CN1314688C - 吡啶并苯并恶嗪类喹诺酮衍生物及其制备方法和用途 - Google Patents
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Abstract
本发明吡啶并苯并恶嗪类喹诺酮衍生物用下述通式(I)表示，该类化合物是在帕苏沙星的结构基础上进行修饰得到，初步抗菌试验表明该类衍生物对于临床大多数菌株的抗菌活性优于或相当于帕苏沙星。其中R1、R2为H、C1-5的烷基或环烷基。
Description
技术领域
本发明涉及吡啶并苯并恶嗪类喹诺酮衍生物及其制备方法。另外，本发明还涉及吡啶并苯并恶嗪类喹诺酮衍生物或其药学上可接受的盐在制备抗菌药中的应用。
背景技术
喹诺酮类抗菌药是目前临床使用较广泛的一类合成抗菌药。目前已上市的喹诺酮产品有几十个品种，是抗感染药物中开发最活跃的领域之一。随着药物化学的发展，现在人们可以推测许多侧链可能具有的某种药化性质，因而可以通过计算机优化结构及选定药物的发展方向，甚至设计具有抗肿瘤作用的喹诺酮类化合物，其发展趋势将有可能超过β内酰胺类药物，成为21世纪的抗感染药物的主要品种。
喹诺酮类抗菌药具有共同药理特性，其抗菌谱广，尤其对革兰阴性杆菌包括绿脓杆菌在内有强大的杀菌作用，对金葡菌及产酶金葡菌也有良好抗菌作用；某些品种对结核杆菌，支原体，衣原体及厌氧菌也有作用；细菌对本类药与其他抗菌药物间无交叉耐药性。通常将喹诺酮类药物的发展分为四个阶段，第四阶段是指20世纪90年代后期开始研制，并已陆续进入临床试验，预计几年内即可正式上市的最新一代喹诺酮产品，这一阶段产品有些结构较前阶段的经典产品有很大的改进，而更重要的是其药理特性较以往又有了巨大的改善，有些产品的抗菌谱及抗菌力达到了新的高峰，对大部分致病菌来讲，已经达到或超过了β内酰胺类抗生素，甚至达到了碳青霉烯类抗生素的指标。从第四阶段开始，喹诺酮产品有希望占据抗感染药物的最大份额。
式III
帕苏沙星(式III)具有氧氟沙星结构的第四代喹诺酮类抗感染药物，它由日本富山化学公司首先研究和开发，成功地在其分子结构中7位引入了氨基环丙基，其中枢神经系统毒性和光毒性等副作用均比同类品种明显降低，帕苏沙星口服吸收良好，对多种感染症，尤其对呼吸道感染、外科手术感染如胆道感染、尿路感染和眼内感染疗效更佳。帕苏沙星的体外抗菌作用显示对G-菌，抗菌活性大于氧氟沙星、环丙沙星、斯帕沙星(比氧氟沙星大2～4倍)，对G+菌的抗菌活性与氧氟沙星相似。体内抗菌作用显示对感染G+菌，G-菌包括耐喹诺酮的粘质沙雷氏菌和绿脓杆菌的小鼠模型均有很好的疗效，其活性强于或相当于氧氟沙星、环丙沙星，其中对耐喹诺酮的粘质沙雷氏菌和绿脓杆菌的活性比参比药物环丙沙星、氧氟沙星、妥舒沙星大2～4倍。
发明内容
本发明的目的在于提供一种具有药用价值的吡啶并苯并恶嗪类喹诺酮衍生物。
本发明的另一目的在于提供一种在帕苏沙星的结构基础上进行修饰得到本发明化合物的方法。
本发明进一步的目的在于提供上述化合物或其药学上可接受的盐在制备治疗抗菌药物中的应用。
本发明的目的可以通过以下措施来达到：
本发明吡啶并苯并恶嗪类喹诺酮衍生物用下述通式(I)表示，该类化合物是在帕苏沙星的结构基础上进行修饰得到，以发现更加有效的新抗菌药。
式I
其中R1、R2为：H、C1-5的烷基或环烷基。
初步抗菌试验表明该类衍生物对于临床大多数菌株的抗菌活性优于或相当于帕苏沙星。
本发明可以通过将式II胺化制得，
式II 式I
其中R1、R2为H、C1-5的烷基或环烷基。
本发明还可以通过将式III硝化制得式IV，再经还原制得，
式IIl 式IV 式I
其中R1和R2均为H。
表1：化合物1～8核磁共振(1H-NMR)
抗菌活性测定
采用琼脂稀释法测定最低抑菌浓度(MIC)。琼脂稀释的操作严格按照临床实验室标准化研究所(CLSI/NCCLS)2005年推荐的指南进行，将8个被检菌同时接种在含定量浓度抗菌药物的平板上，测定抑制被测菌的最低药物浓度。带药培养基含药最高浓度16μg/ml，最低浓度为0.0155μg/ml。
表2：化合物1～8及帕苏沙星的抗菌活性(MIC μg/ml)
| 菌名 | 编号 | ||||||||
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 帕苏沙星 | |
| 大肠杆菌(ATCC25922) | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 |
| 金黄色葡萄球菌(ATCC25923) | 0.125 | 0.031 | 0.25 | 0.062 | 0.062 | 0.062 | 0.062 | 0.125 | 0.125 |
| 枯草杆菌(ATCC9372) | 0.031 | 0.062 | 0.062 | 0.062 | 0.062 | 0.062 | 0.062 | 0.125 | 0.062 |
| 铜绿色假单胞菌(ATCC25922) | 0.5 | 0.25 | 0.25 | 0.125 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
| 乙型溶血性链球菌(32210) | 0.125 | 0.25 | 0.125 | 0.25 | 0.125 | 0.25 | 0.25 | 0.25 | 0.125 |
| 副伤寒沙门氏菌甲(50073) | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.125 |
| 普通变形杆菌(49102) | 0.062 | 0.125 | 0.125 | 0.125 | 0.125 | 0.125 | 0.125 | 0.062 | 0.031 |
| 宋内氏志贺氏菌(51334) | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 | 0.031 |
具体实施方式
实施例1 5-氨基帕苏沙星(化合物1)的制备
在1000ml压力反应釜中加入用氨气饱和的乙醇600ml，5-溴帕苏沙星40g(0.1mol)，加热100℃反应24h，蒸去溶剂，残渣加入水1000ml，调pH中性得5-氨基帕苏沙星35g。用浓酸、盐酸或者甲磺酸即可制得5-氨基帕苏沙星盐。
实施例2～8 5-取代氨基帕苏沙星(化合物2～8)的制备
按实施例1的方法，以甲胺、乙胺等有机胺代替氨气制备得化合物2～8。
实施例9 5-硝基帕苏沙星的制备
浓硫酸75ml，冰浴冷却0℃，搅拌下滴加发烟硝酸12g(0.18mol)，滴加完毕，分多次加帕苏沙星48g(0.15mol)，使温度不超过30℃，加毕，去冰浴，室温搅拌3h，倒入冰水中，过滤，水洗，干燥得5-硝基帕苏沙星52g。
实施例10 5-氨基帕苏沙星的制备
5-硝基帕苏沙星90g(0.28mol)，乙酸1500ml，5％钯碳5g，常压氢化，氢化完毕，过滤去催化剂，回收乙酸，残渣中和pH中性得5-氨基帕苏沙星78g。
Claims (4)
1.下述通式(I)化合物或其药学上可接受的盐：
其中R1、R2为H、C1-5的烷基或环烷基。
2.权利要求1化合物制备方法，该方法可以通过将式II胺化制得，
式1中R1、R2为H、C1-5的烷基或环烷基。
3.权利要求1化合物制备方法，该方法还可以通过将式III硝化制得式IV，再经还原制得，
式I中R1和R2均为H。
4.权利要求1化合物或其药学上可接受的盐在制备抗菌药物中的应用。
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| CN1238774A (zh) * | 1996-09-27 | 1999-12-15 | 第一制药株式会社 | 吡啶并苯并鎓嗪衍生物 |
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