CN111517978A - 环己烯基-dl-天门冬氨酸衍生物及其制备方法、组合物与用途 - Google Patents
环己烯基-dl-天门冬氨酸衍生物及其制备方法、组合物与用途 Download PDFInfo
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- -1 cyclohexene amine compound Chemical class 0.000 claims abstract description 8
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims abstract description 7
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- RNQDCSINGDYZIY-HBNTYKKESA-N (3r,4r,5s)-4,5-diamino-3-pentan-3-yloxycyclohexene-1-carboxylic acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1N RNQDCSINGDYZIY-HBNTYKKESA-N 0.000 claims description 4
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- MKPOADZCFCZMRW-YNEHKIRRSA-N (3r,4r,5s)-5-acetamido-4-amino-3-pentan-3-yloxycyclohexene-1-carboxylic acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](NC(C)=O)[C@H]1N MKPOADZCFCZMRW-YNEHKIRRSA-N 0.000 claims description 4
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Abstract
本发明提供了一种环己烯基‑DL‑天门冬氨酸衍生物及其制备方法、组合物与用途,所述的环己烯基‑DL‑天门冬氨酸衍生物采用环己烯胺类化合物与富马酸经过Michael加成而制备得到。体外试验结果显示,本发明所述的环己烯基‑DL‑天门冬氨酸衍生物对各受试菌的抗菌作用均显著高于反应前对应的环己烯胺类化合物,而且与各种植物提取物的协同作用(依FICI计)也显著高于对应的环己烯胺类化合物。
Description
技术领域
本发明属于医药技术领域,具体涉及一种环己烯基-DL-天门冬氨酸衍生物及其制备方法、组合物与用途。
背景技术
医院感染是影响医院医疗质量的重要问题。随着现代医学技术的不断发展进步,抗菌药物大量使用,临床病原菌的耐药菌株不断增加。因此,提高已有药物的抗菌活性,将会有助于改善细菌性感染患者的治疗效果。
Quosdorf S等人指出(Molecules.2017Nov 17;22(11).),神经氨酸酶(neuraminidase)是流感病毒生命周期中的关键酶,也存在于部分细菌性病原体内,并且发现,神经氨酸酶抑制剂对霍乱弧菌神经氨酸苷酶(VCNA)有中度的抑制作用(IC50为114μM),CN110840871A披露了一系列具有抗菌活性的氨基环己烯羧酸类化合物,但其抗菌活性有待进一步提提高。
植物提取物中富含有多种具有抗菌活性的成分,邓爱华等人(分子植物育种,2018,16(23):7849-7855)报道称金丝桃、海桐、杜茎山、刺槐和桑树五种植物的叶片丙酮提取物对大肠杆菌等病原菌的MIC值均低于1mg/mL。
发明内容
本发明的目的在于提供一种环己烯基-DL-天门冬氨酸衍生物及其制备方法、组合物与用途,所述的环己烯基-DL-天门冬氨酸衍生物的抗流感病毒与抗菌作用均显著高于对应的的环己烯胺类化合物,而且能与金丝桃、海桐、杜茎山、刺槐和桑树五种植物的叶片乙醇提取物产生协同的抗菌作用。
为了实现上述目的,本发明一方面提供了一种环己烯基-DL-天门冬氨酸衍生物,所述的环己烯基-DL-天门冬氨酸衍生物是选自:
((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,2R,6S)-6-乙酰氨基-4-羧基-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-(甲氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5R,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5S,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5S,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-氨基-3-(乙氧基羰基)-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-羧基-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5S,6S)-6-氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5S,6S)-6-氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,2S,6S)-6-乙酰氨基-4-(乙氧基羰基)-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-5-(sec-丁氧基)-3-(乙氧基羰基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-异丙氧基环己-3-烯-1-基)-DL-天门冬氨酸,与
((1R,2R,6S)-6-叠氮基-4-(乙氧基羰基)-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸中的一种。
本发明另一方面提供了如前所述的环己烯基-DL-天门冬氨酸衍生物的制备方法,其特征在于,所述的方法是环己烯胺类化合物与富马酸进行反应;其中,所述环己烯胺类化合物是选自:
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
(3R,4R,5S)-5-乙酰氨基-4-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸,
甲基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4S,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3S,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3S,4S,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4S,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸,
(3R,4R,5S)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸,
乙基(3R,4R,5S)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-羟基环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4,5-二氨基-3-羟基环己-1-烯-1-羧酸酯,
(3R,4R,5S)-4-乙酰氨基-5-氨基-3-羟基环己-1-烯-1-羧酸,
(3S,4S,5R)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸,
乙基(3S,4S,5R)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3S,4R,5S)-5-乙酰氨基-4-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(sec-丁氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-异丙氧基环己-1-烯-1-羧酸酯,与
乙基(3R,4R,5S)-4-氨基-5-叠氮基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯中的一种。
一方面优选的,本发明所述的反应是在碱性条件下进行的。
另一方面优选的,本发明所述的反应是在乙腈与水的混合溶剂中进行的。
本发明另一方面提供了一种含有如前所述环己烯基-DL-天门冬氨酸衍生物的组合物。
一方面优选的,本发明所述的组合物进一步含有药学上可接受的辅料。
进一步优选的,本发明所述的药学上可接受的辅料是选自交联羧甲基纤维素钠、聚维酮K30、预胶化淀粉、硬脂富马酸钠与滑石粉的一种或多种。
另一方面优选的,本发明所述的组合物可制成口服固体制剂。
进一步优选的,本发明所述的口服固体制剂是选自片剂、胶囊剂与颗粒剂中的一种。
本发明另一方面提供了一种如前所述的组合物在制备用于治疗细菌性感染疾病的药物中的用途。
优选的,本发明所述的细菌性感染疾病是由选自金黄色葡萄球菌、溶壁微球菌、肺炎链球菌、粪肠球菌、大肠杆菌、弗氏柠檬酸杆菌、肺炎克雷伯菌、黏质沙雷氏菌、奇异变形杆菌、斯氏普罗威登斯菌、摩氏摩根菌、伤寒沙门菌、福氏志贺氏菌、铜绿假单胞菌、洋葱伯克霍尔德氏菌、嗜麦芽窄食单胞菌、醋酸钙不动杆菌、中间链球菌、痤疮丙酸杆菌、迟缓真细菌、产气荚膜梭状芽孢杆菌、二路普雷沃菌、具核梭杆菌、脆弱拟杆菌和华德萨特菌中的一种细菌感染所致的疾病。
体外试验结果显示,本发明所述的环己烯基-DL-天门冬氨酸衍生物对各受试菌的抗菌作用均显著高于反应前对应的环己烯胺类化合物,而且与各种植物提取物的协同作用(依FICI计)也显著高于对应的环己烯胺类化合物。
具体实施方式
以下通过实施例形式的具体实施方式,对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。
化合物制备实施例1:((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物1P)的制备与结构确证
取1mmol乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物1S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例2:((1R,2R,6S)-6-乙酰氨基-4-羧基-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物2P)的制备与结构确证
取1mmol(3R,4R,5S)-5-乙酰氨基-4-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸(化合物2S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例3:((1S,5R,6R)-6-乙酰氨基-3-(甲氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物3P)的制备与结构确证
取1mmol甲基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物3S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例4:((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物4P)的制备与结构确证
取1mmol乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物4S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例5:((1R,5R,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物5P)的制备与结构确证
取1mmol乙基(3R,4S,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物5S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例6:((1S,5S,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物6P)的制备与结构确证
取1mmol乙基(3S,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物6S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例7:((1R,5S,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物7P)的制备与结构确证
取1mmol乙基(3S,4S,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物7S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例8:((1S,5R,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物8P)的制备与结构确证
取1mmol乙基(3R,4S,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物8S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例9:((1R,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物9P)的制备与结构确证
取1mmol乙基(3R,4R,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物9S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例10:((1S,5R,6R)-6-乙酰氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物10P)的制备与结构确证
取1mmol(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸(化合物10S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例11:((1S,5R,6R)-6-氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物11P)的制备与结构确证
取1mmol(3R,4R,5S)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸(化合物11S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例12:((1S,5R,6R)-6-氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物12P)的制备与结构确证
取1mmol乙基(3R,4R,5S)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物12S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例13:((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸(化合物13P)的制备与结构确证
取1mmol乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-羟基环己-1-烯-1-羧酸酯(化合物13S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例14:((1S,5R,6R)-6-氨基-3-(乙氧基羰基)-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸(化合物14P)的制备与结构确证
取1mmol乙基(3R,4R,5S)-4,5-二氨基-3-羟基环己-1-烯-1-羧酸酯(化合物14S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例15:((1S,5R,6R)-6-乙酰氨基-3-羧基-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸(化合物15P)的制备与结构确证
取1mmol(3R,4R,5S)-4-乙酰氨基-5-氨基-3-羟基环己-1-烯-1-羧酸(化合物15S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例16:((1R,5S,6S)-6-氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物16P)的制备与结构确证
取1mmol(3S,4S,5R)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸(化合物16S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例17:((1R,5S,6S)-6-氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物17P)的制备与结构确证
取1mmol乙基(3S,4S,5R)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物17S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例18:((1R,2S,6S)-6-乙酰氨基-4-(乙氧基羰基)-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物18P)的制备与结构确证
取1mmol乙基(3S,4R,5S)-5-乙酰氨基-4-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物18S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例19:((1S,5R,6R)-6-乙酰氨基-5-(sec-丁氧基)-3-(乙氧基羰基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物19P)的制备与结构确证
取1mmol乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(sec-丁氧基)环己-1-烯-1-羧酸酯(化合物19S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例20:((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-异丙氧基环己-3-烯-1-基)-DL-天门冬氨酸(化合物20P)的制备与结构确证
取1mmol乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-异丙氧基环己-1-烯-1-羧酸酯(化合物20S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
化合物制备实施例21:((1R,2R,6S)-6-叠氮基-4-(乙氧基羰基)-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸(化合物21P)的制备与结构确证
取1mmol乙基(3R,4R,5S)-4-氨基-5-叠氮基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯(化合物21S)与1.2mmol富马酸,溶于70%乙腈得饱和溶液,再用0.1N氢氧化钠调节溶液pH至9。所得溶液于70℃水浴下搅拌24小时。减压蒸馏至干,所得固体用0.01N氢氧化钠洗涤三次,HPLC纯化,得白色粉末状固体。起始物与产物的核磁共振氢谱数据如表1所示。
表1化合物制备实施例1~21的起始物与产物的1H-NMR数据(δ,ppm)
试验例1.化合物1S~化合物21S与化合物1P~化合物21P的菌作用
采用Nash EE等人(Diagn Microbiol Infect Dis.2019Apr;93(4):369-371.)所披露的方法测定如下所述受试物对不同病原菌的MIC值,进而计算对应的FICI值。
受试物①:化合物XP,X选自1~21;
受试物②:化合物YS,Y选自1~21;
受试物③:根据邓爱华等人(分子植物育种,2018,16(23):7849-7855)等人所披露的方法制备得到的金丝桃、海桐、杜茎山、刺槐和桑树五种植物的叶片乙醇提取物,差别在于将其中的提供溶剂从丙酮替换为乙醇,其代号与定义如表2所示。
表2植物提取物的编号与定义
植物材料 | 提取物编号(PEZ) |
金丝桃叶 | PE1 |
海桐叶 | PE2 |
杜茎山叶 | PE3 |
刺槐叶 | PE4 |
桑树叶 | PE5 |
受试物④:受试物①或②与受试物③以特定的质量比R形成的混合物,记为MIX(XP-PEZ)或MIX(YS-PEZ),X、Y的定义如前所述,Z选自1~5。
各受试物对各种受试菌的抑菌作用如表3~表27所示。
表3.各受试物对金黄色葡萄球菌209P-JC的抗菌作用
表4.各受试物对溶壁微球菌2665的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(1P-PE5) | -0.4 | 4 | 25285 | 0.06 | 0.014 |
MIX(1P-PE5) | -0.2 | 4 | 25285 | 0.30 | 0.075 |
MIX(6P-PE5) | -1.4 | 26 | 25285 | 1.27 | 0.050 |
MIX(6P-PE5) | 1.5 | 26 | 25285 | 2.53 | 0.097 |
MIX(9P-PE4) | 0.1 | 18 | 39688 | 1.63 | 0.090 |
MIX(9P-PE4) | 1.1 | 18 | 39688 | 1.00 | 0.055 |
MIX(12P-PE2) | -1.4 | 30 | 58314 | 2.74 | 0.092 |
MIX(12P-PE2) | -1.1 | 30 | 58314 | 2.43 | 0.082 |
MIX(13P-PE5) | -0.2 | 27 | 25285 | 1.16 | 0.043 |
MIX(13P-PE5) | 0 | 27 | 25285 | 2.40 | 0.089 |
MIX(18P-PE4) | 0.1 | 6 | 39688 | 0.22 | 0.036 |
MIX(18P-PE4) | 1.1 | 6 | 39688 | 0.36 | 0.060 |
MIX(21P-PE4) | -0.3 | 13 | 39688 | 0.24 | 0.019 |
MIX(21P-PE4) | 0.6 | 13 | 39688 | 1.07 | 0.082 |
MIX(1S-PE5) | -0.4 | 300 | 25285 | 53.55 | 0.184 |
MIX(1S-PE5) | -0.2 | 300 | 25285 | 134.28 | 0.456 |
MIX(6S-PE5) | -1.4 | 556 | 25285 | 129.83 | 0.362 |
MIX(6S-PE5) | 1.5 | 556 | 25285 | 88.45 | 0.159 |
MIX(9S-PE4) | 0.1 | 462 | 39688 | 108.34 | 0.237 |
MIX(9S-PE4) | 1.1 | 462 | 39688 | 188.59 | 0.409 |
MIX(12S-PE2) | -1.4 | 1027 | 58314 | 334.86 | 0.470 |
MIX(12S-PE2) | -1.1 | 1027 | 58314 | 254.43 | 0.303 |
MIX(13S-PE5) | -0.2 | 914 | 25285 | 122.52 | 0.142 |
MIX(13S-PE5) | 0 | 914 | 25285 | 102.84 | 0.117 |
MIX(18S-PE4) | 0.1 | 418 | 39688 | 201.55 | 0.486 |
MIX(18S-PE4) | 1.1 | 418 | 39688 | 106.54 | 0.255 |
MIX(21S-PE4) | -0.3 | 407 | 39688 | 103.40 | 0.259 |
MIX(21S-PE4) | 0.6 | 407 | 39688 | 47.15 | 0.116 |
表5.各受试物对肺炎链球菌TypeⅢ的抗菌作用
表6.各受试物对粪肠球菌ATCC29212的抗菌作用
表7.各受试物对大肠杆菌ATCC25922的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(2P-PE1) | -1.1 | 45 | 72607 | 3.81 | 0.085 |
MIX(2P-PE1) | 1 | 45 | 72607 | 3.99 | 0.089 |
MIX(4P-PE4) | -0.8 | 17 | 30410 | 1.43 | 0.084 |
MIX(4P-PE4) | -0.1 | 17 | 30410 | 1.51 | 0.089 |
MIX(7P-PE2) | 0.6 | 27 | 59582 | 0.52 | 0.019 |
MIX(7P-PE2) | 1.4 | 27 | 59582 | 1.68 | 0.062 |
MIX(11P-PE3) | 1.7 | 7 | 77379 | 0.16 | 0.023 |
MIX(11P-PE3) | 1.8 | 7 | 77379 | 0.19 | 0.027 |
MIX(15P-PE4) | -2 | 15 | 30410 | 1.23 | 0.086 |
MIX(15P-PE4) | 1.9 | 15 | 30410 | 0.90 | 0.060 |
MIX(17P-PE3) | -1.2 | 22 | 77379 | 1.93 | 0.088 |
MIX(17P-PE3) | 0 | 22 | 77379 | 1.66 | 0.075 |
MIX(20P-PE5) | -0.2 | 19 | 19787 | 0.92 | 0.049 |
MIX(20P-PE5) | 0.1 | 19 | 19787 | 0.61 | 0.032 |
MIX(2S-PE1) | -1.1 | 720 | 72607 | 260.87 | 0.408 |
MIX(2S-PE1) | 1 | 720 | 72607 | 323.33 | 0.450 |
MIX(4S-PE4) | -0.8 | 456 | 30410 | 197.26 | 0.474 |
MIX(4S-PE4) | -0.1 | 456 | 30410 | 130.02 | 0.291 |
MIX(7S-PE2) | 0.6 | 484 | 59582 | 97.49 | 0.202 |
MIX(7S-PE2) | 1.4 | 484 | 59582 | 108.57 | 0.224 |
MIX(11S-PE3) | 1.7 | 659 | 77379 | 222.10 | 0.337 |
MIX(11S-PE3) | 1.8 | 659 | 77379 | 127.34 | 0.193 |
MIX(15S-PE4) | -2 | 354 | 30410 | 50.49 | 0.309 |
MIX(15S-PE4) | 1.9 | 354 | 30410 | 69.03 | 0.195 |
MIX(17S-PE3) | -1.2 | 683 | 77379 | 142.22 | 0.237 |
MIX(17S-PE3) | 0 | 683 | 77379 | 130.17 | 0.192 |
MIX(20S-PE5) | -0.2 | 704 | 19787 | 198.67 | 0.298 |
MIX(20S-PE5) | 0.1 | 704 | 19787 | 315.91 | 0.461 |
表8.各受试物对弗氏柠檬酸杆菌NIH10018·68的抗菌作用
表9.各受试物对肺炎克雷伯菌NCTC 9632的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(3P-PE1) | -1.9 | 22 | 10863 | 0.36 | 0.019 |
MIX(3P-PE1) | 0.5 | 22 | 10863 | 2.15 | 0.098 |
MIX(5P-PE2) | -1.5 | 17 | 99194 | 1.14 | 0.067 |
MIX(5P-PE2) | 0.4 | 17 | 99194 | 1.64 | 0.096 |
MIX(7P-PE3) | 0.3 | 25 | 11508 | 1.48 | 0.059 |
MIX(7P-PE3) | 1.1 | 25 | 11508 | 1.49 | 0.060 |
MIX(11P-PE3) | -0.2 | 22 | 11508 | 1.63 | 0.074 |
MIX(11P-PE3) | 0 | 22 | 11508 | 1.75 | 0.080 |
MIX(13P-PE3) | -1.5 | 55 | 11508 | 4.50 | 0.094 |
MIX(13P-PE3) | 0.5 | 55 | 11508 | 2.93 | 0.053 |
MIX(16P-PE2) | -1.7 | 15 | 99194 | 0.72 | 0.049 |
MIX(16P-PE2) | 1.1 | 15 | 99194 | 1.04 | 0.069 |
MIX(21P-PE2) | -1.6 | 15 | 99194 | 0.77 | 0.052 |
MIX(21P-PE2) | -0.8 | 15 | 99194 | 1.06 | 0.071 |
MIX(3S-PE1) | -1.9 | 424 | 10863 | 12.23 | 0.118 |
MIX(3S-PE1) | 0.5 | 424 | 10863 | 135.44 | 0.323 |
MIX(5S-PE2) | -1.5 | 507 | 99194 | 144.07 | 0.330 |
MIX(5S-PE2) | 0.4 | 507 | 99194 | 178.91 | 0.354 |
MIX(7S-PE3) | 0.3 | 376 | 11508 | 95.52 | 0.258 |
MIX(7S-PE3) | 1.1 | 376 | 11508 | 171.19 | 0.456 |
MIX(11S-PE3) | -0.2 | 650 | 11508 | 222.51 | 0.373 |
MIX(11S-PE3) | 0 | 650 | 11508 | 140.60 | 0.229 |
MIX(13S-PE3) | -1.5 | 1081 | 11508 | 42.57 | 0.156 |
MIX(13S-PE3) | 0.5 | 1081 | 11508 | 353.84 | 0.337 |
MIX(16S-PE2) | -1.7 | 1179 | 99194 | 120.01 | 0.162 |
MIX(16S-PE2) | 1.1 | 1179 | 99194 | 505.80 | 0.429 |
MIX(21S-PE2) | -1.6 | 613 | 99194 | 151.16 | 0.307 |
MIX(21S-PE2) | -0.8 | 613 | 99194 | 263.84 | 0.447 |
表10.各受试物对黏质沙雷氏菌IFO 3736的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(3P-PE1) | -0.2 | 11 | 54961 | 0.77 | 0.070 |
MIX(3P-PE1) | 0.5 | 11 | 54961 | 0.14 | 0.013 |
MIX(6P-PE5) | 1.1 | 7 | 25894 | 0.16 | 0.022 |
MIX(6P-PE5) | 1.6 | 7 | 25894 | 0.47 | 0.067 |
MIX(9P-PE5) | -1.4 | 49 | 25894 | 3.92 | 0.084 |
MIX(9P-PE5) | 1.8 | 49 | 25894 | 3.09 | 0.063 |
MIX(12P-PE3) | -0.8 | 47 | 40670 | 4.52 | 0.097 |
MIX(12P-PE3) | 1.2 | 47 | 40670 | 1.23 | 0.026 |
MIX(14P-PE1) | -1.1 | 46 | 54961 | 0.96 | 0.021 |
MIX(14P-PE1) | 1 | 46 | 54961 | 2.70 | 0.059 |
MIX(18P-PE3) | 0.7 | 53 | 40670 | 3.85 | 0.073 |
MIX(18P-PE3) | 1.8 | 53 | 40670 | 5.02 | 0.095 |
MIX(19P-PE4) | -0.5 | 13 | 49636 | 0.64 | 0.049 |
MIX(19P-PE4) | 0.2 | 13 | 49636 | 0.53 | 0.041 |
MIX(3S-PE1) | -0.2 | 456 | 54961 | 191.17 | 0.425 |
MIX(3S-PE1) | 0.5 | 456 | 54961 | 142.17 | 0.313 |
MIX(6S-PE5) | 1.1 | 445 | 25894 | 157.86 | 0.355 |
MIX(6S-PE5) | 1.6 | 445 | 25894 | 167.60 | 0.377 |
MIX(9S-PE5) | -1.4 | 864 | 25894 | 123.59 | 0.263 |
MIX(9S-PE5) | 1.8 | 864 | 25894 | 282.88 | 0.328 |
MIX(12S-PE3) | -0.8 | 691 | 40670 | 301.18 | 0.483 |
MIX(12S-PE3) | 1.2 | 691 | 40670 | 279.91 | 0.406 |
MIX(14S-PE1) | -1.1 | 1102 | 54961 | 434.99 | 0.494 |
MIX(14S-PE1) | 1 | 1102 | 54961 | 547.40 | 0.498 |
MIX(18S-PE3) | 0.7 | 992 | 40670 | 376.04 | 0.381 |
MIX(18S-PE3) | 1.8 | 992 | 40670 | 203.02 | 0.205 |
MIX(19S-PE4) | -0.5 | 1016 | 49636 | 336.32 | 0.352 |
MIX(19S-PE4) | 0.2 | 1016 | 49636 | 272.99 | 0.272 |
表11.各受试物对奇异变形杆菌ATCC21100的抗菌作用
表12.各受试物对斯氏普罗威登斯菌57的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(1P-PE5) | -1 | 13 | 56868 | 0.88 | 0.068 |
MIX(1P-PE5) | -0.7 | 13 | 56868 | 0.45 | 0.034 |
MIX(4P-PE5) | 0.4 | 34 | 56868 | 1.24 | 0.036 |
MIX(4P-PE5) | 0.8 | 34 | 56868 | 3.13 | 0.092 |
MIX(9P-PE4) | -0.2 | 29 | 99551 | 0.32 | 0.011 |
MIX(9P-PE4) | 1.4 | 29 | 99551 | 1.29 | 0.045 |
MIX(11P-PE3) | -2 | 17 | 88454 | 0.21 | 0.012 |
MIX(11P-PE3) | 0.1 | 17 | 88454 | 0.77 | 0.046 |
MIX(13P-PE2) | -1.3 | 54 | 46138 | 0.81 | 0.015 |
MIX(13P-PE2) | -1 | 54 | 46138 | 3.83 | 0.072 |
MIX(18P-PE3) | -1.6 | 22 | 88454 | 1.41 | 0.065 |
MIX(18P-PE3) | 0.4 | 22 | 88454 | 0.68 | 0.031 |
MIX(19P-PE3) | -1.8 | 17 | 88454 | 0.87 | 0.052 |
MIX(19P-PE3) | 1.5 | 17 | 88454 | 0.49 | 0.029 |
MIX(1S-PE5) | -1 | 1178 | 56868 | 228.63 | 0.234 |
MIX(1S-PE5) | -0.7 | 1178 | 56868 | 246.92 | 0.231 |
MIX(4S-PE5) | 0.4 | 581 | 56868 | 72.71 | 0.126 |
MIX(4S-PE5) | 0.8 | 581 | 56868 | 264.28 | 0.456 |
MIX(9S-PE4) | -0.2 | 440 | 99551 | 140.24 | 0.321 |
MIX(9S-PE4) | 1.4 | 440 | 99551 | 209.78 | 0.477 |
MIX(11S-PE3) | -2 | 1106 | 88454 | 245.17 | 0.499 |
MIX(11S-PE3) | 0.1 | 1106 | 88454 | 275.36 | 0.251 |
MIX(13S-PE2) | -1.3 | 1021 | 46138 | 255.79 | 0.361 |
MIX(13S-PE2) | -1 | 1021 | 46138 | 110.80 | 0.133 |
MIX(18S-PE3) | -1.6 | 959 | 88454 | 307.66 | 0.459 |
MIX(18S-PE3) | 0.4 | 959 | 88454 | 151.00 | 0.158 |
MIX(19S-PE3) | -1.8 | 823 | 88454 | 65.08 | 0.126 |
MIX(19S-PE3) | 1.5 | 823 | 88454 | 147.36 | 0.179 |
表13.各受试物对摩氏摩根菌KONO的抗菌作用
表14.各受试物对伤寒沙门菌O-901的抗菌作用
表15.各受试物对福氏志贺氏菌2aEW-10的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(2P-PE5) | 0.1 | 22 | 79382 | 0.94 | 0.043 |
MIX(2P-PE5) | 0.9 | 22 | 79382 | 1.90 | 0.086 |
MIX(5P-PE3) | 0 | 24 | 74805 | 2.15 | 0.090 |
MIX(5P-PE3) | 1.3 | 24 | 74805 | 2.26 | 0.094 |
MIX(7P-PE2) | 0.3 | 60 | 14494 | 3.65 | 0.061 |
MIX(7P-PE2) | 0.7 | 60 | 14494 | 3.03 | 0.051 |
MIX(10P-PE1) | 1.1 | 25 | 11035 | 1.45 | 0.058 |
MIX(10P-PE1) | 2 | 25 | 11035 | 0.61 | 0.024 |
MIX(15P-PE2) | -1.9 | 3 | 14494 | 0.29 | 0.099 |
MIX(15P-PE2) | 1.8 | 3 | 14494 | 0.27 | 0.091 |
MIX(17P-PE5) | -1.7 | 30 | 79382 | 1.84 | 0.063 |
MIX(17P-PE5) | 1 | 30 | 79382 | 1.73 | 0.058 |
MIX(21P-PE1) | -0.2 | 17 | 11035 | 1.47 | 0.087 |
MIX(21P-PE1) | 0.2 | 17 | 11035 | 0.68 | 0.040 |
MIX(2S-PE5) | 0.1 | 345 | 79382 | 149.27 | 0.434 |
MIX(2S-PE5) | 0.9 | 345 | 79382 | 90.76 | 0.263 |
MIX(5S-PE3) | 0 | 483 | 74805 | 165.39 | 0.345 |
MIX(5S-PE3) | 1.3 | 483 | 74805 | 144.93 | 0.300 |
MIX(7S-PE2) | 0.3 | 1145 | 14494 | 521.70 | 0.474 |
MIX(7S-PE2) | 0.7 | 1145 | 14494 | 550.76 | 0.489 |
MIX(10S-PE1) | 1.1 | 671 | 11035 | 311.27 | 0.466 |
MIX(10S-PE1) | 2 | 671 | 11035 | 174.25 | 0.260 |
MIX(15S-PE2) | -1.9 | 303 | 14494 | 29.22 | 0.257 |
MIX(15S-PE2) | 1.8 | 303 | 14494 | 117.33 | 0.387 |
MIX(17S-PE5) | -1.7 | 929 | 79382 | 67.36 | 0.115 |
MIX(17S-PE5) | 1 | 929 | 79382 | 223.27 | 0.241 |
MIX(21S-PE1) | -0.2 | 533 | 11035 | 147.63 | 0.298 |
MIX(21S-PE1) | 0.2 | 533 | 11035 | 115.76 | 0.224 |
表16.各受试物对铜绿假单胞菌ATCC25619的抗菌作用
表17.各受试物对洋葱伯克霍尔德氏菌ATCC25416的抗菌作用
表18.各受试物对嗜麦芽窄食单胞菌NCTC 13637的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(2P-PE3) | 0.6 | 13 | 10203 | 0.58 | 0.045 |
MIX(2P-PE3) | 1.5 | 13 | 10203 | 0.71 | 0.054 |
MIX(6P-PE1) | -1 | 17 | 88009 | 1.44 | 0.085 |
MIX(6P-PE1) | 0.6 | 17 | 88009 | 1.33 | 0.078 |
MIX(8P-PE1) | -1.7 | 41 | 88009 | 3.94 | 0.098 |
MIX(8P-PE1) | 1.2 | 41 | 88009 | 3.79 | 0.092 |
MIX(11P-PE4) | -0.6 | 50 | 76298 | 2.43 | 0.049 |
MIX(11P-PE4) | -0.4 | 50 | 76298 | 0.83 | 0.017 |
MIX(15P-PE4) | -0.7 | 24 | 76298 | 0.41 | 0.017 |
MIX(15P-PE4) | 0.7 | 24 | 76298 | 1.10 | 0.046 |
MIX(17P-PE2) | -0.1 | 16 | 59263 | 1.32 | 0.082 |
MIX(17P-PE2) | 1.9 | 16 | 59263 | 0.63 | 0.040 |
MIX(20P-PE3) | 0.1 | 36 | 10203 | 0.48 | 0.013 |
MIX(20P-PE3) | 0.6 | 36 | 10203 | 3.22 | 0.090 |
MIX(2S-PE3) | 0.6 | 879 | 10203 | 314.39 | 0.365 |
MIX(2S-PE3) | 1.5 | 879 | 10203 | 398.05 | 0.454 |
MIX(6S-PE1) | -1 | 473 | 88009 | 124.04 | 0.276 |
MIX(6S-PE1) | 0.6 | 473 | 88009 | 234.38 | 0.496 |
MIX(8S-PE1) | -1.7 | 800 | 88009 | 66.97 | 0.122 |
MIX(8S-PE1) | 1.2 | 800 | 88009 | 233.81 | 0.292 |
MIX(11S-PE4) | -0.6 | 774 | 76298 | 245.08 | 0.329 |
MIX(11S-PE4) | -0.4 | 774 | 76298 | 153.88 | 0.204 |
MIX(15S-PE4) | -0.7 | 1138 | 76298 | 111.36 | 0.105 |
MIX(15S-PE4) | 0.7 | 1138 | 76298 | 533.93 | 0.471 |
MIX(17S-PE2) | -0.1 | 447 | 59263 | 204.59 | 0.462 |
MIX(17S-PE2) | 1.9 | 447 | 59263 | 72.97 | 0.163 |
MIX(20S-PE3) | 0.1 | 1079 | 10203 | 412.60 | 0.415 |
MIX(20S-PE3) | 0.6 | 1079 | 10203 | 477.42 | 0.454 |
表19.各受试物对醋酸钙不动杆菌NCTC 7844的抗菌作用
表20.各受试物对中间链球菌ATCC27335的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(2P-PE4) | 0.2 | 10 | 55716 | 0.25 | 0.025 |
MIX(2P-PE4) | 1.9 | 10 | 55716 | 0.38 | 0.038 |
MIX(6P-PE4) | -0.7 | 28 | 55716 | 2.39 | 0.086 |
MIX(6P-PE4) | 1.7 | 28 | 55716 | 1.56 | 0.056 |
MIX(9P-PE4) | -1.2 | 9 | 55716 | 0.62 | 0.070 |
MIX(9P-PE4) | -1 | 9 | 55716 | 0.15 | 0.017 |
MIX(12P-PE5) | -1.6 | 25 | 62662 | 1.84 | 0.075 |
MIX(12P-PE5) | -0.6 | 25 | 62662 | 0.88 | 0.035 |
MIX(13P-PE3) | -0.1 | 22 | 10634 | 2.11 | 0.096 |
MIX(13P-PE3) | 1.4 | 22 | 10634 | 1.32 | 0.060 |
MIX(18P-PE1) | -0.2 | 27 | 17212 | 1.49 | 0.055 |
MIX(18P-PE1) | 1.4 | 27 | 17212 | 2.14 | 0.079 |
MIX(19P-PE3) | -0.7 | 11 | 10634 | 0.84 | 0.077 |
MIX(19P-PE3) | 0.8 | 11 | 10634 | 0.89 | 0.081 |
MIX(2S-PE4) | 0.2 | 493 | 55716 | 116.90 | 0.238 |
MIX(2S-PE4) | 1.9 | 493 | 55716 | 72.35 | 0.147 |
MIX(6S-PE4) | -0.7 | 521 | 55716 | 143.63 | 0.289 |
MIX(6S-PE4) | 1.7 | 521 | 55716 | 57.17 | 0.110 |
MIX(9S-PE4) | -1.2 | 410 | 55716 | 67.64 | 0.184 |
MIX(9S-PE4) | -1 | 410 | 55716 | 123.48 | 0.323 |
MIX(12S-PE5) | -1.6 | 406 | 62662 | 112.12 | 0.347 |
MIX(12S-PE5) | -0.6 | 406 | 62662 | 135.25 | 0.342 |
MIX(13S-PE3) | -0.1 | 655 | 10634 | 104.96 | 0.173 |
MIX(13S-PE3) | 1.4 | 655 | 10634 | 96.89 | 0.148 |
MIX(18S-PE1) | -0.2 | 1137 | 17212 | 106.14 | 0.103 |
MIX(18S-PE1) | 1.4 | 1137 | 17212 | 133.83 | 0.118 |
MIX(19S-PE3) | -0.7 | 310 | 10634 | 97.16 | 0.359 |
MIX(19S-PE3) | 0.8 | 310 | 10634 | 52.22 | 0.169 |
表21.各受试物对痤疮丙酸杆菌ATCC11828的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(1P-PE5) | -1.4 | 18 | 60580 | 1.11 | 0.062 |
MIX(1P-PE5) | -0.9 | 18 | 60580 | 1.62 | 0.090 |
MIX(5P-PE4) | -1.5 | 15 | 78499 | 0.56 | 0.037 |
MIX(5P-PE4) | 0 | 15 | 78499 | 0.37 | 0.025 |
MIX(7P-PE3) | -2 | 10 | 75913 | 0.37 | 0.037 |
MIX(7P-PE3) | 0.7 | 10 | 75913 | 0.95 | 0.095 |
MIX(10P-PE2) | -0.4 | 35 | 35898 | 2.19 | 0.063 |
MIX(10P-PE2) | -0.2 | 35 | 35898 | 2.66 | 0.076 |
MIX(14P-PE1) | 0 | 18 | 17786 | 1.42 | 0.079 |
MIX(14P-PE1) | 1.2 | 18 | 17786 | 0.30 | 0.017 |
MIX(17P-PE2) | -1.1 | 27 | 35898 | 0.61 | 0.023 |
MIX(17P-PE2) | -1 | 27 | 35898 | 0.65 | 0.024 |
MIX(20P-PE5) | -1.1 | 18 | 60580 | 0.32 | 0.018 |
MIX(20P-PE5) | -0.2 | 18 | 60580 | 0.96 | 0.053 |
MIX(1S-PE5) | -1.4 | 633 | 60580 | 149.53 | 0.298 |
MIX(1S-PE5) | -0.9 | 633 | 60580 | 168.51 | 0.288 |
MIX(5S-PE4) | -1.5 | 919 | 78499 | 107.54 | 0.160 |
MIX(5S-PE4) | 0 | 919 | 78499 | 260.45 | 0.287 |
MIX(7S-PE3) | -2 | 461 | 75913 | 36.44 | 0.127 |
MIX(7S-PE3) | 0.7 | 461 | 75913 | 61.30 | 0.133 |
MIX(10S-PE2) | -0.4 | 737 | 35898 | 187.10 | 0.267 |
MIX(10S-PE2) | -0.2 | 737 | 35898 | 249.32 | 0.349 |
MIX(14S-PE1) | 0 | 701 | 17786 | 246.59 | 0.366 |
MIX(14S-PE1) | 1.2 | 701 | 17786 | 188.12 | 0.269 |
MIX(17S-PE2) | -1.1 | 969 | 35898 | 210.47 | 0.291 |
MIX(17S-PE2) | -1 | 969 | 35898 | 238.48 | 0.313 |
MIX(20S-PE5) | -1.1 | 771 | 60580 | 147.69 | 0.222 |
MIX(20S-PE5) | -0.2 | 771 | 60580 | 189.28 | 0.250 |
表22.各受试物对迟缓真细菌ATCC25559的抗菌作用
表23.各受试物对产气荚膜梭状芽孢杆菌ATCC13124的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(1P-PE5) | -0.8 | 12 | 60572 | 0.22 | 0.019 |
MIX(1P-PE5) | 0.8 | 12 | 60572 | 0.34 | 0.029 |
MIX(4P-PE1) | -0.7 | 36 | 70611 | 0.64 | 0.018 |
MIX(4P-PE1) | -0.1 | 36 | 70611 | 1.77 | 0.049 |
MIX(8P-PE1) | 0.3 | 28 | 70611 | 1.34 | 0.048 |
MIX(8P-PE1) | 1.4 | 28 | 70611 | 2.07 | 0.074 |
MIX(11P-PE4) | 0.3 | 22 | 15232 | 0.82 | 0.037 |
MIX(11P-PE4) | 1.8 | 22 | 15232 | 1.85 | 0.084 |
MIX(15P-PE3) | 0.7 | 47 | 13956 | 1.89 | 0.040 |
MIX(15P-PE3) | 1.6 | 47 | 13956 | 0.48 | 0.010 |
MIX(17P-PE2) | 0.7 | 21 | 73398 | 0.90 | 0.043 |
MIX(17P-PE2) | 0.9 | 21 | 73398 | 0.34 | 0.016 |
MIX(21P-PE4) | 1.3 | 56 | 15232 | 2.03 | 0.036 |
MIX(21P-PE4) | 1.9 | 56 | 15232 | 5.37 | 0.096 |
MIX(1S-PE5) | -0.8 | 504 | 60572 | 130.40 | 0.272 |
MIX(1S-PE5) | 0.8 | 504 | 60572 | 72.28 | 0.144 |
MIX(4S-PE1) | -0.7 | 762 | 70611 | 99.14 | 0.137 |
MIX(4S-PE1) | -0.1 | 762 | 70611 | 213.72 | 0.284 |
MIX(8S-PE1) | 0.3 | 483 | 70611 | 187.80 | 0.390 |
MIX(8S-PE1) | 1.4 | 483 | 70611 | 138.73 | 0.287 |
MIX(11S-PE4) | 0.3 | 482 | 15232 | 54.77 | 0.115 |
MIX(11S-PE4) | 1.8 | 482 | 15232 | 206.14 | 0.428 |
MIX(15S-PE3) | 0.7 | 681 | 13956 | 103.65 | 0.154 |
MIX(15S-PE3) | 1.6 | 681 | 13956 | 209.46 | 0.308 |
MIX(17S-PE2) | 0.7 | 684 | 73398 | 208.15 | 0.305 |
MIX(17S-PE2) | 0.9 | 684 | 73398 | 273.38 | 0.400 |
MIX(21S-PE4) | 1.3 | 884 | 15232 | 177.23 | 0.201 |
MIX(21S-PE4) | 1.9 | 884 | 15232 | 332.26 | 0.376 |
表24.各受试物对二路普雷沃菌ATCC29303的抗菌作用
表25.各受试物对具核梭杆菌ATCC25586的抗菌作用
表26.各受试物对脆弱拟杆菌ATCC25285的抗菌作用
受试物 | log(R) | MIC<sub>A</sub>(ng/mL) | MIC<sub>PEZ</sub>(ng/mL) | MIC<sub>a</sub>(ng/mL) | FICI |
MIX(3P-PE2) | -0.9 | 11 | 94033 | 0.95 | 0.086 |
MIX(3P-PE2) | -0.1 | 11 | 94033 | 1.06 | 0.097 |
MIX(5P-PE4) | 0.1 | 20 | 46981 | 0.57 | 0.029 |
MIX(5P-PE4) | 1.8 | 20 | 46981 | 0.54 | 0.027 |
MIX(9P-PE3) | 0.8 | 16 | 15596 | 0.48 | 0.030 |
MIX(9P-PE3) | 1.3 | 16 | 15596 | 0.97 | 0.061 |
MIX(10P-PE1) | -0.3 | 6 | 48927 | 0.33 | 0.055 |
MIX(10P-PE1) | 0.8 | 6 | 48927 | 0.59 | 0.098 |
MIX(15P-PE4) | -0.6 | 24 | 46981 | 0.98 | 0.041 |
MIX(15P-PE4) | 0.3 | 24 | 46981 | 0.28 | 0.012 |
MIX(18P-PE5) | -1.8 | 17 | 42199 | 1.01 | 0.061 |
MIX(18P-PE5) | -1.4 | 17 | 42199 | 0.43 | 0.025 |
MIX(21P-PE2) | -1.3 | 13 | 94033 | 1.04 | 0.080 |
MIX(21P-PE2) | 2 | 13 | 94033 | 0.59 | 0.045 |
MIX(3S-PE2) | -0.9 | 362 | 94033 | 108.17 | 0.308 |
MIX(3S-PE2) | -0.1 | 362 | 94033 | 59.40 | 0.165 |
MIX(5S-PE4) | 0.1 | 323 | 46981 | 148.98 | 0.464 |
MIX(5S-PE4) | 1.8 | 323 | 46981 | 144.97 | 0.449 |
MIX(9S-PE3) | 0.8 | 316 | 15596 | 99.35 | 0.315 |
MIX(9S-PE3) | 1.3 | 316 | 15596 | 53.13 | 0.168 |
MIX(10S-PE1) | -0.3 | 484 | 48927 | 63.45 | 0.134 |
MIX(10S-PE1) | 0.8 | 484 | 48927 | 59.13 | 0.122 |
MIX(15S-PE4) | -0.6 | 730 | 46981 | 220.91 | 0.321 |
MIX(15S-PE4) | 0.3 | 730 | 46981 | 92.74 | 0.128 |
MIX(18S-PE5) | -1.8 | 305 | 42199 | 48.48 | 0.231 |
MIX(18S-PE5) | -1.4 | 305 | 42199 | 95.52 | 0.370 |
MIX(21S-PE2) | -1.3 | 375 | 94033 | 104.67 | 0.301 |
MIX(21S-PE2) | 2 | 375 | 94033 | 70.46 | 0.188 |
表27.各受试物对华德萨特菌ATCC51579的抗菌作用
制剂制备实施例本发明组合物口服制剂的制备
处方
制备方法
(1)片剂的制备方法
取处方量的活性成分与辅料,充分混合后制粒,压片,得每片重约250mg的片剂。
(2)胶囊剂的制备方法
取处方量的活性成分与辅料,充分混合后制粒,灌装胶囊,得每粒重约250mg的胶囊剂。
(3)颗粒剂的制备
取处方量的活性成分与辅料,充分混合后制粒,分装,得每袋重约10g的颗粒剂。
Claims (10)
1.一种环己烯基-DL-天门冬氨酸衍生物,所述的环己烯基-DL-天门冬氨酸衍生物是选自:
((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,2R,6S)-6-乙酰氨基-4-羧基-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-(甲氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5R,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5S,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5S,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6S)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-氨基-3-(乙氧基羰基)-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-羧基-5-羟基环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5S,6S)-6-氨基-3-羧基-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,5S,6S)-6-氨基-3-(乙氧基羰基)-5-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1R,2S,6S)-6-乙酰氨基-4-(乙氧基羰基)-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-5-(sec-丁氧基)-3-(乙氧基羰基)环己-3-烯-1-基)-DL-天门冬氨酸,
((1S,5R,6R)-6-乙酰氨基-3-(乙氧基羰基)-5-异丙氧基环己-3-烯-1-基)-DL-天门冬氨酸,与
((1R,2R,6S)-6-叠氮基-4-(乙氧基羰基)-2-(戊-3-基氧基)环己-3-烯-1-基)-DL-天门冬氨酸中的一种。
2.根据权利要求1的环己烯基-DL-天门冬氨酸衍生物的制备方法,其特征在于,所述的方法是环己烯胺类化合物与富马酸进行反应;其中,所述环己烯胺类化合物是选自:
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
(3R,4R,5S)-5-乙酰氨基-4-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸,
甲基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4S,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3S,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3S,4S,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4S,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5R)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸,
(3R,4R,5S)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸,
乙基(3R,4R,5S)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-羟基环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4,5-二氨基-3-羟基环己-1-烯-1-羧酸酯,
(3R,4R,5S)-4-乙酰氨基-5-氨基-3-羟基环己-1-烯-1-羧酸,
(3S,4S,5R)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸,
乙基(3S,4S,5R)-4,5-二氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3S,4R,5S)-5-乙酰氨基-4-氨基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(sec-丁氧基)环己-1-烯-1-羧酸酯,
乙基(3R,4R,5S)-4-乙酰氨基-5-氨基-3-异丙氧基环己-1-烯-1-羧酸酯,与
乙基(3R,4R,5S)-4-氨基-5-叠氮基-3-(戊-3-基氧基)环己-1-烯-1-羧酸酯中的一种。
3.根据权利要求2的方法,其特征在于,所述的反应是在碱性条件下进行的。
4.根据权利要求2或3的方法,其特征在于,所述的反应是在乙腈与水的混合溶剂中进行的。
5.含有根据权利要求1的环己烯基-DL-天门冬氨酸衍生物的组合物。
6.根据权利要求5和组合物,其特征在于,所述的组合物进一步含有药学上可接受的辅料。
7.根据权利要求6的组合物,其特征在于,所述的药学上可接受的辅料是选自交联羧甲基纤维素钠、聚维酮K30、预胶化淀粉、硬脂富马酸钠与滑石粉的一种或多种。
8.根据权利要求5~7的组合物,其特征在于,所述的组合物可制成口服固体制剂。
9.根据权利要求8的组合物,其特征在于,所述的口服固体制剂是选自片剂、胶囊剂与颗粒剂中的一种。
10.根据权利要求5~7的组合物在制备用于治疗细菌性感染疾病的药物中的用途。优选的,本发明所述的细菌性感染疾病是由选自金黄色葡萄球菌、溶壁微球菌、肺炎链球菌、粪肠球菌、大肠杆菌、弗氏柠檬酸杆菌、肺炎克雷伯菌、黏质沙雷氏菌、奇异变形杆菌、斯氏普罗威登斯菌、摩氏摩根菌、伤寒沙门菌、福氏志贺氏菌、铜绿假单胞菌、洋葱伯克霍尔德氏菌、嗜麦芽窄食单胞菌、醋酸钙不动杆菌、中间链球菌、痤疮丙酸杆菌、迟缓真细菌、产气荚膜梭状芽孢杆菌、二路普雷沃菌、具核梭杆菌、脆弱拟杆菌和华德萨特菌中的一种细菌感染所致的疾病。
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