CN111978312B - 5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物及制备方法和应用 - Google Patents
5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物及制备方法和应用 Download PDFInfo
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- CN111978312B CN111978312B CN202010985094.8A CN202010985094A CN111978312B CN 111978312 B CN111978312 B CN 111978312B CN 202010985094 A CN202010985094 A CN 202010985094A CN 111978312 B CN111978312 B CN 111978312B
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- Prior art keywords
- oxadiazole
- thiadiazole
- compound
- aryl
- amine
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- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明公开了一种5‑芳基‑1,3,4‑噻二唑/1,3,4‑噁二唑‑2‑胺类化合物，结构通式如Ⅰ或Ⅱ所示，
Description
技术领域
本发明属于医药技术领域，涉及一种5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物及其制备方法和应用。
背景技术
流感病毒是引起急性上下呼吸道疾病的病原体，具体表现为发烧、咳嗽、肌痛、咽痛、鼻塞等症状。流感病毒也是每年季节性流行性病(如H3N2)和偶发性流感(如H1N1)的罪魁祸首，严重危害着人类健康，给社会经济造成巨大损失，防控流感亦成为严峻的公共卫生问题。不时凸现的高致病性禽流感如1997H5N1、2009H1N1和2013H7N9，时刻警示着人类新一轮流感大爆发的潜在性。打疫苗是预防流感最好的措施，然而每年季节性流感病毒的亚型和比率是不断变化的，很难预测下一次的流行病毒株，这就使流感大爆发的可能性加大，从而导致疫苗的无效或短缺。因此，抗流感药物是防控流感不可或缺的重要方式。
目前上市的抗流感药物很少，包括M2离子通道抑制剂(金刚烷胺、金刚乙胺)、神经氨酸酶抑制剂(扎那米韦，达菲，帕拉米韦和拉尼米韦)和流感病毒5`-帽状结构依赖性内切酶活性(PA)抑制剂巴洛沙韦(Xofluza)。流感病毒寄生的特性及其抗原的易变异性，使得已上市的抗流感化学药物出现不同程度的耐药，难以长期发挥作用。金刚烷胺和金刚乙胺由于耐药问题，临床上已不再推荐使用；一线药物如达菲及新上市的巴洛沙韦在临床上已经分离到了耐药株。流感疫苗作用的有限性、已有药物不断出现的耐药性以及不同作用机制药物的匮乏，使得人们亟待开发新的抗流感药物，构筑人类抗击流感的第一道防线。
流感病毒M2蛋白是金刚烷胺类药物的靶点，然而跨膜结构区域出现了点突变-S31N变异，使得小分子抑制剂难以结合，这就使得现有的M2抑制剂出现了耐药性。针对M2-S31N变异涉及的小分子抑制剂是目前抗流感药物研发的一个热门方向。
近年来新药研发的失败率越来越高，老药新用研究策略越来越受到研究人员的重视，也发现了一些经典药物如达泊西汀，氯丙嗪和来拿度胺等。保钾利尿药阿米洛利(hexamethylene amiloride，HMA)是多种病毒的蛋白抑制剂，例如丙肝HCV，HIV-1和SARS-CoV等。同时，HMA也能够抑制甲型流感的野生型M2离子通道，而对变异性M2-S31N没有作用；继续结构修饰得到了对变异性流感病毒有作用的化合物。
1,3,4-噻二唑/1,3,4-噁二唑在药物分子中广泛存在，具有多种多样的药理活性，如抗病毒、抗菌、抗炎、抗寄生虫、抗结核、抗惊厥、镇痛和抗分泌作用，目前上市的药物有抗HIV药物拉替拉韦，利尿药乙酰唑胺，抗生素头孢唑林和头孢西酮。从性质上来说，1,3,4-噻二唑和1,3,4-噁二唑结构类似，是生物电子等排体，为五元的缺电子杂环，可以作为氢键受体和两电子供体与靶标结合；同时，它们由于其脂溶性强而易于通过细胞膜。然而，对于1,3,4-噻二唑/1,3,4-噁二唑在抗流感病毒活性研究方面目前没有文献报道。
发明内容
为了克服现有技术的不足，本发明的目的之一在于提供一种5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，结构新颖，对流感病毒具有较好的抑制活性。
本发明的目的之二在于提供合成该化合物的制备方法，制备方法简单且产率高，可同时得到两种具有活性的化合物，经济高效。
本发明的目的之三在于提供该化合物及其药学上可接受的盐、结晶水合物及溶剂合物在制备抗流感病毒药物中的应用。
本发明的目的之四在于提供一种包含有该化合物及其药学上可接受的盐、结晶水合物及溶剂合物中的一种的药物组合物。
本发明的目的之一采用如下技术方案实现：
一种5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，具有以下结构通式Ⅰ或Ⅱ：
其中，通式Ⅰ或Ⅱ中，NR1R2为多元杂环或R1、R2各自独立地为烷基；X，Y和Z中至多2个为N原子；R3为烷基、环烷基、杂环烷基、芳基、杂芳基、芳烷基、杂芳烷基、芳并杂环基、杂芳并杂环基，及上述基团的取代衍生物中的一种；所述取代衍生物的取代基选自卤素、烷基、环烷基、杂环烷基、氨基、硝基、胺基、羟基、烷氧基、氰基、羧基、脒基、胍基、胍脒基、酰基、芳基、杂芳基、芳烷基、杂芳烷基、芳并杂环基中的一种。
进一步地，本发明优选的部分化合物结构如下：
本发明的目的之二采用如下技术方案实现：
上述5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物的制备方法，包括以下步骤：
1)以购买或制备的芳香甲酯1为原料，经肼解反应得到酰肼2；
2)取上述步骤1)得到的酰肼2与不同取代的异硫氰酸酯3在乙醇中回流反应生成氨基硫脲衍生物4；
3)取上述步骤2)得到的氨基硫脲衍生物4在溶剂中经催化剂催化得到目标化合物。
进一步地，所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物的制备方法，步骤3)中氨基硫脲衍生物4与催化剂的摩尔比为1:2-10。
进一步地，所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物的制备方法，步骤3)中反应温度为60-105℃，反应时间1-2h。
进一步地，所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物的制备方法，步骤3)中溶剂选自以下任一种：1,4-二氧六环、四氢呋喃、环己烷、氯仿、二氯甲烷、甲苯、三氟甲苯、二甲苯、氯苯。优选的，所述步骤3)中溶剂选自氯苯或甲苯。
进一步地，所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物的制备方法，步骤3)中催化剂为三氯氧磷。
如5-芳基-1,3,4-噁二唑-2-胺类化合物的用量需求较大，本领域技术人员可以选择用EDC·HCl作为催化剂，DMSO作为溶剂，60℃反应2h即可得到目标产物。
本发明的目的之三是提供5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，及其药学上可接受的盐、结晶水合物及溶剂合物在制备抗流感病毒的药物中的应用。
进一步地，所述流感病毒为甲型流感H3N2或H1N1。
所述“药学上可接受的盐”为5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物与无机酸或有机酸反应形成的常规的无毒盐。例如，盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、草酸盐、柠檬酸盐、扁桃酸盐、烟酸盐、酒石酸盐、棕榈酸盐、苹果酸盐、琥珀酸盐、马来酸盐。
本发明的目的之四是提供一种药物组合物，所述药物组合物包含5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，及其药学上可接受的盐、结晶水合物及溶剂合物中的一种，以及至少一种药学上可接受的药用辅料。所述“药物辅料”是指药物中常规采用的各种辅料，例如赋形剂、控释剂、稳定剂等。
相比现有技术，本发明的有益效果在于：
本发明提供一种5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，结构新颖，对流感病毒具有较好的抑制活性，可以作为潜在的抗流感先导物进一步开发。本发明还提供了上述化合物的制备方法，制备过程简单且产率高，可同时得到两种具有活性的化合物，符合原子经济性，便于商业化生产。本发明还公开了上述化合物以及其药学上可接受的盐、结晶水合物及溶剂合物应用在制备抗流感病毒药物中的应用，对野生型(H3N2)和变异型(H1N1)的流感病毒均具有一定的抑制活性，并且毒副作用较小，显示出良好的开发潜力。本发明还提供了一种包含上述化合物的药物组合物，可根据需要制成各种剂型，对危害人民的健康的流感的预防与治疗具有重要的现实意义和经济效益。
具体实施方式
下面，结合具体实施方式，对本发明做进一步描述，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
实施例1
2-(5-(环己亚胺-1-基)吡嗪-2-基)-5-叔丁基-1,3,4-噁二唑(Ⅰ-1)和2-(5-(环己亚胺-1-基)吡嗪-2-基)-5-叔丁基-1,3,4-噻二唑(Ⅱ-1)的合成
1)以5-氯吡嗪-2-羧酸甲酯为原料，经肼解反应得到5-(环己亚胺-1-基)吡嗪-2-酰肼：取100mL圆底烧瓶，在0℃下，依次加入5-氯吡嗪-2-羧酸甲酯(5.18g,30mmol)，CH3CN(18mL)，环己亚胺(3.27g,33mmol,3.7mL)，搅拌均匀，之后滴加DIPEA(10mL)，加毕，该反应在85℃搅拌回流反应10h。减压旋蒸浓缩，用二氯甲烷(200mL)溶解，依次饱和碳酸氢钠溶液和饱和食盐水洗涤，有机相用无水硫酸钠进干燥，过滤，减压浓缩，得化合物(4.5g)，继续下一步反应。LC-MS(ESI)m/z:[M+H]+calcd for C12H17N3O2,236.17,Found,236.00。
取100mL圆底烧瓶，加入上述得到的化合物(2.0g)，0℃下用注射器少量多次的加入80％水合肼(18mL)，加毕移至80℃油浴中加热搅拌反应。TLC检测反应完全后，多次加入无水乙醇，旋蒸共沸除去水合肼(80％)，浓缩后的反应液呈粘稠状，加入无水乙醇加热溶解，冷却后放入冰箱进行重结晶。将结晶出的固体进行过滤，并用冷的无水乙醇洗涤，得5-(环己亚胺-1-基)吡嗪-2-酰肼共1.72g，产率为86％。
1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.54(d,J＝1.4Hz,1H),8.05(d,J＝1.4Hz,1H),4.41(s,2H),3.70(t,J＝6.0Hz,4H),1.75-1.70(m,4H),1.51-1.45(m,4H).13C NMR(100MHz,DMSO-d6)δ163.1,154.3,141.6,131.6,127.8,47.0,40.1,39.9,39.73,39.5,39.3,39.1,26.8,26.4.LC-MS(ESI)m/z:[M+H]+calcd for C11H17N5O,235.14；Found,235.0。
2)5-(环己亚胺-1-基)吡嗪-2-酰肼与叔丁基异硫氰酸酯反应生成2-(环己亚胺-1-基)吡嗪-2-酰胺基-N-叔丁基-硫脲：取25mL圆底烧瓶，加入上步得到的化合物(235.3mg,1mmol)，叔丁基异硫氰酸酯(126.7mg,1.1mmol)和无水乙醇5mL。加毕，该反应加热至80℃，2h反应完毕。缓慢冷却至室温，再放置冰箱4h，析出固体，过滤并用冷乙醇洗涤固体，干燥得到酰胺基硫脲化合物为淡黄色粉末234mg，产率为66.7％。LC-MS(ESI)m/z:[M+H]+calcdfor C16H26N6OS,351.2；Found:351.2。
3)2-(环己亚胺-1-基)吡嗪-2-酰胺基-N-叔丁基-硫脲在甲苯中，经三氯化磷催化得到2-(5-(环己亚胺-1-基)吡嗪-2-基)-5-叔丁基-1,3,4-噁二唑(Ⅰ-1)和2-(5-(环己亚胺-1-基)吡嗪-2-基)-5-叔丁基-1,3,4-噻二唑(Ⅱ-1)：取10mL圆底烧瓶，依次加入上步得到的酰胺基硫脲化合物(152mg，0.43mmol)，POCl3(131mg，0.86mmol，2equiv.)和甲苯5mL，60℃油浴锅搅拌反应1h。冷却至室温，加入冰水淬灭反应，有白色固体产生，用1M NaOH溶液调pH至碱性，加入二氯甲烷(10mL)萃取三次，有机相经饱和食盐水洗涤，过滤，旋干得粗品110mg。经柱层析纯化得到化合物Ⅰ-1和Ⅱ-1分别为(65mg，产率83.6％)和(43mg，产率78.9％)。
化合物Ⅰ-1：1H NMR(400MHz,Chloroform-d)δ8.75(d,J＝1.4Hz,1H),7.99(d,J＝1.5Hz,1H),4.75(s,1H),3.70(t,J＝6.0Hz,4H),1.85–1.80(m,4H),1.64(s,4H),1.46(s,9H)。13C NMR(100MHz,Chloroform-d)δ162.1,157.3,153.8,141.5,128.7,126.7,52.3,47.6,29.7,29.0,27.4,27.0,26.9.LC-MS(ESI)m/z:[M+K]+calcd for C16H24N6O,317.21；Found,317.2。
化合物Ⅱ-1：1H NMR(400MHz,Chloroform-d)δ8.87(d,J＝1.4Hz,1H),7.89(d,J＝1.4Hz,1H),5.55(d,J＝19.5Hz,1H),3.68(t,J＝6.0Hz,4H),1.81(s,4H),1.57(s,4H),1.45(s,9H)。13C NMR(100MHz,Chloroform-d)δ167.2,159.0,153.8,139.75,132.7,127.8,53.3,47.7,29.8,28.9,27.5,27.1.LC-MS(ESI)m/z:[M+H]+calcd for C16H24N6S,333.19；Found,333.2。
实施例2
2-(5-(环己亚胺-1-基)吡嗪-2-基)-5-叔丁基-1,3,4-噁二唑(Ⅰ-2)和2-(5-(环己亚胺-1-基)吡嗪-2-基)-5-叔丁基-1,3,4-噻二唑(Ⅱ-2)的合成
1)以5-氯吡嗪-2-羧酸甲酯为原料，经肼解反应得到5-(环己亚胺-1-基)吡嗪-2-酰肼：同实施例1中步骤1)。
2)5-(环己亚胺-1-基)吡嗪-2-酰肼与环己基异硫氰酸酯反应生成酰胺基硫脲化合物：取25mL圆底烧瓶，加入上步得到的化合物(300mg,1.28mmol)，环己基异硫氰酸酯(198.1mg,1.4mmol)和无水乙醇5mL。加毕，该反应加热至80℃，4h反应完毕。缓慢冷却至室温，再放置冰箱4h，析出固体，过滤并用冷乙醇洗涤固体，干燥得到环己基酰胺基硫脲化合物为淡黄色粉末378mg，产率为90.3％。LC-MS(ESI)m/z:[M+H]+calcd for C18H29N6OS+,377.21；Found:371.2。
3)环己基酰胺基硫脲化合物在甲苯中，经三氯化磷催化得到2-(5-(环己亚胺-1-基)吡嗪-2-基)-5-叔丁基-1,3,4-噁二唑(Ⅰ-2)和2-(5-(环己亚胺-1-基)吡嗪-2-基)-5-叔丁基-1,3,4-噻二唑(Ⅱ-2)：取20mL圆底烧瓶，环己基酰胺基硫脲化合物(243mg，0.64mmol)，POCl3(392.5mg，2.56mmol，4equiv.)和氯苯5mL，80℃油浴锅搅拌反应2h。冷却至室温，加入冰水淬灭反应，有白色固体产生，用1M NaOH溶液调pH至碱性，加入二氯甲烷(10mL)萃取三次，有机相经饱和食盐水洗涤，过滤，旋干得粗品299mg。经柱层析纯化得到化合物Ⅰ-2和Ⅱ-2分别为(20mg，产率83.3％)和(240mg，产率79.2％)。
化合物I-2：1H NMR(400MHz,Chloroform-d)δ:8.70(d,J＝1.4Hz,1H),7.97(d,J＝1.4Hz,1H),5.02(d,J＝8.0Hz,1H),3.75–3.58(m,5H),2.13–2.05(m,2H),1.80(s,4H),1.72(dt,J＝13.2,4.0Hz,2H),1.65–1.50(m,5H),1.43–1.18(m,5H)；13C:NMR(100MHz,Chloroform-d)δ162.8,157.5,153.8,141.5,128.7,126.7,52.6,47.7,33.3,27.5,27.0,25.5,24.7.LC-MS(ESI)m/z:[M+H]+calcd for C18H26N6O,343.22；Found,343.2。
化合物Ⅱ-2：1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝1.4Hz,1H),8.10(d,J＝1.4Hz,1H),7.79(d,J＝7.4Hz,1H),3.68(t,J＝6.0Hz,4H),3.58–3.47(m,1H),2.03–1.93(m,2H),1.78–1.67(m,6H),1.61–1.53(m,1H),1.51–1.47(m,4H),1.39–1.12(m,6H).13C NMR(101MHz,DMSO-d6)δ167.5,156.4,153.2,138.2,132.2,128.6,53.7,47.0,32.1,26.8,26.4,25.3,24.3.LC-MS(ESI)m/z:[M+H]+calcd for C18H26N6S,359.20；Found,359.2。
如果做活性试验需求较大，化合物I-2的不够，可采用以下方式合成：
取25mL圆底烧瓶，依次加入环己基酰胺基硫脲化合物(282mg,0.75mmol)，EDC·HCl(215.4mg,1.12mmol)，二甲基亚砜DMSO(1.8mL)，60℃油浴锅搅拌反应。TLC跟踪检测反应。待检测反应完全后，向反应液中加入蒸馏水淬灭反应。用二氯甲烷萃取3次，饱和食盐水洗涤2次，合并有机相，并用无水硫酸钠进行干燥，过滤，减压浓缩。残留物经硅胶柱色谱纯化，洗脱剂为环己烷:丙酮＝10:1-6:1，得淡黄色固体产物(222.5mg，产率90.7％)。
化合物Ⅰ-2：1H NMR(400MHz,Chloroform-d)δ:8.70(d,J＝1.4Hz,1H),7.97(d,J＝1.4Hz,1H),5.02(d,J＝8.0Hz,1H),3.75–3.58(m,5H),2.13–2.05(m,2H),1.80(s,4H),1.72(dt,J＝13.2,4.0Hz,2H),1.65–1.50(m,5H),1.43–1.18(m,5H)；13C:NMR(100MHz,Chloroform-d)δ162.8,157.5,153.8,141.5,128.7,126.7,52.6,47.7,33.3,27.5,27.0,25.5,24.7.LC-MS(ESI)m/z:[M+H]+calcd for C18H26N6O,343.22；Found,343.2。
实施例3
5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-((1R,2R,3R,5S)-2,6,6-三甲基二环[3.1.1]庚-3-基)-1,3,4-噁二唑-2-胺(Ⅰ-3)和5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-((1R,2R,3R,5S)-2,6,6-三甲基二环[3.1.1]庚-3-基)-1,3,4-噻二唑-2-胺(Ⅱ-3)的合成
将实施例1中步骤2)叔丁基异硫氰酸酯换成蒎烷基-3-异硫氰酸酯，其他操作同实施例1。得到5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-((1R,2R,3R,5S)-2,6,6-三甲基二环[3.1.1]庚-3-基)-1,3,4-噁二唑-2-胺(Ⅰ-3)和5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-((1R,2R,3R,5S)-2,6,6-三甲基二环[3.1.1]庚-3-基)-1,3,4-噻二唑-2-胺(Ⅱ-3)，经柱层析纯化得到化合物Ⅰ-3和Ⅱ-3分别是(10mg，产率83.3％)和(140mg，产率为85.3％)。
其中蒎烷基-3-异硫氰酸酯合成过程如下：取250mL圆底烧瓶，室温下依次加入蒎烷胺(4.5g,29.4mmol)，CS2(22.4g,293.6mmol)，溶于三乙胺(3.0g,29.4mmol)与无水乙醇(25mL)，加料结束后，蒎烷胺完全溶解，溶解后溶液呈黄褐色，室温搅拌反应1.5h。之后，在0℃下加入DMAP(0.1g)。另外再取25mL圆底烧瓶用无水乙醇(10mL)溶解Boc2O酸酐(6.6g,57.0mmol)，并将该混合液用注射器少量多次地在低温环境下加入上述反应液中。加完后反应0.5h再转至室温继续反应2.5h，TLC检测反应情况。待反应完全后，取出进行减压浓缩去溶剂，用硅胶柱色谱纯化，环己烷作为洗脱剂，得蒎烷基-3-异硫氰酸酯(3.87g,产率67.4％)，冰箱冷藏备用。
化合物Ⅰ-3:1H NMR(400MHz,CDCl3)δ:8.73(d,J＝1.4Hz,1H),7.99(d,J＝1.4Hz,1H,),4.86(d,J＝8.4Hz,1H),4.140-4.039(m,1H),3.74–3.696(m,4H),2.82–2.74(m,1H),2.55–2.399(m,1H),2.01–1.97(m,1H),1.94–1.902(m,1H),1.88–1.82(m,5H),1.75–1.70(m,1H),1.61–1.55(m,4H),1.24(s,3H),1.19(d,J＝7.2Hz,3H),1.05(s,3H),0.95(d,J＝10.0Hz)；13C NMR(100MHz,DMSO-d6)δ:163.1,157.6,153.8,141.6,128.7,126.6,52.9,47.8,47.7,46.6,41.6,38.5,37.4,35.0,28.0,27.5,27.1,23.57,21.0.LC-MS(ESI)m/z:[M+H]+calcd for C22H32N6O,397.27；Found:397.2。
化合物Ⅱ-3：1H NMR(400MHz,Chloroform-d)δ:8.85(d,J＝1.4Hz,1H),7.88(d,J＝1.4Hz,1H),6.13(s,1H),3.85–3.77(m,1H),3.68(t,J＝6.0Hz,4H),2.80–2.72(m,1H),2.45–2.40(m,1H),2.03–1.98(m,2H),1.89–1.74(m,7H),1.58–1.55(m,4H),1.24(s,3H),1.19(d,J＝7.2Hz,3H),1.03(s,3H),1.01(d,J＝10Hz,1H).13C NMR(100MHz,Chloroform-d)δ:170.8,158.0,153.8,139.7,132.8,127.8,57.8,47.7,46.5,41.6,38.6,36.8,35.0,28.0,27.6,27.1,23.5,21.3.LC-MS(ESI)m/z:[M+H]+calcd for C22H32N6S,413.25；Found:413.0。
如果做活性试验时需求较大，化合物Ⅰ-3的量不够，合成方法同实施例2用EDCHCl催化，得到化合物Ⅰ-3 186mg,产率为92％。
化合物Ⅰ-3:1H NMR(400MHz,CDCl3)δ:8.73(d,J＝1.4Hz,1H),7.99(d,J＝1.4Hz,1H,),4.86(d,J＝8.4Hz,1H),4.140-4.039(m,1H),3.74–3.696(m,4H),2.82–2.74(m,1H),2.55–2.399(m,1H),2.01–1.97(m,1H),1.94–1.902(m,1H),1.88–1.82(m,5H),1.75–1.70(m,1H),1.61–1.55(m,4H),1.24(s,3H),1.19(d,J＝7.2Hz,3H),1.05(s,3H),0.95(d,J＝10.0Hz)；13C NMR(100MHz,DMSO-d6)δ:163.1,157.6,153.8,141.6,128.7,126.6,52.9,47.8,47.7,46.6,41.6,38.5,37.4,35.0,28.0,27.5,27.1,23.57,21.0.LC-MS(ESI)m/z:[M+H]+calcd for C22H32N6O,397.27；Found:397.2。
实施例4
N-((3S,5S,7S)-金刚烷-1-基)-5-(5-(环己亚胺-1-基)吡嗪-2-基)-1,3,4-1,3,4-噁二唑-2-胺(Ⅰ-4)和N-((3S,5S,7S)-金刚烷-1-基)-5-(5-(环己亚胺-1-基)吡嗪-2-基)-1,3,4-1,3,4-噻二唑-2-胺(Ⅱ-4)的合成
将实施例1的步骤2)中的叔丁基异硫氰酸酯换做异硫氰酸1-金刚烷酯，其他操作同实施例1，得到N-((3S,5S,7S)-金刚烷-1-基)-5-(5-(环己亚胺-1-基)吡嗪-2-基)-1,3,4-1,3,4-噁二唑-2-胺(Ⅰ-4)和N-((3S,5S,7S)-金刚烷-1-基)-5-(5-(环己亚胺-1-基)吡嗪-2-基)-1,3,4-1,3,4-噻二唑-2-胺(Ⅱ-4)，经柱层析纯化得到化合物Ⅰ-4和Ⅱ-4分别是(90mg，产率97％))和(75.2mg，产率94.1％)。
化合物Ⅰ-4：1H NMR(400MHz,DMSO-d6)δ:8.53(d,J＝1.4Hz,1H),8.19(d,J＝1.4Hz,1H),7.60(s,1H),3.70(t,J＝5.8Hz,4H),2.07(s,3H),1.98(s,7H),1.74(s,4H),1.64(s,6H),1.49(s,4H).13C NMR(100MHz,DMSO-d6)δ:161.6,156.1,153.3,140.3,129.3,126.2,51.1,46.9,40.9,35.9,28.9,26.8,26.4。LC-MS(ESI)m/z:[M+H]+calcd for C22H30N6O,395.26；Found:395.2。
化合物Ⅱ-4：1H NMR(400MHz,Chloroform-d)δ:8.87(d,J＝1.4Hz,1H),7.89(d,J＝1.4Hz,1H),5.45(s,1H),3.68(t,J＝6.0Hz,4H),2.14(s,4H),2.03(s,8H),1.87–1.77(m,6H),1.69(s,9H),1.58–1.56(m,5H),1.24(s,4H).13C NMR(100MHz,Chloroform-d)δ:166.3,159.0,153.8,139.8,132.8,127.8,53.4,47.7,41.8,36.3,29.8,29.6,27.6,27.1.LC-MS(ESI)m/z:[M+H]+calcd for C22H30N6S,411.23；Found:411.1。
实施例5
5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-苯基-1,3,4-噁二唑-2-胺(Ⅰ-5)和5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-苯基-1,3,4-噻二唑-2-胺(Ⅱ-5)的合成
将实施例1的步骤2)中的叔丁基异硫氰酸酯换做异硫氰酸苯酯，其他操作同实施例1，得到5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-苯基-1,3,4-噁二唑-2-胺(Ⅰ-5)和5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-苯基-1,3,4-噻二唑-2-胺(Ⅱ-5)，经柱层析纯化得到化合物Ⅰ-5和Ⅱ-5分别是(50mg，产率96.1％)和(280mg，产率95.3％)。
化合物Ⅰ-5：1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.65(d,J＝1.4Hz,1H),8.24(d,J＝1.5Hz,1H),7.63–7.56(m,2H),7.40–7.30(m,2H),7.03–6.98(m,1H),3.73(t,J＝6.0Hz,4H),1.75(s,4H),1.52–1.49(m,4H).13C NMR(100MHz,DMSO-d6)δ：159.6,156.8,153.5,140.9,138.7,129.6,129.1,125.6,121.8,116.9,47.0,26.8,26.4.LC-MS(ESI)m/z:[M+H]+calcd for C18H20N6O,337.18；Found:317.1。
化合物Ⅱ-5：1H NMR(400MHz,DMSO-d6)δ:10.45(s,1H),8.75(d,J＝1.4Hz,1H),8.16(d,J＝1.4Hz,1H),7.64(d,J＝8.6Hz,2H),7.39–7.32(m,2H),7.04–6.97(m,1H),3.71(t,J＝6.0Hz,4H),1.78–1.72(m,4H),1.52–1.46(m,4H).13C NMR(100MHz,DMSO-d6)δ:163.8,158.6,153.5,140.7,138.7,131.5,129.2,129.0,121.9,117.4,47.1,40.2,39.9,39.7,39.5,39.3,39.1,38.9,26.8,26.4.LC-MS(ESI)m/z:[M+H]+calcd for C18H20N6S,353.15；Found:353.1。
实施例6
5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对甲苯基-1,3,4-噁二唑-2-胺(Ⅰ-6)和5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对甲苯基-1,3,4-噻二唑-2-胺(Ⅱ-6)的合成
将实施例1的步骤2)中的叔丁基异硫氰酸酯换做对甲苯异硫氰酸酯，其他操作同实施例1，得到5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对甲苯基-1,3,4-噁二唑-2-胺(Ⅰ-6)和5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对甲苯基-1,3,4-噻二唑-2-胺(Ⅱ-6)，经柱层析纯化得到化合物Ⅰ-6和Ⅱ-6分别是(24mg，产率83％)和(286mg，产率85.1％)。
化合物Ⅰ-6：1H NMR(400MHz,DMSO-d6)δ:10.57(s,1H),8.63(d,J＝1.4Hz,1H),8.24(d,J＝1.4Hz,1H),7.48(d,J＝8.4Hz,2H),7.16(d,J＝8.4Hz,2H),3.72(t,J＝6.0Hz,4H),2.26(s,3H),1.75(s,4H),1.53–1.49(m,4H).13C NMR(100MHz,DMSO-d6)δ:159.7,156.6,153.5,140.8,136.3,130.6,129.6,129.5,125.7,116.9,47.0,26.8,26.4,20.4.LC-MS(ESI)m/z:[M+H]+calcd for C19H22N6O,351.19；Found:352.2。
化合物Ⅱ-6：1H NMR(400MHz,DMSO-d6)δ:10.73(s,1H),8.73(d,J＝1.4Hz,1H),8.15(d,J＝1.4Hz,1H),7.58(d,J＝8.4Hz,2H),7.14(d,J＝8.4Hz,2H),3.70(t,J＝6.0Hz,4H),2.26(s,3H),1.74(s,4H),1.49 1.51–1.48(m,4H).13C NMR(100MHz,DMSO-d6)δ:163.9,158.2,153.4,138.6,138.5,131.7,130.5,129.4,128.9,117.4,47.1,26.8,26.4,20.4.LC-MS(ESI)m/z:[M+H]+calcd for C19H22N6S,367.17；Found:367.2。
如果做活性试验时需求较大，化合物Ⅰ-6的量不够，合成方法同实施例2用EDCHCl催化，得到化合物Ⅰ-6 120.1mg，产率为93.5％。
化合物Ⅰ-6：1H NMR(400MHz,DMSO-d6)δ:10.57(s,1H),8.63(d,J＝1.4Hz,1H),8.24(d,J＝1.4Hz,1H),7.48(d,J＝8.4Hz,2H),7.16(d,J＝8.4Hz,2H),3.72(t,J＝6.0Hz,4H),2.26(s,3H),1.75(s,4H),1.53–1.49(m,4H).13C NMR(100MHz,DMSO-d6)δ:159.7,156.6,153.5,140.8,136.3,130.6,129.6,129.5,125.7,116.9,47.0,26.8,26.4,20.4.LC-MS(ESI)m/z:[M+H]+calcd for C19H22N6O,351.19；Found:352.2。
实施例7
5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对氟苯基-1,3,4-噁二唑-2-胺(Ⅰ-7)和5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对氟苯基-1,3,4-噻二唑-2-胺(Ⅱ-7)的合成
将实施例1的步骤2)中的叔丁基异硫氰酸酯换做4-氟异硫氰酸苯酯，其他操作同实施例1，得到5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对氟苯基-1,3,4-噁二唑-2-胺(Ⅰ-7)和5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对氟苯基-1,3,4-噻二唑-2-胺(Ⅱ-7)，经柱层析纯化得到化合物Ⅰ-7和Ⅱ-7分别是(50.6mg，产率为76.4％)和(283.2mg，产率为93.7％)。
化合物Ⅰ-7：1H NMR(400MHz,DMSO-d6)δ:10.73(s,1H),8.63(d,J＝1.4Hz,1H),8.23(d,J＝1.4Hz,1H),7.64–7.57(m,2H),7.28–7.05(m,2H),3.72(t,J＝6.0Hz,4H),1.75(s,4H),1.51–1.48(m,4H).13C NMR(100MHz,DMSO-d6)δ:159.6,157.3(d,1JCF＝236.5Hz),156.8,153.5,140.9,135.2,129.6,125.6,118.5(d,3JCF＝7.8Hz),115.7(d,2JCF＝22.3Hz),47.0,26.8,26.4.LC-MS(ESI)m/z:[M+H]+calcd for C18H19N6O,355.17；Found:355.1。
化合物Ⅱ-7：1H NMR(400MHz,DMSO-d6)δ:10.47(s,1H),8.74(d,J＝1.4Hz,1H),8.16(d,J＝1.4Hz,1H),7.71–7.64(m,2H),7.24–7.14(m,2H),3.71(t,J＝6.0Hz,4H),1.74(s,4H),1.51–1.48(m,4H).13C NMR(100MHz,DMSO-d6)δ:163.9,158.6,157.2(d,1JCF＝237.2Hz),153.5,138.7,137.2,131.4,129.0,119.1(d,3JCF＝7.8Hz),115.7(d,2JCF＝22.3Hz),47.10,26.8,26.4.LC-MS(ESI)m/z:[M+H]+calcd for C18H19N6S,371.14；Found:371.1。
实施例8
5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对三氟甲基苯基-1,3,4-噁二唑-2-胺(Ⅰ-8)和5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对三氟甲基苯基-1,3,4-噻二唑-2-胺(Ⅱ-8)的合成
将实施例1的步骤2)中的叔丁基异硫氰酸酯换做4-三氟甲基苯基异硫氰酸酯，其他操作同实施例1，得到5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对三氟甲基苯基-1,3,4-噁二唑-2-胺(Ⅰ-8)和5-(5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-对三氟甲基苯基-1,3,4-噻二唑-2-胺(Ⅱ-8)，经柱层析纯化得到化合物Ⅰ-8和Ⅱ-8分别是(20mg，产率为99％)和387.2mg，产率为96.9％)。
化合物Ⅰ-8：1H NMR(400MHz,DMSO-d6)δ:11.19(s,1H),8.65(d,J＝1.4Hz,1H),8.24(d,J＝1.4Hz,1H),7.78(d,J＝8.6Hz,2H),7.72(d,J＝8.6Hz,2H),3.72(t,J＝6.0Hz,4H),1.75(s,4H),1.75–1.48(m,4H).13C NMR(100MHz,DMSO-d6)δ159.17,157.20,153.57,142.23,141.06,129.71,128.7,126.5(q,J＝3.6Hz),125.4,124.2(q,J＝270.0Hz),116.9,47.0,26.8,26.4.LC-MS(ESI)m/z:[M+H]+calcd for C19H19F3N6O,404.06；Found:404.9。
化合物Ⅱ-8：1H NMR(400MHz,DMSO-d6)δ:8.73(d,J＝1.4Hz,1H),8.14(d,J＝1.4Hz,1H),7.81(d,J＝8.6Hz,2H),7.67(d,J＝8.6Hz,2H),3.68(t,J＝6.0Hz,4H),1.71(s,4H),1.71–1.45(m,4H).13C NMR(100MHz,DMSO-d6)δ:163.2,159.8,153.7,143.9,138.9,131.2,129.2,126.5(q,J＝3.6Hz),126.0,124.4(q,J＝272.3Hz),117.3,47.2,26.8,26.4.LC-MS(ESI)m/z:[M+H]+calcd for C19H19F3N6S,421.14；Found:421.0。
如果做活性试验时需求较大，化合物Ⅰ-8的量不够，合成方法同实施例2用EDCHCl催化，得到化合物Ⅰ-8 193.1mg，产率为95.7％。
化合物Ⅰ-8：1H NMR(400MHz,DMSO-d6)δ:11.19(s,1H),8.65(d,J＝1.4Hz,1H),8.24(d,J＝1.4Hz,1H),7.78(d,J＝8.6Hz,2H),7.72(d,J＝8.6Hz,2H),3.72(t,J＝6.0Hz,4H),1.75(s,4H),1.75–1.48(m,4H).13C NMR(100MHz,DMSO-d6)δ159.17,157.20,153.57,142.23,141.06,129.71,128.7,126.5(q,J＝3.6Hz),125.4,124.2(q,J＝270.0Hz),116.9,47.0,26.8,26.4.LC-MS(ESI)m/z:[M+H]+calcd for C19H19F3N6O,404.06；Found:404.9。
实施例9
5-(6-(环己亚胺-1-基)吡啶-3-基)-N-环己基-1,3,4-噁二唑-2-胺(Ⅰ-9)和5-(6-(环己亚胺-1-基)吡啶-3-基)-N-环己基-1,3,4-噻二唑-2-胺(Ⅱ-9)的合成
将实施例2的步骤1)中的5-氯吡嗪-2-羧酸甲酯换做5-氯吡嗪-2-羧酸甲酯，其他操作同实施例2，得到5-(6-(环己亚胺-1-基)吡啶-3-基)-N-环己基-1,3,4-噁二唑-2-胺(Ⅰ-9)和5-(6-(环己亚胺-1-基)吡啶-3-基)-N-环己基-1,3,4-噻二唑-2-胺(Ⅱ-9)，经柱层析纯化得到化合物Ⅰ-9和Ⅱ-9分别是(35mg，产率为89.3％)和(288.9mg，产率为91.3％)。
化合物Ⅰ-9：1H NMR(400MHz,Chloroform-d)δ:8.57(d,J＝2.4Hz,1H),7.92(dd,J＝9.0,2.4Hz,1H),6.52(d,J＝9.0Hz,1H),4.80(d,J＝7.6Hz,1H),3.66(t,J＝5.8Hz,4H),3.62–3.54(m,1H),2.14–2.08(m,2H),1.82–1.76(m,5H),1.74(t,J＝4.0Hz,1H),1.65–1.61(m,1H),1.58–1.53(m,4H),1.45–1.29(m,5H),1.28–1.16(m,5H).13C NMR(100MHz,Chloroform-d)δ:158.8,158.1,146.3,134.8,108.5,105.3,52.8,47.9,33.4,29.8,27.7,27.2,25.6,24.8.LC-MS(ESI)m/z:[M+H]+calcd for C19H27N5O,342.23；Found:342.2。
化合物Ⅱ-9：1H NMR(400MHz,Chloroform-d)δ:8.41(d,J＝2.4Hz,1H),7.91(dd,J＝9.0,2.4Hz,1H),6.50(d,J＝9.0Hz,1H),5.66(s,1H),3.64(t,J＝6.0Hz,4H),3.44–3.30(m,1H),2.13–2.09(m,2H),1.78(s,6H),1.57–1.51(m,4H),1.44–1.16(m,6H).13C NMR(100MHz,Chloroform-d)δ:167.9,158.6,155.8,147.3,135.2,115.4,105.4,77.5,77.2,76.8,56.4,47.8,33.1,27.8,27.2,25.6,24.8.LC-MS(ESI)m/z:[M+H]+calcd forC19H27N5S,358.21；Found:358.2。
实施例10
5-(6-(环己亚胺-1-基)吡啶-3-基)-N-N-((1R,2R,3R,5S)-2,6,6-三甲基二环[3.1.1]庚-3-基)-1,3,4-噁二唑-2-胺(Ⅰ-10)和5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-((1R,2R,3R,5S)-2,6,6-三甲基二环[3.1.1]庚-3-基)-1,3,4-噻二唑-2-胺(Ⅱ-10)的合成
将实施例3的步骤1)中的5-氯吡嗪-2-羧酸甲酯换成5-氯吡啶-2羧酸甲酯，其他操作同实施例3，得到5-(6-(环己亚胺-1-基)吡啶-3-基)-N-N-((1R,2R,3R,5S)-2,6,6-三甲基二环[3.1.1]庚-3-基)-1,3,4-噁二唑-2-胺(Ⅰ-10)和5-(5-(环己亚胺-1-基)吡嗪-2-基)-N-((1R,2R,3R,5S)-2,6,6-三甲基二环[3.1.1]庚-3-基)-1,3,4-噻二唑-2-胺(Ⅱ-10)，经柱层析纯化得到化合物Ⅰ-10和Ⅱ-10分别是(32mg，产率89.1％)和(323.2mg，产率86.3％)。
化合物Ⅰ-10：1H NMR(400MHz,Chloroform-d)δ:8.58(d,J＝2.4Hz,1H),7.93(dd,J＝9.0,2.4Hz,1H),6.52(d,J＝9.0Hz,1H),4.93(d,J＝8.4Hz,1H),4.06–3.99(m,1H),3.66(t,J＝5.8Hz,4H),2.79–2.71(m,1H),2.45–2.39(m,1H),2.01–1.96(m,2H),1.87–1.84m,1H),1.83–1.70(m,5H),1.58–1.52(m,4H),1.24(s,3H),1.19(d,J＝7.2Hz,3H),1.04(s,3H),0.96(d,J＝10.0Hz,1H).13C NMR(100MHz,Chloroform-d)δ:162.9,158.9,158.2,146.3,134.7,108.6,105.4,53.1,47.9,47.8,46.5,41.7,38.5,37.5,35.1,28.0,27.7,27.2,23.6,21.1.LC-MS(ESI)m/z:[M+H]+calcd for C23H33N5O,396.28；Found:396.2。
化合物Ⅱ-10：1H NMR(400MHz,Chloroform-d)δ:8.43(d,J＝2.4Hz,1H),7.94(dd,J＝9.0,2.4Hz,1H),6.53(d,J＝9.0Hz,1H),5.10(d,J＝7.6Hz,1H),3.93–3.87(m,1H),3.67(t,J＝6.0Hz,4H),2.81–2.74(m,1H),2.49–2.36(m,1H),2.04–1.98(m,1H),1.94–1.85(m,2H),1.80(s,4H),1.77–1.71(m,1H),1.61(s,2H),1.58–1.55(m,4H),1.25(s,4H),1.20(d,J＝7.1Hz,3H),1.05(s,3H),0.94(d,J＝10.0Hz,1H).13C NMR(100MHz,Chloroform-d)δ:168.7,158.7,155.9,147.3,135.2,115.4,105.4,57.0,47.9,47.7,46.6,41.6,38.6,37.1,34.9,28.0,27.8,27.2,23.6,21.3.LC-MS(ESI)m/z:[M+H]+calcd for C23H33N5S,413.25；Found:413.2。
实施例11
N-((3S,5S,7S)-金刚烷-1-基)-5-(6-(环己亚胺-1-基)吡啶-3-基)-1,3,4-噁二唑-2-胺(Ⅰ-11)和N-((3S,5S,7S)-金刚烷-1-基)-5-(6-(环己亚胺-1-基)吡啶-3-基)-1,3,4-噻二唑-2-胺(Ⅱ-11)的合成
将实施例4的步骤1)中的5-氯吡嗪-2-羧酸甲酯换成5-氯吡啶-2羧酸甲酯，其他操作同实施例4，得到N-((3S,5S,7S)-金刚烷-1-基)-5-(6-(环己亚胺-1-基)吡啶-3-基)-1,3,4-噁二唑-2-胺(Ⅰ-11)和N-((3S,5S,7S)-金刚烷-1-基)-5-(6-(环己亚胺-1-基)吡啶-3-基)-1,3,4-噻二唑-2-胺(Ⅱ-11)，经柱层析纯化得到化合物Ⅰ-11和Ⅱ-11分别是(22.5mg，产率为96.3％)和(365.8mg，产率为93.8％)。
化合物Ⅰ-11：1H NMR(400MHz,DMSO-d6)δ:8.43(d,J＝2.4Hz,1H),7.80(dd,J＝9.0,2.4Hz,1H),7.44(s,1H),6.73(d,J＝9.0Hz,1H),3.65(s,4H),2.06(s,3H),1.97(s,6H),1.71(s,4H),1.64(s,6H),1.47(s,4H).13C NMR(100MHz,DMSO-d6)δ:161.1,158.3,156.2,145.3,134.1,105.5,51.1,47.2,40.9,35.9,28.9,27.0,26.5.LC-MS(ESI)m/z:[M+H]+calcd for C23H31N5O,394.29；Found:394.2。
化合物Ⅱ-11：1H NMR(400MHz,Chloroform-d)δ:8.43(d,J＝2.4Hz,1H),7.92(dd,J＝9.0,2.4Hz,1H),6.51(d,J＝9.0Hz,1H),5.28(s,1H),3.65(t,J＝6.0Hz,4H),2.14(s,3H),2.03(s,6H),1.81–1.76(m,4H),1.69(s,6H),1.57–1.53(m,4H).13C NMR(100MHz,Chloroform-d)δ:164.8,158.7,156.7,147.4,135.2,115.3,105.4,53.6,47.8,41.9,36.3,29.6,27.8,27.2.LC-MS(ESI)m/z:[M+H]+calcd for C23H31N5S,410.24；Found:410.1。
实施例12
N-((3S,5S,7S)-金刚烷-1-基)-5-((6S,8S)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基异喹啉-3-yl)-1,3,4-噁二唑-2-胺(Ⅰ-12)和N-((3S,5S,7S)-金刚烷-1-基)-5-((6S,8S)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基异喹啉-3-yl)-1,3,4-噻二唑-2-胺(Ⅱ-12)的合成
1)以(6S,8S)-7,7-二甲基-3-(噻吩-2-基)-5,6,7,8-四氢-6,8-亚甲基异喹啉-3-羧酸甲酯为原料，经肼解反应得到(6S,8S)-7,7-二甲基-3-(噻吩-2-基)-5,6,7,8-四氢-6,8-亚甲基异喹啉-3-甲酰肼：在250mL圆底烧瓶中加入2-乙酰基呋喃(10.0g，90.9mmol)，单质碘(23.1g，90.9mmol)，吡啶(9.54mL,118.2mmol)，回流加热45min，将上述混合物在冰水中冷却，析出固体过滤，在使用甲醇重结晶，收集滤渣，旋蒸后称重，得43g黄色吡啶碘盐衍生物，产率为78％。
在250mL圆底烧瓶中依次加入上步得到的吡啶碘盐衍生物(30.0g，95.2mmol)、乙酸铵(73.4g)、冰乙酸(250mL)，加热到100℃，滴加桃金娘烯醛4.04mL。加毕，将反应混合物加热至120℃，反应6h。冷却至室温，减压蒸除去部分乙酸，加水稀释，用乙酸乙酯萃取，硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析纯化(石油醚/乙酸乙酯，10：1)得到(6S,8S)-7,7-二甲基-3-(呋喃-2-基)-5,6,7,8-四氢-6,8-亚甲基异喹啉为黄色粘稠状液体13.73g，产率为53％。
将制备得到的四氢异喹啉衍生物(7.18g,30mmol)和偏钒酸铵(700mg,5.98mmol)，加入到250mL圆底烧瓶中，加100mL水，之后加入浓硝酸(65mL)，在回流装置中搅拌4h。蒸馏法将水和硝酸从180℃的蒸馏液中蒸除，在蒸馏的末端用真空，以确保反应混合物的干燥，得到(6S,8S)-7,7-二甲基-3-(噻吩-2-基)-5,6,7,8-四氢-6,8-亚甲基异喹啉-3-羧酸为棕红色粘稠状液体(5.2g，产率79.7％)。
取上述制备得到的羧酸(2.25g,10.26mmol)和无水甲醇100mL加入200mL圆底烧瓶中，冷却至0℃，缓慢滴加SOCl2(1.52mL,20.52mmol)并加热回流中(85℃)搅拌反应3.0h。冷却至室温，将反应混合物中的乙醇和过量的SOCl2减压蒸发除去，向残留物中加入饱和的碳酸氢钠溶液80mL。用乙酸乙酯(40mL)萃取3次，饱和食盐水洗涤(80mL)2次，然后将有机层用无水硫酸钠干燥，过滤并旋干得粗品为棕色液体，经硅胶柱层析纯化(石油醚/乙酸乙酯，10:1～2:1)得到(6S,8S)-7,7-二甲基-3-(噻吩-2-基)-5,6,7,8-四氢-6,8-亚甲基异喹啉-3-羧酸甲酯为棕黄色液体(1.3g，产率52％)。LC-MS(ESI):m/z[M+H]+calcd.for C15H19NO2,246.15,Found:246.2。
在50mL圆底烧瓶中加入上步得到的酯(940mg,3.83mmol)和80％水合肼15mL，加毕后转移至80℃油浴锅中回流搅拌，7h后反应完全。多次加入无水乙醇，旋蒸共沸除去部分水合肼，残留物经硅胶柱层析(石油醚/乙酸乙酯，10：1)出化得到(6S,8S)-7,7-二甲基-3-(噻吩-2-基)-5,6,7,8-四氢-6,8-亚甲基异喹啉-3-甲酰肼为棕黄色液体(658mg,74.3％)。LC-MS(ESI)m/z：[M+H]+calcd for C13H11N3O,232.14；found,232.2。
2)(6S,8S)-7,7-二甲基-3-(噻吩-2-基)-5,6,7,8-四氢-6,8-亚甲基异喹啉-3-甲酰肼与异硫氰酸1-金刚烷酯反应生成金刚烷基酰胺基硫脲化合物：在50mL圆底烧瓶中加入上步制备的酰肼(658mg,2.7mmol)和异硫氰酸1-金刚烷酯(630mg,3.24mmol)和无水乙醇15mL，加毕，该反应加热至80℃，TLC板检测跟踪反应(石油醚/乙酸乙酯，2:1)，8h反应完全。冷却至0℃，有白色固体析出，过滤并干燥得到金刚烷基酰胺基硫脲化合物(876.1mg，产率76.8％)。LC-MS(m/z)：[M+H]+calcd for C24H32N4OS,425.23,found,425.2。
3)金刚烷基酰胺基硫脲化合物在甲苯中，经三氯化磷催化得到N-((3S,5S,7S)-金刚烷-1-基)-5-((6S,8S)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基异喹啉-3-yl)-1,3,4-噁二唑-2-胺(Ⅰ-12)和N-((3S,5S,7S)-金刚烷-1-基)-5-((6S,8S)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基异喹啉-3-yl)-1,3,4-噻二唑-2-胺(Ⅱ-12)：取20mL圆底烧瓶，金刚烷基酰胺基硫脲化合物(271mg，0.64mmol)，POCl3(981.25mg，6.4mmol，10equiv.)和甲苯5mL，105℃油浴锅搅拌反应2h。冷却至室温，加入冰水淬灭反应，有白色固体产生，用1M NaOH溶液调pH至碱性，加入二氯甲烷(10mL)萃取三次，有机相经饱和食盐水洗涤，过滤，旋干得粗品N-((3S,5S,7S)-金刚烷-1-基)-5-((6S,8S)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基异喹啉-3-yl)-1,3,4-噁二唑-2-胺(Ⅰ-12)和N-((3S,5S,7S)-金刚烷-1-基)-5-((6S,8S)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基异喹啉-3-yl)-1,3,4-噻二唑-2-胺(Ⅱ-12)的混合物为247mg，经柱层析纯化(环己烷/丙酮，6:1～1:1)得到化合物Ⅰ-12和Ⅱ-12分别为(106.3mg，产率87.8％)和(127.8mg，产率95.8.1％)。
化合物Ⅰ-12：1H NMR(400MHz,CDCl3)δ：8.16(s,1H),7.88(s,1H),4.90(s,1H),3.01(d,J＝2.8Hz,H),2.84(t,J＝5.2Hz,1H),2.72-2.66(m,1H),2.32-2.32(m,1H),2.13(s,3H),2.05(d,J＝2.8Hz,6H),1.69(s,6H),1.40(s,3H),1.23-1.19(m,1H),0.61(s,3H).13CHMR(100MHz，CDCl3)δ：162.0,158.3,146.0,145.9,144.4,142.2,121.2,52.6,44.7,41.8,41.8,39.9,39.2,36.2,36.2,32.9,31.6,29.6,26.0,21.4.LC-MS(ESI)m/z:[M+H]+calcdfor C24H30N4O,391.24；found,391.3。
化合物Ⅱ-12：1H NMR(400MHz,Chloroform-d)δ:8.09(s,1H),7.98(s,1H),5.42(s,1H),3.03(d,J＝2.8Hz,2H),2.84(t,J＝5.2Hz,1H),2.74-2.68(m,1H),2.34-2.69(m,1H),2.16(s,3H),2.03(d,J＝2.8Hz,6H),1.71(t,J＝2.8Hz,6H),1.62-1.60(m,2H),1.41(s,3H),1.23(d,J＝9.6Hz,1H),0.64(s,3H).13C NMR(100MHz,Chloroform-d)δ:167.3,160.7,148.3,145.7,145.5,143.7,119.3,53.2,44.7,41.6,40.0,39.4,36.2,32.9,31.8,29.6,26.0,21.5.LC-MS(ESI)m/z:[M+H]+calcd for C24H30N4S,407.23；found,407.2。
试验例1
体外抗流感病毒活性测试：为评价所合成的化合物的体外抗流感病毒活性，选用病毒株如下：金刚烷胺敏感性病毒株A/Hong Kong/8/68(H3N2)，金刚烷胺耐药病毒株A/WS/33(H1N1)和A/PR/8/34(H1N1)。这些病毒株经鸡胚扩增后，以Reed-Muench法测定其半数感染量(TCID50)。之后，在感染MDCK细胞上通过CPE抑制试验验证待测试化合物的抗流感活性。金刚烷胺(AMD)和奥司他韦磷酸盐(OSV-P)以MEM溶解，测试药物以DMSO溶解，室温保存。
(1)抗病毒药效试验
用10000转/min离心1分钟，把药物离心至管底部，然后加入100μL DMSO，再用含1.5μg/mL TPCK的MEM培养液溶解至待测浓度，DMSO终浓度为0.5％。96孔板单层细胞以PBS洗涤1次，加入含约100TCID50的病毒稀释液100μL/孔，37℃、5％CO2培养箱中孵育2小时，弃去病毒液，加入2倍梯度稀释的药物，浓度范围为37.6-1.2μM，每个浓度设置4个复孔，在37℃、5％CO2培养箱中孵育48h。在显微镜下观察细胞病变(CPE)，如果对照组细胞已全部死亡，表示流感病毒完全感染细胞，引起细胞病变。细胞出现CPE按6级标准记录(如表1所示)。拍打细胞培养板，然后小心用吸液器吸掉培养基，加入1：10的CCK8检测试剂，每孔50μL。然后放到37℃孵箱培养2h，测A450吸收值。用Prism non-regression analysis计算药物半数有效浓度(EC50)，结果如表2所示。
表1 病毒引起CPE的6级标准
| 细胞形态 | 病变范围 |
| 细胞生长正常，无病变出现 | － |
| 细胞病变少于整个单层细胞的10％ | ± |
| 细胞病变约占整个单层细胞的25％ | + |
| 细胞病变约占整个单层细胞的50％ | ++ |
| 细胞病变约占整个单层细胞的75％ | +++ |
| 细胞病变约占整个单层细胞的75％以上 | ++++ |
(2)化合物毒性测试实验步骤
用MTT法测定化合物的细胞毒性。取状态良好的MDCK细胞按每孔2×104接种96孔板，37℃，5％CO2孵育24小时，MDCK细胞长成单层。24小时后，吸去培养上清，用50μL/孔无菌磷酸盐缓冲液(PBS)冲洗96孔板2次。随后稀释化合物，用不含血清的MEM按5倍倍比稀释化合物，取50μL/孔化合物加入96孔板细胞中。并在37℃的CO2培养中培养细胞。48h后，每孔加入5mg/mL新配制的MTT溶液，37℃孵育4h。之后除去溶解介质。每个孔在490nm处的吸光度CLARIOstar全功能多功能酶标仪(BMG Labtech，德国)测定。将甲臜晶体溶解在DMSO中(每孔100μL)。细胞存活率(％)＝化合物孔的OD值/对照孔的平均OD值。每个化合物的TC50值通过软件Graph Prism 6采用非线性回归模型分析数据得到，结果如表2所示。
表2
EC50：半数有效浓度；TC50：半数毒性浓度。
由表2可知，本发明提供的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类两个系列的化合物对野生型(H3N2)和变异性(H1N1)的流感病毒均具有一定的抑制活性，其EC50较低。其中抑制活性性能优异的化合物Ⅰ-3，对三种病毒株的抑制活性分别为4.5μM，5.2μM和8.9μM。在针对金刚烷胺敏感性病毒株A/HK/68H3N2病毒的抗病毒药效试验中，Ⅰ-3、Ⅰ-4、Ⅰ-10、Ⅱ-3等化合物表现的抑制病毒活性性能优于金刚烷胺，Ⅰ-3、Ⅰ-10、Ⅱ-4、Ⅱ-12等化合物表现的抑制病毒活性性能与一线抗流感药物奥司他韦相当；在针对金刚烷胺耐药性病毒株A/WSN/33H1N1病毒的抗病毒药效试验中，Ⅰ-2、Ⅰ-11、Ⅱ-4、Ⅱ-11等化合物对该病毒的抑制活性优于金刚烷胺，Ⅰ-2、Ⅰ-3、Ⅱ-4、Ⅱ-10等化合物对该病毒抑制活性优于奥司他韦。在针对金刚烷胺耐药性A/PR/8/34H1N1病毒的抗病毒药效试验中，Ⅰ-3、Ⅰ-7、Ⅱ-2、Ⅱ-12等化合物对该病毒抑制活性优于金刚烷胺。
由表2可知本发明提供的化合物毒性较小，安全性高。如其中对流感病毒抑制活性最优的化合物Ⅰ-3，测试结果显示细胞毒性TC50是257μM，显示出良好的开发潜力。
综上，本发明提供的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物对野生型(H3N2)和变异型(H1N1)的流感病毒均具有一定的抑制活性，毒副作用较小，显示出良好的开发潜力。可以作为潜在的抗流感先导物进行进一步开发，对危害人民健康的流感的预防与治疗具有重要意义。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
Claims (9)
1.一种5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，其特征在于，其结构为：
2.根据权利要求1所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，其特征在于，所述5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物的制备方法，包括以下步骤：
1)以芳香甲酯1为原料，经肼解反应得到酰肼2；
2)取上述步骤1)得到的酰肼2与不同取代的异硫氰酸酯3在乙醇中回流反应生成氨基硫脲衍生物4；
3)取上述步骤2)得到的氨基硫脲衍生物4在溶剂中经催化剂催化得到目标化合物。
3.根据权利要求2所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，其特征在于，所述步骤3)中氨基硫脲衍生物4与催化剂的摩尔比为1:2-10。
4.根据权利要求2所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，其特征在于，所述步骤3)中反应温度为60-105℃，反应时间1-2h。
5.根据权利要求2所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，其特征在于，所述步骤3)中溶剂选自以下任一种：1,4-二氧六环、四氢呋喃、环己烷、氯仿、二氯甲烷、甲苯、三氟甲苯、二甲苯、氯苯。
6.根据权利要求2所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，其特征在于，所述步骤3)中催化剂为三氯氧磷。
7.如权利要求1所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，及其药学上可接受的盐在制备抗流感病毒药物中的应用。
8.根据权利要求7所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，及其药学上可接受的盐的应用，其特征在于，所述流感病毒为甲型流感H3N2或H1N1。
9.一种药物组合物，其特征在于，该药物组合物包含权利要求1所述的5-芳基-1,3,4-噻二唑/1,3,4-噁二唑-2-胺类化合物，及其药学上可接受的盐中的一种，以及至少一种药学上可接受的药用辅料。
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