tert-butyl 2-[(R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate | 1414782-20-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: tert-butyl 2-[(R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate
• 英文别名: tert-butyl 2-[(1R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate
• CAS: 1414782-20-9
• 化学式: C₂₇H₄₁BN₂O₄
• 分子量: 468.445
• InChiKey: XFXDPQUVTVKNSY-JOCHJYFZSA-N

物化性质

• 沸点：
  559.1±50.0 °C(Predicted)
• 密度：
  1.14±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.31
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  51.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-[(R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 盐酸 、 potassium carbonate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.7h， 生成 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-7-[(5-methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]nonane
  参考文献：
  名称：

  2,3-DIHYDRO-1H-INDEN-1-YL-2,7-DIAZASPIRO[3.5] NONANE DERIVATIVES

  摘要：

  本发明提供了一种式（I）的化合物或其药用盐，其中R1、R2、Ra、L、Z、Z1和Z2如本文所定义，其作为胃泌素拮抗剂或逆向激动剂；以及其药物组合物；以及通过胃泌素受体拮抗作用治疗疾病、紊乱或病况的方法。

  公开号：

  US20110230461A1
• 作为产物：
  描述：

  (R)-1-azido-5-bromo-2,3-dihydro-1H-indene 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride tin(II) chloride dihdyrate 、 potassium acetate 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 47.0h， 生成 tert-butyl 2-[(R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate
  参考文献：
  名称：

  2,3-DIHYDRO-1H-INDEN-1-YL-2,7-DIAZASPIRO[3.5] NONANE DERIVATIVES

  摘要：

  本发明提供了一种式（I）的化合物或其药用盐，其中R1、R2、Ra、L、Z、Z1和Z2如本文所定义，其作为胃泌素拮抗剂或逆向激动剂；以及其药物组合物；以及通过胃泌素受体拮抗作用治疗疾病、紊乱或病况的方法。

  公开号：

  US20110230461A1

文献信息

• Synthesis of PF-6870961, a major hydroxy metabolite of the novel ghrelin receptor inverse agonist PF-5190457
  作者：Agnieszka Sulima、Fatemeh Akhlaghi、Lorenzo Leggio、Kenner C. Rice

  DOI：10.1016/j.bmc.2021.116465

  日期：2021.11

  the discovery and then synthesis of a newly identified major metabolite, PF-6870961 ((R)-1-(2-(5-(2-hydroxy-6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethan-1-one). The metabolite was synthesized and fully characterized through a design that enabled it to be prepared in useful quantities. The synthesis provided direct access

  临床前和人体研究表明生长素释放肽系统参与酒精相关行为，阐明了使用生长素释放肽受体阻滞剂作为酒精使用障碍 (AUD) 的药物干预的可能性。最近进行的 1b 期人体研究的初步数据使用生长素释放肽受体反向激动剂 PF-5190457（2-（2-甲基咪唑 [ 2,1- b ][1,3thiazol-6-yl）-1-2-( 1 R )-5-(6-甲基嘧啶-4-基)-2,3-二氢-1 H-inden-1-yl]-2,7-diazaspiro[3.5]non-7-ylethanone)，提供了该化合物与酒精联合给药时的安全性和耐受性的证据。此外，该研究揭示了有关该化合物生物转化途径的重要信息，并促使发现并合成了一种新鉴定的主要代谢物 PF-6870961 (( R )-1-(2-(5-(2-hydroxy-6) -methylpyrimidin-4-yl)-2,3-dihydro-1 H -inden-1-yl)-2
• Spiroazetidine–piperidine bromoindane as a key modular template to access a variety of compounds via C–C and C–N bond-forming reactions
  作者：Dilinie P. Fernando、Wenhua Jiao、Jana Polivkova、Jun Xiao、Steven B. Coffey、Colin Rose、Allyn Londregan、James Saenz、Ramsay Beveridge、Yingxin Zhang、Gregory E. Storer、Derek Vrieze、Noe Erasga、Ryan Jones、Vishal Khot、Kimberly O. Cameron、Kim F. McClure、Samit K. Bhattacharya、Suvi T.M. Orr

  DOI：10.1016/j.tetlet.2012.09.047

  日期：2012.11

  In the context of our ghrelin inverse agonist program, a functionalized bromoindane 3 provided a versatile intermediate for structure-activity relationship studies. After developing operationally simple cross-coupling reactions, a broad spectrum of chemical space was successfully explored. Optimization of a one-pot borylation/Suzuki sequence provided the desired products in high yield with low loading of the palladium catalyst. High yields of N-linked heterocyclic analogues were obtained through palladium catalyzed C-N bond formation. In addition, carboxylation of the bromoindane provided an indane carboxylic acid for further diversification. (C) 2012 Elsevier Ltd. All rights reserved.
• Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor
  作者：Kim F. McClure、Margaret Jackson、Kimberly O. Cameron、Daniel W. Kung、David A. Perry、Suvi T.M. Orr、Yingxin Zhang、Jeffrey Kohrt、Meihua Tu、Hua Gao、Dilinie Fernando、Ryan Jones、Noe Erasga、Guoqiang Wang、Jana Polivkova、Wenhua Jiao、Roger Swartz、Hirokazu Ueno、Samit K. Bhattacharya、Ingrid A. Stock、Sam Varma、Victoria Bagdasarian、Sylvie Perez、Dawn Kelly-Sullivan、Ruduan Wang、Jimmy Kong、Peter Cornelius、Laura Michael、Eunsun Lee、Ann Janssen、Stefanus J. Steyn、Kimberly Lapham、Theunis Goosen

  DOI：10.1016/j.bmcl.2013.07.044

  日期：2013.10

  The optimization for selectivity and central receptor occupancy for a series of spirocyclic azetidine-piperidine inverse agonists of the ghrelin receptor is described. Decreased mAChR muscarinic M2 binding was achieved by use of a chiral indane in place of a substituted benzylic group. Compounds with desirable balance of human in vitro clearance and ex vivo central receptor occupancy were discovered by incorporation of heterocycles. Specifically, heteroaryl rings with nitrogen(s) vicinal to the indane linkage provided the most attractive overall properties. (C) 2013 Elsevier Ltd. All rights reserved.
• Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate
  作者：Samit K. Bhattacharya、Kim Andrews、Ramsay Beveridge、Kimberly O. Cameron、Chiliu Chen、Matthew Dunn、Dilinie Fernando、Hua Gao、David Hepworth、V. Margaret Jackson、Vishal Khot、Jimmy Kong、Rachel E. Kosa、Kimberly Lapham、Paula M. Loria、Allyn T. Londregan、Kim F. McClure、Suvi T. M. Orr、Jigna Patel、Colin Rose、James Saenz、Ingrid A. Stock、Gregory Storer、Maria VanVolkenburg、Derek Vrieze、Guoqiang Wang、Jun Xiao、Yingxin Zhang

  DOI：10.1021/ml400473x

  日期：2014.5.8

  The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.
• ACS Med. Chem. Lett. 2014, 5, 474-479
  作者：

  DOI：——

  日期：——