CN113548986A - 一种磺酰氟基化合物及其应用 - Google Patents
一种磺酰氟基化合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种磺酰氟基化合物,本发明设计并合成的一系列磺酰氟基化合物,与已报道的靶向氨基酸转运载体、成纤维细胞活化蛋白、囊泡单胺转运蛋白2、五羟色胺受体、前列腺特异性膜抗原蛋白变化相关疾病的PET显像剂相比,具有标记条件简单,产率高,亲和性高的优势。本发明属于放射性药物化学与核医学技术领域。
Description
技术领域
本发明属于放射性药物化学与核医学技术领域,具体涉及一种磺酰氟基化合物及其应用。
背景技术
正电子断层显像技术(PET)可以从体外无创、定量和动态地提供不同癌变部位的分子层面和生理信息,且其灵敏度高、特异性强、安全性好、全身显像,已成为目前肿瘤和心脑血管疾病等临床诊断的强有力手段。实现PET显像的两个重要条件:PET仪器和分子探针。特异性显像探针的研究是当前的重点和难点。寻找与疾病相关的有效靶点、设计与之特异结合的分子、研制理想的放射性分子显像探针,开发新型PET显像药物,是解决相关疾病早期诊断的重要途径。
随着我国经济持续发展,PET显像仪器大幅度增长,国产化PET仪器也于近期投放市场,形成急速发展态势,对新型PET分子探针的需求尤为显著,“瓶颈”效应更加凸现。研发新的PET分子探针成为当务之急,与此配套的现代放射化学快速合成技术、放射性药物分析技术、疾病动物模型及PET显像技术的研究融合、交叉、发展,方可保障PET探针的临床转化顺利有效的进行。而这些放射性核素中,18F半衰期较长,电子能量低,PET图像分辨率高,且18F原子较小不影响原先靶向分子的性质,因此,18F标记的药物广泛被研发。18F标记的放射性分子探针通常是需要能垒高的活化酯亲核加热反应,通常标记条件较苛刻,不利于临床转化。迫切需要开发18F标记条件简单的PET新药,以满足人民健康和临床转化的需要。
发明内容
本发明解决的技术问题是提供一种高亲和磺酰氟基化合物及其应用,将该化合物用于PET显像剂,具有标记条件简单,产率高,亲和性高的显著优势。
为实现上述目的,本发明第一方面提供如下技术方案:
一种磺酰氟基化合物,所述化合物具有如下式1-式5所示的结构:
式1中,R1为H原子或甲基;
式4中,R3为CH2或CF2;
式5中,R8选自碳原子数为0-10的烷基、烷氧基、酰胺基和酯基。
作为本发明的一个实例,式1-式5中磺酰氟基中氟原子选自19F或18F,优选为18F。
作为本发明的一个实例,所述化合物具有式1所述的化合物具有如下式a-式d所示的结构:
作为本发明的一个实例,式4所述的化合物具有如下式e式j所示的结构:
作为本发明的一个实例,式5所述的化合物具有如下式k-式m所示的结构:
本发明第二方面提供上述化合物在制备用于诊断肿瘤和神经系统相关疾病的药物、药剂或试剂盒中的应用。
作为本发明的一个实例,所述药物、药剂或试剂盒包括一种正电子断层扫描成像技术显像剂。
作为本发明的一个实例,所述显像剂包括18F标记的式1-式5所示的化合物。
作为本发明的一个实例,所述肿瘤和神经系统相关疾病包括帕金森病、脑胶质瘤、前列腺癌和乳腺癌中的一种或几种。
本发明提供的上述技术方案至少带来的有益效果:
本发明设计并合成的一系列磺酰氟基化合物,与已报道的靶向氨基酸转运载体、成纤维细胞活化蛋白、囊泡单胺转运蛋白2、五羟色胺受体、前列腺特异性膜抗原蛋白变化相关疾病的PET显像剂相比,具有标记条件简单,产率高,亲和性高的优势。
附图说明
图1为本发明实例26中,在荷瘤鼠体内注射实例1制得的磺酰氟基化合物30min后的显像结果。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将对本发明实施方式作进一步地详细描述。
本发明中“纯化”目的是除去18F-氟化物的过量的副产物,以及浓缩并捕获反应产物。通过任何本领域技术人员已知的、适合放射性示踪物的方法,例如色谱、HPLC、固相萃取盒或固相萃取柱进行纯化。
本发明中磺酰氟基化合物的制备方法如下:
实例1(S)-2-氨基-3-(4-((氟磺酰基)氧基)苯基)丙酸
结构式如下:
合成路线如下:
(1)合成(S)-2-(((叔丁氧羰基)氨基)叔丁基-3-(4-((氟磺酰基)氧基)苯基)丙酸酯
将化合物(S)-2-氨基-3-(4-((氟磺酰基)氧基)苯基)丙酸(0.5g,1.48mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.59mL,5.93mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.36g,58.4%)。1H NMR(300MHz,CDCl3)δ7.30(s,4H),5.09(d,J=4.9Hz,1H),4.47(d,J=5.5Hz,1H),3.09(s,2H),1.42(d,J=7.2Hz,18H).13C NMR(75MHz,CDCl3)δ170.46,155.03,148.97,137.66,131.43,120.67,82.52,79.72,77.44,77.02,76.59,54.67,38.13,28.25,27.89.HRMS calcd for C18H26FNO7S 419.1414;found,420.1421[M+H]+.
(2)合成(S)-2-氨基-3-(4-((氟磺酰基)氧基)苯基)丙酸
将化合物((S)-2-(((叔丁氧羰基)氨基)叔丁基-3-(4-((氟磺酰基)氧基)苯基)丙酸酯(0.5g,1.19mmol)加入2mL的TFA中,室温反应3h,后出去TFA,HPLC半制备分离得产物(0.28g,89.1%)。1H NMR(300MHz,MeOD)δ7.52(d,J=8.3Hz,2H),7.42(d,J=7.9Hz,2H),5.45(s,1H),4.29(s,1H),3.32(m,1H).13C NMR(75MHz,MeOD)δ169.95,167.86,149.62,135.82,131.52,121.08,118.89,114.53,53.67,48.52,48.24,47.96,47.67,47.39,47.10,46.82,35.17,26.63.HRMS calcd for;C9H10FNO5S 263.0264;found,264.1257[M+H]+.
实例2(2S,4S)-2,5-二氨基-4-(4-((氟磺酰基)氧基)苄基)-5-氧戊酸
结构式如下:
合成路线如下:
(1)合成叔丁基(2S,4S)-2-(((叔丁氧羰基)氨基)-4-(4-((氟磺酰基)氧基)苄基)-5-氧代-5-((2,4,5-三甲氧基苄基)氨基)戊酸酯
将化合物(2S,4S)-2-(((叔丁氧羰基)氨基)-4-(4-羟基苄基)-5-氧代-5-((2,4,5-三甲氧基苄基)氨基)戊酸叔丁酯(0.2g,0.34mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.13mL,1.3mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.13g,56.2%)。1H NMR(300MHz,CDCl3)δ7.09(d,J=6.1Hz,2H),6.92(d,J=6.6Hz,2H),5.94(s,2H),5.19(s,1H),4.44(s,1H),4.13(s,1H),3.97(m,2H),3.63(m,9H),2.77(s,2H),2.23(s,2H),1.89(d,J=2.6Hz,2H),1.32(s,18H).13C NMR(75MHz,CDCl3)δ172.63,171.51,170.90,160.77,158.97,155.55,148.31,140.50,130.77,130.65,120.24,120.11,106.27,90.30,81.77,79.45,77.67,77.25,76.82,60.16,55.45,55.01,52.52,46.30,37.22,35.27,31.95,28.11,27.72,20.75,13.99.HRMS calcd for;C31H43FN2O11S670.2572found,671.2674[M+H]+.
(2)合成(2S,4S)-2,5-二氨基-4-(4-((氟磺酰基)氧基)苄基)-5-氧戊酸
将化合物叔丁基(2S,4S)-2-(((叔丁氧羰基)氨基)-4-(4-((氟磺酰基)氧基)苄基)-5-氧代-5-((2,4,5-三甲氧基苄基)氨基)戊酸酯(0.2g,0.3mmol)加入2mL的TFA中,室温反应3h,后出去TFA,HPLC半制备分离(52mg,51.4%)。1H NMR(300MHz,DMSO)δ8.03(s,1H),7.47(d,J=8.2Hz,2H),7.38(d,J=8.4Hz,2H),6.87(s,1H),3.75(s,2H),2.90(d,J=12.4Hz,3H),2.64(d,J=8.0Hz,1H),1.68(s,2H).HRMS calcd for;C12H15FN2O6S334.0635found,335.1623[M+H]+.
实例3 2-氨基-3-(4-((氟磺酰基)氧基)苯基)-2-甲基丙酸
结构式如下:
合成路线如下:
(1)合成2-((叔丁氧基羰基)氨基)-3-(4-((氟磺酰基)氧基)苯基)-2-甲基丙酸叔丁酯
将化合物2-((叔丁氧羰基)氨基)-3-(4-羟基苯基)-2-甲基丙酸叔丁酯(0.2g,0.56mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(2.2mL,2.27mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.15g,63.4%)。HRMS calcd for;C19H28FNO7S 433.1571found,434.1689[M+H]+.
(2)合成2-氨基-3-(4-((氟磺酰基)氧基)苯基)-2-甲基丙酸
将化合物2-((叔丁氧基羰基)氨基)-3-(4-((氟磺酰基)氧基)苯基)-2-甲基丙酸叔丁酯(0.1g,0.23mmol)加入2mL的TFA中,室温反应3h,后出去TFA,HPLC半制备分离(39mg,62.4%)。HRMS calcd for;C10H12FNO5S277.0420found,278.1231[M+H]+。
实例4(2S,4S)-2-氨基-4-(4-((氟磺酰基)氧基)苄基)-5-胍基戊酸
结构式如下:
合成路线如下:
(1)合成叔丁基(2S,4S)-5-((E)-1,2-双(叔丁氧羰基)-3-(4-甲氧基苄基)胍基)-2-((叔丁氧羰基)氨基)-4-(4-((氟磺酰基)氧基)苄基)戊酸酯
将化合物叔丁基(2S,4S)-5-((E)-1,2-双(叔丁氧羰基)-3-(4-甲氧基苄基)胍基)-2-((叔丁氧羰基)氨基)-4-(4-羟基苄基)戊酸酯(0.2g,0.26mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.1mL,1.05mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.11g,53.8%)。1H NMR(300MHz,CDCl3)δ7.35–7.19(m,6H),6.89(d,J=8.6Hz,2H),5.09(s,1H),4.34(s,2H),3.80(s,3H),3.67(s,2H),2.96(d,J=11.6Hz,1H),2.53(m,1H),2.16(s,1H),1.43(dd,J=18.0,14.6Hz,37H).13C NMR(75MHz,CDCl3)δ171.89,159.42,155.75,153.44,148.47,140.62,131.28,129.08,120.52,114.36,82.84,82.03,79.76,77.47,77.25,77.05,76.62,55.25,51.72,50.58,47.37,36.86,36.61,35.98,35.39,28.32,28.17,27.99,27.92,26.39.HRMS calcd for;C40H59FN4O12S 838.3834found,839.4521[M+H]+.
(2)合成(2S,4S)-2-氨基-4-(4-((氟磺酰基)氧基)苄基)-5-胍基戊酸
将化合物叔丁基(2S,4S)-5-((E)-1,2-双(叔丁氧羰基)-3-(4-甲氧基苄基)胍基)-2-((叔丁氧羰基)氨基)-4-(4-((氟磺酰基)氧基)苄基)戊酸酯(0.1g,0.12mmol)加入2mL的TFA中,室温反应3h,后出去TFA,HPLC半制备分离(24mg,56.3%)。1H NMR(300MHz,D2O)δ7.71(d,J=8.1Hz,2H),6.99(d,J=8.1Hz,2H),3.82(t,J=7.2Hz,1H),3.12-2.90(m,2H),2.60(t,J=6.9Hz,2H),2.27–2.05(m,1H),1.91–1.55(m,2H).HRMS calcd for;C13H19FN4O5S 362.1060found,363.1123[M+H]+.
实例5 4-((2-氨基苯基)硫基)-3-((二甲基氨基)甲基)苯基硫代氟酸酯
结构式如下:
合成路线如下:
将化合物4-((2-氨基苯基)硫基)-3-((二甲基氨基)甲基)苯酚(0.1g,0.36mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.15mL,1.45mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(84mg,64.2%)。1H-NMR(300MHz,CDCl3):δ7.35(dd,J=7.6,1.5Hz,1H),7.14(dd,J=7.6,1.5Hz,1H),6.86(d,J=8.4Hz,1H),6.74–6.67(m,3H),6.56-6.51(m,1H),4.51(s,3H),3.54(s,2H),2.21(s,6H).HRMS calcd for;C15H17FN2O3S2 356.0665found,357.1589[M+H]+.
实例6(2R,3R,11bR)-2-羟基-3-异丁基-10-甲氧基-11b-甲基-1,3,4,6,7,11b-六氢-2H-吡啶基[2,1-a]异喹啉-9-基硫代氟化物
结构式如下:
合成路线如下:
(1)合成(2R,3R,11bR)-3-异丁基-10-甲氧基-11b-甲基-2-((四氢-2H-吡喃-2-基)氧基)-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-9-基硫代氟酸酯
将化合物(2R,3R,11bR)-3-异丁基-10-甲氧基-11b-甲基-2-((四氢-2H-吡喃-2-基)氧基)-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-9-醇(0.2g,0.49mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.2mL,1.98mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.15g,65.7%)。HRMS calcd for;C24H36FNO6S 485.2247found,486.2347[M+H]+.
(2)合成(2R,3R,11bR)-2-羟基-3-异丁基-10-甲氧基-11b-甲基-1,3,4,6,7,11b-六氢-2H-吡啶基[2,1-a]异喹啉-9-基硫代氟化物
将化合物(2R,3R,11bR)-3-异丁基-10-甲氧基-11b-甲基-2-((四氢-2H-吡喃-2-基)氧基)-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-9-基硫代氟酸酯(0.1g,0.2mmol)溶于10mL的乙醇中,至于50度下,加入(10mg,0.02mmol)PPTS,反应3h,柱层析得产物(63mg,76.8%)。1HNMR(400MHz,CDCl3)δ6.67(s,1H),6.65(s,1H),3.89(s,3H),3.44-3.35(m,1H),3.17-2.96(m,4H),2.65-2.56(m,2H),2.49-2.43(m,1H),2.01(t,J=2.01Hz,1H),1.79-1.69(m,2H),1.56-1.45(m,3H),1.12-1.09(m,1H),0.98-0.92(m,6H).HRMS calcdfor;C19H28FNO5S 401.1672found,402.2675[M+H]+.
实例7(S)-4-((2-(2-氰基-4,4-二氟吡咯烷-1-基)-2-氧代乙基)氨基甲酰基)喹啉-6-基硫代氟酸酯
结构式如下:
合成路线如下:
将化合物(S)-N-(2-(2-氰基-4,4-二氟吡咯烷-1-基)-2-氧乙基)-6-羟基喹啉-4-羧酰胺(0.2g,0.55mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.2g,2.22mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.16g,69.5%)。HRMS calcd for;C17H13F3N4O5S442.0559found,443.1562[M+H]+.
实例8(S)-4-((2-(2-氰基吡咯烷-1-基)-2-氧代乙基)氨基甲酰基)喹啉-6-基硫代氟酸酯
结构式如下:
合成路线如下:
将化合物(S)-N-(2-(2-氰基吡咯烷-1-基)-2-氧代乙基)-6-羟基喹啉-4-羧酰胺(0.1g,0.3mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.1mL,1.23mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(80mg,65.8%)。HRMS calcd for;C17H15FN4O5S 406.0747found,407.1249[M+H]+.
实例9(S)-4-(4-(3-((4-((2-(2-氰基-4,4-二氟吡咯烷-1-基)-2-氧代乙基)氨基甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-羰基)苯基硫代氟酸酯
结构式如下:
合成路线如下:
将化合物(S)-N-(2-(2-氰基-4,4-二氟吡咯烷-1-基)-2-氧代乙基)-6-(3-(4-(4-羟基苯甲酰基)哌嗪-1-基)丙氧基喹啉-4-羧酰胺(0.1g,0.16mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.2mL,0.64mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(51mg,46.7%)。HRMS calcd for;C31H31F3N6O7S 688.1927found,689.2043[M+H]+.
实例10(S)-4-(2-(4-(3-((4-((2-(2-氰基吡咯烷)-1-基)-2-氧乙基)氨基甲酰基)喹啉-6-基)氧)丙基)哌嗪-1-基)-2-氧乙基)苯基硫氟酸盐
实例10参考实例8和9的合成路线而得到,总产率为28%。HRMS calcd for;C32H35FN6O7S 666.2272found,667.2353[M+H]+.
实例11(S)-4-(2-(4-(3-((4-((2-(2-氰基-4,4-二氟吡咯烷-1-基)-2-氧乙基)氨基甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-基)-2-氧乙基)苯基硫氟酸盐
实例11参考实例8和9的合成路线而得到,总产率为23%。HRMS calcd for;C32H33F3N6O7S 702.2084found,703.3541[M+H]+.
实例12(S)-4-(4-(3-((4-((2-(2-氰基吡咯烷-1-基)-2-氧代乙基)氨基甲酰基)喹啉-6-基)氧基)丙基)哌嗪-1-羰基)苯基硫代氟化物
结构式如下:
合成路线如下:
将化合物(S)-N-(2-(2-氰基吡咯烷-1-基)-2-氧乙基)-6-(3-(4-(4-羟基苯甲酰基)哌嗪-1-基)丙氧基)喹啉-4-羧酰胺(0.1g,0.17mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.7g,0.7mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(53mg,49.1%)。HRMS calcd for;C31H33FN6O7S652.2115found,635.2241[M+H]+.
实例13(((S)-1-羧基-5-(4-((氟磺酰基)氧基)苯甲酰胺基)戊基)氨基甲酰基)-L-谷氨酸
结构式如下:
合成路线如下:
(1)合成二叔丁基(((S)-1-(叔丁氧基)-6-(4-羟基苯甲酰胺基)-1-氧己基-2-基)氨基甲酰基)-L-谷氨酸
将二叔丁基(((S)-6-氨基-1-(叔丁氧基)-1-氧己基-2-基)氨基甲酰基)-L-谷氨酸(0.5g,1mmol)溶于20mL的二氯甲烷中,后加入1mL三乙胺和对羟基苯甲酸(0.14g,1mmol)、10mg HOBt和EDCI(0.38g,2mmol),后反应过夜。将反应液倒入10mL的水中,分层,干燥,柱层析,得产物(0.32g,53.7%)。1H NMR(300MHz,CDCl3)δ7.69(d,J=7.8Hz,2H),7.12(s,1H),6.87(d,J=7.8Hz,2H),5.55(s,2H),4.28(s,2H),3.37(s,2H),2.33(s,2H),1.64(m,18H).13C NMR(75MHz,CDCl3)δ172.51,168.09,159.96,157.41,129.16,115.45,82.32,81.89,80.78,77.42,77.20,77.00,76.57,53.46,53.16,39.85,32.60,31.62,28.89,28.07,27.99,27.96,22.73.HRMS calcd for;C31H49N3O9 607.3469found,608.4519[M+H]+.
(2)合成二叔丁基(((S)-1-(叔丁氧基)-6-(4-((氟磺酰基)氧基)苯甲酰胺基)-1-氧己基-2-基)氨基甲酰基)-L-谷氨酸
将化合物二叔丁基(((S)-1-(叔丁氧基)-6-(4-羟基苯甲酰胺基)-1-氧己基-2-基)氨基甲酰基)-L-谷氨酸(0.2g,0.33mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.12g,1.3mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.12g,54.2%)。1H NMR(300MHz,CDCl3)δ8.08(d,J=8.8Hz,3H),7.35(d,J=8.5Hz,2H),6.12(s,1H),5.64(s,1H),4.05(m,2H),3.30(s,2H),2.20(s,2H),1.50(m,18H).13C NMR(75MHz,CDCl3)δ174.24,172.27,171.86,165.79,157.70,151.57,135.01,130.09,120.60,82.65,81.35,80.62,77.56,77.13,76.71,60.31,54.01,52.99,39.99,32.16,31.36,29.07,27.91,27.85,27.74,27.63,23.87,20.92,14.08.HRMS calcd for;C31H48FN3O11S 689.2994found,690.1259[M+H]+.
(3)合成将二叔丁基(((S)-1-(叔丁氧基)-6-(4-((氟磺酰基)氧基)苯甲酰胺基)-1-氧己基-2-基)氨基甲酰基)-L-谷氨酸(0.1g,0.14mmol)加入2mL的TFA中,室温反应3h,后出去TFA,HPLC半制备分离(51mg,68.2%)。1H NMR(300MHz,MeOD)δ8.00(d,J=8.8Hz,2H),7.56(d,J=8.5Hz,2H),4.31(d,J=5.1Hz,2H),3.41(s,2H),2.42(t,J=7.0Hz,2H),2.19–2.12(m,1H),1.89-1.85(m,2H),1.70-1.65(m,4H),1.54-1.50(m,2H),1.32-1.26(m,1H).13C NMR(75MHz,MeOD)δ175.16,167.01,158.75,151.84,135.20,129.53,120.85,52.60,52.15,48.46,48.18,47.89,47.61,47.33,47.04,46.76,39.50,31.79,29.70,28.47,27.48,22.61.HRMS calcd for;C19H24FN3O11S 521.1116found,522.1124[M+H]+.
实例14(((S)-1-羧基-5-(2-(4-((氟磺酰基)氧基)苯基)乙酰胺基)戊基)氨基甲酰基)-L-谷氨酸
结构式如下:
合成路线如下:
(1)二叔丁基(((S)-1-(叔丁氧基)-6-(2-(4-羟基苯基)乙酰胺基)-1-氧代己基-2-基)氨基甲酰基)-L-谷氨酸
将二叔丁基(((S)-6-氨基-1-(叔丁氧基)-1-氧己基-2-基)氨基甲酰基)-L-谷氨酸(0.5g,1mmol)溶于20mL的二氯甲烷中,后加入1mL三乙胺和对羟基苯乙酸(0.15g,1mmol)、10mg HOBt和EDCI(0.38g,2mmol),后反应过夜。将反应液倒入10mL的水中,分层,干燥,柱层析,得产物(0.31g,49.2%)。1H NMR(300MHz,CDCl3)δ7.25-7.15(m,1H),7.05–6.95(m,2H),6.85–6.77(m,2H),6.27(s,1H),5.64(d,J=40.9Hz,2H),4.34(s,1H),4.22(s,1H),3.52-3.42(m,2H),3.16(d,J=6.4Hz,2H),2.31(s,2H),1.90–1.78(m,2H),1.67–1.58(m,2H),1.52-1.44(m,30H).13C NMR(75MHz,CDCl3)δ172.79,172.68,172.46,157.48,156.10,130.40,130.28,125.85,121.74,116.01,115.82,82.30,81.68,80.68,77.49,77.06,76.64,53.53,53.04,42.62,32.28,31.62,28.75,28.20,28.04,27.97,22.45.
(2)二叔丁基(((S)-1-(叔丁氧基)-6-(2-(4-((氟磺酰基)氧基)苯基)乙酰胺)-1-氧代己基-2-基)氨基甲酰基)-L-谷氨酸
将化合物二叔丁基(((S)-1-(叔丁氧基)-6-(2-(4-羟基苯基)乙酰胺基)-1-氧代己基-2-基)氨基甲酰基)-L-谷氨酸(0.2g,0.32mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.12g,1.3mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.1g,48.3%)。1H NMR(300MHz,CDCl3)δ7.46(d,J=8.6Hz,2H),7.27(d,J=7.1Hz,2H),5.97(s,1H),5.57(s,1H),4.35-4.29(m,1H),4.16-4.05(m,1H),3.66–3.54(m,2H),3.30–3.13(m,2H),2.37–2.31(m,2H),2.10(m,1H),1.88–1.68(m,2H),1.47–1.25(m,30H).13C NMR(75MHz,CDCl3)δ173.88,172.25,172.02,170.37,157.60,148.92,136.76,131.23,120.82,82.79,81.61,80.73,77.47,77.05,76.62,53.79,53.17,42.42,39.28,32.36,31.54,28.84,27.99,27.94.
(3)(((S)-1-羧基-5-(2-(4-((氟磺酰基)氧基)苯基)乙酰胺基)戊基)氨基甲酰基)-L-谷氨酸
将二叔丁基(((S)-1-(叔丁氧基)-6-(2-(4-((氟磺酰基)氧基)苯基)乙酰胺)-1-氧代己基-2-基)氨基甲酰基)-L-谷氨酸(0.1g,0.14mmol)加入2mL的TFA中,室温反应3h,后出去TFA,HPLC半制备分离(42mg,55.3%)。1H NMR(300MHz,MeOD)δ7.48(d,J=8.8Hz,2H),7.40(d,J=8.7Hz,2H),4.36–4.27(m,2H),3.58(s,2H),3.21(t,J=6.7Hz,2H),2.46–2.39(m,2H),2.16–2.05(m,1H),1.89–1.82(m,1H),1.55(m,2H).13C NMR(75MHz,MeOD)δ175.07,174.50,171.67,158.72,149.12,136.98,130.91,120.58,99.99,52.56,52.15,48.44,48.16,48.09,48.06,48.03,48.00,47.97,47.94,47.87,47.79,47.75,47.59,47.52,47.49,47.46,47.43,47.40,47.37,47.31,47.22,47.19,47.16,47.02,46.92,46.89,46.86,46.84,46.80,46.74,41.53,38.97,31.77,29.72,28.41,27.50,22.53.
实例15(15S,19S)-1-(4-((氟磺酰基)氧基)苯基)-2,9,17-三氧-3,10,16,18-四氮杂二十烷-15,19,21-三羧酸
结构式如下:
合成路线如下:
(1)三叔丁基(15S,19S)-1-(4-羟基苯基)-2,9,17-三氧-3,10,16,18-四氮杂二十二烷-15,19,21-三羧酸盐
将二叔丁基(((S)-6-(6-氨基己酰胺)-1-(叔丁氧基)-1-氧代己基-2-基)氨基甲酰基)-L-谷氨酸(0.4g,0.67mmol)溶于20mL的二氯甲烷中,后加入1mL三乙胺和对羟基苯乙酸(0.1g,0.67mmol)、10mg HOBt和EDCI(0.38g,2mmol),后反应过夜。将反应液倒入10mL的水中,分层,干燥,柱层析,得产物(0.25g,52.2%)。1H NMR(300MHz,CDCl3)δ7.05(d,J=8.2Hz,2H),6.82(d,J=8.2Hz,2H),6.69(s,1H),6.13(s,1H),5.91–5.86(m,2H),4.32–4.28(m,2H),3.46(s,2H),3.21–3.11(m,4H),2.32(s,2H),2.10–1.98(m,4H),1.82–1.76(m,2H),1.57-1.34(m,39H).13C NMR(75MHz,CDCl3)δ173.83,172.80,172.53,172.48,172.39,157.67,156.36,130.39,125.75,116.03,82.08,81.62,80.65,77.46,77.24,77.04,76.61,53.39,53.04,42.83,39.28,39.03,36.14,32.34,31.67,28.92,28.70,28.05,27.99,26.07,25.14,22.50.
(2)三叔丁基(15S,19S)-1-(4-((氟磺酰基)氧基)苯基)-2,9,17-三氧-3,10,16,18-四氮杂二十烷-15,19,21-三羧酸盐
将化合物三叔丁基(15S,19S)-1-(4-羟基苯基)-2,9,17-三氧-3,10,16,18-四氮杂二十二烷-15,19,21-三羧酸盐(0.2g,0.27mmol)溶于20mL的二氯甲烷中,至于冰水中,后加入三乙胺(0.1g,1mmol),将SO2ClF的气体的气球插入液体下面,反应过夜。后将反应液加入水中,无水硫酸钠干燥,浓缩,柱层析,得产物(0.11g,53.1%)。1H NMR(300MHz,CDCl3)δ7.38(d,J=8.6Hz,2H),7.21(d,J=8.4Hz,2H),6.93(d,J=7.5Hz,1H),6.85(s,1H),6.00(d,J=8.0Hz,1H),5.87(d,J=7.6Hz,1H),4.27–4.17(m,2H),3.51(s,2H),3.16–3.07(m,4H),2.25-2.01(m,4H),2.02(m,1H),1.89–1.11(m,2H),1.67–1.51(m,2H),1.39–1.19(m,39H).13C NMR(75MHz,CDCl3)δ173.57,172.97,172.43,172.21,170.36,157.64,148.87,136.63,131.39,131.15,121.53,120.82,82.00,81.35,80.53,77.59,77.16,76.74,53.40,52.92,42.47,39.42,38.90,35.96,32.28,31.56,29.57,28.86,28.74,28.13,27.97,27.92,26.24,25.08,22.61.
(3)(15S,19S)-1-(4-((氟磺酰基)氧基)苯基)-2,9,17-三氧-3,10,16,18-四氮杂二十烷-15,19,21-三羧酸
将三叔丁基(15S,19S)-1-(4-((氟磺酰基)氧基)苯基)-2,9,17-三氧-3,10,16,18-四氮杂二十烷-15,19,21-三羧酸盐(0.1g,0.14mmol)加入2mL的TFA中,室温反应3h,后出去TFA,HPLC半制备分离(36mg,45.1%)。HRMS calcd for;C26H37FN4O12S648.2113found,649.2132[M+H]+.
实例16(S)-2-氨基-3-(4-((((氟-18F)磺酰基)氧基)苯基)丙酸
结构式如下:
标记路线如下:
1.吸取含有[18F]的H2 18O(20mCi)溶液通过QMA柱,使[18F]F-被吸附在QMA柱上。
2.吸取1mL K222(0.5mg)/K2CO3(1mg)MeCN/H20=5/2溶液通过0.5M NaHCO3活化的QMA柱,将被吸附的[18F-]从柱上洗脱至反应管。取合适活度的淋洗液在100℃、氮气吹扫下蒸发至干燥。
3.向反应管中加入1mL无水乙腈蒸发至干燥,并且重复蒸干过程3次,可以得到干燥的[18F-]F-/K222/K2CO3络合物,加盖密封后冷却络合物。
4.用1mL乙腈溶解0.1mg标记前体,涡旋混匀后加入到上述干燥且冷却的络合物中。在室温下反应1min,反应结束后冷却反应液。
5.向冷却的反应液中加入9mL水进行稀释,稀释后的溶液用Oasis固相萃取柱纯化中间体,并且用10mL水冲洗上述Oasis固相萃取柱,最后用1mL乙醇淋洗该小柱,得到反应中间体。
6.除去乙醇溶液,加入1mL的TFA,50度,反应5min,产物经HPLC纯化(PhenomenexGemini-Nx C18 110A(250×4.6mm),0.1%甲酸水/乙腈10%-90%=6/4,出峰时间为12.4min,纯度大于95%。
实例17 4-((2-氨基苯基)硫基)-3-((二甲基氨基)甲基)苯基硫代氟酯-18F
结构式如下:
标记路线如下:
1.吸取含有[18F]的H2 18O(20mCi)溶液通过QMA柱,使[18F]F-被吸附在QMA柱上。
2.吸取1mL K222(0.5mg)/K2CO3(1mg)MeCN/H20=5/2溶液通过0.5M NaHCO3活化的QMA柱,将被吸附的[18F-]从柱上洗脱至反应管。取合适活度的淋洗液在100℃、氮气吹扫下蒸发至干燥。
3.向反应管中加入1mL无水乙腈蒸发至干燥,并且重复蒸干过程3次,可以得到干燥的[18F-]F-/K222/K2CO3络合物,加盖密封后冷却络合物。
4.用1mL乙腈溶解0.05mg标记前体,涡旋混匀后加入到上述干燥且冷却的络合物中。在室温下反应1min,反应结束后冷却反应液。
5.向冷却的反应液中加入9mL水进行稀释,稀释后的溶液用Oasis固相萃取柱纯化中间体,并且用10mL水冲洗上述Oasis固相萃取柱,最后用1mL乙醇淋洗该小柱,后经HPLC纯化(Phenomenex Gemini-Nx C18 110A(250×4.6mm),0.1%甲酸水/乙腈10%-90%=65/35,出峰时间为10.5min,纯度大于95%。
实例18(S)-4-((2-(2-氰基吡咯烷-1-基)-2-氧代乙基)氨基甲酰基)喹啉-6-基硫代氟化物-18F
结构式如下:
标记路线如下:
1.吸取含有[18F]的H2 18O(20mCi)溶液通过QMA柱,使[18F]F-被吸附在QMA柱上。
2.吸取1mL K222(0.5mg)/K2CO3(1mg)MeCN/H20=5/2溶液通过0.5M NaHCO3活化的QMA柱,将被吸附的[18F-]从柱上洗脱至反应管。取合适活度的淋洗液在100℃、氮气吹扫下蒸发至干燥。
3.向反应管中加入1mL无水乙腈蒸发至干燥,并且重复蒸干过程3次,可以得到干燥的[18F-]F-/K222/K2CO3络合物,加盖密封后冷却络合物。
4.用1mL乙腈溶解0.05mg标记前体,涡旋混匀后加入到上述干燥且冷却的络合物中。在室温下反应1min,反应结束后冷却反应液。
5.向冷却的反应液中加入9mL水进行稀释,稀释后的溶液用Oasis固相萃取柱纯化中间体,并且用10mL水冲洗上述Oasis固相萃取柱,最后用1mL乙醇淋洗该小柱,后经HPLC纯化(Phenomenex Gemini-Nx C18 110A(250×4.6mm),0.1%甲酸水/乙腈10%-90%=35/75,出峰时间为9.4min,纯度大于95%。
实例19(((S)-1-羧基-5-(4-((((氟-18F)磺酰基)氧基)苯甲酰胺基)戊基)氨基甲酰基)-L-谷氨酸
结构式如下:
反应式如下:
1.吸取含有[18F]的H2 18O(20mCi)溶液通过QMA柱,使[18F]F-被吸附在QMA柱上。
2.吸取1mL K222(0.5mg)/K2CO3(1mg)MeCN/H2o=5/2溶液通过0.5M NaHCO3活化的QMA柱,将被吸附的[18F-]从柱上洗脱至反应管。取合适活度的淋洗液在100℃、氮气吹扫下蒸发至干燥。
3.向反应管中加入1mL无水乙腈蒸发至干燥,并且重复蒸干过程3次,可以得到干燥的[18F-]F-/K222/K2CO3络合物,加盖密封后冷却络合物。
4.用1mL乙腈溶解0.05mg标记前体,涡旋混匀后加入到上述干燥且冷却的络合物中。在室温下反应1min,反应结束后冷却反应液。
5.向冷却的反应液中加入9mL水进行稀释,稀释后的溶液用Oasis固相萃取柱纯化中间体,并且用10mL水冲洗上述Oasis固相萃取柱,最后用1mL乙醇淋洗该小柱,后经HPLC纯化(Phenomenex Gemini-Nx C18 110A(250×4.6mm),0.1%甲酸水/乙腈20%-80%=35/75,出峰时间为5.3min,纯度大于95%。
实例20(S)-4-((2-(2-氰基-4,4-二氟吡咯烷-1-基)-2-氧代乙基)氨基甲酰基)喹啉-6-基硫代氟酸酯的结合性实验
取三组12支试管(平行实验),依次编号1-12,向其中加入等量已知放射性配体[125I]IDAM(0.1-0.2nM,Kd=0.2nM);在2至11号的试管中,加入50μL浓度由低到高(10-10to10-5M)的待测样品(二芳基硫醚衍生物)Tris-HCl溶液;在1号试管中加入50μL不含有待测样品的Tris-HCl溶液作为空白对照,在12号试管中加入浓度为0.1mg/mL的西酞普兰Tris-HCl溶液以测定与SERT的非特异性结合;在1号到12号的试管中,分别加入100μl由Tris-HCl缓冲溶液稀释的LLC-五羟色胺转运体(SERT)匀浆溶液室温竞争反应1小时;利用细胞收集器将细胞膜蛋白收集到玻璃滤膜上(滤膜用1%的聚乙烯亚胺浸润,光面向上,毛面向下),并用冷的Tris-HCl缓冲溶液清洗试管以及滤膜以除去非特异性结合,取下滤膜,放入γ计数器进行测量;将测得数据用Excel处理,得到待测化合物浓度与[125I]IDAM放射性计数曲线图得到待测化合物IC50值,通过公式计算得到(S)-4-((2-(2-氰基-4,4-二氟吡咯烷-1-基)-2-氧代乙基)氨基甲酰基)喹啉-6-基硫代氟酸酯与SERT的Ki值为0.4nM。结果表明,该化合物高亲和SERT,有望应用于SERT相关的疾病如:抑郁症的诊断。
实例21(2R,3R,11bR)-2-羟基-3-异丁基-10-甲氧基-11b-甲基-1,3,4,6,7,11b-六氢-2H-吡啶基[2,1-a]异喹啉-氟代9--18F
大鼠脑纹状组织匀浆保存于-80℃50mM Hepes和0.32M Sucrose溶液中(pH=7.5),;取三组12支试管(平行实验),依次编号1-12,分别向其中加入等量已知放射性配体(2R,3R,11bR)-2-羟基-3-异丁基-10-甲氧基-11b-甲基-1,3,4,6,7,11b-六氢-2H-吡啶基[2,1-a]异喹啉-氟代9--18F(0.15-0.2nM);在2至11号的试管中,加入50μL浓度由低到高(10-12to 10-7M)的待测样品(TBZ衍生物)50mM Hepes/0.32M sucrose(pH=7.5)溶液;在1号试管中加入50μL不含有待测样品的50mM Hepes/0.32M sucrose(pH=7.5)溶液作为空白对照,在12号试管中加入50μL含有抑制剂的50mM Hepes/0.32M sucrose(pH=7.5)溶液,用于测定与VMAT2的非特异性结合;在1号到12号的试管中,分别加入100μl由50mM Hepes/0.32Msucrose(pH=7.5)大鼠脑纹状体组织匀浆溶液室温竞争反应90min;利用细胞收集器将细胞膜蛋白收集到玻璃滤膜上,并用冷的PBS缓冲溶(pH=4)液清洗试管以及滤膜以除去非特异性结合,取下滤膜,放入γ计数器进行测量;将测得数据用Excel处理,得到待测化合物IC50值,通过Cheng-Prusoff方程计算得出(2R,3R,11bR)-2-羟基-3-异丁基-10-甲氧基-11b-甲基-1,3,4,6,7,11b-六氢-2H-吡啶基[2,1-a]异喹啉-氟代9--18F与受体的Ki值为1.52nM。从结果可以看出,该化合物较高的亲和VMAT2,有望应用于VMAT2相关的疾病如:帕金森病的诊断。
实例22实例7-12与成纤维细胞活化蛋白的亲和性
在25℃下测量DPPIV,DPP8,DPP9,FAP和PREP的酶活性,在380nm的激发波长和460nm的发射波长下监测荧光。用于FAP分析的底物是Z-Gly-Pro-AMC。反应混合物包含25μM的酶缓冲液(FAP)和适量的抑制剂(介于10-4和10-11M之间),总体积为210μL。FAP的最终酶浓度分别为0.1、0.8、0.4、1.2和0.6nM。IC 50值定义为在添加底物之前在25℃下与酶预孵育10分钟后,将酶活性降低50%所需的抑制剂浓度。实例7-10的IC50值为3.2,2.5,3.9,5.9,4.3,4.6nM。从结果可以看出,实例7-12高亲和成纤维细胞活化蛋白,可以诊断成纤维细胞活化蛋白相关的肿瘤。
实例23实例13-15与前列腺特异性膜抗原蛋白的亲和性
将LNCaP细胞(每孔约2×105)接种到6孔细胞培养物中,实验前48小时将培养皿上样。洗涤后,将细胞分别与37kBq实例15在37℃和4℃下孵育5、15、30、60、90和120分钟。通过用20μM 2-膦酰基甲基戊二酸竞争性阻断来确定特定的细胞摄取。通过用4mL冰冷的PBS洗涤两次来终止细胞摄取。随后将细胞与在PBS(50mM,pH 2.8)中的0.5mL甘氨酸-HCl孵育两次,持续5分钟,以除去表面结合。用1mL冰冷的PBS洗涤细胞,并使用0.5mL 1N NaOH裂解。在γ计数器中测量探针的放射性。将细胞吸收计算为结合到106个细胞的初始添加的放射活性的百分比[%ID/106细胞]。实例13-15的IC50值为8.5,4.3,3.8nM。从结果可以看出,实例15高亲和前列腺特异性膜抗原蛋白,可以诊断PSMA相关的疾病如前列腺癌。
实例24 18F标记实例1-4的肿瘤细胞摄取实验
实验前24h在孔板中种细胞:培养液倒掉,PBS冲洗两次(2mL*2),0.25%胰酶消化(1mL),吹匀。移液枪取出50μL单细胞悬浮液,加入950μL培养液,稀释20倍。取10μL使用血球计数板计数,四个大格共计为N个。计算:N/4*20=n*104个/mL。根据计算结果再进行稀释至4*105个/mL。孔板用PBS清洗,再用培养液润洗。润洗后将乳腺癌MCF-7细胞株以每孔2×105细胞/孔/4组(每组每个时间点4复孔)置于24孔板中,每孔中放有0.5mL含10%胎牛血清(Fetal bovine serium,FBS)的高糖DMEM low/1640培养基液在培养箱中隔夜孵育,培养条件为37℃,5%CO2湿润培养24h。在30min和120min时,以下化合物的摄取值(%uptake/100ug protein)见表1。从表1可以看出,肿瘤对18F标记实例1-4均有较高的摄取,该类化合物有望应用于肿瘤的诊断。
表1
化合物名称 | 30分钟摄取值 | 60分钟摄取值 |
<sup>18</sup>F标记实例1 | 15.3% | 34.2% |
<sup>18</sup>F标记实例2 | 16.4% | 44.1% |
<sup>18</sup>F标记实例3 | 13.2% | 28.1% |
<sup>18</sup>F标记实例4 | 14.9% | 30.4% |
实例25 18F标记实例1-4,7-11的肿瘤生物分布
为了研究化合物的生物分布及药代动力学,通过不同肿瘤裸鼠体内分布实验评价了专利中实例1-4(MCF-7荷瘤鼠),7-10(HT-1080-FAP),13(22rv1荷瘤鼠)。将放射性精氨酸衍生物用生理盐水稀释到~300μCi/mL(~11MBq/mL)。取出0.1mL稀释后溶液,加入9.9mL生理盐水,混匀后再取出0.1mL,作为标准溶液(1%),在测量组织放射性计数的同时测量该标准溶液放射性计数。
以MCF-7肿瘤裸鼠为例,体重为16±2g,随机5只为一组。从尾静脉注入0.1mL(~30μCi,~1MBq)精氨酸溶液,分别于注射后5、30、60、120min断头处死,取血、肿瘤,擦净后称重,测定放射性计数,计算各脏器和组织的摄取量(%ID/g)及肿瘤/肌肉和肿瘤/血的比。结果见下表2。
表2
从表中可以看出,所有化合物肿瘤与肌肉的比值较高,显像剂在肿瘤内的保留时间长。且在体内血液清除快,成像清晰,适于肿瘤成像。
实例26 18F标记实例1的PET成像
在异氟烷麻醉(2-3%,1L/min氧气)和加热板保暖的条件下,将含有18F精氨酸衍生物的生理盐水注射到MCF-7肿瘤裸鼠的体内,然后开始采集图像。所有操作完成时间不低于过2h(动态,5min/帧),图像通过AMIDE’S医疗成像软件进行分析与重构。从图1可见,18F标记实例1可以用于肿瘤成像,其中白色圈内为肿瘤。
以上所述仅为本发明的较佳实例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (9)
2.根据权利要求1所述的化合物,其特征在于,式1-式5中磺酰氟基中氟原子选自19F或18F,优选为18F。
6.权利要求1-5所述的化合物在制备用于诊断肿瘤和神经系统相关疾病的药物、药剂或试剂盒中的应用。
7.根据权利要求6所述的应用,其特征在于,所述药物、药剂或试剂盒包括一种正电子断层扫描成像技术显像剂。
8.根据权利要求7所述的应用,其特征在于,所述显像剂包括18F标记的式1-式5所示的化合物。
9.根据权利要求6所述的应用,其特征在于,所述肿瘤和神经系统相关疾病包括帕金森病、脑胶质瘤、前列腺癌和乳腺癌中的一种或几种。
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