CN107922448A - 一种氘代噻吩并哌啶衍生物、制备方法及其应用 - Google Patents
一种氘代噻吩并哌啶衍生物、制备方法及其应用 Download PDFInfo
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- CN107922448A CN107922448A CN201680036795.9A CN201680036795A CN107922448A CN 107922448 A CN107922448 A CN 107922448A CN 201680036795 A CN201680036795 A CN 201680036795A CN 107922448 A CN107922448 A CN 107922448A
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- Prior art keywords
- deuterated
- thieno
- acid
- phenyl
- hydrogen
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Abstract
本发明涉及一种氘代噻吩并哌啶衍生物、制备方法及其应用,本发明涉及的氘代噻吩并哌啶衍生物具有如下的式(I)结构,本发明还包括该类氘代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
本发明涉及有机化学和药物化学领域。具体而言,本发明涉及一种氘代噻吩并哌啶衍生物;本发明还涉及该一种氘代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。
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(adenosinediphosphate,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”。
中国专利申请201310428052.4公开了下列结构的氯吡格雷代谢物2-氧氯吡格雷前药噻吩并哌啶衍生物,用以改善“氯吡格雷抵抗”。
然而该系列化合物仍然存在血小板聚集抑制率低、水解速率快等缺陷。为解决上述缺陷,开发临床起效快,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,本发明在中国专利申请201310428052.4基础上开发了一系列新型的氘代噻吩并哌啶衍生物、其制备方法及应用。中国专利申请201310428052.4全文并入本发明中,作为本发明的现有技术。
发明内容
本发明所要解决的技术问题在于克服上述不足,设计、合成新型的光学活性氘代噻吩并吡啶衍生物,以开发疗效好、副作用小的抗血小板凝集药物。
具体而言,本发明一个目的在于提供一种光学活性氘代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氘代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氘代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氘代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氘代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)结构的光学活性氘代噻吩并哌啶衍生物或其可药用盐,溶剂化物,多晶型体,对映体或外消旋混合物:
其中,CD3中的D为氘,其为氢的一种稳定形态同位素,也被称为重氢;
X为P或S;m为0或1;n为0或1;R1选自氢、C1-C4直链或支链被卤素取代或未取代的烷烃基、苯基或取代苯基;R2选自无取代、氢、C1-C4直链或支链被卤素取代或未取代的烷烃基、苯基或取代苯基,其中当R2为无取代时,X与O形成双键。
优选的,其中,X为P,m为0,n为0,R1选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,苯基;R2选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,苯基。
或,其中,X为P,m为1,n为1,R1选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,叔丁基,苯基;R2选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,叔丁基,苯基。
或,其中,X为S,m为0,n为0,R1选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,叔丁基,苯基;R2为无取代,且X与O形成双键。
本发明所述氘代噻吩并哌啶衍生物,优选以下化合物:
本发明还包括所述氘代噻吩并哌啶衍生物的可药用盐,其中,所述盐可以是氘代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,所述药物组合物含本发明所述的氘代噻吩并哌啶衍生物或其可药用盐。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。
本发明所述的氘代噻吩并哌啶衍生物或其可药用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氘代噻吩并哌啶衍生物或其可药用盐,溶剂化物,多晶型体,对映体或外消旋混合物的制备方法,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TSD-9可以通过下述方式制备:
其中,R为氯或羟基。
图1TSD-8和氯吡格雷外酯酶水解速率图。
图2TSD-6和氯吡格雷外酯酶水解速率图。
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
(R)-邻氯扁桃酸氘代甲酯
将(R)-邻氯扁桃酸9.4g溶解于36mL氘代甲醇中,加入4M氯化氢/二氧六环溶液1mL,加热回流5小时,冷却后减压蒸干溶剂,剩余物用二氯甲烷溶解,依次用5%碳酸钾水溶液、水洗涤,无水硫酸钠干燥二氯甲烷溶液,过滤除去干燥剂后蒸干,得无色透明油状物(R)-邻氯扁桃酸氘代甲酯9.2g,收率89.7%。
实施例2
(R)-2-(2-氯苯基)-2-(4-硝基苯磺酰氧基)-乙酸氘代甲酯(Ⅱ-1)
将(R)-邻氯扁桃酸氘代甲酯10.2g溶于50mL无水二氯甲烷中,加入三乙胺65.6g和催化量DMAP,搅拌,降温至0℃,同温下滴加12.2g对硝基苯磺酰氯的50mL无水二氯甲烷溶液,然后保温反应4小时。向反应液中加入100mL水,搅拌,静置,分液,水相再用150mL二氯甲烷分三次萃取,合并有机相后无水硫酸钠干燥,过滤除去干燥剂后减压蒸干二氯甲烷得暗红色油状粗品20.9g,经甲醇重结晶得固体产品(Ⅱ-1)15.8g,收率81.3%。
实施例3
(2S)-2-(2-氯苯基)-2-(2-氧代-7,7a-二氢噻吩并[3,2-c]吡啶-5(2H,4H,6H)-基)-乙酸氘代甲酯(V-1)
将(R)-2-(2-氯苯基)-2-(4-硝基苯磺酰氧基)-乙酸氘代甲酯(Ⅱ-1)58.1g(0.15mol)、5,6,7,7a-四氢噻吩并[3.2-c]吡啶-2(4H)-酮盐酸盐(Ⅳ-1)32.3g(0.17mol)和37.8g(0.38mol)碳酸氢钾加入到500mL乙腈中,反应体系用氮气保护,室温搅拌26小时。反应液静置后过滤不溶物,得暗红色母液。减压蒸干溶剂,经快速柱层析(石油醚:乙酸乙酯=4:1)得油状产品35.4g,收率70%。
实施例4
将2-氧氘代氯吡格雷中间体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,0.72mmol)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TSD-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),3.64-3.60(m,1H),3.51-3.48(m,1H),2.89-2.87(m,2H),2.75-2.73(m,2H),MS:m/z 449[M+1]+。
实施例5
将2-氧氘代氯吡格雷中间体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TSD-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),3.65-3.61(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/z 477[M+1]+。
实施例6
将2-氧氘代氯吡格雷中间体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TSD-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),2.89-2.87(m,2H),2.75-2.73(m,2H),MS:m/z 573[M+1]+。
实施例7
将TSD-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TSD-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),3.56(s,2H),2.85(brs,2H),2.66(brs,2H),MS:m/z 421[M+1]+。
实施例8
将2-氧氘代氯吡格雷中间体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TSD-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),3.64-3.60(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/z 560[M+1]+。
实施例9
将TSD-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TSD-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),3.74-3.66(m,2H),3.15-3.00(m,2H),MS:m/z 451[M+1]+。
实施例10
将2-氧氘代氯吡格雷中间体II(150mg,0.45mmol)溶于5ml无水四氢呋喃,降温至零下20℃,加入二异丙胺锂(2.0M,0.4mL,0.8mmol)搅拌20分钟,将化合物IIIc(108mg,0.54mmol)加入到反应液中,自然升至室温反应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水洗涤有机层,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TSD-3(192mg,收率85%)。
1H NMR(400MHz,CDCl3):δ7.68-7.67(m,1H),7.41-7.39(m,1H),7.34-7.28(m,2H),
6.28(d,1H),4.92(s,1H),4.74(m,2H),4.26-4.17(m,4H),3.64-3.61(m,1H),3.53-3.49(m,1H),1.28(d,12H).MS:m/z 505[M+1]+。
实施例11
将2-氧氘代氯吡格雷中间体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TSD-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),3.64-3.60(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/z 563[M+1]+。
实施例12 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:16个受试品由天士力集团提供,其中TSC-1~4、TSC-6~9的制备方法参照中国专利申请201310428052.4。
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。且本发明的氘代噻吩并哌啶系列衍生物(TSD-1~4、6~9)的抑制血小板聚集的作用,明显优于非氘代的噻吩并哌啶系列衍生物(TSC-1~TSC-4、TSC-6~TSC-9)。
实施例13
式TSD-8化合物与氯吡格雷外酯酶水解速度对比试验
采用体外孵育的方法测定式TSD-8和氯吡格雷硫酸氢盐在大鼠全血中的水解速率。
取大鼠新鲜全血3mL,置于玻璃试管中。加入30μg/mL的式TSD-8和氯吡格雷硫酸氢盐(生理盐水配制),每组平行实验3个。试管37℃恒温震荡,于固定时间点10min,20min,30min,40min,50min,60min,70min,80min,90min,100min,110min,120min取出100μL,加入900μL甲醇立即终止反应,再依次加入100μL甲醇水(1:1,v/v),100μL内标(安定,100ng/mL)。低温13000rpm离心10min,上清转移至另一EP管中,取20μL进样。
表2 TSD-8与氯吡格雷硫酸氢盐外酯酶水解速度对比试验
TSD-8测样结果
氯吡格雷硫酸氢盐测样结果
N/A表示数据缺失,下同。
由图1可以看出,TSD-8各时间点浓度均大于氯吡格雷,故其在大鼠全血中的水解速率要慢于氯吡格雷,全血中的氯吡格雷硫酸氢盐在50min左右时,浓度已低于定量下线,而式TSD-8化合物仍可测出。
实施例14
式TSD-6化合物与氯吡格雷外酯酶水解速度对比试验
采用体外孵育的方法测定式TSD-6和氯吡格雷硫酸氢盐在大鼠全血中的水解速率。
取大鼠新鲜全血3mL,置于玻璃试管中。加入30μg/mL的式TSD-6和氯吡格雷硫酸氢盐(生理盐水配制),每组平行实验3个。试管37℃恒温震荡,于固定时间点10min,20min,30min,40min,50min,60min,70min,80min,90min,100min,110min,120min取出100μL,加入900μL甲醇立即终止反应,再依次加入100μL甲醇水(1:1,v/v),100μL内标(安定,100ng/mL)。低温13000rpm离心10min,上清转移至另一EP管中,取20μL进样。
表3 TSD-6与氯吡格雷硫酸氢盐外酯酶水解速度对比试验
TSD-6测样结果
氯吡格雷硫酸氢盐测样结果
由图2可以看出,TSD-6各时间点浓度也均大于氯吡格雷,其在大鼠全血中的水解速率要明显慢于氯吡格雷,全血中的氯吡格雷硫酸氢盐在50min左右时,浓度已低于定量下线,而式TSD-6化合物仍可测出。
实施例15
式TSD-6,TSC-6,I-1和氯吡格雷大鼠体内代谢为2-oxo-clopidogrel药代动力学对比,化合物结构如下图所示:
试验动物:雄性SD大鼠24只,6-7周龄,动物体重240~290g,购自上海斯莱克实验动物有限公司,动物合格证号为2015000514648。试验前,动物应至少饲养3天以适应环境。静脉注射(IV)组动物不禁食;口服灌胃(PO)组动物给药前禁食过夜,给药后4hr喂食,整个试验中,动物自由饮水。
受试药物:氯吡格雷硫酸氢盐(Clopidogrel)、TSC-6、I-1和TSD-6,由天士力提供。
动物分组和采样时间点:24只SD大鼠,分为8组,每组3只,静脉注射组动物通过足背静脉给予3mg/kg受试药物,灌胃组动物通过强饲法给予15mg/kg受试药物。给药方案见表4。
表4.动物给药和采血方案
样品采集与储存:根据预定时间点,固定相应动物,尾静脉采血约80μL,血液样品用肝素钠抗凝,置于湿冰上。立即取60μL血样加入到600μL内标溶液(40ng/mL双氯芬酸乙腈溶液,含0.1%甲酸),涡旋0.5min,以12000rpm在4℃下离心5min,获得上层清液。上层清液样品先置于干冰中冻存,然后转移至-70℃冰箱长期保存直至样品分析。
试验结果:
通过关键代谢产物2-oxo-clopidogrel的药代动力学对比研究可以看出,我们开发的氘代化合物TSD-6关键代谢中间体的暴露量无论是口服还是静脉注射给药,都要明显高于非氘代化合物TSC-6和同类类似化合物I-1。药代数据显示出TSD-6更好的独特代谢性质,这将有利于提高药效,并克服现有化合物不足。
实施例16
式TSC-6,I-1,TSD-6和氯吡格雷大鼠尾出血模型中的药效对比研究
动物及饲养:种属、品系:SD大鼠,
提供:斯莱克
体重:250-350g
性别:雄
动物数:30
饲养条件:清洁级动物房饲养,温度20.5-22.5℃,湿度50-65%,光照150-250Lx,12小时昼夜交替(6:00-18:00为昼.)
受试物、对照药物及配制方法:将化合物TSC-6,I-1,TSD-6和氯吡格雷溶于5mL0.25%CMC,37度超声20min,搅拌子搅拌至悬浮液。
剂量设置及依据:受试化合物剂量TSC-6,I-1,TSD-6为1mg/kg。阳性化合物氯吡格雷给药剂量为10mg/kg,依据参考文献及本实验室实验结果设定。
给药方式:口服灌胃。
实验方法:
●动物到达后适应环境一周,实验前禁食16个小时。
●测试化合物口服给药2h,氯吡格雷口服给药4h后,开始尾出血时间记录。
●尾出血时间记录前10min用戊巴比妥钠(50mg/kg,ip)将麻醉大鼠,待大鼠完全麻醉后,到达检测时间时,从距离鼠尾尖1.3mm处用剪刀剪断并垂直浸入37℃的生理盐水中,出现血流时,开始计时。
●当血流中断血时间超过20秒时,计时停止。最大的血流观察时间设置为40分钟,超过40分钟时则停止计时,按40分钟计算。
试验结果:
Entry | Compound | Dose(mg/kg) | TailBleedingTime(s) |
1 | Vehicle | — | 158 |
2 | TSC-6 | 1.0 | 635 |
3 | I-1 | 1.0 | 950 |
4 | TSD-6 | 1.0 | 1331* |
5 | Clopidogrel | 10 | 1896*** |
*P<0.05,***P<0.001vs Vehicle
通过对比TSC-6,I-1,TSD-6和氯吡格雷在大鼠尾出血模型中的尾出血时间来评价化合物的抗凝效果。可以看出我们开发的氘代化合物TSD-6抗凝效果要显著优于非氘代的化合物TSC-6和同类类似物I-1,显示出TSD-6独特的抗凝活性。
实施例17
式TSC-6,I-1,TSD-6和氯吡格雷大鼠动静脉血栓回路模型药效对比研究
动物及饲养:种属、品系:SD大鼠,
提供:斯莱克
体重:250-350g
性别:雄
动物数:30
饲养条件:清洁级动物房饲养,温度20.5-22.5℃,湿度50-65%,光照150-250Lx,12小时昼夜交替(6:00-18:00为昼.)
受试物、对照药物及配制方法:将化合物TSC-6,I-1,TSD-6和氯吡格雷溶于5mL0.25%CMC,37度超声20min,搅拌子搅拌至悬浮液。
剂量设置及依据:受试化合物剂量TSC-6,I-1,TSD-6为1mg/kg。阳性化合物氯吡格雷给药剂量为10mg/kg,依据参考文献及本实验室实验结果设定。
给药方式:口服灌胃。
器械与材料
●棉棒,干棉球,酒精棉,安尔碘棉球。
●手术剪,眼科镊,止血钳,显微剪,显微镊,动脉夹。
●3-0手术缝合丝线,粗PE管(I.D.*O.D.=1.14mm*1.63mm,8cm长),细PE管(I.D.*O.D.=0.72mm*1.22mm,6cm长)。
●手术板,绑定绳,计时器,精密电子天平,称量纸。
●注射器,生理盐水。
7.实验方法
●动物到达后适应环境一周,实验前禁食16个小时。
●测试化物口服给药2h,氯吡格雷口服给药4h后,开始动静脉血液回路循环。
●动静脉血液回路循环开启前约15min用戊巴比妥钠(50mg/kg,ip)将麻醉大鼠。
●分离左侧颈外静脉,右侧颈动脉并分别插管细PE管。
●两根PE管用另一根8cm长的粗PE管连接,形成一个循环通路。粗PE管中包含一条6cm长的手术缝合线(3-0)。
●循环通路打开15min后,阻断血流,线栓取出,吸附血液后称重,减去线本身重量既得血栓重量。
试验结果:
Entry | Compound | Dose(mg/kg) | Thrombus(mg) |
1 | Vehicle | — | 52.2 |
2 | TSC-6 | 1.0 | 31.4* |
3 | I-1 | 1.0 | 25.6 |
4 | TSD-6 | 1.0 | 18.4* |
5 | Clopidogrel | 10 | 20.1** |
*P<0.01,**P<0.01vs Vehicle
通过对比TSC-6,I-1,TSD-6和氯吡格雷在大鼠动静脉血栓回路模型中形成的血栓重量来评价化合物的抗凝效果。可以看出我们开发的氘代化合物TSD-6形成的血栓重量要显著低于于非氘代的化合物TSC-6和同类类似物I-1,显示出TSD-6独特的抗凝活性。
Claims (10)
- 一种具有式(I)结构的氘代噻吩并哌啶衍生物或其可药用盐,其中,X为P或S;m为0或1;n为0或1;R1选自氢、C1-C4直链或支链被卤素取代或未取代的烷烃基、苯基或取代苯基;R2选自无取代、氢、C1-C4直链或支链被卤素取代或未取代的烷烃基、苯基或取代苯基,其中当R2为无取代时,X与O形成双键。
- 权利要求1所述氘代噻吩并哌啶衍生物或其可药用盐,其特征在于,其中,X为P,m为0,n为0,R1选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,苯基;R2选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,苯基。
- 权利要求1所述氘代噻吩并哌啶衍生物或其可药用盐,其特征在于,其中,X为P,m为1,n为1,R1选自氢、CH3-、CH3CH2-、异丙基、CCL3CH2-,叔丁基,苯基;R2选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,叔丁基,苯基。
- 权利要求1所述氘代噻吩并哌啶衍生物或其可药用盐,其特征在于,其中,X为S,m为0,n为0,R1选自氢、CH3-、CH3CH2-、异丙基、CCl3CH2-,叔丁基,苯基;R2为无取代,且X与O形成双键。
- 权利要求1所述氘代噻吩并哌啶衍生物或其可药用盐,其特征在于,选自以下化合物:
- 权利要求1所述氘代噻吩并哌啶磷酸酯衍生物或其可药用盐,其中,所述盐可以是氘代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。
- 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所述的氘代噻吩并哌啶磷酸酯衍生物或其可药用盐。
- 权利要求7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。
- 权利要求1所述的氘代噻吩并哌啶磷酸酯衍生物或其可药用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。
- 权利要求1所述的氘代噻吩并哌啶磷酸酯衍生物或其可药用盐,在制备抗血小板凝集的药物中的应用。
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CN115165949A (zh) * | 2021-04-07 | 2022-10-11 | 江苏天士力帝益药业有限公司 | 一种tsl-0202中非氘代tsl-0202含量测定方法 |
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