CN107406419A - Pet显像剂 - Google Patents
Pet显像剂 Download PDFInfo
- Publication number
- CN107406419A CN107406419A CN201680016753.9A CN201680016753A CN107406419A CN 107406419 A CN107406419 A CN 107406419A CN 201680016753 A CN201680016753 A CN 201680016753A CN 107406419 A CN107406419 A CN 107406419A
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- China
- Prior art keywords
- methyl
- compound
- bases
- compound according
- tetrazolium
- Prior art date
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- Granted
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- 150000001875 compounds Chemical class 0.000 claims abstract description 83
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- 108010070600 Glucose-6-phosphate isomerase Proteins 0.000 claims abstract description 32
- 238000003384 imaging method Methods 0.000 claims abstract description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 72
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 30
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- 238000002372 labelling Methods 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 230000003305 autocrine Effects 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 230000005258 radioactive decay Effects 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
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- 125000004429 atom Chemical group 0.000 claims 1
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- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 7
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- 238000003818 flash chromatography Methods 0.000 description 7
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 6
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- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 5
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 5
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- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
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- 241000282414 Homo sapiens Species 0.000 description 4
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- 241001465754 Metazoa Species 0.000 description 4
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- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 4
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Classifications
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Abstract
用作PET显像剂的式(I)的新型2‑苄基‑5‑甲基‑2H‑四唑衍生物的制备。本发明涉及式(I)的新型化合物,它们的制备和在由酶自分泌运动因子介导或与其相关的疾病和障碍的领域中作为用于显像技术和诊断学的PET显像剂的应用。
Description
发明概述
本申请涉及新化合物,特别是新型放射性化合物、所述化合物的盐、它们的制备,以及这些新型放射性化合物,在由酶自分泌运动因子介导和/或与其相关的疾病或病症、如纤维发生、瘙痒、肝硬化、癌症、神经性疼痛和肾脏疾病的领域,作为用于显像技术和诊断工具的放射性示踪剂/标记物的应用。
自分泌运动因子((autotaxin)ATX),还称为外核苷酸焦磷酸酶/磷酸二酯酶(ENPP2),是已知具有溶血磷脂酶D活性的分泌的胞外酶(Umezu-Goto等人,2002),其负责通过溶血磷脂酰胆碱(LPC)的水解产生生物活性脂质介体溶血磷脂酸(LPA)(Tokumura等人,2002)。LPA高度牵涉在病理生理学疾病的发病机制中,包括癌症(Liu等人,2009;Mill&Moolenaar,2003)、神经性疼痛(Inoue等人,2004)和纤维化(Tager等人,2008)。产生LPA后,脂质与存在7种已知同工型的特异性G蛋白偶联受体结合(Noguchi等人,2009)。LPA激活多信号传导途径(Mill&Moolenaar,2003),包括细胞迁移(van Dijk等人,1998)、增殖和存活(Brindley,2004)。其它细胞应答包括平滑肌收缩、细胞凋亡和血小板聚集(Tigyi&Parrill,2003)。
在从人A2058黑素瘤细胞中分离后,ATX最初被鉴定为细胞游动性刺激因子(Stracke等人,1992)。随后对酶的工作由于其在多种癌症类型、包括乳癌和肾癌(Stassar等人,2001)、霍奇金淋巴瘤(Baumforth等人,2005)、滤泡型淋巴瘤(Masuda等人,2008)以及肺和肾脏纤维化(Hama等人,2004)中的异常表达而聚焦于其作为游动性因子的作用。在发现其后10年,ATX被表征为分泌的溶血磷脂酶(lysoPLD)(Tokumura等人,2002;Gesta等人,2002)。自此以后,ATX基因敲除小鼠已经证明,ATX-LPA信号传导轴在心血管和神经系统的胚胎发育期间起重要作用(Tanaka等人,2006;van Meeteren等人,2006),导致早期的胚胎致死率(Bachner等人,1999)。
ATX属于通过基因ENPP编码的称为核苷酸焦磷酸酶/磷酸二酯酶(NPP)的蛋白质家族。该家族由7种在脊椎动物内保守的结构相关的酶(ENPP 1-7)组成,它们按照其发现进行编号。最初通过它们体外水解各种核苷酸和核苷酸衍生物的焦磷酸酯或磷酸二酯键的能力对它们进行定义(Stefan等人,1999;Goding等人,1998;Gijsber等人,2001),虽然ENPP2和磷酸胆碱酯(ENPP6&7)对其它细胞外非核苷酸分子具有特异性活性。在该家族中,ENPP2(ATX)是独特的,因为它是唯一的分泌蛋白质,而其它ENPP成员是跨膜蛋白质(Stefan等人,2005)。
无创核显像技术可用于获得有关活体(包括实验动物、患者和志愿者)的生理学和生物化学的基本信息和诊断信息。这些技术依赖于使用能够检测从施用于活体的放射性示踪剂发出的辐射的成像仪器。获得的信息可以被重建以提供平面和断层图像,其显示作为时间的函数的放射性示踪剂的分布和/或浓度。
正电子发射断层成像术(PET)是无创显像技术,提供所有核医学成像模式中的最高空间和时间分辨率,并具有额外的优点,可以允许对组织中示踪剂浓度进行真实定量。该技术涉及使用标记有发射正电子的放射性核素的放射性示踪剂,其设计为具有体内性质,允许测定活组织中各种进程的与生理学或生物化学有关的参数。
正电子发射断层成像术(PET)是一种核医学、功能显像技术,其产生在身体中功能进程的三维图像。该系统检测由发射正电子的放射性核素(示踪剂)间接发射的伽马射线对,所述放射性核素在生物活性分子上被引入体内。然后通过计算机分析,构建体内示踪剂浓度的三维图像。在现代的PET-CT扫描仪中,通常在同一台机器中,在同一时期借助于在患者身上执行的CT X射线扫描来实现三维成像。
PET扫描中使用的放射性核素通常是半衰期短的同位素,如碳-11(~20分钟),氮-13(~10分钟),氧-15(~2分钟),氟-18(~110分钟)或铷-82(~1.27分钟)。这些放射性核素被掺入通常被身体使用的化合物,如葡萄糖(或葡萄糖类似物)、水或氨,或掺入与受体或其他药物作用位点结合的分子中。所述标记的化合物被称为放射性示踪剂。PET技术可用于追踪人类活体(以及许多其他物种)中任何化合物的生物学途径,只要它可以用PET同位素进行放射性标记。因此,可以用PET探测的具体进程事实上是无限的。
由于大多数发射正电子的放射性同位素的半衰期短,所以放射性示踪剂传统上是使用靠近PET成像设备的回旋加速器来产生的。氟-18的半衰期足够长,可以将用氟-18标记的放射性示踪剂在装置外位置商业化生产,并运送到成像中心。
单光子发射计算机断层成像术(SPECT)是与PET相似的核医学显像技术。它也使用放射性标记的示踪剂,并且基于伽马射线的检测。与PET,SPECT中使用的放射性标记,例如123I,发射直接测定的伽马辐射。我们现在发现,使用放射自显影技术或分子成像方式如PET或SPECT,可以使用某些放射性标记的化合物在体外和体内探测自分泌运动因子。本文所述的化合物可用发射电子、正电子或γ的放射性同位素进行标记,如上述那些,包括但不限于3H、13N、11C、C14、18F、123I、124I、125I和/或131I。
发明描述
在第一个方面,本申请提供了通式(I)的化合物,
和/或其药学上可接受的盐,其中
R是卤素、-CF3、-OCF3、-OCH3、-CH3或CN;且
A是吡啶基或噁唑基,其被至少一个选自卤代-(C1-6-烷基),卤代-(C1-3-烷基)氧基(C2-4-烷基)或卤代-(C1-3-烷基)氧基(C2-4-烷基)氧基(C2-4-烷基)的取代基取代。
在另一个方面,本申请提供了式I的化合物,其任选地任选地包含3H。
在另一个方面,本申请提供了式I的化合物,其中R是-CF3或-OCF3,且其中这些基团中的每一个可任选地包含至少一个18F。
在又一个方面,本申请提供了式I的化合物,其中“卤代”或“卤素”是选自F、Br、Cl或I的基团。在又一个方面,卤代或卤素选自18F、19F、123I、124I、125I或131I。
在进一步的方面,本申请提供了式I的化合物,其中编号为“1”的碳原子选自11C、12C或14C。
本文公开的化合物是自分泌运动因子抑制剂。以其非-放射性形式(即当仅含有12C、19F或127I时),这些化合物可用作涉及自分泌运动因子的疾病的治疗剂。以其放射性标记形式,本发明的化合物可用作诊断剂,用于成像或用于放射治疗。更具体地,以其3H-、11C-、14C、18F-、123I-、124I-、125I-或131I-放射性标记形式,本文所述的化合物可用于诊断或成像,或用作放射治疗剂。特别是,3H-和14C-放射性标记的衍生物可用于体外和离体放射性配体结合测定或放射自显影。11C-、18F-、123I-和124I-放射性标记的衍生物还可以适用于使用SPECT(单光子计算机体断层成像术)或PET(正电子发射断层成像术)的体内成像,例如使自分泌蛋白浓度成像,或者通过结合于自分泌运动因子的分子来测定结合位点的占有率。131I-放射性标记的衍生物可以适合作为显像剂和用于放射治疗,例如,用于治疗表达自分泌运动因子的肿瘤。
放射性标记的自分泌运动因子配体的应用可以包括但不限于定量组织中的自分泌运动因子蛋白浓度、呈现(stage)或监测疾病进展、或测定对自分泌运动因子蛋白表达的治疗性治疗的作用的临床研究(参见例如Hepatology 2012 56(4):1391-400,就ATX表达与胆汁淤积性瘙痒之间的联系而言)。也可以离体或体内使用放射性标记的自分泌运动因子配体,以确定与自分泌运动因子结合的药物的受体占有率,以及使与表达自分泌运动因子的细胞相关的肿瘤(例如人类肝细胞癌)成像(参见例如Molecular Cancer 2010,9:71)。
根据上述,本申请提供作为用于癌症成像的标记物或放射治疗剂的活性剂,或用于监测涉及自分泌运动因子的疗法和疾病的活性剂,所述疾病为例如胆汁淤积性瘙痒、肝硬化、糖尿病、肾脏疾病、疼痛、器官纤维化、例如特发性肺纤维化。
根据另一方面,提供了用于在确认有需要的个体中检测自分泌运动因子的方法,其包括:(i)将本文任何之处所述的式(I)化合物或其药学上可接受的盐施用于所述个体;和(ii)通过体内PET或SPECT成像来检测所述化合物的摄取。认为该方法提供的信息和数据,在涉及自分泌运动因子的疾病的诊断和临床研究中具有效用。在一个实施方案中,个体是哺乳动物,最合适地是人,其具有或被怀疑具有涉及自分泌运动因子的疾病。该方法可以定量地进行,使得自分泌运动因子的量或量的变化或自分泌运动因子的密度或密度的变化可以被确定,以便诊断或跟踪疾病进展。或者,该方法可用于在体内定位自分泌运动因子。
在另一个方面,本发明提供了,施用结合自分泌运动因子的配体后,定量个体中未结合的自分泌运动因子的百分比或百分比变化的方法,其包括:
(i)向所述个体施用如上定义的放射性标记的式(I)的化合物或其盐或溶剂化物;
(ii)通过体内PET或SPECT成像来检测在步骤(i)中施用的所述放射性标记的式(I)的化合物的摄取;
(iii)允许经过合适的时间,使得步骤(i)中施用的化合物已经放射性衰变(decay);然后(iv)施用有效量的(a)非放射性标记的自分泌运动因子配体,或(b)影响自分泌运动因子底物的内源水平的非放射性标记的活性剂,并同时施用如步骤(i)中所定义的放射性标记的式(I)的化合物或其药学上可接受的盐;和(v)通过体内PET或SPECT成像来检测在步骤(iv)中施用的所述式(I)的化合物的摄取。
在步骤(iii)中允许经过合适的时间适合地是所述放射性同位素半衰期的4倍以上,更合适地是所述放射性同位素半衰期的至少6倍,更合适的是使来自在步骤(i)中施用的放射性标记的式(I)的化合物的PET或SPECT信号不再可检出。
在另一方面,本发明提供了在确认有需要的个体中检测自分泌运动因子的方法,其包括:(i)向所述个体施用如本申请中任何地方所述的放射性标记的式(I)的化合物或其药学上可接受的盐;
(ii)通过体内PET或SPECT成像来检测在步骤(i)中施用的所述放射性标记的式(I)的化合物的摄取;
(iii)施用有效量的(a)非放射性标记的自分泌运动因子配体,或(b)影响自分泌运动因子底物的内源水平的非放射性标记的活性剂;和
(iv)通过体内PET或SPECT成像来检测在步骤(i)中施用的所述式(I)的化合物的摄取。
在未经处理(naive)或预处理的动物或人类个体中在示踪剂注射(例如,适当标记的式I化合物)后,PET或SPECT成像实验提供放射性的分布的三维图像。
简言之,在用适于PET或SPECT成像的放射性同位素(例如11C,18F或123I)标记之后,将本发明的化合物注入到未经处理或预处理的动物或人个体的血液循环中。在允许分子在体内分布的可选等待时间之后,将个体置于在PET或SPECT扫描器中,并且在记录足够数量的衰变(disintegration)事件之后重建放射性分布的图像。为了帮助解释,可以与PET或SPECT扫描并行执行磁共振成像或计算机X射线断层扫描。为了测定目标表达(例如,研究涉及自分泌运动因子的疾病,或检测表达自分泌运动因子的肿瘤),可以注射放射性标记的化合物而不预处理治疗。为了测定结合自分泌运动因子的药物的自分泌运动因子的占据,或为了测定治疗对自分泌运动因子表达的作用,在药物处理后或治疗后注射放射性标记化合物,并与基线(即药物处理治疗前观察到的放射性信号)比较。
此外,来自标记的式I化合物的放射性的分布可以通过离体或体外放射自显影来测定。作为通用实施例,对动物注射放射性标记的式I化合物(有或没有通过药物或治疗预处理),随后处死。然后将整个动物或感兴趣的器官冷冻或包埋、切片,并且在将所述切片施加到放射显影片(radiographic film)或成像板上之后产生图像,例如,使用光激发磷光板并用磷相仪产生图像。
实验部分
实施例
以下实施例旨在说明本发明,而不应解释为对其的限制。
通用条件:
质谱在LC-MS、SFC-MS或GC-MS系统上采用电雾化、化学和电子轰击离子化方法从一系列具有以下配置的仪器上获得:Agilent 1100HPLC系统,配有Agilent 6110质谱仪。[M+H]+指化学物质的质子化分子离子。
NMR谱在Bruker AVANCE 400MHz或500MHz NMR波谱仪上采用ICON-NMR在TopSpin程序控制下获得。除非另有指示,否则谱图在298K处测定,并且参比是相对于溶剂共振信号。
测试设备:
MS方法:Agilent 1100HPLC系统,配有Agilent 6110质谱仪
2minLowpHv03:
2minLowpHv01:
2minLowpH:
10minLowpH:
2minHighpHv03:
2分钟最终分析:
分析型HPLC:
缩略语
BOC 叔丁基羧基
br 宽
d 双峰
dd 双双峰
DCM 二氯甲烷
DIPEA 二乙基异丙基胺
DMA N,N-二甲基甲酰胺
DME 1,4-二甲氧基乙烷
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EtOAc 乙酸乙酯
h 小时
HPLC 高压液相色谱法
LCMS 液相色谱法质谱法联用
MeOH 甲醇
MS 质谱法
m或mult 多重峰
mg 毫克
min 分钟
mL 毫升
mmol 毫摩尔
MTBE 甲基叔丁基醚
m/z 质荷比
NMR 核磁共振
ppm 百万分率
rac 外消旋
Rt 保留时间
s 单峰
t 三重峰
TBME 甲基叔丁基醚
TFA 三氟乙酸
THF 四氢呋喃
中间体的制备
中间体A
(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮
步骤1:2-(2-溴-5-氯苄基)-5-甲基-2H-四唑
使用冰浴在0℃下将5-甲基-2H-四唑(77g,913mmol)置于具有无水DMF(400mL)的烧瓶中。分批加入碳酸钾(168g,1217mmol),然后滴加在DMF(400mL)中的1-溴-2-(溴甲基)-4-氯苯(173g,608mmol)。将所得混合物在室温搅拌2小时。将该混合物倒入水中,通过过滤收集所得混悬液。将固体用异己烷研磨,并通过过滤除去未溶解的固体。将滤液减压浓缩,得到白色固体,将其混悬在水中,并搅拌过夜。将产物过滤并用水洗涤,得到标题化合物。
LCMS:Rt 1.15min;MS m/z 289.0[M+H]+;2minLowpHv01
步骤2:(E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酸乙酯
将2-(2-溴-5-氯苄基)-5-甲基-2H-四唑(15g,52.2mmol)、三邻甲苯基膦(0.794g,2.61mmol)和三乙胺(10.56g,104mmol)置于具有干燥、脱气的DMF(80mL)的烧瓶中。加入丙烯酸乙酯(7.83g,78mmol),然后加入二乙酸钯(0.586g,2.61mmol),并将该反应混合物在100℃搅拌过夜。将该混合物冷却,用EtOAc(150mL)稀释,并过滤以除去固体。将该反应混合物在EtOAc和水之间分配。将有机相用水和盐水洗涤,用MgSO4干燥,过滤,真空除去溶剂。当除去约75%的溶剂时,沉淀出固体,通过过滤收集固体,并干燥,得到标题化合物,为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.92(1H,d),7.89(1H,d),7.59(1H,d),7.51(1H,d ofd),6.59(1H,d),6.09(2H,s),4.20(2H,q),2.41(3H,s),1.26(3H,t)。
步骤3:(E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酸
将(E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酸乙酯(8.75g,28.5mmol)置于带有EtOH(100mL)的烧瓶中。加入2M NaOH(57.1mL,114mmol),将该反应混合物在室温搅拌过夜。真空除去乙醇,将该反应混合物用2M HCl水溶液酸化。盐酸。通过过滤收集所得沉淀物,用水洗涤,并干燥,得到标题化合物,为白色固体。
LCMS:Rt 0.99min;MS m/z 279.2[M+H]+;方法2minLowpHv01
步骤4:(R,E)-4-(3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酰基)-3-甲基哌嗪-1-甲酸叔丁基酯
向在NMP(15mL)中的(E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酸(1.29g,4.63mmol)中加入HATU(2.112g,5.55mmol),将该混合物在室温搅拌5分钟。加入(R)-3-甲基哌嗪-1-甲酸叔丁基酯(0.927g,4.63mmol),然后加入DIPEA(1.617mL,9.26mmol),并将该反应混合物在室温搅拌2小时。将该反应混合物倒入水中,用EtOAc萃取。将有机部分用水、碳酸氢钠水溶液、水、盐水洗涤,并经相分离器干燥。减压除去溶剂。将粗产物经硅胶色谱使用0-100%在异己烷中的EtOAc梯度纯化,得到标题化合物。
LC-MS:Rt=1.23min;[M+H]+461.3,方法2minLowpH。
步骤5:(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮
向在DCM(22mL)中的(R,E)-4-(3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酰基)-3-甲基哌嗪-1-甲酸叔丁基酯(2.1g,4.56mmol)中加入TFA(4.21mL,54.7mmol),并将该混合物在室温搅拌4小时。减压除去溶剂。将得到的残余物加载到SCX-2柱上,先用MeOH、随后用MeOH中的2M NH3洗脱。将级分减压浓缩,得到标题化合物。
LC-MS:Rt=2.40min;[M+H]+=361.6,方法10minLowpH。
中间体B
(R,E)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮
步骤1:2-(2-溴-5-(三氟甲基)苄基)-5-甲基-2H-四唑
在10℃,N2下向5-甲基-2H-四唑(19.44g,231mmol)在DMF(154mL)中的搅拌溶液中加入K2CO3(42.6g,308mmol)。将所得混悬液冷却至-2℃(冰盐浴),并历经30分钟滴加1-溴-2-(溴甲基)-4-(三氟甲基)苯(49g,154mmol)在DMF(66mL)中的溶液,保持内部温度低于5℃。完全加入后,将该混合物温热至室温,并将所得白色混悬液搅拌过夜。将水(400mL)缓慢加入到该混合物中,然后将其用EtOAc(2×500mL)萃取。将合并的有机萃取物用盐水(500mL)洗涤,干燥(MgSO4),并在真空下浓缩,得到无色油状物。加入异己烷(150mL),过滤所得浆液,将固体用异己烷(2×50mL)洗涤。将滤液真空浓缩,得到无色油状物。经硅胶色谱用0-50%在异己烷中的EtOAc洗脱纯化,得到标题化合物。
LCMS:Rt 1.30min;MS m/z 321.3[M+H]+;方法2minLowpHv03
步骤2:(E)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙烯酸乙酯
向2-(2-溴-5-(三氟甲基)苄基)-5-甲基-2H-四唑(17g,52.9mmol)DMF(76mL)中的搅拌的溶液中加入三邻甲苯基膦(0.806g,2.65mmol)和三乙胺(14.76mL,106mmol)。通过将N2通入其中20分钟将该溶液除气。加入Pd(OAc)2(0.594g,2.65mmol)和丙烯酸乙酯(8.66mL,79mmol),并将该反应混合物在N2下加热至90℃。冷却至室温后,将该混合物在水(150mL)和EtOAc(250mL)之间分配。分离各相,并将水相用更多的EtOAc(250mL)萃取。将合并的有机层用盐水(2×250mL)洗涤,干燥(MgSO4),并真空浓缩,得到标题化合物,为橙色油状物。
LCMS:Rt 1.36min;MS m/z 341.5[M+H]+;方法2minLowpHv03
步骤3:(E)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙烯酸
向粗制的(E)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙烯酸乙酯(18.02g,假定为53.0mmol)在EtOH(212mL)中的搅拌的溶液中缓慢加入2M NaOH水溶液(79mL,159mmol)。将所得橙色溶液在室温搅拌过夜。将所得混合物真空浓缩至100ml体积,然后过滤。缓慢加入5M HCl(38mL)以将pH调节至2,随后固体开始从溶液中结晶出来。将该混合物在室温搅拌2小时以允许完全结晶。将所得浆液过滤,并将滤饼用50%EtOH水溶液(2×20mL)洗涤。将固体在40℃下真空干燥过夜,得到标题化合物。
LCMS:Rt 1.14min;MS m/z 313.4[M+H]+;方法2minLowpHv03
步骤4:(R,E)-3-甲基-4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙烯酰基)哌嗪-1-甲酸叔丁基酯
将在乙酸乙酯中的50%(4.5mL,7.7mmol)加入(E)-3-(4-(二氟甲基)-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酸(2g,6.41mmol)、(R)-3-甲基哌嗪-1-甲酸叔丁基酯(2.0g,6.4mmol)和TEA(3.6mL,25.6mmol)在DCM(20mL)中的溶液中,并将所得混合物在室温搅拌1小时。将该反应混合物用饱和的碳酸氢钠水溶液(100mL)稀释。将水溶液用乙酸乙酯(3×100mL)萃取。将合并的有机溶液用水(50mL)、盐水(50mL)洗涤,经硫酸钠干燥,过滤,并真空浓缩。经硅胶柱色谱用异己烷至乙酸乙酯的梯度洗脱纯化。将产物级分合并,并真空蒸发,得到白色固体。
LC MS:Rt 1.39min;[M-100+H]+395.3,方法2minLowpHv03
步骤5:(R,E)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮
将TFA(10mL)加入到(R,E)-2-(3-甲基-4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙烯酰基)哌嗪-1-基)乙酸叔丁基酯(2.7g,5.46mmol)在DCM(10mL)中的溶液中,并将所得混合物搅拌1小时。加入甲苯(100mL),并在真空下浓缩该反应混合物。将所得胶状物在乙醚(250mL)中搅拌,加入水(1mL),通过过滤收集所得固体,用乙醚洗涤,并真空干燥,得到标题化合物,为三氟乙酸盐。
LC MS:Rt 0.74min;[M+H]+395.0,397.5,方法2minLowpHv03
中间体C:
5-(2-(2-氟乙氧基)乙氧基)吡啶甲醛
步骤1:2-(2-((6-甲基吡啶-3-基)氧基)乙氧基)乙醇
将6-甲基吡啶-3-醇(1.5g,13.75mmol)、2-氯乙氧基乙醇(diethylene glycolmonochlorohydrin)(5.83mL,55.0mmol)、K2CO3(2.85g,20.62mmol)和NaI(0.11g,0.76mmol)在DMF(18.6mL)中的混悬液在氩气氛下在85℃下搅拌16小时。将该反应混合物冷却至室温,用EtOAc稀释,并用水洗涤两次。将水层用DCM/i-PrOH(4/1)萃取。将合并的有机层用盐水洗涤,用相分离器干燥,并浓缩。将合并的有机层干燥,并浓缩,得到粗产物,为紫色油状物,将其经快速色谱DCM/MeOH(100/0至90/10)纯化,得到5.0g棕色油状物。
LC MS:Rt 0.32min;[M+H]+198.1;2min最终分析
步骤2:4-甲基苯磺酸2-(2-((6-甲基吡啶-3-基)氧基)乙氧基)乙酯
向2-(2-((6-甲基吡啶-3-基)氧基)乙氧基)乙醇(2.35g,4.05mmol)在CH2Cl2(10mL)中的搅拌的溶液中缓慢加入对甲苯磺酰氯(1.87g,9.72mmol),然后在氩气下在0℃下加入三乙胺(2.82mL,20.26mmol)。将该反应混合物在室温搅拌16小时。将该反应混合物用CH2Cl2和水稀释。将有机层用盐水洗涤,用相分离器干燥,并浓缩,得到粗产物,为棕色油状物,将其经快速色谱(环己烷/EtOAc,从100/0至0/100)纯化,得到1.02g所需产物,为黄色油状物。
LC MS:Rt 0.85min;[M+H]+352.4;2min最终分析
步骤3:5-(2-(2-氟乙氧基)乙氧基)-2-甲基吡啶
向4-甲基苯磺酸2-(2-((6-甲基吡啶-3-基)氧基)乙氧基)乙酯(1.02g,2.48mmol)在THF(15.7mL)中的溶液中加入TBAF(1M,在THF中)(12.40mL,12.40mmol),并将得到的溶液在65℃搅拌30min。将溶剂蒸发,将残余物溶于EtOAc中,并用水洗涤。将水层用EtOAc萃取两次。将合并的有机层用盐水洗涤,在相分离器上干燥,并浓缩,得到粗产物,为棕色油状物,将其经快速色谱纯化(环己烷/EtOAc:100/0至0/100),得到标题化合物,为橙色油状物(465mg)。
1H NMR(400MHz,DMSO-d6)δppm 2.41(s,3H)3.64-3.72(m,1H)3.76-3.83(m,3H)4.16(dd,J=5.44,3.73Hz,2H)4.45-4.53(m,1H)4.61-4.64(m,1H)7.18(d,J=8.56Hz,1H)7.31(dd,J=8.50,3.00Hz,1H)8.17(d,J=2.93Hz,1H)
LC MS:Rt 0.44min;[M+H]+200.1;2min最终分析
步骤4:5-(2-(2-氟乙氧基)乙氧基)-2-甲基吡啶1-氧化物
在0℃向5-(2-(2-氟乙氧基)乙氧基)-2-甲基吡啶(465mg,2.1mmol)在CHCl3(10.6mL)中的溶液中加入间氯过苯甲酸(435mg,2.52mmol)。将所得混合物在0℃搅拌3h。将该反应混合液用包含的Na2CO3溶液淬灭,并用CH2Cl2萃取两次。将合并的有机层用盐水洗涤,在相分离器上干燥,并浓缩,得到562mg粗产物,为黄色油状物。
LC MS:Rt 0.48min;[M+H]+216.1;2min最终分析
步骤5:乙酸(5-(2-(2-氟乙氧基)乙氧基)吡啶-2-基)甲酯
在80℃向醋酸酐(2018μl,21.39mmol)中加入5-(2-(2-氟乙氧基)乙氧基)-2-甲基吡啶1-氧化物(562mg,1.645mmol)。将该反应混合液加热至130℃,并搅拌30min。将得到的混合物倾入冰水中,然后在室温搅拌15min。将产物用EtOAc萃取。将有机层用饱和的NaHCO3水溶液和盐水洗涤。将水层用EtOAc萃取。将合并的有机层在相分离器上干燥,并浓缩,得到粗产物,为棕色油状物,将其经快速色谱纯化(环己烷/EtOAc,100:0至60/40),得到352mg标题化合物,为黄色油状物。
LC MS:Rt 0.71min;[M+H]+258.1;2min最终分析
步骤6:(5-(2-(2-氟乙氧基)乙氧基)吡啶-2-基)甲醇
向乙酸(5-(2-(2-氟乙氧基)乙氧基)吡啶-2-基)甲酯(352mg,1.08mmol)在EtOH(4.7mL)和水(0.82mL)中的溶液中加入NaOH(86mg,2.16mmol)。将得到的反应混合物在回流下搅拌1h。将溶剂蒸发,并将残余物用EtOAc萃取两次。将合并的有机层在相分离器上干燥,并浓缩,得到282mg粗产物,为橙色油状物。
LC MS:Rt 0.43min;[M+H]+216.1;2min最终分析
步骤7:5-(2-(2-氟乙氧基)乙氧基)吡啶甲醛
向(5-(2-(2-氟乙氧基)乙氧基)吡啶-2-基)甲醇(282mg,1.05mmol)在CH2Cl2(4.0mL)中的溶液中加入MnO2(911mg,10.5mmol)。将得到的反应混合物在室温搅拌2天。将该反应混合液经Celite过滤,并用EtOAc洗涤三次。将滤液蒸发至干燥,得到185mg粗产物,为黄色油状物。
LC MS:Rt 0.65min;[M+H]+214.0;2min最终分析
中间体D
2-(氟甲基)噁唑-4-甲醛
步骤1:2-(氟甲基)噁唑-4-甲酸甲酯
在室温向2-(氯甲基)噁唑-4-甲酸甲酯(1.0g,5.70mmol)在CH3CN(28.5mL)中的溶液中加入TBAF(1M,在THF中)(17.09mL,17.09mmol)。将得到的绿色溶液在氩气下在室温搅拌21h。将该反应混合液倾入水中,并用EtOAc萃取两次。将合并的有机层用盐水洗涤,在相分离器上干燥,并浓缩,得到粗产物,为橙色油状物。将粗产物经制备型HPLC纯化(WatersSunFire C18ODB,5μm,30x100,洗脱液:1%MeCN/99%H2O至30%MeCN/70%H2O,20min,H2O包含0.1%TFA,流速40mL/min)。合并含有所需产物的级分,用EtOAc稀释,并用饱和的NaHCO3水溶液洗涤。将水层用EtOAc萃取。将合并的有机层用盐水洗涤,在相分离器上干燥,并浓缩,得到291mg白色固体。
1H NMR(400MHz,DMSO-d6)δppm 3.76(s,3H)5.43(s,1H)5.55(s,1H)8.91(d,J=1.34Hz,1H)
LC MS Rt 0.49min;[M+H]+160.0;2min最终分析
步骤2:(2-(氟甲基)噁唑-4-基)甲醇
在-78℃在氩气下向2-(氟甲基)噁唑-4-甲酸甲酯(291mg,1.46mmol)在THF(3.6mL)中的溶液中滴加DIBAL-H(1M,在THF中)(3.22mL,3.22mmol)。然后将该反应混合液在-78℃搅拌3h,并在室温搅拌16h。UPLC/MS显示剩余的原料,因此将该反应混合液冷却至-78℃,并在-78℃加入DIBAL-H(1M,在THF中)(3.22mL,3.22mmol),搅拌3h。将所得混合物在-78℃用CH2Cl2稀释,然后用MeOH/水/2M NaOH水溶液淬灭,并搅拌15min。在室温加入Na2SO4,并将该混悬液搅拌15min。通过过滤除去盐,并将滤液真空浓缩。将粗产物经快速色谱纯化(CH2Cl2/MeOH:100/0至95/5),得到标题化合物,为黄色油状物(79mg)。
1H NMR(400MHz,DMSO-d6)δppm 4.31-4.34(m,2H)5.32(s,1H)5.44(s,1H)7.84-8.03(m,1H)
LC MS Rt 0.32min;[M+H]+132.0;2min最终分析
步骤3:2-(氟甲基)噁唑-4-甲醛
向(2-(氟甲基)噁唑-4-基)甲醇(78mg,0.6mmol)在CH2Cl2(6mL)中的溶液中加入MnO2(517mg,5.95mmol)。将所得混合物在室温搅拌2天。将该反应混合液经Celite过滤,并用CH2Cl2洗涤三次。将滤液蒸发至干燥,得到32mg粗产物。将粗产物不经进一步纯化地用于下一步骤。
LC MS Rt 0.34min;[M+H]+130.0;2min最终分析
实施例的制备
实施例1:
(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮
步骤1:(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-羟基吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮
在0℃将(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮(中间体A)(3.0g,8.3mmol)在DCE(60mL)中的搅拌的溶液用5-羟基吡啶-2-甲醛(2.0g,16.6mmol)、三乙酰氧基硼氢化钠(3.5g,16.62mmol)和乙酸(0.95mL)处理。将所得混合物在室温搅拌17h。将溶剂蒸发,将水加入残余物中,并将水相用EtOAc萃取。将有机层用饱和的NaHCO3水溶液、盐水洗涤,经Na2SO4干燥,过滤,并减压浓缩。将残余物经硅胶快速色谱纯化。
HLPC Rt:5.7min(分析型HPLC)
步骤2:(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮
向(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-羟基吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮(1.5g,3.2mmol)在DMF(15mL)中的溶液中加入Cs2CO3(1.53g,4.8mmol),随后在N2下加入1-溴-2-氟乙烷(488mg,3.8mmol)。将该反应混合液在室温搅拌16h。将该反应混合液用水稀释,并将水溶液用乙酸乙酯萃取。将合并的有机溶液经硫酸钠干燥,过滤,并在真空下浓缩。将粗产物经制备型HPLC纯化。
1H NMR(400MHz,DMSO-d6,100℃)δppm 1.26-1.31(m,4H)2.09(d,J=3.26Hz,1H)2.24(dd,J=11.36,3.83Hz,1H)2.44(s,3H)2.72(d,J=11.29Hz,1H)2.82-2.90(m,1H)3.10-3.24(m,1H)3.52-3.65(m,2H)4.02-4.17(m,1H)4.29-4.34(m,1H)4.36-4.42(m,1H)4.46-4.58(m,1H)4.66-4.74(m,1H)4.78-4.86(m,1H)5.96(s,2H)7.03(d,J=15.43Hz,1H)7.42(d,J=1.76Hz,2H)7.44-7.51(m,2H)7.71(d,J=15.31Hz,1H)7.81(d,J=8.41Hz,1H)8.26(t,J=1.76Hz,1H)
LC MS:Rt 0.87min;[M+H]+514.1;2min最终分析
实施例2:
(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙-2-烯-1-酮
通过类似于实施例1的方法,但从(R,E)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮(中间体B)制备标题化合物。
1H NMR(400MHz,DMSO-d6,100℃)δppm 1.29(d,J=6.78Hz,3H)2.00-2.14(m,1H)2.21-2.29(m,1H)2.44(s,3H)2.66-2.76(m,1H)2.84-2.92(m,1H)3.12-3.25(m,1H)3.60(d,J=10.67Hz,2H)4.06-4.17(m,1H)4.28-4.34(m,1H)4.35-4.42(m,1H)4.45-4.58(m,1H)4.66-4.74(m,1H)4.78-4.87(m,1H)6.06(s,2H)7.11(d,J=15.43Hz,1H)7.42(d,J=1.88Hz,2H)7.77(d,J=5.65Hz,3H)7.92-8.04(m,1H)8.26(s,1H)
LC MS:Rt 0.92min;[M+H]+548.0;2min最终分析
实施例3:
(R)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙-1-酮
将(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙-2-烯-1-酮(46mg,0.084mmol)和Pd/C(10%)(5.72mg,5.38μmol)在EtOH(4.00mL)中的溶液在室温在氢气下搅拌18h。将该反应混合液经Celite过滤,并浓缩。将残余物溶于1mL MeOH中,并经制备型HPLC纯化(WatersSunFire C18ODB,5μm,30x100,洗脱液:5%MeCN/95%H2O至50%MeCN/50%H2O,20min,H2O包含0.1%TFA,流速40mL/min)。将含有产物的级分合并,并冻干过夜。将所得白色粉末用EtOAc稀释,并用饱和的NaHCO3溶液洗涤。将水层用EtOAc萃取,并将合并的有机层用盐水洗涤,通过相分离器干燥,浓缩,并真空干燥,得到标题化合物(22mg,47%)。
1H NMR(400MHz,DMSO-d6)δppm 1.16-1.22(m,3H)1.27-1.31(m,1H)1.92-2.13(m,2H)2.46(s,3H)2.55-2.85(m,4H)3.04-3.07(m,3H)3.48-3.62(m,2H)3.78-4.03(m,1H)4.28-4.41(m,2H)4.66-4.85(m,2H)5.96-6.08(m,2H)7.35-7.44(m,2H)7.53-7.71(m,3H)8.21-8.29(m,1H)
LC MS:Rt 0.89min;[M+H]+550.1;2min最终分析
实施例4:
(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-(2-氟乙氧基)乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮
向在MeOH(2.0mL)中的(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮(中间体A)(80mg,0.22mmol)中加入AcOH(0.2mL)和5-(2-(2-氟乙氧基)乙氧基)吡啶甲醛(中间体C)(93mg,0.33mmol)。搅拌5min后,加入2-甲基吡啶硼烷(44.2mg,0.35mmol)。将该反应混合液在室温搅拌20h。将挥发物蒸发,并将残余物经制备型HPLC纯化(Waters SunFire C18ODB,5μm,30x100,洗脱液:5%MeCN/95%H2O至50%MeCN/50%H2O,20min,H2O包含0.1%TFA,流速40mL/min)。将所需的级分浓缩。将残余物溶于EtOAc中,并用饱和的NaHCO3溶液洗涤。将水层用EtOAc萃取。将合并的有机层用盐水洗涤,在相分离器上干燥,并浓缩,得到63mg黄色油状物。
1H NMR(400MHz,DMSO-d6,100℃)δppm 1.28(d,J=6.78Hz,3H)2.01-2.15(m,1H)2.25(dd,J=11.48,3.07Hz,1H)2.44(s,3H)2.73(d,J=11.42Hz,1H)2.88(d,J=11.29Hz,1H)3.17(br。s.,1H)3.52-3.66(m,2H)3.70-3.76(m,1H)3.78-3.88(m,3H)4.12(d,J=12.55Hz,1H)4.18-4.28(m,2H)4.44-4.56(m,2H)4.57-4.65(m,1H)5.96(s,2H)7.03(d,J=15.31Hz,1H)7.40(d,J=1.76Hz,2H)7.44-7.51(m,2H)7.71(d,J=15.31Hz,1H)7.81(d,J=8.41Hz,1H)8.24(t,J=1.69Hz,1H)
LC MS Rt 0.87min;[M]+558.2,560.1;2min最终分析
实施例5:
(R,E)-1-(4-((5-(2-(2-氟乙氧基)乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙-2-烯-1-酮
通过类似于实施例4的方法,从(R,E)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮(中间体B)和5-(2-(2-氟乙氧基)乙氧基)吡啶甲醛(中间体C)制备标题化合物。
1H NMR(400MHz,DMSO-d6)δppm 1.29(d,J=6.65Hz,3H)2.09(td,J=11.67,3.14Hz,1H)2.24(dd,J=11.36,3.70Hz,1H)2.40-2.46(m,3H)2.72(d,J=11.29Hz,1H)2.88(d,J=11.17Hz,1H)3.12-3.27(m,1H)3.50-3.64(m,2H)3.70-3.75(m,1H)3.78-3.87(m,3H)4.12(d,J=13.80Hz,1H)4.19-4.26(m,2H)4.43-4.54(m,2H)4.57-4.65(m,1H)6.06(s,2H)7.11(d,J=15.43Hz,1H)7.40(d,J=1.13Hz,2H)7.69-7.84(m,3H)7.99(d,J=8.53Hz,1H)8.24(s,1H)
LC MS Rt 0.92min;[M+H]+592.2;2min最终分析
实施例6:
(R,E)-1-(4-((2-(氟甲基)噁唑-4-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙-2-烯-1-酮
通过类似于实施例4的方法,从(R,E)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮(中间体B)和2-(氟甲基)噁唑-4-甲醛(中间体D)制备标题化合物。
1H NMR(400MHz,DMSO-d6)δppm 1.27(d,J=6.97Hz,3H)2.05-2.11(m,1H)2.23-2.27(m,1H)2.44(s,3H)2.76-2.80(m,1H)2.90-2.95(m,1H)3.10-3.20(m,1H)3.5(s,2H)4.1(d,1H)4.5(s,1H)4.45(d,2H)6.06(s,2H)7.1(d,1H)7.70-7.80(m,4H)7.98-8.01(m,1H)
LC MS Rt 0.89min;[M+H]+508.3;2min最终分析
实施例7:(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-[18F]氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮
步骤1:(R,E)-4-甲基苯磺酸2-((6-((4-(3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酰基)-3-甲基哌嗪-1-基)甲基)吡啶-3-基)氧基)乙酯的合成
在氩气下在室温将Cs2CO3(446mg,1.37mmol)加入二对甲苯磺酸乙二醇酯(475mg,1.28mmol)在DMF(20mL)中的溶液中,随后历经1h的时间加入在DMF(20mL)中的(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-羟基吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮(200mg,0.43mmol)。将该反应混合液在室温搅拌2h。将该反应混合液用水稀释,并将水溶液用乙酸乙酯萃取。将合并的有机溶液干燥(相分离器),并浓缩。将粗产物经硅胶快速色谱纯化(环己烷/EtOAc 100:0至0:100),得到所需产物,为无色油状物(180mg,62%)。1H NMR(400MHz,300℃,DMSO-d6)δppm 1.12-1.27(m,3H),1.97(s,1H),2.11(s,1H),2.40(d,J=4.0Hz,6H),2.64(d,J=11.3Hz,1H)2.80(d,J=11.0Hz,1H),3.27(s,1H),3.44-3.59(m,2H),4.01(q,J=7.1Hz,1H),4.22(dd,J=5.3,2.8Hz,2H),4.34(dd,J=5.3,2.8Hz,2H),4.4(s,1H),6.03-5.91(m,2H),7.11(d,J=15.2Hz,1H),7.29(dd,J=8.6,2.9Hz,1H),7.35(d,J=8.6Hz,1H),7.43-7.51(m,4H),7.70(d,J=15.2Hz,1H),7.78(d,J=8.3Hz,2H),7.87(d,J=9.1Hz,1H),8.07(d,J=2.8Hz,1H);LC MS:Rt 1.06min;[M]+666.5;方法:2min最终分析。
步骤2:实施例7的合成
(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-[18F]氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮
在密封的反应小瓶中,将在无水DMSO中的[18F]KF/Kryptofix 222加入(R,E)-4-甲基苯磺酸2-((6-((4-(3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酰基)-3-甲基哌嗪-1-基)甲基)吡啶-3-基)氧基)乙酯中,并在140℃加热10分钟。将标记的产物经半制备型HPLC纯化(Phenomenex Luna C18(2),250x 10mm;洗脱液:CH3CN/H2O/NEt3(50/50/0.1);流速:4mL/min)。通过HPLC分析(Waters XBridge C18,150x 4.6mm;MeOH/H2O/NEt3(70/30/0.08),1mL/min),得到6.37分钟的保留时间。与冷参比HPLC迹线(6.28分钟)的比较证实产物为实施例7,其以8%的衰变校正的放射化学收率获得。
实施例8:(E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-((2R)-4-((5-(2-氟乙氧基-1,2-t2)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮
步骤1:[3H]2-4-(对甲苯基)苯磺酸2-氟乙基酯的合成:
将6.15mg(21.0μmol)(E)-4'-甲基-[1,1'-联苯]-4-磺酸2-氟乙烯基酯和7.07mg(8.78μmol;0.42当量)Crabtree催化剂(Strem 77-9500)溶于0.75mL二氯甲烷(Fluka66740)中。将该橙色溶液在高真空歧管脱气三次,并在室温在氚气体(8.7Ci)气氛下搅拌。溶剂仍然冷冻时的初始压力为347毫巴,而室温下的最大压力为962毫巴。真空除去溶剂,通过加入1mL甲醇(Fluka 65543)、搅拌溶液、并再次真空除去溶剂来交换不稳定的氚。该过程重复三次。最后,将干燥的固体用5mL THF萃取。粗产物活性为1003mCi(37.1GBq)。使用以下HPLC系统测定放射化学纯度(RCP)为:Macherey+Nagel Nucleodur Gravity C18(5μm,4.6x150mm);溶剂:A,10mM NH4OAc水溶液;B,MeCN;梯度:0min 40%B;10min 100%B;14.5min100%B;15min 40%B;在254nm检测;流速1.0ml/min;30℃。将粗产物不经进一步纯化用于下一步骤。
实施例8的合成:
将100mCi(3.7GBq)粗制的[3H]2-4-(对甲苯基)苯磺酸2-氟乙基酯(0.5ml,2.1μmol)蒸发至干燥,并加入3.04mg(6.5μmol;3.1当量)(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-羟基吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮在0.25ml DMF中的溶液。然后将该溶液用4.36mg(13.4μmol;6.4当量)碳酸铯处理,并在水浴中在50℃搅拌2.2h。通过HPLC的反应控制(上述条件)显示了标记的起始物质的定量转化,测定RCP为63%。将该反应混合液使用以下条件经HPLC纯化:Macherey+Nagel NucleodurGravity C18,5μm,8x 150mm;溶剂:A,10mM NH4OAc;B,MeCN;梯度:0min 48.5%B;8min48.5%B;8.5min 95%B;12.5min 95%B;13min 48.5%B.;在254nm和230nm测定;流速3.1ml/min;20℃。6.7分钟后洗脱所需化合物。
通过固相萃取从HPLC溶剂混合物中分离所需产物。在旋转蒸发器部分地降低级分的体积,并将产物用Phenomenex StrataX柱(3mL,100mg)萃取,将其用10mL乙醇洗脱。活性为40.5mCi(1.50GBq)的萃取产物显示>99%的RCP。测定比活性为38.5Ci/mmol(1.43BTq/mmol)。与冷参比HPLC迹线的比较证实了对产品的确认。HPLC条件:Macherey+NagelNucleodur Gravity C18,4.6x 150mm(5μm);流动相:A,10mM NH4OAc;B:MeCN;梯度:0min35%B;10min 95%B;14.5min 95%B;15min35%B;流速1.0mL/min。参考保留时间(UV检测):7.14分钟;产品保留时间(放射性检测):7.25分钟。UV和放射信号之间的延迟是由于串行检测系统。
1)(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-(2-[18F]氟乙氧基)乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮
可通过类似于化合物4的方法,从(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(2-甲基哌嗪-1-基)丙-2-烯-1-酮(中间体A)和4-甲基苯磺酸2-(2-((6-甲酰基吡啶-3-基)氧基)乙氧基)乙酯制备前体(R,E)-4-甲基苯磺酸2-(2-((6-((4-(3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酰基)-3-甲基哌嗪-1-基)甲基)吡啶-3-基)氧基)乙氧基)乙酯。
可通过在极性非质子溶剂如DMF、DMSO或CH3CN中,用[18F]KF/K222或[18F]TBAF处理(R,E)-4-甲基苯磺酸2-(2-((6-((4-(3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酰基)-3-甲基哌嗪-1-基)甲基)吡啶-3-基)氧基)乙氧基)乙酯来进行(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-(2-[18F]氟乙氧基)乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮的合成。
2)(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)[羰基-11C]丙-2-烯-1-酮的合成
在第一个步骤中,用于放射性标记的前体可以如下制备:
使用三乙酰氧基硼氢化钠和乙酸,进行5-羟基吡啶甲醛与(R)-2-甲基哌嗪-1-甲酸苄基酯的还原胺化可提供(R)-4-((5-羟基吡啶-2-基)甲基)-2-甲基哌嗪-1-甲酸苄基酯。该中间体可以在碱如碳酸钾存在下与甲苯磺酸2-氟乙酯进一步反应,然后使用钯碳和氢气进行氢化,得到(R)-1-((5-(2-氟乙氧基)吡啶-2-基)甲基)-3-甲基哌嗪。
(E)-2-(2-(2-溴乙烯基)-5-氯苄基)-5-甲基-2H-四唑可通过在N-溴琥珀酰亚胺和催化量的乙酸锂的存在下微波辐照(E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙烯酸来制备。可使用在THF中的镁将得到的芳基乙烯基溴转化为(E)-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯乙烯基)溴化镁。
可通过用[11C]CO2处理(E)-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯乙烯基)溴化镁来制备标题化合物,形成[11C]羧基卤化镁,然后将其转化为[11C]羧酸。然后将其转化成酰氯,并用(R)-1-((5-(2-氟乙氧基)吡啶-2-基)甲基)-3-甲基哌嗪处理,得到所需的酰胺。
3)(R)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-[18F](三氟甲基)苯基)丙-2-烯-1-酮
可根据与实施例1类似的方案,从5-甲基-2H-四唑和1-溴-2-(溴甲
基)-4-碘苯起始得到前体(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-碘-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮。
根据Huiban等人(Nature Chemistry,2013)报道的用于(杂)芳烃从[18F]氟化物的后期[18F]三氟甲基化的方案,该实施例描述了生成(R)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-[18F](三氟甲基)苯基)丙-2-烯-1-酮的可能的合成途径。[18F]CF3Cu可由氯二氟乙酸甲酯、CuI、TMEDA原位产生,且[18F]氟化物可与(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-碘-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮反应,得到标题化合物。
4)(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-(2-氟[3H2]乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮的合成
Cochrane等人(Journal of Labelled Compounds,2013,56,447-450)报道了[3H]4-甲基苯磺酸2-氟乙基酯的合成。通过在碱如碳酸铯的存在下用[3H]4-甲基苯磺酸2-氟乙基酯处理(R,E)-3-(4-氯-2-((5-甲基-2H-四唑-2-基)甲基)苯基)-1-(4-((5-羟基吡啶-2-基)甲基)-2-甲基哌嗪-1-基)丙-2-烯-1-酮,可得到标题化合物。
5)含[11C]CN-的实施例的合成,例如(R,E)-4-(3-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-氧代丙-1-烯-1-基)-3-((5-甲基-2H-四唑-2-基)甲基)苄腈
可通过钯介导的氰化反应将[11C]CN基团引入(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-异氰基-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮。可将[11C]HCN转化为[11C]CuCN,并通过Rosenmund–von Braun反应与(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-碘-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮反应。
6)[11C]OCH3实施例,例如(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-[11C]甲氧基-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮的合成
标题化合物的前体((R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-羟基-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮)可如下得到:根据实施例1给出的合成方案,使用从相应的醇制备的(3-溴-4-(溴甲基)苯氧基)三异丙基硅烷和5-甲基-2H-四唑,得到(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-((三异丙基硅烷基)氧基)苯基)丙-2-烯-1-酮,随后使用在THF中的TBAF对该酚脱保护可得到所需的前体。
在碱的存在下使用[11C]CH3I甲基化(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-羟基-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮可得到标题化合物。
7)含[123I]-、[124I]-或[131I]-的实施例,例如(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-[123I]碘-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮的合成
可通过在钯催化剂如Pd(PPh3)4的存在下将(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(4-碘-2-((5-甲基-2H-四唑-2-基)甲基)苯基)丙-2-烯-1-酮与双(三丁基锡)反应来制备锡烷前体:
在氧化剂如氯胺-T的存在下用[123I]NaI、[124I]NaI或[131I]NaI处理(R,E)-1-(4-((5-(2-氟乙氧基)吡啶-2-基)甲基)-2-甲基哌嗪-1-基)-3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三丁基甲锡烷基)苯基)丙-2-烯-1-酮,可得到标题化合物(*I=[123I]、[124I]或[131I])
生物学数据:
本文所述的化合物为ATX抑制剂,且可以在如下分析中进行测定。
试剂-LPC(油酰基(18:1))购自Avanti Polar Lipid(Alabaster,AL)并溶于甲醇中至20mM。Amplex Red获自Invitrogen Life Technologie(Paisley,UK)并溶于DMSO中至10mM。胆碱氧化酶和辣根过氧化物酶(HRP)获自Sigma Aldrich(Dorset,UK)并溶于HBSS分别至20U/ml和200U/ml。所有试剂于-20℃以单次使用等分试样进行储存。所有实验测定在临用前制备的测定缓冲液中进行(HBSS,0.01%BSA,基本不含脂肪酸)。
蛋白质-重组人ATX在诺华股份有限公司(Basel,CH)在人胚肾(HEK)细胞制备物中制备,于-80℃以26mg/ml(26μM)储备物的单次使用等分试样进行储存。
方法-所有实验测定应当在黑色384孔聚苯乙烯(低容量,圆底,Corning(3676))板中进行。使用PerkinElmer EnVision(荧光强度/吸收度单色仪)或Tecan Infinite 200PRO系列读板器来检测荧光强度的变化。
评价ATX抑制-ATX活性通过测定在含有ATX(10nM)、胆碱氧化酶(0.1U/ml)、HRP(100U/ml)、amplex red(50μM)和LPC 18:1(10μM)的反应物中释放的胆碱来确定。本发明的化合物应当被制备成从1μM开始的10点系列稀释液,一式两份,在加入其余试剂之前与ATX一起于37℃预温育20分钟。由在37℃每两分钟、历经40分钟时期产物resurofin的荧光强度(λex 530nm,λem 590nm)变化测定了所释放的胆碱。ATX活性作为进展曲线的线性部分的斜率来测定,通常在14至24分钟之间。
数据分析-斜率数据外推至Graphpad prism(Graphpad软件,San Diego,CA),其中数据拟合为等式1。
等式1:
Y=底+(顶-底)/(1+10^((LogIC50-X)*Hill斜率))
IC50值由降低总活性50%的本发明的化合物的浓度确定,表示n≥2的均值。
Claims (16)
1.通式(I)的化合物和/或其药学上可接受的盐,
其中
R是卤素、-CF3、-OCF3、-OCH3、-CH3或CN;且
A是吡啶基或噁唑基,其被至少一个选自卤代-(C1-6-烷基)、卤代-(C1-3-烷基)氧基(C2-4-烷基)或卤代-(C1-3-烷基)氧基(C2-4-烷基)氧基(C2-4-烷基)的取代基取代。
2.根据权利要求1的化合物,其含有3H。
3.根据权利要求1的化合物,其中R是-CF3或-OCF3。
4.根据权利要求3的化合物,其含有至少一个18F。
5.根据权利要求1的化合物,其中R是卤素。
6.根据权利要求5的化合物,其中R选自18F、19F、123I、124I、125I、127I或131I。
7.根据权利要求1的化合物,其中A包含18F、19F、123I、124I、125I、127I或131I中的至少一种。
8.根据权利要求1的化合物,其中编号为“1”的碳原子选自11C、12C或14C。
9.根据权利要求1的化合物和/或其药学上可接受的盐,所述化合物选自
10.根据权利要求9的化合物,其包含至少一个选自3H、18F、11C或14C的原子。
11.用于在确认有需要的个体中检测自分泌运动因子的方法,其包括:(i)将放射性标记的式(I)的化合物或其药学上可接受的盐施用于所述个体;和(ii)通过体内PET或SPECT成像来检测所述化合物的摄取。
12.施用结合自分泌运动因子的配体后,定量个体中的未结合的自分泌运动因子的百分比或百分比变化的方法,其包括:
(i)向所述个体施用放射性标记的依据权利要求1至10中任一项的化合物或其药学上可接受的盐;
(ii)通过体内PET或SPECT成像来检测在步骤(i)中施用的所述放射性标记的化合物的摄取;
(iii)允许经过合适的时间,使得步骤(i)中施用的化合物已经放射性衰变;
(iv)施用有效量的(a)非放射性标记的自分泌运动因子配体,或(b)影响自分泌运动因子底物的内源水平的非放射性标记的活性剂,并同时施用如步骤(i)中所定义的放射性标记的式(I)的化合物或其药学上可接受的盐;和
(v)通过体内PET或SPECT成像来检测在步骤(iv)中施用的所述式(I)的化合物的摄取。
13.权利要求12的方法,其中在步骤(iii)中允许经过的时间大于所述放射性同位素半衰期的4倍。
14.权利要求12的方法,其中在步骤(iii)中允许经过的时间是所述放射性同位素半衰期的至少6倍。
15.组合物,其包含至少一种根据权利要求1至10的化合物或其药学上可接受的盐。
16.根据权利要求15的组合物,其适用于PET成像。
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