N-butyl-3-(2,4-dichlorophenyl)-N-ethyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amine | 202579-59-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-butyl-3-(2,4-dichlorophenyl)-N-ethyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amine
• 英文别名: Pyrazolo(1,5-a)pyrimidin-7-amine, N-butyl-3-(2,4-dichlorophenyl)-N-ethyl-2,5-dimethyl-
• CAS: 202579-59-7
• 化学式: C₂₀H₂₄Cl₂N₄
• 分子量: 391.343
• InChiKey: DVFPSRARRBNMBH-UHFFFAOYSA-N

物化性质

• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  33.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5-氨基-4-(2,4-二氯苯基)-3-甲基吡唑 在 N,N-二乙基苯胺 、 三氯氧磷 作用下， 以 溶剂黄146 、 甲苯 为溶剂， 生成 N-butyl-3-(2,4-dichlorophenyl)-N-ethyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amine
  参考文献：
  名称：

  The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5- a ]-pyrimidine: A corticotropin-releasing factor (hCRF 1 ) antagonist

  摘要：

  Structure-activity relationship studies led to the discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine 11-31 (DMP904), whose pharmacological profile strongly supports the hypothesis that hCRF(1) antagonists may be potent anxiolytic drugs. Compound 11-31 (hCRF(1) K-i= 1.0 +/- 0.2 nM (n = 8)) was a potent antagonist of hCRF(1)-coupled adenylate cyclase activity in HEK293 cells (IC50 = 10.0 +/- 0.01 nM versus 10 nM r/hCRF, I? = 8); alpha-helical CRF(9-41) had weaker potency (IC50 = 286 +/- 63 nM, n = 3). Analogue 11-31 had good oral activity in the rat situational anxiety test; the minimum effective dose for 11-31 was 0.3 mg/kg (po). Maximal efficacy (approximately 57% reduction in latency lime in the dark compartment) was observed at this dose. Chlordiazepoxide caused a 72% reduction in latency at 20 mg/kg (po). The literature compound 1 (CP154526-1. 30 mg/kg (po)) was inactive in this lest. Compound 11-31 did not inhibit open-field locomotor activity at 10, 30, and 100 mg/kg (po) in rats. In beagle dogs, this compound (5 mg/kg, iv, po) afforded good plasma levels. The key iv pharmacokinetic parameters were t(1/2), CL and V-d.ss values equal to 46.4 +/- 7.6 h, 0.49 +/- 0.08 L/kg/h and 23.0 +/- 4.2 L/kg, respectively. After oral dosing. the mean C-max, T-max, t(1/2) and bioavailability values were equal to 1260 +/- 290 nM, 0.75 +/- 0.25 h, 45.1 +/- 10.2 h and 33.1%, respectively. The overall rat behavioral profile of this compound suggests that it may be an anxiolytic drug with a low motor side effect Liability. (C) 2000 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00271-0

文献信息

• 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。
• Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor
  作者：Jeffrey S. Stehouwer、Matthew S. Birnbaum、Ronald J. Voll、Michael J. Owens、Susan J. Plott、Chase H. Bourke、Michael A. Wassef、Clinton D. Kilts、Mark M. Goodman

  DOI：10.1016/j.bmc.2015.06.036

  日期：2015.8

  A series of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines were synthesized and evaluated as potential positron emission tomography (PET) tracers for the corticotropin-releasing factor type-1 (CRF1) receptor. Compounds 27, 28, 29, and 30 all displayed high binding affinity (<= 1.2 nM) to the CRF1 receptor when assessed by in vitro competition binding assays at 23 degrees C, whereas a decrease in affinity (>= 10-fold) was observed with compound 26. The logP(7.4) values of [F-18]26-[F-18] 29 were in the range of similar to 2.2-2.8 and microPET evaluation of [F-18]26-[F-18] 29 in an anesthetized male cynomolgus monkey demonstrated brain penetrance, but specific binding was not sufficient enough to differentiate regions of high CRF1 receptor density from regions of low CRF1 receptor density. Radioactivity uptake in the skull, and sphenoid bone and/or sphenoid sinus during studies with [F-18]28, [F-18]28-d(8), and [F-18]29 was attributed to a combination of [F-18]fluoride generated by metabolic defluorination of the radiotracer and binding of intact radiotracer to CRF1 receptors expressed on mast cells in the bone marrow. Uptake of [F-18]26 and [F-18]27 in the skull and sphenoid region was rapid but then steadily washed out which suggests that this behavior was the result of binding to CRF1 receptors expressed on mast cells in the bone marrow with no contribution from [F-18]fluoride. (C) 2015 Elsevier Ltd. All rights reserved.
• Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists
  作者：David J. Wustrow、Thomas Capiris、Ronald Rubin、James A. Knobelsdorf、Hyacinth Akunne、M.Duff Davis、Robert MacKenzie、Thomas A. Pugsley、Kim T. Zoski、Thomas G. Heffner、Lawrence D. Wise

  DOI：10.1016/s0960-894x(98)00372-2

  日期：1998.8

  A series of 3-phenylpyrazolo[1,5-a]pyrimidines was prepared and found to have affinity for the human CRF-1 receptor. The 3-dimensional structure of one of the most potent analogs in this series, 10d, was determined by X-ray crystallography and suggests the spatial requirements for potent CRF-1 receptor binding affinity in this series. (C) 1998 Elsevier Science Ltd. All rights reserved.
• GENETIC PREDICTORS OF A RESPONSE TO TREATMENT WITH CRHR1 ANTAGONISTS
  申请人：HMNC Value GmbH

  公开号：EP3277835B1

  公开（公告）日：2019-01-09
• CRHR1 ANTAGONISTS FOR USE IN THE TREATMENT OF PATIENTS HAVING CRH OVERACTIVITY
  申请人：HOLSBOERMASCHMEYER NEUROCHEMIE GMBH

  公开号：US20150094310A1

  公开（公告）日：2015-04-02

  The present invention relates to a corticotropin releasing hormone receptor type 1 (CRHR1) antagonist for use in the treatment of depressive symptoms and/or anxiety symptoms in a novel group of patients, i.e. patients having corticotropin releasing hormone (CRH) overactivity.