CN115322190B - 一种吡啶并咪唑类酰基磺酰胺衍生物及其制备方法与应用 - Google Patents
一种吡啶并咪唑类酰基磺酰胺衍生物及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及一种吡啶并咪唑酰基磺酰胺类衍生物及其制备方法和应用。所述化合物具有式I所示的结构。本发明还涉及含有式I结构化合物的制备方法以及药物组合物。本发明还提供上述化合物在制备降尿酸的药物中的应用。
Description
技术领域
本发明涉及制备治疗高尿酸血症和痛风的相关药物领域。具体而言,本发明涉及一种吡啶并咪唑酰基磺酰胺类化合物及其制备方法或含有它们的药物组合,以及其在医药上的用途。
背景技术
高尿酸血症是指正常嘌呤饮食状态下,非同日两次空腹血尿酸水平高于420μmol/L。痛风是指血尿酸浓度长期高于6.8mg/dL,进而导致单钠尿酸盐沉积所致的晶体相关性关节病,与尿酸产生过多活排泄减少所致的高尿酸血症直接相关,特指急性特征性关节炎和慢性痛风石疾病。痛风与高尿酸血症都与人体内的尿酸水平有关,正常成年人每日约产生尿酸750mg,其中1/3经肠道分解代谢,2/3经肾脏排泄,从而维持体内尿酸水平的稳定。目前治疗痛风的药物主要有两类:一类是抑制尿酸生成的黄嘌呤氧化酶抑制剂,另一类是促进尿酸排泄的URAT1抑制剂。尿酸转运蛋白1(URAT1)位于人肾近端小管上皮细胞的刷状缘上,介导90%以上的尿酸重吸收,其基因突变所导致的URAT1活性增加或基因表达增加是尿酸排泄不良型高尿酸血症的重要发病机制之一。Lesinurad是一种用于治疗高尿酸血症和痛风的URAT1抑制剂,因其疗效不佳且具有严重的肝肾毒副作用而逐渐退市。因此,对其进行进一步地结构修饰,有望获得具有更优活性及安全性且具有自主知识产权的新型抗痛风及高尿酸血症药物。
发明内容
针对现有技术的不足,本发明提供了一种吡啶并咪唑酰基磺酰胺类衍生物及其制备方法,本发明还提供了上述化合物作为降尿酸药物的活性筛选结果及其应用。
本发明的技术方案如下:
一、吡啶并咪唑酰基磺酰胺类衍生物
本发明的吡啶并咪唑酰基磺酰胺类衍生物,或其药学上可接受的盐,具有如下通式I所示的结构:
其中,X为氮原子时,Y为碳原子或X为碳原子时,Y为氮原子;R为C1-C5的烷基、苯基、卤素取代噻吩基或取代苯基;所述的取代基选自氟、氯、溴、硝基、三氟甲基、羟基、甲基、乙基、甲氧基、叔丁基。
根据本发明优选的,R为苯基、4-溴苯、4-甲基苯、4-氯苯、4-氟苯、4-硝基苯、2,4-二氟苯、4-叔丁基苯、4-(三氟甲基)苯、5-氯噻吩、4-甲氧基苯、4-羟基苯、4-乙基苯、3,5-二氟苯、3-硝基苯、2-硝基苯、3-溴苯、叔丁基、乙基、甲基。
根据本发明进一步优选的,吡啶并咪唑酰基磺酰胺类衍生物是下列之一:
表1.化合物TS1~TS20及PS1~PS20的结构式
二、吡啶并咪唑酰基磺酰胺类衍生物的制备方法
本发明吡啶并咪唑类衍生物的制备方法如下方法之一:
(1)化合物TS1~TS20的合成:
原料2-硝基-3-羟基吡啶(T-A)和三氟甲磺酸酐在三乙胺的碱性条件下冰浴反应得到中间体T-B,随后T-B经布赫瓦尔德-哈特维希偶联反应(Buchwald-Hartwig crosscoupling)得到TE-B,之后TE-B经氢气钯碳还原得到中间体TE-C。TE-C在N,N'-硫羰基二咪唑的乙腈溶液中回流反应得到关键中间体T-D。T-D在碳酸钾及DMF溶液中发生与2-溴丙酸甲酯反应得到T-E,接着与氢氧化锂在四氢呋喃及乙醇的混合溶液中水解得到T7。最后,在1-乙基-3(3-二甲基丙胺)碳二亚胺、4-二甲氨基吡啶的二氯甲烷溶液中,与不同的磺酰胺基团冰浴条件下酰化反应12小时得到目标产物TS1~20。
路线一:
试剂及条件:(i)三氟甲磺酸酐,三乙胺,二氯甲烷,0℃;(ii)醋酸钯,XantPhos,碳酸铯,氮气,1,4-二氧六环,90℃;(iii)10%钯碳,氢气,四氢呋喃,室温;(iv)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(v)2-溴丙酸甲酯,碳酸钾,N,N-二甲基甲酰胺,室温;(vi)氢氧化锂,四氢呋喃,乙醇,室温;(vi)氢氧化锂,四氢呋喃,乙醇,室温;(vii)酰基磺酰胺,1-乙基-(3-二甲基氨基丙基)碳醯二亚胺盐酸盐,4-二甲氨基吡啶,二氯甲烷,室温。
路线中R为苯基、4-溴苯、4-甲基苯、4-氯苯、4-氟苯、4-硝基苯、2,4-二氟苯、4-叔丁基苯、4-(三氟甲基)苯、5-氯噻吩、4-甲氧基苯、4-羟基苯、4-乙基苯、3,5-二氟苯、3-硝基苯、2-硝基苯、3-溴苯、叔丁基、乙基、甲基。
(2)化合物PS1~PS20的合成:
初始原料4-氯-3-硝基吡啶(P-A)与4-环丙基-1-萘胺在碳酸氢钠和乙醇溶液中经偶联得到中间体PE-B,随后氢气钯碳还原得到中间体PE-C。中间体PE-C在N,N'-硫羰基二咪唑的乙腈溶液中回流反应得到关键中间体P-D。P-D在碳酸钾及DMF溶液中发生与2-溴丙酸甲酯反应得到P-E,接着与氢氧化锂在四氢呋喃及乙醇的混合溶液中水解得到P7。最后,在1-乙基-3(3-二甲基丙胺)碳二亚胺、4-二甲氨基吡啶的二氯甲烷溶液中,与不同的磺酰胺基团冰浴条件下酰化反应12小时得到目标产物PS1~20。
路线二:
试剂及条件:(i)碳酸氢钠,乙醇,60℃;(ii)10%钯碳,氢气,四氢呋喃,室温;(iii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(iv)2-溴丙酸甲酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温;(vi)酰基磺酰胺,1-乙基-(3-二甲基氨基丙基)碳醯二亚胺盐酸盐,4-二甲氨基吡啶,二氯甲烷,室温。
路线中R为苯基、4-溴苯、4-甲基苯、4-氯苯、4-氟苯、4-硝基苯、2,4-二氟苯、4-叔丁基苯、4-(三氟甲基)苯、5-氯噻吩、4-甲氧基苯、4-羟基苯、4-乙基苯、3,5-二氟苯、3-硝基苯、2-硝基苯、3-溴苯、叔丁基、乙基、甲基。
本发明所述的室温是指20-30℃。
三、吡啶并咪唑酰基磺酰胺类衍生物的应用
本发明公开了吡啶并咪唑磺酰胺类衍生物降血尿酸活性筛选结果及其用于制备降尿酸药物的首次应用。通过实验证明本发明的吡啶并咪唑酰基磺酰胺类衍生物可作为降血尿酸药物应用。具体地说,可作为降血尿酸化合物用于制备降尿酸药物。本发明还提供上述化合物在制备降尿酸药物中的应用。
目标化合物的降尿酸活性:
对按照上述方法合成的40个化合物(化合物的结构式见表1),并对其进行了降尿酸活性筛选,它们的降尿酸活性数据列于表2中,以Lesinurad为阳性药物。
由表2和表3可以看出有24种化合物均呈现出较好的抗降尿酸活性,降尿酸活性均强于阳性对照药物Lesinurad。其中代表化合物TS1、TS2、TS15、PS2、PS4、PS8和PS11,在动物体内活性测试中,血尿酸下降率均超过70%,显示出优异的降尿酸活性,可作为制备降尿酸的药物。
因此,本发明的吡啶并咪唑酰基磺酰胺类衍生物是一系列结构新颖的具有降血尿酸活性的化合物,可作为降尿酸的候选药物加以利用,用于制备降尿酸药物。
一种降尿酸药物组合物,包括本发明的吡啶并咪唑酰基磺酰胺类衍生物和一种或多种药学上可接受的载体或赋形剂。
具体实施方式
通过下述实例有助于理解本发明,但是不能限制本发明的内容,在下列实例中,所有目标化合物的编号与表1相同。
化合物TS1~TS20的合成:
试剂及条件:(i)三氟甲磺酸酐,三乙胺,二氯甲烷,0℃;(ii)醋酸钯,XantPhos,碳酸铯,氮气保护,1,4-二氧六环,90℃;(iii)10%钯碳,氢气,四氢呋喃,室温;(iv)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(v)2-溴丙酸甲酯,碳酸钾,N,N-二甲基甲酰胺,室温;(vi)氢氧化锂,四氢呋喃,乙醇,室温;(vi)氢氧化锂,四氢呋喃,乙醇,室温;(vii)酰基磺酰胺,1-乙基-(3-二甲基氨基丙基)碳醯二亚胺盐酸盐,4-二甲氨基吡啶,二氯甲烷,室温。
路线中R为苯基、4-溴苯、4-甲基苯、4-氯苯、4-氟苯、4-硝基苯、2,4-二氟苯、4-叔丁基苯、4-(三氟甲基)苯、5-氯噻吩、4-甲氧基苯、4-羟基苯、4-乙基苯、3,5-二氟苯、3-硝基苯、2-硝基苯、3-溴苯、叔丁基、乙基、甲基。
化合物TE-B的制备
取初始原料2-硝基吡啶-3-醇(T-A)(5.0g,,35.7mmol)、三乙胺(4.33g)共溶于30mL二氯甲烷中。随后在冰浴下,将三氟甲磺酸酐(12.0g,42.8mmol)的二氯甲烷(适量)溶液用恒压滴液漏斗滴加到体系中,并继续在冰浴下搅拌反应3h。TLC检测反应完成,向体系中加入饱和食盐水洗涤有机相(3×20mL),合并有机相,无水硫酸钠干燥,过滤减压浓缩得深棕色油状物中间体2-硝基吡啶-3-基三氟甲磺酸酯粗品(T-B),产率62.3%。
随后将4-溴-1-萘胺(10.0g,45.0mmol)、环丙基硼酸(5.0g,58.0mmol)、磷酸钾(32.0g,0.2mol)和四三苯基膦钯(3.5g,3.0mmol)加入到50mL甲苯及4mL H2O的混合溶剂中,在氮气环境下回流反应12个小时,TLC检测反应完成,冷却至室温,向体系中加入50mL水,用乙酸乙酯萃取(3×20mL),合并有机相,用无水硫酸钠干燥过滤,经减压浓缩得棕色油状物4-环丙基-1-萘胺粗品,收率71.3%。
将乙酸钯(0.007g,0.03mmol)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.04g,0.06mmol)溶解在2mL1,4-二氧六环中,搅拌30分钟备用。随后2-硝基吡啶-3-基三氟甲磺酸酯(0.2g,0.6mmol)、4-环丙基-1-萘胺(0.1g,0.8mmol)和碳酸铯(0.4g,1.3mmol)溶解在10mL 1,4-二氧六环中。将两份溶液混合并在氮气保护下90℃回流反应12个小时,TLC检测反应完毕,冷却至室温,加入30mL二氯甲烷,用饱和氯化钠水溶液(3×20mL)洗涤有机相。分离有机层,无水Na2SO4干燥。过滤、浓缩硅胶拌样,柱层析纯化得黄色固体N-(4-环丙基萘-1-基)-2-硝基-3-胺基吡啶(TE-B)。收率69.5%,熔点76-79℃。ESI-MS:m/z C18H15N3O2,calcdfor 305.12;found 306.41[M+H]+。
化合物TE-C的制备
将中间体TE-B(2.0g,6.6mmol)及10%钯碳(0.2g)共溶于40mL乙醇中,在氢气氛围中室温搅拌12h(TLC检测反应完毕)。反应完全后过滤,收集滤液并减压浓缩,固体残渣于乙酸乙酯重结晶得黄色中间体N-(4-环丙基萘-1-基)吡啶-2,3-二胺(TE-C)。收率73.2%,熔点143.5-144℃。ESI-MS:m/z C18H17N3,calcd for 275.14;found 276.1[M+H]+。
化合物T-D的制备
中间体TE-C(2.0g,7.2mmol)、N,N’-硫代羰基二咪唑(2.0g,11.6mmol)以及三乙胺(0.1mL)共溶于100mL乙腈中,在90℃条件下回流10h,析出大量固体(TLC检测反应完毕)。冷却至室温,过滤收集溶固体并使用二氯甲烷(3×5mL)及石油醚(3×5mL)淋洗三次,干燥收集。过滤所得液相减压蒸馏除去溶剂,向残留物中加入30mL二氯甲烷,饱和氯化钠水溶液洗涤(3×10mL),分取有机层并用无水硫酸钠干燥,过滤减压浓缩后柱层析得到黄色的固体,与反应完毕后后过滤所得固体合并计算收率。产率69.5%。熔点246-248℃。ESI-MS:m/zC19H15N3S,calcd for 317.10;found 316.19[M–H]–。
化合物T-E的制备
取中间体1-(4-环丙基萘-1-基)-1H-咪唑并[4,5-b]吡啶-2-硫醇(2.0g,6.3mmol)与2-溴丙酸甲酯(1.6g,9.5mmol)和碳酸钾(1.0g,7.67mmol)溶解于30mL DMF中,常温下反应8h,TLC检测反应完成,加入50mL乙酸乙酯并用氯化钠水溶液(3×20mL)洗涤,分离有机层,无水硫酸钠干燥,过滤并浓缩。柱层析纯化最终得到无色油状物2-((1-(4-环丙基萘-1-基)-1H-咪唑并[4,5-b]吡啶-2-基)硫代)丙酸甲酯(T-E)。产率57.2%。ESI-MS:m/zC23H21N3O2S,calcd for 403.1354;found 404.14[M+H]+。
化合物T7的制备
取中间体T-E(2.0g,5.0mmol)溶解在30mL四氢呋喃和30mL乙醇的混合物中。将氢氧化锂(1.2g,49.6mmol)的适量水溶液滴加入反应混合物中,然后在室温条件下搅拌反应3h。TLC检测反应完成,旋蒸除去有机溶剂。随后添加30mL水,并在搅拌下滴加1MHCl溶液,调pH值至3-4,此过程中析出大量固体。过滤收集固体,用乙醇重结晶得对应羧酸中间体T7。产率93.9%,熔点156-158℃。ESI-MS:m/z C22H19N3O2S,calcd for 389.1198;found 388.13[M–H]–。
化合物TS1~20的制备通法
取中间体T7(0.2g,0.5mmol,1.0eq)、1-乙基-(3-二甲基氨基丙基)碳醯二亚胺盐酸盐,(0.2g,0.8mmol,1.5eq)和4-二甲氨基吡啶(0.1g,0.8mmol,1.5eq)溶解在20mL二氯甲烷中。冰浴下搅拌0.5小时以活化羧基,然后将对应的取代磺酰胺反应物(1.2eq)加入体系中,并于室温条件搅拌反应约12h。TLC监测反应完成,反应液用饱和食盐水(3×10mL)洗涤,分离收集有机相用无水硫酸钠干燥,过滤并浓缩。柱层析纯化得到相应目标化合物TS1~20。
实施例1.化合物TS1的制备
柱层析纯化得到白色固体,收率36.2%,熔点74-77℃。1H NMR(400MHz,DMSO-d6)δ12.74(s,1H,CONH),8.51(dd,J=8.4,4.9Hz,1H,Pyr-H),8.44–8.37(m,1H,Pyr-H),7.89(d,J=7.6Hz,1H,Naph-H),7.80(d,J=7.6Hz,1H,Pyr-H),7.78–7.74(m,1H,Phe-H),7.66–7.59(m,1H,Naph-H),7.58–7.54(m,1H,Naph-H),7.45(d,J=6.9Hz,2H,Phe-H),7.36(t,J=6.8Hz,1H,Phe-H),7.29(s,1H),7.26(t,J=7.9Hz,1H,Naph-H),7.19(t,J=8.1Hz,1H,Naph-H),7.13–7.06(m,1H,Phe-H),6.79(dd,J=134.5,8.4Hz,1H,Naph-H),4.70(dq,J=14.4,7.1Hz,1H,CH),2.53–2.46(m,1H,CH),1.35(t,J=6.4Hz,3H,CH3),1.08(dd,J=5.5,2.7Hz,2H,CH2),0.82–0.76(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.46,155.67,144.50,142.95,139.52,134.23,134.04,132.24,130.78,129.51,129.39,129.17,128.27,127.77,127.60,127.56,127.16,126.05,125.68,123.37,122.55,118.65,118.04,46.02,45.66,18.01,17.70,13.40,7.79,7.63.HRMS:m/zC28H24N4O3S2,calcd for 528.1290;found527.1213[M–H]–.HPLC purity:96.26%。
实施例2.化合物TS2的制备
柱层析纯化得到白色固体,收率31.2%,熔点90-93℃。1H NMR(400MHz,DMSO-d6)δ12.89(s,1H,CONH),8.63–8.56(m,1H,Pyr-H),8.53–8.35(m,1H,Naph-H),7.89(d,J=8.6Hz,1H,Naph-H),7.79(d,J=8.6Hz,1H,Pyr-H),7.76–7.56(m,3H,Phe-H),7.53(t,J=7.4Hz,1H,Phe-H),7.50–7.40(m,2H,Naph-H),7.27(t,J=7.9Hz,1H,Naph-H),7.22–7.14(m,1H,Py r-H),6.83(dd,J=158.1,8.4Hz,1H,Naph-H),4.87–4.53(m,1H,CH),2.61–2.53(m,1H,CH),1.59(dd,J=15.9,7.3Hz,3H,CH3),1.21–1.13(m,2H,CH2),0.93–0.83(m,2H,CH2).13C NM R(100MHz,DMSO-d6)δ170.76,155.61,144.48,142.96,134.25,132.57,132.14,130.77,130.06,129.86,129.38,128.28,128.22,128.09,127.60,127.57,127.25,127.13,125.67,123.37,122.53,118.67,118.09,45.99,45.59,17.86,17.46,13.41,7.78,7.64.HRMS:m/z C28H23BrN4O3S2,calcd fo r 606.0395;found 605.0324[M–H]–.HPLCpurity:97.16%。
实施例3.化合物TS3的制备
柱层析纯化得到白色固体,收率29.0%,熔点99-102℃。1H NMR(400MHz,DMSO-d6)δ12.65(s,1H,CONH),8.59(t,J=7.0Hz,1H,Pyr-H),8.51–8.39(m,1H,Pyr-H),7.81(d,J=8.1Hz,1H,Phe-H),7.73(d,J=7.9Hz,1H,Pyr-H),7.70(d,J=7.9Hz,1H,Phe-H),7.61(d,J=7.6Hz,1H,Phe-H),7.52(t,1H,Phe-H),7.43(dd,1H,Naph-H),7.30(d,J=8.4Hz,1H,Naph-H),7.25(d,J=9.7Hz,1H,Naph-H),7.20–7.14(m,1H,Naph-H),7.11(d,J=8.1Hz,1H,Naph-H),6.87(dd,J=133.5,8.6Hz,1H,Naph-H),4.83–4.68(m,1H,CH),2.61–2.53(m,1H,CH),2.32(s,3H,CH3),1.64–1.40(m,3H,CH3),1.21–1.11(m,2H,CH2),0.92–0.82(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.37,155.72,144.51,142.92,136.38,134.24,130.75,129.92,129.54,129.40,128.25,128.05,127.89,127.59,127.27,127.13,125.68,125.57,123.38,123.31,122.54,118.57,117.95,46.05,45.69,21.52,18.10,17.74,13.41,7.78,7.62.HRMS:m/z C29H26N4O3S2,calcd for542.1446;found 541.1370[M–H]–.HPLC purity:95.90%。
实施例4.化合物TS4的制备
柱层析纯化得到白色固体,收率37.2%,熔点92-95℃。1H NMR(400MHz,DMSO-d6)δ12.82(s,1H,CONH),8.63–8.55(m,1H,Pyr-H),8.53–8.39(m,1H,Pyr-H),7.97(d,J=8.6Hz,1H,Phe-H),7.88(d,J=8.6Hz,1H,Pyr-H),7.71(t,J=7.7Hz,1H,Naph-H),7.63(d,J=7.6Hz,1H,Phe-H),7.57(d,J=8.7Hz,1H,Phe-H),7.52–7.39(m,2H,Naph-H),7.35(d,J=8.6Hz,1H,Phe-H),7.27(t,J=7.8Hz,1H,Naph-H),7.22–7.15(m,1H,Naph-H),6.85(dd,J=145.4,8.4Hz,1H,Naph-H),4.94–4.58(m,1H,CH),2.61–2.54(m,1H,CH),1.42(dd,J=7.2,2.5Hz,3H,CH3),1.22–1.12(m,2H,CH2),0.92–0.84(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.69,155.59,144.46,142.97,138.85,134.25,130.76,130.04,129.83,129.64,129.19,128.29,128.20,128.07,127.61,127.59,127.26,127.13,125.69,125.60,123.37,122.53,118.63,118.11,46.00,45.58,17.83,17.44,13.41,7.79,7.63.HRMS:m/z C28H23ClN4O3S2,calcd for 562.0900;found561.0832[M–H]–.HPLC purity:98.27%。
实施例5.化合物TS5的制备
柱层析纯化得到白色固体,收率26.9%,熔点94-97℃。1H NMR(400MHz,DMSO-d6)δ12.81(s,1H,CONH),8.59(d,J=8.4Hz,1H,Pyr-H),8.48(t,1H,Pyr-H),8.04(dd,J=8.1,5.3Hz,1H,Phe-H),7.95(dd,J=8.1,5.3Hz,1H,Pyr-H),7.70(t,J=7.6Hz,1H,Naph-H),7.61(dd,1H,Phe-H),7.53–7.39(m,2H,Naph-H),7.34(t,J=8.8Hz,1H,Phe-H),7.26(t,J=8.0Hz,1H,Phe-H),7.22–7.07(m,2H,Naph-H),6.86(dd,J=131.7,8.4Hz,1H,Naph-H),4.87–4.63(m,1H,CH),2.61–2.53(m,1H,CH),1.63–1.35(m,3H,CH3),1.21–1.11(m,2H,CH2),0.93–0.82(m,2H,CH2).13C NMR(150MHz,DMSO-d6)δ169.16,164.70,155.65,143.94,142.96,134.77,131.33,131.15,130.76,129.40,128.25,128.03,127.58,127.26,125.69,123.38,122.55,119.37,118.06,116.76,116.61,116.36,116.21,46.04,17.92,14.12,7.78,7.59.HRMS:m/z C28H23FN4O3S2,cal cd for 546.1196;found 545.1121[M–H]–.HPLCpurity:96.16%。
实施例6.化合物TS6的制备
柱层析纯化得到白色固体,收率39.2%,熔点74-76℃。1H NMR(400MHz,DMSO-d6)δ8.58(d,J=6.1Hz,1H,Pyr-H),8.42(d,J=8.6Hz,1H,Pyr-H),8.31(d,J=8.6Hz,1H,Phe-H),8.24(d,J=8.5Hz,1H,Pyr-H),8.15(s,1H,Phe-H),8.08(d,J=8.5Hz,1H,Naph-H),7.75(s,1H,Naph-H),7.70(t,1H,Naph-H),7.55(t,J=8.6Hz,1H,Phe-H),7.45(q,1H,Phe-H),7.27(dd,J=12.2,7.9Hz,1H,Naph-H),7.17(dd,J=7.9,4.6Hz,1H,Naph-H),6.85(dd,J=144.7,8.3Hz,1H,Naph-H),4.81–4.62(m,1H,CH),2.61–2.53(m,1H,CH),1.45(dd,J=6.6,4.2Hz,3H,CH3),1.20–1.10(m,2H,CH2),0.87(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ171.22,155.39,150.23,149.92,144.16,142.99,134.27,130.83,129.61,129.38,128.19,127.99,127.71,127.60,127.15,125.63,124.89,124.73,124.37,123.33,122.53,118.61,118.22,46.34,46.01,17.83,17.54,13.39,7.78,7.62.HRMS:m/z C28H23N5O5S2,calcd for573.1141;found 572.1067[M–H]–.HPLC purity:96.35%。
实施例7.化合物TS7的制备
柱层析纯化得到白色固体,收率51.2%,熔点106-107℃。1H NMR(400MHz,DMSO-d6)δ8.59(d,J=8.5Hz,1H,Pyr-H),8.46(t,1H,Pyr-H),8.09–7.90(m,1H,Phe-H),7.74–7.68(m,1H,Pyr-H),7.62(dd,J=19.4,7.6Hz,1H,Phe-H),7.56–7.50(m,1H,Phe-H),7.45(t,J=7.6Hz,1H,Naph-H),7.37–7.25(m,2H,Naph-H),7.26–7.19(m,1H,Naph-H),7.17(dd,J=7.9,4.9Hz,1H,Naph-H),6.98(dd,J=54.3,8.4Hz,1H,Naph-H),4.87–4.58(m,1H,CH),2.60–2.53(m,1H,CH),1.47(dd,J=11.1,7.3Hz,3H,CH3),1.23–1.12(m,2H,CH2),0.92–0.81(m,2H,CH2).13CNMR(100MHz,DMSO-d6)δ170.62,155.87,155.44,144.20,143.01,142.97,134.26,133.82,133.73,133.62,130.85,130.83,129.49,129.46,128.27,128.22,128.19,128.14,127.60,127.24,127.19,125.68,125.63,123.37,123.34,122.57,118.64,118.62,118.19,46.25,46.10,18.05,17.92,13.40,7.78,7.61.HRMS:m/z C28H22F2N4O3S2,calcd for564.1101;found 563.1034[M–H]–.HPLC purity:97.74%。
实施例8.化合物TS8的制备
柱层析得到白色固体,收率78.9%,熔点112-115℃。1H NMR(400MHz,DMSO-d6)δ12.75(s,1H,CONH),8.58(d,J=8.6Hz,1H,Pyr-H),8.55–8.47(m,1H,Pyr-H),7.86(d,J=8.5Hz,1H,Phe-H),7.80(d,J=8.4Hz,1H,Pyr-H),7.69(q,J=9.4,8.5Hz,1H,Naph-H),7.58(dd,J=36.4,7.7Hz,1H,Phe-H),7.50(d,J=8.4Hz,1H,Phe-H),7.47–7.30(m,2H,Naph-H),7.27(d,J=8.5Hz,2H,Naph-H),7.20–7.15(m,1H,Naph-H),6.77(dd,J=213.5,8.4Hz,1H,Naph-H),4.80(dq,J=14.7,7.2Hz,1H,CH),2.60–2.53(m,1H,CH),1.47–1.38(m,3H,CH3),1.21–1.09(s,9H,3CH3),1.18–1.13(m,2H,CH2),0.90–0.79(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.40,157.03,155.77,144.48,142.94,136.42,134.25,130.84,129.52,129.44,128.21,127.89,127.70,127.50,127.28,127.07,126.33,125.87,125.68,125.47,123.33,122.62,118.59,118.01,45.93,45.47,35.32,35.18,31.13,31.07,17.95,17.45,13.39,7.78,7.62.HRMS:m/z C32H32N4O3S2,calcd for 584.1916;found 583.1840[M–H]–.HPLC purity:95.15%。
实施例9.化合物TS9的制备
柱层析得到白色固体,收率31.2%,熔点74-77℃。1H NMR(400MHz,DMSO-d6)δ13.16(s,1H,CONH),8.62–8.55(m,1H,Pyr-H),8.46(dd,J=11.8,4.5Hz,1H,Pyr-H),8.11(d,J=8.0Hz,1H,Phe-H),7.99(d,J=8.3Hz,1H,Pyr-H),7.84(d,J=8.2Hz,1H,Phe-H),7.71(d,J=6.5Hz,1H,Naph-H),7.66(d,J=8.5Hz,1H,Phe-H),7.62(d,J=7.1Hz,1H,Phe-H),7.54(t,J=8.9Hz,1H,Naph-H),7.46–7.42(m,1H,Naph-H),7.24(t,J=8.6Hz,1H,Naph-H),7.19–7.11(m,1H,Naph-H),6.83(dd,J=151.5,8.3Hz,1H,Naph-H),4.83–4.49(m,1H,CH),2.62–2.52(m,1H,CH),1.46(dd,J=6.8,4.5Hz,3H,CH3),1.21–1.11(m,2H,CH2),0.87(s,2H,CH2).13CNMR(100MHz,DMSO-d6)δ172.46,155.72,148.32,144.28,144.25,142.87,139.58,134.24,130.76,130.74,129.52,129.43,128.84,128.60,128.22,127.56,127.51,127.27,127.10,126.75,126.71,126.34,126.31,126.02,125.98,125.68,123.40,123.35,122.57,122.50,118.48,117.91,107.42,45.82,18.63,18.15,13.41,7.73,7.55.HRMS:m/zC29H23F3N4O3S2,calcd for 596.1164;found 595.1092[M–H]–.HPLC purity:97.19%。
实施例10.化合物TS10的制备
柱层析得到白色固体,收率31.0%,熔点62-65℃。1H NMR(400MHz,DMSO-d6)δ8.60(d,J=8.5Hz,1H,Pyr-H),8.44(d,J=4.8Hz,1H,Pyr-H),7.75–7.68(m,1H,Naph-H),7.67–7.63(m,1H,Pyr-H),7.63–7.58(m,1H,Naph-H),7.54(t,1H,Naph-H),7.48–7.44(m,1H,Naph-H),7.30(dd,J=11.9,8.0Hz,1H,Naph-H),7.20(dd,J=13.3,4.4Hz,1H,Naph-H),7.14(t,1H,Thio-H),6.99(dd,J=54.3,8.4Hz,1H,Thio-H),4.73(dq,J=14.3,7.2,6.5Hz,1H,CH),2.61–2.53(m,1H,CH),1.47(t,3H,CH3),1.21–1.13(m,2H,CH2),0.93–0.85(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ171.13,155.24,144.49,143.97,143.00,134.27,134.02,133.61,130.94,130.25,129.51,128.28,128.13,127.98,127.90,127.64,127.62,127.26,125.70,123.41,122.55,118.61,118.42,46.49,46.14,18.14,17.79,13.42,7.80,7.63.HRMS:m/z C26H21ClN4O3S3,calcd for 568.0464;found 567.0393[M–H]–.HPLCpurity:97.17%。
实施例11.化合物TS11的制备
柱层析得到白色固体,收率36.2%,熔点59-61℃。1H NMR(400MHz,DMSO-d6)δ12.60(s,1H,CONH),8.59(dt,J=8.8,4.7Hz,1H,Pyr-H),8.52–8.39(m,1H,Pyr-H),7.87(d,J=8.9Hz,1H,Phe-H),7.76(d,J=8.7Hz,1H,Pyr-H),7.73–7.68(m,1H,Phe-H),7.54(d,J=7.5Hz,1H,Naph-H),7.46–7.40(m,1H,Phe-H),7.26(t,J=8.0Hz,1H,Phe-H),7.20(d,J=4.9Hz,1H,Naph-H),7.19–7.14(m,1H,Naph-H),7.09(d,J=8.9Hz,1H,Naph-H),7.01(d,J=8.8Hz,1H,Naph-H),6.79(d,J=8.9Hz,1H,Naph-H),4.76(dq,J=14.4,7.1Hz,1H,CH),3.83(s,3H,CH3),2.61–2.53(m,1H,CH),1.42(dd,J=7.1,2.3Hz,3H,CH3),1.23–1.10(m,2H,CH2),0.93–0.81(m,2H,CH2).13C NMR(150MHz,DMSO-d6)δ169.21,163.28,155.26,143.13,141.83,139.64,134.27,130.22,129.36,128.31,128.15,127.91,127.64,127.12,125.72,123.32,122.45,114.45,112.97,107.48,56.12,47.15,18.16,13.00,7.79,6.97.HRMS:m/zC29H26N4O4S2,calcd for558.1395;found 557.1318[M–H]–.HPLC purity:98.21%。
实施例12.化合物TS12的制备
柱层析得到白色固体,收率87.0%,熔点92-93℃。1H NMR(400MHz,DMSO-d6)δ12.50(s,2H,CONH and OH),8.59(dd,J=10.8,6.2Hz,1H,Pyr-H),8.49–8.40(m,1H,Pyr-H),7.80–7.72(m,1H,Phe-H),7.74–7.66(m,2H,Phe-H),7.67–7.59(m,1H,Pyr-H),7.58–7.53(m,1H,Phe-H),7.47(dt,J=13.8,9.3Hz,2H,Naph-H),7.27(d,J=7.9Hz,1H,Naph-H),7.20–7.11(m,1H,Naph-H),7.05(t,J=9.9Hz,1H,Naph-H),6.86–6.62(m,1H,Naph-H),4.81–4.64(m,1H,CH),2.62–2.54(m,1H,CH),1.60(dd,J=15.7,7.3Hz,3H,CH3),1.20–1.14(m,2H,CH2),0.88(d,J=2.4Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.47,155.82,144.37,142.87,134.28,130.82,130.59,130.48,129.58,128.42,128.26,128.17,127.58,127.28,125.67,123.38,122.70,122.63,118.49,117.96,117.87,115.83,115.47,44.92,44.84,18.80,18.74,13.41,7.78,7.63.HRMS:m/z C28H24N4O4S2,calcd for 544.1239;found 543.1162[M–H]–.HPLC purity:96.66%。
实施例13.化合物TS13的制备
柱层析得到白色固体,收率52.0%,熔点87-90℃。1H NMR(400MHz,DMSO-d6)δ12.65(s,1H,CONH),8.65–8.54(m,1H,Pyr-H),8.53–8.40(m,1H,Pyr-H),7.84(d,J=8.3Hz,1H,Phe-H),7.76(d,J=8.3Hz,1H,Pyr-H),7.73–7.61(m,2H,Phe-H),7.52(dd,J=14.1,7.4Hz,1H,Naph-H),7.45–7.41(m,1H,Phe-H),7.33(d,J=8.3Hz,1H,Naph-H),7.21–7.14(m,1H,Naph-H),7.12(d,J=8.3Hz,2H,Naph-H),7.05(t,J=9.5Hz,1H,Naph-H),4.78(dq,J=14.3,7.1Hz,1H,CH),2.62(dd,J=15.2,7.6Hz,2H,CH2),1.60(dd,J=15.8,7.3Hz,1H,CH),1.42(dd,J=7.2,2.5Hz,2H,CH2),1.21–1.13(m,3H,CH3),1.04(dd,J=26.1,18.5Hz,2H,CH2),0.96–0.78(m,3H,CH3).13C NMR(100MHz,DMSO-d6)δ171.03,155.72,154.86,150.24,144.51,142.94,134.26,130.80,129.54,128.76,128.35,128.27,128.15,127.99,127.60,127.28,127.12,125.68,125.53,123.36,122.56,119.29,118.00,45.65,28.39,18.08,15.17,11.84,7.77,7.62.HRMS:m/z C30H28N4O3S2,calcd for 556.1603;found 555.1526[M–H]–.HPLC purity:98.41%。
实施例14.化合物TS14的制备
柱层析得到白色固体,收率48.8%,熔点78-80℃。1H NMR(400MHz,DMSO-d6)δ8.52(d,J=8.5Hz,1H,Pyr-H),8.34(d,J=4.6Hz,1H,Pyr-H),7.67–7.60(m,1H,Phe-H),7.54(dd,J=18.1,7.6Hz,1H,Pyr-H),7.45(dd,J=11.7,5.9Hz,2H,Phe-H),7.43–7.34(m,3H,Naph-H),7.18(td,J=8.2,1.2Hz,1H,Naph-H),7.07(ddd,J=7.7,4.8,2.5Hz,1H,Naph-H),6.87(dd,J=66.8,8.4Hz,1H,Naph-H),4.58(dq,J=14.3,7.0Hz,1H,CH),2.49(td,J=8.2,4.1Hz,1H,CH),1.40(t,J=7.8Hz,2H,CH2),1.10(d,J=7.4Hz,3H,CH3),0.80(d,J=3.9Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ171.53,161.56,155.89,155.21,145.17,143.89,143.03,134.27,130.78,129.46,128.29,128.16,128.03,127.64,127.15,125.70,123.92,122.51,118.65,118.37,111.66,111.45,110.00,46.26,17.65,12.45,9.06,7.60.HRMS:m/z C28H22F2N4O3S2,calcd for 564.1101;found 563.1034[M–H]–.HPLC purity:96.91%。
实施例15.化合物TS15的制备
柱层析得到白色固体,收率36.6%,熔点78-81℃。1H NMR(400MHz,DMSO-d6)δ8.59(dd,J=7.6,5.0Hz,2H,Pyr-H),8.38(dd,J=10.4,6.8Hz,2H,Phe-H),7.85(dt,J=43.7,8.0Hz,1H,Pyr-H),7.74–7.67(m,2H,Naph-H),7.59(dd,J=25.6,7.6Hz,1H,Phe-H),7.50(dd,J=14.8,7.5Hz,Phe-H),7.46–7.40(m,1H,Naph-H),7.30–7.21(m,1H,Naph-H),7.19–7.11(m,1H,Naph-H),6.91(dd,J=84.1,8.4Hz,1H,Naph-H),4.67(dq,J=14.3,7.1Hz,1H,CH),2.61–2.53(m,1H,CH),1.53–1.37(m,3H,CH3),1.22–1.09(m,2H,CH2),0.93–0.81(m,2H,CH2).13CNMR(100MHz,DMSO-d6)δ172.53,155.20,148.10,146.05,144.37,142.99,134.26,133.94,132.65,131.63,131.37,131.12,130.71,129.45,128.28,128.18,127.61,127.03,125.70,124.02,122.52,121.02,118.60,46.33,21.51,14.33,8.33,7.61.HRMS:m/zC28H23N5O5S2,calcd for573.1141;found 572.1070[M–H]–.HPLC purity:99.40%。
实施例16.化合物TS16的制备
柱层析得到白色固体,收率71.2%,熔点101-102℃。1H NMR(400MHz,DMSO-d6)δ8.64–8.56(m,1H,Pyr-H),8.48(dd,J=4.8,1.0Hz,1H,Pyr-H),8.26(dd,J=27.9,7.4Hz,1H,Phe-H),7.98(t,J=8.0Hz,1H,Pyr-H),7.87–7.80(m,1H,Phe-H),7.76–7.66(m,2H,Phe-H),7.64(dd,J=18.2,7.6Hz,1H,Naph-H),7.50(ddd,J=21.6,14.6,7.6Hz,2H,Naph-H),7.34(d,J=8.0Hz,1H,Naph-H),7.20(dd,J=8.0,4.9Hz,1H,Naph-H),7.03(dd,J=37.3,8.4Hz,1H,Naph-H),4.85–4.73(m,1H,CH),2.61–2.53(m,1H,CH),1.58–1.47(m,3H,CH3),1.21–1.10(m,2H,CH2),0.88(d,J=3.3Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ171.13,157.46,154.24,148.09,144.11,143.06,135.40,134.29,132.93,132.74,131.95,131.60,131.15,129.45,128.31,128.18,128.17,127.28,126.32,125.05,123.40,122.61,119.40,46.42,16.79,13.99,8.32,7.61.HRMS:m/z C28H23N5O5S2,calcd for 573.1141;found572.1073[M–H]–.HPLC purity:98.11%。
实施例17.化合物TS17的制备
柱层析得到白色固体,收率39.2%,熔点84-87℃。1H NMR(400MHz,DMSO-d6)δ8.52(t,J=7.3Hz,1H,Pyr-H),8.44–8.33(m,1H,Pyr-H),7.90(dd,J=9.2,7.3Hz,1H,Phe-H),7.88–7.80(m,1H,Pyr-H),7.75(dd,J=15.3,8.0Hz,1H,Phe-H),7.63(t,J=7.5Hz,1H,Phe-H),7.58(dd,J=11.2,6.2Hz,1H,Naph-H),7.47(dd,J=14.7,7.5Hz,1H,Phe-H),7.38(dt,J=13.9,6.5Hz,2H,Naph-H),7.23–7.17(m,1H,Naph-H),7.13–7.05(m,1H,Naph-H),6.89(dt,J=64.9,9.1Hz,1H,Naph-H),4.72–4.57(m,1H,CH),2.50(dd,J=12.7,7.2Hz,1H,CH),1.57–1.31(m,3H,CH3),1.14–1.02(m,2H,CH2),0.80(d,J=1.7Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.93,155.52,145.48,142.98,136.79,134.27,132.23,131.50,130.83,130.23,130.12,129.49,128.30,128.21,127.62,127.26,126.93,125.68,124.06,122.57,121.99,118.65,118.13,44.46,22.20,12.82,7.78,6.68.HRMS:m/z C28H23BrN4O3S2,calcdfor 606.0395;found 605.0322[M–H]–.HPLC purity:95.92%。
实施例18.化合物TS18的制备
柱层析得到白色固体,收率77.0%,熔点88-91℃。1H NMR(400MHz,DMSO-d6)δ11.42(s,1H,CONH),8.60(d,J=8.5Hz,1H,Pyr-H),8.43(d,J=4.8Hz,1H,Pyr-H),7.75–7.62(m,2H,Naph-H),7.54(td,J=7.6,3.5Hz,1H,Pyr-H),7.46(dd,J=7.7,3.2Hz,1H,Naph-H),7.28(d,J=9.1Hz,1H,Naph-H),7.15(dd,J=8.1,4.6Hz,1H,Naph-H),7.09–7.00(m,1H,Naph-H),4.81(dq,J=14.4,7.2Hz,1H,CH),2.51(d,J=3.7Hz,1H,CH),1.56(ddd,J=29.0,14.7,7.3Hz,3H,CH3),1.36(d,J=17.2Hz,9H,3CH3),1.18(dd,J=8.8,5.6Hz,2H,CH2),0.88(q,J=5.3Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.49,170.32,155.77,144.51,142.97,134.29,131.30,129.59,128.30,128.20,127.62,127.30,125.68,124.06,122.59,118.58,117.52,62.67,47.71,24.19,20.88,14.21,8.32,6.53.HRMS:m/z C26H28N4O3S2,calcd for 508.1603;found 507.1535[M–H]–.HPLC purity:99.05%。
实施例19.化合物TS19的制备
柱层析得到白色固体,收率79.9%,熔点77-80℃。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H,CONH),8.60(d,J=8.5Hz,1H,Pyr-H),8.42(d,J=4.6Hz,1H,Pyr-H),7.77–7.61(m,2H,Naph-H),7.55(t,J=7.6Hz,1H,Pyr-H),7.46(dd,J=7.4,4.2Hz,1H,Naph-H),7.27(t,J=7.7Hz,1H,Naph-H),7.15(dd,J=8.0,4.2Hz,1H,Naph-H),7.06(d,J=8.4Hz,1H,Naph-H),4.78(p,J=7.1Hz,1H,CH),3.38(ddd,J=23.1,14.8,5.7Hz,2H,CH2),2.62–2.53(m,1H,CH),1.56(ddd,J=24.2,16.3,7.3Hz,3H,CH3),1.27(dt,J=21.0,7.3Hz,3H,CH3),1.20–1.09(m,2H,CH2),0.88(d,J=3.9Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.08,155.83,144.48,143.46,135.21,130.80,129.09,128.31,128.25,128.19,127.63,127.30,125.68,124.06,122.64,119.08,117.98,48.21,46.00,17.49,13.42,9.46,7.78,7.62.HRMS:m/zC24H24N4O3S2,calcd for480.1290;found 479.1218[M–H]–.HPLC purity:97.77%。
实施例20.化合物TS20的制备
柱层析得到白色固体,收率36.6%,熔点92-95℃。1H NMR(400MHz,DMSO-d6)δ12.28(s,1H,CONH),8.61(d,J=8.5Hz,1H,Pyr-H),8.42(d,J=4.4Hz,1H,Pyr-H),7.69(ddd,J=15.9,14.3,7.9Hz,2H,Naph-H),7.55(t,J=7.5Hz,1H,Pyr-H),7.47(dd,J=7.5,2.8Hz,1H,Naph-H),7.27(t,J=8.6Hz,1H,Naph-H),7.20–7.10(m,1H,Naph-H),7.07(d,J=8.3Hz,1H,Naph-H),4.75(dd,J=14.6,7.3Hz,1H,CH),3.29(s,3H,CH3),2.63–2.53(m,1H,CH),1.56(ddd,J=25.6,17.1,7.2Hz,3H,CH3),1.17(d,J=8.3Hz,2H,CH2),0.89(d,J=4.0Hz,2H,CH2).13CNMR(100MHz,DMSO-d6)δ171.57,155.90,155.72,146.47,143.01,134.30,131.25,129.55,129.09,128.27,127.59,127.30,125.72,123.94,122.65,119.36,118.06,45.55,44.92,18.03,14.30,8.47,7.65.HRMS:m/z C23H22N4O3S2,calcd for 466.1133;found465.1065[M–H]–.HPLC purity:96.96%。
化合物PS1~PS20的合成路线:
试剂及条件:(i)碳酸氢钠,乙醇,60℃;(ii)10%钯碳,氢气,四氢呋喃,室温;(iii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(iv)2-溴丙酸甲酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温;(vi)酰基磺酰胺,1-乙基-(3-二甲基氨基丙基)碳醯二亚胺盐酸盐,4-二甲氨基吡啶,二氯甲烷,室温。
路线中R苯基、4-溴苯、4-甲基苯、4-氯苯、4-氟苯、4-硝基苯、2,4-二氟苯、4-叔丁基苯、4-(三氟甲基)苯、5-氯噻吩、4-甲氧基苯、4-羟基苯、4-乙基苯、3,5-二氟苯、3-硝基苯、2-硝基苯、3-溴苯、叔丁基、乙基、甲基。
化合物PE-B的制备
将4-氯-3-硝基吡啶(1.0g,6.3mmol)、4-环丙基-1-萘胺(1.4g,7.6mmol)与碳酸氢钠(1.6g,18.9mmol)溶于50mL乙醇溶液中,60℃回流10h(TLC检测反应完毕)。冷却至室温旋蒸移除有机溶剂,随后加入30mL二氯甲烷并用饱和氯化钠水溶液洗涤(3×10mL),分取有机层,无水Na2SO4干燥。过滤收集液相,减压浓缩拌样后柱层析纯化得黄色中间体N-(4-环丙基萘-1-基)-3-硝基-4-胺(PE-B)。收率69.5%,熔点76-79℃。ESI-MS:m/z C18H15N3O2,calcdfor 305.12;found 306.44[M+H]+。
化合物PE-C的制备
合成方法与TE-C相同,所不同为初始原料为中间体PE-B(2.0g,6.6mmol)与10%钯碳(0.2g)在氢气条件下还原得黄色中间体N-(4-环丙基萘-1-基)-3-硝基吡啶-4-胺(PE-C)。收率76.2%,熔点192-193℃。ESI-MS:m/z C18H17N3,calcd for 275.14;found 276.45[M+H]+。
化合物P-D的制备
制备方法同T-D,所不同为使用N4-(4-环丙基萘-1-基)吡啶-3,4-二胺(PE-C)为本步骤初始原料,最终得到黄色固体1-(4-环丙基萘-1-基)-1H-咪唑并[4,5-c]吡啶-2-硫醇,产率80.1%。熔点198-200℃。ESI-MS:m/z C19H15N3S,calcd for 317.10;found 316.11[M–H]–。
化合物P-E的制备
制备方法同T-E相似,所不同为1-(4-环丙基萘-1-基)-1H-咪唑并[4,5-c]吡啶-2-硫醇(P-D)为本步骤初始原料。最终柱层析纯化得到无色油状物2-((1-(4-环丙基萘-1-基)-1H-咪唑并[4,5-c]吡啶-2-基)硫代)丙酸甲酯(P-E),产率74.6%。ESI-MS:m/zC23H21N3O2S,calcd for403.1354;found 404.26[M+H]+。
化合物P7的制备
制备方法同T7,所不同为2-((1-(4-环丙基萘-1-基)-1H-咪唑并[4,5-c]吡啶-2-基)硫代)丙酸甲酯为本步骤初始原料进行水解。最终经过相同后处理获得对应羧酸中间体P7。产率92.1%,熔点161-163℃。ESI-MS:m/z C22H19N3O2S,calcd for 389.1198;found388.51[M–H]–。
化合物PS1~20的制备通法
反应方法同目标化合物TS-1-20,最终柱层析纯化得到相应目标化合物PS-1-20。
实施例21.化合物PS1的制备
柱层析纯化得到白色固体,收率62.1%,熔点102-104℃。1H NMR(400MHz,DMSO-d6)δ9.14–9.01(m,1H,Pyr-H),8.60(d,J=8.5Hz,1H,Pyr-H),8.29(d,J=5.6Hz,1H,Naph-H),7.86(d,J=7.5Hz,1H,Naph-H),7.81(d,J=7.6Hz,1H,Naph-H),7.72(t,J=6.3Hz,1H,Phe-H),7.63(t,1H,Phe-H),7.58(dd,J=11.0,3.6Hz,1H,Naph-H),7.55–7.49(m,2H,Phe-H),7.46(t,1H,Pyr-H),7.40(t,J=7.7Hz,1H,Phe-H),7.08–6.82(m,2H,Naph-H),4.63(dq,J=14.0,7.0Hz,1H,CH),2.57(s,1H,CH),1.46(dd,J=12.1,7.1Hz,3H,CH3),1.23–1.10(m,2H,CH2),0.89(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ171.08,143.80,143.21,140.93,140.57,138.66,134.26,133.29,129.28,129.18,129.03,128.34,128.26,127.74,127.69,127.66,127.19,125.74,123.42,123.36,122.52,122.44,106.20,47.38,47.13,18.73,18.55,13.44,7.83,7.62.HRMS:m/zC28H24N4O3S2,calcd for 528.1290;found 527.1215[M–H]–.HPLC purity:98.40%。
实施例22.化合物PS2的制备
柱层析纯化得到白色固体,收率47.8%,熔点109-111℃。1H NMR(400MHz,DMSO-d6)δ9.18(d,J=3.3Hz,1H,Pyr-H),8.61(d,J=8.5Hz,1H,Pyr-H),8.34(d,J=5.9Hz,1H,Naph-H),7.74(t,J=2.0Hz,1H,Naph-H),7.72(d,J=2.0Hz,1H,Naph-H),7.67(d,J=2.5Hz,2H,Phe-H),7.64(t,1H,Phe-H),7.57(t,J=1.9Hz,1H,Phe-H),7.55–7.52(m,1H,Naph-H),7.47(t,J=7.3Hz,1H,Pyr-H),7.13(dd,J=10.4,5.9Hz,1H,Naph-H),6.97(dd,J=54.5,8.4Hz,1H,Naph-H),4.54(dq,J=14.1,7.1Hz,1H,CH),2.58(dd,J=9.4,4.1Hz,1H,CH),1.55–1.42(m,3H,CH3),1.17(dd,J=5.6,4.0Hz,2H,CH2),0.95–0.84(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.04,144.67,143.35,140.71,139.48,137.17,134.28,131.90,131.79,129.73,129.70,129.21,128.36,128.31,127.68,127.60,127.26,125.72,123.46,123.41,122.48,122.42,106.56,48.58,48.23,19.32,19.06,13.47,7.86,7.61.HRMS:m/zC28H23BrN4O3S2,calcd for 606.0395;found605.0322[M–H]–.HPLC purity:99.10%。
实施例23.化合物PS3的制备
柱层析纯化得到白色固体,收率32.5%,熔点76-77℃。1H NMR(600MHz,DMSO-d6)δ9.00(d,J=10.4Hz,1H,Pyr-H),8.60(d,J=9.0Hz,1H,Pyr-H),8.27(d,J=5.7Hz,1H,Naph-H),7.76–7.68(m,2H,Naph-H),7.60(dd,J=28.0,7.6Hz,1H,Pyr-H),7.56–7.50(m,1H,Naph-H),7.45(dd,J=14.6,7.6Hz,1H,Phe-H),7.38–7.25(m,2H,Phe-H),7.17(d,J=8.0Hz,1H,Phe-H),6.99(dd,J=15.5,7.1Hz,1H,Naph-H),6.96–6.77(m,1H,Naph-H),4.68–4.57(m,1H,CH),2.62–2.53(m,1H,CH),2.37(s,2H,CH2),2.32(s,1H,CH),1.44(dd,J=14.1,7.1Hz,3H,CH3),1.17(t,J=5.5Hz,2H,CH2),0.89(q,J=5.4Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.77,143.85,143.32,143.13,142.32,141.91,141.57,134.25,129.77,129.66,129.48,129.27,128.32,128.18,127.86,127.82,127.65,127.20,126.09,125.73,123.42,122.52,105.95,47.06,46.80,21.38,18.60,18.33,13.44,7.81,7.62.HRMS:m/z C29H26N4O3S2,calcd for 542.1446;found541.1375[M–H]–.HPLC purity:97.60%。
实施例24.化合物PS4的制备
柱层析纯化得到白色固体,收率58.8%,熔点85-88℃。1H NMR(400MHz,DMSO-d6)δ9.17(d,J=3.3Hz,1H,Pyr-H),8.61(d,J=8.5Hz,1H,Pyr-H),8.34(d,J=5.9Hz,1H,Naph-H),7.82(t,J=9.4Hz,2H,Naph-H),7.76(d,J=8.5Hz,1H,Pyr-H),7.74–7.70(m,1H,Phe-H),7.65(dd,J=8.0,6.0Hz,2H,Naph-H),7.53(d,1H,Phe-H),7.49–7.45(m,2H,Phe-H),7.42(d,J=8.6Hz,1H,Naph-H),4.60–4.49(m,1H,CH),2.62–2.54(m,1H,CH),1.49(dd,J=13.2,6.9Hz,3H,CH3),1.20–1.14(m,2H,CH2),0.93–0.86(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.47,143.48,143.35,140.71,137.36,137.02,134.28,129.63,129.59,129.54,128.97,128.85,128.37,128.31,128.08,127.68,127.59,127.27,125.76,125.74,123.46,122.48,106.56,48.55,48.24,19.30,19.06,13.47,7.86,7.61.HRMS:m/z C28H23ClN4O3S2,calcd for 562.0900;found 561.0828[M–H]–.HPLC purity:96.40%。
实施例25.化合物PS5的制备
柱层析纯化得到淡黄色固体,收率41.2%,熔点87-88℃。1H NMR(400MHz,DMSO-d6)δ9.11(d,J=4.4Hz,1H,Pyr-H),8.61(d,J=8.5Hz,1H,Pyr-H),8.31(d,J=5.8Hz,1H,Naph-H),7.91–7.89(m,1H,Naph-H),7.87–7.83(m,1H,Naph-H),7.76–7.70(m,1H,Pyr-H),7.64(dd,J=9.4,7.8Hz,1H,Phe-H),7.54(t,J=7.6Hz,1H,Phe-H),7.47(t,J=7.2Hz,1H,Naph-H),7.30(t,J=8.9Hz,1H,Phe-H),7.20(t,J=8.8Hz,1H,Phe-H),7.07(dd,J=9.0,5.9Hz,1H,Naph-H),6.97(dd,J=50.5,8.4Hz,1H,Naph-H),4.70–4.47(m,1H,CH),2.62–2.54(m,1H,CH),1.48(dd,J=13.5,7.1Hz,3H,CH3),1.19–1.15(m,2H,CH2),0.92–0.86(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ171.58,146.13,143.27,141.11,141.08,140.66,140.60,140.26,134.28,130.86,130.80,130.76,130.71,129.27,129.24,129.06,128.97,128.34,128.25,127.70,127.66,127.23,127.21,125.74,125.71,123.43,123.39,122.50,122.43,116.57,116.34,116.19,116.07,115.97,115.84,106.30,47.97,47.71,19.01,18.82,13.44,7.84,7.61.HRMS:m/z C28H23FN4O3S2,calcd for546.1196;found 545.1123[M–H]–.HPLC purity:97.00%。
实施例26.化合物PS6的制备
柱层析纯化得到白色固体,收率32.6%,熔点118-121℃。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H,Pyr-H),8.62(d,J=8.5Hz,1H,Pyr-H),8.39(d,J=6.1Hz,1H,Naph-H),7.84–7.77(m,1H,Naph-H),7.75(d,J=8.4Hz,1H,Naph-H),7.72–7.68(m,1H,Pyr-H),7.55(td,J=7.6,4.0Hz,1H,Naph-H),7.49(dd,J=7.6,3.6Hz,1H,Phe-H),7.34–7.23(m,2H,Phe-H),7.24–7.15(m,1H,Phe-H),7.14–7.09(m,1H,Naph-H),7.09–7.01(m,1H,Naph-H),4.51(qd,J=6.8,2.8Hz,1H,CH),2.63–2.54(m,1H,CH),1.54(dd,J=19.0,7.0Hz,3H,CH3),1.17(d,J=8.4Hz,2H,CH2),0.91(d,J=4.6Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.72,160.35,145.77,143.55,140.79,137.81,135.46,134.30,133.20,133.07,129.15,128.41,127.72,127.33,125.79,123.48,123.45,122.49,122.40,111.70,111.48,107.04,105.34,49.42,19.74,13.49,7.88,7.60.HRMS:m/z C28H23N5O5S2,calcd for 573.1141;found 572.1065[M–H]–.HPLC purity:95.30%。
实施例27.化合物PS7的制备
柱层析纯化得到白色固体,收率31.2%,熔点136-139℃。1H NMR(400MHz,DMSO-d6)δ9.37(s,1H,Pyr-H),8.62(d,J=8.5Hz,1H,Pyr-H),8.42(dd,J=6.2,2.8Hz,1H,Phe-H),8.23(d,J=8.8Hz,1H,Naph-H),8.17(d,J=8.8Hz,1H,Naph-H),7.94(dd,J=12.8,8.8Hz,2H,Naph-H),7.71(t,J=6.8Hz,1H,Pyr-H),7.60–7.52(m,1H,Phe-H),7.49(dd,J=7.6,2.7Hz,1H,Phe-H),7.33(dd,J=8.7,6.4Hz,1H,Naph-H),7.07(dd,J=18.5,8.4Hz,1H,Naph-H),4.54–4.39(m,1H,CH),2.63–2.54(m,1H,CH),1.55(dd,J=19.7,7.0Hz,3H,CH3),1.17(d,J=8.4Hz,2H,CH2),0.91(d,J=4.8Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.46,150.17,149.92,149.07,149.04,146.29,143.63,140.85,140.81,136.90,136.84,134.62,134.53,134.29,129.10,129.09,128.87,128.86,128.43,127.74,127.37,127.23,127.18,125.80,123.86,123.79,123.49,123.46,122.48,122.38,107.27,107.22,50.17,50.03,20.10,20.02,13.49,7.89,7.64.HRMS:m/zC28H22F2N4O3S2,calcd for 564.1101;found563.1030[M–H]–.HPLC purity:95.72%。
实施例28.化合物PS8的制备
柱层析纯化得到白色固体,收率66.6%,熔点110-113℃。1H NMR(400MHz,DMSO-d6)δ9.03(d,J=23.5Hz,1H,Pyr-H),8.59(dd,J=8.5,5.0Hz,1H,Pyr-H),8.27(dd,J=5.4,3.0Hz,1H,Naph-H),7.78(dd,J=11.7,8.6Hz,2H,Naph-H),7.71(t,1H,Pyr-H),7.65–7.56(m,1H,Phe-H),7.56–7.50(m,2H,Phe-H),7.45(q,J=7.5,6.8Hz,1H,Naph-H),7.38(d,J=8.6Hz,1H,Phe-H),6.99(dd,J=12.3,7.0Hz,1H,Naph-H),6.79(dd,J=114.0,7.0Hz,1H,Naph-H),4.66(dq,J=20.8,7.1Hz,1H,CH),2.61–2.54(m,1H,CH),1.49–1.43(m,3H,CH3),1.24(s,6H,2CH3),1.19–1.15(m,2H,CH2),1.13(s,3H,CH3),0.93–0.84(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.76,156.48,155.85,143.41,143.15,141.56,140.57,139.41,137.70,137.24,134.24,129.32,128.32,128.16,127.82,127.69,127.20,126.11,125.85,125.58,123.29,122.52,105.99,46.93,46.42,35.30,35.17,31.17,31.10,18.48,18.03,13.42,7.80,7.64.HRMS:m/z C32H32N4O3S2,calcd for 584.1916;found 583.1846[M–H]–.HPLC purity:97.40%。
实施例29.化合物PS9的制备
柱层析纯化得到白色固体,收率50.5%,熔点109-112℃。1H NMR(400MHz,DMSO-d6)δ9.30(s,1H,Pyr-H),8.62(d,J=8.5Hz,1H,Pyr-H),8.39(dd,J=5.3,3.0Hz,1H,Naph-H),7.94(t,2H,Naph-H),7.80(d,J=8.1Hz,1H,Pyr-H),7.76–7.70(m,2H,Phe-H),7.68(t,1H,Naph-H),7.56(t,1H,Phe-H),7.52–7.46(m,1H,Phe-H),7.24(dd,J=12.8,6.1Hz,1H,Naph-H),7.01(dd,J=50.1,8.4Hz,1H,Naph-H),4.50(dd,J=11.0,7.1Hz,1H,CH),2.58(d,J=5.6Hz,1H,CH),1.53(dd,J=14.4,7.0Hz,3H,CH3),1.18(d,J=8.4Hz,2H,CH2),0.91(d,J=3.4Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.45,147.57,145.60,145.54,143.50,140.81,140.74,138.09,137.95,135.82,135.65,134.29,129.15,128.42,128.35,127.76,127.70,127.40,127.36,127.32,125.82,125.78,125.75,125.69,123.43,122.46,106.95,106.88,49.58,49.25,19.82,19.59,13.47,7.77,7.59.HRMS:m/z C29H23F3N4O3S2,calcd for596.1164;found 595.1089[M–H]–.HPLC purity:95.19%。
实施例30.化合物PS10的制备
柱层析纯化得到白色固体,收率28.8%,熔点108-111℃。1H NMR(400MHz,DMSO-d6)δ11.97(s,1H,CONH),9.38(d,J=5.9Hz,1H,Pyr-H),8.64(d,J=8.5Hz,1H,Pyr-H),8.44(d,J=5.9Hz,1H,Naph-H),7.75(t,J=8.3Hz,2H,Naph-H),7.60–7.54(m,1H,Pyr-H),7.51(d,J=7.4Hz,1H,Naph-H),7.36(t,J=6.7Hz,1H,Naph-H),7.29(t,J=4.5Hz,1H,Naph-H),7.11(dd,J=8.3,3.6Hz,1H,Thio-H),7.00(dd,J=13.7,4.0Hz,1H,Thio-H),4.65–4.35(m,1H,CH),2.60(ddd,J=13.6,8.4,5.6Hz,1H,CH),1.58(dd,J=18.0,7.0Hz,3H,CH3),1.18(d,J=8.4Hz,2H,CH2),0.91(dd,J=14.0,7.4Hz,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.48,146.52,143.67,136.51,134.30,134.20,130.17,130.09,129.07,128.47,127.77,127.40,127.18,126.66,126.62,125.82,123.53,123.48,122.50,122.38,107.33,50.26,50.12,20.18,20.09,13.51,7.85,7.59.HRMS:m/z C26H21ClN4O3S3,calcd for 568.0464;found567.0381[M–H]–.HPLC purity:98.42%。
实施例31.化合物PS11的制备
柱层析纯化得到白色固体,收率44.9%,熔点84-86℃。1H NMR(400MHz,DMSO-d6)δ11.97(s,1H,CONH),9.00(d,J=9.6Hz,1H,Pyr-H),8.60(d,J=8.5Hz,1H,Pyr-H),8.26(d,J=5.6Hz,1H,Naph-H),7.82(d,J=8.9Hz,1H,Pyr-H),7.76(d,J=9.0Hz,1H,Naph-H),7.74–7.68(m,1H,Phe-H),7.60(dd,J=19.1,7.9Hz,1H,Naph-H),7.53(d,J=7.3Hz,1H,Phe-H),7.49–7.40(m,1H,Phe-H),7.03(d,J=8.8Hz,1H,Phe-H),7.00–6.76(m,3H,Naph-H),4.66(dd,J=14.0,7.1Hz,1H,CH),3.76(d,J=28.6Hz,3H,CH3),2.60–2.54(m,1H,CH),1.44(t,J=7.6Hz,3H,CH3),1.21–1.13(m,2H,CH2),0.94–0.84(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.50,163.15,155.54,143.25,143.16,141.76,140.54,139.49,134.24,130.26,130.21,129.25,128.32,127.85,127.65,127.13,125.72,123.33,122.54,114.43,114.18,105.95,56.12,46.77,46.42,18.48,18.17,13.43,7.81,7.63.HRMS:m/z C29H26N4O4S2,calcd for 558.1395;found 557.1318[M–H]–.HPLC purity:96.91%。
实施例32.化合物PS12的制备
柱层析纯化得到白色固体,收率63.4%,熔点110-113℃。1H NMR(400MHz,DMSO-d6)δ11.94(s,1H,CONH),10.48(d,J=18.0Hz,1H,OH),9.00(d,J=8.3Hz,1H,Pyr-H),8.60(d,J=8.4Hz,1H,Pyr-H),8.26(d,J=4.7Hz,1H,Naph-H),7.72(d,J=8.3Hz,2H,Naph-H),7.65(d,J=8.9Hz,1H,Pyr-H),7.58(d,J=7.6Hz,1H,Naph-H),7.56–7.50(m,1H,Phe-H),7.46(d,J=6.3Hz,1H,Phe-H),7.07–6.96(m,1H,Phe-H),6.96–6.90(m,1H,Phe-H),6.84(d,J=8.5Hz,1H,Naph-H),6.72(d,J=8.6Hz,1H,Naph-H),4.66(dq,J=14.4,7.3Hz,1H,CH),2.62–2.55(m,1H,CH),1.44(dd,J=10.1,7.3Hz,3H,CH3),1.19–1.14(m,2H,CH2),0.89(s,2H,CH2).13CNMR(100MHz,DMSO-d6)δ170.34,162.23,143.10,143.04,142.15,140.54,139.81,134.24,130.43,129.33,128.32,128.20,127.92,127.89,127.63,127.17,125.72,123.40,122.54,122.45,115.69,115.49,105.87,46.64,46.34,18.53,18.27,13.43,7.78,7.60.HRMS:m/z C28H24N4O4S2,calcd for 544.1239;found 543.1162[M–H]–.HPLC purity:97.74%。
实施例33.化合物PS13的制备
柱层析纯化得到白色固体,收率34.2%,熔点94-96℃。1H NMR(400MHz,DMSO-d6)δ9.02(d,J=12.9Hz,1H,Pyr-H),8.60(d,J=8.5Hz,1H,Pyr-H),8.27(d,J=5.4Hz,1H,Naph-H),7.78(d,J=8.2Hz,1H,Pyr-H),7.73(d,J=8.1Hz,2H,Naph-H),7.60(dd,J=23.3,7.6Hz,1H,Naph-H),7.56–7.48(m,1H,Phe-H),7.45(t,J=8.3Hz,1H,Phe-H),7.33(d,J=8.2Hz,1H,Phe-H),7.20(d,J=8.2Hz,1H,Phe-H),7.00(dd,J=10.1,7.2Hz,1H,Naph-H),6.85(dd,J=76.4,7.0Hz,1H,Naph-H),4.65(dq,J=14.5,7.1Hz,1H,CH),2.60(dd,J=17.4,9.3Hz,2H,CH2),2.54(d,J=7.7Hz,1H,CH),1.45(t,J=7.0Hz,3H,CH3),1.17(d,J=7.2Hz,2H,CH2),1.15–0.97(m,3H,CH3),0.92–0.86(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ170.72,149.82,143.38,143.15,141.47,140.53,139.18,137.87,137.53,134.25,129.32,128.55,128.32,128.17,128.00,127.92,127.82,127.64,127.20,125.63,123.32,122.53,105.98,46.99,46.62,28.33,18.53,18.20,15.38,13.43,7.88,7.63.HRMS:m/zC30H28N4O3S2,calcd for 556.1603;found 555.1525[M–H]–.HPLC purity:96.80%。
实施例34.化合物PS14的制备
柱层析纯化得到白色固体,收率74.9%,熔点89-92℃。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H,Pyr-H),8.62(d,J=8.3Hz,1H,Pyr-H),8.37(d,J=5.1Hz,1H,Naph-H),7.85–7.65(m,3H,Naph-H),7.55(t,1H,Pyr-H),7.49(t,1H,Phe-H),7.22(t,J=18.0Hz,2H,Phe-H),7.13–7.01(m,2H,Naph-H),4.55–4.44(m,1H,CH),2.63–2.55(m,1H,CH),1.55(dd,J=20.5,6.6Hz,3H,CH3),1.17(d,J=7.2Hz,2H,CH2),0.91(s,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.46,145.41,143.43,140.85,138.32,136.00,134.27,133.03,132.93,129.18,128.37,127.68,127.50,127.47,127.32,125.77,123.47,122.53,122.42,111.55,111.50,111.38,111.28,106.80,105.56,105.30,105.22,49.75,19.99,13.42,7.86,7.56.HRMS:m/z C28H22F2N4O3S2,calcd for 564.1101;found 563.1033[M–H]–.HPLC purity:95.27%。
实施例35.化合物PS15的制备
柱层析纯化得到白色固体,收率38.8%,熔点116-119℃。1H NMR(400MHz,DMSO-d6)δ9.28(d,J=9.3Hz,1H,Pyr-H),8.55(d,J=8.5Hz,1H,Pyr-H),8.44–8.31(m,2H,Phe-H),8.20(t,1H,Pyr-H),8.05(t,J=8.8Hz,1H,Naph-H),7.67(d,J=7.8Hz,1H,Naph-H),7.64(d,J=5.5Hz,1H,Naph-H),7.63–7.56(m,1H,Naph-H),7.52–7.45(m,1H,Phe-H),7.43(t,J=6.3Hz,1H,Phe-H),7.27(t,J=6.7Hz,1H,Naph-H),7.01(t,J=8.6Hz,1H,Naph-H),4.43–4.35(m,1H,CH),2.56–2.46(m,1H,CH),1.48(dd,J=20.5,6.9Hz,3H,CH3),1.14–1.06(m,2H,CH2),0.89–0.80(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.46,161.72,147.52,146.44,146.19,143.65,140.81,136.63,134.31,133.59,130.45,129.07,128.44,127.74,127.36,127.14,126.04,125.81,123.50,122.47,122.37,122.30,107.28,50.29,50.18,20.17,20.12,13.50,7.90,7.62.HRMS:m/z C28H23N5O5S2,calcd for 573.1141;found572.1066[M–H]–.HPLC purity:98.82%。
实施例36.化合物PS16的制备
柱层析纯化得到白色固体,收率32.1%,熔点142-145℃。1H NMR(DMSO-d6,400MHz)δ9.42(1H,s,Pyr-H),8.62(1H,d,Pyr-H),8.44(1H,d,J=6.2Hz,Naph-H),8.01–7.87(1H,m,Pyr-H),7.73(2H,dd,J=9.3,5.2Hz,Phe-H),7.68–7.64(1H,m,Naph-H),7.64(1H,d,J=3.5Hz,Naph-H),7.59(1H,d,J=5.6Hz,Phe-H),7.57–7.53(1H,m,Phe-H),7.50(1H,d,J=7.6Hz,Naph-H),7.38(1H,d,J=5.0Hz,Naph-H),7.12(1H,t,J=7.6Hz,Naph-H),4.51(1H,q,J=6.9,5.7Hz,CH),2.64–2.54(1H,m,CH),1.60(3H,dd,J=23.4,6.9Hz,CH3),1.21–1.12(2H,m,CH2),0.95–0.84(2H,m,CH2).13C NMR(150MHz,DMSO-d6)δ170.61,156.32,154.36,148.10,143.06,135.38,134.29,133.30,132.72,132.00,131.96,131.14,129.46,128.69,128.16,127.61,127.26,125.70,125.65,125.02,123.39,121.59,118.65,46.39,18.16,13.41,8.55,7.61.HRMS:m/z C28H23N5O5S2,calcd for 573.1141;found 572.1071[M–H]–.HPLC purity:95.55%。
实施例37.化合物PS17的制备
柱层析纯化得到白色固体,收率65.9%,熔点110-113℃。1H NMR(600MHz,DMSO-d6)δ9.24(d,J=15.6Hz,1H,Pyr-H),8.62(d,J=8.5Hz,1H,Pyr-H),8.38(dd,J=6.0,3.1Hz,1H,Phe-H),7.85(d,J=19.3Hz,1H,Pyr-H),7.78–7.64(m,4H,Naph-H),7.55(q,J=8.4Hz,1H,Phe-H),7.51–7.46(m,1H,Phe-H),7.37(dt,J=32.8,7.9Hz,1H,Phe-H),7.23(dd,J=11.3,6.0Hz,1H,Naph-H),7.04(dd,J=30.3,8.4Hz,1H,Naph-H),4.51(dd,J=11.7,7.0Hz,1H,CH),2.62–2.56(m,1H,CH),1.52(dd,J=25.0,7.1Hz,3H,CH3),1.21–1.12(m,2H,CH2),0.91(q,J=2.6Hz,2H,CH2).13C NMR(150MHz,DMSO-d6)δ175.00,145.37,143.49,141.16,138.27,136.72,134.91,134.32,133.54,131.13,130.05,129.19,128.80,128.40,127.72,127.30,126.45,125.79,123.49,122.41,120.94,106.35,49.09,19.53,18.99,13.09,7.87,7.62.HRMS:m/z C28H23BrN4O3S2,calcd for 606.0395;found 605.0326[M–H]–.HPLCpurity:97.00%。
实施例38.化合物PS18的制备
柱层析纯化得到白色固体,收率37.2%,熔点100-103℃。1H NMR(600MHz,DMSO-d6)δ12.40(s,1H,CONH),8.98(d,J=3.7Hz,1H,Pyr-H),8.61(d,J=8.5Hz,1H,Pyr-H),8.23(d,J=6.8Hz,1H,Naph-H),7.72(t,J=7.7Hz,1H,Pyr-H),7.66(dd,J=7.5,3.1Hz,1H,Naph-H),7.55(t,J=7.6Hz,1H,Naph-H),7.47(dd,J=7.6,3.9Hz,1H,Naph-H),7.02(dd,J=8.5,2.7Hz,1H,Naph-H),6.91(dd,J=5.6,2.1Hz,1H,Naph-H),4.66–4.53(m,1H,CH),3.33(s,9H,3CH3),2.58(ddd,J=13.9,8.5,5.4Hz,1H,CH),1.54(dd,J=31.9,7.1Hz,3H,CH3),1.21(dd,J=14.7,7.4Hz,2H,CH2),0.94–0.86(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ172.57,145.45,143.49,140.77,135.92,134.85,134.30,131.11,130.03,128.39,127.72,127.31,126.42,125.78,123.50,122.40,121.52,106.86,66.11,49.19,49.16,21.49,19.60,19.44,13.49,7.83,7.61.HRMS:m/zC26H28N4O3S2,calcd for 508.1603;found 507.1529[M–H]–.HPLC purity:96.19%。
实施例39.化合物PS19的制备
柱层析纯化得到白色固体,收率89.1%,熔点112-113℃。1H NMR(400MHz,DMSO-d6)δ8.95(s,1H,Pyr-H),8.61(d,J=8.5Hz,1H,Pyr-H),8.24(d,J=5.0Hz,1H,Naph-H),7.72(t,J=7.6Hz,1H,Pyr-H),7.66(t,J=7.1Hz,1H,Naph-H),7.55(t,J=7.5Hz,1H,Naph-H),7.47(d,J=6.5Hz,1H,Naph-H),7.01(t,1H,Naph-H),6.91(d,J=5.3Hz,1H,Naph-H),4.68(dd,J=11.6,7.0Hz,1H,CH),2.58(p,J=8.3Hz,1H,CH),1.52(dd,J=16.0,7.0Hz,3H,CH3),1.36(s,9H,Et),1.18–1.16(m,2H,CH2),0.91–0.86(m,2H,CH2).13C NMR(100MHz,DMSO-d6)δ155.37,143.03,142.90,142.57,140.67,140.08,134.29,129.42,128.27,128.13,127.61,127.19,125.68,123.39,122.53,105.70,57.47,56.34,24.58,24.47,24.25,24.21,13.42,7.79,7.65.HRMS:m/zC24H24N4O3S2,calcd for 480.1290;found 479.1222[M–H]–.HPLC purity:99.42%。
实施例40.化合物PS20的制备
柱层析纯化得到白色固体,收率72.0%,熔点70-72℃。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H,Pyr-H),8.61(d,J=8.5Hz,1H,Pyr-H),8.26(d,J=5.5Hz,1H,Naph-H),7.81–7.64(m,2H,Naph-H),7.54(t,J=7.6Hz,1H,Pyr-H),7.51–7.37(m,1H,Naph-H),7.05(d,J=8.4Hz,1H,Naph-H),6.96(d,J=5.5Hz,1H,Naph-H),4.75–4.69(m,1H,CH),3.19(d,J=13.4Hz,3H,CH3),2.62–2.52(m,1H,CH),1.55(dd,J=19.6,7.1Hz,3H,CH3),1.17(d,J=8.3Hz,2H,CH2),0.88(d,J=3.9Hz,2H,CH2).13C NMR(150MHz,DMSO-d6)δ172.09,155.57,143.32,143.16,142.01,140.22,139.65,134.31,129.40,128.83,127.94,127.67,127.25,125.74,123.97,122.57,107.55,43.60,41.92,18.62,14.81,7.80,7.66.HRMS:m/zC23H22N4O3S2,calcd for 466.1133;found465.1060[M–H]–.HPLC purity:95.77%。
实施例41.目标化合物的体内降尿酸活性试验
测试材料和方法:
(1)实验动物:雄性昆明小鼠,由山东大学实验动物中心提供。
(2)样品处理:待测化合物临用前,用DMSO和CMC-Na配成适当的浓度。
(3)造模药物:次黄嘌呤、氧嗪酸钾。
(4)阳性对照药:Lesinurad。
(5)测试方法:每组灌胃次黄嘌呤0.2mL,皮下注射氧嗪酸钾0.2mL,灌胃药物0.2mL并开始计时,在给药4小时后摘眼球取血,30分钟凝血后离心,取上清液血清。用尿酸仪检测血清中的尿酸浓度。
表2.化合物TS1~20的结构及降尿酸的活性
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表3.化合物PS1~20的结构及降尿酸的活性
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结论:由表2和表3可以看出有24种化合物均呈现出较好的抗降尿酸活性,降尿酸活性均强于阳性对照药物Lesinurad。其中代表化合物TS1、TS2、TS15、PS2、PS4、PS8和PS11,在动物体内活性测试中,血尿酸下降率均超过70%,显示出优异的降尿酸活性,可作为抗痛风及高尿酸血症候选药物。
Claims (5)
1.吡啶并咪唑酰基磺酰胺类衍生物,或其药学上可接受的盐,其特征在于,具有如下通式I所示的结构:
其中,X为氮原子时,Y为碳原子或X为碳原子时,Y为氮原子;R为苯基、4-溴苯、4-氯苯、4-氟苯、4-叔丁基苯、4-甲氧基苯、4-羟基苯、4-乙基苯、3-硝基苯、叔丁基。
2.如权利要求1所述的吡啶并咪唑酰基磺酰胺类衍生物,其特征在于,是下列化合物之一:
3.如权利要求2所述的吡啶并咪唑酰基磺酰胺类衍生物的制备方法,其特征在于,为如下方法之一:
(1)化合物TS1、TS2、TS4、TS5、TS11、TS12、TS13、TS15、TS18的合成:
原料2-硝基-3-羟基吡啶T-A和三氟甲磺酸酐在三乙胺的碱性条件下冰浴反应得到中间体T-B,随后T-B经布赫瓦尔德-哈特维希偶联反应得到TE-B,之后TE-B经氢气钯碳还原得到中间体TE-C;TE-C在N,N'-硫羰基二咪唑的乙腈溶液中回流反应得到关键中间体T-D;T-D在碳酸钾及DMF溶液中发生与2-溴丙酸甲酯反应得到T-E,接着与氢氧化锂在四氢呋喃及乙醇的混合溶液中水解得到T7;最后,在1-乙基-3(3-二甲基丙胺)碳二亚胺、4-二甲氨基吡啶的二氯甲烷溶液中,与不同的磺酰胺基团冰浴条件下酰化反应12小时得到目标产物TS1、TS2、TS4、TS5、TS11、TS12、TS13、TS15、TS18;
路线一:
试剂及条件:(i)三氟甲磺酸酐,三乙胺,二氯甲烷,0℃;(ii)醋酸钯,XantPhos,碳酸铯,氮气,1,4-二氧六环,90℃;(iii)10%钯碳,氢气,四氢呋喃,室温;(iv)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(v)2-溴丙酸甲酯,碳酸钾,N,N-二甲基甲酰胺,室温;(vi)氢氧化锂,四氢呋喃,乙醇,室温;(vi)氢氧化锂,四氢呋喃,乙醇,室温;(vii)酰基磺酰胺,1-乙基-(3-二甲基氨基丙基)碳醯二亚胺盐酸盐,4-二甲氨基吡啶,二氯甲烷,室温;
路线中R为苯基、4-溴苯、4-氯苯、4-氟苯、4-甲氧基苯、4-羟基苯、4-乙基苯、3-硝基苯、叔丁基;
(2)化合物PS2、PS4、PS5、PS8、PS11、PS12、PS13、PS15、PS18的合成:
初始原料4-氯-3-硝基吡啶P-A与4-环丙基-1-萘胺在碳酸氢钠和乙醇溶液中经偶联得到中间体PE-B,随后氢气钯碳还原得到中间体PE-C;中间体PE-C在N,N'-硫羰基二咪唑的乙腈溶液中回流反应得到关键中间体P-D;P-D在碳酸钾及DMF溶液中发生与2-溴丙酸甲酯反应得到P-E,接着与氢氧化锂在四氢呋喃及乙醇的混合溶液中水解得到P7;最后,在1-乙基-3(3-二甲基丙胺)碳二亚胺、4-二甲氨基吡啶的二氯甲烷溶液中,与不同的磺酰胺基团冰浴条件下酰化反应12小时得到目标产物PS2、PS4、PS5、PS8、PS11、PS12、PS13、PS15、PS18;
路线二:
试剂及条件:(i)碳酸氢钠,乙醇,60℃;(ii)10%钯碳,氢气,四氢呋喃,室温;(iii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(iv)2-溴丙酸甲酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温;(vi)酰基磺酰胺,1-乙基-(3-二甲基氨基丙基)碳醯二亚胺盐酸盐,4-二甲氨基吡啶,二氯甲烷,室温;
路线中R为4-溴苯、4-氯苯、4-氟苯、4-叔丁基苯、4-甲氧基苯、4-羟基苯、4-乙基苯、3-硝基苯、叔丁基。
4.权利要求1-2任一项所述的吡啶并咪唑酰基磺酰胺类衍生物在制备降尿酸的药物中的应用。
5.一种降尿酸药物组合物,包含权利要求1-2任一项所述的吡啶并咪唑酰基磺酰胺类衍生物和一种或多种药学上可接受载体或赋形剂。
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