CN114907440A - 一种新型芳香基吡唑类齐墩果酸衍生物及其用途 - Google Patents
一种新型芳香基吡唑类齐墩果酸衍生物及其用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域，具体涉及一种新型芳香基吡唑类齐墩果酸衍生物，其结构通式如下所示：
Description
技术领域
本发明涉及一种α-葡萄糖苷酶抑制剂及其应用，芳香基吡唑类齐墩果酸衍生物作为新型α-葡萄糖苷酶抑制剂的应用。
背景技术
糖尿病（diabetes mellitus, DM）是一种由高血糖引起且普遍存在的疾病，正在以惊人的速度上升。主要是由于糖、脂肪、蛋白质类物质代谢紊乱造成，以持续性血糖升高和尿糖为特征，并伴随着多系统、多脏器并发症的发生，如心血管疾病，肾脏损伤和神经病变。现阶段治疗糖尿病的途径之一是通过服用抑制葡萄糖摄入的药物，从而降低体内糖分的吸收。而人体对葡萄糖的摄入主要依赖于碳水化合物消化酶，其大多位于肠道边缘，主要功能是将人体摄入的多糖分解成易于被吸收的单糖。其中，α-葡萄糖苷酶（α-glucosidase）是一种关键的糖苷水解酶，参与了人体对碳水化合物、淀粉、糖蛋白的消化和吸收，与多种代谢紊乱的疾病相关，其负责裂解二糖和低聚糖中的α-吡喃葡萄糖苷键形成单糖，最终调节2型糖尿病患者的血糖供应和餐后高血糖，因此，控制与2型糖尿病相关的高血糖的一种有效治疗方法是靶向α-葡萄糖苷酶。
目前，已发现一些α-葡萄糖苷酶抑制剂，如阿卡波糖、伏格列波糖和米格列醇。这些α-葡萄糖苷酶抑制剂能够阻断碳水化合物的水解，从而降低餐后血糖水平。然而，持续服用这些药物可能会导致严重的副作用，如腹泻、身体疼痛和胃肠道疾病。因而，研发出新型的α-葡萄糖苷酶抑制剂已成为近年来新药研发的热点。
发明内容
本发明人经过将齐墩果酸的羟基在三氧化铬作用下氧化形成羰基，再用甲酸乙酯对羰基的α位进行醛基取代，最后与不同的苯肼化合物进行反应，形成一类结构类似、具备α-葡萄糖苷酶抑制活性的通式I所示的新型芳香基吡唑类齐墩果酸衍生物，由此可能对糖尿病具有治疗作用，从而在制备治疗糖尿病药物领域具有潜在的用途。
本发明的第一方面，提供了一种如通式I所示的化合物，或其药学上可接受的盐、水合物、溶剂化物或前药。
该类化合物的结构如通式I所示
其中R为不同的取代基，包括氢基、4-三氟甲基、4-甲基、4-氟基、4-氯基和4-溴基。
上述通式I所示的芳香基吡唑类齐墩果酸衍生物的制备方法，它包括以下步骤：
a）将式1化合物与三氧化铬反应得到式2化合物，其中，反应溶剂为N,N-二甲基甲酰胺、丙酮、二甲基亚砜、1,4-二氧六环、四氢呋喃、甲醇、乙醇、二氯甲烷、异丙醇、吡啶及水中至少一种；该反应温度为 0℃～140℃；反应时间为 1～8h。
b）将式2化合物与甲酸乙酯反应得到式3化合物，其中，反应溶剂为无水四氢呋喃；该反应温度为 0℃～140℃；反应时间为 8～24h。
c）将式3化合物与对应苯肼化合物反应，其中，反应溶剂为无水乙醇；该反应温度为 0℃～140℃；反应时间为 8～24h。所用的苯肼化合物包括苯肼、4-三氟甲基苯肼、4-甲基苯肼、4-氟苯肼、4-氯苯肼和4-溴苯肼。
本发明的第二方面，一种药物组合物，所述药物组合物包含第一方面所述的式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药和药学上可接受的载体。
本发明的第三方面，提供了第一方面所述的式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药用途，用于：
(i)制备α-葡萄糖苷酶抑制剂；
(ii)制备预防和/或治疗糖尿病相关的疾病的药物。
药学上可接受的载体必须可与配方的其他成分兼容，且不会对其接受者有害，一般为适当载剂、稀释剂及赋形剂是为本领域技术人员所公知且包括诸如碳水化合物、蜡、水溶性及/或泡胀性聚合物、亲水性或疏水性材料、明胶、油、溶剂、 水及类似物。所使用的特定载剂、稀释剂或赋形剂将取决于给予本发明化合物的方式及目的。溶剂通常是基于本领域技术人员所认为安全给予哺乳动物的溶剂(GRAS)而选择。通常，安全溶剂为无毒水性溶剂(诸如水)及其他可溶于水或与水可混溶的无毒溶剂。适当水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400或PEG300)等及其混合物。还可包括一或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、不透明剂、助滑剂、加工助剂、着色剂、甜味剂、香料、调味剂及其他提供药物(即本发明化合物或其医学组合物)精美外观或有助于制造药物产品(即用于制备药剂)的已知添加剂。
有益效果
本发明的化合物，能够抑制α-葡萄糖苷酶，可用于制备预防和/或治疗糖尿病等相关疾病的药物。
具体实施方式
下面对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
本发明人经过将齐墩果酸的羟基在三氧化铬作用下氧化形成羰基，再用甲酸乙酯对羰基的α位进行醛基取代，最后与不同的苯肼化合物进行反应，形成一类结构类似、具备α-葡萄糖苷酶抑制活性的通式I所示的新型芳香基吡唑类齐墩果酸衍生物，其能够有效抑制α-葡萄糖苷酶活性。在此基础上，完成了本发明。
下面结合具体实施例对本发明做进一步的详细说明。这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1 式2化合物的制备
将齐墩果酸(1 mmol)溶解于甲醇中，缓慢向反应液中滴加琼斯试剂(20 mmol)，置于微波炉中。参数设置为80℃、100W、20min。反应结束后，冷却至室温，用水、碳酸氢钠水溶液、饱和食盐水多次萃取，保留有机相并用无水硫酸镁干燥2h。最后经柱色谱分离得到式2化合物。
式2化合物，白色固体，收率43.1%。1H NMR (600 MHz, Chloroform-d) δ 5.30(s, 1H), 2.84 (dd, J = 14.0, 4.6 Hz, 1H), 2.54 (ddd, J = 15.8, 11.2, 7.3 Hz,1H), 2.40 – 2.33 (m, 1H), 1.14 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.03 (s,3H), 0.93 (s, 3H), 0.90 (s, 3H), 0.81 (s, 3H)。
实施例2 式3化合物的制备
将式2(1 mmol)和NaH(20 mmol)溶解于无水四氢呋喃中，缓慢向反应液中滴加甲酸乙酯(20 mmol)，反应液在65℃下搅拌过夜，次日反应完成后加水熄灭反应，用1 M盐酸调节反应溶液的酸度。然后用大量乙酸乙酯稀释，依次用水、饱和碳酸氢钠溶液和饱和盐水洗涤，然后干燥浓缩。最后用硅胶柱层析进行纯化。
式3化合物，白色固体，收率87.9 %。1H NMR (600 MHz, Chloroform-d) δ 14.90(d, J = 3.0 Hz, 1H), 8.58 (d, J = 2.8 Hz, 1H), 5.33 (s, 1H), 2.85 (dd, J =13.9, 4.6 Hz, 1H), 2.28 (d, J = 14.4 Hz, 1H), 1.19 (s, 3H), 1.15 (s, 3H),1.10 (s, 3H), 0.94 (s, 3H), 0.91 (d, J = 5.2 Hz, 6H), 0.82 (s, 3H)。
实施例3 通式I化合物的制备
式3化合物(1 mmol)溶解于无水乙醇中，缓慢向反应液中滴加苯肼化合物(1.2mmol)，反应液回流搅拌2.5h。然后用大量乙酸乙酯稀释，依次用水、饱和碳酸氢钠溶液和饱和盐水洗涤，然后干燥浓缩。最后用硅胶柱层析进行纯化得到相应的通式I化合物。化合物编号、具体结构式以及原料如下表1所示。
其中苯肼化合物，包括苯肼、4-三氟甲基苯肼、4-甲基苯肼、4-氟苯肼、4-氯苯肼和4-溴苯肼。
表1 通式I化合物具体结构式、所用原料
式A-1化合物，白色固体，产率41.5％。1H NMR (600 MHz, DMSO-d 6) δ 12.06 (s,1H), 7.52 – 7.47 (m, 3H), 7.36 (dd, J = 7.6, 2.1 Hz, 2H), 7.29 (s, 1H), 5.25(t, J = 3.7 Hz, 1H), 2.78 (dd, J = 13.9, 4.6 Hz, 1H), 2.54 (d, J = 14.9 Hz,1H), 2.07 (d, J = 15.0 Hz, 1H), 1.13 (s, 3H), 0.98 (s, 3H), 0.94 (s, 3H),0.89 (d, J = 1.9 Hz, 6H), 0.79 (s, 3H). 13C NMR (151 MHz, DMSO-d 6) δ 178.61 ,145.38 , 143.64 , 142.18 , 137.66 , 129.08 , 129.00 , 128.52 , 121.63 ,113.35 , 54.06 , 45.77 , 45.71 , 45.57 , 34.17 , 33.36 , 32.83 , 32.07 ,31.83 , 30.43 , 29.19 , 27.30 , 25.36 , 23.35 , 22.84 , 22.68 , 22.16 , 18.76, 16.57 , 15.06。
式A-2化合物，白色固体，产率38.2％。1H NMR (600 MHz, Chloroform-d) δ 7.71(d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.37 (s, 1H), 5.36 (t, J = 3.7Hz, 1H), 2.86 (dd, J = 13.9, 4.6 Hz, 1H), 2.62 (d, J = 15.0 Hz, 1H), 2.11 (d,J = 15.0 Hz, 1H), 1.16 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.94 (s, 3H),0.93 (s, 3H), 0.91 (s, 3H), 0.82 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ183.59 , 146.75 , 145.53 , 143.55 , 139.06 , 131.34 (d, J = 33.1 Hz), 129.74, 125.91 , 125.88 , 124.74 , 122.93 , 122.73 , 114.89 , 54.66 , 46.77 , 46.58, 45.99 , 41.94 , 41.27 , 39.40 , 38.21 , 36.95 , 34.80 , 33.98 , 33.21 ,32.56 , 32.28 , 30.84 , 29.65 , 27.85 , 25.82 , 23.68 , 23.47 , 23.10 , 22.70, 19.32 , 16.84 , 15.38。
式A-3化合物，淡黄色固体，产率83.7％。1H NMR (600 MHz, DMSO-d 6) δ 12.06(s, 1H), 7.30 – 7.27 (m, 3H), 7.23 (d, J = 8.2 Hz, 2H), 5.25 (s, 1H), 2.38(s, 3H), 1.13 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.89 (d, J = 1.8 Hz, 6H),0.87 (s, 3H), 0.79 (s, 3H). 13C NMR (151 MHz, DMSO-d 6) δ 178.60 , 145.31 ,143.63 , 139.65 , 138.49 , 137.51 , 128.92 , 128.82 , 121.63 , 113.24 , 54.92, 54.07 , 45.75 , 45.69 , 45.57 , 41.50 , 40.95 , 38.82 , 37.68 , 36.43 ,34.16 , 33.36 , 32.83 , 32.07 , 31.82 , 30.42 , 29.18 , 27.30 , 25.36 , 23.34, 22.84 , 22.68 , 22.12 , 20.75 , 18.77 , 16.57 , 15.04。
式A-4化合物，黄色固体，产率54.8％。1H NMR (600 MHz, Chloroform-d) δ 7.38– 7.33 (m, 3H), 7.12 (t, J = 8.2 Hz, 2H), 5.36 (t, J = 3.7 Hz, 1H), 2.89 –2.84 (m, 1H), 2.60 (d, J = 14.9 Hz, 1H), 1.16 (s, 3H), 1.04 (s, 3H), 0.96 (s,3H), 0.94 (s, 3H), 0.91 (s, 6H), 0.81 (s, 3H). 13C NMR (151 MHz, Chloroform-d)δ 183.45 , 163.61 , 161.96 , 146.65 , 143.54 , 138.46 , 131.10 , 131.05 ,122.79 , 115.67 , 115.52 , 114.50 , 54.66 , 53.57 , 46.77 , 46.55 , 45.99 ,41.93 , 41.28 , 39.39 , 38.24 , 36.98 , 34.77 , 33.98 , 33.21 , 32.58 , 32.28, 30.84 , 29.51 , 27.86 , 25.83 , 23.69 , 23.47 , 23.10 , 22.50 , 19.31 ,16.89 , 15.35。
式A-5化合物，淡黄色固体，产率46.6％。1H NMR (600 MHz, Chloroform-d) δ7.42 (d, J = 8.3 Hz, 2H), 7.35 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 5.36 (t, J= 3.7 Hz, 1H), 2.86 (dd, J = 13.8, 4.6 Hz, 1H), 2.60 (d, J = 14.9 Hz, 1H),1.16 (s, 3H), 1.04 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.91 (s, 6H), 0.82(s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 183.13 , 146.66 , 143.54 , 140.88 ,138.65 , 135.16 , 130.58 , 128.91 , 122.78 , 114.63 , 60.56 , 54.66 , 51.03 ,46.75 , 46.55 , 45.99 , 41.94 , 41.30 , 39.39 , 38.23 , 36.96 , 34.78 , 33.98, 33.21 , 32.57 , 32.28 , 31.74 , 30.84 , 29.85 , 29.56 , 27.86 , 25.82 ,23.69 , 23.47 , 23.11 , 22.81 , 22.57 , 19.32 , 16.89 , 15.35 , 14.28。
式A-6化合物，淡色固体，产率39.1％。1H NMR (600 MHz, Chloroform-d) δ 7.57(d, J = 7.6 Hz, 2H), 7.35 (s, 1H), 7.26 (s, 2H), 5.36 (d, J = 3.7 Hz, 1H),2.86 (dd, J = 13.9, 4.5 Hz, 1H), 2.60 (d, J = 14.7 Hz, 1H), 1.16 (s, 3H),1.04 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.91 (s, 6H), 0.81 (s, 3H). 13C NMR(151 MHz, Chloroform-d) δ 183.13 , 146.66 , 143.54 , 140.88 , 138.65 , 135.16, 130.58 , 128.91 , 122.78 , 114.63 , 60.56 , 54.66 , 51.03 , 46.75 , 46.55 ,45.99 , 41.94 , 41.30 , 39.39 , 38.23 , 36.96 , 34.78 , 33.98 , 33.21 , 32.57, 32.28 , 31.74 , 30.84 , 29.85 , 29.56 , 27.86 , 25.82 , 23.69 , 23.47 ,23.11 , 22.81 , 22.57 , 19.32 , 16.89 , 15.35 , 14.28。
实施例4 化合物对α-葡萄糖苷酶的抑制率与抑制活性
α-葡萄糖苷酶购自Sigma，作为底物的对硝基苯基-α-D-葡萄糖苷（PNPG）购自Aladdin，配置缓冲液以及猝灭剂所需要的钠盐、磷酸盐均购自上海麦克林生化科技有限公司。α-葡萄糖苷酶抑制活性测定参考已发表的报道方法进行。96孔板每孔加入99μL的PBS磷酸缓冲液(pH＝6.8)，然后将20mmol的1μL待测化合物溶液或空白对照加入到对应的孔中，随后加入25μL的α-葡萄糖苷酶溶液，置于37℃摇床孵育15min。加入25μL的PNPG溶液， 再置于37℃摇床孵育15min，随后加入50μL的0.2 M碳酸钠溶液，酶标仪测定405nm处的吸光度，计算待测化合物对α-葡萄糖苷酶的抑制率。部分化合物配置出10种不同的梯度浓度进行再一次测定，根据抑制曲线求得化合物的IC50值(抑制酶活力50％时的抑制剂浓度)，实验结果如表2所示。
表2 化合物对α-葡萄糖苷酶抑制率与抑制活性
实验结果表明，上述部分化合物对α-葡萄糖苷酶具有较好的抑制活性。
以上以具体的实施例来举例说明本发明化合物的制备步骤、鉴定过程和α-葡萄糖苷酶抑制活性筛选，但本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (3)
1.一种新型芳香基吡唑类齐墩果酸衍生物，其特征在于，它具有如下通式I所示的结构：
其中，R为不同的取代基，包括氢基、4-三氟甲基、4-甲基、4-氟基、4-氯基和4-溴基。
2.一种权利要求1所述的芳香基吡唑类齐墩果酸衍生物的用途，其特征在于，用于制备抗糖尿病药物。
3.一种用于预防和/或治疗糖尿病的药物，其特征在于，它是以权利要求1中所述的衍生物为活性成分或主要活性成分，辅以药学上可接受的辅料制成。
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