CN115068462A - 一种新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用 - Google Patents
一种新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用 Download PDFInfo
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- CN115068462A CN115068462A CN202111305254.0A CN202111305254A CN115068462A CN 115068462 A CN115068462 A CN 115068462A CN 202111305254 A CN202111305254 A CN 202111305254A CN 115068462 A CN115068462 A CN 115068462A
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Abstract
本发明提供了一种新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用。所述新型益母草碱海洋衍生物具有如下通式的结构：
其中R1选自1‑5个碳原子组成的烷基、3‑6个碳原子组成的环氧基、C2‑C6的饱和或不饱和烷基；R2选自氢或1‑5个碳原子组成的含氟烷基、3‑6个碳原子组成的环氧基、C2‑C6的饱和或不饱和烷基；R3选自氢或者1‑5个碳原子组成的烷氧基团；X选自氧或者氨基；n＝1‑5。经药理学实验证明，本发明的新型益母草碱海洋衍生物具有抑制TNF‑α的释放、中性白细胞或嗜酸性细胞增多的作用，其安全性良好，因此具有重要的开发意义。
Description
技术领域
本发明属于医药技术领域，具体涉及一种新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用。
背景技术
TNF-α是影响多种生物过程的重要的促炎性细胞因子，其能从激活的局势细胞、激活的T淋巴细胞、肥大细胞、嗜碱性粒细胞、成纤维细胞、内皮细胞和脑中的星形细胞释放。TNF-α自身对于中性白细胞、嗜酸性细胞、成纤维细吧和内皮细胞有激活作用，进而释放出不同的组织破坏性介质。在单核细胞、巨噬细胞和T淋巴细胞中，TNF-α导致其他的促炎性细胞因子例如GM-CSF(粒细胞-巨噬细胞集落刺激因子)或白介素-8的含量增加。由于TNF-α促进炎症和分解代谢作用，TNF-α在多种疾病中起着关键作用，这些疾病有例如呼吸道炎症、关节炎症、内毒素性休克、组织排斥、AIDS和多种其它免疫疾病。因此，PDE4抑制剂也是适用于治疗与TNF-α有关的疾病。
性堵塞性肺病(COPD)是一组慢性气流阻塞性疾病的统称，其合并了慢性支气管炎的不同综合征与排痰性咳嗽以及进行性和不可逆肺功能退化的症状。该病的病程是发作性的，并且通常并发有细菌感染。目前治疗慢阻肺的西药主要有支气管扩张剂包括茶碱类、β2激动剂和抗胆碱能药物，并配合氧疗、抗生素、激素及辅助通气等对症处理。但抗菌素长期使用易出现耐药和毒副反应，而反复感染的患者常选用高档抗菌素，其价格昂贵，病者难以承受；而激素则具有较强的副作用。攻击炎性介质、蛋白酶或粘着分子的新的治疗方法可能非常有前途。
在支气管中发现了通过嗜中性粒细胞支配的慢性炎症，其独立于与该疾病并发的细菌感染。除此之外，由嗜中性粒细胞释放的介质和酶是在呼吸道中观察到的结构性变化(肺气肿)的原因。因此，抑制嗜中性粒细胞的活动是预防或延迟COPD进行(肺功能参数退化)的合理起点。激活粒细胞的一个重要刺激是促炎性细胞因子TNF-α。目前已知TNF-α刺激嗜中性粒细胞形成氧自由基。PDE4抑制剂可非常有效地抑制多种细胞释放TNF-α，并因此抑制嗜中性粒细胞的活动。非特异性PDE抑制剂己酮可可碱能够抑制氧自由基生成以及嗜中性粒细胞噬吞细胞的能力。
此外，哮喘也是一种常见呼吸系统疾病，其是由多种细胞特别是肥大细胞、嗜酸性粒细胞和T淋巴细胞参与的慢性气道炎症，已成为严重威胁公众健康的一种主要慢性疾病。目前西医治疗哮喘的方式多依靠支气管扩张药或吸氧使症状缓解，并没有针对哮喘病的发病原因进行治疗。这种治标不治本的方式容易使人产生依赖性并且反复发作，还具有副作用，会严重影响患者正常生活。
尽管已知PDE4抑制剂已经显示了其有益药理作用，但这类抑制剂存在引起腹泻、恶心等不良作用。因此，研究新型的特异性抑制剂来克服这些不良反应，就成为抑制剂药物研究的热点之一。天然中药衍生物是新药研发先导化合物发现的宝库，从中寻找具有新型抑制剂，对于研发疗效高、副作用小的抑制剂抗炎药物具有重要意义。
益母草是一种唇形科的草本开花植物，其地上部分具有广泛的药理活性，数千年来一直作为中药原料被用于治疗痛经闭经、身体水肿等疾病。目前，已知的益母草中所含有的化合物大约有140个，其主要活性成分为生物碱、二萜和黄酮类化合物。在这些活性化合物中，以益母草碱和水苏碱的药理作用最为广泛，但是水苏碱具有脂溶性差、生物利用度低的缺陷；而益母草碱在体内易发生葡萄糖醛酸化，生物利用度低。
发明内容
本发明提供了一种新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用。经药理学实验证明，本发明基于益母草碱结构的新型衍生物具有抑制TNF-α活性以及预防和治疗炎症性疾病或过敏的作用。
为实现上述发明目的，本发明的技术方案如下：
本发明提供了一种新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用，所述新型益母草碱海洋衍生物具有如下通式的结构：
其中，R1选自1-5个碳原子组成的烷基、3-6个碳原子组成的环氧基、C2-C6的饱和或不饱和烷基；R2选自氢或1-5个碳原子组成的含氟烷基、3-6个碳原子组成的环氧基、C2-C6的饱和或不饱和烷基；R3选自氢或者1-5个碳原子组成的烷氧基团；X选自氧或者氨基；n＝1-5。
进一步的：所述新型益母草碱海洋衍生物具有如下通式的结构：
其中，R1选自-CH3、
或者
R2选自-H、-CH3、
或者
R3选自-H、-CH3或者-CH2CH3；X选自O或者NH；n＝3-4。
进一步的：所述新型益母草碱海洋衍生物具体为化合物A、B、C、D、E、F、G、H、I、J、K、L、M、N、O、P，其结构式分别如下：
其中，n＝3-4。
进一步的，所述的新型益母草碱海洋衍生物的制备方法包括以下步骤：
由3-环丙氧基-4-二氟甲氧基苯甲酸作为起始原料，在二异丙基碳酰亚胺的作用下，与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，甲醇重结晶后，在三氟乙酸作用下脱除Boc保护基，再在饱和碳酸氢钠溶解中析出固体，过滤后经乙醇重结晶得到化合物A；
或者由3-异丙氧基-4-二氟甲氧基苯甲酸作为起始原料，在二异丙基碳酰亚胺的作用下，与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，减压蒸馏后于冰甲醇下重晶体，在三氟乙酸作用下脱除Boc保护基，得到化合物B；
或者由3-乙烷氧基-4-二氟甲氧基苯甲酸作为起始原料，溶于二氯甲烷后，与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，加入缩合剂反应完全后抽滤，减压蒸馏后于冰甲醇下重晶体，在三氟乙酸作用下脱除Boc保护基，得到化合物C；
或者由乙酰丁香酸作为起始原料，溶于二氯甲烷和DPTS后，与Boc保护的4-胍基-1-丙醇缩合，加入缩合剂反应完全后抽滤，减压蒸馏后于冰甲醇下重晶体，在强碱作用下脱除乙酰基，在三氟乙酸作用下脱除Boc保护基，得到化合物D；
或者由3-乙基氧-4-甲氧基苯甲酸为起始原料，在二异丙基碳酰亚胺作用下，与Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇缩合，减压蒸馏后得到油状溶液，加入事先冰冻的冰甲醇作用使其析出晶体，晶体溶解后在二氯甲烷和三氟乙酸混合溶液中脱除Boc保护基，得到化合物E；
或者由3-乙基氧-4-乙氧基苯甲酸为起始原料，搅拌至澄清后加入Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇，搅拌加入缩合剂DIC，反应至完全后抽滤，再经减压蒸馏去除二氯甲烷，使用冰甲醇进行2次结晶后，再在二氯甲烷和三氟乙酸混合液中反应脱除Boc保护基，得到化合物F；
或者由3-环丙氧基-4-甲氧基苯甲酸为起始原料，在二异丙基碳酰亚胺作用下，与Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇进行缩合反应10-16小时，除去溶剂后，采用甲醇重结晶制的产物，其产物溶解后再在三氟乙酸作用下脱除Boc保护基，再在饱和碳酸氢钠溶解中析出固体，过滤后经乙醇重结晶，得到化合物G；
或者由3-环丙氧基-4-乙氧基苯甲酸为起始原料，搅拌至澄清后加入Boc保护的4-胍基-1-丁醇或者4-胍基-1-丙醇缩合，搅拌加入缩合剂DIC，反应至完全后抽滤，再经减压蒸馏去除二氯甲烷，使用冰甲醇进行2次结晶后，再在二氯甲烷和三氟乙酸混合液中反应脱除Boc保护基，得到化合物H；
或者由3-异丙氧-4-甲氧基苯甲酸为起始原料，在二异丙基碳酰亚胺作用下，与Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇缩合，减压蒸馏后得到油状溶液，加入事先冰冻的冰甲醇作用使其析出晶体，晶体溶解后在二氯甲烷和三氟乙酸混合溶液中脱除Boc保护基，得到化合物I；
或者由3-异丙氧基-4-乙氧基苯甲酸为起始原料，在二异丙基碳酰亚胺作用下，与Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇进行缩合反应10-16小时，除去溶剂后，采用甲醇重结晶制的产物，其产物溶解后再在三氟乙酸作用下脱除Boc保护基，再在饱和碳酸氢钠溶解中析出固体，过滤后经乙醇重结晶，得到化合物J；
或者由3-环丙氧基-4-二氟甲氧基苯甲酸在四氢呋喃溶剂中与二氯亚砜反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在二氯甲烷溶液中与氢氧化钠作用得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，制备所得粗品经乙酸乙酯重结晶，得到化合物K；
或者由3-环丙氧基-4-乙氧基苯甲酸在甲苯溶剂中与草酰氯或三氯化磷反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在二氯甲烷或者DMF溶液中在氢化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，乙酸乙酯萃取，无水硫酸钠干燥并再次重结晶，得到化合物L；
或者由3-环丙氧基-4-甲氧基苯甲酸在溶剂甲苯中与五氯化磷反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在四氢呋喃或者二氯甲烷溶液中在氢氧化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，乙酸乙酯萃取，无水硫酸钠干燥后并再次重结晶，得到化合物M；
或者由3，4-乙氧基苯甲酸在溶剂二氯甲烷或者DMF中与二氯亚砜或草酰氯反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在四氢呋喃或者DMSO溶液中在氢化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，制备所得粗品经乙酸乙酯重结晶，得到化合物N；
或者由3-乙氧基-4-甲氧基苯甲酸在溶剂二氯甲烷中与二氯亚砜反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在甲苯溶液中在氢氧化钾或者氢化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，乙酸乙酯萃取，无水硫酸钠干燥后并再次重结晶，得到化合物O；
或者由3-异丙氧基-4-乙氧基苯甲酸在溶剂四氢呋喃中与或草酰氯反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在甲苯溶液中在氢化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，乙酸乙酯萃取，无水硫酸钠干燥后并再次重结晶，得到化合物P。
进一步的：所述的新型益母草碱海洋衍生物还包括其药学上可接受的盐，并可通过无机酸或有机酸中和碱的方法获得。
进一步的：所述无机酸包括盐酸、硫酸、磷酸或氢溴酸；所述有机酸包括羧酸、硫代酸、磺酸、乙酸、酒石酸、乳酸、丙酸、乙醇酸、丙二酸、马来酸、富马酸、鞣酸、琥珀酸、藻酸、苯甲酸、2-苯氧基苯甲酸、2一乙酰氧基苯甲酸、肉桂酸、扁桃酸、柠檬酸、苹果酸、水杨酸、3-氨基水杨酸、抗坏血酸、扑酸、烟酸、异烟酸、草酸、氨基酸、甲磺酸、乙磺酸、2-羟基乙磺酸、乙-1,2一二磺酸、苯磺酸、4-甲基苯磺酸或萘-2-磺酸。
进一步的：所述的新型益母草碱海洋衍生物还包括其D型、L型或D,L-混合物。
进一步的：所述的新型益母草碱海洋衍生物还包括其非对映异构体。
进一步的，所述新型益母草碱海洋衍生物能够通过抑制TNF-α的释放、LPS引起的中性白细胞增多或过敏引起的嗜酸性细胞增多，进而减轻炎症性疾病或过敏的症状，达到预防和治疗炎症性疾病或过敏的作用。
进一步的：与抑制TNF-α释放有关的炎症性疾病包括关节炎、类风湿性关节炎、类风湿性脊椎炎、骨关节炎、骨质疏松、脓毒症、脓毒性休克、格兰氏阴性脓毒症、中毒性休克综合征、呼吸窘迫综合征、哮喘和其它慢性肺病、骨吸收疾病或移植排斥反应或其它自身免疫性、红斑狼疮、多发性硬化、肾小球性肾炎和眼色素层炎、胰岛素依赖性糖尿病和慢性脱髓鞘。
进一步的：与嗜酸性细胞增多相关的炎症性疾病或过敏包括支气管哮喘、过敏性鼻炎、过敏性结膜炎、特应性皮炎、湿疹、过敏性脉管炎、嗜酸性细胞引起的炎症，例如嗜酸细胞性筋膜炎、嗜酸细胞性肺炎和PIE综合征(嗜酸性细胞增多的肺浸润)、荨麻疹、溃疡性结膜炎、局限性回肠炎、牛皮癣和角化病。
进一步的：本发明化合物还可用于治疗与TNF相关的感染，例如病毒感染和寄生虫感染，例如治疗疟疾、利什曼病、感染引起的发烧、感染引起的肌肉疼痛、AIDS和恶病质。
进一步的：与LPS引起的中性白细胞增多相关的疾病包括慢性堵塞性肺病。
进一步的：所述的药物为片剂、口服液、气雾剂、丸剂、胶囊剂、颗粒剂、膏剂、滴丸剂、糖浆剂、散剂、冲剂、酊剂、粉针剂或注射液。
进一步的：所述的药物通过口服、非胃肠道、静脉内、透皮、局部、吸入或鼻内给药。
进一步的：所述的药物的剂量为每天施用一次的单一剂量给药，或者每天分成两次或更多次剂量给药，每次为0.001-100mg。
进一步的：所述的药物中还包括辅助剂、载体和添加剂中的至少一种。
进一步的：所述载体包括碳酸钙、磷酸钙、磷酸钠、乳糖、淀粉、甘露醇、藻酸盐、明胶、瓜尔胶、硬脂酸镁、硬脂酸铝、甲基纤维素、滑石粉、高度分散的二氧化硅、硅油、硬脂酸、明胶、琼脂、植物或动物脂肪和油、聚乙二醇。
进一步的：所述辅助剂包括甜味剂、调味剂、防腐剂、稳定剂、润湿剂、渗透剂、乳化剂、涂布剂、助溶剂，用于控制渗透压或用于起缓冲作用的盐、糖或糖醇和/或粘度调节剂。
进一步的：所述添加剂包括酒石酸盐和柠檬酸盐缓冲剂、乙醇、络合剂。
进一步的：为了控制粘度，所述添加剂还能够使用液体聚氧化乙烯、微晶纤维素、聚乙烯吡咯烷酮、葡聚糖或明胶。
进一步的：用于非胃肠道或局部施用的油悬浮液可含有植物的合成或半合成油，包括其在脂肪酸链中具有8-22个碳原子的液体脂肪酸酯，所述脂肪酸包括棕榈酸、月桂酸、十三烷酸、十七烷酸、硬脂酸、二十烷酸、肉豆蔻酸、二十二烷酸、十五烷酸、亚油酸、反油酸、巴西勒酸、芥酸或油酸，这些脂肪酸被具有1-6个碳原子的一元一三元醇酯化，所述醇包括甲醇、乙醇、丙醇、丁醇、戊醇或其异构体，乙二醇或甘油；所述脂肪酸酣包括Miglyole、肉豆蔻酸异丙酯、棕桐酸异丙酯、硬脂酸异丙酯、PEG-6癸酸、饱和脂肪醇的辛酸/癸酸酯、聚氧化乙烯甘油三油酸酯、油酸乙酯、蜡状脂肪酸酯例如合成的鸭尾腺脂肪、椰油脂肪酸的异丙酯、油酸油酯、油酸癸酯、乳酸乙醋、邻苯二甲酸二丁酯、己二酸二异丙酯、多元醇的脂肪酸酯；还能够使用硅油或脂肪醇包括异十三烷醇,2一辛基十二烷醇、鲸蜡基硬脂醇或油醇、油酸以及植物油包括蓖麻油、杏仁油、橄榄油、芝麻油、棉子油、花生油或豆油。
进一步的：作为溶剂、凝胶形成剂和助溶剂，使用水或醇包括乙醇或异丙醇、苯甲醇、2一辛基十二烷醇、聚乙二醇、邻苯二甲酸酯、己二酸酯、丙二醇、甘油、一缩二丙二醇、三丙二醇、蜡、甲基溶纤剂、溶纤剂、酯、呜琳、二氧杂环己烷、二甲亚砜、二甲基甲酰胺、四氢吠喃、环己酮。
进一步的：作为成膜剂，使用可溶解在或膨胀在水和有机溶剂中的纤维素醚，包括羟丙基甲基纤维素、甲基纤维素、乙基纤维素或可溶性淀粉、羧甲基纤维素钠、聚丙烯酸、聚异丁烯酸和其盐、支链淀粉半羟乙酸钠、藻酸或作为钠盐的丙二醇藻酸醋、阿拉伯胶、黄原胶、瓜尔胶或角叉菜胶。
进一步的：作为其它制剂辅料，还能够使用甘油、不同粘度的石蜡、三乙醇胺、胶原、尿囊素、Novantisolsaure。
进一步的：所述药物中还能够包括表面活性剂、乳化剂或润湿剂，包括月桂基硫酸钠、脂肪醇醚硫酸盐、N-月桂基-β-亚氨基二丙酸二钠、聚乙氧基化蓖麻油或脱水山梨醇一油酸醋、脱水山梨醇一硬脂酸酯、聚山梨醇酯、鲸蜡醇、卵磷脂、甘油-硬脂酸酯、聚氧乙烯硬脂酸酯、烷基苯酚聚乙二醇醚、氛化鲸蜡基三甲基铵或烷基或二烷基聚乙二醇醚正磷酸乙醇胺盐；稳定剂包括蒙脱石或胶态二氧化硅；抗氧化剂包括生育酚或丁基羟基茴香醚；防腐剂包括对羟基苯甲酸酯。
本发明还提供了所述的新型益母草碱衍生物在用于制备TNF-α抑制剂中的应用。
与现有技术相比，本发明的优点和有益效果为：
本发明制备得到的新型益母草碱衍生物结构新颖，并通过药理学实验证明，本发明基于益母草碱结构的衍生物具有很好的抑制TNF-α的释放、LPS引起的中性白细胞增多或过敏引起的嗜酸性细胞增多的作用，进而减轻炎症性疾病或过敏的症状，达到预防和治疗炎症性疾病或过敏的作用。本发明的新型益母草碱衍生物能够对多种疾病具有良好的治疗效果，并且均具有良好的安全性，具有进一步开发的价值。
具体实施方式
以下结合具体实施例对本发明的技术方案做进一步详细的说明。
本发明的新型益母草碱海洋衍生物具有如下通式的结构：
其中，R1选自-CH3、
或者
R2选自H、-CH3、
或者
R3选自-H、-CH3或者-CH2CH3；X选自O或者NH；n＝3-4。
实施例1：新型益母草碱海洋衍生物的A-J系列的合成
1、合成通式结构中
R3＝H、X＝O、n＝3的代表化合物
将市售可得的3-环丙氧基-4-二氟甲氧基苯甲酸为起始原料，取33g溶解在100mL经无水处理的二氯甲烷中，搅拌使充分溶解，并分批加入二甲氨基吡啶对甲苯磺酸盐共56g，待溶液澄清后，加入Boc保护的4-胍基-1-丙醇28.7g，搅拌使溶解，然后加入二异丙基碳酰亚胺39g，室温搅拌过夜，TLC检测反应进行完毕，先抽滤掉不溶物，得到油状液体，再减压蒸馏，除去二氯甲烷，然后加入事先冷冻的冰甲醇，直至析出白色晶体，抽滤得到白色粉末状晶体前体26g。取前体化合物4.5mM，加入1：1的二氯甲烷和三氟乙酸的混合溶液10mL，室温反应2h后，TLC测定反应是否完成。减压蒸馏除去二氯甲烷，得到粘稠溶液，用石油醚清洗3遍后，加入适量饱和NaHCO3溶液，调节PH至8-11，析出固体，然后过滤得3-环丙氧基-4-胍基-1-丙烷-4-二氟甲氧基苯甲酯，即为代表产物A1：
A1氢谱：1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.61(s,3H),7.44(s,2H),7.09(s,2H),6.50(d,J＝11.0Hz,6H),4.30(s,2H),4.09(s,2H),3.58(s,2H),3.50(s,1H),2.00(s,2H),0.71(s,3H),0.33(s,3H)。
A1碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.86(s),152.46(s),149.79(s),125.62(d,J＝8.2Hz),123.91(s),118.56(s),118.19(s),62.55(s),58.77(s),38.88(s),30.61(s),7.98(s)。
2、使用上述方法，合成化合物A2：
A2氢谱：1H NMR(400MHz,DMSO-d6)δ7.61(s,5H),7.57(s,2H),7.44(s,5H),7.09(s,4H),6.30(s,8H),5.85(s,4H),5.20(s,4H),4.32(s,8H),3.58(s,8H),3.51(s,3H),1.84(s,7H),1.51(s,7H),0.72(s,8H),0.31(s,8H)。
A2碳谱：13C NMR(101MHz,DMSO-d6))δ166.37(s),156.86(s),152.46(s),149.79(s),125.62(d,J＝8.2Hz),123.91(s),118.56(s),118.19(s),66.74(s),58.77(s),41.46(s),27.93(s),27.36(s),7.98(s)。
3、由3-异丙氧基-4-二氟甲氧基苯甲酸作为起始原料，在二异丙基碳酰亚胺的作用下，与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，减压蒸馏后于冰甲醇下重晶体，在三氟乙酸作用下脱除Boc保护基，得到化合物B1和B2：
B1氢谱：1H NMR(400MHz,DMSO-d6)δ7.71(s,3H),7.61(s,8H),7.44(d,J＝1.2Hz,12H),7.09(s,6H),6.40(s,12H),4.67(s,2H),4.30(s,6H),3.76(s,6H),3.58(s,9H),2.00(s,6H),1.32(s,37H)。
B1碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.86(s),153.55(s),149.78(s),126.37(s),125.93(s),122.44(s),118.56(s),117.51(s),73.89(s),62.55(s),38.88(s),30.61(s),21.81(s)。
B2氢谱：1H NMR(400MHz,DMSO-d6)δ8.00(s,4H),7.59(s,8H),7.42(s,8H),7.07(s,8H),6.55(d,J＝4.6Hz,24H),4.65(s,3H),4.31(s,14H),3.57(d,J＝4.1Hz,17H),1.83(s,9H),1.51(s,6H),1.32(s,49H)。
B2碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.86(s),153.55(s),149.78(s),126.37(s),125.93(s),122.44(s),118.56(s),117.51(s),73.89(s),66.74(s),41.46(s),27.93(s),27.36(s),21.81(s)。
4、由3-乙烷氧基-4-二氟甲氧基苯甲酸作为起始原料，溶于二氯甲烷后，与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，加入缩合剂反应完全后抽滤，减压蒸馏后于冰甲醇下重晶体，在三氟乙酸作用下脱除Boc保护基，得到化合物C1和C2：
C1氢谱：1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.61(s,2H),7.44(s,2H),7.09(s,2H),6.69(s,2H),6.62(s,4H),4.30(s,3H),4.13(s,4H),3.64(s,2H),3.58(s,2H),2.00(s,2H),1.42(s,3H)。
C1碳谱：13C NMR(101MHz,DMSO-d6))δ166.37(s),156.86(s),155.35(s),150.37(s),127.32(s),124.08(s),123.79(s),119.50(s),118.56(s),64.46(s),62.55(s),38.88(s),30.61(s),13.80(s)。
C2氢谱：1H NMR(400MHz,DMSO-d6)δ7.99(s,5H),7.61(s,12H),7.44(s,10H),7.09(s,10H),6.66(s,10H),6.54(s,19H),4.32(s,15H),4.13(s,20H),3.63(s,14H),3.58(s,10H),1.84(s,11H),1.51(s,8H),1.42(s,16H)。
C2碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.86(s),155.35(s),150.37(s),127.32(s),124.08(s),123.79(s),119.50(s),118.56(s),66.74(s),64.46(s),41.46(s),27.93(s),27.36(s),13.80(s)。
5、由乙酰丁香酸作为起始原料，溶于二氯甲烷和DPTS后，与Boc保护的4-胍基-1-丙醇缩合，加入缩合剂反应完全后抽滤，减压蒸馏后于冰甲醇下重晶体，在强碱作用下脱除乙酰基，在三氟乙酸作用下脱除Boc保护基，得到化合物D：
D氢谱：1H NMR(400MHz,DMSO-d6)δ6.95(s,2H),6.78(s,1H),6.50(s,2H),5.12(s,1H),4.30(s,1H),3.83(s,6H),3.71(s,1H),3.58(s,1H),2.00(s,1H)。
D碳谱：13C NMR(101MHz,DMSO-d6)δ166.13(s),156.86(s),148.77(s),142.01(s),122.31(s),108.59(s),62.55(s),56.83(s),38.88(s),30.61(s)。
6、由3-乙基氧-4-甲氧基苯甲酸为起始原料，在二异丙基碳酰亚胺作用下，与Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇缩合，减压蒸馏后得到油状溶液，加入事先冰冻的冰甲醇作用使其析出晶体，晶体溶解后在二氯甲烷和三氟乙酸混合溶液中脱除Boc保护基，得到化合物E1和E2：
E2氢谱：1H NMR(400MHz,DMSO-d6)δ7.61(s,3H),7.44(s,3H),6.82(d,J＝78.2Hz,6H),6.47(s,6H),4.32(s,3H),4.13(s,6H),3.83(s,9H),3.67(s,3H),3.58(s,3H),1.84(s,4H),1.51(s,2H),1.42(s,5H)。
E2碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),157.21(s),156.86(s),149.37(s),121.99(s),120.81(s),116.95(s),116.70(s),66.74(s),64.46(s),56.83(s),41.46(s),27.93(s),27.36(s),13.80(s)。
7、由3-乙基氧-4-乙氧基苯甲酸为起始原料，搅拌至澄清后加入Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇，搅拌加入缩合剂DIC，反应至完全后抽滤，再经减压蒸馏去除二氯甲烷，使用冰甲醇进行2次结晶后，再在二氯甲烷和三氟乙酸混合液中反应脱除Boc保护基，得到化合物F1和F2
F2氢谱：1H NMR(400MHz,DMSO-d6)δ7.61(s,4H),7.44(s,4H),7.09(s,4H),6.72(s,4H),6.23(s,8H),4.32(s,6H),4.13(s,16H),3.96(s,4H),3.58(s,4H),1.84(s,4H),1.51(s,3H),1.42(s,13H)。
F2碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.86(s),155.88(s),149.23(s),122.47(s),122.05(s),119.76(s),119.60(s),66.74(s),64.46(s),41.46(s),27.93(s),27.36(s),13.80(s)。
8、由3-环丙氧基-4-甲氧基苯甲酸为起始原料，在二异丙基碳酰亚胺作用下，与Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇进行缩合反应10-16小时，除去溶剂后，采用甲醇重结晶制的产物，其产物溶解后再在三氟乙酸作用下脱除Boc保护基，再在饱和碳酸氢钠溶解中析出固体，过滤后经乙醇重结晶，得到化合物G1和G2：
G2氢谱：1H NMR(400MHz,DMSO-d6)δ7.59(s,5H),7.42(s,5H),6.80(d,J＝78.0Hz,10H),6.61(s,10H),4.31(s,5H),3.82(s,15H),3.57(d,J＝1.1Hz,10H),3.41(s,2H),1.83(s,4H),1.51(s,4H),0.67(s,10H),0.27(s,7H)。
G2碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.86(s),156.67(s),148.08(s),123.16(s),122.49(s),117.64(s),117.01(s),66.74(s),58.77(s),56.83(s),41.46(s),27.93(s),27.36(s),7.98(s)。
9、由3-环丙氧基-4-乙氧基苯甲酸为起始原料，搅拌至澄清后加入Boc保护的4-胍基-1-丁醇或者4-胍基-1-丙醇缩合，搅拌加入缩合剂DIC，反应至完全后抽滤，再经减压蒸馏去除二氯甲烷，使用冰甲醇进行2次结晶后，再在二氯甲烷和三氟乙酸混合液中反应脱除Boc保护基，得到化合物H1和H2：
H2氢谱：1H NMR(400MHz,DMSO-d6)δ7.61(s,5H),7.44(s,5H),7.09(s,5H),6.60(s,10H),6.02(s,5H),4.39(s,5H),4.32(s,9H),4.13(s,10H),3.58(s,5H),3.49(s,2H),1.84(s,6H),1.51(s,4H),1.42(s,8H),0.60(s,7H),0.34(s,7H)。
H2碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.86(s),156.02(s),147.50(s),125.36(s),122.48(s),120.37(s),119.63(s),66.74(s),64.46(s),58.77(s),41.46(s),27.93(s),27.36(s),13.80(s),7.98(s)。
10、由3-异丙氧-4-甲氧基苯甲酸为起始原料，在二异丙基碳酰亚胺作用下，与Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇缩合，减压蒸馏后得到油状溶液，加入事先冰冻的冰甲醇作用使其析出晶体，晶体溶解后在二氯甲烷和三氟乙酸混合溶液中脱除Boc保护基，得到化合物I2：
I2氢谱：1H NMR(400MHz,DMSO-d6)δ7.61(s,2H),7.44(s,2H),6.90(s,2H),6.75(s,2H),6.14(s,4H),4.67(s,1H),4.32(s,2H),4.05(s,2H),3.83(s,6H),3.58(s,2H),1.84(s,4H),1.51(s,2H),1.32(s,12H)。
I2碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.85(d,J＝4.5Hz),148.70(s),123.34(s),121.01(s),117.23(s),116.90(s),73.89(s),66.74(s),56.83(s),41.46(s),27.93(s),27.36(s),21.81(s)。
11、由3-异丙氧基-4-乙氧基苯甲酸为起始原料，在二异丙基碳酰亚胺作用下，与Boc保护的4-胍基-1-丁醇缩合或者4-胍基-1-丙醇进行缩合反应10-16小时，除去溶剂后，采用甲醇重结晶制的产物，其产物溶解后再在三氟乙酸作用下脱除Boc保护基，再在饱和碳酸氢钠溶解中析出固体，过滤后经乙醇重结晶，得到化合物J2：
J2氢谱：1H NMR(400MHz,DMSO-d6)δ7.58(s,5H),7.41(s,5H),7.06(s,5H),6.71(s,5H),6.45(s,10H),4.65(s,2H),4.30(s,7H),4.11(s,10H),3.67(s,5H),3.56(s,5H),1.83(s,5H),1.50(s,4H),1.41(s,8H),1.31(s,34H)。
J2碳谱：13C NMR(101MHz,DMSO-d6)δ166.37(s),156.86(s),156.46(s),148.57(s),125.45(s),120.93(d,J＝1.5Hz),118.78(s),73.89(s),66.74(s),64.46(s),41.46(s),27.93(s),27.36(s),21.81(s),13.80(s)。
实施例2：新型益母草碱衍生物的K-P苯甲酰胺系列化合物的合成
1、合成通式结构中
R3＝H、X＝NH、n＝3的代表化合物
将2.67g NaH加到50ml干燥的四氢呋喃中，再缓慢加入Boc保护的4-胍基-1-丙胺(76.69mM)，室温下反应1小时待用；再取3-环丙氧基-4-二氟甲氧基苯甲酸(32.92mM)用200ML干燥的四氢呋喃溶解，冰浴条件下缓慢滴加8.2mLSOCL2，加完后回流8小时，蒸除溶剂，用60ML无水四氢呋喃溶解后，室温条件下缓慢滴加到上述反应体系中，50℃反应8小时。冷到室温，加入300ML水并用乙酸酯150ML萃取3次，合并的有机相用无水硫酸钠干燥。减压蒸除溶剂后得到粗品，粗品经乙酸乙酯重结晶后得到代表化合物3-环丙氧基-4-胍基-1-丙烷-4-二氟甲氧基苯甲酰胺K1。
K1氢谱：1H NMR(400MHz,DMSO-d6)δ7.66–7.43(m,13H),7.16(s,5H),6.79(s,5H),6.25(s,5H),6.04(s,10H),4.32(s,5H),3.58(s,5H),3.43(d,J＝14.5Hz,14H),1.90(s,5H),0.65(s,7H),0.40(s,7H)。
K1碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),152.48(s),148.77(s),128.78(s),123.04(s),121.76(s),118.49(d,J＝16.6Hz),58.77(s),39.20(s),38.35(s),28.44(s),7.98(s).
2、使用上述方法，可合成化合物K2：
K2氢谱：1H NMR(400MHz,DMSO-d6)δ7.59(s,4H),7.52(s,2H),7.47(s,4H),7.14(s,5H),6.96(s,4H),6.04(s,4H),5.72(s,8H),4.64(s,4H),3.57(d,J＝5.0Hz,10H),3.29(s,8H),1.55(s,6H),1.49(s,7H),0.76(s,8H),0.12(s,8H)。
K2碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),152.48(s),148.77(s),128.78(s),123.04(s),121.76(s),118.49(d,J＝16.6Hz),58.77(s),41.49(d,J＝7.6Hz),27.39(s),7.98(s)。
3、由3-环丙氧基-4-乙氧基苯甲酸在甲苯溶剂中与草酰氯或三氯化磷反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在二氯甲烷或者DMF溶液中在氢化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，乙酸乙酯萃取，无水硫酸钠干燥并再次重结晶，得到化合物L1和L2：
L1氢谱：1H NMR(400MHz,DMSO-d6)δ7.61(s,5H),7.49(s,5H),7.16(s,5H),6.71(s,5H),6.53(s,10H),6.22(s,5H),4.13(s,10H),3.66(s,5H),3.58(s,5H),3.42(d,J＝1.4Hz,7H),1.90(s,4H),1.42(s,8H),0.66(s,7H),0.30(s,7H)。
L1碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),154.34(s),148.39(s),129.21(s),122.09(s),119.48(s),118.09(s),64.46(s),58.77(s),39.20(s),38.35(s),28.44(s),13.80(s),7.98(s)。
L2氢谱：1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝60.0Hz,157H),7.16(s,79H),6.66(d,J＝10.2Hz,230H),5.95(s,76H),4.13(s,157H),3.88(s,76H),3.58(s,154H),3.47(s,30H),3.30(s,153H),1.52(d,J＝30.0Hz,255H),1.42(s,231H),1.40(s,3H),0.67(s,151H),0.25(s,111H)。
L2碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),154.34(s),148.39(s),129.21(s),122.09(s),119.48(s),118.09(s),64.46(s),58.77(s),41.49(d,J＝7.6Hz),27.39(s),13.80(s),7.98(s)。
4、由3-环丙氧基-4-甲氧基苯甲酸在溶剂甲苯中与五氯化磷反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在四氢呋喃或者二氯甲烷溶液中在氢氧化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，乙酸乙酯萃取，无水硫酸钠干燥后并再次重结晶，得到化合物M1和M2：
M1氢谱：1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝60.0Hz,8H),7.02(s,4H),6.77(s,4H),6.54(s,8H),6.03(s,4H),3.83(s,12H),3.64(s,4H),3.58(s,5H),3.42(d,J＝0.5Hz,6H),1.90(s,7H),0.67(s,6H),0.28(s,6H)。
M1碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),153.51(s),148.80(s),128.31(s),122.37(s),116.54(s),113.88(s),58.77(s),56.83(s),39.20(s),38.35(s),28.44(s),7.98(s)。
M2氢谱：1H NMR(400MHz,DMSO-d6)δ7.54(d,J＝60.0Hz,10H),7.01(s,5H),6.68(s,10H),6.58(s,5H),6.18(s,5H),4.00(s,5H),3.83(s,15H),3.58(s,8H),3.43(s,2H),3.30(s,8H),1.55(s,9H),1.49(s,9H),0.62(s,10H),0.18(s,10H)。
M2碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),153.51(s),148.80(s),128.31(s),122.37(s),116.54(s),113.88(s),58.77(s),56.83(s),41.49(d,J＝7.6Hz),27.39(s),7.98(s)。
5、由3，4-乙氧基苯甲酸在溶剂二氯甲烷或者DMF中与二氯亚砜或草酰氯反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在四氢呋喃或者DMSO溶液中在氢化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，制备所得粗品经乙酸乙酯重结晶，得到化合物N1和N2：
N1氢谱：1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝60.0Hz,2H),7.16(s,1H),6.71(s,1H),6.55(s,2H),6.06(s,1H),4.13(s,4H),3.73(s,1H),3.58(s,1H),3.42(s,1H),1.90(s,1H),1.42(s,3H)。
N1碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),153.13(s),149.93(s),126.21(s),121.82(s),120.45(s),116.75(s),64.46(s),39.20(s),38.35(s),28.44(s),13.80(s)。
N2氢谱：1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝60.0Hz,43H),7.16(s,22H),6.75(s,21H),6.12(s,42H),6.07(s,21H),4.15(d,J＝15.4Hz,107H),3.58(s,41H),3.30(s,42H),1.55(s,32H),1.45(d,J＝35.0Hz,134H),1.40(s,3H)。
N2碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),153.13(s),149.93(s),126.21(s),121.82(s),120.45(s),116.75(s),64.46(s),41.49(d,J＝7.6Hz),27.39(s),13.80(s)。
6、由3-乙氧基-4-甲氧基苯甲酸在溶剂二氯甲烷中与二氯亚砜反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在甲苯溶液中在氢氧化钾或者氢化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，乙酸乙酯萃取，无水硫酸钠干燥后并再次重结晶，得到化合物O2：
O2氢谱：1H NMR(400MHz,DMSO-d6))δ7.52(d,J＝59.8Hz,4H),6.99(s,2H),6.64(s,4H),6.44(s,2H),5.96(s,2H),4.76(s,2H),4.65(s,1H),3.81(s,6H),3.56(s,4H),3.29(s,4H),1.54(s,3H),1.48(s,4H),1.31(s,13H)。
O2碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),153.98(s),149.25(s),127.16(s),120.50(s),117.00(s),114.23(s),73.89(s),56.83(s),41.49(d,J＝7.6Hz),27.39(s),21.81(s)。
7、由3-异丙氧基-4-乙氧基苯甲酸在溶剂四氢呋喃中与或草酰氯反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺、4-胍基-1-乙胺)在甲苯溶液中在氢化钠的作用下得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，然后缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，乙酸乙酯萃取，无水硫酸钠干燥后并再次重结晶，得到化合物P2：
P2氢谱：1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝60.0Hz,145H),7.16(s,73H),6.53(s,140H),6.38(s,70H),6.09(s,70H),4.67(s,27H),4.10(d,J＝28.3Hz,218H),3.58(s,137H),3.30(s,141H),1.55(s,105H),1.45(d,J＝35.0Hz,286H),1.40(s,7H),1.32(s,486H)。
P2碳谱：13C NMR(101MHz,DMSO-d6)δ166.82(s),156.86(s),154.92(s),149.38(s),127.97(s),120.23(s),119.78(s),118.76(s),73.89(s),64.46(s),41.49(d,J＝7.6Hz),27.39(s),21.81(s),13.80(s)。
实施例3新型益母草碱衍生物抑制从鼻息肉细胞释放TNF-α
将鼻息肉组织用RPMI 1640洗涤，然后用蛋白酶(2.5mg/ml)、胶原酶(1.0mg/ml)、透明质酸酶(0.5mg/ml)和DNA酶(0.1mg/ml)于37℃溶解150分钟(1g组织和4mL含有酶的RPMI1640)。将所得细胞(上皮细胞、单核细胞、巨噬细胞、淋巴细胞、成纤维细胞和粒细胞)的混合物过滤，通过在培养溶液中反复离心来洗涤，加入人源IgE来被动致敏，将细胞悬浮液在RPMI 1640(补充杭生素、10％胎牛血清、2mM谷氨酸胺和25mM Hepes)中稀释至2百万个细胞/mL的浓度。将悬浮液分配在6孔细胞培养平板上(1ml/孔)。将细胞与不同浓度的测试物预培养30分钟，然后通过加入抗IgE进行刺激以释放TNF-α，约16小时后发生了向培养基内的最大释放。在该期间，将细胞在37℃和含5％二氧化碳的培养箱中培养。通过离心来收集培养基(上清液)，并在-80℃保持，直至测定细胞因子。用ELISA试剂盒测定上清液中的TNF-α。
未用抗IgE刺激的细胞几乎不产生任何TNF-α，而刺激的细胞分泌大量TNF-α，可通过PDE4抑制剂减少TNF-α的量，减少程度与剂量有关。由不同浓度的化合物的抑制百分比(用抗IgE刺激的细胞TNF-α释放＝100％)计算IC50(达到50％抑制的浓度)。结果如表1所示，实施例1制备的化合物的IC50值为10-10-10-4M。说明新型益母草碱衍生物具有抑制TNF-α释放的作用，可作为TNF-α抑制剂。
表1：化合物的抑制TNF-α释放的结果
实施例4新型益母草碱衍生物抑制大鼠过敏模型的嗜酸性细胞增多
将V级卵清蛋白50mg，氢氧化铝100mg和灭活百日咳杆菌6×109个溶于生理盐水1ml中，配制成混悬液凝胶，并按此比例扩大配成12ml作为致敏液备用(为防止分10次注射使用时挂壁残留损耗，多配制出2ml)。第1天致敏：空白组大鼠给予腹腔注射1ml生理盐水，而模型组给予腹腔注射1ml致敏液致敏；第15天开始激发：将两组大鼠分别置于相同大小的雾化箱内，空白组给予生理盐水6ml雾化激发，模型组给予5％V级卵清蛋白溶液6ml雾化激发，每天激发一次，每次激发30min，连续激发10天。测试化合物是在变应原攻击前2小时，作为在10％聚乙二醇300和0.5％5-羟基乙基纤维素中的悬浮液腹膜内或口服施用的。对照组是依据测试化合物的施用形式用载体治疗。实验结束时固定大鼠四肢，使用75％酒精对颈部消毒，充分暴露气管，在喉部附近插入气管插管针(针头稍磨平)，针头插入一定位置，切勿超过气管分叉处；用2mL预冷的PBS反复灌洗3次，收集肺泡灌洗液到EP管中，1000rpm、4℃离心，收集细胞，经瑞氏-吉姆萨染色，在显微镜下进行细胞分类计数。
白细胞是免疫进程中至关重要的一类细胞，细胞分类计数可以有效分析肺泡灌洗液BALF中白细胞比例的变化。在发病过程中，浸润其支气管的炎症细胞主要是淋巴细胞和嗜酸性细胞。淋巴细胞能够扩大支气管粘膜上嗜酸性细胞的炎症反应，并且随着嗜酸性粒细胞的增多，会增加其在肺内聚集、活化以及与其它炎性细胞、炎性介质、细胞因子的相互作用，进而加重过敏。
结果如表2所示，以1-5mg/kg剂量腹膜内施用后，实施例1制备的化合物将嗜酸性细胞增多症状有效抑制了20％-90％，以10-50mg/kg的剂量口服施用后，各化合物将嗜酸性细胞增多症状抑制了15-75％。因此，本发明的新型益母草碱衍生物适合制备用于治疗和预防与嗜酸性细胞活动有关的疾病的药物。
表2：化合物的抑制嗜酸性细胞增多的结果
实施例5新型益母草碱衍生物抑制脂多糖(LPS)引起的中性白细胞增多
在雄性Wistar大鼠(200±20g)中测试实施例1制备的化合物对肺中性白细胞浸润的抑制作用。在实验的当天，将动物单独置于开口的1L有机玻璃盒子中，该盒子与头鼻暴露装置连接。将动物暴露于脂多糖悬浮液(LPS 100μg/mL溶解于含有0.1％羟基胺的PBS溶液中)的气雾剂中(LPS攻击)，暴露时间是45分钟，标准对照是用含有0.1％羟基胺的PBS溶液的气雾剂喷雾45分钟。LPS攻击6小时后，有大量中性粒细胞迁移到动物的肺内。测试各化合物是在LPS攻击前2小时，作为在10％聚乙二醇300和0.5％5-羟基乙基纤维素中的悬浮液口服施用的。对照组是依据测试物的施用形式用载体治疗。实验结束时固定大鼠四肢，使用75％酒精对颈部消毒，充分暴露气管，在喉部附近插入气管插管针(针头稍磨平)，针头插入一定位置，切勿超过气管分叉处；用2mL预冷的PBS反复灌洗3次，收集肺泡灌洗液到EP管中，1000rpm、4℃离心，收集细胞，经瑞氏-吉姆萨染色，在显微镜下进行细胞分类计数。
结果如表3所示，以10-50mg/kg的剂量口服施用后，本发明化合物将中性白细胞增多症状抑制了30％-93％。因此，本发明的新型益母草碱衍生物适用于制备用于治疗好预防与中性白细胞活动有关的疾病的药物。
表3：化合物的抑制中性白细胞增多的结果
以上实施例仅用以说明本发明的技术方案，而非对其进行限制；尽管参照前述实施例对本发明进行了详细的说明，对于本领域的普通技术人员来说，依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。
Claims (7)
1.一种新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用，其特征在于，所述新型益母草碱海洋衍生物具有如下通式的结构：
其中，R1选自1-5个碳原子组成的烷基、3-6个碳原子组成的环氧基、C2-C6的饱和或不饱和烷基；R2选自氢或1-5个碳原子组成的含氟烷基、3-6个碳原子组成的环氧基、C2-C6的饱和或不饱和烷基；R3选自氢或者1-5个碳原子组成的烷氧基团；X选自氧或者氨基；n＝1-5。
2.根据权利要求1所述的新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用，其特征在于，所述新型益母草碱海洋衍生物具有如下通式的结构：
其中，R1选自-CH3、
R2选自-H、-CH3、
R3选自-H、-CH3或者-CH2CH3；X选自O或者NH；n＝3-4。
3.根据权利要求1所述的新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用，其特征在于，所述新型益母草碱海洋衍生物具体为化合物A、B、C、D、E、F、G、H、I、J、K、L、M、N、O、P，其结构式分别如下：
其中，n＝3或者4。
4.根据权利要求1所述的新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用，其特征在于，所述新型益母草碱海洋衍生物的制备方法包括以下步骤：
由3-环丙氧基-4-氟代烷氧基苯甲酸或3-环丙氧基-4-烷氧基苯甲酸与Boc保护的4-胍基-1-烷基醇缩合，在三氟乙酸作用下脱除Boc保护基，得到化合物A、G或H；
或者由3-异丙氧基-4-氟代烷氧基苯甲酸或3-异丙氧基-4-烷氧基苯甲酸与Boc保护的4-胍基-1-烷基醇缩合，在三氟乙酸作用下脱除Boc保护基，得到化合物B、I或J；
或者由3-乙氧基-4-氟代烷氧基苯甲酸或3-乙基氧-4-烷氧基苯甲酸与Boc保护的4-胍基-1-烷基醇缩合，在三氟乙酸作用下脱除Boc保护基，得到化合物C、E或F；
或者由乙酰丁香酸与Boc保护的4-胍基-1-烷基醇缩合，在强碱作用下脱除乙酰基，再在三氟乙酸作用下脱除Boc保护基，得到化合物D；
或者将3-环丙氧基-4-氟代烷氧基苯甲酸、3-环丙氧基-4-烷氧基苯甲酸、3，4-烷氧基苯甲酸、3-乙氧基-4-烷氧基苯甲酸、3-异丙氧基-4-烷氧基苯甲酸与无机卤化物制得的活性中间体，与Boc保护的4-胍基-1-烷基胺在碱作用下得到的活化氨基负离子进行反应，得到化合物K、L、M、M、O或P。
5.根据权利要求1所述的新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用，其特征在于，所述新型益母草碱海洋衍生物能够通过抑制TNF-α的释放、LPS引起的中性白细胞增多或过敏引起的嗜酸性细胞增多，进而减轻炎症性疾病或过敏的症状，达到预防和治疗炎症性疾病或过敏的作用。
6.根据权利要求1所述的新型益母草碱海洋衍生物在用于制备预防和治疗炎症性疾病或过敏的药物中的应用，其特征在于，所述的药物为片剂、口服液、气雾剂、丸剂、胶囊剂、颗粒剂、膏剂、滴丸剂、糖浆剂、散剂、冲剂、酊剂、粉针剂或注射液。
7.一种新型益母草碱海洋衍生物在用于制备TNF-α抑制剂中的应用，其特征在于，所述新型益母草碱衍生物具有如下通式的结构：
其中，R1选自1-5个碳原子组成的烷基、3-6个碳原子组成的环氧基、C2-C6的饱和或不饱和烷基；R2选自氢或1-5个碳原子组成的含氟烷基、3-6个碳原子组成的环氧基、C2-C6的饱和或不饱和烷基；R3选自氢或者1-5个碳原子组成的烷氧基团；X选自氧或者氨基；n＝1-5。
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