CN1057585A - 醚异腈及其放射性标记配合物的应用 - Google Patents
醚异腈及其放射性标记配合物的应用 Download PDFInfo
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- CN1057585A CN1057585A CN91105401A CN91105401A CN1057585A CN 1057585 A CN1057585 A CN 1057585A CN 91105401 A CN91105401 A CN 91105401A CN 91105401 A CN91105401 A CN 91105401A CN 1057585 A CN1057585 A CN 1057585A
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- Prior art keywords
- ether
- coordination compound
- isonitrile
- amine
- grams
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- 229940075931 sodium dithionate Drugs 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- IMHMACPYENTGSX-UHFFFAOYSA-N technetium(4+) tetracyanide Chemical class [C-]#[N+][Tc]([N+]#[C-])([N+]#[C-])[N+]#[C-] IMHMACPYENTGSX-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
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Abstract
醚取代异腈、醚取代异腈的Tc99m配合物和应
用Tc99m配合物的心肌组织摄象的方法。
Description
本发明涉及新颖的醚取代异腈及其放射性标记配合物在心肌摄象中的应用。
Jones等人于1984年6月5日出版的美国第4,452,77号专利中,叙述了各种不同的放射性异腈配合物及其作为摄象剂的应用。Jones等人所叙述的配合物的通式是:
式中A是选自放射性同位素Tc、Ru、Co、Pt、Fe、Os、Ir、W、Re、Cr、Mo、Mn、Ni、Rh、Pd、Nb和Ta的放射性核,例如,99Tc、99Tc、99Ru、51Cr、59Co、188Re和191Os;
(CN)xR是通过CN基的碳原子与放射性核键合的异腈一合配位体或异腈多合配位体;R是有机基;B和B′是从其他各自选自对于本技术领域专业人员是众所周知的可生成异腈配合物的配位体,其中包括水、氯和溴基、以及包括一个或多个能与上述放射性核形成键的供电子原子;X和Y各自为由1至8的整数;Z和Z′各自为0或由1至7的整数;但是(XY)+Z+Z′必须小于或等于8;而n表示配合物的价数,此价数可等于0(电中性)、或正、负整数,而配合物的具体价数则取决于A的价态和R、B和B′的电荷数。如果此配合物准备用于体内药物时,则任何所需要的相反离子的存在可由配合物上的电荷的需要来确定,但是,这些相反离子必须是药物可接领的离子。
在上述通式中,R可以是脂肪族或芳香族的有机基,而且可取代上各种各样的带电荷的或不带电荷的基。当上述有机基R上有带电荷的取代基时,则所形成的配合物上的电荷数是配位体(R、B、和B′)的电荷数和放射性核的电荷数的总和。可存在的芳香基R是苯基、甲苯基、二甲苯基、萘基、二苯基以及带有取代基的芳香基,该取代芳香基上的取代基可包括象卤基、例如,氯基、溴基、碘基或氟基;羟基、硝基、烷基、烷氧基等;可存在的脂肪基R是烷基、最好是含有1至20个碳原子的烷基,例如,甲基、乙基、正丙基、异丙基、正丁基、异丁基、正己基、2-乙基己基、十二烷基、十八烷基等。脂肪基上的取代基可包括与上述取代芳香基上相同的取代基。
Johes等人认为他们所叙述的配合物可用于观测心血管、检查血液灌注短缺的肺及其有关联部位的血栓、研究肺功能、研究肾排泄和拍摄骨髓和肝胆管系统。
实际上,Jones等人推荐的简单烃类异腈的锝配合物,例如,叔丁基异腈,已证明在人的肝和肺中的浓度稍高〔Holman等人,J.Nucl,Med.,25,1380(1984)〕。肺中放射性核过早的高浓度要求推迟心脏的拍摄,以便在拍取有用的心肌像之前使肺机能恢复正常。此外,肝内放射性核的浓度高,使检查心肌尖部位的灌注短缺更加困难。显然,需要有一种选择性更高的心肌摄象的制剂。
本发明的目的是提供新颖的醚取代异腈及其诊断制剂(diagnostic kits)、这些异腈的放射性标记配合物(最好是Tc99m)、和应用放射性配合物的诊断方法。虽然Jones等人在美国第4,452,774号专利公开的通式包括了本发明的放射性标记的、醚取代的异腈配合物,但是并未具体公开象本发明这样的配合物,同时Jones等人也未设想过这些醚取代异腈所具有的令人注目的优越摄象特性。
更具体地来说,本发明的一个内容是提供一种通式Ⅰ的新颖醚取代异腈(及其制剂):
CN-A-O-R
Ⅰ
式中:A是直链或支链烷基和R是直链或支链烷基,条件是A加R的碳原子总数等于4至6,另一个条件是当A加R的碳原子总数等于6时,与异腈基连接的第一个碳原子是季碳原子,再一个条件是A不是(CH2)3。
本发明的另一个内容是涉及这些通式为〔M(CN-A-O-R)6〕的醚异腈的新颖放射性标记配合物,式中M是放射性核,最好是Tc 99m。本发明的另一个内容是涉及这些放射性标记异腈配合物作为心肌摄象剂的应用。
将通式Ⅱ的一种烷氧基胺甲酰化生成相应的甲酰胺Ⅲ,然后将其脱水为异腈Ⅰ,即可容易地制备本发明的异腈。
文献中有各种各样的甲酰化和脱水反应的方法,这些方法对于有机合成的专业人员都是十分熟悉的。
胺Ⅱ可用本专业人员熟知的各种方法来制备。尤其是可在有酸性催化剂存在的情况下,用一种醇将氮丙啶Ⅳ开环,生成可用蒸馏方法分离的胺Ⅴ和胺Ⅳ二种胺的混合物。
另一方面,胺可用烷氧基酯Ⅶ来制备,其中A′是2或3个碳原子的烃。将烷氧基酯Ⅶ与氨或氢氧化铵起反应生成酰胺Ⅷ,然后用氢化锂铝或另一种熟知的还原剂来还原酰胺即可制得胺Ⅸ。
胺Ⅱ亦可用烷氧基酯Ⅹ来制备。可按上述步骤进行生成酰胺Ⅺ。将Ⅺ进行霍夫曼重排即可产生胺Ⅱ。
另一方面,可将氨基醇Ⅻ首先与一甲酰化剂,例如甲酸乙酯或甲酸乙酸酐起反应,形成甲酰胺-甲酸酯ⅩⅢ来制备醚异腈。可按上述将其他甲酰胺转化为异腈的方法,将甲酰胺-甲酸酯转化为异腈-甲酸酯ⅩⅣ。适度水解可产生异腈-醇ⅩⅤ,然后在象应用氢化钠和卤代甲烷,例如碘代甲烷,的标准烷基化条件下将此异腈-醇ⅩⅤ烷基化。
在本发明的实践中,有用的醚取代异腈包括:
现将制备这些醚取代异腈的具体实例详述如下。
制备1:合成1-甲氧基-2-甲基丙基-2-胺和2-甲氧基-2-甲基丙基-1-胺
A.合成2,2-二甲基氮丙啶
将2-氨基-2-甲基-1-丙醇(100克,1.12摩尔)溶于水(200毫升)中,并置于1000毫升的圆底烧瓶中。将浓硫酸(100克,1.12摩尔)溶于水(200毫升)并加入胺溶液中。将所得的温热溶液在常压下蒸馏。当温度升至120℃时,将压力减至吸气器压力(约20毫米汞柱),继续蒸馏至馏出液的温度达到150℃。将所得的棕色胶置于真空下(约1毫米汞柱)并在170°~200℃下加热1.5小时。有一些碳化,得到一种固体。将烧瓶包在保护垫中,然后再将烧瓶打破,抛弃碎玻璃。用槌子将固体打碎,然后用研杵研磨至大部分成为细粉末,其中碎粒的直径不大于1/4″。将固体加入含有氢氧化钠(100克,2.5摩尔)的水(150毫升)溶液中。用盐水浴将悬浮液加热至110℃,固体即缓缓溶解形成一种黑色溶液。在70~88℃下,将产物从此溶液中蒸馏到氢氧化钠颗粒(25克,0.63摩尔)上。到蒸馏结束时,在容器中形成了一种白色的沉淀。用玻璃毛过滤后,除去水层并将产物用氢氧化钠干燥,过滤,再用金属钠干燥。在70~73℃下将产物从金属钠中蒸馏出来,制得46.2克的透明无色产物(产率58%)。
NMR(CHCl3):δ0.1(s,1H,NH)、1.25(s,6H,CH3)、1.55(s,2H,CH2)
B.合成1-甲氧基-2-甲基丙基-2-胺和2-甲氧基-2-甲基丙基-1-胺
将2,2-二甲基氮丙啶(27.68克,0.39摩尔)溶于新蒸馏的甲醇(50克)中。将此溶液在冰/丙酮浴中冷却至-10℃。将三氟化硼双甲醇配合物(58.32克,0.44摩尔)溶于新蒸馏的甲醇(50克)中并在冰/丙酮浴中冷却至-10℃。将冷却后的三氟化硼溶液在20分钟内缓缓加入冷却后的氮丙啶溶液中。令所得到的溶液慢慢地升至室温。在室温下将溶液搅拌7天,并在产物生成过程中用核磁共振进行检测。用旋转蒸发方法(25毫米汞柱、40℃)将溶液体积减至约原体积的一半。加入甲醇钠在甲醇(95.04克的25%(w/w)溶液,0.594摩尔)中的溶液并得白色沉淀。加入二乙醚并过滤沉淀。将仍然混浊的溶液进行蒸馏,并当温度达到60℃时,将其再进行过滤。继续蒸馏并获得二种胺的混合物(14.24克,35%)。小心地进行分馏,将二种胺分离,即可制得纯2-甲氧基-2-甲基丙基-2-胺(沸点123~124℃),NMR(CDCl3):δ1.2(s,8H,NH2CH3)、2.7(s,2H,CH2)、3.3(s,3H,CH3O)和1-甲氧基-2-甲基丙基-2-胺(沸点103~104℃),NMR(CDCl3):δ1.1(s,6H,CH3)、1.6(bs,2H,NH2)、3.1(s,2H,CH2)、3.4(s,3H,CH3O)。
制备2:合成2-甲氧基-2-甲基丙基-1-胺
A.合成2-甲氧基-2-甲基丙酸甲酯
将二甲基甲酰胺(100毫升)和四氢呋喃(300毫升)置于1000毫升装有温度计、机械搅拌器和滴液漏斗的三口圆底烧瓶中。加入氢化钠在油中的80%的分散体(19.80克,0.66摩尔),形成一种灰色悬浮液。将悬浮液在冰水浴中冷却。将羟基异丁酸甲酯(70.8克,0.60摩尔)溶于四氢呋喃(50毫升)并将其缓缓加入温度保持低于15℃的冷却氢化钠悬浮液中。将所得到的悬浮液搅拌一小时。将四氢呋喃(25毫升)中含有甲基碘(新蒸馏的、108.75克,0.75摩尔)的溶液缓缓加入冷的悬浮液中。用1.5小时来进行滴加,在滴加过程中温度保持低于15℃。搅拌悬浮液并令其升至室温和保持15小时。将悬浮液倾入乙酸乙酯(300毫升)和水(300毫升)中。分离清晰层并用乙酸乙酯(300毫升)提取水相。将合并的有机层用含有亚硫酸氢钠(10克)的水(200毫升)脱色。分离有机相并用硫酸镁进行干燥。用旋转蒸发器(25毫米汞柱、30℃)除去大部分的溶剂。在常压下将所得到的溶液进行蒸馏并在137~146℃下收集产物。产物中含有二甲基甲酰胺(DMF),但是通过核磁共振鉴定,产物的产量为48.8克(61%)。
NMR(CHCl3):δ1.4(s,6H,CH3)、3.3(s,3H,CH3O醚)、3.8(s,3H,CH3O酯)。
B.合成2-甲氧基-2-甲基丙酰胺
将2-甲氧基-2-甲基丙酸甲酯(42.24克,0.32摩尔,并带有10.6克DMF)加入氢氧化铵(200毫升)。将得到的两相系统在25~30℃下搅拌17小时。用旋转蒸发器(25毫米汞柱,50℃)将得到的透明均相溶液浓缩至产生白色沉淀。将湿固体溶于二氯甲烷(200ml)。分离水层并将二氯甲烷层通过二氧化硅塞。用二氯甲烷(100毫升)洗水层并将此二氯甲烷层亦通过二氧化硅塞。最后,将二氯甲烷(100毫升)通过二氧化硅塞并用旋转蒸发器(25毫米汞柱,35℃)蒸发合并的二氯甲烷馏分,即可得到白色的结晶。将此白色结晶在真空中干燥,可得到29.5克(79%)的2-甲氧基-2-甲基丙酰胺。
NMR(CDCl3):δ1.4(s,6H,CH3)、3.3(9,3H,CH3O)、6.4(极宽b,2H,NH2)。
C.合成2-甲氧基-2-甲基丙基-1-胺
将氢化锂铝(3.04克,0.08摩尔)加入250毫升的干双口圆底烧瓶中。在任何时候烧瓶均须保持在干燥氮气中。加入无水四氢呋喃(THF)(25ml)并搅拌悬浮液。将2-甲氧基-2-甲基丙基酰胺(81.9克、0.07摩尔)加入80毫升的无水四氢呋喃中并将此溶液缓缓加入氢化锂铝悬浮液。控制滴加速度使其足以保持进行平缓的回流。用半小时来进行滴加,将所得到的悬浮液再回流一小时。令悬浮液冷却,在搅拌下逐滴加入3毫升水,随后再加入3毫升15%氢氧化钠。最后,加入9毫升水并使温热的悬浮液搅拌15分钟。用中孔熔结玻璃漏斗过滤白色沉淀并反复用THF清洗沉淀。在常压下蒸馏所合并的THF。在低于70℃下除去THF。将产物在约124℃蒸馏。
产量:4.19克(58%)
NMR(CDCl3):δ1.15(s,8H,CH3,NH2)、2.6(s,2H,CH2)、3.2(s,3H,CH3O)。
制备3:合成N-(2-甲氧基-2-甲基丙基)甲酰胺
将甲酸(19.2克,0.40摩尔)与乙酸酐(40.8克,0.40摩尔)混合,并在45~50℃下加热一小时,然后在冰/丙酮浴中冷却至约为0℃。将予先在冰/丙酮浴中冷却至约0℃的2-甲氧基-2-,甲基丙基-1-胺缓缓加入并同时保持混合物的温度低于12℃。在滴加结束后,令混合物缓缓升至室温并在室温下搅拌过夜。将溶液蒸发和将剩余物在97~107℃/1-2毫米汞柱压力下蒸馏,即可得到43.2克(94%)的产物。
NMR(CDCl3):δ1.2(s,6H,CH3)、3.3(m,5H,CH3O和CH2)、6.6(b,1H,NH)、8.2(bs,1H,HCO)。
制备4:N-〔2-(1-甲氧基丙基)〕甲酰胺
将甲酸(16.80克,0.35摩尔)与乙酸酐(37.50克,0.35摩尔)混合并在45~50℃下加热一小时,然后在冰/丙酮浴中冷却至约0℃。将2-氨基-1-甲氧基丙烷(26.7克,0.30摩尔)在冰/丙酮浴中冷却至低于0℃。将甲酸(25毫升)缓缓加入冷却的胺中。将所得到的溶液进一步冷却至低于0℃。将胺溶液加入冷却的甲酸-乙酸酐溶液,搅拌所得到的溶液并令其缓缓升至室温过夜。在低压(约1毫米汞柱)下蒸馏溶液,而甲酸、乙酸和甲酸-乙酸酐则全在低温下蒸馏。在79~85℃下蒸馏产物,得到透明无色油状产物。产量为33.13克(94%)。
NMR(CDCl3):δ1.05(d,3H,CH3-C)、3.4(M,5H,CH3O和CH2O)、4.2(M,1H,CH)、6.8(b,1H,N-H)、8.0(b,1H,HC-O)。
异腈的合成
下列制备2-甲氧基-2-甲基丙基-1-异腈、1-甲氧丙基-2-异腈和3-异腈-3-甲基-1-甲氧基丁烷的合成路线也适用于制备上面详述的醚化合物的其他相应的异腈化合物。
1.制备2-甲氧基-2-甲基丙基-2-异腈
将N-(2-甲氧基-2-甲基丙基)甲酰胺(1.97克,0.015摩尔)加入二氯乙烷(23毫升)中。加入三乙胺(4.04克,0.040摩尔)并将此透明溶液在冰/水浴中冷却。将双光气(氯甲酸三氯甲酯,1.68克,0.0085摩尔)溶于二氯甲烷(10毫升)中并缓缓加入冷却的甲酰胺溶液中(45分钟)。搅拌2小时,令悬浮液升至室温。然后将悬浮液倾入含有磷酸二氢钠(6.90克,0.05摩尔)的水(25毫升)中。分离二氯甲烷层并用碳酸钠干燥。然后在减压(25毫米汞柱)下将溶液进行蒸馏,在56~59℃下将产物进行蒸馏,即可得到0.530克产物(产率31%)。
NMR(CDCl3):δ1.3(s,6H,CH3)、3.25(s,3H,CH3O)、3.4(m,2H,CH2)。
2.制备1-甲氧基丙基-2-异腈
将N-〔2-(1-甲氧基丙基)〕甲酰胺(11.7克,0.10摩尔)溶于二氯甲烷(125毫升)中。加入三乙胺(30.30克、0.30摩尔)并将此透明溶液在冰/水浴中冷却。将双光气(11.88克,0.06摩尔)溶于二氯甲烷(40毫升)中。将此双光气溶液缓缓加入冷却的甲酰胺溶液中。搅拌所得到的悬浮液并令其缓缓升至室温12小时。将悬浮液倾入含有碳酸钠(42.4克,0.40摩尔)的水中。分离二氯甲烷层并用含磷酸二氢钠(55.2克,0.40摩尔)的水洗涤。分离二氯甲烷层并用碳酸钠(无水)干燥。
过滤溶液并在吸气压力(约25毫米汞柱)下蒸馏。在63~66℃下蒸馏产物。产品为5.83克(58.8%)。
NMR(CDCl3):δ1.05(6个相同的峰,3H,CH3C)、3.0(s,3H,CH3-O)、3.1(m,2H,CH2)、3.5(m,1H,CH)。
3.合成3-异腈-3-甲基-1-甲氧基丁烷
A.合成3-甲酰胺-3-甲基-1-丁醇
将3-氨基-3-甲基-1-丁醇(20.60克,0.20摩尔)加入甲酸乙酯(29.60克,0.40摩尔),在氮气氛下将所得的清晰溶液回流加热2小时,然后令其冷却至室温。用旋转蒸馏法(35℃、25托)将甲酸乙酯和乙醇副产品除去。在减压(25℃、0.1托)下将所得的油状物干燥可得产物25.86克(99%)。
NMR(CDCl3):1.4(d,6H,CH3)、2.0(m,2H,C-CH2)、3.9(m,2H,O-CH2)、7.1(bs,1H,NH)、(m,1H,HCO)。
B.合成甲酸(3-甲酰胺-3-甲基-1-丁)酯
将甲酸(6.90克,0.15摩尔)加入乙酸酐(15.30克,0.15摩尔)中并在水浴中温热至45~50℃1小时。在冰/丙酮浴中将所得溶液冷却至低于0℃。加入3-甲酰胺-3-甲基-1-丁醇(13.10克,0.10摩尔)并在不断搅拌下(16小时)令溶液缓缓升至室温。在减压(1托、105~110℃)下将溶液蒸馏,即可获得产物12.43克(78%)。
MNR(CDCl3):1.4(s,6H,CH3)、2.1(t,2H,C-CH2)、4.2(t,2H,O-CH2)、6.0(bs,1H,NH)、8.0(m,2H,HCOO)。
C.合成甲酸(3-异腈-3-甲基-1-丁)酯
将甲酸(3-甲酰胺-3-甲基-1-丁)酯(11.13克,0.07摩尔)和三乙胺(21.21克,0.21摩尔)溶于二氯甲烷(350毫升)中。在氮气氛下,在冰/水浴中将所得溶液冷却。将氯甲酸三氯甲酯(双光气)(8.32克,0.042摩尔)溶于二氯甲烷(50毫升)并在30分钟内逐滴加入搅拌、冷却的甲酰胺溶液中。搅拌所得悬浮液并令其在90分钟内升至室温。将碳酸钠(23克,0.22摩尔)水(250毫升)溶液加入此悬浮液中,并分离下面的有机层。用磷酸二氢钠(30克,0.22摩尔)水(250毫升)溶液洗涤所分离的有机层。用碳酸钠(无水,25克)干燥所得的有机层。将溶液过滤并在吸气压力(25托)下蒸馏。在低于室温下蒸馏溶剂,并在96~102℃下蒸馏产物,即可获得9.22克产品(93%)。
NMR(CDCl3):1.5(m,6H,CH3)、2.0(m,2H,C-CH2)、4.4(t,2H,O-CH2)、8.0(s,1H,HCO)。
D.合成3-异腈-3-甲基-1-丁醇
将碳酸氢钠(8.40克,0.10摩尔)和碳酸钠(10.60克,0.10摩尔)溶于水(200毫升)中。加入甲酸(3-异腈-3-甲基-1-丁)酯并剧烈搅拌。令此混浊溶液在室温下放置5小时。加入氯化钠(10克,0.17摩尔)并将悬浮液搅拌15分钟。用乙酸乙酯(3×100毫升)提取悬浮液。合并三次提取的有机层。用碳酸钠(25克)干燥、过滤并在吸气压力(25托)下蒸馏。将产物在120℃下蒸馏,即可获得产品5.38克(74%)。
NMR(CDCl3):1.5(m,6H,CH3)、2.0(m,2H,C-CH2)、3.0(bs,1H,OH)、4.0(t,2H,O-CH2)。
E.合成3-异腈-3-甲基-1-甲氧基丁烷
将3-异腈-3-甲基-1-甲氧基丁醇(1.13克,0.01摩尔)溶于四氢呋喃(20毫升)和二甲基亚砜(2毫升)中。加入碘代甲烷(1.42克,0.01摩尔)并将溶液在室温下搅拌5分钟。将氢化钠(80%油分散体,0.30克,0.01摩尔)在15分钟内逐次分批加入。加入15毫升水并分离有机层。用乙酸乙酯(2×20毫升)提取有机层,将二次提取的有机层合并用碳酸钠(2克)干燥、过滤并在吸气压力(25托)下蒸馏。将产物在80~90℃下蒸馏,即可获得产品0.48克(38%)。
NMR(CDCl3):1.5(m,6H,CH3)、2.0(m,2H,C-CH2)、3.4(s,3H,CH3)、3.6(t,2H,O-CH2)。
在由室温至回流温度或更高的温度下,将异腈与放射性金属在合适的介质中混合,可制备所需要的放射性标记的醚取代异腈配合物。所需要的标记异腈配合物是不溶解的并可获得高产量。在有些情况中,异腈本身可作为一种还原剂,因此不需要再加还原剂。当需要和希望加速反应时,所应该加入的附加还原剂,对于专业人员来说,是众所周知的。此种众所周知的还原剂包括亚锡盐(通常以制剂(kits)方式应用)、甲脒亚磺酸、连二亚硫酸钠、亚硫酸氢钠、羟胺、抗环血酸等。反应一般在1分钟至2小时后结束,具体结束时间则取决于所用的特殊试剂和条件。
在用象锝一类的放射性核时,例如99TC或99mTC,最好是将适当的还原剂(能够在含水介质中还原锝)和适当的醚取代异腈混合,然后再加入高锝酸盐来制备异腈配合物。另一种方法是,将醚取代异腈与高锝酸盐混合,然后再加入还原剂来制备异腈配合物。
与本发明一致的异腈锝配合物还可用具有氧化态锝,例Ⅲ价、Ⅳ价或Ⅴ价锝的预制锝配合物,通过将这些预制配合物在合适的条件下用过量的醚取代异腈处理来制备。
配合反应中可应用过量高达100倍或更高的过量醚取代异腈与过量的还原剂,以保证从锝放射性核获得最高产量。反应后,可将所希望的配合物从反应混合物中分离出来,需要时,例如可通过结晶或沉淀或通过常规色谱或离子交换色谱来进行分离;见上述美国第4,452,774号专利,文中公开的内容列入本发明的参考文献。
与本发明一致的制剂包含一种无菌的、不发热的、醚取代异腈配位体,必要时,可包含一定数量的还原一种预选放射性核的还原剂。此种制剂最好是含有一种预先确定数量的无菌的、醚取代异腈配位体和一种预先确定数量的能够还原预先确定数量的预选放射性核的无菌还原剂。在可能的时候,此种异腈配位体和还原剂最好还是冷冻干燥的,以促进储存稳定性。如冷冻干燥不切实可行时,制剂可冷冻储存或在室温下以溶液形式储存。醚取代异腈和还原剂最好是装在密封的、不发热的无菌容器内。在此种制剂中的醚取代异腈可以是非放射性金属加合物的形式,例如在与本发明同时待批和共同转让的美国专利申请762,392号中、和已发表的欧洲专利申请183,555号(于1986年6月24日出版)中所叙述的那些加合物,这二份文件中所公开的内容均列入本发明的参考文献。适用于制备这些金属加合物的可置换金属是选自Cu、Mo、Pd、Co、Ni、Cr、Ag、Rh(U.S.S.N.672,392)和Zn(欧洲专利183,555)的物质,并能很容易地将可置换的金属的配合物在一种合适的介质中,和在由室温至回流温度或更高的温度下,与醚取代异腈配位体混合来制备。反应一般在1分钟至2小时后完成,具体完成时间取决于所用的试剂和条件。放射性核的选择将取决于用途。当然,由于Tc 99m发生剂(generator)的有效性,所以尤其是最好使用此种放射性核。
下面举例说明本发明的醚取代异腈比Jones等人(美国专利第4,452,774号)所推荐的简单烃类异腈具有意想不到的优越性。
实例
制备下列TC 99m配合物:
配合物A:
配合物B:
配合物C:
叔丁基异腈配合物(比较):
这些锝配合物应用类似于Jones等人所报导的标准标记条件来制备。将异腈(3~5毫升)在一支10毫升的血清管形瓶中溶于乙醇(1毫升)并将管形瓶封好,然后加入用99Mo/99mTc放射性核发生剂洗脱后得到的100~150微居里的99mTeO- 4。加入连二硫酸钠(0.5毫升由20~25毫克和10毫升蒸馏水配成的水溶液)并将管形瓶置于100℃水浴中15分钟。冷却至室温后,加入1毫升水和1毫升二氯甲烷,于是产物被提取入二氯甲烷中。将有机层蒸发并将产物溶于乙醇中。成品的纯度可用薄层色谱whatman C-18反相板和应用含22%0.5M醋酸铵水溶液、66%甲醇、9%乙腈和3%四氢呋喃的溶剂混合物来测定或用高压液相色谱Brownlee C-8反相柱(5毫米)和一种含有0.05M硫酸铵水溶液和从注射时开始一分钟后在20分钟内具有0~90%的线性梯度的乙醇的溶剂系统来测定。
通过测定天竺鼠的生物分配来评价配合物。在注射后5、30和120分钟测定注射剂效能的器官分配情况。在上述三个测定时间点,用戊巴比妥钠(35毫克/公斤,国际药典)麻醉三只天竺鼠和通过颈静脉注射0.1毫升试验剂。99mTc异腈的注射剂量是1~2.5毫居里。解剖时,取出体内器官用Capintec剂量校准器或γ或计数器测定放射性。称量心、肺和肝的重量。用下表说明配合物在心、肺和肝中的放射性的分配。参看心/肝和心/肺比,可容易地看出本发明的锝-99m配合物,在显示肺的低吸收量和肝的较低吸收量(和/或颇迅速地从肝中洗除)并同时保持高的心肌吸收量方面比简单的烃异腈具有显著的优越性。
表
器官比
心中注射剂量%
心/肺*
心/肝*
5分钟 30分钟 2小时 5分钟 30分钟 2小时 5分钟 30分钟 2小时
a 1.7 1.2 0.8 1.5 2.9 4.8 1.6 1.6 2.7
b 1.4 1.5 1.2 2.3 2.7 5.1 2.0 2.1 5.7
c 1.3 1.4 0.5 3.0 3.8 2.8 2.5 5.0 3.1
d 1.2 1.2 1.0 0.2 0.5 2.0 1.8 1.4 0.8
注:上述所有数值均为三只动物的平均试验值。
*按每个器官的 (注射剂量%)/(组织克数) 的比值计算。
a=[99mTc(C≡NC(CH3)2CH2OCH3)6]+
b=[99mTc(C≡NCH2C(CH3)2OCH3)6]+
c=[99mTc(C≡NCH(CH3)CH2OCH3)6]+
d=[99mTc(C≡NC(CH3)3)6]+
Claims (3)
1、将应用下述方法制得的醚取代异腈或其金属加合物与还原剂混合,以制备无菌的不发热形式的制剂,该醚取代异腈的通式为CN-A-O-R(Ⅰ),式中A是直链或支链烷基,R是直链或支链烷基,条件是A加R的碳原子总数等于4至6,另一个条件是A不是(CH),而再一个条件是当A加R的碳原子总数等于6时,与异腈连接的第一个碳原子是季碳原子,制备方法包括:
(a)下列通式的胺的甲酰化
HN-A-OR(Ⅱ)
式中A和R的定义如上所述,在从-5℃至回流温度下,将此胺与甲酸乙酯或甲酸-乙酐接触,制备下列通式的甲酰胺:
OH
H-C-N-A-O-R(Ⅲ)
(b)步骤(a)制备的甲酰胺的脱水,可在从-10℃至室温的温度下,将此甲酰胺在一种惰性溶剂中,在一种叔胺的存在下与双光气接触或在一种胺碱的存在下与磷酰氯接触,生成醚取代异腈,或
(c)将通式(Ⅰ)的异腈产物与选自Cu、Mo、Pd、Co、Ni、Cr、Rh、和Zn的非放射性金属配合物反应,生成一种醚取代异腈金属加合物。
2、将权利要求1的醚取代异腈或其金属加合物制得的〔Tc99m(CN-A-O-R)6〕配合物(A和R的定义如权利要求1中所述),应用于射线摄象,其中包括(ⅰ)该配合物与适合的生理上可接受的载体的非肠道给药;(ⅱ)使该配合物在心肌中局部停留足够时间后进行心肌摄象。
3、将权利要求1的醚取代异腈或其金属加合物制得的〔Tc99m(CN-A-O-R)6〕配合物,其中A为CH2C(CH3)2、C(CH3)2CH2、CH(CH3)CH2、CH2CH(CH3)、CH(CH3)CH(CH3)、CH2CH(CH3)CH2、CH2CH2CH(CH3)、C(CH3)2、CH(CH2CH3)CH2、CH(CH3)CH2CH2、C(CH3)2CH2CH3、CH2CH(CH2CH3),R为CH3;或A为(CH2)3、CH(CH3)CH2、CH2CH(CH3)、C(CH3)2、(CH2),R为CH2CH3;或A为CH(CH3)2、CHCH3,R为CH(CH3)2,应用于射线摄象,其中包括(ⅰ)该配合物与适合的生理上可接受的载体的非肠道给药;(ⅱ)使该配合物在心肌中局部停留足够时间后进行心肌摄象。
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PT (1) | PT83996B (zh) |
SU (1) | SU1635903A3 (zh) |
Cited By (3)
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CN1057398C (zh) * | 1994-12-16 | 2000-10-11 | 电化学工业有限公司(国际) | 用于不定域地标记物品的组合物及其制备和用途 |
WO2002087633A1 (en) * | 2001-04-27 | 2002-11-07 | Beijing Normal University | Myocardial imaging agent and preparation method thereof |
CN105555759A (zh) * | 2013-07-01 | 2016-05-04 | 麦地那创新药物研究中心基金会 | 具有抗菌活性的化合物 |
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US4885100A (en) * | 1987-09-11 | 1989-12-05 | E. I. Du Pont De Nemours And Company | Tris(isonitrile)copper(I) adducts for preparing radionuclide complexes |
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JPH05508162A (ja) * | 1990-06-18 | 1993-11-18 | マリンクロッド・メディカル・インコーポレイテッド | イソニトリルリガンド含有金属―放射性核種錯化合物 |
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AU3119199A (en) | 1998-04-03 | 1999-10-25 | Du Pont Pharmaceuticals Company | Radiopharmaceuticals for imaging infection and inflammation and for imaging and treatment of cancer |
US6569402B1 (en) * | 1998-12-18 | 2003-05-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
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US6511649B1 (en) * | 1998-12-18 | 2003-01-28 | Thomas D. Harris | Vitronectin receptor antagonist pharmaceuticals |
EP1140864A2 (en) | 1998-12-18 | 2001-10-10 | Du Pont Pharmaceuticals Company | Vitronectin receptor antagonist pharmaceuticals |
US6656448B1 (en) * | 2000-02-15 | 2003-12-02 | Bristol-Myers Squibb Pharma Company | Matrix metalloproteinase inhibitors |
AU2001261728A1 (en) * | 2000-05-17 | 2001-11-26 | Bristol-Myers Squibb Pharma Company | Use of small molecule radioligands for diagnostic imaging |
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US20090062256A1 (en) * | 2001-06-01 | 2009-03-05 | Bristol-Myers Squibb Pharma Company | LACTAMS SUBSTITUTED BY CYCLIC SUCCINATES AS INHIBITORS OF Abeta PROTEIN PRODUCTION |
US6838074B2 (en) | 2001-08-08 | 2005-01-04 | Bristol-Myers Squibb Company | Simultaneous imaging of cardiac perfusion and a vitronectin receptor targeted imaging agent |
HUP0401904A3 (en) * | 2001-08-08 | 2009-01-28 | Bristol Myers Squibb Pharma Co | Simultaneous imaging of cardiac perfusion and a vitronectin receptor targeted imaging agent |
US20050106100A1 (en) * | 2003-09-03 | 2005-05-19 | Harris Thomas D. | Compounds containing matrix metalloproteinase substrates and methods of their use |
WO2007005491A1 (en) * | 2005-06-30 | 2007-01-11 | Bristol-Myers Squibb Pharma Company | Hydrazide conjugates as imaging agents |
US20110236308A1 (en) * | 2006-04-19 | 2011-09-29 | The General Hospital Corporation | Aryl Bidentate Isonitriles and Their Uses |
US7563920B2 (en) | 2006-10-30 | 2009-07-21 | Draximage Limited | Methods for preparing 2-methoxyisobutylisonitrile and tetrakis(2-methoxyisobutylisonitrile)copper(I) tetrafluoroborate |
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DE1215142B (de) * | 1964-07-09 | 1966-04-28 | Bayer Ag | Verfahren zur Herstellung von araliphatischen Isonitrilen |
GB1187755A (en) * | 1968-02-24 | 1970-04-15 | Bayer Ag | A Process for the Production of Isonitriles |
DE1962898A1 (de) * | 1969-12-16 | 1971-06-24 | Bayer Ag | Verfahren zur Herstellung von Isonitrilen |
JPS57165370A (en) * | 1981-03-18 | 1982-10-12 | Ici Ltd | Triazole or imidazole compounds, manufacture and fungicidal or plant growth regulant agent |
US4347251A (en) * | 1981-07-13 | 1982-08-31 | American Cyanamid Company | Novel 3-substituted amino-1-substituted heteroaryl-2-pyrazolines |
US4452774A (en) * | 1982-04-30 | 1984-06-05 | President And Fellows Of Harvard College | Isonitrile radionuclide complexes for labelling and imaging agents |
DE3343673A1 (de) * | 1983-12-02 | 1985-09-05 | Basf Ag, 6700 Ludwigshafen | Verfahren zur gleichzeitigen herstellung von nitrilen und acrylamid bzw. methacrylamid |
US4707544A (en) * | 1984-11-28 | 1987-11-17 | President And Fellows Of Harvard College | Metal-isonitrile adducts for preparing radionuclide complexes for labelling and imaging agents |
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-
1986
- 1986-12-16 CA CA000525461A patent/CA1305160C/en not_active Expired - Lifetime
- 1986-12-20 ES ES86117847T patent/ES2036171T3/es not_active Expired - Lifetime
- 1986-12-20 DE DE8686117847T patent/DE3673000D1/de not_active Expired - Lifetime
- 1986-12-20 EP EP86117847A patent/EP0233368B1/en not_active Expired - Lifetime
- 1986-12-22 DK DK198606238A patent/DK173003B1/da not_active IP Right Cessation
- 1986-12-22 NO NO865247A patent/NO166640C/no unknown
- 1986-12-22 AU AU66842/86A patent/AU594407B2/en not_active Expired
- 1986-12-22 KR KR1019860011046A patent/KR940011456B1/ko not_active IP Right Cessation
- 1986-12-22 CN CN91105401A patent/CN1057470C/zh not_active Expired - Lifetime
- 1986-12-22 ID IDP355186A patent/ID1037B/id unknown
- 1986-12-22 JP JP61304069A patent/JPH0755914B2/ja not_active Expired - Lifetime
- 1986-12-22 PT PT83996A patent/PT83996B/pt active IP Right Revival
- 1986-12-22 FI FI865260A patent/FI91747C/fi not_active IP Right Cessation
- 1986-12-22 MX MX004749A patent/MX168821B/es unknown
- 1986-12-22 HU HU865398A patent/HU201301B/hu unknown
- 1986-12-22 IL IL81055A patent/IL81055A/xx not_active IP Right Cessation
- 1986-12-22 IE IE335386A patent/IE59758B1/en not_active IP Right Cessation
-
1987
- 1987-06-01 US US07/056,003 patent/US4988827A/en not_active Expired - Lifetime
-
1989
- 1989-01-09 SU SU894613202A patent/SU1635903A3/ru active
-
1990
- 1990-07-27 GR GR90400540T patent/GR3000681T3/el unknown
-
1994
- 1994-09-22 JP JP6227693A patent/JP2774940B2/ja not_active Expired - Lifetime
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1057398C (zh) * | 1994-12-16 | 2000-10-11 | 电化学工业有限公司(国际) | 用于不定域地标记物品的组合物及其制备和用途 |
WO2002087633A1 (en) * | 2001-04-27 | 2002-11-07 | Beijing Normal University | Myocardial imaging agent and preparation method thereof |
CN105555759A (zh) * | 2013-07-01 | 2016-05-04 | 麦地那创新药物研究中心基金会 | 具有抗菌活性的化合物 |
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