CN111087388A - 腙基桥连的萘酰亚胺咪唑类化合物及其制备方法和应用 - Google Patents
腙基桥连的萘酰亚胺咪唑类化合物及其制备方法和应用 Download PDFInfo
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- CN111087388A CN111087388A CN201911378848.7A CN201911378848A CN111087388A CN 111087388 A CN111087388 A CN 111087388A CN 201911378848 A CN201911378848 A CN 201911378848A CN 111087388 A CN111087388 A CN 111087388A
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- Prior art keywords
- naphthalimide
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- compound
- bridged
- imidazole
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
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Classifications
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及腙基桥连的萘酰亚胺咪唑类化合物及其制备方法和应用,属于化学合成技术领域,腙基桥连的萘酰亚胺咪唑类化合物如通式I所示,该类化合物对革兰阳性菌、革兰阴性菌和/或真菌中的一种或多种具有一定抑制活性,可以用于制备抗细菌和/或抗真菌药物,从而有机会为临床抗微生物治疗提供更多安全、高效的多样化候选药物。其制备原料简单,廉价易得,合成路线短,在抗感染方面的应用具有重要意义。
Description
技术领域
本发明属于化学合成技术领域,具体涉及腙基桥连的萘酰亚胺咪唑类化合物及其制备方法和应用。
背景技术
萘酰亚胺是一类六元环状酰亚胺稠和萘的芳香氮氧杂环化合物,由于具有较大的共轭体系和强的分子内电子转移能力,使得这种特殊的刚性稠环结构易通过氢键、疏水作用、π-π堆积以及静电相互作用等多种非共价键作用与离子、小分子和生物大分子发生作用而表现出广谱性。近年来,尤其在药物化学领域表现出巨大的开发价值和广阔的应用前景,使得越来越多的研究工作致力于以萘酰亚胺为基本骨架的药物研发,比如在抗肿瘤、抗菌、抗真菌、抗病毒、抗炎,抗抑郁和医学诊断等方面。但由于其肝毒性等毒副作用导致其未能在临床上得到广泛应用,不过,萘酰亚胺环易于进行结构修饰并能方便地引入各种功能基团,在药学领域发挥着越来越重要的作用。
发明内容
有鉴于此,本发明的目的之一在于提供腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐;本发明的目的之二在于提供腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐的制备方法;本发明的目的之三在于提供所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用;本发明的目的之四在于提供含所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐的制剂。
为达到上述目的,本发明提供如下技术方案:
1、腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐,结构如通式I所示:
式中:
R为氢、烷基、环烷基、芳基、卤亚甲基、醇亚甲基、醛基、巯基、炔基、烯基、氰基、酯基或羧基;
n为0-18的整数。
优选的,
R为氢、甲基、乙基、烯基、炔基、环丙基、环己基、羟甲基、邻氯苯基、间氯苯基、对氯苯基、2,4-二氯苯基、邻氟苯基、间氟苯基、对氟苯基、对硝基苯基、吗啉基、氰基或乙氧酰基;
n为0、1、2、3、4或6。
优选的,为下述化合物中的任一种:
优选的,所述可药用盐为盐酸盐、硝酸盐或醋酸盐。
2、所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐的制备方法,所述方法如下:
a、中间体II-1~22的制备:以2-丁基-4-氯-1H-咪唑-5-甲醛为起始原料,乙腈作溶剂,碳酸钾做碱,与溴化物进行取代反应,即得中间体II-1~22;
b、中间体III的制备:以4-溴-1,8-萘二甲酸酐为起始原料,乙醇作溶剂,与乙醇胺反应即得中间体III;
c、中间体IV的制备:以中间体III为起始原料,乙二醇甲醚作溶剂,与水合肼反应,即得中间体IV;
d、通式I-1所示腙基桥连的萘酰亚胺咪唑类化合物的制备,以2-丁基-4-氯-1H-咪唑-5-甲醛和中间体IV为起始原料,乙醇作溶剂,冰醋酸作催化剂,发生还原反应,即得通式I-1所示腙基桥连的萘酰亚胺咪唑类化合物;
f、通式I-2~23所示腙基桥连的萘酰亚胺咪唑类化合物的制备,以中间体II-1~22和中间体IV为起始原料,乙醇作溶剂,冰醋酸作催化剂,发生还原反应,即得通式I-2~23所示腙基桥连的萘酰亚胺咪唑类化合物。
优选的,
步骤a中,所述2-丁基-4-氯-1H-咪唑-5-甲醛与溴化物的摩尔比为1:1.2;所述取代反应的温度为50℃;
步骤b中,所述反应的温度为80℃;所述4-溴-1,8-萘二甲酸酐与乙醇胺的摩尔比为1:1.5;
步骤c中,所述反应的温度为90℃,反应的时间为5h,所述中间体III与水合肼的摩尔比为1:4;所述水合肼的质量分数为80%;
步骤d中,所述还原反应的温度为80℃,所述2-丁基-4-氯-1H-咪唑-5-甲醛、中间体IV和冰醋酸的摩尔比为1.47:1.47:104;
步骤f中,所述还原反应的温度为80℃,所述中间体II-1~22、中间体IV和冰醋酸的摩尔比为1.47:1.47:104。
3、所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用。
优选的,所述细菌为耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC25923、金黄色葡萄球菌ATCC29213、克雷白氏肺炎杆菌、大肠杆菌、大肠杆菌ATCC25922、铜绿假单胞菌、铜绿假单胞菌ATCC27853或鲍曼不动杆菌中的一种或多种;所述真菌为白色念珠菌、热带假丝酵母菌、烟曲霉菌、白色念珠菌ATCC90023或近平滑假丝酵母菌ATCC20019中的一种或多种。
4、含所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐的制剂。
优选的,所述制剂为片剂、胶囊剂、颗粒剂、注射剂、粉针剂、滴眼剂、搽剂、栓剂、软膏剂或气雾剂中的一种。
本发明的有益效果在于:本发明提供了腙基桥连的萘酰亚胺咪唑类化合物及其制备方法和应用,本发明利用药物拼合原理,首次在萘酰亚胺4位通过席夫碱反应(Schiffbase reaction),以腙基桥连引入不同取代的咪唑类化合物,设计合成了一系列结构新颖的腙基桥连的萘酰亚胺咪唑类化合物,这些化合物经体外抗微生物活性检测发现对革兰阳性细菌(耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC25923、金黄色葡萄球菌ATCC29213),革兰阴性细菌(克雷白氏肺炎杆菌、大肠杆菌、大肠杆菌ATCC25922、铜绿假单胞菌、铜绿假单胞菌ATCC27853、鲍曼不动杆菌)以及真菌(白色念珠菌、热带假丝酵母菌、烟曲霉菌、白色念珠菌ATCC90023、近平滑假丝酵母菌ATCC20019)中的一种或多种具有一定抑制活性,可以用于制备抗细菌和/或抗真菌药物,从而有机会为临床抗微生物治疗提供更多安全、高效的多样化候选药物。其制备原料简单,廉价易得,合成路线短,在抗感染方面的应用具有重要意义。
本发明的其他优点、目标和特征在某种程度上将在随后的说明书中进行阐述,并且在某种程度上,基于对下文的考察研究对本领域技术人员而言将是显而易见的,或者可以从本发明的实践中得到教导。本发明的目标和其他优点可以通过下面的说明书来实现和获得。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
实验例1
中间体II-1~22的制备
参照参考文献“Gong,H.H.;Baathula,K.;Lv,J.S.;Cai,G.X.;,Zhou,C.H.Synthesis and biological evaluation of Schiff base-linked imidazolylnaphthalimides as novel potential anti-MRSA agents.Med.Chem.Commun.,2016,7(5),924-931中的方法进行制备。
实验例2
中间体III的制备
在250mL圆底烧瓶中加入4-溴-1,8-萘二酸酐(3.0g,10.8mmol),乙醇(160mL),80℃下回流0.5h,于1h内滴加乙醇胺(1mL,16.2mmol),薄层色谱跟踪至反应结束,冷却至室温,去除溶剂得中间体III(3.0g),产率86.7%。
实验例3
中间体IV的制备
在250mL圆底烧瓶中加入中间体III(5.0g,15.6mmol)和水合肼(3mL,62.4mmol),以乙二醇甲醚(150mL)作溶剂,90℃反应5h,薄层色谱跟踪至反应结束。冷却至室温,经柱层析分离、干燥等后处理即得中间体IV(2.8g),产率53.2%。
实验例4
化合物I-1的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),2-丁基-4-氯-1H-咪唑-5-甲醛(275.2mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-1(444mg),产率:68.5%;橙红色固体;熔点:213.5-214.3℃.1H NMR(400MHz,DMSO-d6)δ11.38(bs,1H,NNH),8.70(d,J=8.4Hz,1H,naphthalimide-7-H),8.46(d,J=7.2Hz,1H,naphthalimide-5-H),8.33(d,J=8.5Hz,1H,naphthalimide-2-H),8.30(s,1H,CHN),7.77(t,J=9.1Hz,2H,naphthalimide-3,6-H,),5.76(s,1H,NH),4.81(t,J=5.9Hz,1H,OH),4.13(t,J=6.7Hz,2H,CH2CH2OH),3.61(q,J=6.2Hz,2H,CH2OH),2.68(t,J=7.5Hz,2H,CH2CH2CH2CH3),1.67(m,2H,CH2CH2CH3),1.35(m,2H,CH2CH3),0.93(t,J=7.4Hz,3H,CH3)ppm。
实验例5
化合物I-2的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-1(295mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-2(416mg),产率:61.5%;橙红色固体;熔点:212-213℃。1H NMR(400MHz,DMSO-d6)δ11.30(bs,1H,NNH),8.69(d,J=8.5Hz,1H,naphthalimide-7-H),8.43(d,J=7.2Hz,1H,naphthalimide-5-H),8.36(s,1H,CHN),8.31(d,J=8.5Hz,1H,naphthalimide-2-H),7.75(t,J=8.1Hz,1H,naphthalimide-6-H),7.44(d,J=8.5Hz,1H,naphthalimide-3-H),4.80(t,J=5.9Hz,1H,OH),4.11(t,J=6.7Hz,2H,CH2CH2OH),3.87(s,3H,NCH3),3.60(m,2H,CH2OH),2.68(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.65(m,2H,CH2CH2CH3),1.39(m,2H,CH2CH3),0.93(t,J=7.3Hz,3H,CH3)ppm。
实验例6
化合物I-3的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-2(319mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-3(456mg),产率:69.6%;橙红色固体;熔点:>250℃。1H NMR(600MHz,DMSO-d6)δ11.41(s,1H,NNH),8.76(d,J=8.4Hz,1H naphthalimide-7-H),8.49(d,J=7.1Hz,1H,naphthalimide-5-H),8.45(s,1H,CHN),8.39(d,J=8.4Hz,1H,naphthalimide-2-H),7.81(t,1H,,naphthalimide-6-H),7.48(d,J=8.4Hz,1H,naphthalimide-3-H),4.79(s,1H,OH),4.42(d,J=6.9Hz,2H,CH2CH3),4.14(t,J=6.5Hz,2H,CH2CH2OH),3.60(t,J=6.5Hz,2H,CH2OH),2.73(d,J=7.5Hz,2H,CH2CH2CH2CH3),1.70–1.67(m,2H,CH2CH2CH3),1.40(d,J=7.1Hz,5H,CH3and CH2CH3),0.94(t,J=7.3Hz,3H,CH3).
实验例7
化合物I-4的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-3((336mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-4(511mg),产率:60.5%;橙红色固体;熔点:225-226℃。1H NMR(400MHz,DMSO-d6)δ11.20(bs,1H,NNH),8.58(d,J=8.5Hz,1H,naphthalimide-7-H),8.45(d,J=7.0Hz,1H,naphthalimide-5-H),8.36(d,J=7.3Hz,1H,naphthalimide-2-H),8.31(s,1H,CHN),7.67(t,J=7.7Hz,1H,naphthalimide-6-H),7.25(d,J=8.4Hz,1H,naphthalimide-3-H),4.82(t,J=5.0Hz,1H,OH),4.20(t,J=15.7Hz,2H,NCH2CH2CH3),4.09(q,J=12.8Hz,2H,CH2CH2OH),3.60(t,J=10.0Hz,2H,CH2OH),2.68(t,J=7.4Hz,2H,CH2CH2CH2CH3),1.70(m,2H,NCH2CH2CH3),1.67(m,2H,CH2CH2CH2CH3),1.41(m,2H,CH2CH2CH2CH3),0.96(m,6H,CH3)ppm。
实验例8
化合物I-5的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-4(377mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-5(511mg),产率:59.4%;橙红色固体;熔点:156-157℃。1H NMR(400MHz,DMSO-d6)δ11.16(bs,1H,NNH),8.55(d,J=8.3Hz,1H,naphthalimide-7-H),8.44(d,J=8.2Hz,1H,naphthalimide-5-H),8.34(d,J=7.7Hz,1H,naphthalimide-2-H),8.29(s,1H,CHN),7.65(t,J=7.7Hz,1H,naphthalimide-6-H),7.19(d,J=8.4Hz,1H,naphthalimide-3-H),4.81(bs,1H,OH),4.15(t,J=12.4Hz,2H,NCH2CH2),4.09(t,J=12.4Hz,2H,CH2CH2OH),3.60(t,J=11.5Hz,2H,CH2OH),2.65(t,J=7.4Hz,2H,CH2CH2CH2CH3),1.67(t,J=11.0Hz,4H,NCH2CH2,CH2CH2CH2CH3),1.39(m,6H,NCH2CH2CH2CH2CH3,CH2CH2CH2CH3),0.93(m,6H,CH3)ppm。
实验例9
化合物I-6的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-6(420mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-6(493mg),产率:62.5%;橙红色固体;熔点:218-219℃。1H NMR(400MHz,DMSO-d6)δ11.20(bs,1H,NNH),8.58(d,J=8.4Hz,1H,naphthalimide-7-H),8.34(d,J=7.2Hz,1H,naphthalimide-5-H),8.28(s,1H,CHN),8.11(d,J=8.5Hz,1H,naphthalimide-2-H),7.64(t,J=7.8Hz,1H,naphthalimide-6-H),7.19(d,J=8.5Hz,1H,naphthalimide-3-H),4.82(bs,1H,OH),4.11(m,4H,NCH2,CH2CH2OH),3.59(t,J=11.5Hz,2H,CH2OH),2.63(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.66(m,4H,CH2CH2CH3),1.35(m,10H,NCH2(CH2)5CH3),0.94(t,J=7.3Hz,3H,CH2CH2CH2CH3),0.83(t,J=6.4Hz,3H,NCH2(CH2)5CH3)ppm。
实验例10
化合物I-7的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-6(334mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-7(511mg),产率:76.3%;橙红色固体;熔点:153-154℃。1H NMR(400MHz,DMSO-d6)δ11.22(bs,1H,NNH),8.62(d,J=8.5Hz,1H,naphthalimide-7-H),8.38(d,J=7.2Hz,1H,naphthalimide-5-H),8.28(s,1H,CHN),8.24(d,J=8.5Hz,1H,naphthalimide-2-H),7.70(t,J=7.9Hz,1H,naphthalimide-6-H),7.29(d,J=8.5Hz,1H,naphthalimide-3-H),6.10(m,1H,CH=CH2),5.20(d,J=10.5Hz,1H,CH=CH2),4.99(bs,2H,CH2CH=CH2),4.87(d,J=17.3Hz,1H,CH=CH2),4.81(t,J=5.9Hz,1H,OH),4.10(t,J=6.7Hz,2H,CH2CH2OH),3.60(q,J=6.5Hz,2H,CH2OH),2.63(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.65(m,2H,CH2CH2CH3),1.37(m,2H,CH2CH3),0.92(t,J=7.3Hz,3H,CH3)ppm。
实验例11
化合物I-8的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-7((331mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-8(466mg),产率:66.4%;橙红色固体;熔点:203.5-204.5℃。1H NMR(400MHz,DMSO-d6)δ11.33(bs,1H,NNH),8.66(d,J=8.5Hz,1H,naphthalimide-7-H),8.41(d,J=7.2Hz,1H,naphthalimide-5-H),8.32(s,1H,CHN),8.27(d,J=8.5Hz,1H,naphthalimide-2-H),7.74(t,J=7.9Hz,1H,naphthalimide-6-H),7.54(d,J=8.5Hz,1H,naphthalimide-3-H),5.22(s,2H,CH2CCH),4.11(t,J=6.5Hz,2H,CH2CH2OH),3.64(bs,1H,OH),3.60(t,J=6.6Hz,2H,CH2OH),3.48(s,1H,CCH),2.75(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.70(m,2H,CH2CH2CH3),1.41(m,2H,CH2CH3),0.94(t,J=7.3Hz,3H,CH3)ppm。
实验例12
化合物I-9的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-8(332mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-9(318mg),产率:45.3%;橙红色固体;熔点:196-197℃。1H NMR(400MHz,DMSO-d6)δ11.33(bs,1H,NNH),8.66(d,J=8.5Hz,1H,naphthalimide-7-H),8.41(d,J=7.2Hz,1H,naphthalimide-5-H),8.32(s,1H,CHN),8.27(d,J=8.5Hz,1H,naphthalimide-2-H),7.74(t,J=7.9Hz,1H,naphthalimide-6-H),7.54(d,J=8.5Hz,1H,naphthalimide-3-H),4.85(s,2H,CH2CN),4.11(t,J=6.5Hz,2H,CH2CH2OH),3.64(bs,1H,OH),3.60(t,J=6.6Hz,2H,CH2OH),2.75(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.70(m,2H,CH2CH2CH3),1.41(m,2H,CH2CH3),0.94(t,J=7.3Hz,3H,CH3)ppm。
实验例13
化合物I-10的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-9(339mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-10(334mg),产率:69.2%;橙红色固体;熔点:186-187℃。1H NMR(400MHz,DMSO-d6)δ11.32(s,1H,NNH),8.71(d,J=8.4Hz,1H,naphthalimide-7-H),8.45(d,J=7.2Hz,1H,naphthalimide-5-H),8.40(s,1H,naphthalimide-2-H),8.32(d,J=8.5Hz,1H CHN),7.78–7.75(t,1H,naphthalimide-6-H),7.39(d,J=8.5Hz,1H,naphthalimide-3-H),5.02(t,J=5.2Hz,1H,OH),4.79(d,J=5.9Hz,1H,OH),4.38(t,J=5.3Hz,2H,CH2CH2OH),4.12(t,J=6.6Hz,2H,CH2CH2OH),3.82(dd,J=10.7,5.3Hz,2H,CH2OH),3.62–3.58(m,2H,CH2OH),2.75(t,J=7.7Hz,2H,CH2CH2CH2CH3),1.71–1.67(m,2H,CH2CH2CH3),1.40(dd,J=14.9,7.4Hz,2H,CH2CH3),0.94(t,J=7.4Hz,3H,CH3)ppm。
实验例14
化合物I-11的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-10(401mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-11(496mg),产率:64.3%;橙红色固体;熔点:180.7-181.5℃。1H NMR(400MHz,DMSO-d6)δ11.20(bs,1H,NNH),8.63(d,J=8.4Hz,1H,naphthalimide-7-H),8.40(d,J=7.2Hz,1H,naphthalimide-5-H),8.29(s,1H,CHN),8.23(d,J=8.5Hz,1H,naphthalimide-2-H),7.73(t,J=7.9Hz,1H,naphthalimide-6-H),7.31(d,J=8.5Hz,1H,naphthalimide-3-H),5.19(s,2H,CH2COO),4.80(t,J=5.9Hz,1H,OH),4.16(t,J=13.9Hz,2H,COOCH2CH3),4.09(t,J=6.7Hz,2H,CH2CH2OH),3.60(q,J=6.5Hz,2H,CH2OH),2.67(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.61(m,2H,CH2CH2CH3),1.37(m,2H,CH2CH3),1.21(t,J=7.1Hz,3H,COOCH2CH3),0.92(t,J=7.3Hz,3H,CH2CH2CH2CH3)ppm。
实验例15
化合物I-12的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-11(441mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-12((370mg),产率:45.6%;橙红色固体;熔点:158-159℃。1H NMR(400MHz,DMSO-d6)δ11.39(bs,1H,NNH),8.74(d,J=8.5Hz,1H,naphthalimide-7-H),8.48(d,J=7.3Hz,1H,naphthalimide-5-H),8.43(s,1H,CHN),8.32(d,J=8.5Hz,1H,naphthalimide-2-H),7.79(t,J=7.9Hz,naphthalimide-6-H),7.56(d,J=8.5Hz,1H,naphthalimide-3-H),4.80(t,J=5.8Hz,1H,OH),4.48(t,J=5.6Hz,2H,CH2CH2OH),4.13(t,J=6.4Hz,2H,CH2OH),3.60(m,8H,morpholine-H),2.75(t,J=8.5Hz,2H,CH2CH2CH2CH3),2.69(t,J=8.5Hz,2H,NCH2CH2N),2.46(t,J=8.5Hz,2H,NCH2CH2N),1.71(m,2H,CH2CH2CH3),1.42(m,2H,CH2CH3),0.95(t,J=7.3Hz,3H,CH3)ppm。
实验例16
化合物I-13的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-12(457mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-13(386mg),产率:46.4%;橙红色固体;熔点:148-149℃。1H NMR(400MHz,DMSO-d6)δ11.39(bs,1H,NNH),8.74(d,J=8.5Hz,1H,naphthalimide-7-H),8.48(d,J=7.3Hz,1H,naphthalimide-5-H),8.43(s,1H,CHN),8.32(d,J=8.5Hz,1H,naphthalimide-2-H),7.79(t,J=7.9Hz,naphthalimide-6-H),7.56(d,J=8.5Hz,1H,naphthalimide-3-H),4.80(t,J=5.8Hz,1H,OH),4.48(t,J=5.6Hz,2H,CH2CH2OH),4.13(t,J=6.4Hz,2H,CH2OH),3.60(m,8H,morpholine-H),2.75(t,J=8.5Hz,2H,CH2CH2CH2CH3),2.69(t,J=8.5Hz,2H,NCH2CH2CH2N),2.45(t,J=8.5Hz,4H,NCH2CH2CH2N),1.71(m,2H,CH2CH2CH3),1.42(m,2H,CH2CH3),0.95(t,J=7.3Hz,3H,CH3)ppm。
实验例17
化合物I-14的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-13(354mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-14(352mg),产率:48.6%;橙红色固体;熔点:187-188℃。1H NMR(400MHz,DMSO-d6)δ11.34(bs,1H,NNH),8.71(d,J=9.1Hz,1H,naphthalimide-7-H),8.46(d,J=7.2Hz,1H,naphthalimide-5-H),8.41(s,1H,CHN),8.28(d,J=8.5Hz,naphthalimide-2-H),7.77(t,J=7.9Hz,naphthalimide-6-H),7.43(d,J=8.5Hz,naphthalimide-3-H),5.76(s,1H,OH),4.18(d,J=7.3Hz,2H,NCH2-cyclopropane),4.12(t,J=6.7Hz,2H,CH2CH2OH),3.60(t,J=6.7Hz,2H,CH2OH),2.68(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.64(m,7H,CH2CH2CH3,cyclopropane-H),1.40(m,2H,CH2CH3),0.93(t,J=7.3Hz,CH3)ppm。
实验例18
化合物I-15的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-14(416mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-15(404mg),产率:51.4%;橙红色固体;熔点:166-167℃。1H NMR(400MHz,DMSO-d6)δ11.32(bs,1H,NNH),8.68(d,J=8.4Hz,1H,naphthalimide-7-H),8.43(d,J=7.2Hz,1H,naphthalimide-5-H),8.39(s,1H,CHN),8.30(d,J=8.6Hz,1H,naphthalimide-2-H),7.74(t,J=7.9Hz,1H,naphthalimide-6-H),7.42(d,J=8.5Hz,1H,naphthalimide-3-H),4.81(s,1H,OH),4.29(d,J=6.6Hz,NCH2-cyclohexane),4.11(t,J=6.6Hz,2H,CH2CH2OH),3.60(t,J=6.6Hz,2H,CH2OH),2.69(t,J=7.6Hz,2H,CH2CH2CH2CH3),2.51(m,10H,cyclohexane-H,DMSO-H),1.69(m,2H,CH2CH2CH3),1.42(m,2H,CH2CH3),1.34(m,1H,cyclohexane-H),0.94(t,J=7.3Hz,3H,CH3),0.55(m,2H,cyclohexane-H),0.48(m,2H,cyclohexane-H)ppm。
实验例19
化合物I-16的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-15(433mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物II-16(511mg),产率:63.6%;橙红色固体;熔点:198-199℃。1H NMR(400MHz,DMSO-d6)δ11.32(bs,1H,NNH),8.45(d,J=7.2Hz,1H,naphthalimide-7-H),8.39(s,1H,CHN),8.34(d,J=7.2Hz,1H,naphthalimide-5-H),8.21(d,J=7.9Hz,1H,naphthalimide-2-H),8.09(d,J=7.9Hz,1H,naphthalimide-3-H),7.89(t,J=7.9Hz,1H,Ph-F-H),7.64(t,J=7.9Hz,1H,naphthalimide-6-H),7.37(d,J=7.3Hz,2H,Ph-F-H),7.15(m,1H,Ph-F-H),5.64(d,J=27.7Hz,2H,NCH2Ph),4.86(t,J=11.4Hz,1H,OH),4.10(m,2H,CH2CH2OH),3.62(m,2H,CH2OH),2.66(m,2H,CH2CH2CH2CH3),1.56(m,2H,CH2CH2CH3),1.31(m,2H,CH2CH3),0.83(m,3H,CH3)ppm。
实验例20
化合物I-17的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-16(433mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-17(524mg),产率:65.2%;橙红色固体;熔点:179-180℃。1H NMR(400MHz,DMSO-d6)δ11.27(bs,1H,NNH),8.62(d,J=8.5Hz,1H,naphthalimide-7-H),8.42(d,J=7.2Hz,1H,naphthalimide-5-H),8.37(s,1H,CHN),8.10(d,J=8.5Hz,1H,naphthalimide-2-H),7.73(t,J=7.9Hz,1H,naphthalimide-6-H),7.43(d,J=7.9Hz,1H,naphthalimide-3-H),7.12(t,J=8.6Hz,1H,Ph-F-H),6.97(d,J=10.0Hz,1H,Ph-F-H),6.90(t,J=15.3Hz,2H,Ph-F-H),5.72(d,J=11.9Hz,2H,NCH2Ph),4.80(bs,1H,OH),4.10(t,J=6.6Hz,2H,CH2CH2OH),3.58(t,J=6.6Hz,2H,CH2OH),2.66(t,J=7.5Hz,CH2CH2CH2CH3),1.57(m,2H,CH2CH2CH3),1.32(m,2H,CH2CH3),0.84(t,J=7.3Hz,3H,CH3)ppm。
实验例21
化合物I-18的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-17(433mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-18(535mg),产率:66.5%;橙红色固体;熔点:>250℃。1H NMR(400MHz,DMSO-d6)δ11.26(bs,1H,NNH),8.62(d,J=8.5Hz,1H,naphthalimide-7-H),8.42(d,J=7.2Hz,1H,naphthalimide-5-H),8.37(s,1H,CHN),8.12(d,J=8.5Hz,1H,naphthalimide-2-H),7.72(t,J=7.9Hz,1H,naphthalimide-6-H),7.22(t,J=8.8Hz,2H,Ph-F-H),7.16(t,J=13.3Hz,2H,Ph-F-H),6.92(d,J=8.5Hz,1H,naphthalimide-3-H),5.72(d,J=28.9Hz,2H,NCH2Ph),4.80(bs,1H,OH),4.10(t,J=6.6Hz,2H,CH2CH2OH),3.59(t,J=6.6Hz,2H,CH2OH),2.65(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.56(m,2H,CH2CH2CH3),1.30(m,2H,CH2CH3),0.84(t,J=7.3Hz,3H,CH3)ppm。
实验例22
化合物I-19的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-18(457mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-19(405mg),产率:49.1%;橙红色固体;熔点:232-233℃。1H NMR(400MHz,DMSO-d6)δ11.19(bs,1H,NNH),8.55(d,J=8.5Hz,1H,naphthalimide-7-H),8.39(d,J=7.2Hz,1H,naphthalimide-5-H),8.28(s,1H,CHN),8.00(d,J=8.5Hz,1H,naphthalimide-2-H),7.69(t,J=7.9Hz,1H,naphthalimide-6-H),7.64(d,J=7.7Hz,1H,Ph-Cl-H),7.28(m,2H,Ph-Cl-H),6.69(d,J=8.5Hz,1H,Ph-Cl-H),6.41(d,J=7.4Hz,1H,naphthalimide-3-H),5.56(s,2H,NCH2Ph),4.79(t,J=5.9Hz,OH),4.08(t,J=6.6Hz,2H,CH2CH2OH),3.57(q,J=6.5Hz,2H,CH2OH),2.62(t,J=7.5Hz,2H,CH2CH2CH2CH3),1.58(m,2H,CH2CH2CH3),1.33(m,2H,CH2CH3),0.84(t,J=7.3Hz,3H,CH3)ppm。
实验例23
化合物I-20的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-19(457mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-20(418mg),产率:50.5%;橙红色固体;熔点:147-148℃。1H NMR(400MHz,DMSO-d6)δ11.29(bs,1H,NNH),8.65(d,J=8.5Hz,1H,naphthalimide-7-H),8.44(d,J=7.2Hz,1H,naphthalimide-5-H),8.40(s,1H,CHN),8.15(d,J=8.5Hz,1H,naphthalimide-2-H),7.75(t,J=7.9Hz,1H,naphthalimide-6-H),7.39(m,2H,Ph-Cl-H),7.24(s,1H,Ph-Cl-H),7.00(d,J=7.5Hz,1H,Ph-Cl-H),6.92(d,J=8.5Hz,1H,naphthalimide-3-H),5.73(s,2H,NCH2Ph),4.76(bs,1H,OH),4.11(t,J=6.6Hz,2H,CH2CH2OH),3.59(t,J=6.6Hz,2H,CH2OH),2.67(t,J=7.5Hz,2H,CH2CH2CH2CH3),1.57(m,2H,CH2CH2CH3),1.32(m,2H,CH2CH3),0.84(t,J=7.3Hz,3H,CH3)ppm。
实验例24
化合物I-21的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-20(457mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-21(396mg),产率:47.8%;橙红色固体;熔点:162-163℃。1H NMR(400MHz,DMSO-d6)δ11.28(bs,1H,NNH),8.62(d,J=8.5Hz,1H,naphthalimide-7-H),8.43(d,J=7.2Hz,1H,naphthalimide-5-H),8.37(s,1H,CHN),8.13(d,J=8.5Hz,1H,naphthalimide-2-H),7.73(t,J=7.9Hz,1H,naphthalimide-6-H),7.45(d,J=8.4Hz,2H,Ph-Cl-H),7.12(d,J=8.4Hz,2H,Ph-Cl-H),6.89(d,J=8.5Hz,1H,naphthalimide-3-H),5.70(s,2H,NCH2Ph),4.79(bs,1H,OH),4.11(t,J=6.6Hz,2H,CH2CH2OH),3.59(t,J=6.6Hz,2H,CH2OH),2.65(t,J=7.6Hz,2H,CH2CH2CH2CH3),1.57(m,2H,CH2CH2CH3),1.32(m,2H,CH2CH3),0.84(t,J=7.3Hz,3H,CH3)ppm。
实验例25
化合物I-22的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-21(508mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-22(418mg),产率:47.7%;橙红色固体;熔点:>250℃。1H NMR(400MHz,DMSO-d6)δ11.29(bs,1H,NNH),8.62(d,J=8.7Hz,1H,naphthalimide-7-H),8.44(d,J=7.3Hz,1H,naphthalimide-5-H),8.36(s,1H,CHN),8.10(d,J=8.4Hz,1H,naphthalimide-2-H),7.87(d,J=1.8Hz,1H,Ph-Cl-H),7.75(t,J=7.9Hz,1H,naphthalimide-6-H),7.38(d,J=10.1Hz,1H,Ph-Cl-H),6.77(d,J=8.5Hz,1H,Ph-Cl-H),6.46(d,J=8.3Hz,1H,naphthalimide-3-H),5.63(s,2H,NCH2Ph),4.80(bs,1H,OH),4.11(t,J=6.5Hz,2H,CH2CH2OH),3.59(t,J=6.6Hz,2H,CH2OH),2.66(t,J=7.4Hz,2H,CH2CH2CH2CH3),1.59(m,2H,CH2CH2CH3),1.33(m,2H,CH2CH3),0.85(t,J=7.3Hz,3H,CH3)ppm。
实验例26
化合物I-23的制备
在100mL圆底烧瓶加入中间体IV(400mg,1.47mmol),中间体II-22(473mg,1.47mmol),冰醋酸(6mL,104mmol),以乙醇(30mL)为溶剂,80℃下回流15h,薄层色谱跟踪至反应结束。将反应液倒入冰水中,过滤,冰水洗涤,经柱层析分离、干燥等后处理即得化合物I-23(544mg),产率:64.5%;橙红色固体;熔点:215-216℃。1H NMR(400MHz,DMSO-d6)δ11.19(bs,1H,NNH),8.54(d,J=8.5Hz,1H,naphthalimide-7-H),8.45(d,J=7.2Hz,1H,naphthalimide-5-H),8.37(d,J=7.2Hz,1H,naphthalimide-2-H),8.34(s,1H,CHN),8.27(d,J=8.3Hz,2H,Ph-NO2-H),7.68(t,J=7.9Hz,1H,naphthalimide-6-H),7.38(d,J=8.5Hz,2H,Ph-NO2-H),6.73(d,J=8.5Hz,1H,naphthalimide-3-H),5.84(s,2H,NCH2Ph),4.82(t,J=9.8Hz,1H,OH),4.10(m,2H,CH2CH2OH),3.60(m,2H,CH2OH),2.67(t,J=7.5Hz,2H,CH2CH2CH2CH3),1.59(m,2H,CH2CH2CH3),1.32(m,2H,CH2CH3),0.85(t,J=7.3Hz,3H,CH3)ppm。
实施例27
腙基桥连的萘酰亚胺咪唑类化合物的体外抗微生物活性
采用符合美国国家委员会制定的临床实验标准(Clinical and LaboratoryStandards Institute,CLSI)的96孔微量稀释法,检测实施例4-26制得的腙基桥连的萘酰亚胺咪唑类化合物对革兰氏阳性菌(耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC25923、金黄色葡萄球菌ATCC29213)、革兰氏阴性菌(克雷白氏肺炎杆菌、大肠杆菌、大肠杆菌ATCC25922、铜绿假单胞菌、铜绿假单胞菌ATCC27853、鲍曼不动杆菌)和真菌(白色念珠菌、热带假丝酵母菌、烟曲霉菌、白色念珠菌ATCC90023、近平滑假丝酵母菌ATCC20019)的最低抑制浓度(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128μg/mL,35℃培养24-72小时,将培养板至振荡器上充分摇匀后,在波长490nm处测定MIC,结果见表1-3。
表1、实施例4-26制备的腙基桥连的萘酰亚胺咪唑类化合物的体外抗革兰阳性菌活性数据(MIC,μg/mL)
从表1可以看出,本发明实施例4-26制备的腙基桥连的萘酰亚胺咪唑类化合物,对所测试的革兰阳性菌表现出一定的抑制作用。部分化合物如I-5对金黄色葡萄球菌ATCC29213表现出良好的抑制活性,与参考药物诺氟沙星相当。所测化合物对金黄色葡萄球菌ATCC25923和粪肠球菌均表现出中等的抑制活性,MIC值分别为4-64μg/ml和8-128μg/ml。其次,化合物I-12能够对多种细菌产生抑制作用,表现出较宽的抗菌谱。
表2、实施例4-26制备的腙基桥连的萘酰亚胺咪唑类化合物的体外抗革兰阴性菌活性数据(MIC,μg/mL)
从表2可以看出,本发明实施例4-26的腙基桥连的萘酰亚胺咪唑类化合物,对所测试的革兰阴性菌表现出一定的抑制作用。I-2,I-7,I-9,I-11~I-22对鲍曼不动杆菌均表现出与参考药物诺氟沙星相当的抑制活性,化合物I-1,I-5,I-18的对鲍曼不动杆菌MIC值为32μg/mL,为参考药物诺氟沙星的两倍。
表3、实施例4-26制备的腙基桥连的萘酰亚胺咪唑类化合物的体外抗真菌活性数据(MIC,μg/mL)
从表3可以看出,本发明实施例4-26制备的腙基桥连的萘酰亚胺咪唑类化合物,I-6对白色念珠菌ATCC90023表现出与参考药物氟康唑相当的抑制活性,I-18对烟曲霉菌的抑制活性是参考药物氟康唑的4倍,I-12、I-16、I-17、I-19对白色念珠菌的抑制活性是参考药物氟康唑的4倍。更重要的是,所测试化合物对近平滑念珠菌ATCC22019表现出良好的抑制活性,均相当于甚至强于参考药物氟康唑。
实施例28
腙基桥连的萘酰亚胺咪唑类化合物的制药用途
根据上述抗微生物活性检测结果,本发明的腙基桥连的萘酰亚胺咪唑类化合物具有较好的抗细菌、抗真菌活性,可以制成抗细菌、抗真菌药物供临床使用。这些药物既可以是单方制剂,例如由一种结构的腙基桥连的萘酰亚胺咪唑类化合物与药学上可接受的辅料制成;也可以是复方制剂,例如由一种结构的腙基桥连的萘酰亚胺咪唑类化合物与已有抗细菌、抗真菌活性成分(如诺氟沙星、磺胺甲噁唑、氟康唑、磷氟康唑、伊曲康唑等)以及药学上可接受的辅料制成,或者由不同结构的几种腙基桥连的萘酰亚胺咪唑类化合物与药学上可接受的辅料制成。所述制剂类型包括但不限于片剂、胶囊剂、散剂、颗粒剂、滴丸剂、注射剂、粉针剂、溶液剂、混悬剂、乳剂、栓剂、软膏剂、凝胶剂、膜剂、气雾剂、透皮吸收贴剂等剂型,以及各种缓释、控释制剂和纳米制剂。
1、化合物I-2片剂的制备
处方:化合物I-2 10g,乳糖187g,玉米淀粉50g,硬脂酸镁3g,体积百分浓度为70%的乙醇溶液适量,共制成1000片。
制法:将玉米淀粉与105℃干燥5小时备用;将化合物I-2与乳糖、玉米淀粉混合均匀,用70%的乙醇溶液制软材,过筛制湿颗粒,再加入硬脂酸镁,压片,即得;每片重250mg,活性成分含量为10mg。
2、化合物I-2胶囊剂的制备
处方:化合物I-2 25g,改性淀粉(120目)12.5g,微晶纤维素(100目)7.5g,低取代羟丙纤维素(100目)2.5g,滑石粉(100目)2g,甜味剂1.25g,橘子香精0.25g,色素适量,水适量,制成1000粒。
制法:将处方量的化合物I-2微粉化粉碎成极细粉末后,与处方量的改性淀粉、微晶纤维素、低取代羟丙纤维素、滑石粉、甜味剂、橘子香精和色素混匀,用水制软材,12–14目筛制粒,40–50℃干燥,过筛整粒,装入空胶囊,即得;每片重50mg,活性成分含量为25mg。
3、化合物I-3颗粒剂的制备
处方:化合物I-3 26g,糊精120g,蔗糖280g。
制法:将化合物I-3、糊精、蔗糖混合均匀,湿法制粒,60℃干燥,分装,即得。
4、化合物I-3注射剂的制备
处方:化合物I-3 10g,丙二醇500mL,注射用水500mL,共制成1000mL。
制法:称取化合物I-3、加入丙二醇和注射水,搅拌溶解,再加入1g活性炭,充分搅拌后静置15分钟,用5μm钛棒过滤脱炭,再依次用孔径为0.45μm和0.22μm的微孔滤膜精滤,最后灌封于10mL安瓿中,100℃流通蒸气灭菌45分钟,即得。
5、化合物I-4粉针剂的制备
制法:化合物I-4无菌粉末在无菌条件下分装,即得。
6、化合物I-4滴眼剂的制备
处方:化合物I-4 3.78g,氯化钠0.9g,硼酸缓冲溶液适量,蒸馏水加至1000mL。
制法:称取化合物I-4、氯化钠加至500mL蒸馏水中,溶解完全后用硼酸缓冲溶液调节pH至6.5,加蒸馏水至1000mL,搅拌均匀,微孔滤膜过滤,灌装,密封,100℃流通蒸气灭菌1小时,即得。
7、化合物I-4搽剂的制备
处方:化合物I-4 4g,钾肥皂7.5g,樟脑5g,蒸馏水加至100mL。
制法:将樟脑用体积百分浓度为95%的乙醇溶液溶解,备用;将钾肥皂加热液化,备用,称取化合物I-4,在不断搅拌下加入钾肥皂液和樟脑乙醇溶液,再逐渐加入蒸馏水,乳化完全后再加入蒸馏水至全量,即得。
8、化合物I-4栓剂的制备
处方:化合物I-4 4g,明胶14g,甘油70g,蒸馏水加至100mL,共制100枚。
制法:称取明胶和甘油,加蒸馏水至100mL,水浴60℃加热熔化呈糊状时加入化合物I-4,搅拌均匀,近凝固时倒入阴道栓模具中,冷却凝固,即得。
9、化合物I-14软膏剂的制备
处方:化合物I-14 0.5–2g,十六醇6–8g,白凡士林8–10g,液体石蜡8–19g,单甘脂2–5g,聚氧乙烯(40)硬脂酸脂2–5g,甘油5–10g,尼泊金乙酯0.1g,蒸馏水加至100g。
制法:将十六醇、白凡士林、液体石蜡、单甘脂和聚氧乙烯(40)硬脂酸脂加热完全溶化后混匀,保温80℃,作为油相备用;将尼泊金乙酯加入甘油和蒸馏水中,加热至85℃溶解,再在不断搅拌下加入油相,乳化后加入化合物I-14,搅拌冷却,即得。
10、化合物I-20与氟康唑复方粉针剂的制备
处方:化合物I-20 50g,氟康唑50g,苯甲酸钠1g,共制成100瓶。
制法:取处方量的化合物I-20、氟康唑和苯甲酸钠,在无菌状态下混合均匀,分装100瓶,即得。
11、化合物I-20气雾剂的制备
处方:化合物I-20 2.5g,Span20 3g,滑石粉(100目)4g,三氯一氟甲烷加至适量。
制法:将化合物I-20V、Span20和滑石粉分别置真空干燥箱内干燥数小时,置干燥器内冷却至室温,用气流粉碎机粉碎成微粉,再按处方量混匀,灌入密闭容器内,加入三氯一氟甲烷至规定量,即得。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
2.如权利要求1所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐,其特征在于,R为氢、甲基、乙基、烯基、炔基、环丙基、环己基、羟甲基、邻氯苯基、间氯苯基、对氯苯基、2,4-二氯苯基、邻氟苯基、间氟苯基、对氟苯基、对硝基苯基、吗啉基、氰基或乙氧酰基;
n为0、1、2、3、4或6。
4.如权利要求1所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐,其特征在于,所述可药用盐为盐酸盐、硝酸盐或醋酸盐。
5.权利要求1-4任一项所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐的制备方法,其特征在于,所述方法如下:
a、中间体II-1~22的制备:以2-丁基-4-氯-1H-咪唑-5-甲醛为起始原料,乙腈作溶剂,碳酸钾做碱,与溴化物进行取代反应,即得中间体II-1~22;
b、中间体III的制备:以4-溴-1,8-萘二甲酸酐为起始原料,乙醇作溶剂,与乙醇胺反应即得中间体III;
c、中间体IV的制备:以中间体III为起始原料,乙二醇甲醚作溶剂,与水合肼反应,即得中间体IV;
d、通式I-1所示腙基桥连的萘酰亚胺咪唑类化合物的制备,以2-丁基-4-氯-1H-咪唑-5-甲醛和中间体IV为起始原料,乙醇作溶剂,冰醋酸作催化剂,发生还原反应,即得通式I-1所示腙基桥连的萘酰亚胺咪唑类化合物;
f、通式I-2~23所示腙基桥连的萘酰亚胺咪唑类化合物的制备,以中间体II-1~22和中间体IV为起始原料,乙醇作溶剂,冰醋酸作催化剂,发生还原反应,即得通式I-2~23所示腙基桥连的萘酰亚胺咪唑类化合物。
6.如权利要求5所述的方法,其特征在于,
步骤a中,所述2-丁基-4-氯-1H-咪唑-5-甲醛与溴化物的摩尔比为1:1.2;所述取代反应的温度为50℃;
步骤b中,所述反应的温度为80℃;所述4-溴-1,8-萘二甲酸酐与乙醇胺的摩尔比为1:1.5;
步骤c中,所述反应的温度为90℃,反应的时间为5h,所述中间体III与水合肼的摩尔比为1:4;所述水合肼的质量分数为80%;
步骤d中,所述还原反应的温度为80℃,所述2-丁基-4-氯-1H-咪唑-5-甲醛、中间体IV和冰醋酸的摩尔比为1.47:1.47:104;
步骤f中,所述还原反应的温度为80℃,所述中间体II-1~22、中间体IV和冰醋酸的摩尔比为1.47:1.47:104。
7.权利要求1-4任一项所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用。
8.如权利要求7所述的应用,其特征在于,所述细菌为耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC25923、金黄色葡萄球菌ATCC29213、克雷白氏肺炎杆菌、大肠杆菌、大肠杆菌ATCC25922、铜绿假单胞菌、铜绿假单胞菌ATCC27853或鲍曼不动杆菌中的一种或多种;所述真菌为白色念珠菌、热带假丝酵母菌、烟曲霉菌、白色念珠菌ATCC90023或近平滑假丝酵母菌ATCC20019中的一种或多种。
9.含权利要求1-4任一项所述的腙基桥连的萘酰亚胺咪唑类化合物及其可药用盐的制剂。
10.如权利要求9所述的制剂,其特征在于,所述制剂为片剂、胶囊剂、颗粒剂、注射剂、粉针剂、滴眼剂、搽剂、栓剂、软膏剂或气雾剂中的一种。
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