CN116082252A - 一种卡莫氟水化物、制备方法、药物组合物及其应用 - Google Patents
一种卡莫氟水化物、制备方法、药物组合物及其应用 Download PDFInfo
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- CN116082252A CN116082252A CN202211150960.7A CN202211150960A CN116082252A CN 116082252 A CN116082252 A CN 116082252A CN 202211150960 A CN202211150960 A CN 202211150960A CN 116082252 A CN116082252 A CN 116082252A
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Abstract
本发明涉及一种卡莫氟水化物、制备方法、药物组合物及其应用,涉及医药领域,所述卡莫氟水化物名称为6‑(5‑氟‑2,4‑二氧代‑1,2,3,4‑四氧嘧啶‑1‑甲酰胺基)乙酸。卡莫氟水化物能抑制细菌耐药性的产生,增强对抗生素的敏感性。卡莫氟水化物能用于制备抑制抗菌药物耐药性的化合物,抑制耐药菌的生长,增强了抗菌效力,并且可以减少细菌耐药性的产生,提高了抗耐药菌感染效果。
Description
技术领域
本发明涉及医药领域,具体涉及一种卡莫氟水化物、制备方法、药物组合物及其应用。
背景技术
抗生素在人类、动物和农业中的过度使用,使抗生素的耐药性逐渐增加,导致曾经可以采用抗生素治疗的细菌无法治疗,需要新的抗生素进行治疗。大肠杆菌(coli)、肺炎链球菌和铜绿假单胞菌等多药耐药、广泛耐药和泛耐药的菌株目前在全世界范围内均有报道,成为一个亟待解决的全球问题。
大肠杆菌是最常见的革兰氏阴性细菌病原体,在临床和流行病学上都面临挑战。主要存在于人类和其他温血动物的下肠道,并通过粪便和废水处理厂排放到环境中。在过去的十年中,由于抗菌药物使用的选择压力越来越大,出现了许多耐药的高危菌株。耐药的高危菌株的有效传播导致其在全球分布由于其对抗生素的产生的耐药性,使这些耐药的高危菌株表现出更强的适应性和致病性,更有效的传播和定植能力。
大肠杆菌对头孢菌素和氨基糖苷类等抗生素经常产生耐药性。一般的细菌产生耐药性的原因有产生灭活酶、药物靶点改变或被保护药物集聚减少、改变代谢途径、牵制机制和形成细菌生物被膜等。但是大肠杆菌是产生耐药基因,且通过质粒加速了耐药性在各菌株间传播。现有的卡那霉素、氨苄霉素等对耐药大肠杆菌抑制、杀灭能力降低,使抗生素的疗效减弱。现有技术中,其它的抗菌药物主要有β-内酰胺抗菌药、氨基糖苷类、磺胺类抗菌药及甲氧苄啶、喹诺酮类抗菌药及多黏菌素类抗生素等,但是存在如下缺陷:会导致过敏反应,耐药性、毒性反应、二重感染等。
鉴于此,有必要提供一种新的抗菌药物,以解决现有技术的不足。
发明内容
本发明所要解决的技术问题是提供一种卡莫氟水化物、制备方法、药物组合物及其应用。目的是通过卡莫氟水化物抑制耐药大肠杆菌的耐药基因的表达,减低大肠杆菌的耐药性的产生和致病性。
本发明解决上述技术问题,本发明的第一个目的是提供一种卡莫氟水化物,所述卡莫氟水化物的结构式如式Ⅰ,
6-(5-氟-2,4-二氧代-1,2,3,4-四氧嘧啶-1-甲酰胺基)乙酸(卡莫氟水化物),英文名称:(IUPAC Name):1-(5-carboxypentylcarbamoyl)-5-fluorouracil CAS号:69519-15-9,分子式为C11H14FN3O5,分子量为287.25。卡莫氟水化物是自行设计合成,批号(LotNO):W017052012P1-00,分析标准品,HPLC≥95.0%。
本发明付出了大量创造性的劳动,分别进行了如下试验:
(1)进行了药物合成试验,得出的试验结论是:得到卡莫氟水化物。
(2)进行了药敏试验,得出的试验结论是:卡莫氟水化物分别与抗生素联用可以增加耐药菌对药物的敏感性。
(3)进行了细菌体外诱导试验,得出的试验结论是:卡莫氟水化物分别与抗生素联用对耐药性的细菌产生抑制。
(4)进行了实时荧光定量PCR试验,得出的试验结论是:卡莫氟水化物可抑制耐药菌的耐药基因的表达;卡莫氟水化物分别与抗生素联用可增强抑制耐药菌的耐药基因的表达。
通过上述药效学试验证明,卡莫氟水化物能抑制细菌耐药性的产生,增强对抗生素的敏感性。并且与抗生素不同,对耐药细菌生长或生存力没有不利影响,能通过与抗生素联用后产生抗菌作用。因此,卡莫氟水化物能用于制备抑制抗菌药物耐药性的化合物,抑制耐药菌的生长,增强了抗菌效力,并且可以减少细菌耐药性的产生,提高了抗耐药菌感染效果。
本发明的第二个目的是提供一种卡莫氟水化物的制备方法,包括如下步骤:
第一步:将W017-01溶于相当于W017-01摩尔比的1~1.2的乙醇中,加入相当于W017-01摩尔比的1.2-1.8溶剂氯化亚砜,回流3~5h,反应结束后浓缩,经石油醚打浆得到白色固体W017-02;
第二步:将第一步得到的W017-02溶于甲苯溶剂中,形成0.7~1.3mol/L的溶液,加入相当于W017-02摩尔比的1~1.2的三光气,85±3℃反应1~3h,浓缩,得到W017-03;
第三步:将W017-04和第二步得到的W017-03按照摩尔比1:(1~1.2)依次加入吡啶中,吡啶与W017-04的摩尔比为0.2~0.6,90±3℃反应2~4h,反应结束后浓缩,洗涤,干燥,重结晶,得到W017-05;
第四步:将第三步得到的W017-05加入相当于W017-05摩尔比的3~5的3.5~4.5moL/L的盐酸,80±3℃反应1~3h,反应结束后冷却至0℃过滤,得到卡莫氟水化物W017-00。
进一步,第一步:将W017-01溶于相当于W017-01摩尔比的1.1的乙醇中,加入相当于W017-01摩尔比的1.5溶剂氯化亚砜,回流4h,反应结束后浓缩,经石油醚打浆得到白色固体W017-02;
第二步:将第一步得到的W017-02溶于甲苯溶剂中,形成0.8mol/L的溶液,加入相当于W017-02摩尔比的1.1的三光气,85℃反应2h,浓缩,得到W017-03;
第三步:将W017-04和第二步得到的W017-03按照摩尔比1:1.1依次加入吡啶中,吡啶与W017-04的摩尔比为0.4,90℃反应3h,反应结束后浓缩,洗涤,干燥,重结晶,得到W017-05;
第四步:将第三步得到的W017-05加入相当于W017-05摩尔比的4的4moL/L的盐酸,80℃反应2h,反应结束后冷却至0℃过滤,得到卡莫氟水化物W017-00。
其反应的流程为:
采用上述方案的有益效果是:通过本方法,能够高收率的、快速的制备卡莫氟水化物。
本发明的第三个目的是提供一种药物组合物,包括上述所述的卡莫氟水化物和抗生素。
采用上述方案的有益效果是:本发明经过研究发现,卡莫氟水化物能用于制备抑制抗菌药物耐药性的化合物,可以抑制耐药菌的生长,增强了抗菌效力,提高了抗耐药菌感染效果,不仅开辟了卡莫氟水化物新的应用领域,发现了新的抗菌药物,具有积极的药学价值和广泛的社会意义。
进一步,所述的抗生素包括β-内酰胺类、大环内酯类、氨基苷类、四环素类、喹诺酮类或磺胺类。
所述β-内酰胺类包括第一代至第四代,第一代如头孢羟氨苄、头孢氨苄、头孢唑啉、头孢拉啶、头孢丙烯。口服主要治疗革兰阳性菌。第二代头孢呋辛脂、头孢克洛、头孢孟多。可为一般革兰阴性菌感染的首选药,另对革兰阳性菌及流感嗜血杆菌也有较强作用。第三代头孢噻肟、头孢曲松、头孢克肟、头孢地尼。口服主要用于革兰阴性菌所致各系统的中度感染。第四代头孢皮罗、头孢吡肟、头孢唑南。用于其他抗生素治疗无效的严重感染或对其他抗生素耐药的细菌引起的各系统严重感染。
所述氨基苷类包括链霉素、庆大霉素、卡那霉素、西索米星以及人工半合成的妥布霉素、阿米卡星、奈替米星等。
所述四环素类天然品有金霉素、土霉素、四环素等;半合成品有多西环素和米诺环素。
所述喹诺酮类包括第一代至第四代,第一代,如:萘啶酸、吡哌酸等。抗菌谱窄,仅用于泌尿道和肠道感染。第二代,如:诺氟沙星、环丙沙星、氧氟沙星等。第三代,如:司帕沙星、左氧氟沙星、格帕沙星等。综合临床疗效达到第三代头孢;第四代,如:克林沙星、加替沙星等。在第三代的基础上增加了抗厌氧菌活性。
所述磺胺类,此类包含如:磺胺嘧啶(SD),磺胺甲噁唑(SMZ),柳氮磺吡啶(SASP),磺胺嘧啶银(SD-Ag)等。
进一步,所述药物组合物还包括卡莫氟水化物和抗生素药学上可接受的载体。
采用上述进一步方案的有益效果是:卡莫氟水化物和抗生素作为有效成分,具有良好的抗菌活性,可以和药学上可接受的载体一起,制成抗菌药物,用于抗菌。
进一步,所述载体为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂和润滑剂中的任意一种或两种以上的混合物。
采用上述进一步方案的有益效果是:上述种类的载体,有利于药物释放、提高用药量准确性,增加药用的稳定性。
进一步,所述药物组合物剂型为口服剂、膏剂、糊剂、涂剂、凝胶剂、胶囊剂和喷雾剂中的任意一种。
采用上述进一步方案的有益效果是:本发明的药物组合物可以制成多种剂型,适用于多种给药途径,更方便不同的病患者使用。
本发明的第四个目的是提供一种药物组合物的应用,所述药物组合物在抑制抗菌药物耐药性的药物中的应用。所述药物组合物中的活性成分的实际剂量应根据多种相关因素来确定,包括待治疗的疾病严重程度、施用途径、患者年龄、性别、体重,因此,上述剂量不应以任何方式限制本发明的保护范围。
采用上述进一步方案的有益效果是:卡莫氟水化物用于制备抗菌药物,可以抑制致病菌的生长,增强了抗菌效力,并且可以减少细菌耐药性的产生,提高了抗细菌感染效果。
进一步,所述抗菌药物的抗菌谱为革兰氏阳性细菌和/或革兰氏阴性细菌及其耐药菌。
更进一步,所述革兰氏阳性细菌为金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌、肺炎链球菌和化脓链球菌中的任意一种或多种。
更进一步,所述革兰氏阴性细菌为鲍曼不动杆菌、肺炎克雷伯杆菌、大肠杆菌、粘质沙雷氏菌、奇异变形杆菌、普通变形杆菌、摩根摩氏菌、异型枸橼酸杆菌、阴沟肠杆菌、产气肠杆菌和雷极氏普鲁菲登杆菌中的任意一种或多种。
附图说明
图1为本发明实施例1中卡莫氟水化物合成后检测结果图;
图2为本发明实施例2中卡莫氟水化物抑制野生型菌株大肠杆菌O157的耐药的结果图;
图3为本发明实施例3中野生型菌株大肠杆菌O157菌株的药敏的实验结果图;
图4为本发明实施例4的实验结果图;
图5为本发明实施例5中实时荧光定量PCR的实验结果;
图6为本发明实施例6中细菌体外诱导试验的实验结果;
图7为本发明实施例7中苏木素-伊红(HE)染色的实验结果,比例尺为200μm。
具体实施方式
以下对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。
下列实施例中所用的方法如无特别说明均是常规的实验方法。所述试剂和生物材料,如无特别的说明,均可从商业途径获得。
本发明采用的实验材料和试剂:野生型菌株大肠杆菌O157,购于山东维真生物科技有限公司;耐药的菌株通过亚致死浓度诱导耐药;小鼠,购于赛业模式生物研究中心有限公司;感染耐药的菌株的小鼠通过灌胃法接种;氨苄青霉素钠购于北京索莱宝科技有限公司。
实施例1:卡莫氟水化物合成
本实施例所述的卡莫氟水化物合成方法,包括如下步骤:第一步:6-氨基乙酸W017-01,60.56g(500mmol)溶于乙醇500mL,加入氯化亚砜55mL,(750mmol,1.5eq)回流4h,反应结束后浓缩,粗品经石油醚打浆得白色固体6-氨基己酸乙酯W017-02,产量97g,收率99%;
第二步:6-氨基己酸乙酯W017-02,97g(495mmol)溶于甲苯450mL,分批加入三光气(二(三氯甲基)碳酸酯),85℃反应2h。直接浓缩除去甲苯得W017-03粗品115g。粗品不做进一步纯化,直接用于下一步反应;
第三步:W017-04 115g(crude)和W017-03 67.3g(520mmol)依次加入吡啶200mL中,加毕,90℃反应3h。反应结束后浓缩除去吡啶,粗品用二氯甲烷400mL溶解后用稀盐酸200mL和饱和食盐水200mL依次洗涤,有机相干燥后浓缩,所得粗品再用乙醇重结晶得W017-05,产量112g,收率68.2%;
第四步:W017-05 112g(353mmol)加入4N盐酸353mL(4eq),80℃反应2h。反应结束后冷却至0℃过滤,滤饼用冰乙醇淋洗后,干燥得目标产物卡莫氟水化物W017-00,产量98.9g,收率80%,白色固体。其反应的流程为:
卡莫氟水化物W017-00:1H NMR(500MHz,DMSO-d6)δ12.25(s,1H),11.99(s,1H),9.13(t,J=5.7Hz,1H),8.39(d,J=7.5Hz,1H),3.27(q,J=6.7Hz,2H),2.21(t,J=7.3Hz,2H),1.52(p,J=7.4Hz,4H),1.30(p,J=8.0Hz,2H)。HPLC purity 99.51%(254nM),HPLCpurity 96.4%(254nM).卡莫氟水化物合成后检测其药物结构详见图1。
实施例2:耐药性研究
体外测得大肠杆菌MIC为8μg/mL,用亚致死浓度4μg/mL诱导大肠杆菌产生耐药性,设计3组实验每组实验重复3次:第1组为阳性对照组,在诱导产生耐药菌液中加入4μg/ml氨苄青霉素钠;第2组在菌液中加入4μg/ml氨苄青霉素钠和2μg/mL的卡莫氟水化物;第3组在菌液中加入4μg/ml氨苄青霉素钠和2μg/mL的卡莫氟。在37℃条件下培养12h,传代。每两代测的各组细菌MIC,依据上述方法连续传16代后,检测卡莫氟与卡莫氟水化物对大肠杆菌耐药性的影响,发现卡莫氟水化物可以明显抑制大肠杆菌耐药性的产生,卡莫氟不能抑制大肠杆菌耐药性的产生,如图2所示。
实施例3:药敏试验
本实施例采用纸片扩散法,用菌株涂在琼脂平板培养基上按照一定要求贴浸有抗菌药的纸片,所述浸有抗菌药的纸片分别为空白,浸有氨苄青霉素钠的纸片,浸有卡莫氟水化物的纸片,及浸有氨苄青霉素钠和卡莫氟水化物的纸片,分别培养一段时间后测量抑菌圈大小,结果发现卡莫氟水化物可以明显增强抗生素对耐药菌的抑菌效果,如图3所示。
实施例4:
本实施例无菌操作,将诱导产生耐药的大肠杆菌用培养基稀释为OD600为0.002,分别加到灭菌的96孔聚苯乙烯板中,每孔200ul。将2倍比稀释后不同浓度的氨苄青霉素钠抗菌药物溶液0μg/mL 0.5μg/mL、1μg/mL、2μg/mL、4μg/mL、8μg/mL、16μg/mL、32μg/mL及64μg/mL,分别加到灭菌的96孔聚苯乙烯板中,每孔10μl,第11孔不加药作为生长对照,结果显示诱导耐药的菌株的最低抑菌浓度显著增高,如图4所示。
实施例5:qRT-PCR检测
本实施例将诱导耐药的菌株培养组在细菌培养基中培养到对数期,取10μl菌液加到5ml细菌培养基中,设计3组实验,每组实验重复3次,第1组为空白组;第2组为阳性对照组,在诱导产生耐药菌液中加入10μg/ml氨苄青霉素钠;第3组在菌液中加入10μg/ml氨苄青霉素钠和5μg/mL的卡莫氟,在37℃条件下培养12h。提取细菌mRNA后逆转录成cDNA,以cDNA此模板,并设计肠出血性大肠杆菌特异性定量β-内酰胺酶相关基因TEM引物,序列F:5'-CGGTCGCCGCATACACTAT-3'R:5'TCATGCCATCCGTAAGATGC3',进行qRT-PCR来检测β-内酰胺酶表达量。如图5所示,卡莫氟水化物可抑制耐药菌的耐药基因的表达;卡莫氟水化物分别与抗生素联用可增强抑制耐药菌的耐药基因的表达。
实施例6:细菌体外诱导实验
本实施例将耐药的菌分别与药物共培养实验,共设计了4组实验,每组实验重复3次。第1组:空白对照组;第2组:氨苄青霉素钠组,耐药的杆菌与氨苄青霉素钠共培养;第3组:卡莫氟水化物组,耐药的杆菌与卡莫氟水化物共培养;及第4组:氨苄青霉素钠和卡莫氟水化组,耐药的杆菌与氨苄青霉素钠和卡莫氟水化共培养。如图6所示,结果显示和第1组至第3组的对照组、氨苄青霉素钠组、加入卡莫氟水化物组相比,第4组的氨苄青霉素钠和卡莫氟水化组明显抑制细菌生长,表明卡莫氟水化物可增加氨苄青霉素钠的抗菌作用。
实施例7:HE染色
本实施例将诱导耐药的菌和药物给正常小鼠灌胃,首先用耐药大肠杆菌灌胃共设计了4组实验,每组实验重复3次。第1组:空白对照组;第2组:苄西林组,灌胃的药物为氨苄青霉素钠;第3组:卡莫氟水化物组,灌胃的药物为卡莫氟水化物;及第4组:氨苄青霉素钠和卡莫氟水化组,灌胃的药物为氨苄青霉素钠和卡莫氟水化物。每次灌胃的剂量为200ul,每天灌胃1次,治疗14天。后结肠切片HE染色,如图7所示,结果显示卡莫氟水化物明显减轻细菌对肠道的损伤,明显增强耐药大肠杆菌对抗生素的敏感性。
综上所述,卡莫氟水化物能以高度选择性的方式抑制β-内酰胺酶,使效应子分泌受到抑制。并且与抗生素不同,对细菌生长或生存力没有不利影响,能通过大大减低大肠杆菌的耐药性治疗疾病。因此,卡莫氟水化物能用于制备抗菌药物,可以抑制致病菌的生长,增强了抗菌效力,并且可以减少细菌耐药性的产生,提高了抗细菌感染效果。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (10)
2.基于权利要求1所述一种卡莫氟水化物的制备方法,其特征在于,包括如下步骤:
第一步:将W017-01溶于相当于W017-01摩尔比的1~1.2的乙醇中,加入相当于W017-01摩尔比的1.2-1.8溶剂氯化亚砜,回流3~5h,反应结束后浓缩,经石油醚打浆得到白色固体W017-02;
第二步:将第一步得到的W017-02溶于甲苯溶剂中,形成0.7~1.3mol/L的溶液,加入相当于W017-02摩尔比的1~1.2的三光气,85±3℃反应1~3h,浓缩,得到W017-03;
第三步:将W017-04和第二步得到的W017-03按照摩尔比1:(1~1.2)依次加入吡啶中,吡啶与W017-04的摩尔比为0.2~0.6,90±3℃反应2~4h,反应结束后浓缩,洗涤,干燥,重结晶,得到W017-05;
第四步:将第三步得到的W017-05加入相当于W017-05摩尔比的3~5的3.5~4.5moL/L的盐酸,80±3℃反应1~3h,反应结束后冷却至0℃过滤,得到卡莫氟水化物W017-00。
3.根据权利要求1所述一种卡莫氟水化物的制备方法,其特征在于,包括如下步骤:
第一步:将W017-01溶于相当于W017-01摩尔比的1.1的乙醇中,加入相当于W017-01摩尔比的1.5溶剂氯化亚砜,回流4h,反应结束后浓缩,经石油醚打浆得到白色固体W017-02;
第二步:将第一步得到的W017-02溶于甲苯溶剂中,形成0.8mol/L的溶液,加入相当于W017-02摩尔比的1.1的三光气,85℃反应2h,浓缩,得到W017-03;
第三步:将W017-04和第二步得到的W017-03按照摩尔比1:1.1依次加入吡啶中,吡啶与W017-04的摩尔比为0.4,90℃反应3h,反应结束后浓缩,洗涤,干燥,重结晶,得到W017-05;
第四步:将第三步得到的W017-05加入相当于W017-05摩尔比的4的4moL/L的盐酸,80℃反应2h,反应结束后冷却至0℃过滤,得到卡莫氟水化物W017-00。
4.一种药物组合物,其特征在于,包括如权利要求1所述的卡莫氟水化物和抗生素。
5.根据权利要求4所述一种药物组合物,其特征在于,所述的抗生素包括β-内酰胺类、大环内酯类、氨基苷类、四环素类、喹诺酮类或磺胺类。
6.根据权利要求4所述一种药物组合物,其特征在于,所述药物组合物还包括卡莫氟水化物和抗生素药学上可接受的载体。
7.根据权利要求6所述一种药物组合物,其特征在于,所述载体为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂和润滑剂中的任意一种或两种以上的混合物。
8.根据权利要求4所述一种药物组合物,其特征在于,所述药物组合物剂型为口服剂、膏剂、糊剂、涂剂、凝胶剂、胶囊剂和喷雾剂中的任意一种。
9.根据权利要求4至8任一项所述一种药物组合物的应用,其特征在于,所述药物组合物在抑制抗菌药物耐药性的药物中的应用。
10.根据权利要求9所述一种药物组合物的应用,其特征在于,所述药物组合物的抗菌谱为革兰氏阳性细菌和/或革兰氏阴性细菌及其耐药菌。
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