CN114072380B - 氨基甲酸酯取代的苯乙烯基砜类化合物及其制备方法和用途 - Google Patents
氨基甲酸酯取代的苯乙烯基砜类化合物及其制备方法和用途 Download PDFInfo
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Abstract
提供一种氨基甲酸酯取代的苯乙烯基砜类化合物及其制备方法和用途,所述氨基甲酸酯取代的苯乙烯基砜类化合物具有通式I的结构,其不但与氨基甲酸酯类阳性药物相比具有显著增强的乙酰胆碱酯酶抑制活性,而且与相似结构的咖啡酸苯乙酯类化合物相比具有显著增强的帕金森病治疗作用(I)。
Description
技术领域
本发明属于药物化学技术领域,具体涉及氨基甲酸酯取代的苯乙烯基砜类化合物及其制备方法和用途。
背景技术
帕金森病是一种临床常见的中枢神经系统退行性疾病,主要发生在65岁以上的中老年人,并随年龄增长呈现发病率逐年增高的趋势,我国65岁以上人群的患病率大约是1.7%。帕金森病是由多种因素引起,目前的研究认为其危险因素包括年龄因素、遗传因素、环境因素等,发病机制主要与脑脊液生物学、p38通路、氧化应激、免疫炎症反应及神经通路异常等有关。
脑脊液生物学方面,帕金森病患者脑脊液内被选择性磷酸化的α-突触核蛋白(p-α-s)远高于非帕金森病患者,诸多研究发现,p-α-s参与形成的路易小体是帕金森病的主要病理特征之一。研究还发现帕金森病小鼠模型多巴胺能神经元的标记物酪氨酸羟化酶(TH)含量显著低于正常对照组。
导致帕金森的主要机制是黑质内的多巴胺神经细胞凋亡。p38丝裂原活化蛋白激酶(p38MAPK)是各种刺激引起的神经细胞凋亡的有力效应器。p38MAPK在去磷酸化状态下无活性。当细胞受到各种刺激时,MKK3和MKK6基因能迅速介导p38MAPK磷酸化,形成pp38从而通过多种途径和调控方式引发炎症反应、细胞分化、细胞周期停滞、细胞凋亡等。对帕金森病患者的死后尸检脑组织内发现有pp38,在帕金森病动物模型和细胞模型中也发现了pp38活性形式,越来越多的证据提示pp38主要通过神经炎症反应和诱导神经元凋亡参与了帕金森病的进程。
氧化应激学说在帕金森病机制研究中占有重要地位,它能很好地解释迟发性和蓄积性神经损害。氧化应激是指机体在遭受各种有害刺激时,体内高活性分子如活性氧自由基和活性氮自由基产生过多,氧化程度超出氧化物的清除,氧化系统和抗氧化系统失衡,从而导致组织损伤。帕金森患者死后尸检发现,黑质中一些氧化损害的标记物显著增加,而具有抗氧化物作用的还原型谷胱甘肽水平下降30~60%。II相解毒酶是一种内源性的保护蛋白,能通过催化自由基转化为无毒产物以及增加其水溶性以有利于自由基排除而发挥保护作用。II相解毒酶包括血红素加氧酶-1(HO-1)、谷氨酸半胱氨酸连接酶催化亚单位(GCLC)等,已有大量研究表明它们在帕金森病种具有神经保护作用。
神经炎症是一把双刃剑。一方面,在正常情况下,小胶质细胞和星形胶质细胞维持着中枢神经系统正常组织的稳态。另一方面,当它们过度产生炎症因子时,这些炎症因子彼此扩大各自的毒性,最终导致神经元的损伤、变性甚至死亡。小胶质细胞是脑内实施防御反应的主要原位免疫细胞,活化的小胶质细胞会表达不同的表面抗原如CD11b等,激活的小胶质细胞可通过多种途径损伤多巴胺能神经元。星形胶质细胞是中枢神经系统内数量最多、分布最广、体积最大的胶质细胞,其特异性标记物是胶质原纤维酸性蛋白(GFAP),激活后的星形胶质细胞也可通过多种途径损伤多巴胺能神经元。
多数研究认为帕金森病是一个典型的由化学性神经递质异常引起的神经退行性疾病,以黑质纹状体系统多巴胺能神经元减少为主要病理学特征。帕金森病患者中额叶、颞叶、顶叶及右侧海马等皮质中胆碱转移酶活性下降,胆碱能神经元受损可能是帕金森病认知功能障碍及痴呆产生的主要生化机制。有较多研究显示,胆碱酯酶抑制剂,尤其是乙酰胆碱酯酶抑制剂有利于改善帕金森病的痴呆患者的预后情况、提高其认知功能。卡巴拉汀是一种氨基甲酸酯类药物,通过可逆性抑制乙酰胆碱酯酶对乙酰胆碱的水解作用来发挥药理作用,已被批准用于治疗帕金森病相关的轻至中度痴呆。
由于发病机制复杂多样,目前的治疗药物主要针对单一靶点,需要在疾病早期阶段根据患者症状选用适当的药物单独或联合治疗。常见药物包括多巴胺类药物(左旋多巴、卡比多巴)、多巴胺受体激动剂(卡麦角林、普拉克索)、多巴胺保留剂(司来吉兰、恩他卡朋)、抗胆碱能药物(盐酸苯海索)、其他药物(金刚烷胺)等,还有部分药物正在临床试验中,如抗炎剂(米诺环素、吡格列酮)、抗氧化剂(辅酶Q10、依达拉奉)、胆碱酯酶抑制剂(多奈哌齐、卡巴拉汀)、兴奋性氨基酸受体拮抗剂(美金刚)等,这些药物中许多仅仅是用于改善帕金森病带来并发症,例如痴呆等等。对于帕金森病本身或者中晚期帕金森病而言,已有治疗药物的症状控制效果常常较有限,对于新的治疗药物仍存在较强的临床需求。因此开发一种有效率高、通过多靶点作用的帕金森病治疗或预防药物具有重要的社会意义和经济价值。
以天然产物咖啡酸苯乙酯为基础改造而来的苯乙烯基砜类化合物是一类具有多靶点神经保护活性的化合物,在咖啡酸苯乙酯的基础上增强了体内稳定性、改善了透过血脑屏障的能力,同时保持或增强了抗氧化活性、抗炎作用、兴奋性毒性损伤抑制作用等。部分化合物、其制备方法和生物活性记载于专利CN104230770B。该专利未对相关化合物的帕金森病治疗作用进行针对性的验证,仅从抗氧化活性试验结果和透膜能力评估结果推测,可能对包括帕金森病在内的多种神经退行性疾病具有治疗作用。胆碱酯酶抑制剂是一类能与胆碱酯酶结合,并抑制胆碱酯酶活性的药物。其作用是使胆碱能神经末梢释放的乙酰胆碱堆积,表现M样及N样作用增强而发挥兴奋胆碱受体的作用,故该类药又称拟胆碱药。其可分为两类:第一类是易逆性或短暂性胆碱酯酶抑制剂,如卡巴拉汀、新斯的明、毒扁豆碱等,它们的共同特征是都具有氨基甲酸酯类官能团;第二类是难逆性或不可逆性胆碱酯酶抑制剂,如有机磷酸酯类,包括农业杀虫剂和战争毒气,人体毒性很强、难以开发成药物。这类化合物一方面可以抑制乙酰胆碱酯酶对乙酰胆碱的水解作用,提高乙酰胆碱浓度、保护胆碱能神经元,从而改善帕金森病相关痴呆症状;另一方面,多种氨基甲酸酯类化合物的长期接触被证实可提高帕金森病患病几率,即使是FDA批准的卡巴拉汀,最常见的不良反应也包括震颤(发生率超过5%),另外与对照组相比还存在帕金森病恶化、运动功能减退或障碍等多种退行性不良反应。
发明内容
本发明所解决的技术问题是在具有神经保护活性的苯乙烯基砜类化合物基础上引入氨基甲酸酯类官能团,从而得到一类可用于治疗和/或预防帕金森病的新型化合物,并提供了其制备方法及其在制备治疗和/或预防帕金森病药物中的应用。本发明的设计初衷是在尽量不影响咖啡酸苯乙酯类化合物的多靶点神经保护活性基础上,引入氨基甲酸酯官能团的乙酰胆碱酯酶抑制活性,以得到一种既具备延缓帕金森病病程进展、又能改善帕金森病痴呆症状的新型药物。通过试验结果,我们惊奇地发现目标化合物不但与氨基甲酸酯类阳性药物相比具有显著增强的乙酰胆碱酯酶抑制活性,而且与相似结构的咖啡酸苯乙酯类化合物相比具有显著增强的帕金森病治疗作用。根据已公开的现有技术,该发现不具备可预见性。本发明通过以下技术方案来解决上述技术问题。
一方面,本发明提供一种通式I的化合物或其可药用盐:
其中,
R1和R2中至少一个独立地选自未取代的或被1至2个R3取代的氨基甲酰氧基;R1和R2中的另一个独立地选自未取代的或被1至2个R3取代的氨基甲酰氧基,未取代的或被1至6个卤素、-N(R4)2或-OR5取代的C1-6烷氧基,未取代的或被1至6个卤素、-N(R4)2或-OR5取代的C1-6烷基酰氧基或C7-10芳基酰氧基,被C1-3烷基或C6-8芳基取代的磺酰氧基,-OSi(R6)3和-OH;
W为未取代的或被1至3个卤素、硝基、C1-6烷基、-N(R4)2或-OR5取代的C1-6亚烷基或C2-6亚烯基;
每个R独立地选自卤素,硝基,-OR7,-N(R4)2,未取代的或被1至6个卤素、硝基、-N(R4)2或-OR5取代的C1-6烷基、C6-10芳基或C5-9杂芳基;
n为0-5的整数;
其中,
每个R3独立地选自未取代或被1至6个卤素、硝基、-N(R4)2或-OR5取代的C1-6饱和烷基、C2-4链烯基、C2-4链炔基、C6-10芳基、C5-9杂芳基、C1-6烷基酰基或C7-10芳基酰基;被C1-3烷基或C6-8芳基取代的磺酰基;或者两个R3与它们相连的氮原子一起组成未取代或被1-2个R6取代的5-7元含氮饱和杂环基(例如1-吡咯烷基、1-哌啶基、4-吗啉基或1-哌嗪基);
每个R4独立地为-H或C1-6饱和烷基;
每个R5独立地选自-H,C1-6饱和烷基,C2-4链烯基,C6-10芳基和C5-9杂芳基;
每个R6独立地选自未取代的或被1-6个卤素取代的C1-6烷基、C1-6烷氧基和C6-8芳基;
每个R7独立地选自H,未取代的或被1至6个卤素、N(R4)2或OR5取代的C1-6饱和烷基、C2-4链烯基、C2-4链炔基、C6-10芳基、C5-9杂芳基、C1-6烷基酰基或C7-10芳基酰基;被C1-3烷基或C6-8芳基取代的磺酰基;Si(R6)3。
优选地,R1和R2中至少一个独立地选自未取代的或被1至2个R3取代的氨基甲酰氧基;R1和R2中的另一个独立地选自未取代的或被1至2个R3取代的氨基甲酰氧基,未取代的或被1至6个卤素或OR5取代的C1-6烷氧基,未取代的或被-N(R4)2或-OR5取代的C1-6烷基酰氧基,被C1-3烷基或C6-8芳基取代的磺酰氧基和-OSi(R6)3;
更优选地,R1和R2中至少一个独立地选自氨基甲酰氧基、N-甲基氨基甲酰氧基、N,N-二甲基氨基甲酰氧基、N,N-二乙基氨基甲酰氧基、N-甲基-N-乙基氨基甲酰氧基、N-甲基-N-(2-甲氧基乙基)氨基甲酰氧基、N-(5-甲基-2-硝基苯胺)基氨基甲酰氧基、N-(2-甲基-5-硝基苯胺)基氨基甲酰氧基、N-(对甲氧基苯基)氨基甲酰氧基、N-(对甲氨基苯基)氨基甲酰氧基、N-甲基-N-苯基氨基甲酰氧基、N-甲基-N-对氯苯基氨基甲酰氧基、N-甲基-N-对溴苯基氨基甲酰氧基、N-甲基-N-对碘苯基氨基甲酰氧基、N-噻吩基氨基甲酰氧基、N-呋喃基氨基甲酰氧基、N-甲基-N-甲磺酰基氨基甲酰氧基和N-甲基-N-对甲苯磺酰基氨基甲酰氧基。
R1和R2中的另一个独立地选自氨基甲酰氧基、N-甲基氨基甲酰氧基、N,N-二甲基氨基甲酰氧基、N,N-二乙基氨基甲酰氧基、N-甲基-N-乙基氨基甲酰氧基、N-甲基-N-(2-甲氧基乙基)氨基甲酰氧基、N-(5-甲基-2-硝基苯胺)基氨基甲酰氧基、N-(2-甲基-5-硝基苯胺)基氨基甲酰氧基、N-(对甲氧基苯基)氨基甲酰氧基、N-(对甲氨基苯基)氨基甲酰氧基、N-甲基-N-苯基氨基甲酰氧基、N-甲基-N-对氯苯基氨基甲酰氧基、N-甲基-N-对溴苯基氨基甲酰氧基、N-甲基-N-对碘苯基氨基甲酰氧基、N-噻吩基氨基甲酰氧基、N-呋喃基氨基甲酰氧基、N-甲基-N-甲磺酰基氨基甲酰氧基、N-甲基-N-对甲苯磺酰基氨基甲酰氧基,或选自甲氧基、乙氧基、叔丁氧基、三氟甲氧基、2,3-二溴丁氧基、2-甲氧基乙氧基、2-苄氧基乙氧基、乙酰氧基、丙酰氧基、特戊酰氧基、甲氧基乙酰氧基、4-甲氧基丁酰氧基、3-氨基丙酰氧基、2-氨基丙酰氧基、甲磺酰氧基、乙磺酰氧基、对甲苯磺酰氧基、三甲基硅氧基、三苯基硅氧基、氯甲基(二甲基)硅氧基和二甲氧基(苯基)硅氧基;
优选地,W为未取代的或被1-2个卤素、硝基、C1-6烷基或-OR5取代的C1-6亚烷基或C2-6亚烯基;
更优选地,W选自-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(F)-、-CH(Cl)-、-CH(Br)-、-CF2-、-CH(Cl)CH2-、-CH2CH(Cl)-、-CH(Cl)CH(Cl)-、-CH2CH(Cl)CH2-、-CH(NO2)-、-CH2CH(NO2)-、-CH2CH(NO2)CH2-、-CH(CH3)-、-CH(CH3)CH2-、-CH(OCH3)-、-CH2CH(OCH2CH3)CH(OCH2CH3)-、-CH2CH(OCH2C6H5)CH2-、-CH2CH(OH)-、-CH=CH-、-CH2CH=CHCH2-、-CH=CHCH2-、-CH=C(CH3)-、-CH(Cl)CH=CHCH2-;
优选地,每个R独立地选自卤素,硝基,-OR7,-N(R4)2和未取代的或被1至6个卤素、硝基、-OR5取代的C1-6烷基、C6-10芳基;
更优选地,每个R独立地选自氟、氯、溴、碘、硝基、羟基、甲氧基、乙氧基、异丙氧基、叔丁氧基、2,2,2-三氟乙氧基、2-甲氨基乙氧基、N,N-二甲氨基甲氧基、烯丙氧基、苯氧基、苄氧基、对甲氨基苄氧基、3,4-二甲氧基苄氧基、甲酰氧基、乙酰氧基、二甲氨基乙酰氧基、苯甲酰氧基、苯乙酰氧基、对甲氧基苯乙酰氧基、三甲基硅氧基、三苯基硅氧基、氯甲基(二甲基)硅氧基、二甲氧基(苯基)硅氧基、氨基、甲氨基、乙氨基、二异丙氨基、甲基、乙基、异丙基、叔丁基、三氟甲基、苯基、苄基、苯乙基、对氯苯基、对硝基苯基和3,4-二甲氧基苯基;
优选地,n为0-3的整数;
优选地,每个R3独立地选自未取代或被1至6个卤素、硝基、-N(R4)2或-OR5取代的C1-6饱和烷基、C6-10芳基、C5-9杂芳基;被C1-3烷基或C6-8芳基取代的磺酰基;
优选地,在一个具体的实施方案中,R1和R2中至少一个独立地选自未取代的或被1至2个R3取代的氨基甲酰氧基;R1和R2中的另一个独立地选自未取代的或被1至2个R3取代的氨基甲酰氧基,未取代的或被1至6个卤素或OR5取代的C1-6烷氧基,未取代的或被-N(R4)2或-OR5取代的C1-6烷基酰氧基,被C1-3烷基或C6-8芳基取代的磺酰氧基和-OSi(R6)3;
W为未取代的或被1-2个卤素、硝基、C1-6烷基或-OR5取代的C1-6亚烷基或C2-6亚烯基;
每个R独立地选自卤素,硝基,-OR7,-N(R4)2和未取代的或被1至6个卤素、硝基、-OR5取代的C1-6烷基、C6-10芳基;
n为0-3的整数;
其中,每个R3独立地选自未取代或被1至6个卤素、硝基、-N(R4)2或-OR5取代的C1-6饱和烷基、C6-10芳基、C5-9杂芳基;被C1-3烷基或C6-8芳基取代的磺酰基。
在一个更具体实施方案中,通式I的化合物选自以下化合物:
另一方面,本发明提供一种上述通式I的化合物的制备方法,该方法包括如下步骤:
a)将通式II的化合物与固体光气在碱性条件下反应生成通式III的化合物;
b)将通式III化合物与NH3、R3NH2或(R3)2NH反应生成通式I化合物,以及
c)任选地,将通式I的化合物转化为其可药用盐;
其中,Ra和Rb中至少有一个独立地为-OH;Ra和Rb中的另一个独立地选自-OH,未取代的或被1至6个卤素、-N(R4)2或-OR5取代的C1-6烷氧基,未取代的或被1至6个卤素、-N(R4)2或-OR5取代的C1-6烷基酰氧基或C7-10芳基酰氧基,被C1-3烷基或C6-8芳基取代的磺酰氧基,-OSi(R6)3;
Rc和Rd中至少有一个独立地为-OCOCl;Rc和Rd中的另一个独立地选自-OCOCl,未取代的或被1至6个卤素、-N(R4)2或-OR5取代的C1-6烷氧基,未取代的或被1至6个卤素、-N(R4)2或-OR5取代的C1-6烷基酰氧基或C7-10芳基酰氧基,被C1-3烷基或C6-8芳基取代的磺酰氧基,-OSi(R6)3,-OH;
其中,W、R、n和R3、R4、R5、R6的定义如前所述。
优选地,步骤a)中使用的碱为中等碱性或弱碱性无机碱或有机碱,无机碱例如氢氧化钠、氢氧化钾、碳酸氢钠、碳酸钠、乙酸钠、碳酸铯等均可用,根据碱的强度调整用量和浓度即可;有机碱如果不含氨基、伯胺和仲胺结构也可用,如吡啶、三乙胺、4-二甲氨基吡啶、DBU(1,8-二氮杂二环十一碳-7-烯)、DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)、MTBD(7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯)。
优选地,步骤b)中可以不使用碱,依靠反应原料NH3、R3NH2或(R3)2NH自身的碱性来完成反应,也可以适量加入步骤a)中所用的中等碱性或弱碱性无机碱或有机碱以促进反应完全。又一方面,本发明还提供一种药物组合物,所述药物组合物包括上述的通式I的化合物或其可药用盐以及至少一种药用载体。
本发明化合物的药物组合物可采用下面的任意方式施用:口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、局部用药、非肠道用药,如皮下、静脉、肌内、腹膜内、鞘内、心内室、胸骨内或静脉内给药方式。本发明的药物组合物可单独给药也可与其它神经保护药物联合用药。被治疗动物包括哺乳动物、爬行动物、甲壳动物、两栖类、鱼类、家禽类。主要范围为哺乳动物特别是人。
当口服用药时,本发明化合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂使用的载体可包括填充剂、润滑剂、崩解剂、粘合剂。填充剂可包括但不限于淀粉、预胶化淀粉、糊精、糖粉、乳糖、甘露醇、微晶纤维素。润滑剂包括但不限于硬脂酸、硬脂酸钙、硬脂酸镁、滑石粉、氧化植物油、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉。崩解剂可包括但不限于交联羧甲基纤维素钠、交联聚维酮、淀粉及其衍生物、低取代羟丙基纤维素、泡腾崩解剂。粘合剂可包括但不限于羟丙基纤维素、聚维酮、淀粉浆、糊精、糖粉、糖浆、胶浆、纤维素及其衍生物。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则是将活性成分与适宜的悬浮液混合使用,悬浮液可包括但不限于润湿剂、絮凝剂、反絮凝剂。任选地,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当局部用药时,特别是治疗局部外敷容易达到的患面或器官,如眼镜、皮肤或下肠道神经性疾病时,可根据不同的患面或器官将本发明的化合物制成不同的局部用药制剂形式,具体说明如下:
当眼部局部施用时,本发明化合物可配制成一种微粉化悬浮液或溶液的制剂形式,所使用的载体为等渗的具有一定PH的无菌盐水,其中可加入也可不加入防腐剂如氯化苄基烷醇盐。对于眼用,也可将化合物制成膏形式如凡士林膏。
当皮肤局部使用时,本发明化合物可制成适当地软膏、洗剂或霜制剂形式,其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于:矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水;洗剂或霜剂可使用的载体包括但不限于:矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
本发明化合物还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮或无菌注射溶液。其中,可使用的载体或溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,灭菌的非挥发油也可用作溶剂或悬浮介质,如单甘油酯或二甘油酯。
再一方面,本发明提供上述通式I的化合物或其可药用盐或药物组合物在制备抗氧化、抗炎、抗神经胆碱酶或保护神经的药物中的用途;
优选地,本发明提供上述通式I的化合物或其可药用盐或药物组合物在制备治疗和/或预防帕金森病中的用途。
还一方面,本发明提供一种治疗帕金森病的方法,该方法包括向有需要的患者施用上述通式I的化合物或其可药用盐或上述药物组合物。
本发明的通式I的化合物具有有价值的药理学性质,特别是具有抗氧化、抗炎、抗神经胆碱酶等药理活性,以及具有神经保护的特性,可用于治疗和/或预防帕金森病。
另外需要指出,本发明化合物的使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、自然健康状况、化合物的活性强度、服用时间、代谢速度、病症的严重程度,具体剂量和使用方法由主治医师根据患者的具体病情判断。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。如无特殊说明,下述实施例中“减压旋干溶剂”一般指“水泵减压条件下用旋转蒸发仪蒸干溶剂”。
本发明的起始原料可以采用CN104230770B中的方法或按照本领域已知的方法来合成,或可以于百灵威科技有限公司、阿拉丁试剂(上海)有限公司、北京偶合科技有限公司等试剂公司处直接购买。
实施例1:(E)-4-{2-[(4-三氟甲基苯基)甲磺酰基]乙烯基}-1,2-亚苯基双(二乙基氨基甲酸酯)(化合物B1-1)的制备
步骤一、(E)-4-{2-[(4-三氟甲基苯基)甲磺酰基]乙烯基}-1,2-亚苯基双氯甲酸酯(化合物B1-1-a)的制备
将固体光气(475mg,1.6mmol)溶于二氯甲烷(10mL)中,置冰水浴中冷却至0℃,在30分钟内缓速滴入(E)-4-{2-[(4-三氟甲基苯基)甲磺酰基]乙烯基}苯-1,2-二醇(860mg,2.4mmol)的二氯甲烷溶液(20mL)。搅拌15分钟后,再在15分钟内缓速滴入吡啶(0.40mL,5.0mmol)的二氯甲烷溶液(5mL)。以上滴加过程中应控制反应液温度不超过5℃。滴加完毕后让反应液自然升温至室温,搅拌反应2小时。将反应液用预冷水洗涤(25mL×3次),经无水硫酸镁干燥后过滤,滤液减压浓缩得到化合物B1-1-a,为微黄色油状液体,不需纯化可用于下步反应。
步骤二、(E)-4-{2-[(4-三氟甲基苯基)甲磺酰基]乙烯基}-1,2-亚苯基双(二乙基氨基甲酸酯)(化合物B1-1)的制备
将步骤一中得到的化合物B1-1-a溶于四氢呋喃(5mL)中,0-5℃下加入到二乙胺(0.52mL,5.0mmol)的四氢呋喃溶液(10mL)中,反应液缓慢升温至室温下搅拌过夜。TLC监测反应完毕后加入30mL水,用乙醚萃取(25mL×3次)。合并有机相,依次用0.01mol/L盐酸水溶液、饱和碳酸氢钠水溶液和饱和食盐水溶液各50mL洗涤一次,经无水硫酸镁干燥后过滤,滤液减压浓缩后的残余物用硅胶柱层析纯化(正己烷/乙酸乙酯体系,v/v=9∶1),可得米白色固体产物即化合物B1-1(606mg,两步收率45%)。
熔点107-109℃。
1H NMR(CDCl3)δ:1.19(t,12H,J=8.1Hz,NCH2CH 3),3.23(q,8H,J=8.1Hz,NCH 2CH3),4.65(s,2H,SO2CH2),7.06-7.17(m,3H,CH=CHSO2,ArH),7.35-7.41(m,3H,ArH),7.52(m,2H,ArH),7.88(d,1H,J=15.0Hz,CH=CHSO2);13C NMR(CDCl3)δ:12.7(NCH2 CH3*4),42.4(NCH2CH3*4),62.8(SO2CH2),118.7(CH=CHSO2),120.6(ArC),121.7(ArC),124.2(CF3),125.8(ArC),126.1(ArC*2),128.8(ArC*2),129.5(ArC),130.1(ArC),132.0(ArC),134.5(CH=CHSO2),143.6(ArC),145.1(ArC),154.3(NCOO),154.8(NCOO);HRMS-EI(M+):C26H31F3N2O6S,计算值:556.1855,实测值:556.1865。
实施例2:(E)-4-[2-(3-苯基丙磺酰基)乙烯基]-1,2-亚苯基双(二乙基氨基甲酸酯)(化合物C1-1)的制备
以(E)-4-{2-[(3-苯丙基)磺酰基]乙烯基}苯-1,2-二醇为起始原料,按实施例1中的制备方法,经两个步骤可制得化合物C1-1,呈淡黄色固体(两步收率42%)。
熔点96-99℃。
1H NMR(CDCl3)δ:1.26(m,12H,NCH2CH 3),2.19(tt,2H,J=7.6,5.4Hz,SO2CH2CH 2CH2),2.81(t,2H,J=7.6Hz,SO2CH2CH2CH 2),3.06(t,2H,J=5.4Hz,SO2CH 2CH2CH2),3.43(m,8H,NCH 2CH3),6.77(d,1H,J=15.4Hz,CH=CHSO2),7.20-7.42(m,8H,ArH),7.54(d,1H,J=15.4Hz,CH =CHSO2);13C NMR(CDCl3)δ:13.3(NCH2 CH3*2),14.1(NCH2 CH3*2),24.2(SO2CH2 CH2CH2),34.2(SO2CH2CH2 CH2),42.0(NCH2CH3*2),42.4(NCH2CH3*2),54.4(SO2 CH2CH2CH2),123.4(ArC),124.3(ArC),125.0(CH=CHSO2),126.5(ArC),126.6(ArC),128.5(ArC*2),128.7(ArC*2),130.1(ArC),139.9(CH=CHSO2),143.6(ArC),143.9(ArC),146.0(ArC),152.8(NCOO),153.0(NCOO);HRMS-EI(M+):C27H36N2O6S,计算值:516.2294,实测值:516.2282。
实施例3:(E)-4-{2-[(4-氯苯基)甲磺酰基]乙烯基}-1,2-亚苯基双(二乙基氨基甲酸酯)(化合物D1-1)的制备
以(E)-4-{2-[(4-氯苯基)甲磺酰基]乙烯基}苯-1,2-二醇为起始原料,按实施例1中的制备方法,经两个步骤可制得化合物D1-1,呈淡黄色固体(两步收率53%)。
熔点108-110℃。
1H NMR(CDCl3)δ:1.28(m,12H,NCH2CH 3),3.46(m,8H,NCH 2CH3),4.31(s,2H,SO2CH2),6.71(d,1H,J=15.4Hz,CH=CHSO2),7.32-7.45(m,8H,CH=CHSO2,ArH);13C NMR(CDCl3)δ:13.3(NCH2 CH3),14.2(NCH2 CH3),42.0(NCH2CH3),42.4(NCH2CH3),61.2(SO2CH2),123.5(ArC),124.1(CH=CHSO2),124.4(ArC),126.5(ArC),129.2(ArC*2),130.0(ArC),132.3(ArC*2),134.9(ArC),135.3(CH=CHSO2),144.0(ArC),144.7(ArC),146.1(ArC),152.8(NCOO),153.0(NCOO);HRMS-EI(M+):C25H31ClN2O6S,计算值:522.1591,实测值:522.1585。
实施例4:(E)-4-{2-[(4-叔丁基苯基)甲磺酰基]乙烯基}-1,2-亚苯基双(二乙基氨基甲酸酯)(化合物G1-1)的制备
以(E)-4-{2-[(4-叔丁基苯基)甲磺酰基]乙烯基}苯-1,2-二醇为起始原料,按实施例1中的制备方法,经两个步骤可制得化合物G1-1,呈白色固体(两步收率56%)。
熔点95-98℃。
1H NMR(CDCl3)δ:1.23(m,12H,NCH2CH 3),1.36(m,9H,t-Bu),3.42(m,8H,NCH 2CH3),4.30(s,2H,SO2CH2),6.70(d,1H,J=15.5Hz,CH=CHSO2),7.24-7.33(m,5H,ArH),7.40(d,1H,J=15.5Hz,CH=CHSO2),7.45(d,2H,J=7.6Hz,ArH);13C NMR(CDCl3)δ:13.3(NCH2 CH3),14.1(NCH2 CH3),31.3(C(CH3)3),34.7(C(CH3)3),42.0(NCH2CH3),42.4(NCH2CH3),61.6(SO2CH2),123.4(ArC),124.3(ArC),124.6(ArC),124.9(CH=CHSO2),125.9(ArC*2),126.4(ArC),130.2(ArC),130.6(ArC*2),143.9(ArC),144.1(CH=CHSO2),145.9(ArC),152.0(t-Bu-ArC),152.8(NCOO),153.0(NCOO);HRMS-EI(M+):C29H40N2O65,计算值:544.2607,实测值:544.2604。
实施例5:(E)-4-{2-[2-氯-2-(4-氯-3-硝基苯基)乙磺酰基]乙烯基}-2-羟基苯基-N-甲基氨基甲酸酯(化合物E2-2)的制备
步骤一、(E)-4-{2-[2-氯-2-(4-氯-3-硝基苯基)乙磺酰基]乙烯基}-2-羟基苯基氯甲酸酯(化合物E2-2-a)的制备
将固体光气(237mg,0.8mmol)溶于二氯甲烷(10mL)中,置冰水浴中冷却至0℃,在30分钟内缓速滴入(E)-4-{2-[2-氯-2-(4-氯-3-硝基苯基)乙磺酰基1乙烯基}苯-1,2-二醇(1003mg,2.4mmol)的二氯甲烷溶液(20mL)。搅拌15分钟后,再在15分钟内缓速滴入吡啶(0.20mL,2.5mmol)的二氯甲烷溶液(5mL)。以上滴加过程中应控制反应液温度不超过5℃。滴加完毕后让反应液自然升温至室温,搅拌反应2小时。将反应液用预冷水洗涤(25mL×3次),经无水硫酸镁干燥后过滤,滤液减压浓缩得到化合物E2-2-a,为黄色油状液体,不需纯化可用于下步反应。
步骤二、(E)-4-{2-[2-氯-2-(4-氯-3-硝基苯基)乙磺酰基]乙烯基}-2-羟基苯基-N-甲基氨基甲酸酯(化合物E2-2)的制备
将步骤一中得到的化合物E2-2-a溶于四氢呋喃(5mL)中,0-5℃下加入到甲胺(2M四氢呋喃溶液,1.25mL,2.5mmol)的四氢呋喃溶液(10mL)中,反应液缓慢升温至室温下搅拌过夜。TLC监测反应完毕后加入30mL水,用乙醚萃取(25mL×3次)。合并有机相,依次用0.01mol/L盐酸水溶液、饱和碳酸氢钠水溶液和饱和食盐水溶液各50mL洗涤一次,经无水硫酸镁干燥后过滤,滤液减压浓缩后的残余物用硅胶柱层析纯化(正己烷/乙酸乙酯体系,v/v=15∶2),可得淡黄色固体产物即化合物E2-2(403mg,两步收率35%)。
熔点211-213℃。
1H NMR(CDCl3)δ:2.89(s,3H,NHCH 3),3.85(dd,1H,J=12.5,7.0Hz,SO2CH 2),4.11(dd,1H,J=12.5,7.0Hz,SO2CH 2),4.82(brs,1H,CONH),5.67(m,1H,CHCl),6.87(d,1H,J=7.5Hz,ArH),6.95-7.33(m,6H,CH=CHSO2,ArOH,ArH),7.41(d,1H,J=7.4Hz,ArH),7.63(d,1H,J=15.5Hz,CH=CHSO2);13C NMR(CDCl3)δ:27.5(NHCH3),49.3(CHCl),62.5(SO2CH2),115.2(ArC),120.9(CH=CHSO2),121.6(ArC),122.7(ArC),126.1(ArC),125.9(ArC),128.7(ArC),130.2(ArC),130.8(ArC),134.9(ArC),139.3(ArC-OCO),142.5(ArC-NO2),143.8(CH=CHSO2),149.1(ArC-OH),155.2(NCOO);HRMS-EI(M+):C18H16Cl2N2O7S,计算值:474.0055,实测值:474.0072。
实施例6:(E)-2-甲氧基-4-{2-[(3,4,5-三甲氧基苯基)甲磺酰基]乙烯基}-苯基-N,N-二苯基氨基甲酸酯(化合物K3-3)的制备
以(E)-2-甲氧基-4-{2-[(3,4,5-三甲氧基苯基)甲磺酰基]乙烯基}苯酚为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物K3-3,呈米白色固体(两步收率51%)。
熔点195-197℃。
1H NMR(CDCl3)δ:3.85(m,12H,OCH3),4.66(s,2H,SO2CH2),6.75-7.21(m,6H,CH=CHSO2,ArH),7.35-7.51(m,10H,N-ArH),7.90(d,1H,J=15.5Hz,CH=CHSO2);13C NMR(CDCl3)δ:56.0(OCH3*2),56.2(OCH3),59.3(SO2CH2),60.7(OCH3),108.9(ArC*2),111.4(ArC),120.5(CH=CHSO2),122.3(ArC),122.6(ArC),126.9(ArC*4),127.2(ArC),128.1(ArC*2),129.9(ArC),130.2(ArC*4),137.1(ArC),137.5(CH=CHSO2),141.2(ArC*2),144.6(ArC),149.9(ArC*2),150.7(ArC),154.7(NCOO);HRMS-EI(M+):C32H31NO8S,计算值:589.1770,实测值:589.1761。
实施例7:4-{(E)-2-[(E)-3-(4-烯丙氧基苯基)丙-1-烯-1-基]磺酰乙烯基}-2-(N,N-二烯丙基氨基甲酰氧基)苯基乙酸酯(化合物K1-4)的制备
以4-{(E)-2-[(E)-3-(4-烯丙氧基苯基)丙-1-烯-1-基]磺酰乙烯基}-2-羟基苯基乙酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物K1-4,呈白色固体(两步收率38%)。
熔点146-149℃。
1H NMR(CDCl3)δ:2.54(s,3H,CH3CO),3.42(m,2H,CH 2Ar),3.66(d,4H,J=6.1Hz,CH2=CHCH 2N),4.63(d,2H,J=6.0Hz,CH2=CHCH 2O),5.19-5.53(m,6H,CH 2=CHCH2N,CH 2=CHCH2O),5.89-6.05(m,3H,CH2=CHCH2N,CH2=CHCH2O),6.36(d,1H,J=15.2Hz,SO2CH=CHCH2),6.73-7.30(m,8H,ArCH=CHSO2,ArH),7.46(dt,1H,j=15.1Hz,6.2Hz,SO2CH=CHCH2),8.05(d,1H,J=15.3Hz,ArCH=CHSO2);13C NMR(CDCl3)δ:20.3(CH3CO),38.1(CH2Ar),49.8(CH2=CHCH2N*2),68.5(CH2=CHCH2O),115.0(ArC*2),117.5(CH2=CHCH2N*2),117.9(CH2=CHCH2O),122.1(ArC),122.6(ArC),124.7(ArC),126.1(ArCH=CHSO2),129.1(ArC*2),130.8(ArC),132.7(CH2=CHCH2N*2),133.1(CH2=CHCH2O),133.9(ArCH=CHSO2),135.0(ArC),137.4(SO2 CH=CHCH2),142.1(ArC),142.9(ArC),143.3(SO2CH=CHCH2),153.6(NCOO),157.4(ArC),168.6(CH3COO);HRMS-EI(M+):C29H31NO7S,计算值:537.1821,实测值:537.1804。
实施例8:4-{(E)-1-[(E)-3-(氯甲基二甲基硅氧基)-4-(N,N-二甲基氨基甲酰氧基)苯乙烯基磺酰基]丙-1-烯-2-基}苯基-2-(4-甲氧基苯基)乙酸酯(化合物P1-7)的制备
以4-{(E)-1-[(E)-3-(氯甲基二甲基硅氧基)-4-羟基苯乙烯基磺酰基]丙-1-烯-2-基}苯基-2-(4-甲氧基苯基)乙酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物P1-7,呈白色固体(两步收率43%)。
熔点123-125℃。
1H NMR(CDCl3)δ:0.13(s,6H,SiCH3*2),2.24(s,3H,CH 3C=CH),2.72(s,2H,ClCH2Si),3.15(s 3H,CH3N),3.27(s 3H,CH3N),3.81(s,3H,OCH3),4.11(s,2H,OCOCH2),6.75(SO2CH=C),6.85-7.05(m,6H,CH=CHSO2,ArH),7.20-7.32(m,6H,ArH),8.08(CH=CHSO2);13C NMR(CDCl3)δ:-1.8(SiCH3*2),15.3(CH3C=CH),29.8(ClCH2Si),36.8(NCH3*2),41.2(OCOCH2),55.3(OCH3),114.4(ArC*2),116.7(ArC),121.0(ArC),121.3(ArC*2),121.5(ArC),124.9(CH= CHSO2),126.7(ArC),126.9(ArC*2),128.7(SO2 CH=C),130.0(ArC),130.5(ArC*2),131.7(CH=CHSO2),137.6(ArC),142.2(ArC),147.8(ArC),148.8(CH3 C=CH),150.9(ArC),154.8(NCOO),158.0(ArC),169.7(OCOCH2);HRMS-EI(M+):C32H36ClNO8SSi,计算值:657.1619,实测值:657.1633。
实施例9:(E)-4-{2-[3-(4-苄氧基-3-羟基苯基)-2,3-二乙氧基丙基]磺酰乙烯基}-2-[N-(4-甲氨基苯基)氨基甲酰氧基]苯基乙酸酯(化合物H2-4)的制备
以(E)-4-{2-[3-(4-苄氧基-3-羟基苯基)-2,3-二乙氧基丙基]磺酰乙烯基}-2-羟基苯基乙酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物H2-4,呈淡黄色固体(两步收率18%)。
熔点182-183℃。
1H NMR(CDCl3)δ:1.19(m,6H,OCH2CH 3*2),2.49(s,3H,CH3CO),2.70(s,3H,CH 3NH),3.03(m,2H,OCH 2CH3),3.40(m,1H,SO2CH2),3.62(m,1H,SO2CH2),3.81(dq,1H,J=12.5,8.1Hz,OCH 2CH3),4.19(dq,1H,J=12.5,8.1Hz,OCH 2CH3),4.30(brs,1H,CH3NH),4.55(m,1H,SO2CH2CH),4.72(m,1H,OCHAr),5.22(m,2H,OCH 2Ph),5.90(brs,1H,Ar-OH),6.48(d,2H,J=7.5Hz,ArH),6.68-6.81(m,3H,NHCOO,ArH),6.98-7.09(m,2H,ArH),7.16(d,1H,J=15.3Hz,CH=CHSO2),7.25-7.45(m,9H,ArH),8.11(d,1H,J=15.2Hz,CH=CHSO2);13C NMR(CDCl3)δ:15.3(OCH2 CH3),15.4(OCH2 CH3),20.5(CH3CO),29.8(CH3NH),50.7(SO2CH2),64.8(OCH2CH3),65.2(OCH2CH3),70.7(OCH2Ph),71.9(SO2CH2 CH),81.5(OCHAr),114.9(ArC),115.8(ArC),116.9(CH=CHSO2),117.1(ArC*2),119.9(ArC),121.9(ArC),122.3(ArC),122.8(ArC*2),125.3(ArC),127.6(ArC*2),127.8(ArC),128.5(ArC*2),129.8(ArC),133.0(ArC),133.3(ArC),134.2(CH=CHSO2),135.1(ArC),142.3(ArC),143.2(ArC),146.1(ArC),146.2(ArC),151.6(ArC),154.1(NHCOO),168.6(CH3 CO);HRMS-EI(M+):C38H42N2O10S,计算值:718.2560,实测值:718.2537。
实施例10:(E)-2-[(甲氨基)甲氧基]-4-{2-[1-(4′-硝基-[1,1′-二苯基]-4-基)乙基磺酰基]乙烯基}苯基氨基甲酸酯(化合物M1-3)的制备
以(E)-2-[(甲氨基)甲氧基]-4-{2-[1-(4′-硝基-[1,1′-二苯基]-4-基)乙基磺酰基]乙烯基}苯酚为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物M1-3,呈黄色固体(两步收率33%)。
熔点256-258℃。
1H NMR(CDCl3)δ:1.12(brs,1H,CH3NH),1.73(d,3H,J=6.8Hz,CHCH 3),2.44(s,3H,CH 3NH),4.39(q,1H,J=6.8Hz,CHCH3),4.89(brs,2H,NH2COO),5.02(d,1H,J=12.5Hz,NHCH 2O),5.53(d,1H,J=12.5Hz,NHCH 2O),6.88(d,1H,J=7.6Hz,ArH),7.12-7.33(m,5H,CH=CHSO2,ArH),7.61(d,2H,J=7.6Hz,ArH),7.68(m,4H,ArH),8.12(d,1H,J=15.2Hz,CH=CHSO2);13C NMR(CDCl3)δ:15.3(CH3CH),35.0(CH3NH),67.5(CH3 CH),82.1(NHCH2O),113.8(ArC),122.6(ArC),123.9(ArC),124.6(CH=CHSO2),126.7(ArC*2),128.2(ArC*2),128.9(ArC*2),129.5(ArC*2),130.9(ArC),134.7(ArC),136.0(ArC),137.5(ArC),138.5(CH=CHSO2),138.9(ArC),142.7(ArC),148.5(ArC),156.1(NH2COO);HRMS-EI(M+):C25H25N3O7S,计算值:511.1413,实测值:511.1418。
实施例11:(E)-5-{2-[(4-[吡啶-2-基-氧]苯基)二氟甲基磺酰基]乙烯基}-2-[N-(2,2,2-三氟乙酰基)氨基甲酰氧基]苯基-2,2,3,3,3-五氟丙酸酯(化合物L1-4)的制备
以(E)-5-{2-[(4-[吡啶-2-基-氧]苯基)二氟甲基磺酰基]乙烯基}-2-羟基苯基-2,2,3,3,3-五氟丙酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物L1-4,呈淡黄色固体(两步收率40%)。
熔点153-156℃。
1H NMR(CDCl3)δ:6.36(brs,1H,CF3CONH),6.79-6.91(m,2H,ArH),7.03-7.09(m,3H,ArH),7.16(d,1H,J=15.1Hz,CH=CHSO2),7.23-7.32(m,1H,ArH),7.33-7.54(m,4H,ArH),8.09(d,1H,J=15.1Hz,CH=CHSO2),8.79(d,1H,J=5.0Hz,ArH);13C NMR(CDCl3)δ:9.3(CF3CF2CO),23.9(CF3CO),27.2(CF3 CF2CO),58.5(SO2CF2),112.9(ArC),119.1(CH=CHSO2),120.4(ArC),120.9(ArC),121.5(ArC*2),123.8(ArC),125.2(ArC),126.9(ArC),129.5(ArC*2),130.7(ArC),134.6(CH=CHSO2),139.4(ArC),141.8(ArC),143.6(ArC),147.7(ArC),151.9(NHCOO),153.0(ArC),162.8(ArC),169.1(CF3 CO),172.8(CF3CF2 CO);HRMS-EI(M+):C26H14F10N2O8S,计算值:704.0311,实测值:704.0336。
实施例12:(E)-2-(2,3-二溴丁氧基)-4-{2-[4-(2,2,2-三氟乙氧基)苯乙磺酰基]乙烯基}苯基-N-(噻吩-3-基)氨基甲酸酯(化合物K1-3)的制备
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以(E)-2-(2,3-二溴丁氧基)-4-{2-[4-(2,2,2-三氟乙氧基)苯乙磺酰基]乙烯基}苯酚为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物K1-3,呈橙黄色固体(两步收率25%)。
熔点110-113℃。
1H NMR(CDCl3)δ:1.79(d,3H,J=7.0Hz,CH 3CHBr),3.09-3.28(m,4H,SO2CH 2CH 2),4.17(m,1H,OCH 2CHBr),4.25-4.35(m,3H,CF3CH 2O,CH3CHBr),4.65(m,1H,OCH2CHBr),4.97(m,1H,OCH 2CHBr),6.12(s,1H,ArH),6.45(m,1H,ArH),6.63(brs,1H,NHCOO),6.85(m,2H,ArH),7.01(d,1H,J=7.6Hz,ArH),7.15-7.29(m,5H,CH=CHSO2,ArH),7.41(d,1H,J=7.5Hz,ArH),8.11(d,1H,J=15.4Hz,CH=CHSO2);13C NMR(CDCl3)δ:14.7(CF3),23.0(CH3CHBr),30.1(SO2CH2 CH2),49.5(CH3 CHBr),52.6(SO2 CH2CH2),60.2(OCH2 CHBr),64.2(OCH2CF3),70.1(OCH2CHBr),105.7(ArC),113.8(ArC),114.7(ArC*2),120.3(CH=CHSO2),122.6(ArC),123.4(ArC),124.1(ArC),126.8(ArC),129.5(ArC*2),130.4(ArC),130.8(ArC),133.1(ArC),136.0(CH=CHSO2),144.4(ArC),149.2(ArC),154.1(NHCOO),157.1(ArC);HRMS-EI(M+):C27H26Br2F3NO6S2,计算值:740.9500,实测值:740.9495。
实施例13:(E)-2-[N-(2-甲氧基乙基)-N-甲基氨基甲酰氧基]-4-{2-[3-(5-甲基呋喃-2-基)苯乙磺酰基]乙烯基}苯基乙酸酯(化合物J1-4)的制备
以(E)-2-羟基-4-{2-[3-(5-甲基呋喃-2-基)苯乙磺酰基]乙烯基}苯基乙酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物J1-4,呈淡黄色固体(两步收率43%)。
熔点191-193℃。
1H NMR(CDCl3)δ:2.34(furan-CH3),2.52(CH3CO),3.13(m,5H,SO2CH2CH 2,CH3N),3.36(CH3O),3.60(t,2H,J=4.0Hz,CH 2NCH3),3.75(m,4H,CH3OCH 2,SO2CH 2CH2),6.10(d,1H,J=7.5Hz,ArH),6.84(d,1H,J=7.5Hz,ArH),6.96(d,1H,J=7.4Hz,ArH),7.08(d,1H,J=15.1Hz,CH=CHSO2),7.15-7.32(m,3H,ArH),7.42(t,1H,J=7.5Hz,ArH),7.55(m,2H,ArH),8.10(d,1H,J=15.2Hz,CH=CHSO2);13C NMR(CDCl3)δ:13.5(furan-CH3),20.7(CH3CO),30.2(SO2CH2 CH2),42.7(CH3N),49.8(CH2NCH3),53.1(SO2 CH2CH2),58.2(CH3O),72.7(CH3OCH2),107.1(ArC),108.5(ArC),120.4(CH=CHSO2),121.9(ArC),122.5(ArC),122.8(ArC),124.8(ArC),127.1(ArC),127.9(ArC),129.6(ArC),130.0(ArC),130.9(ArC),135.9(CH=CHSO2),138.0(ArC),142.1(ArC),143.2(ArC),150.9(ArC),152.6(ArC),154.5(NCOO),168.8(CH3 COO);HRMS-EI(M+):C28H31NO8S,计算值:541.1770,实测值:541.1793。
实施例14:(E)-2-(2-苄氧基乙氧基)-4-{2-[4-(N,N-二异丙基氨基)苯乙磺酰基]乙烯基}苯基-N-(4-碘苯基)-N-甲基氨基甲酸酯(化合物A1-3)的制备
以(E)-2-(2-苄氧基乙氧基)-4-{2-[4-(N,N-二异丙基氨基)苯乙磺酰基]乙烯基}苯酚为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物A1-3,呈橙红色固体(两步收率31%)。
熔点170-172℃。
1H NMR(CDCl3)δ:1.32(m,12H,CH(CH 3)2*2),3.02(t,2H,J=8.3Hz,SO2CH2CH 2),3.77(t,2H,J=8.3Hz,SO2CH 2CH2),3.84(m,5H,BzOCH 2,NCH3),4.18(t,2H,J=7.2Hz,CH 2OAr),4.47(m,4H,PhCH 2O,CH(CH3)2*2),6.67(d,2H,J=7.4Hz,ArH),7.02(d,2H,J=7.5Hz,ArH),7.06-7.21(m,6H,CH=CHSO2,ArH),7.35(m,5H,ArH),7.52(d,2H,J=7.5Hz,ArH),8.12(d,1H,J=15.3Hz,CH=CHSO2);13C NMR(CDCl3)δ:20.9(CH(CH3)2*2),30.3(SO2CH2 CH2),35.1(NCH3),48.9(CH(CH3)2*2),52.8(SO2 CH2CH2),69.3(CH2OAr),70.2(BzOCH2),73.0(PhCH2O),88.2(I-ArC),114.1(ArC),118.1(ArC*2),119.7(CH=CHSO2),120.6(ArC*2),122.8(ArC),123.0(ArC),127.9(ArC*2),128.1(ArC),128.8(ArC*2),129.9(ArC*2),130.2(ArC),131.1(ArC),136.0(CH=CHSO2),136.8(ArC*2),138.1(ArC),143.9(ArC),144.7(ArC),147.6(ArC),149.3(ArC),155.4(NCOO);HRMS-EI(M+):C39H45IN2O6S,计算值:796.2043,实测值:796.2048。
实施例15:(E)-4-{2-[2-(3′,4′-二甲氧基-[1,1′-二苯基]-4-基)2-硝基乙基磺酰基]乙烯基}-1,2-亚苯基双(N-乙基-N-甲基氨基甲酸酯)(化合物M1-1)的制备
以(E)-4-{2-[2-(3′,4′-二甲氧基-[1,1′-二苯基]-4-基)2-硝基乙基磺酰基]乙烯基}苯-1,2-二醇为起始原料,按实施例1中的制备方法,经两个步骤可制得化合物M1-1,呈白色固体(两步收率67%)。
熔点159-161℃。
1H NMR(CDCl3)δ:1.22(t,6H,J=8.0Hz,NCH2CH 3*2),3.16(s,6H,NCH3*2),3.38-3.55(m,4H,SO2CH aHbCH,NCH aHbCH3*2),3.72(m,1H,SO2CHa H bCH),3.85(s,3H,OCH3),3.91(s,3H,OCH3),4.06(m,1H,NCHa H bCH3),4.20(m,1H,NCHa H bCH3),7.02(d,1H,J=7.6Hz,ArH),7.15-7.33(m,6H,CH=CHSO2,ArH),7.46(m,2H,ArH),7.58(d,2H,J=7.5Hz,ArH),8.10(d,1H,J=15.3Hz,CH=CHSO2);13C NMR(CDCl3)δ:12.0(NCH2 CH3*2),32.3(CHNO2),36.1(NCH3*2),46.3(NCH2CH3*2),54.3(SO2CH2),56.5(OCH3*2),112.0(ArC),113.5(ArC),117.6(CH=CHSO2),119.0(ArC),121.6(ArC),123.1(ArC),126.1(ArC),126.8(ArC*2),128.2(ArC*2),128.9(ArC),134.1(ArC),136.2(CH=CHSO2),138.3(ArC),141.9(ArC),143.2(ArC),144.7(ArC),150.6(ArC),151.1(ArC),154.7(NCOO),154.9(NCOO);HRMS-EI(M+):C32H37N3O10S,计算值:655.2200,实测值:655.2174。
实施例16:(E)-4-{1-氨基-2-[4-叔丁氧基-3-(N-甲基-N-苯基氨基甲酰氧基)苯乙烯基磺酰基]乙基}苯基-2-(4-甲氧基苯基)乙酸酯(化合物P1-3)的制备
以(E)-4-{1-氨基-2-[4-叔丁氧基-3-羟基苯乙烯基磺酰基]乙基}苯基-2-(4-甲氧基苯基)乙酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物P1-3,呈米黄色固体(两步收率58%)。
熔点146-149℃。
1H NMR(CDCl3)δ:1.36(brs,11H,NH2,OC(CH3)3),3.69(m,2H,SO2CH aHb,OCOCH aHb),3.81(s,3H,OCH3),3.98(s,3H,NCH3),4.11(m,2H,SO2CHa H b,OCOCHa H b),4.59(m,1H,NH2CH),6.84(d,2H,J=7.5Hz,ArH),6.93(d,2H,J=7.4Hz,ArH),7.10(d,1H,J=7.5Hz,ArH),7.18(m,3H,CH=CHSO2,ArH),7.30-7.42(m,5H,ArH),7.55(d,2H,J=7.6Hz,ArH),7.73(m,2H,ArH),8.09(d,1H,J=15.2Hz,CH=CHSO2);13C NMR(CDCl3)δ:28.2(OC(CH3)3),34.9(NCH3),42.3(OCOCH2),52.9(SO2CH2),54.6(NH2CH),55.8(OCH3),81.5(OC(CH3)3),112.7(ArC*2),116.9(CH=CHSO2),120.3(ArC),121.9(ArC*2),122.2(ArC*2),123.5(ArC),125.3(ArC*2),127.1(ArC),128.2(ArC*2),128.9(ArC),129.7(ArC*2),130.8(ArC*2),134.9(CH=CHSO2),137.8(ArC),142.5(ArC),143.1(ArC),145.9(ArC),151.0(ArC),154.7(NCOO),158.3(ArC),170.1(OCOCH2);HRMS-EI(M+):C37H40N2O8S,计算值:672.2505,实测值:672.2501。
实施例17:(E)-4-{2-[4-(4-二甲氨基苄基)苯基溴甲基磺酰基]乙烯基}-2-[2-(4-二甲氨基苯基)乙酰基]苯基-2-三氟甲基吡咯烷-1-羧酸酯(化合物M1-5)的制备
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以(E)-5-{2-[4-(4-二甲氨基苄基)苯基溴甲基磺酰基]乙烯基}-2-羟基苯基-2-(4-二甲氨基苯基)乙酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物M1-5,呈淡黄色固体(两步收率44%)。
熔点213-215℃。
1H NMR(CDCl3)δ:1.73-2.01(m,4H,NCH2CH 2CH 2),2.98(s,12H,NCH3*4),3.16(m,1H,NCH aHb),3.55(m,1H,NCHaHb),3.68(m,2H,NCHCF3,CH aHbCOO),3.83(s,2H,PhCH 2Ph),4.25(d,1H,J=12.5Hz,CHa H bCOO),6.58(m,5H,CHBr,ArH),6.83(d,1H,J=7.5Hz,ArH),6.91(d,2H,J=7.4Hz,ArH),7.13(d,1H,J=15.0Hz,CH=CHSO2),7.22(m,3H,ArH),7.38(m,3H,ArH),7.63(d,2H,J=7.4Hz,ArH),8.12(d,1H,J=15.1Hz,CH=CHSO2);13C NMR(CDCl3)δ:17.6(CF3),24.9(NCH2 CH2),35.1(NCH2CH2 CH2),40.5(CH2COO),41.2(NCH3*4),41.9(PhCH2Ph),47.0(NCH2),56.4(NCHCF3),61.5(CHBr),114.0(ArC*2),114.5(ArC*2),117.6(CH=CHSO2),120.9(ArC),121.7(ArC),125.0(ArC),126.3(ArC),128.1(ArC*2),129.6(ArC*2),129.8(ArC*2),129.9(ArC*2),130.7(ArC),131.5(ArC),132.5(ArC),135.0(CH=CHSO2),140.2(ArC),142.3(ArC),144.0(ArC),151.1(ArC*2),155.3(NCOO),170.4(CH2 COO);HRMS-EI(M+):C40H41BrF3N3O6S,计算值:827.1852,实测值:827.1829。
实施例18:(E)-4-{2-[4-(二乙基苯基硅氧基)苯基氯甲磺酰基]乙烯基}-2-(3-氯-2-甲氧基苯甲酰氧基)苯基-2,6-二甲基吗啉-4-羧酸酯(化合物R1-5)的制备
以(E)-5-{2-[4-(二乙基苯基硅氧基)苯基氯甲磺酰基]乙烯基}-2-羟基苯基-3-氯-2-甲氧基苯甲酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物R1-5,呈黄色固体(两步收率37%)。
熔点167-170℃。
1H NMR(CDCl3)δ:0.78(m,4H,SiCH2*2),1.02(t,6H,J=7.9Hz,SiCH2CH 3*2),1.25(d,3H,J=6.8Hz,CHCH 3),1.34(d,3H,J=6.8Hz,CHCH 3),3.32(dd,1H,J=12.5,6.9Hz,NCH aHb),3.41(dd,1H,J=12.5,6.9Hz,NCH aHb),3.63(s,3H,OCH3),3.72(m,2H,OCHCH3*2),3.99(dd,1H,J=12.5,6.9Hz,NCHa H b),4.08(dd,1H,J=12.5,6.9Hz,NCHa H b),6.29(s,1H,ClCH),7.15(m,4H,CH=CHSO2,ArH),7.24-7.43(m,8H,ArH),7.55(d,2H,J=7.6Hz,ArH),7.61(dd,1H,J=7.5,1.7Hz,ArH),7.73(dd,1H,J=7.3,2.0Hz,ArH),8.10(d,1H,J=15.0Hz,CH=CHSO2);13C NMR(CDCl3)δ:6.9(SiCH2 CH3*2),11.2(SiCH2CH3*2),18.9(OCHCH3*2),52.1(NCH2*2),62.8(OCH3),71.4(OCHCH3*2),79.5(ClCH),120.1(ArC),121.5(ArC*2),121.8(ArC),123.5(ArC),124.6(ArC),124.9(ArC),125.3(ArC),125.8(CH=CHSO2),126.1(ArC*2),127.9(ArC),130.2(ArC*2),130.4(ArC),131.1(ArC),132.5(ArC),134.1(ArC),134.6(ArC*2),140.2(ArC),142.3(ArC),144.0(ArC),152.8(ArC),154.0(NCOO),155.7(CH=CHSO2),159.2(ArC),167.3(ArCOO);HRMS-EI(M+):C40H43Cl2NO9SSi,计算值:811.1805,实测值:811.1788。
实施例19:(E)-2-[N-(3-甲基-4-硝基苯甲酰基)氨基甲酰氧基]-4-{2-[(全氟苯基)甲磺酰基]乙烯基}苯基乙酸酯(化合物D5-4)的制备
以(E)-2-羟基-4-{2-[(全氟苯基)甲磺酰基]乙烯基}苯基乙酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物D5-4,呈黄色固体(两步收率42%)。
熔点264-267℃。
1H NMR(CDCl3)δ:2.32(s,3H,Ph-CH 3),2.54(s,3H,CH3CO),4.69(s,2H,SO2CH2),5.50(brs,1H,CONH),7.01(d,1H,J=7.5Hz,ArH),7.09(s,1H,ArH),7.18(d,1H,J=15.2Hz,CH=CHSO2),7.23(d,1H,J=7.5Hz,ArH),7.49(m,2H,ArH),7.58(dd,1H,J=7.5,2.0Hz,ArH),8.13(d,1H,J=15.2Hz,CH=CHSO2);13C NMR(CDCl3)δ:19.9(Ph-CH3),20.8(CH3CO),56.1(SO2CH2),105.3(ArC),118.6(CH=CHSO2),122.3(ArC),123.1(ArC),125.2(ArC),127.6(ArC),129.1(ArC),130.4(ArC),130.6(ArC),133.5(ArC),134.8(CH=CHSO2),136.7(ArC),137.8(ArC),138.8(ArC),141.7(ArC),142.2(ArC*2),143.1(ArC),144.0(ArC),145.8(ArC),152.4(NHCOO),165.7(CONHCOO),169.1(CH3 CO);HRMS-EI(M+):C26H17F5N2O9S,计算值:628.0575,实测值:628.0553。
实施例20:(E)-4-{[4-(乙基磺酰氧基)-3-(N-甲基-N-甲磺酰基氨基甲磺酰氧基)苯乙烯磺酰基]甲基}苯基乙磺酸酯(化合物S1-6)的制备
以(E)-4-{[4-(乙基磺酰氧基)-3-羟基苯乙烯磺酰基]甲基}苯基乙磺酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物S1-6,呈淡黄色固体(两步收率29%)。
熔点255-257℃。
1H NMR(CDCl3)δ:1.41(t,3H,J=8.1Hz,CH 3CH2SO2),1.53(t,3H,J=8.0Hz,CH 3CH2SO2),2.75(s,3H,CH3N),2.92(s,3H,CH3SO2),3.07(q,4H,J=8.0Hz,CH3CH 2SO2*2),4.68(s,2H,SO2CH 2Ph),7.15(d,1H,J=15.1Hz,CH=CHSO2),7.25(m,2H,ArH),7.38(d,1H,J=7.6Hz,ArH),7.44(d,2H,J=7.5Hz,ArH),7.67(d,2H,J=7.4Hz,ArH),8.10(d,1H,J=15.2Hz,CH=CHSO2);13C NMR(CDCl3)δ:8.5(CH3CH2SO2*2),31.5(CH3N),42.3(CH3SO2),45.7(CH3 CH2SO2*2),59.3(SO2 CH2Ph),118.8(CH=CHSO2),120.6(ArC),122.3(ArC),123.5(ArC*2),125.0(ArC),126.9(ArC),127.6(ArC*2),128.1(ArC),134.8(CH=CHSO2),141.5(ArC),146.3(ArC),148.6(ArC),150.2(NCOO);HRMS-EI(M+):C22H27NO12S4,计算值:625.0416,实测值:625.0404。
实施例21:(E)-2-(N-甲基-N-对甲苯磺酰基氨基甲酰氧基)-4-{2-[(4-对甲苯磺酰氧基苯基)甲磺酰]乙烯基}苯基对甲苯磺酸酯(化合物S6-6)的制备
以(E)-2-羟基-4-{2-[(4-对甲苯磺酰氧基苯基)甲磺酰]乙烯基}苯基对甲苯磺酸酯为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物S6-6,呈米白色固体(两步收率47%)。
熔点271-274℃。
1H NMR(CDCl3)δ:2.42(s,9H,CH 3Ph*3),3.03(s,3H,CH3N),4.68(s,2H,SO2CH 2Ph),7.11(m,1H,ArH),7.15-7.23(m,4H,CH=CHSO2,ArH),7.26-7.35(m,5H,ArH),7.48(m,4H,ArH),7.73(m,4H,ArH),8.01(d,2H,J=7.6Hz,ArH),8.11(d,1H,J=15.3Hz,CH=CHSO2);13CNMR(CDCl3)δ:21.5(CH3Ph*3),32.6(CH3N),59.5(SO2 CH2Ph),119.3(CH=CHSO2),121.3(ArC),122.0(ArC),124.1(ArC),124.6(ArC*2),126.5(ArC),127.9(ArC*2),128.6(ArC*2),128.8(ArC*2),128.9(ArC),129.3(ArC*2),129.5(ArC*2),130.1(ArC*4),134.6(CH=CHSO2),136.3(ArC),136.8(ArC),137.2(ArC),140.4(ArC*2),142.1(ArC),143.0(ArC),144.5(ArC),146.9(ArC),149.9(NCOO);HRMS-EI(M+):C38H35NO12S4,计算值:825.1042,实测值:825.1019。
实施例22:(E)-4-{2-[4-(二甲氨基)-4-(4-(N,N-二甲基甘氨酰氧基)苯)丁基磺酰基]乙烯基}-2-(N-甲基-N-苯基氨基甲酰氧基)苯基-4-(对甲苯基)哌嗪-1-羧酸酯(化合物P1-1)的制备
以(E)-4-{4-[(3,4-二羟基苯乙烯基)磺酰基]-1-(二甲氨基)丁基}苯基-N,N-二甲基甘氨酸盐为起始原料,按实施例5中的制备方法,经两个步骤可制得(E)-4-{2-[4-(二甲氨基)-4-(4-(N,N-二甲基甘氨酰氧基)苯)丁基磺酰基]乙烯基}-2-羟基苯基-4-(对甲苯基)哌嗪-1-羧酸酯(化合物P1-1-a),两步收率26%;再以化合物P1-1-a为起始原料,按实施例5中的制备方法,经两个步骤可制得化合物P1-1,呈淡黄色固体(两步收率43%)。
熔点271-274℃。
1H NMR(CDCl3)δ:1.44(m,1H,NCHCH aHb),1.77(m,1H,SO2CH2CH aHb),2.03(m,1H,SO2CH2CHa H b),2.24(s,3H,CHNCH 3),2.27(s,3H,CHNCH 3),2.32(s,3H,CH 3Ph),2.39(s,3H,CH 3NCH2),2.48(s,3H,CH 3NCH2),2.85(m,1H,SO2CH aHb),2.99-3.08(m,3H,NCHCHa H b,CH aHbNCO,SO2CHa H b),3.18-3.30(m,3H,ArNCH aHb*2,COCH aHbN),3.39-3.43(m,2H,ArCHN,CH aHbNCO),3.59(s,3H,PhNCH 3),3.72(m,2H,ArNCHa H b,COCHa H bN),3.88(m,1H,CHa H bNCO),4.17(m,1H,ArNCHa H b),4.33(m,1H,CHa H bNCO),6.63(d,2H,J=7.5Hz,ArH),6.95(d,2H,J=7.5Hz,ArH),7.03(m,.3H,ArH),7.05(s,1H,ArH),7.16(d,1H,J=15.2Hz,CH=CHSO2),7.22(m,1H,ArH),7.31-7.37(m,3H,ArH),7.40(d,2H,J=7.4Hz,ArH),7.49(dd,2H,J=7.5,2.0Hz,ArH),8.15(d,1H,J=15.2Hz,CH=CHSO2);13C NMR(CDCl3)δ:18.9(SO2CH2 CH2),21.0(CH3Ph),32.6(CH2CHN),35.7(PhNCH3),42.7(CHN(CH3)2),45.8(CON(CH2)2),46.5(ArN(CH2)2),47.2(CH2N(CH3)2),55.1(SO2CH2),60.6(COCH2N),72.1(ArCHN),112.9(ArC*2),119.3(CH=CHSO2),120.8(ArC),121.5(ArC),121.8(ArC*2),122.3(ArC*2),125.0(ArC),125.5(ArC),127.3(ArC),128.6(ArC*2),129.1(ArC),129.4(ArC*2),130.1(ArC*2),135.6(CH=CHSO2),137.5(ArC),140.1(ArC),141.3(ArC),143.2(ArC),149.0(ArC),149.5(ArC),152.3(CH2NCOO),154.7(CH3NCOO),168.3(CH2 COO);HRMS-EI(M+):C44H53N5O8S,计算值:811.3615,实测值:811.3652。
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实施例23:目标化合物对胎鼠中脑神经元帕金森病损伤的抑制活性评估(以MPP+诱导的原代中脑神经元存活率为评价指标)
一、实验原理
帕金森病(PD)的主要病理特性是中脑黑质-纹状体多巴胺能神经元变性、缺失。1-甲基-4-苯基吡啶离子(1-Methyl-4-phenylpyridinium,MPP+)高度亲和于多巴胺载体,对多巴胺能神经元产生选择性毒性作用,因此MPP+成为制备PD细胞模型最理想的经典神经毒素之一。大鼠胎鼠中脑原代细胞培养近年来常被用于建立PD细胞模型,虽然较细胞株培养繁琐、技术要求高,但更接近于PD的病理特性,因此使用大鼠胎鼠中脑原代细胞培养的神经元在MPP+诱导下建立PD细胞模型,评估目标化合物对该模型神经元的保护作用。
二、实验方法
取孕15天的SD大鼠的胎鼠,剥离中脑,切成碎块,经胰酶消化、吹打、滤网过滤、重悬等步骤,接种于预先用多聚-D-赖氨酸包被的24孔细胞培养板中,于培养后的12h加入阿糖胞苷抑制胶质细胞生长,待神经元生长到第5天可加入毒素MPP+,制作PD细胞模型。检测目标化合物活性时,将目标化合物与中脑神经元预孵3h,然后加入MPP+,共同孵育48h后采用CCK-8法检测神经元活力,计算神经元存活率,用以评估目标化合物对中脑神经元PD损伤抑制活性。实验包含空白对照组、MPP+模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G)以及目标化合物组(由本发明的实施例1-22制备而得)。
其中,原型对照组的结构式如下:
三、实验结果
各组对MPP+诱导的原代中脑神经元损伤作用的影响如下表所示:
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*与等浓度阳性药对照组的数据进行对比分析
**只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比存活率均有统计学显著差异的升高,证明这些化合物对MPP+诱导的原代中脑神经元损伤有明确的保护作用。大部分化合物与阳性对照物CAPE相比存活率有较显著或显著的升高,证明这些化合物对MPP+诱导的原代中脑神经元损伤的保护作用强于阳性对照物CAPE。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比存活率均有显著升高,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对MPP+诱导的原代中脑神经元损伤的保护作用显著增强。
实施例24:目标化合物对神经胶质细胞炎症反应的抑制活性评估(对LPS诱导的原代神经胶质细胞释放NO的抑制作用,以细胞培养液中NO含量为评价指标)
一、实验原理
脂多糖(LPS)是革兰氏阴性菌细胞壁的主要组成部分,它是一种强效的致炎症因子,可直接激活胶质细胞,激活的胶质细胞分泌大量的炎症介质如肿瘤坏死因子、白细胞介素和一氧化氮等,从而引发炎症反应和氧化应激反应,最终导致神经元变性死亡。近年来,将LPS定点注射到大鼠黑质或纹状体诱发神经炎症可成功制作PD模型,此模型能够模拟PD大部分临床表现和病理特征,被用于与PD相关的神经炎症机制研究。LPS诱导的原代神经胶质细胞PD炎性模型适合用于神经保护剂的抗神经炎症初步筛选,用LPS直接激活原代神经胶质细胞,模拟神经炎症致病机制,可考察目标化合物对原代神经胶质细胞炎症反应的抑制活性。
二、实验方法
从胎鼠的脑组织取材,进行原代神经胶质细胞培养,培养至7~10天,加入LPS激活胶质细胞释放一氧化氮(NO),当加入目标化合物后,测定细胞培养液中NO含量的降低值,对化合物的抗神经炎症活性进行评估。实验包含空白对照组、LPS模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,化合物结构如前所述)以及目标化合物组。
三、实验结果
各组对LPS诱导的原代神经角质细胞释放NO的抑制作用如下表所示:
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*其中空白对照组和LPS模型组的试验结果仅作为计算依据,不体现为抑制率。
**比较变化情况时仅与等浓度阳性组或原型组进行对比;只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物各浓度组均体现出了一定的NO抑制率,证明这些化合物对LPS诱导的原代神经角质细胞释放NO有明确的抑制作用。其中部分化合物与等浓度阳性对照组相比具有更高的抑制率,证明这些化合物对LPS诱导的原代神经角质细胞释放NO的抑制作用强于阳性对照物CAPE。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有持平或较高的抑制率,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对LPS诱导的原代神经角质细胞释放NO的保护作用有一定增强。
实施例25:目标化合物对帕金森病模型小鼠的神经保护活性评估(以中脑p-α-s为评价指标)
一、实验原理
利用神经毒素可以建立PD动物模型,1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)是目前唯一被公认的可以诱发人类及非人类灵长类动物及小鼠PD症状的合成毒素。采用MPTP亚急性造模方法,给C57BL/6J雄性小鼠腹腔注射MPTP 30mg/kg,每天一次,连续5天。实验动物分为空白对照组、MPTP模型组、化合物治疗组。MPTP模型组和化合物治疗组在造模结束后连续21天灌胃给予化合物;MPTP模型组在造模结束后连续21天灌胃给予生理盐水;空白对照组先给予5天腹腔注射生理盐水,然后21天灌胃给予生理盐水。
α-突触核蛋白在天然状态下是“非折叠蛋白”,以单体形式存在,参与神经递质的释放、突触连接的建立及调节突触的可塑性等生理功能。在病理状态下,α-突触核蛋白的90%以上在129位丝氨酸发生磷酸化转化为磷酸化的α-突触核蛋白(p-α-s),从而形成路易小体。路易小体的形成是帕金森病主要病理表现和病理机制之一,在PD的形成与发展中扮演重要角色。检测PD模型小鼠中脑和黑质中的p-α-s表达情况,可以评价化合物的神经保护活性。
二、实验方法
取各组一半数量实验小鼠,提取中脑总蛋白,选用GAPDH为内参物,采用western-blot法检测中脑p-α-s蛋白表达量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠中脑p-α-s蛋白表达量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,p-α-s蛋白表达量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠中脑p-α-s蛋白表达量的升高有明确的抑制作用。所有化合物与阳性对照物CAPE相比,p-α-s蛋白表达量持平或者有较显著或显著的降低,证明这些化合物对帕金森病模型小鼠中脑p-α-s蛋白表达量升高的抑制作用与阳性对照物CAPE相当、甚至更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有持平或显著更低的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠中脑p-α-s蛋白表达量升高的抑制作用有较明显的增强。
实施例26:目标化合物对帕金森病模型小鼠的神经保护活性评估(以黑质p-α-s为评价指标)
一、实验原理
同实施例25。
二、实验方法
取各组一半数量实验小鼠,经灌注、固定后取中脑,修剪组织,取黑质-纹状体区域制备石蜡切片,对各组小鼠脑切片进行p-α-s免疫荧光染色,观察p-α-s表达情况,统计p-α-s蛋白表达量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠黑质p-α-s蛋白表达量变化的影响如下表所示:
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*表达量用各组免疫荧光强度占空白对照组免疫荧光强度平均值的百分比来表示
**只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,p-α-s蛋白表达量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠黑质p-α-s蛋白表达量的升高有明确的抑制作用。大部分化合物与阳性对照物CAPE相比,p-α-s蛋白表达量均显著降低,证明这些化合物对帕金森病模型小鼠黑质p-α-s蛋白表达量升高的抑制作用比阳性对照物CAPE更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有持平或显著更低的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠黑质p-α-s蛋白表达量升高的抑制作用有较明显的增强。
实施例27:目标化合物对帕金森病模型小鼠的神经保护活性评估(以中脑TH为评价指标)
一、实验原理
PD模型小鼠的原理和建立方法同实施例25。
PD的主要原因是大脑黑质一纹状体投射系统发生病变,巴胺能神经元的进行性变性缺失。酪氨酸羟化酶(TH)是儿茶酚胺类神经递质生物合成中的第一个酶,也是多巴胺合成的第一限速酶,在神经递质DA的合成代谢中起重要作用,PD动物模型及患者的TH从基因表达到酶蛋白含量及酶活性都有广泛的异常改变。检测PD模型小鼠中脑和黑质中的TH表达情况,可以评价化合物的神经保护活性。
二、实验方法
取各组一半数量实验小鼠,提取中脑总蛋白,选用GAPDH为内参物,采用western-blot法检测中脑TH的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠中脑TH表达量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,TH表达量均有统计学显著差异的升高,证明这些化合物对帕金森病模型小鼠中脑TH表达有明确的保护作用。大部分化合物与阳性对照物CAPE相比,TH表达量持平或者有较显著或显著的升高,证明这些化合物对帕金森病模型小鼠中脑TH表达的保护作用与阳性对照物CAPE相当、甚至更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有显著更高的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠中脑TH表达的保护作用有明显的增强。
实施例28:目标化合物对帕金森病模型小鼠的神经保护活性评估(以黑质TH为评价指标)
一、实验原理
同实施例27。
二、实验方法
取各组一半数量实验小鼠,经灌注、固定后取中脑,修剪组织,取黑质-纹状体区域制备石蜡切片,对各组小鼠脑切片进行TH免疫荧光染色,观察TH的表达情况,统计TH阳性表达神经元数量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠黑质TH表达量变化的影响如下表所示:
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*表达量用各组免疫荧光强度占空白对照组免疫荧光强度平均值的百分比来表示
**只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,TH表达量均有统计学显著差异的升高,证明这些化合物对帕金森病模型小鼠黑质TH表达有明确的保护作用。所有化合物与阳性对照物CAPE相比,TH表达量均持平或有较显著或显著的升高,证明这些化合物对帕金森病模型小鼠黑质TH表达的保护作用与阳性对照物CAPE相当、甚至更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有持平或显著更高的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠黑质TH表达的保护作用有较明显的增强。
实施例29:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对p38MAPK磷酸化激活的抑制作用,以中脑pp38为评价指标)
一、实验原理
p38丝裂原活化蛋白激酶(p38MAPK)在神经元、神经胶质细胞中均表达,是神经元-胶质细胞网络信息调控的交汇点,p38信号通路的激活是神经元变性的重要启动因子,从多个途径持续诱导多巴胺能神经元的凋亡,成为目前治疗PD的研究热点。有研究显示,CAPE对谷氨酸诱导的原代培养小脑颗粒神经元死亡保护机制是通过抑制p38磷酸化激活,继而抑制caspase 3凋亡途径的激活,阻止神经元凋亡。因此,可采用MPTP诱导的PD小鼠模型,从整体动物水平考察目标化合物对p38磷酸化激活的抑制作用。
二、实验方法
取各组一半数量实验小鼠,提取中脑总蛋白,选用GAPDH为内参物,采用western-blot法检测中脑磷酸化p38蛋白表达量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠中脑pp38蛋白表达量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,pp38蛋白表达量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠中脑pp38蛋白表达量的升高有明确的抑制作用。所有化合物与阳性对照物CAPE相比,pp38蛋白表达量持平或者有较显著或显著的降低,证明这些化合物对帕金森病模型小鼠中脑pp38蛋白表达量升高的抑制作用与阳性对照物CAPE相当、甚至更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有持平或显著更低的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠中脑pp38蛋白表达量升高的抑制作用有较明显的增强。
实施例30:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对p38MAPK磷酸化激活的抑制作用,以黑质pp38为评价指标)
一、实验原理
同实施例29。
二、实验方法
取各组一半数量实验小鼠,经灌注、固定后取中脑,修剪组织,取黑质-纹状体区域制备石蜡切片,进行TH和磷酸化p38免疫荧光双重染色,观察TH和磷酸化p38的共表达情况,统计磷酸化p38蛋白表达量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠黑质pp38蛋白表达量变化的影响如下表所示:
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*表达量用各组免疫荧光强度占空白对照组免疫荧光强度平均值的百分比来表示
**只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,pp38蛋白表达量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠黑质pp38蛋白表达量的升高有明确的抑制作用。所有化合物与阳性对照物CAPE相比,pp38蛋白表达量均有显著或较显著的降低,证明这些化合物对帕金森病模型小鼠黑质pp38蛋白表达量升高的抑制作用比阳性对照物CAPE更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有持平或显著更低的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠黑质pp38蛋白表达量升高的抑制作用有较明显的增强。
实施例31:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对神经胶质细胞激活的抑制作用,以中脑CD11b为评价指标)
一、实验原理
越来越多的证据显示,神经胶质细胞在支持神经元发育和维持中枢神经系统的免疫内环境稳态发挥重要作用。神经元一胶质细胞网络稳态失衡是PD中黑质DA能神经元选择性、进行性死亡的重要因素。在MPTP的神经毒性作用中,小胶质细胞和星形胶质细胞的过度激活产生多种致炎细胞因子和活性氧(ROS),这些炎症因子和ROS彼此扩大各自的毒性,介导恶性反馈循环,引起级联瀑布样炎症反应,加剧PD的病理进程。而CD11b和GFAP分别是小胶质细胞和星形胶质细胞活化的标志性蛋白。因此,可考察目标化合物对MPTP诱导的PD小鼠黑质区、海马区及中脑小胶质细胞和星形胶质细胞活化的影响,探讨目标化合物通过抑制神经炎症发挥抗PD的作用机制。
二、实验方法
取各组一半数量实验小鼠,提取中脑总蛋白,选用GAPDH为内参物,采用western-blot法检测中脑CD11b蛋白表达量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠中脑CD11b蛋白表达量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,CD11b蛋白表达量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠中脑CD11b蛋白表达量的升高有明确的抑制作用。大部分化合物与阳性对照物CAPE相比,CD11b蛋白表达量有显著或较显著的降低,证明这些化合物对帕金森病模型小鼠中脑CD11b蛋白表达量升高的抑制作用与阳性对照物CAPE更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有持平或更低的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠中脑CD11b蛋白表达量升高的抑制作用有较明显的增强。
实施例32:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对神经胶质细胞激活的抑制作用,以黑质CD11b为评价指标)
一、实验原理
同实施例31。
二、实验方法
取各组一半数量实验小鼠,经灌注、固定后取中脑,修剪组织,取黑质区域制备石蜡切片,进行CD11b免疫组织化学染色,统计CD11b阳性表达小胶质细胞数量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠黑质CD11b阳性表达小胶质细胞数量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,CD11b阳性表达小胶质细胞数量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠黑质CD11b阳性表达小胶质细胞数量的升高有明确的抑制作用。所有化合物与阳性对照物CAPE相比,CD11b阳性表达小胶质细胞数量均有显著或较显著的降低,证明这些化合物对帕金森病模型小鼠黑质CD11b阳性表达小胶质细胞数量升高的抑制作用比阳性对照物CAPE更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有显著更低的阳性细胞数,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠黑质CD11b阳性表达小胶质细胞数量升高的抑制作用有显著的增强。
实施例33:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对神经胶质细胞激活的抑制作用,以海马CD11b为评价指标)
一、实验原理
同实施例35。
二、实验方法
取各组一半数量实验小鼠,经灌注、固定后取中脑,修剪组织,取海马区域制备石蜡切片,进行CD11b免疫组织化学染色,统计CD11b阳性表达小胶质细胞数量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠海马CD11b阳性表达小胶质细胞数量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,CD11b阳性表达小胶质细胞数量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠海马CD11b阳性表达小胶质细胞数量的升高有明确的抑制作用。所有化合物与阳性对照物CAPE相比,CD11b阳性表达小胶质细胞数量均有显著的降低,证明这些化合物对帕金森病模型小鼠海马CD11b阳性表达小胶质细胞数量升高的抑制作用比阳性对照物CAPE更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有显著更低的阳性细胞数,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠海马CD11b阳性表达小胶质细胞数量升高的抑制作用有显著的增强。
实施例34:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对神经胶质细胞激活的抑制作用,以黑质GFAP为评价指标)
一、实验原理
同实施例31。
二、实验方法
取各组一半数量实验小鼠,经灌注、固定后取中脑,修剪组织,取黑质区域制备石蜡切片,进行GFAP免疫组织化学染色,统计GFAP阳性表达星形胶质细胞数量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠黑质GFAP阳性表达星形胶质细胞数量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,GFAP阳性表达星形胶质细胞数量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠黑质GFAP阳性表达星形胶质细胞数量的升高有明确的抑制作用。所有化合物与阳性对照物CAPE相比,GFAP阳性表达星形胶质细胞数量均有显著的降低,证明这些化合物对帕金森病模型小鼠黑质GFAP阳性表达星形胶质细胞数量升高的抑制作用比阳性对照物CAPE更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有显著更低的阳性细胞数,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠黑质GFAP阳性表达星形胶质细胞数量升高的抑制作用有显著的增强。
实施例35:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对神经胶质细胞激活的抑制作用,以海马GFAP为评价指标)
一、实验原理
同实施例31。
二、实验方法
取各组一半数量实验小鼠,经灌注、固定后取中脑,修剪组织,取海马区域制备石蜡切片,进行GFAP免疫组织化学染色,统计GFAP阳性表达星形胶质细胞数量的变化。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠海马GFAP阳性表达星形胶质细胞数量变化的影响如下表所示:
/>
*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,GFAP阳性表达星形胶质细胞数量均有统计学显著差异的降低,证明这些化合物对帕金森病模型小鼠海马GFAP阳性表达星形胶质细胞数量的升高有明确的抑制作用。所有化合物与阳性对照物CAPE相比,GFAP阳性表达星形胶质细胞数量均有显著的降低,证明这些化合物对帕金森病模型小鼠海马GFAP阳性表达星形胶质细胞数量升高的抑制作用比阳性对照物CAPE更强。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有显著更低的阳性细胞数,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠海马GFAP阳性表达星形胶质细胞数量升高的抑制作用有显著的增强。
实施例36:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对氧化应激损伤的抑制作用,以HO-1为评价指标)
一、实验原理
氧化应激是PD的重要致病机制,多巴胺能神经元对氧化应激更为敏感,更易受氧化应激损伤。血红素加氧酶(HO-1),属于II相酶,也是著名的抗氧化酶,通过催化自由基转化为无毒产物以及增加其水溶性以有利于自由基排除而发挥着重要的保护作用,维持机体氧化还原平衡,在保护细胞抵御氧化应激损伤过程中起重要作用。p38蛋白磷酸化激活对II相酶具有负向调节作用,研究发现在PD小鼠模型及细胞模型中,通过抑制p38的激活下调NADPH氧化酶的表达,可以上调HO-1的表达,抵御氧化损伤。采用HO-1做为指标,可考察目标化合物对MPTP诱导的PD小鼠氧化应激损伤的抑制作用。
二、实验方法
HO-1在星形胶质细胞、小胶质细胞及神经元中均表达,我们提取各实验组小鼠中脑组织总蛋白,选用GAPDH为内参物,通过Westem blot检测小鼠中脑II相酶HO-1表达情况。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠中脑HO-1表达量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,HO-1表达量均有统计学显著差异的升高,证明这些化合物对帕金森病模型小鼠中脑HO-1的表达有明确的上调作用,利于抵御氧化损伤。所有化合物与阳性对照物CAPE相比,HO-1表达量均有显著的升高,证明这些化合物对帕金森病模型小鼠中脑HO-1表达的上调作用比阳性对照物CAPE更强,更能抵御氧化损伤。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有显著更高的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠中脑HO-1表达的上调作用有显著的增强。
实施例37:目标化合物对帕金森病模型小鼠的神经保护作用机制研究(对氧化应激损伤的抑制作用,以GCLC为评价指标)
一、实验原理
氧化应激是PD的重要致病机制,多巴胺能神经元对氧化应激更为敏感,更易受氧化应激损伤。谷光甘肽(GSH)是胞内重要的抗氧化物质,谷氨酸半胱氨酸连接酶(GCL)是GSH合成限速酶,由催化亚单位(GCLC)和调节亚单位(GCLM)组成。GCLC表达的增加,可以促进GSH的合成,增强组织细胞抗氧化应激的能力。GCL属于II相酶,通过催化自由基转化为无毒产物以及增加其水溶性以有利于自由基排除而发挥着重要的保护作用,维持机体氧化还原平衡,在保护细胞抵御氧化应激损伤过程中起重要作用。p38蛋白磷酸化激活对II相酶具有负向调节作用,研究发现在PD小鼠模型及细胞模型中,通过抑制p38的激活下调NADPH氧化酶的表达,可以上调GCLC的表达,抵御氧化损伤。采用GCLC做为指标,可考察目标化合物对MPTP诱导的PD小鼠氧化应激损伤的抑制作用。
二、实验方法
GCLC在星形胶质细胞、小胶质细胞及神经元中均表达,我们提取各实验组小鼠中脑组织总蛋白,选用GAPDH为内参物,通过Westem blot检测小鼠中脑II相酶GCLC表达情况。实验包含空白对照组、MPTP模型组、阳性对照组(咖啡酸苯乙酯CAPE)、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)以及目标化合物组。
三、实验结果
各组对帕金森病模型小鼠中脑GCLC表达量变化的影响如下表所示:
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*只将B1-1、C1-1、D1-1和G1-1四组化合物分别与对应结构的原型化合物(即苯乙烯基砜类3B、3C、3D和3G)进行对比分析
可见所有化合物与模型组相比,GCLC表达量均有统计学显著差异的升高,证明这些化合物对帕金森病模型小鼠中脑GCLC的表达有明确的上调作用,利于抵御氧化损伤。所有化合物与阳性对照物CAPE相比,GCLC表达量均有显著或较显著的升高,证明这些化合物对帕金森病模型小鼠中脑GCLC表达的上调作用比阳性对照物CAPE更强,更能抵御氧化损伤。B1-1、C1-1、D1-1、G1-1四组化合物分别与苯乙烯基砜类原型化合物3B、3C、3D、3G相比具有显著更高的表达量,证明这些化合物与未引入氨基甲酸酯官能团的原型化合物相比,对帕金森病模型小鼠中脑GCLC表达的上调作用有显著的增强。
实施例38:目标化合物对胆碱酯酶的抑制活性评估(以乙酰胆碱酯酶IC50值为评价指标)
一、实验原理
中枢胆碱能系统是中枢神经系统的重要组成部分,乙酰胆碱(ACh)和丁酰胆碱(BCh)是中枢胆碱能神经元合成和分泌的重要神经递质,特异性地作用于各类胆碱能受体,对调节突触可塑性、学习记忆功能等具有重要作用。因此,当神经递质合成、释放及摄取等代谢功能发生障碍或胆碱能受体及受体后信号传导遭到破坏时,可引起学习记忆功能减退。研究表明PD患者中额叶、颞叶、顶叶及右侧海马等皮质中胆碱转移酶活性下降,胆碱能神经元受损可能是PD认知功能障碍及痴呆产生的主要生化机制。通过评价目标化合物对两种胆碱酯酶的抑制活性,可评价其对PD认知功能障碍及痴呆可能的治疗效果。
二、实验方法
采用经改良的Ellman法测定乙酰胆碱酯酶抑制活性,原理为碘代硫代乙酰胆碱在乙酰胆碱酯酶(AchE)作用下分解,生成硫代胆碱,硫代胆碱与显色剂DTNB迅速作用,生成黄色物质,在405nm处有光吸收。在96孔酶标板中依次加入50μl酶反应缓冲液,125μl DTNB(3mM),25μl待测样品或者阳性对照药,25μl AchE(0.2U/ml),室温孵育5min后,加入25μlATCI(15mM),室温孵育8min后,用酶标仪在405nm下测定其吸光度值。同时设立不加酶的空白对照组(25μl PBS代替待测样品)。根据测定结果计算抑制百分率,以相应化合物摩尔浓度的负对数作为横坐标,酶抑制率为纵坐标,得到线性方程。当抑制率50%时,求出该化合物的摩尔浓度,即为该化合物的IC50值。实验包含空白对照组、CAPE对照组、原型对照组(苯乙烯基砜类化合物3B、3C、3D和3G,其结构式如前所述)、阳性药对照组(卡巴拉汀Rivastigmine)以及目标化合物组。
三、实验结果
各组对乙酰胆碱酯酶的抑制作用如下表所示:
可见所有化合物的IC50值均小于100μM,证明这些化合物对乙酰胆碱酯酶有明确的抑制作用;而CAPE对照组和原型对照组的IC50值均大于100μM,证明这些化合物不具备明确的抑制作用,所设计化合物的乙酰胆碱酯酶抑制作用来源于新引入的氨基甲酸酯官能团。所有化合物与阳性对照药组相比具有更低的IC50值,证明这些化合物对乙酰胆碱酯酶的抑制作用强于阳性对照药。
Claims (14)
1.一种通式I的化合物或其可药用盐:
其中,
R1和R2选自被2个R3取代的氨基甲酰氧基;
W为未取代的或被1至3个卤素、硝基、C1-6烷基、-N(R4)2取代的C1-4亚烷基或C2-4亚烯基;
每个R独立地选自卤素,硝基,-OR7,未取代的或被1至6个卤素、硝基或-OR5取代的C1-6烷基、C6-10芳基或C5-9杂芳基;
n为0-5的整数;
其中,
每个R3独立地选自未取代或被1至6个卤素取代的C1-6饱和烷基;
每个R4独立地为-H或C1-6饱和烷基;
每个R5独立地选自C1-6饱和烷基;
每个R7独立地选自未取代的或被1至6个卤素、N(R4)2取代的C1-6饱和烷基、C2-4链烯基、C5-9杂芳基、或C1-6烷基酰基;被C1-3烷基或C6-8芳基取代的磺酰基;Si(R6)3;
每个R6独立地选自C1-6烷基和C6-8芳基。
2.根据权利要求1所述的通式I的化合物或其可药用盐,其特征在于,
R1和R2中至少一个独立地选自N,N-二甲基氨基甲酰氧基、N,N-二乙基氨基甲酰氧基和N-甲基-N-乙基氨基甲酰氧基;
R1和R2中的另一个独立地选自N,N-二甲基氨基甲酰氧基、N,N-二乙基氨基甲酰氧基和N-甲基-N-乙基氨基甲酰氧基。
3.根据权利要求1所述的通式I的化合物或其可药用盐,其特征在于,W为未取代的或被1-2个卤素、硝基或C1-6烷基取代的C1-4亚烷基或C2-4亚烯基。
4.根据权利要求3所述的通式I的化合物或其可药用盐,其特征在于,W选自-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(F)-、-CH(Cl)-、-CH(Br)-、-CF2-、-CH(Cl)CH2-、-CH2CH(Cl)-、-CH(Cl)CH(Cl)-、-CH2CH(Cl)CH2-、-CH(NO2)-、-CH2CH(NO2)-、-CH2CH(NO2)CH2-、-CH(CH3)-、-CH(CH3)CH2-、-CH=CH-、-CH2CH=CHCH2-、-CH=CHCH2-、-CH=C(CH3)-、-CH(Cl)CH=CHCH2-。
5.根据权利要求1至4中任一项所述的通式I的化合物或其可药用盐,其特征在于,每个R独立地选自卤素,硝基,-OR7和未取代的或被1至6个卤素、硝基、-OR5取代的C1-6烷基、和C6-10芳基。
6.根据权利要求5所述的通式I的化合物或其可药用盐,其特征在于,每个R独立地选自氟、氯、溴、碘、硝基、甲氧基、乙氧基、异丙氧基、叔丁氧基、2,2,2-三氟乙氧基、2-甲氨基乙氧基、N,N-二甲氨基甲氧基、烯丙氧基、甲酰氧基、乙酰氧基、二甲氨基乙酰氧基、三甲基硅氧基、三苯基硅氧基、甲基、乙基、异丙基、叔丁基、三氟甲基、苯基、对氯苯基、对硝基苯基和3,4-二甲氧基苯基。
7.根据权利要求1至4中任一项所述的通式I的化合物或其可药用盐,其特征在于,n为0-3的整数。
8.化合物或其可药用盐,其特征在于,所述化合物选自以下化合物:
9.一种权利要求1至7中任一项所述的通式I的化合物的制备方法,该方法包括如下步骤:
a)将通式II的化合物与固体光气在碱性条件下反应生成通式III的化合物;
b)将通式III化合物与(R3)2NH反应生成通式I化合物,以及
c)任选地,将通式I的化合物转化为其可药用盐;
其中,Ra和Rb为-OH;
Rc和Rd为-OCOCl;
其中,W、R、n和R1、R2、R3的定义如权利要求1至7中任一项所述。
10.根据权利要求9所述的方法,其中步骤a)中使用的碱为无机碱或有机碱,所述无机碱选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸钠、乙酸钠和碳酸铯中的一种或多种;所述有机碱选自吡啶、三乙胺、4-二甲氨基吡啶、DBU(1,8-二氮杂二环十一碳-7-烯)、DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)和MTBD(7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯)。
11.根据权利要求9所述的方法,其中步骤b)中使用碱,所述碱为无机碱或有机碱,所述无机碱选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸钠、乙酸钠和碳酸铯中的一种或多种;所述有机碱选自吡啶、三乙胺、4-二甲氨基吡啶、DBU(1,8-二氮杂二环十一碳-7-烯)、DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)和MTBD(7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯)。
12.一种药物组合物,所述药物组合物包括权利要求1至7中任一项所述的通式I的化合物或其可药用盐以及至少一种药用载体。
13.权利要求1至7中任一项所述的通式I的化合物或其可药用盐或药物组合物在制备抗神经胆碱酶或保护神经的药物中的用途。
14.权利要求1至7中任一项所述的通式I的化合物或其可药用盐或药物组合物在制备治疗和/或预防帕金森病中的用途。
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WO2001026645A1 (en) * | 1999-10-12 | 2001-04-19 | Temple University-Of The Commonwealth System Of Higher Education | Method for protecting normal cells from cytotoxicity of chemotherapeutic agents |
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CN104230770A (zh) * | 2013-06-17 | 2014-12-24 | 华夏生生药业(北京)有限公司 | 苯乙烯基砜类化合物、其制备方法以及其作为神经保护剂的应用 |
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WO2001026645A1 (en) * | 1999-10-12 | 2001-04-19 | Temple University-Of The Commonwealth System Of Higher Education | Method for protecting normal cells from cytotoxicity of chemotherapeutic agents |
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CN103936637A (zh) * | 2013-01-18 | 2014-07-23 | 北京大学 | E-3,4-二羟苯乙烯基亚砜类化合物的制备方法及其作为神经保护药物的应用 |
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