4-chloro-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]pyrazolo-1,3,5-triazine | 459856-19-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 4-chloro-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]pyrazolo-1,3,5-triazine
• 英文别名: 4-Chloro-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazine
• CAS: 459856-19-0
• 化学式: C₁₄H₁₄ClN₅O
• 分子量: 303.751
• InChiKey: KBXUAJUNVKYDSM-UHFFFAOYSA-N

物化性质

• 密度：
  1.41±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  65.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-(-)-仲丁胺 、 4-chloro-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]pyrazolo-1,3,5-triazine 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 以2.3 g的产率得到Pexacerfont; 8-(6-甲氧基-2-甲基-3-吡啶基)-2,7-二甲基-N-[(1R)-1-甲基丙基]吡唑并[1,5-a]-1,3,5-三嗪-4-胺
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 8-(Pyrid-3-yl)pyrazolo[1,5-a]-1,3,5-triazines: Potent, Orally Bioavailable Corticotropin Releasing Factor Receptor-1 (CRF₁) Antagonists

  摘要：

  This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF1) receptor antagonists. These CRF1 receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF1 antagonist (hCRF(1) IC50 = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.

  DOI：

  10.1021/jm900025h
• 作为产物：
  描述：

  potassium 1-cyano-1-(6-methoxy-2-methylpyridin-3-yl)prop-1-en-2-olate 在 N-甲基吗啉 、 N,N-二异丙基乙胺 、 三氟乙酸 、 三氯氧磷 作用下， 以 水 、 异丙醇 、 乙腈 为溶剂， 反应 17.0h， 生成 4-chloro-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]pyrazolo-1,3,5-triazine
  参考文献：
  名称：

  The Development of a Robust Process for a CRF₁ Receptor Antagonist

  摘要：

  A scalable and robust process was developed for the preparation of pexacerfont (2), a pyrazolotriazine corticotropin-releasing factor receptor 1 antagonist (CRF1). The formation of the core hydroxypyrazolotriazine moiety was achieved through two consecutive cyclizations of a semicarbazide, employing reaction conditions that are significantly milder than those reported in the literature. Further conversion to the key chloropyrazolotriazine intermediate was accomplished through a novel catalytic process using phosphorous oxychloride as the chlorinating agent. The active pharmaceutical ingredient 2 was obtained in > 99.5% purity with a 68% overall yield for the six synthetic steps.

  DOI：

  10.1021/op100270u

文献信息

• 4 - (2-butylamino) - 2, 7-dimethyl-8- (2-methyl-6-methoxypyrid-3-yl) pyrazolo- [1,5-A] - 1,3,5-triazine, its enantiomers and pharmaceutically acceptable salts as corticotropin releasing factor receptor ligands
  申请人：——

  公开号：US20030125330A1

  公开（公告）日：2003-07-03

  Corticotropin releasing factor (CRF) antagonists of Formula (I): 1 and its use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

  Corticotropin releasing factor (CRF)拮抗剂的化学式(I):1及其在治疗焦虑、抑郁和其他精神、神经系统疾病方面的应用，以及治疗与心理病理障碍和压力相关的免疫、心血管或心脏相关疾病和结肠过敏反应。
• Org. Process Res. Dev. 2011, 15, 343-352
  作者：

  DOI：——

  日期：——
• 4-(2-BUTYLAMINO)-2,7-DIMETHYL-8-(2-METHYL-6-METHOXYPYRID-3-YL) PYRAZOLO- 1,5-A|-1,3,5-TRIAZINE, ITS ENANTIOMERS AND PHARMACEUTICALLY ACCEPTABLE SALTS AS CORTICOTROPIN RELEASING FACTOR RECEPTOR LIGANDS
  申请人：Bristol-Myers Squibb Pharma Company

  公开号：EP1368094B1

  公开（公告）日：2007-02-28
• Synthesis and Structure−Activity Relationships of 8-(Pyrid-3-yl)pyrazolo[1,5-<i>a</i>]-1,3,5-triazines: Potent, Orally Bioavailable Corticotropin Releasing Factor Receptor-1 (CRF₁) Antagonists
  作者：Paul J. Gilligan、Todd Clarke、Liqi He、Snjezana Lelas、Yu-Wen Li、Karen Heman、Lawrence Fitzgerald、Keith Miller、Ge Zhang、Anne Marshall、Carol Krause、John F. McElroy、Kathyrn Ward、Kim Zeller、Harvey Wong、Steven Bai、Joanne Saye、Scott Grossman、Robert Zaczek、Stephen P. Arneric、Paul Hartig、David Robertson、George Trainor

  DOI：10.1021/jm900025h

  日期：2009.5.14

  This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF1) receptor antagonists. These CRF1 receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF1 antagonist (hCRF(1) IC50 = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.
• The Development of a Robust Process for a CRF₁ Receptor Antagonist
  作者：Sévrine Broxer、Monica A. Fitzgerald、Chris Sfouggatakis、Jessica L. Defreese、Evan Barlow、Gerald L. Powers、Michael Peddicord、Bao-Ning Su、Yue Tai-Yuen、Charles Pathirana、James P. Sherbine

  DOI：10.1021/op100270u

  日期：2011.3.18

  A scalable and robust process was developed for the preparation of pexacerfont (2), a pyrazolotriazine corticotropin-releasing factor receptor 1 antagonist (CRF1). The formation of the core hydroxypyrazolotriazine moiety was achieved through two consecutive cyclizations of a semicarbazide, employing reaction conditions that are significantly milder than those reported in the literature. Further conversion to the key chloropyrazolotriazine intermediate was accomplished through a novel catalytic process using phosphorous oxychloride as the chlorinating agent. The active pharmaceutical ingredient 2 was obtained in > 99.5% purity with a 68% overall yield for the six synthetic steps.