CN1810815B - 用于治疗的硝基咪唑衍生物 - Google Patents
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Abstract
本发明涉及用于治疗的硝基咪唑衍生物，该化合物可用于制备抗厌氧菌、抗滴虫的药物。
Description
技术领域
本发明涉及用于治疗的硝基咪唑衍生物，该化合物可用于制备抗厌氧菌、抗滴虫的药物。
技术背景
硝基咪唑类抗菌药，是一种强力抗厌氧菌及抗原虫感染的药物，目前上市的主要有甲硝唑、替硝唑、塞克硝唑和奥硝唑。吗啉硝唑也正在进行临床试验研究，但此类化合物水溶性较差，必需用复合剂以达到满意的水溶性制剂，如静脉制剂。然而，人们总是期望减少配方的成分数以便减少病人可能产生的副反应。
发明内容
本发明的目的在于针对上述问题提供一种水溶性好、水溶液pH值酸度接近人体血液pH值且毒性小的吗啉硝唑磷酸盐及以其为主药加适当辅料制成的制剂。
本发明公开了吗啉硝唑磷酸酯及其药用盐、水合物：
(吗啉硝唑磷酸酯)
更详细的来说，本发明包括吗啉硝唑磷酸酯存在的光学对映体、水合物及其药学上可接受的酸的加成盐。
本发明的目的还提供此类吗啉硝唑磷酸酯的制备方法。
本发明的另一个目的是提供吗啉硝唑磷酸酯的用途，即用于抗厌氧菌、抗滴虫的药物。
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。
本发明化合物的制备方法是将奥硝唑(左旋奥硝唑、右旋奥硝唑)、碘化钠和乙腈混合，搅拌加热至回流，保温反应30-60分钟，冷却到室温后，再加入吗啉和三乙胺，搅拌加热至回流，保温反应3-20小时，回收乙腈，加入蒸馏水适量，加热至全溶，过滤，冷却析晶，过滤，烘干得中间体I。
将中间体I与溶媒、磷酸酯化剂反应，制得氯磷酸中间体II。然后将上述中间体II进行水解，得吗啉硝唑磷酸酯(左旋吗啉硝唑磷酸酯、右旋吗啉硝唑磷酸酯)。
磷酸酯化剂为三氯氧磷、四氯焦磷酸，反应溶媒为乙腈、丙酮、二氯甲烷、氯仿或四氢呋喃，反应温度为0-80℃，三氯氧磷反应温度优选13-18℃，四氯焦磷酸反应温度优选10-20℃。
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。
具体实施方式：
实施例1：吗啉硝唑磷酸酯的制备
将奥硝唑22g，碘化钠30g，乙腈400ml混合，搅拌加热至回流，保温反应30min后，冷却至室温，再加入吗啉13g和三乙胺20g，搅拌加热至回流， 放冷，过滤，水洗，烘干得到类白色固体20.3g，即中间体1。
将中间体140g300ml乙腈中，搅拌下，滴加40ml三氯氧磷，控制反应温度为10-15℃，滴加完后，继续保温反应1小时，冷却析晶5h(0℃)，过滤，滤饼用200ml水溶解，水解40min，减压蒸馏，残留液中加入无水乙醇300ml，冷冻析晶，过滤，得固体，30℃—60℃真空干燥得吗啉硝唑磷酸酯41.2g。
实施例2：左旋吗啉硝唑磷酸酯的制备
按照实施例1的制备方法制备左旋吗啉硝唑磷酸酯，不同的是用左旋奥硝唑(ee值0.99)代替奥硝唑。
实施例3：右旋吗啉硝唑磷酸酯的制备
按照实施例1的制备方法制备左旋吗啉硝唑磷酸酯，不同的是用右旋奥硝唑(ee值0.99)代替奥硝唑。
实施例4：吗啉硝唑磷酸二钠的制备
将80g吗啉硝唑磷酸酯投入到反应瓶中，加100ml水溶解，然后按照吗啉硝唑磷酸酯：碳酸钠为1mol：1—1.5mol的比例，加入碳酸钠到无气泡放出，加入无水乙醇1000ml冷冻析晶，过滤，减压干燥，得吗啉硝唑磷酸二钠白色固体粉末78g。
实施例5：左旋吗啉硝唑磷酸二钠的制备
按照实施例4的制备方法制备左旋吗啉硝唑磷酸二钠，不同的是用左旋吗啉硝唑磷酸酯代替吗啉硝唑磷酸酯。
实施例6：右旋吗啉硝唑磷酸二钠的制备
按照实施例4的制备方法制备右旋吗啉硝唑磷酸二钠，不同的是用右旋吗啉硝唑磷酸酯代替吗啉硝唑磷酸酯。
实施例6：左旋吗啉硝唑磷酸二钠氯化钠输液的制备
处方：
制法：称取处方量的左旋吗啉硝唑磷酸二钠和氯化钠，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，105℃流动蒸汽灭菌45分钟，即得左旋吗啉硝唑磷酸二钠氯化钠输液。
实施例7：左旋奥硝唑磷酸二钠注射液的制备
处方：
制法：称取处方量的左旋吗啉硝唑磷酸二钠，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，即得左旋吗啉硝唑磷酸二钠注射液。
实施例8：注射用左旋吗啉硝唑磷酸二钠的制备
处方：左旋吗啉硝唑磷酸二钠25g(以左旋吗啉硝唑计)
将左旋吗啉硝唑磷酸二钠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，并轧封铝盖即得注射用左旋吗啉硝唑磷酸二钠。
以上实施例中ee值均由HPLC测定，色谱柱：OD-B流动相:正己烷:冰醋酸＝15:85:0.2，测定波长310nm。
Claims (3)
1.吗啉硝唑磷酸酯或其药用盐和吗啉硝唑磷酸酯的光学异构体，所述吗啉硝唑磷酸酯的化学结构式如下所示：
2.根据权利要求1所述吗啉硝唑磷酸酯的光学异构体，其特征在于，所述光学异构体为左旋体或右旋体，其化学结构式如下所示：
3.根据权利要求1所述吗啉硝唑磷酸酯或其药用盐在制备抗厌氧菌感染和抗滴虫感染药物中的应用。
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| CN101250185B (zh) * | 2008-03-31 | 2011-01-05 | 四川百利药业有限责任公司 | 吡酮硝唑酯化合物及其制备方法和用途 |
| CN104628651B (zh) * | 2013-11-06 | 2018-07-24 | 江苏豪森药业集团有限公司 | 吗啉硝唑异构体及其制备方法 |
| CN107365272A (zh) * | 2016-05-12 | 2017-11-21 | 陕西合成药业股份有限公司 | 一种新型咪唑类化合物及其制备方法和在医学上的应用 |
| CN107556304B (zh) * | 2016-06-30 | 2022-06-03 | 华创合成制药股份有限公司 | 一种硝基咪唑类药物及其制备方法和用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1583802A (en) * | 1976-06-26 | 1981-02-04 | Schering Ag | Use of moxnidazole for combating diseases in the veterinary field |
| CN1605586A (zh) * | 2003-10-08 | 2005-04-13 | 连云港恒邦医药科技有限公司 | α－取代的2－甲基－5－硝基咪唑－1－乙醇衍生物 |
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