CN104147019A - 闭花木酮的o-(四氢吡咯基)乙基衍生物在制备预防或治疗胰腺纤维化药物中的应用 - Google Patents
闭花木酮的o-(四氢吡咯基)乙基衍生物在制备预防或治疗胰腺纤维化药物中的应用 Download PDFInfo
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Abstract
本发明涉及有机合成和药物化学领域，具体涉及闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物、制备方法及其在制备预防或治疗胰腺纤维化药物上的用途。本发明合成了一个新的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物，并公开了其制备方法。药理学实验表明，本发明的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物具有预防或治疗胰腺纤维化的作用，具有开发预防或治疗胰腺纤维化药物的价值。
Description
技术领域
本发明涉及有机合成和药物化学领域，具体涉及闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物、制备方法及其用途。
背景技术
胰腺纤维化是各种原因所致慢性胰腺炎的共同特征,同时也是与其伴随的组织病理学特点,表现为大量成纤维细胞增生和富含连接组织的细胞外基质。是多种原因导致胰腺损伤修复的结果，近期发现胰腺星状细胞和多种细胞因子与胰腺纤维化有关，胰腺纤维化目前发病率愈来愈高，急需研发高效低毒的抗胰腺纤维化药物。
胰腺纤维化的治疗目前已有的药物存在毒性大、安全性低的问题，从天然产物中寻找化合物或先导化合物并进行结构修饰获得其衍生物，从而得到高效低毒的潜在药物最有重要价值。
本发明涉及的化合物闭花木酮Cleistanone是一个2011年发表(Van Trinh Thi Thanh et al.,2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton.Volume 2011,Issue 22,pages 4108–4111,August 2011)的化合物，我们对化合物闭花木酮Cleistanone进行了结构修饰，获得了一个新的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物，并对其抗胰腺纤维化活性进行了评价，其具有抗胰腺纤维化活性。
发明内容
本发明公开了一个闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物，其结构为：
本发明闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物(III)可通过下面方法制备：
(1)闭花木酮Cleistanone(I)与1,2-二溴乙烷反应得到闭花木酮Cleistanone的O-溴乙基衍生物(II)；
(2)闭花木酮Cleistanone的O-溴乙基衍生物(II)与吡咯烷发生取代反应制得闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物(III)。
进一步的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物(III)的制备方法为：
(1)将440mg化合物闭花木酮Cleistanone(I)溶于10mL苯，向溶液中加入0.04g的四丁基溴化铵，3.760g的1,2-二溴乙烷和6mL的50％氢氧化钠溶液；混合物在25摄氏度搅拌24h；24h之后将反应液倒入冰水中，立即用二氯甲烷萃取两次，合并有机相溶液；然后对有机相溶液依次用水和饱和食盐水洗涤3次，再用无水硫酸钠干燥，最后减压浓缩去除溶剂得到产物粗品；产物粗品用硅胶柱层析纯化，流动相为：石油醚/丙酮＝100:1，v/v，收集黄色集中洗脱带即得到闭花木酮Cleistanone的O-溴乙基衍生物(II)的黄色固体。
(2)将273mg的闭花木酮Cleistanone的O-溴乙基衍生物溶于20mL乙腈当中，向其中加入345mg的无水碳酸钾，84mg的碘化钾和1420mg的吡咯烷，混合物加热回流8h；反应结束后将反应液倒入冰水中，用等量二氯甲烷萃取三次，合并有机相；依次用水和饱和食盐水洗涤合并之后的有机相，再用无水硫酸钠干燥，减压浓缩去除溶剂得到产物粗品；产物粗品用硅胶柱层析纯化，流动相为：石油醚/丙酮＝100:1，v/v，收集淡黄色集中洗脱带即得到闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物(III)的淡黄色胶状固体。
本发明公开的化合物可以制成药学上可接受的盐或药学上可接受的载体。
药效学实验表明，本发明的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物(III)具有较好的抗胰腺纤维化作用。本发明的药学上可接受的盐与其化合物具有同样的药效。
以下通过实施例对本发明作进一步详细的说明，但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
具体实施方式
实施例1 化合物闭花木酮Cleistanone的制备
化合物闭花木酮Cleistanone(I)的制备方法参照Van Trinh Thi Thanh等人发表的文献(Van Trinh Thi Thanh et al.,2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton.Volume 2011,Issue 22,pages 4108–4111,August 2011)的方法。
实施例2 闭花木酮Cleistanone的O-溴乙基衍生物(II)的合成
将化合物I(440mg，1.00mmol)溶于10mL苯，向溶液中加入四丁基溴化铵(TBAB)(0.04g)，1,2-二溴乙烷(3.760g，20.00mmol)和6mL的50％氢氧化钠溶液。混合物在25摄氏度搅拌24h。24h之后将反应液倒入冰水中，立即用二氯甲烷萃取两次，合并有机相溶液。然后对有机相溶液依次用水和饱和食盐水洗涤3次，再用无水硫酸钠干燥，最后减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为：石油醚/丙酮＝100:1，v/v)，收集黄色集中洗脱带即得到化合物II的黄色固体(344mg，63％)。
1H NMR(500MHz,DMSO-d6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]+calcd for C32H52BrO2:547.3151；found 547.3159.
实施例3 闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物(III)的合 成
将化合物II(273mg，0.5mmol)溶于20mL乙腈当中，向其中加入无水碳酸钾(345mg，2.5mmol)，碘化钾(84mg，0.5mmol)和吡咯烷(1420mg，20mmol)，混合物加热回流8h。反应结束后将反应液倒入冰水中，用等量二氯甲烷萃取三次，合并有机相。依次用水和饱和食盐水洗涤合并之后的有机相，再用无水硫酸钠干燥，减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为：石油醚/丙酮＝100:1，v/v)，收集淡黄色集中洗脱带即得到Cleistanone的O-(四氢吡咯基)乙基衍生物的淡黄色胶状固体(185.3mg,69％)。
1H NMR(500MHz,DMSO-d6)δ5.08(s,1H),4.89(s,1H),4.43(s,1H),3.59(s,2H),2.62(s,2H),2.58(s,4H),2.49(s,1H),2.44(s,1H),2.35(s,1H),2.25(s,1H),2.22(s,1H),1.88(s,1H),1.85–1.63(m,6H),1.61–1.52(m,4H),1.44(d,J＝13.7Hz,3H),1.32(dd,J＝19.4,11.7Hz,4H),1.21(d,J＝1.1Hz,2H),1.11(s,6H),0.95(s,1H),0.93(s,12H),0.86–0.78(m,4H).
13C NMR(125MHz,DMSO-d6)δ216.53(s),154.42(s),105.13(s),74.59(s),66.74(s),59.64(s),55.67(s),54.13(s),52.47(s),50.14(s),47.83(s),45.04(s),43.22(s),41.70(s),40.56(s),40.09(s),39.79(s),38.60(s),37.16(s),36.21(s),34.27(s),32.87(s),28.83(s),27.13(s),25.13(s),24.83(s),24.19(s),23.95(s),20.70(s),18.39(s),17.92(s),14.87(s).
HRMS(ESI):m/z[M+H]+calcd for C36H60NO2:538.4624；found:538.4628。
实施例4 Cleistanone的O-(四氢吡咯基)乙基衍生物抗胰腺纤维化活性
1材料
1.1动物Wistar大鼠，雄性，体重180-200g。
1.2Cleistanone的O-(四氢吡咯基)乙基衍生物剂量：0.9mg/kg。
2实验方法
2.1造模方法：Wistar大鼠以腹腔注射dl-乙硫氨酸250mg/天，连续2个月，可出现胰脏腺细胞减少，间质内脂肪及结缔组织的增生。
2.2分组及给药方法
模型大鼠随机分为模型组，Cleistanone的O-(四氢吡咯基)乙基衍生物0.9mg/kg组，另设空白对照组，于造模开始后给药，口服连续30天；60天时解剖动物。
2.3检测指标
2.3.1实验结束时取胰脏称重，计算脏器系数。
2.3.2胰脏羟脯氨酸含量测定取100mg样本在水中匀浆，110℃10N HCl中水解20小时。HCl用氮气挥发，水解产物用双蒸水溶解后过滤。取0.5ml液体与3ml枸橼酸磷酸缓冲液(0.15M枸橼酸加0.6M磷酸氢二钠)和0.5ml溶于9M磷酸的1M过碘酸混合。加1.75ml提取缓冲液(5份甲苯：5份2-甲基-1-丙醇：2份1-丙醇)，震荡30min，离心。组织相(0.6ml)与Ehrlich,s试剂混合放置15min。在565nm测定吸收度，用4-羟-1-脯氨酸制作标准曲线计算浓度，含量以ug/g组织表示。
2.3.3组织学检查胰脏组织用10％福尔马林固定，石蜡包埋，染色后镜检。对纤维化情况评分(0-3分)。
3结果
3.1Cleistanone的O-(四氢吡咯基)乙基衍生物对大鼠胰脏脏器系数的影响
实验结束时，将大鼠处死、解剖，称量体重和胰脏重并计算其与体重的比值，结果见表1。Cleistanone的O-(四氢吡咯基)乙基衍生物对胰脏脏器系数的影响，与模型组比较有显著性差异。
表1
*表示p<0.05，与模型组比较
3.2胰脏羟脯氨酸含量测定
实验结束时，对各组大鼠进行肺部羟脯氨酸含量测定，结果如表2。Cleistanone的O-(四氢吡咯基)乙基衍生物对羟脯氨酸含量的影响，与模型组比较有显著性差异。
表2
*表示p<0.05，与模型组比较
3.3组织学检查
实验结束时，将大鼠处死、解剖；标本常规包埋、固定、HE染色，镜检。
结果：模型组第60天可见胰导管周围严重炎症反应；嗜中粒细胞核淋巴细胞浸润，间质水肿，出血以及偶见胰泡细胞坏死；胰泡细胞消失位置及胰泡间出现纤维化。
Cleistanone的O-(四氢吡咯基)乙基衍生物可减少炎症反应和纤维化。评分结果见表3。Cleistanone的O-(四氢吡咯基)乙基衍生物对评分的影响，与模型组比较有显著性差异。
表3
*表示p<0.05，与模型组比较；空白对照组的炎症细胞浸润和纤维化评分都为0.
结论：本发明通过Cleistanone的O-(四氢吡咯基)乙基衍生物对大鼠胰腺纤维化的影响，证实了Cleistanone的O-(四氢吡咯基)乙基衍生物具有抗胰腺纤维化的作用。因此，Cleistanone的O-(四氢吡咯基)乙基衍生物可作为活性成分用于制备抗胰腺纤维化的药物。
实施例5 本发明所涉及Cleistanone的O-(四氢吡咯基)乙基衍生物片剂的制备
取20克Cleistanone的O-(四氢吡咯基)乙基衍生物或者其药学上可接受的盐当中的一种，加入制备片剂的常规辅料180克，混匀，常规压片机制成1000片。
实施例6 本发明所涉及Cleistanone的O-(四氢吡咯基)乙基衍生物胶囊的制备
取20克Cleistanone的O-(四氢吡咯基)乙基衍生物或者其药学上可接受的盐当中的一种，加入制备胶囊剂的常规辅料如淀粉180克，混匀，装胶囊制成1000粒。
Claims (4)
1.一种具有式III所示结构的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物及其药学上可接受的盐在治疗胰腺纤维化药物中的应用，
2.如权利要求1所述的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物及其药学上可接受的盐在治疗胰腺纤维化药物中的应用，其特征为：所述闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物及其药学上可接受的盐逆转胰腺纤维化所引起的胰脏脏器系数下降。
3.如权利要求1所述的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物及其药学上可接受的盐在治疗胰腺纤维化药物中的应用，其特征为：所述闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物及其药学上可接受的盐逆转胰腺纤维化所引起的羟脯氨酸含量升高。
4.如权利要求1所述的闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物及其药学上可接受的盐在治疗胰腺纤维化药物中的应用，其特征为：所述闭花木酮Cleistanone的O-(四氢吡咯基)乙基衍生物及其药学上可接受的盐逆转胰腺纤维化所引起的炎症细胞浸润升高。
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| CN104758298A (zh) * | 2015-04-15 | 2015-07-08 | 南京大学 | 闭花木酮的o-(1h-四氮唑基)乙基衍生物在制备治疗或预防肾纤维化药物中的应用 |
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Cited By (5)
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| CN104739846A (zh) * | 2015-04-15 | 2015-07-01 | 南京大学 | 闭花木酮的o-(1h-四氮唑基)乙基衍生物在制备预防或治疗胰腺纤维化药物中的应用 |
| CN104758298A (zh) * | 2015-04-15 | 2015-07-08 | 南京大学 | 闭花木酮的o-(1h-四氮唑基)乙基衍生物在制备治疗或预防肾纤维化药物中的应用 |
| CN104825466A (zh) * | 2015-04-29 | 2015-08-12 | 南京广康协生物医药技术有限公司 | 闭花木酮的o-(苯并咪唑基)乙基衍生物在制备预防或治疗胰腺纤维化药物中的应用 |
| CN104800213A (zh) * | 2015-05-12 | 2015-07-29 | 南京大学 | Daphmalenine A衍生物在制备预防或治疗胰腺纤维化药物中的应用 |
| CN104922122A (zh) * | 2015-05-27 | 2015-09-23 | 南京广康协生物医药技术有限公司 | Daphmalenine A的O-(二乙胺基)乙基衍生物在制备预防或治疗胰腺纤维化药物中的应用 |
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