CN113461633B - 一类2-亚氨基噻唑烷酮烯酯类化合物及其制备方法与应用 - Google Patents
一类2-亚氨基噻唑烷酮烯酯类化合物及其制备方法与应用 Download PDFInfo
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- CN113461633B CN113461633B CN202110936006.XA CN202110936006A CN113461633B CN 113461633 B CN113461633 B CN 113461633B CN 202110936006 A CN202110936006 A CN 202110936006A CN 113461633 B CN113461633 B CN 113461633B
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/54—Nitrogen and either oxygen or sulfur atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
- A61P33/12—Schistosomicides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- 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
本发明提供了一类2‑亚氨基噻唑烷酮烯酯类化合物，属于药物化学技术领域，本发明的2‑亚氨基噻唑烷酮烯酯类化合物，具有杀死血吸虫成虫的作用，克服了现有抗血吸虫病药物长期用药产生的抗药导致的疗效差或治疗无效的技术问题，对寻找新的抗血吸虫病药物具有重要的科学价值和研究价值。
Description
技术领域
本发明涉及药物化学技术领域，具体涉及一类2-亚氨基噻唑烷酮烯酯类化合物及其制备方法与应用。
背景技术
血吸虫病至今仍是严重危害人类身体健康的一种重要人畜共患寄生虫病，血吸虫病是由于感染曼氏血吸虫，埃及血吸虫，日本血吸虫，湄公血吸虫，马来血吸虫，间插血吸虫六种主要的血吸虫而引起的流行病。血吸虫病主要流行于热带和亚热带的70多个国家，每年约有20万人死于血吸虫病。
由于目前还没有有效的抗血吸虫感染疫苗，通过化学治疗消灭传染源，阻断血吸虫病流行已成为一种不可替代的手段。近一个世纪以来，血吸虫病治疗药物研究不断进展，先后出现了用于血吸虫病治疗的药物有酒石酸锑钾、呋喃丙胺、硝硫氰胺、依米替丁、环孢菌素、硫蒽酮、海蒽酮、奥沙尼喹等，这些药物在血吸虫病治疗上均发挥一定的作用，但其副作用大，疗效不显著，导致很快被淘汰。20世纪70年代，吡喹酮的问世是血吸虫病治疗药物发展史上一个重要里程碑，其高效、低毒、可口服用药和疗效短等优点，使之很快就取代了之前所有的血吸虫病治疗药物在全世界推广使用，成为血吸虫病治疗的唯一药物，由于它的广泛和长期使用，增加了血吸虫产生抗药风险，从而导致吡喹酮的治愈率比较低。因此，研究新的高效、低毒能替代吡喹酮的新型抗血吸虫药物对血吸虫病防治工作具有十分重要的意义。
发明内容
本发明的目的在于提供一类2-亚氨基噻唑烷酮烯酯类化合物，该新型2-亚氨基噻唑烷酮烯酯类化合物对血吸虫的成虫具有杀灭作用。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一类2-亚氨基噻唑烷酮烯酯类化合物，所述2-亚氨基噻唑烷酮烯酯类化合物结构如通式I所示：
其中，R1为芳基或含氮烷基，R2为卤素取代的芳基或烷基取代的芳基。
优选地，所述R1为
中的任意一种。
优选地，所述R2为
中的任意一种。
优选地，所述2-亚氨基噻唑烷酮烯酯类化合物为以下任意一种：
本发明还提供了一种上述任意一种2-亚氨基噻唑烷酮烯酯类化合物的制备方法，所述方法通过下列反应方案得到：
其中，R3为卤素或烷基。
优选地，所述R1-NH2、所述R3取代的异硫氰酸苯酯、所述乙炔二羧酸二乙酯的摩尔比为1:1:1。
本发明还提供了一种上述任意一种2-亚氨基噻唑烷酮烯酯类化合物在制备抗血吸虫药物中的应用。
优选地，所述应用用于杀灭血吸虫成虫。
本发明还提供了一种抗血吸虫的药物，所述抗血吸虫药物的活性成分为上述任意一种2-亚氨基噻唑烷酮烯酯类化合物中的一种或几种。
优选地，所述药物还包括药学上可接受的盐。
与现有技术相比，本发明的技术方案的有益效果如下：
(1)本发明首次提供了一类2-亚氨基噻唑烷酮烯酯类化合物，可用于制备治疗血吸虫病的药物，对血吸虫成虫有杀灭作用，克服了现有抗血吸虫病药物长期用药产生的抗药导致的疗效差或治疗无效的技术问题。
(2)本发明所述的2-亚氨基噻唑烷酮烯酯类化合物制备方法，操作简便、产率高。
附图说明
图1为2-亚氨基噻唑烷酮烯酯类化合物结构通式I图
图2为化合物1的红外图谱；
图3为化合物2的红外图谱；
图4为化合物3的红外图谱；
图5为化合物4的红外图谱；
图6为化合物5的红外图谱；
图7为化合物6的红外图谱；
图8为化合物7的红外图谱；
图9为化合物8的红外图谱；
图10为化合物9的红外图谱；
图11为化合物10的红外图谱；
图12为化合物11的红外图谱；
图13为化合物12的红外图谱；
图14为化合物13的红外图谱；
图15为化合物14的红外图谱；
图16为化合物15的红外图谱；
图17为化合物16的红外图谱；
图18为化合物17的红外图谱；
图19为化合物18的红外图谱；
图20为化合物19的红外图谱；
图21为化合物20的红外图谱；
图22为化合物21的红外图谱；
图23为化合物22的红外图谱；
图24为化合物23的红外图谱；
图25为化合物24的红外图谱；
图26为化合物25的红外图谱。
具体实施方式
本发明提供了一类2-亚氨基噻唑烷酮烯酯类化合物，所述2-亚氨基噻唑烷酮烯酯类化合物结构如通式I所示：
其中，R1为芳基或含氮烷基，R2为卤素取代的芳基或烷基取代的芳基。
在本发明中，所述R1优选为
中的任意一种；所述R2优选为
中的任意一种。
所述2-亚氨基噻唑烷酮烯酯类化合物优选为以下任意一种：
本发明还提供了一种上述任意一种2-亚氨基噻唑烷酮烯酯类化合物的制备方法，所述方法通过下列反应方案得到：
其中，R3为卤素或烷基。
在本发明中，所述方法具体为：将摩尔比为1:1:1的氨基取代的R1-NH2、R3取代的异硫氰酸苯酯、乙炔二羧酸二乙酯与2mL乙醇混合，白光下室温反应12h，用TLC分离法分离即得2-亚氨基噻唑烷酮烯酯类化合物。本发明的制备方法操作简便，所得目标化合物的产率高。
本发明还提供了一种上述任意一种2-亚氨基噻唑烷酮烯酯类化合物在制备抗血吸虫药物中的应用。
在本发明中，所述应用优选地用于杀灭血吸虫成虫。
本发明还提供了一种抗血吸虫的药物，所述抗血吸虫药物的活性成分为上述任意一种2-亚氨基噻唑烷酮烯酯类化合物中的一种或几种。
在本发明中，所述药物优选地还包括药学上可接受的盐；所述2-亚氨基噻唑烷酮烯酯类化合物在所述药物中的质量百分含量优选为0.05～99％，更优选为0.1～70％；所述药物的剂型优选为片剂、颗粒剂、散剂、溶液剂、乳剂、混悬剂、糖浆剂、注射剂或胶囊剂。
在本发明中，若无特殊说明，所有的原料组分均为本领域技术人员熟知的市售商品。
下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
(1)化合物1的制备
将0.25mmol化合物1-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到24.9mg化合物1，收率23.9％。对化合物1的进行分析，图谱表征：
IR(KBr,cm-1)2935.40,2794.11,1720.01,1638.86,1592.61,1388.60,1314.82,1190.96,1028.20,854.21,762.15,695.75,476.40；1H NMR(400MHz,CDCl3)δ＝7.34(t,J＝7.9Hz,2H),7.15(t,J＝7.5Hz,1H),6.94(d,J＝7.3Hz,2H),6.87(s,1H),4.23(q,J＝7.1Hz,2H),4.03(t,J＝7.1Hz,2H),2.45(t,J＝7.0Hz,10H),2.24(s,3H),1.94(dd,J＝14.1,7.1Hz,2H),1.28(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.9(s),165.0(s),151.1(s),147.3(s),141.6(s),129.3(s),125.1(s),121.0(s),116.1(s),61.6(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C21H28N4O3S[M+H]+417.19549,found417.19727.鉴定数据表明化合物1制备成功。
(2)化合物2的制备
将0.25mmol化合物2-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到21mg化合物2，产率为24.2％。对化合物2的进行分析，图谱表征：
IR(KBr,cm-1)2942.38,2770.36,1721.20,1641.43,1593.41,1388.39,1315.85,1193.33,1027.68,858.91,764.30,646.49；1H NMR(400MHz,CDCl3)δ＝7.35(dd,J＝8.2,7.6Hz,2H),7.17(t,J＝7.5Hz,1H),6.97(d,J＝7.3Hz,2H),6.89(s,1H),4.24(q,J＝7.1Hz,2H),4.10(t,J＝6.7Hz,2H),2.69(t,J＝6.7Hz,2H),2.31(s,6H),1.29(t,J＝7.1Hz,3H).13CNMR(100MHz,CDCl3)δ＝166.0(s),165.0(s),151.0(s),147.3(s),141.5(s),129.3(s),125.1(s),121.0(s),116.4(s),61.6(s),56.0(s),45.6(s),40.8(s),14.1(s).HRMS(ESI):calcd.for C17H21N3O3S[M+H]+348.13764,found 348.13747.鉴定数据表明化合物2制备成功。
将0.25mmol化合物3-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到26.4mg化合物3，产率为28.2％。对化合物3的进行分析，图谱表征：
IR(KBr,cm-1)2967.95,2800.00,1720.33,1639.22,1593.52,1315.51,1191.92,1028.45,762.48,696.10,470.69；1H NMR(400MHz,CDCl3)δ＝7.37–7.32(m,2H),7.18–7.13(m,1H),6.99–6.94(m,2H),6.88(s,1H),4.26–4.20(m,2H),4.07–4.02(m,2H),2.83–2.78(m,2H),2.58(q,J＝7.1Hz,4H),1.31–1.27(m,3H),1.04–0.99(m,6H).13C NMR(100MHz,CDCl3)δ＝166.0(s),164.9(s),151.0(s),147.4(s),141.6(s),129.3(s),125.1(s),121.0(s),116.2(s),61.6(s),49.0(s),47.3(s),40.9(s),14.1(s),12.2(s).HRMS(ESI):calcd.for C19H25N3O3S[M+H]+376.16894,found 376.17009.鉴定数据表明化合物3制备成功。
将0.25mmol化合物4-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到28.1mg化合物4，产率为31.1％。对化合物4的进行分析，图谱表征：
IR(KBr,cm-1)2934.58,2822.43,1728.97,1644.86,1591.59,1384.11,1314.02,1201.87,1025.23,862.62,758.88,702.80；1H NMR(400MHz,CDCl3)δ＝7.37–7.32(m,2H),7.19–7.14(m,1H),6.99–6.94(m,2H),6.89(s,1H),4.24(q,J＝7.1Hz,2H),4.06–4.00(m,2H),2.39(t,J＝7.2Hz,2H),2.24(s,6H),1.94(dt,J＝14.4,7.2Hz,2H),1.29(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝166.0(s),165.0(s),151.0(s),147.4(s),141.5(s),129.3(s),125.1(s),121.0(s),116.3(s),61.6(s),56.9(s),45.3(s),41.5(s),29.7(s),29.3(s),25.4(s),14.1(s).HRMS(ESI):calcd.for C18H23N3O3S[M+H]+362.15329,found362.15312。鉴定数据表明化合物4制备成功。
将0.25mmol化合物5-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到32.3mg化合物5，产率为32.1％。对化合物5的进行分析，图谱表征：
IR(KBr,cm-1)2956.02,2853.75,1720.01,1640.64,1593.11,1315.78,1193.18,1117.64,1027.53,862.33,762.45,696.74；1H NMR(400MHz,CDCl3)δ＝7.37–7.31(m,2H),7.18–7.13(m,1H),6.94(dt,J＝8.5,1.7Hz,2H),6.87(s,1H),4.28–4.18(m,2H),4.09–4.00(m,2H),3.69–3.62(m,4H),2.47–2.40(m,6H),1.95(p,J＝6.9Hz,2H),1.28(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.9(s),165.0(s),151.1(s),147.3(s),141.6(s),129.3(s),125.1(s),120.9(s),116.2(s),66.9(s),61.6(s),56.3(s),53.6(s),41.6(s),23.8(s),14.1(s).HRMS(ESI):calcd.for C20H25N3O4S[M+H]+404.16385,found 404.16444.鉴定数据表明化合物5制备成功。
将0.25mmol化合物6-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到24.5mg化合物6，产率为25.2％。对化合物6的进行分析，图谱表征：
IR(KBr,cm-1)2957.62,2853.52,2809.39,1720.56,1641.54,1593.13,1444.62,1383.60,1315.97,1117.13,1028.22,858.42,763.9,697.31；1H NMR(400MHz,CDCl3)δ＝7.35(t,J＝7.9Hz,2H),7.17(t,J＝8.5Hz,1H),6.95(d,J＝7.3Hz,2H),6.89(s,1H),4.25(q,J＝7.1Hz,2H),4.11(t,J＝6.4Hz,2H),3.68–3.64(m,4H),2.74(t,J＝6.4Hz,2H),2.56(s,4H),1.30(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝166.0(s),165.0(s),151.1(s),147.3(s),141.5(s),129.4(s),125.2(s),121.0(s),116.4(s),77.3(s),77.0(s),76.7(s),67.0(s),61.7(s),55.2(s),53.6(s),39.8(s),29.8(s),14.1(s).HRMS(ESI):calcd.for C19H23N3O4S[M+H]+390.14820,found 390.14796.鉴定数据表明化合物6制备成功。
将0.25mmol化合物7-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到29.9mg化合物7，产率为31％。对化合物7的进行分析，图谱表征：
IR(KBr,cm-1)2928.12,2787.11,1721.58,1642.04,1315.85,1193.5,1028.2,763.66,697.11；1H NMR(400MHz,CDCl3)δ＝7.37–7.32(m,2H),7.16(t,J＝7.5Hz,1H),6.96(d,J＝7.3Hz,2H),6.88(s,1H),4.24(q,J＝7.1Hz,2H),4.05(t,J＝7.1Hz,2H),2.61(dd,J＝15.9,8.3Hz,6H),2.04–1.99(m,2H),1.81–1.75(m,4H),1.28(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.9(s),165.0(s),151.1(s),147.3(s),141.5(s),129.3(s),125.2(s),121.0(s),116.3(s),54.1(s),53.7(s),41.6(s),29.7(s),26.4(s),23.4(s),14.1(s).HRMS(ESI):calcd.for C20H25N3O3S[M+CH3OH H]+420.19515,found 420.19438.鉴定数据表明化合物7制备成功。
将0.25mmol化合物8-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到27mg化合物8，产率为29％。对化合物8的进行分析，图谱表征：
IR(KBr,cm-1)2961.34,2792.04,1722.32,1643.16,1593.46,1383.87,1315.7,1193.43,1027.88,763.12,696.59；1H NMR(400MHz,CDCl3)δ＝7.35(t,J＝7.9Hz,2H),7.16(t,J＝7.5Hz,1H),6.96(d,J＝7.3Hz,2H),6.89(s,1H),4.27–4.22(m,2H),4.13(t,J＝6.8Hz,2H),2.86(t,J＝6.8Hz,2H),2.63(t,J＝6.6Hz,4H),1.80–1.76(m,4H),1.30(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝166.0(s),165.0(s),151.0(s),147.4(s),141.6(s),129.3(s),125.1(s),121.0(s),116.3(s),61.6(s),54.3(s),52.8(s),41.9(s),23.6(s),14.1(s).HRMS(ESI):calcd.for C19H23N3O3S[M+CH3OH H]+406.17950,found406.17862.鉴定数据表明化合物8制备成功。
(9)化合物9的制备
将0.25mmol化合物9-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到22mg化合物9，产率为22.7％。对化合物9的进行分析，图谱表征：
IR(KBr,cm-1)2934.27,2852.60,2799.31,1721.27,1641.61,1593.59,1443.34,1315.62,1193.19,1123.81,1028.27,859.61,763.34,696.40；1H NMR(400MHz,CDCl3)δ＝7.36–7.31(m,2H),7.15(t,J＝7.5Hz,1H),6.95(d,J＝7.3Hz,2H),6.88(s,1H),4.23(q,J＝7.1Hz,2H),4.10(t,J＝6.8Hz,2H),2.68(t,J＝6.8Hz,2H),2.48(s,4H),1.53(dt,J＝10.9,5.6Hz,4H),1.40(dd,J＝11.2,5.9Hz,2H),1.28(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.9(s),164.9(s),151.0(s),147.4(s),141.6(s),129.3(s),125.0(s),121.0(s),116.1(s),61.5(s),55.3(s),54.6(s),40.3(s),26.0(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C20H25N3O3S[M+H]+388.16894,found 388.17091.鉴定数据表明化合物9制备成功。
将0.25mmol化合物10-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到36.6mg化合物10，产率为40％。对化合物10的进行分析，图谱表征：
IR(KBr,cm-1)3418.16,2980.4,1770.2,1642.58,1383.8,1316.36,1194.65,1028.7,760.11,697.09,532.42；1H NMR(400MHz,CDCl3,ppm)δ＝7.53-7.51(d,J＝8Hz,2H),7.37-7.28(m,5H),7.18-7.15(t,J＝8Hz,1H),6.97-6.95(d,J＝8Hz,2H),6.90(s,1H),5.14(s,2H),4.26-4.21(q,J＝8Hz,2H),1.30-1.27(t,J＝8Hz,3H)；13C NMR(100MHz,CDCl3,ppm)δ＝165.9(s),164.9(s),150.8(s),147.2(s),141.4(s),135.6(s),129.4(s),129.1(s),128.6(s),128.1(s),125.2(s),121.1(s),116.6(s),61.7(s),46.2(s),14.2(s).HRMS(ESI):calcd.for C20H18N2O3S[M+H]+367.11109,found 367.11072.鉴定数据表明化合物10制备成功。
(11)化合物11的制备
将0.25mmol化合物11-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到31.2mg化合物11，产率为26.2％。对化合物11的进行分析，图谱表征：
IR(KBr,cm-1)3063.55,2924.28,2853.30,1719.51,1641.24,1593.17,1391.5,1315.50,1192.88,1028.05,857.01,763.55,696.78；1H NMR(400MHz,CDCl3)δ＝7.35(t,J＝7.9Hz,2H),7.31(d,J＝4.4Hz,4H),7.24(d,J＝4.3Hz,1H),7.17(t,J＝6.9Hz,1H),6.95(d,J＝7.3Hz,2H),6.89(s,1H),4.24(q,J＝7.1Hz,2H),4.05–3.96(m,2H),3.50(s,2H),2.89(d,J＝11.3Hz,2H),1.96(t,J＝10.9Hz,2H),1.78(d,J＝9.1Hz,2H),1.71(dd,J＝13.4,6.6Hz,2H),1.30(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ＝165.9(s),164.9(s),150.9(s),147.3(s),141.5(s),138.3(s),129.3(s),129.2(s),128.1(s),126.9(s),125.1(s),121.0(s),116.3(s),63.3(s),61.6(s),53.6(s),41.0(s),34.0(s),33.5(s),32.0(s),29.7(s),14.1(s).HRMS(ESI):calcd.for C27H31N3O3S[M+H]+478.21589,found 478.21621.鉴定数据表明化合物11制备成功。
将0.25mmol化合物1-1、0.25mmol 12-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到17.9mg化合物12，产率为16.1％。对化合物12的进行分析，图谱表征：
IR(KBr,cm-1)2934.93,2794.48,1720.54,1640.77,1507.48,1388.91,1314.89,1192.25,1029.56,859.81,756.07；1HNMR(400MHz,CDCl3)δ＝7.17(d,J＝8.4Hz,2H),6.90–6.85(m,3H),4.24(q,J＝7.1Hz,2H),4.03(t,J＝7.1Hz,2H),2.64(q,J＝7.6Hz,2H),2.46(t,J＝7.0Hz,10H),2.24(s,3H),1.95(p,J＝7.0Hz,2H),1.31–1.24(m,6H).13C NMR(100MHz,CDCl3)δ＝166.0(s),165.1(s),150.7(s),145.0(s),141.9(s),141.2(s),128.7(s),120.9(s),116.0(s),61.6(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),28.3(s),24.3(s),15.5(s),14.1(s).HRMS(ESI):calcd.for C23H33N4O3S[M+H]+445.22679,found 445.22643.鉴定数据表明化合物12制备成功。
将0.25mmol化合物1-1、0.25mmol 13-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到20mg化合物13，产率为18％。
对化合物13的进行分析，图谱表征：
IR(KBr,cm-1)2936.57,2794.57,1718.56,1637.13,1505.44,1390.13,1244.47,1193.11,1031.94,834.00,761.03,556.79；1H NMR(400MHz,CDCl3)δ＝6.95–6.82(m,5H),4.24(q,J＝7.1Hz,2H),4.02(t,J＝7.1Hz,2H),3.80(s,3H),2.45(t,J＝7.0Hz,10H),2.23(s,3H),1.99–1.89(m,2H),1.29(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝166.0(s),165.0(s),157.2(s),150.7(s),141.8(s),140.5(s),122.2(s),1156.0(s),114.6(s),61.6(s),55.8(s),55.5(s),55.1(s),53.1(s),46.0(s),41.7(s),24.3(s),14.1(s).HRMS(ESI):calcd.for C22H30N4O4S[M+H]+447.20605,found447.20567.鉴定数据表明化合物13制备成功。
将0.25mmol化合物1-1、0.25mmol 14-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到17.2mg化合物14，产率为15％。对化合物14的进行分析，图谱表征：IR(KBr,cm-1)2934.07,2794.63,1725.57,1642.33,1584.15,1458.37,1315.67,1193.50,1030.17,758.62；1H NMR(400MHz,CDCl3)δ＝7.42(dd,J＝8.0,1.3Hz,1H),7.23(td,J＝7.7,1.4Hz,1H),7.10(td,J＝7.8,1.6Hz,1H),6.94(dd,J＝7.8,1.5Hz,1H),6.91(s,1H),4.24(q,J＝7.1Hz,2H),4.06(t,J＝7.0Hz,2H),2.48(t,J＝6.9Hz,10H),2.24(s,3H),2.00(dd,J＝14.1,7.0Hz,2H),1.29(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.9(s),165.0(s),153.0(s),144.5(s),141.3(s),130.2(s),127.6(s),126.5(s),126.1(s),121.7(s),116.7(s),61.7(s),55.8(s),55.0(s),52.9(s),45.9(s),41.8(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C21H27N4O3SCl[M+H]+451.15652,found451.15629.鉴定数据表明化合物14制备成功。
将0.25mmol化合物1-1、0.25mmol 15-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到16.3mg化合物15，产率为13％。对化合物15的进行分析，图谱表征：
IR(KBr,cm-1)2936.43,2793.81,1723.87,1696.71,1641.46,1579.92,1465.83,1315.63,1193.23,1027.82,758.99；1H NMR(400MHz,CDCl3)δ＝7.58(dd,J＝8.0,1.3Hz,1H),7.29–7.24(m,1H),7.01(td,J＝7.8,1.5Hz,1H),6.94–6.87(m,2H),4.22(q,J＝7.1Hz,2H),4.04(t,J＝7.1Hz,2H),2.61–2.29(m,10H),2.22(s,3H),1.98(dd,J＝14.0,7.0Hz,2H),1.27(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.8(s),164.9(s),152.9(s),145.9(s),141.3(s),133.2(s),128.2(s),126.3(s),121.4(s),116.6(d,J＝11.1Hz),61.7(s),55.8(s),55.0(s),52.9(s),45.9(s),41.8(s),24.3(s),14.1(s).HRMS(ESI):calcd.for C21H27N4O3SBr[M+H]+495.10600,found 495.10582.鉴定数据表明化合物15制备成功。
将0.25mmol化合物1-1、0.25mmol 16-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到16.5mg化合物16，产率为13.6％。对化合物16的进行分析，图谱表征：
IR(KBr,cm-1)2937.53,2795.521726.68,1644.29,1579.07,1371.70,1264.02,1194.74,1130.11,1033.22,859.82,761.80；1H NMR(400MHz,CDCl3)δ7.36–7.31(m,2H),7.15(t,J＝7.5Hz,1H),6.95(d,J＝7.3Hz,2H),6.88(s,1H),4.23(q,J＝7.1Hz,2H),4.10(t,J＝6.8Hz,2H),2.68(t,J＝6.8Hz,2H),2.48(s,4H),1.53(dt,J＝10.9,5.6Hz,4H),1.40(dd,J＝11.2,5.9Hz,2H),1.28(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ165.3(d,J＝107.3Hz),164.8(s),152.6(s),145.5(s),141.0(s),132.8(s),126.8(dd,J＝10.5,5.3Hz),124.8(d,J＝18.6Hz),122.2(t,J＝30.2Hz),121.6(d,J＝61.7Hz),116.9(s),61.7(s),55.7(s),55.0(s),52.8(s),45.9(s),41.8(s),24.1(s),14.0(s).HRMS(ESI):calcd.for C22H27N4O3F3S[M+H]+485.18287,found 485.18233.鉴定数据表明化合物16制备成功。
将0.25mmol化合物1-1、0.25mmol 17-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到18mg化合物17，产率为15.9％。对化合物17的进行分析，图谱表征：
IR(KBr,cm-1)2937.53,2795.07,1723.72,1642.36,1460.29,1316.24,1194.28,1028.99,865.13,694.65；1H NMR(400MHz,CDCl3)δ＝7.25(dd,J＝9.5,6.4Hz,1H),7.14–7.10(m,1H),6.93(t,J＝2.0Hz,1H),6.88(s,1H),6.81(ddd,J＝7.9,2.0,1.0Hz,1H),4.23(q,J＝7.1Hz,2H),3.99(t,J＝7.1Hz,2H),2.43(t,J＝6.9Hz,10H),2.22(s,3H),1.96–1.87(m,2H),1.27(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.8(s),164.9(s),152.2(s),148.5(s),141.1(s),134.8(s),130.3(s),125.1(s),121.4(s),119.1(s),116.7(s),61.7(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C21H27N4O3SCl[M+H]+451.15652,found 451.15644.鉴定数据表明化合物17制备成功。
将0.25mmol化合物1-1、0.25mmol 18-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到17.3mg化合物18，产率为14％。对化合物18的进行分析，图谱表征：
IR(KBr,cm-1)2936.52,2795.27,1721.28,1641.73,1581.67,1467.78,1370.53,1194.51,1021.65,864.15,784.15,695.01；1H NMR(400MHz,CDCl3)δ＝7.31–7.27(m,1H),7.20(t,J＝7.9Hz,1H),7.10(t,J＝1.9Hz,1H),6.90(s,1H),6.89–6.85(m,1H),4.24(t,J＝7.1Hz,2H),4.00(t,J＝7.1Hz,2H),2.44(t,J＝6.9Hz,10H),2.25(s,3H),1.97–1.88(m,2H),1.29(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.8(s),164.9(s),152.3(s),148.7(s),141.1(s),130.6(s),128.0(s),124.2(s),122.9(s),119.6(s),116.7(s),61.7(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C21H27N4O3SBr[M+H]+495.10600,found495.10574.鉴定数据表明化合物18制备成功。
将0.25mmol化合物1-1、0.25mmol 19-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到16.4mg化合物19，产率为13.3％。对化合物19的进行分析，图谱表征：
IR(KBr,cm-1)2936.17,2794.92,1721.70,1638.95,1483.26,1315.47,1193.55,1009.94,828.97,761.68；1H NMR(400MHz,CDCl3)δ＝7.49–7.44(m,2H),6.89(s,1H),6.86–6.81(m,2H),4.25(q,J＝7.1Hz,2H),4.01(t,J＝7.1Hz,2H),2.45(t,J＝7.0Hz,10H),2.25(s,3H),1.94(dd,J＝14.1,7.0Hz,2H),1.31(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.9(s),164.9(s),151.9(s),146.4(s),141.1(s),132.4(s),122.8(s),118.3(s),116.7(s),61.7(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C21H27N4O3SBr[M+H]+495.10600,found495.10655.鉴定数据表明化合物19制备成功。
将0.25mmol化合物1-1、0.25mmol 20-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到19.2mg化合物20，产率为17％。对化合物20的进行分析，图谱表征：
IR(KBr,cm-1)2937.00,2795.57,1721.91,1638.59,1588.12,1486.44,1316.10,1194.18,1012.66,834.77,760.89,525.38；1H NMR(400MHz,CDCl3)δ＝7.34–7.28(m,2H),6.91–6.85(m,3H),4.24(q,J＝7.1Hz,2H),4.01(t,J＝7.1Hz,2H),2.44(t,J＝7.0Hz,10H),2.24(s,3H),1.97–1.89(m,2H),1.29(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.8(s),164.9(s),151.9(s),145.9(s),141.1(s),130.6(s),129.4(s),122.4(s),116.6(s),61.7(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C21H27N4O3SCl[M+H]+451.15652,found 451.15633.鉴定数据表明化合物20制备成功。
将0.25mmol化合物1-1、0.25mmol 21-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到19.3mg化合物21，产率为15.9％。对化合物21的进行分析，图谱表征：
IR(KBr,cm-1)2933.34,2796.34,1725.74,1643.23,1459.60,1322.66,1194.69,1065.69,848.81,758.88,615.89,514.95；1H NMR(400MHz,CDCl3)δ＝7.60(d,J＝8.3Hz,2H),7.03(d,J＝8.2Hz,2H),6.90(s,1H),4.23(t,J＝7.1Hz,2H),4.02(t,J＝7.1Hz,2H),2.46(t,J＝6.9Hz,10H),2.24(s,3H),1.93(dd,J＝14.1,7.0Hz,2H),1.28(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ165.8(s),164.9(s),151.4(d,J＝196.1Hz),140.9(s),127.1(d,J＝32.8Hz),126.8–126.4(m),121.3(s),116.9(s),61.8(s),55.8(s),55.0(s),52.9(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C22H27N4O3F3S[M+H]+485.18287,found485.18292.鉴定数据表明化合物21制备成功。
(22)化合物22的制备
将0.25mmol化合物1-1、0.25mmol 22-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到18.2mg化合物22，产率为16.8％。对化合物22的进行分析，图谱表征：
IR(KBr,cm-1)2937.45,2795.83,1721.72,1640.48,1503.27,1389.46,1316.09,1193.21,1029.18,841.07,761.20；1H NMR(400MHz,CDCl3)δ＝7.03(t,J＝8.6Hz,2H),6.94–6.86(m,3H),4.24(q,J＝7.1Hz,2H),4.01(t,J＝7.1Hz,2H),2.45(t,J＝7.0Hz,10H),2.25(s,3H),1.97–1.89(m,2H),1.28(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ165.9(s),164.9(s),160.3(d,J＝244.1Hz),151.7(s),143.4(d,J＝2.9Hz),141.3(s),122.4(d,J＝8.2Hz),116.3(d,J＝22.8Hz),116.0(s),61.7(s),55.8(s),55.0(s),52.9(s),45.8(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C21H27N4O3FS[M+H]+435.18607,found435.18588.鉴定数据表明化合物22制备成功。
将0.25mmol化合物1-1、0.25mmol 23-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到14.9mg化合物23，产率为13.2％。对化合物23的进行分析，图谱表征：
IR(KBr,cm-1)2934.58,2795.10,1728.57,1643.85,1613.50,1496.18,1386.03,1316.22,1194.58,1027.99,861.51,761.53；1H NMR(400MHz,CDCl3)δ＝7.03(td,J＝9.3,4.9Hz,1H),6.89(s,1H),6.82–6.75(m,1H),6.66(ddd,J＝9.2,6.3,3.1Hz,1H),4.22(q,J＝7.1Hz,2H),4.01(t,J＝6.9Hz,2H),2.42(t,J＝6.8Hz,10H),2.19(s,3H),1.92(dd,J＝13.7,6.9Hz,2H),1.27(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ165.7(s),164.8(s),158.5(dd,J＝243.9,2.5Hz),154.4(s),149.8(dd,J＝242.7,2.9Hz),140.8(s),136.0(dd,J＝14.8,9.9Hz),117.1(d,J＝9.6Hz),117.0–116.8(m),112.1(dd,J＝23.9,7.5Hz),109.7(d,J＝25.4Hz),61.7(s),55.8(s),55.0(s),53.4(d,J＝96.3Hz),45.9(s),41.8(s),23.9(s),14.0(s).HRMS(ESI):calcd.for C21H26N4O3F2S[M+Na]+475.15859,found 475.15750.鉴定数据表明化合物23制备成功。
(24)化合物24的制备
将0.25mmol化合物1-1、0.25mmol 24-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到19.7mg化合物24，产率为16.2％。对化合物24的进行分析，图谱表征：
IR(KBr,cm-1)2936.41,2795.27,1724.46,1639.69,1583.51,1467.67,1371.06,1315.87,1194.32,1027.22,871.03,758.88；1H NMR(400MHz,CDCl3)δ＝7.40(d,J＝8.5Hz,1H),7.05(d,J＝2.4Hz,1H),6.90(s,1H),6.80(dd,J＝8.5,2.5Hz,1H),4.25(q,J＝7.1Hz,2H),3.99(t,J＝7.1Hz,2H),2.43(t,J＝6.9Hz,10H),2.23(s,3H),1.91(p,J＝7.0Hz,2H),1.29(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ＝165.8(s),164.8(s),152.8(s),146.8(s),140.7(s),133.1(s),131.0(s),128.7(s),123.1(s),120.5(s),117.0(s),61.8(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),21.0(s),14.1(s).HRMS(ESI):calcd.for C21H26N4O3SCl2[M+H]+485.11754,found 485.11710.鉴定数据表明化合物24制备成功。
(25)化合物25的制备
将0.25mmol化合物1-1、0.25mmol 25-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到20.2mg化合物25，产率为14.6％。对化合物25的进行分析，图谱表征：
IR(KBr,cm-1)2938.16,2796.82,1729.72,1641.45,1458.92,1317.12,1279.33,1137.41,1028.83,890.04,761.68,703.57,613.08；1H NMR(400MHz,CDCl3)δ＝7.67(s,1H),7.37(s,2H),6.94(s,1H),4.25(q,J＝7.1Hz,2H),4.02(t,J＝7.1Hz,2H),2.61–2.35(m,10H),2.25(s,3H),1.98–1.90(m,2H),1.28(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ165.6(s),164.7(s),154.0(s),148.8(s),140.1(s),132.8(q,J＝33.6Hz),127.1(s),124.3(s),121.6(s),121.4(s),118.7–118.3(m),117.8(s),62.0(s),55.7(s),54.9(s),52.9(s),45.8(s),41.8(s),29.5(d,J＝38.3Hz),24.1(s),14.0(s).HRMS(ESI):calcd.forC23H26N4O3F6S[M+H]+553.17026,found 553.17020.鉴定数据表明化合物25制备成功。
实施例2：体外杀成虫的活性试验
(1)体外杀成虫的活性试验
采集活的45天日本血吸虫成虫置于RPMI-1640培养液(10条/3mL/皿)中，每皿分别加入化合物1～25各3μL，每个化合物的终浓度为0.5mmol/L、0.1mmol/L、0.05mmol/L，对照组加3μL DMSO，加药后充分摇匀，放入37℃、5％CO2培养箱中，培养16h后用生理盐水洗涤虫体3次，加入新鲜培养液，在体视显微镜下观察培养24～72h后的血吸虫活力状态，吡喹酮为阳性对照，即向3mL培养液中加3μL 50μmol/mL的吡喹酮溶液，即得到50μmol/L的吡喹酮药液；阴性对照为在培养液中加3μL溶剂DMSO；空白对照不往培养液中加任何试剂。结果见表1。
表1化合物1～25对45天日本血吸虫成虫的灭杀效果
| 化合物 | 死亡等级 | 化合物 | 死亡等级 |
| 1 | B | 14 | A |
| 2 | B | 15 | A |
| 3 | B | 16 | A |
| 4 | B | 17 | A |
| 5 | D | 18 | B |
| 6 | C | 19 | A |
| 7 | C | 20 | A |
| 8 | C | 21 | A |
| 9 | C | 22 | A |
| 10 | C | 23 | A |
| 11 | C | 24 | A |
| 12 | C | 25 | A |
| 13 | B | 吡喹酮 | A |
| 空白对照 | D | 阴性对照 | D |
表1中死亡等级∶A为药物浓度为0.05mmol/L时，成虫在72h内的死亡率为100％；B为药物浓度为0.1mmol/L时，成虫在72h内的死亡率为100％；C为药物浓度为0.5mmol/L时，成虫在72h内的死亡率为100％；D为药物浓度为0.5mmol/L时，成虫在72h内的死亡率为0％。
实施例3：体内抗血吸虫成虫的作用
将12只感染50条尾蚴的小鼠培养至35天，分为A、B、C、D四组，每组3只，并称取体重，分别称取化合物1、化合物2、化合物3各120mg，用5mL食用油超声溶解，分别得到24mg/mL的化合物1、化合物2和化合物3溶液。
A组小鼠以400mg/kg的剂量灌服化合物1，B组小鼠以400mg/kg的剂量灌服化合物2，C组小鼠以400mg/kg的剂量灌服化合物3，D组小鼠灌服相应体积的食用油作为对照组，连续灌服3天，在感染后的第45天处死小鼠解剖观察减虫效果和小鼠肝脏、脾脏的病理特征，结果见表3。
表3化合物1～3体内抗血吸虫成虫的效果
由表3可知，化合物1～3的减虫率分别为67.6％、29％、61.7％，表现出了较高的体内杀灭成虫的活性。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (7)
1.一类2-亚氨基噻唑烷酮烯酯类化合物，其特征在于，所述2-亚氨基噻唑烷酮烯酯类化合物结构如通式I所示：
其中，R1为：
中的任意一种；
R2为：
中的任意一种。
2.根据权利要求1所述的2-亚氨基噻唑烷酮烯酯类化合物，其特征在于，所述2-亚氨基噻唑烷酮烯酯类化合物为以下任意一种：
3.一种权利要求1或2所述2-亚氨基噻唑烷酮烯酯类化合物的制备方法，其特征在于，所述方法通过下列反应方案得到：
其中，R3为卤素或烷基。
4.根据权利要求3所述的制备方法，其特征在于，所述R1-NH2、所述R3取代的异硫氰酸苯酯、所述乙炔二羧酸二乙酯的摩尔比为1:1:1。
5.根据权利要求1或2所述2-亚氨基噻唑烷酮烯酯类化合物在制备抗血吸虫药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述应用用于杀灭血吸虫成虫。
7.一种抗血吸虫的药物，其特征在于，所述抗血吸虫药物的活性成分为权利要求1或2所述2-亚氨基噻唑烷酮烯酯类化合物中的一种或几种。
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