CN108586432B - 一种3-(吲哚-5-基)-吲唑衍生物及其应用 - Google Patents
一种3-(吲哚-5-基)-吲唑衍生物及其应用 Download PDFInfo
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Abstract
本发明公开了一种3‑(吲哚‑5‑基)‑吲唑衍生物,结构如式(I)或(Ⅱ)所示,式(I)中,R1选自取代或者未取代的芳基或烷基;R2选自氢或苄基;R3选自氢或乙醇基。式(Ⅱ)中,R1选自硝基或氨基。研究结果表明,该3‑(吲哚‑5‑基)‑吲唑衍生物大部分具有较好的抗炎活性,而且可以改善其先导化合物的成药性缺陷。
Description
技术领域
本发明属于药物化学领域,具体涉及一种3-(吲哚-5-基)-吲唑衍生物及其应用。
背景技术
炎症是机体对致病因素及其损害作用产生的一种反应,通常可依病程经过分为两大类:急性炎症(acute inflammation)和慢性炎症(chronic inflammation)。大量研究表明炎症与肿瘤、冠心病、动脉粥样硬化和糖尿病在内的多种疾病的发生、发展密切相关,因此,炎症已成为人类多种疾病的一个标志性特征。在炎症发生发展过程中,与其密切相关的炎症因子主要包括肿瘤坏死因子-α(Tumor Necrosis Factor-alpha,TNF-α)、白介素-6(interleukin-6,IL-6)和白介素-1β等(interleukin-1β,IL-1β)。这些炎症因子不仅可以激活放大炎症反应,还可以诱导细胞的凋亡,在炎症反应过程中起着至关重要重要的作用。目前,随着炎症信号传导途径研究的不断深入,TNF-α和IL-6已经成为急慢性炎症有效的治疗靶点,在炎症性疾病治疗过程中扮演着重要角色。
近年来,越来越多的研究表明如姜黄素,黄腐酚,咖啡酸苯乙酯等天然产物能通过与髓样分化蛋白-2(MD2)相互作用来抑制Toll样受体4(TLR4)信号通路传导,从而抑制TNF-α和IL-6等炎症因子的表达。但这些天然产物除了MD2-TLR4通路外,还可能与多个靶标相互作用,并且具有水溶性差、生物利用率低等缺陷。吲哚和吲唑结构广泛存在于小分子上市药物中,其具有广泛的生物应用,它们是药物化学中极具潜力的化合物结构。近年来,一些以吲哚和吲唑环为母核的化合物被评估为具有潜在抗炎活性的药物候选物,至少数个该类药物被批准用于临床使用,因此,将吲哚部分引入吲唑母核可能形成新的一系列有效的抗炎剂。
发明内容
本发明提供了一种3-(吲哚-5-基)-吲唑衍生物及其应用,该3-(吲哚-5-基)-吲唑衍生物具有较好的抗炎活性,而且可以避免成药性缺陷。
一种3-(吲哚-5-基)-吲唑衍生物,结构如式(I)或(Ⅱ)所示:
式(I)中,R1选自取代或者未取代的芳基或烷基;R2选自氢或苄基;R3选自氢或羟乙基。式(Ⅱ)中,R4选自硝基或氨基。
所述的芳基的取代基选自C1~C5烷基、C1~C5烷氧基或卤素。
本发明以吲哚和吲唑结构骨架为基础,通过构象限制药物设计方法设计了新型3-(吲哚-5-基)-吲唑类化合物。体外抗炎活性测试结果表明,本发明的3-(吲哚-5-基)-吲唑衍生物大部分具有较高的抗炎活性。
作为优选,所述的芳基为苯基;
作为优选,所述的芳基上的取代基选自卤素或者甲氧基。
作为优选,所述的R1选自以下基团:
本发明还提供了一种所述的3-(吲哚-5-基)-吲唑衍生物的应用,所述的3-(吲哚-5-基)-吲唑衍生物用于制备抗炎药物。
作为优选,所述的3-(吲哚-5-基)-吲唑衍生物通过抑制TNF-α和IL-6的分泌来治疗炎症以及与炎症相关的疾病。
作为优选,所述与炎症相关的疾病包括脓毒血症、类风湿性关节炎、系统性红斑狼疮及相关综合征、骨关节炎、消化道炎症、多发性肌炎、皮肌炎、血管炎性综合征、痛风性关节炎、神经炎症、风湿性关节炎、化学性疼痛、炎性疼痛、肉芽肿、肉芽肿性血管炎、动脉炎、皮肤炎症、自身免疫性疾病、脂膜炎、腹膜后纤维化、肝炎、肺炎、胰腺炎、过敏性炎症、全身炎症反应综合症、败血症、感染性休克。
作为优选,所述的3-(吲哚-5-基)-吲唑衍生物为化合物14a、14b、14c、14d、14e、14f、14g、14h或14i,进一步优选为化合物14c,14f,14h。
本发明还提供了一种药物制剂,包括有效成分和药用辅料,所述的有效成分包括所述的3-(吲哚-5-基)-吲唑衍生物。
作为优选,所述的药物制剂为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
同现有技术相比,本发明的有益效果体现在:
本研究以吲哚和吲唑结构骨架为基础,通过构象限制药物设计方法设计了新型3-(吲哚-5-基)-吲唑类化合物。体外抗炎活性测试结果表明,本发明的大部分化合物都对促炎因子TNF-α和IL-6具有较好的抑制能力,尤其是化合物14f,对促炎因子TNF-α和IL-6的抑制能力最高,其IC50值分别为0.85μM和0.54μM,可为进一步设计合成活性更高、选择性更强的新型抗炎药物提供参考。
附图说明
图1为测试例1得到的各种化合物对脂多糖LPS诱导的TNF-α和IL-6的分泌的抑制数据,其中X12为阳性对照物,结构如下:
具体实施方式
下面结合具体实施例对本发明做进一步的描述。
仪器和试剂:熔点采用X-4显微熔点仪测定(温度未经校正);核磁共振氢谱采用BrukerAVANCEIII500核磁共振仪测定(CDCl3为溶剂,TMS为内标);质谱采用Agilent 1100四级杆液相色谱质谱联用仪测定。薄层色谱用硅胶GF254购于阿拉丁试剂公司(aladdin,上海晶纯生化科技股份有限公司);柱色谱用硅胶FCP(200~300目)购于国药集团化学试剂有限公司;其他所用试剂和溶剂均为国产分析纯,根据需要经无水干燥处理后使用。
实施例13-碘-5-硝基-1H-吲唑的合成
将5-硝基吲唑(5g,30.8mmol)溶于30mLN,N-二甲基甲酰胺,依次加入碘(15.66g,,61.6mmol)和氢氧化钾固体(3.58g,63.7mmol),于65℃反应3h。反应结束后,加入1M HCl50mL以及10%硫代硫酸钠溶液80mL,搅拌30min后,向反应中加入冰水析出黄色沉底,抽滤,滤饼用二氯甲烷洗涤。滤饼继续用乙酸乙酯重结晶得黄色目标产物7.99g,收率90%。
实施例2 3-碘-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑(9a)
将3-碘-5-硝基-1H-吲唑(2g,6.92mmol)溶液15mLN,N-二甲基甲酰胺,于0℃加入氢化钠(60%;720mg,17.99mmol),30min后加入2-(三甲基甲硅烷基)乙氧基甲基氯(1.50mL,8.30mmol),于室温下搅拌反应3h。反应结束后,加入冰水淬灭,加入乙酸乙酯萃取,饱和氯化钠溶液水洗,无水硫酸镁干燥,旋蒸除去溶剂,粗品经柱层析纯化得2.6g产物,收率90%。
实施例3 1-苄基-3-碘-5-硝基-1H-吲唑的合成(9b)
将3-碘-5-硝基-1H-吲唑(400mg,1.38mmol)溶于10mL丙酮,加入碳酸钾(382mg,2.76mmol)以及苄溴(164μL,1.38mmol),加热回流反应2h。反应结束后,加入饱和氯化铵淬灭,旋蒸除去丙酮溶剂,加入乙酸乙酯萃取,饱和氯化钠溶液水洗,无水硫酸镁干燥,旋蒸除去溶剂,粗品经柱层析纯化得497.5mg产物,收率95%。
实施例4~5 3-(1H-吲哚-5-基)-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑的合成(以10a为例)
将化合物9a(3.48g,8.30mmol)溶于35ml四氢呋喃,加入2M Na2CO3溶液(33ml,66mmol),1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(1.63g,2mmol),5-吲哚硼酸酯(1.77g,9.96mmol),氮气保护,加热回流反应5h。反应结束后,加入饱和氯化铵淬灭,旋蒸除去溶剂,加入乙酸乙酯萃取,饱和氯化钠溶液水洗,无水硫酸镁干燥,旋蒸除去溶剂,粗品经柱层析纯化得2.74g产物,收率67%。
实施例6 3-(1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吲哚-5-基)-5-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑的合成(11)
将化合物10a(1g,2.44mmol)溶于10mLN,N二甲基甲酰胺,于0℃加入氢化钠(190mg,6.34mmol),(2-溴乙氧基)-叔丁基二甲基硅烷(703mg,2.94mmol),于室温下搅拌反应3h。反应结束后,加入饱和氯化铵淬灭,旋蒸除去溶剂,加入乙酸乙酯萃取,饱和氯化钠溶液水洗,无水硫酸镁干燥,旋蒸除去溶剂,粗品经柱层析纯化得1.11g产物,收率86%。
实施例7~93-(1-(2-((叔丁基二甲基硅烷基)氧基)乙基)-1H-吲哚-5-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-5-胺(以12为例)
将化合物11(1.15g,2.03mmol)溶于15mL乙醇和10mL水,依次加入铁粉(976mg,17.44mmol)和氯化铵(238mg,4.46mmol),于78℃下回流反应4h。反应结束后,抽滤除去铁粉,加入乙酸乙酯萃取,饱和氯化钠溶液水洗,无水硫酸镁干燥,旋蒸除去溶剂,粗品经柱层析纯化得972mg产物,收率91%。
实施例10~16 3-(吲哚-5-基)-吲唑衍生物14a-14i的合成通法(以14a为例)
将化合物12(140mg,260.78mmol)溶于二氯甲烷10mL,于0℃加入N,N二异丙基乙胺(51.56mg,391.16mmol),滴加乙酰氯(40.94mg,521.56mmol),于室温下反应2h。反应结束后,加入水淬灭,入乙酸乙酯萃取,饱和氯化钠水洗,无水硫酸镁干燥,旋蒸除去溶剂,粗品经柱层析纯化得131.35mg产物,收率87%。将所得产物100mg(172.74mmol)溶于8mL四氢呋喃,加入乙二胺(155.72mg,2.59mmol)以及四丁基氟化铵(677.49mg,2.59mmol),回流反应24h。反应结束后,加入饱和氯化铵溶液淬灭,加入乙酸乙酯萃取,饱和氯化钠溶液水洗,无水硫酸镁干燥,旋蒸除去溶剂,粗品经柱层析纯化得49.92mg产物,收率38.3%。
合成的9个目标化合物的收率、理化性质及波谱数据见表1,反应路线如下:
表1目标化合物14a~14i的收率和表征数据
所得化合的表征数据如下:
化合物8:
1H-NMR(CD3OD,500MHz)δ:8.42(s,1H),8.30(d,J=7.5Hz,1H),7.66(d,J=5Hz,1H).
13C-NMR(CD3OD,125MHz)δ:143.97,123.15,119.38,112.05,79.17,78.91,78.65.
化合物9a:
1H-NMR(CDCl3,500MHz)δ:8.72-8.27(m,2H),7.69(d,J=5Hz,1H),5.78(s,1H),3.62(t,J=7.5Hz,2H),0.92(t,J=10Hz,2H),-0.02(s,9H).
13C-NMR(CDCl3,125MHz)δ:143.47,142.33,128.80,122.88,119.43,110.59,95.34,78.57,67.25,17.72,-1.48×3.
化合物9b:
1H-NMR(CDCl3,500MHz)δ:8.48(s,1H),8.25(d,J=10Hz,1H),7.37-7.23(m,6H),5.64(s,2H)
13C-NMR(CDCl3,125MHz)δ:143.00,142.10,135.18,129.06×2,128.50,128.42,127.34×2,122.56,119.62,110.07,94.44,54.26
化合物10a:
1H-NMR(CDCl3,400MHz)δ:9.06(s,1H),8.42(s,1H),8.34(d,J=12Hz,1H),8.22(s,1H),7.79(d,J=8Hz,1H),7.66(d,J=4Hz,1H),7.57(d,J=8.0Hz,1H),7.31(s,1H),6.70(s,1H),5.83(s,2H),3.67(t,J=8.0Hz,2H),0.93(t,J=8Hz,2H),-0.05(s,9H).
13C-NMR(CDCl3,100MHz)δ:148.94,143.15,142.93,136.24,128.37,123.46,122.26,121.96×2,120.41,119.86,111.92,110.23,103.36,67.02,17.79,-1.41×3.
化合物10b:
1H-NMR(CDCl3,400MHz)δ:9.07(s,1H),8.41(s,1H),8.31-8.19(m,2H),7.82(d,J=8Hz,1H),7.56(d,J=8.4Hz,1H),7.46-7.24(m,7H),6.70(s,1H),5.70(s,2H).
化合物11:
1H-NMR(CDCl3,500MHz)δ:9.06(s,1H),8.34(d,J=10Hz,1H),8.19(s,1H),7.79(d,J=10Hz,1H),7.66(d,J=10Hz,1H),7.51(d,J=10Hz,1H),0.84(s,9H),-0.05(s,9H),-0.11(s,6H),0.92(t,J=10Hz,2H).
13C-NMR(CDCl3,125MHz)δ:149.04,143.00×2,136.65,129.77,129.14,122.36,121.84,121.31×2,120.54,119.86,110.17,110.13,101.93,78.21,66.98,62.43,48.98,25.81×3,25.65,17.81,-1.45×3,-5.66×2
化合物12:
1H-NMR(CDCl3,400MHz)δ:8.13(s,1H),7.77(d,J=12Hz,1H),7.44(t,J=8Hz,2H),7.34(s,1H),7.19(d,J=4Hz,1H),6.94(d,J=8,1H),6.56(d,J=2.8Hz,1H),5.74(s,2H),4.27(t,J=5.6Hz,2H),3.95(t,J=5.6Hz,2H),3.63(t,J=8Hz,2H),0.91(t,J=8Hz,2H),0.84(s,9H),-0.06(s,9H),-0.12(s,6H).
13C-NMR(CDCl3,100MHz)δ:144.92,140.50×2,136.77,135.86,128.86,124.87,123.66,121.39×2,119.97,118.40,110.54,109.54,101.46,77.70,66.17,62.36,48.82,25.78×3,18.18,17.75,-1.52×3,-5.72×2
化合物15:
1H-NMR(CDCl3,500MHz)δ:8.40(s,1H),8.15(s,1H),7.75(d,J=10Hz,1H),7.46(d,J=5Hz,1H),7.41(d,J=10Hz,1H),7.33(s,1H),7.22(s,1H),6.93(d,J=10Hz,1H),6.62(s,1H),5.73(s,2H),3.63(t,J=10Hz,2H),0.91(t,J=10Hz,2H),-0.06(s,9H).
13C-NMR(CDCl3,125MHz)δ:144.92,140.58,136.89,135.67,128.22,125.53,124.73,123.72,122.09,119.80,118.48,111.34,110.54,104.80,103.04,77.75,66.22,17.81,-1.46×3.
化合物16:
1H-NMR(DMSO,600MHz)δ:11.16(s,1H),8.04(s,1H),7.66(dd,J=6Hz,1H),7.49(d,J=12Hz,1H),7.41(d,J=12Hz,1H),7.38(s,1H),7.34–7.22(m,5H),7.19(s,1H),6.83(d,J=6Hz,1H),6.51(s,1H),5.57(s,2H),4.92(s,2H).
13C-NMR(DMSO,150MHz)δ:143.34,142.25,138.13,135.64,135.39,128.54×2,127.95,127.38×2,125.94,125.28,122.28,120.52,118.08,117.97,110.72,110.43,101.53,101.30,59.84.
化合物14a:
1H NMR(DMSO,600MHz)δ:10.25(s,1H),8.43(s,1H),8.04(s,1H),7.70(d,J=9.0Hz,1H),7.69(d,J=7.8Hz,1H),7.63(d,J=8.4Hz,1H),7.61(d,J=9.0Hz,1H),7.44(d,J=3.0Hz,1H),6.53(d,J=2.4Hz,1H),4.27(t,J=5.4Hz,2H),3.60(t,J=7.8Hz,2H),2.07(s,3H).
13C NMR(DMSO,150MHz)δ:168.16,144.82,138.13,135.84,133.66,130.09,128.36,124.05,121.56,120.41×2,118.86,110.48,110.24,110.05,100.83,60.40,48.43,23.95.
化合物14b:
1H-NMR(DMSO,600MHz)δ:13.04(s,1H),10.43(s,1H),8.55(s,1H),8.09(s,1H),8.06(s,1H),7.97(d,J=7.8Hz,1H),7.79(d,J=9.0Hz,1H),7.75(d,J=8.4Hz,1H),7.67(d,J=7.8Hz,1H),7.63(d,J=8.4Hz,1H),7.58(t,J=7.8Hz,1H),7.57(d,J=3.0Hz,1H),7.43(d,J=3.0Hz,1H),6.54(d,J=3.0Hz,1H),4.93(s,1H),4.27(t,J=5.4Hz,2H),3.76(t,J=5.4Hz,2H).
13C-NMR(DMSO,150MHz)δ:193.13,157.22,140.87,138.21,137.93,136.04,133.96,130.58,129.99,127.49,126.93,126.91,125.84,123.73,108.20,30.87.
化合物14c:
1H-NMR(DMSO,600MHz)δ:13.06(s,1H),10.78(s,1H),8.52(s,1H),8.06(s,1H),7.72(d,J=8.4Hz,1H),7.64(t,J=10.2Hz,1H),7.63(d,J=9.0Hz,1H),7.59(d,J=8.4Hz,1H),7.57(d,J=8.4Hz,2H),7.51(d,J=7.2Hz,1H),7.42(d,J=3.0Hz,1H),6.53(d,J=3.0Hz,1H),4.27(t,J=5.4Hz,2H),3.76(t,J=5.4Hz,2H).
13C-NMR(DMSO,150MHz)δ:161.89,144.83×2,138.89,136.54,135.70,132.15,131.32×2,129.99,128.39,128.25×2,124.80,120.42,120.08,118.60,110.75,110.44×3,60.41,48.43.
化合物14d:
1H-NMR(DMSO,600MHz)δ:13.01(s,1H),10.25(s,1H),8.55(s,1H),8.09(s,1H),7.75(d,J=7.2Hz,1H),7.74(d,J=7.2Hz,1H),7.62(d,J=8.4Hz,1H),7.56(d,J=9.0Hz,1H),7.42(s,1H),7.16(s,2H),6.72(s,1H),6.54(d,J=3.0Hz,1H),4.93(d,J=3.0Hz,1H),4.27(t,J=5.4Hz,2H),3.83(s,6H),3.76(t,J=5.4Hz,2H).
13C-NMR(DMSO,150MHz)δ:166.46,160.39×2,144.74,138.86,137.14,135.67,132.39,129.92,128.38,124.90,121.39,120.42,120.03,118.58,111.73,110.38,110.25,105.58,103.26×2,100.81,60.40,55.51×2,48.42.
化合物14e:
1H-NMR(DMSO,600MHz)δ:13.01(s,1H),10.32(s,1H),8.62(s,1H),8.08(s,1H),7.43(d,J=3.0Hz,1H),7.46(t,J=7.2Hz,2H),7.42(d,J=12Hz,1H),6.88(d,J=15.6Hz,1H),6.54(d,J=2.4Hz,1H),4.28(t,J=6.0Hz,2H),3.77(t,J=5.4Hz,2H).
13C-NMR(DMSO,150MHz)δ:163.41,144.71,139.77,138.65,135.68,134.85,132.81,129.96,129.70,129.05×2,128.40,127.69×2,124.93,122.49,120.43,120.16,120.10,118.58,110.61,110.42,110.11,100.80,60.43,48.45.
化合物14f:
1H-NMR(DMSO,600MHz)δ:11.23(s,1H),10.79(s,1H),8.54(s,1H),8.06(s,1H),7.78-7.47(m,8H),7.40(s,1H),6.53(s,1H).
13C-NMR(DMSO,150MHz)δ:161.95,144.93×2,138.87,136.64,135.68,132.24,131.40×2,128.76,128.34×2,128.00,126.18,124.81,120.65,120.13,118.42,111.93,110.92×2,110.49,101.58.
化合物14g:
1H-NMR(DMSO,600MHz)δ:11.24(s,1H),10.83(s,1H),8.57(s,1H),8.07(s,1H),7.76(d,J=6.0Hz,1H),7.69-7.66(m,2H),7.60(s,1H),7.58(s,1H),7.56(d,J=6.0Hz,1H),7.51(dd,J=8.6,7.6Hz,1H),7.51(dd,J=9.0,7.3Hz,1H),7.42(t,J=2.4Hz,1H),7.35-7.23(m,5H),6.55(s,1H),5.71(s,2H).
13C-NMR(DMSO,150MHz)δ:162.00,144.52,138.34,137.73,136.55,135.76131.44,131.37,128.65×3,128.33×2,128.02,127.57,127.39×3,126.28,124.27,121.02,120.64,120.28,118.55,111.98,110.72,110.60,101.63,59.84.
化合物14h:
1H-NMR(DMSO,500MHz)δ:13.74(s,1H),8.94(s,1H),8.25(d,J=10.0Hz,1H),8.18(s,1H),7.77(d,J=10.0Hz,1H),7.68(d,J=6.0Hz,1H),7.46(d,J=3.0Hz,1H),6.61(d,J=3.0Hz,1H),4.28(t,J=5.5Hz,1H),3.76(t,J=4.5Hz,1H).
13C-NMR(DMSO,150MHz)δ:143.56,141.76,136.20,130.25,128.53,123.07,121.01,120.52,119.42,119.35,118.92,111.41,110.76×2,101.17,60.41,48.45.
化合物14i:
1H-NMR(DMSO,600MHz)δ:12.56(s,1H),8.03(s,1H),7.70(d,J=8.4Hz,1H),7.56(d,J=8.4Hz,1H),7.39(d,J=3.0Hz,1H),7.27(d,J=9.0Hz,1H),7.17(s,1H),6.82(d,J=8.4Hz,1H),6.49(d,J=2.4Hz,1H),4.92(s,1H),4.85(s,2H,),4.25(t,J=5.4Hz,2H),3.76(t,J=7.8Hz,2H).
13C-NMR(DMSO,150MHz)δ:143.56,141.76,136.20,130.25,128.53,123.07,121.01,120.52,119.42,119.35,118.92,111.41,110.76×2,101.17,60.41,48.45.
测试例1化合物抑制脂多糖LPS诱导的TNF-α和IL-6的分泌
采用酶联免疫吸附实验(ELISA)的方法测试目标化合物14a-14i对脂多糖LPS诱导的TNF-α和IL-6的分泌的抑制活性。小鼠巨噬细胞RAW264.7培养于含有10%FBS,1%青链霉素混合液的DMEM高糖培养基中,并放在37℃5%CO2的恒温培养箱培养。细胞加药后2h加LPS(0.5ug/ml),继续孵育22h后收集培养基。促炎细胞因子TNF-α和IL-6的表达用ELISA试剂盒通过双抗夹心ELISA检测,实验步骤简述如下:先用coating buffer包被elisa板,4℃过夜,加入吐温-20的磷酸盐缓冲液(PBST)洗3次甩干,加入assay diluent封闭后加入收集的培养基,PBST洗去没有与包被抗体结合的样品,加入detection antibody孵育后加avidin标记的HRP,最后加入酶作用底物TMB进行显色,15min后加2M H2SO4终止反应并在450nm处测OD值。
为了评价所合成的化合物抑制LPS刺激的小鼠巨噬细胞RAW264.7释放促炎因子TNF-α和IL-6的能力。我们用LPS刺激存在或不存在化合物的巨噬细胞。细胞用化合物(10μM)及DMSO(作为对照)预孵育2h后加LPS(0.5μg/ml)刺激22h,收集细胞的培养基和总蛋白。培养基内的TNF-α和IL-6的总量用酶联免疫吸附试验法(ELISA)检测同时用同一培养皿的总蛋白浓度作为标准。结果见图1,图1给出了9个已合成化合物的相对抗炎数值。由图1可以看到这些化合物都可以不同程度地抑制炎症因子的释放,当芳环上取代基为2,6位氯取代(化合物14c,14f,14h)时,其抗炎活性较高,当R1为2,6-二氯苯基,R2,R3为氢时(化合物14f),对促炎因子TNF-α和IL-6的抑制能力最高,抗炎活性明显优于其他化合物,其IC50值分别为0.85μM和0.54μM。
Claims (10)
2.根据权利要求1所述的3-(吲哚-5-基)-吲唑衍生物,其特征在于,所述的芳基上的取代基选自卤素或甲氧基。
4.一种如权利要求1~3任一项所述的3-(吲哚-5-基)-吲唑衍生物的应用,其特征在于,所述的3-(吲哚-5-基)-吲唑衍生物用于制备抗炎药物。
5.根据权利要求4所述的3-(吲哚-5-基)-吲唑衍生物的应用,其特征在于,所述的3-(吲哚-5-基)-吲唑衍生物通过抑制TNF-α和IL-6的分泌来治疗炎症以及与炎症相关的疾病。
6.根据权利要求5所述的3-(吲哚-5-基)-吲唑衍生物的应用,其特征在于,所述与炎症相关的疾病为脓毒血症、类风湿性关节炎、系统性红斑狼疮及相关综合征、骨关节炎、消化道炎症、多发性肌炎、皮肌炎、血管炎性综合征、痛风性关节炎、神经炎症、风湿性关节炎、化学性疼痛、炎性疼痛、肉芽肿、肉芽肿性血管炎、动脉炎、皮肤炎症、脂膜炎、腹膜后纤维化、肝炎、肺炎、胰腺炎、过敏性炎症、全身炎症反应综合症、败血症、感染性休克。
7.根据权利要求6所述的3-(吲哚-5-基)-吲唑衍生物的应用,其特征在于,所述与炎症相关的疾病为自身免疫性疾病。
9.一种药物制剂,包括有效成分和药用辅料,其特征在于,所述的有效成分包括权利要求1~3任一项所述的3-(吲哚-5-基)-吲唑衍生物。
10.根据权利要求9所述的药物制剂,其特征在于,所述的药物制剂为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
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