5-chloro-1-[(1S)-1-cyclopropyl-2-methoxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethyl-3-pyridinyl]amino]-2(1H)-pyrazinone | 1188407-40-0

• 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: 5-chloro-1-[(1S)-1-cyclopropyl-2-methoxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethyl-3-pyridinyl]amino]-2(1H)-pyrazinone
• 英文别名: (S)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one；(S)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]pyrazin-2(1H)-one；BMS-763534；(S)-5-chloro-1-(cyclopropyl-2-methoxyethyl)-3-[6-(difluoromethoxy)-2,5-dimethyl-pyridin-3-ylamino]pyrazin-2(1H)-one；5-chloro-1-[(1S)-1-cyclopropyl-2-methoxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethylpyridin-3-yl]amino]pyrazin-2-one
• CAS: 1188407-40-0
• 化学式: C₁₈H₂₁ClF₂N₄O₃
• 分子量: 414.84
• InChiKey: CBVDPVDNACOCTI-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  76
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-chloro-1-[(1S)-1-cyclopropyl-2-methoxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethyl-3-pyridinyl]amino]-2(1H)-pyrazinone 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以84%的产率得到5-chloro-1-[(1S)-1-cyclopropyl-2-hydroxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethylpyridin-3-yl]amino]pyrazin-2-one
  参考文献：
  名称：

  氨基甲酸酯和芳基醚取代的吡嗪酮作为促肾上腺皮质激素释放因子-1（CRF 1）受体拮抗剂的合成与评价

  摘要：

  合成了一系列结合氨基甲酸酯基或芳基醚基的基于吡嗪酮的化合物，并将其评估为促肾上腺皮质激素释放因子-1（CRF 1）受体拮抗剂。结构-活性关系研究导致鉴定出高效的CRF 1受体拮抗剂14a（IC 50  = 0.74 nM）和14b（IC 50  = 1.9 nM）。将描述该系列化合物的合成，构效关系以及体外代谢稳定性。

  DOI：

  10.1016/j.bmcl.2016.03.067
• 作为产物：
  描述：

  (2S,1s)-2-环丙基-2-(1-苯基乙基氨基)乙酸 在 四氢呋喃 、 sodium tetrahydroborate 、 5% Pd(II)/C(eggshell) 、 氢气 、 碘 、 sodium hexamethyldisilazane 、 potassium carbonate 、 potassium iodide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， -10.0~50.0 ℃ 、310.27 kPa 条件下， 反应 12.0h， 生成 5-chloro-1-[(1S)-1-cyclopropyl-2-methoxyethyl]-3-[[6-(difluoromethoxy)-2,5-dimethyl-3-pyridinyl]amino]-2(1H)-pyrazinone
  参考文献：
  名称：

  Development of an Efficient Synthesis of Two CRF Antagonists for the Treatment of Neurological Disorders

  摘要：

  BMS-764459 (1) and BMS-763534 (2) are CRF1 antagonists for the treatment of neurological disorders such as depression and anxiety. An efficient synthesis of 1 and 2 is described, which features an efficient palladium-catalyzed cyanation of a 5-chloropyrazinone where zinc acetate suppresses dehalogenation. This synthesis was applied to the preparation of > 5 kg of 1 and 2 for clinical studies.

  DOI：

  10.1021/op1001512

文献信息

• Pyrazinone Modulator of Corticotropin-Releasing Factor Receptor Activity
  申请人：Hartz Richard A.

  公开号：US20100029684A1

  公开（公告）日：2010-02-04

  The invention relates to the compound (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile, pharmaceutical compositions of the compound, and methods of using the compound for the treatment of psychiatric disorders and neurological diseases including depression, anxiety related disorders, irritable bowel syndrome, addiction and negative aspects of drug and alcohol withdrawal, and other conditions associated with CRF.

  这项发明涉及化合物(S)-4-(1-环丙基-2-甲氧基乙基)-6-(6-(二氟甲氧基)-2,5-二甲基吡啶-3-基氨基)-5-氧代-4,5-二氢吡嗪-2-羰基腈，该化合物的药物组合物，以及使用该化合物治疗精神障碍和神经系统疾病，包括抑郁症、焦虑相关障碍、肠易激综合征、成瘾以及药物和酒精戒断的负面影响，以及与CRF相关的其他症状的方法。
• A Strategy to Minimize Reactive Metabolite Formation: Discovery of (<i>S</i>)-4-(1-Cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]-5-oxo-4,5-dihydropyrazine-2-carbonitrile as a Potent, Orally Bioavailable Corticotropin-Releasing Factor-1 Receptor Antagonist
  作者：Richard A. Hartz、Vijay T. Ahuja、Xiaoliang Zhuo、Ronald J. Mattson、Derek J. Denhart、Jeffrey A. Deskus、Vivekananda M. Vrudhula、Senliang Pan、Jonathan L. Ditta、Yue-Zhong Shu、James E. Grace、Kimberley A. Lentz、Snjezana Lelas、Yu-Wen Li、Thaddeus F. Molski、Subramaniam Krishnananthan、Henry Wong、Jingfang Qian-Cutrone、Richard Schartman、Rex Denton、Nicholas J. Lodge、Robert Zaczek、John E. Macor、Joanne J. Bronson

  DOI：10.1021/jm900716v

  日期：2009.12.10

  6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound

  详细的代谢表征8是一种较早的基于吡嗪酮的铅促肾上腺皮质激素释放因子1（CRF 1）受体拮抗剂，表明该化合物形成了显着水平的反应性代谢产物，如体内和体外生物转化研究所测。由于有大量证据表明反应性代谢物可能与特异药物反应有关，因此这一点特别令人关注。基于吡嗪酮的CRF 1受体拮抗剂的结构活性关系和体内性质的进一步优化以及评估反应性代谢产物形成的研究导致了19e（一种高亲和力的CRF 1受体拮抗剂）的发现（IC 50＝ 0.86nM），其中GSH加合物估计仅为通过胆汁和尿液排泄的药物相关物质总量的0.1％，表明体内反应性代谢物形成的水平较低。19e中一个新的6-（二氟甲氧基）-2,5-二甲基吡啶-3-胺基团对该化合物和相关类似物的效力和体内特性作出了贡献。19e在大鼠和狗中具有出色的药代动力学特性，并且在大鼠焦虑性戒断模型中显示出功效。最低有效剂量为1.8 mg / kg。为期两周的19e大鼠安
• Substituted Carbamate Derivatives as Modulators of Corticotropin-Releasing Factor Receptor Activity
  申请人：Hartz Richard A.

  公开号：US20110124662A1

  公开（公告）日：2011-05-26

  The disclosure provides compounds of formula (I), including their salts, as well as compositions and methods of using the compounds. The compounds are CRF receptor antagonists and may be useful for treating disorders associated with abnormal CRF levels or aberrant functioning of CRF receptors.

  本公开提供公式(I)的化合物，包括其盐，以及使用这些化合物的组合物和方法。这些化合物是CRF受体拮抗剂，可能对治疗与异常CRF水平或CRF受体异常功能相关的疾病有用。
• Synthesis and structure–activity relationships of N3-pyridylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists
  作者：Richard A. Hartz、Vijay T. Ahuja、William D. Schmitz、Thaddeus F. Molski、Gail K. Mattson、Nicholas J. Lodge、Joanne J. Bronson、John E. Macor

  DOI：10.1016/j.bmcl.2010.01.129

  日期：2010.3

  A series of N-3-pyridylpyrazinones was investigated as corticotropin-releasing factor-1 receptor antagonists. It was observed that the binding affinity of analogues containing a pyridyl group was influenced not only by the substitution pattern on the pyridyl group, but also by the pK(a) of the pyridyl nitrogen. Analogues containing a novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group were among the most potent N-3-pyridylpyrazinones synthesized. The synthesis and SAR of N-3-pyridylpyrazinones is described herein. (C) 2010 Elsevier Ltd. All rights reserved.
• PYRAZINONE MODULATOR OF CORTICOTROPIN-RELEASING FACTOR RECEPTOR ACTIVITY
  申请人：Bristol-Myers Squibb Company

  公开号：EP2303867A1

  公开（公告）日：2011-04-06