CN114380728B - 新型二芳基-β-内酰胺类有机硒化合物及其制备方法和在制药中的用途 - Google Patents
新型二芳基-β-内酰胺类有机硒化合物及其制备方法和在制药中的用途 Download PDFInfo
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- CN114380728B CN114380728B CN202011111941.4A CN202011111941A CN114380728B CN 114380728 B CN114380728 B CN 114380728B CN 202011111941 A CN202011111941 A CN 202011111941A CN 114380728 B CN114380728 B CN 114380728B
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Abstract
本发明属于新药研发中合成药物化学领域，涉及如下通式结构的具有显著抗肿瘤活性的新型二芳基‑β‑内酰胺类有机硒化合物及其在抗肿瘤药物研发中的应用。本发明还包括所述化合物、其药学盐及其复方药物在制备预防或治疗与肿瘤相关疾病的药物中的应用。本发明提供的化合物或其在药学上可接受的盐能通过抑制微管蛋白聚集抑制肿瘤细胞增殖的调控机制，在体外、体内有效抑制肿瘤细胞的生长，可应用于制备预防或治疗与肿瘤相关疾病的药物。所述与肿瘤相关疾病包括良、恶性肿瘤以及肿瘤引起的其他疾病。
Description
技术领域
本发明属于新药研发中合成药物化学领域，涉及具有显著抗肿瘤活性的新型 二芳基-β-内酰胺类有机硒化合物、制备方法、体内外抗肿瘤活性以及该类化合 物及其可接受的药学盐或以其为成分之一的复方药物在制备预防和治疗肿瘤相 关疾病的药物中的应用。
背景技术
2018年9月世界卫生组织WHO于《CA:A Cancer Journal for Clinicians》杂 志在线发表了《Global Cancer Statistics 2018》报告，报告中显示全球癌症的发病情况日益严峻，其中2018年新发病例高达1810万，同期死亡病例高达960万。 由于人口老龄化、吸烟、不健康饮食等因素，预测到2030年全世界每年新增病 例会达到2200万例，同期癌症的死亡人数也将从每年的960万例上升至1300 万例。由此可见，我们需要立即采取有效的医疗措施来解决癌症对人类健康的威 胁。
药物治疗是癌症最为常见的一种治疗手段，目前被批准上市的抗肿瘤药物已 有近百种，但是由于存在耐药性和缺乏选择性等缺点，传统的化疗药物并不能完 全满足临床的需要。因此，克服传统化疗药物的缺点，寻找到更为高效、低毒的 新型抗肿瘤药物仍然是目前新药研发的热点和急需解决的重要问题。
硒(Selenium)是人体内至关重要的微量元素，它在维持人体正常生命活动 过程中扮演着多种角色，例如甲状腺素的合成、维持正常免疫功能与氧化防御功 能等，被誉为“生命的火种”(Adv.Nutr.2016,7,415-417)。血液中硒元素含量的下降会诱发多种疾病，包括免疫力下降、认知功能衰退、白内障、心肌坏死、 动脉粥样硬化、糖尿病及克山病等。最新研究发现，有机硒化合物具有显著的抗 肿瘤作用，其抗肿瘤机制主要包括抑制肿瘤细胞增殖、阻滞肿瘤细胞周期、诱导 肿瘤细胞凋亡、抑制肿瘤新生血管形成、诱导活性氧的产生以及增强机体免疫功 能等(FreeRadic.Biol.Med.2018,127,80-97)。此外，有机硒化合物与化疗药物联用能够降低化疗药物对正常组织的毒副作用，同时也能增强化疗效果与靶向性(Lancet 2012,379,1256-1268)。目前已有多个有机硒类抗肿瘤药物被报道， 比如乙烷硒啉(Ethaselen)、依布硒啉(Ebselen)、硒代甲硫氨酸(Seleno methionine) 与硒代甲基半胱氨酸(L-Se-methylselenocysteine)等，其中乙烷硒啉作为硫氧还原蛋白还原酶(TrxR)抑制剂已被中国国家药品监督管理局(NMPA)批准进入 二期临床，具有较好的临床应用前景。
近年来以微管为靶点的抗肿瘤药物成为了当前研究的热点之一，特别是以治 疗实体瘤最有效的药物——紫杉醇、长春新碱为代表，更显示出微管作为肿瘤治 疗的靶点具有十分优秀的效果和潜力。微管(Microtubule)是由α-微管蛋白与β- 微管蛋白异二聚体聚合而成的细长中空管状蛋白，是构成细胞骨架的主要成分。 在正常细胞内，微管以其特有的聚集和解聚的动力学特性，在保持细胞形态、细胞运动、细胞分裂与增殖等方面发挥着不可或缺的作用。特别是在细胞有丝分裂 过程中，α-微管蛋白与β-微管蛋白不断地聚合与解聚从而引起微管运动，运动的 微管将复制出的两套DNA分别迁移至细胞两级，最终完成细胞的分裂与增殖。 恶性肿瘤细胞生长速度极快，细胞有丝分裂与转移异常旺盛，因此以微管为靶标， 打破微管蛋白聚合与解聚的动态平衡，影响微管异常旺盛的生理功能，即可有效 地抑制肿瘤细胞的分裂与增殖(Science 2013,339,587-590)。据最新研究表明， 作用于秋水仙碱结合位点的微管蛋白聚集抑制剂能够克服由P-gp,MRP1和 MRP2介导的多药耐药性，目前这类抑制剂的研发也已经取得了重大进展，其中康普立停的磷酸酯二钠盐(CA-4P)与BNC105的磷酸酯二钠盐(BNC105P)已 分别进入III期和II期临床试验，用于多种实体瘤的治疗(J.Med.Chem.2016,59, 8685-8711)。但这些药物在人体内的有效性、毒副作用以及结构稳定性等方面 仍然存在缺点，且在延长患者总生存期等方面也存在不足，截止目前还没有一个 药物被批准上市。
本申请以二芳基-β-内酰胺类微管蛋白聚集抑制剂为先导化合物，运用生物 电子等排的药物设计原理将硒原子引入先导化合物结构中，提供了具有显著抗肿 瘤活性的新型含硒二芳基-β-内酰胺类微管蛋白聚集抑制剂以及血管生成抑制剂，前景十分广阔。
发明内容
本发明的目的是提供新型二芳基-β-内酰胺类有机硒化合物作为微管蛋白聚 集抑制剂以及血管生成抑制剂，具体涉及具有显著抗肿瘤活性的新型二芳基-β- 内酰胺类有机硒化合物及其制备方法以及该类化合物及其药学盐或以其为成分 的复方药物在制备预防和治疗肿瘤相关疾病的药物中的应用。
本发明提供了下述通式Ⅰ结构的新型二芳基-β-内酰胺类有机硒化合物或其 药学盐，
其中，R1与R2取自氢原子、烷基、取代烷基、烷氧基、卤素原子、氨基、羟基、 酰氧基、甲氧甲酰基、烯丙氧基、炔丙氧基、磺酰氧基、烷氨基、酰氨基、磺酰 氨基或者2-3个上述相同或不同基团的组合；R3取自氢原子、烷基、烯基、芳基 以及氰基；X取自碳、氮、氧、酯基、酰胺基；n取自1、2、3、4、5、6。优选 化合物为：
本发明还提供了下述通式Ⅱ结构的新型二芳基-β-内酰胺类有机硒化合物或 其药学盐，
其中，R1与R2取自氢原子、烷基、取代烷基、烷氧基、卤素原子、氨基、羟基、 酰氧基、甲氧甲酰基、烯丙氧基、炔丙氧基、磺酰氧基、烷氨基、酰氨基、磺酰 氨基或者2-3个上述相同或不同基团的组合；R3取自氢原子、烷基、取代烷基、 烷氧基、酰氧基、羟基、苯基、取代苯基、吡啶基、环丙基、乙烯基、氨基、烷 氨基、酰氨基、磺酰氧基、磺酰氨基；R4取自氢原子、烷基、烯基、芳基以及 氰基；X取自碳、氮、氧、酯基、酰胺基；n取自1、2、3、4、5、6。优选化合 物为：
本发明还提供了下述通式Ⅲ结构的新型二芳基-β-内酰胺类有机硒化合物或 其药学盐，
其中，R1与R2取自氢原子、烷基、取代烷基、烷氧基、卤素原子、氨基、羟基、 酰氧基、甲氧甲酰基、烯丙氧基、炔丙氧基、磺酰氧基、烷氨基、酰氨基、磺酰 氨基或者2-3个上述相同或不同基团的组合；R3取自氢原子、烷基、取代烷基、 烷氧基、酰氧基、羟基、苯基、取代苯基、吡啶基、环丙基、乙烯基、氨基、烷 氨基、酰氨基、磺酰氧基、磺酰氨基。优选化合物为：
本发明还提供了下述通式Ⅳ结构的新型二芳基-β-内酰胺类有机硒化合物或 其药学盐，
其中，R1与R2取自氢原子、烷基、取代烷基、烷氧基、卤素原子、氨基、羟基、 酰氧基、甲氧甲酰基、烯丙氧基、炔丙氧基、磺酰氧基、烷氨基、酰氨基、磺酰 氨基或者2-3个上述相同或不同基团的组合；R3取自氢原子、烷基、取代烷基、 烷氧基、酰氧基、羟基、苯基、取代苯基、吡啶基、环丙基、乙烯基、氨基、烷 氨基、酰氨基、磺酰氧基、磺酰氨基。优选化合物为：
本发明中所述的“药学上可接受的盐”，具体地可列举为与苹果酸、乳酸、 樟脑磺酸、枸橼酸、富马酸、草酸等有机酸，以及磷酸、氢卤酸、硫酸、硝酸等 无机酸形成的盐。
本发明的进一步目的是提供上述化合物或这些化合物在药学上可接受的盐 以及包含该化合物或其盐的组合物用于制备预防或治疗与肿瘤相关疾病的药物 中的应用。
所述的与肿瘤相关疾病具体可列举为甲状腺癌、淋巴瘤、前列腺癌、肾癌、 膀胱癌、脑胶质瘤、鼻咽癌，神经内分泌癌、头颈部鳞状细胞癌、宫颈癌、卵巢 癌、乳腺癌、结直肠癌、胰腺癌、食管癌、骨肉瘤、间质肉瘤、绒癌、恶性葡萄 胎、恶性畸胎瘤、胃癌、肺癌、肝癌、黑色素瘤、未分化癌以及良性肿瘤等，但 不受限于此。
本发明提供并证明了具有显著抗肿瘤活性的新型二芳基-β-内酰胺类有机硒 化合物或其在药学上可接受的盐，通过抑制微管蛋白聚集从而抑制肿瘤细胞生长 的调控机制及其在体外、体内的抗肿瘤实验中对肿瘤细胞具有显著的增殖抑制作 用和血管生成抑制作用。
附图说明
图1.化合物22体外抑制微管自组装实验——吸光度-时间曲线。
图2.免疫荧光法检测化合物22对肿瘤细胞微管蛋白形态的影响。
图3.化合物22对肿瘤细胞集落生成的抑制。
图4.化合物22对HUVEC细胞生成血管的抑制。
图5.化合物22对斑马鱼生成血管的抑制。
图6.化合物22对肿瘤细胞周期的影响。
图7.化合物22对肿瘤细胞周期相关蛋白表达的影响。
图8.化合物22诱导细胞凋亡测试。
图9.化合物22对凋亡相关蛋白表达的影响。
图10.化合物22的体内抗肿瘤实验。
具体实施方式
下面结合实施例进一步说明本发明。这些实施例只是用于进一步说明本发 明，并不改变本发明的保护范围。本发明目标化合物的制备方法可以进一步用代 表性化合物制备过程体现如下：
实施例1(3S,4R)-1-(3,4,5-三甲氧基苯基)-3-硒氰基甲基-4-(3-羟基-4-甲氧基苯基)氮杂环丁烷-2-酮(1)的合成
参照文献(J.Med.Chem.2016,59,10329-10334)方法，本发明按如下路线 合成目标化合物1：
试剂与条件:(a)Pd2(dba)3(0.1％),(R,R,R)-Ph-SKP(0.25％),K2CO3,CH2Cl2,25℃, 3h；(b)i)Sn[N(TMS)2]2,toluene,reflux,3h；ii)TBAF,THF,0℃,1h；(c)i)BnCl,K2CO3,MeCN,reflux,12h；ii)B2(pin)2(1.3equiv),CuCl(5％),MeOH(1.5equiv), PPh3(15％),t-BuOLi(10％),THF,25℃,12h；iii)NaBO3·4H2O,H2O,THF,25℃,2 h；(d)i)CBr4,PPh3,THF,25℃,4h；ii)Pd/C,H2,EtOH,25℃,12h；(e)KSeCN, MeCN,reflux,12h.
1.1(S)-2-[1-(3-叔丁基二甲基硅氧基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基氨基)甲基]丙烯酸乙酯(1c)的合成
在50mLSchlenk管中加入原料1a(0.65g,1.59mmol)，3,4,5-三甲氧基苯 胺1b(0.43g,2.07mmol)，碳酸钾(0.66g,4.77mmol)，Pd2(dba)3(1.5mg,0.0016 mmol)和(R,R,R)-Ph-SKP(2.6mg,0.004mmol)，三次抽换气后使体系充满干燥 的氮气，后向体系注入无氧二氯甲烷(7mL)。继续在氮气保护下室温反应3 小时。加水，用二氯甲烷萃取三次，有机相合并后用饱和食盐水洗一次，无水硫 酸钠干燥。旋蒸浓缩后柱层析分离(PE/EA3:1)，得到无色油状液体(1c)0.73g，收率85％。[α]D 20+86.2(c0.41,CHCl3),98％ee[determined by HPLCanalysis using a Chiralcel AS-3 column；n-Hex/i-PrOH＝95:5,1.0mL/min,254nm；tR(major) ＝7.47min；tR(minor)＝9.72min].1H NMR(400MHz,CDCl3):δ6.92(dd,J＝8.3,2.1Hz,1H),6.82(d,J＝2.1Hz,1H),6.80(d,J＝8.3Hz,1H),6.34(s,1H),5.88(s, 1H),5.81(s,2H),5.28(s,1H),4.15(q,J＝7.1Hz,2H),3.77(s,3H),3.77(s,6H),3.74(s,3H),1.22(t,J＝7.1Hz,3H),0.96(s,9H),0.11(s,6H).ESI-MS(m/z):532.1 (M+H+).
1.2(S)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-亚甲基氮杂环丁 烷-2-酮(1d)的合成
在50mLSchlenk管中加入原料1c(0.44g,0.83mmol)，Sn[N(TMS)2]2(0.4 mL,1mmol)和无水甲苯(10mL)。氮气保护下加热回流反应3小时，后直接 快速柱层析分离(PE/EA4:1)，得到无色油状液体，后于冰浴条件下，加入TBAF (0.39g,15mmol)和四氢呋喃(8mL)。继续冰浴反应20分钟后，加水，用 乙酸乙酯萃取三次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。柱层 析分离(PE/EA2:1)，得到淡黄色油状液体(1d)0.19g，收率62％。[α]D 20+33.6 (c1.00,CHCl3),99％ee[determined by HPLC analysis using a Chiralcel AD-Hcolumn；n-Hex/i-PrOH＝80:20,1.0mL/min,254nm；tR(major)＝13.76min；tR(minor)＝17.72min].1H NMR(400MHz,CDCl3):δ6.95(d,J＝2.1Hz,1H),6.90 (dd,J＝8.2,2.0Hz,2H),6.83(d,J＝8.2Hz,1H),6.59(s,2H),5.81(t,J＝1.6Hz, 1H),5.71(s,1H),5.27(s,1H),5.14(s,1H),3.88(s,3H),3.75(s,3H),3.73(s,6H).ESI-MS(m/z):372.1(M+H+).
1.3(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-苄氧基-4-甲氧基苯基)-3-羟甲基氮 杂环丁烷-2-酮(1e)和(3R,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-苄氧基-4-甲氧基苯基)-3-羟甲基氮杂环丁烷-2-酮(1f)的合成
在50mL茄形瓶中加入原料1d(0.22g,0.59mmol)，溴化苄(0.084mL,0.71 mmol)，碳酸钾(0.1g,0.71mmol)和乙腈(5mL)。加热回流反应8小时后， 加水，用乙酸乙酯萃取三次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干 燥。旋蒸浓缩得到白色固体。于50mLSchlenk管中加入该白色固体，联硼酸频 那醇酯(0.2g,0.8mmol)，CuCl(3.0mg,0.09mmol)，三苯基膦(24mg,0.09 mmol)，叔丁醇锂(4.8mg,0.06mmol)，抽换气使体系充满干燥的氮气，后注 入甲醇(15μL,0.9mmol)和无水THF(10mL)。继续在氮气保护下室温反应12小时，加水，用乙酸乙酯萃取三次，有机相合并后用饱和NaCl水溶液洗一次， Na2SO4干燥。蒸去溶剂后加入四水合过硼酸钠(0.46g,1.5mmol)，THF(10mL) 和水(5mL)，室温反应2小时。加水，用乙酸乙酯萃取三次，有机相合并后 用饱和NaCl水溶液洗一次，无水硫酸钠干燥。柱层析分离(PE/EA1:2)，得到 白色固体(1e)180mg，61％。1H NMR(400MHz,CDCl3):δ7.58-7.31(m,5H), 6.94-6.77(m,3H),6.55(s,2H),5.18(s,2H),5.10(d,J＝5.1Hz,1H),3.91(s,3H),3.81(m,2H),3.76(s,3H),3.73(s,6H),3.65(m,1H).ESI-MS(m/z):480.1(M+H+). 同时得到粉色固体(1f)92mg，收率32％。1H NMR(400MHz,CDCl3):δ7.48-7.32 (m,5H),6.97(d,J＝1.5Hz,1H),6.91(dd,J＝8.3,1.5Hz,1H),6.84(d,J＝8.3Hz, 1H),6.56(s,2H),5.16(s,2H),4.92(d,J＝1.8Hz,1H),4.00(dd,J＝11.9,3.3Hz, 1H),3.90(s,3H),3.76(s,3H),3.72(s,7H),3.28(d,J＝2.3Hz,1H).ESI-MS(m/z): 480.1(M+H+).
1.4(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-溴甲基氮杂 环丁烷-2-酮(1g)的合成
在25mLSchlenk管中加入原料1f(20mg,0.04mmol)，四溴化碳(69mg, 0.2mmol)，三苯基膦(54mg,0.2mmol)，三次抽换气后使体系充满干燥的氮 气，后向体系注入无水二氯甲烷(3mL)。继续在氮气保护下室温反应4小时。 加水，用二氯甲烷萃取三次，有机相合并后用饱和NaCl水溶液洗一次，无水硫 酸钠干燥。旋蒸浓缩后加入10％Pd/C(3mg)，乙醇(1.5mL)，常压氢气下 室温反应12小时。过滤除去Pd/C后旋蒸浓缩，用硅胶(300-400目)柱层析法 进行纯化(洗脱剂：PE/EA2:1)。旋干得到淡绿色固体(1g)16mg，收率88％。 mp63-65℃.1H NMR(400MHz,CDCl3):δ6.98(s,1H),6.92(d,J＝8.3Hz,1H), 6.85(d,J＝8.3Hz,1H),6.55(s,2H),5.82(s,1H),4.81(s,1H),3.89(s,3H),3.77(s, 5H),3.73(s,6H),3.51(s,1H).ESI-MS(m/z):453.1(M+H+).
1.5(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-硒氰基甲基 氮杂环丁烷-2-酮(1)的合成
在25mL茄形瓶中加入原料1g(20mg,0.04mmol)，硒氰酸钾(32mg,0.22 mmol)和乙腈(1mL)。加热回流反应8小时后，加水，用乙酸乙酯萃取三次， 有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后用硅胶 (300-400目)柱层析分离纯化(洗脱剂：PE/EA1:1)，得到白色固体(1)18mg， 收率60％。mp155-156℃.[α]D 20＝+27.0(c1.0,CHCl3).1HNMR(400MHz, CDCl3):δ6.98(d,J＝8.7Hz,2H),6.87(d,J＝8.7Hz,1H),6.53(s,2H),5.84(s,1H), 4.86(s,1H),3.90(s,3H),3.77(s,3H),3.72(s,6H),3.57(s,1H),2.05(m,1H),1.26 (m,1H).13CNMR(150MHz,CDCl3):δ163.1,152.9,146.5,145.8,134.3,132.5, 128.6,117.6,111.4,110.5,100.4,94.4,60.3,59.8,59.3,55.5,25.8,13.6.ESI-MS(m/z):479.0(M+H+).ESI-HRMS(m/z):calcd for C21H22N2NaO6Se[M+Na+],501.0535；found,501.0507.。
实施例2化合物2，3，4，5的合成
具体操作如下：于25mL茄型瓶中，称取原料1f(40mg,0.08mmol)，用 2mL二氯甲烷溶解，加入酰氯(0.42mmol)与三乙胺(50μL,0.42mmol)，室 温下搅拌，TLC点板监测反应进程。待反应完全后，加水，用二氯甲烷萃取三 次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。过滤，旋蒸浓缩后加入10％Pd/C(3mg)，乙醇(1mL)，常压氢气下室温反应12小时。过滤除去 Pd/C后蒸干，用硅胶(300-400目)柱层析分离纯化。
2.1(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-(2-氯乙酰氧 甲基)氮杂环丁烷-2-酮(2)的合成
洗脱剂：PE/EA2:1，黄色固体(2)，收率80％。mp76-78℃.[α]D 20＝+15.7 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.98(s,1H),6.86(s,2H),6.56(s,2H), 5.81(s,1H),4.85(s,1H),4.66(s,2H),4.35(s,2H),3.95(s,3H),3.79(s,3H),3.76(s,6H),3.43(s,1H).13CNMR(150MHz,CDCl3):δ167.6,164.7,155.9,143.4,147.7, 135.1,134.8,127.2,115.2,112.6,113.4,96.4,62.4,65.3,57.4,59.3,55.9,53.4,40.0,34.6.ESI-MS(m/z):466.0(M+H+).ESI-HRMS(m/z):calcd for C22H25ClNO8[M+H+],466.1263；found,466.1266.
2.2(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-(3-氯丙酰氧 甲基)氮杂环丁烷-2-酮(3)的合成
洗脱剂：PE/EA2:1，白色固体(3)，收率78％。mp70-71℃.[α]D 20＝+16.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.93(s,1H),6.92-6.81(m,2H),6.54 (s,2H),4.81(s,1H),4.65-4.49(m,2H),3.90(s,3H),3.77(s,3H),3.73(s,6H),3.58(s,1H),3.42(s,1H),3.22(t,J＝6.0Hz,2H),3.08(t,J＝6.1Hz,2H).13CNMR(150 MHz,CDCl3):δ170.4,162.9,152.9,146.4,145.8,134.0,132.8,129.3,117.3,111.3, 110.4,94.2,60.8,60.3,58.3,58.1,55.4,34.3,22.5.ESI-MS(m/z):480.0(M+H+). ESI-HRMS(m/z):calcd forC23H26ClNNaO8[M+Na+],502.1239；found,502.1186.
2.3(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-(4-溴丁酰氧 甲基)氮杂环丁烷-2-酮(4)的合成
洗脱剂：PE/EA2:1，红色固体(4)，收率72％。mp77-78℃.[α]D 20＝+18.8 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.93(s,1H),6.87(d,J＝8.4Hz,1H), 6.85(d,J＝8.4Hz,1H),6.54(s,2H),5.75(s,1H),4.79(s,1H),4.52(m,2H),3.89(s, 3H),3.76(s,3H),3.72(s,6H),3.42(t,J＝7.1Hz,2H),3.39(s,1H),2.53(t,J＝7.2 Hz,2H),2.18-2.11(m,2H).13CNMR(150MHz,CDCl3):δ171.7,163.1,152.9, 146.3,145.8,133.9,132.9,129.5,117.2,111.3,110.4,94.2,60.3,59.9,58.6,58.1,55.4,31.9,31.6,26.9.ESI-MS(m/z):538.0(M+H+).ESI-HRMS(m/z):calcd for C24H28BrNNaO8[M+Na+],560.0890；found,560.0905.
2.4(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-(5-溴戊酰氧 甲基)氮杂环丁烷-2-酮(5)的合成
洗脱剂：PE/EA2:1，红色固体(4)，收率75％。mp62-73℃.[α]D 20＝+14.9 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.93(s,1H),6.90-6.78(m,2H),6.53 (s,2H),5.75(s,1H),4.79(s,1H),4.51(m,2H),3.89(s,3H),3.76(s,3H),3.72(s,6H),3.39(m,1H),3.36-3.24(m,2H),2.38(t,J＝7.1Hz,2H),1.84(m,2H),1.76(m, 2H).13CNMR(150MHz,CDCl3):δ172.2,163.2,152.9,146.3,145.7,133.9,132.9, 129.5,117.2,111.4,110.4,94.2,60.3,59.8,58.7,58.1,55.4,55.4,32.5,32.3,31.2,22.8.ESI-MS(m/z):552.0(M+H+).ESI-HRMS(m/z):calcd for C25H30BrNNaO8[M+Na+],574.1047；found,574.1048.。
实施例3化合物6，7，8，9，10的合成
具体操作如下：于25mL茄型瓶中，称取原料1f(40mg,0.08mmol)，10％ Pd/C(3mg)和乙醇(1mL)，常压氢气下室温反应12小时。过滤除去Pd/C 后蒸干，用乙腈(1mL)溶解，加入碳酸钾(22mg,0.16mmol)与溴代烷烃(0.16 mmol)。加热回流反应8小时后，加水，用乙酸乙酯萃取三次，有机相合并后 用饱和食盐水洗一次，Na2SO4干燥。旋蒸浓缩后用硅胶(300-400目)柱层析分 离纯化。
3.1(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(2-氯乙氧基-4-甲氧基苯基)-3-羟甲基 氮杂环丁烷-2-酮(6)的合成
洗脱剂：PE/EA1:1，黄色固体(6)，收率71％。mp66-67℃.[α]D 20＝+14.9 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.03(d,J＝8.3Hz,1H),6.92(s,1H), 6.90(d,J＝8.3Hz,1H),6.55(s,2H),4.94(s,1H),4.23(t,J＝5.9Hz,2H),4.17-4.13 (m,1H),4.04-3.99(m,1H),3.87(s,3H),3.81(t,J＝5.9Hz,2H),3.76(s,3H),3.71(s,6H),3.29(s,1H).13CNMR(150MHz,CDCl3):δ165.1,152.9,149.5,147.7,133.9, 133.0,129.5,119.6,111.8,111.7,94.2,68.9,61.5,60.3,58.1,56.9,55.4,41.1. ESI-MS(m/z):452.0(M+H+).ESI-HRMS(m/z):calcd for C22H26ClNNaO7[M+Na+],474.1290；found,474.1364.
3.2(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-溴丙氧基-4-甲氧基苯基)-3-羟甲基 氮杂环丁烷-2-酮(7)的合成
洗脱剂：PE/EA1:1，淡红色固体(7)，收率77％。mp67-70℃.[α]D 20＝+30.3 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.99(d,J＝8.1Hz,1H),6.92(s,1H), 6.87(d,J＝8.1Hz,1H),6.55(s,2H),4.94(s,1H),4.16-4.09(m,3H),4.00(m,1H), 3.85(s,3H),3.75(s,3H),3.71(s,6H),3.60(t,J＝6.1Hz,2H),3.30(s,1H),2.33(m,2H).13CNMR(150MHz,CDCl3):δ165.3,152.8,149.2,148.2,133.9,133.1,129.4, 118.8,111.5,110.5,94.2,66.2,61.5,60.3,58.1,57.0,55.4,31.6,29.4.ESI-MS(m/z):510.0(M+H+).ESI-HRMS(m/z):calcd forC23H28BrNNaO7[M+Na+],532.0941； found,532.0924.
3.3(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(4-溴丁氧基-4-甲氧基苯基)-3-羟甲基 氮杂环丁烷-2-酮(8)的合成
洗脱剂：PE/EA1:1，红色固体(8)，收率73％。mp74-75℃.[α]D 20＝+40.1 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.98(d,J＝8.2Hz,1H),6.87-6.85(m, 2H),6.55(s,2H),4.93(d,J＝2.1Hz,1H),4.15(dd,J＝11.8,2.1Hz,1H),4.04-3.95 (m,3H),3.85(s,3H),3.75(s,3H),3.71(s,6H),3.47(t,J＝6.5Hz,2H),3.31-3.28(m, 1H),2.04(m,2H),1.95(m,3H).13CNMR(150MHz,CDCl3):δ165.3,152.8,149.2, 148.4,133.9,133.1,129.3,118.6,111.3,109.9,94.2,67.6,61.5,60.3,58.1,57.1,55.4,32.8,28.8,27.1.ESI-MS(m/z):524.0(M+H+).ESI-HRMS(m/z):calcd for C24H30BrNNaO7[M+Na+],546.1098；found,546.1111.
3.4(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(5-溴戊氧基-4-甲氧基苯基)-3-羟甲基 氮杂环丁烷-2-酮(9)的合成
洗脱剂：PE/EA1:1，淡红色固体(9)，收率79％。mp63-64℃.[α]D 20＝+90.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.97(d,J＝8.2Hz,1H),6.86(d,J＝ 8.3Hz,2H),6.55(s,2H),4.93(s,1H),4.15(d,J＝9.9Hz,1H),4.01-3.95(m,3H), 3.86(s,3H),3.75(s,3H),3.71(s,6H),3.42(t,J＝6.6Hz,2H),3.30(s,1H),1.91(m,2H),1.83(m,2H),1.61(m,2H).13CNMR(150MHz,CDCl3):δ165.3,152.8,149.1, 148.5,133.9,133.1,129.3,118.4,111.3,109.8,68.2,61.5,60.3,58.1,57.1,55.4,32.9,31.8,27.6,24.1.ESI-MS(m/z):538.0(M+H+).ESI-HRMS(m/z):calcd for C25H32BrNNaO7[M+Na+],560.1254；found,560.1252.
3.5(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(6-溴己氧基-4-甲氧基苯基)-3-羟甲基 氮杂环丁烷-2-酮(10)的合成
洗脱剂：PE/EA1:1，淡红色固体(10)，收率83％。mp66-67℃.[α]D 20＝ +85.8(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.95(d,J＝8.4Hz,1H), 6.90-6.80(m,2H),6.54(s,2H),4.93(s,1H),4.18-4.08(m,2H),4.02-3.91(m,3H),3.85(s,3H),3.75(s,3H),3.69(s,6H),3.41(t,J＝6.7Hz,2H),3.30(s,1H),1.86(m, 4H),1.48(m,4H).13CNMR(150MHz,CDCl3):δ165.4,152.8,149.1,148.5,133.9, 133.1,129.2,118.4,111.3,109.7,94.2,68.3,61.5,60.3,58.0,57.1,55.4,33.1,31.9, 28.3,27.3,24.6.ESI-MS(m/z):552.0(M+H+).ESI-HRMS(m/z):calcd for C26H34BrNNaO7[M+Na+],574.1411；found,574.1414.。
实施例4化合物11，12，13，14，15，16，17，18，19的合成
在25mL茄形瓶中分别加入原料2-10(0.04mmol)，硒氰酸钾(32mg,0.22 mmol)和乙腈(1mL)。加热回流反应8小时后，加水，用乙酸乙酯萃取三次， 有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后用硅胶 (300-400目)柱层析分离纯化。
4.1(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-(2-硒氰乙酰 氧甲基)氮杂环丁烷-2-酮(11)的合成
洗脱剂：PE/EA1:1，黄色固体(11)，收率72％。mp74-75℃.[α]D 20＝+5.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.94(s,1H),6.90-6.84(m,2H),6.54 (s,2H),5.82(s,1H),4.81(s,1H),4.63(s,2H),4.36-4.34(m,2H),4.10(s,2H),3.91(s,3H),3.77(s,3H),3.73(s,6H),3.44-3.41(m,1H).13CNMR(150MHz,CDCl3):δ 166.6,162.7,152.9,146.4,145.8,134.0,132.8,129.2,117.2,111.3,110.4,94.3,61.5, 60.3,58.4,58.3,57.9,55.4,40.0,30.8.ESI-MS(m/z):537.0(M+H+).ESI-HRMS (m/z):calcd for C23H24N2NaO8Se[M+Na+],559.0590；found,559.0553.
4.2(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-(3-硒氰丙酰 氧甲基)氮杂环丁烷-2-酮(12)的合成
洗脱剂：PE/EA1:1，淡绿色固体(12)，收率72％。mp79-80℃.[α]D 20＝+14.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.93(s,1H),6.88(d,J＝8.3Hz,1H), 6.84(d,J＝8.3Hz,1H),6.54(s,2H),5.72(s,1H),4.82(d,J＝2.1Hz,1H),4.61-4.52 (m,2H),3.90(s,3H),3.77(s,3H),3.75(t,J＝7.2Hz,2H),3.73(s,6H),3.41-3.38(m,1H),2.83(t,J＝7.3Hz,2H).13CNMR(150MHz,CDCl3):δ169.4,163.1,152.9, 146.3,145.7,133.9,132.8,129.4,117.3,111.3,110.4,94.2,60.3,60.2,58.4,57.9,55.4,38.4,36.8.ESI-MS(m/z):551.0(M+H+).ESI-HRMS(m/z):calcd for C24H26N2NaO8Se[M+Na+],573.0747；found,573.0704.
4.3(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-(4-硒氰丁酰 氧甲基)氮杂环丁烷-2-酮(13)的合成
洗脱剂：PE/EA1:1，淡黄色固体(13)，收率68％。mp80-81℃.[α]D 20＝+15.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.92(s,1H),6.86(m,2H),6.53(s, 2H),5.80(s,1H),4.81(s,1H),4.57(m,1H),4.47(m,1H),3.88(s,3H),3.75(s,3H),3.71(s,6H),3.39(s,1H),3.13-2.92(m,2H),2.55(t,J＝6.4Hz,2H),2.20(t,J＝6.3 Hz,2H).13CNMR(150MHz,CDCl3):δ171.2,163.1,152.9,146.4,145.8,134.1, 132.8,129.4,117.2,111.4,110.4,100.5,94.2,60.3,60.1,58.5,58.1,55.4,32.2,27.7, 25.3.ESI-MS(m/z):565.0(M+H+).ESI-HRMS(m/z):calcd for C25H28N2NaO8Se [M+Na+],587.0903；found,587.0894.
4.4(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-(5-硒氰戊酰 氧甲基)氮杂环丁烷-2-酮(14)的合成
洗脱剂：PE/EA1:1，淡黄色固体(14)，收率63％。mp70-72℃.[α]D 20＝+6.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.92(s,1H),6.88-6.83(m,2H),6.53 (s,2H),5.79(s,1H),4.79(s,1H),4.56-4.46(m,2H),3.88(s,3H),3.75(s,3H),3.71 (s,6H),3.39(s,1H),2.98-2.94(m,2H),2.40(t,J＝7.0Hz,2H),1.89(m,2H), 1.78-1.73(m,2H).13CNMR(150MHz,CDCl3):δ171.9,163.1,152.9,146.3,145.7, 134.0,132.9,129.5,117.2,111.4,110.4,100.7,94.2,60.3,59.9,58.6,58.1,55.4,32.6,29.5,28.2,23.6.ESI-MS(m/z):579.0(M+H+).ESI-HRMS(m/z):calcd for C26H30N2NaO8Se[M+Na+],601.1060；found,601.1129.
4.5(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(2-硒氰乙氧基-4-甲氧基苯基)-3-羟甲 基氮杂环丁烷-2-酮(15)的合成
洗脱剂：PE/EA1:1，淡黄色固体(15)，收率61％。mp65-66℃.[α]D 20＝+57.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.05(d,J＝8.1Hz,1H),6.94(s,1H), 6.90(d,J＝8.2Hz,1H),6.55(s,2H),4.95(s,1H),4.39(t,J＝6.1Hz,2H),4.17-4.13 (m,1H),4.04(m,1H),3.87(s,3H),3.76(s,3H),3.72(s,6H),3.42(t,J＝6.1Hz,2H), 3.29(s,1H).13CNMR(150MHz,CDCl3):δ164.9,152.9,149.6,147.2,134.0,133.0, 129.6,120.1,112.5,111.9,100.5,94.3,67.8,61.6,60.3,58.2,56.9,55.4,27.4.ESI-MS(m/z):523.0(M+H+).ESI-HRMS(m/z):calcd for C23H26N2NaO7Se[M+Na+],545.0797；found,545.0814.
4.6(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(3-硒氰丙氧基-4-甲氧基苯基)-3-羟甲 基氮杂环丁烷-2-酮(16)的合成
洗脱剂：PE/EA1:1，淡黄色固体(16)，收率56％。mp73-74℃.[α]D 20＝+55.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.00(d,J＝8.3Hz,1H),6.87(d,J＝ 8.3Hz,1H),6.54(s,2H),4.94(s,1H),4.11(m,3H),4.00(m,1H),3.84(s,3H),3.75 (s,3H),3.70(s,6H),3.29(t,J＝6.4Hz,3H),2.44-2.36(m,2H).13CNMR(150MHz, CDCl3):δ165.1,152.9,149.3,147.8,133.9,133.1,129.5,119.3,111.5,110.8,101.4, 94.3,67.0,61.6,60.3,58.1,57.0,55.3,29.5,25.7.ESI-MS(m/z):537.0(M+H+). ESI-HRMS(m/z):calcd forC24H28N2NaO7Se[M+Na+],559.0954；found,559.0978.
4.7(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(4-硒氰丁氧基-4-甲氧基苯基)-3-羟甲 基氮杂环丁烷-2-酮(17)的合成
洗脱剂：PE/EA1:1，淡黄色固体(17)，收率66％。mp82-83℃.[α]D 20＝+59.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.98(d,J＝8.1Hz,1H),6.86(d,J＝ 8.1Hz,2H),6.55(s,2H),4.94(s,1H),4.15-4.10(m,1H),4.01(s,3H),3.85(s,3H),3.75(s,3H),3.70(s,6H),3.29(m,1H),3.15(t,J＝6.8Hz,2H),2.10(m,2H),1.97 (m,2H).13CNMR(150MHz,CDCl3):δ165.2,152.8,149.2,148.2,133.9,133.1, 129.4,118.8,111.3,109.9,100.9,94.2,67.8,61.5,60.3,58.1,57.1,55.4,28.8,27.6,27.3.ESI-MS(m/z):551.0(M+H+).ESI-HRMS(m/z):calcd for C25H30N2NaO7Se [M+Na+],573.1110；found,573.1116.
4.8(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(5-硒氰戊氧基-4-甲氧基苯基)-3-羟甲 基氮杂环丁烷-2-酮(18)的合成
洗脱剂：PE/EA1:1，淡黄色固体(18)，收率65％。mp83-84℃.[α]D 20＝+48.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.97(d,J＝8.3Hz,1H),6.86(d,J＝ 8.2Hz,2H),6.56(s,2H),4.93(s,1H),4.16-4.12(m,1H),4.02-3.96(m,3H),3.86(s,3H),3.76(s,3H),3.71(s,6H),3.30(s,1H),3.07(t,J＝7.2Hz,2H),2.00-1.93(m, 2H),1.89-1.82(m,2H),1.66-1.59(m,2H).13CNMR(150MHz,CDCl3):δ165.1, 152.9,149.2,148.4,133.9,133.1,129.4,118.5,111.3,109.9,100.9,94.3,68.1,61.5, 60.3,58.2,57.2,55.4,29.9,28.7,27.7,25.1.ESI-MS(m/z):565.0(M+H+). ESI-HRMS(m/z):calcd for C26H32N2NaO7Se[M+Na+],587.1267；found,587.1256.
4.9(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(6-硒氰己氧基-4-甲氧基苯基)-3-羟甲 基氮杂环丁烷-2-酮(19)的合成
洗脱剂：PE/EA1:1，淡黄色固体(19)，收率68％。mp66-67℃.[α]D 20＝+43.0 (c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.96(d,J＝7.8Hz,1H),6.86(d,J＝ 7.9Hz,2H),6.55(s,2H),4.94(d,J＝2.2Hz,1H),4.18-4.14(m,1H),4.02-3.95(m, 3H),3.86(s,3H),3.75(s,3H),3.70(s,6H),3.30(m,1H),3.05(t,J＝7.2Hz,2H), 1.93(m,2H),1.81(m,2H),1.50(m,4H).13CNMR(150MHz,CDCl3):δ165.2, 152.8,149.1,148.5,133.9,133.1,129.3,118.4,111.3,109.8,100.9,94.2,68.2,61.5, 60.3,58.2,57.2,55.4,30.1,28.8,28.2,24.6.ESI-MS(m/z):579.0(M+H+). ESI-HRMS(m/z):calcd for C27H34N2NaO7Se[M+Na+],601.1423；found,601.1430.。
实施例5(S)-1-(3-甲硒基-4,5-二甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-亚甲基氮杂环丁烷-2-酮(20)的合成
参照文献(J.Med.Chem.2016,59,10329-10334；J.Med.Chem.2017,60, 7300-7314)方法，本发明按如下路线合成目标化合物20：
试剂与条件:(a)HNO3,CH3COOH,25℃,10min；(b)Me2SO4,K2CO3,Acetone, reflux,12h；(c)Zn,CH3COOH,EtOH,25℃,3h；(d)NaNO2,10％HCl,KSeCN,0 ℃,1h；(e)NaBH4,Me2SO4,EtOH,25℃,3h；(f)NH4OH,Cu2O,NMP,120℃,48h； (g)Pd2(dba)3(0.1％),(R,R,R)-Ph-SKP(0.25％),K2CO3,CH2Cl2,25℃,3h；(h)i) Sn[N(TMS)2]2,toluene,reflux,3h；ii)TBAF,THF,0℃,1h.
5.14-溴-2-甲氧基-6-硝基苯酚(20a)的合成
在250mL茄形瓶中加入4-溴-2-甲氧基苯酚(2.3g,10mmol)，乙酸(50mL) 和65％硝酸(0.97mL,12mmol)。室温下反应10分钟后，将反应液倒入500mL 冰水中，过滤析出的固体，得到黄色固体(20a)2.3g，收率93％。1H NMR(400 MHz,CDCl3):δ10.70(s,1H),7.85(s,1H),7.20(s,1H),3.95(s,3H).
5.2 5-溴-2,3-二甲氧基硝基苯(20b)的合成
在50mL茄形瓶中加入20a(0.7g,2.8mmol)，硫酸二甲酯(0.31mL,3.4 mmol)，碳酸钾(0.58g,3.4mmol)和丙酮(10mL)。加热回流反应8小时后， 将反应液倒入100mL水中，过滤析出的固体，得到黄色固体(20b)0.56g，收 率76％。1H NMR(400MHz,CDCl3):δ7.47(s,1H),7.20(s,1H),3.96(s,3H),3.92 (s,3H).
5.3 5-溴-2,3-二甲氧基苯胺(20c)的合成
在50mL茄形瓶中加入20b(0.26g,1mmol)，用乙醇(15mL)溶解后， 加入乙酸(8mL)和锌粉(0.33g,5mmol)，室温下搅拌。反应3小时后，加 入饱和碳酸氢钠溶液将pH值调至中性，用乙酸乙酯萃取三次，有机相合并后用 饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后用硅胶(300-400目)柱层析分离纯化(洗脱剂：PE/EA5:1)，得到黄色油状液体(20c)0.19g，收率80％。1H NMR(400MHz,CDCl3):δ6.56(s,1H),6.47(s,1H),3.82(s,3H),3.79(s,3H), 3.51(s,2H).
5.4 5-溴-2,3-二甲氧基硒氰基苯(20d)的合成
冰浴条件下，于50mL茄形瓶中加入20c(0.23g,1mmol)，亚硝酸钠(0.08 g,1.2mmol)和10％盐酸(2.5mL)，室温下搅拌。原料消失后，加入饱和乙酸 钠水溶液将pH值调至6.0，加入硒氰酸钾(0.21g,1.5mmol)。室温下反应1 小时后，加水，用乙酸乙酯萃取三次，有机相合并后用饱和食盐水洗一次，无水 硫酸钠干燥。旋蒸浓缩后用硅胶(300-400目)柱层析分离纯化(洗脱剂：PE/EA 8:1)，得到黄色固体(20d)0.26g，收率82％。1H NMR(400MHz,CDCl3):δ7.32 (s,1H),7.01(s,1H),3.90(s,3H),3.87(s,3H).
5-溴-2,3-二甲氧基-1-甲硒基苯(20e)的合成
在50mL茄形瓶中加入20d(0.32g,1mmol)，用无水乙醇(8mL)溶解 后，加入硼氢化钠(38mg,1mmol)和硫酸二甲酯(0.11mL,1.2mmol)。室温 下反应2小时后，加水，用乙酸乙酯萃取三次，有机相合并后用饱和食盐水洗一 次，无水硫酸钠干燥。旋蒸浓缩后用硅胶(300-400目)柱层析分离纯化(洗脱剂：PE/EA10:1)，得到黄色油状液体(20e)0.29g，收率95％。1HNMR(400MHz, CDCl3):δ6.87(s,2H),3.83(s,6H),2.25(s,3H).
5.5 4,5-二甲氧基-3-甲硒基苯胺(20f)的合成
在10mL螺纹密封管中加入20e(0.31g,1mmol)，氧化亚铜(43mg,0.3 mmol)，氨水(1mL)和N-甲基吡咯烷酮(0.7mL)。120℃条件下密封反应 48小时后，加水，用乙酸乙酯萃取三次，有机相合并后用饱和食盐水洗一次， 无水硫酸钠干燥。旋蒸浓缩后用硅胶(300-400目)柱层析分离纯化(洗脱剂： PE/EA5:1)，得到黑色固体(20f)0.23g，收率94％。mp108-109℃.1H NMR(400 MHz,CDCl3):δ6.10(s,2H),3.78(s,3H),3.76(s,3H),3.41(s,2H),2.20(s,3H).13C NMR(150MHz,CDCl3):δ152.2,143.2,138.5,127.3,105.1,97.5,59.6,55.1,4.2.ESI-MS(m/z):248.0(M+H+).ESI-HRMS(m/z):calcd for C9H13NNaO2Se[M+Na+],270.0004；found,270.0481.
5.6(S)-2-[1-(3-叔丁基二甲基硅氧基-4-甲氧基苯基)-1-(3-甲硒基-4,5-二甲氧基苯基氨基)甲基]丙烯酸乙酯(20g)的合成
于50mLSchlenk管中加入原料1a(2.04g,5mmol)，20f(1.35g,5.5 mmol)，碳酸钾(2.07g,15mmol)，Pd2(dba)3(4.6mg,0.005mmol)和 (R,R,R)-Ph-SKP(8.3mg,0.0125mmol)，三次抽换气后使体系充满干燥的氮气， 后向体系注入无氧二氯甲烷(20mL)。继续在氮气保护下室温反应3小时。加 水，用二氯甲烷萃取三次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。 旋蒸浓缩后柱层析分离(PE/EA3:1)，得到黑色油状液体(20g)2.52g，收率85％。[α]D 20＝+11.9(c1.0,CHCl3),91％ee[determined by HPLC analysis using aChiralcel OD-H column；n-Hex/i-PrOH＝95:5,1.0mL/min,254nm；tR(major)＝ 5.87min；tR(minor)＝7.41min].1H NMR(400MHz,CDCl3):δ6.90(s,1H),6.82(s, 2H),6.34(s,1H),6.03(s,1H),5.98(s,1H),5.89(s,1H),5.27(s,1H),4.16(m,2H), 3.78(s,3H),3.76(s,6H),2.15(s,3H),1.25(m,3H),0.97(s,9H),0.12(s,6H).13C NMR(150MHz,CDCl3):δ170.2,156.6,154.3,148.6,146.1,137.7,129.2,126.1, 123.6,123.2,115.6,107.8,100.1,76.5,64.6,59.21,29.4,22.2,17.8,8.5,-0.9.ESI-MS(m/z):596.0(M+H+).ESI-HRMS(m/z):calcd for C28H41NNaO6SeSi [M+Na+],618.1761；found,618.2540.
5.7(S)-1-(3-甲硒基-4,5-二甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-亚甲基氮杂环丁烷-2-酮(20)的合成
在50mLSchlenk管中加入原料20g(0.5g,0.84mmol)，Sn[N(TMS)2]2(0.4 mL,1mmol)和无水甲苯(6mL)。氮气保护下加热回流反应12小时，后直接快速柱层析分离(PE/EA4:1)，得到无色油状液体，于冰浴条件下，加入TBAF (0.39g,1.5mmol)和四氢呋喃(6mL)。继续冰浴反应20分钟后，加水，用 乙酸乙酯萃取三次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。柱层 析分离(PE/EA2:1)，得到黄色固体(20)0.24g，收率66％。mp118-119℃.[α]D 20＝+14.0(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.06(s,1H),6.95(s,1H), 6.90(d,J＝8.2Hz,1H),6.83(d,J＝8.2Hz,1H),6.49(s,1H),5.82(s,2H),5.27(s, 1H),5.15(s,1H),3.88(s,3H),3.78(s,3H),3.77(s,3H),2.06(s,3H).13CNMR(150 MHz,CDCl3):δ160.2,151.9,149.1,146.5,145.6,142.1,134.2,128.8,127.6,118.2, 112.4,110.3,110.2,106.7,99.4,63.1,59.4,55.4,55.3,4.1.ESI-MS(m/z):436.0 (M+H+).ESI-HRMS(m/z):calcd for C20H21NNaO5Se[M+H+],436.0658；found, 436.0702.。
实施例6(3R,4R)-1-(3-甲硒基-4,5-二甲氧基苯基)-3-甲基-4-(3-羟基-4-甲氧基苯基)氮杂环丁烷-2-酮(21)的合成
在25mL茄形瓶中加入原料20(24mg,0.055mmol)，10％Pd/C(3mg) 和乙醇(1mL)。通氢气常压室温反应12小时，过滤除去催化剂后，柱层析分 离(展开剂：PE/EA2:1)，得到白色固体(21)21mg，收率90％。mp86-87℃. [α]D 20＝+68.6(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.98(s,1H),6.82(d,J ＝8.2Hz,2H),6.72(d,J＝8.2Hz,1H),6.49(s,1H),5.71(s,1H),5.05(d,J＝5.8Hz, 1H),3.89(s,3H),3.79(s,3H),3.77(s,3H),3.66-3.60(m,1H),2.03(s,3H),0.92(d, J＝7.6Hz,3H).13CNMR(150MHz,CDCl3):δ167.8,151.9,145.8,145.2,141.8, 134.2,127.4,127.2,118.2,112.6,110.0,107.0,99.5,59.4,57.8,55.3,48.7,8.9,4.2.ESI-MS(m/z):438.0(M+H+).ESI-HRMS(m/z):calcd for C20H23NNaO5Se[M+Na+],460.0634；found,460.0636.。
实施例7(3R,4R)-1-(3-甲硒基-4,5-二甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-羟甲基氮杂环丁烷-2-酮(22)和(3S,4R)-1-(3-甲硒基-4,5-二甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-羟甲基氮杂环丁烷-2-酮(23)的合成
氮气保护下，于50mLSchlenk管中加入化合物20(0.13g,0.3mmol)，联 硼酸频呐醇酯(0.1g,0.4mmol)，CuCl(1.5mg,0.045mmol)，三苯基膦(12 mg,0.045mmol)，叔丁醇锂(2.4mg,0.03mmol)，甲醇(15μL,0.45mmol) 和无水THF(5mL)。氮气保护下室温反应12小时，加水，用乙酸乙酯萃取三 次，有机相合并后用饱和NaCl水溶液洗一次，无水硫酸钠干燥。蒸去溶剂后溶 解于5mLTHF，加入四水合过硼酸钠(0.23g,1.5mmol)和水(5mL)，室温 反应2小时。加水，用乙酸乙酯萃取三次，有机相合并后用饱和NaCl水溶液洗 一次，Na2SO4干燥。柱层析分离(展开剂：PE/EA＝2:1)，得到白色固体(22) 40mg，收率29％。mp88-90℃.[α]D 20＝+86.0(c1.0,CHCl3).1H NMR(400MHz, CDCl3):δ6.96(s,2H),6.88(d,J＝8.2Hz,1H),6.83(d,J＝8.2Hz,1H),6.47(s,1H), 5.94(s,1H),4.90(s,1H),4.11(dd,J＝11.5,3.1Hz,1H),3.97(dd,J＝11.5,3.1Hz, 1H),3.87(s,3H),3.76(s,3H),3.74(s,3H),3.28(s,1H),2.03(s,3H).13CNMR(150 MHz,CDCl3):δ165.2,151.8,146.3,145.7,141.9,134.0,129.9,127.5,117.5,111.7, 110.4,106.7,99.4,61.5,59.4,58.0,56.9,55.4,55.2,4.0.ESI-MS(m/z):454.0 (M+H+).ESI-HRMS(m/z):calcd for C20H23NNaO6Se[M+Na+],476.0583；found,476.0593.同时得到白色固体(23)82mg，收率60％。mp106-107℃.[α]D 20＝ +21.0(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.96(s,1H),6.89(s,1H),6.84 (d,J＝3.3Hz,1H),6.82(d,J＝3.3Hz,1H),6.48(s,1H),5.76(s,1H),5.15(d,J＝ 5.1Hz,1H),3.90(s,3H),3.81(m,2H),3.79(s,3H),3.77(s,3H),3.65(m,1H),2.03 (s,3H).13CNMR(150MHz,CDCl3):δ164.4,151.9,146.1,145.5,142.1,133.9, 127.6,126.42,117.9,112.3,110.3,107.1,99.5,59.4,57.5,56.7,56.2,55.3,4.2.ESI-MS(m/z):454.0(M+H+).ESI-HRMS(m/z):calcd forC20H23NNaO6Se[M+Na+],476.0583；found,476.0532.。
实施例8(3S,4R)-1-(3-甲硒基-4,5-二甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-氟甲基氮杂环丁烷-2-酮(24)的合成
于50mL聚四氟乙烯管中，称取原料20(45mg,0.1mmol)和SulFoxFluor (42mg,0.12mmol)，用无水甲苯(1.5mL)溶解，最后加入DBU(16μL,0.12 mmol)，室温下搅拌10分钟，过滤，旋蒸浓缩后用硅胶(300-400目)柱层析 法进行纯化(洗脱剂：PE/EA1:1)，得到淡黄色固体(24)36mg，收率80％。 mp68-69℃.[α]D 20＝+28.2(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.93(s, 1H),6.89(s,1H),6.83(d,J＝8.2Hz,1H),6.78(d,J＝8.2Hz,1H),6.38(s,1H),5.67 (s,1H),4.84(s,1H),4.78-4.64(m,2H),3.83(s,3H),3.70(s,6H),3.34(d,J＝28.7 Hz,1H),1.97(s,3H).13CNMR(150MHz,CDCl3):δ162.6,151.9,146.4,145.8, 142.1,133.9,129.4,127.6,117.4,111.5,110.4,106.7,99.5,78.9,77.9,59.9,59.8,59.4,57.1,55.4,55.3,4.1.ESI-MS(m/z):456.0(M+H+).ESI-HRMS(m/z):calcd for C20H22FNNaO5Se[M+Na+],478.0539；found,478.0541.。
实施例9(3S,4R)-1-(3-甲硒基-4,5-二甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-氯甲基氮杂环丁烷-2-酮(25)的合成
于10mL茄型瓶中，称取原料20(45mg,0.1mmol)，用1.5mL二氯甲烷 溶解后加入氯化亚砜(9μL,0.12mmol)与三乙胺(17μL,0.12mmol)，室温反 应6小时。加水，用二氯甲烷萃取三次，有机相合并后用饱和食盐水洗一次，无 水无水硫酸钠干燥，过滤，旋蒸浓缩，用硅胶(300-400目)柱层析法进行纯化 (洗脱剂：PE/EA2:1)。旋干得到淡绿色固体(25)31mg，收率66％。mp82-83℃.[α]D 20＝+43.5(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ6.99(s,1H),6.96(s, 1H),6.90(d,J＝8.2Hz,1H),6.84(d,J＝8.2Hz,1H),6.45(s,1H),4.84(d,J＝1.9Hz,1H),3.93(d,J＝6.1Hz,2H),3.89(s,3H),3.77(s,6H),3.51-3.47(m,1H),2.03(s,3H).13CNMR(150MHz,CDCl3):δ162.7,151.9,146.3,145.7,142.1,133.8, 129.2,127.6,117.5,111.6,110.4,106.7,99.5,60.4,59.4,58.6,55.4,55.3,40.2,4.1.ESI-MS(m/z):472.0(M+H+).ESI-HRMS(m/z):calcd for C20H23ClNO5Se[M+H+],472.0425；found,472.0424.。
实施例10(3S,4R)-1-(3-甲硒基-4,5-二甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-溴甲基氮杂环丁烷-2-酮(26)的合成
在25mLSchlenk管中加入原料20(45mg,0.1mmol)，四溴化碳(69mg,0.2 mmol)，三苯基膦(54mg,0.2mmol)，三次抽换气后使体系充满干燥的氮气， 后向体系注入无水二氯甲烷(2mL)。继续在氮气保护下室温反应4小时。加 水，用二氯甲烷萃取三次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。 旋蒸浓缩，用硅胶(300-400目)柱层析法进行纯化(洗脱剂：PE/EA2:1)。旋 干得到淡黄色固体(23)45mg，收率88％。mp78-79℃.[α]D 20＝+58.6(c1.0, CHCl3).1H NMR(400MHz,CDCl3):δ6.97(m,2H),6.91(dd,J＝8.2,1.9Hz,1H), 6.84(d,J＝8.2Hz,1H),6.44(d,J＝2.1Hz,1H),5.77(s,1H),4.79(d,J＝2.2Hz, 1H),3.89(s,3H),3.77(s,3H),3.76(s,3H),3.73(m,2H),3.52(m,1H),2.03(s,3H).13CNMR(150MHz,CDCl3):δ162.9,151.9,146.3,145.7,142.1,133.7,129.1,127.7, 117.6,111.7,110.4,106.7,99.5,60.3,59.9,59.4,55.4,55.3,27.7,4.1.ESI-MS(m/z):515.0(M+H+).ESI-HRMS(m/z):calcd for C20H23BrNO5Se[M+H+],515.9919；found, 515.9916.。
实施例11(3S,4R)-1-(3-甲硒基-4,5-二甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-碘甲基氮杂环丁烷-2-酮(27)的合成
在25mLSchlenk管中加入原料20(45mg,0.1mmol)，碘(42mg,0.16 mmol)，三苯基膦(44mg,0.16mmol)，Imidazole(12mg,0.16mmol)，三次 抽换气后使体系充满干燥的氮气，后向体系注入无水二氯甲烷(2mL)。继续 在氮气保护下室温反应4小时。加水，用二氯甲烷萃取三次，有机相合并后用饱 和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩，用硅胶(300-400目)柱层析法 进行纯化(洗脱剂：PE/EA2:1)。旋干得到黄色固体(27)42mg，收率76％。mp76-78℃.[α]D 20＝+22.0(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.00(s, 1H),6.98(s,1H),6.95(d,J＝8.1Hz,1H),6.85(d,J＝8.1Hz,1H),6.43(s,1H),5.72 (s,1H),4.66(s,1H),3.90(s,3H),3.78(s,6H),3.60-3.54(m,1H),3.50-3.35(m,2H), 2.04(s,3H).13CNMR(150MHz,CDCl3):δ167.0,155.6,150.0,149.4,145.9,137.4, 132.7,131.3,121.5,115.6,114.1,110.5,103.2,65.9,64.4,63.1,59.1,58.9,7.8,2.4.ESI-MS(m/z):563.0(M+H+).ESI-HRMS(m/z):calcd for C20H22INNaO5Se[M+Na+],585.9600；found,585.9595.。
实施例12(S)-1-(3,4,5-三甲氧基苯基)-4-(4-甲硒基苯基)-3-亚甲基氮杂环 丁烷-2-酮(28)的合成
参照文献(J.Med.Chem.2016,59,10329-10334；J.Med.Chem.2017,60, 7300-7314)方法，本发明按如下路线合成目标化合物28：
试剂与条件:(a)NaNO2,10％HCl,KSeCN,0℃,1h；(b)NaBH4,Me2SO4,EtOH,25 ℃,3h；(c)i)DMF,n-BuLi,THF,-78℃,20min；ii)25℃,3h；(d)DABCO,ethyl acrylate,MeOH,25℃,3days；(e)Ac2O,Et3N,DMAP,CH2Cl2,25℃,1h；(f) Pd2(dba)3(0.1％),(R,R,R)-Ph-SKP(0.25％),K2CO3,CH2Cl2,25℃,5h；(g) Sn[N(TMS)2]2,toluene,reflux,3h.
12.11-溴-4-硒氰基苯(28b)的合成
于25mL茄形瓶中加入28a(0.17g,1mmol)，亚硝酸钠(0.14g,2mmol) 和10％盐酸(3mL)，冰浴条件下搅拌反应。原料消失后，加入饱和乙酸钠水 溶液将pH值调至6.0，加入硒氰酸钾(0.17g,1.2mmol)。室温下反应1小时后， 加水，用乙酸乙酯萃取三次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干 燥。旋蒸浓缩后用硅胶(300-400目)柱层析分离纯化(洗脱剂：PE/EA20:1)， 得到黄色固体(28b)0.2g，收率77％。1H NMR(400MHz,CDCl3):δ7.32(d,J＝ 8.1Hz,2H),7.29(d,J＝8.1Hz,2H).
12.21-溴-4-甲硒基苯(28c)的合成
在25mL茄形瓶中加入28b(0.12g,0.45mmol)，用无水乙醇(1.5mL) 溶解后，加入硼氢化钠(18mg,0.48mmol)和硫酸二甲酯(0.05mL,0.53mmol)。 室温下反应2小时后，加水，用乙酸乙酯萃取三次，有机相合并后用饱和食盐水 洗一次，无水硫酸钠干燥。旋蒸浓缩后用硅胶(300-400目)柱层析分离纯化(洗脱剂：PE/EA30:1)，得到黄色油状液体(28c)0.23g，收率92％。1H NMR(400 MHz,CDCl3):δ7.19(d,J＝8.5Hz,2H),7.09(d,J＝8.4Hz,2H),2.16(s,3H).
12.34-甲硒基苯甲醛(28d)的合成
在25mLSchlenk管中加入原料28c(0.25g,1mmol)，三次抽换气后使体 系充满干燥的氮气，后向体系注入无水四氢呋喃(2mL)，于-78℃条件下缓缓 加入n-BuLi正己烷溶液(0.6mL)，反应20分钟后加入N,N-二甲基甲酰胺(0.15 mL)，升至室温继续反应3小时。加饱和氯化铵溶液淬灭反应，后加水，用乙 酸乙酯萃取三次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓 缩后，用硅胶(300-400目)柱层析法进行纯化(洗脱剂：PE/EA10:1)。旋干得到黄色固体(28d)0.15g，收率76％。1H NMR(400MHz,CDCl3):δ9.75(s,1H),7.55(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,2H),2.24(s,3H).
12.42-[1-羟基-1-(4-甲硒基苯基)甲基]丙烯酸乙酯(28e)的合成
在25mL茄形瓶中加入28d(0.6g,3mmol)，DABCO(0.5g,4.5mmol)， 丙烯酸乙酯(2mL,4.5mmol)和甲醇(0.06mL,1.5mmol)。室温反应3天后， 用硅胶(300-400目)柱层析法进行纯化(洗脱剂：PE/EA6:1)，得到无色油状 液体(28e)0.58g，收率66％。1H NMR(400MHz,CDCl3):δ7.20(d,J＝7.9Hz,2H), 7.08(d,J＝7.9Hz,2H),6.15(s,1H),5.64(s,1H),5.33(s,1H),4.08(q,J＝7.2Hz, 2H),2.96(s,1H),2.16(s,3H),1.06(t,J＝7.1Hz,3H).13CNMR(150MHz,CDCl3): δ165.6,141.4,138.8,130.7,129.7,126.7,125.2,72.4,60.4,13.4,6.6.ESI-MS(m/z):323.0(M+Na+).ESI-HRMS(m/z):calcd for C13H16NaO3Se[M+Na+],323.0157； found,323.0160.
12.52-[1-乙酰氧基-1-(4-甲硒基苯基)甲基]丙烯酸乙酯(28f)的合成
在50mL茄形瓶中加入原料28e(0.7g,2.34mmol)，三乙胺(1mL,7 mmol)，DMAP(14mg,0.12mmol)和二氯甲烷(10mL)，冰浴冷却，缓慢 滴加乙酸酐(0.7mL,7mmol)。继续冰浴反应20分钟后，加水，用二氯甲烷萃取三次，有机相合并后用饱和NaCl水溶液洗一次，无水硫酸钠干燥。旋蒸浓缩， 用硅胶(300-400目)柱层析法进行纯化(洗脱剂：PE/EA5:1)，得到无色油状 液体0.78g，收率98％。1H NMR(400MHz,CDCl3):δ7.23(d,J＝7.5Hz,2H),7.13(d,J＝7.5Hz,2H),6.49(s,1H),6.26(s,1H),5.72(s,1H),4.01(m,2H),2.20(s,3H), 1.96(s,3H),1.09(t,J＝7.2Hz,3H).13CNMR(150MHz,CDCl3):δ168.7,164.3, 139.1,135.2,131.7,129.5,127.8,124.8,72.2,60.4,20.5,13.4,6.4.ESI-MS(m/z):365.0(M+Na+).ESI-HRMS(m/z):calcd for C15H18NaO4Se[M+Na+],365.0263； found,365.0266.
12.6(S)-2-[1-(4-甲硒基苯基)-1-(3,4,5-三甲氧基苯基氨基)甲基]丙烯酸乙酯(28g)的合成
在50mLSchlenk管中加入原料三甲氧基苯胺(0.55g,3mmol)，28f(0.86 g,2.5mmol)，碳酸钾(1g,7.6mmol)，Pd2(dba)3(4.6mg,0.005mmol)和 (R,R,R)-Ph-SKP(8.3mg,0.0125mmol)，三次抽换气后使体系充满干燥的氮气， 后向体系注入无氧二氯甲烷(10mL)。继续在氮气保护下室温反应5小时。加 水，用二氯甲烷萃取三次，有机相合并后用饱和食盐水洗一次，无水硫酸钠干燥。 旋蒸浓缩后柱层析分离(PE/EA3:1)，得到淡绿色固体(28g)0.96g，收率83％。 mp100-101℃.[α]D 20＝+125.1(c1.0,CHCl3),95％ee[determined byHPLC analysis using a Chiralcel OD-H column；n-Hex/i-PrOH＝95:5,1.0mL/min,254nm； tR(major)＝34.5min；tR(minor)＝29.6min].1H NMR(400MHz,CDCl3):δ7.21(d, J＝6.0Hz,2H),7.10(d,J＝6.0Hz,2H),6.22(s,1H),5.78(s,1H),5.64(s,2H),5.17 (s,1H),4.02-3.98(m,2H),3.60(s,9H),2.18(s,3H),1.06(t,J＝7.8Hz,3H).13C NMR(150MHz,CDCl3):δ165.5,153.2,142.8,139.9,138.03,130.8,129.9,127.4, 125.4,90.7,60.4,60.3,58.4,55.3,13.5,6.5.ESI-MS(m/z):466.0(M+H+). ESI-HRMS(m/z):calcd forC22H27NNaO5Se[M+Na+],488.0947；found,488.0945.
12.7(S)-1-(3,4,5-三甲氧基苯基)-4-(4-甲硒基苯基)-3-亚甲基氮杂环丁烷-2-酮(28)的合成
在50mLSchlenk管中加入原料28g(1g,2.15mmol)，Sn[N(TMS)2]2(1.6mL, 4.3mmol)和无水甲苯(10mL)。氮气保护下加热回流反应3小时，后直接柱层析分离(PE/EA3:1)，得到黄色固体(28)0.72g，收率80％。mp138-139℃. [α]D 20＝+69.0(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.41(d,J＝8.1Hz,2H), 7.30(d,J＝8.1Hz,2H),6.58(s,2H),5.85(s,1H),5.34(s,1H),5.17(s,1H),3.77(s,3H),3.74(s,6H),2.36(s,3H).13CNMR(150MHz,CDCl3):δ160.1,152.9,148.9, 134.2,133.7,133.0,132.5,129.9,126.8,110.3,94.3,62.9,60.3,59.7,55.5,6.8.ESI-MS(m/z):420.0[M+H+].ESI-HRMS(m/z):calcd forC20H21NNaO4Se[M+Na+],442.0528；found,442.0540.。
实施例13(3R,4R)-1-(3,4,5-三甲氧基苯基)-4-(4-甲硒基苯基)-3-羟甲基氮 杂环丁烷-2-酮(29)和(3S,4R)-1-(3,4,5-三甲氧基苯基)-4-(4-甲硒基苯基)-3-羟甲 基氮杂环丁烷-2-酮(30)的合成
氮气保护下，在50mLSchlenk管中加入28(0.2g,0.48mmol)，联硼酸频 那醇酯(0.36g,1.4mmol)，氯化亚铜(14mg,0.14mmol)，三苯基膦(37mg, 0.14mmol)，叔丁醇锂(7.6mg,0.09mmol)，甲醇(56μL,1.4mmol)和无水 THF(5mL)。氮气保护下室温反应12小时，加水，用乙酸乙酯萃取三次，有 机相合并后用饱和NaCl水溶液洗一次，无水硫酸钠干燥。蒸去溶剂后溶解于5 mLTHF，加入四水合过硼酸钠(0.28g,2.4mmol)和水(5mL)，室温反应2 小时。加水，用乙酸乙酯萃取三次，有机相合并后用饱和NaCl水溶液洗一次， Na2SO4干燥。柱层析分离(展开剂：PE/EA＝1:1)，得到白色固体(29)62mg， 收率30％。mp128-129℃.[α]D 20＝+88.9(c1.0,CHCl3).1H NMR(400MHz, CDCl3):δ7.42(d,J＝7.7Hz,2H),7.29(d,J＝7.7Hz,2H),6.53(s,2H),5.78(s,1H), 4.98(s,1H),4.19-4.15(m,1H),4.03-4.00(m,1H),3.76(s,3H),3.72(s,6H),3.28(s,1H),2.36(s,3H).13CNMR(150MHz,CDCl3):δ165.0,152.9,135.0,133.9,133.0, 132.0,131.8,131.5,131.4,130.1,127.9,127.9,126.1,94.2,61.7,60.3,58.0,56.9,55.4,6.5.ESI-MS(m/z):438.0(M+H+).ESI-HRMS(m/z):calcd forC20H23NNaO5Se [M+Na+],460.0634；found,460.0686.同时得到白色固体(30)120mg，收率58％。mp148-149℃.[α]D 20＝+62.8(c1.0,CHCl3).1H NMR(400MHz,CDCl3):δ7.40(d, J＝7.9Hz,2H),7.22(d,J＝7.9Hz,2H),6.53(s,2H),5.22(d,J＝5.5Hz,1H), 3.89-3.83(m,1H),3.82-3.79(m,1H),3.78(s,3H),3.72(s,6H),3.62-3.52(m,1H), 2.36(s,3H).13CNMR(150MHz,CDCl3):δ164.5,152.9,134.1,132.8,132.1,131.2, 129.5,126.9,94.4,60.3,57.3,56.8,56.1,55.5,6.2.ESI-MS(m/z):438.0(M+H+). ESI-HRMS(m/z):calcd forC20H23NNaO5Se[M+Na+],460.0634；found,460.0621.。
实施例14体外肿瘤细胞增殖活性检测实验
取对数生长期的肿瘤细胞，处理后接种于96孔板中，并于37℃、5％CO2的条件下培养24小时。加入6个梯度浓度的供试化合物，并以CA-4作为阳性 对照。同样的条件下继续培养48小时，后加入MTT，培养4小时后弃去含MTT 的上清液，每孔加入DMSO，震荡溶解掉紫色结晶，然后在酶标仪上490nm或 540nm处测得OD值，并计算出抑制率。化合物的半数抑制浓度(IC50值)根据 6个浓度的抑制率计算所得。每个浓度梯度设置三个复孔，重复检测三次。活性 结果如表1所示。
表1.化合物对肿瘤细胞增殖抑制活性(IC50,nM)
其中：化合物的肿瘤增殖抑制活性均由MTT法测定，最终数据取用三次测量的 平均值；HeLa是人宫颈癌细胞株；HUH-7是人肝癌细胞株；SKOV3与A2780 是人卵巢癌细胞株。
实施例15体外微管蛋白自组装实验
用浊度法测试优选化合物22在体外对微管聚集的抑制作用，检测试剂盒购 自于美国Cytoskeleton公司。操作步骤如下，pH＝6.6的微管聚集体系(0.1M PIPES、10mMMgCl2、1mM GTP、1mM EGTA和3.4M甘油)预先在冰上预 孵育，加入不同浓度的受试化合物22，并设置Colchicine处理组作为阳性对照和DMSO(4％，v/v)处理组组作为阴性对照。向以上体系加入微管蛋白(10mM) 后，立刻转移，置于37℃条件下进行聚集反应，保持温度不变，每隔1分钟用 分光光度计(Synergy H4 Hybrid)在340nm下测定吸光度，共持续测试30分钟， 然后绘制吸光度曲线图(如图1所示)。结果显示化合物22能够明显抑制微管 聚集，其IC50为0.9μM(如表2所示)。
表2.化合物22体外抑制微管自组装实验
实施例16免疫荧光检测微管蛋白形态实验
对数生长期HeLa细胞按8000个/皿接种于共聚焦皿中，24小时后加入不同 浓度化合物22，DMSO处理组作为阴性对照。37℃，5％CO2条件下培养24小 时后弃去培养基，PBS洗涤2次，甲醇固定15分钟后再用PBS洗涤3次，0.1％ TritonX-100通透10分钟，PBS洗3次后加入山羊血清，室温封闭0.5小时，一 抗4℃孵育过夜，PBST漂洗3次，每次5分钟。然后加荧光标记二抗，室温 避光孵育1小时，PBST漂洗3次，每次5分钟。60微升DAPI染色液染色10 分钟后PBST洗涤3次，每次5分钟。每皿中加入1毫升PBS，在共聚焦显微镜 下观察微管蛋白的形态，检测受试化合物对微管结构的影响。结果显示化合物 22能明显地抑制微管的聚集(如图2所示)。
实施例17集落形成抑制实验
取对数生长期的HeLa细胞，处理后接种于6孔板中，每孔接种1500个细 胞，并于37℃、5％CO2及湿度饱和的条件下培养24小时，待细胞贴壁后，加 入不同浓度的化合物22处理细胞48小时，并设置DMSO处理组为阴性对照。 更换新鲜培养基并继续培养两周，后弃去上清液，用PBS冲洗两次，细胞用无 水甲醇固定30分钟，并用结晶紫染料染色1小时，洗去染色液，充分干燥后于 显微镜下计数大于50个细胞形成的集落数，结果显示化合物22能够明显地抑制 HeLa细胞集落的形成(如图3所示)。
实施例18体外新生血管生成抑制实验
将购买的细胞外基质胶MatriGel(美国BDBiosciences公司)用PBS按1:1 稀释混匀后，于96孔板中每孔加入60μL。置于37℃、5％CO2培养箱中预热 孵育2小时，待凝胶形成后，将对数生长期的人脐静脉内皮细胞(HUVEC)按 浓度3×104个/孔接种到制备好的凝胶上，加入不含PBS的DMEM培养基，并加 入不同浓度的化合物22，同时设置DMSO处理组为阴性对照，CA-4处理组为 阳性对照，于37℃、5％CO2及饱和湿度的培养箱中培养12小时，于倒置相差 显微镜下观察毛细血管形成情况，并拍摄相关照片，结果显示化合物22能明显 抑制人脐静脉内皮细胞(HUVEC)生成毛细血管样结构(如图4所示)。
实施例19体内新生血管生成抑制实验
取受精后48小时的转基因斑马鱼，处理后接种于6孔板中，后分别与2mL 浓度为0.4nM与2.0nM的化合物22、apatinib(1μM)、DMSO孵育24小时。 绿色荧光蛋白染色后，用共聚焦显微镜观察测试化合物对斑马鱼血管生成的影 响，并计数新生血管的数量。如图5所示，在暴露于化合物22和阳性对照阿帕 替尼之后，与空白对照组相比，斑马鱼的新生血管的生成明显被抑制，表明化合 物22能够有效地阻断斑马鱼新生血管的生成。
实施例20体外细胞周期抑制实验
取对数生长期的HeLa细胞，处理后按2×105个/孔的数量接种于6孔板中， 于37℃、5％CO2及饱和湿度的培养箱中培养12小时，待细胞贴壁后更换新鲜 培养液，用不同浓度的化合物22处理细胞24小时，同时设置DMSO处理组为 阴性对照。弃去上清液，收集贴壁细胞，用PBS冲洗两次，再用75％乙醇固定，-20℃条件下固定过夜，用PI染色后采用流式细胞仪进行测试，结果显示化合 物22能明显将肿瘤细胞周期阻滞于G2/M期(如图6所示)。
实施例21体外细胞周期相关蛋白检测
取对数生长期的HeLa细胞，处理后按2×105个/孔的数量接种于6孔板中， 于37℃、5％CO2及饱和湿度的培养箱中培养24小时，加入梯度浓度的化合物 22处理肿瘤细胞后(同时设置DMSO处理组为阴性对照)，48小时后收集并用 裂解液裂解细胞。蛋白样品经加热变性后，上样于聚丙烯酰胺凝胶，SDS-PAGE 电泳分离，湿法转膜，封闭，依次经一抗反应、二抗反应后，曝光显色。结果如 图7所示，化合物22能明显促进有丝分裂检验点蛋白Bubr-1、磷酸化组蛋白 P-Histone3、细胞周期蛋白B1的表达。
实施例22体外诱导细胞凋亡实验
取对数生长期的HeLa细胞，处理后按2×105个/孔的数量接种于6孔板中， 于37℃、5％CO2及饱和湿度的培养箱中培养24小时，加入梯度浓度的化合物 22，同时设置DMSO处理组为阴性对照。继续培养48小时后，收集上清液细胞 和贴壁细胞，用PI和AnnexinV双染色，采用流式细胞仪进行检测。结果如图8 所示，化合物22能浓度依赖性地诱导细胞凋亡。
实施例23体外凋亡相关蛋白的检测实验
取对数生长期的HeLa细胞，处理后按2×105个/孔的数量接种于6孔板中， 于37℃、5％CO2及饱和湿度的培养箱中培养24小时，加入梯度浓度的化合物 22，同时设置DMSO处理组为阴性对照。48小时后收集并用裂解液裂解细胞。 上样于聚丙烯酰胺凝胶，SDS-PAGE电泳分离，湿法转膜，封闭，依次经一抗反 应、二抗反应后，曝光显色。结果如图9所示，化合物22能明显促进抑癌基因 p53、促凋亡蛋白Bax与剪切的DNA修复酶PAPR-1的表达。
实施例24动物水平的肿瘤治疗作用和机理研究实验
取对数生长期的A2780细胞(卵巢癌细胞)稀释成细胞浓度为1×107个/mL 的PBS悬浮液，后按每只0.2mL腹腔注射接种于6周龄Balb/C裸鼠，建立裸鼠 移植瘤模型，SPF条件下自然生长。待裸鼠皮下A2780移植瘤长至体积约100 mm3，将裸鼠随机分成4组，每组10只，经腹腔给药，分别注射不同浓度的3mg/kg 的化合物22、6mg/kg的化合物22、10mg/kg的紫杉醇和空白对照，记录移植 瘤生长大小。移植瘤体积按以下公式计算：肿瘤体积(mm3)＝a×b2×0.52(a 为最长的直径，b为最短的直径，0.52是经验系数)。当空白对照组移植瘤平均 体积达到2000mm3后，处死裸鼠，剥离瘤组织，称取瘤质量并计算抑瘤率：
抑瘤率＝(1-实验组平均瘤质量/对照组平均瘤质量)×100％
结果如图10所示，化合物22在小鼠体内能明显抑制肿瘤生长，裸鼠内脏组 织用H&E染色，结果也显示出化合物22能够使肿瘤组织产生坏死区，并且对 肝、肾、脾的组织染色并未观察到非正常区域。
Claims (6)
1.一类二芳基-β-内酰胺类有机硒化合物，选自以下化合物：
。
2.一类二芳基-β-内酰胺类有机硒化合物，选自以下化合物：
。
3.一类二芳基-β-内酰胺类有机硒化合物，选自以下化合物：
。
4.一类二芳基-β-内酰胺类有机硒化合物，选自以下化合物：
。
5.权利要求1-4中任一项所述的化合物及其在药学上可接受的盐在制备预防和治疗与肿瘤相关疾病的药物中的应用，所述疾病是宫颈癌、卵巢癌、肝癌；
所述的“药学上可接受的盐”是与苹果酸、乳酸、樟脑磺酸、枸橼酸、富马酸、草酸，以及磷酸、氢卤酸、硫酸、硝酸形成的盐。
6.一种用于预防和治疗与肿瘤相关疾病的复方药物，其特征在于其含有权利要求1-4中任一项所述的化合物，所述疾病是宫颈癌、卵巢癌、肝癌。
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