CN114736194A - 一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物及其制备方法与应用 - Google Patents
一种具有抗病原微生物活性的含吡啶季铵盐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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- CN114736194A CN114736194A CN202210319468.1A CN202210319468A CN114736194A CN 114736194 A CN114736194 A CN 114736194A CN 202210319468 A CN202210319468 A CN 202210319468A CN 114736194 A CN114736194 A CN 114736194A
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- compound
- acid
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- pleuromutilin
- quaternary ammonium
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- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical class C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 55
- 230000000694 effects Effects 0.000 title claims abstract description 31
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 244000005700 microbiome Species 0.000 title description 8
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- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 35
- 229940079593 drug Drugs 0.000 claims description 29
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 claims description 17
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物及其制备方法与应用,属于药物化学领域。对合成的截短侧耳素衍生物进行结构表征后,对革兰氏阳性菌及革兰氏阴性菌的体外抗菌实验表明,本发明合成的含吡啶季铵盐侧链的截短侧耳素衍生物具有较强的抗菌活性,对HepG2、HEK293和A549细胞的体外细胞毒性实验表明,本发明合成的含吡啶季铵盐侧链的截短侧耳素衍生物具有较低的毒性,体外抗支原体活性研究表明,本发明合成的含吡啶季铵盐侧链的截短侧耳素衍生物具有良好的抗支原体活性。本发明提供的制备该截短侧耳素衍生物的方法原料易得,反应条件简单、温和,产物收率高,适合工业化生产,并在抗病原微生物方面具有良好的应用前景。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物及其制备方法与应用。
背景技术
多年来,随着抗生素的滥用,耐药细菌越来越多,耐药范围越来越广,程度也越来越高,多重耐药菌不断出现,多种具有耐药性的“超级细菌”开始在全球蔓延,对人类的健康构成新威胁。因此,探索具有新型抗菌作用机制、且具有良好生物利用度的广谱抗菌药物具有重要意义。
截短侧耳素是一种带有刚性的5-6-8三环结构碳骨架的二萜类化合物,研究显示,它对革兰阳性菌和支原体具有良好的抑制作用。截短侧耳素的抗菌机制不同于市场上现有抗生素的抗菌机制,主要是通过与细菌核糖体肽酰转移中心(PTC)发生作用,干扰tRNA与P-位点和A-位点结合,从而抑制蛋白质的合成,由于PTC高度的保守性,使其耐药率较低。目前以截短侧耳素为骨架进行结构修饰的上市药物泰妙菌素、瑞他莫林、沃尼妙林和来法莫林为研发其他种类的截短侧耳素衍生物提供了思路。由于截短侧耳素及其衍生物特殊的抗菌机制和耐药缓慢的特点,使其成为目前抗生素研究的热点之一。
季铵盐类阳离子表面活性剂除具有表面活性剂的表面吸附、降低表面张力及在溶液中聚集等基本特性外,还具有抑制和杀灭微生物等生物效应。除此之外,季铵盐类化合物对人体毒性低、刺激性轻、腐蚀性小,并且价格低廉,在医疗卫生、食品和日用化工等领域得到广泛应用。
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具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物及其制备方法与应用,治疗由耐药菌或支原体引起的感染性疾病。
为了达到上述目的,本发明采用以下技术方案予以实现:
本发明公开了一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物,为通式Ⅰ化合物或其药学上可接受的盐,以及所述的通式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、R2、R3和R4各自独立地选自氢原子、甲基、三氟甲基、甲氧基、三氟甲氧基、叔丁基、硝基、氰基、卤素原子或苯基。
优选地,代表性化合物如下:
优选地,所述药学上可接受的盐为具有如通式Ⅰ所示结构的化合物与盐酸、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具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物的制备方法,包括以下操作步骤:
1)将截短侧耳素与对甲苯磺酰氯反应,得到中间体Ⅰ;
2)以步骤1)制得的中间体Ⅰ和4-巯基吡啶为原料,有机溶剂溶解,在催化剂催化及加热的条件下反应,后经分离纯化得到中间体Ⅱ;
3)以步骤2)制得的中间体Ⅱ和含不同取代基的溴甲基芳杂环类化合物或碳原子数为3-15的溴代烷烃类化合物为原料进行反应,经分离纯化,即得通式Ⅰ所示结构的具有吡啶季铵盐侧链的截短侧耳素衍生物。
优选地,步骤1)中,截短侧耳素与对甲苯磺酰氯的摩尔比为1:1.2;步骤2)中,中间体Ⅰ与4-巯基吡啶的摩尔比为1:1.2;步骤3)中,中间体Ⅱ与含不同取代的溴苄类化合物的摩尔比为1:(2-6)。
优选地,步骤1)中,所述的反应以二氯甲烷作溶剂,三乙胺和4-二甲氨基吡啶作催化剂,室温下搅拌反应8小时;步骤2)所述的有机溶剂为N,N-二甲基甲酰胺;所述的反应条件为60℃加热反应6小时;步骤3)所述的反应以甲苯、丙酮或乙腈作为溶剂,反应时间为12-48小时。
本发明还公开了上述具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物在制备抗菌产品中的应用。
优选地,所述抗菌产品为治疗感染性疾病的药物制剂。
进一步优选地,所述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。
优选地,所述感染性疾病为人或动物由病原微生物引起的感染性疾病。
进一步优选地,所述病原微生物为耐药菌或支原体。
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,所述支原体为猪肺炎支原体标准菌株J株、猪肺炎支原体临床分离株LH株、猪鼻支原体标准株BTS-7株、鸡毒支原体标准株R株或鸡滑液囊支原体WVU 1853株。
本发明还公开了一种药物组合物,所述药物组合物包含上述含吡啶季铵盐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:
本发明提供的一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物,通过将季铵盐引入到截短侧耳素母核中,制得一类截短侧耳素季铵盐类化合物,该类化合物具有较好的抗病原微生物活性。经初步生物活性测试和安全性评价表明该类截短侧耳素衍生物具有较好的抗菌活性和安全性,对耐甲氧西林的金黄色葡萄球菌等革兰氏阳性菌以及大肠杆菌等革兰氏阴性菌的体外抗菌实验表明,本发明合成的含吡啶季铵盐侧链的截短侧耳素衍生物具有较强的抗菌活性,优选化合物2对沙门氏菌ATCC 14028、表皮葡萄球菌ATCC 12228、金黄色葡萄球菌ATCC 25923和ATCC 29213、耐甲氧西林金黄色葡萄球菌ATCC 33591、大肠杆菌ATCC 25922和CMCC 44103以及鲍曼不动杆菌ATCC 19606均表现出优异的抑菌效果,其对沙门氏菌ATCC 14028、表皮葡萄球菌ATCC 12228、金黄色葡萄球菌ATCC25923和ATCC 29213的抑制作用更是优于三种上市药物(瑞他莫林、泰妙菌素和沃尼妙林)。优选化合物1、2、6对临床分离耐药菌株(MDR-PA 18-126、MDR-KP 18-893、MRSA 18-171、VRE18-80和CR-AB 18-882)显示出不同程度的抑制作用,抗菌活性均近似或优于对照药物瑞他莫林。同时,对HepG2、HEK293和A549细胞的体外细胞毒性实验表明,本发明合成的含吡啶季铵盐侧链的截短侧耳素衍生物具有较低的毒性,受试代表化合物2在浓度大于50μM的条件下处理HepG2、HEK293和A549细胞,细胞存活率均高于泰妙菌素和沃尼妙林。此外,体外抗支原体活性研究表明,本发明合成的含吡啶季铵盐侧链的截短侧耳素衍生物具有良好的抗支原体活性,受试化合物2对测试的几株支原体(Mhp-J、Mhp-LH、Mhr-BTS-7、MG-R和MS-WVU1853)的MIC值结果均优于已上市药物泰妙菌素。因此,本发明合成的截短侧耳素衍生物可应用于治疗感染性疾病,特别是耐药菌或支原体引起的感染性疾病,具有很好的医药开发价值。
本发明提供的上述含吡啶季铵盐侧链的截短侧耳素衍生物的制备方法,该方法操作安全性高、反应条件简单、温和、原料易得、成本低廉、产率较高,适用于工业化生产。
附图说明
图1是化合物1在氘代DMSO中的核磁氢谱图;
图2是化合物1在氘代DMSO中的核磁碳谱图;
图3是化合物2在氘代DMSO中的核磁氢谱图;
图4是化合物2在氘代DMSO中的核磁碳谱图;
图5是化合物3在氘代DMSO中的核磁氢谱图;
图6是化合物3在氘代DMSO中的核磁碳谱图;
图7是化合物4在氘代DMSO中的核磁氢谱图;
图8是化合物4在氘代DMSO中的核磁碳谱图;
图9是化合物5在氘代DMSO中的核磁氢谱图;
图10是化合物5在氘代DMSO中的核磁碳谱图;
图11是化合物6在氘代DMSO中的核磁氢谱图;
图12是化合物6在氘代DMSO中的核磁碳谱图;
图13是化合物7在氘代DMSO中的核磁氢谱图;
图14是化合物7在氘代DMSO中的核磁碳谱图;
图15是化合物8在氘代DMSO中的核磁氢谱图;
图16是化合物8在氘代DMSO中的核磁碳谱图;
图17是化合物9在氘代DMSO中的核磁氢谱图;
图18是化合物9在氘代DMSO中的核磁碳谱图;
图19是化合物10在氘代DMSO中的核磁氢谱图;
图20是化合物10在氘代DMSO中的核磁碳谱图;
图21是化合物11在氘代DMSO中的核磁氢谱图;
图22是化合物11在氘代DMSO中的核磁碳谱图;
图23是化合物12在氘代DMSO中的核磁氢谱图;
图24是化合物12在氘代DMSO中的核磁碳谱图;
图25是化合物13在氘代DMSO中的核磁氢谱图;
图26是化合物13在氘代DMSO中的核磁碳谱图;
图27是化合物14在氘代DMSO中的核磁氢谱图;
图28是化合物14在氘代DMSO中的核磁碳谱图;
图29是化合物15在氘代DMSO中的核磁氢谱图;
图30是化合物15在氘代DMSO中的核磁碳谱图;
图31是化合物16在氘代DMSO中的核磁氢谱图;
图32是化合物16在氘代DMSO中的核磁碳谱图;
图33是化合物17在氘代DMSO中的核磁氢谱图;
图34是化合物17在氘代DMSO中的核磁碳谱图;
图35是化合物18在氘代DMSO中的核磁氢谱图;
图36是化合物18在氘代DMSO中的核磁碳谱图;
图37是化合物19在氘代DMSO中的核磁氢谱图;
图38是化合物19在氘代DMSO中的核磁碳谱图;
图39是化合物20在氘代DMSO中的核磁氢谱图;
图40是化合物20在氘代DMSO中的核磁碳谱图;
图41是化合物21在氘代DMSO中的核磁氢谱图;
图42是化合物21在氘代DMSO中的核磁碳谱图;
图43是化合物22在氘代DMSO中的核磁氢谱图;
图44是化合物22在氘代DMSO中的核磁碳谱图;
图45是化合物3对金黄色葡萄球菌(ATCC 25923)的体外抗菌实验结果;
图46是化合物13对表皮葡萄球菌(ATCC 12228)的体外抗菌实验结果;
图47是化合物14对金黄色葡萄球菌(ATCC 29213)的体外抗菌实验结果;
图48是经不同浓度下沃尼妙林、泰妙菌素和化合物2对HEK293细胞的存活率;
图49是经不同浓度下沃尼妙林、泰妙菌素和化合物2对HepG2细胞的存活率;
图50是经不同浓度下沃尼妙林、泰妙菌素和化合物2对A549细胞的存活率;
图51是化合物2对支原体的MIC测定结果;其中,A为猪肺炎支原体标准菌株J株;B为猪肺炎支原体临床分离株LH株;C为猪鼻支原体标准株BTS-7株;D为鸡毒支原体标准株R株;E为鸡滑液囊支原体WVU 1853株。
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:
本发明提供的一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物,为通式Ⅰ化合物或其药学上可接受的盐,以及所述的通式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、R2、R3和R4各自独立地选自氢原子、甲基、三氟甲基、甲氧基、三氟甲氧基、叔丁基、硝基、氰基、卤素原子或苯基;所述药学上可接受的盐为具有如通式Ⅰ所示结构的化合物与盐酸、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。
本发明提供的上述含吡啶季铵盐侧链的截短侧耳素衍生物的制备方法,包括以下操作步骤:
(1)将截短侧耳素与对甲苯磺酰氯反应,得到中间体Ⅰ,反应式如下:
其中,反应以二氯甲烷为溶剂,三乙胺和4-二甲氨基吡啶作为催化剂,室温下搅拌反应8小时;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)制得的中间体Ⅰ和4-巯基吡啶为原料,有机溶剂溶解,在催化剂催化及加热的条件下反应,后经分离纯化得到中间体Ⅱ,反应式如下:
其中,反应以N,N-二甲基甲酰胺为溶剂,60℃反应6小时;所述的中间体Ⅰ与4-巯基吡啶的摩尔比为1:1.2;催化剂为碳酸钾、三乙胺、碘化钾或碳酸铯,进一步优选为碳酸钾和碘化钾;
(3)以步骤(2)制得的中间体Ⅱ和含不同取代基的溴甲基芳杂环类化合物或碳原子数为3-15的溴代烷烃类化合物为原料进行反应,经分离纯化,即得如通式Ⅰ所示结构的具有吡啶季铵盐侧链的截短侧耳素衍生物,反应式如下:
其中,反应以甲苯、丙酮或乙腈作为溶剂,进一步优选为乙腈作溶剂,反应时间为12-48小时;中间体Ⅱ与含不同取代的溴苄类化合物的摩尔比为1:(2-6),进一步优化为1:4。
1.合成化合物1-22的具体实施例
代表性化合物的结构式、编号如下所示:
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11.4g(30mmol)截短侧耳素与6.9g(36mmol)对甲苯磺酰氯置于反应器中,使用150mL二氯甲烷进行溶解,向其中加入12.6mL(90mmol)三乙胺和366.5mg(2.5mmol)4-二甲氨基吡啶,室温下搅拌反应8小时,TLC监测。反应结束后,将反应液减压浓缩除去溶剂,所得固体使用饱和碳酸氢钠水溶液(120mL)和水(120mL)洗涤,干燥得到中间体Ⅰ,称重为15.39g,产率为96.28%。
(2)中间体Ⅱ的制备
将13.3g(25mmol)中间体Ⅰ和3.3g(30mmol)4-巯基吡啶置于反应器中,使用120mLN,N-二甲基甲酰胺进行溶解,向其中加入6.9g(50mmol)碳酸钾和415mg(2.5mmol)碘化钾,60℃加热反应6小时,TLC监测。反应结束后,使用饱和氯化铵水溶液稀释反应液,乙酸乙酯萃取,收集乙酸乙酯相,柱层析分离纯化(200-300目硅胶粉为固定相,二氯甲烷:甲醇(V:V)=15:1为流动相),干燥得到中间体Ⅱ,称重为10.94g,产率为92.74%。
(3)化合物1的合成
化合物1:1-苄基-4-((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-环戊[8]环烯-5-基)氧基)-2-氧代乙基)硫代吡啶-1-溴化铵的制备
将161.9mg(0.3mmol)中间体Ⅱ和205.2mg(1.2mmol)溴苄置于反应器中,使用5mL乙腈进行溶解,加热回流反应24小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10:1),干燥得到化合物1,称重为164.3mg,产率为85.20%。化合物1在氘代DMSO中的核磁氢谱如图1所示,核磁碳谱如图2所示。
1H NMR(600MHz,DMSO)δ8.96(d,J=6.9Hz,2H),8.01(d,J=7.1Hz,2H),7.52–7.47(m,2H),7.46–7.38(m,3H),6.06(dd,J=17.8,11.1Hz,1H),5.71(s,2H),5.55(d,J=8.3Hz,1H),4.99(dd,J=17.8,1.7Hz,1H),4.93(dd,J=11.1,1.7Hz,1H),4.56(d,J=6.1Hz,1H),4.43–4.32(m,2H),2.38(d,J=2.6Hz,1H),2.24–2.16(m,1H),2.14–1.98(m,3H),1.69–1.58(m,2H),1.51–1.43(m,1H),1.40–1.20(m,8H),1.08–0.96(m,4H),0.81(d,J=7.0Hz,3H),0.58(d,J=7.1Hz,3H).
13C NMR(151MHz,DMSO)δ217.47,166.55,161.87,142.99,141.31,135.12,129.71,129.66,128.95,124.01,115.66,72.96,71.46,62.39,57.61,45.40,44.57,44.07,41.99,36.91,36.74,34.45,33.84,30.53,29.10,26.99,24.91,16.64,14.92,12.00.
实施例2
化合物2:4-(((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)氧基)-2-氧代乙基)硫代)-1-(4-甲基苄基)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和277.6mg(1.5mmol)对甲基溴苄置于反应器中,使用5mL乙腈进行溶解,室温下搅拌反应18小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=8:1),干燥得到化合物2,称重为170.2mg,产率为86.37%。化合物2在氘代DMSO中的核磁氢谱如图3所示,核磁碳谱如图4所示。
1H NMR(600MHz,DMSO)δ9.09(d,J=7.2Hz,2H),8.07(d,J=6.5Hz,2H),7.50(d,J=7.8Hz,2H),7.29(d,J=7.8Hz,2H),6.12(dd,J=17.8,11.2Hz,1H),5.77(s,2H),5.60(d,J=8.3Hz,1H),5.06(d,J=17.8Hz,1H),4.99(d,J=11.1Hz,1H),4.68(d,J=6.0Hz,1H),4.49–4.39(m,2H),2.42(s,1H),2.35(s,3H),2.28–2.22(m,1H),2.17–2.03(m,3H),1.73–1.65(m,2H),1.56–1.48(m,1H),1.45–1.24(m,8H),1.12–1.02(m,4H),0.87(d,J=6.9Hz,3H),0.63(d,J=7.0Hz,3H).
13C NMR(151MHz,DMSO)δ217.50,166.56,161.64,142.89,141.31,139.27,132.25,130.14,129.10,124.00,115.68,72.92,71.41,62.03,57.62,45.39,44.57,44.02,41.97,36.91,36.73,34.46,33.86,30.53,29.12,26.98,24.91,21.22,16.63,14.90,12.03.
实施例3
化合物3:4-(((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)氧基)-2-氧代乙基)硫代)-1-(4-甲氧基苄基)吡啶-1-溴化铵制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和204.4mg(0.9mmol)对甲氧基溴苄置于反应器中,使用5mL丙酮进行溶解,室温下搅拌反应20小时,TLC监测。反应结束后,减压浓缩除去丙酮,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10:1),干燥得到化合物3,称重为164.3mg,产率为81.42%。化合物3在氘代DMSO中的核磁氢谱如图5所示,核磁碳谱如图6所示。
1H NMR(600MHz,DMSO)δ8.95(d,J=7.0Hz,2H),7.99(d,J=6.9Hz,2H),7.50(d,J=8.6Hz,2H),6.98(d,J=8.7Hz,2H),6.06(dd,J=17.8,11.2Hz,1H),5.62(s,2H),5.54(d,J=8.4Hz,1H),5.00(dd,J=17.8,1.8Hz,1H),4.94(dd,J=11.2,1.7Hz,1H),4.59(d,J=6.0Hz,1H),4.41–4.32(m,2H),3.75(s,3H),2.35(s,1H),2.23–2.15(m,1H),2.11–2.06(m,1H),2.05–1.97(m,2H),1.68–1.57(m,2H),1.51–1.42(m,1H),1.39–1.15(m,8H),1.08–0.94(m,4H),0.81(d,J=6.9Hz,3H),0.57(d,J=7.0Hz,3H).
13C NMR(151MHz,DMSO)δ217.47,166.55,161.56,160.40,142.71,141.29,130.85,127.05,124.02,115.69,114.99,72.95,71.42,61.94,57.60,55.74,45.39,44.56,44.01,41.95,36.89,36.72,34.44,33.81,30.51,29.12,26.98,24.91,16.63,14.87,12.01.
实施例4
化合物4:1-(4-氰基苯)-4-((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-环戊[8]环烯-5-基)氧基)-2-氧乙基)硫代)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和235.2mg(1.2mmol)对氰基溴苄置于反应器中,使用5mL丙酮进行溶解,室温下搅拌反应12小时,TLC监测。反应结束后,减压浓缩除去丙酮,柱层析分离纯化(二氯甲烷:甲醇(V:V)=15:1),干燥得到化合物4,称重为164.2mg,产率为81.97%。化合物4在氘代DMSO中的核磁氢谱如图7所示,核磁碳谱如图8所示。
1H NMR(600MHz,DMSO)δ9.12(d,J=6.7Hz,2H),8.05(d,J=7.2Hz,2H),7.92(d,J=8.2Hz,2H),7.75(d,J=8.1Hz,2H),6.05(dd,J=17.8,11.2Hz,1H),5.91(s,2H),5.53(d,J=8.3Hz,1H),5.02–4.89(m,2H),4.62(d,J=6.0Hz,1H),4.40(d,J=3.2Hz,2H),2.36(s,1H),2.23–2.15(m,1H),2.11–1.96(m,3H),1.69–1.59(m,2H),1.50–1.41(m,1H),1.39–1.26(m,3H),1.25(s,3H),1.24–1.19(m,2H),1.11(t,J=7.0Hz,1H),1.01(s,3H),0.80(d,J=6.9Hz,3H),0.57(d,J=7.1Hz,3H).
13C NMR(151MHz,DMSO)δ217.51,166.54,162.22,143.20,141.32,140.36,133.48,129.99,124.11,118.79,115.67,112.37,72.91,71.44,61.22,57.61,45.39,44.58,44.01,41.97,36.92,36.73,34.45,33.91,30.53,29.14,26.98,24.91,16.64,14.88,12.03.
实施例5
化合物5:4-(((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)氧基)-2-氧代乙基)硫代)-1-(4-硝基苄基)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和324.0mg(1.5mmol)对硝基溴苄置于反应器中,使用5mL甲苯进行溶解,室温下搅拌反应16小时,TLC监测。反应结束后,减压浓缩除去甲苯,柱层析分离纯化(二氯甲烷:甲醇(V:V)=15:1),干燥得到化合物5,称重为175.8mg,产率为85.22%。化合物5在氘代DMSO中的核磁氢谱如图9所示,核磁碳谱如图10所示。
1H NMR(600MHz,DMSO)δ9.03(d,J=7.2Hz,2H),8.29(d,J=8.7Hz,2H),8.06(d,J=7.2Hz,2H),7.79(d,J=8.7Hz,2H),6.07(dd,J=17.8,11.2Hz,1H),5.91(s,2H),5.55(d,J=8.3Hz,1H),5.01(dd,J=17.8,1.8Hz,1H),4.96(dd,J=11.1,1.7Hz,1H),4.58(d,J=6.0Hz,1H),4.40(d,J=2.1Hz,2H),2.37(s,1H),2.23–2.15(m,1H),2.10–1.98(m,3H),1.68–1.58(m,2H),1.51–1.42(m,1H),1.39–1.18(m,8H),1.06–0.96(m,4H),0.81(d,J=7.0Hz,3H),0.59(d,J=7.1Hz,3H).
13C NMR(151MHz,DMSO)δ217.48,166.52,162.40,148.32,143.21,142.10,141.31,130.36,124.63,124.14,115.70,72.95,71.48,61.18,57.59,45.40,44.57,44.01,41.98,36.92,36.74,34.45,33.89,30.52,29.11,26.99,24.91,16.66,14.87,12.01.
实施例6
化合物6:1-(4-溴苯)-4-((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-环戊[8]环烯-5-基)氧基)-2-氧乙基)硫代)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和299.9mg(1.2mmol)对溴溴苄置于反应器中,使用5mL乙腈进行溶解,室温下搅拌反应18小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10:1),干燥得到化合物6,称重为182.4mg,产率为84.25%。化合物6在氘代DMSO中的核磁氢谱如图11所示,核磁碳谱如图12所示。
1H NMR(600MHz,DMSO)δ8.95(d,J=6.9Hz,2H),8.01(d,J=6.9Hz,2H),7.65(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),6.07(dd,J=17.8,11.2Hz,1H),5.69(s,2H),5.55(d,J=8.3Hz,1H),5.03–4.92(m,2H),4.56(d,J=6.0Hz,1H),4.37(d,J=3.0Hz,2H),2.37(s,1H),2.24–2.16(m,1H),2.15–2.06(m,1H),2.06–1.98(m,2H),1.69–1.58(m,2H),1.52–1.43(m,1H),1.40–1.19(m,8H),1.08–0.96(m,4H),0.81(d,J=7.0Hz,3H),0.58(d,J=7.1Hz,3H).
13C NMR(151MHz,DMSO)δ217.47,166.52,162.03,142.97,141.31,134.41,132.59,131.31,124.06,123.22,115.67,72.98,71.46,61.59,57.62,45.40,44.57,44.03,41.99,36.91,36.74,34.47,33.85,30.53,29.11,26.99,24.92,16.64,14.91,12.00.
实施例7
化合物7:4-(((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)氧基)-2-氧代乙基)硫代)-1-(4-(三氟甲氧基)苄基)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和229.5mg(0.9mmol)对三氟甲基溴苄置于反应器中,使用5mL甲苯进行溶解,室温下搅拌反应12小时,TLC监测。反应结束后,减压浓缩除去甲苯,柱层析分离纯化(二氯甲烷:甲醇(V:V)=8:1),干燥得到化合物7,称重为176.6mg,产率为81.02%。化合物7在氘代DMSO中的核磁氢谱如图13所示,核磁碳谱如图14所示。
1H NMR(400MHz,DMSO)δ9.02(d,J=6.6Hz,2H),8.05(d,J=6.7Hz,2H),7.70(d,J=8.6Hz,2H),7.47(d,J=8.2Hz,2H),6.10(dd,J=17.8,11.2Hz,1H),5.80(s,2H),5.58(d,J=8.2Hz,1H),5.06–4.94(m,2H),4.55(d,J=5.9Hz,1H),4.45–4.34(m,2H),2.40(s,1H),2.22(dd,J=19.3,10.8Hz,1H),2.16–2.00(m,3H),1.73–1.60(m,2H),1.56–1.46(m,1H),1.42–1.22(m,8H),1.09–0.98(m,4H),0.84(d,J=6.9Hz,3H),0.61(d,J=6.9Hz,3H).
13C NMR(101MHz,DMSO)δ216.75,166.54,162.08,149.31,143.05,141.33,134.41,131.30,124.09,122.11,115.63,72.99,71.50,61.35,57.63,45.40,44.58,44.11,42.00,36.92,36.74,34.45,33.92,30.54,29.07,26.99,24.91,16.63,14.92,11.96.
实施例8
化合物8:1-(4-氟苄基)-4-((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-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基)硫代)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和226.8mg(1.2mmol)对氟溴苄置于反应器中,使用5mL丙酮进行溶解,室温下搅拌反应32小时,TLC监测。反应结束后,减压浓缩除去丙酮,柱层析分离纯化(二氯甲烷:甲醇(V:V)=8:1),干燥得到化合物8,称重为159.6mg,产率为80.53%。化合物8在氘代DMSO中的核磁氢谱如图15所示,核磁碳谱如图16所示。
1H NMR(400MHz,DMSO)δ9.03(d,J=6.5Hz,2H),8.04(d,J=6.4Hz,2H),7.67(t,J=7.0Hz,2H),7.30(t,J=8.7Hz,2H),6.08(dd,J=17.8,11.2Hz,1H),5.75(s,2H),5.56(d,J=7.9Hz,1H),5.06–4.90(m,2H),4.59(d,J=5.8Hz,1H),4.46–4.35(m,2H),2.39(s,1H),2.21(dd,J=19.3,10.9Hz,1H),2.14–2.01(m,3H),1.71–1.59(m,2H),1.54–1.43(m,1H),1.40–1.22(m,8H),1.09–0.96(m,4H),0.83(d,J=6.6Hz,3H),0.60(d,J=6.8Hz,3H).
13C NMR(101MHz,DMSO)δ216.04,166.56,161.87,142.89,141.31,131.71,131.63,124.05,116.66,116.45,115.66,72.94,71.42,61.40,57.60,45.39,44.56,44.02,41.97,36.91,36.73,34.44,33.85,30.53,29.10,26.98,24.91,16.63,14.89,12.01.
实施例9
化合物9:1-(4-(叔丁基)苄基)-4-((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-丙环戊[8]环烯-5-基)氧基)-2-氧乙基)硫代)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和272.6mg(1.2mmol)对叔丁基溴苄置于反应器中,使用5mL甲苯进行溶解,室温下搅拌反应24小时,TLC监测。反应结束后,减压浓缩除去甲苯,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10:1),干燥得到化合物9,称重为164.4mg,产率为78.41%。化合物9在氘代DMSO中的核磁氢谱如图17所示,核磁碳谱如图18所示。
1H NMR(400MHz,DMSO)δ8.98(d,J=6.5Hz,2H),8.02(d,J=6.5Hz,2H),7.59–7.31(m,4H),6.08(dd,J=17.8,11.1Hz,1H),5.70(s,2H),5.57(d,J=8.2Hz,1H),5.10–4.87(m,2H),4.69(s,1H),4.45–4.32(m,2H),2.39(s,1H),2.21(dd,J=18.9,11.2Hz,1H),2.14–1.99(m,3H),1.71–1.59(m,2H),1.54–1.44(m,1H),1.43–1.30(m,6H),1.28(s,10H),1.23–1.15(m,1H),1.07–0.96(m,4H),0.83(d,J=6.8Hz,3H),0.58(d,J=6.9Hz,3H).
13C NMR(101MHz,DMSO)δ215.96,166.57,161.75,152.35,142.95,141.31,132.22,128.79,126.43,124.05,115.65,73.00,71.48,62.14,57.67,45.41,44.58,42.01,36.93,36.76,34.88,34.47,33.89,31.51,31.44,30.55,29.10,27.01,24.92,16.64,14.95,11.98.
实施例10
化合物10:1-(3,5-二氟苄基)-4-((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-丙环戊[8]环烯-5-基)氧基)-2-氧乙基)硫代)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和310.5mg(1.5mmol)3,5-二氟溴苄置于反应器中,使用5mL乙腈进行溶解,室温下搅拌反应20小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=8:1),干燥得到化合物10,称重为165.4mg,产率为81.24%。化合物10在氘代DMSO中的核磁氢谱如图19所示,核磁碳谱如图20所示。
1H NMR(400MHz,DMSO)δ9.00(d,J=6.6Hz,2H),8.04(d,J=6.6Hz,2H),7.41–7.30(m,3H),6.09(dd,J=17.8,11.2Hz,1H),5.75(s,2H),5.58(d,J=8.2Hz,1H),5.09–4.93(m,2H),4.55(d,J=5.9Hz,1H),4.45–4.34(m,2H),2.39(s,1H),2.22(dd,J=19.3,10.7Hz,1H),2.15–2.01(m,3H),1.73–1.59(m,2H),1.55–1.46(m,1H),1.45–1.21(m,8H),1.09–0.97(m,4H),0.84(d,J=6.9Hz,3H),0.62(d,J=7.0Hz,3H).
13C NMR(101MHz,DMSO)δ215.34,166.53,164.31,162.31,161.72,143.10,141.34,124.10,115.59,112.85,112.59,73.00,71.49,61.07,57.62,55.37,45.39,44.55,44.13,41.98,36.91,36.73,34.44,33.91,30.53,29.03,27.00,16.64,14.88,11.96.
实施例11
化合物11:1-(3,5-二甲氧基苄基)-4-((2-((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-丙环五[8]环烯-5-基)氧基)-2-氧乙基)硫代吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和138.7mg(0.6mmol)3,5-二甲氧基溴苄置于反应器中,使用5mL乙腈进行溶解,室温下搅拌反应48小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10:1),干燥得到化合物11,称重为153.1mg,产率为72.61%。化合物11在氘代DMSO中的核磁氢谱如图21所示,核磁碳谱如图22所示。
1H NMR(400MHz,DMSO)δ9.01(d,J=6.7Hz,2H),8.02(d,J=6.6Hz,2H),6.75(d,J=2.2Hz,2H),6.55(s,1H),6.08(dd,J=17.7,11.1Hz,1H),5.63(s,2H),5.57(d,J=8.2Hz,1H),5.06–4.92(m,2H),4.55(d,J=5.9Hz,1H),4.45–4.34(m,2H),3.76(s,6H),2.37(s,1H),2.22(dd,J=19.3,10.8Hz,1H),2.15–1.99(m,3H),1.70–1.59(m,2H),1.55–1.44(m,1H),1.43–1.21(m,8H),1.07–0.97(m,4H),0.84(d,J=6.9Hz,3H),0.61(d,J=6.9Hz,3H).
13C NMR(101MHz,DMSO)δ215.57,166.65,161.96,161.61,143.08,141.44,137.15,124.14,115.77,107.44,101.18,73.13,71.61,62.48,57.77,56.03,45.52,44.69,44.22,42.11,37.04,36.86,34.58,33.99,30.66,29.16,27.12,25.03,16.76,15.01,12.10.
实施例12
化合物12:1-(3,5-二甲基苄基)-4-((2-((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)氧基)-2-氧乙基)硫代)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和179.2mg(0.9mmol)3,5-二甲基溴苄置于反应器中,使用5mL丙酮进行溶解,室温下搅拌反应22小时,TLC监测。反应结束后,减压浓缩除去丙酮,柱层析分离纯化(二氯甲烷:甲醇(V:V)=12:1),干燥得到化合物12,称重为167.7mg,产率为83.34%。化合物12在氘代DMSO中的核磁氢谱如图23所示,核磁碳谱如图24所示。
1H NMR(400MHz,DMSO)δ8.96(d,J=6.6Hz,2H),8.01(d,J=6.6Hz,2H),7.12(s,2H),7.06(s,1H),6.08(dd,J=17.8,11.2Hz,1H),5.64(s,2H),5.57(d,J=8.2Hz,1H),5.07–4.90(m,2H),4.55(d,J=5.9Hz,1H),4.44–4.33(m,2H),2.38(s,1H),2.28(s,6H),2.21(dd,J=19.2,10.8Hz,1H),2.14–1.99(m,3H),1.71–1.58(m,2H),1.55–1.45(m,1H),1.43–1.20(m,8H),1.08–0.97(m,4H),0.83(d,J=6.9Hz,3H),0.60(d,J=7.0Hz,3H).
13C NMR(101MHz,DMSO)δ215.81,166.55,161.73,142.95,141.32,138.89,134.90,131.04,126.63,123.98,115.61,72.98,71.46,62.41,57.63,55.37,45.38,44.56,41.97,36.90,36.73,34.43,33.85,30.53,29.05,26.99,24.90,21.27,16.63,14.88,11.96.
实施例13
化合物13:4-((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-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基)硫代)-1-(4-(三氟甲基)苄基)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和358.5mg(1.5mmol)对三氟甲基溴苄置于反应器中,使用5mL丙酮进行溶解,室温下搅拌反应28小时,TLC监测。反应结束后,减压浓缩除去丙酮,柱层析分离纯化(二氯甲烷:甲醇(V:V)=12:1),干燥得到化合物13,称重为184.9mg,产率为86.71%。化合物13在氘代DMSO中的核磁氢谱如图25所示,核磁碳谱如图26所示。
1H NMR(600MHz,DMSO)δ9.04(d,J=7.1Hz,2H),8.05(d,J=7.2Hz,2H),7.82(d,J=8.1Hz,2H),7.75(d,J=8.1Hz,2H),6.07(dd,J=17.8,11.2Hz,1H),5.86(s,2H),5.55(d,J=8.3Hz,1H),5.00(dd,J=17.8,1.8Hz,1H),4.94(dd,J=11.2,1.7Hz,1H),4.60(d,J=6.0Hz,1H),4.44–4.35(m,2H),2.38(s,1H),2.19(ddd,J=13.4,11.2,6.0Hz,1H),2.11–2.00(m,3H),1.69–1.59(m,2H),1.47(dqd,J=14.1,6.9,3.3Hz,1H),1.38–1.09(m,8H),1.02(s,4H),0.81(d,J=7.0Hz,3H),0.58(d,J=7.1Hz,3H).
13C NMR(151MHz,DMSO)δ215.33,164.40,160.06,141.04,139.17,137.46,127.74,124.34,123.17,121.95,121.37,113.51,70.79,69.31,59.32,55.46,43.25,42.43,41.87,39.85,34.78,34.60,32.30,31.75,28.38,26.97,24.84,22.77,14.50,12.77,9.86.
实施例14
化合物14:1-(4-氯苄基)-4-((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-环戊[8]环烯-5-基)氧基)-2-氧代乙基)硫代吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和246.6mg(1.2mmol)对氯溴苄置于反应器中,使用5mL甲苯进行溶解,室温下搅拌反应36小时,TLC监测。反应结束后,减压浓缩除去甲苯,柱层析分离纯化(二氯甲烷:甲醇(V:V)=8:1),干燥得到化合物14,称重为169.3mg,产率为83.34%。化合物14在氘代DMSO中的核磁氢谱如图27所示,核磁碳谱如图28所示。
1H NMR(600MHz,DMSO)δ9.08(d,J=6.6Hz,2H),8.04(d,J=7.0Hz,2H),7.62(d,J=8.5Hz,2H),7.51(d,J=8.5Hz,2H),6.06(dd,J=17.8,11.2Hz,1H),5.79(s,2H),5.54(d,J=8.3Hz,1H),5.00(dd,J=17.8,1.8Hz,1H),4.94(dd,J=11.2,1.7Hz,1H),4.63(d,J=6.0Hz,1H),4.45–4.34(m,2H),2.37(d,J=2.6Hz,1H),2.20–2.14(m,1H),2.13–2.07(m,1H),2.07–1.97(m,2H),1.68–1.59(m,2H),1.51–1.42(m,1H),1.38–1.21(m,8H),1.02(s,3H),1.00–0.94(m,1H),0.81(d,J=6.9Hz,3H),0.58(d,J=7.1Hz,3H).
13C NMR(151MHz,DMSO)δ217.49,166.54,161.93,143.00,141.31,134.53,134.15,131.16,129.60,124.07,115.66,72.92,71.43,61.25,57.61,45.40,44.57,44.02,41.97,36.91,36.73,34.46,33.87,30.53,29.13,26.98,24.91,16.63,14.90,12.03.
实施例15
化合物15:1-([1,1'-联苯]-4-基甲基)-4-((2-((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-丙环五[8]环-5-基)氧基)-2-氧乙基)硫代吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和222.4mg(0.9mmol)4-溴甲基联苯置于反应器中,使用5mL甲苯进行溶解,室温下搅拌反应40小时,TLC监测。反应结束后,减压浓缩除去甲苯,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10:1),干燥得到化合物15,称重为147.8mg,产率为68.52%。化合物15在氘代DMSO中的核磁氢谱如图29所示,核磁碳谱如图30所示。
1H NMR(400MHz,DMSO)δ9.07(d,J=6.6Hz,2H),8.08(d,J=6.6Hz,2H),7.76(d,J=8.0Hz,2H),7.68(dd,J=15.2,7.8Hz,4H),7.51(t,J=7.5Hz,2H),7.42(t,J=7.3Hz,1H),6.11(dd,J=17.8,11.2Hz,1H),5.82(s,2H),5.58(d,J=8.1Hz,1H),5.10–4.96(m,2H),4.57(d,J=5.8Hz,1H),4.46–4.36(m,2H),2.35(s,1H),2.18–1.98(m,4H),1.72–1.56(m,2H),1.55–1.44(m,1H),1.41–1.20(m,8H),1.11–0.96(m,4H),0.84(d,J=6.8Hz,3H),0.61(d,J=6.9Hz,3H).
13C NMR(101MHz,DMSO)δ216.28,166.52,161.88,143.00,141.52,141.31,139.72,134.22,129.70,129.47,128.33,127.88,127.23,124.14,115.69,73.00,71.48,62.06,57.60,49.05,45.39,44.57,41.96,36.88,36.72,34.39,33.87,30.50,29.10,26.98,24.89,16.62,14.88,11.95.
实施例16
化合物16:4-((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-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基)硫代)-1-((5-硝基呋喃-2-基)甲基)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和309.0mg(1.5mmol)2-溴甲基-5-硝基呋喃置于反应器中,使用5mL乙腈进行溶解,室温下搅拌反应36小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10:1),干燥得到化合物16,称重为104.5mg,产率为51.39%。化合物16在氘代DMSO中的核磁氢谱如图31所示,核磁碳谱如图32所示。
1H NMR(400MHz,DMSO)δ9.07(d,J=6.5Hz,2H),8.11(d,J=6.4Hz,2H),7.75(s,1H),7.27(s,1H),6.10(s,2H),5.79(s,1H),5.57(d,J=8.1Hz,1H),5.00(dd,J=23.6,14.4Hz,2H),4.65(d,J=5.8Hz,1H),4.44(s,2H),2.38(s,1H),2.20(dd,J=19.3,11.0Hz,1H),2.13–1.99(m,3H),1.72–1.60(m,2H),1.54–1.42(m,1H),1.41–1.20(m,8H),1.09–0.96(m,4H),0.83(d,J=6.8Hz,3H),0.62(d,J=6.8Hz,3H).
13C NMR(151MHz,DMSO)δ217.47,166.51,162.86,152.54,151.08,143.15,141.33,124.04,116.17,115.68,114.07,72.91,71.47,57.55,55.44,54.42,45.38,44.57,41.96,36.91,36.71,34.42,33.93,30.53,29.13,26.98,24.90,16.65,14.79,12.03.
实施例17
化合物17:4-((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-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基)硫代)-1-(噻吩-3-基甲基)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和318.7mg(1.8mmol)3-溴甲基噻吩置于反应器中,使用5mL乙腈进行溶解,室温下搅拌反应28小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=12:1),干燥得到化合物17,称重为113.3mg,产率为58.22%。化合物17在氘代DMSO中的核磁氢谱如图33所示,核磁碳谱如图34所示。
1H NMR(600MHz,DMSO)δ9.03(d,J=7.0Hz,2H),8.06(d,J=7.1Hz,2H),7.88(d,J=2.9Hz,1H),7.70(dd,J=5.0,2.9Hz,1H),7.32(d,J=4.9Hz,1H),6.12(dd,J=17.8,11.2Hz,1H),5.77(s,2H),5.61(d,J=8.3Hz,1H),5.15–4.96(m,2H),4.65(d,J=6.0Hz,1H),4.48–4.40(m,2H),2.46(s,1H),2.25(dd,J=19.2,11.0Hz,1H),2.18–2.06(m,3H),1.74–1.65(m,2H),1.58–1.49(m,1H),1.46–1.26(m,8H),1.14–1.03(m,4H),0.87(d,J=7.0Hz,3H),0.64(d,J=7.0Hz,3H).
13C NMR(151MHz,DMSO)δ217.52,166.58,161.68,142.85,141.31,135.47,128.69,127.78,127.14,123.93,115.67,72.95,71.42,57.61,57.42,45.40,44.57,44.02,41.99,36.92,36.74,34.45,33.85,30.54,29.12,26.99,24.92,16.64,14.91,12.03.
实施例18
化合物18:1-(环己基甲基)-4-((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-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基)硫代吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和265.6mg(1.5mmol)溴甲基环己烷置于反应器中,使用5mL丙酮进行溶解,室温下搅拌反应12小时,TLC监测。反应结束后,减压浓缩除去丙酮,柱层析分离纯化(二氯甲烷:甲醇(V:V)=8:1),干燥得到化合物18,称重为94.6mg,产率为48.61%。化合物18在氘代DMSO中的核磁氢谱如图35所示,核磁碳谱如图36所示。
1H NMR(400MHz,DMSO)δ8.83(d,J=6.4Hz,2H),8.02(d,J=6.2Hz,2H),6.10(dd,J=17.8,11.0Hz,1H),5.58(d,J=8.2Hz,1H),5.06–4.94(m,2H),4.40(s,2H),4.36(d,J=7.4Hz,2H),2.56(s,1H),2.41(s,1H),2.25–2.15(m,1H),2.13–2.02(m,3H),1.88(d,J=13.0Hz,1H),1.73–1.62(m,5H),1.47(d,J=12.7Hz,4H),1.41–1.34(m,2H),1.33(s,3H),1.25(d,J=7.4Hz,3H),1.17–1.10(m,4H),1.06(s,3H),1.00(d,J=10.6Hz,1H),0.83(d,J=6.8Hz,3H),0.62(d,J=7.0Hz,3H).
13C NMR(101MHz,DMSO)δ216.17,168.43,160.68,150.52,147.06,143.20,141.39,131.48,126.46,123.55,113.70,75.49,70.48,57.62,56.21,45.89,44.60,42.00,36.95,36.42,34.45,30.18,29.46,29.14,27.00,26.11,25.36,24.92,17.62,15.64,12.44.
实施例19
化合物19:4-(((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)氧基)-2-氧代乙基)硫代)-1-(萘-2-基甲基)吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和398.0mg(1.8mmol)2-溴甲基萘置于反应器中,使用5mL丙酮进行溶解,室温下搅拌反应40小时,TLC监测。反应结束后,减压浓缩除去丙酮,柱层析分离纯化(二氯甲烷:甲醇(V:V)=10:1),干燥得到化合物19,称重为125.5mg,产率为60.38%。化合物19在氘代DMSO中的核磁氢谱如图37所示,核磁碳谱如图38所示。
1H NMR(400MHz,DMSO)δ9.07(d,J=6.4Hz,2H),8.09(s,1H),8.05(d,J=6.4Hz,2H),8.02–7.92(m,3H),7.64–7.57(m,3H),6.07(dd,J=17.8,11.1Hz,1H),5.92(s,2H),5.54(d,J=8.0Hz,1H),4.98(dd,J=21.6,14.4Hz,2H),4.58(d,J=5.8Hz,1H),4.39(s,2H),2.31(s,1H),2.20(dd,J=19.3,10.9Hz,1H),2.15–1.95(m,3H),1.68–1.57(m,2H),1.51–1.42(m,1H),1.37–1.18(m,8H),1.04–0.95(m,4H),0.81(d,J=6.7Hz,3H),0.58(d,J=6.8Hz,3H).
13C NMR(101MHz,DMSO)δ215.48,166.54,161.89,143.09,141.30,133.35,133.15,132.61,129.53,128.55,128.46,128.22,127.52,127.36,126.07,124.05,115.69,72.92,71.42,62.50,57.58,49.06,45.37,44.54,41.94,36.89,36.70,34.45,33.85,30.49,29.08,26.96,24.89,16.64,14.85,12.01.
实施例20
化合物20:1-丁基-4-((2-((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)氧基)-2-氧乙基)硫代吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和205.5mg(1.5mmol)1-溴丁烷置于反应器中,使用5mL乙腈进行溶解,室温下搅拌反应36小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=6:1),干燥得到化合物20,称重为93.6mg,产率为51.24%。化合物20在氘代DMSO中的核磁氢谱如图39所示,核磁碳谱如图40所示。
1H NMR(400MHz,DMSO)δ8.82(d,J=6.3Hz,2H),7.93(d,J=6.3Hz,2H),6.01(dd,J=17.9,11.2Hz,1H),5.49(d,J=7.9Hz,1H),5.00–4.87(m,2H),4.55(s,1H),4.40(d,J=7.2Hz,2H),4.32(s,2H),2.34(s,1H),2.11(dd,J=19.0,11.0Hz,1H),2.05–1.91(m,3H),1.82–1.70(m,2H),1.62–1.52(m,2H),1.40(d,J=7.8Hz,1H),1.31–1.10(m,10H),1.00–0.88(m,4H),0.82(t,J=7.2Hz,3H),0.74(d,J=6.6Hz,3H),0.53(d,J=6.8Hz,3H).
13C NMR(101MHz,DMSO)δ216.28,166.67,161.09,143.06,141.38,123.67,115.68,72.90,71.40,59.52,57.63,45.40,44.60,44.01,42.00,36.95,36.76,34.46,33.78,32.95,30.55,29.16,27.00,24.92,19.14,16.65,14.92,13.78,12.04.
实施例21
化合物21:1-癸基-4-((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-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基)硫代吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和331.8mg(1.5mmol)1-溴十烷置于反应器中,使用5mL乙腈进行溶解,加热回流反应48小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=8:1),干燥得到化合物21,称重为77.3mg,产率为37.29%。化合物21在氘代DMSO中的核磁氢谱如图41所示,核磁碳谱如图42所示。
1H NMR(400MHz,DMSO)δ8.89(d,J=6.5Hz,2H),8.02(d,J=6.6Hz,2H),6.10(dd,J=17.8,11.1Hz,1H),5.58(d,J=8.1Hz,1H),5.09–4.96(m,2H),4.61(d,J=5.9Hz,1H),4.48(t,J=7.2Hz,2H),4.45–4.35(m,2H),2.42(s,1H),2.20(dd,J=19.2,10.8Hz,1H),2.14–2.01(m,3H),1.92–1.80(m,2H),1.70–1.60(m,2H),1.55–1.45(m,1H),1.41–1.31(m,6H),1.30–1.22(m,16H),1.09–0.97(m,4H),0.87(t,J=6.6Hz,3H),0.83(d,J=6.9Hz,3H),0.62(d,J=6.9Hz,3H).
13C NMR(101MHz,DMSO)δ216.31,166.65,161.12,143.04,141.36,123.66,115.68,72.93,71.40,59.80,57.64,45.41,44.61,44.02,42.02,36.95,36.76,34.46,33.75,31.74,30.94,30.54,29.34,29.30,29.13,28.86,27.01,25.79,24.92,22.57,16.66,14.93,14.43,12.02.
实施例22
化合物22:1-十六烷基-4-((2-((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)氧基)-2-氧乙基)硫代吡啶-1-溴化铵的制备
中间体Ⅰ和中间体Ⅱ的制备过程同实施例1。将161.9mg(0.3mmol)中间体Ⅱ和366.4mg(1.2mmol)1-溴十六烷置于反应器中,使用5mL乙腈进行溶解,加热回流反应48小时,TLC监测。反应结束后,减压浓缩除去乙腈,柱层析分离纯化(二氯甲烷:甲醇(V:V)=8:1),干燥得到化合物22,称重为87.4mg,产率为37.51%。化合物22在氘代DMSO中的核磁氢谱如图43所示,核磁碳谱如图44所示。
1H NMR(400MHz,DMSO)δ8.92(d,J=6.5Hz,2H),8.03(d,J=6.3Hz,2H),6.11(dd,J=17.7,11.1Hz,1H),5.59(d,J=8.0Hz,1H),5.03(dd,J=20.2,14.5Hz,2H),4.66(d,J=5.8Hz,1H),4.50(t,J=7.3Hz,2H),4.42(s,2H),2.43(s,1H),2.21(dd,J=19.3,10.9Hz,1H),2.15–2.02(m,3H),1.87(t,J=7.3Hz,2H),1.73–1.61(m,2H),1.57–1.43(m,1H),1.42–1.37(m,1H),1.35(s,3H),1.31–1.18(m,30H),1.07(s,3H),1.05–0.96(m,1H),0.88(d,J=6.2Hz,3H),0.84(d,J=7.3Hz,3H),0.62(d,J=6.8Hz,3H).
13C NMR(101MHz,DMSO)δ216.38,166.65,161.10,143.05,141.36,123.65,115.67,72.90,71.38,59.75,57.62,45.40,44.60,42.01,36.95,36.76,34.45,33.75,31.77,30.96,30.55,29.53,29.49,29.40,29.32,29.19,28.88,27.01,25.79,22.57,16.66,14.92,14.43,12.03.
2.体外抗菌活性测定
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,测试含吡啶季铵盐侧链截短侧耳素衍生物的最低抑菌浓度(Minimum inhibitoryconcentration,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:沙门氏菌ATCC14028、大肠杆菌ATCC 25922、ATCC 44103和鲍曼不动杆菌ATCC 19606(购买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(瑞他莫林、泰妙菌素、沃尼妙林、本发明合成的化合物1-6、化合物13、14和22)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45-图47。
表1受试药物的最小抑菌浓度(μg/mL)
由表1可知,本发明合成的含吡啶季铵盐侧链的截短侧耳素衍生物对受试的革兰氏阳性菌和革兰氏阴性菌均有不同程度的抑制作用。化合物1-6及13-14对沙门氏菌ATCC14028的抑制作用均优于上市药物瑞他莫林、泰妙菌素和沃尼妙林,其中化合物13对沙门氏菌ATCC 14028的最小抑菌浓度能达到2μg/mL。受试的9种化合物对表皮葡萄球菌ATCC12228的抑制作用均优于三种上市药物;对金黄色葡萄球菌ATCC 25923和ATCC 29213的抑菌试验中,化合物2的效果优于三种上市药物,最小抑菌浓度分别为0.5μg/mL和0.125μg/mL;除化合物22之外的8种受试药物对耐甲氧西林金黄色葡萄球菌ATCC 33591的抑制作用均不弱于泰妙菌素和沃尼妙林;化合物4和化合物6表现出对大肠杆菌ATCC 25922和CMCC44103最优的抑制作用;对鲍曼不动杆菌ATCC 19606而言,化合物2表现出最优效果,其最小抑菌浓度为32μg/mL。
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,优选化合物1、2、6对临床分离耐药菌株显示出不同程度的抑制作用,抗菌活性均近似或优于对照药物瑞他莫林,其中三个化合物对临床常见致病菌MRSA的活性最好,且大幅优于瑞他莫林。综合以上结果,化合物1、2、6具有良好的抗菌活性,值得进行进一步研究。
3.体外安全性测定
采用MTT法评估含吡啶季铵盐侧链的截短侧耳素类衍生物体外细胞毒性。
取处于对数生长期的HepG2、HEK293和A549细胞(均购自于美国ATCC库),胰蛋白酶消化后制成细胞悬液,调整细胞密度约为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OD490nm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,记录结果如表3及图48-图50。
表3受试药物的半数抑制浓度(IC50,μM)
表3显示了沃尼妙林、泰妙菌素、代表化合物2、17和21对HepG2细胞、HEK293细胞和A549细胞的半数抑制浓度,由以上数据可以得知化合物2、17和21对HepG2细胞的安全性均优于沃尼妙林和泰妙菌素;化合物2、17和21对HEK293细胞的IC50值均大于沃尼妙林,其中化合物17的IC50值为64.89μM,是沃尼妙林的2倍以上;化合物2、17和21对A549细胞的毒性均弱于沃尼妙林,其IC50值分别为大于200.00μM、182.60μM和130.90μM,其中化合物2和17的IC50值是沃尼妙林的3倍以上。图48-图50表明,代表化合物2在浓度大于50μM的条件下处理HepG2、HEK293和A549细胞,细胞存活率均高于泰妙菌素和沃尼妙林,证实代表化合物2在高浓度(50.00μM-200.00μM)下具有较高的安全性。综合上述数据,受试的代表化合物2和17具有良好的抗菌活性及安全性,可以做进一步研究。
4.体外抗支原体活性测定
采用微量肉汤稀释法,以泰妙菌素(购于上海源叶生物科技有限公司)为阳性对照品,测试含吡啶季铵盐侧链截短侧耳素衍生物对不同支原体的最低抑菌浓度(Minimuminhibitory concentration,MIC),评价化合物对不同支原体的抗菌效果。
实验菌株:猪肺炎支原体标准菌株J株(Mhp-J;NCTC 10110)、猪肺炎支原体临床分离株LH株(Mhp-LH)、猪鼻支原体标准株BTS-7株(Mhr-BTS-7;NCTC10130)、鸡毒支原体标准株R株(MG-R)及鸡滑液囊支原体WVU 1853株(MS-WVU1853;NCTC10124)(购于英国典型菌种保藏中心)。
具体操作步骤如下:
(1)KM2培养基配制:称取KM2培养基(购于广东环凯微生物科技有限公司)38.9g,加入到800mL蒸馏水中,煮沸溶解,115℃高压灭菌20min,备用。
(2)菌液储存液的制备:分别取培养至对数期的Mhp-J、Mhp-LH、Mhr-BTS-7、MG-R、MS-WVU1853各0.5mL,转接到4.5mL KM2液体培养基中,待培养基颜色变黄,分装各菌,每管0.5mL,作为菌液储存液保存于-70℃。
(3)菌液滴度(颜色变化单位,CCU)的测定:从-70℃取出保存的菌液储存液,融化平衡至室温后,96孔板中间4排每孔加入0.18mL KM2培养基(即4个平行),分别取0.02mL加入第1列,依次10倍比稀释到10-11,设置只含有KM2培养基的阴性对照(第12列)。密封后放入37℃培养箱中,逐日观察结果。以培养基颜色能发生变化的最高稀释度为该菌株的CCU/mL。
(4)最小抑菌浓度(MIC)的测定:将各待试药物(泰妙菌素和本发明合成的化合物2)配制浓度为2560μg/mL的母液,将各药物母液用KM2液体培养基进行2倍稀释,测试浓度范围为0.000004~128μg/mL。取适量种子菌液根据其滴度依次倍比稀释至104CCU/mL。在96孔板中依次加入各稀释度的药物,然后加入等量稀释后的菌液,设置稀释后的支原体菌液200μL作为阳性对照,KM2液体培养基200μL作为阴性对照,同时设置溶剂对照组(药物溶剂10μL+支原体菌液190μL)。各实验设置3个平行。所有培养板密封后,于37℃静置培养,逐日观察,记录终末MIC值,记录结果如表4及图51。
表4受试药物对5株支原体的MIC测定结果
受试药物对5株支原体的MIC结果如表3所示,受试化合物2对猪肺炎支原体J株、猪鼻支原体BTS-7株和鸡毒支原体R株的MIC值均为0.015μg/mL,对猪肺炎支原体临床分离株LH株的MIC值为0.004μg/mL,对鸡滑液囊支原体WVU 1853株的MIC值为0.125μg/mL,以上结果均优于已上市的截短侧耳素类抗生素泰妙菌素。
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 (10)
3.根据权利要求1所述的一种具有抗病原微生物活性的含吡啶季铵盐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具有如通式Ⅰ所示结构的化合物与盐酸、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。
5.根据权利要求4所述的一种具有抗病原微生物活性的含吡啶季铵盐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,截短侧耳素与对甲苯磺酰氯的摩尔比为1:1.2;步骤2)中,中间体Ⅰ与4-巯基吡啶的摩尔比为1:1.2;步骤3)中,中间体Ⅱ与含不同取代的溴苄类化合物的摩尔比为1:(2-6)。
6.权利要求1-3任意一项所述的一种具有抗病原微生物活性的含吡啶季铵盐侧链的截短侧耳素衍生物在制备抗菌产品中的应用。
7.根据权利要求6所述的应用,其特征在于,所述抗菌产品为治疗感染性疾病的药物制剂。
8.根据权利要求7所述的应用,其特征在于,所述感染性疾病为人或动物由病原微生物引起的感染性疾病。
9.根据权利要求8所述的应用,其特征在于,所述病原微生物为耐药菌或支原体。
10.一种药物组合物,其特征在于,所述药物组合物包含权利要求1-3任意一项所述的含吡啶季铵盐侧链的截短侧耳素衍生物作为活性成分。
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