CN115417830A - 一种乙烷-1,2-双(3-芳基丙烯酸酯)类化合物及其在药物制备中的应用 - Google Patents
一种乙烷-1,2-双(3-芳基丙烯酸酯)类化合物及其在药物制备中的应用 Download PDFInfo
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Abstract
本发明公开了一种乙烷‑1,2‑双(3‑芳基丙烯酸酯)类化合物在药物制备中的应用，所述的乙烷‑1,2‑双(3‑芳基丙烯酸酯)类化合物用于制备抗炎药物。该类药物能够抑制TNF‑α和IL‑6等炎症因子的释放，可以作为一种治疗急性肺损伤的重要手段。
Description
技术领域
本发明涉及一种乙烷-1,2-双(3-芳基丙烯酸酯)类化合物及其药学上可接受的盐、水合物、溶剂化物或其前药的制备方法以及含有所述化合物的药物组合物，及其在制备治疗和/或预防炎症疾病的药物中的用途。
背景技术
炎症(inflammation)是机体对于刺激的一种防御反应，通常情况下，炎症是有益的，是人体的自动的防御反应，但炎症反应失调导致过度炎症时，机体会产生大量的炎性细胞因子而造成组织或细胞的破坏，严重影响人类生命健康。
急性肺损伤(Acute Lung Inflammation，ALI)是一种急性的、持续性的肺部炎症反应综合征，这种炎症反应引起肺泡毛细血管内膜损伤和导致毛细血管渗透性增加，造成弥漫性肺间质及肺泡水肿，导致的急性低氧性呼吸功能不全，发病率和死亡率都很高，然而目前临床上还没有有效的治疗手段。临床和动物实验证实，脂多糖(LPS)可以激活多种下游促炎信号通路，并触发炎症因子的过度生成，如肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)，进而导致弥漫性肺泡损伤(DAD)、肺水肿以及炎症反应加剧。目前，糖皮质激素等多种药物对炎症风暴的阻断已被广泛探索，作为一种潜在的有希望的预防和治疗急性肺损伤的方法。然而，鉴于临床使用的药物因其低效和不良反应而对急性肺损伤患者没有显示出明显的治疗效果，仍然需要开发更有效和更安全的新型抗炎药来治疗急性肺损伤。因此抑制TNF-α和IL-6等炎症因子的释放成为了治疗急性肺损伤的重要手段。
发明内容
本发明的目的在于提供了一种乙烷-1,2-双(3-芳基丙烯酸酯)类化合物及其新的用途。
本发明首先提供了一种乙烷-1,2-双(3-芳基丙烯酸酯)类化合物，为以下化合物中的一种：
本发明还提供了所述乙烷-1,2-双(3-芳基丙烯酸酯)类化合物在药物制备中的应用，所述的乙烷-1,2-双(3-芳基丙烯酸酯)类化合物用于制备抗炎药物。
作为优选，所述抗炎药物用于预防或者治疗炎症以及与炎症相关的疾病。
作为优选，其中所述抗炎药物是能够通过抑制巨噬细胞释放炎症因子的释放而治疗的炎症；
所述巨噬细胞释放炎症因子为TNF-α和/或IL-6。
本发明涉及一类具有急性肺损伤治疗作用的乙烷-1,2-双(3-芳基丙烯酸酯)类似物及与炎症相关疾病的治疗药物，所述疾病的病因至少部分地是由炎症引起，所述疾病包括但不限于以下疾病：脓毒血症、急性肺损伤、关节炎、结直肠炎、肝炎、脂肪肝或慢性炎症性疾病，所述慢性炎症性疾病包括糖尿病并发症、动脉粥样硬化、肥胖并发症或高血压并发症；所述糖尿病并发症包括糖尿病肾病或糖尿病心肌病。
作为优选，化合物选自如下结构的化合物：
作为优先，所述的抗炎药物用于缓解或治疗急性肺损伤。
下面的合成路线描述了本发明的所涉及的化合物的制备，所有的原料都是通过这些化学式中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些化学式中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些化学式中应用的全部可变因数如下文的定义或如前述内容中的定义。
按照本发明所涉及化合物，R1，R2如合成路线所定义，均按以下路线的方法制备而成。
抑或：
本发明还提供了一种用于治疗炎症的药物组合物，含有治疗有效量的权利要求1所述的乙烷-1,2-双(3-芳基丙烯酸酯)类化合物或其可药用盐和药用辅料。
作为优选，所述的乙烷-1,2-双(3-芳基丙烯酸酯)类化合物或其可药用盐作为唯一的活性成分。
作为优选，所述药物组合物的制剂形式选自注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂和纳米制剂。
附图说明
图1为化合物抑制LPS刺激巨噬细胞释放IL-6和TNF-α的量效关系；
图2为化合物对巨噬细胞的毒性测试；
图3为优选化合物(6h)缓解急性肺损伤小鼠生理学变化效果；
图4为优选化合物(6h)缓解急性肺损伤小鼠肺组织的病理学变化。
具体实施方式
在下面的非限制性实施例中，对本发明进行更详细的说明。
实施例1
乙烷-1,2-二(2E，2’E)-双[3-(4-甲基噻唑-5-基)丙烯酸酯](5d)
步骤一：在50mL圆底烧瓶中将4-甲基噻唑-5-甲醛(635.81mg，5mmol)和丙二酸(1.04g,10mmol)加入2mL吡啶溶剂中，90℃搅拌过夜。当通过TLC监测反应完成时，将3M HCl缓慢滴入混合物中直至沉淀析出。过滤收集形成的沉淀，用冷水洗涤并真空干燥，得到(E)-3-(4-甲基噻唑-5-基)丙烯酸，产率为94.0％。
Yellow solid,94.0％yield,m.p:172.1-173.7℃.1H-NMR(500MHz,DMSO-d6)δ(ppm):12.55(s,1H,-COOH),9.07(s,1H,thiazole-H),7.72(d,J＝15.5Hz,1H,-HC＝CH-thiazole),6.12(d,J＝15.5Hz,1H,-HC＝CH-thiazole),2.48(s,3H,-CH3).ESI-MS(m/z):170.43[M+H]+,calcd for C7H7NO2S:169.20.
步骤二：在25mL的圆底烧瓶中将步骤一中所合成的(E)-3-(4-甲基噻唑-5-基)丙烯酸(84.60mg，0.5mmol)，二环己基碳二亚胺(103.05mg，0.5mmol)和4-二甲氨基吡啶(24.44mg,0.2mmol)和三乙胺(60.71mg,0.6mmol)在10mL的二氯甲烷溶液中溶解,并在冰浴中搅拌。30min后，滴加乙二醇(12.41mg,0.2mmol)的CH2Cl2溶液，在室温下反应5h。TLC监测反应结束之后，将混合物用乙酸乙酯(3×25mL)萃取三次，用饱和NaHCO3洗涤，经无水MgSO4处理后浓缩。通过硅胶色谱法纯化得到的固体(PE:EA＝5:1)，即为目标化合物乙烷-1,2-二(2E，2’E)-双[3-(4-甲基噻唑-5-基)丙烯酸酯]，产率为35.7％。
Light yellow solid,35.7％yield,m.p:169.6-171.1℃,97％purity.1H-NMR(500MHz,CDCl3)δ(ppm):8.69(s,2H,thiazole-H×2),7.84(d,J＝15.4Hz,2H,-HC＝CH-thiazole×2),6.18(d,J＝15.5Hz,2H,-HC＝CH-thiazole×2),4.47(s,4H,-O-CH2-CH2-O-),2.56(s,6H,-CH3×2).13C NMR(125MHz,CDCl3)δ(ppm):166.04(2C),156.17(2C),152.88(2C),134.53(2C),128.20(2C),118.99(2C),62.45(2C),15.65(2C).HRMS m/z(ESI)found 365.0870[M+H]+,calcd for C16H16N2O4S2365.0885.
按照实施例1的方法，制得实施例2化合物
实施例2
乙烷-1,2-二(2E，2’E)-双[3-(5-溴呋喃-2-基)丙烯酸酯(5e)
Light yellow solid,79.1％yield,m.p:112.0-113.4℃,98％purity.1H-NMR(500MHz,CDCl3)δ(ppm):7.34(d,J＝15.7Hz,2H,-HC＝CH-furan×2),6.56(d,J＝3.0Hz,2H,furan-H×2),6.40(d,J＝3.2Hz,2H,furan-H×2),6.34(d,J＝15.7Hz,2H,-HC＝CH-furan×2),4.44(s,4H,-O-CH2-CH2-O-).13C NMR(125MHz,CDCl3)δ(ppm):166.47(2C),152.70(2C),130.38(2C),125.70(2C),117.01(2C),115.73(2C),114.23(2C),62.36(2C).HRMS m/z(ESI)found 460.0755[M+H]+,calcd for C16H12Br2O6 460.0740.
实施例3
乙烷-1,2-二(2E，2’E)-双[3-(4-乙酰氧基-3-甲氧基苯基)丙烯酸酯](6g)
步骤一：在50mL圆底烧瓶中将4-甲基噻唑-5-甲醛(760.75mg，5mmol)和丙二酸(1.04g，10mmol)，加入2mL吡啶溶剂中，90℃搅拌过夜。当通过TLC监测反应完成时，将3MHCl缓慢滴入混合物中直至沉淀析出。过滤收集形成的沉淀，用冷水洗涤并真空干燥，得到(E)-3-(4-羟基-3-甲氧基苯基)丙烯酸，产率为90.7％。
步骤二：将获得的(E)-3-(4-羟基-3-甲氧基苯基)丙烯酸(222.20mg,1mmol)加入含有三乙胺(202.38mg,2mmol)的2mL N,N-二甲基甲酰胺溶剂溶解，并在冰浴中搅拌。将乙酰氯(117.74mg,1.5mmol)逐滴加入上述反应体系，室温反应过夜。TLC监测反应结束后，用饱和NaHCO3和乙酸乙酯(3×25mL)萃取，收集水层，并用3M HCl调节溶液PH至酸性，直到不再析出沉淀为止，过滤收集形成的沉淀并真空干燥，即为化合物(E)-3-(4-乙酰氧基-3-甲氧基苯基)丙烯酸,产率为84.1％。
White solid,84.1％yield,m.p:186.7-187.9℃.1H-NMR(500MHz,DMSO-d6)δ(ppm):12.40(s,1H,-COOH),7.58(d,J＝16.0Hz,1H,-HC＝CH-Ph),7.48(d,J＝1.3Hz,1H,Ar-H),7.26(dd,J＝8.2,1.4Hz,1H,Ar-H),7.12(d,J＝8.1Hz,1H,Ar-H),6.59(d,J＝16.0Hz,1H,-HC＝CH-Ph),3.82(s,3H,-OCH3),2.26(s,3H,-CH3).ESI-MS(m/z):237.08[M+H]+,calcd for C12H12O5:236.22.
步骤三：在25mL的圆底烧瓶中将步骤二中所合成的(E)-3-(4-乙酰氧基-3-甲氧基苯基)丙烯酸(118.11mg，0.5mmol)，二环己基碳二亚胺(103.05mg，0.5mmol)和4-二甲氨基吡啶(24.44mg,0.2mmol)和三乙胺(60.71mg,0.6mmol)在10mL的二氯甲烷溶液中溶解,并在冰浴中搅拌。30min后，滴加乙二醇(12.41mg,0.2mmol)的CH2Cl2溶液，在室温下反应5h。TLC监测反应结束之后，将混合物用CH2Cl2(3×25mL)萃取三次，用饱和NaHCO3洗涤，经无水MgSO4处理后浓缩。通过硅胶色谱法纯化得到的固体(DCM：CH3OH＝50:1)，即为目标化合物乙烷-1,2-二(2E，2’E)-双[3-(4-乙酰氧基-3-甲氧基苯基)丙烯酸酯]，产率为41.7％。
White solid,41.7％yield,m.p:151.9-153.0℃,97％purity.1H NMR(500MHz,CDCl3)δ(ppm):7.69(d,J＝15.9Hz,2H,-HC＝CH-Ph×2),7.12(d,J＝12.3Hz,4H,Ar-H×4),7.05(d,J＝8.0Hz,2H,Ar-H×2),6.43(d,J＝15.9Hz,2H,-HC＝CH-Ph×2),4.50(s,4H,-O-CH2-CH2-O-),3.86(s,6H,-OCH3×2),2.32(s,6H,-CH3×2).13C NMR(125MHz,CDCl3)δ(ppm):168.69(2C),166.52(2C),151.46(2C),144.76(2C),141.63(2C),133.22(2C),123.29(2C),121.35(2C),117.72(2C),111.33(2C),62.42(2C),55.94(2C),20.61(2C).HRMS m/z(ESI)found 499.1556[M+H]+,calcd for C26H26O10 499.1560.
按照实施例3的方法，制得实施例4化合物
实施例4
乙烷-1,2-二(2E，2’E)-双[3-(4-乙酰氧基苯基)丙烯酸酯](6h)
White solid,37.3％yield,m.p:103.3-104.4℃,99％purity.1H-NMR(400MHz,CDCl3)δ(ppm):7.70(d,J＝16.0Hz,2H,-HC＝CH-Ph×2),7.55(d,J＝8.5Hz,4H,Ar-H×4),7.12(d,J＝8.4Hz,4H,Ar-H×4),6.43(d,J＝16.0Hz,2H,-HC＝CH-Ph×2),4.49(s,4H,-O-CH2-CH2-O-),2.31(s,6H,-CH3×2).13C NMR(125MHz,CDCl3)δ(ppm):169.09(2C),166.60(2C),152.27(2C),144.36(2C),132.04(2C),129.31(4C),122.18(4C),117.74(2C),62.42(2C),21.12(2C).HRMS m/z(ESI)found 439.1340[M+H]+,calcd for C24H22O8 439.1348.
实施例5
乙烷-1,2-二(2E，2’E)-双[3-(噻吩-2-基)丙烯酸酯](5f)
实施例5的化合物按照实施例3类似的方法制备得到。
Light yellow solid,41.5％yield,m.p:103.7-104.9℃,97％purity.1H-NMR(500MHz,CDCl3)δ(ppm):7.82(d,J＝15.7Hz,2H,-HC＝CH-thiophene×2),7.38(d,J＝4.7Hz,2H,thiophene-H×2),7.26(s,2H,thiophene-H×2),7.08-7.02(m,2H,thiophene-H×2),6.28(d,J＝15.7Hz,2H,-HC＝CH-thiophene×2),4.46(s,4H,-O-CH2-CH2-O-).13CNMR(125MHz,CDCl3)δ(ppm):166.55(2C),139.45(2C),137.83(2C),131.12(2C),128.67(2C),128.11(2C),116.27(2C),62.38(2C).HRMS m/z(ESI)found 335.0382[M+H]+,calcdfor C16H14O4S2 335.0367.
本发明产物的药理研究
实施例化合物抑制LPS刺激巨噬细胞(MPMs)释放IL-6和TNF-α的量效关系
当用LPS刺激时，MPMs会分泌过多的促炎细胞因子(如IL-6和TNF-α)。我们建立了酶联免疫吸附试验(ELISA)，以测试化合物在LPS刺激的MPMs中对IL-6和TNF-α释放的抗炎活性。二甲基亚砜(DMSO)作为溶媒对照，用10μΜ化合物处理MPMs 2小时后，用LPS(0.5μg/mL)刺激细胞并培养24小时。然后，用ELISA试剂盒测定的IL-6和TNF-α数量。化合物的细胞因子抑制活性如图1所示，结果表明，4种化合物可明显抑制LPS刺激巨噬细胞释放的IL-6(图1A)和TNF-α(图1B)，表现出明显的抗炎作用。
实施例化合物对巨噬细胞的毒性测试
为了评估化合物的安全性，在MPMs中测试了化合物的细胞毒性。简而言之，将MPMs置于含有DMEM培养基的96孔板中，每孔2.0×104个细胞，，添加10％FBS、100U/mL青霉素和100mg/mL链霉素。接下来，用浓度为10μΜ的化合物培养细胞24小时，并向每个孔中添加溶解于NaCl溶液(0.9％)中的MTT(5mg/mL)新鲜溶液。然后，在37℃的5％CO2中培养皿4小时。在490nm处用多孔板读取器测量吸光度。测试结果如图2所示，浓度10μΜ条件下对细胞增殖活性均无明显毒性，表明化合物无毒性。
实施例3优选化合物缓解急性肺损伤小鼠生理学变化效果
我们进一步探索了优选化合物6h对气管内滴注LPS诱导的C57/BL6小鼠急性肺损伤模型的保护作用。二甲基亚砜作为溶媒对照，小鼠给与优选化合物6h(20mg/kg，腹腔注射(ip))或溶媒的预处理，然后以5mg/kg的LPS刺激。肺湿/干比用于量化肺水肿的程度，LPS可提高肺水肿的程度，优选化合物6h后可有效降低肺水肿的程度，如图3A所示。此外，图3B中的结果表明，优选化合物6h可抑制LPS诱导的支气管肺泡灌洗液(BALF)总细胞数的增加。如图3C和3D所示，急性肺损伤模型小鼠的肺泡灌洗液(BALF)中IL-6和TNF-α的释放显著增加，而优选化合物6h显著逆转了这种变化。上述实验结果表明，优选化合物6h对急性肺损伤模型小鼠具有优异的体内抗炎作用。
实施例3优选化合物缓解急性肺损伤小鼠肺组织的病理学变化
为了评估急性肺损伤小鼠肺的组织学变化，我们对肺组织进行了苏木精-伊红(H&E)染色。LPS刺激的小鼠表现出典型的急性肺损伤组织病理学改变，如明显的肺水肿、肺泡壁厚度升高、肺充血、炎性细胞浸润和肺组织破坏，而化合物6h预处理的小鼠显著减少了这些病理变化，甚至显著恢复了正常生理状态，如图4所示，说明化合物可有效缓解急性肺损伤小鼠的肺组织损伤。
Claims (10)
1.一种乙烷-1,2-双(3-芳基丙烯酸酯)类化合物，其特征在于，选自以下化合物中的一种：
2.一种如权利要求1所述的乙烷-1,2-双(3-芳基丙烯酸酯)类化合物在药物制备中的应用，其特征在于，所述的乙烷-1,2-双(3-芳基丙烯酸酯)类化合物用于制备抗炎药物。
3.根据权利要求2所述的应用，其特征在于，所述抗炎药物用于预防或者治疗炎症以及与炎症相关的疾病。
4.根据权利要求3所述的应用，其特征在于，所述抗炎药物通过抑制巨噬细胞释放炎症因子的释放而治疗炎症；
所述巨噬细胞释放炎症因子为TNF-α和/或IL-6。
5.根据权利要求3所述的应用，其特征在于，所述炎症或与炎症相关疾病包括脓毒血症、急性肺损伤、关节炎、结直肠炎、肝炎、脂肪肝或慢性炎症性疾病。
6.根据权利要求5所述的应用，其特征在于，所述慢性炎症性疾病包括糖尿病并发症、动脉粥样硬化、肥胖并发症或高血压并发症；所述糖尿病并发症包括糖尿病肾病或糖尿病心肌病。
7.根据权利要求2所述的应用，其特征在于，所述的乙烷-1,2-双(3-芳基丙烯酸酯)类化合物为如下结构化合物：
8.根据权利要求2或7所述的应用，其特征在于，所述的抗炎药物用于缓解或治疗急性肺损伤。
9.一种用于治疗炎症的药物组合物，其特征在于，含有治疗有效量的权利要求1所述的乙烷-1,2-双(3-芳基丙烯酸酯)类化合物或其可药用盐和药用辅料。
10.根据权利要求9所述的药物组合物，其特征在于，所述的乙烷-1,2-双(3-芳基丙烯酸酯)类化合物或其可药用盐作为唯一的活性成分；
所述药物组合物的制剂形式选自注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂和纳米制剂。
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