[go: up one dir, main page]

CN103864816B - 噻吩并四氢吡啶芳酸醚类化合物、制备方法及其应用 - Google Patents

噻吩并四氢吡啶芳酸醚类化合物、制备方法及其应用 Download PDF

Info

Publication number
CN103864816B
CN103864816B CN201410090389.3A CN201410090389A CN103864816B CN 103864816 B CN103864816 B CN 103864816B CN 201410090389 A CN201410090389 A CN 201410090389A CN 103864816 B CN103864816 B CN 103864816B
Authority
CN
China
Prior art keywords
sffa
och
pharmaceutically acceptable
arh
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410090389.3A
Other languages
English (en)
Other versions
CN103864816A (zh
Inventor
李家明
何广卫
张恩立
王杰
胡敏华
黄伟军
储昭兴
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hefei Medical And Pharmaceutical Co Ltd
Anhui University of Traditional Chinese Medicine AHUTCM
Original Assignee
HEFEI YIGONG MEDICINE CO Ltd
Anhui University of Traditional Chinese Medicine AHUTCM
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by HEFEI YIGONG MEDICINE CO Ltd, Anhui University of Traditional Chinese Medicine AHUTCM filed Critical HEFEI YIGONG MEDICINE CO Ltd
Priority to CN201410090389.3A priority Critical patent/CN103864816B/zh
Publication of CN103864816A publication Critical patent/CN103864816A/zh
Application granted granted Critical
Publication of CN103864816B publication Critical patent/CN103864816B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及药物化学领域，具体涉及一类噻吩并四氢吡啶芳酸醚类化合物（I）（II）、制备方法，以及含有它们的药物组合物，药效学试验证明本发明的噻吩并四氢吡啶芳酸醚类化合物可用于治疗或预防血栓栓塞性疾病。

Description

噻吩并四氢吡啶芳酸醚类化合物、制备方法及其应用
技术领域
本发明涉及药物化学领域，具体涉及一类噻吩并四氢吡啶芳酸醚类化合物、制备方法，以及含有它们的药物组合物，本发明的噻吩并四氢吡啶芳酸醚类化合物可用于治疗或预防血栓栓塞性疾病。
背景技术
心脑血管疾病是当今世界上威胁人类身体健康的最严重疾病之一,大多数心脑血管疾病均与血栓形成关系密切相关。血小板聚集是正常凝血机制中的一个关键环节,血小板的黏附、聚集和释放会导致血栓形成。抗血小板聚集药物能够抑制血小板的黏附和聚集,在治疗血栓病中发挥重要作用,一直是人们研究的热点[参见袁明,赵永海,李家明等.丁香酸衍生物的合成及抗血小板聚集活性.中国新药杂志,2012,20(18):1801-1804]。
血栓烷素(TXA2)是花生四烯酸代谢过程中生成的具有强生理活性的产物，研究表明许多心血管疾病的发生与TXA2的过多生成有关。TXA2的生成是通过体内一系列的酶而发挥作用，在这些途径中都需要TXA2合成酶的参与。奥扎格雷(Ozagrel)和达唑氧苯(Dazoxiben)为选择性TXA2合成酶抑制剂，具有很强的抗血小板聚集作用，奥扎格雷临床上主要用于急性脑梗死、冠心病和心绞痛的治疗，达唑氧苯临床上用于心肌梗死和雷诺氏病的治疗。它们的结构特征均为一端为碱性基团，另一端为酸性基团，且末端氮原子与羧基之间的距离在1.0nm左右抗血小板聚集活性最强。发明人前期研究中以奥扎格雷和达唑氧苯为模型化合物，以阿魏酸、川芎嗪为先导物，设计合成了一系列一端为酸性基团，另一端为碱性基团的化合物，药效筛选发现大多数化合物均具有较好的抗血小板聚集活性，其中川芎嗪和阿魏酸的拼合物吡拉格雷对ADP诱导的血小板聚集具有显著的抑制活性，其IC50是奥扎格雷的5.7倍，是阿魏酸川芎嗪盐的192倍（参见李家明，赵永海，马逢时，等.川芎嗪芳酸衍生物的合成及抗血小板聚集活性.有机化学，2008，28(9):1578-1583）。体内抗血小板聚集实验结果显示，以吗啉、哌啶、二甲氨基等脂肪氨基替代咪唑基合成的阿魏酸衍生物，在给药浓度剂量为2mL/kg，浓度为11.99mmol/L下对ADP诱导的家兔血小板聚集均具有很强的抑制作用，其中化合物(E)-3-(3-甲氧基-4-(2-吗啉乙氧基)苯基)丙烯酸的抑制率达91.4%，显著强于阳性对照药奥扎格雷，（李家明，赵永海，钟国琛，等.阿魏酸衍生物的合成及抗血小板聚集活性.药学学报,2011,46(3):305-310）。
噻吩并吡啶类抗血小板药物噻氯匹定、氯吡格雷和普拉格雷能够选择性地抑制二磷酸腺苷(ADP)与其血小板受体的结合，通过继发的ADP介导的糖蛋白GPIIb/IIIa复合物的活化作用抑制血小板聚集。噻氯匹定和氯吡格雷存在的不足是起效时间滞后，不同患者间的血小板抑制作用差异大，它不能适合所有患者---氯吡格雷“抵抗”或弱应答的患者占据相当比例。普拉格雷是对氯吡格雷进行结构改造得到的药品，普拉格雷在肝脏中代谢为活性代谢物更为容易，其活性代谢物能不可逆地抑制血小板P2Y12受体，活性与氯吡格雷活性代谢物相当。但在接受普拉格雷患者中有时可见到严重的出血，风险较大。为了获得更为安全有效的噻吩并吡啶类抗血小板聚集药物，刘登科课题组设计并合成系列噻吩并吡啶类化合物，大多具有较好的抗血小板聚集作用[参见刘颖,岳南,陈芙蓉,等.一类噻吩并吡啶衍生物,其制备方法和用途[P].CN101830911A(2010-09-15)；刘登科,刘颖,刘默,等.含噻吩并吡啶的哌嗪类衍生物,其制备方法和用途[P].CN101284838A(2008-10-15)]。
发明内容
本发明以氯吡格雷中关键药效团噻吩并四氢吡啶基作为碱性基团，与阿魏酸等芳酸进行拼合，设计并合成噻吩并四氢吡啶芳酸醚类化合物，药效学试验显示本发明化合物具有TXA2合成酶和血小板P2Y12受体双重抑制作用的药物。
本发明化合物包括通式（I）和通式（II）：
其中R1代表H、3-甲氧基或3,5-二甲氧基；R2代表H或4-甲氧基；
n1=1或2；n2=0或1。
本发明的化合物，优先下列任一结构式的化合物：
本发明的化合物其药学上可接受的盐具有同样的药理药效。所述的药学上可接受的盐优选碱金属或碱土金属盐、碱性氨基酸盐、或医药上允许的无机酸或有机酸形成的盐。碱金属盐为钠盐、钾盐；碱土金属盐为钙盐、镁盐；碱性氨基酸盐为精氨酸盐；无机酸盐为盐酸、硫酸、磷酸盐；有机酸盐为马来酸、富马酸、枸橼酸、甲磺酸、对甲苯磺酸、酒石酸、醋酸盐。
本发明的化合物可用下列方法制备：
下面是本发明部分化合物的药效学试验及结果：
普通家兔，雄性，体重1.8-2.0kg，0.38g枸橼酸钠与10mL生理盐水配制成3.8%的枸橼酸钠溶液，用利多卡因局部麻醉，颈动脉插管放血，和枸橼酸钠溶液以9:1混合，以500-800r/min离心10min，取富血小板血浆（PRP），剩余部分以3000r/min离心，取贫血小板血浆（PPP），聚集诱导剂用10ug/mL二磷酸腺苷(ADP)、200ug/mL花生四烯酸(AA)。每管180uLPRP中加入不同浓度的药物10uL，对照组PRP中加入生理盐水10uL，温育3min，然后加入上述不同浓度的诱导剂，用LG-PABER-1型血小板聚集仪检测血小板聚集率。所有实验重复6次，根据各组聚集率平均值与空白组聚集率均值按下列公式计算血小板聚集抑制率。
本发明化合物对AA和ADP诱导的血小板聚集的抑制活性分别见表1和表2。
表1噻吩并四氢吡啶芳酸醚类化合物对AA诱导的血小板聚集的抑制活性
化合物代号 IC50(mmol/L) 化合物代号 IC50(mmol/L)
SFFA1 0.282 SFFA9 0.020
SFFA2 0.518 SFFA10 1.034
SFFA3 0.431 SFFA11 86.035
SFFA4 75.741 SFFA12 156.382
SFFA5 1.694 SFFA13 0.067
SFFA6 0.949 SFFA14 0.101
SFFA7 8.804 奥扎格雷钠 0.041
SFFA8 25.704 硫酸氢氯吡格雷 15.025
表2噻吩并四氢吡啶芳酸醚类化合物对ADP诱导的血小板聚集的抑制活性
化合物代号 IC50(mmol/L) 化合物代号 IC50(mmol/L)
SFFA1 271.831 SFFA9 6.937
SFFA2 0.141 SFFA10 0.224
SFFA3 0.040 SFFA11 42.002
SFFA4 0.861 SFFA12 6.466
SFFA5 0.369 SFFA13 6.429
SFFA6 19.865 SFFA14 0.255
SFFA7 0.018 奥扎格雷钠 0.033
SFFA8 1.241 硫酸氢氯吡格雷 7.677
上述体外抗血小板聚集实验结果显示，本发明的噻吩并四氢吡啶类化合物中SFFA1,SFFA2、SFFA3、SFFA5、SFFA6、SFFA7、SFFA9、SFFA10、SFFA13、SFFA14对AA诱导的血小板聚集均具有较好的抑制作用，均强于硫酸氢氯吡格雷(可能与氯吡格雷为生物前药，体外抗血小板聚集活性较弱有关)，其中SFFA9强于阳性对照药奥扎格雷。本发明化合物中SFFA2,SFFA3、SFFA4、SFFA5、SFFA7、SFFA8、SFFA9、SFFA10、SFFA12、SFFA13、SFFA14对ADP诱导的血小板聚集均具有显著的抑制活性，均强于硫酸氢氯吡格雷(可能与氯吡格雷为生物前药，体外抗血小板聚集活性较弱有关)，其中SFFA7强于阳性对照药奥扎格雷。化合物SFFA9和SFFA7显示出较好的药用前景。
本发明还提供了一种治疗或预防心脑血管疾病的的药物组合物，其中含有治疗有效量的通式I或II化合物和药学上可接受的载体。所述药物组合物可以是普通片剂或胶囊、缓释片剂或胶囊、控释片剂或胶囊、口服液、注射剂等制剂学上常规的制剂形式。
一般地，本发明的化合物用于治疗时，人用剂量范围为lmg～1000mg/天。也可根据剂型的不同和疾病严重程度，使用剂量超出该范围。
具体实施方式
实施例1
(E)-3-(4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-3-甲氧基苯基)丙烯酸(SFFA1)的合成
1.1(E)-3-(4-(3-溴丙基)-3-甲氧基苯基)丙烯酸乙酯合成
将1,3-二溴丙烷(15.0g,75.0mmol)、无水碳酸钾10.0g、丁酮75mL加入带有冷凝回流装置的三颈烧瓶中，搅拌，升温至80℃下回流，分批加入阿魏酸乙酯(5.00g,23.0mmol)，继续回流6h，TLC[V(石油醚):V(乙酸乙酯)=4:1为展开剂]检测显示反应基本完全。冷却，过滤，用少量乙酸乙酯洗涤滤饼，浓缩，得淡黄色油状物，经硅胶柱分离，得(E)-3-(4-(3-溴丙基)-3-甲氧基苯基)丙烯酸乙酯白色晶体5.10g，收率66.0%,m.p.74.4～75.0℃。
1.2(E)-3-(4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-3-甲氧基苯基)丙烯酸乙酯合成
将4,5,6,7-四氢噻吩并[3,2-c]吡啶盐酸盐(3.80g,11.0mmol)、无水碳酸钾6.0g、氢氧化钠(600mg,15.0mmol)及丁酮75mL加入带有冷凝回流装置的三颈烧瓶中，升温至80℃，回流30min，加入(E)-3-(4-(3-溴丙氧基)-3-甲氧基苯基)丙烯酸乙酯(5.00g,15.0mmol)，继续回流6h，TLC[V(石油醚):V(乙酸乙酯)=4:1为展开剂]检测显示反应基本完全。冷却，过滤，用少量乙酸乙酯洗涤滤饼，减压回收溶剂后的淡黄色油状物经硅胶柱分离，得(E)-3-(4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-3-甲氧基苯基)丙烯酸乙酯白色晶体2.50g，收率42.8%,m.p.65.6～67.5℃;1HNMR(CDCl3,400MHz)δ:7.62(d,J=16.0Hz,1H,ArCH=),7.08(d,J=4.0Hz,1H,ThH),7.07-7.05(m,2H,ArH),6.89(d,J=8.4Hz,1H,ArH),6.72(d,J=5.2Hz,1H,ThH),6.30(d,J=16.0Hz,1H,=CH-),4.28(q,J=6.8Hz,2H,CH3CH2O),4.16(t,J=6.4Hz,2H,OCH2CH2CH2N),3.89(s,3H,OCH3),3.59-3.57(m,2H,Py-CH2),2.90-2.88(m,2H,Py-CH2),2.84-2.82(m,2H,Py-CH2),2.74(t,J=6.8Hz,2H,OCH2CH2CH2N),2.17-2.10(m,2H,OCH2CH2CH2N),1.33(t,J=6.8Hz,2H,CH3CH2O);13C-NMR(CDCl3,100MHz)δ:167.2,150.4,149.5,144.5,133.1,132.7,127.5,125.2,123.1,122.5,116.0,112.7,110.1,67.1,60.4,55.9,54.0,52.8,50.7,26.7,24.9,14.4;IR(KBr,cm-1)υ:2952.0,1710.2,1633.8,1593.4,1516.5,1459.8,1259.7,1155.7,1035.9,981.1,943.9,853.1,793.0,731.8;ESI-Mass(+c)forC22H27NO4S:m/z(M++H)402.28。
1.3(E)-3-(4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-3-甲氧基苯基)丙烯酸(SFFA1)的合成
在100mL单颈烧瓶中，依次加入(E)-3-(4-(3-(4H-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-3-甲氧基苯基)丙烯酸乙酯(2.20g,5.50mmol)、甲醇30mL和氢氧化钠(300mg,7.70mmol)水溶液10mL，50℃下搅拌4h，TLC[V(甲醇):V(氯仿)=1:10为展开剂]检测显示反应基本完全，减压回收甲醇，用3mol/L稀HCl调至pH=4-5，抽滤，水(15mL×3)洗涤，得SFFA1白色固体1.28g，收率64.0%；m.p.213.4～214.9℃,1HNMR(DMSO-d6,400MHz)δ:11.31(s,1H,COOH),7.53(d,J=16.0Hz,1H,ArCH=),7.48(d,J=5.2Hz,1H,ThH),7.33(d,J=1.6Hz,1H,ArH),7.22(dd,J=J=8.4,1.6Hz,1H,ArH),7.02(d,J=8.4Hz,1H,ArH),6.92(d,J=5.2Hz,1H,ThH),6.47(d,J=16.0Hz,1H,=CH-),4.53-4.50(m,1H,Py-CH2),4.25-4.19(m,1H,Py-CH2),4.14(t,J=6.0Hz,2H,OCH2CH2CH2N),3.79(s,3H,OCH3),3.74-3.71(m,1H,OCH2CH2CH2N),3.37-3.25(m,4H,Py-CH2×2),3.11-3.07(m,1H,OCH2CH2CH2N),2.34-2.31(m,2H,OCH2CH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:167.8,149.6,149.1,144.0,131.4,128.2,127.5,125.2,125.1,122.5,116.9,112.9,110.5,66.0,55.6,52.6,50.2,49.1,23.5,21.6;IR(KBr,cm-1)υ:3110.6,2941.9,1703.4,1640.0,1598.0,1516.2,1458.9,1417.1,1271.7,1032.0,980.4,807.6,710.8;ESI-Mass(+c)forC20H23NO4S:m/z(M++H)374.15。
实施例2
(E)-3-(4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)乙氧基)-3-甲氧基苯基)丙烯酸(SFFA2)的合成
按实施例1.2,1.3操作得SFFA2类白色固体，m.p.202.4～204.8℃。1HNMR(DMSO-d6,400MHz)δ:11.98(s,1H,COOH),7.54(d,J=15.6Hz,1H,ArCH=),7.49(d,J=4.8Hz,1H,ThH),7.38(d,J=1.6Hz,1H,ArH),7.25(dd,J=J=1.6Hz,8.0Hz,1H,ArH),7.09(d,J=8.0Hz,1H,ArH),6.92(d,J=4.8Hz,1H,ThH),6.50(d,J=16.0Hz,1H,=CH-),4.58-4.56(m,2H,OCH2CH2N),4.41-4.39(m,1H,Py-CH2),3.86(s,3H,OCH3),3.81-3.79(m,1H,Py-CH2),3.67-3.65(m,2H,Py-CH2),3.50-3.48(m,1H,OCH2CH2N),3.39-3.37(m,2H,Py-CH2),3.15-3.11(m,1H,OCH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:167.7,149.3,148.8,143.8,131.3,128.3,128.1,125.1,125.0,122.3,117.4,113.7,110.8,63.9,55.8,53.5,50.9,49.6,21.5;IR(KBr,cm-1)υ:2959.4,1690.8,1591.0,1513.0,1270.1,1021.4,963.0,831.0,800.2,725.7;ESI-Mass(+c)forC19H21NO4S:m/z(M++H)360.15
实施例3
(E)-3-(4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)苯基)丙烯酸(SFFA3)的合成
按实施例1.2,1.3操作得SFFA3白色固体,m.p.206.0-207.7℃。1HNMR(DMSO-d6,400MHz)δ:11.43(s,1H,COOH),7.65(d,J=7.6Hz,2H,ArH),7.55(d,J=16.0Hz,1H,ArCH=),7.48-7.46(m,1H,ThH),6.99(d,J=7.6Hz,2H,ArH),6.92-6.90(m,1H,ThH),6.40(d,J=16.0Hz,1H,-CH=),4.15-4.12(m,3H,Py-CH2andOCH2CH2CH2N),3.71-3.99(m,1H,Py-CH2),3.35-3.31(m,4H,Py-CH2×2),3.16-3.14(m,2H,OCH2CH2CH2N),2.30-2.27(m,2H,OCH2CH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:167.8,160.0,143.6,131.4,130.2,129.9,127.0,125.2,125.0,116.6,114.8,65.2,52.3,50.2,49.0,23.6,21.7;IR(KBr,cm-1)υ:2932.9,1703.0,1632.3,1603.8,1512.6,1470.5,1428.4,1256.1,1034.1,987.5,830.9,706.9;ESI-Mass(+c)forC19H21NO3S:m/z(M++H)344.05。
实施例4
(E)-3-(4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)乙氧基)苯基)丙烯酸(SFFA4)的合成
按实施例1.2,1.3操作得SFFA4白色固体，m.p.207.8-208.5℃。1HNMR(DMSO-d6,400MHz)δ:11.41(s,1H,COOH),7.69(d,J=8.4Hz,2H,ArH),7.56(d,J=16.0Hz,1H,ArCH=),7.49(d,J=5.2Hz,1H,ThH),7.07(d,J=8.4Hz,2H,ArH),6.94(d,J=5.2Hz,1H,ThH),6.42(d,J=16.0Hz,1H,-CH=),4.56-4.54(m,2H,OCH2CH2N),4.36-4.34(m,1H,Py-CH2),3.82-3.80(m,1H,Py-CH2),3.68-3.66(m,2H,Py-CH2),3.49-3.46(m,1H,OCH2CH2N),3.47-3.46(m,2H,Py-CH2),3.25-3.24(m,1H,OCH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:167.8,159.1,143.5,131.3,129.9,128.0,127.6,125.2,125.1,117.0,115.1,62.5,53.6,50.7,49.6,21.6;IR(KBr,cm-1)υ:2944.7,1695.2,1641.7,1603.5,1513.3,1455.1,1424.0,1253.7,1016.7,982.8,832.8,733.0;ESI-Mass(+c)forC18H19NO3S:m/z(M++H)329.99。
实施例5
4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-3-甲氧基苯甲酸(SFFA5)的合成
按实施例1.2,1.3操作得SFFA5类白色固体，m.p.228.4-230.2℃。1HNMR(DMSO-d6,400MHz)δ:11.37(s,1H,COOH),7.57(dd,J=J=8.4,2.0Hz,1H,ArH),7.48(d,J=5.2Hz,1H,ThH),7.46(d,J=2.0Hz,1H,ArH),7.08(d,J=8.4Hz,1H,ArH),6.92(d,J=5.2Hz,1H,ThH),4.53-4.50(m,1H,Py-CH2),4.24-4.22(m,1H,Py-CH2),4.18(t,J=6.0Hz,2H,OCH2CH2CH2N),3.79(s,3H,OCH3),3.75-3.72(m,1H,OCH2CH2CH2N),3.38-3.34(m,4H,Py-CH2×2),3.25-312(m,1H,OCH2CH2CH2N),2.36-2.35(m,2H,OCH2CH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:172.2,156.7,153.6,136.6,133.5,130.4,130.3,128.6,128.3,117.5,117.3,71.3,60.7,57.7,55.4,54.3,28.7,26.8;IR(KBr,cm-1)υ:3085.7,2932.7,1703.0,1592.3,1513.8,1468.0,1268.9,1033.9,983.3,728.6,700.0;ESI-Mass(+c)forC18H21NO4S:m/z(M++H)348.13。
实施例6
4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)乙氧基)-3-甲氧基苯甲酸(SFFA6)的合成
按实施例1.2,1.3操作得SFFA6类白色固体，m.p.190.8-192.5℃。1HNMR(DMSO-d6,400MHz)δ:11.42(s,1H,COOH),7.58(d,J=8.4Hz,1H,ArH),7.50-7.46(m,2H,ThHandArH),7.15(d,J=8.4Hz,1H,ArH),6.93(d,J=4.8Hz,1H,ThH),4.58-4.52(m,3H,Py-CH2andOCH2CH2N),4.41-4.39(m,1H,Py-CH2),3.86(s,3H,OCH3),3.69-3.67(m,2H,Py-CH2),3.51-3.37(m,2H,OCH2CH2N),3.24-3.16(m,2H,Py-CH2);13C-NMR(DMSO-d6,100MHz)δ:166.9,150.7,148.6,131.3,128.1,125.2,125.1,124.0,123.0,112.8,112.2,63.8,55.7,53.5,51.0,49.6,21.5;IR(KBr,cm-1)υ:2947.9,1703.9,1596.1,1514.2,1454.2,1363.8,1029.5,997.9,764.5,720.5;ESI-Mass(+c)forC17H19NO4S:m/z(M++H)334.03。
实施例7
4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-3,5-二甲氧基苯甲酸(SFFA7)的合成
按实施例1.2,1.3操作得SFFA7白色固体，m.p.247.6-249.3℃。1HNMR(DMSO-d6,400MHz)δ:11.29(s,1H,COOH),7.48(d,J=4.8Hz,1H,ThH),7.25(s,2H,ArH),6.93(d,J=4.8Hz,1H,ThH),4.31-4.29(m,2H,Py-CH2),4.03(t,J=5.2Hz,2H,OCH2CH2CH2N),3.84-3.80(m,7H,OCH3×2andOCH2CH2CH2N),3.41-38(m,3H,Py-CH2andOCH2CH2CH2N),3.15-3.13(m,2H,Py-CH2),2.18-2.16(m,2H,OCH2CH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:166.8,152.7,139.8,131.4,126.2,125.2,125.0,106.3,70.0,55.9,52.7,50.3,49.0,24.5,21.7;IR(KBr,cm-1)υ:2945.7,1702.9,1594.2,1507.8,1460.3,1414.5,1257.0,1030.2,839.1,762.8,724.2;ESI-Mass(+c)forC19H23NO5S:m/z(M++H)378.12。
实施例8
4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)乙氧基)-3,5-二甲氧基苯甲酸(SFFA8)的合成
按实施例1.2,1.3操作得SFFA8类白色固体，m.p.192.8-194.6℃。1HNMR(DMSO-d6,400MHz)δ:7.27(d,J=5.2Hz,1H,ThH),7.24(s,2H,ArH),6.80(d,J=5.2Hz,1H,ThH),4.10(t,J=5.6Hz,2H,OCH2CH2N),3.82(s,6H,OCH3×2),3.62-3.60(m,2H,Py-CH2),2.87-2.83(m,4H,Py-CH2andOCH2CH2N),2.80-2.79(m,2H,Py-CH2);13C-NMR(DMSO-d6,100MHz)δ:167.1,152.6,140.1,134.0,132.6,126.5,125.4,122.9,106.4,70.7,56.4,55.9,52.5,50.6,24.9;IR(KBr,cm-1)υ:2936.9,1707.8,1593.6,1502.5,1457.0,1412.5,1316.4,1049.5,1005.7,833.3,721.4;ESI-Mass(+c)forC18H21NO5S:m/z(M++H)364.02。
实施例9
4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-苯甲酸(SFFA9)的合成
按实施例1.2,1.3操作得SFFA9类白色固体，m.p.222.1-223.9℃。1HNMR(DMSO-d6,400MHz)δ:10.80(s,1H,COOH),7.90(d,J=8.4Hz,2H,ArH),7.47(d,J=4.8Hz,1H,ThH),7.03(d,J=8.4Hz,2H,ArH),6.91(d,J=4.8Hz,1H,ThH),4.20-4.18(m,1H,Py-CH2),4.17(t,J=5.2Hz,2H,OCH2CH2CH2N),3.35-3.34(m,1H,Py-CH2),3.33-3.19(m,4H,Py-CH2×2),3.12-3.10(m,2H,OCH2CH2CH2N),2.27-2.23(m,2H,OCH2CH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:167.0,162.1,132.7,132.5,131.3,125.3,123.3,123.0,114.2,65.9,53.2,52.0,50.1,25.7,24.2;IR(KBr,cm-1)υ:3090.4,2853.1,1697.0,1606.2,1512.2,1430.3,1263.1,1036.5,883.9,840.8,768.1;ESI-Mass(+c)forC17H19NO3S:m/z(M++H)318.12。
实施例10
4-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)乙氧基)-苯甲酸(SFFA10)的合成
按实施例1.2,1.3操作得SFFA10类白色固体，m.p.207.6-209.4℃。1HNMR(DMSO-d6,400MHz)δ:11.63(s,1H,COOH),7.93(d,J=7.6Hz,2H,ArH),7.48(d,J=4.0Hz,1H,ThH),7.12(d,J=7.6Hz,2H,ArH),6.94(d,J=4.0Hz,1H,ThH),4.60-4.58(m,2H,OCH2CH2N),4.53-4.51(m,1H,Py-CH2),4.36-4.34(m,1H,Py-CH2),3.82-3.80(m,1H,OCH2CH2N),3.69-3.67(m,2H,Py-CH2),3.50-3.48(m,1H,OCH2CH2N)),3.26-3.14(m,2H,Py-CH2);13C-NMR(DMSO-d6,100MHz)δ:166.9,161.8,132.9,132.1,131.3,125.3,123.9,123.3,114.4,64.6,54.7,51.8,50.2,23.4;IR(KBr,cm-1)υ:2950.9,1681.3,1607.2,1509.6,1469.9,1425.3,1247.8,1023.0,973.0,841.2,727.0;ESI-Mass(-c)forC17H19NO3S:m/z(M++H)302.26。
实施例11
(E)-3-(3-(3-(6,7-二氢噻吩并[3,2-C]吡啶-5(4H)-基)乙氧基)-4-甲氧基苯基)丙烯酸(SFFA11)的合成
按实施例1.2,1.3操作得SFFA11类白色固体，m.p.207.8-208.5℃,1HNMR(DMSO-d6,400MHz)δ:11.87(s,1H,COOH),7.54(d,J=16.0Hz,1H,ArCH=),7.51(d,J=5.2Hz,1H,ThH),7.48(s,1H,ArH),7.29(d,J=8.4Hz,1H,ArH),7.05(d,J=8.4Hz,1H,ArH),6.93(d,J=5.2Hz,1H,ThH),6.50(d,J=16.0Hz,1H,-CH=),4.58-4.56(m,2H,OCH2CH2N),4.12-4.39(m,1H,Py-CH2),3.84(s,3H,OCH3),3.80-3.78(m,1H,Py-CH2),3.67-3.65(m,2H,Py-CH2),3.51-3.49(m,1H,OCH2CH2N),3.40-3.37(m,2H,Py-CH2),3.27-3.16(m,1H,OCH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:167.8,151.0,147.1,143.8,131.3,128.1,127.1,125.2,125.1,123.9,117.0,112.4,111.9,63.9,55.8,53.5,50.9,49.6,21.5;IR(KBr,cm-1)υ:3050.0,1712.0,1635.0,1601.1,1515.4,1373.1,1265.3,1024.2;984.2,828.5,711.6;ESI-Mass(+c)forC19H21NO4S:m/z(M++H)360.04。
实施例12
(E)-3-(3-(3-(6,7-二氢噻吩并[3,2-C]吡啶-5(4H)-基)丙氧基)-4-甲氧基苯基)丙烯酸(SFFA12)的合成
按实施例1.2,1.3操作得SFFA12类白色固体，m.p.206.0-207.7℃,1HNMR(DMSO-d6,400MHz)δ:11.07(s,1H,COOH),7.52(d,J=16.0Hz,1H,ArCH=),7.49(d,J=5.6Hz,1H,ThH),7.37(s,1H,ArH),7.24(d,J=8.0Hz,1H,ArH),7.00(d,J=8.0Hz,1H,ArH),6.93(d,J=5.6Hz,1H,ThH),6.46(d,J=16.0Hz,1H,-CH=),4.56-4.52(m,1H,Py-CH2),4.25-4.20(m,1H,Py-CH2),4.15-4.13(m,2H,OCH2CH2CH2N),3.77(s,3H,OCH3),3.38-3.36(m,4H,Py-CH2×2),3.28-3.24(m,1H,OCH2CH2CH2N),3.17-3.13(m,1H,OCH2CH2CH2N),2.31-2.29(m,2H,OCH2CH2CH2);13C-NMR(DMSO-d6,100MHz)δ:167.8,150.9,147.8,144.0,131.3,128.2,127.0,125.2,125.1,123.1,116.8,111.8,111.7,66.1,55.5,52.6,50.1,49.0,23.6,21.6;IR(KBr,cm-1)υ:2937.6,1683.3,1626.0,1509.4,1396.6,1257.6,1012.4,978.1,834.0,741.8;ESI-Mass(+c)forC20H23NO4S:m/z(M++H)374.15。
实施例13
3-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙氧基)-4-甲氧基苯甲酸(SFFA13)的合成
按实施例1.2,1.3操作得SFFA13白色固体，m.p.219.3-221.2℃,1HNMR(DMSO-d6,400MHz)δ:11.34(s,1H,COOH),7.59(d,J=7.6Hz,1H,ArH),7.48-7.44(m,2H,ThHandArH),7.07(d,J=7.6Hz,1H,ArH),6.93-6.91(m,1H,ThH),4.51-4.49(m,1H,Py-CH2),4.24-4.20(m,1H,Py-CH2),4.13-4.10(m,2H,OCH2CH2CH2N),3.82(s,3H,OCH3),3.78-3.76(m,1H,OCH2CH2CH2N),3.39-3.35(m,4H,Py-CH2×2),3.12-3.10(m,1H,OCH2CH2CH2N),2.33-2.30(m,2H,OCH2CH2CH2N);13C-NMR(DMSO-d6,100MHz)δ:167.0,152.7,147.2,131.3,128.2,125.2,125.1,123.6,122.9,113.4,111.2,66.0,55.7,52.5,50.1,49.0,23.6,21.6;IR(KBr,cm-1)υ:3080.4,2958.2,1691.1,1593.1,1513.8,1431.3,1267.6,1021.8,831.9,769.9,726.9;ESI-Mass(+c)forC18H21NO4S:m/z(M++H)348.03。
实施例14
3-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)乙氧基)-4-甲氧基苯甲酸(SFFA14)的合成
按实施例1.2,1.3操作得SFFA14白色固体，m.p.236.2-238.0℃,1HNMR(DMSO-d6,400MHz)δ:11.58(s,1H,COOH),7.64(d,J=8.4Hz,1H,ArH),7.54(s,1H,ArH),7.49(d,J=5.2Hz,1H,ThH),7.12(d,J=8.4Hz,1H,ArH),6.93(d,J=5.2Hz,1H,ThH),4.61-4.55(m,3H,Py-CH2andOCH2CH2N),4.41-4.38(m,1H,Py-CH2),3.88(s,3H,OCH3),3.68-3.66(m,2H,Py-CH2),3.51-3.37(m,2H,OCH2CH2N),3.24-3.16(m,2H,Py-CH2);13C-NMR(DMSO-d6,100MHz)δ:166.9,152.9,146.5,131.3,128.1,125.2,125.1,124.3,123.0,114.2,111.4,63.9,55.9,53.7,51.0,49.6,21.6;IR(KBr,cm-1)υ:3021.5,2930.1,1706.4,1597.5,1518.5,1434.0,1265.3,1028.0,995.2,834.3,725.7;ESI-Mass(+c)forC17H19NO4S:m/z(M++H)334.02。

Claims (5)

1.通式I或II的噻吩并四氢吡啶芳酸醚化合物或其药学上可接受的盐：
其中R1代表H、3-甲氧基或3,5-二甲氧基；R2代表H或4-甲氧基；
n1＝1或2；n2＝0或1。
2.权利要求1的化合物或其药学上可接受的盐，是下列任一结构的化合物或其药学上可接受的盐：
3.权利要求1的化合物或其药学上可接受的盐，其药学上可接受的盐选自钠盐、钾盐、钙盐、镁盐、精氨酸盐、盐酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐或醋酸盐。
4.权利要求1的化合物或其药学上可接受的盐用于制备治疗或预防血小板聚集疾病的药物的用途。
5.一种药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐和药学上可接受的载体。
CN201410090389.3A 2014-03-12 2014-03-12 噻吩并四氢吡啶芳酸醚类化合物、制备方法及其应用 Active CN103864816B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410090389.3A CN103864816B (zh) 2014-03-12 2014-03-12 噻吩并四氢吡啶芳酸醚类化合物、制备方法及其应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410090389.3A CN103864816B (zh) 2014-03-12 2014-03-12 噻吩并四氢吡啶芳酸醚类化合物、制备方法及其应用

Publications (2)

Publication Number Publication Date
CN103864816A CN103864816A (zh) 2014-06-18
CN103864816B true CN103864816B (zh) 2016-06-15

Family

ID=50903883

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410090389.3A Active CN103864816B (zh) 2014-03-12 2014-03-12 噻吩并四氢吡啶芳酸醚类化合物、制备方法及其应用

Country Status (1)

Country Link
CN (1) CN103864816B (zh)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101830911A (zh) * 2010-06-11 2010-09-15 天津药物研究院 一类噻吩并吡啶衍生物、其制备方法和用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101830911A (zh) * 2010-06-11 2010-09-15 天津药物研究院 一类噻吩并吡啶衍生物、其制备方法和用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
噻吩并[3,2-c]吡啶类衍生物的研究进展;袁媛等;《广州化工》;20130731;第41卷(第13期);25-29页 *
川芎嗪芳酸衍生物的合成及抗血小板聚集活性;李家明等;《有机化学》;20081231;第28卷(第9期);1578-1583页 *

Also Published As

Publication number Publication date
CN103864816A (zh) 2014-06-18

Similar Documents

Publication Publication Date Title
US10105353B2 (en) Anti-thrombotic compounds
ES2360933T3 (es) Derivados de heteroarilo condensados.
AU2014267974B2 (en) Cycloalkyl acid derivative, preparation method thereof, and pharmaceutical application thereof
US20130096136A1 (en) Inhibitors of Protein Tyrosine Kinase Activity
JP2010520293A (ja) 複素環式部分を含有するメタロプロテアーゼ阻害剤
PT1797099E (pt) Compostos de piperidinilamino-tieno[2,3-d]pirimidina
TW201518288A (zh) 稠合雜環化合物、其製備方法、藥物組合物和用途
BR112019014688A2 (pt) Derivados de carbamato de 1,1,1-trifluoro-3-hidroxipropan-2-il como inibidores de magl
US8809366B2 (en) Thienopyridine ester derivative containing cyano group, preparation method, use and composition thereof
WO2017167993A1 (en) Fused pentacyclic imidazole derivatives as modulators of tnf activity
EP3496724B1 (en) Protein kinase regulators
TW200835495A (en) Substituted 8-piperidinyl-2-pyridinyl-pyrimido[1,2-a] pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido[1,2-a] pyrimidin-6-one derivatives
TW202521533A (zh) Glp-1r 激動劑及其治療方法
CN104910174B (zh) 荜茇酰胺类似物、制备方法及其应用
CN104177379B (zh) 一种喹诺酮类化合物或其立体化学异构体、包含该化合物的药物组合物及其用途
CN106883141B (zh) 一种丹皮酚肟醚类化合物、其制备方法及医药用途
CN103864816B (zh) 噻吩并四氢吡啶芳酸醚类化合物、制备方法及其应用
WO2023197914A1 (zh) 一种吡唑并嘧啶类化合物的新用途
CN110698411A (zh) 一类4-(胺烷基)酞嗪-1-酮类化合物、其制备方法和用途
CN102603759B (zh) 喜树碱e环类似物及其作为药物的用途
JP2025508110A (ja) ピリド［１，２－ａ］ピリミジン－４－オン誘導体
CN119371432A (zh) α-倒捻子素衍生物及其制备方法与应用
HK1173148A (zh) 作为抗血栓形成化合物的(7as，2's)-2-氧代-氯吡格雷
NZ738078A (en) Mct4 inhibitors for treating disease
CN104130241A (zh) 四并环激酶抑制剂

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: 230038 No. 70 Meishan Road, Hefei City, Anhui Province

Co-patentee after: Hefei Medical and Pharmaceutical Co., Ltd.

Patentee after: Anhui University of Chinese Medicine

Address before: 230038 No. 70 Meishan Road, Hefei City, Anhui Province

Co-patentee before: Hefei Yigong Medicine Co., Ltd.

Patentee before: Anhui University of Chinese Medicine