CN1903846B - 用于治疗的奥硝唑衍生物、制备方法及用途 - Google Patents
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Abstract
本发明涉及用于治疗的奥硝唑衍生物(特别是用于人和其他哺乳动物厌氧菌感染的治疗)，其应用方法，含有它们的制剂和它们的生产方法。
Description
技术领域：
本发明涉及用于治疗的奥硝唑衍生物(特别是用于人和其他哺乳动物厌氧菌感染的治疗)，其应用方法，含有它们的制剂和它们的生产方法。
技术背景：
奥硝唑为((±)1-(3-氯-2-羟丙基)-2-甲基-5-硝基咪唑(Ornidazole，CAS 16773-42-5)。奥硝唑为硝基咪唑类衍生物，是一种强力抗厌氧菌及抗原虫感染的药物，也是继甲硝唑后新研制的疗效更高、疗程更短、耐受性更好、体内分布更广的第三代硝基咪唑类衍生物。奥硝唑的抗微生物作用是通过其分子中的硝基在无氧环境中还原成氨基，或通过自由基的形成与细胞成分相互作用，从而导致微生物的死亡。
发明内容：
本发明的目的在于提供一类新的奥硝唑的衍生物
本发明的另一目的提供一种含有治疗有效剂量的新化合物的组合物。
本发明的再一目的提供本发明新化合物的用途。
本发明公开了一类新的奥硝唑的衍生物的化学结构是：
其中R为
本发明的一类新的奥硝唑的衍生物包括此类化合物的水合物、药用盐、前体药物、溶剂化合物。
本发明一类新的奥硝唑的衍生物的药用盐包括通常已知在碱性基团部位形成的盐包括与有机酸如马来酸、草酸等形成的盐；无机酸如盐酸、硫酸等形成的盐；
本发明一类新的奥硝唑的衍生物的前体药物是通过羟基的酰基化，烷基化，磷酸化或硼酸化作用衍生得到的化合物。这些化合物能够通过众所周知的方法生产。
本发明一类新的奥硝唑的衍生物或药用盐、水合物、前体药物具有异构体本发明包括这些异构体。
本发明一类新的奥硝唑的衍生物采用2步反应制得：
第一步是以奥硝唑为原料，与碱的水溶液反应制的环氧化物。
第二步是将环氧化物与吡咯烷(3-甲基吡咯烷、哌啶、硫代吗啉氧化物，1，2，3，4-四氢喹啉、十氢喹啉)用甲醇(乙醇，乙腈)溶解加热至回流，回流反应2～6小时，回收甲醇(乙醇，乙腈)，加入蒸馏水适量，加热至全溶，过滤，冷却析晶，过滤，烘干得本发明化合物。
本发明化合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔等。
本发明化合物给药途径可为静脉给药。注射包括静脉注射、肌肉注射、皮下注射和穴位注射等。
给药剂型可以是片剂、胶囊剂、分散片、口服液、大输液、小针、冻干粉针等药学上可接受的制剂。
本发明化合物可用于预防、改善和/或治愈由厌氧菌感染引起的疾病；特别适合用于用作人和兽医用药物的化学疗活性化合物。
本发明化合物按总重量给药，其量为每kg体重0.5-600mg，最好是24h的用量为每kg体重1-120mg，亦可采用几次给药方法。
最佳方案是一天一次给予本发明的一种或多种活性化合物的量为1-250mg/kg体重，优选剂量为1-16mg/kg体重。为了符合人或兽用的理想给药方案，这一剂量可视病情轻重、治疗难易以及所用化合物的不同上下波动，或遵医嘱。
下面结合实施例对本发明作进一步详细说明，但应理解本发明的范围非仅限于这些实施例的范围。
实施例1 1-[3-(吡咯烷基)-2-羟丙基]-2-甲基-5-硝基咪唑(化合物A)的制备
将220g消旋奥硝唑溶于600ml二氯甲烷中，搅拌下，加入20％的NaOH溶液500ml，控制反应温度为-10～30℃，反应1小时，分液，收集二氯甲烷层，加入无水硫酸钠干燥，减压蒸干二氯甲烷得环氧化物155g。
将环氧化物183g溶于500ml甲醇中，加热至回流，加入吡咯烷71g，回流反应2～6h，回收甲醇，残留物用蒸馏水200ml加热溶解，过滤，滤液冷却析晶，过滤，得淡黄色结晶性固体131g化合物A。
实施例2 1-[3-(3-甲基-1-吡咯烷基)-2-羟丙基]-2-甲基-5-硝基咪唑(化合物B)的制备
按照实施例1的相同方法制备，不同的是用3-甲基-1-吡咯烷代替吡咯烷。
实施例3 1-[3-(哌啶基)-2-羟丙基]-2-甲基-5-硝基咪唑(化合物C)的制备
按照实施例1的相同方法制备，不同的是用哌啶代替吡咯烷。
实施例4 1-[3-(硫代吗啉氧化物)-2-羟丙基]-2-甲基-5-硝基咪唑(化合物D)的制备
按照实施例1的相同方法制备，不同的是用硫代吗啉氧化物代替吡咯烷。
实施例5：1-[3-(四氢喹啉)-2-羟丙基]-2-甲基-5-硝基咪唑(化合物E)的制备
按照实施例1的相同方法制备，不同的是用1，2，3，4-四氢喹啉代替吡咯烷。
实施例6：1-[3-(十氢喹啉)-2-羟丙基]-2-甲基-5-硝基咪唑(化合物F)的制备
按照实施例1的相同方法制备，不同的是用十氢喹啉代替吡咯烷。
实施例7：化合物A片的制备方法
处方：
化合物A 150g
淀粉 70g
微晶纤维素 125g
硬酯酸镁 2.0g
羟丙基甲基纤维素(E-30)(4％溶液) 适量
制成1000片
制法：配制4％羟丙基甲基纤维素(E-30)溶液，备用。称取20g淀粉置105℃干燥5小时备用。称取60g淀粉和处方量的化合物A、微晶纤维素，混匀，粉碎过80目筛。用4％羟丙基甲基纤维素(E-30)溶液将物料制软材，用20目筛制粒，于50-60℃干燥至颗粒中的水份3％左右。过20目筛整粒，加入处方量的干淀粉(105℃干燥5小时)、硬酯酸镁，终混，测中间体含量，定片重；压片。
实施例8：化合物A氯化钠输液的制备
处方：
化合物A 15.0g
氯化钠 89g
注射用水 10L
制成10000ml
制法：称取处方量的化合物A和氯化钠，加注射用水10L，搅拌；向上述溶液中加入0.1％活性炭，搅拌，放置15分钟，5微米钛棒脱炭，再经筒式滤器0.45微米和0.22微米的微孔滤膜精滤；灌封于100ml玻璃输液瓶中，115℃流动蒸汽灭菌30分钟，即得化合物A氯化钠输液。
实施例9：化合物A注射液的制备
处方：
化合物A 15.0g
注射用水 1000ml
制成1000ml
制法：称取处方量的化合物A，加注射用水1000ml，搅拌，溶解；向上述溶液中加入0.1％活性炭，搅拌，放置15分钟，5微米钛棒脱炭，再经筒式滤器0.45微米和0.22微米的微孔滤膜精滤；灌封于10ml安瓿瓶中，100℃流动蒸汽灭菌45分钟，即得化合物A注射液。
实施例10：注射用化合物A的制备
处方：化合物A 15.0g
注射用水 1000ml
制成100瓶
化合物A用注射用水溶解后加针用活性炭吸附30分钟后经除炭、除菌过滤(0.22μm)，经检测，滤液符合规定后分装于管制抗生素西林瓶内，放置真空冷冻干燥箱内进行冷冻干燥48小时，加盖丁基胶塞，并轧封铝盖即得化合物A。
试验1：本发明化合物与奥硝唑急性毒性研究；
以奥硝唑为对照药的小鼠急毒试验
小鼠尾静脉注射LD50：
奥硝唑LD50：314mg/kg
化合物A的LD50：912mg/kg LD50平均可信限：912±91.13mg/kg
化合物B的LD50：908mg/kg LD50平均可信限：908±92.07mg/kg
化合物C的LD50：743mg/kg LD50平均可信限：743±92.76mg/kg
化合物D的LD50：914mg/kg LD50平均可信限：914±94.88mg/kg
化合物E的LD50：759mg/kg LD50平均可信限：759±88.07mg/kg
化合物F的LD50：780mg/kg LD50平均可信限：780±89.09mg/kg
试验表明本发明化合物的毒性小于奥硝唑。
试验2：本发明化合物与奥硝唑体外抗菌活性研究；
脆弱类杆菌(ug/ml) 古氏类杆菌
MIC MBC MIC MBC
化合物A 1 2 2.5 4.5
化合物B 1 2 3 4
化合物C 2 3 4 6
化合物D 1 2 3 4
化合物E 2 3 5 6
化合物F： 2 3 4 6
奥硝唑 2 4 5 7
试验表明本发明化合物的体外抗菌效果优于奥硝唑。
Claims (3)
1.通式(I)所示结构的化合物或药学上可接受的盐：
R为-H、-CH3。
2.一种药物组合物，其特征在于含有治疗有效剂量的如权利要求1所述化合物作为活性成分以及药学上可接受的载体。
3.根据权利要求2所述药物组合物的用途，用于生产治疗抗厌氧菌感染的药物。
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