CN102675405A - 熊果酸哌嗪酰胺类化合物及其制备方法和用途 - Google Patents
熊果酸哌嗪酰胺类化合物及其制备方法和用途 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及具有抗癌作用的熊果酸哌嗪酰胺类化合物及其制备方法。
背景技术
熊果酸(ursolic acid,UA)是人们发现较早并且具有很好生物活性的五环三萜类化合物。熊果酸及其衍生物具有抗肿瘤(Kanjoormana M.; Kuttan G. Antiangiogenic activity of ursolic acid [J]. Integr. Cancer Ther., 2010, 9 (2):224-235)、抗炎与抗菌 (Chattopadhyay D.; Arunachalam G.; Mandal A. B. et al. Antimicrobial and anti-inflammatory activity of folklore: Mallotus peltatus leaf extract [J]. J. Ethnopharmacol., 2002, 82: 229-231.)、抗氧化(Ramachandran, S.; Prasad, N. R. Effect of ursolic acid, a triterpenoid antioxidant, on ultraviolet-B radiation-induced cytotoxicity, lipid peroxidation and DNA damage in human lymphocytes [J]. Chem. Bio & Interactions., 2008, 176: 99-107;Ramos A.A., Wilson C.P., Collins A.R. Protective effects of Ursolic acid and Luteolin against oxidative DNA damage include enhancement of DNA repair in Caco-2 cells[J]. Mutat. Res., 2010, 692 (1-2):6-11)、抗HIV(Ma C.M.; Cai S.Q.; Cui J.R. The cytotoxic activity of ursolic acid derivatives [J]. Eur. J. Med. Chem., 2005, 40:582-589.)等生物活性。
目前对其在抗癌活性方面的研究较深入,现代医学证明熊果酸在肿瘤发生发展的多个阶段均有作用,包括了抑制肿瘤细胞的增殖、诱导肿瘤细胞的分化和凋亡,以及抑制肿瘤的发生和转移等。熊果酸由于具有抗肿瘤谱广泛,对正常细胞毒性低,同时能够增强免疫的作用,因此在开发新型的抗肿瘤药物领域,熊果酸以及熊果烷型的化合物得到了越来越多的关注。
2003年Brian (Brian T.; Murphy S.L.; Mac K. Identification of Triterpene Hydroxycinna mates with in Vitro AntitumorActivity from Whole Cranberry Fruit (Vaccinium macrocarpon) [J]. J. Agric. Food Chem., 2003, 51 (12): 3541-3545)以生物活性为指导,从植物Vaccinium macrocarpon中分离得到有活性的熊果烷型的三萜类化合物。生物活性测试表明,该植物果实的乙酸乙酯层粗浸膏对癌细胞的生长有很好的抑制作用,从该层中首次分离得到顺式(1)和反式(2)的3-O-p-hydroxycinn amoylursolic acid,化合物1的活性最好,对MCF-7的GI50为18.8 μM, 对PC3的GI50为24.3 μM 和对ME180的GI50为23.3 μM。
2008年Chadalapaka (Chadalapaka G.; Jutooru I.; McAlees A. Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives [J].Bioorg Med Chem Lett., 2008, 18(8):2633-2639)合成了一系列化合物,通过对KU7,253JB-V baldder以及Panc-1,Panc-28 胰脏癌细胞的活性测试结果表明在熊果酸的A环C-2位导入吸电子基团即含有1-烯-3-酮结构的衍生物具有潜在的抑制肿瘤细胞增长的活性,同时在含有1-烯-3-酮结构的熊果酸衍生物A环C-2位导入-CN和-CF3时化合物的生物活性最好,C-2位导入-I时活性次之,活性最好的化合物对Panc-1,Panv-28胰脏癌细胞抑制增殖活性为IC50分别为0.53和0.97 μM。
2009年Meng (Meng Y.Q.; Liu D.; Cai L.L. The synthesis of ursolic acid derivatives with cytotoxic activity and the investigation of their preliminary mechanism of action[J]. Bioorg Med Chem., 2009, 17(2): 848-854 )设计并合成了熊果酸-氨基酸衍生物。并对其生物活性进行了测试,结果表明C-3乙酰化,同时C-28与氨基酸进行偶联的衍生物的活性最好,IC50可达到1.63 μM,其抑制Hela细胞增长的活性均优于熊果酸。其抑制SKOV3的活性较高,IC50可达到2.24 μM)。其构效关系表明在熊果酸的C-3或C-28位导入供电子基团后会使得整个分子的生物活性有所增加。
2011年Shao (Shao J.W.; Dai Y.C.; Xue J.P. In vitro and in vivo anticancer activity evaluation of ursolic acid derivatives [J]. Eur. J. Med. Chem., 2011, 46: 2652-2661)对熊果酸的C-3和C-28位进行修饰,主要是对C-3位进行酯化,C-28位引入酰胺或是供氢基团。活性测试结果表明其在C-3位酯化后在C-28位引入酰胺基团后对癌细胞HepG2,BGC-823,SH-SY5Y和HeLa表现出了较好的抑制活性,其中活性最好的化合物对以上癌细胞抑制24 h的IC50分别为20.25,15.52,13.24和10.87 μM。
从背景技术可知,熊果酸具有广泛的生物活性,且在抗癌领域可作为先导化合物来开发并得到了一定的理论基础。同时关于熊果酸哌嗪酰胺类化合物目前尚无人合成过。
发明内容
本发明目的在于设计合成一系列结构新颖的熊果酸哌嗪酰胺类化合物,该类化合物以天然产物熊果酸为先导,通过结构修饰合成了一系列熊果酸衍生物,通过抗癌活性测试表明,其衍生物与熊果酸相比抗癌活性明显提高并且对正常细胞NIH3T3的细胞毒性较小。熊果酸哌嗪酰胺类化合物结构由下列通式(I)表示:
(I)
其中R为(1)氢;(2) 苯基或取代苯基;(3) 吡啶或取代吡啶基;(4) C1-6烷基;
本发明内容中,取代苯基可为苯环上含有一个或多个甲基、乙基、甲氧基、乙氧基、正丙基、异丙基、三氟甲基、硝基、胺基以及卤原子,卤原子可为氟、氯、溴、碘;取代吡啶基可为吡啶环上含有一个或多个甲基、乙基、甲氧基、乙氧基、正丙基、异丙基、硝基、胺基以及卤原子,卤原子可为氟、氯、溴、碘;C1-6烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、叔戊基、新戊基、正己基、异己基、叔己基、新己基以及环己基。
本发明内容中,化合物具有抗肿瘤活性,特别是对人胃腺癌细胞(MGC-803)和乳腺癌细胞(Bcap-37)有着良好的活性,用途是在制备抗癌药物中的应用。
本发明通式(I)化合物的制备方法是以熊果酸、卤代烷烃、无水哌嗪、芳香酸以及取代芳香酸,含氮杂环酸、脂肪酸为原料,经两步取代反应和一步缩合反应三步合成目标产物,其合成路线为如下:
三步合成方法为:
第一步:(2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯
在单口瓶中加入原料熊果酸和K2CO3, 用DMF溶解后,加入溴代烷烃,在室温下反应数小时。停止反应后,用水分散,以乙酸乙酯萃取,得到母液依次用HCl,饱和NaHCO3, 饱和NaCl水溶液分别洗涤后,合并乙酸乙酯层以无水硫酸钠干燥后蒸去溶剂,用硅胶柱层析分离,得到目标产物。
第二步:2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
在装有回流冷凝管、温度计的三口瓶中加入(2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯和碳酸钾用DMF溶解,搅拌几分钟后加入无水哌嗪,加热反应数小时。停止反应后,冷却至室温,用水分散,用乙酸乙酯萃取,合并乙酸乙酯层,再用水洗涤,有机相用无水硫酸钠干燥,然后柱层析分离,得到无色油状化合物。
第三步:熊果酸哌嗪酰胺类衍生物的制备
在单口瓶中,在冰浴条件下加入酸类化合物以及EDCI /HOBt,用二氯甲烷溶解后在冰浴下搅拌,加入2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯在室温下反应数小时后,停止反应后用水洗涤反应液,然后无水硫酸钠干燥,然后柱层析分离得到目标产物。
本步骤适用于所有上述目标化合物熊果酸哌嗪酰胺类化合物的合成。
根据发明路线和制备方法已合成并证明有抗癌作用的化合物如下:
化合物a:
2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物b:
2-(4-苯甲酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物c:
2-(4-(2,6-二氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物d:
2-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物e:
2-(4-(2-氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物f:
2-(4-(2-(4-氯苯基)乙酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物g:
2-(4-(2,4-二氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物h:
2-(4-(4-氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物i:
2-(4-(3-氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物j:
2-(4-(2-三氟甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物k:
2-(4-(4-异丙基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物l:
2-(4-(2-甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物m:
2-(4-(3,4-二甲氧基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物n:
2-(4-(4-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物o:
2-(4-(5-氯-2-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物p:
2-(4-(3,5-二硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物q:
2-(4-异烟酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物r:
2-(4-烟酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物s:
2-(4-(2-氯异烟酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物t:
2-(4-(2-氯烟酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物u:
2-(4-肉桂酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物v:
2-(4-(3,5-双烯六烷酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物w:
2-(4-壬酰哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物x:
2-(4-(2-乙基己酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
具体实施方式
实施例一、2-(4-苯甲酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯 (化合物编号为b)的合成
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
在50 mL单口瓶中加入原料熊果酸 1 g和60 mg K2CO3, 用10 mL的DMF溶解后,加入1.6 g溴代乙烷,在室温下反应12 h。停止反应后,用50 mL的水分散,以乙酸乙酯萃取3次,每次10 mL,得到母液依次用1N的HCl,饱和NaHCO3, 饱和NaCl水溶液分别洗涤2次后,合并乙酸乙酯层用无水硫酸钠干燥后蒸去溶剂,用硅胶柱层析分离,石油醚:乙酸乙酯=15:1洗脱,得到目标产物,收率为84 %。
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为a)的制备
在装有回流冷凝管、温度计的100 mL的三口瓶中加入原料(2-溴代乙基)3-羟基-熊果烷-12-烯-28-酸酯1 g,碳酸钾40 mg,用DMF溶解后加入无水哌嗪60 mg,升温到70 0C反应9 h。停止反应后,冷却至室温,用水分散,用乙酸乙酯萃取3次,每次10 mL,合并乙酸乙酯层,再用水洗涤3次,每次用水10 mL,有机相用无水硫酸钠干燥,然后硅胶柱层析分离,氯仿:甲醇=20:1为洗脱液,得到无色油状化合物,收率64 %。
(3) 2-(4-苯甲酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
在50 mL的单口瓶中,在冰浴条件下加入苯甲酸117 mg以及EDCI 141mg /HOBt 100 mg,以10 mL的干燥DCM溶解后一起在冰浴下搅拌30 min然后移去冰浴,加入2-(哌嗪-1-基)乙基-3-羟基-熊果烷-12-烯-28-酸酯350 mg,在室温下反应12 h后停止反应。用水洗涤反应液3次,每次20 mL,无水硫酸钠干燥后硅胶柱层析分离,以氯仿:甲醇=20:1为洗脱液,得到目标产物,产率50 %。
实施例二、2-(4-(2,6-二氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备(化合物编号为c)
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2,6-二氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入117 mg 2,6-二氯苯甲酸。
实施例三、2-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备(化合物编号为d)
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入92 mg 2-氯-6-氟苯甲酸。
实施例四、2-(4-(2-氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备(化合物编号为e)
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2-氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入100 mg 2-氯苯甲酸。
实施例五、2-(4-(2-(4-氯苯基)乙酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备(化合物编号为f)
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2-(4-氯苯基)乙酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入110 mg 4-氯苯乙酸。
实施例六、2-(4-(2,4-二氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备(化合物编号为g)
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2,4-二氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入90 mg 2,4-二氟苯甲酸。
实施例七、2-(4-(4-氟苯酰基)-哌嗪-1-基)乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备(化合物编号为h)
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(4-氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入90 mg 2,4-二氟苯甲酸。
化合物i 合成步骤按实例七的步骤可合成得到目标化合物。
实施例八、2-(4-(2-三氟甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备(化合物编号为j)
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2-三氟甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入127 mg 2-三氟甲基苯甲酸。
实施例九、2-(4-(4-异丙基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯 (化合物编号为K)的合成
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(4-异丙基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对101 mg异丙基苯甲酸。
实施例十、2-(4-(2-甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯 (化合物编号为l)的合成
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2-甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对90 mg 2-甲基苯甲酸。
实施例十一、2-(4-(3,4-二甲氧基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为m)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(3,4-二甲氧基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对120 mg 3,4-二甲氧基苯甲酸。
实施例十二、2-(4-(4-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为n)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(4-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对110 mg 4-硝基苯甲酸。
实施例十三、2-(4-(5-氯-2-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为o)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(5-氯-2-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对123 mg 5-氯-2-硝基苯甲酸。
实施例十四、2-(4-(3,5-二硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为p)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(3,5-二硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对130 mg 3,5-二硝基苯甲酸。
实施例十五、2-(4-异烟酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为q)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-异烟酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对75 mg异烟酸。
化合物r 合成步骤按实例十五的步骤可合成得到目标化合物。
实施例十六、2-(4-(2-氯异烟酰基)哌嗪-1-基)乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为s)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2-氯异烟酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对96 mg2-氯异烟酸。
化合物t 合成步骤按实例十五的步骤可合成得到目标化合物。
实施例十七、2-(4-肉桂酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为u)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-肉桂酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对115 mg肉桂酸。
实施例十八、2-(4-(3,5-双烯六烷酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为v)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(3,5-双烯六烷酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对70 mg 山梨酸。
实施例十九、2-(4-壬酰哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为w)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-壬酰哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对97 mg壬酸。
实施例二十、2-(4-(2-乙基己酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物编号为x)的制备
(1) (2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(1)条件和方法合成;
(2) 2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(2)条件和方法合成;
(3) 2-(4-(2-乙基己酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯的制备
如实施例一(3)条件和方法合成,区别在于加入对130 mg异辛酸。
所得化合物的结构如下所示:
合成的部分熊果酸哌嗪酰胺类衍生物的波谱数据所下:
2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物a):
产率: 55.5 %; 无色油状; ESI-MS: 569[M+H] +, IR (KBr, cm-1) v: 3269, 3163, 2941, 2868, 1730, 1463, 1377, 1220, 1029; 1H NMR (CDCl3, 500 MHz): 5.23 (1H, s, H-12), 4.14 (2H, t, J=5 Hz, CH2), 3.20 (1H, dd, J=10 Hz, 10Hz, H-3,), 2.89 (4H, t, J=5 Hz, H in piperazine ), 2.65 (2H, t, J=5Hz, CH2), 2.48 (4H, brs, H in piperazine), 2.22 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.94 (CH3, s, H-26), 0.93 (CH3, s, H-24,), 0.91 (CH3, s, H-23), 0.86 (CH3, d, J=10 Hz, H-30), 0.77 (CH3, d, J=10Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 138.1 (C-13), 125.6 (C-12), 78.9 (C-3), 61.8 (CH2), 57.2 (CH2), 55.2 (C-5), 54.7 (CH2), 52.9 (C-18), 48.0 (C-17), 47.6 (C-9), 46.1 (CH2), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.7 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.3 (C-2), 24.2 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-苯甲酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物b):
产率: 60 %; 无色油状; ESI-MS: 673[M+H] +; IR (KBr, cm-1) v: 3446, 2924, 2868, 1716, 1606, 1458, 1375, 1139, 754, 709. 1H NMR (CDCl3, 500 MHz): 7.40 (5H, s, PhH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=5 Hz, CH2), 3.78 (2H, s, H in piperazine ), 3.41 (2H, s, H in piperazine), 3.20 (1H, dd, J=10 Hz, 15 Hz, H-3,), 2.64 (2H, t, J=5 Hz, CH2), 2.59 (2H, brs, H in piperazine), 2.44 (2H, brs, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 170.3 (C), 138.1 (C-13), 135.8 (C), 129.7 (CH), 128.5 (CH), 127.1 (CH), 125.6 (C-12), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 53.7 (CH2), 53.0 (C-18), 48.1 (C-17), 47.8 (C-9), 47.5 (CH2), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(2,6-二氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物c)
产率: 51.5 %; 淡黄色油状; ESI-MS: 741[M+H]+, IR (KBr, cm-1) v: 3444, 2924, 2868, 1718, 1637, 1429, 1010, 894, 754; 1H NMR (CDCl3, 500 MHz): 7.34-7.28 (3H, m, PhH), 5.22 (1H, s, H-12), 4.12 (2H, t, J=7.5 Hz, CH2), 3.84 (2H, m, H in piperazine ), 3.23 (2H, t, J=7.5 Hz, H in piperazine), 3.16 (1H, d, J=5 Hz, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.61 (2H, m, H in piperazine), 2.49 (2H, br m, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.94 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 161.9 (C), 159.7 (C), 157.7 (C), 138.1 (C-13), 131.9 (CH2), 130.8 (CH2), 125.6 (C-12), 124.3 (C), 114.5 (CH2), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 53.4 (CH2), 52.9 (C-18), 52.8 (CH2), 48.1 (C-17), 47.5 (C-9), 46.6 (CH2), 42.1 (C-14), 41.8 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物d)
产率: 56 %; 无色油状; ESI-MS: 725 [M+H] +; IR (KBr, cm-1) v: 3458, 2924, 2868, 1720, 1647, 1452, 1369, 1139, 898, 752. 1H NMR (CDCl3, 500 MHz): 7.33-7.26 (2H, m, PhH), 7.05 (1H, t, J=7.5 Hz, PhH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=7.5 Hz, CH2), 3.83 (2H, t, J=5 Hz,H in piperazine ), 3.41 (2H, s, H in piperazine), 3.27 (2H, t, J=2.5 Hz, H in piperazine), 3.20 (1H, dd, J=10, 15Hz, H-3), 2.64 (2H, t, J=5 Hz, CH2), 2.60 (2H, t, J=7.5 Hz, H in piperazine), 2.47-2.44 (2H, brm, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07(CH3, s, H-27), 0.98 (CH3, s, H-25), 0.94 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=15Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 161.9 (C), 159.7 (C), 157.7 (C), 138.1 (C-13), 131.9 (CH), 130.8 (CH), 125.6 (C-12), 124.3 (C), 114.5 (CH), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 53.4 (CH2), 52.9 (C-18), 52.8 (CH2), 48.1 (C-17), 47.5 (C-9), 46.6 (CH2), 42.1 (C-14), 41.8 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(2-氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物e)
产率: 60 %; 无色油状; ESI-MS: 707 [M+H] +; IR (KBr, cm-1) v: 3421, 2924, 2868, 1718, 1635, 1436, 1139, 752. 1H NMR (CDCl3, 500 MHz): 7.41 (1H, d, J=10 Hz, PhH), 7.34-7.28 (3H, m, PhH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=5 Hz, CH2), 3.83 (2H, brs, H in piperazine), 3.30- 3.26(1H, m, H in piperazine), 3.20 (1H, dd, J=10 Hz, 15 Hz, H-3,), 2.65 (2H, t, J=5 Hz, CH2), 2.60 (1H, m, H in piperazine), 2.53-2.51 (1H, brm, H in piperazine), 2.41-2.37 (1H, brm, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.94 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 166.9 (C), 138.1 (C-13), 135.9 (C), 130.4 (CH), 130.2 (CH), 129.7 (CH), 127.8 (CH), 127.2 (CH), 125.6 (C-12), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 53.4 (CH2), 52.9 (C-18), 48.1 (C-17), 47.5 (C-9), 46.6 (CH2), 42.1 (C-14), 41.7 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0(C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(2-(4-氯苯基)乙酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物f)
产率: 55 %; 黄色油状; ESI-MS: 721[M+H] +; IR (KBr, cm-1) v: 3446, 2924, 2868, 1718, 1635, 1456, 1377, 1139, 974, 808. 1H NMR (CDCl3, 500 MHz): 7.30 (2H, d, J=10 Hz, PhH), 7.16 (2H, d, J=5 Hz, PhH), 5.21 (1H, s, H-12), 4.10 (2H, t, J=5 Hz, CH2), 3.68 (2H, s, CH2), 3.62 (2H, t, J=5 Hz, H in piperazine ), 3.42 (2H, t, J=5 Hz, H in piperazine), 3.20 (1H, dd, J=10 Hz, 15Hz, H-3), 2.59 (2H, t, J=7.5 Hz, H in piperazine), 2.45 (2H, t, J=5 Hz, H in piperazine), 2.34 (2H, t, J=5 Hz, H in piperazine), 2.20 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.94 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.78 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 169.0 (C), 138.1 (C-13), 133.5 (C), 132.7 (C), 130.1 (CH), 128.9 (CH), 125.6 (C-12), 79.0 (C-3), 61.6 (CH2), 56.4 (CH2), 55.2 (C-5), 53.2 (CH2), 53.0 (C-18), 52.9 (CH2), 48.0 (C-17), 47.5 (C-9), 47.5 (CH2), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(2,4-二氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物g)
产率: 55 %; 无色油状; ESI-MS: 709[M+H] +; IR (KBr, cm-1) v: 3446, 2924, 2870, 1722, 1635, 1458, 1269, 1139, 756, 663, 578. 1H NMR (CDCl3, 500 MHz): 7.40 (1H, q, J=6.7 Hz, PhH), 6.95 (1H, t, J=7.5 Hz, PhH), 6.86 (1H, t, J=10 Hz, PhH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=7.5 Hz, CH2), 3.79 (2H, brs, H in piperazine), 3.31 (2H, brs, H in piperazine), 3.19 (1H, dd, J=10, 15 Hz, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.59 (2H, t, J=5 Hz, H in piperazine), 2.46 (2H, brs, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 164.3 (C=O), 138.1 (C-13), 130.6 (CH), 125.6 (C-12), 112.3 (C), 112.2 (C), 104.4 (CH), 104.2 (CH), 104.0 (CH), 79.0 (C-3), 61.6 (CH2), 56.5 (CH2), 55.2 (C-5), 53.4 (CH2), 52.9 (C-18), 48.1 (C-17), 47.5 (CH2), 47.2 (C-9), 42.2 (C-14), 42.1 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.1 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(4-氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物h)
产率: 61 %; 无色油状; ESI-MS: 708[M+NH4] +, 729[M+K]+, IR (KBr, cm-1) v: 3444, 2943, 2868, 1722, 1633, 1456, 1377, 1010, 837, 754. 1H NMR (CDCl3, 500 MHz): 7.32 (2H, d, J=10 Hz, PhH), 7.28 (2H, d, J=10 Hz, PhH), 5.15 (1H, s, H-12), 4.07 (2H, t, J=7.5 Hz, CH2), 3.69 (2H, brs, H in piperazine ), 3.33 (2H, brs, H in piperazine), 3.14 (1H, dd, J=10, 5 Hz, H-3), 2.57 (2H, t, J=7.5 Hz, CH2), 2.51 (2H, brs, H in piperazine), 2.37 (2H, brs, H in piperazine), 2.14 (1H, d, J=10 Hz, H-18), 1.00 (CH3, s, H-27), 0.91 (CH3, s, H-25), 0.87 (CH3, s, H-26), 0.86 (CH3, s, H-24), 0.83 (CH3, s, H-23), 0.79 (CH3, d, J=5 Hz, H-30), 0.70 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 169.2 (C), 138.1 (C-13), 135.8 (C), 134.0 (C), 128.8 (CH), 128.7 (CH), 125.6 (C-12), 79.0 (C-3), 61.6 (CH2), 56.5 (CH2), 55.2 (C-5), 53.4 (CH2), 53.5 (CH2), 52.9 (C-18), 48.1 (C-17), 47.8 (CH2), 47.5 (C-9), 42.3 (C-14), 42.1 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.1 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(3-氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物i)
产率: 51 %; 淡黄色油状; ESI-MS: 691 [M+H] +; IR (KBr, cm-1) v: 3444, 2924, 2868, 1722, 1635, 1456, 1425, 1139, 750, 663. 1H NMR (CDCl3, 500 MHz): 7.39-7.36 (1H, m, PhH), 7.18-7.11 (3H, m, PhH), 5.22 (1H, s, H-12), 4.13 -4.12 (2H, m, CH2), 3.77 (2H, brs, H in piperazine ), 3.40 (2H, brs, H in piperazine), 3.19 (1H, dd, J=10 Hz, 10 Hz, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.59 (2H, brs, H in piperazine), 2.45 (2H, brs, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=10 Hz, H-30), 0.77(CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 168.8 (C=O), 161.6 (C), 138.1 (C-13), 130.4 (CH), 130.3 (CH), 125.6 (C-12), 122.7 (CH), 116.9 (CH), 114.5 (CH), 79.0 (C-3), 61.6 (CH2), 56.5 (CH2), 55.2 (C-5), 53.6 (CH2), 52.9 (C-18), 48.1 (C-17), 47.7 (CH2), 47.5 (C-9), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.1 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(2-三氟甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物j)
产率: 53 %; 无色油状; ESI-MS: 741 [M+H] +; IR (KBr, cm-1) v: 3442, 2926, 2876, 1712, 1631, 1458, 1367, 1028, 740. 1H NMR (CDCl3, 500 MHz): 7.71 (1H, d, J=5 Hz, PhH), 7.59 (1H, t, J=7.5 Hz, PhH), 7.52 (1H, t, J=7.5 Hz, PhH), 7.33 (1H, d, J=5 Hz, PhH), 5.22 (1H, s, H-12), 4.12 (2H, t, J=5 Hz, CH2), 3.84-3.70 (2H, brm, H in piperazine ), 3.20 (1H, dd, J=10 Hz, 10Hz, H-3), 3.18 (2H, t, J=7.5 Hz, H in piperazine), 2.64 (2H, t, J=5 Hz, CH2), 2.58 (2H, t, J=7.5 Hz, H in piperazine), 2.40-2.37 (2H, brm, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.94 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 167.3 (C), 138.1 (C-13), 134.8 (C), 132.2 (CH), 129.2 (CH), 127.3 (CH), 126.8 (CH), 126.7 (C), 125.6 (C-12), 122.6 (CF3), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 53.8 (CH2), 52.9 (C-18), 52.8 (CH2), 48.1 (C-17), 47.5 (C-9), 47.2 (CH2), 42.1 (C-14), 41.8 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.7 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.1 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(4-异丙基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物k)
产率: 54 %; 无色油状; ESI-MS: 715 [M+H] +; IR (KBr, cm-1) v: 3444, 2924, 2868, 1718, 1627, 1458, 1010, 840. 1H NMR (CDCl3, 500 MHz): 7.32 (2H, d, J=5 Hz, PhH), 7.27 (2H, d, J=10 Hz, PhH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=10 Hz, CH2), 3.78 (1H, brs, H in piperazine), 3.35 (1H, brs, H in piperazine), 3.19 (1H, dd, J=10 Hz, 10 Hz, H-3), 2.95-2.89 (1H, m, CH), 2.64 (2H, t, J=10 Hz, CH2), 2.62 (1H, brs, H in piperazine), 2.44 (1H, brs, H in piperazine), 2.21 (1H, d, J=15 Hz, H-18), 1.25 (6H, d, J=5 Hz, CH3), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.91 (CH3, s, H-23), 0.86 (CH3, d, J=10 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 170.5 (C=O), 150.8 (C), 141.9 (C), 138.1 (C-13), 133.2 (C), 127.3 (CH), 126.5 (CH), 125.6 (C-12), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 52.9 (C-18), 48.1 (C-17), 47.5 (C-9), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.9 (CH3), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.1 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(2-甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物l)
产率: 55 %; 无色油状; ESI-MS: 709[M+Na] +; IR (KBr, cm-1) v: 3444, 2924, 2868, 1722, 1627, 1458, 1377, 1139, 752. 1H NMR (CDCl3, 500 MHz): 7.26-7.14 (4H, m, PhH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=5 Hz, CH2), 3.82 (2H, brs, H in piperazine ), 3.22-3.19 (1H, m, H-3), 2.63 (2H, t, J=7.5 Hz, CH2), 2.58 (2H, t, J=5 Hz, H in piperazine), 2.39 (2H, brs, H in piperazine), 2.30 (3H, s, CH3), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.95 (CH3, s, H-25), 0.93 (CH3, s, H-26), 0.90 (CH3, s, H-24), 0.86 (CH3, s, H-23), 0.84 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 170.0 (C), 138.1 (C-13), 136.1 (C), 134.2 (CH), 130.5 (CH), 128.9 (CH), 125.9 (C-12), 125.8 (CH), 125.6 (CH), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 53.7 (CH2), 53.2 (CH2), 52.9 (C-18), 48.1 (C-17), 47.5 (C-9), 46.9 (CH2), 42.1 (C-14), 41.5 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30),19.1 (CH3), 18.3 (C-6), 17.2 (C-26), 17.1 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(3,4-二甲氧基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物m)
产率: 59 %; 淡黄色液体; ESI-MS: 733[M+H] +; IR (KBr, cm-1) v: 3408, 2922, 2852, 1718, 1624, 1431, 1375, 1138, 851, 804, 752. 1H NMR (CDCl3, 500 MHz): 6.99-6.98 (1H, m, PhH), 6.96 (1H, d, J=1.5 Hz, PhH), 6.67 (1H, d, J=10 Hz, PhH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=5 Hz, CH2), 3.90 (6H, s, OCH3), 3.53 (2H, brs, H in piperazine), 3.20 (1H, dd, J=15 Hz, 10 Hz, H-3), 2.64 (2H, t, J=5 Hz, CH2), 2.52 (2H, brs, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90(CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=15Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 170.2 (C), 150.3 (C), 148.9 (C), 138.1 (C-13), 127.9 (C), 125.6 (C-12), 120.1(CH), 110.9 (CH), 110.4 (CH), 78.9 (C-3), 61.6 (CH2), 56.5 (CH2), 56.0 (OCH3), 55.2 (C-5), 53.4 (CH2), 52.9 (C-18), 52.9 (CH2), 48.0 (C-17), 47.5 (C-9), 42.0 (C-14), 39.5 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.7 (C-22), 33.0 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.2 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(4-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物n)
产率: 52 %; 无色油状; ESI-MS: 718[M+H] +, IR (KBr, cm-1) v: 3442, 2924, 2868, 1718, 1627, 1436, 1350, 1139, 843; 1H NMR (CDCl3, 500 MHz): 8.27 (2H, d, J=7.5 Hz, CH), 7.56 (2H, d, J=5 Hz, CH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=7.5 Hz, CH2), 3.78 (2H, s, H in piperazine ), 3.34 (2H, s, H in piperazine), 3.19 (1H, s, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.62 (2H, brs, H in piperazine), 2.44 (2H, brs, H in piperazine), 2.21 (1H, d, J=15 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.92 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.87 (CH3, d, J=10 Hz, H-30), 0.77 (CH3, d, J=10 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 167.9 (C=O), 148.4 (C), 141.9 (C), 138.1 (C-13), 128.1 (CH), 125.6 (C-12), 123.9 (CH), 79.0 (C-3), 61.5 (CH2), 56.5 (CH2), 55.2 (C-5), 53.5 (CH2), 52.9 (C-18), 48.1 (C-17), 47.7 (CH2), 47.5 (C-9), 42.3 (CH2), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(5-氯-2-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物o)
产率: 54 %; 无色油状; ESI-MS: 752 [M+H] +; IR (KBr, cm-1) v: 3439, 2924, 2868, 1722, 1647, 1456, 1342, 1141, 822, 758. 1H NMR (CDCl3, 500 MHz): 8.17 (1H, d, J=5 Hz, PhH), 7.54 (1H, dd, J=5, 10 Hz, PhH), 7.37 (1H, d, J=5 Hz, PhH), 5.22 (1H, s, H-12), 4.13 (2H, t, J=7.5 Hz, CH2), 3.88 (1H, brs, H in piperazine), 3.74 (1H, brs, H in piperazine), 3.23 (1H, t, J=5Hz, H-3), 2.66 (2H, t, J=5 Hz, CH2), 2.61 (2H, brs, H in piperazine), 2.46 (2H, d, J= 15 Hz, H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07(CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90(CH3, s, H-23), 0.86 (CH3, d, J=10Hz, H-30), 0.77(CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 164.9 (C=O), 143.6 (C), 141.3 (C), 138.1 (C-13), 134.4 (CH), 130.0 (CH), 128.2 (CH), 126.2 (CH), 125.6 (C-12), 79.0 (C-3), 61.6 (CH2), 56.5 (CH2), 55.2 (C-5), 52.9 (C-18), 52.8 (CH2), 48.1 (C-17), 47.5 (C-9), 46.9 (CH2), 42.1 (C-14), 42.0 (CH2),39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(3,5-二硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物p)
产率: 41 %; 无色油状; ESI-MS: 764[M+H] +; IR (KBr, cm-1) v: 3444, 2924, 2870, 1720, 1645, 1544, 1471, 1344, 1139, 727. 1H NMR (CDCl3, 500 MHz): 9.09 (1H, s, PhH), 8.59 (2H, s, CH), 5.23 (1H, s, H-12), 4.18-4.13 (2H, m, CH2), 3.82 (2H, s, H in piperazine ), 3.42 (2H, s, H in piperazine), 3.21 (1H, dd, J=10 Hz, 10 Hz, H-3), 2.67 (2H, t, J=5 Hz, CH2), 2.52 (2H, brs, H in piperazine), 2.46 (2H, brs, H in piperazine), 2.21 (1H, d, J=15 Hz, H-18), 1.08 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.94 (CH3, s, H-24), 0.91 (CH3, s, H-23), 0.85 (CH3, d, J=10 Hz, H-30), 0.77 (CH3, d, J=10 Hz, H-29). 13C NMR (CDCl3,125 MHz): 177.4 (C-28), 165.1 (C=O), 148.6 (C), 139.1 (C), 138.1 (C-13), 127.5 (CH), 125.6 (C-12), 119.7 (CH), 120.0 (CH), 79.0 (C-3), 61.4 (CH2), 56.4 (CH2), 55.2 (C-5), 52.9 (C-18), 52.8 (CH2), 48.1 (C-17), 47.5 (CH2), 47.5 (C-9), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-异烟酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物q)
产率: 57 %; 黄色油状; ESI-MS: 674[M+H] +, IR (KBr, cm-1) v: 3423, 2924, 2868, 1718, 1627, 1436, 1139, 754. 1H NMR (CDCl3, 500 MHz): 8.70 (2H, d, J=5 Hz, CH), 7.28 (2H, d, J=1.5 Hz, CH), 5.22 (1H, s, H-12), 4.14 (2H, t, J=5 Hz, CH2), 3.78 (2H, s, H in piperazine), 3.35 (2H, s, H in piperazine), 3.22 (2H, dd, J=15, 10 Hz, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.60 (2H, s, H in piperazine), 2.45 (2H, s, H in piperazine), 2.21 (1H, d, J=15 Hz, H-18), 1.08 (CH3, s, H-27), 0.99 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.94 (CH3, s, H-24), 0.91 (CH3, s, H-23), 0.86 (CH3, d, J=10 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 167.6 (C=O), 150.3 (CH), 143.4 (C), 138.1 (C-13), 125.6 (C-12), 124.3 (CH), 121.3 (CH), 78.9 (C-3), 61.5 (CH2), 56.5 (CH2), 55.2 (C-5), 53.4 (CH2), 53.5(CH2), 52.9 (C-18), 48.1 (C-17), 47.5 (C-9), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-烟酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物r)
产率: 54 %; 黄色油状; ESI-MS: 674[M+H] +, IR (KBr, cm-1) v: 3444, 2924, 2868, 1718, 1627, 1436, 1280, 1111, 754, 663. 1H NMR (CDCl3, 500 MHz): 8.67 (1H, d, J=5 Hz, CH), 7.75 (1H, d, J=5 Hz, CH), 7.38 (1H, q, J=3 Hz, CH), 7.28 (1H, s, CH), 5.23 (1H, s, H-12), 4.15 (2H, t, J=7.5 Hz, CH2), 3.79 (2H, brs, H in piperazine ), 3.43 (2H, s, H in piperazine), 3.22 (1H, dd, J=10 Hz, 15Hz, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.61 (2H, brs, H in piperazine), 2.47 (2H, brs, H in piperazine), 2.21 (1H, d, J=15 Hz, H-18), 1.07 (CH3,s,H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=10 Hz, H-30), 0.77 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 167.7 (C=O), 150.8 (CH), 147.9 (CH), 138.1 (C-13), 135.2 (C), 131.6 (CH), 125.6 (C-12), 123.6 (CH), 79.0 (C-3), 61.6 (CH2), 56.5 (CH2), 55.2 (C-5), 53.6 (CH2), 52.9 (C-18), 47.9 (CH2), 48.1 (C-17), 47.5 (C-9), 42.3 (CH2), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(2-氯异烟酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物s)
产率: 51 %; 淡黄色油状; ESI-MS: 708 [M+H] +; IR (KBr, cm-1) v: 3421, 2924, 2870, 1718, 1635, 1456, 1029, 731. 1H NMR (CDCl3, 500 MHz): 8.47 (1H, d, J=5 Hz, CH), 7.32 (1H, s, CH), 7.21 (1H, d, J=5 Hz, CH), 5.22 (1H, s, H-12), 4.15-4.12 (2H, m, CH2), 3.76 (2H, s, H in piperazine), 3.34 (2H, s, H in piperazine), 3.21 (1H, dd, J=10 Hz, 10 Hz, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.59 (2H, brs, H in piperazine), 2.46 (2H, brs, H in piperazine), 2.21 (1H, d, J=15 Hz, H-18), 1.08 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.91 (CH3, s, H-23), 0.86 (CH3, d, J=10Hz, H-30), 0.78 (CH3, d, J=15Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 166.1 (C=O), 152.2 (C), 150.3 (C), 146.4 (CH), 138.1 (C-13), 125.6 (C-12), 122.0 (CH), 120.0 (CH), 79.0 (C-3), 61.5 (CH2), 56.4 (CH2), 55.2 (C-5), 53.4 (CH2), 52.9 (C-18), 52.8 (CH2), 48.1 (C-17), 47.5 (CH2), 47.5 (C-9), 42.2 (CH2), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24)
2-(4-(2-氯烟酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物t)
产率: 47 %; 无色油状; ESI-MS: 708 [M] +; IR (KBr, cm-1) v: 3444, 2924, 2868, 1718, 1635, 1448, 1396, 1139, 731; 1H NMR (CDCl3, 500 MHz): 8.45 (1H, s, CH), 7.66 (1H, d, J=5 Hz, CH), 7.33 (1H, q, J=5 Hz, CH), 5.23 (1H, s, H-12), 4.13 (2H, s, CH2), 3.86 (1H, s, H in piperazine ), 3.76 (1H, s, H in piperazine), 3.30 (1H, s, H in piperazine), 3.20 (1H, s, H-3), 2.65 (2H, t, J=7.5Hz, CH2), 2.54 (1H, brs , H in piperazine), 2.42 (1H, brs,H in piperazine), 2.21 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.99 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.91 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.78 (CH3, d, J=15 Hz, H-29).13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 165.0 (C=O), 150.2 (C), 147.2 (CH), 138.1 (C-13), 137.0 (C), 125.8 (C-12), 122.7 (CH), 79.0 (C-3), 61.6 (CH2), 56.5 (CH2), 55.2 (C-5), 53.3 (CH2), 52.9 (C-18), 52.7 (CH2), 48.1 (C-17), 47.5 (C-9), 46.9 (CH2), 42.2 (C-14), 41.9 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-肉桂酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物u)
产率: 58 %; 无色油状; ESI-MS: 699[M+H] +; IR (KBr, cm-1) v: 3446, 2924, 2868, 1716, 1647, 1456, 1305, 1139, 761. 1H NMR (CDCl3, 500 MHz): 7.68 (1H, d, J=15 Hz, PhH), 7.52 (2H, d, J=5 Hz, PhH), 7.38-7.33 (2H, m, PhH), 6.89 (1H, d, J=15 Hz, CH), 5.29 (1H, s, CH), 5.23 (1H, s, H-12), 4.15 (2H, t, J=5 Hz, CH2), 3.73 (2H, brs, H in piperazine ), 3.64 (2H, brs, H in piperazine), 3.19 (1H, dd, J=15 Hz, 10 Hz, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.54 (4H, t, J=5 Hz, H in piperazine), 2.22 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.90 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=10 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 165.4 (C), 142.9 (CH), 138.1 (C-13), 135.3(C), 129.7 (CH), 128.8 (CH), 127.8(CH), 125.7 (C-12), 117.0 (CH), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 53.5 (CH2), 52.9 (C-18), 48.1 (C-17), 47.5(C-9), 45.9 CH2), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.8 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-(3,5-双烯六烷酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物v)
产率:49 %; 无色油状; ESI-MS: 662[M+H] +; IR (KBr, cm-1) v: 3443, 2924, 2868, 1722, 1657, 1453, 1139. 1H NMR (CDCl3, 500 MHz): 7.25 (1H, t, J=7.5 Hz, CH), 6.22-6.07 (3H, m, CH), 5.23 (1H, s, H-12), 4.13 (2H, t, J=5 Hz, CH2), 3.67 (2H, brs, H in piperazine ), 3.54 (2H, brs, H in piperazine), 3.20 (1H, dd, J=10 Hz, 15 Hz, H-3), 2.62 (2H, t, J=7.5 Hz, CH2), 2.44 (4H, t, J=7.5 Hz, H in piperazine), 2.21 (1H, d, J=15 Hz, H-18), 1.84 (3H, d, J=5 Hz,CH3), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.94 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.91 (CH3, s, H-23), 0.86 (CH3, d, J=10 Hz, H-30), 0.77 (CH3, d, J=10 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 165.7 (C=O), 143.3 (CH), 138.1 (C-13), 137.8 (CH), 130.2 (CH), 128.1 (CH), 125.6 (C-12), 117.6 (CH), 79.0 (C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 52.9 (C-18), 48.0 (C-17), 47.5 (C-9), 42.1 (C-14), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.7 (C-22), 33.1 (C-7), 30.7 (C-21), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 21.2 (C-30), 18.6 (CH3), 18.3 (C-6), 17.2 (C-26), 17.0 (C-29), 15.7 (C-25), 15.5 (C-24).
2-(4-壬酰哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物w)
产率: 52 %; 无色液体; ESI-MS: 709 [M+H] +; IR (KBr, cm-1) v: 3442, 2924, 2854, 1730, 1635, 1456, 1375, 1109; 1H NMR (CDCl3, 500 MHz): 5.23 (1H, s, H-12), 4.14-4.09 (2H, m, CH2), 3.60 (2H, s, H in piperazine), 3.45 (2H, t, J=5 Hz, H in piperazine), 3.19 (1H, d, J=10 Hz, H-3), 2.65 (2H, t, J=5 Hz, CH2), 2.45-2.46 (4H, m, H in piperazine), 2.32 (2H, t, J=7.5 Hz, CH2), 2.22 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24,), 0.91 (CH3, s, H-23), 0.89(CH3, d, J=10 Hz, H-30),0.86 (3H, t, J=5 Hz, CH3), 0.78 (CH3, d, J=15 Hz, H-29). 13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 171.5(C=O), 138.1 (C-13), 125.6 (C-12), 78.9(C-3), 61.6(CH2), 56.5 (CH2), 55.2 (C-5), 53.5 (CH2), 53.1 (C-18), 52.9 (CH2), 48.0 (C-17), 47.5 (C-9), 45.7 (CH2), 42.1 (C-14), 41.5 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.7(C-20), 37.0 (C-10), 36.7 (C-22), 33.4 (C-7), 33.1 (CH2) 30.7 (C-21), 29.5 (CH2), 29.4 (CH2), 29.2 (CH2), 27.9 (C-23), 28.2 (CH2), 28.0 (C-15), 27.2 (C-2), 25.4 (CH2), 24.2 (C-16), 23.6 (C-11), 22.7 (C-27), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.1 (C-29), 15.7 (C-25), 15.5 (C-24), 14.1 (CH3).
2-(4-(2-乙基己酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯(化合物x)
产率: 61 %; 无色油状; ESI-MS: 695 [M+H] +; IR (KBr, cm-1) v: 3442, 2954, 2870, 1722, 1627, 1456, 1377, 1139; 1H NMR(CDCl3,500 MHz):5.23 (1H, s, H-12), 4.13 (2H, t, J=7.5 Hz, CH2), 3.67-3.64 (2H, brm, H in piperazine), 3.54 (2H, brs, H in piperazine ), 3.20 (1H, dd, J=10 Hz, 10 Hz, H-3), 2.62 (2H, t, J=7.5 Hz, CH2), 2.56 (1H, m, CH), 2.48 (4H, t, J=5 Hz, H in piperazine), 2.19 (1H, d, J=10 Hz, H-18), 1.07 (CH3, s, H-27), 0.98 (CH3, s, H-25), 0.95 (CH3, s, H-26), 0.93 (CH3, s, H-24), 0.91 (CH3, s, H-23), 0.86 (CH3, d, J=5 Hz, H-30), 0.77 (CH3, d, J=10 Hz, H-29).13C NMR (CDCl3, 125 MHz): 177.4 (C-28), 174.6 (C=O), 138.1 (C-13), 125.6 (C-12), 79.0(C-3), 61.7 (CH2), 56.5 (CH2), 55.2 (C-5), 53.9 (CH2), 53.5 (CH2), 52.9 (C-18), 48.1 (C-17), 47.5 (C-9), 45.7 (CH), 42.4 (CH2), 42.1 (C-14), 41.8 (CH2), 39.6 (C-8), 39.1 (C-19), 38.9 (C-1), 38.8 (C-4), 38.6 (C-20), 37.0 (C-10), 36.7 (C-22), 33.1 (C-7), 32.5 (CH2), 30.7 (C-21), 29.9 (CH2), 28.2 (C-23), 28.0 (C-15), 27.2 (C-2), 26.0 (CH2), 24.3 (C-16), 23.6 (C-11), 23.3 (C-27), 22.9 (CH2), 21.2 (C-30), 18.3 (C-6), 17.2 (C-26), 17.1 (C-29), 15.7 (C-25), 15.5 (C-24), 14.1 (CH3), 12.2 (CH3).
实施例二十一、化合物对两种癌细胞MGC-803和Bcap-37和正常细胞NIH3T3的体外增殖抑制活性测试方法
癌细胞MGC-803和Bcap-37用10% FBS的RPMI 1640培养,正常细胞NIH3T3用10% FBS的DMEM培养。
将96孔板的上、下行用灭菌二次水封边,每孔200 ??L。取对数生长期细胞,常规消化后,重悬于含10% FBS的RPMI 1640或DMDM培养基中,以2×104 个/mL的终浓度接种于96孔培养板,每孔100 ??L,最右侧一列为空白对照组,加无细胞的有血清RPMI 1640或DMDM培养基。置于37℃、5% CO2的饱和湿度培养箱中培养24 h使细胞贴壁。吸掉培养基,加入含不同药物浓度的有血清培养基,每孔200 ??L,注意培养基中DMSO终浓度不能超过0.1%,空白对照组每孔加200 ??L完全培养基。分别处理实验要求时间,去除上清,加100 ??L/well浓度0.5 mg/mL的MTT。培养4 h后再补加100 ??Lwell的10%的SDS。37℃下10 h使结晶物充分溶解后取出,微震荡5 min,放置室温下30 min,在A595波长下测OD值,并计算细胞活性、抑制率和P值。
以药物浓度或处理时间为横轴,OD值或者抑制率为纵轴,绘制曲线。每样本浓度重复六个孔,每个实验重复三次,取平均值为最终结果。
实验结果以SPSS软件进行方差分析,p<0.05时为差异显著,p<0.01时为差异极显著。 细胞增殖的抑制率计算公式如下:
表1 熊果酸哌嗪酰胺类衍生物对肿瘤细胞MGC-803和Bcap-37的抑制率和IC50值及对正常细胞NIH3T3的细胞毒性
注:NT表示未测试
从表1可以看出,从熊果酸衍生物的IC50相比较可以看出,化合物c、d、e、f、g、h、j、k对人胃腺癌细胞株(MGC-803)和人乳腺癌细胞株(Bcap-37)癌细胞的抑制活性较好,同时在10 μM下对正常细胞NIH3T3的细胞毒性较小,其中活性最好的化合物为化合物c。生物活性测试结果表明这一系列化合物可作为抗癌药物进行进一步的开发。
本发明实施例辅以说明本发明的技术方案,但实施例的内容并不局限于此。
Claims (5)
2.根据权利要求1所述的化合物,其特征在于所述化合物如下所示:
化合物a:
2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物b:
2-(4-苯甲酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物c:
2-(4-(2,6-二氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物d:
2-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物e:
2-(4-(2-氯苯甲酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物f:
2-(4-(2-(4-氯苯基)乙酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物g:
2-(4-(2,4-二氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物h:
2-(4-(4-氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物i:
2-(4-(3-氟苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物j:
2-(4-(2-三氟甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物k:
2-(4-(4-异丙基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物l:
2-(4-(2-甲基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物m:
2-(4-(3,4-二甲氧基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物n:
2-(4-(4-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物o:
2-(4-(5-氯-2-硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物p:
2-(4-(3,5-二硝基苯酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物q:
2-(4-异烟酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物r:
2-(4-烟酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物s:
2-(4-(2-氯异烟酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物t:
2-(4-(2-氯烟酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物u:
2-(4-肉桂酰基哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物v:
2-(4-(3,5-双烯六烷酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物w:
2-(4-壬酰哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
化合物x:
2-(4-(2-乙基己酰基)哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯。
3.根据权利要求1中任意一项所述的化合物在制备抗癌药物中的应用。
5.根据权利要求4所述的熊果酸哌嗪酰胺类衍生物的制备方法,其特征是三步合成,合成方法为:
第一步:(2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯
在单口瓶中加入原料熊果酸和K2CO3, 用DMF溶解后,加入溴代烷烃,在室温下反应数小时;
停止反应后,用水分散,以乙酸乙酯萃取,得到母液依次用HCl,饱和NaHCO3, 饱和NaCl水溶液分别洗涤后,合并乙酸乙酯层以无水硫酸钠干燥后蒸去溶剂,用硅胶柱层析分离,得到目标产物;
第二步:2-(哌嗪-1-基)-乙基-3-羟基-熊果烷-12-烯-28-酸酯
在装有回流冷凝管、温度计的三口瓶中加入(2-溴代乙基)-3-羟基-熊果烷-12-烯-28-酸酯和碳酸钾用DMF溶解,搅拌几分钟后加入无水哌嗪,加热反应数小时;停止反应后,冷却至室温,用水分散,用乙酸乙酯萃取,合并乙酸乙酯层,再用水洗涤,有机相用无水硫酸钠干燥,然后柱层析分离,得到无色油状化合物;
第三步:熊果酸哌嗪酰胺类衍生物的制备
在单口瓶中,在冰浴条件下加入酸类化合物以及1-乙基-3-(3-二甲胺丙基)碳二亚胺(EDCI)/1-羟基苯并三唑(HOBt),用二氯甲烷溶解后在冰浴下搅拌,加入2-(哌嗪-1-基)乙基-3-羟基-熊果烷-12-烯-28-酸酯在室温下反应数小时后,停止反应后用水洗涤反应液,然后无水硫酸钠干燥,然后柱层析分离得到目标产物。
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