CN104447867B - 一种噻吩并哌啶衍生物、制备方法及其应用 - Google Patents
一种噻吩并哌啶衍生物、制备方法及其应用 Download PDFInfo
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- CN104447867B CN104447867B CN201310428052.4A CN201310428052A CN104447867B CN 104447867 B CN104447867 B CN 104447867B CN 201310428052 A CN201310428052 A CN 201310428052A CN 104447867 B CN104447867 B CN 104447867B
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- acid
- thieno
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- piperidine derivative
- addition salts
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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Abstract
本发明涉及一种噻吩并哌啶衍生物、制备方法及其应用，本发明涉及的噻吩并哌啶衍生物具有如下的式（I）结构，本发明还包括该类噻吩并哌啶衍生物作为治疗和预防心脑血管疾病药物的应用。
Description
技术领域
本发明涉及有机化学和药物化学领域。具体而言，本发明涉及一种噻吩并哌啶衍生物；本发明还涉及该一种噻吩并哌啶衍生物的可药用酸加成盐、它们的制备方法，以及它们在制备治疗和预防心脑血管疾病药物中的应用。
背景技术
氯吡格雷（Clopidogrel）是一种噻吩吡啶类药物，能高效地抑制血小板活性，是目前广泛应用于急性冠脉综合征及行经皮冠状动脉介入治疗患者的抗血小板药物。其结构式如下：
氯吡格雷是一种无活性的前体药物，需要经过肝脏细胞色素P450(CYP450)酶转化形成活性代谢物，其代谢过程如下：
该代谢物与血小板膜表面二磷酸腺苷(adenosine diphosphate，ADP)受体P2Y12结合，发挥阻断ADP与血小板受体结合以及继发ADP介导的糖蛋白GPIIbPIIIa复合物活化的作用，从而抑制血小板聚集（Arterio-sclerThromb Vase Biol，1999，19(8):2002-2011）。氯吡咯雷可以明显降低支架内亚急性血栓形成的发生率，减少死亡、再发心梗等心血管事件的发生。但近来研究发现，大约有11%～44%（AmHeart J，2009，157(2):375-382.）患者对氯吡咯雷表现为低反应甚至无反应，这种现象也称为“氯吡格雷抵抗”。
因此，临床需要开发起效快，疗效高，可避免氯吡格雷抵抗的抗血小板聚集新药。同时寻找对制成制剂有利的化合物，以提高生物利用度，减少副作用，有利于溶解，吸收，服用。
发明内容：
本发明的目的在于提供一种新型氯吡格雷代谢物2-氧氯吡格雷前药噻吩并哌啶衍生物，从而开发起效快，口服生物利用度高的抗血小板聚集药物。
具体而言，本发明一个目的在于提供一种光学活性噻吩并哌啶衍生物或其药物可接受的盐，溶剂化物，多晶型体，对映体或外消旋混合物。
本发明的另一个目的在于提供以所述光学活性噻吩并哌啶衍生物或其药物可接受的盐，溶剂化物，多晶型体，对映体或外消旋混合物或药物组合物的制备方法。
本发明的又一个目的在于提供以所述光学活性噻吩并哌啶衍生物或其药物可接受的盐，溶剂化物，多晶型体，对映体或外消旋混合物或药物组合物为活性成分的药物组合物。
本发明的再一个目的在于提供以所述光学活性噻吩并哌啶衍生物或其药物可接受的盐，溶剂化物，多晶型体，对映体或外消旋混合物或药物组合物在制药方面的用途。
本发明的还有一个目的在于提供以所述光学活性噻吩并哌啶衍生物或其药物可接受的盐，溶剂化物，多晶型体，对映体或外消旋混合物或药物组合物或者采用所述药物组合物用于治疗相关疾病的方法。
为了实现上述目的，本发明采取的技术方案如下：
本发明提供一种具有式（I）结构的光学活性噻吩并哌啶衍生物或其药物可接受的盐，溶剂化物，多晶型体，对映体或外消旋混合物或药物组合物：
其中，X为P或S，m为0或1，n为0或1，R为氢、C1-C4直连或支链被卤素取代或未取代的烷烃基、苯基或取代苯基。
优选的，其中，X为P，m为0，n为0，R为氢、CH3-、CH3CH2-、丙基、CCL3CH2-，苯基。或其中，X为P，m为1，n为1，R为氢、CH3-、CH3CH2-、丙基、CCL3CH2-，丁基，苯基。或其中，X为S，m为0，n为0，R为氢、CH3-、CH3CH2-、丙基、CCL3CH2-，丁基，苯基。
本发明所述噻吩并哌啶衍生物，其特征在于所述是以下化合物：
本发明还包括所述噻吩并哌啶衍生物的可药用酸加成盐，其中，所述盐可以是噻吩并哌啶衍生物与硫酸、盐酸、氢溴酸、磷酸、酒石酸、富马酸、马来酸、柠檬酸、乙酸、甲酸、甲磺酸、对甲苯磺酸、草酸或琥珀酸形成的盐。
本发明还提供一种药物组合物，其特征在于，所述药物组合物含本发明所述的噻吩并哌啶衍生物或其可药用酸加成盐。所述药物组合物根据需要还可含有药学上可接受的载体。所述药学上可接受的惰性载体可为固态或液态。可制备粉剂、片剂、可分散粉剂、胶囊剂、栓剂、和胶膏形式的固体或半固体药物制剂，在此情况下通常使用固态载体。可使用的固体载体优选为稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质，或可为包封物质。在粉状制剂中，在载体中含有5%-70%的微粒化活性成分。适宜的固体载体的具体实例包括碳酸镁、硬脂酸镁，滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、黄嗜胶，甲基纤维素、羧甲基纤维素钠、低沸点蜡、可可脂等、由于它们易于给药、片剂、粉剂、胶囊剂代表最有利吸收的口服固体制剂。
液体制剂包括溶液、悬浮液和乳液。例如非肠胃道给药的可注射制剂可为水或水与丙二醇溶液形式，调节其等渗度，pH等适于活体的生理条件。液体制剂还可制成聚乙二醇水溶液中形式。可通过将活性成分溶溶解在水中，再加入适当的着色剂、调味剂、稳定剂和增稠剂，来制备口服水溶液。可将微粒化的活性成分分散在粘性物质如天然或合成胶、甲基纤维素、酸甲基纤维素钠和其它已知悬浮剂中制备使用于口服的水悬浮液。
为了易于给药及剂量均一，将上述药物制剂配制成剂量单位形式是特别有利的。制剂的剂量单位形式指适于作为单一剂量的物理分离单位，每个单位含有产生所期望的治疗效果的计算好的预定量的活性成分。这种剂量单位形式可为包装形式，如片剂、胶囊或装在小管或小瓶中的粉剂，或装在管或瓶中的软膏、凝胶或霜剂。
虽然剂量单位形式中所含活性成分的量可以变化，但一般根据所选择活性成分的效力，调节在1-1000mg范围内。
本领域技术人员可按常规方法确定适于某种情况的优选剂量。一般，开始治疗的量低于活性成分的最佳剂量，然后逐渐增加给药剂量，直到达到最佳治疗效果。为方便起见，总的日剂量可分为几部分，分数次给药。
本发明所述的噻吩并哌啶衍生物或其可药用酸加成盐在制备治疗和预防心力衰竭、中风、不稳定心绞痛等心脑血管疾病药物中的应用。特别是在制备抗血小板凝集药物中的应用。
另一方面，本发明还提供本发明噻吩并哌啶衍生物或其药物可接受的盐，溶剂化物，多晶型体，对映体或外消旋混合物，所述制备方法包括如下反应步骤：
其中取代基如前所述。
根据本发明的具体实施方式，本发明的化合物TSC-9可以通过下述方式制备：
其中，R为氯或羟基
本发明的有益效果在于：本发明提供了一种新型的具有明显抑制血小板聚集的化合物，该化合物为氯吡格雷代谢产物2-氧氯吡格雷前药，在生物体内无需经过CYP2C19酶即可代谢为2-氧氯吡格雷，具有起效快，疗效高，同时该发明有望解决由于不同个体P450（cytoch rome P450，CYP）酶系表达的差异造成的“氯吡格雷抵抗”问题。
具体实施方式：
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1
将2-氧氯吡格雷中间体II（200mg，0.6mmol）溶于5mL无水四氢呋喃，降温至零下20℃，加入二异丙胺锂（2.0M,0.5mL,1mmol）搅拌20分钟，将化合物IIIa（104mg,0.72 mmol）加入到反应液中，自然升温反应12小时，用4%盐酸淬灭反应，加入50mL乙酸乙酯，分别用碳酸氢钠和饱和食盐洗涤有机层，无水硫酸钠干燥，过滤浓缩。经硅胶柱层析（PE:EA=4:1）纯化，得到化合物TSC-1（245mg，收率92%）。
1H NMR(400MHz,CDCl3):δ7.67-7.65(m,1H),7.42-7.40(m,1H),7.31-7.26(m,2H),6.25(d,1H),4.91(s,1H),3.87(s,3H),3.72(s,3H),3.64-3.60(m,1H),3.51-3.48(m,1H),2.89-2.87(m,2H),2.75-2.73(m,2H),MS:m/z446[M+1]+。
实施例2
将2-氧氯吡格雷中间体II（500mg，1.5mmol）溶于10mL无水四氢呋喃，降温至零下20℃，加入二异丙胺锂（2.0M,1.25mL,2.5mmol）搅拌30分钟，将化合物IIIb（311mg，1.8mmoL）加入到反应液中，自然升温反应12小时，用4%盐酸淬灭反应，加入100mL乙酸乙酯，分别用碳酸氢钠和饱和食盐洗涤有机层，无水硫酸钠干燥，过滤浓缩。经硅胶柱层析（PE:EA=4:1）纯化，得到化合物TSC-2（660mg，收率93%）。
1H NMR(400MHz,CDCl3):δ7.69-7.66(m,1H),7.43-7.41(m,1H),7.33-7.28(m,2H),6.27(d,1H),4.91(s,1H),4.27-4.18(m,4H),3.73(s,3H),3.65-3.61(m,1H),3.52-3.49(m,1H),2.90-2.87(m,2H),2.76-2.74(m,2H),1.39-1.36(dt,6H).MS:m/z474[M+1]+。
实施例3
将2-氧氯吡格雷中间体II（100mg，0.3mmol）溶于5mL无水四氢呋喃，降温至零下20℃，加入二异丙胺锂（2.0M,0.25mL,0.5mmol）搅拌20分钟，将化合物IIId（97mg,0.36mmoL）加入到反应液中，自然升温反应12小时，用4%盐酸淬灭反应，加入50mL乙酸乙酯，分别用碳酸氢钠和饱和食盐洗涤有机层，无水硫酸钠干燥，过滤浓缩。经硅胶柱层析（PE:EA=2:1）纯化，得到化合物TSC-4（162mg，收率95%）。
1H NMR(400MHz,CDCl3):δ7.71-7.68(m,1H),7.47-7.42(m,5H),7.35-7.24(m,10H),6.28(d,1H),4.92(s,1H),3.64-3.60(m,1H),3.51-3.48(m,1H),2.89-2.87(m,2H),2.75-2.73(m,2H),MS:m/z570[M+1]+。
实施例4
将TSC-2（500mg,1.04mmol）溶于10mL干燥二氯甲烷中，加入TMSBr（1.7mL,13mmol），室温反应12h，停止反应，减压抽干溶剂，再加入10mL甲醇搅拌1h。反应液直接浓缩，经硅胶柱层析（正丁醇：甲酸：水=5：5：1）纯化，得到化合物TSC-6（390mg，收率90%）。
1H NMR(400MHz,DMSO):δ7.60(d,1H),7.53(d,1H),7.41-7.40(m,2H),6.24(s,1H),4.91(s,1H),3.67(s,3H),3.56(s,2H),2.85(brs,2H),2.66(brs,2H),MS:m/z418[M+1]+。
实施例5
将2-氧氯吡格雷中间体II（500mg，1.5mmol）溶于5mL无水四氢呋喃，降温至零下20℃，加入二异丙胺锂（2.0M,1.25mL,2.5mmol）搅拌20分钟，将化合物IIIe（466mg,1.8mmoL）加入到反应液中，自然升温反应12小时，用4%盐酸淬灭反应，加入100mL乙酸乙酯，分别用碳酸氢钠和饱和食盐洗涤有机层，无水硫酸钠干燥，过滤浓缩。经硅胶柱层析（PE:EA=2:1）纯化，得到化合物TSC-7（269mg，收率32%）。
1H NMR(400MHz,CDCl3):δ7.69-7.65(m,1H),7.42-7.40(m,1H),7.31-7.24(m,2H),6.17(s,1H),5.46(s,1H),5.43(s,1H),4.91(s,1H),3.73(s,3H),3.64-3.60(m,1H),3.50-3.47(m,1H),2.91-2.88(m,2H),2.75-2.72(m,2H),1.50(s,18H).MS:m/z560[M+1]+。
实施例6
将TSC-6(500mg,0.89mmoL),溶于10mL二氯甲烷中，加入三氟乙酸（2mL），室温搅拌1h，减压浓缩，经硅胶柱层析（正丁醇：甲酸：水=5：5：1）纯化，得到化合物TSC-8（140mg，收率35%）。
1H NMR(400MHz,DMSO):δ7.62-7.60(m,1H),7.54-7.41(m,3H),6.18(s,1H),5.84(s,1H),5.37-5.32(d,2H),4.26-3.98(m,2H),3.79(s,3H),3.74-3.66(m,2H),3.15-3.00(m,2H),MS:m/z448[M+1]+。
实施例7
将2-氧氯吡格雷中间体II（500mg，1.5mmol）溶于5mL无水四氢呋喃，降温至零下20℃，加入二异丙胺锂（2.0M,1.25mL,2.5mmol）搅拌20分钟，将化合物IV加入到反应液中，自然升温反应12小时，用4%盐酸淬灭反应，加入100mL乙酸乙酯，分别用碳酸氢钠和饱和食盐洗涤有机层，无水硫酸钠干燥，过滤浓缩。经硅胶柱层析（PE:EA=2:1）纯化，得到化合物TSC-9（269mg，收率32%）。
1H NMR(400MHz,CDCl3):δ7.69-7.65(m,1H),7.42-7.40(m,1H),7.31-7.24(m,2H),6.17(s,1H),5.46(s,1H),5.43(s,1H),4.91(s,1H),3.73(s,3H),3.64-3.60(m,1H),3.50-3.47(m,1H),2.91-2.88(m,2H),2.75-2.72(m,2H),1.50(s,18H).MS:m/z560[M+1]+。
实施例8 本发明化合物药效研究
实验方法
在血小板悬液中加入小量ADP（浓度在0.9μmol/L以下），能迅速引起血小板聚集，但很快又解聚;若加入中等剂量的ADP(1.0μmol/L左右)，则在第一聚集时相结束和解聚后不久，又出现第二个不可逆的聚集时相。不可逆聚集时相的最大聚集率可以用于评价受试品对凝血功能的影响。本实验采用普利生公司NJ4型半自动血小板聚集仪，观察天士力集团提供受试品对血小板凝集的抑制作用。
实验材料：
动物：Wistar大鼠雄性，230-250g，购自维通利华。
试剂：ADP，Sigma公司。
受试品：7个受试品由天士力集团提供。
给药剂量：受试品以0.25%CMC混悬，3mg/kg体重给药，给药体积2ml。
实验步骤：
大鼠给药后2小时，戊巴比妥钠麻醉，腹主动脉取血，以柠檬酸钠1：9抗凝，离心取富血小板血浆和贫血小板血浆，两者混合比例为贫：富=3：1。
实验结果：
表1 本发明化合物对ADP诱导血小板聚集的最大聚集率影响
*P<0.001与正常组相比。
ADP诱导血小板凝集实验中，各受试品均有显著抑制大鼠血小板聚集作用，并且可以逆转血小板第二时相聚集，引起解聚。
Claims (7)
1.一种具有式(I)结构的噻吩并哌啶衍生物或其可药用酸加成盐：
其特征在于，
当X为S，m为0，n为0时，R为氢、CH3-、CH3CH2-、丙基、丁基、苯基。
2.权利要求1所述噻吩并哌啶衍生物或其可药用酸加成盐，其特征在于，所述化合物为：
TSC-9
3.权利要求1所述噻吩并哌啶衍生物或其可药用酸加成盐，其特征在于，所述盐为噻吩并哌啶磷酸酯衍生物与硫酸、盐酸、氢溴酸、磷酸、酒石酸、富马酸、马来酸、柠檬酸、乙酸、甲酸、甲磺酸、对甲苯磺酸、草酸或琥珀酸形成的盐。
4.权利要求1所述的噻吩并哌啶衍生物或其可药用酸加成盐在制备治疗和预防心力衰竭、中风、不稳定心绞痛的心脑血管疾病药物中的应用。
5.权利要求1所述的噻吩并哌啶衍生物或其可药用酸加成盐在制备抗血小板凝集药物中的应用。
6.一种药物组合物，其特征在于，所述药物组合物含有权利要求1所述的噻吩并哌啶衍生物或其可药用酸加成盐。
7.权利要求6所述的药物组合物，其特征在于，所述药物组合物还含有药学上可接受的载体。
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| CA2920410A CA2920410C (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| JP2016541790A JP6622205B2 (ja) | 2013-09-17 | 2014-09-10 | チエノピペリジン誘導体およびその使用 |
| KR1020167005860A KR20160058098A (ko) | 2013-09-17 | 2014-09-10 | 티에노피페리딘 유도체 및 이의 용도 |
| AU2014323812A AU2014323812B2 (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| PCT/CN2014/086191 WO2015039577A1 (zh) | 2013-09-17 | 2014-09-10 | 噻吩并哌啶衍生物及其用途 |
| US14/912,250 US20160200751A1 (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| EP14845625.4A EP3048108B1 (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| IL244214A IL244214B (en) | 2013-09-17 | 2016-02-22 | Thienopiperidine derivative and its use |
| US17/183,616 US20210179632A1 (en) | 2013-09-17 | 2021-02-24 | Thienopiperidine derivative and use thereof |
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| CN105153192B (zh) * | 2014-09-02 | 2019-03-29 | 南京曼杰生物科技有限公司 | 取代的四氢噻吩并吡啶衍生物及其应用 |
| CN107698620A (zh) * | 2015-06-23 | 2018-02-16 | 江苏天士力帝益药业有限公司 | 一种氘代噻吩并哌啶衍生物、制备方法及其应用 |
| CN106831866A (zh) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | 一类烷氧噻吩芳基氧化膦p2y12受体拮抗剂及其用途 |
| CN106831867A (zh) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | 一种腈基噻吩芳基氧化膦p2y12受体拮抗剂及其用途 |
| CN106749408A (zh) * | 2017-02-09 | 2017-05-31 | 广东赛博科技有限公司 | 一种硝基噻吩芳基氧化膦p2y12受体拮抗剂及其用途 |
| CN106831869A (zh) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | 胺基噻吩芳基氧化膦p2y12受体拮抗剂及其用途 |
| CN106831870A (zh) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | 一类腈基噻吩芳基氧化膦p2y12受体拮抗剂及其用途 |
| CN106831868A (zh) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | 一种胺基噻吩芳基氧化膦p2y12受体拮抗剂及其用途 |
| CN106831871A (zh) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | 一类硝基噻吩芳基氧化膦p2y12受体拮抗剂及其用途 |
| CN112778371B (zh) * | 2019-11-05 | 2024-01-30 | 华创合成制药股份有限公司 | 一种噻吩并吡啶衍生物及其制备方法和用途 |
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| CN103068383A (zh) * | 2010-08-26 | 2013-04-24 | Ipca实验室有限公司 | 血栓形成或梗塞的治疗或预防方法 |
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| FR2530247B1 (fr) * | 1982-07-13 | 1986-05-16 | Sanofi Sa | Nouveaux derives de la thieno (3, 2-c) pyridine, leur procede de preparation et leur application therapeutique |
| FR2576901B1 (fr) * | 1985-01-31 | 1987-03-20 | Sanofi Sa | Nouveaux derives de l'acide a-(oxo-2 hexahydro-2,4,5,6,7,7a thieno (3,2-c) pyridyl-5) phenyl acetique, leur procede de preparation et leur application therapeutique |
| JP2009538899A (ja) * | 2006-05-30 | 2009-11-12 | ファイザー・プロダクツ・インク | トリアゾロピリダジン誘導体 |
| AU2010226711B2 (en) * | 2009-03-18 | 2015-06-18 | Janssen Pharmaceutica Nv | Process for the preparation of histamine H3 receptor modulators |
| CN101885730B (zh) * | 2009-05-13 | 2012-07-04 | 连云港恒邦医药科技有限公司 | 抗血栓的化合物 |
| CN102120744B (zh) * | 2010-02-02 | 2013-01-09 | 江苏威凯尔医药科技有限公司 | 光学活性2-羟基四氢噻吩并吡啶衍生物及其制备方法与在制药中的用途 |
| WO2014043895A1 (zh) * | 2012-09-21 | 2014-03-27 | 北京普禄德医药科技有限公司 | 光学活性的2-羟基四氢噻吩并吡啶衍生物及其制备方法和用途 |
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| CN104418891B (zh) * | 2013-08-28 | 2018-04-06 | 江苏威凯尔医药科技有限公司 | 水溶性2‑羟基四氢噻吩并吡啶衍生物的制备及其医药用途 |
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| CN103068383A (zh) * | 2010-08-26 | 2013-04-24 | Ipca实验室有限公司 | 血栓形成或梗塞的治疗或预防方法 |
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| IL244214A0 (en) | 2016-04-21 |
| EP3048108B1 (en) | 2020-07-15 |
| IL244214B (en) | 2018-08-30 |
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| EP3048108A1 (en) | 2016-07-27 |
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| US20210179632A1 (en) | 2021-06-17 |
| JP2016530304A (ja) | 2016-09-29 |
| AU2014323812B2 (en) | 2019-06-20 |
| US20160200751A1 (en) | 2016-07-14 |
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