CN113396139A - 基于苯环超分子相互作用的芳基酰胺类化合物、自组装形态及用途 - Google Patents

基于苯环超分子相互作用的芳基酰胺类化合物、自组装形态及用途 Download PDF

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CN113396139A
CN113396139A CN202080007970.8A CN202080007970A CN113396139A CN 113396139 A CN113396139 A CN 113396139A CN 202080007970 A CN202080007970 A CN 202080007970A CN 113396139 A CN113396139 A CN 113396139A
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易天奇
艾春霞
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Abstract

基于苯环超分子作用的芳基酰胺类化合物、自组装形态及用途。该类化合物结构如式(Ⅰ)和(Ⅱ)所示，可在含水溶剂中自组装形成具有分子间强π‑π堆积作用的球形胶束和Janus粒子，在生物体内可发挥长时间局部麻醉作用，局麻和/或镇痛作用时间可超过48小时，局部神经病理毒性和全身毒性显著低于已公开的长效局麻分子。作为在水中能自组装形成胶束且具有局麻作用的生物材料，同时还可以作为包裹包括治疗疼痛、瘙痒等症状的药物活性分子和/或药物载体的生物材料及传递系统等使用的制剂辅料，都具有良好的前景。

Description

基于苯环超分子相互作用的芳基酰胺类化合物、自组装形态 及用途
技术领域
本发明涉及一种具有长效麻醉效应和低毒性的芳基酰胺类化合物、制备方法、自组装形态及用途。
背景技术
长效局部麻醉药开发的技术瓶颈
局部麻醉药(local anaesthetics，局麻药)是一类在保持病人或动物清醒的情况下，能在用药局部可逆地阻断感觉神经冲动发生与传递，引起局部组织痛觉消失的药物。
局麻药的作用一般局限于给药部位，并随药物从给药部位扩散而迅速失效。目前，临床上所有的局部麻醉药物只能实现不超过4小时的强效局麻与镇痛，不能满足如牙科根管治疗后疼痛、关节骨痛、带状疱疹疼痛、术后创口恢复和晚期癌痛等对12～72小时长效局麻的需求。因此，临床上非常需要能够产生超过12小时作用的新型长效局部麻醉药物。
在临床实践中，局部麻醉药产生的注射局部的神经病理毒性和进入血液后产生的全身毒性，均可能对患者的安全造成严重隐患。其中较为严重的神经病理毒性，造成的局部神经损伤，可能在药效消失后，持续的乃至于不可逆的影响神经的基本功能。而尽管局部麻醉药仅仅是局部注射，但仍可能由于扩散能力过强、局部组织血管丰富、注射误入血管等一个或多个原因进入循环系统，导致心血管毒性等全身毒性，危及患者生命安全。因此，在追求长效局麻的同时，控制和降低长效局麻可能加剧的局部神经病理毒性和全身毒性同样重要。
目前的常规局部麻醉药物含有至少一个叔胺N原子，如图1中的利多卡因。该类药物注射于局部组织后，以游离碱形式快速扩散进入神经细胞膜内。再利用细胞膜内外的pH值差，形成叔胺盐酸盐形式，作用于神经细胞膜内的Na+通道靶点，产生局部麻醉作用。但由于叔胺盐酸盐的形成是可逆的，药物同样会快速以游离碱的形式扩散出神经细胞并远离神经组织，因而很难长效。
再对利多卡因行一次烷基取代能得到相应的季铵盐，使整个分子成为不可逆的阳离子QX-314。由于QX-314分子极性较强，很难穿过细胞膜作用于靶点，无法快速地产生有力的局部麻醉作用，因而无法直接用于临床。然而一旦穿过细胞膜，就能在膜内对钠离子通道进行有力的抑制，并难于从细胞膜内扩散到细胞外，从而产生持久的麻醉作用(K.R.Courtney.JPharmacol ExpTher.1975,195，225-236)。目前已有许多研究发现，QX-314能经TRPV1阳离子通道进入细胞膜，引起持久麻醉作用(C.R.Ries.Anesthesiology2009,111,122-126)。最新研究表明，在外加表面活性剂条件下，亦可通过形成胶束，帮助带电荷的QX-314进入细胞膜，引起超过8小时的局麻作用(D.S.Kohane.PNAS.2010,107,3745-3750)。然而，由于该类季铵阳离子化合物的扩散能力较弱，进入神经细胞膜内作用于钠通道靶点的分子占注射总量的比例较低，只能引起不超过7小时的局麻作用，仍不满足临床实践中对超过12小时长效局麻的需求。由此可见，目标化合物的扩散过程对长效局部麻醉十分关键。
双子表面活性剂与局部麻醉
双子表面活性剂(gemini surfactant)具有特殊的分子结构，在溶剂中自组装后可产生远远强于单体的表面活性(F.M.Menger and J.S.Keiper.Angew.Chem.Int.Ed.2003,39,1906-1920)。常见的双子表面活性剂包括串联型和并联型，如图2。
并联型双子表面活性剂，亲水头基主要为季铵阳离子或伯、仲、叔胺的酸式盐、羧酸或磺酸阴离子以及多羟基或多氮、氧原子的结构片段；疏水尾链多为直链烷基或芳基；中间的连接基团多为直链烷基,如图3(L.Tang.Chem.Commun.2017,53,8675-8678)。串联型双子表面活性剂与并联型类似，只是疏水尾链与连接基团合二为一。利多卡因、布比卡因等常见局麻药的叔胺酸式盐结构，亦可作为表面活性剂的亲水头基；其芳基酰胺结构亦可作为疏水尾链。
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，该类化合物都不可避免的带由表面活性剂结构带来的，显著高于已上市局麻药的局部神经病理毒性和全身毒性，不利于进一步的临床使用。
发明内容
本发明首先提供了一类具有超长效麻醉效应和低毒性的芳基酰胺类化合物，并进一步提供该类化合物的自组装方式和局部麻醉应用。
本发明所述的具有长效局部麻醉作用的芳基酰胺类化合物，结构如下：
Figure BDA0003145480140000031
(Ⅰ)式中R1和R2为饱和形式的C1～2烷基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。(Ⅱ)式中的R1为C1～2烷基；R2为氢原子，或者取代或未取代、饱和或不饱和形式的C1～3烷基。
本发明所涉及的化合物，是由阴离子部分和阳离子部分构成的整体分子。其中阴离子部分并非简单的以药学常用阴离子替换得到，而是出于包括不对称双子表面活性剂结构设计在内的，能够使该类分子在水中超分子自组装后形成产生明显的π-π堆积作用的有机酸根离子。使用磺酸根离子替换羧酸根离子，也能产生类似长效低毒的局部麻醉作用。
本发明涉及化合物为通过在水中自组装形成的超分子结构，通过双子表面活性剂的固有性质以该类化合物特有的强π-π堆积作用实现缓释，并将具有局部麻醉作用的单个药物分子运送进入神经细胞膜内，利用神经细胞膜内外的pH值差异，实现阴离子交换，得到难扩散出细胞的季铵阳离子氯化物单体，作用于神经细胞膜内侧的Na+通道靶点，实现长效局部麻醉作用。而该类化合物进入血液后，通过阴离子交换，会迅速失去双子表面活性剂的结构，降解为低毒性物质。
本发明的系列化合物(Ⅰ)和(Ⅱ)具有以下基本特性：
(1)具有非典型的不对称双子表面活性剂结构特征。
(2)能够在水中自组装形成包括Janus粒子在内的有序的超分子结构。
(3)由于π-π堆积影响，该类分子自组装形成的超分子体系缓释能力更强。
(4)该类分子在进入神经细胞后，受到细胞膜内、外pH值差异影响，形成了阴离子不同(主要为细胞内最常见的氯离子)而扩散能力降低的季铵阳离子氯化物作用于靶点，容易进却难于出神经细胞，作用时间更持久，局部损伤也降低。
(5)进入血液后，能够产生强π-π堆积作用的结构立刻消失，因而全身毒性低。
以上全部或部分特性决定了本发明涉及化合物能产生低毒的长效局麻作用。
双子表面活性剂结构
化合物(Ⅰ)具有非典型的不对称双子表面活性剂结构特征。以化合物A1为例。与传统的季铵阳离子型不对称双子表面活性剂相比，该化合物的季铵阳离子并未通过连接基团与另一亲水头基共价连接，而是由其阴离子与连接基团(亚甲基)、另一亲水头基(碳酸酯基)以及疏水尾链(正己基)依次相连(图4)。简言之，化合物(Ⅰ)是通过离子键而非常规的共价键连接不同亲水头基的双子表面活性剂。
两分子的化合物(Ⅱ)通过π-π堆积，也可形成非典型的串联型双子表面活性剂结构。如图5所示，化合物B1的两个π-π堆积的苯环，可以看作类似于传统串联型双子表面活性剂分子的长疏水尾链；叔胺酸式盐结构则是亲水头基。
π-π堆积与Janus粒子
仍然以化合物A1为例，其在蒸馏水中可自组装形成葫芦型的Janus粒子。此前文章中提到，该类Janus粒子的形成与π-π堆积作用密切相关(L.Tang.Chem.Commun.2017,53,8675-8678.)。以重水为溶剂，进行与TEM等浓度的NOESY谱图检测，可发现2,6-二甲基的氢原子与苯环上3,5-的氢原子相关，说明化合物A1在水中超分子自组装后，分子间的甲基氢与芳环氢在空间位置上接近，且其空间接近程度显著高于其他位置的氢，如图6。
由于芳环和甲基的刚性结构和键角导致同一分子中的两个氢原子无法在空间位置上接近，因而有且仅有芳环以“side by side”的方式发生了π-π堆积才会出现不同分子上的两种氢原子在空间位置上的接近。
尽管不具备双子表面活性剂的结构特征，化合物(Ⅱ)仍然可在水中自组装形成强π-π堆积的超分子粒子，以甲酸利多卡因(化合物B1)为例。在蒸馏水中，该化合物可自组装形成葫芦型的Janus粒子。以重水为溶剂，进行与TEM等浓度的NOESY谱图检测，仍可发现2,6-二甲基的氢原子与3,5-的苯环上的氢原子相关，如图7。从而说明甲酸利多卡因也存在分子间的π-π堆积作用。两分子的甲酸利多卡因会因π-π堆积形成一个非典型的串联型双子表面活性剂结构的超分子体，进一步与单个甲酸利多卡因分子共同自组装形成Janus粒子。同时，由于甲酸为弱酸，形成的两个叔胺甲酸盐离子对的电荷相互排斥能力相对强酸盐较弱，因而有利于实现π-π堆积。
用同样的方法对等浓度的醋酸利多卡因进行了TEM和NOESY检测，发现该化合物无法形成Janus粒子，只能形成球形胶束；2,6-二甲基的氢原子与3,5-位的苯环上的氢原子无相关性，因而没有或没有足够强的π-π堆积作用，如图8。原因在于有机酸根离子的体积过大时，很难形成有效的π-π堆积。类似的情况也出现在氢溴酸利多卡因的自组装中。氢溴酸利多卡因在水中自组装后，只能形成球形胶束，NOESY谱图也无相关氢的响应。
综上，本发明所涉及的化合物(Ⅰ)和(Ⅱ)，均能够在水中自组装形成π-π堆积作用强的，包括球形胶束和Janus粒子在内的有序的超分子结构。
扩散与缓释机制
本发明涉及化合物，在水中自组装形成包括球形胶束和Janus粒子在内的有序的超分子结构。注射于局部，该类粒子扩散至神经细胞膜内，经阴离子交换后，形成季铵阳离子氯化物，阻滞细胞膜内侧的Na+通道，产生局麻作用，如图9。
本发明涉及化合物自组装形成的纳米胶束和/或粒子，具有其特有的强π-π堆积作用，在进入神经细胞膜之前，扩散和缓释能力都强于常见表面活性剂。此特性为该类化合物能实现长效的原因之一。
进入神经细胞后，由于细胞内pH值低于细胞外，而本发明涉及化合物为酸性较弱的羧酸盐，根据强酸置换弱酸的基本原理，容易发生阴离子交换。又因为细胞内主要的阴离子为氯离子，因而交换后的化合物主要为氯化物。亲脂性弱的该类季铵阳离子氯化物较难透过细胞膜，从而也很难扩散失效。此性质为该类化合物实现长效的另一重要原因。
低毒性机理
本发明所涉及的化合物(Ⅰ)为季铵阳离子的羧酸盐。其潜在的局部神经病理毒性，可通过前面提及的，神经细胞内的离子交换而失去其双子表面活性剂的结构特征，大幅降低其扩散能力，进而减少了表面活性剂结构带来的损伤。其它已报道的具有表面活性剂结构的分子，整体结构为共价连接，不具备本发明化合物所独有的通过离子交换快速失去表面活性的特性，因而局部毒性相对较大。
全身毒性的情况类似。由于血液中主要的阴离子为氯离子，且相对本化合物的阴离子大大过量，因而可快速实现离子交换，如图10。同时由于血液的pH为7.35～7.45，相对于本发明所涉及的季铵羧酸类化合物偏酸性，更加促进了该类强碱弱酸盐向强酸强碱盐的离子交换变化。如图10所示，其中的一个化合物LD50(大鼠静脉注射)仅为15.2mg/kg，与已上市最长效的盐酸布比卡因(LD50＝6.0mg/kg，大鼠静脉注射)相比，全身毒性大幅降低。而该化合物的LD50又与相对低毒性的该类季铵氯化物十分接近。该结果说明此类化合物确实可在血液中快速实现离子交换，也通过实施例中更多该类化合物的LD50结果得到验证。
根据以上原理，当羧酸根离子替换为磺酸根离子时，化合物仍能产生近似的低毒长效作用。不同之处在于，有机磺酸根离子的酸性较强，进入神经细胞膜内，交换氯离子能力较弱，容易再次扩散出神经细胞，因而局麻作用时间相对较短，局部毒性和全身毒性也有所增加。而当酸根离子为饱和脂肪酸时，由于失去了双子表面活性剂的基本结构，脂肪长链会干扰芳环的π-π堆积作用，该类超分子结构缓释能力降低，作用时间显著变短(实施例13，表1)。
对于式(Ⅱ)化合物，其产生低毒长效的机理与式(Ⅰ)类似，均与弱酸性的有机酸根和强π-π堆积作用有关。不同之处在于，式(Ⅱ)化合物对有机酸根要求更苛刻。首先酸性需要适中。酸性过强，如盐酸、氢溴酸，则很难产生长效；酸性不足，则水溶性不足，如氢氟酸。其次酸根的体积要小。如冰醋酸以及更大体积的有机酸，会导致局部空间拥挤，难以实现有效的π-π堆积作用(图7)，从而局麻时间较甲酸盐显著缩短。
实验结果已表明，本发明上述式(Ⅰ)和(Ⅱ)结构化合物在水中自组装形成强π-π堆积的纳米粒子后，在生物体内可发挥长时间局部麻醉作用，局部毒性和全身毒性较已报道的长效局麻分子明显降低。此外，作为在水中能自组装形成的该胶束生物材料，同时还可以作为包裹包括治疗疼痛、瘙痒等症状的药物活性分子和/或药物载体的生物材料及传递系统等使用的制剂辅料，具有良好的前景。
附图说明
图1是局部麻醉药物的作用机理示意图；
图2是“并联型”和“串联型”双子表面活性剂示意图；
图3是具有局麻活性的并联型不对称双子表面活性剂结构示意图；
图4是离子键连接的“并联型”双子表面活性剂A1结构示意图；
图5是苯环π-π堆积连接的串联型双子表面活性剂B1结构示意图；
图6是化合物A1在水中自组装的TEM照片和重水中的NOESY谱图；
图7是化合物B1在水中自组装的TEM照片和重水中的NOESY谱图；
图8是醋酸利多卡因在水中自组装的TEM照片和重水中的NOESY谱图；
图9是本发明的扩散与缓释机理示意图；
图10是本发明所涉及化合物在血液中快速降解原理示意图；
图11是实施例12的TEM照片；
图12是实施例13的NOESY谱图。
具体实施方式
以下通过实施例的具体实施方式再对本发明的上述内容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。在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段做出的各种替换或变更，均应包括在本发明的范围内。
实施例1
Figure BDA0003145480140000101
于100mL圆底烧瓶中，加入羟基羧酸钠5mmol，吡啶5mmol，无水乙腈30mL，冰浴下搅拌0.5h。缓慢滴加对应的有机酰氯5mmol的25mL无水乙腈溶液，15min滴毕。过滤，滤液加入1N氯化氢的乙醇溶液10mL，减压浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的羧酸，如下：
Figure BDA0003145480140000102
实施例2
Figure BDA0003145480140000103
方法一：
于100mL圆底烧瓶中，加入羟基羧酸钠5mmol，1，2-二氯乙烷30mL。室温搅拌下加入三聚光气2mmol。缓慢滴加吡啶5mmol，室温搅拌1h。滴加对应的脂肪醇或脂肪胺5mmol，50℃搅拌16h。冷却至室温，过滤。滤液加入1N氯化氢的乙醇溶液10mL，浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的羧酸，如下：
Figure BDA0003145480140000111
方法二：
于100mL圆底烧瓶中，加入羟基羧酸钠5mmol，1,2-二氯乙烷30mL。冰浴搅拌下滴加二氯亚砜5mmol的1,2-二氯乙烷10mL，15min滴毕。撤去冰浴，室温搅拌30min。滴加对应的脂肪醇5mmol，室温搅拌24h。过滤，滤液加入1N氯化氢的乙醇溶液10mL，减压浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的羧酸如下：
Figure BDA0003145480140000112
实施例3
Figure BDA0003145480140000113
于50mL圆底烧瓶中，加入羟基羧酸乙酰胺10mmol，脂肪醇10mmol，室温搅拌下加入70％硫酸10mL，80℃下搅拌加热4h。冷却至室温，残余物倾倒至装有冰水混合物约100mL的烧杯中，二氯甲烷50mL x 4萃取。合并有机相，水20mL x 2萃洗，无水硫酸钠干燥，浓缩。残余物加入4mmol/L的氢氧化钠水溶液，回流搅拌6h。残余物用1N盐酸酸化至pH＝5.0,二氯甲烷50mL x4萃取，浓缩。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的羧酸如下：
Figure BDA0003145480140000114
实施例4
Figure BDA0003145480140000121
于100mL圆底烧瓶中，加入二羧酸单苄酯5mmol，草酰氯5mmol，室温搅拌2h。滴加脂肪醇5mmol的二氯甲烷溶液30mL，室温搅拌24h。浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，得到二羧酸二酯。将得到的该二羧酸酯置于50mL圆底瓶中，加入1mmol 5％Pd/C，甲醇20mL，通入1atm氢气，室温搅拌24h。过滤，浓缩。二氯甲烷-甲醇硅胶柱层析，真空干燥，得到对应的羧酸如下：
Figure BDA0003145480140000122
实施例5
Figure BDA0003145480140000123
于80mL厚壁玻璃容器中，分别加入利多卡因25mmol和有机溴代物25mmol，100℃封管加热24h，冷却至室温。二氯甲烷-甲醇硅胶柱层析，分离得到对应的季铵溴化物。该类季铵溴化物在5℃下，通过强碱性离子交换树脂
Figure BDA0003145480140000124
1X2(CAS:69011-19-4)进行离子交换，得到的水溶液在5℃下用二氯甲烷50mL x 5萃取，有机相合并，用10mL水萃洗，浓缩至干。真空干燥，得到的季铵碱如下：
Figure BDA0003145480140000131
实施例6
Figure BDA0003145480140000132
于80mL厚壁玻璃容器中，分别加入α-氯代酰胺25mmol和对应的叔胺25mmol，100℃封管加热24h，冷却至室温。二氯甲烷-甲醇硅胶柱层析，分离得到对应的季铵氯化物。该类季铵溴化物在5℃下，通过强碱性离子交换树脂
Figure BDA0003145480140000134
1X2(CAS:69011-19-4)进行离子交换，得到的水溶液在5℃下用二氯甲烷50mL x 5萃取，浓缩至干。真空干燥，得到对应的季铵碱如下：
Figure BDA0003145480140000133
实施例7
将实施例1中的有机羧酸分别精密称量1.00g至50mL圆底烧瓶中，30mL二氯甲烷溶解。0℃搅拌下分别缓慢加入对应的实施例5和实施例6中得到的，经精密称量等物质的量的季铵碱，浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到用于配置药液的终产物。得到的化合物及其结构数据如下：
Figure BDA0003145480140000141
化合物1：1H NMR(400MHz，CDCl3)δ:7.02～7.05(m,3H),4.92(br,2H),4.46(br,2H),3.63(q,J＝7.3Hz,6H),2.24(s,6H),2.10(s,3H),1.42(t,J＝7.3Hz,9H).13C NMR(100MHz,CDCl3)δ:7.85,18.52,21.18,54.08,56.20,60.64,64.13,127.02,127.99,132.88,133.71,134.96,162.37,171.20,172.97.
化合物2：1H NMR(400MHz，CDCl3)δ:6.99～7.05(m,3H),4.90(br,2H),4.36～4.41(m,2H),3.49～3.59(m,6H),2.26～2.34(m,2H),2.19～2.22(m,6H),1.54～1.59(m,2H),1.30～1.37(m,9H),1.22～1.26(m,2H),0.84～0.87(m,3H).13C NMR(100MHz,CDCl3)δ:7.70,13.85,18.54,22.22,24.53,31.21,54.01,63.86,126.97,127.92,133.68,134.96,162.13,172.86,173.91.
化合物3：1H NMR(400MHz，CDCl3)δ:7.02～7.05(m,3H),4.91(br,2H),4.46(br,2H),3.63(q,J＝7.3Hz,6H),2.36(t,J＝7.7Hz,2H),2.24(s,6H),1.58～1.63(m,2H),1.42(t,J＝7.3Hz,9H),1.26～1.30(m,4H),0.86(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:7.84,13.90,18.53,22.31,24.61,31.30,34.26,54.05,56.18,63.97,126.99,127.96,133.71,134.95,162.37,173.08,174.02.
化合物4：1H NMR(400MHz，CDCl3)δ:7.01～7.09(m,3H),4.78～4.82(m,2H),4.43～4.45(m,2H),3.55～3.64(m,6H),2.31～2.37(m,2H),2.24(s,6H),1.54～1.63(m,2H),1.35～1.41(m,9H),1.25～1.32(m,6H),0.85～0.89(m,3H).13C NMR(100MHz,CDCl3)δ:7.75,13.98,18.46,22.39,24.82,28.75,31.42,34.20,54.03,56.04,63.64,126.98,127.93,133.71,135.00,162.39,172.86,173.90.
化合物5：1H NMR(400MHz，CDCl3)δ:6.97～7.02(m,3H),4.86～4.89(m,2H),4.42(br,2H),3.56～3.62(m,6H),2.32(t,J＝7.7Hz,2H),2.20(br,6H),1.52～1.59(m,2H),1.36～1.40(m,9H),1.21～1.27(m,8H),0.83(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:7.85,14.05,18.54,22.58,24.93,28.94,29.10,31.62,34.31,54.05,56.19,63.97,126.99,127.97,133.79,134.94,162.37,173.08,174.02.
化合物6：1H NMR(400MHz，CDCl3)δ:7.01～7.06(m,3H),4.89～4.91(m,2H),4.42(br,2H),3.56～3.62(m,6H),2.32(t,J＝7.7Hz,2H),2.20(br,6H),1.52～1.59(m,2H),1.36～1.41(m,9H),1.22～1.29(m,12H),0.85(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:7.78,14.02,18.50,22.58,24.93,28.94,29.04,29.11,29.18,31.42,34.30,54.12,56.24,63.97,126.99,127.97,133.79,134.92,173.08,174.02.
化合物7：1H NMR(400MHz，CDCl3)δ:7.01～7.06(m,3H),4.88～4.91(m,2H),4.45(br,2H),3.52～3.60(m,6H),2.26～2.29(m,2H),2.23(br,6H),1.52～1.59(m,2H),1.36～1.41(m,9H),1.23～1.30(m,16H),0.79～0.82(m,3H).13C NMR(100MHz,CDCl3)δ:7.70,14.11,18.50,22.49,24.90,28.92,28.99,29.06,29.12,29.15,29.17,31.62,34.30,54.12,56.24,63.97,127.02,127.95,133.76,134.89,173.18,174.06.
化合物8：1H NMR(400MHz，CDCl3)δ:6.99～7.06(m,3H),4.87～4.92(m,2H),4.39(br,2H),3.51～3.57(m,6H),2.32～2.36(m,2H),2.25(br,6H),1.52～1.58(m,2H),1.37～1.41(m,9H),1.21～1.31(m,24H),0.82～0.86(m,3H).13C NMR(100MHz,CDCl3)δ:7.83,14.21,18.52,22.53,24.90,28.93,28.99,29.02,29.04,29.06,29.10,29.12,29.15,29.16,29.18,31.65,34.30,54.12,56.24,63.97,127.02,127.95,133.76,134.89,173.18,174.06.
化合物9：1H NMR(400MHz，CDCl3)δ:6.99～7.06(m,3H),4.31～4.35(m,2H),4.39(br,2H),3.51～3.57(m,6H),2.49～2.52(m,2H),2.32～2.36(m,2H),2.28～2.31(m,2H),2.25(br,6H),1.63～1.68(m,2H),1.52～1.58(m,2H),1.37～1.41(m,9H),1.26～1.31(m,12H),0.89(t,J＝6.9Hz,3H).13C NMR(100MHz,CDCl3)δ:7.85,18.52,22.72,24.86,29.02,29.18,29.32,29.37,29.64,31.81,33.72,33.88,54.08,59.79,64.13,127.99,132.88,133.71,134.96,162.37,173.12,177.30.
化合物11：1H NMR(400MHz，CDCl3)δ:6.98～7.06(m,3H),5.61～5.72(m,1H),5.14～5.24(m,2H),4.88(m,2H),4.78～4.82(m,2H),3.52～3.71(m,6H),2.58～2.61(m,3H),2.31～2.37(m,2H),2.23(s,6H),1.54～1.63(m,2H),1.43(t,J＝6.4Hz,6H),1.25～1.32(m,6H),0.85～0.89(m,3H).13C NMR(100MHz,CDCl3)δ:8.20,13.92,18.82,22.36,24.76,26.82,28.77,31.42,34.20,55.37,57.04,58.26,63.64,119.82,127.33,128.13,130.85,133.11,134.96,161.77,172.88,173.92.
化合物12：1H NMR(400MHz，CDCl3)δ:10.96(s,1H),6.99～7.02(m,3H),4.90(br,2H),5.61～5.71(m,1H),5.20(d,J＝17.1Hz,1H),5.14(d,J＝10.1Hz,1H),4.82(br,1H),3.51～3.60(m,6H),2.56～2.62(m,2H),2.26～2.34(m,2H),2.22(s,6H),1.54～1.59(m,2H),1.41(t,J＝6.4Hz,6H),1.22～1.26(m,2H),0.84～0.87(m,3H).13C NMR(100MHz,CDCl3)δ:8.18,13.85,18.81,22.22,26.81,24.53,31.21,57.26,55.29,56.97,58.20,63.86,127.38,128.09,130.86,133.08,135.00,161.81,172.86,173.91.
化合物13：1H NMR(400MHz，CDCl3)δ:7.00～7.04(m,3H),4.91(s,2H),4.61(s,2H),4.02(s,2H),3.68(m,4H),2.36(t,J＝7.7Hz,2H),2.22(s,6H),1.58～1.63(m,2H),1.45(s,6H),1.26～1.30(m,4H),0.86(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.23,13.90,18.81,22.31,24.61,31.30,34.26,56.43,57.58,57.84,60.86,63.97,127.49,128.12,132.90,135.05,154.69,161.75,173.08,174.02.
化合物14：1H NMR(400MHz，CDCl3)δ:10.96(s,1H),7.00～7.03(m,3H),5.63～5.71(m,1H),5.18(d,J＝17.1Hz,1H),5.12(d,J＝10.1Hz,1H),4.93(br,2H),4.82(br,1H),3.51～3.60(m,6H),2.56～2.62(m,2H),2.35(t,J＝7.7Hz,2H),2.22(s,6H),1.59～1.63(m,2H),1.43(t,J＝6.4Hz,6H),1.27～1.31(m,4H),0.87(t,J＝6.7Hz,3H).13CNMR(100MHz,CDCl3)δ:7.98,13.92,18.80,22.32,24.58,26.83,31.32,34.20,57.26,55.29,56.95,58.21,63.98,127.39,128.12,130.84,133.07,135.02,161.79,173.10,174.03.
化合物15：1H NMR(400MHz，CDCl3)δ:7.00～7.04(m,3H),4.79～4.82(m,2H),4.61(s,2H),4.02(s,2H),3.68(m,4H),2.31～2.36(m,2H),2.22(s,6H),1.55～1.62(m,2H),1.45(s,6H),1.25～1.32(m,6H),0.85～0.89(m,3H).13C NMR(100MHz,CDCl3)δ:8.15,13.92,18.82,22.37,24.82,28.81,31.39,34.23,56.43,57.58,57.84,60.86,63.59,127.49,128.12,132.90,135.05,154.69,161.75,172.83,173.88.
化合物16：1H NMR(400MHz，CDCl3)δ:7.01～7.04(m,3H),4.96(br,2H),4.90(br,2H),3.91(Ha,1H),3.83(Hb,1H),3.62～3.81(m,6H),3.40(s,3H),2.26～2.34(m,2H),2.22(s,6H),2.08(br,2H),1.54～1.60(m,2H),1.47(t,J＝7.1Hz,6H),1.23～1.28(m,2H),0.86(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.28,13.86,18.80,22.22,24.52,31.23,56.27,57.35,58.84,59.32,66.07,63.83,127.35,128.09,133.10,134.97,162.03,172.85,173.92.
化合物17：1H NMR(400MHz，CDCl3)δ:7.01～7.05(m,3H),4.95(br,2H),4.87(br,2H),3.87(Ha,1H),3.81(Hb,1H),3.65～3.76(m,6H),3.42(s,3H),2.34(t,J＝7.7Hz,2H),2.23(s,6H),2.08(br,2H),1.58～1.63(m,2H),1.26～1.30(m,4H),1.46(t,J＝7.1Hz,6H),0.86(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.26,18.79,56.28,13.90,22.33,24.58,31.32,34.26,57.37,58.82,59.33,66.05,63.97,127.36,128.09,133.08,134.98,162.00,173.11,174.03.
化合物18：1H NMR(400MHz，CDCl3)δ:7.01～7.05(m,3H),4.97(br,2H),4.86～4.88(m,2H),3.89(Ha,1H),3.82(Hb,1H),3.62～3.78(m,6H),3.40(s,3H),2.33(t,J＝7.7Hz,2H),2.26(s,6H),2.09(br,2H),1.46(t,J＝7.1Hz,6H),1.21～1.27(m,8H),0.86(t,J＝6.7Hz,3H).13CNMR(100MHz,CDCl3)δ:8.31,14.03,18.81,22.56,24.92,28.92,29.13,31.60,34.31,56.28,57.36,58.86,59.36,66.08,63.96,127.33,128.08,133.11,134.95,162.01,173.08,174.05.
化合物19：1H NMR(400MHz，CDCl3)δ:7.00～7.05(m,3H),4.96(br,2H),4.89～4.91(m,2H),3.88(Ha,1H),3.83(Hb,1H),3.63～3.76(m,6H),3.39(s,3H),2.31(t,J＝7.7Hz,2H),2.26(s,6H),2.09(br,2H),1.46(t,J＝7.1Hz,6H),1.22～1.29(m,12H),0.85(t,J＝6.7Hz,3H).13CNMR(100MHz,CDCl3)δ:8.29,14.05,18.80,22.58,24.91,28.97,29.05,29.12,29.20,31.59,34.31,56.31,57.38,58.87,59.35,66.02,63.96,127.36,128.13,133.05,134.93,162.02,173.09,174.03.
化合物20：1H NMR(400MHz，CDCl3)δ:6.99～7.04(m,3H),4.93(br,2H),4.88(br,2H),3.86(br,2H),3.80(br,2H),3.64～3.73(m,4H),3.49～3.56(m,2H),2.37(t,J＝7.7Hz,2H),2.32(s,6H),1.58～1.63(m,2H),1.44(t,J＝6.8Hz,6H),1.26～1.30(m,4H),1.15(t,J＝6.9Hz,3H),0.86(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.26,13.90,14.95,18.81,22.32,24.59,31.33,34.26,56.17,57.26,58.82,63.97,67.19,127.35,128.07,133.09,135.01,162.06,173.07,174.05.
化合物22：1H NMR(400MHz，CDCl3)δ:7.02～7.06(m,3H),4.94(br,2H),4.86(br,2H),4.19～4.21(m,2H),3.73～3.88(m,4H),3.65～3.68(m,2H),2.24(s,6H),2.36(t,J＝7.7Hz,2H),1.58～1.63(m,2H),1.43(t,J＝7.1Hz,6H),1.26～1.31(m,4H),0.86(t,J＝6.7Hz,3H).13CNMR(100MHz,CDCl3)δ:8.15,13.90,18.74,22.33,24.61,31.29,34.18,35.53,55.57,56.04,57.21,59.38,63.89,127.33,128.06,133.21,134.96,161.56,173.08,174.01.
化合物23：1H NMR(400MHz，CDCl3)δ:7.02～7.08(m,3H),4.88(br,2H),4.78～4.83(m,2H),4.19～4.21(m,2H),3.73～3.88(m,4H),3.65～3.68(m,2H),2.31～2.36(m,2H),2.23(s,6H),1.56～1.63(m,2H),1.43(t,J＝7.1Hz,6H),1.25～1.32(m,6H),0.86(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.13,13.97,18.72,22.38,24.85,28.72,31.42,34.21,35.50,55.56,56.07,57.19,59.40,63.64,127.32,128.09,133.18,134.93,161.57,172.87,173.92.
化合物24：1H NMR(400MHz，CDCl3)δ:7.01～7.05(m,3H),4.90(br,2H),4.86～4.88(m,2H),4.19～4.23(m,2H),3.77～3.85(m,4H),3.63～3.67(m,2H),2.32(t,J＝7.7Hz,2H),2.22(s,6H),1.45(t,J＝7.1Hz,6H),1.20～1.27(m,8H),0.84(t,J＝6.7Hz,3H).13CNMR(100MHz,CDCl3)δ:8.19,14.03,22.56,24.88,28.92,29.10,31.58,34.29,18.70,35.51,55.56,56.03,57.19,59.38,127.30,128.01,133.19,134.99,161.57.63.97,173.09,174.02.
化合物25：1H NMR(400MHz，CDCl3)δ:7.02～7.10(m,3H),4.89～4.92(m,2H),4.87(br,2H),4.19～4.22(m,2H),3.73～3.88(m,4H),3.65～3.68(m,2H),2.32(t,J＝7.7Hz,2H),2.24(s,6H),1.43(t,J＝7.1Hz,6H),1.21～1.28(m,10H),0.86(t,J＝6.7Hz,3H).13CNMR(100MHz,CDCl3)δ:8.12,14.06,18.77,22.56,24.91,28.98,29.07,29.16,31.62,34.27,35.5655.54,56.03,57.22,59.36,63.94,127.31,128.11,133.24,134.93,161.55,173.08,174.00.
化合物26：1H NMR(400MHz，CDCl3)δ:6.99～7.05(m,3H),4.92(br,2H),4.84(br,2H),4.59(Ha,1H),4.47(Hb,1H),3.57～3.70(m,6H),2.36(t,J＝7.7Hz,2H),2.32(Ha,1H),2.27(Hb,1H),2.21(s,6H),1.58～1.63(m,2H),1.39(t,J＝6.9Hz,6H),1.26～1.31(m,4H),0.86(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.04,13.88,18.74,22.27,24.00(d,J＝19.6Hz,),24.61,31.30,34.26,55.33,56.31,56.99,63.94,79.65,81.32,127.44,128.12,133.02,135.01,161.82,173.05,174.01.
化合物27：7.00～7.05(m,3H),4.82(br,2H),4.78(br,2H),4.58(Ha,1H),4.45(Hb,1H),3.56～3.67(m,6H),2.32(Ha,1H),2.28(Hb,1H),2.33～2.37(m,2H),2.22(s,6H),1.56～1.62(m,2H),1.39(t,J＝6.9Hz,6H),1.26～1.33(m,6H),0.85～0.89(m,3H).13C NMR(100MHz,CDCl3)δ:8.03,14.00,18.70,22.41,24.02(d,J＝19.6Hz,),24.77,28.76,31.42,34.23,55.32,56.30,56.97,63.61,79.68,81.34,127.42,128.09,133.05,135.04,161.86,172.88,173.92.
化合物28：7.01～7.05(m,3H),4.87～4.90(m,2H),4.83(br,2H),4.58(Ha,1H),4.45(Hb,1H),3.60～3.70(m,6H),2.33(Ha,1H),2.25(Hb,1H),2.30(t,J＝7.7Hz,2H),2.22(s,6H),1.40(t,J＝6.9Hz,6H),1.21～1.26(m,8H),0.84(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.02,14.07,18.75,22.56,24.02(d,J＝19.6Hz,),24.91,28.92,29.13,31.61,34.33,55.32,56.28,57.01,63.98,79.63,81.29,127.42,128.13,133.07,135.04,161.79,173.09,174.00.
化合物29：6.98～7.05(m,3H),4.86～4.90(m,2H),4.83(br,2H),4.58(Ha,1H),4.48(Hb,1H),3.57～3.67(m,6H),2.33(Ha,1H),2.25(Hb,1H),2.31(t,J＝7.7Hz,2H),2.22(s,6H),1.41(t,J＝6.9Hz,6H),1.21～1.27(m,10H),0.85(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.04,14.02,18.74,22.57,24.01(d,J＝19.6Hz,),24.93,28.94,29.10,29.18,31.62,34.31,55.33,56.31,56.99,63.96,79.65,81.32,127.44,128.12,133.02,135.01,161.82,173.08,174.02.
化合物30：6.99～7.05(m,3H),4.90(br,2H),4.83(br,2H),3.78(m,2H),3.57～3.70(m,6H),2.36(m,2H),2.26～2.32(m,2H),2.21(s,6H),1.55～1.59(m,2H),1.43(t,J＝6.9Hz,6H),1.22～1.26(m,2H),0.84～0.87(m,3H).13C NMR(100MHz,CDCl3)δ:8.02,13.83,18.74,43.19,55.33,56.31,56.99,79.65,81.32,127.44,128.12,133.02,135.01,161.82.22.22,24.53,31.21,63.86,172.86,173.91.
化合物31：6.99～7.05(m,3H),4.84(br,2H),4.78～4.81(m,2H),3.78(m,2H),3.57～3.70(m,6H),2.29～2.34(m,2H),2.36(br,2H),2.21(s,6H),1.55～1.62(m,2H),1.42(t,J＝6.9Hz,6H),1.25～1.31(m,6H),0.86～0.90(m,3H).13C NMR(100MHz,CDCl3)δ:8.12,13.98,18.84,22.39,24.82,28.75,31.42,34.20,43.19,55.30,56.30,56.96,63.60,79.63,81.30,127.42,128.10,133.03,135.02,161.85,172.86,173.90.
实施例8
参照实施例7，精密称定部分实施例2～4和实施例5的有机酸、碱，制备得到用于配置药液的终产物。化合物及其结构数据如下：
Figure BDA0003145480140000241
化合物32：1H NMR(400MHz，CDCl3)δ:6.98～7.05(m,3H),4.87(br,2H),4.44(br,2H),4.02(t,J＝6.8Hz,2H),3.61(q,J＝7.3Hz,6H),2.21(s,6H),1.56～1.63(m,2H),1.40(q,J＝7.3Hz,9H),1.24～1.27(m,4H),0.85(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:7.86,13.91,18.63,22.26,27.78,28.92,54.12,56.20,66.07,67.77,127.06,128.00,133.61,134.96,155.55,162.35,172.72.
化合物33：1H NMR(400MHz，CDCl3)δ:7.08～7.14(m,3H),4.86～4.87(m,2H),4.77～4.79(m,1H),4.62(br,1H),4.20(t,J＝6.7Hz,1H),4.12(t,J＝6.8Hz,1H),3.69(q,J＝6.8Hz,6H),2.29(s,6H),1.66～1.74(m,2H),1.48(t,J＝6.7Hz,9H),1.31～1.43(m,6H),0.92～0.96(m,3H).13C NMR(100MHz,CDCl3)δ:7.83,13.95,13.97,18.51,22.47,25.25,25.32,28.50,28.56,31.32,31.37,54.17,56.15,63.37,67.93,68.47,127.15,128.03,133.47,135.01,154.77,155.46,162.30,167.75.
化合物34：1H NMR(400MHz，CDCl3)δ:7.00～7.05(m,3H),4.87(br,2H),4.46(br,2H),4.02(t,J＝6.8Hz,2H),3.63(q,J＝7.3Hz,6H),2.25(s,6H),1.59～1.65(m,2H),1.43(q,J＝7.3Hz,9H),1.24～1.30(m,10H),0.87(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:7.86,13.91,18.63,22.26,27.78,28.92,29.09,29.30,54.15,56.24,66.13,67.72,127.08,128.05,133.64,134.98,155.59,162.32,172.72.
化合物35：1H NMR(400MHz，CDCl3)δ:7.02～7.05(m,3H),5.01(br,2H),4.46(br,2H),3.63(q,J＝7.3Hz,6H),3.16～3.19(m,2H),2.24(s,6H),1.50～1.53(m,2H),1.42(t,J＝7.3Hz,9H),1.28～1.33(m,10H),0.88(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:7.85,14.12,18.52,22.73,26.41,26.73,2933,29.39,31.78,40.29,54.08,61.55,64.13,127.99,132.88,133.71,134.96,155.86,162.37,172.99.
化合物36：1H NMR(400MHz，CDCl3)δ:7.01～7.05(m,3H),5.02(br,2H),4.43(br,2H),3.61(q,J＝7.3Hz,6H),3.16～3.19(m,2H),2.22(s,6H),1.50～1.54(m,2H),1.43(t,J＝7.3Hz,9H),1.26～1.34(m,18H),0.87(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:7.89,14.08,18.60,22.73,26.44,26.76,29.33,29.36,29.61,29.64,29.67,29.69,31.83,40.32,54.13,61.49,64.12,127.96,132.85,133.78,134.98,155.89,162.41,172.92.
化合物37：1H NMR(400MHz，CDCl3)δ:7.02～7.05(m,3H),4.49(br,2H),4.43(br,2H),4.02(br,2H),3.60(q,J＝7.3Hz,6H),2.22(s,6H),1.50～1.57(m,2H),1.41(t,J＝7.3Hz,9H),1.35～1.42(m,10H),0.89～0.92(m,3H).13C NMR(100MHz,CDCl3)δ:7.79,14.12,18.52,22.61,26.11,29.20,29.35,29.60,31.77,54.08,64.13,69.39,72.45,128.01,132.86,133.73,134.92,162.37,172.88.
化合物38：1H NMR(400MHz，CDCl3)δ:7.02～7.05(m,3H),4.46(br,2H),4.30(br,2H),3.63(q,J＝7.3Hz,6H),3.36(t,J＝8.0Hz,2H),2.24(s,6H),1.48～1.52(m,2H),1.43(t,J＝7.3Hz,9H),1.40～1.43(m,2H),1.25～1.30(m,4H),0.88(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:7.76,14.08,18.47,22.65,29.66,31.78,54.05,64.11,64.50,67.36,127.97,132.86,133.68,135.01,162.35,173.01.
化合物39：1H NMR(400MHz，CDCl3)δ:7.01～7.05(m,3H),4.43(br,2H),4.28(br,2H),3.63(q,J＝7.3Hz,6H),3.37(t,J＝8.0Hz,2H),2.24(s,6H),1.48～1.53(m,2H),1.42～1.45(m,2H),1.41(t,J＝7.3Hz,9H),1.26～1.33(m,10H),0.89(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:7.78,14.12,18.50,22.69,29.18,29.26,29.35,29.63,29.68,29.76,54.11,64.15,64.38,67.42,127.96,132.84,133.71,134.93,162.39,173.01.
化合物40：1H NMR(400MHz，CDCl3)δ:7.00～7.04(m,3H),4.43(br,2H),4.13(t,J＝7.8Hz,2H),3.60(q,J＝7.3Hz,6H),2.80～2.84(m,2H),2.71～2.75(m,2H),2.21(s,6H),1.60～1.63(m,2H),1.42～1.45(m,2H),1.40(t,J＝7.3Hz,9H),0.88(t,J＝7.0Hz,3H).13CNMR(100MHz,CDCl3)δ:7.88,13.90,18.54,18.95,29.05,29.15,54.06,64.10,64.89,128.03,132.78,133.69,135.01,162.35,173.22,174.64.
化合物41：1H NMR(400MHz，CDCl3)δ:7.00～7.04(m,3H),4.43(br,2H),3.61(q,J＝7.3Hz,6H),3.00～3.05(m,2H),2.71～2.74(m,2H),2.45～2.48(m,2H),1.50～1.53(m,2H),2.23(s,6H),1.42(t,J＝7.3Hz,9H),1.28～1.32(m,10H),0.90(t,J＝7.0Hz,3H).13CNMR(100MHz,CDCl3)δ:7.79,14.02,18.50,22.46,26.49,29.08,29.22,29.29,29.33,29.36,29.98,30.24,31.82,39.23,54.12,64.11,127.97,132.86,133.75,134.94,162.36,172.18,173.84.
化合物42：1H NMR(400MHz，CDCl3)δ:6.98～7.04(m,3H),5.61～5.72(m,1H),5.18～5.23(m,2H),5.02(br,2H),4.86～4.90(m,2H),3.57～3.71(m,6H),3.16(t,J＝7.8Hz,2H),2.58～2.63(m,3H),2.23(s,6H),1.42(t,J＝6.4Hz,6H),1.49～1.53(m,2H),1.28～1.32,(m,2H),0.90(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:8.18,13.72,18.80,19.81,26.81,32.15,40.03,55.33,57.02,58.30,61.52,119.82,127.36,128.07,130.83,133.14,134.92,155.89,161.75,172.94.
化合物43：1H NMR(400MHz，CDCl3)δ:6.99～7.05(m,3H),5.64～5.73(m,1H),5.16～5.22(m,2H),4.88～4.92(m,2H),4.47(br,2H),4.05(br,2H),3.52～3.71(m,6H),2.58～2.61(m,3H),2.23(s,6H),1.50～1.56(m,2H),1.43(t,J＝6.4Hz,6H),1.36～1.42(m,6H),0.88～0.91(m,3H).13C NMR(100MHz,CDCl3)δ:8.17,14.12,18.80,22.54,26.15,26.81,29.16,31.80,55.33,57.09,58.30,69.43,73.12,119.83,127.32,128.06,130.80,133.13,135.01,161.74,172.53.
化合物44：1H NMR(400MHz，CDCl3)δ:11.05(s,1H),7.01～7.05(m,3H),5.01(br,2H),4.93(br,2H),3.86(Ha,1H),3.80(Hb,1H),3.65～3.76(m,6H),3.41(s,3H),3.15～3.18,(m,2H),2.25(s,6H),2.08(br,2H),1.50～1.54(m,2H),1.45(t,J＝7.1Hz,6H),1.27～1.34(m,10H),0.89(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:8.33,14.10,18.78,22.73,26.41,26.70,29.26,29.32,31.81,40.26,56.24,57.33,58.82,59.37,61.54,66.08,127.34,128.11,133.08,134.96,155.86,162.02,172.96.
化合物45：1H NMR(400MHz，CDCl3)δ:7.01～7.06(m,3H),4.96(br,2H),4.30(br,2H),3.88(Ha,1H),3.81(Hb,1H),3.68～3.77(m,6H),3.41(s,3H),3.36(t,J＝8.0Hz,2H),2.23(s,6H),2.07(br,2H),1.48～1.52(m,2H),1.46(t,J＝7.1Hz,6H),1.42～1.45(m,2H),1.24～1.29(m,4H),0.88(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.32,14.10,18.80,22.63,29.66,31.78,56.28,57.37,58.85,59.35,64.50,66.08,67.35,127.36,128.09,133.08,134.96,162.01,173.01.
化合物46：1H NMR(400MHz，CDCl3)δ:7.01～7.05(m,3H),4.96(br,2H),4.86(br,2H),4.05(t,J＝6.8Hz,2H),3.88(Ha,1H),3.84(Hb,1H),3.70～3.80(m,6H),3.40(s,3H),2.26(s,6H),2.09(br,2H),1.61～1.65(m,2H),1.46(t,J＝7.1Hz,6H),1.26～1.31(m,6H),0.87(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:8.28,13.91,18.79,22.33,27.69,28.95,29.07,56.24,57.35,58.83,59.35,66.02,67.80,127.36,128.11,133.06,134.97,162.02,172.73.
化合物47：1H NMR(400MHz，CDCl3)δ:7.00～7.05(m,3H),4.95(br,2H),4.13(t,J＝7.8Hz,2H),3.86(Ha,1H),3.84(Hb,1H),3.70～3.79(m,6H),3.41(s,3H),2.81～2.84(m,2H),2.70～2.75(m,2H),2.24(s,6H),2.07(br,2H),1.60～1.63(m,2H),1.46(t,J＝7.1Hz,6H),1.42～1.45(m,2H),0.88(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:8.27,13.90,18.76,18.95,29.05,29.15,56.33,57.39,58.86,59.38,64.89,66.08,127.37,128.11,133.09,134.99,162.01,173.22,174.64.
化合物48：1H NMR(400MHz，CDCl3)δ:7.02～7.10(m,3H),4.90(br,2H),4.84(br,2H),4.19～4.21(m,2H),4.03(t,J＝6.8Hz,2H),3.73～3.88(m,4H),3.65～3.68(m,2H),2.24(s,6H),1.60～1.65(m,2H),1.43(t,J＝7.1Hz,6H),1.26～1.30(m,6H),0.88(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:8.15,13.90,18.74,22.32,27.69,28.97,29.07,35.5355.57,56.04,57.21,59.38,67.82,127.33,128.06,133.21,134.96,161.56,172.70.
化合物49：1H NMR(400MHz，CDCl3)δ:7.02～7.06(m,3H),5.01(br,2H),4.88(br,2H),4.18～4.21(m,2H),3.79～3.88(m,4H),3.65～3.68(m,2H),3.16～3.19,(m,2H),2.23(s,6H),1.50～1.54(m,2H),1.43(t,J＝7.1Hz,6H),1.28～1.33(m,10H),0.88(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:8.11,14.12,18.70,22.71,26.43,26.76,29.35,29.40,31.78,35.56,40.33,55.55,56.02,57.26,59.43,61.57,127.29,128.09,133.18,134.93,155.86,161.55,172.98.
化合物50：1H NMR(400MHz，CDCl3)δ:7.01～7.06(m,3H),4.88(br,2H),4.49(br,2H),4.19～4.22(m,2H),4.02(br,2H),3.77～3.86(m,4H),3.64～3.67(m,2H),2.24(s,6H),1.49～1.55(m,2H),1.43(t,J＝7.1Hz,6H),1.35～1.42(m,10H),0.89～0.92(m,3H).13C NMR(100MHz,CDCl3)δ:8.12,14.06,18.71,22.58,26.11,29.20,29.35,29.60,31.77,35.52,55.59,56.06,57.23,59.35,69.39,72.45,127.31,128.07,133.21,134.95,161.54,172.88.
化合物51：1H NMR(400MHz，CDCl3)δ:7.02～7.06(m,3H),4.88(br,2H),4.30(br,2H),4.17～4.20(m,2H),3.79～3.87(m,4H),3.65～3.68(m,2H),3.37(t,J＝8.0Hz,2H),2.22(s,6H),1.48～1.53(m,2H),1.42～1.45(m,2H),1.40(t,J＝7.1Hz,6H,1.26～1.33(m,8H),0.89(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.13,14.12,18.73,22.69,29.18,29.26,29.35,29.68,29.76,35.51,55.57,56.02,57.18,59.40,64.38,67.42,127.32,128.08,133.19,134.94,161.55,173.00.
化合物52：1H NMR(400MHz，CDCl3)δ:7.00～7.07(m,3H),4.88(br,2H),4.18～4.22(m,2H),4.12(t,J＝7.8Hz,2H),3.74～3.86(m,4H),3.65～3.69(m,2H),2.82～2.86(m,2H),2.73～2.79(m,2H),2.23(s,6H),1.56～1.62(m,2H),1.45(t,J＝7.1Hz,6H).1.38～1.42(m,6H),0.90(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:8.10,14.09,18.72,22.69,25.72,28.86,29.10,29.17,35.52,55.52,56.03,57.20,59.42,65.00,127.31,128.04,133.21,134.93,161.54,173.24,174.62.
化合物53：1H NMR(400MHz，CDCl3)δ:7.03～7.08(m,3H),4.88(br,2H),4.18～4.21(m,2H),3.78～3.87(m,4H),3.64～3.68(m,2H),3.03～3.05(m,2H),2.70～2.74(m,2H),2.45～2.48(m,2H),2.24(s,6H),1.42(t,J＝7.1Hz,6H),1.50～1.53(m,2H),1.28～1.32(m,4H),0.89(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:8.11,13.98,18.69,22.39,28.90,29.14,29.73,30.21,35.50,55.58,56.02,57.23,59.42,127.36,128.04,133.19,134.93,161.52,172.22,173.86.
化合物54：1H NMR(400MHz，CDCl3)δ:7.00～7.06(m,3H),4.90(br,2H),4.80(br,2H),4.57(Ha,1H),4.48(Hb,1H),4.05(t,J＝6.8Hz,2H),3.60～3.70(m,6H),2.34(Ha,1H),2.26(Hb,1H),2.21(s,6H),1.60～1.64(m,2H),1.39(t,J＝6.9Hz,6H),1.28～1.30(m,6H),0.86(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:8.02,13.90,18.74,22.33,24.00(d,J＝19.6Hz,),27.66,28.98,29.12,55.33,56.31,56.99,67.80,79.65,81.32,127.44,128.12,133.02,135.01,161.82,172.71.
化合物55：1H NMR(400MHz，CDCl3)δ:6.99～7.05(m,3H),5.00(br,2H),4.81(br,2H),4.59(Ha,1H),4.47(Hb,1H),3.59～3.70(m,6H),3.15～3.18(m,2H),2.31(Ha,1H),2.23(Hb,1H),2.21(s,6H),1.49～1.53(m,2H),1.40(t,J＝6.9Hz,6H),1.27～1.33(m,10H),0.89(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:7.98,14.07,18.72,22.70,24.01(d,J＝19.6Hz,),26.37,26.73,29.36,29.42,31.78,40.26,55.33,56.32,56.96,61.55,79.64,81.30,127.42,128.13,133.05,135.04,155.86,161.79,173.02.
化合物56：1H NMR(400MHz，CDCl3)δ:6.98～7.05(m,3H),4.84(br,2H),4.59(Ha,1H),4.47(Hb,1H),4.30(br,2H),3.63～3.71(m,6H),3.36(t,J＝8.0Hz,2H),2.32(Ha,1H),2.25(Hb,1H),2.21(s,6H),1.48～1.52(m,2H),1.42～1.45(m,2H),1.38(t,J＝6.9Hz,6H),1.25～1.30(m,4H),0.88(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.00,14.08,18.76,22.65,24.03(d,J＝19.6Hz,),29.66,31.78,55.31,56.30,56.96,64.50,67.36,79.62,81.30,127.41,128.12,133.05,135.03,161.80,173.01.
化合物57：1H NMR(400MHz，CDCl3)δ:7.00～7.06(m,3H),4.82(br,2H),4.59(Ha,1H),4.47(Hb,1H),4.12(t,J＝7.8Hz,2H),3.60～3.69(m,6H),2.34(Ha,1H),2.82～2.86(m,2H),2.73～2.79(m,2H),2.24(Hb,1H),2.21(s,6H),1.56～1.62(m,2H),1.42～1.47(m,6H),1.39(t,J＝6.9Hz,6H),0.90(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:8.02,14.09,18.73,22.72,24.01(d,J＝19.6Hz,),25.70,28.87,29.06,29.13,55.30,56.33,57.02,65.02,79.68,81.29,127.42,128.10,133.00,135.04,161.83,173.25,174.60.
实施例9
参照实施例7，精密称定部分实施例1～4和实施例6的有机酸、碱，制备得到用于配置药液的终产物。化合物及其结构数据如下：
Figure BDA0003145480140000331
化合物58：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),4.85～4.89(m,2H),4.40(br,2H),3.31(br,9H),2.32(t,J＝7.7Hz,2H),2.20(br,6H),1.52～1.59(m,2H),1.36～1.40(m,9H),1.21～1.27(m,8H),0.83(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:7.88,14.05,18.54,22.58,24.93,28.94,29.10,31.62,34.31,54.05,56.19,63.97,126.99,127.97,133.79,134.94,162.37,173.08,174.02.
化合物59：1H NMR(400MHz，CDCl3)δ:7.05～7.08(m,3H),4.88(br,2H),4.42(br,2H),3.31(br,9H),2.33(t,J＝7.7Hz,2H),2.22(br,6H),1.51～1.58(m,2H),1.37～1.41(m,9H),1.20～1.27(m,12H),0.84(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:7.88,14.02,18.54,22.57,24.93,28.96,29.11,29.18,29.22,31.60,34.27,54.02,56.21,63.95,127.04,128.03,133.82,134.98,162.35,173.06,174.01.
化合物60：1H NMR(400MHz，CDCl3)δ:7.06～7.11(m,3H),4.90(br,2H),4.45(br,2H),4.03(t,J＝6.8Hz,2H),2.21(br,6H),1.60～1.64(m,2H),1.26～1.29(m,6H),0.87(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:7.78,13.91,18.53,22.29,27.67,28.93,29.05,54.15,63.92,67.82,127.02,127.95,133.76,134.90,162.30,172.73.
化合物61：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),4.99(br,2H),4.42(br,2H),3.15～3.19(m,2H),2.21(br,6H),1.50～1.53(m,2H),1.26～1.32(m,10H),0.89(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:7.82,14.10,18.53,22.73,26.41,26.75,29.33,29.36,31.75,40.33,54.03,61.57,63.92,126.99,127.97,133.79,134.94,155.84,162.37,173.01.
化合物62：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),4.43(br,2H),4.10(t,J＝7.8Hz,2H),2.82～2.86(m,2H),2.73～2.79(m,2H),2.23(br,6H),1.57～1.61(m,2H),1.37～1.42(m,6H),0.89(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:7.88,14.11,18.54,22.72,25.74,28.83,29.09,29.17,54.05,63.97,65.02,126.99,127.97,133.79,134.94,162.37,173.25,174.60.
化合物63：1H NMR(400MHz，CDCl3)δ:7.03～7.08(m,3H),4.89(br,2H),4.45(br,2H),3.58～3.62(m,4H),3.33(br,3H),2.32(t,J＝7.7Hz,2H),2.20(br,6H),1.52～1.59(m,2H),1.37～1.40(m,9H),1.22～1.27(m,8H),0.85(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:7.93,14.16,18.49,22.59,24.96,28.90,29.14,31.65,34.33,54.07,56.23,64.02,126.95,128.03,133.76,134.90,162.35,173.09,174.04.
化合物64：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),5.59～5.63(m,1H),5.07～5.12(m,2H),4.40(br,2H),4.12(t,J＝7.8Hz,2H),3.31(br,6H),2.82～2.86(m,2H),2.73～2.79(m,2H),2.20(br,6H),1.56～1.62(m,2H),1.38～1.43(m,6H),0.90(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:7.98,14.09,18.63,22.72,25.70,28.86,29.09,29.17,54.06,63.78,65.00,65.30,125.42,127.03,127.99,128.56,133.84,134.92,162.38,173.25,174.61.
化合物65：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),5.61～5.64(m,1H),5.08～5.12(m,2H),4.85(br,2H),4.40(br,2H),3.30(br,6H),2.31～2.35(m,2H),2.21(br,6H),1.55～1.63(m,2H),1.26～1.32(m,6H),0.86～0.89(m,3H).13C NMR(100MHz,CDCl3)δ:8.02,13.98,18.60,22.36,24.80,28.73,31.45,34.20,54.01,63.58,63.72,65.33,125.43,127.05,128.02,128.57,133.84,134.96,162.30,172.85,173.92.
化合物66：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),5.59～5.63(m,1H),5.07～5.12(m,2H),4.40(br,2H),4.28(br,2H),3.37(t,J＝8.0Hz,2H),3.30(br,6H),2.23(br,6H),1.48～1.53(m,2H),1.42～1.46(m,2H),1.25～1.32(m,10H),0.88(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ:8.01,14.10,18.60,22.67,29.16,29.24,29.33,29.62,29.69,29.77,54.11,63.74,64.38,65.35,67.45,125.41,127.07,127.98,128.57,133.82,134.93,162.42,173.00.
化合物67：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),5.59～5.63(m,1H),5.07～5.12(m,2H),5.01(br,2H),4.40(br,2H),3.31(br,6H),3.16～3.20(m,2H),2.20(br,6H),1.50～1.53(m,2H),1.28～1.33(m,10H),0.88(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:7.97,14.11,18.60,22.73,26.41,26.77,29.34,29.42,31.76,40.33,54.04,63.80,65.32,61.58,125.41,127.02,128.03,128.59,133.82,134.93,155.84,162.37,173.02.
化合物68：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),4.93(br,2H),4.42(br,2H),5.65～5.69(m,1H),5.01～5.05(m,2H),3.31(br,6H),2.39～2.43(m,2H),2.22(br,6H),2.10(s,3H).13C NMR(100MHz,CDCl3)δ:7.98,18.62,21.18,26.01,54.01,63.74,64.13,65.32,116.56,127.03,127.99,133.84,134.62,134.92,162.38.
化合物70：1H NMR(400MHz，CDCl3)δ:7.03～7.06(m,3H),4.90(br,2H),4.36(br,2H),3.79～3.82(m,2H),3.40～3.43(m,2H),3.30～3.32(m,9H),2.35(t,J＝7.7Hz,2H),2.21(br,6H),1.57～1.62(m,2H),1.27～1.30(m,4H),0.87(t,J＝6.7Hz,3H)..13C NMR(100MHz,CDCl3)δ:7.89,13.93,18.52,22.31,24.63,31.32,34.28,54.04,59.23,63.92,64.00,67.32,69.94,126.93,127.96,133.82,134.92,162.35,173.08,174.02.
化合物71：1H NMR(400MHz，CDCl3)δ:7.02～7.06(m,3H),4.89(br,2H),4.35(br,2H),4.04(t,J＝6.8Hz,2H),3.76～3.80(m,2H),3.40～3.43(m,2H),3.30～3.32(m,9H),1.57～1.61(m,2H),2.23(br,6H),1.24～1.28(m,4H),0.86(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:7.93,13.91,18.51,22.24,27.79,28.90,54.14,59.23,63.99,67.32,67.83,70.01,126.99,127.94,133.84,134.91,162.35,172.72.
化合物72：1H NMR(400MHz，CDCl3)δ:7.03～7.06(m,3H),4.52(br,2H),4.36(br,2H),4.05(br,2H),3.79～3.82(m,2H),3.40～3.43(m,2H),3.30～3.32(m,9H),2.21(br,6H),1.52～1.57(m,2H),1.35～1.42(m,6H),0.89～0.92(m,3H).13C NMR(100MHz,CDCl3)δ:7.94,14.12,18.50,22.58,26.15,29.13,31.80,54.09,59.23,63.81,67.36,69.43,70.03,73.15,127.01,127.98,133.82,134.91,162.35,172.52.
化合物73：1H NMR(400MHz，CDCl3)δ:7.03～7.06(m,3H),4.98(br,2H),4.36(br,2H),3.78～3.82(m,2H),3.40～3.42(m,2H),3.30～3.33(m,9H),3.16～3.19(m,2H),2.21(br,6H),1.50～1.53(m,2H),1.28～1.34(m,10H),0.87(t,J＝7.0Hz,3H)..13C NMR(100MHz,CDCl3)δ:7.90,14.12,18.52,22.74,26.41,26.72,29.31,29.39,31.80,40.32,54.01,59.17,61.52,63.99,67.37,70.03,126.99,127.97,133.79,134.94,155.86,162.37,172.99.
化合物74：1H NMR(400MHz，CDCl3)δ:7.03～7.06(m,3H),4.39(br,2H),4.31～4.35(m,2H),3.79～3.83(m,2H),3.41～3.43(m,2H),3.30～3.32(m,9H),2.50～2.53(m,2H),2.30(t,J＝7.6Hz,2H),2.21(br,6H),1.62～1.65(m,2H),1.28～1.32(m,4H),0.90(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:7.87,14.18,18.52,22.42,31.12,31.24,33.75,33.88,54.05,59.19,59.69,63.95,67.33,69.98,127.01,127.96,133.83,134.94,162.35,173.10,177.32.
化合物75：1H NMR(400MHz，CDCl3)δ:7.03～7.06(m,3H),4.36(br,2H),4.10(t,J＝7.8Hz,2H),3.79～3.82(m,2H),3.40～3.43(m,2H),3.30～3.33(m,9H),2.82～2.85(m,2H),2.72～2.77(m,2H),2.21(br,6H),1.56～1.62(m,2H),1.37～1.42(m,6H),0.90(t,J＝7.0Hz,3H)..13CNMR(100MHz,CDCl3)δ:7.88,14.09,18.54,22.69,25.74,28.90,29.11,29.18,54.07,59.21,63.98,65.02,67.35,69.98,126.96,127.94,133.77,134.92,162.38,173.26,174.62.
化合物76：1H NMR(400MHz，CDCl3)δ:7.04～7.07(m,3H),4.78～4.82(m,2H),4.42(br,2H),3.95(m,2H),3.42(t,J＝7.1Hz,2H),3.26～3.31(m,5H),2.32～2.37(m,2H),2.21(br,6H),1.54～1.63(m,2H),1.40(t,J＝6.8Hz,3H),1.25～1.32(m,6H),0.85～0.89(m,3H).13C NMR(100MHz,CDCl3)δ:7.99,14.01,18.50,22.36,24.82,28.73,31.39,34.22,54.03,57.82,63.61,63.97,64.58,126.96,127.93,133.80,134.90,162.34,172.84,173.91.
化合物77：1H NMR(400MHz，CDCl3)δ:7.05～7.09(m,3H),4.40(br,2H),3.95(m,2H),3.42(t,J＝7.1Hz,2H),3.27～3.31(m,5H),3.02～3.06(m,2H),2.70～2.74(m,2H),2.44～2.47(m,2H),2.20(br,6H),1.50～1.54(m,2H),1.40(t,J＝6.8Hz,3H),1.26～1.33(m,10H),0.90(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ:8.03,14.06,18.46,22.46,26.48,29.07,29.21,29.27,29.32,29.38,30.01,30.27,31.80,39.24,54.11,57.83,63.99,64.63,126.97,127.98,133.77,134.93,162.32,172.16,173.81.
实施例10
Figure BDA0003145480140000391
于100mL圆底瓶中，加入α-氯代酰胺25mmol，三乙胺30mmol，1,2-二氯乙烷30mL，40℃缓慢滴加二取代仲胺25mmol的1,2-二氯乙烷20mL，30min滴毕。60℃搅拌16h，冷却至室温。二氯甲烷-甲醇硅胶柱层析，分离得到对应叔胺。精密称定该叔胺，加入冷却的二氯甲烷20ml，缓慢滴加等物质的量的甲酸，低温浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到对应的叔胺甲酸盐如下：
Figure BDA0003145480140000392
其结构数据如下：
化合物78：1H NMR(400MHz,D2O)δ:7.21～7.10(m,3H),4.24(s,2H),3.29(qd,J＝7.3,1.8Hz,4H),2.12(s,6H),1.29(t,J＝7.3Hz,6H).化合物79：1H NMR(400MHz，CDCl3)δ:7.16～7.19(m,3H),5.82～5.85(m,1H),5.18～5.23(m,2H),3.34(br,2H),3.04～3.07(m,2H),2.25(s,3H),2.12(s,6H).13C NMR(100MHz,CDCl3)δ:17.58,42.79,59.37,59.56,117.40,126.82,127.75,130.72,137.08,165.76,168.48.
化合物80：1H NMR(400MHz，CDCl3)δ:7.16～7.20(m,3H),5.85～5.88(m,1H),5.18～5.23(m,2H),3.33(br,2H),3.03～3.07(m,2H),2.64(q,J＝6.7Hz,2H),2.12(s,6H),1.02(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:12.71,17.60,48.92,56.88,57.03,117.40,126.82,127.73,130.72,137.09,165.76,168.50,168.46.
化合物81：1H NMR(400MHz，CDCl3)δ:7.16～7.19(m,3H),5.85～5.88(m,1H),5.18～5.23(m,2H),3.78(br,2H),3.39(br,2H),2.63～2.67(m,5H),2.12(s,6H),1.02(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:11.74,17.58,45.09,47.65,55.72,73.21,126.79,127.72,130.73,137.12,165.70,168.49.
化合物82：1H NMR(400MHz，CDCl3)δ:7.16～7.19(m,3H),3.49(br,2H),3.32(br,2H),2.64(q,J＝6.8Hz,2H),2.12(s,6H),1.01(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:11.81,17.62,45.01,47.72,55.81,114.83,126.79,127.74,130.73,137.11,165.68,168.49.
实施例11
精密称量有机羧酸1.00g至50mL圆底烧瓶中，30mL二氯甲烷溶解。0℃搅拌下分别缓慢加入经精密称量等物质的量的季铵碱，浓缩至干。二氯甲烷-甲醇硅胶柱层析，浓缩，真空干燥，得到用于配置药液的终产物。得到的对照化合物如下：
Figure BDA0003145480140000401
实施例12
精密称定对照化合物2、化合物14、22、44、52、65、7215x 10-3mmol至5mL玻璃瓶中，精确加入去离子水1mL，室温搅拌2h，静置至泡沫消失。另精密称取化合物7480x 10-3mmol至5mL玻璃瓶中，精确加入去离子水1mL，室温搅拌3h。溶液以220μm水相微孔滤膜过滤,磷钨酸染色，TEM检测，如图11所示。除对照化合物2外，其余7个样品均能形成葫芦型的Janus粒子。
实施例13
精密称定对照化合物2、化合物14、22、52、65、7215x 10-3mmol至5mL玻璃瓶中，精确加氘水1mL，室温搅拌2h，静置至泡沫消失。另精密称取化合物74 80x 10-3mmol至5mL玻璃瓶中，精确加入氘水1mL，室温搅拌3h。NOESY检测，结果如图12所示。除了对照化合物2外，其余样品均能检测出芳环上的甲基氢与芳环氢的相关作用。
实施例14
待测试溶液制备的一般方法：
精密称取上述实施例得到产物75x 10-3mmol，加入蒸馏水3mL，25℃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。
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8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。
其中对照组为0.75％盐酸左布比卡因的水溶液(32mmol/L)。
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：
注射后10min、30min、1h、2h、4h、8h、12h、16h、24h测定。此后以28h、32h、36h、40h、48h测定，每天重复直至大鼠完全恢复。
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3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14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。
脱髓鞘程度评分如下：
0分：无脱髓鞘；1分：轻度脱髓鞘；2分：中度脱髓鞘；3分：重度脱髓鞘。
血管增生评分如下：
0分：无血管增生；1分：每个切片1～2个增生血管(cuffed vessel)；2分：每个切片3～5个增生血管；3分：每个切片增生血管大于5个。
全身毒性测定方法：
选取200～300g体重的大鼠，雌雄各半。随机分组，每组8只。尾静脉注射浓度为25mmol/L的本类化合物纯水溶液，采用序贯法测得半数致死量(LD50)。
测得数据如下：
表1化合物(I)的坐骨神经阻滞时间和毒性数据
Figure BDA0003145480140000431
Figure BDA0003145480140000441
Figure BDA0003145480140000451
*盐酸布比卡因的注射浓度为32mmol/L。QX-314注射浓度为25mmol/L，由于导致的局部阻滞强度不足，在本发明的测试条件下仍未达到完全的感觉阻滞，故记录为未起效。对照化合物的注射浓度均为25mmol/L。部分化合物未精确测定LD50，而是以显著大于已报道的长效低毒化合物(对照化合物8和9)的LD50的10.00mg/kg体重作为测试标准。
Figure BDA0003145480140000452
实施例15
精密称取表2中的化合物，其中盐酸利多卡因、醋酸利多卡因和正丙酸利多卡因，配制为2％的水溶液；盐酸布比卡因配制为0.75％的水溶液；实施例10中的化合物，配制为32mmol/L的水溶液。参照实施例14，进行大鼠坐骨神经阻滞实验，并测定神经损伤和LD50，结果如表2。其中大鼠神经阻滞的测试时间点为1h,2h,4h，此后每2h测试至16h此后的测试时间点为24h。
表2化合物(Ⅱ)的坐骨神经阻滞时间和毒性数据
Figure BDA0003145480140000453
Figure BDA0003145480140000461
*化合物82在16h时间点局麻作用均有效，在24h时间点局麻作用消失。部分化合物未精确测定LD50，而是以显著大于盐酸布比卡因2倍LD50的12.00mg/kg体重作为测试标准。

Claims (17)

1.具有长效麻醉效应的二甲基苯铵长链羧酸盐类化合物，结构如式(Ⅰ)所示：
Figure FDA0003145480130000011
式中的R1和R2为C1～2烷基；R3为氢原子、饱和或不饱和形式的C1～3烷基或取代烷基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。
2.如权利要求1所述的化合物，其特征是所述式(Ⅰ)结构中的R1和R2为C1～2烷基；R3为氢原子、饱和或不饱和形式的C1～3烷基、C1～3取代烷基；X为羰基或氧原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～12的整数。
3.如权利要求1所述的化合物，其特征如式(Ⅰa)所示：
Figure FDA0003145480130000012
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
4.如权利要求1所述的化合物，其特征如式(Ⅰb)所示：
Figure FDA0003145480130000013
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
5.如权利要求1所述的化合物，其特征如式(Ⅰc)所示：
Figure FDA0003145480130000021
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
6.如权利要求1所述的化合物，其特征如式(Ⅰd)所示：
Figure FDA0003145480130000022
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
7.如权利要求1所述的化合物，其特征如式(Ⅰe)所示：
Figure FDA0003145480130000023
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
8.如权利要求1所述的化合物，其特征如式(Ⅰf)所示：
Figure FDA0003145480130000024
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
9.如权利要求1所述的化合物，其特征如式(Ⅰg)所示：
Figure FDA0003145480130000031
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；Y为氧原子或氮原子；R3为氢原子、饱和或不饱和形式的C1～3烷基或C1～3取代烷基；m＝1～2的整数；n＝1～16的整数。
10.如权利要求1所述的化合物，其特征如式(Ⅰh)所示：
Figure FDA0003145480130000032
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。
11.如权利要求1所述的化合物，其特征如式(Ⅰi)所示：
Figure FDA0003145480130000033
其中R1为C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。
12.如权利要求1所述的化合物，其特征如式(Ⅰj)所示：
Figure FDA0003145480130000034
其中R1为饱和形式的C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～3烷基或烷氧基；X为羰基、氧原子或氮原子；Y为氧原子、氮原子、亚甲基、羰基或亚砜基团；Z为亚甲基、氧原子或氮原子；m＝1～2的整数；n＝1～16的整数。
13.具有长效麻醉效应的二甲基苯胺甲酸盐类化合物，结构如式(Ⅱ)所示：
Figure FDA0003145480130000041
式中的R1为饱和形式的C1～2烷基；R2为氢原子、取代或未取代、饱和或不饱和形式的C1～4烷基。
14.权利要求13所述的具体化合物78、79、80、81、82，结构如下：
Figure FDA0003145480130000042
15.权利要求1至12之一所述的二甲基苯铵长链羧酸盐类化合物，其特征是在用于制备包括局部麻醉、镇痛、止痒在内的药物中的应用。
16.权利要求13～14之一所述的二甲基苯胺甲酸盐类化合物，其特征是在用于制备包括局部麻醉、镇痛、止痒在内的药物中的应用。
17.如权利要求1至14之一所述的化合物，其特征是所述的自组装形成的胶束结构在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。
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