CN105503710A - 一种含n-环丙烷取代的姜黄素类似物及其药物应用 - Google Patents

一种含n-环丙烷取代的姜黄素类似物及其药物应用 Download PDF

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CN105503710A
CN105503710A CN201511003141.XA CN201511003141A CN105503710A CN 105503710 A CN105503710 A CN 105503710A CN 201511003141 A CN201511003141 A CN 201511003141A CN 105503710 A CN105503710 A CN 105503710A
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陈通克
王丽花
汤陌生
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Wenzhou Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4

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Abstract

本发明公开了一种含N-丙烷取代的姜黄素类似物，其分子表达式为：(3E,5E)-3-(3-烯丙基-4-羟基苯亚甲基)-1-环丙基-5-(2,4-二甲氧基苯亚甲基)哌啶-4-酮。本发明还公开了该含N-环丙烷取代的姜黄素类似物的药物应用，应用于预防或治疗细菌诱导的脓毒症、化学物质诱导的炎症反应，其中的细菌诱导的脓毒症是指脂多糖LPS诱导的炎症因子释放和LPS诱导的脓毒性死亡；其中的化学物质诱导的炎症反应包括二甲苯诱导的耳肿胀、腹腔注射醋酸导致的血管通透性增加以及醋酸导致的扭体次数增加。

Description

一种含N-环丙烷取代的姜黄素类似物及其药物应用
技术领域
本发明属于医药制剂技术领域，涉及一种含N-环丙烷取代的姜黄素类似物，还涉及该种姜黄素类似物在治疗或预防细菌诱导的脓毒症、化学物质诱导的炎症反应的药物应用。
背景技术
炎症是指当外源和内源性损伤因素作用于机体后，细胞和组织所发生各种各样的损伤性变化，同时局部和全身也发生一系列复杂反应，以局限和消除损伤因素，消除和吸收坏死组织和细胞，并修复损伤的这种综合的机体防御反应。炎症反应介导多种疾病的发生发展，在疾病的进展过程中起重要作用。炎症反应多表现为促炎因子的大量释放，抑制这些炎症因子能缓解炎症下疾病。
然而目前临床上在治疗或预防细菌诱导的脓毒症、化学物质诱导的炎症反应的药物，所使用甾体类和非甾体类抗炎药都存在一定的副反应，影响了患者的治疗效果。
发明内容
本发明的目的之一是提供了一种含N-环丙烷取代的姜黄素类似物，用来制备预防或治疗细菌诱导的脓毒症、化学物质诱导的炎症反应的药物。
本发明的目的之二是提供了一种含N-环丙烷取代的姜黄素类似物的药物应用，应用于预防或治疗细菌诱导的脓毒症、化学物质诱导的炎症反应。
本发明的第一技术方案是，一种含N-丙烷取代的姜黄素类似物，其分子表达式为，(3E,5E)-3-(3-烯丙基-4-羟基苯亚甲基)-1-环丙基-5-(2,4-二甲氧基苯亚甲基)哌啶-4-酮。
本发明的第二技术方案是，一种含N-环丙烷取代的姜黄素类似物的药物应用，预防或治疗细菌诱导的脓毒症、化学物质诱导的炎症反应，其中细菌诱导的脓毒症是指脂多糖LPS诱导的炎症因子释放和LPS诱导的脓毒性死亡；其中化学物质诱导的炎症反应包括二甲苯诱导的耳肿胀、腹腔注射醋酸导致的血管通透性增加以及醋酸导致的扭体次数增加。
本发明的有益效果是，该含N-环丙烷取代的姜黄素类似物，可用于预防或治疗细菌诱导的脓毒症、化学物质诱导的炎症反应的有效药物。
附图说明
图1是本发明含N-环丙烷取代的姜黄素类似物的分子式结构；
图2是本发明含N-环丙烷取代的姜黄素类似物用ELISA法检测巨噬细胞培养液中IL-6的蛋白水平的表达变化；
图3是本发明含N-环丙烷取代的姜黄素类似物用ELISA法检测巨噬细胞培养液中TNF-α的蛋白水平的表达变化；
图4是本发明含N-环丙烷取代的姜黄素类似物缓解小鼠脓毒性死亡对比图；
图5是本发明含N-环丙烷取代的姜黄素类似物耳肿胀验证对比图；
图6是本发明含N-环丙烷取代的姜黄素类似物血管通透性验证对比图；
图7是本发明含N-环丙烷取代的姜黄素类似物扭体验证对比图。
具体实施方式
参照图1，本发明含N-环丙烷取代的姜黄素类似物的分子表达式是：
(3E,5E)-3-(3-烯丙基-4-羟基苯亚甲基)-1-环丙基-5-(2,4-二甲氧基苯亚甲基)哌啶-4-酮，(以下文本中简称S8)。
该化合物的波谱数据如下：黄色固体，产率为25％，熔点为182.6℃-184.5℃；1H-NMR(600MHZ,DMSO-d6)：δ＝10.03(1H,s,Ar-OH),7.79(1H,s,H-β’),7.49(1H,s,H-β),7.24(1H,d,J＝6.0Hz,H-6’),7.23(1H,d,J＝7.8Hz,H-6),7.22(1H,s,H-2),6.69(1H,s,H-3’),6.92(1H,d,J＝7.8Hz,H-5),6.64(1H,d,J＝6.0Hz,H-5’),6.02-5.95(1H,m,A-ArCH2CH＝CH2),5.09-5.04(2H,m,A-ArCH2CH＝CH2),3.89(2H,s,A-ArCH2CH＝CH2),3.85(4H,s,piperidone-CH2-N-CH2),3.83(6H,s,2’,4’-OCH3),1.97-1.94(1H,m,-N-CH-Cyclopropyl),0.45-0.42(2H,m,N-CH2-CH2-Cyclopropyl),0.26-0.23(2H,m,N-CH2-CH2-Cyclopropyl)；13C-NMR(600MHZ,DMSO-d6)：δ＝186.07,159.65,156.47,136.71,135.22,131.31,131.13×2,130.75,130.14,129.85,129.62,126.58,125.89,115.68,115.34,105.26×2,98.46,55.41×2,54.84,54.54,37.57,33.49,6.39×2；ESI-MS,m/z:431.9(M+H)+；calcdforC27H29NO4：431.21。
本发明的含N-环丙烷取代的姜黄素类似物，应用于预防或治疗细菌诱导的脓毒症、化学物质诱导的炎症反应，其中细菌诱导的脓毒症是指脂多糖LPS诱导的炎症因子释放和LPS诱导的脓毒性死亡；其中化学物质诱导的炎症反应包括二甲苯诱导的耳肿胀、腹腔注射醋酸导致的血管通透性增加以及醋酸导致的扭体次数增加。
实验验证
1)抗炎活性验证：
提取小鼠原代腹腔巨噬细胞(MPMs)按5X105/mL接种于六孔板，4小时后换液去除去非贴壁细胞。分为Con(DMSO)、LPS(0.5mg/mL)、S81(S81mM+LPS0.5mg/mL)、S82.5(S82.5mM+LPS0.5mg/mL)、S85(S85mM+LPS0.5mg/mL)、S810(S810mM+LPS0.5mg/mL)六组。加药后于37℃孵育30分钟，加入LPS(0.5mg/mL)，37℃培养箱继续培养24小时后，收集细胞上清液，用ELISA法检测巨噬细胞培养液中IL-6和TNF-α的蛋白水平的表达变化，细胞总蛋白用于定量。
结果参照图2、图3，S8可以剂量依赖性的抑制LPS诱导的炎症因子释放，S8在细胞层面上表现出较强的抗炎活性。
2)化合物S8缓解LPS诱导的小鼠死亡：
C57BL/6小鼠随机分为对照组(Control)、造模组(LPS20mg/kgi.v.)及治疗组(S810mg/kgi.v.+LPS20mg/kgi.v.)。造模组尾静脉注射LPS(20mg/kg)，治疗组小鼠于造模前15分钟尾静脉注射S8(10mg/kg)，对照组及造模组尾静脉注射相应量的生理盐水，造模后连续观察7天小鼠的生存率。
结果参照图4：造模组小鼠于48小时内全部死亡，尾静脉注射S8能显著提高脓毒血症小鼠的生存率.
3)耳肿胀验证：将20mL二甲苯均匀地涂抹在C57BL/6小鼠右耳，左耳涂抹等量的生理盐水作为阴性对照，治疗组造模前15分钟尾静脉注射S8(20mg/kg)。30分钟后用游标卡尺测量左右耳厚度。.
结论：参照图5，与造模组相比，S8能明显减轻二甲苯所致的小鼠耳肿胀。
4)血管通透性验证：C57BL/6小鼠尾静脉注射200uL10％伊文思兰生理盐水溶液，随即每只腹腔注射0.7％醋酸300uL，治疗组造模前15分钟尾静脉注射S8(20mg/kg)，30分钟后脱颈处死，剪开腹部，用1mL无菌PBS洗涤腹腔，吸出洗涤液，用分光光度计在620nm处测定OD值。
结论：参照图6，S8能明显减轻醋酸所致的小鼠毛细血管通透性增加。
5)扭体验证：小鼠腹腔注射0.6％醋酸进行造模，治疗组或对照组小鼠分布于造模前15分钟尾静脉注射S8(20mg/kg)或等量生理盐水，造模后观察两组小鼠扭体次数。
结果：参照图7，与造模组相比，治疗组的扭体次数明显减少，说明尾静脉注射S8能减轻腹腔注射醋酸所致疼痛。
本发明上述的这些实施例只是为了说明的目的，而不是用来限制本发明的范围。
本发明的S8涉及的化合物或其异构体、其药学上可接受的盐及制剂，包括该化合物或其异构体、可药用盐及溶剂化物，以及药学上可接受的载体、赋形剂或稀释剂的组合物，以及化合物或组合物用于预防和/治疗急性炎症性疾病的药物中的用途。

Claims (3)

1.一种含N-丙烷取代的姜黄素类似物，其特征是：
其分子表达式为，(3E,5E)-3-(3-烯丙基-4-羟基苯亚甲基)-1-环丙基-5-(2,4-二甲氧基苯亚甲基)哌啶-4-酮。
2.根据权利要求1所述的含N-丙烷取代的姜黄素类似物，其特征是，其波谱数据如下：
黄色固体，产率为25％，熔点为182.6℃-184.5℃；1H-NMR(600MHZ,DMSO-d6)：δ＝10.03(1H,s,Ar-OH),7.79(1H,s,H-β’),7.49(1H,s,H-β),7.24(1H,d,J＝6.0Hz,H-6’),7.23(1H,d,J＝7.8Hz,H-6),7.22(1H,s,H-2),6.69(1H,s,H-3’),6.92(1H,d,J＝7.8Hz,H-5),6.64(1H,d,J＝6.0Hz,H-5’),6.02-5.95(1H,m,A-ArCH2CH＝CH2),5.09-5.04(2H,m,A-ArCH2CH＝CH2),3.89(2H,s,A-ArCH2CH＝CH2),3.85(4H,s,piperidone-CH2-N-CH2),3.83(6H,s,2’,4’-OCH3),1.97-1.94(1H,m,-N-CH-Cyclopropyl),0.45-0.42(2H,m,N-CH2-CH2-Cyclopropyl),0.26-0.23(2H,m,N-CH2-CH2-Cyclopropyl)；13C-NMR(600MHZ,DMSO-d6)：δ＝186.07,159.65,156.47,136.71,135.22,131.31,131.13×2,130.75,130.14,129.85,129.62,126.58,125.89,115.68,115.34,105.26×2,98.46,55.41×2,54.84,54.54,37.57,33.49,6.39×2；ESI-MS,m/z:431.9(M+H)+；calcdforC27H29NO4：431.21。
3.一种含N-环丙烷取代的姜黄素类似物的药物应用，其特征是：应用于预防或治疗细菌诱导的脓毒症、化学物质诱导的炎症反应，其中的细菌诱导的脓毒症是指脂多糖LPS诱导的炎症因子释放和LPS诱导的脓毒性死亡；其中的化学物质诱导的炎症反应包括二甲苯诱导的耳肿胀、腹腔注射醋酸导致的血管通透性增加以及醋酸导致的扭体次数增加。
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