CN1202115A - 含气金属配合物作为超声造影剂的应用 - Google Patents
含气金属配合物作为超声造影剂的应用 Download PDFInfo
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- CN1202115A CN1202115A CN96198254A CN96198254A CN1202115A CN 1202115 A CN1202115 A CN 1202115A CN 96198254 A CN96198254 A CN 96198254A CN 96198254 A CN96198254 A CN 96198254A CN 1202115 A CN1202115 A CN 1202115A
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- metal complex
- complex
- acid
- coordination
- metal
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Abstract
本发明涉及含气体之金属配合物在超声诊断、特别是功能和鉴定诊断中的应用。
Description
本发明涉及在权利要求书中所表征的主题,即其中配位至少一个原子或分子的金属配合物在超声诊断中的应用,而所述原子或分子在从配合物上解离后为气体形式的。
在病理状况诊断中,超声诊断的使用正逐渐增加,这是因为与X-射线诊断或者放射诊断法相比,它可以避免使用非常麻烦的离子线,而且与磁共振成象相比是经济的。
在此情况下,成象时要利用组织或者体液之不同声学性质(所谓的声密度)。
通过在检查区域中引入与该身体组织/体液之声密度明显不同的介质(造影剂),可提高超声造影。气体即是该种介质。因此,大多数的超声造影剂基本上基于包含气泡和/或含气体之物质的悬浮液。
在最简单的情况下,可通过如摇动或者声辐射的方法在大多数含水悬浮介质中引入小气泡,添加剂如表面活性剂或者增粘剂可选择性地使小气泡稳定在悬浮介质中。例如EP 0 077 752描述了此类造影剂。
其他造影剂的制备由其中配入“预制”之气泡的固态载体开始。该气泡在用合适的稀释剂重新悬浮后释放出来,并产生可使用的气泡悬浮液(见例如EP 0 122 624)。
在最简单的情况下,气泡可如上所述通过表面活性剂(EP 0 077752)来稳定。其他制备方法由脂质双层(WO 94/28780)开始。但是如EP 0 327 490 B1或者EP 0 441 468中所述,也可通过或多或少呈柔性的聚合物壁来确保稳定作用。
除糖类(EP 0 052 575)外,所述(EP 0 357 163)的固态载体也可包括主体-客体配合物,该配合物可在使用前溶解或者悬浮或者乳化在合适的载体中,并产生可使用的气泡分散液。
气体也可仅在制备制剂时产生。这样,可从碳酸盐和碳酸氢盐中释放出酸诱导的二氧化碳,而且如此产生的气泡可用各种方法稳定(EP 0077 752、WO 91/09629)。
气泡也可在体内通过温度诱导的方式例如由液态低沸点前体物质来产生。此类造影剂见EP 0 327 490或者WO 91/09629中所述,其中,由体温活化的向气态的转变可由液体前体物质在体内进行。
其中气泡呈准游离形式存在的造影剂的缺点是,在施用于血流后,气泡存留在血管空间中,因此使在该区域中的诊断仍非常有限。通过例如聚合物壳(EP 0 327 490)稳定的气泡也可通过吞噬作用被网状内皮系统细胞吸收,因此也可进行细胞内空间的诊断。
在诊断间隙空间时,已知的造影剂表现得非常不合适。细胞内空间的诊断限制在包含巨噬细胞的身体区域中[肝(Kupffer细胞)、淋巴结(固定的巨噬细胞)和肺(肺泡巨噬细胞)]。具体而言,已知的造影剂不适合用于功能和鉴别诊断中。
因此,本发明的目的是提供可克服上述缺陷的造影剂,即找出适合于间隙空间或者整个细胞内空间之诊断、特别是适合于功能和鉴别诊断的造影剂。
该目的由本发明来解决。
发现以下水溶性金属配合物特别适合于用作超声诊断的造影剂,所述配合物中配位至少一个原子或者分子,该原子或者分子在从所述配合物上解离后为气态的。
在此情况下,气体的释放取决于所选的配合物以及使用于口服或者血管给药之后,并可通过pH值、温度、氧化或还原反应、以及酶反应来控制。
各种包含气体的金属配合物的此种性质使它们可特别被用于功能和鉴别诊断中。其结果是得到新型的超声造影剂,该造影剂根据所要诊断之身体区域的生理或者病理状况以可控的方式释放气体,并因而使所希望的诊断成为可能。
根据本发明,常规的气泡形成以及选择性的气泡形成在血管系统中都是可能的,常规的气泡形成以血管中占主导地位的条件,如pH值、温度、酶、生理氧化剂、以及还原剂为基础,而选择性气泡形成与限于局部存在的生理或者病理参数或者功能有关。因此,作为疾病征象之症状和病因的病理变化的检查是可能的。
根据本发明,可使用由中心金属原子、至少一个配位体、以及至少一个在正常条件下为气体物质的分子组成的配合物。
虽然实际意义上的配位气体分子可被视作配位体,但是以下术语“配位体”只是用于表示在游离状态下不是气体的分子部分。
众所周知,金属配合物取决于配位数和氧化数可有许多不同的结构。观察到的配位数在2-10之间,其中,已知的金属配合物中的大多数具有4-7的配位数。
该配合物的结构基本上通过配位数来决定。严格的线性、四面体形、平行四角形、三角双锥形、和八面体形配合物,以及扭曲的配合物几何形都是可能的,由此各气体分子或者气体前体(例如在氢化配合物的情况下)可端连、端连-桥连、侧连或者侧连-桥连配位。
文献中已描述了带有各种气体的金属配合物。根据本发明,在此情况下,可使用作为气体前体或者产生CO、CO2、H2、N2、H-、O2的配合物,其中N2是特别优选的。
其他可能的气体配位体产生不饱和的烃(烯或炔烃)或它们的卤化物,特别是氟化衍生物。例如,可提及的有乙炔(C2H2)、乙烯(C2H4)、丙炔(C3H4)和丙二烯(C3H4)。此类烃以及它们的衍生物也可从包含相应去质子形式的气体前体的配合物中释放。
元素周期表中的第二至七族的所有金属基本上都可用作金属(中心)原子,这是因为它们具有一个空轨道,可用于吸收配位体的自由电子对。典型的金属配合物特别是副族元素,这是因为它们中有自由的d-或者f-轨道用于配位键合。
中心原子通常具有多个氧化态。标准的配合物中心原子是原子序数为21-30、39-48、57-81(包括镧系金属)和89-103(包括锕系金属)的过度态金属。特别合适的是以下族的金属原子:
(i)铜族(Cu、Ag、Au)
(ii)锌族(Zn、Cd、Hg)
(iii)钪族(Sc、Y、La)
(iv)钛族(Ti、Zr、Hf)
(v)钒族(V、Nb、Ta)
(vi)铬族(Cr、Mo、W)
(vii)锰族(Mn、Tc、Re)
(viii)铁族(Fe、Co、Ni)或者
(ix)铂族(Os、Ru、Rh、Ir、Pd、Pt),其中,优选带有铁和铂族元素的气体配合物。
但是,没有自由轨道的金属如主族的金属也基本上是合适的。作为形成气体的组份,例如氢离子可如盐一样连接在该化合物上,并在质子存在时产生H2气泡。
所有带有至少一个自由电子对的原子或者分子都可用作配位体。在此情况下,也存在自由电子相对于不只一个而是几个中心原子(桥连配位体)的可能性。然而在例如O2-或者N3-配合物中观察到的在配位体和金属原子之间的多重键也是可能的。
而且,也存在占据多个配位点的配位体(所谓的多配位基配位体)。对此,该配位体分子中必须具有几个供体点。因此,有二配位基(乙二胺,草酸化)、三配位基(二乙基三胺)、四配位基(三乙基四胺)、六配位基(EDTA、CDTA)、八配位基(DTPA)和十配位基(TTHA)配位体。此类配位体也可涉及只带有它们所能连接的最多配位点的一部分的配合物。
通过以各种方式安排不同的配位体,可形成具有cis-trans-异构体和光学异构体的配合物。
能够配合的配位体例如有:
H-(氢)、F-(氟)、Cl-(氯)、Br-(溴)、I-(碘)、H2O(水)、OH-(氢氧)、O2-(氧)、O2(二氧)、ONO-(亚硝酸基)、O2 2-(过氧)、THF(四氢呋喃)、OCN-(氰氧基)、SCN-(硫氰基)、S2-(硫)、S2 2-(二硫)、SH-(巯基)、N2(二氮)、N3 -(叠氮)、NH3(氨基)、NH2 -(酰胺基)、NH2-(亚氨基)、N3 -(次氮基)、烯、二烯、三烯、乙二胺、二乙基三胺、三乙基四胺、NO+(亚硝酰基)、NO2 -(硝基)、NC-(异氰基)、NCR(腈)、NCO-(异氰氧基)、NCS-(异氰硫基)、py(吡啶)、dipy(二吡啶基)、PF3(三氟化磷)、PR3(膦烷(Phosphan))、diphos(二膦烷)、AsR3(胂烷(Arsan))、diars(二胂烷)、甲硼烷、氮杂甲硼烷、硼二环烷、硼二环[3.3.1]壬烷、硼酸(Boronsauren)、HBO2C6H4、HIMDA(N-羟基乙基亚氨基二乙酸)、HEDTA(N-羟基乙二胺-N,N′,N′-三乙酸)、NTA(次氮基三乙酸)、EDTA(乙二胺四乙酸)、CDTA(环己二胺四乙酸)、PDTA(戊二胺四乙酸)、EGTA(1,2-乙二醇-O,O′-二(2-氨基乙基)-N,N,N′,N′-四乙酸)、DTPA(二乙基三胺五乙酸)、TTHA(三乙基四胺-N,N,N′,N″,N,N-六乙酸)、四氮杂环十二烷(EP 0 255 471)的衍生物、配合酸(DE 34 01 052和EP 0 071564)、DTPA的衍生物(EP 0 405 704)、蛋白质、肽、卟啉衍生物(WO 94/07894)、Podanden[开链冠醚和杂冠醚(N、S、P、As)]、Coronanden[单环冠醚和杂冠醚(N、S、P、As)]、Cryptanden[寡环冠醚和杂冠醚(N、S、P、As)]、Dendrimeren的金属配合物(WO 95/17451)、CH3-(甲基)、C2H-(乙炔基)、C2H4(乙烯)、C3H5-(烯丙基)、C4H6(丁二烯)、C5H5-(环戊二烯基)、C5H6(环戊二烯)、C6H6(苯)、C6H8(环己二烯)、C7H7 +(环庚三烯鎓)、C7H8(环庚三烯)、C7H10(环更二烯)、C8H12(环辛二烯)、CO(羰基)、OX2-(草酰基2-)、CN-(氰基-C)、CNR(异腈)、-CNO-(雷酰-C)。
根据本发明,优选的配位体能够按以下方式直接或间接地影响与气体配位体的键连:即在生理状况下释放气体。气体的释放可以诱导,例如根据所在位置的pH,多配位基配位体能够产生另外可配位的电子对。如果发生配位,可进行气体配位体如N2的置换。该多官能配位体是例如EDTA、CDTA、PDTA、ox、以及包含双键的配位体如烯、二烯或三烯。
其他根据pH值诱导气体释放的可能方式是通过中心原子之pH依赖性的氧化还原电势。通常情况下,在氧化后,中心原子失去键合气体组份的能力。对于二氮分子尤为如此。特别是铁和铂族金属(如Fe、Ru、Os)具有pH依赖性的氧化还原电势,使得可通过生理条件下存在或者同时或随后给药的氧化剂来实现所述释放。
也可通过酶如酯酶来改性“配位体臂”,以此提供可配位的新基团。如果该新产生的基团比气体组份具有更高的对中心原子的亲和性,该新的基团则可通过配位置换中心原子中的反衬气体组份。
除二氮配合物外,主要是氢化配合物也可用于本发明,该配合物在文献中已被大量描述。同样,该配合物可用作根据本发明的超声造影剂。在此,气体组份并不直接释放,而只是在与质子反应之后才释放。在氢化配合物中,在含水介质中缓慢反应的配合物如Li[AlH(OC)(CH3)3]或者Selectride(R)如KB[CH(CH3)C2H5]3H是特别适合的。
在含水介质中,稳定的钌-氢配合物是合适的。此类配合物描述于例如Rodriguez等人在An.Quim.Int.Ed.92(3)(1996)131-133中的文章。除金属离子外,这些配合物通常还包含作为配位体的硼-氢基团(硼氢化物)。根据本发明,可使用如下的钌配合物:[RuH(η6-C6H4O2BO2C6H4)(PCy3)2]、[RuH(H2BBN)(PCy3)2]、[RuH(H2BBN)(CO)(PCy3)2]、[RuH(H2BBN)(H2)(PCy3)2]、[RuH(OH)(PCy3)2(H2O)]、[RuH(OH)(H2)(PCy3)2(H2O)]、[RuH(OH)(H2)(PCy3)2(H2O)],其中,η6-C6H4O2BO2C6H4代表基团,该基团衍生自基本儿茶酚结构。在该配合物中,两个儿茶酚环之一通过η6-键连接在金属上。Cy代表环己基、苯基或者苄基;H2BBN代表9-硼二环[3.3.2]壬烷。
另外,配位体具有至少一个α-氨基酸或者一个N-酰基-α-氨基酸的配合物也是合适的。此类可用于本发明中的配合物描述于K.Severin等人在Z.Anorg.Allg.Chem 622(1966)562-570中的文章。例如,可提及的有[RuCl(O2CCHRNHCOR′(CO)(PPh3)2]或者[RuH(O2CCHRNHCOR′(PPh3)2],其中R指氢原子或者异丁基,R′是甲基或苯基,以及铱配合物[IrH2(O2CCH2NHCOPh(PPh3)2]。
为进行呼吸链或者柠檬酸循环,生理氧化还原系统在细胞内是必须的。在象级联般进行的呼吸链中,形成ATP。呼吸链的底物是还原辅酶如NAD和NADH。必须的酶位于线粒体膜中。在进行细胞氧化还原反应时,通常需要作为酶的氧化酶或者还原酶、H-或者电子转移辅酶、以及底物。
辅酶和底物通常具有pH依赖性的氧化还原电势。取决于影响氧化还原电势的现存浓度,也可进行与非生理或者病理物质的氧化还原反应,例如也与带有气体或气体形成配位体之配合物中的这些原子。
特别是通过氧化反应,此类配合物失去它们与配位气体如氮的键合能力,因此可用超声来检测。
例如,通过可生理合适的氧化剂,配合物之溶酶体内的氧化反应是合适的。
其他生理合适的可用于本发明中的氧化或还原剂列于下表中:
标准电势,pH=7
乙醛/乙醇 | -0.20 V |
草酸乙酯/马来酸 | -0.17 V |
富马酸/琥珀酸 | -0.03 V |
脱氢抗坏血酸/抗坏血酸 | +0.06 V |
细胞色素b | +0.07 V |
泛氢醌/泛醌 | +0.10 V |
细胞色素c | +0.25 V |
细胞色素a | +0.29 V |
上述生理上无害的氧化和还原剂可在本发明之造影剂制剂之后或者同时给药。它们可血管内或者局部注射至身体中待检查的部位。该过程也可反过来。
除通过使用氧化还原系统使气体从配合物中释放外,当然也可使用在体内已存在的系统。
在此情况下,在血管内的空间中,可考虑基本氧化还原系统FeII/FeIII和CuI/CuII。
基本上,除pH外,配位体对中心原子的氧化或还原性质具有非常强的影响也是可接受的。因此,如果通过氧化还原反应释放气体是通过在体内的反应物来触发的,那么并非所有的配位体都是适合的。在此情况下,产生电子的配位体稳定低氧化态并产生氧化还原电势,则通常也是可接受的。但是吸电子的配位体稳定更高的氧化态并减低氧化还原电势。
配合物的几何形状对氧化还原电势也有影响。因此,对于在体内条件下控制气体的释放,存在很多的可能性。
配位体以及几何形状对氧化还原电势的影响可通过以下实施例来说明。对于RuII(NH3)5N2 +配合物来说,使用环形电压计在几个研究中测定pH7.0时的氧化电势为860mV(NHE),而287mV的电势表明与Ru(EDTA)N2 2-非常相似(Diamantis和Dubrawski;Inorg.Chem.22,(1983)1934/46)。
根据本发明之释放气体的金属配合物还可用于结构特异性的超声检测。为此目的,可使用具有结构特异性结合位如除配位体之外的抗体、受体、肽、或者核酸的配合物。在如上所述完成结合后,给予可使气体从配合物中释放出来的合适的氧化或还原剂。给予氧化/还原剂应在配合物的非特异性结合部分已通过例如肾滤被从身体中消除时适当地进行。上述释放气体的配合物或带有可被解离之气体组份的分子可按现有技术中已知的方法配制成超声造影剂。
在此情况下,取决于给药的方法,含水溶液、乳液或者悬浮液通常可包含在制药业中通常使用的辅剂。但是上述造影剂也可作为试剂盒来提供,其中,配合物和悬浮剂或溶剂储存在单独的容器中,并仅在给药之前制备待给药的造影剂。制备该造影剂的更为详细的信息可从现有技术中汇集,例如EP 0 071 564。
根据本发明的造影剂通常包含10-2-10-6mol/ml的含气体的金属配合物,并以10-2-10-8mol/kg体重的剂量给药。根据诊断问题,可静脉或口服给药。
以下实施例用于说明本发明的主题,而本发明并非限制于这些实施例中。实施例1
[RuII(NH3)5N2]Br2的合成根据Armor和Taube描述的方法(J.Am.Chem.Soc.92,6170 ff.)进行。将0.2g[RuIII(NH3)5Cl]Cl2溶解在100ml的0.1N HCl中。在该溶液中通过两个含有90ml 1.25%CrIICl2溶液的洗瓶引入笑气(N2O),各10分钟。在反应料中加入22ml 1.25%CrIICl2溶液后,再引入笑气1小时,然后引入氧气30分钟。借助40g溴化钠,过夜沉淀[RuII(NH3)5N2]Br2。离心该沉淀物,用甲醇和丙酮洗涤,然后干燥。实施例2
与实施例1类似地合成[RuII(NH3)5N2]BF4,其中,用NaBF4沉淀出所希望的配合物。实施例3
将10mg实施例1中制备的配合物加至10ml 0.01%H2O2溶液(pH4)中。用诊断用超声仪(HP 77020E)和5MHz声头观察B-像的变化。在平均的声输出时,在短暂的反应时间后可观察到气泡的升起。实施例4
100mg实施例1中制备的氮配合物称量至GC管中。将管中的气体换成氦气,在加入10ml 5%Ce(IV)溶液的前或后,用气相色谱研究头部空间。使用WLD-检测仪,通过添加氧化剂可清楚地证明配位的氮被释放出来。实施例5
分别将2mg实施例2中制备的配合物溶解在0.5ml水中,然后分别加至0.5ml 0.01%H2O2溶液(pH2、4和6)中。在反应10分钟后,用肉眼显微镜观察气泡的产生。
Claims (30)
1、其中配位至少一个原子或分子的金属配合物在超声诊断中的应用,所述原子或分子在从所述配合物上解离后为气体形式的。
2、如权利要求1的金属配合物应用,其是制备用于超声诊断的造影剂。
3、如权利要求1的金属配合物应用,其是用于超声功能诊断和鉴定诊断。
4、如权利要求3的金属配合物应用,其特征在于,通过pH或温度的变化使形成气体的配位体在体内从金属配合物中释放。
5、如权利要求3的金属配合物应用,其特征在于,通过酶反应使形成气体的配位体在体内从金属配合物中释放。
6、如权利要求3的金属配合物应用,其特征在于,通过氧化还原反应使形成气体的配位体在体内从金属配合物中释放。
7、如权利要求6的金属配合物应用,其特征在于,氧化剂与金属配合物同时或者随后注射。
8、如权利要求7的金属配合物应用,其特征在于,注射乙醛/乙醇、草酸乙酯/马来酸、富马酸/琥珀酸、脱氢抗坏血酸/抗坏血酸、细胞色素b、泛氢醌/泛醌、细胞色素c或细胞色素a作为氧化剂。
9、用于超声诊断的介质,其包含其中配位至少一个原子或分子的金属配合物,所述原子或分子在从所述配合物上解离后为气体形式的。
10、如权利要求1的金属配合物应用,其特征在于,在金属上配位CO、CO2、H2、N2、H-、O2和/或C2H4、C2H2、丁二烯、丙烯、甲基乙炔、丙二烯,其任选地完全或部分被氟化。
11、如权利要求1的金属配合物应用,其特征在于,包含铜族、锌族、钪族、钛族、钒族、铬族、锰族、铁族或者铂族元素作为金属。
12、如权利要求1的金属配合物应用,其特征在于,包含铁族或铂族元素作为金属。
13、如权利要求1的金属配合物应用,其特征在于,在金属上配位以下至少一个基团作为配位体:H-、F-、Cl-、Br-、I-、H2O、OH-、O2-、O2、ONO-、O2 2-、THF、OCN-、SCN-、S2-、S2 2-、SH-、N2、N3 -、NH3、NH2 -、NH2-、N3-、烯、二烯、三烯、NO+、NO2 -、NC-、NCR、NCO-、NCS-、py、dipy、PF3、PR3、diphos、AsR3、diarsan、甲硼烷、氮杂甲硼烷、硼二环烷、硼二环[3.3.1]壬烷、硼酸、HBO2C6H4、N-羟基乙基亚氨基二乙酸、N-羟基乙二胺-N,N′,N′-三乙酸、次氮基三乙酸、乙二胺四乙酸、环己二胺四乙酸、戊二胺四乙酸、1,2-乙二醇-O,O′-二(2-氨基乙基)-N,N,N′,N′-四乙酸、二乙基三胺五乙酸、三乙基四胺-N,N,N′,N″,N,N-六乙酸、四氮杂环十二烷、蛋白质、肽、卟啉、Podands、Coronand、Cryptand、Dendrimere、CH3 -、C2H-、C2H4、C3H5 -、C4H6、C5H5 -、C5H6、C6H6、C6H8、C7H7 +、C7H8、C7H10、C8H12、CO、OX2-、CN-、CNR、-CNO-。
14、如权利要求1的金属配合物应用,其特征在于,在金属原子上配位至少一个α-氨基酸作为配位体。
15、如权利要求1的金属配合物应用,其特征在于,在金属原子上配位至少一个N-酰基-α-氨基酸作为配位体。
16、如权利要求1的金属配合物应用,其特征在于,所述金属配合物是氢化配合物。
17、如权利要求16的金属配合物应用,其特征在于,所述金属配合物是钌氢配合物。
18、如权利要求17的金属配合物应用,其特征在于,所述钌氢配合物包含硼氢基团。
19、如权利要求17的金属配合物应用,其特征在于,所述钌氢配合物是[RuH(η6-C6H4O2BO2C6H4)(PCy3)2],Cy代表环己基、苯基或者苄基。
20、如权利要求17的金属配合物应用,其特征在于,所述钌氢配合物是[RuH(H2BBN)(PCy3)2],Cy代表环己基、苯基或者苄基。
21、如权利要求17的金属配合物应用,其特征在于,所述钌氢配合物是[RuH(H2BBN)(CO)(PCy3)2],Cy代表环己基、苯基或者苄基。
22、如权利要求17的金属配合物应用,其特征在于,所述钌氢配合物是[RuH(H2BBN)(H2)(PCy3)2],Cy代表环己基、苯基或者苄基。
23、如权利要求17的金属配合物应用,其特征在于,所述钌氢配合物是[RuH(OH)(PCy3)2(H2O)],Cy代表环己基、苯基或者苄基。
24、如权利要求17的金属配合物应用,其特征在于,所述钌氢配合物是[RuH(OH)(H2)(PCy3)2(H2O)],Cy代表环己基、苯基或者苄基。
25、如权利要求17的金属配合物应用,其特征在于,所述钌氢配合物是[RuH(OH)(H2)(PCy3)2(H2O)],Cy代表环己基、苯基或者苄基。
26、如权利要求17的金属配合物应用,其特征在于,所述金属配合物是[RuH(O2CCHRNHCOR′(PPh3)2],R指氢原子或者异丁基,而R′是甲基或苯基。
27、如权利要求1的金属配合物应用,其特征在于,所述金属配合物是[RuCl(O2CCHRNHCOR′(CO)(PPh3)2],R指氢原子或者异丁基,而R′是甲基或苯基。
28、如权利要求1的金属配合物应用,其特征在于,所述金属配合物是[IrH2(O2CCH2NHCOPh(PPh3)2]。
29、如权利要求1的金属配合物应用,其特征在于,所述金属配合物是[Ru11(NH3)5N2]Br2。
30、如权利要求1的金属配合物应用,其特征在于,所述金属配合物是[Ru11(NH3)5N2](BF4)2。
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KR19990067548A (ko) | 1999-08-25 |
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