Anana R D, Ng H, Howlett S E, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Arch Pharm (Weinheim). 1997 Mar;330(3):53-8. doi: 10.1002/ardp.19973300303.
A group of dialkyl 1,4-dihydro-2,6-dimethyl-4-¿3-(or 4-)[[(Z)-N- oxo-N-[4-substituted-phenylmethylene (or vinylmethylene)]-lambda 5- azanyl]phenyl¿-3,5-pyridinedicarboxylates 7a-n were synthesized. Reaction of the C-4 nitrophenyl compounds 6a-d with an aryl Grignard reagent afforded the corresponding nitrone derivatives 7a-e. Alternatively, reaction of the aryl hydroxylamine compounds 8a-b prepared by reduction of the nitrophenyl compounds 6c-d with Zn/NH4Cl, or the aryl hydroxylamine compounds 8c-d prepared by reduction of the nitrophenyl compounds 6e-f with 5% rhodium-on-charcoal and 65% hydrazine hydrate, with a 4-substituted-benzaldehyde, benzaldehyde or acrolein afforded the respective nitrone compounds 7f-n. In vitro calcium channel (CC) antagonist activities were determined using the guinea pig ileum longitudinal smooth muscle assay. This class of compounds containing a nitrone moiety on the 1,4-dihydropyridine C-4 phenyl ring exhibited CC antagonist activities (10(-5) to 10(-9) M range) relative to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). Structure-activity relationships showed that the position of the nitrone moiety on the C-4 phenyl ring was a determinant of CC antagonist activity where the potency order was always meta-nitrone > para-nitrone. The effect of the ester alkyl substituent was variable depending upon whether the nitrone substituent was at the meta or para-position (meta-nitrone, Et > i-Pr approximately Me; para-nitrone, i-Pr > Me approximately Et). In the diethyl ester series of compounds having a meta-nitrone moiety, the difference in potency for the various R2-nitrone substituents varied by a factor of 15-fold (IC50 = 1.51 x 10(-7) to 9.84 x 10(-9) M range) (4-Cl-C6H4- > or = 4-Me-C6H4- approximately C6H5- > or = 4-O2N-C6H4- 4-F3C-C6H4- > > CH2 = CH-). Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that the 4-¿3-[(Z)-N-oxo-N-(phenylmethylene)-lambda 5-azanyl]-phenyl¿ compound 7c (10 microM) is a calcium channel antagonist which decreased the calcium current (ICa).
合成了一组二烷基 1,4 - 二氢 - 2,6 - 二甲基 - 4 - [3 -（或4 -）- [[(Z)-N - 氧代 - N - [4 - 取代苯基亚甲基（或乙烯基亚甲基）]-λ⁵ - 氮基]苯基] - 3,5 - 吡啶二羧酸酯7a - n。C - 4硝基苯基化合物6a - d与芳基格氏试剂反应得到相应的硝酮衍生物7a - e。或者，用锌/氯化铵还原硝基苯基化合物6c - d制得的芳基羟胺化合物8a - b，或用5%钯 - 炭和65%水合肼还原硝基苯基化合物6e - f制得的芳基羟胺化合物8c - d，与4 - 取代苯甲醛、苯甲醛或丙烯醛反应，得到各自的硝酮化合物7f - n。使用豚鼠回肠纵行平滑肌试验测定了体外钙通道（CC）拮抗剂活性。这类在1,4 - 二氢吡啶C - 4苯环上含有硝酮部分的化合物相对于参比药物硝苯地平（IC50 = 1.43×10⁻⁸ M）表现出CC拮抗剂活性（10⁻⁵至10⁻⁹ M范围）。构效关系表明，硝酮部分在C - 4苯环上的位置是CC拮抗剂活性的决定因素，其效价顺序始终是间位硝酮＞对位硝酮。酯烷基取代基的影响因硝酮取代基是在间位还是对位而异（间位硝酮，Et＞i - Pr≈Me；对位硝酮，i - Pr＞Me≈Et）。在具有间位硝酮部分的二乙酯系列化合物中，各种R2 - 硝酮取代基的效价差异变化了15倍（IC50 = 1.51×10⁻⁷至9.84×10⁻⁹ M范围）（4 - Cl - C6H4 - ≥4 - Me - C6H4 - ≈C6H5 - ≥4 - O2N - C6H4 - 4 - F3C - C6H4 - ＞＞CH2 = CH -）。使用分离的豚鼠心室肌细胞进行的全细胞膜片钳研究表明，4 - [3 - [(Z)-N - 氧代 - N -（苯基亚甲基）-λ⁵ - 氮基] - 苯基]化合物7c（10 μM）是一种钙通道拮抗剂，可降低钙电流（ICa）。
