CN1810815A - 用于治疗的硝基咪唑衍生物 - Google Patents
用于治疗的硝基咪唑衍生物 Download PDFInfo
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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，冷却至室温后，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4-羟基哌啶13g和三乙胺20g，搅拌加热至回流，保温反应5h，反应毕，回收乙腈，加入蒸馏水150ml，加热至全溶，趁热过滤，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140g 300ml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：
| 左旋吗啉硝唑磷酸二钠氯化钠注射用水 | 25g(以左旋吗啉硝唑计)87g10L |
| 制成10000ml | |
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：
| 左旋吗啉硝唑磷酸二钠注射用水 | 25g(以左旋吗啉硝唑计)1000ml |
| 制成1000ml | |
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注射用水 | 25g(以左旋吗啉硝唑计)1000ml |
| 制成100瓶 | |
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 (4)
1、吗啉硝唑磷酸酯及其药用盐、水合物：
2、根据权利要求1所述吗啉硝唑磷酸酯包含其光学活性异构体。
3、根据权利要求2所述吗啉硝唑磷酸酯的光学活性异构体，其结构式为：
4、权利要求1所述吗啉硝唑磷酸酯及其药用盐、水合物的用途，其特征是用于制备抗厌氧菌，抗滴虫的药物。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104628651A (zh) * | 2013-11-06 | 2015-05-20 | 江苏豪森药业股份有限公司 | 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 |
| CN107556304A (zh) * | 2016-06-30 | 2018-01-09 | 陕西合成药业股份有限公司 | 一种新型硝基咪唑类药物及其制备方法和用途 |
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| DE2629237A1 (de) * | 1976-06-26 | 1978-01-05 | Schering Ag | Mittel zur bekaempfung von erkrankungen im veterinaerbereich |
| CN100344626C (zh) * | 2003-10-08 | 2007-10-24 | 连云港恒邦医药科技有限公司 | α－(吗啉－1－基)甲基－2－甲基－5－硝基咪唑－1－乙醇用于制备抗厌氧菌药物的用途 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN104628651A (zh) * | 2013-11-06 | 2015-05-20 | 江苏豪森药业股份有限公司 | 吗啉硝唑异构体及其制备方法 |
| 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 |
| CN107556304A (zh) * | 2016-06-30 | 2018-01-09 | 陕西合成药业股份有限公司 | 一种新型硝基咪唑类药物及其制备方法和用途 |
| 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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| CN1810815B (zh) | 2011-03-16 |
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