CN117304241B - 一种大环内酯类化合物及其制备方法与应用 - Google Patents
一种大环内酯类化合物及其制备方法与应用 Download PDFInfo
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- CN117304241B CN117304241B CN202311620585.2A CN202311620585A CN117304241B CN 117304241 B CN117304241 B CN 117304241B CN 202311620585 A CN202311620585 A CN 202311620585A CN 117304241 B CN117304241 B CN 117304241B
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- tylosin
- macrolide compound
- acid
- macrolide
- reaction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07H1/00—Processes for the preparation of sugar derivatives
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明公开了一种大环内酯类化合物及其制备方法与应用。本发明提供的大环内酯类化合物具有如式I所示的结构，本发明还提供了一种药物组合物或兽药组合物，其包括如式I所示结构的大环内酯类化合物。本发明还提供了一种药物制剂，其包括如式I所示结构的大环内酯类化合物。本发明提供的大环内酯类化合物、兽药组合物及药物制剂可用于治疗病原体感染，特别是治疗动物病原体感染，效果显著。
Description
技术领域
本发明属于杂环化合物合成及动物药学技术领域，具体涉及一种大环内酯类化合物及其制备方法与应用。
背景技术
大环内酯类化合物是一类重要的抗生素，具有抗感染性好、副作用小等优点，广泛应用于畜禽兽医临床（王秀茹 大环内酯类药物的性质、特点及应用.兽医导刊2018, 54-55. 匡宝晓. 新型动物专用抗生素-泰地罗新.今日养猪业,2022, 98-100.）。按照化学结构分类，大环内酯类抗生素分为14元环、15元环与16元环大环内酯类药物。主要品种有红霉素、阿奇霉素、吉他霉素、泰乐菌素、替米考星、泰万菌素、加米霉素等（于志超. 兽用抗生素加米霉素的研究进展.当代畜禽养殖业2020, 22-23. 刘旺; 裴巍. 阿奇霉素的最新研究进展.畜牧兽医科技信息2014, 15.）。主要用于治疗牛支原体感染引起的牛呼吸道疾病、乳腺炎、关节炎和中耳炎，由猪肺炎支原体引起的猪气喘病，由胞内劳森氏菌引起的猪增生性肠炎，鸡支原体引起的鸡慢性呼吸道疾病等疾病（贺承光; 孔令聪; 孙喆. 牛支原体抗生素耐药性的研究进展.吉林畜牧兽医2018,39, 11-13. 万进; 马妮妮; 王聪. 酒石酸泰万菌素对特定畜禽疫病防治功效研究进展. 中国动物检疫,2021,38, 75-78.）。
泰乐菌素，英文名称为Tylosin，是一种重要的大环内酯类畜禽专用抗生素，具有16元大环内酯结构，最早于1959年从弗氏链霉菌（Streptomyces fradiae）的培养液中提取获得。畜禽兽医临床使用产品主要包括酒石酸泰乐菌素、乳酸泰乐菌素、硫酸泰乐菌素、盐酸泰乐菌素与磷酸泰乐菌素（陈东; 张晓强; 纳奇; 锁嘉伟. 泰乐菌素纯化工艺优化研究.当代化工研究,2023, 170-172. 刘佳; 郝生燕; 潘发明. 动物产品中泰乐菌素残留规律研究进展.畜牧与兽医2022,54, 148-152.）。泰乐菌素对于革兰氏阴性菌、革兰阳性菌与支原体等病原体均具有良好的抗菌活性，不仅可以用于治疗猪痢疾、家禽支原体感染、反刍动物肺炎等疾病，而且可以作为饲料添加剂，促进动物生长（王丽霞; 李生龙; 陈砀桐; 王君. 泰乐菌素高效液相色谱检测方法的建立.安徽农业科学2020,48, 206-209.）。
为开发新的大环内酯类抗生素，国内外学者对泰乐菌素的结构进行了各种改造，已合成出一系列泰乐菌素衍生物（赵东峰; 任翔; 朱丽. 泰乐菌素及其衍生物研究进展.医药产业资讯, 2006, 46-48.）。例如，10,11,12,13-四氢-脱碳霉糖泰乐菌素衍生物（Narandja, A.; Kelneric, K.; Kolacny-Babic, L.; Djokic, S. 10,11,12,13-Tetrahydro Derivatives of Tylosin. Ii. Synthesis, Antibacterial Activity andTissue Distribution of 4'-Deoxy-10,11,12,13-Tetrahydrodesmycosin.Journal of Antibiotics.1995,48, 248-253. Narandja, A.; Djokic, S. Derivatives of 10,11,12,13-tetra-hydrodesmycosin, processes for preparation, and use thereof inobtaining pharmaceuticals. Patent EP0490311, 1992-06-17）、9-肟泰乐菌素衍生物（王焕焕; 杨璞; 翟洪进; 张烁; 曹亚权; 杨莹雪; 吴春丽 新型泰乐菌素衍生物的设计合成和活性评价.有机化学2022,42, 557-571.）、12,13-环氧泰乐菌素（Narandja, A.;Lopotar, N. Derivatives of 12,13-Epoxy-tylosin and processes of manufacturethereof. Patent US5688924, 1997-11-18）、泰地罗新（Zhang, C.; Song, M.; Qi, P.;Zhang, G.; Ge, X.; Zhao, M.; Wu, J.; Ma, J.; Wang, D.; Process forpreparation of 20,23-dipiperidinyl-5-O-mycaminosyl-tylonolide. Patent CN104892704 B, 2017-08-08.）、泰万菌素（酒石酸泰万菌素对特定畜禽疫病防治功效研究进展. 中国动物检疫,2021,38, 75-78.）等。
发明内容
本发明的目的是提供一种大环内酯类化合物及其制备方法与应用，该化合物可用于治疗或预防动物病原体感染，效果显著。
为实现上述目的，本发明提供如下技术方案：
第一方面，本发明提供一种大环内酯类化合物，具有如式I所示的结构：
其中：R选自2-羟基乙氨基、3-羟基丙氨基、二(2-羟基乙氨基)、二(3-羟基丙氨基)、(R)-2-羟甲基四氢吡咯基、(S)-2-羟甲基四氢吡咯基、4-羟基哌啶基、4-羟甲基哌啶基。
具体地，所述大环内酯类化合物为：20-(2-羟基乙氨基)泰乐菌素、20-(3-羟基丙氨基)泰乐菌素、20-(二(2-羟基乙氨基) )泰乐菌素、20-(二(3-羟基丙氨基))泰乐菌素、20-((R)-2-羟甲基四氢吡咯基)泰乐菌素、20-((S)-2-羟甲基四氢吡咯基)泰乐菌素、20-(4-羟基哌啶基)泰乐菌素、20-(4-羟甲基哌啶基)泰乐菌素。
优选地，所述大环内酯类化合物具有如式Ia、式Ib、式Ic或式Id中任一项所示的结构：
。
本发明还提供上述大环内酯类化合物在药学上可接受的盐。
所述药学上可接受的盐是指，所述大环内酯化合物与酸生成的盐。
所述酸包括：酒石酸、盐酸、磷酸、硫酸、水杨酸、甲磺酸、乳酸、苹果酸、甲酸、乙酸、丙酸、富马酸、柠檬酸、草酸盐、马来酸、琥珀酸、苯甲酸、乙二磺酸等。
第二方面，本发明进一步提供上述大环内酯类化合物的制备方法，包括如下步骤：
S1、泰乐菌素A与氨基醇反应；
S2、向步骤S1反应得到的体系中加入还原剂或酸，反应得到所述大环内酯类化合物。
进一步地，所述制备方法包括合成路径1和合成路径2：
所述合成路径1包括如下步骤：
（1）泰乐菌素A与氨基醇在极性溶剂中反应，得到亚胺溶液；
（2）向所述亚胺溶液中加入还原剂，反应得到羟基仲氨基修饰的大环内酯类化合物。
步骤（1）中，所述氨基醇为2-氨基乙醇、3-氨基丙醇。
步骤（1）中，所述氨基醇与所述泰乐菌素A的摩尔比为2~5：1，优选为3~3.5：1。
步骤（1）中，所述极性溶剂为甲醇、乙醇、丙醇、异丙醇、正丁醇和乙二醇中的一种或多种。
步骤（1）中，所述反应的条件为：温度为室温，时间为12~13 h。
步骤（2）中，所述还原剂为硼氢化钠、三乙酰氧基硼氢化钠和LiAlH4中的一种或多种。
步骤（2）中，所述还原剂与所述泰乐菌素A的摩尔比为1~4：1，优选为2~2.5：1。
步骤（2）中，所述反应的条件为：温度为室温，时间为2~3h。
进一步地，所述合成路径1还包括：在加入所述还原剂之前，进行TLC监测反应，确保原料完全转化为亚胺。
进一步地，所述合成路径1还包括后处理步骤；所述后处理按照下述操作进行：向反应体系内加入碱的水溶液淬灭反应，然后减压浓缩除去醇溶剂；剩余水溶液用有机溶剂萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩；其中，碱选自碳酸钾、碳酸钠、氢氧化钾或氢氧化钠中的一种或多种；有机溶剂选自二氯甲烷、乙酸乙酯或乙醚中的一种或多种。
示例性地，上述合成路径1的合成路线如下：
所述合成路径2包括如下步骤：
（A）泰乐菌素A与氨基醇在非极性溶剂中反应，得到反应液；
（B）向步骤（A）得到的反应液中加入酸，反应得到羟基叔氨基修饰的大环内酯类化合物。
步骤（A）中，所述氨基醇为2-氨基乙醇、3-氨基丙醇、(R)-脯氨醇、(S)-脯氨醇、4-羟基哌啶、4-羟甲基哌啶。
步骤（A）中，所述氨基醇与所述泰乐菌素A的摩尔比为2~5：1，优选为2.5~3.5:1。
步骤（A）中，所述非极性溶剂为乙二醇二甲醚、苯和甲苯中的一种或多种。
步骤（B）中，所述酸为甲酸。
步骤（B）中，所述酸的加入时机为：反应体系的温度达到75~85℃，优选为80℃。
步骤（B）中，所述酸与所述泰乐菌素A的摩尔比为3~6：1，优选为5~6：1。
步骤（B）中，所述反应的条件为：温度为78~80℃，时间为2~2.5h。
进一步地，所述合成路径2还包括后处理步骤；所述后处理按照下述操作进行：向反应体系内加入蒸馏水，分液后的水相用碱调pH至9~11，水溶液用有机溶剂萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩；其中，碱选自碳酸钾、碳酸钠、氢氧化钾或氢氧化钠中的一种或多种；有机溶剂选自二氯甲烷、乙酸乙酯或乙醚中的一种或多种。
进一步地，本发明提供的大环内酯类化合物的制备方法还包括纯化步骤：将所得粗产物加到硅胶色谱柱内，选两种有机溶剂配成不同极性的洗脱剂，利用梯度洗脱将粗品内的杂质除去，从而得到大环内酯类化合物纯品；其中所述洗脱剂可选自乙醚、乙酸乙酯、甲醇、异丙醇、丙酮或二氯甲烷中的任意两种。
示例性地，上述合成路径2的合成路线如下：
第三方面，本发明进一步提供一种兽药组合物，所述兽药组合物包括上述如式I所示结构的大环内酯类化合物。
第四方面，本发明还进一步提供一种药物制剂，所述药物制剂包括上述如式I所示结构的大环内酯类化合物。
所述药物制剂的剂型为散剂、片剂、预混剂、可溶性粉剂、注射液。
第五方面，本发明进一步提供上述大环内酯类化合物、兽药组合物及药物制剂在制备抗病原体感染药品中的应用。示例性地，所述抗病原体感染药品如畜禽兽医临床使用产品。
所述应用中，所述病原体为支原体、巴氏杆菌、多杀氏巴氏杆菌、噬组织菌、金黄色葡萄球菌、无乳链球菌、肺炎链球菌、乙型溶血性链球菌、大肠杆菌、流感嗜血杆菌、肺炎放线杆菌、沙门氏菌、曼氏杆菌、猪丹毒杆菌。
本发明取得的有益效果如下：
本发明提供了一种大环内酯类化合物及其制备方法与应用，该化合物或其药学上可接受的盐可用于治疗或预防细菌或支原体感染，为畜牧兽医临床提供更多的选择性。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但本发明并不限于以下实施例。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的试剂、材料、仪器等，如无特殊说明，均可从商业途径得到。
以下实施例中使用的原料来源如下：
实施例1
将泰乐菌素A（3.00 g, 3.27 mmol）加入50 mL史莱克瓶，加入甲醇（18 mL），然后用注射器缓慢加入3-氨基-1-丙醇（0.74 g, 9.85 mmol），室温下搅拌反应12 h。
TLC检测原料完全转化为亚胺后，室温下缓慢加入三乙酰氧基硼氢化钠（1.39 g,6.56 mmol），室温下继续搅拌反应2 h。
TLC检测反应完全后，加入1 M的NaOH 水溶液 (3 mL) 淬灭反应。然后减压浓缩除去MeOH，残余物用二氯甲烷（10 mL×3）萃取。合并的萃取液用饱和NaCl水溶液 (10 mL)洗涤，无水硫酸钠干燥。过滤，将滤液减压浓缩得到粗产物。最后，经过硅胶柱色谱纯化（二氯甲烷/甲醇 = 8:1），得到白色固体大环内酯化合物Ia（1.40 g，产率44%）。
1H NMR (500 MHz, CDCl3) δ 7.37 (d,J= 14.7 Hz, 1H), 6.30 (d,J= 14.8 Hz,1H), 5.95 (s, 1H), 5.08 (d,J= 9.6 Hz, 1H), 4.96 (d,J= 10.6 Hz, 1H), 4.58 (t,J= 10.5 Hz, 1H), 4.33 – 4.25 (s, 4H), 4.09 – 4.08 (m, 1H), 4.01 – 3.99 (m,1H), 3.80 – 3.75 (m, 4H), 3.67 – 3.61 (m, 4H), 3.56 (s, 2H), 3.49 – 3.47 (m,2H), 3.29 (t,J= 10.5 Hz, 2H), 3.19 (d,J= 10.4 Hz, 1H), 3.02 – 2.95 (m, 4H),2.87 – 2.80 (m, 3H), 2.72 – 2.68 (m, 4H), 2.51 – 2.44 (m, 8H), 2.06 – 1.95(m, 3H), 1.87 – 1.74 (m, 8H), 1.63 – 1.62 (m, 3H), 1.53 – 1.48 (m, 2H), 1.31– 1.23 (m, 14H), 1.16 – 1.11 (m, 4H), 1.03 (s, 3H), 0.93 (d,J= 8.2 Hz, 3H)。
13C NMR (126 MHz, CDCl3) δ 203.84, 173.60, 148.26, 142.99, 134.55,117.88, 103.71, 101.01, 96.38, 81.69, 79.83, 79.50, 76.32, 75.03, 74.88,72.84, 72.67, 71.67, 70.34, 69.39, 69.02, 68.70, 66.59, 65.88, 61.88, 61.66,59.51, 47.26, 46.07, 45.94, 44.97, 41.91, 41.05, 40.85, 39.32, 33.47, 32.41,30.42, 29.55, 26.14, 25.34, 25.18, 19.03, 18.18, 17.69, 17.52, 12.82, 10.52,9.55。
TLC Rf = 0.4（二氯甲烷/甲醇 = 8:1）
HRMS (ESI, m/z): [M + H]+calcd for C49H87N2O17, 975.59993; found975.60059。
实施例2
将泰乐菌素A（0.50 g, 0.55 mmol）加入装有冷凝管的50 mL三口瓶，加入甲苯（6mL），搅拌溶解。然后加入二乙醇胺（0.17 g, 1.62 mmol），升温至80 ℃，再加入甲酸（0.14g, 3.04 mmol），在80 ℃下继续搅拌反应2 h。
TLC检测反应完全后，加入蒸馏水（5 mL）淬灭反应，分液。水相用5 M的氢氧化钠水溶液调pH至10，然后用二氯甲烷（15 mL×3）萃取。合并的萃取液用无水硫酸钠干燥。过滤，将滤液减压浓缩得到粗产物。最后，经过硅胶柱色谱纯化（二氯甲烷/甲醇=8：1）得到白色固体大环内酯化合物Ib（0.27 g，产率49%）。
1H NMR (500 MHz, CDCl3) δ 7.44 (d,J= 14.4 Hz, 1H), 6.31 (d,J= 15.7 Hz,1H), 5.98 (s, 1H), 5.08 (d,J= 10.2 Hz, 1H), 4.93 (d,J= 9.9 Hz, 1H), 4.58 (t,J= 9.1 Hz, 1H), 4.33 – 4.29 (m, 2H), 4.11 – 4.08 (m, 1H), 4.03 – 3.99 (m, 1H),3.79 – 3.57 (m, 13H), 3.47 – 3.45 (m, 2H), 3.32 – 3.28 (m, 2H), 3.21 – 3.17(m, 1H), 3.05 – 2.95 (m, 3H), 2.72 – 2.60 (m, 7H), 2.51 – 2.49 (m, 8H), 2.42– 2.38 (m, 2H), 2.28 – 2.26 (m, 1H), 2.06 – 2.01 (m, 1H), 1.95 – 1.75 (m,7H), 1.66 – 1.59 (m, 3H), 1.50 – 1.46 (m, 2H), 1.32 – 1.21 (m, 16H), 1.12 –1.05 (m, 7H), 0.96 – 0.91 (m, 3H)。
13C NMR (126 MHz, CDCl3) δ 205.13, 173.62, 149.18, 143.77, 134.55,117.45, 103.57, 101.03, 96.33, 81.66, 80.09, 79.83, 76.33, 75.15, 75.07,72.76, 72.68, 71.74, 70.36, 69.40, 69.10, 68.75, 66.33, 65.89, 61.64, 59.58,59.47, 59.43, 57.17, 53.02, 45.97, 45.94, 45.27, 44.89, 41.93, 41.01, 40.88,39.39, 33.80, 33.65, 26.06, 25.34, 25.25, 19.10, 18.18, 17.69, 17.46, 12.76,10.89, 9.66。
TLC Rf = 0.2（二氯甲烷/甲醇 = 8:1）
HRMS (ESI, m/z): [M + H]+calcd for C50H89N2O18, 1005.61049; found1005.62402。
实施例3
将泰乐菌素A（0.50 g, 0.55 mmol）加入装有冷凝管的50 mL三口瓶，加入甲苯（6mL），然后加入(R)-脯氨醇（0.17 g, 1.68 mmol），搅拌溶解。升温至80 ℃，加入甲酸（0.14g, 3.04 mmol），在80 ℃下继续反应2 h。
TLC检测反应完全后，加入蒸馏水（5 mL）淬灭反应，分液。水相用5 M的氢氧化钠水溶液调pH至10，然后用二氯甲烷（15 mL×3）萃取。合并的萃取液用无水硫酸钠干燥。过滤，将滤液减压浓缩得到粗产物。最后，经过硅胶柱色谱纯化（二氯甲烷/甲醇=8：1），得到白色固体大环内酯化合物Ic（0.32 g，产率58%）。
1H NMR (500 MHz, CDCl3) δ 7.36 (d,J= 17.5 Hz, 1H), 6.30 (d,J= 14.8 Hz,1H), 5.94 (s, 1H), 5.09 – 5.07 (m, 1H), 4.97 – 4.94 (m, 1H), 4.58 – 4.55 (m,1H), 4.29 – 4.26 (m, 2H), 4.11 – 4.06 (m, 1H), 4.02 – 3.98 (m, 1H), 3.83 –3.81 (m, 1H), 3.76 – 3.73 (m, 1H), 3.62 – 3.53 (m, 7H), 3.47 – 3.44 (m, 4H),3.33 – 3.29 (m, 2H), 3.19 – 3.17 (m, 2H), 3.03 – 2.93 (m, 3H), 2.72 – 2.63(m, 3H), 2.59 – 2.54 (m, 6H), 2.50 – 2.46 (m, 5H), 2.36 – 2.26 (m, 2H), 2.04– 2.01 (m, 2H), 1.89 – 1.83 (m, 3H), 1.79 – 1.72 (m, 7H), 1.63 – 1.55 (m,4H), 1.31 – 1.19 (m, 16H), 1.08 – 1.06 (m, 5H), 1.01 – 0.99 (m, 2H), 0.93 –0.91 (m, 3H)。
13C NMR (126 MHz, CDCl3) δ 203.98, 173.63, 162.63, 161.84, 148.07,143.06, 134.38, 117.97, 103.97, 101.01, 96.36, 82.44, 81.69, 79.86, 76.32,75.01, 74.91, 72.95, 72.66, 71.65, 70.35, 69.37, 69.07, 68.80, 66.48, 65.89,65.12, 63.03, 61.64, 59.50, 55.00, 54.69, 46.01, 45.11, 41.93, 41.63, 40.87,39.36, 34.95, 34.22, 27.64, 26.75, 25.34, 25.17, 23.48, 19.13, 18.18, 17.69,12.76, 11.16, 9.60, 9.33。
TLC Rf = 0.3（二氯甲烷/甲醇 = 8:1）
HRMS (ESI, m/z): [M + H]+calcd for C51H89N2O17, 1001.61558; found1001.61896。
实施例4
将泰乐菌素A（1.00 g, 1.09 mmol）加入装有冷凝管的50 mL三口瓶，加入甲苯（8mL），然后加入 (S)-脯氨醇（0.33 g, 3.26 mmol），搅拌溶解。升温至80 ℃，加入甲酸（0.27g, 5.86 mmol），在80 ℃下继续反应2 h。
TLC检测反应完全后，加入蒸馏水（8 mL）淬灭反应，分液。水相用5 M的氢氧化钠水溶液调pH至10，然后用二氯甲烷（15 mL×3）萃取。合并的萃取液用无水硫酸钠干燥。过滤，将滤液减压浓缩得到粗产物。最后，经过硅胶柱色谱（二氯甲烷/甲醇=8：1）纯化得到白色固体大环内酯化合物Id（0.64 g，产率59%）。
1H NMR (500 MHz, CDCl3) δ 7.31 (d,J= 15.4 Hz, 1H), 6.29 (d,J= 15.5 Hz,1H), 5.92 (s, 1H), 5.11 – 5.06 (m, 1H), 4.97 – 4.91 (m, 1H), 4.59 – 4.55 (m,1H), 4.32 – 4.26 (m, 2H), 4.11 – 4.07 (m, 1H), 4.02 – 3.97 (m, 1H), 3.76 –3.72 (m, 2H), 3.65 – 3.61 (m, 4H), 3.57 – 3.53 (m, 3H), 3.50 – 3.42 (m, 4H),3.33 – 3.27 (m, 2H), 3.21 – 3.17 (m, 2H), 3.02 – 2.93 (m, 3H), 2.87 – 2.68(m, 3H), 2.61 – 2.42 (m, 13H), 2.16 – 2.09 (m, 2H), 1.88 – 1.74 (m, 10H),1.65 – 1.56 (m, 4H), 1.33 – 1.19 (m, 16H), 1.10 – 1.02 (m, 7H), 0.96 – 0.90(m, 3H)。
13C NMR (126 MHz, CDCl3) δ 203.54, 172.99, 162.58, 161.82, 147.71,142.84, 134.41, 117.96, 103.63, 100.97, 96.28, 81.63, 79.82, 79.45, 76.29,75.01, 74.77, 72.76, 72.64, 71.71, 70.29, 69.33, 69.12, 68.71, 66.41, 65.83,65.56, 61.65, 61.58, 59.45, 53.48, 53.38, 45.95, 45.14, 41.91, 41.17, 40.84,39.62, 33.60, 32.58, 26.98, 26.66, 25.31, 23.27, 23.21, 19.05, 18.14, 17.65,12.79, 11.10, 9.59。
TLC Rf = 0.3（二氯甲烷/甲醇 = 8:1）
HRMS (ESI, m/z): [M + H]+calcd for C51H89N2O17, 1001.61558; found1001.61746。
测试例1 本发明化合物抗菌活性测定
以泰乐菌素为阳性对照，采用微量肉汤稀释法，测定本发明中实施例1-4获得化合物的抗菌活性。
测试方法如下：
在96孔板加入肉汤培养基，将己经配制药液作微量二倍递减浓度稀释，然后接种适量菌液，经24 h孵育后，观察药物最低抑菌浓度。
试验用培养基为CAMHB肉汤、CAMHB+5%脱纤维羊血肉汤。
将保存菌种接种于血清板培养基，37℃培养16-18小时，将传代培养完毕的适量细菌和生理盐水置于比浊管中，用麦氏比浊仪校正到麦氏比浊标准，将细菌悬浊液以生理盐水稀释10倍，制得一定浓度（5×105~5×106cfu/mL）的试验用菌液，待用。
将泰乐菌素及实施例所获得的化合物用甲醇溶解，使各化合物浓度至所需浓度（1.0 mg/mL），储于灭菌的棕色西林瓶中，加塞、封口待用。其中针对革兰氏阴性菌工作浓度范围0.25 μg/mL~128 μg/mL；针对革兰氏阳性菌工作浓度范围0.098μg/mL~50 μg/mL。
采用96孔板微量二倍稀释法。在96孔板中加入肉汤培养基，将已配制好的药液作微量二倍递减浓度稀释，使第一个孔至第十个孔中的药液浓度呈现二倍递减关系，第十一个孔和第十二个孔不加药液。最后向第一个孔至第十一个孔中加入己配置好的菌液（浓度为5×105～5×106cfu/mL），第十二个孔不加菌液作为空白对照。将96孔板放置于37℃的恒温箱中，静置培养24小时，观察每个孔的细菌生长情况。抑制细菌生长的孔中溶液为透明，不能抑制细菌生长的孔中溶液为浑浊。选择溶液透明的孔所对应的浓度即为即为该样品的最小抗菌浓度(MIC)。
结果如下表。
结果表明：与泰乐菌素相比，实施例1-4中获得化合物对肺炎链球菌（革兰氏阳性菌代表）和大肠杆菌（革兰氏阴性菌代表）的体外抗菌活性表现出优于或相当的效果，说明式I所示化合物对革兰氏阳性菌、部分革兰氏阴性菌和支原体等有抗菌活性。具体来讲，经过3-氨基-1-丙醇反应得到衍生物Ia，对肺炎链球菌ATCC 49169略优于泰乐菌素，对大肠杆菌8099的抗菌效果与泰乐菌素相当，推测R位基团增加了与肺炎链球菌的结合，提升了抗菌活性；经过与（R）-脯氨醇反应得到的衍生物Ic，其对肺炎链球菌ATCC 49169和大肠杆菌8099的抗菌效果均优于泰乐菌素；而(S)-脯氨醇的反应得到的衍生物Id，含N的吡咯环引入虽能进一步增加了抗菌活性，但可能因空间位阻原因，其抗菌活性的增加没有得到实现。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
Claims (5)
1.一种大环内酯类化合物，其特征在于：所述大环内酯类化合物具有如式Ic所示的结构：
2.权利要求1所述大环内酯类化合物的制备方法，其特征在于：包括如下步骤：
(A)泰乐菌素A与氨基醇在非极性溶剂中反应，得到反应液；所述氨基醇为(R)-脯氨醇，所述氨基醇与所述泰乐菌素A的摩尔比为2～5：1；所述非极性溶剂为甲苯；
(B)向所述反应液中加入酸，反应得到羟基叔氨基修饰的大环内酯类化合物；所述酸为甲酸；所述酸的加入时机为：反应体系的温度达到75～85℃；所述酸与所述泰乐菌素A的摩尔比为3～6：1；
步骤(B)中，所述反应的条件为：温度为78～80℃，时间为2～3h。
3.一种兽药组合物，其特征在于：所述兽药组合物包括权利要求1所述的大环内酯类化合物。
4.一种药物制剂，其特征在于：所述药物制剂包括权利要求1所述的大环内酯类化合物。
5.权利要求1所述的大环内酯类化合物、权利要求3所述的兽药组合物或权利要求4所述的药物制剂在制备抗病原体感染药品中的应用，所述病原体为肺炎链球菌和/或大肠杆菌。
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| HAJIME MATSUBAR et al..Chemical modification of tylosin: synthesis of amino derivatives at C-20 position of tylosin and demycarosyltylosin.《Journal of Antibiotics》.1983,第36卷第1713-1721页. * |
| SYNTHESIS AND ANTIMICROBIAL EVALUATION OF 20-DEOXO-20-(3，5-DIMETHYLPIPERIDIN-l-YL)DESMYCOSIN (TILMICOSIN，EL-870) AND RELATED CYCLIC AMINO DERIVATIVES;Manuel Debono et al.;《Journal of Antibiotics》;第8卷;第1253-1267页 * |
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