CN105796545B - 一类腙类化合物在制备抗真菌药物中的应用 - Google Patents

一类腙类化合物在制备抗真菌药物中的应用 Download PDF

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CN105796545B
CN105796545B CN201610352077.4A CN201610352077A CN105796545B CN 105796545 B CN105796545 B CN 105796545B CN 201610352077 A CN201610352077 A CN 201610352077A CN 105796545 B CN105796545 B CN 105796545B
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万坚
任彦亮
韩新亚
朱秀云
洪宗琴
祝帅华
万芬
彭浩
冯玲玲
饶立
张�雄
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Huazhong Normal University
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Abstract

本发明公开了一类腙类化合物在制备抗真菌药物中的应用。通式I各取代基如权利要求书中所述。本发明提供的一类如通式I所述的腙类化合物具有协同唑类抗真菌药物抗耐药真菌作用，可与抗真菌药物尤其是唑类抗真菌药物协同用于抗真菌药物制备，对抗耐药真菌具有优异的协同杀菌效果。

Description

一类腙类化合物在制备抗真菌药物中的应用
技术领域
本发明属抗真菌药物组合物领域，具体涉及一类腙类化合物在制备抗真菌药物中的应用。
背景技术
近年来，由于免疫抑制剂、广谱抗生素、皮质类固醇激素的广泛使用，以及器官移植、恶性肿瘤患者、获得性免疫缺陷综合征(AIDS)患者感染的增加，侵袭性真菌感染的发生呈现上升趋势，真菌感染的病情亦十分严重。在诸多抗真菌药物当中以唑类抗真菌药物居多，如氟康唑、酮康唑等。近年来，随着唑类抗真菌药物的广泛使用，临床上已经出现了对唑类抗真菌药物耐药的菌株。因此寻找发现新的药物的作用靶点，研发新一代作用于新靶标或具有新作用机制的药物是解决现有唑类抗真菌药物抗药性的有效途径。
发明内容
本发明所要解决的技术问题是提供了一类腙类化合物或药学上可接受的盐、溶剂化物或前药在制备抗真菌药物中的应用和抗真菌药物组合物。
本发明的第一方面，提供了一类如通式I的腙类化合物或药学上可接受的盐、溶剂化物或前药在制备抗真菌药物中的应用：
通式I中，当X为羰基、Y为时，R1代表-H，R2代表-Br，R3选自H、卤素、-OH、1,2,4-三唑、-CN、-NO2、苯基和被取代基取代的苯基、C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素；
当X不存在时，Y为中的一种；
其中当Y为时，R1代表-H、-NO2，R2代表-NO2，R3选自H、卤素、-OH、1,2,4-三唑、-CN、-NO2、苯基和被取代基取代的苯基、C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素；
当Y为时，R1代表H、-NO2，R2代表-NO2，R4选自-H、卤素、-NO2、C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素；
当Y为时，R1代表-H、-NO2，R2代表-NO2，R5选自-H、卤素、-CN、-NO2、C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素；
当Y为时，R1代表-H、-OH、-OCH3，R2代表卤素、-NO2、-CH3，R6选自-CH3、-OCH3、-NH2。
按上述方案，所述的应用为：将如通式I所述的腙类化合物或药学上可接受的盐、溶剂化物或前药和唑类抗真菌药物复合用于抗真菌药物的制备。
按上述方案，所述的真菌为耐唑类抗真菌药物的抗耐药真菌。
按上述方案，所述的所述唑类抗真菌药物选自氟康唑、酮康唑、咪康唑、伊曲康唑或硫康唑等。
本发明的第二方面是提供一种抗真菌药物组合物，所述的药物组合物中包含通式I所述的腙类化合物或药学上可接受的盐、溶剂化物或前药和唑类抗真菌药物。
按上述方案，所述的通式I所述的腙类化合物或药学上可接受的盐、溶剂化物或前药和唑类抗真菌药物的质量比为1:128～1:1。
上述一类通式如I的腙类化合物的制备方法：
(a)通式I中，当X为羰基、Y为时，合成方法：将苯甲醛衍生物加入溴代苯甲酰肼溶液中，加热搅拌使其回流反应后处理得到目标产物，反应合成路线：R1代表-H，R2代表-Br R3选自H、卤素、-OH、1,2,4-三唑、-CN、-NO2、苯基和被取代基取代的苯基、C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素。
(b)当X不存在时，Y为中的一种时，合成方法：将苯甲醛衍生物加入硝基取代的苯胺溶液中，加热搅拌使其回流反应后处理得到目标产物，反应合成路线：
R1＝-H,NO2；R2＝NO2；
R3＝-H、卤素、-OH、1,2,4-三唑、-CN、-NO2、苯基和被取代基取代的苯基、C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素。
R4＝-H、卤素、-NO2、C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素。
R5＝-H、卤素、-CN、-NO2、C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素。(c)当X不存在时，Y为时，反应合成路线：
R1＝-H、-OH、-OCH3；R2＝卤素、-NO2、-CH3；R6＝-CH3、-OCH3、-NH2。本发明的有益效果：
本发明提供的一类如通式I所述的腙类化合物可与抗真菌药物尤其是唑类抗真菌药物协同用于抗真菌药物制备中，其对抗耐药真菌具有优异的协同杀菌效果。
具体实施方式
下面通过实施例1、2、3来具体地说明本发明的I式化合物的制备方法。
实例例1
化合物I-1
4-溴-N’-(4-氰基苯亚甲基)苯甲酰肼
称取1.07g(5mmol)对溴苯甲酰肼加入到100mL的茄型瓶中，量取15mL乙醇，部分溶解为白色混浊液；称取0.66g(5mmol)对氰基苯甲醛加入其中，加入磁子，置于油浴中加热搅拌使其回流；加热后固体全部溶解成无色透明溶液，回流半小时后产生白色固体而变浑浊，约3h反应完全；抽滤得到白色固体，并用少量乙醇重结晶即可得到目标产物。
分子式：C15H10BrN3O
白色固体，产率70％.1H NMR(600MHz,DMSO-d6)δ12.18(s,1H,N-H),8.51(s,1H,＝C-H),7.93(s,4H,Ar-H),7.90(d,J＝8.1Hz,2H,Ar-H),7.78(d,J＝8.2Hz,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ162.71(C＝O),146.42,139.02,133.11,132.46,131.93,130.15,128.02,126.16,118.99,112.32.MS(EI)m/z:326.94[M-1]+,328.96
化合物I-2均可按照化合物I-1类似的方法制备
化合物I-2
N’-(1H-1,2,4-三唑苯亚甲基)-4-溴-苯甲酰肼
白色固体，产率85％.1H NMR(600MHz,DMSO-d6)δ12.05(s,1H,N-H),9.42(s,1H,Triazole-H),8.52(s,1H,Triazole-H),8.31(s,1H,＝C-H),8.00(d,J＝8.3Hz,2H,Ar-H),7.93(dd,J＝16.0,8.2Hz,4H,Ar-H),7.78(d,J＝8.1Hz,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ162.62(C＝O),152.97,147.22,142.80,138.00,133.89,132.73,131.91,130.13,128.86,126.01,119.91.MS(EI)m/z:368.83[M-1]+,370.81[M+1]+
实施例2
化合物I-3
4-((2-(4-硝基苯基)亚肼基)甲基)苄腈
称取0.77g(5mmol)对硝基苯胺于100mL的茄型瓶中，加入磁子，量取15mL乙醇加入到反应瓶中；再称取0.66g(5mmol)对氰基苯甲醛加入到反应瓶中，固体全部溶解，置于油浴中加热搅拌回流。回流后反应瓶中有橘黄色固体产生，约2h反应完全；冷去后抽滤并用乙醇重结晶得到橘黄色粉末。
黄色粉末.产率90％.1H NMR(600MHz,DMSO-d6)δ11.52(s,1H,N-H),8.12(d,J＝9.3Hz,2H,Ar-H),8.02(s,1H,＝C-H),7.85(q,J＝8.4Hz,4H,Ar-H),7.20(d,J＝8.7Hz,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ150.47,139.77,139.67,139.47,133.00,127.24,126.45,119.27,112.19,111.10.MS(EI)m/z:266.00[M]+.
化合物I-4–I-16均可按照化合物I-3类似的方法制备
化合物I-4
1-苯亚甲基-2-(4-硝基苯)肼
暗黄色粉末.产率89％.1H NMR(600MHz,DMSO-d6)δ11.35(s,1H,N-H),8.15(d,J＝9.0Hz,2H,Ar-H),8.07(s,1H,＝C-H),7.75(d,J＝7.2Hz,2H,Ar-H),7.45(t,J＝7.5Hz,2H,Ar-H),7.39(t,J＝7.3Hz,1H,Ar-H),7.19(d,J＝8.7Hz,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ150.98,142.17,138.75,135.09,129.62,129.17,126.86,126.57,111.66.MS(EI)m/z:241.02[M]+.
化合物1-5
1-(4-甲基苯亚甲基)-2-(4-硝基苯)肼
黄色粉末,产率92％.1H NMR(600MHz,DMSO-d6)δ11.29(s,1H,N-H),8.14(d,J＝8.9Hz,2H,Ar-H),8.04(s,1H,＝C-H),7.63(d,J＝7.7Hz,2H,Ar-H),7.25(d,J＝7.7Hz,2H,Ar-H),7.17(d,J＝8.4Hz,2H,Ar-H),2.34(s,3H,CH3).13C NMR(151MHz,DMSO-d6)δ151.04,142.36,139.35,138.55,132.37,129.78,126.85,126.57,111.53,21.41(CH3).MS(EI)m/z:255.00[M]+.
化合物1-6
1-(4-硝基苯)-2-(4-三氟甲基苯亚基)肼
黄色粉末,产率87％.1H NMR(600MHz,DMSO-d6)δ11.49(s,1H),8.13(d,J＝8.9Hz,2H),8.07(s,1H),7.90(d,J＝7.9Hz,2H),7.73(d,J＝8.0Hz,2H),7.20(d,J＝8.8Hz,2H).13CNMR(151MHz,DMSO-d6)δ150.61,140.08,139.27,139.10,129.40,129.19,128.98,128.77,127.19,126.43,125.92,125.47,123.67,111.98.MS(EI)m/z:308.95[M]+.
化合物1-7
1-([1,1’-联苯-4甲亚甲基]-2-(4-硝基苯基)肼
橘红色粉末,产率90％.1H NMR(600MHz,DMSO-d6)δ11.38(s,1H),8.17(d,J＝9.1Hz,2H),8.11(s,1H),7.83(d,J＝8.1Hz,2H),7.75(d,J＝8.0Hz,2H),7.72(d,J＝7.6Hz,2H),7.49(t,J＝7.6Hz,2H),7.40(t,J＝7.4Hz,1H),7.22(s,2H).13C NMR(151MHz,DMSO-d6)δ150.93,141.77,141.09,139.82,138.79,134.23,129.40,128.15,127.45,127.39,126.99,126.60,111.72.MS(EI)m/z:317.05[M]+.
化合物I-8
1-(4-氟苯亚甲基)-2-(4-硝基苯基)肼
橘黄色粉末，产率89％.1H NMR(600MHz,DMSO-d6)δ11.37(s,1H,N-H),8.15(d,J＝9.5Hz,2H,Ar-H),8.07(s,1H,＝C-H),7.80(dd,J＝8.6,5.7Hz,2H,Ar-H),7.29(t,J＝8.8Hz,2H,Ar-H),7.19(d,J＝8.2Hz,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ168.09,166.45,155.26,145.31,143.02,136.00,133.20,133.15,130.82,120.54,120.40,115.91.MS(EI)m/z:259.01[M]+.
化合物I-9
1-(4-氯苯亚甲基)-2-(4-硝基苯基)肼
橘黄色粉末，产率91％.1H NMR(600MHz,DMSO-d6)δ11.38(s,1H,N-H),8.15(d,J＝9.5Hz,2H,Ar-H),8.04(s,1H,＝C-H),7.76(d,J＝8.5Hz,2H,Ar-H),7.49(d,J＝8.5Hz,2H,Ar-H),7.19(d,J＝8.3Hz,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ155.10,145.01,143.22,138.36,138.19,133.48,132.68,130.79,116.05.MS(EI)m/z:
化合物I-10
1-(4-硝基苯亚甲基)-2-(4-硝基苯基)肼
橘黄色粉末，产率92％.1H NMR(600MHz,DMSO-d6)δ11.60(s,1H,N-H),8.19(d,J＝8.8Hz,2H,Ar-H),8.11(d,J＝9.4Hz,2H,Ar-H),8.04(s,1H,＝C-H),7.89(d,J＝8.8Hz,2H,Ar-H),7.18(d,J＝8.8Hz,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ150.31,147.25,141.61,139.60,139.16,127.37,126.38,124.36,112.27.MS(EI)m/z:286.00[M]+.
化合物I-11
1-(4-((2-(4-硝基苯基)亚肼基)甲基)苯基)-1H-1,2,4-三唑
橘黄色粉末，产率87％.1H NMR(600MHz,DMSO-d6)δ11.42(s,1H,N-H),9.39(s,1H,Triazole-H),8.29(s,1H,Triazole-H),8.16(d,J＝8.9Hz,2H,Ar-H),8.10(s,1H,＝C-H),7.94(q,J＝8.5Hz,4H,Ar-H),7.22(d,J＝8.0Hz,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ152.89,150.81,142.67,140.85,138.91,137.22,134.47,128.08,126.53,119.89,111.80.MS(EI)m/z:308.01[M]+.
化合物I-12
1-(4-((2-(4-硝基苯基)亚肼基)甲基)苯基)苯酚
橘黄色粉末，产率88％.1H NMR(600MHz,DMSO-d6)δ11.37(s,1H,N-H),10.24(s,1H,O-H),8.40(s,1H,＝C-H),8.16(d,J＝9.3Hz,2H,Ar-H),7.76(d,J＝7.8Hz,1H,Ar-H),7.25(t,J＝7.7Hz,1H,Ar-H),7.13(d,J＝8.8Hz,2H,Ar-H),6.95(d,J＝8.1Hz,1H,Ar-H),6.91(t,J＝7.5Hz,1H,Ar-H).13C NMR(151MHz,DMSO-d6)δ156.34,150.66,140.36,138.51,130.83,126.76,126.56,120.77,119.79,116.42,111.31.MS(EI)m/z:257.02[M]+.
化合物I-13
2-((2-(2,4-二硝基苯基)亚肼基)甲基)苯基)苯酚
橘红色粉末，产率81％.1H NMR(600MHz,DMSO-d6)δ11.67(s,1H,N-H),10.17(s,1H,O-H),8.90(s,1H,＝C-H),8.79(d,J＝2.7Hz,1H,Ar-H),8.32(dd,J＝9.6,2.7Hz,1H,Ar-H),7.99(d,J＝9.6Hz,1H,Ar-H),7.79(d,J＝7.5Hz,1H,Ar-H),7.27(t,J＝7.6Hz,1H,Ar-H),6.91(d,J＝8.2Hz,1H,Ar-H),6.87(t,J＝7.5Hz,1H,Ar-H).13C NMR(151MHz,DMSO-d6)δ157.21,146.73,144.65,137.00,132.20,129.99,129.41,126.68,123.31,120.32,119.76,116.92,116.58.MS(EI)m/z:302.02[M]+.
化合物I-14
2-(2,4-二硝基苯基)-2-(4-氟苯亚甲基)肼
橘黄色粉末，产率92％.1H NMR(600MHz,DMSO-d6)δ11.72(s,1H,N-H),8.91(d,J＝2.7Hz,1H,Ar-H),8.75(s,1H,＝C-H),8.42(dd,J＝9.6,2.7Hz,1H,Ar-H),8.15(d,J＝9.6Hz,1H,Ar-H),7.91(dd,J＝8.7,5.7Hz,2H,Ar-H),7.39(t,J＝8.8Hz,2H,Ar-H).MS(EI)m/z:303.96[M]+.
化合物I-15
5-溴-3-((2-(4-硝基苯基)亚肼基)甲基)-1H-吲哚
暗红色粉末，产率88％.1H NMR(600MHz,DMSO-d6)δ11.81(s,1H,N-H),11.31–11.01(m,1H,N-H),8.37(d,J＝2.0Hz,1H,Ar-H),8.31(s,1H,Pyrrole-H),8.19(d,J＝9.0Hz,2H,Ar-H),7.90(s,1H,＝C-H),7.47(d,J＝8.6Hz,1H,Ar-H),7.37(dd,J＝8.6,2.0Hz,1H,Ar-H),7.11(s,2H,Ar-H).13C NMR(151MHz,DMSO-d6)δ151.15,140.16,137.63,136.17,131.39,126.81,126.13,125.50,124.01,114.40,113.44,111.84,110.68.MS(EI)m/z:357.89[M-1]+,359.87[M+1]+.
化合物I-16：
1-(4-硝基苯基)-2-((5-硝基噻吩-2-取代基)亚甲基)肼
红色粉末，产率85％1H NMR(600MHz,DMSO-d6)δ11.76(s,1H),8.23–8.13(m,3H),8.08(d,J＝4.4Hz,1H),7.43(d,J＝4.4Hz,1H),7.18(d,J＝8.7Hz,2H).13C NMR(151MHz,DMSO-d6)δ149.64,148.28,139.98,134.79,131.19,127.90,126.42,112.47.MS(EI)m/z:291.91[M]+.
实施例3
化合物I-17
3-(2-(2-羟基-4-硝基苯基)肼叉基-2,4-戊二酮
称取0.74g(5mmol)2-氨基-5-硝基苯酚于50mL茄型瓶中，量取3mL乙腈加入其中，加入磁子，置于冰水浴中搅拌冷却，固体部分溶解成为黄色混浊液；量取1mL氟硼酸加入到反应瓶中；称取0.34g(5mmol)NaNO2固体分批加入到反应瓶中，加入后反应放热，充分反应后固体全部溶解，变成棕色透明液的重氮盐体系。量取0.7mL(5mmol)乙酰丙酮加入到反应瓶中，再量取2mL的乙腈加入到反应瓶中；最后称取0.4g(5mmol)的乙酸钠加入到反应瓶中，反应瓶中慢慢产生黄色固体而变浑浊；充分反应后抽滤并用乙醇重结晶得到黄色粉末。
黄色粉末，产率78％.1H NMR(600MHz,DMSO-d6)δ14.17(s,1H,N-H),11.62(s,1H,O-H),7.82(dd,J＝8.8,2.4Hz,1H,Ar-H),7.78(d,J＝8.9Hz,1H,Ar-H),7.71(d,J＝2.4Hz,1H,Ar-H),2.50(s,3H,CH3),2.44(s,3H,CH3).13C NMR(151MHz,DMSO-d6)δ197.75(C＝O),196.88(C＝O),146.33,144.03,136.00,135.59,116.49,114.60,110.55,31.80(CH3),26.91(CH3).MS(EI)m/z:265.05[M]+.
化合物I-18–I-27均可按照化合物I-17类似的方法制备
化合物I-18
3-(2-(4-硝基苯基)肼叉基-2,4-戊二酮
黄色粉末，产率85％.1H NMR(400MHz,DMSO-d6)δ13.29(s,1H,N-H),8.29(dd,J＝15.3,8.7Hz,2H,Ar-H),7.74(d,J＝9.3Hz,2H,Ar-H),2.47(s,3H,CH3),2.45(s,3H,CH3).13CNMR(151MHz,DMSO-d6)δ198.41(C＝O),196.92(C＝O),148.22,143.48,137.32,125.99,116.42,109.99,31.70(CH3),26.64(CH3).MS(EI)m/z:249.03[M]+.
化合物I-19
3-(2-(2-甲氧基-5-硝基苯基)肼叉基-2,4-戊二酮
黄色粉末，产率85％.1H NMR(600MHz,CDCl3)δ14.54(s,1H,N-H),8.50(d,J＝2.6Hz,1H,Ar-H),8.05(dd,J＝9.0,2.6Hz,1H,Ar-H),7.02(d,J＝9.0Hz,1H,Ar-H),4.08(s,3H,CH3),2.62(s,3H,CH3),2.54(s,3H,CH3).13C NMR(151MHz,CDCl3)δ197.96(C＝O),197.06(C＝O),152.54,142.21,134.74,131.39,121.09,110.55,110.29,56.77(CH3),31.74(CH3),26.71(CH3).MS(EI)m/z:279.25[M]+.
化合物I-20
2-(2-(2-羟基-4硝基苯基)肼叉基-3-氧丁酰胺
棕色粉末，产率65％1H NMR(600MHz,DMSO-d6)δ14.56(s,1H,N-H),11.32(s,1H,O-H),8.50(s,1H,NH2-H),8.15(s,1H,NH2-H),7.80(d,J＝8.9Hz,1H,Ar-H),7.70(s,1H,Ar-H),7.67(d,J＝8.9Hz,1H,Ar-H),2.47(s,3H,CH3).13C NMR(151MHz,DMSO-d6)δ198.11(C＝O),165.07(C＝O),145.47,142.95,135.94,129.55,116.32,113.47,110.07,26.07(CH3).MS(EI)m/z:266.03[M]+
化合物I-21
2-(2-(2-羟基-4溴苯基)肼叉基-3-氧丁酰胺
暗绿色粉末，产率68％.1H NMR(600MHz,DMSO-d6)δ14.59(s,1H,N-H),11.01(s,1H,O-H),8.55(s,1H,NH2-H),7.95(s,1H,NH2-H),7.48(d,J＝8.5Hz,1H,Ar-H),7.10–7.03(m,2H,Ar-H),2.43(s,3H,CH3).13C NMR(151MHz,DMSO-d6)δ198.03(C＝O),166.00(C＝O),147.48,129.76,127.38,122.87,118.44,116.62,116.02,26.18(CH3).MS(EI)m/z:
化合物I-22
甲基-2-(2-(4-硝基苯基)肼叉基)-3-氧丁酸甲酯
黄色粉末，产率84％.1H NMR(600MHz,DMSO-d6)δ11.72(s,1H,N-H),8.25(d,J＝8.8Hz,2H,Ar-H),7.57(d,J＝8.7Hz,2H,Ar-H),3.88(s,3H,CH3),2.44(s,3H,CH3).13C NMR(151MHz,DMSO-d6)δ194.33(C＝O),162.89(C＝O-O),148.54,142.44,135.56,125.99,115.15,52.86(CH3),25.46(CH3).MS(EI)m/z:265.02[M]+.
化合物I-23
3-(2-(5-氯-2-羟基苯基)肼叉基-2,4-戊二酮
黄色粉末，产率84％.1H NMR(400MHz,DMSO-d6)δ14.36(s,1H,N-H),10.81(s,1H,O-H),7.56(d,J＝2.6Hz,1H,Ar-H),7.07(dd,J＝8.7,2.6Hz,1H,Ar-H),6.96(d,J＝8.6Hz,1HAr-H),2.49(s,3H,CH3),2.42(s,3H,CH3).13C NMR(151MHz,DMSO-d6)δ197.19(C＝O),196.67(C＝O),145.53,134.11,130.88,125.60,124.29,117.51,114.57,31.72(CH3),26.96(CH3).MS(EI)m/z:254.05[M]+.
化合物I-24
3-(2-(4-氯-2-羟基苯基)肼叉基-2,4-戊二酮
黄色粉末，产率80％.1H NMR(600MHz,DMSO-d6)δ14.45(s,1H,N-H),11.05(s,1H,O-H),7.58(d,J＝9.2Hz,1H,Ar-H),6.94(dd,J＝7.4,2.0Hz,2H,Ar-H),2.47(s,3H,CH3),2.38(d,J＝1.7Hz,3H,CH3).13C NMR(151MHz,DMSO-d6)δ201.64(C＝O),201.22(C＝O),152.20,138.46,134.45,133.69,125.07,121.08,120.51,36.37(CH3),31.54(CH3).MS(EI)m/z:254.06[M]+.
化合物I-25
3-(2-(4-溴-2-羟基苯基)肼叉基-2,4-戊二酮
黄色粉末，产率75％.1H NMR(600MHz,DMSO-d6)δ14.44(s,1H,N-H),11.09(s,1H,O-H),7.56(d,J＝8.9Hz,1H,Ar-H),7.08(s,2H,Ar-H),2.48(s,3H,CH3),2.40(s,3H,CH3).13CNMR(151MHz,DMSO-d6)δ201.75(C＝O),201.29(C＝O),152.46,138.60,134.13,127.93,123.36,122.48,121.50,36.40(CH3),31.60(CH3).MS(EI)m/z:297.92[M-1]+,299.92[M+1]+.
化合物I-26
3-(2-(4-氟-2-羟基苯基)肼叉基-2,4-戊二酮
暗绿色粉末，产率70％.1H NMR(600MHz,DMSO-d6)δ14.57(s,1H,N-H),11.11(s,1H,O-H),7.63(dd,J＝8.7,6.0Hz,1H,Ar-H),6.75(td,J＝11.3,10.5,5.7Hz,2H,Ar-H),2.47(s,3H,CH3),2.39(s,3H,CH3).13C NMR(151MHz,DMSO-d6)δ201.45(C＝O),201.23(C＝O),165.97,164.36,152.68,138.20,131.36,121.10,114.69,111.73,108.20,36.31(CH3),31.57(CH3).MS(EI)m/z:238.01[M]+.
化合物I-27
3-(2-(2-羟基-4-甲基苯基)肼叉基-2,4-戊二酮
黄色粉末，产率82％.1H NMR(600MHz,DMSO-d6)δ14.68(s,1H,N-H),10.44(s,1H,O-H),7.53(d,J＝7.9Hz,1H,Ar-H),6.77(s,1H,Ar-H),6.74(d,J＝8.5Hz,1H,Ar-H),2.47(s,3H,CH3),2.39(s,3H,CH3),2.25(s,3H,CH3).13C NMR(151MHz,DMSO-d6)δ201.24(C＝O),201.21(C＝O),151.46,141.16,137.91,132.07,126.00,121.35,119.96,36.30(CH3),31.59(CH3),26.00(CH3).MS(EI)m/z:234.01[M]+.
实施例4
采用棋盘式稀释法体外药敏实验测试腙类化合物协同抗真菌药物抗耐药真菌作用。
下述实验实施例中的菌株为临床分离得到的耐药白色念珠菌100菌和103菌，购置于第二军医大学药学学院。培养液为RPMI 1640液体培养基，使用前均按照标准方法进行前处理。抗真菌药物氟康唑购购置于大连辉瑞药业有限公司；二甲亚砜购置于中国医药集团上海化学试剂公司。
实验步骤：
取无菌96孔板，每排的1号孔加入200μL RPMI 1640液体培养基作为空白对照，每排的12号孔加入200μL使用RPMI 1640液体培养基新鲜配制的菌液作为阳性对照。每排从2号孔到11号孔分别加入菌液160μL和待测化合物溶液40μL，进行倍比稀释，使得各孔的最终药物浓度分别为64、32、16、8、4、2、1、0.5、0.25和0.125μg/mL，各孔中的DMSO含量均低于1％。每次配制药敏版的同时均制备一块质控菌药敏板(质控菌：根据NCCLS M27A方案的建议，发明人采用近平滑念珠菌ATCC18062为质控菌，每次配制药敏板的同时制备一块质控菌药敏板，其MIC参考值如下：唑类抗真菌药物：MIC值0.25–1.0μg/mL；AmB：MIC值0.25–1.0μg/mL。每次试验均以此菌株为参考菌株，只有当其MIC80值界于上述范围时，方可认为试验操作准确可靠。)各药敏板均在30℃恒温培养中培养。
评价标准：
部分抑菌浓度指数(FICI)是评价联合用药的两药相互作用方式的主要参数。抑菌浓度分数(FIC)，分别为每一种药物联合抑菌时所需最低抑菌浓度(MIC)与单用时MIC的比值。而FICI则等于两种药物FIC之和。当MIC80值高于检测最高限时以最高限浓度的两倍值用以计算FICI。很多文献报道当FICI≤0.5时两药的相互作用确定为协同作用，且FICI越小协同作用越强；0.5<FICI≤1时两药的相互作用确定为相加作用；1<FICI≤4时为无关作用；当FICI>4时两药产生拮抗作用。本发明选用目前国外期刊采用的最新标准：当FICI≤0.5，两药的相互作用确定为协同作用；0.5<FICI≤4时为无关作用；当FICI>4时两药产生拮抗作用。
测试结果：
该发明的腙类化合物与氟康唑(FCZ，16μg/mL)单独用药与联合用药抗临床分离耐药白色念珠菌100菌和103菌的测定结果如下：
腙类化合物协同FCZ抗耐药白色念菌100菌和103菌的FICI与MIC80测定结果
实验结论：
应用棋盘式稀释法体外药敏实验测试上述化合物协同氟康唑抗耐药白色念珠菌100菌和103菌作用，发现该腙类化合物对氟康唑产生耐药的白色念珠菌100菌和103菌有明显的协同作用，可作为抗真菌药物抗耐药真菌增效剂的药物用途。
此处描述的实施例只用于说明(作为例证)，本领域技术人员所做的各种修改或更变也应包括在专利申请的实质和范围内以及附加权利要求范围之内。

Claims (4)

1.一类如通式I的腙类化合物和唑类抗真菌药物复合用于抗真菌药物制备中的应用，所述的真菌为耐药白念珠菌100菌和耐药白念珠菌103菌：
通式I中，当X为羰基、Y为时，R1代表-H，R2代表Br，R3选自H、1,2,4-三唑、-CN；
当X不存在时，Y为中的一种；
其中当Y为时，R1代表-H、-NO2，R2代表NO2，R3为H、卤素、-OH、1,2,4-三唑、-CN-NO2、苯基和C1-C6的烷基和被取代基取代的C1-C6的烷基，所述取代基独立选自卤素；
当Y为时，R1代表H，R2为NO2，R4为-H、-NO2；
当Y为时，R1代表-H，R2为NO2，R5为-H、卤素；
当Y为时，R1代表-H、-OH、-OCH3，R2代表卤素、-NO2、-CH3，R6选自-CH3、-OCH3、-NH2。
2.根据权利要求1所述的应用，其特征在于：所述唑类抗真菌药物选自氟康唑、酮康唑、咪康唑、伊曲康唑或硫康唑。
3.一种抗真菌药物组合物，其特征在于：所述的药物组合物中包含权利要求1的通式I所述的腙类化合物和唑类抗真菌药物。
4.根据权利要求3所述的抗真菌药物组合物，其特征在于：通式I所述的腙类化合物或药学上可接受的盐和唑类抗真菌药物的质量比为1:128～1:1。
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