(2-(4-acetylpiperazin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one) | 569683-18-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (2-(4-acetylpiperazin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one)
• 英文别名: 2-(4-acetylpiperidin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one；KRP-103；9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine；Unii-S8332LV592；2-(4-acetylpiperazin-1-yl)-6-[[3,5-bis(trifluoromethyl)phenyl]methyl]-4-(2-methylphenyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,5]oxazocin-5-one
• CAS: 569683-18-7
• 化学式: C₃₀H₂₉F₆N₅O₃
• 分子量: 621.582
• InChiKey: NCPKXVSLLSEPDP-UHFFFAOYSA-N

物化性质

• 熔点：
  162-164 °C
• 沸点：
  723.1±70.0 °C(Predicted)
• 密度：
  1.356±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  44
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  78.9
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  4,6-二氯-2-(甲巯基)嘧啶-5-甲酸 在 四(三苯基膦)钯 氯化亚砜 、 sodium carbonate 、 potassium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 6.0h， 生成 (2-(4-acetylpiperazin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one)
  参考文献：
  名称：

  设计，合成和评估新型2-取代-4-芳基-6,7,8,9-四氢-5H-嘧啶[4,5-b] [1,5]恶唑啉-5-酮类药物作为NK1拮抗剂。

  摘要：

  制备了一系列新颖的双环嘧啶衍生物，作为寻找旨在治疗尿失禁的NK1拮抗剂的一部分。其中3g，带有4-乙酰基哌嗪基和2-甲基苯基的嘧啶并[4,5-b] [1,5]恶唑啉衍生物，显示出有效的NK1拮抗剂活性，其K（B）值​​为为0.105 nM，显着增加了豚鼠的有效膀胱容量（0.3 mg / kg iv时为59.4％，id 3 mg / kg时为62.8％）。此外，使用尿烷麻醉的豚鼠模型，通过扩张诱导的节律性膀胱收缩试验确定了3g对膀胱功能的影响似乎与另一种经典的抗尿蛋白尿症托特罗定不同。化合物3g有望成为治疗尿失禁的有前途的药物。

  DOI：

  10.1016/j.bmc.2005.06.015

文献信息

• Process Development and Large-Scale Synthesis of NK1 Antagonist
  作者：Ichiro Araya、Shintaro Kanazawa、Hiroyuki Akita

  DOI：10.1248/cpb.56.176

  日期：——

  A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a neurokinin (NK)1 antagonist. The key step in the synthesis is the intramolecular cyclization of N-[3,5-bis(trifluoromethyl)phenylmethyl]-N-(3-hydroxypropyl)-4-chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxamide (15) which was obtained by amide formation between 4-(2-methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (8) and 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3). Treatment of 15 with 1,8-diazabicyclo[5,4,0]undec-7-ene provided 6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (6). This intermediate (6) is transformed into the candidate compound (1) by two steps; oxidation, and substitution reaction of the resultant sulfone (7) with 1-acetylpiperazine. This synthetic method is free of chromatographic purification and is amenable to large scale synthesis.

  本文描述了一种可规模化合成的路线，以获得 2-(4-乙酰基哌啶-1-基)-6-[3,5-双(三氟甲基)苯基甲基]-4-(2-甲基苯基)-6,7,8,9-四氢-5H-嘧啶并[4,5-b][1,5]恶唑啉-5-酮（1，KRP-103），作为神经激肽（NK）1 拮抗剂。合成的关键步骤是 N-[3,5-双（三氟甲基）苯基甲基]-N-（3-羟基丙基）-4-氯-6-（2-甲基苯基）-2-甲硫基嘧啶-5-甲酰胺（15）的分子内环化、4-(2-甲基苯基)-2-甲硫基-6-氧代-1, 6-二氢嘧啶-5-甲酸 (8) 与 3-[3,5-双(三氟甲基)苯基甲基氨基]-1-丙醇 (3) 形成酰胺。用 1,8-二氮杂双环[5,4,0]十一-7-烯处理 15，可得到 6-[3,5-双（三氟甲基）苯基甲基]-4-（2-甲基苯基）-2-甲硫基-6,7,8,9-四氢-5H-嘧啶并[4,5-b][1,5]恶唑啉-5-酮（6）。该中间体（6）通过两个步骤转化为候选化合物（1）：氧化，以及生成的砜类化合物（7）与 1-乙酰基哌嗪发生取代反应。这种合成方法无需色谱纯化，适合大规模合成。
• Analysis of crucial structural requirements of 2-substituted pyrimido[4,5-b][1,5]oxazocines as NK1 receptor antagonist by axially chiral derivatives
  作者：Shigeki Seto、Jun Asano

  DOI：10.1016/j.bmc.2007.05.040

  日期：2007.8

  2-substituted 8-methylpyrimido[4,5-b][1,5]oxazocine derivatives. Axially chiral 8-methylpyrimido[4,5-b][1,5]oxazocines bearing a substituent at the C-2 position were synthesized and evaluated as NK(1) antagonists. The results revealed that (aR, 8S)-stereochemistry and the substituent at the C-2 position are important for NK(1) receptor recognition.

  这项研究旨在确定2-取代的8-甲基嘧啶[4,5-b] [1,5]恶唑啉衍生物的关键结构特征。合成了在C-2位置带有取代基的轴向手性8-甲基嘧啶基[4,5-b] [1,5]恶唑啉，并将其评估为NK（1）拮抗剂。结果表明，（aR，8S）立体化学和C-2位置的取代基对于NK（1）受体识别很重要。
• 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.