CN102126983B - 秋水仙碱衍生物及其制备方法和用途 - Google Patents
秋水仙碱衍生物及其制备方法和用途 Download PDFInfo
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- CN102126983B CN102126983B CN2011100068104A CN201110006810A CN102126983B CN 102126983 B CN102126983 B CN 102126983B CN 2011100068104 A CN2011100068104 A CN 2011100068104A CN 201110006810 A CN201110006810 A CN 201110006810A CN 102126983 B CN102126983 B CN 102126983B
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- colchiceinamide
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Abstract
本发明涉及秋水仙碱衍生物及其制备方法和用途，该衍生物具有较好的存储稳定性，适用于制备引起的人和动物疾病，如白血病、乳腺癌、胃癌、宫颈癌、鼻咽癌、光化性角化病、基底细胞癌、鳞状细胞皮肤原位癌等的治疗或预防的药物中的应用。
Description
技术领域
本发明涉及医药技术领域，具体地说是提供药物——秋水仙碱衍生物及其制备方法和用途。
背景技术
公开的文献仅报道了秋水仙碱衍生物——秋裂胺（C21H24N2O5，分子量：384.43），到目前为止，国内外尚没有公开的文献报道如下结构的秋裂胺结晶水合物C21H24 N2O5·nH2O，n=2.5～3.5]及其制备方法和用途。
发明内容
本发明所涉及的是秋水仙碱衍生物及其制备方法和用途，进一步说，是涉及秋裂胺结晶水合物 [C21H24N2O5·nH2O，n=2.5～3.5，n可以是2.5、2.75、3.0、3.5或其之间的数字]及其制备方法和用途。
本发明获得的含有结晶水的秋裂胺与秋水仙碱相比毒性低，令人惊奇的是，含结晶水的秋裂胺引湿性远低于含有不结晶水的秋裂胺，含有结晶水的秋裂胺水合物比不含结晶水的更能稳定的存在,便于储存和运输，易于制备制剂。此外，无水物的潮解使得在处理时要隔绝空气防止粘连等，而水合物具有良好的滑动性，从而改善制剂的可操作性。令人惊奇的是，特征性的,本发明的水合物的热分析图谱的失重平台下具有对应的吸热峰，如：热分析图谱显示出秋裂胺3水合物。
本发明的秋裂胺水合物能稳定存储。将实施例1中的秋裂胺3水合物和秋裂胺3水合物经过95℃左右、五氧化二磷存在下真空干燥处理得到秋裂胺无水物样品（水分≤2%）分别密闭与西林瓶中，按中国药典要求进行引湿性试验：取秋裂胺无水物和本发明的水合物约5g，置于干燥恒重的表面皿中，精密称重，25℃、相对湿度为75％，分别于试验0h和48h取样，计算引湿增重的百分率，结果显示，无水物引湿性比本发明的水合物都高得多（表1）；本发明的秋裂胺的结晶水合物能更好地稳定存储，在RH75%、30℃避光的条件下，将秋裂胺的结晶水合物和秋裂胺的无水物样品分别密闭与西林瓶中进行加速稳定性试验，色谱条件：色谱柱：Kromasil Cl8(250mm×4.6mm，5μm),流动相:乙腈- [0.02mol/L磷酸二氢钾溶液- 三乙胺(磷酸调节pH=5 )](400:600:2)，检测波长248nm，流速1ml/min，测定有关物质增加的幅度。结果见表2。
说明本发明的秋裂胺水合物具有更好的存储稳定性。
秋裂胺结晶水合物的制备包括如下方法：
方法A. 将秋水仙碱用水或C1-C6低分子醇如甲醇、乙醇、异丙醇、C2-C8低级醚的一种或几种为溶剂，使溶解，加氨气、氨水、碳酸氢铵、碳酸铵的一种或几种或者其溶液，5～50℃搅拌反应2-24小时，减压浓缩，用C1-C6低级卤代烃，包括二氯甲烷、三氯甲烷、二氯乙烷等，C2-C8低级酯，如醋酸丁酯、乙酸乙酯、甲酸乙酯，等的一种或几种提取1-5 次，分去水层，有机层减压浓缩后，用水或C1-C6低分子醇如甲醇、乙醇、异丙醇、C2-C8低级醚、C1-C6低级卤代烃，包括二氯甲烷、三氯甲烷、二氯乙烷等，C5-C10的直链或支链烷烃或环烷烃，包括戊烷、正己烷、环己烷、石油醚，C6-C10的芳香烃，包括苯、甲苯等、C3-C7低分子酮等中的一种或几种进行一次或多次结晶，放置，使结晶完全，过滤，抽干，干燥即得；
方法B. 将秋水仙碱用水或C1-C6低分子醇如甲醇、乙醇、异丙醇、C2-C8低级醚、C1-C6低级卤代烃，包括二氯甲烷、三氯甲烷、二氯乙烷，的一种或几种为溶剂，使溶解，加氨气、氨水、碳酸氢铵、碳酸铵的一种或几种或者其溶液，5～50℃搅拌反应2-24小时，减压浓缩，用C1-C6低级卤代烃，包括二氯甲烷、三氯甲烷、二氯乙烷等，C2-C8低级酯，如醋酸丁酯、乙酸乙酯、甲酸乙酯，等的一种或几种提取1-5 次，分去水层，有机层减压浓缩后，用水或C1-C6低分子醇如甲醇、乙醇、异丙醇等、C2-C8低级醚、C1-C6低级卤代烃，包括二氯甲烷、三氯甲烷、二氯乙烷等，C5-C10的直链或支链烷烃或环烷烃，包括戊烷、正己烷、环己烷、石油醚，C6-C10的芳香烃，包括苯、甲苯等、C3-C7低分子酮等中的一种或几种进行一次或多次结晶，放置，使结晶完全，过滤，抽干，干燥即得。
本发明中的低级酮或低分子酮的碳原子数定义为C3-C7（即碳原子数为3-7个，关于碳原子的标记方法下同），如丙酮，丁酮等；低级醇或低分子醇的碳原子数定义为C1-C6（即：1-6个碳原子的醇），如甲醇、乙醇、异丙醇，低级醚或低分子醚的碳原子数定义为C2-C8，如乙醚、丁醚等。低级卤代烃的碳原子数定义为C1-C6；低级酯的碳原子数定义为C2-C8；低分子直链或支链烷烃或环烷烃的碳原子数定义为C5-C10，低分子芳香烃的碳原子数定义为C5-C10。
秋裂胺水合物的结晶或重结晶溶剂，优选水、甲醇、乙醇、异丙醇、正丁醇、丙酮、丁酮、异己酮、乙酸甲酯、乙酸乙酯、二氯甲烷、氯仿、乙醚、异丙醚、四氢呋喃、石油醚、苯中的一种或几种。
本发明的秋裂胺水合物可具有不同的晶型，例如，从甲醇-水-氯仿、水-氯仿-乙醚、水-二氯甲烷-乙醚、乙醇-水-二氯甲烷-乙酸乙酯、乙醇-水-二氯甲烷-乙醚等体系为结晶或重结晶体系而制备出来的秋裂胺2.5、3、3.5水合物的X-射线粉末衍射图谱可以有所不同。本发明中的结晶水合物或者实施例中的结晶水合物的溶液在同一HPLC条件下的其主峰色谱保留时间具有一致性。
本发明的秋裂胺3水合物经过特殊处理得到秋裂胺无水物样品的方法可以是在不同温度（如70-105℃）、干燥时间（6小时到数日）、或附有其它干燥剂（包括硅胶，五氧化二磷、无水氯化钙、无水硫酸钠、无水碳酸钠、无水碳酸钾、无水硫酸镁、氢氧化钠、氢氧化钾、硅胶等）的环境条件下、或使用常压或减压的方式进行干燥，以及苯共沸带水方法。
本发明的秋裂胺水合物用途：本发明的秋裂胺水合物用于制备注射用冻干粉针制剂、或者大输液制剂、或者小水针注射剂，片剂，胶囊，粉剂，颗粒剂，以及软膏、凝胶、栓剂上的应用等。
用于制备固体制剂的片剂、胶囊、颗粒剂，其中可含有药学上可接受的填充剂，如淀粉、变性淀粉、乳糖、微晶纤维素、环糊精、山梨醇、甘露醇、磷酸钙、氨基酸等；药学上可接受的崩解剂，如淀粉、变性淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙基纤维素、表面活性剂；药学上可接受的润湿剂和粘合剂，如胶化淀粉、甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚乙烯吡咯烷酮、海藻酸及其盐；药学上可接受的润滑剂和助流剂，如硬脂酸、硬脂酸镁、聚乙二醇4000－8000、滑石粉、微粉硅胶、十二烷基硫酸镁等；药学上可接受的甜味剂和香精，如阿斯巴甜、甜蜜素、糖精钠、三氯蔗糖、食用香精等。
本发明的结晶水合物不同于无水物的潮解使得在处理时要隔绝空气防止粘连等，而结晶水合物具有良好的滑动性，从而改善制剂的可操作性；并使制备的固体制剂具有良好的溶出性能，使得其容易被吸收进入血液循环，改善生物利用度，并有利于快速发挥其作用。
秋裂胺水合物的软膏或凝胶制备：秋裂胺水合物与50－95％基质混匀，基质可以是乙醇、甘油、三乙醇胺、甘油明胶、聚乙二醇200－8000、凡士林、泊洛沙姆、聚乙烯吡咯烷酮、半合成硬脂肪酸脂、水溶性单甘酯、卡波姆系列（931、934、940、974、AA-1、1342等）、吐温60－80。软膏或凝胶剂中可含有药学上可接收的防腐剂和稳定剂，制备时可分别将卡波姆用水分散，加入甘油、聚乙二醇200－8000、或凡士林、水浴加热，搅拌混合，加处方量的秋裂胺水合物、搅拌、用药学上可接收的无机碱或者有机碱调节pH＝4.0－8.5左右，加水至全量、搅拌至匀、分装，即得。
秋裂胺水合物的栓剂：秋裂胺水合物的0.01－10％、其余由栓剂基质组成，基质可以是乙醇、甘油、甘油明胶、聚乙二醇200－8000、凡士林、泊洛沙姆、半合成硬脂肪酸脂、卡波姆系列（931、934、940、974、AA-1、1342等）、吐温60－80。制备方法：将主药与基质混合，水浴加热、搅拌、待融化，搅拌至匀、迅速倾入已涂有润滑剂的栓剂的模具中，至稍微溢出栓模，待冷后削平，起模即得。
秋裂胺水合物针剂，其制备方法为：
冻干粉针制剂的制备方法为：取秋裂胺水合物，可以加药学上可接受的助溶剂、冻干支持剂或辅形剂、稳定剂、注射用水，搅拌使溶解，若需要，可用药学上可接受的酸碱调节pH为3.5～8.5，加活性碳0.005～0.5%（W/V）搅拌15～45min，过滤，补水，无菌过滤，按2～40mg /瓶（以主药计）分装，冷冻干燥，压塞，得成品。
秋裂胺水合物小容量注射液及其制备工艺：秋裂胺水合物加注射用水和药学上可接受的附加剂，例如：药学上可接受的pH调节剂、药学上可接受的助溶剂、药学上可接受的抗氧剂、惰性气体，过滤、除菌制成灭菌小容量注射液，其pH值在3.5～8.5之间。
药学上可接受的冻干支持剂或辅形剂可以含有乳糖、葡萄糖、甘露醇、山梨醇、木糖醇、右旋糖酐、氨基酸或其盐（包括甘氨酸、牛磺酸、精氨酸等）、磷酸二氢钠、磷酸氢二钠、去氧胆酸钠等的一种或几种。
其药学上可接受的pH调节剂可以是药学上可接受的无机酸或有机酸、无机碱或有机碱，也可以是广义的路易斯酸或碱，可以含有一种或者几种，可以是盐酸、磷酸、丙酸、醋酸及醋酸盐、如醋酸钠等，乳酸以及乳酸药用盐、枸橼酸药用盐、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、磷酸盐、酒石酸及其药用盐、硼砂、硼酸、丁二酸、己酸、己二酸、反丁烯二酸、顺丁烯二酸、三羟基氨基甲烷、二乙醇胺、乙醇胺、异丙醇胺、二异丙醇胺、2-氨基-2-（羟甲基）1，3-丙二醇胺、1，2-己二胺、N-甲基葡萄胺、二异丙胺以及它们的盐，多羟基羧酸及药用盐，如葡萄糖醛酸、葡萄糖酸、乳糖酸、苹果酸、苏糖酸、葡庚糖酸、氨基酸及氨基酸盐等中的一种或者几种。
其药学上可接受的抗氧剂和稳定剂可以是亚硫酸、亚硫酸盐、亚硫酸氢盐、焦亚硫酸盐、连二亚硫酸盐、硫代硫酸盐，有机硫化合物硫脲、谷胱甘肽、二巯基丙醇、巯基乙酸及盐、硫代乳酸及盐、硫代二丙酸及盐、苯酚类化合物，如没食子酸及盐、咖啡酸、咖啡酸盐、阿魏酸、阿魏酸盐、二叔丁基对苯酚、2，5-二羟基苯甲酸、2，5-二羟基苯甲酸盐、水杨酸或其盐；氨基酸以及其盐；抗坏血酸及抗坏血酸盐、异抗坏血酸及异抗坏血酸盐、烟酰胺、酒石酸、硝酸盐、磷酸盐、醋酸药用盐、柠檬酸盐、EDTA及EDTA盐、如EDTA二钠、EDTA四钠、N－二（2－羟乙基）甘氨酸、α-环糊精、β-环糊精、γ-环糊精、葡糖基-环糊精（G1-CYD）、麦芽糖基-β-环糊精、羟丙基β-环糊精、2-羟丙基β-环糊精（2-HP-β-CYD）、3-羟丙基β-环糊精（3-HP-β-CYD）、磺丁醚-β-环糊精（SBE-β-CD），如（SBE7-β-CD）、SBE4-β-CD等中的一种或者几种。
其药学上可接受的助溶剂可以是葡萄糖、木糖醇、山梨醇、甘露醇、烟酰胺、N-甲基葡萄胺、N-乙基葡萄胺、磷酸及药学上可接受的磷酸盐（可以是磷酸二氢钠、磷酸氢二钠、磷酸钠、磷酸二氢钾等）、乳酸、乳酸钠、枸橼酸、枸橼酸钠、多羟基羧酸及药用盐（如葡萄糖醛酸、葡萄糖酸、乳糖酸、苹果酸、苏糖酸、葡庚糖酸等或其药用盐）、氨基酸及氨基酸盐（可以是门冬氨酸、谷氨酸等）、盐酸、硫酸、酒石酸、吐温20-80、泊洛沙姆（包括泊洛沙姆124，188，237，338，407等）、聚乙二醇200－2000、乙醇、乙二醇、1，2-丙二醇、1，3-丙二醇、丙三醇、葡糖基-环糊精（G1-CYD）、麦芽糖基-β-环糊精、羟丙基β-环糊精、2-羟丙基β-环糊精（2-HP-β-CYD）、3-羟丙基β-环糊精（3-HP-β-CYD）、磺丁醚-β-环糊精（SBE-β-CD），如（SBE7-β-CD）、SBE4-β-CD等、以及水等中的一种或者几种。
其药学上可接受的等渗调节剂可以是葡萄糖、果糖、木糖醇、山梨醇、甘露醇、转化糖、麦芽糖、右旋糖酐、氯化钠、氯化钾、乳酸钠等中的一种或几种。
本发明的注射剂中去热源和除菌方式可以是加入配液量 0.005～3％的活性炭去热源，微孔滤膜除菌和热压灭菌，也可以采用超滤除菌、去热源。超滤方法中，超滤器可选用平板式、卷式、管式、中空纤维式或圆盒式等，优选卷式和中空纤维式超滤器，采用截留相对分子质量为5万至30万的滤膜除去大部分发热性物质和细菌后，再采用截留相对分子质量4000～30000的超滤膜除去剩余热源，优选相对分子质量6000～30000的超滤膜。
本发明的秋裂胺水合物，适用于制备下列所引起的人和哺乳动物疾病的治疗或预防的药物中的应用：即制备用于对白血病、乳腺癌、胃癌、宫颈癌、鼻咽癌、光化性角化病、基底细胞癌、鳞状细胞皮肤原位癌等的治疗或预防的药物中的应用。
用量用法：一般情况下，于成人，肌内注射：2-10mg/次，一日1-2次。静脉注射：2-40mg/次，以25%葡萄糖注射液20ml稀释。静脉滴注：2-40mg，以5%葡萄糖注射液或0.9%氯化钠注射液250～500ml稀释，一日1-2次。儿童减半量以上使用。经胃肠道给药用量用法：10～70 kg体重的人或动物，一般情况下2-80mg/天, 分1-4次给药；儿童减半量以上使用，栓剂一天一次，一次一个；皮肤外用根据情况而定。
附图说明
图1为秋裂胺3水合物的热分析图谱。
图2为秋裂胺3水合物的热分析图谱。
图3为秋裂胺3水合物的DEPT图谱。
具体实施方式
粉末X衍射法
在武汉理工大学材料测试中心利用D/MX-ⅢA X射线衍射仪，衍射角2θ，扫描范围3-60°，测定了秋裂胺3水合物的粉末X射线衍射图。在实施例1的方案中，利用粉末X射线衍射法测量，在衍射角2θ（3-60°）测量范围内，本发明的秋裂胺3水合物可以在包括如下2θ值的位置具有相应的特征值：约6.40，9.97，10.94，11.39，12.72，14.66，17.61，18.72，19.46，20.08，21.72，22.21，23.45，23.87，25.39，26.08，27.79，35.92，41.17。
热分析方法
测试条件：Setaram公司Setsys 16，NETZSCH STA449C，样品量5mg左右，升温速度：10K/min，N2流速：50ml/min，温度：一般为室温～400℃左右。
令人意外的是，特征性的，本发明的水合物的热分析 (TG-DTA 或者TG-DSC)图谱的失重平台下具有对应的吸热峰，热分析图谱显示出秋裂胺3水合物等。
实施例1 秋裂胺3水合物的制备 将秋水仙碱3克、浓氨水50ml于的三颈烧瓶中，搅拌使溶解，控制温度25-40℃，搅拌反应12小时，减压浓缩，用二氯甲烷300ml萃取三次，有机层减压浓缩，在负压下，用乙醇1ml、水2ml、石油醚25ml以及二氯甲烷进行结晶，将其放置于在0℃以下，待固体析出完毕，抽滤，沉淀物用水洗2次，抽滤，所得的固体物用溶剂乙醇1ml、氯仿20ml、水2ml、石油醚20ml进行重结晶，0℃以下放置，待结晶析出充分，抽滤，将结晶于50℃左右干燥4小时，得黄色结晶约1.9g，鉴别分析：取2mg于白色瓷板上，加乙醇溶解后，滴加三氯化铁试液3滴，溶液立即显黑暗色，再加稀盐酸，颜色立即消失；取2mg于白色瓷板上，加亚硝酸钠结晶数粒和盐酸3滴，立即呈深棕色；熔点：257-261℃（ELECTROTHERMAL MELTING POINT APPARATUS,未校正）；室温20-25℃下测比旋度 (10mg/ml 氯仿)：-182.2°，卡氏法测定水分为12.42％, 热分析:平台失重约11.64％，这与样品含有3个结晶水的结果（理论值12.33％）在误差范围内（见附图1）；紫外：λCH3OH max 204nm、248nm、352nm， ESI-MS：m/z:383；红外光谱：νKBr max cm-13439（宽）、3304，3194、2994、2935、2838、1665、1602、1558、1508、1485、1458、1415、1400、1384、1349、1322、1282、1143、1098、1049、1009、856、750；H-NMR(DMSO,D2O) δ8.58(1H,d,重水交换后变小，H-8)，δ7.83(2H，宽单峰，重水交换后消失，NH2)，δ7.10(1H,s, H-12)，δ7.08(1H,s, H-11)，δ6.90(1H,d, H-4)，δ6.74( 1H,s,)，δ4.36(1H,m,)，δ3.82(3H,s,OCH3)，δ3.77(3H,s,OCH3)，δ3.47(3H,s,OCH3)，δ, δ1.84-2.14 (4H,m, 2×CH2)， δ1.86 (3H,s, COCH3)；核磁共振碳谱(13C-NMR)及DEPT谱(DEPT谱见图3)（Mercury VX-300核磁共振仪）：总碳数21个，伯碳4个，仲碳2，叔碳5，季碳10；13C-NMR (DMSO)：l75.2-C-9；169.2, C-16；157.6,C-10；153.1,C-1；151.1,C-7a；150.2,C-3；141.5，C-2；138.8，C-12；135.2，C-12a；129.7，C-4a；127.6，C-1a；124.5，C-8；110.9，C-11；108.4，C-4；61.5，C-2-OCH3；61.4，C-1-OCH3；56.6，C-3-OCH3；52.2，C-7；37.5，C-6；30.3，C-5;22.3，C-17.元素分析 理论值：C 57.52%，H6.90%，N6.39%； 实测值：C 57.69%，H6.71%，N6.23%。
实施例2 秋裂胺3水合物的制备 将秋水仙碱6克、水120ml于三颈烧瓶中，搅拌，加碳酸氢铵20g，浓氨水12ml,搅拌，控制温度25-50℃，搅拌反应8-16小时，减压浓缩，用氯仿300ml萃取三次，有机层减压浓缩，在负压下加乙醇1.5ml、水2ml然后加乙醚致微混浊加热或加少许乙醇又溶，再加少量乙醚，0℃以下放置，待固体析出完毕，抽滤，沉淀物水洗2次，固体物于水浴加热下用少量乙醇溶解，然后加水3ml、氯仿20ml，以及加适量的乙醚进行重结晶,置0℃以下放置，待沉淀析出充分后，抽滤，所得固体在60℃左右干燥4小时左右，得黄色结晶约3.5g；鉴别分析：取2mg于白色瓷板上，加乙醇溶解后，滴加三氯化铁试液3滴，溶液立即显黑暗色，再加稀盐酸，颜色立即消失；取2mg于白色瓷板上，加亚硝酸钠结晶数粒和盐酸3滴，立即呈深棕色；熔点：258-262℃（ELECTROTHERMAL MELTING POINT APPARATUS,未校正），室温下测比旋度 (10mg/ml 氯仿)：-182.6°，卡氏法测定水分为12.65％, 热分析（NETZSCH STA449C）:平台失重约12.03％，这与样品含有3个结晶水的结果（理论值12.33％）在误差范围内；紫外：λCH3OH max 204nm、248nm、352nm，红外光谱：νKBr max cm-13439（宽）、3304，3194、2994、2935、2838、1665、1602、1558、1508、1485、1458、1415、1400、1384、1349、1322、1282、1143、1098、1049、1009、856、750； ESI-MS： m/z:383；核磁共振碳谱(13C-NMR)及DEPT谱（Varian公司Unity-Inova600核磁共振仪, Mercury VX-300核磁共振仪）：总碳数21个，伯碳4个，仲碳2，叔碳5，季碳10；13C-NMR (DMSO)：l75.2，C-9；169.2, C-16；157.6,C-10；153.1,C-1；151.1,C-7a；150.2,C-3；141.5 C-2；138.8，C-12；135.2，C-12a；129.7，C-4a；127.6，C-1a；124.5，C-8；110.9，C-11；108.4，C-4；61.5，C-2-OCH3；61.4，C-1-OCH3；56.6，C-3-OCH3；52.2，C-7；37.5，C-6；30.3，C-5;22.3，C-17.元素分析 理论值：C 57.52%，H6.90%，N6.39%； 实测值：C 57.38%，H7.07%，N6.46%。
实施例3 冻干制剂的制备 取秋裂胺水合物5g（实施例1），加甘露醇15g，磷酸二氢钠4g，柠檬酸2g、盐酸精氨酸1g、3-羟丙基β-环糊精10g，吐温-80 3ml，EDTA二钠0.02g，加20-50℃注射用水800ml左右，搅拌使溶，用1-5M左右的柠檬酸和氢氧化钠溶液调节pH为4.5～6.8，补注射用水至1000ml，加活性碳0.01～0.5%（W/V）搅拌15-30min，过滤，用0.22微米微孔滤膜过滤，按5、10mg/瓶分装，真空冷冻干燥，压塞，得冻干品。
实施例4 秋裂胺水合物注射液的制备 秋裂胺3水合物（按干品计）5g（实施例1），葡萄糖酸钠4g，柠檬酸5g，烟酰胺10g、甘油100ml、EDTA二钠0.06g，避强光下加注射用水、通氮气、搅拌使溶解，1-5M左右的柠檬酸或柠檬酸钠溶液调节pH为3.5～6.8，加活性碳0.01%（W/V）搅拌15～45min,过滤，补水至2000ml，用0.22微米微孔滤膜过滤或者采用截留相对分子质量6000～20000的超滤膜过滤，溶液通氮气饱和，按5、10mg、或20mg/支分装，灭菌得成品。
实施例5 秋裂胺水合物氯化钠输液的制备：将秋裂胺3水合物10g（实施例2）、氯化钠425g、枸橼酸钠3g、酒石酸5g、吐温-80 5ml，丙二醇50ml、烟酰胺15g、EDTA二钠0.6g，加入注射用水中，溶液通高纯氮气饱和，搅拌使溶解完全，用枸橼酸溶液和枸橼酸钠溶液调节pH值在4.0-6.8的范围内，加注射用水至50000ml，加配液量0.05％的活性炭，加热搅拌10-30 分钟左右，过滤脱炭，再经 0.22um 的膜精滤或者采用截留相对分子质量6000～20000的超滤膜过滤，经半成品化验，待其含量、pH值和澄明度合格后，在高纯氮气下，灌装于50ml、100ml或250ml 瓶或塑料袋中，灭菌，包装即得。
实施例6 秋裂胺水合物片或胶囊（10mg/粒）
处方：秋裂胺3水合物（实施例1） 10g
微晶纤维素 65g
淀粉 20g
羧甲基淀粉钠 5g
β-环糊精 5g
5％PVP 30（50%的乙醇水溶液） 适量
硬脂酸镁 2g
将秋裂胺水合物、微晶纤维素、淀粉、β-环糊精、羧甲基淀粉钠过100目筛，用5％PVP 30的50%的乙醇水溶液适量为粘合剂制软材，过18－24目筛制粒，干燥，过14－20目筛整粒后，加硬脂酸镁混合，灌装胶囊或者压片。
实施例7 秋裂胺水合物颗粒 包括秋裂胺3水合物颗粒（2.5mg/包）
处方：秋裂胺水合物 2.5g
甘露醇 47g
微晶纤维素 150g
固体食用香精 1g
5％羟丙基甲基纤维素 适量
将秋裂胺水合物、甘露醇、微晶纤维素、食用香精过100目筛，用5％的羟丙基甲基纤维素的50%乙醇水溶液适量为粘合剂制软材，过18－24目筛制粒，60℃以下干燥，过14－20目筛整粒后，分包装。
实施例8 秋裂胺水合物片（10mg/片）
处方：秋裂胺3水合物（实施例1） 10g
微晶纤维素 180g
低取代羟丙基纤维素 5g
β-环糊精 5g
硬脂酸镁 2g
将秋裂胺水合物、β-环糊精、低取代羟丙基纤维素过100目筛，微晶纤维素过80目筛，混匀，干法制粒，过18－24目筛，加硬脂酸镁混合，压片。
实施例9 秋裂胺3水合物的凝胶
处方：秋裂胺3水合物（实施例2） 1g
聚乙二醇6000 60g
聚乙二醇400 10g
甘油 5ml
卡波姆934 5g
卡波姆1342 3g
水 500-700ml
将分别将卡波姆1342和卡波姆934用水分散，加入甘油、聚乙二醇6000、聚乙二醇400、搅拌混合，加秋裂胺3水合物、水浴加热、搅拌至匀、用磷酸氢二钠和磷酸二氢钠溶液适量调节pH＝4.0～7.5左右，分装即得。
实施例10 秋裂胺3水合物的栓剂（12mg/粒）
处方：秋裂胺3水合物（实施例1） 1.2g（100粒投料）
聚乙二醇4000 180g
甘油 5ml
泊洛沙姆 50g
吐温80 2ml
将秋裂胺3水合物、甘油、聚乙二醇4000、泊洛沙姆、吐温80混合，水浴加热、搅拌、待融化，搅拌至匀、迅速倾入已涂有润滑剂的栓剂的模具中，至稍微溢出栓模，待冷后削平，起模即得。
实施例11,药理作用
1、对胃癌的抑制作用
将处于对数生长期的人胃腺癌SGC-7901细胞株，消化后用PBS制备成浓度约为2×107个/ml的单细胞悬液，于BALB/c裸鼠（体重18-22g，雌雄各半）右后背部皮下注射0.2ml，2天后将裸鼠随机分为空白对照组、给药组(氟尿嘧啶，5-FU 组)、给药组(秋裂胺3水合物组)，每组10只。空白对照组腹腔注射生理盐水0.2ml，每天1次，5-FU 组注射5-FU（生理盐水稀释，体积0.2ml），20mg/kg，隔天1次；秋裂胺3水合物组注射1mg/kg，每周5次，连续注射2周。末次给药24小时后处死动物，处死动物，剥离肿瘤，称取瘤重，并计算抑瘤率=(对照组平均瘤重-给药组平均瘤重)/对照组平均瘤重×100%，结果见表3。（P值为给药组与空白对照组相比的结果，下同）。
2、对宫颈癌的抑制作用
将处于对数生长期的人宫颈癌Hela细胞株，消化后用PBS制备成浓度约为2×107个/ml的单细胞悬液，于昆明种雌性小鼠（体重18-22g）皮下注射0.2ml,种植后第3天，将小鼠随机分为空白对照组、给药组(环磷酰胺组)、给药组(秋裂胺3水合物组)，每组10只。灌胃给药，空白对照组给予生理盐水0.2ml，每天1次，环磷酰胺组注射环磷酰胺（生理盐水稀释，体积0.2ml），25mg/kg，每天1次；秋裂胺3水合物组1.5mg/kg（生理盐水调制的混悬液，体积0.2ml），每天1次，连续2周。末次给药24小时后处死动物，剥离肿瘤，称取瘤重，并计算抑瘤率=(对照组平均瘤重-给药组平均瘤重)/对照组平均瘤重×100%，结果见表4。
3、对乳腺癌的抑制作用
将人乳腺癌MA-737细胞株，于BALB/c裸鼠（体重18-22g，雌性）右后背部皮下注射0.2ml，种植后第3天，将小鼠随机分为空白对照组、给药组(氟尿嘧啶，5-FU 组)、给药组(秋裂胺3水合物组，实施例1)，每组10只。空白对照组腹腔注射生理盐水0.2ml，每天1次，氟尿嘧啶 组注射氟尿嘧啶（生理盐水稀释，体积0.2ml），50mg/kg，隔天1次；秋裂胺3水合物组注射1.2mg/kg（生理盐水调制的混悬液，体积0.2ml），每天1次，连续注射2周。末次给药24小时后处死动物，剥离肿瘤，称取瘤重，并计算抑瘤率=(对照组平均瘤重-给药组平均瘤重)/对照组平均瘤重×100%，结果见表5。
4、对白血病的抑制作用
将处于对数生长期的L615白血病细胞，用PBS制备成浓度约为2×107个/ml的单细胞悬液，于615近交系小鼠（体重18-22g，雌雄各半）皮下注射0.2ml,种植后第3天，将小鼠随机分为空白对照组、给药组(氟尿嘧啶，5-FU 组)、给药组(秋裂胺3水合物组，实施例1）)，每组10只。一律灌胃给药。空白对照组给予生理盐水0.2ml，每天1次；5-FU组按30mg/kg灌胃给药，隔天1次；秋裂胺3水合物组1mg/kg（生理盐水调制的混悬液，体积0.2ml），每天1次，待动物自然死亡，计算生存延长率=(给药组平均生存时间-对照组平均生存时间)/对照组平均生存时间×100%，结果见表6。
可以理解，从本专业角度，很多细节的变化是可能的，这并不因此限制本发明范围和精神，本发明并不限于上述实施例。
Claims (6)
1.秋水仙碱衍生物，其特征在于：秋水仙碱衍生物为秋裂胺水合物，其分子式为C21H24 N2O5·nH2O，n=2.5～3.5之间的数字。
2.根据权利要求1所述的秋水仙碱衍生物，其特征在于：秋水仙碱衍生物为秋裂胺3水合物。
3.根据权利要求1所述的秋水仙碱衍生物的制备方法，其特征在于：包括：
方法A. 将秋水仙碱用水或C1-C6低分子醇、C2-C8低级醚的一种或几种为溶剂，使溶解，加氨气、氨水、碳酸氢铵、碳酸铵的一种或几种或者其溶液，5～50℃搅拌反应2-24小时，减压浓缩，用C1-C6低级卤代烃、C2-C8低级酯的一种或几种提取1-5 次，分去水层，有机层减压浓缩后，用水或C1-C6低分子醇、C2-C8低级醚、C1-C6低级卤代烃、C5-C10的直链或支链烷烃或环烷烃、石油醚，C6-C10的芳香烃、C3-C7低分子酮中的一种或几种进行一次或多次结晶，放置，使结晶完全，过滤，抽干，干燥即得；
或者方法B. 将秋水仙碱用水或C1-C6低分子醇、C2-C8低级醚、C1-C6低级卤代烃中的一种或几种为溶剂，使溶解，加氨气、氨水、碳酸氢铵、碳酸铵中的一种或几种或者其溶液，5～50℃搅拌反应2-24小时，减压浓缩，用C1-C6低级卤代烃、C2-C8低级酯中的一种或几种提取1-5 次，分去水层，有机层减压浓缩后，用水或C1-C6低分子醇C2-C8低级醚、C1-C6低级卤代烃、C5-C10的直链或支链烷烃或环烷烃、石油醚、C6-C10的芳香烃、C3-C7低分子酮中的一种或几种进行一次或多次结晶，放置，使结晶完全，过滤，抽干，干燥即得。
4.根据权利要求1所述的秋水仙碱衍生物的用途，其特征在于：秋裂胺水合物用于制备注射剂、固体制剂、软膏制剂、凝胶制剂上的应用。
5.根据权利要求4所述的秋水仙碱衍生物的制剂，其特征在于：注射剂为冻干粉针制剂、或者大输液制剂、或者小水针注射剂；固体制剂为片剂、胶囊、颗粒剂，栓剂。
6.根据权利要求1所述的秋水仙碱衍生物的用途，其特征在于：适用于制备下列对所引起的人和动物疾病的治疗或预防的药物中的应用：即制备用于对白血病、乳腺癌、胃癌、宫颈癌、鼻咽癌、光化性角化病、基底细胞癌、鳞状细胞皮肤原位癌的治疗或预防的药物中的应用。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA779893A (en) * | 1968-03-05 | Muller Georges | Derives colchiciques | |
| CN1090266A (zh) * | 1993-01-20 | 1994-08-03 | 有限会社尾源研究所 | N-甲基脱乙酰基秋水仙裂碱氨化物衍生物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA779893A (en) * | 1968-03-05 | Muller Georges | Derives colchiciques | |
| CN1090266A (zh) * | 1993-01-20 | 1994-08-03 | 有限会社尾源研究所 | N-甲基脱乙酰基秋水仙裂碱氨化物衍生物 |
Non-Patent Citations (1)
| Title |
|---|
| 安鸿志，袁现明.秋水仙酰胺.《新编抗肿瘤药物手册》.河南科学技术出版社,2003,162-163. * |
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