CN110963988B - 一种可作为gpr35受体激动剂的香豆素衍生物、制备方法及其应用 - Google Patents
一种可作为gpr35受体激动剂的香豆素衍生物、制备方法及其应用 Download PDFInfo
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Classifications
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
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Abstract
本发明提供了一种可作为GPR35受体激动剂的香豆素衍生物、制备方法及其应用。通过将化合物作用于人源GPR35受体，测试了该系列化合物在人源GPR35受体上的活性。通过将其中一个化合物作用于小鼠，测试了其炎症性肠病的活性，确定了其具有治疗炎症性肠病的潜力。以上结果证明该系列化合物具有一定的药物开发前景。
Description
技术领域
本发明属于医药技术领域，尤其涉及一种可作为GPR35受体激动剂的香豆素衍生物、制备方法及其应用。
背景技术
G蛋白偶联受体（GPCR）是一类在药物研发历史上最成功的药物受体，在现代临床所用的药物中有30-40%的药物都是以G蛋白偶联受体作为靶点（Drews, J. Drugdiscovery: a historical perspective. Science, 2000, 287, 1960-1964）。在世界最畅销的100个药物中存在若干GPCR配体。然而，在所有G蛋白偶联受体家族中，仅仅有59个受体作为药物靶点被开发出来。因此，此类靶点在药物研发中具有巨大潜力（Sams-Dodd, F.Target-based drug discovery: is something wrong；Drug Discov. Today. 2005, 10,139-147.）。
G蛋白偶联受体35（GPR35）是一个于1998年首次发现的孤儿受体(O’Dowd, B.F.,Tonai-Kachi, H., and Ichikawa, K. GPR35 is a functional receptor in ratdorsal root ganglion neurons. Biochem. Biophys. Res. Commun. 2008, 365, 344-348.)，到目前为止的研究表明，该受体与许多疾病存在关联。然而，由于缺乏合适的药理学工具以及内源性配体的缺失制约了对该受体的生理学研究。尽管有一些内源性分子比如犬尿酸可以激活GPR35受体，但是由于它们的活性普遍不高，因而不能认为是其内源性的配体。因此，寻找其高效配体有助于研究该受体在体内的生理学意义。
现代药理学研究表明GPR35可能参与多种疾病的治疗，比如癌症、炎症、冠状动脉疾病、过敏、疼痛、哮喘及高血压。而在已经上市的药物中，比如抗哮喘类药物色甘酸钠以及敏喘宁(Taniguchi, Y., Tonai-Kachi, H., and Shinjo, K. Zaprinast, a well-knowncyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is anagonist for GPR35. FEBS Lett. 2006, 580, 5003-5008.)，已经被证实是GPR35受体的激动剂。这些发现提示我们GPR35受体具有成为成药受体的前景。开发新型高效的GPR35受体激动剂具有重要意义。
香豆素类化合物是一类广泛存在于自然接种的一种内酯类化合物，在芸香科和伞形科植物中存在最多，其中抗凝血药物双香豆素已经被证实是GPR35受体激动剂。
发明内容
针对以上不足，本发明的第一个目的是提供一种可作为GPR35受体激动剂的香豆素衍生物，包括其药学上可接受的盐、溶剂化物、水合物或晶型，其结构通式如下：
其中，
结构中的结构中的R为取代或未取代的芳基或杂环芳基，包括苯基、噻吩基、呋喃基、吡啶基或萘基。
进一步地，R的所属基团中，芳基或杂环芳基被至少一个取代基：-H、-C1-4烷基、-OC1-4烷氧基、-CN、卤素、-CF3、-NO2、-OH在任意位取代。
优选地，本发明中具体衍生物包括：
（1）7-羟基-2-氧代-6-苯基-2H-苯并吡喃-3-羧酸
（2）7-羟基-2-氧代-6-(邻甲苯基)-2H-苯并吡喃-3-羧酸
（3）7-羟基-2-氧代-6-(间甲苯基)-2H-苯并吡喃-3-羧酸
（4）7-羟基-2-氧代-6-(对甲苯基)-2H-苯并吡喃-3-羧酸
（5）7-羟基-2-氧代-6-(2-甲氧基苯基)-2H-苯并吡喃-3-羧酸
（6）7-羟基-2-氧代-6-(3-甲氧基苯基)-2H-苯并吡喃-3-羧酸
（7）7-羟基-2-氧代-6-(4-甲氧基苯基)-2H-苯并吡喃-3-羧酸
（8）7-羟基-2-氧代-6-(2-氟苯基)-2H-苯并吡喃-3-羧酸
（9）7-羟基-2-氧代-6-(3-氟苯基)-2H-苯并吡喃-3-羧酸
（10）7-羟基-2-氧代-6-(4-氟苯基)-2H-苯并吡喃-3-羧酸
（11）6-(4-乙基苯基)-7-羟基-2-氧代-2H-苯并吡喃-3-羧酸
（12）7-羟基-2-氧代-6-(4-异丙基苯基)-2H-苯并吡喃-3-羧酸
（13）6-(4-乙氧基苯基)-7-羟基-2-氧代-2H-色酮-3-羧酸
（14）7-羟基-6-(萘-2-基)-2-氧代-2H-苯并吡喃-3-羧酸
（15）7-羟基-2-氧代-6-(噻吩-2-基)-2H-苯并吡喃-3-羧酸
以及上述衍生物在药学上可接受的盐、溶剂化物、水合物或各种晶型。
进一步地，上述所示衍生物在药学上可接受的盐，尤其是锂盐、钠盐、钾盐、钙盐、镁盐、铵盐。
本发明第二个目的是提供一种可作为GPR35受体激动剂的香豆素衍生物的制备方法，可通过图2反应路线所述的步骤制备。
反应条件：(a) Br2, AcOH, rt, 1 h. (b) Piperidine, 80 oC, 6 h. (c)MOMCl, Et3N, DCM, rt, 3 h. (d) Arylboronic acids, PdCl2(Pph3)2, K2CO3, dioxane: H2O = 5 : 1, 80 oC, overnight. (e) HCl (2 M), 80 oC, 2 h.
反应路线中涉及以下步骤：
a）将起始原料1.0当量的1a溶解在20 mL的醋酸中，然后向溶液中逐滴滴加1.2当量的溴素（以适量醋酸溶解）。滴加完毕后在常温下继续反应1小时，反应完毕后向反应液中加入过量冰水，待沉淀完全析出后滤出沉淀并以乙酸乙酯溶解沉淀。最后向溶液中加入适量硅胶并旋干溶剂，过硅胶柱，以二氯甲烷：石油醚为1:1做为流动相过柱即可获得纯品1b。
b）将1.0当量的1b以及2.0当量的丙二酸二乙酯加入到10 mL的乙醇中并搅拌均匀。在常温下向溶液中加入催化量的哌啶，并将体系温度升高至80℃反应6h。反应完毕后待溶液充分冷却后，向反应液中加入过量稀盐酸（2M），然后滤出析出沉淀并以适量甲醇洗涤滤出的固体2次即可获得纯品1c。
c）将1.0当量的1c加入到20 mL的二氯甲烷中，在常温搅拌条件下继续加入1.2当量的三乙胺。待溶液澄清后，向溶液中逐滴滴加1.5当量的氯甲基甲醚，并在常温下继续反应3h。反应完毕后，向溶液中加入过量稀盐酸萃取。分出有机层并以无水硫酸钠干燥溶液，然后向溶液中加入适量硅胶，旋干并以纯二氯甲烷做为流动相过硅胶柱即可获得纯品1d。
d，e）将原料1d，芳基硼酸衍生物，碳酸钾以及双三苯基膦二氯化钯以1:1.5:2:0.05的投料比例在常温下加入到经过除氧的二氧六环与水（4:1~7:1）的混合溶剂中。在氮气保护下加热反应过夜（70℃~100℃）。反应完毕后，向溶液中加入过量稀盐酸酸化溶液并保持70℃~100℃继续反应1~3h。反应完毕后，以适量乙酸乙酯多次萃取溶液，合并有机相并以无水硫酸钠干燥溶液。旋干溶液，然后以适量甲醇洗涤所获得的固体2次即可获得通式所示的香豆素衍生物。
本发明的第三个目的是提供一种可作为GPR35受体激动剂的香豆素衍生物在制备治疗、预防及缓解由GPR35受体活性配体调节的疾病的药物中的应用，所述衍生物包括其药学上可接受的盐、溶剂化物、水合物或各种晶型，所属疾病包括可能由GPR35受体激动剂及部分激动剂调节的癌症、炎症、冠状动脉疾病、过敏、疼痛、炎症性肠病、哮喘及高血压。所述药物为GPR35受体的激动剂。
本发明的第四个目的是提供一种可作为GPR35受体激动剂的香豆素衍生物，包括其药学上可接受的盐、溶剂化物、水合物或各种晶型的药物组合物，并可进一步包含赋形剂、稀释剂及载体。本发明的化合物可以以未溶化的和与药学上可接受的溶剂溶剂化的形式存在。通常认为溶剂化的形式等同于未溶剂化的形式。本发明的药物组合物可包括一种或多种本发明的化合物，典型的配方是通过混合本发明的化合物及其药学上可接受盐、溶剂化物或水合物与载体、赋形剂或稀释剂进行制备。常用载体、赋形剂或稀释剂包括如碳水化合物、纤维素及其衍生物、明胶、油、多元醇、水等物质。所述药物的剂型选用固体制剂或液体制剂，具体的为片剂、胶囊、粉末、颗粒、溶液、糖浆、悬浮液或气雾剂。
本发明的第五个目的是提供了调节GPR35受体活性的方法，该方法包括上述化合物与GPR35受体接触，该化合物是GPR35受体的激动剂。
本发明提供了一种合成香豆素类衍生物的合成方法，合成了一系列以香豆素为母核的香豆素类衍生物。通过将化合物作用于人源GPR35受体，测试了该系列化合物在人源GPR35受体上的活性。通过将其中一个化合物作用于小鼠，测试了其炎症性肠病的活性，确定了其具有治疗炎症性肠病的潜力。以上结果证明该系列化合物具有一定的药物开发前景。
附图说明
图1：本发明衍生物的结构通式图；
图2：本发明衍生物制备方法反应路线图；
图3：3A为化合物12的剂量依赖性DMR信号图；3B为该化合物的剂量依赖性曲线。
图4：化合物6在小鼠体内药理活性评价
具体实施方式
实施例1：
本发明衍生物的通式所示化合物可以通过图2反应路线所述的步骤制备。
反应条件：(a) Br2, AcOH, rt, 1 h. (b) Piperidine, 80 oC, 6 h. (c)MOMCl, Et3N, DCM, rt, 3 h. (d) Arylboronic acids, PdCl2(Pph3)2, K2CO3, dioxane: H2O = 5 : 1, 80 oC, overnight. (e) HCl (2 M), 80 oC, 2 h.
反应路线中涉及以下步骤：
a）将起始原料1.0当量的1a溶解在20 mL的醋酸中，然后向溶液中逐滴滴加1.2当量的溴素（以适量醋酸溶解）。滴加完毕后在常温下继续反应1小时，反应完毕后向反应液中加入过量冰水，待沉淀完全析出后滤出沉淀并以乙酸乙酯溶解沉淀。最后向溶液中加入适量硅胶并旋干溶剂，过硅胶柱，以二氯甲烷：石油醚为1:1做为流动相过柱即可获得纯品1b。
b）将1.0当量的1b以及2.0当量的丙二酸二乙酯加入到10 mL的乙醇中并搅拌均匀。在常温下向溶液中加入催化量的哌啶，并将体系温度升高至80℃反应6h。反应完毕后待溶液充分冷却后，向反应液中加入过量稀盐酸（2M），然后滤出析出沉淀并以适量甲醇洗涤滤出的固体2次即可获得纯品1c。
c）将1.0当量的1c加入到20 mL的二氯甲烷中，在常温搅拌条件下继续加入1.2当量的三乙胺。待溶液澄清后，向溶液中逐滴滴加1.5当量的氯甲基甲醚，并在常温下继续反应3h。反应完毕后，向溶液中加入过量稀盐酸萃取。分出有机层并以无水硫酸钠干燥溶液，然后向溶液中加入适量硅胶，旋干并以纯二氯甲烷做为流动相过硅胶柱即可获得纯品1d。
d，e）将1.0当量的1d，1.5当量的芳基硼酸衍生物，2.0当量的碳酸钾以及0.05当量的双三苯基膦二氯化钯在常温下加入到经过除氧的二氧六环与水（5：1）的混合溶剂中。在氮气保护下80℃反应过夜。反应完毕后，向溶液中加入过量稀盐酸酸化溶液并保持80℃继续反应2h。反应完毕后，以适量乙酸乙酯多次萃取溶液，合并有机相并以无水硫酸钠干燥溶液。旋干溶液，然后以适量甲醇洗涤所获得的固体2次即可获得通式所示的香豆素衍生物。
实施例2：
本发明中具体化合物制备方法如下：
（1）7-羟基-2-氧代-6-苯基-2H-苯并吡喃-3-羧酸.
采用实施例1的合成步骤，产物为黄色固体，产率80%。1H NMR (600 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.85 (s, 1H), 7.57 – 7.53 (m, 2H), 7.44 (t, J = 7.7 Hz,2H), 7.36 (t, J = 7.4 Hz, 1H), 6.90 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ164.73, 161.47, 157.91, 156.38, 149.92, 137.02, 132.57, 129.65, 128.61,127.73, 127.26, 113.36, 111.38, 102.50.
（2）7-羟基-2-氧代-6-(邻甲苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率76%。1H NMR (600 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.65 (s, 1H), 7.31 – 7.26 (m, 2H), 7.25 – 7.21 (m, 1H),7.14 (d, J = 7.3 Hz, 1H), 6.88 (s, 1H), 2.11 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 163.65, 160.51, 156.89, 155.44, 148.81, 136.14, 135.76, 131.70, 129.44,129.01, 127.02, 126.75, 124.96, 112.20, 109.95, 100.97, 19.03.
（3）7-羟基-2-氧代-6-(间甲苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率71%。1H NMR (600 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.83 (s, 1H), 7.32 (dt, J = 10.8, 7.7 Hz, 3H), 7.18 (d, J= 3.5 Hz, 1H), 6.89 (s, 1H), 2.36 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ163.64, 160.43, 156.84, 155.24, 148.83, 136.53, 135.89, 131.46, 129.14,127.40, 127.27, 126.33, 125.73, 112.22, 110.26, 101.38, 20.50.
（4）7-羟基-2-氧代-6-(对甲苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率71%。1H NMR (600 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.83 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0Hz, 2H), 6.88 (s, 1H), 2.35 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 164.73,161.48, 157.92, 156.24, 149.98, 136.99, 134.05, 132.34, 129.49, 129.19,127.21, 113.29, 111.37, 102.45, 21.25.
（5）7-羟基-2-氧代-6-(2-甲氧基苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率82%。1H NMR (600 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.66 (s, 1H), 7.39 – 7.34 (m, 1H), 7.17 (dd, J = 7.4, 1.7Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 7.00 (td, J = 7.4, 0.8 Hz, 1H), 6.84 (s,1H), 3.71 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 163.69, 161.09, 156.99,156.21, 155.40, 148.89, 132.13, 130.48, 128.54, 125.01, 124.02, 119.51,111.88, 110.63, 109.73, 100.87, 54.75.
（6）7-羟基-2-氧代-6-(3-甲氧基苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率78%。 1H NMR (600 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.87 (d, J = 4.8 Hz, 1H), 7.36 (dd, J = 15.0, 7.1 Hz,1H), 7.12 (d, J = 7.8 Hz, 1H), 7.10 – 7.08 (m, 1H), 6.95 – 6.92 (m, 1H), 6.89(s, 1H), 3.79 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 163.63, 160.33, 158.35,156.76, 155.29, 148.89, 137.21, 131.55, 128.55, 125.93, 120.92, 114.32,112.31, 112.05, 110.26, 101.42, 54.46.
（7）7-羟基-2-氧代-6-(4-甲氧基苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率82%。1H NMR (600 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.81 (s, 1H), 7.51 – 7.45 (m, 2H), 7.01 (t, J = 10.8 Hz,2H), 6.88 (s, 1H), 3.80 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 164.73, 161.43,159.02, 157.99, 156.07, 149.99, 132.10, 130.76, 129.16, 126.96, 114.05,113.23, 111.37, 102.42, 55.59.
（8）7-羟基-2-氧代-6-(2-氟苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率64%。1H NMR (600 MHz, DMSO-d6) δ 8.73 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H), 7.47 – 7.43 (m, 1H), 7.40 (td,J = 7.5, 1.5 Hz, 1H), 7.28 (t, J = 8.1 Hz, 2H), 6.90 (s, 1H). 13C NMR (151MHz, DMSO-d6) δ 164.68 (s), 161.71 (s), 159.96 (d, J = 245.9 Hz), 157.77 (s),156.91 (s), 149.75 (s), 133.30 (s), 132.40 (d, J = 3.3 Hz), 130.33 (d, J =8.1 Hz), 124.82 (d, J = 7.8 Hz), 124.75 (d, J = 4.8 Hz), 121.96 (s), 115.92(d, J = 22.0 Hz), 113.56 (s), 111.09 (s), 102.19 (s).
（9）7-羟基-2-氧代-6-(3-氟苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率75%。1H NMR (600 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.26 (s, 1H), 7.26 (s, 1H), 5.46 (s, 2H), 4.29 (q, J =7.1 Hz, 2H), 3.44 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 164.66 (s), 162.36 (d, J = 242.8 Hz), 161.30 (s), 157.71 (s), 156.60(s), 149.81 (s), 139.29 (d, J = 8.3 Hz), 132.75 (s), 130.56 (d, J = 8.6 Hz),125.75 (d, J = 2.2 Hz), 125.70 (s), 116.35 (d, J = 22.0 Hz), 114.53 (d, J =20.6 Hz), 113.63 (s), 111.40 (s), 102.61 (s).
（10）7-羟基-2-氧代-6-(4-氟苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率79%。1H NMR (600 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.85 (s, 1H), 7.61 – 7.55 (m, 2H), 7.28 (dd, J = 12.4,5.4 Hz, 2H), 6.89 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 164.70 (s), 161.96(d, J = 244.62 Hz), 161.42 (s), 157.87 (s), 156.42 (s), 149.83 (s), 133.32(d, J = 3.1 Hz), 132.51 (s), 131.62 (d, J = 8.2 Hz), 126.17 (s), 115.46 (d, J= 21.3 Hz), 113.39 (s), 111.35 (s), 102.52 (s).
（11）6-(4-乙基苯基)-7-羟基-2-氧代-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率83%。1H NMR (600 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.83 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1Hz, 2H), 6.89 (s, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 164.74, 161.52, 157.93, 156.25, 149.97, 143.32,134.33, 132.37, 129.57, 128.02, 127.25, 113.27, 111.37, 102.45, 28.39, 16.17.
（12）7-羟基-2-氧代-6-(4-异丙基苯基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率83%。1H NMR (600 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.83 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.2Hz, 2H), 6.89 (s, 1H), 2.93 (dp, J = 13.7, 6.8 Hz, 2H), 1.24 (d, J = 6.9 Hz,6H). 13C NMR (151 MHz, DMSO-d6) δ 164.74, 161.51, 157.92, 156.26, 149.97,147.92, 134.48, 132.39, 129.59, 127.26, 126.54, 113.27, 111.37, 102.44,33.68, 24.37.
（13）6-(4-乙氧基苯基)-7-羟基-2-氧代-2H-色酮-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率77%。1H NMR (600 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.81 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4Hz, 2H), 6.88 (s, 1H), 4.06 (q, J = 6.8 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H).13C NMR (151 MHz, DMSO-d6) δ 164.73, 161.43, 158.29, 158.00, 156.06, 149.99,132.08, 130.76, 129.02, 126.98, 114.50, 113.23, 111.38, 102.43, 63.49, 15.15.
（14）7-羟基-6-(萘-2-基)-2-氧代-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率77%。1H NMR (600 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.98 (t, J = 8.7 Hz, 2H), 7.80 (s, 1H), 7.58 (dd, J =8.1, 7.2 Hz, 1H), 7.55 – 7.52 (m, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.48 – 7.44(m, 1H), 7.41 (dd, J = 6.9, 0.8 Hz, 1H), 6.97 (s, 1H). 13C NMR (151 MHz,DMSO-d6) δ 164.75, 162.07, 157.90, 156.82, 149.92, 135.41, 133.58, 133.53,131.98, 128.62, 128.43, 128.05, 126.59, 126.39, 126.34, 126.26, 125.97,113.44, 111.19, 102.19.
（15）7-羟基-2-氧代-6-(噻吩-2-基)-2H-苯并吡喃-3-羧酸
采用实施例1的合成步骤，产物为黄色固体，产率68%。1H NMR (600 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.29 (s, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.64 (d, J = 5.1Hz, 1H), 7.21 (dd, J = 6.3, 2.3 Hz, 1H), 6.95 (s, 1H). 13C NMR (151 MHz,DMSO-d6) δ 163.64, 160.43, 156.84, 155.24, 148.83, 136.53, 135.89, 131.46,129.14, 127.40, 127.27, 126.33, 125.73, 112.22, 110.26, 101.38, 20.50.
实施例3：
药理学表征——DMR筛选模型
材料 HT-29细胞购于中国科学院上海细胞库；敏喘宁购于Sigma公司，ML145购于Tocris公司。检测平台为康宁第三代Epic®成像仪，检测的信号为细胞动态质量重置（DMR）引起的波长位移。
将处于对数生长期的HT-29细胞接种于384孔板的细胞板的不同孔中，每孔的接种体积为40μL，每孔接种的细胞数目分别为3.2×104个，将接种好的细胞板放置于细胞培养箱中培养20-22h，至细胞融合度达到95%左右。
首先是激动分析，以化合物12为例，将不同剂量的化合物12作用于HT-29细胞，如图3A给出了化合物12的剂量依赖性DMR信号图。
然后使用脱敏分析的方法验证这些化合物作用于GPR35受体的特异性。HT-29细胞经过不同浓度梯度的化合物12预处理1h后，再加入1μM的敏喘宁继续监测1h。图3B给出了化合物12的剂量依赖性脱敏曲线。
最后使用拮抗分析的方法验证这些化合物作用于GPR35的特异性。HT-29细胞经过不同浓度的ML-145 预处理5min后，加入被测化合物，浓度在EC80至EC100之间。图3B给出了2.07 μM的化合12可以被不同浓度的ML145抑制，且呈现出剂量依赖性。
其它化合物的测试结果列于表1中。以上三种实验可以证明这类香豆素类化合物均是特异性的GPR35激动剂。
通过观察活性测试结果可以发现，当R基为苯环时，当苯环上的取代基相同，对位取代所表现出的活性总体上要优于邻位和间位。当R基为噻吩环时，由于取代基的空间体积与苯环相近，因此所表现出的活性也相近。而对于空间体积较大的萘基，活性则明显降低。
表1. 通式所示化合物在DMR筛选模型中的活性数据
在本实施例中，术语“烷基”表示1到4个碳原子的直链或支链烷基-C1-4。该烃基可以选自甲基、乙基、丙基、丁基，及其异构体。例如丙基包括正丙基和异丙基，丁基包括异丁基、仲丁基和叔丁基等。
术语“卤素”表示-F、-Cl、-Br和-I。
术语“烷氧基”表示具有1到4个碳原子，通过氧原子键连的直链或支链烷基-O-C1-4。下列为可提及的实例：甲氧基、乙氧基、丙氧基、丁氧基，及其异构体。
实施例4：
一种可作为GPR35受体激动剂的香豆素衍生物在制备治疗、预防及缓解由GPR35受体活性配体调节的疾病的药物中的应用。
确定了它们在GPR35上的活性后，选出了其中活性最好的化合物6用于在炎症性肠病小鼠模型上的药理活性研究，结果如图4所示。测试结果表明，通过连续7天给药，给药量为1mg/Kg，化合物6能够增加结肠长度，缓解脾肿，并且能够使体重增加，与阳性对照药地塞米松（DEX）的效果基本相当。该结果证明了这类化合物具有一定的成药前景。
上述仅为本发明专利的优选实施例，并不对本发明专利起到任何限制作用。任何所属技术领域的技术人员，在不脱离本发明专利的技术方案的范围内，对本发明专利揭露的技术方案和技术内容做任何形式的等同替换或修改等变动，均属未脱离本发明专利的技术方案的内容，仍属于本发明专利的保护范围之内。
Claims (1)
1.一种可作为GPR35受体激动剂的香豆素衍生物的制备方法，其特征在于，反应路线如下：
反应路线中涉及以下步骤：
a）将起始原料1.0当量的1a溶解在20 mL的醋酸中，然后向溶液中逐滴滴加1.2当量的溴素，以适量醋酸溶解，滴加完毕后在常温下继续反应1小时，反应完毕后向反应液中加入过量冰水，待沉淀完全析出后滤出沉淀并以乙酸乙酯溶解沉淀；最后向溶液中加入适量硅胶并旋干溶剂，过硅胶柱，以二氯甲烷：石油醚为1:1做为流动相过柱即可获得纯品1b；
b）将1.0当量的1b以及2.0当量的丙二酸二乙酯加入到10 mL的乙醇中并搅拌均匀，在常温下向溶液中加入催化量的哌啶，并将体系温度升高至80℃反应6h；反应完毕后待溶液充分冷却后，向反应液中加入过量稀盐酸2M，然后滤出析出沉淀并以适量甲醇洗涤滤出的固体2次即可获得纯品1c；
c）将1.0当量的1c加入到20 mL的二氯甲烷中，在常温搅拌条件下继续加入1.2当量的三乙胺，待溶液澄清后，向溶液中逐滴滴加1.5当量的氯甲基甲醚，并在常温下继续反应3h；反应完毕后，向溶液中加入过量稀盐酸萃取；分出有机层并以无水硫酸钠干燥溶液，然后向溶液中加入适量硅胶，旋干并以纯二氯甲烷做为流动相过硅胶柱即可获得纯品1d；
e）将原料1d，芳基硼酸衍生物，碳酸钾以及双三苯基膦二氯化钯以1:1.5:2:0.05的投料比例在常温下加入到经过除氧的二氧六环与水，二氧六环与水比例为4:1~7:1的混合溶剂中，在氮气保护下加热反应过夜，加热温度为70℃~100℃，反应完毕后，向溶液中加入过量稀盐酸酸化溶液并保持70℃~100℃继续反应1~3h，反应完毕后，以适量乙酸乙酯多次萃取溶液，合并有机相并以无水硫酸钠干燥溶液，旋干溶液，然后以适量甲醇洗涤所获得的固体2次即可获得通式A所示的香豆素衍生物，所述R为取代或未取代的芳基。
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| CN1955175A (zh) * | 2004-10-28 | 2007-05-02 | 中国医学科学院药物研究所 | 香豆素衍生物及其制法和其药物组合物与用途 |
| WO2007124617A1 (fr) * | 2006-04-28 | 2007-11-08 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | Dérivés de coumarine, leurs procédés de préparation, compositions pharmaceutiques et utilisations |
| CN108069929A (zh) * | 2016-11-18 | 2018-05-25 | 中国科学院大连化学物理研究所 | 3-取代香豆素类衍生物及应用和gpr35受体的激动剂 |
| CN108290841A (zh) * | 2015-12-03 | 2018-07-17 | 国立大学法人冈山大学 | 具有荧光性的类视黄醇x受体结合性分子及其用途 |
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| WO2007124617A1 (fr) * | 2006-04-28 | 2007-11-08 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | Dérivés de coumarine, leurs procédés de préparation, compositions pharmaceutiques et utilisations |
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