(S)-N-[(1S)-1-(3-fluoro-2-piperazin-1-ylphenyl)-2-methylpropyl]-2-methylpropane-2-sulfinamide | 949524-68-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (S)-N-[(1S)-1-(3-fluoro-2-piperazin-1-ylphenyl)-2-methylpropyl]-2-methylpropane-2-sulfinamide
• CAS: 949524-68-9
• 化学式: C₁₈H₃₀FN₃OS
• 分子量: 355.52
• InChiKey: LJXRUDRZIVDWRP-FYSMJZIKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  63.6
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-N-[(1S)-1-(3-fluoro-2-piperazin-1-ylphenyl)-2-methylpropyl]-2-methylpropane-2-sulfinamide 在 盐酸 、 三乙酰氧基硼氢化钠 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 溶剂黄146 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.0h， 生成
  参考文献：
  名称：

  Pyrrolidines as potent functional agonists of the human melanocortin-4 receptor

  摘要：

  A series of pyrrolidine derivatives were synthesized and characterized as potent agonists of the human melanocortin-4 receptor. For example, 28c had a K-i of 13 nM in binding affinity and EC50 of 6.9 nM in agonist potency with an intrinsic activity of 100% of the endogenous ligand alpha-MSH. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.06.088
• 作为产物：
  描述：

  4-{2-fluoro-6-[(S)-2-methyl-1-((S_S)-2-methyl-propane-2-sulfinylamino)-propyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以100%的产率得到(S)-N-[(1S)-1-(3-fluoro-2-piperazin-1-ylphenyl)-2-methylpropyl]-2-methylpropane-2-sulfinamide
  参考文献：
  名称：

  Syntheses of tetrahydrothiophenes and tetrahydrofurans and studies of their derivatives as melanocortin-4 receptor ligands

  摘要：

  Piperazinebenzylamine derivatives from trans-4-(4-chlorophenyl)tetrahydrothiophene-3-carboxylic acid 6 and its S-oxide 7 and sulfone 8, and the tetrahydrofuran 9 and its two regioisomers 11 and 13 were synthesized and studied for their binding affinities at the human melanocortin-4 receptor. These five-membered ring constrained compounds possessed similar or lower potency compared to the acyclic analogs. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.11.128

文献信息

• [EN] LIGANDS OF MELANOCORTIN RECEPTORS AND COMPOSITIONS AND METHODS RELATED THERETO<br/>[FR] LIGANDS DU RECEPTEUR DE LA MELANOCORTINE ET COMPOSITIONS ET METHODES ASSOCIEES
  申请人：NEUROCRINE BIOSCIENCES INC

  公开号：WO2005040109A1

  公开（公告）日：2005-05-06

  Compounds which function as melanocortin receptor ligands and having utility in the treatment of melanocortin receptor-based disorders. The compounds have the following structure (I): (R4)s (R 2)n N~ X1-X2 (CR1aCRlb)q 1~ N R1-lm 1 O R3 (I) including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein m, n, q, s, R1, R1a, R1b, R2, R3, R4, X1 X2 and X3 are as defined herein. Pharmaceutical compositions containing a compound of structure (I), as well as methods relating to the use thereof, are also disclosed.

  化合物作为黑色素皮质激素受体配体，并在治疗基于黑色素皮质激素受体的疾病中具有用途。这些化合物具有以下结构（I）：（R4）s（R 2）n N〜X1-X2（CR1aCRlb）q 1〜N R1-lm 1 O R3（I），包括立体异构体，前药和其药用盐，其中m、n、q、s、R1、R1a、R1b、R2、R3、R4、X1、X2和X3如本文所定义。还公开了含有结构（I）化合物的药物组合物，以及与其使用相关的方法。
• Synthesis and characterization of pyrrolidine derivatives as potent agonists of the human melanocortin-4 receptor
  作者：Wanlong Jiang、Joe A. Tran、Fabio C. Tucci、Beth A. Fleck、Sam R. Hoare、Stacy Markison、Jenny Wen、Caroline W. Chen、Dragan Marinkovic、Melissa Arellano、Alan C. Foster、Chen Chen

  DOI：10.1016/j.bmcl.2007.09.079

  日期：2007.12

  A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S, 4R-compound 20f-1 possessed a K-i of 11 nM and an EC50 of 24 nM, while its 3R, 4S-isomer 20f-2 exhibited a K-i of 8.6 and an IC50 of 65 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats. (c) 2007 Elsevier Ltd. All rights reserved.
• Design and synthesis of 3-arylpyrrolidine-2-carboxamide derivatives as melanocortin-4 receptor ligands
  作者：Joe A. Tran、Fabio C. Tucci、Melissa Arellano、Wanlong Jiang、Caroline W. Chen、Dragan Marinkovic、Beth A. Fleck、Jenny Wen、Alan C. Foster、Chen Chen

  DOI：10.1016/j.bmcl.2008.01.125

  日期：2008.3

  Based on 3-phenylpropionamides, a series of 3-arylpyrrolidine-2-carboxamide derivatives was designed and synthesized to study the effect of cyclizations as melanocortin-4 receptor ligands. It was found that the 2R, 3R-pyrrolidine isomer possessed the most potent affinity among the four stereoisomers. (C) 2008 Elsevier Ltd. All rights reserved.
• Pharmacological and pharmacokinetic characterization of 2-piperazine-α-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists
  作者：Chen Chen、Fabio C. Tucci、Wanlong Jiang、Joe A. Tran、Beth A. Fleck、Sam R. Hoare、Jenny Wen、Takung Chen、Michael Johns、Stacy Markison、Alan C. Foster、Dragan Marinkovic、Caroline W. Chen、Melissa Arellano、John Harman、John Saunders、Haig Bozigian、Daniel Marks

  DOI：10.1016/j.bmc.2008.03.072

  日期：2008.5

  A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8 - 12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1 mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20 mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia. (C) 2008 Elsevier Ltd. All rights reserved.