CN106831694B - 京尼平衍生物及在制备防治神经退行性疾病药物中的应用 - Google Patents
京尼平衍生物及在制备防治神经退行性疾病药物中的应用 Download PDFInfo
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- CN106831694B CN106831694B CN201710035833.5A CN201710035833A CN106831694B CN 106831694 B CN106831694 B CN 106831694B CN 201710035833 A CN201710035833 A CN 201710035833A CN 106831694 B CN106831694 B CN 106831694B
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- C—CHEMISTRY; METALLURGY
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- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种京尼平衍生物的医药新用途，具体为在制备防治神经退行性疾病药物中的应用。如结构式（I）所示，本发明所述的京尼平衍生物通过H2O2诱导PC12细胞氧化损伤模型及PD动物模型试验证实其具有显著的神经保护作用，在制备预防和治疗神经退行性疾病相关药物中具有重要应用前景。
Description
技术领域
本发明属于医药领域，具体是一类京尼平衍生物及其在制备防治神经退行性疾病药物中的应用。
背景技术
随着人口老龄化的加剧，神经退行性疾病已经成为中老年人群中发病率最高的疾病，不仅给患者自身带来巨大的病痛，也给家庭和社会造成了严重的经济和精神负担。神经退行性疾病是大脑和脊髓的细胞神经元丧失的疾病状态，其代表性疾病包括阿尔茨海默病、帕金森综合征、多发性硬化症等，迄今为止其发病机制尚未阐明。目前应用于神经退行性疾病预防和治疗的临床药物种类很多，包括拟多巴胺类药物、中枢胆碱受体阻断药等，但在临床应用中仅能缓解症状，治疗效果有限并且副作用较多。因此，开发治疗神经退行性疾病的新型药物具有十分重大的意义。
以天然活性成分作为先导化合物开发研究新药是目前寻找新药的重要途径。京尼平属于环烯醚萜类化合物，是中药栀子苷(京尼平苷)经β-葡萄糖苷酶水解后的产物。早在传统的中药报道中，中草药栀子就具有益智开窍、缓解老年痴呆功效；随后的研究发现，京尼平还具有促进海马神经元细胞中的神经突生长，并在内质网应激相关的阿尔茨海默氏病和帕金森氏症等神经退行性疾病发挥作用。京尼平具有保肝利胆、抗炎、抗肿瘤、抗血栓、治疗糖尿病等广泛的药理效应，尤其在神经保护方面具有显著的药理作用。然而由于京尼平母体结构中C-3位、C-10位羟基与半缩醛的影响，导致其在生理溶液中稳定性较差、脂溶性低、血脑屏障通透性及生物利用度较差，限制了其药理作用的发挥。因此，本发明研究和开发一种稳定性好、脂溶性高且具有神经保护活性的京尼平衍生物，为制备防治神经退行性疾病提供了一种新的药物来源。
发明内容
本发明的目的是提供一类具有神经保护作用的化合物。具体地说，本发明提供了一类具有神经保护作用的京尼平衍生物。
本发明是通过以下技术方案实现的：一种式(Ⅰ)的化合物、其药学上可接受的盐，
其中，R1选自1-6个碳的烷基、1-20个碳的芳香基、1-6个碳的杂环、2-6个碳原子的链烷酰氨基、1-6个碳原子的链烷磺酰基或者1-6个碳原子的链烷磺酰氨基；
R2、R3、R4、R5和R6选自氢、羟基、卤素、氰基、氨基、酰胺基、三氟甲基、五氟乙基、1-6个碳原子的烷基、1-6个碳原子的烷氧基、或者2-6个碳原子烷酰氧基；
R2、R3、R4、R5和R6中的一种或任意几种取代基的基团可以与苯环稠和形成取代或未取代的稠环化合物；R2、R3、R4、R5和R6中的任一取代基的基团也可以不与苯环稠和形成取代或未取代的稠环化合物；
当R1、R2、R3、R4、R5或R6为1-6个碳的烷基时，烷基上可以没有取代基，也可以有部分取代；
上述结构中3,4,5位的立体构型分别为R构型或S构型(即3,4,5位的立体构型中至少有一位为R构型，其余为S构型；或者全部为R构型；或者全部为S构型)。
术语“杂环”包括饱和的含有杂原子的环基和杂芳基，指单环，双环，或三环体系，其中环上一个或多个原子可以独立任选地被杂原子所取代，环可以是完全饱和的或包含一个或多个不饱和度，包括芳香族类。一个或多个环上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，“杂环”基团是3-7元环的单环(1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团，当所述的环为三元环时，其中只有一个杂原子)，或7-10元的双环(4-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团)。
本发明中所使用的术语“烷氧基”，涉及到烷基，像本发明所定义的，通过氧原子连接到主要的碳链上。这样的实例包括，但并不限于，甲氧基，乙氧基，丙氧基，异丙氧基，叔丁氧基等。
术语“烷基酰基”包括烷基取代的羰基基团，其中烷基和酰基基团具有如本发明所述的含义。这样的实例包括，但并不限于，甲酰基，乙酰基，丙酰基，丁酰基，叔丁酰基等。
术语“烷氧酰基”包括烷氧基取代的酰基，其中烷氧基和酰基基团具有如本发明所述的含义。这样的实例包括，但并不限于，甲氧基酰基，乙氧基酰基，丙氧基酰基，丁氧基酰基，叔丁氧基酰基等。
进一步，本发明提供了一种化合物，选自下列化合物：
3-异丙氧基-7-(苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2-甲基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(4-甲基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(4-甲氧基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2-氯苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(3-氯苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(4-氯苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2-溴苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(3-溴苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2-硝基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(3-硝基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(4-硝基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2-碘苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2,4-二甲氧基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(3,4-二甲氧基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2,5-二氯苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2,6-二氯苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(3,4-二氯苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2-氟-4-甲氧基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2-氟-6-甲氧基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(4-氯-2-甲氧基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(3,4,5-三甲氧基苯甲酰氧基)甲基京尼平；3-异丙氧基-7-(2,4,5-三氟-3-甲氧基苯甲酰氧基)甲基京尼平；3-乙氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-丙氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-正丁氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-异丁氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-叔丁氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-叔丁氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-正戊氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-苯乙氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平；3-苯丙氧基-7-(3,5-二硝基苯甲酰氧基)甲基京尼平。各化合物的结构式如下表所示：
本发明的另一个目的在于提供上述任一的化合物、其药学上可接受的盐在制备防治(预防或/和治疗)神经退行性疾病药物中的应用。所述神经退行性疾病是帕金森病、阿尔茨海默病、多发性硬化症、亨廷顿氏病、肌肉萎缩性侧索硬化症、共济失调毛细血管扩张症的一种疾病或多种疾病。
本发明还提供了一种药物组合物，包含①，以及②、③、④中的至少一种物质；
所述①为上述任一的化合物、其药学上可接受的盐；
所述②为药学上可接受的载体；
所述③为佐剂；
所述④为媒介物。
上述药物组合物是以京尼平衍生物为活性成分，并且该药物还可与一种或多种在药学上可接受的药用辅料成分(载体、佐剂或媒介物等)配制使用，该药物可以按照医药领域的常规方法制成注射剂、片剂、胶囊剂丸剂、散剂、颗粒剂、糖浆剂或溶液剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂、霜剂、喷雾剂、气雾剂、贴剂、凝胶剂或巴布剂等剂型药物(口服制剂、注射剂或局部给药制剂形式)，以期更快更好地发挥临床药效。该药物组合物具体可用于预防和治疗神经退行性疾病如帕金森病、阿尔茨海默病、多发性硬化症、亨廷顿氏病、肌肉萎缩性侧索硬化症、共济失调毛细血管扩张症的一种或多种，或作为研究这些疾病的工具药。
如本发明所述，术语“药学上可接受的载体”包括任何溶剂、分散介质、包衣衣料、表面活性剂、抗氧化剂、防腐剂(例如抗细菌剂、抗真菌剂)、等渗剂、盐、药物稳定剂、粘合剂、赋形剂、分散剂、润滑剂、甜味剂、调味剂、着色剂、或前述任意几种物质的组合物，这些载体都是所属技术领域技术人员的已知的。除了任意常规载体与活性成分不相容的情况外，涵盖其在治疗或药物组合物中的用途。
具体使用时，所述药物组合物通过口服、舌下、经皮、肌肉、皮下、皮肤黏膜、尿道、阴道、静脉途径给药。
本发明中的京尼平衍生物具有稳定性好、脂溶性高等特点，同时与京尼平比较稳定性和脂溶性都有显著提高；通过H2O2诱导PC12细胞氧化损伤模型对京尼平衍生物进行神经细胞保护活性研究，根据细胞活力测定、线粒体膜电位(MMP)、细胞内活性氧(ROS)水平、细胞凋亡等检测结果表明本发明中的京尼平衍生物对H2O2诱导的神经细胞损伤具有保护活性；通过PD动物模型研究表明本发明中的京尼平衍生物能够有效的改善小鼠的运动能力与协调能力。综述所述，本发明中的京尼平衍生物在神经保护活性有显著的药理作用，为制备防治神经退行性疾病提供了一种新的药物来源。
与现有技术相比，本发明具有以下优点：
(1)本发明中的京尼平衍生物解决了现有京尼平稳定性差、脂溶性低的问题，血脑屏障透过性显著提高，改善了药物生物利用度和血药浓度，成药性提高。
(2)本发明中的京尼平衍生物在细胞模型中表现出显著的神经细胞保护活性，可增强细胞活力，升高细胞内线粒体膜电位(MMP)，降低细胞内活性氧(ROS)水平及抑制细胞凋亡；在PD动物模型中能够有效的改善小鼠的运动能力与协调能力。
附图说明
图1是本发明的化合物G1与京尼平的稳定性对比图。
图2是本发明的化合物G2对过氧化氢诱导的PC12神经细胞损伤中细胞活力的影响。
图3是本发明的化合物G3对过氧化氢诱导的PC12神经细胞损伤中细胞内活性氧含量的影响。
图4是本发明的化合物G4对过氧化氢诱导的PC12神经细胞损伤中细胞内线粒体膜电位的影响。
图5是本发明的化合物G5对过氧化氢诱导的PC12神经细胞损伤在PI/AnnexinⅤ-FITC双染下细胞凋亡的影响。
图6和图7分别是本发明的化合物G6对小鼠游泳行为及Rotarod行为实验结果的对比图。
具体实施方式
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
所属领域的专业技术人员也应认识到：本发明实例里所证明的个别化合物的特点(实施例32-38试验数据及结果)，其他本发明那些非例证的化合物也同样具备，同样在神经保护活性方面有显著的药理作用。化合物、药学上可接受的盐(包含例证以及非例证的化合物)只是对实施例中化合物作变化或替换，不会对它们在药物组合物中的效果明显有不利的影响。
实施例中所述实验方法，如无特殊说明；所述试剂和生物材料，如无特殊说明，均可从商业途径获得。
实施例1：化合物G1的制备。京尼平化合物在三氟化硼乙醚催化下与异丙醇反应，生成异丙氧基京尼平。将得到的异丙氧基京尼平(0.5mmol)溶于10ml无水二氯甲烷中，加入等物质的量的苯甲酸，溶解后加入5mg 4-二甲氨基吡啶(DMAP)，920mg二环己基碳二亚胺(DCC)，室温下搅拌，TLC监测。反应结束后，过滤，硅胶柱层析分离(石油醚-乙酸乙酯洗脱)，减压除去溶剂，得到化合物G1。Molecular formula(MW):C21H24O6(372.41g/mol)；whiteoil；63.0％Yield；1H NMR(600MHz,CDCl3)δ1.22(3H,d,J＝6.14Hz),1.29(3H,d,J＝6.21Hz),2.10(1H,m),2.66(1H,t,J＝8.25Hz),2.92(1H,dd,J＝16.57,8.56Hz),3.24(1H,q,J＝8.36Hz),3.73(3H,s),4.06(1H,m),4.66(1H,d,J＝8.35Hz),4.92(1H,d,J＝12.45Hz),5.08(1H,d,J＝14.25Hz),5.93(1H,s),7.45(2H,t,J＝7.80Hz),7.53(1H,s),7.56(1H,m),8.08(2H,d,J＝7.29Hz)；13C-NMR(150MHz,CDCl3)δ21.42,23.25,34.17,38.86,46.24,51.07,62.83,70.85,96.91,111.14,128.37,129.61,130.21,132.74,132.99,136.46,151.45,166.40,168.01；ESI-MS(m/z):373.0([M+H]+).
具体实验步骤参照下方流程图。a，异丙醇既是反应原料又是溶剂，三氟化硼乙醚是催化剂。b，苯甲酸是原料，二氯甲烷是溶剂，DCC是脱水剂，DMAP是催化剂。所有化合物只需调整异丙醇或苯甲酸两个反应原料即可制得。
a:异丙醇，Et2O.BF3:b:苯甲酸，DCC，DMAP，CH2Cl2
按照上述制备方法得到下列化合物。
实施例2：化合物G2，Molecular formula(MW):C22H26O6(386.44g/mol)；lightwhite oil；72.0％Yield；1H NMR(600MHz,DMSO-d6)δ1.01(3H,d,J＝6.09Hz),1.05(3H,d,J＝6.18Hz),2.15(1H,m),2.52(3H,s),2.67(1H,dd,J＝15.24,6.66Hz),3.02(2H,m),3.64(3H,s),3.84(1H,m),4.87(2H,q,J＝7.56Hz),5.39(1H,d,J＝3.06Hz),5.93(1H,s),7.32(2H,m),7.44(1H,d,J＝1.07Hz),7.49(1H,td,J＝7.66,1.25Hz),7.87(1H,d,J＝7.81Hz)；13C-NMR(150MHz,DMSO-d6)δ21.01,21.26,23.05,33.69,38.42,45.73,50.90,62.14,70.34,96.66,110.68,125.92,129.36,130.07,131.32,131.55,132.10,136.81,139.07,151.17,166.56,166.92；ESI-MS(m/z):387.1([M+H]+).
实施例3：化合物G3，Molecular formula(MW):C22H26O6(386.44g/mol)；lightwhite oil；70.0％Yield；1H NMR(600MHz,CDCl3)δ1.14(3H,d,J＝6.11Hz),1.18(3H,d,J＝6.19Hz),2.10(1H,m),2.39(3H,s),2.62(1H,t,J＝8.18Hz),2.76(1H,dd,J＝16.01,8.15Hz),3.08(1H,q,J＝8.54Hz),3.65(3H,s),4.02(1H,m),4.80(1H,d,J＝8.09Hz),4.85(1H,d,J＝12.74Hz),4.99(1H,d,J＝14.25Hz),5.93(1H,s),7.34(2H,d,J＝8.02Hz),7.52(1H,d,J＝0.74Hz),7.90(2H,d,J＝8.17Hz)；13C-NMR(150MHz,CDCl3)δ21.08,21.47,23.23,35.34,38.36,45.90,50.94,62.42,71.52,99.55,110.06,126.85,129.19,129.25,138.36,143.62,152.19,165.26,166.86；ESI-MS(m/z):387.1([M+H]+).
实施例4：化合物G4，Molecular formula(MW):C22H26O7(402.44g/mol)；white oil；65.0％Yield；1H NMR(600MHz,CDCl3)δ1.07(3H,d,J＝6.11Hz),1.12(3H,d,J＝6.19Hz),2.29(1H,m),2.79(1H,dd,J＝15.69,8.37Hz),2.97(1H,d,J＝8.62Hz),3.12(1H,m),3.73(3H,s),3.89(4H,m),4.85(1H,d,J＝13.48Hz),4.97(1H,d,J＝12.1Hz),5.29(1H,d,J＝3.33Hz),5.95(1H,s),6.92(2H,d,J＝8.91Hz),7.44(1H,d,J＝1.32Hz),8.01(2H,d,J＝8.89Hz)；13C-NMR(150MHz,CDCl3)δ21.43,23.26,34.12,38.86,46.16,51.06,55.41,62.53,70.84,96.91,111.14,113.63,122.60,131.64,132.53,136.70,151.41,163.43,166.15,168.04；ESI-MS(m/z):403.0([M+H]+).
实施例5：化合物G5，Molecular formula(MW):C21H23ClO6(406.86g/mol)；lightyellow oil；40.3％Yield；1H NMR(600MHz,CDCl3)δ1.06(3H,d,J＝6.09Hz),1.12(3H,d,J＝6.19Hz),2.29(1H,dd,J＝15.98,7.57Hz),2.79(1H,dd,J＝15.79,8.27Hz),3.01(1H,d,J＝8.43Hz),3.13(1H,q,J＝8.18Hz),3.73(3H,s),3.88(1H,m),4.95(2H,dd,J＝13.30,37.78Hz),5.29(1H,d,J＝3.19Hz),5.98(1H,s),7.32(1H,t,J＝7.07Hz),7.44(3H,m),7.84(1H,d,J＝7.01Hz)；13C-NMR(150MHz,CDCl3)δ21.35,23.26,34.16,38.90,46.25,51.07,63.42,70.79,96.82,111.12,126.57,130.27,131.07,131.34,132.53,133.36,133.63,136.01,151.48,165.59,168.01；ESI-MS(m/z):407.0([M+H]+).
实施例6：化合物G6，Molecular formula(MW):C21H23ClO6(406.86g/mol)；lightyellow oil；45.6％Yield；1H NMR(600MHz,CDCl3)δ1.08(3H,d,J＝6.11Hz),1.13(3H,d,J＝6.20Hz),2.30(1H,m),2.79(1H,dd,J＝8.18,16.10Hz),2.99(1H,d,J＝8.55Hz),3.15(1H,td,J＝1.13,8.70Hz),3.73(3H,s),3.89(1H,m),4.89(1H,d,J＝13.38Hz),4.99(1H,d,J＝12.01Hz)5.26(1H,d,J＝3.27Hz),5.96(1H,s),7.39(1H,t,J＝7.88Hz),7.45(1H,d,J＝1.26Hz),7.54(1H,m),7.94(1H,d,J＝7.81Hz),8.03(1H,t,J＝1.75Hz)；13C-NMR(150MHz,CDCl3)δ21.43,23.25,34.28,38.83,46.38,51.07,63.22,70.90,96.96,111.13,127.73,129.67,129.70,131.97,133.01,133.17,134.57,136.12,151.52,165.19,167.94；ESI-MS(m/z):407.1([M+H]+).
实施例7：化合物G7，Molecular formula(MW):C21H23ClO6(406.86g/mol)；lightwhite oil；55.1％Yield；1H NMR(600MHz,CDCl3)δ1.21(3H,d,J＝6.13Hz),1.28(3H,d,J＝6.21Hz),2.10(1H,m),2.65(1H,t,J＝8.07Hz),2.92(1H,dd,J＝8.61,16.42Hz),3.23(1H,q,J＝8.30Hz),3.73(3H,s),4.06(1H,m),4.89(1H,d,J＝13.38Hz),4.64(1H,d,J＝8.37Hz),4.92(1H,d,J＝14.13Hz),5.06(1H,d,J＝14.07Hz),5.92(1H,s),7.42(2H,d,J＝8.50Hz),7.53(1H,s),8.00(1H,d,J＝8.47Hz)；13C-NMR(150MHz,CDCl3)δ21.68,23.42,35.95,39.01,46.36,51.18,63.29,72.32,100.18,110.55,128.64,128.71,130.11,131.00,138.46,139.42,152.52,165.30,167.84；ESI-MS(m/z):407.0([M+H]+).
实施例8：化合物G8，Molecular formula(MW):C21H23BrO6(451.31g/mol)；lightyellow oil；55.1％Yield；1H NMR(600MHz,CDCl3)δ1.06(3H,d,J＝6.11Hz),1.12(3H,d,J＝6.20Hz),2.29(1H,m),2.79(1H,dd,J＝7.48,15.93Hz),3.02(1H,d,J＝8.62Hz),3.13(1H,q,J＝9.00Hz),3.73(3H,s),3.87(1H,m),4.90(1H,d,J＝13.27Hz),4.99(1H,d,J＝13.32Hz),5.29(1H,d,J＝3.32Hz),5.99(1H,s),7.25(2H,m),7.45(1H,d,J＝1.24Hz),7.67(1H,dd,J＝7.62,1.48Hz),7.79(1H,dd,J＝2.14,7.47Hz)；13C-NMR(150MHz,CDCl3)δ21.33,23.24,34.11,38.88,46.19,51.06,63.46,70.74,96.76,111.08,121.54,127.13,131.21,132.35,132.52,133.50,134.30,135.94,151.44,166.06,167.99；ESI-MS(m/z):474.8([M+Na]+).
实施例9：化合物G9，Molecular formula(MW):C21H23BrO6(451.31g/mol)；lightyellow oil；64.5％Yield；1H NMR(600MHz,CDCl3)δ1.08(3H,d,J＝6.10Hz),1.21(3H,d,J＝6.14Hz),2.09(1H,m),2.78(1H,dd,J＝8.28,15.34Hz),2.97(1H,t,J＝8.63Hz),3.15(1H,q,J＝8.15Hz),3.73(3H,s),3.89(1H,m),4.64(1H,d,J＝8.36Hz),4.96(1H,d,J＝9.04Hz),5.07(1H,d,J＝14.11Hz),5.92(1H,s),7.32(1H,t,J＝7.87Hz),7.49(1H,d,J＝0.96Hz),7.68(1H,d,J＝8.03Hz),7.99(1H,dd,J＝4.60,7.81Hz),8.19(1H,t,J＝2.28Hz)；13C-NMR(150MHz,CDCl3)δ21.44,23.41,34.28,38.82,46.40,51.16,63.44,70.90,96.96,110.58,122.47,128.19,129.94,130.28,132.58,133.21,135.90,138.37,151.52,165.06,167.93；ESI-MS(m/z):474.2([M+Na]+).
实施例10：化合物G10，Molecular formula(MW):C21H22N2O10(462.41g/mol)；lightyellow solid；75.0％Yield；mp:72-74℃；1H-NMR(600MHz,CDCl3)δ1.23(3H,d,J＝6.15Hz),1.29(3H,d,J＝6.22Hz),2.13(1H,m),2.68(1H,t,J＝8.12Hz),2.97(1H,dd,J＝8.56,15.55Hz),3.20(1H,q,J＝7.92Hz),3.74(3H,s),4.08(1H,m),4.65(1H,d,J＝8.39Hz),5.13(2H,m),5.99(1H,s),7.53(1H,s),9.18(2H,d,J＝2.13Hz),9.24(1H,t,J＝2.13Hz)；13C-NMR(150MHz,CDCl3)δ21.68,23.43,35.95,39.07,46.37,51.21,64.78,72.30,100.00,110.54,122.38,129.41,131.82,133.90,137.48,148.72,152.50,162.18,167.71；ESI-MS(m/z):463.2([M+H]+).
实施例11：化合物G11，Molecular formula(MW):C21H23NO8(417.41g/mol)；lightyellow oil；73.4％Yield；1H-NMR(600MHz,CDCl3)δ1.09(1H,d,J＝6.11Hz),1.13(1H,d,J＝6.20Hz),1.23(2H,d,J＝6.14Hz),1.29(2H,d,J＝6.21Hz),2.12(1H,m),2.67(1H,t,J＝8.01Hz),2.94(1H,dd,J＝8.56,16.74Hz),3.26(1H,q,J＝8.66Hz),3.73(3H,s),4.07(1H,m),4.66(1H,d,J＝8.37Hz),5.03(2H,m),5.96(1H,s),7.53(1H,s),7.66(1H,t,J＝7.95Hz),8.39(1H,m),8.42(1H,m),8.89(1H,m)；13C-NMR(150MHz,CDCl3)δ21.67,23.41,35.96,39.04,46.38,51.18,63.89,72.31,97.05,100.12,110.55,124.59,127.41,129.63,130.78,133.62,135.26,138.05,152.52,164.06,167.80；ESI-MS(m/z):418.0([M+H]+).
实施例12：化合物G12，Molecular formula(MW):C21H23IO6(498.31g/mol)；yellowoil；48.2％Yield；1H NMR(600MHz,CDCl3)δ1.22(3H,d,J＝6.14Hz),1.29(3H,d,J＝6.21Hz),2.10(1H,m),2.70(1H,t,J＝8.07Hz),2.92(1H,dd,J＝8.53,16.68Hz),3.23(1H,q,J＝8.61Hz),3.73(3H,s),4.06(1H,m),4.65(1H,d,J＝8.37Hz),4.95(1H,d,J＝13.84Hz),5.05(1H,d,J＝13.75Hz),5.99(1H,s),7.16(1H,td,J＝1.67,7.78Hz),7.41(1H,t,J＝7.48Hz),7.53(1H,s),7.83(1H,dd,J＝1.64,7.77Hz),8.00(1H,d,J＝7.93Hz)；13C-NMR(150MHz,CDCl3)δ21.72,23.43,35.88,39.06,46.36,51.18,63.68,72.28,94.01,100.19,110.57,127.87,130.95,130.97,132.58,135.24,138.17,141.29,152.55,166.14,167.88；ESI-MS(m/z):496.7([M-H]-).
实施例13：化合物G13，Molecular formula(MW):C23H28O8(432.46g/mol)；lightwhite oil；41.5％Yield；1H NMR(600MHz,CDCl3)δ1.22(3H,d,J＝6.14Hz),1.28(3H,d,J＝6.22Hz),2.08(1H,m),2.67(1H,t,J＝7.97Hz),2.91(1H,dd,J＝8.55,16.94Hz),3.21(1H,q,J＝8.61Hz),3.73(3H,s),3.88(3H,s),3.90(3H,s),4.05(1H,m),4.64(1H,d,J＝8.40Hz),4.92(1H,d,J＝13.19Hz),5.05(1H,d,J＝14.65Hz),5.97(1H,s),7.08(2H,m),7.35(1H,dd,J＝2.05,7.33Hz),7.53(1H,s)；13C-NMR(150MHz,CDCl3)δ21.69,23.43,35.99,39.06,46.32,51.15,56.07,61.56,63.22,72.27,100.28,110.61,115.82,122.31,123.79,126.22,130.16,138.62,149.16,152.55,153.55,165.94,167.91；ESI-MS(m/z):433.0([M+H]+).
实施例14：化合物G14，Molecular formula(MW):C23H28O8(432.46g/mol)；lightwhite oil；44.7％Yield；1H NMR(600MHz,CDCl3)δ1.08(3H,d,J＝6.11Hz),1.12(3H,d,J＝6.21Hz),2.29(1H,m),2.79(1H,dd,J＝8.42,15.52Hz),2.98(1H,d,J＝8.58Hz),3.13(1H,q,J＝7.67Hz),3.73(3H,s),3.88(1H,m),3.94(6H,d,J＝3.32Hz),4.86(1H,d,J＝13.49Hz),4.99(1H,d,J＝13.90Hz),5.29(1H,d,J＝3.31Hz),5.95(1H,s),6.86(1H,d,J＝8.46Hz),7.44(1H,d,J＝1.26Hz),7.56(1H,d,J＝1.91Hz),7.70(1H,dd,J＝1.97,8.43Hz)；13C-NMR(150MHz,CDCl3)δ21.44,23.26,34.15,38.84,46.20,51.06,56.00,62.67,70.84,96.92,110.26,111.13,112.10,122.69,123.61,132.59,136.68,148.69,151.44,153.09,166.20,168.01；ESI-MS(m/z):433.0([M+H]+).
实施例15：化合物G15，Molecular formula(MW):C21H22Cl2O6(441.30g/mol)；yellow oil；56.2％Yield；1H NMR(600MHz,CDCl3)δ1.21(3H,d,J＝6.13Hz),1.29(3H,d,J＝6.22Hz),2.11(1H,m),2.67(1H,t,J＝8.09Hz),2.93(1H,dd,J＝8.52,16.68Hz),3.23(1H,q,J＝8.64Hz),3.73(3H,s),4.06(1H,m),4.65(1H,d,J＝8.36Hz),4.95(1H,d,J＝13.80Hz),5.06(1H,d,J＝13.79Hz),5.97(1H,s),7.40(2H,d,J＝1.39Hz),7.53(1H,s),7.84(1H,t,J＝1.40Hz)；13C-NMR(150MHz,CDCl3)δ21.69,23.42,35.90,39.11,46.45,51.17,63.96,72.28,100.13,131.02,131.29,131.42,132.09,132.23,132.48,132.67,137.97,152.56,164.11,167.88；ESI-MS(m/z):442.8([M+H]+).
实施例16：化合物G16，Molecular formula(MW):C21H22Cl2O6(441.30g/mol)；lightyellow oil；56.2％Yield；1H NMR(600MHz,CDCl3)δ1.21(3H,d,J＝6.15Hz),1.29(3H,d,J＝6.22Hz),2.09(1H,m),2.67(1H,t,J＝8.00Hz),2.92(1H,dd,J＝8.53,16.73Hz),3.20(1H,q,J＝8.66Hz),3.73(3H,s),4.05(1H,m),4.65(1H,d,J＝8.32Hz),5.01(1H,d,J＝13.48Hz),5.11(1H,d,J＝13.42Hz),6.04(1H,s),7.30(1H,s),7.32(1H,s),7.34(1H,d,J＝2.89Hz),7.52(1H,s)；13C-NMR(150MHz,CDCl3)δ21.67,23.43,35.85,39.10,46.20,51.15,64.12,72.23,100.15,110.58,127.85,127.87,130.82,131.82,131.93,133.62,137.67,152.56,164.40,167.86；ESI-MS(m/z):442.8([M+H]+).
实施例17：化合物G17，Molecular formula(MW):C21H22Cl2O6(441.30g/mol)；lightyellow oil；41.8％Yield；1H NMR(600MHz,CDCl3)δ1.08(3H,d,J＝6.11Hz),1.13(3H,d,J＝6.21Hz),2.30(1H,m),2.79(1H,dd,J＝8.13,15.23Hz),2.99(1H,d,J＝8.65Hz),3.16(1H,q,J＝8.23Hz),3.73(3H,s),3.90(1H,m),4.89(1H,d,J＝13.37Hz),4.99(1H,d,J＝13.30Hz),5.24(1H,d,J＝3.24Hz),5.96(1H,s),7.45(1H,d,J＝1.26Hz),7.53(1H,d,J＝8.36Hz),7.88(1H,dd,J＝1.98,8.38Hz),8.13(1H,d,J＝1.93Hz)；13C-NMR(150MHz,CDCl3)δ21.44,23.25,34.34,38.80,46.46,51.09,63.40,70.91,96.97,111.12,128.67,130.06,130.55,131.52,132.98,133.35,137.66,151.58,164.54,167.91；ESI-MS(m/z):464.6([M+Na]+).
实施例18：化合物G18，Molecular formula(MW):C22H25FO7(420.43g/mol)；lightyellow oil；40.0％Yield；1H NMR(600MHz,CDCl3)δ1.22(3H,d,J＝6.15Hz),1.28(3H,d,J＝6.20Hz),2.09(1H,m),2.65(1H,t,J＝8.05Hz),2.91(1H,dd,J＝8.47,16.58Hz),3.23(1H,q,J＝8.71Hz),3.73(3H,s),3.85(3H,s),4.05(1H,m),4.65(1H,d,J＝8.32Hz),4.89(1H,d,J＝14.32Hz),5.06(1H,d,J＝14.25Hz),5.94(1H,s),6.64(1H,dd,J＝2.41,12.66Hz),6.73(1H,dd,J＝2.39,8.82Hz),7.53(1H,d,J＝0.88Hz),7.93(1H,t,J＝8.67Hz)；13C-NMR(150MHz,CDCl3)δ21.70,23.41,35.93,39.04,46.48,51.14,55.77,63.07,72.33,100.21,102.42,110.15,110.63,110.94,129.72,133.46,138.55,152.53,162.70,163.76,164.65,167.91；ESI-MS(m/z):421.0([M+H]+).
实施例19：化合物G19，Molecular formula(MW):C22H25FO7(420.43g/mol)；lightyellow oil；42.5％Yield；1H NMR(600MHz,CDCl3)δ1.22(3H,d,J＝6.15Hz),1.29(3H,d,J＝6.21Hz),2.09(1H,m),2.64(1H,t,J＝8.00Hz),2.91(1H,dd,J＝8.56,16.65Hz),3.21(1H,q,J＝8.71Hz),3.73(3H,s),3.86(3H,s),4.06(1H,m),4.65(1H,d,J＝8.27Hz),4.94(1H,d,J＝14.01Hz),5.09(1H,d,J＝13.99Hz),5.98(1H,s),6.73(2H,dt,J＝4.53,8.41Hz),7.33(1H,td,J＝6.58,8.45Hz),7.52(1H,d,J＝0.82Hz)；13C-NMR(150MHz,CDCl3)δ21.66,23.42,35.89,39.09,46.38,51.14,56.27,63.60,72.27,100.16,106.93,108.10,110.63,130.27,131.77,138.15,152.55,158.15,159.50,161.16,163.49,167.92；ESI-MS(m/z):443.0([M+Na]+).
实施例20：化合物G20，Molecular formula(MW):C22H25ClO7(436.88g/mol)；lightwhite oil；53.6％Yield；1H NMR(600MHz,CDCl3)δ1.06(3H,d,J＝6.11Hz),1.12(3H,d,J＝6.20Hz),2.28(1H,m),2.78(1H,dd,J＝7.90,14.99Hz),2.98(1H,d,J＝8.60Hz),3.12(1H,q,J＝8.47Hz),3.73(3H,s),3.86(1H,m),3.90(3H,s),4.85(1H,d,J＝13.44Hz),4.95(1H,d,J＝13.46Hz),5.29(1H,d,J＝3.32Hz),5.94(1H,s),6.97(2H,td,J＝1.83,4.14Hz),7.44(1H,d,J＝1.29Hz),7.77(1H,t,J＝4.36Hz)；13C-NMR(150MHz,CDCl3)δ21.37,23.25,34.09,38.89,46.15,51.06,56.19,62.92,70.75,96.82,111.12,112.70,118.50,120.40,132.66,132.76,136.38,139.46,151.43,159.82,165.17,168.03；ESI-MS(m/z):458.9([M+Na]+).
实施例21：化合物G21，Molecular formula(MW):C24H30O9(462.49g/mol)；lightwhite solid；67.2％Yield；1H NMR(600MHz,CDCl3)δ1.24(3H,d,J＝6.13Hz),1.29(3H,d,J＝6.20Hz),2.11(1H,m),2.65(1H,t,J＝7.85Hz),2.91(1H,dd,J＝8.59,16.58Hz),3.24(1H,q,J＝8.45Hz),3.73(3H,s),3.91(9H,s),4.07(1H,m),4.67(1H,d,J＝8.22Hz),4.90(1H,d,J＝13.52Hz),5.08(1H,d,J＝14.21Hz),5.90(1H,s),7.33(2H,s),7.53(1H,s)；13C-NMR(150MHz,CDCl3)δ21.42,23.24,34.18,38.79,46.26,51.06,56.24,60.88,62.90,70.83,96.91,106.95,111.10,125.13,132.71,136.54,142.36,151.48,152.94,166.06,167.96；ESI-MS(m/z):463.2([M+H]+).
实施例22：化合物G22，Molecular formula(MW):C22H23F3O7(456.41g/mol)；lightwhite solid；41.5％Yield；1H NMR(600MHz,CDCl3)δ1.21(3H,d,J＝6.14Hz),1.28(3H,d,J＝6.22Hz),2.10(1H,m),2.64(1H,t,J＝7.82Hz),2.93(1H,dd,J＝8.61,16.54Hz),3.23(1H,q,J＝8.57Hz),3.73(3H,s),4.06(4H,m),4.63(1H,d,J＝8.41Hz),4.94(1H,d,J＝13.63Hz),5.06(1H,d,J＝14.10Hz),5.96(1H,s),7.49(1H,m),7.53(1H,s)；13C-NMR(150MHz,CDCl3)δ21.66,23.41,35.98,39.05,46.32,51.17,62.23,63.95,72.30,100.15,110.57,112.01,122.15,130.53,133.25,137.96,151.31,151.59,152.52,153.03,162.35,167.82；ESI-MS(m/z):457.2([M+H]+).
实施例23：化合物G23，Molecular formula(MW):C21H23NO8(417.41g/mol)；lightyellow oil；51.4％Yield；1H NMR(600MHz,CDCl3)δ1.06(2H,dd,J＝6.1Hz),1.25(4H,dd,J＝6.2Hz),2.17(1H,dd,J＝16.7,9.2Hz),2.69(1H,t,J＝7.5Hz),2.96(1H,m),3.17(1H,q,J＝8.5Hz),3.73(3H,s),3.95(1H,dt,J＝12.4,6.2Hz),4.65(1H,d,J＝8.4Hz),5.02(2H,dd,J＝46.9,14.0Hz),5.95(1H,s),7.47(1H,s),7.65(2H,m),7.77(1H,t,J＝8.4,7.1,1.6Hz),7.92(1H,m)；13C-NMR(150MHz,CDCl3)δ21.68,23.45,35.84,39.11,46.29,51.20,64.42,72.34,100.15,110.60,123.89,127.53,129.97,131.35,131.82,132.84,137.51,148.32,152.55,164.96,167.87；ESI-MS(m/z):418.1([M+H]+).
实施例24：化合物G24，Molecular formula(MW):C21H23NO8(417.41g/mol)；lightwhite oil；38.2％Yield；1H NMR(600MHz,CDCl3)δ1.24(3H,d,J＝6.1Hz),1.31(3H,d,J＝6.2Hz),2.13(1H,dd,J＝16.7,9.2Hz),2.69(1H,t,J＝7.5Hz),2.96(1H,dd,J＝16.7,8.6Hz),3.26(1H,q,J＝8.5Hz),3.75(3H,s),4.09(1H,dt,J＝12.4,6.2Hz),4.66(1H,d,J＝8.4Hz),5.07(2H,dd,J＝46.9,14.0Hz),5.98(1H,s),7.55(1H,s),8.26(2H,d,J＝9.0Hz),8.32(2H,d,J＝8.9Hz)；13C-NMR(150MHz,CDCl3)δ21.71,23.46,36.02,39.08,46.34,51.25,63.98,72.35,100.17,110.57,123.59,130.77,130.83,135.60,138.09,150.59,152.56,164.32,167.83；ESI-MS(m/z):418.4([M+H]+).
实施例25：化合物G25，Molecular formula(MW):C20H20N2O10(448.38g/mol)；lightwhite oil；63.7％Yield；1H NMR(600MHz,CDCl3)δ1.30(3H,t,J＝7.1Hz),2.16(1H,dd,J＝16.9,8.9Hz),2.72(1H,t,J＝7.9Hz),2.98(1H,dd,J＝16.3,9.1Hz),3.29(1H,q,J＝8.2Hz),3.68(1H,m),3.76(3H,s),4.05(1H,m),4.62(1H,d,J＝8.3Hz),5.14(2H,s),6.02(1H,s),7.56(1H,s),9.21(2H,d,J＝2.0Hz),9.26(1H,t,J＝2.0Hz)；13C-NMR(150MHz,CDCl3)δ15.12,35.72,39.09,46.29,51.29,64.79,65.80,101.50,110.68,122.45,129.47,132.11,133.90,137.29,148.72,152.35,162.20,167.70；ESI-MS(m/z):449.5([M+H]+).
实施例26：化合物G26，Molecular formula(MW):C21H22N2O10(462.41g/mol)；lightwhite oil；56.1％Yield；1H NMR(600MHz,CDCl3)δ0.96(3H,t,J＝7.4Hz),1.68(2H,dd,J＝14.3,7.1Hz),2.14(1H,m),2.71(1H,t,J＝7.5Hz),2.96(1H,dd,J＝16.9,8.5Hz),3.28(1H,q,J＝8.4Hz),3.54(1H,dt,J＝9.4,6.8Hz),3.74(s,3H),3.94(1H,dt,J＝9.4,6.7Hz),4.59(1H,d,J＝8.2Hz),5.12(2H,s),6.00(1H,s),7.54(1H,s),9.18(2H,d,J＝2.1Hz),9.24(1H,t,J＝2.1Hz)；13C-NMR(150MHz,CDCl3)δ10.57,22.87,35.76,39.10,46.29,51.29,64.83,71.86,101.65,110.67,122.45,129.47,132.12,133.89,137.29,148.72,152.38,162.19,167.71；ESI-MS(m/z):463.5([M+H]+).
实施例27：化合物G27，Molecular formula(MW):C22H24N2O10(476.43g/mol)；lightwhite oil；49.2％Yield；1H NMR(600MHz,CDCl3)δ0.93(3H,t,J＝7.4Hz),1.37(2H,m),1.64(2H,m),2.14(1H,m),2.70(1H,t,J＝7.4Hz),2.96(1H,m),3.27(1H,q,J＝7.8Hz),3.58(1H,dt,J＝9.5,6.8Hz),3.74(3H,s),3.98(1H,dt,J＝9.5,6.7Hz),4.58(1H,d,J＝8.2Hz),5.12(2H,s),6.00(1H,s)7.54(1H,d,J＝0.9Hz),9.19(2H,d,J＝2.1Hz),9.24(1H,t,J＝2.1Hz)；13C-NMR(150MHz,CDCl3)δ13.81,19.26,31.62,35.74,39.09,46.30,51.29,64.82,70.00,101.65,110.66,122.45,129.47,132.13,133.91,137.28,148.72,152.38,162.18,167.71；ESI-MS(m/z):477.1([M+H]+).
实施例28：化合物G28，Molecular formula(MW):C22H24N2O10(476.43g/mol)；lightwhite oil；61.2％Yield；1H NMR(600MHz,CDCl3)δ0.95(6H,t,J＝5.4Hz,6.3Hz),1.94(1H,dt,J＝13.4Hz),2.14(1H,dd,J＝8.9,16.9Hz),2.72(1H,t,J＝8.0Hz),2.96(1H,dd,J＝8.5,16.9Hz),3.31(2H,dt,J＝7.2,12.9,25.4Hz),3.74(3H,s),3.77(1H,dd,J＝6.6,9.2Hz),4.59(1H,d,J＝8.2Hz),5.13(2H,s),5.99(1H,s),7.53(1H,s),9.18(2H,d,J＝2.1Hz),9.24(1H,t,J＝2.1Hz)；13C-NMR(150MHz,CDCl3)δ19.32,19.36,28.53,35.77,39.09,46.32,51.28,64.85,76.70,101.67,110.67,122.45,129.47,132.16,133.88,137.25,148.72,152.38,162.19,167.71；ESI-MS(m/z):477.3([M+H]+).
实施例29：化合物G29，Molecular formula(MW):C22H24N2O10(476.43g/mol)；lightyellow oil；65.5％Yield；1H NMR(600MHz,CDCl3)δ0.93(3H,t,J＝9.9Hz),1.23(3H,dd,J＝6.2Hz),1.43(1H,s),2.10(1H,m),2.14(1H,dd,J＝8.4Hz),2.70(1H,s),2.96(1H,dd,J＝8.4Hz),3.27(1H,d,J＝8.3Hz),3.74(3H,s),3.88(1H,d,J＝6.2Hz),4.68(1H,d,J＝8.2Hz),5.13(2H,s),6.00(1H,s),7.53(1H,s),9.18(2H,s),9.24(1H,s)；13C-NMR(150MHz,CDCl3)δ9.69,18.72,28.93,29.91,35.91,39.09,46.42,51.27,64.84,76.20,99.23,110.56,122.45,129.48,131.87,132.17,133.89,137.44,148.70,152.66,162.19,167.79；ESI-MS(m/z):477.3([M+H]+).
实施例30：化合物G30，Molecular formula(MW):C22H24N2O10(476.43g/mol)；lightyellow oil；46.8％Yield；1H NMR(600MHz,CDCl3)δ1.32(9H,s),2.15(1H,dd,J＝16.8,9.3Hz),2.66(1H,t,J＝7.3Hz),2.95(1H,dd,J＝16.8,8.4Hz),3.26(1H,q,J＝8.2Hz),3.73(3H,s),4.80(1H,d,J＝8.3Hz),5.13(2H,q,J＝13.7Hz),6.00(1H,s),7.53(1H,s),9.18(2H,d,J＝2.1Hz),9.24(1H,t,J＝2.1Hz)；13C-NMR(150MHz,CDCl3)δ28.77,36.47,39.04,46.64,51.25,64.89,76.99,96.48,110.37,122.46,129.48,131.99,133.88,137.71,148.72,152.88,162.21,167.84；ESI-MS(m/z):477.7([M+H]+).
实施例31：化合物G31，Molecular formula(MW):C23H26N2O10(490.50g/mol)；lightyellow oil；52.3％Yield；1H NMR(600MHz,CDCl3)δ0.89(3H,s),1.34(4H,d,J＝3.9Hz),1.65(2H,m),2.14(1H,d,J＝8.9Hz),2.71(1H,s),2.96(1H,dd,J＝16.8,8.5Hz),3.27(1H,d,J＝8.5Hz),3.57(1H,d,J＝9.4Hz),3.74(3H,s),3.97(1H,d,J＝9.4Hz),4.59(1H,d,J＝8.2Hz),5.12(2H,s),6.00(1H,s),7.54(1H,s),9.18(2H,s),9.24(1H,s)；13C-NMR(150MHz,CDCl3)δ14.00,22.41,28.20,29.26,35.74,39.09,46.28,51.30,64.84,70.31,101.65,110.66,122.45,129.47,132.13,133.89,137.27,148.70,152.39,162.18,167.72；ESI-MS(m/z):491.7([M+H]+).
实施例32：化合物G32，Molecular formula(MW):C26H24N2O10(524.50g/mol)；lightyellow oil；46.8％Yield；1H NMR(600MHz,CDCl3)δ2.12(1H,m),2.69(1H,t,J＝7.9Hz),2.97(3H,m),3.24(1H,t,J＝8.4Hz),3.73(3H,s),3.82(1H,m),4.24(1H,m),4.59(1H,d,J＝8.1Hz),4.87(2H,d,J＝5.3Hz),5.98(1H,d,J＝34.9Hz),7.17(5H,m),7.47(1H,d,J＝37.8Hz),9.11(2H,dd,J＝29.0,2.1Hz),9.23(1H,t,J＝2.0Hz)；13C-NMR(150MHz,CDCl3)δ35.64,35.97,39.01,46.21,51.31,64.62,70.51,101.50,110.77,122.41,126.40,128.44,128.82,129.44,132.04,133.88,137.16,138.19,148.67,152.20,162.04,167.64.；ESI-MS(m/z):525.6([M+H]+).
实施例33：化合物G33，Molecular formula(MW):C27H26N2O10(538.50g/mol)；lightwhite solid；46.8％Yield；1H NMR(600MHz,CDCl3)δ2.05(1H,s),2.15(1H,dd,J＝16.9,8.7Hz),2.72(3H,dt,J＝15.5,7.9Hz),2.96(1H,dd,J＝16.4,8.7Hz),3.29(1H,q,J＝8.2Hz),3.61(1H,dt,J＝9.5,6.5Hz),3.74(3H,s),3.99(1H,dt,J＝9.5,6.6Hz),4.12(1H,q,J＝7.1Hz),4.60(1H,d,J＝8.1Hz),5.13(2H,s),6.01(1H,s),7.17(4H,m),7.28(1H,d,J＝7.9Hz),7.50(1H,d,J＝24.6Hz),9.16(2H,m),9.22(1H,t,J＝2.1Hz)；13C-NMR(150MHz,CDCl3)δ31.19,32.26,35.70,39.08,46.34,51.33,64.81,69.43,101.57,110.74,122.47,125.99,128.37,128.43,129.47,132.35,133.81,137.14,141.37,148.68,152.32,162.19,167.69；ESI-MS(m/z):538.5([M+H]+).
实施例34：稳定性考察。
取SD(Sprague-Dawley)雄性大鼠，体重250～300g，制备组织匀浆前，动物禁食过夜，次日断头处死，取出肝脏放置于冰袋上，用生理盐水洗净，滤纸吸干，称重后加入3倍于器官重量的PBS缓冲液，于冰浴中制成匀浆。在体外37℃环境下，将京尼平及上述合成的化合物G1放入大鼠肝匀浆中，分别孵育0.5h、1h、2h后，离心取上清液，采用高效液相法进行含量测定，考察其稳定性。图1结果表明，京尼平在0.5h时其峰面积缓慢下降到75％，在1h时达到初始峰面积的一半，2h后峰面积达到初始面积的20％，而本发明中的化合物G1在0.5h及1h时峰面积没有发生变化，在2h时可以到达初始峰面积的80％以上。经过比较分析，可知本发明中的京尼平衍生物在稳定性方面明显优于京尼平，为此类化合物进一步的结构优化奠定基础。进一步也可以推断出本发明的其他化合物也具有相同或相似的稳定性。
实施例35：油水分配系数的测定。
精密称取适量等量的京尼平及化合物G1，加入水饱和的正辛醇溶液，超声使其完全溶解，3000r/min离心15min，得到系列样品的正辛醇溶液，备用。分别精密量取4mL上述制备的正辛醇溶液，置于试管中，再精密加入4mL正辛醇饱和的水溶液，放入恒温振荡仪中，37℃恒温振荡12h后，3000r/min离心15min，分取上层油和下层水相，采用紫外分光光度计在相应的波长下测定其吸光度，计算相应化合物的浓度，并换算表观油水分布系数。结果表明，本发明中的京尼平衍生物的值(logP>1)均明显高于京尼平(logP＝0.609±0.014)，脂溶性有显著的提高，本发明中其它化合物的油水分配系数均采取此方法检测，均明显高于京尼平。因此，在防治神经退行性疾病中可以增加血脑屏障的通过率，发挥更好的药理作用。
实施例36：细胞存活率的测定。
利用H2O2损伤PC12神经细胞，建立体外细胞模型。采用H2O2-PC12细胞模型检验京尼平及上述合成的化合物G2在体外的神经细胞保护，计算相应的保护率。取对数生长期的PC12神经细胞，将PC12神经细胞计数后培养于96孔细胞培养板中，细胞密度为每孔5×104个/mL，分别设定空白对照组，阳性对照组，实验组(低剂量组、中剂量组、高剂量组)，阳性对照组浓度为20μM，不同浓度实验组分别为5μM(低剂量组)、20μM(中剂量组)、80μM(高剂量组)，每一浓度设4个平行孔。在37℃，5﹪二氧化碳培养箱中培养12h后，实验组及模型组分别加入含400μM H2O2的培养基，继续培育2h，取出培养板，每孔加入MTT 10μL后，37℃继续孵育4h，弃去培养液，每孔加入DMSO 100μL，振荡使蓝紫色结晶完全溶解，全自动酶标仪490nm处测定每孔的吸光度。图2结果表明，京尼平及化合物G2在5μM、20μM、80μM浓度时对于H2O2诱导的PC12神经细胞损伤均有保护作用且高于京尼平，其中5μM浓度时保护作用最佳。
实施例37：细胞内活性氧含量水平的测定。
利用H2O2-PC12细胞模型检测京尼平及上述合成的化合物G3在H2O2诱导的PC12神经细胞损伤中细胞内活性氧含量的影响。取对数生长期的PC12神经细胞，将PC12神经细胞计数后培养于6孔细胞培养板中，细胞密度为每孔5×104个/mL，分别设定空白对照组，H2O2模型组，实验组(低剂量组、中剂量组、高剂量组)，每一浓度设3个平行孔。在37℃，5％二氧化碳培养箱中培养12h后，实验组及模型组分别加入含400μM H2O2的培养基，继续培育2h，胰酶消化，收集细胞，利用DCFH-DA荧光探针进行活性氧测定。图3结果表明，H2O2损伤细胞2h后，细胞内活性氧的含量显著升高。与H2O2模型组及京尼平对照组相比，实验组的活性氧的含量有所降低，结果表明化合物G3在5μM、20μM、80μM浓度时可以抑制H2O2诱导的PC12神经细胞损伤中细胞内活性氧含量水平的升高，其中5μM浓度下降到最低值。
实施例38：细胞内线粒体膜电位的测定。
利用H2O2-PC12细胞模型，检测京尼平及上述合成的化合物G4对H2O2诱导的PC12神经细胞损伤中细胞内线粒体膜电位的影响。取对数生长期的PC12神经细胞，将PC12神经细胞计数后培养于6孔细胞培养板中，细胞密度为每孔5×104个/mL，分别设定空白对照组，H2O2模型组，实验组(低剂量组、中剂量组、高剂量组)，每一浓度设3个平行孔。在37℃，5％二氧化碳培养箱中培养12h后，实验组及模型组分别加入含400μM H2O2的培养基，继续培育2h，胰酶消化，收集细胞，利用JC-1荧光探针测定线粒体膜电位。图4结果表明，H2O2损伤细胞2h后，细胞内线粒体膜电位显著降低。与H2O2模型组及京尼平对照组相比，实验组的活性氧的含量显著地升高，结果表明化合物G4在5μM、20μM、80μM浓度时可以抑制H2O2诱导的PC12神经细胞损伤中细胞内线粒体膜电位的降低，5μM浓度时到达最高值。
实施例39：细胞凋亡的测定。
利用H2O2-PC12细胞模型，检测京尼平及上述合成的化合物G5对H2O2诱导的PC12神经细胞损伤在PI/AnnexinⅤ-FITC双染下细胞凋亡的影响。取对数生长期的PC12神经细胞，将PC12神经细胞计数后培养于6孔细胞培养板中，细胞密度为每孔5×104个/mL，分别设定空白对照组，H2O2模型组，实验组(低剂量组、中剂量组、高剂量组)，每一浓度设3个平行孔。在37℃，5％二氧化碳培养箱中培养12h后，实验组及模型组分别加入含400μM H2O2的培养基，继续培育2h，胰酶消化，收集细胞，利用PI/AnnexinV-FITC测定过氧化氢诱导的PC12神经细胞的凋亡。结果表明，H2O2损伤细胞2h后，细胞内凋亡率显著增高。与H2O2模型组及京尼平组相比，实验组的低剂量组细胞内凋亡率显著地降低，图5结果表明化合物G5在5μM、20μM、80μM浓度时可以抑制过氧化氢诱导的PC12神经细胞损伤中细胞的凋亡，其中5μM浓度时抑制率达到最高。
实施例40：游泳行为试验及Rotarod行为试验。
采用1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)腹腔注射小鼠制作PD动物模型。对照组采用相同浓度生理盐水。治疗组采用上述合成的化合物G6腹腔注射小鼠。7天后，PD模型组与治疗组均不再进行MPTP注射，PD模型组改为生理盐水继续注射7天，治疗组改为化合物G6继续连续给药7天。根据游泳行为实验及Rotarod行为实验评价小鼠运动能力。图6及图7结果表明与MPTP组小鼠相比，化合物G6治疗组在小鼠游泳行为及Rotarod行为的评分显著高于MPTP组，表明本发明所述的化合物G6能够有效的缓解MPTP引起的小鼠运动能力，协调能力的损伤，对PD动物模型有治疗效果。
Claims (9)
1.一种化合物，选自下列化合物：
3-异丙氧基-7-(苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2-甲基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(4-甲基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(4-甲氧基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2-氯苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(3-氯苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(4-氯苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2-溴苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(3-溴苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2-硝基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(3-硝基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(4-硝基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2-碘苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2, 4-二甲氧基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(3, 4-二甲氧基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2, 5-二氯苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2, 6-二氯苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(3, 4-二氯苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2-氟-4-甲氧基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2-氟-6-甲氧基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(4-氯-2-甲氧基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(3, 4, 5-甲氧基苯甲酰氧基)甲基京尼平；
3-异丙氧基-7-(2, 4, 5-三氟-3-甲氧基苯甲酰氧基)甲基京尼平；
3-乙氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-丙氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-正丁氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-仲丁氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-异丁氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-叔丁氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-正戊氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-苯乙氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平；
3-苯丙氧基-7-(3, 5-二硝基苯甲酰氧基)甲基京尼平。
2.权利要求1所述的化合物、其药学上可接受的盐在制备防治神经退行性疾病药物中的应用。
3.根据权利要求2所述的应用，其特征在于：所述神经退行性疾病是帕金森病、阿尔茨海默病、多发性硬化症、亨廷顿氏病、肌肉萎缩性侧索硬化症、共济失调毛细血管扩张症的一种疾病或多种疾病。
4.一种药物组合物，包含①，以及②、③、④中的至少一种物质；
所述①为权利要求1所述的化合物、其药学上可接受的盐；
所述②为药学上可接受的载体；
所述③为佐剂；
所述④为媒介物。
5.权利要求4所述药物组合物在制备防治神经退行性疾病药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述神经退行性疾病是帕金森病、阿尔茨海默病、多发性硬化症、亨廷顿氏病、肌肉萎缩性侧索硬化症、共济失调毛细血管扩张症的一种疾病或多种疾病。
7.根据权利要求5所述的应用，其特征在于，所述药物组合物通过口服、舌下、经皮、肌肉、皮肤黏膜、静脉途径给药。
8.根据权利要求5所述的应用，其特征在于，所述药物组合物以口服制剂、注射剂或局部给药制剂形式存在。
9.根据权利要求8所述的应用，其特征在于，所述口服制剂包括片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂或溶液剂；注射剂包括注射液剂型或注射用冻干粉针剂型；局部给药制剂包括霜剂、软膏剂、喷雾剂、气雾剂、贴剂、凝胶剂或巴布剂。
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