CN117024367B - 哌嗪连接的噁唑烷酮截短侧耳素衍生物和应用及其药物组合物 - Google Patents
哌嗪连接的噁唑烷酮截短侧耳素衍生物和应用及其药物组合物 Download PDFInfo
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- CN117024367B CN117024367B CN202311004280.9A CN202311004280A CN117024367B CN 117024367 B CN117024367 B CN 117024367B CN 202311004280 A CN202311004280 A CN 202311004280A CN 117024367 B CN117024367 B CN 117024367B
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Abstract
本发明涉及哌嗪连接的噁唑烷酮截短侧耳素衍生物及其用途，属于抗菌药物技术领域。本发明解决的技术问题是提供一系列结构新颖、抗菌活性良好的哌嗪连接的噁唑烷酮截短侧耳素衍生物。该哌嗪连接的噁唑烷酮截短侧耳素衍生物的结构式为式Ⅰ所示。本发明哌嗪连接的噁唑烷酮截短侧耳素衍生物，其结构新颖，具有优良的抗菌活性。从体外抗菌实验可以明显看出，其对革兰氏阳性菌金黄色葡萄球菌耐药株ATCC33591和ATCC43300、金黄色葡萄球菌敏感株ATCC2913、表皮葡萄球菌耐药株ATCC51625、表皮葡萄球菌敏感株ATCC12228表现出优良的抗菌效果，优于泰妙菌素，有望治疗由革兰氏阳性菌引起的细菌感染。
Description
技术领域
本发明涉及噁唑烷酮截短侧耳素衍生物及其用途，属于抗菌药物技术领域。
背景技术
抗生素过度使用导致耐药菌增多，甚至出现“超级细菌”，包括耐甲氧西林金黄色葡萄球菌(MRSA)、耐多药肠杆菌属、耐多药肺炎克雷伯菌、耐万古霉素屎肠球菌(VRE)等。尤其是近年来，由新型冠状病毒(SARS-CoV-2)引起的2019冠状病毒疾病(COVID-19)导致抗生素类药物的过度使用，使得细菌耐药性问题愈发严峻，对人类公共健康安全及经济发展具有不可小觑的威胁性。因此，开发抗菌活性优异且不易产生交叉耐药性的抗生素迫在眉睫。
1951年，Kavanagh研究组首次从Pleurotus mutilus和P.Passeckerianus中分离出截短侧耳素，其具有三环二萜结构，对革兰氏阳性菌和支原体具有中等的抗菌活性。目前，已上市的截短侧耳素类衍生物共有4种，泰妙菌素(Tiamulin)和沃尼妙林(Valnemulin)分别于1979年、1999年被批准作为家禽专用药物，瑞他帕林(Retapamulin)于2007年被批准作为人局部感染药物，来法莫林(Lefamulin)于2019年被批准作为人全身性治疗药物。除了已上市药物，还有2种处于临床阶段的截短侧耳素类衍生物BC-3205及BC-7013，以及处于临床研究时被终止的阿扎妙林(Azamulin)。
虽然截短侧耳素在兽用药物上的应用较多，但胃肠道副作用、肝毒性、化合物合成方面的挑战性，都是阻碍截短侧耳素作为人用口服或注射制剂的因素。基于以上因素，科研人员对截短侧耳素进行了大量的衍生改造。1982年，阿扎莫林(Azamulin)由于具有出色的体外抑菌活性，使之进入临床研究，但由于该化合物具有较强的毒性，会抑制人肝微粒体的正常代谢(CYP3A4,IC50＝0.03-0.24μM)，因此无法进行后续临床应用。
因此，需要研究更多结构新颖、抗菌活性良好的截短侧耳素衍生物。
发明内容
针对以上缺陷，本发明解决的技术问题是提供一系列结构新颖、抗菌活性良好的哌嗪作为连接的噁唑烷酮截短侧耳素衍生物。
本发明哌嗪连接的噁唑烷酮截短侧耳素衍生物，其结构式为式Ⅰ所示：
其中，R选自氢、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、氰基或-NHBoc。
在本发明的一个实施方式中，R位于间位或对位。
在本发明一个具体实施方式中，R选自氢、卤素、-CH3、-OCH3、三氟甲基、氰基或-NHBoc。
本发明还提供本发明所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物在制备治疗或预防感染性疾病药物中的应用。
在本发明的一个具体实施方式中，所述感染性疾病是由耐药菌引起的，所述耐药菌为革兰氏阳性菌。
在一些具体实施例中，所述耐药菌包括金黄色葡萄球菌或表皮葡萄球菌。
本发明还提供一种药物组合物。
本发明所述药物组合物，含有活性成分以及药学上可接受的辅料，所述活性成分包括本发明所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物或药学上可接受的盐。
与现有技术相比，本发明具有如下有益效果：
本发明哌嗪连接的噁唑烷酮截短侧耳素衍生物，其结构新颖，具有优良的抗菌活性。从体外抗菌实验可以明显看出，其对革兰氏阳性菌金黄色葡萄球菌耐药株ATCC33591和ATCC43300、金黄色葡萄球菌敏感株ATCC2913、表皮葡萄球菌耐药株ATCC51625、表皮葡萄球菌敏感株ATCC12228表现出优良的抗菌效果，优于泰妙菌素，有望治疗由革兰氏阳性菌引起的细菌感染。
附图说明
图1为试验例2中化合物5k和泰妙菌素对MRSAATCC33591的时间杀菌曲线；其中，A为化合物5k对MRSAATCC 33591的时间杀菌曲线，B为泰妙菌素对MRSAATCC 33591的时间杀菌曲线。
图2为在MRSAATCC 33591感染后用20mg/kg和40mg/kg的化合物5k与泰妙菌素治疗以后的小鼠大腿细菌载量。
具体实施方式
本发明哌嗪连接的噁唑烷酮截短侧耳素衍生物，其结构式为式Ⅰ所示：
其中，R选自氢、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、氰基或-NHBoc。
本发明采用哌嗪作为连接基团连接噁唑烷酮和截短侧耳素，得到噁唑烷酮截短侧耳素衍生物，其结构新颖，所得化合物具有优良的抗菌活性。
在本发明的一个实施方式中，R位于间位或对位。即本发明哌嗪连接的噁唑烷酮截短侧耳素衍生物的结构式如下：
在本发明一个具体实施方式中，R选自氢、卤素、-CH3、-OCH3、三氟甲基、氰基或-NHBoc。
在本发明一个实施方式中，R选自氢、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、氰基或-NHBoc。
在本发明一些具体实施例中，所述哌嗪连接的噁唑烷酮截短侧耳素衍生物结构式为以下结构式中的任一种：
本发明所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物，可在制备治疗或预防感染性疾病药物中应用。
在本发明的一个具体实施方式中，所述感染性疾病是由耐药菌引起的，所述耐药菌为革兰氏阳性菌。
在一些具体实施例中，所述耐药菌包括金黄色葡萄球菌或表皮葡萄球菌。
本发明还提供一种药物组合物。
本发明所述药物组合物，含有活性成分以及药学上可接受的辅料，所述活性成分包括本发明所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物或药学上可接受的盐。
本发明中，“药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特征，且所述的游离酸通过与无毒的有机碱或者无机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
在一些具体实施例中，药学上可接受的盐选自盐酸盐、富马酸盐、苹果酸盐、氢溴酸盐、琥珀酸盐、磷酸盐、甲磺酸盐或苯甲酸盐。
“药学上可接受的辅料”是指加入到药物组合物中以促进化合物给药的惰性物质。
本发明化合物的合成，可以采用以下路线：
下面结合实施例对本发明的具体实施方式做进一步的描述，并不因此将本发明限制在所述的实施例范围之中。
实施例1化合物5a的合成
1)中间体S4-a～S4-n的合成
按以下合成路线化合物S4-a～S4-n：
合成中间体S4-a～S4-n的步骤：
将原料S1(15mmol)和(S)-N-缩水甘油邻苯二甲酰亚胺(3.96g,19.5mmol)加入到20mL乙醇/水的混合溶剂中，置于70～85℃下搅拌，TLC检测反应完全后，趁热抽滤、热乙醇/水混合液洗涤即可得纯品S2；将所得产品S2(4mmol)和CDI(1.69g,10.5mmol)加入到15mL干燥的乙酸乙酯溶液中，常温下搅拌，用乙酸乙酯过滤即得纯品S3；将S3(2.5mmol)加入到10mL MeOH溶液中搅拌5min左右，再向其中加入水合肼(790mg,15mmol)，室温下静置搅拌，TLC检测反应完全后，旋干反应液，用蒸馏水和二氯甲烷进行萃取，合并有机相、抽滤，溶剂蒸发完全后用少量干燥的乙酸乙酯(EA)将其溶解，冰浴条件下加入适量HCl/EA使产物成盐析出，减压抽滤，滤饼经冰EA洗涤，干燥即可得白色粉末状产品S4-a～S4-n。
其中S4-a～S4-n结构分别为：
其表征如下：
S4-a:1H NMR(400MHz,DMSO-d6):δ(ppm)8.62(s,3H),7.54(d,J＝7.6Hz,2H),7.49–7.27(m,2H),7.14(t,J＝7.6Hz,1H),5.07–4.94(m,1H),4.19(t,J＝9.2Hz,1H),3.95(dd,J＝9.2,6.8Hz,1H),3.22(d,J＝7.6Hz,2H)；13C NMR(101MHz,DMSO-d6):δ(ppm)154.1,138.7,129.4,124.2,118.7,69.9,47.7,41.9.
S4-b:1H NMR(400MHz,DMSO-d6):δ(ppm)8.61(s,3H),7.57–7.37(m,2H),7.29(dd,J＝8.4,1.6Hz,1H),6.98(td,J＝8.4,1.6Hz,1H),5.07–4.96(m,1H),4.20(t,J＝9.2Hz,1H),4.01–3.88(m,1H),3.30–3.16(m,2H)；13C NMR(101MHz,DMSO-d6):δ(ppm)163.9,161.5,154.0,140.5,140.4,131.2,131.1,114.3,114.3,110.7,110.5,105.8,105.5,70.1,47.7,41.9.
S4-c:1H NMR(400MHz,DMSO-d6):δ(ppm)8.51(s,3H),7.69(s,1H),7.43(dd,J＝4.0,1.2Hz,2H),7.20(dd,J＝4.8,2.0Hz,1H),5.06–4.95(m,1H),4.20(t,J＝9.2Hz,1H),3.95(dd,J＝9.0,6.8Hz,1H),3.32–3.12(m,2H)；13C NMR(101MHz,DMSO-d6):δ(ppm)154.0,140.1,133.8,131.1,123.8,118.2,117.0,70.2,47.6,41.9.
S4-d:1H NMR(400MHz,DMSO-d6):δ(ppm)8.64(s,3H),7.83(d,J＝2.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.42–7.26(m,2H),5.03(q,J＝6.8Hz,1H),4.20(t,J＝9.2Hz,1H),3.95(dd,J＝9.2,6.8Hz,1H),3.32–3.15(m,2H)；13C NMR(101MHz,DMSO-d6):δ(ppm)154.0,140.2,131.3,126.8,122.3,121.1,117.4,70.1,47.6,41.8.
S4-e:1H NMR(400MHz,DMSO-d6):δ(ppm)8.57(s,3H),7.97(t,J＝2.0Hz,1H),7.50(dd,J＝9.2,1.7Hz,2H),7.26–7.10(m,1H),5.08–4.92(m,1H),4.18(t,J＝9.2Hz,1H),3.93(dd,J＝9.2,6.6Hz,1H)；13C NMR(101MHz,DMSO-d6):δ(ppm)153.9,140.0,132.7,131.3,126.9,117.9,95.3,70.1,47.6,41.9.
S4-f:1H NMR(400MHz,DMSO-d6):δ(ppm)8.62(s,3H),7.43–7.21(m,3H),6.96(d,J＝7.2 Hz,1H),5.05–4.92(m,1H),4.17(t,J＝9.2 Hz,1H),3.92(dd,J＝9.2,6.8 Hz,1H),3.21(d,J＝7.8 Hz,2H),2.31(s,3H)；13C NMR(101 MHz,DMSO-d6):δ(ppm)154.1,138.7,129.2,124.9,119.3,115.9,69.9,47.8,41.9,21.7.
S4-g:1H NMR(400 MHz,DMSO-d6):δ(ppm)8.61(s,3H),8.00(s,1H),7.73(d,J＝9.2Hz,1H),7.65(t,J＝8.0 Hz,1H),7.49(d,J＝7.8 Hz,1H),5.10–4.98(m,1H),4.26(t,J＝9.2 Hz,1H),4.01(dd,J＝9.2,6.8 Hz,1H),3.31–3.18(m,2H)；13C NMR(101 MHz,DMSO-d6):δ(ppm)154.1,139.5,130.7,130.5,130.2,129.9,129.6,125.8,123.1,122.2,120.4,120.4,114.9,114.8,70.2,47.641.9.
S4-h:1H NMR(400 MHz,DMSO-d6):δ(ppm)8.62(s,3H),8.02–7.92(m,1H),7.87(dt,J＝7.8,2.0 Hz,1H),7.68–7.54(m,2H),5.12–4.97(m,1H),4.24(t,J＝9.2 Hz,1H),3.99(dd,J＝9.2,6.8 Hz,1H),3.30–3.17(m,2H)；13C NMR(101 MHz,DMSO-d6):δ(ppm)154.1,139.5,130.8,127.54,123.2,121.5,119.0,112.2,70.3,47.5,41.8.
S4-i:1H NMR(400 MHz,DMSO-d6):δ(ppm)9.38(s,1H),7.77(s,1H),7.27–7.19(m,2H),7.17–7.12(m,1H),4.60(dq,J＝11.2,5.2 Hz,1H),4.02(t,J＝8.8 Hz,1H),3.81(dd,J＝8.8,6.8Hz,1H),2.84(qd,J＝13.6,4.8 Hz,2H),1.47(s,9H)；13C NMR(101 MHz,DMSO-d6):δ(ppm)154.8,153.2,140.6,139.5,129.4,113.8,112.2,108.4,79.5,74.2,47.6,44.5,28.6.
S4-j:1H NMR(400 MHz,DMSO-d6):δ(ppm)8.60(s,3H),7.30(t,J＝8.0 Hz,1H),7.20(t,J＝2.4 Hz,1H),7.06(dd,J＝8.0,1.6 Hz,1H),6.73(dd,J＝8.0,2.4 Hz,1H),5.06–4.90(m,1H),4.18(t,J＝9.2 Hz,1H),3.94(dd,J＝9.2,6.8 Hz,1H),3.75(s,3H),3.30–3.12(m,2H)；13C NMR(101 MHz,DMSO-d6):δ(ppm)160.1,154.0,139.9,130.2,110.9,109.5,105.0,69.9,55.7,47.8,41.9.
S4-k:1H NMR(400 MHz,DMSO-d6):δ(ppm)8.61(s,3H),7.62–7.51(m,2H),7.51–7.39(m,2H),5.06–4.95(m,1H),4.18(t,J＝9.2 Hz,1H),3.93(dd,J＝9.2,6.8 Hz,1H),3.18(s,2H)；13C NMR(101 MHz,DMSO-d6):δ(ppm)154.0,137.7,129.2,128.0,120.3,70.0,47.7,41.8.
S4-l:1H NMR(400 MHz,DMSO-d6):δ(ppm)8.58(s,3H),7.67–7.46(m,4H),5.08–4.94(m,1H),4.18(t,J＝9.2 Hz,1H),3.92(dd,J＝9.2,6.8 Hz,1H),3.22(d,J＝32.0 Hz,2H)；13CNMR(101 MHz,DMSO-d6):δ(ppm)154.0,138.1,132.1,120.6,116.1,70.0,47.6,41.9.
S4-m:1H NMR(400 MHz,DMSO-d6):δ(ppm)8.61(s,3H),7.82–7.67(m,4H),5.11–4.98(m,1H),4.25(t,J＝9.2 Hz,1H),4.00(dd,J＝9.2,6.8 Hz,1H)；13C NMR(101 MHz,DMSO-d6):δ(ppm)154.0,142.2,126.6,126.6,126.6,126.5,124.5,124.2,123.9,123.6,118.4,70.2,47.5,41.8.
S4-n:1H NMR(400 MHz,DMSO-d6):δ(ppm)8.57(s,3H),7.58–7.32(m,2H),7.12–6.83(m,2H),5.06–4.95(m,1H),4.14(t,J＝9.2Hz,1H),3.90(dd,J＝9.2,6.8Hz,1H),3.74(s,3H),3.29–3.13(m,2H)；13C NMR(101MHz,DMSO-d6):δ(ppm)156.3,154.3,131.8,120.9,114.6,69.8,55.8,48.2,42.0.
2)中间体4的合成
按以下合成路线合成化合物4
合成中间体2的步骤：
将对甲苯磺酰氯(4.3g,22.7mmol)和截短侧耳素(7.8g,20.6mmol)溶于25mL甲基叔丁基醚和水的混合溶液中(v/v＝4:1)，在冰浴条件下将5mL氢氧化钠溶液(10M)缓慢滴加至上述混合溶液中后，将装置其置于60℃加热反应约1h左右，待反应完毕后将其倾倒入盛有适量水的烧杯中，过滤后，滤饼用水洗涤得到白色固体，经干燥即得到中间体2(产率92.3％)。
1H NMR(400MHz,CDCl3):δ(ppm)7.81(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,2H),6.41(dd,J＝17.2,11.2Hz,1H),5.76(d,J＝8.4Hz,1H),5.33(dd,J＝11.2,1.2Hz,1H),5.19(dd,J＝17.2,1.2Hz,1H),4.48(s,2H),3.34(d,J＝6.4Hz,1H),2.45(s,3H),2.33–1.99(m,5H),1.81–1.41(m,6H),1.40(s,3H),1.38–1.30(m,1H),1.29–1.20(m,1H),1.15(s,3H),1.13–1.05(m,1H),0.87(d,J＝6.8Hz,3H),0.62(d,J＝6.8Hz,3H).
合成中间体3的步骤：
将中间体2(532.70mg，1.00mmol)和NaI(15.00mg，0.10mmol)溶于干燥的乙腈溶液中，回流反应0.5h后，随后将无水哌嗪(172.30mg，2.00mmol)和K2CO3(276.40mg，2.00mmol)添加到上述溶液中，继续搅拌回流，TLC检测反应进程，反应完毕，冷却至室温，将反应液减压浓缩，经柱层析法提纯即可得到白色粉末状的中间体3(产率75.2％)。
1H NMR(400MHz,CDCl3):δ(ppm)7.74(d,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),6.48(dd,J＝17.2,11.2Hz,1H),5.78(d,J＝8.4Hz,1H),5.33(dd,J＝11.2,1.2Hz,1H),5.19(dd,J＝17.2,1.6Hz,1H),3.35(d,J＝6.0Hz,1H),3.20–3.02(m,6H),2.79–2.62(m,4H),2.40–1.99(m,7H),1.81–1.31(m,10H),1.16(s,3H),1.14–1.07m,1H),0.87(d,J＝6.8Hz,3H),0.69(d,J＝6.8Hz,3H).
合成中间体4的步骤：
将中间体3(1.00g，2.24mmol)溶于15mL二氯甲烷中，将K2CO3(0.62g，4.48mmol)添加到上述反应体系中，然后缓慢的加入氯乙酰氯(0.28g，2.46mmol)，在冰浴中反应3小时左右。TLC检测反应进程，反应完毕，在反应液中加入适量的15％氯化钠水溶液，用氯仿(3×20.00mL)萃取，分液收集有机相，用无水硫酸钠干燥，减压浓缩得到白色固体中间体4(产率77.8％)。
1H NMR(400MHz,CDCl3):δ(ppm)6.52(dd,J＝17.2,11.2Hz,1H),5.82(d,J＝8.4Hz,1H),5.37(dd,J＝11.2,1.6Hz,1H),5.22(dd,J＝17.2,1.6Hz,1H),4.08(s,2H),3.70(s,2H),3.59(t,J＝4.8Hz,2H),3.38(dd,J＝10.8,6.8Hz,1H),3.31–3.05(m,2H),2.83–2.48(m,4H),2.46–1.98(m,6H),1.87–1.25(m,14H),1.19(s,3H),1.14(dd,J＝14.0,4.4Hz,1H),0.90(d,J＝7.2Hz,3H),0.74(d,J＝7.2Hz,3H)。
3)实施例1化合物5a的合成
将噁唑烷酮盐酸盐中间体S4-a(0.8mmol)和Et3N(1.6mmol)溶于干燥的DMF(6mL)中，再加入截短侧耳素中间体4(0.8mmol)，氩气保护，置于60℃油浴锅中反应，待TLC检测反应完全后，乙酸乙酯(3×20mL)对反应液进行萃取，合并有机层用饱和食盐水(3×20mL)水洗，抽滤收集滤饼，经柱层析法纯化，得到目标产物。该物质为白色粉末；产率：42.7％；熔点：130.4-131.7℃；1H NMR(400MHz,CDCl3):7.59–7.47(m,2H),7.41–7.29(m,2H),7.17–7.05(m,1H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.77(d,J＝8.4Hz,1H,H14),5.32(dd,J＝11.2,1.6Hz,1H,H20),5.18(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.03(t,J＝8.8Hz,1H),3.90(dd,J＝8.8,6.8Hz,1H),3.65(t,J＝4.4Hz,2H),3.49(s,2H),3.42(t,J＝4.4Hz,3H),3.34(t,J＝7.2Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.04–2.90(m,2H),2.67–2.44(m,4H),2.39–2.03(m,5H,H10,H2,H13,H4),1.76(dq,J＝14.4,3.2Hz,1H,H8),1.71–1.44(m,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.39–1.31(m,1H,H7),1.27(d,J＝16.4Hz,1H,H13),1.15(s,3H,H18),1.10(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝6.8Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.1(C21),168.8,154.6,139.0(C19),138.3,129.0,123.9,118.2,117.2(C20),74.5(C11),72.9,68.5(C14),59.6(C22),58.1(C4),52.6,52.4,52.3,50.6,48.1,45.4(C9),45.0(C13),44.2,43.9(C12),41.7(C5),36.6(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.6(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3444,2933,1735,1645,1600,1504,1458,1409,1306,1221,1140,1012,980,914,758,692；HRMS:calculated for C38H54N4O7([M+H]+):679.4065；found 679.4069。
实施例2化合物5b的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：42.5％；熔点：99.9-102.8℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.43(dt,J＝11.2,2.4Hz,1H),7.30(td,J＝8.4,6.4Hz,1H),7.22(ddd,J＝8.4,2.4,1.2Hz,1H),6.81(tdd,J＝8.4,2.4,1.2Hz,1H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.77(d,J＝8.4Hz,1H,H14),5.33(dd,J＝11.2,1.6Hz,1H,H20),5.19(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.01(t,J＝8.8Hz,1H),3.90(dd,J＝8.8,6.8Hz,1H),3.65(t,J＝5.2Hz,2H),3.49(d,J＝1.6Hz,2H),3.42(t,J＝5.2Hz,2H),3.35(dd,J＝10.0,6.4Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.03–2.92(m,2H),2.65–2.44(m,4H),2.39–2.05(m,5H,H10,H2,H13,H4),1.76(dq,J＝14.4,3.2Hz,1H,H8),1.70–1.44(m,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.39–1.32(m,1H,H7),1.27(d,J＝16.0Hz,1H,H13),1.15(s,3H,H18),1.10(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝6.8Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)217.0(C3),169.1(C21),168.8,164.2,161.8,154.3,139.9,139.8,139.0(C19),130.2,130.1,117.2(C20),113.2,113.2,110.7,110.5,105.8,105.5,74.6(C11),72.9,68.5(C14),59.6(C22),58.1(C4),52.6,52.3,52.2,50.6,48.0,45.4(C9),45.0(C13),44.2,43.9(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3445,2934,1735,1646,1615,1590,1497,1458,1407,1225,1195,1162,1117,1011,980,915,754,682；HRMS:calculated for C38H53FN4O7([M+H]+):697.3971；found 697.3972。
实施例3化合物5c的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：22.3％；熔点：100.0-101.2℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.58(t,J＝2.0Hz,1H),7.44(dd,J＝8.4,2.4Hz,1H),7.32–7.23(m,1H),7.13–7.05(m,1H),6.48(dd,J＝17.2,11.2Hz,1H,H19),5.78(d,J＝8.4Hz,1H,H14),5.33(dd,J＝11.2,1.6Hz,1H,H20),5.19(dd,J＝17.2,1.6Hz,1H,H20),4.81–4.36(m,1H),4.01(t,J＝8.8Hz,1H),3.91(dd,J＝8.8,6.8Hz,1H),3.65(t,J＝5.2Hz,2H),3.49(d,J＝2.4Hz,2H),3.42(t,J＝5.2Hz,2H),3.35(s,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.03–2.90(m,2H),2.68–2.45(m,4H),2.39–2.01(m,5H,H10,H2,H13,H4),1.76(dd,J＝14.0,3.2Hz,1H,H8),1.71–1.42(m,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.40–1.32(m,1H,H7),1.27(d,J＝16.4Hz,1H,H13),1.16(s,3H,H18),1.10(dd,J＝14.0,4.4Hz,1H,H8),0.87(d,J＝6.8Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.0(C21),168.8,154.3,139.5(C19),139.0,134.8,130.0,123.9,118.1,117.2(C20),116.0,74.6(C11),73.0,68.5(C14),60.0(C22),58.1(C4),52.6,52.4,52.1,50.6,47.9,45.4(C9),45.0(C13),44.2,43.9(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3445,2934,1736,1645,1497,1455,1423,1308,1219,1143,1117,1010,981,916,828,781,754；HRMS:calculated for C38H53ClN4O7([M+H]+):713.3676；found 713.3679。
实施例4化合物5d的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：35.2％；熔点：98.4-100.2℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.71(t,J＝2.0Hz,1H),7.50(dt,J＝7.6,2.0Hz,1H),7.26–7.16(m,2H),6.47(dd,J＝17.6,11.2Hz,1H,H19),5.77(d,J＝8.4Hz,1H,H14),5.32(dd,J＝11.2,1.6Hz,1H,H20),5.18(dd,J＝17.6,1.6Hz,1H,H20),4.79–4.65(m,1H),4.00(t,J＝8.8Hz,1H),3.90(dd,J＝8.8,6.8Hz,1H),3.65(t,J＝5.2Hz,2H),3.48(d,J＝2.0Hz,2H),3.41(t,J＝5.2Hz,2H),3.34(t,J＝7.2Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.03–2.90(m,2H),2.68–2.45(m,4H),2.39–2.03(m,5H,H10,H2,H13,H4),1.76(dq,J＝14.4,3.2Hz,1H,H8),1.70–1.44(m,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.40–1.30(m,1H,H7),1.26(d,J＝16.4,1H,H13),1.15(s,3H,H18),1.10(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝6.8Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.0(C21),168.8,154.3,139.6(C19),139.0,130.2,126.8,122.8,120.9,117.2(C20),116.5,74.5(C11),73.0,68.5(C14),59.6(C22),58.1(C4),52.6,52.3,52.1,50.6,47.8,45.41(C9),45.0(C13),44.2,43.9(C12),41.7(C5),36.6(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.6(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3445,2934,1735,1646,1594,1483,1439,1405,1305,1220,1143,1117,1011,915,778,695；HRMS:calculated for C38H53BrN4O7([M+H]+):757.3170；found 757.3172。
实施例5化合物5e的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：23.9％；熔点：115.4-117.8℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.92–7.80(t,J＝2.0Hz,1H),7.57(dd,J＝8.0,2.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.07(t,J＝8.0Hz,1H),6.48(dd,J＝17.2,11.2Hz,1H,H19),5.78(d,J＝8.4Hz,1H,H14),5.33(dd,J＝11.2,1.2Hz,1H,H20),5.19(dd,J＝17.2,1.2Hz,1H,H20),4.77–4.66(m,1H),4.00(t,J＝8.8Hz,1H),3.89(dd,J＝8.8,7.2Hz,1H),3.66(t,J＝4.8Hz,2H),3.49(d,J＝1.6Hz,2H),3.42(t,J＝4.8Hz,2H),3.38–3.30(m,1H,H11),3.19(d,J＝17.2Hz,1H,H22),3.07(d,J＝17.2Hz,1H,H22),3.04–2.90(m,2H),2.63–2.47(m,4H),2.39–2.04(m,5H,H10,H2,H13,H4),1.82–1.72(m,1H,H8),1.71–1.44(m,5H,H6,H7,H1,OH),1.43(s,3H,H15),1.39–1.31(m,1H,H7),1.27(d,J＝17.6Hz,1H,H13),1.16(s,3H,H18),1.11(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝7.2Hz,3H,H17),0.71(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.1(C21),168.8,154.3,139.5,139.0(C19),132.9,130.4,126.7,117.3,117.2(C20),94.2,74.6(C11),73.0,68.5(C14),59.6(C22),58.1(C4),52.6,52.4,52.1,50.6,47.8,45.4(C9),45.0(C13),44.2,43.9(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3436,2932,1735,1645,1588,1565,1479,1435,1405,1219,1144,1012,775,754,686；HRMS:calculated for C38H53IN4O7([M+H]+):805.3032；found 805.3033。
实施例6化合物5f的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：31.8％；熔点：96.3-101.1℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.37(t,J＝2.4Hz,1H),7.31(dd,J＝8.0,2.4Hz,1H),7.23(t,J＝8.0Hz,1H),6.98–6.88(m,1H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.78(d,J＝8.4Hz,1H,H14),5.33(dd,J＝11.2,1.6Hz,1H,H20),5.19(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.02(t,J＝8.8Hz,1H),3.89(dd,J＝8.8,6.8Hz,1H),3.65(t,J＝5.2Hz,2H),3.50(s,2H),3.42(t,J＝5.2Hz,2H),3.35(d,J＝6.4Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.03–2.90(m,2H),2.66–2.45(m,4H),2.38–2.00(m,9H,H10,H2,H13,H4),1.76(dq,J＝14.4,3.2Hz,1H,H8),1.71–1.44(m,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.39–1.32(m,1H,H7),1.32–1.26(m,1H,H13),1.16(s,3H,H18),1.10(dd,J＝14.0,4.4Hz,1H,H8),0.87(d,J＝7.2Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.0(C21),168.8,154.3,141.3,139.1(C19),126.2,126.2,117.6,117.2(C20),74.6(C11),73.0,68.5(C14),59.6(C22),58.1(C4),52.6,52.3,52.1,50.6,47.8,45.4(C9),45.0(C13),44.2,43.9(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3445,2931,1736,1646,1609,1494,1456,1406,1304,1228,1118,1012,987,915,784,691；HRMS:calculated for C39H56N4O7([M+H]+):693.4222；found 693.4221。
实施例7化合物5g的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：39.8％；熔点：89.4-93.2℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.82(dd,J＝8.4,2.4Hz,1H),7.74(s,1H),7.48(t,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.78(d,J＝8.4Hz,1H,H14),5.33(dd,J＝11.2,1.6Hz,1H,H20),5.19(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.06(t,J＝8.8Hz,1H),3.97(dd,J＝8.8,6.8Hz,1H),3.66(t,J＝5.2Hz,2H),3.50(d,J＝2.4Hz,2H),3.42(t,J＝5.2Hz,2H),3.35(dd,J＝10.4,6.4Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.07(d,J＝17.2Hz,1H,H22),3.04–2.94(m,2H),2.67–2.46(m,4H),2.39–2.30(m,1H,H10),2.27–2.05(m,4H,H2,H13,H4),1.81–1.71(m,1H,H8),1.70–1.44(m,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.39–1.32(m,1H,H7),1.27(d,J＝15.6Hz,1H,H13),1.16(s,3H,H18),1.11(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝7.2Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.0(C21),168.8,154.4,139.0(C19),138.9,131.6,131.3,129.6,121.1,120.4,120.4,117.2(C20),114.5,114.5,74.6(C11),73.0,68.5(C14),59.6(C22),58.1(C4),52.6,52.3,52.1,50.6,47.8,45.4(C9),45.0(C13),44.2,43.9(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3420,2972,1735,1645,1595,1498,1459,1408,1339,1219,1127,1096,1075,1048,1012,683；HRMS:calculated for C39H53F3N4O7([M+H]+):747.3939；found 747.3939。
实施例8化合物5h的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：31.6％；熔点：106.8-108.7℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.91–7.76(m,2H),7.46(dt,J＝9.2,2.4Hz,1H),7.39(dt,J＝9.2,2.4Hz,1H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.77(d,J＝8.4Hz,1H,H14),5.32(dd,J＝11.2,1.6Hz,1H,H20),5.18(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.03(t,J＝8.4Hz,1H),3.96(dd,J＝8.4,6.8Hz,1H),3.65(t,J＝5.2Hz,2H),3.49(d,J＝2.4Hz,2H),3.41(t,J＝5.2Hz,2H),3.34(s,1H,H11),3.19(d,J＝17.2Hz,1H,H22),3.07(d,J＝17.2Hz,1H,H22),3.05–2.93(m,2H),2.65–2.44(m,4H),2.37–2.04(m,5H,H10,H2,H13,H4),1.76(dq,J＝14.4,3.2Hz,1H,H8),1.70–1.43(m,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.41–1.30(m,1H,H7),1.26(d,J＝16.4Hz,1H,H13),1.15(s,3H,H18),1.10(dd,J＝13.6,4.0Hz,1H,H8),0.86(d,J＝6.8Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)217.0(C3),169.0(C21),168.8,154.3,139.1,139.0(C19),129.9,127.1,121.9,120.8,118.4,117.2(C20),113.1,74.5(C11),73.1,68.5(C14),59.5(C22),58.1(C4),52.5,52.3,52.0,50.6,47.5,45.4(C9),45.0(C13),44.1,43.9(C12),41.7(C5),36.6(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3445,2934,2230,1735,1645,1602,1488,1445,1405,1333,1221,1135,1011,915,796,682；HRMS:calculated for C39H53N5O7([M+H]+):704.4018；found 704.4017.
实施例9化合物5i的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：42.7％；熔点：130.4-131.7℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.65(t,J＝2.0Hz,1H),7.31–7.17(m,2H),7.11(dt,J＝7.6,2.0Hz,1H),6.66(d,J＝7.6Hz,1H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.78(d,J＝8.4Hz,1H,H14),5.33(dd,J＝11.2,1.6Hz,1H,H20),5.19(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.04(t,J＝8.8Hz,1H),3.89(dd,J＝8.8,6.8Hz,1H),3.65(t,J＝5.2Hz,2H),3.49(s,2H),3.42(t,J＝5.2Hz,2H),3.35(t,J＝7.6Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.03–2.90(m,2H),2.67–2.45(m,4H),2.39–2.03(m,5H,H10,H2,H13,H4),1.76(dq,J＝14.4,3.2Hz,1H,H8),1.71–1.44(m,14H,H6,H7,H1,OH),1.42(s,3H,H15),1.39–1.31(m,1H,H7),1.27(m,J＝16.0,1H,H13),1.16(s,3H,H18),1.10(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝7.2Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)217.0(C3),169.1(C21),168.8,154.6,152.6,139.2,139.0(C19),138.9,129.5,117.2(C20),113.9,112.6,108.2,88.2,80.6,74.6(C11),73.0,68.5(C14),59.6(C22),58.2(C4),52.6,52.4,52.3,50.6,48.2,45.4(C9),45.0(C13),44.2,43.9(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),28.3,26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3444,2933,1732,1645,1608,1499,1455,1406,1368,1238,1160,1012,915,776,689；HRMS:calculated forC43H63N5O9([M+H]+):794.4699；found 794.4698。
实施例10化合物5j的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：37.4％；熔点：98.5-94.2℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.32–7.18(m,2H),7.02(dd,J＝8.0,1.6Hz,1H),6.67(dd,J＝8.0,2.0Hz,1H),6.48(dd,J＝17.2,11.2Hz,1H,H19),5.78(d,J＝8.4Hz,1H,H14),5.33(dd,J＝11.2,1.2Hz,1H,H20),5.19(dd,J＝17.2,1.2Hz,1H,H20),4.77–4.64(m,1H),4.02(t,J＝8.8Hz,1H),3.88(dd,J＝8.8,6.8Hz,1H),3.81(s,3H),3.66(t,J＝5.2Hz,2H),3.50(s,2H),3.42(t,J＝5.2Hz,2H),3.35(dd,J＝10.0,6.4Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.03–2.92(m,2H),2.67–2.45(m,4H),2.34(p,J＝7.2,1H,H10),2.39–2.05(m,5H,H10,H2,H13,H4),1.77(dd,J＝14.0,3.2Hz,1H,H8),1.71–1.42(m,5H,H6,H7,H1,OH),1.43(s,3H,H15),1.41–1.31(m,1H,H7),1.27–1.23(m,1H,H13),1.16(s,3H,H18),1.11(dd,J＝14.0,4.4Hz,1H,H8),0.87(d,J＝7.2Hz,3H,H17),0.71(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.1(C21),168.8,160.2,154.5,139.5(C19),139.0,129.7,117.2(C20),110.3,109.6,104.4,74.6(C11),72.9,68.5(C14),59.6(C22),58.2(C4),55.3,52.6,52.3,50.7,48.2,45.4(C9),45.0(C13),44.2,44.0(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3444,2932,1733,1644,1604,1498,1455,1408,1292,1229,1117,1012,915,861,772,688；HRMS:calculatedfor C39H56N4O8([M+H]+):709.4171；found 709.4170。
实施例11化合物5k的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：41.2％；熔点：91.3-93.8℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.56–7.41(m,2H),7.37–7.27(m,2H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.77(d,J＝8.4Hz,1H,H14),5.32(dd,J＝11.2,1.6Hz,1H,H20),5.18(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.00(t,J＝8.8Hz,1H),3.90(dd,J＝8.8,6.8Hz,1H),3.65(t,J＝5.2Hz,2H),3.49(d,J＝2.0Hz,2H),3.41(t,J＝5.2Hz,2H),3.35(s,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.04–2.91(m,2H),2.69–2.44(m,4H),2.39–2.04(m,5H,H10,H2,H13,H4),1.80-1.72(m,1H,H8),1.71–1.44(m,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.39–1.31(m,1H,H7),1.27(d,J＝16.0Hz,1H,H13),1.15(s,3H,H18),1.10(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝7.2Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.0(C21),168.8,154.5,139.0(C19),136.9,129.1,129.0,119.3,117.2(C20),74.6(C11),72.9,68.5(C14),59.6(C22),58.1(C4),52.6,52.3,52.2,50.6,48.0,45.4(C9),45.0(C13),44.2,43.9(C12),41.7(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3444,2930,1732,1644,1497,1455,1423,1403,1308,1219,1143,1117,1011,982,829；HRMS:calculated for C38H53ClN4O7([M+H]+):713.3676；found 713.3679。
实施例12化合物5l的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：32.8％；熔点：89.8-91.7℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.51–7.38(m,4H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.77(d,J＝8.4Hz,1H,H14),5.32(dd,J＝11.2,1.8Hz,1H,H20),5.19(dd,J＝17.6,1.8Hz,1H,H20),4.77–4.66(m,1H),3.99(t,J＝8.8Hz,1H),3.89(dd,J＝8.8,6.8Hz,1H),3.65(t,J＝5.2Hz,2H),3.48(d,J＝2.0Hz,2H),3.41(t,J＝5.2Hz,2H),3.35(dd,J＝10.0,6.4Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.03–2.90(m,2H),2.65–2.45(m,4H),2.39–2.03(m,5H,H10,H2,H13,H4),1.76(dt,J＝14.4,3.2Hz,1H,H8),1.71–1.44(m,5H,5H,H6,H7,H1,OH),1.42(s,3H,H15),1.35(dd,J＝14.4,3.2Hz 1H,H7),1.27(d,J＝16.0Hz,1H,H13),1.15(s,3H,H18),1.10(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝6.8Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.0(C21),168.8,154.4,139.0(C19),137.4,131.9,119.6,117.2(C20),116.7,74.6(C11),72.9,68.5(C14),59.6(C22),58.1(C4),52.6,52.3,52.2,50.6,47.9,45.4(C9),45.0(C13),44.2,43.9(C12),41.7(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3444,2933,1736,1644,1592,1493,1455,1400,1308,1219,1143,1117,1011,982,916,825；HRMS:calculated for C38H53BrN4O7([M+H]+):757.3170；found757.3171。
实施例13化合物5m的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：29.0％；熔点：107.0-110.5℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.74–7.51(m,4H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.78(d,J＝8.4Hz,1H,H14),5.33(dd,J＝10.8,1.6Hz,1H,H20),5.19(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.06(t,J＝8.8Hz,1H),3.96(dd,J＝8.8,6.8Hz,1H),3.66(t,J＝5.2Hz,2H),3.49(d,J＝1.6Hz,2H),3.41(t,J＝5.2Hz,2H),3.35(s,1H,H11),3.19(d,J＝17.2Hz,1H,H22),3.07(d,J＝17.2Hz,1H,H22),3.04–2.91(m,2H),2.68–2.45(m,4H),2.39–2.04(m,5H,H10,H2,H13,H4),1.77(dq,J＝15.6,3.6Hz,1H,H8),1.71–1.42(m,5H,H6,H7,H1,OH),1.42(s,3H,H5),1.36(dq,J＝14.0,3.6Hz,1H,H7),1.27(d,J＝16.4Hz,1H,H13),1.16(s,3H,H18),1.11(dd,J＝14.0,4.4Hz,1H,H8),0.87(d,J＝7.2Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.0(C21),168.8,154.3,141.3,139.1(C19),126.2,126.2,117.6,117.2(C20),74.6(C11),73.0,68.5(C14),59.6(C22),58.1(C4),52.6,52.3,52.1,50.6,47.8,45.4(C9),45.0(C13),44.2,43.9(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),11.4(C17)；IR(KBr,cm-1):3452,2935,1736,1650,1617,1524,1432,1405,1323,1217,1164,1117,1013,842；HRMS:calculated forC39H53F3N4O7S([M+H]+):747.3939；found 747.3942。
实施例14化合物5n的合成
参照实施例1的合成，制得如下化合物：
该化合物为白色粉末；产率：41.6％；熔点：94.7-96.6℃；
1H NMR(400MHz,CDCl3):δ(ppm)7.49–7.33(m,2H),6.96–6.81(m,2H),6.48(dd,J＝17.6,11.2Hz,1H,H19),5.78(d,J＝8.4Hz,1H,H14),5.33(dd,J＝11.2,1.6Hz,1H,H20),5.19(dd,J＝17.6,1.6Hz,1H,H20),4.77–4.66(m,1H),4.00(t,J＝8.8Hz,1H),3.87(dd,J＝8.8,7.2Hz,1H),3.79(s,3H),3.65(d,J＝5.6Hz,2H),3.50(s,2H),3.42(t,J＝5.6Hz,2H),3.35(dd,J＝10.0,6.4Hz,1H,H11),3.18(d,J＝17.2Hz,1H,H22),3.06(d,J＝17.2Hz,1H,H22),3.05–2.88(m,2H),2.68–2.43(m,4H),2.39–2.04(m,5H,H10,H2,H13,H4),1.86–1.70(m,1H,H8),1.70–1.44(m,5H,H6,H7,H1,OH),1.42(s,3H,H5),1.40–1.32(m,1H,H7),1.27(d,J＝16.0Hz,1H,H13),1.16(s,3H,H18),1.11(dd,J＝13.6,4.4Hz,1H,H8),0.87(d,J＝7.2Hz,3H,H17),0.70(d,J＝6.8Hz,3H,H16)；13C NMR(101MHz,CDCl3):δ(ppm)216.9(C3),169.1(C21),168.8,156.3,154.9,139.0(C19),131.5,120.2,117.2(C20),114.3,74.6(C11),72.9,68.5(C14),60.3,59.6(C22),58.2(C4),55.5,52.6,52.4,50.6,48.6,45.4(C9),45.0(C13),44.2,43.9(C12),41.8(C5),36.7(C6),36.0(C10),34.4(C2),30.4(C8),26.8(C7),26.4(C18),24.8(C1),16.7(C16),14.8(C15),14.2,11.4(C17)；IR(KBr,cm-1):3418,2970,1735,1639,1515,1444,1411,1249,1117,1048,1012,829；HRMS:calculatedfor C39H56N4O8([M+H]+):709.4171；found 709.4173。
试验例1体外抗菌活性研究
实验方法
最低抑菌浓度(MIC)测试方法
1、实验菌株：选取金黄色葡萄球菌耐药株ATCC 33591和ATCC 43300、金黄色葡萄球菌敏感株ATCC 2913、表皮葡萄球菌耐药株ATCC 51625、表皮葡萄球菌敏感株ATCC 12228以及大肠杆菌标准株ATCC 25922为MIC值测定菌株。
2、药物稀释：以DMSO为溶剂将目标化合物和泰妙菌素(T)分别溶解和稀释，配制成浓度为12800μg·mL-1的母液，置于冰箱避光密封保存备用。
3、菌液制备：取各受试菌进行活化，挑取单克隆菌落于0.9％生理盐水中，将菌液配置成0.5麦氏浓度(1.5×108CFU·mL-1)，后用Mueller-Hinton无菌肉汤培养基(MHB)稀释10倍备用。
4、阳性对照：选取泰妙菌素(T)作为阳性对照。
5、MIC测定：在96孔板中除边缘孔和第二列孔外其余孔分别加入100μL MHB，向第二孔加入196μL MHB和4μL母液。采用二倍稀释法分别对化合物和阳性对照进行稀释，共稀释成128–0.25μg·mL-110个不同浓度梯度的稀释液(分别为128μg·mL-1，64μg·mL-1，32μg·mL-1，16μg·mL-1，8μg·mL-1，4μg·mL-1，4μg·mL-1，1μg·mL-1，0.5μg·mL-1，0.25μg·mL-1)，再向除边缘孔外每孔加入100μL菌浮液，充分混匀，最后向边缘孔每孔加入无菌水200μL。37℃恒温培养18–24h，观察受试菌的生长情况，以无生长的药物最低浓度为该药对该受试菌的MIC值；以泰妙菌素(T)为阳性对照，以配制化合物浓度等同的乙醇溶液为阴性对照，每株受试菌进行3个平行实验，实验重复3次。阴性对照组受试菌的生长情况均为良好，其实验结果见表1。
表1
从表1可以看出，本发明化合物对革兰氏阳性菌金黄色葡萄球菌耐药株ATCC33591和ATCC43300、金黄色葡萄球菌敏感株ATCC2913、表皮葡萄球菌耐药株ATCC51625、表皮葡萄球菌敏感株ATCC12228表现出优良的抗菌效果，但对革兰氏阴性细菌大肠杆菌标准株ATCC25922未表现出良好的抑菌活性。综合以上结果，本发明中的哌嗪连接的噁唑烷酮截短侧耳素化合物对革兰氏阳性菌均表现出了优良的抗菌效果，有望治疗由革兰氏阳性菌引起的细菌感染。
试验例2抑菌曲线活性研究
在该实验中，待测菌经过复苏、传代，用生理盐水调节菌液浓度至大约0.6麦氏浓度，后用Mueller-Hinton无菌肉汤培养基(MHB)稀释103倍备用。将化合物5k和泰妙菌素配制成浓度分别为2×MIC、4×MIC和8×MIC的工作液，添加等体积配置好的菌液，使待测化合物终浓度分别为1×MIC、2×MIC和4×MIC，同时制作不含待测化合物的细菌生长曲线作为对照。在0h、2h、4h、6h、8h、12h、24h时分别每个浓度采样100μL，用生理盐水稀释100倍后，取100μL稀释以后的样品均匀的涂布于MHA平板上，37℃继续培养20h，设置三组平行对照。测定平板上的细菌总数(CFU·mL-1)。通过绘制log10 CFU·mL-1与时间的关系绘制杀菌曲线。
实验所测得数据如图1所示，其中，A为化合物5k对MRSAATCC 33591的时间杀菌曲线，B为泰妙菌素对MRSAATCC 33591的时间杀菌曲线。可见，化合物5k和泰妙菌素的细菌数生长趋势相似，空白对照组的细菌在生长的过程中处于指数增长；尤其是2-8h时间段增长达106倍，8h时菌落数约1012CFU·mL-1。在1×MIC，2×MIC浓度组中能观察到化合物5k及泰妙菌素均能对细菌达到抑制作用，能在一定程度上降低细菌菌落数；在4×MIC组中，泰妙菌素需在12h后开始达到杀菌作用。而化合物5k能在8-12h内达到杀菌的作用，由此可见，化合物5k能在更短时间杀灭细菌，杀菌速率高于泰妙菌素。并且化合物5k和泰妙菌素均呈现出药物的时间依赖性及浓度依赖性。
试验例3小鼠大腿组织感染模型实验研究
随机选取9只SPF级5～6周龄雌性ICR小鼠，实验第一天按150mg/kg剂量腹腔注射环磷酰胺，在第四天按100mg/kg剂量腹腔注射环磷酰胺，从小鼠后眼眶静脉丛穿刺采血。通过血常规检测仪测定小鼠血液中中性粒细胞是否小于100个/mm3，若中性粒细胞小于100个/mm3，小鼠达到免疫抑制，则可进行后续实验。将单个MASAATCC 33591菌落接种于含4mLMHB肉汤试管中，放入37℃恒温培养箱静置12h后，放入37℃、210rpm恒温摇床培养箱中培养0.5h，使细菌生长到对数期，用无菌生理盐水稀释菌液，将菌量调整为107CFU/mL备用。将免疫抑制小鼠按仅接种菌液的空白对照组、泰妙菌素治疗组、化合物5k治疗组随机分为3组，每组3只，取0.1mL制备好的107CFU/mL菌液注射入中性粒细胞减少症小鼠的大腿肌肉内，2h后尾静脉注射给药治疗，空白对照组注射剂量为10mL/kg待测化合物溶剂。在给药后24h以CO2窒息处死小鼠，处死后立即将小鼠大腿肌肉分离，置于预冷的3mL无菌生理盐水中，用消毒后的组织匀浆机匀浆。匀浆完成后，取0.1mL浆液于无菌生理盐水中以10比例倍比稀释，取出25μL稀释液置于MHA琼脂培养皿上涂板计数，根据菌落计数结果计算每克肌肉所含菌量。
实验的结果如图2所示。其中，*，显著差异。与无药物对照组相比，泰妙菌素(20mg/kg)，化合物5k(20mg/kg)和化合物5k(40mg/kg)都可降低大腿细菌负荷，并且化合物5k抑菌效果明显优于泰妙菌素。结果表明化合物5k具有有效的体内抗MRAS(金黄色葡萄球菌耐药菌)活性。
Claims (7)
1.哌嗪连接的噁唑烷酮截短侧耳素衍生物，其特征在于：其结构式为式Ⅰ所示：
其中，R选自氢、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、氰基或-NHBoc。
2.根据权利要求1所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物，其特征在于：R位于间位或对位。
3.根据权利要求2所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物，其特征在于：R选自氢、卤素、-CH3、-OCH3、三氟甲基、氰基或-NHBoc。
4.根据权利要求1所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物，其特征在于：其结构式为以下结构式中的任一种：
5.权利要求1～4任一项所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物在制备治疗或预防感染性疾病药物中的应用，所述感染性疾病是由耐药菌引起的，所述耐药菌为革兰氏阳性菌。
6.根据权利要求5所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物在制备治疗或预防感染性疾病药物中的应用，其特征在于：所述耐药菌为金黄色葡萄球菌或表皮葡萄球菌。
7.一种药物组合物，其特征在于：含有活性成分以及药学上可接受的辅料，所述活性成分为权利要求1～4任一项所述的哌嗪连接的噁唑烷酮截短侧耳素衍生物或其药学上可接受的盐。
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