N-hydroxy-2-{1-isopropyl-3-[({4-{(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinyl}acetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-hydroxy-2-{1-isopropyl-3-[({4-{(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinyl}acetamide
• 英文别名: N-Hydroxy-2-{1-isopropyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylmethyl]-pyrrolidin-3-yl}-acetamide；N-hydroxy-2-[3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylmethyl]-1-propan-2-ylpyrrolidin-3-yl]acetamide
• 化学式: C₂₇H₃₃N₃O₅S
• 分子量: 511.642
• InChiKey: AENHIDVKFOYIJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  tert-butyl 3-(2-methoxy-2-oxoethylidene)pyrrolidine-1-carboxylate 在 N-甲基吗啉 、 Oxone 、 sodium tetrahydroborate 、 盐酸羟胺 、 三乙酰氧基硼氢化钠 、 sodium hydride 、 二异丁基氢化铝 、 potassium carbonate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 臭氧 、 丙酸 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-hydroxy-2-{1-isopropyl-3-[({4-{(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)methyl]-3-pyrrolidinyl}acetamide
  参考文献：
  名称：

  Synthesis and structure–activity relationship of a novel sulfone series of TNF-α converting enzyme inhibitors

  摘要：

  Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl}-5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy(4S,5S)-1-methyl-5-1[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl -4-pyrrolidinecarboxamide) exhibited IC50 values of <1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP- 1, -2, -9 and - 13 and was orally bioavailable with an F value of 46% in mice. (C) 2004 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2004.06.049

文献信息

• 1,1-Disubstituted cyclic inhibitors of matrix metalloproteases and TNF-alpha
  申请人：——

  公开号：US20020137734A1

  公开（公告）日：2002-09-26

  The present application describes novel 1,1-disubsituted cyclic derivatives of formula I: 1 or pharmaceutically acceptable salt forms thereof, wherein ring B is a 3-8 membered non-aromatic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and from 0-2 ring heteroatoms selected from O, N, NR 2 , S, S(O), and S(O) 2 and the other variables are defined in the present specification, which are useful as metalloprotease and as TNF-&agr; inhibitors.

  本申请描述了新型的1,1-二取代环状衍生物的公式I：1或其药学上可接受的盐形式，其中环B是由碳原子、0-1个羰基基团、0-1个双键和0-2个从O、N、NR2、S、S（O）和S（O）2中选择的环异原子组成的3-8环非芳香环，其他变量在本说明书中定义，这些衍生物可用作金属蛋白酶和TNF-α抑制剂。
• US6825215B2
  申请人：——

  公开号：US6825215B2

  公开（公告）日：2004-11-30
• Synthesis and structure–activity relationship of a novel sulfone series of TNF-α converting enzyme inhibitors
  作者：Chu-Biao Xue、Xiao-Tao Chen、Xiaohua He、John Roderick、Ronald L. Corbett、Bahman Ghavimi、Rui-Qin Liu、Maryanne B. Covington、Mingxin Qian、Maria D. Ribadeneira、Krishna Vaddi、James Trzaskos、Robert C. Newton、James J.-W. Duan、Carl P. Decicco

  DOI：10.1016/j.bmcl.2004.06.049

  日期：2004.9

  Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl}-5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy(4S,5S)-1-methyl-5-1[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl -4-pyrrolidinecarboxamide) exhibited IC50 values of <1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP- 1, -2, -9 and - 13 and was orally bioavailable with an F value of 46% in mice. (C) 2004 Published by Elsevier Ltd.