CN103848852B - 含有头孢菌素结构的新化合物以及制备方法和用途 - Google Patents

含有头孢菌素结构的新化合物以及制备方法和用途 Download PDF

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CN103848852B
CN103848852B CN201310614909.1A CN201310614909A CN103848852B CN 103848852 B CN103848852 B CN 103848852B CN 201310614909 A CN201310614909 A CN 201310614909A CN 103848852 B CN103848852 B CN 103848852B
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杨子剑
杨静
高强
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Abstract

本发明公开了含有头孢菌素结构的新化合物以及该化合物的制备方法和用途。该含有头孢菌素结构的新化合物制备成的药物比其他形式的药物或药剂在治疗眼内炎疾病的效果更好。

Description

含有头孢菌素结构的新化合物以及制备方法和用途
技术领域
本发明公开了含有头孢菌素结构的新化合物以及该化合物的制备方法和用途。
背景技术
头孢菌素杀菌与β内酰胺类抗生素（如青霉素）有相同的反应模式。头孢菌素破坏细菌细胞壁肽聚糖的合成。肽聚糖对细菌，尤其是革兰氏阳性菌细胞壁的结构完整性起着重要的作用。
眼内炎为一种累及眼球内层、玻璃体、巩膜的炎症，多数眼内炎为细菌或真菌感染所致。细菌感染途径可以为外伤，手术造成的眼球伤口，也可以为血源性（细菌经血流传播至眼内）。眼内炎的症状常常较重，主要有眼痛、充血、严重畏光和视力急剧下降。眼内炎的症状常常较重，主要有眼痛、充血、严重畏光和视力急剧下降。
在本专利制备的含有头孢菌素的新化合物在治疗眼内炎时与聚合物简单直接包裹头孢菌素制成的纳米制剂进行比较，本专利所发明的药物在治疗眼内炎和严重感染的眼部疾病模型时药物治疗效果非常好，效果远超越聚合物简单直接包裹头孢菌素的纳米制剂。
发明内容
本发明的内容如下：
本发明公开了下式I所示的头孢菌素偶联的多嵌段共聚物，其结构如下：
含头孢匹罗的新化合物
含头孢吡肟的新化合物
含头孢噻肟的新化合物
含头孢克肟的新化合物
其中PEG指的是聚乙二醇，分子量为100-100000，n =1-200之间的整数；优选n =1-100之间的整数。
本发明共聚物的制备方法，其特征在于：
1）以甲氧基聚乙二醇胺和柠檬酸反应得到化合物A；
2）化合物A和乙酰基化的癸二酸反应得到聚合物B，其中n=1-200的整数，优选1-100；
3）聚合物B与头孢菌素C反应得到最终产物；
化合物A；
聚合物B；
头孢菌素C
头孢匹罗
头孢吡肟
头孢噻肟
头孢克肟
其中头孢菌素C商购。合成的含有头孢菌素的新化合物的最终产物的所述化学步骤所需溶剂选自：苯、甲苯、吡啶、四氢呋喃、氯仿、四氯化碳、二氯甲烷、甲醇、乙醇、二氯甲烷、二甲基亚砜、N,N-二甲基甲酰胺中的一种或多种。
新制的化合物可以制备成适于局部给药的纳米制剂，微球制剂。用途为制备治疗眼内炎的药物。
本发明的制备方法具体如下：
1）将癸二酸在乙酸酐中回流，形成乙酰基-癸二酸；
2）甲氧基聚乙二醇胺与柠檬酸溶解在溶剂中，混合反应过夜，干燥得到化合物A；
3）将乙酰基-癸二酸与化合物A混合，在100-200℃下反应，反应时间10min至10h；待反应混合物冷却后，洗涤，干燥得到聚合物B；
4）将头孢菌素C与聚合物B至于溶剂中1-96小时，超声反应1-30分钟后，在烘箱中抚育得到式I聚合物，而后在0-零下30℃中均质器高速搅拌1-10分钟，旋转挥发得到粗产物，后处理得到终产物式I聚合物的纳米制剂。
其反应方程式如下：
本发明得到的含有头孢菌素结构的聚合物，易于在水中溶解，并且其半衰期比头孢菌素延长很多，该类新化合物在治疗眼内炎的模型时效果极佳。
在本专利制备的终产物制成的纳米制剂在治疗眼部疾病的比较中，本专利新化合物的药物治疗效果非常好，完全超越由聚合物直接包裹头孢菌素（并未与头孢菌素偶联）的纳米制剂。
附图说明：
图1实施例1-4的终产物的核磁共振图谱。
图2实施例1-4制成的纳米粒子、癸二酸-乙二醇共聚物直接包裹头孢菌素纳米粒和头孢菌素普通制剂的药物累计释放度和时间关系图。
具体实施方式
下面具体实施例对本发明作进一步详细说明，但本发明不仅局限以下实施例。
制备实施例如下：
实施例1
1 ）癸二酸47g在600ml乙酸酐中的混合物回流，以形成乙酰基-癸二酸；
2 ）甲氧基聚乙二醇胺6.0g，柠檬酸73mg，二环己基碳二亚胺162mg和吡啶8.0mg混合加入32ml二氯甲烷，在室温下搅拌过夜；然后用乙醚洗涤，并在真空下干燥，得到聚合物；
3 ）将第1）步和第2）步产品混合放入烧瓶中，在180℃下减压溶聚反应1小时；待聚合物冷却至室温用氯仿溶解，并用石油醚洗涤并干燥；
4 ）将150mg头孢匹罗和步骤3的850mg聚合物放入8ml二甲基亚砜和14ml的二氯甲烷溶液中48小时；超声5分钟；然后置入烘箱中1小时；于零下10-20度中均质器超高速搅拌3分钟，而后放入2%的聚乙烯醇溶液中600转搅拌3小时；离心收集后冻干，即得终产物的纳米粒子。
实施例2
1 ）癸二酸35g在500ml乙酸酐中的混合物回流，以形成乙酰基-癸二酸；
2 ）甲氧基聚乙二醇胺6.5g，柠檬酸70mg，二环己基碳二亚胺168mg和吡啶8.2mg混合加入32ml二氯甲烷，在室温下搅拌过夜；然后用乙醚洗涤，并在真空下干燥，得到聚合物；
3 ）将第1）步和第2）步产品混合放入烧瓶中，在180℃下减压溶聚反应1小时；待聚合物冷却至室温用氯仿溶解，并用石油醚洗涤并干燥；
4 ）将180mg头孢吡肟和步骤3的700mg聚合物放入8ml二甲基亚砜和12ml的二氯甲烷溶液中24小时；超声5分钟；然后置入烘箱中2小时；于零下10-20度中均质器超高速搅拌3分钟，而后放入1%的聚乙烯醇溶液中600转搅拌3小时；离心收集后冻干，即得终产物的纳米粒子。
实施例3
1 ）癸二酸50g在500ml乙酸酐中的混合物回流，以形成乙酰基-癸二酸；
2 ）甲氧基聚乙二醇胺6.5g，柠檬酸73mg，二环己基碳二亚胺168mg和吡啶8.2mg混合加入32ml二氯甲烷，在室温下搅拌过夜；然后用乙醚洗涤，并在真空下干燥，得到聚合物；
3 ）将第1）步和第2）步产品混合放入烧瓶中，在180℃下减压溶聚反应1小时；待聚合物冷却至室温用氯仿溶解，并用石油醚洗涤并干燥；
4 ）将120mg头孢噻肟和步骤3的800mg聚合物放入8ml二甲基亚砜和12ml的二氯甲烷溶液中48小时；超声5分钟；然后置入烘箱中1小时；于零下10-20度中均质器超高速搅拌3分钟，而后放入8%的胆酸溶液中600转搅拌3小时；离心收集后冻干，即得终产物的纳米粒子。
实施例4
1 ）甲氧基聚乙二醇胺3g，柠檬酸45mg，二环己基碳二亚胺200mg和吡啶6mg混合加入20ml二氯甲烷，在室温下搅拌过夜；然后用乙醚洗涤，并在真空下干燥；
2 ）将乙酰基-癸二酸20g（商购）和第1步产品混合放入烧瓶中，在170℃下反应1.5小时；待聚合物冷却至室温用氯仿溶解，并用石油醚洗涤并干燥得到聚合物（结构或与自制的稍有不同，分子量或因商购质量而不同）；
3 ）将50mg头孢克肟和该聚合物150mg放入由1ml甲醇和1ml二氯甲烷混合的溶液中；超声2分钟；然后置入烘箱中24小时；于零下10-20度中，均质器高速搅拌2分钟，产物放入3%的胆酸溶液中600转搅拌4小时；离心收集后冻干，即得新化合物的微球。
效果实验如下：
将实施例1-4制备的样品以及和癸二酸-乙二醇共聚物直接包裹的头孢菌素的纳米粒药物组（未发生化学偶联反应，头孢菌素没有结构变化），头孢菌素普通制剂（粉针剂）分别进行稳定性试验、药物体外释放试验以及眼内炎的药效作用试验。
稳定性试验：
将实施例1组制备的样品以及癸二酸-乙二醇共聚物包裹的头孢菌素的纳米粒药物组，头孢菌素普通制剂取同量（以头孢菌素计）分别测定吸光度值。而后三组放入20度温箱中3个月，随后取出测定纳米吸光度值，结果可见实施例1-4组与普通制剂组的头孢菌素的吸光度值前后无改变，而包裹的纳米粒组吸光度分别下降23%，21%，25%，22%。
药物体外释放试验：
将实施例1-4组，癸二酸-乙二醇共聚物直接包裹的头孢菌素的纳米粒药物组以及头孢菌素普通制剂组分别称取等量的药物（以头孢菌素计，每组含10mg头孢菌素），而后将各组药物至于试管中，用PBS缓冲液浸泡后，在摇床中37摄氏度下振摇，定时取样后，在紫外分光光度计下测定药物的含量，并记录后计算释放的药物含量百分比，做释放曲线图，横坐标为时间（天），纵坐标为释放的百分比。见图2，可见实施例释放的药物更长久，使药物半衰期更长。
水中溶解度试验：
将实施例1-4组，癸二酸 -乙二醇共聚物直接包裹的头孢菌素的纳米粒药物组以及头孢菌素普通制剂组分别称取等量的药物（以头孢菌素计，每组含100mg头孢菌素），分别放入试管中，用10mlPBS缓冲液溶解并振摇，静止后观察溶解状况。记录3分钟和20分钟的溶解状态，结果如下。
表1 溶解度比较
组别 3分钟 20分钟
癸二酸 -乙二醇共聚物直接包裹头孢匹罗制备的纳米粒子 浑浊白色混悬溶液 纳米粒沉降到瓶底（分层）
癸二酸 -乙二醇共聚物直接包裹头孢吡肟制备的纳米粒子 浑浊白色混悬溶液 纳米粒沉降到瓶底（分层）
癸二酸 -乙二醇共聚物直接包裹头孢噻肟制备的纳米粒子 浑浊白色混悬溶液 纳米粒沉降到瓶底（分层）
癸二酸 -乙二醇共聚物直接包裹头孢克肟制备的纳米粒子 浑浊白色混悬溶液 纳米粒沉降到瓶底（分层）
实施例1 稳定溶液 稳定溶液（未分层）
实施例2 稳定溶液 稳定溶液（未分层）
实施例3 稳定溶液 稳定溶液（未分层）
实施例4 稳定溶液 稳定溶液（未分层）
头孢匹罗普通制剂 药物沉降到瓶底 药物沉降到瓶底（分层）
头孢吡肟普通制剂 药物沉降到瓶底 药物沉降到瓶底（分层）
头孢噻肟普通制剂 药物沉降到瓶底 药物沉降到瓶底（分层）
头孢克肟普通制剂 药物沉降到瓶底 药物沉降到瓶底（分层）
药物对眼部炎症的治疗作用
1实验动物
健康Wistar大鼠，雌雄不限，体重在220g，裂隙灯下观察眼内状态良好且无其它眼疾者进行本次试验。
2实验方法
2.1造模方法
进行眼底外伤感染模型，大鼠吸入乙醚麻醉，简单固定与鼠板上，使用眼科显微手术器械以右眼颞上10点位为中心距角巩膜缘后2毫米，做与角巩膜缘平行的弧形切口，长约3.0mm。切开眼球壁全层，深达玻璃体腔。切口处造成色素膜嵌顿，色素膜外露部分与切口缘平行，切口不予缝合，让其产生感染。
2.2分组方法
将造模成功实验动物随机分为模型组、实施例1-4组、头孢菌素普通制剂组，聚合物直接包裹头孢菌素制备的纳米粒子组，各组均玻璃体腔内注射50μl药物，模型组给予等体积的PBS溶液。
3检查项目及方法
常规眼底检查
每日用裂隙灯、间接眼底镜检查。分别于干预后1、4、7天对各组动物进行眼内炎临床分级评分，重点观察前房闪辉、房水细胞及玻璃体混浊程度, 其分级标准为前房闪辉分级打分 (炎性渗出物进入房水，在裂隙灯窄光带斜照下，可见闪光及渗出颗粒在浮动，这种现象称为房水闪辉): 0 级, 无房水闪辉(光束透明发亮)；1 级，轻度房水闪辉 (微弱发白光束)；2 级，中度房水闪辉(中度乳白光束，可辨别虹膜及晶状体细节)；3 级，显著房水闪辉(明显乳白光束, 难以辨别虹膜及晶状体细节)；4 级，严重的前房闪辉, 房水成凝固状态, 伴有大量纤维素性渗出物。
4统计学处理
数据用x±s表示,两组间比较采用组间t检验。P＜0.05，为有显著性差异，具有统计学意义。
5结果
临床炎症评分
暴漏伤口后24h，所有大鼠出现眼睑水肿，角膜水肿明显，结膜明显充血、水肿，前房闪辉（+），前房渗出（+）。干预后4、7天进行临床炎症评分，模型组炎症症状日益加重，治疗组实验动物角膜均逐渐透明，前房闪辉逐渐减轻，渗出趋于吸收，玻璃体混浊不同程度减轻。各治疗组与模型组比较均有显著性差异（表1）。
表1 术后不同时间点各组临床炎症评分情况（n>10 x±s）
组别 4d 7d
模型组 3.75±0.17 3.84±0.19
头孢匹罗普通制剂给药组 3.15±0.20* 2.98±0.24*
头孢吡肟普通制剂给药组 3.14±0.27* 2.96±0.25*
头孢噻肟普通制剂给药组 3.16±0.28* 2.93±0.25*
头孢克肟普通制剂给药组 3.19±0.21* 2.92±0.21*
聚合物直接包裹头孢匹罗给药组 3.01±0.20* 2.89±0.24**
聚合物直接包裹头孢吡肟给药组 3.02±0.22* 2.94±0.21**
聚合物直接包裹头孢噻肟给药组 3.10±0.28* 2.91±0.25**
聚合物直接包裹头孢克肟给药组 3.07±0.27* 2.90±0.22**
实施例1 1.09±0.22** 0.88±0.18**
实施例2 1.09±0.21** 0.95±0.19**
实施例3 1.13±0.22** 0.86±0.16**
实施例4 1.15±0.20** 0.89±0.16**
与模型组比较 *p<0.05，**p<0.01。

Claims (7)

1.如下式所示的结构中含有头孢菌素的化合物，其结构如下：
含头孢匹罗的化合物
含头孢吡肟的化合物
含头孢噻肟的化合物
含头孢克肟的化合物
其中PEG指的是聚乙二醇，分子量为100-100000，其中n＝1-200之间的整数。
2.如权利要求1的化合物的制备方法，其特征在于：
1)以甲氧基聚乙二醇胺和柠檬酸反应得到化合物A；
2)化合物A和乙酰基化的癸二酸反应得到聚合物B，其中n＝1-200的整数；
3)聚合物B与头孢菌素C反应得到最终产物；
头孢菌素C指头孢匹罗，头孢吡肟，头孢噻肟，头孢克肟，其中化学式为：
头孢匹罗
头孢吡肟
头孢噻肟
头孢克肟。
3.权利要求2的方法，其中所述化学步骤1-3选用溶剂选自：苯、甲苯、吡啶、四氢呋喃、氯仿、四氯化碳、二氯甲烷、甲醇、乙醇、二氯甲烷、二甲基亚砜、N,N-二甲基甲酰胺中的一种或多种。
4.权利要求1的化合物，其可以制备成适于局部给药的纳米制剂，微球制剂。
5.根据权利要求4所述的化合物，所述局部给药为玻璃体注射给药，眼部给药。
6.权利要求1的化合物的用途，用途为制备治疗眼部疾病的药物。
7.权利要求1的化合物的用途，用途为制备治疗眼内炎或眼部感染的药物。
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