CN113121467B - 一种苯并噻唑衍生物及其医药用途 - Google Patents

一种苯并噻唑衍生物及其医药用途 Download PDF

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CN113121467B
CN113121467B CN202110421229.2A CN202110421229A CN113121467B CN 113121467 B CN113121467 B CN 113121467B CN 202110421229 A CN202110421229 A CN 202110421229A CN 113121467 B CN113121467 B CN 113121467B
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李文燕
许艳妮
刘洪涛
司书毅
王伟志
田文华
姜新海
姜珊
李霓
巫晔翔
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Hebei Normal University
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Abstract

本发明公开了一种苯并噻唑衍生物及其医药用途。本发明提供了系列苯并噻唑衍生物，研究发现该系列的苯并噻唑衍生物可以有效提高ABCA1的表达水平，因而具有开发成提高ABCA1表达水平的药物的前景，具有开发成治疗通过提高ABCA1表达水平进而得到缓解的疾病的药物的前景。

Description

一种苯并噻唑衍生物及其医药用途
技术领域
本发明属于药物化学领域，具体涉及一种苯并噻唑衍生物及其医药用途。
背景技术
心血管疾病(Cardivascular disease,CVD)是一个全球性疾病，每年死于心血管疾病的人数多于其它任何原因的死亡人数，是全球头号死因。动脉粥样硬化(Atherosclerosis,AS)是CVD的主要病理基础。流行病学研究证实，高密度脂蛋白(Highdensity lipoprotein,HDL)被认为是一种抗AS的血浆脂蛋白，提高密度脂蛋白胆固醇(High density lipoprotein cholesterol,HDL-C)水平有利于减缓和改善AS。HDL发挥抗AS作用的主要机制是参与胆固醇逆转运(Reverse cholesterol transport,RCT)过程。ABCA1介导细胞内胆固醇的流出，是RCT的初始步骤及限速步骤，在HDL代谢以及RCT中起重要作用。
ABCA1基因突变可导致严重的HDL缺乏综合征–—丹吉尔疾病(Tangier disease,TD)，患者以血浆HDL及apoA1严重缺乏和组织巨噬细胞内胆固醇酯增多为主要特征，常伴有高胆固醇血症和AS。ABCA1高表达可以使apoA1介导的胆固醇流出明显增加，血浆HDL水平显著升高，并且ABCA1蛋白水平与胆固醇流出增加水平及HDL升高水平呈明显正相关。ABCA1高表达可以降低AS的风险。
由于ABCA1的抗AS的作用，并且其表达可受小分子化合物的调控，被认为是治疗CVD的新靶点。通过提高ABCA1的表达来降低血浆胆固醇水平成为预防和治疗AS新的方向。因此，寻找ABCA1基因表达的上调剂，将有可能获得可以调节RCT的活性化合物，降低胆固醇水平，为预防和治疗AS提供新的方法。
发明内容
本发明的目的在于提供一种苯并噻唑衍生物及其医药用途。
本发明上述目的通过如下技术方案实现：
一种苯并噻唑衍生物，其化学结构式为如下结构式中的一种：
Figure BDA0003027918580000011
Figure BDA0003027918580000021
Figure BDA0003027918580000031
上述苯并噻唑衍生物用于制备提高ABCA1表达水平的药物的用途。
上述苯并噻唑衍生物用于制备治疗通过提高ABCA1表达水平进而得到缓解的疾病的药物的用途。
有益效果：
本发明提供了系列苯并噻唑衍生物，研究发现该系列的苯并噻唑衍生物可以有效提高ABCA1的表达水平，因而具有开发成提高ABCA1表达水平的药物的前景，具有开发成治疗通过提高ABCA1表达水平进而得到缓解的疾病的药物的前景。
具体实施方式
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
实施例1 4-溴-2-[4-(2,6-二氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯的制备
1.2-氯苯并噻唑-6-甲酸乙酯
将无水CuCl2溶于30mL无水乙腈中，冰浴下加入亚硝酸叔丁酯，将2-氨基苯并噻唑-6-甲酸乙酯分三次加入反应液中，TLC监测反应进程。反应完全后，减压蒸馏除去乙腈，向反应液中加入1N HCl水溶液，依次用水、乙酸乙酯、饱和食盐水洗剂，有机相用无水MgSO4干燥，抽滤，减压浓缩，再进行柱层析分离，得白色固体，产率为79.7％。熔点为134-135℃。1H NMR(400MHz,DMSO)δ8.82(d,J＝1.8Hz,1H),8.13-8.01(m,2H),4.39(q,J＝7.1Hz,2H),1.38(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ165.54,157.38,153.80,136.53,127.98,127.62,124.87,122.87,61.62,14.66,14.58.ESI-MS,m/z:242.1[M+H]+,244.1[M+Na]+.
2.2-(4-叔丁氧羰基哌嗪)苯并噻唑-6-甲酸乙酯
将2-氯苯并噻唑-6-甲酸乙酯溶于DMF中，加入1-Boc-哌嗪和Cs2CO3，加热至120℃。TLC进行反应进程的监测，2h后反应结束，向反应瓶中加入水，乙酸乙酯萃取，合并有机相用饱和食盐水洗涤，无水MgSO4干燥2h，抽滤，减压浓缩，柱层析分离提纯得白色固体，产率为75.3％。熔点为174-175℃。1H NMR(400MHz,CDCl3)δ8.36(d,J＝1.5Hz,1H),8.05(dd,J＝8.5,1.6Hz,1H),7.57(d,J＝8.5Hz,1H),4.42(q,J＝7.1Hz,2H),3.72-3.69(m,4H),3.65-3.62(m,4H),1.53(s,9H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ171.08,165.96,156.72,154.21,131.02,127.92,123.39,122.86,118.44,79.82,60.92,48.18,28.48,14.71.ESI-MS,m/z:392.2[M+H]+,414.2[M+Na]+.
3.4-溴-2-(4-叔丁氧羰基哌嗪)苯并噻唑-6-甲酸乙酯的制备
将化合物2-(4-叔丁氧羰基哌嗪)苯并噻唑-6-甲酸乙酯溶于THF中，加入催化量的浓硫酸，将NBS溶于THF中，25℃下缓慢滴加入反应液中，再移至40℃。TLC进行反应进程的监测，反应结束后，减压蒸馏除去THF，向反应瓶中加入水，乙酸乙酯萃取，合并有机相用饱和食盐水洗涤，无水MgSO4干燥2h，抽滤，减压浓缩得白色固体，收率90％。熔点为140-142℃。1HNMR(400MHz,CDCl3)δ8.22(d,J＝1.5Hz,1H),8.18(d,J＝1.5Hz,1H),4.36(q,J＝7.2Hz,2H),3.69(d,J＝5.1Hz,4H),3.61-3.59(m,4H),1.48(s,9H),1.39(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ170.22,165.33,154.44,154.24,131.15,130.98,130.59,124.49,121.79,121.60,111.55,80.63,61.23,48.29,28.58,28.44,28.37,28.30,28.18,14.45,14.33.ESI-MS,m/z:470.1[M+H]+,492.1[M+Na]+.
4.4-溴-2-[4-(2,6-二氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯
将4-溴-2-(4-叔丁氧羰基哌嗪)苯并噻唑-6-甲酸乙酯溶于二氯甲烷中，加入10倍量三氟乙酸，室温搅拌反应2h，冰浴条件下用饱和碳酸钠溶液将反应液pH值调至碱性，再用二氯甲烷萃取三次，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥。次日浓缩蒸干得棕黄色油状化合物4-溴-2-(1-哌嗪基)苯并噻唑-6-甲酸乙酯，将其溶于THF中，再将吡啶和2,6-二氟苯磺酰氯分三批加入反应液中，每次间隔1h，室温反应12h，反应结束后，将反应液减压蒸除THF，固体中加水，析出大量黄色固体，搅拌后抽滤，水洗滤饼2次，得黄色固体，柱层析，得到黄色粉末固体Z1，收率为84％。熔点为254-256℃。1H NMR(400MHz,CDCl3)δ8.21(d,J＝1.5Hz,1H),8.18(d,J＝1.5Hz,1H),7.58-7.51(m,1H),7.05(t,J＝8.7Hz,2H),4.36(q,J＝7.2Hz,2H),3.86-3.84(m,4H),3.46-3.43(m,4H),1.39(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ170.90,164.88,160.71,158.18,154.37,131.53,123.91,110.83,61.38,45.03.ESI-MS,m/z:545.9[M+H]+,568.9[M+Na]+.
实施例2 4-氯-2-[4-(2,6-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯的制备
根据实施例1步骤的方法制备，第三步卤代用NCS，第四步磺酰化用2,6-二氯苯磺酰氯，得到副标题化合物4-氯-2-[4-(2,6-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，为黄色粉末固体，收率为84％。熔点为198-200℃。1H NMR(400MHz,CDCl3)δ8.19(d,J＝1.5Hz,1H),8.02(d,J＝1.5Hz,1H),7.48(d,J＝7.9Hz,2H),7.37-7.33(m,1H),4.37(q,J＝7.1Hz,2H),3.83–3.81(m,4H),3.61-3.58(m,4H),1.39(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ153.08,153.01,135.81,135.71,132.76,132.69,131.54,131.20,131.13,128.95,128.89,124.54,122.08,122.01,49.87,48.47,46.58,45.19,43.81,15.11.ESI-MS,m/z:533.9[M+H]+,555.9[M+Na]+.
实施例3 4-氯-2-[4-(2,6-二氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯的制备
根据实施例1步骤的方法制备，第三步卤代用NCS得到副标题化合物4-氯-2-[4-(2,6-二氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，为黄色粉末固体，收率为82.7％。熔点为240-242℃。1H NMR(400MHz,CDCl3)δ8.18(d,J＝1.5Hz,1H),8.01(d,J＝1.5Hz,1H),7.58-7.51(m,1H),7.05(t,J＝8.7Hz,2H),4.37(q,J＝7.1Hz,2H),3.87-3.84(m,4H),3.46-3.43(m,4H),1.39(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ170.05,165.38,161.02,158.44,152.92,131.47,128.03,124.50,123.38,121.21,121.06,61.29,48.06,45.05,14.43,14.32.ESI-MS,m/z:502.1[M+H]+.
实施例4 2-[1-(2,6-二氟苯磺酰基)哌啶-4-氨基]苯并噻唑-6-甲酸乙酯的制备
根据实施例1步骤的方法制备，第二步用1-Boc-4-氨基哌啶，无需卤代直接进行磺酰化反应，得到副标题化合物2-[1-(2,6-二氟苯磺酰基)哌啶-4-氨基]苯并噻唑-6-甲酸乙酯，为白色粉末固体，产率68％。熔点为214-215℃。1HNMR(400MHz,DMSO)δ8.47(d,J＝7.6Hz,1H),8.32(d,J＝1.4Hz,1H),7.85-7.83(m,2H),7.43-7.37(m,3H),4.30(q,J＝7.1Hz,2H),3.96(s,1H),3.67-3.64(m,1H),3.02-3.29(m,2H),2.21-2.09(m,2H),1.65-1.56(m,2H),1.32(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ170.56,165.97,156.97,131.22,127.95,122.92,122.70,118.23,114.06,112.66,112.40,60.89,50.36,47.58,14.70.ESI-MS,m/z:482.1[M+H]+,504.1[M+Na]+.
实施例5 2-[4-(2,6-二氟苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸乙酯的制备
根据实施例1步骤的方法制备，第二步用4-Boc-氨基哌啶，无需卤代直接进行磺酰化反应，得到副标题化合物2-[4-(2,6-二氟苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸乙酯，为白色粉末固体，产率63％。熔点为211-212℃。1HNMR(400MHz,DMSO)δ8.47(d,J＝7.6Hz,1H),8.37(d,J＝1.4Hz,1H),7.85(dd,J1＝8.5Hz,J2＝1.6Hz,1H),7.71-7.69(m,1H),7.46(d,J＝8.5Hz,1H),7.31(t,J＝9.0Hz,2H),4.29(q,J＝7.1Hz,2H),3.97-3.94(m,2H),3.57-3.55(m,1H),3.32-3.27(m,2H),1.80-1.78(m,2H),1.56-1.49(m,2H),1.32(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ170.56,165.97,156.97,131.22,127.95,122.92,122.70,118.23,114.06,112.66,112.40,60.89,50.36,47.58,14.70.ESI-MS,m/z:482.1[M+H]+,504.1[M+Na]+.
实施例6 2-[4-(2,4-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯的制备
根据实施例1步骤的方法制备，无需卤代，磺酰化反应用2,4-二氯苯磺酰氯，得到副标题化合物2-[4-(2,4-二氯苯磺酰胺基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，为白色粉末固体，产率58％。熔点为200-202℃。1H NMR(400MHz,DMSO)δ8.44(d,J＝2Hz,1H),8.02(d,J＝8.8Hz,1H),7.96(d,J＝2.0Hz,1H),7.90(dd,J1＝8.8,Hz J2＝2.0Hz,1H),7.69(dd,J1＝8.6,J2＝2.2Hz,1H),7.52(d,J＝8.5Hz,1H),4.32(q,J＝7.1Hz,2H),3.73(d,J＝4.8Hz,4H),3.42(t,J＝5.1Hz,4H),1.34(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ170.24,166.35,156.09,140.04,134.45,133.05,132.15,130.66,128.08,127.56,124.01,122.84,118.73,60.95,48.35,45.15,14.43.ESI-MS,m/z:500.2[M+H]+,522.0[M+Na]+.
实施例7 2-[4-(2,3-二氯苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸乙酯的制备
根据实施例1步骤的方法制备，第二步用4-Boc-氨基哌啶，无需卤代，磺酰化反应用2,3-二氯苯磺酰氯，得到副标题化合物2-[4-(2,3-二氯苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸乙酯，为白色粉末固体，产率55％。熔点为196-197℃。1HNMR(400MHz,DMSO)δ8.50(d,J＝7.2Hz,1H),8.40-8.20(m,1H),8.00(dd,J1＝8.1Hz,J2＝3.8Hz,2H),7.50-7.49(m,1H),7.49(t,J＝8.0Hz,1H),7.43(d,J＝8.4Hz,1H),4.28(q,J＝7.0Hz,2H),3.98(d,J＝7.5Hz,1H),3.68(d,J＝13.0Hz,2H),3.00(t,J＝10.5Hz,2H),2.00(d,J＝11.8Hz,2H),1.32(d,J＝10.7Hz,2H),1.29(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO)δ168.42,166.05,156.92,135.56,134.89,133.56130.96,129.47,129.30,129.15,127.56,122.39,122.63,117.81,60.86,53.60,45.53,31.46,14.21.ESI-MS,m/z:514.0[M+H]+,536.1[M+Na]+.
实施例8 2-[1-(3-三氟甲氧基苯磺酰基)哌啶-4-氨基]苯并噻唑-6-甲酸乙酯的制备
根据实施例1步骤的方法制备，第二步用1-Boc-4-氨基哌啶，无需卤代，磺酰化反应用3-三氟甲氧基苯磺酰氯，得到副标题化合物2-[1-(3-三氟甲氧基苯磺酰基)哌啶-4-氨基]苯并噻唑-6-甲酸乙酯，为白色粉末固体，产率59％。熔点为215-216℃。1H NMR(400MHz,CDCl3)δ8.26(d,J＝1.7Hz,1H),7.99-7.96(m,1H),7.70(d,J＝7.7Hz,1H),7.64(s,1H),7.60-7.58(m,1H),7.52(d,J＝8.5Hz,1H),7.47-7.45(m,1H),6.48(s,1H),4.13(q,J＝7.1Hz,2H),3.83-3.77(m,3H),2.61-2.55(m,2H),2.26-2.22(m,2H),1.74-1.70(m,2H),1.26(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ171.29,170.98,168.12,166.52,156.92,156.12,149.31,137.90,130.97,130.41,127.74,123.57,123.49,122.62,121.53,60.89,60.43,45.13,31.15,14.29.ESI-MS,m/z:530.2[M+H]+,552.1[M+Na]+.
实施例9 2-[4-(4-溴苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯的制备
根据实施例1步骤的方法制备，无需卤代，磺酰化反应用4-溴苯磺酰氯，得到副标题化合物2-[4-(4-溴苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，为白色粉末固体，收率为43％。熔点为264-266℃。1HNMR(400MHz,CDCl3)δ8.29(s,1H),7.99(d,J＝8.5Hz,1H),7.69(d,J＝8.4Hz,2H),7.63(d,J＝8.5Hz,2H),7.50(d,J＝8.5Hz,1H),4.36(q,J＝7.2Hz,2H),3.81-3.79(m,4H),3.19-3.16(m,4H),1.39(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ169.95,166.28,155.90,134.37,132.76,130.57,129.27,128.54,128.04,124.02,122.92,118.56,60.93,47.82,45.35,14.46.ESI-MS,m/z:510.1[M+H]+,532.1[M+Na]+.
实施例10 4-溴-2-[4-(2,6-二氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备4-溴-2-[4-(2,6-二氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，将酯溶于THF中，加入等量乙醇和10％NaOH水溶液，温度升至60℃反应，1小时后结束。反应液减压蒸除大部分溶剂，在冰水浴条件下，用1N HCl的水溶液，调节剩余反应液pH至酸性，析出大量白色固体，抽滤，蒸馏水洗涤滤饼，真空干燥后得得到副标题化合物，为白色粉末固体，收率为92％。熔点为256-258℃。1H NMR(400MHz,DMSO)δ13.09(s,1H),8.44(s,1H),8.03(s,1H),7.86-7.83(m,1H),7.41(t,J＝9.2Hz,2H),3.84(s,4H),3.39(s,4H).13C NMR(101MHz,DMSO)δ170.75,170.64,166.54,161.78,160.76,159.24,158.23,153.99,131.39,131.33,130.71,125.46,122.95,114.45,114.20,110.80,110.53,48.30,47.97,45.39,45.06.ESI-MS,m/z:517.9[M+H]+.
实施例11 4-溴-2-[4-(2,3-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备4-溴-2-[4-(2,3-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，磺酰化反应用2,3-二氯苯磺酰氯，再根据实施例10制备副标题化合物4-溴-2-[4-(2,3-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸，为白色粉末固体，收率为88％。熔点为208-210℃。1H NMR(400MHz,DMSO)δ13.01(s,1H),8.44(s,1H),8.04(t,J＝8.3Hz,3H),7.65(t,J＝7.9Hz,1H),3.80(s,4H),3.51(s,4H).13C NMR(101MHz,DMSO)δ170.75,166.45,154.13,138.29,135.56,135.23,131.40,130.72,129.74,129.19,125.05,122.99,110.83,48.41,45.27.ESI-MS,m/z:547.9[M-H]-.
实施例12 4-溴-2-[4-(2-三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备4-溴-2-[4-(2-三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，磺酰化反应用2-三氟甲基苯磺酰氯，再根据实施例10制备副标题化合物4-溴-2-[4-(2三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸，为白色粉末固体，收率为87％。熔点为232-234℃。1H NMR(400MHz,DMSO)δ8.35(s,1H),8.15(d,J＝7.1Hz,1H),9.10(d,J＝7.9Hz,1H),8.07(s,1H),8.00-7.93(m,2H),3.80(s,4H),3.47(s,4H).13C NMR(101MHz,DMSO)δ169.67,167.79,152.32,137.22,134.12,131.56,131.30,130.90,130.86,129.28,129.21,127.00,126.67,124.45,122.38,110.56,48.32,45.35.ESI-MS,m/z:548.0[M-H]-.
实施例13 4-氯-2-[4-(2,4-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备4-氯-2-[4-(2,4-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，卤代反应用NCS，磺酰化反应用2,4-二氯苯磺酰氯，再根据实施例10制备副标题化合物4-氯-2-[4-(2,4-二氯苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸，为白色粉末固体，收率为87％。熔点为288-290℃。1H NMR(400MHz,DMSO)δ13.07(s,1H),8.40(s,1H),8.04(d,J＝8.6Hz,1H),7.96(d,J＝1.4Hz,1H),7.89(s,1H),7.72(d,J＝8.6Hz,1H),3.79(s,4H),3.47(s,4H).13C NMR(101MHz,DMSO)δ171.08,166.55,152.85,139.20,134.71,133.42,132.82,132.37,132.12,128.59,127.64,124.75,122.47,121.97,48.35,45.23.ESI-MS,m/z:503.9[M-H]-.
实施例14 4-氯-2-[4-(2-三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备4-氯-2-[4-(2-三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，卤代反应用NCS，磺酰化反应用2-三氟甲基苯磺酰氯，再根据实施例10制备副标题化合物4-氯-2-[4-(2-三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸，为白色粉末固体，收率为92％。熔点为252-254℃。1H NMR(400MHz,DMSO)δ13.03(s,1H),8.40(d,J＝1.2Hz,1H),8.14(d,J＝7.0Hz,1H),8.10-8.08(m,1H),7.96(t,J＝6.5Hz,2H),7.89(d,J＝1.2Hz,1H),3.82(s,4H),3.49-3.46(m,4H).13C NMR(101MHz,DMSO)δ171.08,166.55,152.86,152.70,137.20,134.14,132.13,131.55,129.28,129.21,127.64,124.76,122.48,121.98,48.42,45.32.ESI-MS,m/z:504.0[M-H]-.
实施例15 4-氯-2-[4-(2-三氟甲氧基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备4-氯-2-[4-(2-三氟甲氧基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，卤代反应用NCS，磺酰化反应用2-三氟甲氧基苯磺酰氯，再根据实施例10制备副标题化合物4-氯-2-[4-(2-三氟甲氧基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸，为白色粉末固体，收率为91％。熔点为232-234℃。1H NMR(400MHz,DMSO)δ13.06(s,1H),8.39(s,1H),8.02(d,J＝7.5Hz,1H),7.91-7.88(m,2H),7.70-7.66(m,2H),3.81(s,4H),3.38-3.35(m,4H).13C NMR(101MHz,DMSO)δ171.07,166.55,152.83,145.59,136.26,132.13,131.96,129.77,128.47,127.62,124.75,122.45,122.19,121.98,48.23,45.29.ESI-MS,m/z:520.0[M-H]-.
实施例16 4-氯-2-[4-(3-氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备4-氯-2-[4-(3-氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，卤代反应用NCS，磺酰化反应用3-氟苯磺酰氯，再根据实施例10制备副标题化合物4-氯-2-[4-(3-氟苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸，为白色粉末固体，收率为90％。熔点为268-270℃。1H NMR(400MHz,DMSO)δ13.05(s,1H),8.37(d,J＝1.2Hz,1H),7.87(d,J＝1.3Hz,1H),7.77(dd,J＝14.5,8.2Hz,1H),7.68-7.63(m,3H),3.81(s,4H),3.22-3.19(m,4H).13C NMR(101MHz,DMSO)δ170.94,166.52,163.64,161.16,152.79,137.59,137.53,132.50,132.42,132.11,127.61,124.77,124.28,124.25,122.44,121.97,121.28,121.07,115.17,114.93,47.80,45.65.ESI-MS,m/z:454.0[M-H]-.
实施例17 2-[4-(2-三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备-2-[4-(2-三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，无需卤代，磺酰化反应用2-三氟甲基苯磺酰氯，再根据实施例10制备副标题化合物2-[4-(2-三氟甲基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸，为白色粉末固体，收率为90％。1HNMR(400MHz,DMSO)δ8.20(d,J＝1.2Hz,1H),8.09(d,J＝7.1Hz,1H),8.05-8.03(m,1H),7.94-7.87(m,2H),7.82(dd,J＝8.3,1.5Hz,1H),7.32(d,J＝8.3Hz,1H),3.69-3.67(m,4H),3.39-3.36(m,4H).13C NMR(101MHz,DMSO)δ170.40,166.51,156.08,137.24,133.38,132.60,132.34,130.70,128.95,128.26,124.18,123.05,122.97,121.25,118.90,48.43,45.15.ESI-MS,m/z:470.1[M-H]-.
实施例18 2-[4-(2-三氟甲氧基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸的制备
根据实施例1制备-2-[4-(2-三氟甲氧基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸乙酯，无需卤代，磺酰化反应用2-三氟甲氧基苯磺酰氯，再根据实施例10制备副标题化合物2-[4-(2-三氟甲氧基苯磺酰基)-1-哌嗪基]苯并噻唑-6-甲酸，为白色粉末固体，收率为91％。1H NMR(400MHz,DMSO)δ8.20(d,J＝1.0Hz,1H),7.96(dd,J＝8.1,1.6Hz,1H),7.86-7.81(m,2H),7.62(t,J＝7.3Hz,2H),7.32(d,J＝8.3Hz,1H),3.68-3.65(m,4H),3.28-3.25(m,4H).13C NMR(101MHz,DMSO)δ170.43,166.55,156.29,146.36,135.16,135.11,132.13,130.82,130.26,128.24,124.11,123.05,122.95,121.68,48.50,45.33.ESI-MS,m/z:486.1[M-H]-.
实施例19 2-[4-(2-三氟甲氧基苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸的制备
根据实施例1步骤的方法制备2-[4-(2-三氟甲氧基苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸乙酯，第二步用4-Boc-氨基哌啶，无需卤代，磺酰化反应用2-三氟甲氧基苯磺酰氯，得到副标题化合物2-[4-(2-三氟甲氧基苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸，为白色粉末固体，收率为89％。1H NMR(400MHz，DMSO)δ8.17(d,J＝1.6Hz,1H),7.87(dd,J＝7.7,1.6Hz,1H),7.81(dd,J＝8.3,1.5Hz,1H),7.42-7.38(m,1H),7.28(dd,J＝16.1,8.0Hz,3H),3.84-3.81(m,2H),3.23-3.14(m,3H),1.63-1.60(m,2H),1.38-1.29(m,2H).13C NMR(101MHz,DMSO)δ170.66,168.81,153.99,145.64,133.52,131.78,130.31,129.75,127.97,126.85,122.44,121.90,120.56,119.35,117.06,51.05,47.41,34.18.ESI-MS,m/z:500.1[M-H]-.
实施例20 2-[4-(2-三氟甲基苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸的制备
根据实施例1步骤的方法制备2-[4-(2-三氟甲基苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸乙酯，第二步用4-Boc-氨基哌啶，无需卤代，磺酰化反应用2-三氟甲基苯磺酰氯，得到副标题化合物2-[4-(2-三氟甲基苯磺酰胺基)-1-哌啶基]苯并噻唑-6-甲酸，为白色粉末固体，收率为91％。1H NMR(400MHz，DMSO)δ8.17(d,J＝1.6Hz,1H),7.87(dd,J＝7.7,1.6Hz,1H),7.81(dd,J＝8.3,1.5Hz,1H),7.42-7.38(m,1H),7.28(dd,J＝16.1,8.0Hz,3H),3.84-3.81(m,2H),3.23-3.14(m,3H),1.63-1.60(m,2H),1.38-1.29(m,2H).113C NMR(101MHz,DMSO)δ170.37,169.04,153.49,141.23,137.22,134.19,131.66,129.97,128.18,127.04,126.71,124.51,122.75,121.79,117.77,48.36,45.42,32.13.ESI-MS,m/z:484.1[M-H]-.
实施例21 2-[1-(3-氟苯磺酰基)哌啶-4-氧基]苯并噻唑-6-甲酸的制备
根据实施例1步骤的方法制备2-[1-(3-氟苯磺酰基)哌啶-4-氧基]苯并噻唑-6-甲酸乙酯，第二步用4-羟基哌啶，无需卤代和脱保护，磺酰化反应用3-氟苯磺酰氯，得到副标题化合物2-[1-(3-氟苯磺酰基)哌啶-4-氧基]苯并噻唑-6-甲酸，为白色粉末固体，收率为收率为85％。1H NMR(400MHz，DMSO)δ8.26(d,J＝4.9Hz,1H),7.90-7.88(m,1H),7.75(dd,J＝13.4,7.8Hz,1H),7.63(t,J＝7.2Hz,3H),7.47(d,J＝8.3Hz,1H),5.21-5.17(m,1H),3.28-3.23(m,2H),3.05-2.99(m,2H),2.17-2.13(m,2H),1.92-1.87(m,2H).13C NMR(101MHz，DMSO)δ171.95,169.46,163.60,161.13,149.65,138.23,138.16,136.96,130.40,128.07,124.16,122.99,119.25,76.47,43.56,29.85.ESI-MS,m/z:435.2[M-H]-.
实施例22 2-[1-(2,6-二氟苯磺酰基)哌啶-4-氧基]苯并噻唑-6-甲酸的制备
根据实施例1步骤的方法制备2-[1-(2,6-二氟苯磺酰基)哌啶-4-氧基]苯并噻唑-6-甲酸乙酯，第二步用4-羟基哌啶，无需卤代和脱保护，磺酰化反应用2,6-二氟苯磺酰氯，得到副标题化合物2-[1-(2,6-二氟苯磺酰基)哌啶-4-氧基]苯并噻唑-6-甲酸，为白色粉末固体，1H NMR(400MHz，DMSO)δ8.30(s,1H),7.93(d,J＝8.5Hz,1H),7.84-7.77(m,1H),7.50(d,J＝8.3Hz,1H),7.37(t,J＝9.1Hz,2H),5.29-5.26(m,1H),3.42(s,2H),3.22(t,J＝8.7Hz,2H),2.19-2.16(m,2H),1.94-1.86(m,2H).13C NMR(101MHz，DMSO)δ174.05,166.10,161.02,158.48,152.55,131.57,127.64,125.92,123.41,123.31,120.37,115.80,76.30,42.47,30.04.ESI-MS,m/z:453.1[M-H]-.
实施例23药理活性测试
1、实验材料
RPMI 1640培养基、MEM培养基及胎牛血清购自Hyclone；G418购自美国Invitrogen公司；荧光素酶检测试剂盒(LuciferaseAssay System)购自Promega公司。
2、实验方法
细胞培养
人肝癌细胞株HepG2细胞培养于含10％胎牛血清的MEM培养基中；ABCA1p-LUCHepG2培养于含500μg·mL-1G418和10％胎牛血清的MEM培养基中；所有细胞都在5％CO2培养箱中37℃贴壁培养。
质粒转染
采用LipofectamineTM2000(Invitrogen)介导的方法，将重组报告基因质粒pGL3-ABCAp(含有人ABCA1基因上游调控序列)和pcDNA3(含有neo基因)共转染入HepG2细胞。经600μg·mL-1G418处理14天后，带有G418抗性的细胞克隆形成。对形成的细胞克隆进行一系列单克隆化操作，同时跟踪其荧光素酶活性。将高表达荧光素酶且呈现正常细胞周期的稳定细胞克隆命名为ABCA1p-LUC HepG2。
活性筛选
取对数生长期的ABCA1p-LUC HepG2细胞，以细胞数约5×105/mL接种于96孔透明底白板，每孔加入单细胞悬液100μL。将待测化合物分别用含有5％FBS的RPMI-1640细胞培养基、含有5％FBS的MEM细胞培养基稀释浓度为100μM、50μM、25μM、12.5μM、6.25μM、3.125μM、1.5625μM、0.78125μM、0.39μM、0.039μM、0.0039μM，共11个浓度。6-8h待细胞贴壁后，移除原培养基，用PBS漂洗细胞一次。每孔分别加入预先用细胞培养基稀释好的一定浓度的化合物溶液200μl，每个化合物每个浓度设两个复孔。18-24h后移除培养基，用PBS轻轻漂洗后，每孔加入25μl细胞裂解液，37℃裂解细胞30-45min。待细胞完全裂解后，每孔迅速加入50μl萤火虫荧光素酶检测试剂，立即将分析白板放入酶标仪中检测。计算待测样品对ABCA1活性的表达率，表达率(％)＝加入化合物后的荧光素酶活性/加入空白对照样品(DMSO)后的荧光素酶活性×100。
3、实验结果
Figure BDA0003027918580000121
Figure BDA0003027918580000131
Figure BDA0003027918580000141
上述实验结果表明，本发明提供的苯并噻唑衍生物可以有效提高ABCA1的表达水平，因而具有开发成提高ABCA1表达水平的药物的前景，具有开发成治疗通过提高ABCA1表达水平进而得到缓解的疾病的药物的前景。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。

Claims (3)

1.一种苯并噻唑衍生物，其特征在于，其化学结构式为如下结构式中的一种：
Figure FDA0003027918570000011
Figure FDA0003027918570000021
。
2.权利要求1所述的苯并噻唑衍生物用于制备提高ABCA1表达水平的药物的用途。
3.权利要求1所述的苯并噻唑衍生物用于制备治疗通过提高ABCA1表达水平进而得到缓解的疾病的药物的用途。
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