CN101513426A - 肉桂酸脂类化合物及其在制备白三烯a4水解酶功能调节药物中的应用 - Google Patents
肉桂酸脂类化合物及其在制备白三烯a4水解酶功能调节药物中的应用 Download PDFInfo
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- CN101513426A CN101513426A CNA2009100471884A CN200910047188A CN101513426A CN 101513426 A CN101513426 A CN 101513426A CN A2009100471884 A CNA2009100471884 A CN A2009100471884A CN 200910047188 A CN200910047188 A CN 200910047188A CN 101513426 A CN101513426 A CN 101513426A
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Abstract
本发明公开了肉桂酸酯类化合物及其在制备白三烯A4水解酶功能调节药物中的应用，其结构通式如下：试验表明，该肉桂酸酯类化合物具有明显白三烯A4水解酶功能调节剂作用，主要阻断LTA4被白三烯A4水解酶LTA4H水解为LTB4。因此，可以用于制备治疗哮喘、系统性红斑狼疮、炎症、心肌梗塞、非小细胞肺癌、急性髓性白血病、实体瘤的药物。
Description
技术领域
本发明涉及药物，具体涉及一种肉桂酸酯类化合物及其在制备白三烯A4水解酶功能调节药物中的应用。
背景技术
白三烯(leukotriene)是花生四烯酸(5，8，11，14-二十碳四烯酸，简称AA)的代谢产物。在哮喘、炎症性肠病、慢性阻塞性肺疾病、关节炎和动脉粥样硬化等炎症性疾病的相关研究中，都已说明白三烯具有重要的生理、病理功能。白三烯的合成首先是花生四烯酸转化为不稳定的环氧化物白三烯A4(LTA4)开始，这一转化是在脂氧酶的作用下进行的。脂氧酶主要存在于髓系细胞中，尤其是在中性粒细胞、嗜酸性粒细胞、单核细胞、巨噬细胞和肥大细胞中。LTA4可以在LTC4(白三烯C4)合成酶的作用下与谷胱甘肽结合，生成半胱氨酰白三烯，即LTC4；LTA4也可以水解为二醇和LTB4(白三烯B4)。LTC4和他的代谢产物(LTD4(白三烯D4)、LTE4(白三烯E4))可以使平滑肌收缩、气管收缩、血管通透性增强，而LTB4是一种潜在的中性粒细胞的化学吸引剂和激动剂。
LTA4到LTB4这一特异性的水解是在白三烯A4水解酶(LTA4H)的作用下完成的。LTA4H是一种含锌的溶质酶，它分布广泛，在小肠上皮细胞、肺和主动脉高度表达，在白细胞尤其是中性粒细胞中中等程度表达。
LTB4是一种促炎反应的脂质介质，由花生四烯酸经5-LO(5-脂氧酶)路径衍生而来。已知LTB4是白细胞(尤其是中性粒细胞和T细胞)的一种趋化因子和激动剂，在几种过敏和炎症反应中起作用。LTB4能够召集中性粒细胞、嗜酸性粒细胞等炎细胞，也可以激活中性粒细胞。LTB4介导的促炎反应是通过与G蛋白受体(BLT1(白三烯B4受体亚型BLT1)和BLT2(白三烯B4受体亚型BLT2))结合完成的。BLT1主要表达于周围白细胞，尤其是在中性粒细胞、嗜酸性粒细胞、巨噬细胞和单核粒细胞。鼠类的受体也在效应器T细胞上表达，最近在哮喘动物模型中发现，它也介导LTB4依赖的效应器CD8+T细胞转移、TH1和TH2细胞趋化并与内皮细胞粘附、CD4+T和CD8+T细胞的召集。它与BLT1具有42％的氨基酸同源性，但表达更为广泛，脾、卵巢和肝等周围组织和白细胞中均有表达。与BLT1相比，BLT2同LTB4结合的亲和力较低，在LTB4浓度较高时介导趋化性，BLT1和BLT2对拮抗剂的亲和力也不同。LTB4受体拮抗剂对BLT1和BLT2的亲和力也可能不同，用LTA4H抑制剂阻断LTB4的生成，将会同时抑制BLT1和BLT2介导的下游事件。
研究表明，在正常组织中引入外源性LTB4会诱发炎症症状。在很多炎症疾病，例如炎症性肠病、慢性阻塞性肺病、牛皮癣、风湿性关节炎、囊性纤维化病、哮喘等疾病中都观察到了LTB4水平的提高。因此，通过LTA4H抑制剂对LTA4H活性的抑制从而降低LTB4的水平可能会对很多疾病具有潜在治疗作用。
这在对LTA4H缺陷的小鼠研究中得到了证实。而在花生四烯酸诱导的耳炎症和酵母聚糖诱导的腹膜炎小鼠模型身上，中性粒细胞流显著减少。临床前实验已证实LTA4H抑制剂是有效的抗炎药物。例如，在小鼠血体外试验和大鼠腹膜体内试验中，口服LTA4H抑制剂SC57461会导致离子载体介导的LTB4生成减少。使用同样的抑制剂成分治疗8周可以显著改善棉冠獠狨(Cotton Top Tamarin)的肠炎症状。这些动物发生的自发性结肠炎与人类的炎症性肠病非常相似，因此，这些结果提示LTA4H抑制剂将对人类的这一或其他炎症性状态具有治疗作用。
炎症通常是免疫系统对生物病原入侵、化学或者物理损伤发生的急性反应。但有些时候，炎症反应也可以发展为慢性状态，成为炎性疾病的原因。治疗控制这样的慢性炎症是医疗的需要。导致炎症反应包括了促炎反应介质LTB4的生成。LTA4H催化促炎反应介质LTB4的生成，而LTA4H抑制剂阻断LTB4的生成，因此为预防或治疗炎症等白三烯介导的疾病提供了可能性。
有报道(参考文献NIAMH E KIERAN，PAOLA MADERNA，CATHERINE GODSON.Lipoxins：Potential anti-inflammatory，proresolution，and antifibrotic mediators inrenal disease.Kidney International.2004，65：1145-1154)局部应用稳定的脂氧素类似物可以抑制小鼠炎症模型的水肿、中性粒细胞浸润和皮肤通透性增强，因此，增加或维持脂氧素A4(LXA4)的生成可能对炎症有良好的治疗作用。5-LO抑制剂的可能弊端是，它阻断了LTA4的上游通路，这就不仅阻断LTA4、LTB4和半胱氨酰白三烯的合成，还阻断了LXA4的合成。
根据白三烯生物合成路径，本发明人认为LTA4H抑制剂特异性阻断LTA4转化为LTB4，却不影响LTA4转化为脂氧素的过程。脂氧素(例如LXA4)已成为研究热点，是一种天然的抗炎症成分，是消除炎症反应过程中的重要介质，具有重要生理作用。并且，很多炎症性疾病中都发现了内源性的LXA4，例如，与中度哮喘患者相比，重度哮喘患者体内LXA4水平较低。这些数据与LXA4在控制急性炎症反应中发挥重要作用的假设相一致。与LTA4抑制剂不同，5-LO抑制剂阻断LTA4的上游路径。这就不但阻断LTA4、LTB4和半胱氨酰白三烯的合成，还影响LXA4的合成。同时，也存在一种可能，就是LTA4H抑制剂会导致LTA4增加，并通过旁路分流入促炎的半胱氨酰白三烯，尽管目前还没有证据证明这种可能。
紫葳科角蒿属植物Incarvillea L.全球共有15种，中国有11种，多分布于西南地区，此外东北、华北、西北等地区也有分布，其中5种供药用，在民间主要用于治疗肝炎、菌痢等疾病。其化学成分主要有单萜生物碱、大环精胺类生物碱、环烯醚萜苷类、黄酮类、神经酰胺类、甾醇类和三萜类等成分等。其中角蒿和毛子草的化学成分和药理活性研究较多，其他均少有报道。
角蒿属植物角蒿Incarvillea sinensis在中国北方和东北地区被用做“透骨草”，称谓“羊角透骨草”，具有消肿止痛之功效，主要用于治疗跌打损伤和风湿关节痛等症。角蒿属植物大花鸡肉参Incarvillea mairei var.grandiflora(Wehrhahn)Grierson，又名滇川角蒿，主要分布于云南(中甸、丽江)、四川、青海。生于高山草坡，海拔2500-3650米地带。根、叶入药，性甘、淡，温。用来治疗产后乳少，久病虚弱，头晕、贫血。可从角蒿属植物中提取肉桂酸酯类化合物。
发明内容
本发明所要解决的具体问题在于研究设计肉桂酸酯类化合物在制备白三烯A4水解酶功能调节药物中的应用。
本发明提供了一种肉桂酸酯类化合物在制备白三烯A4水解酶功能调节药物中的应用，其特征在于该肉桂酸酯类化合物具有以下结构通式(A)、(B)、(C)或(D)之一种：优选的化合物为角蒿酯碱C、1-O-咖啡酰基甘油、4-羟基肉桂酸、大花鸡肉参酯甲、麦角甾苷、异麦角甾苷、阿魏酸、咖啡酸乙酯、红波罗花酯甲、Eutigoside A、Fuhsioside、Osmanthuside B6、Isomartynoside、Isocrenatoside、3′″-O-methylisocrenatoside、Calceolariosdie A、Plantamajoside
式中R1选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R2选自氢、C1-C6直链或支链的饱和或不饱和烃基、C3-C7环烃基、硝基、卤素、氰基、三氟甲基、三氟甲氧基、苯基、苄基、芳香基Ar、5-7元芳香杂环(含有1-3个选自氧、硫、氮的杂原子，可被苯基和芳香杂环并合，或被一个或多个选自卤素，C1-C6直链或支链烃基，氰基，硝基，氨基，羟基，羟甲基，三氟甲基，三氟甲氧基，羧基，C1-C4烷氧基，巯基，C1-C4酰基，芳香基Ar的基团所取代)、1～5个单元的糖苷键；
式中R1选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R2、R3各自独立地选自氢、羟基、1～4个碳的烃基、乙酰基、异戊酰基；
式中R4选自氢、C1-C6直链或支链的饱和或不饱和烃基、C3-C7环烃基、硝基、卤素、氰基、三氟甲基、三氟甲氧基、苯基、苄基、芳香基Ar、5-7元芳香杂环(含有1-3个选自氧、硫、氮的杂原子，可被苯基和芳香杂环并合，或被一个或多个选自卤素，C1-C6直链或支链烃基，氰基，硝基，氨基，羟基，羟甲基，三氟甲基，三氟甲氧基，羧基，C1-C4烷氧基，巯基，C1-C4酰基，芳香基Ar的基团所取代)、1～5个单元的糖苷键；
式中R1选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R2、R3、R4各自独立地选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R5选自氢、羟基、1～4个碳的烃基、烷氧基、乙酰基、异戊酰基、1～5个单元的糖苷键、硝基、卤素、氰基、三氟甲基、三氟甲氧基；
式中R6选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R1选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R2、R3、R4各自独立地选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R5选自氢、羟基、1～4个碳的烃基、烷氧基、乙酰基、异戊酰基、硝基、卤素、氰基、三氟甲基、三氟甲氧基、1～5个单元的糖苷键；
式中R6选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R1选自氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R2、R3各自独立地选自氢、1～4个碳的烃基、乙酰基、异戊酰基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键；
式中R4选自氢、羟基、烷氧基、1～4个碳的烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基、1～5个单元的糖苷键。
这类肉桂酸酯类化合物分布在植物界的许多种植物中，可以从植物中提取分离制备而得，也可以用化学合成方式获得。
本发明人通过多年的基础研究积累了4000多种化合物，并建立了天然产物库，通过对库中化合物进行虚拟筛选，又通过体内外活性验证，结果发现了上述肉桂酸酯类化合物对白三烯A4水解酶具有特异性抑制作用。
经试验表明本发明肉桂酸酯类化合物具有较好的LTA4H抑制作用，IC50在50～240nM之间。
本发明药物组合物由肉桂酸酯类化合物为活性成分，与一种或多种药学上可接受的载体组成。其中，活性成分的重量含量为0.1-99.5％。
本发明药物组合物可用于制备抑制白三烯A4水解酶的药物，用于治疗哮喘、系统性红斑狼疮、炎症、心肌梗塞、非小细胞肺癌、急性髓性白血病、实体瘤。
所述药学上可接受的载体是指药学领域常规的药物载体，例如：稀释剂、赋形剂如水等；填充剂如淀粉、蔗糖等；粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮；湿润剂如甘油；崩解剂如琼脂、碳酸钙和碳酸氢钠；吸收促进剂如季铵化合物；表面活性剂如十六烷醇；吸附载体如高岭土和皂粘土；润滑剂如滑石粉、硬脂酸钙和镁、和聚乙二醇等。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明化合物可以组合物的形式通过口服、鼻吸入、直肠或肠胃外给药的方式施用于需要这种治疗的患者。用于口服时，可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等或制成液体制剂如水或油悬浮剂，或其它液体制剂如糖浆、酏剂等；用于肠胃外给药时，可将其制成注射用的溶液、水或油性悬浮剂等。优选的形式是片剂、包衣片剂、胶囊、栓剂、鼻喷雾剂和注射剂。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。
附图说明
图1白三烯A4水解酶(LTA4H)在花生四烯酸代谢通道中的作用示意图(细胞膜磷脂被磷脂酶A2(PLA2)水解后释放花生四烯酸(AA)，AA结合到5-脂氧合酶激活蛋白(FLAP)，并被其递呈给已转移到核膜的5-脂氧酶(5-LO)，被5-LO氧化为5-氢过氧化二十碳四烯酸(5-HPETE)，5-HPETE进一步转化为5-HETE，或在5-LO作用下进一步氧化为LTA4；LTA4不稳定，很快被白三烯A4水解酶(LTA4H)水解为LTB4。在这条通道中，5-LO和LTA4H是AA代谢的关键酶。)
具体实施方式
下面的实施例可以使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1：制备大花鸡肉参酯甲((+)2-(1-hydroxyl-4-oxocyclohexyl)ethylcaffeate，(+)2-(1-羟基-4-氧代环己基)咖啡酸乙酯)
大花鸡肉参(Incarvillea Mairei var.Grandiflora)干燥全草，用80％乙醇加热回流提取3次，每次2小时，合并提取液，浓缩至近干得总提取物浸膏。总提取物浸膏以水混悬，加2％HCl，调pH值至2～3，过滤，滤渣放置。滤液加氨水调pH值至11，用氯仿萃取，得氯仿部位。剩余水液调pH值至7，分别用石油醚、乙酸乙酯、正丁醇萃取，得到乙酸乙酯部位、石油醚部位、正丁醇部位及水部位。
将乙酸乙酯部位经硅胶(200～300目)柱色谱，石油醚∶乙酸乙酯(100∶1～5∶1)和氯仿∶甲醇(100∶1～1∶1)梯度洗脱及Sephadex LH-20柱色谱(葡聚糖凝胶柱色谱)，薄层色谱跟踪检测，收集大花鸡肉参酯甲富集的流份，最后经液相色谱制备，得大花鸡肉参酯甲。
本发明的肉桂酸酯类化合物大花鸡肉参酯甲((+)2-(1-hydroxyl-4-oxocyclohexyl)ethyl caffeate)为棕褐色固体，易溶于甲醇，电喷雾离子质谱给出准分子离子峰m/z 343[M+Na]+，高分辨质谱得出该化合物的精密质量数为343.1159[M+Na]+，推算其分子式为C17H20O6(计算值C17H20O6Na 343.1158)。大花鸡肉参酯甲的结构通过1H-NMR，13C-NMR，2D-NMR等手段进行确证。1H和13C核磁共振数据见表1。
实施例2：制备红波罗花酯甲(2-(1，4-dihydroxy cyclohexyl)ethyl caffeate，2-(1，-二羟基环己基)咖啡酸乙酯)
红波罗花(Incarvillea delavayi Bur.et Franch)干燥全草，用80％乙醇加热回流提取3次，每次2小时，合并提取液，浓缩至近干得总提取物浸膏。总提取物浸膏以水混悬，加2％HCl，调pH值至2～3，过滤，滤渣放置。滤液加氨水调pH值至11，用氯仿萃取，得氯仿部位。剩余水液调pH值至7，分别用石油醚、乙酸乙酯、正丁醇萃取，得到乙酸乙酯部位、石油醚部位、正丁醇部位及水部位。
将乙酸乙酯部位经硅胶(200～300目)柱色谱，石油醚∶乙酸乙酯(100∶1～5∶1)和氯仿∶甲醇(100∶1～1∶1)梯度洗脱及Sephadex LH-20柱色谱，薄层色谱跟踪检测，收集红波罗花酯甲富集的流份，最后经液相色谱制备，得红波罗花酯甲。
本发明的肉桂酸酯类化合物红波罗花酯甲(2-(1，4-dihydroxy cyclohexyl)ethylcaffeate)为黄色油状物，易溶于甲醇，电喷雾离子质谱给出准分子离子峰m/z 345[M+Na]+，高分辨质谱得出该化合物的精密质量数为321.1342[M-H]-，推算其分子式为C17H22O6(计算值C17H21O6，321.1338)。红波罗花酯甲的结构通过1H-NMR，13C-NMR，2D-NMR等手段进行确证。1H和13C核磁共振数据见表1。
表1 大花鸡肉参酯甲和红波罗花酯甲的1H和13C核磁共振数据(CD3OD)
**1H-NMR spectrum were recorded in 600MHz，13C-NMR spectrum were recordedin 150MHz in CD3OD
实施例3：肉桂酸酯类化合物对白三烯A4水解酶的抑制作用
一、实验方法：
底物的准备
LTA4底物由LTA4甲酯制备而来，制备条件为：氮气，NaOH 67M当量，室温，反应40分钟。使用前，LTA4底物应以自由酸的形式在-80℃冻存。
LTA4H水解酶活性的测定
待测试化合物均在二甲亚砜中制成10mM的液体储存，测定时稀释，二甲亚砜的最终浓度不超过0.1％。室温条件下，在50μl的测试缓冲液(0.1M磷酸钾，pH 7.4，5mg/ml脱脂小牛血清)中用不同浓度的测试化合物培育重组人LTA4H(36ng)10分钟，然后用测试缓冲液将这一溶液稀释为200μl，再加入25μl的底物(LTA4)(最终浓度40ng/ml，0.13mM；最终容量225μl)。在室温下存放10-30分钟后，用测试缓冲液稀释20倍终止反应。产生的LTB4的量用EIA法测定(Cayman chemical，美国)。重组酶活性抑制到最大值的50％时的化合物浓度用GraphPad非线性回归的方法计算。
二、实验结果：
肉桂酸酯类化合物具有较好的LTA4H抑制作用，IC50在50～240nM之间。
实施例4：制备肉桂酸酯类化合物的制剂
片剂：活性成分 20mg
乳糖 177mg
玉米淀粉 50mg
硬脂酸镁 3mg
制备方法：将活性成分、乳糖和淀粉混合，用水均匀湿润，把湿润后的混合物过筛并干燥，再过筛，加入硬脂酸镁，然后将混合物压片，每片重250mg，活性成分含量为20mg。
Claims (10)
1、一种肉桂酸酯类化合物A在制备白三烯A4水解酶功能调节药物中的应用，其特征在于该肉桂酸酯类化合物具有以下结构通式A：
式中R1为氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基或1～5个单元的糖苷键；
式中R2为氢、C1-C6直链或支链的饱和或不饱和烃基、C3-C7环烃基、硝基、卤素、氰基、三氟甲基、三氟甲氧基、苯基、苄基、芳香基、含有1-3个氧、硫或氮的杂原子，被苯基和芳香杂环并合，或被一个或多个卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C1-C4酰基或芳香基的基团所取代的5-7元芳香杂环或1～5个单元的糖苷键。
2、一种肉桂酸酯类化合物B，其特征在于，该肉桂酸酯类化合物具有以下结构通式B：
式中R1同权利要求1的定义；
式中R2、R3各自独立地为氢、羟基、1～4个碳的烃基、乙酰基或异戊酰基；
式中R4为氢、C1-C6直链或支链的饱和或不饱和烃基、C3-C7环烃基、硝基、卤素、氰基、三氟甲基、三氟甲氧基、苯基、苄基、芳香基、含有1-3个氧、硫或氮的杂原子被苯基和芳香杂环并合或被一个或多个选自卤素、C1-C6直链或支链烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、C1-C4烷氧基、巯基、C1-C4酰基或芳香基基团所取代的5-7元芳香杂环或1～5个单元的糖苷键。
3、一种肉桂酸酯类化合物C，其特征在于，该肉桂酸酯类化合物具有以下结构通式C：
式中R1同权利要求1的定义；
式中R2、R3、R4各自独立地为氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基或1～5个单元的糖苷键；
式中R5为氢、羟基、1～4个碳的烃基、烷氧基、乙酰基、异戊酰基、1～5个单元的糖苷键、硝基、卤素、氰基、三氟甲基或三氟甲氧基；
式中R6为氢、羟基、烷氧基、C1-C6直链或支链的饱和或不饱和烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基或1～5个单元的糖苷键。
4、一种肉桂酸酯类化合物D，其特征在于，该肉桂酸酯类化合物具有以下结构通式D：
式中R1同权利要求1的定义；
式中R2、R3、R4同权利要求3的定义；
式中R5为氢、羟基、1～4个碳的烃基、烷氧基、乙酰基、异戊酰基、硝基、卤素、氰基、三氟甲基、三氟甲氧基或1～5个单元的糖苷键；
式中R6同权利要求3的定义。
5、一种肉桂酸酯类化合物E，其特征在于，该肉桂酸酯类化合物具有以下结构通式E：
式中R1同权利要求1的定义；
式中R2、R3各自独立地为氢、1～4个碳的烃基、乙酰基、异戊酰基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基或1～5个单元的糖苷键；
式中R4为氢、羟基、烷氧基、1～4个碳的烃基、乙酰基、异戊酰基、卤素、氰基、三氟甲基、三氟甲氧基、α-取代乙酰氧基异戊酰基、β-取代乙酰氧基异戊酰基、α-取代异戊酰氧基异戊酰基、异戊烯基、邻羟基苯甲酰基或1～5个单元的糖苷键。
6、根据权利要求2所述的肉桂酸酯类化合物B，其特征在于，所述化合物B为大花鸡肉参酯甲(+)2-(1-羟基-4-氧代环己基)咖啡酸乙酯，，具有以下结构通式
7、根据权利要求2所述的肉桂酸酯类化合物B，其特征在于，所述化合物B为红波罗花酯甲2-(1，4-二羟基环己基)咖啡酸乙酯，具有以下结构通式：
8、如权利要求1-7中任一项所述的肉桂酸酯类化合物在制备白三烯A4水解酶功能调节药物中的应用。
9、如权利要求8所述的应用，其特征在于所述的药物为治疗哮喘、系统性红斑狼疮、炎症、心肌梗塞、非小细胞肺癌、急性髓性白血病或实体瘤的药物。
10、如权利要求6所述的应用，其特征在于所述的药物为肉桂酸酯类化合物作为活性成分与药学上可以接受的载体组成的口服剂、注射剂、栓剂或鼻喷雾剂，所述活性成分的重量含量为0.1-99.5％。
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