1-[[1-(3-Amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]-2,3-dihydro-5-[2-(methylsulfonyl)phenyl]-1H-indole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-[[1-(3-Amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]-2,3-dihydro-5-[2-(methylsulfonyl)phenyl]-1H-indole
• 英文别名: (1-(3-aminobenzo[d]isoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)(5-(2-(methylsulfonyl)phenyl)indolin-1-yl)methanone；[2-(3-amino-1,2-benzoxazol-5-yl)-5-(trifluoromethyl)pyrazol-3-yl]-[5-(2-methylsulfonylphenyl)-2,3-dihydroindol-1-yl]methanone
• 化学式: C₂₇H₂₀F₃N₅O₄S
• 分子量: 567.548
• InChiKey: CFZKVSJVCMVNIK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  133
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 生成 1-[[1-(3-Amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]-2,3-dihydro-5-[2-(methylsulfonyl)phenyl]-1H-indole
  参考文献：
  名称：

  Design, structure–activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors

  摘要：

  A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were pro. led in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.09.091

文献信息

• Nitrogen containing heterobicycles as factor Xa inhibitors
  申请人：——

  公开号：US20030096820A1

  公开（公告）日：2003-05-22

  This invention relates generally to nitrogen containing heterobicycles of formulas A and B: 1 which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

  本发明涉及公式A和B的含氮杂双环化合物，其是胰蛋白酶样丝氨酸蛋白酶酶的抑制剂，特别是因子Xa，包含其的制药组合物，以及将其用作抗凝剂治疗和预防血栓栓塞性疾病的方法。
• NITROGEN CONTAINING HETEROBICYCLES AS FACTOR XA INHIBITORS
  申请人：Bristol-Myers Squibb Pharma Company

  公开号：EP1196412B1

  公开（公告）日：2004-06-09
• US6429205B1
  申请人：——

  公开号：US6429205B1

  公开（公告）日：2002-08-06
• US6716841B2
  申请人：——

  公开号：US6716841B2

  公开（公告）日：2004-04-06
• Design, structure–activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors
  作者：Jeffrey G. Varnes、Dean A. Wacker、Irina C. Jacobson、Mimi L. Quan、Christopher D. Ellis、Karen A. Rossi、Ming Y. He、Joseph M. Luettgen、Robert M. Knabb、Steven Bai、Kan He、Patrick Y.S. Lam、Ruth R. Wexler

  DOI：10.1016/j.bmcl.2007.09.091

  日期：2007.12

  A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were pro. led in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban. (c) 2007 Elsevier Ltd. All rights reserved.