3-benzyloxy-4-iodo-5-(1-methoxycarbonyl-4-piperidyl)isoxazol | 841259-40-3

• 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: 3-benzyloxy-4-iodo-5-(1-methoxycarbonyl-4-piperidyl)isoxazol
• 英文别名: Methyl 4-(4-iodo-3-phenylmethoxy-1,2-oxazol-5-yl)piperidine-1-carboxylate
• CAS: 841259-40-3
• 化学式: C₁₇H₁₉IN₂O₄
• 分子量: 442.253
• InChiKey: BKFAAHACVMVZPS-UHFFFAOYSA-N

物化性质

• 熔点：
  99-101 °C
• 沸点：
  515.9±50.0 °C(Predicted)
• 密度：
  1.567±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  64.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-benzyloxy-4-iodo-5-(1-methoxycarbonyl-4-piperidyl)isoxazol 在 bis-triphenylphosphine-palladium(II) chloride 、 氢溴酸 、 potassium carbonate 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 46.0h， 生成 4-(2-chlorophenyl)-5-(4-piperidinyl)-3-isoxazolol hydrobromide
  参考文献：
  名称：

  4-Aryl-5-(4-Piperidyl)-3-Isoxazolol GABA_A Antagonists:  Synthesis, Pharmacology, and Structure−Activity Relationships

  摘要：

  A series of 4-aryl-5-(4-piperidyl)-3-isoxazolol GABA(A) antagonists have been synthesized and pharmacologically characterized. The meta-phenyl-substituted compounds 9k and 9m and the para-phenoxy-substituted compound 9l all display high affinities (K-i = 10-70 nM) and antagonist potencies in the low nanomolar range (K-i = 9-10 nM). These potencies are significantly higher than those of previously reported 4-PIOL antagonists and considerably higher than that of the standard GABA(A) antagonist SR 95531.

  DOI：

  10.1021/jm070038n
• 作为产物：
  描述：

  3-benzyloxy-5-(1-methoxycarbonyl-4-piperidyl)isoxazol 在 一氯化碘 、 溶剂黄146 作用下， 反应 21.0h， 以75%的产率得到3-benzyloxy-4-iodo-5-(1-methoxycarbonyl-4-piperidyl)isoxazol
  参考文献：
  名称：

  Potent 4-Aryl- or 4-Arylalkyl-Substituted 3-Isoxazolol GABA_A Antagonists:  Synthesis, Pharmacology, and Molecular Modeling

  摘要：

  We have previously described a series of competitive GABA(A) antagonists derived from the low-efficacy partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 4). The 2-naphthylmethyl analogue, 4-(2-naphthylmethyl)-5-(4-piperidyl)-3-isoxazolol (5), provided affinity for the GABA(A) receptor site higher than that of the standard GABA(A) receptor antagonist, SR 95531 (3). Molecular modeling studies of these compounds exposed a cavity at the receptor recognition site capable of accommodating aromatic groups of substantial size in the 4-position in the 3-isoxazolol ring, Here we present a series of analogues of 5, with various substituents in different positions in the naphthyl ring system (6a-k), and compounds with aromatic substituents directly attached to the 4-position of the 3-isoxazolol ring (7l-n). The compounds have been pharmacologically characterized using receptor-binding assays and electrophysiological whole-cell patch-clamp techniques. All of the tested compounds show affinity for the GABA(A) receptor site. While the 5-, 7-, and 8-bromo analogues, 6b-d, showed receptor affinities (K-i = 45, 109, and 80 nM, respectively) comparable with that of 5 (Ki 49 nM), the 1-bromo analogue, 6a, provided the highest receptor affinity of the series (Ki 10 nM). Introduction of a series of different substituents in the 1-position in the 2-naphthyl ring system led to compounds. 6,e-k. with retained high affinity for the GABA(A) receptor (K-i = 16-250 nM). Introduction of a phenyl ring directly into the 4-position on the 3-isoxazolol ring gave a 41-fold increase in affinity relative to that of 4-PIOL. In whole-cell patch-clamp recordings from cultured cerebral cortical neurons. all of the tested compounds were able to inhibit the effect of the Specific GABA(A) agonist, isoguvacine, 6a showing antagonist potency (IC50 = 42 nM) markedly higher than that, of 3 (IC50 = 240 nM). Molecular modeling studies, based on the compounds described, emphasized the importance of the distal ring in 5 for receptor affinity and the considerable dimensions of the proposed receptor cavity. Furthermore, the phenyl rings in 71 and in 6k were shown to represent highly favorable positions for an aromatic ring in previously unexplored receptor regions in terms of a pharmacophore model.

  DOI：

  10.1021/jm049256w