CN104892706A - 具有抗寄生虫活性的异噁唑-核苷杂化体及其制备方法和应用 - Google Patents

具有抗寄生虫活性的异噁唑-核苷杂化体及其制备方法和应用 Download PDF

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CN104892706A
CN104892706A CN201510200847.9A CN201510200847A CN104892706A CN 104892706 A CN104892706 A CN 104892706A CN 201510200847 A CN201510200847 A CN 201510200847A CN 104892706 A CN104892706 A CN 104892706A
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isoxazole
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郭胜海
范学森
王继亮
张新迎
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Henan Normal University
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Abstract

本发明公开了一种具有抗寄生虫活性的异噁唑-核苷杂化体及其制备方法和应用，属于具有抗寄生虫活性化合物的合成技术领域。本发明的技术方案要点为：具有抗寄生虫活性的异噁唑-核苷杂化体，具有如下结构： 或

Description

具有抗寄生虫活性的异噁唑-核苷杂化体及其制备方法和应用
技术领域
本发明属于具有抗寄生虫活性化合物的合成技术领域，具体涉及一种具有抗寄生虫活性的异噁唑-核苷杂化体及其制备方法和应用。
背景技术
异噁唑-核苷杂化体由于在抗病毒以及抗癌领域中表现出较强的生物活性，近年来吸引了大量化学家和药物学家的广泛关注。然而，由于该类杂化体合成方法的匮乏造成了这方面的研究还很不完善并且缺乏系统性。近年来，Kim等开发了一种基于5-乙炔基取代核苷与氯代醛肟的[3+2]环加成反应制备异噁唑-核苷杂化体的方法，该方法主要可用于C5-（异噁唑-5-基）-2'-脱氧尿苷的合成中。尽管该方法的合成效率较高，然而，该方法中所用的原料5-乙炔基取代核苷是通过5-碘代核苷在钯催化下与三甲基硅基乙炔先发生Sonogashira偶联反应而后在KF或TBAF 作用下脱去三甲基硅基而制得的，考虑到在该原料的制备过程中不仅需要使用昂贵的试剂以及催化剂，而且操作也较烦琐（经由了保护和脱保护过程），从而限制了该方法的应用范围。基于以上研究背景，本专利从价廉易得的原料出发，在不使用过渡金属催化剂的前提下，开发了一种简单且实用的方法用于新型异噁唑-核苷杂化体[如：C5-（异噁唑-3-基）-核苷]的合成并对所得杂化体的生物活性进行了研究。
发明内容
本发明解决的技术问题是提供了一种具有抗寄生虫活性的异噁唑-核苷杂化体及其制备方法，此类化合物具有潜在的药用价值，含有此类化合物的药物组合物可用于制备抗寄生虫药物，尤其是抗利什曼原虫药物。
本发明为解决上述技术问题采用如下技术方案，具有抗寄生虫活性的异噁唑-核苷杂化体，其特征在于具有如下结构：或，其中R1为：、、或；R2为、、或；R3为直链烷基、羟甲基、溴甲基、苯基或单取代苯基，其中单取代苯基苯环上的取代基为烷基、氟或溴，取代基的位置为苯环上的对位；Y为氧原子或NH基团。
本发明所述的具有抗寄生虫活性的异噁唑-核苷杂化体的制备方法，其特征在于包括以下步骤：（1）将5-甲酰基嘧啶核苷类化合物1溶于四氢呋喃和水的混合溶液中，加入盐酸羟胺和醋酸钠后于室温搅拌反应制得5-醛肟取代嘧啶核苷类化合物2；（2）将5-醛肟取代嘧啶核苷类化合物2溶于溶剂，加入N-氯代丁二酰亚胺后于室温~40℃的反应温度搅拌至5-醛肟取代嘧啶核苷类化合物2反应完全，然后向反应体系中滴加三乙胺和末端炔类化合物3，室温搅拌反应制得乙酰基保护的异噁唑-核苷杂化体4；（3）将乙酰基保护的异噁唑-核苷杂化体4溶于无水甲醇后加入二丁基氧化锡，回流反应至TLC跟踪监测反应完全制得异噁唑-核苷杂化体5，制备过程中的反应方程式为：
，
其中R1、R2、R3和Y是如上述所定义的。
本发明所述的具有抗寄生虫活性的异噁唑-核苷杂化体的制备方法，步骤（2）中的溶剂为N,N-二甲基甲酰胺、乙腈、四氢呋喃或二氯甲烷。
本发明还涉及具有抗寄生虫活性的药物组合物，该药物组合物是由具有抗寄生虫活性的异噁唑-核苷杂化体和可药用辅料组成的。
本发明所述的具有抗寄生虫活性的药物组合物在制备抗寄生虫药物中的应用，特别是
在制备抗利什曼原虫药物中的应用。
本发明利用5-甲酰基嘧啶核苷类化合物为起始原料，经由几步简单、高效的化学转化，成功地得到一系列新型异噁唑-核苷杂化体，该制备方法具有以下显著优点：起始原料价廉易得、操作简便且反应过程中避免使用过渡金属催化剂、底物适用范围广。此外，本发明所提供的新型异噁唑-核苷杂化体具有显著的抗寄生虫活性，特别是抗利什曼原虫活性。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
5-醛肟取代嘧啶核苷2的合成
以2a的合成为例详细地阐述具体的实验步骤：
将核苷1a（1.7 g, 5.0 mmol）溶于四氢呋喃（40 mL）和水（10 mL）的混合溶液中，加入盐酸羟胺（417 mg, 6.0 mmol），醋酸钠（574 mg, 7.0 mmol）后室温下搅拌至反应完成。二氯甲烷萃取，有机相经水洗后，饱和食盐水洗涤，无水硫酸钠干燥，减压除去溶剂后，残留物经柱色谱分离得到白色固体产物2a，收率97%。利用上述的合成步骤可以以50%-90%的分离收率得到相应核苷2b-2e，其对应的结构式如下：
实施例2
乙酰基保护的异噁唑-核苷杂化体4的合成
以核苷4a的合成为例详细地阐述具体的实验步骤：
将核苷2a（107 mg, 0.3 mmol）溶于四氢呋喃（3.0 mL）中，之后加入N-氯代丁二酰亚胺（NCS）（48 mg, 0.36 mmol），于室温下搅拌2 h。当核苷2a完成消失后，向反应体系中慢慢滴加三乙胺（84 μL 0.6 mmol）和苯乙炔（3a）（66 μL,0.6 mmol），室温下搅拌至反应完成。向体系中加入水和乙酸乙酯萃取，有机相经水洗后，饱和食盐水洗涤，无水Na2SO4干燥，减压除去溶剂后，残留物经柱色谱分离得到白色固体产物4a，收率56%（从核苷2a计算）。利用上述的合成步骤可以以25%-58%的分离收率得到相应新型异噁唑-核苷杂化体4b-4o，其对应的结构式如下：
实施例3
异噁唑-核苷杂化体5的合成
以核苷5a的合成为例详细地阐述具体的实验步骤：
将乙酰基保护的异噁唑-核苷4a（137 mg, 0.3 mmol）溶于无水甲醇（3 mL）中，之后加入二丁基氧化锡（75 mg, 0.3 mmol），回流24 h，TLC跟踪检测至反应结束。减压除去溶剂后，残留物经柱色谱分离得到白色固体产物5a，收率87%。利用上述的合成步骤可以以53%-97%的分离收率得到相应的异噁唑-核苷杂化体5b-5o，其对应的结构式如下：
实施例4
体外抗利什曼原虫活性测定实验
实验中用到杜氏利什曼原虫（L. donovani LV9）无鞭毛体和两种对照药物米替福新（Miltefosine）和两性霉素B（Amphotericin B）。
利什曼原虫前鞭毛体在含有40 mM HEPES缓冲液、100 mM 腺苷、0.5 mg/L 血晶素、质量浓度为10%的热灭活胎牛血清和50 µg/mL庆大霉素的M-199 培养基中生长。通过将1×106的前鞭毛体在5 mL无菌的无鞭毛体介质中（该介质包含以下成分：15 mM氯化钾、8 mM葡萄糖、5 mM谷氨酰胺、1 M-199、4 mM血晶素和质量浓度为20%的胎牛血清）进行稀释，从而促进前鞭毛体向无菌的无鞭毛体分化。之后，无菌的无鞭毛体在pH值为5.5，温度为37℃下进行生长（5% CO2气氛中）。小鼠单核/巨噬细胞株RAW 264.7被保持在含有质量浓度为10%的热灭活胎牛血清的DMEM培养基中。接着，在96孔微量滴定板的每一孔中加入100 µL 含有RAW 264.7细胞的DMEM培养基（5×104个细胞/mL）。将96孔微量滴定板中的RAW 264.7细胞放在5% CO2培养箱中37℃下培养24小时后，旧的培养基被100 µL 含有无鞭毛体的新鲜的DMEM培养基（106个细胞/mL）所替代。在5% CO2培养箱中37℃下再培养24小时后，用100 µL 含有待测试的异噁唑-核苷杂化体的新鲜的DMEM培养基替代旧的培养基再培养48小时。无鞭毛体在巨噬细胞中的存活率可以利用 SYBR®green I掺入法进行测试（SYBR®green I与寄生虫的DNA接触后会有明显的荧光增强）。实验结果用2天培养期后抑制寄生虫生长50%的浓度IC50来表示。在相同条件下，药物对照物米替福新的IC50是5.75±0.62µM，两性霉素B的IC50是0.31±0.09µM。
结构表征数据和抗利什曼原虫活性数据：
核苷4a: mp 164-165 ℃. 1H NMR (400 MHz, CDCl3)δ 2.12 (s, 3H), 2.23 (s, 3H), 2.28-2.36 (m, 1H), 2.54-2.59 (m, 1H), 4.32-4.42 (m, 3H), 5.28-5.29 (m, 1H), 6.40-6.44 (m, 1H), 7.25 (s, 1H), 7.41-7.46 (m, 3H), 7.80 (d, J = 6.4 Hz, 2H), 8.48 (s, 1H), 9.97 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8 (2C), 38.0, 63.9, 74.5, 82.7, 85.5, 99.9, 104.6, 125.7, 127.2, 128.9, 130.1, 138.3, 149.9, 156.2, 161.4, 169.9, 170.4, 170.9. HRMS (ESI) calcd for C22H21N3NaO8 [M + Na]+: 478.1221, found: 478.1233。
核苷4b: mp 179-181 ℃. 1H NMR (400 MHz, CDCl3) δ2.10 (s, 3H), 2.22 (s, 3H), 2.28-2.36 (m, 4H), 2.52-2.57 (m, 1H), 4.31-4.41 (m, 3H), 5.27 (d, J = 6.0 Hz, 1H), 6.39-6.43 (m, 1H), 7.18 (s, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 7.6 Hz, 2H), 8.46 (s, 1H), 10.14 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.9 (2C), 21.4, 38.2, 64.0, 74.5, 82.7, 85.4, 99.2, 104.9, 124.6, 125.7, 129.6, 138.2, 140.5, 149.9, 156.1, 161.2, 170.3, 170.4, 170.8. HRMS (ESI) calcd for C23H23N3NaO8 [M + Na]+: 492.1377, found: 492.1368. 抗利什曼原虫活性：IC50=1.7±0.16µM。
核苷4c: mp 99-102 ℃. 1H NMR (400 MHz, CDCl3)δ 2.08 (s, 3H), 2.18 (s, 3H), 2.28-2.33 (m, 1H), 2.50-2.55 (m, 1H), 4.29-4.38 (m, 3H), 5.25 (d, J = 6.0 Hz, 1H), 6.35-6.38 (m, 1H), 7.08 (t, J = 8.8 Hz, 2H), 7.18 (s, 1H), 7.72-7.75 (m, 2H), 8.43 (s, 1H), 10.46 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8 (2C), 38.1, 64.0, 74.5, 82.7, 85.5, 99.7, 104.4, 116.1 (d, J = 21.3 Hz, 2C), 123.6 (d, J = 3.1 Hz, 1C), 127.9 (d, J = 8.4 Hz, 2C), 138.4, 149.9, 156.2, 161.4, 163.6 (d, J = 250.0 Hz, 1C), 168.9, 170.5, 170.8. HRMS (ESI) calcd for C22H20FN3NaO8 [M + Na]+: 496.1127, found: 496.1141. 抗利什曼原虫活性：IC50=0.7±0.1µM。
核苷4d: mp 162-164 ℃. 1H NMR (400 MHz, CDCl3)δ 2.07 (s, 3H), 2.17 (s, 3H), 2.25-2.33 (m, 1H), 2.50-2.55 (m, 1H), 4.28-4.37 (m, 3H), 5.24 (d, J = 6.4 Hz, 1H), 6.31-6.35 (m, 1H), 7.23 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 8.40 (s, 1H), 10.49 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.88, 20.92, 38.1, 64.0, 74.5, 82.7, 85.5, 100.3, 104.3, 124.4, 126.0, 127.2, 132.1, 138.4, 149.9, 156.2, 161.4, 168.8, 170.5, 170.9. HRMS (ESI) calcd for C22H20BrN3NaO8 [M + Na]+: 556.0326, found: 556.0332。
核苷4e: mp 183-185 ℃. 1H NMR (400 MHz, DMSO-d 6)δ 2.05 (s, 3H), 2.07 (s, 3H), 2.37-2.51 (m, 2H), 4.23-4.26 (m, 3H), 4.57 (d, J = 6.4 Hz, 2H), 5.19-5.21 (m, 1H), 5.66 (t, J = 6.4 Hz, 1H), 6.17-6.20 (m, 1H), 6.76 (s, 1H), 8.25 (s, 1H), 11.81 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ 20.9, 21.1, 37.2, 55.2, 64.1, 74.5, 82.2, 85.8, 102.2, 103.6, 139.2, 150.1, 156.4, 161.4, 170.5, 170.7, 173.3. HRMS (ESI) calcd for C17H19N3NaO9 [M + Na]+: 432.1014, found: 432.1025. 抗利什曼原虫活性：IC50=3.39±0.76µM。
核苷4f: mp 181-183 ℃. 1H NMR (400 MHz, CDCl3)δ 2.11 (s, 3H), 2.19 (s, 3H), 2.27-2.32 (m, 1H), 2.53-2.57 (m, 1H), 4.30-4.40 (m, 3H), 4.47 (s, 2H), 5.26-5.27 (m, 1H), 6.38-6.41 (m, 1H), 7.01 (s, 1H), 8.43 (s, 1H), 9.93 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ 20.3, 20.9, 21.2, 37.2, 64.1, 74.5, 82.3, 85.8, 103.1, 104.6, 139.5, 150.0, 157.0, 161.4, 168.2, 170.5, 170.7. HRMS (ESI) calcd for C17H18BrN3NaO8 [M + Na]+: 494.0169, found: 494.0170。
核苷4g: mp 104-106 ℃. 1H NMR (400 MHz, CDCl3)δ 0.89 (t, J = 6.8 Hz, 3H), 1.28-1.29 (m, 10H), 1.68-1.75 (m, 2H), 2.14 (s, 3H), 2.22 (s, 3H), 2.31-2.39 (m, 1H), 2.54-2.59 (m, 1H), 2.75 (t, J = 7.6 Hz, 2H), 4.33-4.43 (m, 3H), 5.30 (d, J = 6.4 Hz, 1H), 6.42-6.46 (m, 1H), 6.69 (s, 1H), 8.42 (s, 1H), 10.37 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ14.0, 20.75, 20.83, 22.5, 26.7, 27.4, 29.0, 29.1, 31.7, 38.0, 63.9, 74.4, 82.6, 85.3, 101.1, 105.1, 138.1, 150.0, 155.5, 161.3, 170.4, 170.8, 174.0 (one 13C signal was not observed). HRMS (ESI) calcd for C24H33N3NaO8 [M + Na]+: 514.2160, found: 514.2153. 抗利什曼原虫活性：IC50=20.91±8.38µM。
核苷4h: mp 112-113 ℃. 1H NMR (400 MHz, CDCl3)δ 2.15 (s, 3H), 2.43-2.56 (m, 2H), 4.08-4.11 (m, 1H), 4.24-4.37 (m, 3H), 6.20-6.23 (m, 1H), 7.23 (s, 1H), 7.37-7.42 (m, 3H), 7.74-7.76 (m, 2H), 8.38 (s, 1H), 10.47 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8, 38.0, 60.2, 63.1, 82.2, 85.9, 99.9, 104.2, 125.8, 127.1, 128.9, 130.2, 138.8, 149.8, 156.2, 161.5, 170.0, 170.9. HRMS (ESI) calcd for C20H18N6NaO6 [M + Na]+: 461.1180, found: 461.1183。
核苷4i: mp 77-79 ℃. 1H NMR (400 MHz, CDCl3)δ 2.15 (s, 3H), 2.45-2.57 (m, 2H), 4.10-4.12 (m, 1H), 4.25-4.35 (m, 3H), 6.21 (t, J = 6.0 Hz, 1H), 7.09 (t, J = 8.4 Hz, 2H), 7.17 (s, 1H), 7.72-7.75 (m, 2H), 8.38 (s, 1H), 10.40 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8, 38.0, 60.3, 63.1, 82.2, 85.9, 99.7, 104.1, 116.1 (d, J = 22.1 Hz, 2C), 123.5 (d, J = 3.8 Hz, 1C), 127.9 (d, J = 8.4 Hz, 2C), 138.8, 149.7, 156.3, 161.4, 163.7 (d, J = 249.2 Hz, 1C), 169.1, 170.9. HRMS (ESI) calcd for C20H17FN6NaO6 [M + Na]+: 479.1086, found: 479.1088. 抗利什曼原虫活性：IC50 > 12.5µM。
核苷4j: mp 150-152 ℃. 1H NMR (400 MHz, DMSO-d 6)δ 2.04 (s, 3H), 2.38-2.44 (m, 1H), 2.51-2.58 (m, 1H), 4.10 (m, 1H), 4.24, (s, 2H), 4.42-4.44 (m, 1H), 4.57 (d, J = 4.4 Hz, 2H), 5.64 (m, 1H), 6.10 (t, J = 6.0 Hz, 1H), 6.75 (s, 1H), 8.21 (s, 1H), 11.78 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ 20.9, 37.2, 55.2, 60.4, 63.5, 81.9, 85.7, 102.2, 103.3, 139.5, 150.0, 156.4, 161.5, 170.7, 173.3. HRMS (ESI) calcd for C15H16N6NaO7 [M + Na]+: 415.0973, found: 415.0966. 抗利什曼原虫活性：IC50 >12.5µM。
核苷4k: mp 190-192 ℃. 1H NMR (400 MHz, CDCl3)δ 2.07 (s, 3H), 2.10 (s, 3H), 2.22 (s, 3H), 4.32-4.37 (m, 3H), 5.39-5.40 (m, 1H), 5.46-5.48 (m, 1H), 6.19 (d, J = 4.4 Hz, 1H), 7.24 (s, 1H), 7.38-7.40 (m, 3H), 7.76 (d, J = 6.8 Hz, 2H), 8.41 (s, 1H), 10.28 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 20.4, 20.5, 20.8, 63.2, 70.5, 73.1, 80.5, 87.3, 99.9, 105.0, 125.8, 127.2, 128.9, 130.2, 138.5, 149.9, 156.1, 161.2, 169.7, 169.8, 170.0, 170.8. HRMS (ESI) calcd for C24H23N3NaO10 [M + Na]+: 536.1276, found: 536.1282。
核苷4l: mp 235-237 ℃. 1H NMR (400 MHz, CDCl3)δ 2.07 (s, 3H), 2.11 (s, 3H), 2.23 (s, 3H), 4.35-4.39 (m, 3H), 5.39-5.41 (m, 1H), 5.45-5.47 (m, 1H), 6.19 (d, J = 5.6 Hz, 1H), 7.10 (t, J = 8.8 Hz, 2H), 7.19 (s, 1H), 7.74-7.78 (m, 2H), 8.41 (s, 1H), 10.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.4, 20.5, 20.8, 63.2, 70.5, 73.1, 80.5, 87.3, 99.7, 104.9, 116.1 (d, J = 22.1 Hz, 2C), 123.6 (d, J = 3.0 Hz, 1C), 127.9 (d, J = 9.1 Hz, 2C), 138.5, 149.9, 156.1, 161.1, 163.7 (d, J = 249.9 Hz, 1C), 169.1, 169.71, 169.74, 170.8. HRMS (ESI) calcd for C24H22FN3NaO10 [M + Na]+: 554.1181, found: 554.1180. 抗利什曼原虫活性：IC50=0.78±0.08µM。
核苷4m: mp >300 ℃. 1H NMR (400 MHz, DMSO-d 6) δ1.85 (s, 3H), 4.15-4.18 (m, 1H), 4.25-4.28 (m, 1H), 5.06 (s, 1H), 6.12 (s, 1H), 6.49 (d, J = 4.0 Hz, 1H), 6.87 (s, 1H), 7.32 (s, 1H), 7.49-7.51 (m, 3H), 7.86 (d, J = 6.0 Hz, 2H), 8.08 (s, 1H), 11.90 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ20.6, 64.6, 84.6, 90.3, 100.8, 103.3, 126.0, 126.8, 127.1, 129.7, 130.9, 134.8, 139.7, 150.5, 157.4, 161.5, 169.4, 170.7. HRMS (ESI) calcd for C20H17N3NaO6 [M + Na]+: 418.1010, found: 418.1023。
核苷4n: mp 136-138 ℃. 1H NMR (400 MHz, CDCl3) δ 1.98-2.04 (m, 4H), 2.09 (s, 3H), 2.80-2.85 (m, 1H), 4.33-4.34 (m, 1H), 4.45-4.50 (m, 1H), 4.54-4.57 (m, 1H), 5.20 (d, J = 6.0 Hz, 1H), 6.22-6.26 (m, 1H), 6.70 (d, J = 1.2 Hz, 1H), 7.26 (brs, 1H), 7.45-7.49 (m, 3H), 7.79-7.81 (m, 2H), 7.96 (brs, 1H), 8.15 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ20.8, 20.9, 39.1, 63.6, 74.3, 83.3, 87.3, 96.1, 96.7, 125.9, 126.7, 129.1, 130.6, 140.8, 154.0, 158.7, 162.5, 169.6, 170.5, 170.9. HRMS (ESI) calcd for C22H22N4NaO7 [M + Na]+: 477.1381, found: 477.1394. 抗利什曼原虫活性：IC50=1.61±0.31µM。
核苷4o: mp 100-103 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.01 (s, 3H), 2.06 (s, 3H), 2.34-2.39 (m, 1H), 2.52-2.55 (m, 1H), 4.21 (m, 1H), 4.30-4.34 (m, 2H), 4.60 (d, J = 6.0 Hz, 2H), 5.19-5.21 (m, 1H), 5.75 (t, J = 6.0 Hz, 1H), 6.15-6.18 (m, 1H), 6.87 (s, 1H), 7.49 (brs, 1H), 8.10 (brs, 1H), 8.20 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ 21.0, 21.2, 37.1, 55.3, 64.1, 74.7, 82.3, 87.0, 96.3, 99.5, 143.8, 153.7, 158.6, 162.4, 170.5, 170.7, 173.3. HRMS (ESI) calcd for C17H20N4NaO8 [M + Na]+: 431.1173, found: 431.1177. 抗利什曼原虫活性：IC50=3.13±0.34µM。
核苷5a: mp >300 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.21 (t, J = 5.6 Hz, 2H),3.57-3.66 (m, 2H), 3.86 (d, J = 2.8 Hz, 1H), 4.28 (t, J = 3.2 Hz, 1H), 5.13-5.15 (m, 1H), 5.31 (d, J = 4.4 Hz, 1H), 6.20 (t, J = 6.4 Hz, 1H), 7.28 (s, 1H), 7.46-7.53 (m, 3H), 7.87 (d, J = 7.2 Hz, 2H), 8.62 (s, 1H), 11.77 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ 40.8, 61.5, 70.7, 85.5, 88.2, 100.7, 103.1, 126.0, 127.2, 129.7, 130.8, 140.4, 150.2, 157.6, 161.4, 169.1. HRMS (ESI) calcd for C18H17N3NaO6 [M + Na]+: 394.1010, found: 394.1010. 抗利什曼原虫活性：IC50=0.76±0.08µM。
核苷5b: mp 210-213 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.20 (t, J = 4.8 Hz, 2H), 2.33 (s, 3H), 3.57-3.64 (m, 2H), 3.86 (s, 1H), 4.28 (s, 1H), 5.14 (t, J = 4.4 Hz, 1H), 5.31 (d, J = 3.6 Hz, 1H), 6.19 (t, J = 6.4 Hz, 1H), 7.19 (s, 1H), 7.31 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 8.60 (s, 1H), 11.77 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ 21.4, 40.8, 61.5, 70.7, 85.5, 88.1, 100.0, 103.2, 124.5, 125.9, 130.2, 140.3, 140.7, 150.2, 157.6, 161.4, 169.2. HRMS (ESI) calcd for C19H19N3NaO6 [M + Na]+: 408.1166, found: 408.1161. 抗利什曼原虫活性：IC50=0.61±0.3µM。
核苷5c: mp >300 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.20 (t, J = 5.2 Hz, 2H), 3.57-3.65 (m, 2H), 3.86 (d, J = 2.8 Hz, 1H), 4.28 (s, 1H), 5.14 (t, J = 4.4 Hz, 1H), 5.31 (d, J = 3.6 Hz, 1H), 6.19 (t, J = 6.4 Hz, 1H), 7.25 (s, 1H), 7.34 (t, J = 8.8 Hz, 2H), 7.90-7.94 (m, 2H), 8.61 (s, 1H), 11.77 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ 40.8, 61.4, 70.7, 85.5, 88.1, 100.5, 103.0, 116.8 (d, J = 22.1 Hz, 2C), 123.9 (d, J = 3.1 Hz, 1C), 128.5 (d, J = 8.3 Hz, 2C), 140.4, 150.2, 157.7, 161.4, 163.5 (d, J = 246.9 Hz, 1C), 168.1. HRMS (ESI) calcd for C18H16FN3NaO6 [M + Na]+: 412.0915, found: 412.0924. 抗利什曼原虫活性：IC50=0.58±0.16µM。
核苷5d: mp >300 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.19 (t, J = 4.4 Hz, 2H), 3.56-3.63 (m, 2H), 3.84 (d, J = 3.2 Hz, 1H), 4.26 (s, 1H), 5.10 (t, J = 4.4 Hz, 1H), 5.27-5.28 (m, 1H), 6.18 (t, J = 6.4 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.71-7.73 (m, 2H), 7.82-7.84 (m, 2H), 8.61 (d, J = 1.6 Hz, 1H), 11.76 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ40.8, 61.5, 70.7, 85.6, 88.2, 101.2, 103.0, 124.2, 126.4, 127.9, 132.7, 140.4, 150.2, 157.7, 161.4, 168.0. HRMS (ESI) calcd for C18H16BrN3NaO6 [M + Na]+: 472.0115, found: 472.0116。
核苷5e: mp 187-188 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.15-2.18 (m, 2H), 3.51-3.58 (m, 2H), 3.82 (d, J = 3.2 Hz, 1H), 4.24-4.25 (m, 1H), 4.55 (d, J = 6.0 Hz, 2H), 5.09 (t, J = 4.8 Hz, 1H), 5.30 (d, J = 4.0 Hz, 1H), 5.67 (t, J = 6.0 Hz, 1H), 6.16 (t, J = 6.4 Hz, 1H), 6.69 (s, 1H), 8.52 (s, 1H), 11.71 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ40.7, 55.1, 61.5, 70.8, 85.4, 88.1, 102.2, 103.2, 140.1, 150.2, 156.6, 161.5, 173.0. HRMS (ESI) calcd for C13H15N3NaO7 [M + Na]+: 348.0802, found: 348.0802. 抗利什曼原虫活性：IC50=0.73±0.07µM。
核苷5f: 1H NMR (400 MHz, DMSO-d 6) δ2.17(t, J = 5.2 Hz, 2H),3.53-3.6 (m, 2H), 3.83 (d, J = 2.8 Hz, 1H), 4.24 (d, J = 3.2 Hz, 1H), 4.83 (s, 2H), 6.16 (t, J = 6.4 Hz, 1H), 6.93 (s, 1H), 8.56 (s, 1H), 11.73 (s, 1H) (two 1H signal was not observed); 13C NMR (100 MHz, DMSO-d 6) δ20.4, 40.7, 61.4, 70.7, 85.5, 88.2, 102.8, 104.6, 140.4, 150.2, 157.2, 161.4, 167.9. HRMS (ESI) calcd for C13H14BrN3NaO6 [M + Na]+: 409.9958, found: 409.9945。
核苷5g: mp 83-84 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 0.81 (m, 3H), 1.21 (m, 10H), 1.59 (m, 2H), 2.16 (m, 2H), 2.71 (m, 2H), 3.57 (m, 2H), 3.83 (s, 1H), 4.25 (s, 1H), 5.07 (s, 1H), 5.28 (s, 1H), 6.17 (s, 1H), 6.56 (s, 1H), 8.51 (s, 1H), 11.69 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ14.3, 22.5, 26.3, 27.5, 28.9, 29.0, 31.7, 40.7, 61.5, 70.8, 85.4, 88.1, 101.4, 103.4, 139.9, 150.2, 156.6, 161.4, 173.3 (one 13C signal was not observed). HRMS (ESI) calcd for C20H29N3NaO6 [M + Na]+: 430.1949, found: 430.1950. 抗利什曼原虫活性：IC50 > 12.5µM。
核苷5h:mp 176-177 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.35-2.41 (m, 1H), 2.49-2.55 (m, 1H), 3.62-3.72 (m, 2H), 3.91 (d, J = 3.6 Hz, 1H), 4.39-4.44 (m, 1H), 5.37 (t, J = 4.0 Hz, 1H), 6.12 (t, J = 6.0 Hz, 1H), 7.28 (s, 1H), 7.46-7.53 (m, 3H), 7.87 (d, J = 8.0 Hz, 2H), 8.62 (s, 1H), 11.82 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ37.6, 60.1, 60.8, 85.1, 85.3, 100.7, 103.1, 126.0, 127.2, 129.7, 130.8, 140.4, 150.1, 157.6, 161.4, 169.0. HRMS (ESI) calcd for C18H16N6NaO5 [M + Na]+: 419.1074, found: 419.1077。
核苷5i:mp 177-179 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.36-2.41 (m, 1H), 2.48-2.55 (m, 1H), 3.62-3.73 (m, 2H), 3.91 (s, 1H), 4.39-4.43 (m, 1H), 5.34 (t, J = 4.4 Hz, 1H), 6.11 (t, J = 6.0 Hz, 1H), 7.25 (s, 1H), 7.34 (t, J = 8.8 Hz, 2H), 7.90-7.94 (m, 2H), 8.60 (s, 1H), 11.79 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ37.6, 60.1, 60.8, 85.1, 85.3, 100.6, 103.0, 116.8 (d, J = 22.1 Hz, 2C), 123.9 (d, J = 3.1 Hz, 1C), 128.5 (d, J = 8.3 Hz, 2C), 140.3, 150.1, 157.7, 161.4, 163.6 (d, J = 247.0 Hz, 1C), 168.1. HRMS (ESI) calcd for C18H15FN6NaO5 [M + Na]+: 437.0980, found: 437.0995。
核苷5j:mp 63-65 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 2.32-2.38 (m, 1H), 2.46-2.52 (m, 1H), 3.55-3.68 (m, 2H), 3.87-3.90 (m, 1H), 4.36-4.40 (m, 1H), 4.56 (d, J = 4.8 Hz, 2H), 5.28 (t, J = 4.4 Hz, 1H), 5.65 (t, J = 6.0 Hz, 1H), 6.08 (t, J = 6.0 Hz, 1H), 6.70 (s, 1H), 8.51 (s, 1H), 11.73 (brs, 1H); 13C NMR (100 MHz, DMSO-d 6) δ37.5, 55.1, 60.2, 60.9, 85.0, 85.3, 102.2, 103.3, 140.0, 150.1, 156.6, 161.5, 173.0. HRMS (ESI) calcd for C13H14N6NaO6 [M + Na]+: 373.0867, found: 373.0875. 抗利什曼原虫活性：IC50=0.49±1.43µM。
核苷5k:mp 217-220 ℃. 1H NMR (400 MHz, DMSO-d 6) δ 3.58-3.61 (m, 1H), 3.68-3.71 (m, 1H), 3.93 (s, 1H), 4.03 (d, J = 2.8 Hz, 1H), 4.14 (d, J = 4.0 Hz, 1H), 5.13 (d, J = 2.8 Hz, 1H), 5.24 (s, 1H), 5.49 (d, J = 3.6 Hz, 1H), 5.86 (d, J = 4.4 Hz, 1H), 7.27 (s, 1H), 7.47-7.54 (m, 3H), 7.87 (d, J = 7.6 Hz, 2H), 8.70 (s, 1H), 11.77 (brs, 1H); 13C NMR (100 MHz, DMSO-d 6) δ60.9, 70.2, 74.6, 85.4, 89.0, 100.7, 103.4, 126.0, 127.2, 129.7, 130.8, 140.6, 150.5, 157.6, 161.4, 169.1. HRMS (ESI) calcd for C18H17N3NaO7 [M + Na]+: 410.0959, found: 410.0943。
核苷5l:mp >300 ℃. 1H NMR (400 MHz, DMSO-d 6) δ3.57-3.60 (m, 1H), 3.66-3.69 (m, 1H), 3.91 (s, 1H), 4.00-4.02 (m, 1H), 4.10-4.13 (m, 1H), 5.12 (d, J = 4.8 Hz, 1H), 5.23 (t, J = 4.0 Hz, 1H), 5.48 (d, J = 5.6 Hz, 1H), 5.84 (d, J = 4.4 Hz, 1H), 7.26 (s, 1H), 7.37 (t, J = 8.8 Hz, 2H), 7.93-7.96 (m, 2H), 8.68 (s, 1H), 11.79 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ60.9, 70.1, 74.6, 85.4, 89.0, 100.6, 103.3, 116.8 (d, J = 22.1 Hz, 2C), 123.9, 128.5 (d, J = 8.4 Hz, 2C), 140.6, 150.5, 157.7, 161.4, 163.6 (d, J = 246.9 Hz, 1C), 168.2. HRMS (ESI) calcd for C18H16FN3NaO7 [M + Na]+: 428.0864, found: 428.0872. 抗利什曼原虫活性：IC50=1.47±0.16µM。
核苷5m:mp >300 ℃. 1H NMR (400 MHz, DMSO-d 6) δ3.61 (s, 2H), 4.84 (s, 1H), 5.07 (t, J = 4.0 Hz, 1H), 6.00 (d, J = 5.2 Hz, 1H), 6.47 (d, J = 5.6 Hz, 1H), 6.91 (s, 1H), 7.26 (s, 1H), 7.47-7.51 (m, 3H), 7.86 (d, J = 6.8 Hz, 2H), 8.52 (s, 1H), 11.80 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ62.3, 88.2, 90.0, 100.5, 103.0, 125.98, 126.04, 127.2, 129.7, 130.8, 136.2, 141.3, 150.6, 157.5, 161.5, 169.1. HRMS (ESI) calcd for C18H15N3NaO5 [M + Na]+: 376.0904, found: 376.0891. 抗利什曼原虫活性：IC50=4.56±2.07µM。
核苷5n:mp >300 ℃. 1H NMR (400 MHz, DMSO-d 6) δ2.14-2.20 (m, 1H), 2.26-2.32 (m, 1H), 3.69-3.72 (m, 1H), 3.79-3.82 (m, 1H), 3.87 (s, 1H), 4.32 (t, J = 4.0 Hz, 1H), 5.28 (d, J = 3.6 Hz, 1H), 5.54 (s, 1H), 6.17 (t, J = 5.6 Hz, 1H), 7.15 (s, 1H), 7.45 (brs, 1H), 7.49-7.54 (m, 3H), 7.85-7.87 (m, 2H), 8.07 (brs, 1H), 8.85 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ41.6, 60.7, 69.3, 86.2, 87.8, 95.4, 97.7, 126.2, 126.7, 129.8, 131.3, 144.1, 154.0, 159.8, 162.3, 168.9. HRMS (ESI) calcd for C18H18N4NaO5 [M + Na]+: 393.1169, found: 393.1175. 抗利什曼原虫活性：IC50=0.61±0.12µM。
核苷5o:mp 183-185 ℃. 1H NMR (400 MHz, DMSO-d 6) δ2.10-2.16 (m, 1H), 2.21-2.27 (m, 1H), 3.60-3.65 (m, 1H), 3.70-3.74 (m, 1H), 3.84 (d, J = 3.2 Hz, 1H), 4.26 (t, J = 4.4 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 5.23 (d, J = 4.0 Hz, 1H), 5.34 (t, J = 4.4 Hz, 1H), 5.71 (t, J = 5.6 Hz, 1H), 6.15 (t, J = 5.6 Hz, 1H), 6.69 (s, 1H), 7.44 (brs, 1H), 8.02 (brs, 1H), 8.72 (s, 1H); 13C NMR (100 MHz, DMSO-d 6) δ41.5, 55.1, 61.0, 69.8, 86.2, 87.9, 95.6, 99.3, 143.9, 153.9, 158.8, 162.3, 172.8. HRMS (ESI) calcd for C13H16N4NaO6 [M + Na]+: 347.0962, found: 347.0947。
以上实施例描述了本发明的基本原理、主要特征及优点，本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (6)

1.具有抗寄生虫活性的异噁唑-核苷杂化体，其特征在于具有如下结构： 或，其中R1为：、、或；R2为、 、或；R3为直链烷基、羟甲基、溴甲基、苯基或单取代苯基，单取代苯基苯环上的取代基为烷基、氟或溴，取代基的位置为苯环上的对位；Y为氧原子或NH基团。
2.一种权利要求1所述的具有抗寄生虫活性的异噁唑-核苷杂化体的制备方法，其特征在于包括以下步骤：（1）将5-甲酰基嘧啶核苷类化合物1溶于四氢呋喃和水的混合溶液中，加入盐酸羟胺和醋酸钠后于室温搅拌反应制得5-醛肟取代嘧啶核苷类化合物2；（2）将5-醛肟取代嘧啶核苷类化合物2溶于溶剂，加入N-氯代丁二酰亚胺后于室温~40℃的反应温度搅拌至5-醛肟取代嘧啶核苷类化合物2反应完全，然后向反应体系中滴加三乙胺和末端炔类化合物3，室温搅拌反应制得乙酰基保护的异噁唑-核苷杂化体4；（3）将乙酰基保护的异噁唑-核苷杂化体4溶于无水甲醇后加入二丁基氧化锡，回流反应至TLC跟踪监测反应完全制得异噁唑-核苷杂化体5，制备过程中的反应方程式为：
，
其中R1、R2、R3和Y是如权利要求1所定义的。
3.根据权利要求2所述的具有抗寄生虫活性的异噁唑-核苷杂化体的制备方法，其特征在于：步骤（2）中的溶剂为N,N-二甲基甲酰胺、乙腈、四氢呋喃或二氯甲烷。
4.一种具有抗寄生虫活性的药物组合物，其特征在于：该药物组合物是由权利要求1所述的具有抗寄生虫活性的异噁唑-核苷杂化体和可药用辅料组成的。
5.权利要求4所述的具有抗寄生虫活性的药物组合物在制备抗寄生虫药物中的应用。
6.权利要求4所述的具有抗寄生虫活性的药物组合物在制备抗利什曼原虫药物中的应用。
CN201510200847.9A 2015-04-27 2015-04-27 具有抗寄生虫活性的异噁唑-核苷杂化体及其制备方法和应用 Pending CN104892706A (zh)

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