CN106748706A - 一种由β‑紫罗兰酮取代的姜黄素类似物及其制备方法和应用 - Google Patents

一种由β‑紫罗兰酮取代的姜黄素类似物及其制备方法和应用 Download PDF

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CN106748706A
CN106748706A CN201611041375.8A CN201611041375A CN106748706A CN 106748706 A CN106748706 A CN 106748706A CN 201611041375 A CN201611041375 A CN 201611041375A CN 106748706 A CN106748706 A CN 106748706A
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胡万乐
赵承光
卢孔秦
张亚利
卢明东
戴璇璇
史登健
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Zhejiang Kunlong Technology Co.,Ltd.
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Abstract

本发明公开了一种由β‑紫罗兰酮取代的姜黄素类似物及其制备方法和应用，该姜黄素类似物的结构如式(I)所示，其中，R为取代或者未取代的苯基、取代或者未取代的杂芳基；所述的苯基或者杂芳基上的取代基选自一个或者多个烷基、烷氧基、卤素、硝基或二烷基胺。药效试验表明，在姜黄素的母体结构上引入β‑紫罗兰酮片段，可以明显提升这类化合物的抗炎活性，降低TNF‑α和IL‑6的水平，并且提高减少感染性休克发生的概率。

Description

一种由β-紫罗兰酮取代的姜黄素类似物及其制备方法和应用
技术领域
本发明属于药物化学领域，具体涉及一种由β-紫罗兰酮取代的姜黄素类似物及其制备方法和应用。
背景技术
炎症，作为一种重要的病理过程在人体中十分常见，它本身是作为机体对于外来的或者异体的刺激的一种自身免疫应答。而当这种应答失调或者过分应答导致机体的自损伤时，就演变成了炎症。所以大多数的疾病都伴随着炎症的介导和发生，而炎症的介导和发生又使得疾病对于机体的损伤加重，如风湿性关节炎、糖尿病并发症、癌症、动脉粥样硬化、炎性肠病等。在这些过程中，促炎因子如TNF-α(肿瘤坏死因子-α)、IL-6(白介素-6)等都起到了重要的作用。
姜黄素是从姜科、天南星科中的一些植物的根茎中提取的一种化学成份，是植物界很稀少的具有二酮的色素，为二酮类化合物。姜黄素是一个药理活性强、适应症广的化合物。近年来，药物化学和药理学研究发现姜黄素具有抗炎、抗肿瘤、抗血管生成、抗突变、抗菌、抗病毒、抗氧化和神经保护等多种药理作用，姜黄素在美国已经进入I期临床实验阶段。其抗炎活性包括抑制巨噬细胞释放多种炎症因子的释放等。正是因为多生物活性，以及低分子量、无毒等特点，姜黄素曾被认为是理想的化学治疗药物之一。然而，进一步的研究发现姜黄素的抗炎活性还不够高，尤其是体内活性偏低，因此，通过结构修饰进一步发现高活性的姜黄素类似物具有重要的意义。
发明内容
本发明提供了一种由β-紫罗兰酮取代的姜黄素类似物及其制备方法和应用，该β-紫罗兰酮取代的姜黄素类似物具有更好的抗炎活性。
一种由β-紫罗兰酮取代的姜黄素类似物，结构如式(I)所示：
式(I)中，R为取代或者未取代的苯基、取代或者未取代的杂芳基；
所述的苯基或者杂芳基上的取代基选自一个或者多个烷基、烷氧基、卤素、硝基或二烷基胺。
经过细胞试验和动物试验，本发明人发现，在姜黄素的母体结构上引入β-紫罗兰酮片段，可以明显提升这类化合物的抗炎活性，降低TNF-α和IL-6的水平，并且减少感染性休克发生的概率。
作为优选，所述的R为2-甲氧基苯基、2-氟苯基、3,4-二甲氧基苯基、3,4-二氯苯基、2-硝基苯基、苯基、4-二乙胺基苯基、4-叔丁基苯基或2-噻吩基。作为最优选，所述的R为苯基或者2-噻吩基。
本发明还提供了一种所述的由β-紫罗兰酮取代的姜黄素类似物的制备方法，在碱的作用，β-紫罗兰酮和醛类化合物在溶剂中进行缩合反应，反应结束后经过后处理得到所述的β-紫罗兰酮取代的姜黄素类似物。
作为优选，所述的溶剂为乙醇和水的混合物，体积比为1～2：1。
作为优选，所述的碱为氢氧化钠。
本发明还提供了一种所述由β-紫罗兰酮取代的姜黄素类似物在制备抗炎药物中的应用。
作为优选，所述的抗炎药物用于抑制促炎因子TNF-α或IL-6。
作为优选，所述的R为2-硝基苯，当R为2-硝基苯的时候，该姜黄素类似物的活性最好，同时，能够明显减少感染性休克发生的概率。
所述的抗炎药物包括有效成分和药用辅料，所述有效成分为所述的姜黄素类似物及其可药用盐中的几种或几种组成。
此外，本发明的抗炎药物还可以同时包含现已上市的抗炎药物，制备得到防治炎症疾病类药物的组合物，已上市的抗炎药物包括各种甾体类抗炎药物和非甾体类抗炎药物。
所述的药用辅料指药学领域常规的药物载体，包括但不限于任何被美国食品药物管理局批准为可接受用于人或家畜的佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等张剂、溶剂或乳化剂。
适用于本发明的抗炎药物的剂型包括那些适于口服、直肠、局部、口腔、舌下、肠胃外(例如，皮下、肌肉、静脉内)以及经皮给药的制剂，尽管在任何给定的情况下，最适宜的路线将取决于所治疗的病症的性质和严重性以及取决于所使用的特定活性化合物的性质。
同现有技术相比，本发明的有益效果体现在：本发明通过向姜黄素的母体结构上引入β-紫罗兰酮片段，大大提升了该姜黄素类似物的抗炎活性，细胞试验表明这类化合物能够明显降低TNF-α和IL-6的水平，同时，动物试验表明，这些化合物能够明显减少感染性休克发生的概率。
附图说明
图1为本申请的化合物对TNF-α和IL-6释放的抑制活性；
图2为本申请的化合物对TNF-α和IL-6释放的抑制活性的量效关系；
图3为化合物1e缓解大鼠感染性休克的效果图。
具体实施方式
实施例1～9 化合物1a-i的制备
化合物1a-i的制备按照以下方式制得：将β-紫罗兰酮(1.0mmol)和相应的醛类化合物(1.0mmol)溶解到乙醇(6mL)和水(3mL)中，然后在室温条件下，加入1.2mL质量百分比浓度为10％的NaOH水溶液。反应体系在室温下搅拌30分钟，同时用TLC监测反应进度。反应结束后，向反应混合物中加入冰水使产品沉淀下来。得到的粗产物用柱层析进行纯化，产品通过ESI-MS和1H NMR进行分析，产品HPLC纯度都在95％以上，产品的结构和收率见表1。
部分化合物的表征数据如下：
化合物1a
(1E,4E)-1-(2-methoxyphenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one
Yellow oil,1H NMR(500MHz,CDCl3)δ8.01(d,J＝16.2Hz,1H,Ar-CH＝),7.86(dd,J＝7.7,1.8Hz,1H,Ar-H6),7.61(dd,J＝7.8,1.6Hz,1H,Ar-H4),7.50(d,J＝15.4Hz,1H,CH＝),7.09(d,J＝8.2Hz,1H,Ar-H3),6.95(d,J＝8.2Hz,1H,Ar-H5),6.52(d,J＝16.1Hz,1H,CO-CH＝),6.14(d,J＝16.4Hz,1H,CO-CH＝),3.92(s,3H,OCH3),2.32(m,2H,C＝C-CH),2.15–2.04(m,4H,CH2-CH2),1.86(s,3H,CH3),1.13(s,6H,C(CH3)2).
化合物1d
(1E,4E)-1-(3,4-dichlorophenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one
8.01(d,J＝16.0Hz,1H,Ar-CH＝),7.76(d,J＝7.7Hz,1H,Ar-H6),7.60(d,J＝15.4Hz,1H,CH＝C-CO),7.12(d,J＝8.0Hz,1H,Ar-H5),6.89(d,J＝7.8Hz,1H,Ar-H2),6.65(d,J＝16.0Hz,1H,CO-CH＝),6.23(d,J＝15.9Hz,1H,CO-CH＝),2.12(m,2H,C＝C-CH),2.05(s,3H,CH3),2.04-2.00(m,4H,CH2-CH2),1.16(s,6H,C(CH3)2).
化合物1e
(1E,4E)-1-(2-nitrophenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one
1H NMR(500MHz,CDCl3)δ8.07(d,J＝16.3Hz,2H,CH＝C-CO),7.99(t,J＝7.4Hz,1H,Ar-H3),7.70(d,7.5Hz,1H,Ar-H6),7.57(m,2H,Ar-H4,5),6.87(d,J＝15.9Hz,1H,CO-CH＝),6.56(d,J＝16.0Hz,1H,CO-CH＝),2.13(m,2H,C＝C-CH2),1.86(s,3H,CH3),1.66(t,J＝6.2Hz,2H,＞CH2),1.53(dd,J＝7.7,4.2Hz,2H,＞CH2),1.14(s,6H,C(CH3)2).
化合物1f
(1E,4E)-1-phenyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one
1H NMR(500MHz,CDCl3)δ7.69(d,J＝16.0Hz,1H,CH＝C-CO),7.63–7.59(m,2H,Ar-H2,6),7.53(d,J＝16.8Hz,1H,CH＝C-CO),7.42(dd,J＝5.0,2.0Hz,2H,Ar-H3,5),7.02(d,J＝16.0Hz,1H,CO-CH＝),6.58(s,1H,Ar-H4),6.50(d,J＝16.0Hz,1H,CO-CH＝),2.17–2.05(m,2H,C＝C-CH2),1.85(s,3H,CH3),1.65(ddd,J＝12.0,6.0,3.0Hz,2H,＞CH2),1.57–1.47(m,2H,＞CH2),1.13(s,6H,C(CH3)2).
化合物1h
(1E,4E)-1-(4-(tert-Butyl)phenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one
Yellow oil,1H NMR(500MHz,CDCl3)δ8.02(d,J＝16.0Hz,1H,Ar-CH＝),7.66(d,J＝8.0Hz,2H,Ar-H2,6),7.59(d,J＝16.0Hz,1H,CH＝C-CO),7.54(d,J＝8.0Hz,2H,Ar-H3,5),6.55(d,J＝16.1Hz,1H,CO-CH＝),6.17(d,J＝16.4Hz,1H,CO-CH＝),2.16–2.05(m,2H,C＝C-CH2),1.78(s,3H,CH3),1.64(m,4H,CH2-CH2),1.36(s,9H,Ar-C(CH3)3).1.14(s,6H,C(CH3)2).ESI-MS m/z:337.6(M+H)+,calculated for C24H32O:336.25.
化合物1j
(1E,4E)-1-(4-(Pyrrolidin-1-yl)phenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one
Yellow oil,1H NMR(500MHz,CDCl3)δ7.69(d,J＝16.0Hz,1H,CH＝C-CO),7.63–7.59(m,2H,Ar-H2,6),7.53(d,J＝16.8Hz,1H,CH＝C-CO),7.42(dd,J＝5.0,2.0Hz,2H,Ar-H3,5),7.02(d,J＝16.0Hz,1H,CO-CH＝),6.50(d,J＝16.0Hz,1H,CO-CH＝),3.44(t,J＝6.6Hz,4H,N–CH2×2),2.17–2.05(m,2H,C＝C-CH2),1.96(m,4H,CH2–CH2),1.85(s,3H,CH3),1.65(ddd,J＝12.0,6.0,3.0Hz,2H,-CH2-),1.57–1.47(m,2H,-CH2-),1.13(s,6H,C(CH3)2).ESI-MS m/z:350.9(M+H)+,calculated for C24H31NO:349.24.
实施例10 化合物对LPS刺激RAW 264.7巨噬细胞释放炎症因子的抑制
采用化合物对LPS刺激RAW 264.7巨噬细胞释放炎症因子(TNF-α和IL-6)抑制的方法测试了化合物的体外初步抗炎活性，具体方法如下：4×105个RAW 264.7巨噬细胞用DMEM培养液培养于37℃，24小时后更新培养液，并加入受测化合物(终浓度为10μM)预处理2小时，再用0.5μg/mL的LPS继续处理22小时，收集培养液用ELISA法检测TNF-α和IL-6含量；收集细胞检测总蛋白浓度，ELISA结果用相应的总蛋白浓度相除较准，以LPS对照组的TNF-α和IL-6含量定标为100％；每个化合物重复测试3次，计算平均值和误差值。化合物对TNF-α和IL-6释放的抑制活性见图1。大部分有效化合物对LPS刺激的IL-6和TNF-α释放有抑制作用。
实施例11 活性化合物抑制LPS刺激巨噬细胞释放炎症因子的量效关系
进一步测试了活性化合物1a、1b、1d、1e和1f抑制LPS刺激RAW 264.7巨噬细胞释放TNF-α和IL-6的量效关系，方法：同实施例10。实验数据见图2，效果最好的化合物为1e。
实施例12 化合物1e缓解大鼠感染性休克症状
用20％PEG400和化合物1e制成溶液，其中，化合物1e的浓度为1mg/mL。向雄性C57BL/6老鼠(重量为18～22g)注射1e水溶液(200μL,10mg/kg)，15分钟后再静脉注射LPS(15mg/kg)。对照组动物注射200μL赋形剂代替化合物1e溶液，记录七天的死亡率，结果见图3。
结果显示，当用LPS单独处理时候，所有的老鼠(100％)在四天之内死于感染性休克。而在注射LPS之前15分钟接受了1e(10mg/kg)的条件下，与LPS组相比存活率明显增加(相对于单独的LPS组高出了80％)，由此可见，在活体内化合物1e表现出卓越的抗感染性休克活性。
上述详细说明是针对发明的可行实施例的具体说明，该实施例并非用以限制本发明的专利范围，凡未脱离本发明的等效实施或变更，均应当包含于本发明的专利范围内。
另外，本领域技术人员还可在本发明权利要求公开的范围和精神内做其它形式和细节上的各种修改、添加和替换。当然，这些依据本发明精神所做的各种修改、添加和替换等变化，都应包含在本发明所要求保护的范围之内。

Claims (9)

1.一种由β-紫罗兰酮取代的姜黄素类似物，其特征在于，结构如式(I)所示：
式(I)中，R为取代或者未取代的苯基、取代或者未取代的杂芳基；
所述的苯基或者杂芳基上的取代基选自一个或者多个烷基、烷氧基、卤素、硝基或二烷基胺。
2.根据权利要求1所述的由β-紫罗兰酮取代的姜黄素类似物，其特征在于，所述的R为2-甲氧基苯基、2-氟苯基、3,4-二甲氧基苯基、3,4-二氯苯基、2-硝基苯基、苯基、4-二乙胺基苯基、4-叔丁基苯基或2-噻吩基。
3.根据权利要求2所述的由β-紫罗兰酮取代的姜黄素类似物，其特征在于，所述的R为苯基或者2-噻吩基。
4.一种如权利要求1～3任一项所述的由β-紫罗兰酮取代的姜黄素类似物的制备方法，其特征在于，在碱的作用，β-紫罗兰酮和醛类化合物在溶剂中进行缩合反应，反应结束后经过后处理得到所述的β-紫罗兰酮取代的姜黄素类似物。
5.根据权利要求4所述的由β-紫罗兰酮取代的姜黄素类似物的制备方法，其特征在于，所述的溶剂为乙醇和水的混合物，体积比为1～2：1。
6.根据权利要求4所述的由β-紫罗兰酮取代的姜黄素类似物的制备方法，其特征在于，所述的碱为氢氧化钠。
7.一种如权利要求1～3任一项所述由β-紫罗兰酮取代的姜黄素类似物在制备抗炎药物中的应用。
8.根据权利要求7所述的由β-紫罗兰酮取代的姜黄素类似物在制备抗炎药物中的应用，其特征在于，所述的抗炎药物用于抑制促炎因子TNF-α或IL-6。
9.根据权利要求7所述的由β-紫罗兰酮取代的姜黄素类似物在制备抗炎药物中的应用，其特征在于，所述的R为3,4-二甲氧基苯基、3,4-二氯苯基、2-硝基苯或2-噻吩基。
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