CN109053613A - 含有联苯结构的二芳基三嗪类化合物及其制备方法和用途 - Google Patents

含有联苯结构的二芳基三嗪类化合物及其制备方法和用途 Download PDF

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CN109053613A
CN109053613A CN201810722004.9A CN201810722004A CN109053613A CN 109053613 A CN109053613 A CN 109053613A CN 201810722004 A CN201810722004 A CN 201810722004A CN 109053613 A CN109053613 A CN 109053613A
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陈芬儿
金凯军
孟歌
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Abstract

本发明属于医药技术领域,具体为一种含联苯结构的二芳基三嗪类化合物及其制备方法和用途。本发明含有联苯结构的二芳基三嗪类化合物的结构通式为Ⅰ所示。本发明还包括含有联苯结构的二芳基三嗪类化合物的药用盐,其水合物和溶剂化物,其多晶或共晶,其同样生物功能的前体和衍生物。药理实验结果表明,该类化合物具有显著的抗HIV‑1和HIV‑2(ROD)病毒活性,可以有效的抑制病毒感染的MT‑4细胞的复制,并且具有较低的细胞毒性;故该类化合物可用于制备预防和治疗艾滋病的药物。

Description

含有联苯结构的二芳基三嗪类化合物及其制备方法和用途
技术领域
本发明属于医药技术领域,具体涉及一种含联苯结构的二芳基三嗪类化合物及其制备方法和在治疗艾滋病等相关药物中的应用。
背景技术
艾滋病(AIDS)即获得性免疫缺陷综合征(Acquired immune deficiencysyndrome)是由人类免疫缺陷病毒(Human immunodeficiency virus,HIV)所导致的流行性传染病。逆转录酶(Reverse transcriptase,RT)在HIV从mRNA逆转录成DNA的过程中起了决定性作用,因此成为抗艾滋病药物设计的重要靶点之一。
在现有的抗HIV药物研究中,非核苷类逆转录酶抑制剂(NNRTIs)因其高效低毒等优点而成为各国药物化学家关注的热点之一。目前,经美国FDA批准上市的抗HIV逆转录酶抑制剂有五种:奈维拉平(Nevirapine)、德拉韦定(Delavirdine)、依非韦伦(Efavirenz)、依曲韦林(Etravirine)、利匹韦林(Rilpivirine)。另外,RDEA806、IDX899、UK-453061正在进行临床研究。
发明内容
本发明的目的在于提出一种逆转录酶抑制剂含有联苯结构的二芳基三嗪类化合物,具体涉及通式Ⅰ所述含有联苯结构的二芳基三嗪类化合物及其药用盐,其水合物和溶剂化物,其多晶和共晶,其同样生物功能的前体和衍生物。
本发明所提供的含有联苯结构的二芳基三嗪类化合物,具有如下结构式Ⅰ:
其中,R1和R2分别独立选自氢、氰基、硝基、氨基、羟基、卤素、多卤代甲基、多卤代甲氧基、多卤代甲硫基、磺酸基、酯基、羧基,-NR4-,任选被取代的C1~6烷基、任选被取代的C2~6烯基、任选被取代的C2~6炔基或C1~6烷氧基;
R3选自氢、氰基、硝基、氨基、羟基、卤素、羧基、酯基、吗啉、呋喃,氨基醇、氨基酸、糖、寡肽、N3,-NH(OH),C1~4氨基、C1~6烷基、C1~6烷氧基、C1~6烷巯基、C3~6环烷氨基、C2~6烯基;
X为-NR5-,-NH-NH-,-N=N-,-O-,-S-,-SO-,-SO2-,-PO2-,-CH2-,-CH(OH),-CO-,-CH(CN)-或者C1~4烷二基;
R4选自氢、芳基、甲酰基、磺酰基、C1~6烷基羰基、C1~6烷基、C1~6烷氧基羰基或C1~6烷氧基;
R5选自氢、芳基、甲酰基、磺酰基、C1~6烷基羰基、C1~6烷基、C1~6烷氧基羰基或C1~6烷氧基。
本发明中,所述含有联苯结构的二芳基三嗪类化合物的药用盐包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、富马酸盐或苹果酸盐。
药理实验结果表明,本发明的化合物具有显著的抗HIV-1和HIV-2(ROD)病毒活性,可以有效的抑制病毒感染的MT-4细胞的复制,并且具有较低的细胞毒性;故该类化合物可用于制备预防和治疗艾滋病的药物。
本发明还提出含有联苯结构的二芳基三嗪类化合物的制备方法,其制备的反应通式如下:
具体操作步骤如下:
以上述结构式Ⅱ所示的化合物(4-((4,6-二氯-1,3,5-三嗪-2-基)氨基)苯甲腈)为原料,在溶剂中、碱存在下,与相应的取代联苯化合物反应,制得化合物Ⅲ(4-取代联苯基-6-氯-1,3,5-三嗪-2-基)氨基)苯甲腈类化合物);然后Ⅲ再被小分子胺等亲核取代得目标产物Ⅰ。
所述的溶剂为水、二氯甲烷、氯仿、乙酸乙酯、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙腈、四氢呋喃、硝基甲烷、醋酐、萘烷、N,N-二甲基甲酰胺中的一种或者多种;
所述的碱为碳酸锂、碳酸氢钠、碳酸钠、碳酸钾、碳酸铯、醋酸钠、氢氧化锂、氢氧化钠、氢氧化钾、氢化钠、甲醇钠、乙醇钾、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、吡啶、3-甲基吡啶、4-二甲氨基吡啶的一种或者多种;
所述的氧化剂与化合物Ⅱ的摩尔比为1:1~3:1((1~3):1),优选1.2:1~1.8:1;
反应温度为0~90℃,优选20~50℃;
反应时间为1~24h,优选5-10h。
本发明还涉及一种药物组合物,该组合物含有有效剂量的上述化合物和相关的药用载体。
本发明还涉及所述化合物或组合物在制备预防和治疗艾滋病药物中的应用。
本发明基于二芳基三嗪类化合物与逆转录酶结合模式,结合计算机辅助药物设计,在左翼引入各种取代联苯,增强与NNIBP内壁的Tyr181,Tyr181,Phe227和Trp229氨基酸残基之间的疏水性相互作用以及π-π堆积作用;在联苯结构与中心三嗪环之间引入各种连接基团,以考察不同连接基对活性的影响;在三嗪环C4位引入各种水溶性基团,改善目标分子的水溶性提高生物利用度。生物活性测试表明,所有化合物均具有较强抗HIV-1病毒活性和较小的细胞毒性,具有较高的选择性指数。
具体实施方式
通过下述实施实例可以更好地理解本发明内容,但是不能限制本发明的内容。
实施例1:终产物Ⅰ的合成
在20~40℃下,将4-((4,6-二氯-1,3,5-三嗪-2-基)氨基)苯甲腈(Ⅱ)和NaH或者三乙胺加入到溶剂中,搅拌溶解,然后加入取代联苯,搅拌1~5h。TLC显示反应完全。依次用盐酸(1.0N),水、饱和食盐水洗涤,有机相经无水硫酸钠干燥。过滤,浓缩,石油醚和乙酸乙酯重结晶得到所需固体Ⅲ。室温下,将中间体Ⅲ(0.5mmol),二异丙基乙胺(2.2eq.)或碳酸钾溶于溶剂中,然后加入各种胺(1eq.),加热至回流反应,TLC监测至反应完毕。减压浓缩,加水淬灭,用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤后减压浓缩,所得浓缩物用乙酸乙酯和石油醚重结晶得产物Ⅰ,产率60–75%。产物Ⅰ中有关化合物名称、结构式以及波谱数据如下:
(1)甘氨酸甲酯(4-((4’-氰基-3,5-二甲基-[1,1’-联苯]-4-基)氧基)-6-((4-氰基苯基)-氨基)–1,3,5-三嗪-2-基)
产率70%,白色固体,mp 192-194℃;1H NMR(400MHz,DMSO-d6)δ:10.15(m,1H,NH),8.26(s,1H,NH),8.26-7.56(m,10H),3.97(m,2H,CH2),3.61(m,3H,OCH3),2.17(m,6H,CH3×2).13C NMR(101MHz,DMSO-d6)δ:170.84(C=O),169.96(N2=C-O),167.84(N2=C-NH),165.69(N2=C-NH),150.35(ArC),144.62(ArC),144.37(ArC),135.84(ArC),133.23(ArC),131.48(ArC),127.86(ArC),127.56(ArC),120.05(ArC),119.69(ArC),119.37(ArC),110.34(ArC),52.32(COCH2NH),52.12(COCH2NH),42.54(OCH3),16.65(CH3).IR:υ3267,2216,1717,1582,1491cm-1;HRMS calcd for C28H23N7O3[M+Na]+:528.1755,found:528.1751。
(2)4′-((4-((4-氰基苯基)氨基)-6-((2氢-四氢吡喃-4-基)氨基)–1,3,5-三嗪-2-基)氧)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率66%,白色固体,mp>300℃;1H NMR(400MHz,DMSO-d6)δ:10.02(m,1H,NH),8.05-7.50(m,11H,ArH),3.90(m,3H,CH,CH2),3.41(m,2H,CH2),2.18(s,6H,CH3×2),1.78(m,2H,CH2),1.53(m 2H,CH2).13C NMR(101MHz,DMSO-d6)δ:170.23(N2=C-O),169.95(N2=C-NH),166.71(N2=C-NH),165.88(ArC),165.42(ArC),150.48(ArC),144.65(ArC),135.75(ArC),133.28(ArC),133.23(ArC),133.12(ArC),131.57(ArC),127.86(ArC),127.76(ArC),127.62(ArC),119.97(ArC),119.74(ArC),119.36(ArC),110.31(ArC),103.96(ArC),66.53(OCH2),47.41(CHNH),32.68(CH2),16.74(CH3).IR:υ3258,2219,1602,1574,1488cm-1;HRMS calcd for C30H27N7O2[M+Na]+:540.2118,found:540.2104。
(3)4′-((4-((4-氰基苯基)氨基)-6-((四氢呋喃-3-基)甲基)氨基)-1,3,5-三嗪-2-基)氧基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率72%,白色固体,mp 195-197℃;1H NMR(400MHz,DMSO-d6)δ:10.05(m,1H,NH),7.78(m,11H,ArH),3.67(m,4H,CH2),3.16(m,2H,CH2),2.35-1.88(m,7H,CH3×2,CH),1.97(m,2H,CH2).13C NMR(101MHz,DMSO-d6)δ:169.87(N2=C-O),167.58(N2=C-NH),165.86(N2=C-NH),150.43(ArC),144.64(ArC),135.75(ArC),133.26(ArC),131.58(ArC),127.89(ArC),127.77(ArC),120.02(ArC),119.37(ArC),110.31(ArC),70.93(OCH2),67.23(OCH2),44.00(NCH2),43.43(CH2),29.94(CH),16.74(CH3).IR:υ3386,2222,2213,1571,1506,1398cm-1;HRMS calcd for C30H27N7O2[M+Na]+:540.2118,found:540.2113。
(4)(4-((4’-氰基-3,5-二甲基-[1,1’-联苯]-4-基)氧基)-6-((4-氰基苯基)-氨基)-1,3,5-三嗪-2-基)-L-脯氨酸甲酯
产率72%,白色固体,mp 187-189℃(EA/PE);1H NMR(400MHz,DMSO-d6)δ:10.15(m,1H,NH),8.13-7.33(m,10H,ArH),4.71-4.22(m,1H,CH),3.63(m,3H,OCH3),3.47(s,2H,CH2),2.41-1.84(m,10H,CH3×2,CH2).13C NMR(101MHz,DMSO-d6)δ:173.15(C=O),172.73(N2=C-O),169.83(N2=C-NH),169.43(N2=C-NH),165.64(ArC),165.03(ArC),164.93(ArC),164.75(ArC),144.58(ArC),144.31(ArC),133.30(ArC),133.06(ArC),131.44(ArC),127.84(ArC),127.51(ArC),120.05(ArC),119.38(C≡N),110.28(ArC),104.17(ArC),59.06(NCHC=O),52.56(CH3),52.27(CH2),47.37(CH2),29.95(CH2),23.82(CH2),16.80(CH3),16.55(CH3).IR:υ3318,2225,1745,1575,1507cm-1;HRMS calcd for C31H27N7O3[M+H]+:546.2248,found:546.2249。
(5)4′-((4-((4-氰基苯基)氨基)-6-吗啉代-1,3,5-三嗪-2-基)氧基)-3′,5′-二甲基-基-[1,1′-联苯]-4-腈
产率73%,白色固体,mp>300℃(EA/PE);1H NMR(400MHz,DMSO-d6)δ:10.12(s,1H,NH),7.94(s,4H,ArH),7.66(m,6H,ArH),3.73(m,8H,CH2),2.19(s,6H,CH3×2).13C NMR(101MHz,DMSO-d6)δ:170.20(N2=C-O),166.36(N2=C-NH),165.55(N2=C-N),150.43(ArC),144.49(ArC),142.70(ArC),135.73(ArC),133.26(ArC),131.53(ArC),131.41(ArC),127.87(ArC),120.11(ArC),119.67(C≡N),119.38(C≡N),110.33(ArC),104.09(ArC),66.24(CH2),44.26(CH2),43.99(CH2),30.90(CH2),16.69(CH3).IR:υ3288,2222,1576,1504,1405cm-1;HRMS calcd for C29H25N7O2[M+Na]+:526.1962,found:526.1979。
(6)4′-((4-((4-氰基苯基)氨基)-6-(哌嗪-1-基)-1,3,5-三嗪-2-基)氧基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率72%,白色固体,mp 267-269℃;1H NMR(400MHz,DMSO-d6)δ:10.11(m,1H,NH),8.02-7.48(m,10H,ArH),4.11-3.37(m,6H,CH2),2.75(m,3H,CH2,NH),2.19(s,6H,CH3×2).13CNMR(101MHz,DMSO-d6)δ:170.18(N2=C-O),166.09(N2=C-NH),165.54(N2=C-N),150.49(ArC),144.56(ArC),135.67(ArC),133.26(ArC),131.54(ArC),127.79(ArC),120.01(ArC),119.70(C≡N),119.39(C≡N),110.32(ArC),103.96(ArC),70.26(CH2),45.78(CH2),45.11(CH2),44.82(CH2),30.90(CH2),16.79(CH3).IR:υ3311,2223,1574,1504,1404cm-1;HRMS calcd for C29H26N8O[M+H]+:503.2302,found:503.2321。
(7)4′-((4-((4-氰基苯基)氨基)-6-(2-(羟基)甲基吡咯烷-1-基)-1,3,5-三嗪-2-基)氧基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率52%,白色固体,mp 235-237℃;1H NMR(400MHz,DMSO-d6)δ:10.02(m,1H,NH),7.97-7.32(m,10H,ArH),4.73(m,1H,OH),4.10(m,1H,NCH),3.55(m,4H,CH2),2.23-1.70(m,10H,CH2,CH3×2).13C NMR(101MHz,DMSO-d6)δ:169.73(N2=C-O),165.24(N2=C-NH),165.09(N2=C-N),164.99(ArC),164.87(ArC),150.51(ArC),144.68(ArC),135.67(ArC),133.29(ArC),133.17(ArC),131.55(ArC),127.88(ArC),127.67(ArC),119.83(ArC),119.38(C≡N),119.08(C≡N),110.28(ArC),103.83(ArC),70.24(CH),61.15(CH2),59.45(CH2),47.79(CH2),47.63(CH2),27.78(CH2),23.07(CH2),16.75(CH3).IR:υ3431,2224,1573,1496,1396cm-1;HRMS calcd for C30H27N7O2[M+Na]+:540.2118,found:540.2110。
(8)4′-((4-((4-氰基苯基)氨基)-6-(3-羟基吡咯烷-1-基)-1,3,5-三嗪-2-基)-氧)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率67%,白色固体,mp 204-206℃;1H NMR(400MHz,DMSO-d6)δ:10.04(m,1H,NH),7.93-7.57(m,10H,ArH),5.04(m,1H,OH),4.42-4.26(m,1H,OCH),3.78-3.43(m,4H,CH2),2.34-1.69(m,8H,CH2,CH3×2).13C NMR(101MHz,DMSO-d6)δ:169.74(N2=C-O),165.16(N2=C-NH),164.91(N2=C-N),150.53(ArC),144.67(ArC),135.64(ArC),133.22(ArC),131.57(ArC),127.77(ArC),119.82(C≡N),119.38(C≡N),110.30(ArC),103.80(ArC),70.23(CH2),69.18(CH2),55.12(CH),45.03(CH2),44.76(CH2),33.53(CH2),16.78(CH3).IR:υ3191,2226,1576,1489,1410cm-1;HRMS calcd for C29H25N7O2[M+Na]+:526.1962,found:526.1966。
(9)4′-((4-((4-氰基苯基)氨基)-6-(4-羟基哌啶-1-基)-1,3,5-三嗪-2-基)-氧)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率71%,白色固体,mp 228-240℃;1H NMR(400MHz,DMSO-d6)δ:10.06(s,1H,NH),8.09-.15(m,10H,ArH),4.80(s,1H,OH),4.13(m,3H,CH2,CH),3.77(s,1H,CH2),3.42(s,1H,CH2),1.77(m,10H,CH2,CH3×2).13C NMR(101MHz,DMSO-d6)δ:170.27(N2=C-O),165.91(N2=C-NH),165.63(N2=C-N),150.51(ArC),144.57(ArC),135.67(ArC),133.24(ArC),131.54(ArC),127.87(ArC),127.67(ArC),127.32(ArC),119.97(ArC),119.83(C≡N),119.38(C≡N),110.31(ArC),103.93(ArC),65.99(NCH2),41.41(NCH2),41.09(OCH2),34.27(OCH2),16.68(CH3).IR:υ3285,2227,1576,1492,1407cm-1;HRMS calcd for C30H27N7O2[M+Na]+:540.2118,found:540.2110。
(10)4′-((4-((4-氰基苯基)氨基)-6-((2-吗啉乙基)氨基)-1,3,5-三嗪-2-基)-氧基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率73%,白色固体,mp 259-261℃;1H NMR(400MHz,DMSO-d6)δ:10.06(m,1H,NH),7.98-7.49(m,11H,ArH),3.56(s,2H,CH2),3.42(s,3H,CH2),3.24(d,J=5.1Hz,1H,CH2),2.47(s,1H,CH2),2.39(s,2H,CH2),2.32(s,1H,CH2),2.20(m,8H,CH3×2,CH2).13C NMR(101MHz,DMSO-d6)δ:170.15(N2=C-O),169.83(N2=C-NH),167.45(N2=C-N),165.90(ArC),165.52(ArC),144.74(ArC),144.63(ArC),135.74(ArC),135.52(ArC),133.25(ArC),131.54(ArC),127.82(ArC),127.54(ArC),119.90(C≡N),119.37(C≡N),110.30(ArC),66.62(NCH2),57.56(NCH2),53.68(NCH2),38.31(OCH2),37.59(OCH2),16.71(CH3).IR:υ3261,2222,1606,1583,1494cm-1;HRMS calcd for C31H30N8O2[M+H]+:547.2564,found:547.2568。
(11)(4-((4’-氰基-3,5-二甲基-[1,1’-联苯]-4-基)氨基)-6-((4-氰基苯基)氨基)-1,3,5-三嗪-2-基)-甘氨酸甲酯
产率68%,白色固体,mp 197-199℃;1H NMR(400MHz,DMSO-d6)δ:9.57(m,1H,NH),8.74–8.58(m,1H,NH),7.78(m,11H,ArH),4.11(m,2H,CH2),3.66(s,3H,OCH3),2.26(s,6H,CH3×2).13C NMR(101MHz,DMSO-d6)δ:171.61(C=O),166.40(N2=C-NH),165.67(N2=C-NH),164.65(N2=C-NH),145.55(ArC),144.95(ArC),137.43(ArC),136.51(ArC),133.28(ArC),132.88(ArC),127.86(ArC),126.86(ArC),120.03(ArC),119.42(C≡N),110.23(ArC),102.97(ArC),52.18(NHCH2),42.37(OCH3),18.96(CH3).IR:υ3342,2221,1721,1576,1494 cm-1;HRMS calcd for C28H24N8O2[M+Na]+:527.1914,found:527.1913。
(12)4′-((4-((4-氰基苯基)氨基)-6-((2氢-四氢吡喃-4-基)氨基)-1,3,5-三嗪-2-基)氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率73%,白色固体,mp 272-274℃;1H NMR(400 MHz,DMSO-d6)δ:9.58-9.35(m,1H,NH),8.56(m,1H,NH),8.08-7.71(m,7H,ArH),7.49(s,3H,ArH),7.12(s,1H,ArH),4.14-3.81(m,3H,CH,CH2),3.36(s,2H,CH2),2.26(s,6H,CH3×2),1.81(m,2H,CH2),1.53(m,2H,CH2).13C NMR(101MHz,DMSO-d6)δ:170.80(N2=C-NH),165.71(N2=C-NH),164.70(N2=C-NH),145.71(ArC),144.98(ArC),137.54(ArC),136.42(ArC),133.28(ArC),132.92(ArC),127.83(ArC),126.83(ArC),120.09(ArC),119.41(C≡N),110.23(ArC),66.75(NHCH),60.23(OCH2),47.00(OCH2),33.22(CH2),21.22(CH2),19.00(CH3),14.55(CH).IR:υ3354,2220,1611,1569,1484cm-1;HRMS calcd for C30H28N8O[M+Na]+:539.2278,found:539.2278。
(13)4′-((4-((4-氰基苯基)氨基)-6-((四氢-2-氢吡喃-4-基)甲基)氨基)-1,3,5-三嗪-2-基)氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率70%,白色固体,mp 222-224℃;1H NMR(400MHz,DMSO-d6)δ:9.56-9.36(m,1H,NH),8.64-8.45(m,1H,NH),8.00(m,6H,ArH),7.60(m,4H,ArH),7.19(m,1H,ArH),3.77(m,2H,CH2),3.19(m,2H,CH2),2.26(s,6H,CH3×2),1.85(s,1H,CH),1.61(m,2H,CH2),1.22(s,2H,CH2).13C NMR(101MHz,DMSO-d6)δ:166.62(N2=C-NH),166.41(N2=C-NH),164.51(N2=C-NH),145.73(ArC),144.97(ArC),137.52(ArC),136.38(ArC),133.28(ArC),132.89(ArC),127.83(ArC),126.83(ArC),120.11(ArC),119.41(C≡N),110.21(ArC),102.60(ArC),67.28(NHCH2),46.61(OCH2),35.11(OCH2),31.10(CH2),19.00(CH).IR:υ3385,2220,1616,1509,1473cm-1;HRMS calcd for C31H30N8O[M+Na]+:553.2435,found:553.2422。
(14)4′-((4-((4-氰基苯基)氨基)-6-((四氢呋喃-3-基)甲基)氨基)-1,3,5-三嗪-2-基)氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
Yield 70%,white solid,mp 197-199℃;1H NMR(400MHz,DMSO-d6)δ:9.58–9.51(m,1H,NH),8.58(m,1H,NH),8.17–7.19(m,11H,ArH),3.72-3.2(m,4H,OCH2),3.22(s,2H,NHCH2),2.52(s,1H,CH),2.26(s,6H,CH3×2),1.98(s,1H,CH2),1.64(s,1H,CH2).13C NMR(101MHz,DMSO-d6)δ:173.79(N2=C-NH),165.52(N2=C-NH),164.15(N2=C-NH),163.85(ArC),145.33(ArC),144.98(ArC),137.33(ArC),133.28(ArC),132.86(ArC),127.85(ArC),126.90(ArC),119.47(C≡N),110.22(ArC),103.03(ArC),59.05(NCH2),52.37(OCH2),47.17(OCH2),30.23(CH2),23.93(CH),19.05(CH3).IR:υ3419,2224,1614,1567,1484cm-1;HRMS calcd for C30H28N8O[M+H]+:517.2435,found:517.2450。
(15)(4-((4’-氰基-3,5-二甲基-[1,1’-联苯]-4-基)氨基)-6-((4-氰基苯基)氨基)-1,3,5-三嗪-2-基)-L-脯氨酸甲酯
产率68%,白色固体,mp 209-211℃;1H NMR(400MHz,DMSO-d6)δ:9.68-9.46(m,1H),8.69(m,1H,NH),8.11-7.50(m,10H,ArH),4.61-4.07(m,1H,CH),3.70–3.63(m,4H,CH3,CH2),3.27(s,1H,CH2),2.42-1.70(m,10H,CH3×2,CH2).13C NMR(101MHz,DMSO-d6)δ:173.79(C=O),164.51(N2=C-NH),164.15(N2=C-NH),144.98(N2=C-N),137.45(ArC),133.28(ArC),132.86(ArC),127.85(ArC),126.90(ArC),119.98(ArC),119.52(C≡N),119.41(C≡N),110.22(ArC),103.02(ArC),52.37(NCHC=O),30.23(CH2),19.05(CH3).IR:υ2953,2223,1740,1605,1471cm-1;HRMS calcd for C31H28N8O2[M+Na]+:567.2227,found:567.2223。
(16)4′-((4-((4-氰基苯基)氨基)-6-吗啉基-1,3,5-三嗪-2-基)氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率65%,白色固体,mp 279-281℃;1H NMR(400MHz,DMSO-d6)δ:9.62(m,1H,NH),8.74(s,1H,NH),8.11-7.65(m,7H,ArH),7.50(m,3H,ArH),3.67(m,8H,CH2),2.26(s,6H,CH3×2).13C NMR(101MHz,DMSO-d6)δ:165.76(N2=C-NH),165.34(N2=C-NH),164.67(N2=C-N),145.39(ArC),144.95(ArC),137.41(ArC),136.53(ArC),133.27(ArC),132.97(ArC),127.84(ArC),126.86(ArC),119.91(ArC),119.46(C≡N)),110.26(ArC),102.92(ArC),66.47(NCH2),43.84(OCH2),19.04(CH3).IR:υ3411,2220,1620,1574,1597cm-1;HRMS calcdfor C29H26N8O[M+H]+:503.2302,found:503.2291。
(17)4′-((4-((4-氰基苯基)氨基)-6-(哌嗪-1-基)-1,3,5-三嗪-2-基)氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率69%,白色固体,mp 209-211℃;1H NMR(400MHz,DMSO-d6)δ:9.57(m,1H,NH),8.69(s,1H,NH),7.68(m,10H,ArH),3.75(s,6H,CH2),2.72(m,2H,CH2),2.27(s,6H,CH3×2).13C NMR(101MHz,DMSO-d6)δ:165.45(N2=C-NH),164.67(N2=C-N),145.54(ArC),144.99(ArC),137.42(ArC),136.49(ArC),133.54(ArC),133.31(ArC),133.01(ArC),128.59(ArC),127.88(ArC),126.88(ArC),119.70(C≡N),110.26(ArC),102.84(ArC),45.90(NCH2),44.46(HNCH2),19.07(CH3).IR:υ3329,2219,1612,1568,1482cm-1;HRMS calcd forC29H27N9[M+H]+:502.2462,found:502.2453。
(18)4′-((4-((4-氰基苯基)氨基)-6-(4-甲基哌嗪-1-基)-1,3,5-三嗪-2-基)氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率74%,白色固体,mp 224-226℃;1H NMR(400MHz,DMSO-d6)δ:9.59-9.51(m,1H,NH),8.69(d,J=9.8Hz,1H,NH),8.09-7.43(m,10H,ArH),4.76(m,1H,CH),4.29(s,1H,CH2),3.78(s,2H,CH2),3.39(s,3H,NCH3),2.39(s,1H,CH2),2.26(s,7H,CH2,CH3×2),1.81(s,1H,CH2),1.38(s,1H,CH2).13C NMR(101MHz,DMSO-d6)δ:165.83(N2=C-NH),164.86(N2=C-N),145.49(ArC),144.96(ArC),137.66(ArC),137.58(ArC),137.40(ArC),136.44(ArC),135.92(ArC),133.27(ArC),132.96(ArC),127.83(ArC),126.83(ArC),119.93(ArC),119.42(C≡N),110.22(ArC),102.80(ArC),66.49(NCH2),54.85(NCH2),46.24(CH3NCH2),43.17(CH3NCH2),34.53(CH3N),19.05(CH3).IR:υ3295,2221,1744,1608,1472cm-1;HRMScalcd for C30H29N9[M+H]+:516.2619,found:516.2610。
(19)4′-((4-((4-氰基苯基)氨基)-6-(2-(羟甲基)吡咯烷-1-基)-1,3,5-三嗪-2-基)氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率70%,白色固体,mp 257-259℃;1H NMR(400MHz,DMSO-d6)δ:9.48(m,1H,NH),8.83-8.39(m,1H,NH),8.0-7.38(m,10H,ArH),4.82(m,1H,OH),4.21(s,1H,NCH),3.57(s,4H,CH2),2.26(s,6H,CH3×2),1.94(m,4H,CH2).13C NMR(101MHz,DMSO-d6)δ:165.54(N2=C-NH),164.22(N2=C-N),145.67(ArC),145.00(ArC),137.81(ArC),137.57(ArC),136.39(ArC),133.47(ArC),133.27(ArC),132.96(ArC),128.53(ArC),128.28(ArC),127.83(ArC),126.84(ArC),120.00(ArC),119.42(C≡N),119.08(C≡N),110.21(ArC),102.67(ArC),61.88(NCH),59.18(NCH2),58.92(HOCH2),47.42(CH2),27.90(CH2),23.10(CH2),19.02(CH3).IR:υ3318,2218,1610,1567,1477cm-1;HRMS calcd for C30H28N8O[M+Na]+:539.2278,found:539.2273。
(20)4′-((4-((4-氰基苯基)氨基)-6-(3-羟基吡咯烷-1-基)-1,3,5-三嗪-2-基)-氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率75%,白色固体,mp>300℃;1H NMR(400MHz,DMSO-d6)δ:9.52(m,1H,NH),8.61(m,1H,NH),8.09-7.48(m,10H,ArH),5.03(s,1H,OH),4.38(s,1H,OHCH),3.58(s,4H,CH2),2.26(s,6H,CH3×2),1.95(m,2H,CH2).13C NMR(101MHz,DMSO-d6)δ:165.51(N2=C-NH),164.33(N2=C-NH),164.17(N2=C-N),145.73(ArC),145.01(ArC),137.60(ArC),136.37(ArC),133.28(ArC),132.94(ArC),127.84(ArC),126.84(ArC),120.01(ArC),119.39(C≡N),110.19(ArC),102.62(ArC),69.30(NCH2),55.01(NCH2),44.56(HOCH),33.64(CH2),19.03(CH2).IR:υ3387,2225,1608,1576,1568cm-1;HRMS calcd for C29H26N8O[M+Na]+:525.2122,found:525.2116。
(21)4′-((4-((4-氰基苯基)氨基)-6-(4-羟基哌啶-1-基)-1,3,5-三嗪-2-基)-氨基)-3′,5′-二甲基-[1,1′-联苯]-4-腈
产率68%,白色固体,mp 229-231℃;1H NMR(400MHz,DMSO-d6)δ:9.55(m,1H,NH),8.68(s,1H,NH),8.04-7.47(m,10H,ArH),4.74(m,1H,OH),4.28(s,2H,CH2),3.72(m,1H,OHCH),3.34-3.26(m,2H,CH2),2.26(s,6H,CH3×2),1.81(s,2H,CH2),1.30(m,2H,CH2).13CNMR(101MHz,DMSO-d6)δ:165.87(N2=C-NH),164.82(N2=C-N),145.54(ArC),144.98(ArC),137.66(ArC),137.39(ArC),136.65(ArC),133.28(ArC),132.96(ArC),127.84(ArC),126.84(ArC),119.68(C≡N),110.21(ArC),102.75(ArC),66.47(NCH2),34.53(HOCH),19.05(CH3).IR:υ3293,2230,2218,1608,1474cm-1;HRMS calcd for C30H28N8O[M+Na]+:539.2278,found:539.2272。
实施例2:抗HIV生物活性测试
体外细胞水平的抗HIV病毒活性由比利时Katholleke大学的Rega药物研究所测定,主要包括:对HIV感染的MT-4细胞的抑制活性及细胞毒性两方面。方法如下:使化合物在HIV感染的MT-4细胞中,于感染HIV不同时间,用MTT法测定药物对HIV诱变的细胞病变的保护作用,计算使50%的细胞免于HIV诱导的细胞病变所需的浓度半数有效浓度EC50,毒性测定与抗HIV活性实验平行进行,也是在MT-4细胞培养中,用MTT法测定使50%的未感染细胞发生细胞病变的浓度(CC50),并计算选择性指数SI=CC50/EC50
材料与方法:
各化合物的抗HIV活性由药物对HIV在细胞中引起的细胞病变的抑制作用效率来监控。采用MT-4细胞进行细胞培养。采用的病毒株有:HIV-1病毒株ⅢB及HIV-2病毒株ROD。
具体操作如下:将化合物用DMSO或水溶解后在磷酸盐缓冲食盐水溶液稀释,将3×105MT-4细胞用100μL各化合物不同浓度此溶液在37℃预培养1h,然后向该化合物中加入100μL适当的病毒稀释液,将细胞于37℃培养1h。洗涤三次后,将细胞再次分别悬浮于含有或不含有化合物的培养介质中。接着将细胞在5%CO2氛围中,于37℃下再培养7天,并于感染后第三天用含有或不含有化合物的培养介质替换补充培养液。每种培养液条件重复操作两次。对病毒的细胞病变作用每天都用反向光学显微镜监控。典型来讲,本实验中所用的病毒稀释液常常会在病毒感染后第五天导致细胞病变。药物抑制浓度以药物对病毒细胞病变作用产生50%抑制作用而同时对细胞无直接毒性的浓度(CC50)表示。需要强调的是,当化合物水溶性较差,需要DMSO才能溶解时,DMSO比浓度相对于水来讲,一般低于10%(DMSO在MT-4细胞培养介质中最终浓度小于2%)。因为DMSO能影响测试化合物的抗病毒活性,对含有相同浓度DMSO溶液抗病毒活性对比空白实验也应该平行进行。另外,DMSO最终浓度(1/1000)远远低于HIV-1在T细胞中复制所需的浓度。
本发明的生物活性评价用已上市药物奈维拉平(Nevirapine,NVP)、依法韦伦(Efavirenz,EFV)和依曲韦林(Etravirine,ETV)作对照品,部分目标化合物对HIV的抑制活性结果见表1(Anti-HIV activity and cytotoxicity of compounds 1-19 in MT-4cells)。
表1[a]Anti-HIV activity and cytotoxicity of compounds 1-19 in MT-4cells
a所有实验数据均经过三次平行实验所得;bEC50:保护半数细胞免于被病毒感染所需浓度;cCC50:保护半数细胞免于死亡所需浓度;dSI=CC50/EC50(WT)。
实验结果表明,化学通式中所包含的化合物普遍具有较强的抗HIV-1病毒活性,较小的细胞毒性和较高的选择性指数。
本发明不限于上述实例。

Claims (5)

1.一种含有联苯结构的二芳基三嗪类化合物,其特征在于结构式如下:
其中,R1和R2分别独立选自氢、氰基、硝基、氨基、羟基、卤素、多卤代甲基、多卤代甲氧基、多卤代甲硫基、磺酸基、酯基、羧基、-NR4-,任选被取代的C1~6烷基、任选被取代的C2~6烯基、任选被取代的C2~6炔基或C1~6烷氧基;
R3选自氢、氰基、硝基、氨基、羟基、卤素、羧基、酯基、吗啉、呋喃、氨基醇、氨基酸、糖、寡肽、N3,-NH(OH),C1~4氨基、C1~6烷基、C1~6烷氧基、C1~6烷巯基、C3~6环烷氨基、C2~6烯基;
X为-NR5-,-NH-NH-,-N=N-,-O-,-S-,-SO-,-SO2-,-PO2-,-CH2-,-CH(OH),-CO-,-CH(CN)-或者C1~4烷二基;
R4选自氢、芳基、甲酰基、磺酰基、C1~6烷基羰基、C1~6烷基、C1~6烷氧基羰基或C1~6烷氧基;
R5选自氢、芳基、甲酰基、磺酰基、C1~6烷基羰基、C1~6烷基、C1~6烷氧基羰基或C1~6烷氧基。
2.如权利要求1所述的含有联苯结构的二芳基三嗪类化合物的制备方法,其特征在于,具体操作步骤如下:
以下述结构式Ⅱ所示的化合物(4-((4, 6-二氯-1, 3, 5 -三嗪-2-基)氨基)苯甲腈为原料,在溶剂中在相应的碱作用下,与各种取代的联苯类化合物进行反应,制得化合物Ⅲ;然后化合物Ⅲ再被小分子胺类化合物等亲核取代反应,得各种目标产物,化学反应通式如下:
所述的溶剂为水、二氯甲烷、氯仿、乙酸乙酯、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙腈、四氢呋喃、硝基甲烷、醋酐、萘烷、甲苯、N,N-二甲基甲酰胺、N-甲基吡咯烷酮中的一种或者多种;
所述的碱为碳酸锂、碳酸氢钠、碳酸钠、碳酸钾、碳酸铯、醋酸钠、氢氧化锂、氢氧化钠、氢氧化钾、氢化钠、甲醇钠、乙醇钾、叔丁醇钾、三乙胺、N, N-二异丙基乙胺、吡啶、3-甲基吡啶、4-二甲氨基吡啶的一种或者多种;
所述的碱与化合物Ⅱ或者Ⅲ的摩尔比为1:1~3:1;
反应温度为0~90 ℃;
反应时间为1~24 h。
3.一种药物组合物,其特征在于含有有效剂量如权利要求1所述的任一化合物及药用载体。
4.一种如权利要求1所述含有联苯结构的二芳基三嗪类化合物的药用盐,其特征在于包括:盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、富马酸盐或苹果酸盐,以及药学上可接受的前体药物和衍生物。
5.如权利要求1所述的含有联苯结构的二芳基三嗪类化合物在制备预防和治疗艾滋病的药物中的应用。
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