1-methylcyclopropyl 4-(5-fluoro-6-(2-methyl-6-(methylsulfonyl)pyridin-3-yloxy)pyrimidin-4-yloxy)piperidine-1-carboxylate | 1403829-83-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-methylcyclopropyl 4-(5-fluoro-6-(2-methyl-6-(methylsulfonyl)pyridin-3-yloxy)pyrimidin-4-yloxy)piperidine-1-carboxylate
• 英文别名: (1-methylcyclopropyl) 4-[5-fluoro-6-(2-methyl-6-methylsulfonylpyridin-3-yl)oxypyrimidin-4-yl]oxypiperidine-1-carboxylate
• CAS: 1403829-83-3
• 化学式: C₂₁H₂₅FN₄O₆S
• 分子量: 480.517
• InChiKey: TZEYAXGGRICVIJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  129
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  tert-butyl 4-(6-chloro-5-fluoropyrimidin-4-yloxy)piperidine-1-carboxylate 在 盐酸 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-methylcyclopropyl 4-(5-fluoro-6-(2-methyl-6-(methylsulfonyl)pyridin-3-yloxy)pyrimidin-4-yloxy)piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists

  摘要：

  A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.

  DOI：

  10.1016/j.bmcl.2014.06.071

文献信息

• [EN] MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DU RÉCEPTEUR GPR119 ET TRAITEMENT DE TROUBLES LIÉS À CELUI-CI
  申请人：ARENA PHARM INC

  公开号：WO2012145603A1

  公开（公告）日：2012-10-26

  The present invention relates to the GPR119 agonist, 1-methylcyclopropyl 4-(5-fluoro-6-(2-methyl-6-(methylsulfonyl)pyridin-3-yloxy)pyrimidin-4-yloxy)piperidine-1-carboxylate (Compound 1):and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing the secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及GPR119激动剂，1-甲基环丙基4-(5-氟-6-(2-甲基-6-(甲基磺酰基)吡啶-3-氧基)嘧啶-4-氧基)哌啶-1-羧酸甲酯(化合物1)及其药学上可接受的盐、溶剂和水合物，它们可作为单一药物或与一个或多个其他药物（如DPP-IV抑制剂、双胍类药物、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺脲类药物、SGLT2抑制剂、噻唑烷二酮或抗糖尿病肽类似物）结合使用，用于治疗例如以下的疾病:与GPR119受体相关的疾病;通过增加肠促素分泌改善的状况;通过增加血液肠促素水平改善的状况;低骨密度的状况;神经系统疾病;代谢相关疾病;2型糖尿病;肥胖症及相关并发症。
• Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
  申请人：Jones Robert M.

  公开号：US20140038889A1

  公开（公告）日：2014-02-06

  The present invention relates to the GPR119 agonist, 1-methylcyclopropyl 4-(5-fluoro-6-(2-methyl-6-(methylsulfonyl)pyridin-3-yloxy)pyrimidin-4-yloxy)piperidine-1-carboxylate (Compound 1): and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, a DPP-IV inhibitor, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing the secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及GPR119激动剂，1-甲基环丙基4-(5-氟-6-(2-甲基-6-(甲基磺酰基)吡啶-3-氧基)嘧啶-4-氧基)哌啶-1-羧酸甲酯（化合物1）及其药学上可接受的盐、溶剂合物和水合物，它们可作为单一药物或与一个或多个其他药物联合使用，例如DPP-IV抑制剂、双胍类药物、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺脲类药物、SGLT2抑制剂、噻唑烷二酮或抗糖尿病肽类似物，用于治疗例如GPR119受体相关疾病；通过增加肠促素分泌改善的病症；通过增加血液肠促素水平改善的病症；低骨密度症状；神经系统疾病；代谢相关疾病；2型糖尿病；肥胖症及相关并发症。
• Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists
  作者：Daniel J. Buzard、Sun Hee Kim、Juerg Lehmann、Sangdon Han、Imelda Calderon、Amy Wong、Andrew Kawasaki、Sanju Narayanan、Rohit Bhat、Tawfik Gharbaoui、Luis Lopez、Dawei Yue、Kevin Whelan、Hussien Al-Shamma、David J. Unett、Hsin-Hui Shu、Shiu-Feng Tung、Steve Chang、Ching-Fen Chuang、Michael Morgan、Abu Sadeque、Zhi-Liang Chu、James N. Leonard、Robert M. Jones

  DOI：10.1016/j.bmcl.2014.06.071

  日期：2014.9

  A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.