CN116444392A - 一类多肽蛋白类药物口服吸收促进剂及其制备方法与用途 - Google Patents

一类多肽蛋白类药物口服吸收促进剂及其制备方法与用途 Download PDF

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CN116444392A
CN116444392A CN202210011674.6A CN202210011674A CN116444392A CN 116444392 A CN116444392 A CN 116444392A CN 202210011674 A CN202210011674 A CN 202210011674A CN 116444392 A CN116444392 A CN 116444392A
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octanoate
hydroxybenzoamido
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钱海
石炜
刘春霞
尹子煜
邹昱星
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China Pharmaceutical University
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Abstract

本发明属于医药技术领域，公开了一类结构如通式I所示的化合物。本发明通式I所示的化合物符合离子液体的定义。本发明通式I所示的化合物具有口服吸收促进剂的特点，可以减少胃肠道环境和蛋白酶对蛋白和/或多肽类药物的降解，或增加蛋白和/或多肽类药物肠粘膜的通透效果、在胃肠道部位的吸收，或提高多肽蛋白类药物口服给药后的治疗效果。本发明还公开了通式I所示的化合物在作为增加蛋白和/或多肽类药物口服递送的口服吸收促进剂中的应用。

Description

一类多肽蛋白类药物口服吸收促进剂及其制备方法与用途
技术领域
本发明属于医药技术领域，涉及一类新型离子液体及其制备方法与在多肽蛋白类药物口服递送方面的应用。
背景技术
得益于生物技术的发展，生物活性肽进入医药产业的可行性已显著提高。肽类药物口服给药时的相对无效性成为限制性其开发的因素，因此，胰岛素、人生长激素、降钙素和GLP-1受体激动剂类等多肽、蛋白类药物通常通过注射途径给药。
胰岛素用于糖尿病治疗，其最主要的给药途径是注射给药。但是，每天注射给药会给患者造成不便，且注射给药易发生副作用，例如注射位点的脂肪营养不良、皮下脂肪萎缩、皮下结节和偶发性低血糖。此外，皮下注射胰岛素通常无法获得由门静脉分泌到肝脏中的精细、持续的代谢调控。若直接口服胰岛素等多肽蛋白类药物，则药物易受胃内酸性环境及胃肠道内蛋白水解酶降解，同时药物分子量大，难以透过消化道上皮细胞屏障，生物利用度较低。因此，多肽蛋白类药物的口服给药面临着巨大挑战。
研究表明采用合适的载药系统再佐以蛋白酶抑制剂或吸收促进剂可以有效提高多肽蛋白类药物在胃肠道的吸收率。有研究将胰岛素溶于疏水溶剂或油相中制成口服制剂，如专利WO9513795A1把胰岛素溶液溶于油相制剂中，采用减压浓缩，喷雾干燥，或在小于0.1MPa的真空条件下冷冻48h除去亲水性溶剂；此外，多肽蛋白类药物的吸收促进剂如N-(8-[2-羟基苯甲酰基]-氨基)辛酸钠(SNAC，WO2008028859 A1)已被多家公司用于索马鲁肽和胰岛素等口服大分子给药系统的构建。在口服索马鲁肽的临床研究中发现，SNAC由其弱酸强碱盐结构在胃部起缓冲作用，弱酸部分对多肽的跨细胞吸收具有关键作用。但是，研究表明已上市的口服索马鲁肽片剂口服生物利用度较低，而多肽原料占主要成本，短时间内高成本无法显著下降，造成相关疾病社会经济的较大负担。
综上，设计出能促进多肽蛋白类药物口服吸收的口服制剂，且具有简便的制备方法始终是药物制剂工业面临的一个难题。
离子液体是一种新兴的溶剂和反应介质，具有独特的物理化学性质。离子液体是由阴、阳离子组成的盐；低共熔溶剂是由不同比例的酸、碱或盐混合而成的两组分或三组分混合物，具有与离子液体相似的物理化学性质，因此在广义上，也把低共熔溶剂归为离子液体。
由离子液体CAGE参与制备的一种高效口服胰岛素肠溶胶囊，具有良好的生物相容性和长期储存稳定性。离子液体CAGE是一种具有临床前景的口服给药载体，可提高胰岛素在含有胰蛋白酶的小肠环境中的稳定性；CAGE还能突破肠壁黏液层和肠壁上皮细胞之间的紧密连接，增加胰岛素在肠部的吸收。但是，一方面CAGE仅可增加药物在肠部的细胞旁转运，既不能解决多肽胃部降解及吸收问题，又没有增加多肽药物的跨细胞吸收。另一方面，目前仍缺乏对CAGE胰岛素制剂口服生物利用度的考察。
发明内容
本发明的目的在于结合SNAC和离子液体两种技术，分别对CAGE和SNAC的阴阳离子进行替换，首次将苯甲酰胺基辛酸类化合物制备成不同的离子液体，意外发现其具有更优秀的口服吸收促进作用，兼顾了多肽药物的细胞旁吸收和跨细胞吸收，减少了胃肠道环境和蛋白酶对蛋白、多肽类药物的降解，所述的离子液体可同时促进多肽药物的胃、肠部吸收，增加药物的生物利用度，为构建新型多肽药物口服递送技术平台提供了理论和实验基础。
本发明的目的是通过以下技术方案实现的：
一类结构如通式I所示的化合物：
其中，X+选自如式所示的含1～2个N的五元或六元杂环的有机碱阳离子；
B选自N、P；B选自N时，为取代或非取代的季铵碱阳离子；B选自P时，为取代或非取代的季膦碱阳离子；
R1、R2、R3和R4各自独立的选自C1～C4烷基、苄基、且中与碳相连的至少一个氢被羟基取代；p选自0～3的整数，q选自1～3的整数；
R5、R6各自独立的选自H、C1～C4烷基、苄基、且中与碳相连的至少一个氢被羟基取代；p选自0～3的整数，q选自1～3的整数；
R7、R8、R9和R10各自独立的选自选自H、C1～C4烷基；
Y,Z分别独立的选自H、卤素、羟基、羧基、氰基、C1-20烷基、C1-20烷氧基、C1-20环烷基，Y,Z可分别位于苯环现有取代基的邻位、间位或对位；
m选自0～10的整数。
优选的，X+选自2-羟基-N,N,N-三甲基乙铵根离子、四甲基铵根离子、四乙基铵根离子、四丙基铵根离子、四丁基铵根离子、苄基三甲基铵根离子、苄基三乙基铵根离子、四甲基膦离子、四乙基膦离子、四丁基膦离子、苄基三甲基膦离子、N,N,N,N-四甲基胍离子、1-羧基-N,N,N-三甲基甲铵根离子、3-羧基-2-羟基-N,N,N-三甲基丙铵根离子、吡咯鎓离子咪唑鎓离子吗啉鎓离子硫代吗啉鎓离子吡啶鎓离子吡唑鎓离子哌啶鎓离子哌嗪鎓离子N-甲基哌嗪鎓离子
Y,Z分别独立的选自H、卤素、羟基、羧基、氰基、C1-20烷基、C1-20烷氧基或C1-20环烷基，Y,Z可分别位于苯环现有取代基的邻位，间位或对位；
m选自0～5之间的整数。
进一步优选的，X+选自2-羟基-N,N,N-三甲基乙铵根离子、四甲基铵根离子、四乙基铵根离子、四丙基铵根离子、四丁基铵根离子、苄基三甲基铵根离子、苄基三乙基铵根离子、N,N,N,N-四甲基胍离子、1-羧基-N,N,N-三甲基铵根离子、3-羧基-2-羟基-N,N,N-三甲基丙铵根离子、吡咯鎓离子、咪唑鎓离子、吗啉鎓离子、硫代吗啉鎓离子、吡啶鎓离子、吡唑鎓离子、哌啶鎓离子、哌嗪鎓离子、N-甲基哌嗪鎓离子；
Y,Z分别独立的选自H、Cl、羟基、羧基、氰基、甲氧基，Y,Z可分别位于苯环现有取代基的邻位，间位或对位；
m选自0或1。
具体的，本发明通式(I)所述的化合物选自：
2-羟基-N,N,N-三甲基乙铵8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
四乙铵8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
四丁铵8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
N,N,N-三甲基苄基铵8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
四甲基胍8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
1-羧基-N,N,N-三甲基甲铵8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
1H-吡咯8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
3H-咪唑8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
吗啉8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
硫吗啉8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
N-甲基哌嗪8-(2-羟基苯甲酰胺基)辛酸盐，结构式为：
2-羟基-N,N,N-三甲基乙铵8-(4-羟基苯甲酰胺基)辛酸盐，结构式为：
硫吗啉8-(4-羟基苯甲酰胺基)辛酸盐，结构式为：
2-羟基-N,N,N-三甲基乙铵8-(3-羟基苯甲酰胺基)辛酸盐，结构式为：
四乙铵8-(3-羟基苯甲酰胺基)辛酸盐，结构式为：
2-羟基-N,N,N-三甲基乙铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
四乙胺8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
N,N,N-三甲基苄基铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
四丁胺8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
1H-吡咯8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
四甲基胍8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
吗啉8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
硫吗啉8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
N-甲基哌嗪8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
3H-咪唑8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
1-羧基-N,N,N-三甲基甲铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
2-羟基-N,N,N-三甲基乙铵8-(4-氯苯甲酰胺基)辛酸盐，结构式为：
3H-咪唑8-(4-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(4-氯-2-羟基苯甲酰胺基)辛酸盐，结构式为：
2-羟基-N,N,N-三甲基乙铵[8-(2-羟基苯甲酰胺基)辛酸]2盐，结构式为：
2-羟基-N,N,N-三甲基乙铵8-(5-羧基-2-羟基苯甲酰胺基)辛酸盐，结构式为：
本发明的另一个目的是提供一种通式I所示的化合物的制备方法，合成路线为：
其中，W-选自碳酸氢根离子(HCO3 -)、氢氧根离子(OH-)；X+、Y、Z如前所述。
包括：以结构如所示的8-(Y基/Z基苯甲酰胺基)辛酸为起始原料，以丙酮为反应溶剂，8-(Y基/Z基苯甲酰胺基)辛酸和X+W-在45～60℃反应获得式I所示的目标化合物；其中，8-(Y基/Z基苯甲酰胺基)辛酸和X+W-的摩尔比为1:1～11:1。
反应结束后，减压蒸除溶剂，真空干燥，得到纯化的目标化合物。
本发明通式I所示的化合物符合离子液体的定义。本发明通式I所示的化合物具有口服吸收促进剂的特点，可以减少胃肠道环境和蛋白酶对蛋白和/或多肽类药物的降解，或增加蛋白和/或多肽类药物肠粘膜的通透效果、在胃肠道部位的吸收，或提高多肽蛋白类药物口服给药后的治疗效果。因此，本发明的另一个目的是提供通式I所示的化合物在作为增加蛋白和/或多肽类药物口服递送的口服吸收促进剂中的应用。
本发明的另一个目的是提供一种药物组合物，含有本发明通式I所示的化合物、治疗有效量的蛋白和/或多肽类药物及药学上的载体或赋形剂，制成药学上可接受的剂型；其中，式I所示的化合物与蛋白和/或多肽类药物的质量比为1:1～1000:1。
所述的蛋白和/或多肽类药物为胰岛素及其类似物、胰高血糖素、胰高血糖素样肽-1及其类似物、降钙素、重组人甲状旁腺素、促红细胞生成素、人粒细胞集落刺激因子、人生长激素、白细胞介素、环孢菌素、表皮生长因子、干扰素、多肽疫苗、蛋白疫苗。
所述的剂型是药剂学上可接受的片剂、胶囊、酏剂、糖浆、锭剂、吸入剂、喷雾剂、注射剂、膜剂、贴剂、散剂、颗粒剂、块剂、乳剂或栓剂。
本发明的有益效果：
本发明化合物可以缓冲胃局部强酸性环境，抑制胃蛋白酶和胰蛋白酶活性，减少多肽蛋白类药物在胃肠道部位的降解。同时，本发明化合物与蛋白质或多肽组合，具有延长多肽蛋白类药物口服后在吸收部位的停留时间，从而增强吸收效率，增加口服生物利用度，有效提高蛋白和多肽药物的口服治疗效果。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本发明权利要求的保护范围之内。
实施例1
2-羟基-N,N,N-三甲基乙铵8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-1)
将8-(2-羟基苯甲酰胺基)辛酸(3g,10.75mmol)溶于50ml丙酮中，加入2.22g质量分数为80％的胆碱碳酸氢盐水溶液(10.75mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到浅黄色胶状半固体(化合物I-1)4.11g，熔点为67.7℃，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.76(s,1H),7.98(d,J＝7.7Hz,1H),7.28(t,J＝7.2Hz,1H),6.99(d,J＝8.2Hz,1H),6.75(t,J＝8.2Hz,1H),3.92(t,J＝4.9Hz,2H),3.50(d,J＝4.9Hz,2H),3.20(s,9H),2.12(d,J＝17.4Hz,4H),2.04(t,J＝7.3Hz,1H),1.77–1.45(m,3H),1.31(s,6H).13C NMR(75MHz,DMSO-d6)δ177.33,167.98,163.59,132.69,129.68,119.09,118.32,115.60,67.53,55.57,53.64,53.59,53.54,37.59,31.12,29.61,29.49,28.96,26.87,26.23.
实施例2
四乙铵8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-2)
将8-(2-羟基苯甲酰胺基)辛酸1.60g(5.75mmol)溶于50ml丙酮中，加入6.33g质量分数为25％的四乙基氢氧化铵水溶液(5.75mmol)，45℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到浅棕色油状液体(化合物I-2)1.35g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ10.78(s,1H),7.76(d,J＝7.8Hz,1H),7.08(t,J＝6.5Hz,1H),6.65(d,J＝8.3Hz,1H),6.51(t,J＝7.5Hz,1H),3.35–3.25(m,2H)3.22(q,J＝7.3Hz,8H),2.11–1.98(m,2H),1.58–1.48(m,4H),1.40–1.32(m,6H),1.21–1.15(m,12H).13CNMR(75MHz,DMSO-d6)δ176.74,172.41,167.79,165.17,142.20,129.95,123.67,123.59,121.52,119.66,118.92,114.06,51.91,51.87,51.83,31.27,30.02,29.74,29.48,28.89,26.85,26.18,7.48.
实施例3
四丁铵8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-3)
将8-(2-羟基苯甲酰胺基)辛酸2.26g(8.12mmol)溶于50ml丙酮中，加入8.56g质量分数为25％的四丁基氢氧化铵水溶液(8.12mmol)，50℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到无色油状液体(化合物I-3)2.60g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ10.61(s,1H),7.79(d,J＝7.8Hz,1H),7.21–6.97(m,1H),7.11(t,J＝6.9Hz,1H),6.73(d,J＝8.3Hz,1H),6.60–6.27(m,1H),3.31–3.29(m,2H),3.24–3.03(m,8H),2.05(t,J＝6.6Hz,1H),1.69–1.44(m,12H),1.38–1.26(m,14H),0.95(t,J＝7.3Hz,12H).13C NMR(75MHz,DMSO-d6)δ173.95,162.60,161.81,160.38,156.84,129.15,127.24,113.67,111.34,109.51,108.26,57.93,55.18,54.25,53.33,32.73,29.32,24.77,24.65,24.16,23.97,22.04,21.40,20.86,18.80,14.62,14.57,13.92,12.76,9.31,8.67.
实施例4
N,N,N-三甲基苄基铵8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-4)
将8-(2-羟基苯甲酰胺基)辛酸1.45g(5.23mmol)溶于50ml丙酮中，加入7.12g质量分数为25％的N,N,N-三甲基苄基氢氧化铵溶液(5.23mmol)，50℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-4)1.48g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ10.55(s,1H),7.79(d,J＝7.8Hz,1H),7.52(s,5H),7.15–7.03(m,1H),6.71(d,J＝8.2Hz,1H),6.51(t,J＝7.4Hz,1H),4.55(s,2H),3.52–3.21(m,2H),3.05(s,9H),2.12–2.02(m,3H),1.60–1.48(m,4H),1.34(s,6H).13C NMR(75MHz,DMSO-d6)δ208.91,176.59,167.71,163.01,133.26,132.63,130.71,129.33,128.80,128.67,127.96,118.82,115.95,68.96,68.18,57.11,52.10,36.75,32.57,30.05,29.58,26.80,25.89,23.53,13.93.
实施例5
四甲基胍8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-5)
将8-(2-羟基苯甲酰胺基)辛酸0.87g(3.15mmol)溶于50ml丙酮中，加入5.14g质量分数为80％的四甲基胍碳酸氢盐水溶液(3.15mmol)55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到棕色油状液体(化合物I-5)1.55g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ10.36(s,1H),7.80(d,J＝7.8Hz,1H),7.14(d,J＝7.0Hz,1H),6.75(d,J＝8.2Hz,1H),6.67–6.42(m,1H),4.61(s,1H),3.53(d,J＝2.2Hz,1H),3.28(t,J＝6.6Hz,2H),2.89(s,12H),2.11(s,1H),2.04(t,J＝7.6Hz,2H),1.55–1.46(m,4H),1.38–1.26(m,5H).13C NMR(75MHz,DMSO-d6)δ175.10,172.56,169.39,160.68,135.59,134.01,130.57,128.62,128.07,121.96,118.90,117.85,117.05,116.39,115.67,114.89,34.22,29.28,26.82,24.96.
实施例6
1-羧基-N,N,N-三甲基甲铵8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-6)
将8-(2-羟基苯甲酰胺基)辛酸0.81g(2.94mmol)溶于50ml丙酮中，加入6.48g质量分数为80％的甜菜碱碳酸氢盐水溶液(2.94mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-6)2.34g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.84(s,1H),7.82(d,J＝7.6Hz,1H),7.32(t,J＝7.4Hz,1H),8.14(d,J＝8.2Hz,1H),6.95(t,J＝8.4Hz,1H),3.78(t,J＝4.8Hz,1H),3.30(d,J＝4.9Hz,2H),3.30(s,9H),2.32(d,J＝16.3Hz,4H),1.86–1.26(m,3H),1.33(s,6H).13C NMR(75MHz,DMSO-d6)δ176.26,167.94，165.68,164.28,133.59,121.48,118.79,117.82,116.60,66.03,54.87,54.64,53.97,53.44,39.79,37.62,30.11,29.09,28.98,26.78.
实施例7
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-7)
将8-(2-羟基苯甲酰胺基)辛酸0.87g(3.16mmol)溶于50ml丙酮中，加入5.72g质量分数为80％的左旋肉碱碳酸氢盐水溶液(3.16mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到无色油状液体(化合物I-7)1.26g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.85(s,1H),7.63(d,J＝7.6Hz,1H),7.34(t,J＝7.4Hz,1H),6.95(d,J＝8.1Hz,1H),6.84(t,J＝8.1Hz,1H),4.15(t,J＝5.3Hz,2H),3.92(t,J＝4.9Hz,2H),3.21(s,9H),2.58(dd,J＝7.3,2.2Hz,2H),2.46(d,J＝17.3Hz,4H),1.62-1.55(m,4H),1.45(s,6H).13C NMR(75MHz,DMSO-d6)δ178.46,168.26,164.09,132.88,131.55,123.48,118.90,116.39,62.54,61.50,54.59,53.94,49.35,37.89,32.88,32.83,31.22,29.75,29.67,27.10,26.79,25.06.
实施例8
1H-吡咯8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-8)
将8-(2-羟基苯甲酰胺基)辛酸0.70g(2.54mmol)溶于50ml丙酮中，加入6.02g质量分数为80％的1H-吡咯碳酸氢盐水溶液(2.54mmol)，50℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-8)2.58g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.81(t,J＝5.6Hz,1H),7.85(d,J＝8.0Hz,2H),7.45–7.29(m,2H),7.09(s,3H),6.90–6.84(m,4H),2.19(t,J＝7.3Hz,1H),1.55–1.47(m,5H),1.28(d,J＝4.0Hz,7H).13C NMR(75MHz,DMSO-d6)δ174.97,169.45,161.92,160.73,135.18,134.50,134.02,130.67,128.54,127.95,118.96,117.84,117.25,115.53,114.79,34.11,29.26,26.81,24.92.
实施例9
3H-咪唑8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-9)
将8-(2-羟基苯甲酰胺基)辛酸0.27g(1.47mmol)溶于50ml丙酮中，加入5.37g质量分数为80％的3H-咪唑碳酸氢盐水溶液(1.47mmol)，50℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到无色油状液体(化合物I-9)1.38g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.86(s,1H),7.85(d,J＝7.9Hz,1H),7.43-7.35(m,1H),7.09(s,3H),6.91–6.84(m,2H),3.31–3.25(m,2H),2.19(t,J＝7.3Hz,1H),2.16–2.07(m,3H),1.56–1.44(m,4H),1.32–1.24(m,6H).13C NMR(75MHz,DMSO-d6)δ175.10,172.56,169.39,160.68,135.59,134.51,130.57,128.62,121.96,117.85,117.05,116.39,115.67,114.89,34.22,28.95,26.82,24.96.
实施例10
吗啉8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-10)
将8-(2-羟基苯甲酰胺基)辛酸0.42g(2.33mmol)溶于50ml丙酮中，加入6.16g质量分数为80％的吗啉碳酸氢盐水溶液(2.33mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到棕色油状液体(化合物I-10)2.33g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.89(s,1H),7.84(d,J＝7.9Hz,1H),7.37(d,J＝8.5Hz,1H),6.96–6.79(m,2H),3.62–3.48(m,4H),3.43(d,J＝2.1Hz,2H),2.78–2.74(m,4H),2.17(t,J＝7.3Hz,3H),1.61–1.41(m,4H),1.41–1.12(m,7H).13C NMR(75MHz,DMSO-d6)δ169.21,161.58,160.82,134.47,133.89,130.50,128.62,128.17,118.66,117.91,117.87,116.29,115.87,34.84,29.27,29.07,28.92,26.79,25.17.
实施例11
硫吗啉8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-11)
将8-(2-羟基苯甲酰胺基)辛酸0.43g(2.35mmol)溶于50ml丙酮中，加入7.63g质量分数为80％的硫吗啉碳酸氢盐水溶液(2.35mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-11)2.76g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.92(s,1H),7.85(d,J＝7.9Hz,1H),7.28(d,J＝8.7Hz,1H),6.98–6.59(m,2H),3.04–2.92(m,4H),2.62–2.53(m,4H),2.24(t,J＝8.1Hz,3H),2.15(t,J＝7.3Hz,1H),1.64–1.39(m,4H),1.39–1.16(m,7H),0.94(t,J＝5.6Hz,1H).13C NMR(75MHz,DMSO-d6)δ175.43,172.50,169.26,161.59,160.81,134.50,128.61,118.71,117.50,115.80,114.89,47.16,34.63,29.26,28.91,26.96,25.10,23.53,13.95.
实施例12
N-甲基哌嗪8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-12)
将8-(2-羟基苯甲酰胺基)辛酸0.43g(2.35mmol)溶于50ml丙酮中，加入4.44g质量分数为80％的N-甲基哌嗪碳酸氢盐水溶液(2.35mmol)，50℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到深棕色油状液体(化合物I-12)1.61g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.11(s,1H),7.88–7.84(m,1H),7.38–7.33(m,1H),6.89–6.78(m,2H),3.28(t,J＝7.0Hz,2H),2.85(t,J＝5.4Hz,4H),2.71–2.49(m,2H),2.36(t,J＝5.4Hz,4H),2.15(s,3H),2.11–2.06(m,2H),1.54–1.45(m,4H),1.32–1.23(m,6H).13CNMR(75MHz,DMSO-d6)δ176.07,172.37,161.67,134.44,133.76,130.48,128.67,118.63,117.92,116.73,115.01,54.29,46.46,44.41,35.44,29.29,29.15,28.90,26.77,25.40.
实施例13
2-羟基-N,N,N-三甲基乙铵8-(4-羟基苯甲酰胺基)辛酸盐(化合物I-13)
将4.58g 8-(4-羟基苯甲酰胺基)辛酸(1.65mmol)溶于50ml丙酮中，加入质量分数为80％的胆碱碳酸氢盐0.43g(1.65mmol)，50℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到棕色油状液体(化合物I-13)2.38g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.16(s,1H),7.45(d,J＝7.7Hz,1H),7.16(t,J＝7.2Hz,1H),6.87(d,J＝8.2Hz,1H),6.71(t,J＝8.2Hz,1H),3.82(t,J＝4.9Hz,2H),3.50(d,J＝4.9Hz,2H),3.19(s,9H),2.52(d,J＝17.4Hz,4H),1.57–1.35(m,2H),1.29(s,6H).13C NMR(75MHz,DMSO-d6)δ175.31,168.98,162.59,133.69,129.54,123.97,119.67,118.32,115.27,69.83,67.53,55.77,53.64,53.54,36.59,30.12,29.61,29.49,28.96,26.23.
实施例14
硫吗啉8-(4-羟基苯甲酰胺基)辛酸盐(化合物I-14)
将4.58g 8-(4-羟基苯甲酰胺基)辛酸(1.65mmol)溶于50ml丙酮中，加入4.63g质量分数为80％的硫吗啉碳酸氢盐水溶液(1.65mmol)，50℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到棕色油状液体(化合物I-14)3.47g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.55(s,1H),7.63(d,J＝7.8Hz,1H),7.51(d,J＝8.6Hz,1H),6.76–6.43(m,2H),3.11–2.87(m,4H),2.56–2.49(m,4H),2.39(t,J＝8.1Hz,3H),2.12(t,J＝6.8Hz,1H),1.69–1.37(m,4H),1.36–1.14(m,7H),1.02(t,J＝5.4Hz,1H).13C NMR(75MHz,DMSO-d6)δ183.21,173.48,171.02,166.14,159.68,129.44,126.71,116.49,116.11,115.48,110.57,51.43,37.46,30.26,27.51,26.49,26.17,24.16,12.77.
实施例15
2-羟基-N,N,N-三甲基乙铵8-(3-羟基苯甲酰胺基)辛酸盐(化合物I-15)
将4.58g 8-(3-羟基苯甲酰胺基)辛酸(1.65mmol)溶于50ml丙酮中，加入质量分数为80％的胆碱碳酸氢盐0.43g(1.65mmol)，50℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到黄色油状液体(化合物I-15)2.68g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.76(s,1H),7.91(d,J＝7.7Hz,1H),7.38(t,J＝7.2Hz,1H),6.99(d,J＝8.2Hz,1H),3.86(t,J＝4.9Hz,2H),3.43(d,J＝4.9Hz,2H),3.19(s,9H),2.16(d,J＝17.4Hz,4H),1.67–1.48(m,3H),1.31(s,6H).13C NMR(75MHz,DMSO-d6)δ177.33,167.98,163.20,131.53,126.68,121.62,119.09,117.46,111.92,66.33,54.65,53.18,50.21,37.69,33.53,31.08,28.64,27.31,26.41,25.59.
实施例16
四乙铵8-(3-羟基苯甲酰胺基)辛酸盐(化合物I-16)
将4.58g 8-(3-羟基苯甲酰胺基)辛酸(1.65mmol)溶于50ml丙酮中，加入1.01g质量分数为25％的四乙基氢氧化铵水溶液(1.65mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到黄色油状液体(化合物I-16)2.59g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.76(s,1H),7.91(d,J＝7.7Hz,1H),7.38(t,J＝7.2Hz,1H),6.99(d,J＝8.2Hz,1H),3.86(t,J＝4.9Hz,2H),3.43(d,J＝4.9Hz,2H),3.19(s,9H),2.16(d,J＝17.4Hz,4H),1.67–1.48(m,3H),1.31(s,6H).13C NMR(75MHz,DMSO-d6)δ177.33,167.98,163.20,131.53,126.68,121.62,119.09,117.46,111.92,66.33,54.65,53.18,50.21,37.69,33.53,31.08,28.64,27.31,26.41,25.59.
实施例17
2-羟基-N,N,N-三甲基乙铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-17)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入质量分数为80％的胆碱碳酸氢盐1.19g(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到黄色油状液体(化合物I-17)1.87g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.88(s,1H),7.87(d,J＝7.8Hz,1H),7.52(t,J＝7.3Hz,1H),7.47(d,J＝8.4Hz,1H),6.93(t,J＝8.3Hz,1H),3.97(t,J＝5.0Hz,2H),3.86(t,J＝4.3Hz,2H),3.43(d,J＝4.9Hz,2H),3.30(s,9H),2.38(d,J＝16.9Hz,4H),1.78–1.56(m,2H),1.26(s,6H).13C NMR(75MHz,DMSO-d6)δ183.65,165.57,157.59,134.79,129.08,121.20,118.69,117.32,69.73,57.57,56.54,54.68,53.56,37.69,30.03,29.81,29.06,28.78,26.70,25.73.
实施例18
四乙胺8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-18)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入2.68g质量分数为25％的四乙基氢氧化铵水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到无色油状液体(化合物I-18)1.65g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ10.91(s,1H),9.76(s,1H),7.58(d,J＝7.7Hz,1H),7.47(d,J＝8.5Hz,1H),6.93(t,J＝8.1Hz,1H),3.88(t,J＝5.2Hz,1H),3.58(d,J＝5.0Hz,2H),3.30(s,9H),1.58–1.51(m,4H),1.43–1.33(m,6H),1.26–1.15(m,12H).13C NMR(75MHz,DMSO-d6)δ188.68,165.49,164.37,158.72,134.62,127.05,121.22,120.91,118.62,117.26,113.97,56.12,55.13,53.48,52.37,32.27,29.66,28.68,27.73,26.85,26.18,9.47.
实施例19
N,N,N-三甲基苄基铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-19)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入6.21g质量分数为25％的N,N,N-三甲基苄基氢氧化铵溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-19)1.98g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ11.12(s,1H),7.64(d,J＝7.7Hz,1H),7.52(s,5H),7.16–7.02(m,1H),6.93(d,J＝8.4Hz,1H),4.51(s,2H),3.36(s,1H),2.98(s,9H),2.16–2.07(m,3H),1.58–1.39(m,4H),1.26(s,6H).13C NMR(75MHz,DMSO-d6)δ202.76,175.55,168.25,164.78,134.76,131.68,130.52,129.69,127.88,118.38,114.56,69.06,68.28,57.97,52.60,39.65,37.16,31.02,29.88,28.79,27.60,25.82,23.73,18.28,15.03.
实施例20
四丁胺8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-20)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入4.81g质量分数为25％的四丁基氢氧化铵溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-20)2.53g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ11.05(s,1H),7.65(d,J＝7.7Hz,1H),7.47(t,J＝7.1Hz,1H),6.68(d,J＝7.9Hz,1H),6.55–6.14(m,1H),3.44–3.21(m,2H),3.19–2.87(m,8H),2.15(t,J＝5.4Hz,1H),1.71–1.56(m,12H),1.41–1.33(m,14H),0.97(t,J＝7.1Hz,12H).13C NMR(75MHz,DMSO-d6)δ182.65,169.60,167.48,161.22,143.81,121.43,119.65,113.51,110.74,106.51,105.33,58.41,56.10,53.28,49.41,33.48,30.65,24.39,24.12,23.98,22.96,21.46,21.38,19.94,17.42,15.13,13.99,13.57,12.64,8.74,7.17.
实施例21
1H-吡咯8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-21)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入10.81g质量分数为80％的1H-吡咯碳酸氢盐水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-21)3.74g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.93(t,J＝6.5Hz,1H),7.73(d,J＝6.7Hz,2H),7.71–7.28(m,2H),7.19(s,3H),6.99–6.47(m,4H),2.39(t,J＝7.1Hz,1H),1.51–1.49(m,5H),1.17(d,J＝3.9Hz,7H).13C NMR(75MHz,DMSO-d6)δ184.14,177.56,164.45,152.72,140.19,137.21,133.27,130.92,130.55,128.37,118.66,118.14,117.56,114.25,111.64,47.85,32.46,28.71,24.67.
实施例22
四甲基胍8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-22)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入7.44g质量分数为80％的四甲基胍碳酸氢盐水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-22)3.65g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ10.93(s,1H),7.66(d,J＝8.0Hz,1H),7.14(d,J＝7.8Hz,1H),7.43(d,J＝8.1Hz,1H),6.64–6.19(m,1H),4.53(s,1H),3.91(d,J＝2.3Hz,1H),3.44(t,J＝6.1Hz,2H),2.29(s,12H),2.12(t,J＝6.8Hz,2H),1.80–1.65(m,4H),1.44–1.31(m,5H).13C NMR(75MHz,DMSO-d6)δ168.94,174.49,170.23,163.48,141.23,133.92,129.14,128.77,127.04,122.56,117.93,117.35,116.54,116.36,114.97,110.24,35.17,30.25,28.79,28.16.
实施例23
吗啉8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-23)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入1.00g质量分数为80％的吗啉碳酸氢盐水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-23)1.46g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.03(s,1H),7.59(d,J＝8.0Hz,1H),7.17(d,J＝8.2Hz,1H),6.86–6.69(m,2H),3.54–3.44(m,4H),3.37(d,J＝2.1Hz,2H),2.51–2.46(m,4H),2.33(t,J＝7.1Hz,3H),1.73–1.56(m,4H),1.52–1.44(m,7H).13C NMR(75MHz,DMSO-d6)δ172.15,166.28,161.46,135.97,132.15,131.31,128.21,124.56,117.70,117.31,116.97,116.18,110.34,32.91,31.75,30.64,29.16,26.37,24.52.
实施例24
硫吗啉8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-24)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入1.02g质量分数为80％的硫吗啉碳酸氢盐水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-24)1.33g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),7.69(d,J＝7.9Hz,1H),7.37(d,J＝8.2Hz,1H),6.66–6.37(m,2H),3.51–2.93(m,4H),2.46–2.39(m,3H),2.32(t,J＝7.8Hz,3H),2.14(t,J＝6.9Hz,1H),1.72–1.41(m,4H),1.39–1.28(m,6H),0.99(t,J＝4.3Hz,1H).13C NMR(75MHz,DMSO-d6)δ179.65,174.28,168.12,165.48,152.34,149.25,137.26,125.51,119.37,113.49,111.53,55.79,42.54,31.49,30.08,27.81,24.56,24.45,13.47.
实施例25
N-甲基哌嗪8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-25)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入4.81g质量分数为80％的N-甲基哌嗪碳酸氢盐水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-25)2.98g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.42(s,1H),7.94–7.73(m,1H),7.58–7.43(m,1H),6.92–6.72(m,2H),3.14(t,J＝7.2Hz,2H),3.10(t,J＝5.5Hz,4H),2.74–2.57(m,2H),2.41(t,J＝5.2Hz,4H),2.32(s,3H),2.20–2.16(m,2H),1.62–1.59(m,6H),1.58–1.43(m,3H).13CNMR(75MHz,DMSO-d6)δ177.57,173.09,166.41,142.67,138.42,135.22,123.44,117.53,116.91,116.39,114.01,53.39,47.85,43.38,32.55,29.02,28.33,27.29,26.51,24.37.
实施例26
3H-咪唑8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-26)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入7.44g质量分数为80％的3H-咪唑碳酸氢盐水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-26)3.21g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ8.94(s,1H),7.83(d,J＝8.1Hz,1H),7.27-7.05(m,1H),6.98(s,3H),6.74–6.62(m,2H),3.36–3.25(m,2H),2.83(t,J＝7.1Hz,1H),2.25–2.10(m,3H),1.65–1.59(m,4H),1.37–1.16(m,6H).13C NMR(75MHz,DMSO-d6)δ178.35,173.06,170.45,159.77,136.61,135.47,134.58,131.42,120.56,118.93,117.14,116.58,115.34,113.91,33.71,29.15,25.10,23.75.
实施例27
1-羧基-N,N,N-三甲基甲铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-27)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入10.05g质量分数为80％的甜菜碱碳酸氢盐水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-27)3.55g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.69(s,1H),7.81(d,J＝7.7Hz,1H),7.16(t,J＝7.3Hz,1H),6.84(d,J＝8.1Hz,1H),6.63(t,J＝7.9Hz,1H),4.13(t,J＝4.7Hz,1H),3.69(d,J＝5.1Hz,2H),3.17(s,8H),2.54(d,J＝17.1Hz,4H),1.93–1.15(m,3H),1.24(s,6H).13C NMR(75MHz,DMSO-d6)δ177.39,168.21,167.15,163.07,134.06,122.41,119.34,117.39,115.42,55.73,54.39,54.06,53.58,53.53,39.94,36.41,32.51,29.93,28.68,26.44.
实施例28
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-28)
将1.44g 8-(5-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入10.81g质量分数为80％的左旋肉碱碳酸氢盐溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中，干燥48h，得到淡黄色油状液体(化合物I-28)3.47g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.22(s,1H),7.58(d,J＝7.9Hz,1H),7.54(t,J＝7.3Hz,1H),6.80(d,J＝7.9Hz,1H),6.52(t,J＝8.0Hz,1H),4.32(t,J＝5.5Hz,2H),3.87(t,J＝4.8Hz,2H),3.33(s,8H),2.60(dd,J＝8.2,3.1Hz,2H),2.45(d,J＝16.8Hz,4H),1.67-1.59(m,4H),1.51(s,6H).13C NMR(75MHz,DMSO-d6)δ172.66,169.45,165.78,143.69,141.45,128.91,121.60,115.49,62.14,60.93,55.18,54.64,39.85,36.57,33.86,31.42,30.51,29.59,29.81,27.63,25.69,24.10.
实施例29
2-羟基-N,N,N-三甲基乙铵8-(4-氯苯甲酰胺基)辛酸盐(化合物I-29)
将1.44g 8-(4-氯苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入质量分数为80％的胆碱碳酸氢盐1.19g(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-29)2.12g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.81(s,1H),7.85(d,J＝7.9Hz,1H),7.34(t,J＝7.1Hz,1H),7.01(d,J＝8.1Hz,1H),6.47(t,J＝8.0Hz,1H),3.81(d,J＝4.9Hz,2H),3.62(t,J＝5.1Hz,2H),3.57(s,8H),2.34(d,J＝16.8Hz,4H),2.12(t,J＝6.7Hz,1H),1.67–1.38(m,3H),1.30(s,6H).13C NMR(75MHz,DMSO-d6)δ174.69,166.58,164.37,131.67,128.34,121.49,118.07,113.52,69.47,58.94,54.65,53.42,52.17,36.14,31.24,29.87,29.40,28.05,27.11,26.54.
实施例30
3H-咪唑8-(4-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-30)
将1.44g 8-(4-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml的丙酮中，加入7.44g质量分数为80％的3H-咪唑碳酸氢盐水溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到无色油状液体(化合物I-30)3.11g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.72(s,1H),7.73(d,J＝7.9Hz,1H),7.47-7.29(m,1H),7.11(s,3H),6.94–6.76(m,2H),4.57(s,2H),3.41(s,1H),3.30–3.26(m,2H),2.43(t,J＝7.6Hz,1H),1.66–1.54(m,4H),1.43–1.30(m,6H).13C NMR(75MHz,DMSO-d6)δ179.86,175.96,162.57,161.78,159.34,134.83,133.91,129.25,123.54,119.13,117.33,116.32,115.79,114.72,32.82,29.68,26.94,24.91.
实施例31
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(4-氯-2-羟基苯甲酰胺基)辛酸盐(化合物I-31)
将1.44g 8-(4-氯-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入10.81g质量分数为80％的左旋肉碱碳酸氢盐溶液(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中，干燥48h，得到深棕色油状液体(化合物I-31)2.45g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.97(s,1H),7.76(d,J＝7.8Hz,1H),7.23(t,J＝7.3Hz,1H),6.94(d,J＝8.2Hz,1H),6.77(t,J＝8.0Hz,1H),4.26(t,J＝5.2Hz,2H),3.82(t,J＝5.1Hz,2H),3.22(s,9H),2.59(dd,J＝7.1,2.3Hz,2H),2.39(d,J＝16.9Hz,4H),1.58-1.56(m,4H),1.52(s,6H).13C NMR(75MHz,DMSO-d6)δ183.26,172.35,165.56,133.24,130.35,121.58,118.68,116.83,66.58,62.30,54.83,54.10,48.32,37.76,33.53,31.93,30.16,29.51,29.08,26.90,26.73,25.71.
实施例32
2-羟基-N,N,N-三甲基乙铵[8-(2-羟基苯甲酰胺基)辛酸]2盐(化合物I-32)
将8-(2-羟基苯甲酰胺基)辛酸(6g,21.50mmol)溶于75ml丙酮中，加入2.22g质量分数为80％的胆碱碳酸氢盐水溶液(10.75mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到无色油状液体(化合物I-32)7.52g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.40(s,2H),7.86(t,J＝7.8Hz,1H),7.30(t,J＝7.6Hz,2H),6.91(d,J＝8.2Hz,2H),6.77(t,J＝7.5Hz,1H),3.86(t,J＝4.3Hz,2H),3.42(t,J＝4.3Hz,2H),3.13(s,9H),2.13(t,J＝6.3Hz,8H),1.52(t,J＝6.5Hz,8H),1.30(s,12H).13CNMR(75MHz,DMSO-d6)δ206.97,176.24,168.42,161.64,133.27,128.96,118.26,117.50,117.11,67.83,60.07,55.60,53.82,35.95,31.10,29.33,28.90,26.81,25.91,14.55.
实施例33
2-羟基-N,N,N-三甲基乙铵8-(5-羧基-2-羟基苯甲酰胺基)辛酸盐(化合物I-33)
将1.44g 8-(5-羧基-2-羟基苯甲酰胺基)辛酸(4.56mmol)溶于50ml丙酮中，加入质量分数为80％的胆碱碳酸氢盐1.19g(4.56mmol)，55℃加热反应24h，减压蒸除溶剂，将产物置于真空干燥箱中干燥48h，得到淡黄色油状液体(化合物I-33)2.33g，符合离子液体的定义。
1H NMR(300MHz,DMSO-d6)δ9.45(s,1H),8.01(d,J＝7.9Hz,1H),7.33(d,J＝8.1Hz,1H),6.89(t,J＝8.0Hz,1H),4.03(t,J＝4.7Hz,2H),3.49(d,J＝5.1Hz,2H),3.25(s,9H),2.65(d,J＝18.4Hz,4H),2.81(t,J＝7.2Hz,1H),1.68–1.49(m,2H),1.32(s,6H).13C NMR(75MHz,DMSO-d6)δ178.66,168.46,165.57,131.41,126.33,120.19,117.64,116.51,71.63,56.81,53.25,53.10,52.37,36.54,30.84,29.74,29.06,27.36,25.47,24.13.
实施例34
准确称取6g 2-羟基-N,N,N-三甲基乙铵8-(2-羟基苯甲酰胺基)辛酸盐(化合物I-1)和60mg索马鲁肽，将索马鲁肽加入2-羟基-N,N,N-三甲基乙铵8-(2-羟基苯甲酰胺基)辛酸盐中，超声1h至均匀混合，即得2-羟基-N,N,N-三甲基乙铵8-(2-羟基苯甲酰胺基)辛酸盐和索马鲁肽组合物。
实施例35
含2-羟基-N,N,N-三甲基乙铵8-(2-羟基苯甲酰胺基)辛酸盐和索马鲁肽组合物的，配方如下：
按常规方法将原辅料混合，制粒，干燥，压片，制得片剂。
实施例36
含2-羟基-N,N,N-三甲基乙铵8-(2-羟基苯甲酰胺基)辛酸盐和索马鲁肽组合物的胶囊，配方如下：
按常规方法将原辅料混合，制粒，干燥，混匀，装入胶囊中，盖上胶囊帽。
实施例37
本发明化合物I-1～I-33促进多肽蛋白类药物口服吸收的活性测定。
测试例中具体条件的实验方法通常按常规条件或按照商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常用试剂。
多肽药物以索马鲁肽为例，测试化合物保护多肽蛋白类药物不被酶降解的能力，促进索马鲁肽在体内外的吸收及口服索马鲁肽的体内降糖活性。
测试例1
测定含本发明化合物的组合物的口服吸收效果
正常小鼠口服糖耐量试验(OGTT)：10周龄昆明种清洁级小鼠，体重18～22g，雄性，随机分组：空白对照组(空白溶媒：纯净水)，阳性药对照组(SNAC：1g/kg+索马鲁肽：10mg/kg，溶于生理盐水)，受试化合物组(受试化合物：1g/kg+索马鲁肽：10mg/kg，溶于生理盐水)，每组8只；实验前小鼠禁食不禁水12h，各组分别灌胃给予空白溶媒、含阳性药的组合物生理盐水溶液、含受试化合物的组合物生理盐水溶液，断尾取血，测定血糖值(记为-30min)，30min后测定血糖值记为0min，之后立即按10ml/kg灌胃给予浓度为3g/10ml的葡萄糖溶液，并于15，30，60，120min测定血糖值。结果见表1。
表1：SNAC或化合物I-1～I-33对正常小鼠口服糖耐量的影响(n＝8)
注：*P<0.05,**P<0.01,***P<0.001，为相对于空白对照组的Student’s t检验结果。
正常小鼠口服糖耐量试验表明：在本发明化合物帮助下，口服给药起到较好的降糖效果，且对于血糖的稳定作用优于阳性对照SNAC。
测试例2
测定本发明化合物对索马鲁肽在模拟胃液和模拟肠液中的降解保护作用。
按照中国药典分别配制模拟胃液和模拟肠液，空白对照组中加入2ml不含化合物的索马鲁肽水溶液(35μM)，实验组加入2ml SNAC(35mM)或本发明化合物(35mM)与索马鲁肽(35μM)混合水溶液，所有测试组再与3ml胃蛋白酶(35μM)溶液或胰蛋白酶(35μM)溶液混合，涡旋30s后，置于37℃恒温振荡器中孵育。分别在0.5h，1h，2h，4h从上述体系中取出100μl，并立即添加100μl终止液(0.1vol.％三氟乙酸:乙腈＝69:31，v/v)。进行LC-MS/MS分析前，在取出的样品中分别加入蛋白沉淀剂(乙腈:甲醇＝3:1，v/v)300μl，涡旋1min，14000rpm/min离心10min，取400μl上清液，再以14000rpm/min离心10min，进样分析，结果见表2、表3。
表2：SNAC或化合物I-1～I-33对胃蛋白酶降解索马鲁肽的保护作用
结果以均值±标准差表示，n＝3。*P<0.05,**P<0.01,***P<0.001，和空白对照组相比较。
表3：SNAC或化合物I-1～I-33对胰蛋白酶降解索马鲁肽的保护作用
结果以均值±标准差表示，n＝3。*P<0.05,**P<0.01,***P<0.001，和空白对照组相比较。
由表2、表3可知，本发明化合物均可以增加蛋白酶存在时索马鲁肽的稳定性，其中以化合物I-1,I-2,I-4,I-5,I-8,I-10,I-14效果显著，且优于阳性对照SNAC，实现了对胃肠道蛋白酶降解索马鲁肽的保护作用。
测试例3
以化合物I-1,I-2,I-4,I-5,I-8,I-10,I-14为例，测定含化合物和索马鲁肽的口服药代动力学性质。
离子液体对口服索马鲁肽的药代动力学性质研究：10周龄SPF级SD大鼠，体重180～220g，雄性，按体重随机分组：尾静脉注射组(索马鲁肽：0.1mg/kg)，受试化合物灌胃组(受试化合物：300mg/kg+索马鲁肽：3mg/kg，溶于生理盐水)，阳性对照灌胃组(SNAC：300mg/kg+索马鲁肽：3mg/kg，溶于生理盐水)，每组4只，实验前大鼠禁食不禁水12h，各组分别给药，给药后，在0.5h,1h,1.5h,2h,3h,4h,6h,8h,24h通过眼底静脉丛取血，离心后取上清液，使用LC-MS/MS测定血液中索马鲁肽的浓度。使用PKsolver软件绘制相应的药时曲线，并计算药代动力学参数，结果见表4。
表4：索马鲁肽与化合物SNAC或I-1,I-2,I-4,I-5,I-8,I-10,I-14共给药对SD大鼠的口服药代动力学参数的影响
结果以均值±标准差表示，n＝4。*P<0.05,**P<0.01,***P<0.001，和[SNAC+索马鲁肽(op)]组相比较。
正常大鼠口服药代动力学试验表明：在化合物同时给药时，索马鲁肽的口服生物利用度均显著提升，且优于阳性对照SNAC。

Claims (10)

1.一类结构如通式I所示的化合物：
其中，X+选自如式所示的含1～2个N的五元或六元杂环的有机碱阳离子；
B选自N、P；
R1、R2、R3和R4各自独立的选自C1～C4烷基、苄基、且中与碳相连的至少一个氢被羟基取代；p选自0～3的整数，q选自1～3的整数；
R5、R6各自独立的选自H、C1～C4烷基、苄基、且中与碳相连的至少一个氢被羟基取代；p选自0～3的整数，q选自1～3的整数；
R7、R8、R9和R10各自独立的选自选自H、C1～C4烷基；
Y,Z分别独立的选自H、卤素、羟基、羧基、氰基、C1-20烷基、C1-20烷氧基、C1-20环烷基，Y,Z可分别位于苯环现有取代基的邻位、间位或对位；
m选自0～10的整数。
2.根据权利要求1所述的化合物，其特征在于：X+选自2-羟基-N,N,N-三甲基乙铵根离子、四甲基铵根离子、四乙基铵根离子、四丙基铵根离子、四丁基铵根离子、苄基三甲基铵根离子、苄基三乙基铵根离子、四甲基膦离子、四乙基膦离子、四丁基膦离子、苄基三甲基膦离子、N,N,N,N-四甲基胍离子、1-羧基-N,N,N-三甲基甲铵根离子、3-羧基-2-羟基-N,N,N-三甲基丙铵根离子、吡咯鎓离子、咪唑鎓离子、吗啉鎓离子、硫代吗啉鎓离子、吡啶鎓离子、吡唑鎓离子、哌啶鎓离子、哌嗪鎓离子、N-甲基哌嗪鎓离子；
Y,Z分别独立的选自H、卤素、羟基、羧基、氰基、C1-20烷基、C1-20烷氧基或C1-20环烷基，Y,Z可分别位于苯环现有取代基的邻位，间位或对位；
m选自0～5之间的整数。
3.根据权利要求2所述的化合物，其特征在于：X+选自2-羟基-N,N,N-三甲基乙铵根离子、四甲基铵根离子、四乙基铵根离子、四丙基铵根离子、四丁基铵根离子、苄基三甲基铵根离子、苄基三乙基铵根离子、N,N,N,N-四甲基胍离子、1-羧基-N,N,N-三甲基铵根离子、3-羧基-2-羟基-N,N,N-三甲基丙铵根离子、吡咯鎓离子、咪唑鎓离子、吗啉鎓离子、硫代吗啉鎓离子、吡啶鎓离子、吡唑鎓离子、哌啶鎓离子、哌嗪鎓离子、N-甲基哌嗪鎓离子；
Y,Z分别独立的选自H、Cl、羟基、羧基、氰基、甲氧基，Y,Z可分别位于苯环现有取代基的邻位，间位或对位；
m选自0或1。
4.一类化合物，其特征在于：所述的化合物选自：
2-羟基-N,N,N-三甲基乙铵8-(2-羟基苯甲酰胺基)辛酸盐；
四乙铵8-(2-羟基苯甲酰胺基)辛酸盐；
四丁铵8-(2-羟基苯甲酰胺基)辛酸盐；
N,N,N-三甲基苄基铵8-(2-羟基苯甲酰胺基)辛酸盐；
四甲基胍8-(2-羟基苯甲酰胺基)辛酸盐；
1-羧基-N,N,N-三甲基甲铵8-(2-羟基苯甲酰胺基)辛酸盐；
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(2-羟基苯甲酰胺基)辛酸盐；
1H-吡咯8-(2-羟基苯甲酰胺基)辛酸盐；
3H-咪唑8-(2-羟基苯甲酰胺基)辛酸盐；
吗啉8-(2-羟基苯甲酰胺基)辛酸盐；
硫吗啉8-(2-羟基苯甲酰胺基)辛酸盐；
N-甲基哌嗪8-(2-羟基苯甲酰胺基)辛酸盐；
2-羟基-N,N,N-三甲基乙铵8-(4-羟基苯甲酰胺基)辛酸盐；
硫吗啉8-(4-羟基苯甲酰胺基)辛酸盐；
2-羟基-N,N,N-三甲基乙铵8-(3-羟基苯甲酰胺基)辛酸盐；
四乙铵8-(3-羟基苯甲酰胺基)辛酸盐，结构式为；
2-羟基-N,N,N-三甲基乙铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
四乙胺8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
N,N,N-三甲基苄基铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
四丁胺8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
1H-吡咯8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
四甲基胍8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
吗啉8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
硫吗啉8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
N-甲基哌嗪8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
3H-咪唑8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
1-羧基-N,N,N-三甲基甲铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(5-氯-2-羟基苯甲酰胺基)辛酸盐；
2-羟基-N,N,N-三甲基乙铵8-(4-氯苯甲酰胺基)辛酸盐；
3H-咪唑8-(4-氯-2-羟基苯甲酰胺基)辛酸盐；
3-羧基-2-羟基-N,N,N-三甲基丙铵8-(4-氯-2-羟基苯甲酰胺基)辛酸盐；
2-羟基-N,N,N-三甲基乙铵[8-(2-羟基苯甲酰胺基)辛酸]2盐；
2-羟基-N,N,N-三甲基乙铵8-(5-羧基-2-羟基苯甲酰胺基)辛酸盐。
5.一种权利要求1所述的化合物的制备方法，其特征在于：合成路线为：
其中，W-选自碳酸氢根离子、氢氧根离子。
6.根据权利要求5所述的化合物的制备方法，其特征在于：包括：以结构如所示的8-(Y基/Z基苯甲酰胺基)辛酸为起始原料，以丙酮为反应溶剂，8-(Y基/Z基苯甲酰胺基)辛酸和X+W-在45～60℃反应获得式I所示的目标化合物；其中，8-(Y基/Z基苯甲酰胺基)辛酸和X+W-的摩尔比为1:1～11:1。
7.权利要求1-4任一项所述的化合物作为增加蛋白和/或多肽类药物口服递送的口服吸收促进剂中的应用。
8.一种药物组合物，其特征在于：含有权利要求1-4任一项所述的化合物、治疗有效量的蛋白和/或多肽类药物及药学上的载体或赋形剂，制成药学上可接受的剂型；其中，化合物与蛋白和/或多肽类药物的质量比为1:1～1000:1。
9.根据权利要求8所示的药物组合物，其特征在于：所述的蛋白和/或多肽类药物为胰岛素及其类似物、胰高血糖素、胰高血糖素样肽-1及其类似物、降钙素、重组人甲状旁腺素、促红细胞生成素、人粒细胞集落刺激因子、人生长激素、白细胞介素、环孢菌素、表皮生长因子、干扰素、多肽疫苗、蛋白疫苗。
10.根据权利要求8所示的药物组合物，其特征在于：所述的剂型是药剂学上可接受的片剂、胶囊、酏剂、糖浆、锭剂、吸入剂、喷雾剂、注射剂、膜剂、贴剂、散剂、颗粒剂、块剂、乳剂或栓剂。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050272638A1 (en) * 1998-08-07 2005-12-08 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
CN111517980A (zh) * 2020-05-14 2020-08-11 台州浦凯医药科技有限公司 N-[8-(2-羟基苯甲酰基)氨基]辛酸一钾晶型化合物、制备方法及用途
CN111918644A (zh) * 2017-11-17 2020-11-10 哈佛大学校长及研究员协会 用于内部递送的离子液体
CN113171446A (zh) * 2021-05-06 2021-07-27 合肥天汇孵化科技有限公司 利拉鲁肽组合物及其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050272638A1 (en) * 1998-08-07 2005-12-08 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
CN111918644A (zh) * 2017-11-17 2020-11-10 哈佛大学校长及研究员协会 用于内部递送的离子液体
CN111517980A (zh) * 2020-05-14 2020-08-11 台州浦凯医药科技有限公司 N-[8-(2-羟基苯甲酰基)氨基]辛酸一钾晶型化合物、制备方法及用途
CN113171446A (zh) * 2021-05-06 2021-07-27 合肥天汇孵化科技有限公司 利拉鲁肽组合物及其用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHRISTIAN AGATEMOR等: "Choline-Geranate Deep Eutectic Solvent Improves Stability and Half-Life of Glucagon-Like Peptide-1", 《ADV. THERAP.》, vol. 4, no. 3, 31 March 2021 (2021-03-31), pages 2000180, XP009540368, DOI: 10.1002/adtp.202000180 *
NAMDEO R. JADHAV等: "Ionic liquids: Formulation avenues, drug delivery and therapeutic updates", 《JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY》, vol. 65, 2 July 2021 (2021-07-02), pages 102694 *
POOJA PATIDAR等: "Synthesis, self-assembly and micellization characteristics of choline alkanoate ionic liquids in association with a star block copolymer", 《COLLOIDS AND SURFACES A》, vol. 555, 3 August 2018 (2018-08-03), pages 691, XP085458717, DOI: 10.1016/j.colsurfa.2018.08.002 *
朱春柳等: "新型口服给药技术的研发进展", 《中国医药工业杂志》, vol. 52, no. 4, 31 December 2021 (2021-12-31), pages 429 - 439 *

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