di-tert-butyl (1R,2S,4R,5R,6R)-4-[(5-amino-1H-1,2,4-triazol-3-yl)sulfanyl]-2-(tert-butoxycarbonylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylate | 1416166-87-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: di-tert-butyl (1R,2S,4R,5R,6R)-4-[(5-amino-1H-1,2,4-triazol-3-yl)sulfanyl]-2-(tert-butoxycarbonylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylate
• 英文别名: ditert-butyl (1R,2S,4R,5R,6R)-4-(5-amino-[1,3,4]triazol-2-ylsulfanyl)-2-tert-butoxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylate；ditert-butyl (1R,2S,4R,5R,6R)-4-[(5-amino-1H-1,2,4-triazol-3-yl)sulfanyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]bicyclo[3.1.0]hexane-2,6-dicarboxylate
• CAS: 1416166-87-4
• 化学式: C₂₃H₃₇N₅O₆S
• 分子量: 511.643
• InChiKey: GXNVRKCSCLKARF-YGFPKDFOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  184
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  di-tert-butyl (1R,2S,4R,5R,6R)-4-[(5-amino-1H-1,2,4-triazol-3-yl)sulfanyl]-2-(tert-butoxycarbonylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylate 在 zinc dibromide 作用下， 以 二氯甲烷 为溶剂， 以55%的产率得到(1R,2S,4R,5R,6R)-2-amino-4-[(5-amino-1H-1,2,4-triazol-3-yl)sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid
  参考文献：
  名称：

  Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu₂ Receptor Agonist

  摘要：

  Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu(2) and mGlu(3) subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,65)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu(2/3) subtypes, a number of high potency and efficacy mGlu(2) receptor agonists exhibiting low potency mGlu(3) partial agonist/antagonist activity were identified. From this, (1R,2S,4R,512,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicydo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu(2) and hmGlu(3) combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu(2) receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu(2) receptors in vivo.

  DOI：

  10.1021/acs.jmedchem.5b01124
• 作为产物：
  描述：

  3-amino-1H-1,2,4-triazole-5-thiol 、 (1S,2S,4S,5R,6R)-di-tert-butyl 2-[(tert-butoxycarbonyl)amino]-4-(p-tolylsulfonyloxy)bicyclo[3.1.0]hexane-2,6-dicarboxylate 在 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以71%的产率得到di-tert-butyl (1R,2S,4R,5R,6R)-4-[(5-amino-1H-1,2,4-triazol-3-yl)sulfanyl]-2-(tert-butoxycarbonylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylate
  参考文献：
  名称：

  Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu₂ Receptor Agonist

  摘要：

  Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu(2) and mGlu(3) subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,65)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu(2/3) subtypes, a number of high potency and efficacy mGlu(2) receptor agonists exhibiting low potency mGlu(3) partial agonist/antagonist activity were identified. From this, (1R,2S,4R,512,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicydo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu(2) and hmGlu(3) combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu(2) receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu(2) receptors in vivo.

  DOI：

  10.1021/acs.jmedchem.5b01124

文献信息

• [EN] BICYCLO (3.1.0) HEXANE- 2, 6 -DICARBOXYLIC ACID DERIVATIVES AS MGLU2 RECEPTOR AGONIST<br/>[FR] DÉRIVÉS D'ACIDE BICYCLO(3.1.0)HEXANE-2,6-DICARBOXYLIQUE EN TANT QU'AGONISTE DU RÉCEPTEUR MGLU2
  申请人：LILLY CO ELI

  公开号：WO2012173850A1

  公开（公告）日：2012-12-20

  The present invention provides novel mGlu2 agonists useful in the treatment of bipolar disorder, schizophrenia, and generalized anxiety disorder.

  本发明提供了一种新型mGlu2激动剂，可用于治疗双相情感障碍、精神分裂症和广泛性焦虑障碍。
• BICYCLO (3.1.0) HEXANE-2, 6-DICARBOXYLIC ACID DERIVATIVES AS MGLU2 RECEPTOR AGONIST
  申请人：Man Teresa Tse Ki

  公开号：US20140113944A1

  公开（公告）日：2014-04-24

  The present invention provides novel mGlu2 agonists useful in the treatment of bipolar disorder, schizophrenia, and generalized anxiety disorder.

  本发明提供了一种新型的mGlu2激动剂，可用于治疗双相情感障碍、精神分裂症和广泛性焦虑障碍。
• BICYCLO(3.1.0)HEXANE-2,6-DICARBOXYLIC ACID DERIVATIVES AS MGLU2 RECEPTOR AGONIST
  申请人：Eli Lilly and Company

  公开号：EP2721012B1

  公开（公告）日：2016-05-25
• US9296710B2
  申请人：——

  公开号：US9296710B2

  公开（公告）日：2016-03-29
• Synthesis and Pharmacological Characterization of <i>C</i>4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1<i>R</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>R</i>)-2-Amino-4-(1<i>H</i>-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu₂ Receptor Agonist
  作者：James A. Monn、Lourdes Prieto、Lorena Taboada、Junliang Hao、Matthew R. Reinhard、Steven S. Henry、Christopher D. Beadle、Lesley Walton、Teresa Man、Helene Rudyk、Barry Clark、David Tupper、S. Richard Baker、Carlos Lamas、Carlos Montero、Alicia Marcos、Jaime Blanco、Mark Bures、David K. Clawson、Shane Atwell、Frances Lu、Jing Wang、Marijane Russell、Beverly A. Heinz、Xushan Wang、Joan H. Carter、Brian G. Getman、John T. Catlow、Steven Swanson、Bryan G. Johnson、David B. Shaw、David L. McKinzie

  DOI：10.1021/acs.jmedchem.5b01124

  日期：2015.9.24

  Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu(2) and mGlu(3) subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,65)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu(2/3) subtypes, a number of high potency and efficacy mGlu(2) receptor agonists exhibiting low potency mGlu(3) partial agonist/antagonist activity were identified. From this, (1R,2S,4R,512,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicydo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu(2) and hmGlu(3) combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu(2) receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu(2) receptors in vivo.