(4-{[(4-Chloro-pyridine-2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-(3,4-dichloro-phenyl)-methanone | 208110-41-2

• 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: (4-{[(4-Chloro-pyridine-2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-(3,4-dichloro-phenyl)-methanone
• 英文别名: (4-{[(4-Chloropyridin-2-ylmethyl)amino]methyl}-piperidin-1-yl)-(3,4-dichlorophenyl)methanone；[4-[[(4-Chloropyridin-2-yl)methylamino]methyl]piperidin-1-yl]-(3,4-dichlorophenyl)methanone
• CAS: 208110-41-2
• 化学式: C₁₉H₂₀Cl₃N₃O
• 分子量: 412.746
• InChiKey: ZUIIRJOZQKJSMP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  45.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  二甲胺 、 (4-{[(4-Chloro-pyridine-2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-(3,4-dichloro-phenyl)-methanone 以 四氢呋喃 为溶剂， 反应 17.0h， 以53%的产率得到(3,4-Dichloro-phenyl)-(4-{[(4-dimethylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone
  参考文献：
  名称：

  Design and Synthesis of a Series of 6-Substituted-2-pyridinylmethylamine Derivatives as Novel, High-Affinity, Selective Agonists at 5-HT_1A Receptors

  摘要：

  A search for novel, selective agonists with high intrinsic activity at the 5-HT1A subtype of serotonin (5-HT) receptors was undertaken. Mechanistic and thermodynamic considerations led to the design of 6-substituted-2-pyridinylmethylamine as a potential 5-HT1A pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT1A, alpha(1)-adrenergic, and D-2-dopaminergic receptors. Compounds with high affinity for 5-HT1A receptors (pK(i) greater than or equal to 8) were examined for agonist properties by measuring their ability to inhibit forskolin-stimulated cAMP production in HA7 cells (i.e., HeLa cells permanently transfected with the h5-HT1A receptor gene and expressing the h5-HT1A receptor protein). Several compounds of the type aryl{4-[(6-substituted-pyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone had nanomolar affinity for 5-HT1A binding sites and were more than 500-fold selective with respect to alpha(1) and D-2 sites. Importantly, their 5-HT1A agonist properties were demonstrated in HA7 cells where they behaved as potent inhibitors of cAMP accumulation. In particular, (3,4-dichlorophenyl){4-[(6-oxazol-5-ylpyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone (70) and (3,4-dichlorophenyl){4-[(6-azetidinopyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone (36) appeared to be more potent than, and at least as efficacious as, the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. SAR studies revealed that the pyridine nitrogen atom and the nature and the position of the substituents on the pyridine ring were critically involved in the ability of the compounds to recognize and activate 5-HT1A receptors. Structural modifications of the nonpharmacophoric part of the molecule showed, however, that the entire structure was required for affinity at 5-HT1A binding sites.

  DOI：

  10.1021/jm9804329
• 作为产物：
  描述：

  4-氯-2-吡啶甲醛 在 钾硼氢 、 TEA 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 为溶剂， 反应 8.0h， 生成 (4-{[(4-Chloro-pyridine-2-ylmethyl)-amino]-methyl}-piperidine-1-yl)-(3,4-dichloro-phenyl)-methanone
  参考文献：
  名称：

  Design and Synthesis of a Series of 6-Substituted-2-pyridinylmethylamine Derivatives as Novel, High-Affinity, Selective Agonists at 5-HT_1A Receptors

  摘要：

  A search for novel, selective agonists with high intrinsic activity at the 5-HT1A subtype of serotonin (5-HT) receptors was undertaken. Mechanistic and thermodynamic considerations led to the design of 6-substituted-2-pyridinylmethylamine as a potential 5-HT1A pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT1A, alpha(1)-adrenergic, and D-2-dopaminergic receptors. Compounds with high affinity for 5-HT1A receptors (pK(i) greater than or equal to 8) were examined for agonist properties by measuring their ability to inhibit forskolin-stimulated cAMP production in HA7 cells (i.e., HeLa cells permanently transfected with the h5-HT1A receptor gene and expressing the h5-HT1A receptor protein). Several compounds of the type aryl{4-[(6-substituted-pyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone had nanomolar affinity for 5-HT1A binding sites and were more than 500-fold selective with respect to alpha(1) and D-2 sites. Importantly, their 5-HT1A agonist properties were demonstrated in HA7 cells where they behaved as potent inhibitors of cAMP accumulation. In particular, (3,4-dichlorophenyl){4-[(6-oxazol-5-ylpyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone (70) and (3,4-dichlorophenyl){4-[(6-azetidinopyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone (36) appeared to be more potent than, and at least as efficacious as, the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. SAR studies revealed that the pyridine nitrogen atom and the nature and the position of the substituents on the pyridine ring were critically involved in the ability of the compounds to recognize and activate 5-HT1A receptors. Structural modifications of the nonpharmacophoric part of the molecule showed, however, that the entire structure was required for affinity at 5-HT1A binding sites.

  DOI：

  10.1021/jm9804329

文献信息

• DERIVES DE LA PYRIDIN-2-YL-METHYLAMINE, LEUR PROCEDE DE PREPARATION ET LEUR APPLICATION COMME MEDICAMENTS
  申请人：PIERRE FABRE MEDICAMENT

  公开号：EP0946546B1

  公开（公告）日：2003-06-25
• UTILISATION DE DERIVES DE PYRIDIN-2-YL-METHYLAMINE POUR LE TRAITEMENT DES SYMPTOMES DE LA DOULEUR CHRONIQUE D'ORIGINE NEUROPATHIQUE OU PSYCHOGENE
  申请人：PIERRE FABRE MEDICAMENT

  公开号：EP1603564A2

  公开（公告）日：2005-12-14
• Use of pyridin-2-ylmethylamine derivatives for the production of a medicament for the treatment of chronic pain symptoms of neuropathological or psychogenic origin
  申请人：Colpaert Francis

  公开号：US20060241141A1

  公开（公告）日：2006-10-26

  This invention relates to a treatment of chronic pain symptoms, especially of neuropathological or psychogenic origin, with pyridin-2-yl methylamine derivatives or pharmaceutically acceptable additive salts thereof.
• US6020345A
  申请人：——

  公开号：US6020345A

  公开（公告）日：2000-02-01
• US8609694B2
  申请人：——

  公开号：US8609694B2

  公开（公告）日：2013-12-17