CN113087686A - 一类含氰基的双季铵类化合物及其制备方法和用途 - Google Patents
一类含氰基的双季铵类化合物及其制备方法和用途 Download PDFInfo
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- CN113087686A CN113087686A CN202010301495.7A CN202010301495A CN113087686A CN 113087686 A CN113087686 A CN 113087686A CN 202010301495 A CN202010301495 A CN 202010301495A CN 113087686 A CN113087686 A CN 113087686A
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- Prior art keywords
- ammonium compound
- quaternary ammonium
- stereoisomer
- solvate
- salt
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- 230000036640 muscle relaxation Effects 0.000 claims abstract description 24
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- 239000013078 crystal Substances 0.000 claims abstract description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 14
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- -1 halide ions Chemical class 0.000 claims description 7
- 150000001450 anions Chemical class 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960003682 rocuronium bromide Drugs 0.000 description 1
- 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
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JUDUFOKGIZUSFP-UHFFFAOYSA-M silver;4-methylbenzenesulfonate Chemical compound [Ag+].CC1=CC=C(S([O-])(=O)=O)C=C1 JUDUFOKGIZUSFP-UHFFFAOYSA-M 0.000 description 1
- ZFCDJOVFDDEYKY-UHFFFAOYSA-M silver;benzenesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C1=CC=CC=C1 ZFCDJOVFDDEYKY-UHFFFAOYSA-M 0.000 description 1
- 229940125706 skeletal muscle relaxant agent Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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Abstract
本发明涉及一类含氰基的双季铵类化合物及其制备方法和用途,具体公开了式(Ⅰ)所示的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐。上述双季铵类化合物中不含硝基,有效避免了含硝基化合物的安全隐患;同时,该双季铵类化合物的单次用药剂量低,起效快,并能够提供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。所以,本发明提供的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐在制备低剂量、起效快、恢复快、毒副作用小的骨骼肌松弛药物中具有非常好的应用前景。
Description
技术领域
本发明属于药物合成领域,具体涉及一类含氰基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(又称骨骼肌松弛药物或肌松药)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。肌松药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)。
去极化肌松药能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只有琥珀胆碱。琥珀胆碱的优点是作用时间短,例如在人体上持续时间为10分钟且起效迅速,这种特点特别适合急症,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。但是由于作用机制特殊,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。
非去极化肌松药又称竞争型肌松药,能与ACh竞争骨骼肌运动终板膜上的N2胆碱受体,其本身无内在活性,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。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一大弊端。因此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40~60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隐患,如过量的半胱氨酸可能会引起气管痉挛,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。
中国专利申请201810828371.7公开了一种非去极化肌肉松弛剂,其为苄基双季铵化合物,这类化合物具有快速和短效的肌松作用,但其分子中含有被硝基和卤素取代的芳环。而硝基的存在可能会增加药物的毒性,硝基化合物可能导致高铁血红蛋白血症;另外硝基还可能产生硝基自由基阴离子、亚硝基衍生物或酯化羟胺,这些物质的累积效应可能致突变和致癌(Journal of Medicinal Chemistry,2019,62,6,2851-2893)。由于硝基的上述安全隐患,在药物分子中引入硝基时需格外谨慎。另外,该专利申请公开的苄基双季铵化合物起效剂量较高,有的甚至高达4.0mg/kg,进一步限制了其临床应用。
因此,开发一种不需要逆转剂的,不含硝基取代基的,起效剂量低、起效快、恢复快、毒副作用小的骨骼肌松弛药物具有非常重要的意义。
发明内容
本发明的目的在于提供一类不需要逆转剂的,不含硝基取代基的,起效剂量低、起效快、恢复快、毒副作用小的骨骼肌松弛药物。
本发明提供了式(Ⅰ)所示的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐:
其中,L1为C1~C8的亚烷基;L2为C1~C8的亚烷基;
Z1为氰基或甲氧基;Z2为氰基或甲氧基;Z3为氰基或甲氧基;Z1、Z2、Z3中至少有1个为氰基,且式(Ⅰ)化合物中至少含1个氰基;
a,b,c各自独立地选自0~5的整数,且a,b,c不能同时为0;
R为H或C1~C6的烷基;
M1、M2各自独立地选自阴离子。
进一步地,L1为C1~C4的亚烷基;L2为C1~C4的亚烷基。
进一步地,L1为C1~C3的亚烷基;L2为C2~C4的亚烷基。
进一步地,Z2、Z3均为氰基,或者Z2、Z3中一个为氰基、另一个为甲氧基。
进一步地,a,b,c各自独立地选自0~2的整数,优选为0~1的整数。
进一步地,R为H或甲基。
进一步地,所述的双季铵类化合物为如下化合物之一:
本发明还提供了上述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐在制备骨骼肌松弛药物中的用途。
本发明还提供了一种骨骼肌松弛药物,它是以上述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
实验证明,本发明提供的双季铵类化合物中不含硝基,有效避免了含硝基化合物的安全隐患;同时,该双季铵类化合物的单次用药剂量低,起效快,并能够提供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。所以,本发明提供的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐在制备低剂量、起效快、恢复快、毒副作用小的骨骼肌松弛药物中具有非常好的应用前景。
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。
本发明式(I)中,当a,b或c为0时,表示对应的苯环上没有取代基。
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(Cn~Cm)的烷基表明任何含“n”至“m”个碳原子的烷基。因此,例如,C1~C6的烷基是指包含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。
所述C1~C8的亚烷基是指包含1~8个碳原子的亚烷基,例如亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基等等。
所述的同位素替代物是指将本专利所述化合物结构中某一个或多个原子替换为对应的同位素原子而获得的分子。
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
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
本发明式(I)所示化合物均是由两个含季铵盐结构的中间体偶联而得,两个含季铵盐结构的中间体的结构和制备式(I)所示化合物的反应通式如下所示:
实施例1、化合物1的制备
将1.36克4-氯丁酸甲酯溶于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1.51克4-氰基苄氯,75℃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2N稀盐酸调节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2.33克。
将1.90克羟乙基-4-氰基苄基-甲基胺(Reaxy ID 13575492)溶于30毫升乙腈,加入1.51克4-氰基苄氯于75℃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)2.51克。
将1.72克中间体1-1与2.17克中间体1-2溶解在50毫升N,N-二甲基甲酰胺中,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0.87克,即化合物1,产率24.2%。
1HNMR(400MHz,DMSO-d6)δ:1.40~1.46(1H,m),1.62~1.65(1H,m),1.77~1.88(4H,m),2.03~2.12(2H,m),2.57~2.62(2H,m),3.09(3H,s),3.13~3.23(4H,m),3.40~3.45(2H,m),3.63~3.75(2H,m),4.66~4.76(6H,m),4.85~4.96(2H,m),5.77(2H,s),7.66~7.68(2H,m),7.80~7.82(4H,m),7.94~8.00(6H,m).
实施例2、化合物2的制备
中间体1-2的制备参考实施例1的制备方法。
中间体2-1的制备:将1.36克4-氯丁酸甲酯溶于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1.26克苄氯,75℃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2N稀盐酸调节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(2-1)粗品2.16克。
将1.60克中间体2-1和2.17克中间体1-2溶解在50毫升N,N-二甲基甲酰胺中,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0.93克,即化合物2,产率26.7%。
1HNMR(400MHz,DMSO-d6)δ:1.43~1.48(1H,m),1.62~1.66(1H,m),1.78~1.88(4H,m),2.04~2.13(2H,m),2.56~2.60(2H,m),3.05(3H,s),3.15~3.27(4H,m),3.40~3.45(2H,m),3.64~3.76(2H,m),4.66~4.77(6H,m),4.87~4.95(2H,m),5.76(2H,s),7.51~7.69(5H,m),7.82~7.86(4H,m),7.92~8.04(4H,m).
实施例3、化合物3的制备
中间体1-1的制备参考实施例1的制备方法。
中间体3-2的制备:将1.65克羟乙基-苄基-甲基胺溶于30毫升乙腈,加入1.51克4-氰基苄氯于75℃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(3-2)2.31克。
将1.72克中间体1-1和2.04克中间体3-2溶解在50毫升N,N-二甲基甲酰胺中,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0.95克,即化合物3,产率27.3%。
1HNMR(400MHz,DMSO-d6)δ:1.42~1.46(1H,m),1.63~1.67(1H,m),1.75~1.89(4H,m),2.03~2.14(2H,m),2.56~2.62(2H,m),3.08(3H,s),3.13~3.26(4H,m),3.42~3.46(2H,m),3.63~3.75(2H,m),4.64~4.77(6H,m),4.87~4.95(2H,m),5.73(2H,s),7.51~7.69(5H,m),7.80~7.84(4H,m),7.94~8.01(4H,m).
实施例4、化合物4的制备
中间体3-2的制备方法参考实施例3。
中间体4-1的制备方法:将1.36克4-氯丁酸甲酯溶于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1.51克2-氰基苄氯,75℃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2N稀盐酸调节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(4-1)粗品2.29克。
将2.04克中间体3-2和1.72克中间体4-1溶解在50毫升N,N-二甲基甲酰胺中,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0.83克,即化合物4,产率23.8%。
1HNMR(400MHz,DMSO-d6)δ:1.40~1.44(1H,m),1.62~1.66(1H,m),1.74~1.88(4H,m),2.03~2.15(2H,m),2.54~2.60(2H,m),3.11(3H,s),3.12~3.24(4H,m),3.41~3.46(2H,m),3.63~3.76(2H,m),4.63~4.77(6H,m),4.84~4.95(2H,m),5.72(2H,s),7.26~7.37(8H,m),7.42~7.49(3H,m),7.82~7.89(2H,m).
实施例5、化合物5的制备
中间体5-1的制备:将1.81克4-溴丁酸甲酯溶于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1.96克4-氰基苄溴,75℃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2N溴化氢水溶液调节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(5-1)粗品2.41克。
中间体5-2的制备:将1.90克羟乙基-4-氰基苄基-甲基胺(Reaxy ID13575492)溶于30毫升乙腈,加入1.96克2-氰基苄溴于75℃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(5-2)2.66克。
将1.95克中间体5-1和2.39克中间体5-2溶解在50毫升N,N-二甲基甲酰胺中,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1.15克,即化合物5,产率28.4%。
1HNMR(400MHz,DMSO-d6)δ:1.41~1.45(1H,m),1.61~1.65(1H,m),1.73~1.86(4H,m),2.04~2.15(2H,m),2.52~2.59(2H,m),3.15(3H,s),3.11~3.23(4H,m),3.42~3.47(2H,m),3.62~3.75(2H,m),4.63~4.78(6H,m),4.83~4.95(2H,m),5.70(2H,s),7.26~7.37(5H,m),7.52~7.59(3H,m),7.81~7.86(4H,m).
实施例6、化合物6的制备
中间体5-1的制备方法参考实施例5。
中间体6-2的制备方法:将1.90克羟乙基-4-氰基苄基-甲基胺(ReaxyID13575492)溶于30毫升乙腈,加入2.0克4-甲氧基苄溴于75℃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(6-2)2.93克。
将2.44克中间体5-1和2.42克中间体6-2溶解在50毫升N,N-二甲基甲酰胺中,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1.02克,即化合物6,产率25.1%。
1HNMR(400MHz,DMSO-d6)δ:1.42~1.47(1H,m),1.61~1.64(1H,m),1.75~1.85(4H,m),2.02~2.13(2H,m),2.56~2.62(2H,m),3.12(3H,s),3.14~3.22(4H,m),3.41~3.46(2H,m),3.61~3.75(2H,m),3.88(3H,s),4.65~4.74(6H,m),4.84~4.95(2H,m),5.73(2H,s),7.01~7.05(2H,m),7.33~7.35(2H,m),7.66~7.69(4H,m),7.95~7.99(4H,m).
实施例7、化合物7的制备
中间体7-1的制备:将1.81克4-溴丁酸甲酯溶于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2.01克4-甲氧基苄溴,75℃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2N溴化氢水溶液调节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(7-1)粗品2.91克。
中间体7-2的制备:将1.90克羟乙基-4-氰基苄基-甲基胺(Reaxy ID13575492)溶于30毫升乙腈,加入1.96克4-氰基苄溴于75℃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(7-2)3.01克。
将1.97克中间体7-1和2.40克中间体7-2溶解在50毫升N,N-二甲基甲酰胺中,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0.82克,即化合物7,产率20.1%。
1HNMR(400MHz,DMSO-d6)δ:1.40~1.45(1H,m),1.62~1.65(1H,m),1.76~1.85(4H,m),2.01~2.13(2H,m),2.55~2.62(2H,m),3.11(3H,s),3.14~3.23(4H,m),3.41~3.46(2H,m),3.60~3.75(2H,m),3.84(3H,s),4.63~4.74(6H,m),4.84~4.96(2H,m),5.72(2H,s),7.00~7.04(2H,m),7.32~7.35(2H,m),7.65~7.69(4H,m),7.96~8.01(4H,m).
实施例8、化合物8的制备
中间体5-1的制备参考实施例5。
中间体8-2的制备:将1.95克羟乙基-4-甲氧基苄基-甲基胺(CAS:151696-86-5)溶于30毫升乙腈,加入2.01克4-甲氧基苄溴于75℃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(8-2)3.28克。
将1.97克中间体5-1和2.44克中间体8-2溶解在50毫升N,N-二甲基甲酰胺中,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0.72克,即化合物8,产率17.7%。
1HNMR(400MHz,DMSO-d6)δ:1.39~1.43(1H,m),1.61~1.65(1H,m),1.73~1.81(4H,m),2.01~2.13(2H,m),2.55~2.62(2H,m),3.13(3H,s),3.15~3.24(4H,m),3.41~3.46(2H,m),3.60~3.75(2H,m),3.87(6H,s),4.63~4.74(6H,m),4.84~4.96(2H,m),5.71(2H,s),7.00~7.04(4H,m),7.32~7.35(4H,m),7.65~7.69(2H,m),7.96~8.01(2H,m).
实施例9、化合物9的制备
将500mg化合物8溶于200mL水中,搅拌下缓慢滴入含等摩尔苯磺酸银的水溶液,析出沉淀,过滤,滤液冷冻干燥,得到白色粉末状固体413mg,即化合物9。
1HNMR(400MHz,MeOD)δ:1.40~1.44(1H,m),1.60~1.65(1H,m),1.74~1.81(4H,m),1.99~2.10(2H,m),2.54~2.62(2H,m),3.12(3H,s),3.16~3.25(4H,m),3.40~3.45(2H,m),3.61~3.74(2H,m),3.88(6H,s),4.62~4.74(6H,m),4.83~4.96(2H,m),5.70(2H,s),7.01~7.04(4H,m),7.33~7.35(4H,m),7.65~7.69(6H,m),7.96~8.01(8H,m).
实施例10、化合物10的制备
将500mg化合物1溶于200mL水中,搅拌下缓慢滴入含等摩尔对甲苯磺酸银的水溶液,析出沉淀,过滤,滤液冷冻干燥,得到白色粉末状固体398mg,即化合物10。
1HNMR(400MHz,MeOD)δ:1.41~1.45(1H,m),1.61~1.65(1H,m),1.78~1.88(4H,m),2.02~2.12(2H,m),2.44(6H,s),2.57~2.62(2H,m),3.06(3H,s),3.14~3.23(4H,m),3.40~3.45(2H,m),3.64~3.75(2H,m),4.65~4.76(6H,m),4.84~4.96(2H,m),5.75(2H,s),7.47~7.49(4H,m),7.66~7.68(2H,m),7.76~7.82(8H,m),7.94~8.00(6H,m).
实施例11、化合物11的制备
将500mg化合物3溶于200mL水中,搅拌下缓慢滴入含等摩尔甲烷磺酸银的水溶液,析出沉淀,过滤,滤液冷冻干燥,得到白色粉末状固体405mg,即化合物11。
1HNMR(400MHz,MeOD)δ:1.41~1.46(1H,m),1.62~1.67(1H,m),1.74~1.89(4H,m),2.04~2.14(2H,m),2.57~2.62(2H,m),2.83(6H,s),3.06(3H,s),3.12~3.26(4H,m),3.43~3.46(2H,m),3.64~3.75(2H,m),4.65~4.77(6H,m),4.88~4.95(2H,m),5.72(2H,s),7.52~7.69(5H,m),7.78~7.83(4H,m),7.95~8.00(4H,m).
实施例12、化合物12的制备
中间体12-1的制备: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1.96克4-氰基苄溴,75℃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2N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(12-1)粗品2.51克。
中间体12-2的制备:将1.03克羟丁基-甲基胺溶于30毫升乙腈,加入3.92克4-氰基苄溴于75℃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(12-2)3.01克。
将1.80克中间体12-1与2.53克中间体12-2溶解在50毫升N,N-二甲基甲酰胺中,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0.93克,即化合物12,产率23.0%。
1HNMR(400MHz,DMSO-d6)δ:1.54~1.59(4H,m),1.62~1.96(6H,m),2.95(3H,s),3.18~3.19(2H,m),3.49~3.52(2H,m),3.72~3.75(2H,m),4.23(2H,t,J=6.4Hz),4.47(2H,s),4.57~4.60(2H,m),4.74~4.77(2H,m),4.87(2H,s),5.84(2H,s),7.65~7.67(2H,m),7.79~7.81(4H,m),7.94~8.00(6H,m).
实施例13、化合物13的制备
中间体12-1的制备参考实施例12。
中间体13-2的制备:将1.93克4-(N-甲基-N-苄基)丁醇(CAS:98901-97-4)溶于30毫升乙腈,加入1.96克4-氰基苄溴于75℃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(13-2)3.55克。
将1.80克中间体12-1与2.41克中间体13-2溶解在50毫升N,N-二甲基甲酰胺中,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0.82克,即化合物13,产率21.0%。
1HNMR(400MHz,DMSO-d6)δ:1.54~1.67(4H,m),1.91~2.01(6H,m),2.92(3H,s),3.15~3.17(2H,m),3.50~3.52(2H,m),3.72~3.76(2H,m),4.23(2H,t,J=6.4Hz),4.47~4.87(8H,m),5.84(2H,s),7.50~7.57(5H,m),7.65~7.67(2H,m),7.80~7.82(2H,m),7.94~8.00(4H,m).
实施例14、化合物14的制备
中间体12-1的制备参考实施例12。
中间体14-2的制备:将2.22克4-(N-甲基-N-对甲氧基苄基)丁醇(PubChem ID:61417702)溶于30毫升乙腈,加入1.96克4-氰基苄溴于75℃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(14-2)3.18克。
将1.80克中间体12-1与2.56克中间体14-2溶解在50毫升N,N-二甲基甲酰胺中,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0.72克,即化合物14,产率17.7%。
1HNMR(400MHz,MeOD)δ:1.59~1.69(4H,m),1.92~2.01(6H,m),2.88(3H,s),3.11~3.14(2H,m),3.51~3.53(2H,m),3.73~3.76(2H,m),3.80(3H,s),4.24(2H,t,J=6.4Hz),4.45~4.62(6H,m),4.81(2H,s),5.87(2H,s),7.03~7.05(2H,m),7.50~7.57(2H,m),7.64~7.66(2H,m),7.80~7.82(2H,m),7.93~8.01(4H,m).
实施例15、化合物15的制备
中间体12-1的制备参考实施例12。
中间体15-2的制备:将1.79克3-(N-甲基-N-苄基)丙醇(CAS:5814-42-6)溶于30毫升乙腈,加入1.96克4-氰基苄溴于75℃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(15-2)2.98克。
将1.80克中间体12-1与2.33克中间体15-2溶解在50毫升N,N-二甲基甲酰胺中,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0.52克,即化合物15,产率13.5%。
1HNMR(400MHz,DMSO-d6)δ:1.55~1.66(4H,m),1.90~2.02(4H,m),2.86(3H,s),3.12~3.15(2H,m),3.50~3.52(2H,m),3.74~3.76(2H,m),4.23(2H,t,J=6.4Hz),4.46~4.62(6H,m),4.80(2H,s),5.83(2H,s),7.51~7.57(5H,m),7.66~7.67(2H,m),7.81~7.83(2H,m),7.93~8.01(4H,m).
实施例16、化合物16的制备
中间体12-1的制备参考实施例12;
中间体16-2的制备:将1.65克羟乙基-苄基-甲基胺溶于30毫升乙腈,加入1.96克4-氰基苄溴于75℃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(16-2)2.93克。
将1.80克中间体12-1与2.76克中间体16-2溶解在50毫升N,N-二甲基甲酰胺中,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0.49克,即化合物16,产率13.0%。
1HNMR(400MHz,DMSO-d6)δ:1.51~1.62(4H,m),1.90~2.00(2H,m),2.84(3H,s),3.13~3.15(2H,m),3.51~3.53(2H,m),3.73~3.76(2H,m),4.25(2H,t,J=6.4Hz),4.43~4.61(6H,m),4.78(2H,s),5.85(2H,s),7.50~7.56(5H,m),7.65~7.67(2H,m),7.82~7.84(2H,m),7.92~8.00(4H,m).
实施例17、化合物17的制备
中间体17-1的制备:将1.08克2-氯乙酸甲酯溶于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1.51克3-氰基苄氯,75℃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2N稀盐酸调节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(17-1)粗品2.31克。
中间体17-2的制备:将1.93克4-(N-甲基-N-苄基)丁醇(CAS:98901-97-4)溶于30毫升乙腈,加入1.51克4-氰基苄氯于75℃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(17-2)2.81克。
将1.58克中间体17-1与2.18克中间体17-2溶解在50毫升N,N-二甲基甲酰胺中,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0.55克,即化合物17,产率15.8%。
1HNMR(400MHz,DMSO-d6)δ:1.51~1.65(4H,m),1.90~2.02(6H,m),2.93(3H,s),3.14~3.17(2H,m),3.50~3.53(2H,m),3.72~3.77(2H,m),4.22(2H,t,J=6.4Hz),4.46~4.87(8H,m),5.85(2H,s),7.48~7.57(6H,m),7.66~7.81(4H,m),7.95~8.01(3H,m).
实施例18、化合物18的制备
中间体18-1的制备:将1.08克2-氯乙酸甲酯溶于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1.51克4-氰基苄氯,75℃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2N稀盐酸调节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(18-1)粗品2.39克。
中间体18-2的制备:将1.93克4-(N-甲基-N-苄基)丁醇(CAS:98901-97-4)溶于30毫升乙腈,加入1.51克3-氰基苄氯于75℃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(18-2)2.96克。
将1.58克中间体18-1与2.18克中间体18-2溶解在50毫升N,N-二甲基甲酰胺中,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0.63克,即化合物18,产率18.1%。
1HNMR(400MHz,DMSO-d6)δ:1.50~1.64(4H,m),1.91~2.02(6H,m),2.92(3H,s),3.13~3.17(2H,m),3.52~3.55(2H,m),3.72~3.76(2H,m),4.20(2H,t,J=6.4Hz),4.45~4.87(8H,m),5.82(2H,s),7.47~7.57(6H,m),7.65~7.80(4H,m),7.94~8.01(3H,m).
实施例19、化合物19的制备
中间体1-1的制备参考实施例1。
中间体19-2的制备:将1.93克4-(N-甲基-N-苄基)丁醇(CAS:98901-97-4)溶于30毫升乙腈,加入1.51克4-氰基苄氯于75℃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1-氯乙酯(CAS:50893-53-3)1.45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(19-2)2.58克。
将1.72克中间体1-1与2.24克中间体19-2溶解在50毫升N,N-二甲基甲酰胺中,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0.43克,即化合物19,产率11.7%。
1HNMR(400MHz,DMSO-d6)δ:1.41~1.47(1H,m),1.61~1.65(1H,m),1.76~1.84(4H,m),2.03~2.13(5H,m),2.55~2.62(2H,m),3.11(3H,s),3.12~3.23(4H,m),3.39~3.44(2H,m),3.64~3.75(2H,m),4.65~4.75(6H,m),4.84~4.96(2H,m),6.82(1H,m),7.65~7.69(2H,m),7.81~7.84(4H,m),7.95~8.02(6H,m).
以下通过试验例来说明本发明的有益效果。
试验例1、本发明化合物的肌肉松弛实验
(1)实验方法
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。具体方法为: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等效剂量的对照药物(琥珀胆碱和顺阿曲库铵)和本专利实施例制得的各化合物,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。
(2)实验结果
表1药物对兔的肌松作用起效和持续时间
上述结果显示,本发明所述的化合物单次用药剂量低(0.8mg/kg以下),起效快,能够在动物体内快速产生肌肉松弛作用(<30秒),且肌张力完全恢复所需时间短,肌肉松弛的维持时间明显短于顺阿曲库铵,甚至短于琥珀胆碱。所以与对照药物相比,本发明的化合物,特别是化合物1~5、7~12、15,19在更低的使用剂量下(0.3mg/kg以下),反而同时具备显著更佳的快速起效和快速恢复效果。
此外,在给予本发明所述的化合物后,受试动物的TOF1~4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)所示的双季铵类化合物,该双季铵类化合物中不含硝基,有效避免了含硝基化合物的安全隐患;同时,该双季铵类化合物的单次用药剂量低,起效快,并能够提供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。所以,本发明提供的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐在制备低剂量、起效快、恢复快、毒副作用小的骨骼肌松弛药物中具有非常好的应用前景。
Claims (10)
2.如权利要求1所述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐,其特征在于:L1为C1~C4的亚烷基;L2为C1~C4的亚烷基。
3.如权利要求2所述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐,其特征在于:L1为C1~C3的亚烷基;L2为C2~C4的亚烷基。
4.如权利要求1所述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐,其特征在于:Z2、Z3均为氰基,或者Z2、Z3中一个为氰基、另一个为甲氧基。
5.如权利要求1所述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐,其特征在于:a,b,c各自独立地选自0~2的整数,优选为0~1的整数。
6.如权利要求1所述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐,其特征在于:R为H或甲基。
9.权利要求1~8任一项所述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐在制备骨骼肌松弛药物中的用途。
10.一种骨骼肌松弛药物,其特征在于:它是以权利要求1~8任一项所述的双季铵类化合物、或其晶型、或其溶剂合物、或其立体异构体、或其同位素替代物、或其盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
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