CN109336854B - 一种6-取代平板霉素衍生物、制备方法、药物制剂及用途 - Google Patents

一种6-取代平板霉素衍生物、制备方法、药物制剂及用途 Download PDF

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CN109336854B
CN109336854B CN201811351777.7A CN201811351777A CN109336854B CN 109336854 B CN109336854 B CN 109336854B CN 201811351777 A CN201811351777 A CN 201811351777A CN 109336854 B CN109336854 B CN 109336854B
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段燕文
沈奔
黄勇
邓友超
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Abstract

本发明公开了一种6‑取代平板霉素衍生物，所述6‑取代平板霉素衍生物化学结构式如式Ⅰ所示：

Description

一种6-取代平板霉素衍生物、制备方法、药物制剂及用途
技术领域
本发明属于医药化工领域，具体涉及一种6-取代平板霉素衍生物、制备方法、药物制剂及用途。
背景技术
平板霉素(platensimycin)最早是由默克公司于2006年从南非土壤样本中分离获得的平板链球菌产生的代谢产物，它是革兰阳性菌敏感的广谱、强效抗生素，对耐甲氧西林金葡菌(MRsA)和耐万古霉素肠球菌等有效，且未见与其他抗生素交叉耐药。
脂肪酸生物合成酶对病原菌的存活至关重要，平板霉素主要作用位点为脂肪酸缩合酶(β酮脂酰-ACP-合成酶，KAS)，也就是FabF。FabF是细菌脂肪酸生物合成的关键酶，也是新型抗菌药物的靶标。实验证实，平板霉素通过选择性抑制FabF，从而实现抗菌活性。
Figure BDA0001865050770000011
平板霉素体外活性较强，但体内活性却有局限。以感染金葡菌的小鼠为模型，对其持续输入平板霉素可有效治疗金葡菌感染，而口服或皮下注射平板霉素治疗效果较差。这表明其体内清除率高，药效学性能不理想，所以通过化学修饰有望获得药效学特性优良的新药。
截止目前，对平板霉素进行化学修饰的工作已有一些报道。对平板霉素芳香环结构的改造，得到的类似物都失去了抑菌活性，表明其芳香环结构是严格的保守区。而对平板霉素酮内酯结构的改造，多数表现出了较强的抑菌活性，表明其酮内酯结构具有一定的结构容忍性。
发明内容
本发明通过深入的研究和创造性的劳动，得到了一系列结构新颖的6-取代平板霉素衍生物(式I化合物)，这不仅是平板霉素笼状结构6位修饰工作的首次公开，而且本发明提供的合成方法可以非常经济高效地获得大量结构多样的平板霉素类似物。更重要的是，部分化合物在体外及体内抗菌活性方面，与平板霉素相比，有非常明显的提高，且对正常细胞没有明显毒性，具有很好的成药性。由此提供了一种6-取代平板霉素衍生物、制备方法、药物制剂及用途：
一种6-取代平板霉素衍生物：
Figure BDA0001865050770000021
其中R基团选自于：
A)烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，酰基或取代酰基，环丙基或取代环丙基，杂环烷基或取代杂环烷基：其中的取代基选自羟基，磺酰基，羰基，氨基，氰基，卤素，烷氧基，芳基或杂环芳基；
B)芳基或取代芳基，杂环芳基或取代杂环芳基：基中的取代基选自羟基，氨基，氰基，卤素，磺酰基，羰基，硝基，烷基，烷氧基，环烷基或杂环烷基。
C)烷胺基，芳胺基，醇，酚，硫醇或硫酚：基中的取代基选自羟基，氨基，氰基，卤素，磺酰基，羰基，硝基，烷基，烷氧基，环烷基或杂环烷基。
所述6-取代平板霉素衍生物具体为如下化合物(表1)：
表1：
Figure BDA0001865050770000022
Figure BDA0001865050770000031
Figure BDA0001865050770000041
上述6-取代平板霉素衍生物的制备方法如下：
Figure BDA0001865050770000042
对于上述方法中各符号的含义独立地如前面任一项所述
对于该方法，平板霉素在硫酸作用下发生水解，得到中间体1，中间体1与碘反应得到中间体2，中间体2再发生缩合反应得到中间体3，中间体3最后通过偶联反应得到终产物。或者平板霉素与双氧水反应得到中间体4，中间体4再与亲核性反应物脱水得到终产物。该方法涉及的所有反应，其反应温度可以是0-120℃,反应溶剂可以是含羟基、羧基、活泼氢的质子性有机溶剂，催化剂可以是无机酸、有机酸、无机碱、有机碱、金属催化剂。必要时，反应后处理试剂可以是含无机酸、有机酸、无机碱、有机碱的水溶液。
本发明还提供了一种药物制剂，所述药物制剂中包含上述6-取代平板霉素衍生物，以及任选的药学上可接受的辅料。
本发明所涉及的一系列化合物在弱酸性、弱碱性水溶液中均将具有极好的溶解性，方便制备成为多种剂型。当口服用药时，本发明化合物可制成任意口服可接受的制剂形式包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镜。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。必要时，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
本发明化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化铀溶液。
本发明的化合物或者本发明的药物制剂的给药剂量取决于许多因素，例如所要治疗或辅助治疗的疾病的性质和严重程度，患者或动物的性别、年龄、体重及个体反应，所用的具体化合物，给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个，例如二、三、四个剂量形式给药。
本发明的再一方面涉及本发明中任一项所述的化合物在制备抑菌药物、杀菌药物、抑制脂肪酸合成通路的药物、抗肿瘤药物、促进肿瘤细胞凋亡的药物、治疗糖尿病的药物、降血脂药物或减肥药物中的用途；具体地，所述抑菌及杀菌药物指治疗和/或预防和/或辅助治疗由所有革兰氏阳性菌、结核分枝杆菌引起的表皮、粘膜、血液、内脏感染；所述抗肿瘤药物为治疗和/或预防和/或辅助治疗肾癌、淋巴瘤、肺癌、肝癌、乳腺癌、神经内分泌癌或胃癌的药物。
在本发明中
术语‘C1-C6烷基’是指具有1-6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊丁基、2-戊基、异戊基、新戊基、已基、2-已基、3-已基等；C1-C4烷基、C1-C3烷基或C11C2烷基也可做类似理解。具体的烷基是C1-C4烷基、C1-C3烷基或C1-C2烷基。
术语‘C1-C6烷氧基’是指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基等；C1-C4烷氧基、C1-C3烷氧基或C1-C2烷氧基也可做类似理解。具体的烷氧基是C1-C4烷氧基、C1-C3烷氧基或C1-C2烷氧基。
术语‘C1-C6烷硫基’可与术语‘C1-C6烷氧基’做类似理解，不同之处在于将氧原子替换为硫原子。
术语‘C3-C10环烷基’是指具有3-10个碳原子饱和碳环基团。该环烷基可以是单环或者多环稠合系统，而且可以稠合在芳环上。这些基团的实例包括环丙基、环丁基、环戊基和环已基。本文的环烷基可以是未取代的或者如详细说明，在一个或多个可取代的位置被各种基团取代。例如，这些环烷基可任选被以下基团取代：C1-C6烷基、C1-C6烷氧基、腈基、卤素、羟基、氨基、硝基、单(C1-C6)烷基氨基、(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基。C3-C6环烷基也可做类似理解。
术语‘C3-C10环烷氧基’是指具有3-10个碳原子的饱和碳环烷氧基基团。该环烷氧基可以是单环或者多环稠合系统，而且可以稠合在芳环上。这些基团的实例包括环丙氧基、环丁氧基、环戊氧基和环己氧基。本文的环烷基可以是未取代的或者如详细说明，在一个或多个可取代的位置被各种基团取代。例如，这些环烷氧基可任选被以下基团取代：C1-C6烷基、C1-C6烷氧基、腈基、卤素、羟基、氨基、硝基、单(C1-C6)烷基氨基、(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基。C3-C6环烷基也可做类似理解。
术语‘C2-C6烯基’是指具有2-6个碳原子以及至少一个双键的烯基，并且包括乙烯基、丙烯基、1-丁-3-烯基、1-戊-3-烯基、1-己-5-烯基等；C3-C5烯基也可做类似理解。优选的是C3-C5烯基。
术语‘C2-C6炔基’是指具有2-6个碳原子以及至少一个炔键的炔基，并且包括乙炔基、丙炔基、丁炔基、戊炔-2-基等；C3-C5炔基也可做类似理解。优选的是C3-C5炔基。
术语‘卤素’是指氟、氯、溴以及碘原子。
术语‘芳香环’或‘芳基’是指具有单环(如苯基)、多环(如联苯基)或其中至少一个环是芳香性的多个稠合环(如1，2，3，4四氢萘基、萘基)的芳族碳环基，其任选被例如卤素、低级烷基、低级烷氧基、三氟甲基、芳基、杂芳基和羟基单、二或三取代。
术语“芳基烷基”是指被一个或多个芳基(如上定义的)取代的烷基(如上定义的)。更优选的芳基烷基是芳基C1-C3烷基。实例包括苄基、苯基乙基等。
术语‘芳香杂环’或‘杂芳基’是指五元、六元或七元环的一个或多个芳族环系，其包括5-10个原子的稠合环系(其中至少一个环是芳香性的)，所述环系含有至少一个和最多四个选自氮、氧或硫的杂原子。杂芳基的实例为吡啶基、咪唑基、嘧啶基、吡唑堕基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯环、喹啉环、异喹啉环、吲哚环、苯并咪唑、苯并呋喃环、苯并噻吩环、苯并噻唑环、哒嗪环等。其任选被例如卤素、低级烷基、低级烷氧基、三氟甲基、芳基、杂芳基和羟基单、二或三取代。
术语‘杂环’或‘杂环基’是指五元、六元或七元环的一个或者多个碳环环系，其包括4-10个原子的稠合环系，所述环系含有至少一个和最多四个选自氮、氧或硫的杂原子，条件是该基团的环不含两个相邻的O或S原子。稠合环系可以是稠合在芳香基团上的杂环。优选的杂环包括但不限于吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、哌啶基、吗啉环、环己环、哌嗪环等，它们可以被以下基团取代：C1-C6烷基、C1-C6烷氧基、腈基、卤素、羟基、氨基、硝基、单(C1-C5)烷基氨基、二(C1-C5)烷基氨基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基。
当用于‘在体内’时，术语‘有效量’是指可在受试者中实现治疗、预阳、减轻和/或缓解本发明所述疾病或病症的剂量。
术语‘疾病和/或病症’是指所述受试者的一种身体状态，该身体状态与本发明所述疾病和/或病症有关。
附图说明
图1为化合物11对金黄色葡萄球菌的体内抗菌活性，万古霉素为阳性对照。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
lH-NMR、C13-NMR光谱由Brucker 500MHz或400MHz型核磁仪测定；质谱由BrukerULTRAFLEXⅢTOF/TOF 200高分辨质谱仪测定。
实施例1:中间体1的制备
将4.41g(10.0mmol)平板霉素溶于50ml的乙醇溶液中，加入980.0mg(10.0mmol)浓硫酸，回流搅拌反应72小时。减压除去溶剂，再加入乙酸乙酯及水进行萃取。萃取液浓缩后用硅胶柱进行分离(石油醚：乙酸乙酯＝10：3)，最后得到化合物1(2.61g，90％)。
实施例2:中间体2的制备
将2.9g(10.0mmol)平板霉素溶于20ml四氯化碳及20ml吡啶的混合溶液中，加入7.6g(30.0mmol)碘，回流搅拌反应12至24小时。反应完成之后，减压除去溶剂，再加入乙酸乙酯、水及硫代硫酸钠进行萃取。萃取液浓缩后用硅胶柱进行分离(石油醚：乙酸乙酯＝10：3)，最后得到中间体2(4.3g，95％)。
HRMS(ESI)m/z calcd for C19H25IO4,[M+H]+445.0798；Found:445.0798.1H NMR(500MHz,Chloroform-d)δ7.28(s,1H),4.32(s,1H),4.05(tdd,J＝9.3,6.3,2.1Hz,2H),2.41–2.33(m,2H),2.32–2.21(m,2H),2.20–2.09(m,1H),2.07–1.97(m,2H),1.94(d,J＝11.6Hz,1H),1.85(dd,J＝11.2,3.5Hz,1H),1.79–1.74(m,1H),1.73–1.67(m,1H),1.59(d,J＝11.0Hz,1H),1.39(s,3H),1.20(s,3H),1.18(dd,J＝7.3,1.4Hz,3H).13C NMR(101MHz,CDCl3)δ196.21,172.94,162.37,102.29,86.73,76.25,60.40,54.55,50.17,47.04,45.88,44.27,42.89,40.39,31.63,29.21,24.58,22.91,14.20.
实施例3:中间体3(化合物1)的制备
将200mg溶于15ml甲醇及7ml水中，加入0.5ml 2M的氢氧化锂溶液，常温搅拌反应2小时。反应结束，加入稀盐酸、乙酸乙酯及水进行萃取。萃取液浓缩后用6ml二氯甲烷及3mlN,N-二甲基甲酰胺溶解，加入三乙胺200μl及PyBOP 234mg，室温下搅拌5分钟，再加入3-胺基-2，4-二羟基苯甲酸82mg,并继续搅拌反应25分钟。反应结束后，加入水、二氯甲烷及稀盐酸进行萃取。萃取液浓缩后用硅胶柱进行分离(石油醚：乙酸乙酯：乙酸＝60：40：0.5)，最后得到中间体3(198mg，80％)。
1H NMR(500MHz,CDCl3)δ11.66(s,1H),11.09(s,1H),8.03(s,1H),7.60(d,J＝8.9Hz,1H),7.35(s,1H),6.50(d,J＝8.9Hz,1H),4.63(s,1H),2.72(ddd,J＝15.7,12.0,4.6Hz,1H),2.60(s,1H),2.54(q,J＝8.7,6.9Hz,2H),2.49–2.42(m,1H),2.17(dd,J＝12.0,4.1Hz,2H),2.07(s,1H),2.05–2.01(m,1H),1.93–1.82(m,2H),1.71(d,J＝11.5Hz,1H),1.53(s,3H),1.33(s,3H)；13C NMR(126MHz,CDCl3)δ196.54,173.14,172.52,162.11,155.00,154.11,128.26,114.21,111.12,103.70,102.07,88.03,76.66,54.37,50.25,47.18,45.74,44.43,42.68,40.18,31.71,31.00,24.55,22.56.
实施例4:中间体4的制备
将1.0g平板霉素溶于36ml二氯甲烷及24ml双氧水(30％)中，加入100μl四丁基氟化铵及1.5ml 2M氢氧化锂溶液，常温下搅拌反应8小时。反应结束后，加入二氯甲烷、水及稀盐酸进行萃取。萃取液浓缩后用硅胶柱进行分离(石油醚：乙酸乙酯：乙酸＝40：60：0.5)，最后得到中间体4(984mg，95％)。
1H NMR(400MHz,Chloroform-d)δ11.83(s,1H),10.94(s,1H),8.08(s,1H),7.62(dd,J＝8.9,2.0Hz,1H),6.50(d,J＝8.9Hz,1H),4.45(s,1H),3.45(d,J＝3.9Hz,1H),3.21(d,J＝3.8Hz,1H),2.56(ddd,J＝23.6,12.7,7.3Hz,2H),2.47(s,1H),2.39(d,J＝6.2Hz,1H),2.28–2.12(m,2H),2.09(s,1H),2.05(d,J＝4.8Hz,3H),1.97(ddd,J＝19.2,11.3,4.5Hz,1H),1.76(dd,J＝12.0,7.2Hz,1H),1.67(d,J＝11.5Hz,1H),1.49(s,3H),1.26(s,3H).13C NMR(101MHz,CDCl3)δ209.88,173.02,172.69,155.01,154.28,128.33,114.16,111.09,104.01,87.58,61.96,55.57,52.16,46.42,44.44,44.41,44.17,40.22,40.13,36.32,31.53,29.69,22.60,21.95.
实施例5:6-炔基平板霉素(化合物2)的制备
将100mg(0.18mmol)化合物1溶于5ml四氢呋喃中，加入19mg Pd(PPh3)2Cl2、11mg碘化亚铜、环丙基乙炔(0.36mmol)及63μl二异丙胺,除空气后，室温下反应1小时。反应结束反，加入乙酸乙酯、水及稀盐酸进行萃取。萃取液浓缩后用硅胶柱进行分离(石油醚：乙酸乙酯：乙酸＝40：60：0.5)，最后得到化合物2(70mg，85％)。
1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.62(d,J＝9.0Hz,1H),6.76(s,1H),6.51(d,J＝8.9Hz,1H),4.60(s,1H),2.64(td,J＝13.7,12.8,4.8Hz,1H),2.58–2.51(m,1H),2.49(d,J＝7.0Hz,2H),2.43(dd,J＝12.7,4.0Hz,1H),2.20–2.11(m,2H),2.07(s,1H),2.03(s,1H),1.95(dd,J＝11.5,3.3Hz,1H),1.92–1.86(m,1H),1.83(dd,J＝12.0,6.8Hz,1H),1.67(d,J＝11.4Hz,1H),1.50(s,3H),1.31(s,3H),0.84(ddt,J＝11.5,5.1,2.7Hz,4H).13C NMR(126MHz,CDCl3)δ200.99,173.48,172.69,156.13,155.06,154.25,128.20,122.49,114.26,111.08,103.78,97.50,87.94,76.51,69.99,54.84,46.64,46.17,45.29,44.66,43.18,40.33,31.48,31.35,24.24,22.72,8.68,8.68.
实施例6:6-苯乙炔基平板霉素(化合物3)的制备
制备方法参见实施实例5。
1H NMR(400MHz,CDCl3)δ11.80(s,1H),11.18(s,1H),8.15(s,1H),7.57(d,J＝8.9Hz,1H),7.54(dd,J＝6.5,3.2Hz,2H),7.35(d,J＝2.1Hz,2H),7.33(d,J＝1.7Hz,1H),6.95(s,1H),6.50(d,J＝9.0Hz,1H),4.66(s,1H),2.75–2.64(m,1H),2.57(dd,J＝10.4,5.0Hz,2H),2.54–2.47(m,1H),2.24–2.15(m,2H),2.14–2.06(m,2H),2.03(dd,J＝11.4,3.4Hz,1H),1.99–1.85(m,2H),1.74(d,J＝11.4Hz,1H),1.54(s,3H),1.38(s,3H).13C NMR(126MHz,CDCl3)δ200.42,176.28,173.37,172.57,156.97,155.06,154.22,131.81,128.70,128.30,128.21,122.42,114.25,111.07,103.74,93.00,88.05,83.53,76.54,54.92,46.76,46.41,45.34,44.73,43.28,40.36,31.43,24.24,22.71,20.62.
实施例7:6-庚炔基平板霉素(化合物4)的制备
制备方法参见实施实例5。
1H NMR(500MHz,CDCl3)δ11.76(s,1H),11.15(s,1H),8.12(s,1H),7.60(d,J＝8.9Hz,1H),6.76(s,1H),6.50(d,J＝8.9Hz,1H),4.61(s,1H),2.69–2.59(m,1H),2.49(d,J＝4.5Hz,2H),2.47–2.42(m,1H),2.38(t,J＝7.3Hz,2H),2.11(s,1H),2.06(s,1H),1.98–1.94(m,1H),1.91(dd,J＝13.4,4.6Hz,1H),1.83(dd,J＝11.9,7.0Hz,1H),1.68(d,J＝11.4Hz,1H),1.61–1.57(m,2H),1.50(s,3H),1.46(s,2H),1.39(d,J＝7.9Hz,2H),1.32(s,3H),1.27(s,2H),0.90(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ200.86,173.46,172.60,156.00,155.02,154.23,128.18,122.64,114.26,111.03,103.79,94.55,87.96,87.04,76.55,74.68,54.85,46.64,46.16,45.33,44.67,43.18,40.33,31.45,31.35,31.16,28.25,24.26,22.72,22.22,19.44,13.99.
实施例8:6-(3-氟苯乙炔基)平板霉素(化合物5)的制备
制备方法参见实施实例5。
1H NMR(500MHz,CDCl3)δ8.14(s,1H),7.58(d,J＝9.0Hz,1H),7.29(d,J＝7.2Hz,2H),7.23(d,J＝9.1Hz,1H),7.05(t,J＝7.0Hz,1H),6.96(s,1H),6.49(d,J＝8.9Hz,1H),4.66(s,1H),2.75–2.64(m,1H),2.55(d,J＝8.5Hz,2H),2.54–2.47(m,1H),2.18(d,J＝11.4Hz,2H),2.10(d,J＝14.0Hz,1H),2.06(s,1H),2.05–1.99(m,1H),1.98–1.86(m,2H),1.74(d,J＝11.3Hz,1H),1.53(s,3H),1.37(s,3H).13C NMR(126MHz,CDCl3)δ173.33,172.34,163.25,161.29,157.64,154.96,154.19,129.96,127.70,127.68,124.35,122.12,118.46,115.99,114.21,111.02,103.85,91.65,91.62,88.16,84.41,76.53,54.87,46.75,46.44,45.28,44.72,43.24,40.32,31.35,31.29,24.22,22.66.
实施例9:6-(叔丁氧丙烯酰基)平板霉素(化合物6)的制备
将100mg(0.18mmol)化合物1溶于15ml乙腈中，加入13mg醋酸钯、13mg三苯基膦、丙烯酸叔丁酯(0.36mmol)及60μl三乙胺,除空气后，回流反应2小时。反应结束反，加入乙酸乙酯、水及稀盐酸进行萃取。萃取液浓缩后用硅胶柱进行分离(石油醚：乙酸乙酯：乙酸＝40：60：0.5)，最后得到化合物6(80mg，80％)。
1H NMR(500MHz,CDCl3)δ11.68(s,1H),11.12(s,1H),8.07(s,1H),7.60(d,J＝8.9Hz,1H),7.28(d,J＝16.1Hz,1H),6.72(s,1H),6.51(d,J＝3.8Hz,1H),6.48(d,J＝3.3Hz,1H),4.63(s,1H),2.68(ddd,J＝14.4,12.2,4.9Hz,1H),2.57–2.53(m,1H),2.51(d,J＝8.6Hz,2H),2.49–2.43(m,1H),2.17(ddd,J＝21.1,11.4,7.3Hz,2H),2.06(d,J＝8.5Hz,1H),1.99(dd,J＝11.5,3.6Hz,1H),1.90–1.80(m,2H),1.73(d,J＝11.4Hz,1H),1.53(s,3H),1.49(s,9H),1.29(s,3H).13C NMR(126MHz,CDCl3)δ201.12,173.39,172.51,166.24,155.02,154.14,153.62,137.92,131.59,128.21,123.56,114.24,111.10,103.74,88.35,80.62,76.70,54.84,46.83,46.28,45.38,44.73,43.25,40.29,31.18,31.07,28.11,23.95,22.61.
实施例10:6-(N-吗啉丙烯酰基)平板霉素(化合物7)的制备
制备方法参见实施实例9。
1H NMR(500MHz,DMSO-d6)δ9.10(s,1H),7.52(d,J＝8.7Hz,1H),7.26(d,J＝15.5Hz,1H),7.17(s,1H),7.15(d,J＝15.6Hz,1H),6.31(d,J＝8.6Hz,1H),4.41(s,1H),3.56(d,J＝24.9Hz,8H),2.39(q,J＝6.3Hz,2H),2.32(s,1H),2.20–2.09(m,2H),2.00(dd,J＝11.5,4.5Hz,2H),1.96–1.90(m,1H),1.84(dd,J＝11.9,6.9Hz,1H),1.79(dd,J＝11.4,3.0Hz,1H),1.74(d,J＝10.5Hz,2H),1.38(s,3H),1.17(s,3H).13C NMR(126MHz,DMSO-d6)δ201.99,172.62,172.45,165.01,159.55,154.86,136.91,130.95,130.10,128.96,119.74,113.42,113.31,107.18,87.00,75.98,66.80,66.64,54.98,46.69,46.26,45.56,44.75,43.26,32.05,30.82,30.78,24.41,23.40.
实施例11:6-苯基平板霉素(化合物8)的制备
将100mg(0.18mmol)化合物1溶于5ml二甲基乙二醚中及2.5ml水中，加入10mg钯碳、37mg碳酸钠及苯硼酸(0.36mmol)常温下搅拌反应12小时。反应结束反，加入乙酸乙酯、水及稀盐酸进行萃取。萃取液浓缩后用硅胶柱进行分离(石油醚：乙酸乙酯：乙酸＝40：60：0.5)，最后得到化合物8(77mg，85％)。
HRMS(ESI)m/z calcd for C30H32NO7,[M+H]+517.2179；Found:518.2174.1H NMR(400MHz,Chloroform-d)δ11.75(s,1H),11.17(s,1H),8.09(s,1H),7.58(d,J＝8.9Hz,1H),7.36(q,J＝7.7,7.0Hz,3H),7.32–7.26(m,3H),6.57(s,1H),6.50(d,J＝8.9Hz,1H),4.70(s,1H),2.74(ddd,J＝15.5,12.7,4.8Hz,1H),2.64(s,1H),2.57(dt,J＝12.7,4.9Hz,3H),2.30–2.17(m,2H),2.11(d,J＝11.6Hz,1H),2.05(dd,J＝11.4,3.5Hz,1H),1.97–1.84(m,2H),1.76(d,J＝11.3Hz,1H),1.56(s,3H),1.42(s,3H).13C NMR(101MHz,CDCl3)δ201.97,173.55,172.35,154.95,154.11,150.53,137.78,136.29,128.73,128.18,128.10,127.95,114.26,111.03,103.82,88.31,76.86,54.93,46.73,46.12,45.77,44.77,43.26,40.36,31.22,29.80,24.06,22.70.
实施例12:6-(3-三氟甲氧基苯基)平板霉素(化合物9)的制备
制备方法参见实施实例11。
HRMS(ESI)m/z calcd for C31H31F3NO8,[M+H]+602.2002；Found:602.1999.1H NMR(400MHz,Chloroform-d)δ11.73(s,1H),11.15(s,1H),8.08(s,1H),7.58(d,J＝8.9Hz,1H),7.39(t,J＝8.0Hz,1H),7.27–7.13(m,3H),6.60(s,1H),6.50(d,J＝8.9Hz,1H),4.70(s,1H),2.84–2.69(m,1H),2.65(s,1H),2.57(td,J＝9.5,4.8Hz,3H),2.30–2.17(m,2H),2.15–1.99(m,2H),1.97–1.83(m,2H),1.78(d,J＝11.4Hz,1H),1.57(s,3H),1.42(s,3H).13C NMR(101MHz,CDCl3)δ201.35,173.40,172.32,154.97,154.08,151.42,148.98,138.20,136.49,129.88,129.34,128.18,127.28,121.54,120.33,114.24,111.07,103.77,88.37,76.81,54.89,46.77,46.16,45.67,44.75,43.21,40.33,31.13,31.07,24.06,22.65.
实施例13:6-菲基平板霉素(化合物10)的制备
制备方法参见实施实例11。
HRMS(ESI)m/z calcd for C38H36NO7,[M+H]+618.2492；Found:618.2489.1H NMR(400MHz,Chloroform-d)δ11.63(s,1H),11.09(s,1H),8.72(d,J＝8.4Hz,1H),8.67(d,J＝8.3Hz,1H),8.13(s,1H),7.83(d,J＝7.8Hz,1H),7.69–7.61(m,2H),7.60–7.51(m,3H),7.32(d,J＝8.9Hz,1H),6.71(s,1H),6.40(s,1H),4.71(s,1H),2.86–2.66(m,2H),2.64–2.43(m,3H),2.31(dd,J＝11.9,3.4Hz,1H),2.21(q,J＝5.7,4.9Hz,1H),2.17–2.11(m,2H),1.92(dt,J＝11.9,6.0Hz,2H),1.76(d,J＝11.2Hz,1H),1.56(s,6H).13C NMR(101MHz,CDCl3)δ202.60,173.65,172.45,154.97,154.15,133.49,131.31,130.34,128.55,128.16,126.90,126.77,126.53,125.73,123.07,122.55,114.15,110.89,103.71,88.15,77.27,55.05,47.06,46.23,46.16,44.81,43.25,40.46,31.40,29.72,24.47,22.75.
实施例14:6-芘基平板霉素(化合物11)的制备
制备方法参见实施实例11。
HRMS(ESI)m/z calcd for C40H36NO7,[M+H]+642.2492；Found:642.2489.1H NMR(500MHz,Chloroform-d)δ11.63(s,1H),11.09(s,1H),8.29–8.16(m,2H),8.16–8.09(m,2H),8.06(s,2H),8.02(s,1H),7.98(s,1H),7.75(s,2H),7.28(s,1H),6.72(s,1H),6.37(dd,J＝9.0,2.2Hz,1H),4.73(s,1H),2.79(d,J＝20.2Hz,2H),2.62(d,J＝10.3Hz,1H),2.55(q,J＝5.9Hz,2H),2.31(s,1H),2.21(q,J＝6.3,5.3Hz,2H),2.14(s,1H),1.94(dt,J＝19.0,10.7Hz,2H),1.77(d,J＝10.8Hz,1H),1.56(s,6H).13C NMR(126MHz,CDCl3)δ173.58,172.33,154.93,154.07,131.62,131.26,131.16,130.73,128.06,127.71,127.63,127.31,126.00,125.36,125.14,124.75,124.69,124.41,124.22,114.13,110.89,103.64,88.19,77.20,55.07,47.04,46.32,46.23,44.81,43.26,40.45,31.56,31.43,24.41,22.74.
实施例15:6-(4-氟苯硫基)平板霉素(化合物12)的制备
将100mg(0.22mmol)中间体4溶于10ml乙醇中及2.5ml水中，加入4-氟苯硫酚(0.23mmol)及0.5ml 2M氢氧化钠溶液，常温下搅拌反应2小时。反应结束反，加入乙酸乙酯、水及稀盐酸进行萃取。萃取液浓缩后用硅胶柱进行分离(石油醚：乙酸乙酯：乙酸＝40：60：0.5)，最后得到化合物12(103mg，85％)。
1H NMR(500MHz,Chloroform-d)δ11.72(s,1H),8.07(s,1H),7.59(d,J＝9.0Hz,1H),7.48–7.35(m,2H),7.08(t,J＝8.6Hz,2H),6.49(d,J＝8.9Hz,1H),5.90(s,1H),4.63(s,1H),2.78–2.66(m,1H),2.54(s,1H),2.52(q,J＝3.2,2.5Hz,1H),2.51–2.47(m,1H),2.46(d,J＝6.6Hz,1H),2.15(dt,J＝11.4,5.3Hz,1H),2.06(s,1H),2.05–2.00(m,1H),1.93–1.82(m,2H),1.72(dd,J＝12.0,6.9Hz,1H),1.55(d,J＝11.4Hz,1H),1.47(s,3H),1.32(s,3H).13C NMR(126MHz,CDCl3)δ199.08,173.31,172.44,164.08,162.10,154.99,154.15,146.54,136.42,136.35,136.22,128.20,116.88,116.71,114.24,111.06,103.79,88.06,76.65,54.78,47.33,46.98,45.69,44.57,43.12,40.21,31.14,31.09,24.31,22.57.
实施例16:6-环己硫基平板霉素(化合物13)的制备
制备方法参见实施实例15。
1H NMR(500MHz,Chloroform-d)δ11.69(s,1H),11.13(s,1H),8.08(s,1H),7.61(d,J＝8.8Hz,1H),6.49(d,J＝8.9Hz,1H),6.46(s,1H),4.62(s,1H),3.01(s,1H),2.68(ddd,J＝15.1,12.7,4.8Hz,1H),2.51(d,J＝7.4Hz,2H),2.50–2.45(m,1H),2.19–2.14(m,1H),2.06(d,J＝1.9Hz,1H),1.96(dd,J＝11.4,3.6Hz,2H),1.86(td,J＝13.9,4.2Hz,3H),1.77(dt,J＝10.2,5.1Hz,2H),1.70(d,J＝11.4Hz,1H),1.62(dd,J＝10.6,4.3Hz,1H),1.51(s,3H),1.32(s,3H).13C NMR(126MHz,CDCl3)δ200.15,173.46,172.61,155.06,154.18,149.90,132.70,128.23,114.26,111.09,103.76,88.03,76.67,54.96,47.28,47.07,45.64,44.64,43.28,42.95,40.28,33.20,32.63,31.35,31.19,29.68,25.91,25.77,24.31,22.67.
实施例17:6-(4-甲基苯硫基)平板霉素(化合物14)的制备
制备方法参见实施实例15。
1H NMR(500MHz,Chloroform-d)δ11.64(s,1H),8.10(s,1H),7.60(d,J＝8.9Hz,1H),7.32(d,J＝7.9Hz,2H),7.18(d,J＝7.9Hz,2H),6.50(d,J＝8.9Hz,1H),5.91(s,1H),4.59(s,1H),2.69(ddd,J＝15.5,12.6,4.8Hz,1H),2.49(d,J＝17.7Hz,2H),2.43(t,J＝6.6Hz,1H),2.36(s,3H),2.13(d,J＝9.6Hz,1H),2.06(s,2H),2.03(s,1H),1.93–1.83(m,2H),1.70(dd,J＝12.3,6.8Hz,1H),1.53(d,J＝11.3Hz,1H),1.45(s,3H),1.32(s,3H).13CNMR(126MHz,CDCl3)δ199.31,173.50,172.89,155.15,154.26,146.24,138.84,136.34,134.27,130.36,128.27,127.65,114.28,111.13,103.74,87.86,76.61,54.78,47.34,46.95,45.75,44.55,43.14,40.26,31.37,31.24,24.34,22.63.
实施例18:6-苄硫基平板霉素(化合物15)的制备
制备方法参见实施实例15。
1H NMR(500MHz,Chloroform-d)δ11.74(s,1H),8.08(s,1H),7.61(d,J＝8.9Hz,1H),7.28(d,J＝6.3Hz,4H),7.23(td,J＝6.0,2.5Hz,1H),6.50(d,J＝8.9Hz,1H),6.35(s,1H),4.57(s,1H),3.98–3.85(m,2H),2.71–2.59(m,1H),2.47(d,J＝14.2Hz,1H),2.46–2.42(m,2H),2.12(d,J＝8.9Hz,1H),2.06(s,1H),2.01–1.92(m,2H),1.83(td,J＝15.7,13.8,4.8Hz,2H),1.69(dd,J＝12.1,6.8Hz,1H),1.58(d,J＝11.4Hz,1H),1.48(s,3H),1.19(s,3H).13C NMR(126MHz,CDCl3)δ199.80,173.43,172.62,155.03,154.19,150.62,136.56,132.90,129.12,128.43,128.24,127.25,114.26,111.07,103.83,88.01,76.62,54.81,47.20,46.95,45.50,44.58,43.05,40.18,36.38,31.30,31.15,24.31,22.63.
实施例19:化合物抑菌活性测试
利用平板稀释法测定化合物对金黄色葡萄球菌的最小抑菌浓度。首先，细菌在LB培养基中，37℃环境下培养16个小时。菌液在250转下离心，稀释到吸光度值为0.25后，再稀释一万倍后得到稀释菌液。然后，将2微升稀释菌液滴到含有不同浓度化合物的平板上，并在37℃环境下培养16个小时。细菌在平板上完全没有生长的最低化合物浓度即为该化合物最小抑菌浓度。
表2：化合物1-13对金黄色葡萄球菌的最小抑菌浓度，平板霉素及利奈唑胺为阳性对照。
表2：
Figure BDA0001865050770000151
Figure BDA0001865050770000161
实施例20:化合物体内抑菌活性测试
利用小鼠腹膜炎模型测定化合物对金黄色葡萄球菌的体内抑菌能力。首先，将25只6至8周大的C57BL/6j平均分成5组，给每只小鼠注射0.5ml含5％黏蛋白及2×107个金黄色葡萄球菌的生理盐水溶液。分别在小鼠被感染1小时及5小时，连续两次给药。给药剂量如下，模型组为生理盐水，万古青霉素组为50mg/kg，平板霉素组为10mg/kg，化合物11第一组为10mg/kg，化合物11第一组为50mg/kg。连续7天，每天观察两次，记录每组小鼠的存活数，从而评价其体内抗菌活性。从图1中可以看出，化合物11的体内抗菌活性与平板霉素相比，有非常大的提高。也说明化合物11的药代动力学性质有了比较大的改善。

Claims (7)

1.一种6-取代平板霉素衍生物，其特征在于，所述6-取代平板霉素衍生物化学结构式如式Ⅰ所示：
Figure DEST_PATH_IMAGE002
式Ⅰ
其中，所示R 基团选自于：
芳基，所述芳基是指苯基、联苯基、1，2，3，4四氢萘基、萘基、菲基、芘基，其任选被卤素、三氟甲氧基、芳基和羟基单、二或三取代。
2.一种6-取代平板霉素衍生物，其特征在于，所述6-取代平板霉素衍生物具体为如下化合物：
Figure DEST_PATH_IMAGE004
、
Figure DEST_PATH_IMAGE006
、
Figure DEST_PATH_IMAGE008
、
Figure DEST_PATH_IMAGE010
、
Figure DEST_PATH_IMAGE012
、
Figure DEST_PATH_IMAGE014
、
Figure DEST_PATH_IMAGE016
、
Figure DEST_PATH_IMAGE018
、
Figure DEST_PATH_IMAGE020
、
Figure DEST_PATH_IMAGE022
、
Figure DEST_PATH_IMAGE024
。
3. 如权利要求1 或2 所述的6-取代平板霉素衍生物的制备方法，其特征在于，所述方法是将平板霉素在硫酸作用下发生水解，得到中间体1，中间体1 与碘反应得到中间体2，中间
体2 再发生缩合反应得到中间体3，中间体3 最后通过偶联反应得到终产物；或者，将平
板霉素与双氧水反应得到中间体4，中间体4 再与亲核性反应物脱水得到终产物；具体反
应过程如下：
Figure DEST_PATH_IMAGE026
。
4. 一种药物制剂，其特征在于，所述药物制剂中包含权利要求1 或2 所述的6-取代平板霉素衍生物。
5.如权利要求4所述的药物制剂，其特征在于，所述药物制剂的给药方式为口服、鼻内、静脉内、经皮、肠胃外、皮下、肌内、眼内或腹膜的方式给哺乳动物给药。
6. 如权利要求1 或2 所述的6-取代平板霉素衍生物在制备治疗细菌感染的药物中的应用。
7. 如权利要求6 所述的应用，其特征在于，所述细菌感染指由所有革兰氏阳性菌、结核分枝杆菌引起的表皮、粘膜、血液、内脏感染。
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