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CN111170997A - 咔唑类化合物及其制备方法和应用 - Google Patents

咔唑类化合物及其制备方法和应用 Download PDF

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CN111170997A
CN111170997A CN201911415794.7A CN201911415794A CN111170997A CN 111170997 A CN111170997 A CN 111170997A CN 201911415794 A CN201911415794 A CN 201911415794A CN 111170997 A CN111170997 A CN 111170997A
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刘寿平
林水木
刘家勇
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Guangzhou Medical University
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Abstract

本发明涉及一种咔唑类化合物及其制备方法和应用。该咔唑类化合物具有如下结构通式，可用于制备抗菌药物，能够有效减缓或克服细菌耐药性的产生，且能有效避免与传统抗菌药物发生交叉耐药。

Description

咔唑类化合物及其制备方法和应用
技术领域
本发明涉及药物化学技术领域，特别是涉及咔唑类化合物及其制备方法和应用。
背景技术
近年来，耐药细菌感染导致的疾病正严重威胁着全球人类的健康。由于抗菌药物的滥用和错误使用以及获批准的新型抗菌药物的大量减少，病原体对抗菌药物产生耐药性的现象正日益增加。抗菌药物耐药性问题已经被世界卫生组织(WHO)列为2019年对全球健康的十大威胁之一。
目前，对耐药性细菌感染的临床有效治疗方案非常有限，已经遇到了巨大的挑战。此外，大多数的传统抗菌药物都包含相同的分子骨架。自上世纪90年代初以来，临床研究中具有新分子实体(NME)的抗菌药物一直严重缺乏。目前批准的大多数抗菌药物仍然基于传统的抗菌分子骨架，例如大环内酯类，喹诺酮类，四环素和头孢菌素等。通常，具有类似的作用机制或分子骨架的抗菌药物比较容易发生交叉耐药。
因此，开发出基于新分子实体的高效低毒抗菌药物来应对细菌耐药性问题已经迫在眉睫。
发明内容
基于此，有必要提供一种咔唑类化合物。该咔唑类化合物可用于制备抗菌药物，能够有效减缓或克服细菌耐药性的产生，且能有效避免与传统抗菌药物发生交叉耐药。
具体的技术方案如下：
具有如下结构通式的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子：
Figure BDA0002351153870000011
其中，R1选自：至少一个Ra取代或未取代的C1-C10直链或支链烷基、至少一个Ra取代或未取代的C3-C8直链或支链烯基；
Ra分别独立地选自：H、卤素；
R2为阳离子基团，选自：至少一个Rb取代或未取代的C2-C5环烷氧基、至少一个Rb取代或未取代的C1-C5烷基胺；
Rb分别独立地选自：H、OH、羰基、C1-C15直链或支链烷基、C1-C15直链或支链烷基醇、C1-C15直链或支链烷基巯基、C1-C10烷基胺、C5-C10含氮杂芳基、C1-C5氨基亚胺烷基或前述基团的组合，当每两个前述基团连接在同一碳原子上时，互相连接成环或不连接成环。
本发明还提供如上所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子的制备方法，采用如下合成路线(I)-(III)之一进行制备：
合成路线(I)：
Figure BDA0002351153870000012
合成路线(II)：
Figure BDA0002351153870000021
合成路线(III)：
Figure BDA0002351153870000022
其中原料可采用合成路线(II)进行制备。
本发明还提供如上所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子在制备具有抗菌功效的药物中的应用。
本发明还提供如上所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，以及锌离子的组合物在制备具有抗菌功效的药物中的应用。
本发明的原理及优点如下：
目前，已商业化的含有咔唑骨架的临床药物包括降压药卡维地洛和咔唑心安，以及抗癌药玫瑰树碱和依利醋铵。但是，目前尚无批准用于临床的咔唑类抗菌药物。咔唑具备特殊的分子结构特征，并且各种官能团可以较容易地引入到咔唑骨架中。因此，咔唑可用作抗菌药物开发的优势骨架，具有避免与传统抗菌药物发生交叉耐药的潜力。
在这项工作中，我们设计并合成了一系列模拟抗菌肽的咔唑类小分子。将疏水脂质链和阳离子模块分别引入咔唑母核，形成阳离子型的两亲性结构。引入的阳离子基团(例如脂肪族胺和碱性氨基酸)可以通过静电吸引作用促进咔唑衍生物与带负电荷的细菌膜之间的相互作用，而引入的疏水脂肪链则与细菌磷脂双层之间存在强烈的疏水相互作用，促使细菌细胞膜通透性改性，甚至破裂，引发细菌细胞内容物的泄露，导致细菌细胞死亡。细菌的细胞膜带负电荷，因为细菌细胞膜的磷脂成分主要包括电负性的磷脂酰甘油(PG)和心磷脂(CL)以及电中性的磷脂酰乙醇胺(PE)。而真核细胞膜是电中性的，因为真核细胞膜的磷脂成分主要包括电中性的磷脂酰乙醇胺(PE)，磷脂酰胆碱(PC)，鞘磷脂(SM)等。因此，本发明的咔唑类化合物可以选择性地作用于细菌，有效地对抗耐药性细菌感染。
本发明的制备方法以4-环氧丙烷氧基咔唑为起始原料，该起始原料是合成降压药卡维地洛和咔唑心安的中间体，比较常用且廉价，因此制备成本较低，且步骤简单。
附图说明
图1为化合物29和诺氟沙星诱导细菌(金黄色葡萄球菌ATCC29213)耐药性试验结果图；
图2为化合物29和万古霉素在金黄色葡萄球菌ATCC29213导致的小鼠角膜炎模型中的抗菌实验结果图。
具体实施方式
以下结合具体实施例对本发明的咔唑类化合物及其制备方法和应用作进一步详细的说明。
本发明提供具有如下结构通式的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子：
Figure BDA0002351153870000031
其中，R1选自：至少一个Ra取代或未取代的C1-C10直链或支链烷基、至少一个Ra取代或未取代的C3-C8直链或支链烯基；
Ra分别独立地选自：H、卤素；
R2为阳离子基团，选自：至少一个Rb取代或未取代的C2-C5环烷氧基、至少一个Rb取代或未取代的C1-C5烷基胺；
Rb分别独立地选自：H、OH、羰基、C1-C15直链或支链烷基、C1-C15直链或支链烷基醇、C1-C15直链或支链烷基巯基、C1-C10烷基胺、C5-C10含氮杂芳基、C1-C5氨基亚胺烷基或前述基团的组合，当每两个前述基团连接在同一碳原子上时，互相连接成环或不连接成环。
具体地，对于上述咔唑类化合物的药学上可接受的盐的相关方案如下：若化合物是碱性的，盐可以从医药上可接受的无毒酸中制备，包括无机和有机酸。这样的酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡萄糖酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、苦杏仁酸，甲基磺酸、粘液酸、硝酸、双羟萘酸、泛酸、磷酸、硫酸、琥珀酸、酒石酸、对甲苯磺酸等等。特定的实施方式包括柠檬酸、氢溴酸、盐酸、磷酸、硫酸、马来酸、酒石酸。其它示例性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐，硫酸盐，磷酸盐、酸性磷酸盐、异烟酸、乳酸、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、富马酸盐、马来酸盐、龙胆酸盐、葡萄糖酸盐，葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲基磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐。
在其中一个具体的实施例中，R2选自：C2-C5环烷氧基或如下所示结构通式的基团：
Figure BDA0002351153870000032
其中m+n＝1～5。
在其中一个具体的实施例中，n≠0。
在其中一个具体的实施例中，Rb分别独立地选自：H、OH、羰基、C1-C10直链或支链烷基、C1-C5直链或支链烷基醇、C1-C5直链或支链烷基巯基、C2-C6烷基胺、C5-C8含氮杂芳基、C1-C2氨基亚胺烷基或前述基团的组合，当每两个前述基团连接在同一碳原子上时，互相连接成环或不连接成环。
在其中一个具体的实施例中，所述C5-C8含氮杂芳基的结构如下：
Figure BDA0002351153870000033
其中，所述w＝0、1、2或3，V每次出现时独立地为C或N。
在其中一个具体的实施例中，所述C5-C8含氮杂芳基的结构如下：
Figure BDA0002351153870000041
其中，所述w＝0、1、2或3，V每次出现时独立地为C或N。
在其中一个具体的实施例中，R1选自：至少一个Ra取代或未取代的C1-C10直链烷基、至少一个Ra取代或未取代的C3-C6支链烯基。
在其中一个具体的实施例中，所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，选自如下化合物：
Figure BDA0002351153870000042
Figure BDA0002351153870000051
Figure BDA0002351153870000061
Figure BDA0002351153870000071
本发明还提供如上所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子的制备方法，采用如下合成路线(I)-(III)之一进行制备：
合成路线(I)：
Figure BDA0002351153870000072
合成路线(II)：
Figure BDA0002351153870000073
合成路线(III)：
Figure BDA0002351153870000074
其中原料可采用合成路线(II)进行制备。
本发明还提供如上所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子在制备具有抗菌功效的药物中的应用。
本发明还提供如上所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，以及锌离子的组合物在制备具有抗菌功效的药物中的应用。
以下提供化合物制备的具体实施例。
合成路线如下：
(一)
Figure BDA0002351153870000081
(二)
Figure BDA0002351153870000082
(三)
Figure BDA0002351153870000091
(四)
Figure BDA0002351153870000092
化合物的制备方法如下：
化合物2的合成
Figure BDA0002351153870000093
将4-环氧丙烷氧基咔唑(100mg，0.42mmol)溶于DMF(10mL)溶液中，然后加入碘甲烷(52μL，0.84mmol)和NaOH(33.43mg，0.84mmol)，将混合物在60℃下搅拌反应2小时。反应完成后，将混合物用乙酸乙酯稀释并用水萃取3次。对有机层进行减压浓缩，所得粗产物通过硅胶色谱法(乙酸乙酯/石油醚＝1/4)纯化，获得化合物2为浅黄色固体(86.2mg，81％)。1H NMR(400MHz,CDCl3)δ8.36–8.33(m,1H),7.47–7.41(m,1H),7.38–7.33(m,2H),7.25–7.22(m,1H),7.03(d,J＝8.2Hz,1H),6.65(d,J＝8.0Hz,1H),4.48–4.21(m,2H),3.81(s,3H),3.56–3.50(m,1H),2.99–2.83(m,2H).13C NMR(100MHz,CDCl3)δ155.09,142.65,140.36,126.44,124.98,123.27,122.07,119.29,112.17,107.98,102.10,101.06,68.89,50.47,44.96,29.38.HRMS(ESI+):calculated for C16H16NO2[M+H]+254.1181,found 254.1169。
化合物3的合成
Figure BDA0002351153870000101
按照化合物2的合成方法，以4-环氧丙烷氧基咔唑(73.1mg，0.31mmol)，NaOH(24.4mg，0.61mmol)和1-碘丙烷(59μL，0.61mmol)为起始原料，制得化合物3为浅黄色固体(79.8mg，93％)。1H NMR(400MHz,CDCl3)δ8.37–8.33(m,1H),7.45–7.33(m,3H),7.25–7.20(m,1H),7.04(d,J＝8.2Hz,1H),6.65(d,J＝7.9Hz,1H),4.50–4.19(m,4H),3.57–3.52(m,1H),3.02–2.84(m,2H),1.96–1.83(m,2H),0.95(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ155.17,142.19,139.89,126.33,124.89,123.35,122.13,119.18,112.22,108.28,102.42,100.90,68.89,50.48,44.96,44.89,22.42,11.85.HRMS(ESI+):calculated for C18H20NO2[M+H]+282.1494,found 282.1490。
化合物4的合成
Figure BDA0002351153870000102
按照化合物2的合成方法，以4-环氧丙烷氧基咔唑(104.2mg，0.44mmol)，NaOH(33.4mg，0.84mmol)和1-碘戊烷(114μL，0.87mmol)为起始原料，制得化合物4为浅黄色固体(102.5mg，76％)。1H NMR(400MHz,CD3OD)δ8.28(d,J＝7.9Hz,1H),7.45–7.29(m,3H),7.20–7.14(m,1H),7.10–7.06(m,1H),6.72–6.68(m,1H),4.60–4.49(m,1H),4.35–4.25(m,2H),4.15–4.08(m,1H),3.55–3.50(m,1H),2.97–2.85(m,2H),1.87–1.77(m,2H),1.38–1.28(m,4H),0.89–0.79(m,3H).13C NMR(100MHz,CD3OD)δ156.43,143.29,141.05,127.45,125.77,124.08,123.28,119.89,113.14,109.35,103.39,101.96,70.13,51.52,45.09,43.80,30.35,29.73,23.50,14.29.HRMS(ESI+):calculated for C20H24NO2[M+H]+310.1807,found310.1794。
化合物5的合成
Figure BDA0002351153870000103
按照化合物2的合成方法，以4-环氧丙烷氧基咔唑(100mg，0.42mmol)，NaOH(33.43mg，0.84mmol)和1-碘庚烷(137μL，0.84mmol)为起始原料，制得化合物5为浅黄色固体(106.7mg，76％)。1H NMR(400MHz,CD3OD)δ8.28(d,J＝7.8Hz,1H),7.43–7.29(m,3H),7.20–7.14(m,1H),7.07(d,J＝8.2Hz,1H),6.69(d,J＝7.9Hz,1H),4.56–4.48(m,1H),4.29(t,J＝7.1Hz,2H),4.15–4.06(m,1H),3.54–3.48(m,1H),3.00–2.81(m,2H),1.87–1.73(m,2H),1.32–1.18(m,8H),0.84(t,J＝6.4Hz,3H).13C NMR(100MHz,CD3OD)δ156.42,143.28,141.04,127.45,125.76,124.09,123.28,119.89,113.14,109.36,103.40,101.95,70.11,51.52,45.09,43.81,32.86,30.16,30.01,28.12,23.56,14.35.HRMS(ESI+):calculatedfor C22H28NO2[M+H]+338.2120,found 338.2106。
化合物6的合成
Figure BDA0002351153870000111
按照化合物2的合成方法，以4-环氧丙烷氧基咔唑(80mg，0.33mmol)，NaOH(26.4mg，0.66mmol)和1-碘壬烷(125μL，0.67mmol)为起始原料，制得化合物6为浅黄色固体(82.3mg，70％)。1H NMR(400MHz,CD3OD)δ8.28(d,J＝7.8Hz,1H),7.45–7.36(m,2H),7.34(t,J＝8.1Hz,1H),7.20–7.14(m,1H),7.08(d,J＝8.2Hz,1H),6.71(d,J＝7.9Hz,1H),4.57–4.51(m,1H),4.31(t,J＝7.1Hz,2H),4.17–4.10(m,1H),3.56–3.50(m,1H),2.99–2.86(m,2H),1.88–1.76(m,2H),1.34–1.19(m,12H),0.86(t,J＝7.0Hz,3H).13C NMR(100MHz,CD3OD)δ156.46,143.32,141.07,127.45,125.77,124.10,123.30,119.90,113.17,109.38,103.43,101.98,70.17,51.54,45.11,43.84,32.95,30.53,30.46,30.26,29.98,28.12,23.66,14.39.HRMS(ESI+):calculated for C24H32NO2[M+H]+366.2433,found 366.2421。
化合物7的合成
Figure BDA0002351153870000112
将4-环氧丙烷氧基咔唑(2.01g，6.54mmol)溶于DMF(30mL)溶液中，然后加入叔丁醇钾(2.83g，25.20mmol)和碘化钾(2.09g，12.60mmol)，随后缓慢滴加1-溴-3-甲基-2-丁烯(2.89mL，25.20mmol)。将反应混合物在50℃下搅拌30分钟。反应完成后，将混合物用乙酸乙酯稀释并用水萃取3次。对有机层进行减压浓缩，所得粗产物通过硅胶色谱法(乙酸乙酯/石油醚)纯化，获得化合物7，为白色固体(1.46g，57％)。1H NMR(400MHz,CDCl3)δ8.36(d,J＝7.8Hz,1H),7.46–7.40(m,1H),7.35(t,J＝8.0Hz,2H),7.26–7.22(m,1H),7.03(d,J＝8.2Hz,1H),6.65(d,J＝8.0Hz,1H),5.31–5.22(m,1H),4.87(d,J＝6.4Hz,2H),4.48–4.24(m,2H),3.57–3.52(m,1H),3.00–2.87(m,2H),1.92(s,3H),1.70(s,3H).13C NMR(100MHz,CDCl3)δ156.66,143.12,140.87,136.17,127.47,125.67,124.14,123.50,121.20,119.92,113.28,109.37,103.21,101.86,75.31,70.28,59.53,41.94,25.71,18.20.HRMS(ESI+):calculated for C20H22NO2[M+H]+308.1651,found 308.1642。
化合物8的合成
Figure BDA0002351153870000113
将化合物2(54.3mg，0.33mmol)溶于MeOH(5mL)溶液中，然后加入二甲胺(0.5mL)。将混合物在65℃下搅拌反应6小时。反应完成后，将反应混合液中的有机溶剂减压蒸发。所得粗产物通过硅胶色谱法(乙酸乙酯/石油醚＝1/1)纯化，获得化合物8，为浅黄色固体(58.8mg，92％)。1H NMR(400MHz,CDCl3)δ8.32(d,J＝7.7Hz,1H),7.48–7.43(m,1H),7.41–7.36(m,2H),7.27–7.23(m,1H),7.04(d,J＝8.0Hz,1H),6.70(d,J＝7.8Hz,1H),4.35–4.19(m,3H),3.84(s,3H),2.79–2.58(m,2H),2.40(s,6H).13C NMR(100MHz,CDCl3)δ155.27,142.61,140.35,126.56,124.88,123.01,122.13,119.20,112.04,108.03,101.87,100.98,70.42,66.42,62.58,45.71(2×CH3),29.38.HRMS(ESI+):calculated for C18H23N2O2[M+H]+299.1760,found 299.1746。
化合物9的合成
Figure BDA0002351153870000121
按照化合物8的合成方法，以3(37.6mg，0.13mmol)和二甲胺(0.5mL)为起始原料，制得化合物9为浅黄色固体(38.9mg，89％)。1H NMR(400MHz,CDCl3)δ8.34–8.31(m,1H),7.47–7.35(m,3H),7.26–7.22(m,1H),7.05(d,J＝7.9Hz,1H),6.69(d,J＝7.9Hz,1H),4.34–4.21(m,5H),2.77–2.58(m,2H),2.39(s,6H),1.97–1.85(m,2H),0.97(t,J＝7.4Hz,3H).13CNMR(100MHz,CDCl3)δ155.41,142.13,139.86,126.42,124.76,123.12,122.20,119.08,112.10,108.30,102.14,100.79,70.49,66.52,62.56,45.80(2×CH3),44.88,22.41,11.85.HRMS(ESI+):calculated for C20H27N2O2[M+H]+327.2073,found 327.2069。
化合物10的合成
Figure BDA0002351153870000122
按照化合物8的合成方法，以4(65.7mg，0.21mmol)和二甲胺(0.5mL)为起始原料，制得化合物10为浅黄色固体(60.7mg，81％)。1H NMR(400MHz,CDCl3)δ8.32(d,J＝7.8Hz,1H),7.46–7.34(m,3H),7.26–7.21(m,1H),7.04(d,J＝8.2Hz,1H),6.69(d,J＝8.0Hz,1H),4.35–4.20(m,5H),2.79–2.58(m,2H),2.40(s,6H),1.91–1.81(m,2H),1.39–1.33(m,4H),0.88(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ155.41,142.06,139.79,126.42,124.76,123.12,122.20,119.06,112.10,108.25,102.09,100.77,70.48,66.50,62.55,45.79(2×CH3),43.32,29.46,28.78,22.56,14.03.HRMS(ESI+):calculated for C22H31N2O2[M+H]+355.2386,found355.2373。
化合物11的合成
Figure BDA0002351153870000123
按照化合物8的合成方法，以5(61.9mg，0.18mmol)和二甲胺(0.5mL)为起始原料，制得化合物11为浅黄色固体(65.3mg，93％)。1H NMR(400MHz,CDCl3)δ8.33–8.28(m,1H),7.45–7.33(m,3H),7.25–7.20(m,1H),7.02(d,J＝7.9Hz,1H),6.67(d,J＝7.7Hz,1H),4.34–4.20(m,5H),2.77–2.57(m,2H),2.38(s,6H),1.91–1.78(m,2H),1.35–1.21(m,8H),0.85(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ155.41,142.05,139.78,126.42,124.75,123.12,122.20,119.06,112.09,108.25,102.10,100.76,70.48,66.53,62.55,45.81(2×CH3),43.35,31.80,29.16,29.09,27.32,22.67,14.13.HRMS(ESI+):calculated for C24H35N2O2[M+H]+383.2699,found 383.2689。
化合物12的合成
Figure BDA0002351153870000131
按照化合物8的合成方法，以6(53.7mg，0.18mmol)和二甲胺(0.5mL)为起始原料，制得化合物12为浅黄色固体(53.4mg，88％)。1H NMR(400MHz,CDCl3)δ8.32(d,J＝7.7Hz,1H),7.46–7.34(m,3H),7.26–7.21(m,1H),7.04(d,J＝8.2Hz,1H),6.69(d,J＝8.0Hz,1H),4.37–4.20(m,5H),2.79–2.58(m,2H),2.39(s,6H),1.92–1.76(m,2H),1.39–1.23(m,12H),0.87(t,J＝6.9Hz,3H).13C NMR(100MHz,CDCl3)δ155.41,142.05,139.78,126.41,124.75,123.12,122.20,119.05,112.10,108.25,102.10,100.76,70.48,66.51,62.54,45.80(2×CH3),43.34,31.89,29.54,29.49,29.31,29.06,27.35,22.70,14.16.HRMS(ESI+):calculated for C26H39N2O2[M+H]+411.3012,found 411.3003。
化合物13的合成
Figure BDA0002351153870000132
按照化合物8的合成方法，以7(41.5mg，0.14mmol)和二甲胺(0.5mL)为起始原料，制得化合物13为白色固体(38.6mg，81％)。1H NMR(400MHz,CD3OD)δ8.35–8.31(m,1H),7.38(d,J＝0.9Hz,1H),7.37–7.36(m,1H),7.33(t,J＝8.1Hz,1H),7.20–7.13(m,1H),7.03(d,J＝8.2Hz,1H),6.71(d,J＝7.9Hz,1H),5.25–5.18(m,1H),4.88(d,J＝6.5Hz,2H),4.32–4.25(m,1H),4.21–4.17(m,2H),2.78–2.59(m,2H),2.35(s,6H),1.91(s,3H),1.71–1.68(m,3H).13C NMR(100MHz,)δ156.58,143.09,140.84,136.14,127.47,125.69,124.14,123.46,121.16,119.90,113.24,109.41,103.27,101.88,71.72,68.68,63.55,46.11(2×CH3),41.90,25.71,18.19.HRMS(ESI+):calculated for C22H29N2O2[M+H]+353.2229,found353.2227。
化合物14的合成
Figure BDA0002351153870000141
按照化合物8的合成方法，以7(100mg，0.32mmol)和二乙胺(0.5mL)为起始原料，制得化合物14为白色固体(97.3mg，79％)。1H NMR(400MHz,CD3OD)δ8.35(d,J＝7.7Hz,1H),7.43–7.38(m,2H),7.36(t,J＝7.8Hz,1H),7.18(t,J＝6.5Hz,1H),7.06(d,J＝8.2Hz,1H),6.74(d,J＝8.0Hz,1H),5.24(t,J＝6.2Hz,1H),4.91(d,J＝6.6Hz,2H),4.35–4.27(m,1H),4.25(d,J＝4.7Hz,2H),3.06–2.73(m,6H),1.93(s,3H),1.72(s,3H),1.15(t,J＝7.2Hz,6H).13C NMR(100MHz,CD3OD)δ156.57,143.14,140.88,136.25,127.51,125.72,124.13,123.45,121.17,119.88,113.24,109.44,103.30,101.85,71.48,71.46,68.45,56.88,41.97(2×CH2),25.73,18.21,11.32(2×CH3).HRMS(ESI+):calculated for C24H33N2O2[M+H]+381.2542,found 381.2537。
化合物15的合成
Figure BDA0002351153870000142
按照化合物8的合成方法，以7(80.39mg，0.26mmol)和二丙胺(0.5mL)为起始原料，制得化合物15为白色固体(80.6mg，75％)。1H NMR(400MHz,CD3OD)δ8.34(d,J＝7.8Hz,1H),7.39–7.29(m,3H),7.18–7.12(m,1H),7.06–6.98(m,1H),6.75–6.64(m,1H),5.25–5.17(m,1H),4.92–4.86(m,2H),4.29–4.15(m,3H),2.91–2.65(m,2H),2.54–2.44(m,4H),1.93–1.87(m,3H),1.69(s,3H),1.54–1.45(m,4H),0.88–0.83(m,6H).13C NMR(100MHz,CD3OD)δ156.73,143.12,140.86,136.13,127.46,125.65,124.22,123.53,121.21,119.84,113.30,109.37,103.15,101.83,71.37,69.13,58.42,58.08(2×CH2),41.94,25.72,21.14(2×CH2),18.20,12.18(2×CH3).HRMS(ESI+):calculated for C26H37N2O2[M+H]+409.2855,found 409.2851。
化合物16的合成
Figure BDA0002351153870000143
按照化合物8的合成方法，以7(80.35mg，0.26mmol)和二丁胺(0.5mL)为起始原料，制得化合物16为白色固体(81.4mg，71％)。1H NMR(400MHz,CD3OD)δ8.38–8.31(m,1H),7.39–7.36(m,2H),7.33(t,J＝8.1Hz,1H),7.19–7.11(m,1H),7.03(d,J＝8.2Hz,1H),6.71(d,J＝8.0Hz,1H),5.25–5.17(m,1H),4.89(d,J＝6.4Hz,2H),4.29–4.22(m,2H),4.22–4.15(m,1H),2.94–2.65(m,2H),2.55–2.48(m,4H),1.91(s,3H),1.70(s,3H),1.48–1.40(m,4H),1.29–1.21(m,4H),0.83(t,J＝7.3Hz,6H).13C NMR(100MHz,CD3OD)δ156.73,143.14,140.88,136.12,127.47,125.64,124.22,123.56,121.23,119.86,113.33,109.38,103.14,101.82,71.22,69.14,58.31,55.92(2×CH2),41.95,30.28(2×CH2),25.73,21.68(2×CH2),18.21,14.34(2×CH3).HRMS(ESI+):calculated for C28H41N2O2[M+H]+437.3168,found 437.3164。
化合物17的合成
Figure BDA0002351153870000151
按照化合物8的合成方法，以7(41.5mg,0.14mmol)和四氢吡咯(0.5mL)为起始原料，制得化合物17为白色固体(49.3mg，84％)。1H NMR(400MHz,CD3OD)δ8.31(d,J＝7.8Hz,1H),7.41–7.37(m,2H),7.34(t,J＝8.1Hz,1H),7.23–7.15(m,1H),7.05(d,J＝8.1Hz,1H),6.71(d,J＝7.8Hz,1H),5.25–5.16(m,1H),4.47–4.37(m,1H),4.30–4.17(m,2H),3.30–3.25(m,2H),3.24–3.16(m,4H),2.03–1.97(m,4H),1.90(s,3H),1.69(s,3H).13C NMR(100MHz,CD3OD)δ156.37,143.21,140.97,136.37,127.58,125.89,124.15,123.39,121.13,120.08,113.30,109.59,103.64,102.07,71.37,67.70,59.50,55.69(2×CH2),42.02,25.77,24.03(2×CH2),18.26.HRMS(ESI+):calculated for C24H31N2O2[M+H]+379.2386,found379.2382。
化合物18的合成
Figure BDA0002351153870000152
按照化合物8的合成方法，以7(57.2mg，0.19mmol)和哌啶(0.5mL)为起始原料，制得化合物18为白色固体(61.8mg，76％)。1H NMR(400MHz,CDCl3)δ8.32(d,J＝7.7Hz,1H),7.45–7.40(m,1H),7.38(d,J＝3.8Hz,1H),7.36–7.34(m,1H),7.26–7.21(m,1H),7.02(d,J＝8.1Hz,1H),6.69(d,J＝7.9Hz,1H),5.30–5.23(m,1H),4.88(d,J＝6.4Hz,2H),4.35–4.26(m,2H),4.25–4.17(m,1H),2.73–2.63(m,4H),2.50–2.39(m,2H),1.94–1.90(m,3H),1.72–1.69(m,3H),1.68–1.59(m,4H),1.53–1.45(m,2H).13C NMR(100MHz,CDCl3)δ155.49,141.90,139.64,135.11,126.43,124.75,123.20,122.38,120.10,119.15,112.26,108.32,102.11,100.89,70.63,65.69,61.87,54.96,41.37(2×CH2),26.23(2×CH2),25.67,24.35,18.29.HRMS(ESI+):calculated for C25H33N2O2[M+H]+393.2542,found 393.2537。
化合物19的合成
Figure BDA0002351153870000161
按照化合物8的合成方法，以7(51mg，0.17mmol)和N-甲基哌嗪(0.5mL)为起始原料，制得化合物19为黄色油状物(46.5mg，64％)。1H NMR(400MHz,CD3OD)δ8.32(d,J＝7.7Hz,1H),7.38–7.35(m,2H),7.32(t,J＝8.1Hz,1H),7.21–7.12(m,1H),7.02(d,J＝8.2Hz,1H),6.69(d,J＝8.0Hz,1H),5.19(t,J＝6.5Hz,1H),4.85(d,J＝6.6Hz,2H),4.31–4.24(m,1H),4.21(d,J＝4.9Hz,2H),2.97–2.69(m,10H),2.55(s,3H),1.89(s,3H),1.68(s,3H).13C NMR(100MHz,CD3OD)δ156.62,143.13,140.88,136.26,127.53,125.75,124.11,123.44,121.13,119.95,113.25,109.48,103.31,101.95,71.50,68.45,61.64,54.95(2×CH2),52.85(2×CH2),44.46,41.95,25.73,18.21.HRMS(ESI+):calculated for C25H34N3O2[M+H]+408.2651,found 408.2648。
化合物20的合成
Figure BDA0002351153870000162
按照化合物8的合成方法，以7(53.6mg，0.17mmol)和二乙醇胺(0.5mL)为起始原料，制得化合物20为白色固体(64.8mg，87％)。1H NMR(400MHz,CDCl3)δ8.28(d,J＝7.7Hz,1H),7.43–7.37(m,1H),7.33(t,J＝8.0Hz,2H),7.24–7.19(m,1H),6.99(d,J＝8.1Hz,1H),6.61(d,J＝7.9Hz,1H),5.28–5.22(m,1H),4.84(d,J＝6.4Hz,2H),4.38–4.29(m,1H),4.25–4.15(m,2H),3.83–3.74(m,2H),3.67–3.60(m,2H),2.92–2.76(m,4H),2.62–2.54(m,2H),1.91(s,3H),1.72–1.67(m,3H).13C NMR(100MHz,CDCl3)δ155.23,141.85,139.59,135.12,126.47,124.81,123.11,122.24,120.05,119.14,112.09,108.37,102.17,100.83,70.04,67.62,59.52,58.71,57.44,50.81,41.32(2×CH2),25.65,18.26.HRMS(ESI+):calculatedfor C24H33N2O4[M+H]+367.2368,found 367.2381。
化合物21的合成
Figure BDA0002351153870000171
按照化合物8的合成方法，以7(62.5mg，0.20mmol)和硫代吗啉(0.5mL)为起始原料，制得化合物21为白色固体(80.5mg，91％)。1H NMR(400MHz,CDCl3)δ8.31–8.24(m,1H),7.44–7.39(m,1H),7.38–7.32(m,2H),7.24–7.20(m,1H),7.01(d,J＝8.2Hz,1H),6.67(d,J＝8.0Hz,1H),5.28–5.22(m,1H),4.87(d,J＝6.4Hz,2H),4.33–4.25(m,2H),4.24–4.17(m,1H),3.03–2.94(m,2H),2.82–2.73(m,4H),2.73–2.63(m,4H),1.91(s,3H),1.69(s,3H).13CNMR(100MHz,CDCl3)δ155.32,141.91,139.65,135.19,126.44,124.83,123.05,122.28,120.03,119.18,112.22,108.42,102.27,100.88,70.31,65.82,61.88,55.54(2×CH2),41.39,28.12(2×CH2),25.67,18.29.HRMS(ESI+):calculated for C24H31N2O2S[M+H]+411.2106,found 411.2102。
化合物22的合成
Figure BDA0002351153870000172
按照化合物8的合成方法，以7(50mg，0.17mmol)和乙胺(0.5mL)为起始原料，制得化合物22为白色固体(38.8mg，68％)。1H NMR(400MHz,CD3OD)δ8.30(d,J＝7.7Hz,1H),7.42–7.38(m,2H),7.35(t,J＝8.1Hz,1H),7.22–7.16(m,1H),7.07(d,J＝8.2Hz,1H),6.74(d,J＝8.0Hz,1H),5.27–5.16(m,1H),4.94–4.91(m,2H),4.51–4.18(m,3H),3.43–3.35(m,1H),3.30–3.23(m,1H),3.14(q,J＝7.0Hz,2H),1.92(s,3H),1.70(s,3H),1.34(t,J＝7.2Hz,3H).13C NMR(100MHz,CD3OD)δ156.17,143.15,140.91,136.32,127.52,125.85,124.00,123.28,121.06,120.03,113.19,109.56,103.66,101.97,70.90,66.90,51.16,44.19,41.95,25.72,18.21,11.42.HRMS(ESI+):calculated for C22H29N2O2[M+H]+353.2229,found 353.2224。
化合物23的合成
Figure BDA0002351153870000173
按照化合物8的合成方法，以7(50mg，0.16mmol)和正丙胺(0.5mL)为起始原料，制得化合物23为白色固体(40.5mg，68％)。1H NMR(400MHz,CD3OD)δ8.29(d,J＝7.6Hz,1H),7.44–7.32(m,3H),7.23–7.14(m,1H),7.08(d,J＝8.2Hz,1H),6.74(d,J＝8.0Hz,1H),5.27–5.16(m,1H),4.98–4.90(m,2H),4.53–4.17(m,3H),3.43–3.34(m,1H),3.29–3.22(m,1H),3.08–2.94(m,2H),1.92(s,3H),1.80–1.65(m,5H),1.02(t,J＝7.1Hz,3H).13C NMR(100MHz,CD3OD)δ156.18,143.19,140.95,136.36,127.52,125.87,123.98,123.29,121.08,120.02,113.23,109.58,103.69,101.99,70.95,66.92,51.57,50.69,41.99,25.72,20.59,18.21,11.24.HRMS(ESI+):calculated for C23H31N2O2[M+H]+367.2386,found 367.2380。
化合物24的合成
Figure BDA0002351153870000181
按照化合物8的合成方法，以7(56.7mg,0.18mmol)和异丙胺(0.5mL)为起始原料，制得化合物24为白色固体(58.2mg，87％)。1H NMR(400MHz,CDCl3)δ8.31(d,J＝7.8Hz,1H),7.46–7.40(m,1H),7.39–7.34(m,2H),7.26–7.21(m,1H),7.02(d,J＝8.2Hz,1H),6.68(d,J＝8.0Hz,1H),5.30–5.24(m,1H),4.88(d,J＝6.4Hz,2H),4.34–4.20(m,3H),3.10–3.04(m,1H),2.97–2.86(m,2H),2.63(br,2H),1.92(s,3H),1.71(s,3H),1.15–1.11(m,6H).13C NMR(100MHz,CDCl3)δ155.30,141.90,139.63,135.17,126.45,124.82,123.08,122.27,120.04,119.19,112.20,108.39,102.25,100.92,70.55,68.63,49.61,49.13,41.38,25.65,23.09,22.92,18.28.HRMS(ESI+):calculated for C23H31N2O2[M+H]+367.2368,found 367.2381。
化合物25的合成
Figure BDA0002351153870000182
按照化合物8的合成方法，以7(53.7mg,0.17mmol)和正戊胺(0.5mL)为起始原料，制得化合物25为白色固体(64.6mg,93％)。1H NMR(400MHz,CDCl3)δ8.30(d,J＝7.7Hz,1H),7.45–7.41(m,1H),7.39–7.34(m,2H),7.26–7.21(m,1H),7.02(d,J＝8.2Hz,1H),6.68(d,J＝8.0Hz,1H),5.30–5.23(m,1H),4.88(d,J＝6.3Hz,2H),4.35–4.19(m,3H),3.08–2.90(m,2H),2.75–2.63(m,2H),2.45(br,2H),1.92(s,3H),1.71(s,3H),1.36–1.25(m,6H),0.90(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ155.28,141.90,139.63,135.17,126.45,124.83,123.07,122.26,120.04,119.21,112.19,108.39,102.25,100.92,70.53,68.31,52.19,49.96,41.37,29.64,29.49,25.65,22.64,18.28,14.12.HRMS(ESI+):calculated forC25H35N2O2[M+H]+395.2699,found 395.2698。
化合物26的合成
Figure BDA0002351153870000191
按照化合物8的合成方法，以7(59.2mg，0.19mmol)和正辛胺(0.5mL)为起始原料，制得化合物26为白色固体(77.5mg，92％)。1H NMR(400MHz,CDCl3)δ8.30(d,J＝7.7Hz,1H),7.45–7.33(m,3H),7.24(t,J＝7.4Hz,1H),7.03(d,J＝8.1Hz,1H),6.69(d,J＝7.9Hz,1H),5.31–5.22(m,1H),4.88(d,J＝6.1Hz,2H),4.33–4.19(m,3H),3.07–2.90(m,2H),2.77–2.61(m,2H),2.33(br,2H),1.92(s,3H),1.71(s,3H),1.35–1.23(m,12H),0.91–0.85(m,3H).13CNMR(100MHz,CDCl3)δ155.30,141.90,139.63,135.17,126.44,124.82,123.06,122.26,120.04,119.20,112.19,108.38,102.24,100.92,70.56,68.44,52.21,50.07,41.38,31.92,30.17,29.59,29.35,27.36,25.65,22.74,18.28,14.18.HRMS(ESI+):calculatedfor C28H41N2O2[M+H]+437.3168,found 437.3168。
化合物27的合成
Figure BDA0002351153870000192
按照化合物8的合成方法，以7(50.3mg,0.16mmol)和正壬胺(0.5mL)为起始原料，制得化合物27为白色固体(60.8mg，82％)。1H NMR(400MHz,CDCl3)δ8.29(d,J＝7.8Hz,1H),7.45–7.40(m,1H),7.39–7.33(m,2H),7.25–7.21(m,1H),7.02(d,J＝8.2Hz,1H),6.68(d,J＝8.0Hz,1H),5.30–5.22(m,1H),4.88(d,J＝6.4Hz,2H),4.33–4.20(m,3H),3.07–2.89(m,2H),2.77–2.60(m,2H),1.92(s,3H),1.70(s,3H),1.34–1.23(m,16H),0.88(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ155.31,141.90,139.63,135.16,126.44,124.82,123.06,122.27,120.04,119.20,112.19,108.38,102.24,100.92,70.58,68.50,52.23,50.10,41.38,31.99,30.24,29.71,29.67,29.65,29.42,27.37,25.65,22.77,18.28,14.21.HRMS(ESI+):calculated for C30H45N2O2[M+H]+465.3481,found 465.3471。
化合物28的合成
Figure BDA0002351153870000193
按照化合物8的合成方法，以7(50mg，0.17mmol)和氨水(2mL)为起始原料，制得化合物28为白色固体(26.5mg，50％)。1H NMR(400MHz,(CD3)2SO)δ8.32–8.21(m,1H),7.49(d,J＝7.9Hz,1H),7.43–7.29(m,2H),7.19(t,J＝7.4Hz,1H),7.12(d,J＝8.1Hz,1H),6.75(d,J＝7.9Hz,1H),5.23–5.06(m,1H),4.95(d,J＝6.1Hz,2H),4.22–4.07(m,2H),4.03–3.93(m,1H),2.97–2.72(m,2H),1.90(s,3H),1.66(s,3H).13C NMR(100MHz,(CD3)2SO)δ155.09,141.31,139.08,134.80,126.66,124.69,122.68,121.65,119.96,118.90,111.26,108.78,102.20,100.95,79.24,70.12,70.02,44.63,25.37,18.07.HRMS(ESI+):calculated forC20H25N2O2[M+H]+325.1916,found 325.1911。
化合物29的合成
Figure BDA0002351153870000201
将化合物28(200mg，0.62mmol)溶于DMF(15mL)溶液中，然后加入1H-吡唑-1-甲脒盐酸盐(225.90mg，1.54mmol)和N,N-二异丙基乙胺(254.72μL，1.54mmol)。将混合物在室温搅拌过夜。反应完成后，将混合物用1-丁醇稀释和用水萃取三次。合并有机层，并在真空条件下浓缩。所得粗产物通过HPLC纯化，获得化合物29，为白色固体(116.5mg，52％)。1H NMR(400MHz,CD3OD)δ8.30(d,J＝7.7Hz,1H),7.42–7.32(m,3H),7.21–7.15(m,1H),7.07(d,J＝8.2Hz,1H),6.74(d,J＝8.0Hz,1H),5.22(t,J＝6.3Hz,1H),4.91(d,J＝6.5Hz,2H),4.38–4.18(m,3H),3.70–3.48(m,2H),1.92(s,3H),1.70(s,3H).13C NMR(100MHz,CD3OD)δ159.78,156.34,143.18,140.92,136.32,127.50,125.80,124.04,123.35,121.11,120.03,113.23,109.50,103.55,101.92,70.43,69.90,46.09,41.99,25.72,18.21.HRMS(ESI+):calculated for C21H27N4O2[M+H]+367.2134,found 367.2133。
化合物30的合成
Figure BDA0002351153870000202
将14(51mg，0.13mmol)溶于MeOH(10mL)溶液中，然后加入碘甲烷(0.5mL)。将混合物在室温搅拌4小时。反应完成后，将反应混合液中的有机溶剂减压蒸发掉。所得粗产物通过HPLC纯化，获得化合物30，为白色固体(48.4mg，69％)。1H NMR(400MHz,CD3OD)δ8.26(d,J＝7.8Hz,1H),7.38–7.29(m,3H),7.20–7.13(m,1H),7.04(t,J＝7.6Hz,1H),6.76–6.68(m,1H),5.18–5.13(m,1H),4.84(d,J＝6.4Hz,2H),4.72–4.62(m,1H),4.33–4.17(m,2H),3.63–3.31(m,6H),3.08(s,3H),1.87(s,3H),1.66(s,3H),1.30(t,J＝7.3Hz,6H).13C NMR(100MHz,CD3OD)δ155.95,143.22,140.95,136.43,127.60,125.98,123.89,123.18,120.99,120.05,113.21,109.71,103.88,102.14,71.33,70.96,65.57,64.25,59.15,58.83,41.99,25.73,18.22,9.05,8.24.HRMS(ESI+):calculated for C25H35IN2O2[M-I]+395.2699,found 395.2695。
化合物31的合成
Figure BDA0002351153870000211
按照化合物30的合成方法，以16(60.0mg，0.14mmol)和碘甲烷(0.5mL)为起始原料，制得化合物31，为白色固体(58.1mg，64％)。1H NMR(400MHz,CD3OD)δ8.23(d,J＝7.8Hz,1H),7.37–7.28(m,3H),7.14(t,J＝6.2Hz,1H),7.01(d,J＝8.2Hz,1H),6.74(t,J＝6.7Hz,1H),5.22–5.08(m,1H),4.81(d,J＝5.1Hz,2H),4.66–4.57(m,1H),4.39–4.11(m,2H),3.65–3.47(m,2H),3.40–3.31(m,2H),3.24(t,J＝7.9Hz,2H),3.12–3.03(m,3H),1.89–1.81(m,3H),1.71–1.50(m,7H),1.30–1.16(m,4H),0.82(t,J＝7.3Hz,6H).13C NMR(100MHz,CD3OD)δ155.70,143.28,141.00,136.44,127.65,126.03,123.86,123.19,120.99,120.13,113.25,109.76,103.92,102.13,70.82,65.16,65.12,64.32,63.91,42.01(2×CH2),25.75,25.23,25.20,20.64,20.61,18.23,13.85,13.83.HRMS(ESI+):calculated for C29H43IN2O2[M-I]+451.3319,found451.3323。
化合物34的合成
Figure BDA0002351153870000212
将化合物28(100mg，0.308mmol)溶于DMF(10mL)中，然后加入Fmoc-Lys(Fmoc)-OH(455.2mg，0.77mmol)，HATU(292.99mg，0.77mmol)和N，N-二异丙基乙胺(254.72μL，1.54mmol)，将混合物在室温搅拌反应过夜。反应完成后，将混合物用乙酸乙酯稀释，并用水萃取三次。有机层进行减压浓缩，即得到粗产物32，其未进一步纯化即用于下一步反应。在室温下将得到的粗产物32添加到20％哌啶/DMF(v/v)溶液(5mL)中，室温搅拌反应30分钟。反应完成后，将混合物用1-丁醇稀释，并用水萃取三次。合并的有机层在减压条件下浓缩。所得粗产物通过HPLC纯化，得到21.1mg化合物34，为白色固体，两步反应总产量为22％。1HNMR(400MHz,CD3OD)δ8.40–8.31(m,1H),7.43–7.33(m,3H),7.20–7.15(m,1H),7.07(d,J＝8.2Hz,1H),6.73(d,J＝7.9Hz,1H),5.27–5.19(m,1H),4.93(d,J＝6.4Hz,2H),4.35–4.18(m,3H),3.84–3.69(m,2H),3.67–3.47(m,1H),2.92–2.80(m,2H),1.94(s,3H),1.89–1.76(m,2H),1.71(s,3H),1.68–1.61(m,2H),1.52–1.42(m,2H).13C NMR(100MHz,CD3OD)δ172.00,156.59,143.15,140.89,136.30,127.50,125.75,124.29,123.42,121.13,120.03,113.26,109.42,103.39,101.85,70.96,69.99,54.54,44.06,41.98,40.20,32.73,28.13,25.74,22.99,18.24.HRMS(ESI+):calculated for C26H37N4O3[M+H]+453.2688,found453.2865。
化合物35的合成
Figure BDA0002351153870000221
将化合物28(100mg，0.308mmol)溶于DMF(10mL)中，然后加入Fmoc-Arg-OH(305.5mg，0.77mmol)，HATU(292.99mg，0.77mmol)和N，N-二异丙基乙胺(254.72μL，1.54mmol)，将混合物在室温搅拌反应过夜。反应完成后，将混合物用乙酸乙酯稀释，并用水萃取三次。有机层进行减压浓缩，即得到粗产物32，其未进一步纯化即用于下一步反应。在室温下将得到的粗产物32添加到20％哌啶/DMF(v/v)溶液(5mL)中，室温搅拌反应30分钟。反应完成后，将混合物用1-丁醇稀释，并用水萃取三次。合并的有机层在减压条件下浓缩。所得粗产物通过HPLC纯化，得到42.8mg化合物35，为白色固体，两步反应总产量为30％。1HNMR(400MHz,CD3OD)δ8.39–8.31(m,1H),7.42–7.31(m,3H),7.20–7.14(m,1H),7.05(d,J＝8.2Hz,1H),6.72(d,J＝7.2Hz,1H),5.21(t,J＝6.4Hz,1H),4.95–4.90(m,2H),4.35–4.19(m,3H),3.93–3.68(m,2H),3.64–3.48(m,1H),3.22–3.11(m,2H),1.97–1.81(m,5H),1.76–1.61(m,5H).13C NMR(100MHz,CD3OD)δ158.79,156.54,143.19,140.93,136.32,127.53,125.78,124.28,124.26,123.46,121.19,120.04,113.29,109.46,103.43,101.87,70.99,69.99,54.31,44.03,42.02,41.77,30.18,25.77,25.44,18.25.HRMS(ESI+):calculatedfor C26H37N6O3[M+H]+481.2927,found 481.2927。
化合物36的合成
Figure BDA0002351153870000222
按照化合物8的合成方法，以7(52.7mg，0.17mmol)和二甲基吡啶胺(0.5mL)为起始原料，制得化合物36，为暗绿色油状物(23.5mg，27％)。1H NMR(400MHz,CDCl3)δ8.58–8.54(m,2H),8.16(d,J＝7.8Hz,1H),7.61–7.54(m,2H),7.42–7.31(m,5H),7.16–7.07(m,3H),6.99(d,J＝8.1Hz,1H),6.65(d,J＝8.0Hz,1H),5.28–5.22(m,1H),4.86(d,J＝6.4Hz,2H),4.43–4.35(m,1H),4.34–4.16(m,2H),4.13–3.96(m,4H),3.27–2.98(m,2H),1.94–1.89(m,3H),1.71–1.67(m,3H).13C NMR(100MHz,CDCl3)δ158.91(2×C),155.43,148.86(2×CH),141.85,139.57,136.93(2×CH),135.08,126.41(2×C),124.62,123.38(2×CH),123.16,122.35(2×CH),120.09,119.10,112.17,108.21,101.97,100.79,70.13,68.03,60.44,58.54,41.35,25.65,18.28.HRMS(ESI+):calculated for C32H35N4O2[M+H]+507.2760,found 507.2761。
对如上化合物进行活性测试：
一、测试方法如下：
抗菌活性(最低抑制浓度)测定
最低抑制浓度(MIC)测定采用微量肉汤二倍稀释法，参照美国临床和实验室标准协会(CLSI)标准。将样品首先溶解于DMSO/H2O中以制备1000μg/mL的样品储备液(DMSO的最终浓度≤2.5％)。将储备液用Muller Hinton Broth(MHB)培养基连续稀释。将细菌在MHA平板上于37°孵育24小时，然后将细菌浓度调节至约106CFU/mL。将细菌悬浮液(100μL)与样品的两倍系列稀释液(100μL)在96孔板中混合(最终样品浓度为50、25、12.5、6.25、3.125、1.56、0.78、0.39μg/mL)。在37℃下孵育24小时后，使用酶标仪读取混合物在600nm处的吸收波长。未见细菌明显增长的最低化合物浓度即为MIC值。
溶血活性测定
将兔红细胞(RBCs)以2500rpm离心3分钟，并用PBS洗涤两次，然后将其重悬于PBS中制成8％v/v RBCs悬浮液。将RBCs悬浮液(100μL)与等体积的化合物的两倍系列稀释液(100μL)于37℃孵育1小时。随后将混合物以2500rpm离心5分钟，然后将上清液(100μL)转移到96孔板中，使用酶标仪读取其在576nm处的吸光度。2％Triton X-100溶液处理组用作阳性对照，0.5％DMSO处理组用作阴性对照。溶血活性通过以下公式计算：溶血活性％＝[(Abs样品–Abs阳性对照)/(Abs阳性对照–Abs阴性对照)]×100％。
诱导细菌耐药性试验
根据上述MIC测定方法获得化合物对金黄色葡萄球菌ATCC29213的初始MIC。然后使用来自0.5×MIC的孔中的细菌来制备细菌悬浮液，以用于下一次MIC值测定。该实验每天重复进行，持续21天。
体内抗菌活性测定
所有动物实验均经华南农业大学实验动物中心批准，并按照卫生部的政策进行。在这项研究中使用了雌性小鼠(6-8周，平均体重20克)。在感染前5天，对小鼠进行腹膜注射环磷酰胺(100mg/kg)3次，以制备小鼠免疫抑制模型。将小鼠麻醉后，利用无菌针头对小鼠右眼角膜进行划痕。然后将15μL细菌(金黄色葡萄球菌ATCC29213)滴到受伤的角膜上。将这些小鼠随机分为3组(n＝5)。感染后一天开始治疗。每两小时滴药一次，一天四次，持续给药三天。给药第三天后，处死小鼠，摘取眼球。通过标准平板(MHA板)计数法对角膜上的活菌数进行计数。
二、测试结果
2.1体外抗菌和溶血活性的结果如表1和2所示。
表1咔唑衍生物1-35对革兰氏阳性菌的抗菌活性和对兔红细胞的溶血活性
Figure BDA0002351153870000231
Figure BDA0002351153870000241
表2咔唑衍生物36和锌离子(6.25μg/mL)联用对革兰氏阴性菌和阳性菌的抗菌活性
Figure BDA0002351153870000242
其中化合物29和36对革兰氏阳性菌的MIC值为0.78-3.125μg/mL，均展示出非常优异的抗菌活性，而且化合物36和6.25μg/mL的锌离子联用时也对革兰氏阴性菌表现出十分优异的抗菌活性，MIC值为3.13μg/mL。而且这两个化合物都对兔红细胞表现非常低的溶血毒性。
2.2诱导细菌耐药性试验研究结果
膜活性抗菌药物的最大优势是它们诱导产生耐药性的概率非常低。为了评估化合物29诱导细菌耐药性发展的倾向，本发明对化合物29进行了耐药性发展的实验室模拟研究。如图1所示，化合物29的MIC值在21天的测试时间内是恒定不变的，这表明化合物29可以有效避免金黄色葡萄球菌耐药性的产生。相反，诺氟沙星经过10次传代后，其MIC增长了128倍，这表明诺氟沙星极易诱导细菌耐药性的产生。这结果表明化合物29可有效减缓甚至克服细菌耐药性的产生。
2.3动物体内抗菌功效评估结果
通过局部给药方式评价化合物29在金黄色葡萄球菌ATCC29213诱导的小鼠角膜感染模型中的体内功效。在小鼠角膜感染金黄色葡萄球菌ATCC29213后24小时，每组小鼠(n＝5)每天分别使用0.5％的化合物29、5％的万古霉素(用作阳性对照)或5％的葡萄糖(用作阴性对照)进行局部给药治疗，一天给药4次，连续给药三天。如图2所示，化合物29(0.5％)和万古霉素(5％)分别能够使细菌菌落总数降低了4.17和3.99log，化合物29的治疗效果与万古霉素(5％)的相当。这些结果表明化合物29在动物体内仍保持了优异的抗菌活性，可有效治愈由革兰氏阳性菌(金黄色葡萄球菌ATCC29213)诱发的小鼠角膜感染。
综上可知，经过一系列结构优化，本发明获得了一些高效低毒的抗菌候选化合物。其中化合物29对革兰氏阳性菌表现出优异的抗菌活性(MIC＝0.78-1.56μg/mL)，对哺乳动物细胞的毒性比较低，且具备非常低的溶血活性(HC50>200μg/mL)。化合物29能够破坏细菌细胞膜，导致细菌死亡，其具备快速的杀菌性能，且能够在实验室耐药性模拟研究中有效克服细菌耐药性的产生。更重要的是，化合物29在金黄色葡萄球菌ATCC29213导致的小鼠细菌性角膜炎模型中也显示出优异的体内抗菌活性。
另外，化合物36对革兰氏阳性菌表现出优异的抗菌活性和非常低的溶血毒性。与单独应用相比，化合物36和6.25μg/mL的锌离子联用时对革兰氏阳性菌的MIC值降低了一倍，对革兰氏阴性菌的抗菌活性则大大增强，MIC值由>50μg/mL降低为3.125μg/mL。该结果表明化合物36和锌离子联用时表现出优异且广谱的抗菌活性。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

1.具有如下结构通式的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子：
Figure FDA0002351153860000011
其中，R1选自：至少一个Ra取代或未取代的C1-C10直链或支链烷基、至少一个Ra取代或未取代的C3-C8直链或支链烯基；
Ra分别独立地选自：H、卤素；
R2为阳离子基团，选自：至少一个Rb取代或未取代的C2-C5环烷氧基、至少一个Rb取代或未取代的C1-C5烷基胺；
Rb分别独立地选自：H、OH、羰基、C1-C15直链或支链烷基、C1-C15直链或支链烷基醇、C1-C15直链或支链烷基巯基、C1-C10烷基胺、C5-C10含氮杂芳基、C1-C5氨基亚胺烷基或前述基团的组合，当每两个前述基团连接在同一碳原子上时，互相连接成环或不连接成环。
2.根据权利要求1所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，其特征在于，R2选自：C2-C5环烷氧基或如下所示结构通式的基团：
Figure FDA0002351153860000012
其中m+n＝1～5。
3.根据权利要求1或2所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，其特征在于，Rb分别独立地选自：H、OH、羰基、C1-C10直链或支链烷基、C1-C5直链或支链烷基醇、C1-C5直链或支链烷基巯基、C2-C6烷基胺、C5-C8含氮杂芳基、C1-C2氨基亚胺烷基或前述基团的组合，当每两个前述基团连接在同一碳原子上时，互相连接成环或不连接成环。
4.根据权利要求3所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，其特征在于，所述C5-C8含氮杂芳基的结构如下：
Figure FDA0002351153860000013
其中，所述w＝0、1、2或3，V每次出现时独立地为C或N。
5.根据权利要求4所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，其特征在于，所述C5-C8含氮杂芳基的结构如下：
Figure FDA0002351153860000014
其中，所述w＝0、1、2或3，V每次出现时独立地为C或N。
6.根据权利要求1或2所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，其特征在于，R1选自：至少一个Ra取代或未取代的C1-C10直链烷基、至少一个Ra取代或未取代的C3-C6支链烯基。
7.根据权利要求1所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，其特征在于，选自如下化合物：
Figure FDA0002351153860000021
Figure FDA0002351153860000031
Figure FDA0002351153860000041
Figure FDA0002351153860000051
8.权利要求1-7任一项所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子的制备方法，其特征在于，采用如下合成路线(I)-(III)之一进行制备：
合成路线(I)：
Figure FDA0002351153860000052
合成路线(II)：
Figure FDA0002351153860000053
合成路线(III)：
Figure FDA0002351153860000054
其中原料采用合成路线(II)进行制备。
9.权利要求1-7任一项所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子在制备具有抗菌功效的药物中的应用。
10.权利要求1-7任一项所述的咔唑类化合物或者其药学上可接受的盐或者其立体异构体或者其溶剂化物或者其前药分子，以及锌离子的组合物在制备具有抗菌功效的药物中的应用。
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