新型N-(2-氧代-2-苯基乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶酯类衍生物的合成及其抗血小板聚集活性
|
摘要
以5-三苯甲基-5,6,7,7a-四氢噻吩[3,2-c]吡啶-2(4H)-酮为起始原料,依次经酯化、脱保护和亲核取代反应合成了17个新型的N-(2-氧代-2-苯基乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶酯(1a～1q);并以2-溴-1-环丙基-2-(2-氟苯基)乙酮合成了新的普拉格雷衍生物(6),其结构均经~1H NMR和MS(ESI)表征。并通过"ADP对大鼠血小板聚集的影响"的药效学模型初步评价了其抗血小板聚集活性。结果表明:1f,1p,1q和6对血小板聚集有一定的抑制作用,其中6在低剂量(3 mg·kg~(-1))下的活性优于阳性对照药氯吡格雷。
A series of novel N-( 2-oxo-2-phenylethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl esters( 1a ～ 1q) were synthesized from 5-trityl-5,6,7,7a-tetrahydrothiophene [3,2-c] pyridine-2( 4H)-one via esterification,deprotection,and nucleophilic substitution reactions. In addition,a new prasugrel derivative( 6) was synthesized from 2-bromo-1-cyclopropyl-2-( 2-fluorophenyl) ethanone. The structures were characterized by ~1H NMR and MS( ESI). The anti-platelet aggregation activities were evaluated by pharmacodynamic model of the effect of ADP-induced platelet aggregation in rats. The results showed that 1f,1p,1q and 6 exhibited certain anti-platelet aggregation activity,and the activity of 6 was superior to that of the positive control clopidogrel at low dose( 3 mg·kg-1).
A series of novel N-( 2-oxo-2-phenylethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl esters( 1a ～ 1q) were synthesized from 5-trityl-5,6,7,7a-tetrahydrothiophene [3,2-c] pyridine-2( 4H)-one via esterification,deprotection,and nucleophilic substitution reactions. In addition,a new prasugrel derivative( 6) was synthesized from 2-bromo-1-cyclopropyl-2-( 2-fluorophenyl) ethanone. The structures were characterized by ~1H NMR and MS( ESI). The anti-platelet aggregation activities were evaluated by pharmacodynamic model of the effect of ADP-induced platelet aggregation in rats. The results showed that 1f,1p,1q and 6 exhibited certain anti-platelet aggregation activity,and the activity of 6 was superior to that of the positive control clopidogrel at low dose( 3 mg·kg-1).
引文
[1]洪文.小议血小板输注方法及其无效性[J].中国卫生产业,2011,8(11):100.
[2] STOREY R F,OLDROYD K G,WILCOX R D. Open multicenter study of the P2T receptor antagonist ARC69931MX assessing safety,tolerability and activity inpatients with acute coronary syndromes[J]. Thromb Haemost,2001,85(3):401-407.
[3]杨学平,李成建,杨亦军.氯吡格雷不良反应[J].中国误诊学杂志,2007,7(8):1913.
[4] SUGIDACHI A,ASAI F,OGAWA T,et al. The in vivo pharmacological profile of CS-747,a novel antiplatelet agent with platelet ADP receptor antagonist properties[J]. Br J Pharmacol,2000,129(7):1439-1446.
[5] SAVI P,NURDEN P,NURDEN A T,et al. Clopidogrel:A review of its mechanismof action[J]. Platelets,1998,9(3-4):251-255.
[6] FARID N A,KURIHARA A,WRIGHTON S A. Metabolism and disposition of the thienopyridine antiplatele drugs ticlopidine,clopidogrel,and prasugrel in humans[J]. J Clin Pharmacol,2010,50(2):126-142.
[7] SHAN J Q,ZHANG B Y,ZHU Y Q,et al. Overcoming clopidogrel resistance:Discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent[J]. J Med Chem,2012,55(7):3342-3352.
[8] CHENG D,LIU D K,LIU M,et al. Synthesis and activity evaluation of some novel derivatives of 4,5,6,7-tetrahydrothieno[3,2-c]-pyridine[J]. Chin Chem Lett,2008,19(6):689-692.
[9]刘颖,成蝶,刘登科,等.新型N-取代-2-(2-氯苯基)-2-{6,7-二氢噻吩并[3,2-c]吡啶-5-(4H)-基}乙酰胺的合成及其抗血小板聚集活性[J].合成化学,2011,19(6):718-722.
[10] CHALLA N R,MAMIDISETTY B,PADI P R. Synthesis and antithrombotic activity study of some new thienopyridine derivatives[J]. Lett Org Chem,2011,8(6):412-415.
[11] ALAIN B,DANIEL F,JIAN-PIERRE M,et al. Derivatives of alpha-(2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridyl)phenyl acetic acid,and their use as platelet and thrombotic aggregation inhibitors:US 4740510[P]. 1988.
[12] KRAHWINKEL R,MARKERT R,RITZER E,et al. Method for producing sorbic anhydride and also use thereof as a preservative in foods:US20140087039[P]. 2014.
[13] NIITSU Y,SUGIDACHI A,OGAWA T,et al. Repeat oral dosing of prasugrel,a novel P2Y12receptor inhibitor,results in cumulative and potent antiplatelet and antithrombotic activity in several animal species[J]. Eur J Pharmacol,2008,579(1):276-282.
[14]王相泉,孙铁民,岳珊珊,等.普拉格雷的合成[J].中国医药工业杂志,2014,45(10):913-915.
[2] STOREY R F,OLDROYD K G,WILCOX R D. Open multicenter study of the P2T receptor antagonist ARC69931MX assessing safety,tolerability and activity inpatients with acute coronary syndromes[J]. Thromb Haemost,2001,85(3):401-407.
[3]杨学平,李成建,杨亦军.氯吡格雷不良反应[J].中国误诊学杂志,2007,7(8):1913.
[4] SUGIDACHI A,ASAI F,OGAWA T,et al. The in vivo pharmacological profile of CS-747,a novel antiplatelet agent with platelet ADP receptor antagonist properties[J]. Br J Pharmacol,2000,129(7):1439-1446.
[5] SAVI P,NURDEN P,NURDEN A T,et al. Clopidogrel:A review of its mechanismof action[J]. Platelets,1998,9(3-4):251-255.
[6] FARID N A,KURIHARA A,WRIGHTON S A. Metabolism and disposition of the thienopyridine antiplatele drugs ticlopidine,clopidogrel,and prasugrel in humans[J]. J Clin Pharmacol,2010,50(2):126-142.
[7] SHAN J Q,ZHANG B Y,ZHU Y Q,et al. Overcoming clopidogrel resistance:Discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent[J]. J Med Chem,2012,55(7):3342-3352.
[8] CHENG D,LIU D K,LIU M,et al. Synthesis and activity evaluation of some novel derivatives of 4,5,6,7-tetrahydrothieno[3,2-c]-pyridine[J]. Chin Chem Lett,2008,19(6):689-692.
[9]刘颖,成蝶,刘登科,等.新型N-取代-2-(2-氯苯基)-2-{6,7-二氢噻吩并[3,2-c]吡啶-5-(4H)-基}乙酰胺的合成及其抗血小板聚集活性[J].合成化学,2011,19(6):718-722.
[10] CHALLA N R,MAMIDISETTY B,PADI P R. Synthesis and antithrombotic activity study of some new thienopyridine derivatives[J]. Lett Org Chem,2011,8(6):412-415.
[11] ALAIN B,DANIEL F,JIAN-PIERRE M,et al. Derivatives of alpha-(2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridyl)phenyl acetic acid,and their use as platelet and thrombotic aggregation inhibitors:US 4740510[P]. 1988.
[12] KRAHWINKEL R,MARKERT R,RITZER E,et al. Method for producing sorbic anhydride and also use thereof as a preservative in foods:US20140087039[P]. 2014.
[13] NIITSU Y,SUGIDACHI A,OGAWA T,et al. Repeat oral dosing of prasugrel,a novel P2Y12receptor inhibitor,results in cumulative and potent antiplatelet and antithrombotic activity in several animal species[J]. Eur J Pharmacol,2008,579(1):276-282.
[14]王相泉,孙铁民,岳珊珊,等.普拉格雷的合成[J].中国医药工业杂志,2014,45(10):913-915.