CN113845439B - 双苄酰胺类cxcr4拮抗剂及其制备和应用 - Google Patents

双苄酰胺类cxcr4拮抗剂及其制备和应用 Download PDF

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CN113845439B
CN113845439B CN202111180420.9A CN202111180420A CN113845439B CN 113845439 B CN113845439 B CN 113845439B CN 202111180420 A CN202111180420 A CN 202111180420A CN 113845439 B CN113845439 B CN 113845439B
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CN113845439A (zh
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白仁仁
谢恬
叶向阳
蒋筱莹
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Hangzhou Normal University
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Abstract

本发明公开了双苄酰胺类CXCR4拮抗剂及其制备方法和在制备抗炎、抗肿瘤、通过拮抗CXCR4靶点来防治相关疾病的药物中的应用。双苄酰胺类CXCR4拮抗剂为具有如下通式(I)或(II)的化合物和/或及其可药用盐：

Description

双苄酰胺类CXCR4拮抗剂及其制备和应用
技术领域
本发明涉及药物化学领域，具体涉及双苄酰胺类CXCR4拮抗剂及其制备和应用。
背景技术
趋化因子是一类具有诱导细胞定向迁移作用的小细胞因子或信号蛋白，通过与G蛋白偶联受体相互作用而发挥生物学效应。
趋化因子受体CXCR4是一种七次跨膜G-蛋白偶联受体，首次在外周血白细胞中发现，并在多种细胞类型中高表达，包括淋巴细胞、内皮细胞、上皮细胞、造血干细胞、间质成纤维细胞和癌细胞。此外，CXCR4在神经发生、生殖细胞发育、心脏发生和血管形成等大量生理过程中也发挥着关键作用。
CXCR4主要与趋化因子配体CXCL12特异性结合，CXCL12和CXCR4之间的相互作用会将细胞动员到CXCL12高表达的器官部位，触发下游通路，从而诱导炎症、动员干细胞、促进癌细胞转移等。
基于CXCR4在多种细胞中的高表达以及CXCR4-CXCL12轴在炎症、感染、肿瘤等疾病的病理机制中发挥的关键作用，CXCR4拮抗剂的开发为炎症、自身免疫疾病、感染或癌症转移的治疗提供了新的方向和途径。众多小分子CXCR4拮抗剂已经被研究和报道，并证明了其具有抗炎活性和抑制癌症转移的能力，如公开号为CN 103282360 A、CN 108602829 A的专利说明书等。
发明内容
本发明基于前期研究基础，进一步进行结构优化，设计合成了苯环间位和对位取代的双苄酰胺类衍生物及其药学上可接受的盐，对CXCR4表现出优异的拮抗活性，可应用于制备抗炎、抗肿瘤、通过拮抗CXCR4靶点来治疗感染、自身免疫疾病或其它疾病药物。
本发明基于受体和配体的药物设计、药效团的拼接和融合原理、合理药物设计和类药性等原则设计合成了具有双苄酰胺结构的新型CXCR4拮抗剂。
双苄酰胺类CXCR4拮抗剂，为具有如下通式(I)或(II)的化合物和/或及其可药用盐：
式(I)、(II)中：
R1、R2、R3、R4分别独立选自有取代或无取代的C1-C8直链或支链烷基、 其中：
X1、Y1、Z1分别独立选自H、CH3、F、Cl、Br、I、CF3、CN、NH2、NO2、OH、OCH3、CH(CH3)2、C(CH3)3、N(CH3)2。
优选地，式(I)、(II)中：
R1、R2、R3、R4分别独立选自CH3、CH2CH3、CH2CH2CH3、
在一优选例中，所述的双苄酰胺类CXCR4拮抗剂为具有如下结构的化合物Ia～Iy、IIa～IIx和/或及其可药用盐：
本发明还提供了所述的双苄酰胺类CXCR4拮抗剂的制备方法。
1、所述双苄酰胺类CXCR4拮抗剂为具有如下通式(I)的化合物，其制备方法包括：
将化合物3和碱性物质溶于第一有机溶剂中，在-15～5℃(优选-5～0℃)下反应5～20min(优选5～10min)，将化合物1、化合物2溶于第二有机溶剂后置于恒压滴液漏斗中，滴加完毕后经后处理得到式(I)化合物；
2、所述双苄酰胺类CXCR4拮抗剂为具有如下通式(II)的化合物，其制备方法包括：
将化合物4、化合物5、缩合剂、催化剂溶于第三有机溶剂中，在10～40℃(优选20～30℃)下反应0.2～2h(优选0.5～1h)，将化合物6溶于第四有机溶剂后置于恒压滴液漏斗中，滴加完毕后经后处理得到式(II)化合物；
第一有机溶剂、第二有机溶剂、第三有机溶剂、第四有机溶剂分别独立选自丙酮、二氯甲烷、氯仿、四氯化碳、乙腈、甲苯、二甲基亚砜、二氧六环、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或两者以上任意比例的混合溶剂，优选为二氯甲烷、四氢呋喃或N,N-二甲基甲酰胺。
在一优选例中，第一有机溶剂、第二有机溶剂用量之和以化合物3的物质的量计为2～5mL/mmol；
在一优选例中，第三有机溶剂、第四有机溶剂用量之和以化合物6的物质的量计为2～5mL/mmol。
式(I)化合物的制备方法中，可优选采用以下技术方案：
化合物1和化合物2的物质的量之和与化合物3、碱性物质的物质的量之比为2～6:1:2～6，优选为2.2～3:1:3～4；
所述碱性物质为碳酸钾、氢氧化钾、氢氧化钠、碳酸钠、碳酸氢钠、三乙胺、吡啶、二异丙基乙胺中的一种或两者以上任意比例的混合物，优选为三乙胺、碳酸钾或二异丙基乙胺；
所述的后处理方法为：反应结束后，抽滤得固体，固体用甲醇溶解，再加入乙醚重结晶得到式(I)化合物，甲醇和乙醚体积比为1:4。
式(II)化合物的制备方法中，可优选采用以下技术方案：
化合物4和化合物5的物质的量之和与缩合剂、催化剂、化合物6的物质的量之比为1:1～6:0.01～0.2:0.2～1，优选为1:1.2～3.5:0.05～0.1:0.3～0.5；
所述缩合剂为二环己基碳二亚胺(DCC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)、N,N’-二异丙基碳二亚胺(DIC)、羰基二咪唑(CDI)、四甲基脲六氟磷酸酯(HATU)、四甲基脲四氟硼酸酯(TBTU)中的一种，优选为DCC或EDCI；
所述催化剂为羟基苯并三氮唑(HOBT)、二甲氨基吡啶(DMAP)、4-吡咯烷基吡啶(4-PPy)中的一种，优选为HOBT或DMAP；
所述的后处理方法为：反应结束后，反应液减压浓缩，进行硅胶柱层析，以体积比为100:1的二氯甲烷/甲醇混合液为洗脱剂，分离得到式(II)化合物。
本发明式(I)、式(II)化合物可通过本领域常规方法成盐，例如：在最后一步后处理方法的重结晶过程中加入盐酸、氢溴酸、三氟乙酸、枸橼酸等常用羧酸使其成盐。
本发明还提供了所述的双苄酰胺类CXCR4拮抗剂在制备抗炎、抗肿瘤、通过拮抗CXCR4靶点来防治相关疾病的药物中的应用。
本发明与现有技术相比，主要优点包括：本发明采用简便高效的一步法合成了一系列新型的双苄酰胺类CXCR4拮抗剂，具有抗肿瘤、抗炎、抗感染、抗自身免疫等多种药理活性，在众多疾病中具有广泛的应用优势。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的操作方法，通常按照常规条件，或按照制造厂商所建议的条件。
实施例1 N,N'-1,3-双苄-二丙酰胺的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将丙酰氯(1.11g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率96％。
1H NMR(400MHz,DMSO-d6)δ8.27(t,J＝6.0Hz,2H),7.09-7.27(m,4H),4.23(d,J＝6.0Hz,4H),2.13(q,J＝7.6Hz,4H),1.02(t,J＝7.6Hz,6H)；13C NMR(100MHz,DMSO-d6)δ172.79,139.77,128.19,125.90,125.55,41.89,28.48,9.99；ESI-HRMS:m/z calcd forC14H21O2N2 249.15975[M+H]+,found 249.15942.
实施例2 N,N'-1,3-双苄-二丁酰胺的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将丁酰氯(1.28g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率95％。
1H NMR(400MHz,DMSO-d6)δ8.30(t,J＝6.0Hz,2H),7.09-7.27(m,4H),4.23(d,J＝6.0Hz,4H),2.10(t,J＝7.4Hz,4H),1.54(h,J＝7.4Hz,4H),0.86(t,J＝7.4Hz,6H)；13C NMR(100MHz,DMSO-d6)δ171.89,139.78,128.17,125.88,125.50,41.88,37.30,18.71,13.68；ESI-HRMS:m/z calcd for C16H25O2N2 277.19105[M+H]+,found 277.19061.
实施例3 N,N'-1,3-双苄-二(2-甲基丙酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将异丁酰氯(1.28g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率93％。
1H NMR(400MHz,DMSO-d6)δ8.27(t,J＝6.0Hz,2H),7.25(t,J＝8.0Hz,1H),7.09(s,1H),7.08(s,2H),4.22(d,J＝6.0Hz,4H),2.41(hept,J＝6.8Hz,2H),1.03(s,6H),1.02(s,6H)；13C NMR(100MHz,DMSO-d6)δ175.98,139.87,128.17,125.57,125.35,45.38,33.98,19.60；ESI-HRMS:m/z calcd for C16H25O2N2 277.19105[M+H]+,found 277.19057.
实施例4 N,N'-1,3-双苄-二苯甲酰胺的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将苯甲酰氯(1.68g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率95％。
1H NMR(400MHz,DMSO-d6)δ9.09(t,J＝6.0Hz,2H),7.86-7.88(m,4H),7.51-7.55(m,2H),7.43-7.47(m,4H),7.19-7.30(m,4H),4.46(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ166.16,139.79,134.37,131.16,128.26,128.20,127.21,125.84,125.63,42.53；ESI-HRMS:m/z calcd for C22H21O2N2 345.15975[M+H]+,found 345.15916.
实施例5 N,N'-1,3-双苄-二(2-甲基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将2-甲基苯甲酰氯(1.85g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率97％。
1H NMR(400MHz,DMSO-d6)δ8.82(t,J＝6.0Hz,2H),7.30-7.38(m,6H),7.19-7.24(m,6H),4.44(d,J＝6.0Hz,4H),2.33(s,6H)；13C NMR(100MHz,DMSO-d6)δ169.05,139.77,136.97,135.29,130.46,129.30,128.30,127.06,125.78,125.59,125.49,42.31,19.51；ESI-HRMS:m/z calcd for C24H25O2N2 373.19022[M+H]+,found 373.19045.
实施例6 N,N'-1,3-双苄-二(3-甲基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将3-甲基苯甲酰氯(1.85g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率95％。
1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝6.0Hz,2H),7.64-7.70(m,4H),7.18-7.34(m,8H),4.45(d,J＝6.0Hz,4H),2.34(s,6H)；13C NMR(100MHz,DMSO-d6)δ166.26,139.81,137.51,134.37,131.71,128.20,128.15,127.79,125.91,125.64,124.35,42.54,20.94；ESI-HRMS:m/z calcd for C24H15O2N2 373.19105[M+H]+,found 373.19074.
实施例7 N,N'-1,3-双苄-二(4-甲基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将4-甲基苯甲酰氯(1.85g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率96％。
1H NMR(400MHz,DMSO-d6)δ8.97(t,J＝6.0Hz,2H),7.76(d,J＝8.2Hz,4H),7.17-7.29(m,8H),4.44(d,J＝6.0Hz,4H),2.35(s,6H)；13C NMR(100MHz,DMSO-d6)δ166.04,140.99,139.87,131.58,128.78,128.18,127.23,125.82,125.60,42.48,20.95；ESI-HRMS:m/z calcd for C24H25O2N2 373.19105[M+H]+,found 373.19054.
实施例8 N,N'-1,3-双苄-二(2-甲氧基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将2-甲氧基苯甲酰氯(2.05g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ8.69(t,J＝6.0Hz,2H),7.73(dd,J＝7.8,1.8Hz,2H),7.47(ddd,J＝8.2,7.4,2.0Hz,2H),7.28-7.31(m,2H),7.21(d,J＝7.4,2H),7.12(d,J＝8.4Hz,2H),7.01(td,J＝7.4,1.0Hz,2H),4.49(d,J＝6.0Hz,4H),3.85(s,6H)；13C NMR(100MHz,DMSO-d6)δ165.11,139.74,132.11,130.33,128.21,125.52,125.39,123.20,120.42,111.94,55.79,42.54；ESI-HRMS:m/z calcd for C24H25O4N2 405.18088[M+H]+,found 405.18024.
实施例9 N,N'-1,3-双苄-二(3-甲氧基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将3-甲氧基苯甲酰氯(2.05g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率92％。
1H NMR(400MHz,DMSO-d6)δ9.08(t,J＝6.0Hz,2H),7.42-7.47(m,4H),7.35(t,J＝8.0Hz,2H),7.18-7.30(m,4H),7.09(dd,J＝2.6,1.0Hz,1H),7.07(dd,J＝2.6,1.0Hz,1H),4.45(d,J＝6.0Hz,4H),3.78(s,6H)；13C NMR(100MHz,DMSO-d6)δ165.86,159.14,139.76,135.76,129.38,128.22,125.93,125.68,119.46,117.09,112.32,55.22,42.57；ESI-HRMS:m/z calcd for C24H25O4N2 405.18088[M+H]+,found 405.18186.
实施例10 N,N'-1,3-双苄-二(4-甲氧基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将4-甲氧基苯甲酰氯(2.05g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率92％。
1H NMR(400MHz,DMSO-d6)δ8.91(t,J＝6.0Hz,2H),7.83-7.86(m,4H),7.16-7.29(m,4H),6.96-6.98(m,4H),4.44(d,J＝6.0Hz,4H),3.80(s,6H)；13C NMR(100MHz,DMSO-d6)δ165.64,161.51,139.96,129.04,128.17,126.58,125.81,125.57,113.45,55.31,42.47；ESI-HRMS:m/z calcd for C24H25O4N2 305.18088[M+H]+,found 405.18165.
实施例11 N,N'-1,3-双苄-二(2-氟苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将2-氟苯甲酰氯(1.90g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率96％。
1H NMR(400MHz,DMSO-d6)δ8.89(t,J＝6.0Hz,2H),7.61-7.66(m,2H),7.50-7.56(m,2H),7.21-7.33(m,8H),4.47(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ163.73(d,4J＝1.3Hz),160.37(d,1J＝247.7Hz),139.38,132.41(d,3J＝8.4Hz),130.09(d,4J＝2.9Hz),128.29,125.73,125.57,124.46(d,4J＝3.4Hz),124.12(d,3J＝14.7Hz),116.20(d,2J＝22.3Hz),42.55；ESI-HRMS:m/z calcd for C22H19O2N2F2 381.14091[M+H]+,found381.14065.
实施例12 N,N'-1,3-双苄-二(3-氟苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将3-氟苯甲酰氯(1.90g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率92％。
1H NMR(400MHz,DMSO-d6)δ9.16(t,J＝6.0Hz,2H),7.72(dt,J＝7.8,1.2Hz,2H),7.68-7.61(m,2H),7.50(td,J＝8.0,5.8Hz,2H),7.36-7.41(m,2H),7.19-7.31(m,4H),4.47(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ164.85(d,4J＝2.5Hz),163.17,160.74,139.53,136.71(d,3J＝6.8Hz),130.49(d,3J＝8.0Hz),128.28,125.81(d,3J＝7.4Hz),123.37(d,4J＝2.6Hz),118.21(d,2J＝21.1Hz),114.13(d,2J＝22.7Hz),42.62；ESI-HRMS:m/z calcd for C22H19O2N2F2 381.14091[M+H]+,found 381.14109.
实施例13 N,N'-1,3-双苄-二(4-氟苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将4-氟苯甲酰氯(1.90g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率93％。
1H NMR(400MHz,DMSO-d6)δ9.09(t,J＝6.0Hz,2H),7.91-7.95(m,4H),7.18-7.30(m,8H),4.45(d,J＝5.9Hz,4H)；13C NMR(100MHz,DMSO-d6)δ165.09,162.61,139.69,130.79(d,4J＝3.0Hz),129.88(d,3J＝8.9Hz),128.25,125.80,125.67,115.29(d,2J＝21.6Hz),42.57；ESI-HRMS:m/z calcd for C22H19O2N2F2 381.14091[M+H]+,found 381.14098.
实施例14 N,N'-1,3-双苄-二(2-氯苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将2-氯苯甲酰氯(2.10g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝6.0Hz,2H),7.43-7.52(m,6H),7.32-7.40(m,4H),7.25-7.27(m,2H),4.46(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ166.39,139.21,136.90,130.74,129.89,129.60,128.87,128.30,127.06,125.93,125.66,42.38；ESI-HRMS:m/z calcd for C22H19O2N2Cl2 413.08181[M+H]+,found 413.08166.
实施例15 N,N'-1,3-双苄-二(3-氯苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将3-氯苯甲酰氯(2.10g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率91％。
1H NMR(400MHz,DMSO-d6)δ9.18(t,J＝6.0Hz,2H),7.90(t,J＝2.0Hz,2H),7.83(t,J＝1.4Hz,1H),7.81(t,J＝1.4Hz,1H),7.61(dd,J＝2.2,1.0Hz,1H),7.59(dd,J＝2.2,1.0Hz,1H),7.49(t,J＝8.0Hz,2H),7.19-7.31(m,4H),4.46(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ164.75,139.52,136.28,133.21,131.10,130.33,128.31,127.06,125.98,125.90,125.80,42.66；ESI-HRMS:m/z calcd for C22H19O2N2Cl2413.08181[M+H]+,found 413.08239.
实施例16 N,N'-1,3-双苄-二(4-氯苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将4-氯苯甲酰氯(2.10g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ9.14(t,J＝6.0Hz,2H),7.85-7.89(m,4H),7.50-7.53(m,4H),7.18-7.30(m,4H),4.46(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ165.13,139.62,136.05,133.04,129.17,128.38,128.29,125.76,125.71,42.59；ESI-HRMS:m/zcalcd for C22H19O2N2Cl2 413.08181[M+H]+,found 413.08230.
实施例17 N,N'-1,3-双苄-二(3,4-二氟苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将3,4-二氟苯甲酰氯(2.12g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率91％。
1H NMR(400MHz,DMSO-d6)δ9.17(t,J＝6.0Hz,2H),7.88(ddd,J＝11.6,7.8,2.2Hz,2H),7.74-7.77(m,2H),7.53(dt,J＝10.6,8.2Hz,2H),7.18-7.31(m,4H),4.46(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ163.96(d,4J＝1.9Hz),152.62(d,3J＝12.5Hz),150.38(q,3J＝12.5Hz),147.92(d,3J＝12.7Hz),139.44,131.70,128.28,125.73(d,3J＝8.7Hz),124.70(q,4J＝3.5Hz),117.59(d,3J＝17.6Hz),116.67(d,3J＝18.3Hz),45.56,42.63；ESI-HRMS:m/z calcd for C22H17O2N2F4 417.12207[M+H]+,found 417.12158.
实施例18 N,N'-1,3-双苄-二(2,4-二氟苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将2,4-二氟苯甲酰氯(2.12g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率96％。
1H NMR(400MHz,DMSO-d6)δ8.89(t,J＝6.0Hz 2H),7.68-7.74(m,2H),7.28-7.38(m,4H),7.14-7.22(m,4H),4.45(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ164.62(dd,1J＝248.8Hz,3J＝12.4Hz),162.87(d,4J＝1.3Hz),161.03(dd,1J＝250.7Hz,3J＝12.9Hz),139.29,131.91(d,4J＝4.5Hz),128.30,125.75(d,3J＝13.2Hz),120.74(d,4J＝3.6Hz),120.60(d,4J＝3.7Hz),111.88(dd,2J＝21.4Hz,4J＝3.6Hz),104.54(t,2J＝26.4Hz),42.59；ESI-HRMS:m/z calcd for C22H17O2N2F4 417.12207[M+H]+,found 417.12186.
实施例19 N,N'-1,3-双苄-二(3,4-二氯苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将3,4-二氯苯甲酰氯(2.51g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率93％。
1H NMR(400MHz,DMSO-d6)δ9.24(t,J＝6.0Hz,2H),8.07(d,J＝2.0Hz,2H),7.83(d,J＝2.0Hz,1H),7.81(d,J＝2.0Hz,1H),7.73(s,1H),7.71(s,1H),7.19-7.31(m,4H),4.46(d,J＝5.9Hz,4H)；13C NMR(100MHz,DMSO-d6)δ163.92,139.37,134.55,134.07,131.28,130.67,129.17,128.33,127.52,125.82,125.71,42.67；ESI-HRMS:m/z calcd forC22H17O2N2Cl4 481.00387[M+H]+,found 481.00140.
实施例20 N,N'-1,3-双苄-二(3,5-二氯苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将3,5-二氯苯甲酰氯(2.51g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率92％。
1H NMR(400MHz,DMSO-d6)δ9.27(t,J＝6.0Hz,2H),7.86(d,J＝2.0Hz,4H),7.79(t,J＝2.0Hz,2H),7.19-7.31(m,4H),4.46(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ163.43,139.22,137.37,134.28,130.65,128.32,126.04,125.88,125.80,42.73；ESI-HRMS:m/z calcd for C22H17O2N2Cl4 481.00387[M+H]+,found 481.00096.
实施例21 N,N'-1,3-双苄-二(2,4,6-三氯苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将2,4,6-三氯苯甲酰氯(2.93g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率93％。
1H NMR(400MHz,DMSO-d6)δ9.22(t,J＝6.0Hz,2H),7.76(s,4H),7.27-7.38(m,4H),4.46(d,J＝6.0Hz,4H).；13C NMR(100MHz,DMSO-d6)δ162.95,138.55,135.51,134.30,132.11,128.31,127.93,126.62,126.11,42.44；ESI-HRMS:m/z calcd for C22H15O2N2Cl6548.92592[M+H]+,found 548.92797.
实施例22 N,N'-1,3-双苄-二(2-氟-5-甲基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将2-氟-5-甲基苯甲酰氯(2.07g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率94％。
1H NMR(400MHz,DMSO-d6)δ8.91(t,J＝6.0Hz,2H),7.14-7.35(m,10H),4.44(d,J＝6.0Hz,4H),2.29(s,6H)；13C NMR(100MHz,DMSO-d6)δ167.74,161.10(d,1J＝241.1Hz),139.53,138.36(d,3J＝6.1Hz),132.34(d,3J＝7.6Hz),131.44(d,4J＝3.1Hz),128.37,125.84,125.73,116.09(d,2J＝20.7Hz),114.00(d,2J＝22.2Hz),42.38,18.70；ESI-HRMS:m/z calcd for C24H23O2N2F2 409.17221[M+H]+,found 409.17131.
实施例23 N,N'-1,3-双苄-二(3-氟-4-甲基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将3-氟-4-甲基苯甲酰氯(2.07g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率95％。
1H NMR(400MHz,DMSO-d6)δ9.08(t,J＝6.0Hz,2H),7.58–7.63(m,4H),7.35(t,J＝8.1Hz,2H),7.18–7.30(m,4H),4.45(d,J＝6.0Hz,4H),2.28(s,6H)；13C NMR(100MHz,DMSO-d6)δ164.80,161.55(d,1J＝242.0Hz),139.64,134.07(d,3J＝6.8Hz),131.54(d,4J＝4.9Hz),128.27,127.85,127.68,125.77(d,3J＝6.2Hz),123.10(d,4J＝3.1Hz),113.79(d,2J＝23.6Hz),45.48,42.56；ESI-HRMS:m/z calcd for C24H23O2N2F2 409.17221[M+H]+,found 409.17171.
实施例24 N,N'-1,3-双苄-二异烟酰胺的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将异烟酰氯(2.14g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ9.28(t,J＝6.0Hz,2H),9.03(dd,J＝2.4,1.0Hz,2H),8.71(d,J＝1.8Hz,1H),8.70(d,J＝1.8Hz,1H),8.21(t,J＝2.0Hz,1H),8.18(t,J＝2.0Hz,1H),7.50(dd,J＝4.8,1.0Hz,1H),7.48(dd,J＝4.8,1.0Hz,1H),7.21-7.32(m,4H),4.49(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ164.79,151.91,148.44,139.48,134.97,129.78,128.37,125.92,125.83,123.47,42.55；ESI-HRMS:m/z calcd for C21H17O2N2Cl2399.06616[M+H]+,found 399.06545.
实施例25 N,N'-1,3-双苄-二(4-二甲氨基苯甲酰胺)的制备方法
于100mL单口瓶中加入间苯二甲胺(0.68g，5mmol)，三乙胺(1.51g，15mmol)，二氯甲烷(10mL)，0℃搅拌5min，将4-二甲氨基苯甲酰氯(2.20g，12mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，抽滤，固体用甲醇/乙醚重结晶得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ8.68(t,J＝6.0Hz,2H),7.75(d,J＝9.0Hz,4H),7.15-7.27(m,4H),6.68(d,J＝9.0Hz,4H),4.42(d,J＝6.0Hz,4H),2.96(s,12H)；13C NMR(100MHz,DMSO-d6)δ166.07,152.07,140.29,128.60,128.11,125.88,125.49,121.06,110.79,42.39,39.75；ESI-HRMS:m/z calcd for C26H31O2N4 431.24415[M+H]+,found 431.24362.
实施例26 N,N'-1,4-双苄-二甲酰胺的制备方法
于100mL单口瓶中加入甲酸(0.55g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ8.34(t,J＝6.0Hz,2H),7.18(s,4H),4.20(d,J＝6.0Hz,4H),1.85(s,6H)；13C NMR(100MHz,DMSO-d6)δ169.00,138.07,127.22,41.83,22.55；ESI-HRMS:m/z calcd for C12H17O2N2 221.12845[M+H]+,found 221.12860.
实施例27 N,N'-1,4-双苄-二乙酰胺的制备方法
于100mL单口瓶中加入丙酸(0.89g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率97％。
1H NMR(400MHz,DMSO-d6)δ8.23(s,2H),7.18(s,4H),4.21(d,J＝6.0Hz,4H),2.13(q,J＝7.6Hz,4H),1.01(t,J＝7.6Hz,6H)；13C NMR(100MHz,DMSO-d6)δ172.74,138.15,127.15,41.72,28.46,9.97；ESI-HRMS:m/z calcd for C14H21O2N2 249.15975[M+H]+,found249.15984.
实施例28 N,N'-1,4-双苄-二(2-甲基丙酰胺)的制备方法
于100mL单口瓶中加入异丁酸(1.06g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率96％。
1H NMR(400MHz,DMSO-d6)δ8.23(t,J＝6.0Hz,2H),7.16(s,4H),4.21(d,J＝6.0Hz,4H),2.41(hept,J＝6.8,6.4Hz,2H),1.02(d,J＝6.8Hz,12H)；13C NMR(100MHz,DMSO-d6)δ175.94,138.21,126.98,41.57,33.97,19.58；ESI-HRMS:m/z calcd for C16H25O2N2277.19105[M+H]+,found 277.19109.
实施例29 N,N'-1,4-双苄-二丙酰胺的制备方法
于100mL单口瓶中加入丁酸(1.06g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率92％。
1H NMR(400MHz,DMSO-d6)δ8.27(t,J＝6.0Hz,2H),7.17(s,4H),4.22(d,J＝6.0Hz,4H),2.09(t,J＝7.4Hz,4H),1.53(h,J＝7.4Hz,4H),0.85(t,J＝7.4Hz,6H)；13C NMR(100MHz,DMSO-d6)δ171.86,138.18,127.10,41.68,37.28,18.70,13.65；ESI-HRMS:m/zcalcd for C16H25O2N2 277.19105[M+H]+,found 277.19113.
实施例30 N,N'-1,4-双苄-二苯甲酰胺的制备方法
于100mL单口瓶中加入苯甲酸(1.47g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率95％。
1H NMR(400MHz,DMSO-d6)δ9.04(t,J＝6.0Hz,2H),7.88-7.90(m,4H),7.44-7.54(m,6H),7.28(s,4H),4.46(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ166.13,138.15,134.37,131.15,128.26,127.20,42.38；ESI-HRMS:m/z calcd for C22H21O2N2 345.15975[M+H]+,found 345.15975.
实施例31 N,N'-1,4-双苄-二(2-甲基苯甲酰胺)的制备方法
于100mL单口瓶中加入2-甲基苯甲酸(1.63g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率96％。
1H NMR(400MHz,DMSO-d6)δ8.80(t,J＝6.0Hz,2H),7.32-7.37(m,4H),7.31(s,4H),7.21-7.25(m,4H),4.42(d,J＝6.0Hz,4H),2.33(s,6H)；13C NMR(100MHz,DMSO-d6)δ169.01,138.10,137.02,135.15,130.39,129.23,127.13,126.99,125.47,42.09,19.40；ESI-HRMS:m/z calcd for C24H24O2N2K 411.14694[M+K]+,found 411.14712.
实施例32 N,N'-1,4-双苄-二(3-甲基苯甲酰胺)的制备方法
于100mL单口瓶中加入3-甲基苯甲酸(1.63g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率97％。
1H NMR(400MHz,DMSO-d6)δ8.97(t,J＝6.0Hz,2H),7.65-7.71(m,4H),7.33-7.36(m,4H),7.27(s,4H),4.44(d,J＝5.9Hz,4H),2.35(s,6H)；13C NMR(100MHz,DMSO-d6)δ166.22,138.16,137.50,134.37,131.69,128.14,127.76,127.19,124.33,42.35,20.92；ESI-HRMS:m/z calcd for C24H25O2N2 373.19105[M+H]+,found 373.19136.
实施例33 N,N'-1,4-双苄-二(4-甲基苯甲酰胺)的制备方法
于100mL单口瓶中加入4-甲基苯甲酸(1.63g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率95％。
1H NMR(400MHz,DMSO-d6)δ8.94(t,J＝6.0Hz,2H),7.78(d,J＝8.0Hz,4H),7.26(s,8H),4.43(d,J＝6.0Hz,4H),2.34(s,6H)；13C NMR(100MHz,DMSO-d6)δ165.98,140.98,138.21,131.57,128.77,127.21,127.17,42.32,20.91；ESI-HRMS:m/z calcd forC24H25O2N2 373.19105[M+H]+,found 373.19118.
实施例34 N,N'-1,4-双苄-二(2-甲氧基苯甲酰胺)的制备方法
于100mL单口瓶中加入2-甲氧基苯甲酸(1.83g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率91％。
1H NMR(400MHz,DMSO-d6)δ8.67(t,J＝6.0Hz,2H),7.74(dd,J＝7.8,1.9Hz,2H),7.44-7.49(m,2H),7.29(s,4H),7.14(d,J＝8.4Hz,2H),7.03(tt,J＝7.6,1.0Hz,2H),4.47(d,J＝6.2Hz,4H),3.88(s,6H)；13C NMR(100MHz,DMSO-d6)δ165.06,156.91,138.06,132.09,130.32,127.00,123.21,120.42,111.94,55.83,42.31；ESI-HRMS:m/z calcd forC24H25O4N2 405.18088[M+H]+,found 405.18091.
实施例35 N,N'-1,4-双苄-二(3-甲氧基苯甲酰胺)的制备方法
于100mL单口瓶中加入3-甲氧基苯甲酸(1.83g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率94％。
1H NMR(400MHz,DMSO-d6)δ9.03(t,J＝6.0Hz,2H),7.35-7.48(m,6H),7.27(s,4H),7.09(d,J＝7.8Hz,2H),4.44(d,J＝6.0Hz,4H),3.79(s,6H)；13C NMR(100MHz,DMSO-d6)δ165.83,159.14,138.12,135.77,129.39,127.21,119.43,117.08,112.33,55.23,42.41；ESI-HRMS:m/z calcd for C24H25O4N2 405.18088[M+H]+,found 405.18076.
实施例36 N,N'-1,4-双苄-二(4-甲氧基苯甲酰胺)的制备方法
于100mL单口瓶中加入4-甲氧基苯甲酸(1.83g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率96％。
1H NMR(400MHz,DMSO-d6)δ8.87(t,J＝6.0Hz,2H),7.86(d,J＝8.8Hz,4H),7.25(s,4H),6.99(d,J＝8.8Hz,4H),4.42(d,J＝6.0Hz,4H),3.80(s,6H)；13C NMR(100MHz,DMSO-d6)δ165.58,161.50,138.29,129.01,127.15,126.57,113.45,55.30,42.30；ESI-HRMS:m/zcalcd for C24H25O4N2 405.18088[M+H]+,found 405.18149.
实施例37 N,N'-1,4-双苄-二(2-氟苯甲酰胺)的制备方法
于100mL单口瓶中加入2-氟苯甲酸(1.68g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率92％。
1H NMR(400MHz,DMSO-d6)δ9.13(t,J＝6.0Hz,2H),7.74(d,J＝7.8Hz,2H),7.67(d,J＝10.0Hz,2H),7.50-7.55(m,2H),7.38(td,J＝8.6,2.8Hz,2H),7.28(s,4H),4.45(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ164.78(d,4J＝2.5Hz),163.15(d,1J＝243.1Hz),137.93,136.72(d,3J＝6.5Hz),130.49(d,3J＝7.8Hz),127.26,123.37(d,4J＝3.0Hz),118.18(d,2J＝21.0Hz),114.12(d,2J＝23.0Hz),42.48；ESI-HRMS:m/z calcd forC22H19O2N2F2 381.14091[M+H]+,found 381.14096.
实施例38 N,N'-1,4-双苄-二(3-氟苯甲酰胺)的制备方法
于100mL单口瓶中加入3-氟苯甲酸(1.68g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率91％。
1H NMR(400MHz,DMSO-d6)δ9.13(t,J＝6.0Hz,2H),7.65-7.75(m,4H),7.52(td,J＝8.0,6.0Hz,2H),7.38(td,J＝8.4,8.0Hz,2H),7.28(s,4H),4.45(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ164.78(d,4J＝2.7Hz),163.15(d,1J＝243.1Hz),137.93,136.72(d,3J＝6.5Hz),130.49(d,3J＝8.0Hz),127.27,123.37(d,4J＝2.7Hz),118.18(d,2J＝21.0Hz),114.12(d,2J＝22.6Hz),42.48；ESI-HRMS:m/z calcd for C22H19O2N2F2 381.14091[M+H]+,found 381.14102.
实施例39 N,N'-1,4-双苄-二(4-氟苯甲酰胺)的制备方法
于100mL单口瓶中加入4-氟苯甲酸(1.68g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率93％。
1H NMR(400MHz,DMSO-d6)δ9.05(t,J＝6.0Hz,2H),7.93-7.97(m,4H),7.27-7.32(m,8H),4.44(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ165.06,162.59,138.08,130.82(d,4J＝2.6Hz),129.88(d,3J＝8.9Hz),127.23,115.28(d,2J＝21.7Hz),42.43；ESI-HRMS:m/z calcd for C22H19O2N2F2 381.14091[M+H]+,found 381.14093.
实施例40 N,N'-1,4-双苄-二(2-氯苯甲酰胺)的制备方法
于100mL单口瓶中加入2-氯苯甲酸(1.88g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ8.98(s,2H),7.37-7.52(m,8H),7.33(s,4H),4.44(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ166.32,137.66,136.90,130.71,129.82,129.57,128.83,127.15,127.08,42.17；ESI-HRMS:m/z calcd for C22H18O2N2Cl2Na 435.06375[M+Na]+,found 435.06412.
实施例41 N,N'-1,4-双苄-二(3-氯苯甲酰胺)的制备方法
于100mL单口瓶中加入3-氯苯甲酸(1.88g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率91％。
1H NMR(400MHz,DMSO-d6)δ9.16(t,J＝5.8Hz,2H),7.83-7.92(m,4H),7.49-7.62(m,4H),7.28(s,4H),4.44(d,J＝5.8Hz,4H)；13C NMR(100MHz,DMSO-d6)δ164.68,137.89,136.30,133.16,131.02,130.30,127.29,127.03,125.98,42.51；ESI-HRMS:m/z calcd forC22H18O2N2Cl2Na 435.06375[M+Na]+,found 435.06423.
实施例42 N,N'-1,4-双苄-二(4-氯苯甲酰胺)的制备方法
于100mL单口瓶中加入4-氯苯甲酸(1.88g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率92％。
1H NMR(400MHz,DMSO-d6)δ9.11(t,J＝6.0Hz,2H),7.88-7.91(m,4H),7.52-7.56(m,4H),7.27(s,4H),4.44(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ165.06,138.00,135.99,133.07,129.14,128.35,127.26,42.45；ESI-HRMS:m/z calcd for C22H19O2N2Cl2413.08181[M+H]+,found 413.08192.
实施例43 N,N'-1,4-双苄-二烟酰胺的制备方法
于100mL单口瓶中加入烟酸(1.48g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率89％。
1H NMR(400MHz,DMSO-d6)δ9.22(t,J＝6.0Hz,2H),9.04(s,2H),8.70-8.71(m,2H),8.21(dt,J＝8.0,2.0Hz,2H),7.50(dd,J＝8.0,4.8Hz,2H),7.30(s,4H),4.47(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ164.71,151.85,148.38,137.87,134.94,129.78,127.32,123.42,42.40；ESI-HRMS:m/z calcd for C20H19O2N4 347.15025[M+H]+,found 347.15007.
实施例44 N,N'-1,4-双苄-二(4-甲基-1,2,3-噻二唑-5-甲酰胺)的制备方法
于100mL单口瓶中加入4-甲基-1,2,3-噻二唑-5-甲酸(1.73g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率88％。
1H NMR(400MHz,DMSO-d6)δ9.34(t,J＝5.8Hz,2H),7.31(s,4H),4.45(d,J＝5.8Hz,4H),2.78(s,6H)；13C NMR(100MHz,DMSO-d6)δ158.80,158.59,143.98,137.30,127.50,42.77,13.23；ESI-HRMS:m/z calcd for C16H17O2N6S2 389.08489[M+H]+,found 384.08522.
实施例45 N,N'-1,4-双苄-二(1,3-二甲基-1H-吡唑-5-甲酰胺)的制备方法
于100mL单口瓶中加入1,3-二甲基-1H-吡唑-5-甲酸(1.68g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ8.91(t,J＝6.0Hz,2H),7.25(s,4H),6.65(s,2H),4.38(d,J＝6.0Hz,4H),3.96(s,6H),2.14(s,6H)；13C NMR(100MHz,DMSO-d6)δ159.35,145.26,137.87,135.62,127.19,106.42,41.77,38.38,13.04；ESI-HRMS:m/z calcd for C20H25O2N6381.20335[M+H]+,found 381.20279.
实施例46 N,N'-1,4-双苄-二(1-甲基-1H-吡唑-5-甲酰胺)的制备方法
于100mL单口瓶中加入1-甲基-1H-吡唑-5-甲酸(1.51g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ8.99(t,J＝6.0Hz,2H),7.45(d,J＝2.0Hz,2H),7.27(s,4H),6.89(d,J＝2.0Hz,2H),4.41(d,J＝6.1Hz,4H),4.05(s,6H)；13C NMR(100MHz,DMSO-d6)δ159.29,137.85,137.11,135.07,127.27,107.21,41.82,38.88；ESI-HRMS:m/z calcd forC18H21O2N6 353.17205[M+H]+,found 353.17169.
实施例47 N,N'-1,4-双苄-二(吡唑[1,5-α]并吡啶-2-甲酰胺)的制备方法
于100mL单口瓶中加入吡唑[1,5-α]并吡啶-2-甲酸(1.95g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率89％。
1H NMR(400MHz,DMSO-d6)δ8.92(s,2H),8.66(d,J＝7.2Hz,2H),7.76(d,J＝9.0Hz,2H),7.25-7.29(m,6H),6.99-7.03(m,4H),4.45(d,J＝6.4Hz,4H)；13C NMR(100MHz,DMSO-d6)δ161.32,147.93,140.60,138.09,128.71,127.27,124.23,118.98,113.98,97.38,41.91；ESI-HRMS:m/z calcd for C24H20O2N6Na 447.15400[M+Na]+,found 447.15410.
实施例48 N,N'-1,4-双苄-二(苯并1,3-二氧戊环-4-甲酰胺)的制备方法
于100mL单口瓶中加入苯并1,3-二氧戊环-4-甲酸(1.99g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率90％。
1H NMR(400MHz,DMSO-d6)δ8.25(t,J＝6.0Hz,2H),7.28(s,4H),7.25(dd,J＝8.2,1.2Hz,2H),7.07(dd,J＝7.8,1.2Hz,2H),6.92(t,J＝8.0Hz,2H),6.12(s,4H),4.46(d,J＝6.0Hz,4H)；13C NMR(100MHz,DMSO-d6)δ162.98,147.65,145.22,137.91,127.30,121.53,121.19,116.43,110.88,101.57,42.34；ESI-HRMS:m/z calcd for C24H21O6N2 433.13941[M+H]+,found 433.13939.
实施例49 N,N'-1,4-双苄-二(2-(4-氯苯基硫乙酰胺))的制备方法
于100mL单口瓶中加入2-(4-氯苯硫)乙酸(2.43g，12mmol)，DCC(3.09g，15mmol)，DMAP(18mg，0.15mmol)，二氯甲烷(10mL)，25℃搅拌1h，将对苯二甲胺(0.68g，5mmol)溶于二氯甲烷(15mL)，置于恒压滴液漏斗中，缓慢滴加，TLC监测反应，待原料转化完全后，停止反应，减压浓缩，进行硅胶柱层析(二氯甲烷：甲醇＝100：1)，得白色固体，收率88％。
1H NMR(400MHz,DMSO-d6)δ8.60(t,J＝6.0Hz,2H),7.34-7.39(m,8H),7.08(s,4H),4.23(d,J＝6.0Hz,4H),3.71(s,4H)；13C NMR(100MHz,DMSO-d6)δ167.57,137.58,135.08,130.58,129.78,128.79,127.07,42.12,36.35；ESI-HRMS:m/z calcd for C24H21O2N2S2Cl2505.05725[M+H]+,found 505.05788.
药理实验数据
1.CXCR4结合亲和力测定
采用CXCR4肽拮抗剂——生物素化的TN14003与化合物进行竞争性CXCR4结合试验，对化合物的活性水平进行半定量的初步筛选。用起效浓度(EC)来衡量亲和力，其定义为罗丹明荧光颜色显著降低时的最低浓度。分别在1、10、100和1000nM浓度下测试化合物Ia-Iy和IIa-IIx的CXCR4结合亲和力。通过前期对数百种化合物的CXCR4结合亲和测试，发现EC值在100nM以下的化合物是有潜力的化合物，具有很强的亲和力，有可能成为潜在的候选化合物，值得进一步研究。
实验结果表明，本发明实施例中的化合物大部分能够有效阻断TN14003与CXCR4的结合，其中7个化合物(Iv,IIa,IIg,IIh,IIi,IIk,IIs)的结合亲和力较弱(EC>1000nM)。而实施例中有12个化合物(If,Ij,Ip,Is,It,Iu,IIf,IIj,IIn,IIo,IIp,IIw)的EC值为100nM，5个化合物(IIc,IId,IIm,IIv,IIx)的EC值为10nM，4个化合物(Ih,Ii,Ir,IIe)的EC值仅为1nM，说明双苄酰胺结构是一种新颖有效的小分子CXCR4拮抗剂，并将EC值1-100nM的21个化合物继续进行下一步活性研究。
表1实施例Ia-Iy,IIa-IIx的CXCR4亲和力起效浓度(EC)
2.细胞体外侵袭能力测定
为了建立体外趋化/侵袭模型，采用基质凝胶侵袭实验作为功能实验。将EC值小于100nM的实施例化合物进行测定，以检测它们在100nM的单一浓度下是否能阻断CXCR4/CXCL12介导的趋化和侵袭。化合物和细胞被加到血管的上室，CXCL12作为无血清培养基中的化学引诱剂被添加到血管的下室，一层基质膜将上室和下室分隔开。如果化合物的CXCR4拮抗作用强，则很少会有细胞能够穿过基质膜。
实验结果表明，除了化合物IIv的抗侵袭作用低于50％，其他所选的化合物均表现出中等到强效的抑制活性(51％-100％)。11个化合物(Ih,Ii,Ij,Ir,It,Iu,IIc,IIm,IIo,IIp,IIw)的抑制率大于85％，其中有3个化合物(Ii,Iu,IIp)的抑制率接近于100％，证明这些化合物能有效阻断CXCR4通路的侵袭功能。因此，进一步对这11个化合物进行体内抗炎活性的研究。
表2 100nM下优选实施例的细胞侵袭抑制活性
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3.体内抗炎活性研究
采用角叉菜胶诱导的小鼠足肿胀模型作为抗炎动物模型来评估所选化合物的体内抗CXCR4活性。在系列I中，只有化合物It具有较好的抗炎活性，对小鼠足肿胀抑制率达34.84％；在系列II中，化合物IIm,IIo和IIp均具有较强的体内抗炎活性，对小鼠足肿胀抑制率达48.4％、35.6％、31.5％，证明优选化合物可以有效阻断炎症细胞在炎症组织中的积聚，具有较好的CXCR4拮抗活性。
表3部分实施例的体内抗炎活性
4.化合物IIm,IIo和IIp的抗CXCR4活性的分子水平评价
肿瘤坏死因子-α(TNF-α)水平的升高与多种炎症过程有关，前期研究表明，抑制CXCR4可减弱巨噬细胞对致病性大肠杆菌感染时TNF-α的诱导作用，因此，对化合物IIm,IIo和IIp是否具有降低TNF-α水平的能力进行了评价。结果表明，化合物IIm和IIo能够分别降低47.6％和41.8％的TNF-α水平，表明化合物IIm和IIo能有效抑制宿主对克罗恩氏病相关的侵袭性大肠杆菌的应答。
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (1)

1.双苄酰胺类CXCR4拮抗剂在制备抗炎、通过拮抗CXCR4靶点来防治相关疾病的药物中的应用，其特征在于，所述双苄酰胺类CXCR4拮抗剂为具有如下结构的化合物Ih、Ii、Ij、It、IIm、IIo或IIp，及其可药用盐：
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