CN102225913B - 大黄酸衍生物以及它们的治疗用途 - Google Patents
大黄酸衍生物以及它们的治疗用途 Download PDFInfo
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Abstract
大黄酸衍生物以及它们的治疗用途，属医药领域。可具有生物活性的化合物是通式(I)的化合物或其盐、溶剂化物或水和物；其中，X3为具有生物活性化合物残基，X1、X2各自独立地为H或乙酰基；X3是川芎嗪、精氨酸、赖氨酸、肉毒碱残基；X3是匍甲胺、氨基葡萄糖、葡萄糖；X3是葡甲胺、氨基葡萄糖和葡萄糖乙酰化物的残基。治疗用途是用于制备治疗或预防心脑血管疾病的药物；用于制备治疗或预防与T-细胞增殖有关或由促炎细胞因子介导的疾病的药物。
Description
技术领域
本发明属医药领域，特别是大黄酸衍生物以及它们的治疗用途。
技术背景
大黄酸(Rhein，RH)是一种蒽醌类物质，广泛存在于蓼科(Polygonaceae)大黄属(Rheum)植物掌叶大黄(R.palmatum L.)、唐古特大黄(R.tanguticum.Maximex Regel)及药用大黄(R.officinal.Baill)的根及根基中，研究发现RH具有较广泛的药理活性，如抗肿瘤、抗炎、抗菌及调节肾功能等作用，尤其在抗炎方面的活性已经得到应用。目前，大黄酸已经成为配制保健品的最佳原料，可用于降脂减肥、通便排毒，清洁内环境，预防胃癌，延缓衰老。大力开发富含大黄酸的各种天然保健食品，将具有良好的经济效益。
目前临床上用于抗炎的药物主要是经典的抗炎药物，可分为两大类：即非甾体类抗炎药(non-steroidal anti-inflammatory drugs，NSAIDs)和甾体类抗炎药(steroidal anti-inflammatory drugs，SAIDs)。前者因同时抑制COX-1和COX-2，在抗炎的同时较常见胃肠道等不良反应，病人不易耐受；后者因是机体正常时分泌的激素，生理作用广泛，副作用多，也不易被病人接受。因此针对炎症的治疗，研究开发新型药物对临床应用具有非常重要的意义。大黄酸为蒽醌类衍生物的单体，主要分布于蓼科植物中，具有明显的抗炎，抗菌及调节肾功能等作用，近代研究发现大黄酸单体具有广泛的药理作用及低毒性、低成本等特点。
但是由于大黄酸单体化合物不溶于水，且不能完全被胃肠道所吸收，导致生物利用度低，这些都使大黄酸的应用受到了一些限制。将大黄酸类化合物与金属离子形成盐，可改变大黄酸类化合的溶解度，但是大黄酸与金属离子形成盐一般水溶液呈碱性，做成水针pH值较高，人体生理上难以接受；如降低pH值，则制剂稳定性不好。
为寻找更加有效合理的大黄酸类化合物，本发明以大黄酸和生物活性化合物为先导物，根据药物化学中的拼合原理，以大黄酸为母体，将大黄酸与另一生物活性物质采用化学修饰方法拼合，设计合成大黄酸羧酸酯衍生物，并发现其具有高效、低毒、选择性高的特点。
发明内容
本发明的目的是提供一类新的大黄酸类化合物与其它具有生物活性化合物拼合形成的化合物，不仅使其水溶性增加，而且可以克服大黄酸类化合物的强碱盐水溶液呈碱性，做成水针pH值较高，人体生理上难以接受；如降低pH值，则制剂稳定性不好的缺点。合成新的大黄酸衍生物，使其进入体内后，经血清酯酶降解，缓慢释放出母体药物大黄酸和其它具有生物活性化合物而发挥协同作用。
大黄酸的衍生物，其特征在于：
通式(I)的化合物或其盐、溶剂化物或水和物，
其中，X3为具有生物活性化合物残基，X1、X2各自独立地为H或乙酰基。
具有生物活性化合物X3是川芎嗪、精氨酸、赖氨酸、肉毒碱残基。
具有生物活性化合物X3是匍甲胺、氨基葡萄糖、葡萄糖、麦芽糖、呋喃糖残基。
具有生物活性化合物X3是葡甲胺、氨基葡萄糖、葡萄糖麦芽糖、呋喃糖乙酰化物残基。
通式(I)的化合物是通过包括下列步骤获得
①制备X3的卤代化物；
②将摩尔比为0.8-5的大黄酸或二乙酰大黄酸与X3的卤代化物在碱性条件经脱去HX的缩合反应制备化合物(I)。
其药用盐选自碱金属或碱土金属盐、氨基酸或含有氨基的碱性化合物形成的盐或医药上允许的无机酸或有机酸形成的盐。
其药用盐选自钾盐、钠盐、盐酸盐、硫酸盐、枸橼酸盐或马来酸盐。
含有通式(I)要求的化合物或其药用盐的药物组合物。
含有通式(I)要求化合物或其药用盐在用于治疗或预防心脑血管疾病药物中的应用。
含有通式(I)要求化合物或其药用盐在用于治疗或预防与T-细胞增殖有关或由促炎细胞因子介导的疾病的药物的应用。
应认识到本发明的化合物可含有一个或多个不对称取代的碳原子。通式(I)化合物中一个或多个这些不对称中心的存在可产生立体异构体，且在各情况下，本发明应被理解为扩展到所有这种立体异构体，包括对映异构体和非耐映异构体，及其混合物，包括外消旋混合物。
术语“卤素”是指氟、氯、溴或碘。
通式(I)化合物的盐包括药学可接受的盐，例如从无机或有机酸衍生的酸加成盐，如盐酸盐、氢溴化物、对-甲苯磺酸盐、磷酸盐、硫酸盐、高氯酸盐、醋酸盐、三氟醋酸盐、丙酸盐、柠檬酸盐、丙二酸盐、丁二酸盐、乳酸盐、草酸盐、酒石酸盐和苯甲酸盐等。
还可以与碱形成盐。这种盐包括从无机或有机碱衍生的盐，例如碱金属盐如镁或钙盐，和有机胺盐如吗啉、哌啶、二甲胺或二乙胺盐等。
本发明的化合物可通过下列方法制备。在下面的描述和通式中，除非另有说明，基团X3是如上面所定义的。应认识到在任何反应开始之前，存在于下述各种化合物中且希望保留的官能团，如氨基、羟基或羧基可能需要是被保护的形式。在这种情况下，保护基团的除去可以是特定反应中的最后一步。这种官能度的适宜保护基团对本领域技术人员而言是显而易见的。
可根据组分的物理-化学差异，按已知的方式，将所得终产物或中间体的任何混合物分离成纯的终产物或中间体，例如通过色谱法、蒸馏法、分步结晶，或在适当或可能的情况下形成盐。
由于本发明是对大黄酸的羧基和其它活性化合物的拼合修饰。利用拼合原理和其它基团结合不但可以改变化合物的理化常数，而且可以得到一种具有双重活性成分的新化合物。因为合成新的大黄酸衍生物是一类新的羧酸酯类化合物，其进入体内后，经血清酯酶降解，缓慢释放出母体药物大黄酸和其它具有生物活性化合物可发挥协同作用。实验药理研究表明大黄酸衍生物和大黄酸一样具有明显的药理活性。
以下结合具体实施方式对本发明作进一步说明
具体实施方式
实施例1
大黄酸川芎嗪酯的合成
1.12-溴甲基-3，5，6-三甲基吡嗪的合成(溴代川芎嗪的合成)
在250ml三颈瓶中依次加入原料2，3，5，6-四甲基吡嗪(20g，0.147mol)、NBS(26.75g，0.15mol)，过氧化苯甲酰(0.05g，0.0002mol)，溶剂四氢呋喃(75mL)。溶液呈橙黄色浑浊，白炽灯照射，油浴升温至75℃，回流反应8小时，TLC[V(乙酸乙酯)∶V(石油醚)＝1∶2为展开剂]检测显示反应完全(原料Rf＝0.38，产物Rf＝0.56)，反应液呈紫红色，过滤除去生成的丁二酰亚胺，得紫红色滤液，减压回收四氢呋喃后的紫红色粘稠液体，经减压蒸馏，收集产物99～101℃/2mmHg馏分，得2-溴甲基-3，5，6-三甲基吡嗪无色液体23g，冷却后固化，m.p.41.2～44℃，收率为72.8％。IR(KBr)υ::2972.6，2921.1，1542.4，1438.9，1365.3，1407.3，714.2.
1.2大黄酸川芎嗪酯的合成
反应式：
反应步骤：
在250mL三颈瓶中依次加入大黄酸(0.68g，0.0024mol)，四氢呋喃(20mL)，吡啶10mL，搅拌溶解后滴加2-溴甲基-3，5，6-三甲基吡嗪(0.62g，0.0029mol)的四氢呋喃(20mL)溶液，加热至60℃，搅拌、反应12h，TLC检测显示反应完全，过滤得红色滤液，加水(30mL)，用氯仿(3×30mL)萃取，合并氯仿层用水(2*20mL)洗涤后，经无水硫酸钠干燥，减压回收氯仿后的淡红色油状物，经硅胶柱分离，收集产物，减压回收溶剂后，得大黄酸川芎嗪酯0.60g，收率为60.1％。1H-NMR(CDCl3，300MHz)δ：11.9(s，2H)，8.1(s，1H)，7.8(t，1H)，7.7(m，2H)，7.4(d，1H)，5.3(s，2H)，2.5～2.6(m，9H)。
下列实施例以类似方式进行。
实施例2
大黄酸2，3，4，6-四乙酰葡萄糖酯的合成；
在250mL三颈瓶中依次加入大黄酸(0.68g，0.0024mol)，K2CO30.69g，水(10ml)，升温至30℃搅拌溶解，控溶液PH≈9。加入四丁基溴化铵0.20g的二氯甲烷10ml，30℃继续搅拌30min，滴加1.02g(0.0025mol)溴代2，3，4，6-四乙酰葡萄糖的二氯甲烷溶液10ml，滴加完毕后加热至50℃，搅拌反应6h，TLC检测显示反应完全，分取有机层，水层用二氯甲烷萃取3次，合并有机相，有机相依次用2％的NaOH溶液洗至中性，经无水硫酸钠干燥，减压回收氯仿，无水乙醇重结晶得红色固体0.75g，收率51％。
反应式：
实施例1的化合物已在二甲苯诱导小鼠耳肿胀和10％蛋清诱导大鼠足肿胀模型中显示有功效。
二甲苯诱导小鼠耳肿胀实验
昆明种小鼠40只，随机分为模型组、实施例一化合物组用药组、大黄酸组和阳性对照组(双醋瑞因)，每组10只。ig给药，每天一次，连续7天，模型组则ig给予等体积溶媒(1.0％羧甲基纤维素钠)。末次给药后1h于小鼠左耳前后两面涂抹二甲苯0.05ml，右耳作对照，2h后将小鼠脱臼处死，沿耳廓基线剪下两耳，用直径8mm的打孔器分别在同一部位打下圆耳片，称重，以左右耳片重量之差为肿胀度。结果显示实施例一化合物对二甲苯致小鼠耳廓肿胀有明显的抑制作用。
二甲苯诱导小鼠耳肿胀实验结果
与模型组比较：*P＜0.05
10％蛋清诱导大鼠足肿胀实验
Wistar种大鼠40只，
随机分为模型组、实施例一化合物组用药组、大黄酸组和阳性对照组(双醋瑞因)，，每组10只，ig给药，每天1次，连续7d，模型组则ig给予等体积溶媒(1.0％羧甲基纤维素钠)。给药1h后于每鼠右足趾皮下注射10％蛋清0.1mL致炎，分别在致炎前和致炎后0.25、0.5、1、2、4h，用Volume meter测量致炎侧足容积，以各鼠致炎前、后容积的差值为肿胀度。结果显示实施例一化合物对10％蛋清所致足跖肿胀有明显的抑制作用。
10％蛋清诱导大鼠足肿胀实验结果
与模型组比较：*P＜0.05
Claims (5)
1.大黄酸的衍生物，其特征在于：
其为具有通式（I）的化合物的药用盐，
其中，X3为具有生物活性化合物川芎嗪残基， X1、X2各自独立地为H或乙酰基。
2.根据权利要求1所述大黄酸衍生物，其特征在于：其药用盐选自碱金属或碱土金属盐或与医药上允许的无机酸或有机酸形成的盐。
3.根据权利要求1所述大黄酸衍生物，其特征在于：其药用盐选自钾盐、钠盐、盐酸盐、硫酸盐、枸橼酸盐或马来酸盐。
4.一种大黄酸衍生物的药物组合物，其特征在于：含有所述权利要求1通式（I）化合物的药用盐。
5.权利要求1所述通式（I）化合物的药用盐作为制备治疗或预防心脑血管疾病药物中的应用。
6.权利要求1所述通式（I）化合物的药用盐作为制备治疗或预防与T-细胞增殖有关或由促炎细胞因子介导的疾病的药物中的应用。
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