3-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid | 166809-89-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid
• 英文别名: 3-(2-Cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl) pyridine-5-carboxylic acid；5-(2-cyanoethoxycarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid
• CAS: 166809-89-8
• 化学式: C₁₈H₁₇N₃O₆
• 分子量: 371.349
• InChiKey: WWQYPSMSFMRQME-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  145
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid 在 4-二甲氨基吡啶 、 sodium hydroxide 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 12.5h， 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
• 作为产物：
  描述：

  2-氰基乙酰乙酸乙酯 在 palladium on activated charcoal 哌啶 、 甲酸 、 溶剂黄146 作用下， 以 甲醇 、 乙醇 、 异丙醇 为溶剂， 反应 77.0h， 生成 3-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-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

• Dihydropyridines and new uses thereof
  申请人：Synaptic Pharmaceutical Corporation

  公开号：US05767131A1

  公开（公告）日：1998-06-16

  The invention provides a method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of a compound having the structure: ##STR1## wherein Y is --(CH.sub.2).sub.n --, where n is 1, 2, 3, 4 or 5; --(CH.sub.2).sub.h --O--(CH.sub.2).sub.k --, where h and k are independently the same or different and are 2, 3 or 4; --(CH.sub.2).sub.h --CH.dbd.CH--(CH.sub.2).sub.k --; or --(CH.sub.2).sub.h --C.tbd.C--(CH.sub.2).sub.k --, where h and k are independently the same or different and are 1, 2, 3 or 4; wherein Z is O, NH, or CH.sub.2 ; wherein R.sup.1 is a linear or branched chain alkyl, alkoxyalkyl or arylalkyl group; wherein R.sup.2 and R.sup.4 are independently the same or different and are H, or a linear or branched chain alkyl group; wherein R.sup.3 is H, a linear or branched chain alkyl, alkoxy, alkoxyalkyl or acyl group; and wherein R.sup.5 and R.sup.6 are independently the same or different and are H, OH, Cl, Br, F, NO.sub.2, CN, CF.sub.3, or NH.sub.2, or a linear or branched chain alkyl, alkoxy, alkoxycarbonyl, acyl, alkylsulfoxide, alkylsulfone, or mono- or dialkylamino group. Other active compounds containing one, two or three rings are also disclosed as well as pharmaceutical compositions prepared therefrom and methods of use in the treatment of BPH, inhibition of cholesterol synthesis, and reduction of intraocular pressure.

  该发明提供了一种治疗良性前列腺增生的方法，包括向受试者施用具有以下结构的化合物的治疗有效量： 其中Y为--(CH.sub.2).sub.n --，其中n为1、2、3、4或5；--(CH.sub.2).sub.h --O--(CH.sub.2).sub.k --，其中h和k独立且相同或不同，为2、3或4；--(CH.sub.2).sub.h --CH.dbd.CH--(CH.sub.2).sub.k --；或--(CH.sub.2).sub.h --C.tbd.C--(CH.sub.2).sub.k --，其中h和k独立且相同或不同，为1、2、3或4；其中Z为O、NH或CH.sub.2；其中R.sup.1为线性或支链烷基、烷氧基烷基或芳基烷基；其中R.sup.2和R.sup.4独立且相同或不同，为H，或线性或支链烷基；其中R.sup.3为H、线性或支链烷基、烷氧基、烷氧基烷基或酰基；其中R.sup.5和R.sup.6独立且相同或不同，为H、OH、Cl、Br、F、NO.sub.2、CN、CF.sub.3或NH.sub.2，或线性或支链烷基、烷氧基、烷氧羰基、酰基、烷基亚砜、烷基砜、或单烷基或二烷基氨基基团。还公开了含有一、两个或三个环的其他活性化合物，以及由此制备的药物组合物和在治疗BPH、抑制胆固醇合成和降低眼压中的使用方法。
• US5767131A
  申请人：——

  公开号：US5767131A

  公开（公告）日：1998-06-16
• US6211198B1
  申请人：——

  公开号：US6211198B1

  公开（公告）日：2001-04-03
• US6310076B1
  申请人：——

  公开号：US6310076B1

  公开（公告）日：2001-10-30
• US6608086B2
  申请人：——

  公开号：US6608086B2

  公开（公告）日：2003-08-19