RO 0505082 | 588941-45-1

• 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: RO 0505082
• 英文别名: 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide；PharmaGSID_48506；(2R)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-N-pyrazin-2-ylpropanamide
• CAS: 588941-45-1
• 化学式: C₁₉H₂₂ClN₃O₃S
• 分子量: 407.921
• InChiKey: QULLOTSYPAOTIW-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  97.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (3-chloro-4-methylsulfanyl-phenyl)-N-[2(R)-hydroxy-1(R)-methyl-2(R)-phenyl-ethyl]-N-methyl acetamide 在 正丁基锂 、 甲酸 、 草酰氯 、 硫酸 、 双氧水 、 N,N-二甲基甲酰胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正己烷 、 二氯甲烷 、 水 为溶剂， 反应 65.5h， 生成 RO 0505082
  参考文献：
  名称：

  Discovery of Piragliatin—First Glucokinase Activator Studied in Type 2 Diabetic Patients

  摘要：

  Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase beta-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.

  DOI：

  10.1021/jm3008689

文献信息

• Heteroaromatic glucokinase activators
  申请人：Hoffman-La Roche Inc.

  公开号：US06610846B1

  公开（公告）日：2003-08-26

  2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 3-position being a substituted phenyl group and at the 2-position being a methyl cycloalkyl ring, said propionamides being glucokinase activators which increase insulin secretion in the treatment of type II diabetes.

  2,3-二取代N-杂环丙酰胺，其中3位取代为取代苯基，2位取代为甲基环烷基环，这些丙酰胺是葡萄糖激酶激活剂，可增加胰岛素分泌，用于治疗2型糖尿病。
• CHEMOSELECTIVE METHYLENE HYDROXYLATION IN AROMATIC MOLECULES
  申请人：The Board of Trustees of the University of Illinois

  公开号：US20200087331A1

  公开（公告）日：2020-03-19

  A chemoselective and reactive Mn(CF 3 -PDP) catalyst system that enables for the first time the strategic advantages of late-stage aliphatic C—H hydroxylation to be leveraged in aromatic compounds. This discovery will benefit small molecule therapeutics by enabling the rapid diversification of aromatic drugs and natural products and identification of their metabolites.

  一种化学选择性和反应性的Mn(CF3-PDP)催化体系首次实现了后期脂肪族C—H羟基化在芳香化合物中的战略优势。这一发现将有助于小分子药物的快速多样化和芳香类药物以及天然产物的代谢产物的鉴定。
• Chemoselective methylene hydroxylation in aromatic molecules
  申请人：The Board of Trustees of the University of Illinois

  公开号：US10961266B2

  公开（公告）日：2021-03-30

  A chemoselective and reactive Mn(CF3-PDP) catalyst system that enables for the first time the strategic advantages of late-stage aliphatic C—H hydroxylation to be leveraged in aromatic compounds. This discovery will benefit small molecule therapeutics by enabling the rapid diversification of aromatic drugs and natural products and identification of their metabolites.

  一种化学选择性和反应性 Mn（CF3-PDP）催化剂系统，首次在芳香化合物中发挥了后期脂肪族 C-H 羟基化的战略优势。这一发现将使芳香族药物和天然产物迅速多样化并鉴定其代谢物，从而有利于小分子疗法。
• Nickel-catalysed enantioselective alkene dicarbofunctionalization enabled by photochemical aliphatic C–H bond activation
  作者：Xia Hu、Iván Cheng-Sánchez、Wangqing Kong、Gary A. Molander、Cristina Nevado

  DOI：10.1038/s41929-024-01153-0

  日期：——

  chiral molecules from readily available feedstocks is a long-term pursuit in the chemistry community. Radical-mediated alkene difunctionalizations represent an excellent platform towards this goal. However, asymmetric versions remain highly challenging, and more importantly, examples featuring simple hydrocarbons as reaction partners are elusive. Here we report an asymmetric three-component alkene

  开发从现有原料快速构建复杂手性分子的新策略是化学界的长期追求。自由基介导的烯烃双官能化是实现这一目标的绝佳平台。然而，不对称版本仍然极具挑战性，更重要的是，以简单碳氢化合物作为反应伙伴的例子是难以捉摸的。在这里，我们报道了一种不对称三组分烯烃二碳官能化，利用光催化氢原子转移和镍催化的结合直接激活C( sp 3 )-H键。该协议提供了一个有效的平台，以原子经济的方式在烯烃上安装两个邻位碳-碳键，提供了一系列高价值的手性α-芳基/烯基羰基和膦酸酯，以及1,1-二芳基烷烃普遍存在的烷烃、醚和醇原料。该方法具有操作简单、底物范围广以及优异的区域选择性、化学选择性和对映选择性的优点。与生物活性基序的兼容性和药学相关分子的便捷合成突出了该方案的合成潜力。
• US6610846B1
  申请人：——

  公开号：US6610846B1

  公开（公告）日：2003-08-26