CN1088911A - 5,6,7,9-四氢-1,2,3-三甲氧基-9-氧代苯并[α]庚搭烯衍生物 - Google Patents
5,6,7,9-四氢-1,2,3-三甲氧基-9-氧代苯并[α]庚搭烯衍生物 Download PDFInfo
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- CN1088911A CN1088911A CN93104964A CN93104964A CN1088911A CN 1088911 A CN1088911 A CN 1088911A CN 93104964 A CN93104964 A CN 93104964A CN 93104964 A CN93104964 A CN 93104964A CN 1088911 A CN1088911 A CN 1088911A
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- deacetylation
- salt
- colchicine
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Abstract
公开了式(I)所示的化合物,式中R1和R2各代
表氢或羟基保护基,或R1和R2一起代表羟基保护
基,R3代表CH3O-或CH3NH-。这些化合物具有
很强的抑制癌细胞增殖的作用,可期望用作制癌剂。
Description
本发明涉及新的5,6,7,9-四氢-1,2,3-三甲氧基-9-氧代苯并[α]庚搭烯衍生物,更具体地讲,涉及下式所示的化合物和它们的盐以及它们的制备方法和它们作为抗肿瘤剂的应用:
式中R1和R2各代表氢或羟基保护基,或R1和R2一起代表羟基保护基,
R3代表CH3O-或CH3NH-。
已经知道,下二式分别所表示的秋水仙碱和N-甲基秋水仙裂碱氨化物对癌细胞、痛风等具有药理作用[参见E.E.van Tamelen,T.A. Spencer,Jr.,D.S.Allen,Jr.,和R.L.Orvis,Tetrahedron 14(8)(1961);以及Journal of National Cancer Institute,13 731-739(1952)]:
然而,上述秋水仙碱和N-甲基秋水仙裂碱氨化物具有强毒性,制癌作用不够强,因此,不能提供实际的药物应用。
因此,本发明人广泛地研究了具有更优良的制癌作用的秋水仙碱或N-甲基秋水仙裂碱氨化物的衍生物,结果,现在发现,式(Ⅰ)所示的化合物及其盐具有很强的抑制癌细胞增殖的作用,可期望用作制癌剂,从而完成了本发明。
作为在上式(Ⅰ)中R1和R2各自可表示的羟基保护基的实例,可提及的有C1-10(优选C2-6)链烷酰基如乙酰基、丙酰基、丁酰基或新戊酰基;以及酰基如芳酰基如苯甲酰基。此外,作为R1和R2可以一起表示的羟基保护基的实例,可提及的有下式表示的缩醛或缩酮:
式中R4代表氢或低级烷基,
R5代表低级烷基或苯基,
更具体地有:
在上文中,术语“低级”是指与该术语有关的基团或化合物的碳数为6或6以下,优选为4或4以下。
此外,作为式(Ⅰ)化合物的盐,可提及的有例如无机酸盐如盐酸盐和硫酸盐;以及有机酸盐如乙酸盐、丙酸盐、丁酸盐、乳酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、葡糖酸盐、琥珀酸盐、马来酸盐、富马酸盐、glytyllytinate、苯甲酸盐等。
本发明的上式(Ⅰ)化合物可以例如通过下法制备,即使式(Ⅱ)所示的化合物与式(Ⅲ)所示的其中羟基可被适当保护的甘油醛反应,并还原所得的式(Ⅳ)所示的化合物:
上述的式(Ⅱ)化合物与式(Ⅲ)醛的反应是一个形成席夫碱的反应,例如可以在合适的溶剂中通过使式(Ⅱ)化合物和式(Ⅲ)的醛相接触来进行,溶剂的例子有囟代烃如氯仿、二氯甲烷或二氯乙烷;脂族醚如乙醚或甲基溶纤剂;芳烃如苯或甲苯;等等。在这种情况下,脱水剂如分子筛、无水硫酸镁或无水硫酸钠的存在是极其有效的。该反应通常可以在室温下进行,但在一些情况下,也可以在高至40℃以上的升高的温度下进行,相对于式(Ⅱ)化合物而言,式(Ⅲ)化合物的用量没有严格限制,但通常来说,就每摩尔式(Ⅱ)化合物而言,方便地使用0.8-2.5摩尔、优选0.9-1.5摩尔的醛。
由此,得到了式(Ⅳ)席夫碱。本发明的式(Ⅰ)化合物可通过所述的席夫碱还原得到。该还原反应可以在形成式(Ⅳ)的席夫碱之后进行,也可以与席夫碱的形成同时进行。
这样,该还原反应可以例如通过将还原剂加到式(Ⅱ)化合物和式(Ⅲ)的醛的反应体系中进行,或通过用还原剂就地处理或从反应混合物中分离后处理所得的式(Ⅳ)席夫碱来进行。作为可用的还原剂,可被提及的例子是金属氢化物复合物如氰基硼氢化钠、硼氢化钠、三丁基氢化锡。就每摩尔作为起始原料的式(Ⅱ)化合物而言,通常使用0.8-1.2、特别是0.9-1.1摩尔的这种还原剂是合适的。
上述还原反应通常可在约-5℃至约20℃之间的温度下进行,优选的温度范围为约0℃至约15℃。
由上述还原反应得到了式(Ⅰ)所示的化合物
式中R1、R2和R3具有上述意义。此外,当R1和R2中的一个或两个都代表羟基保护基或R1和R2一起代表羟基保护基时,根据还原条件不同,产生这样一种情况,即,由于保护基的断裂,形成了式(Ⅰ-1)所示的化合物,
式中R3具有上述意义,此外,当R1和R2都代表羟基保护基时,也产生这样一种情况,即由于其部分裂解,形成了下二式所示的化合物;
式中R11和R21各代表羟基保护基,
R3具有上述意义。
其中R3为CH3NH-的式(Ⅰ)化合物即下式(Ⅰ-4)所示的化合物也可以例如通过其中R3代表CH3O-的式(Ⅰ)化合物即下式(Ⅰ-5)所示的化合物进行甲氨基化反应来制备,其中化合物(Ⅰ-5)可按前述方法制备。
式中R1和R2具有上述意义。
式(Ⅰ-5)化合物的甲氨基化反应可通过本身已知的方法进行[例如,参见Patrick J.Davis,Antimicrobial Agents and Chemotherapy,Mar.1981,P465-469;J.L.Hartwell等人,J.Am.Chem.Soc.,74,3180(1952)],例如,例如通过使式(Ⅰ-5)化合物与甲胺反应,用甲氨基取代10-位的甲氧基。
上述反应通常在室温至溶剂的回流温度下进行,优选约40℃至约90℃。此外,虽然与式(Ⅰ-5)化合物反应的甲胺的用量并无严格限制但就每摩尔式(Ⅰ-5)化合物而言,其用量通常为约2至30摩尔,特别是约10至约20摩尔。
上述甲氨基化反应通常可以在密闭容器中在含水介质存在下进行。
由此得到的本发明的式(Ⅰ)化合物可通过本身已知的方法分离和纯化,例如通过提取、层析、结晶或其结合等方法来分离和纯化。
可以使其中R1和/或R2代表羟基保护基的本发明化合物脱去保护基,例如通过水解除去保护基。
此外,需要时,可按照本身已知的成盐方法,例如,通过用合适的酸处理,将如此得到的式(Ⅰ)化合物转化成上述盐。
按本发明得到的化合物在侧链上具有不对称碳原子,可以以D-、L-或DL-形式存在。例如,在上述制备方法中,当使用D-形式的起始原料式(Ⅲ)化合物时,可得到D-形式的式(Ⅰ)化合物,当使用L-形式的式(Ⅲ)化合物时,可得到L-形式的式(Ⅰ)化合物,而当使用DL-形式的式(Ⅲ)的甘油醛时,则可得到DL-形式的式(Ⅰ)化合物。
在上述反应中,式(Ⅱ)化合物中,其中R3代表CH3O-的式(Ⅱ)化合物脱乙酰基秋水仙碱本身是已知的[参见J.Am.Chem.Soc,75,5292(1953)],可以按已知方法制备,或者,脱乙酰基秋水仙碱也可以按照本发明人新建立的方法(EP-A-493064)制备,即通过使秋水仙碱与氟硼酸三乙氧鎓(米尔文试剂)反应,然后用水处理产物来制备(至于细节,参考下文所述的参考实施例1)
另一方面,其中R3代表CH3NH-的式(Ⅱ)化合物N-甲基脱乙酰基秋水仙裂碱氨化物例如可以通过使脱乙酰基秋水仙碱与甲胺反应或通过秋水仙碱与甲胺反应来制备N-甲基秋水仙裂碱氨化物[参考J.L.Hartwell等人,J.Am.Chem.Soc.,74,3180(1952)],然后在稀硫酸中水解(脱乙酰基)来制备[至于细节,参考下文所述的参考实施例2]。
从下面对癌细胞的体外试验可明显看出,本发明所提供的上述式(Ⅰ)化合物具有优良的制癌作用,仅有很低的毒性。
试验实施例1
体外癌细胞增殖抑制试验
(1)将小鼠白血病细胞p388/S和耐阿霉素小鼠白血病细胞p388/ADR各106个分别悬浮在各含10%胎牛血清的RPMI1640培养基中,在试验化合物存在下培养2天(将试验化合物溶在二甲基亚砜中制成1mg/ml溶液,溶液用磷酸盐缓冲液稀释,然后使用之)。观察试验化合物对细胞增殖的影响,测定50%增殖抑制浓度:IC50值(μg/ml),结果示于表1中。
表1
试验化合物 IC50值(μg/ml)
p388/S p388/ADR
D-N-(0,0-异亚丙基甘油
基脱乙酰基秋水仙碱 0.014 0.038
DL-N-(0,0-异亚丙基甘油
基脱乙酰基秋水仙碱 0.013 0.13
L-N-(0,0-异亚丙基甘油
基脱乙酰基秋水仙碱 0.018 0.14
秋水仙碱 0.0041 0.48
(2)将次培养移植在小鼠腹腔中的小鼠白血病细胞p388/S和耐阿霉素小鼠白血病细胞p388/ADR与其中的asites一起分别取出,洗涤后,分别悬浮在RPMI 1640培养基(各含10%胎牛血清和10μM2-巯基乙醇)中,得到2×105个细胞/ml悬浮液。
将试验溶液(下述实施例3的化合物在磷酸盐缓冲的生理盐水中的溶液)分别加到数份每一种细胞悬浮液中;将混合物分别加到24孔培养平皿中,在5%CO2培养容器中培养2天。向每一细胞培养肉汤中加入等量的0.5%台盼篮溶液,通过在显微镜下对作为活细胞而没染色的细胞计数,测定试验化合物的50%增殖抑制浓度(IC50)。三次试验结果示于下述表2中。
表2
试验化合物 IC50(ng/ml)
p388/S p388/ADR
N-(0,0-异亚丙基甘油
基)-N-甲基脱乙酰基 13.5 18.0
秋水仙裂碱氨化物的酒 12.8 16.4
石酸盐 14.9 19.2
试验实施例2
急性毒性试验
将数份试验溶液(下述实施例3的化合物在生理盐水中的溶液)腹膜内给予各组CDF雄性小鼠,每组分别包括8只小鼠,观察体重、症状、死亡日期等10天。以432mg/kg作为最大量,按1.2的通常比率降低使用量,用Litchfield Wilcoxon方法计算其LD50值,结果,实施例3化合物的LD50值是269mg/kg(233-310mg/kg)。
对于急性毒性症状,在高用量组,毛发的分布在给药后那天或那天后变坏,也观察到了所引起的腹泻和脱毛的情况。此外,就重量变化而言,在每种情况下,体重在给药后最多2-4天倾向于减轻,但其后又逐渐增加。
从上面的试验结果明显看出,本发明化合物对癌细胞具有很强的抑制作用,仅有很低的毒性,可望用作制癌剂。
当本发明的化合物用作药物如制癌剂时,所述化合物可被口服或非经胃肠道给药(例如,静脉注射、肌内注射、皮下注射等)。其有效剂量可在很宽范围内变化,取决于服用所述化合物的病人的症状、体重和年龄、医生的判断等,但例如在注射情况下,通常可为约10至约50mg/kg/天,所述化合物可一天服用一次,或分成几次服用。
当将本发明的化合物作为药物使用时,可将有效量的化合物与可药用的载体或稀释剂(如赋形剂、溶剂、其它辅助剂等)一起配制成适于给药的给药单位形式,例如配制成下述剂型:片剂、粉剂、颗粒剂、胶囊、肠内吸收剂、锭剂、糖浆、酏剂、液体制剂、悬浮液和乳液。
作为适用于上述制剂中的载体或稀释剂,可提及的有例如赋形剂如淀粉、乳糖、蔗糖、甘露糖醇和羧甲基纤维素;润滑剂如硬脂酸镁、月桂基硫酸钠和滑石;粘结剂如糊精、微晶纤维素、聚乙烯吡咯烷酮、阿拉伯胶、玉米淀粉和明胶;崩解剂如土豆淀粉和羧甲基纤维素;稀释剂如注射用蒸馏水、生理盐水、葡萄糖水溶液、注射用植物油、丙二醇和聚乙二醇;等等,此外,需要时,可以加入调味剂、着色剂、张力剂、稳定剂、防腐剂、使本发明化合物无痛的试剂等。
此外,需要时,也可以将另外的药理活性物质配入本发明的药物中。
下面用实施例更详细地描述本发明。
参考实施例 1
脱乙酰基秋水仙碱的制备
将秋水仙碱(4.00g,10mmol)溶于无水二氯甲烷中。将溶液冷却至0℃,滴加氟硼酸三乙氧鎓(米尔文试剂)的二氯甲烷溶液(15mmol)。将混合物在0℃下搅拌1小时,然后在室温下搅拌5小时,向反应混合物中加入30ml水,将所得混合物搅拌1小时。然后用分液漏斗分出水层,用每份50ml水提取二氯甲烷层5次。用硫酸镁干燥二氯甲烷层,用来回收未反应的秋水仙碱。用1N氢氧化钠将水层调整至pH10,用氯仿提取。氯仿层用硫酸镁干燥,然后在蒸发器中浓缩。残留物溶于30ml乙醇中,加入1g D-酒石酸,加热混合物1小时,混合物冷至室温后,滤出形成的沉淀物。在干燥器中干燥所得的酒石酸盐(在219-220℃的熔点时分解)。
将酒石酸盐溶于50ml水中,用1N氢氧化钠将溶液重新调整至pH10,用氯仿提取,提取液用硫酸镁干燥,在蒸发器中减压浓缩,得到1.38g油状脱乙酰基秋水仙碱。收率39%。
将最初的二氯甲烷层进行硅胶层析,用苯-丙酮溶剂洗脱,从洗脱液中回收未反应的秋水仙碱(1.71g)。扣除此量后的脱乙酰基秋水仙碱的实际收率为61%。
参考实施例 2
N-甲基脱乙酰基秋水仙裂碱氨化物的制备
使秋水仙碱(5.00g,12.5mmol)、40%甲胺水溶液(10ml,130mmol)和乙醇(10ml)的混合溶液在密闭容器中于120℃和搅拌下反应20小时。蒸除溶剂,向残留物中加入水(10ml),用氯仿提取混合物。分出氯仿层,用水洗涤后干燥。蒸发溶剂,通过硅胶柱层析(氯仿:甲醇(20∶1)]分离和纯化残留物。由此得到了4.18g N-甲基秋水仙裂碱氨化物,为黄色晶体(收率84%)。
将N-甲基秋水仙裂碱氨化物(3.00g,7.5mmol),水(50ml)和浓硫酸(15ml)的混合溶液在100℃搅拌5小时进行水解(脱乙酰基反应)。在冰冷却下用无水碳酸钠碱化反应溶液,用氯仿提取。分出氯仿层,用水洗后干燥。蒸发溶剂至干。通过硅胶柱层析[氯仿:甲醇(20∶1)]分离和纯化残留物。由此得到2.20g黄色晶状的N-甲基脱乙酰基秋水仙裂碱氨化物(收率62%)。
实施例1
将脱乙酰基秋水仙碱酒石酸盐(4.06g,8.0mmol)悬浮在水(50ml)中用1N NaOH将悬浮液调至大约pH10。用氯仿提取混合物,用硫酸镁干燥提取液,除去溶剂,残留物用作脱乙酰基秋水仙碱。将DL-0,0-异亚丙基甘油醛(1.04g,8mmol)和硫酸镁(1.50g)加到脱乙酰基秋水仙碱在无水氯仿(30ml)中的溶液中,将混合物在室温下搅拌3小时。反应完后过滤除去硫酸镁,在蒸发器中浓缩滤液。加入无水甲醇(20ml)溶解残留物,在冰冷却下加入NaBH3CN(0.76g,8.0mmol),将混合物在0℃下搅拌1小时,然后在室温下搅拌10小时,搅拌期间,棕色反应混合物逐渐变成黄色。反应完后,将反应混合物倾到入100ml水中,用氯仿提取混合物。氯仿层用饱和盐水洗涤后,用硫酸镁干燥,减压下蒸除氯仿,通过硅胶层析分离残留物,从苯-丙酮(6∶1)洗脱液中得到1.85g(49%)DL-N-(0,0-异亚丙基甘油基)脱乙酰基秋水仙碱(1)。
无定形固体
IR:1260,1140,1100 cm-1(-0-)
NMR:δ=1.28(3H,s),1.33(3H,s),2.22-2.73(4H,m),3.29-3.56(2H,m),3.58(3H,s),3.87(3H,s),3.89(3H,s),3.96(3H,s),3.67-4.18(3H,m),6.53(1H,s),6.84(1H,s),7.16(1H,d),7.80(1H,s)
此外,从同一洗脱液中还得到1.63g(47%)DL-N-(甘油基)脱乙酰基秋水仙碱(2)
无定形固体
IR:3450 cm-1(OH),1260,1140,1100 cm-1(-O-)
NMR:δ=1.98-2.89(8H,m),3.60(3H,s),3.87(3H,s),3.89(3H,s),3.93(3H,s),3.53-4.00(3H,m),6.51(1H,s),6.53(1H,s),7.18(1H,s),7.31(1H,s)
实施例 2
用D-0,0-异亚丙基甘油醛(1.04g,8.0mmol)作为起始原料进行与实施例1相同的反应,得到0.87g(23%)D-N-(0,0-异亚丙基甘油基)脱乙酰基秋水仙碱和1,25g(36%)D-N-(甘油基)脱乙酰基秋水仙碱。
其IR和NMR与DL-形式的那些化合物几乎相同。
实施例 3
用L-0,0-异亚丙基甘油醛(1.04g,8.0mmol)作为起始原料进行与实施例1相同的反应,得到0.84g(22%)L-N-(0,0-异亚丙基甘油基)脱乙酰基秋水仙碱。
其IR和NMR与DL-形式的那些化合物几乎相同。在NMR中,异亚丙基中的甲基的吸收位置稍有不同,其吸收在1.29ppm和1.31ppm。
实施例 4
将3.40g(7.2mmol)在实施例1中得到的DL-N-(0,0-异亚丙基甘油基)脱乙酰基秋水仙碱溶于50ml乙醇中,向该溶液中加入1.08g(7.2mmol)D-酒石酸,将混合物在50-60℃温热30分钟,然后,减压下蒸除乙醇,直至混合物体积减至大约1/4,在冰冷却下向残留的乙醇溶液中加入乙醚,使结晶物沉出。抽滤出结晶物,减压下干燥,得到黄色晶状的DL-N-(0,0-异亚丙基甘油基)脱乙酰基秋水仙碱D-酒石酸盐。熔点96-98℃。收率3.20g(72%)。
1H-NMR(60 MHz)CDCl3,δ:1.02,1.03(各 3H,各s),1.43-2.92(5H,m),3.40-4.40(5H,m),3.68(3H,s),4.00(6H,s),4.36(3H,s),6.86(1H,s),7.30(1H,s),7.40,7.49(各 1H,d,J=11Hz)
实施例 5
将0,0-异亚丙基甘油醛(0.73g,5.6mmol)的苯(20ml)溶液加到装在配备有其中装有分子筛的索格利特萃取器的烧瓶中的N-甲基脱乙酰基秋水仙裂碱氨化物(2.00g,5.6mmol)的氯仿(30ml)溶液中,将混合物回流5小时。反应完毕,在蒸发器中浓缩反应混合物,向残留物中加入无水甲醇(30ml)溶解残留物。将该溶液冷却至0℃,分批加入氰基硼氢化钠(0.43g,5.6mmol),将反应混合物在0℃下搅拌1小时,然后在室温下搅拌10小时。将反应混合物倒入150ml水中,用氯仿提取所得混合物,氯仿层用饱和盐水洗涤后,用硫酸镁干燥。减压下浓缩氯仿层,通过硅胶柱层析分离。从苯-丙酮(3∶1)洗脱液中得到0.70g(收率27%)的N′-(0,0-异亚丙基甘油基)-N-甲基脱乙酰基秋水仙裂碱氨化物。
IR:3500 cm-1(NH)
NMR:δ=1.30,1.32(3H,s),1.35,1.39(3H,s),2.25-2.50(2H,m),3.09(3H,d,J=5.4Hz),3.59(3H,s),3.76-3.82(1H,m),3.90(3H,s),3.93(3H,s),3.89-4.03(2H,m),6.54(1H,s),7.27(1H,s),7.64(1H,s),7.77(1H,s)
实施例 6
将按实施例1所述的相同方法得到的N-(0,0-异亚丙基甘油基)脱乙酰基秋水仙碱(2.74g,5.8mmol)和10ml40%甲胺水溶液置于密封的管中,加热至75-80℃的同时搅拌20小时。反应完毕,在蒸发器中浓缩反应混合物,残留物溶于氯仿中。氯仿层用饱和盐水洗涤,用硫酸镁干燥。减压下蒸除氯仿,通过硅胶柱层析分离纯化残留物,结果,从苯-丙酮(3∶1)洗脱液中得到1.91g(收率70%)的与实施例5相同的N′-(0,0-异亚丙基甘油基)-N-甲基脱乙酰基秋水仙裂碱氨化物。
实施例7
将D-酒石酸(1.08g,7.2mmol)加到实施例5中得到的N-[(0,0-异亚丙基)甘油基]-N-甲基脱乙酰基秋水仙裂碱氨化物(3.40g,7.2mmol)的乙醇(50ml)溶液中,将混合物在50-60℃温热30分钟。蒸掉部分乙醇(直到体积变成约1/4),在冰冷却下向残留的乙醇溶液中加入乙醚使结晶物沉出。抽滤出结晶物,减压干燥,得到3.30g(收率74%)N′-(0,0-异亚丙基甘油基)-N-甲基脱乙酰基秋水仙裂碱酒石酸盐。
实施例 A
注射剂的制备
将30g N′-(0,0-异亚丙基甘油基)-N-甲基脱乙酰基秋水仙裂碱氨化物酒石酸盐溶于1升注射用蒸馏水中,用氯化钠使所述溶液等渗,将混合物装入安瓿中,密封。1ml该注射液含30mg有效成分。
Claims (9)
3、根据权利要求1的化合物,选自N-(0,0-异亚丙基甘油基)脱乙酰基秋水仙碱和N′-(0,0-异亚丙基甘油基)-N-甲基脱乙酰基秋水仙裂碱氨化物。
6、一种药物,其中含有权利要求1所公开的式(Ⅰ)化合物或其可药用盐。
7、一种抗肿瘤剂,其中含有权利要求1所公开的式(Ⅰ)化合物或其可药用的盐。
8、一种药物制剂,其中包含有效量的权利要求1所公开的式(Ⅰ)化合物或其可药用的盐和可药用的载体或稀释剂。
9、一种治疗肿瘤的方法,其中包括服用抗肿瘤有效量的权利要求1所公开的式(Ⅰ)化合物或其可药用的盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP4358821A JPH06199749A (ja) | 1992-12-28 | 1992-12-28 | N−メチルデアセチルコルヒセインアミド誘導体 |
JP358821/92 | 1992-12-28 |
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CN1088911A true CN1088911A (zh) | 1994-07-06 |
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CN93104964A Pending CN1088911A (zh) | 1992-12-28 | 1993-05-04 | 5,6,7,9-四氢-1,2,3-三甲氧基-9-氧代苯并[α]庚搭烯衍生物 |
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US (1) | US5326786A (zh) |
EP (1) | EP0605078B1 (zh) |
JP (1) | JPH06199749A (zh) |
KR (1) | KR940014309A (zh) |
CN (1) | CN1088911A (zh) |
AT (1) | ATE148688T1 (zh) |
AU (1) | AU658502B2 (zh) |
CA (1) | CA2094753A1 (zh) |
DE (1) | DE69308009T2 (zh) |
DK (1) | DK0605078T3 (zh) |
ES (1) | ES2101951T3 (zh) |
GR (1) | GR3023322T3 (zh) |
Cited By (3)
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US7056055B1 (en) | 2005-08-04 | 2006-06-06 | Wen-Nan Kuo | Traffic cone (2) |
CN113024400A (zh) * | 2021-03-08 | 2021-06-25 | 沈阳药科大学 | 一种秋水仙碱衍生物及其制备方法和应用 |
WO2024146555A1 (zh) * | 2023-01-06 | 2024-07-11 | 沈阳药科大学 | 一种甲氨基秋水仙碱及盐的应用 |
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JPH06211762A (ja) * | 1993-01-20 | 1994-08-02 | Bigen Kenkyusho:Kk | N−メチルデアセチルコルヒセインアミド誘導体 |
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AU6179690A (en) * | 1989-08-09 | 1991-03-11 | Michael Reese Hospital And Medical Center | Method for detection and treatment of multiple drug-resistant tumor cells and useful colchicine derivative probes |
AU634921B2 (en) * | 1990-12-25 | 1993-03-04 | Ohgen Research Laboratories Ltd. | Deacetylcolchicine derivatives |
IT1244660B (it) * | 1991-03-06 | 1994-08-08 | Giorgio Bonura | Preparati farmaceutici per la terapia dei tumori contenenti colchicina come principio attivo e metodi per l'impiego degli stessi. |
-
1992
- 1992-12-28 JP JP4358821A patent/JPH06199749A/ja active Pending
-
1993
- 1993-04-23 US US08/051,297 patent/US5326786A/en not_active Expired - Fee Related
- 1993-04-23 DE DE69308009T patent/DE69308009T2/de not_active Expired - Fee Related
- 1993-04-23 CA CA002094753A patent/CA2094753A1/en not_active Abandoned
- 1993-04-23 EP EP93303190A patent/EP0605078B1/en not_active Expired - Lifetime
- 1993-04-23 AT AT93303190T patent/ATE148688T1/de not_active IP Right Cessation
- 1993-04-23 AU AU37094/93A patent/AU658502B2/en not_active Ceased
- 1993-04-23 DK DK93303190.8T patent/DK0605078T3/da active
- 1993-04-23 ES ES93303190T patent/ES2101951T3/es not_active Expired - Lifetime
- 1993-04-28 KR KR1019930007246A patent/KR940014309A/ko not_active Application Discontinuation
- 1993-05-04 CN CN93104964A patent/CN1088911A/zh active Pending
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1997
- 1997-05-02 GR GR970400980T patent/GR3023322T3/el unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US7056055B1 (en) | 2005-08-04 | 2006-06-06 | Wen-Nan Kuo | Traffic cone (2) |
CN113024400A (zh) * | 2021-03-08 | 2021-06-25 | 沈阳药科大学 | 一种秋水仙碱衍生物及其制备方法和应用 |
WO2024146555A1 (zh) * | 2023-01-06 | 2024-07-11 | 沈阳药科大学 | 一种甲氨基秋水仙碱及盐的应用 |
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CA2094753A1 (en) | 1994-06-29 |
ATE148688T1 (de) | 1997-02-15 |
AU3709493A (en) | 1994-07-14 |
DK0605078T3 (da) | 1997-08-18 |
JPH06199749A (ja) | 1994-07-19 |
GR3023322T3 (en) | 1997-08-29 |
US5326786A (en) | 1994-07-05 |
EP0605078A1 (en) | 1994-07-06 |
DE69308009T2 (de) | 1997-08-28 |
DE69308009D1 (de) | 1997-03-20 |
EP0605078B1 (en) | 1997-02-05 |
AU658502B2 (en) | 1995-04-13 |
KR940014309A (ko) | 1994-07-18 |
ES2101951T3 (es) | 1997-07-16 |
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