CN103288897B - 4”-o-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物 - Google Patents
4”-o-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物 Download PDFInfo
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Abstract
本发明公开了4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,具有通式I、II或III的结构:其中,R1代表氢、乙酰基或苯甲酰基;R2代表苄基、取代苄基或烷基;R3代表苄基、取代苄基、β-苯乙基、取代β-苯乙基或吡啶-4-甲基。本发明的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,具有抗菌活性,对革兰氏阳性菌耐药菌抗菌作用明显,尤其对各种肺炎链球菌耐药菌活性表现良好,可以用于制备治疗细菌感染的药物。
Description
技术领域
本发明涉及一类4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,及其制备方法,以及在抗菌中的应用。
背景技术
大环内酯类抗生素,是一类天然和半合成抗生素,是现今临床上应用最广泛的抗菌药物之一。大环内酯类与青霉素类和其他一些临床常用的抗生素相比,具有良好的耐受性和安全性,其中阿奇霉素作为大环内酯类抗生素最杰出的代表药物之一,其药代动力学特性表现优异,被广泛应用于呼吸道感染、软组织感染和泌尿系统感染。
抗生素的使用不可避免的会对细菌突变产生选择作用,引起细菌耐药性,而细菌耐药产生的速度远远快于我们新抗菌药开发的速度。针对大环内酯类为骨架的半合成修饰成为当今抗菌药物研究重点之一,是当今药物研究开发领域解决细菌耐药性的一条安全而有效的途径。
目前,已报道的4"-氨基甲酸酯大环内酯衍生物有美国专利US6025350、US20080249033;世界专利WO2004101589、WO2005108413、WO2006050941、WO2006050942、WO2006050943、WO2008014221;中国专利:CN1980945、CN200710015049、CN200710015050、CN200810238167、CN201010011838、CN201010224597、CN201010224599、CN201110146229、CN201210002070、CN201210002065、CN201210240489等。4"-氨基甲酸酯大环内酯衍生物的研究受到广泛关注,多在抗耐药菌方面有较好表现。C-4"位是大环内酯抗生素十分有潜力的修饰位点,在这个位点引入不同的氨基甲酸酯侧链是开发抗耐药菌大环内酯抗生素的有效方法。
主要的呼吸道致病菌有金黄色葡萄球菌、肺炎链球菌、化脓性链球菌。erm基因介导的耐药肺炎链球菌、mef基因介导的耐药性肺炎链球菌以及erm和mef基因介导的混合耐药性肺炎链球菌,是三种主要大环内酯耐药菌。本发明提供了一系列新颖的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,对多种革兰氏阳性菌和阴性菌做了体外抗菌活性研究,发现目标化合物对以上三种耐药菌具有显著的体外抗菌活性。
发明内容
本发明提供了一类4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,及其制备方法,以及在抗菌中的应用。
本发明是通过以下技术方案实现的:
4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,具有通式I、II或III的结构:
其中,R1代表氢、乙酰基或苯甲酰基;R2代表苄基、取代苄基或烷基;R3代表苄基、取代苄基、β-苯乙基、取代β-苯乙基或吡啶-4-甲基。
优选的,所述R2代表苄基,2-甲基苄基、3-甲基苄基、4-甲基苄基、4-硝基苄基、4-溴苄基、2-氟苄基、3-氟苄基、4-氟苄基、2,6-二氯-苄基、2,4-二氯-苄基、4-氯-苄基、3-氯-苄基、2-氯-苄基或环己基;R3代表苄基、4-甲氧基苄基、β-苯乙基或吡啶-4甲基。
4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物的中间体,具有通式Ⅳ的结构:
其中,R1代表氢、乙酰基或苯甲酰基。
优选的,上述化合物I是下列之一:
4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(2-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(4-溴苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(2-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(3-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(4-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(2,6-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(2,4-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(4-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(3-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-(2-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4''-O-[1-环己基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯。
优选的,上述化合物II是下列之一:
4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4''-O-[1-(2-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素;
4''-O-[1-(2,6-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4''-O-[1-(2,4-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4''-O-[1-(4-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4''-O-[1-(3-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4''-O-[1-(2-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素。
优选的,上述化合物III是下列之一:
4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4''-O-[1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4''-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4''-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4''-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4''-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4''-O-[1-(2-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-苯乙基基氨甲酰基-阿奇霉素;
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(吡啶-4甲基氨甲酰基)-阿奇霉素;
4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4''-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4''-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4''-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4''-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4''-O-[1-(2氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素。
具有通式IV结构的化合物是下列之一:
4"-O-(炔丙基-氨基甲酰基)-2'-O-乙酰基-阿奇霉素-11,12-环碳酸酯;
4"-O-(炔丙基-氨基甲酰基)-2'-O-苯甲酰基-阿奇霉素-11,12-环碳酸酯;
4"-O-(炔丙基-氨基甲酰基)-阿奇霉素-11,12-环碳酸酯。
所述的具有通式I的4''-O-(1-芳烷基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素-11,12-环碳酸酯的制备方法(合成路线见图1),步骤如下:
(1)通式1化合物的合成参照已有方法(CN201010011838,101906123A)完成,其中,R1代表氢、乙酰基或苯甲酰基;
(2)将上述得到的通式1的化合物与炔丙胺混合,加入适量溶剂,再加入催化剂,催化剂为1.8-二氮杂二环(5.4.0)十一烯-7(DBU),于0~60℃反应2~24小时,生成通式IV的化合物;
(3)上述得到的通式IV的化合物,以低级醇作溶剂,在存在或不存在有机或无机弱碱的条件下,于0~65℃反应2~24小时,脱去2’-OH上的保护基,生成通式2的化合物;
(4)将上述得到的通式2的化合物和叠氮代烷(R2-N3,其中,R2代表苄基、取代苄基或烷基),溶于醇-水混合溶剂中,加入硫酸铜溶液和抗坏血酸钠溶液,0~50℃下搅拌2~12小时,生成通式I的化合物。
上述步骤(2)中:溶剂为N,N-二甲基甲酰胺、四氢呋喃或乙腈,优选N,N-二甲基甲酰胺;通式1的化合物与炔丙胺的摩尔比优选1:1.5;通式1的化合物与催化剂DBU的摩尔比为1:(0.1~2);优选室温下反应10小时。
上述步骤(3)中:低级醇优选甲醇,反应温度为55℃,反应时间12小时。
上述步骤(4)中:醇-水混合溶剂中的醇选自甲醇、乙醇、丙醇或叔丁醇,醇-水体积比为1:(0.5~2);优选叔丁醇,叔丁醇-水配比优选为1:1。
上述步骤(4)中:通式3的化合物和叠氮代烷的摩尔比为1:(1~2);通式3的化合物、硫酸铜与抗坏血酸钠摩尔比优选10:1:2。
上述步骤(4)中:优选室温条件下反应8小时。
上述步骤(4)反应结束,后处理方法如下:蒸除溶剂中的醇,在碱介质(如NaHCO3溶液)中,优选在pH8.0~10.0下萃取,通过分离有机层并蒸干溶剂来分离产物;萃取之后,使用20:1的二氯甲烷-甲醇系统的硅胶柱层析进行纯化,可产生纯度达95%以上的具有Rf值为0.55(DCM:MeOH=5:1)的通式I的化合物。
所述的具有通式II的4''-O-(1-芳烷基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素的制备方法(合成路线见图2),步骤如下:
(1)将通式6的化合物(其中,R1代表氢、乙酰基或苯甲酰基)在无水甲苯中,在无机或有机碱存在下,与N,N-羰基二咪唑(CDI)于0~100℃反应2~72小时,通式6的化合物与N,N-羰基二咪唑的的摩尔比1:(1~3),生成具有通式4的化合物;
(2)将炔丙胺盐酸盐和叠氮代烷(R2-N3,其中,R2代表苄基、取代苄基或烷基)溶于醇-水混合溶剂中,加入硫酸铜溶液和抗坏血酸钠溶液,0~50℃下搅拌2~12小时,生成通式3的化合物;
(3)将得到的通式4的化合物与通式3的化合物混合,加入适量溶剂中,再加入有机碱和催化剂,催化剂为1.8-二氮杂二环(5.4.0)十一烯-7(DBU),于0~60℃反应2~24小时,生成通式II的化合物;
(4)上述得到的通式II的化合物,以低级醇作溶剂,在存在或不存在有机或无机弱碱的条件下,于0~65℃反应2~24小时,脱去2’-OH上的保护基,生成通式5的化合物。
上述步骤(1)中:通式6的化合物与N,N-羰基二咪唑的的摩尔比优选1:(1~1.2)。
上述步骤(2)中:醇-水混合溶剂中的醇选自甲醇、乙醇、丙醇或叔丁醇,醇-水体积比为1:(0.5~2);优选叔丁醇,叔丁醇-水配比优选为1:1。
上述步骤(2)中:炔丙胺盐酸盐与叠氮代烷摩尔比为1:(1~2),优选1:1;炔丙胺盐酸盐、硫酸铜与抗坏血酸钠摩尔比优选10:1:2。
上述步骤(2)中:优选室温条件下反应8小时。
上述步骤(2)反应结束,后处理方法(纯化产物)如下:反应完毕,滴加4mol/L氢氧化钠调pH至12,减压蒸除tBuOH,溶液以乙酸乙酯萃取,无水硫酸钠干燥,过滤,减压浓缩,加足量乙酸乙酯的HCl溶液,析出固体,抽滤洗涤,干燥,得通式3的化合物。
上述步骤(3)中:溶剂为N,N-二甲基甲酰胺、四氢呋喃或乙腈,优选N,N-二甲基甲酰胺。通式1的化合物与催化剂DBU的摩尔比为1:(0.1~4);通式4的化合物与通式3的化合物的摩尔比1:(1~4),优选1:2;优选室温下反应10小时。
上述步骤(4)中:低级醇优选甲醇,反应温度为55℃,反应时间12小时。
所述的具有通式III的4''-O-(1-芳烷基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素-11-O-芳烷基氨基甲酰基衍生物的制备方法(合成路线见图3),步骤如下:
(1)将具有通式I结构的化合物以相应的芳烷基伯胺(R3-NH2,其中,R3代表苄基、取代苄基、β-苯乙基、取代β-苯乙基或吡啶-4-甲基)溶解,在盐酸吡啶的催化下,0~60℃下反应1~5天,生成具有通式III的衍生物。
上述步骤(1)中:通式I结构的化合物与相应的芳烷基伯胺摩尔比为1:(10~50)。
上述步骤(1)中:催化剂选用盐酸吡啶,具有通式I的化合物与盐酸吡啶的摩尔量之比为1:3;温度优选20~40℃。
本发明的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,具有抗菌活性,对革兰氏阳性菌耐药菌抗菌作用明显,尤其对各种肺炎链球菌耐药菌活性表现良好,通过实验证明,对敏感型金黄色葡萄球菌(S.aureus ATCC25923)、耐甲氧西林金黄色葡萄球菌(S.aureus ATCC29213)、大肠杆菌(E.coli ATCC25922)、铜绿假单胞菌(P.aeruginosa ATCC27853)、化脓性链球菌敏感菌(S.pyogenes1)、化脓性链球菌耐药菌(S.pyogenes2)、敏感型肺炎链球菌(S.pneumoniae ATCC49619)、ermB型耐药的肺炎链球菌(S.pneumoniae B1)、mefA型耐药的肺炎链球菌(S.pneumoniae22072)和ermB+mefA型耐药的肺炎链球菌(S.pneumoniae AB11)均具有抑制作用,可以用于制备治疗细菌感染的药物,具体制备时,该药物包含有治疗量的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物或其药学上可接受的盐,以及其它常规的药用辅料或载体。
本发明的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,其特点在于:C4"侧链中含有三氮唑环结构,且末端有各种取代芳基,侧链具有一定柔性,有利于与核糖体23S rRNA肽通道表面核苷酸残基相结合。该系列衍生物除具有阿奇霉素内酯大环的作用外,还引入了C4"的1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酸酯侧链以获得二级作用机制;体外抗菌活性测定表明,C4"该侧链的引入对于获得抗耐药菌活性极为重要。C11芳烷基氨甲酸酯侧链的引入对抗菌活性提高明显。4''-O-(1-芳烷基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素-11-O-芳烷基氨基甲酰基衍生物表现出极好的抗革兰氏阳性菌活性,一些化合物尤其对化脓性链球菌和肺炎链球菌耐药菌的活性突出。
(1)对敏感型化脓性链球菌活性最好的化合物(化合物R1~R9、S1~S9)(MIC≤0.002μg/mL)是对照药物阿奇霉素抗菌活性的15倍以上。
(2)对ermB型耐药的肺炎链球菌活性最好的化合物(化合物S3、S8)(MIC=0.06μg/mL)是对照药物阿奇霉素抗菌活性的2133倍。
(3)对mefA型耐药的肺炎链球菌活性最好的化合物(化合物S2~S4)(MIC=0.03μg/mL)是对照药物阿奇霉素抗菌活性的133倍。
(4)对ermB+mefA型耐药的肺炎链球菌活性最好的化合物(化合物S3、S6、S8)(MIC=0.125μg/mL)是对照药物阿奇霉素抗菌活性的2048倍。
采用96孔板微量稀释法测定目标化合物对敏感型金黄色葡萄球菌(S.aureus ATCC25923)、耐甲氧西林金黄色葡萄球菌(S.aureus ATCC29213)、大肠杆菌(E.coli ATCC25922)、铜绿假单胞菌(P.aeruginosa ATCC27853)、化脓性链球菌敏感菌(S.pyogenes1)、化脓性链球菌耐药菌(S.pyogenes2)、敏感型肺炎链球菌(S.pneumoniae ATCC49619)、ermB型耐药的肺炎链球菌(S.pneumoniae B1)、mefA型耐药的肺炎链球菌(S.pneumoniae22072)和ermB+mefA型耐药的肺炎链球菌(S.pneumoniae AB11)的体外抗菌活性(MIC值表示),结果如表1、表2所示:
表1:抗敏感菌活性
表2:抗耐药菌活性
其中化合物代表:
(P1)4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P2)4''-O-[1-(2-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P3)4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12- 环碳酸酯;
(P4)4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P5)4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素-11,12-环碳酸酯;
(P6)4''-O-[1-(4-溴苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P7)4''-O-[1-(2-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P8)4''-O-[1-(3-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P9)4''-O-[1-(4-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P10)4''-O-[1-(2,6-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P11)4''-O-[1-(2,4-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P12)4''-O-[1-(4-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P13)4''-O-[1-(3-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P14)4''-O-[1-(2-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(P15)4''-O-[1-环己基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
(Q1)4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(Q2)4''-O-[1-(2-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(Q3)4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(Q4)4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(Q5)4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素;
(Q6)4''-O-[1-(2,6-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(Q7)4''-O-[1-(2,4-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(Q8)4''-O-[1-(4-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(Q9)4''-O-[1-(3-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(Q10)4''-O-[1-(2-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
(R1)4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
(R2)4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
(R3)4''-O-[1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
(R4)4''-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
(R5)4''-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
(R6)4''-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
(R7)4''-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
(R8)4''-O-[1-(2-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
(R9)4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-苯乙基基氨甲酰基-阿奇霉素;
(R10)4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(吡啶-4甲基氨甲酰基)-阿奇霉素;
(S1)4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
(S2)4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
(S3)4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
(S4)4''-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
(S5)4''-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
(S6)4''-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
(S7)4''-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
(S8)4''-O-[1-(2氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
(S9)4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素。
附图说明
图1:通式I的化合物的合成路线。
图2:通式II的化合物合成路线。
图3:通式III的化合物合成路线。
具体实施方式
下面结合实施例对本发明作进一步的说明。
实施例1.
2'-O-乙酰基-阿奇霉素的制备
取阿奇霉素(5.0g,6.68mmol)溶解于50mL无水二氯甲烷,加入醋酐1.3ml(1.41g,13.8mmol)和无水三乙胺2.9ml(2.11g,20.9mmol),室温搅拌24h。反应完毕后,加入足量饱和NaHCO3溶液,DCM(40ml×2)萃取分液。有机层合并,以饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压旋干,得白色泡沫状固体,丙酮:水(2:1)重结晶,得白色目标产物4.93g,收率93.3%。熔点167~170°C,Rf值0.40(DCM:MeOH=10:1;浓硫酸显色)。
实施例2.
4"-O-(1-H-咪唑-1-羰基)-2'-O-乙酰基-阿奇霉素-11,12-环碳酸酯的制备
将2'-O-乙酰基-阿奇霉素(4.0g,5.06mmol)溶于50mL无水甲苯中,加入无水三乙胺1.4mL(1.02g,10.1mmol)和N,N′-二羰基咪唑(CDI)(2.46g,15.2mmol),55°C搅拌40h。反应毕,减压旋去溶剂甲苯,加适量饱和碳酸氢钠溶液,以二氯甲烷30mL×2萃取。有机层合并,以饱和食盐水洗涤,无水Na2SO4干燥有机相,过滤,减压旋干,得白色泡沫状固体 4.34g,收率94.3%。熔点117~120°C;Rf值0.70(DCM:MeOH=10:1;浓硫酸显色)。
实施例3.
4"-O-(炔丙基-氨基甲酰基)-2'-O-乙酰基-阿奇霉素-11,12-环碳酸酯的制备
将4"-O-(1-H-咪唑-1-羰基)-2'-O-乙酰基-阿奇霉素-11,12-环碳酸酯(4.0g,4.39mmol)溶解于无水DMF(20mL)中,加入炔丙胺(0.37g,6.72mmol),滴加DBU约1.0ml,室温搅拌10h。反应完毕后,加乙酸乙酯50ml,水50ml,分液,水相以40ml乙酸乙酯萃取。合并有机层,以饱和食盐水40ml×2洗涤、无水硫酸钠干燥,过滤,减压旋干,得白色泡沫固体3.79g,收率96.1%。熔点110~114°C;Rf=0.62(DCM:MeOH=10:1)。
实施例4.
4"-O-(炔丙基-氨基甲酰基)-阿奇霉素-11,12-环碳酸酯的制备
4"-O-(炔丙基-氨基甲酰基)-2'-O-乙酰基-阿奇霉素-11,12-环碳酸酯以适量甲醇溶解,55°C搅拌12h,减压旋干甲醇,得到淡黄色固体。硅胶柱层析,所用洗脱剂为DCM:MeOH=25:1,得白色泡沫状固体,收率70.2%。熔点128~131°C;Rf=0.59(DCM:MeOH=7:1)
实施例5.
4"-O-(3-甲基苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素-11,12-环碳酸酯(P1)的制备
取上步得到的4"-O-(炔丙基-氨基甲酰基)-阿奇霉素-11,12-环碳酸酯(2.0g,2.34mmol),溶于tBuOH40ml、水30ml中,加入中间体I(0.52g,3.54mmol),加入硫酸铜溶液5ml(0.08g,0.50mmol),抗坏血酸钠溶液5ml(0.20g,1.01mmol),搅拌过夜。反应完毕,减压蒸除tBuOH,溶液以乙酸乙酯40ml×2提取,合并有机相,以饱和食盐水30ml洗涤,无水硫酸钠干燥,过滤,减压旋干。得淡黄色的泡沫状固体,硅胶柱层析,洗脱剂为DCM:MeOH=15:1,得白色泡沫状固体(2.02g,2.01mmol),收率86%。Rf=0.55(DCM:MeOH=5:1)。
化合物P2-P15依上述方法制备。
实施例6.
4"-O-(1-H-咪唑-1-羰基)-2'-O-乙酰基-阿奇霉素的制备
将化合物7(3.0g,3.79mmol)溶于40mL无水甲苯中,加入0.50mL无水三乙胺(3.6mmol)和N,N′-二羰基咪唑(CDI)(0.65g,4.01mmol),55°C搅拌48h。反应毕,向溶液中加适量饱和碳酸氢钠溶液,以二氯甲烷30mL×2萃取。有机层合并,以饱和食盐水40mL×2洗涤,无水Na2SO4干燥有机相,过滤,减压旋干,得白色泡沫状固体3.20g,收率95.3%。熔点117–120°C,Rf值0.68(DCM:MeOH=10:1)。
实施例7.
1-(3-甲基苄基)-4-氨甲基-1H-1,2,3-三氮唑盐酸盐的合成
取3-甲基苄基叠氮(1.2g,8.1mmol),溶于tBuOH30ml,水20ml中,加入炔丙胺盐酸盐(0.73g,8mmol),加入硫酸铜溶液5ml(0.16g,0.8mmol),抗坏血酸钠溶液5ml(0.26g,1.6mmol),搅拌过夜。反应完毕,滴加4mol/L氢氧化钠调pH至12,减压蒸除tBuOH,溶液以乙酸乙酯30ml×3提取,合并有机相,以饱和食盐水30ml洗涤,无水硫酸钠干燥,过滤,减压浓缩,加足量乙酸乙酯的HCl溶液,析出固体,抽滤洗涤,干燥,得1-(3-甲基苄基)-4-氨甲基-1H-1,2,3-三氮唑盐酸盐,为白色疏松片状晶体(1.1g,4.6mmol),收率57%。Rf=0.41(DCM:MeOH=5:1;紫外荧光、茚三酮显色)
实施例8.
4"-O-(1-间甲基苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-2'-O-乙酰基-阿奇霉素的制备
将4"-O-(1-H-咪唑-1-羰基)-2'-O-乙酰基-阿奇霉素(1.5g,1.69mmol)溶解于DMF(10mL)中,加入1-(3-甲基苄基)-4-氨甲基-1H-1,2,3-三氮唑盐酸盐(0.81g,3.39mmol),三乙胺1.4ml(1.02g,10.1mmol),边搅拌边滴加DBU至溶液澄清,室温搅拌8h。反应毕,加乙酸乙酯50ml,水50ml,分液,以30ml乙酸乙酯萃取。合并有机层,以饱和食盐水40ml×2洗涤、无水硫酸钠干燥,过滤,减压旋干,得淡黄色泡沫固体1.67g,收率96.5%。Rf=0.53(DCM:MeOH=10:1)。
实施例9.
4"-O-(1-间甲基苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素(Q1)的制备
取4"-O-(1-间甲基苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-2'-O-乙酰基-阿奇霉素(1.5g,1.47mmol),溶于适量甲醇,55℃搅拌12h。反应完毕,减压蒸除甲醇。得淡黄色泡沫状固体,硅胶柱层析,洗脱剂为DCM:MeOH=20:1,得白色泡沫状固体(1.25g,1.28mmol),收率87%。Rf=0.30(DCM:MeOH=5:1)
化合物Q2-Q9以上依方法制备
实施例10.
4''-O-(1-间甲基苄基-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-苄基氨甲酰基-阿奇霉素(R1)的制备
将4''-O-(1-间甲基苄基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素11,12-环碳酸酯(P1)(0.50g,0.50mmol)溶解于苄胺2.0mL,加入盐酸吡啶(0.14g,1.21mmol),室温搅拌4d。反应完毕,分别加入EtOAc40ml、饱和NaH2PO4(10mL),充分振摇,分液,饱和食盐水30ml×2洗涤。有机层用无水硫酸钠干燥,过滤后减压旋干,得白色固体。经硅胶柱层析,洗脱剂为二氯甲烷:甲醇(15:1),得白色泡沫状固体(0.40g,0.38mmol),收率72.3%。熔点143–146°C,Rf=0.21(DCM:MeOH=5:1)。
化合物R2–R10、S1–S9按上述方法制备。
结构确证:
4"-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P1)
White solid,yield87%,mp133–136°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3437,3310,2975,2879,2832,2789,1814,1732,1639,1511,1460,1383,1238,1168,1045,835,773,642cm-1;1H NMR(600MHz,CDCl3,δppm):7.42(s,1H),7.25–7.23(t,1H),7.17–7.15(d,1H),7.06–7.03(t,2H),5.45(m,2H),5.38(s,1H),5.07(s,1H),4.88–4.86(m,1H),4.52–4.50(m,1H),4.52–4.49(m,1H),4.45–4.44(m,3H),4.40–4.43(m,2H),4.38–4.31(m,1H),3.62–3.60(m,1H),3.59–3.58(m,1H),3.28(m,4H),2.86–2.84(m,2H),2.44–2.36(m,6H),2.33(m,5H),2.20(m,4H),2.06–2.02(m,1H),2.00(s,1H),1.90(s,1H),1.84–1.81(m,2H),1.62–1,55(m,3H),1.44–1.38(m,4H),1.30–1.24(m,5H),1.20–1.17(m,4H),1.13–1.12(m,6H),1.08–1.04(m,10H),0.93–0.90(m,7H);MS(ESI)m/z calcd.for C51H82N6O141002.6,found[M+H]+1004.1.
4''-O-[1-(2-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P2)
White solid,yield85%,mp136–138°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3445,2974,2938,2878,2831,2788,1812,1731,1637,1509,1460,1383,1237,1168,1112,1045,1015,901,745,480cm-1;1H NMR(600MHz,CDCl3,δppm):7.30–7.27(m,2H),7.20–7.22(m,2H),7.14–7.12(m,1H),5.51–5.47(m,2H),5.38(s,1H),5.05(s,1H),4.88–4.86(m,1H),4.51–4.49(m,1H),4.46–4.40(m,4H),4.37–4.31(m,2H),3.63–3.57(m,2H),3.31–3.28(m,4H),2.86–2.84(m,2H),2.44–2.42(m,4H),2.36–2.33(m,2H),2.25–2.20(m,7H),2.04–2.00(m,2H),1.90–1.81(m,3H),1.62–1.56(m,3H),1.44–1.41(m,4H),1.30–1.24(m,5H),1.19–1.13(m,4H),1.13–1.10(m,6H),1.08–1.03(m,10H),0.93–0.90(m,7H);MS(ESI)m/z calcd.for C51H82N6O141002.6,found[M+H]+1004.0.
4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P3)
White solid,yield87%,mp135–139°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3442, 2975,2936,2878,1812,17730,1666,1517,1462,1384,1238,1168,1123,1044,901,774,477cm-1;1H NMR(600MHz,CDCl3,δppm):7.47(s,1H),7.15(m,4H),5.45(s,2H),5.00(s,1H),4.87–4.85(m,1H),4.60–4.59(m,1H),4.50–4.48(m,1H),4.45-4.44(m,2H),4.40(s,1H),4.25(s,2H),3.63–3.57(m,2H),3.28(m,4H),2.86–2.84(m,2H),2.46–2.32(m,9H),2.21(m,4H),2.04–2.02(m,2H),1.90(s,1H),1.84–1.82(m,2H),1.61–1.54(m,3H),1.45–1.41(m,4H),1.29–1.26(m,5H),1.23–1.20(m,4H),1.16–1.12(m,6H),1.11–1.07(m,6H),0.98–0.97(m,4H),0.94–0.91(m,7H);MS(ESI)m/z calcd.for C51H82N6O141002.6,found[M+H]+1003.9.
4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P4)
White solid,yield83%,mp148–152°C;TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3442,2975,2938,2879,1811,1730,1638,1526,1460,1384,1348,1238,1168,1110,1044,1015,805,471cm-1;1H NMR(600MHz,CDCl3,δppm):8.23–8.21(m,2H),7.57(s,1H),7.42–7.40(m,2H),5.63–5.60(m,3H),5.05(s,1H),4.88(s,1H),4.52–4.51(m,1H),4.48–4.46(m,3H),4.40(s,1H),4.36–4.29(m,2H),3.67–3.64(m,1H),3.58–3.57(m,1H),3.28(m,4H),2.86–2.83(m,2H),2.54–2.34(m,6H),2.22–2.17(m,4H),2.06–2.00(m,2H),1.91–1.81(m,3H),1.44(m,4H),1.33–1.03(m,25H),0.93–0.91(m,7H);MS(ESI)m/z calcd.for C50H79N7O161033.6,found[M+H] +1035.0.
4''-O-[1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P5)
White solid,yield88%,mp131–134°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3448,2974,2938,2879,2831,2788,1813,1731,1511,1459,1382,1237,1168,1046,901,773,724,482cm-1;1H NMR(600MHz,CDCl3,δppm):7.43(s,1H),7.37–7.35(m,3H),7.25–7.23(m,2H),5.53–5.47(m,2H),5.07(s,1H),4.88–4.86(m,1H),4.51–4.50(m,1H),4.44–4.41(m,5H),4.4.35–4.32(m,1H),3.61–3.57(m,2H),3.28(m,3H),3.25–3.20(m,1H),2.43–2.41(m,1H),2.60–2.32(m,6H),2.20(m,4H),2.07–2.03(m,1H),2.00(s,1H),1.90(s,1H),1.85–1.80(m,1H),1.70(s,1H),1.62–1.56(m,3H),1.44–1.40(m,4H),1.33–1.23(m,5H),1.20–1.19(m,5H),1.15–1.11(m,6H),1.08–1.05(m,9H),0.93–0.88(m,7H).MS(ESI)m/z calcd.for C50H80N6O14988.6,found[M+H]+989.9.
4''-O-[1-(4-溴-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P6)
White solid,yield89%,mp139–143°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3445,2974,2938,2878,2832,2788,1811,1729,1638,1459,1382,1238,1168,1113,1073,1046,1014,775,479cm-1;1H NMR(600MHz,CDCl3,δppm):7.50–7.48(d,2H,J=2.4Hz),7.45(s,1H,J=2.4Hz),7.12–7.11(d,2H),5.45(s,1H),5.38(s,1H),5.07(s,1H),4.88–4.86(m,1H),4.52–4.50(m,1H),4.44–4.40(m,5H),4.35–4.34(m,1H),3.62–3.57(m,2H),3.29(m,4H),2.87–2.84(m,2H),2.43–2.34(m,7H),2.20(m,3H),2.06–2.00(m,2H),1.91–1.79(m,3H),1.63–1.54(m,3H),1.44–1.40(m,4H),1.28–1.04(m,25H),0.93–0.91(m,7H);MS(ESI)m/z calcd.for C50H79BrN6O141066.5,found[M+H]+1067.8.
4''-O-[1-(2-氟-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P7)
White solid,yield85%,mp135–139°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3447,2974,2939,2879,2831,2788,1813,1731,1620,1590,1496,1459,1381,1236,1167,1046,902,837,760,641,570,469cm-1;1H NMR(600MHz,CDCl3,δppm):7.52(s,1H),7.38–7.34(m,1H),7.27–7.23(m,1H),7.15–7.10(m,2H),5.59–5.53(m,2H),5.39(s,1H),5.06(s,1H),4.88–4.86(m,1H),4.52–4.51(m,1H),4.48–4.44(m,3H),4.41-4.38(m,2H),4.34-4.31(m,1H),3.61–3.57(m,2H),3.28(m,4H),2.86–2.85(m,2H),2.44–2.34(m,7H),2.20(m,3H),2.07–2.00(m,2H),1.90(s, 1H),1.85–1.81(m,2H),1.63–1.55(m,3H),1.44–1.39(m,4H),1.28–1.19(m,9H),1.15–1.04(m,16H),0.93–0.91(m,7H);MS(ESI)m/z calcd.for C50H79FN6O141006.6,found[M+H]+1008.2.
4''-O-[1-(3-氟-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P8)
White solid,yield85%,mp133–136°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3446,2974,2938,2879,2832,2789,2101,1812,1729,1620,1457,1383,1257,1168,1122,1045,902,774,481cm-1;1H NMR(600MHz,CDCl3,δppm):7.49(s,1H),7.38–7.33(m,1H),7.07–7.02(m,2H),6.93–6.92(d,1H,J=9.0Hz),5.50(s,1H),5.41(s,1H),5.07(s,1H),4.55–4.51(m,1H),4.46–4.44(m,3H),4.41–4.33(m,3H),3.63–3.62(m,1H),3.59–3.56(m,1H),2.31–3.24(m,4H),2.86–2.84(m,2H),2.53–2.43(m,5H),2.37–2.34(m,2H),2.20(m,3H),2.07–2.01(m,2H),1.91(s,1H),1.86–1.82(m,2H),1.63–1.55(m,3H),1.45–1.39(m,4H),1.29–1.26(m,5H),1.21–1.20(m,4H),1.16–1.13(m,6H),1.09–1.04(m,10H),0.94-0.91(m,7H);MS(ESI)m/z calcd.for C50H79FN6O141006.6,found[M+H]+1008.0.
4''-O-[1-(4-氟-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P9)
White solid,yield87%,mp135–138°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3447,2974,2938,2879,2832,1813,1730,1632,1513,1459,1383,1234,1167,1045,1015,903,773,478cm-1;1H NMR(600MHz,CDCl3,δppm):7.45(s,1H),7.27–7.24(m,2H),7.08–7.05(t,2H,J=2.7Hz),5.48(s,1H),5.39(s,1H),5.07(s,1H),4.89–4.87(m,1H),4.55–4.51(m,1H),4.47–4.44(m,3H),4.41–4.31(m,3H),3.63(s,1H),3.59–3.58(m,1H),3.32–3.29(m,4H),2.86–2.85(m,2H),2.54–2.35(m,7H),2.21(s,3H),2.07–2.01(m,2H),1.91(s,1H),1.86–1.82(m,2H),1.65–1.55(m,3H),1.45–1.39(m,4H),1.33–1.25(m,6H),1.21–1.20(m,4H),1.16–1.14(m,6H),1.09–1.00(m,9H),0.99–0.89(m,7H);MS(ESI)m/z calcd.for C50H79FN6O141006.6,found[M+H]+1008.2.
4''-O-[1-(2,6-二氯-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P10)
White solid,yield89%,mp142–146°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3447,2974,2877,2788,2102,1813,1730,1634,1459,1383,1238,1168,1111,1044,1015,902,767cm-1;1H NMR(600MHz,CDCl3,δppm):7.45(s,1H),7.41–7.39(d,2H,J=8.4Hz),7.32–7.29(m,1H),5.86–5.81(m,2H),5.38(s,1H),5.04(s,1H),4.88–4.86(m,1H),4.55–4.30(m,7H),3.62–3.61(m,1H),3.58–3.53(m,1H),3.34–3.22(m,4H),2.86–2.82(m,2H),2.53–2.34(m,7H),2.20(m,3H),2.06–2.00(m,2H),1.89(s,1H),1.85–1.82(m,2H),1.66–1.55(m,3H),1.44–1.38(m,4H),1.33–1.02(m,25H),0.93–0.84(m,7H);MS(ESI)m/z calcd.for C50H78Cl2N6O141056.5,found[M+H]+1057.9.
4''-O-[1-(2,4-二氯-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P11)
White solid,yield84%,mp144–147°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3449,2974,2938,2879,2831,2788,2097,1813,1731,1639,1591,1511,1459,1384,1237,1168,1045,902,836,773,469cm-1;1H NMR(600MHz,CDCl3,δppm):7.58(s,1H),7.44(s,1H),7.25–7.24(d,1H,J=8.1Hz),7.13–7.12(d,1H,J=8.1Hz),5.80(s,1H),5.60(s,1H),5.05(s,1H),4.88–4.86(m,1H),4.53–4.49(m,2H),4.46–4.45(m,2H),4.41(s,1H),4.37–4.32(m,2H),3.67(s,1H),3.58(s,1H),3.39–3.36(m,1H),3.32–3.29(m,3H),2.87–2.83(m,2H),2.62–2.35(m,7H),2.20(m,3H),2.08–2.04(m,1H),2.00(m,2H),1.91(s,1H),1.63–1.57(m,3H),1.45(s,3H),1.40–1.03(m,26H),0.93–0.91(m,7H);MS(ESI)m/z calcd.for C50H78Cl2N6O141056.5,found[M+H]+1059.8.
4''-O-[1-(4-氯-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P12)
White solid,yield81%,mp147–151°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3446,2975,2938,2879,2832,1811,1730,1638,1515,1495,1461,1383,1238,1168,1122,1077,1045,901,774,483cm-1;1H NMR(600MHz,CDCl3,δppm):7.46(s,1H),7.35–7.33(d,2H,J=8.4Hz),7.20–7.19(d,2H,J=8.4Hz),5.73(s,1H),5.48(s,1H),5.02(s,1H),4.88–4.86(m,1H),4.55–4.51(m,2H),4.45–4.44(m,2H),4.39(s,1H),4.28(m,2H),3.72–3.71(m,1H),3.59–3.58(m,1H),3.51(s,1H),3.31–3.27(m,3H),2.85–2.76(m,7H),2.46–2.45(m,1H),2.37–2.32(m,1H),2.20(m,3H),2.06–2.02(m,3H),1.91(s,1H),1.86–1.82(m,2H),1.63–1.58(m,3H),1.45–1.42(m,4H),1.34–0.99(m,25H),0.94–0.91(m,7H);MS(ESI)m/z calcd.for C50H79ClN6O141022.5,found[M+H]+1024.0.
4''-O-[1-(3-氯-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P13)
White solid,yield86%,mp151–154°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3446,2974,2938,2878,1812,1726,1637,1517,1459,1383,1257,1168,1113,1076,1044,1015,901,835,804,753cm-1;1H NMR(600MHz,CDCl3,δppm):7.52(s,1H),7.43–7.42(d,1H,J=7.8Hz),7.33–7.31(t,1H,J=7.8Hz),7.26–7.25(t,1H),7.19–7.17(d,1H,J=7.8Hz),5.66–5.61(m,2H),5.46(s,1H),5.05(s,1H),4.88–4.86(m,1H),4.53–4.51(m,1H),4.48–4.42(m,3H),4.40(s,1H),4.36–4.32(m,2H),3.65(s,1H),3.59–3.58(m,1H),3.34–3.28(m,4H),2.86–2.81(m,2H),2.51(m,4H),2.46–2.34(m,3H),2.20(m,3H),2.07–2.00(m,3H),1.90(s,1H),1.85–1.81(m,2H),1.62–1.55(m,3H),1.44(s,3H),1.40–1.37(m,1H),1.28–1.03(m,25H),0.93–0.91(m,7H);MS(ESI)m/z calcd.for C50H79ClN6O141022.5,found[M+H]+1024.1.
4''-O-[1-(2-氯-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P14)
White solid,yield85%,mp145–149°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3448,2974,2938,2878,2831,2789,1813,1732,1636,1513,1460,1382,1238,1168,1112,1045,1015,901,754,481cm-1;1H NMR(600MHz,CDCl3,δppm):7.52(s,1H),7.43–7.42(d,1H,J=7.8Hz),7.33–7.31(t,1H,J=7.8Hz),7.27–7.25(t,1H,J=7.8Hz),7.20–7.17(d,1H,J=7.8Hz),5.66–5.61(m,2H),5.45(s,1H),5.04(s,1H),4.88–4.86(m,1H),4.53–4.51(m,1H),4.48–4.44(m,3H),4.40(s,1H),4.35–4.30(m,2H),3.66–3.63(m,1H),3.59–3.58(m,1H),3.34–3.31(m,1H),3.28(m,3H),2.86–2.81(m,2H),2.51–2.34(m,7H),2.20(m,3H),2.18–2.00(m,2H),1.91(s,2H),1.85–1.81(m,1H),1.63–1.55(m,3H),1.44(m,3H),1.41–1.30(m,2H),1.28–1.24(m,5H),1.21–1.90(m,3H),1.13–1.03(m,15H),0.93–0.91(m,7H);MS(ESI)m/z calcd.for C50H79ClN6O141022.5,found[M+H]+1024.0.
4''-O-[1-环己基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯(P15)
White solid,yield77%,mp144–147°C,TLC Rf=0.44(DCM/MeOH,10:1);IR(KBr):3443,2973,2938,2863,1813,1726,1634,1513,1456,1382,1238,1168,1122,1045,1015,899,774,477cm-1;1H NMR(600MHz,CDCl3,δppm):7.55(s,1H),5.05(s,1H),4.89–4.87(m,1H),4.57–4.32(m,7H),3.72–3.70(m,1H),3.61–3.59(m,1H),3.33–3.30(m,4H),2.88–2.87(m,1H),2.82–2.80(m,1H),2.69(m,5H),2.47–2.45(m,1H),2.39–2.37(m,1H),2.13–2.18(m,5H),2.08–2.02(m,2H),1.95–1.92(m,3H),1.87–1.83(m,1H),1.79–1.59(m,7H),1.50–1.44(m,6H),1.40–1.37(m,2H),1.33–1.28(m,7H),1.23–1.27(m,9H),1.15(m,3H),1.09–1.08(m,4H),1.04–1.03(m,3H),0.95–0.90(m,7H);MS(ESI)m/z calcd.for C49H84N6O14980.6,found[M+H]+982.1.
4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q1)
White solid,yield87%,mp133–137°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3456, 2972,2936,2875,2832,2788,2734,1727,1635,1511,1460,1380,1257,1170,1044,899,838,773,641,572,479cm-1;1H NMR(600MHz,CDCl3,δppm):7.43(s,1H),7.26–7.23(t,1H,J=7.8Hz),7.26–7.15(d,1H,J=7.8Hz),7.06–7.03(m,2H),5.48–5.43(m,2H),5.36(s,1H),5.02(s,1H),4.47–4.65(m,1H),4.54–4.48(m,2H),4.44–4.43(m,2H),4.40–4.29(m,1H),4.27–4.26(m,1H),3.67–3.57(m,3H),3.35–3.22(m,6H),2.86–2.84(m,1H),2.72–2.71(m,1H),2.57(m,1H),2.53–2.51(m,1H),2.49–2.47(m,1H),2.39–2.33(m,13H),2.10–2.06(m,1H),2.00–1.98(m,2H),1.89–1.86(m,1H),1.79–1.58(m,4H),1.52–1.47(m,1H),1.31-0.88(m,33H);MS(ESI)m/z calcd.for C50H84N6O13976.6,found[M+H]+978.0.
4''-O-[1-(2-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q2)
White solid,yield86%,mp136–140°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3447,2973,2937,2877,2832,2787,1814,1726,1642,1513,1462,1383,1256,1170,1044,900,744,480cm-1;1H NMR(600MHz,CDCl3,δppm):7.30–7.28(m,2H),7.22–7.20(m,2H),7.14–7.12(m,1H),5.54–5.50(m,2H),5.33(s,1H),5.10(s,1H),4.70(m,1H),4.54–4.54(m,1H),4.50–4.48(m,1H),4.43–4.42(m,2H),4.30(m,1H),4.25(s,1H),3.72–3.61(m,4H),3.31–3.28(m,5H),2.84–2.20(m,17H),2.09–1.91(m,3H),1.90–1.87(m,2H),1.75–1.73(m,2H),1.61–1.58(m,1H),1.49–1.45(m,1H),1.30–1.88(m,33H);MS(ESI)m/z calcd.for C50H84N6O13976.6,found[M+H] +978.4.
4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q3)
White solid,yield86%,mp132–145°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3456,2973,2937,2877,2831,2789,1814,1727,1639,1517,1459,1381,1257,1169,1045,900,838,792,572,478cm-1;1H NMR(600MHz,CDCl3,δppm):7.42(s,1H),7.17–7.13(m,4H),5.45–5.42(m,3H),5.00(s,1H),4.69–4.67(m,1H),4.54–4.53(m,1H),4.50–4.48(m,1H),4.44–4.42(m,2H),4.33–4.30(m,1H),4.26(m,1H),3.66–3.63(m,4H),3.31–3.24(m,5H),2.86–2.84(m,1H),2.73–2.72(m,1H),2.64–2.61(m,1H),2.52–2.18(m,14H),2.11–2.06(m,1H),2.00–1.98(m,2H),1.90–1.86(m,1H),1.78–1.58(m,4H),1.52–1.44(m,1H),1.30–0.87(m,33H);MS(ESI)m/z calcd.for C50H84N6O13976.6,found[M+H]+978.0.
4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q4)
White solid,yield79%,mp150–153°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3444,2973,2936,2875,2789,1810,1725,1636,1526,1460,1382,1348,1256,1170,1111,1075,1043,1016,900,859,799,732,468cm-1;1H NMR(600MHz,CDCl3,δppm):8.22-8.21(d,2H,J=7.2Hz),7.59(s,1H),7.44–7.39(m,2H),5.65–5.61(m,2H),5.49(s,1H),5.09(s,1H),4.71–4.69(m,1H),4.51–4.43(m,4H),4.35–4.33(m,1H),4.25(m,1H),3.68–3.60(m,4H),3.34–3.28(m,5H),2.79–2.77(m,1H),2.72–2.71(m,1H),2.64(m,1H),2.53–2.51(m,1H),2.38–2.31(m,10H),2.10–2.05(m,1H),1.99–1.98(m,2H),1.90–1.87(m,1H),1.78–1.55(m,4H),1.50–1.43(m,1H),1.39–0.86(m,33H);MS(ESI)m/z calcd.for C49H81N7O151007.6,found[M+H]+1009.0.
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素(Q5)
White solid,yield83%,mp124–128°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3447,2973,2937,2877,2832,2789,1812,1726,1633,1500,1458,1381,1257,1169,1046,901,838,796,724,467cm-1;1H NMR(600MHz,CDCl3,δppm):7.42(s,1H),7.35–7.34(m,3H),7.26–7.22(m,2H),5.48(m,2H),5.27(s,1H),5.10(s,1H),4.67–4.66(m,1H),4.52-4.46(m,2H),4.42–4.41(m,2H),4.32–4.29(m,1H),4.24(m,1H),3.66–3.59(m,3H),3.32–3.20(m,6H),2.84(m,1H),2.77–2.75(m,1H),2.69–2.68(m,1H),2.50–2.49(m,2H),2.36–2.31(m,9H),2.07–2.02(m,1H),1.98(m,2H),1.89–1.86(m,1H),1.77–1.71(m,2H),1.61–1.56(m,2H),1.48–1.45(m,1H),1.29–0.86(m,33H);MS(ESI)m/z calcd.for C49H82N6O13962.6,found[M+H]+963.8.
4''-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q6)
White solid,yield87%,mp145–147°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3448,2973,2936,2876,2788,1813,1726,1636,1512,1459,1382,1255,1169,1045,900,767,477cm-1; 1H NMR(600MHz,CDCl3,δppm):7.45(s,1H),7.43–7.40(d,2H,J=8.4Hz),7.31(m,1H),5.86–5.81(m,2H),4.68–4.24(m,7H),3.67–3.54(m,3H),3.38–3.27(m,6H),2.86–2.20(m,14H),2.05–1.99(m,3H),1.90–1.58(m,5H),1.49–1.44(m,1H),1.28–0.84(m,33H);MS(ESI)m/z calcd.for C49H80Cl2N6O131032.5,found[M+H]+1034.0.
4''-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q7)
White solid,yield89%,mp150–153°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3424,2974,2937,2878,2831,1726,1636,1592,1517,1464,1384,1257,1170,1121,1077,1047,1015,900,838,793,468cm-1;1H NMR(600MHz,CDCl3,δppm):7.56(s,1H),7.45(s,1H),7.25(m,1H),7.13–7.12(d,1H,J=8.4Hz),5.60(m,2H),5.02(s,1H),4.70(m,1H),4.54–4.54(m,1H),4.50–4.48(m,1H),4.43–4.42(m,2H),4.30(m,1H),4.25(s,1H),3.72–3.61(m,4H),3.31–3.28(m,5H),2.84–2.20(m,17H),2.09–1.91(m,3H),1.90–1.87(m,2H),1.75–1.73(m,2H),1.61–1.58(m,1H),1.49–1.45(m,1H),1.30-1.88(m,33H);MS(ESI)m/z calcd.for C49H80Cl2N6O131032.5,found[M+H]+1033.8.
4''-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q8)
White solid,yield82%,mp142–145°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3448,2972,2935,2874,2787,1811,1723,1636,1494,1458,1382,1257,1169,1092,1046,1016,959,900,807,641,571,481cm-1;1H NMR(600MHz,CDCl3,δppm):7.47(s,1H),7.34–7.30(m,2H),7.22–7.18(m,2H),5.51–5.45(m,2H),5.34(s,1H),5.10(s,1H),4.65–4.64(m,1H),4.50–4.40(m,4H),4.36–4.35(m,1H),4.28(m,1H),3.67–3.60(m,4H),3.36–3.20(m,5H),2.78(m,1H),2.67(m,1H),2.52–2.47(m,1H),2.38–2.35(m,1H),2.30–2.20(m,10H),2.07–2.03(m,1H),1.98–1.97(m,2H),1.90–1.86(m,1H),1.78–1.67(m,3H),1.57–1.55(m,1H),1.49–1.45(m,1H),1.34–0.85(m,33H);MS(ESI)m/z calcd.for C49H81ClN6O13996.6,found[M+H]+998.0.
4''-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q9)
White solid,yield81%,mp140–143°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3442,2974,2937,2878,2832,1812,1725,1638,1517,1461,1383,1257,1170,1122,1076,1041,1015,900,753,481cm-1;1H NMR(600MHz,CDCl3,δppm):7.53(s,1H),7.43–7.42(d,1H,J=7.8Hz),7.34–7.31(t,1H,J=8.4Hz),7.28–7.25(t,1H),7.19–7.18(d,1H,J=7.8Hz),5.64–5.63(m,3H),5.09(s,1H),4.61–4.60(m,1H),4.53–4.43(m,4H),4.24–4.11(m,2H),3.78–3.51(m,4H),3.31–3.27(m,5H),2.96–2.20(m,14H),2.10–1.39(m,9H),1.32–0.89(m,33H);MS(ESI)m/z calcd.for C49H81ClN6O13996.6,found[M+H]+998.0.
4''-O-[1-(2-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素(Q10)
White solid,yield84%,mp138–141°C,TLC Rf=0.30(DCM/MeOH,10:1);IR(KBr):3448,2973,2936,2877,2832,1813,1727,1633,1513,1458,1381,1257,1170,1075,1042,1015,900,838,753,480cm-1;1H NMR(600MHz,CDCl3,δppm):7.55(s,1H),7.45–7.44(d,1H,J=7.2Hz),7.35–7.32(m,1H),7.29–7.26(m,1H),7.20–7.19(d,1H,J=7.2Hz),5.65(m,2H),5.48(s,1H),5.07(s,1H),4.70(m,1H),4.56–4.55(m,1H),4.53–4.50(m,1H),4.47–4.46(m,2H),4.33–4.30(m,1H),4.26–4.25(m,1H),3.70–3.63(m,3H),3.33–3.28(m,6H),2.83–2.81(m,1H),2.75–2.74(m,1H),2.69(m,1H),2.54–2.37(m,11H),2.14–2.10(m,1H),2.00(m,2H),1.91–1.88(m,1H),1.82–1.76(m,2H),1.69–1.60(m,2H),1.52–1.47(m,1H),1.35–0.89(m,33H);MS(ESI)m/z calcd.for C49H81ClN6O13996.6,found[M+H]+998.0.
4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素(R1)
White solid,yield72%,mp143–145°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3447, 2974,2934,2875,2852,2788,1725,1643,1529,1456,1383,1254,1169,1038,1016,746,698cm-1;1H NMR(600MHz,CDCl3,δppm):7.41–7.39(m,1H),7.34–7.29(m,4H),7.25–7.22(m,1H),7.15–7.14(d,1H,J=7.2Hz),7.04–7.01(m,2H),5,47–5,43(m,2H),5.39–5.33(m,1H),5.00–4.98(d,1H),4.91(m,1H),4.60(m,1H),4.49–4.26(m,7H),4.10–4.05(m,1H),3.6(m,1H),3.51(m,1H),3.26–3.19(m,6H),2.60(m,2H),2.34–2.14(m,15H),2.00(m,2H),1.88(m,2H),1.75–1.70(m,1H),1.57–1.41(m,4H),1.31-0.86(m,33H);MS(ESI)m/z calcd.for C58H91N7O141109.7,found[M+H]+1111.1.
4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素(R2)
White solid,yield75%,mp148–151°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3445,2975,2937,2878,2832,2789,1811,1727,1635,1518,1457,1383,1256,1169,1122,1046,1017,898,756,700,478cm-1;1H NMR(600MHz,CDCl3,δppm):7.39(s,1H),7.35–7.34(m,2H),7.31–7.30(m,3H),7.18–7.14(m,4H),5.45(m,3H),4.99–4.94(m,2H),4.67(m,1H),4.43–4.17(m,8H),3,65(m,1H),3.53(m,1H),2.96–2.60(m,17H),1.99–1.87(m,4H),1.61–1.45(m,5H),1.24–0.88(m,33H);MS(ESI)m/z calcd.for C58H91N7O141109.7,found[M+H]+1110.9.
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-苄基氨甲酰基-阿奇霉素(R3)
White solid,yield75%,mp152–155°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3416,3064,3032,2975,2937,2878,2832,1725,1641,1526,1458,1382,1258,1169,1123,1077,1042,1016,898,700cm-1;1H NMR(600MHz,CDCl3,δppm):7.35(m,6H),7.31(m,2H),7.25(m,3H),5.50(m,3H),4.99–4,93(m,2H),4.44–4.08(m,9H),3,65–3.54(m,2H),3.24(m,6H),3.09–2.20(m,14H),1.87–1.71(m,4H),1.59–1.40(m,5H),1.36–0.89(m,33H);MS(ESI)m/z calcd.for C57H89N7O141095.7,found[M+H]+1097.1.
4''-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素(R4)
White solid,yield81%,mp145–148°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3446,2975,2938,2877,2832,2788,1813,1727,1637,1582,1520,1457,1383,1256,1168,1111,1091,1045,1016,899,766,700cm-1;1H NMR(600MHz,CDCl3,δppm):7.44(s,1H),7.41–7.39(m,2H),7.36–7.28(m,6H),5.83(m,2H),5.39(m,1H),5.01(d,1H),4.93(m,1H),4.54–4.39(m,6H),4.35–4.29(m,3H),3.70–3.57(m,1H),3.53–3.52(m,1H),3.38-3.21(m,6H),2.62(m,1H),2.46–2.42(m,6H),2.36–2.21(m,7H),2.04–2.01(m,2H),1.89(m,2H),1.61–1.49(m,4H),1.44(m,1H),1.33–0.82(m,33H);MS(ESI)m/z calcd.for C57H87Cl2N7O141163.6,found[M+H]+1165.1.
4''-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素(R5)
White solid,yield77%,mp150–152°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3437,2972,2931,2874,2854,2099,1813,1727,1607,1526,1458,1383,1256,1169,1046,899,837,745,699,468cm-1;1H NMR(600MHz,CDCl3,δppm):7.52(s,1H),7.45(d,1H,J=7.8Hz),7.36–7.34(m,2H),7.32–7.30(m,2H),7.29–7.28(m,1H),7.26–7.24(m,1H),7.13–7.11(m,1H),5.60(s,2H),5.50(m,1H),5.01–5.00(d,1H),4.94(m,1H),4.66(m,1H),4.52–4.41(m,5H),4.35–4.27(m,3H),3.63(m,1H),3.53(m,1H),3.40–3.38(m,1H),3.27–3.22(m,5H),2.61–2.44(m,6H),2.37–2.20(m,8H),2.01(m,2H),1.88(m,2H),1.64–1.60(m,3H),1.52–1.49(m,2H),1.30–0.84(m,33H);MS(ESI)m/z calcd.for C57H87Cl2N7O141163.6,found[M+H]+1164.9.
4''-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素(R6)
White solid,yield82%,mp143–146°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3447, 2975,2938,1811,1723,1641,1496,1458,1383,1254,1168,1120,1045,1016cm-1;1H NMR(600MHz,CDCl3,δppm):7,44(s,1H),7.36–7.31(m,6H),7.28–7.26(m,1H),7.19–7.18(m,2H),5.50–5.44(m,3H),5.01–5.00(m,1H),4.95–4.94(m,1H),4,62(m,1H),4.49–4.29(m,8H),3.61(m,1H),3.53(m,1H),3.35–3.20(m,6H),2.77(m,1H),2.63(s,1H),2,46(m,5H),2.35–2.18(m,6H),2.01–1.98(m,2H),1.90(m,2H),1.59–1.44(m,3H),1.37–1.24(m,3H),1.23–0.80(m,33H);MS(ESI)m/z calcd.for C57H88ClN7O141129.6,found[M+H]+1131.1.
4''-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素(R7)
White solid,yield77%,mp141–144°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3446,3065,2975,2938,2878,2831,1812,1726,1642,1515,1458,1382,1255,1168,1113,1044,752,700cm-1;1H NMR(600MHz,CDCl3,δppm):7.53–7.52(d,1H,J=6.0Hz),7.43–7.42(m,1H),7.36–7.31(m,5H),7.28–7.25(m,2H),7.18–7.17(d,1H,J=7.2Hz),5.05(m,1H),4.93–4.86(m,1H),4.63(m,1H),4.52–4.40(m,6H),4.36–4.31(m,2H),3.62–3.61(m,1H),3.58–3.52(m,1H),3.35–3.20(m,6H),2.86–2.83(m,1H),2.74(m,1H),2.63(m,1H),2.44–2.20(m,11H),2.06–2.01(m,2H),1.89–1.81(m,3H),1.62–1.50(m,3H),1.44–0.80(m,34H);MS(ESI)m/z calcd.for C57H88ClN7O141129.6,found[M+H]+1131.1.
4''-O-[1-(2-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素(R8)
White solid,yield73%,mp137–140°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3447,2973,2937,2877,1811,1726,1640,1515,1457,1383,1255,1168,1114,1045,1016,752,700cm-1;1H NMR(600MHz,CDCl3,δppm):7.51(s,1H),7.43–7.42(m,1H),7.36–7.32(m,5H),7.28–7.24(m,2H),7.18–7.17(m,1H),5.64(m,2H),5.36(s,1H),5.01(d,1H),4.93(m,1H),4.61(m,1H),4.50–4.28(m,8H),3.59–3.52(m,2H),3.26–3.18(m,6H),2.62–2.61(m,2H),2.32–2.14(m,12H),2.01(m,2H),1.90(m,2H),1.70(m,1H),1.59–1.57(m,2H),1.50–1.48(m,1H),1.37–0.81(m,34H);MS(ESI)m/z calcd.for C57H88ClN7O141129.6,found[M+H]+1131.0.
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(β-苯乙基氨甲酰基)-阿奇霉素(R9)
White solid,yield68%,mp143–147°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3445,2974,2937,2877,2832,2789,1811,1727,1607,1515,1458,1381,1254,1169,1046,700,465cm-1;1H NMR(600MHz,CDCl3,δppm):7.46(m,1H),7.38(m,2H),7.33–7.31(m,2H),7.27–7.22(m,5H),5.52(m,3H),5.10–5.00(m,2H),4.73–4.27(m,9H),3.71–3.55(m,2H),3.46–3.44(m,1H),3.37–3.24(m,4H),2.88–2.65(m,3H),2.43–2.12(m,14H),2.01–1.46(m,9H),1.33–0.88(m,33H);MS(ESI)m/z calcd.for C58H91N7O141109.7,found[M+H]+1111.1.
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(吡啶-4甲基氨甲酰基)-阿奇霉素(R10)
White solid,yield74%,mp138–141°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3448,2974,2936,2877,1811,1725,1605,1526,1460,1381,1256,1168,1123,1045,1015,724,475cm-1;1H NMR(600MHz,CDCl3,δppm):8.56(m,2H),7.42(s,1H),7.36–7.35(m,4H),7.27–7.23(m,3H),5.50–5.46(m,3H),5.00(s,1H),4.94–4.88(m,1H),4.68–4.26(m,9H),3.70–3.64(m,1H),3.58–3.55(m,1H),3.43–3.26(m,6H),2.72–2.64(m,7H),2.35–2.20(m,7H),2.04–1.94(m,4H),1.56(m,2H),1.44(m,3H),1.34–0.88(m,33H);MS(ESI)m/z calcd.for C56H88N8O141096.6,found[M+H]+1097.9
4''-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S1)
White solid,yield71%,mp132–134°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3448, 2974,2935,2875,1805,1725,1643,1513,1458,1383,1248,1170,1040,1017,420cm-1;1H NMR(600MHz,CDCl3,δppm):7.43–7.41(m,2H),7.35–7.33(m,1H),7.25–7.23(m,1H),7.17–7.15(d,1H,J=7.8Hz),7.07–7.03(m,2H),6.89–6.88(d,2H,J=7.8Hz),5.45–5.43(m,3H),5.02–5.00(m,1H),4.94–4.91(m,1H),4.47–4.21(m,9H),3.85–3.77(m,3H),3.60(m,1H),3.53(m,1H),3.34–3.21(m,6H),2.62(m,1H),2.44–2.17(m,16H),2.02(m,2H),1.89(m,3H),1.68–1.49(m,4H),1.34–0.85(m,34H);MS(ESI)m/z calcd.for C59H93N7O151139.7,found[M+H]+1141.0
4''-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S2)
White solid,yield77%,mp136–138°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3443,2973,2934,2875,2788,1811,1726,1640,1614,1514,1460,1381,1249,1172,1113,1038,834,478cm-1;1H NMR(600MHz,CDCl3,δppm):7.38(s,1H),7.25–7.23(m,2H),7.18–7.14(m,4H),6.89–6.88(m,2H),5.45–5.40(m,3H),5.01–5.00(d,1H),4.92(m,1H),4.42–4.17(m,9H),3.89–3.78(m,3H),3.61(m,1H),3.53(m,1H),3.37–3.19(m,6H),2.61(m,1H),2.45(m,4H),2.35–2.30(m,5H),2.27–2.24(m,5H),2.00(m,2H),1.88(m,3H),1.72(m,1H),1.59(m,2H),1.49(m,1H),1.26–0.87(m,33H);MS(ESI)m/z calcd.for C59H93N6O151139.7,found[M+H]+1141.0
4''-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S3)
White solid,yield73%,mp129–132°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3444,2975,2937,1722,1632,1514,1459,1384,1249,1173,1037cm-1;1H NMR(600MHz,CDCl3,δppm):7.43(s,1H),7.35(m,3H),7.24-7.23(m,4H),6.9–6.7(m,2H),5.54–5.50(m,3H),5.02–5.00n(d,1H),4.90(m,1H),4.64(m,1H),4.44–4.43(m,3H),4.37–4.11(m,5H),3.79(s,3H),3.62(m,1H),3.52(m,1H),3.40(m,1H),3.33–3.26(m,1H),3.24(m,4H),2.80(m,1H),2.59–2.52(m,7H),2.41–2.20(m,6H),2.04–2.00(m,2H),1.88(m,2H),1.73–1.51(m,5H),1.31–0.87(m,33H),MS(ESI)m/z calcd.for C58H91N7O151125.7,found[M+H]+1127.1
4''-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S4)
White solid,yield82%,mp135–138°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3449,2974,2937,2877,2834,2788,1726,1642,1614,1514,1460,1381,1248,1171,1038,898,766,479cm-1;1H NMR(600MHz,CDCl3,δppm):7.44(s,1H),7.41–7.39(m,2H),7.32–7.30(m,1H),7.25–7.23(m,2H),6.89–6.88(m,2H),5.83(m,2H),5.37(m,1H),5.02–5.00(d,1H),4.91–4.90(m,1H),4.63(m,1H),4.43–4.42(m,2H),4.40–4.32(m,5H),4.23–4.21(m,1H),3.80(s,3H),3.59(m,1H),3.53–3.52(m,1H),3.32–3.19(m,6H),2.62–2.17(m,14H),2.00(m,1H),1.88(m,2H),1.62–1.56(m,1H),1.52–1.50(m,1H),1.37–1.31(m,2H),1.30–0.83(m,35H);MS(ESI)m/z calcd.for C58H89Cl2N7O151192.6,found[M+H]+1194.9
4''-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S5)
White solid,yield86%,mp145–147°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3450,2974,2937,2877,2835,2789,1812,1727,1614,1590,1514,1461,1381,1248,1171,1040,899,836,469cm-1;1H NMR(600MHz,CDCl3,δppm):7.53(s,1H),7.46(d,1H,J=2.4),7.27–7.24(m,3H),7.13–7.12(m,1H),6.90–6.89(m,1H),5.61(m,2H),5.46(m,1H),5.02–5.01(d,1H),4.93(m,1H),4.65(m,1H),4.50–4.46(m,2H),4.43–4.35m(,4H),4.30–4.23(m,2H),3.81(s,3H),3.63(m,1H),3.54(m,1H),3.38(m,1H),3.29–3.22(m,4H),3.12–3.08(m,1H),2.61–2.17(m,14H),2.09–2.02(m,2H),1.88(m,2H),1.63–1.51(m,3H),1.45–1.40(m,2H),1.31–0.88(m,33H);MS(ESI)m/z calcd.for C58H89Cl2N7O151193.6,found[M+H]+1195.1
4''-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S6)
White solid,yield81%,mp133–135°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3445,2974,2937,2876,2835,2788,1812,1726,1640,1614,1514,1460,1383,1248,1172,1111,1036,1016,898,810,481cm-1;1H NMR(600MHz,CDCl3,δppm):7.43(s,1H),7.34–7.33(m,2H),7.25–7.23(m,2H),7.19–7.17(m,2H),6.89–6.87(m,2H),5.50–5.45(m,1H),5.39(m,1H),5.20–5.00(d,1H),4.94–4.91(m,1H),4.61(m,1H),4.47–4.42(m,2H),4.40–4.33(m,5H),4.24–4.20(m,1H),3.80(s,3H),3.59(m,1H),3.53(m,1H),3.29–3.18(m,6H),2.63–2.58(m,2H),2,31(m,7H),2.27–2.20(m,4H),2.18–2.14(m,1H),2.01–1.98(m,1H),1.89(m,2H),1.70–1.68(m,1H),1.61–1.55(m,2H),1.51–1.49(m,1H),1.35–1.31(m,2H),1.26–0.83(m,33H);MS(ESI)m/z calcd.for C58H90ClN7O151159.6,found[M+H]+1161.1
4''-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S7)
White solid,yield83%,mp137–139°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3434,2926,2854,1812,1726,1613,1514,1462,1380,1248,1171,1123,1076,1040,1017,960,899,817,753,480cm-1;1H NMR(600MHz,CDCl3,δppm):7.52(s,1H),7.45–7.42(m,1H),7.36(m,1H),7.33–7.30(m,1H),7.25–7.23(m,2H),7.18–7.17(m,1H),6.89–6.88(m,2H),5.64–5.50(m,3H),5.00(d,1H),4.93–4.91(m,1H),4.63–4.30(m,7H),4.24–4.20(m,2H),3.80(s,3H),3.68–3.60(m,1H),3.52(m,1H),3.38–3.23(m,6H),2.61–2.53(m,7H),2.37–2.21(m,7H),2.01(m,1H),1.88(m,1H),1.70(m,1H),1.60–1.58(m,2H),1.51–1.49(m,1H),1.43–0.84(m,35H);MS(ESI)m/z calcd.for C58H90ClN7O151159.6,found[M+H]+1161.1
4''-O-[1-(2-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S8)
White solid,yield79%,mp133–136°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3444,2973,2936,2875,2835,2788,1813,1727,1613,1514,1459,1382,1249,1173,1110,1038,900,834,752,567cm-1;1H NMR(600MHz,CDCl3,δppm):7.51(s,1H),7.44–7.42(m,1H),7.33–7.31(m,1H),7.26–7.23(m,3H),7.18–7.17(m,1H),6.89–6.88(m,2H),5.64(m,2H),5.39(m,1H),5.02–5.00(d,1H),4.94–4.91(m,1H),4.60(m,1H),4.45–4.44(m,2H),4.40–4.34(m,5H),4.23–4.20(m,1H),3.80(s,3H),3.59(m,1H),3.53–3.52(m,1H),3.30–3.18(m,6H),2.62–2.61(m,2H),2.33–2.29(m,8H),2.27–2.20(m,3H),2.18–2.14(m,1H),2.00(m,1H),1.90(m,2H),1.72–1.71(m,1H),1.61–1.55(m,2H),1.51–1.49(m,1H),1.36–0.84(m,35H);MS(ESI)m/z calcd.for C58H90ClN7O151159.6,found[M+H]+1161.1
4''-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素(S9)
White solid,yield79%,mp133–136°C,TLC Rf=0.21(DCM/MeOH,5:1);IR(KBr):3434,2974,2935,2878,1805,1725,1641,1612,1517,1462,1383,1347,1248,1171,1122,1038,471cm-1;1H NMR(600MHz,CDCl3,δppm):8.23–8.21(m,2H),7.44–7.42(m,2H),7.24–7.18(m,3H),6.89(m,2H),5.67–5.64(m,2H),5.01–4.93(m,2H),4.69–4.15(m,9H),3.96–3.90(m,1H),3.81(s,3H),3.69–3.53(m,2H),3.29–3.10(m,6H),2.97–2.06(m,14H),1.82–1.72(m,4H),1.59–1.48(m,3H),1.43–1.41(m,2H),1.30–0.87(m,33H);MS(ESI)m/z calcd.for C58H90ClN8O171170.6,found[M+H]+1172.0 。
Claims (7)
1.4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,具有通式I、II或III的结构:
其中,R1代表氢;R2代表苄基,2-甲基苄基、3-甲基苄基、4-甲基苄基、4-硝基苄基、4-溴苄基、2-氟苄基、3-氟苄基、4-氟苄基、2,6-二氯-苄基、2,4-二氯-苄基、4-氯-苄基、3-氯-苄基、2-氯-苄基或环己基;R3代表苄基、4-甲氧基苄基、β-苯乙基或吡啶-4-甲基。
2.根据权利要求1所述的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物,其特征在于,所述化合物I是下列之一:
4”-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(2-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(4-溴苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(2-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(3-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(4-氟苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(2,6-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(2,4-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(4-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(3-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-(2-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
4”-O-[1-环己基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素-11,12-环碳酸酯;
所述化合物II是下列之一:
4”-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4”-O-[1-(2-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4”-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4”-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4”-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-阿奇霉素;
4”-O-[1-(2,6-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4”-O-[1-(2,4-二氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4”-O-[1-(4-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4”-O-[1-(3-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
4”-O-[1-(2-氯-苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-阿奇霉素;
所述化合物III是下列之一:
4”-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4”-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4”-O-[1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4”-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4”-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4”-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4”-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4”-O-[1-(2-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-苄基氨甲酰基-阿奇霉素;
4”-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-β-苯乙基氨甲酰基-阿奇霉素;
4”-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(吡啶-4甲基氨甲酰基)-阿奇霉素;
4”-O-[1-(3-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4”-O-[1-(4-甲基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4”-O-(1-苄基-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基)-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4”-O-[1-(2,6-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素
4”-O-[1-(2,4-二氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4”-O-[1-(4-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4”-O-[1-(3-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4”-O-[1-(2-氯苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素;
4”-O-[1-(4-硝基苄基)-1H-1,2,3-三氮唑-4-甲基-氨基甲酰基]-11-O-(4-甲氧基苄基氨甲酰基)-阿奇霉素。
3.权利要求1或2所述的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物的制备方法,其特征在于:所述的具有通式I的化合物的制备方法,步骤如下:
(1)通式1化合物的合成参照已有方法完成,其中,R1代表氢;
(2)将上述得到的通式1的化合物与炔丙胺混合,加入溶剂,再加入催化剂,催化剂为1.8-二氮杂二环(5.4.0)十一烯-7,于0~60℃反应2~24小时,生成通式IV的化合物;
(3)上述得到的通式IV的化合物,以低级醇做溶剂,在存在或不存在有机或无机弱碱的条件下,于0~65℃反应2~24小时,脱去2′-OH上的保护基,生成通式2的化合物;
(4)将上述得到的通式2的化合物和叠氮代烷,溶于醇-水混合溶剂中,加入硫酸铜溶液和抗坏血酸钠溶液,0~50℃下搅拌2~12小时,生成通式I的化合物;所述叠氮代烷的结构为R2-N3,其中,R2代表苄基,2-甲基苄基、3-甲基苄基、4-甲基苄基、4-硝基苄基、4-溴苄基、2-氟苄基、3-氟苄基、4-氟苄基、2,6-二氯-苄基、2,4-二氯-苄基、4-氯-苄基、3-氯-苄基、2-氯-苄基或环己基;
其中,通式1化合物的结构式为:
通式IV化合物的结构式为:
通式2化合物的结构式为:
4.权利要求1或2所述的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物的制备方法,其特征在于:所述的具有通式II的化合物的制备方法,步骤如下:
(1)将通式6的化合物在无水甲苯中,在无机或有机碱存在下,与N,N-羰基二咪唑于0~100℃反应2~72小时,通式6的化合物与N,N-羰基二咪唑的摩尔比1:(1~3),生成具有通式4的化合物;通式6的化合物中,R1代表氢;
(2)将炔丙胺盐酸盐和叠氮代烷溶于醇-水混合溶剂中,加入硫酸铜溶液和抗坏血酸钠溶液,0~50℃下搅拌2~12小时,生成通式3的化合物;所述叠氮代烷的结构为R2-N3,其中,R2代表苄基,2-甲基苄基、3-甲基苄基、4-甲基苄基、4-硝基苄基、4-溴苄基、2-氟苄基、3-氟苄基、4-氟苄基、2,6-二氯-苄基、2,4-二氯-苄基、4-氯-苄基、3-氯-苄基、2-氯-苄基或环己基;
(3)将得到的通式4的化合物与通式3的化合物混合,加入溶剂中,再加入有机碱和催化剂,催化剂为1.8-二氮杂二环(5.4.0)十一烯-7,于0~60℃反应2~24小时,生成通式II的化合物;
其中,通式6化合物的结构式为:
通式4化合物的结构式为:
通式3化合物的结构式为:
5.权利要求1或2所述的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物的制备方法,其特征在于:所述的具有通式III的化合物的制备方法,步骤如下:
(1)将具有通式I结构的化合物以芳烷基伯胺溶解,在盐酸吡啶的催化下,0~60℃下反应1~5天,生成具有通式III的衍生物,所述芳烷基伯胺的结构为R3-NH2,其中,R3代表苄基、4-甲氧基苄基、β-苯乙基或吡啶-4-甲基。
6.权利要求1或2所述的4"-O-(1-芳烷基-1,2,3-三氮唑-4-甲基-氨基甲酰基)阿奇霉素衍生物在制备治疗细菌感染的药物中的应用。
7.根据权利要求6所述的应用,其特征在于:所述细菌包括:敏感型金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、大肠杆菌、铜绿假单胞菌、化脓性链球菌敏感菌、化脓性链球菌耐药菌、敏感型肺炎链球菌。
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