(R)-3-(2,4-dichlorophenyl)-2-methylpropanoic acid | 521098-39-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (R)-3-(2,4-dichlorophenyl)-2-methylpropanoic acid
• 英文别名: (2R)-methyl-3-(2,4-dichlorophenyl)propionic acid；(R)-3-(2,4-dichlorophenyl)-2-methylpropionic acid；(2R)-3-(2,4-dichlorophenyl)-2-methylpropanoic acid
• CAS: 521098-39-5
• 化学式: C₁₀H₁₀Cl₂O₂
• 分子量: 233.094
• InChiKey: WHLRMUPIJBFDSX-ZCFIWIBFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (R)-3-(2,4-dichlorophenyl)-2-methylpropanoic acid 在 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Pharmacological and pharmacokinetic characterization of 2-piperazine-α-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2008.03.072
• 作为产物：
  描述：

  2,4-二氯苄醇 在 Amberlyst 、 sodium iodide 作用下， 生成 (R)-3-(2,4-dichlorophenyl)-2-methylpropanoic acid
  参考文献：
  名称：

  新型聚合物支持的Evans型恶唑烷酮的设计与合成：固相不对称烷基化反应中的有效手性助剂

  摘要：

  Wang树脂支撑的Evans手性助剂（23）是基于一种新颖的聚合物固定策略设计的，该策略利用了恶唑烷酮环的5位，并开发了适用于一天之内多克制备的新合成路线。23衍生的N上的固相Evans不对称烷基化-酰酰亚胺树脂和随后的氢过氧化物锂介导的化学选择性水解，可提供所需的高立体选择性（最高97％ee）和中等至良好的总收率（3步最高可达70％）的相应α-支链羧酸。与传统的固溶相方法相比。此外，在不降低产物的立体选择性的情况下，成功地实现了聚合物负载的手性助剂的回收和再循环。因此，这是在固体载体上有效地进行固相埃文斯不对称烯醇烷基化的第一个成功实例，并且得出的结论是，通过恶唑烷酮环的5-位与固体载体的连接是固相埃文斯手性助剂的理想策略。

  DOI：

  10.1016/j.tet.2005.01.135

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
• A new series of potent benzodiazepine γ-secretase inhibitors
  作者：Ian Churcher、Kate Ashton、John W. Butcher、Earl E. Clarke、Timothy Harrison、Huw D. Lewis、Andrew P. Owens、Martin R. Teall、Susie Williams、Jonathan D.J. Wrigley

  DOI：10.1016/s0960-894x(02)00909-5

  日期：2003.1

  A new series of benzodiazepine-containing gamma-secretase inhibitors with potential use in the treatment of Alzheimer's disease is disclosed. Structure-activity relationships of the pendant hydrocinnamate side-chain which led to the preparation of highly potent inhibitors are described. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Design and synthesis of a new polymer-supported Evans-type oxazolidinone: an efficient chiral auxiliary in the solid-phase asymmetric alkylation reactions
  作者：Tomoya Kotake、Yoshio Hayashi、S. Rajesh、Yoshie Mukai、Yuka Takiguchi、Tooru Kimura、Yoshiaki Kiso

  DOI：10.1016/j.tet.2005.01.135

  日期：2005.4

  ee) and moderate to good overall yield (up to 70%, for 3 steps), which were comparable to those of the conventional solution-phase methods. Furthermore, recovery and recycling of the polymer-supported chiral auxiliary were successfully achieved without decreasing the stereoselectivity of the product. Therefore, this is the first successful example that the solid-phase Evans' asymmetric enolate-alkylation

  Wang树脂支撑的Evans手性助剂（23）是基于一种新颖的聚合物固定策略设计的，该策略利用了恶唑烷酮环的5位，并开发了适用于一天之内多克制备的新合成路线。23衍生的N上的固相Evans不对称烷基化-酰酰亚胺树脂和随后的氢过氧化物锂介导的化学选择性水解，可提供所需的高立体选择性（最高97％ee）和中等至良好的总收率（3步最高可达70％）的相应α-支链羧酸。与传统的固溶相方法相比。此外，在不降低产物的立体选择性的情况下，成功地实现了聚合物负载的手性助剂的回收和再循环。因此，这是在固体载体上有效地进行固相埃文斯不对称烯醇烷基化的第一个成功实例，并且得出的结论是，通过恶唑烷酮环的5-位与固体载体的连接是固相埃文斯手性助剂的理想策略。
• 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.