CN102516301B - 用于治疗的汉黄芩素衍生物 - Google Patents
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Abstract
本发明提供汉黄芩素的衍生物及其制备方法和用途，汉黄芩素的衍生物是通过对其结构的羟基基团进行化学修饰所得，所涉及的汉黄芩素的衍生物可以在药物组合物中使用，用于生产治疗乙肝及白血病治疗用的药物。
Description
技术领域：
本发明涉及用于治疗的汉黄芩素衍生物及其制备方法和用途。
技术背景：
汉黄芩素(wogonin)为黄芩是唇形科植物黄芩ScutellariabaicalensisGeorgi.中提取的一种黄酮类成分。不仅有抑菌、利尿、解痉作用，而且还具有较强的抗病毒作用。近几年来的研究表明，汉黄芩素可以降低转基因小鼠血清乙肝表面抗原的量和减轻鸭乙型肝炎病毒模型肝脏炎症。可以延长NB4细胞诱导的白血病小鼠存活时间。在对汉黄芩素的进一步研究中，我们发现他有较强的抗肿瘤作用，可以诱导肿瘤细胞的凋亡，进一步的作用机制正在研究中。关于汉黄芩素的治疗作用。
因此汉黄芩素作为一种新型抗乙肝病毒药物，对减轻广大癌症患者的痛苦，提高患者的生活质量具有非常重要的作用，在国内外有着广阔的市场和大量需求。
但是由于其十分低的口服生物利用度，通常认为汉黄芩素在商业上可得的制剂不适合除了肠胃外给药的其它给药方式，并且一般必须静脉注射或输入。当汉黄芩素在临床环境下静脉给予时，建议可以通过其它非口服途径来用于一定的适应症。
我们再通过对汉黄芩素衍生物的研究中发现，通过衍生，可以得到多种具有疗效的衍生物，这些衍生物在化学性质上和汉黄芩素有一定程度的差异，存在使得其具有更好的稳定性及制剂成型性，是具有进一步开发价值的化合物。
发明内容：
本发明的目的在于提供一种新的汉黄芩素的衍生物。
其结构是：
n代表0、1、2
本发明的另一目的在于提供汉黄芩素衍生物的制备方法。
R1、R2可为氨基酸、磷酸、羧酸的残基或同时具有以上两种残基的复合结构。可按以下流程进行A制备：
流程A
流程A中丝氨酸保护的基团Pg1和Pg2在特定的条件下是可以除去的，对于氮原子有用的保护基的非限制性的例子包括丁氧基羰基(Boc)、苄氧基羰基(CBz)和9-芴基甲氧基羰基(Fmoc)部分，用于羧基的保护基包括叔丁基、苄基和9-芴基甲基酯。
在制备时，也可通过事先对衍生物残基部分修饰后再与汉黄芩素进行进一步反应，如流程B制备。
流程B
流程B中1步骤用2-溴乙醇，N，N-二甲氨基吡啶，二环己基碳二亚胺，反应温度0-25℃，反应时间6-48小时；2步骤用氯碘甲烷，碳酸氢钠，反应温度0-50℃，反应时间1-18小时；3步骤1、3-二氯丙烷，N，N-二甲氨基吡啶，二环己基碳二亚胺，反应温度0-25℃，反应时间18-60小时。
本发明所用的氨基酸中包含存在手性氨基酸的，本发明包含这些手性氨基酸。
本发明所述的化合物根据需要可以制备成相应的药学上可接受的盐。例如，与化合物氨基部分成盐如无机酸硫酸、盐酸、磷酸或有机酸如柠檬酸、马来酸等；与化合物羧基部分形成的盐如钠盐、钾盐、镁盐或有机碱形成的盐。
本发明典型化合物为：
本发明化合物有效给药量范围80mg～5000mg范围内，可用于治疗和预防乙肝，也可用于白血病治疗。
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。
实施例1：化合物A的制备
将汉黄芩素1.78g，溶解在20ml乙腈中，室温下慢慢滴加三氯氧磷溶液3ml，滴毕，室温搅拌反应5小时，慢慢加入冰水搅拌水解反应2小时，加乙酸乙酯提取10ml×3次，水层蒸干，得化合物A0.63g。
实施例2：化合物B的制备
将汉黄芩素2g，溶解在20ml四氢呋喃中，30℃下加入20ml氯碘甲烷，搅拌反应16小时，60℃减压蒸干，加入20ml乙腈溶解残留物作为中间体，另取三乙胺9ml溶于10ml乙腈中，滴加3.6ml磷酸，滴加结束后，搅拌下缓缓滴入中间体，继续60℃搅拌反应12小时，蒸除溶剂，残留物加水20ml溶解，加入乙酸乙酯10ml×3次洗涤水层，水层过滤澄清，冻干即得化合物B0.31g。
实施例3：化合物C的制备
将BOC保护的丝氨酸3克、2-溴乙醇2.5g、N，N-二甲氨基吡啶3g和二环己基碳二亚胺3g溶解在四氢呋喃中，室温搅拌10小时，真空浓缩，用色谱法纯化(用正己烷至30％的乙酸乙酯/正己烷洗脱)粗产品，合并滤液，蒸干得中间体A；将汉黄芩素2g和中间体A2.5g用四氢呋喃30ml溶解，加入三苯基磷2g，慢慢滴加偶氮二甲酸二乙酯溶液2ml，室温反应5小时，反应毕，减压蒸干，加入乙酸乙酯50ml溶解，过滤不溶物，用色谱法纯化(用正己烷至10％的乙酸乙酯/正己烷洗脱)粗产品，合并滤液，蒸干，然后用二氯甲烷20ml溶解，通入氯化氢气体至饱和，搅拌反应5小时，过滤，得化合物D的盐酸盐，用蒸馏水溶解后调pH为8左右，水层冷冻干燥得化合物C0.27g。
实施例4：化合物D的制备
按照实施2的方法制备不同的是用丙二酸代替磷酸。
实施例5：化合物E的制备
取化合物B1.3g，溶解在30ml乙腈，分批加入5gBoc-Ser-OBZL，50℃搅拌反应，HPLC监控反应至化合物B小于5％，加入0.1M盐酸溶液10ml，60℃加热水解5小时，调节pH至7，减压蒸干，残留物加20ml水溶解，分批加入乙酸乙酯10ml×3次洗涤，水层蒸干，加入无水乙醇溶解，过滤除去不溶物，减压蒸干，加入5ml水溶解，滤清，冷冻干燥得化合物E0.18g
实施例6：化合物A注射液制备
处方
取处方量辅料及原料，加入至90000ml注射用水，加入10g活性炭，80℃搅拌脱色30分钟，0.22μm的滤膜过滤除去活性炭，测定中间体含量，补加注射用水，灌装，灭菌既得化合物A注射液。
实施例7：注射用化合物B制备
处方：
取处方量的原料及各辅料，加入100ml注射用水，搅拌，加入0.2g活性炭，60℃搅拌30分钟，0.22μm的滤膜过滤澄清，检测中间体含量，按每瓶35mg的规格分装至管制西林瓶中，-50℃冷冻4小时，抽真空，升温冻干，控制水分不大于5％，既得注射用化合物B。
实施例8：化合物B在动物体内代谢研究
HBV转基因鼠40只，按照血清HbsAg浓度高低分为5组，分别给药化合物B，高剂量组50mg/kg，中剂量组25mg/kg，低剂量组12.5mg/kg，阳性对照组(拉米夫定100mg/kg)，空白实验组(生理盐水)。每组8只鼠，给药10天，高、中、低剂量组每隔2天通过尾静脉注射给药；拉米夫定组每天灌胃给药。血清样本分别采自给药前，给药5天，给药10天以及停药5天。最后一次给药的24h后每组各随机处死3只鼠，取肝脏、肾脏等器官标本；其余鼠在最后一次给药取血后处死，取肝脏、肾脏等器官标本。
血清HBsAg检查使用乙肝抗原表面定量试剂盒，操作参照试剂盒说明书进行。标注曲线使用重组乙肝表面抗原构建。血清样本用生理盐水稀释20倍后进行检测。
治疗第10天，高剂量组小鼠血清HBsAg含量明显下降，与治疗前相比下降约27.1％，与生理盐水对照组和给药前相比有显著差异；中剂量组小鼠血清HBsAg含量下降约41.7％。停药5天之后，高剂量组和中剂量组小鼠血清HBsAg含量保持稳定，并未发生反跳现象，相反，拉米夫定组小鼠血清HBsAg含量较给药10天有所升高。
结论：治疗乙肝转基因鼠10天，能够明显降低血清乙肝表面抗原的量，与对照组及治疗组相比有显著意义。
实施例9：化合物B对白血病细胞体内诱导分化作用。
取SCID小鼠随机分为四组，每组8只，空白对照组给予生理盐水(NS)20ml/kg。
化合物B高剂量组浓度是50mg/kg，中剂量组浓度是25mg/kg，低剂量组浓度是12.5mg/kg，阳性对照组给予维甲酸15mg/kg。分别将NB4细胞(106)100μl腹腔注射接种于SCID小鼠，第二天开始给药，各组分别给药两周，观察小鼠存活天数，
试验结果表明，与空白对照组相比，高、中剂量可以显著延长SCID小鼠存活时间。
Claims (6)
1.通式（Ⅰ）的化合物和它们的药用盐：
n代表1、2
R1为氨基酸或磷酸残基，R2为氨基酸或磷酸残基。
2.权利要求1的化合物，其特征在于，R1为氨基酸残基，R2为磷酸残基。
3.权利要求1的化合物，其特征在于，R1为磷酸残基，R2为氨基酸残基。
4.权利要求1的化合物，其特征在于，R1、R2为氨基酸残基。
5.权利要求1的化合物，其特征在于，R1、R2为磷酸残基。
6.一种药用组合物，其特征在于，含有治疗有效剂量如权利要求1-5所述化合物作为活性成分以及药学上可接受的载体。
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| WO2004037193A2 (en) * | 2002-10-22 | 2004-05-06 | Jenken Biosciences, Inc. | Chromones and chromone derivatives and uses thereof |
| AU2003269928A1 (en) * | 2003-03-06 | 2004-09-30 | The Medical Research And Education Trust | Botanical extract compositions with anti-cancer or phytoestrogenic activity comprising prenyl flavonoids |
| CN1556101A (zh) * | 2003-12-31 | 2004-12-22 | 中国药科大学 | 汉黄芩素的提取工艺、药用组合物及制剂制备工艺 |
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| WO2010040254A1 (zh) * | 2008-10-06 | 2010-04-15 | 大百汇生物科技（深圳）有限公司 | 黄芩黄酮在制备治疗肠道病毒感染药物的应用 |
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| US3549662A (en) * | 1967-10-12 | 1970-12-22 | Takeda Chemical Industries Ltd | Derivatives of baicalein |
| WO2004037193A2 (en) * | 2002-10-22 | 2004-05-06 | Jenken Biosciences, Inc. | Chromones and chromone derivatives and uses thereof |
| CN1705473A (zh) * | 2002-10-22 | 2005-12-07 | 詹肯生物科学公司 | 色酮和色酮衍生物及其用途 |
| AU2003269928A1 (en) * | 2003-03-06 | 2004-09-30 | The Medical Research And Education Trust | Botanical extract compositions with anti-cancer or phytoestrogenic activity comprising prenyl flavonoids |
| CN1556101A (zh) * | 2003-12-31 | 2004-12-22 | 中国药科大学 | 汉黄芩素的提取工艺、药用组合物及制剂制备工艺 |
| WO2010040254A1 (zh) * | 2008-10-06 | 2010-04-15 | 大百汇生物科技（深圳）有限公司 | 黄芩黄酮在制备治疗肠道病毒感染药物的应用 |
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