CN112876408B - 一类短效双季铵化合物及其制备方法和用途 - Google Patents
一类短效双季铵化合物及其制备方法和用途 Download PDFInfo
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- CN112876408B CN112876408B CN202011323173.9A CN202011323173A CN112876408B CN 112876408 B CN112876408 B CN 112876408B CN 202011323173 A CN202011323173 A CN 202011323173A CN 112876408 B CN112876408 B CN 112876408B
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- 206010021118 Hypotonia Diseases 0.000 claims abstract description 24
- 230000036640 muscle relaxation Effects 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 21
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 16
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
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- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 1
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- RZVWBASHHLFBJF-UHFFFAOYSA-N methyl piperidine-4-carboxylate Chemical compound COC(=O)C1CCNCC1 RZVWBASHHLFBJF-UHFFFAOYSA-N 0.000 description 1
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- NPIJXCQZLFKBMV-YTGGZNJNSA-L pancuronium bromide Chemical compound [Br-].[Br-].C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 NPIJXCQZLFKBMV-YTGGZNJNSA-L 0.000 description 1
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- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- OYTJKRAYGYRUJK-FMCCZJBLSA-M rocuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 OYTJKRAYGYRUJK-FMCCZJBLSA-M 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一类短效双季铵化合物及其制备方法和用途，该双季铵化合物如式(I)所示。本发明化合物具备快速起效且超短效的非去极化肌松分子活性，在低给药剂量下，起效快，能产生完全的肌肉松弛作用，且肌力完全恢复所需时间短，明显短于阳性药顺阿曲库铵和去极化肌松药琥珀胆碱，有效克服了现有技术中非去极化肌松药存在的问题，可用于制备效果优良的非去极化肌松药物，具有良好的前景。
Description
技术领域
本发明属于化学药物合成领域，具体涉及一种双季铵盐化合物及其制备方法和用途。
背景技术
N2胆碱受体阻滞药又称骨骼肌松弛药(简称肌松药，skeletal muscularrelaxants)，是一种重要麻醉手术药物。肌松药能选择性地作用于运动神经终板膜上的N2受体，阻断神经冲动向骨骼肌传递，导致骨骼肌松弛，主要用于外科手术过程中和气管插管时产生肌肉松弛作用。肌松药按其作用机制不同，主要可以分为去极化型(depolarizingmuscular relaxants)和非去极化型(nondepolarizing muscular relaxants)两大类。肌松药按其肌松作用时间长度，可分为超短效、短效、中效和长效肌松药。
去极化肌松药与运动神经终板膜上的N2受体结合，使肌细胞膜产生持久去极化作用，对ACh的反应减弱或消失，从而导致骨骼肌松弛。目前临床正在使用的去极化肌松药物有琥珀胆碱(succinylcholine，司可林，scoline)。使用琥珀胆碱后，由于不同部位的骨骼肌在药物作用下去极化出现的时间先后不同，首先出现不协调的肌束颤动，然后迅速转为肌松，以颈部、四肢和腹部肌松最明显，作用快而短暂。既可用于气管插管、气管镜、食管镜等短时的小手术，也可作全麻手术时的辅助用药，使在较浅麻醉下的骨骼肌完全松弛，减少全麻药的用量，以提高外科手术的安全性。由于琥珀胆碱作用时间短，人体持续时间为10分钟左右且起效迅速，因此在临床中常作为超短效肌松药物使用，尤其适合应用于急诊病人，从而避免了使用作用时间较长的肌松药物，在急症情况下导致的严重脑损伤甚至死亡。因此，目前去极化肌松药物琥珀胆碱是最适合用于急诊的肌松药物。但由于去极化肌松药特殊的作用机制，在使用时会产生严重的副作用，诸如血钾升高、恶心高热、心率失常、眼内压增加和胃紧张等，从而大大限制了其在临床的应用。
非去极化肌松药又称竞争型肌松药(competitive muscular relaxants)，能与ACh竞争骨骼肌运动终板膜上的N2胆碱受体，本身无内在活性，但可通过阻断ACh与N2胆碱受体结合，使终板膜不能去极化，导致骨骼肌松弛。抗胆碱酯酶药如新斯的明能拮抗其骨骼肌肌松作用，过量时可用适量新斯的明解救。吸入性全麻药如麻醉乙醚和氨基苷类抗生素如链霉素能增强和延长该类药物的作用。该类药物的代表药物为筒箭毒碱。非去极化肌松药没有去极化肌松药的众多副作用，因此被公认为是临床上更安全的肌松药，但其肌松作用时间过长同样也被认为是其一大弊端。目前已经上市的所有非去极化肌松药，单次给药后骨骼肌松弛持续时间均超过10分钟，都不具有满足临床恢复快的需求。例如：已上市的临床肌松药中，米库氯铵单次给药后的肌松持续时间约为15～20分钟，顺阿曲库铵和罗库溴铵单次使用后的肌松持续时间约为40～60分钟，而泮库溴铵单次使用后肌松持续时间甚至超过60分钟，无法实现肌肉松弛的快速恢复。因此，目前临床急需起效快、恢复快的非去极化肌松药。
发明内容
为了解决上述问题，本发明提供了一类短效双季铵化合物及其制备方法和用途。
本发明提供了式(I)所示的化合物，或其盐，或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物：
其中，
R1、R2、R3、R4分别独立选自取代或未取代的C1～C20饱和烃基、取代或未取代的C2～C20不饱和烃基；所述饱和烃基或不饱和烃基骨架中0～5个碳原子被杂原子取代，所述杂原子为O、S；所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基；所述芳基的取代基为C1～C10饱和烃基、C1～C10烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基；
L1为不存在、取代或未取代的C1～C5亚烃基；所述亚烃基骨架中0～5个碳原子被杂原子取代，所述杂原子为O、S；所述亚烃基的取代基为C1～C20烷基、卤素；
R5选自氢、C1～C6烷基、3～8元环烷基；
n、m、a、b分别为0～3的整数，且n+m大于等于3，a+b大于等于3；
k＝0或1；
L2为不存在、取代或未取代的C1～C5亚烃基；所述亚烃基骨架中0～5个碳原子被杂原子取代，所述杂原子为O、S；所述亚烃基的取代基为C1～C20烷基、卤素；
M为药学上可接受的阴离子。
进一步地，
R1、R2、R3、R4分别独立选自取代或未取代的C1～C10饱和烃基、取代或未取代的C2～C10不饱和烃基；所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基；所述芳基的取代基为C1～C6饱和烃基、C1～C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基；
L1为不存在、取代或未取代的C1～C5亚烃基；所述亚烃基的取代基为C1～C10烷基、卤素；
R5选自氢、C1～C6烷基、3～6元环烷基；
n、m、a、b分别为0～3的整数，且n+m大于等于3，a+b大于等于3；
k＝0或1；
L2为不存在、取代或未取代的C1～C5亚烃基；所述亚烃基的取代基为C1～C10烷基、卤素；
M为药学上可接受的阴离子。
进一步地，所述化合物为式(II)所示化合物：
其中，
R1、R2、R3、R4分别独立选自取代或未取代的C1～C10饱和烃基、取代或未取代的C2～C10不饱和烃基；所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基；所述芳基的取代基为C1～C6饱和烃基、C1～C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基；
L1为不存在、取代或未取代的C1～C5亚烃基；所述亚烃基的取代基为C1～C10烷基、卤素；
R5选自氢、C1～C6烷基、3～6元环烷基；
n、m、a、b分别为0～3的整数，且n+m大于等于3，a+b大于等于3；
L2为不存在、取代或未取代的C1～C5亚烃基；所述亚烃基的取代基为C1～C10烷基、卤素；
M为药学上可接受的阴离子。
进一步地，
R1、R2、R3、R4分别独立选自取代或未取代的C1～C3烷基、未取代的C2～C3烯基；所述烷基的取代基选自卤素、取代的芳基；所述芳基的取代基为C1～C3烷基、C1～C3烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基；
L1为不存在、未取代的C1～C2亚烷基；
R5选自氢、C1～C3烷基；
n、m、a、b分别为0～3的整数，且n+m等于3或4，a+b等于3或4；
L2为不存在、未取代的C1～C2亚烷基；
M为溴离子，氯离子，磺酸根离子。
进一步地，所述化合物为式(III)所示化合物：
其中，
R1、R2、R3、R4分别独立选自取代或未取代的C1～C10饱和烃基、取代或未取代的C2～C10不饱和烃基；所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基；所述芳基的取代基为C1～C6饱和烃基、C1～C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基；
L1为不存在、取代或未取代的C1～C5亚烃基；所述亚烃基的取代基为C1～C10烷基、卤素；
n、m、a、b分别为0～3的整数，且n+m大于等于3，a+b大于等于3；
L2为不存在、取代或未取代的C1～C5亚烃基；所述亚烃基的取代基为C1～C10烷基、卤素；
M为药学上可接受的阴离子。
进一步地，
R1、R2、R3、R4分别独立选自取代或未取代的C1～C3烷基；所述烷基的取代基选自卤素、取代的芳基；所述芳基的取代基为C1～C3烷基、C1～C3烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基；
L1为不存在、未取代的C1～C2亚烷基；
n、m、a、b分别为0～3的整数，且n+m等于3或4，a+b等于3或4；
L2为不存在、未取代的C1～C2亚烷基；
M为溴离子，氯离子，磺酸根离子。
进一步地，所述化合物为如下化合物之一：
本发明还提供了前述的化合物，或其盐，或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物在制备肌肉松弛药物中的用途。
进一步地，所述肌肉松弛药物为非去极化肌肉松弛药物。
本发明还提供了一种药物，它是由前述的化合物，或其盐，或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物为活性成分，加上药学上可接受的载体或其他活性成分制备而成的混合物或组合物。
上述化合物均由两个季铵盐结构片段经某些偶联片段连接而得，因此其制备方法的一般路线为先合成目标化合物一端的季铵盐片段分子，再合成另一端季铵结构片段分子，最后将两个片段偶联后得到目标物。本发明中所述的大部分化合物的合成路线如下所示：
本发明中所述的其余部分化合物因季铵片段和偶联片段不同而有所不同，具体合成情况见相关实施例。
式(Ⅰ)所述的化合物，单次用药具有起效快，并提供2～10分钟的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，在大剂量和持续用药后仍表现出肌松作用的快速消退，同时可使用新斯的明等传统非去极化肌松药物解救剂来加快药物作用的消退，适合急诊和各类手术使用。
鉴于上述特点，具有式(Ⅰ)结构的化合物，其立体异构体或异构体混合物，其药学上可接受的盐与溶剂化物，上述物质与药学上可接受的载体和赋形剂组成的混合物，可在制备肌肉松弛药物领域中的应用，提供符合临床需求的快速和超短效肌松作用，并在持续用药后依然保持肌松作用的快速消退。
综上，本发明化合物具备快速起效且超短效的非去极化肌松分子活性，在低给药剂量下，起效快，能产生完全的肌肉松弛作用，且肌力完全恢复所需时间短，明显短于阳性药顺阿曲库铵和去极化肌松药琥珀胆碱，有效克服了现有技术中非去极化肌松药存在的问题，可用于制备效果优良的非去极化肌松药物，具有良好的前景。
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
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1、本发明化合物1的制备
1、中间体1-1的制备
将1.01克4-羟基哌啶溶于30毫升乙腈，加入1.89克4-氟苄溴和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，得黄色固体3.6克，加入30毫升二氯甲烷，随后加入1.3克氯甲酸氯甲酯，冷水冷却下滴入1.6克吡啶，搅拌5小时。减压蒸干溶剂，残余物经柱层析得2.0克中间体1-1。
2、中间体1-2的制备
将1.43克4-哌啶甲酸甲酯和1.89克4-氟苄溴溶解在30毫升乙腈中，加入1.4克无水碳酸钾，于55℃搅拌8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1.78克亮黄色中间体1-2。
3、化合物1的制备
将0.52克中间体1-1与0.48克中间体1-2溶解在50毫升乙腈中，50℃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0.21克，即化合物1，产率22.5％。
1HNMR(DMSO-d6,400MHz)δ:2.07～2.28(m,2H),2.33～2.40(m,6H),2.67～2.73(m，1H)，2.09～3.15(m,2H),3.34(s,broad,6H),4.58～5.02(m,9H),5.63～5.65(m,2H),7.34～7.39(m,4H),7.65～7.68(m,4H),7.91～7.93(m,4H),8.32～8.40(m,4H).
实施例2、本发明化合物2的制备
参照实施例1的方法制备出中间体2-1和中间体2-2。将0.40克中间体2-1与0.50克中间体2-2溶解在50毫升乙腈中，50℃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0.17克，即化合物2，产率20.3％。
1HNMR(DMSO-d6,400MHz)δ:2.07～2.11(m,3H),2.29～2.41(m,4H),2.84～2.98(m,1H),3.02(s,3H),3.16～3.22(m,2H),3.38～3.41(m,3H),3.56～3.59(m,4H),4.61(s,2H),4.71(s,2H),4.84～4.92(m,1H),5.00(s,2H),5.75(s,2H),7.32～7.40(m,4H),7.64～7.87(m,7H).
实施例3、本发明化合物3的制备
参照实施例1的方法制备出中间体3-1和中间体1-2。将0.53克中间体3-1与0.47克中间体1-2溶解在50毫升乙腈中，50℃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0.18克，即化合物3，产率19.0％。
1HNMR(DMSO-d6,400MHz)δ:1.82～1.84(m,1H),2.07～2.24(m,2H),2.34～2.41(m,6H),2.65～2.71(m，1H)，2.08～3.15(m,2H),3.35(s,broad,6H),4.20～4.24(m,2H),4.55～5.02(m,8H),5.62～5.65(m,2H),7.33～7.39(m,4H),7.64～7.69(m,4H),7.90～7.93(m,4H),8.33～8.41(m,4H).
实施例4、本发明化合物4的制备
参照实施例1的方法制备出中间体4-1和中间体4-2。将0.52克中间体4-1与0.46克中间体4-2溶解在50毫升乙腈中，50℃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0.15克，即化合物4，产率20.5％。
1HNMR(DMSO-d6,400MHz)δ:1.79～1.82(m,1H),2.06～2.20(m,2H),2.32～2.44(m,6H),2.62～2.75(m，1H)，2.03～3.16(m,2H),3.38(s,broad,6H),4.21～4.25(m,2H),4.50～5.01(m,8H),5.61～5.68(m,2H),7.56～7.65(m,8H),7.88～7.95(m,8H).
实施例5、本发明化合物5的制备
参照实施例1的方法制备出中间体5-1和中间体1-2。按照实施例1～6的方法，将中间体5-1与中间体1-2溶解在50毫升乙腈中，50℃搅拌12小时，减压蒸干溶剂，残余物经反相制备色谱分离，得化合物5。
1HNMR(DMSO-d6,400MHz)δ:2.06～2.26(m,2H),2.31～2.38(m,6H),2.65～2.74(m，1H)，2.08～3.16(m,2H),3.37(s,broad,6H),4.59～5.04(m,9H),5.61～5.64(m,2H),7.32～7.39(m,6H),7.63～7.69(m,6H),7.90～7.95(m,2H),8.31～8.42(m,2H).
实施例6、本发明化合物6～35的制备
本发明所述的其他具体化合物6～35，均可通过本发明合成路线制备得到，本发明合成路线如下：
其制备通法参考实施例1～5：将等摩尔(1mmol)的中间体1和中间体2溶于50毫升乙腈中，50℃搅拌12小时，减压蒸干溶剂，残余物经反相制备色谱分离得到化合物Ⅰ，产率9～22％。比如，对于化合物6，其中间体1中R1、R2分别为对硝基苄基、对氟苄基，m与n的和为4，L1为亚甲基，R5为氢，中间体2中L2不存在，a与b的和为4，R3、R4为对硝基苄基、对氟苄基。若需要变换化合物Ⅰ中的阴离子，可以使用离子交换的常见方式实现。其他具体化合物及其质谱数据见表1。
表1.具体化合物及其质谱数据
实施例7、本发明化合物作为肌肉松弛剂的效果
体重2～3kg的成年雄性大白兔，使用丙泊酚按5mg/kg剂量经静脉进行麻醉诱导，实施气管插管，呼吸机供氧，丙泊酚以0.6mg/kg/min静脉输注速度维持麻醉。随后，按体重经静脉给予含一定剂量本发明所述化合物、阳性对照药顺阿曲库铵和琥珀胆碱的生理盐水溶液，使用TOF肌松监测仪检测肌力变化，记录起效(T1≤5％)所需时间和肌张力完全恢复(TOF>90％)所需时间，每组6只动物。本发明化合物与对照药物琥珀胆碱、顺阿曲库铵均使用各自的两倍ED95作为给药剂量，作为肌肉松弛剂的效果如表2所示。
表2.各化合物肌松活性测试数据
上述实验结果显示：本发明化合物给药剂量小，起效快，能产生完全的肌肉松弛作用，且肌力完全恢复(TOF>90％)所需时间远比顺阿曲库铵和去极化肌松药琥珀胆碱短。此外，本发明化合物起效时T1～4的比例逐步消失，恢复时T1～4的比例也是逐步恢复，这种TOF的变化特征属于非去极化肌松药物所特有。上述实验证明，本发明化合物具备快速起效且超短效的非去极化肌松分子活性。
综上，本发明化合物具备快速起效且超短效的非去极化肌松分子活性，在低给药剂量下，起效快，能产生完全的肌肉松弛作用，且肌力完全恢复所需时间短，明显短于阳性药顺阿曲库铵和去极化肌松药琥珀胆碱，有效克服了现有技术中非去极化肌松药存在的问题，可用于制备效果优良的非去极化肌松药物，具有良好的前景。
Claims (6)
1.一种化合物或其盐，其特征在于：所述化合物为式(II)所示化合物：
其中，
R1、R2、R3、R4分别独立选自取代或未取代的C1～C3烷基；所述烷基的取代基选自取代的苯基；所述苯基的取代基为C1～C3烷基、C1～C3烷氧基、卤素、氰基、硝基、三氟甲基、羟基；
L1为不存在、未取代的C1～C2亚烷基；
R5选自氢；
n、m、a、b分别为0～3的整数，且n+m等于3或4，a+b等于3或4；
L2为不存在、未取代的C1亚烷基；
M为溴离子、氯离子、磺酸根离子。
2.根据权利要求1所述的化合物或其盐，其特征在于：所述化合物为如下化合物之一：
3.一种化合物或其盐，其特征在于：所述化合物为如下化合物之一：
4.权利要求1～3任一项所述的化合物或其盐在制备肌肉松弛药物中的用途。
5.根据权利要求4所述的用途，其特征在于：所述肌肉松弛药物为非去极化肌肉松弛药物。
6.一种药物，它是由权利要求1～3任一项所述的化合物或其盐为活性成分，加上药学上可接受的载体或其他活性成分制备而成的组合物。
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