(R)-N-4'-(((3''-fluoro)phenoxy)methyl)benzyl 2-N-(tert-butoxycarbonyl)amino-3-hydroxypropionamide | 1226776-09-5

• 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
• 英文名称: (R)-N-4'-(((3''-fluoro)phenoxy)methyl)benzyl 2-N-(tert-butoxycarbonyl)amino-3-hydroxypropionamide
• 英文别名: (R)-N-(4-(3-fluorophenoxymethyl)benzyl)-2-t-butoxycarbonylamino-3-hydroxypropionamide；tert-butyl N-[(2R)-1-[[4-[(3-fluorophenoxy)methyl]phenyl]methylamino]-3-hydroxy-1-oxopropan-2-yl]carbamate
• CAS: 1226776-09-5
• 化学式: C₂₂H₂₇FN₂O₅
• 分子量: 418.465
• InChiKey: NVGMWUQCCYYQSZ-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  30
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  96.9
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-N-4'-(((3''-fluoro)phenoxy)methyl)benzyl 2-N-(tert-butoxycarbonyl)amino-3-hydroxypropionamide 在 三氟乙酸 、 silver(l) oxide 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 97.0h， 生成 (R)-N-(4-(3-fluorophenoxymethyl)benzyl)-2-amino-3-methoxypropionamide
  参考文献：
  名称：

  Primary Amino Acid Derivatives: Substitution of the 4′-N′-Benzylamide Site in (R)-N′-Benzyl 2-Amino-3-methylbutanamide, (R)-N′-Benzyl 2-Amino-3,3-dimethylbutanamide, and (R)-N′-Benzyl 2-Amino-3-methoxypropionamide Provides Potent Anticonvulsants with Pain-Attenuating Properties

  摘要：

  Recently, we reported that select N'-benzyl 2-substituted 2-amino acetamides (primary amino acid derivatives (PAADs)) exhibited pronounced activities in established whole animal anticonvulsant (i.e., maximal electroshock seizure (MES)) and neuropathic pain (i.e., formalin) models. The anticonvulsant activities of C(2)-hydrocarbon N'-benzyl 2-amino acetamides (MES ED50 = 13-21 mg/kg) exceeded those of phenobarbital (ED50 = 22 mg/kg). Two additional studies defining the structure activity relationship of PAADs are presented in this issue of the journal. In this study, we demonstrated that the anticonvulsant activities of (R)-N'-benzyl 2-amino-3-methylbutanamide and (R)-N'-benzyl 2-amino-3,3-dimethyl-butanamide were sensitive to substituents at the 4'-N'-benzylamide site; electron-withdrawing groups retained activity, electron-donating groups led to a loss of activity, and incorporating either a 3-fluorobenzyloxy or 3-fluorophenoxymethyl group using a rationally designed multiple ligand approach improved activity. Additionally, we showed that substituents at the 4'-N'-benzylamide site of (R)-N'-benzyl 2-amino-3-methoxypropionamide also improved anticonvulsant activity, with the 3-fluorophenoxymethyl group providing the largest (similar to 4-fold) increase in activity (ED50 = 8.9 mg/kg), a value that surpassed phenytoin (ED50 = 9.5 mg/kg). Collectively, the pharmacological findings provided new information that C(2)-hydrocarbon PAADs represent a novel class of anticonvulsants.

  DOI：

  10.1021/jm200759t
• 作为产物：
  描述：

  4-(((3'-fluoro)phenoxy)methyl)benzylamine 、 7C3Cvm6gpq 以 四氢呋喃 为溶剂， 以5.2 g的产率得到(R)-N-4'-(((3''-fluoro)phenoxy)methyl)benzyl 2-N-(tert-butoxycarbonyl)amino-3-hydroxypropionamide
  参考文献：
  名称：

  Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

  摘要：

  Functional amino acids (FAAs) and alpha-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4'-((3 ''-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED50 values of 13, 14, similar to 10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.

  DOI：

  10.1021/jm100185c

文献信息

• Novel N-Benzylamide Substituted Derivatives of 2-(Acylamido)acetic Acid and 2-(Acylamido)propionic Acids: Potent Neurological Agents
  申请人：Kohn Harold L.

  公开号：US20120232015A1

  公开（公告）日：2012-09-13

  A first aspect of the invention is a compound (sometimes also referred to herein as an “active agent” or “active compound”) of Formula Ia, or more particularly Formula Ib, or a pharmaceutically acceptable salt or prodrug thereof. Compositions thereof and methods of using the same (e.g. for the treatment of a neurological disease) are also described.

  本发明的第一个方面是公式Ia的化合物（有时也在此处称为“活性剂”或“活性化合物”）或更具体地为公式Ib的化合物，或其药物可接受的盐或前药。还描述了其组成物和使用方法（例如，用于治疗神经系统疾病）。
• US20140342989A1
  申请人：——

  公开号：US20140342989A1

  公开（公告）日：2014-11-20
• US8829033B2
  申请人：——

  公开号：US8829033B2

  公开（公告）日：2014-09-09
• US8933065B2
  申请人：——

  公开号：US8933065B2

  公开（公告）日：2015-01-13
• [EN] NOVEL N-BENZYLAMIDE SUBSTITUTED DERIVATIVES OF 2-(ACYLAMIDO)ACETIC ACID AND 2-(ACYLAMIDO)PROPIONIC ACIDS: POTENT NEUROLOGICAL AGENTS<br/>[FR] NOUVEAUX DÉRIVÉS À SUBSTITUTION N-BENZYLAMIDE D'ACIDE 2-(ACYLAMIDO)ACÉTIQUE ET D'ACIDES 2-(ACYLAMIDO)PROPIONIQUES : AGENTS NEUROLOGIQUES PUISSANTS
  申请人：UNIV NORTH CAROLINA

  公开号：WO2011037833A2

  公开（公告）日：2011-03-31

  A first aspect of the invention is a compound (sometimes also referred to herein as an "active agent" or "active compound") of Formula Ia, or more particularly Formula Ib, or a pharmaceutically acceptable salt or prodrug thereof. Compositions thereof and methods of using the same (e.g. for the treatment of a neurological disease) are also described.