CN115960013A - 一类具有双子表面活性剂结构特征的季铵甲酸盐化合物、超分子自组装及应用 - Google Patents
一类具有双子表面活性剂结构特征的季铵甲酸盐化合物、超分子自组装及应用 Download PDFInfo
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- CN115960013A CN115960013A CN202010448698.9A CN202010448698A CN115960013A CN 115960013 A CN115960013 A CN 115960013A CN 202010448698 A CN202010448698 A CN 202010448698A CN 115960013 A CN115960013 A CN 115960013A
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- quaternary ammonium
- ammonium formate
- formate compound
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Abstract
一类具有双子表面活性剂结构特征的季铵甲酸盐化合物、超分子自组装及应用。该类化合物结构如式(Ⅰ)所示，可在水中自组装形成均一稳定的球形胶束和/或Janus粒子，在生物体内可发挥长时间局部麻醉作用。该类甲酸盐的药效和神经病理毒性的个体差异及严重神经毒性发生率均显著小于此前报道的同类化合物。该类化合物内的基团为仲胺或叔胺取代时，与阿司匹林或布洛芬形等解热镇痛药形成的盐类化合物，结构如式(Ⅱ)所示，该盐类化合物可用于长效局部麻醉时，可提高效价，并进一步降低局部炎症发生程度。
Description
技术领域
本发明涉及一类具有双子表面活性剂结构特征的季铵甲酸盐化合物、超分子自组装形态及其在长效局部麻醉领域的应用。该甲酸盐的局部麻醉持续时间和神经病理毒性的个体差异,以及严重神经毒性发生率均显著小于此前报道的同类化合物。
背景技术
局部麻醉药(local anaesthetics，局麻药)是一类能在给药局部可逆地阻断神经冲动的发生与传递，从而引起局部组织痛觉消失的药物。局部麻醉药主要通过脂溶性扩散达到神经细胞膜内的阻滞位点，当局部浓度达到有效阻滞浓度后即可实现感觉阻滞；当药物继续扩散低于有效阻滞浓度后，局麻作用消失。目前，临床上所有的局部麻醉药物只能实现不超过4～6小时的强效局麻与镇痛，不能满足如术后创口疼痛、牙痛、烧伤疼痛和晚期癌痛等对12～72小时长效局麻的需求。
具有双子表面活性剂结构特征的长效局麻分子，不仅能够协助难于扩散的季铵阳离子从局部注射位点扩散进入神经细胞膜内，还能通过其超分子结构产生缓释作用。然而，这些分子会因为其双子表面活性剂特性自组装形成粒径大小差异较大的超分子结构而具有两亲性，既容易快速高效的扩散进入神经细胞膜的作用靶点，也容易在扩散起效和失效过程中，损伤亲脂性的神经细胞及局部肌肉组织。因此，此前报道的该类分子，在产生长效局麻的同时，也会导致中度甚至重度局部神经损伤；药效和毒性的在不同个体上的差异也较大。例如，此前报道的某化合物，局麻持续时间平均为48h，但最短为32h，最长56h，个体差异达到24h，不利于临床使用；神经损伤平均评分为0.8，低于轻度损伤1.0分的标准，但由于毒性的个体差异较大，损伤最低评分为0，最高为2，部分个体达到中度损伤的标准，难以用于临床。
发明内容
本发明提供了一类具有个体差异小特点的，具有双子表面活性剂结构特征的季铵甲酸盐类长效麻醉化合物、超分子自组装方式及其在局部麻醉领域的应用。
本发明所述的具有长效局部麻醉作用的季铵甲酸盐类化合物，结构如下：
(Ⅰ)式中的A为-O-CO-,-O-CO-O-,-NH-,-NCH3-,-NH2OOCH-或 -NHCH3OOCH-；s＝0或1；n＝1～6的整数。
本发明所述化合物的季铵阴离子部分为甲酸根离子。与已报道的氯离子、溴离子、甲磺酸根离子等的类似化合物不同，该类甲酸盐化合物具有能够在神经细胞膜内进行阴离子交换的特性，使得该类化合物能够实现个体差异小的长效局麻。具体原理解释如下：
首先，相对强酸共轭的阴离子季铵盐，作为有机弱酸的甲酸与季铵盐化合物成盐，能够自组装形成均一稳定的超分子结构，在脂溶性组织中的传递能力更强，更容易进入神经细胞。而进入神经细胞后，又可利用神经细胞膜内pH偏低和氯离子为主要阴离子的内环境，实现阴离子交换，生成扩散出细胞膜更困难的季铵盐酸盐。因此，该类甲酸季铵盐化合物，有着比此前报道化合物更优的扩散达到作用靶点的能力，而扩散失效的能力则和此前近似。因此，等浓度下，本发明报道的甲酸季铵盐化合物能产生持续时间更长的局部麻醉，如图1所示。
通过该机理，该类季铵甲酸盐具备了以下可减少个体差异，降低中度或重度神经毒性的特性：(1)与阳离子部分结构相同的其它季铵盐相比，季铵甲酸盐的效价提高。因此，达到相同局麻持续时间，季铵甲酸盐的使用浓度降低，发生中度或重度神经毒性的概率随之降低。(2)局部神经肌肉组织的生理结构个体差异大，而甲酸根离子和氯离子交换所处的神经细胞内环境个体差异小。因此，引入该阴离子交换机制，可以引入一个新的个体差异小的长效产生方式，导致该类化合物总体的长效局麻个体差异变小。实际结果如实施例所示，中度或中度神经毒性几乎消失；局麻持续时间和神经病理毒性的个体差异也显著变小。
其次，尽管其它的有机弱酸共轭的阴离子，如乙酸根、丙酸根、苯甲酸根等，也可能根据上述机理产生与甲酸根类似的效果，但是由于这些有机阴离子的离子半径太大，导致双子表面活性剂的两个亲水头基所处环境过于拥挤，很难在水中自组装形成均一稳定的胶束体系(如图2)。而这些自组装形成的不均匀超分子结构，在扩散进入神经细胞内作用靶点的过程中，较大的个体差异很难避免；而进入神经细胞内，与氯离子进行阴离子交换的过程，个体差异同样很难避免。因而这些差异将导致局麻持续时间和神经毒性的个体差异增大，如实施例中表一和表二所示。甲酸根作为离子半径最小的有机酸根，则恰好能维持整个胶束体系的均一稳定,如图3所示。而离子半径更小的无机弱酸根氟离子，则存在酸性太弱而使得化合物溶解度下降，作用于局部，个体差异反而更大，实验结果如表一所示。同时该类氟化物的神经病理毒性显著增强，达到了中度到重度的评分结果，因而无法进一步使用。
此外，将本发明所述甲酸根离子，用于其它具有QX-314及类似结构的季铵阳离子片段和局部麻醉效应的，具有双子表面活性剂结构特征的化合物。如季铵-羰酰胺“并联型”双子表面活性剂化合物A及A1，将X替换为甲酸根，也能够起到类似的提高效价、降低中度和重度局部神经毒性发生率以及降低局麻持续时间和毒性的个体差异的作用。“串联型”的季铵-叔胺双子表面活性剂化合物B，则既可将X替换为甲酸根，又可进一步与1分子甲酸形成叔胺甲酸盐。这些与本发明相同的手段，均能起到提高效价、降低中度和重度局部神经毒性发生率以及降低局麻持续时间和毒性的个体差异的作用。区别在于此种类型的化合物，水中溶解度不足，自组装形成的超分子结构不够稳定，因而药效和神经病理毒性的均一性不如本发明所述化合物。
本发明所述的具有长效局部麻醉作用和解热镇痛作用的具有双子表面活性剂结构特征的季铵甲酸盐类化合物，结构如式(Ⅱ)所示：
式中的A为-NH-或-NCH3-；s＝1；n＝3～6的整数；
等含有单个羧基的常见解热镇痛药。
该类化合物在含有仲胺或叔胺结构的季铵甲酸盐基础上，与仲胺或叔胺以接近1:1的比例与含有羧基的解热镇痛药成盐，形成新的第二亲水头基，从而生成一种新的具有双子表面活性剂结构特征的化合物，结构如式(Ⅱ)。如图3所示，该类双子表面活性剂结构的化合物，仍然能够在水中自组装形成均一稳定的超分子结构。该类化合物在长效局麻应用中，不仅保持了季铵甲酸盐药效和神经毒性个体差异小的优势，还提高了效价，并降低了肌肉炎症，如表三所示。
综上，实验结果表明，本发明上述式(Ⅰ)和(Ⅱ)结构化合物在水中自组装形成均一稳定的超分子结构后，在生物体内可发挥长时间局部麻醉作用。其中药效和神经毒性的个体较已报道的长效局麻分子明显降低，不可接受的中度至重度神经损伤的发生率也显著降低。对于式(Ⅱ)结构化合物，局麻效价有所提高，局部肌肉炎症水平也有所降低。总之，该类化合物在长效局部麻醉领域具有良好的临床应用前景。此外，该类同时具有局部麻醉和缓释能力的化合物，可与其它药物如抗病毒、抗生素、抗癌、激素等药物，共同实现超分子组装，用于包含局部麻醉、镇痛以及上述药物药理作用在内的“双作用靶点”药物的研发。
附图说明
图1是具有超分子自组装能力的化合物产生长效局麻的作用机制图。
图2是非甲酸根的具有双子表面活性剂结构特征的季铵阳离子有机酸盐的结构及其在水中超分子自组装的TEM电镜图。
图3是实施例6对应的供试液的TEM电镜图。
具体实施方式
实施例1
于100mL圆底瓶中加入羟基取代的季铵盐5mmol，三聚光气2mmol，1,2- 二氯乙烷20mL，室温搅拌均匀。室温下滴加吡啶5.5mmol的1,2-二氯乙烷 10mL。滴毕，50℃搅拌1h。滴加吡啶5.5mmol和长链脂肪醇5mmol混合的1,2- 二氯乙烷10mL，50℃搅拌过夜。
反应液冷却至室温，加入二氯甲烷200mL。饱和甲酸钠水溶液20mL x 10 萃洗，分离有机相，浓缩至干。以二氯甲烷-甲醇混合溶剂为洗脱液，硅胶柱层析，得到终产物，具体结构如下：
对应化合物的分析数据如下：
化合物1a:1H NMR(400MHz，CDCl3)δ:7.01～7.08(m,3H),5.01(m,2H), 4.63(br,2H),4.15(t,J＝6.8Hz,2H),4.06(m,2H),3.68～3.76(m, 4H),2.22(s,6H),1.60～1.63(m,2H),1.53～1.57(m,8H),0.86(t,J ＝7.2Hz,3H).Elemental Analysis(％):C,63.65；H,8.98；N,6.18；O, 21.18.
化合物1b:1H NMR(400MHz，CDCl3)δ:7.01～7.08(m,3H),4.99(m,2H), 4.62(br,2H),4.15(t,J＝6.8Hz,2H),4.07(m,2H),3.67～3.75(m, 4H),2.23(s,6H),1.59～1.63(m,2H),1.51～1.57(m,10H),0.87(t,J ＝7.2Hz,3H).Elemental Analysis(％):C,64.31；H,9.12；N,5.98；O, 20.59.
实施例2
于100mL圆底瓶中加入羟基取代的季铵盐5mmol，吡啶5.5mmol,1,2- 二氯乙烷30mL，室温搅拌均匀。室温下滴加的脂肪酰氯5mmol的1,2-二氯乙烷10mL。滴毕，50℃搅拌过夜。
反应液冷却至室温，加入二氯甲烷200mL。饱和甲酸钠水溶液20mL x 10 萃洗，分离有机相，浓缩至干。以二氯甲烷-甲醇混合溶剂为洗脱液，硅胶柱层析，得到终产物，具体结构如下：
对应化合物的分析数据如下：
化合物2a:1H NMR(400MHz，CDCl3)δ:7.04～7.10(m,3H),5.08(s,2H), 4.64(m,2H),3.99(m,2H),3.97(m,2H),3.72(m,4H),2.35(t,J＝7.6Hz,2H),2.27(s,6H),1.58～1.63(m,2H),1.52(t,J＝7.2Hz,6H), 1.28～1.42(m,2H),0.91(t,J＝7.2Hz,3H).Elemental Analysis(％): C,64.64；H,8.92；N,6.82；O,19.61.
化合物2b:1H NMR(400MHz，CDCl3)δ:7.04～7.09(m,3H),5.08(s,2H), 4.62(m,2H),3.99(m,2H),3.96(m,2H),3.72(m,4H),2.34(t,J＝ 7.6Hz,2H),2.27(s,6H),1.57～1.64(m,2H),1.53(t,J＝7.2Hz,6H), 1.28～1.41(m,4H),0.92(t,J＝7.2Hz,3H).Elemental Analysis(％): C,65.36；H,9.06；N,6.64；O,18.93.
化合物2c:1H NMR(400MHz，CDCl3)δ:7.03～7.09(m,3H),5.09(s,2H), 4.63(m,2H),4.01(m,2H),3.98(m,2H),3.73(m,4H),2.33(t,J＝ 7.6Hz,2H),2.27(s,6H),1.56～1.63(m,2H),1.53(t,J＝7.2Hz,6H), 1.27～1.43(m,4H),0.91(t,J＝7.2Hz,3H).Elemental Analysis(％): C,66.01；H,9.25；N,6.40；O,18.33.
化合物2d:1H NMR(400MHz，CDCl3)δ:7.03～7.09(m,3H),5.08(s,2H), 4.62(m,2H),4.02(m,2H),4.00(m,2H),3.75(m,4H),2.33(t,J＝ 7.6Hz,2H),2.28(s,6H),1.56～1.63(m,2H),1.53(t,J＝7.2Hz,6H), 1.26～1.43(m,6H),0.92(t,J＝7.2Hz,3H).Elemental Analysis(％): C,66.61；H,9.40；N,6.21；O,17.77
实施例3
于100mL圆底瓶中加入氯代季铵盐5mmol，吡啶5.5mmol,1,2-二氯乙烷 30mL，室温搅拌均匀。室温下滴加的脂肪胺5mmol的1,2-二氯乙烷10mL。滴毕，50℃搅拌过夜。
反应液冷却至室温，加入二氯甲烷200mL。饱和甲酸钠水溶液20mL x 10 萃洗，分离有机相，浓缩至干。以二氯甲烷-甲醇混合溶剂为洗脱液，硅胶柱层析，得到终产物。
部分含有仲胺或叔胺基团的化合物，溶解于大过量的二氯甲烷中，10N 氢氧化钠水溶液10mL x 6萃洗，有机相浓缩至干，得到季铵碱。
再进一步与等当量的甲酸，于二氯甲烷中混合，浓缩浓缩至干。以二氯甲烷-甲醇混合溶剂为洗脱液，硅胶柱层析，得到终产物。
对应化合物结构如下：
对应化合物的分析数据如下：
化合物3a:1H NMR(300MHz，CDCl3)δ:7.02～7.10(m,3H),4.81(br,2H), 4.48(t,J＝4.8Hz,2H),4.04(t,J＝4.8Hz,2H),3.69～3.77(m,4H), 2.22(s,6H),1.35～1.43(m,14H),0.90(t,J＝7.2Hz,3H).Elemental Analysis(％):C,68.35；H,10.29；N,9.96；O,11.39.
化合物3b:1H NMR(300MHz，CDCl3)δ:7.01～7.08(m,3H),4.82(br,2H), 4.48(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.70～3.76(m,4H), 2.21(s,6H),1.32～1.42(m,14H),0.90(t,J＝7.2Hz,3H).Elemental Analysis(％):C,64.20；H,9.71；N,8.98；O,17.12
化合物3c:1H NMR(300MHz,CDCl3)δ:7.00～7.08(m,3H),4.81(br,2H), 4.46(t,J＝4.8Hz,2H),4.06(t,J＝4.8Hz,2H),3.69～3.77(m,4H), 2.22(s,6H),1.31～1.40(m,16H),0.90(t,J＝7.2Hz,3H).Elemental Analysis(％):C,68.92；H,10.42；N,9.65；O,11.01.
化合物3d:1H NMR(300MHz，CDCl3)δ:7.01～7.08(m,3H),4.80(br,2H), 4.52(t,J＝4.8Hz,2H),4.06(t,J＝4.8Hz,2H),3.71～3.78(m,4H), 2.27(s,3H),2.17(s,6H),1.31～1.42(m,16H),0.90(t,J＝7.2Hz, 3H).Elemental Analysis(％):C,69.44；H,10.55；N,9.33；O,10.67.
化合物3e:1H NMR(400MHz,CDCl3)δ:7.01～7.08(m,3H),4.82(br,2H), 4.49(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.70～3.79(m,4H), 2.23(s,6H),1.31～1.42(m,18H),0.89(t,J＝7.2Hz,3H).Elemental Analysis(％):C,69.44；H,10.54；N,9.33；O,10.68.
化合物3f:1H NMR(400MHz，CDCl3)δ:7.01～7.08(m,3H),4.81(br,2H), 4.50(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.70～3.78(m,4H), 2.21(s,6H),1.31～1.43(m,18H),0.90(t,J＝7.2Hz,3H).Elemental Analysis(％):C,65.40；H,9.97；N,8.47；O,16.16.
化合物3g:1H NMR(300MHz,CDCl3)δ:7.00～7.07(m,3H),4.82(br,2H), 4.50(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.69～3.78(m,4H), 2.17～2.22(m,2H),2.03(s,6H),1.30～1.40(m,16H),0.89(t,J＝7.2 Hz,3H).Elemental Analysis(％):C,68.92；H,10.41；N,9.64；O,11.03.
化合物3h:1H NMR(300MHz,CDCl3)δ:7.00～7.10(m,3H),4.83(br,2H), 4.50(t,J＝4.8Hz,2H),4.06(t,J＝4.8Hz,2H),3.70～3.77(m,4H), 2.18～2.22(m,2H),2.04(s,6H),1.30～1.41(m,16H),0.90(t,J＝7.2 Hz,3H).Elemental Analysis(％):C,64.82；H,9.84；N,8.71；O,16.62.
化合物3i:1H NMR(400MHz,CDCl3)δ:7.00～7.07(m,3H),4.81(br,2H), 4.51(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.70～3.77(m,4H), 2.17～2.21(m,2H),2.04(s,6H),1.30～1.42(m,18H),0.90(t,J＝7.2 Hz,3H).Elemental Analysis(％):C,69.46；H,10.54；N,9.33；O,10.67.
化合物3j:1H NMR(400MHz,CDCl3)δ:7.01～7.07(m,3H),4.81(br,2H), 4.52(t,J＝4.8Hz,2H),4.06(t,J＝4.8Hz,2H),3.71～3.79(m,4H), 2.16～2.20(m,2H),2.03(s,6H),1.29～1.43(m,18H),0.90(t,J＝7.2 Hz,3H).Elemental Analysis(％):C,65.41；H,9.97；N,8.47；O,16.14.
化合物3k:1H NMR(400MHz,CDCl3)δ:7.01～7.08(m,3H),4.80(br,2H), 4.50(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.71～3.77(m,4H), 2.17～2.21(m,2H),2.13(s,3H),2.05(s,6H),1.31～1.42(m,16H),0.90 (t,J＝7.2Hz,3H).Elemental Analysis(％):C,69.93；H,10.65；N,9.05；O,10.36.
化合物3l:1H NMR(400MHz,CDCl3)δ:7.01～7.09(m,3H),4.79(br,2H), 4.50(t,J＝4.8Hz,2H),4.06(t,J＝4.8Hz,2H),3.70～3.78(m,4H), 2.16～2.22(m,2H),2.12(s,3H),2.05(s,6H),1.29～1.40(m,16H),0.90 (t,J＝7.2Hz,3H).Elemental Analysis(％):C,65.98；H,10.08；N,8.23； O,15.69.
化合物3m:1H NMR(300MHz，CDCl3)δ：7.00～7.08(m,3H),4.80(br,2H), 4.51(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.70～3.78(m,4H), 2.16～2.21(m,2H),2.04(s,6H),1.30～1.43(m,20H),0.90(t,J＝7.2 Hz,3H).Elemental Analysis(％):C,69.92；H,10.65；N,9.06；O,10.36.
化合物3n:1H NMR(300MHz，CDCl3)δ：7.01～7.08(m,3H),4.79(br,2H), 4.50(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.69～3.78(m,4H), 2.16～2.22(m,2H),2.04(s,6H),1.30～1.42(m,20H),0.90(t,J＝7.2 Hz,3H).Elemental Analysis(％):C,65.97；H,10.08；N,8.23；O,15.69.
化合物3o:1H NMR(300MHz,CDCl3)δ:7.01～7.07(m,3H),4.81(br,2H), 4.49(t,J＝4.8Hz,2H),4.02(t,J＝4.8Hz,2H),3.71～3.79(m,4H), 2.17～2.20(m,2H),2.12(s,3H),2.04(s,6H),1.30～1.42(m,18H),0.90 (t,J＝7.2Hz,3H).Elemental Analysis(％):C,70.40；H,10.77；N,8.78； O,10.05.
化合物3p:1H NMR(300MHz,CDCl3)δ:7.00～7.08(m,3H),4.80(br,2H), 4.50(t,J＝4.8Hz,2H),4.03(t,J＝4.8Hz,2H),3.71～3.78(m,4H), 2.18～2.22(m,2H),2.12(s,3H),2.03(s,6H),1.29～1.43(m,18H),0.90 (t,J＝7.2Hz,3H).Elemental Analysis(％):C,66.50；H,10.20；N,8.01； O,15.27.
实施例4
取实施例3制备得到的季铵碱，溶解于过量二氯甲烷-甲醇的混合溶剂中。加入等当量的阿司匹林或布洛芬，搅拌使其完全溶解。减压浓缩至干。以二氯甲烷-甲醇混合溶剂为洗脱液硅胶柱层析，得到终产物。对应化合物结构如下：
对应化合物的分析数据如下：
化合物4a:1H NMR(300MHz,CDCl3)δ:7.82～7.86(m,2H),7.67～7.70(m, 1H),7.42～7.47(m,1H),7.00～7.07(m,3H),4.82(br,2H),4.50(t, J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.69～3.78(m,4H),2.27(s, 3H),2.17～2.22(m,2H),2.03(s,6H),1.30～1.40(m,16H),0.90(t,J ＝7.2Hz,3H).Elemental Analysis(％):C,66.31；H,8.68；N,6.81；O,18.20.
化合物4b:1H NMR(300MHz,CDCl3)δ:7.24(d,J＝7.0Hz,2H),7.00～7.07 (m,5H),4.82(br,2H),4.50(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz, 2H),3.80(q,J＝7.0Hz,1H),3.69～3.78(m,4H),2.46(Ha,1H),2.40 (Hb,1H),2.17～2.22(m,2H),2.03(s,6H),1.30～1.40(m,16H),1.82 (m,1H),1.54(d,J＝7.0Hz,3H),0.88～0.91m,9H).Elemental Analysis(％):C,71.10；H,9.89；N,6.54；O,12.46.
化合物4c:1H NMR(400MHz,CDCl3)δ:7.82～7.85(m,2H),7.67～7.70(m, 1H),7.42～7.47(m,1H),7.00～7.07(m,3H),4.81(br,2H),4.51(t, J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.69～3.75(m,4H),.28(s, 3H),2.17～2.20(m,2H),2.03(s,6H),1.30～1.43(m,18H),0.90(t,J ＝7.2Hz,3H).Elemental Analysis(％):C,66.73；H,8.80；N,6.66；O,17.78.
化合物4d:1H NMR(400MHz,CDCl3)δ:7.23(d,J＝7.0Hz,2H),7.00～7.07 (m,5H),4.81(br,2H),4.51(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz, 2H),3.81(q,J＝7.0Hz,1H),3.72～3.78(m,4H),2.45(Ha,1H),2.40 (Hb,1H),2.17～2.22(m,2H),2.04(s,6H),1.81(m,1H),1.52(d,J ＝7.0Hz,3H),1.30～1.42(m,18H),0.89～0.91(m,9H).Elemental Analysis(％):C,71.08；H,9.89；N,6.54；O,12.47.
化合物4e:1H NMR(400MHz,CDCl3)δ:7.81～7.85(m,2H),7.68～7.71(m, 1H),7.43～7.48(m,1H),7.01～7.08(m,3H),4.80(br,2H),4.50(t, J＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.71～3.77(m,4H),2.27(s, 3H),2.17～2.21(m,2H),2.13(s,3H),2.05(s,6H),1.31～1.42(m,16H), 0.90(t,J＝7.2Hz,3H).Elemental Analysis(％):C,67.15；H,8.92； N,6.52；O,17.39.
化合物4f:1H NMR(400MHz,CDCl3)δ:7.24(d,J＝7.0Hz,2H),7.01～7.08 (m,5H),4.79(br,2H),4.50(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz, 2H),3.80(q,J＝7.0Hz,1H),3.70～3.78(m,4H),2.45(Ha,1H),2.40 (Hb,1H),2.16～2.22(m,2H),2.12(s,3H),2.05(s,6H),1.80～1.82(m, 1H),1.54(d,J＝7.0Hz,3H),1.29～1.40(m,16H),0.88～0.91(m,9H).Elemental Analysis(％):C,71.70；H,10.08；N,6.26；O,11.94.
化合物4g:1H NMR(300MHz，CDCl3)δ：7.82～7.85(m,2H),7.68～7.72(m, 1H),7.42～7.47(m,1H),7.00～7.07(m,3H),4.81(br,2H),4.51(t,J ＝4.8Hz,2H),4.05(t,J＝4.8Hz,2H),3.70～3.78(m,4H),2.28(s, 3H),2.16～2.21(m,2H),2.04(s,6H),1.30～1.42(m,20H),0.90(t,J ＝7.2Hz,3H).Elemental Analysis(％):C,67.16；H,8.92；N,6.53；O,17.39.
化合物4h:1H NMR(300MHz，CDCl3)δ：7.23(d,J＝7.0Hz,2H),7.01～7.08 (m,5H),4.79(br,2H),4.50(t,J＝4.8Hz,2H),4.05(t,J＝4.8Hz, 2H),3.80(q,J＝7.0Hz,1H),3.72～3.77(m,4H),2.45(Ha,1H),2.40 (Hb,1H),2.16～2.22(m,2H),2.04(s,6H),1.82(m,1H),1.54(d,J ＝7.0Hz,3H),1.31～1.42(m,20H),0.88～0.91(m,9H).Elemental Analysis(％):C,71.69；H,10.08；N,6.26；O,11.95.
实施例5
于10mL西林瓶中，精密称取上述实施例得到产物，加入蒸馏水3mL，30℃下以1200rpm转速磁力搅拌3小时，室温静置至气泡消失。溶液以220μm 水相微孔滤膜无菌过滤至另一经灭菌处理的西林瓶中，加塞密封，静置备用。
实施例6
经实施例5制备得到的供试品，经磷钨酸染色，TEM检测，如图3。
实施例7
动物实验的一般方法：
选取200～300g体重的大鼠，雌雄各半。待其完全适应环境后，随机分组，每组6只。每只大鼠给药或对照的注射体积为0.2ml，通过神经定位器导向定位，注射于大鼠坐骨神经附近。
其中对照组之一为2％盐酸左布比卡因的水溶液(84mmol/L)；另一部分对照组采用化合物，制备方法参见实施例1～4。测试品制备方式见实施例5。
坐骨神经阻滞：
将待测大鼠至于操作台上，使其吸入5％异氟烷，翻正反射消失后继续经自制面罩吸入1.5％异氟烷以维持麻醉。左侧卧位，骶尾部相应注射区域剃毛，常规消毒铺巾。扪出股骨大转子及坐骨结节两个骨性解剖标志，两者连线中点为进针部位。绷紧皮肤，以1ml注射器垂直皮肤进针，针尖抵至坐骨后，停止进针。抽吸无回血后，缓慢注射药液0.2ml。退针，关闭异氟烷。将动物放至观察笼中待其自然苏醒。
神经阻滞效果观察：
根据n＝4的预实验结果，在每个药物失效的时间点前后4h，以每2h 直至大鼠完全恢复，专由两人对大鼠进行如下行为学观察，该两人对大鼠所接受的处理均不知情。
机械痛阈(VFH)：
大鼠置于底部为光滑金属筛板的透明观察笼内，用校对标准的von freyfilament由下至上刺激大鼠足部外侧皮肤(坐骨神经支配区域)。von frey filaments的应用自0.4g开始，逐级增加至60g。每次刺激时，filament 有轻微弯曲为准，要么大鼠移开该侧肢体，否则刺激时间达3s后人为停止刺激。每个测试时点测试6次，每次测试间隔时间为5min以避免敏化。
机械痛阈超过60g即认为神经阻滞有效。自注射完毕至第一次机械痛阈超过60g的测量时点之间的时间间隔为机械痛觉阻滞起效时间；自注射完毕至第一次机械痛阈降至60g以下的时间为机械痛觉阻滞失效时间；两者的差值为机械痛觉阻滞维持时间。
神经病理损伤评估：
坐骨神经注射后第10天，将实验大鼠异氟醚麻醉下心脏注射布比卡因安乐死。取注射部位坐骨神经约1.5cm，保存于10％甲醛溶液中48h，HE 染色并切成5μm厚度的切片。
光镜下观察并评分如下：
0分：无炎症；
1分：局部轻微炎症；
2分：中度水肿及炎症；
3分：弥漫性水肿及重度炎症反应。
经纤维变性程度评分如下：
0分：无神经纤维变性；
1分：轻度神经纤变性；
2分：中度神经纤变性；
3分：重度神经纤变性。
实施例8
按照实施例7的操作方式，对化合物1a～1b，2a～2d进行局部麻醉测试，实验结果如表一所示。
表一大鼠局麻效果实验1
*盐酸利多卡因溶液的浓度为2％；其余化合物均为12mmol/L.
*除利多卡因外，其它待测化合物的测定时间点，均为预实验测定值前后 2h,4h。因此最大误差为2h。
*对照化合物结构如下：
实施例9
按照实施例7的操作方式，对化合物3a～3p进行局部麻醉测试，实验结果如表一所示。
表二大鼠局麻效果实验2
*盐酸利多卡因溶液的浓度为2％；其余化合物均为10mmol/L.
*除利多卡因外，其它待测化合物的测定时间点，均为预实验测定值前后 2h,4h。因此最大误差为2h。
*本次实验中，每个时间点采用60g刺激，全部6次刺激无异常，判定为完全阻滞。
*对照化合物结构如下：
实施例10
表三大鼠局麻效果实验3
*阿司匹林-利多卡因和布洛芬-利多卡因溶液的浓度为2％；其余化合物均为8mmol/L.
*除对照外，其它待测化合物的测定时间点，均为预实验测定值前后2h,
4h。因此最大误差为2h。
*本次实验中，每个时间点采用60g刺激，全部6次刺激大鼠无异常，判定为完全阻滞。
Claims (10)
1.具有双子表面活性剂结构特征的季铵甲酸盐化合物，其特征在于，结构如式(Ⅰ)所示：
式中的A为-O-CO-,-O-CO-O-,-NH-,-NCH3-,-NH2OOCH-或-NHCH3OOCH-.；s＝0或1；n＝1～6的整数。
2.如权利要求1所述的具有双子表面活性剂结构特征的季铵甲酸盐化合物，其特征在于，所述式(Ⅰ)结构中的A为-O-CO-，s＝1，n＝1～6的整数。
3.如权利要求1所述的具有双子表面活性剂结构特征的季铵甲酸盐化合物，其特征在于，所述式(Ⅰ)结构中的A为-O-CO-O-，s＝1，n＝1～3的整数。
4.如权利要求1所述的具有双子表面活性剂结构特征的季铵甲酸盐化合物，其特征在于，所述式(Ⅰ)结构中的A为-NH-,-NCH3-,-NH2OOCH-或-NHCH3OOCH-.；s＝0或1；n＝2～6的整数。
5.二甲基苯铵长链甲酸盐类化合物与具有羧酸基团的解热镇痛药以1:1形式形成的季铵甲酸盐类化合物，其特征在于，结构如式(Ⅱ)所示：
式中的A为-NH-或-NCH3-；s＝1；n＝3～6的整数；
6.如权利要求5所述的季铵甲酸盐类化合物，其特征在于，所述式(Ⅱ)结构中的A为-NH-或-NCH3-；s＝1；n＝3～6的整数；
7.权利要求1至4之一所述的季铵甲酸盐化合物用于制备包括局部麻醉、镇痛、止痒在内的药物中的应用。
8.权利要求1至4之一所述的季铵甲酸盐化合物自组装形成的超分子自组装形态。
9.权利要求1至4之一所述的季铵甲酸盐化合物自组装形成的超分子自组装形态，用于制备生物材料和/或药物包裹辅料的载体或传递系统中的应用。
10.权利要求5至6之一所述的季铵甲酸盐类化合物于制备包括局部麻醉、抗炎镇痛、止痒在内的药物中的应用。
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB939607A (en) * | 1961-04-13 | 1963-10-16 | Ici Ltd | Treatment of cellulosic materials |
| BE664600A (zh) * | 1964-05-30 | 1965-09-16 | ||
| FR1430615A (fr) * | 1964-04-03 | 1966-03-04 | Hoechst Ag | Prévention des corrosions des installations pétrolières dues à des microbes |
| US5378578A (en) * | 1992-11-12 | 1995-01-03 | Fuji Photo Film Co., Ltd. | Silver halide photographic photosensitive materials |
| CN105315170A (zh) * | 2014-08-01 | 2016-02-10 | 四川大学华西医院 | 二甲基苯铵类长链化合物、制备、自组装结构及用途 |
| CN109574866A (zh) * | 2019-01-15 | 2019-04-05 | 中国科学院成都有机化学有限公司 | 一种2,6-二甲基苯胺类长链化合物的制备方法 |
| CN110092731A (zh) * | 2018-01-31 | 2019-08-06 | 四川大学华西医院 | 长链胺取代的二甲基苯铵类化合物、制备、自组装结构及用途 |
| CN110156666A (zh) * | 2018-02-11 | 2019-08-23 | 四川大学华西医院 | 一种阳离子类化合物及其制备方法与用途 |
-
2020
- 2020-05-25 CN CN202010448698.9A patent/CN115960013B/zh active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB939607A (en) * | 1961-04-13 | 1963-10-16 | Ici Ltd | Treatment of cellulosic materials |
| FR1430615A (fr) * | 1964-04-03 | 1966-03-04 | Hoechst Ag | Prévention des corrosions des installations pétrolières dues à des microbes |
| BE664600A (zh) * | 1964-05-30 | 1965-09-16 | ||
| US5378578A (en) * | 1992-11-12 | 1995-01-03 | Fuji Photo Film Co., Ltd. | Silver halide photographic photosensitive materials |
| CN105315170A (zh) * | 2014-08-01 | 2016-02-10 | 四川大学华西医院 | 二甲基苯铵类长链化合物、制备、自组装结构及用途 |
| CN110092731A (zh) * | 2018-01-31 | 2019-08-06 | 四川大学华西医院 | 长链胺取代的二甲基苯铵类化合物、制备、自组装结构及用途 |
| CN110156666A (zh) * | 2018-02-11 | 2019-08-23 | 四川大学华西医院 | 一种阳离子类化合物及其制备方法与用途 |
| CN109574866A (zh) * | 2019-01-15 | 2019-04-05 | 中国科学院成都有机化学有限公司 | 一种2,6-二甲基苯胺类长链化合物的制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| TANG, LEI: "Janus particles self-assembled from a small organic atypical asymmetric gemini surfactant", 《 CHEMICAL COMMUNICATIONS (CAMBRIDGE, UNITED KINGDOM)》, 31 December 2017 (2017-12-31), pages 8675 - 8678, XP055445421, DOI: 10.1039/C7CC03973E * |
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