CN106032367B - 香兰胺/香兰醇衍生物及其制备方法和应用 - Google Patents
香兰胺/香兰醇衍生物及其制备方法和应用 Download PDFInfo
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- CN106032367B CN106032367B CN201510120796.9A CN201510120796A CN106032367B CN 106032367 B CN106032367 B CN 106032367B CN 201510120796 A CN201510120796 A CN 201510120796A CN 106032367 B CN106032367 B CN 106032367B
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Abstract
本发明涉及一种香兰胺/香兰醇衍生物及其制备和应用。所述香兰胺/香兰醇化合物以其良好的抗菌活性，适合于尤其是对于耐药菌株的抑制作用在制备抗菌药物中的应用，属于药物及其制备和应用技术领域。
Description
技术领域
本发明属于医药技术领域，涉及一种香兰胺/香兰醇衍生物及其制备方法和应用。
背景技术
细菌性感染是感染性疾病中最常见的类型，特别是临床耐药性菌株，对多种抗生素的抗药性在不断加强。目前对临床耐药性菌株真正起效的抗生素已为数不多，临床常用的为万古霉素、达托霉素、利奈唑胺和头孢吡普等药物。万古霉素可抑制细菌细胞壁的合成，对金黄色葡萄球菌、化脓链球菌、肺炎链球菌等具有较强作用，但目前已出现了可抵抗万古霉素的细菌，如耐万古霉素肠球菌(VRE)。达托霉素是继万古霉素之后第二代糖肽类抗生素药，用于治疗由一些革兰氏阳性敏感菌株引起的并发性皮肤及皮肤结构感染，如脓肿、手术切口感染和皮肤溃疡；还可以用于由金黄色葡萄球菌引起的右侧感染性心膜炎等。而2010年FDA警告达托霉素或致嗜酸粒细胞肺炎。利奈唑胺为细菌蛋白质合成抑制剂，对甲氧西林敏感或耐药葡萄球菌、万古霉素敏感或耐药肠球菌、青霉素敏感或耐肺炎链球菌均显示了良好的抗菌作用，对厌氧菌亦具抗菌活性，上市后见于报道的不良反应有骨髓抑制、周围神经病和视神经病、乳酸性酸中毒等。第五代头孢菌素头孢吡普对革兰阳性菌、革兰阴性菌以及厌氧菌都有抗菌活性，是第一个对耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素金黄色葡萄球菌(VRSA)有效的头孢菌素类药物，但多剂量输注时，有出现头痛和轻中度的丙氨酸氨基转氨酶(ALT)上升不良反应的个别现象。因此，依然迫切需要研究开发化学结构新颖、副作用低的新型抗耐药菌药物。
发明内容
本发明提出一种式(I)香兰胺/香兰醇衍生物及其制备方法和应用。本发明利用酰胺键/酯键将香兰胺/香兰醇与硝基呋喃/硝基噻吩类化合物有机结合，构建系列双活性结构单元化合物。
本发明提出的一种香兰胺/香兰醇衍生物，其结构如下式(I)所示：
式(I)中，
R1为：
R2为：
X为：NH或O。
本发明提出的式(I)所示香兰胺/香兰醇衍生物的制备方法，X为NH时，其制备路线如下所示：
式(I)中，
R1为：
R2为：
优选地，R1为：
优选地，R2为：
本发明提出的式(I)所示的香兰胺衍生物的制备方法，路线一(X为NH)，所述制备路线如下所示：
式(I)中，
R1为：
R2为：
所述步骤包括：
步骤(1)，以硝基杂环类羧酸为原料与香兰胺盐酸盐在N，N-二甲基甲酰胺中，在缩合剂与缚酸剂作用下，缩合得到式(i)所示的香兰酰胺；
步骤(2)，式(i)所示的香兰酰胺与硝基杂环类酰氯在二氯甲烷中在缚酸剂作用下缩合得到式(I)香兰胺衍生物。
所述步骤(1)中，所用缩合剂为1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(简称EDC·HCl)和1-羟基-苯并三氮唑(简称HOBt)。所述缩合剂的加入量为香兰胺盐酸盐摩尔量的1.5倍。其中，两种缩合剂按1:1摩尔比配制。
所述步骤(1)中，缚酸剂选用3-甲基吡啶。
所述步骤(1)中，反应温度为室温，适合的范围在22～25℃。
所述步骤(1)中，反应时间为12-18小时。
所述步骤(2)中，香兰酰胺(i)与硝基杂环类酰氯在二氯甲烷中缩合得到香兰胺衍生物(I)，缚酸剂为三乙胺，加入量为式(i)化合物摩尔量的1.2～2倍。
优选地，R1为：
优选地，R2为：
本发明还提出了式(I)所示的香兰醇衍生物的制备方法，路线二(X为O)，所述制备方法为：香兰醇与硝基杂环类酰氯在二氯甲烷中缩合得到香兰醇双酯类衍生物(I)。
其中，缚酸剂为三乙胺，加入量为香兰醇摩尔量的2.5～3倍。
所述制备路线如下所示：
式(I)中，
R1为：
R2为：R1CO-。
本发明还提出了式(I)所示的香兰胺/香兰醇衍生物在制备抗耐药菌药物中的应用。例如，对革兰氏阳性细菌具有抑制作用。所述香兰胺/香兰醇衍生物对5株耐药菌株具有显著的抑制活性。通过体外抑制细菌实验表明，本发明的香兰胺/香兰醇衍生物对耐甲氧西林金黄色葡萄球菌(MRSA)具有很强的抑制作用，I-464抗金黄色葡萄球NRS-1、NRS-70、NRS-100、NRS-108、NRS-271的MIC最佳值为0.3-0.63(μg/ml)，甚至优于对照药物卡那霉素、万古霉素和四环素，可见，本发明的香兰胺/香兰醇衍生物可用于制备抗耐药菌株药物。
本发明将辣椒素类化合物的核心结构与硝基呋喃/硝基噻吩有效键合，形成一类新结构化合物，有可能通过协同作用改善化合物的性质和活性。此外，该类化合物易于合成。
具体实施方式
结合以下具体实施例，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。以下实施例所用的原料均为市售分析纯化学品。
本发明制备方法中，所用原料5-硝基杂环甲酰氯由对应的5-硝基杂环甲酸经氯化亚砜或草酰氯制得，按已有技术制备。
实施例1
化合物ia的合成：
5-硝基呋喃-2-甲酸(0.16g，1mmol)、香兰胺盐酸盐(0.19g，1mmol)、EDC(0.27g，1.5mmol)和HOBt(0.19g，1.5mmol)溶于N，N-二甲基甲酰胺(10mL)中，搅拌10min后，向上述反应液中加入3-甲基吡啶(0.26mL)，搅拌反应18h后，加入饱和碳酸氢钠溶液30ml和乙酸乙酯30ml萃取有机相3次，饱和食盐水洗涤一次后用无水硫酸钠干燥、过滤、浓缩、柱层析分离(乙酸乙酯：石油醚＝1：2)得产物香兰酰胺衍生物ia(R1＝5-硝基呋喃基，R2＝H)0.20g，收率：65％；白色固体；1H NMR(400MHz,DMSO)δ9.29(t,J＝5.8Hz,1H),8.87(s,1H),7.74(d,J＝3.9Hz,1H),7.43(d,J＝3.9Hz,1H),6.91(s,1H),6.72(s,2H),4.35(d,J＝6.0Hz,2H),3.75(s,3H).13C NMR(101MHz,DMSO)δ155.93,151.43,148.31,147.41,145.67,129.42,120.11,115.50,115.23,113.41,112.12,55.58,42.20.
MS(ESI)calcd for C13H12N2O6：293.4[M+H]+.
实施例2
化合物ib的合成：
合成方法参照实施例1，其中将5-硝基噻吩-2-甲酸替代5-硝基呋喃-2-甲酸得产物香兰酰胺衍生物ib(R1＝5-硝基噻吩基，R2＝H)0.48g，收率：68％；白色固体；1H NMR(400MHz,DMSO)δ9.59(t,J＝5.5Hz,1H),8.92(s,1H),8.13(d,J＝4.3Hz,1H),7.94(d,J＝4.4Hz,1H),6.93(s,1H),6.75(d,J＝8.1Hz,2H),4.36(d,J＝5.8Hz,2H),3.75(s,3H).13CNMR(101MHz,DMSO)δ159.28,152.80,147.43,146.58,145.71,130.15,129.30,127.44,120.07,115.25,112.13,55.59,42.70.MS(ESI)calcd for C13H12N2O5S:：309.4[M+H]+.
实施例3
化合物ic的合成
合成方法参照实施例1，其中将5-(4-硝基苯基)-2-呋喃甲酸替代5-硝基呋喃-2-甲酸得产物香兰酰胺衍生物ic(R1＝5-(4-硝基苯基)-2-呋喃基，R2＝H)0.33g，收率：48％；棕色固体；1H NMR(400MHz,DMSO)δ9.12(t,1H),8.85(s,1H),8.32(d,J＝8.7Hz,2H),8.18(d,J＝8.7Hz,2H),7.42(d,J＝3.4Hz,1H),7.28(d,J＝3.4Hz,1H),6.93(s,1H),6.74(s,2H),4.39(d,J＝5.8Hz,2H),3.76(s,3H).13C NMR(101MHz,DMSO)δ157.22,152.19,148.70,147.41,146.64,145.56,135.17,130.05,125.07,124.29,119.94,115.88,115.26,112.00,111.53,99.49,55.60,41.83.MS(ESI)calcd for C19H16N2O6：369.5[M+H]+.
实施例4
化合物I-431的合成：
将新制的5-硝基呋喃甲酰氯(66mg，0.38mmol)，催化量DMF和ia(R1＝5-硝基呋喃基，R2＝H，0.34mmol，100mg)溶于二氯甲烷(10mL)中，在氮气保护冰水浴条件下，缓慢加入三乙胺(0.15mL)，自然升至室温后反应4小时。减压浓缩近干，然后再用乙酸乙酯20ml*3萃取有机层，随后依次用5％NaOH、5％HCl、饱和食盐水洗涤有机层。无水硫酸钠干燥后、过滤、浓缩后柱层析分离(乙酸乙酯：石油醚＝1：2)得产物I-431(R1＝5-硝基呋喃基，R2＝5-硝基呋喃基)0.11g，收率：71％；白色固体；1H NMR(400MHz,DMSO)δ9.46(t,J＝5.8Hz,1H),7.85(s,2H),7.77(d,J＝3.8Hz,1H),7.46(d,J＝3.9Hz,1H),7.24(m,2H),6.99(d,J＝8.0Hz,1H),4.51(d,J＝5.9Hz,2H),3.77(d,J＝14.9Hz,3H).13C NMR(101MHz,DMSO)δ156.18,154.79,152.76,151.47,150.36,148.13,142.84,138.64,137.04,122.48,121.50,119.59,115.75,113.42,113.01,112.35,55.85,42.16.
MS(ESI)calcd for C18H13N3O10：432.21[M+H]+.
实施例5
化合物I-463的合成：
合成方法参照实施例4，其中将新制的5-硝基噻吩甲酰氯替代新制的5-硝基呋喃甲酰氯和ib(R1＝5-硝基噻吩基，R2＝H)替代ia(R1＝5-硝基呋喃基，R2＝H)得产物化合物I-463(R1＝5-硝基噻吩基，R2＝5-硝基噻吩基)，收率：75％；白色固体；1H NMR(400MHz,DMSO)δ9.56(t,J＝5.8Hz,1H),8.20(d,J＝4.4Hz,1H),8.15(d,J＝4.4Hz,1H),8.04(t,J＝11.0Hz,1H),7.86(t,J＝8.6Hz,1H),7.28(d,J＝8.1Hz,1H),7.20(d,J＝1.2Hz,1H),6.99(dd,J＝8.1,1.3Hz,1H),4.54(d,J＝5.8Hz,2H),3.78(d,J＝15.1Hz,3H).13C NMR(101MHz,DMSO)δ159.59,158.40,155.25,152.96,150.45,146.09,138.50,137.49,136.28,134.06,130.10,129.78,127.48,122.60,119.47,112.25,55.92,42.67.MS(ESI)calcd for C18H13N3O8S2：464.09[M+H]+.
实施例6
化合物I-306的合成：
合成方法参照实施例4，其中将碘甲烷替代新制的5-硝基呋喃甲酰氯，得产物I-306收率：80％；黄色固体；1H NMR(400MHz,DMSO)δ9.40(t,J＝5.8Hz,1H),7.81(d,J＝3.9Hz,1H),7.49(d,J＝3.9Hz,1H),7.01(d,J＝1.3Hz,1H),6.96(d,J＝8.2Hz,1H),6.90(d,J＝8.2Hz,1H),4.45(d,J＝6.0Hz,2H),3.79(d,J＝4.9Hz,6H).13C NMR(101MHz,DMSO)δ155.98,151.44,148.58,148.23,147.92,131.04,119.69,115.56,113.42,111.67,111.62,55.51,55.40,42.12.MS(ESI)calcd forC14H14N2O6：306.95[M+H]+.
实施例7
化合物I-432的合成：
将新制的5-硝基呋喃甲酰氯(370mg，2.1mmol)，催化量DMF和香兰醇(154mg，1mmol)溶于二氯甲烷(10mL)中，在氮气保护冰水浴条件下，缓慢加入三乙胺(0.15mL)，自然升至室温后反应6个小时。减压浓缩近干，然后再用乙酸乙酯20ml*3萃取有机层，随后依次用5％NaOH、5％HCl、饱和食盐水洗涤有机层。无水硫酸钠干燥后、过滤、浓缩后柱层析分离(乙酸乙酯：石油醚＝1：2)得产物I-432(R1＝5-硝基呋喃基，R2＝5-硝基呋喃基)0.24g，收率：55％；白色固体:；1H NMR(400MHz,CDCl3)δ7.48(d,J＝3.8Hz,1H),7.41(d,J＝3.8Hz,1H),7.34(dd,J＝8.7,3.8Hz,2H),7.18(d,J＝8.0Hz,1H),7.13–7.07(m,2H),5.40(s,2H),3.86(s,3H).13C NMR(101MHz,CDCl3)δ156.79,154.64,151.09,144.58,143.95,138.98,134.44,122.80,121.33,120.27,119.27,113.12,111.55,111.49,67.31,56.06.MS(ESI)calcd for C18H12N2O11：450.27[M+NH4]+.
实施例8
化合物I-464的合成：
合成方法参照实施例7，其中将新制的5-硝基噻吩甲酰氯替代新制的5-硝基呋喃甲酰氯得产物I-464(R1＝5-硝基噻吩基，R2＝5-硝基噻吩基)，收率：68％；白色固体；1H NMR(400MHz,CDCl3)δ7.94(d,J＝4.3Hz,1H),7.88(dd,J＝4.3,3.0Hz,2H),7.73(d,J＝4.3Hz,1H),7.21–7.17(m,1H),7.08(dd,J＝6.5,1.9Hz,2H),5.37(s,2H),3.86(d,J＝5.0Hz,3H).13CNMR(101MHz,DMSO)δ160.03,158.32,155.32,154.62,150.59,138.42,137.74,136.16,135.03,134.18,132.98,129.82,129.75,122.87,120.49,113.04,67.05,56.05.
MS(ESI)calcd forC18H12N2O9S2：465.18[M+H]+.
实施例9
化合物I-584的合成
合成方法参照实施例7，其中将新制的5-(4-硝基苯基)-2-呋喃酰氯替代新制的5-硝基呋喃-甲酰氯得产物化合物I-584(R1＝5-(4-硝基苯基)-2-呋喃基，R2＝5-(4-硝基苯基)-2-呋喃基)，收率：55％；黄色固体；1H NMR(400MHz,CDCl3)δ8.30(dd,J＝8.8,4.2Hz,4H),7.96(dd,J＝16.6,8.9Hz,4H),7.51(d,J＝3.6Hz,1H),7.34(d,J＝3.6Hz,1H),7.20(d,J＝7.8Hz,1H),7.11(d,J＝8.4Hz,2H),7.03(d,J＝3.6Hz,1H),6.96(d,J＝3.6Hz,1H),5.39(s,2H),3.87(d,J＝6.4Hz,3H).13C NMR(101MHz,DMSO)δ157.53,155.56,155.20,154.51,150.82,147.25,147.09,144.35,143.38,138.35,135.16,134.53,134.34,125.66,125.44,124.52,123.01,122.39,120.99,120.51,112.95,112.00,111.79,65.86,55.93.MS(ESI)calcd for C30H20N2O11：602.26[M+NH4]+.
实施例1-9所用的试剂均为市售分析纯化学品。
实施例10：香兰胺/香兰醇衍生物体外抗革兰氏阳性细菌活性测试
1、实验样品及实验方法
被测样品溶液的配制：测试样品为上述实施例1、2、4、5、6、7中制备的纯品化合物ia、ib、I-431、I-463、I-306、I-432和I-464。用电子天平准确称取待测化合物，以无菌DMSO为溶剂配制成10mg/ml的母液，供活性测试。阳性对照药物分别为红霉素、卡拉霉素、万古霉素、四环素。
初筛：分别挑单克隆Newman、AB1157、BS168 37℃摇菌过夜；稀释菌液至OD为0.01，37℃继续摇菌5-8小时；菌液稀释至OD为0.6；将菌液稀释400倍后，将1ul化合物加入100ul的体系(50ul菌液+50ul TSB)中。
复筛：步骤如初筛；加入0.5ul化合物至100ul体系。
2、实验结果
部分化合物抗菌活性的测试结果见表1、表2和表3。
实验表明本发明香兰胺/香兰醇衍生物可以显著抑制5株耐药菌株的生长。因此，本发明的香兰胺/香兰醇衍生物可用于制备抗菌药物或作为抗菌药物的先导化合物。
表1.香兰胺/香兰醇衍生物抗MRSA8325-4、MRSA USA300以及表皮葡萄球菌SE1457的活性结果
表2.香兰胺/香兰醇衍生物抗MRSA Newman和枯草杆菌BS168的活性结果
表3.香兰胺/香兰醇衍生物抗耐药金黄色葡萄球菌NRS-1、NRS-70、NRS-100、NRS-108、NRS-271的活性结果
Claims (4)
1.一种香兰胺/香兰醇衍生物，其特征在于，所述香兰胺/香兰醇衍生物的结构如下式(I)所示：
式(I)中，
R1为：
R2为：
X为：NH或O。
2.式(I)香兰醇衍生物的制备方法，其特征在于，在二氯甲烷中，在缚酸剂作用下，香兰醇与硝基杂环类酰氯缩合得到香兰醇双酯类衍生物，所述制备路线如以下所示：
式(I)中，
R1为：
R2为：R1CO-。
3.如权利要求2所述的制备方法，其特征在于，所述缚酸剂为三乙胺，其加入量为香兰醇摩尔量的2.5～3倍。
4.如权利要求1所述的香兰胺/香兰醇衍生物在制备抗耐药菌药物中的应用。
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| Title |
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| CAS RN:1348691-52-0;CHEMICAL ABSTRACT SERVICE, COLUMBUS, OHIO, US;《STN DATABASE REGISTRY[ONLINE]》;20111204;第2页 * |
| Comparative QSAR studies of nitrofuranyl amide derivatives using theoretical structural properties;Payel Ghosh等;《Molecular Simulation》;20091012;第35卷(第14期);摘要，第1185页左栏第1段，第1187-1189页表1 * |
| Synthesis and Evaluation of Nitrofuranylamides as Novel Antituberculosis Agents;Rajendra P. Tangallapally等;《J. Med. Chem.》;20040903;第47卷;第5277页图1，第5278页表1，第5280页右栏第3段 * |
| 香兰胺（醇）衍生物的设计、合成及其抗菌活性研究;李佳;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20151015;第二、三章 * |
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