CN1511840A - 含水溶性基团的葛根素化合物及其制法和用途 - Google Patents
含水溶性基团的葛根素化合物及其制法和用途 Download PDFInfo
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- CN1511840A CN1511840A CNA02159418XA CN02159418A CN1511840A CN 1511840 A CN1511840 A CN 1511840A CN A02159418X A CNA02159418X A CN A02159418XA CN 02159418 A CN02159418 A CN 02159418A CN 1511840 A CN1511840 A CN 1511840A
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- Prior art keywords
- hydrogen
- compound
- puerarin
- ylmethyl
- methyl
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- -1 Puerarin compound Chemical class 0.000 title claims abstract description 30
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Abstract
本发明涉及通式I所示含水溶性基团的葛根素化合物、可作为药用的盐，式中R1、R2、和R3如正文所述，其制备方法，以及含有效剂量的通式I化合物的药物组合物。该组合物用于治疗或预防心脑血管疾病，特别是治疗各类心脑缺血缺氧症。
Description
所属技术领域
本发明涉及一类含水溶性基团的葛根素化合物、可作为药用的盐，其制备方法，以及含有效剂量的通式I化合物的药物组合物。该组合物用于治疗或预防心脑血管疾病，特别是治疗各类心脑缺血缺氧症。
背景技术
葛根素(Puerarin普乐林，式I，R1＝R2＝R3＝H)是豆科属植物葛根中的有效成分，化学名为4’，7-二羟基-8-β-D-葡萄糖异黄酮，分子量为416。几十年以来，人们对葛根素的基础与应用研究做了大量的工作，证明它确有扩张冠状动脉，改善心肌收缩功能，保护全心缺血心肌，促进血液循环等作用。临床曾用于治疗冠心病，心绞痛，心肌梗塞，视网膜动脉和静脉阻塞，突发性耳聋等疾病。目前心脑血管疾病是我国成人死亡的首要病因，作为改善心脑血管循环的新药葛根素，由于其结构新颖，疗效确切，因而具有重要的应用价值。
现有技术披露葛根素具有增加心肌耗氧量，扩张血管作用，据认为是与其具有β肾上腺素阻滞作用相关。此外近年来深入研究还发现具有多种药理学新作用。葛根素具有较强的清除氧自由基和抗氧化作用：正常情况下，生物体内自由基的产生和清除处于动态平衡中，参与杀菌，物质代谢等重要生理功能，一旦平衡破坏，则会导致多种疾病如炎症，衰老，休克，动脉粥样硬化，心肌缺血，缺钙，药物及酒精中毒等。因而能够用抗氧化剂治疗这些疾病。袁林等(现代中西医结合杂志；2000，9：2197-2199)研究得出普乐林能有效清除高血压患者和缺血性脑卒中患者过多的氧自由基，能增强脑组织对葡萄糖的利用率，同时使高能磷酸键形成增多，增强线粒体和细胞质中酶的功能，促进受损脑组织细胞康复。葛根素对小鼠肠缺血再灌注肝损伤的保护作用也与其抗氧化作用有关。
现有技术还揭示，葛根素可使高血压和不稳定型心绞痛患者的缩血管物质ET水平显著下降，并能使舒血管因子NO和血浆降钙素基因相关肽水平显著升高(齐华阁 李跃恒等，中国中西医结合杂志2000 20(9)：694-695)。其作用机理为：①葛根素可扩张冠状动脉，增加组织灌注，改善微循环，使内皮细胞的供氧量增加，代谢改善，减轻损伤；②葛根素使氧自由基生成减少，并增加其清除率，减轻自由基对内皮细胞的损伤；③血粘度增高可损伤内皮，而葛根素能降低血度，减轻损伤。内皮功能改善后，合成和释放NO增加，ET的合成则减少，这可能是葛根素治疗冠心病的机制之一。
现有技术进一步揭示，葛根素对于血小板活化功能，一氧化氮合成酶，血液流变学以及脑血流均有较强的影响。血小板活化和凝血系统的共同作用是血栓形成的基础。应用葛根素治疗UAP四周后，血小板膜活性蛋白标志CD63、CD62P、纤溶因子PAI-1及炎症反应物C-RP的水平均明显下降，与治疗前比较有显著差异(刘佩献等，铁道医学2000，28(4)：237-238)。NO是通过一氧化氮合酶(NOS)产生的，现已证明NO参与了脑缺血再灌流的损伤。NOS按功能和特性分为原生型(cNOS)和诱生型(iNOS)两类。大鼠实验结果表明，葛根素对全脑缺血再灌流损伤有保护作用。动物实验表明，葛根素能改善视网膜微循环，与降眼压药噻吗心安联用产生正协同作用，显著改善视神经轴浆传输，起到保护视神经的作用，还具有改善脑循环和脑代谢的作用。葛根素可能还具有调节心力衰竭时神经内分泌和降低ox-LDL的作用。除此之外，富含葛根素的野葛提取物对嗜酒大鼠的乙醇摄入量有抑制作用；葛根提取物可使急性非淋巴性细胞白血病(ANLL)患者骨髓细胞bcl-2、c-myc基因蛋白表达明显下调，说明葛根提取物可诱导ANLL细胞和HL-60细胞发生凋亡。
临床研究证明，葛根素对梗死面积和心功能具有较强的作用。许荣延等(山东医科大学学报，2000 38(4)360-363)观测到37例心肌梗死患者普乐林治疗两周后，梗死面积由治疗前的37.31％下降至24.67％，血浆脂质过氧化物(LPO)和血管内皮细胞数(CEC)显著降低，而红细胞超氧化物歧化(SOD)显著升高，同时左室收缩和舒张功能改善。研究表明，葛根素具有降低正常区和梗死区心肌耗氧、减轻细胞内钙负荷、阻滞β-受体、限制梗死面积扩展、稳定血压及改善心功能等作用。葛根素加脉安定对AMI溶栓RA的疗效显著，临床症状和心功能显著改善。葛根素还具有促血管内皮生长因子样的作用，多次、长期应用，可促进缺血心肌原有测支血管的开放和成长，促进新的测支形成。当缺血心肌需氧量倍增时，通过测支循环得到正常的血氧供应，避免心绞痛的发生。李为厚等(华北煤炭医学院学报，2000 2(6)611-612)对64例冠心病心绞痛患者应用葛根素注射液治疗10-14d后，疗程和症状明显改善，总的有效率达93.8％，其中显效率为59.4％，对照组总的有效率为84.4％，尽管两组总的有效率无显著性差异(P＞0.05)，但其显效率差异显著P＜0.05)，心电图改善率分别为75.0％和65.6％，两者比较无差异，但对用药前后NST和∑ST结果改善较明显，差异显著(P＜0.01)。对血压的影响主要是使收缩压下降，治疗前后平均收缩压下降幅度为7.72％(P＜0.05)。此药对血糖、肝肾功能和血生化均无明显影响，而对血脂有明显的调节作用，可降低胆固醇、甘油三醇和低密度脂蛋白，增加高密度脂蛋白。
葛根素还具有治疗急性脑梗塞的作用。50例急性脑梗死患者随机分成两组，观察组30例采用葛根素400mg，，对照组20例采用丹参注射液10ml。每日一次。一疗程(14d)后临床效应对比，观察组总有效率73.3％，对照组总有效率40％，有显著差异(P＜0.001)。血液流变学在观察组病例治疗前后变化有显著差异(P＜0.001)(张嘉祥，李志刚，武警医学院学报，2001，10(1)：25-26)。急性脑梗塞120例随机分为治疗组(A组)68例和对照组(B组)52例。采用双盲对照方法，A组葛根素注射液2ml，B组注射用水1ml。一次/日，7天/疗程。临床疗效显示：A组治疗后68例(基本痊愈+显著进步)分别为45例(69.2％)和23例(44.2％)，两组差异显著(P＜0.01)。A组白细胞表面CD11a、CD18、CD18/CD11a(LFA-1)的免疫阳性细胞数较治疗前明显降低(P＜0.05)。提示葛根素增加脑微循环血流量的机制可能与封闭白细胞表面粘附分子CD11a、CD18结合位点，阻断白细胞与血管内皮细胞粘附、抑制PMNS活性有关(邓娟等，微循环学杂志2001，11(1)：14-15)。对椎-基质动脉供血不足(VBI)作用较好。102例VBI眩晕患者随机分为两组，治疗组60例葛根素静滴，对照组42例川芎嗪静滴。治疗15天后观察疗效，治疗组痊愈13例，显效19例，有效23例，无效15例，总有效率91.7％；对照组痊愈5例，显效11例，有效14例，无效2例，总有效率71.4％。两组总有效率比较有显著差异(P＜0.01)。两组治疗前各相应动脉平均流速无明显差异(P＞0.05)，治疗后有显著差异(P＜0.05)。对照组治疗前后有显著差异(P＜0.05)，治疗组则改善更显著(P＜0.01)(朱玲华，时珍国医国药2001 12(2) 143-144)。王忠良用葛根素治疗VBI患者40例，痊愈17例，有效20例，无效3例，总有效率94.1％(江苏中医2001，22(4)：12-13)。葛根素对高血压，肺心病，视盘血管炎也有较好的疗效。
葛根素的不良反应主要为发热，程伟进等(药物流行病杂志2000 9(3) 129-130)对568例使用过普乐林的患者调查表明，发热的总发生率为5.81％，年龄、性别差异无显著性，日剂量高低组间也无显著差异，主要与持续用药天数有关。停药或同时给予退热处理，体温逐渐降至正常。抗生素治疗无效。这可能因为疗程过长，药物积累引起毒性作用；药物透过血脑屏障，直接刺激下丘脑体温调节中心，影响人体产热和散热过程；以及迟发性变态发应。葛根素还会引起的过敏反应。31例患者，用葛根素者14例，其中发热11例，皮疹4例，腹痛2例，腰痛2例，溶血2例；用普乐林者17例，发热12例，皮疹5例，腹痛4例，腰痛1例，溶血2例，过敏性休克2例。发热、皮疹、瘙痒及腹痛及时发现并停药后均能自行缓解(叶艳平 刘羽翔等，中国新药杂志，2001，10(4)：289-290)。葛根素注射液曾引起药物性皮炎1例。普乐林致一过性血红蛋白尿1例，机理尚不清楚。
曾经对葛根素的酚羟基和糖醇羟基进行修饰，合成了一系列酯和醚类衍生物(杨若林，李娜等，中国药科大学学报，1999，30(2)：81-85)。但是其对心脑血管的药效以及毒性未作深入研究。
葛根素的水溶性和脂溶性都很差，其在水中的溶解度为0.462g/100ml。制剂中需添加助溶剂，常用的有聚乙烯吡咯烷酮(PVP)等。在4.3％PVP水溶液中葛根素溶解度为1.332g/100ml。pH对葛根素的溶解度也有影响，葛根素水溶液在pH偏高时，其稳定性较差。在葛根素络合助溶过程中，通常应将pH控制在6.5以下(吴正红 朱延勤等，江苏药学与临床研究，1999，7(1)：9-12)。
葛根素口服生物利用度较差，约为30％，临床一般为静注给药。葛根素水溶性差，口服生物利用度差以及所存在的副反应的缺点限制了其作为药用的价值。
在现有文献中，迄今尚未见到本发明之含有水溶性基团的葛根素类化合物的报道，以及它们在涉及心脑血管疾病防治作用方面的用途。
发明内容
为了克服现有技术的不足，本发明的目的在于提供一类含有Mannich碱的水溶性葛根素化合物；
本发明的另一目的在于提供制备含Mannich碱类取代葛根素化合物的方法；
本发明的再一目的在于提供一种含有一个或多个这种化合物的药物组合物；
本发明的又一目的在于提供一种在防治心脑血管疾病尤其是缺血和缺氧相关疾病的药物中的用途。
为了完成本发明之目的，本发明采取如下技术方案：
本发明涉及具有通式I所示的新型葛根素化合物：
式中，
R1和R2分别选自的取代基是氢，二甲胺基甲基，二乙胺基甲基，二正丙胺基甲基，二异丙胺基甲基，二正丁胺基甲基，二异丁胺基甲基，二叔丁胺基甲基，1-四氢吡咯基甲基，1-哌啶基甲基，吗啉基甲基，1-六氢哌嗪基甲基，N-甲基哌嗪基甲基，叔丁胺基甲基，二环己基胺甲基；R1和R2不同时代表氢；R3选自氢，丙酰基，丁酰基，异丁酰基，2-甲基丁酰基，3-甲基丁酰基，2，2-二甲基丙酰基，戊酰基，己酰基，庚酰基，辛酰基，壬酰基，葵酰基，月桂酰基。可作为药用的盐含选自可作为药用的各种有机和无机羧酸盐，包括盐酸，氢溴酸，磷酸、亚磷酸、硫酸、甲磺酸、对甲苯磺酸，马来酸，富马酸，酒石酸，各种天然或非天然氨基酸等。
为了制备本发明通式I中所述的化合物，本发明包括，将葛根素原料与合适的醛和胺类化合物，在有机溶剂中，于室温至回流温度下，进行Mannich反应，制备相应的Mannich碱类化合物及其盐。具体地讲，合适的醛包括小分子烷基醛和芳香醛及其活化形式，如甲醛，乙醛，丙醛，异丙醛，双二甲胺基甲烷，双二乙胺基甲烷，苯甲醛，取代苯甲醛等；溶剂包括水，低级醇，低级醇选自甲醇，乙醇，丙醇，异丙醇，丁醇，叔丁醇，异丁醇，戊醇，特戊醇，戊醇-2，戊醇-3，己醇等。
本发明所涉及的化合物，在常温下水中的溶解度优于葛根素。
本发明还涉及一种含有药物有效剂量的如通式I所述的化合物和药学上可接受的载体的药物组合物。
药理学研究表明，本发明通式I化合物具有对血管具有舒张作用；对因缺氧而致小鼠的死亡时间，本发明化合物有明显的延长作用；在大鼠离体心脏缺血—再灌注损伤有保护作用。本发明化合物具有血管扩张作用，有扩张冠状动脉和脑血管，降低心肌耗氧量，改善微循环和抗血小板作用，具有潜在的防治心脑血管缺血和缺氧作用。
本发明化合物是一类具有葛根素母核的新化合物，它们可用于预防和治疗冠心病，各型心绞痛，心肌梗塞，脑血管病。
运用本领域技术人员熟知的药物载体可以制成含有有效剂量的本发明化合物的药物组合物。
本发明化合物或其组合物可用口服方法或非肠胃道用药。口服用药可以是片剂、胶囊剂、包衣剂、非经肠用药剂型有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟知的方法制备的。为了制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂，例如淀粉，明胶，阿拉伯胶，硅石，聚乙二醇，液体剂型所用的溶剂例如水，乙醇，丙二醇，植物油类如玉米油，花生油，橄榄油等。含有本发明化合物的制剂中还可有其它助剂，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂，色素等。另一方面，本发明化合物的水溶性优于葛根素，因此易于制成全身给药制剂用于心脑血管疾病的防治。
在片剂、胶囊剂、包衣剂、注射剂和栓剂中含有本发明式I化合物的剂量是以单元剂型中存在的化合物量计算的。在单元剂型中本发明式I化合物一般含量为10-500mg，优选的单元剂型含有20-200mg。
以下将结合实施例对本发明作进一步说明，但并不限制本发明的范围。
本文中使用的测定仪器为，熔点用XY-1型电热熔点仪，核磁共振光谱用JNM-ECA-400型核磁共振仪。
实施例1
取560mg葛根素，与40ml无水乙醇混合，加入1ml33％二甲胺水溶液和0.3ml 37％甲醛水溶液。油浴加热回流5小时。蒸馏除去溶剂。硅胶柱层析，得340mg淡黄色结晶。mp195-196℃。1HNMR(CDCl3)：8.33(1H，s，2-ArH)，7.94(1H，d，5-ArH)，7.35(1H，d，6-ArH)，7.34(1H，s，2’-ArH)，6.99(1H，d，5’-ArH)，6.78(1H，d，4’-ArH)，4.83(1H，d)，4.03(1H，t)，3.72(1H，d)，3.47(1H，m)，3.27(3H，m)，3.18(2H，s)，2.28(6H，s，N(CH3)2)。
实施例2
取280mg葛根素，溶解于20ml无水乙醇中，加入0.5ml二乙胺溶液和0.2ml 37％甲醛水溶液。油浴加热回流7小时。蒸馏除去溶剂。硅胶柱层析得70mg淡黄色结晶。mp162-165℃。1HNMR(CDCl3)：8.31(1H，s，2-ArH)，7.96(1H，d，5-ArH)，7.30(1H，d，6-ArH)，7.32(1H，s，2’-ArH)，6.98(1H，d，5’-ArH)，6.75(1H，d，4’-ArH)，4.85(1H，d)，4.05(1H，t)，3.70(1H，d)，3.45(1H，m)，3.30(3H，m)，3.15(2H，s)，2.26(4H，br，2NCH2)，1.80(6H，t，2CH3)。
实施例3
取280mg葛根素，溶解于20ml无水乙醇中，加入0.5ml四氢吡咯溶液和0.2ml 37％甲醛水溶液。油浴加热回流10小时。蒸馏除去溶剂。硅胶柱层析得50mg淡黄色结晶。mp155-156℃。1HNMR(CDCl3)：8.35(1H，s，2-ArH)，7.94(1H，d，5-ArH)，7.30(1H，d，6-ArH)，7.33(1H，s，2’-ArH)，6.97(1H，d，5’-ArH)，6.78(1H，d，4’-ArH)，4.8 5(1H，d)，4.00(1H，t)，3.71(1H，d)，3.48(1H，m)，3.26(3H，m)，3.16(2H，s)，2.28(4H，br，2NCH2)，1.6-2.1(4H，br，2CH2)。
实施例4
取280mg葛根素，溶解于20ml无水乙醇中，加入0.5ml N-甲基哌嗪溶液和0.2ml 37％甲醛水溶液。油浴加热回流14小时。蒸馏除去溶剂。硅胶柱层析得40mg淡黄色结晶。m p 171-173℃。1H NMR(CDCl3)：8.31(1H，s，2-ArH)，7.95(1H，d，5-ArH)，7.35(1H，d，6-ArH)，7.30(1H，s，2’-ArH)，7.00(1H，d，5’-ArH)，6.91(1H，d，4’-ArH)，4.87(1H，d)，4.05(1H，t)，3.72(1H，d)，3.48(1H，m)，3.20(3H，m)，3.16(2H，s)，2.00-2.28(8H，br，4NCH2)，1.98(3H，s，CH3)。
实验例1：体外血管环舒张试验
本实验采用本领域技术人员熟悉的方法进行。
wistar大鼠断头处死后，迅速开胸腹，取主动脉胸腹段，置于盛有血管营养液的培养皿中，分离血管周围组织，剪成长约3mm的动脉条，分别将两根直径约为0.1mm的不锈钢丝小心穿入，组成三角环，随后置于盛有10mg血液营养液的37℃恒温浴槽内，固定并与张力传感器相连，信号进一步输入自动台式平衡记录仪，通入95％O2和5％混合气。稳定后开始平筛药物。用去甲肾上腺素使得血管收缩达到最大收缩平衡后，取0.1ml待选药物溶液加入浴槽中，使药物浓度达到10-5M，观察10分钟。换液后加去甲肾上腺素使得血管收缩达到最大值，然后用10-6M的Ach检测血管内皮的完整性。在波形记录图上量取最大收缩幅度和给药后的收缩幅度，计算舒张率。
实验例2：小鼠常压耐缺氧试验
本实验采用本领域技术人员熟悉的方法进行。昆明种小鼠24只，雌雄各半。随机分成对照组和给药组，每组各12只动物。腹腔注射试验溶液后，置于广口瓶中，密封。记录死亡时间。
化合物 舒张率(％) 死亡时间(min)
实施例1
2.5 71
实施例2 5.7 58
实施例3 9.3 55
实施例4 5.0 69
葛根素 0.2 44
生理盐水 0.0 41
经过上述试验结果，本领域技术人员所熟知，本发明的化合物对脯乳动物具有抗缺氧缺血作用。本发明在制备脯乳动物包括人抗心脑血管药物尤其是抗缺氧和缺血药物的应用上具有良好的前景。
Claims (9)
1.如通式I所示的含水溶性基团的葛根素化合物：
式中，
R1和R2分别选自氢、(C1-C12)直链或支链烷基或芳基胺基(C1-C6)烷基；R3选自氢、(C1-C12)直链或支链碳酰基；其中R1和R2不同时代表氢；D-葡萄糖基的1位与异黄酮8位以β构型相联结；及其可作为药用的盐。
2.如权利要求1所述的化合物，其特征在于所述的化合物(I)中R1和R2分别选自的取代基是氢，二甲胺基甲基，二乙胺基甲基，二正丙胺基甲基，二异丙胺基甲基，二正丁胺基甲基，二异丁胺基甲基，二叔丁胺基甲基，1-四氢吡咯基甲基，1-哌啶基甲基，吗啉基甲基，1-六氢哌嗪基甲基，N-甲基哌嗪基甲基，叔丁胺基甲基，二环己基胺基甲基，R1和R2不同时代表氢；R3选自氢，丙酰基，丁酰基，异丁酰基，2-甲基丁酰基，3-甲基丁酰基，2，2-二甲基丙酰基，戊酰基，己酰基，庚酰基，辛酰基，壬酰基，葵酰基，月桂酰基。可作为药用的盐含选自可作为药用的各种有机和无机羧酸盐，包括盐酸，氢溴酸，磷酸、亚磷酸、硫酸、甲磺酸、对甲苯磺酸，马来酸，富马酸，酒石酸，各种天然或非天然氨基酸等。
3.根据权利要求2所述的化合物，其特征是化合物(I)是R1和R2选自的取代基是氢和二甲胺基甲基；其中R1和R2不同时为氢；R3选自氢。
4.根据权利要求2所述的化合物，其特征是化合物(I)是R1和R2选自的取代基是氢和二乙胺基甲基；其中R1和R2不同时为氢；R3选自氢。
5.根据权利要求2所述的化合物，其特征是化合物(I)是R1和R2选自的取代基是氢和1-四氢吡咯基甲基；其中R1和R2不同时为氢；R3选自氢。
6.根据权利要求2所述的化合物，其特征是化合物(I)是R1和R2选自的取代基是氢和4-甲基哌嗪基甲基；其中R1和R2不同时为氢；R3选自氢。
7.一种制备权利要求1或者2中所述化合物的方法，其特征在于，将葛根素原料与相应的醛或其等当物和胺类化合物，在水和低级醇溶剂和室温至回流温度下，进行Mannich反应，制备相应的Mannich碱类化合物及其盐。
8.如权利要求1或2所述的化合物在制备抗心脑血管疾病药物以及抗缺血或缺氧药物中的应用。
9.一种含有药物有效剂量的如权利要求1或2所述化合物和药学上可接受的载体的药物组合物。
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| CN1944448B (zh) * | 2005-01-11 | 2011-07-20 | 中国医学科学院药物研究所 | 葛根素衍生物及其药物用途 |
| CN106977500A (zh) * | 2017-04-17 | 2017-07-25 | 牡丹江医学院 | 一种用于治疗脑梗塞的药物及其制备方法 |
| CN109280067A (zh) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | 香叶木苷衍生物、其制备方法以及医药用途 |
| CN110075067A (zh) * | 2018-07-02 | 2019-08-02 | 中国人民解放军军事科学院军事医学研究院 | 一种盐酸葡酮胺微乳制剂及其制备方法与应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1944448B (zh) * | 2005-01-11 | 2011-07-20 | 中国医学科学院药物研究所 | 葛根素衍生物及其药物用途 |
| CN106977500A (zh) * | 2017-04-17 | 2017-07-25 | 牡丹江医学院 | 一种用于治疗脑梗塞的药物及其制备方法 |
| CN109280067A (zh) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | 香叶木苷衍生物、其制备方法以及医药用途 |
| CN109280067B (zh) * | 2017-07-21 | 2022-07-05 | 南京正大天晴制药有限公司 | 香叶木苷衍生物、其制备方法以及医药用途 |
| CN110075067A (zh) * | 2018-07-02 | 2019-08-02 | 中国人民解放军军事科学院军事医学研究院 | 一种盐酸葡酮胺微乳制剂及其制备方法与应用 |
| CN110075067B (zh) * | 2018-07-02 | 2021-03-23 | 中国人民解放军军事科学院军事医学研究院 | 一种盐酸葡酮胺微乳制剂及其制备方法与应用 |
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Application publication date: 20040714 Assignee: Hubei Kangqin Pharmaceutical Co.,Ltd. Assignor: INSTITUTE OF RADIATION MEDICINE, ACADEMY OF MILITARY MEDICAL SCIENCES, PLA Contract record no.: 2015420000152 Denomination of invention: Puerarin compound containing water soluble group and its preparation and use Granted publication date: 20081210 License type: Exclusive License Record date: 20150729 |
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