CN102260305B - 4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物及其中间体 - Google Patents
4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物及其中间体 Download PDFInfo
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Abstract
本发明涉及4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物及其中间体,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、R3代表脂肪烃基、取代芳香脂肪烃基或取代芳杂环脂肪烃基;n是2~8的整数。本专利所涉及的化合物的C-4″位为含有两个酰胺键的(取代苯甲酰胺基)烷基)氨基甲酸酯侧链,其通过氢键作用、π电子堆积和静电相互作用与耐药核糖体产生较含有单酰胺键的侧链更强的结合,从而使衍生物的抗耐药菌活性增强。
Description
技术领域
本发明涉及一种药物,特别涉及一种4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物及其中间体。
背景技术
大环内酯类抗生素作为一类重要的抗感染药物,因其抗菌活性好,无过敏反应,副作用小,安全性高,经过近50年的发展,已成为临床应用仅次于β-内酰胺类抗生素的第二大类抗感染药物,在临床治疗上具有重要的地位。但抗生素在临床上过于广泛的使用,且一直缺乏正确的指导,致使细菌耐药性逐年增加,使抗生素的疗效明显降低,甚至趋于无效。临床上出现了一些比较棘手的耐药菌株,如耐甲氧西林金黄色葡萄球菌(MRSA)、耐红霉素肺炎链球菌、耐青霉素肺炎链球菌以及一些多药耐药的菌株,研发抗菌活性强、抗菌谱广的新颖大环内酯抗生素对抗这些耐药菌已经迫在眉睫。
红霉素A(EMA)是第一代大环内酯类药物的代表,主要用于治疗金黄色葡萄球菌、肺炎链球菌及肺炎支原体等革兰氏阳性菌引起的呼吸道、性病、皮肤及软组织感染,尤其适用于青霉素过敏者红霉素虽然具备价格便宜、疗效确切等优点,但其对革兰氏阴性菌的活性较差,酸性条件下易发生降解,其降解产物会产生很大的胃肠道刺激,诸如此类的缺点严重限制了其在临床上的使用。针对红霉素A酸性条件下失活的缺点,对其C-6、C-8、C-9、C-11和C-12位等位点进行结构修饰产生了第二代大环内酯类抗生素,如克拉霉素(CAM)和阿奇霉素(AZM)。阿奇霉素(9-脱氧-9a-甲基-9a-氮杂-9a-高红霉素A)是对红霉素A经过肟化、贝克曼重排、甲基化及还原反应扩环得到的第一个十五元氮杂大环内酯抗生素(见美国专利US4474768;4517357)。与克拉霉素及红霉素相比,阿奇霉素的骨架结构中多了一个氮原子,使其酯水分布系数改变,具备细胞膜穿透力增强,半衰期延长,血药浓度提高等优点。此外,N-9a的引入使骨架结构的构象发生改变,与核糖体50S亚基的结合方式改变,结合力增强,从而使抗菌活性增强,尤其是对一些重要的革兰阴性杆菌如流感嗜血杆菌等具有良好的抗菌活性,弥补了大环内酯抗生素在抗革兰氏阴性菌方面的不足。但遗憾的是,其抗耐药菌活性并没有明显的改善。
4″-芳烷基氨基甲酸酯大环内酯类化合物自1998年首次被报道以来已经引起了医药研究者的广泛关注。该类化合物是在大环内酯结构中C-3位克拉定糖的C-4″位引入氨基甲酸酯侧链而得到的。研究表明:C-4″-氨基甲酸酯类衍生物的抗菌活性与酮内酯和酰内酯相似,而且不受耐药菌携带基因种类的影响。因此,C-4″-OH是非常有潜力的结构修饰位点,对此位点进行合理的结构修饰有望开发出抗耐药菌活性显著增强的大环内酯类抗生素。目前,已报道的4″-芳烷基氨基甲酸酯大环内酯衍生物(见美国专利US6025350、US20080249033;世界专利WO2004101589、WO2005108413、WO2006050941、WO2006050942、WO2006050943、WO2008014221;中国专利:CN1980945等)在抗耐药菌方面均有较好表现。但是不难发现,此类化合物的抗菌活性、药代动力学特性及毒副作用等受到其C-4″位引入的氨基甲酸酯侧链的影响较大,因此,寻找长度及末端基团适当的C-4″氨基甲酸酯侧链对研发新型大环内酯类抗菌药物至关重要。
为探索C-4″氨基甲酸酯侧链的长度及末端芳环的类型对大环内酯类的抗耐药菌活性的影响,我们研究小组已经设计合成了侧链长度(从C-4″位氧原子到末端芳环)为3个、4个、8个或9个原子的阿奇霉素衍生物,并进行了体外生物活性测试及构效关系研究。活性测定表明,C-4″氨基甲酸酯侧链的引入可以增强大环内酯类的抗耐药菌活性;更值得注意的是,含有长侧链(8个或9个原子长度)的衍生物的抗耐药肺炎链球菌的活性优于含有较短侧链(3个或4个原子长度)的衍生物。
同时,大环内酯C-11-OH的修饰也越来越受到重视,可通过醚化、酰化等反应在此位置上引入不同侧链,得到具有抗耐药菌活性的大环内酯衍生物。已报道的11-氨基甲酸酯大环内酯类化合物的抗耐药菌活性明显增强,如11-氨基甲酸酯阿奇霉素衍生物(见美国专利US6043227及中国专利ZL200810238167.6)。
C-4″位和C-11位是大环内酯十分有潜力的修饰位点,在这两个位点同时引入氨基甲酸酯侧链是研发抗耐药菌大环内酯抗生素的有效方法。本课题小组的专利ZL200810238167.6报道了一系列在C-4″、C-11位同时引入氨基甲酸酯侧链的阿奇霉素衍生物。这些衍生物的C-4″位的氨基甲酸酯侧链长度为3个或4个原子,活性最好的化合物的抗erm基因、mef基因或erm+mef基因介导的耐药菌株的活性分别是阿奇霉素的512倍、64倍或128倍。因此对C-4″位和C-11位两个位点进行修饰,有望研发出抗耐药菌活性增强的大环内酯类衍生物。
发明内容
本发明的目的是提供一种4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物及其中间体,该种衍生物抗耐药菌活性大大增强。
本发明采取的技术方案如下:
4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物,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、R3代表脂肪烃基、取代芳香脂肪烃基或取代芳杂环脂肪烃基(优选取代苄基或取代苯乙基);n是0~8的整数。
进一步优选的,R2是4-甲氧基苄基、2-甲氧基苄基、4-氯苄基、4-甲基苄基、3,4-二甲氧基苄基或3,5-二硝基苄基;R3是苄基、4-甲氧基苄基、3,4-二甲基苄基、4-氟苄基、3,4-二氟苄基、苯乙基、4-甲氧基苯乙基、4-氟苯乙基或2-氯苯乙基;n=0、2或4。
优选的,上述化合物(Ⅰ)是下列之一:
1)2′-O-乙酰基-4″-O-酰肼基-阿奇霉素11,12-环碳酸酯
2)2′-O-乙酰基-4″-O-((氨基)乙基)氨基甲酰基-阿奇霉素11,12-环碳酸酯
3)2′-O-乙酰基-4″-O-((氨基)正丁基)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)4″-O-(2-甲氧基苯甲酰胺基)氨基甲酰基阿奇霉素11,12-环碳酸酯
5)4″-O-((4-氯苯甲酰胺基)氨基甲酰基阿奇霉素11,12-环碳酸酯
6)4″-O-((4-甲氧基苯甲酰胺基)乙基)氨基甲酰基阿奇霉素11,12-环碳酸酯
7)4″-O-((3,4-二甲氧基苯甲酰胺基)乙基)氨基甲酰基阿奇霉素11,12-环碳酸酯
8)4″-O-((3,5-二硝基苯甲酰胺基)乙基)氨基甲酰基阿奇霉素11,12-环碳酸酯
9)4″-O-((4-甲氧基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯
10)4″-O-((2-甲氧基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯
11)4″-O-((3,4-二甲氧基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯
12)4″-O-((3,5-二硝基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯。
优选的,上述化合物(Ⅲ)是下列之一:
13)11-O-(苄基氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
14)11-O-((4-甲氧基苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
15)11-O-((3,4-二甲基苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
16)11-O-((4-氟苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
17)11-O-((3,4-二氟苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
18)11-O-(苯乙基氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
19)11-O-((4-甲氧基)苯乙基氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
20)11-O-((4-氟苯乙基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
21)11-O-((2-氯苯乙基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
22)11-O-(苯乙基氨基甲酰基)-4″-O-((2-甲氧基苯甲酰胺基)氨基甲酰基)阿奇霉素
23)11-O-(苯乙基氨基甲酰基)-4″-O-((4-氯苯甲酰胺基)氨基甲酰基)阿奇霉素
24)11-O-(苯乙基氨基甲酰基)-4″-O-((4-甲基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素
25)11-O-(苯乙基氨基甲酰基)-4″-O-(((3,4-二甲氧基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素
26)11-O-(苯乙基氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素
27)11-O-(苯乙基氨基甲酰基)-4″-O-(((2-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
28)11-O-(苯乙基氨基甲酰基)-4″-O-(((3,4-二甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
29)11-O-((3,4-二氟苄基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
30)11-O-((4-甲氧基苯乙基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
31)11-O-((2-氯苯乙基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素。
4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物制备所用的中间体:
第一中间体具有如下通式(Ⅳ)的结构:其中R1代表乙酰基或苯甲酰基。
第二中间体具有如下通式(Ⅴ)的结构:其中R1代表乙酰基或苯甲酰基。
所述的4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物的制备方法(合成路线见图1),步骤如下:
(1)将阿奇霉素的2′-位上的-OH酰化保护,在无机或有机碱类存在下,以丙酮、乙酸乙酯、四氢呋喃或二氯甲烷作为溶剂,将阿奇霉素加入酰化试剂,在0~40℃的温度下反应3~24h,生成具有上述通式(Ⅳ)的化合物,阿奇霉素与酰化试剂的摩尔比1:1~5;阿奇霉素与溶剂的比例优选1mmol:10mL;
(2)将通式(Ⅳ)的化合物在惰性溶剂中,在无机或有机碱存在下,与N,N-羰基二咪唑(CDI)于0~110℃反应2~72h,生成具有通式(Ⅴ)的化合物,通式(Ⅳ)的化合物与N,N'-羰基二咪唑(CDI)的摩尔比1:1~6;
(3)a)将得到的通式(Ⅴ)的化合物与二胺试剂,在反应溶剂中加催化剂反应,催化剂为1.8-二氮杂二环(5.4.0)十一烯-7(DBU),于0~65℃反应2~24h,生成通式(Ⅰ)的化合物;
或者b)将得到的通式(Ⅴ)的化合物按a)所述的反应得到通式(Ⅰ)的化合物,将通式(Ⅰ)的化合物与取代苯甲酸,加催化剂在四氢呋喃中于-10~25℃反应6~12h,生成通式(Ⅱ)的化合物,所述的催化剂为二环己基碳二亚胺(DCC)和1-羟基苯并三氮唑(HOBt)按照1:1比例的混合物;
或者c)将得到的通式(Ⅴ)的化合物按照b)所述的步骤得到R1为乙酰基或苯甲酰基的通式(Ⅱ)的化合物,将R1为乙酰基或苯甲酰基的通式(Ⅱ)的化合物在低级醇类溶剂中醇解脱去2′-位上的酰基,并在有机碱催化下与取代芳香胺反应,于25~45℃反应48~72h,生成通式(Ⅲ)的化合物。
上述步骤(1)中:酰化试剂用醋酐、醋酸,乙酰氯,苯甲酸酐、苯甲酸或苯甲酰氯,阿奇霉素与酰化试剂的摩尔比优选1:3。
上述步骤(1)中:优选的酰化试剂是乙酸酐。
上述步骤(1)中:所述的无机或有机碱选自碳酸氢钠、碳酸钠、碳酸钾、三乙胺、吡啶或4-二甲氨基吡啶,优选三乙胺;无机或有机碱与阿奇霉素的摩尔比优选8:1。
上述步骤(1)中:优选的溶剂是二氯甲烷。
上述步骤(1)中:优选在25℃条件下进行反应3~24h。
优选的,上述步骤(1)反应之后进行如下处理:在碱介质中,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;或者萃取之后,再通过丙酮-水重结晶或使用15:1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0.52(二氯甲烷:甲醇=10:1)的通式(Ⅳ)的化合物。
上述步骤(2)中:通式(Ⅳ)的化合物与N,N'-羰基二咪唑(CDI)的摩尔比优选1:4,通过丙酮-水重结晶或使用15:1的二氯甲烷-甲醇系统的硅胶柱层析进行纯化,可以产生纯度90%以上的Rf值为0.61(二氯甲烷:甲醇=10:1)的通式(Ⅳ)的化合物;
上述步骤(2)中:优选在55℃条件下反应48h,可产生90%以上的通式(V)的化合物。
上述步骤(2)中:惰性溶剂选自二氯甲烷、四氢呋喃或甲苯,优选甲苯。通式(Ⅳ)的化合物与惰性溶剂的用量比为1mmol:10mL。
上述步骤(2)中:所述的无机或有机碱选自碳酸氢钠、碳酸钠、碳酸钾、三乙胺、吡啶或4-二甲氨基吡啶,优选三乙胺;无机或有机碱与通式(Ⅳ)的化合物的摩尔比优选3:1。
上述步骤(3)中:
a)所述的二胺试剂为水合肼(85%,wt%)或乙二胺或1,4-丁二胺盐酸盐;反应溶剂为N,N-二甲基甲酰胺、四氢呋喃、乙腈、或乙腈-水,优选N,N-二甲基甲酰胺;通式(Ⅴ)的化合物与二胺试剂的摩尔比优选1:1~1.5;通式(Ⅴ)的化合物与催化剂的摩尔比优选1:1.5;通式(Ⅴ)的化合物与反应溶剂的用量比优选1mmol:10mL。
b)所述的通式(Ⅰ)的化合物与取代苯甲酸的摩尔比优选1:1.2;取代苯甲酸与催化剂DCC摩尔比优选1:1.1;取代苯甲酸与催化剂HOBt摩尔比优选1:1.1;通式(Ⅰ)的化合物与溶剂THF的用量比例优选1mmol:10mL。
步骤b)中:反应温度及时间优选-8℃反应2h后25℃反应6h。
上述步骤c)中:低级醇优选甲醇,反应温度为55℃,反应时间为24h;通式(Ⅱ)的化合物与取代芳香胺用量比优选1mmol:4~5mL;通式(Ⅱ)的化合物与有机碱的摩尔比优选1:2。
上述步骤c)中:反应催化剂有机碱优选吡啶盐酸盐。
一种药物组合物,包含有治疗量的上述4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物或其药学上可接受的盐。
本发明在阿奇霉素C-4″位上引入侧链长度为4个、6个或8个原子的双酰胺侧链的同时,在C-11位引入了末端基团变化更为丰富的氨基甲酸酯侧链。本专利所涉及的化合物的C-4″位为含有两个酰胺键的(取代苯甲酰胺基)烷基)氨基甲酸酯侧链,其通过氢键作用、π电子堆积和静电相互作用与耐药核糖体产生较含有单酰胺键的侧链更强的结合,从而使衍生物的抗耐药菌活性增强。同时,本专利的C-4″位侧链更长,有望到达氯霉素或克林霉素的结合位点(肽酰转移酶中心的A位和P位)并与之产生有效结合,增强抗菌活性。活性测试结果表明,本专利所涉及的4″,11-二氨基甲酸酯阿奇霉素衍生物的活性高于中国专利ZL200810238167.6中衍生物的活性,特别是抗mef基因介导的外排泵耐药肺炎链球菌A22072的活性。
1)所有活性最好的化合物抗erm基因介导的甲基化耐药肺炎链球菌B1的活性(MIC=0.25μg/mL)是对照药物AZM的512倍;
2)活性最好的化合物抗mef基因介导的外排泵耐药肺炎链球菌A22072的活性(MIC=0.03μg/mL)是对照药物AZM的128倍;
3)活性最好的化合物抗erm+mef基因介导的混合型耐药菌AB11的活性(MIC=2μg/mL)是对照药物AZM的128倍。
4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物的抗菌活性
4″-((取代苯甲酰基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物主要用于抗细菌感染的用途。
采用试管二倍稀释法测定了部分目标化合物对敏感金黄色葡萄球菌ATCC25923、耐药金黄色葡萄球菌29213、敏感肺炎链球菌ATCC49619、MLSB型耐药肺炎链球菌B1(erm)、M型耐药肺炎链球菌A22072(mef)、混合型耐药肺炎链球菌(erm+mef)的体外抗菌活性。测定结果见表1:
表14″-((取代苯甲酰基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物与现有主要大环内酯抗生素的抗菌活性MIC值(μg/mL)
其中,1~31依次代表的化合物:
1)2′-O-乙酰基-4″-O-酰肼基-阿奇霉素11,12-环碳酸酯
2)2′-O-乙酰基-4″-O-((氨基)乙基)氨基甲酰基-阿奇霉素11,12-环碳酸酯
3)2′-O-乙酰基-4″-O-((氨基)正丁基)氨基甲酰基-阿奇霉素11,12-环碳酸酯。
4)4″-O-(2-甲氧基苯甲酰胺基)氨基甲酰基阿奇霉素11,12-环碳酸酯
5)4″-O-((4-氯苯甲酰胺基)氨基甲酰基阿奇霉素11,12-环碳酸酯
6)4″-O-((4-甲氧基苯甲酰胺基)乙基)氨基甲酰基阿奇霉素11,12-环碳酸酯
7)4″-O-((3,4-二甲氧基苯甲酰胺基)乙基)氨基甲酰基阿奇霉素11,12-环碳酸酯
8)4″-O-((3,5-二硝基苯甲酰胺基)乙基)氨基甲酰基阿奇霉素11,12-环碳酸酯
9)4″-O-((4-甲氧基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯
10)4″-O-((2-甲氧基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯
11)4″-O-((3,4-二甲氧基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯
12)4″-O-((3,5-二硝基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯
13)11-O-(苄基氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
14)11-O-((4-甲氧基苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
15)11-O-((3,4-二甲基苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
16)11-O-((4-氟苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
17)11-O-((3,4-二氟苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
18)11-O-(苯乙基氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
19)11-O-((4-甲氧基)苯乙基氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
20)11-O-((4-氟苯乙基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
21)11-O-((2-氯苯乙基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
22)11-O-(苯乙基氨基甲酰基)-4″-O-((2-甲氧基苯甲酰胺基)氨基甲酰基)阿奇霉素
23)11-O-(苯乙基氨基甲酰基)-4″-O-((4-氯苯甲酰胺基)氨基甲酰基)阿奇霉素
24)11-O-(苯乙基氨基甲酰基)-4″-O-((4-甲基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素
25)11-O-(苯乙基氨基甲酰基)-4″-O-(((3,4-二甲氧基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素
26)11-O-(苯乙基氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素
27)11-O-(苯乙基氨基甲酰基)-4″-O-(((2-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
28)11-O-(苯乙基氨基甲酰基)-4″-O-(((3,4-二甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
29)11-O-((3,4-二氟苄基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
30)11-O-((4-甲氧基苯乙基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
31)11-O-((2-氯苯乙基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素
由表1可知:所列的目标化合物4~31对敏感肺炎链球菌表现出较强的抗菌活性;与对照药物红霉素、克拉霉素、阿奇霉素相比,所列的目标化合物4~31中的大部分化合物对不同耐药基因(erm或mef基因)介导的耐药肺炎链球菌表现出明显增强的抑制活性。
附图说明
图1为本发明4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物的合成路线图。
具体实施方式
术语解释:
CDI:N,N'-羰基二咪唑。
DBU:1.8-二氮杂二环(5.4.0)十一烯-7。
DMF:N,N-二甲基甲酰胺。
(BOC)2O:二碳酸二叔丁酯。
HOBt:N-羟基苯并三氮唑。
DCC:N,N'-二环己基碳化二亚胺。
THF:四氢呋喃。
下面结合实施例对本发明做进一步的说明,但不限于此。
实施例1.
2′-O-乙酰基-阿奇霉素(Ⅳ)的制备
将阿奇霉素(2.0g,2.67mmol)溶解在无水二氯甲烷(20mL)中,加入醋酐(0.70mL,7.38mmol)以及三乙胺(3.00mL,21.65mmol),室温搅拌12h。反应完毕后,加入5%碳酸氢钠溶液(20mL),二氯甲烷提取(10mL×3)。合并的有机相经饱和食盐水洗,无水硫酸钠干燥,过滤,减压蒸干,得白色泡沫状固体(2.02g),收率95.6%,熔点167~170℃,Rf为0.52(展开剂为二氯甲烷–甲醇,10:1)。
实施例2.
4″-O-(1-H-咪唑-1-羰基)-2′-O-乙酰基-阿奇霉素(Ⅴ)的制备
将2′-O-乙酰基-阿奇霉素(1.50g,1.90mmol)溶解于无水甲苯(20mL)中,加入CDI(1.34g,7.60mmol)和三乙胺(0.80mL,5.70mmol),55℃加热搅拌48h。反应完毕后,将反应体系中的甲苯减压蒸干,残留物用二氯甲烷(20mL)溶解,加入5%碳酸氢钠溶液(20mL),二氯甲烷提取(20mL×2)。合并的有机相经饱和食盐水(20mL)洗,无水硫酸钠干燥,过滤,减压蒸干,得白色泡固体1.50g,收率86.6%。熔点117~120℃,Rf为0.61(展开剂为二氯甲烷–甲醇,10:1)。
实施例3.
a):2′-O-乙酰基-4″-O-酰肼基-阿奇霉素11,12-环碳酸酯(目标化合物1)的制备
将2′-O-乙酰基-4"-O-(1-H-咪唑-1-羰基)-阿奇霉素11,12-环碳酸酯(0.5g,0.55mmol)溶解于N,N-二甲基甲酰胺(DMF)(5mL)中,加入水合肼(85%)(0.04mL,0.66mmol)和DBU(0.11mL,0.75mmol),室温搅拌4h。反应完毕后,加入水(10mL),5%碳酸氢钠溶液(10mL),乙酸乙酯(10mL×3)萃取,合并有机层,饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色固体,Rf为0.57(展开剂为二氯甲烷–甲醇,10:1)。
b):2′-O-乙酰基-4″-O-((氨基)乙基)氨基甲酰基-阿奇霉素11,12-环碳酸酯(目标化合物2)的制备
将2′-O-乙酰基-4″-O-(1-H-咪唑-1-羰基)-阿奇霉素11,12-环碳酸酯(0.5g,0.55mmol)溶解于N,N-二甲基甲酰胺(DMF)(5mL)中,加入乙二胺(0.05mL,0.75mmol)和DBU(0.11mL,0.75mmol),室温搅拌4h。反应完毕后,加入水(10mL),5%碳酸氢钠溶液(10mL),乙酸乙酯(10mL×3)萃取,合并有机层,饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色固体,Rf为0.30(展开剂为二氯甲烷–甲醇,10:1)。
c):2′-O-乙酰基-4″-O-((氨基)正丁基)氨基甲酰基-阿奇霉素11,12-环碳酸酯(目标化合物3)的制备
将2′-O-乙酰基-4″-O-(1-H-咪唑-1-羰基)-阿奇霉素11,12-环碳酸酯(0.5g,0.55mmol)溶解于N,N-二甲基甲酰胺(DMF)(5mL)中,加入1,4-丁二胺盐酸盐(0.09g,0.72mmol)、三乙胺(0.10mL,1.44mmol)和DBU(0.11mL,0.75mmol),室温搅拌4h。反应完毕后,加入水(10mL),5%碳酸氢钠溶液(10mL),乙酸乙酯(10mL×3)萃取,合并有机层,饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色固体,Rf为0.25(展开剂为二氯甲烷–甲醇,10:1)。
实施例4.
4″-O-((取代苯甲酰胺基)烷基)氨基甲酰基阿奇霉素11,12-环碳酸酯
a)将2-甲氧基苯甲酸(0.09g,0.60mmol)及HOBt(0.09g,0.66mmol)加入至适量THF(10mL)中,冰水浴条件下搅拌,滴加DCC(1.36g,0.66mmol)的THF(5mL)溶液,保持0℃,搅拌6h。滴加化合物1(0.44g,0.50mmol)的THF(5mL)溶液,室温搅拌2h。反应完毕后,将THF减压蒸干,加入适量的乙酸乙酯(20mL),室温搅拌约2h,过滤取滤液。在滤液中加入适量5%碳酸氢钠溶液(20mL),分液,取有机相,乙酸乙酯(10mL×3)萃取,合并有机层,饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色固体。将此白色固体(0.5mmol)溶解于甲醇(10mL)中,55℃搅拌12h,减压蒸干得白色泡沫状固体。硅胶柱层析(洗脱剂为二氯甲烷–甲醇,30:1),得白色泡沫状固体,即为化合物4。收率85.9%,mp147–148℃,TLC Rf=0.50(methanol/dichlormethane,1:10);IR(KBr):3404,2973,2938,2880,1812,1739,1679,1601,1481,1465,1381,1353,1297,1277,1236,1166,1110,1073,1047,1016cm-1;1H NMR(600MHz,CDCl3,δppm)8.20(dd,1H,Ar-H,J=7.8Hz,J=6.0Hz),7.55–7.45(m,1H,Ar-H),7.15–7.05(m,1H,Ar-H),7.05–6.95(m,1H,Ar-H),4.95(d,1H,1′-CH,J=4.2Hz),4.85(dd,1H,1″-CH,J=9.0Hz,J=5.4Hz),4.63(d,1H,13-CH,J=9.6Hz),4.50(d,1H,10-CH,J=9.6Hz),4.45–4.30(m,2H,4″-CH and5″-CH),4.02(s,3H,Ar-O-CH3),3.80–3.70(m,2H,2′-CH and5′-CH),3.40–3.30(m,5H,10-CH,3″-OCH3and3-CH),2.90–2.75(m,3H,2-CH,5-CH,3'-CH),2.80–2.40(m,7H,9a-CH and3′-N(CH3)2),2.24–2.16(s,3H,9a-NCH3),2.08–2.00(m,3H,2″a-CH,9b–CH and4-CH),1.94–1.88(m,1H,8-CH),1.88–1.80(m,2H,2″b-CH and4′a-CH),1.68–1.62(m,2H,4'b-CH and7a-CH),1.45(s,3H,12-CH3),1.42–1.34(m,2H,13-CH 2 CH3),1.32–1.20(m,16H,6-CH3,7b-CH,3″-CH3,5″-CH3,5′-CH3and2-CH3),1.10–1.02(m,6H,10-CH3and13-CH2 CH 3),0.96–0.88(m,6H,4-CH3and8-CH3);MS(ESI)m/z calcd.for C48H78N4O16966.5;found(M+H+)968.0。
b)将4-甲氧基苯甲酸(0.12g,0.80mmol)及HOBt(0.12g,0.88mmol)加入至适量THF(10mL)中,冰水浴条件下搅拌,滴加DCC(1.81g,0.66mmol)的THF(5mL)溶液,保持0℃,搅拌4-6h。滴加化合物2(0.60g,0.67mmol)的THF(7mL)溶液,室温搅拌2h。反应完毕后,将THF减压蒸干,加入适量的乙酸乙酯(25mL),室温搅拌约2h,过滤取滤液。在滤液中加入适量5%碳酸氢钠溶液(25mL),分液,取有机相,乙酸乙酯(15mL×3)萃取,合并有机层,饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色固体。将此白色固体(0.7mmol)溶解于甲醇(15mL)中,55℃搅拌15h,减压蒸干得白色泡沫状固体。硅胶柱层析(洗脱剂为二氯甲烷–甲醇,30:1),得白色泡沫状固体,即为化合物6,收率82.9%,mp158–161℃,TLC Rf=0.36(methanol/dichlormethane,1:10);IR(KBr):3416,2973,2937,2880,2830,2788,1813,1727,1654,1613,1534,1505,1457,1379,1353,1334,1302,1276,1256,1235,1166,1110,1073,1046,1015cm-1;1H NMR(600MHz,CDCl3,δppm)7.77(d,2H,Ar-H,J=8.4Hz),6.90(d,2H,Ar-H,J=9.0Hz),5.01(d,1H,1′-CH,J=4.2Hz),4.88(dd,1H,1″-CH,J=9.6Hz,J=6.6Hz),4.56–4.46(m,2H,13-CH and11-CH),4.36–4.24(m,2H,4″-CH and5″-CH),3.85(s,3H,Ar-O-CH3),3.70–3.64(m,1H,2′-CH),3.64–3.52(m,3H,5′-CH and4″-OCONHCH2 CH 2 NHCOAr),3.52–3.42(m,2H,4″-OCONHCH 2 CH2NHCOAr),3.40–3.32(m,2H,10-CH and3-CH),3.27(s,3H,3″-OCH3),2.88–2.78(m,2H,2-CH and3′-CH),2.59(s,6H,3′-N(CH3)2),2.44–2.40(m,2H,9a-CH and5-CH),2.36–2.30(m,2H,9b-CH and4-CH),2.20(s,3H,9a-NCH3),2.30–2.20(m,1H,2″a-CH),1.94–1.88(m,1H,8-CH),1.86–1.78(m,2H,2″b-CHand4′a-CH),1.66–1.50(m,2H,4′b-CH and7a-CH),1.44(s,3H,12-CH3),1.38–1.24(m,6H,7b-CH,13-CH 2 CH3and6-CH3),1.22–1.16(m,6H,2-CH3and3″-CH3),1.14–1.10(m,3H,5″-CH3),1.10–1.04(m,6H,5′-CH3and10-CH3),1.02–0.98(m,3H,13-CH2 CH 3),0.96–0.88(m,6H,4-CH3and8-CH3);MS(ESI)m/z calcd.for C50H82N4O16994.6;found(M+H+)996.0.
c)将4-甲氧基苯甲酸(0.07g,0.50mmol)及HOBt(0.07g,0.55mmol)加入至适量THF(10mL)中,冰水浴条件下搅拌,滴加DCC(1.13g,0.55mmol)的THF(4mL)溶液,保持0℃,搅拌4-6h。滴加化合物3(0.39g,0.42mmol)的THF(4mL)溶液,室温搅拌2h。反应完毕后,将THF减压蒸干,加入适量的乙酸乙酯(15mL),室温搅拌约2h,过滤取滤液。在滤液中加入适量5%碳酸氢钠溶液(15mL),分液,取有机相,乙酸乙酯(8mL×3)萃取,合并有机层,饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色固体。将此白色固体(0.4mmol)溶解于甲醇(8mL)中,55℃搅拌16h,减压蒸干得白色泡沫状固体。硅胶柱层析(洗脱剂为二氯甲烷–甲醇,30:1),得白色泡沫状固体,即为化合物9,收率86.8%,mp163–166℃,TLC Rf=0.35(methanol/dichlormethane,1:10);IR(KBr):3419,3076,2972,2936,2877,1812,1723,1643,1607,1575,1540,1505,1458,1382,1353,1300,1254,1169,1109,1074,1044,1015cm-1;1H NMR(600MHz,CDCl3,δppm)7.75(d,2H,Ar-H,J=9.0Hz),6.92(d,2H,Ar-H,J=9.6Hz),5.07(d,1H,1′-CH,J=4.8Hz),4.89(dd,1H,1″-CH,J=9.6Hz,J=6.6Hz),4.54(d,1H,13-CH,J=10.2Hz),4.42–4.30(m,3H,11-CH,4″-CH and5″-CH),3.85(s,3H,Ar-O-CH3),3.70–3.58(m,2H,2′-CH and5′-CH),3.50–3.44(m,2H,10-CH and3-CH),3.36–3.30(s,5H,3″-OCH3and4''-OCONHCH2CH2CH2 CH 2 NHCOAr),3.30–3.20(m,2H,4″-OCONHCH 2 CH2CH2CH2NHCOAr),2.90–2.82(m,2H,2-CH and3′-CH),2.82–2.78(m,1H,5-CH),2.48–2.38(s,7H,3′-N(CH3)2and9a-CH),2.38–2.32(m,1H,4-CH),2.21(s,4H,9b-CHand9a-NCH3),2.06–2.02(m,1H,2″a-CH),1.96–1.88(m,1H,8-CH),1.86–1.80(m,1H,4′a-CH),1.70–1.50(m,7H,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,2''b-CH and4′b-CH),1.48–1.40(m,5H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr,13-CH 2 CH3and7a-CH),1.32–1.24(m,6H,3″-CH3and6-CH3),1.23–1.18(m,10H,7b-CH,5″-CH3,5′-CH3and2-CH3),1.14(s,3H,10-CH3),1.10–1.02(m,6H,8-CH3and13-CH2 CH 3),0.96–0.88(m,3H,4-CH3);MS(ESI)m/z calcd.forC52H86N4O141022.6;found(M+H+)1024.1.
d)采用与实施例4a)相同的方法,但用2-氯苯甲酸代替2-甲氧基苯甲酸,得到4″-O-((4-氯苯甲酰胺基)氨基甲酰基阿奇霉素11,12-环碳酸酯(目标化合物5)白色固体,收率83.6%,mp156–158℃,TLC Rf=0.49(methanol/dichlormethane,1:10);IR(KBr):3431,2973,2937,2879,1812,1739,1683,1579,1459,1383,1353,1298,1276,1238,1209,1167,1110,1089,1075,1046,1014cm-1;1H NMR(600MHz,CDCl3,δppm)7.75(d,2H,Ar-H,J=6.6Hz),7.38(d,2H,Ar-H,J=8.4Hz),5.02–4.96(m,1H,1′-CH),4.88(d,1H,1″-CH,J=8.4Hz),4.61(d,1H,13-CH,J=9.6Hz),4.58–4.46(m,1H,11-CH),4.46–4.36(m,2H,4″-CH and5″-CH),3.74–3.54(m,2H,2′-CHand5′-CH),3.38–3.26(m,5H,10-CH,3-CH and3″-OCH3),3.00–2.76(m,3H,5-CH,2-CH and3′-CH),2.52–2.28(m,8H,3′-N(CH3)2,9a-CH and4-CH),2.20(s,3H,9a-NCH3),2.10–1.76(m,6H,9b-CH,2″a-CH,2″b-CH,8-CH,4′a-CH and4′b-CH),1.70–1.54(m,3H,13-CH 2 CH3and7a-CH),1.43(s,3H,12-CH3),1.34–1.10(m,16H,7b-CH,2-CH3,6-CH3,3″-CH3,5″-CH3and5′-CH3),1.10–0.98(m,6H,13-CH2 CH 3and10-CH3),0.96–0.86(m,6H,4-CH3and8-CH3);MS(ESI)m/z calcd.for C47H75ClN4O15970.5;found(M+H+)971.9.
e)采用与实施例4a)相同的方法,但用3,4-二甲氧基苯甲酸代替4-甲氧基苯甲酸,得到4″-O-((3,4-二甲氧基苯甲酰胺基)乙基)氨基甲酰基阿奇霉素11,12-环碳酸酯(目标化合物7)白色固体,收率83.7%,mp159–162℃,TLC Rf=0.37(methanol/dichlormethane,1:10);IR(KBr):3411,3083,2972,2937,2879,2836,1812,1726,1647,1604,1584,1507,1459,1383,1353,1311,1269,1232,1166,1110,1074,1045,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.45(d,1H,Ar-H,J=1.8Hz),7.32(dd,1H,Ar-H,J=8.4Hz,J=6.6Hz),7.04–6.98(m,1H,Ar-H),5.07(d,1H,1′-CH,J=4.8Hz),4.88(dd,1H,1″-CH,J=9.6Hz,J=6.6Hz),4.53(d,1H,13-CH,J=9.6Hz)4.46–4.30(m,3H,11-CH,4″-CH and5″-CH),3.96–3.90(m,6H,Ar-O-CH3),3.70–3.60(m,3H,2′-CH,5′-CH and3-CH),3.60–3.44(m,5H,4″-OCONHCH 2 CH 2 NHCOAr and10-CH),3.28(s,3H,3″-OCH3),2.90–2.82(m,2H,2-CH and3′-CH),2.74–2.64(m,1H,5-CH),2.46–2.30(m,8H,3′-N(CH3)2,9a-CH and4-CH),2.24–2.16(m,4H,9a-NCH3and9b-CH),2.08–2.02(m,2H,2″a-CHand4′a-CH),1.88–1.74(m,2H,8-CH and2″b-CH),1.64–1.58(m,3H,12-CH3)1.48–1.38(m,4H,13-CH 2 CH3,4′b-CH and7a-CH),1.30–1.22(m,6H,6-CH3and2″-CH3),1.22–1.12(m,7H,7b-CH,2-CH3and10-CH3),1.12–1.00(m,9H,5″-CH3,5′-CH3and8-CH3),0.96–0.86(m,6H,4-CH3and13-CH2 CH 3);MS(ESI)m/z calcd.for C51H84N4O171024.6;found(M+H+)1025.9.
f)采用与实施例4b)相同的方法,但用3,5-二硝基苯甲酸代替4-甲氧基苯甲酸,得到4″-O-((3,5-二硝基苯甲酰胺基)乙基)氨基甲酰基阿奇霉素11,12-环碳酸酯(目标化合物8)白色固体,收率75.8%,mp129–131℃,TLC Rf=0.30(methanol/dichlormethane,1:10);IR(KBr):3431,3104,2973,2937,2880,1812,1729,1672,1629,1544,1458,1382,1344,1304,1258,1236,1167,1111,1074,1045,10145cm-1;1H NMR(600MHz,CDCl3,δppm)9.15(t,1H,Ar-H,J=7.8Hz),9.05(d,1H,Ar-H,J=1.2Hz),7.30(dd,1H,Ar-H,J=8.4Hz,J=6.6Hz),5.09(d,1H,1′-CH,J=4.8Hz),4.89(dd,1H,1″-CH,J=9.6Hz,J=6.6Hz),4.61(d,1H,13-CH,J=9.6Hz),4.46–4.34(m,3H,11-CH,4″-CH and5″-CH),3.70–3.64(m,2H,2′-CH and5′-CH),3.64–3.46(m,5H,4''-OCONHCH 2 CH 2 NHCOAr and10-CH),3.30(s,4H,3″-OCH3and3-CH),2.94–2.88(m,1H,3′-CH),2.88–2.80(m,1H,2-CH),2.70–2.60(s,1H,5-CH),2.40–2.43(m,8H,3′-N(CH3)2,4-CHand9a-CH),2.19(s,3H,9a-NCH3),2.08–2.02(m,1H,9b-CH),1.84–1.74(m,2H,8-CH and2″a-CH),1.70–1.62(m,2H,2''b-CH and4′a-CH),1.62–1.50(m,2H,7a-CH and4′b-CH),1.44(s,3H,12-CH3),1.30–1.20(m,7H,7b-CH,6-CH3and3″-CH3),1.22–1.16(m,6H,5″-CH3and5′-CH3),1.12–1.08(m,3H,10-CH3),1.10–1.02(m,5H,2-CH3and13-CH 2 CH3),0.96–0.82(m,9H,8-CH3,4-CH3and13-CH2 CH 3);MS(ESI)m/z calcd.for C49H78N6O191054.5;found(M+H+)1055.9.
g)采用与实施例4c)相同的方法,但用2-甲氧基苯甲酸代替4-甲氧基苯甲酸,得到4″-O-((2-甲氧基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯(目标化合物10)白色固体,收率83.2%,mp166–168℃,TLC Rf=0.38(methanol/dichlormethane,1:10);IR(KBr):3407,3077,2972,2937,2877,1812,1721,1649,1600,1536,1484,1458,1383,1353,1334,1299,1278,1238,1166,1109,1085,1074,1046,1015cm-1;1H NMR(600MHz,CDCl3,δppm)7.98–7.86(m,1H,Ar-H),7.45(t,1H,Ar-H,J=7.8Hz),7.08(t,1H,J=7.8Hz),6.98(d,1H,Ar-H,1′-CH),5.06(d,1H,J=3.0Hz),4.88(dd,1H,1″-CH,J=9.0Hz,J=6.0Hz),4.55(d,1H,13-CH,J=9.6Hz),4.42–4.30(m,3H,11-CH,4″-CH and5″-CH),3.97(s,3H,Ar-O-CH3),3.68–3.62(m,1H,2′-CH),3.62–3.56(m,1H,5′-CH),3.52–3.44(m,2H,10-CH and3-CH),3.36–3.20(s,7H,3''-OCH3and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),2.90–2.76(m,3H,2-CH,3′-CH and5-CH),2.50–2.30(m,8H,3′-N(CH3)2,9a-CH and4-CH),2.19(s,4H,9b-CH and9a-NCH3),2.06–2.04(m,1H,2″a-CH),1.96–1.88(m,1H,8-CH),1.88–1.78(m,3H,4′a-CH and13-CH 2 CH3),1.68–1.56(m,6H,4″-OCONHCH2 CH 2 CH 2 CH2NHCOAr,4′b-CH and2″b-CH),1.44(s,4H,12-CH3and7a-CH),1.32–1.24(m,7H,7b-CH,3″-CH3and6-CH3),1.22–1.16(m,9H,5″-CH3,5′-CH3and2-CH3),1.15(s,3H,10-CH3),1.10–1.02(m,6H,8-CH3and13-CH2 CH 3),0.96–0.86(m,3H,4-CH3);MS(ESI)m/z calcd.for C52H86N4O141022.6;found(M+H+)1024.0.
h)采用与实施例4c)相同的方法,但用3,4-二甲氧基苯甲酸代替4-甲氧基苯甲酸,得到4″-O-((3,4-二甲氧基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯(目标化合物11)白色固体,收率79.9%,mp165–167℃,TLC Rf=0.34(methanol/dichlormethane,1:10);IR(KBr):3403,3083,2972,2936,2872,1812,1724,1644,1603,1584,1540,1507,1458,1382,1352,1336,1306,1269,1232,1167,1126,1110,1074,1045,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.45(d,1H,Ar-H,J=1.8Hz),7.21(d,1H,J=7.8Hz),6.86(d,1H,Ar-H,J=8.4Hz),5.06(d,1H,1′-CH,J=3.6Hz),4.89(dd,1H,1″-CH,J=9.6Hz,J=6.0Hz),4.55(d,1H,13-CH,J=9.6Hz),4.42–4.32(m,3H,11-CH,4″-CH and5″-CH),3.76–3.70(m,6H,Ar-O-CH3),3.68–3.56(m,2H,2′-CH and5′-CH),3.52–3.44(m,2H,10-CH and3-CH),3.36–3.22(m,7H,3″-OCH3and4''-OCONHCH 2 CH2CH2 CH 2 NHCOAr),2.90–2.72(m,3H,2-CH,3′-CH and5-CH),2.50–2.30(m,8H,3′-N(CH3)2,4-CH and9a-CH),2.20(s,4H,9b-CH and9a-NCH3),2.06–2.02(m,1H,2″a-CH),1.96–1.88(m,1H,8-CH),1.86–1.80(m,1H,4′a-CH),1.76–1.50(m,9H,4″-OCONHCH2CH2 CH 2 CH 2 NHCOAr,12-CH3,2″b-CH and4′b-CH),1.48–1.40(m,3H,13-CH 2 CH3and7a-CH),1.32–1.24(m,6H,3″-CH3and6-CH3),1.24–1.18(m,10H,7b-CH,5″-CH3,5′-CH3and2-CH3),1.15(s,3H,10-CH3),1.10–1.00(m,6H,8-CH3and13-CH2 CH 3),0.94–0.90(m,3H,4-CH3);MS(ESI)m/z calcd.for C53H88N4O171052.6;found(M+H+)1054.1.
i)采用与实施例4c)相同的方法,但用3,5-二硝基苯甲酸代替4-甲氧基苯甲酸,得到4″-O-((3,5-二硝基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯(目标化合物12)白色固体,收率83.5%,mp128–130℃,TLC Rf=0.28(methanol/dichlormethane,1:10);IR(KBr):3423,3105,2972,2936,2878,1812,1726,1670,1629,1543,1457,1382,1344,1301,1277,1237,1167,1110,1074,1045,1015cm-1;1H NMR(600MHz,CDCl3,δppm)9.24–9.18(m,2H,Ar-H),9.18–9.12(m,1H,Ar-H),5.09(d,1H,1′-CH,J=4.8Hz),4.89(dd,1H,1″-CH,J=9.6Hz,J=6.6Hz),4.63(d,1H,13-CH,J=9.6Hz),4.46–4.30(m,3H,11-CH,4″-CH and5″-CH),3.70–3.54(m,4H,2'-CH,5′-CH,10-CH and3-CH),3.38–3.22(m,7H,3″-OCH3and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),2.92–2.82(m,2H,2-CH and3′-CH),2.78–2.68(m,1H,5-CH),2.50–2.34(m,8H,3′-N(CH3)2,4-CH and9a-CH),2.20(s,4H,9b-CH and9a-NCH3),2.08–1.50(m,10H,2″a-CH,8-CH,4′a-CH,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,2″b-CH and4′b-CH),1.48–1.38(m,5H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr,13-CH 2 CH3and7a-CH),1.32–1.24(m,6H,3″-CH3and6-CH3),1.24–1.14(m,10H,7b-CH,5″-CH3,5′-CH3and2-CH3),1.12–1.02(m,6H,10-CH3and13-CH2 CH 3),0.96–0.88(m,6H,4-CH3and8-CH3);MS(ESI)m/z calcd.for C51H82N6O191082.6;found(M+H+)1083.9.
实施例5.
a)11-O-(苄基氨基甲酰基)-4″-O-((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基阿奇霉素(目标化合物13)
将4″-O-((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯(化合物9,0.51g,0.5mmol)溶解于苄胺(2mL)中,加入盐酸吡啶(0.11g,1.00mmol),室温搅拌3d。反应完毕后,加入适量乙酸乙酯(10mL),过滤取滤液。在滤液中加入适量水(10mL)及饱和磷酸二氢钠溶液(5mL),过滤除去白色固体。滤液分液,取有机相,二氯甲烷(10mL×3)萃取,合并有机层,无水硫酸钠干燥,减压蒸干得白色固体。硅胶柱层析(洗脱剂为二氯甲烷–甲醇,30:1),得白色固体,即为目标化合物13,收率74.5%,mp108–111℃,TLC Rf=0.28(methanol/dichlormethane,1:5);IR(KBr):3380,2973,2575,2350,2220,2050,1954,1903,1810,1724,1636,1606,1540,1506,1465,1455,1381,1255,1216,1175,1112,1075,1039,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.78(d,2H,Ar-H,J=8.4Hz),7.35–7.70(m,5H,Ar-H),6.91(d,2H,Ar-H,J=8.4Hz),5.04–4.98(m,1H,1′-CH),4.92–4.87(m,1H,1″-CH),4.45–4.31(m,6H,13-CH,11-CH,4″-CH,C-11-OCONHCH 2 -Ar and5″-CH),3.84(s,3H,Ar-O-CH3),3.76–3.64(m,2H,2′-CH and5′-CH),3.49–3.40(m,2H,10-CH and3-CH),3.34–3.15(m,7H,3″-OCH3and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),2.82–2.65(s,7H,3′-N(CH3)2and5-CH),2.42–2.04(m,8H,9a-CH,2-CH,3′-CH,4-CH,9b-CH and9a-NCH3),2.01–2.00(m,1H,2″a-CH),1.96–1.92(m,1H,8-CH),1.88–1.80(m,1H,4′a-CH),1.78–1.48(m,7H,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,2″b-CH and4′b-CH),1.45–1.21(m,11H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr,13-CH 2 CH3,7a-CH,3″-CH3and6-CH3),1.20–1.00(m,16H,7b-CH,5″-CH3,5′-CH3,2-CH3,10-CH3and13-CH2 CH 3),0.93–0.87(m,6H,8-CH3and4-CH3);MS(ESI)m/z calcd.forC59H95N5O161129.7;found(M+H+)1131.1.
b)11-O-(苯乙基氨基甲酰基)-4″-O-((2-甲氧基苯甲酰胺基)氨基甲酰基)阿奇霉素(目标化合物22)
将4″-O-(2-甲氧基苯甲酰胺基)氨基甲酰基阿奇霉素11,12-环碳酸酯(化合物4,0.58g,0.6mmol)溶解于苯乙胺(2.5mL)中,加入盐酸吡啶(0.20g,1.20mmol),室温搅拌4d。反应完毕后,加入适量乙酸乙酯(10mL),过滤取滤液。在滤液中加入适量水(10mL)及饱和磷酸二氢钠溶液(6mL),过滤除去白色固体。滤液分液,取有机相,二氯甲烷(10mL×3)萃取,合并有机层,无水硫酸钠干燥,减压蒸干得白色固体。硅胶柱层析(洗脱剂为二氯甲烷–甲醇,30:1),得白色固体,即为目标化合物22,收率78.5%,mp113–115℃,TLC Rf=0.30(methanol/dichlormethane,1:5);IR(KBr):3325,2971,2934,1814,1739,1659,1602,1587,1507,1463,1413,1379,1352,1337,1297,1268,1225,1169,1109,1074,1045,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.76–7.74(m,2H,Ar-H),7.31–7.27(m,2H,Ar-H),7.23–7.19(m,3H,Ar-H),6.93–6.91(m,2H,Ar-H),5.01–4.96(m,2H,1′-CH and1″-CH),4.55–4.52(m,2H,13-CH and10-CH),4.44–4.38(m,2H,4″-CH and5″-CH),3.85(s,3H,Ar-O-CH3),3.68–3.62(m,2H,2′-CHand5′-CH),3.50–3.40(m,2H,10-CH and3-CH),3.34(s,3H,3″-OCH3),3.28–3.26(m,2H,11-OCONHCH 2 CH2-Ar),2.86–2.80(m,5H,2-CH,5-CH,3′'-CH and11-OCONHCH2 CH 2 -Ar),2.42–2.26(m,7H,9a-CH and3′-N(CH3)2),2.23–2.19(s,3H,9a-NCH3),2.08–1.92(m,3H,2″a-CH,9b–CH and4-CH),1.88–1.78(m,1H,8-CH),1.68–1.56(m,4H,2″b-CH,4′a-CH,4′b-CH and7a-CH),1.30–1.16(m,18H,13-CH 2 CH3,12-CH3,6-CH3,7b-CH,3″-CH3,5″-CH3and5′-CH3),1.15(s,3H,2-CH3),1.11–1.08(m,3H,10-CH3),1.06–1.00(m,3H,13-CH2 CH 3),0.96–0.92(m,3H,4-CH3),0.88–0.85(m,3H,8-CH3);MS(ESI)m/z calcd.for C56H89N5O161087.6;found(M+H+)1089.0.
c)11-O-((3,4-二氟苄基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物29)
将4″-O-((3,5-二硝基苯甲酰胺基)丁基)氨基甲酰基阿奇霉素11,12-环碳酸酯(化合物12,0.43g,0.4mmol)溶解于3,4-二氟苄胺(2mL)中,加入盐酸吡啶(0.13g,0.8mmol),室温搅拌5d。反应完毕后,加入适量乙酸乙酯(10mL),过滤取滤液。在滤液中加入适量水(10mL)及饱和磷酸二氢钠溶液(5mL),过滤除去白色固体。滤液分液,取有机相,二氯甲烷(10mL×3)萃取,合并有机层,无水硫酸钠干燥,减压蒸干得白色固体。硅胶柱层析(洗脱剂为二氯甲烷–甲醇,30:1),得红褐色固体,即为目标化合物29,收率63.5%,mp102–104℃,TLC Rf=0.24(methanol/dichlormethane,1:5);IR(KBr):3434,3063,2973,2935,2875,1810,1725,1668,1629,1592,1542,1474,1388,1375,1344,1298,1252,1169,1110,1074,1049,1016cm-1;1HNMR(600MHz,CDCl3,δppm)9.17–9.15(m,3H,Ar-H),7.32–7.28(m,1H,Ar-H),6.86–6.76(m,2H,Ar-H),5.02–4.86(m,2H,1′-CH and1″-CH),4.68–4.58(m,2H,13-CH and11-CH),4.48–4.30(m,4H,11-OCONHCH 2 -Ar,4″-CH and5″-CH),3.66–3.50(m,4H,2′-CH,5′-CH,10-CH and3-CH),3.38–3.22(m,7H,3″-OCH3and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),3.02–2.72(m,3H,2-CH,5-CH and3′-CH),2.66–2.52(m,2H,4-CH and9a-CH),2.28(s,6H,3′-N(CH3)2),2.23(s,3H,9a-NCH3),2.19–2.10(m,2H,9b-CH and2″a-CH),2.04–1.96(m,2H,8-CH and4′a-CH),1.94–1.50(m,9H,4″-OCONHCH2 CH 2 CH 2 CH2NHCOAr,12-CH3,2″b-CH and4′b-CH),1.48–1.30(m,3H,13-CH 2 CH3and7a-CH),1.30–1.18(m,7H,3″-CH3,7b-CH and6-CH3),1.16(s,6H,5″-CH3and5′-CH3),1.14–1.09(m,3H,2-CH3),1.03–1.98(m,6H,10-CH3and13-CH2 CH 3),0.90–0.85(m,6H,4-CH3and8-CH3);HRMS(ESI)m/z calcd.for C58H89F2N7O191226.3598;found(M+H+)1227.2825.
d)采用与实施例5a)相同的方法,但用4-甲氧基苄胺代替其中的苄胺,得11-O-((4-甲氧基苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物14)白色固体,收率76.7%,mp109–111℃,TLC Rf=0.27(methanol/dichlormethane,1:5);IR(KBr):3323,2972,2936,2876,1726,1640,1606,1540,1505,1456,1376,1256,1176,1092,1037,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.75(d,2H,Ar-H,J=8.4Hz),7.20(dd,2H,Ar-H,J=7.2Hz,J=2.4Hz),6.91(d,2H,Ar-H,J=8.4Hz),6.90(d,2H,Ar-H,J=8.4Hz),5.03–5.00(m,1H,1′-CH),4.91–4.90(m,1H,1″-CH),4.60–4.50(m,1H,13-CH),4.45–4.30(m,5H,11-CH,4″-CH,C-11-OCONHCH 2 -Ar and5″-CH),3.85–3.68(s,8H,Ar-O-CH3,Ar-O-CH3,2′-CH and5′-CH),3.56–3.39(m,2H,10-CH and3-CH),3.35–3.10(m,7H,3″-OCH3and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),3.05–2.50(m,3H,2-CH,3′-CH and5-CH),2.40–2.10(m,12H,3′-N(CH3)2,9a-CH,4-CH,9b-CH and9a-NCH3),2.10–1.80(m,3H,2″a-CH,8-CH and4′a-CH),1.75–1.50(m,7H,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,2″b-CH and4′b-CH),1.48–1.39(m,5H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr,13-CH 2 CH3and7a-CH),1.38–1.18(m,16H,3″-CH3,6-CH3,7b-CH,5″-CH3,5′-CH3and2-CH3),1.16–0.84(m,12H,10-CH3,8-CH3,13-CH2 CH 3and4-CH3);MS(ESI)m/z calcd.for C60H97N5O171159.7;found(M+NH4 +)1177.1.
e)采用与实施例5a)相同的方法,但用3,4-二甲基苄胺代替其中的苄胺,得11-O-((3,4-二甲基苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物15)白色固体,收率77.6%,mp105–107℃,TLC Rf=0.27(methanol/dichlormethane,1:5);IR(KBr):3317,2926,2871,2854,2623,2498,1725,1640,1607,1540,1505,1458,1378,1255,1174,1110,1076,1039,1017cm-1;1H NMR(600MHz,CDCl3,δppm)7.78(d,2H,Ar-H,J=8.4Hz),7.10(t,2H,Ar-H,J=7.8Hz),7.04–7.02(m,1H,Ar-H),6.92(d,2H,Ar-H,J=9.0Hz),5.02–4.95(m,2H,1′-CH and1″-CH),4.56–4.40(m,1H,13-CH),4.28–4.15(m,5H,11-CH,4″-CH,C-11-OCONHCH 2 -Ar and5″-CH),3.85(s,3H,Ar-O-CH3),3.60–3.42(m,4H,2′-CH,3-CH,5′-CHand10-CH),3.28–3.09(m,7H,3″-OCH3and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),2.90–2.58(m,9H,2-CH,3′-CH,5-CH,Ar-CH3and Ar-CH3),2.40–2.10(m,14H,3′-N(CH3)2,9a-CH,4-CH,2″a-CH,9b-CH,4′a-CH and9a-NCH3),1.96–1.58(m,8H,8-CH,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,2″b-CH and4′b-CH),1.56–1.38(m,5H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr,13-CH 2 CH3and7a-CH),1.30–1.08(m,19H,3″-CH3,6-CH3,7b-CH,5″-CH3,5′-CH3,2-CH3and10-CH3),1.05–0.88(m,9H,8-CH3,4-CH3and13-CH2 CH 3);MS(ESI)m/z calcd.for C61H99N5O161157.7;found(M+H+)1159.2.
f)采用与实施例5a)相同的方法,但用4-氟苄胺代替其中的苄胺,得11-O-((4-氟苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物16)白色固体,收率79.3%,mp105–107℃,TLC Rf=0.29(methanol/dichlormethane,1:5);IR(KBr):3377,2973,2575,2350,2219,2050,1954,1903,1810,1724,1636,1606,1540,1506,1465,1455,1381,1255,1216,1175,1112,1075,1039,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.74(d,2H,Ar-H,J=8.4Hz),7.29–7.26(m,4H,Ar-H),7.03(t,2H,Ar-H,J=8.4Hz),5.99(d,1H,1′-CH,J=10.2Hz),4.93(d,1H,1″-CH,J=4.2Hz),4.41–4.37(m,6H,13-CH,11-CH,4″-CH,5″-CH andC-11-OCONHCH 2 -Ar),3.85(s,3H,Ar-O-CH3),3.60–3.52(m,2H,2′-CH and5′-CH),3.48–3.40(m,2H,10-CH and3-CH),3.32–3.22(s,7H,3″-OCH3and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),3.19–3.13(m,3H,2-CH,5-CH and3′-CH),2.34–2.28(s,8H,3′-N(CH3)2,4-CH and9a-CH),2.23(s,3H,9a-NCH3),2.04–1.98(m,2H,9b-CH and2″a-CH),1.94–1.84(m,2H,8-CH and4′a-CH),1.70–1.46(m,12H,4''-OCONHCH2 CH 2 CH 2 CH2NHCOAr,12-CH3,2″b-CH,4′b-CH,13-CH 2 CH3and7a-CH),1.30–1.18(m,16H,3″-CH3,6-CH3,7b-CH,5″-CH3,5′-CH3and2-CH3),1.16–0.98(m,9H,10-CH3,8-CH3and13-CH2 CH 3),0.94–0.86(m,3H,4-CH3);MS(ESI)m/z calcd.forC59H94FN5O161147.7;found(M+H+)1148.9.
g)采用与实施例5a)相同的方法,但用3,4-二氟苄胺代替其中的苄胺,得11-O-((3,4-二氟苄基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物17)白色固体,收率70.5%,mp103–105℃,TLC Rf=0.26(methanol/dichlormethane,1:5);IR(KBr):3373,2972,2936,2875,1725,1639,1607,1540,1505,1459,1377,1255,1177,1109,1088,1039,1016cm-1;1H NMR(600MHz,CDCl3,δppm)1H NMR(600MHz,CDCl3,δppm)7.78(d,2H,Ar-H,J=8.4Hz),6.92(d,2H,Ar-H,J=8.4Hz),6.86–6.82(m,3H,Ar-H),4.99–4.96(m,2H,1′-CH and1″-CH),4.52–4.30(m,6H,13-CH,11-CH,4″-CH,5″-CH and11-OCONHCH 2 -Ar),3.85(s,3H,Ar-O-CH3),3.69–3.65(m,2H,2′-CH and5′-CH),3.52–3.42(m,2H,10-CH and3-CH),3.32–3.22(s,7H,3″-OCH3and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),3.10–3.00(m,3H,2-CH,5-CH and3′-CH),2.78–2.60(s,8H,3′-N(CH3)2,4-CH and9a-CH),2.23(s,3H,9a-NCH3),2.04–1.96(m,2H,9b-CH and2″a-CH),1.94–1.84(m,2H,8-CH and4′-CH),1.68–1.52(m,12H,4″-OCONHCH2 CH 2 CH 2 CH2NHCOAr,12-CH3,2″b-CH,4′b-CH,13-CH 2 CH3and7a-CH),1.28–1.18(m,16H,3″-CH3,6-CH3,7b-CH,5″-CH3,5′-CH3and2-CH3),1.16–1.12(m,6H,10-CH3and13-CH2 CH 3),1.12–0.98(m,6H,4-CH3and8-CH3);MS(ESI)m/z calcd.for C59H93F2N5O161165.7;found(M+H+)1167.1.
h)采用与实施例5a)相同的方法,但用苯乙胺代替其中的苄胺,得11-O-(苯乙基氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物18)白色固体,收率73.8%,mp110–112℃,TLC Rf=0.27(methanol/dichlormethane,1:5);IR(KBr):3426,3062,2973,2936,2875,1725,1642,1607,1538,1505,1456,1376,1254,1176,1110,1091,1073,1034,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.76(d,2H,Ar-H,J=8.4Hz),7.30(m,3H,Ar-H),7.21(d,2H,Ar-H,J=8.4Hz),6.93(d,2H,Ar-H,J=7.2Hz),5.04–4.97(m,2H,1′-CH and1″-CH),4.55–4.53(m,2H,13-CH and11-CH),4.44–4.39(m,2H,4″-CH and5″-CH),3.85(s,3H,Ar-O-CH3),3.64–3.61(m,2H,2′-CH and5′-CH),3.53–3.52(m,2H,10-CH and3-CH),3.49–3.41(s,2H,4″-OCONHCH2CH2CH2 CH 2 NHCOAr),3.31(s,3H,3″-OCH3),3.29–3.19(m,4H,4″-OCONHCH 2 CH2CH2CH2NHCOAr and11-OCONHCH 2 CH2-Ar),2.87–2.80(m,3H,5-CH,2-CH and3′-CH),2.68–2.62(m,4H,4-CH,9a-CH and11-OCONHCH2 CH 2 -Ar),2.41–2.21(m,7H,3′-N(CH3)2and9b-CH),2.21(s,3H,9a-NCH3),2.04–1.98(m,2H,2″a-CH and8-CH),1.75–1.59(m,8H,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,4′a-CH,2″b-CH and4′b-CH),1.48–1.43(m,5H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr,13-CH 2 CH3and7a-CH),1.33–1.22(m,6H,3″-CH3and6-CH3),1.18–1.10(m,10H,7b-CH,5″-CH3,2-CH3and5′-CH3),1.15(s,3H,10-CH3),1.05–0.94(m,6H,8-CH3and13-CH2 CH 3),0.89–0.85(m,3H,4-CH3);MS(ESI)m/z calcd.forC60H97N5O161143.7;found(M+H+)1145.1.
i)采用与实施例5a)相同的方法,但用4-甲氧基苯乙胺代替其中的苄胺,得11-O-((4-甲氧基)苯乙基氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物19)白色固体,收率80.1%,mp108–1101℃,TLC Rf=0.28(methanol/dichlormethane,1:5);IR(KBr):3377,2972,2936,2874,2874,2836,2057,1811,1724,1643,1608,1575,1512,1459,1377,1300,1250,1176,1110,1090,1074,1036,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.74–7.71(m,2H,Ar-H),7.27–7.11(m,2H,Ar-H),6.97–6.78(m,4H,Ar-H),5.04–4.92(m,2H,1′-CH and1″-CH),4.55–4.53(m,1H,13-CH),4.44–4.38(m,2H,11-CH and4″-CH),4.32–4.29(m,1H,5″-CH),3.81(s,3H,Ar-O-CH3),3.85–3.75(m,5H,Ar-O-CH3,2′-CH and5′-CH),3.52–3.49(m,1H,10-CH),3.47–3.45(m,3H,3-CH and4″-OCONHCH2CH2CH2 CH 2 NHCOAr),3.40–3.36(m,2H,4″-OCONHCH 2 CH2CH2CH2NHCOAr),3.33(s,3H,3″-OCH3),2.96–2.88(m,2H,2-CHand3′-CH),2.80–2.73(m,4H,5-CH,9a-CH and11-OCONHCH 2 CH2-Ar),2.72–2.66(m,4H,11-OCONHCH2 CH 2 -Ar,4-CH and9b-CH),2.28(s,6H,3′-N(CH3)2),2.24–2.18(m,3H,9a-NCH3),2.04–1.95(m,1H,2″a-CH),1.89–1.80(m,2H,8-CH and4′a-CH),1.68–1.54(m,7H,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,2″b-CH and4′b-CH),1.49–1.42(m,5H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr,13-CH 2 CH3and7a-CH),1.28–1.16(m,16H,3″-CH3,6-CH3,7b-CH,5″-CH3,5′-CH3and2-CH3),1.16–1.08(m,6H,10-CH3and13-CH2 CH 3),1.02–0.84(m,6H,8-CH3and4-CH3);MS(ESI)m/z calcd.for C61H99N5O171173.7;found(M+H+)1175.1.
j)采用与实施例5a)相同的方法,但用4-氟苯乙胺代替其中的苄胺,得11-O-((4-氟苯乙基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物20)白色固体,收率70.9%,mp107–110℃,TLC Rf=0.29(methanol/dichlormethane,1:5);IR(KBr):3378,2973,2933,2727,2416,2049,1811,1721,1639,1605,1511,1469,1418,1378,1353,1308,1255,1229,1160,1143,1109,1074,1044,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.78–7.75(m,2H,Ar-H),7.27–7.16(m,2H,Ar-H),6.99–6.82(m,4H,Ar-H),5.02–4.94(m,2H,1′-CH and1″-CH),4.63–4.52(m,2H,13-CH and11-CH),4.44–4.34(m,2H,4″-CH and5″-CH),3.85(s,3H,Ar-O-CH3),3.68–3.60(m,2H,2′-CH and5′-CH),3.50–3.43(m,2H,10-CH and3-CH),3.36–3.28(m,5H,3″-OCH3and4″-OCONHCH2CH2CH2 CH 2 NHCOAr),3.28–3.23(m,2H,4″-OCONHCH 2 CH2CH2CH2NHCOAr),3.04–2.96(m,2H,11-OCONHCH 2 CH2-Ar),2.86–2.74(m,4H,2-CH,3′-CH and11-OCONHCH2 CH 2 -Ar),2.44–2.30(m,8H,3′-N(CH3)2,5-CH and9a-CH),2.22–2.10(m,4H,4-CH and9a-NCH3),2.04–1.94(m,2H,2″a-CH and9b-CH),1.90–1.78(m,2H,8-CH and4′a-CH),1.68–1.54(m,8H,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,2″b-CH,7a-CH and4′b-CH),1.50–1.40(m,2H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr),1.28–1.12(m,18H,6-CH3,13-CH 2 CH3,3″-CH3,7b-CH,5″-CH3,5′-CH3and2-CH3),1.12–1.04(m,3H,10-CH3),1.04–0.96(m,6H,8-CH3and13-CH2 CH 3),0.89–0.84(m,3H,4-CH3);MS(ESI)m/z calcd.forC60H96FN5O161161.7;found(M+H+)1163.1.
k)采用与实施例5a)相同的方法,但用2-氯苯乙胺代替其中的苄胺,得11-O-((2-氯苯乙基)氨基甲酰基)-4″-O-(((4-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物21)淡黄色固体,收率63.9%,mp113–115℃,TLC Rf=0.26(methanol/dichlormethane,1:5);IR(KBr):3365,2972,2871,2854,2624,2498,1809,1724,1639,1607,1574,1539,1505,1461,1377,1254,1175,1123,1109,1074,1035,1017cm-1;1H NMR(600MHz,CDCl3,δppm)7.75–7.74(m,2H,Ar-H),7.43–7.36(m,2H,Ar-H),7.24–7.18(m,2H,Ar-H),7.08–6.93(m,2H,Ar-H),5.00–4.90(m,2H,1′-CH and1″-CH),4.72–4.30(m,4H,13-CH,11-CH,4″-CH and5″-CH),3.85(s,3H,Ar-O-CH3),3.66–3.60(m,1H,2′-CH),3.56–3.52(m,1H,5′-CH),3.49–3.43(m,2H,10-CH and3-CH),3.31–3.20(m,7H,3″-OCH3,4″-OCONHCH2CH2CH2 CH 2 NHCOAr and11-ONHCH 2 CH2-Ar),3.00–2.94(m,2H,11-ONHCH2 CH 2 -Ar),2.64–2.58(m,3H,2-CH,5-CH and3′-CH),2.42–2.12(m,12H,3′-N(CH3)2,9a-CH,4-CH,9b-CH and9a-NCH3),2.02–1.94(m,1H,2″a-CH),1.88–1.78(m,2H,8-CH and4′a-CH),1.74–1.56(m,12H,4″-OCONHCH2 CH 2 CH 2 CH2NHCOAr,12-CH3,2″b-CH,4′b-CH,13-CH 2 CH3and7a-CH),1.32–1.16(m,16H,3″-CH3,6-CH3,7b-CH,5″-CH3,5′-CH3and2-CH3),1.16–1.06(m,3H,10-CH3),1.06–1.00(m,3H,8-CH3),1.00–0.94(m,3H,13-CH2 CH 3),0.90–0.84(m,3H,4-CH3);MS(ESI)m/z calcd.for C60H96ClN5O161177.6;found(M+H+)1179.0.
l)采用与实施例5b)相同的方法,但用化合物5代替其中的化合物4,得11-O-(苯乙基氨基甲酰基)-4″-O-((4-氯苯甲酰胺基)氨基甲酰基)阿奇霉素(目标化合物23)白色固体,收率71.3%,mp106–109℃,TLC Rf=0.29(methanol/dichlormethane,1:5);IR(KBr):3412,2973,2936,2879,1813,1739,1687,1604,1502,1457,1379,1353,1298,1236,1209,1166,1110,1074,1046,1015cm-1;1H NMR(600MHz,CDCl3,δppm)7.74–7.72(m,4H,Ar-H),7.40–7.38(m,2H,Ar-H),7.27–7.25(m,3H,Ar-H),5.06(s,1H,1′-CH),4.87(d,1H,1″-CH,J=7.8Hz),4.59(d,1H,13-CH,J=9.6Hz),4.49(s,1H,11-CH),4.43–4.37(m,2H,4″-CH and5″-CH),3.72–3.64(m,2H,2′-CHand5′-CH),3.60–3.56(m,2H,10-CH and3-CH),3.34–3.30(m,5H,11-OCONHCH 2 CH2-Ar and3″-OCH3),2.86–2.80(m,5H,5-CH,2-CH,3′-CH and11-OCONHCH2 CH 2 -Ar),2.48–2.34(m,8H,3′-N(CH3)2,9a-CH and4-CH),2.21(s,3H,9a-NCH3),2.06–1.94(m,2H,9b-CH and2''a-CH),1.96–1.76(m,4H,2″b-CH,8-CH,4′a-CH and4′b-CH),1.66–1.52(m,3H,13-CH 2 CH3and7a-CH),1.41(s,3H,12-CH3),1.32–1.16(m,16H,7b-CH,2-CH3,6-CH3,3″-CH3,5″-CH3and5′-CH3),1.08–1.02(m,6H,13-CH2 CH 3and10-CH3),0.94–0.88(m,6H,4-CH3and8-CH3);HRMS(ESI)m/z calcd.for C55H86ClN5O151092.7487;found(M+H+)1092.2546.
m)采用与实施例5b)相同的方法,但用化合物6代替其中的化合物4,得11-O-(苯乙基氨基甲酰基)-4″-O-((4-甲基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素(目标化合物24),收率75.7%,mp110–113℃,TLC Rf=0.28(methanol/dichlormethane,1:5);IR(KBr):3385,2972,2935,1813,1725,1647,1607,1575,1537,1505,1459,1378,1302,1255,1167,1110,1074,1045,1015cm-1;1H NMR(600MHz,CDCl3,δppm)7.75(d,2H,Ar-H,J=9.0Hz),7.31–7.26(m,2H,Ar-H),7.23–7.19(m,3H,Ar-H),6.92(d,2H,Ar-H,J=9.0Hz),5.01–4.97(m,2H,1′-CH and1″-CH),4.70–4.64(m,1H,13-CH),4.56–4.52(m,1H,11-CH),4.44–4.36(m,2H,4″-CH and5″-CH),3.85(s,3H,Ar-O-CH3),3.68–3.60(m,1H,2′-CH),3.54–3.50(m,1H,5′-CH),3.54–3.42(m,4H,4″-OCONHCH 2 CH 2 NHCOAr),3.34(s,4H,3″-OCH3and3-CH),3.28–3.22(m,3H,10-CH and11-OCONHCH 2 CH2-Ar),2.86–2.78(m,4H,2-CH,3′-CH and11-OCONHCH2 CH 2 -Ar),2.42–2.24(m,8H,3′-N(CH3)2,9a-CH and5-CH),2.21(s,3H,9a-NCH3),2.18–1.76(m,5H,2″a-CH,9b-CH,4-CH,8-CH and4′a-CH),1.68–1.54(m,6H,4′b-CH,2″b-CH,12-CH3and7a-CH),1.28–1.16(m,15H,7b-CH,13-CH 2 CH3,6-CH3,2-CH3,3″-CH3,5″-CH3),1.14(s,3H,5′-CH3),1.12–1.08(m,3H,10-CH3),1.04–1.00(m,3H,13-CH2 CH 3),0.98–0.94(m,3H,4-CH3),0.90–0.84(m,3H,8-CH3);HRMS(ESI)m/z calcd.for C58H93N5O151100.3837;found(M+H+)1100.2968.
n)采用与实施例5b)相同的方法,但用化合物7代替其中的化合物4,得11-O-(苯乙基氨基甲酰基)-4″-O-(((3,4-二甲氧基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素(目标化合物25)白色固体,收率67.0%,mp112–115℃,TLC Rf=0.27(methanol/dichlormethane,1:5);IR(KBr):3416,3083,2972,2937,2879,2836,1812,1725,1647,1603,1584,1507,1461,1378,1353,1337,1310,1269,1232,1167,1110,1074,1045,1016cm-1;1H NMR(600MHz,CDCl3,δppm)7.48(s,1H,Ar-H),7.40–7.36(m,2H,Ar-H),7.32–7.28(m,2H,Ar-H),7.24–7.18(m,2H,Ar-H),6.87–6.84(m,1H,Ar-H),5.00–4.96(m,2H,1′-CH and1″-CH),4.56–4.52(m,1H,13-CH),4.48–4.34(m,3H,11-CH,4″-CH and5″-CH),3.94(s,3H,Ar-O-CH3),3.92(s,3H,Ar-O-CH3),3.70–3.58(m,3H,2′-CH,5′-CH and3-CH),3.52–3.40(m,7H,4″-OCONHCH 2 CH 2 NHCOAr,11-OCONHCH 2 CH2-Ar and10-CH),3.29–3.28(m,3H,3″-OCH3),2.86–2.78(m,3H,2-CH and11-OCONHCH2 CH 2 -Ar),2.66–2.52(m,7H,3′-N(CH3)2and5-CH),2.46–2.30(m,3H,9a-CH,3′-CH and4-CH),2.24–2.18(m,4H,9a-NCH3and9b-CH),2.08–1.94(m,2H,2''a-CH and4′a-CH),1.90–1.78(m,2H,8-CH and2″b-CH),1.62–1.56(m,4H,13-CH 2 CH3,4′b-CH and7a-CH),1.44(s,3H,12-CH3),1.36–1.18(m,6H,6-CH3and2″-CH3),1.17–1.12(m,7H,7b-CH,2-CH3and10-CH3),1.10–1.05(m,6H,5″-CH3and5′-CH3),1.04–0.94(m,6H,8-CH3and13-CH2 CH 3),0.92–0.84(m,3H,4-CH3);MS(ESI)m/z calcd.for C59H95N5O171145.7;found(M+H+)1146.9.
o)采用与实施例5b)相同的方法,但用化合物8代替其中的化合物4,得11-O-(苯乙基氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)乙基)氨基甲酰基)阿奇霉素(目标化合物26)淡黄色固体,收率60.3%,mp102–103℃,TLC Rf=0.25(methanol/dichlormethane,1:5);IR(KBr):3427,3105,2973,2937,2880,1812,1730,1674,1629,1544,1458,1378,1344,1303,1258,1236,1167,1111,1074,1045,1015cm-1;1H NMR(600MHz,CDCl3,δppm)9.25(s,2H,Ar-H),9.11(s,1H,Ar-H),7.24–7.20(m,2H,Ar-H),7.20–7.12(m,3H,Ar-H),5.05(s,1H,1′-CH),4.97(d,1H,1″-CH,J=10.2Hz),4.65–4.60(m,2H,13-CH and11-CH),4.42–4.22(m,2H,4″-CH and5″-CH),3.63–3.58(m,2H,2′-CH and5′-CH),3.56–3.54(m,3H,4″-OCONHCH 2CH2NHCOAr and10-CH),3.47–3.42(m,3H,4″-OCONHCH2 CH 2 NHCOAr and3-CH),3.32(s,3H,3″-OCH3),3.00–2.94(m,5H,3′-CH and11-OCONHCH 2 CH 2 -Ar),2.65–2.61(m,2H,2-CH and5-CH),2.40–2.30(m,8H,3′-N(CH3)2,4-CH and9a-CH),2.26(s,3H,9a-NCH3),2.16–2.10(m,1H,9b-CH),2.02–1.80(m,2H,8-CH and2″a-CH),1.78–1.60(m,4H,2″b-CH,7a-CH,4′a-CH and4′b-CH),1.30–1.12(m,15H,7b-CH,12-CH3,6-CH3,3″-CH3,5″-CH3and13-CH 2 CH3),1.12–1.06(m,6H,5′-CH3and2-CH3),1.04–0.96(m,6H,13-CH2 CH 3and10-CH3),0.90–0.84(m,6H,8-CH3and4-CH3);MS(ESI)m/z calcd.for C57H89N7O191175.6;found(M+H+)1176.9.
p)采用与实施例5b)相同的方法,但用化合物10代替其中的化合物4,得11-O-(苯乙基氨基甲酰基)-4″-O-(((2-甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物27)白色固体,收率72.6%,mp109–110℃,TLC Rf=0.30(methanol/dichlormethane,1:5);IR(KBr):3361,3062,2973,2936,2875,1726,1643,1607,1537,1505,1456,1375,1254,1176,1110,1091,1073,1034cm-1;1H NMR(600MHz,CDCl3,δppm)7.75–7.35(m,2H,Ar-H),7.13–7.11(m,2H,Ar-H),6.92(d,2H,Ar-H,J=8.4Hz),6.86–6.83(m,3H,Ar-H),5.00–4.95(m,2H,1′-CH and1″-CH),4.60–4.20(m,4H,13-CH,11-CH,4″-CH and5″-CH),3.85(s,3H,Ar-O-CH3),3.64–3.58(m,1H,2′-CH),3.54–3.34(m,5H,4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr and3-CH),3.32(s,3H,3″-OCH3),3.28–3.18(m,4H,5′-CH,10-CH and11-OCONHCH 2 CH2-Ar),2.96–2.90(m,1H,2-CH),2.80–2.68(m,4H,3′-CH,5-CH and11-OCONHCH2 CH 2 -Ar),2.32–2.26(m,8H,3′-N(CH3)2,9a-CH and4-CH),2.23–2.18(m,4H,9b-CH and9a-NCH3),2.00–1.80(m,2H,2″a-CHand8-CH),1.68–1.56(m,9H,4′a-CH,13-CH 2 CH3,4″-OCONHCH2 CH 2 CH 2 CH2NHCOAr,4′b-CHand2″b-CH),1.44(s,3H,12-CH3),1.30–1.16(m,17H,7a-CH,7b-CH,3″-CH3,6-CH3,5″-CH3,5′-CH3and2-CH3),1.16–1.10(m,3H,10-CH3),1.10–0.85(m,9H,8-CH3,13-CH2 CH 3and4-CH3);HRMS(ESI)m/z calcd.for C60H97N5O161144.4363;found(M+H+)1144.3542.
q)采用与实施例5b)相同的方法,但用化合物11代替其中的化合物4,得11-O-(苯乙基氨基甲酰基)-4″-O-(((3,4-二甲氧基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物28)白色固体,收率66.9%,mp107–110℃,TLC Rf=0.27(methanol/dichlormethane,1:5);IR(KBr):3409,3076,2972,2937,2878,1813,1723,1653,1604,1534,1484,1458,1378,1353,1334,1299,1279,1238,1166,1109,1086,1074,1046,1015cm-1;1H NMR(600MHz,CDCl3,δppm)7.45(s,2H,Ar-H),7.32–7.30(m,3H,Ar-H),6.87–6.86(m,3H,Ar-H),5.07(d,1H,1′-CH,J=4.2Hz),4.89(dd,1H,1″-CH,J=9.0Hz,J=6.6Hz),4.56–4.52(m,1H,13-CH),4.48–4.32(m,3H,11-CH,4″-CH and5″-CH),3.94(s,3H,Ar-O-CH3),3.93(s,3H,Ar-O-CH3),3.68–3.57(m,2H,2′-CH and5′-CH),3.50–3.46(m,2H,10-CH and3-CH),3.31(s,3H,3″-OCH3),3.29–3.24(m,6H,4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr and11-OCONHCH 2 CH2-Ar),2.90–2.80(m,2H,11-OCONHCH2 CH 2 -Ar),2.44(s,6H,3′-N(CH3)2),2.39–2.34(m,5H,2-CH,3′-CH,5-CH,4-CHand9a-CH),2.20(s,4H,9b-CH and9a-NCH3),2.08–1.78(m,3H,2″a-CH,8-CH and4′a-CH),1.68–1.58(m,6H,4″-OCONHCH2CH2 CH 2 CH 2 NHCOAr,2″b-CH and4′b-CH),1.44(s,6H,12-CH3and13″-CH3),1.30(s,6H,6-CH3,3-CH 2 CH3and7a-CH),1.22–1.18(m,7H,7b-CH,5″-CH3and5′-CH3),1.15(s,3H,10-CH3),1.08–1.02(m,6H,13-CH2 CH 3and2-CH3),0.94–0.90(m,6H,4-CH3and8-CH3);HRMS(ESI)m/z calcd.for C61H99N5O171174.4623;found(M+H+)1174.2590.
r)采用与实施例5c)相同的方法,但用4-甲氧基苯乙胺代替其中的3,4-二氟苄胺,得11-O-((4-甲氧基苯乙基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物30)淡黄色固体,收率65.0%,mp103–106℃,TLC Rf=0.25(methanol/dichlormethane,1:5);IR(KBr):3369,3062,2973,2936,2876,1722,1702,1667,1630,1542,1475,1456,1376,1344,1299,1253,1169,1110,1074,1050,1016cm-1;1H NMR(600MHz,CDCl3,δppm)9.18(s,2H,Ar-H),9.13(s,1H,Ar-H),7.10–7.08(m,2H,Ar-H),6.82–6.79(m,2H,Ar-H),5.02–4.96(m,2H,1′-CH and1″-CH),4.72–4.64(m,1H,13-CH),4.50–4.28(m,3H,11-CH,4″-CH and5″-CH),3.82–3.76(m,3H,Ar-O-CH3),3.66–3.46(m,4H,2′-CH,5′-CH,10-CH and3-CH),3.42–3.36(m,6H,4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr and11-OCONHCH 2 CH2-Ar),3.34–3.26(m,3H,3″-OCH3),2.80–2.56(m,4H,2-CH,3′-CH and11-OCONHCH 2 CH2-Ar),2.42–2.34(m,3H,5-CH,9a-CH and4-CH),2.29(s,6H,3′-N(CH3)2),2.26(s,3H,9a-NCH3),2.04–1.46(m,11H,2″a-CH,9b-CH,8-CH,4′a-CH,4″-OCONHCH2CH2 CH 2 CH2NHCOAr,12-CH3,2″b-CH and4′b-CH),1.28–1.22(m,5H,4″-OCONHCH2 CH 2 CH2CH2NHCOAr,13-CH 2 CH3and7a-CH),1.22–1.14(m,10H,7b-CH,5″-CH3,3″-CH3and6-CH3),1.14–1.10(m,6H,2-CH3and5′-CH3),0.98–0.96(m,6H,10-CH3and13-CH2 CH 3),0.90–0.84(m,6H,4-CH3and8-CH3);MS(ESI)m/z calcd.for C60H95N7O201233.7;found(M+H+)1235.0.
s)采用与实施例5c)相同的方法,但用2-氯苯乙胺代替其中的3,4-二氟苄胺,得11-O-((2-氯苯乙基)氨基甲酰基)-4″-O-(((3,5-二硝基苯甲酰胺基)正丁基)氨基甲酰基)阿奇霉素(目标化合物31)红褐色固体,收率62.7%,mp101–104℃,TLC Rf=0.23(methanol/dichlormethane,1:5);IR(KBr):3430,3062,2973,2936,2876,1723,1668,1629,1542,1475,1457,1376,1344,1301,1299,1253,1169,1111,1074,1050,1016cm-1;1H NMR(600MHz,CDCl3,δppm)9.21(s,2H,Ar-H),9.01(s,1H,Ar-H),7.32–7.28(m,1H,Ar-H),7.26–97.12(m,3H,Ar-H),5.03–5.00(m,2H,1′-CH and1″-CH),4.67–4.65(m,1H,13-CH),4.45–4.35(m,3H,11-CH,4″-CH and5″-CH),3.54–3.48(m,8H,2′-CH,5′-CH,10-CH,3-CH and4″-OCONHCH 2 CH2CH2 CH 2 NHCOAr),3.30(s,3H,3″-OCH3),3.00–2.90(m,5H,2-CH and11-COCONHCH 2 CH 2 -Ar),2.54–2.52(m,2H,5-CHand3′-CH),2.42–2.25(m,8H,3′-N(CH3)2,4-CH and9a-CH),2.23(s,3H,9a-NCH3),2.04–2.02(m,2H,9b-CH and2″a-CH),2.02–1.95(m,2H,8-CH and4′a-CH),1.90–1.40(m,12H,4″-OCONHCH2 CH 2 CH 2 CH2NHCOAr,12-CH3,2″b-CH,4′b-CH,13-CH 2 CH3and7a-CH),1.36–1.22(m,9H,5″-CH3,3″-CH3and6-CH3),1.22–1.14(m,10H,7b-CH,5′-CH3,10-CH3and2-CH3),1.14–1.00(m,3H,13-CH2 CH 3 ),1.04–0.96(m,3H,8-CH3),0.92–0.86(m,3H,4-CH3);HRMS(ESI)m/z calcd.for C59H92ClN7O191238.8503;found(M+H+)1238.2801。
Claims (2)
1.4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物,具有通式(Ⅲ)的结构:
其中,R1为氢;R2是4-甲氧基苄基、2-甲氧基苄基、4-氯苄基、4-甲基苄基、3,4-二甲氧基苄基或3,5-二硝基苄基;R3是苄基、4-甲氧基苄基、3,4-二甲基苄基、4-氟苄基、3,4-二氟苄基、苯乙基、4-甲氧基苯乙基、4-氟苯乙基或2-氯苯乙基;n=2或4。
2.一种药物组合物,其特征是,包含有治疗量的权利要求1所述的4″-((取代苯甲酰胺基)烷基)氨基甲酸酯阿奇霉素11-氨基甲酸酯衍生物或其药学上可接受的盐。
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CN102718816B (zh) * | 2012-07-11 | 2014-11-05 | 山东大学 | 4''-O-(反式-β-芳基烯丙酰胺)氨基甲酰基阿奇霉素衍生物 |
CN103130848B (zh) * | 2013-02-22 | 2015-07-08 | 中国人民解放军第二军医大学 | 一种大环内酯类抗菌化合物及其制备方法和应用 |
RU2570425C1 (ru) * | 2014-12-22 | 2015-12-10 | Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт по изысканию новых антибиотиков имени Г.Ф. Гаузе" | Химерные антибиотики на основе гликопептидов и 11,12-циклического карбоната азитромицина и способ их получения |
CN104844671B (zh) * | 2015-05-19 | 2017-07-04 | 山东大学 | 11‑o‑芳烷基氨基甲酸酯克拉霉素衍生物及其制备方法与应用 |
CN110330539B (zh) * | 2019-08-26 | 2020-11-13 | 山东大学第二医院 | 一种阿奇霉素类化合物及制备方法与应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006050941A1 (en) * | 2004-11-11 | 2006-05-18 | Glaxo Group Limited | Macrolone compounds |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006050941A1 (en) * | 2004-11-11 | 2006-05-18 | Glaxo Group Limited | Macrolone compounds |
CN101423539A (zh) * | 2008-12-09 | 2009-05-06 | 山东大学 | 4″,11-二氨基甲酸酯阿奇霉素衍生物、制备方法及其药物组合物 |
Non-Patent Citations (2)
Title |
---|
葛涵,等.阿奇霉素衍生物的合成及抗菌活性.Ⅱ.4"-取代酰基肼基甲酸酯.《中国医药工业杂志》.2009,第40卷(第08期),567-572. |
葛涵,等.阿奇霉素衍生物的合成及抗菌活性.Ⅱ.4"-取代酰基肼基甲酸酯.《中国医药工业杂志》.2009,第40卷(第08期),567-572. * |
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