CN102504005B - 一类具有新型结构的化合物及其制备方法和用途 - Google Patents
一类具有新型结构的化合物及其制备方法和用途 Download PDFInfo
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- CN102504005B CN102504005B CN201110312179.0A CN201110312179A CN102504005B CN 102504005 B CN102504005 B CN 102504005B CN 201110312179 A CN201110312179 A CN 201110312179A CN 102504005 B CN102504005 B CN 102504005B
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Abstract
Description
技术领域
本发明涉及医药领域,具体涉及一类奇墩果酸衍生物及其药学上可接受的盐,其制备方法、含有这些衍生物的药用组合物以及它们的医药用途,特别是在制备抗炎、抗肿瘤和抗心血管疾病药物中的应用。
背景技术:
齐墩果酸(oleanolic acid,OA ) 是五环三萜类化合物, 是一种天然产物化学成分, 广泛分布于植物界, 据不完全统计,有126种植物含有OA。在常用的植物中,如丁香、大枣、川西獐牙菜、女贞子、牛膝、西洋参、苏合香、连翘、青叶胆、琵琶叶、柿叶、景天三七、人参、山芝麻、甘草、关木通、东北龙胆、雪胆、摁木、小茴香、夏枯草中都含有OA。OA在五加科、葫芦科、铁青树科、毛茛科等植物的根和根茎(如雪胆、摁木)中主要以游离或结合成苷的形式存在。
OA 为五环三萜类化合物, 化学名为(3β)-3-Hydroxyolean-12-en-28-oic acid, 分子式为C30H48O3,为白色簇状针晶, 无色、无味、无臭、不溶于水, 可溶于乙醇、氯仿、乙醚、丙酮等。熔点: 310℃, 比旋度:[α]12D+79.50 (氯仿中) ,Liebermann-Burchard 反应呈紫红色。
OA 是植物化学成分,毒性很低,具有多种生物活性:抗病毒、消炎、增强免疫和抑制免疫(免疫双向调解作用)、抑制血小板凝集、降血脂、降糖、保肝、护肾、抗艾滋病毒等。OA 对恶性肿瘤化疗造成的免疫功能下降的恢复和对抗结核药物的肝损害的保护意义重大, 恶性肿瘤是对人类生命威胁最严重的疾病, 而结核病近10 年来全球性漫延迅速,损害人类健康。降血脂、降糖、抗病毒,特别是抗艾滋病病毒活性的发现,说明OA有非常广阔的应用前景。但目前齐墩果酸制剂种类单一, 生物利用度不高, 和大部分中药有效成分一样, 具有多种药理作用, 但活性都不高。因此制备齐墩果酸衍生物,增强药理活性,提高生物利用度,是解决其临床应用的有效途径[张蜀艳,李政.齐墩果酸研究进展.食品与发酵科技,2010,46(4):20-24.]。
在生物体及细胞内存在着复杂多样的信号途径,其中气体信号分子以其独有的可连续产生、迅速传播、快速弥散等特点引起科学界的广泛关注,气体信号分子的发现使生物医学研究进入了全新一页。最先发现的两个气体信号分子分别是一氧化氮( nitric oxide, NO)和一氧化碳( carbon monoxide, CO)。前者被发现具有舒张血管、抑制血小板聚集和抑制细胞增殖等广泛的生物学效应,后者也被证实可影响学习和记忆过程、脊索神经痛觉传递、嗅觉受体神经的发育和功能和具有舒张血管、抑制平滑肌细胞增殖等功能[Wang R, Wang ZZ, Wu L. Carbonmonoxide-induced vasorelaxation and the underlying mechanisms. Br J Pharmacol, 1997, 121(5):927-934.1]。
H2S是一种有臭鸡蛋样味道的气体。一直以来,人们都认为它仅仅是一种有毒并且对环境有害的气体。直到20世纪80年代末期,相继在大鼠、牛和人类等脑中发现了含量相当高的内源性H2S后,才逐渐认识到它可能具有生理和病理功能。目前,越来越多的研究证明,H2S是继NO和CO之后发现的一种新的气体信号分子,它们具有某些共同的特点:都是小分子质量的气体分子,能自由穿透细胞膜且不依赖受体产生信号转导,能按需要进行内源性合成,释放后能迅速降解,有特定的细胞和分子靶标,在很多水平上能彼此密切关联共同发挥作用。人们相继发现H2S在心血管、神经、炎症反应、呼吸、消化、血液、新陈代谢、炎症等多系统或疾病过程中具有重要的病理生理作用, 它可以舒张血管平滑肌;抑制低氧时肺动脉高压的形成,调节肺血管结构的重建;显著降低高血压大鼠的血压,并抑制平滑肌细胞增殖;明显减少心肌缺血再灌注损伤;减轻脂多糖诱导的大鼠水肿和血管通透性增高等炎症反应;H2S在炎症发生早期具有抗炎、抗氧化性损伤的作用,还能使非甾体类消炎药引起的胃黏膜损伤减轻60%~70%。
人体内源性H2S是以L-半胱氨酸(L-cysteine, L-Cys) 为底物,L-半胱氨酸是由食物中摄取的含硫氨基酸(L-半胱氨酸)通过转硫途径以同型半胱氨酸(Hcy)作为中间产物产生的,或由内源性蛋白质直接分解产生的。在吡多醛-5′-磷酸依赖性酶胱硫醚-β-合成酶(cystathionine-β-synthase, CBS)、胱硫醚-γ-裂解酶(cystathionine-γ-lyase,CSE)和半胱氨酸转移酶催化下产生的[S. Kubo, M. Kajiwara and A. Kawabata. Dual modulation of the tension of isolated gastric artery and gastric mucosal circulation by hydrogen sulfide in rats. Inflammopharmacol 2007;15: 288–292; Zhao P, Huang X, Wang ZY, Qiu ZX, Han YF, Lu HL, et al. Dual effect of exogenous hydrogen sulfide on the spontaneous contraction of gastric smooth muscle in guinea-pig. Eur. J. Pharmacol 2009;616:223–228; Tang, C.S, Li, X.H, Du, J.B, Hydrogen sulfide as a new endogenous gaseous transmitter in the cardiovascular system. Curr. Vasc. Pharmacol. 2006; 4: 17–22]。
由于硫化氢上述奇特的生物学效应的发现,使得人们对许多生命现象有了新的理解和认识,同时人们也逐渐认识到硫化氢可以被用于疾病的治疗当中。很幸运的是,本发明人在经过大量的研究和试验后发现,某些化合物在被接入硫化氢释放基团后形成了具有较低副作用的衍生物,而且其活性与母体化合物相比有所增强或基本相当。例如,本发明的衍生物基本不产生或少产生胃肠和/或心血管副作用。
近年来,研究发现人类的恶性肿瘤与炎症密切相关[Lisa M, Zena W. Inflammation and cancer. Nature 2002,420: 860-867.], 比如肝癌与慢性肝炎, 胃癌与胃炎, 结肠癌与溃疡性结肠炎, 胰腺癌与胰腺炎, 黑色素瘤与皮肤炎症等, 据估计与炎症相关的恶性肿瘤占了人类癌症的15%左右。研究显示,炎症诱发肿瘤的分子生物学机制包含两个方面:首先,炎症细胞造成活性氧簇(ROS)和活性氮簇(RNS)的产生,导致细胞DNA损伤;其次,炎症细胞释放的细胞因子或炎症介质(如ROS、蛋白酶、基质金属蛋白酶(MMPs)、肿瘤坏死因子 (TNF-α)、白细胞介素(IL)、干扰素(IFN)、环氧合酶-2(COX-2)及核转录因子(NF-κB)增强了细胞增殖信号,促进了细胞增殖、细胞迁移和血管生成,直至肿瘤生长和转移[Chiara P, Paola Li, Monica R, Maria G, Paola A, Alberto M, Antonio S. Cellular and molecular pathways linking inflammation and cancer. Immunobiology 2009,214:761-777;Sgambato A, Cittadini A. Inflammation and cancer: a multifaceted link. Eur Rev Med Pharmacol Sci 2010,14:263-268; Mary P, Donald A, Hans S. Inflammation as a tumor promoter in cancer induction. Mut Res 2008,659:15-30.]。
由于恶性肿瘤与炎症有密切的联系,使得人们对抗炎药物用于预防/治疗恶性肿瘤的认识也日益深入[Kashfi K. Anti-inflammatory agents as cancer therapeutics. Adv Pharmacol 2009,57:31-89.]。近年流行病学、动物模型及临床应用的研究均表明NSAIDs能够通过诱导肿瘤细胞的凋亡、阻滞细胞周期、抑制肿瘤的侵袭和转移等而发挥抗肿瘤的作用。Harris等根据结果的一致性、关联性、不同剂量的效果及可能的生物学机制等流行病学的判断标准[Harris R, Beebe-Donk J, Doss H, Burr Doss D.Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non- selective COX-2 blockade. Oncol Rep 2005,13:559-583.],总结了NSAIDs对10种人类恶性肿瘤的作用:结果显示,在7-10种恶性肿瘤中,每日服用NSAIDs可使结肠癌的患病风险降低63%,乳腺癌降低39%,肺癌降低36%,前列腺癌降低39%,食道癌降低73%,胃癌降低62%,卵巢癌降低47%,且用药时间越长效果越好。其中,NSAIDs对食道癌、胃癌及结肠癌的效果较好,对恶性黑色素瘤、霍奇金病及成人白血病也有保护作用。
但非甾体抗炎药长期应用存在疗效不满意和/或不良反应严重的问题[Arroyo M, Lanas A. NSAIDs-induced gastrointestinal damage. Minerva Gastroenterol Dietol 2006,52:249-259;Sostres C, Gargallo C, Arroyo M, Lanas A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol 2010,24:121-132.]:经典的非甾体抗炎药长期或大量用药会对胃肠道产生副作用,给病人造成二次损害,给个人和社会带来继发性经济负担,甚至最终导致死亡的病例也不鲜见。新一代的非甾体抗炎药如昔布类药物虽然胃肠道副作用大大减轻,但是会引发心血管事件如血压升高、中风、心肌梗塞等,仍然难以满足临床要求[Scheiman J, Hindley C. Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events. Clin Ther 2010,32:667-677;Davies N, Reynolds J, Undeberg M, Gates B, Ohgami Y, Vega-Villa K. Minimizing risks of NSAIDs: cardiovascular, gastrointestinal and renal. Expert Rev Neurother 2006,6:1643-1655.]。因此,寻找更安全有效的具有抗肿瘤作用的非甾体抗炎药物仍然是一项长期而艰巨的任务。
发明内容
为了解决现有技术存在的问题,本发明人经过大量的实验,在齐墩果酸的结构上,引入硫化氢释放基团,合成了一系列新的化合物,有效地克服了现有技术的缺陷。
根据本发明,提供具有下列通式的化合物:
(式YLXYⅢ)
在一个优选的方案中,式YLXYⅢ的R代表氢、乙酰基、哌啶乙酰基、哌啶乙酰基;Y=氧;Z= (CH2)n,n=2,3或4;S代表。然而,应当理解的是,在本发明中可以使用任何无毒性、能释放硫化氢的有效部位。
优选的化合物如下所示:齐墩果酸2-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]乙酯 (R=H;Y= O;Z= (CH2)n,n=2;S=4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚,即YLXYⅢ-1),齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯 (R=H;Y= O;Z= (CH2)n,n=3;S=4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚,即YLXYⅢ-2),齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(R=H;Y= O;Z= (CH2)n,n=4;S=4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚,即YLXYⅢ-3)。
根据本发明,还提供具有下列通式的化合物,
(式YLXYⅣ)
通式YLXYⅣ中, R代表氢,羟基;X=氢,氧;Y=氮,氧;Z= (CH2)n、CH2CO,其中n=2~4;S是能释放硫化氢的部分。
在一个优选的方案中,式YLXYⅣ的R代表氢或羟基;X=氢;Y=氧;Z= (CH2)n, n=3或4;S代表。然而,应当理解的是,在本发明中可以使用任何无毒性、能释放硫化氢的有效部位。
优选的化合物如下所示:3-氧代齐墩果酸3-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(R=H;Y=H2;Z= (CH2)n, n=3;Y= O;S= 4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚,即YLXYⅣ-1),3-氧代齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(R=H;Y=H2;Z= (CH2)n, n=4;Y= O;S= 4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚,即YLXYⅣ-2),2-羟基-3-氧代齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(R=OH;Y=H2;Z= (CH2)n, n=3;Y= O;S= 4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酚,即YLXYⅣ-3)。
本发明所述的化合物药理活性相当高,而且具有良好的安全性和耐受性,可以用于治疗和预防各种疾病,例如,各种氧化应激参与的疾病状态,呼吸系统疾病、心血管疾病、癌症、弥散性硬皮病、系统性硬结、溃疡性结肠炎、成胶质病变、Crohnn氏病(局部性回肠炎)、病毒性肝炎、药物性肝炎、肝硬、小动脉纤维性病变、动脉硬化、糖尿病、急、慢性肾小球肾炎、间质性肾炎、肾盂肾炎、肾动脉硬化、肾功能不全、急慢性胃炎、消化道溃疡、胃癌、大骨节病、克山病。同时,所述化合物可以用于各种跟炎症显著相关的疾病,例如,但不限于,癌症、哮喘、脑中风、心肌梗塞、心肌缺血、冠状动脉硬化、心绞痛、高血压、风湿性心脏病、心肌炎、克山病、心包炎、动脉粥样硬化。
更相关的是,本发明的化合物可以用于,但不限于,治疗炎症,或用于治疗与炎症有关的疾病,例如,用作解热镇痛抗炎药。例如,本发明的化合物可以用于治疗关节炎,包括但不限于,类风湿性关节炎、骨关节炎、风湿性关节炎、痛风性关节炎、红斑狼疮综合症。与皮肤有关的炎症,牛皮癣、湿疹、烧伤、皮炎。也可以用于治疗胃肠道病症,例如炎性肠病、克劳恩病、胃炎、过敏性肠综合症和溃疡性结肠炎。本发明的化合物可以用于治疗哮喘、支气管炎、滑囊炎、腱鞘炎。用于预防或治疗癌症,例如结肠直肠癌。该类化合物也可以用于治疗疼痛,包括但不限于,头痛、牙痛、颌面痛、颈项痛、肩、上肢痛、胸痛、腹痛、腰背痛、盆腔痛、下肢痛、肛门、会阴痛、手术痛、肌肉痛、癌性疼痛。也可以用于某些疾病中的炎症,这些疾病包括但不限于,血管疾病、偏头痛、结节性动脉炎、甲状腺炎、再生障碍性贫血、硬化病、风湿热、糖尿病、重症肌无力、牙龈炎、肾炎、过敏症、损伤后发生的肿胀、心肌缺血等;也可以用于肺部炎症,急性肺损伤、急性呼吸窘迫综合症、各种感染性(如细菌性、病毒性、支原体性、真菌性和寄生虫性)肺炎、理化性(如放谢性、吸入性的类脂性)肺炎以及变态反应性(如过敏性和风湿性)肺炎、慢性阻赛性肺病、内毒素休克症。与痔疮有关的炎症、痉挛性肛部痛和直肠裂;肝胆囊和/或胆道病症,例如,胆管炎、硬化性胆管炎、原发性胆汁性肝硬变和胆囊炎、肠痈。也可以用于治疗中枢神经系统疾病,如阿尔茨海默症(老年痴呆症)、帕金森病、动脉粥样硬化和由中风、缺血、创伤导致的中枢神经损害。除了用于人类疾病的治疗外,还可以用于其它哺乳动物,包括猪、牛、马、羊、猫、狗、鼠。
本发明的化合物可以用于预防或治疗各种疾病,特别是GI道的炎症,包括但不限于,口腔炎症例如粘膜炎、感染性疾病(例如,病毒、细菌、真菌疾病)和克劳恩病、食管的炎症例如食管炎、化学伤导致的疾病(例如,摄取碱液)、胃食管返流疾病、胆汁酸返流、巴雷特食管、食管狭窄、炎症例如胃炎(例如,幽门螺旋杆菌、酸、消化性疾病和萎缩性胃炎)、乳糜泻、消化性溃疡、胃的癌前期病变、非溃疡性消化不良和克劳恩病、胃部的炎症例如克劳恩病、溃疡性结肠炎、沙门氏菌肠炎、志贺氏杆菌感染、耶尔森菌病、隐孢子虫病、微孢子虫感染和病毒感染、辐射诱导的结肠炎、免疫妥协的宿主中的结肠炎(例如,盲肠炎)、结肠的癌前期病变(例如,发育异常、肠的炎症和结肠息肉)、直肠炎。
医生或患者可以根据各自的特殊情况或疾病状态,调整剂量来使用本发明的化合物,只要该剂量在有效和安全范围内。这是本领域技术人员很容易知晓的。一般情况下,这些化合物成人每天的服用量大概在1-5000mg之间,可以一次,也可以多次服用,当然,根据治疗疾病的需要和患者的体重或疾病状态可进行必要的个体化调整,以达到最佳疗效。但是,最适合的剂量水平应该在0.1-500mg/kg,优选为5-100mg/kg,但是根据要治疗的患者的体重、情况及它们对所述药物的反应灵敏度,以及所选择的药物制剂的类型和在进行使用时的时间和间隔期,可以进行改变。有时,低于上述范围下限的剂量水平或高于上限的剂量水平也可以,只要不产生任何影响治疗的副作用。
本发明的化合物可以制成各种药物剂型,其性质取决于给药途径,可以通过常规方法,使用相容的、药学可接受的赋形剂或载体来制备这些药物组合物。这些组合物剂型可以是片剂、胶囊、颗粒剂、喷雾剂、透皮贴剂、糖锭、锭剂、糖浆、粉末、凝胶、栓剂等等,制备临时溶液、可注射制剂、直肠、眼部、阴道制剂等等,优选的给药途经是口服和直肠给药。
当用于口服时,可以使用各种赋形剂例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸以及各种崩解剂如淀粉、海藻酸钠和某些复合硅酸盐、以及粒状粘合剂例如聚乙烯吡啰烷酮、蔗糖、明胶和阿拉伯胶。此外,为进行压片可以使用润滑剂如硬脂酸镁、月桂硫酸钠和滑石、相似类型的固体组合物也可以在胶囊中使用填充剂,与其相关的优选物质还包括乳糖或牛奶糖以及高分子量聚乙二醇。当希望水性混悬液用于口服时,活性成分可以与增甜剂或调味剂、着色物质和乳化剂和/或悬浮剂组合,与稀释剂例如水、乙醇、丙二醇、甘油及其各种组合在一起。
可以将剂型设计为缓慢释放、控制释放、立即释放、延迟释放或靶向延迟释放。这些术语的定义是本领域技术人员所共知的。
当胃肠外使用时,可以使用活性化合物的芝麻或花生油或水性丙二醇溶液,如果必要,水性溶液应当是适当缓冲的(优选pH大于8),液体稀释剂首先是等张的,水性溶液适合静脉注射的目的。在无菌条件下制备所有这些溶液都是通过本领域普通技术人员公知的标准制药技术即可完成的。
实验结果表明,本发明化合物具有优秀的抗炎作用,而且未发现明显的胃肠道损伤。并且本发明中的化合物由于会释放出适量的硫化氢,会减少心血管事件的发生 [陈雯,谢晓华.医学综述, 2008,14(24):3704]。因此,本发明中的化合物有可能避免临床正在应用的非甾体抗炎药所致的胃肠道损伤和/或心血管不良事件或其它毒副反应,有可能取代现有的临床用药,有着十分广阔的应用前景。
下面的实施例进一步描述,并使本领域的普通技术人员能够实施和使用本发明。然而,应当认识到,这些实施方案是用于解释本发明的目的,而不应理解为限制由权利要求所定义的本发明的范围。
附图说明
图1是部分YLXYⅢ和Ⅳ类化合物对二甲苯致小鼠耳肿胀的影响。
图2是部分YLXYⅢ和Ⅳ类化合物对巴豆油致小鼠耳肿胀的影响。
图3是部分受试YLXYⅢ和Ⅳ类化合物对肿瘤细胞MCF-7、HT-29增殖作用的影响。
图4是受试化合物单次给药对大鼠胃肠道的影响。
图5是受试化合物连续给药对大鼠胃肠道的影响。
具体实施方式
化合物制备
实施例一:
1、5-(4-羟基苯基)- 3H-1,2-二硫环戊基-4-烯-3-硫酮(ADT-OH)合成
(1)5-(4-甲氧基苯基)- 3H-1,2-二硫杂环戊烯-3-硫酮(ADT-OCH3)的合成
将茴香脑(3.17g,0.021mol),硫(4.70g,0.146mol)和DMF30mL加入烧瓶中,搅拌回流6h。反应完毕倒入冷水中,析出大量沉淀,过滤,乙醇-水重结晶,得到红色晶体,产率78%,mp: 110~111℃。
1H NMR (400MHz, DMSO-d6), δ(ppm): 7.62 (d, 2H, J = 8.9 Hz, ArH), 7.40 (s, 1H, =CH), 6.98 (d, 2H, J = 8.8 Hz, ArH), 3.88 (s, 3H, OCH3)。
(2)5-(4-羟基苯基)- 3H-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)的合成
将ADT-OCH3 (20.6g, 0.1mol)和盐酸吡啶(69.0g, 0.6mol)加热回流1h,冷却,变成固体,捣碎,加水洗涤数遍,过滤,滤饼用丙酮-水重结晶,产率98.0%,mp: 191~192℃。
1H NMR (400MHz, DMSO-d6), δ(ppm):10.46 (s, 1H, OH), 7.78 (d, 2H, J = 8.7 Hz, ArH), 7.66 (s, 1H, =CH), 6.90 (d, 2H, J = 8.7 Hz, ArH)。
(3)5-[4-(2-溴乙氧基)苯基]- 3H-1,2-二硫杂环戊烯-3-硫酮(3a)的合成
将ADT-OH(0.325g, 1.4mmol)、1,2-二溴乙烷(0.50mL, 5.8mmol)和无水K2CO3 (0.396g, 2.8mmol)加至10mL干燥的DMF中,120℃反应2h。冷却后加20mL乙酸乙酯稀释,水洗(3×20mL),合并有机相,无水Na2SO4干燥,蒸干溶剂,丙酮-水重结晶,得到黑褐色产物0.388g,产率81.5%,mp:126.0~127.0℃。
1H NMR(400MHz, CDCl3), δ(ppm): 7.59(d, 2H, J = 8.9 Hz, ArH), 7.36(s, 1H, =CH), 6.96(d, 2H, J = 8.9 Hz, ArH), 4.33(t, 2H, CH2), 3.65(t, 2H, CH2) .
13C NMR(400MHz, CDCl3), δ(ppm): 212.554, 170.180, 158.775, 132.260, 126.120, 122.226, 113.014, 65.455, 26.026。
(4)5-[4-(3-溴丙氧基)苯基]- 3H-1,2-二硫杂环戊烯-3-硫酮(3b)的合成
参照3a的合成方法由ADT-OH和1,3-二溴丙烷制备,黑褐色产物,产率83.2%,mp:79.0~80.0℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.62(d, 2H, J = 8.8 Hz, ArH), 7.40(s, 1H, =CH), 7.00(d, 2H, J = 8.7 Hz, ArH), 4.19(t, 2H, CH2), 3.62(t, 2H, CH2), 2.36(p, 2H, CH2).
13C NMR (400MHz, CDCl3), δ(ppm): 212.460, 170.437, 159.454, 132.073, 126.065, 121.751, 112.886, 63.118, 29.453, 27.178。
(5)5-[4-(4-溴丁氧基)苯基]- 3H-1, 2-二硫杂环戊烯-3-硫酮(3c)的合成
参照3a的合成方法由ADT-OH和1, 4-二溴丙烷制备,黑褐色固体,产率79.4%,mp:70.0~71.0℃。
1H NMR (400MHz,CDCl3),δ(ppm): 7.60(d, 2H, J = 8.7 Hz, ArH), 7.38(s, 1H, =CH), 6.96(d, 2H, J = 8.7 Hz, ArH), 4.07(t, 2H, CH2), 3.50(t, 2H, CH2), 2.08(m, 2H, CH2), 1.99(m, 2H, CH2).
13C NMR (400MHz, CDCl3), δ(ppm): 212.439, 170.554, 159.670, 132.006, 126.057, 121.553, 112.834, 64.759, 30.795, 26.729, 25.133。
、齐墩果酸中间体的合成
(1)齐墩果酸-2-溴乙酯(9a)的合成
将齐墩果酸(0.228g, 0.5mmol),1,2-二溴乙烷(0.17mL, 2.0mmol)和三乙胺 (0.14mL, 1.0mmol)加至10mL丙酮中,回流搅拌10h。冷却后减压蒸干溶剂,柱层析[石油醚(60~90℃):乙酸乙酯=5:1(v/v)],得到白色固体,产率68.1%,mp: 150.0~ 152.0℃(与文献一致,张奕华, 陈莉, 田季德, 等. 齐墩果酸偶联衍生物及其药物用途[P] . CN 200410041376.3,产率:65.0%)。
(2)齐墩果酸-3-溴丙酯(9b)的合成
参照9a的制备方法由齐墩果酸和1, 3-二溴丙烷制备,白色粉末,产率69.6%,mp:151.6~152.6℃。
1H NMR (400 MHz, CDCl3), δ:5.21 (brs, 1H, C12-H), 4.25 (dt, 1H, CH2), 4.18 (dt, 1H, CH2), 4.12 (m, 2H, OCH2), 3.19 (dd, 1H, 3α-H), 2.85 (dd, 1H, C18-H), 2.15 (p, 2H, CH2), 1.35 (m, 4H, CH2), 1.10 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.73 (s, 3H, CH3), 0.65 (s, 3H, CH3)。
(3)齐墩果酸-4-溴丁酯(9c)的合成
参照9a的制备方法由齐墩果酸和1, 4-二溴丁烷制备,白色粉末,产率70.6%,mp:101.1~102.1℃。
1H NMR (400 MHz, CDCl3) δ:5.28 (brs, 1H, C12-H), 4.12 (t, 2H, OCH2), 4.08 (t, 2H, OCH2), 3.20 (dd, 1H, 4.5 Hz, 3α-H), 2.87 (dd, 1H, C18-H), 1.88 (m, 7H, CH2 & CH), 1.63 (m, 13H, CH2 & CH), 1.44 (d, 1H, CH), 1.34 (t, 2H, CH2), 1.27 (d, 1H, CH), 1.18 (d, 1H, CH), 1.13 (s, 3H, CH3), 1.06 (d, 2H, CH2), 0.98 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.88 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.73 (s, 3H, CH3)。
(4)3-乙酰基-O-齐墩果酸的合成
将齐墩果酸(1.82g, 4.0mmol)溶于10mL吡啶中,室温搅拌,滴加乙酸酐(3.78mL, 40.0mmol),反应12h后倒入冰水中,析出固体,过滤,干燥,丙酮-水重结晶得到白色固体1.92g,产率96.5%,mp: 266.0~268.0℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.27 (brs, 1H, C12-H) 2.81 (dd, 1H, C18-H), 2.04 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.11-1.03 (m, 2H, CH2), 0.93 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.86 (s, 3H, CH3), 0.85 (s, 3H, CH3), 0.74 (s, 3H, CH3)。
(5)3-O-(2-哌啶基乙酰基)齐墩果酸(10)的合成
将齐墩果酸(1.37g, 3.0mmol)溶于10mL四氢呋喃中,加入吡啶(0.36mL, 4.5mmol),室温搅拌下滴加氯乙酰氯(0.29mL, 3.9mmol),反应4h。然后倒入40mL水中,过滤,干燥,得到白色固体3- (2-氯乙酰基) -O-齐墩果酸1.53g,产率95.7%,mp:281.2~281.6℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.28 (brs, 1H, C12-H), 4.06 (s, 2H, CH2), 2.88-2.78 (m, 1H, C18-H), 1.13 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.89 (s, 3H, CH3), 0.87 (s, 3H, CH3), 0.75 (s, 3H, CH3).
将上述产物 (1.066g, 1.95mmol)溶于15mL四氢呋喃中,加入三乙胺(0.28mL, 1.95mmol),室温搅拌下加入哌啶(0.252mL, 2.54mmol),加热回流10h。蒸去大部分四氢呋喃,加水20mL,出现大量固体,过滤,干燥,丙酮-水重结晶,得到白色固体(10)1.03g,产率89.2%,mp:243.5~244.4℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.34-5.21 (s, 1H, C12-H), 3.21 (s, 2H, CH2), 2.90-2.74 (m, 1H, C18-H), 1.13 (s, 3H, CH3), 0.93 (s, 6H, CH3), 0.90 (s, 3H, CH3), 0.86 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.75 (s, 3H, CH3)。
(6)3-氧代齐墩果酸的合成
将齐墩果酸(2.0g, 4.4mmol)加入50 mL二氯甲烷和50mL丙酮混合液中,冰浴下滴加Jones’试剂2.0mL,保持温度0~5℃反应15min。然后加入200mL二氯甲烷,依次用饱和NaHCO3水溶液100 mL和饱和NaCl水溶液洗涤,无水Na2S04干燥,蒸干溶剂,甲醇重结晶,得到针状白色结晶,产率100%。mp:178.0~179.0℃.
1H NMR (400MHz, CDCl3), δ(ppm): 5.30 (s, 1H, C12-H), 2.88-2.79 (m, 1H, C18-H), 2.60-2.50 (m, 1H, C2-H), 2.41-2.33 (m, 1H, C2-H), 1.14 (s, 3H, CH3), 1.08 (s, 3H CH3), 1.05 (s, 3H CH3), 1.03 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.81 (s, 3H, CH3).
HR-MS: Calcd. For C30H47O3 [M+H]+ 455.3520, Found: 455.3521。
(7)2-羟基-3-氧代齐墩果酸(11)的合成
将3-氧代齐墩果酸(0.227g,0.5mmol)、催化量浓H2SO4加至10mL甲醇和5mL二氯甲烷混合液中,然后加入mCPBA(0.224g, 0.65mmol),室温搅拌6h,加水20mL,然后依次用饱和NaHCO3(30mL×3)和饱和NaCl(30mL×3)洗涤,无水MgSO4干燥。蒸干溶剂,柱层析[石油醚(60~90℃):乙酸乙酯=2:1(v/v)],得到白色固体,产率68.1%,mp:64.2~65.2℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.25 (s, 1H, C12-H), 4.53-4.44 (m, 1H), 2.83-2.74 (m, 1H, C18-H), 2.39-2.31 (m, 1H, C2-H), 1.21 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.05 (d, J = 2.35 Hz, 6H, CH3), 0.88 (s, 3H, CH3), 0.87 (d, J = 10.99 Hz, 6H, CH3).
HR-MS: Calcd. For C30H47O4 [M+H]+, 471.3469 Found: 471.3468。
(8)3,11-二羰基齐墩果烷-12-烯-28-酸(12)的合成
将齐墩果酸(1.37g, 3.0mmol)溶解于100mL 含5%乙酸酐的乙酸溶液中,加入GrO3(0.90g, 3.0mmol),室温搅拌。4h后加入60mL水和60mL二氯甲烷。水层用二氯甲烷萃取(40mL×2),合并有机相,用饱和Na2CO3溶液洗至微碱性,无水MgSO4干燥。蒸干溶剂,柱层析[石油醚(60~90℃):乙酸乙酯=10:1(v/v)],得到白色无定形固体0.92g,产率65.8%,mp: 145.8~146.8℃。
1H NMR (400MHz, CDCl3), δ(ppm): 5.67 (s, 1H, C12-H), 3.04~2.92 (m, 2H, C1-H, C18-H), 2.42~2.32 (m, 1H, C9-H), 1.37 (s, 3H, CH3), 1.22 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.94 (s, 3H, CH3).
HR-MS: Calcd. For C30H45O4 [M+H]+, 469.3312 Found: 469.3313。
(9)N-(3-氧代齐墩果酰)甘氨酸(13)的合成
将3-氧代齐墩果酸(0.311g, 0.685mmol)溶于10mL干燥的二氯甲烷中,冰浴下滴加草酰氯(0.26mL, 2.74mmol),搅拌2h后蒸干,得到白色固体3-氧代齐墩果酸酰氯,产率100%。
将3-氧代齐墩果酸酰氯(53mg, 0.11mmol)溶于5mL干燥的二氯甲烷中,冷却至0℃,加入甘氨酸甲酯盐酸盐(69mg,0.55mmol)和三乙胺(111μL 1.10mmol),搅拌4h。然后加入50mL二氯甲烷和50mL水,有机层用饱和氯化钠水溶液洗涤(30mL×3),干燥。蒸干溶剂,硅胶柱色谱[石油醚(60~90℃):乙酸乙酯=15:1(v/v)],得到淡黄色固体N-(3-氧代齐墩果酰)甘氨酸甲酯55.3mg,收率93.0%,mp:101.0~102.0℃。
1H NMR (400MHz, CDCl3), δ(ppm): 6.54-6.48 (m, 1H, NH), 5.48 (s, 1H, C12-H), 3.77 (s, 3H, CH3), 2.67-2.60 (m, 1H, C18-H), 2.58-2.50 (m, 1H, C2-H), 2.41-2.32 (m, 1H, C2-H), 1.17 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.04 (s, 6H, CH3), 0.92 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.76 (s, 3H, CH3).
HR-MS: Calcd. For C33H52NO4 [M+H]+, 526.3891, Found: 526.3878。
将N-(3-氧代齐墩果酰)甘氨酸甲酯(262.5mg, 0.5mmol)溶于2mL四氢呋喃:水(v:v=4:1)的混合溶液中,再加入4mol.L-1的氢氧化钠水溶液(500μL,2.0mmol),室温搅拌4h。加入50mL水,用1.0mol.L-1的稀盐酸调pH=2后,用二氯甲烷萃取(50mL×3),合并有机层,用饱和氯化钠水溶液洗涤(30mL×2),无水MgSO4干燥。蒸干溶剂,硅胶柱色谱[石油醚(60~90℃):乙酸乙酯=8:1(v/v)],得到白色固体13,收率为95.0%,mp:140.8~141.8℃。
1H NMR (400MHz, CDCl3) δ(ppm): 6.69 (m, 1H, NH), 5.48 (s, 1H, C12-H), 2.57-2.50 (m, 1H, C18-H), 2.43-2.33 (m, 1H, C2-H), 1.17 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.92 (s, 6H, CH3), 0.77 (s, 3H, CH3)。
实施例二:
YLXYⅢ和Ⅳ类化合物的合成
(1)齐墩果酸2-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]乙酯 (YLXYⅢ-1)的合成
将ADT-OH(0.147g, 0.65mmol)、齐墩果酸-2-溴乙酯(9a)(0.365g, 0.65mmol)、无水K2CO3(0.178g, 1.30mmol)和催化量KI加至10mL干燥的DMF中,室温搅拌12h,然后加10mL乙酸乙酯稀释,水洗(3×10mL),无水Na2SO4干燥,蒸干溶剂,柱层析[石油醚(60-90):乙酸乙酯=20:1(v/v)],得到红色固体0.259g,产率56.2%,mp:101.0~102.0℃。
1H NMR (400 MHz, CDCl3) , δ: 7.62 (d, 2H, J = 8.8 Hz, ArH), 7.39 (s, 1H, =CH), 6.97 (d, 2H, J = 8.8 Hz, ArH), 5.24 (brs, 1H, C12-H), 4.41 (m, 2H, OCH2), 4.21 (t, 2H, OCH2), 3.19 (dd, 1H, 3α-H), 2.86 (d, 1H, C18-H), 1.11 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.89 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.75 (s, 3H, CH3), 0.62 (s, 3H, CH3).
13C NMR (300 MHz, CDCl3), δ: 209.85, 172.46, 167.53, 156.64, 138.25, 129.49, 123.36, 122.84, 117.28, 110.29, 73.71, 61.03, 56.93, 49.89, 42.27, 41.58, 40.53, 36.40, 36.00, 34.03, 33.48, 33.14, 31.72, 28.55, 27.83, 27.19, 25.44, 24.45, 22.86, 22.35, 21.88, 20.61, 18.37, 18.13, 17.70, 13.05, 11.75, 10.36, 10.02.
IR(KBr, cm-1): 3443.1 (OH), 1734.8 (C=O), 1659.8, 1636.1, 1602.9, 1489.9 (C=C), 1175.9 (C=S).
HR-MS: Calcd. For C41H57O4S3 [M+H]+ 709.3413, Found: 709.3392。
(2)齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯 (YLXYⅢ-2)的合成
参照YLXYⅢ-1的合成方法由9b和ADT-OH制备,红色粉末,产率62.3%,mp:124.0~125.0℃。
1H NMR (400 MHz, CDCl3), δ:7.62 (d, 2H, J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.8 Hz, ArH), 5.24 (brs, 1H, C12-H), 4.27 (dt, 1H, CH2), 4.18 (dt, 1H, CH2), 4.10 (m, 2H, OCH2), 3.19 (dd, 1H, 3α-H), 2.85 (dd, 1H, C18-H), 2.15 (p, 2H, CH2), 1.37 (m, 4H, CH2), 1.10 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.74 (s, 3H, CH3), 0.59 (s, 3H, CH3).
13C NMR (300 MHz, CDCl3) δ: 209.79, 172.45, 167.63, 156.93, 138.49, 129.34, 123.34, 118.97, 117.14, 110.11, 73.75, 59.28, 55.23, 49.83, 42.25, 41.54, 40.53, 36.39, 36.05, 33.93, 33.44, 33.12, 31.68, 28.56, 27.83, 27.27, 25.45, 24.46, 23.09, 22.84, 22.33, 21.84, 20.64, 18.38, 18.08, 17.75, 13.09, 11.58, 10.34, 10.00.
IR(KBr, cm-1): 3420.7 (OH), 1728.7 (C=O), 1653.2, 1635.6, 1604.0, 1468.8 (C=C), 1176.4 (C=S).
HR-MS: Calcd. For C42H59O4S3 [M+H]+ 723.3575, Found: 723.3553。
(3)齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅢ-3)的合成
参照YLXYⅢ-1的合成方法由9c和ADT-OH制备,红色粉末,产率66.7%,mp:134.5~135.5℃。
1H NMR (400 MHz, CDCl3) δ: 7.61 (d, 2H, J = 8.8 Hz, ArH), 7.39 (s, 1H, =CH), 6.96 (d, 2H, J = 8.8 Hz, ArH), 5.28 (brs, 1H, C12-H), 4.10 (t, 2H, OCH2), 4.06 (t, 2H, OCH2), 3.21 (dd, 1H, 3α-H), 2.87 (dd, 1H, C18-H), 1.34 (t, 2H, CH2), 1.13 (s, 3H, CH3), 0.98 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.87 (s, 3H, CH3), 0.77 (s, 3H, CH3), 0.72 (s, 3H, CH3).
13C NMR (300MHz, CDCl3), δ: 209.81, 172.48, 167.78, 157.05, 138.52, 129.34, 123.34, 118.85, 117.15, 110.18, 73.71, 62.50, 58.35, 49.92, 42.32, 41.49, 40.58, 36.47, 36.11, 34.08, 33.49, 33.18, 31.76, 28.61, 27.86, 27.49, 27.27, 25.47, 22.87, 22.40, 21.93, 20.64, 20.53, 20.07, 18.40, 18.16, 17.78, 13.08, 11.83, 10.36, 10.07.
IR(KBr, cm-1): 3443.4 (OH), 1717.7 (C=O), 1652.9, 1602.5, 1490.9 (C=C), 1177.2 (C=S).
HR-MS: Calcd. For C43H61O4S3 [M+H]+ 737.3726, Found: 737.3717。
(4)3-乙酰-O-齐墩果酸3-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯 (YLXYⅢ-4)的合成
参照YLXYⅢ-1的合成方法由3-乙酰-O-齐墩果酸和3b制备,红色粉末,产率78.6%,mp:135.6~ 136.6℃。
1H NMR (400 MHz, CDCl3) δ:7.62 (d, 2H, J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.8 Hz, ArH), 5.24 (brs, 1H, C12-H), 4.27 (dt, 1H, CH2), 4.18 (dt, 1H, CH2), 4.10 (m, 2H, OCH2), 3.19 (dd, 1H, 3α-H), 2.85 (dd, 1H, C18-H), 2.15 (p, 2H, CH2), 2.04(s, 3H, CH3), 1.37 (m, 4H, CH2), 1.10 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.74 (s, 3H, CH3), 0.59 (s, 3H, CH3).
IR(KBr, cm-1): 1733.0 (C=O), 1698.9 (C=O), 1603.2, 1554.2, 1492.4, 1468.5, (C=C), 1177.5 (C=S).
HR-MS: Calcd. For C44H61O5S3 [M+H]+ 765.3575, Found: 765.3649。
(5)3-乙酰-O-齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯 (YLXYⅢ-5)的合成
参照YLXYⅢ-1的合成方法由3-乙酰-O-齐墩果酸和3c制备,红色粉末,产率79.7%,mp:106.8~107.8℃。
1H NMR (400 MHz, CDCl3) δ: 7.61 (d, 2H, J = 8.5Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.6 Hz, ArH), 5.28 (brs, 1H, C12-H), 4.16-4.00 (m, 4H, CH2), 2.87 (m, 1H, C18-H), 2.05 (s, 3H, CH3), 1.13 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 6H, CH3), 0.86 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.72 (s, 3H, CH3).
13C NMR (300MHz, CDCl3), δ: 215.282, 177.969, 173.272, 171.304, 162.523, 144.004, 134.804, 128.812, 124.307, 122.531, 115.635, 81.077, 67.958, 63.796, 55.451, 47.697, 46.950, 46.000, 41.912, 41.560, 39.538, 38.297, 37.883, 37.109, 34.066, 33.323, 32.873, 32.721, 30.934, 28.258, 27.838, 26.054, 25.984, 25.531, 23.866, 23.724, 23.619, 23.228, 21.584, 18.417, 17.279, 16.928, 15.595.
HR-MS: Calcd. For C45H63O5S3 [M+H]+ 779.3832, Found: 779.3849。
(6)3-[(2-哌啶基乙酰基)]-O-齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(YLXYⅢ-6)的合成
参照YLXYⅢ-1的合成方法由10和3b制备,白色粉末,产率78.6%,mp:119.8~ 121.4℃。
1H NMR (400MHz, CDCl3), δ(ppm):7.62 (d, 2H, J = 8.6 Hz, ArH), 7.40 (s, 1H, CH=CH), 6.96 (d, 2H, J = 8.7 Hz, ArH), 5.27-5.22 (s, 1H, C12-H), 3.19 (s, 2H, CH2), 2.88-2.81 (m, 1H, C18-H), 1.09 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3), 0.82 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.80 (s, 3H, CH3).
IR(KBr, cm-1): 1741.0 (C=O), 1719.1 (C=O), 1603.3, 1576.1, 1529.2, 1492.6 (C=C), 1175.1 (C=S).
HR-MS: Calcd. For C49H70O5S3 [M+H]+ 848.4411, Found: 848.4360。
(7)3-[(2-哌啶基乙酰基)]-O-齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅢ-7)的合成
参照YLXYⅢ-1的合成方法由10和3c制备,白色粉末,产率80.0%,mp:77.5~ 78.5℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.61 (d, 2H, J = 8.2 Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.3 Hz, ArH), 5.34-5.23 (s, 1H, C12-H), 4.17-3.96 (m, 4H, CH2), 3.19 (s, 2H, CH2), 2.85(m, 1H, C18-H), 1.13 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.90 (s, 6H, CH3), 0.85 (s, 6H, CH3), 0.72 (s, 3H, CH3).
IR(KBr, cm-1): 1740.8 (C=O), 1723.4 (C=O), 1653.2, 1601.8, 1576.4, 1491.2 (C=C), 1177.6 (C=S).
HR-MS: Calcd. For C50H72O5S3 [M+H]+ 862.4567, Found: 862.4567。
实施例三:
(1)3-氧代齐墩果酸3-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(YLXYⅣ-1)的合成
参照YLXYⅢ-1的合成方法由3-氧代齐墩果酸和3b制备,红色粉末,产率82.6%,mp:91.6~ 92.5℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.62 (d, 2H, J = 8.7 Hz, ArH), 7.40 (s, 1H, =CH), 6.96 (d, 2H, J = 8.7 Hz, ArH), 5.26 (s, 1H, C12-H), 4.30-4.16 (m, 2H, OCH2), 4.15-4.05 (m, 2H, OCH2), 2.88 (m, 1H, C18-H), 2.57-2.47 (m, 1H, C2-H), 2.39-2.28 (m, 1H, C2-H), 2.15 (p, 2H, CH2), 1.10 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.89 (s, 3H, CH3), 0.66 (s, 3H, CH3).
IR(KBr, cm-1): 1716.7 (C=O), 1701.0 (C=O), 1662.4, 1601.0, 1576.8, 1490.3 (C=C), 1177.5 (C=S).
HR-MS: Calcd. For C42H57O4S3 [M+H]+ 721.3413, Found: 721.3413。
(2)3-氧代齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅣ-2)的合成
参照YLXYⅢ-1的合成方法由3-氧代齐墩果酸和3c制备,红色粉末,产率83.0%,mp:141.8~ 142.8℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.62 (d, 2H,J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.97 (d, 2H,J = 8.76 Hz, ArH), 5.31 (s, 1H, C12-H), 4.11 (t, 2H, OCH2), 4.06 (t, 2H, OCH2), 2.89 (m, 1H, C18-H), 2.61-2.47 (m, 1H, C2-H), 2.42-2.32 (m, 1H, C2-H), 1.15 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.02 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.78 (s, 3H, CH3).
IR(KBr, cm-1): 1728.1 (C=O), 1703.9 (C=O), 1653.2, 1601.1, 1576.8, 1487.6 (C=C), 1184.9 (C=S).
HR-MS: Calcd. For C43H59O4S3 [M+H]+ 735.3570, Found: 735.3570。
(3)2-羟基-3-氧代齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(YLXYⅣ-3)的合成
参照YLXYⅢ-1的合成方法由11和3b制备,红色粉末,产率82.5%,mp:68.0~ 69.0℃。
1H NMR (400MHz, CDCl3), δ(ppm): 8.02 (s, 1H, OH), 7.62 (d, 2H, J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.93 (d, 2H, J = 8.8 Hz, ArH), 5.26 (s, 1H, C12-H), 4.61-4.43 (m, 1H), 4.30-4.16 (m, 2H, OCH2), 4.11 (t, 2H, OCH2), 2.86(m, 1H, C18-H), 2.36 (s, 2H, C2-H), 2.21-2.09 (m, 2H, CH2), 1.28 (s, 3H, CH3), 1.13 (d, 6H, CH3), 1.10-1.05 (d, 6H, CH3), 0.91 (s, 3H, CH3), 0.90 (s, 3H, CH3).
IR(KBr, cm-1): 3446.6 (OH), 1716.9( C=O), 1704.8 (C=O), 1662.2, 1653.2, 1601.1, 1576.4 (C=C), 1177.8 (C=S).
HR-MS: Calcd. For C42H57O5S3 [M+H]+ 737.3363, Found: 737.3363。
(4)2-羟基-3-氧代齐墩果酸4-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅣ-4)的合成
参照YLXYⅢ-1的合成方法由11和3c制备,红色粉末,产率82.5%,mp:49.9~52.1℃。
1H NMR (400MHz, CDCl3), δ(ppm): 8.02 (s, 1H, OH), 7.61 (d, 2H, J = 8.8 Hz, ArH), 7.40 (s, 1H, =CH), 6.97 (d, 2H, J = 8.8 Hz, ArH), 5.30 (s, 1H, C12-H), 4.56-4.51 (m, 1H), 4.13-4.09 (m, 2H, OCH2), 4.09-4.05 (m, 2H, OCH2), 2.86(m, 1H, C18-H), 1.23 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.10 (s, 6H, CH3), 0.98 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.90 (s, 3H, CH3).
IR(KBr, cm-1): 3446.6 (OH), 1719.4( C=O), 1701.6 (C=O), 1668.5, 1653.2, 1601.9, 1570.4 (C=C), 1176.8 (C=S).
HR-MS: Calcd. For C43H59O5S3 [M+H]+ 751.3519, Found: 751.3520。
(5)3,11-二羰基齐墩果烷-12-烯-28-酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯(YLXYⅣ-5)的合成
参照YLXYⅢ-1的合成方法由12和3b制备,红色粉末,产率82.5%,mp:141.2~142.1℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.63(d, 2H, J = 8.8 Hz, ArH), 7.40(s, 1H, =CH), 6.96(d, 2H, J = 8.8 Hz, ArH), 5.66 (s, 1H, C12-H), 4.12~4.05(m, 2H, CH2), 3.04~2.92 (m, 2H, C1-H, C18-H), 2.42~2.32 (m, 1H, C9-H), 2.19~2.13(m, 2H, CH2), 1.34 (s, 3H, CH3), 1.14 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.02 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.85 (s, 3H, CH3).
IR(KBr, cm-1): 1719.9( C=O), 1710.2 (C=O), 1704.0 (C=O), 1662.2, 1658.2, 1576.4 (C=C), 1177.8 (C=S).
HR-MS: Calcd. For C42H55O5S3 [M+H]+, 735.3206 Found: 735.3204。
(6)3,11-二羰基齐墩果烷-12-烯-28-酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯(YLXYⅣ-6)的合成
参照YLXYⅢ-1的合成方法由12和3c制备,红色粉末,产率82.5%,mp:86.7~87.8℃。
1H NMR (400MHz, CDCl3), δ(ppm): 7.61(d, 2H, J = 8.8 Hz, ArH), 7.40(s, 1H, =CH), 6.96(d, 2H, J = 8.8 Hz, ArH), 5.68(s, 1H, C12-H), 4.06(t, 2H, J = 5.6 Hz, CH2), 3.05 ~2.94(m, 2H, C1-H, C18-H), 2.34 ~2.39(m, 1H, C9-H), 1.37(s, 3H, CH3), 1.21(s, 3H, CH3), 1.10(s, 3H, CH3), 1.05(s, 3H, CH3), 0.95(s, 3H, CH3), 0.94(s, 6H, CH3)
IR(KBr, cm-1): 1716.0( C=O), 1709.5 (C=O), 1704.0 (C=O), 1662.2, 1649.2, 1601.9, 1576.4 (C=C), 1177.6 (C=S).
HR-MS: Calcd. For C43H57O5S3 [M+H]+, 749.3363 Found: 749.3365。
(7) N-(3-氧代齐墩果酰)-甘氨酸4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯酯(YLXYⅣ-7)的合成
由13和ADT-OH制备,红色固体,产率89.1%,mp: 116.6~ 117.6℃
1H NMR (400MHz, CDCl3), δ(ppm): 7.56 (d, 2H, J = 8.6 Hz, ArH), 7.40 (s, 1H, =CH), 6.97 (d, 2H, J = 8.4 Hz, ArH), 6.58 (m, 1H, NH), 5.49 (s, 1H, C12-H), 3.78 (s, 2H, CH2), 2.59-2.51 (m, 1H C18-H), 2.43-2.32 (m, 1H, C2-H), 1.18 (s, 3H, CH3), 1.09 (s, 3H CH3), 1.05 (s, 6H, CH3), 0.92 (d, 6H, CH3), 0.77 (s, 3H, CH3).
IR(KBr, cm-1): 1772.3 (C=O), 1699.3 (C=O), 1628.7, 1576.7, 1527.4, 1490.5 (C=C), 1170.2 (C=S).
HR-MS: Calcd. For C41H53NNaO4S3 [M+Na]+, 742.3029, Found: 742.3026.
实施例四:部分药理学实验及结果:
一、抗炎作用
1 二甲苯致小鼠耳肿胀试验
昆明种小鼠,购于中国科学院上海实验动物中心,体重18-22g,雄性。温度20-24℃,湿度(65-70%),标准饲料喂养,每天及时更换垫料和食物,保持鼠笼清洁。
受试化合物均用0.5% CMC-Na溶液配制成混悬液,给药前禁食12h,自由饮水。小鼠灌胃给药,给药容量为0.2mL/10g体重。给药1h后将小鼠右耳廓两侧用微量进样器均匀涂布二甲苯20μL致炎,左耳廓做对照。致炎1h后将小鼠脱颈椎处死,沿耳廓基线取下两耳,用打孔器(直径7mm)于同一部位各取下一耳片用电子天平称重。致炎耳片重量减去对照侧耳片重量即为肿胀度。按下式计算肿胀抑制率,并将对照组与给药组的肿胀度进行统计学处理:
肿胀抑制率(%)= (模型组平均肿胀度 - 给药组平均肿胀度)/模型组平均肿胀度×100%。
部分YLXYⅢ和Ⅳ类化合物对二甲苯致小鼠耳肿胀的影响
用二甲苯致小鼠耳肿胀模型评价了部分YLXYⅢ和Ⅳ类化合物的抗炎活性,结果见图1。
从图1中可以看出受试化合物都表现出较好的耳肿胀抑制作用,最高抑制率达到65%,超过阳性药十几个百分点,表明本组的化合物有较强的抗炎活性。
巴豆油致耳肿胀实验
将巴豆油按照如下比例配成混合溶液,巴豆油:乙醇:乙醚:水=2:20:73:5(v/v),用作致炎剂。选用健康成年雄性ICR种小鼠,购于南通大学动物实验中心,体重18-22g,将动物分为溶媒组、阳性对照组、受试药组。标准饲料喂养,每天及时更换垫料和鼠食,保持鼠笼清洁。
受试化合物均用0.5% CMC-Na溶液配制成混悬液,给药前禁食12h,自由饮水。小鼠灌胃给药,给药容量为0.2mL/10g体重。给药0.5h后将小鼠右耳廓两侧用微量进样器均匀涂布巴豆油致炎剂0.1mL致炎,左耳廓做对照。致炎4h后将小鼠脱颈椎处死,沿耳廓基线取下两耳,用打孔器于同一部位各取下一耳片用电子天平称重。致炎耳片重量减去对照侧耳片重量即为肿胀度。按下式计算肿胀抑制率,并将对照组与受试药组的肿胀度进行统计学处理:
肿胀抑制率(%)= (模型组平均肿胀度 - 给药组平均肿胀度)/模型组平均肿胀度×100%。
部分YLXYⅢ和Ⅳ类化合物对巴豆油致小鼠耳肿胀的影响
用巴豆油致小鼠耳肿胀模型评价了部分YLXYⅢ和Ⅳ类化合物的抗炎活性,结果见图2。
从图2中可以看出受试化合物都表现出较好的耳肿胀抑制作用,最高抑制率大于70%,超过阳性药二十几个百分点,表明本组的化合物有优秀的抗炎活性。
二、抗肿瘤作用
材料
MCF-7、HT-29细胞株(中国科学院上海细胞库),经复苏后传代培养。RPMI1640(或DMEM)培养液,四甲基偶氮唑蓝(MTT,Sigma公司),胰蛋白酶(吉诺生物医药技术有限公司),胎牛血清(杭州四季青公司),二甲基亚砜(DMSO,广州化学试剂厂),SDS,96孔板。
样品处理
将受试化合物溶于DMSO中,配成高浓度的溶液,然后用培养液稀释至所需浓度,备用。用培养液配制DMSO,均是现配现用。
细胞培养
将肿瘤细胞株接种于含10%灭活胎牛血清的RPMI1640(或DMEM)培养液中,在5% CO2 37℃充分湿化条件下的培养箱中培养,每周更换2~3次培养液。
法癌细胞体外增殖抑制试验方法
取对数生长期状态良好的细胞一瓶,加入0.25%胰蛋白酶消化,使贴壁细胞脱落,制成每毫升含5×106~6×106个细胞的悬液。取细胞悬液种于96孔板上,置恒温CO2培养箱中培养24h。换液,加入受试化合物(化合物用DMSO溶解后用培养液稀释,受试化合物浓度分别为10,20,40,80,160 μmol.L-1,部分化合物浓度为5,10,20,40,80 μmol.L-1),培养48小时。将MTT加入96孔板中,每孔20 μL,培养箱中反应4h。然后加入SDS,用酶联免疫测试仪在波长570nm处测定每孔的吸收度,计算细胞抑制率。
抑制率(%)=(对照孔平均OD值-实验孔平均OD值)/对照空平均OD值×100%。
部分受试YLXYⅢ和Ⅳ类化合物对肿瘤细胞MCF-7、HT-29增殖作用的影响见图3。由图可知大部分受试化合物的抗肿瘤活性显著强于OA,并且有的可强约至50多倍。
三、胃肠道损伤实验
1 受试化合物单次给药对大鼠胃肠道的影响
取健康雄性SD大鼠,购于上海斯莱特实验动物中心,体重(平均100g),随机分组,实验前禁食24h,不禁水。标准饲料喂养,每天及时更换垫料和鼠粮,保持鼠笼清洁。实验时,分别设溶媒对照组,双氯芬酸组,受试药物组。溶媒对照组每只动物溶媒灌胃给药;双氯芬酸对照组,每只动物按20mg/kg的剂量灌胃双氯芬酸钠溶液;受试药物组,每组动物按62.8μmol/kg灌胃给药,每组动物给药6h后处死,按以下方法观察、比较药物对大鼠胃肠道的影响,并计算相关指数。沿胃大弯侧将胃剪开展平,按Guth标准计算胃溃疡指数(UI):溃疡面的长度小于1mm为1 分,1~2mm为2分,2~3mm为3 分,3~4mm为4分,大于4mm将其分割为若干段,每段按上法计算。溃疡宽度> 1mm 则分值×2,点状出血点按每个0.5分计算,每只大鼠的累积相加得分即为该大鼠的总胃溃疡指数。采用t检验, 分析各组间胃溃疡指数有无显著性差异。实验结果见图4。
图4的结果显示,与双氯芬酸组比较,各受试物组的胃溃疡指数非常小,有极显著性差异(P<0.01)。同时,我们解剖后发现,双氯芬酸组大鼠胃部有不同程度的颜色改变,主要呈黄白或苍白色,而受试物各组大鼠,胃部肉眼未观察到上述变化,其它的异样变化也未明显察觉。
受试化合物连续给药对大鼠胃肠道的影响
取健康雄性SD大鼠,购于上海斯莱特实验动物中心,体重(平均100g),随机分组,实验前禁食24h,不禁水。标准饲料喂养,每天及时更换垫料和鼠粮,保持鼠笼清洁。实验时,分别设溶媒对照组,双氯芬酸组,受试药物组。溶媒对照组每只动物溶媒灌胃给药;双氯芬酸对照组,每只动物按40 μmol/kg的剂量灌胃双氯芬酸钠溶液;受试药物组,每组动物按40 μmol/kg灌胃给药,每日一次,连续5天。给药期间对食物和饮水不加控制。第5天时,每组动物给药6h后将动物处死,按上述方法观察、比较药物对大鼠胃肠道的影响,并计算相关指数。采用t检验, 分析各组间胃溃疡指数有无显著性差异。实验结果如图5所示:
图5的结果显示,与双氯芬酸组比较,各受试物组的胃溃疡指数非常小,有极显著性差异(P<0.01)。同时,实验过程中我们发现双氯芬酸组大鼠大鼠腹部胀大,剪开腹腔有黄色甚至褐色腹水流出。覆盖于腹腔的粘膜变硬,胃粘膜弹性很小,有糜烂,有的大鼠实验过程中已经不能进食。以上两个实验显示,不论是单次给药还是连续给药,受试物均未发现明显的线状胃肠道出血性损伤,而双氯芬酸在试验过程中所致胃损伤十分明显,表明受试物的胃肠道安全性非常好。
Claims (8)
2.根据权利要求1所述的的化合物,其特征在于所述化合物是:齐墩果酸2-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]乙酯,齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯,齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯。
4.根据权利要求3所述的化合物,其特征在于所述化合物是:3-氧代齐墩果酸3-[4-(3H-1, 2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯,3-氧代齐墩果酸4-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丁酯,2-羟基-3-氧代齐墩果酸3-[4-(3H-1,2-二硫杂环戊烯-3-硫酮-5-基)-苯氧基]丙酯。
5.一种药物组合物,由治疗上有效剂量的权利要求1-2之一的化合物和药学上可接受的载体或辅料组成。
6.一种药物组合物,由治疗上有效剂量的权利要求3-4之一的化合物和药学上可接受的载体或辅料组成。
7.权利要求1所述的通式YLXYⅢ类化合物在制备预防和治疗炎症及肿瘤药物中的用途。
8.权利要求3所述的通式YLXYⅣ类化合物在制备预防和治疗炎症及肿瘤药物中的用途。
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