7-chloro-3-(2,4-dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine | 948553-53-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 7-chloro-3-(2,4-dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine
• CAS: 948553-53-5
• 化学式: C₁₄H₁₀Cl₃N₃
• 分子量: 326.613
• InChiKey: CPJRAWVFMHHRJM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  30.2
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  7-chloro-3-(2,4-dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine 在 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基乙酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 6.0h， 生成 4-((3-(2,4-dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)(methyl)amino)butyl-1,1,2,2,3,3,4,4-d8 4-methylbenzenesulfonate
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2015.06.036
• 作为产物：
  描述：

  5-氨基-4-(2,4-二氯苯基)-3-甲基吡唑 在 三氯氧磷 作用下， 以 1,4-二氧六环 为溶剂， 反应 23.0h， 生成 7-chloro-3-(2,4-dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2015.06.036

文献信息

• 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.
• 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.