2-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocine-7-carbonitrile | 367260-32-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocine-7-carbonitrile
• 英文别名: 15-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-16-oxo-12-oxa-15-azatricyclo[8.6.0.02,7]hexadeca-1(10),2,4,6,8-pentaene-9-carbonitrile
• CAS: 367260-32-0
• 化学式: C₂₅H₂₀Cl₂N₂O₃
• 分子量: 467.351
• InChiKey: AWQKXSJDTLVFPJ-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  70.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocine-7-carbonitrile 在 sodium cyanoborohydride 、 溶剂黄146 、 三乙胺 作用下， 以 甲醇 为溶剂， 反应 2.5h， 生成 2-[(2S)-2-(3,4-dichlorophenyl)-4-(dimethylamino)-butyl]-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]-oxazocine-7-carbonitrile
  参考文献：
  名称：

  Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

  摘要：

  We have previously described a series of antagonists that showed high potency and selectivity for the NK1 receptor. However, these compounds also had the undesirable property of existing as a mixture of four interconverting rotational isomers. Through biological and structural analysis of the atropisomers, a binding model was developed and used to guide the design of compounds, which were rigidified by installation of a cyclizing linkage. These compounds existed as a mixture of two atropisomers. Further elaboration of the ring system reinforced the desired conformation and eliminated atropisomeric properties. We found that the region distal to the 8-membered ring system could be modified while retaining NK1 potency, and optimization led to further improvements in the in vivo activity. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2004.03.054
• 作为产物：
  描述：

  (S)-2-(3',4'-dichlorophenyl)pent-4-enoic acid 在 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 吡啶盐酸盐 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 sodium hydride 、 sodium carbonate 、 臭氧 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 6.83h， 生成 2-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocine-7-carbonitrile
  参考文献：
  名称：

  Naphtho[2,1-b][1,5] and [1,2-f][1,4]oxazocines as selective NK1 antagonists

  摘要：

  Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-naphthamide NK1 antagonists that includes 3 and 4. Here we report our efforts to alleviate a troublesome atropisomeric property of those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a purported NK1 pharmacophore conformation. Using 3 as a starting point, the naphtho[2, 1-b][1,5]oxazocine, 17, was found to contain the optimal ring tether size (8) for retaining NK1 activity, was more NK1 versus NK2 selective, and reduced the number of atropisomers from four to two. Cyclic derivatives 29 and 32, which exist as essentially single atropisomers in the purported pharmacophore conformation. were prepared in the closely related naphtho[1,2-f][1,4]oxazocine series as part of an effort to use mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as NK1 antogonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss the above findings in the context of a previously proposed NK1 pharmacophore model and present a further refinement of that model. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.03.015