3-[4-[2-(4-Fluorophenyl)-2-(4-methyl-1-piperazinyl)ethyl]-1-piperazinyl]-2-methyl-1-phenyl-1-propanone | 89011-87-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-[4-[2-(4-Fluorophenyl)-2-(4-methyl-1-piperazinyl)ethyl]-1-piperazinyl]-2-methyl-1-phenyl-1-propanone
• 英文别名: 3-[4-[2-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)ethyl]piperazin-1-yl]-2-methyl-1-phenylpropan-1-one
• CAS: 89011-87-0
• 化学式: C₂₇H₃₇FN₄O
• 分子量: 452.615
• InChiKey: KNHNIKFGCWUBOJ-UHFFFAOYSA-N

物化性质

• 沸点：
  559.4±50.0 °C(Predicted)
• 密度：
  1.122±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  30
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-溴-4'-氟苯乙酮 在 盐酸 、 氢氧化钾 、 sodium tetrahydroborate 、 氯化亚砜 、 TEA 作用下， 以 乙醇 、 二氯甲烷 、 苯 为溶剂， 生成 3-[4-[2-(4-Fluorophenyl)-2-(4-methyl-1-piperazinyl)ethyl]-1-piperazinyl]-2-methyl-1-phenyl-1-propanone
  参考文献：
  名称：

  Structure−Activity Relationship of (1-Aryl-2-piperazinylethyl)piperazines:  Antagonists for the AGRP/Melanocortin Receptor Binding

  摘要：

  Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin action.(1) In the hypothalamus, melanocortin peptide agonists act as satiety-inducing factors that mediate their action through the melanocortin-4 receptor (MC4R) whereas AGRP is an opposing orexigenic agent. Novel inhibitors of the AGRP/MC4 binding based on (piperazinylethyl)piperazines were prepared, and their structure-activity relationship was established.

  DOI：

  10.1021/jm0255522

文献信息

• Potential antitussives: Synthesis and pharmacology of a series of 1-[2-amino-2-(4-fluorophenyl)ethyl]-4-(2-benzoylpropyl)piperazines
  作者：Zdeněk Vejdělek、Miroslav Protiva

  DOI：10.1135/cccc19832977

  日期：——

  Compound V, obtained by a reaction of 2-chloro-4'-fluoroacetophenone with 1-(ethoxycarbonyl)piperazine, was reduced with sodium borohydride to the amino alcohol VIf. The hydrochloride of VIf was treated with thionyl chloride to give the hydrochloride of 1-[2-chloro-2-(4-fluorophenyl)ethyl]-4-(ethoxycarbonyl)piperazine (VIg). The crude VIg was subjected to substitution reactions with diethylamine, pyrrolidine, piperidine, morpholine and 1-methylpiperazine in benzene at 60 °C. The obtained aminocarbamates VIa-VIe were hydrolyzed with concentrated ethanolic potassium hydroxide and gave the amines VIIa-VIIe. Mannich reactions of the hydrochlorides of these compounds with paraformaldehyde and propiophenone (and 4-hydroxypropiophenone, respectively) resulted in the title compounds IIIa-IIIe, IVa,b and IVd,e. Only substances IIIa and IIId were found to have an antitussic activity in rats and guinea-pigs comparable to that of eprazinone (I). In higher doses they brought about central depression, ataxia and ptosis in mice and some of them adrenolytic and hypotensive effects in rats.

  通过将2-氯-4'-氟乙酰苯酮与1-(乙氧羰基)哌嗪反应得到化合物V，然后用硼氢化钠还原为氨基醇VIf。将VIf的盐酸盐与亚硫酰氯处理得到1-[2-氯-2-(4-氟苯基)乙基]-4-(乙氧羰基)哌嗪的盐酸盐（VIg）。粗制的VIg在苯中与二乙胺、吡咯烷、哌啶、吗啉和1-甲基哌嗪进行取代反应，产生氨基氨基甲酸酯VIa-VIe。用浓缩的乙醇钾氢氧化物水解VIa-VIe，得到胺类物质VIIa-VIIe。这些化合物的盐酸盐与多聚甲醛和丙酮苯酮（和对羟基丙酮苯酮，分别）进行Mannich反应，得到标题化合物IIIa-IIIe、IVa,b和IVd,e。只有IIIa和IIId这两种物质在大鼠和豚鼠中显示出与依普拉津酮（I）相当的止咳活性。在较高剂量下，它们会导致小鼠出现中枢抑制、共济失调和上睑下垂，部分物质在大鼠中还表现出肾上腺素拮抗和降压作用。
• Pharmacological chaperones for treating obesity
  申请人：Amicus Therapeutics, Inc.

  公开号：EP2933265A2

  公开（公告）日：2015-10-21

  The invention relates to methods of enhancing normal melanocortin-4 receptor (MC4R) activity, and to enhancing activity of an MC4R having a mutation which affects protein folding and/or processing of the MC4R. The invention provides a method of treating an individual having a condition in which increased activity of an MC4R at the cell surface would be beneficial, for example in obesity, by administering an effective amount of a pharmacological chaperone for the MC4R. The invention provides MC4R pharmacological chaperones which enhance the activity of MC4R. The invention further provides a method of screening to identify pharmacological chaperones which enhance folding of an MC4R in the endoplasmic reticulum (ER), in order to enhance the activity of the MC4R at the cell surface.

  本发明涉及增强正常黑色素皮质素-4受体（MC4R）活性的方法，以及增强具有影响MC4R蛋白质折叠和/或加工的突变的MC4R活性的方法。本发明提供了一种治疗方法，通过施用有效量的 MC4R 药理伴侣，治疗细胞表面 MC4R 活性增加有益的病症，例如肥胖症。本发明提供了可增强 MC4R 活性的 MC4R 药理合剂。本发明进一步提供了一种筛选方法，以确定可增强MC4R在内质网（ER）中折叠的药理伴侣，从而增强MC4R在细胞表面的活性。
• VEJDELEK, Z.;PROTIVA, M., COLLECT. CZECH. CHEM. COMMUN., 1983, 48, N 10, 2977-2988
  作者：VEJDELEK, Z.、PROTIVA, M.

  DOI：——

  日期：——
• PHARMACOLOGICAL CHAPERONES FOR TREATING OBESITY
  申请人：Amicus Therapeutics, Inc.

  公开号：EP1885366B1

  公开（公告）日：2018-05-30
• Structure−Activity Relationship of (1-Aryl-2-piperazinylethyl)piperazines:  Antagonists for the AGRP/Melanocortin Receptor Binding
  作者：Premilla N. Arasasingham、Christopher Fotsch、Xiaohu Ouyang、Mark H. Norman、Michael G. Kelly、Kevin L. Stark、Bill Karbon、Clarence Hale、James W. Baumgartner、Martha Zambrano、Janet Cheetham、Nuria A. Tamayo

  DOI：10.1021/jm0255522

  日期：2003.1.1

  Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin action.(1) In the hypothalamus, melanocortin peptide agonists act as satiety-inducing factors that mediate their action through the melanocortin-4 receptor (MC4R) whereas AGRP is an opposing orexigenic agent. Novel inhibitors of the AGRP/MC4 binding based on (piperazinylethyl)piperazines were prepared, and their structure-activity relationship was established.