CN112079842A - 一种依托度酸离子盐及其制备方法与应用 - Google Patents

一种依托度酸离子盐及其制备方法与应用 Download PDF

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CN112079842A
CN112079842A CN202010988061.9A CN202010988061A CN112079842A CN 112079842 A CN112079842 A CN 112079842A CN 202010988061 A CN202010988061 A CN 202010988061A CN 112079842 A CN112079842 A CN 112079842A
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ionic salt
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张嘉恒
扈圆圆
潘光兴
杨志雄
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Shenzhen Shanhai Innovation Technology Co ltd
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Shenzhen Graduate School Harbin Institute of Technology
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Abstract

本发明属于医药、化妆品用化合物领域，公开了一种依托度酸离子盐及其制备方法与应用。所述依托度酸离子盐的阳离子由生物碱形成，阴离子由依托度酸形成。所述依托度酸离子盐的制备方法，包括以下步骤：(1)在惰性气体氛围下，将依托度酸和生物碱加入至有机溶剂中，经离子化改性反应，制得依托度酸离子盐溶液；(2)在真空条件下对步骤(1)制得的依托度酸离子盐溶液进行浓缩，再经冷冻干燥，制得依托度酸离子盐。所述依托度酸离子盐完全保留了阳离子和阴离子的主体分子骨架及官能团，同时具有两种物质的生物活性和功效，表现出良好的抗炎效果、水溶性和较低的细胞毒性。

Description

一种依托度酸离子盐及其制备方法与应用
技术领域
本发明属于医药、化妆品用化合物领域，特别涉及一种依托度酸离子盐及其制备方法与应用。
背景技术
依托度酸属吲哚乙酸类非甾体抗炎药，镇痛作用较强。临床上广泛用于缓解类风湿性关节炎和骨关节炎的症状，延缓关节炎所引起的骨病理改变，也用于对术后疼痛的治疗。非甾体类抗炎药的共同作用机制是抑制环氧合酶-2(COX-2)的活性，减少炎症部位前列腺素的生物合成，从而控制炎症和减轻疼痛。此外，依托度酸的口服吸收良好，多剂量使用下不产生明显的蓄积作用，对肝肾功能无持续性影响，且其安全性和耐受性较好。但是目前对依托度酸的应用范围多停留在其单体的选择使用上，从而限制了其更广阔的应用效果和应用前景。
因此，希望对依托度酸进行改良，从而得到性能更好的依托度酸类化合物。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此，本发明提出一种依托度酸离子盐及其制备方法与应用，该依托度酸离子盐完全保留了阳离子和阴离子的主体分子骨架及官能团，同时具有两种物质的生物活性和功效，表现出良好的抗炎效果、水溶性和较低的细胞毒性。
一种依托度酸离子盐，所述依托度酸离子盐的阳离子由生物碱形成，阴离子由依托度酸形成。
优选的，所述生物碱选自甜菜碱、左旋肉碱或苦参碱。
甜菜碱是一种生物碱，具有抗炎、抗肿瘤、降血压、抗消化性溃疡及胃肠功能障碍，可治疗肝脏疾病；甜菜碱作为饲料添加剂具有提供甲基供体功能，可节省部分蛋氨酸，具有调节体内渗透压，缓和应激，促进脂肪代谢和蛋白质合成的作用。
左旋肉碱是脂肪代谢过程中的一种关键的物质，有抗炎症作用及调节血压作用，并能够促进脂肪酸进入线粒体氧化分解，即左旋肉碱是转运脂肪酸的载体。在长时间大强度运动中，左旋肉碱提高了脂肪的氧化速率，减少了糖原的消耗，同时也延缓了疲劳。
苦参碱具有抗过敏、抗炎作用，能调节免疫和升高白细胞。近年有研究发现苦参碱有抗过敏作用，可抑制炎症介质的释放，可调节小鼠和大鼠腹腔肥大细胞组织胺释放，具有稳定细胞膜的作用。
优选的，所述生物碱与依托度酸的摩尔比为(1-8):(1-8)。更优选的，所述生物碱与依托度酸的摩尔比为1:1或4:1。
本发明通过氢键作用来确定不同配比之间是否形成离子键相互作用，并经筛选得到性能更优的化合物结构。
上述依托度酸离子盐的制备方法，包括以下步骤：
(1)在惰性气体氛围下，将依托度酸和生物碱加入至有机溶剂中，经离子化改性反应，制得依托度酸离子盐溶液；
(2)在真空条件下对步骤(1)制得的依托度酸离子盐溶液进行浓缩，再经冷冻干燥，制得依托度酸离子盐。
本发明以生物碱作为阳离子前驱体，以依托度酸作为阴离子前驱体，通过离子化改性反应合成依托度酸类离子盐，反应结束后通过浓缩结晶实现产品的分离纯化。
优选的，步骤(1)中所述有机溶剂选自乙腈、甲醇、乙醇或乙酸乙酯中的一种或多种。更优选的，所述溶剂选自甲醇或乙醇，以提高产品的结晶分离效果。
优选的，步骤(1)中发生离子化改性反应的温度为20-80℃。在该反应温度下，反应能够正常进行。更优选的，步骤(1)中发生离子化改性反应的温度为50-80℃。在该反应温度下，具有较快的反应速率。
优选的，步骤(1)中发生离子化改性反应的时间为12-24h。在该反应时间下，能使反应完全。
优选的，步骤(2)中依托度酸离子盐溶液浓缩至原体积的1/6至1/10。
还可对上述制得的依托度酸离子盐经进一步纯化处理，具体步骤为：对制得的依托度酸离子盐依次进行过滤分离和真空干燥。通过进一步的纯化处理可彻底除去产品中的剩余溶剂。
优选的，所述真空干燥的时间为48-72h。
上述依托度酸离子盐可应用于化妆品或药品领域，作为化妆品原料或药品原料使用。
本发明生成的依托度酸离子盐完全保留了甜菜碱、左旋肉碱、苦参碱等生物碱和依托度酸单体的主体分子骨架及官能团，因而同时具有两种物质的生物活性和功效，实现对依托度酸性能的改良。所述依托度酸离子盐用于化妆品领域可涂抹外用，用于药品领域可口服或注射。
相对于现有技术，本发明的有益效果如下：
(1)经过离子化改性，使依托度酸羧基上羟基的氢离子化，从而与生物碱形成氢键，氢键的生成提高了水溶性，因此所述依托度酸离子盐的水溶性与单体依托度酸相比有明显的提升，从而大大提高了吸收度，增强了应用效果；
(2)本发明所述依托度酸离子盐的细胞毒性与前驱体依托度酸相比没有明显变化，具有良好的安全性；
(3)本发明中依托度酸离子盐的制备方法可用普通溶剂作为反应介质，且具有合成步骤简洁，后处理方便，所得产品纯度高，收率高的优点；
(4)本发明所述依托度酸离子盐完全保留了甜菜碱、左旋肉碱、苦参碱等生物碱和依托度酸单体的主体分子骨架及官能团，因而同时具有两种物质的生物活性和功效，而对于同时具备抗炎活性的两种物质来说，成盐后将显著增强其抗炎活性。
附图说明
图1为实施例1制得的依托度酸甜菜碱离子盐的核磁氢谱；
图2为实施例1制得的依托度酸甜菜碱离子盐的核磁碳谱；
图3为实施例2制得的依托度酸左旋肉碱离子盐的核磁氢谱；
图4为实施例2制得的依托度酸左旋肉碱离子盐的核磁碳谱；
图5为实施例3制得的依托度酸苦参碱离子盐的核磁氢谱；
图6为实施例3制得的依托度酸苦参碱离子盐的核磁碳谱；
图7和图8表示实施例4中9种依托度酸左旋肉碱离子盐对人胚胎肾细胞(293T)的细胞毒性；
图9表示实施例4中2种经筛选后的依托度酸左旋肉碱离子盐对小鼠成纤维细胞(L929)细胞系的细胞毒性。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案，现列举以下实施例进行说明。需要指出的是，以下实施例对本发明要求的保护范围不构成限制作用。
以下实施例中所用的原料、试剂或装置如无特殊说明，均可从常规商业途径得到，或者可以通过现有已知方法得到。
实施例1
本实施例提供一种依托度离子盐，具体为依托度酸甜菜碱离子盐，其通过以下步骤制备得到：
(1)在氩气氛围下，用5mL的乙醇溶解3mmol依托度酸于反应器中，以5mL的乙醇溶解3mmol甜菜碱，将甜菜碱的乙醇溶液逐滴加入溶解有依托度酸的反应器中，加热至60℃，离子化改性反应24小时；
(2)反应完毕后，在真空条件下浓缩溶液至反应液的1/8，冷冻结晶，并经过滤、洗涤分离得到依托度酸甜菜碱离子盐的产物，在真空干燥箱中干燥48小时，得到纯净的依托度酸甜菜碱离子盐。
图1和图2分别表示该依托度酸甜菜碱离子盐的核磁共振氢谱、碳谱图，具体核磁数据为：1H NMR(600MHz,DMSO-d6)δ:10.61(s,1H),7.22(d,J＝7.0Hz,1H),6.93–6.86(m,2H),3.93(d,J＝18.0Hz,2H),3.62(s,2H),3.18(s,3H),3.15(s,6H),2.93(d,J＝13.6Hz,1H),2.84(d,J＝7.2Hz,2H),2.77(d,J＝13.6Hz,1H),2.64(dd,J＝32.1,11.0Hz,2H),2.06(d,J＝7.0Hz,2H),1.25(t,J＝6.9Hz,3H),0.63(t,J＝6.2Hz,3H)ppm；13C NMR(150MHz,DMSO-d6)δ:172.0,165.2,136.8,134.9,127.0,126.5,120.1,119.2,115.8,107.6,75.8,60.4,52.6,49.1,43.4,31.1,24.2,22.4,14.9,8.3ppm.
实施例2
本实施例提供一种依托度离子盐，具体为依托度酸左旋肉碱离子盐，其通过以下步骤制备得到：
(1)在氩气氛围下，以5mL的乙醇溶解3mmol依托度酸于反应器中，以5mL的乙醇溶解3mmol左旋肉碱，将左旋肉碱的乙醇溶液逐滴加入溶解有依托度酸的反应器中，加热至60℃，离子化改性反应24小时；
(2)反应完毕后，在真空条件下浓缩溶液至反应液的1/8，冷冻结晶，并经过滤、洗涤分离得到依托度酸左旋肉碱离子盐的产物，在真空干燥箱中干燥60小时，得到纯净的依托度酸左旋肉碱离子盐。
图3和图4分别表示该依托度酸左旋肉碱离子盐的核磁共振氢谱、碳谱图，具体核磁数据为：1H NMR(600MHz,DMSO-d6)δ:12.00(s,1H),10.46(s,1H),7.25–7.21(m,1H),6.94–6.86(m,2H),4.00–3.87(m,2H),2.93(d,J＝13.6Hz,1H),2.84(m,J＝7.5Hz,2H),2.76(d,J＝13.6Hz,1H),2.67(dd,J＝8.8,5.4Hz,1H),2.60(m,J＝15.0,3.5Hz,1H),2.06(m,J＝7.2Hz,2H),1.26(t,J＝7.5Hz,3H),0.63(t,J＝7.3Hz,3H)ppm；13C NMR(150MHz,DMSO-d6)δ:173.7,172.8,138.0,134.8,126.9,126.6,119.8,119.0,115.8,106.9,75.6,70.6,63.6,60.2,53.9,49.1,44.7,30.9,24.3,22.5,14.8,8.3ppm.
实施例3
本实施例提供一种依托度离子盐，具体为依托度酸苦参碱离子盐，其通过以下步骤制备得到：
(1)在氩气氛围下，以5mL的乙醇溶解3mmol依托度酸于反应器中，以5mL的乙醇溶解3mmol苦参碱，将苦参碱的乙醇溶液逐滴加入溶解有依托度酸的反应器中，加热至60℃，离子化改性反应24小时；
(2)反应完毕后，在真空条件下浓缩溶液至反应液的1/10，冷冻结晶，并经过滤、洗涤分离得到依托度酸苦参碱离子盐的产物，在真空干燥箱中干燥60小时，得到纯净的依托度酸苦参碱离子盐。
图5和图6分别表示该依托度酸苦参碱离子盐的核磁共振氢谱、碳谱图，具体核磁数据为：1H NMR(600MHz,DMSO-d6)δ:10.52(s,1H),7.22(d,J＝7.2Hz,1H),6.89(m,J＝6.9Hz,2H),4.18(dd,J＝12.2,2.9Hz,1H),3.99–3.86(m,2H),3.71(dd,J＝15.0,9.1Hz,1H),3.17(s,3H),2.92(d,J＝13.0Hz,2H),2.84(dd,J＝15.1,7.7Hz,2H),2.71(dd,J＝24.4,13.9Hz,4H),2.60(d,J＝15.0Hz,1H),2.24–2.11(m,2H),2.08–1.97(m,4H),1.87(dd,J＝23.7,11.8Hz,3H),1.69(s,1H),1.63–1.47(m,5H),1.42–1.31(m,4H),1.25(t,J＝7.3Hz,3H),0.62(t,J＝7.0Hz,3H)ppm；13C NMR(150MHz,DMSO-d6)δ:172.0,168.5,136.8,134.9,127.0,126.5,120.1,119.2,115.8,107.6,75.8,63.6,60.4,57.1,53.1,49.1,42.9,41.3,35.5,32.9,31.1,27.9,26.8,26.4,24.2,22.4,21.1,20.6,18.9,14.9,8.3ppm.
实施例4
细胞毒性测试
采用CCK8法检测生物碱与依托度酸在不同摩尔比所合成的比依托度酸离子盐对人胚胎肾细胞(293T)的细胞毒性。
选用左旋肉碱与依托度酸的摩尔比为1:1，1:2，2:1，3:1，4:1的5种依托度酸左旋肉碱离子盐进行细胞毒性实验。实验结果由图7所示，随着依托度酸左旋肉碱离子盐浓度的上升，细胞存活率有所降低，但即使以500μg/mL的浓度进行培养，所选离子化合物的细胞存活率仍大于85％，表明这些离子化合物分子对人胚胎肾细胞(293T)没有明显的毒性。
选用依托度酸与左旋肉碱的摩尔比为2:1，3:1，4:1，5:1的4种依托度酸左旋肉碱离子盐进行细胞毒性实验。实验结果由图8所示，随着依托度酸左旋肉碱离子盐浓度的上升，细胞存活率有所降低，但即使以500μg/mL的浓度进行培养，所选离子化合物的细胞存活率仍大于85％，表明这些离子化合物分子对人胚胎肾细胞(293T)没有明显的毒性。
为进一步筛选最优结构，从上述9个依托度酸左旋肉碱离子盐中筛选得到2个最优配比，即化合物1(左旋肉碱：依托度酸＝1:1)和化合物2(左旋肉碱：依托度酸＝4:1)。采用CCK8法检测化合物1和化合物2对小鼠成纤维细胞(L929)细胞系的细胞毒性，并与依托度酸的细胞毒性进行比较。实验结果如图9所示，即使以500μg/mL的浓度培养，选用化合物1、化合物2的细胞存活率依然接近85％，并且与前驱体依托度酸对比，细胞毒性没有明显的增强变化甚至存活率稍有提升，表明这些离子化合物对小鼠成纤维细胞(L929)没有明显的毒性。

Claims (10)

1.一种依托度酸离子盐，其特征在于，所述依托度酸离子盐的阳离子由生物碱形成，阴离子由依托度酸形成。
2.根据权利要求1所述的依托度酸离子盐，其特征在于，所述生物碱选自甜菜碱、左旋肉碱或苦参碱。
3.根据权利要求1所述的依托度酸离子盐，其特征在于，所述生物碱与依托度酸的摩尔比为(1-8):(1-8)。
4.权利要求1-3中任一项所述的依托度酸离子盐的制备方法，其特征在于，包括以下步骤：
(1)在惰性气体氛围下，将依托度酸和生物碱加入至有机溶剂中，经离子化改性反应，制得依托度酸离子盐溶液；
(2)在真空条件下对步骤(1)制得的依托度酸离子盐溶液进行浓缩，再经冷冻干燥，制得依托度酸离子盐。
5.根据权利要求4所述的制备方法，其特征在于，步骤(1)中所述有机溶剂选自乙腈、甲醇、乙醇或乙酸乙酯中的一种或多种；优选的，所述溶剂选自甲醇或乙醇。
6.根据权利要求4所述的制备方法，其特征在于，步骤(1)中发生离子化改性反应的温度为20-80℃；优选的，步骤(1)中发生离子化改性反应的温度为50-80℃。
7.根据权利要求4所述的制备方法，其特征在于，步骤(1)中发生离子化改性反应的时间为12-24h。
8.根据权利要求4所述的制备方法，其特征在于，步骤(2)中依托度酸离子盐溶液浓缩至原体积的1/6至1/10。
9.根据权利要求4所述的的制备方法，其特征在于，对制得的依托度酸离子盐经进一步纯化处理，具体步骤为：对制得的依托度酸离子盐依次进行过滤分离和真空干燥。
10.权利要求1-3中任一项所述的依托度酸离子盐作为化妆品原料或药品原料的应用。
CN202010988061.9A 2020-09-18 2020-09-18 一种依托度酸离子盐及其制备方法与应用 Pending CN112079842A (zh)

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EP2128123A1 (en) * 2007-01-29 2009-12-02 Medrx Co., Ltd. Salt of nonsteroidal anti-inflammatory drug and organic amine compound and use thereof
CN109575024A (zh) * 2018-12-21 2019-04-05 深圳市萱嘉生物科技有限公司 一种苦参碱酚酸盐及其制备方法与应用
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EP2128123A1 (en) * 2007-01-29 2009-12-02 Medrx Co., Ltd. Salt of nonsteroidal anti-inflammatory drug and organic amine compound and use thereof
CN109575024A (zh) * 2018-12-21 2019-04-05 深圳市萱嘉生物科技有限公司 一种苦参碱酚酸盐及其制备方法与应用
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