methyl-1N-(4-methoxyphenylsulfonyl)-4-methylenepyrrolidine-(2R)-carboxylate | 247058-82-8

• 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: methyl-1N-(4-methoxyphenylsulfonyl)-4-methylenepyrrolidine-(2R)-carboxylate
• 英文别名: methyl (2R)-1-(4-methoxyphenyl)sulfonyl-4-methylidenepyrrolidine-2-carboxylate
• CAS: 247058-82-8
• 化学式: C₁₄H₁₇NO₅S
• 分子量: 311.359
• InChiKey: NFWYNGRNIOAAPB-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  81.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl-1N-(4-methoxyphenylsulfonyl)-4-methylenepyrrolidine-(2R)-carboxylate 在 羟胺 作用下， 以 甲醇 为溶剂， 以70%的产率得到(R)-1-(4-Methoxy-benzenesulfonyl)-4-methylene-pyrrolidine-2-carboxylic acid hydroxyamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Matrix Metalloproteinase Inhibitors Derived from a Modified Proline Scaffold

  摘要：

  The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.

  DOI：

  10.1021/jm9904699
• 作为产物：
  描述：

  顺式-4-羟基-D-脯氨酸 在 4-二甲氨基吡啶 、 氯化亚砜 、 jones reagent 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 丙酮 为溶剂， 反应 42.25h， 生成 methyl-1N-(4-methoxyphenylsulfonyl)-4-methylenepyrrolidine-(2R)-carboxylate
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Matrix Metalloproteinase Inhibitors Derived from a Modified Proline Scaffold

  摘要：

  The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.

  DOI：

  10.1021/jm9904699

文献信息

• Substituted pyrrolidine hydroxamate metalloprotease inhibitors
  申请人：The Procter & Gamble Company

  公开号：US06329418B1

  公开（公告）日：2001-12-11

  The invention provides compounds which are potent inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to compounds having a structure according to the following Formula (I): wherein R1, R2, X, Z, m, and n are defined below. to This invention also includes optical isomers, diastereomers and enantiomers of the formula above, and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof. The compounds of the present invention are useful for the treatment of diseases and conditions which are characterized by unwanted metalloprotease activity. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for metalloprotease-related maladies using these compounds or the pharmaceutical compositions containing them.

  本发明提供了一些化合物，它们是金属蛋白酶的有效抑制剂，并且可用于治疗这些酶活性过高引起的疾病。具体而言，本发明涉及具有以下式子(I)结构的化合物：其中R1、R2、X、Z、m和n如下所定义。本发明还包括上述式子的光学异构体、对映异构体和对映体以及其药学上可接受的盐、生物水解酰胺、酯和亚酰胺。本发明的化合物对于治疗由于金属蛋白酶活性过高引起的疾病和症状非常有用。因此，本发明还提供了包含这些化合物的药物组合物。本发明还提供了使用这些化合物或含有它们的药物组合物进行金属蛋白酶相关疾病治疗的方法。
• Design, Synthesis, and Biological Evaluation of Matrix Metalloproteinase Inhibitors Derived from a Modified Proline Scaffold
  作者：Menyan Cheng、Biswanath De、Neil G. Almstead、Stanislaw Pikul、Martin E. Dowty、Charles R. Dietsch、C. Michelle Dunaway、Fei Gu、Lily C. Hsieh、Michael J. Janusz、Yetunde O. Taiwo、Michael G. Natchus、Tomas Hudlicky、Martin Mandel

  DOI：10.1021/jm9904699

  日期：1999.12.1

  The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.