CN114805468A - 一类齐墩果酸类衍生物的制备及其用途 - Google Patents
一类齐墩果酸类衍生物的制备及其用途 Download PDFInfo
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- oleanolic acid
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- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 title claims abstract description 16
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0042—Nitrogen only
- C07J71/0047—Nitrogen only at position 2(3)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物化学领域，具体涉及三种具有抑制α‑葡萄糖苷酶活性的齐墩果酸衍生物，其结构如下所示：
Description
技术领域
本发明涉及一类α-葡萄糖苷酶抑制剂及其应用，齐墩果酸类衍生物作为新型α-葡萄糖苷酶抑制剂的应用。
背景技术
糖尿病（diabetes mellitus, DM）是因胰岛素作用障碍或分泌不足而导致的一种慢性代谢性疾病，主要是由于糖、脂肪、蛋白质类物质代谢紊乱造成，其基本特征是具有较高的血糖水平，并伴随着多系统、多脏器并发症的发生。在全世界糖尿病已和肿瘤、心血管疾病一起成为威胁人类健康的三大疾病。现在糖尿病的患病人数和致死人数在逐年升高，国际糖尿病联合会（International Diabetes Federation IDF）网站的最新统计数据显示，2021年超过5.37亿的成年人(20-79岁)患有糖尿病，并且预计到2030年这一数字将达到6.43亿，到2045年将增加到7.84亿。
近年来研究发现，餐后高血糖是糖尿病的发病过程中最先出现的症状，能够诱发各种并发症，提高糖尿病患者的死亡率。食物中的糖类是血糖的主要来源，而食物中的碳水化合物经过α-葡萄糖苷酶水解生成单糖后才能被吸收。因此，α-葡萄糖苷酶是调节餐后血糖的关键酶，是治疗糖尿病的一个有效靶点。
α-葡萄糖苷酶（α-glucosidase）主要包括麦芽糖酶、蔗糖酶、异构麦芽糖酶、乳糖酶等酶类，广泛分布在机体小肠绒毛粘膜细胞刷状缘中，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。α-葡萄糖苷酶抑制剂能够抑制α-葡萄糖苷酶的活性，减少血糖的生成，具有降血糖的临床应用价值。综上所述，开发出新型的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
本发明人经过三条途径制备齐墩果酸类衍生物：①将齐墩果酸的羟基在琼斯试剂作用下形成羰基基团，再与碘甲烷反应将羧基保护成酯基，最后与水合肼进行反应，形成式I所示的新型齐墩果酸衍生物；②将齐墩果酸的羟基在琼斯试剂作用下形成羰基基团，最后与不同的苯肼盐酸盐类化合物进行反应，形成一类结构类似、具备α-葡萄糖苷酶抑制活性的通式Ⅱ所示的新型吲哚类齐墩果酸衍生物；③将齐墩果酸的羟基在琼斯试剂作用下形成羰基基团，再与碘甲烷反应形成酯基基团，再与甲酸乙酯反应形成甲醛基团，最后与不同的苯肼盐酸盐化合物进行反应，形成一类结构类似、具备α-葡萄糖苷酶抑制活性的通式Ⅲ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，提供了如式I、通式Ⅱ、通式Ⅲ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式I、通式Ⅱ、通式Ⅲ所示
其中R1为不同的取代基，包括4-甲基和4-甲氧基；R2为不同的取代基，包括-氢、4-甲基、4-甲氧基、4-三氟甲基、4-氯基、4-氟基、4-溴基。
上述式I、通式Ⅱ、通式Ⅲ所示的齐墩果酸类化合物的制备方法，它包括以下步骤：
a)将式1化合物发生氧化反应得到目标式2化合物，其中，所用的氧化剂为琼斯试剂；反应溶剂为丙酮；该反应温度为室温；反应时间为15分钟。
b)将式2化合物与碘甲烷反应，在催化剂作用下得到目标式3化合物；所用的催化剂为K2CO3；所用溶剂为 N,N-二甲基甲酰胺；反应温度为室温；反应时间为8～10小时。
）将式3化合物与水合肼置于微波反应器中反应，得到目标式Ⅰ化合物；所用溶剂为甲醇；反应温度为80 ℃；反应时间为20分钟。
d）将式2化合物与对应苯肼盐酸盐类化合物反应，得到目标通式Ⅱ化合物；所用溶剂为乙酸；反应温度为130 ℃；反应时间为1小时；所用苯肼盐酸盐类化合物为4-甲基苯肼盐酸盐，4-甲氧基苯肼盐酸盐。
e）将式3化合物先与甲酸乙酯反应，再与对应苯肼盐酸盐类化合物反应，得到目标通式Ⅲ化合物；所用溶剂分别为四氢呋喃和乙醇；反应温度分别为65 ℃和95 ℃；反应时间均为3～6小时；所用苯肼盐酸盐类化合物为4-甲基苯肼盐酸盐、4-甲氧基苯肼盐酸盐、4-三氟甲基苯肼盐酸盐、4-氯苯肼盐酸盐、盐酸苯肼、4-氟苯肼盐酸盐、4-溴苯肼盐酸盐。
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、通式Ⅱ、通式Ⅲ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。
经过三条途径制备齐墩果酸类衍生物：①将齐墩果酸的羟基在琼斯试剂作用下形成羰基基团，再与碘甲烷反应将羧基保护成酯基，最后与水合肼进行反应，形成式I所示的新型齐墩果酸衍生物；②将齐墩果酸的羟基在琼斯试剂作用下形成羰基基团，最后与不同的苯肼盐酸盐类化合物进行反应，形成一类结构类似、具备α-葡萄糖苷酶抑制活性的通式Ⅱ所示的新型吲哚类齐墩果酸衍生物；③将齐墩果酸的羟基在琼斯试剂作用下形成羰基基团，再与碘甲烷反应形成酯基基团，再与甲酸乙酯反应形成甲醛基团，最后与不同的苯肼盐酸盐化合物进行反应，形成一类结构类似、具备α-葡萄糖苷酶抑制活性的通式Ⅲ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。在此基础上，完成了本发明。
实施方式
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(1.37 g，3 mmol)溶解在丙酮中，并在0 ℃预冷。将琼斯试剂(3 mL，6mmol)缓慢加入反应溶液中，五分钟后将其移至室温进行搅拌，并在TLC监测反应完成后停止。用大量异丙醇淬灭反应，滤出不溶物，浓缩后纯化滤液。最后经硅胶柱色谱分离得到式2化合物。
式2化合物，白色固体，产率88.2 %。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化合物(1 mmol)、CH3I (3 mmol)和K2CO3 (2 mmol)溶解在DMF中，并在室温下搅拌过夜。第二天，用大量乙酸乙酯稀释反应液，用水萃取三次，饱和盐水萃取两次。剩余的有机相用无水硫酸钠干燥，过滤并浓缩，经硅胶柱色谱分离纯化得到相应的式3化合物。
式3化合物，白色固体，产率69.7 %。 1H NMR (600 MHz, Chloroform-d) δ 5.30(t, J = 3.7 Hz, 1H), 3.63 (s, 3H), 2.87 (dd, J = 14.0, 4.6 Hz, 1H), 2.54(ddd, J = 15.9, 11.2, 7.3 Hz, 1H), 2.36 (ddd, J = 15.9, 6.8, 3.6 Hz, 1H),2.01 – 1.94 (m, 2H), 1.89 (dtd, J = 20.5, 7.4, 6.9, 3.9 Hz, 2H), 1.14 (s,3H), 1.08 (s, 3H), 1.04 (d, J = 1.1 Hz, 6H), 0.93 (s, 3H), 0.90 (s, 3H), 0.78(s, 3H)。
实施例3式Ⅰ化合物的制备
将式3化合物(1 mmol)溶解在甲醇中，加入水合肼(20 mmol)并置于微波反应器中。参数设置为80 ℃，100 W，20 min。反应后，将其冷却至室温并通过硅胶柱色谱纯化，得到相应的式Ⅰ化合物。
式Ⅰ化合物，白色固体，产率43.1 %。1H NMR (600 MHz, DMSO-d 6) δ 5.56 (s,2H), 5.21 (t, J = 3.7 Hz, 1H), 3.54 (s, 3H), 2.78 (dd, J = 13.9, 4.6 Hz, 1H),2.44 (ddd, J = 16.4, 5.9, 3.0 Hz, 1H), 2.02 – 1.94 (m, 2H), 1.85 (dd, J =9.0, 3.7 Hz, 2H), 1.09 (s, 3H), 1.05 (s, 3H), 0.92 (d, J = 4.5 Hz, 6H), 0.88(d, J = 1.8 Hz, 6H), 0.70 (s, 3H). 13C NMR (151 MHz, DMSO-d 6) δ 177.24 ,143.47 , 121.97 , 55.07 , 51.52 , 46.27 , 46.17 , 45.40 , 41.38 , 41.06 ,37.37 , 36.36 , 33.20 , 32.80 , 32.06 , 32.04 , 30.41 , 28.87 , 27.18 , 25.56, 24.26 , 23.41 , 23.02 , 22.67 , 19.20 , 17.48 , 16.60 , 14.26 。
实施例4通式Ⅱ化合物的制备
式2化合物 (1 mmol)和相应的苯肼盐酸盐类化合物，包括4-甲基苯肼盐酸盐和4-甲氧基苯肼盐酸盐(1.05 mmol)的混合物在乙酸中回流，1小时后停止反应，冷却后用乙醚稀释，分别用水、饱和碳酸氢钠溶液和饱和盐水洗涤，剩余的有机相用无水硫酸钠干燥，过滤并浓缩，最后通过硅胶柱色谱纯化得到相应的通式Ⅱ化合物。化合物编号、具体结构式以及原料如下表1所示。
表1通式Ⅱ化合物具体结构式、所用原料
化合物HL-1，白色固体，产率47.7 %。 1H NMR (600 MHz, Chloroform-d) δ 7.60(s, 1H), 7.21 (s, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H),5.40 (t, J = 3.7 Hz, 1H), 2.88 (dd, J = 13.9, 4.6 Hz, 1H), 2.74 (d, J = 14.8Hz, 1H), 2.43 (s, 3H), 1.27 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H), 0.96 (s,3H), 0.94 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H). 13C NMR (151 MHz, Chloroform-d)δ 183.56 , 143.48 , 134.54 , 128.62 , 128.24 , 123.07 , 122.50 , 117.91 ,110.12 , 106.55 , 68.12 , 53.31 , 46.79 , 46.52 , 46.01 , 41.96 , 41.29 ,39.56 , 38.25 , 34.11 , 33.99 , 33.23 , 32.62 , 32.30 , 31.12 , 30.85 , 27.90, 25.95 , 25.76 , 23.71 , 23.58 , 23.45 , 21.61 , 19.42 , 17.04 , 15.66 。
化合物HL-2，白色固体，产率50.3 %。 1H NMR (600 MHz, Chloroform-d) δ 7.58(s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.77 (dd, J =8.6, 2.5 Hz, 1H), 5.40 (t, J = 3.6 Hz, 1H), 3.85 (s, 3H), 2.91 – 2.86 (m,1H), 2.72 (d, J = 14.8 Hz, 1H), 1.28 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H),0.96 (s, 6H), 0.92 (s, 3H), 0.86 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ183.62 , 153.92 , 143.51 , 142.02 , 131.32 , 128.74 , 123.02 , 111.09 ,110.82 , 106.96 , 100.57 , 66.01 , 56.18 , 46.80 , 46.54 , 46.01 , 41.98 ,41.30 , 39.56 , 38.26 , 36.98 , 34.18 , 33.99 , 33.23 , 32.62 , 32.31 , 31.14, 30.85 , 27.89 , 25.95 , 23.72 , 23.62 , 23.52 , 23.13 , 19.41 , 17.05 ,15.71 。
实施例5通式Ⅲ化合物的制备
将式3化合物 (1 mmol)的四氢呋喃溶液冷却至0 ℃，缓慢加入NaH (20 mmol)和甲酸乙酯(20 mmol)，然后将反应溶液移至65 ℃并搅拌3小时。反应完成后，用冰水将其熄灭，用0.5 M盐酸将反应溶液的pH调节至5。然后用二氯甲烷萃取三次，与有机相合并，依次用水和饱和盐水洗涤。浓缩有机相，将残余物与相应的苯肼盐酸盐类化合物，包括4-甲基苯肼盐酸盐、4-甲氧基苯肼盐酸盐、4-三氟甲基苯肼盐酸盐、4-氯基苯肼盐酸盐、苯肼盐酸盐、4-氟基苯肼盐酸盐、4-溴基苯肼盐酸盐(1.2 mmol)一起溶解在乙醇中，并在回流下搅拌3小时。反应后，浓缩反应溶液并通过硅胶柱色谱纯化，得到相应的通式Ⅲ化合物。化合物编号、具体结构式以及原料如下表2所示。
表2通式Ⅲ化合物具体结构式、所用原料
化合物HL-3，浅黄色固体，产率37.1 %。1H NMR (600 MHz, Chloroform-d) δ7.35 (s, 1H), 7.27 (s, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.39 (t, J = 3.7 Hz,1H), 3.65 (s, 3H), 2.92 (dd, J = 13.9, 4.5 Hz, 1H), 2.63 (d, J = 14.9 Hz,1H), 2.43 (s, 3H), 2.12 (d, J = 14.9 Hz, 1H), 1.18 (s, 3H), 1.07 (s, 3H),1.03 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.81 (s, 3H). 13C NMR(151 MHz, Chloroform-d) δ 178.44 , 146.34 , 143.72 , 139.90 , 139.01 , 138.16, 129.18 , 128.98 , 122.63 , 114.15 , 54.75 , 51.70 , 46.97 , 46.55 , 46.02 ,41.95 , 41.58 , 39.40 , 38.24 , 37.09 , 34.81 , 34.04 , 33.26 , 32.52 , 32.34, 30.86 , 29.49 , 27.90 , 25.84 , 23.76 , 23.50 , 23.28 , 22.43 , 21.40 ,19.39 , 16.71 , 15.36 。
化合物HL-4，浅黄色固体，产率41.9 %。 1H NMR (600 MHz, Chloroform-d) δ7.32 (s, 1H), 7.29 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.37 (t, J= 3.6 Hz, 1H), 3.85 (s, 3H), 3.63 (s, 3H), 2.90 (dd, J = 13.9, 4.5 Hz, 1H),2.60 (d, J = 14.9 Hz, 1H), 1.16 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s,3H), 0.92 (s, 3H), 0.91 (s, 3H), 0.79 (s, 3H). 13C NMR (151 MHz, Chloroform-d)δ 178.45 , 159.91 , 143.73 , 138.08 , 130.38 , 122.62 , 114.16 , 113.68 ,55.67 , 54.74 , 51.71 , 46.97 , 46.56 , 46.02 , 41.96 , 41.58 , 39.41 , 38.25, 37.09 , 34.81 , 34.04 , 33.26 , 32.52 , 32.34 , 30.87 , 29.46 , 27.90 ,25.85 , 23.76 , 23.51 , 23.28 , 22.40 , 19.39 , 16.72 , 15.37 。
化合物HL-5，黄色固体，产率52.6 %。 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), 5.37 (t, J = 3.7Hz, 1H), 3.63 (s, 3H), 2.90 (dd, J = 13.9, 4.5 Hz, 1H), 2.62 (d, J = 14.9 Hz,1H), 2.11 (d, J = 15.0 Hz, 1H), 1.16 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H),0.94 (d, J = 5.5 Hz, 6H), 0.91 (s, 3H), 0.79 (s, 3H). 13C NMR (151 MHz,Chloroform-d) δ 178.44 , 146.82 , 145.58 , 143.78 , 139.04 , 131.40 , 131.18, 129.74 , 125.95 , 125.92 , 125.90 , 124.75 , 122.95 , 122.52 , 114.91 ,54.70 , 51.72 , 51.01 , 46.96 , 46.57 , 46.02 , 41.96 , 41.58 , 39.40 , 38.22, 36.98 , 34.83 , 34.03 , 33.26 , 32.50 , 32.30 , 30.86 , 29.68 , 27.89 ,25.83 , 23.75 , 23.50 , 23.26 , 22.72 , 19.38 , 16.70 , 15.38 。
化合物HL-6，浅黄色固体，产率54.2 %。 1H NMR (600 MHz, Chloroform-d) δ7.41 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 6.0 Hz, 2H), 7.31 (s, 1H), 5.37 (s,1H), 3.63 (s, 3H), 2.90 (dd, J = 13.9, 4.5 Hz, 1H), 2.60 (d, J = 14.9 Hz,1H), 1.16 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H),0.91 (s, 3H), 0.79 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 178.43 , 146.61, 143.75 , 141.05 , 138.74 , 135.04 , 130.58 , 128.88 , 122.56 , 114.60 ,54.71 , 51.71 , 46.96 , 46.55 , 46.01 , 41.95 , 41.58 , 39.40 , 38.23 , 37.01, 34.80 , 34.03 , 33.26 , 32.51 , 32.31 , 30.86 , 29.58 , 27.89 , 25.83 ,23.76 , 23.49 , 23.26 , 22.58 , 19.38 , 16.70 , 15.36 。
化合物HL-7，浅黄色固体，产率60.5 %。 1H NMR (600 MHz, Chloroform-d) δ7.43 (dd, J = 5.1, 2.3 Hz, 3H), 7.38 (dd, J = 7.6, 2.1 Hz, 2H), 7.35 (s, 1H),5.37 (t, J = 3.7 Hz, 1H), 3.63 (s, 3H), 2.90 (dd, J = 14.0, 4.5 Hz, 1H), 2.62(d, J = 14.9 Hz, 1H), 1.16 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.94 (s, 3H),0.93 (s, 3H), 0.91 (s, 3H), 0.79 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ178.44 , 143.74 , 142.48 , 129.28 , 129.12 , 128.63 , 122.61 , 114.30 , 54.75, 51.71 , 46.97 , 46.56 , 46.02 , 41.96 , 41.59 , 39.41 , 38.24 , 37.07 ,34.83 , 34.04 , 33.27 , 32.52 , 32.33 , 30.87 , 29.51 , 27.90 , 25.84 , 23.76, 23.51 , 23.28 , 22.47 , 19.39 , 16.71 , 15.37 。
化合物HL-8，浅黄色固体，产率56.1 %。 1H NMR (600 MHz, Chloroform-d) δ7.36 (dd, J = 8.8, 4.8 Hz, 2H), 7.33 (s, 1H), 7.11 (t, J = 8.5 Hz, 2H), 5.37(t, J = 3.7 Hz, 1H), 3.63 (s, 3H), 2.90 (dd, J = 14.0, 4.5 Hz, 1H), 2.60 (d,J = 14.9 Hz, 1H), 1.16 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H),0.92 (s, 3H), 0.91 (s, 3H), 0.79 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ178.43 , 146.62 , 143.76 , 138.52 , 131.09 , 131.03 , 122.57 , 115.64 ,115.48 , 114.48 , 54.71 , 51.71 , 46.97 , 46.56 , 46.02 , 41.96 , 41.58 ,39.40 , 38.24 , 37.02 , 34.79 , 34.04 , 33.27 , 32.51 , 32.32 , 30.87 , 29.53, 27.90 , 25.84 , 23.76 , 23.50 , 23.27 , 22.51 , 19.38 , 16.71 , 15.36 。
化合物HL-9，黄色固体，产率1.9 %。 1H NMR (600 MHz, Chloroform-d) δ 7.57(d, J = 8.4 Hz, 2H), 7.34 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 5.37 (t, J =3.7 Hz, 1H), 3.63 (s, 3H), 2.90 (dd, J = 13.9, 4.5 Hz, 1H), 2.60 (d, J = 14.9Hz, 1H), 1.16 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.92 (s,3H), 0.91 (s, 3H), 0.79 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 178.43 ,141.55 , 138.75 , 131.89 , 130.90 , 122.55 , 54.71 , 51.71 , 46.96 , 46.56 ,46.02 , 41.96 , 41.58 , 39.40 , 38.23 , 37.01 , 34.81 , 34.04 , 33.26 , 32.51, 32.31 , 30.87 , 29.60 , 27.90 , 25.84 , 23.76 , 23.50 , 23.27 , 22.61 ,19.38 , 16.71 , 15.36 。
实施例6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20 mmol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15 min。加入25μL的PNPG溶液，再置于37℃摇床孵育15 min，随后加入50μL的0.2 M碳酸钠溶液，酶标仪测定405 nm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3所示。
表3.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)
1.三种齐墩果酸类化合物，其特征在于，它具有如下式Ⅰ、通式Ⅱ、通式Ⅲ所示的结构：
其中，R1为不同的取代基，包括4-甲基和4-甲氧基；R2为不同的取代基，包括-氢、4-甲基、4-甲氧基、4-三氟甲基、4-氯基、4-氟基、4-溴基。
2.一种权利要求1所述的齐墩果酸类化合物通式Ⅱ的用途，其特征在于，用于制备抗糖尿病药物。
3.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中所述的通式Ⅱ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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