CN106715446B - 使含至少一个酚基(或芳羟基)的药物分子提高生物利用度和降低剂量要求的硼基前药策略 - Google Patents
使含至少一个酚基(或芳羟基)的药物分子提高生物利用度和降低剂量要求的硼基前药策略 Download PDFInfo
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Abstract
提供了含酚羟基或芳羟基的治疗分子(“原药”)的基于硼的前药,其用途,以及制备其的方法,用于实现例如提高的生物利用度,延长的滞留时间(例如,在循环系统中)以及,具体地,显著降低的治疗有效剂量,以便在降低副作用的同时保留原药的期望的治疗效果。
Description
技术领域
本公开内容涉及基于硼的前药,制备其的方法,以及合成和使用其的方法,以及使含一个或多个酚基的药物分子提高生物利用度和降低剂量要求的方法。此外,本公开内容示教所述前药作为改良药物的使用具有低剂量和长疗效的优势。
作为改良药物使用所述基于硼的前药能通过使用显著降低的剂量而达到与未修饰药物相同的疗效,因此特别有利于减少药物副作用和无意识的过量。此外,本文所述的前药提供了改善的药代动力学特性,具有更长的血浆半衰期,从而能够减少用药的频率。
背景技术
许多活性药物分子含有一个或多个取代或未取代的酚基或芳羟基,适合于所描述的基于硼的修饰成为期望的前药,以增加生物利用度和生物保留。该方法尤其能显著降低治疗有效剂量,从而减少副作用。运用本公开内容示教的方法,任何如上描述的含有一个或多个羟基的活性药物分子都可以经化学修饰成任何硼酸前药。
氟维司群(Fulvestrant)
氟维司群是一种选择性雌激素受体下调剂(SERD),于2003年被FDA批准用于他莫昔芬和/或芳香化酶抑制剂(AI)失败后的乳腺癌的治疗。氟维司群是一种纯粹的抗雌激素,没有已知的激动剂作用。临床上已经证明用于治疗他莫昔芬或AI治疗后复发的病人时和阿那曲唑一样有效。由于氟维司群的口服生物利用率极低,目前只能通过肌内(IM)注射以250毫克的核准剂量施用(Croxtall et al.Drugs.2011;71(3):363-80)。进一步的药理学和临床前研究显示,用更高的500毫克剂量可能更有效,临床试验已经测试了以更高剂量施用氟维司群的益处(Stevez et al.Cancer Treat Rev.2013;39(2):136-41)。这些数据凸显了提高氟维司群生物利用度的需求,以使氟维司群成为一种对他莫昔芬耐药的乳腺癌更为有效的治疗方案。
对乙酰氨基酚
泰诺是美国最流行的非处方镇痛药(止痛药)和退热药(退烧药)之一,占北美止痛药市场的35%左右(Lee,NEJM.2003;349:474-485)。美国人用来治疗疼痛症状和发烧的泰诺消耗量每年超过80亿粒(片剂或胶囊)。根据制药公司强生的一个报告,对乙酰氨基酚也是一种出现在多达600种各类非处方药物中的常见活性成分(见www.cnn.com/2013/08/29/health/tylenol-cap-warning/index.html)。例如,阿那辛3号(Anacin-3),力快普林(Liquiprin),扑热息痛(Panadol),以及各种感冒和流感的药物中都含有对乙酰氨基酚。在美国,英国和其他许多国家,过量服用对乙酰氨基酚是目前急性肝衰竭最常见的原因(Larson et al.Hepatology.2005;42:1364-1372)。每年与对乙酰氨基酚相关的过量的急诊病人约56000例,需住院的有约26,000例(Nourjah et al.Pharmacoepidemiol DrugSaf.2006;15(6):398-405)。2001年,对乙酰氨基酚服用过量的所有患者中,近50%属于误用,半数以上需要医院治疗。总体而言,2001年与对乙酰氨基酚相关的死亡人数占TESS报道的总死亡人数1074的16%。与对乙酰氨基酚有关的死亡有约50%发生在服用了作为非处方药物销售的只含对乙酰氨基酚的产品的个体中。从2013年10月始,为减少每年发生意外过量服用对乙酰氨基酚的人数,泰诺的母公司强生公司,将在超强型泰诺瓶的瓶盖上标示新的警告:“含对乙酰氨基酚。请务必阅读标签”。强生这一最新举措凸显了减少乙酰氨基酚服用过量,防止肝衰竭和死亡的持续需求。
雷洛昔芬(Raloxifene)
雷洛昔芬在2007年由美国食品和药物管理局批准,用于降低患有骨质疏松的绝经后女性以及易患侵入性乳腺癌的绝经后女性罹患侵入性乳腺癌的风险。雷洛昔芬为每天服用60毫克的片剂。常见的不良反应包括潮热和腿部抽筋。雷洛昔芬可能导致少数人腿,肺,或眼睛中严重的血栓形成。其他所经历的反应包括腿部肿胀/疼痛,呼吸困难,胸部疼痛,视力变化。雷洛昔芬也可以引起发育异常如先天缺陷。雷洛昔芬的相对高剂量要求(例如,相对于他莫昔芬20毫克/天,和阿那曲唑1毫克/天的剂量)是由于其生物利用度差(Kemp etal.Drug Metab Dispos.2002;30:694-700.Jeong et al.Drug Metab Dispos.2005;33:785-94)。
伊立替康(SN-38)
伊立替康通过羧酸酯酶水解成其活性代谢物SN-38(Garcia-Carbonero etal.Clin Cancer Res.2002;8(3):641-61)。硼-SN-38的使用保证了SN-38的所需的浓度水平,而不依赖于伊立替康代谢转化。此外,硼-SN-38优先地在血浆和肿瘤位点富集,因此显著较低的剂量能达到若干倍高剂量伊立替康治疗同样的治疗效果。这样低剂量要求反过来将降低药物对健康组织和器官的细胞毒性。
氯硝柳胺
氯硝柳胺在动物研究中已显示能抑制结肠癌的扩散。该药物通过阻断S100A4/转移蛋白(metastasin)的基因表达而达到疗效,而S100A4/转移蛋白可以促使大肠癌转移。然而,氯硝柳胺水溶性差,口服生物利用度低(Navab et al.JLipid Res.2009;50:1538-1547),从而限制了其临床发展为癌症治疗方案。
这个技术问题可通过权利要求中表征的实施方案来解决。
发明内容
本申请提供含酚基或芳羟基的治疗分子的基于硼的前药的制备和使用的方法,目的是改善生物利用度,延长在患者体内特别是在血液循环系统中的滞留时间。对这些前药已选择了实施例在体内进行了测试,发现活性药物形式的血浆浓度有显著增加。以相同口服剂量给予硼前药的小鼠,比喂养相同剂量原药的小鼠,具有高5-10倍浓度的活性药物形式。因此,对于各种现有的小分子药物,基于硼的前药解决本领域中的提高生物利用度和滞留时间,提供口服生物利用度,并降低治疗有效剂量的重要需求。
在一个实施方案中,硼-氟维司群前药提供潜在地比现有氟维司群疗效更高的口服制剂或IM注射选择。在另一个实施方案中,含硼醋氨酚(对乙酰氨基酚)前药的对乙酰氨基酚血浆浓度增加5-10倍,因此将治疗有效剂量要求降低到过量误用的可能性大大减少的程度。在另一个实施方案中,硼-雷洛昔芬前药使剂量降低5-10倍以实现相同的药物血浓度,从而显著减少潜在的副作用。在又一个实施方案中,相对于氯硝柳胺,硼-氯硝柳胺前药方法使口服生物利用度增加5-10倍,反映在小鼠口服施用后血浓度的升高。
因此,在一个实施方案中,本公开内容的含硼的前药是(I)式的化合物:
其中R是:
或KF3B、(HO)2B、NaF3B,并且R与药物分子的取代的或未取代的酚基或芳羟基的取代连接点是R上的取代硼原子,如下表1中的示例前药结构所更详细地描述的。
本文所用术语“含硼的前药”和“基于硼的前药”是指具有至少一个取代的或未取代的酚基或芳羟基的药物分子,所述至少一个取代的或未取代的酚基或芳羟基由R基团取代。本文所用术语“原药”和“原始药物分子”是指具有至少一个取代的或未取代的酚基或芳羟基的药物分子,其中至少一个取代的或未取代的酚基或芳羟基可由R基团取代。
在一个优选的实施方案中,含硼的前药是指具有下面的用于R的结构的化合物,记作前药1:
前药1
为了清楚起见,前药1中的苯环代表来自原药的取代或未取代的酚基或芳羟基,并且是前药1的“各药物部分”的一部分。表1的实施例显示更多的细节。
在一个实施方案中,本公开提供了一种药物组合物,所述药物组合物是用于治疗本来由原始药物分子治疗的疾病和/或症状的至少一种含硼前药的形式(即,-OH部分代替前药R部分的前药分子)。该组合物可以包含至少一种基于硼的前药,与原药相比,所述前药的量在治疗上有等同或更好的疗效。
因此,本公开内容涉及符合分子式I的基于硼的前药在治疗本来由原始药物分子治疗的疾病和/或症状中的用途。
本公开内容的药物组合物可以是本领域的技术人员公知的任何形式。例如,在一些实施方案中,药物组合物是用于口服的产品的形式,所述产品形式选自浓缩物、干燥的粉末、液体、胶囊、片剂和丸剂。在其他实施方案中,本公开的药物组合物是用于肠胃外施用如静脉内、皮内、肌内和皮下施用的产品的形式。本文公开的药物组合物还可以进一步包含载体、粘合剂、稀释剂和赋形剂。
另外,在其他方面,本公开涉及新的基于硼的前药化合物和其药学上可接受的盐;药物组合物包括新的基于硼的前药化合物,单独使用或者与至少一种另外的治疗剂组合,带有药学上可接受的载体;和新的基于硼的前药化合物,单独使用或与至少一种另外的治疗剂组合,在治疗本来由原药治疗的疾病和/或症状中的用途。与另外的治疗剂的组合可以是新的基于硼的前药化合物与任何已知的治疗剂组合的形式。
此外,在对小鼠口服施用后,当前示教的基于硼的前药平台允许硼-芳基碳键快速氧化裂解以在小鼠的血液中形成所需的活性药物形式的芳羟基结构。因此,本公开的前药可用于治疗目前由本文描述的各种药物治疗的任何症状,但只用显著降低的剂量,由此可能杜绝任何意外过量。本文所示的方法可涉及对有需要的患者施用所公开的前药。
本公开的进一步的目的是提供硼酸前药化合物,合成前药化合物的方法,制造该前药化合物的方法,以及使用该前药化合物的方法。
本公开的另一目的是提供一种组合物,例如药物组合物,其包含至少一种以有效量用于原药针对的适应症的基于硼的前药,所述适应症包括但不限于:减轻疼痛和发热,减少感冒症状,缓解关节炎引起的不适,疼痛或炎症。
本公开的另一个目的是一种试剂盒,其包括一种组合物,所述组合物含有至少一种用于治疗原药所针对的(多种)适应症的基于硼的前药。试剂盒的组合物可包含至少一种载体,至少一种粘合剂,至少一种稀释剂,至少一种赋形剂,至少一种其它治疗剂,或它们的混合物。
通过本文所公开的基于硼的前药化合物治疗临床适应症的方法可通过对有需要的患者施用治疗有效量的前药实行,该治疗有效量可包括以1毫克/千克/天,2毫克/千克/天,3毫克/千克/天,4毫克/千克/天,5毫克/公斤/天,10毫克/千克/天和20毫克/千克/天对病人施用前药。或者,也可考虑使用在以下范围中的量:约0.001毫克/千克/天至约0.01毫克/千克/天,或约0.01毫克/千克/天至约0.1毫克/千克/天,或约0.1毫克/千克/天至约1毫克/千克/天,或约1毫克/千克/天至10毫克/千克/天,或约10毫克/千克/天至约100毫克/千克/天。
在某些方面,所述至少一种基于硼的前药类似物具有≥75%,≥80%,≥85%,≥90%,≥95%,≥96%,≥97%,或者≥98%的纯度,最好是≥99%。
虽然在所附的权利要求书中指出了下面所描述和显示的本发明的某些特征,本发明不打算限于特定的细节,因为相关领域的普通技术人员会理解,在不以任何方式脱离本发明的精神的情况下可进行本发明及其操作中在形式和细节上的各种省略,修改,替换和变化。除非本发明中有明确声明为“关键”或“必要”,否则本发明的任何特征都不是“关键”或“必要”的。
结合以下说明书,权利要求书,以及以下解释的附图可以更好地理解本公开的这些和其他特征,方面,和实施方案的优势。
附图说明
为了进一步理解本公开的性质,目的和优点,应当参考下面的详细描述,结合以下附图阅读,其中相似的参考标号表示相同的元件。
图1显示从各种含至少一个芳羟基基团的药物分子制备基于硼的前药的一般合成方案。
图2显示在生理条件下硼-对乙酰氨基酚前药到原药的快速转换。
图3显示在小鼠血浆中硼-对乙酰氨基酚的药代动力学。
图4显示用于制备氟维司群的硼酸频哪醇酯前药的合成方案。
图5显示在生理条件下硼-氟维司群前药到原药的快速转换。
图6显示在小鼠血浆中硼-氟维司群的药代动力学。
图7显示用于制备雷洛昔芬的硼酸频哪醇酯前药的合成方案。
图8显示在小鼠血浆中硼-雷洛昔芬的药代动力学曲线。
图9显示用于制备拉索昔芬的硼酸频哪醇酯前药的合成方案。
图10显示在小鼠血浆中硼-拉索昔芬的药代动力学曲线。
图11显示用于制备巴多昔芬的硼酸频哪醇酯前药的合成方案。
图12显示用于制备SN-38的硼酸频哪醇酯前药的合成方案。
图13显示用于制备芬维A胺的硼酸频哪醇酯前药的合成方案。
图14显示用于制备大豆黄素的硼酸频哪醇酯前药的合成方案。
图15显示用于制备白藜芦醇的硼酸频哪醇酯前药的合成方案。
图16显示用于制备雌马酚的硼酸频哪醇酯前药的合成方案。
具体实施方式
在进一步描述本公开的主题之前,应该理解本公开并不限于下面描述的公开内容的具体实施方案,因为具体实施方案可有各种变异的形式,但仍然属于所附权利要求的范围内。也应理解,所用的术语旨在描述具体实施方案,而不应理解为限制性的。相反,本公开的范围将由所附的权利要求来确定。
在本说明书和所附的权利要求中,单数形式“一”,“一个”和“该”包括复数引用,除非上下文另有明确说明。除非另有定义,本文使用的所有技术和科学术语具有如本公开所属领域中普通技术人员通常理解的相同含义。
在一个方面,本公开的主旨特征是通过修改各种现有的治疗药物分子中的酚结构合成基于硼的前药。为了确定这些前药是否具有更好的体内生物利用度,进行了药代动力学研究,其中以5mg/kg的单剂量对小鼠口服施用所选的硼-前药并在24小时内监测小鼠血液中的药物浓度。
本文所用的术语“减少”或“降低”,或其意义的沿用,包括对特定的生物效应的完全或部分抑制(在术语“减少”或“降低”出现的上下文中其含义显而易见)。
可以利用硼-前药平台的现有原药的实例中R是或KF3B、(HO)2B、NaF3B,其中R取代连接点在硼原子上,如表1的结构式1至57所示,以及相应的原药。
优选地,R是
本公开还提供了式1至57中的至少一种化合物在治疗由其中所述R是-OH的化合物治疗或可治疗的疾病或症状中的用途,在有需要的哺乳动物中。
本公开还提供了用作药物的式1至57的化合物,用于在有需要的哺乳动物中治疗癌症,或用于提供镇痛或在有需要的哺乳动物中减少炎症,用于调节雌激素受体,或在有需要的哺乳动物中治疗细菌、病毒、真菌或支原体感染。
在一个实施方案中,疾病或症状选自以下:细菌、病毒、真菌或支原体感染;癌症;溃疡;帕金森氏病;结核病;麻风病;布氏杆菌病;阿片类药物成瘾;关节炎;骨性关节炎;类风湿性关节炎;白血病;抑郁;咳嗽或感冒;人免疫缺陷病毒(HIV);炭疽病;哮喘;支气管炎;甲状腺功能减退症;高血压;低血压;充血性心脏衰竭;移植物抗宿主病;寄生虫感染;结核分枝杆菌复合体(MAC)疾病;溃疡性结肠炎;膀胱过度活动症;尿失禁;和食管静脉曲张出血。
一种制备各类含有至少一个芳羟基的药物活性化合物的硼衍生物的合成步骤包括用上述化合物与三氟甲磺酸酐或1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺反应形成三氟甲磺酸酯。该反应在有机碱如吡啶的存在下使用二甲基甲酰胺(DMF)溶剂。这样形成的三氟甲磺酸酯在催化剂PdCl2(dppf)的存在下与双(频哪醇)二硼反应,形成所述活性化合物的硼酸频哪醇酯前药。
例如,通过用连接到各种官能团的硼原子取代羟基而设计的对乙酰氨基酚的硼衍生物作为前药候选物。硼-对乙酰氨基酚前药的合成示意图见图2。
第一步水解在含水环境中迅速进行,而第二步水解已知需要生理条件如肝微粒体或血浆,其中由P450酶催化的氧化脱硼导致硼前药完全转化为原始的含羟基的药物分子,这与先前关于其它硼酸化合物的报告一致(Pekol et al,Drug Metab Dispos.2005;33(6):771-7)。如图2所示,硼-对乙酰氨基酚在水溶液中迅速水解形成其硼酸对应物,在5小时内,硼酸酯与酸中间体的比率达到了9∶1。在氧化剂如H2O2的存在下,或在酸性或碱性条件下的氧化脱硼形成原始的含羟基的药物分子。
作为前药候选物的氟维司群的硼衍生物是由连接到各种官能团的硼原子取代羟基而设计的。硼-氟维司群前药的合成示意图见图4。
下面的实施例将进一步说明本文所示的基于硼的前药化合物的各种实施方案的化学结构。此外,实施例证明所公开的前药化合物的各种实施方案的功效。下面的科学数据表明,所公开的基于硼的前药化合物比母体化合物显示了出奇优异的生物利用度。
实施例1
对乙酰氨基酚的硼酸频哪醇酯前药(图2和3)
为了确定硼-对乙酰氨基酚衍生物具有更好的体内生物利用度,在小鼠中进行药代动力学研究,其中单剂量的硼-对乙酰氨基酚以5mg/kg口服施用并在24小时内持续监测小鼠血液中的药物浓度。
含硼对乙酰氨基酚前药表现出5-10倍对乙酰氨基酚血浆浓度的增加,因此可降低治疗有效剂量要求到大大减少过量误用的可能性的程度。
这些研究的结果如图3所示,并证明了与施用相等剂量的对乙酰氨基酚的小鼠相比,施用硼-对乙酰氨基酚的小鼠的对乙酰氨基酚血浆浓度(生物利用度)显著增加。
实施例2
氟维司群的硼酸频哪醇酯前药(图4-6)
步骤1:在-10℃的温度下,于N-2(0.80克)和吡啶(0.24毫升)的DCM(15mL)溶液中逐滴加入三氟甲磺酸酐(0.2毫升),所得的混合物搅拌直至反应完成。加饱和碳酸钠水溶液终止反应,然后用乙酸乙酯萃取。将合并的有机层经MgSO4干燥并浓缩。粗产物通过快速柱层析分离纯化,得到产物(0.70克)。
步骤2:将N-2的三氟甲磺酸酯(0.76克),双(频哪醇)二硼(0.378克),乙酸钾(0.268克,9.72毫摩尔),醋酸钯(30毫克)和三环己基膦(60毫克)在乙腈(20mL)中混合物在80℃氮气保护下搅拌过夜。在真空下除去溶剂,将粗品通过快速柱层析分离纯化,得到产物(0.50克)。
步骤3:在0℃下,将KOH(0.132克)的MeOH(2mL)溶液缓慢加入N-2的硼酸频哪醇酯(0.5克)的MeOH-THF(1∶1,4毫升)溶液中。将所得混合物在室温下搅拌4h。用乙酸将反应溶液中和后,在真空下除去溶剂,将粗产物纯化,得到液体产物(0.40克)。
步骤4:在0℃下,向N-2(0.55克)的脱乙酰硼酸频哪醇酯的DCM(10mL)溶液中加入m-CPBA(0.135克)。将所得混合物在0℃下搅拌直到原料几乎完全转化为产物。将反应溶液用DCM稀释,然后用饱和Na2CO3洗涤并干燥。在真空下除去溶剂,将粗产物纯化,得到固体产物(0.42克)。1H-NMR(CDCl3,300MHz):7.60(d,J=7.2Hz,1H),7.55(s,1H),7.33(d,J=7.2Hz,1H),3.76(m,1H),2.89-2.63(m,6H),2.42-2.14(m,7H),1.93(d,J=12.3Hz,1H),1.80-1.00(m,41H),0.79(s,3H).13C-NMR(CDCl3,75MHz):143.2,136.7,134.9,132.0,125.4,83.6,82.0,52.7,51.0,46.6,43.3,41.7,38.9,37.0,34.3,33.2,30.6,30.0,29.6,29.3,29.2,28.8,28.3,26.9,25.7,24.9,24.8,22.64,22.56,14.6,11.1。HR-MS(ESI(+)):计算值:C38H59BF5O4S(M+H):717.4147;实测值:717.4160。
为了确定硼-氟维司群衍生物是否具有增强的体内生物利用度,在小鼠中进行药代动力学研究,对小鼠口服施用单剂量的硼-氟维司群5mg/kg,24小时内持续监测小鼠血液中的药物浓度。
口服施用氟维司群或硼-氟维司群后24小时内,口服施用硼-氟维司群导致的氟维司群血浆浓度显著大于口服未修饰的氟维司群的小鼠的氟维司群血浆浓度。
图6呈现这些研究的结果并证明相比于施用相等剂量的氟维司群的小鼠,施用硼-氟维司群的小鼠的氟维司群血浆浓度(生物利用度)显著增加。
实施例3
雷洛昔芬的硼酸频哪醇酯前药(图7和8)
步骤1:在0℃,将三氟甲磺酸酐(0.84克,0.48毫升,3.0毫摩尔)的CH2Cl2(5.0毫升)溶液滴加到吡啶(0.25毫升,3.0毫摩尔)和雷洛昔芬(0.47克,1毫摩尔)的无水二氯甲烷(10mL)溶液中。加入完成后,将混合物温热至室温并搅拌1小时。然后用Et2O稀释该混合物,用10%HCl水溶液淬灭,并用饱和NaHCO3溶液和盐水依次洗涤。用MgSO4干燥后,减压除去溶剂,将残余物通过快速柱色谱法纯化,得到双(三氟甲磺酸酯)(0.16克)。1H-NMR(300MHz,CD3Cl):7.86-7.83(m,2H),7.68(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.33(dd,J=8.7and 1.5Hz,1H),7.16(d,J=8.7Hz,2H),6.77(d,J=8.4Hz,2H),4.34(t,J=3.3Hz,2H),3.36(t,J=3.3Hz,2H),3.10(m,4H),1.92(m,4H),1.62(m,2H).13C-NMR(75MHz,CD3Cl):191.4,163.5,149.7,147.1,144.8,139.6,139.1,133.1,132.6,132.3,131.0,129.7,125.4,121.8,118.7(q,J=323Hz),115.1,114.5,66.1,57.5,55.0,25.7,24.0。HR-MS(ESI(+)):计算值:C30H26F6NO8S3(M+H):738.0725实测值:738.0721。
步骤2:向上述双(三氟甲磺酸酯)(0.15克,0.20毫摩尔)的1,4-二噁烷溶液中加入双(频哪醇)二硼(0.16克,0.60毫摩尔),PdCl2(dppf)(0.030克,5%摩尔)和KOAc(0.14克,1.4毫摩尔),并将混合物在120℃下微波照射1h。将溶液冷却后,在真空下除去二噁烷。粗产物通过快速柱色谱纯化,得到产物(87毫克)。1H-NMR(300MHz,CD3Cl):8.14(s,1H),7.84(d,J=6.6Hz,2H),7.63(m,2H),7.45(m,2H),7.32(d,J=6.9Hz,2H),6.81(d,J=8.1Hz,2H),6.70(d,J=8.1Hz,2H),5.16(s,2H),4.22(m,2H),3.13(m,4H),2.31(s,3H),1.84(m,4H),1.66(m,4H),1.26(s,24H).13C-NMR(75MHz,CD3Cl):156.8,139.0,137.5,134.7,131.5,131.2,129.8,128.7,128.3,127.4,126.8,114.6,110.4,109.6,83.5,83.4,83.1,82.8,80.3,75.0,69.7,56.0,55.3,46.9,26.8,25.0,24.9,24.5,24.1,22.7,9.5。HR-MS(ESI(+)):计算值:C42H57B2N2O5(M+H):691.4454;实测值:691.4460。
为了确定硼-雷洛昔芬衍生物是否具有增强的体内生物利用度,给予小鼠单剂量的雷洛昔芬或硼-雷洛昔芬5mg/kg,并监测每组小鼠中的雷洛昔芬血浆浓度。口服施用硼-雷洛昔芬组的小鼠血浆中的雷洛昔芬浓度明显高于口服施用雷洛昔芬组的小鼠的血浆中的雷洛昔芬浓度(图8)。
实施例4
拉索昔芬的硼酸频哪醇酯前药(图9和10)
步骤1:在0℃,将三氟甲磺酸酐(0.84克,0.48毫升,3.0毫摩尔)的CH2Cl2(5.0mL)溶液滴加到吡啶(0.25毫升,3.0毫摩尔)和拉索昔芬(0.41克,1毫摩尔)的无水二氯甲烷(10mL)溶液中。加入完成后,将混合物温热至室温并搅拌1小时。然后用Et2O稀释该混合物,用10%HCl水溶液淬灭,并用饱和NaHCO3溶液和盐水依次洗涤。用MgSO4干燥后,减压除去溶剂,将残余物通过快速柱色谱纯化,得到拉索昔芬的三氟甲磺酸酯(0.15克)。
步骤2:向拉索昔芬的三氟甲磺酸酯(0.15克,0.27毫摩尔)的1,4-二噁烷溶液中加入双(频哪醇)二硼(80毫克,0.30毫摩尔),PdCl2(dppf)(0.015克,5%摩尔)和KOAc(70毫克,0.7毫摩尔),并将混合物在微波辐射下于120℃照射1小时。将溶液冷却后,在真空下除去二噁烷,将粗品通过快速柱色谱纯化,得到产物(0.13克)。1H-NMR(300MHz,CD3Cl):7.74(s,1H),7.53(d,J=7.2Hz,1H),7.19-7.18(m,3H),6.96(d,J=7.2Hz,1H),6.83(m,2H),6.52(d,J=7.8Hz,2H),6.32(d,J=8.4Hz,2H),4.32-4.30(m,3H),3.42-3.14(m,9H),2.16-2.09(m,4H),1.88(m,2H).13C-NMR(75MHz,CD3Cl):155.6,143.9,143.1,136.0,135.7,135.5,132.0,131.7,130.1,128.1,127.8,126.1,112.9,64.0,42.6,54.2,51.1,45.0,29.6,24.9,23.2。HR-MS(ESI(+)):计算值:C34H43BNO3(M+H):524.3336;实测值:524.3329。
为了确定硼-拉索昔芬衍生物是否具有增强的体内生物利用度,给予小鼠单剂量的拉索昔芬或硼-拉索昔芬5mg/kg,监测每组小鼠中的拉索昔芬血浆浓度。与直接口服施用拉索昔芬相比,施用硼-拉索昔芬时拉索昔芬的系统生物利用度明显改善(图10)。
实施例5
巴多昔芬(bazedoxifene)的硼酸频哪醇酯前药(图11)
步骤1:在0℃,将三氟甲磺酸酐(0.84克,0.48毫升,3.0毫摩尔)的CH2Cl2(5.0mL)溶液滴加到吡啶(0.25毫升,3.0毫摩尔)和巴多昔芬(0.47克,1毫摩尔)的无水二氯甲烷(10mL)溶液中。加入完成后,将混合物温热至室温并搅拌1小时。然后用Et2O稀释该混合物,用10%HCl水溶液淬灭,并用饱和NaHCO3水溶液和盐水依次洗涤。用MgSO4干燥后,减压除去溶剂,将残余物通过快速柱色谱纯化,得到双(三氟甲磺酸酯)(0.87克)。1H-NMR(300MHz,CD3Cl):7.50(d,J=1.8Hz,1H),7.36(m,4H),7.20(d,J=9.0Hz,1H),7.08(dd,J=8.7 and2.1Hz,1H),6.82-6.75(m,4H),5.15(s,2H),4.35(t,J=3.9Hz,2H),3.64-3.61(m,4H),3.18(m,2H),3.26(s,3H),1.97(m,4H),1.75(m,4H).13C-NMR(75MHz,CD3Cl):156.5,149.4,143.6,137.9,135.7,132.2,131.7,130.9,128.9,127.5,121.7,120.2(q,J=317Hz),118.9(q,J=319Hz),118.8(q,J=321Hz),115.6,114.9,111.7,111.1,111.0,62.8,56.7,56.1,47.3,26.3,23.5,9.3。HR-MS(ESI(+)):计算值:C32H33F6N2O7S2(M+H):735.1633;实测值:735.1635。
步骤2:向双(三氟甲磺酸酯)(0.15克,0.20毫摩尔)的1,4-二噁烷溶液中加入双(频哪醇合)二硼(0.16毫克,0.30毫摩尔),PdCl2(dppf)(0.030克,5%摩尔)和KOAc(0.14克,1.4毫摩尔),并将混合物在微波下于120℃照射1小时。将溶液冷却后,在真空下除去二噁烷,将粗品通过快速柱色谱纯化,得到产物(87毫克)。1H-NMR(300MHz,CD3Cl):.13C-NMR(75MHz,CD3Cl):.HR-MS(ESI(+)):计算值:C42H57B2N2O5(M+H):691.4454;实测值:691.4460。
实施例6
SN-38的硼酸频哪醇酯前药(图12)
步骤1:向SN-38(1.2克,3.05毫摩尔)的DMF(30mL)溶液中加入二乙胺(0.85毫升,6.12毫摩尔)和1,1,1-三氟-N-苯基N-((三氟甲基)磺酰基)甲磺酰胺(1.64克,4.58毫摩尔)。将所得的混合物于50℃搅拌3小时。用DCM稀释反应混合物,并用水骤冷。将有机层经硫酸钠干燥并浓缩。粗产物通过快速柱色谱纯化,得到固体三氟甲磺酸酯产物(2.1克)。
步骤2:将SN-38的三氟甲磺酸酯(1.7克,3.24毫摩尔),双(频哪醇合)二硼(1.2克,4.86毫摩尔),乙酸钾(0.875克,9.72毫摩尔),Pd(OAc)2(40mg)和三环己基膦(100毫克)在乙腈(60毫升)中的混合物在N2保护下在80℃下搅拌4小时。在真空下除去溶剂,将粗品通过快速柱色谱纯化,得到产物(0.80克)。1H-NMR(CDCl3,300MHz):8.60(s,1H),8.18-8.17(m,2H),7.68(s,1H),5.76(d,J=16.2Hz,1H),5.34-5.27(m,3H),3.79(s,1H),3.28(m,2H),1.90(m,2H),1.46-1.42(m,15H),1.04(t,J=7.5Hz,3H).13C-NMR(CDCl3,75MHz):174.0,157.7,152.7,151.0,150.2,147.1,146.5,135.0,131.2,129.7,126.8,126.3,118.6,98.2,84.4,72.8,66.4,49.5,31.6,24.9,23.0,14.4,7.8.HR-MS(ESI(+)):计算值:C28H32BN2O6(M+H);503.5353;实测值:503.2357。
实施例7
芬维A胺的硼酸频哪醇酯前药(图13)
将视黄酸(0.5克,1.6毫摩尔),4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺(0.36克,1.6毫摩尔),EDCI(0.36克,2.0毫摩尔)和DMAP(0.2克,1.6毫摩尔)在20毫升二氯甲烷中的混合物在室温下搅拌过夜,直至反应完全完成。将反应混合物施加到硅胶柱色谱并用乙酸乙酯/己烷洗脱,得到产物(0.12克),为黄色油状物,静置固化。1H-NMR(CDCl3,300MHz):7.76(d,J=7.2Hz,2H),7.58(d,J=7.2Hz,2H),7.28(m,1H),7.05-6.92(m,2H),6.30-6.12(m,2H),5.80(s,1H),2.43-0.86(m,33H).13C-NMR(CDCl3,75MHz):165.2,151.2,141.0,139.4,137.7,137.3,135.8,135.2,130.7,130.0,129.5,128.6,121.0,118.4,83.7,39.6,34.3,33.1,29.0,24.9,21.7,19.2,13.7,12.9。MS(ESI(+)):502.2(M+)。
实施例8
大豆黄素的硼酸频哪醇酯前药(图14)
步骤1:将大豆黄素(1.27克,0.005摩尔)溶解在DCM(30mL)中,然后加入三氟甲磺酸酐(3.2克,0.011摩尔,d 1.677,1.86毫升)和4-二甲基氨基吡啶(1.22克,0.01摩尔)并搅拌所得混合物直至反应完成。将反应物用饱和碳酸钠水溶液淬灭,并用乙酸乙酯萃取。将合并的有机层经MgSO4干燥并浓缩。粗产物通过快速柱色谱纯化,得到固体产物(0.40克)。1H-NMR(CDCl3,300MHz):8.43(d,J=8.7Hz,1H),8.08(s,1H),7.66(d,J=8.7Hz,2H),7.50(m,1H),7.42-7.33(m,3H).13C-NMR(CDCl3,75MHz):174.5,156.4,153.7,152.4,149.6,131.4,130.8,129.3,124.5,124.1,121.7,119.1,118.8(q,J=319Hz),111.6。GC-MS:518.1(M+)。
步骤2:将三氟甲磺酸酯(0.26克,0.5毫摩尔)和二硼试剂(0.36克,3.6毫摩尔),PdCl2(dppf)(0.014克,0.16毫摩尔)和乙酸钾(0.24克,2.4毫摩尔)溶解在二噁烷(3mL)中,然后将混合物在微波辐射下在80℃下搅拌。在真空下除去溶剂,并通过快速柱色谱纯化粗品,得到产物(0.12克)。1H-NMR(CDCl3,300MHz):8.29(d,J=7.8Hz,1H),8.06(s,1H),7.93-7.87(m,3H),7.81(d,J=7.8Hz,1H),7.60(d,J=7.8Hz,2H),1.38(s,12H),1.36(s,12H).13C-NMR(CDCl3,75MHz):176.2,155.6,153.5,134.9,134.8,130.7,128.2,126.3,125.5,125.4,124.5,84.6,83.9,24.90,24.88。GC-MS:474.3(M+).HRMS(ESI(+)):计算值:C15H13B2O6(二硼酸)(M+H):311.0898。实测值:311.0897。
实施例9
白藜芦醇的硼酸频哪醇酯前药(图15)
步骤1:在0℃,将三氟甲磺酸酐(d 1.487,3.7毫升,19.5毫摩尔)的二氯甲烷溶液(5.0毫升)滴加到吡啶(d,0.9819,1.96毫升,24.3毫摩尔)和相应的酚(1.2克,5.3毫摩尔)的无水二氯甲烷(10mL)溶液中。加入完成后,将混合物温热至室温并搅拌过夜。然后用乙酸乙酯稀释该混合物,然后用盐水淬灭。将有机层分离。用乙酸乙酯萃取水溶液。合并的有机溶液经MgSO4干燥。干燥后,减压除去溶剂,将残余物通过快速柱色谱纯化,得到定量的三氟甲磺酸酯(3.3g)。1H-NMR(CDCl3,300MHz):7.63(d,J=8.7Hz,2H),7.46(d,J=1.5Hz,2H),7.33(d,J=8.4Hz,2H),7.21-7.04(m,3H).13C-NMR(CDCl3,75MHz):149.8,149.6,141.3,136.0,131.6,128.7,126.7,122.0,119.3,118.8(q,J=319Hz),118.7(q,J=319Hz),114.1。
步骤2:在氮气下在120℃下将在二噁烷(5mL)中的白藜芦醇三氟甲磺酸酯(1.24克,2毫摩尔),双(频哪醇合)二硼(1.66克,6.6毫摩尔),PdCl2(dppf)(0.14克,2.5摩尔%)和KOAc(0.88克,9毫摩尔)搅拌2小时。TLC和MS显示三氟甲磺酸酯完全消耗并且没有产物形成。在真空下除去溶剂并通过快速色谱纯化粗品,得到产物(0.86克)。1H-NMR(CDCl3,300MHz):8.19(s,1H),8.07(s,2H),7.81(d,J=8.1Hz,2H),7.52(d,J=7.8Hz,2H),7.23(s,2H),1.37(s,12),1.28(s,24H).13C-NMR(CDCl3,75MHz):140.6,140.2,135.8,135.1,129.5,128.6,125.7,83.9,83.5,25.0,24.9。HRMS(ESI(+)):计算值C14H18B3O6(三硼酸)(M+H):313.1226。实测值:313.1228。
实施例10
雌马酚的硼酸频哪醇酯前药(图16)
步骤1:雌马酚(1.22克,0.005摩尔)溶解在DCM(30mL)中,然后加入三氟甲磺酸酐(1.6克,0.0055摩尔,0.93毫升)和4-二甲基氨基吡啶(0.61克,0.005摩尔)并搅拌所得混合物直至反应完成。将反应用饱和碳酸钠水溶液淬灭,并用乙酸乙酯萃取。将合并的有机层经MgSO4干燥并浓缩。粗产物通过快速柱色谱纯化,得到固体产物(1.71克)。1H-NMR(CDCl3,300MHz):7.35-7.22(m,4H),7.15(d,J=9.0Hz,1H),6.83-6.81(m,2H),4.33(m,1H),4.06(m,1H),3.29(m,1H),3.06-3.03(m,2H).13C-NMR(CDCl3,75MHz):155.0,148.7,148.5,141.1,130.8,129.2,121.9,121.8,118.7(q,J=318Hz),113.4,109.9,70.4,37.5,31.8.GC-MS:506.1(M+)。
步骤2:在二噁烷(3mL)中溶解三氟甲磺酸酯(0.51克,1.0毫摩尔),双(频哪醇合)二硼(0.63克,2.5毫摩尔),PdCl2(dppf)(0.014克,0.16毫摩尔)和乙酸钾(0.24克,2.4毫摩尔),在微波辐射下在80℃下搅拌混合物。在真空下除去溶剂并通过快速色谱纯化粗品,得到产物(0.10克)。1H-NMR(CDCl3,300MHz):7.80(d,J=7.8Hz,2H),7.31-7.27(m,4H),7.10(d,J=7.5Hz,1H),6.83-6.81(m,2H),4.33(m,1H),4.02(t,J=10.2Hz,1H),3.25(m,1H),3.08-3.03(m,2H),1.34(s,24H).13C-NMR(CDCl3,75MHz):154.0,144.6,135.3,129.3,126.8,126.5,125.2,122.8,83.8,83.7,70.7,38.8,32.5,24.8.GC-MS:462.4(M+)。HRMS(ESI(+)):计算值:C15H17B2O5(二硼酸)(M+H):299.1262.实测值:299.1268。
在本说明书中引用的所有参考文献通过引用并入本文,每个参考文献被具体和单独地指定通过引用并入。任何参考文献的引用是为先于申请日的公开内容,不应被解释为承认本公开内容无权先于根据先前发明的这种引用。
应当理解为上述的每个部分,或两个或多个一起也可以以不同于上述类型的其它类型的方法找到有用的应用。无需进一步分析,上述内容将完全揭示本公开的主旨,其他人可以通过应用现有的知识,从现有技术的角度,容易地使该主旨适用于各种应用,而不省略相当构成所附权利要求中阐述的本公开的通用或具体方面的必要特征的特征。前述实施方案仅作为示例的方式给出;本公开的范围由下面的权利要求来限定。
Claims (13)
1.一种式29的化合物:
其中R选自以下:
KF3B;(HO)2B;和NaF3B;
其中
R取代连接点是R上的取代硼原子,
及其任何盐。
2.权利要求1所述的化合物,其中R是
3.权利要求1所述的化合物,其中R是:
4.权利要求1所述的化合物,其中R是:
5.权利要求1所述的化合物,其中R是:
6.权利要求1所述的化合物,其中R是:
7.权利要求1所述的化合物,其中R是:KF3B。
8.权利要求1所述的化合物,其中R是:(HO)2B。
9.权利要求1所述的化合物,其中R是:NaF3B。
10.权利要求1所述的化合物在制备用于治疗与其中所述R为-OH的化合物形式所针对的疾病或症状相同的疾病或症状的药物中的用途。
11.权利要求1-9中任一项所述的化合物在制备用于对有需要的哺乳动物治疗由其中所述R为-OH的化合物治疗的疾病或症状的药物中的用途。
12.权利要求1所述的化合物在制备用于治疗癌症的药物中的用途。
13.权利要求1所述的化合物在制备用于下调雌激素受体的药物中的用途。
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WO2017192991A1 (en) * | 2016-05-06 | 2017-11-09 | Xavier University Of Louisiana | Selective estrogen receptor down-regulators (serds) |
WO2018017426A1 (en) | 2016-07-16 | 2018-01-25 | Florida State University Research Foundation, Inc. | Compounds and methods for treatment and prevention of flavivirus infection |
US10413583B2 (en) | 2016-11-30 | 2019-09-17 | The University Of Chicago | Synthetic substrates for enzymes that catalyze reactions of modified cysteines and related methods |
US10555942B2 (en) | 2017-10-10 | 2020-02-11 | Florida State University Research Foundation, Inc. | Emetine compounds for treatment and prevention of flavivirus infection |
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US11419834B2 (en) | 2019-02-25 | 2022-08-23 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide |
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