CN104016990B - 一种咪唑并吡嗪类衍生物及其制备方法与应用 - Google Patents
一种咪唑并吡嗪类衍生物及其制备方法与应用 Download PDFInfo
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- CN104016990B CN104016990B CN201410276052.1A CN201410276052A CN104016990B CN 104016990 B CN104016990 B CN 104016990B CN 201410276052 A CN201410276052 A CN 201410276052A CN 104016990 B CN104016990 B CN 104016990B
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- dimethyl
- imidazopyrazines
- analog derivative
- pyrazine
- room temperature
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Abstract
本发明公开了一种咪唑并吡嗪类衍生物及其制备方法和应用。所述的咪唑并吡嗪类衍生物是具有通式Ⅰ所示结构的化合物及其药学上可接受的盐、酯或前药。本发明还提供了化合物的制备方法,以及含有一个或多个此类化合物的组合物在治疗和预防人免疫缺陷病毒(HIV)感染药物中的应用。
Description
技术领域
本发明涉及一种衍生物及其制备方法与应用,特别涉及一种咪唑并吡嗪类衍生物及其制备方法与应用,属于医药技术领域。
背景技术
艾滋病亦称获得性免疫缺陷综合征(Acquired immunodeficiency syndrome,AIDS),是由艾滋病的病原体即人类免疫缺陷病毒(Human immumodeficiency virus,HIV)引起的以T细胞免疫功能缺陷为主的一种传染性疾病。自20世纪80年代被发现以来,艾滋病已经成为严重危害人类健康的重大传染性疾病之一。目前临床上最常用的防治艾滋病的方法为高效抗逆转录病毒疗法(Highly Active Antiretroviral Therapy,HAART),此疗法的实施虽然大大提高了HIV病毒的抑制效率,但是由于HIV病毒极易产生变异以及长期服药的毒性问题很大程度上限制了该疗法的应用。因此研究并开发新型的抗耐药性艾滋病治疗药物依然具有十分重要的意义。非核苷类逆转录酶抑制剂(Non-nucleoside ReverseTranscriptase Inhibitors,NNRTIs)作为HAART的重要组成部分,具有活性高、选择性强、毒性低等优点,一直以来是抗艾滋病药物研究的热点。但是由于NNRTIs结合位点的氨基酸容易发生突变,导致耐药毒株的产生而使得该类药物迅速丧失临床效价。因此研发新型、高效、抗耐药的NNRTIs是目前抗艾滋病药物研究的重要方向。
第二代NNRTIs由于分子的柔韧性使得它们与RT结合时能够通过扭转(摆动)和复位(微动)适应靶酶的突变,因而具有良好的抗耐药性。其中,上市药物依曲韦林和利匹韦林作为第二代NNRTIs的典型代表,受到了广泛的关注,但是由于这两个药物存在口服利用度差或者副作用等问题,因此需要对其进行进一步的结构改造以克服以上问题。对于该类化合物的结构改造产生了一系列的DAPY类似物,表现出了良好的抗野生型与变异型HIV-1活性。对发现广谱高效、体内活性良好且具有自主知识产权的抗HIV药物具有重要的意义。
发明内容
针对现有技术的不足,本发明提供了一种咪唑并吡嗪类衍生物,本发明还提供该类化合物的制备方法及应用。
本发明的技术方案如下:
一、咪唑并吡嗪类衍生物
一种咪唑并吡嗪类衍生物,或其药学上可接受的盐、酯或前药,结构通式Ⅰ如下:
其中,
X为NH或O;
Ar为2,4,6-三甲基苯基、2,4,6-三氯苯基、2,4,6-三溴苯基、2,4,6-三氟苯基、2,6-二溴-4-甲基苯基、2,6-二甲基-4-溴苯基、2,6-二甲基-4-氰基苯基、2,6-二甲基-4-氯苯基、2,6-二甲苯基、2,6-二氯苯基或2,6-二甲氧苯基;
R1为CN,Me,OMe,Cl,NO2或-CH2CN。
优选的,上述通式I的化合物是下列之一:
二、咪唑并吡嗪类衍生物的制备方法
一种咪唑并吡嗪类衍生物的制备方法,以2-氨基-3,5-二溴吡嗪为原料,经与质量体积比40%的氯乙醛水溶液成环生成化合物MP-1,MP-1再与取代苯酚或芳胺发生亲核取代反应生成中间体MP-2至MP-7,最后与对位取代苯胺在Pd(OAc)2催化下进行偶联得到相应的终产物。
合成路线如下:
试剂和条件:(i)氯乙醛,2-异丙醇,氮气保护,回流;(ii)取代苯酚或芳胺,碳酸钾,二甲基甲酰胺;(iii)对位取代苯胺,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,Cs2CO3,回流;
其中,Ar、X、R1的定义如通式I中所述。
所述的取代苯酚为2,4,6-三甲基苯酚、2,4,6-三氯苯酚、2,4,6-三溴苯酚、2,4,6-三氟苯酚、2,6-二溴-4-甲基苯酚、2,6-二甲基-4-溴苯酚、2,6-二甲基-4-氰基苯酚、2,6-二甲基-4-氯苯酚、2,6-二甲苯酚、2,6-二氯苯基或2,6-二甲氧苯酚,取代芳胺与取代苯酚取代基相同。
所述的对位取代苯胺的对位取代基为CN,Me,OMe,Cl,NO2或CH2CN。
本发明更为详细的,一种咪唑并吡嗪类衍生物的制备方法,步骤如下:
(1)将2mmol 2-氨基-3,5-二溴吡嗪溶于20ml 2-异丙醇中,随后加入4mmol氯乙醛,N2保护下加热回流24h,冷却至室温,加入25ml DCM和1ml Et3N减压蒸干,残渣用体积比10:1的水/2-异丙醇混合溶液洗涤2次,每次11ml,真空干燥至恒重得褐色固体MP-1,无需纯化,直接用于下步反应;
(2)将7mmol取代苯酚或芳胺及14mmol K2CO3溶于30ml二甲基甲酰胺中,室温搅拌30min,加入7mmol MP-1,室温搅拌过夜,加入100ml H2O至沉淀完全析出,过滤,真空干燥,产物(MP-2—MP-7)无需纯化直接用于下步反应;
(3)将0.05mmol醋酸钯和0.05mmol 4,5-双二苯基膦-9,9-二甲基氧杂蒽溶于二氧六环中,室温搅拌30min,依次加入2mmol碳酸铯,上步1mmol中间体及1.1mmol对位取代苯胺,N2保护下加热回流至TLC监测中间体完全消失,冷却至室温,过滤,向滤液中直接加入硅胶拌样,使用柱层析色谱分离并重结晶得终产物。
三、咪唑并吡嗪类衍生物的应用
本发明通式Ⅰ的咪唑并吡嗪类衍生物在HIV-1逆转录酶抑制活性实验中显示出显著的抑酶活性。因此,本发明还提供:
通式Ⅰ的咪唑并吡嗪类衍生物在制备抗HIV的药物中的应用。
一种抗HIV药物组合物,包含本发明所述咪唑并吡嗪类衍生物或其药学上可接受的盐以及一种或多种药学上可接受载体或赋形剂。
本发明化合物既可以其本身也可以其药学上可接受的盐或溶剂化物的形式使用。通式Ⅰ化合物的药学上可接受的盐包括与药学上可接受的无机酸或有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括与盐酸、硫酸、磷酸、硝酸、氢溴酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基苯甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括与钠、锂、钾、镁、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖按和普鲁卡因等形成的盐。本文中涉及到本发明化合物时,包括通式Ⅰ化合物及其药学上可接受的盐或溶剂化物。
根据本发明,本发明式I化合物可与常规药物载体或赋形剂组成药物组合物。该药物组合物可通过口服或非肠道途径给药。本发明的药物组合物可按本领域常规方法制备成各种剂型,包括但不限于片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂等,经口服或非肠道途径给药。
在本发明的化合物上进行新的结构修饰及深入研究有助于开发出新的抗HIV药物。
具体实施方式
下面结合实施例对本发明做进一步说明,但本发明所保护范围不限于此。
实施例1:4-((8-(2,6-二甲基苯酚)咪唑并[1,2-a]吡嗪-6-基)氨基)苯腈(MP-2a)的制备
将2mmol 2-氨基-3,5-二溴吡嗪溶于20ml 2-异丙醇中,随后加入4mmol氯乙醛,氮气保护下加热回流24h,冷却至室温,加入25ml二氯甲烷和1ml三乙胺,减压蒸干,残渣用体积比10:1水/2-异丙醇混合溶液11ml洗涤2次,真空干燥至恒重得褐色固体MP-1,无需纯化,直接用于下步反应。
将7mmol 2,6-二甲基苯酚及14mmol碳酸钾溶于30ml二氯甲烷中,室温搅拌30min,加入7mmol MP-1,室温搅拌过夜,加入100ml H2O至沉淀完全析出,过滤,真空干燥,产物MP-3无需纯化直接用于下步反应。
将0.05mmol醋酸钯和0.05mmol 4,5-双二苯基膦-9,9-二甲基氧杂蒽溶于二氧六环中,室温搅拌30min,依次加入2mmol碳酸铯,1mmol MP-3及1.1mmol对氰基苯胺,氮气保护下加热回流至薄层板监测中间体完全消失,冷却至室温,过滤,向滤液中直接加入硅胶拌样,使用柱层析色谱分离并重结晶得终产物。产物为白色固体,产率28%,熔点:163-165℃。
ESIMS:m/z 356.5(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.19(s,1H,NH),8.18(s,1H,imidazole-H),7.96(s,1H,pyrazine-H),7.74(s,1H,imidazole-H),7.35-7.06(m,7H,benzene-H),2.11(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.81,150.09,147.50,137.65,134.87,133.22,130.80,130.18,129.25,126.25,120.26,117.22,116.04,102.28,100.10,16.48
实施例2:8-(2,6-二甲基苯酚)-N-(4-硝基苯)咪唑[1,2-a]吡嗪-6-胺(MP-2b)
试剂:2,6-二甲基苯酚,对硝基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为黄色固体,产率27%,熔点:259-261℃
ESIMS:m/z 376.5(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.62(s,1H,NH),8.22(s,1H,imidazole-H),8.03(s,1H,pyrazine-H),7.83-7.09(m,7H,benzene-H),7.77(s,1H,imidazole-H),2.12(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.87,150.12,149.83,138.78,137.22,135.02,130.86,130.28,129.25,126.23,125.47,117.40,115.13,103.15,16.46
实施例3:2-(4-((8-(2,6-二甲基苯酚)咪唑并[1,2-a]吡嗪-6-基)氨基)苯基)乙腈(MP-2c)
试剂:2,6-二甲基苯酚,对氨基苯乙腈,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率31%,熔点:98-100℃
ESIMS:m/z 370.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:8.47(s,1H,NH),8.11(s,1H,imidazole-H),7.84(s,1H,pyrazine-H),7.68(s,1H,imidazole-H)7.22-6.95(m,7H,benzene-H),3.84(s,2H,CH2),2.11(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.72,150.12,142.64,139.44,134.54,130.85,129.98,129.14,128.78,126.06,121.94,120.03,117.13,116.77,99.65,22.02,16.54
实施例4:N-(4-氯苯)-8-(2,6-二甲基苯酚)咪唑并[1,2-a]吡嗪-6-胺(MP-2d)
试剂:2,6-二甲基苯酚,对氯苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率21%,熔点:167-169℃
ESIMS:m/z 365.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:8.61(s,1H,NH),8.12(s,1H,imidazole-H),7.84(s,1H,pyrazine-H),7.69(s,1H,imidazole-H)7.24-6.96(m,7H,benzene-H),2.10(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.72,150.13,142.16,139.15,134.61,130.84,129.95,129.19,128.61,126.13,122.96,118.15,116.84,99.86,16.52
实施例5:N-(4-氯苯)-8-(2,6-二甲基苯酚)咪唑并[1,2-a]吡嗪-6-胺(MP-2d)
试剂:2,6-二甲基苯酚,对氯苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率21%,熔点:167-169℃
ESIMS:m/z 365.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:8.61(s,1H,NH),8.12(s,1H,imidazole-H),7.84(s,1H,pyrazine-H),7.69(s,1H,imidazole-H)7.24-6.96(m,7H,benzene-H),2.10(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.72,150.13,142.16,139.15,134.61,130.84,129.95,129.19,128.61,126.13,122.96,118.15,116.84,99.86,16.52
实施例6:8-(2,4,6-三甲基苯酚)-N-(4-硝基苯)咪唑[1,2-a]吡嗪-6-胺(MP-3b)
试剂:2,4,6-三甲基苯酚,对硝基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为黄色固体,产率55%,熔点:138-140℃
ESIMS:m/z 390.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.60(s,1H,NH),8.21(s,1H,imidazole-H),8.02(s,1H,pyrazine-H),7.76(s,1H,imidazole-H),7.84-7.06(m,6H,benzene-H),2.34(s,3H,CH3),2.07(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:151.02,149.85,147.93,138.76,137.16,135.17,134.95,130.46,130.33,129.70,125.44,117.38,115.22,103.10,20.80,16.39
实施例7:2-(4-((8-(2,4,6-三甲基苯酚)咪唑并[1,2-a]吡嗪-6-基)氨基)苯基)乙腈(MP-3c)
试剂:2,4,6-三甲基苯酚,对氨基苯乙腈,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率38%,熔点:185-187℃
ESIMS:m/z 384.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:8.50(s,1H,NH),8.11(s,1H,imidazole-H),7.84(s,1H,pyrazine-H),7.68(s,1H,imidazole-H),7.05-6.96(m,6H,benzene-H),3.86(s,2H,benzene-CH2-CN),2.32(s,3H,CH3),2.06(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.86,147.90,142.58,139.43,135.01,134.46,130.40,129.99,129.62,128.70,121.90,120.02,117.20,116.73,99.43,22.05,20.84,16.48
实施例8:N-(4-氯苯)-8-(2,4,6-三甲基苯酚)咪唑并[1,2-a]吡嗪-6-胺(MP-3d)
试剂:2,4,6-三甲基苯酚,对氯苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率56%,熔点:105-107℃
ESIMS:m/z 379.5(M+1)
1H NMR(DMSO-d6,400MHz)δ:8.59(s,1H,NH),8.11(d,1H,J=0.72Hz,imidazole-H),7.84(s,1H,pyrazine-H),7.68(d,1H,J=0.72Hz,imidazole-H),7.04-6.98(m,6H,benzene-H),2.31(s,3H,CH3),2.05(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.88,147.90,142.19,139.12,134.98,134.53,130.40,130.04,129.63,128.61,123.01,118.29,116.81,99.83,20.82,16.46
实施例9:4-((6-((4-氰基苯基)胺)咪唑并[1,2-a]吡嗪-8-基)氧基)-3,5-二甲基苯腈(MP-4a)
试剂:3,5-二甲基-4-羟基苯腈,对氰基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率66%,熔点:184℃dec
ESIMS:m/z 381.5(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.19(s,1H,NH),8.21(d,1H,J=0.84Hz,imidazole-H),8.03(s,1H,pyrazine-H),7.76(d,1H,J=0.64Hz,imidazole-H),7.79-7.03(m,6H,benzene-H),2.16(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:153.92,150.14,147.40,137.24,135.18,133.26,133.19,129.97,120.22,119.01,117.47,115.97,109.11,103.20,100.34,16.20
实施例10:3,5-二甲基-4-((6-((4-硝基苯基)胺基)咪唑并[1,2-a]吡嗪-8-基)氧基)苯腈(MP-4b)
试剂:3,5-二甲基-4-羟基苯腈,对硝基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为黄色固体,产率30%,熔点:133-135℃
ESIMS:m/z 401.5(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.60(s,1H,NH),8.24(s,1H,imidazole-H),8.10(s,1H,pyrazine-H),7.89-7.04(m,7H,benzene-H,imidazole-H),2.17(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:153.91,150.20,149.72,138.90,136.78,135.33,133.32,133.19,130.05,125.53,118.97,117.66,115.02,109.13,104.09,16.19
实施例11:4-((6-((4-氰甲基苯基)胺)咪唑并[1,2-a]吡嗪-8-基)氧基)-3,5-二甲基苯腈(MP-4c)
试剂:3,5-二甲基-4-羟基苯腈,对氨基苯乙腈,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率19%,熔点:174-176℃
ESIMS:m/z 395.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:8.48(s,1H,NH),8.13(d,1H,J=0.44Hz,imidazole-H),7.90(s,1H,pyrazine-H),7.70(s,1H,imidazole-H),7.76-7.01(m,6H,benzene-H),3.86(s,2H,CH3),2.16(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:153.97,150.06,142.45,139.12,134.86,133.30,133.06,129.73,128.82,122.28,119.94,119.01,117.24,117.04,109.02,100.31,22.08,16.26
实施例12:4-((6-((4-氯苯基)胺)咪唑并[1,2-a]吡嗪-8-基)氧基)-3,5-二甲基苯腈(MP-4d)
试剂:3,5-二甲基-4-羟基苯腈,对氯苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率20%,熔点:195-197℃
ESIMS:m/z 390.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:8.63(s,1H,NH),8.15(d,1H,J=0.52Hz,imidazole-H),7.72(d,1H,J=0.52Hz,imidazole-H),7.89-6.95(m,7H,pyrazine-H,benzene-H),2.15(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:154.01,150.04,141.95,138.86,134.93,133.31,133.14,129.69,128.65,123.24,119.05,118.23,117.10,109.00,100.53,16.23
实施例13:4-((8-(2,4,6-三氟苯酚)咪唑并[1,2-a]吡嗪-6-基)氨基)苯腈(MP-5a)
试剂:2,4,6-三氟苯酚,对氰基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为白色固体,产率19%,熔点:269℃dec
ESIMS:m/z 382.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.32(s,1H,NH),8.24(s,1H,imidazole-H),8.11(s,1H,pyrazine-H),7.80(s,1H,imidazole-H),7.60-7.12(m,6H,benzene-H)
13C NMR(100MHz,DMSO-d6)δ:154.38,149.51,147.24,136.60,135.63,133.43,129.59,120.22,117.74,116.00,104.25,102.38(t,JC-F=27.00Hz,3C,OPh-C),100.60
实施例14:N-(4-硝基苯基)-8-(2,4,6-三氟苯酚)咪唑并[1,2-a]吡嗪-6-胺(MP-5b)
试剂:2,4,6-三氟苯酚,对硝基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为黄色固体,产率16%,熔点:268-270℃
ESIMS:m/z 402.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.71(s,1H,NH),8.28(s,1H,imidazole-H),8.18(s,1H,pyrazine-H),7.98-7.14(m,7H,imidazole-H,benzene-H)
13C NMR(100MHz,DMSO-d6)δ:160.82,158.37,158.23,156.96,156.90,156.80,156.74,154.48,154.42,154.32,154.26,149.61,139.20,139.15,136.17,135.76,129.72,126.82,125.64,117.90,115.07,105.20,102.65,102.38,102.10
实施例15:4-((8-(4-溴-2,6-二甲基苯酚)咪唑并[1,2-a]吡嗪-6-基)氨基)苯腈(MP-6a)
试剂:2,6-二甲基-4-溴苯酚,对氰基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为淡黄色固体,产率29%,熔点:268℃dec
ESIMS:m/z 434.4,436.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.20(s,1H,NH),8.19(d,1H,J=0.6Hz,imidazole-H),7.99(s,1H,pyrazine-H),7.74(d,1H,J=0.6,imidazole-H),7.48-7.06(m,6H,benzene-H),2.10(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.43,149.49,147.45,137.45,135.00,133.79,133.22,131.64,130.08,120.24,118.33,117.34,116.12,102.64,100.26,16.20
实施例16:8-(4-溴-2,6-二甲基苯酚)-N-(4-硝基苯基)咪唑并[1,2-a]吡嗪-6-胺(MP-6b)
试剂:2,6-二甲基-4-溴苯酚,对硝基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为黄色固体,产率32%,熔点:223℃dec.
ESIMS:m/z 454.3,456.3(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.60(s,1H,NH),8.22(d,1H,J=0.8Hz,imidazole-H),8.05(s,1H,pyrazine-H),7.90-7.08(m,7H,imidazole-H,benzene-H),2.11(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.48,149.72,149.49,138.87,137.06,135.15,133.83,131.65,130.14,125.51,118.41,117.51,115.16,103.37,55.37,16.18
实施例17:4-((8-(4-氯-2,6-二甲基苯酚)咪唑并[1,2-a]吡嗪-6-基)氨基)苯腈(MP-7a)
试剂:2,6-二甲基-4-氯苯酚,对氰基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为淡黄色固体,产率33%,熔点:256℃dec.
ESIMS:m/z 390.3(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.19(s,1H,NH),8.19(d,1H,J=0.84Hz,imidazole-H),8.00(s,1H,pyrazine-H),7.74(d,1H,J=0.68Hz,imidazole-H),7.39-7.07(m,6H,benzene-H),2.10(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.49,148.94,147.47,137.41,135.00,133.37,133.22,130.09,130.00,128.70,120.25,117.34,116.08,102.70,100.23,16.30
实施例18:8-(4-氯-2,6-二甲基苯酚)-N-(4-硝基苯基)咪唑并[1,2-a]吡嗪-6-胺(MP-7b)
试剂:2,6-二甲基-4-氯苯酚,对硝基苯胺,中间体MP-1,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,碳酸钾,二氧六环,二甲基甲酰胺。产物为黄色固体,产率40%,熔点:184-186℃.
ESIMS:m/z 410.4(M+1)
1H NMR(DMSO-d6,400MHz)δ:9.60(s,1H,NH),8.22(s,1H,imidazole-H),8.05(s,1H,pyrazine-H),7.89-7.08(m,7H,imidazole-H,benzene-H),2.11(s,6H,CH3)
13C NMR(100MHz,DMSO-d6)δ:150.55,149.75,148.96,138.66,137.04,135.15,133.43,130.16,130.09,128.72,125.49,117.51,115.14,103.45,16.28
实施例19:体外HIV-1逆转录酶抑制活性测定
本实验采用色度法逆转录酶活性测定实验,所使用试剂盒ReverseTranscriptase Assay,colorimetric Version 13.0购自罗氏公司,阳性对照药物选用Nevirapine和TMC125。(参见[1]Hofman,A.D.&Banapour,B.&Levy,J.A.(1985)Virology147,326–335.[2]Ukkonen,P.et al.(1988)Eur.J.Clin.Microbiol.&Infect.Dis.7,518–523.)
测试原理
色度法逆转录酶活性测定使用模板/引物聚合物poly(A)×oligo(dT)作为起始原料,并用地高辛和生物素标记的核苷酸代替用放射性同位素[3H]-或[32P]-标记的核苷酸,这些是此方法的优势之处。所合成出的DNA是测定逆转录酶活性的重要参数,检测和定量DNA使用了以下三明治式的ELISA测定方法:生物素标记的DNA能够与包被了抗生物素链霉菌素的微版模块(MP)的表面进行结合。在接下来的一步中,聚合了过氧化物酶的地高辛抗体需要结合到地高辛标记的DNA上。最终,加入过氧化物酶的底物ABTS,使它们在酶的催化作用下分解,产生带有明显颜色的产物。通过酶标仪测定载有样品的微板吸光度,此吸光度值与逆转录酶的活性呈现直接的相关性,通过公式计算可得到化合物对逆转录酶的抑制浓度。
测试方法
(1)首先配置各种工作溶液,并将样品用适量DMSO溶解,并用裂解缓冲液稀释成5个浓度梯度。在各个不同的反应管中,将4–6ng重组HIV-1-RT用裂解缓冲液(20μL/well)稀释。同时,准备只有裂解缓冲液而没有RT的阴性对照组。然后每个反应罐加入20μL含有不同浓度所测试样品的缓冲溶液以及20μL反应物混合液,在37℃孵育1小时。
(2)准备足够的微版模块,按照方向牢固地安装在框架内。将孵育好的60μL样品转移到微板的孔中,用薄膜覆盖好后第二次37℃孵育1小时。
将溶液移除,每孔用洗液仔细地冲洗5遍,每遍用250μL,保留30秒。每孔加入200μL抗地高辛-过氧化物酶聚合物,将微板用薄膜覆盖好后第三次在37℃孵育1小时。
(3)将溶液移除,每孔用洗液仔细地冲洗5遍,每遍用250μL,保留30秒。每孔加入200μLABTS溶液,15-25℃孵育,直到绿颜色出现并足够通过光度检测,一般为10-30分钟。
(4)用酶标仪测定载有样品在波长405nm处的吸光度值,通过以下公式计算可得化合物对逆转录酶的抑制浓度。
抑制率%=(阳性对照荧光强度-样品荧光强度)/(阳性对照荧光强度-背景荧光强度)×100%
进行线性回归,将抑制率带入线性方程,求得IC50,单位是μg/mL,再根据化合物分子量转化为μM。
活性结果
本实验选择奈韦拉平,依曲韦林为阳性对照药,逆转录酶抑制活性实验结果见表1:
表1咪唑并吡嗪类衍生物结构通式及活性数据
a IC50:使50%HIV-1逆转录酶活性得到抑制时的化合物浓度。
从活性数据可以看出,大部分化合物具有抑制逆转录酶活性。其中化合物MP-4c(IC50=0.174μM)的活性与TMC125(IC50=0.130μM)相当,有9个化合物的活性超过了奈韦拉平(NVP)。
此外,该类化合物骨架新颖,具有多个可修饰位点,根据初步构效关系可进行进一步的结构优化,因此本发明的化合物具有发展成为全新结构的抗艾滋病新药的潜力。
Claims (6)
1.一种咪唑并吡嗪类衍生物,其特征在于,结构通式Ⅰ如下:
其中,X为O;
Ar为2,4,6-三甲基苯基、2,4,6-三氟苯基、2,6-二甲基-4-溴苯基、2,6-二甲基-4-氰基苯基、2,6-二甲基-4-氯苯基、2,6-二甲苯基;
R1为CN,Cl,NO2或-CH2CN。
2.权利要求1所述的咪唑并吡嗪类衍生物其特征在于,是下列化合物之一:
3.一种如权利要求1所述的咪唑并吡嗪类衍生物的制备方法,以2-氨基-3,5-二溴吡嗪为原料,经与质量体积比40%的氯乙醛水溶液成环生成化合物MP-1,MP-1再与取代苯酚发生亲核取代反应生成中间体,最后与对位取代苯胺在Pd(OAc)2催化下进行偶联得到相应的终产物;
合成路线如下:
试剂和条件:(i)氯乙醛,2-异丙醇,氮气保护,回流;(ii)取代苯酚,碳酸钾,二甲基甲酰胺;(iii)对位取代苯胺,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,Cs2CO3,回流;
其中,Ar、X、R1的定义如权利要求1中所述;
所述的取代苯酚为2,6-二甲基苯酚、2,4,6-三甲基苯酚、2,6-二甲基-4-氰基苯酚、2,4,6-三氟苯酚、2,6-二甲基-4-溴苯酚、2,6-二甲基-4-氯苯酚;
所述的对位取代苯胺的对位取代基为CN、Cl、NO2或-CH2CN。
4.权利要求3所述的咪唑并吡嗪类衍生物的制备方法,步骤如下:
(1)将2mmol2-氨基-3,5-二溴吡嗪溶于20mL2-异丙醇中,随后加入4mmol氯乙醛,N2保护下加热回流24h,冷却至室温,加入25mL二氯甲烷和1mL Et3N减压蒸干,残渣用体积比10:1的水/2-异丙醇混合溶液洗涤2次,每次11mL,真空干燥至恒重得褐色固体MP-1,无需纯化,直接用于下步反应;
(2)将7mmol取代苯酚及14mmol K2CO3溶于30ml二甲基甲酰胺中,室温搅拌30min,加入7mmol MP-1,室温搅拌过夜,加入100mLH2O至沉淀完全析出,过滤,真空干燥,产物无需纯化直接用于下步反应;
(3)将0.05mmol醋酸钯和0.05mmol 4,5-双二苯基膦-9,9-二甲基氧杂蒽溶于二氧六环中,室温搅拌30min,依次加入2mmol碳酸铯,上步1mmol中间体及1.1mmol对位取代苯胺,N2保护下加热回流至TLC监测中间体完全消失,冷却至室温,过滤,向滤液中直接加入硅胶拌样,使用柱层析色谱分离并重结晶得终产物。
5.权利要求1或2所述的咪唑并吡嗪类衍生物在制备抗HIV的药物中的应用。
6.一种抗HIV药物组合物,包含权利要求1或2所述的咪唑并吡嗪类衍生物或其药学上可接受的盐以及一种或多种药学上可接受载体或赋形剂。
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