CN111793044B - 哌嗪脲截短侧耳素衍生物及其用途 - Google Patents
哌嗪脲截短侧耳素衍生物及其用途 Download PDFInfo
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- CN111793044B CN111793044B CN202010703129.4A CN202010703129A CN111793044B CN 111793044 B CN111793044 B CN 111793044B CN 202010703129 A CN202010703129 A CN 202010703129A CN 111793044 B CN111793044 B CN 111793044B
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- Prior art keywords
- benzene ring
- piperazine urea
- pleuromutilin derivative
- pleuromutilin
- substituted
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- -1 Piperazine urea pleuromutilin derivatives Chemical class 0.000 title claims abstract description 68
- 239000003814 drug Substances 0.000 claims abstract description 20
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 13
- 241000588724 Escherichia coli Species 0.000 claims abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 26
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 26
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 26
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 26
- 150000001555 benzenes Chemical group 0.000 claims description 21
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000003222 pyridines Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
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- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 8
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
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- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims 2
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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Abstract
本发明涉及哌嗪脲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种抗菌活性良好的哌嗪脲截短侧耳素衍生物。该哌嗪脲截短侧耳素衍生物的结构式为式I所示。本发明哌嗪脲截短侧耳素衍生物，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，其对金黄色葡萄球菌标准耐药株ATCC33591和ATCC43300、对大肠杆菌ATCC25922和ATCC25923均表现出优异的抗菌效果，有望应用在治疗由金黄色葡萄球菌和大肠杆菌引起的细菌感染中，为抗感染药物提供了新的选择。
Description
技术领域
本发明涉及哌嗪脲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
抗生素的发现在人类发展史上具有重大的意义，而现如今由于临床上广泛长期滥用抗生素，导致细菌耐药性日益严重，这无疑对人类的生命安全构成了巨大威胁。为了应对有效抗菌药物逐年减少和耐药性细菌日益增加的困局，急需找到一种有效途径来解决这一棘手的全球性问题。面对不断恶化的趋势，2012年，美国食品药品监督管理局(FDA)发起了一项旨在促进抗生素研发的激励计划(generating antibiotics incentives now,GAIN)。在上市的抗感染(抗细菌、抗真菌、防治寄生虫和抗病毒)药物中，近70％是直接来源于天然产物或是通过对其结构进行修饰得到的。
截短侧耳素(Pleuromutilin)是Kavanagh和他的同事于1951年从高等真菌Pleurotus multilus(Fr.)Sacc.和Pleurotus Passecke-rianus Pilat中分离出来的一种具有良好抗菌活性的三环二萜类结构的化合物。研究表明，截短侧耳素结合在细菌核糖体50S亚基的23S rRNA上，通过其三环母核定位在核糖体50S亚基的肽基转移酶(PTC)中心，在A位点形成一个紧密的口袋，同时，其C14侧链部分覆盖了tRNA结合的P位点，可阻止氨酰基转移核糖核酸与P位点结合而抑制肽基转移酶的活性，进一步阻止了细菌蛋白质的翻译过程，从而抑制细菌的生长。该类化合物只选择性地抑制原核细胞蛋白质的合成，对真核细胞没有影响，也不与哺乳动物的核糖体相互作用，正是由于这种特殊的作用机制，使其不易于其他抗生素产生交叉耐药性。尽管截短侧耳素有一定的抗菌活性，但由于在水中微溶，体内吸收率较低，很难开发为有效的抗菌药物。因此，自截短侧耳素发现以来，研究人员一直对其进行构效关系研究和结构修饰，尝试引入各种极性基团，以期找到抗菌活性高、水溶性较好和生物利用度较高的截短侧耳素类衍生物。
构效关系(SAR)研究表明其母核三环结构、C-14位的酯基、C-2位的羰基和C-11位的羟基都是抗菌活性所必需的官能团。近年来，不少科研工作者在对其C14位侧链的衍生取得了较好的成果。在1979年，截短侧耳素衍生物的第一个上市药物—泰妙菌素(Tamulin)成功被批准为兽用抗生素。随后，1999年沃尼妙林(Valnemulin)成功上市，成为第二个被批准为兽用抗生素的衍生物。此外，在1980年，阿扎莫林(Azamulin)进入临床阶段，阿扎莫林具有优秀抗菌效果，但由于其对人体细胞色素P450的强烈抑制作用以及其低口服生物利用度和半衰期过短而宣告终止。在2007年，葛兰素史克(GlaxoSmithKline)公司开发了第一个用于治疗人类皮肤感染的外用截短侧耳素衍生物—瑞他妙林(Ratapamulin)。在2006年，Nabriva公司开发出Lafemulin(BC-3781)，这是一种新型半合成截短侧耳素抗菌剂，主要是用于治疗急性细菌性皮肤和皮肤结构感染(ABSSSI)和社区获得性细菌性肺炎(CABP)。2019年8月19日，FDA通过了Nabriva提交的关于Lafemulin经过口服和静脉注射两种方式治疗CABP的新药申请(NDAs)。
截短侧耳素(Pleuromutilin)、泰妙菌素(Tamulin)、沃尼妙林(Valnemulin)、阿扎莫林(Azamulin)、瑞他妙林(Ratapamulin)和Lafemulin(BC-3781)的结构式如下：
截短侧耳素在兽用药物发展上比较迅速，但在人类抗菌药物研究进程中的作用还未能完全体现。基于未满足的临床需求，开发具有新颖结构、独特作用机制的较高抗菌活性的药物迫在眉睫。哌嗪环是美国FDA批准上市药物中最常见的25个氮杂环中之一。从药物化学设计的角度来看，这个环不仅具有良好的三维结构，而且具有这个结构的化合物通常都有优良的药动学性质，能够很好地增加化合物的水溶性和代谢稳定性。同时，哌嗪环上的氮原子可以通过烷基化或者酰化向外延伸。基于此，不少研究人员在截短侧耳素的C-14侧链引入了哌嗪环来改善其活性和药动学性质。
申请号为201611115910.X的中国发明专利公开了一种具有酰基哌嗪基侧链的截短侧耳素类化合物及其制备方法和用途。该化合物具有良好的抑制金黄色葡萄球菌和支原体活性的抗菌活性，但是，该化合物与现有的泰妙菌素等抗菌药物相比，其体外抗菌效果并未有太大优势。
发明内容
针对以上缺陷，本发明解决的技术问题是提供一种抗菌活性良好的哌嗪脲截短侧耳素衍生物。
本发明哌嗪脲截短侧耳素衍生物的结构式为式I所示：
其中，n＝0、1、2或3；
R1选自苯环、被取代的苯环、喹啉、哌啶、吗啉、吡啶、氨基取代的吡啶或卤素取代的吡啶；所述被取代的苯环为苯环上任意一个氢被C1-4烷氧基、C1-4烷基、C1-4氟代烷基、硝基、氨基、卤素、乙酰胺基或Boc保护的氨基取代；
R2选自氢或C1-4烷基。
在一个实施方式中，n＝0、1或2。
在一个实施方式中，R2选自氢或甲基。
在一种实施方式中，R1选自喹啉、吗啉、哌啶、吡啶、氨基取代的吡啶或卤素取代的吡啶。在一个具体实施方式中，R1选自
在另一种实施方式中，R1选自苯环或被取代的苯环。
在一个具体实施方式中，所述被取代的苯环为苯环上任意一个氢被甲基、甲氧基、三氟甲基、氨基、氟或Boc保护的氨基取代。在一些实施方式中，所述被取代的苯环为
作为优选的实施方式，R1选自苯环、
n＝0或1；R2为氢。
在具体的实施例中，本发明哌嗪脲截短侧耳素衍生物的结构式如下：
本发明还提供本发明所述的哌嗪脲截短侧耳素衍生物的立体异构体或药学上可接受的盐。
在一个具体实施方式中，所述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。
本发明还提供本发明所述的哌嗪脲截短侧耳素衍生物、立体异构体或药学上可接受的盐在制备治疗感染性疾病药物中的用途。
在一个具体实施方式中，所述感染性疾病是由支原体或耐药菌引起的。
本发明还提供一种治疗感染性疾病的药物组合物。
该治疗感染性疾病的药物组合物，含有本发明所述的哌嗪脲截短侧耳素衍生物以及药学上可接受的辅料。
本发明哌嗪脲截短侧耳素衍生物，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，其对金黄色葡萄球菌标准耐药株ATCC33591和ATCC43300、对大肠杆菌ATCC25922和ATCC25923均表现出优异的抗菌效果，有望应用在治疗由金黄色葡萄球菌和大肠杆菌引起的细菌感染中，为抗感染药物提供了新的选择。
具体实施方式
本发明哌嗪脲截短侧耳素衍生物，其结构式为式I所示：
其中，n＝0、1、2或3；R1选自苯环、被取代的苯环、喹啉、哌啶、吗啉、吡啶、氨基取代的吡啶或卤素取代的吡啶；所述被取代的苯环为苯环上任意一个氢被C1-4烷氧基、C1-4烷基、C1-4氟代烷基、硝基、氨基、卤素、乙酰胺基或Boc保护的氨基取代；R2选自氢或C1-4烷基。
本发明中，“C1-4烷氧基”为具有1～4个碳原子的直链或支链烷氧基。在一些具体实施例中，C1-4烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基或叔丁氧基等。
“C1-4烷基”为具有1～4个碳原子的直链或支链烷基。在一些具体实施例中，C1-4烷基为甲基、乙基、丙基、异丙基、正丁基、仲丁基或叔丁基等。
“C1-4氟代烷基”为具有1～4个碳原子的直链或支链氟代烷基，氟代烷基为烷基上的一个或多个氢原子被氟原子取代。在一些具体实施例中，C1-4氟代烷基为三氟甲基、二氟甲基或全氟乙基等。
“氨基取代的吡啶”为吡啶环上的一个氢被氨基(-NH2)取代。
“Boc保护的氨基”的结构式为-NH-Boc，其中，Boc为叔丁氧羰基。
在本发明的一个实施方式中，n＝0、1或2，R1选自苯环、被取代的苯环、喹啉、哌啶、吗啉、吡啶、氨基取代的吡啶或卤素取代的吡啶；所述被取代的苯环为苯环上任意一个氢被C1-4烷氧基、C1-4烷基、C1-4氟代烷基、硝基、氨基、卤素、乙酰胺基或Boc保护的氨基取代；R2选自氢或C1-4烷基。
在本发明的一个实施方式中，n＝0、1、2或3；R1选自苯环、被取代的苯环、喹啉、哌啶、吗啉、吡啶、氨基取代的吡啶或卤素取代的吡啶；所述被取代的苯环为苯环上任意一个氢被C1-4烷氧基、C1-4烷基、C1-4氟代烷基、硝基、氨基、卤素、乙酰胺基或Boc保护的氨基取代；R2选自氢或甲基。
在本发明的一个实施方式中，n＝0、1或2；R1选自苯环、被取代的苯环、喹啉、哌啶、吗啉、吡啶、氨基取代的吡啶或卤素取代的吡啶；所述被取代的苯环为苯环上任意一个氢被C1-4烷氧基、C1-4烷基、C1-4氟代烷基、硝基、氨基、卤素、乙酰胺基或Boc保护的氨基取代；R2选自氢或甲基。
在本发明的一个实施方式中，n＝0、1、2或3；R1选自喹啉、吗啉、哌啶、吡啶、氨基取代的吡啶或卤素取代的吡啶；R2选自氢或C1-4烷基。在一个具体实施方式中，n＝0、1、2或3；R1选自
R2选自氢或C1-4烷基。
在本发明的一个实施方式中，n＝0、1或2；R1选自喹啉、吗啉、哌啶、吡啶、氨基取代的吡啶或卤素取代的吡啶；R2选自氢或C1-4烷基。在一个具体实施方式中，n＝0、1或2；R1选自
R2选自氢或C1-4烷基。
在本发明的一个实施方式中，n＝0、1、2或3；R1选自喹啉、吗啉、哌啶、吡啶、氨基取代的吡啶或卤素取代的吡啶；R2选自氢或甲基。在一个具体实施方式中，n＝0、1、2或3；R1选自
R2选自氢或甲基。
在本发明的一个实施方式中，n＝0、1或2；R1选自喹啉、吗啉、哌啶、吡啶、氨基取代的吡啶或卤素取代的吡啶；R2选自氢或甲基。在一个具体实施方式中，n＝0、1或2；R1选自
R2选自氢或甲基。
在本发明的另一个实施方式中，n＝0、1、2或3；R1选自苯环或被取代的苯环；R2选自氢或C1-4烷基。
被取代的苯环为苯环上1-4号位置上的任意一个氢被取代。在一个实施方式中，被取代的苯环为苯环上任意一个氢被甲基、甲氧基、三氟甲基、氨基、硝基、氟、乙酰胺基或Boc保护的氨基取代。在一个具体的实施方式中，被取代的苯环为
作为优选的实施方式，R1选自苯环、
n＝0或1；R2为氢。这些化合物对金黄色葡萄球菌标准耐药株ATCC33591和ATCC43300、对大肠杆菌ATCC25922和ATCC25923均表现出优异的抗菌效果，优于现有的药物泰妙菌素。
在具体的实施例中，本发明哌嗪脲截短侧耳素衍生物的结构式如下：
本发明还提供本发明所述哌嗪脲截短侧耳素衍生物的立体异构体或药学上可接受的盐。
其中，药学上可接受的盐包括但不限于式Ⅰ化合物与无机酸如盐酸、硫酸、磷酸、亚磷酸、氢溴酸和硝酸所成的盐以及与各种有机酸，如苹果酸、马来酸、柠檬酸、延胡索酸、酒石酸、琥珀酸、乙酸、乳酸、苯甲酸、对甲苯磺酸、甲磺酸、棕榈酸等所成的盐。在具体的实施方式中，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。
本发明哌嗪脲截短侧耳素衍生物、其立体异构体或药学上可接受的盐，可用于制备治疗感染性疾病药物。
在本发明的一些实施例中，所述感染性疾病是由支原体或耐药菌引起的感染性疾病。
该哌嗪脲截短侧耳素衍生物、立体异构体或药学上可接受的盐，可以单独使用，也可与可药用的载体或赋形剂一起以药物组合物的形式使用，当以药物组合物的形式使用时，通常将治疗有效量的哌嗪脲截短侧耳素衍生物、立体异构体或药学上可接受的盐以及一种或多种可药用载体或稀释剂结合制成适当的施用形式或剂量形式。因此，本发明还提供了一种治疗感染性疾病的药物组合物，它包含治疗有效量的哌嗪脲截短侧耳素衍生物、立体异构体或药学上可接受的盐以及至少一种药学上可接受的辅料。
所述辅料包括但不局限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血清蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二纳，磷酸氢钾，氧化纳，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素纳，聚丙烯酸酯，蜂蜡，羊毛酯等。
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6a-v的合成
按以下合成路线合成化合物6a-v：
反应试剂和反应条件：(i)TsCl,三乙胺,DCM,25℃；(ii)哌嗪,K2CO3,NaI,THF,回流；(iii)9a～e,NaI,K2CO3,MeCN,70℃；(iv)10f～u,K2CO3,DMF,80℃；(v)11,DMAP,MeCN,70℃；(vi)SnCl2,EtOH,回流；(vii)TFA,DCM,25℃；(viii)(1)CDI,三乙胺,N-Bocpiperazine,MeCN and DMF,25℃for 9a and 9b,or BTC,triethylamine,N-Boc哌嗪,THFand DCM,25℃for 9c～e,(2)TFA,DCM,25℃；(ix)三氯乙酰氯,三乙胺,DCM,25℃；(x)4-硝基苯基碳酰氯,NMM,DCM,25℃.
化合物7的合成：
将对甲苯磺酰氯(1.91g，10.0mmol)、截短侧耳素(3.56g，9.4mmol)溶于DCM(10mL),再加入三乙胺(4.54g，12.0mmol)，于室温下反应20h，反应毕，加入水(50mL)，分离有机层，用无水Na2SO4干燥。随后减压蒸除溶剂得淡黄色固体粗品，该粗品通过乙醇重结晶得到白色固体截短侧耳素磺酸酯7(6.3g，产率78.3％)。通过核磁证实了结构，数据如下。
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,8H),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).
化合物8的合成：
将截短侧耳素磺酸酯7(532.7mg,1.0mmol)和NaI(15.0mg,0.1mmol)溶于经重蒸的THF溶液中，随后将哌嗪(172.3mg,2.0mmol)和K2CO3(276.4mg,2.0mmol)添加到已经回流0.5h的上述溶液中，继续搅拌回流，直至截短侧耳素磺酸酯被转换完全。待反应完全，将反应液浓缩，经柱层析提纯即可的白色粉末，即化合物8。后通过核磁证实了结构，数据如下。
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).
1.1化合物6a～e的合成
将截短侧耳素磺酸酯7(213mg,0.4mmol)和NaI(14.9mg,0.1mmol)置于乙腈(5mL)中，25℃搅拌反应0.5h，然后加入化合物9a～e(0.5mmol)和K2CO3(111mg,0.8mmol)，70℃搅拌5小时。蒸发溶剂后，将粗产物通过硅胶柱色谱法纯化，得到纯产物6a～e。
6a:白色粉末；产率:78.3％；熔点:98.6-100.4℃.1H NMR(400MHz,CDCl3):δ(ppm)7.39–7.11(m,4H),6.95(t,J＝6.8Hz,1H),6.61(s,1H),6.43(dd,J＝17.2,11.2Hz,1H),5.73(d,J＝8.0Hz,1H),5.27(d,J＝10.8Hz,1H),5.13(d,J＝17.2Hz,1H),3.47(s,4H),3.29(s,1H),3.11(ABq,J＝17.2Hz,2H),2.70–2.38(m,4H),2.36–1.92(m,5H),1.81–1.26(m,11H),1.10(s,3H),1.07–0.98(m,1H),0.82(d,J＝6.8Hz,3H),0.66(d,J＝6.8Hz,3H).13CNMR(101MHz,CDCl3):δ(ppm)217.3,169.0,155.1,139.2,139.1,128.9,123.2,120.2,117.3,74.6,68.6,59.8,58.3,52.6,45.5,45.1,44.0,43.9,41.8,36.8,36.1,34.5,30.5,26.9,26.5,24.9,16.8,15.0,11.6.HRMS:calculated for C33H47N3O5([M+H]+):566.3588；found 566.3588.
6b:白色粉末；产率:87.6％；mp:121.6-122.4℃.1H NMR(400MHz,DMSO):δ(ppm)8.33(s,1H,NH),7.33(d,J＝8.8Hz,2H),6.81(d,J＝8.8Hz,2H),6.18(dd,J＝17.2,11.2Hz,1H),5.60(d,J＝8.0Hz,1H),5.09–5.05(m,2H),4.54(d,J＝6.0Hz,1H),3.70(s,3H),3.53–3.34(m,5H),3.30–3.01(m,2H),2.45–2.35(m,4H),2.28–2.01(m,5H),1.75–1.21(m,11H),1.07(s,3H),1.03–0.95(m,1H),0.83(d,J＝6.8Hz,3H),0.64(d,J＝6.8Hz,3H).13C NMR(100MHz,DMSO):δ(ppm)217.3,155.2,154.4,141.0,133.5,121.5,115.2,113.5,72.6,68.3,59.8,58.9,57.3,55.1,51.8,45.0,44.1,43.7,41.5,36.5,36.4,34.0,30.2,28.6,26.6,24.5,20.8,16.0,14.6,11.6.HRMS:calculated for C34H49N3O6([M+H]+):596.3694；found 596.3693.
6c:白色粉末；产率:86.4％；mp:107.9-109.1℃.1H NMR(400MHz,CDCl3):δ(ppm)7.42–7.13(m,5H),6.46(dd,J＝17.2,11.2Hz,1H),5.74(d,J＝8.4Hz,1H),5.29(d,J＝11.2Hz,1H),5.15(d,J＝17.2Hz,1H),4.75(d,J＝5.2Hz,1H),4.37(d,J＝5.2Hz,2H),3.39(t,J＝4.8Hz,4H),3.31(s,1H),3.11(ABq,J＝17.2Hz,2H),2.71–2.40(m,4H),2.40–1.96(m,5H),1.83–1.29(m,11H),1.12(s,3H),1.10–1.02(m,1H),0.84(d,J＝6.8Hz,3H),0.67(d,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3):δ(ppm)217.2,169.0,157.6,139.4,139.2,128.7,127.9,127.4,117.4,74.7,68.5,59.9,58.3,52.6,45.6,45.1,44.1,43.8,41.9,36.8,36.2,34.6,30.5,26.9,26.5,24.9,16.8,15.0,11.6.HRMS:calculated forC34H49N3O5([M+H]+):580.3745；found 580.3741.
6d:黄色粉末；产率:88.5％；mp:87.6-88.9℃.1H NMR(400MHz,CDCl3):δ(ppm)8.19–8.09(m,2H),7.55–7.46(m,2H),6.94(s,1H),6.49(dd,J＝17.2,11.2Hz,1H),5.79(d,J＝8.4Hz,1H),5.33(dd,J＝11.2,1.2Hz,1H),5.19(dd,J＝17.2,1.2Hz,1H),3.57(t,J＝4.8Hz,4H),3.41–3.30(m,1H),3.15(ABq,J＝17.2Hz,2H),2.71–2.53(m,4H),2.39–2.02(m,5H),1.93–1.32(m,11H),1.16(s,3H),1.14–1.07(m,1H),0.87(d,J＝6.8Hz,3H),0.71(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.3,169.0,153.8,145.5,142.6,139.2,125.2,118.6,117.4,74.7,68.7,59.7,58.3,52.5,45.6,45.1,44.2,44.1,41.9,36.8,36.2,34.6,30.5,27.0,26.5,25.0,16.9,15.0,11.6.HRMS:calculated for C33H46N4O7([M+H]+):611.3439；found 611.3440.
6e:白色粉末；产率:92.3％；mp:138.1-139.3℃.1H NMR(400MHz,CDCl3):δ(ppm)8.98–8.85(m,1H),8.22–812(m,1H),7.96–7.89(m,1H),7.69–7.60(m,1H),7.57–7.48(m,1H),7.43–7.34(m,1H),6.70(d,J＝16.0Hz,1H),6.59–6.43(m,1H),5.80(d,J＝8.0Hz,1H),5.35(d,J＝11.2Hz,1H),5.21(d,J＝17.2Hz,1H),3.59(d,J＝4.8Hz,4H),3.42–3.30(m,1H),3.15(ABq,J＝17.2Hz,2H),2.77–2.51(m,4H),2.45–2.00(m,5H),1.87–1.33(m,11H),1.17(s,3H),1.14–1.07(m,1H),0.88(d,J＝5.6Hz,3H),0.73(d,J＝5.6Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.2,169.1,155.9,150.4,148.9,139.2,134.2,130.9,129.3,127.2,122.1,121.0,117.4,74.7,68.7,59.9,58.3,52.6,45.6,45.2,44.3,44.1,41.9,36.8,36.2,34.6,30.6,27.0,26.6,25.0,16.9,15.0,11.6.HRMS:calculated forC36H48N4O5([M+H]+):617.3697；found 617.3695.
1.2化合物6f～u的合成
化合物8(402mg,0.9mmol)溶解在无水DMF(10mL)中，25℃搅拌，加入化合物10f～u(1.0mmol)和K2CO3(276mg,2.0mmol)，然后升温至80℃反应，当化合物8完全转化后，加水稀释，并用DCM(20mL×3)萃取。随后，合并有机相，盐水洗涤，无水MgSO4干燥。蒸发溶剂，然后将粗产物通过硅胶柱色谱纯化，得到化合物6f～u。
6f:白色粉末；产率:81.5％；mp:110.9-113.2℃.1H NMR(400MHz,CDCl3):δ(ppm)7.65(s,1H),7.59(s,1H),7.20–7.03(m,3H),6.65(s,1H),6.50(dd,J＝17.2,11.2Hz,1H),5.79(d,J＝8.4Hz,1H),5.33(dd,J＝11.2,1.2Hz,1H),5.20(dd,J＝17.2,1.6Hz,1H),3.55-3.50(m,4H),3.36(s,1H),3.15(ABq,J＝17.2Hz,2H),2.68–2.46(m,4H),2.40–2.04(m,8H),1.81–1.32(m,11H),1.16(s,3H),1.14–1.08(m,1H),0.87(d,J＝6.8Hz,3H),0.72(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.2,169.1,168.7,155.1,139.7,139.2,138.6,129.4,117.4,116.1,114.7,111.9,74.7,68.7,59.9,58.3,52.7,45.6,45.2,44.1,44.0,41.9,36.9,36.2,34.6,30.6,27.0,26.6,25.0,24.6,16.9,15.0,11.6.HRMS:calculated for C35H50N4O6([M+H]+):623.3803；found 623.3804.
6g:白色粉末；产率:77.4％；mp:109.7-111.2℃.1H NMR(400MHz,CDCl3):δ(ppm)7.51(s,1H),7.20–7.10(m,2H),6.88(dd,J＝7.6,1.6Hz,1H),6.63–6.36(m,3H),5.79(d,J＝8.4Hz,1H),5.34(dd,J＝11.2,1.6Hz,1H),5.20(dd,J＝17.2,1.6Hz,1H),3.51(t,J＝5.0Hz,4H),3.35(s,1H),3.13(ABq,J＝17.2Hz,2H),2.68–2.47(m,4H),2.42–2.04(m,5H),1.90–1.33(m,20H),1.16(s,3H),1.14–1.08(m,1H),0.87(d,J＝6.8Hz,3H),0.72(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.2,169.1,154.8,152.9,139.8,139.2,139.0,129.5,117.5,114.5,113.1,109.8,80.7,74.7,68.6,60.5,59.9,58.3,52.7,45.6,45.2,44.1,44.0,41.9,36.9,36.2,34.6,30.6,28.5,27.0,26.5,25.0,16.9,15.0,11.6.HRMS:calculated for C38H56N4O7([M+H]+):681.4222；found 681.4258.
6h:白色粉末；产率:82.3％；mp:103.2-104.4℃.1H NMR(400MHz,CDCl3):δ(ppm)7.30–7.27(m,1H),7.23–7.15(m,1H),6.99(dd,J＝8.0,1.2Hz,1H),6.71(td,J＝8.4,2.0Hz,1H),6.56–6.43(m,2H),5.79(d,J＝8.4Hz,1H),5.34(dd,J＝11.2,1.2Hz,1H),5.20(dd,J＝17.2,1.6Hz,1H),3.53(t,J＝5.2Hz,4H),3.35(d,J＝5.6Hz,1H),3.15(ABq,J＝17.2Hz,2H),2.71–2.50(m,4H),2.39–2.04(m,5H),1.85–1.33(m,11H),1.16(s,3H),1.14–1.07(m,1H),0.88(d,J＝6.8Hz,3H),0.72(d,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3):δ(ppm)217.2,169.0,163.2(J＝244Hz),154.6,140.8,140.7,139.2,130.0(J＝9.4Hz),117.4,115.0(J＝3.2Hz),114.9,109.8(J＝21Hz),107.4,107.1,74.7,68.7,60.5,59.8,58.3,52.6,45.6,44.1,41.9,36.8,36.2,34.6,30.6,27.0,26.5,25.0,16.9,15.0,11.6.HRMS:calculated for C33H46FN3O5([M+H]+):584.3494；found 584.3488.
6i:白色粉末；产率:81.5％；mp:116.3-117.7℃.1H NMR(400MHz,CDCl3):δ(ppm)7.62(s,1H),7.55(d,J＝8.0Hz,1H),7.37(t,J＝8.0Hz,1H),7.30–7.26(m,1H),6.61(s,1H),6.50(dd,J＝17.2,11.2Hz,1H),5.79(d,J＝8.4Hz,1H),5.34(dd,J＝11.2,1.2Hz,1H),5.20(dd,J＝17.2,1.6Hz,1H),3.55(t,J＝5.2Hz,4H),3.35(s,1H),3.27(ABq,J＝17.2Hz,2H),2.73–2.51(m,4H),2.39–2.04(m,5H),1.83–1.33(m,11H),1.16(s,3H),1.14–1.08(m,1H),0.88(d,J＝6.8Hz,3H),0.72(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.2,169.0,154.6,139.7,139.2,131.5,131.2,129.5,123.0,119.8,117.4,116.6,74.7,68.7,60.5,59.8,58.3,52.6,45.6,45.2,44.1,41.9,36.9,36.2,34.6,30.6,27.0,26.5,25.0,16.9,15.0,11.6.HRMS:calculated for C34H46F3N3O5([M+H]+):634.3462；found 634.3468.
6j:白色粉末；产率:73.2％；mp:127.9-129.5℃.1H NMR(400MHz,CDCl3):δ(ppm)8.33(d,J＝6.6Hz,2H),7.66(d,J＝6.2Hz,2H),6.50(dd,J＝17.2,11.2Hz,1H),5.80(d,J＝8.4Hz,1H),5.34(dd,J＝11.2,1.6Hz,1H),5.20(dd,J＝17.2,1.6Hz,1H),3.64(t,J＝4.8Hz,4H),3.36(d,J＝6.6Hz,1H),3.16(ABq,J＝17.2Hz,2H),2.72–2.54(m,4H),2.41–2.05(m,5H),1.83–1.33(m,11H),1.17(s,3H),1.15–1.08(m,1H),0.88(d,J＝6.8Hz,3H),0.72(d,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3):δ(ppm)217.2,169.0,153.8,150.4,146.7,139.2,117.4,113.4,74.7,68.7,59.8,58.3,52.5,45.6,45.2,44.2,44.1,41.9,36.8,36.2,34.6,30.6,27.0,26.6,25.0,16.9,15.0,11.6.HRMS:calculated for C32H46N4O5([M+H]+):567.3541；found 567.3546.
6k:白色粉末；产率:67.8％；mp:129.6-130.9℃.1H NMR(400MHz,CDCl3):δ(ppm)7.43–7.35(m,1H),7.31(d,J＝8.0Hz,1H),6.96(s,1H),6.49(dd,J＝17.2,11.2Hz,1H),6.14(d,J＝7.6Hz,1H),5.78(d,J＝8.4Hz,1H),5.33(d,J＝11.2Hz,1H),5.19(dd,J＝17.2,1.2Hz,1H),4.25(s,2H),3.54(t,J＝4.8Hz,4H),3.42–3.29(m,1H),3.12(ABq,J＝17.2Hz,2H),2.72–2.39(m,4H),2.39–2.01(m,5H),1.82–1.31(m,11H),1.15(s,3H),1.13–1.06(m,1H),0.86(d,J＝6.8Hz,3H),0.70(d,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3):δ(ppm)217.3,169.0,157.0,153.9,151.2,140.2,139.1,117.5,102.9,102.5,74.7,68.6,59.8,58.3,52.6,45.6,45.1,44.1,43.9,41.9,36.8,36.2,34.6,30.5,26.9,26.5,25.0,16.9,15.0,11.6.HRMS:calculated for C32H47N5O5([M+H]+):582.3650；found 582.3658.
6l:白色粉末；产率:77.2％；mp:149.9-151.8℃.1H NMR(400MHz,CDCl3):δ(ppm)8.20(d,J＝2.4Hz,1H),7.88(dd,J＝8.8,2.8Hz,1H),7.38(d,J＝8.8Hz,1H),6.91(s,1H),6.50(dd,J＝17.2,11.2Hz,1H),5.80(d,J＝8.4Hz,1H),5.34(dd,J＝11.2,1.2Hz,1H),5.21(dd,J＝17.2,1.2Hz,1H),3.56(t,J＝4.8Hz,4H),3.45–3.31(m,1H),3.15(ABq,J＝17.2Hz,2H),2.69–2.51(m,4H),2.40–2.06(m,5H),1.84–1.34(m,11H),1.17(s,3H),1.15–1.07(m,1H),0.89(d,J＝6.8Hz,3H),0.72(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.3,169.0,154.4,141.1,139.2,135.9,134.6,130.3,127.9,117.4,74.7,68.7,59.8,58.3,52.5,45.6,45.1,44.1,41.9,36.8,36.2,34.6,30.5,26.9,26.5,24.9,16.9,15.0,11.6.HRMS:calculated for C32H46BrN4O5([M+H]+):645.2646；found 645.2648,647.2638.
6m:白色粉末；产率:56.2％；mp:102.3-103.7℃.1H NMR(400MHz,CDCl3):δ(ppm)7.19(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,2H),6.50(dd,J＝17.2,11.2Hz,1H),5.79(d,J＝8.4Hz,1H),5.33(dd,J＝11.2,1.2Hz,1H),5.19(dd,J＝17.2,1.2Hz,1H),4.63(t,J＝5.2Hz,1H),4.37(d,J＝5.2Hz,2H),3.47–3.31(m,5H),3.13(ABq,J＝17.2Hz,2H),2.57-2.50(m,4H),2.33(s,3H),2.25–2.04(m,5H),1.80–1.74(m,1H),1.70–1.42(m,10H),1.16(s,3H),1.13–1.08(m,1H),0.87(d,J＝6.8Hz,3H),0.71(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.2,169.0,157.4,139.0,137.1,136.3,129.3,127.9,117.4,74.6,68.4,59.9,58.2,52.6,45.5,45.0,44.8,44.0,43.6,41.8,36.7,36.1,34.5,30.4,26.8,26.4,24.9,21.1,16.8,14.9,11.6.HRMS:calculated for C35H51N3O5([M+H]+):594.3901；found594.3904.
6n:白色粉末；产率:60.1％；mp:104.2-105.8℃.1H NMR(400MHz,CDCl3):δ(ppm)7.22(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),6.49(dd,J＝17.2,11.2Hz,1H),5.78(d,J＝8.4Hz,1H),5.33(d,J＝11.2Hz,1H),5.19(d,J＝17.2Hz,1H),4.61(t,J＝5.6Hz,1H),4.34(d,J＝5.2Hz,2H),3.79(s,3H),3.45–3.41(m,4H),3.35(dd,J＝10.4,6.4Hz,1H),3.15(ABq,J＝17.2Hz,2H),2.62–2.46(m,4H),2.36–2.03(m,5H),1.81–1.40(m,11H),1.16(s,3H),1.13–1.08(m,1H),0.87(d,J＝6.8Hz,3H),0.71(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.2,169.0,157.4,139.0,131.4,129.2,117.3,114.0,74.6,68.4,59.9,58.2,55.3,45.5,45.0,44.5,44.0,43.6,41.8,36.7,36.1,34.5,30.4,26.8,26.4,24.9,16.8,14.9,11.5.HRMS:calculated for C35H51N3O6([M+H]+):610.3851；found 610.3831.
6o:白色粉末；产率:53.1％；mp:109.6-110.7℃.1H NMR(400MHz,CDCl3):δ(ppm)7.58(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),6.50(dd,J＝17.2,11.2Hz,1H),5.79(d,J＝8.4Hz,1H),5.34(dd,J＝11.2,1.2Hz,1H),5.20(d,J＝17.2Hz,1H),4.83(t,J＝5.6Hz,1H),4.48(d,J＝5.6Hz,2H),3.48(t,J＝4.4Hz,4H),3.35(d,J＝6.2Hz,1H),3.25(ABq,J＝17.2Hz,2H),2.67–2.45(m,4H),2.38–2.03(m,5H),1.81–1.37(m,11H),1.16(s,3H),1.14–1.09(m,1H),0.88(d,J＝6.4Hz,3H),0.72(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.1,168.3,157.4,143.6,139.1,129.7(q,J＝33Hz),127.9,125.6(q,J＝4Hz),117.5,74.7,69.0,59.3,58.3,52.7,45.6,45.1,44.6,44.1,43.5,41.9,36.8,36.2,34.6,30.5,26.9,26.5,25.0,16.9,15.0,11.6.HRMS:calculated for C35H48F3N3O5([M+H]+):648.3619；found 648.3597.
6p:浅黄色粉末；产率:55.1％；mp:115.2-116.5℃.1H NMR(400MHz,CDCl3):δ(ppm)8.14(d,J＝8.4Hz,2H),7.44(d,J＝8.4Hz,2H),6.49(dd,J＝17.2,11.2Hz,1H),5.79(d,J＝8.4Hz,1H),5.33(d,J＝11.2Hz,1H),5.21-5.15(m,2H),4.50(d,J＝5.6Hz,2H),3.46(t,J＝4.4Hz,4H),3.36(s,1H),3.15(ABq,J＝17.2Hz,2H),2.62-2.50(m,4H),2.38–2.05(m,5H),1.82–1.41(m,11H),1.16(s,3H),1.11(d,J＝13.6Hz,1H),0.88(d,J＝6.8Hz,3H),0.71(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.1,168.9,157.3,147.4,147.1,139.1,128.0,123.8,117.2,74.6,68.5,60.41,59.7,58.2,52.4,45.5,45.0,44.2,44.0,43.7,41.8,36.7,36.1,34.5,30.4,26.8,26.5,24.8,16.7,14.9,11.5.HRMS:calculated forC34H48N4O7([M+H]+):625.3596；found 625.3596.
6q:白色粉末；产率:45.6％；mp:107.6-108.7℃.1H NMR(400MHz,CDCl3):δ(ppm)7.61(d,J＝7.6Hz,1H),7.57(d,J＝7.6Hz,1H),7.49(t,J＝7.6Hz,1H),7.34(t,J＝7.6Hz,1H),6.47(dd,J＝17.2,11.2Hz,1H),5.76(d,J＝8.4Hz,1H),5.31(d,J＝11.2Hz,1H),5.17(d,J＝17.2Hz,1H),4.93(d,J＝5.6Hz,1H),4.57(d,J＝5.6Hz,2H),3.40(t,J＝4.8Hz,4H),3.33(dd,J＝10.4,6.8Hz,1H),3.11(ABq,J＝17.2Hz,2H),2.58–2.44(m,4H),2.35–2.04(m,5H),1.80–1.39(m,11H),1.14(s,3H),1.12–1.06(m,1H),0.86(d,J＝6.8Hz,3H),0.69(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.1,168.9,157.2,139.1,137.9,132.3,130.6,127.4,125.9,125.9,117.3,74.6,68.5,59.8,58.2,52.5,45.5,45.0,44.0,43.6,41.8,41.4,36.7,36.1,34.5,30.4,26.8,26.4,24.8,16.7,14.9,11.5.HRMS:calculatedfor C35H48F3N3O5([M+H]+):648.3619；found 648.3620.
6r:白色粉末；产率:65.1％；mp:136.5-137.9℃.1H NMR(400MHz,CDCl3):δ(ppm)7.32–7.27(m,2H),7.24–7.15(m,3H),6.49(dd,J＝17.2,11.2Hz),5.78(d,J＝8.4Hz),5.33(dd,J＝11.2,1.2Hz),5.19(dd,J＝17.2,1.2Hz),4.44(t,1H,J＝5.6Hz),3.47(dd,J＝12.4,6.8Hz,2H),3.35(t,J＝4.8Hz,4H),3.10(ABq,J＝17.2Hz,2H),2.81(t,J＝6.8Hz,2H),2.58–2.42(m,4H),2.37–2.02(m,5H),1.79–1.24(m,11H),1.15(s,3H),1.13–1.07(m,1H),0.87(d,J＝6.4Hz,3H),0.70(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.3,169.0,157.6,139.1,139.5,129.0,128.7,126.5,117.5,74.7,68.5,59.9,58.3,52.6,45.6,45.1,44.1,43.6,42.1,41.9,36.8,36.4,36.2,34.6,30.5,26.9,26.5,25.0,16.9,15.0,11.6.HRMS:calculated for C35H51N3O5([M+H]+):594.3901[M+H]+；found 594.3905.
6s:白色粉末；产率:61.7％；mp:105.8-107.1℃.1H NMR(400MHz,CDCl3):δ(ppm)7.22(t,J＝7.6Hz,1H),6.78–6.73(m,3H),6.50(dd,J＝17.2,11.2Hz,1H),5.78(d,J＝8.4Hz,1H),5.33(d,J＝11.2Hz,1H),5.20(d,J＝17.2Hz,1H),4.42(t,J＝5.6Hz,1H),3.79(s,3H),3.47(dd,J＝12.4,6.8Hz,2H),3.36(t,J＝4.8Hz,4H),3.12(ABq,J＝17.2Hz,2H),2.79(t,J＝6.8Hz,2H),2.54–2.49(m,4H),2.37–2.03(m,5H),1.80–1.42(m,11H),1.16(s,3H),1.13–1.09(m,1H),0.87(d,J＝6.8Hz,3H),0.71(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.3,169.1,159.9,157.6,139.1,141.1,129.7,121.3,114.6,111.9,117.5,74.7,68.5,59.9,58.3,55.3,52.6,45.6,45.1,44.1,43.6,42.0,41.9,36.8,36.5,36.2,34.6,30.5,26.9,26.5,25.0,16.9,15.0,11.6.HRMS:calculated for C36H53N3O6([M+H]+):624.4007；found 624.3995.
6t:白色粉末；产率:82.7％；mp:119.5-122.2℃.1H NMR(400MHz,CDCl3):δ(ppm)6.49(dd,J＝17.2,11.2Hz,1H),5.77(d,J＝8.4Hz,1H),5.35(s,1H),5.32(dd,J＝11.2,1.6Hz,1H),5.18(dd,J＝17.2,1.6Hz,1H),3.40(t,J＝4.8Hz,4H),3.36–3.24(m,3H),3.12(ABq,J＝17.2Hz,2H),2.63–1.99(m,16H),1.83–1.31(m,17H),1.15(s,3H),1.13–1.03(m,1H),0.86(d,J＝6.8Hz,3H),0.70(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.3,169.1,162.6,157.9,139.2,117.4,77.5,77.2,76.8,74.7,68.5,60.0,58.3,57.6,54.3,52.7,45.6,45.1,44.0,43.6,41.9,37.3,36.8,36.6,36.2,34.6,31.5,30.5,26.9,26.5,26.0,25.0,24.4,16.8,15.0,11.6.HRMS:calculated for C34H56N4O5([M+H]+):601.4323；found 601.4326.
6u:白色粉末；产率:79.2％；mp:92.1-93.8℃.1H NMR(400MHz,CDCl3):δ(ppm)7.98(s,1H),6.47(dd,J＝17.2,11.2Hz,1H),5.76(d,J＝8.4Hz,1H),5.30(d,J＝11.2Hz,1H),5.22–5.07(m,2H),3.78–3.62(m,4H),3.49–3.24(m,6H),3.10(ABq,J＝17.2Hz,2H),2.63–2.37(m,10H),2.36–1.96(m,5H),1.81–1.29(m,11H),1.13(s,3H),1.11–1.04(m,1H),0.85(d,J＝6.8Hz,3H),0.69(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.2,169.0,157.8,139.2,117.3,74.6,68.5,67.0,59.9,58.3,57.6,53.4,52.6,45.5,45.1,44.0,43.6,41.9,37.0,36.1,34.5,30.5,26.9,26.5,24.9,16.8,15.0,11.6.HRMS:calculatedfor C33H54N4O6([M+H]+):603.4116；found 603.4144.
1.3化合物6v的合成
化合物11(128mg,0.47mmol)溶于乙腈(10mL)中，加入化合物8(210mg,0.47mmol)和DMAP(57mg,0.47mmol)，加热回流24h，然后去除溶剂后，溶于EtOAc(10mL)中，有机相用1NNaOH和盐水洗涤，然后用无水Na2SO4干燥。过滤，滤液浓缩至干，然后通过硅胶色谱纯化，得到化合物6v。
6v:白色粉末；产率:40.5％；mp:105.1-106.3℃.1H NMR(400MHz,CDCl3):δ(ppm)7.33–7.31(m,2H),7.11–7.06(m,3H),6.47(dd,J＝17.2,11.2Hz,1H),5.74(d,J＝8.4Hz,1H),5.30(dd,J＝11.2,1.2Hz,1H),5.17(dd,J＝17.2,1.2Hz,1H),3.33(dd,J＝10.4,6.8Hz,1H),3.25(t,J＝4.9Hz,4H),3.21(s,3H),3.02(ABq,J＝17.2Hz,2H),2.40–2.23(m,7H),2.26–1.99(m,2H),1.80–1.38(m,11H),1.14(s,3H),1.12–1.05(m,1H),0.85(d,J＝7.2Hz,3H),0.66(d,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ(ppm)217.2,168.9,160.9,146.7,139.0,129.5,124.6,123.8,117.3,74.6,68.3,59.8,58.2,52.5,45.5,45.4,44.9,43.9,41.8,39.6,36.7,36.0,34.5,30.4,26.8,26.4,24.9,16.7,14.9,11.5.HRMS:calculated for C34H49N3O5([M+H]+):580.3745；found 580.3744.
1.4化合物6w的合成
将化合物6d(122mg,0.2mmol),SnCl2(474mg,2.5mmol)和乙醇(5mL)混合，搅拌回流5h后，冷却至25℃，加入1N NaOH，用DCM(10mL×3)萃取分离，有机相经Na2SO4干燥后浓缩，然后通过硅胶色谱纯化，得到化合物6w。
6w:yellow powder；产率:92.5％；mp:137.4-138.7℃.1H NMR(400MHz,CDCl3):δ(ppm)7.08(d,J＝8.4Hz,2H),6.62(d,J＝8.4Hz,2H),6.50(dd,J＝17.2,11.2Hz,1H),6.18(s,1H),5.79(d,J＝8.4Hz,1H),5.34(d,J＝11.2Hz,1H),5.20(d,J＝17.2Hz,1H),3.50(t,J＝4.8Hz,4H),3.35(d,J＝5.2Hz,1H),3.14(ABq,J＝17.2Hz,2H),2.67–2.49(m,4H),2.41–2.01(m,5H),1.83–1.32(m,13H),1.16(s,3H),1.14–1.07(m,1H),0.87(d,J＝6.8Hz,3H),0.72(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.3,169.1,155.8,142.9,139.2,130.2,123.1,117.5,115.7,74.7,68.6,59.9,58.3,52.7,45.6,45.2,44.1,44.0,41.9,36.8,36.2,34.6,30.6,29.8,27.0,26.5,25.0,16.9,15.0,11.6.HRMS:calculated forC33H48N4O5([M+H]+):581.3697；found 581.3705.
1.5化合物6x的合成
将化合物6g(136mg,0.2mmol)加入6mL DCM和TFA(v/v＝10/1)的混合溶剂中，25℃搅拌直至完全反应。用饱和NaHCO3水溶液中和后，收集有机相，并用无水Na2SO4干燥，过滤，滤液浓缩，然后通过硅胶色谱纯化，得到化合物6x。
6x:白色粉末；产率:95.6％；mp:146.2-147.5℃.1H NMR(400MHz,CDCl3):δ(ppm)7.02(t,J＝8.0Hz,1H),6.95(t,J＝2.0Hz,1H),6.56–6.44(m,2H),6.38–6.31(m,2H),5.79(d,J＝8.4Hz,1H),5.34(dd,J＝11.2,1.6Hz,1H),5.20(dd,J＝17.2,1.2Hz,1H),3.52(t,J＝4.8Hz,4H),3.35(d,J＝6.0Hz,1H),3.12(ABq,J＝17.2Hz,2H),2.68–2.49(m,4H),2.41–2.02(m,7H),1.86–1.21(m,13H),1.16(s,3H),1.14–1.07(m,1H),0.87(d,J＝6.8Hz,4H),0.72(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ(ppm)217.3,169.1,155.0,147.3,140.0,139.2,129.7,117.5,110.2,109.9,106.8,74.7,68.6,59.9,58.3,52.7,45.6,45.2,44.1,44.0,41.9,36.8,36.2,34.6,30.6,27.0,26.5,25.0,16.9,15.0,11.6.HRMS:calculatedfor C33H48N4O5([M+H]+):581.3697；found 581.3704.
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：选取耐甲氧西林金黄色葡萄球菌(ATCC33591)和耐甲氧西林金黄色葡萄球菌(ATCC43300)以及普通菌株大肠杆菌(ATCC25922)和金黄色葡萄球菌(ATCC25923)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，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，其余实验结果见表1。
表1
从表1可以看出，本发明化合物对金黄色葡萄球菌标准耐药株ATCC33591和ATCC43300都表现出优良的抗菌效果，特别是化合物6c、6d、6o、6p、6q等，对两种金黄色葡萄球菌耐药菌株的MIC均达到0.125～0.5μg·mL-1，均优于泰妙菌素。同时，本发明化合物对大肠杆菌ATCC25922和ATCC25923也表现出优良的抗菌效果，尤其是化合物6d、6n、6o、6p对两种大肠杆菌的MIC均达到0.5μg·mL-1。综合以上结果，本发明中的哌嗪脲截短侧耳素化合物均表现出了优良的抗菌效果，有望治疗由金黄色葡萄球菌和大肠杆菌引起的细菌感染。
Claims (18)
1.哌嗪脲截短侧耳素衍生物，其特征在于，其结构式为式I所示：
其中，n＝0、1、2或3；
R1选自苯环、被取代的苯环、喹啉、哌啶、吗啉、吡啶、氨基取代的吡啶或卤素取代的吡啶；所述被取代的苯环为苯环上任意一个氢被C1-4烷氧基、C1-4烷基、C1-4氟代烷基、硝基、氨基、卤素、乙酰胺基或Boc保护的氨基取代；
R2选自氢或C1-4烷基。
2.根据权利要求1所述的哌嗪脲截短侧耳素衍生物，其特征在于：n＝0、1或2。
3.根据权利要求1或2所述的哌嗪脲截短侧耳素衍生物，其特征在于：R2选自氢或甲基。
4.根据权利要求1或2所述的哌嗪脲截短侧耳素衍生物，其特征在于：R1选自喹啉、吗啉、哌啶、吡啶、氨基取代的吡啶或卤素取代的吡啶。
5.根据权利要求3所述的哌嗪脲截短侧耳素衍生物，其特征在于：R1选自喹啉、吗啉、哌啶、吡啶、氨基取代的吡啶或卤素取代的吡啶。
6.根据权利要求4所述的哌嗪脲截短侧耳素衍生物，其特征在于：R1选自
7.根据权利要求5所述的哌嗪脲截短侧耳素衍生物，其特征在于：R1选自
8.根据权利要求1或2所述的哌嗪脲截短侧耳素衍生物，其特征在于：R1选自苯环或被取代的苯环。
9.根据权利要求3所述的哌嗪脲截短侧耳素衍生物，其特征在于：R1选自苯环或被取代的苯环。
10.根据权利要求8所述的哌嗪脲截短侧耳素衍生物，其特征在于：所述被取代的苯环为苯环上任意一个氢被甲基、甲氧基、三氟甲基、氨基、硝基、氟、乙酰胺基或Boc保护的氨基取代。
11.根据权利要求9所述的哌嗪脲截短侧耳素衍生物，其特征在于：所述被取代的苯环为苯环上任意一个氢被甲基、甲氧基、三氟甲基、氨基、硝基、氟、乙酰胺基或Boc保护的氨基取代。
12.根据权利要求10所述的哌嗪脲截短侧耳素衍生物，其特征在于：所述被取代的苯环为
13.根据权利要求11所述的哌嗪脲截短侧耳素衍生物，其特征在于：所述被取代的苯环为
14.根据权利要求8所述的哌嗪脲截短侧耳素衍生物，其特征在于：R1选自苯环、
n＝0或1，R2为氢。
15.根据权利要求1所述的哌嗪脲截短侧耳素衍生物，其特征在于，其结构式选自以下结构之一：
16.权利要求1～15任一项所述的哌嗪脲截短侧耳素衍生物的立体异构体或药学上可接受的盐；所述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。
17.权利要求1～15任一项所述的哌嗪脲截短侧耳素衍生物、权利要求16所述的哌嗪脲截短侧耳素衍生物的立体异构体或药学上可接受的盐在制备治疗感染性疾病药物中的用途，所述感染性疾病是由金黄色葡萄球菌或大肠杆菌引起的。
18.一种治疗感染性疾病的药物组合物，其特征在于：含有权利要求1～15任一项所述的哌嗪脲截短侧耳素衍生物以及药学上可接受的辅料。
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