CN1125905A - 用作造影剂的2-吡啶基亚甲基多氮杂大环膦酸及其络合物和衍生物 - Google Patents
用作造影剂的2-吡啶基亚甲基多氮杂大环膦酸及其络合物和衍生物 Download PDFInfo
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- CN1125905A CN1125905A CN94192527.7A CN94192527A CN1125905A CN 1125905 A CN1125905 A CN 1125905A CN 94192527 A CN94192527 A CN 94192527A CN 1125905 A CN1125905 A CN 1125905A
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Abstract
本发明公开了2-吡啶基亚甲基多氮杂大环膦酸化合物及其衍生物,其可与Gd,Mn或Fe离子形成惰性络合物。络合物的总电荷可以是不同的,以改变体内生物定位。该络合物可用作用于诊断目的的造影剂。
Description
本发明涉及在磁共振成像(MRI)中用作造影剂的配位体2—吡啶基亚甲基多氮杂大环膦酸及其络合物和衍生物。为了更好地理解本发明,在下述部分提供了有关MRI的简要背景。
MRI是一种非侵袭性诊断技术,其可在动物体内,尤其在人体内形成软组织的高分辨截面像。此技术基于特定原子核(例如水质子)的性质,该原子核具有一种在外加磁场中排列的磁矩〔由数学等式定义;见G.M.Barrow,Physical Chemistry,3rd Ed.,McGraw—Hill,NY(1973)〕。一旦排列后,这一平衡态可通过施加一个外部射频(RF)脉冲而被破坏,射频脉冲使质子倾斜出磁场的排列。当RF脉冲终止后,核返回到其平衡态,发生此过程所需的时间称为驰豫时间。弛豫时间由两个参数组成,即自旋—晶格(T1)和自旋—自旋(T2)弛豫。正是这些弛豫的数值提供了有关分子组织的程度和质子与周围环境相互作用的信息。
由于活组织的水分含量很大,并且在组织类型中存在含量和环境的差异,所获得的生物组织的诊断性成像反映了质子密度和弛豫时间。被检组织中质子的弛豫时间(T1和T2)差异越大,所获得图像的对比度越大〔例如,J.Magnetic Resonance 33,83—106(1979)〕。
已知具有对称电子基态的顺磁螯合物可大大影响并置水质子的T1和T2弛豫率,并且螯合物的这一效应部分与产生磁矩的不成对电子的数目有关〔例如,Magnetic Resonance Annual,231—266,Raven Press,NY(1985)〕。而且也已知了当将这种顺磁螯合物给予活动物时,其对不同组织的T1和T2的影响可在磁共振(MR)成像中直接观察到,而且在螯合物定位区域观察到对比度增加。因此已建议可给予动物稳定的、无毒的顺磁螯合物,从而增加通过MRI所获得的诊断性信息〔例如,Frontiers of Biol.Energetics 1,752—759(1978);J.Nucl.Med.25,506—513(1984);Proc.of NMR Imaging Symp.(Oct.26—27,1980);F.A.Cotton et al.,Adv.Inorg.Chem.634—639(1966)〕。以此方式使用的顺磁金属螯合物称为造影增强剂或造影剂。
当进行MRI造影剂的设计时,可考虑许多顺磁金属离子。但实际上,最有用的顺磁金属离子有钆(Gd+3),铁(Fe+3),锰(Mn+3)和(Mn+2),以及铬(Cr+1),因为这些离子可通过其大的磁矩对水质子施加最大的效应。如果以非络合的形式(如GdCl3)存在,这些金属对动物体有毒,因此避免使用其简单盐形式。所以,有机螯合剂(也称配位体)的一个基本作用是使顺磁金属对动物体无毒,同时保持其对周围水质子的T1和T2弛豫率的适当影响。
MRI领域的现有技术很广泛,下列概要,不意在尽数,仅提供本领域的概述和其它结构上可能类似的化合物。美国专利4,899,755公开了一种使用Fe+3—亚乙基—二(2—羟基苯基甘氨酸)络合物及其衍生物来改变动物体肝或胆小管中质子NMR弛豫时间的方法,并且表明在各种其它化合物中,可能使用的为吡啶大环亚甲基羧酸。美国专利4,880,008(美国专利4,899,755的部分继续申请)公开了大鼠肝组织的另一些成像数据,但是没有指出任何别的络合物。美国专利4,980,148公开了用于MRI的钆络合物,其为无环化合物。C.J.Broan等〔J.Chem.Soc.,Chem.Commun.,1739—1741(1990)〕描述了一些双官能大环膦酸化合物。C.J.Broan等〔J.Chem.Soc.,Chem.Commun.,1738—1739(1990)〕描述了三氮杂双环化合物。L.K.Adzamli等〔J.Med.Chem.32,139—144(1989)〕描述了用于NMR成像的钆络合物的无环膦酸衍生物。
目前,美国市售的唯一造影剂是钆与二亚乙基三胺五乙酸的络合物(Schering的DTPA—GD+3—MegnevistTM)和DO3A衍生物〔1,4,7—三(羧甲基)—10—(2—羟丙基)-,4,7,10—四氮杂环十二烷〕钆(Squibb的ProhanceTM)。MegnevistTM和ProhanceTM被认为是非特异性/灌注剂,因为其可自由分布在细胞外液,随后通过肾脏系统而被有效地消除。已证明MegnevistTM在脑损伤的诊断中特别有用,因为伴随而来的血脑屏障的崩溃使造影剂可灌注到受损区域。除了MegnevistTM以外,Guerbet为市售的一种大环灌注剂〔1,4,7,10—四(羧甲基)—1,4,7,10—四氮杂环十二烷〕钆(DotaremTM),它仅在欧洲有售。ProhanceTM比MegnevistTM的副作用小。许多其它潜在的造影剂正处于不同的发展阶段。
其中:R是OH,C1—C5烷基或—O—(C1—C5烷基);
R1是OH或OCH3;
R2是NO2,NH2,异硫氰酸根合,脲氨基,硫脲氨基,马来酰亚氨基,溴乙酰氨基或羧基;
其中R1和R2如前定义。
当上述通式(I)的配位体中:
所有T等于P(O)ROH,其中R是OH,或者其药学上可接受的盐时,该配位体称为PD3P:
所有T等于COOH,或者其药学上可接受的盐时,此配位体称为PD3A;
所有T等于P(O)ROH,其中R是—O—(C1—C5烷基),或者其药学上可接受的盐时,该配位体称为PD3(O—Alk)P;和
所有T等于P(O)ROH,其中R是C1—C5烷基,或者其药学上可接受的盐时,此配位体称为PD3(Alk)P。
本发明的络合物可设计成为具有特定的总电荷,以有利地影响体内生物定位和成像对比度。例如,当金属离子为+3时,可得到下列:
通式(I)是PD3P时,总电荷为—3,其可用作钙化组织造影剂;
通式(I)具有两个等于—CH2—PO3H2的T以及一个T具有COOH时,总电荷为-2,其可用作钙化组织造影剂;
通式(I)具有一个等于—CH2—PO3H2的T以及另一个T具有COOH时,总电荷为-1,其可用作钙化组织造影剂;
通式(I)具有一个等于—CH2—PO3HR的T,其中R为是—O—(C1—C5烷基)或C1—C5烷基,以及两个T具有COOH;或者所有三个T等于—CH2—PO3HR,其中R是—O—(C1—C5烷基)或C1—C5烷基;或者所有三个T等于—CH2—COOH(PD3A)时,总电荷为0,其可用作全身灌注、血液、大脑或肝造影剂。
该络合物可制成可对动物给药的一种药学上可接受的形式。
当一个T是
R1和R2如前所定义时,该化合物为双官能配位体/络合物,并可通过R2连接一个生物活性分子。
通式(I)化合物为了命名的目的而编号为
本发明的一个方面是关于通过对顺磁螯合物进行合成修饰,开发能位点特异性地释放造影剂到预计组织的造影剂。其优点是,与非特异性灌注产生的对比度相比,基于组织亲和性的有关区域的对比度提高,其中非特异性灌注可对胞外试剂明显或不明显。通式(I)配位体的特异性可通过调节总电荷和络合物的亲脂性来控制。该络合物电荷的总体范围为如上所述的-3至0。例如,对于具有3个PO3H2基团(PD3P)的络合物而言,总电荷为高负性,预计骨骼可吸收;而当总电荷是0(中性,PD3A,PD3(O—Alk)P和PD3(Alk)P),络合物具有穿过血脑屏障的能力,正常大脑吸收是可能的。出乎意料地,对于总电荷为0的〔PD3(O—Pr)P〕络合物而言,该络合物表现出肝吸收。
虽不意于被理论所限制,但确信当本发明带电的络合物制成后(例如,可能-3对骨骼,-1对肝,+1对心脏),螯合物离子带电的不同会影响生物定位。
螯合物通过离子或共价连接到具有对目的靶组织具有特异性的天然或合成分子(例如通过R2)上而实现组织特异性。这一方法的一种可能应用是通过螯合物偶联的单克隆抗体的使用,该抗体可将顺磁螯合物转运到患病组织,从而可通过MRI显示。此外,将顺磁螯合物连接到大分子上可进一步提高造影剂的效果,从而得到相对于游离螯合物改良的对比度。Lauffer最近的工作(美国专利4,880,008和4,899,755)证实,亲脂性的变化可产生组织特异性药剂,并且也证实了增加亲脂性有利于与血蛋白的非共价相互作用,导致弛豫率提高。
具有非配位N—取代基的典型DO3A衍生物可产生中性镧系元素螯合物,但是已发现其在酸条件下动力学不稳定。DO3A衍生物PROHANCETM由于一个侧链羟基而使动力学稳定性提高,该侧链羟基可与金属离子配位,但是可能改变总的螯合离子性质。
相比之下,本发明涉及通式(I)的一组DO3A衍生物,其具有一个可形成配位键但不改变总的螯合离子性质的2—吡啶侧基。此外,已发现2—吡啶取代基可增加螯合物在酸条件下(pH低于7)的动力学稳定性。本发明的螯合物,其中配位部分为PO3HR,其中R是—O—(C1—C5烷基),已证实其作为肝造影剂的潜力。
通式(I)和本发明中所用术语进一步定义为下:
“C1—C5烷基”,包括直链和支链烷基。
“动物”包括温血哺乳动物,优选人。
“络合物”是指本发明化合物如通式(I)化合物与金属离子络合形成的络合物,其中至少一个金属原子被螯合。
“生物学活性物质”是指葡聚糖,肽或对受体具有特异亲和力的分子,或者优选抗体或抗体片段。
“抗体”是指任何多克隆、单克隆、嵌合抗体或杂合抗体,优选单克隆抗体;“抗体片段”包括Fab片段和F(ab′)2片段,和对目的抗原决定簇具有特异性的任何抗体部分。当使用“放射性金属螯合物/抗体偶联物”或“偶联物”时,“抗体”意在包括整个抗体和/或抗体片段,包括半合成的或者其基因工程变体。可能的抗体是1116—NS—19—9(抗结肠直肠癌),1116—NS—3d(抗CEA),703D4(抗人肺癌),704A1(抗人肺癌),CC49,CC83和B72.3。保藏在美国典型培养物保藏中的(American Type Culture Collection)的杂交瘤细胞系1116—NS—19—9,1116—NS—3d,703D4,704A1,CC49,CC83和B72.3,保藏号分别为ATCC HB8059,ATCCCRL 8019,ATCC HB 8301,ATCC HB 8302,ATCC HB 9459,ATCC HB 9453和ATCC HB 8108。
本文所述的双官能螯合剂〔由通式(I)代表〕可用以螯合金属离子以形成金属离子螯合物(本文中也称为“络合物”)。由于存在官能化残基〔由通式(I)的R2代表〕,该络合物可共价连接到生物活性物质上,例如葡聚糖,具有受体特异亲和性的分子,或者优选共价连接到抗体或抗体片段上。因此,本文所述的络合物可以共价连接到一个抗体或抗体片段上或者其对受体具有特异亲和性,并且在本文中称为“偶联物”。
本文中所用的“药学上可接受的盐”意指任何通式(I)化合物的盐或盐的混合物,其足够无毒可用于动物的诊断,尤其是哺乳动物。例如这些盐可用于本发明。从下列有机和无机酸通过标准反应形成具有代表性的盐,包括,例如硫酸、盐酸、磷酸、乙酸、琥珀酸、柠檬酸、乳酸、马来酸、富马酸、棕榈酸、胆酸、palmoic、粘酸、谷氨酸、葡糖酸、d—樟脑酸、戊二酸、乙醇酸、苯二甲酸、酒石酸、甲酸、月桂酸、steric、水杨酸、甲磺酸、苯磺酸、山梨酸、苦味酸、苯甲酸、肉桂酸和其它适宜的酸。同时也包括从下列有机和无机物通过标准反应形成的盐,例如铵或1—脱氧—1—(甲基氨基)—D—glucitol,碱金属离子,碱土金属离子以及其它类似离子。特别优选的是通式(I)化合物的盐,其中该盐为钾、钠或铝盐。同时也包括以上盐的混合物。
通式(I)化合物可通过各种途径制备。下述反应方案提供了这些途径的典型的一般合成方法。
这些方案中所示的通式(II)的起始物通过1,4,7,10—四氮杂环十二烷(“cyclen”)与2—氯甲基吡啶在室温下于惰性有机溶剂如氯仿中烷基化制备而得。
方案1中,制备了通式(I)化合物,其中所有的T为—CH2—COOH。
碱水溶液为碱金属的氢氧化物,例如氢氧化钠或氢氧化钾。反应的pH值保持在约8—12。温度为约60—90℃之间。压力并不关键,常压即可。
方案2中的水解是通过在已知的酸水溶液条件下完成的,例如使用3到12M的盐酸。反应pH值维持在低于3。温度为回流温度。压力并不关键,常压即可。或者,当反应一步完成时,使用磷酸、盐酸和过量的甲醛。反应的pH值低于2。温度为回流温度。压力并不关键,常压即可。
其中:R是—O—(C1—C5烷基)。
方案3中的水解是通过在已知的碱水溶液条件下完成的,例如使用过量的碱金属氢氧化物,例如氢氧化钠或氢氧化钾。反应的pH值高于9。温度为回流温度。压力并不关键,常压即可。
方案4中的水解是通过在已知的碱水溶液条件下完成的,例如使用过量的碱金属氢氧化物,如氢氧化钠或氢氧化钾。反应的pH值高于9。温度为回流温度。压力并不关键,常压即可。
方案5表明了当R为乙基的通式(I)化合物的制备。
方案5中的反应是在盐酸的酸条件下完成的。反应的pH值低于3。温度为回流温度。压力并不关键,常压即可
方案7中表明了当一个T为PO3HR,其中R如通式(I)所定义,并且其它两个T是COOH的通式(I)化合物的制备。
方案7
方案7中的水解步骤通过前述方案所述来进行。甲醛/亚硫酸氢盐加成复合反应在含水碱性条件下完成,以在4,10—位选择性烷基化。膦酸基选择性引入到7—位。
上述方案中,总过程的描述阐明了可用以完成预计反应步骤的特异步骤。这些方法步骤的概述如下。
方案1中所描述的羧酸衍生物是通过常规的烷基化步骤利用氯代或溴代乙酸在碱水溶液条件下制备的。
方案2中所描述的膦酸衍生物可通过胺先与亚磷酸三烷酯及多聚甲醛的烷基化,得到一种有机可溶性全酯。该酯然后在回流酸条件下水解而得预计的氨基膦酸。或者,该膦酸可在酸条件下通过使用亚磷酸和甲醛与盐酸制备而得。
膦酸半酯可按照方案3制备,先生成膦酸二烷基酯,随后在碱条件下水解制备而得。碱水解后完全转化为半酯。
方案4阐述了利用二乙氧基甲基膦作为亲核试剂以及多聚甲醛来合成甲基次膦酸衍生物的方法。在例如四氢呋喃(THF)、二甲基甲酰胺(DMF)、二噁烷、乙腈或醇溶剂中进行缩合。所得次膦酸酯然后在酸条件下(例如6N HCl,80—100C)或碱条件下(过量碱,40—100℃)水解而得到相应的甲基次膦酸。或者,如方案5所述,使用由A.D.Sherry等(Inorg.Chem.,submitted 1991)设计的利用就地形成的乙基膦酸的方法来获得具有增加了亲脂性的次膦酸衍生物。
方案6阐述了通式(I)双官能化合物的制备,其接着可连接到一个生物活性的物质上。
方案7描述了一种利用甲醛/亚硫酸氢盐加成物进行4,10—位选择性烷基化的一般步骤。所得中间体转化为相应的腈,随后在7—位引入膦酸酯部分。酸或碱水解得到相应的水解终产物。
用以形成本发明络合物的金属离子是Gd+3,Mn+2,Fe+3,可购得,例如从Aldrich化学公司。存在的阴离子为卤离子,优选氯离子或者为游离盐(金属氧化物)。
本发明的“顺磁核素”意指一种具有自旋角动量和/或轨道角动量的金属离子。这两种类型的动量联合而得到可观测的顺磁矩,其在很大程度上依赖于具有未成对电子的原子,并且稍少程度上依赖于该原子的环境。发现可用于实现本发明的顺磁核素有钆(Gd+3),铁(Fe+3)和锰(Mn+2),优选Gd+3。
络合物通过本领域熟知的方法制备。例如,见ChelatingAgents and Metal Chelates,Dwyer & Mellor,Academic Press(1964),第7章。制备氨基酸的方法也见Synthetic Productionand Utilization of Amino Acid,(Kameko等编)John Wiley &Sons(1974)。
制备络合物的一个实例包括将双环聚氮杂大环膦酸与金属离子在pH值5—7的含水条件下反应。所形成的络合物通过化学键连接,并且得到的是一个稳定的顺磁核素组合物,例如对顺磁核素从配位体解离是稳定的。
本发明络合物以配位体与金属的摩尔比至少约1∶1,优选从1∶1到1∶3,更优选1∶1到1.5∶1的比例给药。太过量的配位体是不可取的,因为未络合的配位体可能对动物有毒或者可导致心博停止或血钙过少性惊厥。
本发明是与生理上可接受的载体和赋形剂一起使用的。制备这样的制剂的方法是熟知的。该制剂可以为悬浮液、注射用溶液或其它适当的制剂形式。可使用生理上可接受的悬浮介质,使用或者不用佐剂。
一种“有效量”的制剂可用于诊断。剂量依动物的疾病和体格参数,例如体重的不同而不同。使用本发明的制剂也考虑体内诊断学。
本发明的一些螯合剂的其它用途包括从体内消除不需要的金属(如铁),为了不同目的(例如作为诊断剂)而连接到聚合物载体上,以及通过选择性提取而除去金属离子。具有至少两个以R表示的T等于—CH2—P(O)R1OH的通式(I)配位体可用作金属离子对照的标准抑制剂(scale inhibitors)。一些这样的配位体可以少于化学计量的数量使用。在美国专利2,609,390;3,331,773;3,336,221和3,434,969中所描述的化合物已知有类似的用法。
本发明通过下述实施例将进一步阐明,这些实施例只是作为本发明的举例。
下述实施例中所使用的一些术语定义如下:
LC=液相色谱,在低压下使用手工填料的Q—SepharoseTM的阴离子交换柱(23×2cm)用Dionex2010i体系进行纯化。
DMF=二甲基甲酰胺
AcOH=乙酸
g=克
mg=毫克
kg=千克
ml=毫升
μl=微升
测定pH稳定性的一般步骤
将2μl3×10-4M159GdCl3的0.1N HCl溶液加入至2ml3×10-4M的159GdCl3的载体溶液中而制备备用159GdCl3(或153SmCl3)溶液。然后在去离子水中制备适当的配位体溶液。接着通过将配位体(溶于100—500μl去离子水中)和2ml储备
159GdCl3溶液混合而制备1∶1配位体/金属络合物,随后混合而得一种酸溶液(pH=2)。用0.1N NaOH将溶液的pH值升至7.0。络合物中金属的百分比是通过将络合物溶液样品通过一个SepharoseTMG—50柱测定的,用4∶1的盐水(85%NaCl/NH4OH)洗脱,并收集2×3ml流份。将合并洗脱液中放射性的量与残留在树脂中的量(非络合的金属保留在树脂上)相比较。pH稳定性分布图通过用1MNaOH或1MHCl调节络合物溶液的等分试样的pH,并用上述离子交换法确定络合物中金属的百分比,测得pH稳定性。通过实验比较而得Sm结果,本发明配位体的络合及生物分布完全相同。
配位体的合成
一般材料和方法:
所有的试剂都由市售而得,并直接使用而不进一步纯化。在配有多核四探头(1H,13C,31P和19F)的Bruker AC—250MHZ光谱仪上于297°K(除非另外提示)记录NMR谱。用溶剂抑制脉中序列(“PRESAT”,单核预饱和)记录D2O中的1H谱。
1H谱以δ7.26的残余氯仿(在CDCl3中)或δ3.55的外来二噁烷(在D2O中)定位。所记录的13C和31P谱是质子去偶的(宽带)。利用DEPT(通过极化转移的非变形增益)实验有助于 13C{1H}化学位移的指定。13C{1H}谱以δ77.00的CDCl3中央峰(在CDCl3中)和δ66.66的外来二噁烷(在D2O中)定位。31p{1H}谱以δ0.00的外来85%H3PO4定位。通过毛细管熔融法确定熔点,并且未校正。用配有手工填料的Q—SepharoseTM(阴离子交换)或SP—SepharoseTM(阳离子交换)玻璃柱的标准玻璃柱,并且用联机UV检测器在263nm监测洗脱下,于低压下(<600psi)进行半制备离子交换色谱分离。在Hewlett Packard5890A气相色谱/5970质量选择检测器上测定GC/MS谱。
起始物质
实施例A
N—(2—吡啶基甲基)—1,4,7,10—四氮杂环十二烷的制备
碱化3ml 1.03g(6.3mmol)的氯化2—吡啶甲基盐酸盐水溶液至pH>14,并萃取到氯仿中,制得氯化2—吡啶甲基的氯仿溶液。向搅拌下的2.03g(11.8mmol)1,4,7,10—四氮杂环十二烷的氯仿溶液中一次加入10ml制备好的氯化2—吡啶甲基的氯仿溶液。室温下搅拌30分钟后,反应混合物在真空中浓缩得残余物,将其在硅胶(柱,2.5×20cm)上进行层析,用CHCl3:CH3OH:NH3OH(10∶4∶1)洗脱,SiO2板上的Rf=0.29。洗脱液浓缩后,分离得到稠的淡黄色液体状单烷基化产物,其经静置固化得1.17g灰白色粉末(72%,基于氯化2—吡啶甲基),进一步的特征为:δ2.54-2.82(m,16H),3.75(s,2H),7.11-7.14(m,1H),7.42-7.46(m,1H),7.64-7.65(m,1H),8.46-8.48(m,1H);and13C{1H}NMR(CDCl3)δ45.02,46.31,47.04,51.51,61.03.122.122.87,136.61.148.83,150.53
实施例B
N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸二乙酯)—1,4,7,10—四氮杂环十二烷的制备
向如实施例A制备的331mg(1.27mmol)的N—(2—吡啶基甲基)—1,4,7,10—四氮杂环十二烷中加入229mg(7.63mmol,过量)的多聚甲醛和1.3ml 1.27g(7.62mmol,过量)的亚磷酸三乙酯。将混合液缓缓搅拌10分钟后得到充分混合的浆,将其加热至90℃1小时。过量的试剂和副产物在真空(125℃/0.01mmHg)中除去,得到896mg(99%)的黄色油状目标产物,进一步的特征为:δ1.25-1.39(m,18H),2.66-2.95(m,22H),3.71(s,2H),4.01-4.22(m,12H),7.10-7.15(m,1H),7.57-7.65(m,2H),8.46-8.52(m,1H);13C{1H}NMR(CDCl3)δ16.38,16.46,50.45,50.67,52.41,53.19,53.29,53.48,53.58,61.37,61.47,61.52,121.67,123.28,136.19,148.61,159.90;and31P{1H}NMR(CDCl3,297°K)δ26.21;31P{1H}NMR(CDCl3,217°K)δ24.18(1P),24.32(2P).
实施例C
N—(2—比啶基甲基)—N′,N″,N—三(亚甲基膦酸二丙基酯)—1,4,7,10—四氮杂环十二烷的制备
向如实施例A制备的445mg(1.71mmol)的N—(2—吡啶基甲基)—1,4,7,10—四氮杂环十二烷中加入154mg(5.12mmol,过量)的多聚甲醛和3.5ml 3.20g(5.12mmol,过量)的亚磷酸三丙基酯。将混合液缓缓搅拌10分钟后得到充分混合的浆,将其加热至100℃30分钟。过量的试剂和副产物在真空(4小时,160℃/0.01mmHg)中除去,得到1.36g(定量)的稠的黄色油状目标产物,进一步的特征为:δ0.91-1.00(m,18H),1.60-1.76(m,12H),2.67-2.99(m,22H),3.73(s,2H),3.94-4.08(m,12H),7.12-7.15(m,1H),7.46-7.67(m,2H),8.48-8.52(m,1H);13C{1H}NMR(CDCl3)δ9.93,10.21,23.71,23.80,50.17,50.44,52.38,53.09,53.44,61.44,66.79,66.83,121.61,123.23.136.14,148.54,159.92;and31P{1H}NMR(CDCl3)δ26.20(1P),26.23(2P).
终产物
配位体:如方案1所示制备二亚甲基羧酸。
实施例1
N—(2—吡啶基甲基)—N′,N″,N—三乙酸—1,4,7,10—四氮杂环十二烷(PD3A)的制备
向如实施例A制备的201.4mg(0.51mmol)的N—(2—吡啶基甲基)—1,4,7,10—四氮杂环十二烷的2ml水溶液中加入350mg(2.52mmol,65%过量)的溴乙酸,反应混合液的pH值通过加入少量的浓缩氢氧化钠维持在11以上,直到不需要碱以维持pH>11(约30分钟)。然后将反应混合液加热(60℃)1小时。反应混合液冷却至室温后,调节反应混合液的pH值至7,并将该中性溶液在阳离子交换(SP—SepharoseTM)柱(1.5×50cm)上进行层析,先用去离子水洗脱,然后再用1M盐酸洗脱。将含有产物的酸性流份蒸发干燥,随后与新制去离子水(3×2ml)共同(共沸物)蒸发以除去过量的盐酸。将水溶液冷冻干燥分离得白色固体终产物,进一步的特征为:δ2.79-4.13(m,24H),7.88-8.01(m,2H),8.35-8.42(m,1H),8.63-8.66(m,1H);and13C{1H}NMR(D2O)δ51.04,51.25,53.73,55.47,56.00,56.90,57.52,129.86,131.21,145.49,150.82,153.54,171.61,178.76.
配位体:如方案3所示制备二亚甲基膦酸半酯
实施例2
N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸乙酯)—1,4,7,10—四氮杂环十二烷(PD3EP)的制备
向如实施例B制备的102.7mg(0.14mmol)的N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸二乙酯)—1,4,7,10—四氮杂环十二烷中加入1ml 0.1M的氢氧化钾并于90℃加热6小时。冷却至室温后,将水溶液冷冻干燥得褐色固体,将其在阴离子交换(Q—SepharoseTM)柱(1.5×50cm)上进行层析,先用去离子水洗脱,然后再用1M盐酸洗脱。将洗脱液冷冻干燥后,分离得棕色固体产物,进一步的特征为:δ1.41-1.57(m,9H),3.28-3.89(m,22H),4.09-4.64(m,8H),8.22-8.26(m,2H),8.70-8.75(m,1H),9.00-9.12(m,1H);and13C{1H}NMR(D2O,338°K)δ19.41,19.51,52.58,53.00,52.31,53.75,53.82,56.04,59.53,64.60,64.76,129.86,131.41,147.31,149.06,154.34;and31P{1H}NMR(D2O,338°K)δ9.64(2P),19.79(1P).
实施例3
N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸丙酯)—1,4,7,10—四氮杂环十二烷(PD3PP)的制备
向如实施例C制备的0.71g(0.89mmol)的N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸二丙基酯)—1,4,7,10—四氮杂环十二烷中加入3ml0.1M的氢氧化钾,并加热回流18小时。冷却至室温后,过滤水溶液,并冷冻干燥而得褐色残余物,将其再溶入CH2Cl2/C2H5OH(95∶5),并且过滤。随后蒸发溶剂并且在真空中浓缩,分离得褐色固体产物,进一步的特征为:δ1.24-1.36(m,9H),1.95-2.04(m,6H),3.03-3.29(m,22H),4.10-4.25(m,8H),7.74-7.92(m,2H),8.23-8.29(m,1H),8.87-8.96(m,1H);and13C{1H}NMR(D2O,353°K)δ13.15,27.20,50.43,53.89,54.48,54.98,55.42,64.33,69 41,126.38,128.30,141.24,152.46,161.45;and31P{1H}NMR(D2O,353°K)δ21.61(2P),21.95(1P).
络合物:为生物分布研究制备金属/配位体络合物。
一般步骤
金属配位体络合物可通过不同的方法制备。该方法包括在水溶液中混合金属和配位体,并且调节pH至期望值。在含有盐和/或缓冲剂及水的溶液中进行络合。有时发现热溶液中络合率高于在室温下进行络合时的络合率。
例如,将配位体溶于去离子水(约pH=2)中制备配位体溶液。然后将配位体溶液与含有示踪剂153SmCl3的SmCl3.H2O(3×10-4M,在0.01N HCl中)水溶液混合。充分混合后,将络合物溶液通过一个SephadexTM柱确定络合金属的百分比,用4∶1盐水(0.85%NaCl/NH4OH)洗脱,并收集2×3ml流份。然后将总洗脱液中放射性的数量与残留在树脂中的相比较。在这种情况下,络合物和洗脱液一起被除去,而非络合的金属保留在树脂中。通过这种方法确定的络合率通常为约95%或更高。
使用上述步骤,可制备钐与
N—(2—吡啶基甲基)—N′,N″,N—三乙酸—1,4,7,10—四氮杂十二烷(PD3A);
N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸乙酯)—1,4,7,10—四氮杂十二烷(PD3EP);
N一(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸丙酯)—1,4,7,10—四氮杂十二烷(PD3PP);和
N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸—1,4,7,10—四氮杂十二烷(PD3P)的络合物。与钆的络合物用类似的方式制备。
下表阐明了由PD3A、PD3PP和PD3EP衍生而来的Sm络合物的动力学惰性。
153Sm—PD3A的pH稳定性
153Sm—PD3PP的pH稳定性
153Sm—PD3A的pH稳定性
pH | 络合百分率 |
1 | 98.30 |
2 | 99.38 |
4 | 99.62 |
7 | 99.86 |
9 | 99.86 |
11 | 99.80 |
14 | 99.96 |
pH | 络合百分率 |
1 | 72.52 |
3 | 87.56 |
5 | 92.99 |
7 | 95.06 |
9 | 95.22 |
11 | 92.74 |
14 | 87.65 |
pH | 络合百分率 |
1 | 78.95 |
3 | 93.80 |
5 | 93.02 |
7 | 93.77 |
9 | 95.89 |
11 | 95.77 |
14 | 94.07 |
生物分布
一般步骤
让Sprague Dawley大鼠适应5天,然后经尾静脉注射100μl络合物溶液。注射时大鼠体重在150和200g之间。30分钟后,颈脱臼处死大鼠并解剖。通过耦合到多道分析器上的NaI闪烁计数器计数确定每种组织的放射性数量。将该计数与100μl标准的计数比较来确定每种组织或器官中的剂量百分比。
假定血液为总体重的6.5%来估计血液中的百分剂量。将股骨中的百分剂量乘以25来估计骨中的百分剂量。假定肌肉为总体重的43%来估计肌肉中的百分剂量。计算平均值所用大鼠的个数为n。
除了器官的生物分布外,评价通式(I)化合物的螯合物的骨定位效率,因为已知膦酸能结合到羟基磷灰石上。这些试验的结果如下。
实施例I
当评价络合物153Sm〔N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸乙酯)—1,4,7,10—四氮杂十二烷〕(153Sm—PD3EP)时,结果如下表I所示。数值代表注射后2小时时每个数据点最少2只大鼠的平均值。
表I
153Sm—PD3EP的生物分布,注射剂量的百分数
实施例II
器官 | 平均值 |
骨 | 0.82 |
肝 | 0.36 |
肾 | 1.24 |
脾 | 0.01 |
肌肉 | 0.62 |
血液 | 0.45 |
心脏 | 0.01 |
肺 | 0.02 |
脑 | 0.01 |
尿 | 97.00 |
当评价络合物153Sm〔N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸丙酯)—1,4,7,10—四氮杂十二烷〕(153Sm—PD3PP)时,结果如下表II所示。数值代表注射后2和24小时时每个数据点最少3只大鼠的平均值。
表II
153Sm—PD3PP的生物分布
注射剂量的百分数
器官 | 2小时后的平均值 | 24小时后的平均值 |
骨 | 5.93 | 12.39 |
肝 | 20.36 | 2.31 |
肾 | 0.86 | 0.89 |
脾 | 1.19 | 0.22 |
肌肉 | 0.82 | 0.27 |
血液 | 0.68 | 0.03 |
心脏 | 0.04 | 0.02 |
肺 | 0.20 | 0.40 |
脑 | 0.04 | 0.00 |
胃 | 1.39 | 0.04 |
小肠 | 13.56 | 0.13 |
大肠 | 0.18 | 0.16 |
尿 | 50.00 | 83.00 |
粪便 | - | 5.33 |
根据在此公开的说明书和实施方式,本发明的其它方案对于本领域的专业人员是显而易见的。而且说明书和实施例仅作为举例,本发明真正的范围和实质如下面的权利要求书所述。
Claims (17)
2.权利要求1的化合物或其药学上可接受的盐,其中T等于—CH2—P(O)ROH,R是OH,并且命名为N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸)—1,4,7,10—四氮杂环十二烷。
3.权利要求1的化合物或其药学上可接受的盐,其中T等于—CH2—COOH,并且命名为N—(2—吡啶基甲基)—N′,N″,N—三乙酸—1,4,7,10—四氮杂环十二烷。
4.权利要求1的化合物或其药学上可接受的盐,其中T等于—CH2—P(O)ROH,R是—O—(C1—C5烷基)。
5.权利要求4的化合物或其药学上可接受的盐,其中R是乙氧基,并且命名为N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸乙酯)—1,4,7,10—四氮杂环十二烷。
6.权利要求4的化合物或其药学上可接受的盐,其中R是丙氧基,并且命名为N—(2—吡啶基甲基)—N′,N″,N—三(亚甲基膦酸丙酯)—1,4,7,10—四氮杂环十二烷。
7.权利要求1的化合物,其中T等于—CH2—P(O)ROH,R是C1—C5烷基。
10.权利要求9的络合物,其中金属为Gd+3。
11.权利要求9的络合物,其中T是—CH2—P(O)ROH,R是OH,并且金属为Gd+3。
12.权利要求9的络合物,其中T是—CH2—COOH,并且金属为Gd+3。
13.权利要求9的络合物,其中T是—CH2—P(O)ROH,R是—O—(C1—C5烷基),并且金属为Gd+3。
14.权利要求9的络合物,其中T是—CH2—P(O)ROH,R是C1—C5烷基,并且金属为Gd+3。
15.一种药物制剂,其包括一种权利要求9的络合物及药学上可接受的载体。
16.一种用于诊断动物疾病的方法,其包括给予所述动物有效量的权利要求15的制剂。
其中:R为OH,C1—C5烷基或—O—(C1—C5烷基);该方法包括下述任意一种:
与X—CH2—COOH反应,其中X是氯或溴原子,在碱金属的氢氧化物的水溶液存在下,pH值约8—10之间,温度为约60—90℃之间反应;得到上述通式(I)化合物,其中T等于—CH2—COOH;或者
与P(OR)3,其中R是C1—C4烷基,在甲醛中反应,接着用3至12M的盐酸进行水解,pH值低于约3,回流温度;得到上述通式(I)化合物,其中T等于—CH2—PO3H2;或者
与P(OR)3,其中R是C1—C4烷基,在甲醛中反应,接着用过量的碱金属氢氧化物进行水解,pH值高于约12,回流温度;得到上述通式(I)化合物,其中T等于—CH2—PO2HR,R是—O—(C1—C5烷基);或者
与H3C—P(OEt)2在甲醛和四氢呋喃中反应,接着用过量的碱金属氢氧化物进行水解,pH值高于约12,回流温度,或者与HP(O)OH—C2H5在甲醛和盐酸中反应,pH值低于约3,回流温度;得到上述通式(I)化合物,其中T等于—CH2—PO(OH)R,R是C1—C5烷基。
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US2609390A (en) * | 1950-06-01 | 1952-09-02 | Frederick C Bersworth | Phosphonic alkylene polyamino acids and method of producing same |
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FR2672051B1 (fr) * | 1991-01-24 | 1993-05-21 | Guerbet Sa | Nouveaux ligands macrocycliques azotes, procede de preparation, complexes polymetalliques, composition de diagnostic et therapeutique. |
IL106159A0 (en) * | 1992-06-30 | 1993-10-20 | Dow Chemical Co | Targeted delivery of growth factors for bone regeneration |
EP0588229A3 (en) * | 1992-09-12 | 1994-06-15 | Hoechst Ag | Macrocyclic chelating agents for the preparation of technetium or rhenium complexes |
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1993
- 1993-05-06 US US08/057,588 patent/US5462725A/en not_active Expired - Fee Related
-
1994
- 1994-05-05 JP JP6525558A patent/JPH08510245A/ja not_active Ceased
- 1994-05-05 AU AU69447/94A patent/AU678583B2/en not_active Ceased
- 1994-05-05 SG SG1996004873A patent/SG46458A1/en unknown
- 1994-05-05 CZ CZ952895A patent/CZ289595A3/cs unknown
- 1994-05-05 CA CA002162174A patent/CA2162174A1/en not_active Abandoned
- 1994-05-05 HU HU9503174A patent/HUT74565A/hu unknown
- 1994-05-05 WO PCT/US1994/005009 patent/WO1994026275A1/en active IP Right Grant
- 1994-05-05 AT AT94917922T patent/ATE227297T1/de not_active IP Right Cessation
- 1994-05-05 DE DE69431660T patent/DE69431660T2/de not_active Expired - Fee Related
- 1994-05-05 PL PL94311643A patent/PL311643A1/xx unknown
- 1994-05-05 CN CN94192527.7A patent/CN1125905A/zh active Pending
- 1994-05-05 EP EP94917922A patent/EP0711300B1/en not_active Expired - Lifetime
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1995
- 1995-11-06 FI FI955319A patent/FI955319A/fi unknown
- 1995-11-06 NO NO954440A patent/NO301829B1/no unknown
- 1995-12-05 BG BG100192A patent/BG100192A/xx unknown
- 1995-12-06 LV LVP-95-362A patent/LV11430B/en unknown
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ATE227297T1 (de) | 2002-11-15 |
LV11430B (en) | 1997-04-20 |
CZ289595A3 (en) | 1997-01-15 |
FI955319A (fi) | 1995-12-22 |
NO301829B1 (no) | 1997-12-15 |
PL311643A1 (en) | 1996-03-04 |
HUT74565A (en) | 1997-01-28 |
EP0711300A4 (en) | 1996-03-12 |
BG100192A (en) | 1996-12-31 |
EP0711300B1 (en) | 2002-11-06 |
SG46458A1 (en) | 1998-02-20 |
JPH08510245A (ja) | 1996-10-29 |
AU678583B2 (en) | 1997-06-05 |
CA2162174A1 (en) | 1994-11-24 |
DE69431660D1 (de) | 2002-12-12 |
AU6944794A (en) | 1994-12-12 |
DE69431660T2 (de) | 2003-08-21 |
WO1994026275A1 (en) | 1994-11-24 |
NO954440L (no) | 1996-01-05 |
LV11430A (lv) | 1996-08-20 |
NO954440D0 (no) | 1995-11-06 |
HU9503174D0 (en) | 1996-01-29 |
FI955319A0 (fi) | 1995-11-06 |
US5462725A (en) | 1995-10-31 |
EP0711300A1 (en) | 1996-05-15 |
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