CN111388489A - 安普霉素在制备细菌感染性疾病治疗中的应用 - Google Patents
安普霉素在制备细菌感染性疾病治疗中的应用 Download PDFInfo
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- CN111388489A CN111388489A CN202010313967.0A CN202010313967A CN111388489A CN 111388489 A CN111388489 A CN 111388489A CN 202010313967 A CN202010313967 A CN 202010313967A CN 111388489 A CN111388489 A CN 111388489A
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- Prior art keywords
- apramycin
- amino
- alkyl
- hydroxy
- acyl
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Abstract
本发明涉及式(I)的安普霉素或其药学上可接受的酸加成盐在制备用于治疗人类患者的革兰氏阴性菌感染的药物中的应用。经证明,安普霉素令人惊奇地不具有所预期的在相关氨基糖苷抗生素中观察到的高水平的毒性,而实际上甚至显著地比已经用于人的药物,诸如庆大霉素的化合物毒性更小。
Description
本申请是分案申请,其原申请的国际申请号为PCT/EP2011/065701,国际申请日为2011年09月12日,中国国家申请号为201180043882.4,进入中国国家阶段的进入日为2013年03月12日,发明名称为“细菌感染性疾病的治疗”。
发明领域
本发明涉及一种新的对人的细菌感染性疾病的药物治疗。本发明具体涉及应用安普霉素(apramycin)和安普霉素衍生物以治疗人的细菌感染性疾病。
发明背景
安普霉素是一种源于名为尼拉霉素(nebramycin)因子II(美国专利号3,691,279)的氨基糖苷类抗生素。其在兽药中的应用已经在美国专利号3,876,767中公开。安普霉素及其某些酰化的或烷化的衍生物还已经在美国专利号4,360,665中被描述为广谱抗生素。然而,安普霉素从未用于人,因为考虑到其具有相当高的毒性风险(Kondo等,Angew.Chem.Int.Ed.2006,45:3310-3314)。安普霉素甚至未被批准用于供人消费的产奶的牛或羊。
发明简述
本发明提供治疗人细菌感染性疾病的方法,该方法包括给予有需要的患者有效治疗量的式(I)安普霉素或安普霉素衍生物。
此外,本发明涉及用于这样的治疗的安普霉素或安普霉素衍生物,涉及安普霉素或安普霉素衍生物在制备用于治疗人的细菌感染性疾病的药物中的应用,和涉及某些特别的新的安普霉素衍生物。
图的简述
图1:体外耳蜗毒性
A=对照组
B=安普霉素0.5mM:很少(<5%)内外耳毛细胞缺失。
C=庆大霉素0.5mM:所有的(>80%)内外耳毛细胞丢失。
D=新霉素0.5mM:所有的(>80%)内外耳毛细胞丢失。
图2:耳蜗移植物中的毛细胞丢失和体内耳毒性
(a)药物引起的耳蜗移植物中毛细胞丢失的剂量-效应关系。沿着移植物的全长量化毛细胞丢失并且相对于药物浓度作图。%=%外耳毛细胞缺失。
圆圈●和实线---:庆大霉素;方块■和虚线-----:安普霉素。
数据点代表均值±sem,每个数据点n=3-12。
(b)体内慢性氨基糖苷治疗对听觉脑干反应的作用。
dB=于12kHz的听阈位移。“听阈位移”是治疗前和治疗后三周听觉阈值的差异。
圆圈●和实线---:庆大霉素;方块■和虚线-----:安普霉素。
数据点代表均值±sem,每个数据点n=3-11(除了160mg庆大霉素只有1只存活的动物之外)。注意,听阈位移以dB给定,其相应于对数标度,即每10dB指能量1log10差异。
安普霉素的体外耳蜗毒性显著小于庆大霉素的体外耳蜗毒性,且相比于庆大霉素,安普霉素治疗后体内听觉反应实质上较少受影响。
发明详述
本发明提供治疗人的细菌感染性疾病的方法。本发明的治疗包括给予有需要的患者有效治疗量的安普霉素或安普霉素衍生物或其酸加成盐,特别是有效治疗量的安普霉素或其酸加成盐。
此外,本发明涉及安普霉素或安普霉素衍生物或其酸加成盐,用于治疗人的细菌感染性疾病,和涉及安普霉素或安普霉素衍生物或其酸加成盐的应用,用于制备治疗人的细菌感染性疾病的药物。优选地,使用安普霉素或其酸加成盐。
经证明,安普霉素令人惊奇地不具有所预期的在相关氨基糖苷抗生素中观察到的高水平的毒性,而实际上甚至显著地比已经用于人的药物,诸如庆大霉素的化合物毒性更小。
安普霉素是式(I)氨基糖苷
(环III)
依据本发明的安普霉素的衍生物,例如,式(I)安普霉素的衍生物,其中
-一个或多个氨基是烷化的、环烷化的、烯化的和/或酰化的或被羟基替代,和/或
-一个或多个羟基是烷化的、烯化的、酰化的,和/或被氨基替代,和/或
-两个相邻的羟基经环化以形成缩醛(acetal)或碳酸酯,和/或
-相邻的羟基和氨基或N-酰化的氨基经环化以形成氨基乙缩醛或氨基甲酸脂,和/或
-7'-NHCH3基团被氨基NH2、烷化的、环烷化的、烯化的和/或酰化的氨基、羟基、烷化的、环烷化的、烯化的或乙酰化的羟基替代,和/或
-3'碳原子被氨基NH2或烷化的、环烷化的、烯化的和/或酰化的氨基取代,或被羟基OH或烷化的、烯化的或酰化的羟基替代,和/或
-5和/或6羟基被单糖糖基化,和/或
-环I或环III被不同的单糖替代。
被认为是使羟基和/或氨基烷化的烷基是直链或支链C1-C7-烷基,优选,C1-C4-烷基,例如甲基、乙基、正-丙基、异丙基或异丁基,特别是甲基或乙基;环丙基甲基、任选取代的苄基,例如苄基或对-甲氧基苄基;和氨基-、乙酰基氨基-和/或羟基-C1-C4-烷基,例如2-氨基乙基、2-乙酰基氨基乙基、2-羟基乙基、4-氨基-2-羟基丁基或3-氨基-2-羟基丙基。
被认为是使氨基环烷化的环烷基是C3-C7-环烷基,特别是环丙基。
被认为是使羟基和/或氨基烯化的烯基是直链或支链C1-C7-烯基,优选,C1-C4-烯基,例如烯丙基或异丁烯基,特别是烯丙基。
被认为是使羟基和/或氨基酰化的酰基是C1-C7-酰基,优选,C1-C4-酰基,例如乙氧基羰基、丙酰基或乙酰基,特别是乙酰基;氨基-、乙酰基氨基-和/或羟基-C1-C7-酰基,例如羟基乙酰基、氨基乙酰基、乙酰基氨基乙酰基、γ-氨基-α-羟基丁酰基、γ-乙酰基氨基-α-羟基丁酰基、β-氨基-α-羟基丙酰基或β-乙酰基氨基-α-羟基丙酰基;源于20个天然存在的必需α-氨基酸,优选地,源于中性或碱性α-氨基酸,例如源于丙氨酸、缬氨酸、亮氨酸、异亮氨酸、丝氨酸、苏氨酸、苯丙氨酸或赖氨酸的氨基乙酰基;芳酰基,例如任选取代的苯甲酰基,诸如苯甲酰基、对-甲氧基苯甲酰基或3,4,5-三甲氧基苯甲酰基;和杂芳酰基,例如吡啶基羰基,诸如2-、3-或4-吡啶基羰基、噻吩羰基,诸如2-或3-噻吩羰基或呋喃基羰基,诸如2-或3-呋喃基羰基。被认为是使羟基酰化的其他的酰基为硫酸酯和磷酸酯。
由两个相邻的羟基形成的环状缩醛是源于C1-C7-烷基醛,优选C1-C4-烷基醛,例如甲醛、乙醛、苯甲醛、二(C1-C7-烷基)酮,优选地,二(C1-C4-烷基)酮,例如丙酮,源于环戊酮或源于环己酮的缩醛。由相邻的羟基和氨基形成的环氨基乙缩醛(cyclicaminoacetal)同样源于C1-C7-烷基醛、苯甲醛、二(C1-C7)酮、环戊酮或环己酮;其可被C1-C4酰基N-酰化。
在取代的苄基和取代的苯甲酰基中,取代基可为C1-C4-烷基,例如甲基、C1-C4-烷氧基,例如甲氧基或乙氧基、氯代、溴代、氟代、氰基或硝基。这样的取代的苄基或苯甲酰基可携带一个、两个或三个提及的取代基。
被认为是环I或环III替代物或作为5或6羟基的取代基的单糖是,例如,葡萄糖、葡萄糖胺、3-氨基-3-脱氧葡萄糖、3,4-二氨基-3,4-二脱氧葡萄糖、4-氨基-3,4二脱氧葡萄糖、4-氨基-3,6-二脱氧葡萄糖、6-氨基-6-脱氧葡萄糖、4-氨基-4-脱氧阿洛糖(allose)、4-氨基-4-脱氧艾杜糖(idose)、核糖、5-氨基-5-脱氧核糖、3,5-二氨基-3,5-二脱氧核糖、木糖、5-氨基-5-脱氧木糖、3,5-二氨基-3,5-二脱氧木糖、阿拉伯糖、4-氨基-4-脱氧阿拉伯糖(D和L)、5-氨基-5-脱氧阿拉伯糖、3,5-二氨基-3,5-二脱氧阿拉伯糖、6-氨基-3,4,6-三脱氧-D-赤型-己-3-烯桥吡喃糖(enopyranose)或6-氨基-4,5,6-三脱氧-L-苏型-己-4-烯桥吡喃糖。
安普霉素的任何氨基或取代基氨基-烷基或氨基-酰基的氨基可处于保护形式。认为保护基团是,例如,那些在介绍保护基团的书,诸如T.W.Greene和P.G.M.Wuts,"有机合成中的保护基团(Protective Groups in Organic Synthesis)",Wiley,第3版,1999中所提到的基团。氨基保护基团的具体的实例是邻苯二甲酰基、丁二酰基、戊二酰基、叔-丁氧基羰基、苄氧基羰基等。
安普霉素的具体的衍生物是式(I)衍生物,其中
-一个或多个氨基是烷化的、环烷化的、烯化的和/或酰化的和/或
-一个或多个羟基是烷化的、烯化的或酰化的,和/或
-两个相邻的羟基经环化以形成缩醛或碳酸酯,和/或
-相邻的羟基和氨基经环化以形成氨基乙缩醛或氨基甲酸脂,和/或
-7'-NHCH3基团被氨基NH2或烷化的、环烷化的、烯化的和/或酰化的氨基替代,和/或
-3'碳原子被氨基NH2或烷化的、环烷化的、烯化的和/或酰化的氨基取代或被羟基OH或烷化的、烯化的或酰化的羟基取代。
更为特别地,安普霉素衍生物是式(II)化合物,
其中
R1是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C3-C7-环烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;
R2是氢、C1-C4-烷基或C1-C4-烯基;
R3是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C3-C7-环烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;
R4是氢、C1-C4-烷基或C1-C4-烯基;
R5是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、源于天然存在的戊糖和己糖和相应的单氨基-脱氧或二氨基-二脱氧衍生物的单糖、芳酰基、杂芳酰基、SO2OH或PO(OH)2;
R6是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、源于天然存在的戊糖和己糖和相应的单氨基-脱氧或二氨基-二脱氧衍生物的单糖、芳酰基、杂芳酰基、SO2OH或PO(OH)2;或
R1和R6一起代表C1-C7-烷基-CH、苯基-CH、(C1-C7-烷基)2C、环-(CH2)4C、环-(CH2)5C或C=O;或
R5和R6一起代表C1-C7-烷基-CH、苯基-CH、(C1-C7-烷基)2C、环-(CH2)4C、环-(CH2)5C或C=O;
R7是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C3-C7-环烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;
R8是氢、C1-C4-烷基或C1-C4-烯基;
R9是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;
R10是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C3-C7-环烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;或
R9和R10一起代表C1-C7-烷基-CH、苯基-CH、(C1-C7-烷基)2C、环-(CH2)4C、环-(CH2)5C或C=O;
R11是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;
R12是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;或
R11和R12一起代表C1-C7-烷基-CH、苯基-CH、(C1-C7-烷基)2C、环-(CH2)4C、环-(CH2)5C或C=O;
R13是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C3-C7-环烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;或
R12和R13一起代表C1-C7-烷基-CH、苯基-CH、(C1-C7-烷基)2C、环-(CH2)4C、环-(CH2)5C或C=O;
R14是氢、C1-C4-烷基或C1-C4-烯基;
R15是氢、C1-C7-烷基、环丙基甲基、任选取代的苄基、氨基-C1-C7-烷基、乙酰基氨基-C1-C7-烷基、羟基-C1-C7-烷基、氨基-羟基-C1-C7-烷基、乙酰基氨基-羟基-C1-C7-烷基、C1-C4-烯基、C1-C7-酰基、氨基-C1-C7-酰基、乙酰基氨基-C1-C7-酰基、羟基-C1-C7-酰基、氨基-羟基-C1-C7-酰基、乙酰基氨基-羟基-C1-C7-酰基、源于20个天然存在的必需α-氨基酸的氨基乙酰基、芳酰基、杂芳酰基、SO2OH或PO(OH)2;或
R13和R15一起代表C1-C7-烷基-CH、苯基-CH、(C1-C7-烷基)2C、环-(CH2)4C、环-(CH2)5C或C=O;
R16是氢、C1-C4-烷基、环丙基甲基、环丙基或C1-C4-烯基;或,任选地,N-R10和R16一起代表饱和的或部分未饱和的杂环,诸如氮丙啶、吖啶、吡咯烷、哌啶、哌嗪或吗啉;和
R17是氢;氨基、C1-C7-烷基氨基、环丙基甲基氨基、任选取代的苄基氨基、氨基-C1-C7-烷基氨基、乙酰基氨基-C1-C7-烷基氨基、羟基-C1-C7-烷基氨基、氨基-羟基-C1-C7-烷基氨基、乙酰基氨基-羟基-C1-C7-烷基氨基、C3-C7-环烷基氨基、C1-C4-烯基氨基、C1-C7-酰基氨基、氨基-C1-C7-酰基氨基、乙酰基氨基-C1-C7-酰基氨基、羟基-C1-C7-酰基氨基、氨基-羟基-C1-C7-酰基氨基、乙酰基氨基-羟基-C1-C7-酰基氨基、氨基乙酰基氨基,其中氨基乙酰基源于20个天然存在的必需α-氨基酸、芳酰基氨基、杂芳酰基氨基、NHSO2OH、NHPO(OH)2;羟基、C1-C7-烷氧基、环丙基甲氧基、任选取代的苄基氧基、氨基-C1-C7-烷氧基、乙酰基氨基-C1-C7-烷氧基、羟基-C1-C7-烷氧基、氨基-羟基-C1-C7-烷氧基、乙酰基氨基-羟基-C1-C7-烷氧基、C1-C4-烯基氧基、C1-C7-酰基氧基、氨基-C1-C7-酰基氧基、乙酰基氨基-C1-C7-酰基氧基、羟基-C1-C7-酰基氧基、氨基-羟基-C1-C7-酰基氧基、乙酰基氨基-羟基-C1-C7-酰基氧基、氨基乙酰氧基,其中氨基乙酰基源于20个天然存在的必需α-氨基酸、芳酰基氧基、杂芳酰基氧基、OSO2OH或OPO(OH)2;
前提条件是,当R16是甲基和R17是氢时,取代基R1至R15中的至少一个不同于氢;
及其衍生物,其中一个或多个氨基处于被保护的形式。
优选的是式(II)化合物,其中R17是氢。在这样的化合物中,5个仲羟基的任一个和一个伯羟基(OR15)可为烷化的、烯化的或酰化的,或被氢原子替代,或2、3、4、5个或所有的6个羟基也是这样。
优选的是式(II)化合物,其中R5、R6、R9、R11、R12和R15之一,特别是R15是C1-C4-烷基,例如甲基或C1-C4-酰基,例如乙酰基、R16是甲基,而其他的取代基都是氢。同样,优选这样的化合物,其中R5、R6、R9、R11、R12和R15都是C1-C4-烷基,例如甲基或C1-C4-酰基,例如乙酰基,R16是甲基,而其他取代基都是氢。
优选这样的衍生物,其中R15是C1-C4-烷基、C1-C4-烯基或C1-C4-酰基,R16是甲基,而所有其他的取代基都是氢。也优选这样的衍生物,其中R5、R6和R12中的一个、两个或三个是C1-C4-烷基、C1-C4-烯基或C1-C4-酰基,R16是甲基,而所有其他的取代基都是氢。
同样,在式(II)化合物中,其中R17是氢,4个伯氨基中的任何一个可为烷化的、二烷化的、烯化的、二烯化的或酰化的,或2、3或所有的4个伯氨基也是这样,例如以四乙酸酯的形式。
优选的是式(II)化合物,其中R1、R3、R7和R13之一,特别是R13是C1-C4-烷基,例如甲基、C3-C7-环烷基,例如环丙基、C1-C4-酰基,例如乙酰基、氨基-、乙酰基氨基-和/或羟基-C1-C4-酰基,例如羟基乙酰基、氨基乙酰基、乙酰基氨基乙酰基、γ-氨基-α-羟基丁酰基、γ-乙酰基氨基-α-羟基丁酰基、β-氨基-α-羟基丙酰基或β-乙酰基氨基-α-羟基丙酰基,R16是甲基,而其他的取代基都是氢。同样,优选的是这样的化合物,其中R1、R3、R7和R13都是C1-C4-酰基,例如乙酰基,R16是甲基,而其他的取代基都是氢。同样,优选的是这样的化合物,其中这样优选的取代基氨基乙酰基、γ-氨基-α-羟基丁酰基或β-氨基-α-羟基丙酰基的氨基处于被保护的形式,如用苄氧基羰基或邻苯二甲酰基保护。
仲氨基NR10R16,其中R16是CH3,可被第二个甲基(R10是CH3)、被环丙基甲基(R10是环-C3H5-CH2-)或环丙基(R10是环-C3H5-)烷化,被烯丙基(R10是CH2=CHCH2-)烯化或为乙酰化(R10是CH3CO-)。任选、NR10R16也可代表饱和的或部分未饱和的杂环,诸如氮丙啶、氮杂环丁烷、吡咯烷、哌啶、哌嗪或吗啉。
优选的是式(II)化合物,其中R1或R7或R13,特别是R13是氨基-、乙酰基氨基-和/或羟基-C1-C7-酰基,例如羟基乙酰基、氨基乙酰基、乙酰基氨基乙酰基、γ-氨基-α-羟基丁酰基、γ-乙酰基氨基-α-羟基丁酰基、β-氨基-α-羟基丙酰基或β-乙酰基氨基-α-羟基丙酰基,R16是甲基,而所有其他的取代基都是氢。
同样,优选的是式(II)化合物,其中R9R10是C=O,R13是氨基-、乙酰基氨基-和/或羟基-C1-C7-酰基,例如羟基乙酰基、氨基乙酰基、乙酰基氨基乙酰基、γ-氨基-α-羟基丁酰基、γ-乙酰基氨基-α-羟基丁酰基、β-氨基-α-羟基丙酰基或β-乙酰基氨基-α-羟基丙酰基,R16是甲基,而所有其他的取代基都是氢。
还优选的是式(II)化合物,其中R10是甲基或烯丙基,R16是甲基,而所有其他的取代基都是氢;或其中R16是乙基、环丙基甲基、环丙基或烯丙基,而所有其他的取代基都是氢。
安普霉素的酸加成盐为与有机酸或无机酸所成的盐,特别是药学上可接受的盐。适宜的无机酸是,例如,卤酸,诸如盐酸、硫酸或磷酸。适宜的有机酸是,例如,羧酸、膦酸、磺酸或氨基磺酸,例如乙酸、丙酸、辛酸、癸酸、十二酸、甘醇酸、乳酸、反丁烯二酸、丁二酸、己二酸、庚二酸、辛二酸、壬二酸、苹果酸、酒石酸、柠檬酸、氨基酸,诸如谷氨酸或天冬氨酸、顺丁烯二酸、羟基顺丁烯二酸、甲基顺丁烯二酸、环己烷羧酸、金刚烷羧酸、苯甲酸、水杨酸、4-氨基水杨酸、酞酸、苯基乙酸、扁桃酸、肉桂酸、甲烷-或乙烷-磺酸、2-羟基乙烷磺酸、乙烷-1,2-二磺酸、苯磺酸、2-萘磺酸、1,5-萘-二磺酸、2-、3-或4-甲基苯磺酸、甲基硫酸、乙基硫酸、十二烷基硫酸、N-环己基氨基磺酸、N-甲基-、N-乙基-或N-丙基-氨基磺酸或其他有机质子酸,诸如抗坏血酸。
如在上文中定义的安普霉素衍生物不包括这样的衍生物,其中如在式(I)中指出的安普霉素结构的环I中的5和6位缺失氨基或羟基,或安普霉素的结构上还有添加的其他衍生物,除了以上指出的那些或安普霉素的结构的部分的消除或删除。
安普霉素、安普霉素衍生物或其酸加成盐特别有效对抗细菌和细菌-样生物体。在预防或化学治疗由这些病原体引起的局部或全身感染以及与细菌性感染相关的紊乱的人用药物中是适宜的,所述细菌感染包括与由肺炎链球菌(Streptococcus pneumoniae)、流感嗜血杆菌(Haemophilus influenzae)、卡他摩拉克氏菌(Moraxella catarrhalis)、金黄色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(S.epidermidis)或溶血葡萄球菌(S.haemolyticus)感染相关的肺炎、中耳炎、鼻窦炎、支气管炎、扁桃体炎和乳突炎;与由化脓性链球菌(streptococcus pyogenes)、C群和G群链球菌(Groups C和G streptococci)或白喉棒状杆菌(Corynebacterium diphtheriae)感染相关的咽炎、风湿热和肾小球肾炎;与由肺炎支原体(Mycoplasma pneumoniae)、嗜肺军团菌(Legionella pneumophila)、肺炎链球菌(Streptococcus pneumoniae)、流感嗜血杆菌(Haemophilus influenzae)或肺炎衣原体(Chlamydia pneumoniae)感染相关的呼吸道感染;由金黄色葡萄球菌(S.aureus)、溶血葡萄球菌(S.haemolyticus)、粪肠球菌(E.faecalis)、屎肠球菌(E.faecium)、坚韧肠球菌(E.durans),包括耐已知的抗菌素,诸如,但不限于β-内酰胺类、万古霉素、喹诺酮类、氯霉素、四环素和大环内酯的菌株所引起的血液和组织感染,包括心内膜炎和骨髓炎;与由金黄色葡萄球菌(Staphylococcus aureus)、凝固酶阴性葡萄球菌(如表皮葡萄球菌(S.epidermidis)、溶血葡萄球菌(S.haemolyticus))、化脓性链球菌(streptococcuspyogenes)、无乳链球菌(Streptococcus agalactiae)、链球菌群C-F(Streptococcalgroups C-F)(微小菌落链球菌)、草绿色链球菌(viridans streptococci)、微小组织棒状杆菌(Corynebacterium minutissimum)或汉赛巴尔通氏体(Bartonella henselae)感染相关的皮肤和软组织感染和脓肿和产褥热;与由肠杆菌(Enterobacteriaceae spp.)、金黄色葡萄球菌(Staphylococcus aureus)、凝固酶阴性葡萄球菌种(staphylococcal species)或肠球菌(Enterococcus spp.)感染相关的泌尿道感染;尿道炎和子宫颈炎;与由沙眼衣原体(Chlamydia trachomatis)、杜克雷嗜血杆菌(Haemophilus ducreyi)、梅毒螺旋体(Treponema pallidum)、解脲支原体(Ureaplasma urealyticum)或淋病奈瑟菌(Neiserriagonorrheae)感染相关的性传播疾病;与由金黄色葡萄球菌(S.aureus)(食物中毒和中毒性休克综合征)或A、B和C群链球菌(Groups A、B and C streptococci)感染相关的中毒性疾病;与由幽门螺杆菌(Helicobacter pylori)感染相关的溃疡;与由回归热疏螺旋体(Borrelia recurrentis)感染相关的全身发热综合征;与由伯氏疏螺旋体(Borreliaburgdorferi)感染相关的莱姆病(Lyme disease);与由沙眼衣原体(Chlamydiatrachomatis)、淋病奈瑟菌(Neisseria gonorrhoeae)、金黄色葡萄球菌(S.aureus)、肺炎链球菌(S.pneumoniae)、产脓链球菌(S.pyogenes)、流感嗜血杆菌(Hinfluenzae)或李斯特氏菌(Listeria spp.)感染相关的结膜炎、角膜炎和泪囊炎;与由非结核性分枝杆菌(NTM),诸如鸟-胞内分枝杆菌(Mycobacterium avium-intracellulare)、脓肿分枝杆菌(M.abscessus)、博氏分枝杆菌(M.Bolletii)或马赛分枝杆菌(M.Massiliense)感染相关的播散性疾病;由结核分枝杆菌(Mycobacterium tuberculosis)、麻风杆菌(M.leprae)、副结核分支杆菌(M.paratuberculosis)、堪萨斯分支杆菌(M.kansasii)、龟分支杆菌(M.chelonei)或偶然分支杆菌(M.fortuitum)引起的感染;与由空肠炎弯曲杆菌(Campylobacter jejuni)感染相关的肠胃炎;与由隐孢子虫(Cryptosporidium spp.)感染相关的肠道原虫;与由草绿色链球菌(viridans streptococci)感染相关的牙源性感染;与由百日咳杆菌(Bordetella pertussis)感染相关的持续性咳嗽;与由幽门螺杆菌(Helicobacter pylori)或肺炎衣原体(Chlamydia pneumonia)感染相关的动脉粥样硬化或心血管病;和由土拉弗朗西斯氏菌(Francisella tularensis)、立克次体(Rickettsiaspp.)、布鲁氏菌(Brucella spp.)、肠杆菌科(Enterobateriaceae)和革兰氏阴性非发酵杆菌(如假单胞菌(Pseudomonas spp.))引起的播散性感染。
安普霉素、安普霉素衍生物或其酸加成盐在治疗在囊肿性纤维化患者中由于假单胞菌(Pseudomonas spp.)感染的肺炎,或由于土拉弗朗西斯氏菌(Francisellatularensis)、立克次体(Rickettsia spp.)、布鲁氏菌(Brucella spp.)、肠杆菌(Enterobateriaceae spp.)和假单胞菌(Pseudomonas spp.)的播散性感染中特别有用。
将要用安普霉素、安普霉素衍生物或其酸加成盐治疗的一个具体的细菌感染性疾病是结核病。下一个特别考虑的疾病是由细菌病原体引起的败血症。第三个特别考虑的疾病是在囊肿性纤维化患者中由于假单胞菌(Pseudomonas spp.)感染的肺炎。第四个特别考虑的疾病是由非结核性分支杆菌,诸如鸟-胞内分枝杆菌(M.avium-intracellulare)、脓肿分枝杆菌(M.abscessus)、博氏分枝杆菌(M.bolletii)或马赛分枝杆菌(M.massiliense)引起的感染。
对于给药,活性成分优选呈现药用制剂的形式,所述制剂包含化学纯形式的安普霉素、安普霉素衍生物或其酸加成盐,和任选的药学上可接受的载体和任选的辅助剂。以有效对抗人的细菌感染性疾病的量使用安普霉素、安普霉素衍生物或其酸加成盐。活性成分的剂量取决于人的年龄、体重和个体状况、个体药动学数据和给药方式。在个人的体重为约70kg的情况下,安普霉素或其衍生物的给药日剂量为从0.01mg/kg体重至1000mg/kg体重,优选从0.1mg/kg体重至100mg/kg体重,更优选从1mg/kg至25mg/kg体重,以单一剂量或多剂量给予。可单独使用或与其他药物联合使用安普霉素、安普霉素的衍生物或其酸加成盐。
适于经肠给药,诸如经鼻、口颊、直肠,特别是口服给药和胃肠外给药,诸如皮下、静脉、肝内或肌肉给药的药用组合物是特别优选的。药用组合物包含从大约1%至大约95%的活性成分,优选从大约20%至大约90%的活性成分。
对于胃肠外给药,偏好优选应用安普霉素、安普霉素衍生物或其酸加成盐的溶液剂,还有混悬剂或分散剂,特别是例如,可在使用前即配的等张水溶液剂、分散剂或混悬剂。可对药用组合物进行灭菌处理和/或药用组合物可包含赋形剂,例如防腐剂、稳定剂、润湿剂和/或乳化剂、增溶剂、增粘剂、调节渗透压的盐和/或缓冲剂,并且以本身已知的方式,例如通过常规的溶解和冻干加工的方式制备。
对于口服药用制剂,适宜的载体特别是填充剂,诸如糖,例如乳糖、蔗糖、甘露醇或山梨醇、纤维素制备物和/或磷酸钙,还有粘合剂,诸如淀粉、纤维素衍生物和/或聚乙烯吡咯烷酮,和/或,如果需要,崩解剂、流量调节剂(flow conditioners)和滑润剂,例如硬脂酸或其盐,和/或聚乙二醇。可与适宜的、任选肠溶的包衣料一起提供片芯。可在片剂或片剂包衣料中加入染料或色素,例如目的是用于识别或用于指明活性成分的不同剂量。适于口服给药的药用组合物也包括由明胶组成的硬胶囊剂,还有由明胶和塑化剂,诸如丙三醇或山梨醇组成的密封软胶囊剂。胶囊剂可含颗粒形式或溶解于或悬浮于适宜的液体赋形剂,诸如油中的形式的活性成分。
也考虑经皮/腹膜内和静脉应用,例如采用透皮贴片,其使给药经过延长的时期,如从一天至十二天。
同样考虑作为气雾剂的应用。提供预定粒径的固体形式或作为溶液的活性成分。固体可与适宜的填充剂,诸如糖,例如乳糖混合使用。溶液剂优选为水性溶液剂,任选含防腐剂、稳定剂、增溶剂、用于调节渗透压的盐和/或缓冲剂。借助适宜的喷雾器或任选与抛射剂一起施用气雾剂,所述抛射剂为例如压缩形式的HFA134a(1,1,1,2,-四氟乙烷)、HFA227(1,1,1,2,3,3,3-七氟丙烷)、二氯二氟甲烷、1,1-或1,2-二氯四氟乙烷、三氯氟代甲烷或其组合。
静脉、肌肉或皮下应用是特别优选的。在囊性纤维化患者中由假单胞菌(Pseudomonas spp.)感染造成的肺炎中,气雾剂的施用是特别优选的。
通过本领域已知的方法,尤其是通过常规的混合、包衣、制粒、溶解或冻干工艺制备依据本发明的药物。
可单独或联合一个或多个其他的治疗剂一起给予安普霉素、安普霉素衍生物或其酸加成盐,可能的联合疗法采用安普霉素或安普霉素衍生物和一个或多个其他的治疗剂的固定组合的形式,所述治疗剂在治疗人的细菌感染性疾病中是已知的,给药可错开进行,或各自独立地进行,或以固定组合的形式给予。
所考虑的可能的组合配对药物(combination partners)为β-内酰胺、大环内酯、喹诺酮类(chinolones)、利福霉素或异烟肼。
本发明也涉及新的安普霉素衍生物本身及其酸加成盐。所考虑的具体化合物为
式(II)化合物,其中R1是γ-氨基-α-羟基丁酰基,R16是甲基,而所有其他的取代基都是氢;
式(II)化合物,其中R7是γ-氨基-α-羟基丁酰基,R16是甲基,而所有其他的取代基都是氢;和
式(II)化合物,其中R9R10是C=O,R13是γ-氨基-α-羟基丁酰基,R16是甲基,而所有其他的取代基都是氢。
所考虑的其它化合物为
式(II)化合物,其中R10是甲基,R16是甲基,而所有其他的取代基都是氢;
式(II)化合物,其中R10是烯丙基,R16是甲基,而所有其他的取代基都是氢;
式(II)化合物,其中R16是乙基,而所有其他的取代基都是氢;
式(II)化合物,其中R16是环丙基甲基,而所有其他的取代基都是氢;
式(II)化合物,其中R16是环丙基,而所有其他的取代基都是氢;和
式(II)化合物,其中R16是烯丙基,而所有其他的取代基都是氢。
以下的实例起阐述本发明的作用而不限制本发明于其范围内。
数据显示,安普霉素表现出潜在的包括抗结核分枝杆菌(M.tuberculosis)的抗菌活性,并且显示,安普霉素的抗菌活性并不被许多已知的氨基糖苷耐药决定子所削弱(compromised)。
具体地,这些数据证明:
i)安普霉素对细菌核糖体的活性类似于妥布霉素、庆大霉素、新霉素和巴龙霉素。相比妥布霉素、庆大霉素、新霉素和巴龙霉素而言,安普霉素显示对具有人序列多态性的单一rRNA残基指标的突变体细菌核糖体,如1408G、1491A、1491C显著低的活性。相比妥布霉素、庆大霉素、新霉素和巴龙霉素而言,安普霉素显示对携带人化药物结合位点的细菌杂交核糖体,如线粒体杂种(mitohybrid)、胞质杂种(cytohybrid)、1555G耳聋、1494U耳聋显著低的活性(就其原理和方法学而言,参见专利申请号WO2007/112965;Hobbie等,Nucl.AcidsRes.2007,35:6086-6093;Hobbie等,Proc.Natl.Acad.Soc.USA 2008,105:20888-20893)。总起来说,这些数据证实,安普霉素在药物靶水平的选择性,即原核细胞和真核细胞核糖体之间的区别(等,EMBO Rep.2001,2:318-323),比其他氨基糖苷类更高。
ii)与庆大霉素,安普霉素相比,令人惊奇地显示小的体外耳蜗毒性(离体(exvivo)耳蜗器官培养)、较少的体内肾毒性(豚鼠)和较少的体内耳毒性(豚鼠)。于是,安普霉素适宜人使用。
实施例1:相比于商业上可获得的氨基糖苷类而言,安普霉素对抗临床甲氧西林耐
药的金黄色葡萄球菌(Staphylococcusaureus)(MRSA)分离菌的活性(表1)
通过如在Pfister等,Antimicrob.Agents Chemother.2003,47:1496-1502中描述的,测定最小抑菌浓度(MIC)评估活性。使得自单一菌落的培养物在LB培养基中生长并用于在微滴定格式板的MIC测试。起始培养物含200μl的细菌细胞,其于600nm的光密度为0.025,和以两倍稀释系列加入相应的药物。将MIC定义为经25℃、24h的孵育后培养物的生长完全被抑制时的药物浓度。
与临床上已获确认的氨基糖苷类庆大霉素、西索米星、妥布霉素、卡那霉素、阿米卡星、新霉素和巴龙霉素形成对照的是,安普霉素不受存在于临床MRSA分离菌中的任何耐药决定子的影响。
结果示于表1中。
表1:相比于商业上可获得的氨基糖苷类,安普霉素对抗临床甲氧西林耐药的金黄
色葡萄球菌(Staphylococcus aureus)(MRSA)分离菌的活性–MICs(mg/l),LB微量稀释分析
法
a MSRA指定编号全称(No.)是AG038等,仅显示最后两个数字。
b菌株指定全称,对于以S接尾的菌株是70-26S GmS等,而对于以R或I.接尾的菌株是07-12R GmR等。
实施例2:相比于商业上可获得的氨基糖苷类,安普霉素对抗革兰氏阴性细菌的活
性(表2)
如在实施例1中描述的通过测定最小抑菌浓度(MIC)评估活性。
相比于如对庆大霉素、西索米星、妥布霉素、卡那霉素、新霉素和巴龙霉素所观察到的不同的活性概况(heterogeneous activity profiles)而言,安普霉素显示独特的活性概况(unique activity profile)基本上不受主要的氨基糖苷耐药决定子影响。
结果示于表2。
表2:相比于商业上可获得的氨基糖苷类,如由最小抑菌浓度(MICs,mg/l)所测定
的安普霉素对抗革兰氏阴性细菌的活性
a指定编号全称(No.)是AG01等。仅显示最后两个数字。所有的检测的细菌属于大肠埃希菌(E.coli)种。
bclin.isol.=临床分离菌;RM=耐药机制
实施例3:相比于阿米卡星和链霉素,安普霉素对抗结核分枝杆菌
(M.tuberculosis)的临床分离菌的活性(表3)
相比于阿米卡星和链霉素而言,采用MGIT960 EpiCenter仪器检测的安普霉素(μg/ml)对抗结核分枝杆菌(M.tuberculosis)的临床分离菌的活性。
R=耐药、S=敏感;关于方法学,参见Springer等,J.Clin.Microbiol.2009,47:1773-1780。结果示于表3中。
表3
实施例4:安普霉素对抗多重-耐药结核分枝杆菌(M.tuberculosis)的临床分离菌
的活性(表4)
如在实施例3中测试安普霉素(μg/ml)的活性。R=耐药,S=敏感。
表4
实施例5:相比于阿米卡星,安普霉素对抗非结核缓慢生长分枝杆菌(non-
tuberculous slow-growing mycobacterium)临床分离菌的活性(表5)
如在实施例3中那样测试安普霉素和阿米卡星的活性(μg/ml)。
R=耐药、S=敏感
表5
实施例6:相比于商业上可获得的氨基糖苷类,安普霉素对抗非结核缓慢生长分枝
杆菌属临床分离菌的活性(μg/ml)(表6)
在标准微量稀释分析法中评估安普霉素的活性并表达为最小抑菌浓度(MIC),表示为μg/ml。
表6
实施例7:药物选择性–相比于妥布霉素、庆大霉素和新霉素,安普霉素对多种核糖
体的活性(表7)
耻垢分枝杆菌(Mycobacteriumn smegmatis)的单一rRNA等位菌株用于rRNA突变发生(Sander等,Mol.Microbiol.1996,22:841-848)。区别原核与真核生物的编码位置的关键核苷酸是rRNA位置1408(细菌核糖体:A、真核胞浆核糖体:G)和1491(细菌核糖体:G、真核胞浆核糖体:A、真核线粒体核糖体)。
将多种版本的真核药物结合位点移植进入细菌核糖体(WO 2008/092690)以导致杂种核糖体,命名为线粒体杂种核糖体、胞质杂种核糖体、耳聋1555G核糖体、耳聋1494U核糖体(关于方法学、原理和杂种核糖体,参见Hobbie等,Nucleic Acids Res.2007,35:6086-6093;Proc.Natl.Acad.Sci.USA 2008,105:3244-3249;Proc.Natl.Acad.Sci.USA 2008,105:20888-20893)。
通过如在Pfister等,Animicrob.Agents Chemother.2003,47:1496-1502中描述的那样,检测最小抑菌浓度研究核糖体的药物敏感性(Ribosomal drug susceptibility)。携带各自突变改变(mutational alterations)的重组体经最小抑菌浓度(MIC)测定,以评估核糖体的药物敏感性。将来自单一菌落的培养物在补充了0.05%吐温80和用于在微滴定格式板中的MIC测试的LB培养基中生长。起始培养物含200μl的细菌细胞,其于600nm的光密度为0.025,和以两倍稀释系列加入相应的药物。将MIC定义为经25℃、72h的孵育相应于第24代传代后培养物的生长完全被抑制时的药物浓度。
如示于表7中的结果,相比妥布霉素、庆大霉素和新霉素,安普霉素对细菌核糖体更具选择。此通过以下发现得以证明,即与妥布霉素、庆大霉素和新霉素类似,安普霉素具有对抗野生型细菌核糖体的活性,但是对抗具有“人化药物结合位点”的突变体核糖体的活性大大减少。因此,安普霉素比可用到的4,5-和4,6-氨基糖苷类较少影响哺乳动物线粒体和胞浆核糖体。
表7:安普霉素对抗重组核糖体的活性
实施例8:体外耳蜗毒性(表8)
用0.5mM氨基糖苷化合物,处理自新生小鼠的的耳蜗移植物24h;随后通过表面荧光显微镜(epifluorescence microscopy)评估毛细胞损害。结果示于表8和图1中。
表8
实施例9:一般毒性
豚鼠接受全身施用氨基糖苷类,按表9指示的剂量每天一次计14天,然后再监测另外14天。结果示于表9。
表9
对于各给予432和649mg/kg安普霉素剂量的一头动物,在实验末进行尸检。动物显示良好的一般状况;皮肤系统、呼吸系统、心血管系统、泌尿生殖系统、内分泌系统、神经系统、淋巴系统、肌肉骨骼系统和胃肠系统没有观察到显著的损害或总体发现。
肾组织病理学,432mg/kg安普霉素:
描述:在肾间质很少、小的淋巴浆细胞性聚集物(lymphoplasmacyticaggregates)。这些变化影响少于5%的切片中的肾实质。
解释:轻度、多病灶淋巴浆细胞性炎症。
评论:间质内的炎症程度极小并且被认为是该种动物中的背景中的偶然发现。肾小管坏死或肾毒性的其他证据不是组织学证据。
肾组织病理学,649mg/kg安普霉素:
描述:在表面皮质很少、小的肾小管变性和再生灶。这些变化影响少于5%的切片中的肾实质。
解释:轻度、多病灶肾小管病变。
评论:在这些切片中肾小管病变灶极少和似乎不可能显著影响肾功能。
实施例10:如由听觉脑干反应(ABR)测定的体内耳蜗毒性(图2b)
豚鼠接受全身施用氨基糖苷类,按指出的剂量每天一次计14天,使其休息14天,然后接受治疗后ABR。结果示于图2b。
实施例11:安普霉素衍生物的合成
基于标准工艺方法合成以下化合物:
ETH 99:式(II)化合物,其中R9R10是C=O,R13是γ-氨基-α-羟基丁酰基,R16是甲基,而所有其他的取代基都是氢、四乙酸盐;
ETH 100:式(II)化合物,其中R7是γ-氨基-α-羟基丁酰基,R16是甲基,而所有其他的取代基都是氢、四乙酸盐;
ETH 101:式(II)化合物,其中R3和R7为γ-氨基-α-羟基丁酰基,R16是甲基,而所有其他的取代基都是氢、四乙酸盐;
ETH 102:式(II)化合物,其中R1是γ-氨基-α-羟基丁酰基,R16是甲基,而所有其他的取代基都是氢、四乙酸酯盐;
ETH 103:式(II)化合物,其中R7是γ-邻苯二甲酰基氨基-α-羟基丁酰基,R16是甲基,而所有其他的取代基都是氢、四乙酸盐;
ETH 105:式(II)化合物,其中R13是γ-氨基-α-羟基丁酰基、R16是甲基,而所有其他的取代基都是氢、四乙酸盐。
流程1
试剂和条件:a)ZCl、Na2CO3、MeOH/H2O;74%。b)NaH、DMF;68%。c)Pd(OH)2/C、H2(1atm)、二氧六环/AcOH/H2O 4:4:1;95%的10·3AcOH;90%的12·4AcOH;85%的14·4AcOH=ETH 99和12%的15=ETH 105(得自13)。d)Ba(OH)2·H2O、二氧六环/H2O 2:1;11的70%。e)(苄基氧基-(S)-4-羰基氨基)-2-羟基丁酸、N-羟基琥珀酰亚胺、DCC、Et3N、THF;85%。
1,3,2’,7’,4”-五聚-N-(苄基氧基羰基)安普霉素(8)。
于0℃,将苄基氧基羰基氯化物(26.9g,157mmol)滴加至剧烈搅动的安普霉素(1;10g,18.5mmol)和Na2CO3(29.5g,278mmol)于3:7H2O/MeOH(240ml)的混合物中。于0℃搅动混合物30min和于26℃搅动20h。在加入MeOH(200ml)之后,经过滤去除无机沉淀,并蒸发滤液。用H2O研磨残余物。丢弃水相。将有机相溶解于MeOH/AcOEt中,并预先吸附于硅胶上。FC(AcOEt/CHCl3/MeOH 4:4:0→4:4:1),得到8(8.95g,74%)。
白色固体。Rf
(CHCl3/AcOEt/MeOH 4:4:1)0.35.IR(ATR):3388w,3331w,2944w,1692s,1520m,1454m,1405m,1306m,1246m,1141m,1074m,1016s,996s,772m,735m,695s.[α]D 25=+68.7(c=1.0,MeOH).1H-NMR(600MHz,CD3OD):7.44-7.19(m,25H芳族的);5.34-5.24(m,H-C(1’),H-C(8’),H-C(1”));5.17-4.97,4.18-4.09,3.89-3.73,3.70-3.37,3.24-3.18(几个m,H-C(1),H-C(3),(H-C(4),H-C(5),H-C(6),H-C(2’),H-C(4’),H-C(5’),H-C(6’),H-C(7’),H-C(8’),H-C(2”),H-C(3”),H-C(4”),H-C(5”),H-C(6”),5CH2Ph);3.11(s,NMe);2.09-2.03(m,Heq-C(2),Heq-C(3’));1.77(q,J=11.8,Hax-C(3’));1.46(q,J=12.5,Hax-C(2)).13C-NMR(150MHz,CD3OD):159.77,159.11,158.68,158.67,158.20(5s,5C=O);138.36,138.31,138.27,138.05,138.02(5s芳族的);129.52-128.89(几个d芳族的);101.15(d,C(1’));99.60(d,C(1”));98.50(d,C(8’));96.29,95.75(2d);92.30(d);85.30,82.78,78.62,76.64,76.34(5d);74.10,74.04,73.78,71.87,71.66,71.48(6d);68.71,67.78,67.69,67.66,67.56(5t,5PhCH2);68.09,67.98(2d);66.69(d);63.19(t,(6”));62.83,60.97(2d);55.51,54.78,52.91,52.15,51.88,51.71,51.45(7d);33.39,31.40(2t,C(2),C(3’));30.11(q,NMe).HR-MALDl-MS:1232.4540(100,[M+Na]+,C61H71N5NaO21 +;calc.1232.4539).
1,3,2’-三-N-(苄基氧基羰基)-7’-N,6’-O-羰基-4”-N-6”-O-羰基-安普霉素(9)。
于0℃,用NaH(198mg,5.16mmol,60%分散于矿物油中)处理8(3.123g,2.58mmol)于无水DMF(20ml)中的溶液。2h内使反应混合物温热至26℃,并于26℃再搅动2h。用1Naq.AcOH(5ml)猝灭混合物并蒸发至干。使得到的浆液溶解于MeOH/AcOEt和预吸附于硅胶上。FC(AcOEt/CHCl3/MeOH 4:4∶0→4∶4∶1),得到9(1.75g,68%),白色固体。
Rf(CHCl3/AcOEt/MeOH 4∶4∶1)0.20.IR(ATR):3317w(br.),2937w,1750(sh.),1704s,1697s,1525m,1454m,1410m,1339m,1256m,1139m,1075s,1027s,1002s,980s,757m,739s,697s.[α]D 25=+64.6(c=1.0,MeOH/45μlDMSO).1H-NMR(600MHz,Pyr-d5):9.49(s,HN-C(4”));8.35(s,HN-C(1),HN-C(3));7.79(s,HN-C(2’));7.45-7.26(m,15H芳族的);5.83-5.63(m,H-C(1’),H-C(1”));5.40-5.06(m,H-C(6’),H-C(8’),3CH2Ph);5.00(br.s,4OH);4.50.-4.46(H-C(4”),Heq-C(6”));4.33(t,J=10.3,Hax-C(6”));4.24-4.12(m,H-C(4),H-C(2’),H-C(2”),H-C(5”));4.02-3.97(m,H-C(1),H-C(5));3.87-3.78(m,H-C(3),H-C(4’),H-C(5’));3.68(t,J=9.7,H-C(3”));3.43(br.d,J=9.0,H-C(7’));2.87(s,NMe);2.61-2.58(m,Heq-C(3’));2.39-2.37(m,Heq-C(2));2.31(q,J=11.6,Hax-C(3’));2.23-2.19(m,Hax-C(2)).13C-NMR(150MHz,Pyr-d5):157.91,157.19,156.70,156.46,153.19(5s,5C=O);138.14,137.95,137.34(3s芳族的);128.99-128.14(几个d芳族的);100.29(d,C(1’));96.04(d,C(1”));91.07(d,C(8’));84.03(d,C(4));78.16,76.31,73.11(3d,C(4’),C(5’),C(2”));71.83(d,C(4”));70.31(d,C(6’));68.37(t,C(6”));66.69,66.27,66.29(3t,3PhCH2);66.21(d,C(5));65.81(d,C(6));63.88(d,C(5”));59.65(d,(7’));58.13(d,C(3”));52.82(d,C(1));51.79(d,C(3));51.39(d,C(2’));35.23,32.49(2t,C(2),C(3’));29.66(q,NMe).HR-MALDI-MS:1016.3383(100,[M+Na]+,C47H55N5NaO19 +;calc.1016.3389).
7’-N,6’-O-羰基-4”-N,6”-O-羰基-安普霉素三乙酸盐(10)。
用20%Pd(OH)2/C(30mg)处理9(30mg,30μmol)于80%aq.AcOH(1.0ml)和二氧六环(0.8ml)中的溶液,并于H2(1atm)下搅动15h。混合物经硅藻土过滤,用H2O洗涤和蒸发滤液。用CH2Cl2洗涤于H2O中的残余物溶液。冷冻干燥含水溶液,得到10·3AcOH(22mg,95%)。浅棕色固体。
IR(ATR):3349w(br),3222w(br),2924w,1747m,1707m,1552s,1407s,1147m(sh),1098m(sh),1078m(sh),1026s(sh),980s,760m.1H-NMR(500MHz,D2O):5.63(d,J=3.4,H-C(1’));5.35(d,J=3.8,H-C(1”));5.24(d,J=1.7,H-C(8’));5.06(dd,J=9.4,3.2,H-C(6’));4.67(被HOD信号遮蔽),H-C(5’));4.30(dd,J=9.8,4.9,Heq-C(6”));4.20(dd,J=9.4,1.7,H-C(7’));4.13(t,J=10.4,Hax-C(6”));3.98(td,J=10.1,4.8,H-C(5”));3.88(td,J=10.9,4.0,H-C(4’));3.82(t,J=9.7,H-C(4));3.70(dd,J=9.5,4.0,H-C(2”));3.64-3.60(m,H-C(3”);3.54(m,H-C(5),H-C(2’));3.47(t,J=9.7,H-C(6));3.40-3.34(m,H-C(3));3.27-3.19(m,H-C(1),H-C(4”));2.82(s,NMe);2.40(dt,J=12.8,4.0,Heq-C(2)),2.28(dt,J=10.9,4.3,Heq-C(3’));1.98(q,J=12.0,Hax-C(3’)),1.82(br.s,3MeCO2);1.73(q,J=12.9,Hax-C(2)).13C-NMR(125MHz,D2O):180.17(s,4OC=O);159.02(s,MeNC=O);155.21(s,HNC=O);95.56(d,C(1’));94.56(d,C(1”));90.18(d,C(8’));78.27(d,C(4));74.97(d,C(5));72.35(d,C(6));70.52(d,C(2”));69.63(d,C(3”));69.20(d,C(6’));67.62(t,C(6”));65.11(d,C(5’));64.03(d,C(4’));61.99(d,C(5”));58.87(d,C(7’));55.52(d,C(4”));49.58(d,C(1));48.42(d,C(3));47.71(d,C(2’));29.08(q,NMe);28.51,28.39(2t,C(2),C(3’));22.81(q,3MeC=O).HR-MALDI-MS:566.2670(100,[M+H]+,C22H40N5O12 +;calc.566.2673).
1,3,2’-Tris-N-(苄基氧基羰基)-7’-N,6’-O-羰基-安普霉素(11)
用Ba(OH)2.H2O(76mg,0.4mmol)处理9(0.2g,0.2mmol)在2∶1二氧六环/H2O(15ml)中的溶液并于70℃搅动3h。冷却至室温后,用CO2中和该混合物并蒸发。经与甲苯共同蒸发去除H2O。使残余物溶于MeOH并经硅藻土过滤。蒸发合并的滤液和洗液。FC(CHCl3/MeOH/aq.NH3(25%)80∶20∶0→80∶15∶5),得到11(136mg,70%),白色固体。
Rf(CHCl3/MeOH/aq.NH3(25%)70:15∶2)0.20.IR(ATR):3306w(br.),2937w,1744m(sh.),1690s,1530m,1455m,1392m,1302m(sh.),1255m,1224m,1131m,1070m(sh.),1032s,1000s,852m,736m,696s.[α]D 25=+64.7(c=0.5,MeOH).1H-NMR(600MHz,Pyr-d5):8.56(d,J=8.1,HN-C(1));8.41(d,J=8.4,HN-C(3));8.00(d,J=7.3,HN-C(2’));7.46-7.22(m,15H芳族的);5.80-576(m,H-C(1’),H-C(1”));5.47-5.01(m,H-C(6’),H-C(7’),H-C(8’),3CH2Ph,NH2,5OH);4.44(t,J=9.2,H-C(5”));4.38(dd,J=11.7,2.6,H-C(6”));4.23-4.17,4.07-4.04,4.00-3.84(几个m,H-C(1),H-C(3),H-C(4),H-C(5),H-C(6),H-C(2’),H-C(4’),H-C(1”),H-C(2”),H-C(3”));3.43(dd,J=8.8,2.3,H-C(5’));3.34(t,J=9.6,H-C(4”));2.87(s,NMe);2.55-2.52(m,Heq-C(3’));2.45-2.41(m,Heq-C(2));2.34(q,J=11.7,Hax-C(3’));2.22(q,J=12.7,Hax-C(3’)).13C-NMR(150MHz,Pyr-d5):157.87,157.22,156.76,156.59(4s,4C=O);138.15,137.98,137.49(3s芳族的);129.03-128.16(几个d芳族的);100.16(d,C(1’));95.29(d,C(1”));91.00(d,C(8’));83.73(d);78.24,76.34,76.04,74.67,73.37,70.74(6d);66.72,66.30,66.25,(3t,3PhCH2);66.35,65.84(d);63.30(t,C(6”));59.65(d);55.72(d);52.81,51.79,51.31(3d);35.50,32.73(2t,C(2),C(3’));29.77(q,NMe).HR-MALDI-MS:990.3590(100,[M+Na]+,C46H57N5NaO18 +;calc.990.3590).
7’-N,6’-O-羰基-安普霉素四乙酸酯(12)
用20%Pd(OH)2/C(30mg)处理11(30mg,31μmol)于80%aq.AcOH(1.0ml)和二氧六环(0.8ml)中的溶液,并于H2(1atm)下搅动15h.。该混合物经硅藻土过滤,用H2O洗涤。蒸发合并的滤液和洗液。用CH2Cl2洗涤于H2O中的残余物溶液。冷冻干燥含水溶液,得到12·4AcOH(22.5mg,90%),亮棕色固体。IR(ATR):3321w(br),3162w(br.),2928w,1742m,1539s,1403s,1338m,1030m(sh),988s,925m,759m.1H-NMR(500MHz,D2O):5.64(br.s,H-C(1’));5.39(d,J=3.4,H-C(1”));5.28(br.s,H-C(8’));5.09(dd,J=9.3,3.3,H-C(6’));4.76(被HOD信号遮蔽),H-C(5’));4.24(dd,J=9.3,1.5,H-C(7’));3.97-3.88(m,H-C(4’),H-C(3”));3.82-3.69(m,H-C(4),H-C(2”),H-C(5”),2H-C(6”));3.60-3.56(m,H-C(5),H-C(2’));3.51(t,J=9.7,H-C(6));3.35-3.29(m,H-C(3));3.26(td,J=14.1,6.9,H-C(1));3.20(t,J=10.0,H-C(4”));2.88(s,NMe);2.41-2.39(m,Heq-C(2)),2.36-2.33(m,Heq-C(3’));2.03(q,J=12.0,Hax-C(3’)),1.88(br.s,4MeCO2);1.73(q,J=12.9,Hax-C(2)).13C-NMR(125MHz,D2O):181.07(s,4OC=O);159.16(s,MeNC=O);95.84(d,C(1’));93.57(d,C(1”));90.46(d,C(8’));79.45(d,C(4));75.18(d,C(5));72.63(d,C(6));70.52(d,C(2”));69.63,69.20(2d,C(6’),C(3”));65.52(d,C(5’));64.24(d,C(4’);62.41(d,C(5”));60.16(t,C(6”));59.08(d,C(7’));52.17(d,C(4”));49.84(d,C(1));48.50(d,C(3));47.88(d,C(2’));29.25(q,NMe);28.56,28.26(2t,C(2),C(3’));22.99(q,4MeC=O).HR-MALDI-MS:588.2495(27,[M+Na]+,C22H39N5NaO12 +;calc.588.2493),566.2673(52,[M+H]+,C22H40N5O12;calc.566.2673).
1,3,2’-三-N-(苄基氧基羰基)-7’-N,6’-O-羰基-4”-N-[(2S)-4-氨基-2-羟基丁
酰基]安普霉素(13)
将(苄基氧基-(S)-4-羰基氨基)-2-羟基丁酸(19mg,75μmol)、N-羟基琥珀酰亚胺(8.6mg,75μmol)和DCC(15.4mg,75μmol)在THF(2ml)中的混合物于26℃搅动2.0h。用11(60mg,62μmol)和三乙胺(17μl,122μmol)在无水THF(3ml)中的溶液处理该混合物并搅动20h。蒸发得到白色固体,将其溶解于CH2Cl2/MeOH中和预吸附于硅胶上。FC(CHCl3/MeOH/aq.NH3(25%)90:10:0→90:10:1),得到13(63mg,85%),白色固体。Rf(CHCl3/MeOH/aq.NH3(25%)75:15:2)0.39.IR(ATR):3330m(br.),2936w,1748w(sh),1696s,1527s,1454w,1407w,1263m,1141m,1033s,1002s,738m,697m.[α]D 25=+52.6(c=0.5,MeOH).1H-NMR(500MHz,CD3OD):7.44-7.25(m,20H芳族的);5.23(d,J=3.8,H-C(1’));5.14(br.s,H-C(8’),H-C(1”));5.09-5.00(m,4CH2Ph);4.99(br.d,J=7.8,H-C(6’));4.66(dd,J=9.3,2.1,H-C(7’));4.58(dd,J=10.5,2.7,CH(OH)CH2CH2);4.12(m,H-C(4’));3.95(t,J=9.5,H-C(4));3.70-3.43(m,H-C(5),H-C(6),H-C(2’),H-C(5’),H-C(2”),H-C(3”),H-C(4”),H-C(5”),2H-C(6”));3.33-3.20(m,H-C(1),H-C(3),CH(OH)CH2CH2);2.78(s,NMe);2.15-2.07(m,Heq-C(2),Heq-C(3’));2.01-1.85(m,CH(OH)CH2CH2),Hax-C(3’));1.55(q,J=12.1,Hax-C(2)).13C-NMR(125MHz,CD3OD):177.67(s,NC=O);159.79(s,MeNC=O);159.03,158.70,158.13,158.05(5s);138.44,138.38,13826,138.03(4s芳族的);129.79-128.83(几个d芳族的);101.12(d,C(1’));96.18(d,C(1”));92.46(d,C(8’));85.20(d,C(6));78.11(d);76.31(d);73.87(d);73.71(d);71.58(d);70.94,67.92,67.63,67.44(4t,4PhCH2);66.65(t,(6”));63.14(d);60.88(d);53.48(d);52.74(d);52.19(d);51.88(d);38.12(t);35.81(t);35.39(t);33.00(t);30.03(q,NMe).HR-MALDI-MS:1225.4458(100,[M+Na]+,C58H70N6NaO22 +;calc.1225.4435).
7’-N,6’-O-羰基-4”-N-[(2S)-4-氨基-2-羟基丁酰基]安普霉素四乙酸酯(14=
ETH99)
用20%Pd(OH)2/C(25mg)处理13(25mg,21μmol)于80%aq.AcOH(1.0ml)和二氧六环(0.8ml)中的溶液并于H2(1atm)搅动15h。混合物经硅藻土过滤,用H2O洗涤。蒸发合并的滤液和洗液。用CH2Cl2洗涤于H2O中的残余物溶液。冷冻干燥含水溶液,得到14=ETH 99(16mg,85%),亮棕色固体。IR(ATR):3170w(br.),2936w,1747w,1548s,1403s,1339m,1038m(sh),992s,759m.1H-NMR(500MHz,D2O):5.69(d,J=3.6,H-C(1’));5.41(d,J=3.8,H-C(1”));5.33(d,J=2.1,H-C(8’));5.16(dd,J=9.3,3.4,H-C(6’));4.80(被HOD信号遮蔽),H-C(5’));4.35(dd,J=8.2,4.0,CH(OH)CH2);4.29(dd,J=9.3,2.1,H-C(7’));3.99(td,J=11.0,4.1,H-C(4’));3.90-3.74(m,H-C(4),H-C(2”),H-C(3”),H-C(4”),H-C(5”));3.68-3.54(m,H-C(5),H-C(6),H-C(2’),2H-C(6”));3.32-3.26(m,H-C(1),H-C(3));3.21-3.14(m,CH(OH)CH2CH2);2.94(s,NMe);2.43-2.38(m,Heq-C(2),Heq-C(3’));2.22-2.16(m,CH(OH)CHa);2.11(q,J=12.1,Hax-C(3’)),2.06-2.00(m,CH(OH)CHb);1.88(br.s,4MeCO2);1.76(q,J=12.1,Hax-C(2)).13C-NMR(125MHz,D2O):180.17(s,4OC=O);175.83(s,NC=O);159.03(s,MeNC=O);95.67(d,C(1’));93.57(d,C(1”));90.12(d,C(8’));80.15(d,C(4));75.13(d,C(5));72.67(d,C(6));71.29(d,C(2”));70.73(d,C(3”));69.44,69.33,69.30(3d,CH2CH(OH)CO),C(6’),C(5”));65.12,64.12(2d,C(4’),C(5’));60.46(t,C(6”));59.02(d,C(7’));51.11(d,C(4”));49.85(d,C(1));48.40(d,C(3));47.82(d,C(2’));36.34(t,CH(OH)CH2CH2);30.68(t,CH(OH)CH2CH2);29.85(d,C(2));29.10(q,NMe);28.65(t,C(3’));22.98(q,4MeC=O).HR-MALDI-MS(阴性模式):665.3001(100,[M-H]-,C26H45N6O14 -;calc.665.2994).
4”-N-[(2S)-4-氨基-2-羟基丁酰基]安普霉素(15=ETH 105)
用Ba(OH)2.H2O(15.7mg,83μmol)处理13(50mg,41.6μmol)于2∶1二氧六环/H2O(9ml)中的溶液并于50℃搅动6h。冷却至室温后,用CO2中和该混合物并蒸发(H2O经与甲苯共蒸发去除)。将残余物溶于MeOH中和经硅藻土过滤。蒸发合并的滤液和洗液。残余物经短硅胶垫过滤(CHCl3/MeOH/aq.NH3(25%)80∶20∶0→80∶15∶1)。收集用CHCl3/MeOH/aq.NH3(25%)80∶15∶1(MALDI-MS;1196.5)洗提的部分并蒸发。用20%Pd(OH)2/C(5mg)处理于80%aq.AcOH(1.0ml)中的残余物(5.0mg)溶液,并于H2(1atm)下搅动15h。混合物经硅藻土过滤,用H2O洗涤。蒸发合并的滤液和洗液。用CH2Cl2洗涤于H2O中的残余物溶液。冷冻干燥和FC(MeOH/aq.NH3(25%)7:3),得到15=ETH 105(3.2mg,12%),白色固体。IR(ATR):3284w(br.),2928w,1637m,1573m,1455m,1387m,1336m,1086s 1028s,993s,834m.1H-NMR(600MHz,D2O):5.37(d,J=3.7,H-C(1’));5.05(d,J=3.6,H-C(1”));4.85(d,J=9.0,H-C(8’));4.33-4.26(m,H-C(6’),CH(OH)CH2CH2);3.90-3.45(几个m,H-C(2’),H-C(5’),H-C(2”),H-C(3”),H-C(4”),H-C(5”),2H-C(6”));3.47(td,J=9.0,3.7,H-C(5));3.29(t,J=9.0,H-C(6));3.17-2.97(m,H-C(4),H-C(4’),CH(OH)CH2CH2);2.88-2.84(m,H-C(1));2.80-2.72(m,H-C(3));2.70(dd,J=8.8,2.8,H-C(7’));2.34(s,NMe);2.12-2.06(m,Heq-C(3’),CH(OH)CHaCH2);2.02-1.90(m,Heq-C(2),CH(OH)CHbCH2);1.72-1.63(m,Hax-C(3’);1.26-1.19(m,Hax-C(2).HR-MALDI-MS:663.3178(39,[M+Na]+,C25H48N6NaO13 +;calc.663.3177),641.3359(100,[M+H]+,C25H49N6O13 +;calc.641.3358).
流程2
试剂和条件:a)Zn(OAc)2.2H2O,DMF/H2O;42%。b)Pd(OH)2/C、H2(1atm)、二氧六环/AcOH/H2O4∶4∶1;90%的18·4AcOH=ETH 102;80%的21·4AcOH=ETH 101;90%的22·4AcOH=ETH 100。c)Ni(OAc)2.4H2O,DMF/H2O;10%的19和45%的20。
1-N-[(2S)-4-(苄基氧基羰基氨基)-2-羟基丁酰基]安普霉素(17)。
用脱水乙酸锌(I1)(652mg,2.97mmol,参见Kirst等,Tet.Lett.1981,22:295;Allen等,J.Med..Chem.1987,30:333)处理1(400mg,0.74mmol)于1∶5H2O/DMF(30ml)中的溶液并搅动1h。用N-[(2S)-4-(苄基氧基羰基氨基)-2-羟基丁酰基]琥珀酰亚胺,DE2555405)(16;372mg,1.1mmol)处理该混合物并于26℃搅动15h。蒸发溶剂后,将残余物溶解于CHCl3/MeOH/aq.NH3(25%)3∶3∶1中和预吸附于硅胶上。FC(CHCl3/MeOH/aq.NH3(25%)10∶10∶1→3∶3∶1→0∶4∶1)和冷冻干燥,得到17(240mg,42%),白色蓬松固体。Rf(MeOH/25%aq.NH34∶1)0.29.IR(ATR):33280w(br.),2944w,1692w 1644w,1531m,1454w,1407w,1337w,1265w,1058s,1033s,1000s,858m,735m,695s.1H-NMR(500MHz,D2O):7.48-7.40(m,5H芳族的);5.69(d,J=3.7,H-C(1’));5.51(d,J=3.9,H-C(1”));5.21(d,J=8.5,H-C(8’));5.13(br.s,PhCH2);4.59(t,J=2.7,H-C(6’));4.21(dd,J=8.4,3.8,CH(OH)CH2CH2);4.01-3.93(m,H-C(4’),H-C(3”),H-C(5”));3.90-3.86(m,H-C(3));3.84-3.79(m,H-C(6),H-C(5’),H-C(6”));3.72-3.62(m,H-C(5),H-C(2’),H-C(2”));3.55(t,J=12.0,H-C(4));3.41-3.38(m,H-C(1));3.36(dd,J=8.5,2.8,H-C(7’));3.32-3.27(m,CH(OH)CH2CH2);3.13(t,J=10.2,H-C(4”));2.81(s,NMe);2.40(dt,J=7.8,3.3,Heq-C(3’));2.23(dt,J=13.0,4.1,Heq-C(2));2.05(q,J=11.6,Hax-C(3’));2.03-1.97(m,CH(OH)CHaCH2);1.88-1.78(m,CH(OH)CHbCH2);1.71(q,J=12.7,Hax-C(2)).13C-NMR(125MHz,D2O):176.24(s,C=O);158.15(s,C=O);136.29(s,芳族的);128.57-127.44(几个d,芳族的);95.74(d,C(1’));94.37(d,C(1”));92.94(d,C(8’));75.61(d,C(5));73.56(d,C(4));70.27-69.01(several d,C(6),C(4’),C(5’),C(2”),C(5”),CH(OH)CH2CH2);66.64(t,PhCH2);65.94(d,C(3”));62.78(d,C(6’));60.30(t,C(6”));59.38(d,C(7’));51.92(d,C(4”));48.76(d,C(1));48.60(d,C(3));47.91(d,C(2’));36.35(t,CH(OH)CH2CH2);33.25(t,CH(OH)CH2CH2);30.88(t,C(2));30.06(q,NMe);30.27(t,C(3’)).HR-MALDI-MS:797.3538(63,[M+Na]+,C33H54N6NaO15 +;calc.797.3545),775.3707(100,[M+H]+,C33H55N6O15 +;calc.775.3725).
1-N-[(2S)-4-氨基-2-羟基丁酰基]安普霉素四乙酸酯(18=ETH 102)。
用20%Pd(OH)2/C(25mg)处理17(25mg,32μmol)于80%aq.AcOH(1.0ml)和二氧六环(0.8ml)中的溶液,并于H2(1atm)下搅动15h。混合物经硅藻土过滤,用H2O洗涤。蒸发合并的滤液和洗液。用CH2Cl2洗涤于H2O中的残余物溶液。冷冻干燥含水溶液,得到18·4AcOH=ETH 102(25.6mg,90%),白色蓬松固体。IR(ATR):3205m(br.),1633m,1540s,1404s,1339m,1131s(sh.),1102s,996s.1H-NMR(500MHz,D2O):5.66(d,J=3.5,H-C(1’));5.44(d,J=3.9,H-C(1”));5.16(d,J=8.5,H-C(8’));4.54(t,J=1.7,H-C(6’));4.28(dd,J=7.8,4.1,CH(OH)CH2CH2);3.96(t,J=10.3,H-C(3”),H-C(5”));3.89(td,J=10.8,6.8,H-C(3));3.85-3.72(m,H-C(6),H-C(5’));3.67-3.58(m,H-C(4),H-C(2’),H-C(4’),H-C(2”),H-C(6”));3.50(t,J=9.8,H-C(5));3.43-3.37(m,H-C(1));3.33(dd,J=8.4,2.5,H-C(7’));3.13-3.08(m,H-C(4’),CH(OH)CH2CH2);2.76(s,NMe);2.34(dt,J=10.8,5.0,CH(OH)CHaCH2);2.20(dt,J=12.9,4.2,Heq-C(2));2.17-2.08(m,Heq-C(3’));2.03-1.92(m,CH(OH)CHbCH2),Hax-C(3’));1.71(q,J=12.7,Hax-C(2)).13C-NMR(125MHz,D2O):181.30(s,MeCO2H);175.61(s,C=O);95.77(d,C(1’));94.65(d,C(1”));93.11(d,C(8’));75.87(d,C(4));73.78(d,C(5));70.51(d,C(2”));69.74-69.54(几个d,C(6),C(4’),C(5’),C(4”),C(5”),CH(OH)CH2CH2);66.15(d,C(3”));62.93(d,C(6’));60.54(t,C(6”));59.56(d,C(7’));52.23(d,C(4”));49.06(d,C(1));48.78(d,C(3));48.12(d,C(2’));36.58(t,CH(OH)CH2CH2);30.89(t,C(2));30.70(t,C(3’));30.27(q,NMe);27.24(t,CH(OH)CH2CH2);23.29(MeCO2H).HR-MALDI-MS:663.3180(24,[M+Na]+,C25H48N6NaO13 +;calc.663.3177),641.3363(52,[M+H]+,C25H49N6O13 +;calc.641.3358).
3,2’-双-N-[(2S)-4-(苄基氧基羰基氨基)-2-羟基丁酰基]安普霉素(19)和2’-N-
[(2S)-4-(苄基氧基羰基氨基)-2-羟基丁酰基]安普霉素(20)。
用乙酸镍(I1)四水合物(369mg,1.48mmol,参见Kirst等,Tet.Lett.1981,22:295;Allen等,J.Med.Chem.1987,30:333)处理1(200mg,0.37mmol)于1∶4H2O/DMF(25ml)中的溶液并搅动1h。用N-[(2S)-4-(苄基氧基羰基氨基)-2-羟基丁酰基]琥珀酰亚胺(16;194mg,0.55mmol)处理该混合物并于26℃搅动15h。蒸发溶剂后,将残余物溶解于CHCl3/MeOH/aq.NH3(25%)3∶3∶1中并预吸附于硅胶上。FC(CHCl3/MeOH/aq.NH3(25%)10∶10∶1→3∶3∶1→0∶4∶1)和冷冻干燥,得到19(37mg,10%)和20(129mg,45%)。19的数据:白色蓬松固体。Rf(MeOH/25%aq.NH34∶1)0.42.IR(ATR):3242w(br.),2940w,1692w,1646w,1532w,1455w,1341w,1267w,1054s,1033s,1000s,860w,735m,697m.1H-NMR(400MHz,D2O):7.41-7.32(m,10H芳族的);5.40,5.38(2d,J=3.7,H-C(1’),H-C(1”));5.10(d,J=8.5,H-C(8’));5.05(t,J=10.6,2PhCH2);4.50(t,J=2.6,H-C(6’));4.18-4.12(m,2CH(OH)CH2CH2);4.07-3.34(m,12H);3.28-3.14(m,H-C(7’),2CH(OH)CH2CH2);3.06-2.98(m,1H);2.73(s,NMe);2.42-2.30(m,2CH(OH)-CHaCH2);2.14-2.02(m,Heq-C(2));1.98-1.88(m,2H);1.84-1.69(m,2H);1.66-1.56(m,Hax-C(2)).HR-MALDI-MS:1032.4340(63,[M+Na]+,C45H67N7NaO19 +;calc.1032.4349),1010.4579(100,[M+H]+,C45H68N7O19 +;calc.1010.4570).20的数据:白色固体.Rf(MeOH/25%aq.NH34∶1)0.15.IR(ATR):3280w(br.),2944w,1692w,1644w,1531w,1454w,1337w,1265w,1058s,1033s,1000s,858w,735m,695m.1H-NMR(400MHz,D2O):7.44-7.35(m,5H芳族的);5.50(d,J=3.0,H-C(1’));5.43(d,J=3.9,H-C(1”));5.15(d,J=8.5,H-C(8’));5.07(br.s,PhCH2);4.58(t,J=2.6,H-C(6’));4.15(dd,J=7.7,4.5,CH(OH)CH2CH2);4.11-4.03(m,H-C(2’),H-C(3”),H-C(5”));3.88-3.78(m,H-C(4),H-C(4’),2H-C(6”));3.68-3.63(m,H-C(5’),H-C(2”));3.55(q,J=9.4,H-C(5),H-C(6));3,47-3.40(m,H-C(3));3.37(dd,J=8.6,2.8,H-C(7’));3.29-3.21(m,H-C(1),H-C(4”),CH(OH)CH2CH2);2.82(s,NMe);2.48(dt,J=12.6,6.6,Heq-C(2));2.10-2.04(m,Heq-C(3’));2.04-1.75(m,Hax-C(2),Hax-C(3’),CH(OH)CH2CH2).13C-NMR(100MHz,D2O):175.48(s,(OH)CHC=O);158.31(s,C=O);136.52(s,芳族的);128.86,128.45,127.70(3d,芳族的);96.68(d,C(1’));94.50(d,C(1”));92.83(d,C(8’));75.40(d);72.74(d);70.52(d);69.80,69.46,69.17(3d);68.28(d);66.81(t,PhCH2);62.85(d);60.51(t,C(6”));59.50(d);52.27(d);49.86(d);49.15(d);47.11(d);36.60(t,CH(OH)CH2CH2);33.37(t,CH(OH)CH2CH2);30.18(q,NMe);28.44(t,C(2));28.21(t,C(3’)).HR-MALDI-MS:797.3538(63,[M+Na]+,C33H54N6NaO15 +;calc.797.3545),775.3707(100,[M+H]+,C33H55N6O15 +;calc.775.3725).
3,2’-双-N-[(2S)-4-氨基-2-羟基丁酰基]安普霉素四乙酸酯(21=ETH 101)。
用20%Pd(OH)2/C(10mg)处理19(10mg,9.9μmol)于80%aq.AcOH(1.0ml)和二氧六环(0.8ml)中的溶液,并于H2(1atm)下搅动15h。混合物经硅藻土过滤,用H2O洗涤。蒸发合并的滤液和洗液。用CH2Cl2洗涤于H2O中的残余物溶液。冷冻干燥含水溶液,得到21’·4AcOH=ETH 101(7.8mg,80%),白色固体。IR(ATR):3205m(br.),2936m,1641s,1550s,1406s,1341m,1268w,1099s,1056s,1014s,994s,862w.1H-NMR(600MHz,D2O):5.52(d,J=4.2,H-C(1’));5.46(d,J=3.6,H-C(1”));5.21(d,J=9.0,H-C(8’));4.60(br.s,H-C(6’));4.36-4.29(m,2CH(OH)CH2CH2);4.19-3.27(m,13H);3.21-3.09(m,2CH(OH)CH2CH2);2.81(s,NMe);2.50-2.42(m,1H);2.24-2.11(m,3H);2.07-1.94(m,3H);1.92(s,MeCO2H);1.80-1.72(m,1H).HR-MALDI-MS:764.3680(23,[M+Na]+,C29H55N7NaO15 +;calc.764.3657),742.3837(100,[M+H]+,C25H49N6O13 +;calc.742.3834).
2’-N-[(2S)-4-氨基-2-羟基丁酰基]安普霉素四乙酸酯(22=ETH 100)。
用20%Pd(OH)2/C(25mg)处理20(25mg,32.3μmol)于80%aq.AcOH(1.0ml)和二氧六环(0.8ml)中的溶液,并于H2(1atm)下搅动15h。混合物经硅藻土过滤,用H2O洗涤。蒸发合并的滤液和洗液。用CH2Cl2洗涤于H2O中的残余物溶液。冷冻干燥含水溶液,得到22’·4AcOH=ETH 100(25.6mg,90%)。IR(ATR):3178w(br.),3067w,2940w,1631w,1531w,1462w,1407w,1331w,1274w,1045s,994s,973w(sh.),863w.1H-NMR(600MHz,D2O):5.42(d,J=3.7,H-C(1’));5.37(d,J=3.9,H-C(1”));5.09(d,J=8.5,H-C(8’));4.50(t,J=2.4,H-C(6’));4.20(dd,J=8.5,4.0,CH(OH)CH2CH2);4.05(dt,J=12.8,4.1,H-C(2’));3.99(t,J=12.0,H-C(3”),H-C(5”));3.84(td,J=10.8,4.3,H-C(4’));3.77-3.74(m,2H-C(6”));3.70(dd,J=15.0,5.4,H-C(5’));3.62(dd,J=10.0,2.3,H-C(4));3.57(dd,J=9.8,3.9,H-C(2”));3.52(dd,J=9.8,8.2,H-C(5));3.48(t,J=9.7,H-C(6));3.39(ddd,J=15.5,12.6,4.8,H-C(3));3.29(dd,J=8.6,2.7,H-C(7’));3.22(ddd,J=12.3,10.1,4.1,H-C(1));3.15(t,J=10.3,H-C(4”);3.04(t,J=7.5,CH(OH)CH2CH2);2.73(s,NMe);2.40(dt,J=12.6,4.2,Heq-C(2));2.08-2.00(m,Heq-C(3’),CH(OH)CHaCH2);1.91-1.76(m,Hax-C(2),Hax-C(3’),CH(OH)CHbCH2));1.79(s,MeCO2H).13C-NMR(150MHz,D2O):174.58(s,C=O);96.60(d,C(1’));94.27(d,C(1”));92.63(d,C(8’));78.40,75.02,72.40(3d,C(5),C(6),C(2”));70.23(d,C(4));69.58,69.27,69.21(3d,C(5’),C(5”),CH(OH)CH2CH2);67.97(d,C(3”));66.62(d,C(4’));62.58(d,C(6’));60.17(t,C(6”));59.21(d,C(7’));51.92.(d,C(4”));49.61(d,C(1));48.89(d,C(3));46.91(d,C(2’));36.49(t,CH(OH)CH2CH2);30.59(t,CH(OH)CH2CH2);29.86(q,NMe);28.14(t,C(2));27.92(t,C(3’)).HR-MALDI-MS:663.3147(53,[M+Na]+,C25H48N6NaO13 +;calc.663.3177),641.3339(100,[M+H]+,C25H49N6O13 +;calc.641.3358).
实施例12:安普霉素衍生物对于多种核糖体的活性(表10)
通过如在实施例1中描述的测定最小抑菌浓度(MIC)评估活性。关于更详细的方法学参见在实施例7中的描述。结果示于表10。
表10:安普霉素衍生物的MIC测定(μg/ml)
Claims (5)
2.依据权利要求1所述的式(I)的安普霉素或其药学上可接受的酸加成盐的应用,其中,所述感染由以包含在AAC(3)、ANT(2”)、AAC(6’)、ANT(4’)和APH(3’)的组中的耐药性为特征的菌引起。
3.依据权利要求1或2所述的式(I)的安普霉素或其药学上可接受的酸加成盐的应用,其中,所述安普霉素或其药学上可接受的酸加成盐配制为用于静脉内给药。
4.依据权利要求1或2所述的式(I)的安普霉素或其药学上可接受的酸加成盐的应用,其中,所述安普霉素或其药学上可接受的酸加成盐作为气雾剂给药。
5.依据权利要求1或2所述的式(I)的安普霉素或其药学上可接受的酸加成盐的应用,其中,所述安普霉素或其药学上可接受的酸加成盐以1mg/kg至25mg/kg体重的日剂量给药。
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US4468512A (en) * | 1980-09-22 | 1984-08-28 | Eli Lilly And Company | 1-N-Acylated and 1-N-alkylated derivatives of 4-O-substituted-2-deoxystreptamine aminoglycosides |
JPS5772998A (en) * | 1980-10-24 | 1982-05-07 | Shionogi & Co Ltd | Novel appamycin derivative |
US4360665A (en) | 1981-12-24 | 1982-11-23 | Eli Lilly And Company | 4"-N-(Substituted)-apramycin antibiotic derivatives and intermediates therefor |
US4458065A (en) * | 1983-02-17 | 1984-07-03 | Eli Lilly And Company | 7-N-(Substituted-apramycin antibiotic derivatives and intermediates therefor |
PT1273292E (pt) * | 2001-07-02 | 2004-10-29 | Chiesi Farma Spa | Formulacao optimizada de tobramicina para aerossolizacao |
ATE460487T1 (de) | 2006-03-31 | 2010-03-15 | Eidgenoess Tech Hochschule | Screening-test für ribosomale antibiotika |
EP1953171A1 (en) | 2007-02-02 | 2008-08-06 | Eidgenössische Technische Hochschule Zürich | Aminoglycoside antibiotics targeting bacterial 16S ribosomal RNA |
CN101422477A (zh) * | 2007-10-31 | 2009-05-06 | 天津生机集团有限公司 | 复方硫酸安普霉素注射液 |
-
2011
- 2011-09-12 CN CN202010313970.2A patent/CN111481562A/zh active Pending
- 2011-09-12 JP JP2013527630A patent/JP5922660B2/ja active Active
- 2011-09-12 RU RU2013116742/15A patent/RU2604665C2/ru active
- 2011-09-12 WO PCT/EP2011/065701 patent/WO2012034955A1/en active Application Filing
- 2011-09-12 US US13/820,258 patent/US9271993B2/en active Active
- 2011-09-12 EP EP11754424.7A patent/EP2616079B1/en active Active
- 2011-09-12 CN CN2011800438824A patent/CN103228282A/zh active Pending
- 2011-09-12 CN CN202010313967.0A patent/CN111388489A/zh active Pending
Also Published As
Publication number | Publication date |
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CN111481562A (zh) | 2020-08-04 |
EP2616079A1 (en) | 2013-07-24 |
US9271993B2 (en) | 2016-03-01 |
JP2013537177A (ja) | 2013-09-30 |
EP2616079B1 (en) | 2015-10-14 |
RU2013116742A (ru) | 2014-10-20 |
US20130165397A1 (en) | 2013-06-27 |
JP5922660B2 (ja) | 2016-05-24 |
CN103228282A (zh) | 2013-07-31 |
WO2012034955A1 (en) | 2012-03-22 |
RU2604665C2 (ru) | 2016-12-10 |
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