CN109180552A - 取代的5-氧代吡咯烷类衍生物及其制备方法和应用 - Google Patents
取代的5-氧代吡咯烷类衍生物及其制备方法和应用 Download PDFInfo
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- CN109180552A CN109180552A CN201811120475.9A CN201811120475A CN109180552A CN 109180552 A CN109180552 A CN 109180552A CN 201811120475 A CN201811120475 A CN 201811120475A CN 109180552 A CN109180552 A CN 109180552A
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- oxopyrrolidine
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Abstract
本发明属于医药技术领域，涉及通式Ⅰ所示的取代的5‑氧代吡咯烷类衍生物及其制备方法和应用，具体涉及该类衍生物在作为神经保护剂，在制备抗脑缺血药物中的应用。本发明还涉及以该类衍生物及其在药学上可接受的盐作为活性成分的药物组合物，包含上述衍生物及其可药用赋形剂和/或稀释剂。本发明涉及的通式Ⅰ中的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X、Y、n的定义见说明书和权利要求书。
Description
技术领域
本发明属于医药技术领域，涉及取代的5-氧代吡咯烷类衍生物及其制备方法和应用，具体涉及5-氧代吡咯烷类衍生物及其在制备神经保护剂中的应用。
背景技术
脑血管疾病(Cerebrovascular Disease)是发生在脑部血管，因颅内血液循环障碍而造成脑组织损害的一组疾病，临床上以急性脑血管疾病发病居多，俗称中风(Stroke)或脑卒中。脑卒中是中老年人的常见病，医学界把它同冠心病、癌症并列为威胁人类健康的三大疾病(周世玲,海南医学,2009,20(4):122-127.)。脑卒中分为缺血性和出血性两类，缺血性脑卒中(Ischemic Stroke)又称脑缺血，是最常见的脑卒中类型，占所有脑卒中的80％(王瑞雪等,世界临床药物,2013,34(12):760-764.)。我国每年因为缺血性脑卒中直接或间接的经济损失高达200亿元，给社会和家庭造成极大的经济和精神负担。然而，由缺血所致的神经元损伤以及脑组织损伤，目前在临床上仍缺少安全有效的治疗药物。因此，对缺血性脑卒中发病机制的深入研究，从根源上寻找预防和治疗缺血性脑血管疾病的合理用药靶点，并从中开发出相应的治疗药物，依然任重而道远(Yahia ZA,et al.WorldNeurosurgery,2010,73(6):654-667.)。
缺血性脑卒中的治疗策略主要有两种：一种是早期再灌注以限制脑缺血程度(血管再通)，目的是防止位于缺血部位中心的梗死区域的扩大；另一种是抑制可导致二次损伤的病理级联反应(神经保护)，保护梗死区域周边的半暗带区域。血管再通被认为是治疗急性脑缺血的标准策略，但在某些情况下，血管再通会促进细胞的损伤与凋亡，即再灌注损伤，对大脑产生有害作用。因此，神经保护的治疗策略越来越受到学者们的关注(曹长春.北方药学,2014,11(4):60.程文伟等,山东医药,2014,54(29):95-97.傅瑜等,中国新药杂志,2011,20(11),973-977.)。
神经保护剂能够干预脑缺血级联反应的各个环节，阻断缺血后脑组织损伤涉及的一系列病理过程，保护仍有活力的神经元，延长脑细胞缺血耐受时间和治疗时间窗，逆转半暗带，减小梗死面积。因此，寻找和发现结构新颖的具有神经保护活性的先导化合物，是当前研究和治疗缺血性脑卒中的一个热点(Chen XP,et al.Current Psychopharmacology,2012,1(1):103-110.Gursoy O,et al.Journal of Neurochemistry,2012,123(2):2-11.Min JY,et al.Clinical Investigation,2013,3(12):1167-1177.Turner RC,etal.Journal of Neurosurgery,2013,118(5):1072-1085.)。
由于缺血级联反应的每个环节都是神经保护治疗的靶点，因此神经保护剂的种类繁多，主要分为：兴奋性氨基酸受体拮抗剂、钙通道阻断剂、γ-氨基丁酸受体激动剂、自由基清除剂、抗细胞间黏附因子、神经营养药物等。与脑缺血损伤有关的兴奋性氨基酸(EAA)主要为谷氨酸，在脑缺血病理情况下谷氨酸爆发性释放，过度刺激EAA受体，引起兴奋毒性。EAA受体拮抗剂可分为N-甲基-D-天冬氨酸(NMDA)受体拮抗剂和非NMDA受体拮抗剂。在缺血性脑损伤中，NMDA受体介导的兴奋性毒性起关键性作用，是神经元凋亡的启动者和执行者，因此发展NMDA受体拮抗剂已经成为了神经性疾病治疗药物的重要研究领域。
综上所述，本发明在大量的文献调研的基础上，设计并合成了一些列新型的5-氧代吡咯烷类衍生物，并进行了初步活性筛选，大部分化合物可以有效的拮抗NMDA诱导的细胞损伤，且都有剂量依赖性。
发明内容
本发明的目的在于衍生设计和合成一类新型取代5-氧代吡咯烷类衍生物，该类衍生物可以作为神经保护剂，用于制备抗脑缺血方面的药物。
本发明的另一目的在于提供一种制备取代5-氧代吡咯烷类衍生物的方法。
为了完成本发明之目的，可采用如下技术方案：
本发明提供了通式I所示的取代的5-氧代吡咯烷类化合物或药学上可接受的盐，及其光学异构体：
X为O或NH；
Y为O或NH；
n＝0～4，优选为n＝1；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10为下列基团中的任意一个基团：(1)H原子，(2)羟基，(3)卤原子，(4)氰基，(5)硝基，(6)卤代C1-C6烷基，(7)C1-6烷基、C3-8环烷基、C2-6链烯基、C2-6链炔基、C1-6烷磺酰氨基、C1-18烷氧羰基、C1-18烷氧磺酰基、C1-6烷氧基、C2-6链烯氧基、C2-6链炔氧基、C1-6烷硫基、C2-6链烯硫基、C2-6链炔硫基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基亚磺酰基、C2-6链烯基亚磺酰基、C2-6链炔基亚磺酰基、C3-8环烯基，上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代，(8)被各种取代的羰基，其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代，(9)被各种取代的氨基，其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基和C2-6链炔基羰基中的一种或多种取代基所取代。
其中吡咯环中含有一个手性中心。
本发明优选通式I所示的取代的5-氧代吡咯烷类化合物或药学上可接受的盐，及其光学异构体：
X为O；
Y为O；
n＝0～4；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10为下列基团中的任意一个基团：(1)H原子，(2)羟基，(3)卤原子，(4)氰基，(5)硝基，(6)卤代C1-C6烷基，(7)C1-6烷基、C3-8环烷基、C2-6链烯基、C2-6链炔基、C1-6烷磺酰氨基、C1-18烷氧羰基、C1-18烷氧磺酰基、C1-6烷氧基、C2-6链烯氧基、C2-6链炔氧基、C1-6烷硫基、C2-6链烯硫基、C2-6链炔硫基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基亚磺酰基、C2-6链烯基亚磺酰基、C2-6链炔基亚磺酰基、C3-8环烯基，上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代，(8)被各种取代的羰基，其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代，(9)被各种取代的氨基，其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基和C2-6链炔基羰基中的一种或多种取代基所取代。
其中吡咯环中含有一个手性中心。
本发明优选通式I所示的取代的5-氧代吡咯烷类化合物或药学上可接受的盐，及其光学异构体：
X为NH；
Y为NH；
n＝0～4；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10为下列基团中的任意一个基团：(1)H原子，(2)羟基，(3)卤原子，(4)氰基，(5)硝基，(6)卤代C1-C6烷基，(7)C1-6烷基、C3-8环烷基、C2-6链烯基、C2-6链炔基、C1-6烷磺酰氨基、C1-18烷氧羰基、C1-18烷氧磺酰基、C1-6烷氧基、C2-6链烯氧基、C2-6链炔氧基、C1-6烷硫基、C2-6链烯硫基、C2-6链炔硫基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基亚磺酰基、C2-6链烯基亚磺酰基、C2-6链炔基亚磺酰基、C3-8环烯基，上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代，(8)被各种取代的羰基，其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代，(9)被各种取代的氨基，其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基和C2-6链炔基羰基中的一种或多种取代基所取代。
其中吡咯环中含有一个手性中心。
本发明优选通式I所示的取代的5-氧代吡咯烷类化合物或药学上可接受的盐，及其光学异构体：
X为O；
Y为O；
n＝0～4；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10为下列基团中的任意一个基团：(1)H原子，(2)羟基，(3)卤原子，(4)氰基，(5)硝基，(6)三卤甲基，(7)C1-4烷基、C3-8环烷基、C1-4烷磺酰氨基、C1-4烷氧基、C1-6烷基亚磺酰基、C3-8环烯基，上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代，(8)被各种取代的羰基，其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代，(9)被各种取代的氨基，其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基和C2-6链炔基羰基中的一种或多种取代基所取代。
其中吡咯环中含有一个手性中心。
本发明优选通式I所示的取代的5-氧代吡咯烷类化合物或药学上可接受的盐，及其光学异构体：
X为NH；
Y为NH；
n＝0～4；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10为下列基团中的任意一个基团：(1)H原子，(2)羟基，(3)卤原子，(4)氰基，(5)硝基，(6)三卤甲基，(7)C1-4烷基、C3-8环烷基、C1-4烷磺酰氨基、C1-4烷氧基、C1-6烷基亚磺酰基、C3-8环烯基，上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代，(8)被各种取代的羰基，其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代，(9)被各种取代的氨基，其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基和C2-6链炔基羰基中的一种或多种取代基所取代。
其中吡咯环中含有一个手性中心。
本发明优选通式I所示的取代的5-氧代吡咯烷类化合物或药学上可接受的盐，及其光学异构体：
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10可以为下列基团中的任意一个基团：H原子、硝基、羟基、氟原子、甲氧基、甲基、氨基、磺酰氨基。
X为O，Y为O；
或者：
X为NH，Y为NH；
n＝0～4。
本发明优选如下的取代的5-氧代吡咯烷类化合物或药学上可接受的盐：
本发明还提供了所述的通式I所示的取代的5-氧代吡咯烷类化合物或药学上可接受的盐的制备方法：包括如下步骤：
利用取代的邻硝基苯甲醛和(R)或(S)型的谷氨酸在硼氢化钠的存在下进行还原胺化反应得到中间体A-1，中间体A-1在乙醇中回流，经环合反应得到中间体A-2，中间体A-2在酸催化下和醇反应，得到通式Ⅰ中的酯类化合物。如果将中间体A-2和乙醇进行反应，制备乙酯类中间体A-3，A-3和氨水反应制备酰胺类中间体A-4，中间体A-4经过脱水反应，得到腈类中间体A-5，中间体A-5经过pinner反应得到通式Ⅰ的脒类化合物。
具体实施方式：
联系如下实施例，将更好地理解本发明的化合物和它们的制备，这些实施例旨在阐述而不是限制本发明的范围。
实施例1，(S)-1-苄基-2-苄酯基-5-氧代吡咯烷(A1)
步骤A：(S)-(+)-2-苄胺基-戊二酸(A-1)的制备
室温下将L-谷氨酸(66.2g,450mmol)加入氢氧化钠(3M,300mL)水溶液中，搅拌下滴加苯甲醛(31.8g,300mmol)的乙醇溶液(400mL)，滴毕，室温下反应1h，冰盐浴冷却至0℃，将硼氢化钠(16.7g,450mmol)分批加入到反应液中，此过程控制温度不超过5℃，加毕，室温下反应3h。抽滤，浓缩滤液，以乙醚提取(100mL×3)，水层以浓盐酸调pH至3，抽滤得到白色粉末状固体46.2g，收率65％。
步骤B：(S)-(+)-1-(苄基)-5-氧代吡咯-2-羧酸(A-2)的制备
将(S)-(+)-2-(2-硝基-苄胺基)-戊二酸(A-1)(46.2g,195mmol)加入到乙醇(400mL)中，加热回流3小时。将反应后的悬浊液抽滤，滤液减压浓缩除去溶剂，得乳白色粉末状固体30.7g，收率72％。
(S)-1-苄基-2-苄酯基-5-氧代吡咯烷(A1)的制备。
将(S)-(+)-1-(苄基)-5-氧代吡咯-2-羧酸(A-2,10g,45.7mmol)和苯甲醇(9.9g,91.4mmol)，溶解于乙腈中，通入一定量盐酸气，室温搅拌5小时，蒸干溶剂，用碳酸钾调节PH值为7左右。之后进行柱层析分离。
得到白色固体7克，收率50％。ESI-MS：251.1[M+1]+；1H NMR(CD3OD，300MHz)δ:2.18～2.20(m,1H,2-Ha),2.47～2.53(m,1H,2-Hb),2.82～2.93(m,2H,3-H),4.14～4.18(1H,dd,J1＝9.1HZ,J2＝4.5HZ,1-H),4.63(1H,d,J＝15.1Hz,9-Ha),4.88(1H,d,J＝15.0Hz，9-Hb),6.87(1H,d,J＝8.5Hz,5-H),7.29～7.30(1H,d,J＝2.0Hz，8-H),7.35～7.38(1H,dd,J1＝8.4HZ,J2＝2.2HZ,6-H)
实施例2，(S)-1-苄基-2-(4-甲氧基-苄酯基)-5-氧代吡咯烷(A2)的制备
制备方法同上，收率43.1％。ESI-MS：340.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.32～7.26(5H,m),7.15～7.13(2H,m),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06Hz),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06Hz),3.76(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例3，(S)-1-苄基-2-(4-甲基-苄酯基)-5-氧代吡咯烷(A3)的制备
制备方法同上，收率45.3％。ESI-MS：324.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.32～7.26(5H),7.15～7.13(2H,m),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),2.13(3H,s),1.97～1.91(1H,m).
实施例4，(S)-1-苄基-2-(4-羟基-苄酯基)-5-氧代吡咯烷(A4)的制备
制备方法同上，收率40.1％。ESI-MS：326.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.88(1H,br),7.32～7.26(5H),7.15～7.12(2H,m),6.95～6.92(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例5，(S)-1-苄基-2-(4-氨基-苄酯基)-5-氧代吡咯烷(A5)的制备
制备方法同上，收率33.0％。ESI-MS：325.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.32～7.26(5H),7.15～7.13(2H,m),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.44(2H,br),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例6，(S)-1-苄基-2-(4-甲磺酰胺基-苄酯基)-5-氧代吡咯烷(A6)的制备
制备方法同上，收率41.1％。ESI-MS：403.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.32(1H,s),7.32～7.26(5H),7.15～7.13(2H,m),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.22(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例7，(S)-1-(4-氟-苄基)-2-苄酯基-5-氧代吡咯烷(A7)的制备
制备方法同上，收率43.3％。ESI-MS：328.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.32～7.26(4H),7.15～7.07(4H),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.794.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例8，(S)-1-(4-氟-苄基)-2-(4-甲氧基-苄酯基)-5-氧代吡咯烷(A8)的制备
制备方法同上，收率45.7％。ESI-MS：358.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.32～7.26(4H),7.15～7.07(4H),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.794.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.76(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例9，(S)-1-(4-氟-苄基)-2-(4-甲基-苄酯基)-5-氧代吡咯烷(A9)的制备
制备方法同上，收率42.9％。ESI-MS：342.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.32～7.26(4H),7.15～7.07(4H),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),2.13(3H,s),1.97～1.91(1H,m).
实施例10，(S)-1-(4-氟-苄基)-2-(4-羟基-苄酯基)-5-氧代吡咯烷(A10)的制备
制备方法同上，收率36.1％。ESI-MS：344.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.88(1H,br),7.32～7.26(4H),7.15～7.07(4H),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例11，(S)-1-(4-氟-苄基)-2-(4-氨基-苄酯基)-5-氧代吡咯烷(A11)的制备
制备方法同上，收率30.2％。ESI-MS：343.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.32～7.26(4H),7.15～7.07(4H),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.44(2H,br),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例12，(S)-1-(4-氟-苄基)-2-(4-4-甲磺酰胺基-苄酯基)-5-氧代吡咯烷(A12)的制备
制备方法同上，收率40.1％。ESI-MS：421.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.32(1H,s),7.32～7.26(4H),7.15～7.07(4H),6.95～6.93(2H,m),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.22(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例13，(S)-1-(4-硝基-苄基)-2-苄酯基-5-氧代吡咯烷(A13)的制备
制备方法同上，收率48.7％。ESI-MS：355.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:8.20-8.19(2H,d,J＝8.4Hz),7.56～7.55(2H,d,J＝8.4Hz),7.33～7.20(5H),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06Hz),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06Hz),3.76(3H,s),1.97～1.91(1H,m).
实施例14，(S)-1-(4-硝基-苄基)-2-(4-甲氧基-苄酯基)-5-氧代吡咯烷(A14)的制备
制备方法同上，收率45.2％。ESI-MS：385.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:8.20-8.19(2H,d,J＝8.4Hz),7.56～7.55(2H,d,J＝8.4Hz),7.13～7.09(4H),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06Hz),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06Hz),3.76(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例15，(S)-1-(4-硝基-苄基)-2-(4-甲基-苄酯基)-5-氧代吡咯烷(A15)的制备
制备方法同上，收率41.9％。ESI-MS：369.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:8.20-8.19(2H,d,J＝8.4Hz),7.56～7.55(2H,d,J＝8.4Hz),7.13～7.09(4H),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),2.13(3H,s),1.97～1.91(1H,m).
实施例16，(S)-1-(4-硝基-苄基)-2-(4-羟基-苄酯基)-5-氧代吡咯烷(A16)的制备
制备方法同上，收率38.1％。ESI-MS：371.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.88(1H,br),8.20-8.19(2H,d,J＝8.4Hz),7.56～7.55(2H,d,J＝8.4Hz),7.13～7.09(4H),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例17，(S)-1-(4-硝基-苄基)-2-(4-氨基-苄酯基)-5-氧代吡咯烷(A17)的制备
制备方法同上，收率34.3％。ESI-MS：370.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:8.20-8.19(2H,d,J＝8.4Hz),7.56～7.55(2H,d,J＝8.4Hz),7.13～7.09(4H),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.44(2H,br),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例18，(S)-1-(4-硝基-苄基)-2-(4-4-甲磺酰胺基-苄酯基)-5-氧代吡咯烷(A18)的制备
制备方法同上，收率45.1％。ESI-MS：448.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.32(1H,s),8.20-8.19(2H,d,J＝8.4Hz),7.56～7.55(2H,d,J＝8.4Hz),7.13～7.09(4H),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.22(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例19，(S)-1-(4-甲基-苄基)-2-苄酯基-5-氧代吡咯烷(A19)的制备
制备方法同上，收率43.8％。ESI-MS：324.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.35～7.31(5H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06Hz),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06Hz),3.76(3H,s),2.19(3H,s),1.97～1.91(1H,m).
实施例20，(S)-1-(4-甲基-苄基)-2-(4-甲氧基-苄酯基)-5-氧代吡咯烷(A20)的制备
制备方法同上，收率45.9％。ESI-MS：354.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06Hz),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06Hz),3.76(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例21，(S)-1-(4-甲基-苄基)-2-(4-甲基-苄酯基)-5-氧代吡咯烷(A21)的制备
制备方法同上，收率42.4％。ESI-MS：338.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),2.13(3H,s),2.19(3H,s),1.97～1.91(1H,m).
实施例22，(S)-1-(4-甲基-苄基)-2-(4-羟基-苄酯基)-5-氧代吡咯烷(A22)的制备
制备方法同上，收率36.1％。ESI-MS：340.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.88(1H,br),7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),7.13～7.09(4H),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),2.38～2.24(3H,m),2.19(3H,s),1.97～1.91(1H,m).
实施例23，(S)-1-(4-甲基-苄基)-2-(4-氨基-苄酯基)-5-氧代吡咯烷(A23)的制备
制备方法同上，收率31.2％。ESI-MS：339.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.44(2H,br),2.38～2.24(3H,m),2.19(3H,s),1.97～1.91(1H,m).
实施例24，(S)-1-(4-甲基-苄基)-2-(4-4-甲磺酰胺基-苄酯基)-5-氧代吡咯烷(A24)的制备
制备方法同上，收率40.3％。ESI-MS：417.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.32(1H,s),7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.22(3H,s),2.38～2.24(3H,m),2.19(3H,s),1.97～1.91(1H,m).
实施例25，(S)-1-(4-甲氧基-苄基)-2-苄酯基-5-氧代吡咯烷(A25)的制备
制备方法同上，收率43.3％。ESI-MS：340.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.35～7.31(5H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06Hz),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06Hz),3.81(3H,s),3.76(3H,s),1.97～1.91(1H,m).
实施例26，(S)-1-(4-甲氧基-苄基)-2-(4-甲氧基-苄酯基)-5-氧代吡咯烷(A26)的制备
制备方法同上，收率43.7％。ESI-MS：370.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06Hz),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06Hz),3.76(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例27，(S)-1-(4-甲氧基-苄基)-2-(4-甲基-苄酯基)-5-氧代吡咯烷(A27)的制备
制备方法同上，收率44.9％。ESI-MS：354.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.81(3H,s),2.38～2.24(3H,m),2.19(3H,s),1.97～1.91(1H,m).
实施例28，(S)-1-(4-甲氧基-苄基)-2-(4-羟基-苄酯基)-5-氧代吡咯烷(A28)的制备
制备方法同上，收率37.1％。ESI-MS：356.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.88(1H,br),7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),7.13～7.09(4H),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.81(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例29，(S)-1-(4-甲氧基-苄基)-2-(4-氨基-苄酯基)-5-氧代吡咯烷(A29)的制备
制备方法同上，收率30.5％。ESI-MS：355.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.81(3H,s),3.44(2H,br),2.38～2.24(3H,m),1.97～1.91(1H,m).
实施例30，(S)-1-(4-甲氧基-苄基)-2-(4-4-甲磺酰胺基-苄酯基)-5-氧代吡咯烷(A30)的制备
制备方法同上，收率41.5％。ESI-MS：433.1[M+1]+；1H NMR(400MHz,DMSO-d6)δ:9.32(1H,s),7.35～7.31(4H),7.12～7.11(2H,d,J＝8.4Hz),7.10～7.09(2H,d,J＝8.4Hz),5.04～4.99(4H,q,J＝11.88Hz),4.79～4.77(1H,d,J＝15.06),4.03～4.01(1H,m),3.95～3.92(1H,d,J＝15.06),3.81(3H,s),3.22(3H,s),2.38～2.24(3H,m),1.97～1.91(1H,m).
(S)-(+)-1-(苄基)-5-氧代吡咯-2-羧酸乙酯(A-3)制备
取(S)-(+)-1-(苄基)-5-氧代吡咯-2-羧酸(A-2)(30.7g，140mmol)
加入到300mL的乙醇中，于0℃下滴加30mL氯化亚砜，滴毕，室温搅拌6h。浓缩滤液，用5％的K2CO3水溶液调pH值为7～8，乙酸乙酯萃取，合并有机相，饱和食盐水洗三次，加入无水硫酸钠干燥过夜。次日，过滤，浓缩滤液，至冰箱中冷冻析出产品。抽滤，乙酸乙酯洗两次。得白色固体(21g，87mmol)，收率为62.7％
1-苄基-5-氧代吡咯烷-2-甲酰胺(A-4)的制备
将化合物(S)-(+)-1-(苄基)-5-氧代吡咯-2-羧酸乙酯(A-3)(21g，87mmol)，加入到100mL的氨水中，加热至60℃，剧烈搅拌，反应3h。反应结束后，抽滤，滤饼用蒸馏水洗3次，得到白色固体(10g，48mmol)，收率为55.7％。
苄基-5-氧代吡咯烷-2-甲腈(A-5)的制备
取1-苄基-5-氧代吡咯烷-2-甲酰胺(A-4)(10g，48mmol)，于250mL茄形瓶中，加入30ml DMF，加入10ml三乙胺。冰浴下滴加8ml三氟乙酸酐，滴毕，室温反应3小时结束后，将反应液倒到200ml水中，用乙酸乙酯萃取，用水洗一次，经硅胶柱层析分离，得到白色固体(7g，35mmol)收率73.4％。
实施例31(S)-N，1-二苄基-5-氧代吡咯烷-2-甲脒(A31)的制备。
将1-苄基-5-氧代吡咯烷-2-甲腈(A-5)(1g，5mmol)溶于无水乙醇中，冰浴下通入干燥的氯化氢气体30分钟，蒸干溶剂，再加入无水乙醇，滴加三乙胺调节PH至弱碱性，加入苄胺，常温反应5小时，蒸干反应液，进行柱层析得到A31(300mg，0.97mmol)收率19.4％。ESI-MS：308.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:10.11(1H,s),9.38～9.30(2H,m),7.45～7.41(2H,m),7.39～7.31(6H,m),7.20～7.18(2H,m),4.86～4.82(1H,d,J＝15.2Hz),4.48～4.47(2H,m),4.35～4.33(1H,m),3.87～3.83(1H,d,J＝15.2Hz),2.50～2.37(3H,m),1.98～1.91(1H,m)。
实施例32(S)-1-苄基-N-(4-甲氧基苄基)-5-氧代吡咯烷-2-甲脒(A32)
将1-苄基-5-氧代吡咯烷-2-甲腈(A-5)(1g，5mmol)溶于无水乙醇中，蒸干溶剂，再加入无水乙醇，滴加三乙胺调节PH至弱碱性，加入对甲氧基苄胺，常温反应5小时，蒸干反应液，进行柱层析得到得到固体(320mg，0.95mmol)收率19％。ESI-MS：338.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:10.05(1H,s),9.35～9.28(2H,m),7.38～7.25(5H,m),7.18～7.16(2H,m),6.99～6.97(2H,d,J＝8.8Hz),4.85～4.81(1H,d,J＝15.2Hz),4.39(2H,s),4.33～4.30(1H,m),3.85～3.81(1H,d,J＝15.2Hz),3,77(3H,s),2.48～2.35(3H,m),1.94～1.87(1H,m)。
实施例33(S)-1-苄基-N-(4-甲基苄基)-5-氧代吡咯烷-2-甲脒(A33)
制备方法同上,将1-苄基-5-氧代吡咯烷-2-甲腈(A-5)(1g，5mmol)溶于无水乙醇中，冰浴下通入干燥的氯化氢气体30分钟，蒸干溶剂，再加入无水乙醇，滴加三乙胺调节PH至弱碱性，加入对甲基苄胺，常温反应5小时，蒸干反应液，进行柱层析得到固体(370mg，1.15mmol)收率23％。。
ESI-MS：322.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.91-1.96(m,1H),δ:2.19(s,3H),δ:2.41-2.47(m,3H),δ:3.83-3.87(d,1H,J＝16Hz),δ:4.31-4.35(m,1H),δ:4.46-4.48(m,2H),δ:4.82-4.86(d,1H,J＝16Hz),δ:7.18-7.20(m,2H),δ:7.30-7.40(m,5H),δ:7.42-7.47(m,2H).
实施例34(S)-1-苄基-N-(4-羟基苄基)-5-氧代吡咯烷-2-甲脒(A34)
制备方法同上将1-苄基-5-氧代吡咯烷-2-甲腈(A-5)(1g，5mmol)溶于无水乙醇中，冰浴下通入干燥的氯化氢气体30分钟，蒸干溶剂，再加入无水乙醇，滴加三乙胺调节PH至弱碱性，加入对羟基苄胺，常温反应5小时，蒸干反应液，进行柱层析得到固体(270mg，0.84mmol)收率16.7％。ESI-MS：324.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:9.61～9.39(4H,br),7.37～7.30(3H,m),7.18～7.14(4H,m),6.81～6.79(2H,d,J＝8.4Hz),4.84～4.81(1H,d,J＝15.2Hz),4.31～4.26(3H,m),3.83～3.79(1H,d,J＝15.2Hz),2.47～2.34(3H,m),1.95～1.87(1H,m).
实施例35(S)-N-(4-氨基苄基)-1-苄基-5-氧代吡咯烷-2-甲脒(A35)
制备方法同上将1-苄基-5-氧代吡咯烷-2-甲腈(A-5)(1g，5mmol)溶于无水乙醇中，冰浴下通入干燥的氯化氢气体30分钟，蒸干溶剂，再加入无水乙醇，滴加三乙胺调节PH至弱碱性，加入4-氨基苄胺，常温反应5小时，蒸干反应液，进行柱层析得到固体(400m g，1.24mmol)收率24.8％。ESI-MS：323.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.91-1.95(m,1H),δ:2.40-2.47(m,3H),δ:3.83-3.87(d,1H,J＝16Hz),δ:4.31-4.35(m,1H),δ:4.47-4.48(m,2H),δ:4.83-4.87(d,1H,J＝16Hz),δ:4.95(s,2H),δ:7.18-7.20(m,2H),δ:7.31-7.40(m,5H),δ:7.41-7.47(m,2H).
实施例36(S)-1-苄基-N-(4-(甲基磺酰氨基)苄基)-5-氧代吡咯烷-2-甲脒(A36)
制备方法同上将1-苄基-5-氧代吡咯烷-2-甲腈(A-5)(1g，5mmol)溶于无水乙醇中，冰浴下通入干燥的氯化氢气体30分钟，蒸干溶剂，再加入无水乙醇，滴加三乙胺调节PH至弱碱性，加入N-(4-(氨基甲基)苯基)甲磺酰胺，常温反应5小时，蒸干反应液，进行柱层析得到固体(480m g，1.2mmol)收率24％。
ESI-MS：401.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.91-1.96(m,1H),δ:2.41-2.47(m,3H),δ:3.18-3.23(m,3H),δ:3.83-3.87(d,1H,J＝16Hz),δ:4.30-4.33(m,1H),δ:4.45-4.48(m,2H),δ:4.82-4.86(d,1H,J＝16Hz),δ:7.19-7.20(m,2H),δ:7.29-7.40(m,5H),δ:7.41-7.47(m,2H).
实施例37(S)-N-苄基-1-(4-氟苄基)-5-氧代吡咯烷-2-甲脒(A37)
制备方法同上得到固体(450m g，1.38mmol)收率27.7％。
ESI-MS：326.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:10.00(1H,s),9.63(1H,s),9.28(2H,s),7.24～7.14(6H,m),6.81～6.79(2H,d,J＝8.8Hz),4.77～4.73(1,d,J＝11.2Hz),4.32～4.29(3H,m),3.87～3.84(1H,d,J＝11.2Hz),2.46～2.32(3H,m),1.93～1.88(1H,m)
实施例38(S)-1-(4-氟苄基)-N-(4-甲氧基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(420m g，1.18mmol)收率23.7％。ESI-MS：356.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:10.17(1H,s),9.42～9.37(2H,m),7.32～7.30(2H,d,J＝8.4Hz),7.23～7.14(4H,m),6.98～6.96(2H,d,J＝8.8Hz),4.76～4.72(1H,d,J＝14.8Hz),4.42～437(3H,m),3.88～3.84(1H,d,J＝15.2Hz),3.76(3H,s),2.47～2.33(3H,m),1.95～1.86(1H,m)
实施例39(S)-1-(4-氟苄基)-N-(4-甲基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(420m g，1.24mmol)收率24.8％。
ESI-MS：340.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.91-1.93(m,1H),2.19(s,3H),2.39-2.45(m,3H),3.87-3.90(d,1H,J＝12Hz),4.34-4.37(m,1H),4.47-4.49(m,2H),4.72-4.78(m,1H),7.12-7.19(m,2H),7.21-7.25(m,2H),7.34-7.36(m,2H),7.41-7.44(m,1H),9.34-9.40(d,2H,J＝24Hz),10.17(s,1H).
实施例40(S)-1-(4-氟苄基)-N-(4-羟基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(470m g，1.38mmol)收率27.6％。ESI-MS：342.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:10.00(1H,s),9.63(1H,s),9.28(2H,s),7.24～7.14(6H,m),6.81～6.79(2H,d,J＝8.8Hz),4.77～4.73(1,d,J＝11.2Hz),4.32～4.29(3H,m),3.87～3.84(1H,d,J＝11.2Hz),2.46～2.32(3H,m),1.93～1.88(1H,m)
实施例41(S)-N-(4-氨基苄基)-1-(4-氟苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(410m g，1.21mmol)收率24％。
ESI-MS：341.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.91-1.93(m,1H),2.39-2.45(m,3H),3.87-3.90(d,1H,J＝12Hz),4.34-4.37(m,1H),4.47-4.49(m,2H),4.74-4.78(m,1H),4.92(s,2H),7.14-7.19(m,2H),7.21-7.26(m,2H),7.34-7.36(m,2H),7.41-7.44(m,1H),9.34-9.40(d,2H,J＝24Hz),10.17(s,1H).
实施例42(S)-1-(4-氟苄基)-N-(4-(甲基磺酰氨基)苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(540m g，1.3mmol)收率25.8％。
ESI-MS：419.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.91-1.93(m,1H),2.39-2.45(m,3H),3.17-3.22(m,3H),3.88-3.91(d,1H,J＝12Hz),4.30-4.37(m,1H),4.47-4.49(m,2H),4.74-4.78(m,1H),7.14-7.19(m,2H),7.21-7.25(m,2H),7.34-7.36(m,2H),7.41-7.44(m,1H),9.34-9.40(d,2H,J＝24Hz),10.17(s,1H).
实施例43(S)-N-苄基-1-(4-硝基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(540m g，1.53mmol)收率30.7％。
ESI-MS：353.2[M+1]+；1H-NMR(DMSO-d6,600MHz)δ:9.47(2H,br),8.21～8.19(2H,d,J＝9.0Hz),7.51～7.49(2H,d,J＝8.4Hz),7.42～7.40(2H,m),7.36～7.33(3H,m),4.86～4.84(1H,d,J＝16.2Hz),4.45～4.42(3H,m),4.16～4.13(1H,d,J＝15.6Hz),2.53～2.43(3H,m),2.03～1.95(1H,m)
实施例44(S)-N-(4-甲氧基苄基)-1-(4-硝基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(520m g，1.36mmol)收率27.2％。ESI-MS：383.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:10.63(2H,s),10.28(1H,s),8.19～8.17(2H,d,J＝8.4Hz),7.49～7.47(2H,d,J＝8.4Hz),7.31～7.29(2H,d,J＝8.8Hz),6.96～6.94(2H,d,J＝8.8Hz),4.83～4.79(1H,d,J＝16.0Hz),4.52～4.48(1H,m),4.44～4.40(2H,m),4.15～4.11(1H,d,J＝16.0Hz),3.76(3H,s),2.54～2.42(3H,m),1.99～1.92(1H,m)
实施例45(S)-N-(4-甲基苄基)-1-(4-硝基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(470m g，1.28mmol)收率25.7％。
ESI-MS：367.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.97-2.01(m,1H),δ:2.18(s,3H),δ:2.47-2.51(m,3H),δ:4.13-4.16(d,1H,J＝12Hz),δ:4.42-4.45(t,3H),δ:4.85-4.86(d,1H,J＝8Hz),δ:7.33-7.37(t,2H),δ:7.40-7.42(m,2H),δ:7.50-7.51(d,2H,J＝4Hz),δ:8.19-8.21(d,2H,J＝8Hz).
实施例46(S)-N-(4-羟基苄基)-1-(4-硝基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(480m g，1.31mmol)收率26.1％。
ESI-MS：369.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:8.20～8.18(2H,d,J＝8.8Hz),7.48～7.46(2H,d,J＝8.8Hz),7.11～7.09(2H,d,J＝8.4Hz),6.75～6.73(2H,d,J＝8.4Hz),4.86～4.82(1H,d,J＝15.6Hz),4.16(3H,s),4.08～4.06(1H,d,J＝15.6Hz),2.46～2.31(3H,m),1.99～1.89(1H,m)
实施例47(S)-N-(4-氨基苄基)-1-(4-硝基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(440m g，1.2mmol)收率24％。
ESI-MS：368.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.97-2.01(m,1H),δ:2.44-2.51(m,3H),δ:4.13-4.16(d,1H,J＝12Hz),δ:4.42-4.45(t,3H),δ:4.93(s,2H),δ:4.85-4.87(d,1H,J＝8Hz),δ:7.33-7.37(m,2H),δ:7.40-7.42(t,2H),δ:7.50-7.51(d,2H,J＝4Hz),δ:8.19-8.21(d,2H,J＝8Hz).
实施例48(S)-N-(4-(甲基磺酰氨基)苄基)-1-(4-硝基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(520m g，1.17mmol)收率23.3％。
ESI-MS：446.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.97-2.01(m,1H),δ:2.44-2.51(m,3H),δ:3.17-3.22(m,3H),δ:4.15-4.18(d,1H,J＝12Hz),δ:4.42-4.45(t,3H),δ:4.84-4.86(d,1H,J＝8Hz),δ:7.33-7.36(m,2H),δ:7.40-7.42(t,2H),δ:7.50-7.51(d,2H,J＝4Hz),δ:8.19-8.21(d,2H,J＝8Hz).
实施例49(S)-N-苄基-1-(4-甲基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(410m g，1.28mmol)收率25.5％。ESI-MS：322.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:10.24(1H,s),9.46(2H,s),7.44～7.36(5H,m),7.16～7.14(2H,d,J＝8.0Hz),7.06～7.05(2H,d,J＝7.6Hz),4.82～4.78(1H,d,J＝14.8Hz),4.53(2H,s),4.38～4.36(1H,m),3.78～3.75(1H,d,J＝15.2Hz),2.48～2.37(3H,m),2.29(3H,s),1.98～1.88(1H,m)
实施例50(S)-N-(4-甲氧基苄基)-1-(4-甲基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(430m g，1.23mmol)收率24.5％。ESI-MS：352.2[M+1]+；7.26～7.24(2H,d,J＝8.8Hz),7.15～7.13(2H,d,J＝7.6Hz),7.06～7.04(2H,d,J＝8.0Hz),6.94～6.92(2H,d,J＝8.8Hz),4.83～4.79(1H,d,J＝14.8Hz),4.07～4.03(1H,m),3.75～3.70(4H,m),2.46～2.21(6H,m),1.90～1.83(1H,m)
实施例51(S)-N，1-双(4-甲基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(430m g，1.28mmol)收率25.7％。
ESI-MS：336.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.88-1.96(m,1H),δ:2.15(s,3H),δ:2.29(s,3H),δ:2.38-2.48(m,3H),δ:3.74-3.78(d,1H,J＝16Hz),δ:4.36-4.38(m,1H),δ:4.53(s,2H),δ:4.78-4.82(d,1H,J＝16Hz),δ:7.04-7.06(d,2H,J＝8Hz),δ:7.14-7.16(d,2H,J＝8Hz),δ:7.36-7.38(m,2H),δ:7.41-7.44(m,2H).
实施例52(S)-N-(4-羟基苄基)-1-(4-甲基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(440m g，1.31mmol)收率26.3％。ESI-MS：338.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:9.99(1H,s),9.63(1H,s),9.31～9.26(2H,m),7.17～7.14(4H,m),7.06～7.04(2H,d,J＝8.0Hz),6.82～6.80(2H,d,J＝8.4Hz),4.81～4.77(1H,d,J＝15.2Hz),4.34～4.26(3H,m),3.76～3.72(1H,d,J＝15.2Hz),2.46～2.34(3H,m),2.29(3H,s),1.94～1.85(1H,m)
实施例53(S)-N-(4-氨基苄基)-1-(4-甲基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(410m g，1.22mmol)收率24.3％。
ESI-MS：337.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.88-1.96(m,1H),δ:2.29(s,3H),δ:2.38-2.48(m,3H),δ:3.74-3.78(d,1H,J＝16Hz),δ:4.36-4.38(m,1H),δ:4.53(s,2H),δ:4.78-4.82(d,1H,J＝16Hz),δ:4.95(s,2H),δ:7.03-7.05(d,2H,J＝8Hz),δ:7.14-7.16(d,2H,J＝8Hz),δ:7.36-7.38(m,2H),δ:7.41-7.44(m,2H).
实施例54(S)-1-(4-甲基苄基)-N-(4-(甲基磺酰氨基)苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(490m g，1.18mmol)收率23.6％。
ESI-MS：415.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.88-1.96(m,1H),δ:2.29(s,3H),δ:2.38-2.48(m,3H),δ:3.18-3.22(m,3H),δ:3.74-3.78(d,1H,J＝16Hz),δ:4.36-4.38(m,1H),δ:4.53(s,2H),δ:4.78-4.82(d,1H,J＝16Hz),δ:7.04-7.06(d,2H,J＝8Hz),δ:7.14-7.16(d,2H,J＝8Hz),δ:7.36-7.38(m,2H),δ:7.41-7.44(m,2H).
实施例55(S)-N-苄基-1-(4-甲氧基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(450m g，1.36mmol)收率26.7％。ESI-MS：338.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:9.51(3H,br),7.43～7.41(2H,m),7.36～7.35(3H,m),7.10～7.09(2H,d,J＝5.6Hz),6.89～6.88(2H,d,J＝5.6Hz),4.77～4.75(1H,d,J＝10.0Hz),4.51～4.46(2H,m),4.31～4.29(1H,m),3.77～3.74(4H,m),2.48～2.33(3H,m),1.93～1.88(1H,m)
实施例56(S)-N，1-双(4-甲氧基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(490m g，1.34mmol)收率26.7％。ESI-MS：368.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:10.06(1H,s),9.35～9.31(2H,m),7.32～7.30(2H,d,J＝8.4Hz),7.10～7.08(2H,d,J＝8.4Hz),6.99～6.97(2H,d,J＝8.4Hz),6.90～6.88(2H,d,J＝8.4Hz),4.77～4.73(1H,d,J＝14.8Hz),4.42～4.40(2H,m),4.31～4.28(1H,m),3.77～3.74(7H,m),2.46～2.33(3H,m),1.92～1.85(1H,m)
实施例57(S)-1-(4-甲氧基苄基)-N-(4-甲基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(410m g，1.17mmol)收率23.4％。
ESI-MS：352.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.84-1.93(m,1H),δ:2.20(s,3H),δ:2.31-2.45(m,3H),δ:3.72-3.76(t,4H),δ:4.23-4.25(s,1H),δ:4.32(s,2H),δ:4.74-4.77(d,1H,J＝12Hz),δ:6.79-6.81(d,2H,J＝8Hz),δ:6.88-6.90(d,2H,J＝8Hz),δ:7.08-7.10(d,2H,J＝8Hz),δ:7.15-7.17(d,2H,J＝8Hz).
实施例58(S)-N-(4-羟基苄基)-1-(4-甲氧基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(370m g，1.05mmol)收率21％。ESI-MS：354.2[M+1]+；1H-NMR(DMSO-d6,400MHz)δ:9.61～9.28(4H,m),7.17～7.15(2H,d,J＝8.4Hz),7.10～7.08(2H,d,J＝8.4Hz),6.90～6.88(2H,d,J＝8.8Hz),6.81～6.79(2H,d,J＝8.4Hz),4.77～4.74(1H,d,J＝15.2Hz),4.32(2H,s),4.25～4.23(1H,m),3.76～3.72(4H,m),2.45～2.29(3H,m),1.91～1.84(1H,m)
实施例59(S)-N-(4-氨基苄基)-1-(4-甲氧基苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(440m g，1.25mmol)收率25％。
ESI-MS：353.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.84-1.93(m,1H),δ:2.31-2.45(m,3H),δ:3.72-3.76(t,4H),δ:4.23-4.25(s,1H),δ:4.33(s,2H),δ:4.74-4.77(d,1H,J＝12Hz),δ:4.93(s,2H),δ:6.80-6.82(d,2H,J＝8Hz),δ:6.88-6.90(d,2H,J＝8Hz),δ:7.08-7.10(d,2H,J＝8Hz),δ:7.15-7.17(d,2H,J＝8Hz).
实施例60(S)-1-(4-甲氧基苄基)-N-(4-(甲基磺酰氨基)苄基)-5-氧代吡咯烷-2-甲脒
制备方法同上得到固体(510m g，1.19mmol)收率23.7％。
ESI-MS：431.2[M+1]+；1H NMR(400MHz,DMSO-d6)δ:1.84-1.93(m,1H),δ:2.31-2.45(m,3H),δ:3.19-3.22(m,3H),δ:3.72-3.76(t,4H),δ:4.23-4.25(s,1H),δ:4.32(s,2H),δ:4.74-4.77(d,1H,J＝12Hz),δ:6.79-6.81(d,2H,J＝8Hz),δ:6.88-6.90(d,2H,J＝8Hz),δ:7.08-7.10(d,2H,J＝8Hz),δ:7.15-7.17(d,2H,J＝8Hz).
药理活性测试
抗NMDA-NR2B活化引发的兴奋性毒性活性化合物筛选
模型细胞1：SH-SY5Y
培养条件1：DMEM(Hyclone)+10％胎牛血清(Clark)，37℃，5％CO2培养，基于NMDA-NR2B激活后会造成的细胞毒性(兴奋性毒性)
试验药物：浓度：常规筛选100μM；
用量：200μL/孔，常规每板设三复孔，进行至少三次试验，通常进行五次
试验方法：MTT法
实验流程：1、消化细胞，铺于96孔板中，每孔约4000-5000个细胞，培养约12h；
2、向培养液中加入适当浓度的无菌药物，作用24h；
3、完全吸出孔中的培养液；
4、向每孔加入无镁缓冲液缓冲液(ECS/Lock’s)配制的NMDA，2mM，30min进行造模；
5、完全吸出造模液，每孔加入完全培养液及MTT，作用4-6h；
6、进行检测
实验结果(1)
实验结果(2)：
低浓度，中浓度，高浓度分别为0.05、0.5、5微摩尔/升
神经保护率(％)＝[OD值(加药组)－OD值(NMDA组)]/[OD值(空白组)－OD值(NMDA组)]×100％。
Claims (9)
1.通式I的取代的5-氧代吡咯烷类衍生物或药学上可接受的盐，及其光学异构体：
其中：
X为O或NH；
Y为O或NH；
n＝0～4，优选为n＝1；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10为下列基团中的任意一个基团：(1)H原子，(2)羟基，(3)卤原子，(4)氰基，(5)硝基，(6)卤代C1-C6烷基，(7)C1-6烷基、C3-8环烷基、C2-6链烯基、C2-6链炔基、C1-6烷磺酰氨基、C1-18烷氧羰基、C1-18烷氧磺酰基、C1-6烷氧基、C2-6链烯氧基、C2-6链炔氧基、C1-6烷硫基、C2-6链烯硫基、C2-6链炔硫基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基亚磺酰基、C2-6链烯基亚磺酰基、C2-6链炔基亚磺酰基、C3-8环烯基，上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代，(8)被各种取代的羰基，其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代，(9)被各种取代的氨基，其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基和C2-6链炔基羰基中的一种或多种取代基所取代；
其中吡咯环中含有一个手性中心。
2.权利要求1所述的衍生物，药学上可接受的盐，及其光学异构体：
X、Y同时为O或同时为NH。
3.权利要求1或2所述的衍生物，药学上可接受的盐，及其光学异构体：其中：
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10为下列基团中的任意一个基团：(1)H原子，(2)羟基，(3)卤原子，(4)氰基，(5)硝基，(6)三卤甲基，(7)C1-4烷基、C3-8环烷基、C1-4烷磺酰氨基、C1-4烷氧基、C1-6烷基亚磺酰基、C3-8环烯基，上述各基团任意被选自H原子、卤原子、羟基、氰基、硝基和氨基中的一种或多种取代基所取代，(8)被各种取代的羰基，其任意被选自H原子、羟基、C1-6烷基、氨基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基和C3-8环烷基中的一种或多种取代基所取代，(9)被各种取代的氨基，其任意被选自H原子、C1-6烷基、C2-6链烯基、C2-6链炔基、C1-6烷基磺酰基、C2-6链烯基磺酰基、C2-6链炔基磺酰基、C1-6烷基羰基、C2-6链烯基羰基和C2-6链炔基羰基中的一种或多种取代基所取代。
4.权利要求1-3任何一项所述的衍生物，药学上可接受的盐，及其光学异构体：其中，
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10可以为下列基团中的任意一个基团：H原子、硝基、羟基、氟原子、甲氧基、甲基、氨基、磺酰氨基。
5.如下的衍生物，药学上可接受的盐，及其光学异构体：
6.一种药物组合物，包含权利要求1-5任何一项所述的衍生物，药学上可接受的盐，及其光学异构体和药学上可接受的载体或赋形剂。
7.如权利要求1所述的衍生物，药学上可接受的盐，及其光学异构体的制备方法，其特征在于，
利用取代的邻硝基苯甲醛和(R)或(S)型的谷氨酸在硼氢化钠的存在下进行还原胺化反应得到中间体A-1，中间体A-1在乙醇中回流，经环合反应得到中间体A-2，中间体A-2在酸催化下和醇反应，得到通式Ⅰ中的酯类化合物；将中间体A-2和乙醇进行反应，制备乙酯类中间体A-3，A-3和氨水反应制备酰胺类中间体A-4，中间体A-4经过脱水反应，得到腈类中间体A-5，中间体A-5经过pinner反应得到通式Ⅰ的脒类化合物；
8.权利要求1-5中任何一项所述的衍生物，药学上可接受的盐，及其光学异构体或权利要求6所述的组合物在制备神经保护药物中的应用。
9.权利要求1-5中任何一项所述的衍生物，药学上可接受的盐，及其光学异构体或权利要求6所述的组合物在制备抗脑缺血药物中的应用。
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| CN109180552B (zh) | 2021-10-26 |
| WO2020063388A1 (zh) | 2020-04-02 |
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