CN110776481A - 一类双阳离子化合物及其制备方法和用途 - Google Patents

一类双阳离子化合物及其制备方法和用途 Download PDF

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CN110776481A
CN110776481A CN201910595295.4A CN201910595295A CN110776481A CN 110776481 A CN110776481 A CN 110776481A CN 201910595295 A CN201910595295 A CN 201910595295A CN 110776481 A CN110776481 A CN 110776481A
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刘进
杨俊�
张文胜
柯博文
张伟义
周诚
唐磊
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West China Hospital of Sichuan University
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Abstract

本发明公开了一类双阳离子化合物及其制备方法和用途，具体公开了式(Ⅰ)所示双阳离子化合物。具有式(Ⅰ)结构的立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂化物或共晶及其组合物，以及它们与药学上可接受载体形成的组合物可产生神经肌肉接头阻滞作用，在制备肌肉松弛药物领域的应用。

Description

一类双阳离子化合物及其制备方法和用途
技术领域
本发明属于药物合成领域，具体涉及一类双阳离子化合物及其制备方法和用途。
背景技术
在外科手术麻醉期间，神经肌肉阻滞剂(又称肌松药物)可产生肌肉松弛作用，用于在外科手术和气管插管期间使骨骼肌松弛。上述肌松药物根据其作用机制分为去极化和非去极化型两类，根据其作用持续时间可分为超短效、短效、中效和长效四类(Anesthesiology,82(1),33a,1995)。
去极化肌松药物中仍在临床使用的仅有琥珀胆碱，由于作用机制特殊，琥珀胆碱具有严重的副作用，如血钾升高、恶性高热、心率失常、眼内压增加和胃紧张等。琥珀胆碱的优点是作用时间短，例如人体上是持续时间为10分钟且起效迅速，在临床上作为超短效肌松药物使用，这种特点特别适合急诊，因为在急症情况下如果使用了作用时间较长的肌松药物，可能会导致严重的脑损伤甚至死亡。目前，去极化肌松药物琥珀胆碱是用于急诊的最适合的肌松药物。
除了不能具有超短效作用，非去极化肌松药物被认为是更加安全的肌松药物。临床医生一直在寻求具有超短效作用的非去极化肌松药物(Anesthesia and Analgsia,61(9),721,1982；Cueernt opinion in anaethesiology,8,362,1995)。然而，目前临床使用的所有非去极化肌松药物均不具备超短效特点(指单次给药肌松持续时间<10分钟)。如米库氯铵单次使用为肌松持续时间是15～20分钟，顺阿曲库铵和罗库溴铵单次使用作用时间为25～60分钟，泮库溴铵单次使用作用时间超过60分钟。CN101588803A中披露了一种非去极化肌松药物，可以给予其剂量200倍的半胱氨酸快速逆转其肌松作用，虽然做到了肌松的快速消退，但必须借助大量巯基氨基酸(如半胱氨酸)来实现，这显然会增加医疗操作，大量的巯基氨基酸也会增加安全性方面的不确定，如过量的半胱氨酸引起气管痉挛，呕吐等。因此，不需要逆转剂的超短效非去极化肌松药物更加符合临床需求，能够为病人减轻经济负担，增加患者安全性，同时减少医疗人员的操作，节省医疗资源。
发明内容
本发明的目的在于提供一种非去极化肌松药物及其制备方法和用途。
本发明首先提供了式(Ⅰ)所示双阳离子化合物：
Figure BDA0002117468530000021
其中，n＝1、2、3；a＝0、1、2；
Y为O、取代或未取代的亚甲基，所述取代的基团为卤素、C1～C6的烷基；
L1、L2分别独立地选自取代或未取代的C1～C8的亚烷基，其中，所述取代是指亚烷基中的C被O或S取代和/或H被烷基或卤素取代；
R1、R2、R3、R4分别独立地选自卤素，C1～C20的取代或无取代、饱和或不饱和的烃基，所述取代的基团选自单个或多个卤素、烷氧基、硝基、氰基、羟基、C1～C6的烷基、三氟甲基、C3～C6的杂环基、酯基、烷氧羰基，R1、R2、R3、R4的骨架中含有或不含有杂原子；
R5选自H、C1～C6的烷基、C3～C6的环烷基；
M为药学上可接受的阴离子。
进一步地，Y为O、CH2、CHCH3、CF2；所述杂原子为S或O。进一步地，L1、L2分别独立地选自取代或未取代的C1～C6的亚烷基，其中，所述取代是指亚烷基中的C被O或S取代和/或H被C1～C3的烷基取代。
进一步地，R1、R2、R3、R4分别独立地选自卤素、取代或未取代的C1～C3的烷基、C2～C3的烯基、
Figure BDA0002117468530000022
其中，R6选自一个或多个H、硝基、卤素、甲氧基、羟基、氰基、C1～C3的烷基、苯基、三氟甲基。
进一步地，n＝1、2；a＝0、1。
进一步地，M为溴离子、氯离子、R-SO3 -，所述R为烃基；优选地，所述R-SO3 -选自对甲基苯磺酸根离子、甲磺酸根离子、苯磺酸根离子。
进一步地，所述卤素为F、Cl、Br、I。
进一步地，当a＝1时，所述化合物为如下化合物之一：
Figure BDA0002117468530000031
Figure BDA0002117468530000051
进一步地，当a＝0时，所述化合物为如下化合物之一：
Figure BDA0002117468530000052
本发明还提供了上述双阳离子化合物的制备方法，其特征在于：它包括以下步骤：
Figure BDA0002117468530000053
(1)季胺中间体1的制备：
(1-i)化合物a-1与化合物a-2反应，制得化合物a-3；
(1-ii)化合物a-3与化合物R1-Br反应，制得化合物a-4；
(1-iii)化合物a-4与氢氧化钠反应，制得季胺中间体1；
(2)季胺中间体2的制备：
(2-i)化合物b-1与R4-Br反应，制得化合物b-2；
(2-ii)化合物b-2与偶联分子反应，制得季胺中间体2；
(3)季胺中间体1与季胺中间体2反应，制得双阳离子化合物；
其中，化合物a-1为
Figure BDA0002117468530000054
化合物a-2为
Figure BDA0002117468530000055
化合物a-3为
Figure BDA0002117468530000061
化合物a-4为
Figure BDA0002117468530000062
季胺中间体1为化合物b-1为
Figure BDA0002117468530000064
化合物b-2为偶联分子为
Figure BDA0002117468530000066
季胺中间体2为
Figure BDA0002117468530000067
双阳离子化合物为
Figure BDA0002117468530000068
N、Y、L1、L2、R1、R2、R3、R4、R5
如上所述。
本发明还提供了上述双阳离子化合物、或其立体异构体或立体异构体混合物、或其药学上可接受的盐、或其溶剂化物、或其晶体在制备肌肉松弛药物中的用途。
本发明还提供了一种肌肉松弛药物，它是以上述双阳离子化合物、或其立体异构体或立体异构体混合物、或其药学上可接受的盐、或其溶剂化物、或其晶体为活性成分，再加上药学上可接受的辅料制备而成的制剂。
本发明的化合物，单次用药起效快，并提供2～10分钟彻底的肌肉松弛作用，这些化合物只需依赖机体本身的代谢就可以实现超短效非去极化肌松作用，在发挥超短效的肌松作用后快速自行消退。实验证明，相比于阳性对照药物顺阿曲库铵和琥珀胆碱，本发明化合物具备更加显著的快速起效和快速恢复特点，属于典型的非去极化肌肉松弛剂。
鉴于上述特点，具有式(Ⅰ)结构的化合物，其立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂化物或共晶及其组合物，以及它们与药学上可接受载体形成的组合物，可在制备肌肉松弛药物领域中应用，提供符合临床需求的快速和超短效非去极化肌松作用。关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(Ca～Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，(C1～C6)烷基是指包含1～6个碳原子的烷基。
所述C1～C6烷基是指C1、C2、C3、C4、C5、C6的烷基，即具有1～6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。
本发明所述中，R6选自一个或多个H、硝基、卤素、甲氧基、羟基、氰基、C1～C3的烷基、苯基、三氟甲基，是指在
Figure BDA0002117468530000072
中，有一个或多个取代基(R6)，且当有多个时，多个R6各自独立地选自H、硝基、卤素、甲氧基、羟基、氰基、C1～C3的烷基、苯基、三氟甲基。
所述环烷基是指环状烷基，例如环丙基、环丁基、环戊基、环己基等等。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
实施例1、化合物1的制备
Figure BDA0002117468530000081
将1.53克2-溴乙酸甲酯溶于30毫升乙腈，加入0.85克哌啶和1.38克无水碳酸钾，50℃搅拌10小时，随后加入2.16克对硝基苄溴，55℃搅拌6小时，过滤，减压蒸干溶剂，向剩余物中加入2N氢氧化钠水溶液40毫升，室温搅拌2小时，用氢溴酸水溶液调节pH值至9，减压蒸干溶剂，向残余物中加入50毫升二氯甲烷，加热至微沸，趁热过滤，滤液蒸干得亮黄色中间体(1-1)粗品1.71克。
将1.93克4-羟丁基-甲基-苄胺溶于30毫升乙腈，加入2.16克对硝基苄溴于55℃搅拌8小时，减压蒸干溶剂，析出黄色固体，将该固体溶解在50毫升二氯甲烷中，加入1.6克吡啶，冷却至5℃，滴加氯甲酸氯甲酯1.3克，滴毕后室温搅拌3小时。减压蒸干溶剂，残余物经柱层析得中间体(1-2)1.32克。
将1.32克中间体1-2与1.0克中间体1-1溶解在50毫升乙腈中，40℃搅拌12小时，减压蒸干溶剂，残余物经反相制备色谱分离，得白色粉末0.53克，即化合物1，产率23.5％。
1HNMR(DMSO-d6,400MHz)δ:1.52～1.56(2H，m),1.61～1.84(8H,m)，3.01(3H，s),3.13～3.24(4H,m),3.41～3.43(2H,m),3.65～3.74(2H,m),4.51(1H,d,J＝12.8Hz),4.67-4.77(5H,m),4.85(1H,d,J＝12.8Hz),4.96(1H,d,J＝12.8Hz),5.74(2H,s),7.52～7.55(3H,m),7.62～7.64(2H,m),7.75～7.77(2H,m),7.96～7.98(2H，m),8.28～8.36(4H,m).
实施例2、化合物2的合成
季铵盐中间体1-1和2-2的制备参照实施例1。将1.91克中间体1-1和2.36克中间体2-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末1.03克，即化合物2，产率25.9％。
1HNMR(DMSO-d6,400MHz)δ:1.58～1.59(2H,m),1.92(4H,s,broad),3.06(3H,s),3.51～3.53(3H,m),3.71～3.76(3H,m),4.52～4.55(3H,m),4.75～4.77(3H,m),4.90～5.08(4H,m),5.86(2H,s),7.51～7.55(3H,m),7.61～7.62(2H,m),7.75～7.77(2H,m),7.95～7.96(2H,m),8.29～8.36(4H,m).
实施例3、化合物3的合成
Figure BDA0002117468530000092
季铵盐中间体3-1和3-2的制备参照实施例1。将2.05克中间体3-1和2.95克中间体3-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末1.1克，即化合物3，产率25.7％。
1HNMR(DMSO-d6,400MHz)δ:1.43(1H,s,broad),1.60～1.64(1H,m),1.83(4H,s,broad),2.08(2H,s,broad),2.57～2.61(2H,m),3.04(3H,s),3.23～3.28(3H,m),3.41～3.44(3H,m),3.67(2H,s),4.54～4.57(1H,m),4.68～4.78(5H,m),4.91～5.03(2H,m),5.78(2H,s),7.36～7.40(2H,m),7.67～7.71(2H,m),7.85～7.95(4H,m),8.32～8.38(4H,m).
实施例4、化合物4的合成
Figure BDA0002117468530000093
季铵盐中间体3-1和4-2的制备参照实施例1。将2.05克中间体3-1和2.51克中间体4-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末1.19克，即化合物4，产率27.2％。
1HNMR(DMSO-d6,400MHz)δ:1.42(1H,s,broad),1.60(1H,s,broad),1.83～1.88(4H,m),2.08～2.09(2H,m),2.57～2.60(2H,m),3.05(3H,s),3.24～3.33(4H,m),3.41～3.44(2H,m),2.68(2H,s，broad),4.57(1H,d,J＝12Hz),4.69～4.78(5H,m),4.93(1H,d,J＝12Hz),5.03(1H,d,J＝12Hz),5.77(2H,s),7.58～7.67(4H,m),7.84～7.95(4H,m),8.31～8.36(4H,m).
实施例5、化合物5的合成
Figure BDA0002117468530000101
季铵盐中间体3-1和5-2的制备参照实施例1。将2.05克中间体3-1和2.71克中间体5-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末1.02克，即化合物5，产率20.6％。
1HNMR(DMSO-d6,400MHz)δ:1.41(1H,s,broad),1.60(1H,s,broad),1.83(4H,s,broad),2.07(2H,s,broad),2.55～2.65(2H,m),3.05(3H,s),3.22～3.26(4H,m),3.39～3.42(2H,m),3.72～3.81(2H,m),4.59～4.62(1H,m),4.67～4.78(5H,m),4.91～4.99(2H,m),5.77(2H,s),7.64～7.65(1H,m),7.82～7.96(6H,m),8.33～8.38(4H,m).
实施例6、化合物6的合成
Figure BDA0002117468530000102
季铵盐中间体3-1和6-2的制备参照实施例1。将2.05克中间体3-1和2.54克中间体6-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末0.75克，即化合物6，产率17.4％。
1HNMR(DMSO-d6,400MHz)δ:1.44(1H,s,broad),1.60(1H,s,broad),1.84(4H,s,broad),2.05(2H,s,broad),2.56～2.59(2H,m),3.05(3H,s),3.22～3.28(3H,m),3.41～3.45(3H,m),3.70～3.73(1H,m),3.85～3.88(1H,m),4.54～4.58(1H,m),4.77(4H,s,broad),4.90～5.00(3H,m),5.78(2H,s),7.31～7.36(2H,m),7.72～7.76(1H,m),7.84～7.86(2H,m),7.99～8.01(2H,m),8.32～8.38(4H,m).
实施例7、化合物7的合成
Figure BDA0002117468530000111
季铵盐中间体3-1和7-2的制备参照实施例1。将2.05克中间体3-1和2.59克中间体7-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末1.13克，即化合物7，产率26.0％。
1HNMR(DMSO-d6,400MHz)δ:1.43(1H,s,broad),1.60(1H,s,broad),1.84(4H,s,broad),2.08(2H,s,broad),2.57～2.60(2H,m),3.10(3H,s),3.25～3.29(2H,m),3.42～3.44(4H,m),3.73(2H,s,broad),4.72～4.77(6H,m),5.08(2H,s,broad),5.78(2H,s),7.85～7.87(2H,m),7.94～7.95(4H,m),8.32～8.38(6H,m).
实施例8、化合物8的合成
Figure BDA0002117468530000112
季铵盐中间体2-1和13-2的制备参照实施例1。将2.05克中间体3-1和2.5克中间体8-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末0.69克，即化合物8，产率16.2％。
1HNMR(DMSO-d6,400MHz)δ:1.43(1H,s,broad),1.60～1.63(1H,m),1.83(4H,s,broad),2.08～2.09(2H,m),2.53～2.59(2H,m),3.08(3H,s),3.25～3.28(4H,m),3.41～3.44(2H,m),3.70(2H,s,broad),4.65～4.78(6H,m),5.03～5.10(2H,m),5.78(2H,s),7.85～7.86(4H,m),7.93～7.95(2H,m),8.02～8.04(2H,m),8.32～8.37(4H,m).
实施例9、化合物9的合成
Figure BDA0002117468530000113
季铵盐中间体3-1和9-2的制备参照实施例1。将2.05克中间体3-1和2.7克中间体9-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末0.73克，即化合物9，产率16.4％。
1HNMR(DMSO-d6,400MHz)δ:1.43(1H,s,broad),1.60～1.63(1H,m),1.83(4H,s,broad),2.08～2.09(2H,m),2.57～2.61(2H,m),3.09(3H,s),3.24～3.44(6H,m),3.71～3.75(2H,m),4.65～4.78(6H,m),4.94～5.09(2H,m),5.78(2H,s),7.85～7.96(8H,m),8.33～8.39(4H,m).
实施例10、化合物10的合成
季铵盐中间体10-1和2-2的制备参照实施例1。将2.16克中间体10-1和2.37克中间体2-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末0.88克，即化合物10，产率20.8％。
1HNMR(DMSO-d6,400MHz)δ:1.44(1H,s,broad),1.61(1H,s,broad),1.84(4H,s,broad),2.1(2H,m),2.58～2.59(2H,m),3.06(3H,s),3.26～3.29(3H,m),3.41～3.44(3H,m),3.69(2H,s,broad),4.55～4.58(1H,m),4.74(5H,s,broad),4.94～5.08(2H,m),5.78(2H,s),7.53～7.63(5H,m),7.80～7.99(6H,m),8.36～8.38(2H,m).
实施例11、化合物11的合成
Figure BDA0002117468530000122
季铵盐中间体3-1和11-2的制备参照实施例1。将2.05克中间体3-1和2.75克中间体11-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末1.16克，即化合物11，产率25.1％。
1HNMR(DMSO-d6,400MHz)δ:1.43(1H,s,broad),1.60(1H,s,broad),1.84(4H,s,broad),2.33～2.34(2H,m),2.51～2.53(2H,m),3.07(3H,s),3.19～3.28(4H,m),3.39～3.42(2H,m),3.69(2H,s,broad),4.55～4.58(1H,m),4.71～4.76(5H,m),4.86～4.89(1H,m),4.96～4.99(1H,m),5.79(2H,s),7.41～7.45(1H,m),7.49～7.53(2H,m),7.69～7.75(4H,m),7.83～7.86(4H,m),7.94～7.96(2H,m),8.33～8.40(4H,m).
实施例12、化合物12的合成
Figure BDA0002117468530000131
季铵盐中间体12-1和12-2的制备参照实施例1。将2.12克中间体12-1和2.74克中间体12-2溶于50毫升乙腈，40℃搅拌10小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末1.04克，即化合物12，产率22.7％。
1HNMR(DMSO-d6,400MHz)δ:1.45-1.30(m,1H),1.70-1.55(m,1H),1.90-1.75(m,4H),2.07-1.95(m,2H),2.65-2.55(m,2H),3.01(s,3H),3.41-3.31(m,2H),3.63(d,J＝13.2Hz,2H),3.79(s,18H),3.92(s,3H),4.63-4.43(m,4H),4.88-4.67(m,4H),5.76(s,2H),7.06(d,J＝6.4Hz,4H),7.27(s,2H),7.18(s,3H).
实施例13、化合物13的合成
Figure BDA0002117468530000132
季铵盐中间体13-1和13-2的制备参照实施例1。将1.82克中间体13-1和2.56克中间体13-2溶于50毫升乙腈，40℃搅拌12小时，减压蒸干溶剂，残余物经制备色谱分离，得到白色粉末克1.07克，即化合物13，产率26.1％。
1HNMR(DMSO-d6,400MHz)δ:1.69-1.50(m,4H),2.03-1.86(m,6H),2.26(d,J＝4.4Hz,18H),2.88-2.78(m,3H),3.15-3.01(m,2H),3.58-3.46(m,2H),3.71(d,J＝12.4Hz,2H),4.24(t,J＝6.4Hz,2H),4.47-4.34(m,4H),4.60-4.51(m,2H),5.87(s,2H),4.72(s,2H),7.20-7.13(m,2H),7.27(td,J＝8.0,15.2Hz,5H),7.34(s,2H).
实施例14、化合物14的合成
参考实施例1，将季铵中间体1-1和1-2中分别使用到的2-溴乙酸甲酯和对硝基苄溴更换为2-氯乙酸甲酯和对硝基苄氯，将可以保证最后制备得到的目标化合物(Ⅰ)的阴离子为氯离子。即化合物14。
实施例15、化合物15的合成
将100mg化合物14溶解在300mL水中，搅拌下滴入含40mg对甲苯磺酸银盐的水溶液，过滤去除沉淀，滤液冻干后得阴离子为对甲苯磺酸根的目标化合物(Ⅰ)109mg，即化合物15。
实施例16、其余部分化合物的合成
本专利披露的其余具体化合物，其合成方法可以参考实施例1所述的制备方法，分别合成得到季铵中间体1和季铵中间体2，将等摩尔的两种中间体在DMF或乙腈等非质子型极性溶剂中，与室温～80℃范围内加热搅拌6～24小时，经分离纯化而获得。这些优选的化合物结构和质谱数据见表1。
表1部分优选具体化合物的结构和质谱数据
Figure BDA0002117468530000141
Figure BDA0002117468530000151
Figure BDA0002117468530000161
Figure BDA0002117468530000171
Figure BDA0002117468530000181
以下通过试验例来说明本发明的有益效果。
试验例1、肌肉松弛实验
以体重2～3.5公斤的雄性新西兰大白兔为实验动物，进行肌肉松弛实验。具体为：使用丙泊酚乳剂经静脉诱导并维持动物全身麻醉(诱导剂量：10mg/kg，维持剂量：105mg/hr/kg)。实施气管插管并给予呼吸支持。静脉注射2倍ED95等效剂量的阳性对照药物和本发明所述各化合物，使用肌松检测仪(TOF)观察药物的起效(TOF＝0)时间和肌松作用的恢复(TOF＝90％)时间。结果见表1。
表1药物对兔的肌松作用起效和持续时间(N＝8)
Figure BDA0002117468530000182
Figure BDA0002117468530000191
上述结果显示，本发明所述的化合物能够在动物体内快速产生肌肉松弛作用(<40秒)，且肌肉松弛的维持时间明显短于阳性对照药物顺阿曲库铵，甚至短于阳性对照药物琥珀胆碱，上述特点说明本发明所述化合物具备显著的快速起效和快速恢复特点。此外，受试动物在给予琥珀胆碱后其TOF 1～4为同步等比例降低，直至消失，显示出典型的去极化型肌松药物特点；而受试动物在给予本发明所述的化合物和顺阿曲库铵后，受试动物的TOF 1～4是依次逐步减小，而非等比例减小，这种TOF的变化特点说明本发明所述化合物属于典型的非去极化肌肉松弛剂。
综上，本发明提供了式(Ⅰ)所示双阳离子化合物、或其立体异构体或立体异构体混合物、或其药学上可接受的盐、或其溶剂化物、或其晶体及其制备方法。实验证明，相比于阳性对照药物顺阿曲库铵和琥珀胆碱，本发明化合物具备更加显著的快速起效和快速恢复特点，属于典型的非去极化肌肉松弛剂，具有很好的应用前景。

Claims (12)

1.式(Ⅰ)所示双阳离子化合物：
Figure FDA0002117468520000011
其中，n＝1、2、3；a＝0、1、2；
Y为O、取代或未取代的亚甲基，所述取代的基团为卤素、C1～C6的烷基；
L1、L2分别独立地选自取代或未取代的C1～C8的亚烷基，其中，所述取代是指亚烷基中的C被O或S取代和/或H被烷基或卤素取代；
R1、R2、R3、R4分别独立地选自卤素，C1～C20的取代或无取代、饱和或不饱和的烃基，所述取代的基团选自单个或多个卤素、烷氧基、硝基、氰基、羟基、C1～C6的烷基、三氟甲基、C3～C6的杂环基、酯基、烷氧羰基，R1、R2、R3、R4的骨架中含有或不含有杂原子；
R5选自H、C1～C6的烷基、C3～C6的环烷基；
M为药学上可接受的阴离子。
2.根据权利要求1所述的双阳离子化合物，其特征在于：Y为O、CH2、CHCH3、CF2；所述杂原子为S或O。
3.根据权利要求1或2所述的双阳离子化合物，其特征在于：L1、L2分别独立地选自取代或未取代的C1～C6的亚烷基，其中，所述取代是指亚烷基中的C被O或S取代和/或H被C1～C3的烷基取代。
4.根据权利要求1～3任一项所述的双阳离子化合物，其特征在于：R1、R2、R3、R4分别独立地选自卤素取代或未取代的C1～C3的烷基、C2～C3的烯基、
Figure FDA0002117468520000012
Figure FDA0002117468520000013
其中，R6选自一个或多个H、硝基、卤素、甲氧基、羟基、氰基、C1～C3的烷基、苯基、三氟甲基。
5.根据权利要求1～4任一项所述的双阳离子化合物，其特征在于：n＝1、2；a＝0、1。
6.根据权利要求1～5任一项所述的双阳离子化合物，其特征在于：M为溴离子、氯离子、R-SO3 -，所述R为烃基；优选地，所述R-SO3 -选自对甲基苯磺酸根离子、甲磺酸根离子、苯磺酸根离子。
7.根据权利要求1～6任一项所述的双阳离子化合物，其特征在于：所述卤素为F、Cl、Br、I。
8.根据权利要求1～7任一项所述的双阳离子化合物，其特征在于：当a＝1时，所述化合物为如下化合物之一：
Figure FDA0002117468520000021
Figure FDA0002117468520000031
9.根据权利要求1～7任一项所述的双阳离子化合物，其特征在于：当a＝0时，所述化合物为如下化合物之一：
Figure FDA0002117468520000042
10.权利要求1～9任一项所述双阳离子化合物的制备方法，其特征在于：它包括以下步骤：
Figure FDA0002117468520000043
(1)季胺中间体1的制备：
(1-i)化合物a-1与化合物a-2反应，制得化合物a-3；
(1-ii)化合物a-3与化合物R1-Br反应，制得化合物a-4；
(1-iii)化合物a-4与氢氧化钠反应，制得季胺中间体1；
(2)季胺中间体2的制备：
(2-i)化合物b-1与R4-Br反应，制得化合物b-2；
(2-ii)化合物b-2与偶联分子反应，制得季胺中间体2；
(3)季胺中间体1与季胺中间体2反应，制得双阳离子化合物；
其中，化合物a-1为
Figure FDA0002117468520000051
化合物a-2为
Figure FDA0002117468520000052
化合物a-3为
Figure FDA0002117468520000053
化合物a-4为季胺中间体1为
Figure FDA0002117468520000055
化合物b-1为
Figure FDA0002117468520000056
化合物b-2为
Figure FDA0002117468520000057
偶联分子为季胺中间体2为
Figure FDA0002117468520000059
双阳离子化合物为
Figure FDA0002117468520000061
N、Y、L1、L2、R1、R2、R3、R4、R5
如权利要求1-9任一项所述。
11.权利要求1～9任一项所述双阳离子化合物、或其立体异构体或立体异构体混合物、或其药学上可接受的盐、或其溶剂化物、或其晶体，在制备肌肉松弛药物中的用途。
12.一种肌肉松弛药物，其特征在于：它是以权利要求1～9或11任一项所述双阳离子化合物、或其立体异构体或立体异构体混合物、或其药学上可接受的盐、或其溶剂化物、或其晶体为活性成分，再加上药学上可接受的辅料制备而成的制剂。
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