CN100475217C - 一种Ocotillol型皂苷元在制备治疗戒毒、促智的药物中的应用 - Google Patents
一种Ocotillol型皂苷元在制备治疗戒毒、促智的药物中的应用 Download PDFInfo
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- CN100475217C CN100475217C CNB2004100235107A CN200410023510A CN100475217C CN 100475217 C CN100475217 C CN 100475217C CN B2004100235107 A CNB2004100235107 A CN B2004100235107A CN 200410023510 A CN200410023510 A CN 200410023510A CN 100475217 C CN100475217 C CN 100475217C
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Abstract
本发明提供一种Ocotillol型皂苷元在制备治疗促智和戒毒药物中的应用，具体地提供了其在制备治疗促进学习和记忆，改善脑功能障碍所致的学习记忆损伤的药物中的应用，其在有效戒断吗啡样作用的药物中的应用。
Description
技术领域
本发明涉及一种Ocotillol型皂苷元在制备治疗促进学习和记忆，改善脑功能障碍所致的学习记忆损伤，有效戒断吗啡样作用的药物中的应用。
背景技术
阿片类药物的依耐性和耐受性极易造成吸毒者不断复吸，从而恶性循环，给当今社会带来巨大危害，然而目前对阿片类药物的依耐性和耐受性还没有非常理想的预防和治疗方法。研究能够有效戒断阿片类依耐性和耐受性的药物也成为当前新药开发热点之一。目前，临床应用替代疗法或综合疗法的戒毒药物，虽能部分解除对阿片类药物的依耐性，但多数药物仍不能解除心理依耐性问题。
近年来国内外报道人参的皂苷成分能够对抗阿片类的成瘾和耐受作用。国内专利申请(公开号CN 1300593A)报道了拟人参皂苷F11有拮抗吗啡样作用和促智作用。国外还有报道越南人参中的Ocotillol型皂苷具有抗吗啡样作用。但对式(I)化合物具有拮抗吗啡样作用和促智作用未见相关研究。
本发明所述的式(I)化合物在人参属植物中含量极低，显然没有实际应用价值。虽目前国内已有制备拟人参皂苷F11方法的专利申请(公开号：CN1251369A)。但对式(I)化合物大规模制备方法尚未见相关文献报道。
根据本发明提供的大规模高效制备式(I)化合物的方法，获得式(I)化合物，我们又对式(I)化合物在戒毒和促智方面进行了深入研究，结果发现，式(I)化合物具有促智和拮抗吗啡样作用，从而完成本发明。
发明内容
本发明提供了一种如式(I)所示结构的Ocotillol型皂苷元在制备治疗促进学习和记忆，改善脑功能障碍所致的学习记忆损伤和有效戒断吗啡样作用的药物中的应用。
(I)
本发明还提供了大规模制备式(I)化合物的方法，其包括如下步骤：用来制备式(I)化合物的起始原料人参皂苷(II)的结构通式如下：
(II)R＝糖基
首先从西洋参、西洋参茎叶、越南人参、越南人参茎叶等人参属植物中获得的富含(I)化合物为母核的结构通式如(II)所示人参皂苷，如含有拟人参皂苷F11、拟人参皂苷-RT4、珠子参苷(majonoside)-R1、珠子参苷(majonoside)-R2或它们的混和物。加入由碱金属氢氧化物与低级醇类组成的溶液中，碱浓度一般为0.2％～60％，优选浓度为5～20％，在高压或常压下加热进行碱降解，彻底水解掉人参皂苷(II)6位上的糖链，从而获得富含式(I)化合物的降解产物，反应液倾入冷水，搅拌，析出固体，用水洗至中性，过滤。得到式(I)化合物粗品，经硅胶柱色谱分离。洗脱剂由底剂和极性调节剂组成。底剂是：石油醚、氯仿、正己烷、环己烷、正戊烷中的中的一种、两种或两种以上组合，极性调节剂是乙酸乙酯、乙酸甲酯、乙酸丁酯、丙酮、乙醚、含有1-4个碳原子的一元醇中的一种、两种或两种以上组合。
由式(I)化合物粗品经重结晶得精制式(I)化合物。重结晶溶剂是：乙酸乙酯、甲醇、乙醇、丙酮一种、两种或两种以上组合。
经硅胶柱层析或纯结晶，从而获得式(I)化合物单体。
当反应介质低级醇为1-4个碳原子的一元醇时，优选为乙醇，正丁醇，甲醇。反应状态优选在0.05～5Mpa压力和100～320℃温度下进行。当反应介质低级醇为1-4个碳原子的多元醇时，优选为丙三醇、丙二醇、乙二醇、1.3-丁二醇、1.4-丁二醇、甘二醇，反应状态在0-4Mpa压力和150～230℃温度下进行，优选为在常压和150～230℃温度下进行。反应时间取决于降解原料，反应温度和碱的浓度，反应时间在5分钟至3小时。
本发明制备方法的优点是提供了一种大规模高效制备式(I)化合物的方法。碱降解反应简单，适合工业化生产，能够制备出高纯度的式(I)化合物，为其应用提供了方便。
本发明提供的药物，是以片剂、滴丸、颗粒剂、胶囊、糖浆、注射剂、口嚼剂或贴剂形式存在，均可以采用药学上常规方法制备而成。
具体实施方式
实施例1：式(I)化合物的制备
取200ml95％乙醇加入高压反应釜内，加入30g固体氢氧化钾，搅拌溶解，再加入富含式(II)所示结构通式的五环三萜皂苷的西洋参茎叶皂苷10g，继续搅拌并持续升温，升温至160℃。于大约1.15Mpa的压力下，保温下反应2.5小时，反应完毕，将反应液倾入冷水中，稀释至3倍，约600ml，再用等体积的乙酸乙酯萃取三次，合并萃取液，回收溶剂，得到4.3g黄褐色固体，再将此固体经硅胶柱层析，以石油醚/乙酸乙酯(1∶1)洗脱，以乙酸乙酯重结晶得到0.3g无色结晶式(I)化合物，收率3％。
实施例2：式(I)化合物的制备
将10升甘油加入小型具油浴加热和搅拌的反应罐中，再分别加入1kg的氢氧化钠和1kg西洋参茎叶皂苷，搅拌，常压下持续加热升温，升温至210℃下保温反应40分钟，反应完毕，将反应液倾入60倍冷水中并搅拌，析出沉淀。静置，过滤，水洗至中性，即得式(I)化合物粗品。再将此粗品经硅胶柱层析，以正己烷/乙酸乙酯(2∶1)洗脱，回收溶剂，以甲醇-乙酸乙酯混合溶剂重结晶得到40g式(I)化合物，收率4％。
无色方晶，1H-NMR(400MHz C5D5N)δ：0.89(3H，s，CH3-30)，0.94(3H，s，CH3-19)，1.08(3H，s，CH3-18)，1.19(1H，d，J＝10.4Hz，H-5)，1.23(3H，s，CH3-21)，1.24(3H，s，CH3-26)，1.40(3H，s，CH3-29)，1.44(3H，s，CH3-27)，1.95(3H，s，CH3-28)，3.49(1H，dd，J＝11.3Hz，5.2Hz，H-3)，3.69(1H，dt，J＝10.4Hz，4.6Hz，H-12)，3.92(1H，dd，J＝8.4Hz，6.7Hz，H-24)，4.38(1H，m，H-6)
实施例3：注射用式(I)化合物冻干粉针的制备
称取由制备例2得到式(I)化合物1.00g，加入20ml乙醇使其完全融解，再加入40ml甘油混合均匀。将0.20g盐酸丁卡因、0.02g的EDTA-2Na加入到40ml注射用水中，使辅料完全溶解。并将上述水溶液加入到药物溶液中，混合均匀。以0.01mol/L的氢氧化钠和稀盐酸调节pH值为5.5±1.0。加入0.1％的针用活性炭85度保温15分钟，G3垂熔玻璃漏斗过滤，0.22μm的微孔滤膜过滤。滤液分装于7ml西林瓶中，每支装量2ml。分装好的注射剂半压塞，于冻干机冻干。冻干后压塞，压铝盖制成冻干粉针剂，20mg/支。
实施例4：式(I)化合物片剂的制备
称取由制备例1得到式(I)化合物10.00g，将其与60g淀粉混匀，加入15％淀粉浆适量，混合制成软材，14目筛制粒，70℃干燥，14目筛整粒后，加入0.5g硬脂酸镁和1g羧甲基淀粉钠，混匀，压制200片，100mg/片
实施例5：式(I)化合物软胶囊剂的制备
称取明胶100g，甘油30g和水130g。取明胶加入适量的水使其吸水膨胀。另将甘油及余下的水置煮胶锅中加热至70-80℃，混合均匀，加入膨胀的明胶搅拌，熔融。保温1～2小时，静置，使泡沫上浮，刮去上浮的泡沫，以洗净白布过滤，加入0.0075mg Fe2O3粉末，混匀，保温待用。配成的胶液粘度一般为2.8-3.2度。
称取式(I)化合物5g溶于90g聚乙二醇中，加热使其充分溶解，放至室温。
压制软胶囊：将已制好的明胶甘油和式(I)化合物聚乙二醇药液装入自动旋转轧囊机中，温度控制在40~50℃，压制出每囊含50mg式(I)化合物的软胶囊。
实施例6：对纳洛酮催促所引起的吗啡依赖大鼠戒断反应的影响
用吗啡对大鼠进行预处理(d1＝10、d2＝20、d3＝30、d4＝40、d5＝50mg/kg，每日2次，sc)能诱发大鼠发生身体依赖。于每次给吗啡前30min ig式(I)化合物，完成末次给吗啡6h，ip纳洛酮5mg/kg，观察给纳洛酮后15min内戒断综合征发生情况。在纳洛酮催促下出现典型的戒断综合征，表现为跳跃、湿狗样摇体、扭体、摇头、打哈欠、齿颤、咀嚼、流涎、流泪、毛发直立、眼下垂和腹泻等一系列戒断症状。称量用纳洛酮后1h后体重的改变。根据Rasmussen K.(J Neurosci，1990，10：2308-2317)的评分标准判定戒断症状的轻重，实验结果见表1。
表1 式(I)化合物对用纳洛酮后15min内吗啡依赖大鼠戒断综合征分数的抑制作用(n＝10)
*p＜0.05，#p＜0.01，与吗啡比较。
实施例7：式(I)化合物对吗啡诱导的条件性位置偏爱的影响
位置偏爱箱(穿梭箱)由两个大小完全相等的盒子组成，中间由可以抽拉的隔板隔开，其中一个盒子为白色，底板铺一有纹理的壁纸；另一盒子为黑色，底板光滑。对照组皮下注射生理盐水后，立即放入黑盒子，给药组口服式(I)化合物60min后，皮下注射吗啡，放入白盒子。实验前3天，让小鼠在两盒之间自由活动，观察小鼠的天然嗜好。此后5天用隔板封闭两盒间通道，每只小鼠每天上、下午各注射一次，两次间隔时间为6h，其中一次为吗啡(给药组式(I)化合物+吗啡)，另一次为生理盐水。给吗啡后，将小鼠放入白盒，给生理盐水后，将小鼠放入黑盒，每次在盒中停留60min。第9天打开洞口，让小鼠自由跑动，记录15min内小鼠在白盒子中的时间，实验结果见表2。
表2 式(I)化合物对吗啡诱导的条件性位置偏爱的影响
*p＜0.05与吗啡组比较，#p＜0.01，与空白组比较。
条件性位置偏爱实验是评价药物精神依赖性的方法，偏爱效应能够较好地反映药物的奖赏效应。本实验表明，吗啡可引起明显的位置偏爱行为，而式(I)化合物能够部分拮抗这种作用。
实施例8：对吗啡致小鼠自主活动增加的影响
采用小动物自主活动测定仪测定，给药7天，每天皮下注射吗啡一次，注射前60min口服式(I)化合物。注射吗啡后将小鼠放入测定仪中，适应5min，在第1、7天测定小鼠2min的自主活动数，实验结果见表3。
表3 式(I)化合物对吗啡致小鼠自主活动增加的影响
*p＜0.05与吗啡组比较
式(I)化合物能够拮抗吗啡诱发的自主活动增加。
实施例9：对东莨菪碱所致记忆障碍的影响
跳台实验中，东莨菪碱2mg/kg致小鼠错误次数显著增加，式(I)化合物4mg/kg使错误次数显著减少，实验结果见表4。
表4 对东莨菪碱(Scop)所致记忆障碍的影响(跳台法)
*p＜0.05与Scop组比较，#p＜0.01与空白组比较。
避暗实验中，式(I)化合物能够显著延长错误潜伏期，降低错误百分率，提示式(I)化合物能够改善东莨菪碱致小鼠记忆获得障碍，实验结果见表5。
表5 对东莨菪碱(Scop)所致记忆障碍的影响(避暗法)
*p＜0.05与Scop组比较，#p＜0.01，与空白组比较，n＝12。
实施例10：对氯霉素致小鼠记忆巩固障碍的影响
跳台实验结果表明：氯霉素(Chlo)200mg/kg显著增加小鼠的错误次数，缩短潜伏期；式(I)化合物可以改善这些症状，显示其减轻氯霉素诱导的小鼠记忆巩固障碍的作用，实验结果见表6。
表6 对氯霉素(Ch1o)致小鼠记忆巩固障碍的影响(跳台法)
*p＜0.05与Chlo组比较，#p＜0.01，与空白组比较，n＝12-14。
实施例11：对乙醇致小鼠记忆再现障碍的影响
暗室实验表明，式(I)化合物能够明显减少小鼠进入暗室的错误次数，并延长错误潜伏期，表明式(I)化合物能够明显改善乙醇致小鼠记忆再现障碍，对正常动物学习记忆也有改善作用，实验结果见表7。
表7 对乙醇致小鼠记忆再现障碍的影响
*p＜0.05与乙醇组比较，#p＜0.01，与空白组比较
Claims (2)
1、一种如式(I)所示结构的Ocotillol型皂苷元在制备促进学习和记忆，改善脑功能障碍所致的学习记忆损伤和有效戒断吗啡样作用的药物中的应用
2、根据权利要求1所述的应用，其中所述药物剂型是以片剂、丸剂、颗粒剂、胶囊、糖浆、注射剂、口嚼剂或贴剂形式存在。
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| Triterpene Saponins from Vietnamese Ginseng (Panaxvietnamensis) and Their Hepatocytoprotective Activity. Quan Le Tran, et al.J Nat Prod,Vol.64 . 2001 * |
| 人参化学成分及其抗癌抗心律失常构效关系的研究. 陈英杰等.中国科学基金，第4期. 1995 |
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