1-哌啶丁酸,4-(二苯基甲氧基)- | 133993-23-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 1-哌啶丁酸,4-(二苯基甲氧基)-
• 英文名称: 1-Piperidinebutanoic acid, 4-(diphenylmethoxy)-
• 英文别名: 4-(4-benzhydryloxypiperidin-1-yl)butanoic acid
• CAS: 133993-23-4
• 化学式: C₂₂H₂₇NO₃
• 分子量: 353.461
• InChiKey: RQYHUNZRHKSYQA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  ethyl 4-(diphenylmethoxy)-1-piperidinecarboxylate 在 sodium hydroxide 、 potassium carbonate 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 生成 1-哌啶丁酸,4-(二苯基甲氧基)-
  参考文献：
  名称：

  Amphoteric Drugs. I. Synthesis and Antiallergic Activity of (4-(Diphenylmethoxy)piperidino)-, (4-(Diphenylmethyl)piperazinyl)- and (4-(Diphenylmethylene)piperidino)alkanoic Acid Derivatives.

  摘要：

  描述了一种将经典抗组胺药物转化为具有强效的非镇静抗过敏剂的简单方法，该方法在大鼠模型中进行了测试。合成并检查了多种[4-(二苯基甲氧基)哌啶]（A系列）、[4-(二苯基甲基)哌嗪]（B系列）和[4-(二苯基亚甲基)哌啶]酸衍生物（C系列）的抗过敏活性及对中枢神经系统（CNS）的影响，与相应的N-甲基衍生物（1a-c）进行了比较。N-烷基羧酸（5a-c）对化合物48/80诱导的大鼠致死作用显示出比相应的N-甲基衍生物（1a-c）更强的抑制效果。特别是A系列中的N-烷基羧酸（5a）表现出大约100倍于1a的更强抑制效果，并且在所有系列中，对于延长戊巴比妥诱导的麻醉睡眠时间的效果最差。通过对A系列进行化学修饰发现，在（二苯基甲氧基）哌啶体系中，在一个苯环的对位引入甲基可以有效降低CNS副作用，而不减少抗过敏活性。(+) -3-[4-[(4-甲基苯基)苯基甲氧基]哌啶]丙酸((+) -5l)，是5l的光学活性异构体，在48小时同源被动皮肤过敏反应（PCA）测试中展现出比酮替芬和特非那定更强的抗过敏效果（ED50 = 0.17 mg/kg，口服），而且在30 mg/kg的口服剂量下没有表现出延长戊巴比妥诱导的麻醉睡眠时间等CNS副作用。因此，化合物(+) -5l被证明是一个有前景的非镇静抗过敏剂候选药物。

  DOI：

  10.1248/cpb.42.2276

文献信息

• GABA uptake inhibitors. Syntheses and structure—activity studies on GABA analogues containing diarylbutenyl and diarylmethoxyalkyl N-substituents
  作者：E Falch、P Korgsgaard-Larsen

  DOI：10.1016/0223-5234(91)90214-8

  日期：1991.1

  A number of analogues of GABA or B-alanine containing 4,4-diphenyl-3-butenyl (DPB), benzhydryl ethyl ether (BEE), or benzhydryl propyl ether N-substituents have been synthesized and tested as inhibitors of synaptosomal GABA uptake. N-methylation of these analogues resulted in increased potency and reduced pKa II values of the reaction products 4a and 8a, respectively. Incorporation of the alkyl groups of the benzhydryl alkyl ether moieties of N-methyl-N-BEE-B-alanine (12), N-methyl-N-BEE-GABA (8a), or the benzhydryl propyl ether analogue of N-methyl-GABA (10) into the cyclized piperidine analogues gave the less active compounds 17, 18, and 19, respectively. This loss of in vitro activity was most pronounced for the GABA analogues 18 and 19. These results suggest that the basic character of the amino groups as well as the conformational flexibility of the spacer-arm connecting the amino acid 'heads' and the aromatic moieties of this class of GABA uptake inhibitors are factors of importance for GABA uptake affinity.
• FALCH, E.;KROGSGAARD-LARSEN, P., EUR. J. MED. CHEM., 26,(1991) N, C. 69-78
  作者：FALCH, E.、KROGSGAARD-LARSEN, P.

  DOI：——

  日期：——
• US7189757B2
  申请人：——

  公开号：US7189757B2

  公开（公告）日：2007-03-13
• US7317026B2
  申请人：——

  公开号：US7317026B2

  公开（公告）日：2008-01-08
• Amphoteric Drugs. I. Synthesis and Antiallergic Activity of (4-(Diphenylmethoxy)piperidino)-, (4-(Diphenylmethyl)piperazinyl)- and (4-(Diphenylmethylene)piperidino)alkanoic Acid Derivatives.
  作者：Nobuhiko IWASAKI、Jun SAKAGUCHI、Tetsuo OHASHI、Eiji TAKAHARA、Nobuo OGAWA、Shingo YASUDA、Eiichi KOSHINAKA、Hideo KATO、Yasuo ITO、Hiroyuki SAWANISHI

  DOI：10.1248/cpb.42.2276

  日期：——

  A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidino]- (series A), [4-(diphenylmethyl)piperazinyl]- (series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a-c). N-Alkylcarboxylic acids (5a-c) showed stronger ingibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a-c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activityl. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy]piperidino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic effect (ED50=0.17mg/kg, p.o.) than ketotifen and terfenadine in the 48h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30mg/kg. Compound (+)-5l was thus proved to be a promising candidate as a nonsedative antiallergic agent.

  描述了一种将经典抗组胺药物转化为具有强效的非镇静抗过敏剂的简单方法，该方法在大鼠模型中进行了测试。合成并检查了多种[4-(二苯基甲氧基)哌啶]（A系列）、[4-(二苯基甲基)哌嗪]（B系列）和[4-(二苯基亚甲基)哌啶]酸衍生物（C系列）的抗过敏活性及对中枢神经系统（CNS）的影响，与相应的N-甲基衍生物（1a-c）进行了比较。N-烷基羧酸（5a-c）对化合物48/80诱导的大鼠致死作用显示出比相应的N-甲基衍生物（1a-c）更强的抑制效果。特别是A系列中的N-烷基羧酸（5a）表现出大约100倍于1a的更强抑制效果，并且在所有系列中，对于延长戊巴比妥诱导的麻醉睡眠时间的效果最差。通过对A系列进行化学修饰发现，在（二苯基甲氧基）哌啶体系中，在一个苯环的对位引入甲基可以有效降低CNS副作用，而不减少抗过敏活性。(+) -3-[4-[(4-甲基苯基)苯基甲氧基]哌啶]丙酸((+) -5l)，是5l的光学活性异构体，在48小时同源被动皮肤过敏反应（PCA）测试中展现出比酮替芬和特非那定更强的抗过敏效果（ED50 = 0.17 mg/kg，口服），而且在30 mg/kg的口服剂量下没有表现出延长戊巴比妥诱导的麻醉睡眠时间等CNS副作用。因此，化合物(+) -5l被证明是一个有前景的非镇静抗过敏剂候选药物。