DMP 696 | 202578-52-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: DMP 696
• 英文别名: 4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazin；8-(2,4-dichlorophenyl)-N-(1,3-dimethoxypropan-2-yl)-2,7-dimethylpyrazolo[5,1-f][1,3,5]triazin-4-amine；8-(2,4-dichlorophenyl)-N-(1,3-dimethoxypropan-2-yl)-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin-4-amine
• CAS: 202578-52-7
• 化学式: C₁₈H₂₁Cl₂N₅O₂
• 分子量: 410.303
• InChiKey: MDWRPTOUDPFXKK-UHFFFAOYSA-N

物化性质

• 熔点：
  120-121 °C
• 密度：
  1.39±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  73.6
• 氢给体数：
  1
• 氢受体数：
  6

制备方法与用途

生物活性

DMP 696 是一种促肾上腺素皮质激素释放激素受体1 (CRHR1) 拮抗剂，常用于焦虑和抑郁症的研究。

体内研究

DMP696 (3 mg/kg, p.o.) attenuates consolidation of remote fear memories of mice, without affecting their expression and retention. WT mice treated with DMP696 for 1 week starting 24 h after foot shock also show reduced synaptosomal GluR1 levels than do shocked vehicle-treated controls. Rats treated with different doses of DMP696 (1, 3, 10, 30 mg/kg) show very little freezing during the 2-minute preshock interval. Rats treated with DMP696 exhibit a significant overall reduction in CREB phosphorylation, in both the LA, and BLA, but not in the CeA. DMP696 treatment reduces levels of LA and BLA pCREB across all time intervals that do not differ significantly from homecage pCREB levels (P>0.05). In the CeA, both vehicle- and DMP696-treated rats exhibit significantly higher pCREB expression at each post-conditioning time interval than homecage pCREB levels. Rats in the 30 ng DMP696 group exhibit significantly less freezing in comparison to vehicle-treated animals.

反应信息

• 作为产物：
  描述：

  在 sodium ethanolate 、 N,N-二乙基苯胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 29.75h， 生成 DMP 696
  参考文献：
  名称：

  4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine:  A Potent, Orally Bioavailable CRF₁ Receptor Antagonist

  摘要：

  Structure-activity studies; in the pyrazolo[1,5-a]-1,3,5-triazine series led to the discovery that compound 11i (DMP696) is a potent hCRF(1) receptor antagonist (K-i = 1.7 nM vs 7.5 nM for alpha-hel-CRF(9-41), hCRF(1) adenylate cyclase IC50 = 82 nM vs 286 nM for alpha-hel-CRF(9-41)). Compound 11i has excellent oral pharmacokinetic profiles in rats and dogs (37% and 50% oral bioavailabilities, respectively). This compound displays good activity in the rat situational anxiety model (MED = 3 mg/kg (po)), whereas a literature standard 1 (CP154526-1) was inactive (MED > 30 mg/kg (po)). Analogue 11i reduced stereotypical mouth movements in rhesus monkeys by 50% at 21 mg/kg (po) using the human intruder paradigm. Overall, the profile of pyrazolotriazine 11i indicates that hCRF1 receptor antagonists may be anxiolytic agents, which have reduced motor side effect profiles.

  DOI：

  10.1021/jm9904351

文献信息

• Synthesis of [O-methyl-11C]-4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]pyrazolo-1,3,5-triazine ([11C]DMP696): a potential PET ligand for CRF1 receptors
  作者：J. S. Dileep Kumar、Vattoly J. Majo、Norman R. Simpson、Jaya Prabhakaran、Ronald L. Van Heertum、J. John Mann

  DOI：10.1002/jlcr.885

  日期：2004.11

  Synthesis of [O-methyl-11C]-4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]pyrazolo-1,3,5-triazine ([11C]DMP696), a highly selective CRF1 antagonist has been achieved. The total time required for the synthesis of [11C]DMP696 is 30 min from EOB using [11C]methyl triflate in THF, with a 16% yield (EOS) and >99% chemical and radiochemical purities along with a specific activity of >2000 Ci/mmol (EOS). Copyright © 2004 John Wiley & Sons, Ltd.

  高选择性 CRF1 拮抗剂[O-甲基-11C]-4-(1,3-二甲氧基-2-丙基氨基)-2,7-二甲基-8-(2,4-二氯苯基)[1,5-a]吡唑并-1,3,5-三嗪（[11C]DMP696）的合成已经完成。在 THF 中使用 [11C]methyl triflate 从 EOB 合成 [11C]DMP696 总共需要 30 分钟，收率为 16%（EOS），化学纯度和放射化学纯度大于 99%，比活度大于 2000 Ci/mmol（EOS）。Copyright © 2004 John Wiley & Sons, Ltd. All Rights Reserved.
• Azolo triazines and pyrimidines
  申请人：Bristol-Myers Squibb Pharma Company

  公开号：US06358950B1

  公开（公告）日：2002-03-19

  Corticotropin releasing factor (CRF) antagonists of formula I or II: and their 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.

  公告释放因子（CRF）拮抗剂I或II的公式：及其在治疗焦虑，抑郁和其他精神，神经系统疾病以及免疫，心血管或心脏相关疾病的治疗中的使用，以及与心理病理障碍和压力相关的结肠过敏性治疗。
• 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。
• DIAGNOSIS AND TREATMENT OF NON-ULCER DYSPEPSIA BASED ON HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ABNORMALITY
  申请人：Malope Company Limited

  公开号：EP1305637A2

  公开（公告）日：2003-05-02
• 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