CN116003402A - 一种三环类化合物、其中间体、制备方法和应用 - Google Patents
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Abstract
本发明提供一种三环类化合物、其中间体、制备方法和应用，具体地，提供一种如式I所示的化合物或其药学上可接受的盐；其中，M为O或NH，R1、R2、R3和R4中的一个为
其余三个为H，n为0、1或2；该化合物能够较好地与人类AD脑组织结合、对淀粉样蛋白显像，且可以作为正电子断层扫描剂，可用于对老年痴呆症的提前诊断，及对药物疗效的跟踪。
Description
技术领域
本发明涉及一种三环类化合物、其中间体、制备方法和应用。
背景技术
阿尔茨海默氏病(AD)是痴呆最常见的原因，其特点是逐步偿失认知功能和逐步増加行为障碍。这种渐进的，不可逆转的大脑功能紊乱影响了千百万人的生命，并在世界范围内造成一场毁灭性的健康负担。在过去二十年来，在破译的发病机制及开发新的治疗方法已取得重大进展。AD的病理特征包括β淀粉样蛋白的神经斑块和超磷酸化tau蛋白的神经纤维缠结。最近发展治疗AD药物的方向是控制淀粉蛋白的产生，聚集，和在大脑中的沉积,以及加速淀粉样蛋白从大脑中的代谢。
非侵入性检测淀粉样蛋白在大脑中的沉积已经被用来开发抗淀粉样蛋白的治疗方案。直接在AD患者体内对淀粉样蛋白显像对AD的早期诊断及治疗方案的制定和评估有用。为此，适用于在体内给人类大脑淀粉样蛋白沉积显像的化合物，已经进行了大规模的研发。在这些化合物中有针对Aβ的单克隆抗体，但这些都不被大脑吸收。含Aβ多肽-腐胺-钆的共合物注入Aβ淀粉样蛋白过度表达的转基因小鼠身上，已经在MRI上观察到鼠脑中淀粉样蛋白。淀粉样蛋白沉积，也可以用易于进入大脑的小分子，以非侵入性方式进行成影和定量分析。
用小分子给淀粉样蛋白成像是迄今最成功的方法。最有希望给淀粉样蛋白成像的一些化合物都是刚果红，硫黄素，二苯乙烯和FDDNP的衍生物。刚果红和硫黄素的衍生物已经用在AD病人脑组织切片和转基因小鼠脑组织切片的染色上。目前正在进行人体临床试验做F18的两个化合物是Eli Lilly公司的Florbetapir和GE公司的Flutemetamol。这两个成像剂都没有碳-11标记做的PIB所显示的动力学范围。
对AD症的有效管理方法就是，诊断，监测，治疗和预防这种疾病。
发明内容
本发明所要解决的技术问题是对淀粉样蛋白显像的现有显影剂种类较少，为此，本发明提供了一种三环类化合物、其中间体、制备方法和应用，该化合物能够对淀粉样蛋白显像，且可以作为正电子断层扫描剂，可用于对老年痴呆症的提前诊断，及对药物疗效的跟踪。
本发明提供了一种如式I所示的化合物或其药学上可接受的盐；
其中，M为O或NH，R1、R2、R3和R4中的一个为
其余三个为H，n为0、1或2。
在某一方案中，上述如式I所示的化合物或其药学上可接受的盐里，所述的如式I所示的化合物为如式I-a所示的化合物或如式I-b所示的化合物：
在某一方案中，上述如式I所示的化合物或其药学上可接受的盐里，所述
为
在某一方案中，上述如式I所示的化合物或其药学上可接受的盐里，所述的如式I所示的化合物的为：
在某一方案中，上述如式I所示的化合物或其药学上可接受的盐里，所述的如式I所示的化合物的为：
本发明还提供了一种上述的如式I所示的化合物或其药学上可接受的盐的制备方法，其包括下述步骤：溶剂中，将如式II所示的化合物与CsF进行反应，制备得到上述的如式I所示的化合物或其药学上可接受的盐即可；
R5、R6、R7和R8中的一个为
其余三个为H；S为Ts或不存在。
其中，所述的取代反应可为本领域此类反应的常规方法和条件。较佳地，所述溶剂优选为强极性非质子性溶剂，例如二氯甲烷或DMF。
本发明中，所述的如式I所示的化合物的制备方法，可采用下述反应任一路线进行：
或者，
其中，各基团的定义同前所述。本发明还提供了一种化合物或其药学上可接受的盐：
其中，各基团的定义同前所述。
本发明还提供了一种如式I所示化合物在制备体外组织的萤光显色剂上或治疗由超磷酸化淀粉样蛋白聚合引起的病症的药物中的应用。
本发明还提供了一种上述如式I所示化合物作为正电子断层扫描剂的应用。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
除特殊说明外，本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的化合物能够较好地与人类AD脑组织结合、对淀粉样蛋白显像，且可以作为正电子断层扫描剂，可用于对老年痴呆症的提前诊断，及对药物疗效的跟踪。
附图说明
图1第一排为AD病人组织切片使用放射性LL8显色，左上图同时使用非放射性的6-OH-BTA-1预先占位，AD病人脑组织切片在有1μM非放射性的6-OH-BTA-1(PIB)时的自显影。图中第二排左下为非AD病人、右下为AD病人，使用放射性LL8显色，不使用非放射性的6-OH-BTA-1占位，脑组织切片在没占位剂时的自显影。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1化合物X1-X3的制备
一般合成步骤:1.0毫摩尔
1.2当量NaH，用
作为溶剂，反应混合物加热至120摄氏度，搅拌直至反应完成。反应混合物在乙酸乙脂和饱和盐水中分离.有机溶剂相在硫酸镁中干燥。抽干溶剂，粗产品用硅胶柱分离。
化合物X1,1H NMR(400MHz；CDCl3),δ7.67(s,1H,Ar-H),7.54(d,3JHH＝8.6Hz,1H,Ar-H),6.88(d,3JHH＝8.6Hz,4JHH＝2.6Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.69(t,3JHH＝6.0Hz,2H)。
化合物X2,1H NMR(400MHz；CDCl3),δ7.75(s,1H,Ar-H),7.56(d,3JHH＝8.6Hz,1H,Ar-H),6.94(d,3JHH＝8.6Hz,4JHH＝2.6Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.77(t,3JHH＝6.0Hz,2H),3.54(t,3JHH＝6.0Hz,2H),3.70(t,3JHH＝6.0Hz,2H)。
化合物X3,1H NMR(400MHz；CDCl3),δ7.78(s,1H,Ar-H),7.59(d,3JHH＝8.6Hz,1H,Ar-H),6.97(d,3JHH＝8.6Hz,4JHH＝2.6Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.77(t,3JHH＝6.0Hz,2H),3.70(t,3JHH＝6.0Hz,2H),3.50-3.60(m,6H)。
实施例2化合物Y1-Y3系列的制备
化合物Y1-Y3的一般合成步骤:1.0毫摩尔底物X1-X3，1.2当量联硼酸频那醇酯，1.5当量碱(KOAc)，0.2当量1,1'-双二苯基膦二茂铁二氯化钯，5.0毫升乙腈，反应混合物加热至80摄氏度，搅拌直至反应完成，反应混合物在乙酸乙脂和饱和盐水中分离。有机溶剂相在硫酸镁中干燥，抽干溶剂，粗产品用硅胶柱分离。
化合物Y1,1H NMR(400MHz；CDCl3),δ7.65(d,3JHH＝8.6Hz,1H,Ar-H),7.46(s,1H,Ar-H),6.54(d,3JHH＝8.6Hz,4JHH＝2.6Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.69(t,3JHH＝6.0Hz,2H),1.20(s,12H)。
化合物Y2,1H NMR(400MHz；CDCl3),δ7.67(d,3JHH＝8.6Hz,1H,Ar-H),7.43(s,1H,Ar-H),6.58(d,3JHH＝8.6Hz,4JHH＝2.6Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.77(t,3JHH＝6.0Hz,2H),3.70(t,3JHH＝6.0Hz,2H),3.54(t,3JHH＝6.0Hz,2H),1.20(s,12H)。
化合物Y3,1H NMR(400MHz；CDCl3),δ7.68(d,3JHH＝8.6Hz,1H,Ar-H),7.45(s,1H,Ar-H),6.59(d,3JHH＝8.6Hz,4JHH＝2.6Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.78(t,3JHH＝6.0Hz,2H),3.70(t,3JHH＝6.0Hz,2H),3.50-3.60(m,6H),1.20(s,12H)。
实施例3化合物A4-A6系列的制备
化合物A4-A6的一般合成步骤:1.0毫摩尔
1.2当量3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-4-醇，0.2当量Pd(PPh3)4,1.2当量NaOH，5.0毫升THF/H2O，反应混合物加热至回流，搅拌直至反应完成。把反应混合物倒入冰水中，加乙酸调节pH至中性，在反应混合物加入乙酸乙脂和饱和盐水，进行分离。有机溶剂相在硫酸镁中干燥，抽干溶剂，粗产品直接使用。
化合物A4,1H NMR(400MHz；CDCl3),δ9.10(s,1H,Ar-H),8.10(d,3JHH＝9.0Hz,1H,Ar-H),7.40-7.70(m,4H,Ar-H),6.77(d,3JHH＝9.0Hz,1H,Ar-H)。
化合物A5,1H NMR(400MHz；CDCl3),δ9.11(s,1H,Ar-H),8.12(d,3JHH＝9.0Hz,1H,Ar-H),7.67(d,3JHH＝9.0Hz,1H,Ar-H),7.40-7.50(m,3H,Ar-H),6.79(d,3JHH＝9.0Hz,1H,Ar-H)。
化合物A6,1H NMR(400MHz；CDCl3),δ9.14(s,1H,Ar-H),8.11(d,3JHH＝9.0Hz,1H,Ar-H),7.50-7.60(m,4H,Ar-H),6.73(d,3JHH＝9.0Hz,1H,Ar-H).
实施例4化合物B4-B7系列的制备
化合物B4-B7的一般合成步骤:1.0毫摩尔底物A4-A6，3当量PhCO3tBu，0.2当量Pd(OAc)2，5.0毫升C6F6/1,3-dimethyl-2-imidazolidinone，反应混合物在室温下，搅拌一晚直至反应完成。反应混合物在乙酸乙脂和饱和盐水中分离。有机溶剂相在硫酸镁中干燥，抽干溶剂，粗产品用硅胶柱分离。
化合物B4,1H NMR(400MHz；CDCl3),δ9.52(s,1H,py-H),8.74(d,3JHH＝9.0Hz,1H,py-H),7.86(d,3JHH＝9.0Hz,1H,py-H),7.53(d,3JHH＝9.0Hz,1H,Ar-H),7.20-7.30(m,2H,Ar-H)。
化合物B5,1H NMR(400MHz；CDCl3),δ9.50(s,1H,py-H),8.75(d,3JHH＝9.0Hz,1H,py-H),8.06(s,1H,Ar-H),7.82(d,3JHH＝9.0Hz,1H,py-H),7.50(d,3JHH＝9.0Hz,1H,Ar-H),7.38(d,3JHH＝9.0Hz,1H,Ar-H)。
化合物B6,1H NMR(400MHz；CDCl3),δ9.51(s,1H,py-H),8.74(d,3JHH＝9.0Hz,1H,py-H),8.26(s,1H,Ar-H),7.82(d,3JHH＝9.0Hz,1H,py-H),7.71(d,3JHH＝9.0Hz,1H,Ar-H),7.30(d,3JHH＝9.0Hz,1H,Ar-H)。
化合物B7,1H NMR(400MHz；CDCl3),δ9.49(s,1H,py-H),8.74(d,3JHH＝9.0Hz,1H,py-H),7.92(d,3JHH＝9.0Hz,1H,Ar-H),7.84(d,3JHH＝9.0Hz,1H,py-H),7.36(d,3JHH＝9.0Hz,1H,Ar-H),7.21(t,3JHH＝8.8Hz,1H,Ar-H)。
实施例5化合物C4-E7系列的制备
化合物C4-E7的一般合成步骤:1.0毫摩尔底物B4-B7，1.2当量Y1-Y3，0.2当量Pd(PPh3)4，5.0毫升THF/H2O，反应混合物在120摄氏度下，搅拌一晚直至反应完成。反应混合物在乙酸乙脂和饱和盐水中分离.有机溶剂相在硫酸镁中干燥。抽干溶剂，粗产品用硅胶柱分离。
化合物C4,1H NMR(400MHz；CDCl3),δ9.50(s,1H,py-H),8.75(d,3JHH＝9.0Hz,1H,py-H),8.10(d,3JHH＝9.0Hz,1H,py-H),8.06(d,3JHH＝9.0Hz,1H,Ar-H),8.03(s,1H,Ar-H),7.82(d,3JHH＝9.0Hz,1H,Ar-H),7.70(d,3JHH＝9.0Hz,1H,Ar-H),7.60(t,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.69(t,3JHH＝6.0Hz,2H)。
化合物C5,1H NMR(400MHz；CDCl3),δ9.55(s,1H,py-H),8.71(d,3JHH＝9.0Hz,1H,py-H),8.10(d,3JHH＝9.0Hz,1H,py-H),8.03(s,1H,Ar-H),7.80-7.90(m,4H,3Ar-H+py-H),6.73(d,3JHH＝9.0Hz,1H,Ar-H),4.32(t,3JHH＝6.0Hz,2H),3.71(t,3JHH＝6.0Hz,2H)。
化合物C6,1H NMR(400MHz；CDCl3),δ9.51(s,1H,py-H),8.70(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,Ar-H+2py-H),7.70-7.90(m,3H,2Ar-H+1py-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.70(t,3JHH＝6.0Hz,2H)。
化合物C7,1H NMR(400MHz；CDCl3),δ9.48(s,1H,py-H),8.72(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,4H,2Ar-H+2py-H),7.86(d,3JHH＝9.0Hz,1H,Ar-H),7.50(t,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.72(t,3JHH＝6.0Hz,2H)。
化合物D4,1H NMR(400MHz；CDCl3),δ9.50(s,1H,py-H),8.75(d,3JHH＝9.0Hz,1H,py-H),8.10(d,3JHH＝9.0Hz,1H,py-H),8.06(d,3JHH＝9.0Hz,1H,Ar-H),8.03(s,1H,Ar-H),7.80-7.90(m,2H,Ar-H+py-H),7.70(d,3JHH＝9.0Hz,1H,Ar-H),7.57(t,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.54(t,3JHH＝6.0Hz,2H)。
化合物D5,1H NMR(400MHz；CDCl3),δ9.52(s,1H,py-H),8.71(d,3JHH＝9.0Hz,1H,py-H),8.10(d,3JHH＝9.0Hz,1H,py-H),8.06(d,3JHH＝9.0Hz,1H,Ar-H),8.02(s,1H,Ar-H),7.80-7.90(m,3H,2Ar-H+py-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.51(t,3JHH＝6.0Hz,2H)。
化合物D6,1H NMR(400MHz；CDCl3),δ9.53(s,1H,py-H),8.70(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,Ar-H+2py-H),7.80-7.90(m,3H,2Ar-H+py-H)，6.73(d，3JHH＝9.0Hz，1H，Ar-H)，4.32(t，3JHH＝6.0Hz，2H)，3.70-3.80(m,4H),3.50(t,3JHH＝6.0Hz,2H)。
化合物D7,1H NMR(400MHz；CDCl3),δ9.49(s,1H,py-H),8.73(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,4H,2Ar-H+2py-H),7.86(d,3JHH＝9.0Hz,1H,Ar-H),7.51(t,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.35(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.52(t,3JHH＝6.0Hz,2H)。
化合物E4,1H NMR(400MHz；CDCl3),δ9.55(s,1H,py-H),8.75(d,3JHH＝9.0Hz,1H,py-H),8.10(d,3JHH＝9.0Hz,1H,Ar-H),8.03(s,1H,py-H),7.80-7.90(m,2H,Ar-H+py-H),7.70(d,3JHH＝9.0Hz,1H,Ar-H),7.55(t,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H)。
化合物E5,1H NMR(400MHz；CDCl3),δ9.50(s,1H,py-H),8.71(d,3JHH＝9.0Hz,1H,py-H),8.11(d,3JHH＝9.0Hz,1H,Ar-H),8.00(s,1H,py-H),7.80-7.90(m,4H,3Ar-H+py-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.35(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H)。
化合物E6,1H NMR(400MHz；CDCl3),δ9.52(s,1H,py-H),8.70(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,Ar-H+2py-H),7.80-7.90(m,3H,2Ar-H+py-H),8.11(d,3JHH＝9.0Hz,1H,Ar-H),8.00(s,1H,py-H),7.80-7.90(m,4H,3Ar-H+py-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.32(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H)。
化合物E7,1H NMR(400MHz；CDCl3),δ9.49(s,1H,py-H),8.75(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,4H,2Ar-H+2py-H),7.86(d,3JHH＝9.0Hz,1H,py-H),7.50(t,3JHH＝9.0Hz,1H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.36(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H)。
实施例7化合物C8-E11系列的制备
化合物C8-E11的一般合成步骤:1.0毫摩尔底物B8-B11，1.2当量Y1-Y3，0.2当量Pd(PPh3)4，5.0毫升THF/H2O，反应混合物在120度下，搅拌一晚直至反应完成。反应混合物在乙酸乙脂和饱和盐水中分离。有机溶剂相在硫酸镁中干燥。抽干溶剂，粗产品用硅胶柱分离。
化合物C8,1H NMR(400MHz；CDCl3),δ9.34(s,1H,py-H),8.40(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,2py-H),7.90(d,3JHH＝9.0Hz,1H,py-H),7.71(d,3JHH＝9.0Hz,1H,Ar-H),7.50-7.60(m,2H,Ar-H+py-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.71(t,3JHH＝6.0Hz,2H)。
化合物C9,1H NMR(400MHz；CDCl3),δ9.35(s,1H,py-H),8.42(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.90(s,1H,py-H),7.77(d,3JHH＝9.0Hz,1H,Ar-H),7.45(d,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.73(t,3JHH＝6.0Hz,2H)。
化合物C10,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.40(d,3JHH＝9.0Hz,1H,py-H),8.31(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H+Ar-H),7.91(d,3JHH＝9.0Hz,1H,Ar-H),7.74(s,1H,Ar-H),7.45(d,3JHH＝9.0Hz,1H,Ar-H),6.68(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.68(t,3JHH＝6.0Hz,2H)。
化合物C11,1H NMR(400MHz；CDCl3),δ9.30(s,1H,py-H),8.37(d,3JHH＝9.0Hz,1H,py-H),8.29(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.40-7.50(m,2H,Ar-H+py-H),6.69(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.65(t,3JHH＝6.0Hz,2H)。
化合物D8,1H NMR(400MHz；CDCl3),δ9.30(s,1H,py-H),8.41(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,2py-H),7.90(d,3JHH＝9.0Hz,1H,py-H),7.71(d,3JHH＝9.0Hz,1H,Ar-H),7.50-7.60(m,2H,Ar-H+py-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.29(t,3JHH＝6.0Hz,2H),3.67(t,3JHH＝6.0Hz,2H)。
化合物D9,1H NMR(400MHz；CDCl3),δ9.35(s,1H,py-H),8.43(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.90(s,1H,py-H),7.77(d,3JHH＝9.0Hz,1H,Ar-H),7.50-7.60(m,2H,Ar-H+py-H),7.46(d,3JHH＝9.0Hz,1H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.52(t,3JHH＝6.0Hz,2H)。
化合物D10,1H NMR(400MHz；CDCl3),δ9.30(s,1H,py-H),8.41(d,3JHH＝9.0Hz,1H,py-H),8.31(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,2py-H),7.90(d,3JHH＝9.0Hz,1H,py-H),7.74(s,1H,Ar-H),7.45(d,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50(t,3JHH＝6.0Hz,2H)。
化合物D11,1H NMR(400MHz；CDCl3),δ9.28(s,1H,py-H),8.39(d,3JHH＝9.0Hz,1H,py-H),8.28(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.40-7.50(m,2H,py-H+Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.52(t,3JHH＝6.0Hz,2H)。
化合物E8,1H NMR(400MHz；CDCl3),δ9.32(s,1H,py-H),8.45(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H+Ar-H),7.91(d,3JHH＝9.0Hz,1H,Ar-H),7.71(d,3JHH＝9.0Hz,1H,Ar-H),7.56(t,3JHH＝9.0Hz,1H,Ar-H),7.45(d,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.32(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H)。
化合物E9,1H NMR(400MHz；CDCl3),δ9.34(s,1H,py-H),8.41(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.89(s,1H,Ar-H),7.77(d,3JHH＝9.0Hz,1H,Ar-H),7.45(d,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H)。
化合物E10,1H NMR(400MHz；CDCl3),δ9.30(s,1H,py-H),8.39(d,3JHH＝9.0Hz,1H,py-H),8.31(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,2py-H),7.91(d,3JHH＝9.0Hz,1H,Ar-H),7.74(s,1H,Ar-H),7.45(d,3JHH＝9.0Hz,1H,Ar-H),6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.35(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H)。
化合物E11,1H NMR(400MHz；CDCl3),δ9.35(s,1H,py-H),8.38(d,3JHH＝9.0Hz,1H,py-H),8.27(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.40-7.50(m,2H,py-H+Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H)。
实施例8化合物F4-H7系列(化合物II)的制备
化合物F4-H7的一般合成步骤:1.0毫摩尔化合物C4-E7，1.2当量Ts-Cl，3.0当量Et3N，5.0毫升CH2Cl2，反应混合物在常温下，搅拌一晚直至反应完成。反应混合物在乙酸乙脂和饱和盐水中分离。有机溶剂相在硫酸镁中干燥。抽干溶剂，粗产品用硅胶柱分离。
化合物F4,1H NMR(400MHz；CDCl3),δ9.51(s,1H,py-H),8.78(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,5H,py-H+4Ar-H),7.57(t,1H,3JHH＝9.0Hz,py-H),7.45(d,3JHH＝9.0Hz,2H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.96(t,3JHH＝6.0Hz,2H),2.44(s,3H,CH3)。
化合物F5,1H NMR(400MHz；CDCl3),δ9.48(s,1H,py-H),8.70(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,5H,py-H+4Ar-H),7.45(d,3JHH＝9.0Hz,2H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.34(t,3JHH＝6.0Hz,2H),3.92(t,3JHH＝6.0Hz,2H),2.45(s,3H,CH3)。
化合物F6,1H NMR(400MHz；CDCl3),δ9.53(s,1H,py-H),8.71(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.70-7.90(m,5H,py-H+4Ar-H),7.45(d,3JHH＝9.0Hz,2H,Ar-H),6.75(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.93(t,3JHH＝6.0Hz,2H),2.43(s,3H,CH3)。
化合物F7,1H NMR(400MHz；CDCl3),δ9.50(s,1H,py-H),8.69(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.86(d,3JHH＝9.0Hz,1H,Ar-H),7.75(d,3JHH＝9.0Hz,2H,Ar-H),7.40-7.50(m,3H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.34(t,3JHH＝6.0Hz,2H),3.95(t,3JHH＝6.0Hz,2H),2.44(s,3H,CH3)。
化合物G4,1H NMR(400MHz；CDCl3),δ9.49(s,1H,py-H),8.71(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,5H,py-H+4Ar-H),7.54(t,1H,3JHH＝9.0Hz,py-H),7.43(d,3JHH＝9.0Hz,2H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50(t,3JHH＝6.0Hz,2H),2.43(s,3H,CH3)。
化合物G5,1H NMR(400MHz；CDCl3),δ9.55(s,1H,py-H),8.74(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,6H,py-H+5Ar-H),7.45(d,3JHH＝9.0Hz,2H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.52(t,3JHH＝6.0Hz,2H),2.44(s,3H,CH3)。
化合物G6,1H NMR(400MHz；CDCl3),δ9.51(s,1H,py-H),8.69(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.70-7.90(m,5H,py-H+4Ar-H),7.43(d,3JHH＝9.0Hz,2H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.34(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50(t,3JHH＝6.0Hz,2H),2.42(s,3H,CH3)。
化合物G7,1H NMR(400MHz；CDCl3),δ9.51(s,1H,py-H),8.75(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.86(d,3JHH＝9.0Hz,1H,Ar-H),7.71(d,3JHH＝9.0Hz,2H,Ar-H),7.40-7.50(m,3H,Ar-H),6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.51(t,3JHH＝6.0Hz,2H),2.44(s,3H,CH3)。
化合物H4,1H NMR(400MHz；CDCl3),δ9.53(s,1H,py-H),8.75(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,5H,py-H+4Ar-H),7.58(t,1H,3JHH＝9.0Hz,py-H),7.45(d,3JHH＝9.0Hz,2H,Ar-H),6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.34(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.44(s,3H,CH3)。
化合物H5,1H NMR(400MHz；CDCl3),δ9.51(s,1H,py-H),8.69(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,6H,py-H+5Ar-H),7.44(d,3JHH＝9.0Hz,2H,Ar-H),6.73(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.43(s,3H,CH3)。
化合物H6,1H NMR(400MHz；CDCl3),δ9.54(s,1H,py-H),8.75(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.70-7.90(m,5H,py-H+4Ar-H),7.45(d,3JHH＝9.0Hz,2H,Ar-H),6.73(d,3JHH＝9.0Hz,1H,Ar-H),4.35(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.44(s,3H,CH3)。
化合物H7,1H NMR(400MHz；CDCl3),δ9.53(s,1H,py-H),8.71(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.84(d,3JHH＝9.0Hz,1H,Ar-H),7.73(d,3JHH＝9.0Hz,2H,Ar-H),7.40-7.50(m,3H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.43(s,3H,CH3)。
实施例9化合物F8-H11系列(化合物II)的制备
化合物F8-H11的一般合成步骤:1.0毫摩尔化合物C8-E11，2.4当量Ts-Cl，5.0当量Et3N，5.0毫升CH2Cl2，反应混合物在常温下，搅拌一晚直至反应完成。反应混合物在乙酸乙脂和饱和盐水中分离。有机溶剂相在硫酸镁中干燥。抽干溶剂，粗产品用硅胶柱分离。
化合物F8,1H NMR(400MHz；CDCl3),δ9.32(s,1H,py-H),8.35(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.75(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,6H,py-H+5Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.33(t,3JHH＝6.0Hz,2H),3.91(t,3JHH＝6.0Hz,2H),2.44(s,6H,CH3)。
化合物F9,1H NMR(400MHz；CDCl3),δ9.35(s,1H,py-H),8.30-8.40(m,3H,py-H+2Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.73(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,5H,py-H+4Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.95(t,3JHH＝6.0Hz,2H),2.43(s,6H,CH3)。
化合物F10,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.62(d,3JHH＝9.0Hz,1H,Ar-H),8.34(d,3JHH＝9.0Hz,1H,Ar-H),8.21(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.15(m,3H,2py-H+Ar-H),7.74(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,5H,py-H+4Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.34(t,3JHH＝6.0Hz,2H),3.91(t,3JHH＝6.0Hz,2H),2.44(s,6H,CH3)。
化合物F11,1H NMR(400MHz；CDCl3),δ9.34(s,1H,py-H),8.62(d,3JHH＝9.0Hz,1H,Ar-H),8.30-8.40(m,2H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.76(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,6H,py-H+5Ar-H),6.72(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.89(t,3JHH＝6.0Hz,2H),2.43(s,6H,CH3)。
化合物G8,1H NMR(400MHz；CDCl3),δ9.35(s,1H,py-H),8.31(d,3JHH＝9.0Hz,1H,py-H),8.11(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.74(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,6H,py-H+5Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.52(t,3JHH＝6.0Hz,2H),2.42(s,6H,CH3)。
化合物G9,1H NMR(400MHz；CDCl3),δ9.32(s,1H,py-H),8.30-8.40(m,3H,py-H+2Ar-H),8.00-8.15(m,3H,2py-H+Ar-H),7.74(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,5H,py-H+4Ar-H),6.73(d,3JHH＝9.0Hz,1H,Ar-H),4.29(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.52(t,3JHH＝6.0Hz,2H),2.42(s,6H,CH3)。
化合物G10,1H NMR(400MHz；CDCl3),δ9.33(s,1H,py-H),8.60(d,3JHH＝9.0Hz,1H,Ar-H),8.32(d,3JHH＝9.0Hz,1H,Ar-H),8.22(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.15(m,3H,2py-H+Ar-H),7.74(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,5H,py-H+4Ar-H),6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.28(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.54(t,3JHH＝6.0Hz,2H),2.43(s,6H,CH3)。
化合物G11,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.66(d,3JHH＝9.0Hz,1H,Ar-H),8.30-8.40(m,2H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.74(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,6H,py-H+5Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.29(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.52(t,3JHH＝6.0Hz,2H),2.42(s,6H,CH3)。
化合物H8,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.30(d,3JHH＝9.0Hz,1H,py-H),8.10(d,3JHH＝9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H)，7.73(d，3JHH＝9.0Hz，4H，Ar-H)，7.40-7.50(m， 6H，py-H+5Ar-H)，6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.32(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.44(s,6H,CH3)。
化合物H9,1H NMR(400MHz；CDCl3),δ9.34(s,1H,py-H),8.30-8.40(m,3H,py-H+2Ar-H),8.00-8.15(m,3H,2py-H+Ar-H),7.76(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,5H,py-H+4Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.30(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.43(s,6H,CH3)。
化合物H10,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.63(d,3JHH＝9.0Hz,1H,Ar-H),8.29(d,3JHH＝9.0Hz,1H,Ar-H),8.21(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.15(m,3H,2py-H+Ar-H),7.76(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,5H,py-H+4Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.31(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.42(s,6H,CH3)。
化合物H11,1H NMR(400MHz；CDCl3),δ9.34(s,1H,py-H),8.61(d,3JHH＝9.0Hz,1H,Ar-H),8.30-8.40(m,2H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.76(d,3JHH＝9.0Hz,4H,Ar-H),7.40-7.50(m,6H,py-H+5Ar-H),6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.35(t,3JHH＝6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.42(s,6H,CH3)。
实施例10化合物L4-LLL7系列(化合物I)的制备
化合物L4-LLL7的一般合成步骤:1.0毫摩尔化合物F4-H7，1.5当量CsF，溶于5毫升DMF，反应混合物在120度下，搅拌一晚直至反应完成。反应混合物在乙酸乙脂和饱和盐水中分离。有机溶剂相在硫酸镁中干燥。抽干溶剂，粗产品用硅胶柱分离。
化合物L4,1H NMR(400MHz；CDCl3),δ9.52(s,1H,py-H),8.70(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.80-7.90(m,2H,py-H+Ar-H),7.70(d,3JHH＝9.0Hz,4H,Ar-H),7.57(t,3JHH＝9.0Hz,1H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.51(dt,2JHF＝46Hz,3JHH＝7.1Hz,2H),4.12(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物L5,1H NMR(400MHz；CDCl3),δ9.49(s,1H,py-H),8.72(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.80-7.90(m,4H,2py-H+2Ar-H),7.70(d,3JHH＝9.0Hz,4H,Ar-H),7.57(t,3JHH＝9.0Hz,1H,Ar-H),6.73(d,3JHH＝9.0Hz,1H,Ar-H),4.49(dt,2JHF＝46Hz,3JHH＝7.1Hz,2H),4.17(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物L6,1H NMR(400MHz；CDCl3),δ9.52(s,1H,py-H),8.70(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.80-7.90(m,3H,py-H+2Ar-H),6.75(d,3JHH＝9.0Hz,1H,Ar-H),4.53(dt,2JHF＝46Hz,3JHH＝7.1Hz,2H),4.21(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物L7,1H NMR(400MHz；CDCl3),δ9.55(s,1H,py-H),8.72(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.86(d,3JHH＝9.0Hz,1H,Ar-H),7.51(t,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.55(dt,2JHF＝46Hz,3JHH＝7.1Hz,2H),4.11(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LL4,1H NMR(400MHz；CDCl3),δ9.49(s,1H,py-H),8.72(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.80-7.90(m,2H,py-H+Ar-H),7.71(d,3JHH＝9.0Hz,4H,Ar-H),7.55(t,3JHH＝9.0Hz,1H,Ar-H),6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.77(t,3JHH＝7.1Hz,2H),3.54(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LL5,1H NMR(400MHz；CDCl3),δ9.54(s,1H,py-H),8.70(d,3JHH＝9.0Hz，1H，Ar-H)，8.00-8.10(m，2H，py-H+Ar-H)，7.80-7.90(m，4H，py-H+3Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.81(t,3JHH＝7.1Hz,2H),3.50(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LL6,1H NMR(400MHz；CDCl3),δ9.50(s,1H,py-H),8.68(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.80-7.90(m,3H,py-H+2Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.71(t,3JHH＝7.1Hz,2H),3.49(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LL7,1H NMR(400MHz；CDCl3),δ9.50(s,1H,py-H),8.69(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.84(d,3JHH＝9.0Hz,1H,Ar-H),7.54(t,3JHH＝9.0Hz,1H,Ar-H),6.76(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.75(t,3JHH＝7.1Hz,2H),3.59(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LLL4,1H NMR(400MHz；CDCl3),δ9.53(s,1H,py-H),8.76(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.80-7.90(m,2H,py-H+Ar-H),7.65(d,3JHH＝9.0Hz,4H,Ar-H),7.54(t,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.79(t,3JHH＝7.1Hz,2H),3.50-3.60(m,6H)。
化合物LLL5,1H NMR(400MHz；CDCl3),δ9.50(s,1H,py-H),8.72(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.80-7.90(m,4H,py-H+3Ar-H),6.73(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.72(t,3JHH＝7.1Hz,2H),3.50-3.60(m,6H)。
化合物LLL6,1H NMR(400MHz；CDCl3),δ9.53(s,1H,py-H),8.78(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.80-7.90(m,3H,py-H+2Ar-H),6.75(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.81(t,3JHH＝7.1Hz,2H),3.50-3.60(m,6H)。
化合物LLL7,1H NMR(400MHz；CDCl3),δ9.55(s,1H,py-H),8.74(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.85(d,3JHH＝9.0Hz,1H,Ar-H),7.51(t,3JHH＝9.0Hz,1H,Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.75(t,3JHH＝7.1Hz,2H),3.50-3.60(m,6H)。
实施例11化合物L8-LLL11系列(化合物I)的制备
化合物L8-LLL11的一般合成步骤:1.0毫摩尔化合物F8-H11，3.0当量CsF，溶于5毫升DMF，反应混合物在120摄氏度下，搅拌一晚直至反应完成.反应混合物在乙酸乙脂和饱和盐水中分离.有机溶剂相在硫酸镁中干燥.抽干溶剂，粗产品用硅胶柱分离.
化合物L8,1H NMR(400MHz；CDCl3),δ9.32(s,1H,py-H),8.40(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.91(d,3JHH＝9.0Hz,4H,Ar-H),7.72(d,3JHH＝9.0Hz,4H,Ar-H),7.50-7.60(m,2H,py-H+Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.55(dt,2JHF＝46Hz,3JHH＝7.1Hz,2H),4.22(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物L9,1H NMR(400MHz；CDCl3),δ9.30(s,1H,py-H),8.37(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.75(d,3JHH＝9.0Hz,4H,Ar-H),7.45(d,3JHH＝9.0Hz,4H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.47(dt,2JHF＝46Hz,3JHH＝7.1Hz,2H),4.16(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物L10,1H NMR(400MHz；CDCl3),δ9.36(s,1H,py-H),8.47(d,3JHH＝9.0Hz,1H,Ar-H),8.33(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.90(d,3JHH＝9.0Hz,4H,Ar-H),7.74(s,1H,Ar-H),7.45(d,3JHH＝9.0Hz,4H,Ar-H),6.73(d,3JHH＝9.0Hz,1H,Ar-H),4.57(dt,2JHF＝46Hz,3JHH＝7.1Hz,2H),4.26(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物L11,1H NMR(400MHz；CDCl3),δ9.34(s,1H,py-H),8.37(d,3JHH＝9.0Hz,1H,Ar-H),8.28(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.40-7.50(m,2H,py-H+Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.50(dt,2JHF＝46Hz,3JHH＝7.1Hz,2H),4.16(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LL8,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.29(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.90(d,3JHH＝9.0Hz,4H,Ar-H),7.71(d,3JHH＝9.0Hz,4H,Ar-H),7.50-7.60(m,2H,py-H+Ar-H),6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.75(t,3JHH＝7.1Hz,2H),3.55(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LL9,1H NMR(400MHz；CDCl3),δ9.30(s,1H,py-H),8.37(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.89(s,1H,Ar-H),7.75(d,3JHH＝9.0Hz,4H,Ar-H),7.45(d,3JHH＝9.0Hz,4H,Ar-H),6.69(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.79(t,3JHH＝7.1Hz,2H),3.53(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LL10,1H NMR(400MHz；CDCl3),δ9.33(s,1H,py-H),8.42(d,3JHH＝9.0Hz,1H,Ar-H),8.31(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.89(d,3JHH＝9.0Hz,4H,Ar-H),7.72(s,1H,Ar-H),7.42(d,3JHH＝9.0Hz,4H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.71(t,3JHH＝7.1Hz,2H),3.55(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LL11,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.30(d,3JHH＝9.0Hz,1H,Ar-H),8.24(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.40-7.50(m,2H,py-H+Ar-H),6.74(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.76(t,3JHH＝7.1Hz,2H),3.51(dt,3JHF＝25Hz,3JHH＝7.1Hz,2H)。
化合物LLL8,1H NMR(400MHz；CDCl3),δ9.35(s,1H,py-H),8.33(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.89(d,3JHH＝9.0Hz,4H,Ar-H),7.68(d,3JHH＝9.0Hz,4H,Ar-H),7.55(t,3JHH＝9.0Hz,1H,Ar-H),7.45(t,3JHH＝9.0Hz,1H,Ar-H),6.70(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.75(t,3JHH＝7.1Hz,2H),3.50-3.60(m,6H)。
化合物LLL9,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.47(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.85(s,1H,Ar-H),7.75(d,3JHH＝9.0Hz,4H,Ar-H),7.43(d,3JHH＝9.0Hz,4H,Ar-H),6.75(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.76(t,3JHH＝7.1Hz,2H),3.50-3.60(m,6H)。
化合物LLL10,1H NMR(400MHz；CDCl3),δ9.31(s,1H,py-H),8.32(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.75-7.85(m,3H,py-H+2Ar-H),6.72(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.74(t,3JHH＝7.1Hz,2H),3.50-3.60(m,6H)。
化合物LLL11,1H NMR(400MHz；CDCl3),δ9.34(s,1H,py-H),8.34(d,3JHH＝9.0Hz,1H,Ar-H),8.22(d,3JHH＝9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.40-7.50(m,2H,py-H+Ar-H),6.71(d,3JHH＝9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.79(t,3JHH＝7.1Hz,2H),3.50-3.60(m,6H)。
效果实施例1
体外结合实验
人类AD脑组织匀浆在1:500PBS中，在每个试管中使用800μL。[3H]BTA-1(氚标BTA-1)浓度用乙醇从1mCi/毫升原液稀释到1μCi/100微升。进一步稀释至2.7×10-2μCi/100μL，每管中使用100μL。"冷"的6-OH-BTA-1或其他待测化合物(如本发明的化合物I)溶于二甲亚砜中，得到1×10-3M溶液，用二甲亚砜配制1×10-4至1×10-10M溶液，每管中使用10μL。组装后，涡旋试管，并在37摄氏度下反应2小时。使用细胞收集器分离，用含10％乙醇的PBS洗涤滤纸。将滤纸放入4毫升塑料瓶，加入2mL闪烁液。对样品进行计数。使用GraphPad对数据进行分析，从而得到结合常数。
本发明的化合物I的结合常数Ki列于表1：
表1
| 化合物 | X/n | cLogD7.4 | Ki(nM) |
| L4 | O/0 | 2.5 | 2.8 |
| L5 | O/0 | 2.5 | 5.5 |
| L6 | O/0 | 2.5 | 7.7 |
| L7 | O/0 | 2.5 | 12 |
| LL4 | O/1 | 2.3 | 1.2 |
| LL5 | O/1 | 2.3 | 4.1 |
| LL6 | O/1 | 2.3 | 5.7 |
| LL7 | O/1 | 2.3 | 8.3 |
| LLL4 | O/2 | 2.2 | 1.2 |
| LLL5 | O/2 | 2.2 | 3.9 |
| LLL6 | O/2 | 2.2 | 6.0 |
| LLL7 | O/2 | 2.2 | 8.7 |
| L8 | NH/0 | 2.4 | 2.8 |
| L9 | NH/0 | 2.4 | 5.2 |
| L10 | NH/0 | 2.4 | 7.5 |
| L11 | NH/0 | 2.4 | 13 |
| LL8 | NH/1 | 2.3 | 0.8 |
| LL9 | NH/1 | 2.3 | 3.5 |
| LL10 | NH/1 | 2.3 | 4.7 |
| LL11 | NH/1 | 2.3 | 7.3 |
| LLL8 | NH/2 | 2.1 | 1.0 |
| LLL9 | NH/2 | 2.1 | 4.5 |
| LLL10 | NH/2 | 2.2 | 4.9 |
| LLL11 | NH/2 | 2.1 | 9.1 |
| [3H]BTA-1 | 37 |
效果实施例2
人类AD病人脑组织切片的自显影研究结果，结果见图1。图中第―排为AD病人组织切片使用放射性LL8显色，左上图同时使用非放射性的6-OH-BTA-1预先占位，AD病人脑组织切片在有1μM非放射性的6-OH-BTA-1(PIB)时的自显影。图中第二排左下为非AD病人、右下为AD病人，使用放射性LL8显色，不使用非放射性的6-OH-BTA-1占位，脑组织切片在没占位剂时的自显影。
从图1上可以看出，放射性标记分子LL8清楚地显示大脑皮层中淀粉样蛋白沉积的斑点。显影点在用6-OH-BTA-1预处理后，不再显影。因此，放射性标记分子LL8能够对淀粉样蛋白沉积的特征性显影。
结论
本发明描述了新一类放射性标记化合物的合成，放射性标记。这类放射性标记化合物在AD病人脑切片上显示特征吸收，是一种良好的显影剂，有望为老年性痴呆症的早期诊断提供灵敏的分子探针。
Claims (10)
1.一种如式I所示的三环类化合物或其药学上可接受的盐；
其中，M为O或NH，R1、R2、R3和R4中的一个为
其余三个为H，n为0、1或2。
2.如权利要求1所述如式I所示的三环类化合物或其药学上可接受的盐，其特征在于，所述如式I所示的三环类化合物为如式I-a所示的化合物或如式I-b所示的化合物：
3.如权利要求1所述如式I所示的三环类化合物或其药学上可接受的盐，其特征在于，所述
为
4.如权利要求1所述如式I所示的三环类化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的三环类化合物为：
5.如权利要求1所述如式I所示的三环类化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的三环类化合物为：
6.一种如权利要求1～5所述如式I所示的三环类化合物或其药学上可接受的盐的制备方法，其包括下述步骤：溶剂中，将如式II所示的化合物与CsF进行反应，制备得到如式I所示的化合物即可；
R5、R6、R7和R8中的一个为
其余三个为H；S为Ts或不存在。
7.如权利要求6所示的制备方法，其特征在于，所述溶剂为强极性非质子性溶剂，例如二氯甲烷或DMF；
和/或，所述的如式I所示的化合物的制备方法，可采用下述反应任一路线进行：
或者，
8.一种化合物或其药学上可接受的盐：
9.一种如权利要求1～5所述如式I所示的三环类化合物或其药学上可接受的盐在制备体外组织的萤光显色剂上或治疗由超磷酸化淀粉样蛋白聚合引起的病症的药物中的应用。
10.一种如权利要求1～5所述如式I所示的三环类化合物或其药学上可接受的盐作为正电子断层扫描剂的应用。
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