1-[[(2-硝基苯基)氨基]羰基]-l-丙基-N-甲基-3-(2-萘yl)-N-(苯基甲基)-l-丙氨酰胺 | 180046-99-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 1-[[(2-硝基苯基)氨基]羰基]-l-丙基-N-甲基-3-(2-萘yl)-N-(苯基甲基)-l-丙氨酰胺
• 中文别名: 1-[[(2-(硝基苯基)酰胺基]羰基] -L-脯氨酰基-N-甲基-3-(2-萘基萘)-N-(苯甲基)-L-丙氨酰胺
• 英文名称: SDZ NKT-343
• 英文别名: (2-nitrophenylcarbamoyl)-(S)-prolyl-(S)-3-(2-naphthyl)-alanyl-N-benzyl-N-methylamide；SDZ NKT343；SDZ NKT 343；(2S)-2-N-[(2S)-1-[benzyl(methyl)amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]-1-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide
• CAS: 180046-99-5
• 化学式: C₃₃H₃₃N₅O₅
• mdl: MFCD00949605
• 分子量: 579.656
• InChiKey: PCVSIMQAFWRUEC-JDXGNMNLSA-N

物化性质

• 沸点：
  892.8±65.0 °C(Predicted)
• 密度：
  1.327±0.06 g/cm3(Predicted)
• 溶解度：
  在 DMSO 中溶解度为 100 mM，在乙醇中溶解度为 100 mM

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  43
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.242
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 储存条件：
  -20°C，密闭保存，置于干燥处

制备方法与用途

SDZ NKT 343是一种选择性口服活性的NK1受体拮抗剂，其IC50值为0.62 nM，能够有效对抗人NK1受体。该化合物展现出良好的镇痛活性[1][2]。

反应信息

• 作为反应物：
  描述：

  1-[[(2-硝基苯基)氨基]羰基]-l-丙基-N-甲基-3-(2-萘yl)-N-(苯基甲基)-l-丙氨酰胺 在 吡啶 、 乙醇 、 calcium chloride 、 锌 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 生成 (2S)-1-N-(2-acetamidophenyl)-2-N-[(2S)-1-[benzyl(methyl)amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]pyrrolidine-1,2-dicarboxamide
  参考文献：
  名称：

  2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide (SDZ NKT 343), a Potent Human NK₁ Tachykinin Receptor Antagonist with Good Oral Analgesic Activity in Chronic Pain Models

  摘要：

  A lead compound which had sub-micromolar affinity for the rabbit NK1 receptor but negligible affinity for rat NK1 receptors, 3a, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2-chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified to a phenylthiourea providing that an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO2 phenylthiourea analogues which led directly to the analogous urea, 5f(2-nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide, SDZ NKT 343), a highly potent ligand for the human NK1 receptor (K-i = 0.16 nM). In addition to its high in vitro potency, 5f proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substituent was found to be critical for oral activity in this series. Clinical evaluation of 5f as a novel analgesic agent is currently underway.

  DOI：

  10.1021/jm970499g
• 作为产物：
  描述：

  L-脯氨酸 在 N-甲基吗啉 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 反应 2.58h， 生成 1-[[(2-硝基苯基)氨基]羰基]-l-丙基-N-甲基-3-(2-萘yl)-N-(苯基甲基)-l-丙氨酰胺
  参考文献：
  名称：

  Prashad, Mahavir; Prasad, Kapa; Repic, Oljan, Organic Process Research and Development, 1999, vol. 3, # 6, p. 409 - 415

  摘要：

  DOI：

文献信息

• Methods and compositions for treating vasomotor symptoms
  申请人：UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION

  公开号：US11083726B2

  公开（公告）日：2021-08-10

  The present disclosure is generally directed to compositions and methods for treating or limiting development of vasomotor symptoms in a subject.

  本公开总体上涉及用于治疗或限制受试者血管运动症状发展的组合物和方法。
• Org. Process Res. Dev. 1999, 3, 409-415
  作者：

  DOI：——

  日期：——
• METHODS AND COMPOSITIONS FOR TREATING VASOMOTOR SYMPTOMS
  申请人：UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION

  公开号：US20150272927A1

  公开（公告）日：2015-10-01

  The present disclosure is generally directed to compositions and methods for treating or limiting development of vasomotor symptoms in a subject.
• Methods and Compositions for Treating Vasomotor Symptoms
  申请人：UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION

  公开号：US20170020855A1

  公开（公告）日：2017-01-26

  The present disclosure is generally directed to compositions and methods for treating or limiting development of vasomotor symptoms in a subject.
• 2-Nitrophenylcarbamoyl-(<i>S</i>)-prolyl-(<i>S</i>)-3-(2-naphthyl)alanyl-<i>N</i>-benzyl-<i>N</i>- methylamide (SDZ NKT 343), a Potent Human NK₁ Tachykinin Receptor Antagonist with Good Oral Analgesic Activity in Chronic Pain Models
  作者：C. Walpole、S. Y. Ko、M. Brown、D. Beattie、E. Campbell、F. Dickenson、S. Ewan、G. A. Hughes、M. Lemaire、J. Lerpiniere、S. Patel、L. Urban

  DOI：10.1021/jm970499g

  日期：1998.8.1

  A lead compound which had sub-micromolar affinity for the rabbit NK1 receptor but negligible affinity for rat NK1 receptors, 3a, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2-chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified to a phenylthiourea providing that an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO2 phenylthiourea analogues which led directly to the analogous urea, 5f(2-nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide, SDZ NKT 343), a highly potent ligand for the human NK1 receptor (K-i = 0.16 nM). In addition to its high in vitro potency, 5f proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substituent was found to be critical for oral activity in this series. Clinical evaluation of 5f as a novel analgesic agent is currently underway.