CN116407529A - 3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的药物用途 - Google Patents
3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的药物用途 Download PDFInfo
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- 229930006727 (-)-endo-fenchol Natural products 0.000 title claims abstract description 21
- IAIHUHQCLTYTSF-UHFFFAOYSA-N fenchyl alcohol Natural products C1CC2(C)C(O)C(C)(C)C1C2 IAIHUHQCLTYTSF-UHFFFAOYSA-N 0.000 title claims abstract description 21
- IAIHUHQCLTYTSF-MRTMQBJTSA-N Fenchyl alcohol Chemical compound C1C[C@]2(C)[C@H](O)C(C)(C)[C@H]1C2 IAIHUHQCLTYTSF-MRTMQBJTSA-N 0.000 title claims abstract description 18
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Abstract
3‑硝基‑2,6‑二羟基苯甲酸右崁醇或葑醇的酯治疗炎症相关疾病的药物用途。3‑硝基‑2,6‑二羟基苯甲酸右崁醇或葑醇的酯具有良好的消炎作用，较好的水溶解性，可用于治疗炎症相关疾病。
Description
技术领域
本发明属于制药领域，提供3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯治疗炎症相关疾病的药物用途。
背景技术
炎症可以引起病变部位红、肿、热、痛、功能障碍。如果是妇科炎症，会引起子宫内膜炎、附件炎、继发性不孕、输卵管堵塞等，如果是呼吸系统炎症，会引起支气管炎、肺炎等，如果是心脏疾病，会引起心肌炎，导致心脏功能降低等。
在炎症反应过程中，巨噬细胞在启动、维护和解决炎症反应方面起着重要的作用。脂多糖(LPS)是革兰氏阴性菌细胞壁的主要成分之一，具有强大的免疫刺激能力。RAW264.7巨噬细胞作为一种鼠源性免疫细胞，在受到外界因素(如LPS)刺激时会被激活，分泌众多炎症因子(如IL-1β、TNF-α等)，产生炎症反应。炎症因子的多少可间接地反映出炎症的严重程度，是炎症轻重的量化指标。右莰醇能够抑制脂多糖诱导的RAW264.7巨噬细胞炎症模型IL-1β、TNF-α的增加，依达拉奉右莰醇浓溶液临床已经用于治疗脑卒中。但是，右莰醇口服生物利用度低，当制成注射液时，难溶于水中，需要加入大量有机溶剂，给药物制剂增加了难度，给临床用药增加了风险。
中国发明专利2021113312181公开了2,6-二羟基苯甲酸右崁醇类化合物及其药物用途，结构符合通式
其中：R＝-H，-OH，-NR1R2，/>
或-CONR3R4；R1，R2＝-H、1-4个碳原子的酰基或1-6个碳原子的烷基，/>
或-COR5；R3，R4，R5＝-H或1-3个碳原子的烷基。
发明人研究发现：中国发明专利2021113312181实施例化合物1(对照化合物1)水溶解性较低。而在其苯环3-位引入氨基获得的化合物3-氨基-2,6-二羟基苯甲酸右崁醇酯(对照化合物2)，其水溶解性仍然较低。专利申请人意外的发现：制备3-氨基-2,6-二羟基苯甲酸右崁醇酯的中间体3-硝基-2,6-二羟基苯甲酸右崁醇酯，不仅具有较好的水溶解性，可以方便的以5％碳酸氢钠水溶液溶解(实验数据见实施例3)，而且具有良好的消炎作用(实验数据见实施例2)。
葑醇(fenchol)可以帮助保护大脑免受阿尔茨海默病病理的影响。葑醇通过刺激FFAR2信号传导，即肠道微生物组感应机制，显著减少了过量的Aβ积累和神经元的死亡。患有阿尔茨海默病患者的大脑中的僵尸细胞停止复制并缓慢死亡，在患病和衰老的器官中堆积，创造了一种破坏性的炎症环境，并向邻近的健康细胞发送应激或死亡信号，这些细胞最终也会变成有害的僵尸细胞或死亡(Frontiers in Aging Neuroscience，2021)。但是，葑醇口服生物利用度低，当制成注射液时，难溶于水中，需要加入大量有机溶剂，给药物制剂增加了难度，给临床用药增加了风险。
发明人研究发现：3-硝基-2,6-二羟基苯甲酸葑醇酯，不仅具有较好的水溶解性，可以方便的以5％碳酸氢钠水溶液溶解(实验数据见实施例3)，同时具有良好的消炎作用(实验数据见实施例2)。
5％碳酸氢钠水溶液是临床常见的碳酸氢钠注射液，具有较好的安全性。本发明化合物可以方便的以5％碳酸氢钠水溶液溶解，因此能够方便的制备为注射液，以注射方式给药。
发明内容
为解决现有技术中存在的上述技术问题，本发明提供3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯及其药学上可接受的盐，3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯具有良好的消炎的作用，较好的水溶解性，可用于制备治疗炎症相关疾病的药物。
本发明的技术方案如下：
本发明的第一个目的是提供3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯在制备治疗治疗炎症相关疾病的药物中的应用，所述3-硝基-2,6-二羟基苯甲酸右崁醇结构式为
3-硝基-2,6-二羟基苯甲酸葑醇酯结构式为/>
本发明的第二个目的是提供前述3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的药学上可接受的盐在制备治疗炎症相关疾病药物中的应用。
本发明所述3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯及其药学上可接受的盐，包含但不限于钠盐、钾盐、锂盐、钙盐等。
炎症相关疾病包含但不限于妇科炎症，如子宫内膜炎、附件炎、继发性不孕、输卵管堵塞等；呼吸系统炎症如支气管炎、肺炎等；心脏炎症疾病如心肌炎等。
本发明的第三个目的是提供治疗炎症相关疾病的药物，所述药物的有效成分包括前述3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯及其药学上可接受的盐。
进一步的，所述药物为注射剂。
与现有技术相比，本发明技术方案具有以下有益效果：
本发明化合物具有良好的消炎作用，较好的水溶解性，可用于制备治疗炎症相关疾病的药物。
需要指出的是：和对照化合物相比，3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的活性显著增加。在细胞模型中，3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯对脂多糖诱导的RAW264.7巨噬细胞炎症模型IL-1β、TNF-α增加的抑制作用显著优于对照化合物(实施例2)。提示：本发明所述化合物，在3位引入硝基对于提高其抗炎作用具有重要作用。同时，由于硝基的引入，化合物在水中溶解性增加，可以方便的以5％碳酸氢钠水溶液溶解(实施例3)。该类化合物在制备治疗炎症相关疾病的药物中具有良好的应用前景。
附图说明
图1是3-硝基-2,6-二羟基苯甲酸右崁醇酯、3-硝基-2,6-二羟基苯甲酸葑醇酯对脂多糖诱导的RAW264.7巨噬细胞炎症模型IL-1β、TNF-α增加的的抑制率。
具体实施方式
以下结合实施例来进一步解释本发明，但实施例并不对本发明做任何形式的限定。
实施例1目标化合物的合成
1)3-硝基-2,6-二羟基苯甲酸右崁醇酯：按照中国发明专利2021113312181方法，以2,6-二羟基苯甲酸右崁醇和硝酸为原料合成。1H NMR(400MHz,DMSO-d6)δ8.00(d,J＝9.4Hz,1H),6.54(d,J＝9.5Hz,1H),5.04(d,J＝9.2Hz,1H),2.32(ddd,J＝13.7,9.2,4.5Hz,1H),1.86(ddd,J＝12.3,9.2,4.3Hz,1H),1.71–1.60(m,2H),1.24–1.13(m,2H),1.05(dd,J＝13.7,3.5Hz,1H),0.88(s,3H),0.82(d,J＝4.4Hz,6H).13C NMR(101MHz,Chloroform-d)δ169.08,168.16,160.37,129.43,127.39,107.43,105.78,82.74,49.28,48.14,44.91,36.75,28.11,27.42,19.77,18.94,13.72.
2)3-硝基-2,6-二羟基苯甲酸葑醇酯：参考3-硝基-2,6-二羟基苯甲酸右崁醇酯的合成方法，以2,6-二羟基苯甲酸右崁醇和硝酸为原料合成。1H NMR(400MHz,Chloroform-d)δ8.22(dd,J＝9.6,1.5Hz,1H),6.58(dd,J＝9.6,1.4Hz,1H),4.69(d,J＝2.0Hz,1H),2.10–2.00(m,1H),1.81–1.71(m,2H),1.65(dd,J＝10.4,2.5Hz,1H),1.52(s,1H),1.30–1.20(m,2H),1.18(s,3H),1.11(s,3H),0.85(s,3H).13C NMR(101MHz,Chloroform-d)δ170.94(d,J＝4.6Hz),159.91,131.49,127.03,110.79,102.47,89.90,48.65,48.51,41.40,39.95,29.66,27.02,25.86,20.47,19.51.
实施例2化合物对脂多糖诱导的RAW264.7巨噬细胞炎症模型IL-1β、TNF-α增加的抑制作用
2.1实验方案
实验设立空白组、模型组、药物组(右崁醇组，葑醇组，对照化合物1组，对照化合物2组，目标化合物1组也即3-硝基-2,6-二羟基苯甲酸右崁醇酯组，目标化合物2组也即3-硝基-2,6-二羟基苯甲酸葑醇酯组)。取对数生长期的RAW264.7小鼠腹腔巨噬细胞按1∶9的比例稀释接种于6孔板中，各组先加1mL含有细胞的培养液，贴壁生长2h。待细胞贴壁后将药物组的培养基吸出(空白组、模型组不做处理)，分别加入配好的药液(右崁醇，葑醇，对照化合物1，对照化合物2，目标化合物1也即3-硝基-2,6-二羟基苯甲酸右崁醇酯，目标化合物2也即3-硝基-2,6-二羟基苯甲酸葑醇酯)(4μg/mL)1mL，继续培养30min。30min后空白组加1mL完全培养基；模型组与药物组各加入2.4μg/mL脂多糖(LPS)溶液1mL，使LPS终浓度为1.2μg/mL。细胞用药(2μg/mL)24h后，从培养箱中取出6孔板，收集细胞培养上清液，4℃，3000rpm，离心10min，按照试剂盒说明书测定IL-1β、TNF-α含量。
结果显示：2μg/mL浓度下，右崁醇，葑醇，对照化合物1，对照化合物2对脂多糖诱导的RAW264.7巨噬细胞炎症模型IL-1β、TNF-α增加无显著的抑制作用。目标化合物1、2对脂多糖诱导的RAW264.7巨噬细胞炎症模型IL-1β、TNF-α的增加有显著的抑制作用，显著强于对照化合物(图1)。
实施例3化合物在5％碳酸氢钠水溶液中的溶解性实验
3.1实验方案
量取25mL的5％碳酸氢钠水溶液，于25℃，加入研磨到细粉的化合物，振摇30分钟，观察样品是否完全溶解。
3.2实验结果
表1化合物在25mL 5％碳酸氢钠水溶液中的溶解性实验
3.3实验结论：目标化合物在5％碳酸氢钠水溶液中的溶解性显著大于对照化合物。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (4)
1.3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯在制备治疗治疗炎症相关疾病的药物中的应用，其特征在于，所述3-硝基-2,6-二羟基苯甲酸右崁醇结构式为
3-硝基-2,6-二羟基苯甲酸葑醇酯结构式为/>
2.权利要求1所述3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯的药学上可接受的盐在制备治疗炎症相关疾病药物中的应用。
3.治疗炎症相关疾病的药物，其特征在于，所述药物的有效成分包括权利要求1所述3-硝基-2,6-二羟基苯甲酸右崁醇或葑醇的酯及其药学上可接受的盐。
4.权利要求4所述的药物，其特征在于，所述药物为注射剂。
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