4-{2-fluoro-6-[(S)-2-methyl-1-((S_S)-2-methyl-propane-2-sulfinylamino)-propyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester | 851484-97-4

• 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)-2-methyl-1-((S_S)-2-methyl-propane-2-sulfinylamino)-propyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester
• 英文别名: 1-{2-[(1S)-1-[(S)-(tert-butylsulfinyl)amino]-2-methylpropyl]-6-fluorophenyl}-4-(tert-butoxycarbonyl)piperazine；tert-butyl 4-[2-[(1S)-1-[[(S)-tert-butylsulfinyl]amino]-2-methylpropyl]-6-fluorophenyl]piperazine-1-carboxylate
• CAS: 851484-97-4
• 化学式: C₂₃H₃₈FN₃O₃S
• 分子量: 455.637
• InChiKey: KRVZEGNTPYTNPP-RQZFFVEVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.7
• 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)-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
• 作为产物：
  描述：

  N-Boc-哌嗪 在 titanium(IV) tetraethanolate 、 potassium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 正戊烷 为溶剂， 反应 65.0h， 生成 4-{2-fluoro-6-[(S)-2-methyl-1-((S_S)-2-methyl-propane-2-sulfinylamino)-propyl]-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

• Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor
  作者：Chen Chen、Wanlong Jiang、Joe A. Tran、Fabio C. Tucci、Beth A. Fleck、Stacy Markison、Jenny Wen、Ajay Madan、Sam R. Hoare、Alan C. Foster、Dragan Marinkovic、Caroline W. Chen、Melissa Arellano、John Saunders

  DOI：10.1016/j.bmcl.2007.10.115

  日期：2008.1

  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 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a K-i of 1.0 nM and an EC50 of 3.8 nM while its 3R,4S-isomer 13b-2 exhibited a K-i of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats. (C) 2007 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.
• Syntheses of tetrahydrothiophenes and tetrahydrofurans and studies of their derivatives as melanocortin-4 receptor ligands
  作者：Joe A. Tran、Caroline W. Chen、Fabio C. Tucci、Wanlong Jiang、Beth A. Fleck、Chen Chen

  DOI：10.1016/j.bmcl.2007.11.128

  日期：2008.2

  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.
• 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.