2-(tert-butoxycarbonylamino)-4-[(N-diethylphosphonomethyl)carbamoyl]thiazole | 261373-12-0

• 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-(tert-butoxycarbonylamino)-4-[(N-diethylphosphonomethyl)carbamoyl]thiazole
• 英文别名: tert-butyl N-[4-(diethoxyphosphorylmethylcarbamoyl)-1,3-thiazol-2-yl]carbamate
• CAS: 261373-12-0
• 化学式: C₁₄H₂₄N₃O₆PS
• 分子量: 393.401
• InChiKey: IQBDQOCOFDDGRU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  25
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  144
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-(tert-butoxycarbonylamino)-4-[(N-diethylphosphonomethyl)carbamoyl]thiazole 在 磷酸三甲酯 、 四(三苯基膦)钯 、 溴 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.0h， 生成 2-(tert-butoxycarbonylamino)-4-[(N-diethylphosphonomethyl)carbamoyl]-5-(2-thienyl)thiazole
  参考文献：
  名称：

  Discovery of a Series of Phosphonic Acid-Containing Thiazoles and Orally Bioavailable Diamide Prodrugs That Lower Glucose in Diabetic Animals Through Inhibition of Fructose-1,6-Bisphosphatase

  摘要：

  Oral delivery of previously disclosed purine and benzimidazole fructose-1,6 bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular wright (> 600) Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was Implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%) Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM

  DOI：

  10.1021/jm101035x
• 作为产物：
  描述：

  二乙基氨基甲烷膦酸酯 、 2-BOC-氨基噻唑-4-羧酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以97%的产率得到2-(tert-butoxycarbonylamino)-4-[(N-diethylphosphonomethyl)carbamoyl]thiazole
  参考文献：
  名称：

  Discovery of a Series of Phosphonic Acid-Containing Thiazoles and Orally Bioavailable Diamide Prodrugs That Lower Glucose in Diabetic Animals Through Inhibition of Fructose-1,6-Bisphosphatase

  摘要：

  Oral delivery of previously disclosed purine and benzimidazole fructose-1,6 bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular wright (> 600) Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was Implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%) Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM

  DOI：

  10.1021/jm101035x

文献信息

• Novel bisamidate phosphonate prodrugs
  申请人：METABASIS THERAPEUTICS, INC.

  公开号：US20020173490A1

  公开（公告）日：2002-11-21

  Novel bisamidate phosphonate prodrugs of FBPase inhibitors of the Formula IA: 1 and their use in the treatment of diabetes and other conditions associated with elevated blood glucose.

  新颖的双酰胺磷酸酯前药，用于治疗糖尿病和其他与血糖升高相关的疾病的Formula IA:1中的FBPase抑制剂及其用途。
• Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes
  申请人：——

  公开号：US20040167178A1

  公开（公告）日：2004-08-26

  Pharmaceutical compositions containing an FBPase inhibitor and an insulin sensitizer are provided as well as methods for treating diabetes and diseases responding to increased glycemic control, an improvement in insulin sensitivity, a reduction in insulin levels, or an enhancement of insulin secretion.

  提供了含有FBPase抑制剂和胰岛素敏感剂的制药组合物，以及治疗糖尿病和对增加血糖控制、改善胰岛素敏感性、降低胰岛素水平或增强胰岛素分泌有反应的疾病的方法。
• Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase
  申请人：——

  公开号：US20040058892A1

  公开（公告）日：2004-03-25

  Novel FBPase inhibitors of the formula I and X 1 are useful in the treatment of diabetes and other conditions associated with elevated blood glucose.

  化合物I和X1的新型FBPase抑制剂对于治疗糖尿病和其他与血糖升高有关的疾病是有用的。
• Novel Heteroaromatic Inhibitors of Fructose-1,6-Bisphosphatase
  申请人：Dang Qun

  公开号：US20070232571A1

  公开（公告）日：2007-10-04

  Novel FBPase inhibitors of the formula I and X are useful in the treatment of diabetes and other conditions associated with elevated blood glucose.

  化学式为I和X的新型FBPase抑制剂在治疗糖尿病和其他与高血糖有关的疾病中有用。
• Combination of FBPase Inhibitors and Insulin Sensitizers for the Treatment of Diabetes
  申请人：Erion D. Mark

  公开号：US20080004226A1

  公开（公告）日：2008-01-03

  Pharmaceutical compositions containing an FBPase inhibitor and an insulin sensitizer are provided as well as methods for treating diabetes and diseases responding to increased glycemic control, an improvement in insulin sensitivity, a reduction in insulin levels, or an enhancement of insulin secretion.

  提供含有FBPase抑制剂和胰岛素增敏剂的药物组合物，以及治疗糖尿病和对增加血糖控制、改善胰岛素敏感性、降低胰岛素水平或增强胰岛素分泌有反应的疾病的方法。