ethyl 1-(isoquinolyn-7'-yl)-3-methyl-5-pyrazole carboxylate | 218301-10-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: ethyl 1-(isoquinolyn-7'-yl)-3-methyl-5-pyrazole carboxylate
• 英文别名: ethyl 1-(isoquinolin-7'-yl)-3-methyl-5-pyrazole carboxylate；Ethyl 1-(isoquinolin-7-yl)-3-methyl-1H-pyrazole-5-carboxylate；ethyl 2-isoquinolin-7-yl-5-methylpyrazole-3-carboxylate
• CAS: 218301-10-1
• 化学式: C₁₆H₁₅N₃O₂
• 分子量: 281.314
• InChiKey: LKNJAKNQJPGQBA-UHFFFAOYSA-N

物化性质

• 沸点：
  465.4±30.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  57
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 1-(isoquinolyn-7'-yl)-3-methyl-5-pyrazole carboxylate 在 三甲基铝 、 三氟乙酸 作用下， 以 正己烷 、 二氯甲烷 为溶剂， 反应 15.5h， 生成 1-(isoquinol-7'-yl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carbonylamino]pyrazole
  参考文献：
  名称：

  Structure-Based Design of Novel Guanidine/Benzamidine Mimics:  Potent and Orally Bioavailable Factor Xa Inhibitors as Novel Anticoagulants

  摘要：

  As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K-i of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.

  DOI：

  10.1021/jm020578e
• 作为产物：
  描述：

  7-氨基异喹啉 在 盐酸 、 溶剂黄146 、 sodium nitrite 作用下， 反应 15.5h， 生成 ethyl 1-(isoquinolyn-7'-yl)-3-methyl-5-pyrazole carboxylate
  参考文献：
  名称：

  Structure-Based Design of Novel Guanidine/Benzamidine Mimics:  Potent and Orally Bioavailable Factor Xa Inhibitors as Novel Anticoagulants

  摘要：

  As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K-i of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.

  DOI：

  10.1021/jm020578e

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。
• 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
• Structure-Based Design of Novel Guanidine/Benzamidine Mimics:  Potent and Orally Bioavailable Factor Xa Inhibitors as Novel Anticoagulants
  作者：Patrick Y. S. Lam、Charles G. Clark、Renhua Li、Donald J. P. Pinto、Michael J. Orwat、Robert A. Galemmo、John M. Fevig、Christopher A. Teleha、Richard S. Alexander、Angela M. Smallwood、Karen A. Rossi、Matthew R. Wright、Stephen A. Bai、Kan He、Joseph M. Luettgen、Pancras C. Wong、Robert M. Knabb、Ruth R. Wexler

  DOI：10.1021/jm020578e

  日期：2003.10.1

  As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K-i of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.