CN113614092A - 提供抗革兰氏阳性细菌增强的抗菌活性的组合物及其用途 - Google Patents
提供抗革兰氏阳性细菌增强的抗菌活性的组合物及其用途 Download PDFInfo
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- CN113614092A CN113614092A CN202080015048.3A CN202080015048A CN113614092A CN 113614092 A CN113614092 A CN 113614092A CN 202080015048 A CN202080015048 A CN 202080015048A CN 113614092 A CN113614092 A CN 113614092A
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Abstract
一种抑制、降低革兰氏阳性菌生长或破坏革兰氏阳性菌的方法,包括使所述革兰氏阳性菌与有效量的2‑(取代氨基‑)咪唑化合物以及与另外的抗菌化合物单独地、同时地或依次地接触,由此所述两种化合物提供针对所述革兰氏阳性细菌的抗生素增强作用。所述另外的抗菌化合物可以包括青霉素、达托霉素、万古霉素、苯唑西林、利奈唑胺或相关抗生素。
Description
相关申请的交叉引用
本申请要求享有于2019年2月22日提交的美国临时专利申请号62/808,900的权益,其公开内容通过引用以其整体结合于本文中。
技术领域
本文描述了提供增强的抗革兰氏阳性细菌的抗菌活性的抗菌组合物。抗菌组合物可以与另外的抗革兰氏阳性菌的抗生素化合物和/或组合物组合使用而提供抗生素增强作用。在实施方式中,抗菌组合物包括2-(取代氨基)-咪唑化合物。抗菌组合物可以用于人类和动物健康应用以抑制或减少革兰氏阳性菌的生长和/或破坏革兰氏阳性菌。
背景技术
随着越来越多的抗生素用于各种疾病和其他病症,耐药性细菌的发展是医学中的一个主要问题。更多抗生素的使用和表现出耐药性的细菌数量已经促使治疗时间延长。此外,人们还更频繁地使用广泛的非特异性抗生素,这些抗生素的一些会对受试者具有不利影响。
葡萄球菌(Staphylococci)、肠球菌(Enterococci)和梭状芽胞杆菌(Clostridia,)等革兰氏阳性菌是人类和兽医学中的重要病原体。革兰氏阳性细菌包括,但不限于,放线菌属(Actinomyces)、芽孢杆菌属(Bacillus)、李斯特菌属(Listeria)、乳球菌属(Lactococcus)、葡萄球菌属(Staphylococcus)、链球菌属(Streptococcus)、肠球菌属(Enterococcus)、分枝杆菌属(Mycobacterium)、棒状杆菌属(Corynebacterium)和梭状杆菌属(Clostridium)。医学相关物种包括化脓性链球菌(Streptococcus pyogenes)、肺炎链球菌(Streptococcus pneumoniae)、金黄色葡萄球菌(Staphylococcus aureus)和粪肠球菌(Enterococcus faecalis)。芽孢杆菌属会形成孢子,会引起炭疽(anthrax)和肠胃炎。形成孢子的梭状杆菌属会导致肉毒杆菌中毒(botulism)、破伤风(tetanus)、气性坏疽(gasgangrene)和伪膜性结肠炎(pseudomembranous colitis)。棒状杆菌属会引起白喉(diphtheria),而李斯特菌属引起脑膜炎(meningitis)。
由于人类医学和动物饲养中大量使用抗生素药物、滥开处方做法以及患者不遵守治疗方案,细菌的抗生素耐药性已经出现。用于治疗耐药微生物,尤其是革兰氏阳性菌的治疗选择正变得越来越有限。耐药性生物的传播和细菌之间耐药基因的散播加剧了抗生素耐药性问题。抗生素耐药性的发展和传播对成功管理细菌感染构成的威胁是医疗保健和兽医学药物中的一个重大问题。
葡萄球菌是严重的医疗保健相关感染(HAI)的主要原因。特别值得注意的是对抗生素如甲氧西林(methicillin,meticillin)产生或获得不同程度耐药性的葡萄球菌菌株。这些难以治疗性的生物体通常称为耐甲氧西林金黄色葡萄球菌(MRSA)和耐甲氧西林表皮葡萄球菌(MRSE)。从器械相关感染中分离出的表皮葡萄球菌中约有80%具有甲氧西林耐药性(MRSE)和多重耐药性。
用于治疗革兰氏阳性感染的临床使用的广谱抗生素的使用和应用会受限于耐药性的发展,特别是与持续或长期使用有关的耐药性的发展。
从与当前传统抗菌剂相关的缺陷和问题显而易见的是,本领域仍然需要额外的特定细菌剂、组合和治疗方式,特别是没有所获得的耐药性的高风险。因此,商业上需要新的抗菌方法,尤其是那些通过新方式发挥作用或提供新组合以有效杀死病原菌的方法。
此处引用的参考文献不应当解释为承认这是本发明的现有技术。
发明内容
本发明的第一方面包括治疗活性的通式(式I)的2-(取代氨基)-咪唑化合物、其盐、对映异构体或衍生物:
其中,
R1、R2和R4可以相同或不同,各自选自由氢、低级烷基、卤素和卤代烷基组成的组中,和
R3是低级烷基氨基、低级异烷基氨基或苯甲酰胺。
在第一方面的特征中,该2-(取代氨基)-咪唑化合物选自由以下化合物(化合物1-5)组成的组中:
在本发明的第二个方面中,抑制、减少革兰氏阳性菌的生长或破坏革兰氏阳性菌的方法包括使革兰氏阳性菌与有效量的通式(式I)的2-(取代氨基)-咪唑化合物、其盐、对映异构体或衍生物,以及与另外的抗菌化合物单独、同时或依次接触:
其中,
R1、R2和R4可以相同或不同,各自选自由氢、低级烷基、卤素和卤代烷基组成的组中,和
R3是低级烷基氨基、低级异烷基氨基或苯甲酰胺。
在第二方面的特征中,该咪唑化合物能够选自化合物1-5中的一种或多种。
在本发明的第三个方面,增强第一抗菌化合物针对革兰氏阳性菌的抗菌活性的方法包括使革兰氏阳性菌与有效量的第一抗菌化合物和有效量的2-(取代氨基)-咪唑抗菌化合物、其盐、对映异构体或衍生物单独、同时或依次接触。
在第三方面的特征中,该咪唑化合物能够选自化合物1-5中的一种或多种。
在第二或第三方面的特征中,第一抗菌化合物(或另外的抗菌化合物)包括青霉素(penicillin)、达托霉素(daptomycin)、万古霉素(vancomycin)、苯唑西林(oxacillin)、利奈唑胺(linezolid)或相关抗生素。关于第二和第三方面,革兰氏阳性细菌包括放线菌属、芽孢杆菌属、李斯特菌属、乳球菌属、葡萄球菌属、链球菌属、肠球菌属、分枝杆菌属、棒状杆菌属或梭状杆菌属中的一种或多种。
在第三方面的特征中,当第一抗菌化合物与该2-(取代氨基)-咪唑抗菌化合物、其盐、对映异构体或衍生物组合施用时,所述第一抗菌化合物的最小抑菌浓度(MIC)降低至少10倍,其中组合施用包括单独、同时或依次施用于革兰氏阳性菌。在其他特征中,该第一抗菌化合物的MIC降低至少15倍或降低至少25倍。
在本发明的第四个方面中,治疗患有由革兰氏阳性菌造成或引起的感染的受试者的方法包括单独、同时或依次给药有效量的治疗活性的2-(取代氨基)-咪唑化合物、其对映体或盐,以及另外的抗菌化合物。革兰氏阳性细菌可以包括放线菌属、芽孢杆菌属、李斯特菌属、乳球菌属、葡萄球菌属、链球菌属、肠球菌属、分枝杆菌属、棒状杆菌属或梭状杆菌属中的一种或多种。受试者可以是人或动物。该治疗活性的2-(取代氨基)-咪唑化合物和所述抗菌化合物可以口服给药、局部给药于感染部位,通过静脉内、经粘膜或经皮进行给药。感染可能是牛乳腺炎。
具体实施方式
以足够的细节介绍本公开的主题以提供对更广泛的发明主题的一个或多个具体实施方式的理解。这些描述阐述和举例说明了那些实施方式的特征而并未将本发明主题限制于明确描述的实施方式和特征。在不脱离本公开的主题的范围的情况下,鉴于这些描述的考虑将可能会产生额外的和类似的实施方式和特征。
除非另有定义,本文中使用的所有技术和科学术语具有与本公开的主题所属领域的普通技术人员通常理解的相同的含义。尽管与本文描述的那些相似或等效的任何方法、装置和材料能够用于本公开的主题的实践或测试中,但现在要描述代表性方法、装置和材料。
按照长期存在的专利法惯例,术语“一种”、“一个”和“该”在主题说明书,包括权利要求书中使用时是指“一个或多个”。因此,例如,提及“膜”能够包括多个这样的膜,等等。
除非另有说明,否则在本说明书和权利要求书中使用的所有表示组分数量、条件等的数字都应该理解为在所有情况下都被术语“约”修饰。因此,除非有相反的指示,本说明书和所附权利要求中阐述的数值参数是近似值,其能够根据本公开的主题寻求获得的期望性能而变化。
正如本文所用,术语“约”在涉及质量、重量、时间、体积、浓度和/或百分比的值或量时能够涵盖从指定量在一些实施方式中+/-20%、在一些实施方式+/-10%,在一些实施方式中+/-5%,在一些实施方式中为+/-1%,在一些实施方式中+/-0.5%,而在一些实施方式中+/-0.1%的变化,因为这种变化适用于所公开的包装和方法。
本文描述的是当与其他抗生素化合物(本文也称为抗生素和抗生素试剂)组合时会有效增强针对革兰氏阳性细菌的抗生素活性的咪唑化合物。具体而言,一组五种2-(取代氨基)-咪唑化合物,下文描述为化合物1-5,已证实对革兰氏阳性菌的抗生素活性的增强作用。
术语“增强”是指两种或更多种药物或药剂之间的相互作用,导致药理反应大于每种药物或药剂的各自反应的总和。当化合物对另一种活性物质或药物具有增强作用时,增强化合物具有使活性物质或药物比单独使用时更有效或更具活性的作用。增强化合物提高、改善或增强药物或活性物质的活性。
具有治疗活性的2-(取代氨基)-咪唑化合物具有由通式(式I)表示的结构。本文所述的咪唑化合物包括该化合物的盐、对映异构体或衍生物。该通式表示如下:
其中,
R1、R2和R4可以相同或不同,各自选自由氢、低级烷基、卤素和卤代烷基组成的组中,并且
R3是低级烷基氨基、低级异烷基氨基或苯甲酰胺。
该2-(取代氨基)-咪唑化合物的示例性实施方式包括以下化合物,其代表化合物1、化合物2、化合物3、化合物4和化合物5:
该2-(取代氨基)-咪唑化合物可以用于抑制、减少革兰氏阳性细菌的生长或破坏革兰氏阳性细菌的方法。该方法包括使革兰氏阳性细菌与有效量的通式(式I)的2-(取代氨基)-咪唑化合物、其盐、对映异构体或衍生物以及与另外的抗菌化合物单独、同时或依次接触:
其中,
R1、R2和R4可以相同或不同,各自选自由氢、低级烷基、卤素和卤代烷基组成的组中,和
R3是低级烷基氨基、低级异烷基氨基或苯甲酰胺。
在实施方式中,该革兰氏阳性细菌可以与化合物1-5中一种或多种与另外的抗菌化合物组合接触。当该2-(取代氨基)-咪唑化合物和另外的抗菌化合物组合使用时,它们提供了对革兰氏阳性菌的抗生素增强作用。在实施方式中,另外的抗菌化合物包括青霉素、达托霉素、万古霉素、苯唑西林、利奈唑胺或相关抗生素。
该2-(取代氨基)-咪唑化合物可以用于增强第一抗菌化合物对革兰氏阳性菌的抗菌活性的方法。该方法包括将革兰氏阳性细菌与有效量的第一抗菌化合物和有效量的2-(取代氨基)-咪唑抗菌化合物、其盐、对映异构体或衍生物单独、同时或依次进行接触。在实施方式中,该2-(取代氨基)-咪唑抗菌化合物是化合物1-5中的一种或多种。在实施方式中,该第一抗菌化合物包括青霉素、达托霉素、万古霉素、苯唑西林、利奈唑胺或相关抗生素。该革兰氏阳性细菌可以包括放线菌属、芽孢杆菌属、李斯特菌属、乳球菌属、葡萄球菌属、链球菌属、肠球菌属、分枝杆菌属、棒状杆菌属或梭状杆菌属中的一种或多种。
该2-(取代氨基)-咪唑抗菌化合物可以有效降低第一种抗菌化合物对革兰氏阳性菌的最小抑菌浓度(MIC)。事实上,该2-(取代氨基)-咪唑抗菌化合物的实施方式能够将第一种抗菌化合物的MIC降低至少10倍。即,在直接比较中,与2-(取代氨基)-咪唑抗菌化合物组合使用的第一种抗菌化合物的MIC对于相同革兰氏阳性细菌能够比单独使用的第一种抗菌化合物的MIC小10倍。事实上,该2-(取代氨基)-咪唑抗菌化合物的实施方式能够将第一抗菌化合物的MIC降低至少15倍、至少25倍和至少30倍。不同数量和浓度的2-(取代氨基)-咪唑抗菌化合物是有效的并且可以被使用。例如,0.1-100μM范围内的浓度可能是合适的。示例性浓度包括1μM-5μM,例如,2μM-4μM。
该2-(取代氨基)-咪唑化合物可以用于治疗患有由革兰氏阳性菌造成或引起的感染的受试者的方法。该方法包括单独、同时或依次给药有效量的治疗活性的2-(取代氨基)-咪唑化合物、其对映异构体或盐和另外的抗菌化合物。革兰氏阳性细菌可以包括放线菌属、芽孢杆菌属、李斯特菌属、乳球菌属、葡萄球菌属、链球菌属、肠球菌属、分枝杆菌属、棒状杆菌属或梭状杆菌属中的一种或多种。例如,该革兰氏阳性细菌可以包括一种或多种葡萄球菌属。在实施方式中,该2-(取代氨基)-咪唑抗菌化合物是化合物1-5中的一种或多种。在实施方式中,该第一抗菌化合物包括青霉素、达托霉素、万古霉素、苯唑西林、利奈唑胺或相关抗生素。
该受试者可以是人或动物。该治疗活性的2-(取代氨基)-咪唑化合物和抗菌化合物可以口服、局部给药于感染部位,通过静脉内、经粘膜或经皮进行给药。在实施方式中,该感染可以是影响动物的感染,包括,例如,牛乳腺炎。
治疗或药物组合物可以包含2-(取代氨基)-咪唑化合物和另外的抗生素与多种载体组合以治疗由革兰氏阳性菌引起的疾病。该载体可以合适地包含少量添加剂如增强等渗性和化学稳定性的物质。这些材料在所采用的剂量和浓度下对接受者是无毒的,并且包括缓冲剂,如磷酸盐、柠檬酸盐、琥珀酸盐、乙酸和其他有机酸或其盐;抗氧化剂,如抗坏血酸;低分子量(小于约十个残基)多肽,例如,聚精氨酸或三肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡咯烷酮;甘氨酸;氨基酸,如谷氨酸、天冬氨酸、组氨酸或精氨酸;单糖、二糖和其他碳水化合物,包括纤维素或其衍生物、葡萄糖、甘露糖、海藻糖或糊精;螯合剂如EDTA;糖醇,如甘露糖醇或山梨糖醇;反离子,如钠;非离子表面活性剂,如聚山梨醇酯、泊洛沙姆(poloxamer)或聚乙二醇(PEG);和/或中性盐。甘油或丙三醇(1,2,3-丙三醇)可商购获得而用于药物用途。DMSO是一种非质子溶剂,能够增强许多局部应用药物的渗透。载体还可以包括林格(Ringer)氏溶液、缓冲溶液和右旋糖(葡萄糖)溶液,尤其是在制备静脉内溶液时。
该2-(取代氨基)-咪唑化合物的有效剂量率或量将部分取决于该化合物是旨在用于治疗还是预防、受试者暴露于感染性细菌的持续时间、受试者的尺寸和体重等。使用含2-(取代氨基)-咪唑化合物的组合物的持续时间还取决于该用途是否用于预防目的,对于短期时间,其中该用途可以是小时、天或周,或该用途是否将用于治疗目的,其中该组合物的使用可能需要更强烈的方案,使得该使用可以持续数小时、数天或数周,和/或基于每天,或在白天的定时间隔。采用的任何剂型都应该在最短的时间内提供最少的单位数。被归类为“长”或“慢”释放载体的载体(如,例如,某些鼻腔喷雾剂或锭剂)能够拥有或提供较低浓度的活性单位/mL,但需要更长期的时间段,而“短”或“快”释放载体(如,例如,漱口剂)能够拥有或提供高浓度的活性单位/mL,但需要更短期的时间段。活性单位/mL的量和暴露持续时间取决于感染的性质、治疗是预防性还是治疗性以及其他变量。在某些情况下,可能需要更高的单位/mL剂量或更低的单位/mL剂量。
温和的表面活性剂能够以有效增强该2-(取代的氨基)-咪唑化合物的治疗效果的量包括于治疗或药物组合物中。合适的温和表面活性剂尤其包括聚氧乙烯脱水山梨糖醇和脂肪酸的酯(吐温系列)、辛基苯氧基聚乙氧基乙醇(Triton-X系列)、正辛基-β-D-吡喃葡萄糖苷、正辛基-β-D-硫代吡喃葡萄糖苷、正-癸基-β-D-吡喃葡萄糖苷、正十二烷基-β-D-吡喃葡萄糖苷和生物产生的表面活性剂,例如,脂肪酸、甘油酯、甘油单酯、脱氧胆酸盐和脱氧胆酸酯。
防腐剂也可以用于治疗或药物组合物。如果组合物被微生物污染,则防腐剂的使用能够有助于防止或减少微生物生长。合适的防腐剂可以包括对羟基苯甲酸甲酯(methylparaben)、对羟基苯甲酸丙酯(propylparaben)、对羟基苯甲酸丁酯(butylparaben)、氯二甲苯酚(chloroxylenol)、苯甲酸钠、DMDM乙内酰脲(DMDMHydantoin)、3-碘-2-丙基丁基氨基甲酸酯、山梨酸钾、二葡萄糖酸氯己啶或其组合。
包含2-(取代氨基)-咪唑化合物和抗生素的治疗组合物的施用方式包括,但不限于,直接、间接、载体和特殊方式或任何方式组合。组合物的直接施用可以通过任何合适的方式直接使2-(取代氨基)-咪唑化合物和抗生素与感染或细菌定植部位接触,如表皮或皮肤施用(例如,局部软膏或制剂)等。
此外,2-(取代氨基)-咪唑化合物和抗生素的施用模式能够包括多种不同类型和载体组合,其包括,但不限于,水性液体、醇基液体、水溶性凝胶、乳液、软膏、非水性液体基质、矿物油基质、矿物油和凡士林的混合物、羊毛脂、脂质体、蛋白质载体如血清白蛋白或明胶、粉状纤维素焦糖(carmel)及其组合。局部组合物的载体可以包含半固体和凝胶状载体,其包括聚合物增稠剂、水、防腐剂、活性表面活性剂或乳化剂、抗氧化剂和溶剂或混合溶剂系统。
2-(取代的氨基)-咪唑化合物和抗生素可以通过任何可药用或药学可接受的方式给药以供使用,包括局部、口服或肠胃外。例如,该2-(取代氨基)-咪唑化合物和抗生素能够肌肉内、鞘内、真皮下、皮下或静脉内给药以治疗革兰氏阳性菌感染。在肠胃外注射是所选择的给药方式的情况下,能够使用等渗制剂。用于等渗的合适添加剂能够包括氯化钠、右旋糖、甘露糖醇、山梨糖醇和乳糖。在某些情况下,等渗溶液如磷酸盐缓冲盐水可以是优选的。稳定剂包括明胶和白蛋白。向制剂中能够加入血管收缩剂。能够提供无菌且无热原的药物制剂。
包含2-(取代氨基)-咪唑化合物和抗生素的组合物可以口服、局部给药至感染部位,经粘膜、经皮或经静脉内进行给药。因此,包含2-(取代氨基)-咪唑化合物和抗生素的组合物可以配制成包含药用载体或赋形剂的无菌药物组合物。此类载体或赋形剂是本领域技术人员众所周知的,并且可以包括,例如,水、盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇、离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、乳酸、水盐或电解质,如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、环糊精如α-环糊精、β-环糊精、磺丁基醚7-β-环糊精和羟丙基-β-环糊精、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚丙烯-嵌段聚合物、聚乙二醇和羊毛脂等,及其组合。
对于2-(取代氨基)-咪唑化合物,治疗有效剂量最初能够在细胞培养试验中或在动物模型,例如,小鼠、兔、狗或猪模型中进行估算。动物模型也能够用于实现所需的浓度范围和给药途径。然后可以使用此类信息确定用于人类或其他动物的有用剂量和给药途径。剂量和给药经过调节而提供足够水平的活性部分或保持所需的效果。可以考虑的其他因素包括疾病的严重程度、患者的年龄、体重和性别;饮食、所需的治疗持续时间、给药方法、给药时间和频率、药物组合、反应敏感性和对治疗的耐受性/反应。取决于特定制剂的半衰期和清除率,长效药物组合物可能每3-4天、每周给药或每两周给药一次。
有待给药的2-(取代氨基)-咪唑化合物和抗生素的有效剂量率或量以及治疗持续时间将部分取决于感染的严重性、患者尤其是人类的体重、受试者暴露于传染性细菌的持续时间、受感染皮肤或组织的平方厘米数、感染深度、感染严重性以及许多其他变量。包含2-(取代氨基)-咪唑化合物和抗生素的组合物可以一天或一周局部施用一次至数次,并且可以施用短时间,如数天或最长达数周,或长期,如数周或最长达数月。使用可能会持续数天或数周。采用的任何剂型都应该在最短的时间内提供最少的单位数量。据信提供治疗有效量或剂量的2-(取代氨基)-咪唑化合物和抗生素的浓度可以根据需要进行选择。
在本文所述的组合物和方法中使用和施用的2-(取代氨基)-咪唑化合物和抗生素可以同时或按序给药。该2-(取代氨基)-咪唑化合物和抗生素可以以单剂量或多剂量、单独或组合给药。该2-(取代氨基)-咪唑化合物和抗生素可以通过相同的给药方式或不同的给药方式进行给药,并且可以一次、两次或多次、一种或多种组合或单独给药。因此,2-(取代氨基)-咪唑化合物可以以初始剂量给药,然后是随后的一个或多个剂量给药,具体要取决于反应和细菌杀死或去定植情况,并且可以与抗生素剂量组合或交替进行。
术语“治疗有效量”是指药物、化合物、抗微生物剂、抗体、多肽或药剂引起医生或其他临床医生正在寻求的受试者的生物学或医学反应的量。具体而言,关于革兰氏阳性菌感染和革兰氏阳性菌的生长,术语“有效量”旨在包括导致革兰氏阳性菌感染的量或程度产生生物学意义降低,包括具有杀菌和/或抑菌作用的化合物或药剂的有效量。
在一个实施方式中,术语任何疾病或感染的“治疗”或“治疗处理”是指减少疾病或感染(即,阻止疾病或感染原或细菌的生长,或降低其至少一种临床症状的表现、程度或严重程度)。在还有的另一个实施方式中,“治疗”或“治疗处理”是指在身体上(例如,可辨别症状的稳定)、生理上(例如,身体参数的稳定)或两者调节疾病或感染。在一个进一步的实施方式中,“治疗”或“治疗处理”涉及减缓疾病的进展或减少感染。
应该注意的是,在根据本申请和权利要求的体内进行的治疗方法或医学和临床治疗方法的上下文中,术语受试者旨在是指人或动物。
术语“革兰氏阳性细菌”、“革兰氏阳性菌”、“革兰氏阳性”和未具体列出的任何变体在本文中可互换使用,并且正如在本申请和权利要求中通篇所用,是指革兰氏阳性菌,其是已知的和/或能够通过某些细胞壁和/或细胞膜特性的存在和/或通过革兰氏染色而进行识别。革兰氏阳性细菌是已知的并且能够很容易进行鉴定并且可以选自,但不限于,李斯特菌属、葡萄球菌属、链球菌属、肠球菌属、分枝杆菌属、棒状杆菌属和梭状杆菌属,并且包括其任何和所有已识别或未被识别的物种或菌株。
短语“药用”是指生理上可耐受的分子实体和组合物,并且当给药于人时通常不会产生过敏或类似的不良反应,如胃部不适、头晕等。
参考以下非限制性实施例可以更好地理解本发明,这些实施例作为本发明的示例而提供。提供以下实施例用于更全面举例说明本发明的优选实施方式,而决不应该将其解释为限制本发明的广泛范围。
实施例
以下实施例已经包括在内从而为本领域普通技术人员实践本公开的主题的代表性实施方式提供指导。根据本公开和本领域技术人员的一般水平,技术人员能够理解的是,以下实施例仅仅旨在是示例性的,并且在不脱离本公开的主题的范围的情况下能够采用多种改变、修改和变更。
实施例1
合成制剂
通过如下所示的合成方案制备2-氨基咪唑环的N-2上含有脂族取代基的2-(取代氨基)-咪唑化合物。
在第一步骤中通过2-氯嘧啶的氯原子的取代而建立所需的脂族取代基。所得产物与2'-溴-3-硝基苯乙酮缩合,而提供咪唑并嘧啶盐,其通过过滤进行分离。用一水合肼处理该盐而导致Dimroth重排,从而提供在2位具有氨基脂族取代的芯4-苯基咪唑。咪唑环的内部氮的保护通过用二碳酸二叔丁酯处理而完成。在催化氢化条件下还原硝基提供苯胺,其与异氰酸酯缩合而提供倒数第二化合物(penultimate compund)。用合适的酸对叔丁氧羰基进行脱保护,得到作为盐的所需最终化合物。
在咪唑环的2-位上具有N-酰基取代基的2-(取代氨基)-咪唑化合物通过如下所示的合成方案进行制备。
2'-溴-3-硝基苯乙酮与叔丁氧羰基胍的缩合提供了2-氨基-4-硝基苯基咪唑产物,其中一个内部咪唑氮被叔丁氧羰基保护。酰胺的形成是通过在合适的偶联剂存在下使先前的产物与所需的羧酸反应而完成的。在催化氢化条件下还原硝基会产生相应的苯胺,然后将其与所需的异氰酸酯缩合而提供最终的脲。
实施例2
中间体A的合成:叔丁基5-(3-氨基苯基)-2-(异丙基氨基)-1H-咪唑-1-羧酸盐
步骤1:2-N-异丙基嘧啶的合成
在可密封的烧瓶中,在乙醇中溶解2-氯嘧啶(1当量)和异丙胺(2.5当量)。将反应加热至85℃,然后密封并搅拌过夜。将所得反应冷却至室温并通过旋转蒸发除去乙醇。残余物吸收于乙腈中并将所得混合物过滤而除去固体。滤液原样用于下一步。
步骤2:N-异丙基-5-(3-硝基苯基)-1H-咪唑-2-胺
部分1:将来自上一步的滤液用2'-溴-3-硝基苯乙酮(1当量)进行处理,并将所得混合物加热至85℃,然后密封。将反应在85℃下搅拌三天,然后使之冷却至室温。在过滤器上收集所得固体并用乙腈洗涤。
部分2:将洗涤过的固体溶解于EtOH中并用过量的一水合肼处理。将黄色溶液加热至温和回流一小时,然后通过旋转蒸发除去溶剂。将残余物溶于水中并用乙酸乙酯萃取。有机萃取液用硫酸钠干燥;过滤除去干燥盐,并将滤液浓缩成深红色油状物,原样用于下一步。
步骤3:2-(异丙基氨基)-5-(3-硝基苯基)-1H-咪唑-1-甲酸叔丁酯
将来自上一步骤的产物溶解于THF中,并用二碳酸二叔丁酯(1.5当量)和催化量的N',N'-二甲基-4-氨基吡啶进行处理。反应在室温下搅拌2小时,然后浓缩至干。残余物通过硅胶色谱法纯化而提供标题化合物。
步骤4:5-(3-氨基苯基)-2-(异丙基氨基)-1H-咪唑-1-甲酸叔丁酯
将来自步骤3的产物(1质量)溶解于1:1乙酸乙酯/甲醇中并置于氮气氛下。向其中加入10%Pd/C(0.1质量)并将氮气气氛替换为氢气气氛。反应在室温下搅拌直至原料耗尽(约2小时)。然后反应通过硅藻土(Celite)过滤。滤液浓缩至干并通过硅胶色谱法进行纯化。
实施例3
中间体B的合成:5-(3-氨基苯基)-2-(甲基氨基)-1H-咪唑-1-甲酸叔丁酯
步骤1:2-N-甲基嘧啶的合成
将2-氯嘧啶溶解于IPA中,并加入甲胺(30%在乙醇中)和碳酸钾(2当量)。在微波中将反应在150℃下加热1小时。浓缩而除去溶剂并将残余物溶于水中。用乙酸乙酯萃取,然后用硫酸钠干燥萃取物。通过过滤除去干燥盐并将滤液浓缩成油。
部分1:将来自步骤1的粗产物溶解于乙腈中。添加2'-溴-3-硝基苯乙酮(1.1当量)并在微波中120℃下加热1小时。在过滤器上收集所得固体。用乙腈洗涤固体并风干而得到灰白色粉末,其用于下一步。
部分2:将来自前一步骤的洗涤过固体溶解于EtOH中并加入水合肼(12当量)。在80℃下加热1小时。浓缩至干并在稀碳酸氢钠溶液中吸收残留物。用乙酸乙酯萃取并用硫酸钠干燥萃取物。过滤除去干燥盐并将滤液浓缩至干。将残余物吸收于乙酸乙酯中并进行超声处理。在过滤器上收集所得固体而获得标题产物。
步骤3:2-(甲基氨基)-5-(3-硝基苯基)-1H-咪唑-1-甲酸叔丁酯
将来自上一步的产物溶解于THF中,并用二碳酸二叔丁酯(1.5当量)和催化量的N',N'-二甲基-4-氨基吡啶进行处理。反应在室温下搅拌2小时,然后浓缩至干。残余物通过硅胶色谱法纯化而提供标题化合物。
步骤4:5-(3-氨基苯基)-2-(异丙基氨基)-1H-咪唑-1-甲酸叔丁酯
将原料溶解于甲醇中并将反应置于氮气氛下。添加10%Pd/C(10质量%)并用氢气气氛代替氮气气氛。在室温下搅拌30分钟。用乙酸乙酯稀释并通过硅藻土(Celite)过滤。滤液浓缩成油并通过硅胶色谱法纯化。收集所需馏分并浓缩成淡黄色油状物,得到关键中间体B。
实施例4
中间体C的合成:N-(5-(3-氨基苯基)-1H-咪唑-2-基)苯甲酰胺
步骤1:2-氨基-5-(3-硝基苯基)-1H-咪唑-1-甲酸叔丁酯
将2'-溴-3-硝基苯乙酮(1当量)溶解在四氢呋喃中,加入叔丁氧基羰基胍(1.2当量)和催化量的N',N'-二甲基-4-氨基吡啶。反应在70℃下加热数小时。将反应浓缩至干并在乙醚中研磨残余物。在过滤器上收集所得固体而获得所需产物。
步骤2:N-(5-(3-硝基苯基)-1H-咪唑-2-基)苯甲酰胺
使用外部加热将来自前一步骤的产物(1当量)溶解于DMF中,然后加入二异丙基乙胺(4当量)和苯甲酸(1.4当量)。加入固体HATU(1.2当量)并在65℃搅拌2天。浓缩除去DMF,将残余物吸收于碳酸氢钠饱和溶液中并用乙酸乙酯萃取。有机萃取液用硫酸钠干燥,然后过滤除去干燥盐,滤液浓缩至干。残余物通过硅胶色谱法纯化,而获得不再含有叔丁氧基羰基保护基团的所需产物。
步骤3:N-(5-(3-氨基苯基)-1H-咪唑-2-基)苯甲酰胺
将从前一步骤获得的起始原料溶解于EtOAc/MeOH(4:1)中并置于氮气氛下。向其中加入10%Pd/C(30质量%)并将反应置于氢气氛下。在室温下搅拌2小时,然后通过硅藻土(Celite)过滤而除去钯催化剂。滤液浓缩至干并在乙醚中研磨残余物。在过滤器上收集所得黄色固体而获得中间体C。
实施例5
制备1-(3-(2-(烷基氨基)-1H-咪唑-5-基)苯基)-3-苯基脲的通用方案
从中间体C和异氰酸苯酯:
将中间体(1当量)溶解于THF中并加入异氰酸苯酯(1.2当量)的THF溶液中。在室温下搅拌直至中间体被消耗。反应经过浓缩而除去THF并将残余物吸收于DCM中。加入等体积的TFA并在室温下搅拌3小时。浓缩至干并从DCM/MeOH中重新浓缩。在合适的溶剂中研磨残余物并在过滤器上收集固体而获得呈TFA盐形式的所需产物。如果研磨没有产生固体,则通过硅胶色谱法使用DCM/MeOH/NH3混合物洗脱所述产物而纯化残余物,提供作为游离碱的所需物质。
以下化合物由中间体A和合适的异氰酸酯进行制备:
1.1-(3,4-二氯苯基)-3-(3-(2-(异丙基氨基)-1H-咪唑-5-基)苯基)脲
化合物1:TFA盐盐:1H NMR(d6-DMSO):12.22ppm(br s,2H),9.32ppm(s,1H),9.13ppm(s,1H),7.93ppm(d,J=9Hz,1H),7.87ppm(d,J=3Hz,1H),7.76ppm(s,1H),7.46ppm(d,J=9Hz,1H),7.35-7.16ppm(m,5H),3.86-3.67ppm(m,1H),1.15ppm(d,J=6Hz,6H)
2.1-(3,5-二氯苯基)-3-(3-(2-(异丙基氨基)-1H-咪唑-5-基)苯基)脲
化合物2:TFA盐:1H NMR(d6-DMSO):12.22ppm(br s,2H),9.38ppm(s,1H),9.20ppm(s,1H),7.90ppm(d,J=6Hz,1H),7.76ppm(t,J=3Hz,1H),7.50ppm(d,J=3Hz,2H),7.37-7.16ppm(m,4H),7.10ppm(t,J=3Hz,1H),3.84-3.68ppm(m,1H),1.16ppm(d,J=6Hz,6H)
3.1-(3-氯-4-(三氟甲基)苯基)-3-(3-(2-(异丙基氨基)-1-H-咪唑-5-基)苯基)脲
化合物3:TFA盐:1H NMR(d6-DMSO):12.22ppm(br s,2H),9.67ppm(s,1H),9.28ppm(s,1H),7.91ppm(m,2H),7.77ppm(d,J=3Hz,1H),7.76ppm(s,1H),7.68ppm(d,J=9Hz,1H),7.42ppm(d,J=9Hz,1H),7.35-7.20ppm(m,4H),3.82-3.68ppm(m,1H),1.18ppm(d,J=6Hz,6H)
以下化合物由中间体B和3,4-二氯苯基异氰酸酯制备:
4.1-(3,4-二氯苯基)-3-(3-(2-(甲基氨基)-1H-咪唑-5-基)苯基)脲
化合物4:TFA盐:1H NMR(d6-DMSO):12.37ppm(br s,2H),9.45ppm(s,1H),9.23ppm(s,1H),7.85ppm(s,1H),7.76ppm(br s,1H),7.44ppm(d,J=6Hz,1H),7.36-7.15ppm(m,4H),7.05ppm(s,1H),6.87ppm(s,1H),2.84ppm(d,J=6Hz,3H)
以下化合物由中间体C和3,4-二氯苯基异氰酸酯制备:
5.N-(5-(3-(3-(3,4-二氯苯基)脲基)苯基)-1H-咪唑-2-基)苯甲酰胺
化合物5:游离碱:1H NMR(d6-DMSO):11.90ppm(br s,1H),11.61ppm(br s,1H),8.98ppm(s,1H),8.75ppm(s,1H),8.01ppm(d,J=6Hz,2H),7.94ppm(s,1H),7.84ppm(t,J=3Hz,1H),7.59-7.39ppm(m,4H),7.36-7.03ppm(m,5H)
实施例6
最低抑菌浓度的评价
测试了与抗生素化合物组合的2-(取代氨基)-咪唑化合物的示例性实施方式以评价对最小抑制浓度(MIC)的影响。
在存在或不存在2-(取代氨基)-咪唑化合物的情况下评价苯唑西林和青霉素对示例性细菌菌株的最小抑制浓度(MIC),如下表1所示。在这些实验中,将冷冻的细菌菌株原液划线于无菌脑心浸液琼脂平板(brain heart infusion agar plate)上,并在37℃下培养16-20小时。培养期结束后,从脑心浸液琼脂平板培养物中取出3-5个充分分离的相同形态类型的细菌菌落,并使用无菌环用于接种含有4-5mL阳离子调整的穆勒(Mueller)亨顿(Hinton)(MHII)肉汤的管。使培养物在37℃下以220rpm在摇动培养箱中生长,直到培养物达到对数期,这通过测量并达到600nm处测量的0.3-0.5的光密度(OD)而确定。然后通过添加MHII肉汤调节培养物的细菌浓度以使用1×109CFU/mL等于OD 600nm=1的近似值达到1×106菌落形成单位(CFU)/mL的当量。然后在环境条件下用指定量的测试化合物(显示于表1中)或溶剂对照(二甲亚砜)处理细胞30分钟。然后将细胞转移到96孔圆底孔板中,并暴露于指定抗生素的2倍系列稀释液中。孔板在37℃下孵育16-20小时;此时,将导致没有可见细菌颗粒沉淀形成(即,防止细菌颗粒形成)的最低抗生素浓度记录为MIC值。比较测试化合物处理的样品与溶剂处理的对照样品之间的MIC值并在下表中列出而评价每种测试化合物的抗生素增强活性。
表1显示了在化合物1的2-(取代氨基)-咪唑化合物存在和不存在下,青霉素对各种金黄色葡萄球菌和凝固酶(Coagulase)阴性葡萄球菌菌株的最小抑制浓度。使用的每种化合物以μM计的浓度显示于括号中。
表1
表2显示了在化合物1、2、3、4和5的存在和不存在下苯唑西林对金黄色葡萄球菌的最小抑制浓度。所用的化合物的浓度(μM)在括号中给出。
表2
Claims (21)
5.根据权利要求3所述的方法,其中两种化合物提供针对所述革兰氏阳性菌的抗生素增强作用。
6.根据权利要求3所述的方法,其中所述另外的抗菌化合物包括青霉素、达托霉素、万古霉素、苯唑西林、利奈唑胺或相关抗生素。
7.一种增强第一抗菌化合物针对革兰氏阳性菌的抗菌活性的方法,包括使所述革兰氏阳性菌与有效量的所述第一抗菌化合物和有效量的2-(取代氨基)-咪唑抗菌化合物、其盐、对映异构体或衍生物单独地、同时地或依次地接触。
9.根据权利要求7所述的方法,其中所述第一抗菌化合物包括青霉素、达托霉素、万古霉素、苯唑西林、利奈唑胺或相关抗生素。
10.根据权利要求3-9中任一项所述的方法,其中所述革兰氏阳性菌包括放线菌属(Actinomyces)、芽孢杆菌属(Bacillus)、李斯特菌属(Listeria)、乳球菌属(Lactococcus)、葡萄球菌属(Staphylococcus)、链球菌属(Streptococcus)、肠杆球菌属(Enterococcus)、分枝杆菌属(Mycobacterium)、棒状杆菌属(Corynebacterium)或梭状芽孢杆菌属(Clostridium)中的一种或多种。
11.根据权利要求7所述的方法,其中当所述第一抗菌化合物与所述2-(取代氨基)-咪唑抗菌化合物、其盐、对映异构体或衍生物组合施用时,所述第一抗菌化合物的最小抑制浓度(MIC)降低至少10倍,其中组合施用包括单独地、同时地或依次地施用于所述革兰氏阳性菌。
12.根据权利要求11所述的方法,其中所述第一抗菌化合物的MIC降低至少15倍。
13.根据权利要求12所述的方法,其中所述第一抗菌化合物的MIC降低至少25倍。
14.治疗患有由革兰氏阳性菌造成或引起的感染的受试者的方法,包括单独地、同时地或依次地给予有效量的治疗活性的2-(取代氨基)-咪唑化合物、其对映异构体或盐,以及另外的抗菌化合物。
15.根据权利要求14所述的方法,其中所述革兰氏阳性菌包括放线菌属、芽孢杆菌属、李斯特菌属、乳球菌属、葡萄球菌属、链球菌属、肠球菌属、分枝杆菌属、棒状杆菌属或梭状杆菌属中的一种或多种。
16.根据权利要求14所述的方法,其中所述革兰氏阳性菌包括葡萄球菌属中的一种或多种。
18.根据权利要求14所述的方法,其中第一抗菌化合物包括青霉素、达托霉素、万古霉素、苯唑西林、利奈唑胺或相关抗生素。
19.根据权利要求14所述的方法,其中所述受试者是人或动物。
20.根据权利要求14所述的方法,其中所述治疗活性的2-(取代氨基)-咪唑化合物和所述抗菌化合物经口服、局部给药于感染部位,静脉内、经粘膜或经皮进行给药。
21.根据权利要求14所述的方法,其中所述感染是牛乳腺炎。
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WO2018169752A1 (en) * | 2017-03-15 | 2018-09-20 | North Carolina State University | 2-aminoimidazole-phenyl derivatives useful for controlling microbial growth |
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WO2009081117A1 (en) * | 2007-12-21 | 2009-07-02 | E-Therapeutics Plc | Antibacterial combination therapy for the treatment of gram positive bacterial infections |
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CN114349707A (zh) * | 2022-01-20 | 2022-04-15 | 中国医学科学院医药生物技术研究所 | 一种n-取代脲类化合物及其制备方法和应用 |
CN114349707B (zh) * | 2022-01-20 | 2024-01-09 | 中国医学科学院医药生物技术研究所 | 一种n-取代脲类化合物及其制备方法和应用 |
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US20220125763A1 (en) | 2022-04-28 |
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