CN106588955B - 咪唑并苯并噻唑衍生的氟康唑类似物及其制备方法和应用 - Google Patents
咪唑并苯并噻唑衍生的氟康唑类似物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了通式I所示的咪唑并苯并噻唑衍生的氟康唑类似物;还公开了该类化合物的制备方法,路线短、原料商业化程度高、价廉易得、方法简便。本发明的咪唑并苯并噻唑衍生的氟康唑类似物对部分革兰阳性菌、革兰阴性菌和真菌有一定抑制活性,可用于制备潜在的抗细菌和/或抗真菌药物分子。通用分子式中的R1、R2、R3、R4、R5、R6、X1、X2、X3和Im如权利要求书所定义。
Description
技术领域
本发明属于化学领域,涉及一类新的有机化合物,还涉及该化合物的制备方法及其医药用途。
背景技术
氟康唑是治疗全身性真菌感染的首选药物,也是抗真菌领域的一线药物。氟康唑具有抗菌能力强,肝毒性小,口服吸收好,生物利用度高,组织分布广等优点,但氟康唑在临床上的广泛使用甚至滥用,使其耐药菌株不断出现;且对临床上非白色念珠菌如曲霉菌的治疗效果不明显,因此对氟康唑的进一步研究备受重视。近些年来对氟康唑的研究主要集中在以下三方面:a)前药研究,提高生物利用度,进一步提高疗效;b)保留一个三唑环和醇羟基,对氟康唑的另一侧链进行改造,期望得到能高效地与真菌羊毛甾醇14α-去甲基化酶活性位点结合的衍生物;c)设计合成分子基本骨架与氟康唑类似的化合物,期望开发比氟康唑更有优势的新型抗真菌药物。其中,方法b是目前研究较多的方向之一。
杂环化合物如三唑类、咪唑类、噻唑类等,由于其唑环结构的富电子性,使其能与生物体的活性位点通过多种非共价键相结合,从而发挥或加强药物的药效,因而具有广泛的生物活性,包括抗细菌、抗真菌、抗癌、抗氧化等。咪唑并苯并噻唑是一类多环稠和的杂环化合物,不仅具有更强的富电子性,且能方便地引入各种功能基团。因此,保留氟康唑的一个三唑环和醇羟基,用咪唑并苯并噻唑化合物对其另一侧链进行修饰,有望得到抗菌活性高、抗菌谱广并克服耐药性的新型抗感染药物。
发明内容
有鉴于此,本发明的目的在于提供一类新型结构的咪唑并苯并噻唑衍生的氟康唑类似物,以及这些化合物的制备方法与其在制药领域中的应用。
经过大量研究,本发明提供如下技术方案:
1.通式I所示的咪唑并苯并噻唑衍生的氟康唑类似物:
式中:
R1为氢、甲基、甲氧基、氟、氯、硫氰基;
R2为氢、甲基、氟、氯、溴;
R3为氢、甲基、甲氧基、乙氧基、甲砜基、硫氰基、三氟甲基、氟、氯、溴;
R4为氢、甲基、氟、氯;
R5为氢、甲基、氟、氯;
R6为氢、甲基、氟、氯;
X1为氢、甲基、甲氧基、氟、氯、溴;
X2为氢、甲基、甲氧基、氟、氯、溴;
X3为氢、甲基、甲氧基、氟、氯、溴;
Im为1,2,4-三唑基、2,4-二氟三唑、2-甲基-5-硝基咪唑基、4-硝基咪唑基、咪唑基、2-甲基咪唑基、2-乙基咪唑基、2-丙基咪唑、2-异丙基咪唑、2-乙基-4-甲基咪唑、2-苯基咪唑、3-巯基-1,2,4-三唑基、吡唑基、苯并咪唑基、5,6-二甲基苯并咪唑基、2-巯基苯并咪唑基、1,2,3,4-四唑基、5-甲基-1,2,3,4-四唑基、1,2,3-三唑基、苯并-1,2,3-三唑基、5-甲基苯并-1,2,3-三唑基。
作为本发明优选的技术方案:
R1为氢;R2为氢;R3为氢,甲氧基;R4为氢、氟;R5为氢;R6为氢、氟;X1为氢;X2为氢;X3为氢;
Im为1,2,4-三唑基、苯并咪唑基。
作为本发明进一步优选的技术方案,为下述化合物中的任一种:
2.所述的咪唑并苯并噻唑衍生的氟康唑类似物的制备方法,a)以取代2-氨基苯并噻唑和2-溴苯乙酮为原料发生环化缩合反应得到咪唑并苯并噻唑骨架结构,再经曼尼希、脱Boc保护反应获得中间体II;
b)以取代苯为原料,经付克酰基化、亲电取代反应制得多种含唑类化合物,后者发生环氧化反应得到环氧化物III;
c)中间体II与环氧化物III再在碱性的乙醇溶液中,于70℃下发生开环反应即制得通式I所示的咪唑并苯并噻唑衍生的氟康唑类似物;
通式II和III中R1、R2、R3、R4、R5、R6、X1、X2、X3和Im的定义与通式I中R1、R2、R3、R4、R5、R6、X1、X2、X3和Im的定义相同。
作为本发明优选的技术方案,碱性的乙醇溶液中所述碱试剂为碳酸氢钠;所述通式II和III与碱试剂的摩尔比为1∶1.2~1.5;
3.所述的咪唑并苯并噻唑衍生的氟康唑类似物在制备抗细菌和/或抗真菌药物中的应用。
作为本发明优选的技术方案,所述细菌为金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、藤黄微球菌、枯草杆菌、大肠杆菌、铜绿假单胞菌、变形杆菌、痢疾志贺菌和伤寒沙门菌中的任一种或多种;所述真菌为产朊假丝酵母菌、黄曲霉菌、啤酒酵母菌、白色念珠菌和假丝酵母菌中的任一种或多种。
本发明的有益效果在于:本发明通过药物设计拼合原理,将生物活性分子咪唑并苯并噻唑与氟康唑药效片段结合,通过改变咪唑并苯并噻唑环和苯环上的取代基,并引入不同的唑环,设计合成了一系列新型结构的咪唑并苯并噻唑衍生的氟康唑类似物。这些化合物经体外抗微生物活性检测,发现对革兰阳性菌(金黄色葡萄球菌、MASR、藤黄微球菌、枯草杆菌)、革兰阴性菌(大肠杆菌、铜绿假单胞菌、变形杆菌、痢疾志贺菌、伤寒沙门菌)和真菌(产朊假丝酵母菌、黄曲霉菌、啤酒酵母菌、白色念珠菌、假丝酵母菌)有一定程度的抑制活性,可用于制备抗细菌和/或抗真菌药物,从而为临床抗微生物治疗提供更多高效、安全的候选药物,有助于解决日趋严重的耐药性、顽固的致病性微生物以及新出现的有害微生物等临床治疗问题。此外,这些化合物的制备方法简单,原料易得,成本较低。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚,下面对本发明的代表性实施例进行详细的描述。
实施例1、化合物I-1的制备
在50mL圆底烧瓶中加入中间体II(0.348g,1mmol)、NaHCO3(0.126g,1.5mmol)和环氧化物III(0.237g,1mmol),以乙醇(10mL)作溶剂,70℃下搅拌反应至反应结束(TLC跟踪反应),冷却、酸化、减压蒸馏溶剂,再经萃取、柱层析分离、干燥得到化合物I-10.216g,产率37%。
化合物I-1:白色固体;173–174℃;1H NMR(600MHz,CDCl3)δ:8.24(s,1H,Tri 3-H),8.00(d,1H,J=5.5Hz,Ar-H),7.81(s,1H,Tri 5-H),7.69–7.64(m,3H,Ar-H),7.54–7.51(m,1H,Ar-H),7.45(t,2H,CH2),7.42–7.35(m,2H,Ar-H),7.31(t,1H,J=6Hz,Ar-H),6.82–6.65(m,2H,Ar-H),5.22(br,1H,J=6Hz,Ar-H),4.58–4.46(m,2H,Tri-CH2),3.98(s,2H),2.87(d,1H,J=6.5Hz,Pip-CH2),2.69(d,1H,J=6.5Hz,OH),2.50(br,4H,Piperzine-H),2.30(br,4H,Piperzine-H)ppm.
实施例2、化合物I-2的制备
在50mL圆底烧瓶中加入中间体II(0.393g,1mmol)、NaHCO3(0.126g,1.5mmol)和环氧化物III(0.237g,1mmol),以乙醇(10mL)作溶剂,70℃下搅拌反应至反应结束(TLC跟踪反应),冷却、酸化、减压蒸馏溶剂,再经萃取、柱层析分离、干燥得到化合物I-20.208g,产率33%。
化合物I-2:白色固体;165–166℃;1H NMR(600MHz,CDCl3)δ:8.24(s,1H,Tri 3-H),7.81(s,1H,Tri 5-H),7.75(d,1H,J=6.0Hz,Ar-H),7.67(d,2H,J=6.0Hz,Ar-H),7.46(t,2H,J=5.5Hz,Ar-H),7.45–7.37(m,2H,Ar-H),7.22(d,1H,J=6.0Hz,Ar-H),7.02(d,1H,J=6.0Hz,Ar-H),6.82–6.65(m,2H,Ar-H),5.22(br,1H,OH),4.58–4.46(m,2H,Tri-CH2),4.22(s,2H),4.09(q,2H,J=6.5Hz,OCH2CH3),2.88(d,1H,J=6.5Hz,Pip-CH2),2.72(d,1H,J=6.5Hz,Pip-CH2),2.54(br,4H,Piperzine-H),2.32(br,4H,Piperzine-H),1.48(t,3H,J=6.8Hz,OCH2CH3)ppm.
实施例3、化合物I-3的制备
在50mL圆底烧瓶中加入中间体II(0.348g,1mmol)、NaHCO3(0.126g,1.5mmol)和环氧化物III(0.287g,1mmol),以乙醇(10mL)作溶剂,70℃下搅拌反应至反应结束(TLC跟踪反应),冷却、酸化、减压蒸馏溶剂,再经萃取、柱层析分离、干燥得到化合物I-30.191g,产率30%。
化合物I-3:白色固体;熔点:73–74℃;1H NMR(600MHz,CDCl3)δ:8.05–7.85(m,2H,Ar-H),7.80–7.71(m,4H,Ar-H),7.58–7.31(m,8H,Ar-H),6.85–6.67(m,2H,Ar-H),5.22(br,1H,OH),4.12(s,2H),4.58–4.46(m,2H,Tri-CH2),2.87(d,1H,J=6.5Hz,Pip-CH2),2.70(d,1H,J=6.5Hz,Pip-CH2),2.50(br,4H,Piperzine-H),2.31(br,4H,Piperzine-H)ppm.
实施例4、化合物I-4的制备
在50mL圆底烧瓶中加入中间体II(0.393g,1mmol)、NaHCO3(0.126g,1.5mmol)和环氧化物III(0.287g,1mmol),以乙醇(10mL)作溶剂,70℃下搅拌反应至反应结束(TLC跟踪反应),冷却、酸化、减压蒸馏溶剂,再经萃取、柱层析分离、干燥得到化合物I-40.218g,产率32%。
化合物I-4:白色固体;熔点:78–79℃;1H NMR(600MHz,CDCl3)δ:8.05–7.85(m,3H,Ar-H),7.79–7.65(m,3H,Ar-H),7.45–7.29(m,6H,Ar-H),7.02(d,1H,J=6.0Hz,Ar-H),6.82–6.65(m,2H,Ar-H),5.22(br,1H,OH),4.58–4.46(m,2H,Tri-CH2),4.11(s,2H),4.09(q,2H,J=6.5Hz,OCH2CH3),2.87(d,1H,J=6.5Hz,Pip-CH2),2.70(d,1H,J=6.5Hz,Pip-CH2),2.54(br,4H,Piperzine-H),2.33(br,4H,Piperzine-H),1.51(t,3H,J=6.8Hz,OCH2CH3)ppm.
实施例5:体外抗微生物活性实验
采用符合1993年美国国家委员会制定的临床实验标准(National Committee forClinical Laboratory Standards,NCCLS)的96孔微量稀释法,检测实施例I制得的咪唑并苯并噻唑衍生的氟康唑类似物对MRSA、金黄色葡萄球菌、藤黄微球菌、枯草杆菌、变形杆菌、大肠杆菌、痢疾志贺菌、伤寒沙门杆菌、铜绿假单胞菌、产朊假丝酵母菌、黄曲霉菌、啤酒酵母菌、白色念珠菌、假丝酵母菌的最低抑菌浓度(MIC),将待测化合物用少量二甲亚砜溶解,再加水稀释制成浓度为1.28mg/mL的溶液,再用培养液稀释至1024μg/mL,37℃培养24~72小时,将培养板置振荡器上充分搅匀后,在波长490nm处测定MIC(μg/mL)。结果见表1和表2。
表1咪唑并苯并噻唑衍生的氟康唑类似物的抗细菌活性(MIC,μg/mL)
由表1可以看出,化合物I-2和I-4对部分测试细菌表现出较好的抗菌活性,甚至强于参考药物氯霉素,而化合物I-1和I-3几乎对所有测试细菌的生长均无抑制作用,这一结果说明咪唑并苯并噻唑环上供电子基团的引入利于目标分子发挥抗菌活性。
表2咪唑并苯并噻唑衍生的氟康唑类似物的抗真菌活性(MIC,μg/mL)
由表2可以看出,化合物I-2和I-4对除白色念珠菌以外的测试真菌均表现出一定的抗菌活性,且其对黄曲霉菌的抑制活性(MIC=32/64μg/mL)优于参考药物氟康唑(MIC=256μg/mL)。而化合物I-1和I-3对所有测试真菌的生长均无抑制作用,这一结果说明咪唑并苯并噻唑环上供电子基团的引入利于目标分子发挥抗真菌活性。
最后说明的是,以上实施例仅用于说明本发明的技术方案,并不构成对本发明内容的限制。尽管通过上述实施例已经对本发明做了较为详细的例举,但本领域技术人员仍然可以根据发明内容部分和实施例部分所描述的技术内容,在形式上和细节上对其作出各种各样的改变,而不偏离所附权利要求书所限定的本发明的精神和范围。
Claims (4)
3.权利要求1或2任一项所述的咪唑并苯并噻唑衍生的氟康唑类似物在制备抗细菌和/或抗真菌药物中的应用。
4.根据权利要求3所述的应用,其特征在于,所述细菌为金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、藤黄微球菌、枯草杆菌、大肠杆菌、铜绿假单胞菌、变形杆菌、痢疾志贺菌和伤寒沙门菌中的任一种或多种;所述真菌为产朊假丝酵母菌、黄曲霉菌、啤酒酵母菌、白色念珠菌和假丝酵母菌中的任一种或多种。
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