2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride | 754193-45-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride
• 英文别名: 2-(3-Cyano-4-fluorophenyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride
• CAS: 754193-45-8
• 化学式: C₁₂H₄ClF₄N₃O
• 分子量: 317.63
• InChiKey: BCAUPVLKEIGTFB-UHFFFAOYSA-N

物化性质

• 沸点：
  380.4±42.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  58.7
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride 在 四(三苯基膦)钯 、 sodium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 2-(3-Cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (3-fluoro-2'-formyl-biphenyl-4-yl)-amide
  参考文献：
  名称：

  Aminobenzisoxazoles with biaryl P4 moieties as potent, selective, and orally bioavailable factor Xa inhibitors

  摘要：

  We have previously reported on a series of aminobenzisoxazoles as potent, selective, and orally bioavailable factor Xa inhibitors. which culminated in the discovery of razaxaban. Herein, we describe another approach to improve factor Xa inhibitory potency and pharmacokinetic profile by incorporating basic and water soluble functionalities on the terminal ring of the P4 biaryl group found ill our earlier Xa inhibitors. This approach resulted in a series of potent, selective, and orally bioavailable factor Xa inhibitors. (C) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.01.010
• 作为产物：
  描述：

  5-氨基-2-氟苯腈 在 盐酸 、 ruthenium trichloride 、 sodium periodate 、 草酰氯 、 N,N-二甲基甲酰胺 、 sodium nitrite 作用下， 以 四氯化碳 、 二氯甲烷 、 乙腈 为溶剂， 反应 37.5h， 生成 2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride
  参考文献：
  名称：

  Discovery of 1-(3‘-Aminobenzisoxazol-5‘-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2‘-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide Hydrochloride (Razaxaban), a Highly Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor

  摘要：

  Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).

  DOI：

  10.1021/jm0497949

文献信息

• Guanidine mimics as factor Xa inhibitors
  申请人：DuPont Pharmaceuticals Company

  公开号：US06339099B1

  公开（公告）日：2002-01-15

  The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula I: or pharmaceutically acceptable salt forms thereof, wherein rings D—E represent guanidine mimics, which are useful as inhibitors of factor Xa.

  本申请描述了含氮杂环化合物及其衍生物的化学式I：或其药用可接受的盐形式，其中环D—E代表胍嘧啶模拟物，这些化合物可作为凝血因子Xa的抑制剂。
• Sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds as factor Xa inhibitors
  申请人：——

  公开号：US20040209863A1

  公开（公告）日：2004-10-21

  The present application describes sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds and derivatives thereof of Formula I: P 4 —P—M—M 4 I or pharmaceutically acceptable salt forms thereof, wherein M is a ring, P is an optional ring, and P 4 and M 4 are as defined below. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.

  本申请描述了含有磺酰胺基和四氢嘧啶基的化合物及其衍生物，其化学式为I：P4-P-M-M4I，或其药学上可接受的盐形式，其中M是环，P是可选环，P4和M4如下定义。本发明的化合物可用作胰蛋白酶样丝氨酸蛋白酶的抑制剂，特别是Xa因子的抑制剂。
• NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS
  申请人：Bristol-Myers Squibb Pharma Company

  公开号：EP0946508B1

  公开（公告）日：2009-09-23
• NOVEL GUANIDINE MIMICS AS FACTOR Xa INHIBITORS
  申请人：Bristol-Myers Squibb Pharma Company

  公开号：EP0991638B1

  公开（公告）日：2005-08-17
• 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.