CN114394947A - 一种恶嗪类近红外荧光染料及其制备方法和应用 - Google Patents
一种恶嗪类近红外荧光染料及其制备方法和应用 Download PDFInfo
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/38—[b, e]-condensed with two six-membered rings
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Abstract
本发明公开了一种恶嗪类近红外荧光染料及其制备方法和应用，该恶嗪类近红外荧光染料包含如式I所示化合物，其中，X选自环烷基。该恶嗪类近红外荧光染料在静脉注射后靶向神经，表现出较高的信号背景比，同时能够实现快速和长期的神经可视化，具备一定的临床应用前景，用于荧光引导外科手术来减少术中神经损伤。
Description
技术领域
本发明涉及一种荧光染料及其制法和应用，具体为一种恶嗪类近红外荧光染料及其制备方法和应用。
背景技术
外科手术仍然是许多疾病和损伤的最有效的治疗选择，全世界每年进行超过3亿例外科手术。外科手术的最终目标是通过保留神经和血管等重要结构来移除或修复组织，同时最大限度地减少并发症。医源性神经损伤是最令人恐惧的外科并发症之一，其引起的慢性神经疾病限制了患者的生活质量，增加了医疗费用。
虽然外科技术和设备有所进步，但由于在外科手术中解剖结构的变化以及直接观察神经的能力有限，因此在术中很难识别和保留神经。目前，肌电图、超声波、光学相干断层扫描和共聚焦显微内镜检查已被用于帮助术中神经识别。然而，这些技术缺乏特异性、分辨率和宽视场成像功能，使得实时神经检测变得困难。因此，能够在术中对神经组织进行广泛、实时识别的成像方式将极大地有利于外科医生对神经的保护，降低医源性神经损伤的发生率，提高患者术后的生活质量。
荧光引导手术(FGS)通过增强术中特定组织的可视化，有效地将术前成像和手术指导联系起来，具有革新手术的潜力。荧光引导手术非常适合帮助保护重要的神经结构。目前，已经发现了八类神经特异性荧光团，包括二苯乙烯衍生物、二苯乙烯基苯(DSB)、香豆素衍生物、苯乙烯基吡啶(FM)、三碳菁、神经特异性多肽、钠通道选择性多肽和恶嗪类荧光团。然而，所有的神经特异性造影剂都受到非特异性组织摄取较高的困扰。
其中，恶嗪类荧光团是在可见波长发射的神经特异性衍生物，具有较强的荧光信号和结构多样性。但是，如何对取代基进行修饰能够进一步提升恶嗪荧光团的神经特异性是科研人员需要研究的问题。
发明内容
发明目的：本发明的目的在于提供一种恶嗪类近红外荧光染料，其具有神经靶向性。本发明还有一个目的是提供所述恶嗪类近红外荧光染料的制备方法。本发明还有一个目的是提供所述恶嗪类近红外荧光染料在制备光学影像诊断试剂中应用。
技术方案：本发明所述的恶嗪类近红外荧光染料，包含如式I所示化合物：
其中，X选自环烷基。
所述的恶嗪类近红外荧光染料，所述化合物具有神经特异性。
所述的恶嗪类近红外荧光染料，所述化合物选自如式I-1、I-2、I-3或I-4所示的化合物：
化合物I-1以下简称为YQN-3，化合物I-2以下简称为YQN-4，化合物I-3以下简称为YQN-5，化合物I-4以下简称为YQN-6。
所述恶嗪类近红外荧光染料的制备方法，具体包括以下步骤：
组合物，包含所述的恶嗪类近红外荧光染料。
所述的恶嗪类近红外荧光染料在制备光学影像诊断试剂中应用。
所述的恶嗪类近红外荧光染料在制备神经可视化试剂中应用。
所述的恶嗪类近红外荧光染料在制备外科手术中神经可视化试剂中应用。
所述的恶嗪类近红外荧光染料在制备荧光引导外科手术中神经可视化试剂中应用。
有益效果：本发明与现有技术相比，具有如下优点：本发明在恶嗪类染料Oxazine4的结构基础上进行修饰，在氮原子上引入环丙基、环丁基、环戊基、环己基，在不改关键基团和溶解性的情况下，以期改善恶嗪类染料对神经的特异性。研究过程中，本发明关键性问题在于提高恶嗪类近红外荧光染料对神经的特异性。
附图说明
图1是YQN-3的图谱；A为质谱图，B为核磁氢谱图；
图2是YQN-4的图谱；A为质谱图，B为核磁氢谱图；
图3是YQN-5的图谱；A为质谱图，B为核磁氢谱图；
图4是YQN-6的图谱；A为质谱图，B为核磁氢谱图；
图5是Oxazine4、YQN-3、YQN-4的光谱性质，依次是图A、B、C；
图6是Oxazine4、YQN-3、YQN-4的坐骨神经及臂丛神经显像，图A为坐骨神经显像，图B为臂丛神经显像。
具体实施方式
以下结合实施例对本发明做进一步详细说明。所用试剂或者仪器设备未注明生产厂商的，均视为可以通过市场购买的常规产品。本发明化合物的反应路线图如下：
实施例1
YQN-3(即化合物I-1)的合成
1.取间溴苯甲醚1.50g，环丙胺0.73g，叔丁醇钾1.36g，四(三苯基膦)钯0.05g在甲苯(8ml)中于80℃加热回流8h。反应结束后，将溶液旋干，剩余固体柱层析纯化，可得到棕色油状液体N-环丙基-3-甲氧基苯胺。m/z：164.14。
2.取N-环丙基-3-甲氧基苯胺200mg溶解在2M冰冷的稀盐酸溶液(5ml)中，将亚硝酸钠103mg加入到溶液中，同时溶液温度保持在5℃以下。加毕，再搅拌溶液2h，然后将其滴入饱和碳酸钾溶液中，用乙酸乙酯萃取，用无水硫酸钠干燥有机层，旋干得黄绿色固体N-环丙基-3-甲氧基-4-亚硝基苯胺。m/z：192.09。
3.在80℃下，将间羟基-N.N-二乙基苯胺86mg溶解在i-PrOH/H2O(9∶1，4ml)中30min。将N-环丙基-3-甲氧基-4-亚硝基苯胺100mg和高氯酸(70％，47μl)在i-PrOH/H2O(9∶1，4ml)中的悬浮液加入到上述溶液中。然后将所得混合物搅拌8h。在此期间，反应混合物的颜色由棕色变为绿色，最后变为深蓝色。然后用无水硫酸钠除去混合物中的水，旋干后，剩余固体柱层析纯化，得深蓝色固体YQN-3。其质谱和核磁氢谱如图1所示，具体数据如下：m/z：308.22，1H NMR(400MHz，DMSO-d6)δ9.53(s，1H)，7.80(d，J＝9.6Hz，1H)，7.73(d，J＝8.9Hz，1H)，7.43(dd，J＝9.7，2.7Hz，1H)，7.11(d，J＝9.1Hz，1H)，7.04(d，J＝2.7Hz，1H)，6.98(t，J＝2.4Hz，1H)，3.76(q，J＝7.1Hz，4H)，2.89(tq，J＝7.2，3.6Hz，1H)，1.26(t，J＝7.1Hz，6H)，0.97(dt，J＝6.9，3.4Hz，2H)，0.76-0.64(m，2H).
实施例2
YQN-4(即化合物I-2)的合成
YQN-4的合成参照实施例1。其质谱和核磁氢谱如图2所示，具体数据如下：m/z：322.21，1H NMR(400MHz，DMSO-d6)δ9.67(d，J＝6.4Hz，1H)，7.79(d，J＝9.4Hz，1H)，7.73(d，J＝9.3Hz，1H)，7.46-7.31(m，1H)，7.15(d，J＝9.3Hz，1H)，6.97(s，1H)，6.67(s，1H)，4.43-4.25(m，1H)，3.74(q，J＝7.1Hz，4H)，2.47(d，J＝9.3Hz，2H)，2.09(p，J＝9.6Hz，2H)，1.84(q，J＝8.6Hz，2H)，1.25(t，J＝7.0Hz，6H).
实施例3
YQN-5(即化合物I-3)的合成
YQN-5的合成参照实施例1。其质谱和核磁氢谱如图3所示，具体数据如下：m/z：336.22，1H NMR(400MHz，DMSO)δ9.31(s，1H)，7.79(d，J＝9.5Hz，1H)，7.72(d，J＝9.4Hz，1H)，7.37(d，J＝8.6Hz，1H)，7.17(d，J＝10.0Hz，1H)，7.11-6.96(m，1H)，6.95(d，J＝16.1Hz，1H)，3.73(dd，J＝14.0，6.9Hz，4H)，1.95(d，J＝9.9Hz，2H)，1.76(d，J＝13.2Hz，2H)，1.64(d，J＝13.7Hz，1H)，1.36(dt，J＝22.3，11.5Hz，4H)，1.23(t，J＝7.0Hz，6H).
实施例4
YQN-6(即化合物I-4)的合成
YQN-6的合成参照实施例1。其质谱和核磁氢谱如图4所示，具体数据如下：m/z：350.24，1H NMR(400MHz，DMSO)δ9.39(s，1H)，7.80(d，J＝9.1Hz，1H)，7.73(d，J＝9.3Hz，1H)，7.39(d，J＝9.0Hz，1H)，7.17(d，J＝9.1Hz，1H)，6.97(s，1H)，6.85(s，1H)，4.19(s，2H)，3.74(dd，J＝13.8，6.8Hz，4H)，2.67(s，1H)，2.33(s，1H)，2.08(d，J＝6.8Hz，2H)，1.74(s，1H)，1.63(s，3H)，1.29-1.19(m，6H)，1.08(d，J＝6.9Hz，1H).
实施例5
Oxazine4、YQN-3、YQN-4对大鼠坐骨神经与臂丛神经成像效果的对比
为了考察Oxazine4、YQN-3、YQN-4与神经特异性结合的能力，通过近红外荧光成像技术，实时监测恶嗪Oxazine4、YQN-3、YQN-4在大鼠坐骨神经与臂丛神经部位的结合效果。实验过程中采用620nm激发，接受信号选取670nm波段(成像设备采用的是美国珀金埃尔默公司的IVIS Lumia III)，Oxazine4、YQN-3、YQN-4在该波段下的图谱如图5所示。各染料按Oxazine42mg/kg给药，给药方式为尾静脉给药。
实验结果显示，从SD大鼠坐骨神经和臂丛神经4、6、10小时成像图见图6，可见，Oxazine4、YQN-3、YQN-4在4-10小时内均与坐骨神经和臂丛神经结合产生较强的荧光。其中，YQN-3、YQN-4均显示出比Oxazine4更高的神经特异性，非神经组织对染料的摄取较小，而YQN-3的神经特异性最好。
Claims (9)
1.一种恶嗪类近红外荧光染料，其特征在于，包含如式I所示化合物：
其中，X选自环烷基。
2.根据权利要求1所述的恶嗪类近红外荧光染料，其特征在于，所述化合物具有神经特异性。
3.根据权利要求1所述的恶嗪类近红外荧光染料，其特征在于，所述化合物选自如式I-1、I-2、I-3或I-4所示的化合物：
4.一种权利要求1所述恶嗪类近红外荧光染料的制备方法，其特征在于，具体包括以下步骤：
5.一种组合物，其特征在于，包含权利要求1所述的恶嗪类近红外荧光染料。
6.权利要求1或3所述的恶嗪类近红外荧光染料在制备光学影像诊断试剂中应用。
7.权利要求1或3所述的恶嗪类近红外荧光染料在制备神经可视化试剂中应用。
8.权利要求1或3所述的恶嗪类近红外荧光染料在制备外科手术中神经可视化试剂中应用。
9.权利要求1或3所述的恶嗪类近红外荧光染料在制备荧光引导外科手术中神经可视化试剂中应用。
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