5-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylcarbamoyl]-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid | 166808-37-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 5-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylcarbamoyl]-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid
• CAS: 166808-37-3
• 化学式: C₃₁H₃₆N₄O₇
• 分子量: 576.649
• InChiKey: YSNYWXWAQFVCJP-UHFFFAOYSA-N

物化性质

• 熔点：
  139-141 °C
• 沸点：
  778.6±60.0 °C(predicted)
• 密度：
  1.264±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  154
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  乙胺 、 5-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylcarbamoyl]-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 在 4-二甲氨基吡啶 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 14.0h， 以41.5%的产率得到Methyl 1-[3-[[5-(ethylcarbamoyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carbonyl]amino]propyl]-4-phenylpiperidine-4-carboxylate
  参考文献：
  名称：

  Design and Synthesis of Novel α_1a Adrenoceptor-Selective Dihydropyridine Antagonists for the Treatment of Benign Prostatic Hyperplasia

  摘要：

  We report the synthesis and evaluation of novel alpha(1a) adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha(1a), antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a K-i of 2.8 nM, in agreement with the cloned human receptor binding data (K-i = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a K-i of 3.6 nM and confirmed it to be a potent antagonist (K-b = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP K-b/IUP K-b ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha(1a) adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha(1) antagonists such as prazosin and terazosin, with fewer side effects.

  DOI：

  10.1021/jm980506g
• 作为产物：
  描述：

  4-苯基哌啶-4-羧酸甲酯 在 4-二甲氨基吡啶 、 sodium hydroxide 、 potassium carbonate 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 potassium iodide 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 36.5h， 生成 5-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylcarbamoyl]-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid
  参考文献：
  名称：

  Design and Synthesis of Novel α_1a Adrenoceptor-Selective Dihydropyridine Antagonists for the Treatment of Benign Prostatic Hyperplasia

  摘要：

  We report the synthesis and evaluation of novel alpha(1a) adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha(1a), antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a K-i of 2.8 nM, in agreement with the cloned human receptor binding data (K-i = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a K-i of 3.6 nM and confirmed it to be a potent antagonist (K-b = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP K-b/IUP K-b ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha(1a) adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha(1) antagonists such as prazosin and terazosin, with fewer side effects.

  DOI：

  10.1021/jm980506g

文献信息

• Design and Synthesis of Novel α_1a Adrenoceptor-Selective Dihydropyridine Antagonists for the Treatment of Benign Prostatic Hyperplasia
  作者：Dhanapalan Nagarathnam、John M. Wetzel、Shou Wu Miao、Mohammad R. Marzabadi、George Chiu、Wai C. Wong、Xingfang Hong、James Fang、Carlos Forray、Theresa A. Branchek、William E. Heydorn、Raymond S. L. Chang、Theodore Broten、Terry W. Schorn、Charles Gluchowski

  DOI：10.1021/jm980506g

  日期：1998.12.1

  We report the synthesis and evaluation of novel alpha(1a) adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha(1a), antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a K-i of 2.8 nM, in agreement with the cloned human receptor binding data (K-i = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a K-i of 3.6 nM and confirmed it to be a potent antagonist (K-b = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP K-b/IUP K-b ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha(1a) adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha(1) antagonists such as prazosin and terazosin, with fewer side effects.