2-[(4-chloro-1-oxo-2H-isoquinolin-7-yl)amino]-2-(3,4-dimethoxyphenyl)acetic acid | 1036390-34-7

• 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: 2-[(4-chloro-1-oxo-2H-isoquinolin-7-yl)amino]-2-(3,4-dimethoxyphenyl)acetic acid
• CAS: 1036390-34-7
• 化学式: C₁₉H₁₇ClN₂O₅
• 分子量: 388.807
• InChiKey: VRGCPELMMCQAJE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  96.9
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-[(4-chloro-1-oxo-2H-isoquinolin-7-yl)amino]-2-(3,4-dimethoxyphenyl)acetic acid 、 methyl N-(4-propan-2-ylsulfonyl-3-pyrrolidin-2-ylphenyl)carbamate 在 N-羟基-7-氮杂苯并三氮唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 methyl 3-(1-(2-(4-chloro-1-oxo-1,2-dihydroisoquinolin-7-ylamino)-2-(3,4-dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate
  参考文献：
  名称：

  Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors

  摘要：

  Inhibitors of Factor Vila (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the Si binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the Si pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this PI binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

  DOI：

  10.1021/acsmedchemlett.6b00282
• 作为产物：
  描述：

  2-甲基-5-硝基苯甲酰氯 在 N-氯代丁二酰亚胺 、 tin(II) chloride dihdyrate 、 氯化铵 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 6.67h， 生成 2-[(4-chloro-1-oxo-2H-isoquinolin-7-yl)amino]-2-(3,4-dimethoxyphenyl)acetic acid
  参考文献：
  名称：

  Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors

  摘要：

  Inhibitors of Factor Vila (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the Si binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the Si pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this PI binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

  DOI：

  10.1021/acsmedchemlett.6b00282

文献信息

• BICYCLIC LACTAM FACTOR VIIA INHIBITORS USEFUL AS ANTICOAGULANTS
  申请人：Wurtz Nicholas Ronald

  公开号：US20100041664A1

  公开（公告）日：2010-02-18

  The present invention provides novel bicyclic lactams derivatives, and analogues thereof, of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the variables A, B, C, W, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 8 , and R 9 are as defined herein. These compounds are selective inhibitors of factor VIIa which can be used as medicaments.

  本发明提供了新型双环内酰胺衍生物及其类似物，其化学式为(I)：或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。其中，变量A、B、C、W、Y、Z1、Z2、Z3、Z4、R8和R9的定义如本文所述。这些化合物是选择性因子VIIa抑制剂，可用作药物。
• US8039506B2
  申请人：——

  公开号：US8039506B2

  公开（公告）日：2011-10-18
• [EN] BICYCLIC LACTAM FACTOR VIIA INHIBITORS USEFUL AS ANTICOAGULANTS<br/>[FR] INHIBITEURS AU LACTAME BICYCLIQUE DU FACTEUR VIIA UTILES EN TANT QU'ANTICOAGULANTS
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2008079759A1

  公开（公告）日：2008-07-03

  [EN] The present invention provides novel bicyclic lactams derivatives, and analogues thereof, of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the variables A, B, C, W, Y, Z¹, Z², Z³, Z⁴, R⁸, and R⁹ are as defined herein. These compounds are selective inhibitors of factor VIIa which can be used as medicaments.
  [FR] La présente invention concerne de nouveaux dérivés de lactames bicycliques ainsi que les analogues de ces derniers qui sont représentés par la formule (I) ou encore un stéréoisomère, un tautomère, un sel, un solvate ou un précurseur de médicament pharmaceutiquement acceptable correspondant, dans lequel les variables A, B, C, W, Y, Z¹, Z², Z³, Z⁴, R⁸ et R⁹ sont telles que définies dans le descriptif. Ces composés sont des inhibiteurs sélectifs du facteur VIIa qui peuvent être utilisés en tant que médicaments.
• Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors
  作者：Nicholas R. Wurtz、Brandon L. Parkhurst、Wen Jiang、Indawati DeLucca、Xiaojun Zhang、Vladimir Ladziata、Daniel L. Cheney、Jeffrey R. Bozarth、Alan R. Rendina、Anzhi Wei、Joseph M. Luettgen、Yiming Wu、Pancras C. Wong、Dietmar A. Seiffert、Ruth R. Wexler、E. Scott Priestley

  DOI：10.1021/acsmedchemlett.6b00282

  日期：2016.12.8

  Inhibitors of Factor Vila (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the Si binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the Si pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this PI binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.