4-{2-fluoro-6-[(S)-3-methyl-1-((S_S)-2-methyl-propane-2-sulfinylamino)-butyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester | 851753-47-4

• 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: 4-{2-fluoro-6-[(S)-3-methyl-1-((S_S)-2-methyl-propane-2-sulfinylamino)-butyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester
• 英文别名: 4-{2-[(1S)-1-((S)-tert-butylsulfinylamino)-3-methylbutyl]-6-fluorophenyl}piperazine-1-carboxylic acid tert-butyl ester；4-{2-[(1S)-((S)-tert-butanesulfinylamino)-3-methylbutyl]-6-fluorophenyl}-1-piperazinecarboxylic acid tert-butyl ester；2-[4-(tert-butoxycarbonyl)-1-piperazinyl]-3-fluoro-1-[S-(S-t-butanesulfinamido)-3-methylbutyl]benzene；tert-butyl 4-[2-[(1S)-1-[[(S)-tert-butylsulfinyl]amino]-3-methylbutyl]-6-fluorophenyl]piperazine-1-carboxylate
• CAS: 851753-47-4
• 化学式: C₂₄H₄₀FN₃O₃S
• 分子量: 469.664
• InChiKey: OBHXYUXYVYGZOS-WEZXKFLESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  81.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-{2-fluoro-6-[(S)-3-methyl-1-((S_S)-2-methyl-propane-2-sulfinylamino)-butyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester 在 盐酸 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-{4-[2-((S)-1-Amino-3-methyl-butyl)-6-fluoro-phenyl]-piperazin-1-yl}-3-(2,4-dichloro-phenyl)-propan-1-one
  参考文献：
  名称：

  Arylpropionylpiperazines as antagonists of the human melanocortin-4 receptor

  摘要：

  A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.05.088
• 作为产物：
  描述：

  N-Boc-哌嗪 在 titanium(IV) tetraethanolate 、 三辛基铝 、 potassium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 正己烷 、 正庚烷 为溶剂， 反应 65.0h， 生成 4-{2-fluoro-6-[(S)-3-methyl-1-((S_S)-2-methyl-propane-2-sulfinylamino)-butyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Practical Asymmetric Synthesis of α-Branched 2-Piperazinylbenzylamines by 1,2-Additions of Organometallic Reagents to N-tert-Butanesulfinyl Imines

  摘要：

  2-[4-(tert-Butoxycarbonyl)piperazinyl]benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting alpha-branched N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides confirms different mechanisms depending on the organometallic reagent used. Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the dehydration byproducts have been identified and characterized. To avoid the formation of byproducts in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corresponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein described constitutes an attractive method for extensive structure-activity studies in the search for novel ligands of the human melanocortin 4 receptor.

  DOI：

  10.1021/jo051514p

文献信息

• Design, Synthesis, In Vitro, and In Vivo Characterization of Phenylpiperazines and Pyridinylpiperazines as Potent and Selective Antagonists of the Melanocortin-4 Receptor
  作者：Joe A. Tran、Wanlong Jiang、Fabio C. Tucci、Beth A. Fleck、Jenny Wen、Yang Sai、Ajay Madan、Ta Kung Chen、Stacy Markison、Alan C. Foster、Sam R. Hoare、Daniel Marks、John Harman、Caroline W. Chen、Melissa Arellano、Dragan Marinkovic、Haig Bozigian、John Saunders、Chen Chen

  DOI：10.1021/jm701137s

  日期：2007.12.13

  Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K-i value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
• [EN] LIGANDS OF MELANOCORTIN RECEPTORS AND COMPOSITIONS AND METHODS RELATED THERETO<br/>[FR] LIGANDS DE RECEPTEURS DE LA MELANOCORTINE, COMPOSITIONS ET PROCEDES ASSOCIES
  申请人：NEUROCRINE BIOSCIENCES INC

  公开号：WO2005042516A3

  公开（公告）日：2005-12-01
• Pyrrolidinones as orally bioavailable antagonists of the human melanocortin-4 receptor with anti-cachectic activity
  作者：Joe A. Tran、Fabio C. Tucci、Wanlong Jiang、Dragan Marinkovic、Caroline W. Chen、Melissa Arellano、Stacy Markison、Beth A. Fleck、Jenny Wen、Nicole S. White、Joseph Pontillo、John Saunders、Daniel Marks、Sam R. Hoare、Ajay Madan、Alan C. Foster、Chen Chen

  DOI：10.1016/j.bmc.2007.05.026

  日期：2007.8

  A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model. (c) 2007 Elsevier Ltd. All rights reserved.
• Practical Asymmetric Synthesis of α-Branched 2-Piperazinylbenzylamines by 1,2-Additions of Organometallic Reagents to <i>N</i>-<i>tert</i>-Butanesulfinyl Imines
  作者：Wanlong Jiang、Chen、Dragan Marinkovic、Joe A. Tran、Caroline W. Chen、L. Melissa Arellano、Nicole S. White、Fabio C. Tucci

  DOI：10.1021/jo051514p

  日期：2005.10.1

  2-[4-(tert-Butoxycarbonyl)piperazinyl]benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting alpha-branched N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides confirms different mechanisms depending on the organometallic reagent used. Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the dehydration byproducts have been identified and characterized. To avoid the formation of byproducts in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corresponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein described constitutes an attractive method for extensive structure-activity studies in the search for novel ligands of the human melanocortin 4 receptor.
• Arylpropionylpiperazines as antagonists of the human melanocortin-4 receptor
  作者：Wanlong Jiang、Fabio C. Tucci、Caroline W. Chen、Melissa Arellano、Joe A. Tran、Nicole S. White、Dragan Marinkovic、Joseph Pontillo、Beth A. Fleck、Jenny Wen、John Saunders、Ajay Madan、Alan C. Foster、Chen Chen

  DOI：10.1016/j.bmcl.2006.05.088

  日期：2006.9

  A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability. (c) 2006 Elsevier Ltd. All rights reserved.