tert-butyl N-(3-(4-methoxyphenyl)-5-methylisoxazole-4-carbonyl)(methylthio)carbonoimidoylcarbamate | 917388-78-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: tert-butyl N-(3-(4-methoxyphenyl)-5-methylisoxazole-4-carbonyl)(methylthio)carbonoimidoylcarbamate
• 英文别名: tert-butyl (NE)-N-[[[3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carbonyl]amino]-methylsulfanylmethylidene]carbamate
• CAS: 917388-78-4
• 化学式: C₁₉H₂₃N₃O₅S
• 分子量: 405.475
• InChiKey: UDGAJOQJYZBJBB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  128
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl N-(3-(4-methoxyphenyl)-5-methylisoxazole-4-carbonyl)(methylthio)carbonoimidoylcarbamate 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 N-(amino(3,5-dichloro-4-(cyclopropanecarboxamido)-benzylamino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-4-carboxamide
  参考文献：
  名称：

  Acyl Guanidine Inhibitors of β-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis

  摘要：

  This report describes the discovery and optimizition of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-pi interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma A beta levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain A beta levels were not obtained.

  DOI：

  10.1021/jm300931y
• 作为产物：
  描述：

  二碳酸二叔丁酯 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 9.0h， 生成 tert-butyl N-(3-(4-methoxyphenyl)-5-methylisoxazole-4-carbonyl)(methylthio)carbonoimidoylcarbamate
  参考文献：
  名称：

  Acyl Guanidine Inhibitors of β-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis

  摘要：

  This report describes the discovery and optimizition of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-pi interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma A beta levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain A beta levels were not obtained.

  DOI：

  10.1021/jm300931y

文献信息

• Aminoacetamide acyl guanidines as beta-secretase inhibitors
  申请人：Gerritz Samuel

  公开号：US20060287287A1

  公开（公告）日：2006-12-21

  There is provided a series of substituted acyl guanidines of Formula (Ik) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 25 , R 26 and R 27 as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of Aβ-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.

  提供了一系列的取代酰基胍类化合物，符合以下化学式（Ik）或其立体异构体；或其药学上可接受的盐，其中R2、R3、R4、R5、R25、R26和R27如本文所定义，它们的药物组合物和使用方法。这些化合物抑制β-分泌酶对淀粉样前体蛋白（APP）的加工，更具体地说，抑制Aβ肽的产生。本公开涉及对β-淀粉样蛋白产生相关的神经疾病的治疗有用的化合物，如阿尔茨海默氏病和其他受抗淀粉样活性影响的病症。
• Acyl guanidines as beta-secretase inhibitors
  申请人：Gerritz Samuel

  公开号：US20070015754A1

  公开（公告）日：2007-01-18

  There is provided a series of substituted acyl guanidines of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 and R 5 as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of Aβ-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.

  提供了一系列的取代酰基鸟氨酸化合物（I）或其立体异构体；或其药学上可接受的盐，其中R1、R2、R3、R4和R5如本文所定义，以及它们的药物组合物和使用方法。这些化合物抑制β-分泌酶对淀粉样前体蛋白（APP）的加工，更具体地抑制Aβ-肽的产生。本公开涉及用于治疗与β-淀粉样蛋白产生有关的神经系统疾病，例如阿尔茨海默病和其他受抗淀粉样蛋白活性影响的疾病的化合物。
• US7273882B2
  申请人：——

  公开号：US7273882B2

  公开（公告）日：2007-09-25
• US7612069B2
  申请人：——

  公开号：US7612069B2

  公开（公告）日：2009-11-03
• [EN] ACYL GUANIDINES AS BETA-SECRETASE INHIBITORS<br/>[FR] ACYLGUANIDINES EN TANT QU'INHIBITEUR DE BETA-SECRETASE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2007002214A2

  公开（公告）日：2007-01-04

  [EN] There is provided a series of substituted acyl guanidines of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R₁, R₂. R₃, R₄ and R₅ as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by Beta-secretase and, more specifically, inhibit the production of ABeta-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to Beta-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.
  [FR] L'invention concerne une série de guanidines à substitution acyle représentées par la formule (I) ou un de leurs stéréoisomères ou un de leurs sels acceptables sur le plan pharmaceutique, dans laquelle R₁, R₂. R₃, R₄ et R₅ correspondent à leur définition dans le descriptif, leurs compositions pharmaceutiques et méthodes d'utilisation. Ces composés inhibent l'effet exercé sur la protéine précurseur d'amyloïde (APP) par béta-sécrétase et, de façon plus spécifique, inhibent la production du Abéta-peptide. L'invention concerne des composés utiles pour le traitement de troubles neurologiques relatifs à la production des béta-amyloïdes, tels que la maladie d'Alzheimer ou d'autres états associés à l'activité anti-amyloïde.