CN114591255B - 一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物及其制备方法与应用 - Google Patents
一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物及其制备方法与应用 Download PDFInfo
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- CN114591255B CN114591255B CN202210326510.2A CN202210326510A CN114591255B CN 114591255 B CN114591255 B CN 114591255B CN 202210326510 A CN202210326510 A CN 202210326510A CN 114591255 B CN114591255 B CN 114591255B
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- acid
- triazole
- side chain
- acrylamide
- pleuromutilin
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- -1 1,2, 4-triazole acrylamide side chain Chemical group 0.000 title claims abstract description 52
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- 239000002994 raw material Substances 0.000 claims abstract description 9
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Abstract
本发明公开了一种含1,2,4‑三氮唑丙烯酰胺侧链的截短侧耳素衍生物及其制备方法与应用,属于医药化学领域。该类化合物以截短侧耳素、不同取代丙烯酸为原料,在催化剂作用下,以3‑巯基‑1,2,4‑三氮唑为连接体,合成了一类未见报道的具有抗耐药菌活性的含1,2,4‑三氮唑丙烯酰胺侧链的截短侧耳素衍生物。该合成方法操作安全性高,反应条件温和,适用于工业化生产。经初步生物活性测试和安全性评价表明该类具有抗耐药菌活性的含1,2,4‑三氮唑丙烯酰胺侧链的截短侧耳素衍生物有较好的抗耐药菌活性和安全性,因此可应用于治疗感染性疾病,特别是耐药菌引起的感染性疾病,具有很好的医药开发价值。
Description
技术领域
本发明属于药物化学领域,具体涉及一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物及其制备方法与应用。
背景技术
截短侧耳素是由担子菌纲侧耳属Pleurotus mutilus.和Pleurotus Passeckerianus菌发酵液中分离提取到的白色晶体,是一种三环二萜类化合物,其分子式为C22H34O5。据研究显示,它对革兰氏阳性菌具有良好的抑制作用。截短侧耳素抗菌类药物与其他已上市的抗菌药物不同,它作用于细菌核糖体肽酰转移中心(PTC),干扰tRNA与P-位点和A-位点结合,从而抑制蛋白质的合成。而由于PTC的高度保守性,使其耐药性较低。因此,截短侧耳素类抗菌药物对耐药的革兰氏阳性菌,如耐甲氧西林的金黄色葡萄球菌、耐万古霉素的金黄色葡萄球菌、耐青霉素的肺炎链球菌、耐药性支原体等以及敏感的革兰氏阳性菌和部分革兰氏阴性菌如卡他莫拉菌和流感嗜血杆菌等,均具有很强的抗菌活性。
含氮杂环化合物有着独特的生物活性,毒性低,内吸性高,常被用作医药和农药的结构组成单元,在医药和农药合成方面起着重要的作用。其中三唑环是一种具有良好抗菌活性的基团,可作为优势片段用于抑菌药物的研发。
芳基丙烯酸类化合物被报道普遍具有良好的抗菌活性,如肉桂酸等被广泛利用作为食品添加剂和医药中间体,由于其出色的抗菌活性,常用于新型抗生素的开发。
发明内容
为了克服上述现有技术的缺点,本发明的目的在于提供一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物及其制备方法与应用,治疗耐药菌感染引起的感染性疾病。
为了达到上述目的,本发明采用以下技术方案予以实现:
本发明公开了一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物,具有如式Ⅰ化合物或其药学上可接受的盐,以及所述的式Ⅰ化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物,包括外消旋混合物:
其中:
R1为氢原子和氰基中的一种;R2为氢原子和氰基中的一种;
R为其中R3、R4和R5独立选自氢原子、卤素、氟原子、硝基、甲氧基、三氟甲基或二甲氨基;连接位置为芳环中取代基及杂原子除外的任意位置。
优选地,所述含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的代表性化合物如下所示:
优选地,所述药学上可接受的盐为式Ⅰ化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
本发明还公开了上述一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的制备方法,包含如下步骤:
1)以截短侧耳素与对甲苯磺酰氯为原料反应得到中间体Ⅰ;
其中,中间体Ⅰ为
2)以步骤1)所得中间体Ⅰ与3-巯基-1,2,4-三氮唑为原料,反应并纯化得到中间体Ⅱ;
其中,中间体Ⅱ为
3)以步骤2)所得的中间体Ⅱ与各种取代芳基丙烯酸反应,纯化,得到如式Ⅰ所示结构的含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物。
优选地,步骤1)中,反应所用溶剂为二氯甲烷、乙腈、甲醇、丙酮或N,N-二甲基甲酰胺;反应条件为在室温下反应4-6h;所述截短侧耳素与对甲苯磺酰氯摩尔比为1:1.1步骤2)中,反应所用溶剂为二氯甲烷。
优选地,步骤3)中,反应所用溶剂为二氯甲烷、乙腈、丙酮或N,N-二甲基甲酰胺;反应具体步骤为:各种取代的芳基丙烯酸在缩合剂和碱的条件下进行活化30min,再加入中间体Ⅱ反应6-10h;所述缩合剂为N,N-二环己基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑或2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯;所述碱为三乙胺、4-二甲氨基吡啶、N,N-二异丙基乙胺或N-甲基吗啉。
本发明还公开了含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物在制备抗耐药菌药物制剂中的应用。
优选地,所述抗耐药菌药物为治疗耐药菌感染引起的感染性疾病的药物。
进一步优选地,所述耐药菌为多重耐药铜绿假单胞菌、多重耐药肺炎克雷伯菌、耐甲氧西林金黄色葡萄球菌、耐万古霉素粪肠球菌或耐碳青霉烯鲍曼不动杆菌。
优选地,所述抗耐药菌药物制剂为单独使用或与可药用的赋形剂、稀释剂混合制成口服给药的片剂、胶囊剂、颗粒剂、糖浆剂、预混剂或微丸剂,或者制成非口服方式给药的搽剂或注射剂。
本发明还公开了一种药物组合物,所述药物组合物包括上述含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物作为活性成分。
与现有技术相比,本发明具有以下有益效果:
本发明提供的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物,利用芳基丙烯酸及其衍生物对截短侧耳素进行结构改造,将具有抑菌性的三唑环将优势片段与母核进行连接,进行广泛的生物活性筛选,获得了一类新型丙烯酰胺类截短侧耳素化合物。对合成的含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物进行初步的体外抗耐药菌活性实验,实验证明该截短侧耳素衍生物对耐甲氧西林金黄色葡萄球菌具有较好的抗菌作用,优选化合物3、6和7对表皮葡萄球菌的抑制作用均优于三种受试的上市药物(瑞他莫林、泰妙菌素和沃尼妙林),化合物1、3、6和7对金黄色葡萄球菌(ATCC 25923)的抑制能力强于三种受试的上市药物,化合物1、3和6对金黄色葡萄球菌(ATCC 29213)也显示出较强的抑制作用,化合物3、6、7和14对大肠杆菌和鲍曼不动杆菌能够产生一定的抑制作用;化合物3、6、7对所测试的五种临床耐药菌株(MDR-PA 18-126、MDR-KP 18-893、MRSA 18-171、VRE 18-80和CR-AB 18-882)有着中等至良好的抑制作用,且均不弱于上市药物瑞他莫林;对合成的含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物进行体外细胞毒性实验,实验证明优选化合物3、6和7对HEK293细胞的IC50值均大于200μM,显著高于瑞他莫林、沃尼妙林和泰妙菌素,相较于受试的三种上市药物,化合物3对细胞的毒性较小,在高浓度时细胞存活率高,具有较好的安全性,经不同浓度的化合物3处理的HepG2、HEK293和A549细胞,细胞形态正常,细胞透明度大,折光性强,轮廓清楚。实验证明本发明提供的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物有潜力作为新型的抗生素应用于感染性疾病的治疗中,治疗动物或人全身系统感染性疾病,特别是由耐药菌引起的感染性疾病。
本发明提供的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的制备方法,该制备方法操作方便、安全性高且成本低廉,以截短侧耳素、不同取代丙烯酸为原料,在催化剂作用下,以3-巯基-1,2,4-三氮唑为连接体,合成含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物,反应产率为75%-86.4%,产率较高,适合用于工业化生产。
附图说明
图1是本发明中化合物8在氘代氯仿中的核磁氢谱图;
图2是本发明中化合物8在氘代氯仿中的核磁碳谱图;
图3是本发明中化合物9在氘代氯仿中的核磁氢谱图;
图4是本发明中化合物9在氘代氯仿中的核磁碳谱图;
图5是本发明中化合物15在氘代氯仿中的核磁氢谱图;
图6是本发明中化合物15在氘代氯仿中的核磁碳谱图;
图7是本发明中化合物3对表皮葡萄球菌(ATCC 12228)的体外抗菌活性测定结果图;
图8是本发明中化合物3对金黄色葡萄球菌(ATCC 29213)的体外抗菌活性测定结果图;
图9是本发明中化合物3对耐甲氧西林金黄色葡萄球菌(ATCC 33591)的体外抗菌活性测定结果图;
图10是本发明中不同浓度化合物3对HepG2、HEK293和A549细胞处理的细胞存活率图;
图11是本发明中不同浓度瑞他莫林处理的HepG2、HEK293和A549细胞存活率图;
图12是本发明中经不同浓度化合物3处理的HepG2细胞形态图;其中,A为0μM(细胞存活率100%);B为0.78μM(细胞存活率82.94%);C为1.56μM(细胞存活率85.91%);D为3.13μM(细胞存活率85.21%);E为6.2μM(细胞存活率85.30%);F为12.5μM(细胞存活率86.11%);G为25μM(细胞存活率83.31%);H为50μM(细胞存活率73.10%);I为100μM(细胞存活率50.02%);J为200μM(细胞存活率33.54%);
图13是本发明中经不同浓度化合物3处理的HEK293细胞形态图;其中,A为0μM(细胞存活率100%);B为0.78μM(细胞存活率82.57%);C为1.56μM(细胞存活率82.74%);D为3.13μM(细胞存活率85.38%);E为6.2μM(细胞存活率82.68%);F为12.5μM(细胞存活率83.30%);G为25μM(细胞存活率81.49%);H为50μM(细胞存活率81.08%);I为100μM(细胞存活率60.13%);J为200μM(细胞存活率57.25%);
图14是本发明中经不同浓度化合物3处理的A549细胞形态图;其中,A为0μM(细胞存活率100%);B为0.78μM(细胞存活率79.19%);C为1.56μM(细胞存活率77.21%);D为3.13μM(细胞存活率76.30%);E为6.2μM(细胞存活率76.07%);F为12.5μM(细胞存活率73.40%);G为25μM(细胞存活率76.62%);H为50μM(细胞存活率79.81%);I为100μM(细胞存活率82.38%);J为200μM(细胞存活率64.29%)。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分的实施例,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,都应当属于本发明保护的范围。
需要说明的是,本发明的说明书和权利要求书及上述附图中的术语“第一”、“第二”等是用于区别类似的对象,而不必用于描述特定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换,以便这里描述的本发明的实施例能够以除了在这里图示或描述的那些以外的顺序实施。此外,术语“包括”和“具有”以及他们的任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
下面结合附图对本发明做进一步详细描述:
本发明提供的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的结构式如式Ⅰ所示:
其中:R1为氢原子和氰基中的一种;R2为氢原子和氰基中的一种;
R为其中R3、R4和R5独立选自氢原子、卤素、氟原子、硝基、甲氧基、三氟甲基和二甲氨基中的一种;连接位置为芳环中取代基及杂原子除外的任意位置。
本发明提供的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物涉及所述化合物的药学上可接受的盐,所述的药学上可接受的盐为式Ⅰ化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐,代表性衍生物的可药用盐如下图所示:
本发明提供的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物还包括所述式Ⅰ化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物,包括外消旋混合物。
本发明提供的合成上述含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的制备方法如下:
(1)以截短侧耳素与对甲苯磺酰氯为原料反应得到中间体Ⅰ,反应式如下:
其中,反应所用溶剂为二氯甲烷、乙腈、甲醇、丙酮或N,N-二甲基甲酰胺,进一步优选为二氯甲烷;反应条件为在室温下反应4-6h,进一步优选为5h;所述截短侧耳素与对甲苯磺酰氯的摩尔比为1:1.2;
(2)以步骤(1)所得中间体Ⅰ与3-巯基-1,2,4-三氮唑为原料,反应并纯化得到中间体Ⅱ,反应式如下:
其中,反应所用溶剂为二氯甲烷;反应的具体步骤为:先向3-巯基-1,2,4-三氮唑甲醇溶液中滴加1,8-二氮杂二环十一碳-7-烯(DBU),室温反应30min,再向其滴加中间体Ⅰ的二氯甲烷溶液,室温反应6-9h,进一步优选为8h;所述中间体Ⅰ与3-巯基-1,2,4-三氮唑的摩尔比为1:1.2;
(3)以步骤(2)所得的中间体Ⅱ与各种取代芳基丙烯酸反应,纯化,得到如式Ⅰ所示结构的具有抗耐药菌活性的含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物,反应式如下:
其中,反应所用溶剂为二氯甲烷、乙腈、丙酮或N,N-二甲基甲酰胺,优选溶剂为二氯甲烷;反应具体步骤为:各种取代丙烯酸在缩合剂的条件下进行活化30min,再加入中间体Ⅱ反应6-10h,进一步优选为9h,其中,所述缩合剂为N,N-二环己基碳二亚胺(DCC)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)、1-羟基苯并三唑(HOBT)或2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU),进一步优选为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)或1-羟基苯并三唑(HOBT);所述碱为三乙胺(TEA)、4-二甲氨基吡啶(DMAP)、N,N-二异丙基乙胺(DIEPA)或N-甲基吗啉(NMM),进一步优选为N,N-二异丙基乙胺(DIEPA);
1、合成化合物1-15的具体实施例
本发明部分优选实施方案中化合物结构式如下所示:
下面给出上述化合物合成的实施例,化合物的结构经NMR表征。
实施例1
(1)中间体Ⅰ的制备
将截短侧耳素(757.0mg,2mmol)与对甲苯磺酰氯(418.0mg,2.2mmol)溶于二氯甲烷(30mL),置于反应器中,加入TEA(0.8mL,6mmol)和DMAP(24.4mg,0.2mmol),室温搅拌5h。减压浓缩反应液,使用饱和碳酸氢钠水溶液(50mL)洗涤浓缩后的产物,得到中间体Ⅰ(1012.1mg,1.9mmol),产率95.0%。所制备中间体Ⅰ用于中间体Ⅱ的原料。
(2)中间体Ⅱ的制备
向3-巯基-1,2,4-三氮唑(242.7mg,2.4mmol)的二氯甲烷(10mL)溶液中逐滴滴加1,8-二氮杂二环十一碳-7-烯(DBU)(1.3mL,9mmol),并将混合物在室温下搅拌30min,然后将中间体Ⅰ(1065.4mg,2.0mmol)的二氯甲烷(10mL)溶液滴入上述混合溶液中,反应8h。将反应液减压浓缩,向残余物中加入乙酸乙酯(50mL),依次用饱和氯化铵水溶液(50mL)和饱和氯化钠水溶液(50mL)洗涤有机相,收集有机层并加入无水硫酸钠干燥,滤除无水硫酸钠并减压浓缩,残余物经硅胶柱层析分离纯化(200-300目硅胶粉为固定相,流动相为二氯甲烷:甲醇(V:V)=30:1),干燥,得中间体Ⅱ675.4mg,产率73.2%。
(3)化合物1的制备
化合物1:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙基环戊[8]环烯-5-基2-((1-肉桂酰-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
将肉桂酸(24.8mg,0.17mmol)溶于二氯甲烷(10mL),置于反应器中,加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DIEPA(0.029mL,0.17mmol),室温活化30min,随后向混合溶液中加入步骤(2)所得中间体Ⅱ(64.6mg,0.14mmol),室温反应9h,减压浓缩反应液,残余物柱层析分离纯化(200~300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物1(70.9mg,0.12mmol),产率85.7%。
1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.04(t,J=14.7Hz,1H),7.73(d,J=7.9Hz,2H),7.62(d,J=16.8Hz,2H),7.46(dd,J=17.4,9.0Hz,2H),6.56–6.41(m,1H),5.83(t,J=9.3Hz,1H),5.38–5.24(m,2H),4.00(d,J=6.0Hz,2H),3.39(dd,J=12.4,6.5Hz,1H),2.38–2.22(m,3H),2.11(d,J=11.1Hz,2H),1.80(d,J=13.9Hz,1H),1.64(d,J=11.3Hz,4H),1.49(d,J=8.6Hz,5H),1.44–1.38(m,1H),1.31(d,J=7.5Hz,1H),1.22(s,1H),1.14(s,2H),0.90(d,J=6.8Hz,3H),0.79(d,J=7.1Hz,3H).
13C NMR(101MHz,CDCl3)δ217.53,169.94,163.21,161.63,150.71,148.49,146.26,135.95,129.62,128.29,127.61,114.27,112.58,72.89,70.88,57.60,55.27,44.34,43.94,41.97,36.84,36.72,36.36,34.44,30.52,28.80,27.02,24.89,16.57,14.90,11.96.
实施例2
化合物2:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙基环戊[8]环烯-5-基2-((1-((E)-3-(4-(三氟甲基)苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将4-三氟肉桂酸(23.9mg,0.17mmol)溶于二氯甲烷(10mL),置于反应器中,向反应液中加入DCC(41.2mg,0.2mmol)和NMM(0.019mL,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应7h,减压浓缩反应液,残余物进行柱层析(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物2(51.632mg,0.112mmol),产率80.0%。
1H NMR(400MHz,CDCl3)δ9.02(s,1H),8.76(t,J=14.8Hz,1H),7.83–7.61(m,2H),7.51(s,1H),7.29(d,J=8.5Hz,1H),6.63–6.53(m,1H),5.80(t,J=9.5Hz,1H),5.40–5.31(m,2H),4.16(d,J=6.7Hz,2H),3.68(dd,J=11.4,6.6Hz,1H),2.54–2.31(m,3H),2.16(d,J=11.3Hz,2H),1.77–1.63(m,4H),1.53(d,J=10.4Hz,4H),1.37(s,1H),1.31–1.24(m,2H),1.21(s,2H),1.10(s,2H),0.92(d,J=6.4Hz,3H),0.81(t,J=8.3Hz,3H).
13C NMR(101MHz,CDCl3)δ217.29,169.33,163.37,161.96,150.17,148.83,146.36,135.67,129.65,128.37,127.27,114.22,112.63,72.07,70.61,57.67,55.33,44.89,43.17,41.36,36.33,36.49,36.22,34.97,30.26,28.37,27.07,24.00,16.67,14.91,11.95.
实施例3
化合物3:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(噻吩-3-基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将反-3-(3-噻吩基)丙烯酸(24.7mg,0.16mmol)溶于乙腈(5mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和TEA(0.023mL,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应9h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为二氯甲烷:甲醇(V:V)=30:1),干燥,得最终产物化合物3(50.67mg,0.11mmol),产率78.6%。
1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.91(t,J=15.8Hz,1H),8.01–7.87(m,1H),7.62(s,1H),7.32(d,J=8.6Hz,1H),6.72–6.56(m,1H),5.89(t,J=9.6Hz,1H),5.48–5.33(m,2H),4.20(d,J=6.8Hz,2H),3.71(dd,J=11.2,6.7Hz,1H),2.64–2.49(m,3H),2.20(d,J=12.6Hz,2H),1.89–1.78(m,4H),1.61(d,J=11.4Hz,4H),1.40(s,1H),1.29–1.21(m,2H),1.18(s,2H),1.12(s,2H),1.01(d,J=6.5Hz,3H),0.89(t,J=8.1Hz,3H).
13C NMR(101MHz,CDCl3)δ217.51,169.97,163.37,161.65,150.77,148.51,146.39,135.61,129.52,128.30,127.57,115.27,111.59,75.81,71.89,57.67,54.25,44.35,43.93,41.91,35.13,35.01,34.55,34.21,30.54,28.81,27.52,24.93,16.63,14.94,11.95.
实施例4
化合物4:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(吡啶-3-基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将3-(3-吡啶)丙烯酸(23.8mg,0.16mmol)溶于乙腈(5mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DIEPA(0.029ml,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应9h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物4(65.2mg,0.11mmol),产率78.6%。
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.96(t,J=15.9Hz,2H),8.03–7.94(m,1H),7.73(s,1H),7.41(d,J=8.6Hz,1H),6.68–6.60(m,1H),5.91(t,J=9.5Hz,1H),5.50–5.42(m,2H),4.26(d,J=6.9Hz,2H),3.75(dd,J=11.3,6.8Hz,1H),2.61–2.53(m,3H),2.24(d,J=12.5Hz,2H),1.86–1.75(m,4H),1.64(d,J=11.3Hz,4H),1.45(s,1H),1.28–1.24(m,2H),1.19(s,2H),1.10(s,2H),1.03(d,J=6.7Hz,3H),0.92(t,J=8.1Hz,3H).
13C NMR(101MHz,CDCl3)δ217.23,169.30,163.261,161.63,150.77,148.19,147.81,146.26,135.30,129.33,128.21,127.61,114.21,112.58,72.79,70.88,57.61,55.27,44.30,43.61,41.97,36.19,36.01,35.36,34.46,30.59,28.81,27.23,24.21,16.63,14.91,11.96.
实施例5
化合物5:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧基-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(3-氯苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将3-氯肉桂酸(29.2mg,0.16mmol)溶于丙酮(10mL),置于反应器中,向反应液中加入HATU(76.0mg,0.2mmol)和DIEPA(0.073mL,0.42mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应6h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物5(68.2mg,0.109mmol),产率77.9%。
1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.11(t,J=14.0Hz,1H),7.72(d,J=6.5Hz,2H),7.61(d,J=15.9Hz,1H),7.50(d,J=7.7Hz,2H),6.52–6.42(m,1H),5.82(t,J=10.2Hz,1H),5.38–5.16(m,2H),3.98(s,2H),3.37(dd,J=15.1,6.3Hz,1H),2.34(q,J=7.5,6.8Hz,1H),2.24(q,J=9.5Hz,2H),2.08(s,2H),1.78(d,J=13.5Hz,1H),1.68(t,J=11.2Hz,2H),1.56(d,J=12.7Hz,2H),1.47(s,3H),1.36(s,1H),1.30(q,J=7.2,6.0Hz,2H),1.20(s,2H),1.12(s,2H),0.88(d,J=7.1Hz,3H),0.78(d,J=7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ216.53,167.95,164.21,162.61,151.72,149.41,145.96,135.01,129.33,128.24,126.62,114.24,112.30,72.22,70.84,57.61,55.23,44.31,43.97,41.91,36.81,36.36,36.11,34.20,30.17,28.17,27.00,24.81,16.53,14.20,11.93.
实施例6
化合物6:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-2-氰基-3-苯丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将α-氰基肉桂酸(29.4mg,0.17mmol)溶于二氯甲烷(10mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DIEPA(0.029mL,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应8h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物6(69.7mg,0.113mmol),产率为80.7%。
1H NMR(400MHz,CDCl3)δ9.01(s,1H),8.23(t,J=13.7Hz,1H),8.01(d,J=7.7Hz,2H),7.72(d,J=16.8Hz,2H),7.52(m,1H),6.62–6.53(m,1H),5.92(t,J=9.1Hz,1H),5.42–5.31(m,2H),4.01(d,J=6.2Hz,2H),3.42(dd,J=11.4,6.6Hz,1H),2.40–2.24(m,3H),2.14(d,J=11.5Hz,2H),1.84(d,J=13.7Hz,1H),1.63(d,J=10.6Hz,4H),1.46(d,J=8.8Hz,5H),1.42–1.36(m,1H),1.30(d,J=7.6Hz,1H),1.21(s,1H),1.12(s,2H),0.96(d,J=6.7Hz,3H),0.81(d,J=7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ217.13,169.96,163.23,161.67,150.76,148.40,146.38,135.91,129.31,128.29,127.31,116.87,114.21,112.48,72.89,70.88,57.60,55.27,44.34,43.94,41.97,36.84,36.82,36.31,34.42,30.52,28.80,27.02,24.84,16.57,14.90,11.95.
实施例7
化合物7:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-氰基-3-(噻吩-2-基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将(Z)-3-氰基-3-(噻吩-2-基)丙烯酸(32.6mg,0.15mmol)溶于二氯甲烷(10mL),置于反应器中,向反应液中加入HATU(76.0mg,0.2mmol)和DIEPA(0.073mL,0.42mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应10h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物7(71.7mg,0.115mmol),产率为82.1%。
1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.21(t,J=11.7Hz,1H),8.02(d,J=7.6Hz,1H),7.74(d,J=16.9Hz,2H),7.54(m,1H),6.60–6.51(m,1H),5.90(t,J=9.2Hz,1H),5.43–5.34(m,2H),3.96(d,J=6.1Hz,2H),3.44(dd,J=11.6,6.7Hz,1H),2.43–2.26(m,3H),2.12(d,J=11.6Hz,2H),1.83(d,J=13.1Hz,1H),1.61(d,J=10.7Hz,4H),1.41(d,J=8.6Hz,5H),1.39–1.31(m,1H),1.29(d,J=7.5Hz,1H),1.22(s,1H),1.13(s,2H),0.98(d,J=6.5Hz,3H),0.86(d,J=7.6Hz,3H).
13C NMR(101MHz,CDCl3)δ217.43,169.94,163.21,161.61,150.61,148.41,146.26,135.95,129.22,128.34,127.51,119.34,114.29,112.51,72.79,70.81,57.64,55.23,44.31,43.74,41.97,36.84,36.72,36.31,34.45,30.52,28.80,27.07,24.88,16.57,14.90,11.96.
实施例8
化合物8:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-(E)-3-(4-(二甲氨基)苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将4-二甲氨基肉桂酸(32.5mg,0.17mmol)溶于甲醇(10mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和TEA(0.023mL,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应9h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为二氯甲烷:甲醇(V:V)=20:1),干燥,得最终产物化合物8(76.8mg,0.121mmol)化合物8在氘代氯仿中的核磁氢谱如图1所示,核磁碳谱如图2所示,产率为86.4%。
1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.07(d,J=15.6Hz,1H),7.62(d,J=8.5Hz,2H),7.35(s,1H),6.74(d,J=8.5Hz,2H),6.47(dd,J=17.5,11.0Hz,1H),5.81(d,J=8.4Hz,1H),5.31(d,J=11.2Hz,1H),5.17(d,J=17.4Hz,1H),3.98(s,2H),3.36(d,J=6.4Hz,1H),3.13(s,6H),2.39–2.30(m,1H),2.31–2.17(m,2H),2.08(d,J=22.4Hz,2H),1.83–1.53(m,6H),1.43(d,J=40.6Hz,6H),1.13(s,3H),0.89(d,J=7.0Hz,3H),0.79(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ217.08,167.44,162.14,152.92,151.40,144.66,138.84,131.60,121.81,117.29,111.68,107.70,74.57,70.05,58.15,45.45,44.57,43.92,41.87,40.12,36.76,35.99,34.48,30.41,26.85,26.30,24.82,16.78,14.87,11.49.
实施例9
化合物9:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧基-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(3,4-二甲氧基苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将3,4-二甲氧基肉桂酸(32.2mg,0.17mmol)溶于丙酮(10mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DMAP(0.002mg,0.014mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应7h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=3:2),干燥,得最终产物化合物9(75.3mg,0.116mmol),化合物9在氘代氯仿中的核磁氢谱如图3所示,核磁碳谱如图4所示,产率为82.9%。
1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.04(dd,J=16.0,11.3Hz,1H),7.48(dd,J=32.2,15.8Hz,1H),7.33–7.26(m,2H),6.94(t,J=7.6Hz,1H),6.53–6.39(m,1H),5.80(dd,J=13.7,8.5Hz,1H),5.35–5.22(m,2H),4.00(s,2H),3.97(d,J=6.1Hz,6H),3.36(dd,J=13.2,6.4Hz,1H),2.40–2.18(m,3H),2.08(q,J=12.0,10.8Hz,2H),1.77(d,J=12.6Hz,1H),1.65(q,J=9.9,9.3Hz,4H),1.54(d,J=12.8Hz,1H),1.46(d,J=11.1Hz,4H),1.36(d,J=13.7Hz,1H),1.29(d,J=9.9Hz,1H),1.19(s,1H),1.12(s,2H),0.88(t,J=6.9Hz,3H),0.77(t,J=8.7Hz,3H).
13C NMR(101MHz,CDCl3)δ216.97,167.31,167.04,163.71,161.76,152.65,151.68,150.61,149.42,144.74,138.88,117.24,111.96,111.10,110.47,74.54,70.10,58.12,56.12,53.46,45.43,44.59,43.91,41.87,36.71,36.01,34.49,30.39,26.83,26.36,24.83,16.74,14.91,14.82,11.48.
实施例10
化合物10:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧基-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(4-甲氧基苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将4-甲氧基肉桂酸(30.3mg,0.17mmol)溶于乙腈(10mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DIEPA(0.029ml,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应10h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物10(74.9mg,0.12mmol),产率为85.7%。
1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.06(d,J=15.7Hz,1H),7.67(d,J=8.3Hz,2H),7.45(d,J=15.9Hz,1H),6.99(d,J=8.3Hz,2H),6.45(dd,J=17.5,10.8Hz,1H),5.79(d,J=8.6Hz,1H),5.37–5.24(m,2H),3.96(s,2H),3.90(s,3H),3.34(d,J=6.5Hz,1H),2.37–2.18(m,3H),2.14–2.01(m,2H),1.77(d,J=14.5Hz,1H),1.66(t,J=11.5Hz,3H),1.46(s,5H),1.37(d,J=14.4Hz,2H),1.29(d,J=13.9Hz,1H),1.11(s,3H),0.87(d,J=6.9Hz,3H),0.76(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ217.56,169.95,163.27,161.65,150.76,148.23,146.06,135.03,129.02,128.22,127.65,114.26,112.57,72.76,70.08,57.37,55.96,55.21,44.76,43.03,41.03,36.89,36.39,36.03,34.43,30.51,28.71,27.09,24.81,16.73,14.86,11.27.
实施例11
化合物11:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧基-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(3,4,5-三氟苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将3,4,5-三氟肉桂酸(38mg,0.16mmol)溶于二氯甲烷(10mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DIEPA(0.029ml,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应7h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物11(67.8mg,0.105mmol),产率为75.0%。
1H NMR(400MHz,CDCl3)δ9.01(s,1H),8.63(t,J=14.8Hz,1H),7.86–7.61(m,1H),7.37(s,1H),7.27(d,J=8.6Hz,1H),6.32–6.26(m,1H),5.63(t,J=9.6Hz,1H),5.31–5.17(m,2H),3.93(d,J=6.8Hz,2H),3.31(dd,J=10.6,6.6Hz,1H),2.29–2.21(m,3H),2.11(d,J=11.3Hz,2H),1.77–1.61(m,4H),1.47(d,J=12.2Hz,4H),1.38(s,1H),1.30–1.26(m,2H),1.24(s,2H),1.13(s,2H),0.91(d,J=6.4Hz,3H),0.81(t,J=8.2Hz,3H).
13C NMR(101MHz,CDCl3)δ217.53,169.95,163.21,161.63,150.69,148.19,146.03,135.07,129.62,128.21,127.61,114.27,112.58,72.89,70.88,57.60,55.27,49.34,43.94,41.97,37.84,36.92,36.86,34.96,30.57,28.80,27.12,24.93,16.59,14.81,11.37.
实施例12
化合物12:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(4-氟苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将对氟肉桂酸(26.6mg,0.16mmol)溶于甲醇(5mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DMAP(0.002mg,0.014mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应7h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物12(60.9mg,0.11mmol),产率为78.6%。
1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.08(t,J=14.3Hz,1H),7.74(d,J=7.1Hz,2H),7.60(dd,J=36.8,15.9Hz,1H),7.22(d,J=8.3Hz,1H),6.53–6.42(m,1H),5.84(t,J=10.3Hz,1H),5.39–5.26(m,2H),4.01(d,J=5.8Hz,2H),3.39(dd,J=12.7,6.3Hz,1H),2.31(dt,J=27.6,10.8Hz,3H),2.17–2.08(m,2H),1.86–1.76(m,1H),1.70(t,J=10.6Hz,2H),1.59(s,1H),1.50(d,J=10.0Hz,5H),1.43(d,J=11.1Hz,1H),1.31(t,J=7.8Hz,1H),1.22(s,2H),1.15(s,3H),0.91(d,J=6.8Hz,3H),0.80(t,J=8.0Hz,3H).
13C NMR(101MHz,CDCl3)δ217.22,169.30,163.26,161.16,150.03,148.19,146.03,135.08,129.64,128.33,127.67,114.38,112.63,72.71,70.87,57.50,55.21,44.37,43.96,41.91,36.85,36.73,36.37,34.41,30.54,28.87,27.05,24.83,16.58,14.91,11.98.
实施例13
化合物13:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(4-硝基苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将对硝基肉桂酸(38mg,0.16mmol)溶于乙腈(5mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和NMM(0.019ml,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应9h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1),干燥,得最终产物化合物13(65.9mg,0.103mmol),产率为73.6%。
1H NMR(400MHz,CDCl3)δ8.97(s,1H),8.12(t,J=13.2Hz,1H),7.53(d,J=7.3Hz,2H),7.43(dd,J=36.8,15.9Hz,1H),7.32(d,J=8.1Hz,1H),6.43–6.28(m,1H),5.80(t,J=11.3Hz,1H),5.41–5.25(m,2H),4.03(d,J=5.9Hz,2H),3.42(dd,J=12.6,6.3Hz,1H),2.33(dt,J=12.1,10.8Hz,3H),2.23–2.10(m,2H),1.87–1.73(m,1H),1.69(t,J=10.9Hz,2H),1.60(s,1H),1.54(d,J=10.3Hz,5H),1.46(d,J=11.2Hz,1H),130(t,J=7.9Hz,1H),1.20(s,2H),1.16(s,3H),0.89(d,J=6.9Hz,3H),0.81(t,J=8.2Hz,3H).
13C NMR(101MHz,CDCl3)δ219.53,167.95,163.21,161.63,150.72,148.49,146.21,135.96,129.65,128.31,127.06,114.00,112.59,72.91,70.80,57.61,55.27,44.34,43.95,41.97,37.84,36.93,36.52,34.03,30.52,28.80,27.02,24.89,16.57,14.90,11.96.
实施例14
化合物14:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(萘-1-基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将(E)-3-(萘-1-基)丙烯酸(31.7mg,0.16mmol)溶于二氯甲烷(5mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DIEPA(0.029ml,0.17mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应10h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1)进行纯化,干燥,得最终产物化合物14(68.2mg,0.11mmol),产率为78.6%。
1H NMR(400MHz,CDCl3)δ9.01(s,1H),,8.63(t,J=14.6Hz,1H)8.47(m,2H)7.98(d,J=8.1Hz,2H),7.63(d,J=16.9Hz,2H),7.41(dd,J=17.5,9.3Hz,2H),6.63–6.39(m,1H),5.53(t,J=9.2Hz,1H),5.41–5.32(m,2H),4.06(d,J=6.5Hz,2H),3.43(dd,J=12.5,6.6Hz,1H),2.41–2.23(m,3H),2.14(d,J=11.6Hz,2H),1.76(d,J=12.9Hz,1H),1.69(d,J=10.6Hz,4H),1.51(d,J=8.5Hz,5H),1.43–1.36(m,1H),1.30(d,J=7.6Hz,1H),1.21(s,1H),1.16(s,2H),0.91(d,J=6.7Hz,3H),0.82(d,J=7.3Hz,3H).
13C NMR(101MHz,CDCl3)δ218.51,169.30,163.71,161.63,150.71,148.52,146.26,135.16,133.63,133.08,132.30,129.97,129.62,129.13,128.81,128.29,127.61,114.27,112.58,72.17,70.63,57.60,55.27,44.32,43.94,41.97,36.84,36.72,36.61,34.51,30.51,28.80,27.02,24.80,16.57,14.91,11.97.
实施例15
化合物15:(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧基-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基2-((1-((E)-3-(3,4-二氟苯基)丙烯酰)-1H-1,2,4-三唑-3-基)硫代)乙酸酯的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1,将3,4-二氟肉桂酸(31.3mg,0.17mmol)溶于二氯甲烷(5mL),置于反应器中,向反应液中加入EDCI(38.4mg,0.2mmol),HOBT(27mg,0.2mmol)和DMAP(0.002mg,0.014mmol),活化30min,加入中间体Ⅱ(64.6mg,0.14mmol),室温反应7h,减压浓缩反应液,残余物进行柱层析分离纯化(200-300目硅胶粉为固定相,流动相为石油醚:乙酸乙酯(V:V)=1:1)进行纯化,干燥,得最终产物化合物15(65.9mg,0.105mmol),化合物15在氘代氯仿中的核磁氢谱如图5所示,核磁碳谱如图6所示,产率为75.0%。
1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.00(t,J=14.8Hz,1H),7.62–7.50(m,2H),7.47(s,1H),7.28(d,J=8.5Hz,1H),6.53–6.43(m,1H),5.82(t,J=9.4Hz,1H),5.36–5.18(m,2H),3.99(d,J=6.6Hz,2H),3.38(dd,J=10.4,6.6Hz,1H),2.38–2.22(m,3H),2.10(d,J=11.0Hz,2H),1.75–1.62(m,4H),1.48(d,J=10.2Hz,4H),1.36(s,1H),1.33–1.28(m,2H),1.21(s,2H),1.14(s,2H),0.89(d,J=6.3Hz,3H),0.79(t,J=8.2Hz,3H).
13C NMR(101MHz,CDCl3)δ217.07,167.25,166.92,163.07,161.13,158.13,151.88,147.75,146.99,144.86,138.93,118.31,117.23,116.03,115.84,74.54,70.20,58.11,45.44,43.93,41.87,36.70,36.01,35.48,34.44,30.38,26.84,26.36,24.82,16.76,14.90,14.82,11.50.
2.化合物体外抗耐药菌活性测定
采用微量肉汤稀释法,以莫西沙星(购于上海麦克林生化科技有限公司)为阳性对照品,测试含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的最低抑菌浓度(Minimuminhibitory concentration,MIC),同时与已上市的截短侧耳素类抗生素瑞他莫林(购于南京康满林化工实业有限公司)、泰妙菌素(购于上海源叶生物科技有限公司)和沃尼妙林(购于上海吉至生化科技有限公司)进行比较,以筛选出活性更优的截短侧耳素类衍生物。
标准菌株包括革兰氏阳性菌:表皮葡萄球菌ATCC 12228、金黄色葡萄球菌ATCC29213、ATCC 25923和耐甲氧西林金黄色葡萄球菌ATCC 33591;革兰氏阴性菌:鲍曼不动杆菌ATCC19606和大肠杆菌ATCC 25922,所有菌株均购自于美国模式培养物集存库。
临床耐药菌包括多重耐药铜绿假单胞菌(MDR-PA)18-126、多重耐药肺炎克雷伯菌(MDR-KP)18-893、耐甲氧西林金黄色葡萄球菌(MRSA)18-171、耐万古霉素粪肠球菌(VRE)18-80和耐碳青霉烯鲍曼不动杆菌(CR-AB)18-882,所有临床耐药菌株均来源于复旦大学附属华山医院。
具体操作步骤如下:
(1)MHB培养基配制:称取MHB培养基(购于广州环凯微生物科技有限公司)20.0g,加入到1L蒸馏水中,加热煮沸至完全溶解,分装于锥形瓶中,121℃高压灭菌15min,备用;
(2)实验菌株培养至对数生长期:无菌条件下,将复苏后的实验菌株接种到100mLMHB培养基中,置于37℃恒温恒湿培养箱中培养20-22h,备用;
(3)样品液制备:称取待测样品和已上市的对照品抗生素(瑞他莫林、泰妙菌素和沃尼妙林)用DMSO溶液溶解,配制成浓度为10.24mg/mL的样品液,阳性对照品(莫西沙星)用DMSO溶液溶解,配制成浓度为5.12mg/mL的样品液。
(4)菌悬液制备:无菌条件下,将培养至对数生长期的实验菌株用MHB培养基校正到0.5麦氏单位浊度标准后按1:200的比例进行稀释,备用;
(5)微量二倍稀释法测定MIC:取无菌96孔板,在第2孔加入10μL莫西沙星样品液,第4-11孔加入10μL DMSO溶液,第3、4孔加入10μL按梯度设置稀释过的样品液,并对药物进行二倍稀释至第10孔,第11孔为溶剂对照。然后每孔加入190μL稀释过的菌悬液,使每孔最终的菌液浓度为5×105CFU/mL,置37℃恒温恒湿箱中培育20-22h。
(6)MIC终点判读:黑色背景下肉眼观察96孔板中所见能完全抑制细菌生长的浓度为该样品对该种细菌的最低抑菌浓度,记录结果见表1及图7至图9(其中,小孔自左向右依次对应为阳性、256、128、64、32、16、8、4、2、阴性)。
表1受试药物的最低抑菌浓度(μg/mL)
表1结果显示,化合物3、6、7对表皮葡萄球菌(ATCC 12228)能起到很好的抑制作用,MIC达到8μg/mL,其效果均优于三种受试的上市药物;化合物1、3、6、7、9对革兰氏阳性菌金黄色葡萄球菌(ATCC 25923)起到不同程度的抑制作用,MIC从4到16μg/mL不等,其中化合物1、3、6、7化合物对金黄色葡萄球菌(ATCC 25923)的抑制能力强于三种受试的上市药物;此外,化合物1、3、6对另一株金黄色葡萄球菌(ATCC 29213)也显示出较强的抑制作用,MIC达到了2μg/mL。
通过对比化合物1-15与三种上市药物对耐甲氧西林金黄色葡萄球菌的抑制作用,发现化合物3的抑菌效果优于三种上市药物;此外,化合物3、6、7和14都可以对大肠杆菌和鲍曼不动杆菌产生一定的抑制作用,其中化合物3对上述两种菌株的抑制程度最好,并且化合物3对大肠杆菌的抑菌效果优于瑞他莫林。
表2受试药物对临床耐药菌的最小抑菌浓度(μg/mL)
由表2可知,化合物3、6和7对所测试的五种临床耐药菌株有着中等至良好的抑制作用,且均不弱于上市药物瑞他莫林。
综上,本发明的含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物可以对不同的菌株均产生抑制作用,特别是对临床分离的耐药菌株也有较好的抗菌效果,具有进一步进行临床研究的意义。
3.化合物体外细胞毒性测定
采用MTT法评估含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物体外细胞毒性。
取处于对数生长期的HepG2、HEK293和A549细胞(购于美国ATCC库),胰蛋白酶消化后制成细胞悬液,调整细胞密度为105个/mL,每孔100μL接种于无菌96孔细胞培养板,置于37℃,5%CO2恒温培养箱中培养24h。待细胞贴满孔板底部后,分别在每孔中加入浓度梯度的药液(瑞他莫林、沃尼妙林、泰妙菌素、化合物3、化合物6和化合物7)10μL,平行设6个复孔,同时设置调零组(不含细胞和药物组)和对照组(不含药物组)。置于37℃,5%CO2恒温培养箱内孵育24h后,每孔加入5g/L MTT溶液20μL继续培养4h。培养结束后,轻轻吸去孔内培养液,每孔加入DMSO 150μL,置摇床上低速振荡10min,使结晶物充分溶解后,于酶联免疫检测仪OD490 nm处测量各孔的吸光值,计算细胞存活率,并在光学显微镜下观察细胞的形态变化。根据半数抑制浓度(IC50)来评价药物对HepG2、HEK293和A549细胞的细胞毒性。部分记录结果见表2及图10-图14。
表3受试药物的半数抑制浓度(IC50,μM)
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表3显示了不同试验药物的半数抑制浓度(IC50),化合物3、6、7对HEK293细胞的IC50值均大于200μM,显著高于瑞他莫林、沃尼妙林和泰妙菌素。图10、图11分别显示了不同稀释度的化合物3、瑞他莫林对HepG2、HEK293和A549细胞处理后的细胞存活率,表明化合物3在高浓度时细胞存活率高,具有较好的安全性。细胞形态观察发现(图12-图14),经不同浓度的化合物3处理的HepG2、HEK293和A549细胞,细胞形态正常,细胞透明度大,折光性强,轮廓清楚,进一步说明化合物3对三种细胞的毒性较小。此外,化合物6对A549细胞的IC50值(194.5μM)低于化合物3和7,但对HepG2细胞的IC50值(185.9μM)高于化合物3(120.5μM)和7(121.2μM),约为瑞他莫林(36.48μM)的5倍。综上,三个优选的化合物在细胞毒性方面均优于所选上市药物,具有良好的安全性。
以上内容仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明权利要求书的保护范围之内。
Claims (9)
1.一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物,其特征在于,具有如式Ⅰ化合物或其药学上可接受的盐:
式Ⅰ
其中:
R1为氢原子和氰基中的一种;R2为氢原子和氰基中的一种;
R为、/>、/>、/>或/>,其中R3、R4和R5独立选自氢原子、卤素、硝基、甲氧基、三氟甲基或二甲氨基;连接位置为芳环中取代基及杂原子除外的任意位置。
2.根据权利要求1所述的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物,其特征在于,所述含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的代表性化合物如下所示:
。
3.根据权利要求1所述的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物,其特征在于,所述药学上可接受的盐为式Ⅰ化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
4.权利要求1-3任意一项所述的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的制备方法,其特征在于,包含如下步骤:
1)以截短侧耳素与对甲苯磺酰氯为原料反应得到中间体Ⅰ;
其中,中间体Ⅰ为;
2)以步骤1)所得中间体Ⅰ与3-巯基-1,2,4-三氮唑为原料,反应并纯化得到中间体Ⅱ;
其中,中间体Ⅱ为;
3)以步骤2)所得的中间体Ⅱ与各种取代丙烯酸反应,纯化,得到如式Ⅰ所示结构的含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物。
5.根据权利要求4所述的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的制备方法,其特征在于,步骤1)中,反应所用溶剂为二氯甲烷、乙腈、甲醇、丙酮或N,N-二甲基甲酰胺;反应条件为在室温下反应4-6h;所述截短侧耳素与对甲苯磺酰氯摩尔比为1:1.1,步骤2)中,反应所用溶剂为二氯甲烷。
6. 根据权利要求4所述的一种含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物的制备方法,其特征在于,步骤3)中,反应所用溶剂为二氯甲烷、乙腈、丙酮或N,N-二甲基甲酰胺;反应具体步骤为:各种取代的丙烯酸在缩合剂和碱的条件下进行活化30min,再加入中间体Ⅱ反应6-10h;所述缩合剂为N,N-二环己基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑或2-(7-偶氮苯并三氮唑)- N,N,N’,N’-四甲基脲六氟磷酸酯;所述碱为三乙胺、4-二甲氨基吡啶、N,N-二异丙基乙胺或N-甲基吗啉。
7.权利要求1-3任意一项所述的含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物在制备抗耐药菌药物制剂中的应用,其特征在于,所述耐药菌为多重耐药铜绿假单胞菌、多重耐药肺炎克雷伯菌、耐甲氧西林金黄色葡萄球菌、耐万古霉素粪肠球菌或耐碳青霉烯鲍曼不动杆菌。
8.根据权利要求7所述的应用,其特征在于,所述抗耐药菌药物制剂为单独使用或与可药用的赋形剂、稀释剂混合制成口服给药的片剂、胶囊剂、颗粒剂、糖浆剂、预混剂或微丸剂,或者制成非口服方式给药的搽剂或注射剂。
9.一种药物组合物,其特征在于,所述药物组合物包括权利要求1-3任意一项所述的含1,2,4-三氮唑丙烯酰胺侧链的截短侧耳素衍生物作为活性成分。
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