2'-chloro-N-[6-[(dimethylamino)methyl]-5,6,7,8-tetrahydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2'-chloro-N-[6-[(dimethylamino)methyl]-5,6,7,8-tetrahydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide
• 英文别名: (2'-chlorobiphenyl-4-yl)-N-[2-(N,N-dimethylamino)methyl-6-tetralinyl]carboxamide；4-(2-chlorophenyl)-N-[6-[(dimethylamino)methyl]-5,6,7,8-tetrahydronaphthalen-2-yl]benzamide
• 化学式: C₂₆H₂₇ClN₂O
• 分子量: 418.966
• InChiKey: KTDMCLCTLWFDGI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  32.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  [(6-氨基-1,2,3,4-四氢-2-萘)甲基]二甲基胺 在 四(三苯基膦)钯 、 sodium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 乙二醇二甲醚 为溶剂， 反应 21.0h， 生成 2'-chloro-N-[6-[(dimethylamino)methyl]-5,6,7,8-tetrahydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide
  参考文献：
  名称：

  Discovery, synthesis, and structure–activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists

  摘要：

  Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4'-fluoro-N[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.07.038

文献信息

• Melanin concentrating hormone antagonist
  申请人：Kato Kaneyoshi

  公开号：US20070173498A1

  公开（公告）日：2007-07-26

  A melanin-concentrating hormone antagonist which comprises a compound of the formula: wherein Ar 1 is a cyclic group which may have substituents; X is a spacer having a main chain of 1 to 6 atoms; Y is a bond or a spacer having a main chain of 1 to 6 atoms; Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8 membered non-aromatic ring, and may have further substituents; R 1 and R 2 are independently hydrogen atom or a hydrocarbon group which may have substituents; R 1 and R 2 , together with the adjacent nitrogen atom, may form a nitrogen-containing hetero ring which may have substituents; R 2 may form a spiro ring together with Ar; or R 2 , together with the adjacent nitrogen atom and Y, may form a nitrogen-containing hetero ring which may have substituents; or a salt thereof; which is useful as an agent for preventing or treating obesity, etc.

  一种黑色素浓集激素拮抗剂，包括一个化合物，其化学式为：其中Ar1是一个环状基团，可能具有取代基；X是一个具有1到6个原子主链的间隔物；Y是一条键或具有1到6个原子主链的间隔物；Ar是一个单环芳香环，可以与一个4到8个成员的非芳香环融合，并且可能有进一步的取代基；R1和R2分别是氢原子或一个可能具有取代基的碳氢基团；R1和R2连同相邻的氮原子可以形成一个含氮杂环，该杂环可能具有取代基；R2可以与Ar一起形成一个螺环；或者R2连同相邻的氮原子和Y可以形成一个含氮杂环，该杂环可能具有取代基；或其盐；用作预防或治疗肥胖等的药剂。
• Discovery, synthesis, and structure–activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists
  作者：Makoto Kamata、Toshiro Yamashita、Toshihiro Imaeda、Toshio Tanaka、Jun Terauchi、Maki Miyamoto、Taiichi Ora、Michiko Tawada、Satoshi Endo、Shiro Takekawa、Asano Asami、Nobuhiro Suzuki、Yasutaka Nagisa、Yoshihide Nakano、Kaoru Watanabe、Hitomi Ogino、Koki Kato、Kaneyoshi Kato、Yuji Ishihara

  DOI：10.1016/j.bmc.2011.07.038

  日期：2011.9

  Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4'-fluoro-N[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity. (C) 2011 Elsevier Ltd. All rights reserved.