CN101778910A - 谷氨酸的异质二聚体 - Google Patents
谷氨酸的异质二聚体 Download PDFInfo
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- CN101778910A CN101778910A CN200780049490A CN200780049490A CN101778910A CN 101778910 A CN101778910 A CN 101778910A CN 200780049490 A CN200780049490 A CN 200780049490A CN 200780049490 A CN200780049490 A CN 200780049490A CN 101778910 A CN101778910 A CN 101778910A
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- compound
- urea
- radionuclide
- carboxyl
- alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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Abstract
本发明公开了式(Ia)化合物:其中R是C6-C12取代或未取代的芳基,C6-C12取代或未取代的杂芳基C1-C6取代或未取代的烷基或-NR’R’,Q是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,Y是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,Z是H或C1-C4烷基,R’是H、C(O)、S(O)2、C(O)2、C6-C12取代或未取代的芳基,C6-C12取代或未取代的杂芳基或C1-C6取代或未取代的烷基,当被取代时,芳基、杂芳基和烷基被卤素、C6-C12杂芳基、-NR’R’或COOZ取代,该化合物具有诊断和治疗的性质,例如前列腺癌和与N-乙酰基化α-连接的酸性二肽酶(NAALADase)抑制相关的其它疾病的治疗和处理。放射性标记物可以通过多种辅基掺入该化合物结构中,所述辅基通过碳原子键或杂原子键附到X氨基酸侧链上。
Description
相关申请的交叉引用
本申请要求2006年11月8日提交的美国临时申请第60/857,490号和2007年1月5日提交的美国临时申请第60/878,678号的优先权,这两个临时申请的公开内容通过引用整体结合入本文。
背景技术
至少100万男性遭受前列腺癌的痛苦,据估计每六个60至80岁年龄的美国男人中就有一个受到该疾病侵袭。每年会诊断出的超过300,000名前列腺新病例。前列腺影响每六个美国男性中的一个,该病的死亡率仅次于肺癌。当前全世界花费估计有10亿美元用于手术、放射、药物治疗和最小侵袭性处理,在美国则花费10亿美元。目前对于复发、转移、雄激素非依赖性前列腺癌还没有有效的治疗。能够实现迅速观察到前列腺癌和特异靶向性而允许放射治疗的新型制剂为当前所需要。
N-乙酰化的α连接的酸性二肽酶(NAALADase),也称作谷氨酸羧肽酶II(GCPII),是一种神经肽酶,在神经系统中该酶分裂N-乙酰-天冬氨酰-谷氨酸盐(NAAG)生成N-乙酰天冬氨酸盐和谷氨酸盐,见下面,描述NAALDase通过四面体中间体水解分裂NAAG。该酶是金属肽酶的共催化类II型蛋白,在活性位点含有两个锌原子。
不依赖于其在神经系统中的特性,NAALADase的一种亚型在人前列腺腺癌中高水平表达并被命名为前列腺特异性膜抗原(PSMA)。已经知道NAALADase/PSMA基因产生多种mRNA剪接体。基于以前的免疫组化证据,已推断人脑和前列腺表达该酶的不同亚型。
人前列腺特异性膜抗原(PSMA),也称作叶酸水解酶I(FOLH1),是一种跨膜、750个氨基酸的II型糖蛋白,该酶主要在正常人前列腺上皮细胞表达,但是在前列腺癌包括转移性疾病中被上调。PSMA是一种独特的肽链端解酶,具有针对聚-γ-谷氨酸的叶酸的活性,能够顺序移除聚--谷氨酰末端。既然PSMA在几乎所有前列腺癌中表达,并且其表达在低分化的、转移的和激素非依赖性癌症中进一步增高,因此对于前列腺成像和治疗,PSMA是一个吸引人的靶点。开发能够与PSMA相互作用的配基并且携带合适的放射性核素可以提供有希望的和新颖性的靶向选择用于前列腺癌的检测、治疗和处理。
抗-PSMA单克隆抗体(mAb)7E11的放射免疫偶联形式,目前正被用于诊断前列腺癌转移和复发,称为PROSTASCINT扫描。前期源于多种I期和II期试验的有希望的结果已经使用PSMA作为治疗靶点。PROSTASCINT靶向于PSMA的胞内结构域,并被认为主要结合前列腺肿瘤的坏死部分。14最近发展的单克隆抗体结合PSMA的胞外结构域,并且已被放射性标记,且显示在动物PSMA阳性前列腺肿瘤模型中聚集。
虽然单克隆抗体对肿瘤的检测和治疗很有希望,但由于它们在固体瘤中的低穿透性,很少获得除淋巴瘤外的临床上的成功。
发明内容
发明概述
本发明的一个方面涉及式(I)化合物或式(I)化合物的药学上可接受的盐。
其中R是C6-C12取代或未取代的芳基,C6-C12取代或未取代的杂芳基,C1-C6取代或未取代的烷基或-NR’R’,
Q是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p
Y是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p
Z是H或C1-C4烷基,
m是0、1、2、3、4或5,
n是0、1、2、3、4、5或6,
p是0、1、2、3、4、5或6,
R’是H、C(O)、S(O)2、C(O)2、C6-C12取代或未取代的芳基,C6-C12取代或未取代的杂芳基或C1-C6取代或未取代的烷基,当被取代时,所述芳基、杂芳基和烷基被卤素、C6-C12杂芳基、-NR’R’或COOZ取代,
进一步地,其中
(i)R或R’中至少一个是经卤素取代的C6-C12芳基或C6-C12杂芳基或
(ii)R或R’中至少一个是C6-C12杂芳基。
本发明的另一个方面涉及式(Ia)化合物或式(I)化合物的药学上可接受的盐。
其中R是C6-C12取代或未取代的芳基,C6-C12取代或未取代的杂芳基,C1-C6取代或未取代的烷基或-NR’R’,
Q是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,
Y是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,
Z是H或C1-C4烷基,
m是0、1、2、3、4或5,
n是0、1、2、3、4、5或6,
n’是0、1、2、3、4、5或6,
p是0、1、2、3、4、5或6,
R’是H、C(O)、S(O)2、C(O)2、C6-C12取代或未取代的芳基,C6-C12取代或未取代的杂芳基或C1-C6取代或未取代的烷基,当被取代时,所述芳基、杂芳基和烷基被卤素、C6-C12杂芳基、-NR’R’或COOZ取代,
进一步地,其中
(i)R或R’中至少一个是被至少一个卤素取代的C6-C12芳基或C6-C12杂芳基或
(ii)R或R’中至少一个是取代或未取代的C6-C12杂芳基。
在式(I)、(Ia)、(II)或(IIa)的化合物的优选实施方案中,n是0或1和n’是0或1。
本发明也涉及谷氨酸盐-尿素-赖氨酸PSMA-结合部分和它们在诊断和治疗性处理中的应用。在一个实施方案中,本文所描述的基于尿素的类似物是通过α-NH2或β-NH2基团偶合的谷氨酸盐-尿素-α或β-氨基酸异质二聚体。放射性标记物通过多种辅基可被掺入该化合物结构中,所述辅基通过碳原子键或杂原子键附到X氨基酸侧链上。本发明的化合物可以用作靶向试剂和诊断和治疗试剂,用于前列腺癌和与NAALADase抑制相关的其它疾病的治疗和处理。
适合的化学基部分、化学基部分的定义、赋形剂和给药的方法和模式可以在美国公开申请第2004/0054190号和第2004/0002478号和国际申请WO 02/22627和WO 03/060523中发现,这些申请通过引用整体结合入本文。
附图说明
图1A-1C分别是共注射TC-99m-谷氨酸-尿-DpK(Tc-99m-MIP1008)、铼类似物和铼二酯混合物的HLPC色谱图;
图2A-2D显示了37℃,分别在pH7.2的PBS中,在含0.1M半胱氨酸的PBS中,在含0.1M DTPA的PBS中和在含5%鼠血清的PBS中经历6小时,谷氨酸-尿-DpK(Tc-99m-MIP 1008)的Tc-99m混合物的稳定性;
图3A-3B分别是N-[N-[(S)-1,3-二羧丙基]氨甲酰基]-S-3-碘-L-酪氨酸(I-131 DCIT)粗反应物(图3A,顶部),在2小时纯化物(图3B,中部)和在2天纯化物(图3C,底部)的HPLC色谱图;
图4A-4D是3天,在37℃,在A)DMSO,B)3%龙胆酸盐-6%抗坏血酸盐/抗坏血酸,C)PBS,pH=7.2,D)10%乙醇盐溶液中,纯化的I-131 MIP 1072的放射性-HPLC色谱图。如上面所显示,I-131-1072(12分钟时的色谱峰)经过这些实验仍然保持稳定;
图5显示I-123 DCIT特异结合到LnCap细胞而不是PC3细胞(左系列,通过在LnCap细胞中用非放射标记的化合物(中系列)或PMPA(右系列)替换后的计数,该结论是显然的。柱状图显示的是平均值±SEM,每个实验重复进行两次;
图6是在用冷2-{3-[1-羧基-2-(4-羟基-苯基)-乙基]-脲基}-戊二酸(DCT)的PSMA细胞结合试验中的斯卡查德分析;
图7显示在PSMA-阳性LNCaP细胞中所选择的化合物的生物学评估;
图8显示在PSMA-阳性LNCaP细胞中先导化合物的生物学评估;
图9显示在用MIP1072的PSMA细胞结合试验中的斯卡查德分析;
图10显示I-131-MIP1072的内化;
图11A和11B分别显示I-131 MIP-1072及DCT和非那西汀在大鼠微粒体中经历60分钟的稳定性;
图12显示在异种移植肿瘤小鼠中I-131 MIP1072的组织生物分布;
图13显示来自LNCaP细胞裂解液的NAALADase活性的抑制;
图14显示来自LNCaP细胞裂解液的NAALADase活性的抑制;
图15显示来自LNCaP细胞裂解液的NAALADase活性的抑制;
图16显示在LNCap细胞中检测试验化合物抑制已知NAALADase抑制剂131I-DCIT结合到PSMA能力,细胞与各种浓度的试验化合物和131I-DCIT孵育1小时,然后洗涤并计数测定IC50值;
图17是MIP-1072的直接结合分析。在存在或不存在非放射性10μM MIP-1072或10μM特异PSMA抑制剂(PMPA)的情况下,123I-MIP-1072(3nM,>1,000mCi/μmole)与PSMA阳性LNCaP细胞或PSMA阴性PC3细胞孵育(300,000细胞/孔);
图18显示123I-MIP-1072在LNCaP细胞中的饱和结合分析;
图19显示123I-MIP-1072的内化;
图20显示在荷LNCaP异种移植物小鼠中123I-MIP-1072的摄取。在来自荷LNCaP(PSMA阳性)肿瘤裸鼠的选定组织中评测123I-MIP-1072(2μCi/鼠,>1,000mCi/μmole)的组织生物分布,结果显示为每克选定组织注射剂量的百分数(%ID/g);
图21显示在荷LNCaP和PC3异种移植物小鼠中123I-MIP-1072的摄取,在来自用(阻断的)或不用(正常的)50mg/kg PMPA预处理的荷LNCaP(PSMA阳性)和PC3(PSMA阴性)肿瘤裸鼠的选定组织中评测123I-MIP-1072(2μCi/鼠,>1,000mCi/μmole)的组织生物分布。
具体实施方式
发明详述
定义
“药学上可接受的盐”指维持游离碱生物有效性和特性的那些盐和与无机酸(例如盐酸、氢溴酸、硫酸、硝酸、磷酸、甲磺酸、乙磺酸、p-甲苯磺酸、水杨酸等)反应获得的那些盐。
″烷基″指直链、支链或环饱和脂肪烃。典型的烷基包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等。烷基可任选地被一种或多种选自羟基、氰基或烷氧基的取代基取代。当烷基是R’取代基时,它是1至6个碳的低烷基,更优选为1至4个碳。
“芳基”指具有共轭的π电子系统的至少一个环的芳香基团,和包括碳环芳基、杂环芳基和联芳基。芳基可任选地被一种或多种取代基取代,该取代基选自卤素、三卤甲基、羟基、SH、OH、NO2、胺基、硫醚、氰基、烷氧基、烷基和氨基。芳基的实例包括苯基、萘基和蒽基基团,优选为苯基和取代的苯基。
“杂芳基”指具有1至3个杂原子作为环原子的芳基,其余的环原子为碳。杂原子包括氧、硫和氮。因此,杂环芳基基团包括呋喃基、噻吩基、吡啶基、吡咯基、N-低烷基、吡咯并、嘧啶基、吡嗪基、咪唑基等。
合成
除非另有说明,所有反应在氩气中于干燥玻璃器皿中进行。在中等压力下通过Biotage SP4柱层析或通过制备型高压液相色谱纯化反应物。
在Bruker 400MHz仪器上记录1H NMR。光谱报告为ppm并参照在CDCl3,DMSO-d6或甲醇-d4.中的溶剂共振峰。所有溶剂购自Sigma-Aldrich。试剂购自Sigma Aldrich、Bachem、Akaal、Fisher、Alfa Aesar、Acros和Anaspec。采用下列缩写二氯甲烷(DCM)、乙酸乙酯(EA)、己烷(Hex)、二氯乙烷(DCE)、二甲基甲酰胺(DMF)、三氟乙酸(TFA)、四氢呋喃(THF)、羰基二咪唑(CDI)、二甲氨基吡啶(DMAP)、三乙胺(TEA)、三氟甲烷磺酸甲酯(MeOTf)、(S)-2-氨基-6-(二吡啶-2-基甲基-氨基)-己酸(dpK)、谷氨酸(Glu)、二异丙基乙胺(DIEA)、苄氧羰酰基(CBZ)。
中间体合成
下列化合物按照方案1描述制备,总体产量范围在20-40%。第一步,谷氨酸的二叔丁酯和CDI在碱的存在下形成中间体谷氨酸-脲-咪唑衍生物2,该步在惰性条件下于0℃进行。该中间体在碱性条件下通过MeOTf活化得到甲基化的咪唑3,其在多性条件下容易和胺反应。在DCM中用20%TFA室温反应1到4小时移去叔丁酯保护基团。一旦去保护完成,反应物经旋转蒸发仪浓缩或用氮气吹干,并在硅柱上纯化或重结晶。最终产物经体内和体外测试。
方案1.PSMA化合物合成的大体途径
L-(S)-2-[(咪唑-1-羰基)-氨基]-戊二酸-二叔丁酯(2)
二叔丁酯盐酸盐(15.0g,51mmol)悬于预冷到0℃的DCM(150mL),并加入TEA(18mL)和DMAP(250mg)。搅动5分钟后,加入CDI(9.0g,56mmol)并搅拌反应过夜,逐渐升温至室温。反应物用DCM(150mL)稀释并用饱和的碳酸氢钠(60mL)、水(2X100mL)和盐水(100mL)洗涤。有机层用硫酸钠干燥并浓缩获得半固体状粗产物,该粗产物静置慢慢固化。在己烷/乙酸乙酯中将粗料磨碎获得白色固体,经过滤己烷(100mL)洗涤和干燥得到想要的白色固体产物(15.9g,45mmol,88%)。1H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.00(br,2H),6.31(d,1H),4.02(m,1H),2.19(m,2H),1.86(m,1H),1.67(m,1H),1.39(s,9H),1.38(s,9H)。ESMSm/z:354(M+H)+。
另外,该类似物可通过异氰酸盐用三光气原位生成。该方法可通过谷氨酸残基活化并与赖氨酸残基偶联(路线A)或通过赖氨酸残基活化并将其与谷氨酸偶联(路线B)来完成,如下面方案2所示。
方案2.
L-(S,S)-2-[3-(5-苄氧羰基氨基-1-叔丁酯基-戊基-脲基)-戊二酸-二叔丁酯(3)
路线A.在圆底烧瓶中1.8mL TEA(13.2mmol)与1.8克(6mmol)L-谷氨酸二叔丁酯盐酸盐混合于20mL DCM。该溶液0℃下经45分钟滴加入10mL DCM和三光气溶液(0.7g,2.2mmol)。再搅拌30分钟后,包含TEA(1.8mL,13mmol)的H-赖氨酸-(Z)-O-叔丁酯盐酸(2.2g,6mmol)的15mL DCM溶液被一次全部加入。溶液搅拌1小时。反应物浓缩,用50mL乙酸乙酯稀释,经2N NaHSO4(2x 50mL)、盐水(50mL)洗涤和硫酸钠干燥生成黄色油。经柱色谱纯化获得所要的清油,该清油静置后固化成白色固体(1.9g,54%)。
路线B.在圆底烧瓶中三光气(2.9g,10mmol)悬浮于DCM(50mL)中并在0℃搅拌。将H-赖氨酸(Z)自由基(9.1g,27mmol)和DIEA(10.4mL,60mmol)DCM(50mL)溶液经历2.5小时滴加到三光气溶液中。2.5小时后含有DIEA(10.4mL,60mmol)的L-谷氨酸二叔丁酯盐酸盐(8g,27mmol)DCM(50mL)溶液被一次性全部加入,并搅拌45分钟。该反应物浓缩至干燥,用150mL乙酸乙酯稀释,经2N NaHSO4(2x200mL)、盐水(150mL)洗涤和硫酸钠干燥生成黄色油。经柱色谱(SiO2)纯化获得所要的清油,该清油静置后固化成白色固体(12.0g,72%)。1HNMR(400MHz,CDCl3)δ7.34(m,5H),5.33-5.28(m,3H),5.08(d,J=7.4Hz,2H),4.38-4.29(m,2H),3.15(m,2H),2.32-2.01(m,2H),1.90-1.50(m,8H),1.43-1.40(m,27H,t-Bu’s)。ESMS m/z:622(M+H)+。
2-[3-(5-氨基-1-叔丁酯基-戊基)-脲基]-戊二酸-二叔丁酯(4)。
将甲酸铵(630mg,10eqv)加入到2-[3-(5-苄氧羰基氨基-1-叔丁酯基-戊基)-脲基]-戊二酸-二叔丁酯(630mg,1.0mmol)乙醇溶液(20mL)中,随后加入10%Pd-C,并且该悬液静置过夜偶尔搅动,直到完成。反应物经过硅藻土过滤并浓缩得到所要的蜡状固体产物(479mg,98%)。1H NMR(400MHz,CDCl3)δ7.15-6.0(bm,4H,NH’s),4.29(m,2H),3.02(m,2H),2.33(m,2H),2.06-1.47(m,8H),1.45-1.40(m,27H,t-Bu’s)。ESMS m/z:488(M+H)+。
系链核心模型化合物(Tether Core Model Compounds)谷氨酸-尿素-谷氨酸的合成。
在该系列中,在偶联形成尿素二聚物之前,系链(Tether)被引入谷氨酸或赖氨酸的支链。在下面的实施方案中一个谷氨酸支链的羧酸被修饰成一个系链来悬挂本身就是或包含放射性核素的一个螯合物、原子或功能基(方案4)。
方案4.2-{3-[3-(4-氨基-丁基氨基甲酰基)-1-甲氧羰基-丙基]-脲基}-戊二酸-二叔丁酯(28)
将EDC(845mg,1.3eqv)和TEA(1.3mL)加入到冷却至0℃的N-BOC谷氨酸α-甲酯BOC-Glu(OH)-Ome(960mg,3.7mmol)的DMF溶液。搅拌10分钟后,加入单保护的二胺N-CBZ-1,4-二氨基丁烷盐酸盐(1g,3.8mmol),反应物搅拌过夜,并加热到室温。粗反应物用EA(100mL)稀释,并用水(30mL)、5%柠檬酸水溶液(30mL)、碳酸氢钠盐液(30mL)、水(30mL)和盐水(30mL)洗涤。有机层经硫酸钠干燥并浓缩得到稠糖浆状粗产物(2.1g)。将4N HCl的二僫烷溶液(10mL)加入到所获得的糖浆状物中,并且反应物在室温下搅拌3小时。浓缩获得蜡状盐酸盐固体(1.8g)。如先前试验部分所描述的,该盐被偶合到活化的L-(S)-2-[(咪唑-1-羰基)-氨基]-戊二酸-二叔丁酯(2)获得所要的全保护二聚物x(1.9g)。该物质被悬于纯乙醇(20mL)中,加入过量的甲酸铵(5g),随后加入20%Pd(OH)2碳(100mg),并且轻轻搅拌该悬液过夜来实现CBZ保护基团的断裂。通过硅藻土过滤并浓缩获得所要的自由胺(1.4g,2.7mmol,73%,4步)。1H NMR(400MHz,CDCl3)δ8.41(br,2H),7.36 9br,1H),6.44(bs,1H),6.37(bs,1H),4.37-4.29(m,2H),3.71(s,3H),3.20-1.50(m,16H),1.45(s,9H),1.43(s,9H)。ESMS m/z:517(M+H)+。
Re(CO)3-2-(3-{3-[4-(二-吡啶-2-基甲基-氨基)-丁基氨基甲酰基]-1-羧基-丙基}-脲基)-戊二酸[溴](29)(MIP-1100)
如之前所描述,用吡啶-2-甲醛通过还原胺化制备保护的中间体。用2M LiOH的甲醇溶液处理实现甲酯的水解。去除甲醇并加入过量的DCM∶TFA(1∶1),反应物在室温搅拌过夜。按照上面所描述步骤,粗提物被转化成所要的铼偶联物。制备型HPLC获得所要的分子(9.5mg,16%)。1H NMR(400MHz,DMSO-d6)δ8.78(m,2H),8.31(br,1H),7.95(m,2H),7.59(m,2H),7.39(m,2H),6.60-6.33(m,2H),4.89(m,4H),4.00(m,1H),3.76(m,1H),3.20-1.2(m,16H)(3CO2H未见) ESMS 842(M-H)+。
谷氨酸-尿素-X-苄基-赖氨酸核心模型化合物的合成
下列化合物都应用方案3中所述路径制备,总产量范围是20-40%。Z去保护的谷氨酸-尿素-赖氨酸与适量的乙醛(0.9当量)混合室温下经历1小时形成西夫碱中间体。用1当量的三乙酰氧基硼氢化钠还原该西夫碱。用50%TFA的DCM去保护该化合物,在室温下经历1小时。一旦完成,该反应物通过旋转蒸发仪或氮气吹干浓缩并且用二氯甲烷和水来萃取。水层经蒸发干燥得到40-80%产量的去保护产物。
方案3.合成卤化PSMA化合物的大体途径。
4-三甲基锡烷基-苯甲醛(5)。
将六甲基乙基烯(4.1mL,19.8mmol)加入到4-碘苯甲醛(1.92g,8.27mmol)的干二噁烷(60mL)中,随后加入Pd(Ph3P)Cl2(150mg),并且反应混合物回流加热3小时直至判定结束。反应物经硅藻土过滤并用己烷/乙酸乙酯(9/1)作为洗脱液经柱色谱纯化而获得清油物(2.24g,98%)。1H NMR(400MHz,CDCl3)δ9.97(s,1H),7.81(d,J=7.8Hz,2H),7.72(d,J=7.8Hz,2H),0.29(s,9H)。ESMSm/z:268(Sn-簇)。
2-{3-[1-叔丁酯基-5-(4-三甲基锡烷基-苄氨基)-戊基]-脲基}-戊二酸-二叔丁酯(6)。
将4-三甲基锡烷基-苯甲醛(82mg,0.31mmol)加入到2-[3-(5-氨基-1-叔丁酯基-戊基)-脲基]-戊二酸-二叔丁酯(150mg,0.31mmol)的DCE(10mL)溶液中,随后加入三乙酰氧基硼氢化钠(98mg,0.47mmol),并且反应物在40℃搅拌反应过夜。该反应物经浓缩并用己烷/乙酸乙酯作为洗脱液经柱色谱纯化而获得所要的稠糖浆状产物(88mg,38%),该稠糖浆状产物经静置开始固化。1H NMR(400MHz,DMSO-d6)δ7.48(d,J=7.4Hz,2H),7.30(d,J=7.4Hz,2H),6.27(m,2H,NH’s),3.96(m,4H),2.74(bm,2H),2.21(m,2H),1.87(m,2H),1.65-1.19(m,7H),1.35(m,27H,t-Bu’s),0.23(s,9H)。ESMS m/z:742(Sn-簇)。
(S,S)-2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸(7)(MIP1033)
同样的试验步骤如方案1所述,生成8%的2-[3-(5-苄氧羰基氨基-1-叔丁酯基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物经前述方法去保护并利用HPLC纯化获得所要的产物。1H NMR(Z-保护胺的三叔丁酯)(400MHz,CDCl3,)δ12.2(s,3H),6.4(s,2H),4.15(m,2H),3.45(m,1H),2.75(bs,1H),2.2(m,4H),1.90(m,2H),1.65(m,2H),1.50(s,2H),1.35(m,2H)。ESMS m/z:622(M-H)+。
(S)-2-(3,3-二-吡啶-2-基甲基-脲基)-戊二酸(8)(MIP 1025)
同样实验步骤如常规合成方法,生成0.65g,48%的2-(3,3-二-吡啶-2-基甲基-脲基)-戊二酸-二叔丁酯。该化合物用前面所述方法去保护并用HPLC进行纯化获得所要的产物。1H NMR(400MHz,DMSO-d6)δ,12.0(bs,2H),8.68(d,2H),8.00(m,2H),7.41(d,4H),7.14(d,1H),4.73(d,4H),3.96(s,1H),2.18(m,2H),1.80(m,2H)。
(S,S)-2-{3-[3-(二-吡啶-2-基甲基-氨基)-1-羧基-丙基]-脲基]-戊二酸(9)(MIP 1028)
同样实验步骤如方案1中的常规合成方法,生成0.16g,35%的2-{3-[3-(二-吡啶-2-基甲基-氨基)-1-羧基-丙基]-脲基}-戊二酸-二叔丁酯。该化合物用前面所述方法去保护并用HPLC进行纯化获得所要的产物。1H NMR(400MHz,DMSO-d6)δ12.4(br,2H),9.37(s,1H),8.52(d,2H),7.80(t,2H),7.14(dd,4H),6.45(m,2H),4.49(br,4H),4.12(s,1H),4.05(s,1H),3.21(m,2H),2.24(m,2H),1.80(m,2H),1.40(m,2H)。ESMS m/z:(二乙酯)429(M)+,451(M+Na)。
(S,S)-2-{3-[5-(二-吡啶-2-基甲基-氨基)-1-羧基-戊基]-脲基}-戊二酸(10)(MIP 1008)
同样实验步骤如常规合成方法,生成0.09g,12%的2-{3-[5-(二-吡啶-2-基甲基-氨基)-1-羧基-戊基]-脲基}-戊二酸-二叔丁酯。该化合物用前面所述方法去保护并用HPLC进行纯化获得所要的产物。1HNMR(400MHz,DMSO-d6)δ12.7(s,2H),8.97(s,1H),8.65(dd,2H),7.91(dd,2H),7.45(m,4H),6.44(d,1H),6.28(d,1H),4.45(br,4H),4.10(m,2H),3.15(br,2H),2.60(m,2H),2.25(m,2H),1.90(m,2H),1.78(m,2H),1.45(m,2H)。
(S)-2-{3-[1-羧基-2-(4-碘-苯基)-乙基]-脲基}-戊二酸(11)(MIP-1034)
同样实验步骤如常规合成方法,生成0.038g,5%的2-{3-[1-羧基-2-(4-碘-苯基)-乙基]-脲基}-戊二酸-二叔丁酯。该化合物用前面所述方法去保护。1H NMR(400MHz,DMSO-d6)δ12.40(s,3H),7.65(dd,2H),7.05(dd,2H),6.30(m,2H),4.25(s,1H),4.05(s,1H),2.90(m,2H),2.2(m,2H),1.80(m,2H)。ESMSm/z:429(M)+,451(M+Na)。
(S,S)-2-{3-[1-羧基-5-(2-碘-苄氨基)-戊基]-脲基}-戊二酸(12)(MIP 1035)。
同样的常规步骤,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护(5.5mg,66%)。1H NMR(400MHz,DMSO-d6)δ12.4(s,3H),8.8(s,1H),7.94(m,1H),7.5(m,1H),7.16(t,1H),6.38(m,2H),4.15(m,5H),3.06(s,2H),2.85(s,1H),2.2(m,2H),1.90(m,1H),1.70(m,2H),1.50(s,2H),1.35(m,2H)。ESMSm/z:536(M+H)+。
(S,S)-2-{3-[1-羧基-5-(3-碘-苄氨基)-戊基]-脲基}-戊二酸(13)(MIP 1089)。
同样的常规步骤,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护(4.1mg,53%)。1H NMR(400MHz,DMSO-d6)δ12.4(s,3H),8.7(s,2H),7.9(s,1H),7.8(d,1H),7.44(d,1H),7.22(t,1H),6.25(s,2H),4.09(m,5H),2.89(s,1H),2.75(s,1H),2.2(d,2H),1.90(m,2H),1.65(m,2H),1.40(m,2H)。
(S,S)-2-{3-[1-羧基-5-(4-碘-苄氨基)-戊基]-脲基}-戊二酸(14)(MIP 1072)。
同样的常规步骤,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护(12mg,66%)。1H NMR(400MHz,DMSO-d6)δ12.4(bs,3H),8.8(br,1H),7.8(d,2H),7.27(d,2H),6.35(br,2H),4.1(m,4H),2.89(m,2H),2.2(d,2H),1.90(m,2H),1.65(m,4H),1.35(m,2H)。ESMS m/z:536(M+H)+。
(S,S)-2-{3-[1-羧基-5-(4-氟-苄氨基)-戊基]-脲基}-戊二酸(15)(MIP 1090)。
同样的常规步骤,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护。
1H NMR(400MHz,DMSO-d6)δ12.4(br,3H),8.7(br,1H),7.5(m,2H),7.3(m,2H),6.35(m,2H),4.1(m,4H),2.9(m,2H),2.2(d,2H),1.90(m,2H),1.60(m,4H),1.35(m,2H)。ESMSm/z:428(M+H)+,450(M+Na)。
(S,S)-2-{3-[1-羧基-5-(4-溴-苄氨基)-戊基]-脲基}-戊二酸(16)(MIP 1094)。
同样的常规步骤,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。1HNMR(三t-丁酯)(400MHz,CDCl3)δ7.52(d,2H),7.32(d,2H),6.28(m,2H),3.98(m,2H),2.55(t,2H),2.48(t,2H),2.22(m,2H),1.85(m,2H),1.62(m,2H),1.45(m,2H),1.37(s,27H),1.28(m,2H)ESMS m/z:642(M+H)+。该化合物用前面所述方法去保护。ESMS m/z:474(M+H)+。
(S,S)-2-{3-[1-羧基-5-(4-碘-苄氨基)-戊基]-脲基}-戊二酸(17)(MIP 1044)。
同样的常规步骤,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护。
1H NMR(400MHz,DMSO-d6)δ12.4(s,3H),8.45(s,1H),7.8(dd,2H),7.6(dd,2H),6.3(s,2H),5.75(s,1H),4.1(m,4H),3.2(s,2H),2.25(d,2H),1.90(m,1H),1.65(m,2H),1.4(m,2H)。
2-{3-[1-羧基-5-(4-碘-苯磺酰氨基)-戊基]-脲基}-戊二酸(18)。(MIP 1097)。
在圆底烧瓶中,2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯(300mg,0.62mmol)悬于水(10mL)中并且加入1,4二噁烷(10mL)和TEA(1.75mL,1.25mmol),随后加入4-碘-苯磺酰氯并且混合物在50℃搅拌过夜。反应混合物经蒸干,溶于DCM,通过硅胶色谱获得所要的清油产物(375mg,80%)。该化合物用前面所述方法去保护,随后用HPLC纯化获得所要的白色固体产物MIP-1097(270g,产率90%)。1H NMR(400MHz,DMSO-d6)δ7.97(d,2H),7.68(t,1H),7.53(d,2H),6.35(dd,2H),4.10(m,1H),4.00(m,1H),2.65(m,2H),2.22(m,2H),1.9(m,1H),1.7(m,1H),1.55(m,1H),1.45(m,1H),1.35(m,2H),1.25(m,2H),(3 CO2H未见)。ESMSm/z:565(M+H)+。
2-(3-{1-羧基-5-[3-(4-碘-苯基)-脲基]-戊基}-脲基)-戊二酸(19)(MIP 1095)
在圆底烧瓶中,4-碘-苯基异氰酸酯(100mg,0.41mmol)溶于含TEA(0.057mL,0.4mmol)的DCM(10mL)中。加入2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯(200mg,0.41mmol)并搅拌3小时。该反应混合物经蒸干,粗混合物溶于甲醇(5mL)。逐滴加入水(20mL)中获得白色沉淀,收集该白色沉淀并用水(20mL)洗涤,干燥以获得所要的白色固体状三叔丁酯,该三叔丁酯直接用前面所述的方法去保护获得所要的白色固体状产物(158mg,53%)。1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),7.5(d,2H),7.22(d,2H),6.3(t,2H),6.16(t,1H),4.05(m,2H),3.05(m,2H),2.24(m,2H),1.9(m,1H),1.68(m,2H),1.52(m,1H),1.38(m,2H),1.28(m,2H),(3 CO2H not seen)。ESMS m/z:565(M+H)+。
谷氨酸-尿素-β-苯基甘氨酸的合成
(±)3-氨基-3-(3-碘-苯基)-丙酸(20)。
丙二酸(2.2g,21.5mmol)和3-碘苯甲醛(5g,21.5mmol)悬于乙醇(50mL),并且加入醋酸铵(1.66g,21.5mmol),反应物加热回流过夜。反应物冷却至室温,过滤并用乙醇洗涤,随后用乙醚并干燥获得白色固体产物(3.4g,11.6mmol,54%)。1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.64(dd,J=7.8Hz,1H),7.42(dd,J=7.6Hz,1H),7.16(dd,J=7.8Hz,1H),7.14(dd,J=7.6Hz,1H),4.21(m,1H),2.36(m,2H)。
(±)-3-氨基-3-(3-碘-苯基)-丙酸 甲酯(21)。
将亚硫酰氯(0.95mL,12.7mmol)加入到(±)3-氨基-3-(3-碘-苯基)-丙酸(3.1g,10.6mmol)的甲醇中,反应物室温搅拌过夜。浓缩并用乙醚研碎产生白色产物。固体经过滤,乙醚洗涤和干燥获得所要的白色固体产物(3.5g,10mmol,95%)。1H NMR(400MHz,DMSO-d6)δ8.79(br,2H),8.01(s,1H),7.74(d,J=8.1Hz,1H),7.57(d,J=7.8Hz,1H),7.21(dd,J=8.1,7.8Hz,1H),4.56(br,1H),3.54(s,3H),3.23-3.17(m,1H),3.04-2.98(m,1H)。
(S,R)和(S,S)-2-{3-[1-(3-碘-苯基)-2-甲氧羰基-乙基]-脲基}-戊二酸-二叔丁酯(22)。
2-[(咪唑-1-羰基)-氨基]-戊二酸-二叔丁酯(370mg,1.05mmol)溶于DCE(10mL)并冷却至0℃。加入MeoTf(142μL,1.25mmol)并且反应继续20分钟。加入(±)3-氨基-3-(3-碘-苯基)-丙酸甲酯(356mg,1.045mmol),反应物加热到室温,然后加热到55℃并搅拌过夜。反应物经DCM(50mL)稀释并用水(30mL)、5%柠檬酸水溶液(30mL)、碳酸氢钠盐液(30mL)、水(30mL)和盐水(30mL)洗涤。有机层经硫酸钠干燥和浓缩而获得粗产物。该产物经过柱色谱纯化而获得所要的白乳状产物(303mg,0.51mmol,49%)。1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.57(d,J=7.6Hz,1H),7.29(s,1H),7.07-7.02(m,1H),5.74(br,1H),5.17(br,2H),4.30(m,1H),3.63(s,1.5H),3.62(s 1.5H),2.88-2.76(m,2H),2.38-2.24(m,2H),2.10-2.00(m,1H),1.90-1.80(m,1H),1.46(s,9H),1.44(s,9H)。
(S,R)和(S,S)-2-{3-[2-羧基-1-(3-碘-苯基)-乙基]-脲基}-戊二酸(23)。
(±)2-{3-[1-(3-碘-苯基)-2-甲氧羰基-乙基]-脲基}-戊二酸-二叔丁酯(289mg,0.49mmol)溶于甲醇(3mL)并且将2M LiOH(0.5mL)加入到该溶液中,反应物室温搅拌过夜。反应物经水(20mL)稀释,用乙酸乙酯(2X20mL)萃取有机层,然后用1N盐酸酸化至pH~2。水层用乙酸乙酯(3X20mL)萃取,经硫酸钠干燥和浓缩而获得白色固体粗产物(206mg,0.36mmol,73%)。向粗料中加入DCM(2mL),随后加入TFA(2mL),反应物室温搅拌过夜。浓缩,随后从乙酸乙酯中重结晶而得到所要的白色固体产物(22mg,0.047mmol,10%)。1H NMR(400MHz,DMSO-d6)δ12.39(br,3H),7.64(br,1H),7.56(m,1H),7.30(bm,1H),7.10(bm,1H),6.72(bm,1H),6.34(bm,1H),4.94(br,1H),4.03(bm,1H),2.64(br,2H),2.20(br,2H),1.86(br,1H),1.71(br,1H)。ESMS m/z:463(M-H)+。
(S,S)-2-{3-[1-羧基-5-(2-氯-苄氨基)-戊基]-脲基}-戊二酸(7)(MIP-1137)。
同样的常规步骤如方案1所示用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护生成所要的黄白色固体产物(100mg,45%)。1H NMR(400MHz,DMSO-d6)δ9.0(br,3H),7.63(d,1H),7.2(m,2H),7.15(d,1H),6.30(d,2H),4.1(m,4H),2.9(br,2H),2.2(m,2H),1.90(m,2H),1.60(m,4H),1.35(m,2H)。ESMS m/z:444(M+H)+。
(S,S)-2-{3-[1-羧基-5-(3-氯-苄氨基)-戊基]-脲基}-戊二酸(8)(MIP 1131)。
同样的常规步骤如方案1所示用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护生成所要的黄白色固体产物(200mg,90%)。1H NMR(400MHz,DMSO-d6)δ8.9(br,3H),7.6(s,H),7.43(m,3H),6.39(br,2H),4.1(m,4H),2.9(br,2H),2.2(m,2H),1.90(m,2H),1.60(m,4H),1.35(m,2H)。ESMS m/z:444(M+H)+。
(S,S)-2-{3-[1-羧基-5-(4-氯-苄氨基)-戊基]-脲基}-戊二酸(9)(MIP 1135)。
同样的常规步骤如方案1所示用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护生成所要的黄白色固体产物(10mg,66%)。ESMS m/z:444(M+H)+。
(S)-2-(3-((R)-5-(苄氨基)-1-羧基戊基)脲基)戊二酸(10)。(MIP-1106)。
同样的常规步骤,如方案1所示,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护生成所要的黄白色固体产物(5mg,47%)。ESMS m/z:410(M+H)+。
2-(3-{1-羧基-5-[3-(苯基)-脲基]-戊基}-脲基)-戊二酸(11)(MIP 1111)。
在圆底烧瓶中,苯基异硫氰酸盐(100mg,0.84mmol)溶于DCM(10mL),加入2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸二叔丁酯(409mg,0.84mmol),搅拌经历3小时。蒸干反应混合物,粗体反应物用快速住色谱2∶1己烷/乙酸乙酯纯化而获得白色固体状叔丁酯,该白色固体叔丁酯用TFA/CH2Cl2去保护获得所要的产物。1HNMR(400MHz,DMSO-d6)δ12.5(s,3H),8.54(s,1H),7.40(dd,2H),7.26(dd,2H),6.30(t,2H),6.17(t,1H),4.05(m,2H),3.05(m,2H),2.44(m,2H),1.90(m,1H),1.68(m,2H)1.52(m,1H),1.40(m,2H),1.29(m,2H)。ESMSm/z:439(M+H)+。
2-(3-{1-羧基-5-[3-(4-溴-苯基)-脲基]-戊基}-脲基)-戊二酸(12)(MIP 1129)
在圆底烧瓶中,4-溴-苯基异氰酸盐(100mg,0.50mmol)溶于DCM(10mL)。加入2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸二叔丁酯(246mg,0.50mmol)并搅拌经历3小时。蒸干反应混合物,粗体反应物用快速住色谱2∶1己烷/乙酸乙酯纯化而获得白色固体状叔丁酯,该白色固体叔丁酯用TFA/CH2Cl2去保护获得所要的产物。1H NMR(400MHz,DMSO-d6)δ12.5(s,3H),8.55(s,1H),7.35(d,4H),6.30(t,2H),6.18(t,1H),4.08(m,2H),3.05(m,2H),2.22(m,2H),1.90(m,1H),1.68(m,2H),1.52(m,1H),1.40(m,2H),1.30(m,2H)。ESMS m/z:518(M+H)+。
2-(3-{1-羧基-5-[3-(4-氯-苯基)-脲基]-戊基}-脲基)-戊二酸(13)(MIP 1110)
在圆底烧瓶中,4-氯-苯基异氰酸盐(100mg,0.65mmol)溶于DCM(10mL),加入2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸二叔丁酯(318mg,0.65mmol)并搅拌经历3小时。蒸干反应混合物,粗体反应物用快速住色谱2∶1己烷/乙酸乙酯纯化而获得白色固体状叔丁酯(470mg,96%),该白色固体叔丁酯用TFA/CH2Cl2去保护获得所要的产物。1H NMR(400MHz,DMSO-d6)δ12.5(s,3H),8.35(s,1H),7.40(dd,2H),7.19(dd,2H),6.30(t,2H),6.10(t,1H),4.08(m,2H),3.05(m,2H),2.32(m,2H),1.90(m,1H),1.68(m,2H),1.52(m,1H),1.40(m,2H),1.30(m,2H)。ESMS m/z:474(M+H)+。
(S)-2-(3-((R)-1-羧基-5-(吡啶-1-基甲基氨基)戊基)脲基)戊二酸(14)(MIP-1108)。
同样的常规步骤,如方案A所示,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护生成所要的黄白色固体产物(51mg,70%)。1H NMR(400MHz,DMSO-d6)δ8.9(br,3H),7.95(m,5H),7.6(m,2H),6.35(br,2H),4.1(m,4H),2.9(br,2H),2.55(m,2H),2.25(m,2H),1.70(m,4H),1.3(m,2H)。ESMS m/z:460(M+H)+。
2-(3-{1-羧基-5-[3-(3-碘-苄基)-脲基]-戊基}-脲基)-戊二酸(15)(MIP-1101)。
同样的常规步骤,如方案2所示,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护生成所要的产物。ESMS m/z:579(M+H)+。
(19S,23S)-2-(4-碘苄基)-1-(4-碘苯基)-13,21-二氧代-2,14,20,22-四氮杂二十五烷-19,23,25-三羧酸(16)(MIP-1130)。
同样的常规步骤,如方案A所示,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面所述方法去保护生成所要的黄白色固体产物(8.3mg,10%)。1H NMR(400MHz,DMSO-d6)δ7.8(d),7.3(d),6.3(dd),4.25(br),4.05(m),2.97(m),2.85(br),2.22(m),2.05(m),.90(m),1.64(m),1.48(m),1.35(m),1.2(m)。ESMS m/z:936(M+H)+。
铼常规试验:
SAAC-抑制剂的铼复合物可以从易于获得的前体[Net4]2[Re(CO)3Br3]与SAAC-抑制剂的反应物中方便的分离得到。已有大量文献证明,SAAC末端提供的供体部位是{M(CO)3}+1核心的有效鳌合剂,并已被设计用于所需的金属位点面排列,该复合体的制备也是平常的。
{Re(I)(CO)3}+系统遵照Tc-99m三羧酸核心的相似反应化学。使用[Net4]2[ReBr3(CO)3]作为起始原料导致易于形成fac-{Re(CO)3(L)3}核心。[Net4]2[ReBr3(CO)3]可很容易的从[ReBr(CO)5]衍生获得。通过将[Net4]2[ReBr3(CO)3]和合适的TEC配基以1∶1.2的比例在10ml甲醇中反应来完成Re(I)复合体的合成。该反应经加热,80℃经历4小时。冷却后,所有下列反应物用小的硅色谱柱纯化,产率范围在10-30%。
谷氨酸-尿素-赖氨酸-PEG2-ReDP:
[Re(CO)3{(17R,21S)-11,19-二氧代-1-(吡啶-2-基)-2-(吡啶-2-基甲基)-5,8-二氧杂-2,12,18,20-四氮杂二十三烷-17,21,23-三羧酸}][Br]。(17)(MIP-1133)。
用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸二叔丁酯,采用如方案1所示的同样常规步骤制备PEG2联吡啶化合物(17R,21S)-11,19-二氧代-1-(吡啶-2-基)-2-(吡啶-2-基甲基)-5,8-二氧杂-2,12,18,20-四氮杂二十三烷-17,21,23-三羧酸。铼酯复合体采用常规铼试验中所述的同样步骤来制备。该化合物用前面所述方法去保护生成所要的黄白色固体产物(2mg,20%)。1H NMR(400MHz,DMSO-d6)8.8(d),8.00(dd),7.55(d),7.42(dd),6.45(s),3.95(m),3.4-3.6(m),2.45(m),1.25(m),1.1(m),0.8(m)。ESMS m/z:931(M+H)+。
谷氨酸-尿素-赖氨酸-PEG4-ReDP:
[Re(CO)3{(23R,27S)-17,25-二氧代-1-(吡啶-2-基)-2-(吡啶-2-基甲基)-5,8,11,14-四氧杂-2,18,24,26-四氮杂二十九烷-23,27,29-三羧酸}][Br]。(18)(KM11-200)。
用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸二叔丁酯,采用如方案A所示的同样常规步骤制备PEG4联吡啶化合物(23R,27S)-17,25-二氧代-1-(吡啶-2-yl)-2-(吡啶-2-基甲基)-5,8,11,14-四氧杂-2,18,24,26-四氮杂二十九烷-23,27,29-三羧酸。铼酯复合体采用常规铼试验中所述的同样步骤来制备。该化合物用前面所述方法去保护生成所要的白色固体产物(5.1mg,29.6%)。ESMS m/z:1019(M+H)+。
谷氨酸-尿素-赖氨酸-PEG8-ReDP:
[Re(CO)3{(35R,39S)-29,37-二氧代-1-(吡啶-2-基)-2-(吡啶-2-基甲基)-5,8,11,14,17,20,23,26-八氧杂-2,30,36,38-四氮杂四十-烷-35,39,41-三羧酸}][Br]。(19)(MIP-1132)。
用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸二叔丁酯,采用如方案A所示的同样常规步骤制备PEG8联吡啶化合物(35R,39S)-29,37-二氧代-1-(吡啶-2-基)-2-(吡啶-2-基甲基)-5,8,11,14,17,20,23,26-八氧杂-2,30,36,38-四氮杂四十一烷-35,39,41-三羧酸。铼酯复合体采用常规铼试验中所述的同样步骤来制备。该化合物用前面所述方法去保护生成所要的白色固体产物(8.0mg,30.4%)。ESMS m/z:1195(M+H)+。
谷氨酸-尿素-赖氨酸-C11PAMA-Re:
[Re(CO)3{(19R,23S)-13,21-二氧代-2-(吡啶-2-基甲基)-2,14,20,22-四氮杂二十五烷-1,19,23,25-三羧酸}](20)(MIP-1109)。
用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸二叔丁酯,采用如方案A所示的同样常规步骤制备C11-PAMA化合物(19R,23S)-13,21-二氧代-2-(吡啶-2-基甲基)-2,14,20,22-四氮杂二十五烷-1,19,23,25-三羧酸。铼酯复合体采用常规铼试验中所述的同样步骤来制备。该化合物用前面所述方法去保护生成所要的黄白色固体产物(3.0mg,75%)。ESMS m/z:922(M+H)+。
下列表1是合成的所研究的PSMA抑制剂的汇总。
表1:其它的或再测试的谷氨酸-尿素-赖氨酸衍生物的体外细胞结合数据汇总。
MIP # | X | 化合物描述 | IC50(nM) |
- | - | PMPA | 10 |
1033 | - | 谷氨酸-尿素-赖氨酸 | 498 |
1137 | 2-Cl | 2-Cl-苄基 | 245 |
1131 | 3-Cl | 3-Cl-苄基 | 277 |
1135 | 4-Cl | 4-Cl-苄基 | 2 |
1106 | H | Des-卤代苄基 | 2960 |
1111 | H | Des-卤代二尿 | 12 |
1129 | 4-Br | 4-Br-二尿 | 2 |
1110 | 4-Cl | 4-Cl-二尿 | 4 |
1108 | - | 2-萘 | 154 |
1101 | 3-I | 3-I-二尿 | 10 |
1130 | 4-二-I | C11 4-二-碘 | 300 |
1133 | - | PEG2Re | 227 |
KM11-200 | - | PEG4Re | NA |
1132 | - | PEG8Re | 1747 |
1109 | - | C11PAMA-Re | 696 |
1027 | 4-I | 4-I-苯甲酰 | 3* |
1095 | 4-I | 4-I-二尿 | 10* |
β-氨基酸类似物
除了扩展到其它类似物例如锝偶联物和其它卤素类似物,MIP-1072,MIP-1095,MIP-1027的β-氨基酸类似物尤其适合。在此,我们没有新的实施方案来支持这一权利要求。
MIP-1072β-氨基酸类似物
MIP-1095β-氨基酸类似物
{Re(CO)3}+1核心模式复合物的合成
由于它们的周期关系,第VII族金属锝和铼的性质非常近似。预期这些金属将显示相似的反应化学,这两种金属的三羰基、氮和噻唑化学反应也常是这种情况。同样地,由于它们稳定M(I)的自旋成对的d6电子结构的大小相似,高铼酸盐和高锝酸盐具有非常相似的反应性能。合成铼-TECs使得我们有较容易的路线在结构上鉴定产物。Tc和Re之间的周期关系显示Tc-99m放射性药品可以通过模拟类似的铼复合物来设计。
一些新化合物可以通过用常规方法可测量的铼合成,该常规方法包括质谱分析、1H and 13C NMR谱分析。随后纯化,为了纯化和测定相对于Tc反应产物的保留时间,合成的铼复合物穿过HPLC柱。铼-TEC复合物还要被结晶。
SAAC-抑制剂的铼复合物可方便的从易于获得的前体{Re(CO)3(H2O)3}+1和[Net4]2[Re(CO)3Br3]与SAAC-抑制剂的反应物中分离。因为已有大量文献证明SAAC末端提供的供体部位是{M(CO)3}+1核心的有效螯合剂,并已被设计用于所需的金属位点面排列(facialarrangement),该复合物的制备是平常的。
常规试验
{Re(I)(CO)3}+系统遵循与Tc-99m三羰基核心相似的化学反应。使用[Net4]2[ReBr3(CO)3]作为初始原料,导致易于形成fac-{Re(CO)3(L)3}核心。[Net4]2[ReBr3(CO)3]容易从[ReBr(CO)5]中获得。在10ml甲醇中,通过[Net4]2[ReBr3(CO)3]和适当的TEC配基以1∶1.2比例反应来完成Re(I)复合物的合成。该反应物在80℃加热4小时。冷却后,所有下列的反应产物都使用小的硅色谱柱纯化,产率范围为10-30%。
[Re(CO)3(2-{3-[3-(二-吡啶-2-基甲基-氨基)-1-羧基-丙基]-脲基}-戊烷二乙基酯)][Br](24)。1H NMR(400MHz,DMSO-d6)δ8.65(dd,2H),7.85(dd,2H),7.7(dd,4H),7.25(dd,2H),6.42(dd,1H),6.0(dd,1H),4.5(m,2H),4.16(m,2H),3.80(m,4H),2.45(m,2H),2.0(dd,2H),1.5(m,4H),1.25(m,6H)。ESMSm/z:812-815。
[Re(CO)3(2-{3-[5-(二-吡啶-2-基甲基-氨基)-1-羧基-戊基]-脲基}-戊二酸)][Br](25)(MIP 1029)。1H NMR(400MHz,DMSO-d6)δ12.6(s,2H),8.91(s,1H),8.63(dd,2H),7.85(dd,2H),7.75(dd,4H),7.3(dd,2H),6.44(d,H),6.28(d,1H),4.45(s,2H),4.10(m,2H),3.15(s,1H),2.60(m,2H),2.25(m,2H),1.90(m,1H),1.78(m,2H),1.45(m,2H)。ESMS m/z:770-774。
2-{3-[1-羧基-5-(羧甲基-吡啶-2-基甲基-氨基)-戊基]-脲基}-戊二酸(26)。
同样的常规步骤,用前面制备和保护的2-[3-(5-氨基-1-羧基-戊基)-脲基]-戊二酸-二叔丁酯。该化合物用前面描述的方法去保护(2.2mg,65%)。1H NMR(400MHz,DMSO-d6)δ8.65(d,1H),7.91(dd,1H),7.56(d,1H),7.45(dd,1H),6.31(m,2H),4.34(s,2H),4.08(m,4H),3.10(m,2H),2.24(m,2H),1.95(m,1H),1.68(m,4H),1.5(m,1H),1.22(m,2H)。ESMS m/z:469(M+H)+。M+1 469。
[Re(CO)3(2-{3-[1-羧基-5-(羧甲基-吡啶-2-基甲基-氨基)-戊基]-脲基}-戊二酸)](27)。1H NMR(400MHz,DMSO-d6)δ8.75(d,1H),8.13(dd,1H),7.69(d,1H),7.57(dd,1H),6.45(m,2H),4.75(m,1H),4.50(m,1H),4.20(m,2H),3.61(m,4H),3.15(m,2H),2.38(m,1H),2.0(m,2H),1.75(m,4H),1.62(m,1H),1.25(m,2H)。ESMS m/z 779-782(M+2Na)+。
谷氨酸-尿素-赖氨酸(N-苄基-X)类似物(3)的合成。
通过方案A中描述的常规路线制备常规结构3的化合物,其全部的产率范围为20-40%。在室温下,关键合成中间体(1)与适当的乙醛反应1小时形成吡啶碱(yridi base)中间体。吡啶碱不经分离而是在原位用三乙酰氧基硼氢化钠还原。用50%TFA的DCM去除叔丁酯保护基团,在室温下经历1小时。去保护一旦完成,该反应物在旋转蒸发仪上浓缩,并且用HPLC或快速色谱纯化获得所要的产物(3),其产率为40-80%。
方案A.卤化的谷氨酸-尿素-赖氨酸(N-苄基-X)类似物(3)合成的常规路线。
谷氨酸-尿素-脲基(苯基-X)类似物的合成
通过方案B中描述的路线制备常规结构8的下列化合物,其全部的产率范围为20-60%。在室温下,关键合成中间体(4)与适当的异氰酸苯酯反应以好的产率生成所要的被保护的中间体(5)。用50%TFA的DCM去除叔丁酯保护基团,在室温下经历1小时。一完成,该反应物在旋转蒸发仪上浓缩,用HPLC或重结晶纯化获得所要的产物(6),其产率为40-90%。
方案B.卤化的谷氨酸-尿素-脲基(苯基-X)类似物合成的常规路线。
放射性标记复合物的制备和鉴定
锝-99m标记
通过将100μL含[99mTc(CO)3(H2O)3]+的溶液加入到500μL10-4M抑制剂-SAAC溶液中,完成99mTc-标记复合物的制备。该混合物在70℃加热30分钟。通过反相HPLC分析产物的放射化学纯度。
放射标记化合物在溶液和血清中的稳定性取决于作用时间和溶液情况。特定地,标记和分离后,产物在室温下储存6小时,然后进行HPLC分析来检测标记保持度,和潜在的产物降解度。并分析TcO4 -的重新形成和还原原料TcO2的存在。
为了有助于预测体内稳定性,进行配基挑战。特定地,在室温和37℃条件下,通过在5%鼠血清中孵育HPLC纯化复合物来研究99mTc复合物的稳定性。
通过将纯化的复合物在含竞争性配基的溶液(PBS pH7.2,终浓度为0.1M)中孵育来研究竞争性配基(例如半胱氨酸和DTPA)从复合物中提取Tc-99m的能力。标记性竞争研究结果显示Tc-99m-复合物在血清或竞争性配基研究中超过6小时未降解。图2中显示37℃6小时后的孵育结果。
DCT的碘化
通过将100ul[I-131]NaI的0.1N NaOH溶液加入到碘试管TM(Fisher Scientific,Pierce)中的含DCT(1mg/mL)的PBS(pH7.2)溶液来完成碘-131标记化合物N-[N-[(S)-1,3-二羧基丙基]氨基甲酰基]-S-3-碘-L-络氨酸(I-131-DCIT)的制备。该混合物涡旋3分钟并在室温下储存20分钟。
溶液中放射性标记化合物的稳定性取决于作用时间。特定地,标记和分离后,产物在室温下储存48小时,然后用HPLC分析确定标记保持度,和潜在的产物降解度。并分析NaI的重新形成和还原的碘酸盐的存在。标记稳定性研究结果显示I-131 DCIT在室温下超过2天未有显著降解。图3中显示了研究结果。
通过将含30μl甲醇、0.5%乙酸的100ul[I-131]NaI的0.1NNaOH溶液加入到含MIP 1072(1mg/mL)的碘试管(FisherScientific)中完成碘-131标记的化合物2-{3-[1-羧基-5-(4-碘-苯甲酰氨基)-戊基]-脲基}-戊二酸(I-131-MIP 1072)的制备。该混合物涡旋3分钟并在室温下储存20分钟。
溶液中放射性标记化合物的稳定性取决于作用时间。特定地,标记和分离后,产物在37℃储存3天,然后用HPLC分析确定标记保持度,和潜在的产物降解度。并分析NaI的重新形成和还原的碘酸盐的存在。标记稳定性研究结果显示室温下,I-131 1072在DMSO、10%乙醇/盐液、PBS pH7.2和6%抗坏血酸/3%龙胆酸溶液中超过3天未有显著降解。图4中显示了研究结果。
SAAC-尿素-谷氨酸盐偶联物的生物学鉴定
用PSMA-阳性的LnCap细胞和PSMA-阴性的PC3细胞在人前列腺癌细胞结合试验中筛选新制备的SAAC-尿素-谷氨酸偶联物。显示特定的摄入或结合到PSMA-阳性细胞的化合物将被用于体内肿瘤定位研究。
1-131 DCIT的体外冷筛选试验。
LNCaP和PC3人前列腺癌细胞来源于美国典型微生物菌种保藏组织,Rockville,MD。LNCaP细胞在具有10%胎牛血清(FBS)的RPMI-1640培养基中维持生长。PC3细胞在具有10%FBS的F12K培养基中生长。根据适当改进的唐等人的方法(Tang,H.;Brown,M.;Ye,Y.;Huang,G.;Zhang,Y.;Wang,Y.;Zhai,H.;Chen,X.;Shen,T.Y.;Tenniswood,M.,Prostate targeting ligands basedon N-acetylated alpha-linked acidic dipeptidase,Biochem.Biophys.Res.Commun.2003,307,8-14),进行放射性标记化合物与LNCaP和PC-3细胞的结合以及与冷衍生物的竞争。将细胞铺到12孔板,大约4x105细胞/孔。并且在加入化合物前,在湿润的培养箱中,在37℃/5%二氧化碳条件下培养48小时。准备每种SAAC-尿素-谷氨酸偶联物,并且在含0.5%牛血清白蛋白(BSA)的无血清细胞培养基中稀释并加入3nM I-131 DCIT(抑制抑制剂)。通过在孵育I-131 DCIT而无实验化合物来确定总结和量。培养板室温孵育1小时。通过轻轻吸取从培养板移出细胞并转移至eppendorff管。样本在10K x g微型离心15秒。吸除培养基并且通过分散于新鲜试验培养基随后微型离心来洗涤沉淀两次。用自动gamma计数仪通过计数细胞沉淀来确定I-131的细胞结合。通过计数与2uM未标记的化合物或2-膦酰基甲基-戊二酸(PMPA)孵育后的细胞来确定非特异性结合。对照化合物如下所述。
对照化合物
用于结合试验的两个关键化合物,上面已经显示:I-DCIT(Kozikowski等人)和2-膦酰基甲基-戊二酸(PMPA-右侧),IC50=6nM的有效抑制剂。
(ii)体外剂量筛选。I-131 DCIT特异结合到LnCap细胞而不是PC3细胞,这可以通过仅在LnCap细胞中被未标记化合物或PMPA所置换的计数来证明(图5)。结合常数通过将LnCap细胞与各种量的未标记的DCIT在恒量I-131 DCIT存在下孵育来确定并用每种溶液的特定活性来确定fmoles化合物结合数目(图6)。测定Kd是264nM最大是254 fmoles。2uM化合物MIP-1008和MIP-1033与I-131DCIT竞争结合LnCap细胞,多种剂量被重复试验来确定IC-50值(图7和8)。化合物MIP-1072、MIP-1095和MIP-1097显示IC50值<50nm,而MIP-1008和MIP-1033 IC-50s分别显示为98nM和497nM。化合物MIP-1025、MIP-1028和MIP-1029没有竞争结合(表1)。
为了确定表示MIP-1072内化进入LNCaP细胞的图7斯卡查德分析的结果,监测在LNCaP细胞中的MIP-1072的摄入率。在4℃和37℃每孔加药100nM MIP-1072(2uCi/孔)。在4℃通过曲线的平台期证明15分钟后与PSMA的结合达到平衡。达到平衡后,在37℃孵育细胞继续使MIP-1072内化。图10,该结果确定了斯卡查德分析并表明MIP-1072确实被内化。
(iii)微粒体检测试验
为了监测试验化合物的突发降解,将收集的雄性大鼠肝微粒体(1mg/mL,BD生物科学),NADPH再生系统(1.3mM NADP,3.3mM葡萄糖6-磷酸和0.4U/mL葡萄糖6-磷酸脱氢酶,BD生物科学)和试验化合物加入到0.1M磷酸钾缓冲溶液中。该混合物在37℃进行孵育并且在指示时间(0,15,60分钟)通过加入等体积的冰冷甲醇(500μL)停止该反应。将得到的浆液以21,000xG的速度离心10分钟并收集悬浮物,并且注射到Agilent LCMS model MSD SL中用水∶乙腈95∶5(含0.1%甲酸)至水∶乙腈40∶60(含0.1%甲酸)梯度洗脱,仅在单离子模式下监测母离子。如图11A和11B所示,结果表示相关于0分钟时间点母离子降解。
用大鼠肝微粒体评估MIP-1072的稳定性。在37℃,MIP-1072(50μM)和非那西汀(100μM)与大鼠肝微粒体孵育指示的时间。非那西汀作为对照物质,已知道其能被降解。在孵育期间MIP-1072没有被大鼠肝微粒体降解,而非那西汀孵育60分钟后被降解22%。
先导化合物MIP 1072是I-131-标记的,用于移植了LNCaP(PSMA阳性)和PC3(PSMA阴性)肿瘤的大鼠中组织分布的研究。该化合物通过下面显示的路线被放射性标记。
组织生物分布的结果与体外试验数据一致,并表明在LNCaP(PSMA阳性)肿瘤中明显的摄取。这些结果也表现出高度的特异性,在PC3(PSMA阴性)肿瘤中仅有非常少的活性。描述小鼠组织分布的图见下面(图12)。
用N-[N-[(S)-1,3-二羧丙基]氨甲酰基]-S-3-碘-L-酪氨酸(I-131-DCIT)对“冷”复合物的生物学评估被证明是一种快速的初步筛选,随后用过剂量曲线离开确定精确的的IC50值。先导系列化合表现出IC50值<50nM。先到系列的体内试验数据显示高亲和力,有3%ID/g聚集于LNCAP肿瘤中;并表现出高特异性,LNCaP对PC3的比例超过15∶1。
LNCaP细胞裂解试验方案:
T75瓶汇合度2,
通过用培养基上下吹吸将细胞从培养盘洗下,
0.32M蔗糖洗涤,再离心,
细胞重悬于1毫升50mM Tris-HCl,pH7.4,0.5%TritonX-100,
14000rpm离心1分钟来沉淀细胞核,
移取上清液并分装成50uL液体,
在-80℃保存,
蛋白测定,
Bio-Rad蛋白标准II-1.44mg/ml,
既然裂解步骤中应用了去污剂,制备工作试剂,A’通过将20uL试剂S加入到每1mL试剂A,试剂A是运行所需要的。(如果有沉淀形成,温热并漩涡震荡),
制备5蛋白稀释液-0,0.2,0.4,0.8,1.6mg/mL,
也要制备未知样品的1/10,1/100和1/1000稀释液,
混合25uL标准/未知样品、100uL A’,800uL试剂B,并制备双份。混匀,
在~15分钟后,测定750nm处的吸收值
NAALADase测定:
Rxn缓冲液:50mM Tris-HCl,pH7.4,20mM CoCl2,32mM NaCl,
制备冷NAAG(100mM储存液)在Rxn缓冲液按1/100稀释到1mM,
合并600uL缓冲液和LNCaP细胞裂解液(200μg)37℃预孵育3分钟,
37℃预孵育Rxn缓冲液和LNCaP细胞裂解液3分钟,
加入6μL 1mM NAAG(1μM终浓度)掺加1000000CPM的3H-NAAG(100μL的1mM NAAG+10μL的3H-NAAG(10μCi))。加入PMPA来竞争,
孵育30分钟
在既定时间,通过移取100uL反应混合液并加入等体积冰冷的0.25M KH2PO4,pH 4.3来终止rxn而终止反应,
取用1/2混合物到250mg AG 50W-X4阳离子交换柱(200-400网孔,H+形式,s用前用DI水溶胀树脂)。保存其余1/2用于计数,
用500μL 1∶1 Rxn缓冲液/0.25MKH2PO4洗涤色谱柱,
用3M KCl(1.5mL)洗脱,
计数100uL负载液、洗脱液和反应液(1∶6稀释)来使淬灭最小化,
注意:
时间=0对照值将会从试验时间点减去,
结果以pmol形成的3H-谷氨酸盐/min/mg蛋白的形式表示
Grant说仅反应10分钟以确保线性,然而Luthi-Carter,等人(J Pharm Exp Therap 1998 286(2))说2小时对线性仍没有影响并且少于20%的底物被消耗。
治疗处理
本文化合物可用于在治疗处理上抑制NAALADase。适用于NAALADase处理的疾病包括糖尿病痛性神经病、神经元损伤或前列腺癌、精神分裂症、结肠癌、炎症、肌萎缩性侧索硬化或糖尿病性神经病变。本发明化合物也可用做止痛剂。这些治疗处理的造模指南可参见Goodman & Gilman的治疗学药理基础(The PharmacologicalBasis of Therapeutics),McGraw Hill,10版,2001;药物处方与配方:从候选药物到商业剂型实用指南(PharmaceuticalPreformulation and Formulation:A Practical Guide fromCandidate Drug Selection to Commercial Dosage Form)CRC,2001和药物赋形剂工具书(Handbook of Pharmaceutical Excipients),AphA Publications,5版,2005。
类似物的竞争性结合(图16)
在PSMA阳性人前列腺癌细胞株LNCaP细胞中测试非放射性类似物与131I-DCIT竞争结合的能力。在添加有0.5%牛血清白蛋白的RPMI-1640培养基中,LNCaP细胞(300,000细胞/孔)与3nM[131I]-DCIT在1-10,000nM MIP-1072存在下孵育1小时,然后洗涤并在gamma计数仪中计数。在本说明书中所有引用的文献包括专利申请通过引用整体结合入本文。
MIP-1072的直接结合和内化
123I-MIP-1072与前列腺癌细胞的直接结合被检测(图17)。在添加有0.5%牛血清白蛋白的RPMI-1640培养基中,LNCaP细胞,或PSMA阴性细胞株PC3细胞,与单独3nM 123I-MIP-1072或在10M未标记MIP-1072或10M 2-(膦酰基甲基)-戊二酸(PMPA)(一个结构上不相关的NAALADase抑制剂)的存在下,共同孵育。洗涤细胞并在gamma计数仪中计数。
通过饱和结合分析确定MIP-1072的亲和常数(Kd)(图18)。在4℃或37℃,在10M未标记的MIP-1072(已确定非特异结合)存在或不存在下,LNCaP细胞与30-100,000pM 131I-MIP-1072在HBS(50mMHepes,pH7.5,0.9%氯化钠)中孵育1小时。洗涤细胞并在gamma计数仪上测定放射活性量。特异性结合通过总结合和非特异形结合的差值来计算。在过量未标记MIP-1072(10μM)存在或不存在的情况下滴度测量123I-MIP-1072(3pM-1,000nM),通过饱和结合分析来确定LNCaP细胞上MIP-1072与PSMA结合的亲和常数(Kd)。在4℃下Kd 4.8nM,Bmax fmoles/106细胞通过用Graph Pad Prism软件非线性回归分析来确定(图18)。37℃时的Kd无显著性差异,为8.1nM。然而,37℃时的Bmax大于4℃,分别为1490对4400fmol/106细胞,表明MIP-1072的内化。下列结果是两次独立分析的代表。
MIP-1072向LNCaP细胞中的内化能力通过酸洗试验确定(图19)。在HBS中LNCaP细胞与100nM 123I-MIP-107在4℃和37℃孵育0-2小时。在即定时间,移去培养基,细胞在问核算缓冲液(50mM甘氨酸,150mM NaCl,pH3.0)中4℃孵育5分钟。短暂孵育后,细胞在20000xg离心5分钟。上清液和细胞沉淀在gamma计数仪上计数。未确定在饱和结合实验中表明的MIP-1072内滑入LNCaP细胞,我们检测了LNCaP对MIP-1072的摄取率。在4℃和37℃,每孔加药100nMMIP-1072(2uCi/well)。在4℃通过曲线的平台期证明15分钟后与PSMA的结合达到平衡。达到平衡后,在37℃孵育细胞继续使MIP-1072内化。结果显示出时间依赖性,37℃而非4℃沉淀的放射性酸钝性增加,表明MIP-1072在37℃而非4℃被内化(图19)。123I-MIP-1072的肿瘤摄取和组织分布
在荷PSMA阳性LNCaP异体移植物(约100-200mm3)的独立种群的雄性NCr Nude-/-中,以0.05ml等体积注射尾静脉弹丸注射(大约2μCi/鼠)。注射后0.25,1,2,4,8,和24小时,用二氧化碳窒息对动物实施安乐死(n=5/时间点)。组织(血、心脏、肺、肝、脾、肾、肾上腺、胃、大小肠(含内容物)、睾丸、骨骼肌、骨、脑、脂肪和肿瘤)被剖开、取下、称重、转移到塑料管并用自动γ-计数仪(LKB Model 1282,Wallac Oy,Finland)计数。为了比较123I-MIP-1072在LNCaP和PC3肿瘤中的摄取,并且证明该化合物的机制是通过与2-(膦酰基甲基)-戊二酸(PMPA)的竞争,一些荷LNCaP或PC3异体移植物的小鼠在注射123I-MIP-1072之前用50mg/kgPMPA预处理5分钟。注射后1小时收获所选的组织。在高水平表达PSMA的的肾脏和LNCaP异体移植物中MIP-1072的摄取和曝光最强。肝脏中的摄取峰是在2小时时的158±46%ID/g,LNCaP异体移植物则是在1小时时的17±6%ID/g(图20)。靶组织的摄取迅速,但是在LNCaP异体移植物中清除较慢。体内实验证明了123I-MIP-1072的机制,因为其定位于表达PSMA的LNCaP肿瘤而不是不表达PSMA的PC3肿瘤(图21)。另外,用PMSA的潜在抑制剂PMPA预处理小鼠,肿瘤和肾被阻断。
Claims (65)
1.一种式(I)化合物或式(I)化合物的药学上可接受的盐:
其中R是C6-C12取代或未取代的芳基,C6-C12取代或未取代的杂芳基,C1-C6取代或未取代的烷基或-NR’R’,
Q是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,
Y是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,
Z是H或C1-C4烷基,
m是0、1、2、3、4或5,
n是0、1、2、3、4、5或6,
p是0、1、2、3、4、5或6,
R’是H、C(O)、S(O)2、C(O)2、C6-C12取代或未取代的芳基、C6-C12取代或未取代的杂芳基或C1-C6取代或未取代的烷基,当被取代时,所述芳基、杂芳基和烷基被卤素、C6-C12杂芳基、-NR’R’或COOZ取代,
进一步地,其中
(i)R或R’中至少一个是经卤素取代的C6-C12芳基或C6-C12杂芳基或
(ii)R或R’中至少一个是C6-C12杂芳基。
2.权利要求1的化合物,其中所述卤素是放射性卤素、I-123、I-125、I-131、I-124、Br-75、Br-77或F-18。
3.权利要求1的化合物,其中
n是0或1,
m是0、1、2、3或4,
Q是NR’,
Y是C(O)或CH2,且
R是C6-C12取代或未取代的芳基。
4.权利要求3的化合物,其中R是被卤素取代的苯基部分。
7.权利要求1的化合物,其中
n是0或1,
m是0、1、2、3或4,
Q是NR’,
Y是C(O)或CH2,并且
R是-CH2(CH2)1-4CHNR’R’,并且
R’是被吡啶或羧基取代的C1-C2烷基。
9.权利要求1的化合物,其中
n是0或1,
m是0,
Q是CH2,
Y是CH2,并且
R是-NR’R’,并且
R’是被吡啶或羧基取代的C1-C2烷基。
13.一种放射性核素螯合物,其包括权利要求1所述的化合物或盐。
14.权利要求13的放射性核素螯合物,其中所述放射性核素是成像的放射性核素。
15.权利要求13的放射性核素螯合物,其中所述放射性核素是治疗性放射性核素。
16.权利要求14的放射性核素螯合物,其中所述放射性核素是(锝-99m)Tc(CO)3螯合物或(铼-186/188)Re(CO)3螯合物。
18.一种谷氨酸盐-尿素-赖氨酸PSMA-结合部分,其抑制PSMA的IC50小于20nM,其中所述谷氨酸盐-尿素-赖氨酸PSMA-结合部分是通过α-NH2或β-NH2基团偶合的谷氨酸盐-尿素-α或β-氨基酸异质二聚体。
19.权利要求18的化合物,其中PSMA-结合部分和放射性成像部分是通过酰胺键、酯键、胺键或醚键偶联的。
20.一种使哺乳动物一种或多种器官或组织或两者成像的方法,该方法包括给哺乳动物施用有效量的偶联到放射性成像部分的谷氨酸盐-尿素-赖氨酸PSMA-结合部分和获得所述哺乳动物的一种或多种器官或组织或两者的图像,其中所述谷氨酸盐-尿素-赖氨酸PSMA-结合部分是通过α-NH2或β-NH2基团偶合的谷氨酸盐-尿素-α或β-氨基酸异质二聚体。
21.权利要求20的方法,其中所述一种或多种器官或组织或两者包括前列腺组织、肾组织、脑组织、维管组织或肿瘤组织。
22.一种试剂盒,其包括:(i)包括偶联到金属螯合部分的谷氨酸盐-尿素-赖氨酸PSMA-结合部分的化合物,和(ii)放射性核素。
23.权利要求21的试剂盒,其中所述放射性核素选自锝-99m、铼-186、铼-188或其组合。
24.一种确定与哺乳动物一种或多种器官或组织或两者相关的病态的阶段的方法,该方法包括(i)给哺乳动物施用有效量的包含偶联到放射性成像部分的谷氨酸盐-尿素-赖氨酸PSMA-结合部分的化合物,(ii)获得所述哺乳动物的一种或多种器官或组织或两者的图像,(ii i)从所述图像中确定存在于所述哺乳动物一种或多种器官或组织或两者中的PSMA的量,和(iv)利用所确定的量和对照量来确定病态的阶段,其中所述谷氨酸盐-尿素-赖氨酸PSMA-结合部分是通过α-NH2或β-NH2基团偶合的谷氨酸盐-尿素-α或β-氨基酸异质二聚体。
25.权利要求24的方法,其中所述病态选自癌症、前列腺癌、血管新生、心力衰竭、心肌症、肺病、肾功能不全、肾衰竭、炎症、动脉硬化症、易损动脉斑块或肿瘤。
26.一种监测哺乳动物对治疗与哺乳动物一种或多种器官或组织或两者有关的病态的反应的方法,该方法包括(i)给哺乳动物施用有效量的包含偶联到放射性成像部分的谷氨酸盐-尿素-赖氨酸PSMA-结合部分的化合物,(ii)获得所述哺乳动物的一种或多种器官或组织或两者的图像,(iii)从所述图像中确定存在于所述哺乳动物一种或多种器官或组织或两者中的肽酶的量,和(iv)如果有反应,利用所确定的量和对照量来评估哺乳动物对于治疗的反应,其中谷氨酸盐-尿素-赖氨酸PSMA-结合部分是通过α-NH2或β-NH2基团偶合的谷氨酸盐-尿素-α或β-氨基酸异质二聚体。
27.权利要求26的方法,其中所述对照量获自一组正常受治疗者中发现的量。
28.权利要求26的方法,其中所述对照量获自所述哺乳动物的一种或多种器官中发现的基线量。
29.一种定量哺乳动物的一种或多种器官或组织或两者中肽酶表达的方法,该方法包括给哺乳动物施用有效量的包含偶联到放射性成像部分的谷氨酸盐-尿素-赖氨酸PSMA-结合部分的化合物,获得所述哺乳动物的一种或多种器官或组织或两者的图像,从图像和一连串标准图像中定量所述哺乳动物的一种或多种器官或组织或两者中的肽酶表达量。
30.一种治疗患有糖尿病痛性神经病、神经元损伤或前列腺癌、精神分裂症、结肠癌、炎症、肌萎缩性侧索硬化或糖尿病性神经病变的患者的方法,该方法包括给患者施用治疗有效量的谷氨酸盐-尿素-赖氨酸PSMA-结合部分,其中所述谷氨酸盐-尿素-赖氨酸PSMA-结合部分是通过α-NH2或β-NH2基团偶合的谷氨酸盐-尿素-α或β-氨基酸异质二聚体。
31.一种治疗需要止痛的患者的方法,该方法包括给患者施用治疗有效量的谷氨酸盐-尿素-赖氨酸PSMA-结合部分,其中所述谷氨酸盐-尿素-赖氨酸PSMA-结合部分是通过α-NH2或β-NH2基团偶合的谷氨酸盐-尿素-α或β-氨基酸异质二聚体。
32.一种式(Ia)化合物或式(I)化合物的药学上可接受的盐:
其中R是C6-C12取代或未取代的芳基,C6-C12取代或未取代的杂芳基,C1-C6取代或未取代的烷基或-NR’R’,
Q是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,
Y是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,
Z是H或C1-C4烷基,
m是0、1、2、3、4或5,
n是0、1、2、3、4、5或6,
n’是0、1、2、3、4、5或6,
p是0、1、2、3、4、5或6,
R’是H、C(O)、S(O)2、C(O)2、C6-C12取代或未取代的芳基、C6-C12取代或未取代的杂芳基或C1-C6取代或未取代的烷基,当被取代时,所述芳基、杂芳基和烷基被卤素、C6-C12杂芳基、-NR’R’或COOZ取代,
进一步地,其中
(i)R或R’中至少一个是被至少一个卤素取代的C6-C12芳基或C6-C12杂芳基或
(ii)R或R’中至少一个是取代或未取代的C6-C12杂芳基。
33.权利要求32的化合物,其中所述卤素是放射性卤素、I-123、I-125、I-131、I-124、Br-75、Br-77或F-18。
34.权利要求32的化合物,其中
n是0或1,
n’是0或1,
m是0、1、2、3或4
Q是NR’,
Y是C(O)或CH2,且
R是C6-C12取代或未取代的芳基。
35.权利要求34的化合物,其中R是被卤素取代的苯基部分。
36.权利要求34的化合物,其中
n是0或1,
n’是0或1
m是0、1、2、3或4
Q是NR’,
Y是C(O)或CH2,且
R是-CH2(CH2)1-4CHNR’R’,且
R’是被吡啶或羧基取代的C1-C2烷基。
37.权利要求36的化合物,其中所述化合物是
其中任何上述化合物的羧基可以被C1-C4烷基取代。
38.权利要求32的化合物,其中
n是0或1,
n’是0或1,
m是0、1、2、3或4,
Q是CH2,
Y是CH2,且
R是-NR’R’,且
R’是被吡啶或羧基取代C1-C2烷基。
41.一种放射性核素螯合物,其包括权利要求31的化合物或盐。
42.权利要求44的放射性核素螯合物,其中所述放射性核素是成像的放射性核素。
43.权利要求44的放射性核素螯合物,其中所述放射性核素是治疗性放射性核素。
44.权利要求45的放射性核素螯合物,其中所述放射性核素是(锝-99m)Tc(CO)3螯合物或(铼-186/188)Re(CO)3螯合物。
48.权利要求45的化合物,所述化合物选自:
(S)-2-(3-((S)-5-氨基-1-羧基戊基)脲基)戊二酸,
(S,S)-2-{3-[1-羧基-5-(2-氯-苄氨基)-戊基]-脲基}-戊二酸,
(S,S)-2-{3-[1-羧基-5-(3-氯-苄氨基)-戊基]-脲基}-戊二酸,
(S,S)-2-{3-[1-羧基-5-(4-氯-苄氨基)-戊基]-脲基}-戊二酸,
(S)-2-(3-((R)-5-(苄氨基)-1-羧基戊基)脲基)戊二酸,
2-(3-{1-羧基-5-[3-(苯基)-脲基]-戊基}-脲基)-戊二酸,
2-(3-{1-羧基-5-[3-(4-溴-苯基)-脲基]-戊基}-脲基)-戊二酸;
2-(3-{1-羧基-5-[3-(4-氯-苯基)-脲基]-戊基}-脲基)-戊二酸;
(S)-2-(3-((R)-1-羧基-5-(吡啶-1-基甲基氨基)戊基)脲基)戊二酸;和
2-(3-{1-羧基-5-[3-(3-碘-苄基)-脲基]-戊基}-脲基)-戊二酸。
51.一种放射性核素螯合物,其包括权利要求45的化合物或盐。
52.权利要求57的放射性核素螯合物,其中所述放射性核素是成像的放射性核素。
53.权利要求57的放射性核素螯合物,其中所述放射性核素是治疗性放射性核素。
54.权利要求51的放射性核素螯合物,其中所述放射性核素是(锝-99m)Tc(CO)3螯合物或(铼-186/188)Re(CO)3螯合物。
55.一种式III化合物或其药学上可接受的盐:
其中
L是键,任选取代的C1-C15烷基、烯基或炔基,或-[(CH2)qO]s--,其中q和s独立地是1至10的整数,
E是-NR’R’,
Q是C(O)、O、NR’、S、S(O)2、C(O)2(CH2)p,
Y是C(O),、O、NR’、S、S(O)2、C(O)2(CH2)p
Z是H或C1-C4烷基,
m是0、1、2、3、4或5,
n是0、1、2、3、4、5或6,
n’是0、1、2、3、4、5或6,
p是0、1、2、3、4、5或6,
R’独立地是H、C(O)、S(O)2、C(O)2、C6-C12取代或未取代的芳基、C6-C12取代或未取代的杂芳基或C1-C14取代或未取代的烷基,当被取代时,芳基、杂芳基和烷基被卤素、C6-C12杂芳基、-NR’R’或COOZ取代。
56.一种放射性核素螯合物,其包括权利要求55的化合物或盐。
58.权利要求57的化合物,其中n是9,并且所述化合物是(19S,23S)-2-(4-碘苄基)-1-(4-碘苯基)-13,21-二氧代-2,14,20,22-四氮杂二十五烷-19,23,25-三羧酸。
61.权利要求60的放射性核素螯合物,其具有下列结构:
[Re(CO)3{(17R,21S)-11,19-二氧代-1-(吡啶-2-基)-2-(吡啶-2-基甲基)-5,8-二氧杂-2,12,18,20-四氮杂二十三烷-17,21,23-三羧酸}][Br];
[Re(CO)3{(23R,27S)-17,25-二氧代-1-(吡啶-2-基)-2-(吡啶-2-基甲基)-5,8,11,14-四氧杂-2,18,24,26-四氮杂二十九烷-23,27,29-三羧酸}][Br];和
[Re(CO)3{(35R,39S)-29,37-二氧代-1-(吡啶-2-基)-2-(吡啶-2-基甲基)-5,8,11,14,17,20,23,26-八氧杂-2,30,36,38-四氮杂四十一烷-35,39,41-三羧酸}][Br]或其盐。
63.一种放射性核素螯合物,其包括具有下列结构的权利要求62的化合物的盐形式:
[Re(CO)3{(19R,23S)-13,21-二氧代-2-(吡啶-2-基甲基)-2,14,20,22-四氮杂二十五烷-1,19,23,25-四羧酸}]。
64.权利要求13、41或51的放射性核素螯合物,其中所述放射性核素是放射性铜。
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CN113166087A (zh) * | 2018-09-21 | 2021-07-23 | 恩多塞特公司 | 屏蔽剂及其用途 |
CN113166087B (zh) * | 2018-09-21 | 2024-05-10 | 恩多塞特公司 | 屏蔽剂及其用途 |
CN111548305A (zh) * | 2020-05-12 | 2020-08-18 | 北京师范大学 | 一种可用于靶向psma的喹啉类化合物及其制备方法 |
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