(S)-benzyl 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate | 1215197-36-6

• 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: (S)-benzyl 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate
• 英文别名: 6-[[(S)-2-[4-(Trifluoromethyl)-1H-imidazole-1-yl]-3-cyclopentylpropanoyl]amino]pyridine-3-carboxylic acid benzyl ester；benzyl 6-[[(2S)-3-cyclopentyl-2-[4-(trifluoromethyl)imidazol-1-yl]propanoyl]amino]pyridine-3-carboxylate
• CAS: 1215197-36-6
• 化学式: C₂₅H₂₅F₃N₄O₃
• 分子量: 486.494
• InChiKey: REXOAXWAIAVMSP-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  86.1
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (S)-benzyl 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate 以90.6的产率得到6-[[((2S)-3-环戊基-1-氧代-2-[4-(三氟甲基)-1H-咪唑-1-基]丙基]氨基]-3-吡啶甲酸
  参考文献：
  名称：

  Substituted imidazole propanamide glucokinase activators

  摘要：

  本发明提供了作为葡萄糖激酶激活剂的化合物公式（1A）；其制药组合物；以及通过葡萄糖激酶介导的疾病、障碍或病况的治疗方法。其中X、Y、Z、R1、R2、R3和R4如本文所述。

  公开号：

  US07977367B2
• 作为产物：
  描述：

  (R)-methyl 3-cyclopentyl-2-hydroxypropanoate 在 吡啶 、 2,6-二甲基吡啶 、 propylphosphonic anhydride 、 potassium carbonate 、 sodium hydroxide 作用下， 以 正己烷 、 水 、 乙酸乙酯 、 甲苯 、 乙腈 为溶剂， 反应 29.33h， 生成 (S)-benzyl 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate
  参考文献：
  名称：

  Multikilogram Synthesis of a Hepatoselective Glucokinase Activator

  摘要：

  This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone a-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.

  DOI：

  10.1021/op300194c

文献信息

• [EN] HETEROARYLS AMIDE DERIVATIVES AND THEIR USE AS GLUCOKINASE ACTIVATORS<br/>[FR] DÉRIVÉS D'AMIDES D'HÉTÉROARYLES ET LEUR UTILISATION COMME ACTIVATEURS DE LA GLUCOKINASE
  申请人：PFIZER

  公开号：WO2010029461A1

  公开（公告）日：2010-03-18

  The present invention provides Formula (1A) compounds that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase. X, Y, Z, R1, R2, R3, and R4 are as described herein.

  本发明提供了作为葡糖激酶激活剂的式(1A)化合物；其药物组合物；以及治疗由葡糖激酶介导的疾病、紊乱或状况的方法。其中，X、Y、Z、R1、R2、R3和R4如本文所述。
• Substituted imidazole propanamide glucokinase activators
  申请人：Pfizer Inc

  公开号：US07977367B2

  公开（公告）日：2011-07-12

  The present invention provides Formula (1A) compounds that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase. X, Y, Z, R1, R2, R3, and R4 are as described herein.

  本发明提供了作为葡萄糖激酶激活剂的化合物公式（1A）；其制药组合物；以及通过葡萄糖激酶介导的疾病、障碍或病况的治疗方法。其中X、Y、Z、R1、R2、R3和R4如本文所述。
• General and Scalable Amide Bond Formation with Epimerization-Prone Substrates Using T3P and Pyridine
  作者：Joshua R. Dunetz、Yanqiao Xiang、Aaron Baldwin、Justin Ringling

  DOI：10.1021/ol201875q

  日期：2011.10.7

  The mild combination of T3P (n-propanephosphonic acid anhydride) and pyridine has been developed for low-epimerization amide bond formation and implemented for the synthesis of a key intermediate to a glucokinase activator. This robust method is general for the coupling of various racemization-prone acid substrates and amines, including relatively non-nucleophilic anilines, and provides amides in high yields with very low epimerization. With easy reaction setup and product isolation, this protocol offers several practical and experimental benefits.
• Multikilogram Synthesis of a Hepatoselective Glucokinase Activator
  作者：Joshua R. Dunetz、Martin A. Berliner、Yanqiao Xiang、Timothy L. Houck、Fabrice H. Salingue、Wang Chao、Chen Yuandong、Wang Shenghua、Yun Huang、Douglas Farrand、Steven J. Boucher、David B. Damon、Teresa W. Makowski、Mark T. Barrila、Raymond Chen、Isamir Martínez

  DOI：10.1021/op300194c

  日期：2012.10.19

  This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone a-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.
• Discovery of (<i>S</i>)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1<i>H</i>-imidazol-1-yl)propanamido)nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus
  作者：Jeffrey A. Pfefferkorn、Angel Guzman-Perez、John Litchfield、Robert Aiello、Judith L. Treadway、John Pettersen、Martha L. Minich、Kevin J. Filipski、Christopher S. Jones、Meihua Tu、Gary Aspnes、Hud Risley、Jianwei Bian、Benjamin D. Stevens、Patricia Bourassa、Theresa D’Aquila、Levenia Baker、Nicole Barucci、Alan S. Robertson、Francis Bourbonais、David R. Derksen、Margit MacDougall、Over Cabrera、Jing Chen、Amanda Lee Lapworth、James A. Landro、William J. Zavadoski、Karen Atkinson、Nahor Haddish-Berhane、Beijing Tan、Lili Yao、Rachel E. Kosa、Manthena V. Varma、Bo Feng、David B. Duignan、Ayman El-Kattan、Sharad Murdande、Shenping Liu、Mark Ammirati、John Knafels、Paul DaSilva-Jardine、Laurel Sweet、Spiros Liras、Timothy P. Rolph

  DOI：10.1021/jm2014887

  日期：2012.2.9

  Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic beta-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.