CN117843568A - 一种芳烷基取代-1-甲基喹啉季铵盐类衍生物及其制备方法和用途 - Google Patents
一种芳烷基取代-1-甲基喹啉季铵盐类衍生物及其制备方法和用途 Download PDFInfo
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- CN117843568A CN117843568A CN202410006139.0A CN202410006139A CN117843568A CN 117843568 A CN117843568 A CN 117843568A CN 202410006139 A CN202410006139 A CN 202410006139A CN 117843568 A CN117843568 A CN 117843568A
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- Prior art keywords
- acid
- compound
- methylquinoline
- quaternary ammonium
- ammonium salt
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Abstract
本发明属于医药,具体涉及一种芳烷基取代‑1‑甲基喹啉季铵盐类衍生物及其制备方法和用途。寻求新型抗菌靶点及开发新的化学实体对于解决目前日益严峻的细菌耐药问题具有重要意义,设计作用于细菌分裂蛋白FtsZ靶点的化合物实体有望被开发得到对宿主无影响的抗菌药物。本发明提供一种芳烷基取代‑1‑甲基喹啉季铵盐类衍生物及其制备方法,所述化合物对革兰氏阳性菌具有显著的杀菌和/或抑菌活性,并且具有良好的抑制细菌分裂蛋白FtsZ的作用,可用于制备抗菌产品。
Description
技术领域
本发明属于医药技术领域,具体涉及一种芳烷基取代-1-甲基喹啉季铵盐类衍生物及其制备方法和用途,这类化合物能够作为细菌分裂蛋白FtsZ的抑制剂。
背景技术
丹麦微生物学家Hans Christian Gram在19世纪后期发现细菌可分为革兰氏阳性菌和革兰氏阴性菌。革兰氏阳性菌的细胞壁由一层厚而致密的肽聚糖和磷壁酸组成,而革兰氏阴性菌的细胞壁则是多层结构,从内到外依次是:薄薄的肽聚糖层,脂蛋白层/周质层,磷脂层和脂多糖层。这种特殊的结构导致许多抗生素(如万古霉素)可通过革兰氏阳性菌的外肽聚糖表面到达其靶标,却不能通过革兰氏阴性菌的外膜。近半个世纪以来,全球依然没有能够有效针对革兰氏阴性菌的抗生素被批准。恰巧,大多数产生多重耐药性的病原体,即所谓的超级细菌,也属于革兰氏阴性菌。令人担忧的是,不仅“武器库”数量稀少,我们拥有的许多“武器”也越来越无效。一旦这些具有抗药性的细菌感染人体,在没有任何有效药物可使用的情况下,后果将会非常危险,甚至可能致命。
FtsZ蛋白是一种具有GTP酶活性的重要的细胞分裂蛋白,在细胞分裂过程中,GTP结合到FtsZ单体上时,FtsZ单体头尾相连形成FtsZ原丝,许多的FtsZ原丝通过横向的相互作用形成原丝束并最终在细胞中央形成一个高度动态的Z环。Z环结构作用于组装多蛋白复合物的细胞生存所必需的支架,Z环形成后招募并协调一系列的辅助蛋白形成分裂体,招募完成后,Z环收缩,隔膜关闭,完成细胞分裂。干预FtsZ的正常生物学功能将导致细菌细胞异常分裂,持续的增长使它们不断变大,并且对其环境物理性质的变化更敏感,细胞最终会裂解死亡。由于FtsZ分布的广泛性和高保守性及尚未作为抗菌药物靶点被充分地开发的特点,并且FtsZ与人类细胞微管蛋白序列差异明显,因此可以设计作用于FtsZ靶点而不干扰宿主细胞的新型抗菌药物。目前已报道的多种FtsZ抑制剂显示出了优良的抗菌活性,生物碱类化合物血根碱对革兰氏阴性菌及革兰氏阳性菌均有中等程度的抑制作用,抗菌活性广谱,但是其对真核细胞中的微管蛋白也有轻微的抑制作用。由于微管蛋白在保持细胞形状、运动、胞内物质运输等方面都发挥着不可或缺的作用,上述化合物在发挥抑菌作用的同时可能会对机体造成严重的不良影响。因此,进一步筛选和开发抑菌活性高并且副作用较小化合物具有重要的意义。
发明内容
发明目的:本发明目的之一在于提供一种如通式I的4-芳烷基-1-甲基喹啉季铵盐类衍生物或其药学上可接受的盐或酯或溶剂化物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物或前药:
其中,所述R1和R2选自单取代或者多取代的芳香基团的;R2取代位点为喹啉的C-5、C-6、C-7或C-8位;X-为药学上可接受的阴离子。
所述R1和R2选自苯基、对正丁基苯基、对叔丁基苯基、对环己基苯基、对正己基苯基、3-甲酰基苯基;
在一些优选的实施方式中,所述药学上可接受的盐包括但不限于通式I化合物中的阳离子与下列酸中的阴离子部分形成的加成盐:盐酸、硫酸、磷酸、氢碘酸、氢溴酸、氢碘酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸、琥珀酸、甲磺酸、对甲苯磺酸、萘磺酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
本发明通式I的化合物优选以下化合物:
本发明涉及的上述通式I化合物还可以其盐的形式存在,它们在体内转化为通式I化合物。例如,在本发明的范围内,按照本领域已知的工艺,将本发明化合物转化为药学上可接受的盐的形式,并且以盐形式使用它们。
本发明另一目的在于提供具有通式I的化合物的制备方法,包括以下步骤:
反应通式一:
反应通式二:
其中,所述R3为氢、甲酰基、正丁基、叔丁基、环己基、正己基;
步骤一:化合物Ⅲa/Ⅲb与取代的苯硼酸在四三苯基膦钯催化下反应得到化合物Ⅳa/Ⅳb;
步骤二:化合物Ⅳa/Ⅳb与碘甲烷在乙腈溶剂中反应得到目标化合物。
本发明通式I化合物都可以用上述或类似上述的制备方法制备得到,根据取代基的不同和取代基位置的不同选用相应的起始原料即可。本领域技术人员应当认识到,上述路线有助于理解本发明,但并不限制本发明的内容,除非另有规定,变量如同通式I中提及的一样定义。
本发明另一目的在于提供一种药物组合物,所述药物组合物包括通式I的4-芳烷基-1-甲基喹啉季铵盐类衍生物或其药学上可接受的盐,以及药学上可接受的载体或赋形剂。
本发明的药物组合物可以采用各种已知的方式施用,例如口服、胃肠外施用、通过吸入喷雾施用或经由植入的贮库施用。本发明的药物组合物可单独给药也可与其他药物联合用药。口服组合物可以是任何口服可接受的剂型,包含但不限于片剂、胶囊、丸剂以及混悬剂、软胶囊和口服液。药学上可接受的药物载体是指药学领域常规的药物载体,如可以是一种或几种惰性的、非毒性的固体或液体填充物、稀释剂、助剂等,它们不逆向与活性化合物或病人发生作用。常用的药学上可接受的载体或赋形剂包括稳定剂、稀释剂、表面活性剂、润滑剂、抗氧化剂、粘合剂、着色剂、填充剂、乳化剂等。
注射液可按照本领域已知的技术使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、甘露醇、氯化钠溶液等。
可以改变本发明的药物组合物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的的剂量水平取决于多种因素,包括所用的具体的本发明的化合物或其盐的活性、施用途径、施用时间、所用的具体组合物的排泄速率、治疗的持续时间、与所用的具体组合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
本发明另一目的在于提供通式I的化合物或其药学上可接受的盐在制备用于治疗细菌感染的药物中的用途。本发明芳烷基取代-1-甲基喹啉季铵盐类衍生物或其药学上可接受的盐能够作为细菌分裂蛋白FtsZ抑制剂。
所述的感染或细菌感染是指一种疾病或病症,其特征在于致病因子(例如致病细菌)侵入生物体的身体组织,它们的繁殖,以及宿主组织对感染因子及其产生的毒素的反应。传染病,也称为传染性疾病,是由感染引起的疾病。细菌感染可能是由革兰氏阳性或革兰氏阴性细菌引起的。
所述细菌感染包括由以下细菌感染引起的疾病:脑膜炎败血伊丽莎白菌、铜绿假单胞菌、荧光假单胞菌、食酸假单胞菌、产碱假单胞菌、恶臭假单胞菌、嗜麦芽寡养单胞菌、洋葱伯克霍尔德菌、嗜水气单胞菌、大肠杆菌、弗氏柠檬酸杆菌、鼠伤寒沙门菌、伤寒沙门菌、副伤寒沙门菌、肠炎沙门菌、痢疾志贺菌、弗氏志贺菌、索氏志贺菌、阴沟肠杆菌、产气肠杆菌、肺炎克雷伯菌、产酸克雷伯菌、粘质沙雷菌、土拉弗朗西斯菌、摩氏摩根菌、奇异变形菌、普通变形菌、产碱普罗威登斯菌、雷氏普罗威登斯菌、斯氏普罗威登斯菌、鲍氏不动杆菌、醋酸钙不动杆菌、溶血不动杆菌、小肠结肠炎耶尔森菌、鼠疫耶尔森菌、假结核耶尔森菌、中间耶尔森菌、百日咳鲍特菌、副百日咳鲍特菌、支气管炎博德特菌、流感嗜血杆菌、副流感嗜血杆菌、溶血嗜血菌、副溶血嗜血菌、杜克氏嗜血桿菌、多杀巴斯德菌、溶血巴斯德菌、粘膜炎布兰汉菌、幽门螺杆菌、胚胎弯曲杆菌、空肠弯曲杆菌、大肠弯曲杆菌、伯氏疏螺旋体菌、霍乱弧菌、副溶血弧菌、嗜肺军团菌、单核细胞增生李斯特菌、淋病奈瑟球菌、脑膜炎奈瑟球菌、金菌、莫拉菌、阴道加德纳菌、脆弱拟杆菌、吉氏拟杆菌、普通拟杆菌、卵形拟杆菌(Bacteroides ovalus)、多型拟杆菌、单形拟杆菌、爱格斯拟杆菌、内脏拟杆菌、艰难梭菌、结核杆菌、鸟分枝杆菌、胞内分枝杆菌、麻风分枝杆菌、白喉棒杆菌、溃疡棒杆菌、肺炎链球菌、无乳链球菌、化脓链球菌、粪肠球菌、屎肠球菌、金黄色葡萄球菌、表皮葡萄球菌、腐生葡萄球菌、中间葡萄球菌、猪链球菌、猪葡萄球菌猪亚种溶血葡萄球菌、人葡萄球菌或解糖葡萄球菌。
有益效果:
(1)本发明制备的通式I的化合物及其药学上可接受的盐具有优异的细菌分裂蛋白FtsZ抑制作用,该类化合物通过抑制细菌分裂蛋白FtsZ,阻断细菌的正常分裂过程,导致细菌无法形成正常的子体细胞,发挥抑菌作用。因此,上述化合物可以用于制备预防、治疗或改善细菌感染的药物。例如:制备金黄色葡萄球菌、粪肠球菌、化脓链球菌、大肠杆菌等细菌感染引起疾病的治疗药物。
(2)本发明化合物的合成路线简单,实施性强,易于实现工业化生产。
具体实施方式
下面通过具体实施例对本发明技术方案进行详细说明,但是本发明的保护范围不局限于所述实施例。
以下实施例中,“室温”是指大约20~30℃。混合溶剂表示的比例是体积混合比例,除非另作说明,否则%是指wt%。M表示摩尔浓度。
在硅胶柱色谱中,碱性硅胶是指使用氨基丙基硅烷结合的硅胶。在高效液相色谱(HPLC)中,C18是指使用十八烷基结合的硅胶。洗脱溶剂的比例是体积混合比例,除非另作说明,洗脱溶剂为石油醚、二氯甲烷、乙酸乙酯、甲醇。
在下面实施例中,使用下列缩写:四氢呋喃THF,二氯甲烷DCM,二甲基亚砜DMSO,乙腈(ACN),N,N-二异丙基乙胺DIEA,醋酸钾K2CO3,四(三苯基膦)钯Pd(PPh3)4。
利用Fourier变换类型NMR,测定1H-NMR(质子核磁共振波谱)。使用ACD/SpecManager等软件分析。不描述活性氢(例如羟基、氨基等等)的峰。
利用LC/MS(液相色谱质谱仪)测定MS(质谱),使用ESI(电喷射离子化)方法。在盐的情况下,通常观察到游离形式的分子离子峰或碎片离子峰。
实施例1中间体4-(4-正丁基-苯基)喹啉的制备
将4-溴-喹啉(2.06g),对正丁基苯硼酸(2.13g),碳酸钾(2.76g),四(三苯基膦)钯(58mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得4-(4-正丁基-苯基)喹啉(2.14g)。即中间体4-(4-正丁基-苯基)喹啉产率为82%。
实施例2 1-甲基-4-(4-正丁基-苯基)喹啉碘盐的制备
将4-(4-正丁基-苯基)喹啉(1.3g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-4-(4-正丁基-苯基)喹啉碘盐(1.75g)。即1-甲基-4-(4-正丁基-苯基)喹啉碘盐产率为87%
实施例3中间体4-苯基喹啉的制备
将4-溴-喹啉(2.06g),对苯硼酸(1.45g),碳酸钾(2.86g),四(三苯基膦)钯(53mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得4-苯基喹啉(1.18g)。即中间体4-苯基喹啉产率为57.4%。
实施例4 1-甲基-4-苯基喹啉碘盐的制备
将4-苯基喹啉(1.03g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-4-苯基喹啉碘盐(1.36g)。即1-甲基-4-苯基喹啉碘盐产率为78.3%
实施例5中间体4-(3-甲酰基-苯基)喹啉的制备
将4-溴-喹啉(2.07g),对3-甲酰基苯硼酸(1.8g),碳酸钾(2.88g),四(三苯基膦)钯(57mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得4-(3-甲酰基-苯基)喹啉(2.03g)。即中间体4-(4-正丁基-苯基)喹啉产率为87%。
实施例6 1-甲基-4-(3-甲酰基-苯基)喹啉碘盐的制备
将4-(3-甲酰基-苯基)喹啉(1.3g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-3-(4-甲酰基-苯基)喹啉碘盐(1.40g)。即1-甲基-4-(3-甲酰基-苯基)喹啉碘盐产率为75%
实施例7中间体4-(4-环己基-苯基)喹啉的制备
将4-溴-喹啉(2.06g),对环己基苯硼酸(2.45g),碳酸钾(2.76g),四(三苯基膦)钯(57mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得4-(4-环己基-苯基)喹啉(2.47g)。即中间体4-(4-环己基-苯基)喹啉产率为86%。
实施例8 1-甲基-4-(4-环己基-苯基)喹啉碘盐的制备
将4-(4-环己基-苯基)喹啉(1.44g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-4-(4-环己基-苯基)喹啉碘盐(1.55g)。即1-甲基-4-(4-环己基-苯基)喹啉碘盐产率为72%
实施例9中间体4-(4-叔丁基-苯基)喹啉的制备
将4-溴-喹啉(2.08g),对叔丁基苯硼酸(2.17g),碳酸钾(2.76g),四(三苯基膦)钯(60mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得4-(4-叔丁基-苯基)喹啉(2.36g)。即中间体4-(4-正丁基-苯基)喹啉产率为90%。
实施例10 1-甲基-4-(4-叔丁基-苯基)喹啉碘盐的制备
将4-(4-正丁基-苯基)喹啉(1.3g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-4-(4-叔丁基-苯基)喹啉碘盐(1.4g)。即1-甲基-4-(4-叔丁基-苯基)喹啉碘盐产率为70%
实施例11中间体4-(4-正己基-苯基)喹啉的制备
将4-溴-喹啉(2.06g),对正丁基苯硼酸(2.48g),碳酸钾(2.76g),四(三苯基膦)钯(60mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得4-(4-正己基-苯基)喹啉(1.97g)。即中间体4-(4-正己基-苯基)喹啉产率为68%。
实施例12 1-甲基-4-(4-正己基-苯基)喹啉碘盐的制备
将4-(4-正己基-苯基)喹啉(1.45g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-4-(4-正己基-苯基)喹啉碘盐(1.47g)。即1-甲基-4-(4-正己基-苯基)喹啉碘盐产率为69%
实施例13中间体5-(4-正丁基-苯基)喹啉的制备
将5-溴-喹啉(2.06g),对正丁基苯硼酸(2.13g),碳酸钾(2.79g),四(三苯基膦)钯(55mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得5-(4-正丁基-苯基)喹啉(2.07g)。即中间体5-(4-正丁基-苯基)喹啉产率为79%。
实施例14 1-甲基-5-(4-正丁基-苯基)喹啉碘盐的制备
将5-(4-正丁基-苯基)喹啉(1.3g),碘甲烷(1.7ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-5-(4-正丁基-苯基)喹啉碘盐(1.68g)。即1-甲基-5-(4-正丁基-苯基)喹啉碘盐产率为84%
实施例15中间体6-(4-正丁基-苯基)喹啉的制备
将6-溴-喹啉(2.15g),对正丁基苯硼酸(2.19g),碳酸钾(2.93g),四(三苯基膦)钯(62mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得6-(4-正丁基-苯基)喹啉(2.26g)。即中间体6-(4-正丁基-苯基)喹啉产率为87%。
实施例16 1-甲基-4-(6-正丁基-苯基)喹啉碘盐的制备
将6-(4-正丁基-苯基)喹啉(1.3g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-6-(4-正丁基-苯基)喹啉碘盐(1.45g)。即1-甲基-6-(4-正丁基-苯基)喹啉碘盐产率为72%
实施例17中间体4-(8-正丁基-苯基)喹啉的制备
将8-溴-喹啉(2.05g),对正丁基苯硼酸(2.17g),碳酸钾(2.88g),四(三苯基膦)钯(60mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得8-(4-正丁基-苯基)喹啉(1.68g)。即中间体8-(4-正丁基-苯基)喹啉产率为64%。
实施例181-甲基-8-(4-正丁基-苯基)喹啉碘盐的制备
将8-(4-正丁基-苯基)喹啉(1.3g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-8-(4-正丁基-苯基)喹啉碘盐(1.83g)。即1-甲基-8-(4-正丁基-苯基)喹啉碘盐产率为91%
实施例19中间体4-(7-正丁基-苯基)喹啉的制备
将7-溴-喹啉(2.07g),对正丁基苯硼酸(2.09g),碳酸钾(2.82g),四(三苯基膦)钯(63mg)溶于20ml 1,4-二氧六环与水(V/V=1:1)混合液中,回流反应6小时。反应结束减压旋去有机溶剂,乙酸乙酯萃取三次,取有机相旋干,经砫胶柱色谱纯化得7-(4-正丁基-苯基)喹啉(1.83g)。即中间体7-(4-正丁基-苯基)喹啉产率为70%。
实施例201-甲基-7-(4-正丁基-苯基)喹啉碘盐的制备
将7-(4-正丁基-苯基)喹啉(1.3g),碘甲烷(1.6ml)置于密封管中,加入10ml乙腈,60℃封管反应8小时。经砫胶柱色谱纯化得1-甲基-7-(4-正丁基-苯基)喹啉碘盐(1.42g)。即1-甲基-7-(4-正丁基-苯基)喹啉碘盐产率为71%
化合物I1-I6均依上述方法制备。
通式I的目标产物,即I1-I6的相关表征信息如表1中所示
表1.
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实施例3:生物学活性(最低抑菌浓度试验)
通过采用微量稀释法,检测化合物对不同菌株的最小抑菌浓度,评价化合物的抑菌活性。
肉汤稀释法是最早使用的细菌药物敏感性测定方法之一,其又可分为常量肉汤稀释法和微量肉汤稀释法。这两种方法的基本原理相同。利用一定浓度的抗菌药物与含有待试菌的培养液进行系列稀释,经适温培养后,以肉眼观察无细菌生长的试管中所含的最低药物浓度为最低抑菌浓度MIC。
实验步骤:
1、菌悬液的制备:
(1)菌液培养:取待测菌保存液10μL加入1mL MH肉汤(可根据实际需要做调整),置37℃温箱过夜静止培养12小时左右;
(2)OD600值测定:利用紫外分光光度仪测定OD值,MH肉汤调整菌液浓度使其OD600值=0.1,此时菌液浓度约108cfu/mL(大约需将培养菌液稀释7-10倍左右);
(3)上样菌液稀释:将待测菌液在步骤②所得稀释倍数的基础上再稀释1000倍,此时菌液浓度约105cfu/mL,此时的菌液即为上样菌悬液;
注意:测定OD值所需菌液应在超净台中无菌取样,剩余菌液还需实验。
2、抗菌药物的制备:
抗生素母液配制:参照CLSI标准上抗菌药物相应的R(抗药)值制备待测抗菌药物(母液浓度要远远大于R值,至少160倍),分装于无菌小管置-20℃备用。
注意:无菌操作,抗菌药物的稀释液均需灭菌,溶解后还应过滤(滤膜孔径为0.22μm)。
3、药敏试验的操作:
(1)将待测抗菌药物进行10倍稀释;
(2)无菌96孔板第1-11列加入灭菌MH肉汤100μL(一药一板);
(3)无菌96孔板第1列加入10倍稀释的药液100μL,逐次倍比稀释至第11列(每孔液体终体积是100μL);
(4)无菌96孔板的每一孔加入待测菌液100μL,每孔液体终体积是200μL(由于整板都是一种药物,所以96孔板的每一行可进行一种细菌的药敏试验,为了保证实验的可靠性,每株菌设置4个复孔,一块板可做2株细菌的药敏试验);
(5)无菌96孔板的第12列上4孔加入200μL/孔灭菌MH肉汤作为阴性对照,第12列下4孔加入200μL/孔菌液作为阳性对照;
(6)药物和菌液上样完毕后,盖好板盖,置37℃温箱培养18-22小时观察结果(结果的判读参照CLSI抗菌药物敏感性试验解释标准)。
表2生物活性实验结果
结果显示,上述化合物对细菌有良好的抑菌效果,其中实施例I2、I5最佳。实施例I2、I5对金黄色葡萄球菌、化脓链球菌、肺炎克雷伯菌的抑制效果较其他菌株好,抑菌效果高于或接近于阳性药氨苄西林。且发现本发明对应化合物对不同细菌具有选择性,对于不同细菌抑菌效果不同。
因此,本发明制备的通式I的化合物及其药学上可接受的盐具有优异的细菌分裂蛋白FtsZ抑制作用,该类化合物通过抑制细菌细菌分裂蛋白FtsZ,导致细菌细胞异常分裂,持续的增长使它们不断变大,并且对其环境物理性质的变化更敏感,细胞最终会裂解死亡,发挥抑菌作用。因此,上述化合物可以用于制备预防、治疗或改善细菌感染的药物。例如:制备金黄色葡萄球菌、粪肠球菌、化脓链球菌、大肠杆菌等细菌感染引起疾病的治疗药物。
如上所述,尽管参照特定的优选实施例已经表示和表述了本发明,但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下,可对其在形式上和细节上作出各种变化。
Claims (10)
1.一种通式I的芳烷基取代-1-甲基喹啉季铵盐类衍生物:
其中,所述R1和R2分别选自单取代或者多取代的芳香基团的;R2取代位点为喹啉的C-5、C-6、C-7或C-8位;X-为阴离子。
2.根据权利要求1所述的芳烷基取代-1-甲基喹啉季铵盐类衍生物,其特征在于,所述R1和R2分别选自苯基、对正丁基苯基、对叔丁基苯基、对环己基苯基、对正己基苯基、3-甲酰基苯基。
3.根据权利要求1所述的芳烷基取代-1-甲基喹啉季铵盐类衍生物,其特征在于,阴离子由通式I所示的化合物中阳离子部分与下列酸中阴离子部分加成形成的加成盐:盐酸、硫酸、磷酸、氢溴酸、氢碘酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸、琥珀酸、甲磺酸、对甲苯磺酸、萘磺酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
4.根据权利要求1所述的芳烷基取代-1-甲基喹啉季铵盐类衍生物化合物,其特征在于所述芳烷基取代-1-甲基喹啉季铵盐类衍生物选自以下化合物中任意一个:
5.一种权利要求1-4任意一项所述的芳烷基取代-1-甲基喹啉季铵盐类衍生物化合物的制备方法,其特征在于,包括以下步骤:
反应通式一:
步骤一:化合物Ⅲa与取代的苯硼酸反应得到化合物Ⅳa;
步骤二:化合物Ⅳa与碘甲烷反应得到目标化合物。
反应通式二:
其中,所述R3为氢、甲酰基、正丁基、叔丁基、环己基、正己基;
步骤一:化合物Ⅲb与取代的苯硼酸反应得到化合物Ⅳb;
步骤二:化合物Ⅳb与碘甲烷反应得到目标化合物。
6.根据权利要求5所述的制备方法,其特征在于,步骤一中制备化合物Ⅳa或Ⅳb时选择醋酸钯作为催化剂,步骤二中选用碘甲烷作为甲基化试剂并使用乙腈作为溶剂在密封管中反应。
7.一种药物组合物,其特征在于,包括权利要求1-4任一项所述的芳烷基取代-1-甲基喹啉季铵盐类衍生物,以及药学上可接受的赋形剂。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物组合物的剂型为片剂、胶囊、丸剂、软胶囊、口服液、混悬剂或注射液。
9.根据权利要求1-4任一项所述的芳烷基取代-1-甲基喹啉季铵盐类衍生物及权利要求7或8所述的药物组合物在制备用于治疗细菌感染的药物中的用途。
10.根据权利要求9所述的用途,其特征在于,所述细菌感染包括由以下细菌感染引起的疾病:脑膜炎败血伊丽莎白菌、铜绿假单胞菌、荧光假单胞菌、食酸假单胞菌、产碱假单胞菌、恶臭假单胞菌、嗜麦芽寡养单胞菌、洋葱伯克霍尔德菌、嗜水气单胞菌、大肠杆菌、弗氏柠檬酸杆菌、鼠伤寒沙门菌、伤寒沙门菌、副伤寒沙门菌、肠炎沙门菌、痢疾志贺菌、弗氏志贺菌、索氏志贺菌、阴沟肠杆菌、产气肠杆菌、肺炎克雷伯菌、产酸克雷伯菌、粘质沙雷菌、土拉弗朗西斯菌、摩氏摩根菌、奇异变形菌、普通变形菌、产碱普罗威登斯菌、雷氏普罗威登斯菌、斯氏普罗威登斯菌、鲍氏不动杆菌、醋酸钙不动杆菌、溶血不动杆菌、小肠结肠炎耶尔森菌、鼠疫耶尔森菌、假结核耶尔森菌、中间耶尔森菌、百日咳鲍特菌、副百日咳鲍特菌、支气管炎博德特菌、流感嗜血杆菌、副流感嗜血杆菌、溶血嗜血菌、副溶血嗜血菌、杜克氏嗜血桿菌、多杀巴斯德菌、溶血巴斯德菌、粘膜炎布兰汉菌、幽门螺杆菌、胚胎弯曲杆菌、空肠弯曲杆菌、大肠弯曲杆菌、伯氏疏螺旋体菌、霍乱弧菌、副溶血弧菌、嗜肺军团菌、单核细胞增生李斯特菌、淋病奈瑟球菌、脑膜炎奈瑟球菌、金菌、莫拉菌、阴道加德纳菌、脆弱拟杆菌、吉氏拟杆菌、普通拟杆菌、卵形拟杆菌、多型拟杆菌、单形拟杆菌、爱格斯拟杆菌、内脏拟杆菌、艰难梭菌、结核杆菌、鸟分枝杆菌、胞内分枝杆菌、麻风分枝杆菌、白喉棒杆菌、溃疡棒杆菌、肺炎链球菌、无乳链球菌、化脓链球菌、粪肠球菌、屎肠球菌、金黄色葡萄球菌、表皮葡萄球菌、腐生葡萄球菌、中间葡萄球菌、猪链球菌、猪葡萄球菌猪亚种溶血葡萄球菌或人葡萄球菌或解糖葡萄球菌。
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