1,4-二氢-2,6-二甲基-4-(吡啶基)-5-[2-(4,5-二氢-4,4-二甲基恶唑啉-2-基)]-3-吡啶羧酸烷基酯的合成及其对平滑肌钙通道的拮抗作用

Synthesis and smooth muscle calcium channel antagonist effects of alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-5-[2-(4,5-dihydro- 4,4-dimethyloxazolin-2-yl)]-3-pyridinecarboxylates.

作者信息

Anana R D, Knaus E E

机构信息

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.

出版信息

Arch Pharm (Weinheim). 1996 Aug-Sep;329(8-9):408-12. doi: 10.1002/ardp.19963290807.

DOI:10.1002/ardp.19963290807

PMID:8915102

Abstract

A group of racemic alkyl 1,4-dihydro-2,6-dimethyl-4-(3- or 4-pyridinyl)-5-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)-3- pyridinecarboxylates 11a-e were prepared by using the Hantzsch reaction involving condensation of the Knoevenagel adducts 9a-e with 1-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)]-1-propen-2-ami ne (10). In contrast, the 4-(2-pyridinyl) analogue 11f was prepared by thionyl chloride mediated cyclization of the 5-¿N-(1,1-dimethyl-2-hydroxyethyl)aminocarbonyl¿ moiety of 16 to the 5-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)] ring system (11f). In vitro calcium channel antagonist activity was determined by using the guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Compared to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M), the title compounds 11 exhibited weak calcium channel antagonist activity (10(-5) to 10(-6) M range). A comparison of compounds 11 having a C-4 3-pyridinyl substituent showed that with respect to the alkyl ester R2-substituent, the relative potency order was i-Bu (11c) > or = i-Pr (11e) > Me (11a). The point of attachment of the C-4 pyridinyl substituent in the isopropyl ester isomeric series of compounds was a determinant of activity where the potency profile was 4-py (11d) > or = 3-py (11e) > 2-py (11f). Although less effective, the 4,5-dihydro-4,4-dimethyloxazolin-2-yl moiety acts as a bioisostere of the alkyl ester substituent present in classical 1,4-dihydropyridine calcium channel antagonists. The 4,5-dihydro-4,4-dimethyl-oxaxolin-2-yl ring system is not an effective bioisostere of the 3-nitro group present in 1,4-dihydropyridine calcium channel agonists since isopropyl 1,4-dihydro-2,6-dimethyl-4-(2-pyridinyl)-5- [2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)]-3-pyridinecarboxyla te (11f) produced a modest 10% increase in the in vitro contractile force of guinea pig left atrium at a concentration of 1.64 x 10(-7) M, relative to the reference 3-nitro analogue 1 (EC50 = 9.6 x 10(-6) M).

摘要

通过涉及克脑文格尔加合物9a - e与1 - [2 - (4,5 - 二氢 - 4,4 - 二甲基恶唑啉 - 2 - 基)] - 1 - 丙烯 - 2 - 胺(10)缩合的汉茨希反应，制备了一组外消旋烷基1,4 - 二氢 - 2,6 - 二甲基 - 4 - (3 - 或4 - 吡啶基) - 5 - [2 - (4,5 - 二氢 - 4,4 - 二甲基恶唑啉 - 2 - 基)] - 3 - 吡啶羧酸酯11a - e。相比之下，4 - (2 - 吡啶基)类似物11f是通过将16的5 - {N - (1,1 - 二甲基 - 2 - 羟乙基)氨基羰基}部分用亚硫酰氯介导环化到5 - [2 - (4,5 - 二氢 - 4,4 - 二甲基恶唑啉 - 2 - 基)]环系统(11f)制备的。使用豚鼠回肠纵行平滑肌(GPILSM)试验测定体外钙通道拮抗剂活性。与参比药物硝苯地平(IC50 = 1.43×10⁻⁸ M)相比，标题化合物11表现出较弱的钙通道拮抗剂活性(10⁻⁵至10⁻⁶ M范围)。对具有C - 4 3 - 吡啶基取代基的化合物11的比较表明，就烷基酯R2 - 取代基而言，相对效价顺序为异丁基(11c)≥异丙基(11e)＞甲基(11a)。在化合物的异丙基酯异构体系列中，C - 4吡啶基取代基的连接点是活性的决定因素，效价分布为4 - 吡啶基(11d)≥3 - 吡啶基(11e)＞2 - 吡啶基(11f)。虽然效果较差，但4,5 - 二氢 - 4,4 - 二甲基恶唑啉 - 2 - 基部分作为经典1,4 - 二氢吡啶钙通道拮抗剂中存在的烷基酯取代基的生物电子等排体。4,5 - 二氢 - 4,4 - 二甲基恶唑啉 - 2 - 基环系统不是1,4 - 二氢吡啶钙通道激动剂中存在的3 - 硝基的有效生物电子等排体，因为异丙基1,4 - 二氢 - 2,6 - 二甲基 - 4 - (2 - 吡啶基) - 5 - [2 - (4,5 - 二氢 - 4,4 - 二甲基恶唑啉 - 2 - 基)] - 3 - 吡啶羧酸酯(11f)在浓度为1.64×10⁻⁷ M时，相对于参比3 - 硝基类似物1(EC50 = 9.6×10⁻⁶ M)，使豚鼠左心房的体外收缩力适度增加了10%。