz,对两种旋转异构体是6H),0.87(t,J=7.2Hz,3H);13C NMR(75MHz)δ174.35,174.23,174.18,173.64,172.0,171.93,130.98,130.25,129.75,129.0,48.86,45.99,43.77,41.79,41.62,41.48,34.05,33.95,31.85,31.79,31.13,29.62,29.51,29.35,29.31,29.23,28.85,28.81,27.83,27.44,27.34,27.21,27.02,26.90,26.03,25.87,25.80,25.75,22.75,21.54,20.70,14.29。HRMS的计算值为C25H47N2O4[M+1]+439.3536,测定值为439.3531。
合成类似物31。
1-(5-(叔丁基二苯基甲硅烷氧基)戊基)-3-正戊基脲。将5-(叔丁基二苯基甲硅烷氧基)戊烷-1-胺5(3.0g,8.78mmol)与上述异氰酸正戊基酯(995mg,8.78mmol)反应以生成无色油状物的标题脲(85%)。TLC:EtOAc/己烷(2:3),Rf~0.40;1H NMR(300MHz)δ7.60-7.70(m,4H),7.30-7.40(m,6H),4.24(br s,-NH,2H),3.64(t,J=7.9Hz,2H),3.06-3.20(m,4H),1.20-1.60(m,12H),1.03(s,9H),0.89(t,J=7.2Hz,3H);13CNMR(75MHz)δ159.7,134.90,132.47,132.40,129.70,128.81,128.71,127.92,63.2,40.91,40.81,32.42,29.60,29.28,27.11,23.30,22.35,19.38。HRMS的计算值为C27H43N2O2Si[M+1]+455.3094,测定值为455.3093。
1-(5-羟基戊基)-3-正戊基脲。将1-(5-(叔丁基二苯基甲硅烷氧基)戊基)-3-正戊基脲(3.0g,6.60mmol)如上述去甲硅烷化(de-silylate)以生成无色油状物的标题醇(1.31g,92%),mp81.4-81.8℃。TLC:EtOAc/己烷(7:3),Rf~0.40;1H NMR(CD3OD,300MHz)δ3.54(t,J=5.8Hz,2H),3.06(q,J=6.4Hz,4H),1.22-1.60(m,12H),0.89(t,J=7.3Hz,3H);13C NMR(CD3OD,100MHz)δ160.17,61.67,39.82,39.77,32.17,30.02,29.91,29.03,23.04,22.34,13.25。HRMS的计算值为C11H25N2O2[M+1]+217.1916,测定值为217.1916。
1-(5-溴戊基)-3-正戊基脲。上述方案之后,将1-(5-羟基戊基)-3-正戊基脲(1.30g,6.02mmol)转化成所得的无色油状物的对应的溴化物(1.45g,87%)。TLC:EtOAc/己烷(2:3),Rf~0.40;1H NMR(300MHz)δ4.44(br s,-NH,2H),3.40(t,J=6.7Hz,2H),3.10-3.20(m,4H),1.82-1.92(m,2H),1.40-1.58(m,6H),1.24-1.38(m,4H),0.89(t,J=7.3Hz,3H);13C NMR(100MHz)δ159.46,40.02,33.88,33.02,30.29,29.92,29.36,25.83,22.12,14.02。HRMS的计算值为C11H24BrN2O[M+1]+279.1072,测定值为279.1073。
N-(4-(5-(3-正戊基脲基)戊氧基)苯并[d]噻唑-2-基)乙酰胺(31)。在60℃下加热1-(5-溴戊基)-3-正戊基脲(100mg,0.37mmol)、市售N-(4-羟基苯并[d]噻唑-2-基)乙酰胺(100mg,0.48mmol)和K2CO3(67mg,0.48mmol)的混合物的DMF(5mL)。6小时后,反应混合物冷却到室温,用水(25mL)稀释,并用EtOAc(3×10mL)萃取。合并的有机萃取物用水(2×5mL)、盐水(10mL)洗涤,(Na2SO4)干燥并且真空浓缩。因此所得的残留物通过硅胶柱色谱纯化以生成31(61mg,40%),mp61.6-61.8℃。TLC:EtOAc/己烷(3:2),Rf~0.40;1H NMR(300MHz)δ7.39(dd,J=0.9,7.3Hz,1H),7.20(dd,J=7.8,7.3Hz,1H),6.86(dd,J=0.9,7.8Hz,1H),4.42(br s,-NH,2H),4.17(t,J=5.4Hz,2H),3.19-3.30(m,4H),2.33(s,3H),1.82-1.98(m,2H),1.64-1.80(m,4H),1.42-1.60(m,2H),1.24-1.40(m,4H),0.88(t,J=7.3Hz,3H);13C NMR(75MHz)δ170.16,159.91,158.94,151.37,139.10,133.67,124.40,113.94,108.68,68.21,40.64,39.98,30.27,29.30,28.33,26.54,23.25,22.64,22.33,14.26。HRMS(ESI-阴性)的计算值为C20H29N4O3S[M-1]-405.1960,测定值为405.1938。
合成类似物32。
N1-正丁基-N2-(5-(叔丁基二苯基甲硅烷氧基)戊基)草酰胺(oxalamide)2-(正丁基氨基)-2-氧代乙酸(oxoacetic acid)(22mg,0.15)、5-(叔丁基二苯基甲硅烷氧基)戊烷-1-胺5(50mg,0.15mmol)、N,N-二异丙基乙胺(40mg,0.30mmol)和2-(1H-7-杂氮苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐甲铵(methanaminium)(HATU,72mg,0.19mmol)的混合物的干DMF(5mL)在氩气、室温下搅拌过夜,然后用水(2mL)淬灭。反应混合物用EtOAc(3×5mL)萃取。合并的有机萃取物用水洗涤,干燥并真空浓缩。残留物通过快速SiO2柱色谱、使用10%EtOAc/己烷(1:3)作为洗脱液纯化,以生成无色油状物的标题草酰胺(oxamide)(65mg,91%)。TLC:50%EtOAc/己烷,Rf~0.56;1H NMR(400MHz)δ7.55-7.70(m,4H),7.60(br s,-NH,2H),7.35-7.40(m,6H),3.65(t,J=6.0Hz,2H),3.35-3.25(m,4H),1.55-1.35(m,10H),1.05(s,9H),0.92(t,J=7.3Hz,3H);13C NMR(100MHz)δ160.28,160.25,135.80,134.20,129.85,127.90,63.80,40.0,39.70,32.40,31.50,29.20,27.10,27.05,23.40,20.30,19.45,14.0。HRMS的计算值为C27H41N2O3Si[M+1]+469.2886,测定值为469.2892。
N1-正丁基-N2-(5-羟基戊基)草酰胺(oxalamide)。N1-正丁基-N2-(5-(叔丁基二苯基甲硅烷氧基)戊基)草酰胺(65mg,0.14mmol)和正四丁基氟化铵(0.41mL,1M溶液,0.42mmol)的混合物的干THF溶液在氩气下室温搅拌12小时。真空蒸发所有挥发物,残留物溶解在EtOAc(30mL)中,并且有机层用水(10mL)、盐水(15mL)洗涤,干燥和蒸发。残留物通过SiO2柱色谱、使用EtOAc/己烷(1:2)作为洗脱液纯化以生成无色固体的标题化合物(30mg,92%),mp136-137℃。TLC:50%EtOAc/己烷,Rf~0.28;1H NMR(300MHz)δ7.65(br s,NH,1H),7.60(br s,-NH,1H),3.65(t,J=6.0Hz,2H),3.35-3.25(m,4H),1.90(br s-OH,1H),1.60-1.50(m,6H),1.40-1.35(m,4H),0.92(t,J=7.3Hz,3H);13C NMR(100MHz)δ160.25,160.10,62.70,39.80,39.65,32.40,31.45,29.20,23.25,20.20,13.85。HRMS的计算值为C11H23N2O3[M+1]+231.1709,测定值为231.1701。
N1-(5-溴戊基)-N2-正丁基草酰胺。氩气下,将四溴化碳(51mg,0.15mmol)的CH2Cl2(5mL)溶液搅拌加入三苯膦(48mg,0.18mmol)和N1-正丁基-N2-(5-羟基戊基)草酰胺(30mg,0.130mmol)的干CH2Cl2(5mL)的0℃溶液中。2小时后,反应混合物用水(5mL)、盐水(10mL)洗涤,通过无水Na2SO4干燥,并且减压除去所有挥发物。残留物通过SiO2柱色谱、使用EtOAc/己烷(1:4)纯化以生成无色固体的标题化合物(32mg,84%),mp109-110℃。TLC:50%EtOAc/己烷,Rf~0.50;1H NMR(300MHz)δ7.55(br s,NH,1H),7.50(br s,-NH,1H),3.40(t,J=6.0Hz,2H),3.25-3.35(m,4H),1.80-1.85(m,2H),1.40-1.60(m,6H),1.25-1.35(m,2H),0.92(t,J=7.3Hz,3H);13CNMR(100MHz)δ160.30,160.15,39.65,33.65,32.45,31.40,28.60,25.60,20.20,13.90。HRMS的计算值为C11H22BrN2O2[M+1]+293.0865,测定值为293.0870。
N1-(5-(2-乙酰胺基苯并[d]噻唑-4-基氧基)戊基)-N2-正丁基草酰胺。N1-(5-溴戊基)-N2-正丁基草酰胺(32mg,0.11mmol)、市售N-(4-羟基苯并[d]噻唑-2-基)乙酰胺(22mg,0.11mmol)和K2CO3(45mg,0.32mmol)的混合物的DMF(3mL)在80℃加热3小时,然后冷却到室温,用水(15mL)稀释,并且用EtOAc(3×10mL)萃取。合并的有机萃取物用水(2×5mL)、盐水(10mL)洗涤,(Na2SO4)干燥并且真空浓缩。残留物通过硅胶柱色谱、使用EtOAc/己烷(1:2)作为洗脱液纯化以生成无色固体的类似物32(35mg,76%),mp154-155℃。TLC:70%EtOAc/己烷,Rf~0.35;1H NMR(300MHz)δ11.05(br s,NH,1H),8.30(br s,NH,1H),7.70(br s,NH,1H),7.40(d,J=7.4Hz,1H),7.25(dd,J=7.4,7.8Hz,1H),6.85(d,J=7.8Hz,1H),4.20(t,J=6.0Hz,2H),3.50(q,J=7.2Hz,2H),3.35(q,J=7.0Hz,2H),2.35(s,3H),1.95-1.90(m,2H),1.85-1.80(m,2H),1.70-1.65(m,2H),160-1.55(m,2H),1.40-1.35(m,2H),0.95(t,J=7.3Hz,3H);13CNMR(75MHz)δ169.40,160.55,159.90,157.85,151.50,139.10,134.00,124.75,113.75,108.10,68.90,39.80,39.30,31.35,28.20,27.40,23.70,23.45,20.25,13.90。HRMS的计算值为C20H29N4O4S[M+1]+421.1910,测定值为421.1906。
合成类似物30。
5-(叔丁基二苯基甲硅烷氧基)-N-异丙基戊烷-1-胺。根据先前的文献2,将1-(叔丁基二苯基甲硅烷氧基)-5-碘戊烷6(1.50g,3.32mmol)、异丙胺(1.70mL,19.92mmol)和K2CO3(1.37g,10.03mmol)的混合物反应以生成无色体液的标题胺(0.92g,72%)。TLC:MeOH/CH2Cl2(1:4),Rf~0.30;1H NMR(300MHz)δ7.65-7.67(m,4H),7.30-7.40(m,6H),3.65(t,J=6.4Hz,2H),2.70-2.82(m,1H),2.55(t,J=7.3Hz,2H),1.50-1.64(m,2H),1.32-1.48(m,4H),1.05(d,J=5.8Hz,3H),1.04(s,9H);13C NMR(100MHz)δ135.68,134.21,129.63,127.70,63.95,48.81,47.64,32.60,30.27,27.0,23.76,23.15,19.34。HRMS的计算值为C24H38NOSi[M+1]+384.2723,测定值为384.2724。
N-(5-(叔丁基二苯基甲硅烷氧基)戊基)-N-异丙基庚烷酰胺。根据先前的文献2,用庚酸(0.26g,2.0mmol)将5-(叔丁基二苯基甲硅烷氧基)-N-异丙基戊烷-1-胺(0.90g,2.30mmol)浓缩以生成粘性油状的标题酰胺(0.90g,79%)。TLC:EtOAc/己烷(3:8),Rf~0.60;1H NMR(300MHz,旋转异构体的混合物1:1)δ7.65-7.67(m,4H),7.30-7.40(m,6H),4.62-4.72(m,0.5H),4.00-4.80(m,0.5H),3.62(t,J=4.8Hz,1H),3.68(t,J=4.8Hz,1H),3.02(t,J=5.2Hz,1H),3.16(t,J=5.2Hz,1H),2.38(t,J=5.3Hz,1H),2.24(t,J=5.3Hz,1H),1.50-1.68(m,6H),1.26-1.44(m,8H),1.18(d,J=7.3Hz3H),1,12,(d,J=7.3Hz3H),1.03(s,4.5H),1.04(s,4.5H),0.88(t,J=7.3Hz,3H);13CNMR(125MHz)δ173.38,172.76,135.80,135.78,134.36,134.12,129.85,129.73,127.88,127.82,64.22,63.68,48.43,45.62,43.64,41.27,34.13,34.05,32.61,32.36,31.96,31.93,31.51,29.63,29.47,27.10,27.03,25.94,25.78,24.03,23.77,22.81,21.63,20.78,19.47,14.33,14.28。HRMS的计算值为C31H50NO2Si[M+1]+496.3611,测定值为496.3615。
N-(5-羟基戊基)-N-异丙基庚烷酰胺。将N-(5-(叔丁基二苯基甲硅烷氧基)戊基)-N-异丙基庚烷酰胺(0.70g,1.37mmol)如上述去甲硅烷化(de-silylate)以生成无色固体的标题醇(0.34g,96%)。TLC:EtOAc/己烷(2:3),Rf~0.30;1H NMR(300MHz,旋转异构体的混合物53/47)δ4.58-4.66和3.96-4.08(m,对两种旋转异构体是1H),3.56和3.70(t,J=5.4Hz,对两种旋转异构体是2H),3.02-3.16(m,2H),2.30和2.26(t,J=6.3Hz,对两种旋转异构体是2H),1.50-1.64(m,6H),1.22-1.40(m,8H),1.13和1.09(d,J=7.5Hz,对两种旋转异构体是6H),0.84(t,J=7.3Hz,3H);13C NMR(100MHz)δ172.8162.66,62.60,48.41,45.55,43.56,41.04,34.08,34.0,32.46,32.43,31.86,31.57,29.40,25.87,25.70,23.77,23.73,22.75,21.57,20.72,14.26。HRMS的计算值为C15H32NO2[M+1]+258.2433,测定值为258.2436。
N-(5-溴戊基)-N-异丙基庚烷酰胺。将N-(5-羟基戊基)-N-异丙基庚烷酰胺(0.25g,0.97mmol)转化成上述对应的溴化物,以生成无色油状的标题化合物(0.25g,82%)。TLC:EtOAc/己烷(3:7),Rf~0.40;1H NMR(300MHz,旋转异构体的混合物55/45)δ4.60-4.70和3.96-4.10(m,对两种旋转异构体是1H),3.46和3.36(t,J=5.8Hz对两种旋转异构体是2H),3.02-3.10(m,2H),2.30和2.22(t,J=7.9Hz,对两种旋转异构体是2H),1.80-1.97(m,2H),1.40-1.70(m,6H),1.20-1.40(m,6H),1.16和1.10,(d,J=7.3Hz,对两种旋转异构体是6H),0.86(t,J=7.3Hz,3H);13C NMR(75MHz)δ172.79,172.39,48.17,45.47,43.32,40.70,33.89,33.87,33.49,32.48,32.30,31.81,31.78,30.78,29.27,28.74,26.05,25.84,25.69,25.54,22.64,21.47,20.62,14.17。HRMS的计算值为C15H31BrNO[M+1]+320.1589,测定值为320.1588。
N-(5-(2-乙酰胺基苯并[d]噻唑-4-基氧基)戊基)-N-异丙基庚烷酰胺(30)。用上述市售的N-(4-羟基苯并[d]噻唑-2-基)乙酰胺(54mg,0.26mmol)将N-(5-溴戊基)-N-异丙基庚烷酰胺(75mg,0.23mmol)烷化以生成粘性固体的类似物30(43mg,42%)。TLC:EtOAc/己烷(1:4),Rf~0.30;1H NMR(300MHz,旋转异构体的混合物45/55)δ11.50(br s,-NH,1H),7.37-7.42(m,1H),7.18-7.26(m,1H),6.84-6.88(m,1H),4.58-4.78和4.00-4.10(m,对两种旋转异构体是1H),4.02(t,J=6.3Hz,2H),3.12(t,J=7.3Hz,2H),2.22-2.45(m,5H),1.82-1.92(m,2H),1.44-1.70(m,4H),1.20-1.40(m,8H),1.11-1.19(m,6H),0.82-0.95(m,3H);13C NMR(75MHz)δ173.94,172.78,169.40,169.36,157.89,151.62,138.43,138.32,133.91,133.87,124.92,124.85,114.02,113.87,109.66,108.35,69.46,69.08,48.53,48.33,45.94,43.61,41.20,34.26,34.09,31.91,31.88,31.39,29.55,29.45,29.37,29.30,25.88,25.77,25.71,24.43,24.16,23.55,22.77,21.59,20.80,14.28。HRMS(ESI-阴性)的计算值为C24H36N3O3S[M-1]-446.2477,测定值为446.2434。
合成类似物33。
1-(叔丁基二苯基甲硅烷氧基)-8-(四氢-2H-吡喃-2-基氧基)辛-3-炔。将4-(叔丁基二苯基甲硅烷氧基)-1-丁炔7(5.0g,16.23mmol)与上述2-(4-溴丁氧基)四氢-2H-吡喃8(4.59g,19.48mmol)偶联以生成无色油状的标题乙炔(5.57g,74%)。TLC:EtOAc/己烷(1:9),Rf~0.40;1H NMR(300MHz)δ7.66-7.69(m,4H),7.34-7.42(m,6H),4.57(t,J=4.3Hz,1H),3.78-3.86(m,2H),3.73-3.90(m,3H),3.32-3.40(m,3H),2.40-2.45(m,2H),2.06-2.10(m,2H),1.93-2.02(m,2H),1.40-1.80(m,6H),1.02(s,9H);13C NMR(100MHz)δ137.87,133.96,129.70,128.0,99.0,81.0,77.41,67.32,63.15,62.51,30.97,29.20,27.0,26.98,26.0,25.74,23.18,19.83,19.44,18.88。HRMS的计算值为C29H41O3Si[M+1]+465.2825,测定值为465.2829。
8-(叔丁基二苯基甲硅烷氧基)辛-5-炔-1-醇。将1-(叔丁基二苯基甲硅烷氧基-8-(四氢-2H-吡喃-2-基氧基)辛-3-炔(5.50g,11.84mmol)如上述去甲硅烷化以生成无色油状物的标题化合物(3.87g,86%)。TLC:EtOAc/己烷(2:3),Rf~0.40;1H NMR(300MHz)δ7.60-7.68(m,4H),7.30-7.40(m,6H),3.77(t,J=7.4Hz,2H),3.60-3.72(m,2H),2.40-2.48(m,2H),2.22-2.40(m,2H),1.50-1.70(m,4H),1.03(s,9H);13C NMR(100MHz)δ135.83,133.96,129.90,127.92,81.31,63.16,62.60,32.0,27.0,25.43,23.17,19.43,18.78。HRMS的计算值为C24H33O2Si[M+1]+381.2250,测定值为381.2256。
8-(叔丁基二苯基甲硅烷氧基)辛-5(Z)-烯-1-醇。将8-(叔丁基二苯基甲硅烷氧基)辛-5-炔-1-醇(5.32g,14.0mmol)如上述半氢化(semi-hydrogenate)以生成无色油状物8-(叔丁基二苯基甲硅烷氧基)辛-5(Z)-烯-1-醇(5.18g,97%),其光谱值与文献数据一致。9TLC:EtOAc/己烷(2:3),Rf~0.45;1H NMR(300MHz)δ7.60-7.70(m,4H),7.30-7.40(m,6H),5.34-5.44(m,2H),3.65(t,J=7.0Hz,2H),3.58-3.64(m,2H),2.23(q,J=4.2Hz,2H),1.98-2.20(m,2H),1.30-1.60(m,4H),1.03(s,9H);13C NMR(100MHz)δ135.84,134.21,131.64,129.82,127.87,126.28,63.94,63.12,32.54,31.12,27.23,27.11,26.02。
1-叔丁基二苯基甲硅烷氧基-8-叠氮基-辛-3(Z)-烯。上述步骤之后,将8-(叔丁基二苯基甲硅烷氧基)辛-5(Z)-烯-1-醇(5.20g,13.61mmol)转化成无色油状的标题叠氮化物(3.98g,72%)。TLC:EtOAc/己烷(1:9),Rf~0.60;1H NMR(300MHz)δ7.60-7.70(m,4H),7.30-7.40(m,6H),5.34-5.44(m,2H),3.63(t,J=7.0Hz,2H),3.22(t,J=6.4Hz,2H),2.31(q,J=3.6Hz,2H),1.95-2.05(m,2H),1.50-1.60(m,2H),1.30-1.40(m,2H),1.03(s,9H);13C NMR(100MHz)δ135.98,135.90,134.28,131.24,130.05,129.79,128.10,127.87,126.76,63.98,51.64,31.24,28.74,27.29,27.16,27.07,27.0,19.55;IR(纯样)2931,2858,2095,1111cm-1。HRMS的计算值为C24H34N3OSi[M+1]+408.2471,测定值为408.2470。
1-(8-(叔丁基二苯基甲硅烷氧基)辛-5(Z)-烯基)-3-正戊基脲。使用上述三苯膦将1-(叔丁基二苯基甲硅烷氧基-8-叠氮基-辛-3(Z)-烯还原成对应的胺。将粗胺与上述异氰酸正戊基酯的THF反应,并且产物通过SiO2柱色谱、用20%EtOAc/己烷洗脱纯化以提供粘性油状的标题化合物(1.94g,84%)。TLC:EtOAc/己烷(2:3),Rf~0.45;1H NMR(300MHz)δ7.60-7.70(m,4H),7.30-7.40(m,6H),5.35-5.42(m,2H),4.65(br s,-NH,2H),3.64(t,J=5.5Hz,2H),3.06-3.18(m,4H),2.24-2.34(q,J=3.9Hz,2H),1.94-2.02(q,J=3.6Hz,2H),1.20-1.50(m,10H),1.03(s,9H),0.83(t,J=7.3Hz,3H);13C NMR(100MHz)δ159.52,135.85,134.21,131.53,129.85,127.90,126.28,63.93,40.58,40.50,31.13,30.43,30.41,29.45,27.35,22.77,19.47,14.36。HRMS的计算值为C30H47N2O2Si[M+1]+495.3407,测定值为495.3406。
1-(8-羟基辛-5(Z)-烯基)-3-正戊基脲。将1-(8-(叔丁基二苯基甲硅烷氧基)辛-5(Z)-烯基)-3-正戊基脲(3.0g,6.07mmol)如上述去甲硅烷化(de-silylate)以生成无色固体的标题醇(1.44g,93%),mp57.8-57.9℃。TLC:EtOAc/己烷(1:4),Rf~0.30;1H NMR(300MHz)δ5.30-5.60(m,2H),4.40(br s,-NH,2H),3.63(t,J=6.4Hz,2H),3.08-3.22(m,4H),2.29(q,J=5.3Hz,2H),2.09(q,J=5.2Hz,2H),1.20-1.58(m,10H),0.88(t,J=7.3Hz,3H);13C NMR(100MHz)δ159.48,132.35,126.21,62.28,40.54,40.15,31.12,30.28,29.96,29.35,27.02,26.98,22.68,14.27。HRMS的计算值为C14H29N2O2[M+1]+257.2229,测定值为257.2236。
1-(8-溴辛-5(Z)-烯基)-3-正戊基脲。获得无色油状物,产率82%。TLC:EtOAc/己烷(2:3),Rf~0.60;1H NMR(300MHz)δ5.30-5.58(m,2H),4.70(br s,2H),3.35(t,J=6.8Hz,2H),3.08-3.19(m,4H),2.60(q,J=5.6Hz,2H),2.05(q,J=5.4Hz,2H),1.24-1.54(m,10H),0.88(t,J=7.3Hz,3H);13C NMR(100MHz)δ159.54,132.73,126.45,40.53,40.33,32.85,30.98,30.33,30.30,29.36,27.36,27.0,22.69,14.28。HRMS的计算值为C14H28BrN2O[M+1]+319.1385,测定值为319.1392。
N-(4-(8-(3-正戊基脲基)辛-3(Z)-烯氧基)苯并[d]噻唑-2-基)乙酰胺(33)。获得无色固体,产率40%,mp113.7-113.8℃。TLC:EtOAc/己烷(3:2),Rf~0.40;1H NMR(300MHz)δ12.10(br s,-NH,1H),7.40(dd,J=0.8,7.8Hz,1H),7.22(dt,J=0.6,8.9Hz,1H),6.90(dd,J=0.5,6.9Hz,1H),5.40-5.50(m,2H),4.60(br s,-NH,2H),4.20(t,J=5.3Hz,2H),3.05-3.20(m,4H),2.65(q,J=3.9Hz,2H),2.29(s,3H),2.15(q,J=3.9Hz,2H),1.40-1.70(m,10H),0.87(t,J=7.3Hz,3H);13C NMR(100MHz)δ170.07,159.21,158.52,151.46,138.41,133.84,132.26,126.13,124.81,113.81,108.29,68.46,40.75,40.64,30.20,29.30,27.78,26.84,26.47,23.42,22.62,14.24。HRMS的计算值为C23H35N4O3S[M+1]+447.2430,测定值为447.2431。
合成类似物4。
1-(四氢-2H-吡喃-2-基氧基)-10-(叔丁基二苯基甲硅烷氧基)癸-5-炔。获得无色油状物,产率73%。TLC:15%EtOAc/己烷,Rf~0.50;1H NMR(500MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),4.62(t,J=4.3Hz,1H),3.78-3.92(m,2H),3.68(t,J=6.3Hz,2H),3.40-3.56(m,2H),2.14-2.26(m,4H),1.42-1.90(m,14H),1.04(s,9H);13C NMR(75MHz)δ135.83,132.02,129.80,127,88,99.0,80.52,80.30,67.31,63.74,62.49,32.0,31.06,29.21,27.14,26.21,25.82,25.78,19.89,18.90,18.81。HRMS的计算值为C31H45O3Si[M+1]+493.3138,测定值为493.3140。
10-(叔丁基二苯基甲硅烷氧基)癸-5-炔-1-醇。获得无色油状物,产率88%,其光谱值与文献数据一致。10TLC:EtOAc/己烷(3:7),Rf~0.40;1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),3.67(t,J=5.3Hz,4H),2.06-2.22(m,4H),1.50-1.64(m,8H),1.04(s,9H);13C NMR(75MHz)δ135.82,135.08,134.27,129.80,127.87,80.74,80.60,63.67,62.69,32.09,31.99,27.12,26.83,25.78,25.58,25.48,19.49,18.79,18.76。
10-(叔丁基二苯基甲硅烷氧基)癸-5(Z)-烯-1-醇。获得无色油状物,产率92%,其光谱值与文献数据一致。10TLC:EtOAc/己烷(3:7),Rf~0.45;1H NMR(300MHz)δ7.64-7.68(m,4H),7.42-7.25(m,6H),5.30-5.40(m,2H),3.67(t,J=5.3Hz,4H),2.06-2.22(m,4H),1.40-1.64(m,8H),1.04(s,9H);13C NMR(75MHz)δ135.90,135.81,134.37,129.92,129.87,129.84,127.98,127.80,64.09,63.05,32.47,27.24,27.22,27.13,26.21,26.14,19.51。
1-(10-叠氮基癸-5(Z)-烯氧基)(叔丁基二苯基硅烷。获得无色油状物,产率71%。TLC:EtOAc/己烷(1:9),Rf~0.60;1H NMR(300MHz)δ7.64-7.68(m,4H),7.25-7.42(m,6H),5.30-5.40(m,2H),3.65(t,J=5.3Hz,2H),3.24(t,J=4.9Hz,2H),2.06-2.22(m,4H),1.40-1.64(m,8H),1.04(s,9H);13C NMR(75MHz)δ137.87,134.35,130.69,129.74,127.91,64.02,51.62,32.44,28.67,27.21,27.16,27.08,26.91,26.16,19.48;IR(纯样)2930,2861,2331,2324,2096,1106cm-1。HRMS的计算值为C26H38N3OSi[M+1]+436.2784,测定值为436.2784。
1-(10-(叔丁基二苯基甲硅烷氧基)癸-5(Z)-烯基)-3-正戊基脲。获得无色油状物,产率78%。TLC:EtOAc/己烷(2:3),Rf~0.60;1H NMR(300MHz)δ7.64-7.68(m,4H),7.34-7.42(m,6H),5.22-5.43(m,2H),4.50(br s,-NH,2H),3.65(t,J=6.2Hz,2H),3.10-3.40(m,4H),1.96-2.06(m,4H),1.20-1.60(m,14H),1.03(s,9H),0.88(t,J=7.3Hz,3H);13C NMR(75MHz)δ159.08,136.03,134.02,130.03,128.26,126.82,63.28,40.67,40.47,32.91,30.48,29.28,27.26,27.22,26.93,26.02,22.64,19.39,14.26。HRMS的计算值为C32H51N2O2Si[M+1]+523.3720,测定值为523.3724。
1-(10-羟基癸-5(Z)-烯基)-3-正戊基脲。获得无色油状物,产率94%。TLC:EtOAc/己烷(7:3),Rf~0.30;1H NMR(400MHz)δ5.30-5.43(m,2H),4.28(br s,2H),3.63(q,J=4.6Hz,2H),3.10-3.20(m,4H),2.00-2.10(m,4H),1.24-1.64(m,14H),0.88(t,J=7.3Hz,3H);13C NMR(75MHz)δ158.67,130.17,129.88,62.71,40.59,40.34,32.52,30.23,30.0,29.32,27.09,26.96,25.99,22.52,14.25。HRMS的计算值为C16H33N2O2[M+1]+285.2542,测定值为285.2545。
2-(10-(3-正戊基脲基)癸-5(Z)-烯氧基)乙酸(4)。10℃下搅拌1-(10-羟基癸-5(Z)-烯基)-3-正戊基脲(66mg,0.23mmol)和四正丁基硫酸铵(39mg,0.12mmol)的苯/50%水性KOH(4mL,1:1)溶液。15分钟后,溴乙酸叔丁基酯(136mg,0.70mmol)加入到反应混合物中,并且在相同温度下再搅拌1小时。然后反应混合物用水(10mL)稀释,并用EtOAc(2×10mL)萃取。合并的有机萃取物用水、盐水洗涤,和用(Na2SO4)干燥,并且真空浓缩。残留物在CH2Cl2(4mL)中溶解,冷却到0℃,然后逐滴加入三氟乙酸(1mL)。反应混合物用更多CH2Cl2(5mL)稀释,用水、盐水洗涤,并(Na2SO4)干燥。残留物通过SiO2柱色谱纯化以生成粘性固体的类似物4(37mg,47%)。TLC:EtOAc,Rf~0.30;1H NMR(400MHz)δ5.30-5.42(m,2H),4.06(s,2H),3.54(t,J=6.6Hz,2H),3.07-3.15(m,4H),2.00-2.12(m,4H),1.21-1.66(m,14H),0.88(t,J=7.3Hz,3H);13C NMR(75MHz)δ174.32,160.08,130.33,129.71,71.60,68.12,41.11,41.02,29.68,29.40,29.17,28.96,27.20,27.07,26.64,25.96,22.55,14.20。HRMS的计算值为C18H35N2O4[M+1]+343.2597,测定值为343.2594。
实施例2:合成(S)-2-(13-(3-戊基脲基)十三碳-8(Z)-烯酰氨基)琥珀酸钠(NIH-F=EET A或JLJ)
如图16A和16B所示,如下所示合成EET A:
7-溴庚烷-1-醇1(2):庚烷-1,7-二醇(36.0g,272mmol;阿法埃莎公司(Alfa Aesar))和水性48%HBr(38mL,0.9当量)在苯(400mL)中回流加热,使用迪安斯塔克(Dean-Stark)设备除去水。16小时后,真空除去所有挥发物,并且残留物通过SiO2柱色谱、使用10-30%梯度的EtOAc/己烷作为洗脱液纯化,以生成无色油状物的7-溴庚烷-1-醇(26.22g,62%)。TLC:50%EtOAc/己烷,Rf≈0.40;1H NMR(400MHz,CDCl3)δ3.61(t,2H,J=7.1Hz),3.39(t,2H,J=6.8Hz),1.80-1.88(m,2H),1.52-1.58(m,2H),1.30-1.46(m,6H)。
2-(7-溴庚氧基)四氢-2H-吡喃2(3):二氢吡喃(5.20g,6.11mmol)加入到0℃下搅拌的7-溴庚烷-1-醇(2)(11.0g,56.7mmol)和催化量PTSA的CH2Cl2溶液中。室温下搅拌12小时后,反应混合物用CH2Cl2(200mL)稀释,用水(100mL×2)、盐水(100mL×3)洗涤,通过无水硫酸钠干燥,并且蒸发。残留物通过硅胶柱色谱、使用10-20%梯度的乙酸乙酯/己烷作为洗脱液纯化以生成无色油状物2-(7-溴庚氧基)四氢2H-吡喃(3)(14.50g,92%)。TLC:10%EtOAc/己烷,Rf≈0.55;1H NMR(400MHz,CDCl3)δ4.58-4.56(m,1H),3.84-3.88(m,1H),3.68-3.77(m,1H),3.46-3.51(m,1H),3.33-3.43(m,3H),1.80-1.81(m,2H),1.30-1.62(m,14H)。
叔丁基(己-5-炔-1-基氧基)二苯基硅烷3(5):氩气下,叔丁基二苯基氯硅烷(3.2mL,12.4mmol)逐滴加入到0℃下搅拌的5-己炔-1-醇(4,1.07g,10.9mmol)和无水咪唑(1.84g,27.1mmol)的无水CH2Cl2(20mL)溶液中。全部加入后,反应混合物室温下搅拌12小时,然后用饱和NH4Cl水溶液(50mL)淬灭,并用Et2O(3×50mL)萃取。合并的醚萃取物用饱和NaCl水溶液(25mL)洗涤,通过Na2SO4干燥,并真空除去溶剂。残留物通过快速色谱(5%乙酸乙酯/己烷)纯化以生成无色油状物1-叔丁基二苯基甲硅烷氧基-己-5-炔(5)(3.54g,10.5mmol,96%)。TLC:5%EtOAc/己烷,Rf≈0.65;1H NMR(400MHz,CDCl3)δ7.77-7.65(m,4H),7.40-7.30(m,6H),3.70(t,2H,J=5.6Hz),2.40-2.25(m,2H),2.05(t,1H,J=2.8Hz),1.90-1.70(m,4H),1.18(s,9H)。
叔丁基二苯基((四氢-2H-吡喃-2-基氧基)十三碳-5-炔-1-基)氧基)硅烷(6):氩气下,正丁基锂(14.3mL,35.9mmol,2.5M的己烷溶液)逐滴加入到叔丁基(己-5-炔基氧基)二苯基硅烷(10g,29.76mmol)的THF和干HMPA(4:1,200mL)的-78℃溶液中。30分钟后,反应混合物在1小时时间内加温到0℃,并且保持2小时。反应混合物再冷却到-78℃,并且加入溴化物3的THF溶液(50mL)(8.20g,29.3mmol)。3小时内使反应温度加温到室温,并且在这个温度保持12小时,然后通过加入饱和NH4Cl水溶液(5mL)淬灭。使用1M草酸将反应混合物的pH调节到~4,并用EtOAc(2×250mL)萃取。合并的有机萃取物用水(2×100mL)和盐水(100mL)顺序洗涤,有机层使用无水Na2SO4干燥,并且真空浓缩。残留物通过硅胶柱色谱、使用10%EtOAc/己烷纯化以提供无色浓稠油状物6(12.4g,78%)。1H NMR(CDCl3,400MHz)δ7.68-7.64(m,4H),7.42-7.34(m,6H),4.57(t,J=4.3Hz,1H),3.86-3.78(m,1H),3.65(t,J=6.3Hz,3H),3.54-3.32(m,4H),2.22-2.10(m,4H),1.84-1.24(m,18H),1.04(s,9H);13C NMR(CDCl3,100MHz)δ135.82,135.77,134.25,129.72,127.85,127.80,127.77,99.09,99.05,80.59,80.22,67.84,67.74,63.70,62.58,62.54,31.00,25.73,19.92,19.44,18.97,18.77。
13-(叔丁基二苯基甲硅烷氧基)十三碳-8-炔-1-醇(7):6(15.0g,0.59mmol)和催化量PPTS(10mg)的MeOH(20mL)溶液在0℃下搅拌10小时,然后用饱和NaHCO3水溶液淬灭。真空蒸发掉大部分甲醇。残留物用水(100mL)稀释,并用乙酸乙酯(100mL×3)萃取。减压下浓缩合并的有机萃取物,并且残留物通过硅胶柱色谱、使用20-30%乙酸乙酯/己烷作为洗脱液纯化以提供无色油状物7(8.80g,78.7%)。TLC:20%EtOAc/己烷,Rf≈0.36;1H NMR(CDCl3,400MHz)δ7.68-7.65(m,4H),7.41-7.35(m,6H),3.66-3.62(m,4H),2.10-1.95(m,4H),1.64-1.50(m,2H),1.48-1.20(m,10H),1.04(s,9H);13C NMR(CDCl3,100MHz)δ135.79,135.77,134.26,129.73,127.84,127.83,127.80,127.78,80.56,80.28,63.72,63.22,32.96,31.90,29.01,25.78,19.45,18.95,18.77。
13-(叔丁基二苯基甲硅烷氧基)十三碳-8(Z)-烯-1-醇(8):氢气气氛(1个大气压(atm))下,在双颈圆底烧瓶中,NaBH4(176mg,4.65mmol)分成小份加入到Ni(OAc)2·4H2O(1.16g,9.3mmol)的无水乙醇(10mL)溶液中。15分钟后,加入干乙二胺(0.56g,9.3mmol),再过15分钟后,再加入醇7(8.0g,18.7mmol)的无水乙醇(25mL)溶液。通过TLC监测还原,直到全部完成,然后再用醚(50mL)稀释,通过小硅胶垫以除去无机杂质。减压浓缩滤液以提供粘稠的无色油状物8(7.60g,95%)。TLC:50%EtOAc/己烷,Rf≈0.42;1H NMR(CDCl3,400MHz)δ7.68-7.65(m,4H),7.41-7.35(m,6H),5.40-5.30(m,2H),3.58-3.65m,4H),1.88-2.10(m,4H),1.50-1.61(m,4H),1.25-1.45(m,10H),1.04(s,9H);13C NMR(CDCl3,100MHz)δ135.83,134.36,130.30,129.98,129.77,127.85,64.09,63.17,32.48,29.96,29.53,27.49,27.37,27.21,27.16,26.23,26.01,19.50。
13-(叔丁基二苯基甲硅烷氧基)十三碳-8(Z)-烯酸(9):琼斯(Jones)试剂(5.8mL10N水溶液)的丙酮(25mL)加入到搅拌的醇8(5.0g,11.8mmol)的丙酮(75mL)的-40℃溶液中。1小时后,反应混合物加温到-10℃,并且再维持2小时,然后用过量(5.0当量)异丙醇淬灭。通过过滤除去绿色的铬盐,并且用丙酮洗涤滤饼。真空浓缩合并的滤液和洗涤液,并且所得的残留物溶解在EtOAc(100mL)中,用水(50mL)洗涤,通过无水硫酸钠干燥,并真空浓缩。残留物通过SiO2柱色谱、使用15%EtOAc/己烷作为洗脱液纯化,以生成液体9(3.84g,74.20%)。TLC:40%EtOAc/己烷,Rf≈0.40。1H NMR(CDCl3,400MHz)δ7.68-7.64(m,4H),7.43-7.34(m,6H),5.40-5.26(m,2H),3.66(t,J=6.6Hz,2H),2.35(t,J=7.3Hz,2H),2.10-1.90(m,4H)1.64-1.50(m,2H),1.48-1.20(m,10H),1.04(s,9H);13C NMR(CDCl3,100MHz)δ180.62,135.81,134.34,130.10,130.07,129.73,127.82,127.80,127.79,64.06,32.44,29.12,27.38,27.18,27.12,26.19,24.87,19.47。
13-羟基十三碳-8(Z)-烯酸甲酯4(10):9(7.60g,3.49mmol)和对甲苯磺酸(50mg;PTSA)的MeOH(50mL)溶液在室温下搅拌4小时,然后真空浓缩。残留物通过SiO2柱色谱、使用25%EtOAc/己烷作为洗脱液纯化,以生成无色油状物10(3.41g,87%)。TLC:40%EtOAc/己烷,Rf≈0.35;1H NMR(CDCl3,400MHz)δ5.40-5.36(m,2H),3.60-3.66(m,5H),2.30(t,J=7.3Hz,2H),2.10-1.90(m,4H)1.64-1.50(m,2H),1.48-1.20(m,10H)。
13-叠氮基十三碳-8(Z)-烯酸甲酯5(11):氩气下,偶氮二羧酸二异丙酯(DIAD;3.0g,14.8mmol)逐滴加入到-20℃下三苯膦(3.9g,14.8mmol)的干THF(100mL)溶液中。搅拌10分钟后,逐滴加入10(3.0g,4.75mmol)的无水THF(5mL)溶液。-20℃下30分钟后,反应混合物加温到0℃,并且逐滴加入二苯基磷酰基叠氮化物(DPPA,4.0g,14.5mmol)。室温下搅拌6小时后,反应用水(3mL)淬灭,用醚(100mL)稀释,并用盐水(40mL)洗涤。水层用醚(2×150mL)反萃取。合并的有机萃取物通过Na2SO4干燥,并减压浓缩。残留物通过SiO2柱色谱、使用5%EtOAc/己烷作为洗脱液纯化,以提供浅黄色油状物11(2.72g,82%)。TLC:10%EtOAc/己烷,Rf≈0.45;1H NMR(CDCl3,400MHz)δ5.40-5.34(m,2H),3.64(s,3H),3.26(t,J=6.7Hz,2H),2.30(t,J=7.7Hz,2H)2.10-1.98(m,4H)1.66-1.54(m,2H),1.48-1.24(m,10H)。
13-(3-正戊基脲基)十三碳-8(Z)-烯酸甲酯6(12):三苯膦(2.7g.,11.0mmol)加入到11(1.4g,5.24mmol)的干THF(25mL)的室温溶液中。2小时后,加入水(200μL),并且再持续搅拌8小时。然后反应混合物用EtOAc(100mL)稀释,用水(20mL)和盐水(25mL)洗涤。水层用EtOAc(2×30mL)反萃取。合并的有机萃取物通过Na2SO4干燥,减压下浓缩,并高真空下再干燥4小时。粗胺不用其他纯化即可用于下一步骤。步骤参考文献:S.Chandrasekhar;S.S.Sultana;N.Kiranmai;Ch.NarsihmuluTetrahedron Lett.2007:48,2373。
异氰酸正戊基酯(0.78g.,6.9mmol)加入到上述粗胺(1.4g,5.8mmol)的干THF(25mL)的室温溶液中。6小时后,减压浓缩反应混合物,并且残留物通过SiO2柱色谱、使用30%EtOAc/己烷作为洗脱液纯化以生成无色粘性油状物12(1.70g,85%)。TLC:50%EtOAc/己烷,Rf≈0.40;1H NMR(CDCl3,400MHz)δ5.40-5.26(m,2H),4.46-4.32(m,NH,2H),3.66(s,3H),3.18-3.10(m,4H),2.34(t,J=7.7Hz4H),2.06-1.94(m,4H),1.66-1.56(m,2H),1.54-1.42(m,14H),0.88(t,J=7.0Hz,3H)。
甲基13-(3-正戊基脲基)十三碳-8(Z)-烯酸7(13):LiOH(6.2mL,2.0M水溶液,3.0当量)加入到12(1.80g,5.8mmol)的THF(25mL)和去离子H2O(4mL)的0℃溶液中。室温下搅拌过夜后,反应混合物冷却到0℃,用1M水性草酸把pH调节到4.0,并且用乙酸乙酯(2×20mL)萃取。合并的萃取物用水(30mL)、盐水(25mL)洗涤,用无水Na2SO4干燥,并且真空浓缩。残留物通过SiO2柱色谱、使用25%EtOAc/己烷作为洗脱液纯化,以生成白色固体13(1.48g,86%),m.p.=67.1℃。TLC:80%EtOAc/己烷,Rf≈0.30;1H NMR(CDCl3,400MHz)δ5.40-5.26(m,2H),3.17-3.10(m,4H),2.32(t,J=6.7Hz,2H),2.09-1.95(m,4H),1.65-1.48(m,6H),1.44-1.22(m,12H),0.89(t,J=7.1Hz,3H);13C NMR(CDCl3,75MHz)δ178.5,159.6,130.5,129.5,40.9,40.8,34.4,29.9,29.8,29.2,28.7,28.5,27.2,26.7,24.9,22.6,14.2。
(S)-2-(13-(3-戊基脲基)十三碳-8(Z)-烯酰氨基)琥珀酸酯(14):氩气下,L-天冬氨酸二甲酯(38mg,0.191mmol)和HATU(67mg,0.176mmol)加入到搅拌的13(50mg,0.147mmol)和DIPEA(74mg,0.573mmol)的无水DMF(2mL)溶液中。5分钟后,加入固体的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(33.8mg,0.176mmol;EDCI)。室温搅拌12小时后,反应混合物用EtOAc(15mL)稀释,并用水(5mL)和盐水(10mL)洗涤。合并的水层用EtOAc(3×10mL)反萃取。合并的有机萃取物用Na2SO4干燥,减压浓缩,并且残留物通过SiO2柱色谱、使用50%的EtOAc/己烷作为洗脱液纯化,以生成粘性油状物14(60mg,84%)。TLC:60%EtOAc/己烷,Rf≈0.35;1H NMR(CDCl3,400MHz)δ6.64(d,J=7.9Hz,1H),5.38-5.30(m,2H),4.90-4.82(m,1H),4.58-4.44(m,2H),3.75(s,3H),3.66(s,3H),3.20-3.10(m,4H),3.04(dd,J1=4.3Hz,J2=13.1Hz,1H),2.84(dd,J1=4.6Hz,J2=12.8Hz,1H),2.22(t,J=6.3Hz,2H),2.05-1.98(m,4H),1.70-1.60(m,2H),1.50-1.20(m,16H),0.88(t,J=6.7Hz,3H)。
(S)-2-(13-(3-戊基脲基)十三碳-8(Z)-烯酰氨基)琥珀酸(15):LiOH(2mL,2M溶液,6.0当量)水溶液加入到14(60mg,0.124mmol)的THF(8mL)和去离子H2O(2mL)的0℃溶液中。室温下搅拌过夜后,反应混合物冷却到0℃,用1M水性草酸把pH调节到4.0,并且用乙酸乙酯(2×10mL)萃取。合并的萃取物用水(5mL)、盐水(5mL)洗涤,用无水Na2SO4干燥,并且真空浓缩。残留物通过SiO2柱色谱、使用70-90%EtOAc/己烷作为洗脱液纯化,以生成粘稠的无色油状物15(48mg,85%)。TLC:5%MeOH/EtOAc,Rf≈0.20;1H NMR(CD3OD,400MHz)δ5.38-5.30(m,2H),4.72(t,J=4.3Hz,1H),3.12-3.05(m,4H),2.90-2.72(m,2H),2.22(t,J=7.7Hz,2H),2.10-1.98(m,4H),1.60-1.22(m,18H),1.20(t,J=7.1Hz,3H);13C NMR(CDCl3,75MHz)δ174.9,173.0,172.8,160.1,129.9,129.3,51.8,49.8,39.8,39.7,35.7,35.6,29.9,29.8,29.5,29.0,28.8,26.9,26.7,25.7,22.3,13.2。
(S)-2-(13-(3-戊基脲基)十三碳-8(Z)-烯酰氨基)琥珀酸二钠(16):在室温下,将碳酸氢钠(93mg,1.1mmol)加入搅拌的15(100mg,0.22mmol)的THF/H2O(4:1,5mL)溶液中。2小时后,真空除去THF,并且残留的水相用SM-2生物珠(Bio-Bead)(伯乐公司(Bio-Rad),20-50网;2g)搅拌。1小时后,生物珠通过烧结玻璃漏斗过滤收集,并用水(5mL×2)和最后用95%乙醇(20mL×3)洗涤。真空蒸发乙醇洗液以生成白色固体16(72mg,84%),m.p.=258.5℃。TLC:10%MeOH/CH2Cl2,Rf~0.15;1H NMR(CD3OD,500MHz)δ5.25-5.23(m,2H),4.40(t,1H,J=4.0),3.01-2.97(m,4H),2.58-2.56(m,2H),2.13(t,2H,J=7.0),1.96-1.94(m,4H),1.51-1.47(m,2H),1.30-1.19(m,16H),0.83(t,3H,J=7.0);13C NMR(75MHz,CDCl3)δ178.52,178.38,173.99,160.21,129.93,129.37,52.66,39.81,39.74,36.27,29.50,28.93,26.76,22.34,13.26。
实施例3:合成N-异丙基-N-(5-(2-新戊(pival)酰氨基苯并[d]噻唑-4-基氧基)戊基)庚烷酰胺(MV=EET-B或SRD-2)
如图15所示,如下所示合成EET B:
5-(叔丁基二苯基甲硅烷氧基)戊烷-1-醇(2):氩气、0℃下,咪唑(0.65g,9.60mmol)加入到搅拌的戊烷-1,5-二醇(1.00g,9.60mmol)的干二氯甲烷(10mL)溶液中,然后逐滴加入叔丁基氯二苯基硅烷(3.85mL,9.60mmol)的CH2Cl2(2mL)溶液。使反应缓慢升温至室温。12小时后,反应混合物用水(2×30mL)、盐水(20mL)洗涤,通过Na2SO4干燥,并且减压浓缩。残留物通过SiO2快速色谱、使用30%乙酸乙酯/己烷作为洗脱液纯化,以提供2(1.35g,46%),回收的SM和双保护(di-protected)的化合物。TLC:30%EtOAc/己烷,Rf~0.38;1H NMR(CDCl3,400MHz)δ7.67-7.62(m,4H),7.45-7.35(m,6H),3.67(t,2H,J=6.0Hz),3.52(t,2H,J=6.7Hz),2.03-1.93(m,2H),1.72-1.64(m,4H),1.04(s,9H)。
叔丁基(5-碘戊氧基)二苯基硅烷(3):咪唑(310mg,4.40mmol)、碘(440mg,3.5mmol),以及2(1g,2.98mmol)的CH2Cl2(2mL)溶液顺序加入到0℃下PPh3(450mg,3.5mmol)的CH2Cl2(15mL)溶液中,并且在黑暗中保存。2小时后,反应混合物通过加入20%水性Na2S2O3(5mL)来淬灭。水层用CH2Cl2(2×50mL)萃取。合并的有机萃取物用盐水(30mL)洗涤,通过无水Na2SO4干燥,并且真空除去溶剂。残留物通过精细(careful)柱色谱、使用5%EtOAC/己烷纯化以提供碘化物3(1.25mg,92%)。TLC:10%EtOAc/己烷,Rf~0.85;1H NMR(CDCl3,400MHz)δ7.67-7.62(m,4H),7.45-7.35(m,6H),3.67(t,2H,J=6.0Hz),3.41(t,2H,J=6.7Hz),2.03-1.93(m,2H),1.72-1.64(m,4H),1.04(s,9H)。
5-(叔丁基二苯基甲硅烷氧基)-N-异丙基戊烷-1-胺(4):氩气下,K2CO3(1.50g,11.05mmol)、异丙胺(0.65mL,11.05mmol)和碘化物3(2.50g,5.83mmol)的干THF(15mL)在密封管中在66℃加热。12小时后,水(5mL)加入到反应混合物中,然后用EtOAc(3×50mL)萃取反应混合物。合并的有机萃取物通过MgSO4干燥,并且减压下浓缩以提供无色液体4(1.90g,92%),其足够纯,不用进一步纯化即可用于下一步骤。TLC:MeOH/CH2Cl2(1:4),Rf~0.30;1H NMR(400MHz)δ7.65-7.67(m,4H),7.30-7.40(m,6H),3.65(t,J=6.4Hz,2H),2.70-2.82(m,1H),2.55(t,J=7.3Hz,2H),1.50-1.64(m,2H),1.32-1.50(m,4H),1.05(d,J=5.8Hz,3H),1.04(s,9H);13C NMR(100MHz)δ135.68,134.21,129.63,127.70,63.95,48.81,47.64,32.60,30.27,27.0,23.76,23.15,19.34。
N-(5-(叔丁基二苯基甲硅烷氧基)戊基)-N-异丙基庚烷酰胺(5):氩气下,庚酸(2.06g,15.86mmol)和二异丙基乙胺(2.72mL,21.14mmol;DIPEA)加入到搅拌的胺4(4.00g,10.57mmol)的无水DMF(20mL)溶液中。5分钟后,加入固体的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(3.04g,15.86mmol;EDCI)。室温搅拌12小时后,反应混合物用EtOAc(100mL)稀释,并用水(2×30mL)和盐水(20mL)洗涤。合并的水层用EtOAc(3×30mL)反萃取。合并的有机萃取物用Na2SO4干燥,减压浓缩,并且残留物通过SiO2柱色谱、使用30%的EtOAc/己烷作为洗脱液纯化,以生成粘性油状物的胺5(4.75g,91%)。TLC:EtOAc/己烷(3:7),Rf~0.60;1H NMR(400MHz,旋转异构体的混合物1:1)δ7.65-7.67(m,4H),7.30-7.40(m,6H),4.62-4.72和3.96-4.80(m,1H,旋转异构体),3.62和3.68(t,J=4.8Hz,2H,旋转异构体),3.02和3.16(t,J=5.2Hz,2H,旋转异构体),2.38和2.24(t,J=5.3Hz,2H,旋转异构体),1.50-1.68(m,6H),1.26-1.44(m,8H),1.18和1,12,(d,J=7.3Hz,6H,旋转异构体),1.03和1.04(s,9H,旋转异构体),0.88(t,J=7.3Hz,3H);13C NMR(100MHz,旋转异构体的混合物1:1)δ173.38,172.76,135.80,135.78,134.36,134.12,129.85,129.73,127.88,127.82,64.22,63.68,48.43,45.62,43.64,41.27,34.13,34.05,32.61,32.36,31.96,31.93,31.51,29.63,29.47,27.10,27.03,25.94,25.78,24.03,23.77,22.81,21.63,20.78,19.47,14.33,14.28。
N-(5-羟基戊基)-N-异丙基庚烷酰胺(6):5(4.75g,9.02mmol)和对甲苯磺酸的MeOH(50mL)溶液室温搅拌12小时,然后用固体NaHCO3淬灭,并过滤。真空蒸发滤液,并且残留物在乙酸乙酯(50mL)中溶解。乙酸乙酯层用水(2×50mL)、盐水(50mL)洗涤,通过无水Na2SO4干燥,并且减压浓缩。残留物通过硅胶快速柱色谱、使用50-60%乙酸乙酯/己烷作为洗脱液纯化,以提供无色粘稠液体醇6(2.35g,93%)。TLC:EtOAc/己烷(1:1),Rf~0.30;1H NMR(400MHz,旋转异构体的混合物55/45)δ4.58-4.66和3.96-4.08(m,1H,旋转异构体),3.56和3.70(t,J=5.4Hz,2H,旋转异构体),3.02和3.16(t,J=5.2Hz,2H,旋转异构体),2.38和2.26(t,J=6.3Hz,2H,旋转异构体),1.50-1.64(m,6H),1.22-1.40(m,8H),1.13和1.09(d,J=7.5Hz,6H,旋转异构体),0.84(t,J=7.3Hz,3H);13C NMR(100MHz,旋转异构体的混合物55/45)δ172.81,62.66,62.60,48.41,45.55,43.56,41.04,34.08,34.0,32.46,32.43,31.86,31.57,29.40,25.87,25.70,23.77,23.73,22.75,21.57,20.72,14.26。
N-(5-溴戊基)-N-异丙基庚烷酰胺(7):TPP(4.45g,9.34mmol)加入到醇6(2.00g,7.78mmol)的干CH2Cl2(50mL)的0℃溶液中。10分钟后,加入CBr4(3.10g,9.34mmol),并且0℃下持续搅拌。2小时后,加入水(20mL),并且反应混合物用EtOAc(3×50mL)萃取。合并的萃取物用水(2×20mL)、盐水(20mL)洗涤,通过Na2SO4干燥,并且减压下浓缩。残留物通过SiO2柱色谱、使用30-35%乙酸乙酯/己烷纯化以提供7(2.20g,91%)。TLC:EtOAc/己烷(3:7),Rf~0.40;1H NMR(400MHz,旋转异构体的混合物5/55)δ4.60-4.70和3.96-4.10(m,1H,旋转异构体),3.46和3.36(t,J=5.8Hz,旋转异构体),3.02-3.10(m,2H),2.30和2.22(t,J=7.9Hz,2H),1.80-1.97(m,2H),1.40-1.70(m,6H),1.20-1.40(m,6H),1.16和1.10,(d,J=7.3Hz,6H,旋转异构体),0.86(t,J=7.3Hz,3H);13C NMR(100MHz,旋转异构体)δ172.79,172.39,48.17,45.47,43.32,40.70,33.89,33.87,33.49,32.48,32.30,31.81,31.78,30.78,29.27,28.74,26.05,25.84,25.69,25.54,22.64,21.47,20.62,14.17。
异丙基-N-(5-(2-新戊(pival)酰氨基苯并[d]噻唑-4-基氧基)戊基)-庚烷酰胺(11):溴化物7(0.35g,1.09mmol)、N-(4-羟基苯并[d]噻唑-2-基)新戊酰胺(10)(0.27g,1.09mmol)和K2CO3(0.30g,2.18mmol)的DMF(10mL)的溶液在80℃加热。4小时,反应混合物冷却到室温,加入水(5mL),并且混合物用乙酸乙酯(3×30mL)萃取。合并的有机萃取物用H2O(2×20mL)、盐水(20mL)洗涤,通过Na2SO4干燥并且过滤。减压蒸发滤液,并且残留物通过硅胶柱色谱(50-70%EtOAc/己烷)纯化以生成粘稠液体11(0.39g,72%)。TLC:EtOAc/己烷(7:3),Rf~0.26;1H NMR(400MHz,旋转异构体的混合物45/55)δ7.24和7.20(d,J=7.4Hz,1H,旋转异构体),7.16和7.14(dd,J=7.4Hz,J=7.4Hz,1H,旋转异构体),6.90和6.80(d,J=7.4Hz,1H,旋转异构体),4.58-4.78和3.96-4.10(m,1H,旋转异构体),4.02(t,J=6.3Hz,2H),3.12(t,J=7.3Hz,2H),2.30和2.27(t,J=5.6Hz,2H,旋转异构体),1.82-1.92(m,2H),1.44-1.70(m,4H),1.38-1.32(m,8H),1.20(d,J=6.4Hz,3H),1.13(d,J=6.4Hz,3H),1.11(d,J=6.4Hz,3H),0.88-085(m,6H);13C NMR(100MHz,旋转异构体的混合物45/55)δ189.64,189.62,173.04,172.57,172.55,167.16,167.09,167.06,146.85,146.77,146.67,128.90,128.87,125.90,125.79,124.24,124.13,115.32,115.06,111.00,110.09,110.05,68.97,68.74,58.50,48.34,45.62,41.24,41.10,40.95,34.10,29.52,29.15,25.72,24.28,21.66,20.7614.30。
N-(4-羟基苯并[d]噻唑-2-基)新戊酰胺(10)室温下,2-氨基苯并[d]噻唑-4-基(0.50g,3.01mmol)的甲苯(10mL)悬浮液中加入三甲基乙酰氯(trimethyacetyl chloride)(3.60mL,30.10mmol)。反应混合物在115℃下搅拌22小时。蒸发溶剂,并且残留物用EtOAc共沸以生成棕褐色的固体9(0.78g,78%)。用K2CO3(0.20g,3.50mmol)处理上述固体(0.78g)的MeOH(15mL)悬浮液,并且室温搅拌6小时。蒸发MeOH,并且残留物用H2O稀释。所得的混合物用浓(concd)HCl中和到pH=7,并用EtOAc(3×30mL)萃取。合并的有机相通过硫酸钠干燥,过滤,并且真空浓缩以提供棕褐色固体10(0.48g,82%)。TLC:EtOAc/己烷(7:3),Rf~0.32;1H NMR(400MHz,CDCl3)δ10.25(br s,1H),9.66(br s,1H),7.33(d,J=7.4Hz,1H),7.09(dd,J=7.4,7.4,Hz,1H),6.82(d,J=7.4Hz,1H),1.45(s,9H).13C NMR(100MHz,CDCl3)δ177.15,159.12,148.10,136.55,133.00,125.55,113.40,111.50,39.70,27.38。
实施例4:体外筛选EET类似物文库
在本实施例中,本发明人使用新合成的化合物进行血管舒张试验和可溶环氧化物水解酶抑制试验。这些试验的结果记录在上面表1的后三列和图14中。作为这些试验的结果,选定四种化合物(化合物26、20、7和30)以进一步体内测试,如后面实施例所示。
可溶的环氧化物水解酶抑制。测试化合物抑制重组的可溶环氧化物水解酶(sEH)蛋白的能力。所述试验使用(3-苯基-环氧乙烷基)-乙酸氰基-(6-甲氧基-萘-2-基)-甲酯(PHOME),其是sEH的灵敏底物,能用于监测人和鼠酶的活性。将底物环氧化物水解以生成高荧光产物(6-甲氧基-2-萘甲醛),其能分别用于监测激发和发射波长330和465nm。参见Wolf等,Anal Biochem355:71-80,2006PMID:16729954。人重组sEH与底物和化合物在浓度范围0.1-1000nM内孵育。将各浓度残留的活性百分比绘图,并且使用统计软件测定IC50(50%抑制时的浓度)。
血管扩张剂活性。在牛冠状动脉中测量血管舒张活性。取得牛心脏,并且解剖冠状动脉左前降支,并清洁结缔组织。如上述,将直径1mm的血管切成宽3mm的环(3,27,39)。血管存储在Krebs缓冲液中,所述缓冲液由(以mM计)119NaCl、4.8KCl、24NaHCO3、1.2KH2PO4、1.2MgSO4、11葡萄糖、0.02EDTA和3.2CaCl2构成。在6-ml水套器官腔室中,用一对不锈钢钩形件悬浮所述血管。器官腔室充满Krebs缓冲液,并且37℃下用95%O2-5%CO2鼓泡。一个钩形件锚定在钢杆,而另一个钩形件锚定在力传感器(型号FT-03C;罗得岛西沃威克的GI公司(GrassInstruments))。血管张力通过ETH-400桥式(bridge)放大器测量,并且数据通过MacLab8e类似物-数字转化器和MacLab软件版本3.5.6(马萨诸塞州密耳佛德的AD仪器公司(AD Instruments))获得,并且存储在Macintosh计算机上以随后分析数据。
3.5g长度最大值时设定基本(basal)张力并且平衡1.5小时。KCl(40mM)加入到腔室中,直到维持可重复的最大收缩时。U-46619(10–20nM)(血栓烷受体激动剂)用于把血管从基本张力预先收缩(precontract)到最大KCl收缩的50%-90%。向腔室中累积加入化合物。在浓度-反应曲线之间,腔室用新鲜Krebs缓冲液清洗,给予40mM KCl以测定最大收缩,并且清洗血管。用14,15-EET作出连续浓度-反应曲线,然后对化合物作出浓度-反应曲线。总是用激动剂反向顺序重复所述实验。在用对14,15-EET的连续浓度-反应曲线的实验中,化合物的第二浓度-反应曲线与第一曲线一致。张力表示为舒张百分比,而100%舒张是预先U-46619的基本张力。将舒张对比化合物浓度绘图,并且使用统计软件测定EC50。
血管扩张剂的结果和sEH抑制活性试验表1总结了33种合成化合物的血管舒张的效果和sEH抑制活性。使用EET药效团部分,通过可溶的环氧化物水解酶(sEH)将很多EET类似物设计成可溶性增加和对自氧化、醚化和代谢的抗性增加。观察到这些化合物具有与EET类似的活性,如其在牛冠状动脉中血管舒张活性和sEH抑制(sEHi)活性所示。其中,就潜在的抗高血压效果研究了其中的四种化合物,所述四种化合物通过用电子等排取代(isosteric replacement)或杂环替代来取代EET药效团的COOH基团。下面表2总结了这些化合物的血管扩张剂的结果和sEH抑制活性。
表2:选定在体内模型测试的化合物的特性。
实施例5:使用大鼠高血压模型体外测试四种化合物。
测量遥测(Telemetry)血压。为了精确检测血压和心率的变化,根据生产商说明书,在实验期前一周在戊巴比妥钠麻醉下,将遥测发射机(明尼苏达州圣保罗的数据科学公司(Data Sciences Inc.))植入到大鼠内。简单说,制成切口以暴露股动脉,阻塞所述动脉以插入发射机导管。用组织胶在适当位置固定所述导管,并且在适当位置缝合所述发射机,以及封闭切口线(incision line)。使大鼠从手术中恢复,并且回到各自住所(housing)。在实验期前记录基线动脉压。在整个实验期内持续记录平均动脉压。
血管紧张素高血压。遥测发射机如所述植入到雄性Sprague-Dawley大鼠(225-275g)中。记录基本血压后,(s.c.)植入渗透泵从而以60ng/分钟剂量递送血管紧张素。EET类似物通过渗透泵(2mg/d,i.p.)给药,并且持续监测血压。
自发性高血压大鼠(SHR)。遥测发射机如所述植入到雄性SHR中。手术恢复期后,记录基线平均动脉压。在这一系列实验中,EET类似物通过渗透泵(2mg/d,i.p.)给药,并且持续监测血压。
测量蛋白排出。动物置于代谢笼(metabolic cage)中,并且在锥形管收集尿。在试验之前,样品保存在-80℃。测量尿蛋白排出作为肾损伤的指数。蛋白通过Bradford比色法测定,并且肌酸酐通过苦味酸比色法测定。
遥测和尿分析方法进一步描述在下列出版物中:Imig JD,Zhao X,Zaharis CZ,Olearczyk JJ,Pollock DM,Newman JW,Kim IH,Hammock BD.,An orally activeepoxide hydrolase inhibitor lowers blood pressure and provides renal protection insalt-sensitive hypertension(“口服活性环氧化物水解酶抑制剂降低血压并提供盐敏感型高血压的肾保护”)Hypertension46:975-981,2005.PMID:1615779;ElmarakbyAA,Quigley JE,Olearczyk JJ,Srindhar A,Cook AK,Inscho EW,Pollock DM,Imig JD.,Chemokine receptor2b blockade inhibition provides renal protection in angiotensin II-salthypertension(“趋化因子受体2b的阻断抑制提供了血管紧张素II-盐高血压的肾保护”),Hypertension50:1069-1076,2007.PMID:17938380;和Olearczyk JJ,Quigley JE,Mitchell B,Yamamoto T,Kim IH,Newman JW,Lauria A,Hammock BD,Imig JD.,Inhibition of the soluble epoxide hydrolase protects the kidney from damage inhypertensive Goto-Kakizaki rats(“抑制可溶的环氧化物水解酶保护了高血压Goto-Kakizaki大鼠的肾免于损伤”),Clinical Science116:61-70,2009.PMID:18459944。这些出版物通过引用纳入本文。
统计学分析。所有数据表示为平均值±SEM。就重复测量而言,使用方差分析(ANOVA)来分析平均动脉血压数据。与对照相比p<0.05,认为有统计学显著区别。使用GraphPad Prism4.0版本软件(加利福尼亚州拉由拉市格拉夫派得(GraphPad)软件公司)进行分析。
结果-对血压和心率的效果。自发性高血压大鼠(SHR)。在这个高血压模型中,研究四种选定化合物降低血压的能力。观察到这四种化合物中的两种有降低血压的效果。SHR中,SRD(化学结构如图1A所示)和LGK(化学结构如图2A所示)缺少降低血压的作用。在SRD治疗的SHR组中,治疗两周后,血压与载剂治疗的SHR组相似(150±5.0对比141±3.0mmHg)(见图1B-C)。治疗两周后,在SHR中,LGK与载剂相比,没有改变血压(137±1.0对比141±3.0mmHg)(图2C-D)。与其对血压的效果相似,SRD和LGK与载剂SHR相比而言,都不影响心率(SRD,344±23.0对比331±17.0BPM;LGK,325±11.0对比331±17.0BPM)。
JLJ(化学结构如图3A所示)治疗两周造成SHR中血压与载剂治疗组相比的中度下降(131±2.0对比141±3.0mmHg),并且从治疗的第一周可观察到其血压降低的效果(图3B-C)。化合物MV(化学结构如图4A所示)也显示了相似的降低SHR血压的效果,并且与载剂相比而言,造成了血压下降12mmHg(129±2.0对比141±3.0mmHg)。另外,与JLJ相似,观察到MV在治疗SHR四天内开始降低血压,并且直到两周治疗期结束前都维持这种效果(见图4B-C)。与其血压降低效果形成对比,还观察到JLJ和MV与载剂SHR相比而言,对心率没有任何影响(JLJ,316±23.0对比331±17.0BPM;MV,318±24.0对比331±17.0BPM)。考虑到JLJ和MV有降低SHR模型血压的效果,进一步在另一种高血压模型(血管紧张素II(Ang II)高血压)中测试了这些化合物。
Ang II高血压大鼠。化合物JLJ显示了从治疗开始就对由Ang II诱导升高的血压具有减弱效果,并且这存在于整个治疗期中。观察到两周治疗期结束时,JLJ与载剂相比显著减弱了Ang II诱导的高血压(135±5.0对比150±3.2mmHg)(图5A-B)。与JLJ相似,化合物MV也显示了对Ang II高血压有显著减弱的效果(107±2.0对比150±3.2mmHg),并且在整个治疗期内都观察到了这种减弱效果(图6A-B)。与SHR相似,两周治疗后,在ANG II高血压中,JLJ(410±25.0对比396±25.0BPM)和MV(385±16.0对比396±25.0BPM)与载剂相比而言,显示对心率都没有任何影响。
Ang II高血压中MV对钠排出和蛋白排出的影响。本研究的Ang II高血压中,观察到化合物MV(化学结构如图4A所示)的两周治疗相比载剂造成尿钠增多(natriuresis)(2.7±0.3对比1.9±0.7mmol/d)。观察到化合物MV降低了Ang II高血压中尿蛋白-肌酸酐比率(1.5±0.2对比2.8±0.7),所述比率是肾损伤的指示物。
实施例6:EET类似物对治疗顺铂肾脏毒性的效果
本实施例中,发明人研究了在两种新开发的口服活性EET类似物在顺铂诱导的肾脏毒性中的肾保护作用。显示了EET类似物在顺铂给药中有显著的肾脏保护作用,并且这种作用与其抗氧化、抗炎性、抗ER应激和抗细胞凋亡活性有关。还显示了经这些EET类似物保护肾免于顺铂的有害肾脏毒性作用,但是这些EET类似物没有顺铂的化疗作用。
肾脏毒性严重限制了抗癌药物顺铂的应用。氧化应激、炎症和内质网(ER)应激对顺铂诱导的肾脏毒性起作用。通过修饰EET药效团的羧酸酯、烯烃、和环氧化物部分从而开发了口服活性的EET类似物(包括但不限于化合物EET-A和EET-B)。测定给予权利要求的EET类似物是否会降低肾脏毒性,包含顺铂诱导的肾脏毒性。向用EET类似物(10mg/kg/d p.o.,n=5)或载剂(n=7)预处理7天的大鼠中给予顺铂(7mg/kg i.p.)。顺铂注射后第5天,收集尿、血浆和肾。在BUN、血浆肌酸酐(PCr)、尿N-乙酰-(D)-葡萄糖苷酶活性(NAG)、肾损伤分子-1(KIM-1)和肾小管管型形成增加了3-5倍表明了顺铂诱导的肾脏毒性。EET类似物在BUN(载剂:241±51对比EET-A:108±30和EET-B:120±33mg/dL)、PCr(3.1±0.2对比2.0±0.2和1.4±0.2mg/dL)、KIM-1(296±94对比85±29和57±13ng/d)和NAG(3.0±0.6对比0.5±0.1和0.6±0.2U/d)(P<0.05)中减弱了顺铂诱导的增加。EET类似物治疗使顺铂诱导的肾小管管型形成降低了50%。EET类似物减弱顺铂诱导的肾TBARS形成(载剂:16±2对比EET-A:7±1;EET-B:8±1μmol/g),并且造成NOX1和gp91phox mRNA肾表达的下降了2-3倍(P<0.05)。顺铂诱导的肾脏毒性伴有肾炎症和ER应激的升高,造成炎性(TNF-α,IL-6,IL-1β)和ER应激(胱冬酶12,GRP78)基因的肾mRNA表达的增加。EET类似物造成这些炎性和ER应激表达下降30-70%(P<0.05)。顺铂引起肾中凋亡信号,并伴有Bak/Bcl2和Bax/Bcl2mRNA表达比率和肾皮质胱冬酶3活性的升高。EET类似物造成肾Bak/Bcl2和Bax/Bcl2mRNA表达比率下降2-14倍以及肾胱冬酶3活性下降50%(P<0.05)。在数种癌细胞系的体外研究中,本发明还显示了EET类似物的肾保护效果不损害顺铂的抗癌特性。总体来说,这些数据显示了口服活性的EET类似物保护免受肾脏毒性(包含顺铂诱导的肾脏毒性),所述保护是通过降低氧化应激、炎症、和ER应激,而不影响顺铂化疗效果。另外,EET类似物也保护免受其他常见的顺铂副作用,包含听力的丧失。
动物体内实验。根据美国密尔沃基的威斯康星医学院的动物护理和使用委员会的指导原则,实验得到批准和实施,雄性Wistar-Kyoto(WKY)大鼠体重为180-200g(马萨诸塞州威尔明顿的查尔斯河公司(Charles River))。所有动物保持在温度可控的环境中,有12小时光照/黑暗循环,并且在任何时间可自由获取食物和水。实验前,使大鼠有6天的习服期间。大鼠分成四个组。第1组(WKY,n=5-7):大鼠随意接受饮用水7天,并且在第7天给予DMSO(美国密苏里州圣路易斯的西格马-阿德瑞奇公司(Sigma Aldrich))(300-500μl i.p.)。DMSO用于制备本研究中使用的顺铂(CP)(美国密苏里州圣路易斯的西格马-阿德瑞奇公司)溶液,并且最大注射体积设定在500μl。第2组(CP+载剂,n=5-7):大鼠用含有载剂(0.05%乙醇和0.1%PEG-400v/v)的饮用水预处理七天,然后在第7天给予CP(7mg/kg i.p.),随后再用载剂处理五天。第3组(CP+EET-A,n=5-7):这些大鼠用有EET类似物EET-A(10mg/kg/天p.o.)的饮用水预处理七天,然后在第7天单独注射给予CP(7mg/kg i.p.),随后再用EET-A处理五天。第4组(CP+EET-B,n=5-7):这组大鼠用有另一个EET类似物EET-B(10mg/kg/天)的饮用水预处理七天,然后在第7天单独注射给予CP(7mg/kg i.p.),随后再用EET-B处理五天。第2、3和4组大鼠分别可自由获得载剂、EET-A和-B的饮用水。处死大鼠前一天,24小时时期内收集各只大鼠的尿,并且测量体积。给予CP或DMSO后五天,将大鼠麻醉以收集血液样品,然后将大鼠安乐处死并收集组织。到分析前,尿和血浆样品冷冻保存在-80℃。除去肾,用生理盐水洗涤,并且保存在-80℃,直到用于RT-PCR分析、硫代巴比妥酸活性物质(TBARS)测量和胱冬酶3活性试验。肾的一部分也保存在10%缓冲的福尔马林中以组织检测。
生物化学分析。血液尿素氮(BUN)(美国加利福尼亚州海沃德的生物试验系统公司(BioAssay Systems))和血清肌酸酐(美国密歇根州安娜堡的卡曼(Cayman)化学公司)的水平使用市售试剂盒用分光光度法测量。肌酸酐和蛋白的尿含量使用市售试剂盒(美国密歇根州安娜堡的卡曼化学公司)测量,并且尿中的尿N-乙酰-b-葡萄糖苷酶(NAG)活性通过来自Diazyme(美国加利福尼亚州波韦的Diazyme实验室公司)试剂盒来测量。而肾损伤分子-1(KIM-1)的尿含量使用ELISA(美国明尼苏达州明尼阿波利斯的R&D系统公司)测量。
测定肾中的丙二醛。丙二醛(MDA)是硫代巴比妥酸活性物质(TBARS),其作为脂质过氧化的终产物形成,并且作为氧化应激的重要指数。为了测定肾MDA水平,大鼠肾用包含1.5%的氯化钾缓冲液匀浆以获得1:10(w/v)全肾匀浆物。使用市售可得的试剂盒(美国密歇根州安娜堡的卡曼化学公司),用硫代巴比妥酸反应后用分光光度法测定MDA。
测定胱冬酶3活性。使用市售荧光测定试验试剂盒(美国密苏里州圣路易斯市的希格玛-艾尔德里奇公司)测定肾匀浆物中胱冬酶3的活性。肾匀浆物使用裂解缓冲液(50mM HEPES,pH7.4,有5mM CHAPS和5mM DTT)制备。肾匀浆物在10,000g离心10分钟,并且所得的上清液用于试验。胱冬酶3荧光测定试验基于胱冬酶3水解肽底物乙酰-Asp-Glu-ValAsp-7-酰氨基-4-甲基香豆素(Ac-DEVD-AMC),造成释放荧光7-氨基-4-甲基香豆素(AMC)部分。.胱冬酶3活性表示为AMC/分钟/μL的nmol。
实时PCR分析。进行实时分析以评价肾中氧化性(gp91phox、NOX1、SOD1、SOD2、SOD3)、炎性(TNF-α、IL-6、IL-1β)、凋亡(Bax、Bak、Bcl-2)和内质网应激(GRP78、胱冬酶12)相关基因的表达。根据生产商说明书,使用TRIzol LS试剂(美国加利福尼亚州卡尔斯巴德的英杰生命技术公司)从肾匀浆物中分离总RNA。分离的RNA用无RNA酶的DNA酶(美国加利福尼亚州卡尔斯巴德的英杰公司)处理以除去痕量的基因组DNA污染。mRNA样品通过分光光度法在260nm定量,并且使用iScriptTM选定cDNA合成试剂盒(美国加利福尼亚州赫库斯的伯乐公司)把1μg的总RNA逆转录成cDNA。
靶标基因表达通过有SYBR绿的iScript一步RT-PCR试剂盒,使用MyiQTM单色实时PCR检测系统(美国加利福尼亚州赫库斯的伯乐实验室公司)来定量。就均匀性分析所有孔中的各扩增样品,所述分析使用iQ5光学系统软件2.1版本(美国加利福尼亚州赫库斯的伯乐实验室公司)的解离曲线来进行。95℃下变性2分钟后,进行40轮循环,在95℃下10秒和在60℃下30秒。各样品一式三份地进行,并且比较阈值循环(Ct)方法用于定量在靶标基因表达中与对照相比增加的倍数(2–ΔΔCt)。在分析靶标基因的相对表达中,用管家基因(pgk1)标准化Ct值。在各实验组中,对至少5-7个实验样品进行统计学分析。根据数篇更早的报导来设计本研究使用的引物。用10%缓冲的福尔马林固定肾后,把肾组织切片,并且用高碘酸-席夫(Schiff)(PAS)试剂染色以组织检测。在×200放大下检测包含蛋白性形状(cast)的细管的数目,从而使用图像分析软件NIS Elements AR3.0版本(美国纽约州梅尔维尔市的尼康仪器公司(Nikon instruments inc.))来评价管损伤。从各个肾样品的8个皮层区域和5个髓质区域(×200)的均值来计算形状为阳性的面积百分比。为了将观察者的偏见最小化,依盲法进行形状面积的计算,而没有告诉组织是源于哪个处理组。
是否存在EET类似物下,顺铂的体外抗肿瘤的活性。这个研究中,HEK293、U87MG、Hela细胞系获自ATCC(美国弗吉尼亚州马纳萨斯)(HEK293、U87MG、Hela),并且从美国德克萨斯州达拉斯的德克萨斯大学西南医学中心的儿科系收集NCCIT。所有细胞系在购自生命技术公司(Life Technologies)(美国纽约州格兰德岛)的含10%胎牛血清和青霉素/链霉素的DMEM或RPIM中培养。顺铂购自西格玛公司(美国密苏里州圣路易斯市)或卡巴开公司(CalBiochem)/EMD生物科学公司(美国马塞诸塞州比尔瑞卡)。细胞接种在96孔板中,根据细胞类型每孔接种500-4,000个细胞。二十四小时后,细胞用顺铂或载剂和/或EET类似物EET-A在不同浓度处理72小时。根据生产商说明书,使用刃天青(西格玛-奥德里奇公司)通过阿拉马蓝来测量细胞活性。通过BMG实验室技术公司(美国北卡罗来纳州卡雷)96孔板读数仪的荧光/吸光来测量活性结果,并且IC50通过GraphPad Prism5软件(美国加利福尼亚州拉由拉市的格拉夫派得软件公司)计算。
统计学分析。结果表示为平均值±S.E.M.。两次测量的统计学显著性通过使用4.0版本软件(美国加利福尼亚州拉由拉市的格拉夫派得软件公司),由双尾未配对学生t检验来测量(组与组之间由重复测量单向方差分析和随后的图基事后(Tukey’s post-hoc)分析来测量)。P<0.05的概率值认为有显著性,而P关键值是双侧的。
结果。EET类似物处理使得给予顺铂的大鼠肾功能障碍和损伤减弱。为了研究EET类似物对顺铂(CP)诱导的肾功能障碍的效果,给予CP五天后,在EET类似物治疗和未治疗的大鼠血清中测量尿素(血液尿素氮或BUN)和肌酸酐的水平。图8所示,CP给药分别造成血清肌酸酐和BUN水平增加3倍和9倍(图7a和7b)(P<0.05)。与给予载剂(DMSO)的那些大鼠相比,在给予CP的大鼠中,用EET类似物(EET-A和-B)治疗造成已经升高的血清肌酸酐和BUN水平下降30-50%(P<0.05)。为了测定EET类似物对CP诱导肾功能障碍的影响,进一步研究了给予CP五天后,KIM-1、NAG和蛋白的尿排出(图7c和7d)。与给予载剂的对照相比,给予CP的大鼠中,NAG和KIM-1的尿排出增加了5和10倍(P<0.05)。另外,也显示了与给予载剂相比,给予顺铂造成了明显的蛋白尿现象(载剂对比顺铂,25.7±1对比53±5.1mg/d,P<0.05)。与载剂治疗的给予CP的大鼠相比,EET类似物EET-A和EET-B都造成NAG和KIM-1的尿排出下降30-50%(P<0.05)(图7c-d)。
也观察到两种EET类似物造成了顺铂诱导的蛋白尿下降至少40%(载剂对比EET-A和-B;53±5对比33±8和32±3mg/d,P<0.05)。本研究中,还使用肾组织检测来评价CP诱导的肾功能障碍。与给予载剂的大鼠相比,给予CP造成肾皮质和髓质区域中的管损伤(如肾上皮细胞的空泡化和脱皮所示)以及严重的管内蛋白性管型形成。与载剂治疗的给予CP的大鼠相比,EET类似物保护给予CP的大鼠,使其皮质和髓质管型区域下降≥50%(P<0.05)(图8a-b)。
EET类似物治疗使得顺铂诱导的肾氧化应激、炎性反应和内质网应激减弱。对NADPH氧化酶亚基NOX1和gp91phox的mRNA表达的实时PCR分析(图9)显示了在给予顺铂(CP)大鼠中增加了这些氧化标记基因的表达(P<0.05)。EET类似物A和B使顺铂诱导的NOX1和gp91phox mRNA肾表达的增加下降了2-3倍(P<0.05)(图9a-b)。给予CP也造成丙二醛(MDA)肾含量的显著增加,丙二醛是氧化应激最重要的指示剂之一。EET类似物治疗造成给予CP大鼠的肾中MDA水平下降50%(P<0.05)(图9c)。也观察到给予CP造成超氧化物歧化酶(SOD)1和SOD3的mRNA表达下降2-5倍(P<0.05),而SOD2的表达没有变化。EET类似物治疗造成了给予CP大鼠中SOD1的表达增加2-3倍(P<0.05),而SOD3表达在整个实验组中保持不变(图9d-f)。
为了研究EET类似物对肾功能障碍相关的CP诱导炎症的影响,研究了编码肿瘤坏死因子α(TNF-α)、白介素-6(IL-6)和白介素-1β的mRNA的肾表达。这些变化显示了与给予载剂的大鼠相比,载剂治疗的给予CP大鼠中其表达增加2-50倍(P<0.05)(图10a-c)。EET类似物(EET-A和B)治疗造成了给予CP的大鼠中,所有炎性标记的肾mRNA表达下降40-60%(所有P<0.05)。
也观察到与给予载剂的大鼠相比,载剂治疗的给予CP大鼠中ER应激标记GRP78/BiP和胱冬酶12的mRNA表达增加4倍(P<0.05)(图11a-b)。与载剂治疗相比,在给予CP大鼠中,EET类似物(EET-A和B)治疗都造成了GRP78和胱冬酶12的mRNA肾表达的增加下降了2-4倍(P<0.05)(图11a-b)。
EET类似物治疗使得顺铂诱导的肾凋亡减弱。与给予载剂的大鼠相比,在载剂治疗的给予CP的大鼠中,Bcl-2mRNA的肾表达下降70%(P<0.05)(图12a)。与载剂治疗的给予CP的大鼠相比,EET类似物治疗造成给予CP的大鼠中抗凋亡Bcl-2表达增加2-10倍(P<0.05)(图12a)。另外,给予CP造成Bax/Bcl-2和Bak/Bcl-2比率上升4-20倍,并且因此指示了给予CP大鼠中凋亡信号的增加(图12b-c)(P<0.05)。与载剂治疗的给予CP的大鼠相比,EET类似物治疗造成了Bax/Bcl-2和Bak/Bcl-2比率下降2-3倍(P<0.05)(图12c-d)。与给予载剂大鼠相比,给予CP大鼠中CP诱导的凋亡信号升高还表征为胱冬酶3活性的升高(图12d)(P<0.05)。与载剂治疗的给予CP的大鼠相比,EET类似物治疗使得这种CP诱导的胱冬酶3活性减弱50%(P<0.05)(图12d)。这些结果清楚地表明EET类似物治疗使得CP诱导的凋亡信号减弱。
EET类似物治疗不损害顺铂的化疗效果。显示了在三种不同的癌细胞系(Hela、NCCIT和U87)中,顺铂显著抑制细胞生长,IC50范围是1.1–9.24μM(图13a)。用这些细胞系的相似方案中,没有观察到EET-A对细胞数目的影响(图13b)。另外,同时使用EET-A和顺铂不影响顺铂对正常肾细胞(数据未显示)和NCCIT癌细胞系(图13c)的化疗效果。显示了当同时使用顺铂和EET-A时,在NCCIT细胞中使用0、1和10ng/ml EET,顺铂的IC50是2.60、2.55和2.44μM。
讨论。顺铂化疗的关键局限性是诱导肾小管间质(tubulointestinal)炎症、肾氧化应激、ER应激和管细胞凋亡,这些造成急性肾损伤。报导了顺铂治疗的癌症患者中40%患有急性肾损伤。不幸的是,没有可用的有效药物治疗以使得这种广泛使用的化疗(如顺铂)的使人虚弱的(debilitating)并发症减弱。为了试图对这个领域有作用,本研究探索了环氧化二十碳三烯酸(EET)类似物的长期治疗对顺铂诱导肾脏毒性的肾保护作用。
有较强证据显示EET能通过涉及其抗炎性、抗细胞凋亡和抗氧化活性的机制来保护器官。本发明背景下,假设了具有这种强的器官保护能力,EET保护肾免于顺铂的肾脏毒性。我们努力合成了两种新的EET类似物,并且研究了其对顺铂诱导的肾脏毒性的肾保护作用,所述研究使用临床相关方法,在饮用水中长期给予大鼠EET类似物。显示了单独给予顺铂造成的肾损伤明显,如表征为增加的PCr、BUN、肾小管损伤标记(如NAG和KIM-1)的尿排出、以及显著的蛋白尿和管型形成。结果支持了多个更早的研究中所报导的、临床前动物模型中顺铂诱导的肾脏毒性。令人感兴趣的是,也显示了饮用水中EET类似物的长期治疗显著地保护了肾免于顺铂诱导的肾脏毒性损伤,在研究中所研究的所有肾损伤标记均下降。与本研究的方案有关,近期研究显示了sEH抑制剂的急性给药可以使得小鼠中顺铂诱导的肾功能障碍降低。然而,已知sEH抑制剂经历代谢并且整合到膜上,目前sEH抑制剂的效果受到限制36,因此指示了这个发现在临床转化应用中的局限。另外,Parrish等35进行的研究没有提供证据以证明关于EET或sEH抑制剂在顺铂诱导的肾脏毒性中使得肾功能障碍降低的可能机理。
目前,显示了顺铂诱导的肾脏毒性中NADPH氧化酶主要成分(NOX1和gp91phox)的mRNA有明显的过量表达。在给予顺铂的大鼠中,这些氧化标记基因的过量表达还伴有ROS生成的增多,其证据是肾脂质过氧化作用(per-oxidation)的升高。也显示了肾SOD1和SOD3表达降低,并且认为这种降低对给予顺铂大鼠中氧化应激起作用。更早研究中有相似的观察结果:顺铂诱导的肾脏毒性伴有增加的MDA水平和升高的NADPH氧化酶的表达和活性。令人感兴趣的是,本研究也显示了EET类似物显著降低了肾氧化应激,所述降低是通过降低肾脂质过氧化作用、显著降低主要的NADPH氧化酶亚基表达、以及降低SOD1表达来实现。确实,近期研究报导了在毒性损害中,EET使得SOD的表达和活性上调,因而促进ROS清除和降低氧化应激。与我们的发现相似,另一个肾损伤的病理模型报导了氧化应激和肾损伤中EET介导的下降。除了氧化应激以外,也显示了顺铂诱导的肾脏毒性还伴有肾炎性反应的升高,并且支持了更早的相关证据:炎性机理在顺铂诱导的肾脏毒性发病机制中有重要作用。确实,顺铂诱导使得各种炎性趋化因子和细胞因子(如TNF-α和IL-1β)肾的表达增加。
还显示了EET类似物治疗使得这些炎性标记在顺铂诱导肾脏毒性中的肾表达降低。数据支持了更早的关于EET抗炎性活性的报导,所述报导关于在很多器官损伤为特征的病理中,EET介导器官保护。例如,sEH抑制增加了EET生物可利用性,这在链脲霉素诱导的糖尿病中提供了肾保护。另外,EET生成酶CYP2J2的过量表达在5/6肾切除的长期肾衰竭模型中显著保护了肾。因此,数据清楚地指出与氧化应激的显著一起,顺铂诱导的肾炎性反应减弱是使EET类似物保护肾免于顺铂诱导的肾脏毒性的另一个机理。
还研究了EET类似物对顺铂诱导的内质网(ER)应激的影响。有证据表明ER是毒素的亚细胞靶标之一并且ER在外源性物质诱导的肾脏毒性中起重要作用。本研究检测了胱冬酶12和GRP78(葡萄糖调节蛋白78)mRNA的肾表达从而研究ER应激参与顺铂诱导的肾脏毒性。认为GRP78是ER应激的特点,而胱冬酶12是ER应激活化的ER特异性胱冬酶,并且胱冬酶12特异性参与ER应激诱导的凋亡。观察到这些ER应激标记的肾表达显著上调,所述标记由于EET类似物的治疗而减弱。研究支持了更早的关于顺铂诱导的肾脏毒性与ER应激相关联的观察。更重要地是,本研究也提供了关于EET生物学作用的令人感兴趣的和新的发现,并且显示了这种脂质调节剂对治疗顺铂诱导肾脏毒性有重要的治疗潜力。
顺铂和其他药物相关的肾脏毒性与凋亡相关联10,所述凋亡是由于氧化应激、炎症和ER应激升高而引起。报导了在顺铂诱导的肾脏毒性,氧化应激、炎症和ER应激引起的细胞应激在肾中造成了减少抗凋亡Bcl2,并且活化促凋亡Bcl2家族蛋白,如Bcl-2相关X蛋白(Bax)和Bcl-2拮抗剂/杀伤蛋白(Bak)。这种增强的促凋亡信号引起胱冬酶3活化,然后肾细胞凋亡。本文显示了EET类似物治疗保护肾免于顺铂诱导的细胞死亡,所述保护是通过增加抗凋亡Bcl2的表达和降低促凋亡Bak/Bcl2与Bax/Bcl2的比率,以及显著降低胱冬酶3的活性来实现。
也显示了EET类似物调节使得胱冬酶12的肾表达减弱,所述胱冬酶12在ER应激介导的凋亡中起重要作用。确实,更早的报导显示了EET使得多个主要的凋亡事件减弱,所述事件包含升高的Bcl2蛋白介导的促凋亡信号和胱冬酶3的活性。这些观察支持了我们关于EET类似物能使得顺铂诱导的肾脏毒性中肾细胞死亡降低的观察,所述降低通过EET类似物对Bcl2蛋白、ER应激特异的胱冬酶12和凋亡执行胱冬酶(胱冬酶3)的影响。
本发明清楚地显示了EET类似物治疗通过多种机理提供了保护以避免针对顺铂诱导的肾脏毒性,并且显著表明了可能的治疗前景。然而,重要地是在新的细胞保护试剂的临床应用前,本发明不仅显示了其保护免于毒性,而且显示了所述试剂对所用细胞毒性剂的抗癌活性没有干扰。为此目的,在体外方案研究正常肾细胞(HEK293)或多种人癌细胞(Hela、NCCIT、U87)体外暴露于多种浓度EET类似物(EET-A)是否影响细胞生长或者顺铂的细胞毒性效果。考虑到本研究使用的两种EET类似物的肾保护效果相似,选定一种EET类似物以用于此特定实验。显示了无论是否存在EET类似物(EET-A),顺铂发挥化疗效果的能力是相同。另外,也研究了EET-A是否影响本研究使用的任意癌细胞系的生长,并且清楚地显示了EET-A对任意癌细胞系的生长没有影响。
总之,提供了有力证据表明上面鉴定的EET类似物在药物诱导的肾脏毒性(包含顺铂诱导的肾脏毒性)中有肾保护作用。显示了这些EET类似物通过多个信号通路提供肾保护,所述信号通路关键性地参与顺铂诱导的肾脏毒性的病理-生理学。本研究突出了新EET类似物的数种重要的生物学作用,例如其抗氧化、抗炎性、抗ER应激和抗凋亡活性。本研究的结果强化了我们对这些新的EET类似物有治疗前景的观点,所述类似物治疗顺铂诱导的肾脏毒性,而不损伤顺铂的化疗能力。
虽然结合上述各示例性实施方式描述了本发明,但已知的或可能目前无法预料的各备选方案、改进、变化、改善、和/或实质等价物对至少本领域普通技术人员是显而易见的。因此,以上所列的本发明的实施方式应为说明性,而非限制性。在不背离本发明的精神和范围下,可进行各种变动。因此,本发明旨在包括这些示例性实施方式的所有已知或随后开发的备选方案、改进、变化、改善、和/或实质等价物。本文引用的所有技术出版物、专利和公开的专利申请通过引用全文纳入本文以用于所有目的。
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Claims (11)
1.一种选自下组的化合物:
2.如权利要求1所述的化合物,其特征在于,所述结构是:
3.如权利要求1所述的化合物,其特征在于,所述结构是:
4.一种选自下组的化合物:
5.一种包含如权利要求1或4所述的化合物和药学可接受运载体的组合物。
6.如权利要求1或4所述的化合物在生产用于治疗对象高血压的药剂中的应用。
7.如权利要求1或4所述的化合物在生产用于降低对象肾脏毒性的药剂中的应用。
8.如权利要求7所述的应用,其特征在于,所述肾脏毒性是药物诱导的。
9.如权利要求8所述的应用,其特征在于,所述肾脏毒性是顺铂诱导的。
10.如权利要求1或4所述的化合物在生产药剂中的应用,所述药剂用于治疗对象中药物诱导的肾脏毒性。
11.如权利要求1或4所述的化合物在生产用于治疗对象顺铂肾脏毒性的药剂中的应用。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161472410P | 2011-04-06 | 2011-04-06 | |
US61/472,410 | 2011-04-06 | ||
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PCT/US2012/032090 WO2012138706A1 (en) | 2011-04-06 | 2012-04-04 | Epoxyeicosatrienoic acid analogs and methods of making and using the same |
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MX337597B (es) * | 2011-04-06 | 2016-03-11 | Mcw Res Found Inc | Analogos de acido epoxieicosatrienoico y metodos para fabricar y usar los mismos. |
US20150322001A1 (en) * | 2012-11-21 | 2015-11-12 | The University Of Sydney | Omega-3 analogues |
CA2934964C (en) * | 2014-01-22 | 2022-03-01 | Board Of Regents, The University Of Texas System | Novel cyp-eicosanoid derivatives |
WO2017013265A1 (en) | 2015-07-22 | 2017-01-26 | Omeicos Therapeutics Gmbh | Metabolically robust analogs of cyp-eicosanoids for the treatment of cardiac disease |
US11690825B2 (en) | 2016-03-09 | 2023-07-04 | Board Of Regents, The University Of Texas System | 20-HETE receptor (GPR75) antagonists and methods of use |
MX2018011986A (es) * | 2016-04-01 | 2019-07-10 | Omeicos Therapeutics Gmbh | Analogos de eicosanoides de cyp para su uso en el tratamiento o la prevencion de un trastorno asociado a neovascularizacion y/o a inflamacion. |
KR102433731B1 (ko) * | 2016-04-01 | 2022-08-22 | 오메이코스 테라퓨틱스 게엠베하 | 혈관신생 및/또는 염증과 연관된 장애의 치료 또는 예방에서 사용하기 위한 cyp-에이코사노이드의 유사체 |
KR102012554B1 (ko) | 2016-07-13 | 2019-08-23 | 주식회사 노브메타파마 | 사이클로 히스티딘-프롤린을 유효성분으로 포함하는 세포 보호용 조성물 |
CN111247149A (zh) * | 2017-09-15 | 2020-06-05 | 威斯康星州医药大学股份有限公司 | 肾脏靶向的环氧二十碳三烯酸(eet)类似物 |
WO2021067590A1 (en) * | 2019-10-01 | 2021-04-08 | University Of Kentucky Research Foundation | Method for treatment of alzheimer's disease |
CN111548366B (zh) * | 2020-05-27 | 2023-05-02 | 广东德美精细化工集团股份有限公司 | 一种无甲醛棉用阻燃剂、制备方法及应用 |
JP7166475B1 (ja) | 2022-02-14 | 2022-11-07 | 悠 澤村 | 腎毒性軽減用組成物 |
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US4256108A (en) | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
US4160452A (en) | 1977-04-07 | 1979-07-10 | Alza Corporation | Osmotic system having laminated wall comprising semipermeable lamina and microporous lamina |
US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
US4777049A (en) | 1983-12-01 | 1988-10-11 | Alza Corporation | Constant release system with pulsed release |
US4663308A (en) | 1984-07-18 | 1987-05-05 | Medical College Of Ohio | Method of use of polymers containing cross-linked azo bonds for releasing therapeutic agents into the lower gastrointestinal tract |
US7550617B2 (en) | 2006-10-02 | 2009-06-23 | Medical College Of Georgia Research Institute | Compositions and methods for the treatment of renal and cardiovascular disease |
US7732470B2 (en) | 2006-10-02 | 2010-06-08 | Medical College Of Georgia Research Institute | Compositions and methods for the treatment of renal and cardiovascular disease |
EP2208720A1 (en) * | 2009-01-13 | 2010-07-21 | Max-Delbrück-Centrum für Molekulare Medizin (MDC) | Novel eicosanoid derivatives |
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