5-氨基-4-(2,4-二氯苯基)-3-甲基吡唑 | 214416-40-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 5-氨基-4-(2,4-二氯苯基)-3-甲基吡唑
• 英文名称: 5-amino-4-(2,4-dichlorophenyl)-3-methylpyrazole
• 英文别名: 3-methyl-4-(2,4-dichlorophenyl)-5-aminopyrazole；4-(2,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-amine
• CAS: 214416-40-7
• 化学式: C₁₀H₉Cl₂N₃
• 分子量: 242.108
• InChiKey: VTGZEYUCWOOCLP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  54.7
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-氨基-4-(2,4-二氯苯基)-3-甲基吡唑 在 sodium ethanolate 、 N,N-二乙基苯胺 、 三氯氧磷 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 45.0h， 生成 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]pyrazolo-1,3,5-triazine
  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
• 作为产物：
  描述：

  2,4-二氯苯乙腈 在 sodium 、 一水合肼 、 溶剂黄146 作用下， 以 甲苯 为溶剂， 反应 6.0h， 生成 5-氨基-4-(2,4-二氯苯基)-3-甲基吡唑
  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

• 一种3-芳基-6-甲酰胺吡唑并[1,5-a]嘧啶类 化合物及其应用
  申请人：陕西理工大学

  公开号：CN106866680B

  公开（公告）日：2019-02-01

  本发明属于医药技术领域，具体的说是一种3‑芳基‑6‑甲酰胺吡唑并[1,5‑a]嘧啶类化合物及其应用。化合物是由乙酰乙酸乙酯和N,N‑二甲基甲酰胺二甲缩醛反应制得2‑二甲胺基亚甲基‑3‑氧代丁酸乙酯(1)，1与3‑甲基‑4‑(2,4‑二氯苯基)‑5‑氨基吡唑经环合、水解、酰胺化制备了6个2,7‑二甲基‑3‑芳基‑6‑甲酰胺吡唑并[1,5‑a]嘧啶类化合物，其结构经核磁共振氢谱和红外光谱进行了表征。采用MABA法，测定所合成的化合物对结核分枝杆菌H37Rv的抑制作用。经测定结果表明：部分化合物的药理活性筛选结果显示其对结核分支杆菌H37Rv和草分枝杆菌M.phlei1180都有很好的抑制作用，具有良好的抗结核病方面开发应用前景。
• 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.
• 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
  作者：Paul J. Gilligan、Caryn Baldauf、Anthony Cocuzza、Dennis Chidester、Robert Zaczek、Lawrence W. Fitzgerald、John McElroy、Mark A. Smith、H.-S.L. Shen、Jo Anne Saye、David Christ、George Trainor、David W. Robertson、Paul Hartig

  DOI：10.1016/s0968-0896(99)00271-0

  日期：2000.1

  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.
• 6,7-Dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives as novel corticotropin-releasing factor 1 receptor antagonists
  作者：Tetsuji Saito、Tetsuo Obitsu、Takashi Kondo、Toshiaki Matsui、Yuuki Nagao、Kensuke Kusumi、Naoya Matsumura、Sonoko Ueno、Akihiro Kishi、Seishi Katsumata、Yoshifumi Kagamiishi、Hisao Nakai、Masaaki Toda

  DOI：10.1016/j.bmc.2011.07.055

  日期：2011.9

  To identify an orally active corticotropin-releasing factor 1 receptor antagonist, a series of 6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives were designed, synthesized and evaluated. An in vitro study followed by in vivo and pharmacokinetic studies of these heterotricyclic compounds led us to the discovery of an orally active CRF1 receptor antagonist. The results of a structure-activity relationship study are presented. (C) 2011 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.