8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,7-naphthyridine | 1133853-58-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,7-naphthyridine
• 英文别名: 8-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-1,7-naphthyridine
• CAS: 1133853-58-3
• 化学式: C₁₅H₁₃F₃N₂
• 分子量: 278.277
• InChiKey: NVYNTNWZKUHRQY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  24.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,7-naphthyridine 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 (R)-N-(4-fluorophenyl)-8-(4-(trifluoromethyl)phenyl)-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxamide
  参考文献：
  名称：

  Optimization of Potency and Pharmacokinetic Properties of Tetrahydroisoquinoline Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists

  摘要：

  Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values < 3 mg/kg.

  DOI：

  10.1021/jm401955h
• 作为产物：
  描述：

  2-溴-3-吡啶甲醛 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 甲酸 、 sodium azide 、 偶氮二异丁腈 、 三(三甲基硅基)硅烷 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 53.5h， 生成 8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,7-naphthyridine
  参考文献：
  名称：

  通过自由基Pictet-Spengler反应由醛和HARP试剂合成四氢萘啶

  摘要：

  醛与新设计的HARP（卤素胺自由基方案）试剂的组合可使用α-取代的四氢萘啶。通过使用不同的HARP试剂，可以在一次操作中制备各种区域异构结构。这些产品在药物化学中具有很高的价值，它们是通过可预测的方式通过贫电子吡啶的正式Pictet-Spengler反应形成的，而该不良电子吡啶不会参与相应的极性反应。

  DOI：

  10.1021/acs.orglett.6b00523

文献信息

• Vanilloid receptor ligands and their use in treatments
  申请人：Nishimura Nobuko

  公开号：US20090082358A1

  公开（公告）日：2009-03-26

  Bicyclic 3,4-fused piperidine compounds, and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotizing agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

  双环3,4-融合哌啶化合物及含有它们的组合物，用于治疗急性、炎症性和神经性疼痛、牙痛、普通头痛、偏头痛、集群头痛、混合血管和非血管综合征、紧张性头痛、一般炎症、关节炎、风湿性疾病、骨关节炎、炎症性肠道疾病、炎症性眼部疾病、炎症性或不稳定膀胱疾病、牛皮癣、伴有炎症成分的皮肤疾病、慢性炎症症状、炎症性疼痛及相关的过敏性疼痛和触痛、神经性疼痛及相关的过敏性疼痛和触痛、糖尿病性神经病痛、烧灼性疼痛、交感神经维持性疼痛、感觉缺失综合征、哮喘、上皮组织损伤或功能障碍、单纯疱疹、呼吸、泌尿、消化或血管区域内脏运动障碍、伤口、烧伤、过敏性皮肤反应、瘙痒、白癜风、一般胃肠道疾病、胃溃疡、十二指肠溃疡、腹泻、坏死性剂引起的胃病变、毛发生长、血管运动性或过敏性鼻炎、支气管疾病或膀胱疾病。
• [EN] CONDENSED PIPERIDINE DERIVATIVES USEFUL AS VANILLOID RECEPTOR LIGANDS<br/>[FR] DÉRIVÉS DE PIPÉRIDINE CONDENSÉE, UTILES EN TANT QUE LIGANDS DES RÉCEPTEURS VANILLOÏDES
  申请人：AMGEN INC

  公开号：WO2009038812A1

  公开（公告）日：2009-03-26

  Bicyclic 3,4-fused piperidiπe compounds having the structure of formula (I) and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, differentiation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
• Optimization of Potency and Pharmacokinetic Properties of Tetrahydroisoquinoline Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists
  作者：Daniel B. Horne、Nuria A. Tamayo、Michael D. Bartberger、Yunxin Bo、Jeffrey Clarine、Carl D. Davis、Vijay K. Gore、Matthew R. Kaller、Sonya G. Lehto、Vu V. Ma、Nobuko Nishimura、Thomas T. Nguyen、Phi Tang、Weiya Wang、Beth D. Youngblood、Maosheng Zhang、Narender R. Gavva、Holger Monenschein、Mark H. Norman

  DOI：10.1021/jm401955h

  日期：2014.4.10

  Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values < 3 mg/kg.
• Synthesis of Tetrahydronaphthyridines from Aldehydes and HARP Reagents via Radical Pictet–Spengler Reactions
  作者：Moritz K. Jackl、Imants Kreituss、Jeffrey W. Bode

  DOI：10.1021/acs.orglett.6b00523

  日期：2016.4.15

  with newly designed HARP (halogen amine radical protocol) reagents gives access to α-substituted tetrahydronaphthyridines. By using different HARP reagents, various regioisomeric structures can be prepared in a single operation. These products, which are of high value in medicinal chemistry, are formed in a predictable manner via a formal Pictet–Spengler reaction of electron-poor pyridines that would

  醛与新设计的HARP（卤素胺自由基方案）试剂的组合可使用α-取代的四氢萘啶。通过使用不同的HARP试剂，可以在一次操作中制备各种区域异构结构。这些产品在药物化学中具有很高的价值，它们是通过可预测的方式通过贫电子吡啶的正式Pictet-Spengler反应形成的，而该不良电子吡啶不会参与相应的极性反应。