(3S,4S)-1-tert-Butyl 3-methyl 4-aminopyrrolidine-1,3-dicarboxylate

• 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: (3S,4S)-1-tert-Butyl 3-methyl 4-aminopyrrolidine-1,3-dicarboxylate
• 英文别名: 1-O-tert-butyl 3-O-methyl (3S,4S)-4-aminopyrrolidine-1,3-dicarboxylate
• 化学式: C₁₁H₂₀N₂O₄
• 分子量: 244.291
• InChiKey: MOKVJORVJPSZHK-JGVFFNPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  81.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoic acid 、 (3S,4S)-1-tert-Butyl 3-methyl 4-aminopyrrolidine-1,3-dicarboxylate 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 生成
  参考文献：
  名称：

  TNF-α转换酶（TACE）的强效，选择性极强，口服生物利用度较高的抑制剂：新型2取代的1H-苯并[d]咪唑--1-基）甲基）苯甲酰胺P1'取代基。

  摘要：

  发现新型（（2-取代的-1H-苯并[d]咪唑-1-基）甲基）苯甲酰胺是出色的P1'取代基，结合独特的受约束的β-氨基异羟肟酸支架，可发现有效的TNF选择性抑制剂-alpha转换酶（TACE）。优化的实例证明了对TACE的有效作用，对多种MMP和ADAM蛋白酶具有极高的选择性，对抑制人全血中LPS诱导的TNF-α具有有效作用，并且具有口服生物利用度。

  DOI：

  10.1016/j.bmcl.2008.01.075
• 作为产物：
  描述：

  1-O-tert-butyl 3-O-methyl (3S,4S)-4-(phenylmethoxycarbonylamino)pyrrolidine-1,3-dicarboxylate 在 palladium dihydroxide 氢气 作用下， 以 甲醇 为溶剂， 生成 (3S,4S)-1-tert-Butyl 3-methyl 4-aminopyrrolidine-1,3-dicarboxylate
  参考文献：
  名称：

  α,β-Cyclic-β-benzamido hydroxamic acids: Novel templates for the design, synthesis, and evaluation of selective inhibitors of TNF-α converting enzyme (TACE)

  摘要：

  Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.11.059

文献信息

• Triazolone and triazolethione derivatives as inhibitors of matrix metalloproteinases and/or TNF-alpha converting enzyme
  申请人：——

  公开号：US20040116491A1

  公开（公告）日：2004-06-17

  The present application describes novel hydantoin derivatives of formula (I): 1 or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, L, and R 11 are defined in the present specification, which are useful as inhibitors of matrix metalloproteinases (MMP), TNF-&agr; converting enzyme (TACE), aggrecanase, or a combination thereof.

  本申请描述了式 (I) 的新型海因衍生物： 1 或其药学上可接受的盐或原药形式，其中 A、L 和 R 11 可用作基质金属蛋白酶 (MMP)、TNF-&agr; 转换酶 (TACE)、凝集素酶或其组合的抑制剂。
• Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-α converting enzyme (TACE): Discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1′ substituents
  作者：Zhonghui Lu、Gregory R. Ott、Rajan Anand、Rui-Qin Liu、Maryanne B. Covington、Krishna Vaddi、Mingxin Qian、Robert C. Newton、David D. Christ、James Trzaskos、James J.-W. Duan

  DOI：10.1016/j.bmcl.2008.01.120

  日期：2008.3

  Potent and selective inhibitors of tumor necrosis factor-a converting enzyme ( TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC50 value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F% > 90%) in rat n-in-1 PK studies. (C) 2008 Elsevier Ltd. All rights reserved.
• US7074810B2
  申请人：——

  公开号：US7074810B2

  公开（公告）日：2006-07-11
• Potent, exceptionally selective, orally bioavailable inhibitors of TNF-α Converting Enzyme (TACE): Novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1′ substituents
  作者：Gregory R. Ott、Naoyuki Asakawa、Zhonghui Lu、Rajan Anand、Rui-Qin Liu、Maryanne B. Covington、Krishna Vaddi、Mingxin Qian、Robert C. Newton、David D. Christ、James M. Trzaskos、James J.-W. Duan

  DOI：10.1016/j.bmcl.2008.01.075

  日期：2008.3

  Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression

  发现新型（（2-取代的-1H-苯并[d]咪唑-1-基）甲基）苯甲酰胺是出色的P1'取代基，结合独特的受约束的β-氨基异羟肟酸支架，可发现有效的TNF选择性抑制剂-alpha转换酶（TACE）。优化的实例证明了对TACE的有效作用，对多种MMP和ADAM蛋白酶具有极高的选择性，对抑制人全血中LPS诱导的TNF-α具有有效作用，并且具有口服生物利用度。
• α,β-Cyclic-β-benzamido hydroxamic acids: Novel templates for the design, synthesis, and evaluation of selective inhibitors of TNF-α converting enzyme (TACE)
  作者：Gregory R. Ott、Naoyuki Asakawa、Zhonghui Lu、Rui-Qin Liu、Maryanne B. Covington、Krishna Vaddi、Mingxin Qian、Robert C. Newton、David D. Christ、James M. Traskos、Carl P. Decicco、James J.-W. Duan

  DOI：10.1016/j.bmcl.2007.11.059

  日期：2008.1

  Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability. (c) 2007 Elsevier Ltd. All rights reserved.