1-<2-(4-benzyloxyphenyl)ethoxy>-4-hydroxy-4-(4-methylbenzyl)piperidine

• 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: 1-<2-(4-benzyloxyphenyl)ethoxy>-4-hydroxy-4-(4-methylbenzyl)piperidine
• 英文别名: 1-[2-(4-benzyloxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol；4-[(4-methylphenyl)methyl]-1-[2-(4-phenylmethoxyphenoxy)ethyl]piperidin-4-ol
• 化学式: C₂₈H₃₃NO₃
• 分子量: 431.575
• InChiKey: AVWXLZZGUKIPPQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  41.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-苄氧基苯酚 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 24.2h， 生成 1-<2-(4-benzyloxyphenyl)ethoxy>-4-hydroxy-4-(4-methylbenzyl)piperidine
  参考文献：
  名称：

  4-Hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine:  A Novel, Potent, and Selective NR1/2B NMDA Receptor Antagonist

  摘要：

  A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC50 = 0.63 mu M). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K+ channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a similar to 25-fold increase in NR1A/2B potency (IC50 = 0.025 mu M). p-Methyl substitution on the benzyl ring (10b) produced a similar to 3-fold increase in MES activity (ED50 = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of Kf channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(methylbenzyl)piperidine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.

  DOI：

  10.1021/jm990246i

文献信息

• 4-hydroxy-piperodine derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US05889026A1

  公开（公告）日：1999-03-30

  The present invention relates to compounds of the formula ##STR1## wherein x is --O--, --NH--, --CH.sub.2 --, --CH.dbd., --CO.sub.2 --, --CONH--, --CON(lower alkyl)--, --S-- and --SO.sub.2 --; R.sup.1 -R.sup.4 are, independently from each other hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, 1- or 2-imidazolyl, 1-(1,2,4-triazolyl) or acetamido; R.sup.5, R.sup.6 are, independently from each other hydrogen, lower-alkyl, hydroxy, lower alkoxy or oxo; R.sup.7 -R.sup.10 are, independently from each other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; n is 0 or 1; and to pharmaceutically acceptable acid addition salts thereof. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers.

  本发明涉及公式##STR1##的化合物，其中x为--O--，--NH--，--CH.sub.2--，--CH.dbd.，--CO.sub.2--，--CONH--，--CON（较低烷基）--，--S--和--SO.sub.2--；R.sup.1-R.sup.4分别为氢，卤素，羟基，氨基，硫酰基化较低烷基，1-或2-咪唑基，1-(1,2,4-三唑基)或乙酰胺基；R.sup.5，R.sup.6分别为氢，较低烷基，羟基，较低烷氧基或氧代基；R.sup.7-R.sup.10分别为氢，较低烷基，卤素，三氟甲基或较低烷氧基；n为0或1；以及其药学上可接受的酸盐。本发明的化合物是NMDA（N-甲基-D-天门冬氨酸）受体亚型选择性阻滞剂。
• 4-hydroxy-piperidine derivatives
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0824098B1

  公开（公告）日：2001-10-31
• US5889026A
  申请人：——

  公开号：US5889026A

  公开（公告）日：1999-03-30
• 4-Hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine:  A Novel, Potent, and Selective NR1/2B NMDA Receptor Antagonist
  作者：Zhang-Lin Zhou、Sui Xiong Cai、Edward R. Whittemore、Christopher S. Konkoy、Stephen A. Espitia、Minhtam Tran、David M. Rock、Linda L. Coughenour、Jon E. Hawkinson、Peter A. Boxer、Christopher F. Bigge、Lawrence D. Wise、Eckard Weber、Richard M. Woodward、John F. W. Keana

  DOI：10.1021/jm990246i

  日期：1999.7.1

  A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC50 = 0.63 mu M). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K+ channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a similar to 25-fold increase in NR1A/2B potency (IC50 = 0.025 mu M). p-Methyl substitution on the benzyl ring (10b) produced a similar to 3-fold increase in MES activity (ED50 = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of Kf channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(methylbenzyl)piperidine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.