2-((2S)-2-(3,4-dichlorophenyl)-4-{4-[(S)-2-(methylsulfinyl)phenyl]piperidin-1-yl}butyl)-1-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b][1,5]oxazocine-7-carbonitrile

• 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: 2-((2S)-2-(3,4-dichlorophenyl)-4-{4-[(S)-2-(methylsulfinyl)phenyl]piperidin-1-yl}butyl)-1-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b][1,5]oxazocine-7-carbonitrile
• 英文别名: 15-[(2S)-2-(3,4-dichlorophenyl)-4-[4-[2-[(S)-methylsulfinyl]phenyl]piperidin-1-yl]butyl]-16-oxo-11-oxa-15-azatricyclo[8.6.0.02,7]hexadeca-1(10),2,4,6,8-pentaene-9-carbonitrile
• 化学式: C₃₇H₃₇Cl₂N₃O₃S
• 分子量: 674.691
• InChiKey: BOVJIWMAZLOIGK-XMGMBJFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  46
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  92.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-Methoxy-3-cyano-1-naphthoyl Chloride 在 4-二甲氨基吡啶 、 sodium hydroxide 、 草酰氯 、 氢氟酸 、 碘 、 sodium hydride 、 sodium cyanoborohydride 、 potassium carbonate 、 magnesium 、 溶剂黄146 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 、 苯 为溶剂， 反应 8.84h， 生成 2-((2S)-2-(3,4-dichlorophenyl)-4-{4-[(S)-2-(methylsulfinyl)phenyl]piperidin-1-yl}butyl)-1-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b][1,5]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

文献信息

• New neurokinin antagonists for use as medicaments
  申请人：Albert Scott Jeffrey

  公开号：US20070021406A1

  公开（公告）日：2007-01-25

  The present application relates to internally cyclized naphthamide compounds of the formula Ia (wherein R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X 1 , X 2 , Y, Z, and n are as defined herein), which are useful, for example, for antagonizing the pharmacological actions of the neurokinin 1 (NK 1 ) receptor. In particular, these compounds are useful in the treatment of diseases in which Substance P is involved such as, for example, major depressive disorder, severe anxiety disorders, stress disorders, major depressive disorder with anxiety, eating disorders, bipolar disorder, substance use disorder, schizophrenic disorders, psychotic disorders, movement disorders, cognitive disorders, depression and/or anxiety, mania or hypomania, aggressive behaviour, obesity, rheumatoid arthritis, Alzheimer's disease, cancer, oedema, allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility, Huntington's disease, chronic obstructive pulmonary disorder (COPD), hypertension, migraine, bladder hypermotility, and urticaria.

  本申请涉及公式Ia的内环化萘酰胺化合物（其中R1a，R1b，R1c，R2，R3，R4，R5，R6，R7，R8，X1，X2，Y，Z和n的定义如本文所述），这些化合物可用于拮抗神经激肽1（NK1）受体的药理作用。特别地，这些化合物可用于治疗与物质P有关的疾病，例如重度抑郁障碍、严重焦虑障碍、应激障碍、伴有焦虑的重度抑郁障碍、进食障碍、躁狂障碍、物质使用障碍、精神分裂障碍、精神病性障碍、运动障碍、认知障碍、抑郁和/或焦虑、狂躁或亢进行为、肥胖症、类风湿性关节炎、阿尔茨海默病、癌症、水肿、过敏性鼻炎、炎症、疼痛、胃肠道高动力性、亨廷顿病、慢性阻塞性肺疾病（COPD）、高血压、偏头痛、膀胱高动力性和荨麻疹。
• Novel Method
  申请人：Ferrari Giulio

  公开号：US20140128395A1

  公开（公告）日：2014-05-08

  There is provided inter alia a compound which is an NK-1 receptor antagonist for use in the treatment or prevention of CNV. There is also provided a compound which is an NK-1 antagonist for use in the treatment of chemical burns of the eye particularly alkali burns of the eye. There is also provided a pharmaceutical composition for topical administration to the eye comprising an NK-1 antagonist and an antibiotic agent.
• TREATMENT OF CORNEAL NEOVASCULARIZATION
  申请人：IRBM SCIENCE PARK S.p.A.

  公开号：US20180021327A1

  公开（公告）日：2018-01-25

  There is provided inter alia a compound which is an NK-1 receptor antagonist for use in the treatment or prevention of CNV. There is also provided a compound which is an NK-1 antagonist for use in the treatment of chemical burns of the eye particularly alkali burns of the eye. There is also provided a pharmaceutical composition for topical administration to the eye comprising an NK-1 antagonist and an antibiotic agent.
• NK-1 ANTAGONISTS FOR USE IN THE TREATMENT OF OCULAR PAIN
  申请人：OSPEDALE SAN RAFFAELE S.R.L.

  公开号：US20210015834A1

  公开（公告）日：2021-01-21

  The invention relates to compounds, in particular NK-1 antagonists, for use in the treatment of ocular sensitivity and/or ocular pain.
• US7235541B2
  申请人：——

  公开号：US7235541B2

  公开（公告）日：2007-06-26