CN116063237A - 一类no供体型川芎嗪衍生物、制备方法、组合物及用途 - Google Patents
一类no供体型川芎嗪衍生物、制备方法、组合物及用途 Download PDFInfo
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- CN116063237A CN116063237A CN202310137013.2A CN202310137013A CN116063237A CN 116063237 A CN116063237 A CN 116063237A CN 202310137013 A CN202310137013 A CN 202310137013A CN 116063237 A CN116063237 A CN 116063237A
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- ligustrazine
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Abstract
本发明公开了一类NO供体型川芎嗪衍生物、制备方法、组合物及用途，本发明提供了一类NO供体型川芎嗪衍生物及其制备方法，同时还提供了NO供体型川芎嗪衍生物或其药学上可接受的盐与药用辅料制成的不同剂型的组合物，以及该组合物在制备预防或治疗血栓栓塞性心脑血管疾病、血小板聚集所导致疾病的药物中的应用。
Description
技术领域
本发明涉及药物化学技术领域，具体是指一类NO供体型川芎嗪衍生物、制备方法、组合物及用途。
背景技术
心血管疾病是危害人类健康的第一杀手。心血管疾病中，仅仅是缺血性心脏病的死亡人数就超过全部肿瘤的死亡人数。各种原因形成的血栓可导致心肌梗塞、脑中风、肺栓塞，引起相应器官组织供血的突然减小，造成血栓相关性的心脑血管疾病。其中心肌梗死和脑中风是常见的心脑血管疾病，具有高发病率、高死亡率、高致残率的特点，严重危害人类健康。
目前临床上预防和治疗血栓相关性心脑血管疾病的药物主要有溶血栓药、抗凝血药和抗血小板聚集药。其中针对动脉血栓的抗血小板聚集药应用最为广泛，在血栓栓塞的治疗和预防上都有应用，代表药物有环氧合酶抑制剂阿司匹林、P2Y12受体抑制剂氯吡格雷、替格瑞洛等。
川芎嗪(Tetramethylpyrazine，TMP)是分离自药用植物川芎的生物碱，是川芎最重要的活性成分之一，具有扩张血管、保护血管内皮、抗血小板聚集、抗氧化应激等广泛的心脑血管药理活性，临床上常应用于缺血性心脑血管疾病，以扩张血管、减轻缺血损伤和改善预后。但由于川芎嗪在体内极易氧化，造成半衰期短、生物利用度低、疗效不强，需频繁给药、易造成积蓄中毒的缺点。对川芎嗪的药代动力学和结构改造研究表明，川芎嗪的母核吡嗪环是决定其药理作用的药效基团，在保留吡嗪环的基础上对川芎嗪的侧链进行改造，可以得到疗效更好、药代动力学性质优异的川芎嗪衍生物。
一氧化氮(NO)是一类重要的气体信使分子，在缺血性损伤或缺血再灌注的损伤的初期，NO能够起调节血管张力，维持正常血管及组织器官灌流、抗血小板聚集和粘附、抑制炎症因子释放等作用，从而起到对缺血组织的保护作用。NO供体作为NO在体内外的储存及运输形式，其可在体内经酶或非酶作用释放NO，从而增加进入机体后的稳定性，延长其释放半衰期。常见的NO供体有硝酸酯、亚硝酸酯，以及偶氮鎓二醇盐、呋咱N-氧化物、亚硝基硫醇等。
将NO供体引入川芎嗪衍生物结构中合成NO供体型川芎嗪衍生物，使其在体内释放NO和川芎嗪衍生物，则得到同时具有一氧化氮分子活性和川芎嗪活性的新型药物，有望发挥抗血小板聚集和粘附、扩张血管、减轻缺血再灌注损伤等作用，更好的预防、治疗血栓栓塞性心脑血管疾病。
发明内容
本发明要解决的技术问题是克服上述技术的缺陷，提供一类NO供体型川芎嗪衍生物、制备方法、组合物及用途。
为解决上述技术问题，本发明提供的技术方案为一类NO供体型川芎嗪衍生物，所述衍生物包括川芎嗪中间体母核、活性基团、连接臂、NO供体结构，其结构通式如式I所示：
其中X为连接臂，选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、正己基或者这类烷基结构中的任意一种；其中R为NO供体结构，选自硝酸酯。
进一步地，所述衍生物的结构式为式II中的任一种：
进一步地，其反应路线如下：
其中X选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、正己基或者这类烷基结构中的任意一种。
进一步地，所述组合物包括NO供体型川芎嗪衍生物或其药学上可接受的盐，所述组合物为NO供体型川芎嗪衍生物或其药学上可接受的盐与药用辅料制成的不同剂型的药物。
进一步地，所述组合物在制备预防或治疗血栓栓塞性心脑血管疾病的药物中的应用。
进一步地，所述组合物在制备预防或治疗血小板聚集所导致疾病的药物中的应用。
进一步地，所述疾病指动脉粥样硬化、血栓形成性脑中风、暂时性脑缺血、冠心病、心肌梗死中任一种。
本发明与现有技术相比的优点在于：本发明提供了一类NO供体型川芎嗪衍生物及其制备方法，同时还提供了NO供体型川芎嗪衍生物或其药学上可接受的盐与药用辅料制成的不同剂型的组合物，以及该组合物在制备预防或治疗血栓栓塞性心脑血管疾病、血小板聚集所导致疾病的药物中的应用，具体的，本发明提供了9种化合物，其中的5种在体外对ADP和AA介导的血小板聚集的抑制作用实验中，化合物TN-1表现出良好的抑制活性，均优于川芎嗪单体，优于川芎嗪中间体T1，还优于对照化合物T2。
附图说明
图1是本发明部分组合物在体外对ADP介导的血小板聚集的抑制作用结果，*p<0.05vs TMP，n＝5。
图2是本发明部分组合物在体外对AA介导的血小板聚集的抑制作用结果，*p<0.05vs TMP，n＝5
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明，各实施例及试验例中所用的设备和试剂如无特殊说明，均可从商业途径得到。此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
根据本申请包含的信息，对于本领域技术人员来说可以轻而易举地对本发明的精确描述进行各种改变，而不会偏离所附权利要求的精神和范围。应该理解，本发明的范围不局限于所限定的过程、性质或组分，因为这些实施方案以及其他的描述仅仅是为了示意性说明本发明的特定方面。实际上，本领域或相关领域的技术人员明显能够对本发明实施方式作出的各种改变都涵盖在所附权利要求的范围内。
为了更好地理解本发明而不是限制本发明的范围，在本申请中所用的表示用量、百分比的所有数字、以及其他数值，在所有情况下都应理解为以词语“大约”所修饰。因此，除非特别说明，否则在说明书和所附权利要求书中所列出的数字参数都是近似值，其可能会根据试图获得的理想性质的不同而加以改变。各个数字参数至少应被看作是根据所报告的有效数字和通过常规的四舍五入方法而获得的。本发明中，“约”指给定值或范围的10％以内，优选为5％以内。
本发明下述各实施例中未特别限定温度时，则均为常温条件。常温是指四季中自然室温条件，不进行额外的冷却或加热处理，一般常温控制在10～30℃，最好是15～25℃。
除非另外说明，在说明书和权利要求中使用的以下术语具有下面讨论的含义：
“烷基”包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、正己基。
本发明中所指的“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、三氟乙酸、丙酸、丙烯酸、己酸、环戊烷丙酸、羟乙酸、丙酮酸、草酸、(D)或(L)苹果酸、富马酸、酒石酸、马来酸、抗坏血酸、苯甲酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、樟脑酸、草酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、肉桂酸、十二烷基硫酸、葡糖酸、谷氨酸、天冬氨酸、硬脂酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺、奎宁等。
本发明中的“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的辅料，混合。药物组合物的目的是促进给药给动物的过程。
本发明中的“药用辅料”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
本发明提供了一种药物组合物，它以本发明所述的化合物、异构体或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的盐。该药物组合物的活性成分可以只为本发明化合物，也可以与现有的其他药物配伍使用。
本发明中，在给予哺乳动物通式I化合物及其药学上可接受的盐，以及这些化合物的溶剂化物(这里统称为“治疗药物”)时，可以单独使用，或者最好是按照规范的制药方法将其与适于药用的载体或稀释剂配合后使用。给药方式可以经各种途径，包括口服、非胃肠道给药或局部给药。这里所指的非胃肠道给药包括但并不限于静脉注射、肌肉注射、腹腔注射、皮下注射和透皮给药。
本发明的化合物、异构体或其药学上可接受的盐可应用在治疗和/或预防血栓栓塞性心脑血管疾病，治疗和/或预防血小板聚集导致的疾病，或者可应用在治疗或预防与缺血性有关的疾病方面。
本发明披露了一类NO供体型川芎嗪衍生物、制备方法、药物组合物及用途。下面将结合本发明实施例，对本发明的技术方案进行清楚、完整的描述。
实施例1
本实施例中共合成9种化合物，分别简称为TN-1至TN-9。
化合物TN-1名称：2-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-2-硝基氧基乙酯，结构式如下：
化合物TN-2名称：3-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-2-硝基氧基乙酯，结构式如下：
化合物TN-3名称：4-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-2-硝基氧基乙酯，结构式如下：
化合物TN-4名称：2-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-4-硝基氧基丁酯，结构式如下：
化合物TN-5名称：3-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-4-硝基氧基丁酯，结构式如下：
化合物TN-6名称：4-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-4-硝基氧基丁酯，结构式如下：
化合物TN-7名称：2-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-6-硝基氧基己酯，结构式如下：
化合物TN-8名称：3-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-6-硝基氧基己酯，结构式如下：
化合物TN-9名称：4-(E)-(3-(3,5,6-三甲基吡嗪-2-基)丙烯酰氧基)苯甲酸-6-硝基氧基己酯，结构式如下：
本发明本实施例中涉及的反应路线如下：
步骤a：称取川芎嗪三水合物(20.4g，107mmol)，将其溶解在30ml冰醋酸中，加入30％过氧化氢溶液(12.1m1，107mmol)于90℃反应2h，之后补充加入30％过氧化氢(12ml，107mmol)，继续反应2h，TLC监测反应完全后，将反应液冷却至室温。冰水浴下，以50％氢氧化钠溶液调节反应液pH至10，此时会有大量的白色固体析出，加入二氯甲烷萃取(150ml，50ml×3次)，用无水硫酸钠干燥4h，过滤二氯甲烷溶液，减压旋转蒸发去溶剂，得到白色的川芎嗪单氮氧化合物(1)粗品。
步骤b：将所得川芎嗪单氮氧化合物粗品(13.8g，90.6mmol)置于单口瓶，加入醋酐(17.1ml，181.2mmol)后，缓慢加热至140℃回流2.5h，TLC监测至反应完全后，得到深棕色浆状川芎嗪乙酰化物(2)。
步骤c：将深棕色浆状川芎嗪乙酰化物(2)冷却至室温，冰水浴下，慢慢加入20％氢氧化钠溶液(100m1)，室温下搅拌过夜(12h)，二氯甲烷提取(160ml，40ml×4次)，无水硫酸钠干燥4h，过滤二氯甲烷溶液，减压旋转蒸去溶剂，得到棕黄色的2-羟甲基-3,5,6-三甲基吡嗪粗品。粗品以石油醚乙酸乙酯混合溶剂(PE:EA＝10:1，V/V)重结晶，得淡黄色结晶5.5g，为化合物3。总产率33.7％。
步骤d：将2-羟甲基-3,5,6-三甲基吡嗪(3，6.09g，40mmol)置于50mL单口瓶中，加入无水乙醇(20mL)溶解，加入活性二氧化锰(20.8g，240mmol)加热回流反应6h，TLC监测反应结束后，在玻璃砂芯漏斗中垫一层滤纸，再铺适量的硅藻土(中位粒径13μm，煅烧)和一层滤纸，倒入反应混合物抽滤，滤液减压蒸干得黄色固体5.67g，为化合物4，产率94.4％。
步骤e：将3,5,6-三甲基吡嗪-2-甲醛(4，5.50g，36.6mmol)置于50mL单口瓶中，加入50mL的甲苯，搅拌下，向溶液中慢慢加入氢化钠(1.76g，73.2mmol)，用锡箔纸包裹反应瓶，向反应液中滴加膦酰基乙酸三乙酯(9.0g，40.3mmol)，室温避光反应8-10h，TLC监测反应。反应完全后，加入等体积乙酸乙酯稀释，用食盐水洗涤(50mL×2次)，分液后用无水硫酸钠干燥8h，过滤，滤液减压蒸去溶剂得(E)-3-(3,5,6-三甲基吡嗪-2-基)丙烯酸乙酯粗品。粗品经硅胶柱层析纯化(PE/EA＝8:1，V/V)后得亮黄色油状物6.45g，为化合物5，产率80.0％。
步骤f：将(E)-3-(3,5,6-三甲基吡嗪-2-基)丙烯酸乙酯(5，6.45g，29.3mmol)溶于四氢呋喃和水的混合溶液(V(THF)/V(H2O)＝2:1，30mL)中，加入氢氧化钠(2.35g，58.6mmol)，室温下搅拌4h，TLC监测反应完全。反应完全后，用2N的盐酸调节反应液pH至3，加入固体氯化钠至饱和，用乙酸乙酯萃取(50mL×3次)，合并有机相后用无水硫酸钠干燥8h。过滤，滤液减压旋转蒸去溶剂，得白色固体5.50g，为化合物6，产率97.8％。
步骤g：中间体7a～i的合成：将羟基苯甲酸(1.22g，5mmol)溶于20ml丙酮中，加入二溴代烷(7.5mmol，1.5eq)和三乙胺(0.76g，7.5mmol，1.5eq)，在氮气保护下加热回流5h，反应结束后冷却至室温，上旋转蒸发仪旋干，加入适量乙酸乙酯后搅拌5min，抽滤，向滤液中加入适量柱层析硅胶后旋干，经柱层析分离得中间体7a～i。
7a，经柱层析(PE/EtOAc＝8/1，v/v)分离得到无色液体0.27g，产率22.1％。
7b，经柱层析(PE/EtOAc＝8/1，v/v)分离得到无色液体0.33g，产率27.1％。
7c，经柱层析(PE/EtOAc＝6/1，v/v)分离得到白色固体0.36g，产率29.5％。
7d，经柱层析(PE/EtOAc＝10/1，v/v)分离得到无色油状物0.83g，产率61.1％。
7e，经柱层析(PE/EtOAc＝8/1，v/v)分离得到无色油状物0.67g，产率49.3％。
7f，经柱层析(PE/EtOAc＝10/1，v/v)分离得到无色油状物0.80g，产率58.9％。
7g，经柱层析(PE/EtOAc＝10/1，v/v)分离得到无色油状物0.90g，产率59.8％。
7h，经柱层析(PE/EtOAc＝10/1，v/v)分离得到无色油状物1.35g，产率89.7％。
7i，经柱层析(PE/EtOAc＝10/1，v/v)分离得到无色油状物0.59g，产率39.2％。
步骤h：中间体8a～i的合成：将化合物6(0.19g，1mmol)和DCC(0.23g，1.1mmol)溶于20mL无水二氯甲烷中，加入催化量的DMAP(0.1mmol)，室温下搅拌15min。再加入中间体7a～i(1.1mmol)，室温搅拌反应4～6h，反应结束后抽滤，将所得滤液上旋转蒸发仪旋干，加入适量乙酸乙酯后搅拌5min，再次抽滤，向滤液中加入适量柱层析硅胶后旋干，经柱层析分离得中间体10a～i。
8a，经柱层析(PE/EtOAc＝5/1，v/v)分离得白色粉末0.28g，产率67.6％。
8b，经柱层析(PE/EtOAc＝5/1，v/v)分离得白色粉末0.29g，产率70.0％。
8c，经柱层析(PE/EtOAc＝5/1，v/v)分离得白色粉末0.29g，产率70.0％。
8d，经柱层析(PE/EtOAc＝5/1，v/v)分离得黄色黏性固体0.20g，产率42.7％。
8e，经柱层析(PE/EtOAc＝5/1，v/v)分离得黄色黏性固体0.41g，产率92.7％。
8f，经柱层析(PE/EtOAc＝5/1，v/v)分离得白色片状固体0.42g，产率95.0％。
8g，经柱层析(PE/EtOAc＝4/1，v/v)分离得白色固体0.44g，产率93.6％。
8h，经柱层析(PE/EtOAc＝4/1，v/v)分离得白色固体0.46g，产率98.0％。
8i，经柱层析(PE/EtOAc＝5/1，v/v)分离得白色固体0.45g，产率95.8％。
步骤i：目标产物TN-1～9的合成：将中间体8a～i(1.0eq)溶于20ml乙腈中，加入AgNO3(1.5eq)，避光下于70℃反应3～4h，反应结束后抽滤，将所得滤液上旋转蒸发仪旋干，加入适量乙酸乙酯后搅拌5min，再次抽滤，再滤液中加入适量柱层析硅胶后旋干，经柱层析分离得目标产物。或将滤液浓缩后经制备薄层层析板分离得目标产物TN-1～9。
TN-1,经柱层析(PE/EtOAc＝2/1，v/v)分离得淡黄色黏性固体0.10g，产率37.2％。
TN-2，经柱层析(PE/EtOAc＝2/1，v/v)分离得黄色黏性固体0.08g，产率64.3％。
TN-3，经柱层析(PE/EtOAc＝2/1，v/v)分离得黄色黏性固体0.06g，产率49.8％。
TN-4，经柱层析(PE/EtOAc＝4/1，v/v)分离得淡黄色黏性固体0.03g，产率38.8％。
TN-5，经柱层析(PE/EtOAc＝5/1，v/v)分离得淡黄色黏性固体0.27g，产率68.6％。
TN-6，经GF254薄层板层析(DCM/MeOH＝50/1,v/v)分离得黄色固体0.26g，产率64.5％。
TN-7，经GF254薄层板层析(DCM/MeOH＝50/1,v/v)分离黄色油状物0.25g，产率59.0％。
TN-8，经柱层析(PE/EtOAc＝5/1，v/v)分离得黄色油状物0.12g，产率27.1％。
TN-9，经GF254薄层板层析(DCM/MeOH＝50/1,v/v)分离黄色固体0.28g，产率64.7％。
所有合成的化合物均经1HNMR、13CNMR和HRMS谱图分析，确认为正确结构：
TN-1,2-(nitrooxy)ethyl(E)-2-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.1H NMR(600MHz,Chloroform-d):δ8.08(d,1H,J＝6.4Hz,6-ArH),8.05(d,1H,J＝15.6Hz,ArCH＝CH),7.60(t,1H,J＝7.8Hz,4-ArH),7.36(t,1H,J＝7.6Hz,5-ArH),7.31(d,1H,J＝15.3Hz,ArCH＝CH),7.19(d,1H,J＝8.0Hz,3-ArH),4.38(t,2H,J＝4.5Hz,CH2 CH2 NO3),3.84(t,2H,J＝4.5Hz,CH2 CH2NO3),2.66(s,3H,ArCH3),2.56(d,6H,J＝5.9Hz,ArCH3)；13C NMR(151MHz,CDCl3)δ165.28,164.98,152.75,150.56,150.22,148.86,142.79,140.50,133.99,132.03,126.19,123.78,123.43,122.71,77.22,77.01,76.80,66.93,60.71,21.63,21.61,20.29；HRMS(ESI):m/z:402.1301calc.for C19H20N3O7[M+H]+,found402.1291,ppm error-2.5.
TN-2,2-(nitrooxy)ethyl(E)-3-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.1H NMR(600MHz,Chloroform-d)δ8.03(d,1H,J＝15.2Hz,ArCH＝CH),7.96(d,1H,J＝7.8Hz,6-ArH),7.86(s,1H,2-ArH),7.49(m,1H,J＝7.9Hz,5-ArH),7.39(d,1H,J＝8.1Hz,4-ArH),7.24(d,1H,J＝15.3Hz,ArCH＝CH),4.47(t,2H,J＝4.6Hz,CH2CH2NO3),3.96(t,2H,J＝4.6Hz,CH2CH2NO3),2.64(s,3H,ArCH3),2.55(s,6H,ArCH3)；13CNMR(151MHz,CDCl3)δ165.93,164.95,153.15,150.68,150.26,149.17,142.28,140.95,131.41,129.49,127.12,126.51,122.89,121.88,77.22,77.01,76.80,66.90,61.19,21.95,21.71,20.58；HRMS(ESI):m/z:402.1301 calc.for C19H20N3O7[M+H]+,found402.1300,ppm error-0.2.
TN-3,2-(nitrooxy)ethyl(E)-4-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.1H NMR(600MHz,Chloroform-d):δ8.12(d,2H,J＝8.5Hz,2,6-ArH),8.03(d,1H,J＝15.2Hz,ArCH＝CH),7.31-7.24(m,3H,3,5-ArH and ArCH＝CH),4.48(t,2H,J＝4.7Hz,CH2 CH2 NO3),3.97(t,2H,J＝4.6Hz,CH2 CH2NO3),2.67(s,3H,ArCH3),2.58(d,6H,J＝7.2Hz,ArCH3)；13C NMR(151MHz,CDCl3)δ166.11,164.47,154.54,152.61,150.83,148.59,142.77,140.60,131.29,127.43,122.34,121.63,77.21,77.00,76.79,66.77,61.33,21.71,21.52,20.12；HRMS(ESI):m/z:402.1301 calc.for C19H20N3O7[M+H]+,found402.1299,ppm error-0.5.
TN-4,4-(nitrooxy)butyl(E)-2-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.1H NMR(600MHz,Chloroform-d)δ8.06(d,1H,J＝14.7 Hz,ArCH＝CH),8.04(d,1H,J＝7.9Hz,6-ArH),7.60(t,1H,J＝7.8Hz,4-ArH),7.36(t,1H,J＝7.7Hz,5-ArH),7.32(d,1H,J＝15.2Hz,ArCH＝CH),7.19(d,1H,J＝8.1Hz,3-ArH),4.43(t,2H,J＝5.9Hz,CH2NO3),4.30(t,2H,J＝5.6Hz,COOCH2),2.65(s,3H,ArCH3),2.55(d,6H,J＝5.6Hz,ArCH3),1.87–1.77(m,4H,CH2 CH2CH2 CH2)；13C NMR(151MHz,CDCl3)δ165.17,164.62,153.10,150.39,150.23,149.14,142.28,140.79,133.91,131.78,126.11,123.84,123.52,122.00,77.22,77.01,76.79,72.53,64.18,24.99,23.62,21.97,21.70,20.58；HRMS(ESI):m/z:430.1614 calc.for C21H24N3O7[M+H]+,found 430.1617,ppm error 0.7.
TN-5,4-(nitrooxy)butyl(E)-3-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.
1H NMR(600MHz,Chloroform-d)δ8.04(d,1H,J＝15.2Hz,ArCH＝CH),7.93(dt,1H,J＝7.8,1.3Hz,6-ArH),7.83(t,1H,J＝2.0Hz,2-ArH),7.50(t,1H,J＝7.9Hz,5-ArH),7.40(ddd,1H,J＝8.1,2.4,1.1Hz,4-ArH),7.26(d,1H,J＝15.3Hz,ArCH＝CH),4.55–4.49(m,2H,CH2NO3),4.41–4.35(m,2H,COOCH2),2.65(s,3H,ArCH3),2.55(s,6H,ArCH3),1.91(m,4H,J＝3.0Hz,CH2 CH2CH2 CH2)；13C NMR(151MHz,CDCl3)δ165.53,164.95,153.17,150.73,150.21,149.19,142.26,140.97,131.58,129.50,126.98,126.44,122.77,121.89,77.23,77.01,76.80,72.54,64.22,25.08,23.70,21.99,21.72,20.61；HRMS(ESI):m/z:430.1614calc.for C21H24N3O7[M+H]+,found 430.1614,ppm error 0.0.
TN-6,4-(nitrooxy)butyl(E)-4-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.
1H NMR(600MHz,Chloroform-d)δ8.10(d,2H,J＝8.7Hz,2,6-ArH),8.04(d,1H,J＝15.2Hz,ArCH＝CH),7.27(d,3H,J＝8.2Hz,3,5-ArH and ArCH＝CH),4.57–4.50(m,2H,CH2NO3),4.38(m,2H,COOCH2),2.65(s,3H,ArCH3),2.56(s,6H,ArCH3),1.92(m,4H,J＝3.3Hz,CH2 CH2CH2 CH2)；13C NMR(151MHz,CDCl3)δ165.70,164.60,154.51,153.15,150.34,149.14,142.31,141.05,131.83,131.14,127.72,127.57,121.91,121.66,121.62,115.24,77.20,76.99,76.78,72.63,72.55,64.06,63.61,25.14,25.12,23.76,23.72,21.92,21.72,20.54；HRMS(ESI):m/z:430.1614 calc.for C21H24N3O7[M+H]+,found 430.1618,ppm error0.9.
TN-7,6-(nitrooxy)hexyl(E)-2-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.1H NMR(600MHz,Chloroform-d):δ8.01(d,1H,J＝15.3Hz,ArCH＝CH),8.00(d,1H,J＝8.5Hz,6-ArH),7.55(t,1H,J＝7.7Hz,4-ArH),7.31(t,1H,J＝6.8Hz,5-ArH),7.29(d,1H,J＝15.4Hz,ArCH＝CH),7.15(d,1H,J＝8.1Hz,3-ArH),4.34(t,2H,J＝6.6Hz,CH2NO3),4.22(t,2H,J＝6.6Hz,COOCH2),2.61(s,3H,ArCH3),2.51(d,6H,J＝4.1Hz,ArCH3),1.65(m,4H,J＝14.5,7.6Hz,CH2 CH2 CH2CH2 CH2 CH2),1.37(m,4H,J＝11.7,10.4,6.8Hz,CH2CH2 CH2CH2 CH2CH2)；13C NMR(151MHz,CDCl3)δ165.15,164.69,153.08,150.38,150.08,149.15,142.27,140.63,133.71,133.68,131.78,131.74,126.04,126.02,123.81,123.79,123.77,122.12,122.09,77.27,77.06,76.85,73.06,65.07,64.92,28.44,28.39,26.55,25.62,25.54,25.29,25.17,22.03,22.01,21.73,21.69,20.67,20.65；HRMS(ESI):m/z:458.1927calc.for C23H28N3O7[M+H]+,found 458.1927,ppm error 0.0.
TN-8,6-(nitrooxy)hexyl(E)-3-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.1H NMR(600MHz,Chloroform-d)δ8.04(d,1H,J＝15.3Hz,ArCH＝CH),7.95(d,1H,J＝7.8Hz,6-ArH),7.85–7.82(m,1H,2-ArH),7.50(t,1H,J＝7.9Hz,5-ArH),7.39(dd,1H,J＝8.1,1.3Hz,4-ArH),7.26(d,1H,J＝15.3Hz,ArCH＝CH),4.46(t,2H,J＝6.6Hz,CH2NO3),4.34(t,2H,J＝6.6Hz,COOCH2),2.69(s,3H,ArCH3),2.58(d,6H,J＝13.3Hz,ArCH3),1.83–1.73(m,4H,CH2CH2CH2CH2CH2CH2),1.50(m,4H,J＝3.6,2.7Hz,CH2CH2CH2CH2CH2CH2)；13C NMR(151MHz,CDCl3)δ165.66,164.97,153.18,150.69,150.18,149.21,142.25,140.95,131.90,129.43,126.98,126.26,122.75,121.91,77.23,77.02,76.81,73.14,64.97,28.47,26.66,25.63,25.37,22.01,21.72,20.63；HRMS(ESI):m/z:458.1927calc.for C23H28N3O7[M+H]+,found 458.1931,ppm error 0.9.
TN-9,6-(nitrooxy)hexyl(E)-4-((3-(3,5,6-trimethylpyrazin-2-yl)acryloyl)oxy)benzoate.1H NMR(600MHz,Chloroform-d)δ8.10(d,2H,J＝8.6Hz,2,6-ArH),8.04(d,1H,J＝15.3Hz,ArCH＝CH),7.29–7.25(m,3H,3,5-ArH and ArCH＝CH),4.46(t,2H,J＝6.7Hz,CH2NO3),4.34(t,2H,J＝6.6Hz,COOCH2),2.65(s,3H,ArCH3),2.56(d,6H,J＝4.0Hz,ArCH3),1.78(m,4H,J＝20.2,6.9Hz,CH2CH2CH2CH2CH2CH2),1.52–1.48(m,4H,CH2CH2CH2CH2CH2CH2)；13C NMR(151MHz,CDCl3)δ165.81,164.61,154.38,153.24,150.20,149.23,142.19,141.08,131.10,127.87,121.82,121.58,77.25,77.03,76.82,73.14,64.79,28.51,26.67,25.62,25.37,22.00,21.71,20.61；HRMS(ESI):m/z:458.1927calc.for C23H28N3O7[M+H]+,found 458.1928,ppm error 0.2.
实施例2
本实施例中合成1种化合物，简称为T2，为化合物TN-1\TN-2\TN-3等的药理实验对照化合物。
化合物T2名称：(E)-3-(3,5,6-三甲基吡嗪-2-基)丙烯酸-2-硝基氧基-乙酯，结构式如下：
本发明本实施例中涉及的反应路线如下：
步骤a：中间体9的合成：将2-溴乙醇(10mmol)溶于50ml乙腈中，加入AgNO3(2.55g，15mmol)，避光下于70℃反应3h，反应结束后抽滤，将所得滤液上旋转蒸发仪旋干，加入适量乙酸乙酯后搅拌5min，再次抽滤、旋干，得浅黄色液体0.82g，为中间体9，产率76.6％。
步骤b：将化合物6(0.74g，3.8mmol)和DCC(0.79g，1.0mmol)溶于30mL无水二氯甲烷中，加入催化量的DMAP(0.1mmol)，室温下搅拌15min。再加入中间体9(3.5mmol)，室温搅拌反应8h，反应结束后抽滤，将所得滤液上旋转蒸发仪旋干，加入适量乙酸乙酯后搅拌5min，再次抽滤，向滤液中加入适量柱层析硅胶后旋干，经柱层析(PE/EtOAc＝5/1，v/v)分离得到白色蜡质固体0.40g，为化合物T2，产率47.0％。1H NMR(600MHz,Chloroform-d):δ7.88(d,1H,J＝15.3Hz,ArCH＝CH),7.06(d,1H,J＝15.3Hz,ArCH＝CH),4.79–4.72(m,2H,CH2CH2NO3),4.55–4.48(m,2H,CH2CH2NO3),2.62(s,3H,ArCH3),2.52(d,6H,J＝4.6Hz,ArCH3)；13C NMR(151MHz,CDCl3)δ166.28,153.01,150.02,149.12,142.25,140.06,121.87,77.20,76.99,76.77,70.44,60.36,22.02,21.69,20.66；HRMS(ESI):m/z:281.1112calc.forC12H15N3O5[M+H]+,found281.1109,ppm error-1.1。
实施例3本发明的代表化合物的抗血小板聚集药理试验及结果
采用Born比浊法测定不同化合物对花生四烯酸(Arachidonic Acid,AA)或二磷酸腺苷(Adenosine5'-diphosphate,ADP)介导的血小板聚集的IC50。具体实施方法如下：
富血小板血浆(PRP)和贫血小板浆(PPP)制备：取禁食12-18h的家兔，用20％乌拉坦溶液腹腔注射麻醉，分离颈总动脉，***聚乙烯管取血，注入含1/10容量的3.8％枸橼酸钠溶液的硅化离心管中，将血液与抗凝剂轻轻混均，以1000转/min，离心15min，吸出上层米黄色悬液约即为富血小板血浆(PRP)。余下的血浆再以3000转/min，离心15min，吸取上清液，制得贫血小板血浆(PPP)，以PPP调PRP使血小板数在1×108/mL。
实验药物分组：阳性对照组：TMP；实验组：T1、T2(即实施例1中中间体6)、TN-1、TN-2、TN-3、TN-4、TN-7。所有药物设置6个浓度0.1、0.2、0.4、0.8、1.6、3.2mmol/L。
采用Born比浊法在37℃条件下测定血小板聚集率。取260μl PRP于比浊管中，随后分别加入10μl不同浓度的待测化合物、阳性对照药或DMSO溶液，37℃条件下孵育5min，再依次加入诱导剂30μl，诱导剂ADP终浓度为10μM，诱导剂AA终浓度为1mM。采用血小板聚集仪测定对照管和测试管5min内的最大聚集率，计算出药物对血小板聚集的抑制率，血小板聚集抑制率(IRPA)＝(对照组血小板聚集率-实验组血小板聚集率)/对照组血小板聚集率×100％。利用GraphPadPrism软件绘制量效曲线得到IC50。数据均以means±SD表示，组间统计学差异采用one-wayANOVA和Tukey’s检验，P值小于0.05认为有显著性差异。
表1化合物对ADP/AA诱导的血小板聚集的抑制作用(Mean±SD,n＝5,*P<0.05vsTMP.)
如表1所示，化合物TN-1对ADP诱导的血小板聚集的具有良好的抑制作用，IC50为0.7736，与川芎嗪单体相比具有显著性差异；对AA诱导的血小板聚集的也具有良好的抑制作用，IC50为0.6232，与川芎嗪单体相比具有显著性差异。这表明化合物TN-1具有较好的抗血小板聚集活性，且综合活性比原化合物川芎嗪更优。
初步分析化合物的构效关系发现，NO供体通过碳链连接在苯环上的邻位时，活性最好，连接在间位和对位时，活性依次减弱；NO供体的碳链长度对化合物的抗血小板聚集活性也有影响，当碳链长度为2个碳时，活性最好，延长碳链长度为4个和6个碳时，活性依次减弱。为探究活性基团水杨酸对化合物活性的影响和贡献，我们合成了对照化合物T2，其结构由川芎嗪中间体和NO供体连接而成。抗血小板聚集实验结构表明，与川芎嗪单体和化合物TN-1相比，其活性大幅减弱，说明水杨酸结构对化合物TN-1的活性有重要影响。为进一步说明NO供体结构对化合物活性的影响，我们同时对川芎嗪中间体T1进行了实验，结果表明，在由ADP诱导的抗血小板聚集实验中，其活性减弱，而由AA诱导的抗血小板聚集实验中，其活性更优，考虑到T1含游离的羧酸结构，对抗血小板聚集实验存在影响，但仍初步表明NO供体结构在AA诱导的抗血小板聚集活性中提供更多的贡献。综合分析可知，化合物TN-1结构的活性基团水杨酸结构、NO供体结构对其整体活性都是必需的，都发挥了增强活性的作用。
以上对本发明及其实施方式进行了描述，这种描述没有限制性，所列举的实施例中也只是本发明的较佳实施例而已，并不用以限制本发明。总而言之如果本领域的普通技术人员受其启示，在不脱离本发明创造宗旨的情况下，不经创造性的设计出与该技术方案相似的结构方式及实施例，均应属于本发明的保护范围。
Claims (7)
1.一类NO供体型川芎嗪衍生物，其特征在于，所述衍生物包括川芎嗪中间体母核、活性基团、连接臂、NO供体结构，其结构通式如式I所示：
其中X为连接臂，选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、正己基或者这类烷基结构中的任意一种；其中R为NO供体结构，选自硝酸酯。
2.根据权利要求1所述的一类NO供体型川芎嗪衍生物，其特征在于，所述衍生物的结构式为式II中的任一种：
3.根据权利要求1或2任意一项所述的一类NO供体型川芎嗪衍生物的制备方法，其特征在于，其反应路线图如下：
其中X选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、正己基或者这类烷基结构中的任意一种。
4.根据权利要求1或2任意一项所述的一类NO供体型川芎嗪衍生物的组合物，其特征在于，所述组合物包括NO供体型川芎嗪衍生物或其药学上可接受的盐，所述组合物为NO供体型川芎嗪衍生物或其药学上可接受的盐与药用辅料制成的不同剂型的药物。
5.根据权利要求4所述的组合物的用途，其特征在于：所述组合物在制备预防或治疗血栓栓塞性心脑血管疾病的药物中的应用。
6.根据权利要求4所述的组合物的用途，其特征在于：所述组合物在制备预防或治疗血小板聚集所导致疾病的药物中的应用。
7.根据权利要求5或6所述的组合物的用途，其特征在于：所述疾病指动脉粥样硬化、血栓形成性脑中风、暂时性脑缺血、冠心病、心肌梗死中任一种。
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