(1S,4'R,5R,5'R)-4',5'-diphenylspiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] | 625826-94-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (1S,4'R,5R,5'R)-4',5'-diphenylspiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane]
• 英文别名: (1'S,4R,5R,5'R)-4,5-diphenylspiro[1,3-dioxolane-2,2'-bicyclo[3.1.0]hexane]
• CAS: 625826-94-0
• 化学式: C₂₀H₂₀O₂
• 分子量: 292.378
• InChiKey: ZNMPUKLOSWDAFL-FCGDIQPGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  18.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1S,4'R,5R,5'R)-4',5'-diphenylspiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] 在 正丁基锂 、 草酰氯 、 碘代三甲硅烷 、 硫酸 、 二甲基二环氧乙烷 、 potassium carbonate 、 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 、 丙酮 、 甲苯 为溶剂， 反应 42.5h， 生成 Piragliatin
  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
• 作为产物：
  描述：

  (2R,3R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-6-ene 以68%的产率得到(1S,4'R,5R,5'R)-4',5'-diphenylspiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane]
  参考文献：
  名称：

  Substituted-cycloalkyl and oxygenated-cycloalkyl glucokinase activators

  摘要：

  2,3-二取代N-杂环丙酰胺，其中2-位置的取代物是取代苯基，3-位置的取代物是极性环，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。

  公开号：

  US20030225283A1

文献信息

• A Practical and Scalable Synthesis of a Glucokinase Activator via Diastereomeric Resolution and Palladium-Catalyzed C–N Coupling Reaction
  作者：Yohei Yamashita、Yasuhiro Morinaga、Makoto Kasai、Takao Hashimoto、Yuji Takahama、Atsushi Ohigashi、Satoshi Yonishi、Motohiro Akazome

  DOI：10.1021/acs.oprd.6b00415

  日期：2017.3.17

  the practical synthesis of glucokinase activator (R)-1 as a potential drug for treating type-2 diabetes. The key intermediate, chiral α-arylpropionic acid (R)-2, was synthesized in high diastereomeric excess through the diasteromeric resolution of 7 without the need for a chiral resolving agent. The counterpart 2-aminopyrazine derivative 3 was synthesized using a palladium-catalyzed C–N coupling reaction

  在这里，我们描述了实际合成葡萄糖激酶激活剂（R）-1作为治疗2型糖尿病的潜在药物的方法的研究和开发。关键中间体，手性α-芳基丙酸（R）-2，通过非对映异构体拆分为7（非对映异构体过量）而合成，不需要手性拆分剂。相应的2-氨基吡嗪衍生物3是使用钯催化的C–N偶联反应合成的。这个有效的过程在中试规模上得到了证明，并产生了19.0 kg （R）-1。而且，通过差向异构化过程获得（R）-7从不需要的（S）-7中发展出来。
• Substituted-cycloalkyl and oxygenated-cycloalkyl glucokinase activators
  申请人：——

  公开号：US20030225283A1

  公开（公告）日：2003-12-04

  2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 2-position being a substituted phenyl group and at the 3-position being a polar 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2-位置的取代物是取代苯基，3-位置的取代物是极性环，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。
• Discovery of Piragliatin—First Glucokinase Activator Studied in Type 2 Diabetic Patients
  作者：Ramakanth Sarabu、Fred T. Bizzarro、Wendy L. Corbett、Mark T. Dvorozniak、Wanping Geng、Joseph F. Grippo、Nancy-Ellen Haynes、Stanley Hutchings、Lisa Garofalo、Kevin R. Guertin、Darryl W. Hilliard、Marek Kabat、Robert F. Kester、Wang Ka、Zhenmin Liang、Paige E. Mahaney、Linda Marcus、Franz M. Matschinsky、David Moore、Jagdish Racha、Roumen Radinov、Yi Ren、Lida Qi、Michael Pignatello、Cheryl L. Spence、Thomas Steele、John Tengi、Joseph Grimsby

  DOI：10.1021/jm3008689

  日期：2012.8.23

  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.