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 | 459856-18-9

• 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
• 中文名称: 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
• 中文别名: 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；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
• 英文名称: [14C]-Pexacerfont
• 英文别名: Pexacerfont；4-(2-R-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxy-3-pyridyl)[1,5-α]pyrazolo-1,3,5-triazine；4-((R)-2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]pyrazolo-1,3,5-triazine；BMS-562,086；N-[(2R)-butan-2-yl]-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin-4-amine
• CAS: 459856-18-9
• 化学式: C₁₈H₂₄N₆O
• 分子量: 340.428
• InChiKey: LBWQSAZEYIZZCE-SNVBAGLBSA-N

物化性质

• 熔点：
  118℃
• 密度：
  1.24
• 溶解度：
  DMSO：30mg/mL；乙醇：30mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  77.2
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8℃

制备方法与用途

生物活性方面，Pexacerfont 是一种选择性促肾上腺皮质激素释放因子（CRF1）受体拮抗剂，能有效作用于人 CRF1 受体，其 IC50 值为 6.1±0.6 nM。

反应信息

• 作为产物：
  描述：

  2-(6-甲氧基-2-甲基吡啶-3-基)乙腈 在 N-甲基吗啉 、 potassium tert-butylate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 三氯氧磷 作用下， 以 四氢呋喃 、 水 、 异丙醇 、 乙腈 为溶剂， 反应 17.5h， 生成 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：

  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。
• 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：Gilligan J. Paul

  公开号：US20070054913A1

  公开（公告）日：2007-03-08

  Corticotropin releasing factor (CRF) antagonists of Formula (I): 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）及其在治疗焦虑、抑郁和其他精神、神经系统疾病方面的用途，以及治疗与心理病理障碍和压力相关的免疫、心血管或心脏疾病和结肠过敏反应。
• Method for predicting a treatment response to a CRHR1 antagonist and/or a V1B antagonist in a patient with depressive and/or anxiety symptoms
  申请人：MAX-PLANCK-GESELLSCHAFT ZUR FÖRDERUNG DER WISSENSCHAFTEN E.V.

  公开号：US10190168B2

  公开（公告）日：2019-01-29

  The present invention relates to a method for predicting a treatment response to a corticotropin releasing hormone receptor type 1 (CRHR1) antagonist and/or a vasopressin receptor 1B (V1B) antagonist in a patient with depressive and/or anxiety symptoms. The present invention furthermore relates to a V1B receptor antagonist and/or CRHR1 antagonist for use in the treatment of depressive symptoms and/or anxiety symptoms in a patient. Also, kits, diagnostic compositions, devices and microarrays allowing the determination of the presence or absence of at least one polymorphic variant in the AVPR1B gene in combination with the presence or absence of at least one polymorphic variant in the patient's genome excluding the AVPR1B gene in the nucleic acid sample are described.

  本发明涉及一种预测抑郁和/或焦虑症状患者对促肾上腺皮质激素释放激素受体1型（CRHR1）拮抗剂和/或血管加压素受体1B（V1B）拮抗剂的治疗反应的方法。本发明还涉及用于治疗患者抑郁症状和/或焦虑症状的V1B受体拮抗剂和/或CRHR1拮抗剂。此外，本发明还描述了试剂盒、诊断组合物、装置和微阵列，这些试剂盒、诊断组合物、装置和微阵列可结合核酸样本中患者基因组中排除 AVPR1B 基因的至少一种多态变体的存在与否来确定 AVPR1B 基因中至少一种多态变体的存在与否。
• Treatment of congenital adrenal hyperplasia
  申请人：Neurocrine Biosciences, Inc.

  公开号：US10905690B2

  公开（公告）日：2021-02-02

  CRF1 receptor antagonists have the potential to directly inhibit ACTH release in patients with CAH and thereby allow normalization of androgen production while using lower, more physiologic doses of hydrocortisone, and thus reducing treatment-associated side effects.

  CRF1 受体拮抗剂有可能直接抑制 CAH 患者的促肾上腺皮质激素释放，从而使雄激素分泌正常化，同时使用更低、更符合生理剂量的氢化可的松，从而减少与治疗相关的副作用。
• 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.