CN1120437A - 含生化活性基团的铼二肟和锝-99m二肟配合物的硼酸加合物的制备方法 - Google Patents
含生化活性基团的铼二肟和锝-99m二肟配合物的硼酸加合物的制备方法 Download PDFInfo
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- CN1120437A CN1120437A CN95109333A CN95109333A CN1120437A CN 1120437 A CN1120437 A CN 1120437A CN 95109333 A CN95109333 A CN 95109333A CN 95109333 A CN95109333 A CN 95109333A CN 1120437 A CN1120437 A CN 1120437A
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Abstract
锝-99m与放射活性的铼二肟配合物的硼酸加合物,其中的每一个包括生化活性基团,这些加合物作为诊断和治疗剂是有效的。
Description
放射性标记生化活性基团在诊断图象领域显得越来越重要。基本上说来,生化活性基团是一种代谢底物或抑制剂,要么是一种对特殊受体有亲合力的分子。有关各种生化活性基团某些性质(例如与受体结合或新陈代谢)的知识显示(至少在理论上),这些基团的放射性标记模式可用于显像特定器官的功能和/或状况,而不仅仅表现出血液流向该器官而已。一种有效的配合物其放射性核素与生化活性基团相互稳定结合,并且,其配合物表现行为(或者说所起作用)本质上如游离生物活性基团一样。
制备具此类性质的有效配合物的许多尝试已有报导,例如Fowler等人(Int.J.Appl.Radiat.Isot.1986,27,P.663—8“2—脱氧—2〔18F〕氟—D—葡萄糖的新陈代谢研究:目前状况”)研究过用18F标记新陈代谢底物脱氧葡萄糖、用于脑诊断显像。Winchell等人也尝试过脑和肺显像(J.Nucl.Med.,1980,21,P.940—6,“I—123—标记胺用于脑研究的进展:I—123碘代苯基烷基胺在鼠脑中的定位”和J.Nucl.Med.,1980,21,P.947—52,“N—异丙基—〔123I〕P—碘代苯异丙胺:单一通道脑摄取排出;与脑触突体结合;以及在狗和猴脑中的定位”),他们报道过苯异丙胺类化合物(已知与特定受体相互作用)的120I放射性标记。称之为“Spectamine”的放射性碘化苯异丙胺目前已投放市场用于脑显像。
游离脂肪酸是通常充满心肌层的重要底物,因此将它作为研究游离脂肪酸的β—氧化代谢途径可能是有用的。因此,Van derWall等人(Eur.J.Nucl.Med.,1986,12,P.S11—S15,“放射性标记游离脂肪酸的心肌显像:应用及局限性”)研究过用发射正电子的同位素,如11C、13N和15O标记的,以及用γ—放射同位素123I标记的游离脂肪酸。另外、Jones等人(J.Nucl.Med.,1988,29(5),P.935,“新型〔Tc99m〕—二氨基二硫醇—脂肪酸〔TcN2S2FA〕配合物的合成及其作为心肌显像剂的评价”)已报道过使用带锝—99m(99mTc)的脂肪酸显像正常心肌层的尝试。
乳癌中特异雌激素受体的发现导自对各种类固醇,例如雌激素类及其衍生物如雌二醇等放射性标记的研究。人们相信,放射性标记雌激素能显示受体水平,并有助于确定乳癌类型及治疗水平。为此,Jagoda等人(J.Nucl.Med.,1984,25,P.472—7,“〔125I〕—17—碘代乙烯基11—甲氧基雌二醇:高亲合性雌激素受体放射药物学的体外体内性质”)研究了用于此类诊断的125I标记甲氧雌二醇。
Gibson等人(Biochem Pharm.,Vol.32,No.12,P.1851—56,1983,“蝇蕈碱乙酰胆碱受体拮抗剂对脑和心脏受体亲和力之区别”和J.Nucl.Med.,Vol.25,No.2,P.214—222,1984年2月,“I—125 4—IQNB和H—3QNB在体内及体外的特征”)研究了在心脏和脑组织中用125I和3H放射性标记的蝇蕈碱受体底物,例如二苯乙醇酸3—喹宁环酯(QNB)及其衍生物。
正如Martin等人(“缺氧细胞标记物〔3H〕氟—米索硝唑的增强结合”J.Nucl.Med.,Vol 30,No.2,194—201(1989))及Hoffman等人(“大脑局部缺血症中缺氧示踪物〔H—3〕米索硝唑的结合”,Stroke,1987,18,168),所报道的,缺氧症介导的硝基—杂环基团(如硝基咪唑类及其衍生物)已知保留于缺氧(即氧气不足)机体组织中。脑心脏中的缺氧组织,一般因动脉阻塞或者因需血增加而供血不足引起的局部缺血而产生。另外, Koh等人(J.Nucl.Med.,1989,30,P.789,“使用〔F—18〕氟米索硝唑对肿瘤缺氧症的显像”)尝试了用18F放射性标记的硝基咪唑作肿瘤的诊断显象。
上面提到的以各种放射性标记生化活性基团作诊断显象的尝试远未提供理想的结果。例如,正电子放射同位素由迥旋加速器产生,需要不能广泛采用的精良设备使之显象。同样123I的半衰期为13小时,生产成本很高。再者,99mTc与脂肪酸配合物并未表现出心肌摄入的游离脂肪酸特征。最后,氚标记硝基咪唑系β—放射核素,仅能用于自动射线照相研究,而不适宜诊断显像。
保持了其生化活性和这些基团的亲和性并且用适当的,易于使用的放射性核素标记的生化活性基团放射标记配合物,于此技术领域中极为有用。
根据本发明,铼二肟和锝—99m二肟配合物的硼酸加合物均与生化活性基团结合,并且在例如用锝—99m作为诊断显像剂时,用铼放射性核素作为放射治疗剂时是有用的。这些新的配合物由下式代表:
I MX(Y3)Z其中M是锝—99m或铼。除非特别指明,“铼”包括186Re和188Re放射性核素及其混合物,也可包括185Re和187Re之总合。在式I及整个说明书中该符号定义如下:
X是阴离子;
Y是具有下式结构的连二肟或其可药用的盐,而R1和R2各自分别是氢、卤素、烷基、芳基、氨基或含氮或氧的5—,6—元杂环,要么R1和R2结合起来形成—(CR8R9)n—,其中n是3、4、5或6,而R8、R9各自独立地为氢或烷基;
Z是有下式结构的硼衍生物,
III B—(A1)p—R3其中R8是(或者含有)一个生化活性基团,并且当P=0时(A1)p不存在,P≥1则(A1)p表示间隔基团。
如上所示,当由于生化活性基紧贴配合物的其余部份,而使其作用可能抑制时,则它(该生化活性基团)可通过间隔或者连结基团(A1)p与配合物结合。该间隔基团可以是任何化学组成部份,它的作用只是从物理意义上拉开(或者说隔离)R3上的生化活性基团与式I配合物的其余部份之间的距离。例如,在间隔基团中,若P为1时的A1,或者P>1时形成直链或支链的各种A1单元各自独立地选自如下基团:—CH2—、—CHR4—、—CR4R5—、—CH=CH—、—CH=CR4—、—CR4=CR5—、—C≡C—环烷基、环烯基、芳基、杂环基、氧、氧、
—NH—、—HC=N—、—CR4=N—、—NR4—、—CS—;其中R4和R5各自独立地选自:烷基、链烯基、烷氧基、芳基、5—或6—元氮或氧杂环、卤素、羟基或羟烷基。
在本技术领域中使用的对各种间隔基团的考虑是已知的,视所需配合物的设计要求,采用适当的P值。优选P≤100,最好P≤20。
下面定义用于描述本发明的配合物的各种术语。这些定义适用于整个说明书采用的术语(除非特殊情况下另有限制),这些术语既可单独使用,也可作为一个较大基团的一部份。
“烷基”、“链烯基”和“烷氧基”既指直链也指支链基团,其碳原子数优选1—10。
“芳基”代表苯基或取代苯基,优选的是苯基和以1、2、3烷基、卤代烷基、氨基烷基、烷基氨烷基、二烷基氨烷基、烷氧基、烷氧烷基、卤素、氨基、羟基或甲酰基取代的苯基。
“卤化物”“卤代”和“卤素”意指氟、氯、溴、碘。
短语“含氮5—或6—元杂环”指至少含一个氮的所有5—和6—元杂环。典型的脂族基团为结构如下式的化合物的脱氢衍生物:其中m是0或1,而A是—O—、—N—R6、—S—或—CH—R6其中R6是氢、烷基、芳基或芳烷基。这些基团包括:吡咯烷基、哌啶基、吗啉基、哌嗪基、4—烷基—哌嗪基、4—烷基—哌啶基和3—烷基—吡咯烷基。也包括在“5—和6—元含氮杂环”这一短语中的是芳香基团。典型的芳香基团是吡咯基、咪唑基、噁唑基、吡唑基、吡啶基和嘧啶基。上面的基团可通过杂原子或碳原子相连。
短语“5—或6—元含氮或氧杂环”表示含至少一个氮原子或氧原子的所有5—元和6—元杂环。典型的基团是如上述的在定义“5—或6—无含氮杂环”这一短语时举出的那些,其它典型基团是1,4—二噁烷基和呋喃基。
M为铼的本发明配合物,其生化活性基团联结到美国专利4,871,836(1989年10月3日批准)中定义的配合物上,而式I中M是Tc—99m的配合物,其生化活性基团连结到于美国专利4705849(1987年11月10日)中定义的配合物上。
本发明提供含放射性标记的生化活性基团的配合物。适合本发明采用的生化活性基团系任何新陈代谢底物或抑制剂、或者是与特定受体有亲合力的一种分子。需明白,用于本发明目的的生化活性基团(对特定受体位点具有亲合性的分子)的范畴,限定于能按此后叙述的方法结合到式I配合物上的这类基团。
这类合适的生化活性基团的例子包括但并不局限于缺氧症—介导的硝基—杂环基团、苯异丙胺类、类固醇类(例如雌激素或雌二醇)、糖类(如葡萄糖衍生物)、脂肪酸、巴比土盐、磺胺、单胺氧化酶底物,和抑制剂、抗高血压药物、蝇蕈碱受体底物(如二(对溴苯基)乙醇酸3—喹宁环酯)以及多巴胺受体底物如螺环哌啶酮。
本发明的配合物在此以前从未被公开过,并能有效利用它们特殊生化活性基团的种种性能(比如受体结合、新陈代谢)提供某特定位点的显像或治疗。M为99mTc的本发明配合物,提供高效,十分容易使用的诊断显像产物,其特征是放射性核素配合物与生化活性基团之间的共价键合,而基本上保留该游离生物基团的摄入特性。本发明用于诊断的M为99mTc的配合物有一系列典型实例很有价值,这些实例包括但不仅限于,例如当生化活性基团是由缺氧症介导的硝基部份的还原作用捕获的硝基杂环基(此后称为“缺氧症介导的硝基杂环基团”)时,用于例如心脏、脑、肺和肿瘤的缺氧组织显像。当生化活性基团是亲油含胺化合物(如苯异丙胺)时,用于脑和肺显像;当生化活性基团是糖(如葡萄糖衍生物)时用于脑、心脏或肿瘤显像;当生化活性基团是脂肪酸时用于心脏显像;当生化活性基团是类固醇(如显像乳癌的雌激素)时显像类固醇受体位点。
此外,当M是Re,本发明提供用于放射性治疗适应症的稳定键合配合物。例如,上面提到的U.S4,871,836(1989.10.3批准)叙述了用于放射治疗的Re配合物。本发明的含有雌二醇的Re配合物可用于治疗乳癌。并且,基于已知肿瘤中存在缺氧组织,其中生化活性基团是缺氧症介导硝基杂环基的本发明的Re配合物也宜于作放射性治疗用。当M是Re的本发明化合物在用于放射性治疗时,可注射入人体并在所希望的部位浓缩。它能使放射性核素定靶于具有极大特异性的所希望的位点,且然而必需注意,只有当这些区域存在足够相互作用位点(如雌激素受体或缺氧组织)使之提供该需治疗区域的铼的治疗水平时,放射性治疗才是可能的。
除了Koh等人和Hoffman等人(上面提到的参考文献)外,缺氧症介导的硝基杂环基(即由缺氧症介导的硝基部份的还原作用捕的硝基杂环基团)的实例包括下述文章中所描述的这些:“硝基—杂环治疗剂的新陈代谢活化作用”(G.L.Kedderis等人,Drug Metabolism Reviews,19(1),P.33—62,1988);“癌症放射和化学治疗中的缺氧症介导的硝基—杂环药物”(G.E.Adams等人,BiochemPharmacology,Vol.35,No.1,P.71—76,1986);“1—取代2—硝基咪唑类化合物结构与活性的关系:于体外试验中分配系数和侧链羟基基团对放射性敏化的影响”“D.M.Brown等人,Rad.Research,90,98—108,1982);“缺氧细胞放射性敏化剂研制中结构与活性之间关系”(G.E.Adams等人Int。J.Radiat.Biol.,Vol.35,No.2,133—50,1979);以及“缺氧细胞放射性敏化剂研制中结构与活性之间关系”(G.E.Adams等人,Int.J. Radiat.Biol.,Vol.38,No.6,613—626,1980)。所有公开的这些适合本发明配合物R3采用的硝基杂环基化合物,均通过参考结合在本文中。这些化合物包括可以含有侧链A1的硝基杂环基,A1可作为间隔基团,将硝基杂环部份连结到硼原子和本发明式I配合物的其余部份上。
当生化活性基团是缺氧症介导硝基杂环基时,配合物的间隔基团—R3部份可由下式表示:其环部份是5—或6—元环或者芳香环其中
n是5—或6—元环上可供取代位的总数;
一个或多个R取代基各自独立地选自氢、卤素、烷基芳基烷氧基、氧杂烷基、羟基烷氧基、链烯基、芳烷基、芳烷基酰胺、烷基酰胺、烷基胺和(烷基胺)烷基;
X1可以是氮、氧、硫、—CR=或—CRR—;而
(A1)P可以不存在,这种情况是当式IV、IV′或IV″的R3基团通过氮原子或碳原子连接到本发明配合物的其余部份时,或者(A1)P是连接基团,正如上面所定义过的。
上述有关缺氧症介导硝基杂环基团的参考文献,反映了在此技术领域中目前的观点:即硝基杂环基的还原势直接影响它在缺氧组织中的滞留。因此,间隔基团(A1)P的挑选(在R3是缺氧症介导硝基杂环基的情况下)不但取决于它隔断R3与配合物其余部份的能力,也要考虑它对缺氧症介导硝基杂环基团还原势的影响。同样,本领域的现有知识使该领域的技术人员会理解根据文献中指出的已知还原势效应在式IV、IV′、IV″的基团中选择A1、R、X1和—No2的值或/和位置。
优选的缺氧症介导硝基杂环基团是2—、4—和5—硝基咪唑类,由下式表示:还可是硝基呋喃和硝基噻唑衍生物,例如典型基团(包括(A1)P间隔基)包括但并不只限于):当R3是缺氧症介导硝基杂环基时最优选的是2—硝基咪唑及其衍生物。
当R3上的生化活性基团是类固醇时,采用类固醇,取代类固醇衍生物或者非类固醇衍生物均可使选择的R3基团对类固醇受体有亲和力。例如,当R3是雌二醇:(A1)P连接基团或硼原子(P=O的情况)可连在分子的任何可能位置上,但优选A1既可连于B环的一个原子上或者也可连于D环的一个原子上。此外,雌二醇分子可以在各适宜位置上由一个或多个R取代,此外R正如上面定义过的一样。另外,类固醇分子可由已知对准激素受体具有已知亲和力的非甾族二醇置换,例如:其中(A1)P和R与上面定义相同。
当生化活性基团是蝇蕈碱受体底物时,配合物的间隔基—R3部份由下式表示:其中(A1)P和R和上面定义相同,R′是叔胺或者季胺,例如3—喹宁环醇或取代的3—喹宁环醇。
所有实施例和下述方法的叙述除特别指明外均以M是铼,包括采用“载体铼”(carrier rhenium)的情况。此短语“载体铼”意味着所使用的铼化合物含有10—7M—10—5M浓度非放射性铼。
制备本发明M是铼的配合物,可采用+3、+4、+5或+7氧化态的铼完成。能得到的+3氧化态铼化合物的例子是ReCl3(CH3CN)(PPh3)2和〔Re2Cl3〕(NBu4)2,其中Ph=苯基、Bu=丁基。Re(IV)可使用K2ReCl6、而Re(VII)可采用NH4ReO4或KReO4制备。Re(V)则采用〔ReOCl4〕(NBu4)和〔ReOCl4〕(AsPh4)以及ReOCl3(PPh3)2和ReO2(吡啶)4 。其它本领域专业人员所知的Re(III)、Re(IV)、Re(V)、Re(VII)试剂也可使用。
本发明的Re配合物较宜采用下式的Re中间配合物制备:
V ReX(Y)3(其中X和Y和上面定义同),在1989年8月28日申请的,题为“铼三(二肟)配合物”,尚未审批的U.S序号398879申请案中有所描述。将式V的中间体与硼酸衍生物(如下式)反应:便可得到本发明的铼配合物。式V的中间体可使用上面介绍过的Re(III)、Re(IV)、Re(V)或Re(VII)试剂与提供阴离子部份(X)的原料,以及式II的连二肟相结合制备,混合物于25℃—100℃左右加热反应约5分钟至8小时。若是使用Re(IV)、Re(V)或Re(VII),应当采用已知方法,即加入还原剂,将初始原料充分还原为Re(III)。
制备本发明M为锝—99m的配合物,最好采用高锝酸盐离子形式的锝—99m。高锝酸盐离子则可从市售购得的锝—99m母—子体发生器获得,这种锝是+7氧化态。在本技术领域中,使用这种类型的生成元素来产生高锝酸盐是已知的并在美国专利3,369,121和3,920,995中均有详细叙述。这些生成元素通常用盐水洗脱,并以钠盐形式便获得高锝酸离子。
99mTc配合物制备方法可选用本发明制备Re配合物的方法,包括将Re(III)、Re(IV)、Re(V)、Re(VII)或高锝酸离子(盐的形式)与一种阴离子源、一种式VI的硼酸衍生物或其可药用的盐(其中R2和R′7各自是氢、烷基或芳基、或者R7和R′7连在一起为—(CR8R9)-n、这里n是2—6)以及下式的一种二肟或其可药用的盐相结合。式VI化合物,若其中R3是如式IV、IV′、IV″,所定义的缺氧症介导硝基杂环基,则系新的中间体,属本发明的一部份。这类中间体结构如下:这些化合物可以用已知的方法制备,例如下式的硼酸衍生物其中L是离去基团,例如卤素等等,可于溶剂中(如二甲基甲酰胺)和有碱(如碳酸钾)存在时与下式化合物偶合
阴离子基(X)源可以是水或者能解离释放出适当阴离子的酸、盐。典型的阴离子基是羟基、卤离子、异硫氰酸酯基(N=C-=-S)和硫氰酸酯基(S—C=N)。优选的阴离子基是卤离子,以氯最好。假如阴离子源不是水,那么它应当具有适当浓度,以便在反应期间能有效地与可能存在的水竞争。业已发现,在反应混合物中应具有的阴离子源浓度大约为0.1—2.0摩尔。
式VI、VII、VII′和VII″的硼酸衍生物最好具有5—400左右毫摩尔的浓度,而式II的二肟的浓度优选9—250毫摩尔。
假如将高锝酸离子、阴离子源、硼酸衍生物和二肟混合物于约2 5℃—100℃加热5分钟—3小时左右,则99mTc配合物形成最为顺利。反应最好在含水介质或含水、醇混合物中,于pH小于或等于5左右进行。以Re(III)、Re(IV)、Re(V)或(VII)为初始原料的Re配合物也可使用此法形成。但是,正如前面提到的R3或(A1)P基团可能对上述温度和pH参数敏感的Re配合物以及Tc—99m配合物则最好采用中间体配合物MX(Y)3与式VI、VII、VII′或VII″硼酸衍生物反应。反应可以在水介质或含水乙醇混合物中,于25—100℃左右,pH≤5进行约5分钟至8小时。
假如采用的是含高锝酸或Re(IV)、Re(V)、Re(VII)化合物、反应混合物中也应当含有还原剂。亚锡离子是较好的还原剂,可以以亚锡盐的形式,例如卤代亚锡(氯化亚锡或氟化亚锡)引入。还原剂的浓度为约10毫摩尔至150毫摩尔。
制备药盒时,可加入各种配位剂(在本领域也称作螯合剂),作为配位反应的一部分,当然这些配位剂应当是可供药用的。典型的配位剂是二亚乙基三胺—五乙酸(DTPA)、亚乙基二醇—二(β—氨基乙基醚)—N、N′—四乙酸(EGTA)、乙二胺四乙酸(EDTA)柠檬酸、酒石酸和丙二酸等。
配位反应混合物中也可有促进剂(催化剂)用于增进产品放射性化学纯度(即所需要的化学形式的放射活性百分数)。典型的促进剂是α—羟基羧酸、例如柠檬酸、酒石酸、丙二酸。
以锝—99或铼,研究了本发明配合物的结构,证明是:其中M=99mTc或Re
在欲使用的地方(或附近)配制本发明的配合物是很方便的。含有各成份的药盒属本发明的组成部份,即除了铼和锝离子外,尚需准备式I铼或锝二肟配合物的硼加合物。这样的药盒含一种阴离子源,一种式VI、VII、VII′、VII″的硼酸衍生物或其可药用盐、一种式II的二肟或其可药用盐以及一种还原剂,还可按需选择性地加入配位剂。
本发明M是锝的药盒可在水溶液中配制,化合物于约100℃加热10—30分钟左右。为使药盒达极大稳定性并使标记产物的放射化学纯度达最大值,药盒的pH值可用药学上可接受的酸或碱(如盐酸或氢氧化钠)调至约2.0—5.5范围内药盒的pH最好是大约3.0。药盒最好采用冻干形式,也可使用在溶液中含一些或所有成份的药盒,但它们不如相应的冻干药盒有效。可采用本领域常用的已知分离方法、分离所需配合物。
采用高浓快速静脉法注射的方式,可将本发明的配合物施用于宿主。注射剂量视需要而定,比如正如本领域所熟知需要产生有效的诊断影象或所需放射性治疗效果。
本发明优选的配合物是R3为缺氧症介导硝基杂环基、苯异丙胺、类固醇或蝇蕈碱受体底物。最为优选的是R3为2—硝基咪唑或其衍生物,〔4—〔2—〔(1—甲基乙基)—氨基〕丙基苯基〕,雌二醇或其衍生物,或者二(对溴苯基)乙酸酯3—喹宁环酯。
本发明的配合物中的(A1)P优选烷基,氧杂烷基、羟烷基羟烷氧基、链烯基、芳烷基、芳烷基酰胺、烷基酰胺、烷基氨和(烷基胺)烷基。
(A1)P最为优选的是如下基团:
—(CH2)2—3,—CH2—CH=CH—CH2—,(CH2)1—2,—(CH2)2O—,—CH2CH(OH)CH2OCH2—,—(A3—O—A3′)1—3和—(A3—NH—A3′)1—3;其中A3和A′3系相同或不同的烷基。
下面各例是本发明的具体实施方案。
实施例1
〔99Tc(氯)(二甲基乙二肟)3〔4—〔2—〔(1—甲基乙基)氨基〕丙基〕苯基〕硼〕PF6
将0.20429g(1.76mmol)二甲基乙二肟和0.13508g(0.6mmol)〔4—〔2—〔(1—甲基乙基)氨基〕丙基〕苯基〕硼酸溶于20ml乙醇和5ml水中。加入溶解于6ml 3M HCl中的0.09035g(0.5mmol)高锝酸铵。伴随搅拌,用5分钟的时间,滴加入溶解于5ml 4MHCl中的0.21492g(1.1mmol)氯化亚锡。溶液的颜色变成浓橙棕色,加入20ml水,并把该反应混合物回流搅拌2小时。用二氯甲烷抽提尽反应混合物,用六水硫酸钠干燥合并的CH2Cl2组分,并用旋转蒸发浓缩。将甲醇4M HCl和NH4PF6的甲醇溶液加到CH2Cl2浓缩物中。如PF6 -盐的所需产物,通过蒸发沉淀。通过过滤收集橙色沉淀物,用水洗涤并真空干燥。产率:0.122g(31%)。
TcClC24H39N7O6BPF6 CH2Cl2原素分析计算值:
C,34.43;H,4.68;N,11.48;实测值:C,34.25;H,4.45;N,11.66。
实施例2
99mTc(氯化)(二甲基乙二肟)3〔4—〔2—〔(1—甲基乙基)氨基〕丙基〕苯基〕硼
在5ml硅血清管瓶中,定量加入1.7mg二甲基乙二朊,7.0mg〔4—〔2—〔(1—甲基乙基)氨基〕丙基〕苯基〕硼酸,20mg柠檬酸,2mg DTPA,100mg NaCl和50μg SnCl2(于4M HCl中)(以0.5ml总体积的盐水的形式)。加入0.5ml 99mTc O- 4发生器洗脱剂,在100℃加热该混合物15分钟,通过HPLC测定,所需产物的产率为76%,用色谱提纯产物,得到纯度为91%的产品。
实施例3
胺—取代的硼配合物,99mTc(氯化)(二甲基乙二肟)3B—R(其中R是或含有胺)的生物分布结果
由于亲脂性胺通过特异结合表现出高的肺摄取是已知的,测定了在硼酸“冠”含有胺取代的一系列(BATO)配合物,包括实施例2中所描述的配合物在鼠肺中的摄取。其他列举的配合物是使用如实例2中所描述的方法制备的。记录这些化合物静脉给药后5和60分钟时的肺摄取量。下列表1列出了含胺配合物的肺摄取。
表1
含有胺的量
注射后5分钟和60分钟时在肺部注射剂量% | |||
二肟 | 胺 | 在肺部% | |
注射后5分钟 | 注射后60分钟 | ||
DMG1DMG1DMG1DMG1DMG1DMG1 | 4—〔2—〔(1—甲基乙基)氨基〕丙基〕苯基硼酸N,N—二甲基—P—氨基甲基苯基硼酸N—甲基—N—苯乙基—P—氨基甲基苯基硼酸N—异丙基—P—氨基苯基苯基硼酸N,N—二—异丙基—P—氨基甲基苯基硼酸P—(N,N—二异丙基—1—氨基乙基)苯基硼酸 | 3.251.0510.591.490.983.37 | 2.190.524.02-0.461.71 |
1DMG=二甲基乙二肟
表1(续)
胺含有量
注射后5分钟和60分钟在肺部注射剂量% | |||
二肟 | 胺 | 在肺部% | |
注射5分钟后 | 注射60分钟后 | ||
CDO2CDO2CDO2CDO2CDO2CDO2 | N,N—二甲基—P—氨基甲基苯基硼酸N—甲基—N—苯乙基—P—氨基甲基苯基硼酸N—异丙基—P—氨基苯基苯基硼酸N,N—二—异丙基—P—氨基甲基苯基硼酸P—(N,N—二异丙基—1—氨基乙基)苯基硼酸N—乙基—N—异丙基—P—氨基甲基苯基硼酸 | 1.154.763.075.893.125.59 | 0.632.771.373.501.583.89 |
2CDO=1,2—环己烷二酮二肟
实施例4
99Tc(氯)(二甲基乙二肟)3(雌二醇硼)把0.02796g(0.058mmol)99Tc(氯化)(二甲基乙二肟)3溶解于10ml乙腈中。伴随搅拌。加入固体的0.02449g(0.072mmol)雌二醇硼酸,〔17α(E)—3,17—二羟—1,3,5(10)—雌三烯—17—基〕乙烯基硼酸。加入2ml 1M HCl,并伴随缓慢加热搅拌反应混合物1到2小时。加1M HCl(3到5ml)使之产生沉淀用乙腈/1M HCl重结晶该产物。产率:0.022g(48%)。
TcClC32H45H6O8BH2O元素分析计算值:
C,48.27;H,5.78;N,10.56;实测值: C,48.26;H,5.70;N,10.50。
实施例5
99Tc(氯化)(二甲基乙二肟)3(雌二醇硼)
在5ml硅血清管瓶中,称量放入2.0mg二甲基乙二肟,2.2mg雌二醇硼酸,20mg柠檬酸,100mg NaCl和使总体积为0.6ml 33%乙醇/盐水的100μg SnCl2(在4M HCl中)。加入0.5ml 99m TcO- 4发生洗脱剂,并在100℃加热混合物15分钟,通过HPLC测定,所需产物的产率为70%。
实施例6
用于研究离体雌激素结合受体的已知特异活性的99m/99Tc(氯化)(二甲基乙二肟)3(雌二醇硼)
为了准确测定特异活性(Ci/mmol),制备了即含有99Tc,又含有99mTc的样品。通过下述方法制备样品:2mg雌二醇硼酸,0.2ml二甲基乙二肟(10mg/ml乙醇),0.2ml柠檬酸(100mg/ml水),0.2ml饱和NaCl(于H2O中),0.100ml NH4 99TcO4(在水中3.66×10-4M)和0.1ml到0.5ml的99mTcO- 4(从Mo99/Tc99m发生剂中洗脱),为了得到所需的特异活性,把它们合并在5ml硅管瓶中。把溶解于1ml浓HCl中并稀释到4ml(用水)的10μl SnCl2(0.100g),加入到反应管瓶中。在100℃加热样品15分钟,冷却5分钟并用色谱纯化(PRP—树脂),得到纯度>95%的产品。
实施例7
用99m/99Tc(氯化)(二甲基乙二肟)3(雌二醇硼)研究离体雌激素受体结合
E.M.Jagoda et at.,J.Nucl.Med.1984.25 472—7已在先描述了研究受体结合采用的方法。“〔125I〕—17—碘乙烯基—11—甲氧雌二醇:”高亲和性雌激素受体放射药学的体内和体外性质。用20—25天令雌鼠离体子宫的细胞溶质制剂,测定锝标记的雌二醇对雌激素受体的亲合性来研究受体结合。化合物制剂的特异活性在400到2000Ci/mmol范围内且特异结合范围是全部结合活性的10—30%。
实施例8
用于离体蝇蕈碱受体结合的已知特异活性研究的99m/99TcCl(二甲基乙二肟)3(QNB—硼)
为了准确地测定特异活性(Ci/mmol)制备了含有99Tc和99mTc的样品,用下述的方法制各样品:2mg3—喹宁核基—(4—二羟硼基二苯乙醇酸酯)(用G.W.kabalka et alNucl.Med.Biol 1989,16(4),359—360描述的方法制备QNB—硼酸),0.2ml二甲基乙二肟(10mg/ml乙醇),0.2ml柠檬酸(100mg/ml水),0.2ml饱和NaCl(水中),0.1ml DTPA(20mg/ml 0.5M NaOH),0.2ml γ—环糊精(25%w/v水),0.100ml NH4 99TcO4(在水中3.66×10-4M)和0.1至0.5ml 99mTcO4 —(用Mo99/Tc99m发生剂洗脱),为了得到所需特异活性,将它们合并在5ml硅管瓶中,把10μl SnCl2(0.100g溶解在1ml浓HCl中。且用水稀释到4ml)加到反应管瓶中。在100℃加热样品约15分钟,冷却5分钟并用色谱法提纯((PRP—1树脂),得到纯度90—95%的产品。
实施例9
用99m/99Tc(氯化)(二甲基乙二肟)3(QNB硼)研究离体蝇蕈碱受体结合,
R.E.Gibson,W.J.Rzeszotarski,W.C.Eckelman,E.M.Jagoda,D.J.Weckstein,R.C.Reba,Biochemical pharmacology,1983,32(12),1851—1856,已在前公开了研究受体结合所采用的方法。用从鼠脑分离的鼠尾状核,对锝标记的QNB对蝇蕈碱受体的亲合性进行测定,以研究受体结合。化合物制剂的特异活性在600—1000Ci/mmol之间,且特异结合是总结合活性的5—20%。
实施例10
1—(2—硝基咪唑)—苯甲基硼酸的制备A.对—甲苯基硼酸的制备
对在200ml反应容器中的,溶解在30ml乙醚中的镁(2.5g、0.105mole)混合物,滴加入溶于150ml乙醚中的对一溴甲苯(17.1g、0.1mole)。在室温下,搅拌反应混合物过夜。凭借氮气的压力,将暗棕色的溶液通过转移针,转移到加液漏斗中。
在氮气条件下,在-78℃,用1.5小时的时间,把该格利雅试剂滴加到在200ml乙醚中的三甲基硼酸酯(10.4g,0.1mol)的溶液中。在环境温度下搅拌过夜后,所得的灰白色的反应混合物,用200ml水水解,并用35ml 3N硫酸酸化。用乙醚(4×80ml)提取水层。洗涤合并的有机层并用硫酸钠干燥。除去溶剂得到白色固体,用水重结品该固体。得到6.1g(45%)的产物。m. p.251—256℃(文献259℃)1HNMR(DMSO)δ2.25(S,3H,—CH3);7.12和7.64(d,4H,ArH);7.86(S,2H,—BOH)。B.对—溴甲基苯硼酸
把在20ml四氯化碳中的5ml溴溶液(2.4g,1.5×10-2mole),加入到在40ml四氯化碳中的对一甲苯基硼酸(2.0g,1.47×10-2mole)溶液中。用150瓦日光灯泡照明,启动反应。5分钟后,溴褪色,用15分钟的时间加入剩下的溴溶液。在加入溴时,沉淀出固体产物,过滤该固体并用氯仿重结晶,产率1.5g(49%),m.p.154—156℃,1H NMR(DMSO)δ4.18(S,2H,—CH2Br);7.37和7.74(d,4H,—ArH)。C.1—(2—硝基咪唑基)苯甲基硼酸的制备
2—硝基咪唑(100mg,8.85×10-4mole,事先通过升华提纯)和对—溴甲基苯硼酸(190mg,8.85×10-4mole),在装有回流冷凝管的50ml单颈园底烧瓶中,与在30ml干燥丙酮中的20mg碳酸钾混合。在氮气条件下,搅拌并加热回流反应混合物16小时。过滤淡绿黄色溶液。在减压条件下,把滤液蒸发至干燥,得到淡黄色固体。用水重结晶产物。产率150mg(69%)。m.p.212—214℃,1H NMR(DMSO)δ5.6(S,2H,CH2Ar),7.1和7.75(d,4H,ArH);7.25和7.75(S,2H,CH=CH)。
实施例11
4—(2—硝基咪唑基乙基)苯基硼酸的制备A.2—(4—溴苯基)—1—邻—特—丁基二甲基甲硅烷基乙烷
4—溴苯基乙基醇(4.0g,20mmol)和咪唑(3.4g,50mmol)溶于干燥的二氯甲烷(100ml)中,用特—丁基二甲基甲硅烷基氯化物(3.1g,20mmol)处理,并在室温和氮气条件下搅拌6小时。用水洗涤所得产物,干燥,在真空下蒸馏浓缩。产率: 6.0g(95%),b.p.115—117℃/0.7mm,M.S.314和316(m/e)1H NMR(CDCl3),0.05(s,6H),0.9(s,9H),2.8(t,2H),3.85(t,2H)和7.5(AB q,4H)。B.4—(2—羟乙基)苯基硼酸的制备
在氮气条件下,对在干燥四氢呋喃(10ml)的镁(0.264g11mmol)悬浮浮液,用小时,滴加入特—丁基二甲基甲硅烷基醚的4—溴苯基乙基醇(a,3.45g,10.9mmol)的四氢呋喃溶液(10ml)。然后加入二溴乙烷(0.1g)活化镁。用8小时的时间将金属缓慢进入溶液,把该格利雅试剂冷却到-78℃。并用新鲜蒸馏的三甲基硼酸盐(1.15g,11mmol)处理,滴加时伴随搅拌。使反应混合物加温至室温并搅拌过夜。然后用2N盐酸处理至酸性,从水层上分离四氢呋喃层。水层用乙酸乙酯(5×50ml)彻底提取,合并有机层,用水并且最后用饱和氯化钠洗涤有机层。然后干燥有机相,浓缩并用色谱分离(硅胶闪层析)。用乙酸乙酯/甲醇(95∶5)洗脱,得到的硼酸用乙酸乙酯/己烷重结晶。产率: 0.69g(38%),m.p.218—220℃,M.S.184(M+NH4),156,140,1H NMR(DMSO—d6):2.7(t,2H),4.6(t,2H),7.1和7.7(2d,4H)和7.9(s,2H)。C.4—(2—溴乙基)苯基硼酸的制备
对4—(2—羟乙基)苯基硼酸(1.66g,10mmol)的干燥的二甲基甲酰胺(25ml)溶液,加入亚乙基二醇(0.62g,10mmol)。在氮气和室温下,搅拌混合物16小时。在减压条件下除去二甲基甲酰胺,所得到的油状物,再保持在真空下6个多小时,该油状物再次溶解到干燥二甲基甲酰胺中(10ml),用冰浴冷却,用三苯基膦(5.25g,20mmol)和N—溴琥珀酰亚胺(3.56g,20mmol)处理,在氮气和室温条件下搅拌6小时。在减压条件下除去溶剂。残留物用乙醚(100ml)吸收。乙醚溶液用水洗涤、干燥并浓缩,得到的油用色谱分离,得到无色固体的溴硼酸(硅胶闪层析,1∶1乙酸乙酯/己烷)。产物用二氯甲烷/己烷重结晶,产率:1.4g,m.p.146—148℃。D.4—(2—硝基咪唑基乙基)—苯基硼酸的制备
在氮气条件下,伴随搅拌,4—(2—溴乙基)苯基硼酸(0.525g,2.72mmol)和2—硝基咪唑(0.3g,2.72mmol),在干燥二甲基甲酰胺(15ml)中,在无水碳酸钾(1.38g,10mmol)存在下,在60—70℃加热48小时。减压除去二甲基甲酰胺,所得的胶溶解在少量水中,用2N盐酸酸化。过滤掉沉淀的固体,用水洗涤溶液。合并的水层再次用乙酸乙酯(5×50ml)提取。干燥并浓缩有机层,得到的固体与以前的沉淀固体合并,然后用色谱分离(硅胶闪层析)。用1∶1乙酸乙酯/己烷洗脱,得到一些未反应的起始溴化物(0.1g);继续用2∶1乙酸乙酯/己烷洗脱,得到所需的如浅黄色结晶固体的硼酸。用四氢呋喃/己烷重结晶产物。产率:0.25g(36%),m.p.229-231℃,M.S.(M+H)+262.1H NMR(DMSO-d6):3.1(t,2H),4.65(t,2H),711(d,2H),7.14(s,1H),7.5(s,1H),7.69(d,2H)和7.94.(s,2H).
实施例12
99mTc(氯化)(1.2—环己二酮二肟)31—(2—硝基咪唑基)苯甲基硼
对10mg柠檬酸,100mg的氯化钠,2mg1,2—环己二酮二肟,2mg二亚乙基三胺—五—乙酸,50mgγ环糊精,50μg氯化亚锡,和3mg1—(2—硝基咪唑基)苯甲基硼酸的混合物,加入1ml高锝酸钠(99mTcO4 —)的生理盐水。在100℃加热反应混合物15分钟。标题化合物的产率,用高压液相色谱(HPLC)测定,为91.4%。配合物的样品用NucleosilHPLC柱洗脱,保留时间与如下制备的99Tc可倍标样相同。
实施例13
99Tc(氯化)(1,2—环己二酮二肟)31—(2—硝基咪唑基)苯甲基硼的制备
对溶解在10ml热乙腈中的90.3mg(0.11mmol)99Tc(1.2—环己二酮二肟)3(u—OH)SnCl3,加入1—(2—硝基咪唑基)苯甲基硼酸(31mg,0.125mmol)和1.5ml 3N盐酸。伴随搅拌,缓慢加热溶液。30分钟后,加入10ml 1M盐酸,并把溶液冷却至室温。所得的橙色沉淀(61mg,78%产率)用热乙腈/1M盐酸重结晶。
对C28H34N9BClO8Tc分析计算值:
C,43.59;H,4.43;N,16.20;实测值:C,43.68;H,4.45;N,16.37。
在m/z=770观测到了强质子化了的分子的离子(M+H)+配合物的样品用Nucleosil HPLC柱洗脱,保留时间为2.34分钟(80/20 ACN/0.1M柠檬酸,1.5mL/分钟)。
实施例14
99mTc(氯化)(二甲基乙二肟)3—1—(2—硝基咪唑基)苯甲基硼的制备
对2mg二甲基乙二肟,18mg柠檬酸,100mg氯化钠,1mg二亚乙基三胺—五—乙酸,50mgγ环糊精,50μg氯化亚锡,和3mg1—(2—硝基咪唑基)苯甲基硼酸的冻干混合物,加入1ml高锝酸(99mTcO4 —)钠的生理盐水溶液。在100℃加热该药盒15分钟,标题化合物的产率,用高压液相色谱(HPLC)测定,为73.4%。该配合物的样品用Nucleosil HPLC柱洗脱,保留时间与如下制备的99Tc可溶标样相同。
实施例15
99Tc(氯化)(二甲基乙二肟)3—1—(2—硝基咪唑基)苯甲基硼
对55mg 99Tc(二甲基乙二肟)3(u—OH)SnCl3(0.074mmol)、加入溶于10ml乙腈中的25mg(0.10mmol)1—(2—硝基咪唑基)苯甲基硼酸。加入1ml 3N盐酸,缓慢加热溶液30分钟,加入10ml 1M盐酸,使溶液冷却至室温。得到的橙色结晶(32mg,62.3%产率)用热乙腈/1M盐酸溶液重结晶,得到分析纯的络合物,以0.5H2O水合物分离。
对C22H29N9BClO8.5Tc分析:
计算值:C,37.62;H,4.33;N,17.63;
实测值:C,37.71;H,4.17;N,17.99。
配合物的样品用Nucleosil HPLC柱洗脱。保留时间3.45分钟(60/40 ACN/0.1M柠檬酸,1.5ml/分钟)。
实施例16
99mTc(氯化)(二甲基乙二肟)3—4—(2—硝基咪唑基乙基)苯基硼的制备
对18mg柠檬酸、100mg氯化钠、2mg二甲基乙二肟、1mg二亚乙基三胺—五—乙酸,50mgγ环糊精、50μg氯化亚锡和3mg 4—(2—硝基咪唑基乙基)苯基硼酸的混合物,加入20mCi 99mTcO4 —的1ml生理盐水。在100℃加热反应该药盒15分钟,用HPLC测定产率,得到产率93%的标题配合物。
实施例17
含有硝基杂环基团的化合物,通过这些基团中的硝基部分被还原保留在缺氧组织中。因此,硝基—杂环基团的氧化还原电位可成为这些基团保留在低氧组织中的程度的指示。
用标准的3—电极构型(Heinze,J.Ang.Chem.Int.,Ed.Eng.23,831.1984)对在DMF溶剂中的环电压进行研究。用PAR174A极谱分析仪和PAR303静电滴汞电极仪相接获得数据,显示和记录在PAR RE0074X—Y记录仪上。参比电极是乙腈中的Ag/AgNO3;测量电极是汞。
样品溶液一般为0.3—1.2mM,含有0.1M四丁基铵四氟硼酸盐支持电解质,在测量前用溶剂饱和N2排除气体。
表2
DMF峰电位(EP)值—(扫描率=100mv/sec)的
电化学结果
化 合 物 | 硝基 | |
阴极的 | 阳极的 | |
单纯的硝基咪唑1—(2—硝基咪唑基)苯甲基硼酸 | -1.54 | -1.43 |
2—甲基—5—硝基—1—咪唑基—乙醇 | -1.63 | -1.55 |
2—甲氧甲基—2—硝基咪唑—1—乙醇 | -1.51 | -1.43 |
单纯的BATO1TcCl(DMG)3BMe2 | - | - |
BATO硝基咪唑实施例15的络合物 | -1.58 | -1.51 |
实施例13的络合物 | -1.56 | -1.50 |
1BATO是硼酸锝肟并涉及到锝的硼酸三肟的络合物
2锝(氯化)(二甲基乙二肟)3(甲基硼)
实施例18
在离体和活体、对含有硝基咪唑的化合物的研究,证实了细胞内硝基咪唑的结合的可能机制,是由于该硝基基团的酶还原所导致的—种化学反应物。(例如,Clarke,Wardman,和Goulding,Biochem.Pharmacol.(1980)29,2684—2687)。用黄嘌呤氧化酶测定方法,测定本发明中的硝基咪唑硼酸。测定溶液含有如下成份:次黄嘌呤 1ml 0.01M 溶液=10μmole底物
黄嘌呤氧化酶, 0.5单位500μl pH7.4磷酸钠
磷酸钠缓冲液, 1.0ml,0.1M,pH7.4,10
mg/LNa2EDTA
硝基化合物 0.25μMole 20μl二甲基甲酰胺
在隔膜封闭的比色杯中,在加好其它所有试剂的溶液中,加入酶使反应发生,所有的试剂在混合之前用氩气通过其表面20分以排气用UV/可见分光光度计在326nm,每5分钟,测定减少的硝基(还原反应的指征)。对所有研究的化合物,用对数(浓度)mmol/ml对时间作图来测定硝基化合物的半衰期。结果示于表2,有两个化合物醚醇硝唑和甲硝哒唑的两组数据作为对比。
表 2
半衰期化合物 (酶测定) Epc(DMF)* Epc(水)*甲硝哒唑 >24hr -1.62V -0.46 V(OH)2BB4NO2 95min -1.80V -0.50V醚醇硝唑 45min -1.49V -0.33V(OH)2BPhEtNO2 42.5min -1.53V -0.30V(OH)2BPropeneNO2 24min -1.56V -0.30V(OH)2BBNO2 11min -1.52V -0.32V
实施例19
2—硝基咪唑—N1—〔2—丙烯基〕—3—硼酸(BpropenNO2)的制备
用无水碳酸钾(6.9g,50mmol)处理在干燥二甲基甲酰胺(15ml)中的2—硝基咪唑(1.0g,8.84mmol),在室温和氮气条件下搅拌0.5小时。使溶液冷却到0℃,伴随搅拌和氮气,在0℃,用在干燥四氢呋喃(10ml)中的2—溴乙基—2—乙烯基—1,3,2—苯并二氧硼硫酸钾钠(4.23g,17.7mmol)处理一个小时。伴随搅拌在氮气下,在60—70℃加热反应混合物48小时。减压条件下除去二甲基甲酰胺,残留物溶解在甲醇中(100ml)。用Dowex 50×8树脂(H+)酸代并过滤。用甲醇洗涤树脂,合并滤液,洗涤,浓缩,色谱分离得到半固体物质(硅胶,230—400目,乙酸乙酯的2%甲醇溶液)用二氯甲烷重结晶,该半固体物质得到浅黄色结晶固体:产率:0.3g,m.p.138—140℃。
1H NMR(DMSO-d6):δ5.2(d,2H),6.6(m,1H),7.15
(s,1H),7.4(s,1H)和7.7(s,2H)分析:
计算值C6H8BN3O4,C36.59,H4.09,N
21.34,实测C36.79,H3.66,N21.41.
实施例20
2—硝基咪唑基—N1—丙基—3—硼酸(BpropNO2)的制备
把羟胺氢氯化物(0.417g,6mmol),乙酸钠(0.492g,6mmol),乙酸乙酯(0.176g,2mmol)和在乙醇(25ml)中的BpropenNO2(实施例19,0.2g,1mmol)的混合物,伴随搅拌,在氩气下回流30小时。冷却后,除去溶剂,粗产物直接加到闪硅胶色谱柱上,进行色谱分离。分离的产物,再至少二次用色谱分离得到浅黄色固体的产物。产率:0.02至0.025g(20—25%)m.p.122—124℃。1H NMR(DMSO-d6):δ0.8(t,2H,B-CH2),1.9(m,2H),4.4(t,2H,N-CH2),7.2(s,1H),7.8(s,2H,B-OH)和7.85(s,1H)M.S.(M+H)+-200,172,154和109.分析:计算为C6H10N3BO4::C36.22,H5.02,N21.11实测:C36.87,H4.84,N21.56.
实施例21
1—(4—硝基咪唑)—苯甲基硼酸(BB4NO2)的制备
本化合物通过实施例10描述的方法,使4—硝基咪唑(1.13g,10mmol)和4—溴甲基苯基硼酸(3.25g,15mmol)反应来制备。产率1.7g,m.p.163—165℃。
1H NMR[DMSO-d6]:δ5.4(s,2H),7.4(d,2H),7.9
(d,2H),8.2(bs,2H)a和8.6(s,1H).13C NMR
[DMSO-d6]:δ50.76,121.59,126.86,134.54,
134.6,137.45,137.89 and 147.18.分析:
计算为C10H10BN3O4 C48.62,H4.08 N
17.01.实测C49.39,H4.21,N16.83.M.S.
[M+Gly-2H2O+H]+304.
实施例22
99TcCl(DMG)3BphEtNO2的制备
对Tc(DMG)3(μ—OHSnCl3·3H2O)(77.1mg,0.104mmol)的5ml乙腈溶液,接着加入(OH)2BphEtNO2(实施例11,28.8mg,0.11mmol)加入2滴浓HCl,把溶液加热沸腾30分钟,其间生成橙色固体沉淀(68mg,产率93%)。过滤分离沉淀,用乙腈充分洗涤,在真空下干燥。该固体溶解于1ml二甲基甲酰胺,2ml乙腈和1ml 1M盐酸中,使溶液沸腾约30分钟,产物的结晶体(31mg,全部产率40%)冷却过夜后生成。分析计算TcCl(DMG)3BPhEtNO2·0.5DMF,C24.5H33N9.5BClO8.5Tc.
实测值:C,39.80;H,4.60;N,17.55。
计算值:C,39.64;H,4.81;N,17.92。
实施例23
99mTc(氯)(二甲基乙二肟)3—1—(n—丙基—2—硝基咪唑基)硼的制备
除了1—(2—硝基咪唑基)—苯甲基硼酸被4mgBpropNO2(实施例20)代替之外如实施例14所述,制备标题化合物。用高压液相色谱测定标题络合物的产率,为52%,配合物样品从Nucleosil HPLC洗脱产率为52%。洗脱络合物样品的NucleosilHPLC柱的保留时间,与如实施例24所述方法制备的99Tc可溶标样相同。
实施例24
99Tc(氯)(二甲基乙二肟)3—1—(n—丙基—2—硝基咪唑基)硼的制备
对Tc(DMG)3(μ—OH)SnCl3—3H2O的10ml乙腈溶液,加入(OH)2BpropNO2(实施例20,41.8mg,0.21mmol)后加入3ml 2NHCl,缓慢加热反应混合物30分钟,加入50ml 1N盐酸,将溶液冷却至室温。通过抽滤分离所得絮状橙色固体,用1M盐酸和H2O洗涤固体产物,并真空干燥,得到97mg(78%)粗产物。使粗产物溶解在1mlCHCl3中,并用1×10cm硅胶色谱柱分离,色谱柱预先充满CHCl3,并用CHCl3洗脱。把主要的橙色带收集,蒸发干燥。再溶解在3ml CH2Cl2中,用30ml己烷处理。分析分离的纯固体,全部产率57%。分析计算为C18H28N9BClO8Tc。
实测值: C,33.66;H,4.20;N,19.28;
计算值: C,33.58;H,4.38;N,19.58。
实施例25
99mTc(氯)(二甲基乙二肟)3—1—(丙烯—2—硝基咪唑基)硼(KL L498—178)的制备
除了用3mg BpropenNO2(实施例19)代替1—(2—硝基咪唑基)—苯甲基硼酸,用实施例14所述的方法制备标题化合物。用高压液相色谱(HPLC)测定标题络合物的产率。为58%。
实施例26
99mTc(氯)(二甲基乙二肟)3—1—(4—硝基咪唑基)苯甲基硼的制备
除了用3mg BB4NO2(实施例21)代替1—(2—硝基咪唑基)—苯甲基硼酸。用实施例14所述的方法制备标题化合物。用高压液相色谱(HPLC)测定标题络合物的产率,为82%。络合物样品用PRP-1HPLC柱洗脱。保留时间与实施例27所述的。99Tc可倍标样相同。
实施例27
99Tc(氯)(二甲基乙二肟)3—1—(4—硝基咪唑基)苯甲基硼的制备
TcCl(DMG)3(32.7mg,0.068mmol)和BB4NO2(实施例21,17.7mg,0.073mmol)的5ml乙腈溶液,以及0.5ml 2NHCl的混合物伴随搅拌加热15分钟。然后蒸发除去溶剂。产物用硅胶色谱柱提纯,洗脱液为40/60 ACN/CH2Cl2。将主要的橙色带蒸发至于燥,并用乙醚重结晶(产率61%)。分析计算为
TcCl(DMG)3BB4NO2.0.2
C4H10O(C22H8N9O8BCITc.0.2C4H10O.实测:C,
38.39;H,4.21;N,1/.44.计算:C,38.75;H,
4.28;N,17.84.FAB-MS(+):m/z692,[M+H];656,
[M-Cl;579,[M-4-硝基咪唑].1H NMR(270
MHz,CDCl3):δ2.9(m,12H,CDO),3.0(m,12H,
CDO),5.2(s,2H,Bz),7.2(d,2H,Ph),7.4(s,
1H,咪唑),7.7(s,1H,咪唑),7.8(d,
2H,Ph),14.8(s,2H,二肟).IR(KBr)(cm-1):
3505br,1634,1545,1491,1399,1338,1228,1206
s,1089s,990s,928,909,824,808.UV-VIS
(CH3CN):λmax(Logε)288(4.08),382(3.80),460(3.41)
实施例28
99mTc(氯)(1,2—环己二酮二肟)3—1—(4—硝基咪唑基)苯甲基硼的制备
除了用3mg BBNO2(实施例21)代替1—(2—硝基咪唑基)—苯甲基硼酸外,用实施例12所述的方法制备标题化合物。用高压液相色谱(HPLC)测定标题络合物的产率,为86%。络合物样品用PRP—1 HPLC柱洗脱,保留值与下述制备的99TC可倍标样相同。
实施例29
99mTc(氯)(1,2—环己二酮二肟)3—1—(4—硝基咪唑基)苯甲基硼的制备
TcCl(CDO)3(25.7mg 0.046mmol)和BB4NO2(实施例21,11.6mg,0.48mmol)溶解在5ml ACN和0.5ml 3M盐酸中的混合物,伴随搅拌加热30分钟。加入5ml 1M盐酸后,生成橙色固体沉淀,并过滤收集(粗产率83%)。分析计算锝
C28H34N9O8ClBTc.0.5C4H10O:C,
44.65;H,4.87;N,15.62.实测:C,44.81;H,
4.95;N,16.05.FAB-MS(+):m/z769.M:734,
[M-Cl];657,[M4-硝基咪唑].1H NMR(270
MHz,CDCl3):δ7.4(m,18H,Me),5.2(s,2H,Bz),
7.2(d,2H,Pn),7.5(s,1H,咪唑),7.7(s,
1H,咪唑),7.8(d,2H,Ph),14.8(s,2H,
二肟),IR(KBr)(cm-1):3450br,1631,1546,
1446,1430,1380,1337,1286,1229,1203s,1061
s,960s,924,902,866,847.UV-VIS
(CH3CN):λmax(Logε)290(4.35),386(4.11),
462(3.76).
实施例30
99mTc(羟)(二甲基乙二肟)3—1—(2硝基咪唑基)苯甲基硼的制备
按照实施例14所述的方法制备化合物99mTc(氯化)(二甲基乙二肟)3—1—(2—硝基咪唑基)苯甲基硼。然后用PRP—1反相树脂吸附提纯。用1ml盐水和1ml 1∶1乙醇/盐水洗涤,然后用0.4ml 95%乙醇洗脱配合物。把400μl等分的pH8.0磷酸缓冲液(0.1M)加入到混合物中,在37℃加热30分钟。在其间,氯配位体轴被羟基置换用HPLC测定产率96%该络合物样品与99Tc(OH(二甲基乙二肟)3—1—(2—硝基咪唑基)—苯甲基硼标准样品共同洗脱。该物质通过用氢氧化钠液体处理99Tc—氯配合物制备。
实施例31
99mTc(氯)(1,2—环己二酮二肟)3—1—(丙烷—硝基咪唑基)硼的制备
除了用3mg BpropNO2(实施例20)代替1—(2—硝基咪唑基)—苯甲基硼酸外,用实施例12所述的方法制备标题化合物。用高压液相色谱(HPLC)测定标题配合物的产率为95%。
实施例32
99mTc(氯)(1,2—环己二酮二肟)3—1—(丙烯—硝基咪唑基)硼的制备
除了用3mg BpropenNO2(实施例19)代替1—(2—硝基咪唑基)—苯甲基硼酸外,用实施例12所述的方法制备标题化合物。用高压液相色谱(HPLC)测定标题络合物的产率,为83%。
实施例33
(R)—1—氮杂二环〔2,2,2〕辛—3—基—(R)—α—(4)—苯基硼酸—α—苯基乙酸乙酯(R,R—QNB硼酸)的制备
用乙酐(100ml)处理(RS)—3—奎宁环醇(25g,0.2mmol)的吡啶(100ml)溶液,保持在50℃4小时,然后放置在室温下15小时。真空条件下除去吡啶和过量的乙酐,然后把澄清的浅棕色油状物溶解在水中(25ml),用饱和碳酸钾使其呈弱碱性。然后用氯仿(5×50ml)提取酯,提取物用用K2CO3充分干燥。真空蒸发掉溶剂,残留物产率20.6g(62%)。为无色液态的(RS)—3—乙酰氧奎宁环
1HNMR(CDCl3)δ1.31-2.01(m,6H),2.11(s,3H,
OCOCH3),2.62-2.95(m,5H),3.18-3.31(m,1H),
4.80(m,1H,3H).
B.(R)—(+)—3—乙酰氧基奎宁环
把(RS)—3—乙酰氧基奎宁环(34g,0.2mmol)加入到L—(+)—酒石酸(30.13g,0.2mmol)的乙醇溶液中(80%,142ml)。使溶液保持在室温过夜,过滤生成的无色结晶固体(40g),并用乙醇(80%,280ml)重结晶两次,得到25.5g(65%)的拆分的(R)—(+)—3—乙酰氧基奎宁环的酒石酸盐mp96—98℃ Lit.2mp94—95.5℃。将拆分了的(R)—(+)—3—乙酰氧基奎宁环酒石酸盐(25.0g)的水(5ml)溶液。用饱和K2CO3使溶液呈弱碱性,并用氯仿(5×25ml)提取溶液。用Na2SO4充分干燥合并的CHCl3提取物,并过滤。真空蒸发除去溶剂后,蒸馏出无色液体的(R)—(+)—3—乙酰氧基奎宁环。产率:
10.7g(88%)
[α]D 25+29.96°(c2.93,乙醇.).Lit.(Cohen et
al.J.Pharm.Sci.,(1989),78,833-836
[α]D 25+29.8°(c3.0,乙醇).
1H NMR(CDCl3)δ1.30-2.01(m,6H),2.13(s,3H,
OCOCH3),2.62-2.98(m,5H),3.18-3.30(m,1H),
4.82(m,1H,3-H).
C.(R)—(+)—4—硝基二苯乙醇酸
对在沸腾乙酸乙酯(250ml)中的奎宁(39.6g,90%,1.1mmol)的悬浮液,加入外消旋的(RS)—4—硝基二苯乙醇酸(30.0g,1.1mmol),并保持在室温18小时。过滤结晶生成的盐,用乙酸乙酯四次重结晶后,具有不变的熔点120—122℃;产率19.5g(59.4%)TLC(硅胶,甲苯—HOAC9:1)Rf0.24。
然后用过量的6M盐酸处理奎宁盐(1g,1.68mmol)并用乙酸乙酯提取。提取物用无水MgSO4干燥,在减压条件下除去容剂,然后把得到的产物加到硅胶(8g)柱上,用CH2Cl2—MeOH(95∶5)洗脱,合并含有化合物的组分,并蒸发得到无色的糊状物,糊状物缓慢结晶生成乳色的固体。产率:0.35(77%)mp104—106℃薄层色谱〔硅胶,甲苯—HOAc〕9∶1〕Rf0.3;〔α〕25 D+50.11°(C1.34,丙酮),Lit.(Rzeszotarski et al.J.Med.Chem.,(1981),27,156—160)。〔α〕D 24+49.4(C1.34,丙酮)。
1H NMR(CDCl3)δ4.80(bs,2H,COOH和OH,7.35(m,5H,C6H5),7.71和8.21(2d,4H,C6H4)。D.(R)—4—氨基二苯乙醇酸
(R)—4—硝基二苯乙醇酸(2.0g,7.33mmol)的乙醇溶液(25ml),用肼(1.0ml)和阮内—Ni(0.8g)处理,并在氮气条件下于室温搅拌18小时。过滤除去阮内—Ni的粉末,用乙醇洗涤,把乙醇层浓缩到很小的体积,并用水稀释(75ml)。用乙醚(2×50ml)提取水层,在减压下蒸发水层,得到浅黄色(R)—4—氨基二苯乙醇酸的固体,产率82%(1.46g);mp139—140℃(分解);TLC〔硅胶,丙酮〕Rf0.20;1H NMR(D2O)δ6.75和7.18(2d,4H,C6H4)和7.31(s,5H,C6H5)E.(R)—4—碘二苯乙醇酸
碘二苯乙醇酸的制备是通过在-5℃,用30分钟的时间,把亚硝酸钠(1.7g,24.64mmol)的水(10ml)溶液滴加到(R)—4—(氨基二苯乙醇酸)(3.0g,12.35mmol)的10%盐酸(100ml)溶液中。在-5℃,继续搅拌附加的30分钟。然后缓慢加入碘化钾(4.09g,24.64mmol)的水(10ml)溶液。然后在0℃搅拌反应混合物1个小时,在环境温度下搅拌1个小时。用乙酸乙酯(3×75ml)提取所得的混合物,合并的提取液用硫代硫酸钠(10%,2×50ml),水(2×50ml)洗涤,用硫酸钠充分干燥。除去溶剂,得到棕色的糊状物,用色谱柱(硅胶,乙醇/二氯甲烷洗脱)提纯,得到浅黄色固体的产物。产率2.18g(50%);mp80—81℃;TLC〔硅胶,甲苯—乙酸9∶1〕Rf0.40;〔α〕D 25+24.7°(C0.132,acetone);1H NMR(CDCl3)δ5.50(bs,2H,COOH和OH),7.21和7.69(2d;4H,C6H4)和7.41(s,5H,C6H5)。F.(R)—3—奎宁环基—(R)—4—碘二苯乙醇酯
对(R)—4—碘二苯乙醇酸(0.26g,0.74mmol的干燥二甲基甲酰胺(2ml)的溶液,用少量的1,1′—羰基二咪唑(0.12g,0.74mmol)处理,在氮气条件下,于室温搅拌1个小时。在该浅黄色溶液中,加入(R)—3—奎宁环醇(0.93g,0.73mmol),在室温下继续搅拌另外的15小时。在真空条件下浓缩反应混合物,然后加入水(50ml)并用乙醚(3×30ml)提取。合并的醚提取液用饱和碳酸氢钠(2×20ml),水(2×20ml)洗涤。用无水硫酸钠充分干燥。对所得的糊状物,加入硅胶(0.5g),乙醚(5ml)并干燥。含有化合物的干燥硅胶粉末,被加到硅胶柱(10g)上,用5%甲醇在二氯甲烷溶剂中的混合物洗脱。合并含有化合物的馏分,用旋转蒸发仪蒸发,得到浅黄色的固体,产率75%,
(0.256g);mp124-127℃;TLC硅
胶,MeOH-NH4OH 98:2]Rf0.65;1H NMR(CDCl3)δ
1.15-1.89(m,4H),2.01(s,1H)2.42-2.81(m,
5H),3.21(m,1H),4.52(bs,1H,OH),5.01(m,
1H),5.01(m,1H)和7.15-7.82(m,9H,Ar-H).G.(RR)—QNB硼酸
在-78℃,在干燥的10ml RB烧瓶中,对(R)—3—奎宁环基—(R)—4—碘二苯乙醇酸酯(0.60g,1.3mmol)的新蒸四氢呋喃(2.0ml)的溶液,借助注射器缓慢加入n—BuLi(0.2g,2.5M,1.25ml,3.13mmol)。在上述温度下搅拌20分钟。然后把新蒸馏的三乙基硼酸酯(0.378g,0.441ml,2.59mmol)加入到反应混合物中,在-78℃,再搅拌1个小时,使温度升到环境温度,搅拌18小时。然后用几滴水处理反应反应混合物,倾倒除去溶液相。得到半固体物质,然后对该物质用乙醚反复洗涤,最后用乙醚研磨,得到无色的固体。把该固体溶解于含有<5%乙腈的水溶液中,过滤并加到反相C18HPLC柱上(Dynamax C18,4.14×25cm,8micron)在isocratic条件下用含有0.1%三氟乙酸/水的12.5%乙腈洗脱。馏分的鉴定借助分析HPLC(DynamaxC18,0.46×25cm,8micron,18%乙腈与在0.1%三氟乙酸中的0.1%三氟乙酸,收集纯度>98%标题化合物的馏分,冷冻干燥得到以三氟乙酸盐形式存在的(RR)—QNB硼酸的无色固体,产率:0.025g(4.4%);1HNMR(CD3OD)δ1.68(m,2H),1.95(m,2H),2.35(s,1H),2.81—3.35(m,5H),3.80(m,1H),5.31(m,1H)和7.28—7.71(m,9H,Ar—H)。MS:C24H29O6NB的准确计算值:438.2092;实测值:438.2088。
实施例34
(S)—1—氮杂双环〔2,2,2〕辛—3—基—(R)—α—羟—α—(4)—苯基硼酸—α—苯基乙酸酯(R,S—QNB硼酸)
该化合物通过实施例33的反应制备用S—奎宁环醇取代R—奎宁环醇A.(S)—3—乙酰氧基奎宁环
从实施例33A得到的母液(制备(R)—3—乙酰氧基奎宁环的),被真空浓缩且残留物用碳酸钾使之显碱性。用氯仿(3×50ml)提取该酶,用硫酸钠干燥。蒸发掉溶剂得到7.5g的粗酯,把酯加到(—)—酒石酸6.5g的80%乙醇溶液中,形成的盐用实施例33A所述的方法提纯。mp:95—96℃。文献(Cohenet al.J.Pharm.Sci.,(1989),78,83.3836)mp:94—96℃。B.(S)—3—奎宁环基—(R)—4—碘二苯乙醇酸酯
用(R)—4—碘二苯乙醇酸(0.26g,0.73mmol)1,1′—羰基二咪唑(0.12g,0.74mmol)和(R)—3—奎宁环醇(0.93g,0.73mmol)在干燥二甲基甲酰胺(2ml)中如合成(R)—3—奎宁环基—(R)—4—碘二苯乙醇酸酯(实施例33)的方法,制备无色糊状的标题化合物,产率73%(0.25g)。TLC〔硅胶,MeOH—NH4OH98:2〕Rf0.69;1H NMR(CDCl3)δ1.15—1.89(m,4H),2.01(s,1H),2.42—2.81(m,5H),3.21(m,1H),4.52(bs,1H,OH),5.01(m,1H),5.01(m,1H)和7.15—7.82(m,9H,Ar—H)。C.(S)—1—氮杂双环〔2,2,2〕辛—3—基—(R)—α—羟基—α—(4)—苯基硼酸—α—苯基乙酸乙酯
用(S)—3—奎宁环基—(R)—4—碘二苯乙醇酸酯(0.6g,1.3mmol),n—BuLi(0.2g,2.5M,1.25ml,3.13mmol)和三乙基硼酸酯(0.378g,0.441ml,2.59mmol)在干燥四氢呋喃中,在-78℃,用如合成(RR)—QNB硼酸(实施例33)所述的方法,合成无色固体(TFA盐的形式)的上述化合物,产率11%(58mg)。1H NMR(CD3OD)δ1.68(m,2H)1.95(m,2H),2.35(s,1H),2.81—3.35(m,5H),3.80(m,1H),5.31(m,1H))和7.28—7.71(m,9H,Ar—H)。MS:准确计算分子量为C24H29O6NB:438.2092;实测值438.1190。
实施例35
(S)—1—氮杂双环〔2,2,2〕辛—3—基—(S)—α—羟基—α—(4)—苯基硼酸—a—苯基乙酸乙酯(S,S—QNB硼酸)的制备
通过下述的反应式制备本化合物:A.(RS)—4—溴二苯乙醇酸
对4—溴二苯酮(54.81g,0.21mol)的干燥二氯甲烷(500ml)溶液,加入碘化锌(0.5g),在氮气条件下,在室温下搅拌。然后从另一个烧瓶,用1小时的时间,滴加入三甲基硅氰化物(25g,0.25mol),并在室温下搅拌72小时。然后用饱和碳酸氢钠(200ml)处理反应混合物并搅拌1小时。分离出有机层,用水洗涤(2×150ml)并浓缩。残留物悬浮在H2O:HCl:AcOH(1:3L3;500ml)中,并用油浴在85—90℃加热48小时。然后在真空浓缩溶液至约100ml,并用饱和碳酸氢钠(400ml)处理,用乙醚(3×100ml)提取。然后用6 N盐酸酸化水层,分离得到的固体溶于乙醚中(300ml)。用水洗涤有机层,过滤并蒸发滤液,得到无色的(RS)—4—溴二苯乙醇酸的结晶固体,产率19%(12g);mp125—126℃;TLC〔硅胶,甲苯—乙酸〕Rf0.32;1H NMR(DMSO—d6)δ2.38(bs,2H,COOH和OH)和7.38—7.70(m,9H,AR—H)。B.3—S—奎宁环基4′—溴二苯乙醇酸酯
N,N′—羰二咪唑(0.810g,0.005mol)在氮气条件下被加到外消旋对一溴二苯乙醇酸(1.53g,0.005mol)的二甲基甲酰胺(5ml)的溶液中,并在40℃搅拌反应混合物1小时。加入S—奎宁环醇(0.8g,0.0063mol)并在40℃搅拌混合物24小时。完成反应后,得到1.12g 3—S—奎宁环基4′—溴二苯乙醇酸酯。mp.151—53℃,1H NMR(DMSO—d6)δ1.3—3.3(m,奎宁环基质子),4.9(m,1H,CHO),7.3—7.7(m,9H,ArH)。MS:(M2+H)+=416+和418+。C:(S)-1—氮杂二环〔2.2.2〕辛—3—基—(S)—α—羟—α—(4)—苯基硼酸—α—苯基乙酸酯
对冷却(-78℃)的3—S—奎宁环基4′—溴二苯乙醇酸酯(417mg,0.001mol)的干燥四氢呋喃(30ml)的溶液用注射器加入n—BuLi(2.5M的己烷溶液,1.0ml,0.165g,0.0025mol)。在-78℃搅拌混合物1小时。并在-78℃加入三乙基硼酸酯2ml。在-78℃再搅拌另外的1小时,并在室温下搅拌4小时。除去四氢呋喃,残留物用水处理并用乙酸乙酯提取,用硫酸钠干燥。蒸发掉溶剂得到半固体物质,用乙醚研磨得到100mg的(RS),S—QNB—硼酸。mp212—215℃(分解)。如实施例33G所述。通过制备HPLC,从非对映异构体的混合物中分离出S,S对映异构体。S,S—对映异构体的1H NMR(D2O):δ1.40-1.70(m,2H),1.17
-3.03(m,2H),2.32(s,1H),2.65-2.85(m,1H),
3.))-3.22(m,4H),3.60(m,1H),5.28(m,1H),
7.35(m,7H),7.72(d,2H).
实施例36
(R)—1—氮杂双环〔2.2.2〕辛—3—基—(S)—α—(4)—苯基硼酸—α—苯基乙酸酯(S,R—QNB硼酸)
通过示于实施例35的反应式制备本化合物。A.3—R—奎宁环基4′—溴二苯乙醇酸酯
在氮气下把N,N′—羰基二咪唑(0.810g,0.005mmol)加到对—溴二苯乙醇酸(实施例35A,1.53g,
0.005mmol)的二甲基甲酰胺(5ml)的溶液中,在40
℃搅拌反应混合物1小时。在40℃,R—奎宁环醇(0.8g,
0.0063mol)被加到混合物中,搅拌混合物24小时。真空
条件下除去二甲基甲酰胺,并把残留物倒入水中。过滤沉淀的固体并
在空气中干燥。产率:1.2g(58%)。
1H NMR(DMSO—d6)δ1.3—3.3(m,奎宁环基质
子),4.9(m,1H,CHO),7.3-7.7(m,9H,
ArH)。MSM2—H)+=416+和418+。
B.(R)—1—氮杂双环〔2.2.2〕辛—3—基—(S)—α
—羟—α—(4)—苯基硼酸—α—苯基乙酸酯
对冷却的(-78℃)3—奎宁环基4′—溴二苯酸酯(316
mg,0.00076mol)的干燥四氢呋喃(30ml)的溶液,
用注射器加入n—BuLi(2.5M己烷溶液,0.72ml,
0.12g,0.0018mol)。在-78℃搅拌混合物1小时,
并在此温度下加入三乙基硼酸酯(1ml)。在-78℃再搅拌混合
物1小时,并在室温下搅拌4小时。除去四氢呋喃,用水处理残留物。
并用乙酸乙酯提取,用硫酸钠干燥。蒸发掉溶剂得到的半固体用乙醚
研磨。得到固体,产率50mg。实施例33G中所述。通过制备
HPLC从非对映异构体的混合物中,分离出S.R对映异构体,mpz13—215℃(分解)1H NMR(D2O)δ1.41-1.70(m,2H),
1.71-2.02(m,2H),2.32(s,1H),2.65-2.85(m,
1H),3.00-3.22(m,4H),3.60(m,1H),5.28(m,
1H),7.35(m,7H),7.72(d,2H)
实施例37
99mTcCl(DMG)3〔(RR或RS)QNB硼〕的制
备
在5ml硅血清管瓶中,定量加入2.0mg的二甲基乙二肟,1.5mg 3—R—奎宁环基—(4—硼—R—二苯乙醇酸酯)(RR—QNB—硼酸)或3—R—奎宁环基—(4—硼—S—二苯乙醇酸酯)(RS—QNB—硼酸),20mg柠檬酸,100mgNaCl,2.0mg二亚乙基三胺五—乙酸,和125μgSnCl2(在4M HCl中)(全部体积0.7ml 28%乙醇/盐水)。加入0.5ml 99mTcO4 —发生洗脱剂,并把混合物加热到70℃15分钟,用HPLC测定所需化合物的产率为60—70%。反应混合物用PRP—1树脂,进行色谱提纯得到产物的纯度大于90%。
实施例38
99mTcCl(CDO)3(QNB—硼)的制备
对5ml硅血清管瓶定量加入2.0mg1,2—环己二酮二肟1.5mg3—奎宁环基—(4—硼—二苯乙醇酸酯)(QNB—硼酸),20mg柠檬酸,100mg NaCl,2.0mg二亚乙基三胺五一乙酸,和125μg SnCl2(在4M HCl中)(全部体积0.7ml的28%乙醇/盐水)。加入0.5ml99mTcO4 —发生洗脱剂。在70℃加热混合物约15分钟,用HPLC测定所需化合物的产率为83%。用PRP—1树脂色谱分离提纯反应混合物,得到的产物的纯度>90%。
Claims (6)
1.一种适合以99mTc或铼放射性核素标记的药盒,该药盒包括:
(i)一种阴离子源;
(ii)能够就地反应形成硼残基的硼化合物或其可药用盐,所述化合物具有下式:其中R7和R′7各自分别为H、烷基、芳基,或R7和R′7结合在一起形成亚烷基-(CR8R9)2-6-,R8和R9各自分别为H或烷基;R3是一个生化活性基团,选自缺氧症介导的硝基杂环类;苯异丙胺类;类固醇类,如雌激素或雌二醇;糖类;脂肪酸类,但不包括C2-19羧烷基和羧烯基;巴比妥酸盐类;磺酰胺类;单胺氧化酶底物和抑制剂,但不包括R4R5N-烷基,其中R4和R5各自分别是H或烷基,或R4、R5和N形成5元或6元杂环;抗高血压剂;蝇蕈碱受体底物;多巴胺受体底物;A1是化学键或间隔基团;
(iii)一种式HO-N=C(R1)-(R2)C=N-OH的二肟化合物或其可药用盐,其中R1和R2各自分别是氢、卤素、烷基、芳基、氨基或者5元或6元含氮或氧的杂环,或者R1和R2相结合形成-(CR8R9)n-,其中n是3、4、5或6,R8和R9各自分别是氢或烷基;
(iv)任选的一种还原剂。
2.权利要求1的药盒,其中阴离子源是卤离子源。
3.权利要求2的药盒,其中阴离子是Cl或Br。
4.权利要求1或2的药盒,其中所述二肟是1,2-环己二酮二肟、1,2-环戊二酮二肟、或3-甲基-1,2-环戊二酮二肟。
5.权利要求1-4中任一项的药盒,其中R3选自雌二醇即[17(α(E)-3,17-二羟基-1,3,5(10)-雌三烯-17-基]乙烯基和MIVE即[[11-β,17α(E)]-3,17-二羟基-11-甲氧基-1,3,5(10)-雌三烯基]乙烯基、4-[2-[(1-甲基乙基)氨基]丙基]苯基、一种蝇蕈碱受体底物、以及二(对溴苯基)乙醇酸3-奎宁环酯。
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US3369121A (en) | 1966-04-06 | 1968-02-13 | Squibb & Sons Inc | Radioactive package and container therefor |
US3920995A (en) | 1973-05-04 | 1975-11-18 | Squibb & Sons Inc | Radioactive material generator |
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US4705849A (en) * | 1985-04-15 | 1987-11-10 | E. R. Squibb & Sons, Inc. | Boronic acid adducts of technetium-99m dioxime complexes |
US4871836A (en) | 1987-10-13 | 1989-10-03 | E. R. Squibb & Sons, Inc. | Boronic acid adducts of rhenium and radioactive isotopes of rhenium dioxime complexes |
CN1022562C (zh) * | 1989-04-08 | 1993-10-27 | 中国人民解放军第二军医大学 | 一种消瘤药——甲硝唑氨酸的合成方法 |
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1991
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- 1991-01-14 MY MYPI91000058A patent/MY105482A/en unknown
- 1991-01-15 IL IL9694691A patent/IL96946A/en not_active IP Right Cessation
- 1991-01-15 ZA ZA91300A patent/ZA91300B/xx unknown
- 1991-01-16 AU AU69385/91A patent/AU651076B2/en not_active Ceased
- 1991-01-16 NZ NZ236789A patent/NZ236789A/en unknown
- 1991-01-16 IE IE013391A patent/IE910133A1/en unknown
- 1991-01-17 MX MX2417791A patent/MX24177A/es unknown
- 1991-01-17 NO NO91910201A patent/NO910201L/no unknown
- 1991-01-17 HU HU91155A patent/HU910155D0/hu unknown
- 1991-01-18 YU YU26691A patent/YU26691A/sh unknown
- 1991-01-18 CN CN91101146A patent/CN1034078C/zh not_active Expired - Fee Related
- 1991-01-18 JP JP3019465A patent/JPH04212099A/ja active Pending
- 1991-01-18 PT PT96518A patent/PT96518B/pt not_active IP Right Cessation
- 1991-01-18 EP EP91300414A patent/EP0441491A1/en not_active Ceased
- 1991-01-18 FI FI910274A patent/FI910274A/fi not_active Application Discontinuation
- 1991-01-18 KR KR1019910000787A patent/KR100191568B1/ko not_active IP Right Cessation
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1992
- 1992-01-07 US US07/818,705 patent/US5387409A/en not_active Expired - Lifetime
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1994
- 1994-12-01 AU AU79147/94A patent/AU7914794A/en not_active Abandoned
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1995
- 1995-03-22 CN CN95103488A patent/CN1111621A/zh active Pending
- 1995-08-01 CN CN95109333A patent/CN1120437A/zh active Pending
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CN1111621A (zh) | 1995-11-15 |
IL96946A0 (en) | 1992-03-29 |
NZ236789A (en) | 1995-03-28 |
AU651076B2 (en) | 1994-07-14 |
EP0441491A1 (en) | 1991-08-14 |
AU6938591A (en) | 1991-07-25 |
CN1034078C (zh) | 1997-02-19 |
IL96946A (en) | 1995-12-08 |
KR100191568B1 (ko) | 1999-06-15 |
MY105482A (en) | 1994-10-31 |
FI910274A (fi) | 1991-07-19 |
KR910014385A (ko) | 1991-08-31 |
YU26691A (sh) | 1994-05-10 |
NO910201L (no) | 1991-07-19 |
JPH04212099A (ja) | 1992-08-03 |
PT96518B (pt) | 1998-06-30 |
NO910201D0 (no) | 1991-01-17 |
CA2034042A1 (en) | 1991-07-19 |
ZA91300B (en) | 1991-11-27 |
US5387409A (en) | 1995-02-07 |
HU910155D0 (en) | 1991-08-28 |
CN1054070A (zh) | 1991-08-28 |
MX24177A (es) | 1993-12-01 |
IE910133A1 (en) | 1991-07-31 |
CA2034042C (en) | 1999-08-17 |
AU7914794A (en) | 1995-02-16 |
PT96518A (pt) | 1991-10-15 |
FI910274A0 (fi) | 1991-01-18 |
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