CN100443476C - 能够络合金属离子的多配基氮杂配体及其在诊断学和治疗学中的用途 - Google Patents
能够络合金属离子的多配基氮杂配体及其在诊断学和治疗学中的用途 Download PDFInfo
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- CN100443476C CN100443476C CNB028142020A CN02814202A CN100443476C CN 100443476 C CN100443476 C CN 100443476C CN B028142020 A CNB028142020 A CN B028142020A CN 02814202 A CN02814202 A CN 02814202A CN 100443476 C CN100443476 C CN 100443476C
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Abstract
本发明涉及通式(I)的化合物,其中R1为氢、C1-C20烷基、C3-C10环烷基、C4-C20环烷基烷基、芳基、芳基烷基,或两个R1共同形成直链或环状C2-C10亚烷基或邻二取代的亚芳基;R2为氢、C1-C20烷基、C3-C10环烷基、C4-C20环烷基烷基、芳基或芳基烷基,所述基团任选被可与适宜的、能与生理系统相互作用的分子共轭的官能团取代;R3、R4和R5为氢、C1-C20烷基、C3-C10环烷基、C4-C20环烷基烷基、芳基、芳基烷基;以及它们与原子序数为20至31、39、42、43、44、49、57至83的金属元素以及选自203Pb、67Ga、68Ga、72As、111In、113In、90Y、97Ru、62Cu、64Cu、52Fe、52mMn、140La、175Yb、153Sm、166Ho、149Pm、177Lu、142Pr、159Gd、212Bi、47Sc、149Pm、67Cu、111Ag、199Au、161Tb和51Cr的放射性同位素的二价-三价离子形成的螯合物,以及其与生理相容的碱或酸形成的盐。
Description
本发明涉及新的能够络合金属离子、尤其是顺磁性离子的氮杂配体以及相应的络合物作为磁共振成像(MRI)对比剂的用途。
已知顺磁性金属离子与环状和非环状氮杂配体形成的大量络合物在MRI诊断技术中作为对比剂(参见例如:医疗磁共振成像的对比剂化学,Merbach A.E.和Toth E.编辑,John Wiley和sons,Chichester,2001;Caravan P.等人,Chem.Rev.1999,99,2293-2352以及US 4,885,363、US4,916,246、US 5,132,409、US 6,149,890)。这些络合物中的一些(Gd-DTPA、Gd-DOTA、Gd-HPDO3A等)最近已经上市。
MRI诊断学中使用最广泛的顺磁性金属离子或属于过渡金属或属于镧系元素。关于镧系元素,注意力主要集中于Gd(III)离子,因为它既是高顺磁体(7个未成对电子),又在电子弛豫方面具有良好的特性。这种金属在哺乳动物中不具有任何生理功能,并且其以游离离子形式施用时,即使在低剂量下(10至20micromol/Kg)也具有强大的毒性。为此必须使用可与镧系元素离子形成具有高度热力学和动力学稳定性的螯合物的配体。这就意味着螯合配体对相关顺磁性离子与对生理学有关离子相比应该表现出高水平的亲和性和选择性。此外配体应显示适宜的药动学性质(排泄、与血浆蛋白结合、代谢惰性等)以及最佳的弛豫率(relaxivity)特性,也就是说这个参数的数值应该并保持在高水平,不受周围环境、尤其是与生理有关的阴离子的存在和pH变化的影响。
现已发现一类新配体,这类配体可形成尤其在稳定性和弛豫率方面具有特别良好特性的络合物。
弛豫率(rlp)是以增加邻近质子的核磁弛豫率能力为特征的顺磁性络合物的内在性质。高弛豫率可确保影像的对比增强,而对比增强使短时间内获得在影像质量和经济花费方面都具有明显优势的生理学信息成为可能。
Gd(III)络合物的弛豫率是直接与金属离子内配位层中的水分子数(q)相关的性质。如前所述,用于磁共振成像(MRI)的对比剂主要以稳定的Gd(III)离子络合物为代表,其中的绝大部分基于八配基配体以确保高度的热力学稳定性。但是,这种选择意味着只有一个水分子可进入配位数为9的Gd(III)离子的内配位层(医疗磁共振成像的对比剂化学,由Merbach A.E.和Toth E.编辑,John Wiley和sons,Chichester,2001)。
所观测到的(含有顺磁性络合物的水溶液中水质子的)弛豫率的另一部分来自配位水分子和剩余溶剂分子之间的交换。具体而言,观测弛豫率的增加与在内配位层中与顺磁性中心配位的水分子质子的停留时间(τM)呈负相关。在快速交换条件下可获得较高的弛豫率。
本发明的配体可形成络合物,所述络合物的高起始弛豫率与内配位层中两个水分子的存在以及同时具有的良好的τM值相一致。
本发明的配体具有以下通式(I):
其中:
R1为氢、任选被一个或多个羧基取代的C1-C20烷基;C3-C10环烷基、C4-C20环烷基烷基、芳基、芳基烷基,或两个R1基团共同形成直链或环状C2-C10亚烷基或邻二取代的亚芳基;
R2为氢、C1-C20烷基、C3-C10环烷基、C4-C20环烷基烷基、芳基或芳基烷基,所述基团任选被可与适宜的、能与生理系统相互作用的分子共轭的官能团取代;
R3、R4和R5可以相同或不同,其为氢、C1-C20烷基、C3-C10环烷基、C4-C20环烷基烷基、芳基、芳基烷基;
FG可以相同或不同,其为羧基、-PO3H2或-RP(O)OH基团,其中R为氢、C1-C20烷基、C3-C10环烷基、C4-C20环烷基烷基、芳基、芳基烷基。
本发明还涉及式(I)化合物与顺磁性或放射性金属离子、尤其是与原子序数为20至31、39、42、43、44、49、57至83的金属元素的二价-三价离子形成的螯合物,以及其与生理可相容的碱或酸形成的盐。
对于作为MRI对比剂的诊断用途而言,特别优选的络合物是与顺磁性离子如Fe(2+)、Fe(3+)、Cu(2+)、Cr(3+)、Gd(3+)、Eu(3+)、Dy(3+)、La(3+)、Yb(3+)或Mn(2+)形成的络合物,尤其是钆络合物。
另一方面,用于放射治疗或放射诊断时,优选的络合物是那些与203Pb、67Ga、68Ga、72As、111In、113In、90Y、97Ru、62Cu、64Cu、52Fe、52mMn、140La、175Yb、153Sm、166Ho、149Pm、177Lu、142Pr、159Gd、212Bi、47Sc、149Pm、67Cu、111Ag、199Au、161Tb和51Cr形成的络合物。
当配体具有成盐功能时,本发明的螯合物也可以是盐的形式。
适合用于使本发明的络合物成盐的优选的无机碱阳离子包括碱或碱土金属如钾、钠、钙、镁的离子。
优选的有机碱阳离子尤其包括伯、仲和叔胺如乙醇胺、二乙醇胺、吗啉、葡糖胺、N-甲基葡糖胺、N,N-二甲基葡糖胺的阳离子。
适合用于使本发明的络合物成盐的优选的无机酸阴离子包括卤素酸如氯化物、溴化物、碘化物的离子,或其它离子如硫酸根离子。
优选的有机酸阴离子包括药学技术中常规用于碱性物质成盐的那些酸的阴离子,如乙酸、琥珀酸、柠檬酸、富马酸、马来酸、草酸的阴离子。
优选的氨基酸的阳离子和阴离子包括例如牛磺酸、甘氨酸、赖氨酸、精氨酸或鸟氨酸的阳离子和阴离子,或天冬氨酸和谷氨酸的阳离子和阴离子。
C1-C20烷基为直链或支链基团,且优选为C1-C6基团,更优选甲基、乙基、丙基、异丙基。
C3-C10环烷基优选为环丙基、环戊基或环己基,而环上的一个位置任选被以上定义的烷基取代。
C4-C20环烷基烷基优选为环丙基甲基、环己基乙基、环己基甲基、环戊基甲基、环戊基乙基。
芳基优选为苯基或被1至5个取代基取代的苯基,所述取代基可以相同或不同且选自羟基、C1-C2烷氧基、卤素、氰基、硝基、甲基、乙基、羧基、氨基、C1-C2烷基-或二烷基氨基,或被1至3个取代基如羟基、C1-C2烷氧基、卤素、氰基、硝基、甲基、乙基、羧基、氨基、C1-C2烷基-或二烷基氨基以不同方式取代的烷基。
邻二取代的亚芳基优选为以上所述的任选被取代的1,2-亚苯基。
被羧基取代的C1-C20烷基优选为羧基甲基。
FG优选为羧基。
R2优选为甲基、以上定义的烷基或芳基,其均任选被官能团如保护或未保护的羧基、氨基、甲酰基、羟基或巯基取代,所述官能团可用作与其它化合物的结合位点,只要不干扰分子的结构完整性即可。
R3优选为氢。
R4优选为氢或甲基。
R5优选为氢。
优选的式(I)化合物是那些化合物,其中两个R1基团共同形成亚烷基、尤其是亚乙基或亚丙基、优选亚乙基,且其它基团如式(I)所定义或具有如上所指出的优选含义。
其中R1为氢、烷基、环烷基、环烷基烷基或芳基的化合物(I)可以通过包括下列步骤的方法进行制备:
a)使其中R2如上所定义的化合物(II)
与甲醛和其中R1如上所定义的胺(III)反应,
R1-NH2 III
生成式(IV)的化合物;
b)将化合物(IV)的硝基还原成氨基,生成式(V)的化合物,
使式(V)的化合物与卤代乙酸酯反应,生成其中R6为C1-C6烷基的化合物(VI),
随后水解以生成化合物(I),或使化合物(V)与甲醛和亚磷酸或其中R如上所定义的式RP(OH)2的化合物反应,生成其中FG为-PO3H2或RP(O)OH的相应的化合物(I)。
其中两个R1基团共同形成亚烷基的式(I)化合物是通过包括以下步骤的方法获得的:
a)使化合物(II)与甲醛和式(VII)的二胺反应,
其中R1如上所定义,且Bz为苄基或氨基保护基团,
生成式(VHI)的化合物;
b)例如通过催化氢化将硝基还原并自化合物(VIII)中除去苄基,生成式(IX)的化合物;
c)使(IX)与卤代乙酸酯反应,生成其中R6如上所定义的化合物(X),
或使(IX)与甲醛和亚磷酸或其中R如上所定义的式RP(OH)2的化合物反应,生成其中FG为-PO3H2或RP(O)OH的相应的化合物(I);
d)使羧酯基水解,生成其中R1基团共同形成亚烷基的化合物(I)。
其中羧基和膦酰基均存在的式(I)化合物可通过适当改变上述反应顺序、在预先脱保护的式(VIII)化合物上引入羧甲基或膦酰基甲基而获得,例如如上所述首先与卤代乙酸酯反应,然后将硝基还原并进一步与甲醛和H3PO3或RP(OH)2反应,或反之亦然。根据这种方法,也可以制备其中环中氮原子上的FG基团与环外氨基上的FG基团不同的式(I)化合物。
保护和未保护形式的通式(IX)的胺都是新的化合物且作为中间体是本发明的另一目的。
本发明的化合物还可以与能够与生理系统相互作用的适宜的分子共轭。其有用的例子有胆酸、肽、蛋白质、激素、低聚核苷酸等。
化合物(I)的络合物可作为MRI对比剂经胃肠外施用,优选将其配制为pH可处于例如6.0至8.5范围内的无菌水溶液或混悬液。
所述水溶液或混悬液可以以0.002至1.0摩尔的浓度施用。
所述制剂可以是冻干制剂并就此提供,使用前需进行重构。对于胃肠道使用或体腔注射,可将这些活性剂配制成溶液或混悬液,其含有适宜的添加剂以例如控制粘度。
对于口服施用,可按照制药技术中常规使用的制备方法对它们进行配制,也可以任选地配制为包衣制剂,以便获得额外的保护而免受胃内酸性pH的破坏、抑制螯合金属离子的释放,这种释放通常发生在典型的胃液pH值条件下。
根据已知的药物制剂技术,也可加入其它赋形剂,如甜味剂和/或矫味剂。
与具有式(I)配体的顺磁性Gd(III)络合物具有特别好的起始弛豫率,这可以通过所述络合物的内配位层中存在两个水分子以及同时具有的配位水分子的良好的快速交换速率来解释。
已报道;对于一些q=2的Gd(III)络合物(即Gd-DO3A样系统),观察到溶液pH值增加时,弛豫率降低。这种降低最可能是由于以下事实:一些存在于溶液中的阴离子如碳酸根离子和氢氧根离子与水分子竟争Gd(III)上的配位点,并通过和金属螯合物形成三元络合物而显著地降低了其弛豫率(S.Aime等人,J.Biol.Inorg.Chem.,5,488-497,2000)。当溶液中存在双配位基配体时,也可以观察到弛豫率降低。表现出这种行为的系统通常具有以下特点:与蛋白质如HSA结合时会出现小的弛豫增强。这是因为蛋白质上的配位原子替代了水分子。
相反,用本发明实施例1的Gd(III)络合物进行的试验非常有趣地表明:本发明的配体对溶液中存在的任何阴离子和阴离子性代谢物均表现出非常低的亲和性。
该结果明确表明:本发明络合物的弛豫率即使在高浓度的双配位基阴离子存在时也不会降低。
所述结果进一步表明:本发明的配体可优选用于制备q=2的顺磁性络合物;能与人血清白蛋白或其它适宜的大分子共轭或以非共价方式相互作用,只要所述大分子不具有配位原子即可(例如来自天冬氨酸盐或谷氨酸盐的配位原子);能与Gd(III)的配位点相互作用并使可得到的弛豫率降低。
最有可能的是:所述配体的结构与DO3A和相应的DO3MA三甲基衍生物的结构相比的主要变化是络合物对双配位基阴离子具有完全不同表现的原因。
下列实施例更详细地对本发明进行了阐述。
实施例1
在250mL圆底烧瓶中将N,N’-二苄基乙二胺二乙酸盐(18.4g,51.0mmol)和硝基乙烷(3.66mL,50.9mmol)溶于乙醇(80mL)中。将低聚甲醛(5.00g,166.5mm0l)逐份加入至溶液中,并将得到的混悬液回流。在约60℃下,混合物变得均匀(低聚甲醛溶解),并发生轻微放热的反应。回流3小时后,将混合物蒸发、用饱和Na2CO3水溶液处理并用二氯甲烷反复萃取有机产物。用水洗涤合并的有机萃取物并用Na2SO4干燥。过滤并使二氯甲烷蒸发后,用硅胶色谱法纯化蜡状残余物。
用二氯甲烷洗脱,生成纯的标题化合物(15.65g,90.6%)。增加洗脱液的极性(CH2Cl2/MeOH 9∶1),得到非环状衍生物N,N’-二苄基-N-(2-硝基丙基)乙二胺(0.350g,2.1%)。
蜡状白色固体,m.p.49.5-50℃(正己烷)
1H-NMR(CDCl3)
7.32(m,10H),3.78(d,2H,J=13.2Hz),3.65(d,2H,J=13.2Hz),3.60(d,2H,J=14.1Hz),2.96(d,2H,J=14.1Hz),2.60(m,4H),1.35(s,3H)。
13C-NMR(CDCl3)
139.0(s),128.8(d),128.1(d),127.1(d),91.5(s),63.7(t),63.4(t),58.1(t),24.2(q)。
MS(Cl)340(MH+)。
对C20H25N3O2(339.43)的分析计算:C,70.77;H,7.42;N,12.38。实测值:C,70.57;H,7.60;N,12.27。
向a)中所得化合物(6.00g,17.7mmol)在乙醇(45mL)和水(5mL)混合物的溶液中加入由10%钯碳组成的催化剂(1.0g)。将该混合物加入至Parr装置中,在28个大气压(2.84MPa)和室温下进行氢化。2小时后,氢不再被吸收。使反应混合物通过过滤。将滤液蒸发,得到纯度足以用于随后步骤的标题化合物(2.25g,98.3%),为无色油状物形式。
1H-NMR(CDCl3)
2.82(m,4H),2.63(d,2H,J=13.6Hz),2.57(d,2H,J=13.6Hz),1.86(bs,4H,与D2O交换),0.96(s,3H)。
13C-NMR(CDCl3)
62.2(t),53.8(s),51.7(t),26.5(q)。
MS(Cl)130(MH+)。
对C6H15N3(129.21)的分析计算:C,55.78;H,11.70;N,32.52。实测值:C,55.56;H,11.91;N,32.29。
向b)中所得化合物(0.909g,7.04mmol)的无水乙腈(25mL)溶液中加入粉末状的碳酸钾(6.53g,47.24mmol)和硫酸钠(约3g)。冷却至0-5℃(冰浴)后,于10分钟内加入溴乙酸叔丁酯(4.50mL,30.45mmol)并将混合物在此温度下放置15分钟。随后,将反应混合物回流4小时,再冷却至室温,过滤除去无机盐并在真空条件下蒸发滤液。通过“快速”硅胶色谱法对得到的残余物进行纯化。用正己烷/乙酸乙酯8∶2洗脱,生成纯的标题化合物(3.15g,76.4%),为无色油状物。
1H-NMR(CDCl3)
3.68(s,4H),3.27(s,4H),3.03(d,2H,J=14.1Hz),2.72(m,4H),2.61(d,2H,J=14.1Hz),1.44(s,36H),1.09(s,3H)。
13C-NMR(CDCl3)
172.6(s),170.8(s),80.6(s),80.1(s),66.1(t),62.3(t),60.6(s),59.1(t),51.5(t),28.1(q),28.0(q),24.1(q)。
MS(Cl)586(MH+)。
对C30H55N3O8(585.78)的分析计算:C,61.51;H,9.46;N,7.17。实测值:C,61.42;H,9.62;N,6.98。
在50mL圆底烧瓶中,将c)中所得的酯(3.03g,5.17mmol)溶于三氟乙酸(10mL)中。将得到的溶液于室温下放置过夜,然后于真空下蒸发,加入浓盐酸并蒸发至干。将固体残余物装载于XAD 1600树脂柱(3cm ID×30cm)上。用水/丙酮(100/0→70/30)洗脱,得到纯的标题化合物(1.33g,71.1%),为白色结晶,m.p.178-181℃(分解)(H2O)。
1H-NMR(D2O)
3.65(s,8H),3.51(m,4H),3.38(m,4H),1.06(s,3H)。
13C-NMR(D2O)
175.9(s),173.3(s),65.7(s),61.2(t),61.1(t),56.1(t),54.3(t),19.5(q)。
MS(FAB+)362(MH+)。
对C14H23N3O8(361.35)的分析计算:C,46.53;H,6.42;N,11.63。实测值:C,46.56;H,6.70;N,11.39。
按照与上述步骤类似的方法操作,可获得下列化合物:
尤其是制备了下列配体:
在100mL圆底烧瓶中,将d)中所得配体(3.61g,10mmol)混悬于30mL水中,加入1N的NaOH(10mL),得到澄清溶液,向该溶液中加入Gd2O3(1.81g,5mmol)并在50℃下加热15小时。冷却至室温后,将溶液过滤并蒸发至干,得到白色固体。
对C14H19GdN3NaO8(537.56)的分析计算:C,31.28;H,3.56;N,7.82;Na,4.28;Gd,29.25。实测值:C,30.98;H,3.71;N,7.99;Na,4.01;Gd,29.59。
实施例2
N,N”-二异丙基-2-甲基-1,2,3-丙烷三氨基-N,N’,N’,N”-四乙酸
e)N,N”-二异丙基-2-甲基-2-硝基-1,3-丙二胺
将装有异丙基胺(20.6g,349mmol)的250mL圆底烧瓶用冰浴冷却至3-5℃,并于约30分钟内加入37%的甲醛水溶液(26.3mL,350mmol),以使反应温度不超过10℃。加完后,将混合物搅拌15分钟,然后一次性加入硝基乙烷(13.1g,174.5mmol)。将混合物放置,使其温度升至室温,然后加入Na2SO4(20g),搅拌至完全溶解。将形成的两相分离,弃去下面的水层。再向有机相中加入Na2SO4(20g)并放置60小时。将混合物过滤并用二乙醚反复洗涤固体。合并滤液和洗涤液并在真空下蒸发。将残余物于真空下蒸馏,在3mmHg下收集88-90℃的馏分,即相应的标题化合物(25.9g,68.2%),为无色油状物,p.eb.88-90℃(3mmHg)。
1H-NMR(CDCl3)
1.01(d,12H,J=6.2Hz),1.50(bs,2H,与D2O交换),1.55(s,3H),2.73(sept,2H,J=6.2Hz),2.99(AB,4H,J=12.8Hz)。
13C-NMR(CDCl3)
20.7(q),22.8(q),48.9(t),52.5(d),91.9(s)。
MS(Cl)218(MH+)。
对C10H23N3O2(217.31)的分析计算:C,55.27;H,10.67;N,19.34。实测值:C,55.11;H,10.81;N,19.39。
b)N,N”-二异丙基-2-甲基-1,2,3-丙三胺
向a)中所得化合物(18.50g,85.1mmol)的甲醇(100mL)溶液中加入处于水中的50%阮内镍(3.5g)。将混合物置于Parr装置中并于60大气压和室温下进行氢化。约3小时后,观察到氢不再被吸收。用过滤混合物并用CH3OH(2×15mL)洗涤残余物。合并滤液和洗涤液并使之蒸发。在真空下蒸馏残余物,在3mmHg压力下收集98-100℃的馏分,即相应的标题化合物(15.15g,95.0%),为浅黄色透明油状物,p.eb.88-90℃(3mmHg)。
1H-NMR(CDCl3)
1.02(s,3H),1.03(d,12H,J=6.2Hz),1.40(bs,4H,与D2O交换),2.46(AB,4H,J=11.6Hz),2.71(sept,2H,J=6.2Hz)。
13C-NMR(CDCl3)
22.9(q),25.4(q),49.2(t),51.6(s),56.9(d)。
MS(Cl)188(MH+)。
对C10H25N3(187.33)的分析计算:C,64.12;H,13.45;N,22.43。实测值:C,63.89;H,13.61;N,22.49。
c)N,N”-二异丙基-N,N’,N’,N”-四(叔丁氧基羰基甲基)-2-甲基-1,2,3-丙三胺
向b)中所得的三胺(1.25g,6.67mmol)的乙腈(10mL)溶液中加入N,N-二异丙基乙胺(11.6mL,66.6mmol)。在搅拌和冰浴冷却条件下于30分钟内滴加溴乙酸叔丁酯(5.90mL,36.5mmol);滴加完毕后,除去冰浴并继续将混合物在室温下放置30分钟,然后回流15小时。之后,使混合物冷却并使之在真空下蒸发。使残余物在CH2Cl2和10%Na2CO3水溶液之间分配,水相用CH2Cl2(2×20mL)进一步萃取。有机相用Na2SO4干燥、过滤并在真空下蒸发。用柱色谱法(SiO2,梯度:己烷/乙醚100/0→50/50,30mL级分)纯化残余物,获得纯的标题化合物四酯(3.57g,83.0%),为浅黄色透明油状物。
Rf(SiO2,CHCl3)0.70。
1H-NMR(CDCl3)
0.91(d,6H,J=6.6Hz),0.96(d,6H,J=6.8Hz),1.16(s,3H),1.41(s,36H),2.57(AB,4H,J=14.3Hz),2.87(sept,2H,J=6.6Hz),3.38(s,4H),3.52(s,4H)。
13C-NMR(CDCl3)
17.7(q),19.8(q),19.9(q),27.9(q),51.2(s),53.9(t),54.0(t),55.0(t),63.1(d),79.7(d),80.0(s),172.0(s),172.9(s)。
MS(EI)645,644(MH+),530,457,343,287,231,186,160,130,112,88,70。
对C34H65N3O8(643.91)的分析计算:C,63.42;H,10.18;N,6.53。实测值:C,63.29;H,10.33;N,6.39。
d)N,N”-二异丙基-2-甲基-1,2,3-丙烷三氨基-N,N’,N’,N”-四乙酸
将c)中所得的酯(5.96g,9.10mmol)置于100mL圆底烧瓶中,加入浓盐酸(20mL)。将混合物回流7小时,然后冷却,用H2O(20mL)稀释并用CH2Cl2(3×15mL)萃取。将水相蒸发至干;残余物用浓盐酸/乙醇重结晶,生成二盐酸盐形式的标题配体(4.08g,91.0%)。
1H-NMR(CDCl3)
1.14(d,6H,J=6.3Hz),1.17(d,6H,J=6.3Hz),1.33(s,3H),3.21(AB,4H,J=15.1Hz),3.57(sept,2H,J=6.3Hz),3.68(s,8H)。
MS(FAB+)420(MH+),442(MNa+),458(MK+)[C18H33N3O8的计算值:419.47]。
C18H33N3O8·2HCl(492.39)的分析计算值:C,43.91;H,7.16;N,8.57。实测值:C,43.66;H,7.30;N,8.41。
实施例3
实施例1的Gd(III)络合物的稳定性
1.5电位计量测量
所有pH计量测量(pH=-log[H+])均使用配有Metrohm 6.0203.100复合pH电极的Metrohm 670滴定仪、在脱气的0.1mol dm-3NMe4NO3溶液中于298.1K下进行。每次电位滴定前,要对作为氢浓度探测器的复合Metrohm电极进行校准,方法是用不含CO2的NMe4OH溶液滴定已知量的盐酸,且通过Gran法测定等当点,其可测定标准电位E°和水的离子积。在该络合实验中,金属离子浓度为配体浓度的约80%。在2.5至10.5的pH范围内,对每个系统至少进行三次测定(每次测定约100个数据点),并用计算机程序SUPERQUAD和HYPERQUAD处理相关的电动势数据,提供质子化常数和络合常数。
反应 | LogK<sub>H</sub> |
H+L=HL | 11.80(2) |
HL+H=H<sub>2</sub>L | 6.55(2) |
H<sub>2</sub>L+H=H<sub>3</sub>L | 4.09(3) |
H<sub>3</sub>L+H=H<sub>4</sub>L | 2.60(3) |
H<sub>4</sub>L+H=H<sub>5</sub>L | 1.44(4) |
反应 | LogK<sub>Gd</sub> |
M+L=ML | 21.52(1) |
LogKGd(在pH7.4的条件下)=17.06
实施例1的Gd(III)络合物的弛豫(relaxometric)特性
在25℃、pH 7和20MHZ下测定的所述络合物的弛豫率为7.1mM-1s-1。
根据以上引用文献中Aime等人所述的方法,通过测量不同温度下水17O NMR的横向弛豫时间,对实施例1的Gd(III)络合物的交换时间(τM)值进行了估算。结果总结于图1。在298K下获得的数值为90ns。尽管没有达到最优值(约30ns),但可以认为该交换速率尤其是与参比Gd(III)络合物(Gd-DO3A)的交换速率相比较时是非常快的,(Gd-DO3A)的内层有两个水分子,其τM值为160ns。
图2显示了实施例1的Gd(III)络合物的NMRD曲线,由其拟合结果我们可以计算出τR值(分子重排时间)为80ps,且电子弛豫时间值与其它小型Gd(III)络合物的时间值相似(参见以上引用的Merbac A.E.的文献)。
还将该络合物的弛豫率作为pH的函数进行了测定。图3显示了所获得的结果。
足以令人惊讶的是:发现实验络合物的弛豫率在所有所研究的pH范围内基本上保持恒定。该结果清楚地表明:具有本发明配体的Gd络合物对碱性pH溶液中存在的氢氧根和氨基甲酸根阴离子表现出低亲和性。相反,它们会显著地降低所测定的弛豫率。
为进一步评价三元络合物的形成缺失,进行了一项实验。作为非限制性实施例,我们测定了实施例1的化合物对乳酸根和磷酸根离子的亲和性。测定是通过将递增量的每种阴离子加入至1mM的Gd(III)络合物溶液中直接进行的。所得结果显示于图4,该结果表明:即使在高浓度的双配位基内源性阴离子存在下,也完全没有发生相互作用。
按类似的方法用乳酸根离子对Gd-DO3A和Gd-DO3MA(q均为2)进行反滴定,得到的KA值分别为150M-1和110M-1。
配体1的Gd络合物不显示任何可测量的络合常数,的确是对该阴离子具有较低亲合性的络合物。
该结果表明:具有本发明配体的Gd络合物的弛豫率即使在高浓度的双配基内源性阴离子存在时也不降低。
此外,一旦该类顺磁性络合物的分子运动例如因与大分子结合而减慢,配位水的高交换率就会使其非常有趣地获得高弛豫率(r1和/或r2)。正如本领域专业人员所知,有很多方法可以用来使配体和/或其金属络合物(共价的和非共价的)与有关分子结合(共价方式和非共价方式)。
Claims (19)
2.权利要求1的化合物、其螯合物或盐,其中FG为羧基。
3.权利要求1的化合物、其螯合物或盐,其中R2为C1-C20烷基,任选被保护或未保护的羧基取代。
4.权利要求3的化合物、其螯合物或盐,其中R2为甲基,任选被保护或未保护的羧基取代。
5.权利要求1的化合物、其螯合物或盐,其中两个R1基团共同形成亚烷基,选自亚乙基或亚丙基。
6.权利要求5的化合物、其螯合物或盐,其中两个R1基团形成亚乙基。
7.权利要求1的化合物的螯合物在制备磁共振成像对比剂中的用途。
8.权利要求7的用途,其中螯合物为Gd(3+)、Eu(3+)、Dy(3+)、La(3+)、Yb(3+)或Mn(2+)的螯合物。
9.权利要求8的用途,其中螯合物为钆螯合物。
10.权利要求1的化合物与放射性同位素的螯合物在制备放射治疗剂或放射诊断剂中的用途。
11.权利要求10的用途,其中螯合物为选自203Pb、67Ga、68Ga、72As、111In、113In、90Y、97Ru、62Cu、64Cu、52Fe、52mMn、140La、175Yb、153Sm、166Ho、149Pm、177Lu、142Pr、159Gd、212Bi、47Sc、149Pm、67Cu、111Ag、199Au、161Tb和51Cr的放射性同位素的螯合物。
12.药物或诊断组合物,其含有权利要求1至6的化合物的螯合物与适宜的载体。
14.权利要求13的式(IX)化合物,其中两个R1基团为亚乙基或亚丙基。
15.磁共振成像对比剂,包含权利要求1至6任一项的螯合化合物。
16.权利要求15的磁共振成像对比剂,其中螯合物是与选自下组的金属离子形成的螯合物:Gd(3+)、Eu(3+)、Dy(3+)、La(3+)、Yb(3+)或Mn(2+)。
17.权利要求16的磁共振成像对比剂,其中的金属离子是Gd(3+)。
18.放射诊断或放射治疗剂,包含权利要求1至6任一项的化合物与放射性同位素的螯合物。
19.权利要求18的放射诊断或放射治疗剂,其中放射性同位素选自203Pb、67Ga、68Ga、72As、111In、113In、90Y、97Ru、62Cu、64Cu、52Fe、52mMn、140La、175Yb、153Sm、166Ho、149Pm、177Lu、142Pr、159Gd、212Bi、47Sc、149Pm、67Cu、111Ag、199Au、161Tb和51Cr。
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US7226577B2 (en) | 2003-01-13 | 2007-06-05 | Bracco Imaging, S. P. A. | Gastrin releasing peptide compounds |
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