CN1887871A - 2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物及其合成方法与应用 - Google Patents
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Abstract
本发明涉及一类药物化合物,公开了2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物及其合成方法与应用。其结构如式(I),其中R1代表芳环上3,4,5位的取代基,或代表芳环上的二取代或多取代基,可以是CH3O、CH3、H或卤素;R2代表芳环上4位上的取代基,可以是CH3O、CH3、H或卤素。本发明以芳香胺、芳香醛和丙二腈为原料,以乙醇为溶剂,以哌啶和路易斯酸为催化剂,合成了2,6-二氨基-3,5-二腈基-4-芳基吡啶。该合成方法操作简便,易于分离,产率高,对环境友好,有利于产业化。所合成的2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的具有抗幽门螺旋杆菌活性,可以用于制备抗幽门螺旋杆菌药物。
Description
技术领域
本发明涉及一类药物化合物,具体的说,涉及2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物及其合成方法与应用。
技术背景
吡啶环结构广泛存在于天然产物和许多药物分子结构中,具有诸多药用价值,如烟酰胺可以用于治疗皮肤病,异烟肼可以用于抗结核,TPP-17是阿糖腺苷受体拮抗剂(A3 adenosine receptor antagonist),具有抗炎和抗哮喘作用,FDNP为5HT1A受体激动剂,具有抗抑郁作用,FR173657可以拮抗(bradykinn(BK)B2)受体,起到减轻疼痛、炎症、哮喘(asthma)、低血压(hypotension)等症状,BPPC是Endothelin受体拮抗剂,具有抗心力衰竭(heart failure)和低血压(hypertension)作用等。基于上述原因,合成吡啶衍生物,从中寻找新的药物一直都是一个活跃的研究领域。2,6-二氨基-3,5-二氰基吡啶衍生物由于其表现出的良好生物活性,如抑制腺苷受体(adenosine receptors)、抑制癌细胞生长、抗菌作用等,吸引了许多人来研究它的合成方法。
吡啶结构的合成方法研究已经有很长的历史,最早报道的是韩奇(Hantzsch)合成法(Heterocyclic chemistry.3rd ed.Chapman and Hall:London,1995,72.及相关的引文)。但是2,6-二氨基-3,5-二氰基吡啶衍生物的合成方法研究还不够深入,报道的方法不多。Cocco和Congiu等发展了一种2,6-二氨基-3,5-二腈基-4-芳基吡啶的合成方法(Cocco M.T.,Congiu C.,Lilliu V.,Onnis V.EuropeanJournal of Medicinal Chemistry,2005,40,1365.)采用3-氨基-2-腈基丙烯腈为原料与苯胺反应,然后再与芳香醛反应得到2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物。这一方法得到结构对称的2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物,即2,6位置取代基相同,3,5位置的取代基相同;同时,2,6位置的氨基上都有苯环。该方法操作简单,但是存在三个主要缺点。一是原料昂贵,3-氨基-2-腈基丙烯腈价格较贵;二是反应需要使用毒性大的乙腈作反应溶媒,对环境具有危害;三是多数产品产率较低,在60%以下。Raghukumar和Thirumalai Cocco和Congiu等发展了一种2,6-二氨基-3,5-二腈基-4-芳基吡啶的合成方法(Raghukumar V.,Thirumalai D.,Ramakrishnan V.T.,Karunakarac V.,Ramamurthy P.Tetrahedron,2003,59,3761.),采用四氢吡咯、丙二腈和芳香醛为原料,得到2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物,但这些化合物结构上有局限性,特点是2位置的取代基只局限于吡咯。同时这个方法的产率较低,在41-56%之间。
有报道2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的抗癌药物活性研究(Cocco M.T.,Congiu C.,Lilliu V.,Onnis V.European Journal ofMedicinal Chemistry,2005,40,1365.),但是未查到有文献报道2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的抗幽门螺旋杆菌药物活性。
发明内容
本发明的目的克服现有2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的合成方法上存在的不足,提供一种步骤简单、成本低、产率高,环保的2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的合成方法。
本发明的另一个目的是提供利用上述合成方法所得到2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物。
本发明的进一步目的是提供上述2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物在制备抗幽门螺旋杆菌药物中的应用。
本发明的2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物,其结构式如(I)式
其中R1代表芳环上3,4,5位的取代基,或代表芳环上的二取代或多取代基,可以是CH3O、CH3、H、卤素等但不仅仅局限于这些取代基。R2代表芳环上4位上的取代基,可以是CH3O、CH3、H、卤素等但不仅仅局限于这些取代基。
本发明的2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的合成方法采用式(II)来表示:
其中R1代表芳环上3,4,5位的取代基,或代表芳环上的二取代或多取代基,可以是CH3O、CH3、H、卤素等但不仅仅局限于这些取代基。R2代表芳环上4位上的取代基,可以是CH3O、CH3、H、卤素等但不仅仅局限于这些取代基。
具体步骤如下:
(1)将芳香醛与丙二腈混合,加入乙醇,再加入催化剂哌啶,在20~60℃反应30min~2h,分离纯化得到中间产物;香醛与丙二腈的摩尔比为1∶1.1~2;
(2)将所得中间产物和芳香胺混合,加入乙醇,再加入酸作为催化剂,在70~90℃反应1~6h,分离纯化得到2,6-二氨基-3,5-二腈基-4-芳基吡啶。中间产物与芳香胺的摩尔比为1∶1~2.5。
上述合成方法中,步骤(1)所述温度为30~50℃,所述反应时间为50min~1.5h。
上述合成方法中,步骤(2)所述温度为75~85℃,所述反应时间为1.5~3.5h。
上述合成方法中,步骤(2)所述酸是路易斯酸。
本发明采用乙醇作为反应溶剂,毒性小,对环境危害小;芳香醛和芳香胺可以是取代或非取代的。
与现有技术相比,本发明具有如下有益效果:
本发明的2,6-二氨基-3,5-二腈基-4-芳基吡啶合成方法与文献方法相比,可以得到2,6位取代基不同的2,6-二氨基-3,5-二腈基-4-芳基吡啶,6位置的取代基是芳香胺。所提供的合成方法操作简便,易于分离,产率高。采用乙醇作反应溶剂,毒性小,对环境友好,有利于产业化。
本发明采用两倍稀释法考察了所合成的2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的抗幽门螺旋杆菌活性,其对幽门螺旋杆菌具有强弱不等的体外抗菌活性,均优于对照药物奥硝唑、甲硝唑、吗啉硝唑和克拉霉素,并且有显著性差异。改变菌液的接种浓度,对所试验的样品的体外抗菌作用没有明显影响,其MIC值不因为接种菌量的改变而改变。可见,本发明的2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物可以用于制备抗幽门螺旋杆菌药物。
具体实施方式
实施例1
2-(4-甲氧基苯基氨基)-3,5-二腈基-4-苯基-6-氨基-吡啶(P1)的制备:
将1.06g(10.0mmol)的苯甲醛和0.73g(11.0mmol)摩尔的丙二腈溶于100ml的无水乙醇中,温度控制在40~60℃,滴加滴催化量的哌啶,搅拌0.5~1h,TLC监测反应。等醛消失后,停止反应,静止冷却,用柱层析分离,洗脱剂用乙酸乙酯和石油醚,得到中间体产品1.43g,产率93%。
将0.15g(1.0mmol)上述产品及0.22g(1.8mmol)对甲氧基苯胺溶于20ml的无水乙醇中,加热到76~81℃,加入路易斯酸催化剂,继续搅拌0.5~12h,出现沉淀,TLC监测反应。反应完全后,过滤沉淀,用丙酮和甲醇混和溶剂重结晶,得到0.16g P1,产率92%。m.p.230-232℃.1H NMR(DMSO,300MHz)d:3.75(s,3H),6.87(d,J=9.0Hz,2H),7.33-7.42(br s,2H,NH2),7.45-7.57(m,7H),8.98(s,1H,NH).13C NMR(DMSO,300MHz)d:56.1,81.6,82.4,114.4,116.9,117.0,125.7,129.2,129.5,130.8,132.5,136.0,156.9,158.4,161.5.R(KBr)v:3483,3314,3223,2211,1636,1558,1509,1420,1242,822,696.FAB-MS m/z(%):342(M++H,4).Anal.calcd.for C20H15N5O:C 70.37,H 4.43,N 20.52;found C 69.92,H 4.50,N20.46.
实施例2
2-(4-溴苯基氨基)-3,5-二腈基-4-苯基-6-氨基-吡啶(P5)的制备
将1.06g(10.0mmol)的苯甲醛和0.73g(11.0mmol)摩尔的丙二腈溶于100ml的无水乙醇中,温度控制在40~60℃,滴加滴催化量的哌啶,搅拌0.5~1h,TLC监测反应。等醛消失后,停止反应,静止冷却,用柱层析分离,洗脱剂用乙酸乙酯和石油醚,得到中间体产品1.43g,产率93%。
将0.15g(1.0mmol)上述产品及0.28g(1.6mmol)对溴苯胺溶于20ml的无水乙醇中,加热到76~81℃,加入路易斯酸,继续搅拌0.5~12h,出现沉淀,TLC监测反应。反应完全后,过滤沉淀,用丙酮和甲醇混和溶剂重结晶,得到0.16g P5,产率81%。m.p.275-277℃.1H NMR(DMSO,300MHz)d:7.44-7.54(m,9H),7.64(d,J=9.0Hz,2H),9.25(s,1H,NH).13C NMR(DMSO,300MHz)d:82.2,82.8,116.2,116.5,125.2,128.9,129.2,130.6,131.7,135.5,138.9,157.6,160.9,161.1.IP(KBr)v:3469,3337,3225,2212,1643,1591,1549,1489,816,737,696,601.FAB-MS m/z(%):391(M++H,8).Anal.calcd.for C19H12BrN5:C 58.48,H 3.10,N 17.95;found C58.34,H 3.21,N 17.81.
实施例3
2-(4-甲基苯基氨基)-3,5-二腈基-4-(4-溴苯基)-6-氨基-吡啶(P7)的制备
将1.84g(10.0mmol)的对溴苯甲醛和0.73g(11.0mmol)摩尔的丙二腈溶于100ml的无水乙醇中,温度控制在40~60℃,滴加滴催化量的哌啶,搅拌0.5~1h,TLC监测反应。等醛消失后,停止反应,静止冷却,用柱层析分离,洗脱剂用乙酸乙酯和石油醚,得到中间体产品2.23g,产率96%。
将0.23g(1.0mmol)上述产品及0.16g(1.5mmol)对甲基苯胺溶于20ml的无水乙醇中,加热到76~81℃,加入路易斯酸催化剂,继续搅拌0.5-12h,出现沉淀,TLC监测反应。反应完全后,过滤沉淀,用丙酮和甲醇混和溶剂重结晶,得到0.19g P7,产率92%。m.p.225-226℃.1H NMR(DMSO,300MHz)d:2.30(s,3H),7.13(d,J=8.4Hz,2H),7.47-7.52(m,6H,ArH+NH2),7.78(d,J=8.4Hz,2H),9.09(s,1H,NH).13C NMR(DMSO,300MHz)d:21.1,81.4,82.3,116.6,123.6,124.2,129.4,131.1,132.3,133.7,134.9,136.7,157.9,159.6,161.1.IR(KBr)v:3500,3324,3225,2211,1628,1531,1513,1425,822,779,669.FAB-MS m/z(%):404(M++H,20).Anal.calcd.for C20H14BrN5:C 59.42,H 3.49,N 17.32;found C 58.99,H 3.68,N17.88.
实施例4
2-(4-氯苯基氨基)-3,5-二腈基-4-(4-溴苯基)-6-氨基-吡啶(P9)的制备
将1.84g(10.0mmol)的对溴苯甲醛和0.73g(11.0mmol)摩尔的丙二腈溶于100ml的无水乙醇中,温度控制在40~60℃,滴加滴催化量的哌啶,搅拌0.5~1h,TLC监测反应。等醛消失后,停止反应,静止冷却,用柱层析分离,洗脱剂用乙酸乙酯和石油醚,得到中间体产品2.23g,产率96%。
将0.23g(1.0mmol)上述产品及0.23g(1.8mmol)对氯苯胺溶于20ml的无水乙醇中,加热到76~81℃,加入路易斯酸催化剂,继续搅拌0.5~12h,出现沉淀,TLC监测反应。反应完全后,过滤沉淀,用丙酮和甲醇混和溶剂重结晶,得到0.15g P9,产率70%。m.p.210-211℃.1H NMR(DMSO,300MHz)d;7.33(d,J=8.7Hz,2H),7.46(d,J=8.4Hz,2H),7.60(br s,2H,NH2),7.68(d,J=9.0Hz,2H),7.76(d,J=8.4Hz,2H),9.29(s,1H,NH).13C NMR(DMSO,300MHz)d;82.0,82.6,116.4,124.3124.9,128.1,128.7,131.1,132.3,134.7,138.4,157.6,159.8,161.0.IR(KBr)v:3383,3285,3239,2212,1581,1489,1424,1072,881,820,667.FAB-MSm/z(%):426(M++H,6).Anal.calcd.for C19H11BrClN5:C 53.74,H 2.61,N 16.49;found C 53.99,H 2.65,N 16.40.
实施例5
2-(4-甲氧基苯基氨基)-3,5-二腈基-4-(4-甲氧基苯基)-6-氨基-吡啶(P11)的制备
将1.36g(10.0mmol)的茴香醛和0.73g(11.0mmol)摩尔的丙二腈溶于100ml的无水乙醇中,温度控制在40~60℃,滴加滴催化量的哌啶,搅拌0.5~1h,TLC监测反应。等醛消失后,停止反应,静止冷却,用柱层析分离,洗脱剂用乙酸乙酯和石油醚,得到中间体产品1.75g,产率95%。
将0.18g(1.0mmol)上述产品及0.18g(1.5mmol)对甲氧基苯胺溶于20ml的无水乙醇中,加热到76~81℃,加入路易斯酸催化剂,继续搅拌0.5~12h,出现沉淀,TLC监测反应。反应完全后,过滤沉淀,用丙酮和甲醇混和溶剂重结晶,得到0.18g P11,产率95%。m.p.220-221℃.1H NMR(DMSO,300MHz)d:3.75(s,3H),3.84(s,3H),6.89(d,J=9.0Hz,2H),7.11(d,J=9.0Hz,2H),7.34(br s,2H,NH2),7.46(d,J=8.5Hz,2H),7.15(d,J=9.0Hz,2H),8.93(s,1H,NH).13C NMR(DMSO,300MHz)d:55.2,55.3,80.7,81.5,113.5,113.9,116.4,124.7,127.0,130.0,131.6,156.0,157.6,160.0,160.5,160.6.IR(KBr)v:3478,3431,3372,3211,2198,1638,1544,1459,1225,1180,840,779,651.EI-MS m/z(%):370([M-H]-,100).Anal.calcd.for C21H17N5O2:C 67.91,H 4.61,N 18.86;found C 65.04,H 5.19,N16.94.
实施例6
2-(苯基氨基)-3,5-二腈基-4-(4-甲氧基苯基)-6-氨基-吡啶(P13)的制备
将1.36g(10.0mmol)的茴香醛和0.73g(11.0mmol)摩尔的丙二腈溶于100ml的无水乙醇中,温度控制在40~60℃,滴加滴催化量的哌啶,搅拌0.5~1h,TLC监测反应。等醛消失后,停止反应,静止冷却,用柱层析分离,洗脱剂用乙酸乙酯和石油醚,得到中间体产品1.75g,产率95%。
将0.18g(1.0mmol)上述产品及0.19g(2.0mmol)苯胺溶于20ml的无水乙醇中,加热到76~81℃,加入路易斯酸催化剂,继续搅拌0.5~12h,出现沉淀,TLC监测反应。反应完全后,过滤沉淀,用丙酮和甲醇混和溶剂重结晶,得到0.15g P13,产率90%。m.p.235-237℃.1H NMR(DMSO,300MHz)d:3.83(s,3H),7.04-7.10(m,3H),7.29(t,J=7.8Hz,2H),7.45(d,J=8.7Hz,4H,ArH+NH2),7.63(d,J=7.8Hz,2H),9.00(s,1H,NH).IR(KBr)v:3838,3760,3320,2981,2213,1581,1420,1240,1162,825,743,694.ESI-MS m/z(%):340([M-H]-,100).Anal.calcd.for C20H15N5O:C 70.37,H 4.43,N 20.52;found C 69.98,H 4.29,N 20.24.
实施例7
2-(4-氯苯基氨基)-3,5-二腈基-4-(4-甲氧基苯基)-6-氨基-吡啶(P14)的制备
将1.36g(10.0mmol)的茴香醛和0.73g(11.0mmol)摩尔的丙二腈溶于100ml的无水乙醇中,温度控制在40~60℃,滴加滴催化量的哌啶,搅拌0.5~1h,TLC监测反应。等醛消失后,停止反应,静止冷却,用柱层析分离,洗脱剂用乙酸乙酯和石油醚,得到中间体产品1.75g,产率95%。
将0.18g(1.0mmol)上述产品及0.32g(2.5mmol)对氯苯胺溶于20ml的无水乙醇中,加热到76~81℃,加入路易斯酸催化剂,继续搅拌0.5~12h,出现沉淀,TLC监测反应。反应完全后,过滤沉淀,用丙酮和甲醇混和溶剂重结晶,得到0.15g P14,产率80%。m.p.275-276℃.1H NMR(DMSO,300MHz)d:3.85(s,3H),7.10(d,J=8.4,Hz 2H),7.33(d,J=8.7Hz,2H),7.46(d,J=8.4Hz,2H),7.51(br s,2H,NH2),7.69(d,J=8.7Hz,2H),9.21(s,1H,NH).IR(KBr)v:3469,3348,3210,2212,1624,1548,1502,1243,1151,1014,887,816.ESI-MS m/z(%):374([M-H]-,100).Anal.calcd.for C20H14ClN5O:C 63.92,H 3.75,N 18.64;found C 64.00.,H 3.89,N 18.86.
实施例8
2-(4-溴苯基氨基)-3,5-二腈基-4-(4-甲氧基苯基)-6-氨基-吡啶(P15)
将1.36g(10.0mmol)的茴香醛和0.73g(11.0mmol)摩尔的丙二腈溶于100ml的无水乙醇中,温度控制在40~60℃,滴加滴催化量的哌啶,搅拌0.5~1h,TLC监测反应。等醛消失后,停止反应,静止冷却,用柱层析分离,洗脱剂用乙酸乙酯和石油醚,得到中间体产品1.75g,产率95%。
将0.18g(1.0mmol)上述产品及0.43g(2.5mmol)对溴苯胺溶于20ml的无水乙醇中,加热到76~81℃,加入路易斯酸催化剂,继续搅拌0.5~12h,出现沉淀,TLC监测反应。反应完全后,过滤沉淀,用丙酮和甲醇混和溶剂重结晶,得到0.17g P15,产率81%。m.p.224-225℃.1H NMR(DMSO,300MHz)d:3.83(s,3H),7.09(d,J=8.7Hz,2H),7.43-7.50(m,6H,4ArH+NH2),7.62(d,J=9.0Hz,2H),9.19(s,1H,NH).IR(KBr)v:3478,3376,3312,3194,2926,2205,1616,1558,1507,1260,1179,1027,889,824,772.ESI-MS m/z(%):420([M-H]-,100).Anal.calcd.forC20H14BrN5O:C 57.16,H 3.36,N 16.66;found C 57.25,H 3.59,N 16.86.
实施例9 2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物对幽门螺旋杆菌的抑制作用
本研究采用两倍稀释法考察了2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的抗幽门螺旋杆菌活性,部分结果见表1。从表1可以看出,本次所试验的样品对所试验的临床分离幽门螺旋杆菌具有强弱不等的体外抗菌活性。其中P9和P14两个样品对所试验菌株的体外抗菌活性较好,其MIC50均为8μg/ml,MIC90值分别为8和32μg/ml,较其他样品的MIC90小1~3倍,显示出这两个样品对大部分的受试菌株都有较好的体外抗菌活性。改变菌液的接种浓度,对所试验的样品的体外抗菌作用没有明显影响,其MIC值不因为接种菌量的改变而改变。
将本次试验所得的MIC数据用SPSS软件进行统计学处理,可以看出所试验样品的体外抗菌活性是否存在差异,分析结果表明:1)在本次试验条件下,受试样品对临床分离幽门螺旋杆菌体外抗菌作用最好的是P14,其次是P9。这两个样品的体外抗菌活性相当,没有显著性差异(P>0.05),但这两个样品都显著优于其他受试样品(P<0.05)。2)在本次试验条件下,P14、P9对临床分离幽门螺旋杆菌的体外抗菌作用优于对照药物奥硝唑、甲硝唑、吗啉硝唑和克拉霉素,并且有显著性差异(P<0.05)。
表1为部分2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的抗幽门螺旋杆菌活性MIC(μg/ml)。
表1
菌株(株数) | 药物 | MIC值(μg/ml g/ml) | ||
MIC50 | MIC90 | MICrange | ||
幽门螺旋杆菌(11株) | P1P5P7P9P11P13P14P15奥硝唑甲硝唑吗啉硝唑克拉霉素 | 321616816168321286412864 | 6432168323232641286412864 | 32-6416-12816-1288-6416-6416-644-6432-12864-12816-12864-12864 |
Claims (6)
2、权利要求1所述2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物的合成方法,其特征在于包括如下步骤:
(1)将芳香醛与丙二腈混合,加入乙醇,再加入催化剂哌啶,在20~60℃反应30min~2h,分离纯化得到中间产物;香醛与丙二腈的摩尔比为1∶1.1~2;
(2)将所得中间产物和芳香胺混合,加入乙醇,再加入酸作为催化剂,在70~90℃反应1~6h,分离纯化得到2,6-二氨基-3,5-二腈基-4-芳基吡啶。中间产物与芳香胺的摩尔比为1∶1~2.5。
3、如权利要求2所述的合成方法,其特征在于,步骤(1)所述温度为30~50℃,所述反应时间为50min~1.5h。
4、如权利要求2所述的合成方法,其特征在于,步骤(2)所述温度为75~85℃,所述反应时间为1.5~3.5h。
5、如权利要求2所述的合成方法,其特征在于,步骤(2)所述酸是路易斯酸。
6、权利要求1所述2,6-二氨基-3,5-二腈基-4-芳基吡啶衍生物在制备抗幽门螺旋杆菌药物中的应用。
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