CN103384522B - 咖啡酸衍生物和它们在改善神经细胞生存力中的用途 - Google Patents
咖啡酸衍生物和它们在改善神经细胞生存力中的用途 Download PDFInfo
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- CN103384522B CN103384522B CN201180054991.6A CN201180054991A CN103384522B CN 103384522 B CN103384522 B CN 103384522B CN 201180054991 A CN201180054991 A CN 201180054991A CN 103384522 B CN103384522 B CN 103384522B
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Abstract
本发明涉及咖啡酸衍生物以及通过用咖啡酸衍生物接触神经细胞来改善神经细胞的生存力，如说明书所示。
Description
对相关申请的交叉引用
本申请要求于2010年11月15日提交的美国临时申请序号61/413,741的优先权。该在先申请的内容通过引用完整地结合于此。
背景
神经细胞死亡发生于神经变性疾病(包括帕金森病(Parkinson′sdisease)、亨廷顿病(Huntington′s disease)、阿尔茨海默病(Alzheimer′sdisease)、多发性硬化(multiple sclerosis)和肌萎缩性侧索硬化(amyothrophiclateral sclerosis))、卒中、缺氧-缺血性(hypoxic-ischemic)脑或脊髓损伤、移植和听力丧失中。改善神经细胞生存力的化合物是用于治疗这些病症的潜在药物。
虽然在该领域中已经进行了大量研究，但成功很少。参见，例如，Quinn等，Neurology，1998，51，S25-29。急迫地需要用于治疗上述疾病的有效药物。
概述
本发明是基于以下令人惊奇的发现，即某些咖啡酸的衍生物可以有效防止NO诱导的或谷氨酸诱导的神经元损失。
本发明的一方面涉及咖啡酸的衍生化合物，所述化合物具有以下显示的式(I)：
其中A是芳基，L是-CH2-，并且R1和R2中的每个独立地是-OH、-OR、或-OC(O)R，每个R是C1-C6烷基；或者A是芳基，L是C2-C6亚烷基或C2-C6亚烯基，并且R1和R2中的一个是-OC(O)R而另一个是-OH、-OR、或-OC(O)R，R是C1-C6烷基。
本发明的另一方面涉及通过将神经细胞与以上所示的式(I)的化合物接触来改善神经细胞生存力的方法，其中(1)A是芳基，L是C3-C6亚烷基或C2-C6亚烯基，并且R1和R2中的每个独立地是-OH、-OR、或-OC(O)R，R是C1-C6烷基；(2)A是芳基，L是-CH2-，并且R1和R2中的每个独立地是-OH、-OR、或-OC(O)R，R是C1-C6烷基；或者(3)A是芳基，L是-CH2CH2-，R1和R2中的每个独立地是-OR或-OC(O)R，R是C1-C6烷基。
上述化合物还可以具有以下特征：L是C3-C4亚烷基(例如，-CH2CH2CH2-)或C2-C4亚烯基(例如，-CH2＝CH2-或-CH2CH＝CH-)，并且R1和R2中的每个是-OH，或R1和R2中的每个独立地是-OR或-OC(O)R，R是甲基或乙基。
术语“烷基”是指含有(除非另外说明)1-20个碳原子(例如，C1-C10)的直链、支链或环状单价烃。烷基的实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基和环己基。
术语“亚烷基”是指含有(除非另外说明)1-10个碳原子(例如，C1-C10)的直链、支链或环状二价烃。亚烷基的实例包括但不限于：亚甲基(-CH2-)、亚乙基(-CH2CH2-)和正亚丙基(-CH2CH2CH2-)。
术语“亚烯基”是指含有一个或多个双键以及(除非另外说明)2-10个碳原子(例如，C2-C10)的直链、支链或环状二价烃。亚烷基的实例包括但不限于：亚乙烯基(-CH＝CH-)和正亚丙烯基(-CH2CH＝CH-)。
术语“芳基”是指单价6碳单环、10碳双环、14碳三环芳环系统。芳基的实例包括但不限于：苯基、萘基和蒽基。
上述烷基、亚烷基、亚烯基和芳基包括取代的和未取代的部分。在氨基、环烷基、杂环烷基、环烯基、杂环烯基、芳基和杂芳基上的可能的取代基包括但不限于：C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、C1-C10烷基氨基、芳基氨基、羟基、卤代、氧代(O＝)、硫代(S＝)、硫基(thio)、甲硅烷基、C1-C10烷硫基、芳硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨基酰基、氨基硫酰基、脒基、巯基、酰氨基、硫脲基、氰硫基、亚磺酰氨基、胍、脲基、氰基、硝基、酰基、硫酰基、酰氧基、脲基、氨基甲酰基(-C(O)NH2)、羧基(-COOH)和羧酸酯。另一方面，在烷基、烯基或炔基上的可能的取代基包括所有上述取代基，除了C1-C10烷基以外。环烷基、环烯基、杂环烷基、杂环烯基、芳基和杂芳基还可以彼此稠合。
本文所述的化合物包括化合物自身，以及它们的盐、它们的溶剂合物和它们的前药(如果是可适用的)。例如，盐可以在阴离子和化合物上带正电的基团(例如，氨基)之间形成。合适的阴离子包括氯离子、溴离子、碘离子、硫酸根、硫酸氢根、氨基磺酸根、硝酸根、磷酸根、柠檬酸根、甲磺酸根、三氟乙酸根、谷氨酸根、葡糖醛酸根、戊二酸根、苹果酸根、马来酸根、琥珀酸根、富马酸根、酒石酸根、甲苯磺酸根、水杨酸根、乳酸根、萘磺酸根和乙酸根。同样，盐也可以在阳离子和在异羟肟酸吲哚酯或异羟肟酸二氢吲哚酯化合物上的带负电的基团(例如，羧酸根)之间形成。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵阳离子如四甲基铵离子。上述化合物还包括那些包含季氮原子的盐。前药的实例包括酯和其他药用衍生物，其在向受试者给药后，能够提供上述活性化合物。
以下显示示例性化合物：
为了将式(I)的化合物与有此需要的受试者中的神经细胞接触，可以经由合适的途径(例如，腹膜内注射)将有效量的该化合物施用于受试者(例如，遭受神经变性疾病、卒中、缺氧-缺血性脑或脊髓损伤、移植或听力丧失的患者)。
因此，本发明的另一个方面涉及通过一种或多种式(I)的化合物治疗上述疾病的方法。
同样在本发明的范围中的是含有这些化合物中的一种或多种的药物组合物用于治疗神经变性疾病、卒中、缺氧-缺血性脑或脊髓损伤、移植或听力丧失的用途，以及上述治疗和用于制备用于这些治疗的药物的用途。
在以下说明书中描述本发明的实施方式的细节。从说明书和权利要求，本发明的其他特征、目的和优点将是明显的。
详述
上述式(I)的化合物可以通过常规方法制备。例如，它们可以通过以下方法合成：化学改性市售咖啡酸以将其COOH和/或OH基团转化为酯或醚基团。
进行的用以制备所需化合物的化学转化在本领域中是公知的。它们包括但不限于，在R.Larock，Comprehensive Organic Transformations(有机转化大全)，VCH出版社(1989)；T.W.Greene和P.G.M.Wuts，Protective Groupsin Organic Synthesis(有机合成中的保护基)，第3版，John Wiley & Sons(1999)；L.Fieser和M.Fieser，Fieser and Fieser’s Reagents for OrganicSynthesis(用于有机合成的Fieser和Fieser氏试剂)，John Wiley & Sons(1994)；和L.Paquette编辑，Encyclopedia ofReagents forOrganicSynthesis(有机合成试剂百科全书)，John Wiley & Sons(1995)及其随后版本中所述的那些。
如此合成的化合物可以通过急骤柱色谱法、高效液相色谱法、结晶或任何其他合适的方法进一步纯化。
本文所述的化合物包含非芳族双键。因此，它们可以以顺式或反式异构体形式存在。所有这样的异构体形式是预期的。
同样在本发明的范围内的是(1)改善神经细胞生存力的方法和(2)通过有效量的至少一种式(I)的化合物治疗神经变性疾病、卒中、缺氧-缺血性脑损伤、缺氧-缺血性脊髓损伤、移植，或听力丧失的方法。
神经变性疾病表征为进行性神经系统功能障碍。实例包括但不限于：帕金森病、亨廷顿病、阿尔茨海默病、多发性硬化和肌萎缩性侧索硬化。
当用于本文中时，术语“治疗”是指将化合物施用于遭受神经细胞损失或具有该疾病症状或易患此病的受试者，以医治、治愈、减轻、缓解、改变、治疗、改善、改进、影响或减少神经细胞损失的风险、其症状或易患此病的体质。术语“有效量”是指在受试者中给予所需的治疗效果所需的活性试剂的量。如本领域技术人员所知，有效量将根据给药途径、赋形剂使用和与其他药剂共同使用的可能性而变化。
为实施本发明的方法，一种上述化合物可以经口服给药，经肠胃外给药，通过吸入喷雾给药，经局部给药，经直肠给药，经鼻给药，经口腔给药，经阴道给药或经由植入型贮器(implanted reservoir)给药。术语“肠胃外”当在本文中使用时包括皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输注技术。为有助于给药，可以加工所述化合物以形成多种合适的药物组合物。
无菌可注射组合物，例如，无菌可注射水性或油性混悬液，可以根据本领域中已知的技术使用合适的分散剂或湿润剂(如Tween80)和悬浮剂来配制。无菌可注射制剂也可以是在非毒性肠胃外可用稀释剂或溶剂中的无菌可注射溶液或混悬剂，例如，作为在1，3-丁二醇中的溶液。可以采用的可接受的载体和溶剂有甘露醇、水、林格氏液(Ringer′s solution)和等渗氯化钠溶液。此外，无菌的、固定油类通常被用作溶剂或悬浮介质(例如，合成的甘油单酯或甘油二酯)。脂肪酸，如油酸及其甘油酯衍生物可以用于制备注射剂(injectable)，同样可以使用的有天然的药用油类，如橄榄油或蓖麻油，尤其是它们的聚氧乙烯化形式。这些油溶液或混悬液也可以含有长链醇稀释剂或分散剂，或羧甲基纤维素或类似的分散剂。对制剂来说，也可以使用其他常用的表面活性剂如Tween或Span或在制备药用固体、液体或其他剂型中常用的其他类似的乳化剂或生物利用度增强剂。
口服组合物可以是任何可口服剂型，其包括但不限于：胶囊、片剂、乳剂和水性混悬剂、分散液和溶液。在口服用片剂的情况中，通常使用的载体包括乳糖和玉米淀粉。还典型地添加润滑剂如硬脂酸镁。对于胶囊形式的口服给药，有用的稀释剂包括乳糖和无水玉米淀粉。当水性混悬剂或乳剂经口服给药时，可以将活性成分与乳化剂或悬浮剂组合混悬或溶解在油相中。如果需要，可以添加特定增甜剂、调味剂或着色剂。可以根据药物制剂领域中公知的技术制备鼻气溶胶或吸入剂组合物。含有一种本发明的化合物的组合物也可以以用于直肠给药的栓剂的形式给药。
药物组合物中的载体从以下角度来说必须是“可接受的”：其与制剂的活性成分相容(并且优选地，能够使其稳定)并且对被治疗的对象不是有害的。与本发明的化合物形成更可溶的复合物的一种或多种增溶剂(例如，环糊精)可以用作用于递送活性化合物的药物载体。其他载体的实例包括胶体二氧化硅、硬脂酸镁、十二烷基硫酸钠和D&C Yellow#10。
合适的体外测定可以用于预先地评价上述化合物在防止神经细胞损失中的效力。见以下提供的实际例子。对于有效的化合物，也可以在体内进一步检验其在治疗各种疾病中的效力。例如，可以将化合物施用于具有神经变性疾病、卒中、缺氧-缺血性脑或脊髓损伤、移植或听力丧失的动物(例如，小鼠模型)，并且然后评估其治疗作用。基于结果，也可以确定适当的剂量范围和给药途径。
在不需要进一步详尽细节的情况下，据信以上描述已经充分地使本发明可实施。因此，以下实施例仅应被视为说明性的，而无论如何不会限制其余的公开内容。本文中引用的所有出版物通过引用完整地结合于此。
化学合成
合成化合物1-3
将300mg(1.66mmol)的咖啡酸溶解在3.15ml DMSO中。搅拌的同时加入K3PO4(2.00mmol)。持续搅拌30分钟。最后，在30分钟内缓慢加入1.70mmol的苄基溴在1.05ml DMSO中的溶液。将所得的反应混合物在室温搅拌9小时，然后在15℃搅拌12小时。在搅拌的同时将反应混合物缓慢地加入到20ml冰水中，并用乙酸乙酯(3×10ml)萃取。通过逐滴加入1.0M HCl水溶液将水层酸化，并用乙酸乙酯萃取。将合并的有机层相继用1.0M HCl(2.5ml)和饱和氯化钠溶液(3×10ml)洗涤，用无水Na2SO4干燥，过滤，并在减压下浓缩。将粗制物通过硅胶色谱法使用石油醚/乙酸乙酯梯度洗脱液(从20∶1至3∶1V/V)纯化，并且以超过80％的产率获得化合物1。
以相同方式制备化合物2和3，不同之处在于分别使用萘甲基溴和溴丙基苯代替苄基溴。
化合物1：1H NMR(300MHz，DMSO-D6)δ：9.63(s，1H，OH)，9.16(s，1H，OH)，7.53(d，J＝15.6Hz，1H，C3-H)，6.75～7.43(m，8H，Ar-H)，6.33(d，J＝15.9Hz，1H，C2-H)，5.20(s，2H，CH2)；MS(ESI+)：[M+H]+m/z271，[M+Na]+m/z293；m.p.：150-151℃.
化合物2：1H NMR(300MHz，DMSO-d6)δ：9.371(brs，2H，2×OH)，7.91～9.94(m，4H，Ar-H)，7.55(d，J＝15.9Hz，1H，C3-H)，7.50～7.54(m，3H，Ar-H)，7.00～7.07(m，2H，Ar-H)，6.76(d，J＝8.1Hz，1H，Ar-H)，6.36(d，J＝15.9Hz，1H，C2-H)，5.35(s，2H，CH2)；13C NMR(75MHz，DMSO-d6)δ：166.5，148.5，145.7，145.6，134.1，132.8，132.6，128.2，127.9，127.6，126.8，126.4，126.3，125.9，125.5，121.6，115.7，114.9，113.7，65.4；MS(ESI-)：[M-H]-m/z319；m.p.：172-175℃.
化合物3：1H NMR300MHz，DMSO-d6)δ：9.21(brs，2H，OH)，7.46(d，J＝15.9Hz，1H，C3-H)，6.75～7.34(m，8H，Ar-H)，6.24(d，J＝15.9Hz，1H，C2-H)，4.32(t，J＝6.9Hz，2H，COOCH 2 CH 2 )，2.95(t，J＝6.9Hz，2H，COOCH2 CH 2 )；MS(FAB)：[M+H]+m/z285；m.p.：102～103℃.
合成化合物4-7
将2.5mmol咖啡酸苯乙酯溶解在6ml乙酸酐中。在搅拌的同时向其加入5mmol(0.43ml)无水吡啶。在室温搅拌5分钟后，然后在搅拌的同时将反应混合物缓慢加入到30ml冰水中，然后用乙酸乙酯(3×10ml)萃取。将合并的有机层用饱和氯化钠溶液(3×10ml)洗涤。将有机层用无水MgSO4干燥，过滤，并在减压下浓缩。将粗制物通过硅胶色谱法使用石油醚/乙酸乙酯梯度洗脱液(从20∶1至8∶1V/V)纯化，从而以96％的产率获得化合物6。
以相同的方式制备化合物4-7，不同之处在于使用不同的起始材料。
化合物4：1HNMR(300MHz，CDCl3)δ：7.66(d，J＝15.9Hz，1H，C3-H)，7.20～7.40(m，8H，Ar-H)，6.43(d，J＝15.9Hz，C2-H)，5.24(s，2H，CH2)，2.29(s，6H，2XCH3)；13CNMR(75MHz，CDCl3)δ：168.0，167.9，166.3，143.5，143.1，142.3，135.8，133.1，128.5，128.2，126.3，123.9，122.7，119.0，66.4，20.6，20.5；MS(+FSI-TOF)：[M+NH4]+m/z372，[M+Na]+m/z377；m.p.：101～103℃.
化合物5：1H NMR(300MHz，CDCl3)δ：7.60(d，J＝16.2Hz，1H，C3-H)，7.20～7.43(m，8H，Ar-H)，6.39(d，J＝15.9Hz，1H，C2-H)，4.22(t，J＝6.6Hz，2H，phCH2CH2 CH 2 )，2.74(t，J＝7.5Hz，2H，phCH 2 CH2CH2)，2.31(s，3H，CH3)，2.30(s，3H，CH3)，2.04(m，2H，phCH2 CH 2 CH2)；13C NMR(75MHz，CDCl3)δ：168.0，167.9，166.5，143.4，142.7，142.4，141.1，133.2，128.5，126.3，126.0，123.9，123.8，122.7，122.6，119.3，63.9，32.2，30.2，20.7，20.5；MS(ESI)：[M+H]+m/z383，[M+NH4]+m/z400；m.p.：65～67℃.
化合物6：1H NMR(300MHz，CDCl3)δ：7.60(d，J＝15.9Hz，1H，C3-H)，7.20～7.57(m，8H，Ar-H)，6.36(d，J＝15.9Hz，1H，C2-H)，441(t，J＝7.2Hz，2H，COOCH 2 CH2)，3.01(t，J＝7.2Hz，2H，COOCH2 CH 2 )，2.30(6H2XCH3)；13C NMR(75MHz，CDCl3)δ：168.0，167.9，166.4，143.4，142.8，142.4，137.7，133.2，128.9，128.5，126.5，126.4，123.9，122.7，119.2，65.1，35.1，20.6；MS(+ESI-TOF)：[M+NH4]+m/z369，[M+NH4]+m/z386，[M+Na]+m/z391，[M+K]+m/z407；m.p.：82～83℃.
化合物7：1H NMR(300MHz，CDCl3)δ：7.66(d，J＝16.2Hz，1H，C3-H)，7.21～7.43(8H，Ar-H)，6.71(d，J＝15.9Hz，1H，CH2CH＝CH)，6.42(d，J＝15.9Hz，1H，C2-H)，6.30～6.38(m，1H，CH2 CH＝CH)，4.87(d，J＝7.5Hz，2H，CH2)，2.30(s，6H，2X CH3)；13CNMR(75MHz，CDCl3)δ：168.0，167.9，166.3，143.5，143.1，142.4，136.1，134.3，133.2，128.6，128.0，126.6，123.9，123.8，123.0，122.8，122.6，119.0，65.2，20.6，20.5)；MS(+ESI-TOF)：[M+NH4]+m/z398，[M+Na]+m/z403；m.p.：86～88℃.
生物测定
根据Du等，Proc.Natl.Acad.Sci.，1997，94：11657-11662；和Du等，Proc.Natl.Acad.Sci.，2001，98：14669-14674中所述的方法来评估咖啡酸衍生物对改善神经细胞生存力的效力。
简言之，破坏新鲜解剖的小脑，并且将小脑颗粒神经元(CGN)细胞以1.2至1.5x106个细胞/ml的密度接种到聚L-赖氨酸包被的平板上、在补充以10％胎牛血清(FBS)、25mM KCL和庆大霉素(0.1mg/ml)的基础培养基Eagle中。在初始平板接种后24小时，将阿糖胞苷(10μM)加入培养基中。在所有实验中，在于体外7-8天后使用CGN。将用谷氨酸(30μM)或硝普钠(SNP，50μM)处理24小时的CGN用作对照。将CGN首先用在DMSO中的化合物1-7(10μM)处理2小时，然后用谷氨酸(30μM)或SNP(50μM)处理24小时。如下通过MTT测定评估神经元的生存力：加入MTT(3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴盐，500μM)并且之后在37℃培养15分钟。在用盐水洗涤培养物后，在黑暗中(因为MTT)加入DMSO以溶解紫色的甲膳染料晶体。在37℃、15分钟后，通过读板器在570nm测量吸光度，参比波长为650nm。
结果显示，用谷氨酸和SNP处理CGN导致神经元的死亡，而用化合物1-7中的每个预处理CGN显著地防止了谷氨酸和SPN诱导的神经元的死亡。
其他实施方案
本说明书中公开的所有特征可以以任意组合来组合。本说明书中公开的每种特征可以用服务于相同、相当或相似目的的备选特征代替。因此，除非另外明确说明，所公开的每种特征仅是大量相当或相似特征中的一个实例。
从以上说明书中，本领域技术人员可以容易地确定本发明的基本特征，并且在不偏离其实质和范围的情况下，可以对本发明进行不同的改变和修改以使其适应于不同的用途和条件。因此，其他实施方案也在以下权利要求的范围内。
Claims (5)
1.有效量的式(I)的化合物在制备改善神经细胞生存力的药物中的应用，其中所述式(I)的化合物适合于与神经细胞接触：
其中
A是芳基；
L是C3-C4亚烷基，并且R1和R2中的每个是-OH；
或者，L是-CH2CH2CH2-或-CH2-CH＝CH-，并且R1和R2中的每个独立地是-OC(O)R，R是甲基或乙基。
2.根据权利要求1所述的应用，其中所述化合物是
3.根据权利要求1所述的应用，其中所述接触步骤如下进行：将所述化合物施用于患者，以使所述化合物到达所述患者中的神经细胞并改善它们的生存力。
4.根据权利要求3所述的应用，其中所述患者遭受神经变性疾病、卒中、缺氧-缺血性脑损伤或缺氧-缺血性脊髓损伤。
5.式(I)的化合物：
其中
A是芳基；
L是-CH2CH2CH2-；并且
R1和R2中的一个是-OC(O)R而另一个是-OH、-OR、或-OC(O)R，R是C1-C6烷基。
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