CN87104027A - 新顺铂铬合物,其小鼠抗肿瘤组合物及其制备过程 - Google Patents
新顺铂铬合物,其小鼠抗肿瘤组合物及其制备过程 Download PDFInfo
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- CN87104027A CN87104027A CN87104027.1A CN87104027A CN87104027A CN 87104027 A CN87104027 A CN 87104027A CN 87104027 A CN87104027 A CN 87104027A CN 87104027 A CN87104027 A CN 87104027A
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
Abstract
本发明涉及通式(I)表示的具有小鼠抗肿瘤活性的新顺铂二氨络合物及其制备过程,上述式(I)中取代基的定义与说明书相同。本发明还涉及以上述化合物为活性成份的小鼠抗肿瘤组合物以及这些化合物在制备小鼠抗肿瘤药剂中的用途。
Description
本发明涉及新顺铂络合物、含有它们作为活性成份的抗小鼠肿瘤组合物、以及制备这些化合物的方法。
1965年罗斯伯里(Rosenberg B.)等人偶然发现了顺式二氯二氨合铂(Ⅱ)(以下简称顺铂)[Rosenberg B.et al.,Nature 250(1965)698],并报导了该化合物对Sarcoma和Leukemia L的抗肿瘤活性[Rosenberg B.et al.,Nature 222(1969)385],1978年底美国食品及药物管理局正式批准顺铂为抗癌药以治疗睾丸癌和子宫癌。不久又被获准治疗膀胱癌。
顺铂虽是目前较好的抗癌药之一,但毒性很强,其中对神经、胃和肾的毒性尤其明显,它与其它抗癌药物一样,亦有致癌和不育等涉及对DNA作用的慢性毒性。
迄今,顺铂类似物已合成了不下1500种以上,所谓第二代顺铂类似物即该类似物上氨基取代基,是各种类型脂族基团的取代氨基顺铂类似物,此类衍生物中有些已获专利保护(见美国专利4,410,544)。
前人在此领域虽做了大量研究,但疗效堪与顺铂相提并论的药物至今未曾出现,至于如何降低抗癌药物本身的致癌性问题,由于机理不明,仍属难题。
发明人根据本人提出的双区理论[Scientia Sinica(1979)964-977]进而从事探寻非致癌性抗癌药的工作,并致力于新的毒性低、非致癌的顺铂衍生物的研究。双区理论认为,致癌作用的关键步骤是DNA互补碱对间的横向交联。为了加强抗癌剂对正常细胞和癌细胞作用的选择性,设计的抗癌剂应起到降低上述交联趋势,加强非互补碱间交联的作用。
发明人对改变顺铂类似物上的取代基进行了广泛研究,合成了一系列任意取代的芳基、杂芳基取代的烷基或环烷基二氨合铂(Ⅱ)和(Ⅳ)络合物,发现上述化合物具有卓越的抗肿瘤活性,本发明化合物的特点是任意取代的芳基、杂芳基团与络合物中心金属原子间存在一脂肪键结构,有效地防止了络合物中心金属原子与非脂族取代基间电子的离域作用。
顺铂类似物通常难溶于水和有机溶剂,因此不易被肠吸收,根据不同的给药方式,有时它们难于显示抗肿瘤活性,药物在腹腔投予后,难以达到治疗目的。本发明化合物的溶解度较已知的顺铂类似物为佳在抗小鼠的肿瘤中是有效的,用简单的给药方法和简单的配方就显示出优越的抗肿瘤活性。本发明以上述发现为依据,这些化合物是文献上未曾记载过的新化合物。
本发明提供了通式(Ⅰ)表示的顺式二氨合铂(Ⅱ)和(Ⅳ)络合物
其中,
Q1和Q2可以相同或不同,各自代表脂族基团,或饱和脂族杂环二价基团;
Ar1和Ar2可以相同或不同,各自代表芳族基团、杂芳族基团,或两者合在一起代表两价芳族基团或杂芳族基团;
R3和R4可以相同或不同,各自代表氢原子、C1-5烷基以及C1-10杂烷基;
代表一饱和杂环;
X代表阴离子配位体如囟素阴离子配位体或二价阴离子配位体如有机或无机酸根,限制条件是:Z不存在以及X不是囟素则Ar1、Q1和R3中至少一个基团必须为含杂原子或含氧基团;
本发明还提供了含有上述一种或多种化合物为活性成份的抗肿瘤组合物,以及制备这些化合物及组合物的方法。下面对本发明作更为详细的描述。
本文中的术语脂族或饱和脂族杂环二价基团是指直链或支链脂族C1-5亚烷基或任意含一、二或更多个氧、氮或硫原子的脂族5至6元环,例如:
芳基是指任意被一个或多个卤素(例如:氟原子、氯原子、溴原子或碘原子)、羟基、硝基、或羧基取代的苯基、萘基、菲基。
杂芳基是指任意取代的杂环基、环中至少一个杂原子是氧、氮或硫,所述杂环基团选自呋喃、吡咯、吡啶及噻吩基。
含氧基团是指羟基、羟甲基或羧基。
C1-5烷基是指直链或支链C1-5烷基,较好的是甲基、乙基、正丙基、异丙基,更好的是甲基。
术语囟素阴离子是指氟、氯、溴或碘阴离子,当X代表有机或无机酸根时,所述的酸根可以是下述酸根中的一个酸根,它们是:乙酸根、氯乙酸根、草酸根、马来酸根、1,2-苯二甲酸根、4-羟基-1,2苯二甲酸根、环-1,1-丁二甲酸根、葡糖酸根及硫酸根。
通式(Ⅰ)表示的本发明化合物可用以下方程式表示的方法制备:
其中X′表示除碘离子以外的囟素阴离子,Am表示合成铂络合物所需的氨类配体。通式(Ⅰ)表示的化合物可以在溶剂存在下使氯亚铂酸钾与相应当量的氨基配体反应来制备,亦可先从氯亚铂酸钾制成相应的碘化物,再与硝酸银作用生成水合物,然后与所需的囟化钾交换,如果需要,可用乙酸、氯乙酸、草酸、丙二酸、羟基邻苯二甲酸、葡萄糖酸、硫酸等有机或无机酸进一步转换成相应的络合物。在上述方法所得的二价铂(Ⅱ)络合物中加入过量约30%H2O2在50-110℃的温度范围内反应可制成相应的四价铂络合物。
用于合成本发明化合物的溶剂可提及的有例如,水;含C1-5碳原子的醇类如甲醇、乙醇、丙醇,异丙醇、丁醇、叔丁醇、戊醇、优选的是乙醇;含C1-5个碳原子的酮类如丙酮;二甲基亚砜;二甲基甲酰胺,这些溶剂可单独或混合使用,其中优选用水。
反应温度可从10-50℃范围内进行选择,但特别可取的反应温度是室温。
反应时间可从0.5到24小时的范围内适当地选择。
反应完成后反应物用常规方法处理,例如,过滤、干燥,然后可以或无需用常规精制即得纯品。
可取的精制溶剂有二甲基亚砜,二甲基甲酰胺、丙酮、水或上述溶剂的混合物。
上述反应中作起始原料的一系列胺类配体,其中苄胺及其衍生物可以按下式用Leuckart反应制备;
其中R5、P的定义如前所述。
该法描述于以下文献:来惠斯、美国化学会志(K.G.Lewis.J.Chem.Soc.)(1950)2247-2250,Leuckart法主要用于从酮制备脂族胺类,以芳香醛为原料时,则胺的收率很低。本发明的特点是在反应体系中加入过量甲酸并添加Raney镍催化剂,收率高于已有技术,从而使从芳醛合成苄胺的方法成为工业上可用的方法。
任意取代的呋喃甲胺及羟苯基甲胺的制备,采用相应醛肟在酸性介质中还原法,可用以下方程式表示;
其中R表示任意取代的呋喃基、噻吩基或羟苯基。用于本反应的酸可提供及的有:有机或无机酸如醋酸、硫酸或盐酸等。
二齿胺类配体例如邻二氨甲芳烃衍生物的制备,可先将相应的原料二溴化生成邻二氨甲芳烃衍生物,再与邻苯二甲酰亚胺钠盐作用,用水合肼水解,可用下式表示:
4-苯基-5-氨基-1,3二氧六环可按下式例示的方法制备,该方法系发明人在下述文献中公布过的方法(Dai Qianhuan,Kexue Tongbao 1977(9)381)
其中X表示氯或溴原子,然后用酒石酸与其成盐进行拆分,用常规方法进行后处理,得旋光异构体[R∶R]-(-)-4-苯基-5-氨基-1,3-二氧六环,残剩物用甲醇重结晶可得其对映异构体。这一拆分方法系本发明首先提出。
本发明化合物的典型实例及部分铂络合物的溶解度列于表Ⅰ、Ⅱ、Ⅲ、Ⅳ、及Ⅵ中,但本发明不受此限制。
表Ⅵ(a)
铂络合物的溶解度
表Ⅵ(b)
表Ⅵ(c)
表Ⅵ(d)
实验测得的本发明化合物的抗肿瘤活性描述于下:
本发明化合物,特别是表Ⅰ、Ⅱ、Ⅲ、Ⅳ、、所列的化合物对小鼠黑色素瘤、B16细胞株、Hela宫颈癌细胞和胃癌细胞MGC-803有高于顺铂的杀伤活性。对小鼠S180腹水及小鼠白血病L1210皆有治疗作用。
试验实施例1
对DBA/2种小鼠腹腔内接种L1210白血病细胞,其量为1×106细胞/小鼠。试验药在腹腔内给药一次(即在接种24小时后)对小鼠的存活或死亡观察30天,将试验组动物和对照组动物相比,其延命率(%)按下法获得,即将对照小鼠给以生理盐水之存活天数指定为100,其结果如表Ⅴ所示,对于部分溶解度较小的受试化合物是在受试化合物中加入少量表面活性剂(例如吐温80)以制得受试药混悬体。
试验实施例2
对DBA/2种小鼠腹腔内接种S180肿瘤细胞,其量约为1×106细胞/小鼠。试验药在腹腔内给药一次(即在接种24小时后),对小鼠的存活或死亡之观察30天,试验动物和对照动物存活时间之比(%)按下法获得,即将对照小鼠给以生理盐水之存活天数指定为100,结果如Ⅴ所示,对于部分溶解度较小的受试化合物是在受试化合物中加入少量表面活性剂以制得受试药物悬浮体。
表Ⅴ
表Ⅴ(a)
表Ⅴ(b)
表Ⅴ(c)
表Ⅴ(d)
表Ⅴ(e)
本发明化合物如上所述可望用作抗肿瘤制剂。本发明化合物可以口服给药或非肠道给药如皮下、静脉内,肌肉或腹膜或直肠给药。
根据采用的药物剂型及其它因素铂络合物在每单位药剂中的含量可有大幅度变化。但通常铂络合物的含量比可从0.01到100%,较好的是0.1到70%(重量百分比)药剂的其它组成部分是载体和佐剂。考虑到动物试验结果和各种情况,上述化合物可在一范围内连续或间竭给药,使其总剂量不超过某一水平,剂量可随给药途径和被治疗的患者或动物的状况(如年龄、体重、性别、敏感性、食物等)、给药间隔、与上述化合物联合使用的药物和病程而做适当改变。在某种状况下的最优剂量和给药次数必须由于医学专家来决定。
当口服给药时,本发明化合物可制成固体或液体制剂如胶囊、药片、锭剂、熔融剂、粉剂、溶液、悬浮液或乳液。固体剂型通常有如:胶囊或片剂。胶囊可以是通常的明胶型含附加的赋形剂如,表面活性剂,润滑剂及惰性填充料如乳糖,蔗糖以及玉米淀粉。本发明化合物亦可与通常的片剂基质如乳糖、蔗糖以及玉米淀粉及粘合剂,如阿拉伯胶,玉米淀粉或明胶,崩解剂如马铃薯淀粉或藻朊酸,以及润滑剂如硬酯酸镁合并制成片剂。
当非肠道给药时,可将化合物与生理可接受的稀释剂及药物载体相混制成溶液或悬浮液,当注射剂型给药时,则用适合的稀释剂或载体包括无菌液体如水或油,加或不加表面活性剂或其它药学上可接受的佐药,本发明实践中可应用的各种油作为例子的有:动物油、植物油或合成来源的油例如,花生油、豆油及矿物油等。一般来说水,盐水、右旋糖酐的水溶液及有关糖溶液,乙醇及二醇如丙二醇或聚乙二醇是较好的液体载体,特别适宜用于制备注射溶液。
以下具体实施例将进一步阐明本发明,但本发明不受此限止。
实施例1
对氯苯甲胺的制备
于三口并中加入25克甲酸胺,18,4克甲酸,1克Raney镍,加热至125-130℃搅拌下于半小时内滴加13.7克对氯苯甲醛,升温至140-145℃反应3小时。冷却后加入浓盐酸调节PH值至<3,回流2小时。冷却后用氢氧化钠液中和至强碱性,水蒸汽蒸馏,馏出液收集于浓盐酸(18% W/V)与水的混合液(1∶1)中,减压浓缩至干,残剩物用15%氢氧化钠水溶液碱化至取碱性,氯仿提取,有机层用水洗,无水硫酸镁干燥,浓缩,减压蒸馏得无色油状产物,收率51-67%。
同法用相应的取代苯甲醛可制备一系列苄胺衍生物。
实施例2
呋喃甲胺的制备
将10克用常规方法制得的糠醛肟加到75毫升95%乙醇和80毫升乙酸的混合液中,用水浴加热,搅拌下分四次加入70克锌粉,搅拌5小时,放置过夜,反应液倾入400毫升水中,滤除残余锌粉,用20%氢氧化钠溶液碱化,乙醚提取,用固体氢氧化钠干燥,蒸馏,收集沸点为143℃的产物,收率56-63%(具酚基并易与甲酸反应的芳香醛均用此法制备相应的胺)
实施例3
4-氯-邻苯二甲胺的制备
0.1毫克分子4-氯-邻二甲苯,在干燥四氯化碳中与40克溴代丁二酰胺,0.5克过氧化二苯甲酰回流1.5小时,冷却,过滤后蒸去四氯化碳,加入100毫升二甲基甲酰胺,30克邻苯二甲酰亚胺钾,于90-100℃加热两小时,冷却,加入500毫升水,用氯仿提取三次,合并氯仿提取液,以水及氢氧化钠液洗涤,浓缩至结晶开始拆出,冷却,加入100毫升乙醚,干燥后过滤,得4-氯-1,2-二-[邻苯二甲酰亚胺甲基]苯,为无色结晶形产物。
在0.5克分子上述产物中加入100毫升乙醇,0.1毫升水合肼,回流2小时,加入50毫升浓盐酸,继续回流2小时,冷却至0℃,过滤,滤液减压浓缩至干,得固体,稀盐酸重结晶,得4-氯邻苯二甲胺二盐酸盐。总收率48-55%
同法用相应取代邻二甲苯可合成一系列邻苯二甲胺衍生物二盐酸盐。
实施例4
反式4-苯基-5-氨基-1,3-二氧六环的制备
在高压釜中加入反式4-苯基-5-氯-1,3-二氧六环(0.5克分子),以甲醇500毫升为溶剂,通入2克分子氨气(过量),在100大气压下150℃氨化,常规处理,得顺式4-苯基-5-氨基-1,5-二氧六环。收率:72%,沸点:170-172℃/4mmHg。
上述顺式4-苯基-5-氨基-1,3-二氧六环与等当量右旋酒石酸成盐,在水中重结晶四次,用氢氧化钠液碱化,乙醚提取,用无水硫酸镁干燥,蒸除乙醚,减压蒸馏得[R∶R]-(-)-4-苯基-5-氨基-1,3-二氧六环。[α]16 D=(-)65.2°,滤液合并后,浓缩至干,用甲醇重结晶六次,20%氢氧化钠液碱化,乙醚提取,干燥,蒸除乙醚后,减压蒸馏,得[S∶S]-4-苯基-5-氨基-1,3-二氧六环,[α]16 D=+62。
实施例5
顺式二碘-二邻氯苄胺合铂(Ⅱ)络合物的制备
83.克(20毫克分子)氯亚铂酸钾溶液于200毫升水中,加入40克(240毫克分子)碘化钾饱和溶液,水浴加热至70℃,立即停止加热,避光放置1/2小时,过滤,滤液中加入邻氯苄胺44毫克分子,30℃搅拌至溶液变为无色。滤出沉淀,相继用水、乙醇、无水乙醇洗涤,真空干燥,得纯净的题述二碘-二邻氯苄胺合铂(Ⅱ)络合物,无需进一步精制即可得分析纯样品。如果需要,可将其溶于二甲基甲酰胺中,再加乙醇和水(1∶1)混合液,使结晶拆出,过滤,相继用水、乙醇、无水乙醇洗涤,真空干燥,收率80-84%
同法可制得表1中各相应化合物。
实施例6
顺式二氯-二(邻氯苯甲胺合)铂(Ⅱ)络合物的制备
实施例5制得的二碘化物5克,用少量水将其搅成糊状,取少于当量4%的硝酸银,将其溶于50毫升水中,搅拌下加入糊状物中,直至溶液中不能检出银离子(Ag+)为止。过滤除去碘化银,滤液中加入比等当量多10%的固体KCl,摇动,放置半小时,放入冰箱,半小时后过滤,相继用冰水、无水乙醇及无水乙醚淋洗,所得产品溶于二甲基甲酰胺中,用0.1N盐酸使沉淀析出,放入冰箱,2小时后过滤,沉淀用冰水、无水乙醇及无水乙醚洗,真空干燥,得淡黄色产物。
同法用相应原料可以制得表Ⅰ中各相应化合物。
实施例7
二氯二(对甲氧苯甲胺合)铂(Ⅱ)络合物的制备
4.2克氯铂酸钾(10毫克分子)溶于50毫升水中,过滤,除去可能的不溶物,滤液中加入对甲氧基苯甲胺(20毫克分子),30℃搅拌反应,直到溶液无色,滤出沉淀,将其溶于二甲基甲酰胺中,过滤,除去不溶的Magnus盐,加水使结晶析出,过滤,沉淀相继用水和乙醇淋洗,真空干燥。得产品。
实施例8
按实施例6的方法制得:二碘-二[R-(+)-α-苯乙胺合]铂(Ⅱ)络合物;二氯-二[R-(+)-α-苯乙胺合]铂(Ⅱ)络合物;二碘-二[S-(-)α-苯乙胺合]铂(Ⅱ)络合物;二氯-二[sl-α-苯乙胺合]铂(Ⅱ)络合物;
二碘-二[dl-α-苯乙胺合]铂(Ⅱ)络合物;
二氯-二[dl-α-苯乙胺合]铂(Ⅱ)络合物,以及列于表2中的其它相应化合物
实施例9
按实施例6的方法制得:
二碘-二[(R∶R)-(-)-4-苯-1,3-二氧六环胺基合]铂(Ⅱ)络合物;二氯-二[(R∶R)-(-)-4-苯基-1,3-二氧六环胺基合]铂(Ⅱ)络合物;二碘-二[(S∶S)-(+)-4-苯基-1,3-二氧六环胺基合]铂(Ⅱ)络合物;二氯-二[(S∶S)-(+)-4-苯基-1,3-二氧六环胺基合]铂(Ⅱ)络合物。
实施例10
按实施例6的方法制得二碘-二[呋喃甲胺合]铂(Ⅱ)络合物;二氯-二[呋喃甲胺合]铂(Ⅱ)络合物。
实施例11
按实施例6的方法用等当量相应的邻苯二甲胺为起始原料,制得表Ⅱ中所列的各化合物。
实施例12
按实施例6的方法制得相应的二碘-[二氨合]铂(Ⅱ)络合物,在其反应液中加入乙酸、氯乙酸、草酸、丙二酸、1,1-环丁二酸或羟基邻苯二甲酸等酸的银盐后,减压浓缩,可制得表Ⅳ中所列的相应酸根络合物。
实施例13
反-羟基-顺二氯-二[对氯苄胺合]铂(Ⅳ)络合物的制备
按实施例7的方法制得二氯-二(对氯苄胺合)铂(Ⅱ)络合物,加入过量过氧化氢,约过量30%,于水浴95℃反应分钟,析出沉淀,用水洗涤,用二甲基甲酰胺精制,得黄色固体。同法可制得表Ⅲ中所列的各化合物。
Claims (15)
2、根据权利要求1所述的化合物,其中当X代表阴离子配位体或二价阴离子配位体时限制条件是:Z不存在及X不是卤素则Ar1、Q1和R中至少一个基团必须含杂原子或含氧基团。
3、根据权利要求1所述的化合物,其中X表示丙二酸根或环丁-1,1-二酸根,Z为羟基或不存在。
4、根据权利要求2所述的化合物,其中含氧基团是羟基、羟甲基、羧甲基或羧基。
5、根据权利要求1所述的化合物,其中Ar1是具有羟基或羧基的芳族基团。
6、根据权利要求2或3所述的化合物,其中Ar2是杂芳族基团,该基中至少含一个以下杂原子,它们是氧、氮或硫原子。
7、根据权利要求4所述的化合物,其中Ar1上的取代基是羟基或羧基。
8、根据权利要求1所述的化合物,其中Q1是饱和脂族杂环,该环上至少有一个杂原子是氧原子或氮原子。
9、根据权利要求1至6中任一项所述的化合物,其中芳族或杂芳族基团选自苯基、萘基、呋喃基、吡啶基、吡咯基、噻吩基和菲基。
10、根据权利要求1至6中任一项所述的化合物,其中Q1和Q2可以相同或不同,各自为C1-5亚烷基或任意含一、二或更多个氧、氮、或硫原子的脂族5至6元杂。
12、含有权利要求1至11中一项定义的至少一种化合物作为活性成份以及药学上可接受的佐剂的药物组合物。
13、权利要求1至11中任一项定义的化合物用作药物以治疗肿瘤,特别是用于治疗睾丸、膀胱和子宫癌。
14、权利要求1至11中任一项定义的化合物用于制备肿瘤药物和制剂。
15、本申请中描述及例举的所有化合物。
Priority Applications (3)
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CN87104027A CN1016693B (zh) | 1987-06-05 | 1987-06-05 | 新顺铂铬合物的制备方法 |
GB8813192A GB2209161B (en) | 1987-06-05 | 1988-06-03 | Cis-platinum-diamine complexes, anti-tumorous compositions containing them, and methods for their preparation |
US07/203,041 US5198564A (en) | 1987-06-05 | 1988-06-06 | Cis-platinum-diamine complexes and antitumorous compositions containing them, and process for their preparation |
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CN87104027A CN1016693B (zh) | 1987-06-05 | 1987-06-05 | 新顺铂铬合物的制备方法 |
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CN1016693B CN1016693B (zh) | 1992-05-20 |
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GB (1) | GB2209161B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100411628C (zh) * | 2000-05-18 | 2008-08-20 | 阿诺麦德股份有限公司 | 空间位阻的铂配位化合物与非铂抗癌剂的组合及其应用 |
CN105541920A (zh) * | 2015-12-04 | 2016-05-04 | 罗梅 | 一种手性(R)-α-苯乙胺铂配合物晶体 |
CN105753922A (zh) * | 2016-02-05 | 2016-07-13 | 南开大学 | 用于肿瘤治疗四价铂糖基配合物及其制备方法 |
Families Citing this family (4)
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US7138520B2 (en) * | 2003-01-13 | 2006-11-21 | Massachusetts Institute Of Technology | Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same |
EP1988925A2 (en) * | 2006-02-24 | 2008-11-12 | Mallinckrodt, Inc. | Bifunctional resorcinol, thioresorcinol, and dithioresorcinol derivative metal chelating conjugates |
DE102007060918A1 (de) | 2007-12-14 | 2009-06-18 | Rheinisch-Westfälische Technische Hochschule Aachen | Verfahren zur Herstellung von cycloplatinierten Platin-Komplexen, durch dieses Verfahren hergestellte Platin-Komplexe sowie deren Verwendung |
US10533029B1 (en) * | 2018-09-18 | 2020-01-14 | King Fahd University Of Petroleum And Minerals | Anticancer trans-diaminoplatinum(II) complexes of selenones |
Family Cites Families (5)
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US4053587A (en) * | 1973-04-13 | 1977-10-11 | Research Corporation | Method of treating viral infections |
GB2131020B (en) * | 1982-11-25 | 1986-10-01 | Gerald Edward Adams | Improvements relating to compounds useful in radiotherapy or chemotherapy |
US4565884A (en) * | 1983-05-10 | 1986-01-21 | Andrulis Research Corporation | Bis-platinum complexes as antitumor agents |
ATE63919T1 (de) * | 1984-06-27 | 1991-06-15 | Johnson Matthey Plc | Platinkoordinationsverbindungen. |
NO860509L (no) * | 1985-02-23 | 1986-08-25 | Asta Werke Ag Chem Fab | Tumorhemmende (1,2-difenyl-etylendiamin)-platin(ii)-komplekser. |
-
1987
- 1987-06-05 CN CN87104027A patent/CN1016693B/zh not_active Expired
-
1988
- 1988-06-03 GB GB8813192A patent/GB2209161B/en not_active Expired - Lifetime
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100411628C (zh) * | 2000-05-18 | 2008-08-20 | 阿诺麦德股份有限公司 | 空间位阻的铂配位化合物与非铂抗癌剂的组合及其应用 |
CN105541920A (zh) * | 2015-12-04 | 2016-05-04 | 罗梅 | 一种手性(R)-α-苯乙胺铂配合物晶体 |
CN105753922A (zh) * | 2016-02-05 | 2016-07-13 | 南开大学 | 用于肿瘤治疗四价铂糖基配合物及其制备方法 |
CN105753922B (zh) * | 2016-02-05 | 2019-07-02 | 南开大学 | 用于肿瘤治疗四价铂糖基配合物及其制备方法 |
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Publication number | Publication date |
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GB2209161B (en) | 1991-10-02 |
US5198564A (en) | 1993-03-30 |
CN1016693B (zh) | 1992-05-20 |
GB8813192D0 (en) | 1988-07-06 |
GB2209161A (en) | 1989-05-04 |
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