CN108299531A - 甲哌泰万菌素可药用盐及其制备方法 - Google Patents
甲哌泰万菌素可药用盐及其制备方法 Download PDFInfo
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- CN108299531A CN108299531A CN201810063952.6A CN201810063952A CN108299531A CN 108299531 A CN108299531 A CN 108299531A CN 201810063952 A CN201810063952 A CN 201810063952A CN 108299531 A CN108299531 A CN 108299531A
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- Prior art keywords
- piperazine
- safe
- acid
- thousand
- rhzomorphs
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- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical class CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims abstract description 8
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Abstract
本发明属于抗生素合成领域，特别是涉及高纯度甲哌泰万菌素盐及其制备方法。该方法以酒石酸泰万菌素，N‑甲基哌嗪，甲酸为原料，加热回流反应，脱色，用碱调PH值，抽滤得甲哌泰万菌素。将甲哌泰万菌素和酸加热回流，抽滤得甲哌泰万菌素药用盐。用于治疗猪支原体感染，疗效确切，生物利用率高，治愈率达96.0%以上，副作用小，此外工艺操作简便，便于工业化生产。
Description
技术领域
本发明属于抗生素合成领域，特别是涉及高纯度甲哌泰万菌素盐及其制备方法，根据本法所获得的盐是药学可接受的药用盐，并制备成相应的制剂。
背景技术
长期以来，猪支原体肺炎一直被认为是对养猪业造成重大经济损失最常发生、流行最广最难净化的重要疫病之一。本病虽为老病，但近年来由于经常和蓝耳病、圆环病毒等其它病原混合感染，造成重大的经济损失而突显出了其重要性。猪呼吸道复合症是猪肺炎支原体与环境及多种病原微生物协同作用的结果，这里的病原微生物有猪瘟，猪流感工、伪狂犬病、猪繁殖与呼吸综合症、克雷伯氏杆菌、副嗜血杆菌、猪圆环病毒、猪传染性胸膜肺炎放线杆菌、猪多杀性巴氏杆菌、猪霍乱沙门氏菌等。
我国各禽畜支原体病频繁发生，猪支原体导致的猪气喘病的感染率、发病率居高不下，有的地方已达90％；鸡毒支原体感染阳性率为50％～80％；规模化奶牛场牛支原体血清抗体阳性率为76.43％，发病率为50％～100％，病死率高达10％～50％，给养殖业造成了巨大的经济损失。目前，国内外还没有用于预防动物支原体的商业化疫苗，主要采用大环内酯类药物等进行治疗。欧盟主要采用专业公司负责技术指导，养猪场实行隔离封闭式管理，实施严格的追溯制度。与国外相比，我国畜牧业发展不平衡，饲养管理技术、疾病诊断与防治技术落后，畜禽疾病发病率高，而且支原体疫苗短缺，动物专用药物少，国内外兽医临床能用于抗支原体的抗生素大部分选择大环内酯类药物和喹诺酮类药物。我国目前呼吸道疾病占整个畜禽疫病的35％，化学药物治疗大约占整个呼吸道治疗药物的40％，大环内酯类药物占化学药物治疗的50％，市场占有量非常大。
大环内酯类是一类具有12碳～22碳内酯环化学结构的庞大的抗生素类群。迄今所研发的品种已逾100种，但目前兽用抗支原体的大环内酯类药物有泰乐菌素、替米考星、乙酰异戊酰泰乐菌素、泰拉霉素和泰地罗新。大环内酯类抗生素的抗菌谱广泛，对部分厌氧菌、支原体、衣原体、军团菌、螺旋体和立克次体均有活性；另外，大环内酯类抗生素可通过抑制单核细胞合成炎症介质而发挥抗炎作用。已经验证病毒感染通过增加NF-κB介导的ICAM-1受体而表达，大环内酯类抗生素可通过减少ICAM-1受体表达的数量而抑制NF-kB活化，从而减少病毒在呼吸道黏膜的附着，呈现抗病毒作用。是一类治疗支原体引起的混合感染不可多得的好药。优化大环内酯结构，开发新一代大环内酯类药物也是新兽药发展的方向。
甲哌泰万菌素就是目前比乙酰异戊酰泰乐菌素更优的抗支原体活性的化合物，该化合物的结构如下结构式(I)所示：
上述化合物被记载于中国专利CN103059084A，该文献的相关内容可作为本申请的参考。在不同的实验室支原体活性水平检测中己发现甲哌泰万菌素对支原体具有很强的选择性抑制作用，为0.065μg/ml左右，但是在药物研究过程中，我们发现CN103059084A所体现的合成工艺是以乙酰异戊酰泰乐菌素为原料，用乙酸乙酯为溶剂反应生成甲哌泰万菌素，在合成收率、纯度、生物利用度等方面仍然不能令人满意。
发明内容
针对该化合物在使用过程中存在的合成收率、纯度、生物利用度等问题，本发明目的在于提供一种高纯度甲哌泰万菌素盐的制备方法；同时提供其药学可接受的药用盐，并制备成相应的制剂。
为实现本发明目的，本发明选用酒石酸泰万菌素为原料，通过制备方法的改进制备甲哌泰万菌素，并将甲哌泰万菌素制备成相应的可药用盐解决这一问题。
本发明所述高纯度酒石酸甲哌泰万菌素的合成方法如下:
(1)将酒石酸泰万菌素、有机溶剂、甲酸、N-甲基哌嗪加入反应器中，回流反应，反应完全后，回收有机溶剂，得到甲哌泰万菌素。反应式如下:
(2)将甲哌泰万菌素溶于PH6.0～7.5，0.5M的盐溶液缓冲溶液中，加热溶解，加吸附剂脱色，过滤，滤液用碱调pH值至10-11，冷却至0-20℃，冷却，离心，用纯化水洗涤，收集得甲哌泰万菌素。
(3)将甲哌泰万菌素溶于醇中，加入有机酸或无机酸，酸与甲哌泰万菌素的摩尔比为1:1.0～1.2，加热回流反应，冰浴冷却至0-5℃，析出结晶，离心，得甲哌泰万菌素药用盐。
将甲哌泰万菌素药用盐和不同辅料按照药物制剂制备工艺制成可口服或注射的药物制剂。
步骤(1)中所述有机溶剂为三氯甲烷、二氯甲烷、甲醇、乙醇、异丙醇、异戊醇,优选有机溶剂为甲醇，有机溶剂的加入量与酒石酸泰万菌素体积质量比为5～10：1。
步骤(1)中酒石酸泰万菌素与N-甲基哌嗪与甲酸的摩尔比为1:1.5～9.0:1.7～9.0，优选的,酒石酸泰万菌素与N-甲基哌嗪与甲酸的摩尔比1:7.0:7.0；步骤(1)中回流时间5-15h，优选回流6h。
步骤(2)中优选PH值为6.5，0.5M的盐溶液缓冲溶液溶解，优选磷酸氢二钠溶液；脱色剂为活性炭或硅藻土，优选活性炭；其中，活性炭或硅藻土用量为滤液体积的0.1-0.5％，优选为活性炭的0.3％。
步骤(2)所述碱液为氢氧化钠或氢氧化钾溶液，优选氢氧化钠溶液，调溶液PH值为10；步骤(3)所述的醇优选乙醇。
本发明甲哌泰万菌素的可药用盐为无机盐或者有机盐，进一步的，所述的无机盐优选为其盐酸盐、氢溴酸盐、硫酸盐、硝酸盐以及磷酸盐。所述的有机盐优选为其甲磺酸盐、马来酸盐、酒石酸盐、琥珀酸盐、醋酸盐、三氟乙酸盐、富马酸盐、柠檬酸盐、枸橼酸盐、苯磺酸盐、苯甲酸盐、苯磺酸盐、乳酸盐、苹果酸盐。尤其优选可药用盐为其酒石酸盐或磷酸盐。酒石酸与甲哌泰万菌素的摩尔比为1:1.5～3.0，优选为1:1.5～1.8。磷酸与甲哌泰万菌素的摩尔比为1:1.0～3.0，优选为1:1.0～1.2。其相对于其他盐在稳定性、性状以及生物利用度方面更具优势。
以含有治疗有效量的本发明甲哌泰万菌素可药用盐为活性成分制成药物。其剂型为口服制剂或注射制剂，可将其制成散剂、粉剂、预混剂、可溶性粉剂、颗粒剂、口服液剂、小容量注射剂、大容量注射剂、粉针剂、片剂、胶囊剂。优选地，其剂型为可溶性粉剂和小容量和大容量注射剂。
固体制剂所述药学可接受辅料优选为葡萄糖或乳糖或糊精或聚乙二醇6000-12000或PVPK30或β-环糊精或蔗糖或玉米淀粉或玉米粉或淀粉或米糠或豆粕或玉米芯粉或沸石粉或麸皮或麦饭石粉或者前述各物以任意比例构成的混合物，优选的无水葡萄糖；甲哌泰万菌素药用盐与无水葡萄糖的质量比例为1:1～5；液体制剂所述药学可接受辅料优选注射用水与丙二醇或丙三醇或注射用油或聚乙二醇系列等一种或两种任意比例构成的混合辅料，优选丙二醇，优选甲哌泰万菌素注射液的规格为5～30％。
本发明甲哌泰万菌素可药用盐应用在制备治疗抗猪支原体感染的药物中。
本发明优点：以酒石酸泰万菌素为原料，通过制备方法的改进之制备甲哌泰万菌素，并将甲哌泰万菌素制备成相应的可药用盐，合成收率达80％以上，纯度高，达88％以上，生物利用率高，经实验验证，用于治疗猪支原体感染，疗效确切，治愈率达92.0％以上，副作用小。此外工艺操作简便，绿色环保，便于工业化生产。
附图说明
图1为本发明制得的甲哌泰万菌素核磁氢谱图；
图2为本发明制得的甲哌泰万菌素核磁碳谱图；
图3为本发明制得的甲哌泰万菌素质谱图。
具体实施方式
为对本发明进行更好地说明，举实施例如下：
实施例1甲哌泰万菌素的制备
取10g酒石酸泰万菌素，溶于6倍量甲醇中，加5.9g N-甲基哌嗪，加热回流，将2.7g甲酸溶于甲醇中，缓慢滴加，反应大约为6小时，得甲哌泰万菌素。将甲哌泰万菌素溶于PH6.5，0.5M的磷酸氢二钠溶液中，加热溶解，加1％活性炭脱色，过滤，滤液用碱调pH值至10，冷却至0-20℃，冷却，离心，用纯化水洗涤，收集得淡黄色固体甲哌泰万菌素9.5g，纯度88％，收率90.7％。熔点：115-116℃；MS:1126.700；核磁数据见表1：
表1 甲哌泰万菌素样品的1H-NMR数据及归属
实施例2酒石酸甲哌泰万菌素的制备
将9.5g甲哌泰万菌素溶解到6倍量的乙醇中，加入1.9g酒石酸，加热回流1小时，冷却至5℃，抽滤，析出结晶，离心得酒石酸甲哌泰万菌素9.6g，收率为84％，纯度为90.4％。
实施例3磷酸甲哌泰万菌素的制备
将9.5g的甲哌泰万菌素溶解到6倍量的乙醇中，加入0.83g磷酸，加热回流1小时，冷却至5℃，抽滤，析出结晶，离心得磷酸甲哌泰万菌素8.3g，收率为80.34％，纯度为90.01％。
实施例4本发明甲哌泰万菌素药用盐的相关性质见表2
1.相关性质
表2 甲哌泰万菌素药用盐的相关性质
2.稳定性见表3
表3 甲哌泰万菌素药用盐的稳定性
结论:从上述稳定性试验的结果可以看出酒石酸盐的稳定性最令人满意，特别是磷酸盐的稳定性较差。
实施例5可溶性粉剂的制备
称取本发明酒石酸甲哌泰万菌素120g，加无水葡萄糖至1000g，混合均匀，制成质量百分含量10％酒石酸甲哌泰万菌素(以甲哌泰万菌素计)可溶性粉剂。
称取本发明磷酸甲哌泰万菌素120g，加无水葡萄糖至1000g，混合均匀，制成质量百分含量10％磷酸甲哌泰万菌素(以甲哌泰万菌素计)可溶性粉剂。
称取本发明酒石酸甲哌泰万菌素240g，加无水葡萄糖至1000g，混合均匀，制成质量百分含量20％酒石酸甲哌泰万菌素(以甲哌泰万菌素计)可溶性粉剂。
称取本发明酒石酸甲哌泰万菌素600g，加无水葡萄糖至1000g，混合均匀，制成质量百分含量50％酒石酸甲哌泰万菌素(以甲哌泰万菌素计)可溶性粉剂。
实施例6甲哌泰万菌素注射液的制备
称取本发明甲哌泰万菌素5g，加丙二醇溶解至100ml，过滤，灌封，灭菌，分装，得5％甲哌泰万菌素注射液。
称取本发明甲哌泰万菌素20g，加丙二醇溶解至100ml，过滤，灌封，灭菌，分装，得20％甲哌泰万菌素注射液。
实施例7本发明制剂的相关性质见表4
1.相关性质
表4 制剂的相关性质
2.稳定性见表5
表5 制剂的稳定性
结论:从上述稳定性试验的结果可以看出注射剂和可溶性粉剂在稳定性试验过程中都会含量下降，可溶性粉剂含量下降速度要低于注射剂，都在合格范围内。实施例8本发明注射剂和可溶性粉剂在制备预防和治疗猪支原体肺炎药物中的应用
养殖场自然发病的仔猪360头，病猪主要症状为呈腹式呼吸，严重时出现痉挛性咳嗽甚至呕吐，不愿走动，食欲减少，身体消瘦，皮毛粗乱。剖检可见肺有不同程度的水肿和气肿，两肺的尖叶和心叶呈对称性、融合性支气管肺炎病变。在病猪肺部的肺门和纵隔淋巴结明显肿大、质硬、灰白色、切面多汁。通过临床症状、血清学诊断、剖检症状、光透视片检等诊断方法确诊为猪肺炎支原体阳性。随机分为四组，第一组用5％甲哌泰万菌素注射液注射治疗，按0.005g/公斤体重注射给药，一天一次，连用3日；第二组用本发明10％酒石酸甲哌泰万菌素可溶性粉剂治疗，按每公斤饲料用药0.1g拌料给药，一天一次，连用3日；第三组用本发明10％磷酸甲哌泰万菌素可溶性粉剂治疗，按每公斤饲料用药0.1g拌料给药，一天一次，连用3日；
第四组为磷酸泰乐菌素可溶性粉剂，按每公斤饲料用药0.1g拌料给药，一天一次，连用3日；第五组用20％泰乐菌素注射液治疗，按0.005g/公斤体重注射给药，一天一次，连用3日；第六组为空白对照组。
使用效果：病猪咳嗽、呼吸困难的症状逐渐减轻，精神好转，采食、采水也逐渐恢复正常，食欲明显增加，用药后，本发明药物组对自然发病的猪支原体肺炎疗效显著，能迅速减轻病猪的临床症状，缓解了呼吸困难这一症状。受试药物与对照药物组疗效相比差异显著(P<0.05)。结果见表6.
表6 本发明药物的疗效对比
通过试验结果表明，本发明药物适合用于猪支原体肺炎的治疗，并且治疗效果显著。
Claims (5)
1.甲哌泰万菌素药用盐,其特征在于，甲哌泰万菌素药用盐为其盐酸盐，氢溴酸盐，硫酸盐，硝酸盐，磷酸盐;或其甲磺酸盐，马来酸盐，酒石酸盐，琥珀酸盐，醋酸盐，三氟乙酸盐，富马酸盐，柠檬酸盐，枸橼酸盐，苯磺酸盐，苯甲酸盐，苯磺酸盐，乳酸盐，苹果酸盐。
2.如权利要求1所述的甲哌泰万菌素药用盐,其特征在于，选其酒石酸盐或磷酸盐。
3.制备如权利要求1所述的甲哌泰万菌素药用盐的方法,其特征在于，通过如下步骤实现：
（1）将酒石酸泰万菌素、有机溶剂、甲酸、N-甲基哌嗪加入反应器中，回流反应，反应完全后，回收有机溶剂，得到甲哌泰万菌素；
（2）将甲哌泰万菌素溶于PH6.0~7.5，0.5M的盐溶液缓冲溶液中，加热溶解，加吸附剂脱色，过滤，滤液用碱调PH值至10-11，冷却至0-20℃，冷却，离心，用纯化水洗涤，收集得甲哌泰万菌素；
（3）将甲哌泰万菌素溶于醇中，加入有机酸或无机酸，加热回流反应，冰浴冷却至0-5℃，析出结晶，离心，得甲哌泰万菌素药用盐。
4.如权利要求3所述的甲哌泰万菌素药用盐的制备方法,其特征在于，
步骤（1）中所述有机溶剂为三氯甲烷、二氯甲烷、甲醇、乙醇、异丙醇或异戊醇；
步骤（1）中酒石酸泰万菌素与N-甲基哌嗪与甲酸的摩尔比为1:1.5~9.0:1.7~9.0；
步骤（2）中选PH值为6.5，0.5M的磷酸氢二钠溶液溶解；
步骤（2）所述碱液为氢氧化钠或氢氧化钾溶液；
步骤（3）所述的醇选乙醇，有机酸或无机酸与甲哌泰万菌素的摩尔比为3:2.0~2.5。
5.如权利要求3或4所述的甲哌泰万菌素药用盐的制备方法,其特征在于，所述有机酸或无机酸选盐酸，氢溴酸，硫酸盐，硝酸，磷酸;或甲磺酸，马来酸，酒石酸，琥珀酸，醋酸，三氟乙酸，富马酸，柠檬酸，枸橼酸，苯磺酸，苯甲酸，苯磺酸，乳酸，苹果酸。
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