3-cyano-4-hydroxybenzoic acid hydrazide | 219685-69-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-cyano-4-hydroxybenzoic acid hydrazide
• 英文别名: 3-cyano-4-hydroxybenzohydrazide
• CAS: 219685-69-5
• 化学式: C₈H₇N₃O₂
• 分子量: 177.162
• InChiKey: QPLVXBAFXHZXEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  99.1
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-cyano-4-hydroxybenzoic acid hydrazide 、 在 溶剂黄146 作用下， 以 二甲基亚砜 为溶剂， 生成 N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-(4-trifluoromethylphenyl)propionamide
  参考文献：
  名称：

  Optimization of Alkylidene Hydrazide Based Human Glucagon Receptor Antagonists. Discovery of the Highly Potent and Orally Available 3-Cyano-4-hydroxybenzoic Acid [1-(2,3,5,6-Tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide

  摘要：

  Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-eyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylenelhydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, K-B = 760 pM) and of the isolated rat receptor IC50 = 430 pM, K-B = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K-i = 14 nM). This compound was orally available in dogs (F-po = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.

  DOI：

  10.1021/jm0208572
• 作为产物：
  描述：

  tert-butoxycarbonyl (3-cyano-4-hydroxy)benzoic acid hydrazide 在 三氟乙酸 作用下， 生成 3-cyano-4-hydroxybenzoic acid hydrazide
  参考文献：
  名称：

  Human glucagon receptor antagonists based on alkylidene hydrazides

  摘要：

  A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxy-methylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(01)00819-8

文献信息

• Glucagon antagonists/inverse agonists
  申请人：Novo Nordisk A/S

  公开号：US06613942B1

  公开（公告）日：2003-09-02

  Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof are disclosed. The compounds act to antagonize the action of the glucagon peptide hormone.

  本发明公开了包含中央腙基结构的非肽化合物及其合成方法。这些化合物具有拮抗胰高血糖素肽激素作用的作用。
• [EN] GLUCAGON ANTAGONISTS/INVERSE AGONISTS<br/>[FR] ANTAGONISTES/AGONISTES INVERSES DU GLUCAGON
  申请人：NOVO NORDISK AS

  公开号：WO1999001423A1

  公开（公告）日：1999-01-14

  Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof. The compounds act to antagonize the action of the glucagon peptide hormone.

  非肽化合物包含一个中心肼基结构，并且其合成方法。这些化合物作用是拮抗胰高血糖素肽激素的作用。
• [EN] GLUCAGON ANTAGONISTS/INVERSE AGONISTS<br/>[FR] ANTAGONISTES DE GLUCAGON/AGONISTES INVERSES
  申请人：NOVO NORDISK AS

  公开号：WO2000039088A1

  公开（公告）日：2000-07-06

  Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof. The compounds act to antagonize the action of the glucagon peptide hormone.

  非肽类化合物包括中心腙基团和其合成方法。这些化合物的作用是拮抗葡萄糖肽激素的作用。
• Human glucagon receptor antagonists based on alkylidene hydrazides
  作者：Anthony Ling、Michael Plewe、Javier Gonzalez、Peter Madsen、Christian K. Sams、Jesper Lau、Vlad Gregor、Doug Murphy、Kimberly Teston、Atsuo Kuki、Shenghua Shi、Larry Truesdale、Dan Kiel、John May、James Lakis、Kenna Anderes、Eugenia Iatsimirskaia、Ulla G. Sidelmann、Lotte B. Knudsen、Christian L. Brand、Alex Polinsky

  DOI：10.1016/s0960-894x(01)00819-8

  日期：2002.2

  A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxy-methylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats. (C) 2002 Elsevier Science Ltd. All rights reserved.
• GLUCAGON ANTAGONISTS/INVERSE AGONISTS
  申请人：NOVO NORDISK A/S

  公开号：EP0994848A1

  公开（公告）日：2000-04-26