CN113185511B - 一种嘧啶类化合物及其制备方法和应用 - Google Patents
一种嘧啶类化合物及其制备方法和应用 Download PDFInfo
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- CN113185511B CN113185511B CN202110567939.6A CN202110567939A CN113185511B CN 113185511 B CN113185511 B CN 113185511B CN 202110567939 A CN202110567939 A CN 202110567939A CN 113185511 B CN113185511 B CN 113185511B
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Abstract
本发明提供一种嘧啶类化合物及其制备方法和应用,该嘧啶类化合物具有如式I所示的结构,R1选自氢、卤素、被取代或未被取代的C1~6烷基、被取代或未被取代的C1~6烷氧基、苯基、氰基、醛基、硝基中的至少一个;R2选自氢、卤素、C1~6烷基取代的氨基、被取代或未被取代的氮杂环烷基;R3位于苯环的3位和5位,分别独立地选自三氟甲基或氟;X选自氧、硫、氮中的一种;A、B、C、Z独立地选自碳或氮。本发明提供的嘧啶类化合物是一种有效的SecA抑制剂,具有广谱的抗菌活性,对MRSA,MRSE,VISA和VRE等耐药菌株均具有良好的抗菌活性。
Description
技术领域
本发明属于药物化学领域,涉及一种嘧啶类化合物及其制备方法和应用。
背景技术
细菌耐药性的产生和蔓延再次引发了一系列的公共卫生危机,然而全世界对于新型抗菌药物的研发却呈现出一种下降趋势,过去三十年间,在抗菌药物领域仅有利奈唑胺和达托霉素两类新型化学药物被推出,开发具有全新分子结构和作用机制的抗菌药物已是当务之急。
常见的抗生素作用机制包括通过对细菌体内酶催化过程的干预,达到干扰DNA复制,转录,翻译,或细胞壁合成等作用。近些年来,SecA作为细菌跨膜蛋白转运加工的关键酶,引起了人们以SecA作为新靶点的开发兴趣。在胞质核糖体合成的蛋白中,超过30%的细菌蛋白(跨膜蛋白或分泌蛋白)需要穿越质膜发挥作用。在细菌进化出的多种蛋白转运机制中,secretion pathway对细菌活力起着至关重要的作用,并且广泛存在与各种细菌中。SecA ATP酶是细菌分泌系统的核心组分,是蛋白转运的动力泵,已有研究证明,SecA ATP酶在细菌生存,毒力因子分泌,细菌外排泵(对细菌耐药性有重要作用)组装等方面起着至关重要的作用。将SecA作为抗菌靶点有如下优势:首先,SecA对细菌的生存至关重要,承担着功能蛋白的转运,加工,细菌毒素及毒力因子分泌等功能;其次,SecA广泛存在于各类细菌之中,但在人类体内没有与之对应的对应体;并且,SecA需要在质膜上发挥作用,因此其抑制剂并不需要在胞内积累到一定浓度,进而可以绕开外排泵的作用,甚至影响外排泵的装配。
目前,关于SecA抑制剂的研究较少,叠氮化钠是较早被研究的毫摩尔级的SecA抑制剂,但其缺乏选择性无法成药;天然产物CJ-21058能够抑制SecA ATP酶的活性,阻断ATP依赖的蛋白跨膜转运过程,显示出抗菌活性(IC50=7μM,T.brucei);美国佐治亚州立大学的王炳和课题组在世界专利WO2013184755A2中报道了嘧啶酮和三唑嘧啶类化合物显示了微摩尔级的SecA ATP酶抑制活性和抗菌活性,但其中大多数化合物理化性质较差,抑菌活性有待提高。因此,仍需要对这些化合物进行结构改造,提高其理化性质及成药性,增强抑菌活性,以期发现具有新结构的SecA抑制剂用于抗菌药物的研发。
发明内容
本发明提供一种嘧啶类化合物或其盐,可作为一种SecA抑制剂,具有广谱的抗菌活性,对耐甲氧西林的金黄色葡萄球菌、耐甲氧西林表皮葡萄球菌、万古霉素中度耐药的金葡菌和耐万古霉素肠球菌等耐药菌株具有良好的抗菌活性。
本发明还提供一种上述嘧啶类化合物的制备方法,合成路线简单,易于操作。
本发明还提供一种药物组合物,包括上述嘧啶类化合物作为药物组合物中的活性组分。
本发明还提供一种上述嘧啶类化合物在制备抗菌药物中的应用。
本发明提供一种嘧啶类化合物或其盐,嘧啶类化合物具有如式I所示的结构:
其中,R1选自氢、卤素、被取代或未被取代的C1~6烷基、被取代或未被取代的C1~6烷氧基、苯基、氰基、醛基、硝基中的至少一个;R2选自氢、卤素、C1~6烷基取代的氨基、被取代或未被取代的氮杂环烷基;R3位于苯环的3位和5位,分别独立地选自三氟甲基或氟;X选自氧、硫、氮中的一种;A、B、C、Z独立地选自碳或氮。
本发明提供的嘧啶类化合物,R2所连接的六元环为嘧啶环,因此如式I所示结构的化合物称为嘧啶类化合物。
在本发明嘧啶类化合物的各取代基中,对R1的取代位置不作特殊限定,如下结构式中的编号所示,R2位于嘧啶环的6位,R3分别位于苯环的3位和5位。
上述R1取代基的定义中,被取代或未被取代的C1~6烷基指的是含有取代基的C1~6烷基或不含取代基的C1~6烷基,C1~6烷基是指碳原子个数为1~6个的直链烷基,例如可以是甲基、乙基、丙基、正丁基、正戊基、正己基等、或者是碳原子个数为3~6个的支链烷基,例如可以是异丙基、异丁基、仲丁基、叔丁基、异戊基、异己基等,其中取代基可以是卤素、氨基、羟基、氰基等;被取代或未被取代的C1~6烷氧基指的是碳原子个数为1~6个的直链烷氧基或支链烷氧基,例如可以是甲氧基、乙氧基、正丙氧基、异丙氧基等,其中取代基可以是卤素、氨基、羟基、氰基等;卤素可以为-F、-Cl、-Br、-I。
上述R2取代基的定义中,C1~6烷基取代的氨基是指被1个或2个碳原子数为1~6个的直链烷基或支链烷基取代的氨基,例如可以是甲氨基、乙氨基、二甲氨基、二乙氨基等;被取代或未被取代的氮杂环烷基可以是含取代基或不含取代基的碳原子个数为3~5个,氮原子个数为1-4个的氮杂环烷基,取代基可以是氨基或Boc(叔丁氧羰基)保护的氨基,对取代基的位置不作特别限定,示例性的,被取代或未被取代的氮杂环烷基具体可以是1-氮杂环丁基、1-氮杂环戊基、4-氨基甲酸叔丁酯-1-氮杂环己基等。
上述R3位于苯环的3位和5位,分别独立地选自三氟甲基或氟,例如,R3可以是3,5-二(三氟甲基)、3-氟-5-三氟甲基、3-三氟甲基-5-氟、3,5-二氟等。
本发明的X选自氧、硫、氮中的一种,当X为氧时,X所在的五元环为噁唑环;当X为硫时,X所在的五元环为噻唑环;当X为氮时,X所在的环为咪唑环。
本发明的A、B、C、Z独立地选自碳或氮,例如当A、B、C、Z均选自碳时,A、B、C、Z所在的六元环为苯环;当A、B、C、Z均为氮时,A、B、C、Z所在的六元环为1,2,3,4-四嗪;当A、B、C、Z中的任一个为氮,其余为碳时,A、B、C、Z所在的六元环为吡啶。
经发明人研究发现,当R2选自氯,R3选自3,5-二(三氟甲基),A、B、C、D均选自碳,以其为母体的嘧啶类化合物制得的抗菌药物具有较为优异的广谱抗菌活性效果,对耐药菌的抗菌效果优于现有的抗菌药物左氧氟沙星。
在R2选自氯,R3选自3,5-二(三氟甲基),A、B、C、D均选自碳的基础上,当R1优选自氢、卤素、未取代的C1~6烷基、苯基中的一种,更近一步优选自R1选自氢、甲基、溴中的一种时,所获得的嘧啶化合物的广谱抗菌活性更为优异。
进一步地,当X选自硫或氧时,所获得的嘧啶类化合物的广谱抗菌活性更为优异。
作为非限定性实例,本发明的嘧啶类化合物可以为编号为1-14的化合物:
本发明还提供一种上述嘧啶类化合物的制备方法,包括以下步骤:
使式IV的化合物与式VII的化合物在碱性条件下反应,得到式I所示的化合物;
其中,L2选自卤素。上述反应在碱性条件下完成,反应的本质是式VII的化合物作为亲核试剂与式IV化合物发生亲核取代反应,因此,常规的碱性条件即可得到预期产物,当该反应进一步在微波条件下进行时,能够使反应具有较高的产率,并缩短反应时间,提高制备效率。
例如,上述反应过程具体可以为:在无水条件下,将式IV化合物,式VII的化合物,无水碳酸钾溶于无水DMF中,在60℃微波辅助反应,反应进程可以采用本领域常规测试方法(如TLC、HPLC或NMR)监测测,当检测到反应原料消失后即可判定反应结束,反应结束后柱层析分离提纯(PE:EA=5:(1~2),V/V),即可得到式I的化合物。该反应在常规的60℃油浴加热需要2~4h才能够完成反应,而当使用微波助力反应时,反应仅需30~40min即可完成,可明显提高制备效率。
一般的,式IV的化合物可以通过式VII的化合物通过式V的化合物与式VI的化合物在碱性条件下反应得到:
其中,L1和L2分别选自卤素。上述反应的本质是式II的化合物作为亲核试剂与式III的化合物发生亲核取代反应,式III的化合物中的L1和L2都有被取代的可能,为避免L1和L2同时被取代,可以控制式II的化合物与式II的化合物的摩尔比为1:1。
上述反应过程具体可以为:在无水条件下,将式II的化合物、式III化合物、无水碳酸钾溶于无水DMF中,60℃微波辅助下反应,反应进程可以采用本领域常规测试方法(如TLC、HPLC或NMR)进行监测,当检测到反应原料结束后即可判定反应结束,反应结束后柱层析分离提纯(PE:EA=(20~10):1,V/V),得式IV的化合物。
一般的,式VII的化合物可以通过式V的化合物与式VI的化合物反应得到:
上述反应过程具体可以为:无水条件下,将式V的化合物、式VI的化合物溶于无水THF中,在0℃下反应2h后,升温至室温继续反应10h,通过TLC、HPLC或NMR检测反应完毕,浓缩除去溶剂,浓缩物用乙酸乙酯萃取,将萃取液干燥后旋干得到式VIII的化合物,在式VIII的化合物中加入质量浓度为5%的氢氧化钠溶液,加热回流6h后,降至室温,向反应体系中加入2N盐酸溶液调节pH至6-7,直至沉淀完全析出,抽滤得到式VII的化合物。
本发明还提供一种药物组合物,包括上述嘧啶类化合物,除嘧啶类化合物外,还可以包括药学上可接受的药物辅料。
可将上述嘧啶类化合物本身或其与可药用赋形剂、稀释剂等的混合物制成片剂、胶囊、颗粒剂、散剂或糖浆剂的形式。上述制剂可通过常规制药方法制备。
药学上可接受的药物辅料可使用在常规制药方法中的物质。可用的药物辅料的例子包括赋形剂(例如糖类衍生物诸如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇;淀粉衍生物诸如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉;纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠;阿拉伯胶;右旋糖酐;硅酸盐衍生物如偏硅酸镁铝;磷酸盐衍生物如碳酸钙;硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)、稀释剂和注射液用溶剂(例如水、乙醇和甘油等)。
本发明还提供上述嘧啶类化合物在制备抗菌药物中的应用。
发明人对上述嘧啶类化合物进行了研究,发现该类化合物是一种有效的SecA抑制剂,具有广谱的抗菌活性,尤其是对耐甲氧西林的金黄色葡萄球菌(MRSA),耐甲氧西林表皮葡萄球菌(MRSE),万古霉素中度耐药的的金黄色葡萄球菌(VISA)和耐万古霉素的屎肠球菌(VRE)等菌株具有良好的抗菌活性,最低抑菌浓度MIC可达0.25-2μg/mL。
本发明提供的嘧啶类化合物是一种有效的SecA抑制剂,具有广谱的抗菌活性,对MRSA,MRSE,VISA和VRE等菌株均具有良好的抗菌活性。此外,该嘧啶类化合物的合成路线简单、原料易得、易于操作,有利于化合物扩展的实施。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将结合本发明的实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:化合物1的制备
1、在无水条件下,将苯并[d]噻唑-2-硫醇(100.0mg,0.60mmol)、2,4,6-三氯嘧啶(109.7mg,0.60mmol)、无水碳酸钾(99.1mg,0.72mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噻唑(193.9mg,收率:54.7%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噻唑(100.0mg,0.32mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(100.2mg,0.32mmol),无水碳酸钾(53.0mg,0.38mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)苯并[d]噻唑(108.4mg,收率:57.3%)。
化合物1表征如下:
1HNMR(500MHz,CDCl3)δppm 7.92(s,1H),7.85(s,1H),7.66(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.34(dt,J=23.5,7.5Hz,3H).
13C NMR(101MHz,CDCl3)δppm 171.48,169.22,158.26,155.63,151.73,136.26,131.16(q,J=33.4Hz),126.50,126.28,126.00,123.93,122.99(q,J=274.1Hz),122.51,121.92,112.60.
ESI-HRMS(m/z)Calcd for C21H10N6ClF6S3[M+H]+590.97163;Found590.97058.
实施例2:化合物2的制备
1、在无水条件下,将苯并[d]噁唑-2-硫醇(100.0mg,0.66mmol)、2,4,6-三氯嘧啶(121.3mg,0.66mmol)、无水碳酸钾(109.3mg,0.79mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(99.8mg,收率:50.7%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.34mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(106.5mg,0.34mmol),无水碳酸钾(56.3mg,0.41mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-苯并[d]噁唑(131.2mg,收率:67.1%)。
化合物2表征如下:
1HNMR(500MHz,DMSO-d6)δppm 8.54(s,2H),8.09(d,J=8.5Hz,1H),7.91(d,J=9.0Hz,2H),7.55(t,J=8.5Hz,1H),7.48(t,J=8.5Hz,1H),7.41(s,1H).
13C NMR(101MHz,MeOD)δppm 173.45,169.78,160.75,156.79,153.05,149.31,142.07,132.16(q,J=33.8Hz),132.13,127.57,127.52,126.10,124.67,123.08(q,J=273.1Hz),120.60,114.01,111.71.
ESI-HRMS(m/z)Calcd for C21H10ON6ClF6S2[M+H]+574.99447;Found574.99333.
实施例3:化合物3的制备
1、在无水条件下,将5-甲基苯并[d]噁唑-2-硫醇(100.0mg,0.61mmol)、2,4,6-三氯嘧啶(111.9mg,0.61mmol)、无水碳酸钾(101.1mg,0.73mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物5-甲基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(83.4mg,收率:43.8%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将5-甲基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.32mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(100.2mg,0.32mmol),无水碳酸钾(53.0mg,0.39mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-5-甲基苯并[d]噁唑(128.7mg,收率:68.3%)。
化合物3表征如下:
1HNMR(500MHz,CDCl3)δppm 8.56(s,2H),7.92(s,2H),7.52(s,1H),7.42(d,J=8.5Hz,1H),7.21(d,J=8.5Hz,1H),2.47(s,3H).
13C NMR(101MHz,CDCl3)δppm 168.56,167.66,160.20,159.53,154.89,150.01,146.51,141.29,135.48,132.23(q,J=33.7Hz),132.02,127.70,126.50,123.21,123.17(q,J=273.7Hz),119.99,114.17,110.17,21.45.
ESI-HRMS(m/z)Calcd for C22H12ON6ClF6S2[M+H]+589.01012;Found589.00925.
实施例4:化合物4的制备
1、在无水条件下,将5-硝基苯并[d]噁唑-2-硫醇(100.0mg,0.51mmol)、2,4,6-三氯嘧啶(93.5mg,0.51mmol)、无水碳酸钾(84.5mg,0.62mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=10/1,V/V),得白色絮状物5-硝基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(96.8mg,收率:55.3%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将5-硝基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.29mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(90.8mg,0.29mmol),无水碳酸钾(48.1mg,0.35mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/2,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-5-硝基苯并[d]噁唑(118.3mg,收率:65.8%)。
化合物4表征如下:
1HNMR(500MHz,CDCl3)δppm 8.52(s,2H),8.04(s,1H),8.02(s,1H),7.94(s,1H),7.75(d,J=9.0Hz,1H),7.52(d,J=9.0Hz,1H).
13C NMR(101MHz,CDCl3)δppm 168.28,166.36,160.33,159.86,154.77,146.52,145.90,141.50,132.48(q,J=33.8Hz),131.95,131.17,126.65,123.53,123.24(q,J=273.9Hz),122.27,116.42,115.11,111.20.
ESI-HRMS(m/z)Calcd for C21H9O3N7ClF6S2[M+H]+619.97955;Found619.97858.
实施例5:化合物5的制备
1、在无水条件下,将5-甲氧基苯并[d]噁唑-2-硫醇(100.0mg,0.55mmol)、2,4,6-三氯嘧啶(101.2mg,0.55mmol)、无水碳酸钾(91.1mg,0.66mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=15/1,V/V),得白色絮状物5-甲氧基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(104.9mg,收率:58.1%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将5-甲氧基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.31mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(97.1mg,0.31mmol),无水碳酸钾(53.0mg,0.38mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-5-甲氧基苯并[d]噁唑(124.3mg,收率:66.3%)。
化合物5表征如下:
1HNMR(500MHz,CDCl3)δppm 8.55(s,2H),7.92(s,1H),7.88(s,1H),7.43(d,J=9.0Hz,1H),7.20(d,J=2.5Hz,1H),6.99(dd,J=9.0,2.5Hz,1H),3.86(s,3H).
13C NMR(101MHz,CDCl3)δppm 168.68,159.67,157.99,155.42,146.58,142.11,132.39(q,J=33.8Hz),132.10,131.09,128.99,126.61,123.30(q,J=273.8Hz),123.28,115.58,114.24,111.14,102.82,56.10.
ESI-HRMS(m/z)Calcd for C22H12O2N6ClF6S2[M+H]+605.00504;Found605.00410.
实施例6:化合物6的制备
1、在无水条件下,将5-氟苯并[d]噁唑-2-硫醇(100.0mg,0.60mmol)、2,4,6-三氯嘧啶(109.7mg,0.60mmol)、无水碳酸钾(99.1mg,0.72mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物5-氟-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.4mg,收率:52.9%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将5-氟-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.32mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(100.2mg,0.32mmol),无水碳酸钾(53.0mg,0.38mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-5-氟苯并[d]噁唑(93.5mg,收率:49.3%)。
化合物6表征如下:
1HNMR(500MHz,CDCl3)δppm 8.56(s,2H),8.00(s,1H),7.93(s,1H),7.49(dd,J=9.0,4.0Hz,1H),7.37(dd,J=8.0,2.5Hz,1H),7.13(td,J=9.0,2.5Hz,1H).
13C NMR(101MHz,CDCl3)δppm 168.35,167.78,160.40(d,J=244.3Hz),160.26,159.72,157.35,148.06,146.62,141.86(d,J=13.3Hz),132.46(q,J=33.8Hz),131.89,126.59,123.41,123.25(q,J=273.9Hz),114.42(d,J=26.6Hz),114.41,111.35(d,J=9.90Hz),106.66(d,J=26.2Hz).
ESI-HRMS(m/z)Calcd for C21H9ON6ClF7S2[M+H]+592.98505;Found592.98416.
实施例7:化合物7的制备
1、在无水条件下,将5-氯苯并[d]噁唑-2-硫醇(100.0mg,0.54mmol)、2,4,6-三氯嘧啶(98.8mg,0.54mmol)、无水碳酸钾(89.4mg,0.65mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物5-氯-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(112.3mg,收率:68.1%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将5-氯-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.30mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(94.0mg,0.30mmol),无水碳酸钾(49.7mg,0.36mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-5-氯苯并[d]噁唑(126.7mg,收率:69.3%)。
化合物7表征如下:
1HNMR(500MHz,CDCl3)δppm 8.56(s,2H),8.02(s,1H),7.93(s,1H),7.62(s,1H),7.45(d,J=8.7Hz,1H),7.34(d,J=8.7Hz,1H).
13C NMR(101MHz,CDCl3)δppm 168.14,167.59,160.32,159.72,157.22,150.22,146.60,142.13,132.45(q,J=33.8Hz),131.96,131.18,126.87,126.60,123.48,123.26(q,J=273.9Hz),120.14,114.57,111.61.
ESI-HRMS(m/z)Calcd for C21H9ON6Cl2F6S2[M+H]+608.95550;Found608.95496.
实施例8:化合物8的制备
1、在无水条件下,将5-溴苯并[d]噁唑-2-硫醇(100.0mg,0.43mmol)、2,4,6-三氯嘧啶(79.7mg,0.43mmol)、无水碳酸钾(71.2mg,0.52mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物5-溴-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(96.8mg,收率:59.7%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将5-溴-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.27mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(84.6mg,0.27mmol),无水碳酸钾(44.7mg,0.32mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-5-溴苯并[d]噁唑(112.1mg,收率:63.5%)。
化合物8表征如下:
1HNMR(500MHz,CDCl3)δppm 8.58(s,2H),8.09(s,1H),7.94(s,1H),7.88(s,1H),7.53(d,J=9.0Hz,1H),7.45(d,J=9.0Hz,1H),7.26(s,1H).
13C NMR(101MHz,CDCl3)δppm 167.86,167.59,160.36,159.73,157.05,150.67,146.55,142.63,132.44(q,J=33.8Hz),132.08,131.10,129.61,126.65,123.48,123.28(q,J=273.7Hz),118.41,114.68,112.09.
ESI-HRMS(m/z)Calcd for C21H9ON6BrClF6S2[M+H]+652.90553;Found652.90603.
实施例9:化合物9的制备
1、在无水条件下,将5-苯基苯并[d]噁唑-2-硫醇(100.0mg,0.44mmol)、2,4,6-三氯嘧啶(80.7mg,0.44mmol)、无水碳酸钾(72.9mg,0.53mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物2-((4,6-二氯嘧啶-2-基)硫代)-5-苯基苯并[d]噁唑(99.5mg,收率:60.4%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将2-((4,6-二氯嘧啶-2-基)硫代)-5-苯基苯并[d]噁唑(100.0mg,0.27mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(84.6mg,0.27mmol),无水碳酸钾(45.5mg,0.33mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-5-苯基苯并[d]噁唑(119.4mg,收率:67.9%)。
化合物9表征如下:
1HNMR(500MHz,CDCl3)δppm 8.57(s,2H),8.05(s,1H),7.96(s,1H),7.90(s,1H),7.66-7.61(m,4H),7.49(t,J=7.5Hz,2H),7.42(d,J=8.0Hz,1H).
13C NMR(101MHz,CDCl3)δppm 168.21,167.70,160.28,159.70,155.84,151.28,146.59,141.83,140.33,139.53,132.36(q,J=33.8Hz),132.08,129.15,127.87,127.55,126.61,126.21,123.33,123.25(q,J=273.9Hz),118.59,114.52,110.94.
ESI-HRMS(m/z)Calcd for C27H14ON6ClF6S2[M+H]+651.02577;Found651.02462.
实施例10:化合物10的制备
1、在无水条件下,将5-叔丁基苯并[d]噁唑-2-硫醇(100.0mg,0.48mmol)、2,4,6-三氯嘧啶(88.5mg,0.48mmol)、无水碳酸钾(79.5mg,0.58mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物5-叔丁基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(93.7mg,收率:55.1%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将5-叔丁基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.28mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(87.7mg,0.28mmol),无水碳酸钾(46.4mg,0.34mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-5-叔丁基苯并[d]噁唑(109.0mg,收率:61.7%)。
化合物10表征如下:
1HNMR(500MHz,CDCl3)δppm 8.58(s,2H),7.96(s,1H),7.92(s,1H),7.81(s,1H),7.50(s,2H),1.40(s,9H).
13C NMR(101MHz,CDCl3)δppm 168.52,167.74,160.30,159.70,154.97,149.92,149.35,146.50,141.16,132.39(q,J=33.8Hz),132.10,126.62,124.56,123.34,123.26(q,J=273.9Hz),116.71,114.36,110.10,35.18,31.77.
ESI-HRMS(m/z)Calcd for C25H18ON6ClF6S2[M+H]+631.05707Found631.05623.
实施例11:化合物11的制备
1、在无水条件下,将6-甲基苯并[d]噁唑-2-硫醇(100.0mg,0.61mmol)、2,4,6-三氯嘧啶(111.0mg,0.61mmol)、无水碳酸钾(101.0mg,0.73mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=20/1,V/V),得白色絮状物5-甲基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(95.9mg,收率:50.4%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将6-甲基-2-((4,6-二氯嘧啶-2-基)硫代)苯并[d]噁唑(100.0mg,0.32mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(100.2mg,0.32mmol),无水碳酸钾(53.0mg,0.38mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)-6-甲基苯并[d]噁唑(113.3mg,收率:60.1%)。
化合物11表征如下:
1HNMR(500MHz,CDCl3)δppm 8.56(s,2H),7.92(s,1H),7.85(s,1H),7.59(d,J=8.0Hz,1H),7.36(s,1H),7.18(d,J=8.0Hz,1H),2.50(s,3H).
13C NMR(101MHz,CDCl3)δppm 168.74,160.14,159.65,154.23,152.14,146.79,139.02,137.45,132.38(q,J=33.8Hz),131.95,128.98,126.72,126.59,123.31,123.27(q,J=273.8Hz),119.52,113.91,110.96,21.91.
实施例12:化合物12的制备
1、在无水条件下,将噁唑并[4,5-b]吡啶-2-硫醇(100.0mg,0.65mmol)、2,4,6-三氯嘧啶(119.2mg,0.65mmol)、无水碳酸钾(107.64mg,0.78mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得淡黄色絮状物2-((4,6-二氯嘧啶-2-基)硫代)噁唑[4,5-b]吡啶(85.9mg,收率:44.2%)。
2、在无水条件下,将3,5-二(三氟甲基)苯甲酰氯(1g,3.63mmol),氨基硫脲(0.73g,7.98mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3,5-双(三氟甲基)苯甲酰)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(772.6mg,两步收率:68%)。
3、在无水条件下,将2-((4,6-二氯嘧啶-2-基)硫代)噁唑[4,5-b]吡啶(100.0mg,0.34mmol),5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(106.5mg,0.34mmol),无水碳酸钾(56.3mg,0.41mmol)溶于无水DMF(3.0mL)中,室温下搅拌12h,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=1/1,V/V),得白色絮状物2-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)噁唑并[4,5-b]吡啶(111.6mg,收率:57.0%)。
化合物12表征如下:
1HNMR(500MHz,CDCl3)δppm 8.56(s,2H),8.51(s,1H),8.45(s,1H),7.92–7.85(m,2H),7.38–7.33(m,1H).
13C NMR(101MHz,CDCl3)δppm 165.55,162.20,159.38,154.41,146.58,143.74,132.50(q,J=33.8Hz)131.09,130.68,128.98,126.70,123.65,123.15(q,J=273.9Hz),121.21,119.28,118.56,117.02,114.52.
ESI-HRMS(m/z)Calcd for C20H9ON7ClF6S2[M+H]+575.98972Found575.98811.
实施例13:化合物13的制备
1、在无水条件下,将苯并[d]噻唑-2-硫醇(100.0mg,0.60mmol)、2,4,6-三氯嘧啶(109.7mg,0.60mmol)、无水碳酸钾(99.1mg,0.72mmol)溶于无水DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4,6-二氯嘧啶-2-基)硫基)苯并[d]噻唑(193.9mg,收率:54.7%)。
2、在无水条件下,将3-氟-5-(三氟甲基)苯甲酰氯(1g,4.41mmol),氨基硫脲(0.81g,8.82mmol)溶于无水THF(30.0mL)中,0℃下反应2h后升温至室温继续反应10h,TLC监测反应结束,向反应液中加入饱和碳酸氢钠溶液淬灭反应,反应液用乙酸乙酯萃取、水洗、无水硫酸钠干燥后过滤旋干得淡黄色粗产物2-(3-氟-5-(三氟甲基)苯甲酰基)肼硫代酰胺,加入质量分数为5%NaOH溶液50mL,回流6h,反应液加2N的盐酸溶液调节pH至6-7,溶液中析出白色絮状沉淀,待沉淀析出完毕后抽滤干燥得5-(3-氟-5-(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(728.4mg,两步收率:62.7%)。
3、在无水条件下,将2-((4,6-二氯嘧啶-2-基)硫基)苯并[d]噻唑(100.0mg,0.32mmol),5-(3-氟-5-(三氟甲基)苯基)-4H-1,2,4-三唑-3-硫醇(84.2mg,0.32mmol),无水碳酸钾(53.0mg,0.38mmol)溶于无水DMF(3.0mL)中,60℃微波辅助40min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(PE/EA=5/1,V/V),得白色絮状物2-((4-氯-6-((5-(3-氟-5-(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)嘧啶-2-基)硫代)苯并[d]噁唑(73.7mg,收率:43.9%)。
化合物13表征如下:
1HNMR(500MHz,CDCl3)δppm 8.14(d,J=4.6Hz,1H),7.95–7.93(m,1H),7.86(s,1H),7.72–7.67(m,1H),7.55–7.52(m,1H),7.43–7.32(m,3H).
13C NMR(101MHz,CDCl3)δppm 168.47,168.27,162.82(d,J=250.2Hz),160.37,159.68,155.35,151.75,146.58,141.06,133.30(dq,J=33.7,8.0Hz),132.83,126.62,125.44,123.17(dq,J=273.8,3.0Hz),120.17,119.24,116.93(d,J=24.2Hz),114.17,114.15(q,J=24.2,3.0Hz),110.89.
实施例14:化合物14的制备
在无水条件下,将4-N-叔丁氧羰基氨基哌啶(84.1mg,0.42mmol)、NaH(60%分散在矿物油中)(16.8mg,0.42mmol)、12-((4-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)-6-氯嘧啶-2-基)硫代)苯并[d]噻唑(200.0mg,0.34mmol)溶于DMF(3.0mL)中,60℃微波辅助下反应30min,TLC监测反应结束,反应液用乙酸乙酯萃取、水洗、饱和食盐水洗,无水硫酸钠干燥后过滤旋干,柱层析分离提纯(DCM/EA=5/1,V/V),得白色絮状物(1-(2-(苯并[d]恶唑-2-基硫代)-6-((5-(3,5-双(三氟甲基)苯基)-4H-1,2,4-三唑-3-基)硫代)嘧啶-4-基)哌啶-4-基)氨基甲酸酯(111.3mg,收率:44.3%)。
化合物14通过核磁共振氢谱表征如下:
1HNMR(500MHz,CDCl3)δppm 8.54(s,2H),7.90(s,1H),7.67(d,J=7.4Hz,1H),7.47(d,J=7.6Hz,1H),7.33–7.28(m,2H),6.56(s,1H),4.55(s,1H),4.34–4.17(m,2H),3.64(s,1H),2.98–2.87(m,2H),1.86–1.84(m,2H),1.44(s,1H),1.24–1.18(m,2H).
13C NMR(101MHz,CDCl3)δppm 166.38,166.05,160.57,159.22,156.82,155.37,151.96,149.48,141.20,132.22,132.21(q,J=33.8Hz),126.48,126.18,125.01,123.22(q,J=273.3Hz),123.04,120.01,110.53,103.50,79.98,47.96,42.88,31.99,29.74,28.43.
一、抗菌活性评价
1、试剂和材料
实验样品:化合物1-6以及7-12;
培养基:1)MH琼脂培养基(Mueller Hinton Agar),购自中国药品生物制品检定所;2)MH肉汤(Mueller Hinton Broth)培养基;购自中国药品生物制品检定所;3)脑心浸液(Brain Heart Infusion)培养基,美国BD公司产品;
阳性对照:左氧氟沙星(Levofloxacin),购自中国药品生物制品检定所;
实验菌:34株实验室保存的标准菌和临床分离菌;
质控菌:选用金黄色葡萄球菌ATCC29213、粪肠球菌ATCC29212、大肠埃希菌ATCC25922、铜绿假单胞菌ATCC27853。
2、实验方法
参照美国临床和实验室标准协会(CLSI)标准,采用平皿二倍稀释法和Denlay多点接种器进行药敏实验。
1)将实验菌用MH肉汤或脑心浸液进行增菌培养,药物用DMSO溶解,然后用MH肉汤稀释至所需浓度后,分别将适量的上述经过增菌培养后的实验菌和溶解后的药物DMSO加到平皿中;
2)将MH琼脂培养基熔化后,定量注入到上述含药物DMSO和实验菌的平皿内混匀,平皿中样品的终浓度分别为128、64……0.06、0.03μg/mL(平皿中样品的终浓度呈现按照1/2倍逐渐递减的方式);
3)培养基凝固后接种实验菌(接种量为104cfu/点),在35℃的恒温下培养18h后观察结果,无菌生长的平皿中所含药物最小的浓度即为最低抑菌浓度(Minimal InhibitoryConcentration,MIC)。
3、实验结果
化合物1-5以及左氟沙星的抗菌实验结果如表1所示,表1中的MIC的单位为(μg/mL):
表1
化合物6以及化合物8-12的抗菌实验结果如表2所示,表2中的MIC的单位为(μg/mL):
表2
通过表1-2可以看出,化合物1,2,3,8,11对于上述革兰氏阳性菌菌株都具有明显的抑菌效果,特别是化合物2和8,对于敏感型的菌株表现出与阳性药左氧氟沙星相当的抑菌活性,对于耐甲氧西林的金黄色葡萄球菌(MRSA),耐甲氧西林表皮葡萄球菌(MRSE),耐甲氧西林及万古霉素中度耐药的金黄色葡萄球菌(MRSA,VISA)和耐万古霉素的屎肠球菌(VRE)具有较强的抑菌效果,效果明显优于现有的抗菌药物左氧氟沙星。
二、SecA ATP酶活性抑制测试
测试方法参考:赵莉莉,李秋萍,魏玉珍,等.以SecA为靶点的新型抗绿脓杆菌药物细胞水平筛选模型的建立和应用[J].微生物学通报,2008,35(12):1926-1931.
具体测试方法如下所示:
1、测试蛋白:绿脓杆菌SecA N75。
2、试剂与仪器
(1)酶反应缓冲液:0.5mol/L Tris-HCl,0.2mol/L KCl,0.2mol/L NH4Cl,10mmol/L DTT,20mmol/L Mg(OAc)2,将酶反应缓冲液置于4℃保存。
(2)显色试剂:将4.2%钼酸铵溶解于4mol/L HCl,与0.45%孔雀绿按1:3混合并过滤,然后加入Triton X-100,至终浓度0.1%。
3、实验方法:
将SecA酶活测定反应体系在37℃孵育30min,加入160μL颜色试剂反应1min,然后加入20μL质量分数为34%柠檬酸钠溶液终止反应。SecA酶活测定反应体系内同时设置空白对照组和阴性对照组,见表3。用酶标仪测定样品在660nm波长下的吸光值。
计算Sec A酶活的抑制百分率,公式如下:抑制率(%)={1-[A660(供试品)-A660(空白对照)]/[A660(阴性对照)-A660(空白对照)]}×100
表3
组分 | 阴性对照组 | 空白对照组 | 供试样品组 |
酶反应缓冲液 | + | + | + |
20mmol/L ATP | + | + | + |
ATPase | + | - | + |
去离子水 | + | + | + |
供试样品 | - | - | + |
通过SecAATP酶活性抑制测试实验,对化合物1和2及SecA抑制剂SCA-112进行SecAATP酶活性抑制实验,初步筛查化合物在200μM浓度下,对SecA ATP酶活性的抑制作用,以抑制率的形式给出,抑制率越高,抑制活性越强,初筛结果见表4。
表4
通过表4可以看出,本发明合成出的化合物1和化合物2在200μM浓度下对SecA ATP酶具有中等程度的抑制活性,且抑制活性明显高于现有的SecA抑制剂SCA-112,因此化合物1和化合物2具有的母核结构,即本发明提供的嘧啶类化合物可以作为新的先导化合物,进行进一步地深入研究,具有较高的开发价值。
以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
2.根据权利要求1所述的嘧啶类化合物或其盐,其特征在于,所述R2选自氯;R3选自3,5-二(三氟甲基);A、B、C、Z 均选自碳。
3.根据权利要求2所述的嘧啶类化合物或其盐,其特征在于,所述R1选自氢、卤素、未被取代的C1~6烷基、苯基中的一种。
4.根据权利要求3所述的嘧啶类化合物或其盐,其特征在于,所述R1选自氢、甲基、溴中的一种。
9.一种药物组合物,其特征在于,包括权利要求1-4任一项所述的嘧啶类化合物。
10.根据权利要求1-4任一项所述的嘧啶类化合物在制备抗菌药物中的应用;
所述菌包括抗耐甲氧西林的金黄色葡萄球菌、耐甲氧西林表皮葡萄球菌、耐甲氧西林及万古霉素中度耐药的金黄色葡萄球菌以及耐万古霉素的屎肠球菌。
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